Indian Patents
Title of Invention

A THIOACETAMIDE COMPOUND
Abstract A compound of formula (I-A): wherein: Ar1 and Ar2 are each independently selected from phenyl, thienyl, isothiazolyl, oxazolyl, isoxazolyl, and thiazolyl; Y is selected from C1-C4 alkylene, -C(R1)(R2)-, phenylene, and oxazolylene, wherein R1 and R2 are each independently H or C1-C6 alkyl; R3 and R4 are the same or different and are each selected from H and C1- C6 alkyl, wherein said alkyl is optionally substituted with OH or a heterocyclyl ring selected from piperidyl, morpholinyl and pyridyl; or R3 and R4, together with the nitrogen to which they are attached, form an optionally substituted morpholinyl or pyrrolidyl ring; m is 0, 1 or 2; n is 0, 1 or 2; and q is 1; with the proviso that when An and Ar2 are both phenyl, then Y cannot be C1-C4 alkylene; and the stereoisomeric forms, mixtures of stereoisomeric forms, or pharmaceutically acceptable salt and ester forms thereof.
Full Text SUBSTITUTED TfflOACETAMIDES
FIELD OF THE INVENTION
The present invention is related to chemical compositions, processes for the
preparation thereof and uses of the composition. Particularly, the present invention
relates to compositions that include substituted thioacetamides, and their use in the
treatment of diseases, including treatment of sleepiness, promotion of wakefulness,
treatment of Parkinson's disease, cerebral ischemia, stroke, sleep apneas, eating
disorders, stimulation of appetite and weight gain, treatment of attention deficit
hyperactivity disorder ("ADHD"), enhancing function in disorders associated with
hypofunctionality of the cerebral cortex, including, but not limited to, depression,
schizophrenia, fatigue, in particular, fatigue associated with neurologic disease, such as
multiple sclerosis, chronic fatigue syndrome, and improvement of cognitive dysfunction.
BACKGROUND OF THE INVENTION
The compounds disclosed herein are related to the biological and chemical
analogs of modafinil. Modafinil, C15H15NO2S, also known as 2-(benzhydrylsulfinyl)
acetamide, or 2-[(diphenylmethyl) sulfinyl] acetamide, is a synthetic acetamide
derivative with wake-promoting activity, the structure of which has been described in
French Patent No. 78 05 510 and in U.S. Patent No.477,290 ('290), and which has
been approved by the United States Food and Drug Administration for use in the
treatment of excessive daytime sleepiness associated with narcolepsy. Modafinil has
been tested for treatment of several behavioral conditions in combination with various
agents including apomorphine, amphetamine, reserpine, oxotremorine, hypnotics,
yohimbine, 5-hydroxytryptophan, and monoamine oxidase inhibitors, as described in the
cited patents. A method of preparation of a racemic mixture is described in the 290
patent and a method of preparation of a levorotatory isomer is described in U.S. Patent
No. 4,927,855 (both incorporated herein by reference). The levorotatory isomer is
reported to be useful for treatment of hypersomnia, depression, Alzheimer's disease and
to have activity towards the symptoms of dementia and loss of memory, especially in the
elderly.
The primary pharmacological activity of modafinil is to promote wakefulness.
Modafinil promotes wakefulness in rats (Touret et al., 1995; Edgar and Seidel, 1997),
cats (Lin et al., 1992), canines (Shelton et al., 1995) and non-human primates (Hernant et
al, 1991) as well as in models mimicking clinical situations, such as sleep apnea (English
bulldog sleep disordered breathing model) (Panckeri et al, 1996) and narcolepsy
(narcoleptic canine) (Shelton et al, 1995).
Modafinil has also been described as an agent with activity in the central nervous
system, and as a useful agent in the treatment of Parkinson's disease (U.S. Patent No.
5,180,745); in the protection of cerebral tissue from ischemia (U.S. Patent No.
5,391,576); in the treatment of urinary and fecal incontinence (U.S. Patent No.
5,401,776); and in the treatment of sleep apneas and disorders of central origin (U.S.
Patent No. 5,612,379). U.S. Patent No. 5,618,845 describes modafinil preparations of a
defined particle size less than about 200 microns. In addition, modafinil may be used in
the treatment of eating disorders, or to promote weight gain or stimulate appetite in
humans or animals (US Provisional Patent Application No. 60/150,071, incorporated
herein by reference), or in the treatment of attention deficit hyperactivity disorder
(ADHD)j or fatigue, especially fatigue associated with multiple sclerosis (US Provisional
Patent Application No. 60/149,612, incorporated herein by reference).
