Title of Invention

"NOVEL 17B HYDROSYSTEROID DEHYDROGENASE TYPE 1 INHIBITORS"

Abstract The present invention relates to novel 3, 15 substituted estrone derivatives which represent inhibitory compounds of the 17ß-hydroxysteroid dehydrogenase type I (17ß-HSD1), to their salts, to pharmaceutical preparations containing these compounds and to processes for the preparation of these compounds. Furthermore, the invention concerns the therapeutic use of said novel 3,15 substituted estrone derivatives, particularly their use in the treatment or prevention of steroid hormone dependent diseases or disorders, such as steroid hormone dependent diseases or disorders requiring the inhibition of 17ß-hydroxysteroid dehydrogenase type I enzymes and/or requiring the lowering of the endogenous 17ß-estradiol concentration. In addition, the present invention relates to the general use of selective 17ß-hydroxysteroid dehydrogenase type 1 inhibitors which possess in addition no or only pure antagonistic binding affinities to the estrogen receptor for the treatment and prevention of benign gynaecological disorders, in particular endometriosis.
Full Text The present invention relates to a 3, 15-substituted estrone compound of general formula 1.
The present invention relates to novel 3, 15 substituted estrone derivatives which represent inhibitory compounds of the 17ß-hydroxysteroid dehydrogenase type 1 (17ß-HSD1) enzyme, to their salts, to pharmaceutical preparations containing these compounds and to processes for the preparation of these compounds. Furthermore, the invention concerns the therapeutic use of said novel 3,15 substituted estrone derivatives, particularly their use in the treatment or prevention of steroid hormone dependent diseases or disorders, such as steroid hormone dependent diseases or disorders requiring the inhibition of the 17ß-HSD1 enzyme and/or requiring the towering of the endogenous 17ß-estradiol concentration. In addition, the present invention relates to the general use of selective 17ß-HSD1 inhibitors which possess in addition no or only pure antagonistic binding affinities to the estrogen receptor for the treatment and prevention of benign gynaecological disorders, in particular endometriosis.
BACKGROUND
The publications and other materials used herein to illuminate the background of the invention, and in particular, cases to provide additional details respecting the practice, are incorporated by reference.
Mammalian 17ß-hydroxysteroid dehydrogenases (17ß-HSDs) are NAD(H) or NADP(H) dependent enzymes which catalyse - besides other reactions - the final steps in male and female sex hormone biosynthesis. These enzymes convert inactive 17-keto-steroids into their active 17ß-hydroxy-forms or catalyse the oxidation of the 17ß-hydroxy-forms into the 17-keto-steroids. Because both estrogens and androgens have the highest affinity for their receptors in the 17ß-hydroxy form, 17ß-HSD enzymes play an essential rote in the tissue-selective regulation of the activity of sex steroid hormones.
At present 10 human members of the 17ß-HSD enzyme family have been described (types 1-5, 7, 8, 10-12). The human 17ß-HSD family members share less than 30% similarity in their primary structure. The 17ß-HSDs are expressed in distinct, though in some cases, overlapping pat-
terns. The different types of 17J}-HSDs also differ in their substrate and cofactor specificities. In intact cells in culture, the 17|3-HSDs catalyse the reaction in a unidirectional way: types 1,3, 5 and 7 use NADP(H) as a cofactor and catalyse the reductive reaction (activation), while types 2, 4, 8 and 10 catalyse the oxidative reaction (inactivation) using NAD(H) as a cofactor [see e.g. Labrie et al. (2000) Trends Endocrinol Metab, 11:421-7, and Adamski & Jakob (2001) Mol Cell Endocrinol, 171:1-4].
Due to their essential role in the tissue-selective regulation of the activity of sex steroid hormones 17β-HSDs can be involved in the occurrence and development of estrogen-sensitive pathologies (f. ex. breast, ovarian, and endometrium cancers etc.) and androgen-sensitive pathologies (f. ex. prostate cancer, benign prostatic hyperplasia, acne, hirsutism, etc). Furthermore, many types of17β-HSD have been shown to be involved in the pathogenesis of particular human disorders. For example, the17β-HSD3 is known to be involved in the development of pseudohermaph-roditism, the 17β-HSD8 plays a role in polycystic kidney disease and the 17β-HSD4 is related to the occurrence of bifunctional enzyme deficiency. Therefore treatment of sex steroid-sensitive diseases by administration of specific inhibitors of the 17f3-HSDs enzymes have been suggested, optionally in combination with potent and specific anti-estrogens and anti-androgens [Labrie F et al. (1997) Steroids, 62:148-58].
Due to the fact that each type of17β-HSD has a selective substrate affinity, directional (reductive or oxidative) activity in intact cells, and a particular tissue distribution, the selectivity of drug action could be achieved-by targeting a particular 17β-HSD Isozyme. By individual modulation of the particular 17β-HSDs It is possible to influence or even control the local and paracrine concentration of estrogens and androgens in different target tissues.
The best characterized member of the17β-HSD family is the17β-HSD1 [EC 1.1.1.62]. This enzyme could be crystallized in different states of functionality (e.g. with and without ligand and/or co-factor). In vitro, the17β-HSD1 enzyme catalyses the reduction and the oxidation between es-trone (E1) and estradiol (E2). However, under physiological in vivo conditions the enzyme only catalyses the reductive reaction from the estrone (E1) to the estradiol (E2). The 17β-HSD1 was found to be expressed in a variety of hormone-dependent tissues, e.g. placenta, mammary gland tissue or uterus and endometrium tissue, respectively. Estradiol itself is, especially in comparison to the significantly less active estrone, a very potent hormone, which regulates the expression of a variety of genes by binding to the nuclear estrogen receptor and plays an essential role in the proliferation and differentiation of the target cell. Physiological as well as pathological cell proliferations can be estradiol dependent Especially many breast cancer cells are stimulated by a locally raised estradiol concentration. Furthermore, the occurrence or course of benign pathologies such as en-
dometriosis, uterine leiomyomas (fibroids or myomas), adenomyosis, menorrhagia, metrorrhagia and dysmenorrhoea is dependent from the existence of significantly high estradiol levels.
Endometriosis is a well-known gynaecological disorder that affects 10 to 15% of women in the reproductive age. It is a benign disease defined as the presence of viable endometrial gland and stroma cells outside the uterine cavity. It is most frequently found in the pelvic area, in women developing endometriosis, the endometrial cells entering the peritoneal cavity by retrograde menstruation (the most likely mechanism) nave the capacity to adhere to and invade the peritoneal lining, and are then able to implant and grow. The implants respond to steroid hormones of the menstrual cycle in a similar way as the endometrium in the uterus. The infiltrating lesions and the blood from these lesions which are unable to leave the body cause inflammation of the surrounding tissue. The most common symptoms of endometriosis are dysmenorrhoea, dyspareunia and (chronic) abdominal pain. The occurrence of these symptoms is not related to the extent of the lesions. Some women with severe endometriosis are asymptomatic, while women with mild endometriosis may have severe pain. Up to now, no reliable non-invasive test is available to diagnose endometriosis. Laparoscopy has to be performed to diagnose the disease. Endometriosis is classified according to the 4 stages set up by the American Fertility Society (AFS). Stage I corresponds to minimal disease while stage IV is severe, depending on the location and the extent of the endometriosis. Endometriosis is found In up to 50% of the women with infertility. However, currently no causal relation has been proven between mild endometriosis and infertility. Moderate to severe endometriosis can cause tubal damage and adhesions leading to infertility. The aims of treatment of endometriosis are pain relief, resolution of the endometriotic tissue and restoration of fertility (if desired). The two common treatments are surgery or anti-inflammatory and/or hormonal therapy or a combination thereof.
Uterine leiomyomas (fibroids or myomas), benign clonal tumours, arise from smooth muscle cells of the human uterus. They are clinically apparent in up to 25% of women and are the single, most common indication for hysterectomy. They cause significant morbidity, including prolonged and heavy menstrual bleeding, pelvic pressure and pain, urinary problems, and, In rare cases, reproductive dysfunction. The pathophysiology of myomas is not well understood. Myomas are found submucosally (beneath the endometrium), intramuralty (within the myometrium) and subserosally (projecting out of the serosal compartment of the uterus), but mostly are mixed forms of these 3 different types. The presence of estrogen receptors in leiomyoma cells has been studied by Tamaya et al. [Tamaya et al. (1985) Acta Obstet Gynecol Scand. 64:307-9]. They have shown that the ratios of estrogen receptor compared to progesterone and androgen receptor levels were higher in leiomyomas than in the corresponding normal myometrium. Surgery has long been the main treatment for myomas. Furthermore, medical therapies that have been proposed to treat myomas include administration of a variety of steroids such as the androgenic steroids danazol or
gestrinone, GnRH agonists and progestogens, whereby the administration is often associated a variety of serious side-effects.
Everything that has been said above in relation to the treatment of uterine leiomyomas and endometriosis equally applies to other benign gynaecological disorders, notably adenomyosis, functional menorrhagia and metrorrhagia. These benign gynaecological disorders are all estrogen sensitive and are treated in a comparable way as described herein before in relation to uterine leiornyomas and endometriosis, The available pharmaceutical treatments, however, suffer from the same major drawbacks, i.e. they have to be discontinued once the side-effects become more serious than the symptoms to be treated and symptoms reappear after discontinuation of the therapy.
Since the aforementioned malign and benign pathologies are all 17j3-estradiol dependent, a reduction of the endogenous 17|3-estradiol concentration in the respective tissue will result in an impaired or reduced proliferation of 17(3-estradiol cells in said tissues. Therefore, it may be concluded that selective inhibitors of the17β-HSD1 enzyme are well suited for their use to impair endogenous productions of estrogens, in particular of 17β-estradiol, in myomas, endometriotic, ade-nomyotic and endometrial tissue. The application of a compound acting as selective inhibitor on the17β-HSD1 which preferentially catalyses the reductive reaction will result in a lowered intracellular estradiol-concentration since the reductive conversion of the estrone into the active estradiol is reduced or suppressed. Therefore, reversible or even irreversible inhibitors of the 17β-HSD1 may play a significant role in the prophylaxis and/or treatment of steroid-hormone, in particular 17(3-estradiol, dependent disorders or diseases.-Furthermore, the reversible or even irreversible inhibitors of the 170-HSD1 should have no or only pure antagonistic binding activities to the estradiol receptor, in particular to the estrogen receptor a subtype, since agonistic binding of the estrogen receptor would lead to activation and therefore - by regulation of a variety of genes - to the proliferation and differentiation of the target cell. In contrast, antagonists of the estrogen receptor, so called anti-estrogens, bind competitively to the specific receptor protein thus preventing access of endogenous estrogens to their specific binding site.
At present it is described in the literature that several malignant disease as breast cancer, prostate carcinoma, ovarian cancer, uterine cancer, endometrial cancer and endometrial hyperpla-sia may be treated by the administration of a selective 1?p-HSD1 inhibitor. Furthermore, a selective 17β-HSD1 inhibitor may be useful for the prevention of the aforementioned hormone-dependent cancers, especially breast cancer. The international patent application WO 2004/080271 discloses the use of a particular17β-HSD1 inhibitor, so called compound A, for prevention or treatment of disorders caused by the 17HSD1 enzyme activity, in particular breast cancer. Furthermore, the international patent application WO 03/017973 describes the use of a selective estrogen enzyme modulator (SEEM) in the manufacture of a drug delivery vehicle for use in a method of treating or
preventing a benign gynaecological disorder in a mammalian female, said benign gynaecological disorder being selected from the group consisting of uterine leiomyomas, endometriosis, adenomy-osis, functional menorrhagia and metrorrhagia, wherein the method comprises the intravaginal administration of the SEEM to the female suffering from the benign gynaecological disorder in a therapeutically effective dosage to prevent or reduce the symptoms of said benign gynaecological disorder, said SEEM being selected from the group consisting of aromatase inhibitors, cydo-oxygenase2 (COX-2) inhibitors, 17(3-HSD1 inhibitors and combinations thereof.
Several reversible or irreversible inhibitors of the 17β-HSD1 enzyme of steroidal and even non-steroidal origin are already known from the literature. The characteristics of these inhibitory molecules, which mainly have a substrate or cofactor-like core structure, have been reported in the literature [reviewed in: Poirier D. (2003) Curr Med Chem. 10:453-77].
For example, Tremblay and Poirier describe an estradiol derivative, 16-[carbamoyl-(bromo-methyl)-alkyl]-estradiol, and tested the same in respect of its inhibition of the estradiol formation catalysed by the enzyme 17J3-HSD1 [Tremblay & Poirier (1998) J. Steroid Biochem. Molec. BioL, 66:179-191]. Poirier and colleagues describe a 6p-1hiaheptan-butyl-methyl-amide derivative of estradiol as a potent and selective inhibitor of the 17HSD1 enzyme [Poirier et al. (1998) J. Steroid Biochem. Molec. BioL, 64:83-90]. Furthermore, Poirier and colleagues describe new derivatives of 17β-estradiol with N-butyl, N-methyl alkylamide side chains of three different lengths (n=8, 10 or 12) at position 15, which might be potential inhibitors of the 17B-HSD enzyme [Poirier et al. (1991) Tetrahedron,'47(37):7751-7766]. The biological activity of these compounds was prtly tested with, regard to .estrogen receptor binding affinity, estrogenic and anti-estrogenic activity [Poirier et al. (1996) Bioorg Med Chem Lett 6(21):2537-2542]. In addition, Pelletier and Poirier describe novel 17B-estradiol derivatives with different bromo-alkyl side chains, which might be potential inhibitors of the 173-HSD enzyme [Pelletier & Poirier (1996) Bioorg Med Chem, 4(10):1617-1628]. Sam and colleagues describe several estradiol derivatives with a halogenated alkyl side chain in 16a or 17a position of the steroidal D ring which possess 17B-HSD1 inhibiting properties [Sam et al. (1998) Drug Design and Discovery, 15:157-180]. Furthermore, the finding that some anti-estrogens, such as tamoxifen, possess weak 17B-HSD inhibiting properties suggested that it may be possible to develop a potent 17B-HSD1 inhibitor that is also anti-estrogenic [reviewed in: Poirier D. (2003) Curr Med Chem. 10:453-77]. Several of the aforementioned already known compounds also display anti-estrogenic properties (e.g. the 6B-thiaheptan-butyl-methyl-amide derivative of estradiol described by Poirier and colleagues [Poirier et al. (1998) J. Steroid Biochem. Molec. Biol., 64:83-90]). None of the aforementioned compounds has been clinically used so far.
6
Furthermore, the international patent application WO 2004/085457 discloses a variety of es-tron derivatives with different subs'rtuents in C3, C6, C16 and/or C17 position as potent 17β-HSD1 inhibitors.
Furthermore, the synthesis of different B-, C- and D-ring substituted estradiol carboxylic esters was described by Labaree et al. [Labaree et al. (2003) J. Med. Chem. 46:1886-1904]. However, these esters were only analysed with regard to their estrogenic potential. The related international patent application WO 2004/085345 discloses 15a substituted estradiol compounds bearing a - Accordingly, there is a need for the development of compounds which are suited for the treatment and/or prevention of steroid hormone dependent diseases or disorders such as breast cancer, endometriosis and uterine leiomyomas by selectively Inhibiting the 17β-HSD1 enzyme, while desirably failing to substantially inhibit other members of the17β-HSD protein family or other catalysts of sex steroid degradation or activation. In particular, it is an aim of the present invention to develop selective inhibitors of the17β-HSD1 enzyme, whereby in addition the compounds have no or only pure antagonistic binding affinities to the estrogen receptor (both subtypes a and (3). Furthermore, there is still a need to provide a new type of therapy regimen for estrogen dependent benign gynaecological disorders, particularly for pre.-,and psri-menopausal females, whereby the therapy should not cause serious side-effects.
SUMMARY OF THE INVENTION
Therefore, it Is an object of the present invention to develop novel inhibitors of the enzyme17β-HSD1, which have valuable pharmacological properties and which are suited for the treatment Df estrogen dependent diseases and disorders.
It has now been found that the novel 3, 15 substituted estrone derivatives bearing a side :hain of the amide, ester, carbonyl, hydrazone, alcohol, ether, urea, carbamate, "retro°-amide, sul-:onyl urea, sulfamide, sulfamate, "retro'-sulfonamide, "retro'-carbamate, "retro"-ester or sulfonyl-arbamate type in position 15 would be valuable in therapy, especially in the treatment or preven-:ion of steroid hormone dependent diseases or disorders requiring the inhibition of17β-HSD enzymes. In particular, compounds of formula (I) represent potent inhibitors of the17β-HSD1 enzyme and possess valuable pharmacological properties for the treatment and/or prophylaxis of malignant jteroid dependent diseases or disorders such as breast cancer, prostate carcinoma, ovarian can-
car, uterine cancer, endometrial cancer and endometrial hyperplasia, but also for the treatment and/or prophylaxis of benign steroid dependent diseases or disorders such as endometriosis, uterine fibroids, uterine leiomyoma, adenomyosis, dysmenorrhoea, menorrhagia, metrorrhagia, pros-tadynia, benign prostatic hyperplasia, urinary dysfunction or lower urinary tract syndrome. Further estrogen-dependent diseases which may be treated and/or prevented with an effective amount of a compound of the invention are multiple sclerosis, rheumatoid arthritis, colon cancer, tissue wounds, skin wrinkles and cataracts.
Furthermore, it was an objective of the present invention to provide a new therapy regimen for the treatment of estradiol dependent benign gynaecological diseases or disorders such as endometriosis, uterine fibroids, uterine leiomyoma, adenomyosis, dysmenorrhoea, menorrhagia, metrorrhagia, or urinary dysfunction by the administration of an effective amount of a selective inhibitor of the17β-HSD1 enzyme. Preferably the selective inhibitor of the 170-HSD1 enzyme possesses no or only pure antagonistic binding affinities to the estrogen receptor. In particular, this novel type of therapy regimen for estrogen dependent benign disorders is suited for pre- and peri-menopausal females.
Accordingly, the present invention relates to a compound having the structural formula(Figure Removed)
(i) X represents:
(a) a bond,
(b) -NR3-, or
(c) -0-;
A represents:
(a) -CO-, or
(b) under the proviso that X represents -NR3-, A represents -SOz-;
Y represents:
(a) -NR4-,
(b) -O-, under the proviso that X represents a bond or -NR3-,

(c) a bond,
(d) -NH-SOz-, under the proviso that X represents -NR3- and A represents
-CO-,
(e) -NH-SOa-NR4-, under the proviso that X represents -O-, or
(f) -NH-NR4-, under the proviso that X represents a bond;
or
(ii) -X-A-Y- together represent -O-; and wherein
R1 and Rs are independently selected from:
(a) -H,
(b) -(d-CsJaikyl, which is optionally substituted with halogen, nltril, -OR6, -SR6, or
-COOR6; the number of said substituents being up to three for halogen, and up to two for
any combination of said halogen, nltril, -OR6, -SR6, or-COOR6 moieties,
(c) -phenyl, which is optionally substituted with halogen, nitril, -OR6, -SR8, -R6, or
-COOR6, the number of said substituents being up to perhalo for halogen, and up to two
for any combination of said halogen, nitril, -OR6, -SR6, -R6 or-COOR6 moieties,
(d) -(CrC4)alkyl-phenyl, In which the alkyl portion is optionally substituted with up to three
halogens; and the phenyl portion is optionally substituted with halogen, nitril, -OR6,
-SR8, -R8 or -COOR8, the number of substituents on said phenyl portion being up to
perhalo for halogen, and up to two for any combination of said halogen, nitril, -OR8, -
SR8, -R8 or -COOR6 moieties;
R2 and R4 are independently selected from:
(a) -H, wherein if X represents a bond, A represents -CO- and Y represents -O- or a bond,
then R2 is different from -H;
(b) optionally substituted alkyl,
(c) optionally substituted acyl, under the proviso that Y represents -NH-NR4-,
(d) optionally substituted aryl,
(e) optionally substituted heteroary), and
(f) optionally substituted cycloheteroalkyl,
or, under the proviso that Y represents -NR4-, -NH-NR4- or -NH-SOz-NR4-,
R2 and R4 form together with the nitrogen atom, where R2 and R4 are attached, a heterocyclic 4-, 5-, 6-, 7- or 8-memberred ring, which is optionally saturated, partly unsaturated, or aromatic; which optionally contains up to three additional heteroatoms selected from N, O or S, the num-
ber of additional N atoms being 0,1, 2 or 3 and the number of O and S atoms each being 0, 1 or 2; and which ring is optionally part of a multiple condensed ring-system, wherein the ring or the ring-system is optionally substituted;
R6 represents H, -{Ci-C4)alkyl or halogenated -(CrC^alkyl; and
n represents 0, 1,2,3,4, 5 or 6, wherein, If X represents -NR3- or -O-, then n is different from 0,
and all stereoisomers, pharmacologically acceptable salts and prodrugs thereof.
Accordingly, the present inventions relates to a compound of the general formula I, wherein -X-A-Y- together represent
(a) -CO-NR4-.
(b) -CO-0-,
(c) -CO-.
(d) -CO-NH-NR4-,
(e) -NR3-CO-NR4-,
(f) -NR3-CO-0-,
(g) -NR3-CO-,
(h) -NR3-CO-NH-SO?-,
(i) -NR3-SO2-NR4-.
(j) -NR3-S02-O-,
(k) -NR3-SOz-
(I) -O-CO-NR4-,
(m) -O-CO-,
(n) -O-CO-NH-SOr-NR4-. or
(o) -0-.
In a further embodiment, the present invention relates to a compound of the general formula I, which is an optically pure 15a enantiomer having the formula (II) (Figure Removed)

or a physiologically acceptable salt thereof. In a further embodiment, the present invention relates to the 15aenantiomer having formula (II), wherein n represents 1, 2, 3 or 4, if X represents -NR3- or -O-, or wherein n represents 0, 1,2, or 3, if X represents a bond.
In another embodiment, the present invention relates to a compound of the general formula I, which is an optically pure 15p enantiomer having the formula (III)
O
or a physiologically acceptable salt thereof. In a further embodiment the present invention relates to the 15J3 enantiomer having formula (III), wherein n represents 2, 3,4, or 5, if X represents a bond, or wherein n represents 3,4, 5 or 6, if X represents -NR3- or -O-.
One preferred embodiment of the present invention relates to compounds of the general formula I, wherein R1 and R3, If R3 is present, are Independently selected from H, (d-C^alkyl, preferably methyl, and phenyl(Ci-C4)alkyl, preferably benzyl.
A.further preferred embodiment of the present invention relates to compounds of the general formula I, wherein R1 and R3, if R3 is present, are independently selected from H and methyl.
A further preferred embodiment of the present invention relates to compounds of the general formula I, wherein, If X represents -NR3- or -O- and Y represents -NR2R4-, then R4 is -H.
A preferred embodiment of the present invention relates to compounds of the general formula I, wherein R2 and R4 are independently selected from:
(a) -H, wherein If X represents a bond, A represents -CO- and Y represents -O- or a bond,
then R2 is different from -H,
(b) -(Ci-Ci2)alkyl, optionally substituted with up to five substituents independently selected
from the group consisting of halogen, hydroxyl, thlol, nitrile, alkoxy, aryloxy,
arylalkyloxy, amino, amido, alkytthio, arylthio, arylalkylthio, sulfamoyl, sulfonamide, acyl,
carboxyl, acylamino,
aryl, which aryl is optionally substituted with up to three substituents independently selected from the group consisting of halogen, hydroxyl, (C1-C6)alkoxy, (Ci-C6)alkyl, halogenated (CrC6)alkyl, halogenated (Ci-C6)alkoxy, carboxyl^d-CeJalkyl, thiol,
(Figure Removed)