Several published patent applications describe derivative forms of modafinil and
the use of modafinil derivatives in the treatment of various disorders. For example, PCT
publication WOJ99/25329 describes analogs of modafinil in which the phenyl groups are
substituted with a F, Cl, Br, CF3, NO2, NH2, C1-C4 alkyl, C1C4 alkoxy, or
methylenedioxy, and in which the amide is substituted with OH, C1-C4 alkyl, C1-C4
hydroxyalkyl, or a C1-C4 hydrocarbon radical. These compositions are described as
being useful for treating drug-induced sleepiness, especially sleepiness associated with
administration of morphine to cancer patients.
Similarly, U.S. Pat. No. 4,066,686 describes benzhydrylsulphinyl derivatives,
including modafinil derivatives with an extended alkyl chain between the sulfinyl and
carbonyl groups and where NR3R4 is NHOH. These compounds are described as being
useful in therapy for treating disturbances of the central nervous system.
PCT publication WO 95/01333 describes modafinil derivatives that are useful for
modifying feeding behavior. Hie modifications to modafinil described include a chloro
group at the 3 position of one of the phenyl groups, and a pyridyl substituted for the
second phenyl, substitution of one or two methyl groups for hydrogens at the 2-carbon
position, the amide hydrogens may be substituted with one or two groups selected from
H, a pyridyl-methyl or ethyl groups, and further where the sulfur may not be oxidized.
PCT publication WO 95/01171 also describes modified modafinil compounds
that are said to be useful for modifying eating behavior. The described compounds
include substitutions of 4-fluoro-, 3-fluoro-, and 4 chloro- in a first phenyl group and 4-
fluoro- or 3-fluoro- substitutions in the second phenyl. Also described are substitutions
in which the amide contains substitutions with an OH or isopropyl group.
Terauchi, H, et al. described nicotinamide derivatives useful as ATP-ase
inhibitors (Terauchi, H, et al,J Mied. Chem., 1997,40,313-321). In particular, several
N-alkyl substituted 2-(Benzhydrylsulfinyl) nicotinamides are described.
U.S. Pat. Nos. 4,980,372 and 4,935,240 describe benzoylaminophenoxybutanoic
acid derivatives. In particular, sulfide derivatives of modafinil containing a phenyl and
substituted phenyl linker between the sulfide and carbonyl, and a substituted aryl in the
terminal amide position, are disclosed.
Other modafinil derivatives have been disclosed wherein the terminal phenyl
groups are constrained by a linking group. For example, in U.S. Pat. No. 5,563,169,
certain xanthenyl and thiaxanthenyl derivatives having a substituted aryl in the terminal
amide position are reported.
Other xanthenyl and thiaxanthenyl derivatives are disclosed in Annis, I; Barany,
G. Pept. Proc. Am. Pept. Symp. 15Th (Meeting Date 1997) 343-344, 1999 (preparation of
a xanthenyl derivative of Ellman's Reagent, useful as a reagent in peptide synthesis);
Han, Y.; Barany.. G. J. Org. Chem., 1997, 62,3841-3848 (preparation of S-xanthenyl
protected cysteine derivatives, useful as a reagent in peptide synthesis); and El-Sakka,
LA., et al. Arch. Pharm. (Weinheim), 1994,327, 133-135 (thiaxanthenol derivatives of
thioglycolic acid).
Thus, there is a need for novel classes of compounds that possess beneficial
properties. It has been discovered that a class of compounds, referred to herein as
substituted thioacetamides, are useful as agents for treating or preventing diseases or
disorders, including treatment of sleepiness, promotion of wakefulness, treatment of
Parkinson's disease, cerebral ischemia, stroke, sleep apneas, eating disorders, stimulation
of appetite and weight gain, treatment of attention deficit hyperactivity disorder,
enhancing function in disorders associated with hypofunctionality of the cerebral cortex,
including, but not limited to, depression, schizophrenia, fatigue, in particular, fatigue
associated with neurologic disease, such as multiple sclerosis, chronic fatigue syndrome,
and improvement of cognitive dysfunction. The present invention is directed to these, as
well as other, important ends.
SUMMARY OF THE INVENTION
One aspect of the present invention provides, in part, various novel substituted
thioacetamides. Other aspects of the invention also include their pharmaceutical
compositions, methods of their preparation, and use of the compounds in the treatment of
diseases.
In one aspect of the invention, there are provided compounds of formula (I-A):
Constituent members and preferred embodiments are disclosed in detail infra.
In another aspect of the invention, there are provided compounds of formula (I):
Constituent members and preferred embodiments are disclosed in detail infra.
Another object of the present invention is to provide compounds of formula (II-
A):
Constituent members and preferred embodiments are disclosed in detail infra.
An additional object of the present invention is to provide compounds of formula
(II):
Constituent members and preferred embodiments are disclosed in detail infra.
Another object of the present invention is to provide methods of treating or
preventing diseases or disorders, including treatment of sleepiness, promotion of
wakefulness, treatment of Parkinson's disease, cerebral ischemia, stroke, sleep apneas,
eating disorders, stimulation of appetite and weight gain, treatment of attention deficit
hyperactivity disorder, enhancing function in disorders associated with hypofunctionality
of the cerebral cortex, including, but not limited to, depression, schizophrenia, fatigue, in
particular, fatigue associated with neurologic disease, such as multiple sclerosis, chronic
fatigue syndrome, and improvement of cognitive dysfunction.
Another object of the present invention is to provide pharmaceutical
compositions comprising the compounds of the present invention wherein the
compositions comprise one or more pharmaceutically acceptable excipients and a
therapeutically effective amount of at least one of the compounds of the present
invention, or a pharmaceutically acceptable salt or ester form thereof.
These and other objects, features and advantages of the substituted
thioacetamides will be disclosed in the following detailed description of the patent
disclosure.
BRIEF DESCRIPTION OF THE (DRAWINGS
FIG. 1 is a graph of data indicating EEG-determined wakefulness in rats treated with
Compound 1-9 (100 mg/kg, ip; solid line) or methylcellulose vehicle (stippled line).
Wakefulness is quantified in 5-minute bins. N= 13 rats/group. *p treated animals.
FIG. 2 is a graph of data indicating EEG-determined wakefulness in rats treated with
compound 11-23 (100 mg/kg, ip; solid triangles) or methylcellulose vehicle (open
circles). Each point represents the mean percent of time awake for the succeeding half
hour. *p DETAILED DESCRIPTION OF THE INVENTION
In one embodiment, the present invention provides novel compounds of formula
(I-A):
wherein:
Ar1 and Ar2 are each independently selected from C1-C10 aryl or heteroaryl;
wherein each of Ar1or Ar2 may be independently optionally substituted with 1-3
substituents independently selected from:
a) H, C6-Cl0 aryl, heteroaryl, F, Cl, Br, I, -CN, -CF3, -NO2, -OH, -OR7, -
CKCH2)pNR9R10, -OC(=O)R7, -OC(=O)NR9R10, -O(CH2)pOR8, -CH2OR8,
-NR9R10, -NR8S(=O)2R7, -NR8C(=O)R7, or-NR8C(=S)R7;
b) -CH2OR11;
c) -NR8C(=0)NR9R10, -NR8C(=S)NR9R10, -CO2Rl2, -C(=O)R13, -
C(=0)NR9R10, -C(=S)NR9R10, -CH=NOR12, -CH=NR7, -(CH2)pNR9R10, -
(CH2)pNHR11, -CH=NNR12R12, -C(=NR8)NR8aR8b -NR8(=NH)R8A, -
d) -S(O)yR7, -(CH2)pS(O)yR7, -CH2S(O)yR7; and
e) C1-C8 alkyl, C2-C8 alkenyl, or C2-C8 alkynyl, where:
1) each alkyl, alkenyl, or alkynyl group is unsubstituted; or
2) each alkyl, alkenyl or alkynyl group is independently substituted
with 1 to 3 groups independently selected from C1-C10 aryl,
heteroaryl, F, Cl, Br, I, CF3, -CN, -NO2, -OH, -OR7, -CH2OR8, -
NR9R10, -O-(CH2)p-OH, -S-(CH2)p-OH, - X1(CH2)pOR7,