nitrile, sulfamoyl, sulfonamide, carboxyl, aryloxy. arylalkyloxy, (CrC6)a!kylthio, aryl-thio, arylalkyithio, amino, amido, acyl, acylamino and heteroaryl; or which aryl is optionally substituted by two groups which are attached to adjacent carbon atoms and are combined into a saturated or partly unsaturated cyclic 5, 6,7, or 8 mem-bered ring system, optionally containing up to three heteroatoms, such as N, O or S, the number of N atoms being 0-3 and the number of O and S atoms each being 0-2;
heteroaryl, which heteroaryl is optionally substituted with up to three substituents independently selected from the group consisting of halogen, hydroxyl, (CrC6)alkoxy, (d-Ce^lkyl, halogenated (CrCe)alkyl, halogenated (C1-C6)alkoxy, carboxyl-(d-Ce)alkyl, thiol, nitrile, sulfamoyl, sulfonamide, carboxyl, aryloxy, arylalkyloxy, (d-Ce)alkylthio, arylthio, arylalkyithio, amino, amido, acyl, acylamino, aryKd-C^alkyl and aryl;
whereby each aryl group is optionally substituted with up to three substituents independently selected from the group consisting of hydroxyl, halogen, (d-C6)alkoxy, (CrC6)alkyl, halogenated (d-QOalkyl and halogenated (d-CB)alkoxy; and
cycloheteroalkyl, which cycloheteroalkyl group is optionally substituted with up to three substituents independently selected from the group consisting of oxo, (d-Ca)-alkyl, aryl, aryl-(d-d)-alkyl, hydroxyl, (d-Cyalkoxy, carboxyl-(d-Ce)alkyl, thiol, nitrile, sulfamoyl, sulfonamide, carboxyl, aryloxy, arylalkyloxy, (d-Ce)alkylthio, arylthio, arylalkyithio, amino, amido, acyl, and acylamino,
whereby each aryl group is optionally substituted with up to three substituents independently selected from the group consisting of hydroxyl, halogen, (d-C4)-alkyl, (C rC^alkoxy, halogenated (d-C^alkyl, and halogenated (d-C4)-alkoxy);
(c) acyl -(COJ-R1, wherein R' represents hydrogen, (d-d)alkyl, aryl, or aryl-(d-C4>alkyl,
or heteroaryl-(d-C4)alkyl;
which aryl is optionally substituted with up to three substituents independently selected from the group consisting of hydroxyl, halogen, (d-C4)alkoxy, (Crd)-alkyl or halogenated (d-d)alkyl;
(d) aryl
which aryl is optionally substituted with up to three substituents independently selected from the group consisting of halogen, hydroxyl, (d-CeJalkoxy, (d-Cs)alkyI, halogenated (d-C6)aIkyl, halogenated (d-C8)alkoxy, carboxyl-(d-C6)alkyl, thiol, nitrile, nitro, sulfamoyl, sulfonamide, carboxyl, aryloxy, arylalkyloxy, (C1-C6)alkylsulfonyl, arylsulfonyl, (d-C8)alkyIthio, arylthio, arylalkyithio, amino, amido, acyl, acylamino and heteroaryl; or
which aryl is optionally substituted by two groups which are attached to adjacent carbon atoms and are combined into a saturated or partly unsaturated cyclic 5, 6, 7, or 8-membered ring system, optionally containing up to three heteroatoms, such as N, O or S, the number of N atoms being 0-3 and the number of O and S atoms each being 0-2;
(e) heteroaryl,
which heteroaryl is optionally substituted with up to three substituents independently selected from the group consisting of halogen, hydroxyl, (C-rC6)alkoxy, (d-Ce)alkyl, halogenated (d-C6)alkyl, halogenated (d-C6)alkoxy, carboxyHd-CsJalkyl, thiol, nitrile, sulfamoyl, sulfonamide, arylsulfoxy, carboxyl, aryloxy, arylalkyloxy, (d-Cajalkylsulfonyl, arylsulfonyl, (d-CeJalkylthio, arylthio, arylalkylthio, amlno, amido, acyl, acylamino, aryl-(CrC4)-alkyl and aryl,
whereby each aryl group is optionally substituted with up to three substituents Independently selected from the group consisting of hydroxyl, halogen, (d-C8)alkoxy, (Ci-C6)alkyl, halogenated (d-C6)alkyl and halogenated (d-C6)alkoxy; or
(f) cycloheteroalkyl,
which cycloheteroalkyl is optionally substituted with up to three substituents independently selected from the group consisting of oxo, (d-d.»)-alkyl. aryl, aryl-(d-C4)-alkyl, hydroxyl, (d-C6)alkoxyt carboxyl-(CrC6)alkyl, thiol, nitrile, sulfamoyl, sulfonamide, carboxyl, aryloxy, arylalkyloxy, (C-t-CsJalkylthio, arylthio, arylalkylthio, amino, amido, acyl, and acylamino,
whereby each aryl group is optionally further substituted with up to three substituents independently selected from the group consisting of hydroxyl, halogen, (d-dValkyl, (Ci-C4)-alkoxy, halogenated (d-C4)-alkyl, and halogenated (d-d)-alkoxy;
or wherein, under the proviso that Y represents -NR4-, -NH-NR4- or -NH-SOjj-NR4-,
R2 and R4 form together with the nitrogen atom, where R2 and R4 are attached, a heterocydic 4-, 5-, 6-, 7- or 8-memberred ring, which is optionally saturated or partly unsaturated; which optionally contains up to three additional heteroatoms selected from N, O or S, the number of additional N atoms being 0-3 and the number of 0 and S atoms each being 0-2; and which ring is optionally part of a multiple condensed ring-system, wherein the ring or the ring-system is optionally substituted
(i) with up to three substituents independently selected from the group consisting of (d-Ce)-alkyl, halogen, hydroxyl, carboxyl, thiol, nitrile, (d-C6}-alkoxy, carboxyl-(d-Cs)alkyl, aryloxy, arylalkyloxy, amino, amido, alkylthio, arylthio, arylalkylthio, sulfamoyl, sulfonamide, aryl, aryl-(d-d)-alkyl, heteroaryl, and cycloheteroalkyl,
wherein the (CrC8)-alkyl group is optionally substituted with up to three substituents independently selected among hydroxyl, halogen, (C1-C4)-alkoxy, or halogenated (CrO))-alkoxy, whereby the alkyl-chain of the (CrC4)-alkoxy moiety is optionally substituted with
hydroxyl;
wherein the aryl is optionally substituted with up to three substituents independently selected from the group consisting of hydroxyl, halogen, (Ci-C4)-alkyl, (C1-C4>-alkoxy, halogenated (d-QO-alkyl, halogenated (CrC4)-alkoxy and carboxyl-(Ci-C6)alkyl, or wherein the aryl moiety is optionally substituted by two groups which are attached to adjacent carbon atoms and are combined into a saturated or partly unsaturated cyclic 5, 6, 7, or 8 membered ring system, optionally containing up to three het-eroatoms, such as N, O or S, the number of N atoms being 0-3 and the number of O and S atoms each being 0-2;
wherein the heteroaryi is optionally substituted with up to three substituents independently selected from the group consisting of hydroxyl, halogen, (Ct-C^-alkyl, (d-C4)-alkoxy, halogenated (Ci-C4)-alkyl, halogenated (Ci-C4)-alkoxy) and carboxyl-(d-C6)alkyl;
wherein the cycloheteroalkyl is optionally substituted with up to three substituents independently selected from the group consisting of oxo, (d-CgJ-alkyl, aryl, aryKd-C4)-alkyl, hydroxyl, (CrC6)alkoxy, carboxyHd-CeJalkyl, and carboxyl, whereby each aryl group is optionally further substituted with up to three substituents independently selected from the group consisting of hydroxyl, halogen, (Oi-C4)-alkyl, (Ci-C4)-alkoxy, halogenated (d-d)-alkyl, and halogenated (d-C4)-aIkoxy); or
(ii) by two groups which are attached to the same carbon atom and are combined into a saturated or partly unsaturated cyclic 4, 5, 6, 7, or 8-membered ring system, optionally containing up to three heteroatoms, such as N, 0 or S, the number of N atoms being 0-3 and the number of O and S atoms each being 0-2,
whereby the cyclic ring system is optionally substituted by up to two substituents independently selected from oxo, (CrC6)-alkyl, aryl and aryl-(C-i-C4)-alkyl;
and wherein n represents
(a) 1,2,3, 4,5 or 6, under the proviso that X represents -NR3- or -O-, or
(b) 0,1,2, 3,4, or 5, under the proviso that X represents a bond.
In one preferred embodiment of the present invention, in the compounds of the general formula I the residues R2 and R4 may independently represent -H, wherein if X represents a bond, A represents -CO- and Y represents -O- or a bond, then R2 is different from -H.
In a further embodiment of the present invention, the term "optionally substituted alkyl", wherefram R2 and/or R4 can be independently selected, refers to
(i) -{d-C8)alkyl, optionally substituted with substituents independently selected from the group consisting of
(a) hydroxyl,
(b) nitrite,
(c) -0-R7';
(d) -O-phenyl,
(e) -O-(Ci-C4)alkyH>henyl,
(f) alkylamino,
(g) alkylamido, preferably carbamoyl,
(h) -S-R7l,and
(i) _(c=O)-OR81;
the number of substituents on said alkyl portion being up to five for hydroxyl and one, two or three, more preferably up to two for any combination of said other substituents; and wherein
R7 R8' represents hydrogen, (Cj-C^alkyl, preferably methyl, or (Ci-C4)alkyl-phenyl, preferably benzyl;
(ii) -(d-C4)alkyi, substituted with one or two substituents independently selected from the group consisting of
(a) aryl, wherein the aryl is preferably selected among pherryl, naphthyl, indanyl,
indenyl, and 1,2,3,4-tetrahydro-naphthalen-1-yl, more preferably the aryl is
phenyl or naphthyl, and
which aryl is optionally substituted with halogen, hydroxyl, (d-Q>)alkoxy, (d-C6)alkyl, halogenated (CrC4)alkyi, halogenated (C,-C4)alkoxy, sulfamoyl, or alkylamido; the number of substituents on said aryl portion being up to five, more preferably up to three, for halogen and up to three, more preferably up to two for any combination of said other substituents; or
which aryl is optionally substituted by two groups which are attached to adjacent carbon atoms and are combined into a saturated cyclic 5 or 6 membered ring system, optionally containing up to three heteroatoms, such as N or O, the number of N atoms being 0-3 and the number of O atoms each being 0-2;
(b) heteroaryl, wherein the heteroary! is preferably selected among pyrrolyl, thienyl,
furyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrazolyl, pyridinyl,
pyrimidinyl, pyrazinyl, pyridazinyl, benzothiazolyl, indolyl, quinolinyl, isoquino-
linyl, benzoimidazolyl, benzofuran and benzo[b]thiophene, more preferably the heteroaryl is thienyl, furyl, imidazolyl, pyridinyl, indolyl, or benzoimidazolyl, and which heteroaryl is optionally substituted with up to two, preferably one sub-stituent independently selected from the group consisting of (Ci-C4)alkoxy, preferably methoxy, or (Ci-CXOalkyl, preferably methyl; and (c) cycloheteroalkyl, wherein the cycloheteroalkyl group is preferably selected from the group consisting of pyrrolidinyl, tetrahydrofuranyl, dihydro-1 H-pyrrolyl, tetra-hydrothiophenyl, tetrahydropyridinyl, azetidinyl, thiazolidinyl. oxazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, 1,3-dihydro-benzoimidazolyl, azepanyl, diazepanyl, oxazepanyl and thiazepanyl, preferably the cycloheteroalkyl group is piperidinyl or morpholinyl; and which cycloheteroalkyl is optionally substituted with up to three substituents independently selected from the group consisting of oxo. hydroxyl, (Ct-C4)-alkyl, phenyl, -(CrC^alkyl-phenyl, preferably benzyl, -(C=O)-O-(ci-C4)alkyl, and alkylamino, preferably the cycloheteroalkyl moiety is not substituted;
(Hi) -cycIo(Ca-Ca)alkyl, optionally substituted with hydroxyl; (iv) -{Ci-C4)alkyl-cyclo(C3-C8)alkyl, optionally substituted with hydroxyl; (v) a bicyclic ring system of 6 to 10 carbon atoms, preferably Bicyclo[2.1.1]hexyt, Bicy-clo[2.2.1]heptyl, Bicyclo[3.2.1]octyl, Bicyclo[2.2.2]octyl, Bicyclo[3.2.2]nonanyl, Bicy-clo[3.3.1]nonanyl. Bicyclo[3.3.2]decanyl; or (vi) a fused ring system of up to 10 carbon atoms, preferably adamantly.
In a further embodiment of the present invention, the term "optionally substituted acyl", wherefrom R2 and/or R* can be independently selected under the proviso that Y represents -NH-NR4-, refers to acyl -(OOJ-R1, wherein R' represents hydrogen, (CrC4)alkyl, aryl, or aryl-fCp C4)alkyl, or heteroary)-(Ci-C4)alkyl; which aryl or aryl-(Ci-C4)alky! is optionally substituted in the aryl, preferably phenyl, moiety with up to three substituents independently selected from the group consisting of hydroxyl, halogen, (Ci-C4)alkoxy, (CrC4)-alkyl or halogenated (Ci-C4)alkyl.
in a further embodiment of the present invention, the term "optionally substituted aryl", wherefrom R2 and/or R4 can be independently selected, refers to aryl, which is preferably selected among phenyl, naphthyl, indanyl, indenyl, and 1,2,3,4-tetrahydro-naphthalen-l-yl. According to one aspect of the Invention, the aryl is optionally substituted with up to five, more preferably up to three substituents independently selected from the group consisting of
(I) hydroxyl,
(ii) halogen, preferably fluorine or chlorine,
(iii) (CrC6)alkoxy, preferably (d-Cyatkoxy
(iv) (Ci-C8)alkyl, preferably (CrC4)alkyl
(v) halogenated (Cn-C6)alkyl, preferably halogenated (Ci-C^lky!, more preferably trifluoromethyl,
(vi) halogenated (C-rC6)alkoxy, preferably halogenated (d-C4)alkoxy, more preferably trifluoromethoxy;
(vii) --ORB'
(viii) nitrile,
(ix) nitro,
(x) sulfamoyl,
(xi) ~(C=0)-R8',
(xii) ~(C=O>-ORB',
(xiii) -NH-(C=0}-R8',
(xiv) -S-R8',
(xv) -SOz-R8',
(xvi) alkylamino,
(xvii) alkylamido, preferably carbamoyl,
(xviii) phenyl, and
(xix) a further heteroaryl group, optionally substituted with (C|-C4)alkyl, preferably 6-methyl-benzothiazolyl;
wherein
R8' represents hydrogen, (Ci-C4)alkyl, preferably methyl, or (Ci-C4)alkyl-phenyl, preferably
benzyl;
or which aryl may be optionally substituted by two groups which are attached to adjacent carbon atoms and are combined into a saturated or partly unsaturated cyclic 5, 6, 7, or 8 mem-bered ring system, optionally containing up to three heteroatoms, such as N, O or S, the number of N atoms being 0-3 and the number of O and S atoms each being 0-Z
In a further embodiment, the aryl moiety, wherefrom R2 and/or R4 can be independently selected, is optionally substituted with halogen, (CrC6)alkoxy, halogenated (CrC4)alkyl, preferably halogenated methyl, nitro, nitrile, -CO-(CrC4)a!kyl, -CO-O^Cn^Jalkyl, -NH-CO-(Ci-C4)alkyl, (Ci-C4)alkyl-sutfonyl, phenyl or heteroaryl, the number of substituents on said aryl portion being up to perhalo for halogen, and up to two for any combination of said (CrC6)alkoxy or halogenated (Cr C4)alkyl moieties.
In a further embodiment of the present invention, the term "optionally substituted heteroaryl", wherefrom R2 and/or R4 can be independently selected, refers to heteroaryl, which is preferably selected among pyrrolyl, thienyl, furyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyra-zolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzothiazolyl, indolyl, quinolinyl, isoquinolinyl, benzoimidazolyl, benzofuran and benzo[b]thiophene; more preferably heteroaryl is furyl, thiazolyl,
pyrazolyl, pyridinyl, quinolinyi, or benzo[b]thiophene. The heteroaryl is optionally substituted with up to three, preferably up to two substituents independently selected from the group consisting of
(i) halogen,
(ii) (d-d)alkyl,
(Hi) hydroxyl,
(iv) halogenated (d-C4)alkyl.
(v) -{d-C-Oalkoxy,
(vi) -(C1-C4)alkyl-(C=0)-OR8>l
(vii) -O-Ar1',
(viii) -SOz-Ar1',
(ix) phenyl,
(x) -(d-C4)alkyl-phenyl,
(xi) nitrile,
(xii) alkylamino, and
(xiii) alkylamido, preferably carbamoyl;
wherein
RB| represents hydrogen, (Ct-C4)alkyl, preferably methyl, or (Ci-C4)alkyl-phenyl, preferably
benzyl; and
Ar1' represents phenyl optionally substituted with up to three halogen.
Furthermore, the heteroaryl moiety, wherefrom R2 and/or R4 can be independently selected, is optionally substituted with up to three, preferably up to two substituents independently selected from the group consisting of halogen, (C1-C4)alkyll preferably methyl, halogenated (Ci-C4)alkyl, preferably halogenated methyl, -(CrC4)alkyl-{C=O)-O-(Ci-C4)alkyl. -SOz-phenyl, -O-phenyl, and phenyl.
In a further embodiment of the present invention, the term "optionally substituted cydoheteroalkyl", wherefrom R2 and/or R4 can be independently selected, refers to cydoheteroalkyl, which is preferably selected among pyrrolidinyl, tetrahydrofuranyl, dihydro-1H-pyrrolyl, tetrahydrothio-phenyl, tetrahydropyridinyi, azetidinyl, thiazolidinyl, oxazolidinyl, piperidinyl, morpholinyl, ttiiomor-phoiinyl, piperazinyl, 1,3-dihydro-benzoimidazolyl, azepanyl, diazepanyl, oxazepanyl and thiaze-panyl; more preferably cydoheteroalkyl is pyrrolidinyl, morpholinyl, tetrahydrofuranyl, piperidinyl or azepanyl, and which cydoheteroalkyl is optionally substituted with up to three, preferably one or two substituents independently selected from the group consisting of
(i) oxo,
(ii) (d-C4)alkyl,
(iii) phenyl,
(iv) -(d-C4)alkyl-phenyl,
(v) hydroxyl,
(vi) (Ci-GOalkoxy, and
(vii) -{Ci-C4)a!ky1-{C=0)-OR81;
wherein
R8' represents hydrogen, (Ci-C4)alkyl, preferably methyl, or (C^^alkyl-phenyl, preferably
benzyl.
Furthermore, the cycloheteroalkyl group, wherefrom R2 and/or R4 can be independently selected, is optionally substituted with one or two substituents independently selected from the group consisting of oxo, (d-C4)alkyl, preferably methyl, and (C^-^Jalkyl-phenyl, preferably benzyl.
In a further embodiment, the invention relates to a compound of the general formula I, wherein, under the proviso that Y represents -NR4-, -NH-NR4- or -NH-SOa-NR4-, R2 and R4 can form together with the nitrogen atom, where R2 and R4 are attached, a heterocyclic 4-, 5-, 6-, 7- or 8-membered ring, which can be saturated or partly unsaturated, which can contain up to three additional heteroatoms selected from N, O or S, the number of additional N atoms being 0-3 and the number of O and S atoms each being 0-2, and which ring can be part of a multiple condensed ring-system. According to one embodiment, said ring or ring system is selected from the (Figure Removed)
Said ring or the ring-system may be optionally substituted with up to three substituents independently seleded from the group consisting of
(i) hydroxyl,
(ii) (C1-C4)-alkyl optionally substituted with up to two hydroxyl and/or (d-C4)-alkoxy groups, whereby the alkyl-chain of the (CVC^alkoxy moiety may optionally be further substituted with up to two, preferably one hydroxyl;
(iii) cyclo(C3-CB)aIkyl;
(iv) -(C=O)-0-(Ci-C4>-alkyl;
(v) phenyl optionally substituted with halogen, (Ci-C4)-aIkyl, preferably methyl, (CrC4)-alkoxy, or halogenated (C1-C4)-alkyl, preferably halogenated methyl, the number of said substituents on the phenyl moiety being up to three for halogen, and one or two for any combination of said other substituents;
(vl) phenyl-(C|-C4)alkyl, preferably benzyl, optionally substituted in the phenyl group by up to three halogen, or optionally substituted in the phenyl group by two groups which are attached to adjacent carbon atoms and are combined into a saturated or partly un-saturated cyclic 5 or 6-membered ring system, optionally containing up to two O atoms;
(vii) alkylamido, preferably carbamoyl;
(viii) heteroaryl, wherein the heteroaryl is preferably selected from the group consisting of pyridinyl, furyl, thienyl, thiazolyl, imidazolyl, pyrazolyl, indolyl, quinolinyl, benzoimida-zolyl or benzo[b]thiophene, more preferably the heteroaryl is pyridinyl; and
(ix) cydoheteroalkyl, wherein the cydoheteroalkyl is preferably selected from the group consisting of pyrrolidinyl, 1,3-dihydro-benzoimidazolyl, morpholinyl, tetranydrofuranyl, piperidinyl and azepanyl; more preferably the cydoheteroalkyl group Is pyrrolidinyl or 1,3-dihydro-benzoimidazolyl, which cydoheteroalkyl group is optionally substituted with oxo.
Alternatively, said ring or the ring-system may be optionally substituted by two groups which are attached to the same carbon atom and are combined into a saturated or partly unsaturated cydic 4,5,6,7, or 8-membered ring system, optionally containing up to three heteroatoms, such as
N, O or S, the number of N atoms being 0-3 and the number of O and S atoms each being 0-2, whereby the cyclic ring system may optionally be further substituted with up to two substitutents Independently selected from oxo and phenyl.
In a further preferred embodiment, the invention relates to a compound of the general formula I, wherein R4 represents
(a) -H, under the proviso that X represents -NR3- or that X represents a bond and Y
represents-NR4-,
(b) an alky) group selected from
(i) -(Ci-CeJalkyli optionally substituted with substituents independently selected from the group consisting of hydroxyl, nitrile, alkylamino -O-(C1-C4)alkyl, the number of substituents on said alkyl portion being up to five for hydroxyl and up to three, more preferably up to two for any combination of said other substituents;
(ii) -(Cr-GOalkyl, preferably -(Ci-C^alkyl, substituted with up to two, preferably one substituent independently selected among aryl and heteroaryl, wherein the aryl is preferably phenyl or naphthyl, and wherein the heteroaryl is preferably pyridinyl;
(iii) cyclofCrCsJalkyl, preferably cyclofCs-dOalkyl;
(iv) cyclofCVCaJalkyMCrC-Oalkyl-, preferably cydofCa-CeJalkyHCrC^alkyl-; or
(c) cydoheteroalkyl, wherein the cycloheteroalkyl preferably is piperidinyl, which cyclo-
heteroalkyl group is optionally substituted with one or two, preferably one (C|-C4)alkyl,
preferably methyl, group.
In one embodiment, the invention relates to a compound of the following formula VI
(Figure Removed)

wherein
R1 represents H, (Ci-C4)alkyl, preferably methyl, or phenyl(CrC4)alkyl, preferably benzyl;
and n represents 0,1,2, 3,4, or 5.
In this embodiment, R2 preferably represents (!) -{d-COalkyl, (ii) - (iii) -{Ci-C^alkyl-aryl, wherein the aryl is phenyl or naphthyl,
which phenyl is optionally substituted with one or two substituents independently selected from the group consisting of hydroxyl, halogen, and (CpCXOalkoxy; or
which phenyl is optionally substituted by two groups which are attached to adjacent carbon atoms and are combined into a saturated cyclic 5 or 6-membered ring system, containing 1 or 2 0 atoms; or (iv) heteroaryl or -{Ct-C^aikyl-heteroaryl, wherein the heteroaryl is fury!, thienyl, thiazolyl,
pyridinyl, indolyl, or benzoimidazolyl;
which heteroaryl is optionally substituted with one or two substituents independently selected from the group consisting of (CrC^alkyl and -{d-C4)alkyl-{C=O)-O-(d-COalkyl;
and preferably R4 is independently selected from H or -(Ci-C4)-alkyl; or
R2 and R4 may form together with the nitrogen atom, where R2 and R4 are attached, a ring or ringsystem, which is selected from the group consisting of morpholine and thiomorpholine.
In a further embodiment the invention relates to a compound of the following formula XL
(Figure Removed)
R3 is as defined above; preferably R3 represents H;
Y represents -NH-, a bond, or -O-;
R1 represents H, (Ci-C4)alkyl, preferably methyl, or phenyl(CrC4)alkyl, preferably benzyl;
and n represents 1,2,3,4,5 or 6, preferably 1, 2,3 or 4.
A further embodiment of the invention relates to a compound of the following formula XVII, (Figure Removed)wherein
R3 is as defined above; preferably R3 represents H;
R1 represents H, (Ci-C4)alkyl, preferably methyl, or phenyl(d-C4)alkyl, preferably benzyl; and
n represents 1,2, 3, or 4, preferably 3 or 4.
In this embodiment, R2 preferably represents (i) -(CrC4)alkyl, (ii) -(Ca-C^cycloalkyl, (iii) - which phenyl is optionally substituted with one or two substituents independently selected from the group consisting of hydroxyl, halogen, -CO-O(CrC4)alkyl and (CrC4)aIkoxy; or
which phenyl is optionally substituted by two groups which are attached to adjacent carbon atoms and are combined into a saturated cyclic 5 or 6-membered ring system, containing 1 or 2 O atoms, or (v) - A further embodiment of the invention relates to a compound of the following formula XXIII, (Figure Removed)wherein
R3 is as defined above; preferably R3 represents H;
R1 represents H, (CrC4)alkyl, preferably methyl, or phenyl(Ci-C4)alkyl, preferably benzyl; and n represents 1,2, 3, or 4.
(Figure Removed)In this embodiment, R2 preferably represents (i) -(CrC4)alkyl, (fi) -{Cg^cycloalkyl,
(iii) - (iv) -{Ci-C4)alkyl, substituted with one or two substituents independently selected from the
group consisting of-O-^Gt-C^alkyl and -O-(Ci-C4)alkyl-phenyl, (v) phenyl,
which phenyl is optionally substituted with one, two or three substituents independently selected from the group consisting of halogen and (Ci-C,i)alkoxy; (vi) -{CrC^alkyl-phenyl; or (vii) adamantly.
A further embodiment of the invention relates to a compound of the following formula XXIV,
wherein
R3 is as defined above; preferably R3 represents H
R1 represents H, (Ci-C4)alkyl, preferably methyl, or phenyl(Ct-C4)alkyl, preferably benzyl;
n represents 1,2, 3, or 4.
In this embodiment, R2 preferably represents
(i) aryl, wherein the aryl is selected among phenyl and naphthyl,
which aryl is optionally substituted with one or two substituents independently selected from the group consisting of halogen, nitro, (Ci-C4)alkoxy, and -(CrC^alkyl; or (ii) heteroaryl, wherein the heteroaryl is furyl, thienyl, or thiazolyl, or indolyl,
which heteroaryl is optionally substituted with one or two substituents independently selected from the group consisting of-SO2-phenyl and (d-C4)alkyl-
A further embodiment of the invention relates to a compound of the following formula XXVI,
wherein
R1 represents H, (CrC4)alkyl, preferably methyl, or phenyl(C1-C4)aIkyl, preferably benzyl;
n represents 3,4, 5 or 6.
In this embodiment, R2 preferably represents phenyl or naphthyl,
which phenyl is optionally substituted with one or two substituents independently selected from the group consisting of hydroxyi, halogen, nitro, -CO-O(Ci-C4)alkyl and (C-r C4)alkoxy and halogenated (CrC4)aIkyl; or
which phenyl Is optionally substituted by two groups which are attached to adjacent carbon atoms and are combined Into a saturated cyclic 5 or 6-membered ring system, containing 1 or 2 O atoms.
A further embodiment of the invention relates to a compound of the following formula XXVIII,
wherein
R1 represents H, (Ci-C4)alkyl, preferably methyl, or phenyl(Ci-C4)alkyli preferably benzyl;
n represents 3,4,5 or 6.
In this embodiment, R2 preferably represents
(i) - (ii) -{Ca-CaXycloalkyl,
(iii) -{CrC4)alkyl-phenyl,
(iv) phenyl, or
(v) heteroaryl or -{(VC^alkyl-heteroaryl, wherein the heteroaryl is furyl, thienyl, thiazolyl,
pyridinyl, indolyl, or benzoimidazolyl; and preferably R4 is independently selected from H, -(CrC^alkyl and -{C1-C4)alkyl-phenyl; or
R2 and R4 may form together with the nitrogen atom, where R2 and R4 are attached, a ring, which is selected from the group consisting of morpholine, thiomorpholine and piperazyl, and which is optionally substituted with (CrC4)-alky|.
A further embodiment of the invention relates to a compound of the following formula XXXI,
(XXXI)
wherein
R1 represents H, (Ci-C^lkyl, preferably methyl, or phenyl(Ci-C4)all n represents 1 , 2, 3, 4, 5 or 6, preferably 3 or 4.
Preferred embodiments of the invention relate to the following compounds: No.1.3-Hydroxy-15p-(4-morpholin-4-yl-4-oxo-butyl)-estra-1,3l5(10)-trien-17-one No.2. 3-Methoxy-15p-(4-morpholin-4-yl-4-oxo-butyl)-estra-1 ,3,5(1 0)-trien-17-one No.3B. N-Benzyl-4-(3-methoxy-17-oxo-estra-1 ,3,5(1 0)-trien-15p-yl)-butyramide No.3A. N-Benzyl-4-(3-Hydroxy-17-oxo-estra-1 ,3,5(1 0)-trien-15{i-yl)-butyramide No.31 . 4-(3-Methoxy-17-oxo-estra-1 ,3,5(1 0)-trien-15p-yl)-N-[2-(7-methyl-1 H-indol-3-yl)-ethyI]-butyramide
No.36.4-(3-Hydroxy-17-oxo-estra-1,3,5(10)-trien-15p-yl)-N-[2^HTiethyl-1H-4ndol-3-vl)-ethyl]-butyramide
No.37. N-(2,4-Difluoro-benzyl)-4-(3-hydroxy-17-oxo-estra-1 ,3,5(1 0)-trien-15p-yl)-butyramide No.38. N-Benzyl-^(3-hydroxy-17-oxo-estra-1,3,5(10)-trien-15p-yl)-N-methyl-butyramide No.39. N-Benzyl-4-(3-hydroxy-17-oxo-estra-1,3l5(10)-trien-15a-yl)-butyramide No.40. 3-Hydroxy-15a-(4-morpholin-4-yl-4-oxo-butyl)-estra-1l3,5(10)-trien-17-one No.105. 3-Methoxy-17-oxo-estra-1 ,3,5(1 0)-trien-15a-carboxyIicacid(5-methyl-thiazol-2-yl)-amide No.310. N-Cyclohexyl-3-(3-methoxy-17-oxo-estra-1,3,5(10)-trlen-15p-yl)-propionamide No.311.N-Cyclooctyl-3-(3-methoxy-17-oxo-estra-1,3,5(10)-trien-15p-yl)-propionamide No.313. N-Cyclohexyl-3-(3-methoxy-17-oxo-estra-1,3,5(10)-trien-15p-yl)-N-methyl-propionamide No.324. N-[2-(4-Hydroxy-phenyl)-ethyl]-3-(3-methoxy-17-oxo-estra-1 ,3,5(1 0)-trien-1 5p-yl)-propionamide No.329. 3-(3-Methoxy-17-oxo-estra-1,3,5(10)-trien-15p-yl)-N-(5-methyl-thiazol-2-yl)-propionamide
No.331.5-(3-Methoxy-17-oxo-estra-1,3,5(10)-trien-15p-yl)-pentanoic acid cyclohexylamide
No.332.5-(3-Methoxy-17-oxo-estra-1,3,5(10)-trien-15£-yl)-pentanoic acid cyclooctylamide
No.333.5-(3-Methoxy-17-oxo-estra-1,3,5(10)-trien-15p-yl)-pentanoic acid (furan-2-ylmethyI)-amide
No.335.5-(3-Methoxy-17-oxo-estra-1,3l5(10)-trien-15p-yl)-pentanoic acid (benzo[1,3]dioxol-5-
ylmethyl)-amide
No.338.5-(3-Methoxy-17-oxo-estra-1,3,5(10)-trien-15p-yl)-pentanoic acid (pyridin-3-ylmethyl)-
amide
No.339.5-(3-Methoxy-17-oxo-estra-1,3,5(10)-trien-15(3-yl)-pentanoic acid (pyridin-4-ylmethyl)-
amide
No.340.5-(3-Methoxy-17-oxo-estna-1,3,5(10}-trien-15p-yl)-pentanoic acid benzylamide
No.341.5-(3-Methoxy-17oxo-estra-1,3,5(10}-trien-15p-yl)-pentanoic acid 2-methoxy-benzylamide
No.342.5~(3-Methoxy-17-oxo-estra-1,3.5(10)-trien-15{J-yl)-pentanoic acid 3-fluoro-benzyIamide
No.343.5-(3-Methoxy-17-oxo-estra-1,3,5(10)-trien-15(J-yl)-pentanoic acid 4-chloro-benzylamide
No.344.5-{3-Methoxy-17-oxo-estra-1,3,5(10)-trien-15p-yl)-pentanoic acid benzyl-methyl-amide
No.345.5-{3-Methoxy-17-oxo-estra-1,3,5(10)-trien-15p-yl)-pentanoic acid butylamide
No.346.5-(3-Methoxy-17-oxo-estra-1,3,5(10)-trien-15p-yl)-pentanoic acid (2-thiophen-2-yl-ethyl>-
amide
No.347.5-(3-Methoxy-17-oxo-estra-1,3,5(10)-trien-15p-yl)-pentanoic acid [2-(7-niethyl-1H-indol-3-
yl)-ethyl]-amide
No.348.6-(3-Methoxy-17-oxo-estra-1,3,5(10)-1rien-15p-yl)-hexanoic acid cyclohexylamide
No.350.6-(3-Methoxy-17-oxo-estra-1,3,5(10)-trien-15p-yl)-hexanoic add (furan-2-ylmethyI}-amide
No.353. 6-(3-Methoxy-17-oxo-estra-1,3,5(10)-trien-15p-yl)-hexanoic acid (benzo[1,3]dioxol-5-
**.'•' ylmethyl)-amide
No.354.3-Methoxy-15p-(6-morpholin-4-yl-6-oxo-hexyl)-estra-,3,5(10)-trien-17-one
No.355.3-Methoxy-15p-(6-oxo-6-thiomorpholin-4-yl-hexyl)-estra-1,3,5(10)-trien-17-one
No.356.6-(3-Methoxy-17-oxo-estra-1,3,5(10)-trien-15p-yl)-hexanoic acid (pyridin-3-ylmethyl)-amide
No.357.6-(3-Methoxy-17-oxo-estra-1,3,5(10)-trien-15p-yl)-hexanoic acid (pyridin-4-ylmethyl)-amide
No.359.6-(3-Methoxy-17-oxo-estra-1,3,5(10)-trien-15p-yl)-hexanoic add benzylamide
No.360.6-(3-Methoxy-17-oxo-estra-1,3,5(10)-trien-153-yl)-hexanoic add 2-methoxy-benzylamide
No.361.6-(3-Methoxy-17-oxo-esttB-1,3,5(10)-ti1en-15|3-yl)-hexanoicacid3-fIuoro-benzylatnide
No.363.6-(3-Methoxy-17-oxo-estra-1,3,5(10)-trien-15p-y!)-hexanoic add [2-(4-hydroxy-phenyl)-
ethylj-amide
No.364.6-(3-Methoxy-17-oxo-estra-1,3,5(10)-trien-15p-yi)-hexanoic acid benzyl-methyl-amide
No.365.6-(3-Methoxy-17-oxo-estra-1,3,5(10)-trien-15p-yl)-exanoic add butylamide
No.366.6-(3-Methoxy-17-oxo-estra-1,3,5(10)-trien-15p-yl)-hexanoic add (2-thiophen-2-yl-ethyl)-
amide
No.443.1-[3-(3-Methoxy-17-oxo-estra-1,3,5(10)-trien-15p-yl)-propyfl-3-(3-methoxy-phenyl)-urea
No.446.1-[3-(3-Methoxy-17-oxo-estra-1,3,5(10)-trien-15p-yl)-propyl]-3-(4-methoxy-phenyl)-urea
No.449.1 -!sopropyl-3-[3-(3-methoxy-17-oxo-estra-1,3,5(10)-trien-15p-yl)-propyf]-urea
No.450.1-Cyclohexyl-3-[3-(3-methoxy-17-oxo-estra-1,3,5(10>-trien-15p-yl)-propyl]-urea
No.452.1 -Benzyl-3-[3-(3-methoxy-17-oxo-estra-1,3,5(10)-trien-15p-yi)-propyf|-urea
No.464.1-(3,4-Dimethoxy-phenyI)-3-[3-(3-methoxy-17-oxo-estra-1,3,5(10)-trien-15p-yl)-propyl]-
urea
No.465.1-Benzo[1,3Jdioxol-5-yl-3-[3-(3-methoxy-17-oxo-estra-1,3)5(10)-trien-15p-yl)-propyri-urea
No.477.1-Benzyl-3-[4-(3-methoxy-17-oxo-estra-1,3,5(10)-trien-15p-yl)-butyI]-urea
No.488. l-CS^-Dimethoxy-phenylJ-S-^S-methoxy-^-oxo-estra-I.S.SCIOJ-trien-ISp-yO-butyri-urea
No.490.4-{3-[4-(3-Hydroxy-17-oxo-estna-1,3,5(10)-trien-15a-yl)-bLityl]-ureido}-benzoic acid ethyles-
terNo.491.1-Cyclohexylmethyl-3-[4-(3-hydraxy-17-oxo-estra-1,3I5(10)-trien-15a-yl)-butyl]-urea
No.661. Naphthalene-2-sulfonic acid (3-hydroxy-17-oxo-estra-1,3,5(10)-trien-15a-ylmethyl)-amide
No.662. Thiophene-2-sulfonic acid (3-hydroxy-17-oxo-estra-1,3,5(10)-trien-15a-yimethyl)-amide
No.664. N-(3-Hydrbxy-17-oxo-estra-1,3,5(10)-trien-15a-ylmethyl)-benzenesulfonamide
No.665.4-Fluoro-N-(3-hydroxy-17-oxo-estra-1,3,5(10)-trien-15a-ylmethyl)-benzenesulfonamide
No.668. N-(3-Hydraxy-17-oxo-estra-1,3,5(10)-trien-15a-ylmethyl)-4-methoxy-benzenesulfbnamide
No.677. N-(3-Hydroxy-17-oxo-estra-1,3,5(10)-trien-15a-ylmethyl)-3-methyl-ben2enesulfbnamide
No.681. Naphthalene-2-sulfonic acid (3-hydraxy-17-oxo-estra-1,3,5(10)-trien-15a-ylmethyl)-methyl-
amide
No.682. Thiophene-2-sulfonic acid (3-hydroxy-17-oxo-estra-1,3,5(10)-trien-15a-ylme1hyl)-melhyl-
amlde
No.684. N-(3-Hydroxy-17-oxo-estra-1,3,5(10)-trien-15a-ylmethyl}-N-methyl-benzenesulfonamide
No.eSS^-Fluoro-N-tS-hydroxy-^-oxo-estra-I.S.SflOJ-trien-ISa-ylmethylJ-N-methyl-
benzenesulfonamide
No.688. N-(3-Hydroxy-17-oxo-estra-1l3l5(10)-trien-15a-ylmethyl)-4-niethoxy-N-methyl-
benzenesutfonamide
No.693.3-Chloro-N-(3-hydroxy-17-oxo-estra-1,3,5(10)-trien-15a-ylmelhyl)-N-methyl-
benzenesulfonamide
No.694. N-(3-Hydroxy-17-oxo-estra-1,3,5(10)-trien-15a-ylmethyl)-3,N-dimethyl-
benzenesulfonamide
No.696.4-BenzenesuIfonyl-thiophene-2-sulfonic acid (3-hydroxy-17-oxo-estra-1,3,5(10)-trien-15a-
ylmethyl)-methyl-amide
No.748. Ben2X3[1,3]dioxol-5-yl-carbamic acid 3-(3-methoxy-17-oxo-estra-1,3,5(10)-trien-15p-yl)-
propylester
No.823.3-Hydroxy-l5p-(3-hydroxypropyl)-estra-1I3,5(10)-trien-17-one or a physiologically acceptable salt thereof.
Pharmaceutically acceptable salts of the compounds of the invention as well as commonly used pro-drugs and active metabolites of these compounds are also within the scope of the invention.Additionally, the invention relates to a compound of the invention for use as a medicament
The invention also relates to pharmaceutical compositions comprising one or more of the compounds of the invention, or their salts or pro-drugs, as active agent and at least one pharma-ceutically acceptable carrier.
Furthermore, the invention relates to the use of an effective amount of a compound of the invention for the treatment or prevention of a steroid hormone dependent disease or disorder in a mammal, in particular a human. Preferably the steroid hormone dependent disease or disorder is an estradlol dependent disease or disorder.
In addition, the invention relates to the use of a compound of the Invention for the manufacture of a medicament for the treatment or prevention of a steroid hormone dependent disease or disorder in a mammal, In particular a human. Preferably the steroid hormone dependent disease or disorder is an estradiol dependent disease or disorder.
In a further embodiment of the invention, the steroid hormone dependent disease or disorder requires the inhibition of a 17|3-HSD enzyme, preferably the human 17J3-HSD1 enzyme.
Furthermore, the invention also relates to a method of treating a mammal such as a human having a condition related to 1?p-HSD1 activity, comprising administering to the mammal an amount of a compound of this Invention, or a salt or a prodrug thereof, which amount is effective to treat the condition. Administration of compounds of this invention in combination with other phar-maceutlcals used in treatment of the listed conditions is contemplated.
The conditions to be treated include but are not limited to malign estradiol dependent disease or disorder such as breast cancer, ovarian cancer, uterine cancer, endometrial cancer, and endometrial hyperplasia.
According to a further aspect of the invention, the estradiol dependent disease is breast cancer and the mammal is a human post-rnenopausal female.
Furthermore, the conditions to be treated include but are not limited to benign estradlol dependent diseases or disorders such as endometriosis, uterine fibroids, uterine leiomyoma, adeno-myosis, dysmenorrhea, menorrhagia, metrorrhagia, and urinary dysfunction.
In a further embodiment, the invention relates to use of an effective amount of a compound of the invention for the treatment or prevention of one of the aforementioned benign gynaecological
diseases or disorders in a mammal whereby the mammal is a human, preferably a female and most preferably a pre- or peri-menopausal female.
According to one aspect of the present invention, the steroid hormone dependent disease or disorder is selected from the group consisting of prostate carcinoma, prostadynia, benign prostatic hyperplasia, urinary dysfunction and lower urinary tract syndrome.
According to one aspect of the invention, the steroid hormone dependent disease or disorder to be treated requires the lowering of the endogenous 17β-estradiol concentration in a generalized and/or tissue specific manner.
Therefore, further estrogen-dependent diseases which may be treated with an effective amount of a compound of the invention are rheumatoid arthritis, colon cancer, tissue wounds, skin wrinkles and cataracts.
The disclosed compounds are also useful as diagnostic agents (e.g. in diagnostic kits or for use in clinical laboratories) for screening for the presence or absence of 17J3-HSD1 activity.
In addition, the present invention relates to the use of a selective inhibitor of the17β-HSD1 enzyme for the treatment and/or prophylaxis of a benign estradiol dependent disease or disorder in a mammal, in particular a human, preferably a female and most preferably a pre- or peri-menopausal female.
In a preferred embodiment of the present invention the selective inhibitor of the17β-HSD1 enzyme used for the treatment and/or prophylaxis of a benign estradiol dependent disease or disorder possesses no or only pure antagonistic binding affinities to the estrogen receptor.The invention also relates to a method of treating a mammal such as a human having a benign estradiol dependent condition, comprising administering to the mammal an amount of a selective inhibitor of the 17β-HSD1 enzyme, whereby said inhibitor preferably possesses in addition no or only pure antagonistic binding affinities to the estrogen receptor, and which amount is effective to treat the condition. Administration of a selective inhibitor of the 17β-HSD1 enzyme which additionally possesses no or only pure antagonistic binding affinities to the estrogen receptor of this invention in combination with other Pharmaceuticals used in treatment of the listed conditions is contemplated.
The benign estradiol dependent conditions to be treated with a selective inhibitor of the 1?p-HSD1 enzyme include but are not limited to endometriosis, uterine fibroids, uterine leiomyoma, adenomyosis, dysmenormea, menorrhagia, metrorrhagia, and urinary dysfunction.
The invention also relates to the use of a selective inhibitor of the 17β-HSD1 enzyme for the manufacture of a pharmaceutical composition for the treatment and/or prevention of a benign estradiol dependent disease or disorder in a mammal. The benign estradiol dependent disease or disorder is preferably endometriosis, uterine fibroids, uterine leiomyoma, adenomyosis, dysmenor-rhea, menorrhagia, metrorrhagia, or urinary dysfunction. Furthermore, the inhibitor of the 17(3-HSD1 enzyme preferably possesses in addition no or only pure antagonistic binding affinities to the estrogen receptor.
In a preferred embodiment the invention relates to use of an effective amount of a selective inhibitor of the17β-HSD1 enzyme for the manufacture of a pharmaceutical composition for the treatment and/or prevention of a benign estradiol dependent disease or disorder in a mammal, whereby the mammal is a human, preferably a female and most preferably a pre- or peri-menopausal female.
In addition, the present invention relates to the use of a selective inhibitor of the 17β-HSD1 enzyme showing no or only pure antagonistic binding affinities to the estrogen receptor for the prevention of breast cancer in a post-menopausal female, and to the use of said selective inhibitors for the.manufacture of a medicament for the prevention of breast cancer in a postmenopausal female.
DESCRIPTION OF THE INVENTION Definitions:The following terms are used to describe various constituents of the chemical composition useful in this invention. The terms are defined as follows:
As used herein, the terms "comprising" and "including" are used herein in their open, non-limiting sense.
The word "compound" shall here be understood to cover any and all isomers (e. g., enantiomers, stereoisomers, diastereomers, rotomers, tautomers) or any mixture of isomers, prodrugs, and any pharmaceutically acceptable salt of said compound.
Where the plural form is used for compounds, salts, and the like, this is taken to mean also a single compound, salt, or the like.
The term "substituted" means that the specified group or moiety bears one or more substituents. Where any group may carry multiple substituents and a variety of possible substituents is provided, the substituents are independently selected and need not be the same. The term "unsubstrtuted11 means that the specified group bears no substituents. The term "optionally substituted" means that the specified group is unsubstituted or substituted by one or more substituents.
Any asymmetric carbon atoms may be present in the (R)-, (S)- or (R,S)-configuration, preferably in the (R)- or (S)-configuration, whichever is most active. Substituents at a double bond or a ring may be present in ds- (.=Z-) or trans (=E-) form.
The compounds of the formula I contain at least one chiral carbon atom, namely the carbon atom carrying the side chain in the 15-position of the steroide structure. The compounds can thus be present in two optically active stereoisomeric forms or as a racemate. The present invention includes both the racemic mixtures and the isomerically pure compounds of the formula I. The position of the substituents within the C15 position is characterized by a or p. A C15a derivative according to the present invention is represented by a compound of the following formula (II)
(Figure Removed)
whereas a C15P derivative according to the present invention is represented by a compound of the following formula (III)
(Figure Removed)


the compounds of the present invention may contain further asymmetric centers on the molecule, depending upon the nature of the various substituents. In certain instances, asymmetry
may also be present due to restricted rotation about the central bond adjoining the two aromatic rings of the specified compounds. It is Intended that all isomers (including enantiomers and diastereomers), either by nature of asymmetric centers or by restricted rotation as described above, as separated, pure or partially purified isomers or racemic mixtures thereof, be included within the ambit of the instant invention.
The term "halogen" refers to fluorine (F, Fluoro-), bromine (Br, Bromo-), chlorine (Cl, Chloro), and iodine (J, lodo-) atoms.
The terms "dihalogen", "trihalogen" and "perhalogen" refer to two, three and four substitu-ents, respectively, each individually selected from the group consisting of fluorine, bromine, chlorine, and iodine atoms.
The term "hydroxyP refers to the group -OH
The term "oxo" refers to the group =O
The term "carbamoy!" refers to the group -CO-NHZ
The term "thio" refers to the group =S
The term "thiol" refers to the group -SH
The term "sulfanyT refers to the group -S-
The term "sulfoxy" or "sulfonyl" refers to the group -SOz-
The term "suIfamoyP refers to the group -SOr-NHa
The term "nrtro" refers to the group -NO2
The term "nitrite" or "cyano" refers to the group -CN
For the purpose of the present invention, the carbon content of various hydrocarbon containing moieties is indicated by a prefix designating the minimum and maximum number of carbon atoms in the moiety, i.e., the prefix Q-Cj defines the number of carbon atoms present from the integer T to the integer "j" inclusive. Thus d-C4-alkyl refers to alkyl of 1-4 carbon atoms, inclusive, or methyl, ethyl, propyl, butyl and isomeric forms thereof.
The term "alky!" stands for a hydrocarbon radical which may be linear, cyclic or branched, with single or multiple branching, whereby the alkyl group comprises 1 to 12 carbon atoms. In one embodiment, the term "alkyl" stands for a linear or branched (with single or multiple branching) alkyl chain of 1 to 8 carbon atoms, exemplified by the term (Ci-Cs)alkyl, more preferably of 1 to 6 carbon atoms exemplified by the term (C,-C6)alkyl. The term (Ci-C8)alkyl is further exemplified by such groups as methyl; ethyl; n-propyl; isopropyl; n-butyl; sec-butyl; isobutyl; tert-butyl; n-pentyl; isopenfyl; neopentyl; tert-pentyl; 2- or 3-methylpentyI; n-hexyl; isohexyl, heptyl, octyl and the like. The alkyl or (C1-C8)aikyl group may be partially unsaturated, forming such groups as, for example, vinyl, propenyl (allyl), butenyl, pentenyl, pentinyl, hexenyl, octadienyl, and the like. The term "aikyl" further comprises cycloalkyl groups, preferably cyclo(C3-C8)alkyl which refers to cyclopropyl, cyclobutyl, cydopentyl, cyclohexyl, cycloheptyl, cyclooctyl and isomeric forms thereof such as me-thylcydopropyl; 2- or 3-methylcyclobutyl; 2-, or 3-methylcyclopentyl, and the like. The cycloalkyl group may also be partly unsaturated, forming such groups as, for example, cyclohexenyl, cyclopentenyl, cyclooctadienyl, and the like. Furthermore, the term "alkyl" comprises a cydoalkyl-alkyl group comprising 4 to 12 carbon atoms, preferably °-{CrC4)alkyl-cyclo(C3-Ca)alkyl" which refers to a alkyl group of 1 to 4 carbon atoms as described above substituted with a cyclo(C3-C8)alky) group as described above, forming such groups as for example cyclopropylmethyl, cydo-hexylmethyl, cyclopentylethyl or cydohexenylethyl. The term "alkyl" further comprises bicyclic ring systems of 6 to 10 carbon atoms, preferably Bicydo[2.1.1]hexyl, Bicyclo[2.2.1]heptyl, Bicy-clo[3.2.1]octyl, Bicyclo[2.2.2]octyl, Bicydo[3.2.2]nonanyl, Bicyclo[3.3.1]nonanyl, Bicy-clo[3.3.2]decanyl; and the like, preferably Bicyclo[2.2.1]heptyl, and fused ring systems of up to 10 carbon atoms such as adamantyl and the like.
The alkyl group may optionally be substituted by up to five, more preferably by up to three substituents independently selected from the group consisting of halogen, hydroxyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloheteroalkyl, thiol, nitro, nitrite, alkoxy, aryloxy, arylalkyloxy, amino, amido, alkylthio, arylthio, aryl alkyIthio, sulfamoyl, sul-fonamide, acyl, carboxyl, and acylamino, as defined herein. These groups may be attached to any carbon atom of the alkyl moiety. Substituted alkyl is preferably substituted with halogen, nitrite, hydroxyl, CrC4-alkoxy (wherein the alkyl chain may be optionally further substituted with up to three hydroxyl groups), phenoxy, benzyloxy, Cn-C^alkylthio, alkylamino, a carboxyl group -(C=O)-OR', and alkylamido (preferably carbamoyl), the number of substituents on said alkyl portion being up to five for hydroxyl and up to three, more preferably up to two for any combination of said other substituents; as well as with optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloheteroalkyl as defined herein. Cycloalkyl is preferably substituted with hydroxyl.
The alkyl group substituted with up to three independently selected aryl groups preferably refers to "aryl-(Ci-C4)-alkyr or diaryl-(C1-C4)-alkyl, wherein the aryl is phenyl, naphthyl, indanyl, inde-nyl, or 1,2,3,4-tetrahydro-naphthalen-1-yl, preferably ary! is phenyl or naphthyl, forming such
groups as for example benzyl, diphenylmethyl, phenethyl, phenylpropyl, diphenylpropyl, phenylbu-tyl, naphthylmethyl or naphthylethyl. The alkyl chain may be further substituted as defined above; for example the alkyl chain may carry an additional hydroxyl group. Furthermore, the alkyl chain may be partially unsaturated, such as a vinyl group. The aryl moiety may optionally be substituted as defined herein; preferably the aryl moiety is substituted with substituents selected from the group consisting of halogen, hydroxyl, (C-rCeJ-alkoxy, (Ci-C6)-alkyl, halogenated (CrC^-alkyl, halogenated (Ct-C^-alkoxy, alkylamido, preferably carbamoyl, and sulfamoyl; the number of said substituents being up to five for halogen, and up to three for any combination of said other substituents. Furthermore, said aryl may be optionally substituted by two groups which are attached to adjacent carbon atoms and are combined into a saturated cyclic 5 or 6 membered ring system, optionally containing up to three heteroatoms, such as N or O, the number of N atoms being 0-3 and the number of O atoms each being 0-2, as for example substituted with an [1,3]-dioxol group.
The alkyl group substituted with up to three independently selected heteroaryl group preferably refers to "heteroaryl-(C1-C4)-alkyri, wherein the heteroaryl is pyrrolyl, thienyl, furyl, Imida-zolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, quinolinyl, isoquinolinyl, benzoimidazolyl, benzofuran, benzo[b]thiophene, preferably heteroaryl Is furyl, indolyl, benzoimidazolyl, pyridinyl, thienyl or imidazolyl, forming such groups as for example benzoimidazolylmethyl, pyridinylmethyl, thlenylmethyl, furylmethyl, indolylethyl, thienylethyl, pyridinylethyl, or Imidazolylpropyl. The heteroaryl moiety may optionally be substituted as defined herein; preferably the heteroaryl moiety is substituted with substituents selected from the group consisting of (G1-C4)-alkoxy, preferably methoxy, (CVC^-alkyl, preferably methyl, or halogenated (Ci-C4)-alkyl, the number of said substituents being up to two for any combination of said substituents.
The alkyl group substituted with up to three independently selected cycloheteroalkyl groups preferably refers to "cycloheteroalkyl-(CrC,»)-alkyr, wherein the cycloheteroalkyl is pyrrolidinyl, tetrahydrofuryl, tetrahydrothiophenyl, piperidinyl, morpholinyl, thiomorphoiinyl, piperazinyl, aze-panyl, diazepanyl, oxazepanyl or thiazepanyl, preferably cycloheteroalkyl is piperidinyl, pyrrolidinyl, or morpholinyl, forming such groups as for example morpholinylethyl, morpholinylpropyl, piperid-inylethyl or pyrrolidinylethyl.
The term "alkoxy" refers to a group -OR, where R may be alkyl (wherein the alkyl chain may be optionally further substituted as defined herein, preferably with up to three hydroxyl groups or up to five halogen residues), carbonyl, or acyl as defined herein. Preferably, the term "alkoxy" refers to -O-(CrC6)alkyl (or (CrC6)alkoxy), with the (Ci-CaJalkyl group as defined above and optionally substituted with up to three hydroxyl groups.
The term "aryloxy" refers to a group —OAr, where Ar represents aryl as defined herein, which is optionally substituted in the aryl group with up to five independently selected substituents, in particular hydroxyl, halogen, (d-d)-alkyl. (CrC4)-alkoxy, halogehated (d-C4)-alkyl, or halogenated (d-C4)-alkoxy; the number of said substituents being up to five for halogen, and up to three for any combination of said other substituents. Preferably, aryloxy refers to phenoxy, optionally substituted as defined above.
The term "aryialkyloxy" refers to a group -O-(d-C4)alkyl-Ar, where AT represents aryl, which is optionally substituted in the aryl group with up to five independently selected substituents, in particular hydroxyl, halogen, (d-d)-alkyl. (C1-C4)-alkoxyl halogehated (d-C4)-alkyl, or halo-genated (C1-C4)-alkoxy; the number of said, substituents being up to five for halogen, and up to three for any combination of said other substituents. Preferably, aryialkyloxy refers to benzyloxy, optionally substituted as defined above.
The term "acyl" refers to a group - The term "carbonyl" represents a preferred selection of the term "acyl" and refers to the group -CHO.
The term "alkylacyl" represents a preferred selection of the term "acyl" and refers to a group -{C=O)-alky], preferably -(C=OHCi-C4)alkyl.
The term "carboxyl" refers to a group - lar hydroxyl, halogen, (C1-C4)-alkyll (Ci-C4)-alkoxy, halogenated (CrC4)-alkyl, or halogenated (Cn-C4)-alkoxy, the number of said substituents being up to five for halogen, and up to three for any combination of said other substituents), heteroaryl or heteroaryl-(Ci-C4)-alkyl (both optionally substituted in the heteroaryl group with up to three independently selected substituents as defined herein), as defined herein. Preferably, the term "carboxyl" refers to a group - The terms "carboxyKCi-CeJalkyl" and "carboxyKCrGOalkyr refer to groups -(Ci-C6)alkyl-(C=O)-OR and -(Ci-C4)alkyl-(C=O)-OR, respectively, which refer to an alkyl group of 1 to 6 and 1 to 4 carbon atoms, respectively, as described above, substituted with a -(C=O)-OR group as described above. Preferably the carboxyl group refers to -{C=O)-OR', wherein R' represents hydrogen, (CrC4)alkyl, phenyl, or (CrC^alkyl-phenyl, preferably benzyl. Preferred examples of such carboxyl-(Ci-C6)alkyl groups include acetic acid methyl ester, acetic acid ethyl ester, propionic acid benzyl ester, propionic acid ethyl ester, butyric acid methyl ester, and 3-methyl-butyric acid methyl ester.
The term "amino" refers to the group -NRR', where R and R' may independently be hydrogen, alkyl (optionally substituted in the alkyl chain with up to five independently selected substituents as defined herein, in particular hydroxyl, halogen or (d-C4)-alkoxy)1 aryl or aryl-(d-C4)-alkyl (both optionally substituted in the aryl group with up to five independently selected substituents as defined herein, in particular hydroxyl, halogen, (Ci-C4)-alkyl- (CrC4)-alkoxy, halogenated (Ci-C4)-alkyl, or halogenated (Ci-C4)-alkoxy, the number of said substituents being up to five for halogen, and up to three for any combination of said other substituents), heteroaryl or heteroaryi-(Ci-C4)-alkyl (both optionally substituted in the heteroaryl group with up to three independently selected substituents as defined herein), as defined herein.
The term "alkylamino" represents a preferred selection of the term "amino" and refers to the group -NRR', where R and R1 may independently be hydrogen or (Ci-C4)alkyl.
The term "alkylthio" or "alkylsulfanyl" refers to a group -SR, where R represents alkyl, optionally substituted in the alkyl chain with up to five substituents as defined herein, preferably hydroxyl, (d-C^alkoxy or halogen; preferably R represents (Ci-C6)alkyl, In particular (C^^alkyl, as defined above.
The term "arylthio" or "arylsulfanyl" refers to a group -S-Ar, where AT represents aryl, which Is optionally substituted in the aryl group with independently selected substituents as defined herein, in particular hydroxyl, halogen, (C,-C4)-alkyl, (C1-C4)-alkoxy, halogenated (Ci-C4)-alkyl, or halogenated (CrC4)-alkoxy, the number of said substituents being up to five for halogen, and up to three for any combination of said other substituents. Preferably, arylthio refers to phenylsulfartyl, optionally substituted as defined above.
The term "arylalkylthio" or "arylalkylsulfanyl" refers to a group -S-{CrC4)alkyl-Ar, where Ar represents aryl, which is optionally substituted in the aryl group with independently selected substituents as defined herein, in particular hydroxyl, halogen, (CrC4)-alkyl, (Ci-C4)-alkoxy, halo-. genated (Cn-C4) alkyl, or halogenated (d-C4)-alkoxyf the number of said substituents being up to five for halogen, and up to three for any combination of said other substituents. Preferably, arylalkylthio refers to benzylsulfanyl, optionally substituted as defined above.
The term "alkylsulfonyl" refers to a group -SO2-R, where R represents alkyl, optionally substituted in the alkyl chain with up to five substituents as defined herein, preferably hydroxyl, (d-C4)-alkoxy or halogen; preferably R represents (C1-C6)alkyl, in particular (C1-C4)alkyI, as defined above.
The term "arylsulfonyl" refers to a group -SO2-Ar, where Ar represents aryl, which is optionally substituted in the aryl group with independently selected substituents as defined herein, in particular hydroxyl, halogen, (CrC4)-alkyI, (C1-C4)-alkoxy, halogenated (C1-C4)-aIkyl, or halogenated (CrC4)-alkoxy, the number of said substituents being up to five for halogen, and up to three for any combination of said other substituents. Preferably, arylsulfonyl refers to benzenesulfonyl, optionally substituted as defined above.
The term "arylalkylsurfonyl" refers to a group -SOr(C1-C4)alkyl-Ar, where Ar represents aryl, which is optionally substituted in the aryl group with independently selected substituents as defined herein, in particular hydroxyl, halogen, (CrC4)-alkyl, (CrC4)-alkoxy, haiogenated (CrC4)-alkvl, or halogenated (CrC4)-alkoxy, the number of said substituents being up to five for halogen, and up to three for any combination of said other substituents. Preferably, arylalkylsulfonyl refers to benzyl-sulfonyl, optionally substituted as defined above.
The term "amido" refers to the group -(CsQHMRR1, where R and R' may independently be hydrogen, alkyl (optionally substituted in the alkyl chain with up to five independently selected substituents as defined herein, in particular hydroxyl, halogen or (d-C4)-aIkoxy), aryl or aryl-(d-C4)-alkyl (both optionally substituted in the aryl group with independently selected substituents as defined herein, in particular hydroxyl, halogen, (CrC4)-alkyl, (d-C4)-alkoxy, halogenated (d-C4>-alkyl, or halogenated (Ct-C4}-alkoxy, the number of said substituents being up to five for halogen, and up to three for any combination of said other substituents), heteroaryl or heteroaryl -(CrC4>-
alkyl (both optionally substituted in the heteroaryl group with up to three independently selected substituents as defined herein), as defined herein.
The term "alkylamido" represents a preferred selection of the term "amido" and refers to the group - The term "acylamino" refers to the group -NR-CO-R', where R and R1 may independently be hydrogen, alkyl (optionally substituted in the alkyl chain with up to five independently selected substituents as defined herein, in particular hydroxyl, halogen or (CrC4)-alkoxy), aryl or aryKd-C*)-alkyl (both optionally substituted in the aryl group with independently selected substituents as defined herein, in particular hydroxyl, halogen, (CrC4)-alkyI, (C^C^alkoxy, halogenated (CrC4)-alkyl, or halogenated (d-C4)-alkoxy, the number of said substituents being up to five for halogen, and up to three for any combination of said other substituents), heteroaryl or heteroaryl-(Cr(X,)-alkyl (both optionally substituted in the heteroaryl group with up to three independently selected substituents as defined herein), as defined herein. Preferably, acylamino refers to -NH-CO-(CrCX,}-alkyl.
The term "carbonylamino" represents a preferred selection of the term "acylamino" and refers to the group -NR-CO-CH2-R', where R and R' may be independently selected from hydrogen or(CrC4)alkyl.
The term "sulfonamide" refers to the group -SOj-NRR', wherein R and R' may independently be selected from hydrogen or (d-C4)alkyl.
Halogenated alkyl, halogenated alkoxy and halogenated alkylthio are substituents in which the alkyl moieties (preferably (d-C6)alkyl, more preferred (Cr-C^alky!, and most preferred methyl) are substituted either partially or in full with halogens, generally with chlorine and/or fluorine. Preferred examples of such substituents are trifluoromethyl, trifluoromethoxy, trifluoromethylthlo, dl-chloromethyl, pentafluoroethyl, dichloropropyl, fluoromethyl and difluoromethyl.
The term "cycloheteroalkyP refers to a four- to eight-membered heterocyclic ring containing at least one heteroatorn, such as N, 0 or S, the number of N atoms being 0-3 and the number of 0 and S atoms each being 0-1, which system may be saturated, partly unsaturated or hydroaromatic, and which ring can be part of a multiple condensed ring-system in which some rings may be aromatic. Examples of such cydoheteroalkyls include pyrroiidinyl, tetrahydrofury), tetrahydrothio-phenyl, tetrahydropyridinyl, azetidinyl, thiazolidinyl, oxazolidinyl, piperidinyl, morpholinyl, thiomor-pholinyl, piperazinyl, azepanyl, diazepanyl, oxazepanyl, thiazepanyl, dlhydro-1H-pyrro!yl, 3,6-
dihydro-2H-pyridinyl, 1,3-dihydro-benzoimidazolyl and the like. Preferred examples of such cyclo-heteroalkyl groups are pyrrolidinyl, morpholinyl, tetrahydrofuryl, piperidinyl or azepanyi.
The cydoheteroalkyl group may optionally be substituted by up to three substituents, inde-
,. . • • •)',
pendently selected from the group consisting of oxo, alkyl, aryl or aryl-(CrC4)-alkyl. hydroxyl, (C-r C6)alkoxy, halogenated (Ci-C6)alkyl, halogenated (Ci-C8)alkoxy, carboxyl-(C1-C6)alkyl, thiol, nitrite, sulfamoyl, sulfonamide, carboxyl, aryloxy or arylalkyloxy, (C1-C6)alkylttiio, aryjthio or arylalkylthio, amino, amido, acyl, and acylamino, as defined herein, whereby the aryl groups are optionally substituted with independently selected substituents as defined herein, in particular hydroxyl, halogen, (Ci-64}-alkyl, (Ci-C4)-alkoxy, halogenated (CrC4)-alkyl, or halogenated (d-C^alkoxy, the number of said substituents being up to five for halogen, and up to three for any combination of said other substituents. The substituents of the cydoheteroalkyl groups may be attached to any carbon atom of the cydoheteroalkyl moiety. Substituted cydoheteroalkyl is preferably substituted with oxo, (Ct-C4)a!kyl, preferably methyl, phenyl and/or phenyl-(CrG,)alkyl, in particular benzyl.
The terms "aryl" or "Ar" refer to an aromatic carbocyclic group comprising 6 to 14, more preferably 6 to 10, carbon atoms and having at least one aromatic ring or multiple condensed rings in which at least one ring is aromatic. Preferably, aryl is phenyl, naphthyl, indanyl, indenyl, or 1,2,3,4-tetrahydro-naphthalen-1 -yl.
The term "heteroaryl" refers to an aromatic carbocyclic group of having a single 4 to 8 mem-bered ring or multiple condensed rings comprising 6 to 14, more preferably 6 to 10, ring atoms and containing at least one heteroatom, such as N, O or S, within at least one ring, the number of N atoms being 0-3 and the number of O and S atoms each being 0-1; in which group at least one heterocyclic ring is aromatic. Examples of such groups include pyrrolyl, thienyl, furyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, quinolinyl, isoqulnolinyl, benzothiazolyl, benzoimidazolyl, 1,3-dihydro-benzoimidazolyl, ben-zofuran, benzo[b]thiophene and the like. Preferably, heteroaryl is quinolinyl, furyl, benzoimidazolyl, pyridinyl, thienyl, indolyl, benzo[b]thiophene, pyridinyl, imidazolyl, pyrazolyl or thiazolyl.
The aryl and the heteroaryl group may optionally be substituted by substituents independently selected from the group consisting of halogen, hydroxyl, (CrC6)alkoxy, (d-CeJalkyl, halogenated (CrC6)alkyl, halogenated (Ci-C6)alkoxy, carboxyl-(CrC6)alkyl, oxo, thiol, nitro, nitrile, sulfamoyl, sulfonamide, carboxyl, aryloxy or arylalkyloxy, (Ci-C6)alkyithio, arylthio or arylalkylthio, alkylsulfonyl, arylsulfonyl, amino, amido, acyl, and acylamino, as defined herein, the number of said substiluents being up to five for halogen, and up to three for any combination of said other substituents; whereby the aryloxy, aryialkyloxy, arylthio or arylalkyithio group may be further optionally substituted in the aryl moiety with independently selected substituents as defined herein, in particular hydroxyl, halogen, (CrC4)-alkyl, (d-C4)-alkoxy, halogenated (CrC4)-alkyl, or halogenated (C-r
C4)-alkoxy, the number of said substituents being up to five for halogen, and up to three for any combination of said other substituents. The heteroaryl group may further be optionally substituted with an aryl group, which may be optionally substituted in the aryl moiety with substituents, especially hydroxyl, halogen, (Ci-C6)alkoxy, (d-CeJalkyl, halogenated (Ci-C6)alkyl or halogenated (d-C6)alkoxy the number of said substituents being up to five for halogen, and up to three for any combination of said other substituents. The aryl group may further be optionally substituted with a heteroaryl group or a second aryl group.
Substituted aryl is preferably substituted by substituents selected from the group consisting of (Ci-C4)alkyl. halogen, halogenated (CrC4)alkyl, preferably halogenated methyl, (C1-Ce)alkoxy, halogenated (d-CaJalkoxy, hydroxyl, alkylacyl, carboxyl, nitro, nitrile, acyiamino, (Cr C4)alkylsulfonyl, arylsulfonyl, and sulfamoyl, the number of said substituents being up to five for halogen, and up to three, preferably up to two, for any combination of said other substituents. Preferably substituted aryl is substituted phenyl.
The aryl may be further substituted by two groups which are attached to adjacent carbon atoms and are combined into a saturated or partly unsaturated cyclic 5, 6, 7, or 8 membered ring system, optionally containing up to three heteroatoms, such as N, O or S, the number of N atoms being 0-3 and the number of 0 and S atoms each being 0-2. Preferably, the two groups which are attached to adjacent carbon atoms, are combined into a saturated cyclic 5 or 6 membered ring system, optionally containing up to three heteroatoms, such as N or O, the number of N atoms being 0-3 and the number of O atoms each being 0-2. This cyclic ring system may optionally be. further substituted by an oxo group. Preferred examples of such a substituted aryl groups are benzo[1,3]dioxol and 1,3-dihydro-benzoimidazol-2-one.
Substituted heteroaryl is preferably substituted by up to three, preferably up to two substituents selected from the group consisting of halogen, (Ci-C4)-alkoxy, (d-C4)-alkyl. preferably methyl, halogenated (d-C4)-alkyl. preferably halogenated methyl, halogenated (d-C4)-alkoxy, phenoxy (optionally substituted with up to three, preferably one halogen), benzyloxy, benzenesulfonyl, phenyl or carboxyl-{d-d)-alkyl with a carboxyl group -{C=0)-OR', wherein R' represents hydrogen, (Ci-d)alkyl, preferably methyl, or (CrC4)alkyl-phenyI, preferably benzyl.
The statement is made that when two side chains are found on a single N, they can be combined, including the N to which they are attached, into a heterocyclic ring of 4-, 5-, 6-, 7- or 8 atoms, which can be saturated, partly unsaturated or aromatic, which can optionally contain up to three additional heteroatoms selected from N, O or S, the number of N atoms being 0-3 and the number of O and S atoms each being 0-2; and which ring can be part of a multiple condensed ring-system, in which some rings may be aromatic. Preferred examples of such heterocyclic ring systems, including the N to which the respective side chains are attached, (Figure Removed) aforementioned heterocyclic ring system can be optionally substituted by up to three substituents, which can be attached to any carbon or nitrogen atom of the heterocyclic ring system. (Figure Removed)e optional up to three independently selected substituents for the heterocyclic ring system may be chosen among optionally substituted alkyl, halogen, hydroxyl, oxo, thiol, nitro, nitrite, (Cr C6)-alkoxy, aryl, heteroaryl, optionally substituted cycloheteroalkyl, aryloxy, arylalkyloxy, amino, amido, alkylthio, arylthio, arylalkylthio, sulfamoyl, sulfonamide, acyl, carboxyl, and acylamino, as defined herein, whereby all aryl or heteroaryl moieties may be optionally substituted with up to five, preferably up to three independently selected substituents as defined herein. Preferably, the heterocyclic ring system is optionally substituted with substituents independently selected from the group of hydroxyl, oxo, carboxyl, carboxyl-(C1-CB)alkyl, amido; optionally substituted cycloheteroalkyl; aryl or aryl-(Ci-CXj}-alkyl (both optionally substituted in the aryl group with substituents independently selected among hydroxyl, halogen, (d-C^alky!, (Ci-C4)-alkoxy, halogenated (Ci-C4)-alkyl, or halogenated (CrC,i)-a1koxy, the number of said substituents being up to five for halogen, and up to three for any combination of said other substituents, or wherein the aryl moiety may be optionally substituted by two groups which are attached to adjacent carbon atoms and are combined into a saturated or partly unsaturated cyclic 5, 6, 7, or 8 membered ring system, optionally containing up to three heteroatoms, such as N, O or S, the number of N atoms being 0-3 and the
number of O and S atoms each being 0-2), heteroaryl, and (CrC8)-alkyl (optionally substituted with up to five substituents independently selected among hydroxyl, halogen, (d-C4)-alkoxy, or halo-genated (CrC^-alkoxy, whereby the alkyl-chain of the (CrC4)-alkoxy moiety may optionally be further substituted with up to three hydroxyl), the number of said substituents being up to three, more preferably up to two for any combination of said substituents. Even more preferred, the het-erocyclic ring system is optionally substituted with substituents independently selected from the group of hydroxyl, oxo, alkylamido, preferably carbamoyl; (C rC4)-alkyl; cyclo(C3-C8)alkyl; a car-boxyl group -(C=O)-OR' where R' represents hydrogen or (CrC4)alkyl; (Ci-C4)-alkyl optionally substituted with up to two hydroxyl and/or (C1-C4)-alkoxy groups (whereby the alkyl-chain of the (CrC4)-alkoxy moiety may optionally be further substituted with up to two, preferably one, hydroxyl groups); phenyl optionally substituted with halogen, (CrC4)-alkyl, preferably methyl, (Ct-C4)-alkoxy or halogenated (CrC4)-alkyl, preferably halogenated methyl, the number of said substituents on the phenyl moiety being up to five for halogen, and up to three for any combination of said other substituents; phenyl-(Ci-C4)alkyl, preferably benzyl, optionally substituted in the phenyl group by substituents independently selected among halogen, (C^^alkyl, (C-t-C^alkoxy or halogenated (Ci-C4)-alkyl, preferably halogen, the number of said substituents being up to five for halogen, and up to three for any combination of said other substituents, or optionally substituted In the phenyl group by two groups which are attached to adjacent carbon atoms and are combined into a saturated or partly unsaturated cyclic 5 or 6-membered ring system, optionally containing up to two O atoms; heteroaryl, preferably pyridinyl, heteroaryKd-C^alkyl or cycloheteroalkyl, preferably pyr-rolidinyl or 1,3-dlhydro-benzoimidazolyl, which cycloheteroalkyl group is optionally substituted with oxo.
Furthermore, the aforementioned heterocyclic ring system may be substituted by two groups which are attached to the same carbon atom and are combined into a saturated or partly unsaturated cyclic 4, 5, 6, 7, or 8 membered ring system, optionally containing up to three heteroatoms, such as N, 0 or S, the number of N atoms being 0-3 and the number of O and S atoms each being 0-2. This cyclic ring system may optionally be further substituted by up to three substitutents independently selected from oxo, (Ci-CeJ-alkyI, aryl, preferably phenyl, and aryKCVC^-alkyl. preferably benzyl. Preferred examples of such substituted heterocyclic ring systems are 1,4-dioxa-8-aza-spiro[4.5]decane, 1,3,8-triaza-spiro[4.5]decane, 1,3,8-triaza-spiro[4.5ldecan-4-one, l-Phenyl-1,3,8-triaza-spiro[4.5]decane, and 1-Phenyl-1,3,8-triaza-spiro[4.5]decan-4-one.
The term "pro-drug" as used herein, represents derivatives of the compounds of the invention that are drug precursors which, following administration to a patient, release the drug in vivo via a chemical or physiological process. In particular, pro-drugs are derivatives of the compounds of the invention in which functional groups carry additional substituents which may be cleaved under physiological conditions in vivo and thereby releasing the active principle of the compound (e.
g., a pro-drug on being brought to a physiological pH or through an enzyme action is converted to the desired drug form).
The term "pharmaceutically acceptable salts" refers to salt forms that are pharmacologically acceptable and substantially non-toxic to the subject being administered the compounds of the invention. Pharmaceutically acceptable salts of compounds of formula I include conventional and stoichiometrical acid-addition salts or base-addition salts formed from suitable non-toxic organic or inorganic acids or inorganic bases. Acid addition salts, for example, from compounds of formula I with a basic nitrogen atom are formed preferably with organic or inorganic acids. Suitable inorganic acids are, for example, halogenic acids such as hydrochloric acid, sulfuric add, or phosphoric acid. Suitable organic acids are, for example, carboxylic, phosphonic, orsulfonic acids, for example acetic acid, propionic acid, glycolic acid, lactic acid, hydroxybutyric acid, malic acid, malenic acid, malonic acid, salicylic acid, fumaric acid, succinic acid, adipic acid, tartaric acid, citric acid, glutaric acid, 2- or 3-glycerophosphoric acid and other mineral and carboxylic acids well known to those skilled in the ait The salts are prepared by contacting the free base forms with a sufficient amount of the desired acid to produce a salt in the conventional manner. Compounds containing acidic substrtuents may also form salts with inorganic or organic bases. Examples of suitable bases for salt formation include, but are not limited to, inorganic bases such as alkali or alkaline earth-metal (e.g., sodium, potassium, lithium, calcium, or magnesium) hydroxides, and those derived from ammonium hydroxides (e.g., a quaternary ammonium hydroxide such as tetramethylammonium hydroxide). Also contemplated are salts formed with pharmaceutical acceptable amines such as ammonia, alkyl amines, hydroxyalkylamines, N-methylglucamine, benzylamines, piperidines, and pyr-rblidines and the like. Certain compounds will be acidic in nature, e. g. those compounds which possess a carboxyl or phenolic hydroxyl group. Salts of phenols can be made by heating acidic compounds with any of the above mentioned bases according to procedures well known to those skilled in the art.
As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
The phrase "effective amount" as used herein, means an amount of a compound or composition which is sufficient enough to significantly and positively modify the symptoms and/or conditions to be treated (e. g., provide a positive clinical response). The effective amount of an active ingredient for use in a pharmaceutical composition will vary with the particular condition being treated, the severity of the condition, the duration of the treatment, the nature of concurrent therapy, the particular active ingredients) being employed, the particular pharmaceutically acceptable excipient(s)/carrier(s) utilized, and like factors within the knowledge and expertise of the attending physician.
Administration forms
The method of the invention is primarily intended for treatment in a mammal, preferably in humans and other primates, of steroid hormone dependent diseases or disorders, in particular estradiol dependent diseases or disorders, wherein the steroid hormone dependent disease or disorder preferably requires the inhibition of a 17β-HSD enzyme, preferably the17β-HSD1 enzyme.
The compounds may be administered orally, dermally, parenterally, by injection, by pulmonal or nasal delivery, or sublingually, rectally or vaginally in dosage unit formulations. The term "administered by injection" includes intravenous, intraarticular, intramuscular (e.g. by depot injection where the active compounds are released slowly into the blood from the depot and carried from there to the target organs), intraperitoneal, intradermal, subcutaneous, and intrathecal injections, as well as use of infusion techniques. Dermal administration may include topical application or transdermal administration. One or more compounds may be present in association with one or more non-toxic pharmaceutically acceptable auxiliaries such as excipients, adjuvants (e.g. buffers), carriers, inert solid diluents, suspensing agents, preservatives, fillers, stabilizers, anti-oxidants, food additives, bioavailability enhancers, coating materials, granulating and disintegrating agents, binding agents etc., and, if desired, other active ingredients.
The pharmaceutical composition may be formulated for example as immediate release, sustained release, pulsatile release, two or more step release, depot or other kind of release formulations.
The manufacture of the pharmaceutical compositions according to the invention may be performed according to methods known in the art and will be explained in further detail below. Commonly known and used pharmaceutically acceptable auxiliaries as well as further suitable diluents, flavorings, sweetening agents, coloring agents etc. may be used, depending on the intended mode of administration as well as particular characteristics of the active compound to be used, such as solubility, bioavailability etc. Suitable auxiliaries and further ingredients may be such as recommended for pharmacy, cosmetics and related fields and which preferably are listed in the European Pharmacopoeia, FDA approved or cited in the "GRAS" list (FDA List of food additives that are 'generally recognized as safe' (GRAS)).
One mode of application of the compounds of general formula (I) or of pharmaceutical compositions comprising one or more of said compounds is oral application, e. g., by tablets, pills, dragees, hard and soft gel capsules, granules, pellets, aqueous, lipid, oily or other solutions, emulsions such as oil-in-water emulsions, liposomes, aqueous or oily suspensions, syrups, elixiers,
solid emulsions, solid dispersions or dispersible powders. For the preparation of pharmaceutical compositions for oral administration, the compounds suitable for the purposes of the present invention as defined above can be admixed with commonly known and used adjuvants and excipients such as for example, gum arable, talcum, starch, sugars (such as, e. g., mannitose, methyl cellulose, lactose), gelatin, surface-active agents, magnesium stearate, aqueous or non-aqueous solvents, paraffin derivatives, cross-linking agents, dispersants, emulsifiers, lubricants, conserving agents, flavoring agents (e. g., ethereal oils), solubility enhancers (e. g., benzyl benzoate or benzyl alcohol) or bioavailabilrty enhancers (e.g. Gelucire™). In the pharmaceutical composition, the active ingredients may also be dispersed in a microparticle, e. g. a nanoparticulate, composition.
For parenteral administration, the active agents can be dissolved or suspended in a physiologically acceptable diluent, such as, e. g., water, buffer, oils with or without solubilizers, surface-active agents, dispersants or emulsifiers. As oils for example and without limitation, olive oil, peanut oil, cottonseed oil, soybean oil, castor oil and sesame oil may be used. More generally spoken, for parenteral administration the active agent can be in the form of an aqueous, lipid, oily or other kind of solution or suspension or even administered in the form of liposomes or nano-suspensions.
Transdermal application can be accomplished by suitable patches, as generally known in the art, specifically designed for the transdermal delivery of active agents, optionally in the presence of. specific permeability enhancers. Furthermore, also emulsions, ointments, pastes, creams or gels may be used for transdermal delivery.
Another suitable mode of administration Is via intravaginal devices (e. g. vaginal rings) or intrauterine systems (IDS) containing reservoirs for controlled release of active agents over extended periods of time. For rectal or vaginal administration of the drug the compounds may also be administered In the form of suppositories. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which Is solid at ordinary temperatures but liquid at the rectal or vaginal temperature and will therefore melt in the rectum or vagina to release the drug.
Another mode of application is by implantation of a depot implant comprising an inert carrier material, such as biologically degradable polymers or synthetic silicones such as e. g. silicone rubber. Such implants are designed to release the active agent in a controlled manner over an extended period of time (e. g., 3 to 5 years).
It will be appreciated by those skilled in the art that the particular method of administration will depend on a variety of factors, all of which are considered routinely when administering therapeutics. It will also be understood, however, that the actual dosages of the agents of this
invention for any given patient will depend upon a variety of factors, including, but not limited to the activity of the specific compound employed, the particular composition formulated, the mode of administration, time of administration, route of administration and the particular site, host, and disease being treated, and furthermore the age of the patient, the body weight of the patient, the general health of the patient, the gender of the patient, the diet of the patient, rate of excretion, drug combinations, and the severity of the condition undergoing therapy. It will be further appreciated by one skilled in the art that the optimal course of treatment, i.e., the mode of treatment and the daily number of doses of a compound of Formula I or a pharmaceufically acceptable salt thereof given for a defined number of days, can be ascertained by those skilled in the art using conventional treatment tests. Optimal dosages for a given set of conditions may be ascertained by those skilled in the art using conventional dosage-determination tests in view of the experimental data for a given compound. For oral administration, an exemplary daily dose generally employed will be from about 0.01 pg/kg to about 100 mg/kg of total body weight, whereby courses of treatment may be repeated at appropriate time intervals. Administration of pro-drugs may be dosed at weight levels that are chemically equivalent to the weight levels of the fully active compounds. The daily dosage for parenteral administration will generally be from about 0.01 ug/kg to about 100 mg/kg of total body weight. A daily rectal dosage regimen will generally be from about 0.01 pg/kg to about 200 mg/kg of total body weight A daily vaginal dosage regimen will generally be from about 0.01 ug/kg to about 100 mg/kg of total body weight The dally topical dosage regimen will generally be from about 0.1 ug to about 100 mg administered between one to four times daily. The transdemnal concentration will generally be that required to maintain a daily dose of from 0.01 ug/kg to 100 mg/kg of total body weight
Abbreviations and Acronyms
As employed herein, the fallowing terms have the indicated meanings.
ACN acetonitrile
Bn benzyl
BOG tert-butoxycarbonyl
cone. concentrated
EtOAc ethyl acetate
d day(s)
DCM dichloromethane CH2CI2
DHP 3,4-dihydro-[ 2H ]-pyran
Dibal Dilsobutyl-aluminiumhydride
DMF N,N-dimethylfomnamide
DMSO dimethylsulfoxide
DIPEA N,N-diisopropylethylamine
E1 estron
E2 . estradfol
EDCI-HCl 1-(3-dimethylaminoprapyl)-3-ethylcarbodiimide hydrochloride
ER estrogen receptor
h hour(s)
HMPA hexamethylphosphoramide
HOBT 1-Hydroxybenzotriazole Hydrate
HSD hydroxysteroid dehydrogenase
NAD(P)[H] nicotlnamlde-adenine-dinudeotide (phosphate) [reduced NAD(P)]
NMR nuclear magnetic resonance
MeOH methanol
min minute(s)
PG protection group
pTosOH para-toluene sulphonic acid
RT room temperature
TBME tert-butyl methyl ether
THF tetrahydrofuran
THP tetrahydropyran
TLC thin-layer chnomatography
TMSCI trimethylsllylchloride
General Preparative MethodsThe compounds of the present invention may be prepared by use of known chemical reactions and procedures. Nevertheless, the following general preparative methods are presented to aid the reader in synthesizing the17β-HSD1 inhibitors, with specific details provided below in the experimental section to illustrate working examples.
All variable groups of these methods are as described in the generic description if they are not specifically defined below.
It is recognized that compounds of the invention With each claimed optional functional group may not be prepared by each of the below-listed methods. Within the scope of each method, optional substituents may appear on reagents or intermediates which may act as protecting or otherwise non-participating groups. Utilizing methods well known to those skilled in the art, these groups are introduced and/or removed during the course of the synthetic schemes which provide the compounds of the present invention.
Flow Diagrams
Certain formula I compounds, in which X represents a bond, A represents CO, Y represents NH or NR4 and n represents an integer from 0 to 5, may be prepared by a reaction as shown in Flo (Figure Removed)free acid (IV) may be converted to the reactive acyl halide (V), in particular the add chloride, by reaction with SOCI2, COCI2, PCI5 or PBr3 or the like. The amide derivatives (VI) may be prepared by a base catalyzed addition-elimination reaction, where the halogen residue is substituted with the appropriate amine R2NH2 or R2NHR4 in the presence of a base, for example DIPEA. Alternatively, especially suited for derivatives with n > 2, the amide derivatives may be prepared directly from the free adds by nucleophilic substitution with the appropriate amine. Alternatively, the
amide derivatives may be prepared directly from the free acids by nucleophilic substitution with the appropriate amine as shown in Flow Diagram Ib (Figure Removed) (Figure Removed)Certain formula I compounds, in which X represents a NR3, A represents CO, Y represents NH-SO2, and n represents an integer from 1 to 6, may be prepared by a reaction as shown in Flow Diagram XI:

57
Numbering of compound formulas and intermediates
The general structure formulas are typically designated with a number in roman format, followed by a or p indicating the stereochemistry at the C15 atom of the estron core if necessary. If the number of methylen groups attached at the C15 position is specified (i.e. the value of "n"), the roman number is followed by a hyphen and a number indicating the amount of methylen groups. Finally, a letter a, b or c is attached after the number "n", indicating the nature of the substituent R1 at the O-atom in C3 position of the estron core (a = hydrogen, b = methyl, and c = benzyl).
For example, compound I Vis the general acid building bl (Figure Removed)n be prepared according to a procedure described by Labaree and depicted within the following scheme 1 [La-baree et al. (2003) J. Med. Chem. 46:1886-1904].
(Figure Removed) starting compound - the ketal - of the formula (IXa) for example can be prepared according to Nambara [Nambara et al. (1 976) Steroids 27:1 1 1 -122]. The methyl derivative, of formula (IXb, R1=CH3) is prepared using MeJ and acetone, whereas the Benzyl-derivative of formula (IXc, R1=benzyl) is prepared using Benzylbromld, DIPEA and acetone. Enone intermediates with other substituents in R1, in particular optionally substituted d-C IL The ketal derivative of the Estron-15a-vl-carbaldehvde of formula Xlll (Figure Removed)tected aldehyde intermediate of formula XIII-0 with R1 = CH3 (Xlllb) or R1=Benzyl (XI lie) can be prepared according to a procedure depicted within the following scheme 2:
(Figure Removed)5,16-unsaturated estrone of formula (X) was converted into the corresponding cyano-estrone (XI) by a cyanide Michael addition at the D-ring. The nitrite was introduced in the beta configuration as was proven by 2D-NMR. Epimerization of this stereocenter had been accomplished in a following step. First the ketone functionality was protected as the acetal (XII), followed by conversion of the nitrite to the corresponding aldehyde (Xlll-0) by the addition of Dibal-H to the nitrile and the consecutive hydrolysis of the imine product. At this stage the epimerization took place for about 90% (2D-NMR). Consecutive washing of the mixture with aqueous bicarbonate gave the a-isomer withad.es 98%.
Detailed Synthesis
Cvanoestrone Xlb: 3-Methoxv-17-oxo-estra-1.3.5(1 QV-triene-15p-carbonltrlle
Cvanoestrone Xlc: 3-Benzvloxv-17-oxo-estra-1.3.5(1 OHriene-15B-carbonitrile
KCN (17.0g, 261mmol) (NaCN can also be used) was added to DMF (200mL) at ambient temperature. H2O (100-200mL; minimum amount) was added until an almost clear solution was obtained. Unsaturated estrone Xb or Xc (25mmol) was dissolved in DMF (400mL) and added dropwise to the KCN solution as slow as possible during 8-1 Oh and that a clear solution is maintained. After addition is complete the reaction mixture was stirred overnight Water (1-2L) was slowly added to the stirring reaction mixture. The product was isolated by filtration and triturated two times with H2O. The white solid was dissolved in DCM, the residual water was removed, and the organic layer was dried with Na2SO.<. evaporation to dryness gave cyano estrone xlb as a white foam in yields varying from mot scale xlc needed additional purification by column chromatography gradient yield when carried out on scale.> Ketal Xllb: Kelal of 3-Methoxv-17-oxo-estra-1,3.5(1 OVtriene-15B-carbonitrile Ketal Xllc: Ketal of 3-Benzvloxy-17-oxo-estra-1.3.5(1 OVtri6ne-15B-carbonitrile
A suspension of cyano estrone Xlb or Xlc (89.2mmol), ethyiene glycoi (11.7mL, 178mmol), and p-TSA (0.5g, cat.) in diglyme (500mL) was stirred overnight. In most cases a dear solution was obtained. The reaction mixture was concentrated in vacuo on a water bath at 70°C until precipitation started. After cooling to RT, the product was collected by filtration. The mother liquor was evaporated to dryness and the residue was recrystallized from diglyme. Yield of Xllb: 28.6g (100%) as white flakes. On a 4.4mmol scale, compound Xllc was also obtained in 100% yield.
Aldehyde XIU-Qb: Ketal of 3-Methoxv-17-oxo-estra-1.3.5(10Vtriene-15g-carbaldehvde Aldehyde XIII-Oc: Ketal of 3-Benzvloxv-17-oxo-estra-1.3.5(10)-triene-15a-carbaldehvde
A solution of ketal Xllb or Xllc (3.7 mmol) in dry THF (50mL) was added dropwise to Dibal-H (20mL, 25% in toluene, 30mmol) in THF at -80°C. After addition is complete the reaction is stirred for 20min and slowly warmed to RT overnight The reaction is quenched at -10-0CC by dropwise addition of 30% AcOH in H2O (100-300mL) until no gas evolves anymore and a clear solution is obtained. EtOAc (200mL) was added and the layers were separated. The aqueous layer was extracted with EtOAc (3x200mL). The combined organic layers were washed with NaHCO3(aq) until no gas evolves and dried with Na2SO4. Column chromatography (DCM to remove Impurities, TBME/DCM (1:1) to collect the product) gave XIII-Oc (1.0g) in 62% yield and Xlll-Ob in 85% yield (0.14mol flash CH2CI2).
III. Compounds of formula IV (acid building block): Estron-15-vl-Ca-Cralkvl-carboxvtic acid
Acid building block IV-O: (n = 0)
IV-Ob: (n = 0 and R1 = CH3V 3-Methoxv-17-oxo-estra-1.3.5(1 OVtrien-15a-vl-carboxvlic acid IV-Oc: (n = 0 and R1 = Bn): 3-benzvloxv-17-oxo-estra-1,3.5(10)-trien-15g-vl-carboxvl (Figure Removed)e 17-oxo- estra-1,3,5(10)-trien-15a-yl-carbaldehyde of formula XIII-0 is oxidized to the corresponding carboxylic acid and converted into the unprotected 15a-substituted estrone derivative of formula IV-0.
Detailed Synthesis
IV-Ob: (n = 0 and R1 = CH3): 3-Methoxv-17-oxo-estra-1.3.5(1 OMrien-15c^vl-carboxvlic acid
KMnO4 (7.5g, 47.6mmol) dissolved in H2O (80mL) was added dropwise to a solution of aldehyde Xlll-Ob (10.0g, 28mmol) in acetone (400mL) at such a rate that 45°C •,V.'
were extracted with 4N NaOH (3x200mL). The aqueous layer was acidified to pH~1 and extracted with CH2CI2. The organic layer was dried with Na2SO4 and concentrated to ~20mL and transferred onto a silca column (CH2CI2). Elutlon with CH2Cl2/AcOH 99:1 gave compound IV-Ob (4.6g, 50%, 90% purity). Final purification was a recrystallization from CH2CI2/heptane (3x) by evaporation of CH2CI2 at ambient pressure and at reflux temperature until crystallization occurs.
Acid building block IV-1: (n = 11:
IV-1b: (n = 1 and R1 = CH3>: 3-Methoxv-17-oxo-estra-1.3.5(10)-lrien-15a-vl-aceticacid IV-1c: (n = 1 and R1 = EM: 3-Benzvloxv-17-oxo-estra-1.3.5(10Vtrien-15a-vl-acelicacid
p
e acid building block IV-1 could be synthesized via two different routes. The individual steps of the first synthesis route of acid building block IV-1 are depicted in the following scheme
The same kind of procedure can be applied for n = 2 and for other side chains within the R1 position (Figure Removed) ketal derivative of the 17-oxo-estra-1,3,5(10)-trien-15a-yl-carbaldehyde of formula XIII-0 is converted into the methyl enol ether of the formula XXXIV via a WHtig reaction with MeOCH2LJP(Ph)3. Hydrolysis with HCI(8q) delivered the unprotected acetaldehyde derivative XXXIII-1. The acetaldehyde derivative is then further oxidized to the corresponding carboxylic add IV-1.
Detailed Synthesis XXXIVb:3-Methoxv-15a-(2-methoxv-vinvlVe8tra-1.3.5f10Vtrien-17-one
n-BuLJ (16.8mL, 2.5M, In hexanes, 42mmol) was added dropwise to a suspension of (meth-oxymethyl)triphenylphosphonium chloride (14.4g, 42mmol) in THF (120mL) at-78°C. Upon slowly warming the reaction to RT, the orange suspension turned into an intense red dear solution. After 3h, the reaction mixture was cooled to -78°C and a solution of the aldehyde Xlll-Ob (10.0g, 28mmol) in THF (100mL) was added. The reaction mixture was allowed to warm to RT overnight and was evaporated to dryness. The residue was suspended in NaOH (1K1, 200mL). Extraction with CH2CI2 followed by flash column chromatography (CH2CI2/heptane, 1:1) to remove the main impurities (OP(Ph)3) gave a crude mixture of XXXIVb as a white foam (8.9g).
XXXIIl-1b:3-Methoxv-17-oxo-estra-1.3.5nQV-trien-15a-vl-acetaldehvde
HCta) (6N, 200mL) was added to a mixture containing XXXIVb (8.9g) dissolved in CH2d2
(200mL) and this reaction mixture was stirred overnight. Drying the organic layer (N^SO.*) and evaporation to dryness was followed by column chromatography (CH2CI2/heptane, 1:1 gradually
increasing the polarity to CH2CI2/TBME, 8:3). Aldehyde XXXIll-lb was isolated as the main product (2.89g, 30%).
IV-1b: fri = 1 and R1 = CHal: 3-Methoxv-17-oxo-estra-1.3.5(10)-trien-15a-vl-acetic acid
Oxidation of XXXIIMb (2.3g, 6.7mmol), analogously to the procedure for IV-Ob (see above), gave compound IV-1b (2.1g, 91%. almost 95% pure). The product was further purified by column chromatography (CH2CI2/AcOH, (95:5)) and by a consecutive crystallization from CH2Cl2/heptane (3x).
Alternative synthesis route for the acid building block IV-1: m = 1):
lV-1b: (n = 1 and R1 =CHaV 3-Methoxv-17-oxo-estra-1.3.5(10Vtrien-15a-vl-aceticacid
Alternatively, compound IV-1b can be prepared directly from the enone derivative of formula X according to the following synthesis scheme 5:
SCHEMES
(Figure Removed)XXXVIb: Dimethvlester of the estrone-carbaldehvde
The dimethyl malonate anion was prepared by the dropwise addition of a dimethylmalonate (18.7g, 142mmol) solution in THF (200mL) to a suspension of NaH (7.42g, 170mmol) in THF (200mL) at 0°C. The reaction mixture was kept at 0°C for 1h. The reaction mixture became a grey solid mass which disappears upon reaction by the dropwise addition of enone Xb (10g, 35.5mmol, in 240mL THF) and stirring at RT during a weekend. The reaction was quenched by the dropwise addition of H20. Consecutively, H2O (400mL) was added and most of the THF was removed by evaporation in vacuo. The product was isolated by filtration and was triturated with heptane. The
solid was dissolved in EtOAc (200-300mL) and dried with Na2SO,,. Evaporation to dryness gave XXXVIb (11 .Og, 84%) as colourless oil which solidifies upon standing.
IV-1b: (n = 1 and R1 = CH3): 3-Methoxv-17-oxo-estra-1.3.5(1 OHrien-15a-vl-acetic acid
Hydrolysis of diester XXXVIb (11 .Og, 29.8mmol) by dissolving in THF and adding concentrated NaOH(aq) (50mL) and stirring overnight. The organic solvent was removed by evaporation in vacuo, and the residue was acidified with HCI (30%) until pH~1. The product was extracted with CHaClz (2x200mL). The combined organic layers were dried with Na2SO4 and evaporated to dry-ness. The residue was a mixture of compounds (partly decarboxylated). Dissolving the residue in AcOH (200mL) and refluxing overnight gave complete decarboxylation. Evaporation to dryness and column chromatography (CH2Cl2/AcOH, (95:5)) gave a white solid material IV-1b (4.92g, 52%). The product was further purified by column chromatography (CH2Cls/AcOH, (95:5)) and by a consecutive crystallization from CH2CI2/heptane (3x).
Acid building blocks IV IVB-3b m = 3 and R1 = CH,): 4-(3-Methoxv-17-oxo-estra-1.3.5(10Vtrien-15B-vlVbutvric acid (Figure Removed)eme 6. The same kind of procedure can be applied for n = 4, 5, or 6 and for other alkyl side chains within the R1 position using the appropriate BrMg-Ce-Cr-alkoxy-THP as Grignard Reagent. Furthermore, this reaction scheme also delivers the estrone-alcohol building block in form of the intermediate of formula XXXI p-4b.
(Figure Removed)solution to refluxing THF. The resulting bromide was dissolved in CH2CI2, p-TosOH and DHP were added at 0°C to give the pro-tepted alcohol. This was filtered over SiO2 and further purified by column chromatography, yielding 9.3% over 2 steps. The protected alcohol was dissolved in THF and added to activated magnesium, and the resulting Grignard reagent added to Cul2 in HMPA. The 15, 16-unsaturated Estrone derivative of formula Xb, dissolved in dry THF and TMSCI, was added at -40±5°C. Subsequently, after hydrolysis of the silyl ether, the resulting compound XXX-4b-THP was deprotected with p-TosOH/MeOH to give the alcohol derivative XXXI-4b, which was converted, without purification, into the free acid IV-3b by a Jones oxidation. The oil was purified by column chromatography, yielding the free acid of formula IV-3b in 30% yield over three steps.

Detailed Synthesis: 4-bromo-butanol
HBr solution (48% HBr in water, 1280 ml, 11.22 mol) was added dropwise to refluxing dry THF (810 ml, 9.99 mol) over a period of 2.25 hour. After complete addition, 1H-NMR analysis of a sample showed that the reaction was completed. The reaction mixture was cooled to RT, transferred to a 10 I reaction flask and, while stirred mechanically, carefully neutralized with NaHCO3 solution. The layers were separated and the organic layer was washed with brine, dried over NaaSO4 and the solvent was removed on the rotary evaporator. The resulting yellow oil was used in the next step without further purification
2-(4-Bromo-butoxvVtetrahvdro-pvran
Crude product 4-bromo-butanol was dissolved in DCM (500 ml) and dried over Na2SO4 and pTosOH (500 mg) was added. Dihydropyran (1181 ml) was added dropwise at 0°C and during the addition the temperature was kept under 8°C. The reaction was allowed to reach RT overnight, washed with saturated NaHC03 solution (2x 300 ml) and brine (9.3 I). The aqueous layers were washed with TBME (300 ml) and the combined organic layers were dried over anhydrous K2CO3. The mixture was filtered off and the solvent was removed on the rotary evaporator. This yielded
593 g (yield = 25% over 2 steps). The obtained 4-bromo-butanol-THP ether was filtrated twice over SiO2 (DCM with 1 % MeOH). Finally, the compound was purified by column chromatography (20 I SiO2, DCM with 1% MeOH). This yielded 220.6 g of 2-(4-Bromo-butoxy)-tetrahydro-pyran (yield = 9.3% over 2 steps) as a TLC-pure light yellow oil.
3-Methoxv-15B-r4-(tetrahydro-pvran-2-vloxvVbutvn-estra-1.3.5(10Vtrien-17-one(XXX-4b-THP^
Magnesium (29.6 g, 2.0 mol) was stirred overnight with broken glass under N2 in a flame dried 3 neck flask. The magnesium was extra activated by the addition of some iodine and by adding a few drops pure 2-(4-Bromo-butoxy)-tetrahydro-pyran. After the Grignard reaction had started, 2-(4-Bromo-butoxy)-tetrahydro-pyran (121 g, 510 mmol) in 500 ml dry THF was added dropwise, maintaining a gentle reflux. After complete addition of the reaction mixture, it was stirred for 0.5 hour. The solution was transferred to a flame dried 3-neck flask containing copper (I) iodide (9 g, 47 mmol) and HMPA (100 ml). The resulting reaction mixture was cooled to -40 ± 5°C after which a mixture of the 15,16-unsaturated estron of the formula Xb (24 g, 85 mmol) and TMSCI (21 ml, 196 mmol), dissolved in dry THF (500 ml), was added dropwise. After complete addition, the mixture was allowed to reach RT over 3 days.
10% NH4CI (in water and ice, 11) was added to the reaction mixture. The layers were separated and the water layer was extracted with EtOAc (2x 500 ml). The combined organic layers were washed with brine (500 ml), dried over Na2SO4 and the solvent was removed on the rotary evaporator. This yielded 103.6 g of yellow oil, containing HMPA. The oil was then stirred with K2CO3 (12.1 g, 87 mmol) in methanol (2.75 I) under N2 to hydrolyze the silyl ether. The hydrolysis was; followed by TLC (EtOAc / heptane: 1/9), which after 40 minutes showed that the reaction was complete. 0.75 I water was added and most of the methanol was removed on the rotary evaporator. 500 ml EtOAc was added, the layers were separated and the water layer was extracted with EtOAc (2x 500 ml). The organic layers were combined, dried over Na2SO4 and the solvent was removed on the rotary evaporator. This yielded 82.5 g yellow oil which contains product XXX-4b-THP, HMPA and silyl residues.
15p-f4-Hvdroxv-butvlV3-methoxv-estra-1.3.5(10Hrien-17-one (XXXI g-4b)
Crude compound XXX-4b-THP (82.5 g yellow oil) was dissolved in MeOH (2,5 L) and p-TosOH (6 g, 32 mmol) was added. The reaction was followed by TLC (toluene / acetone: 3/1) and 1H-NMR. After 1 hour the reaction was completed. Most of the MeOH was removed on the rotary evaporator and after this 1 I water was added. The resulting mixture was extracted with DCM (3x 400 ml). The organic layers were combined, dried over Na2S04 and the solvent was removed on the rotary evaporator. This yielded 46.8 g, which was purified by column chromatography (400 g SiO2 toluene / acetone: 3/1) to yield 31.9 g of XXXI p-4b as an impure yellow oil.
4-(3-Methoxv-17-oxo-estra-1.3.5(1 OVtrien-15B-vn-butvric acid (IVB-3b^
To a cooled solution of alcohol XXXI0-4b (31.9 g 89 mmol) at 0°C in acetone (11) was added dropwise 140 ml of Jones reagent (prepared from 700 ml of water, 300 ml of H2S04 and 100 g of CrO3). Each drop leaves an orange color, which disappeared shortly after being formed. The color finally changes to green. After complete addition, the reaction was followed by TLC (EtOAc / heptane: 1/1) and was complete after 10 minutes. The reaction was stirred for 30 minutes more and then quenched with 500 ml of a cold saturated NaS2O3 solution and 500 ml of water. The resulting mixture was extracted with EtOAc (3x 400 ml). The organic layers were combined, dried over Na2SO4 and the solvent was removed on the rotary evaporator. The resulting oil was purified by column chromatography (SiO2; toluene / acetone: 3/1). This yielded 9.2 g (30% over 3 steps) of the compound of formula (IVp-3b) as a yellow solid with a purity of 93%.
IVB-2b (n = 2 and R1 = CHaV 3-f3-lvlethoxv-17-oxo-estra-1.3.5(1 OMrien-15B-vn-propanoic ac (Figure Removed)n = 2, the corresponding carboxylic acid IVp-2b can be prepared by oxidation of the alcohol derivative of formula XXXIf3-3b according to the preparation of the carboxylic acid IVp-3b (see section for the preparation of the alcohol derivatives below for synthesis of XXXIj3-3b).
LC-MS (ES-): rt 525 min, m/z (rel. Intens) 355 [(M-H)', 100%]
[a],,-*0 = +79.6 (c = 0.304, MeOH)
1H NMR (400 MHz, CDCI3) (ppm) 1.05 (s, 3H), 1.42-1.58 (m, 4H), 1.63-1.81 (m, 3H), 1.90-2.05 (m, 2H), 2.09-2.14 (m, 1H), 2.28-2.51 (m, 7H), 2.85-3.01 (m, 2H), 3.78 (s, 3H), 6.65 (d, 1H), 6.71 (dd, 1H),7.19(d.1H).
13C NMR (100.6 MHz, CDCI3) 8 (ppm) 17.8, 25.5, 26.0, 26.7, 29.5, 33.6, 33.9, 34.0, 36.0. 42.0, 44.6, 47.1, 52.7, 55.3, 111.5, 114.0,126.0,132.2, 137.7,157.8, 178.5, 220.4.
Acid building block IVB-3c: 4-(3-Benzvloxv-17-oxo-estra-1.3.5(10Hrien-15S-vn-butvric a (Figure Removed)30) OH
The individual steps in the synthesis of acid building block of the formula IVj3-3c are performed according to the procedure depicted in scheme 7. Furthermore, this reaction scheme also delivers the estrone-alcohol building block in form of the intermediate of formula XXXIp-4c. The
same kind of procedure can be applied for n = 4, 5, or 6 and for other alkylaryt substitutents within the R1 position using the appropriate BrMg-C5-C7-alkoxy-THP as Grignard Reagent.
SCHEME7 (Figure Removed)ether was prepared by adding HBr solution to refluxing THF. The resulting bromide was dissolved In CH2Cl2, p-TosOH and DHP were added at O'C to give the protected alcohol. This was filtered over SiO2 and further purified by column chromatography, yielding 9.3% over 2 steps. The protected alcohol was dissolved in THF and added to the activated magnesium, and the resulting Grignard reagent added to Cul2 in HMPA. The 15,16-unsaturated Estrone derivative of formula Xc, dissolved In dry THF and TMSCJ, was added at -40±5°C. Subsequently, the resulting compound XXX-4c-THP was deprotected with p-TosOH/MeOH to give XXXI|3-4c in 47% over 2 steps, which was converted, without purification, into the free acid IVj3-3c by a Jones oxidation in a yield of 96%.
Detailed Synthesis;
4-bromo-butanol and 2-(4-Bromo-butoxvVtetrahvdro-pyran: see above
3-Berizvloxv-1SB-r4-ftetrahvdro-DVTarH2-vloxv^-butvr|-estra-1.3.5(10Vtrien-17-oneOO
Magnesium (10 g, 425 mmol) was stirred overnight with broken glass under N2 in a flame dried 3 neck flask The magnesium was extra activated by the addition of some iodine and by adding a few drops pure 2-(4-Bromo-butoxy)-tetrahydro-pyran. After the Grignard reaction had started, 2-(4-Bromo-butoxy)-tetrahydro-pyran (25.2 g, 106 mmol) in 200 ml dry THF was added dropwise, maintaining a gentle reflux. After complete addition of the reaction mixture, it was stirred for 0.5 hour. The solution was transferred to a flame dried 3-neck flask containing copper (I) iodide (1.8 g, 9.5 mmol) and HMPA (20 ml). The resulting reaction mixture was cooled to -40 ± 5°C after which a mixture of the 15,16-unsaturated estron derivative of formula Xc (6 g, 18 mmol) and TMSCI (4.5 ml,
35 mmol), dissolved in dry THF (100 ml), was added dropwise. After complete addition, the mixture was allowed to reach RT over 3 days.
10% NH4Cl (in water and ice, 200 ml) was added to the reaction mixture. The layers were separated and the water layer was extracted with EtOAc (2x 150 ml). The combined organic layers were washed with brine (150 ml), dried over Na2SO4 and the solvent was removed on the rotary evaporator. This yielded 22.7 g of yellow oil, containing HMPA. The oil was then stirred with K2CO3 (3 g, 22 mmol) in MeOH (650 ml) under N2 to hydrolyze the silyl ether. The hydrolysis was followed by TLC (EtOAc/ heptane: 1/9), which after 60 minutes showed that the reaction was complete. 200 ml water was added and most of the methanol was removed on the rotary evaporator. 150 ml EtOAc was added, the layers were separated and the water layer was extracted with EtOAc (2x 150 ml). The organic layers were combined, dried over Na2SO4 and the solvent was removed on the rotary evaporator. This yielded 15.1 g yellow oil which contains product HMPA and silyl residues.
3-Benzvloxv-15B-f4-Hvdroxv-birtvlVestra-1.3.5(10)-trien-17-one (XXXI g-4c)
Crude compound (XXX-4C-THP) (15.1 g yellow oil) was dissolved in MeOH (500 ml) and p-TosOH (1.2 g, 6.3 mmol) was added. The reaction was followed by TLC (toluene / acetone: 3/1) and 1 H-NMR. After 1.5 hour the reaction was completed. Most of the MeOH was removed on the rotary evaporator and after this 200 ml water was added. The resulting mixture was extracted with DCM (3x 100 ml). The organic layers were combined, dried over Na^O* and the solvent was removed on the rotary evaporator. This yielded 8.2 g, which was purified by column chromatography (400 g Si02, toluene / acetone : 3/1) to yield 3.6 g (8.3 mmol, 47% over 2 steps) of XXXIP-4C as a yellow oil.
4-(3-Benzvloxv-17-oxo-estra-1.3.5(10)-trien-15B-vlV-butvric acid flV3-3c)
To a cooled solution of alcohol XXXI p-4c (3.6 g 8.3 mmol) at 0°C in acetone (100 ml) was added dropwise 13.3 ml of Jones reagent (prepared from 700 ml of water, 300 ml of H2S04 and 100 g of CrOa). Each drop leaves an orange color, which disappeared shortly after being formed. The color finally changes to green. After complete addition, the reaction was followed by TLC (EtOAc / heptane: 1/1) and was complete after 10 minutes. The reaction was then quenched with 100 ml of a cold saturated NaSjOs solution, during which the temperature rose from 6 to 18°C, and 300 ml of water and 200 ml of EtOAc. The resulting mixture was stirred overnight and then the layers were separated and the aqueous layer was extracted with EtOAc (2x 100 ml). The organic layers were combined, dried over Na2SO4 and the solvent was removed on the rotary evaporator. This yielded 3.6 g of IVp-3c (8.0 mmol, y = 97%) as a yellow solid.
Acid building block with a stereochemistry at C15:
lVcc-3a (n = 3 and R1 = H): 4-(3-Hydroxy-17-oxo-estra-1,3,5(10)-trien-15oc-y I) -butyric ac (Figure Removed)ndividual steps in the synthesis of acid building block of the formula lVoc-3a are performed according to the procedure depicted in scheme 8. Furthermore, this reaction scheme also delivers the still ketal-protected estrone-alcohol building block in form of the intermediate of formula XLlVa-1c. Debenzylation and deprotection delivers the estrone-alcohol XXXlOrla.
(Figure Removed)Reduction of the aldehyde XIII-Oc with NaBH4 (EtOH, 2h, RT) gave the alcohol XLIVa-1c, which was further treated with iodine, triphenylphosphine and imidazole to give the iodide XLV. Subsequently, ethylacrylate was coupled to iodine XLV and gave compound XLVI after purification by column chromatography. Reduction of compound XLVi was performed under H2 atmosphere to give compound XLVI I, which was transformed into the protected carboxylic acid building block XLVIIIa-3a by saponification. The carboxylic add IVa-3a was obtained by deprotection.
Detailed Synthesis
17-Ketal derivative of 3-Benzvloxv-15-hvdroxvmethvl-estra-1.3.5(1 OVtrien-17-one fXLIVa-1c>
Aldehyde XIII-Oc (1.23 g, 2.84 mmol) was dissolved in EtOH (13 mL) and cooled to 0°C. NaBhLi (32.8 mg, 0.89 mmol) was added and the temperature was allowed to reach RT. After 2h at RT acetic acid (0.313 mL) and H2O (33 mL) were added carefully. The reaction mixture was stirred at RT for 30 min. and was subsequently extracted with CH2CI2 (2 x 25 mL). The organic layer was separated, dried over Na2S04 and concentrated to yield 1.2g of colorless oil. Purification was performed by column chromatography (eluent: heptane / ethylacetate 3:1, Rf = 0.3) to give 1.09g (88%) of alcohol XLIV Ketal derivative of 3-Benzvloxv-15-iodomethvl-estra-1.3.5(10)-trien-l7-one (XLXO
Imidazole (749 mg, 11.0 mmol), PPh3 (1.44 g, 5.5 mmol) and I2 (1.33 g, 5.2. mmol) were stirred in CH2CI2 (20 mL) for 30 min. The mixture was cooled to 0 °C. Dropwise a solution of alcohol XLIVo-1c (1.09 g, 2.50 mmol) in CH2Q2 (10 mL) was added over a period of 10 min. The reaction flask was covered with aluminium foil and tjie mixture was stirred for 90 min at RT. The solids were filtered off over celite and the filtrate was washed with 10% aq. Na2S2O4. The organic layer was separated, dried over Na2S04 and concentrated to yield an oil which was purified by column chromatography (eluent: heptane / ethylacetate 1:1, Rf = 0.8) to give 0.944g (69%) of iodide XLV as a white foam.
Ketal derivative of 4-(3-Ben2?/loxv-17-oxo-estra-1.3.5(10Vtrien-15-vn-butvric acid ethvl ester (XLVI) NiCI2.6H2O (409 mg, 1.72 mmol) was suspended in pyridine (7.3 mL). Subsequently activated zinc (566 mg, 8.66 mmol) and ethylacrylate (868 pi, 8.0 mmol) were added and the mixture was stirred at 56°C for 20 min. A catalytic amount of iodine was added and the heating was switches off. When the temperature became 40°C, a solution of XLV (944 mg. 1.73 mmol) in pyridine (5.2 mL) was added dropwise and the stirring was continued for 90 min at RT. Solids were filtered off and the filtrate was concentrated. EtOAc (25mL) was added and the organic layer was washed with brine (3 x 10 mL). The organic layer was separated, dried over Na2SO4 and concentrated to yield 1.18 g of an oil which was purified by column chromatography (eluent: heptane / ethylacetate 5:1, Rf = 0.4) to give 0.449 g (50%) of ethylester XLVI as a colorless oil.
Ketal derivative of 4-(3-Hvdroxv-17-oxo-estra-1.3.5(1 OV-trien-15-vn-butvric acid ethyl ester (XLVIH
Ethylester XLVI (0.449 g, 0.86 mmo!) was dissolved in THF (15 ml). A suspension of a small spoon of Pd/C in THF (2 ml) was added and the reaction mixture was stirred for three days at RT with 1 bar H2 pressure. The solids were filtered off over celite and washed with THF (10 mL). Concentration of the organic layer gave 0.375 mg of compound XLVIl as yellow foam. Purification was performed by column chromatography (eluent heptane / ethylacetate 5:1, Rf = 0.2) to give 0.313 g (84 %) of compound XLVIl as a white solid.
Ketal derivative of 4-(3-Hvdroxv-17-oxo-estra-1.3.5(1 OV-trien-15-vn-butvric acid OCLVIIIg-Sal
To a heated (60°C) solution of Phenol XLVIl (0.313 g, 0.73 mmol) in MeOH (12 mL) 2N aq. KOH (3.52 mL) was added. The mixture was stirred for 30 min. 60°C. The mixture was cooled by adding ice to the mixture. The pH was adjusted carefully to 3 a 4 using 5N aq. HCI. The carboxylic acid XLVIIIa-3a was extracted with TBME (50 mL), the organic layer was dried over Na2SO4 and concentrated to yield 0.266g (91%) of carboxylic acid XLVIIIa-3a as a white solid. No purification was needed.
4-(3-Hvdroxv-17-oxo-estra-1.3.5(1 OVtrien-15-vlVbutvriG acid nVcc-3a^
If necessary, the unprotected carboxylic acid may be obtained by treatment of the ketal derivative XLVIIIa-3a with an anorganic add and subsequent purification.
IV. Compounds of formula XXXI (alcohol derivatives^: 15-Hvdroxv-Ci-Cg-alkvl-Estron
Alcohol XXX|g-1a: 15g-Hvdroxvnnethvl-3-hvdroxv-estra-1.3.5(10Vtrien-17-one Alcohol XXXIa-1b: 15a-Hvdroxvmethyl-3-mQthoxv-estra-1.3.5MOVtrien-17-one Alcohol XXXIa-1c: 3-Benzvloxv-15a-hydroxymethyl-estra-1.3.5(10)-trien-17 (Figure Removed)sis gave the corresponding alcohols XXXIolb and XXXIa-1c. The alcohol XXXIa-1c was debenzylated to give XXXIa-1a using Pd/C and a 5 bar hydrogen atmosphere.
Detailed Synthesis
Alcohol XXXIa-1b: 15g-Hvdroxvmethvl-3-metrioxv-estra-1.3,5(10)-trien-17-one
Alcohol-XXXIa-1c: 3-Benzvloxv-15a-hvdroxvmethvl-estra-1.3.5(1 OVtrien-17-one
NaBH» (SOOmg, 13.2mmol) was added in aliquots of 100mg per 10min to a solution of aldehyde Xlll-Ob or XIII-Oc (2.3mmol) in THF (20mL) and reaction was continued overnight. The reaction was quenched upon the addition of MeOH (20mL). The reaction mixture was evaporated to dryness (high vacuum). The residue was dissolved in CH2CI2 (50mL) and stirred with HCI (15%, 50mL) during 72h. CH2CI2 (50mL) was added and the organic layer was dried with Na2SO4 and evaporated to dryness. A yield of 95-98% was obtained for both products (HPLC-MS: 90% pure). A sample of XXXMb (230mg) with a 95%+ purity was obtained by crystallization from CH2CI2/MeOH upon standing to air. Compound XXXI Alcohol XXXIa-1a: 15a-Hvdroxvmethvl-3-hvdroxv-estra-1.3.5(10Vtrien-17-one
A suspension of estrone XXXIa-1c (0.81 g, 90% pure), Pd/C (50-1 OOmg, cat) in MeOH (100mL) was stirred in a 5 bar H2-atmosphere for SOmin. Pd/C was removed by filtration through Celrte. Evaporation to dryness (0.52g, 90% pure) and recrystallization of the residue from MeOH gave XXXIa-1a as an off-white solid (308mg).
74
Alcohol building blocks XXXI-3 (n = 3^:
15|3-(3-Hvdroxvpropv1V3-methoxvestra-1.3.5(10Vtrien-17-one(XXXI-3b):
0
{XXXl-3t>)
Detailed Synthesis:
To a solution of 2-(3-bromopropyloxy)-tetrahydro-2W-pyran (4.45 g, 19.95 mmol) in dry THF (50 ml) at -78°C under nitrogen atmosphere was added f-BuLi (1.5 M solution in pentane, 25 ml, 37.5 mmol). After 30 min stirring CuCN (0.89 g, 9.94 mmol) was added. The mixture was stirred for additional 30 min while the reaction mixture is allowed to reach -40 °C. After cooling to -78 °C a solution of the 15,16-unsaturated estron derivative of formula Xb (1.50 g, 5.24 mmol) and TMSCI (1.3 mL, 10 mmol) in 50 ml THF was added dropwise over a period of 15 min. The mixture was allowed to reach 0°C (over a period of 4h). Then saturated Nt-UCI-solution was added, the layers were separated and the aqueous phase was extracted with ethyl acetate. The crude product was dissolved in methanol (250 mL) and K2C03 (0.80 g, 5.97 mmol) was added. After 2 h stirring at RT water (50 mL) was added and most of the methanol was evaporated. The mixture was diluted with EtOAc, the layers were separated and the water layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4 and the solvent was evaporated. The crude product was dissolved in methanol (250 mL) and p-TosOH (0.80 g, A-?"! mmol) was added. The reaction mixture was stirred for 90 min. Most of the methanol was removed on the rotary evaporator. Water was added and aqueous phase was extracted with DCM (3x). The combined organic layers were dried over Na2SC>4 and the solvent was removed. The crude product was purified by column chromatog-raphy (SIO2, cyclohexane/ ethyl acetate 1:1) to yield compound XXXI-3b (0.81 g, 45 %) as colourless oil.
LC-MS (ES+): rt 5.75 min, m/z (rel. Intens) 343 [(M+H)*, 40%], 360 [(M+NlV, 100 %]
1H NMR (400 MHz, CDCI3) 8 (ppm) 1.03 (s, 3H), 1.44-1.76 (m, 9H), 1.88-1.92 (m, 1H), 2.03-
2.07 (m, 1H), 2.27-2.48 (m, 5H), 2.91-2.95 (m, 2H), 3.65-3.69 (m, 2H), 3.78 (s, 3H), 6.65 (d, 1H),
6.71 (dd, 1H),7.19(d, 1H).
13C NMR (100.6 MHz, CDCI3) 5 (ppm) 17.8, 25.5, 26.8, 27.2, 9.5, 32.8, 34.0, 34.2, 36.1,
42.7,44.6,47.1, 52.9, 55.2, 62.6, 76.7,77.0,77.4,111.5,113.9,126.0,132.4, 137.7,157.7,221.0. = +79.6 (c = 0.314, MeOH)
Alcohol building blocks XXXI-3c and XXXI-3a (n = 3. R1=benzyl. n = 3. R1= 3-Benzvloxv-15S-(3-hvdroxvpropvn-estra-1.3.5(1 OVtrien-17-one (XXXI-3c^ 3-Hvdroxv-15B-(3-hvdroxvpropvn-estra-1.3.5(1 (Figure Removed)
A 3-neck flask was charged with Cul (18.76 g; 98.5 mol) and lithium chloride (4.17 g; 98.4 mol) and evacuated and purged with N2 (2x). THF (dry, 150 ml) was added and the mixture was stirred at RT during 20 minutes. The resulting clear green solution was cooled to -78°C. Allylmag-nesiumbromide (1.0 M solution in diethyl ether; 100 ml; 100 mmol) was added dropwise at - 78°C. After complete addition trimethyl silylchloride (9.1 mL; 71.2 mol) was added, immediately followed by the dropwise addition of a solution of the 15,16-unsaturated estron Xc (10.08 g; 28.1 mol) in THF (dry, 120 mL). After the complete addition the suspension was stirred during 1 hour at - 78 °C. The mixture was warmed up to RT and stirred for 3 d. Saturated NH4CI solution (500 mL) was
added and the layers were separated. The aqueous layer was extracted with EtOAc (2x 300 mL). The combined organic layers were washed with HCI (1M, 2x 300 mL) and aqueous ammonia (25%, 3x 300 ml). The organic layer was dried over Na2SO4 and the solvent was evaporated. The resulting brown oil was crystallized from EtOAc to yield XXXV-3c (5.81 g; 51%).
3-Benzvloxv-15B-f prop-2-envl)-estra-1.3,5(1 OVtrien-17-dioxolane (XXXV-3c-ketal)
Triethyl orthoformate (25 mL; 150 mmol) and ethylene glycol (11 mL; 197 mmol) were added to XXXV-3c (10 g; 25.0 mmol). p-TosOH (0.40 g; 2.10 mmol) was added to the slurry which was heated to 35°C overnight. Then the reaction mixture was poured into ice (100 mL) and pyridine (3 mL) was added. This mixture was stirred for 5 h. The mixture was diluted with ethyl acetate, the layers were separated and the aqueous layer was extracted with ethyl acetate (100 mL). The organic layers were washed with water (2x 100 mL), dried over NaaSO4 and evaporated. The crude product was purified by column chromatography (heptane / EtOAc 9:1) to yield XXXV-3c-ketal (9.94 g; 90 %).
3-Benzvloxv-15B-(3-hvdroxvDropvlVestra-1,3.5(10^-trien-17-dioxolaneXXXII-3c
Compound XXXV-3c-ketal (9.94g; 22.36 mmol) was dissolved in THF (500 mL). Borane di-methylsulfide (2M in diethylethen 72 mL; 144 mmol) was added and the solution was heated at reflux for 2 hours. The solution was then cooled in ice bath and NaOH (3M; 99 mL) was added dropwise. Then H2O2 (35%; 50 mL) was added and the resulting biphasic system was stirred overnight at 40°C. The excess of peroxide was destroyed by addition of dimethylsulfide. After work-up ,) 3-BenzvlQxv-15S-(3-hvdroxvpropvlVestra-1 t3.5(10>-trien-17-one XXX-3c
Crude compound XXXII-3c (8.82 g) was dissolved in acetone (88 mL) and water (22 mL) and p-TosOH (0.36 g; 1.89 mmol) was added. The solution was stirred for 3 d at RT. After work-up the crude product was purified by column chromatography (heptane /EtOAc 1:1, Rf 0.3) to yield compound XXX-3c (2.90 g; 31 % over 2 steps).
3-Hvdroxv-15B-(3-HvdroxvDropvn-estra-1.3.5(10)-trien-17-one XXX-3a
Compound XXX-3c (2.90 g; 6.93 mmol) was dissolved in MeOH (250 mL) and Pd/C was added as a slurry in MeOH. The mixture was stirred overnight at RT under a H2 atmosphere. The reaction mixture was filtered over Celite. The filtrate was evaporated and the product was dissolved in EtOAc (50 mL) and crystallized as needles, which were filtered off and washed with pentane to yield compound XXX-3a (1.63 g; 72 %). (LC-MS (ES-): rt 5.75 min, m/z (rel Intens) 327 [(M-H)+, 100%]).
Alcohol building blocks XXXI-4b. XXXI-Sb. XXXI-6b (n = 4, 5. Q): 156-f4-Hvdroxv-CrCfi-alkvn-3-rnetrioxv-estra-1,3.5(1 OVtrien-17-one:
(Figure Removed)Magnesium (3-1 Oeq) is added in a dry three-neck flask under N2 atmosphere and activated by Iodine. The bromo compound (2-6.5 eq) dissolved in dry THF is added dropwise to the magnesium. The reaction mixture is allowed to react for 1-2 h at RT or reflux. The solution is transferred to dry three-neck flask containing Cul (0.06-0.7 eq) and DMPU or HMPA (2-7 eq) in dry THF cooled to -40 °C. The resulting mbdure is stirred for 30 min at -40 °C after which a mixture of 15,16-unsaturated estron derivative of formula X (1 eq) and TMSCI (2-2.5 eq) dissolved in THF is added dropwise. After complete addition the mixture is allowed to reach RT. Then NH4CI-solution is added, the layers are separated and the aqueous phase is extracted with ethyl acetate (3x). The combined organic phases are dried over Na2SO4 and the solvent is evaporated. The crude product is dissolved in methanol and K2CO3 (1eq) is added to hydrolyse the silyl ether. After complete hydrolysis water is added and most of the methanol is evaporated. The mixture is diluted with EtOAc, the layers are separated and the water layer is extracted with EtOAc. The combined organic layers are dried over Na2SO4 and the solvent is evaporated. The resulting product of general formula XXX is then further worked-up to give the alcohol of general formula XXXI.
XXI-4b fn = 4 and R1 = CHaV l5B-M-HvdroxvbutvlV3-rnethoxv-estra-1 .3.5(1 0)-frien-17-one
The detailed synthesis of this compound is already displayed within the section for the synthesis of acid building block of the formula lV-3b above.
XXXI-5b m = 5 and R1 = CHaV l5B-(5-Hvdroxvpentvl\-3-methQXV-estra-1.3.5(10Vtrien-17-one
According to the general procedure displayed in SCHEME 11, the copper reagent was prepared from magnesium (3.80 g, 156 mmol), 2-{5-bromopentyloxy)-THP (23.6 g, 94.00 mmol), Cul (0.54 g, 2.83 mmo!) and DMPU (12 ml_, 100 mmol) in THF. A mixture of estron derivative of formula Xb (13.68 g, 48.5 mmol) and TMSCI (13 mL, 100 mmol) in THF was added dropwise. The reaction mixture was allowed to reach RT and was stirred for two days. After work-up and hydrolysis of the silyl ether the crude product was dissolved in methanol (50 mL) and p-TosOH (1 1 .4 g, 60 mmol) was added. The reaction mixture was stirred overnight. Most of the methanol was removed on the rotary evaporator. Water was added and aqueous phase was extracted with DCM (3x). The combined organic layers were dried over Na2SO4 and the solvent was removed. The crude product was purified by column chromatography (SiO2, cyclohexane/ ethyl acetate gradient from 10:1 to 2:1) to yield XXXI-5b (14.21 g, 79 %).
LC-MS (ES+): rt 6.31 min, mfe (rel. Intens) 388 [(M+NH.T. 100 %] = +85.7 (c = 0.105, CH2d2)
XXXI-6b (n = 6 and R1 = CH3): 15B-f6-Hvdroxvhexvl)-3-methoxv-estra-1.3.5(10Vtrien-17-one
According to the general procedure displayed in SCHEME 11, the copper reagent was prepared from magnesium (2.19 g, 91.00 mmol), 2-(6-bromohexyloxy)-THP (20.67 g, 78.00 mmol), Cul (1.98 g, 10.40 mmol) and DMPU (9.4 mL, 78 mmol) in THF. A mixture of estron derivative of formula Xb (7.33 g, 26.00 mmol) and TMSCI (5.56 g, 52.00 mmol) in THF was added dropwise. The reaction mixture was allowed to reach RT and was stirred for two days. After work-up and hydrolysis of the silyl ether the crude product was dissolved in methanol (200 mL) and p-TosOH (0.95 g, 5.00 mmol) was added. The reaction mixture was stirred for 1 h. Most of the methanol was removed on the rotary evaporator. Water was added and aqueous phase was extracted with DCM (3x). The combined organic layers were dried over NazSO* and the solvent was removed. The crude product was purified by column chromatography (SiO2, cyclohexane/ ethyl acetate gradient from 10:1 to 2:1) to yield XXXI-6b (7.50 g, 75 %).
LC-MS (ES-): rt 6.63 min, m/z (rel. Intens) 443 [(M+OAcT, 1 00 %]
lcohol building block XXXI-4c (n =4, R1=benzvl) and XXXI~4a (n = 4. R1=hO 3-Benzvloxv-15B-f4-hvdroxvbutvlVestra-1.3.5(10Vtri6n-17-one(XXXI-4c) 3-Hvdroxv-15B-(4-hvdroxvbutvn-estra-1.3.5(1 OVtrien-17-one (XXX\-4a)
The detailed synthesis of this compound is already displayed within the section for the synthesis of acid building block of the formula IV-3c above. The 3-Hydroxy-Derivative can be obtained by hydrolysis of the XXXI-4c compound.
Alcohol building blocks XXXI-Sc and XXXI-5a (n = 5. R1=benzvl. n = 3. R1=ffl: 3-Benzvloxv-15B-(5-hvdroxvpentvn-estra-1.3.5nO)-trien-17-one OOQCI-Sc) 3-Hvdroxv-153-(5-Hvdroxvpentvn-estra-1.3.5f10)-trien-17-onefXXXI-5a (Figure Removed) synthesis of the alcohol building block of formula XXXI-5c and XXXI-5a is depicted in the following scheme 12.
SCHEME 12
(Figure Removed)3-Benzvloxv-15B-foent-4-envlVestra-1.3,5(10V-trien-17-one OQOCV-Sc)
Magnesium turnings (4.43 g; 0.182 mol) were activated by addition of a fe crystal and a drop of pure bromide. A solution of 5-bromo-1-pentene (19.5 ml; 0.164 mol) in THF (dry, 160 mL) was added drop wise, while maintaining reflux. After complete addition the mixture was stirred at RT for 1 hour. A 3-neck flask was charged with Cul (30.47 g; 0.159 rnoi) and lithium chloride (6.78 g; 0.159 mol) and evacuated and purged with N2 (2x). THF (dry, 240 ml) was added and the mixture was stirred at RT during 20 minutes. The resulting clear green solution was cooled to -78°C. The Grignard reagent was added drop wise between -78°C and -70°C. After complete addition trimethyl silylchloride (20.4 mL; 0.159 mol) was added to the brown reaction mixture at -78°C, immediately followed by the drop wise addition of a solution of 15,16-unsaturated estron Xc (22.94 g; 0.064 mol) in THF (dry, 280 mL). After the complete addition the suspension was stirred during 1 hour at - 78 °C. The mixture was warmed up to RT and stirred for 3 d. Saturated NH4CI solution (500 mL) was added and the layers were separated. The aqueous layer was extracted with EtOAc (2x 300 mL). The combined organic layers were washed with HCI (1M, 2x 300 mL) and aqueous ammonia (25%, 3x 300 mL). The organic layer was dried over Na^O., and the solvent was evaporated. The resulting brown oil was crystallized from EtOAc to yield XXXV-5c (18 g; 66%).
3-Benzvloxv-15B-(pent-4-enyl)-estra-1.3.5(1 OMrien-17-dioxolane OQ(XV-5c-ketal)
Triethyl orthoformate (42 mL; 252 mmol) and ethylene glycol (19 mL; 340 mmol) were added to compound XXXV-5c (18 g; 42.0 mmol). pTosOH (0.67 g; 3.52 mmol) was added to the slurry which was heated to 35°C overnight. Then the reaction mixture was poured into ice (100 mt) and pyridine (3 mL) was added. This mixture was stirred for 5 h. The mixture was diluted with ethyl acetate, the layers were separated and the aqueous layer was extracted with ethyl acetate (100 mL). The oiiganic layers were washed with water (2x 100 mL), dried over Na2SO4 and evaporated. The crude product was purified by column chromatography (heptane / EtOAc 9:1) to yield XXXV-5c-ketal (18.85 g; 95 %).
3-Benzvloxv-153-f5-hvdroxvpentvlVestra-1.3.5(10Vtrien-17-dioxolaneOO(XII-5c)
Compound XXXV-5C (18.85 g; 39.88 mmol) was dissolved in THF (850 mL). Borane di-methylsulfide (2M in diethylether; 128 mL; 256 mmol) was added and the solution was heated at reflux for 2 hours. The solution was then cooled in ice bath and NaOH (3M; 176 mL) was added dropwise. Then H2O2 (35%; 89 mL) was added and the resulting biphasic system was stirred overnight at 40°C. The excess of peroxide was destroyed by addition of dimethylsulfide (380 mL). The solvent was evaporated and water (500 mL) and ethyl acetate (500 mL) was added. The layers were separated and the aqueous layer was extracted with ethyl acetate (500 mL). The organic layer was dried over Na2SO4 and the solvent was evaporated to yield XXXII-5c (15.36 g). The crude product was used in the next step without further purification.
3-Benzvloxv-15|3-f5-hydroxvpentvl)-estra-1.3.5(10Vtrien-17-one(XXXI-5c)
Crude compound XXXIl-5c (15.36 g) was dissolved in acetone (135 ml_) and water (35 mL) and p-TosOH (0.62 g; 3.26 mmol) was added. The solution was stirred for 3 d at RT. Saturated NaHCO3 solution (50 ml) was added and the solvent was evaporated. More sat. NaHC03 solution (20 ml) was added and the mixture was extracted with CH2CI2 (2x 100 mL). The organic layer was dried overNa2SO4 and the solvent was evaporated. The crude product was purified by column chromatography (heptane /EtOAc 1:1, Rf 0.3) to yield XXXI-5c (8.65 g; 49 % over 2 steps).
3-Hvdroxv-1 SB-fS-HydroxvpentvO-estra-l .3.5f 10ltrien-17-one
Compound XXXI-5C (8.65 g; 19.37 mmol) was dissolved in MeOH (95 ml) and Pd/C (2.3 g) was added as a slurry in some MeOH. Ammonium formate (9.77 g; 154.9 mmol) was added and the solution was stirred at RT. After 1 hour 45 minutes NMR (in CD3OD) showed complete conversion. The reaction mixture was filtered over Celite and washed with MeOH (300 mL). The filtrate was evaporated, remaining a sticky material which was stirred in water (100 ml) at RT. The compound became a solid and the water was decanted after 5 hours. EtOH (100 mL) was added and evaporated to remove the water. The oil was evaporated twice from EtOAc (100 mL), yielding 6 g of an white foam, which contained 10 % of the secondary alcohol as an impurity. The side product was removed by transformation to the acetic acid ester (with pyridine and acetic anhydride) and separation by column chromatography (heptane/EtOAc from 2:1 to 1:2). The ester was cleaved by heating with potassium carbonate in MeOH. After work-up the product XXXI-5a (2.21 g; 32 %) was obtained as a colourless foam.
,' V '
LC-MS (ES-): rt 5.23 min, m/z (re! Intens) 355 [(M-H)*, 100 %]
Alcohol building blocks XXXI-6C and XXXI-6a (n = 6. R1=benzvl. n = 3. R1=H): 3-Benzvloxv-15B-f6-hvdroxvhexvn-estra-1.3.5(10)-trien-17-one(XXXI-6c) 3-Hvdroxv-15B-(6-hvdroxvhexvlVestra-1.3.5(10)-trien-17-one (XXXI-6a)
p
3-Benzvloxv-15B-(6-hvdroxvhexvn-estra-1.3.5(1 OVtrien-17-one (XXXI -6cl
According to the general procedure displayed in SCHEME 11, the copper reagent was prepared from magnesium (6.56 g, 270 mmol), 2-(6-bromohexyloxy)tetrahydro-2W-pyran (47.2 g, 180 mmol), Cul (3.18 g, 17 mmol) and HMPA (33 mL, 190 mmol) in THF. A mixture of the 15,16 un-
saturated estron derivative Xc (10.1 g, 28.00 mmol) and TMSCI (8 ml, 63 mmol) in THF was added dropwlse. The reaction mixture was allowed to reach RT and was stirred overnight. After work-up and hydrolysis of the silyl ether the crude product was dissolved in methanol (890 mL) and p-TosOH (3.30 g, 17.35 mmol) was added. The reaction mixture was stirred overnight Most of the methanol was removed on the rotary evaporator. Water was added and aqueous phase was extracted with DCM (3x). The combined organic layers were dried over Na2SO4 and the solvent was removed. The crude product was purified by column chromatography (SiO2, heptane/ ethyl acetate 2:1) to yield XXXI-6c (7.99 g, 62 %).
3-Hvdroxv-15B-(6-hvclroxvhexvl)-3-estra-1.3.5f10Vtrien-17-oneOOQ(l-6a)
Compound XXXI-6c (7.99 g; 17.35 mmol) was dissolved in MeOH. Pd/C (in water; 2.3 g) was added, followed by ammonium formate (8.58 g; 136 mmol). The mixture was stirred at RT for 1.5 hour after which the mixture was filtered over Celite. The filtrate was evaporated and dissolved in EtOAc (200 ml) and water (150 ml). The layers were separated, the organic layer was dried over Na2SO4 and the solvent was evaporated. Purification by column chromatography (SiO2, heptane /EtOAc 1:1) yielded # (2.69 g; 42 %).
LC-MS (ES-): rt 5.49 min, m/z (rel Intens) 369 [(M-H)*, 100 %]
V. Compounds of formula XV (protected amine building block) (n = 1 -6): R3 preferably = H
V-1:m = 1V
XV-1b: Ketal derivative of the 15a-amlnomethvl-3-methoxv-estra-1.3.5f10Hrien-17-one
XV-1c: Ketal derivative of the 15a-aminomethyl-3-benzvl6xv-estra-1.3.5(10)-trien-17-one
Dissolving aldehydes Xlll-Ob (R1=CH3) or XIII-Oc (R1=benzyl) in benzylamine and reduction of the residual imine in THF gave benzylamine XIV-1b (R1=CH3) and XIV-1c (R1=benzyl), which were debenzylated to XV-1b (R1=CH3) and XV-1a (R1=H), using Pd/C and H2 at 5 bar, and dissolved in dilute HCI to give the respective ammonium chlorides XXIX-1b (R1=CH3) and XXIX-1a (R1=H). Standard purification methods failed due to what seems to be instability of these ammonium salts. For these amines it was known that these should be treated as HCI salts since the Iree amine is not stable (ene-amines), but even the salts seem to be at least heat-sensitive. The crude reaction mixture has a purity of ~90% (HPLC-MS).
Detailed Synthesis
XIV-1 b: Ketal of 1 5a-(Benzvlamino-methvl)-3-methoxv- estra-1 ,3.5(1 0)-trien-17-one
XIV-1c: Ketal of 15a-(Benzvtemino-methvlV-3-benzvloxv- estra-1.3.5(10)-trien-17-one
The aldehyde Xlllb or Xlllc (0.93mmol) was dissolved in benzylamine (0.4 ml_, 3.9mmol) and MeOH (10mL) upon heating and the mixture was stirred for SOmin and evaporated to dryness. The residue was dissolved in dry THF and aliquots of 50mg of NaBH, were added each hour until SOOmg (4.0mmol) was added. The mixture was stirred overnight only a baseline spot was observed on TLC (TBME). The mixture was evaporated to dryness and the residue was stirred with NaHCO3(aq) (200 mL) until no gas evolved anymore. The suspension was extracted with CHaCU (2x200mL) and upon drying the organic layer with NazS04 and evaporation to dryness, compounds XlVb and XIVc were obtained as colourless oils: yield 92-100%.
XV-1b: Ketal derivative of the 15a-Aminomethvl-3-methoxv-estra-1.3.5(1 OVtrien-17-one XV-1a: Ketal derivative of the 15a-Aminomethvl-3-hydroxv-estra-1.3.5(10)-trien-17-one
A suspension of benzylamines XlVb or XIVc (22 mmol) and Pd/C (10%, 1.0g, cat) in MeOH (500m L) was stirred in a 5 bar H2-atmosphere for48h. Filtration through Celite and evaporation to dryness gave crude amines XV-1a and XV-1b. Amine X\Ma was purified by column chromatogra-
y (CHCI2/MeOH (7N NH3); 925:75) giving XV-1a as a colourless oil (5.0g, 63% for three steps starting from aldehyde XII Ic). Amine XV-1b decomposed in many products upon standing overnight. Therefore in a second attempt it was used instantly without purification in the next step. (Figure Removed)Wittig reagent. (LC-MS (ES+): rt4.57 min, m/z (rel. Intens) 386 [(M+H)+, 100%])
88
XVft-1b: Ketal derivative of the 15p-Aminobutvl-3-methoxv-estra-1.3.5(10>-trien-17-one XVB-1c: Ketal derivative of the 15B-Aminobutvl-3-benzvloxv-estra-1.3,5nO)-trieps in the synthesis of amine building block of the formula XVp-4 with (3 configuration at the C15 atom of the steroidal core are depicted in the following scheme 17.
SCHEME 17 derivative of the formula XXXIP-4 (for synthesis of XXXIp-4 see above) is converted into the ketal group (compound of formula XXXIIp-4). Then, the alcohol function is selectively reduced to the aldehyde giving compound of the formula XIIIp-3. The protected aldehyde derivative of the formula Xlllp-3 is converted into a secondary amine by addition of Benzylamine and subsequent reduction (reductive animation). Further reduction of the secondary amine delivers the desired, still protected amine building block of the formula XVp-4. The protecting ketal group can be converted into the 17-oxo group via acid hydrolysis.
The same kind of procedure can be applied for n = 5 or 6 and for other substituents within the R1 positionFurthermore, the compound XIVJ3-4 is an example for a secondary amine which can be used as building block for the further synthesis of the compounds according to the invention, in which the R3 residue is other than hydrogen. Further secondary amines which can be used as building blocks may be synthesized by the addition of the appropriate primary amines in the first step of the above indicated synthesis scheme 17.

Amine building block (n = 1 - 6V R3 preferably = H of general formula XXIX
Alternatively, the synthesis of the amine building blocks of general formula XXIX can also be performed starting with an activated alcohol function and a subsequence substitution reaction, and does not need any protection of the Estron-C17 keto function according to the following general scheme 18.
7-onembined, dried with NaS04 and evaporated yielding 4.4 g oil XLIIIp-4b (LC-MS: MH+=382, rt 7.32 min, still containing some solvent residues), which can be used without further purification.
XXIXB-4b: 1 5B-Aminobutvl-3-methoxv-estra-1 .3.5(1 OVtrien-17-one
3,3 g azide (XLIIIp-4D) were dissolved in 300 ml ethanol. 20 m! 18 % HCUq and 50 mg Pd/C 5% were added. The suspension was put in a shaker unit which was pesurized with 3 bar hydrogen for 6 hours. After filtration the filtrate was evaporated and the remaining solid dried for 4 hours at 60°C in a vaccum drying oven yielding 3.2 g of the amine hydrochloride salt XXIXp-4b. (LC-MS: MH+: 356; rt: 4.84 min)
Experimental
Examples of preparations of compounds of the invention are provided in the following detailed synthetic procedures. In the tables of compounds to follow, the synthesis of each compound is referenced back to these exemplary preparative steps.
In single compound synthesis as well as in combinatorial synthesis all reactions were stirred magnetically or shaked with an orbital shaker unless otherwise indicated. Sensitive liquids and solutions were transferred via syringe or cannula, and introduced into reaction vessels through rubber septa, in these cases the reaction were carried out under a positive pressure of dry argon or dry nitrogen. Commercial grade reagents and solvents were used without further purification.
Unless otherwise stated, the term "concentration under reduced pressure" refers to use of a Buchi or Heidolph rotary evaporator ("Rotavapor") or vaccum centrifuges ("GeneVac") at approximately 15 mm of Hg. All temperatures are reported uncorrected in degrees Celsius (°C). Unless otherwise indicated, all parts and percentages are by volume.
Thin-layer chromatography (TLC) was performed on Merck® pre-coated glass-backed silica gel or aluminium sheets 60A F-254 250 urn plates. Visualization of plates was effected by one or more of the following techniques: (a) ultraviolet illumination (254 nm or 266 nm), (b) exposure to iodine vapor, (c) spraying of the plate with Schlittler's reagent solution followed by heating, (d) spraying of the plate with anisaldehyde solution followed by heating, and/or (e) spraying of the plate with Rauxz reagent solution followed by heating. Column chromatography (flash chromatography) was performed using 230-630 mesh ICN, SiliTech 60A silica gel.
Melting points (mp) were determined using a Reichert Thermovar melting point apparatus or a Mettler DSC822 automated melting point apparatus and are uncorrected.
Fourier transform infrared spectra were obtained using a Perkin Elmer spectrophotometer.
Proton (1H) nuclear magnetic resonance (NMR) spectra were measured with a Bruker ARX (400 MHz) or Bruker ADVANCE (500 MHz) spectrometer with either Me^Sl (5 0.00) or residual protonated solvent (CHCI3 8 7.26; CHD2OD 5 3.30; DMSO-ds 8 2.50) as standard. Carbon (13C) NMR spectra were measured with a Bruker ARX (100 MHz) spectrometer with either Me^Si (8 0.00) or solvent (CDCI3 5 77.05; CD3OD 5 49.0; DMSO-d6 8 39.45) as standard.
HPLC electrospray mass spectra (HPLC ES-MS) were obtained using the following method and equipment Samples were separated by reversed phase high pressure liquid chromatography [RP-HPLC) coupled to a quadrupol MS. HPLC was performed at a flow of 1000 ul/min using Xter-
raMS C18 columns (Ld. 4.6 mm, length 50 mm, particle size 2.5 |jm) or or Phenomenex Luna C18(2) 30*4.6mm columns. For most samples, a gradient from 0% eluent B to 95% B was run In 10 min, with eluent A consisting of water, 10 mM ammonium-acetate at pH 5 + 5% acetonitrile and eluent B consisting of acetonitrile. Two different setups were used: 1. Waters Alliance 2795 coupled to a Waters ZQ MS, a Waters 2996 diode array detector (DAD) and an evaporative light scattering detector (ELSD, EL-ELS1000, PolymerLabs). lonization: electrospray positive and negative mode ES +/-. Or 2. LC200 pump (PE) coupled to an AP1100 MS (Applied Biosystems Sciex), a variable wavelength detector Waters 2487 set to 225 nm, and an ELSD (Sedex 75), ES+. In both setup versions spectra were scanned with a scan range of mfe 100 to 800 or 100 to 900.
Gas chromatography - mass spectra (GC-MS) analyses were performed with an Agilent 6890 gas chromatograph equipped with an DB-5MS column (0.25 i.d., length 30 m) and an Agilent 5973 MSD quadrupol detector (ionizatlon with electron impact (El) at 70eV; source temperature 230°C).
Elemental analyses were conducted by a VarioEL elemental analyzer (Elementar Analysen-systeme) for determination of C, H, and N. Acetanilide was used for conditioning and calibration.
NMR spectra, LRMS, elemental analyses and HRMS of the compounds were consistent with the assigned structures.
Examples
In order to more fully illustrate the nature of the invention and the manner of practicing the same, the following examples are presented, but they should not be taken as limiting.
EXAMPLES 1.2,3A, 3B and 4B:
No. 1.3-Hydroxy-15p-(4-morpholin-4-yl-4-oxo-butyl)-estra-1,3,5(10)-trien-17-one (Vfp-3a)-1 No. 2.3-Methoxy-15p-(4-morpholin^-yl-4-oxo-butyl)-estra-1,3I5(10)-trien-17-one (Vlp-3b)-2 No. 3.A. N-Benzyl-4-(3-hydroxy-17-oxo-estra-1,3,5(10)-trien-15p-yl)-butvramide (Vlp-3a)-3A No. 3.B. N-Ben2yl-4-(3-methoxy-17-oxo-estra-1,3l5(10)-trien-15p-yI)-butyramide (Vlp-3b}3B No. 4.B. 4-(3-Methoxy-17-oxo-estra-1,3,5(10)-trien-15p-yl)-N-methyl-butyramide (Vlp-3b)-4B
The individual steps in the synthesis of the examples 1, 2,3.A., 3.B. and 4.B. are depicted in the following scheme 19.
SCHEME 19
Starting with the free acid building block of formula IVp-3b, the corresponding acid chloride was prepared using oxalylchloride. The acid chloride was reacted with an amine of general structure R2R4NH, which represents morpholine for the synthesis of compounds No. 1 and 2, ben-zylamine for compounds No. 3A and 3B, and methylamine for compound No. 4B, delivering after the first synthesis step the amides of general formula (Vl|3-3b): compound No. 2 (with -NR2R4 = morpholine), 3B (with -NR2R4 = -NH-benzyl) and 4B (with -NR2R4 = -NH-CH3). Compound 3B was purified by column chromatography followed by trituration with Et2O and isolated in 8% yield. Compound 4B was purified by trituration with Et2O and some MeOH and isolated in a yield of 48%. Compound 2 was purified by column chromatography and obtained in a yield of 33%.
Demethylation of the 3-hydroxyfunction was successful for compound No. 2 and No. 3B with BBr3, resulting in the amide of general formula (Vlp-3a) representing compounds No. 1 and No. 3A in respectively 21 and 48% yield. Compound No. 1 was obtained, after column chromatography, as a mixture of a and p isomer. Purification of the compound No. 3A was accomplished by column chromatography.
Detailed Synthesis
EXAMPLE No. 2:
3-Methoxv-15B-(4-morpholin~4-vl"4-oxo-butvlVestra-1.3.5(10Vtrien-17-one of formula (VIB-3bV2
The acid building block IVp-3b (1.1 g, 2.7 mmol) was dissolved in DCM (20 ml) and 1 drop DMF was added. The reaction mixture was cooled to 0°C and oxalylchloride (0.25 ml, 2.7 mmol) was added dropwise. After stirring the mixture for 1 hour at O'C, the solvent was removed on the rotary evaporator. The acid chloride was dissolved in DCM (20 ml) and mor-pholine (0.31 ml, 3.51 mmol) was added dropwise. The reaction mixture was stirred overnight Water (20 ml) and DCM (30 mi) were added. After separating the layers, the water layer was extracted with DCM (2x 25 ml). The combined organic layers were washed with water (20 ml) and brine (60 ml). The organic layer was dried ovef Na2SO4 and the solvent was removed on the rotary evaporator. This yielded 1.3 g of yellow oil, which was dissolved In TBME and Et2O/EtOH, some brown solid precipitated. The liquid phase was decanted and the solvent was removed on the rotary evaporator. This yielded 865 mg yellow/white solid. HPLC analysis showed that the compound was ca. 80% pure. The solid was purified by column chromatography (50 g SiO2, EtOAc/heptane: 1/2). This yielded 670 mg with a purity of 86% according to HPLC. A second purification by column chromatography (25 g SiO2, EtOAc/heptane: 2/1) finally gave 414 mg (0.94 mmol, 33%) of the desired compound No. 2 as a white solid with a purity of 96% according to HPLC [MS m/z 439.1].
EXAMPLE No. 1:
3-Hvdroxv-15B-(4-moroholin-4-vl-4-oxo-butvlVestra-1.3.5(1 OV-trien-17-one of formula (VIB-3aV1
Methoxy compound (VIB-3b)-2 (898 mg, 2.0 mmol) was dissolved In DCM (20 ml) and cooled to 0°C. BBr3 solution (12.3 ml, 1 M in CH2CI2) was added dropwise while the temperature was maintained at 0°C. The color changed from colorless to yellow/orange to orange/red to pink. The reaction was followed by TLC (SiO2, EtOAc) and after 1 3/4 hour the reaction was completed. 40 ml of water was added followed by 30 ml of a saturated NaHCO3 solution and further 200 ml of water. The layers were separated and the water layer was extracted with DCM. The combined organic layers were dried over NaaSCu and the solvent was removed on the rotary evaporator. This yielded 915 mg yellow oily solid. The product was purified by column chromatography (50 g SiO2, toluene/acetone: 3/1) to afford 183 mg (0.43 mmol, 21%) of the desired compound No. 1 as a yellow solid, with a purity of 95% [MS m/z 425.2]
Example No. 3B
N-Benzvl-4-(3-methoxv-17-oxo-estra-1.3.5(10V-trien-15B-vl)-biitvramide of formula (VIB-3bV3B

The acid building block IVB-3b (1.2 g, 3.3 mmol) was dissolved in DCM (20 ml) and 1 drop DMF was added. The reaction mixture was cooled to 0°C and oxalylchloride (0.28 ml, 3.3 mmol) was added dropwise. The mixture was stirred for 1 hour at 0°C and the solvent was removed on the rotary evaporator. The acid chloride was dissolved in 20 ml DCM and benzylamine (0.48 ml, 4.34 mmol) was added dropwise. The yellow/orange solution turned turbid yellow/white. Stirring was continued for 0.5 hour at RT followed by the addition of 20 ml water and 25 ml DCM. The water layer was extracted with DCM (2x 20 ml) and the combined organic layers were washed with water (20 ml) and brine (20 ml). The organic layer was dried over Na2SO4 and the solvent was removed on the rotary evaporator. This yielded 1.3 g of yellow oil (56% pure according to HPLC analysis), which was then purified by column chromatography (53 g Si02, TBME / heptane: 2/1). This purification yielded 668 mg of a white solid (44%, 87% pure according to HPLC analysis). 400 mg was used for demethyla-tion to prepare (Vlp-3a)-3A; 268 mg was triturated with Et2O to yield 124 mg white solid (0.27 mmol, 8%) with a purity of 94% according to HPLC [MS m/z459.1].
EXAMPLE: No. 3A
N-Benzvl-4-f3-hvdroxv-17-oxQrestra-1.3.5(10Vtrien-15B-vn-butvramide of formula (VIB-3aV-3A
To a solution of the methoxy compound (VI|3-3a)-3B (400 mg, 0.87 mmol) in DCM (100 ml) at 0°C, 5.2 ml of an 1 M solution of BBr3 in DCM was added dropwise at such a rate that the temperature was maintained at 0"C. The color changes from colorless to orange. After complete addition, the reaction was monitored by TLC (EtOAc / heptane: 2/1). The reaction was complete after 1.5 h. Then, water (40 ml), saturated NaHCO3 solution and more water (150 ml) were added. The layers were separated and the aqueous layer was extracted with DCM (2x 100 ml). The organic layers were combined, dried over Na2SO4 and the solvent was removed on the rotary evaporator. This yielded 310 mg red/purple product, which was purified by column chromatography (15 g SIO2, toluene / acetone: 3/1) to afford 173 mg yellow foam with a purity of 82%. The product was again purified by column chromatography (11 g SiO2, toluene / acetone: 3/1). This purification yielded 160 mg yellow solid (0.36 mmol, 41%) with a purity of 93% according to HPLC [MS mte 445.1].
EXAMPLE No. 4B:
4-(3-Methoxv-17-oxo-estra-1.3.5(10Vtrien-15B-vlVN-methvl-butvramide of formula (VIB-3bV4B
The acid building block IVp-3b (846 mg, 2.3 mmol) was dissolved in DCM (20 ml) and 1 drop DMF was added. The reaction mixture was cooled to 0°C and oxalylchloride (0.20 ml, 2.3 mmol) was added dropwise. After stirring for 1 hour at 0°C, the solvent was removed on the rotary evaporator. The acid chloride was dissolved in DCM (20 ml) and 5.7 ml of a 2 M solution of methylamine in THF was added dropwise. The reaction mixture was stirred for 0.5 hour. Water (20 ml) and DCM (25 ml) were added. After separating the layers, the water layer was extracted with DCM (2x 25 ml). The combined organic layers were washed with water (20 ml) and brine (20 ml). The organic layer was dried over Na2SO4 and the solvent was removed on the rotary evaporator. This yielded 593 mg solid, which was stirred in Et2O and some MeOH. The white solid was isolated, filtered and dried. This yielded 424 mg (1.1 mmol, 48%) with a purity of 95% according to HPLC [MS m/z 383.2].
EXAMPLES 4A and 4C:
No. 4.A. 4-(3-Hvdroxv-17-oxo-estra-1.3.5(1 OVtrien-15B-vn-N-methvl-butvramide (VIB-3a)
No. 4.C. 4-(3-Benzvloxv-17-oxo-estra-1.3.5{10^-trien-15B-vl)-N-methvl-butvramlde (VIB-3a)
The individual steps in the synthesis of the examples No. 4A (compound (VIB-3a)-4A) and No. 4C (compound (Vl|3-3c)-4C) are depicted in the following scheme 20 (according to general flow diagram Ib).
SCHEME 20

Starting with the free acid building block of formula IVp-3c, the corresponding acid chloride was prepared using oxalylchloride and this was converted into the amide (VJ-B3c)-4C (y = 26%). Finally .this amide was debenzylated to yield compound (VIB-3a)-4A (y = 13%) as a white solid with a purity of 83% (mixture of a and B isomer).
Detailed Synthesis
No. 4C: 4-(3-Benzvloxv-17-oxo-estra-1.3.5(10Vtrien-15B-vl)-N-methvl-biitvramide (VIB-3cV4C

The acid building block IVB-3c (1.9 g, 4.4 mmol) was dissolved in DCM (40 ml) and 1 drop DMF was added. The reaction mixture was cooled to 0°C and oxalylchloride (0.38 ml, 4.4 mmol) was added dropwlse. After stirring for 1 h at 0°C, the solvent was removed on the rotary evaporator. The acid chloride was dissolved in DCM (20 ml) and 13.1 ml of a 2 M solution of methylamine in THF was added dropwise. The reaction mixture was stirred overnight. To the light yellow mixture was added water (40 ml) and DCM (50 ml) were added. After separating the layers, the water layer
was extracted with DCM (2x 40 ml). The combined organic layers were washed with water (40 ml) and brine (40 ml). The organic layer was dried over Na2SO4 and the solvent was removed on the rotary evaporator. This yielded 1.4 g solid, which was purified by column chromatography (42 g SiO2, toluene/acetone: 3/1). This yielded 509 mg (11.2 mmol, 26%) of the compound (Vlp-3c)-4C as a yellow/white solid with a purity of 91% according to HPLC.
(Figure Removed)
No. 4A: 4-{3-Hvdroxv-17-oxo-estra-1,3.5(10Hrien-15B-vn-N-methvl-utvramide (VIB-3aV4A

The compound (Vlp-3c)-4C (509 mg, 11.2 mmol) was dissolved MeOH (75 ml) and N2was bubbled through for a few minutes. Pd/C (500 mg) was added and a H2 balloon was placed on the flask. The mixture was stirred overnight. The mixture was then filtered over Cellte and the MeOH was removed on the rotary evaporator until crystallization started. The white precipitate was filtered off and dried. This purification yielded 54 mg (0.146 mmole) of the compound (VI|3-3a)-4A (13%) as a mixture of a and p isomer, with a purity of 83% according to HPLC [MS m/z 369.1].
i
EXAMPLES 5 to 35
A variety of formula I compounds (examples 5 to 35), in which X represents a bond, A represents CO, Y represents NR4, n is 3, R1 represents CH3, and C15 is substituted in the p position, was prepared by parallel chemistry using a reaction as shown in the following scheme 21 (according to general flow diagram Ib):
SCHEME 21
(Figure Removed)A mixture of 0.13 mmol of the acid building block of formula (IVp-3b), 0.19 mmol of the respective amine (R2-NH2 or R2-NH-R4), 0.19 mmol hydroxybenzotriazole, 0.19 mmol N-methylmorpholine and 0.19 mmol EDCI were dissolved in DCM and stirred for 24h at RT. DCM was evaporated and replaced by EtOAc. The organic layer was washed twice with water. If necessary the material was purified by flash chromatography. The material thereafter was analysed by LC-MS.
The following group of compounds was prepared by this method (table 1):
Table 1: Compounds of the formula Vl|3-3b, wherein R4 is H and R2 is varied, and with the general name N-"R2"-4-(3-methoxy-17-oxo-estra-1,3,5(10)-trien-15-yl)-butyramide:

(Table Removed)EXAMPLES 36 to 38
Furthermore, the following compounds No. 36-38 of general formula (Vl(3-3a) were prepared by debenzylation of the acid building block (IVp 3c) by the method described for the synthesis of Example No. 4A but using THF as solvent and subsequent reaction of the obtained acid building block (IV|3 3a) with the correspondent amine according to the method described in SCHEME 21.
No. 36: 4-f3-Hvdroxv-17-oxo-eslra-1.3.5f 10Vtrien-15|3-vn-N-[2-f7-methvl-1 H-indol-3-vn-ethvl]-butvramide (VIB-3aV36
(solvent dDMSO): 16.6, 17.15, 25.33, 26.09, 28.84, 29.63, 33.47, 33.54, 35.15, 35.6, 39.24, 39.45, 41.97, 43.85, 46.28, 51.76, 112.22, 112.58, 114.83, 115.71, 118.28, 120.27, 121.26,122.09,125.58,126.8, 130.15,135.64, 136.99,154.94,171.76,219.82 pprh.
No. 37: N-f2.4-Difluoro-benzvl)-4-(3-hvdroxv-17-oxo-estra-1.3.5f10)-trien-15B-vlVbutvramicle (VIB-3aV37

LC-MS: MH+ 482; rt 5.50 min; fragments: M-17: 464; M-17:464; M-287:194; M-324:157; M-354:127
No. 38: N-Benzvl~4-(3-hvdroxv-17-oxo-estra-1.3.5(10)-frlen-15|3-vlVN-methvl-butvramlde (VIB-3aV-38

(Figure Removed)Mp: 160-162 °C
LC-MS: MH+ 560. R15.77 min
C13-NMR: 221.23, 173.42/172.95 (amide rotamer), 154.13, 137.92, 13728/136.53 (amide rotamer), 131.88, 128.99, 128.62,128.02.127.72/127.43 (amide rotamer), 126.20, 126.00,115.34, 112.80, 53.48/50.97 (amide rotamer), 52.84, 47.15, 44.51, 42.76/42.72 (amide rotamer), 35.99, 34.89/34.38 (amide rotamer), 34.33/34.27 (amide rotamer), 33.89, 33.36/332.83 (amide rotamer), 30.85,29.29, 26.70,25.53, 25.41/25.17 (amide rotamer). 17.72/17.68 (amide rotamer)
101 EXAMPLE 39: N-Benzvl-4-(3-hvdroxv-17-oxo-estra-1.3.5f10Vtrlen-15a-vh-birtvramlde (Vla-3a)- (Figure Removed)Compound (Vla-3a)-39 was prepared in a two step synthesis starting from the ketal protected acid building block XLVIIla-3a as depicted in the following scheme 22. In the first step, the acid building block XLVIIIa-3a is reacted with benzylamine using EDCi, HOBt as coupling reagent and subsequent purification. Deprotection of the ketone gave the desired compound (Vlex-3a).
SCHEME 22 (Figure Removed)
Ketal of N-Benzvl-4-(3-hvdroxv-17-oxo-estra-1.3.5(1 OVtrien-15a-vO-butvramide OCLIXcc-3al
To a solution of carboxylic acid XLVIHa-3a (0.266 g, 0.664 mmol) in THF (12.4 ml) were added benzylamine (85 mg, 796 mmol), N-methylmorpholine (218 uL, 1.98 mmol), HOBt (107 mg, 793 mmol) and EDCi (152 mg, 796 mmol). The reaction mixture was stirred for 32h at RT, concentrated and taken up in CH2Q2 (50 mL) and washed with 1N aq. HCI. The organic layer was dried over Na2SO4 and concentrated to yield 0.353g of crude benzylamide XLIXa-3a Purification was performed by column chromatography (eluent: heptane / ethytacetate 1:1, Rf = 0.4) to give 0.220 g (67 %) of benzylamide XLIXoc-3a as a nearly white oil.
N-Benzvl-4-(3-hvdroxv-17-oxo-estra-1.3.5(10)-trien-15(X-vh-butvramideA/la-3aV39
To a solution of benzylamide XLIXcc-3a (0.220 g, 0.44 mmol) in THF (11 mL) was added 4N aq. HCI (2.8 mL). After 1 h at RT CH2Cl2 (25 mL) and H2O (25 mL) were added. The organic layer was dried over Na2SC>4 and concentrated to yield 0.178g white foam. Purification was performed by column chromatography (eluent ethylacetate, Rf = 0.8) to give 0.170 g white solid. The solid was further purified by stirring in Et2O (50 mL) for 30 min. The solid was filtered off, washed with Et2O
102
(20mL) and dried to give 120mg (60%) pure (Vla-3a)-39 as a white solid (purity 95+% based on LC-MS).
C" NMR: (solvent CDCI3): 219.6; 172.5; 153.7; 138.2; 137.6; 131.8; 128.8(*2); 127.9(*2); 127.7; 127.0; 115.0; 113.1; 54.8; 50.4; 44.2; 43.8; 43.1; 39.7; 36.8; 36.3; 36.1; 31.6; 29.8; 27.8; 26.5; 24.4; 15.7 ppm
EXAMPLE40 3-Hvdroxv-15a-(4-morpholin-4-vl-4-oxo-butvlVes1ra-1.3.5^10Vtiien-17-one^Vla-3aV-40
(Figure Removed)Furthermore, the following compound No. 40 of general formula (Vla-3a) representing the a stereoisomer of compound No. 1 was prepared according to the method displayed in SCHEME 22 starting with the acid building block of formula (XLVIIIcc-3a) and the appropriate amine (mor-pholine), and subsequent ketal cleavage according to the procedures described for the synthesis of compounds No. 39.
C13 NMR: (solvent CDCI3): 219.7; 171.7; 154.2; 137.5; 131.3; 126.82;115.1; 113.14; 66.9; 66.8; 54.7; 50.4; 46.1; 44.1; 43.1; 42.1; 39.6; 36.3; 36.1; 33.2; 31.6; 29.8; 27.75; 26.5; 23.8; 15.7 ppm
EXAMPLES 41 to 309 - amides
A variety of formula I compounds (examples 41 to 309), in which X represents a bond, A represents CO, Y represents NR4, R1 represents CH3, n is 0 (Scheme 23) or 1 (Scheme 24), and C15 is substituted in the a position were prepared by parallel chemistry using a reaction as shown in the following reaction schemes 23 and 24 (according to general flow diagram la):
SCHEME23
(Figure Removed)Preparation of the acid chlorides V-Ob and V-1b:
1.714g of compound IV-Ob (5.219 mmol) were dissolved in 85ml toluene, 55.2ml of a 0.189 M SOCI2 solution (10.438 mmol SOCI2), which was prepared by dissolving 5.613 g SOCI2 in toluene till 25 ml solution was obtained, were added and stirred for 17 h at RT. Since the reaction was still not completed, again 55.2 ml of a 0.189 M SOCI2 solution (10.438 mmol SOCI2) were added and stirred for further 24 h at RT. The analysis by LC-MS shows a conversion of 96% of the educt to the add chloride V-Ob (detection with pyrolidine).
1.670g of compound IV-1b (4.877 mmol) were dissolved in 85ml toluene, 51.6ml of a 0.189 M SOCI2 solution (9.754 mmol SOCI2), which was prepared by dissolving 5.613 g SOCI2 in toluene till 25 ml solution was obtained, were added and stirred for 17 h at RT. The analysis by LC_MS shows a conversion of 99% of the educt to the acid chloride V-1b (detection with pyrolidine).
Both solutions were evaporated at 40°C> using the rotavapor. The oily residues were dissolved in THF at a concentration of 0.25 M.
Preparation of the amides Vl-Ob and Vl-1b:
DIPEA was dissolved In THF to yield a 0.25 M solution. Stock solutions (B) of different amines R2NH2 and R2NHR* are prepared in THF at a concentration of 0.25 M. The reactions were carried out in a 24 well format In each well 100 ul of the respective acid chloride V-Ob or V-1b were mixed with 100 ul of a amine solution (B) and with 100 pi of the DIPEA solution. The reaction mixtures in the 24 well plates were allowed to react for 17 h at 30°C with shaking and for additional 48 h at 15°C with shaking. The solutions were evaporated at40°C for 180 min with final pressure of 5 mbar using the Gene Vac. To each oily residue were added 1000 ul of a 5% NaHCO3 solution. The solution was extracted two times with 1.5 ml of EtOAc, and the obtained extracts were washed two times with 500 ul of water. The washed EtOAc-solut'ons were transferred into collection vials and then evaporated In the GeneVac under the same conditions as above. The obtained products were analyzed by ESI-MS.
The following groups of compounds were prepared by this method (tables 2 to 4 for n = 0, and tables 5 to 7 for n = 1):
Table 2: Compounds of the formula Vl-Ob, wherein R4 is H and R2 is varied, of the general name 3-Methoxy-17-oxo-estra-1,3,5(10)-trien-15-carboxylic acid "R^-amide:

(Table Removed) (Figure Removed)120
Detailed Synthesis
Step 1:0.11 mmol Isocyanate (R2—N=C=0) were dissolved in 2 ml ACN. To this solution, 2 mi of the amine building block of formula XV-1a orXXXVHMa (0.09 mmol) dissolved in ACN were added. The reaction mixture was stirred at RT for 24 h. In order to remove unreacted isocyanate or amine, polymer bound isocyante and trisamine were added. Again the reaction mixture was stirred for 24 h at RT. The solid material was removed by filtration. The solvent was evaporated in a vacuum centrifuge. Without further purification this material was used in the next step.
Step 2: The material obtained in step 1 was dissolved in 2 ml acetone. 2 mg of pTsOH were added. The reaction mixture was kept in a microwave oven in a sealed tube at 150°C for 3 minutes. Thereafter, the solvent was removed in a vacuum centrifuge. The obtained material was separated between EtOAc and NaHCO3 solution. The organic layer was collected and evaporated again. The material thereafter was analysed by LC-MS.
Two groups of compounds according to formula XVlMb were prepared by this method as depicted in the following tables 15 and 16.
Further compounds of formula I, in which X: represents NH, A represents CO, Y represents NH and n represents 3 or 4 and C15 is substituted in the {3 position, were prepared by parallel chemistry using a reaction as shown in the following schemes 29A and 29B (according to general flow diagram Vb):
SCHEME 29A
Detailed Synthesis
0.11 mmol Isocyanate (Rz—N=C=0) were dissolved in 2 ml ACN. To this solution, 2 ml of the amine building block of formula XXIX-3b or XXIX-4b (0.09 mmol) dissolved in ACN and approximately 40 mg polymers bound diisopropylethylamine were added. The reaction mixture was stirred at RT for 24 h. In order to remove unreacted isocyanate or amlne, polymer bound isocyante and trisamine were added. Again the reaction mixture was stirred for 24 h at RT. The solid material was removed by filtration. The solvent was evaporated in a vacuum centrifuge. The obtained material was analyzed by LC-MS.
Two groups of compounds according to formula XVII-3b and XVII-4b were prepared by this method as depicted in the following tables 17 and 18.
(Figure Removed)Detailed Synthesis
Step 1: TerL butyl alcohol (6.5 ml = 5.13 g = 69.3 mmol) in 30 ml DCM is added dropwise to a cold solution of 6.0 ml (9.76 g = 68.9 mmol.) chlorosulfonyl isocyanate in 40 nil DCM. After 30 min the mixture is diluted with DCM up to 100 ml to get a 0.854 molar stock solution. (18.29 g /100 ml; density 1.318 g/ml; LC-MS found the mass M+H 216). 2 ml of this solution are added to the amine building block of formula XV-1b (0.5 mMol) and (1 mMol) triethylamine dissolved in DCM at 0°C. The mixture is stirred overnight at RT. The reaction mixture is worked up by liquid/liquid extraction with DCM/water. The crude product is purified on silica gel with DCM as eiuerrt.
Step 2:0.1 mMol of the Boc-protected suKamide obtained in step 1 are dissolved in acetone. 0.3 mMol K2CO3 and 0.1 mMol bromo-alkane (or correspondent bromoreagent) are added. The reaction Is kept at 60°C for 24 h. After filtration and concentration the crude mixture is purified by column chromatography on silica gel.
Step 3: The material obtained in'step 2 is dissolved in 2 ml acetone. 2 mg of p-TosOH were added. The reaction mixture is kept in a microwave oven in a sealed tube at 150°C for 3 minutes. Thereafter the solvent is removed in a vacuum centrifuge. The obtained material is separated between EtOAc and NaHCO3 solution. The organic layer is collected and evaporated again. Thereafter the material is analysed by LC-MS.
A group of compounds according to formula XlX-25 may be prepared by this method; the compounds listed in Table 12represent reaction products of a compound of formula XV-2b with a bromo-reagent (R2—Br).
Table 12: Compounds of the formula XIX-2b, which are prepared by reaction with variable R2-Br compounds:

(Table Removed)
EXAMPLES 538 and 539 - carbamates
Two compounds of formula I, in which X represents NH, A represents CO, Y represents O, n represents 1, and C15 is substituted in the a position, were prepared using a reaction as shown in the following scheme 31 (according to general flow diagram VII):SCHEME
EXAMPLES 540 to 543 - sulfamates
A variety of compounds of formula I, in which X represents NH, A represents SOZ, Y represents O, and n represents for example 1, and C15 is substituted in the a position, may be prepared by parallel chemistry using a reaction as shown in the following scheme 32 (according to general flow diagram VIII) (Figure Removed)
Step 1: To a solution of 0.132 mmol chlorosulfonic acid ester (R2-O-SOz-CI) in 2 ml DCM 0.112 mmol of the amine building block XV-1b, dissolved in 2 ml DCM, and an excess of polymer bound morpholine are added subsequently at -40°C. After an hour the reaction mixture is heated to 20°C and left over night. To remove unreacted chlorosulfonic acid ester and amine polymere bound isocyanate and trisamine are added. Again the reaction mixture is stirred for 24 h at RT. The solid material is removed by filtration. The solvent is evaporated in a vacuum centrifuge. Without further purification this material is used in the next step.
Step 2: The material obtained in step 1 is dissolved in 2 ml acetone. 2 mg of p-TosOH are added. The reaction mixture is kept in a microwave oven In a sealed tube at 150°C for 3 minutes. Thereafter the solvent is removed in a vacuum centrifuge. The obtained material Is separated between EtOAc and NaHCO3 solution. The organic layer Is collected and evaporated again. The material thereafter is analysed by LC-MS.
A group of compounds according to formula XXIMb may be prepared by this method; the compounds represent reaction products of a compound of formula XV-1b with a chlorosulfuric acid ester (R2-O-SO2^CI). Table 14 shows the number of the reaction products together with the corresponding chlorosulfuric acid ester (R2-0-SO2-CI).
Table 14: Compounds of the formula XXII-1b, prepared by reaction with (R2-O-SO2-CI)
EXAMPLES 544 to 570 - "retro'-amides
A variety of formula I compounds, in which X represents -NH, A represents CO, Y represents a bond, n represents 1, R1 represents CH3, and R2 is varied, and C15 is substituted in the a position, were prepared by parallel chemistry using a reaction as shown in the following scheme 33 (according to general flow diagram IXa). The group of compounds prepared by this method is listed in table 23.
SCHEME 33 XXIIMb R2"
Detailed Synthesis
Step 1: 0.132 mMol of the appropriate acid chloride R2-CO-CI were dissolved in 2 ml DCM. To this solution 2 ml of the amine building block of the formula XV-1b (0.112 mMol) dissolved in DCM and 160 mg morpholine polymer bound were added. The reaction mixture was stirred at RT for 48 h. To remove unreacted acid chloride or amine polymer bound isocyanate and trisamine had been added. Again the reaction mixture was stirred for 24 h at RT. The solid material was removed by filtration. The solvent was evaporated in a vacuum centrifuge. Without further purification this material was used in the next step.
Step 2: The material obtained in step 1 was dissolved in 2 ml acetone. 2 mg of p-toluene sul-fonic acid were added. The reaction mixture was kept in a microwave oven in a sealed tube at 150"C for 3 minutes. Thereafter the solvent was removed in a vacuum centrifuge. The obtained material was separated between EtOAc and NaHC03 solution. The organic layer was collected and evaporated again. The material thereafter was analysed by LG-MS.
ybiethyl Detailed Synthesis:
0.132 mMol of the appropriate acid chloride R2-CO-CI were dissolved in 2 ml DCM. To this solution 2 ml of the amine building block of the formula XXIXo-3a, XXIXp-3b, or XXIXp-4b (0.112 mMol) dissolved in DCM and 160 mg morpholine polymer bound were added. The reaction mixture was stirred at RT for 48 h. To remove unreacted acid chloride or amine polymer bound isocyanate and trisamine was added. Again the reaction mixture was stirred for 24 h at RT. The solid material was removed by filtration. The solvent was evaporated in a vacuum centrifuge. The material thereafter was analysed by LC-MS.
Three groups of compounds according to general formulas XXIIIar3a, XXIIIp-3b and XXIIIp-4b were prepared by this method as depicted in the following tables 25, 26 and 27, respectively.
(Table Removed)
Step 2: The material obtained in step 1 was dissolved in 2 ml acetone acetone/ methanol/ water (1:10:0.1). 2 mg of p-TosOH were added. The reaction mixture was kept in a microwave oven in a sealed tube at 150°C for 3 minutes. Thereafter the solvent was removed in a vacuum centrifuge. The obtained material was separated between EtOAc and NaHCO3 solution. The organic layer was collected and evaporated again. The material thereafter was analysed by LC-MS.
Two groups of compounds according to formula XXIV-1a and XXIV-1a* were prepared by this method (Tables 28 and 29).
(Table Removed)
Detailed Synthesis
According to the general procedure described for SCHEME 11, the copper reagent was prepared from magnesium (0.212 g, 8.72 mmol), 3-phenoxybutylbromid (0.917 g, 4.00 mmol), Cul (0.133 mg, 0.70 mmol) and DMPU (0.45 mL, 3.73 mmol) in THF. A mixture of the 15,16-unsaturated estron Xb (0.282 mg, 1.00 mmol) and TMSCI (0.32 mL. 2.5 mmol) in THF was added dropwise. The reaction mixture was allowed to reach RT and was stirred over night After work-up and hydrolysis of the silyl ether the crude product was purified by column chromatography (SiO2, cydohexane/ ethyl acetate 10:1) to yield (XXXp-4b)-836 (0.240 g, 55 %).
LC-MS (ES+): rt7.77 mln, m/z(rel Intens) 450 [(M+NH4f, 100 %]
BIOLOGICAL TESTING MATERIALS AND METHODS
1. Inhibition of the 17B-hvdroxvsteroid dehvdrooenase type 1 enzyme
17|3-HSD1 purification: Recombinant baculovirus was generated by the "Bac to Bac Expression System" (Invitrogen). Recombinant bacmid was transfected to Sf9 insect cells using "Ceilfectin Reagent" {Invitrogen). 60h later cells were harvested; the microsomal fraction was isolated as described by Puranen etal. 1994. Aliquots were stored frozen until determination of enzymatic activity.
Assay - Inhibition of recombinant human 17(3-hydroxysteroid dehydrogenase type 1: Recombinant protein (0.1ug/ml) was incubated in 20 mM KH2PO4 pH 7.4 with 30 nM 3H-estrone and 1 mM NADPH for 30 min at RT, in the presence of potential inhibitors at concentrations of 1 uM or 0.1 pM. Inhibitor stock solutions were prepared in DMSO. Rnal concentration of DMSO was adjusted to 1 % in all samples. The enzyme reaction was stopped by addition of 10 % tri-chloroacetic acid (final concentration). Samples were centrifuged in a microtiter plate at 4000 rpm for 10 min. Supsmatants were applied to reverse phase HPLC on a Waters Symmetry C18 column, equipped with a Waters Sentry Guard column. Isocratic HPLC runs were performed at RT at a flow rate of 1 ml/min of acetonitrile:water 48:52 as running solvent Radioactivity was monitored in the eluate by a Packard Flow Scintillation Analyzer. Total radioactivity for estrone and estradiol were determined in each sample and percent conversion of estrone to estradiol was calculated according to the following formula:
% conversion = 100 *
{(cpm estradiol in sample with inhibitor) / [(cpm estrone in sample with inhibitor) + (cpm estradiol in sample with inhibitor)]}
{(cpm estradiol in sample without inhibitor) / [(cpm estrone in sample without inhibitor) + (cpm estradiol in sample without inhibitor)]}.
Percent inhibition was calculated as follows: % Inhibition = 100 - %conversion
The values "% inhibition" were determined for exemplified compounds, and the results are summarized in Table 42.
(Table Removed)
2. Estrogen Receptor Binding Assay
The binding affinity of the compounds of the invention to the estrogen receptor a and to the estrogen receptor p may be determined according to the in vitro ER binding assays described by Koffmann et al. [Koffmann et al. (1991) J. Steroid. Biochem. Mol. Biol. 38:135]. Alternatively, an estrogen receptor binding assay may be performed according to international patent application PCT/US/17799 (published as WO 00/07996).
3. Estrogen Receptor Transactivation Assays
Compounds of the invention showing binding affinity towards the estrogen receptor may be further tested with regard to their individual estrogenic or anti-estrogenic potential (agonistic binding or antagonistic binding to the ERa or ERjJ). The determination of the estrogen receptor agonist activity may be performed according to an in vitro assay system using the MMTV-ERE-LUC reporter system which is for example described within US patent application No. 10/289079 (published as US 2003/0170292):
To assay estrogen receptor agonist activity, Hela cells are grown In 24-well microtiter plates and then transiently co-transfected with two plasmids using lipofedamine. The first plasmid comprises DNA encoding human estrogen receptor (either ER-alpha or ER-beta), and the second plasmid comprises an estrogen-driven reporter system comprising: a luciferase reporter gene (LUC) whose transcription is under the control of upstream regulatory elements comprising 4 copies of the vitellogenin estrogen response element (ERE) cloned into the mouse mammary tumor virus (MMTV) promoter (the full name for the reporter system being "MMTV-ERE-LUC"). Cells are exposed to the compounds of the invention in RPMI 1640 medium, supplemented with 10% char-
coal-treated fetal calf serum, 2 rnM L-glutamine, 0.1 mM non-essential amino acids and 1 mM sodium pyruvate for 42-48 hours at 37°C in a 5% carbon dioxide incubator. Concurrently, cells exposed to estradiol (1 nM) serve as positive controls. Replicate wells exposed to the solvent in which the compounds of the invention are dissolved (i.e. ethanol or methanol) are used as negative controls. After the 42-48.hr incubation period, cells are rinsed with phosphate buffered saline (PBS), lysis buffer (Promega Corp) is added, and cell lysates are collected for measurement of luciferase activity with a luminometer. Estrogenic activity of the compounds of the invention is expressed as fold-increase in luciferase activity as compared to that observed in negative control cells.
Alternatively, the determination of the estrogen receptor transactivation activity (estrogenicity assay or agonist assay) and of the inhibitory potency of transactivation activity (anti-estrogenicity assay or antagonist assay) may be performed according to international patent application PCT/US/17799 (published as WO 00/07996).
CITED LITERATURE
• Adamski J & Jakob FJ (2001) "A guide to 17β-hydroxysteroid dehydrogenases", Molecular
and Cellular Endocrinology, 171:1-4
• Koffmann B et al. (1991) J. Steroid. Biochem. Mol. Biol. 38:135
• Labaree DC et al. (2003) "Synthesis and Evaluation of B-, C- and D-rlng substituted estradiol
carboxylic acid esters as locally active estrogens" J. Med. Chem. 46:1886-1904
• Labrie F et al. (2000) "Role of 17 beta-hydroxysteroid dehydrogenases in sex steroid forma
tion in peripheral intracrine tissues" Trends Endocrinol Metab., 11:421-7
• Labrie F et al. (1997) The key role of 17 beta-hydroxysteroid dehydrogenases in sex steroid
biology." Steroids, 62:148-58
• Nambara T et al. (1976) "Synthesis of Estetrol Monoglucuronides" Steroids 27:111 -122
• Reliefer JD & Poirier D (1996) "Synthesis and evaluation of estradiol derivatives with 16o-
(bromoalkylamide), 16o(bromoalkyl) or 16cx-(bromoa!kynyl) side chain as inhibitors of 17β-
hydroxysteroid dehydrogenase type 1 without estrogenic activity" Bioorg Med Chem,
4(10):1617-1628.
• Poirier D (2003) "Inhibitors of 17 beta-hydroxysteroid dehydrogenases" Curr Med Chem.
10:453-77
• Poirier D et al. (1998) "A 6p-(Thiaheptanamide) Derivative of Estradiol as inhibitor of 17(5-
Hydroxysteroid Dehydrogenase Type 1", J. Steroid Biochem. Molec. Biol., 64:83-90
• Poirier D et al. (1996) "D-Ring alkylamine derivatives of estradiol: effect on ER-binding affin
ity and antiestrogenic activity" Bioorg Med Chem Lett 6(21):2537-2542.
Poirier D et al. (1991) "Synthesis of 17β-estradiol derivatives with N-Butyl, N-methyl alkyla-mide side chain at position 15." Tetrahedron, 47(37):7751-7766
Sam KM et al. (1998) "C16 and C17 Derivatives of Estradiol as Inhibitors of 17(3-Hydroxysteroid Dehydrogenase Type 1: Chemical Synthesis and Structure-Activity Relationships", Drug Design and Discovery, 15:157-180
Tamaya et al. (1985) "Comparison of cellular levels of steroid receptors in uterine leiomyoma and myometrium." Acta Obstet Gynecol Scand., 64:307-9
Tremblay MR & Poirier D (1998) "Overview of a Rational Approach to Design Type I 17£-Hydroxysteroid Dehydrogenase Inhibitors Without Estrogenic Activity: Chemical Synthesis and Biological Evaluation", J. Steroid Biochem. Molec. Biol., 66:179-191 WO 03/017973 - A METHOD OF TREATING BENIGN GYNAECOLOGICAL DISORDERS AND A DRUG DELIVERY VEHICLE FOR USE IN SUCH A METHOD
WO 2004/080271 - METHOD FOR PROGNOSTICATING THE PROGRESS OF BREAST CANCER AND COMPOUNDS USEFUL FOR PREVENTION OR TREATMENT THEREOF WO 2004/085345 - 15a-SUBSTITUTED ESTRADIOL CARBOXYUC ACID ESTERS AS LOCALLY ACTIVE ESTROGENS WO 2004/085467 - Compound








We claim:
1. A 3,15-substituted estrone compound of general formula 1.
(Formula Removed)
wherein
(i) X represents:
(a) a bond
(b) -NR3-, or
(c) -O-; A represents:

(a) -CO-, or
(b) under the proviso that X represents -NR3-, A represents -SO2-; Y represents:

(a) -NR4-
(b) -O-, under the proviso that X represents a bond or -NR3-,
(c) a bond,
(d) -NH-SO2-, under the proviso that X represents -NR3- and A represents -CO-,
(e) -NH-SO2 -NR4-, under the proviso that X represents -O-, or
(f) -NH-NR4-, under the proviso that X represents a bond;
or
(ii) -X-A-Y- together represent -O-;
and wherein
R1 and R3 are independently selected from:
(a) -H,
(b) -(C1-C6)alkyl, which is optionally substituted with halogen, nitril, -OR6, -SR6, or
-COOR6; the number of said substitutents being up to three for halogen, and up to two for any combination of said halogen, nitril, -OR6, -SR6, or -COOR6 moieties,
(c) -phenyl, which is optionally substituted with halogen, nitril, -OR8, -SR6, -R8, or -COOR8, the number of said substituents being up to perhaio for halogen, and up to two for any combination of said halogen, nitril, -OR8, -SR8, -R8 or -COOR8 moieties,
(d) -(C1-C4)alkyi-phenyl, in which the alkyl portion is optionally substituted with up to.three halogens; and the phenyl portion is optionally substituted with halogen, nitril, -OR8, -SR8, -R6 or -COOR8, the number of substituents on said phenyl portion being up to per¬haio for halogen, and up to two for any combination of said halogen, nitril, -OR6, -SR8, -R8 or-COOR6 moieties,
R2 and R4 are Independently selected from:
(a) -H, wherein if X represents a bond, A represents -CO- and Y represents -O- or a bond, then R2 is different from -H,
(b) -(C1-C12)alkyl, optionally substituted with up to five substituents independently selected from the group consisting of halogen, hydroxy!, thiol, nitrite, alkoxy, aryloxy, arylalkyioxy, amino, amido, alkylthio, aryithio, arylalkylthio, sulfamoyl, sulfonamide, acyl, carboxyi, acylamlno,
aryl wherein aryl is optionally substituted with up to three substituents independently se¬lected from the group consisting of halogen, hydroxy!, (C1-C6)alkoxy, (C1-C6)alkyl, halogenated {C1-C6)alkyl, halogenated (C1-C6)alkoxy, carboxyl-(C1-C6)alkyl, thiol, nitrite, sulfamoyl, sulfonamide, carboxyl, aryloxy, arylalkyloxy, (C1-C6}alkylthio, aryl¬thio, arylalkylthio, amino, amido, acyl, acylamino and heteroaryi; or which aryl is optionally substituted by two groups which are attached to adjacent carbon atoms and are combined into a saturated or partly unsaturated cyclic 5, 6, 7, or 8 mem-bered ring system, optionally containing up to three heteroatoms, such as N, O or S, the number of N atoms being 0-3 and the number of O and S atoms each being 0-2;
heteroaryl, wherein heteroaryi is optionally substituted with up to three substituents inde¬pendently selected from the group consisting of halogen, hydroxy!, (C1-C6)alkoxy, (C1-Cs)a(kyl, halogenated (C1-C6)alkyl, halogenated (C1-C4)alkoxy, carboxyl-(C1-C6)alkyl, thiol, nitrile, sulfamoyi, sulfonamide, carboxyi, aryioxy, arylalkyioxy, (C1-C8)alkylthio, aryithio, arylalkylthio, amino, amido, acyl, acylamino, aryl-(C1-C4)-alkyl and aryl;
whereby each aryl group is optionally substituted with up to three substituents in¬dependently selected from the group consisting of hydroxy!, halogen, (C1-C6)alkoxy, (C1-C6)alkyl, halogenated {C1-C6)alkyl and halogenated (C1-C6}alkoxy; and
cycloheteroalkyl, which cycloheteroaikyl group is optionally substituted with up to three substituents independently selected from the group consisting of oxo, (C1-C8)-alkyi, aryl, aryl-(C1-C4)-alkyl, hydroxyl. (C1-C6)alkoxy, carboxyl-(C1-C6)alkyl, thiol, nitrile,
sulfamoyl, sulfonamide, carboxyl, aryloxy, arylalkyloxy, (C1-C6)alkylthio, arylthio,
arylalkylthio, amino, amido, acyl, and acylamino,
whereby each aryl group is optionally substituted with up to three substituents in¬dependently selected from the group consisting of hydroxyl, halogen, (C1-C4)-alkyl, (C1-C4)-alkoxy, halogenated (C1-C4)-alkyl, and halogenated (C1-C4)-alkoxy);
(c) acyl ~(C=O)-R', wherein R' represents hydrogen, (C1-C4)alkyl, aryl, or aryl-(C1-C4)alkyl, or heteroaryl-(C1-C4)alkyl; which aryl or aryl-(C1-C4)alkyl is optionally substituted in the aryl moiety with up to three substituents independently selected from the group consisting of hydroxyl, halo¬gen, {C1-C4)alkoxy, (C1-C4)alkyl or halogenated (C1-C4)alkyl;
(d)aryl
wherein aryl is optionally substituted with up to three substituents independently selected
from the group consisting of halogen, hydroxyl, (C1-C6)alkoxy, (C1-C6)alkyl, halo¬genated (C1-C6)alkyl, halogenated (C1-C6)alkoxy, carboxyl-(C1-C6)alkyl, thiol, nltrile, nitro, sulfamoyl, sulfonamide, carboxyl, aryloxy, arylalkyloxy, (C1-C6)aikylsulfonyl, arylsulfonyl. {C1-C6)alkylthio, arylthio, arylalkylthio, amino, amido, acyl, acylamino and heteroaryl; or
wherein aryl is optionally substituted by two groups which are attached to adjacent carbon
atoms and are combined into a saturated or partly unsaturated cyclic 5, 6, 7, or 8-membered ring system, optionally containing up to three heteroatoms, such as N, O or S, the number of N atoms being 0-3 and the number of O and S atoms each being 0-2;
(e) heteroaryl,
wherein heteroaryl contains at least one heteroatom, such as N, O or S and is optionally
substituted with up to three substituents independently selected from the group consisting of halogen, hydroxyl, (C1-C6)akoxy, {C1-C6)alkyI, halogenated (C1-C8)alkyl, halogenated (C1-C6)alkoxy, carboxyl-(C1-C6)alkyl, thiol, nitrite, sulfamoyl, sulfonamide, arylsulfoxy, carboxyl, aryloxy, arylalkyloxy, (C1-C6)alkylsulfonyl, aryl-sulfonyl. (C1-C6)alkylthio, arylthio, arylalkylthio, amino, amido, acyl, acylamino, aryl-(C1-C4)-alkyl and aryl,
whereby each aryl group Is optionally substituted with up to three substituents in¬dependently selected from the group consisting of hydroxyl, halogen, (C1-C6)a!koxy, (C1-C6)alkyf, halogenated (C1-C6)alkyl and halogenated (C1-C6)alkoxy; or
(f) cycloheteroalkyl,
wherein cycloheteroalkyl contains at least one heteroatom, such as N, O or S and is op¬tionally substituted with up to three substituents independently selected from the group consisting of oxo, (C1-C14)-alkyl, aryl, aryl-(C1-C4)-alkyI, hydroxyl, (C1-
C6)alkoxy, carboxyl-(C1-C6)alkyl, thiol, nitrite, sulfamoyl, sulfonamide, carboxyl, ary¬loxy, arylalkyloxy, (C1-C6)alkylthio, arylthlo, aryiaikylthio, amino, amido, acyl, and acylamino,
whereby each aryl group is optionally further substituted with up to three substitu¬ents independently selected from the group consisting of hydroxyl, halogen, (C1-C4)-alkyl, (C1-C4)-alkoxy, halogenated (C1-C4)-alkyl, and halogenated (C1-C4)-alkoxy;
or wherein, under the proviso that Y represents -NR4-, -NH-NR4- or -NH-SO2-NR4-,
R2 and R4 form together with the nitrogen atom, where R2 and R4 are attached, a heterocyclic 4-, 5-, 6-, 7- or 8-memberred ring, which is optionally saturated, partly unsaturated, or aromatic; which optionally contains up to three additional heteroatoms selected from N, O or S, the num¬ber of additional N atoms being 0,1,2 or 3 and the number of O and S atoms each being 0,1 or 2; and which ring is optionally part of a multiple condensed ring-system, wherein the ring or the ring-system is optionally substituted;
(i) with up to three substituents independently selected from the group consisting of (C1-C8)-alkyl, halogen, hydroxy), carboxyl, thiol, nitrite, (C1-C6)-alkoxy, carboxyl-(C1-C6)alkyl, ary¬loxy, arylalkyloxy, amino, amido, aJkylthlo, arylthio, aryiaikylthio, sulfamoyl, sulfonamide, aryl, aryi-(C1-C4)-alkyl heteroaryi, and cycloheteroalkyl,
wherein the (C1-C8)-alkyl group is optionally substituted with up to three substituents in¬dependently selected among hydroxyl, halogen, (C1-C4)-alkoxy, or halogenated (C1-C4)-alkoxy,
whereby the alkyl-chain of the (C1-C4)-alkoxy moiety Is optionally substituted with hydroxy!; wherein the aryl Is optionally substituted with up to three substituents independently se¬lected from the group consisting of hydroxy!, halogen, (C1-C4)-alky!. (C1-C4)-alkoxy, halogenated (C1-C4)-alkyl, halogenated (C1-C4)-alkoxy and carboxyi-(C1-C6)alkyl, or wherein the aryl moiety is optionally substituted by two groups which are attached to adjacent carbon atoms and are combined into a saturated or partly unsaturated cyclic 5, 6, 7, or 8 membered ring system, optionally containing up to three het-eroatoms, such as N, O or S, the number of N atoms being 0-3 and the number of O and S atoms each being 0-2;
wherein the heteroaryl is optionally substituted with up to three substituents independ¬ently selected from the group consisting of hydroxy), halogen, (C1-C4)-allcyl, (C1-C4)-alkoxy, halogenated (C1-C4)-a!kyl, halogenated (C1-C4)-alkoxy) and carboxyl-(C1-C6)alkyl;
wherein the cycloheteroaJkyl is optionally substituted with up to three substituents inde¬pendently selected from the group consisting of oxo, (C1-C6)-alkyl, aryl, aryl-(C1-C4)-alkyl, hydroxy!, (C1-C6)alkoxy, carboxyl-(C1-C6)alkyi, and carboxyl,
whereby each aryl group is optionally further substituted with up to three substitu¬ents independently selected from the group consisting of hydroxy!, halogen, (C1-C4)-alkyl, (C1-C4)-alkoxy, halogenated (C1-C4)-alkyl, and halogenated (C1-C4)-alkoxy); or
(ii) by two groups which are attached to the same carbon atom and are combined into a saturated or partly unsaturated cyclic 4, 5, 6, 7, or 8-membered ring system, optionally containing up to three heteroatoms, such as N, O or S, the number of N atoms being 0-3 and the number of O and S atoms each being 0-2,
whereby the cyclic ring system is optionally substituted by up to two substituents inde¬pendently selected from oxo, (C1-C6)-alkyl. aryl and aryl-(C1-C4)-alkyl;
R6 represents H, -(C1-C4)alkyl or halogenated -(C1-C4)alkyl; and
and wherein n represents
(a) 1,2, 3,4, 5 or 6, under the proviso that X represents -NR3- or -O- or under the proviso that -X-A-Y- represent -O- and R2 represents -H
(b) 0,1, 2,3,4, or 5, under the proviso that X represents a bond.
and all stereoisomers, including enantiomers, and pharmacologically acceptable salts thereoi
2. The compound as claimed in claim 1, wherein
R2 and R4 are independently selected from:
(a) -H. wherein if X represents a bond, A represents -CO- and Y represents -O- or a bond, then R2 is different from -H,
(b) -{C1-C12)alkyl, optionally substituted with up to five substituents independently selected from the group consisting of halogen, hydroxyl, nitrile, -O-R7; -O-Ar1, -O-{C1-C4)alkyl-Ar1, alkylamino, alkylamido, -S-R7, -S-Ar1, -S-(C1-C4)alkyl-Ar1, -(C=O)-OR8, aryl, het-eroaryl, and cycloheteroalkyl,
wherein the aryl Is optionally substituted with up to three substituents independently se¬lected from the group consisting of halogen, hydroxy!, (C1-C6)alkoxy, (C1-C6)alkyl, haiogenated (C1-C6)alkyl, halogenated (C1-C6)alkoxy, -(C1-C6)alkyl-(C=O)-OR8, nitrite, suifamoyl, -(C=0}-OR8, -O-Ar1, -O-(C1-C4)alkyl-Ar1, (C1-C4)alkylthio, -S-Ar1, -S-{C1-C4)aIkyl-Ar1 alkylamino, and alkylamido; or wherein the aryl is option¬ally substituted by two groups which are attached to adjacent carbon atoms and are combined into a saturated cyclic 5 or 6 membered ring system, optionally con¬taining up to three heteroatoms, such as N or 0, the number of N atoms being 0-3 and the number of O atoms each being 0-2;
wherein the heteroary) is optionally substituted with up to three substituents independ¬ently selected from the group consisting of halogen, hydroxy!, (C1-C6)alkoxy, (C1-C6)alkyl, halogenated (C1-C6)alkyl, halogenated (C1-C6)alkoxy, -{C1-C6)alkyl-(C=O)-OR8, nitrite, suifamoyl, -(C=OOR8. -O-Ar1, -O-(C1-C4)alkyl, (C1-C6)alkylthio, -S-Ar1, -S-{C1-C4)alkyl-Ar1, alkylamino, alkylamido, -{C1-C4)alkyl-Ar1 and Ar1; and
wherein the cycloheteroalkyl group is optionally substituted with up to three substituents Independently selected from the group consisting of oxo, (C1-C4)-alky!, Ar1-(C1-C4)alkyl-Ar1, hydroxy!, (C1-C6)alkoxy, -(C1-C6)alkyl-(C=O)-OR8, nitrile, -(C=O)-OR8, -O-Ar1, -O-(C1-C4)alkyl-Ar1, (C1-C6)alkylthio, -S-Ar1, -S-(C1-C4)alkyl-Ar1, alkylamino and alkylamido;
(c) aryl,
wherein aryl is optionally substituted with up to three substituents independently selected
from the group consisting of halogen, hydroxyl, (C1-C6)alkoxy) (C1-C6)alkyl, haio¬genated (C1-C4)alkyl, halogenated (d-djalkoxy, -(d-Ca)alkyl-(00)-OR8, nitro, nitrile, suifamoyl, -(C=O)-OR8, -(C=O)-R6, -O-Ar1, -O-(C1-C4)alkyl-Ar1, (C1-C6)alkylthio. -S-Ar1, -S-(C1-C4)alkyl-Ar1, (C1-C6)alkylsulfonyl, -SO2-Ar1, al¬kylamino, alkylamide, -NH-CO-R8. Ar1 and heteroary); or
wherein aryl is optionally substituted by two groups which are attached to adjacent carbon
atoms and are combined into a saturated cyclic 5 or 6 membered ring system, op¬tionally containing up to three heteroatoms, such as N or O, the number of N atoms being 0-3 and the number of O atoms each being 0-2;
(d) heteroaryl,
wherein heteroaryl is optionally substituted with up to three substituents independently se¬lected from the group consisting of halogen, hydroxyl, (C1-C6)alkoxy, (C1-C6)alkyl, halogenated (C1-C6)alkyl, halogenated (C1-C6)alkoxy, -(C1-C6)alkyl-{C=O)-OR8, nitrile, sulfamoyl, -(C=O)-OR8, -O-Ar1, -O-(C1-C4)alkyl-Ar1, (C1-C6)alkylthio, -S-Ar1, -S-(C1-C4)alkyl-Ar1, (C1-C6)alkylsulfonyl, -SOr-Ar1, alkylamino, alkylamido, -(C1-C4)alkyl-Ar1 and Ar1; or
(e) cycloheteroalkyl
wherein cycloheteroalkyl group is optionally with up to three substituents inde¬pendently selected from the group consisting of oxo, (C1-C8)-alkyl, Ar1,-(C1-C4)alkyl-Ar1, hydroxyl. (C1-C6)alkoxy, -(C1-C6)alkyl-(CO)-OR8, nitrite, -(C=O)-OR', -O-Ar1, -O-(C1-C4)alcyl-Ar1, (C1-C6)alkylthio, -S-Ar1, -S-(C1-C4)alkyl-Ar1, alkylamino and alkyJamido; wherein
R7 represents (C1-C6)alkyl, optionally substituted with up to three hydroxy groups In the alkyl chain or halogenated (C1-C6)alkyl,
R8 represents hydrogen, (C1-C4)alkyl, phenyl, or (C1-C4)alkyl-phenyl, wherein the phenyl-molety is optionally substituted with up to three substituents independently selected from the group consisting of hydroxyl, halogen, (C1-C4)a(koxy, (C1-C4)-alkyl, halogenated (C1-C4)alkyl and halogenated (C1-C4)alkoxy; and
AR1 represents phenyl or naphthyl, which sere optionally substituted with up to three substitu¬ents independently selected from the group consisting of hydroxyl, halogen, (C1-C4)-alkyl, (C1-C4)-alkoxy, halogenated (C1-C4)-alkyl, or halogenated (C1-C4)halkoxy;
or wherein, under the proviso that Y represents -NR4-, -NH-NR4- or -NH-SO2-NR4-,
the ring or ringsystem formed by R2 and R4 together with the nitrogen atom, where R2 and R4 are attached, is selected from the group consisting of
(Formula Removed)
wherein the ring or the ring-system is optionally substituted
(i) with up to three substituents independently selected from the group consisting of (C1-C8) alkyl, oxo, hydroxyl, (C1-C6)alkoxy, -(C1-C6)alkyl-(C=O)-OR8', nitrite, -(C=O}-OR8, -O-Ar2, -O-(C1-C4)alkyl-Ar2, (C1-C6)alkylthio, alkylamino, alkylamido, aryl, aryl-(C1-C4)alkyl, heteroaryl, and cycloheteroalkyl,
wherein the aryl and aryl-(C1-C4)alkyl group are optionally substituted in the aryl moiety with up to three substituents independently selected from the group consisting of hydroxyl, halogen, (C1-C4)-alkyl, (C1-C4)-alkoxy, halogenated (C1-C4)-alkyl, halo¬genated (C1-C4)-alkoxy and carboxy)-(C1-C4)aIkyl, or wherein the aryl moiety is op¬tionally substituted by two groups which are attached to adjacent carbon atoms and are combined into a saturated or partly unsaturated cyclic 5, 6, 7, or 8 mem-bered ring system, optionally containing up to three heteroatoms, such as N, O or
S, the number of N atoms being 0-3 and the number of O and S atoms each being 0-2; and
wherein the (C1-C8)-alkyl group is optionally substituted with up to three substituents in¬dependently selected among hydroxyl, halogen, halogenated (C1-C4)-alkoxy or (C1-C4)-alkoxy,
whereby the alkyl-chain of the (C1-C4alkoxy moiety is optionally substituted with up to three hydroxyl; wherein the heteroaryl is optionally substituted with up to three substituents independ¬ently selected from the group consisting of hydroxyl, halogen, (C1-C4)-alkyl, (C1-C4)-alkoxy, halogenated (C1-C4)-alkyl, halogenated (C1-C4)-alkoxy) and carboxyl-(C1-C6)alkyl; and
wherein the cycloheteroalkyl Is optionally substituted with up to three substituents Inde¬pendently selected from the group consisting of oxo, (C1-C6)-alkyl, hydroxyl, (C1-C6)alkoxy, -{C=O)-OR8, and -(C1-C8)alkyl-(C=O)-OR9; or
(ii) by two groups which are attached to the same carbon atom and are combined into a saturated or partly unsaturated cyclic 4, 5, 6, 7, or 8-membered ring system, optionally containing up to three heteroatoms, such as N, O or S, the number of N atoms being 0-3 and the number of O and S atoms each being 0-2,
whereby the cyclic ring system is optionally substituted by up to three substitutents inde¬pendently selected from oxo, (C1-C6)-alkyl, aryl and aryl-(C1-C4}-alkyl.
wherein
Ar2 represents phenyl or naphthyl, which are optionally substituted with up to three substitu¬ents independently selected from the group consisting of hydroxyl, halogen, (C1-C4)alkyl, (C1-C4)-alkoxy, halogenated (C1-C4)-alkyl, or haiogenated (C1-C4)-alkoxy
R9 represents hydrogen, (C1-C4)alkyl. phenyl, or (C1-C4)alkyl-phenyl; whereby the phenyl is optionally substituted with up to three substituents Independently selected from the group consisting of hydroxy], halogen, (d-d)alkoxy, (C1-C4)-alkyl. halogenated (d-d)alkyl and halogenated (C1-C4)alkoxy.
3. The compound as claimed in claim 2, wherein
R2 and R4 can be independently selected from:
(a) -H, wherein if X represents a bond, A represents -CO- and Y represents -O- or a bond, then R8 is different from -H,
(b) an alkyl group selected from
(i) -(C1-C6)alkyl, optionally substituted with substituents Independently selected from the group consisting of hydroxyl, nitrite, -O-R7'; -O-phenyl, -O-(C1-C4)alkyl-phenyl, alkylamino, alkyiamido, -S-R7', and -(C=O)-OR8', the number of substitu¬ents on said alkyl portion being up to five for hydroxyl and one, two or three for any combination of said other substituents;
(ii) -(C1-C4)alkyl, optionally substituted with one or two substituents independently se¬lected from the group consisting of aryl, heteroaryl, and cycloheteroalkyl,
wherein aryl is optionally substituted with halogen, hydroxyl, (C1-C6)alkoxy, (C1-
C8)alkyl, halogenated (C1-C4)alkyl, halogenated (C1-C4)alkoxy, sulfamoyl, or alkylamido, the number of substituents on said aryl portion being up to three for halogen and one or two for any combination of said other substituents; or which aryl Is optionally substituted by two groups which are attached to ad¬jacent carbon atoms and are combined into a saturated cyclic 5 or 6 mem-bered ring system, optionally containing up to three heteroatoms, such as N or O, the number of N atoms being 0-3 and the number of O atoms each be¬ing 0-2;
wherein heteroaryl is optionally substituted with one or two substituents independently selected from the group consisting of (C1-C4)alkoxy or (C1-C4)alkyl;
(iii) -cyclo(C3-C8)alkyl, optionally substituted with hydroxy!;
(iv) -(C1-C4)alkyl-cyclo(C3-C8)alkyl. optionally substituted with hydroxyl;
(v) a bicyclic ring system of 6 to 10 carbon atoms selected from the group consisting of Bicyclo[2.1.1]hexyl, Bicyclo[2.2.1]heptyi, Bicyclo[3.2.1]octyl, Bicyclo[2.2.2]octyl, Bicyclo[3.2.2]nonanyl, Bicyclo[3.3.1]nonanyl, and Bicyclo[3.3.2]decanyl; and
(vi) adamantyl;
(c) aryl,
wherein aryl is optionally substituted with halogen, (C1-C6)alkoxy, halogenated (C1-C4)alkyl,
halogenated (C1-C6)alkoxy, nitro, nitrile, -CO-(C1-C4)alkyl, -CO-O-(C1-C4)alkyl, -NH-CO-(C1-C4)alkyl, (C1-C4)alkyl-sulfonyl, phenyl or heteroaryl, the number of substitu¬ents on said aryl portion being up to three for halogen, and one or two for any combination of said other moieties; or which aryl is optionally substituted by two groups which are attached to adjacent carbon atoms and are combined into a satu¬rated cyclic 5 or 6 membered ring system, optionally containing up to three het¬eroatoms, such as N or O, the number of N atoms being 0-3 and the number of 0 atoms each being 0-2
(d) heteroaryl,
wherein heteroaryl is optionally substituted with up to two substituents independently se¬lected from the group consisting of halogen, (C1-C4)alkyl, halogenated (C1-C4)alkyl, -{C1-C4)alkyl-(C=O)-OR8,-O-Ar1',-SO2-Ar1'and phenyl; or
(e) cycloheteroalkyl,
wherein cycloheteroalkyl group is optionally substituted with one or two substitutents independently selected from the group consisting of oxo, (C1-C4)alkyl, and (C1-C4)alkyl-phenyl;
wherein
R7' represents (C1-C4)alkyl, optionally substituted in the alkyl chain with one or two hydroxyl
groups, R8' represents hydrogen, (C1-C4)alkyl or {C1-C2)alkyl-phenyl; and AR1, represents phenyl optionally substituted with up to three halogen atoms;
or wherein, under the proviso that Y represents -NR4-, -NH-NR4- or -NH-SOr-NR4-,
the ring or ringsystem formed by R2 and R4 together with the nitrogen atom, where R2 and R4 are attached, is selected from the group consisting of
(Formula Removed)
wherein the ring or the ring-system is optionally substituted
(0 with up to three substituents independently selected from the group consisting of
(a) hydroxyl,
(b) oxo,
(c) (C1-C4)-alkyl optionally substituted with up to two hydroxyl and/or (C1-C4)-alkoxy groups, whereby the alkyl-chain of the (C1-C4)alkoxy moiety may optionally be fur¬ther substituted with one or two hydroxyl group;

(d) cyclo(C3-C8)alkyl;
(e) -(C=O)-O-C1-C4)-alkyl;
(f) phenyl, optionally substituted with halogen, (C1-C4)-alkyl, (C1-C4)-alkoxy, or halo-genated (C1-C4)-alkyl. the number of said substituents on the phenyl moiety being up to three for halogen, and one or two for any combination of said other substitu¬errts;
(g) phenyl-(C1-C4)alkyl, optionally substituted in the phenyl group by up three halogen, or optionally substituted in the phenyl group by two groups which are attached to adjacent carbon atoms and are combined into a saturated or partly unsaturated cy¬clic 5 or 6-membered ring system, optionally containing up to two O atoms;
(i) heteroaryl, wherein the heteroaryl is selected from the group consisting of pyridinyl, fury), thienyl, thiazolyl, imidazolyl, pyrazolyl, indoiyl, quinolinyl, benzoimidazolyl or benzo[b]thiophene; and
(j) cycloheteroalkyi, wherein the cycloheteroalkyi is selected from the group consisting of pyrroiidinyl. 1,3-dihydro-benzoimidazoiyl, morpholinyl, tetrahydrofuranyl, piperid-inyl or azepanyl, which cycloheteroalkyi group is optionally substituted with oxo; or
([() by two groups which are attached to the same carbon atom and are combined into a saturated or partly unsaturated cyclic 5, 6, or 7-membered ring system, optlonally con¬taining up to three heteroatoms, such as N or O, the number of N atoms being 0-3 and the number of O atoms being 0-2,
whereby the cyclic ring system may optionally be further substituted with up to two sub-stituents independently selected from oxo and phenyl.
4. The compound of the general formula I as claimed in any one of the preceding claims 1
to 3, which is an enantiomer having the formula (II)
(Formula Removed)
or a physiologically acceptable salt thereof.
5. The compound of the general formula I as claimed in any of the preceding claims 1 to 3,
which is an enantiomer having the formula (III)
(Formula Removed)
or a physiologically acceptable salt thereof.
6. The compound as claimed in any of the claims 1 to 5, wherein R1 represents H, (C1-C4)alkyl, or phenyl (C1-C4)alkyl.
7. The compound as claimed in claim 6, wherein R1 represents H, methyl or benzyl.
8. The compound as claimed in any of the claims 1 to 7, wherein R3, if present, represents H, (C1-C4)alkyl, or phenyl (C1-C4)alkyl.
9. The compound as claimed in claim 8, wherein R3 represents H, methyl or benzyl.
10. The compound as claimed in any of the claims 1 to 9, wherein R4, if present, represents

(a) -H,
(b) an alkyl group selected from
(1) -(C1-C6)alkyl, optionally substituted with substituents independently selected from the group consisting of hydroxyl, nitrite, alkylamino, (C1-C4)-alkaxy, the number of substituents on said alkyl portion being up to five for hydroxyl and up to two for any combination of said other substituents;
(ii) aryl-(C1-C4)alkyl or heteroaryl-(C1-C4)lkyl, wherein the aryl is phenyl or naphthyl and the heteroaryl is pyridinyl;
(iii) cyclo(C3-C6)alkyi;
(iv) cyclo(C3-C6)alkyl-(C1-C2)alkyl-; or
(c) piperidlnyl, which is optionally substituted with a (C1-C4)alkyl group.
11. The compound as claimed in claim 10, wherein, if X represents -NR3- or -O- and Y represents -NR4-, then R4 is -H.
12. The compound as claimed in claim 1, wherein
X represents a bond; A represents -CO-, Y represents
(a) -NR4-,
(b)-O-
(c) a bond, or
(d) -NH-NR4-;
and n represents 0,1,2,3,4 or 5.
13. The compound as claimed in claim 12, wherein Y represents -NR4- and n represents 0, 1, 2, 3,4 or 5.
14. The compound as claimed in claim 13, wherein R represents
(i) -(C1-C4)alkyl,
(ii) -(C3-C8)cycloalkyl
(iii) -((1-C4)alkyl-aryl, wherein the aryl Is phenyl or naphthyl,
wherein phenyl is optionally substituted with one or two substituents independently selected from the group consisting of hydroxyl, halogen, and (C1-C4)alkoxy; or wherein phenyl is optionally substituted by two groups which are attached to adjacent carbon atoms and are combined into a saturated cyclic 5 or 6-membered ring system, containing 1 or 2 O atoms, or
(iv) heteroaryl or -(C1-C4)alkyl-heteroaryl, wherein the heteroaryl is fury), thienyl, thiazolyl, pyrldinyl, indoiyl, or benzoimidazoiyl;
wherein heteroaryl is optionally substituted with one or two substitutents independently selected from the group consisting of (C1-C4)alkyl and -(C1-C4)alkyl-(C=O)-O-(C1-C4)alkyl;
and R* is Independently selected from H or -(C1-C4)-alkyl; or
R2 and R4 form together with the nitrogen atom, where R3 and R4 are attached, a ring or ringsystem, which is selected from the group consisting of morpholine, thiomorpholine and piperazyl.
15. The compound as claimed in claim 1, wherein
X represents -NH-; A represents -CO-; Y represents:
(a) -NH-,
(b) -O-, or
(c) a bond,
and n represents 1,2,3,4, 5 or 6.
16. The compound as claimed in claim 15, wherein
X represents -NH-,
Y represents -NH- or a bond, and
n represents 1,2, 3 or 4.
17. The compound as claimed in claim 16, wherein Y represents -NH-.
18. The compound as claimed in claim 17, wherein R2 represents
(i) -{C1-C4)alkyl,
(ii) -(C3-C8)cycloalkyl,
(iii) -(C1-C4)alkyl-(C3-C8)cycloalkyl,
(iv) aryl, wherein the aryl is phenyl or naphthyl,
wherein phenyl is optionally substituted with one or two substituents independently selected from the group consisting of hydroxyl, halogen, -CO-O(C1-C4)alkyl and (C1-C4)alkoxy; or
wherein phenyl is optionally substituted by two groups which are attached to adjacent carbon atoms and are combined into a saturated cyclic 5 or 6-membered ring system, containing 1 or 2 O atoms, or (v) -{C1-C4)alkyl-phenyl.
19. The compound as claimed in clam 16, wherein Y represents a bond.
20. The compound as claimed in claim 19, wherein R2 represents
(i) -{C1-C4)alkyl,
(it) -(C3-C7)cycloalkyl,
(iii) -(C1-C4)alkyl-(C3-C8)cycloalkyl,
(iv) -(C1-C4)alkyl, substituted with one or two substituents Independently selected from the
group consisting of -O-(C1-C4)alkyl and -O-(C1-C4)alkyl-phenyl. (v) phenyl,
wherein phenyl is optionally substituted with one, two or three substituents independently selected from the group consisting of halogen and (C1-C4)alkoxy;
(vi) -(C1-C4) alkyl-phenyl; or
(vii) adamantly
21. The compound as claimed in claim 1, wherein
X represents -NR3-; A represents -SO2-; Y represents:
(a) -NH-,
(b) -O-, or
(c) a bond;
and n represents 1, 2, 3, or 4.
22. The compound as claimed in claim 21, wherein Y represents a bond and R3 represents H or -(C1-C4)alkyl.
23. The compound as claimed in claim 22, wherein R2 represents
(i) aryl, wherein the aryl is selected among phenyl and naphthyi,
which aryl is optionally substituted with one or two substituents independently selected from the group consisting of halogen, nitro, (C1-C4)alkoxy, and -(C1-C4)alkyl; or (ii) heteroaryl, wherein the heteroaryl is furyl, thlenyl, or thlazolyl, or indolyl,
which heteroaryl is optionally substituted with one or two substituents independently selected from the group consisting of-SO2-rphenyl and (C1-C4)alkyl.
24. The compound as claimed in claim 1, wherein
X represents -O-; A represents -CO-; Y represents:
(a) -NH-,
(b) a bond, or
(c) -NH-SO2-NR4-;
and n represents 1,2,3,4,5 or 6.
25. The compound as claimed in claim 24, wherein Y represents -NH- and n represents 3, 4, 5 or 6.
26. The compound as claimed in claim 25, wherein R2 represents phenyl or naphthyl,
wherein phenyl is optionally substituted with one or two substituents independently selected
from the group consisting of hydroxy!, halogen, nitro, -CO-O{C1-C4)alkyl and (C1-C4)alkoxy and halogenated (C1-C4)alkyl; or
wherein phenyl is optionally substituted by two groups which are attached to adjacent carbon
atoms and are combined into a saturated cyclic 5 or 6-membered ring system, con¬taining 1 or 2 O atoms.
27. The compound as claimed in claim 24, wherein Y represents -NH-SO2-NR4-.
28. The compound as claimed in claim 27, wherein R2 represents
(i) -(C1-C4)akyl, (ii) -(C3-C6)cycloalkyl, (iii) -{C1-C4)alkyl-phenyl,
(iv) phenyl, or
(v) heteroaryl or -(C1-C4)alkyl-heteroaryl, wherein the heteroaryl is furyl, thienyl, thiazolyl, pyridinyl, indoiyl, or benzoimidazolyl;
and R4 is independently selected from H, -(C1-C4)-alkyl and -(C1-C4)aikyl-phenyl; or
R2 and R4 form together with the nitrogen atom, where R2 and R4 are attached, a ring, which is selected from the group consisting of morpholine, thiomorphollne and piperazy), and which is optionally substituted with (C1-C4}-alkyl.
29. The compound as claimed in claim 1, wherein -X-A-Y-represent -O-, and wherein R2
represents -H and n represents 1,2, 3,4, 5 or 6.
30. The compound as claimed in claim 1, selected from the group consisting of exemplary compounds:
3-Hydroxy-15ß-(4-morpholin-4-yl-4-oxo-butyl)-estra-1,3,5(10)-trien-17-one,
3-Methoxy-15ß-(4-morpholin-4-yl-4-oxo-butyl)-estra-1,3,5(10)-trien-17-one,
N-Benzyl-4-(3-methoxy-17-oxo-estra-1,3,5( 10)-trien-15ß-yl)-butyramide,
N-Benzyl-4-(3-Hydroxy-17-oxo-estra-1,3,5(10)-trien-15ß-yl)-butyramide,
4-(3-Methoxy-17-oxo-estra-1,3,5(10)-trien-15ß-yl)-N-[2-(7-methyl-1H-indol-3-yl)-ethyl]-butyramide,
4-(3-Hydroxy-17-oxo-estra-1,3,5{10)-trien-15ß-yl)-N-[2-(7-methy-1H-indol-3-yl)-ethyl]-butyramide,
N-(2,4-Difluoro-benzyl)-4-(3-hydroxy-17-oxo-estra-1,3,5(10)-trien-15ß-yl)-butyramide,
N-Benzyl-4-(3-hydroxy-17-oxo-estra-1,3,5(10)-trien-15ß-yl)-N-methyl-butyramide,
N-Benzyl-4-(3-hydroxy-17-oxo-estra-1,3,5(10)-trien-15α-yl)-butyramide,
3-Hydroxy-15α-{4-morpholin-4-yl-4-oxo-butyl)-estra-1,3,5(10)-trien-17-one
3-Methoxy-17-oxo-estra-1,3,5(10)-trien-15α--carboxylicacid(5-methyl-thiazol-2-yl)-amide,
N-Cyclohexyl-3-(3-methoxy-17-oxo-estra-1,3,5(10}-trien-15ß-yl)-propionamide,
N-Cyclooctyl-3-{3-methoxy-17-oxo-estra-1,3,5(10)-trien-15ß-yl)-propionamide,
N-Cyciohexyl-3-(3-methoxy-17-oxo-estra-1,3,5(10)-trien-15ß-yl)-N-methyl-propionarnide,
N-[2-(4-Hydroxy-phenyl)-thyl)-3-(3-methoxy-17-oxo-estra-1,3,5.(10)-trien-15ß-yl)-propionamide, 3-(3-Methoxy-17-oxo-estra-1,3,5(10)-trien-15ß-yl)-N-(5-rnethyl-thiazol-2-yl)-propionamide, 3-(3-Hydroxy-17-oxc-estra-1,3,5(10)-trien-15ß-yl)-N-(5-methyl-thiazol-2-yl)-propionamide, 5-(3-Methoxy-17-oxo-estra-1,3,5(10)-trien-15ß-yl)-pentanoic acid cyclohexylamide, 5-(3-Methoxy-17-oxo-estra-1,3,5(10)-trien-15ß-yl)-pentanoic acid cyclooctylamide, 5-(3-Methoxy-17-oxo-estra-1,3,5(10)-trien-15ß-yl)-pentanoic acid (furan-2-ylmethyl)-amide, 5-(3-Methoxy-17-oxo-estra-1,3,5(10)-trien-153-yl}-pentanoic acid (benzo[1,3]dioxol-5-ylmethyl)-amide,
5-{3-Methoxy-17-oxc-estra-1,3,5(10)-trien-15ß-yl)-pentanoic add (pyridin-3-ylmethyl)-amide, 5-(3-Methoxy-17-oxo-estra-1,3.5(10)-trien-15ß-yl)-pentanoic acid (pyridin-4-ylmethyl)-amide, 5-(3-Methcxy-17-oxo-estra-1,3,5(10)-trien-15ß-y))-pentanoic acid benzylamide, 5-(3-Methoxy-17-oxo-estra-1,3,5(10)-trien-15ß-yl)-pentanoic acid 2-methoxy-benzylamide, 5-{3-Methoxy-17-oxo-estra-1,3,5(10)-trien-15ß-yl)-pentanoic acid 3-fluoro-benzylamide, 5-(3-Methoxy-17-oxo-estra-1,3,5(10)-trien-15ß-yl)-pentanoic acid 4-chloro-benzylamide, 5-(3-Methoxy-17-oxo-estra-1,3,5(10)-trien-15ß-yl)-pentanoic acid benzyl-methyl-amide, 5-(3-Methoxy-17-oxo-estra-1,3,5(10)-trien-15ß-yl)-pentanoic acid butylamide, 5-(3-Methoxy-17-oxo-estra-1,3,5(10)-trien-15ß-yl)-pentanoic acid (2-thiophen-2-yl-ethyl)-amide, 5-(3-Methoxy-17-oxo-estra-1,3,5(10)-trien-153-yl)-pentanoic acid[2-(7-rnethyl-1H-indol-3-yl)-ethyl] amide,
6-(3-Methoxy-17-oxo-estra-1,3,5(10)-trien-15ß-yl)-hexanoic acid cyclohexylamide, 6-(3-Methoxy-17-oxo-estra-1,3,5(10)-trien-15ßyl)-hexanoic acid (furan-2-ylmethyl)-amide, 6-(3-Methoxy-17-oxo-estra-1,3,5(10)-trien-15ß-yl)-hexanoic acid (benzo[1,3]dioxol-5-ylmethyl)-amide,
3-Methoxy-15ß-(6-morpholin-4-yl-6-oxo-hexyl)-estra-1,3,5(10)-trten-17-one, 3-Methoxy-15ß-(6-oxo-6-thiomorpholin-4-yl-hexyl)-estra-1,3,5{10)-trien-17-one, 6-(3-Methoxy-17-oxo-estra-1,3,5(10)-trien-15ß-yl)-hexanoic acid (pyridin-3-ylmethyl)-amide, 6-(3-Methoxy-17-oxc-estra-1,3,5(10)-trien-15ß-yl)-hexanoic acid(pyridin-4-ylmethyl)-amide, 6-{3-Methoxy-17-oxo-estra-1,3,5(10)-trien-15ß-yl)-hexanoic acid benzylamide, 6-(3-Methoxy-17-oxo-estra-1,3,5(10)-trien-15ß-yl)-hexanoic acid 2-methoxy-benzylamide, 6-(3-Methoxy-17-oxo-estra-1,3,5(10)-trien-15ß-yl)-hexanoic acid 3-fluoro-benzylamide, 6-(3-Methoxy-17-oxo-estra-1,3,5(10)-trien-15ß-yl)-hexanoic acid [2-(4-hydroxy-phenyl)-ethyl]-amide,
6-(3-Methoxy-17-oxc-estra-1,3,5(10)-trien-15ß-yl)-hexanoic acid benzyl-methyl-amide, 6-(3-Methoxy-17-oxo-estra-1,3,5(10)-trien-15ß-yl)-hexanoic acid butylamide, 6-{3-Methoxy-17-oxo-estra-1,3,5(10)-trien-15ß-yl)-hexanoic acid (2-thtophen-2-yl-ethyl)-amide, 1 -[3-(3-Methoxy-17-oxo-estra-1.3,5(10)-trien-15ß-yl)-propyl}-3-(3-methoxy-phenyl)-urea, 1 -[3-(3-Methoxy-17-oxo-estra-1,3,5(10}-trien-15ß-yl)-propyl]-3-(4-methoxy-phenyl)-urea, 1-lsopropyl-3-[3-(3-methoxy-17-oxc-estra-1,3,5(10)-trien-15ß-yl)-propyl]-urea, 1 -Cyclohexyl-3-[3-(3-methoxy-17-oxo-estra-1,3,5(10)-trien-15ß-yl)-propyl]-urea,
1 -Benzy1-3-[3-(3-methoxy-17-oxo-estra-1,3,5(10)-trien-15ß-yl)-propyl]-urea,
1 -{3,4-Dimethoxy-pheny1)-3-[3-(3-methoxy-17-oxo-estra-1,3,5( 10)-trien-15ß-yl)-propyl]-urea,
1 -Benzo{1,3]dioxol-5-yl-[3-(3-methoxy-17-oxo-estra-1,3,5(10)-trien-15ß-yl)-propyl]-urea,
1-Benzyl-3-[4-(3-methoxy-17-oxo-estra-1,3,5(10)-trien-15ß-yl)-butyl]-urea,
1-(3,4-Dimethoxy-phenyl)-3-[4-(3-methoxy-17-oxo-estra-1,3,5(10)-trien-15ß-yl)-butyl]-urea,
4-{3-[4-(3-Hydroxy-17-oxo-estra-1,3,5(10)-trierv15α-yl)-butyl)-ureido}-benzoic acid ethylester,
1 -Cyclohexylmethyl-3-{4-(3-hydroxy-17-oxo-estra-1,3,5(10)-trien-15α-yl)-butyl]-urea,
Naphthalene-2-sulfonic acid(3-hydroxy-17-oxo-estra-1,3,5(10)-trien-15α-ylmethyl)-amide, Thiophene-2-sulfonic acid (3-hydroxy-17-oxo-estra-1,3,5(10)-trien-15α-ylmethyl)-amide> N-(3-Hydroxy-17-oxo-estra-1,3,5(10)-trien-15a-yimethyl)-benzenesulfonamide, 4-Fluoro-N-(3-hydroxy-17-oxo-estra-1,3,5(10)-trien-15α-ylmethyl)-benzenesuIfonamide, N-(3-Hydroxy-17-oxo-estra-1,3,5(10)-trien-15α-ylmethyl)-4-methoxy-benzenesulfonamide, N-(3-Hydroxy-17-oxo-estra-1,3,5(10)-trien-15a-ylmethyl)-3-methyl-benzenesulfbnamide,
Naphthalene-2-sulfonic acid (3-hydroxy-17-oxo-estra-1,3,5(10)-trien-15α-ylmethyl)-methyl-amide, Thiophene-2-sulfbnic acid(3-ydroxy-17-oxo-stra-1,3,5(10)-trien-15a-ylmethyl)-methyl-amide, N-(3-Hydroxy-17-oxo-estra-1,3,5-(10)-trien-15α-ylmethyl)-N-methyl-benzenesulfbnamide, 4-Fluoro-N-(3-hydroxy-17-oxo-estra-1,3,5(10)-trien-15α-ylmethyl)-N-methyl-benzenesulfonamide, N-(3-Hydroxy-17-oxo-estra-1,3,5( 10)-trien-15α-ylmethyl)-4-methoxy-N-methyl-benzenesuifonamide,
3-Chloro-N-(3-hydroxy-17-oxo-estra-1l3,5{10)-trien-15α-ylmethyl)-N-methyl-benzenesutfonamide, N-(3-Hydroxy-17-oxo-estra-1,3,5(O)-trien-15α-ylmethyl)-3,N-dimethyl-benzenesulfonamide, 4-Benzenesulfony-thiophene-2-sulfonic acid (3-hydroxy-17-oxo-estra-1,3,5(10)-trien-15α-ylmethyl)-
methyl-amide, Benzo[1,3]dloxol-5-yl-carbamic acid 3-{3-methoxy-17-oxo-estra-1,3,5(10)-trien-150-yl)-propylester,
and 3-Hydroxy-15ß-(3-hydroxypropyl)-estra-1,3.5(10)-trien-17-one, or a physiologically acceptable salt thereof.
31. The compound as claimed in any of the claims 1 to 30, for use as a medicament for the
prevention or treatment of steroid hormone dependent diseases or disorders selected
from breast cancer, prostate carcinoma, ovarian cancer, uterine cancer, endometrial
cancer, endometrial hyperplasia, endometriosis, uterine fibroids, uterine leiomyoma,
adenomyosis, dysmenorrhoea, menorrhagia, metrorrhagia, prostadynia, benign prostatic
hyperplasia, urinary dysfunction, lower urinary tract syndrome, multiple sclerosis,
rheumatoid arthritis, colon cancer, tissue wounds, skin wrinkles and cataracts.
32. A pharmaceutical composition comprising as active agent a compound of formula (I) as claimed in any of the claims 1 to 30, and at least a pharmaceutically acceptable carrier, wherein said composition comprises from 0.01µg/kg to 100 mg/kg of total body weight of said active agent.

Documents:

2115-DELNP-2006-Abstract-(07-01-2010).pdf

2115-DELNP-2006-Abstract-(07-05-2012).pdf

2115-delnp-2006-Abstract-(26-02-2010).pdf

2115-delnp-2006-abstract.pdf

2115-DELNP-2006-Claims-(07-01-2010).pdf

2115-DELNP-2006-Claims-(07-05-2012).pdf

2115-delnp-2006-Claims-(26-02-2010).pdf

2115-delnp-2006-Claims-(28-08-2012).pdf

2115-delnp-2006-claims.pdf

2115-DELNP-2006-Correspondence Others-(07-05-2012).pdf

2115-delnp-2006-Correspondence Others-(28-08-2012).pdf

2115-DELNP-2006-Correspondence-Others (02-03-2010).pdf

2115-DELNP-2006-Correspondence-Others-(06-10-2010).pdf

2115-DELNP-2006-Correspondence-Others-(07-01-2010).pdf

2115-delnp-2006-Correspondence-Others-(26-02-2010).pdf

2115-delnp-2006-correspondence-others-1.pdf

2115-delnp-2006-correspondence-others.pdf

2115-DELNP-2006-Description (Complete)-(07-01-2010).pdf

2115-delnp-2006-description (complete).pdf

2115-delnp-2006-form-1.pdf

2115-delnp-2006-form-18.pdf

2115-delnp-2006-form-2.pdf

2115-DELNP-2006-Form-3-(06-10-2010).pdf

2115-DELNP-2006-Form-3-(07-01-2010).pdf

2115-delnp-2006-form-3.pdf

2115-delnp-2006-form-5.pdf

2115-DELNP-2006-GPA-(07-01-2010).pdf

2115-delnp-2006-gpa.pdf

2115-delnp-2006-pct-210.pdf

2115-delnp-2006-pct-237.pdf

2115-delnp-2006-pct-304.pdf

2115-delnp-2006-pct-326.pdf

2115-DELNP-2006-Petition-137-(07-01-2010).pdf


Patent Number 253996
Indian Patent Application Number 2115/DELNP/2006
PG Journal Number 37/2012
Publication Date 14-Sep-2012
Grant Date 12-Sep-2012
Date of Filing 19-Apr-2006
Name of Patentee SOLVAY PHARMACEUTICALS GMBH
Applicant Address HANS-BOCK-LER-ALLEE 20,30173 HANNOVER,GERMANY.
Inventors:
# Inventor's Name Inventor's Address
1 JOSEF MESSINGER FRIEDRICH OTTO SCHOTT WEG 3,31319 SEHNDE,GERMANY.
2 HEINRICH-HUBERT THOLE GROSS BUCHHOIZER KIRCHWEG 32,30655 HANNOVER, GERMANY
3 BETTINA HUSEN ALTENBEKENER DAMM 37,30173 HANNOVER, GERMANY;
4 GYULA SCHNEIDER BECSI KORT 7, WIENERRINGSTR,H-6722 SZEGED, HUNGARY
5 NINA JOHA NSSON, SIKKALANKATU 35 B 7, FIN-20700 TURKU, FINLAND;
6 JERZY ADAMSKI STRASSBERGERSTR. 10, 80809 MUNCHEN, GERMANY;
7 BARTHOLOMEUS JOHANNES VAN STEEN, POORTSTRAAT 53, NL-3572 HD UTRECHT, THE NETHERLANDS;
8 JOHANNES BERNARDUS EVERARDUS HULSHOF WATERMOLENDIJK 2, NL- 9761 VH EEIDE, THE NETHERLANDS,
9 PASI KOSKIMIES LAUKLAHTEENKATU 6 A 8, FIN-20740 TURKU, FINLAND ;
PCT International Classification Number C07J 1/00
PCT International Application Number PCT/EP2004/052925
PCT International Filing date 2004-11-11
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 03104169.2 2003-11-12 EPO
2 04105313.3 2004-10-26 EPO