X1(CH2)pNR9R10, -X1(CH2)pC(=O)NR9Rl0, -
X,(CH2)pC(=S)NR9R1o, -X1(CH2)pOC(=0)NR9R10, -
X1(CH2)PCO2R8, -Xi(CH2)pS(O)yR7, -X,(CH2)pNR8C(=O)NR9R10,
-C(=O)R13, -CO2R12, -OC(=O)R7, -C(=0)NR9R10, -
OC(=O)NR12R12A, O-tetrahydropyranyl, -C(=S)NR9R10, -
CH=NNRI2RI2As -CH=NOR12, -CH=NR7, -
CH=NNHCH(N=NH)NH2, -NR8CO2R7, -NR8C(=O)NR9R10, -
NR8C(=S)NR9R,10, -NHC(=NH)NH2, -NR8C(=O)R7, -
NR8C(=S)R7, -NR8S(=O)2R7, -S(O)yR7, -S(=O)2NR12R12A, -
P(=O)(OR8)2, -OR11, and a C5-C7 monosaccharide where each
hydroxyl group of the monosaccharide is independently either
unsubstituted or is replaced by H, C1-C4 alkyl, C1-C4 alkoxy, or -
O-C(=O)R7;
X1 is -O-, -S-, -N(R8)-;
Y is selected from C1-C4 alkylene, C6-C10 arylene, heteroarylene, C3-C5 cycloalkylene,
heterocyclylene, -O-, -N(R8)-, -S(O)y, -CR8A=CR5B-, -CH=CH-CH(R8)-, -
CH(R8>CH=CH-, or C=C -; with the proviso that when Y is -O-, -N(R8)-, or -
S(O)y, m and n cannot be 0;
R3 and R4 are the same or different and are each selected from H, C1-C6 alkyl, -OH, and -
CH(R6)-CONR8aR8b, provided that R3 and R4 are not both OH; or R3 and R4,
together with the nitrogen to which they are attached, form a 3-7 member
heterocyclyl ring;
R6 is H, C1-C4 alkyl or the side chain of an a-amino acid;
R7 is C1-C6 alkyl, C6-C10 aryl, or heteroarYl;
R8, R8a and R8b are each independently H, C1-C4 alkyl, or C6-C10 aryl;
R9 and R10 are independently selected from H, C1-C4 alkyl, and C6-C10 aryl; or R9 and
R10 together with the nitrogen to which they are attached, form a 3-7 member
heterocyclyl ring;
R11 is the residue of an amino acid after the hydroxyl group of the carboxyl group is
removed;
R12 and R12a are each independently selected from H2 c1 c6 alkyl, cycloalkyl, C6-C10
aryl, and heteroaryl; or R12 and R12A together with the nitrogen to which they are
attached, form a 5-7 member heterocyclyl ring;
R13is H2 C1-C6 alkyl, cycloalkyl, C6-C10 aryl, heteroaryl, -C(=O)R7, -C(=0)NR9R10, or -
C(=S)NR9R10;
m is0, 1,2 or 3;
n is O, 1,2or 3;
p is from 1,2,3, or 4;
qisO, 1,or2;
tis2,3, or 4;
y is 0,1 or 2;
with the proviso that when Ar1 is phenyl and Aft is phenyl or pyridyl, then Y cannot be
C1-C4 alkylene;
with the further proviso mat when Ari and Ar2 are phenyl, q=l, m and n = 0, Y is
and the stereoisomeric forms, mixtures of stereoisomeric forms, or phannaceutically
acceptable salt and ester forms thereof.
In an additional embodiment of the invention, there are provided compounds of
formula (I):
wherein Ari and Ax2 are the same or different and are each selected from
thiophene, isothiazole, phenyl, pyridyl, oxazole, isoxazole, thiazole, imidazole, and other
five or six membered heterocycles comprising 1-3 atoms of-N-, -O-, or -S-, provided
that Ari and Ar2 are not both phenyl and when Ar1 is phenyl, Ar2 is not pyridyl; R1-R4
are the same or different and are each selected from H, lower alkyl, -OH, -CH(R6)-
CONR6aR6b, or any of R1-R4 can be taken together to form a 3-7 member carbocyclic or
heterocyclic ring, provided that R3 and R4 are not both OH; R6a and R6b are
independently H or lower alkyl; and n is 0,1, or 2; and
in addition, each of Ar1 or Ar2 may be independently optionally substituted with one or
more substituents independently selected from:
a) H, aryl, heterocyclyl, F, Cl, Br, I, -CN, -CF3, -NO2, -OH, -OR7, -
0(CH2)pNR9R10, -OC(=O)R7, -OC(=O)NR9R10, -O(CH2)pOR8, -CH2OR8,
-NR9R10, -NR8S(=O)2R7, -NR8C(=O)R7, or-NR8C(=S)R7;
b) -CH2OR11, where R11 is the residue of an amino acid after the hydroxyl
group of the carboxyl group is removed;
c) -NR8C(=0)NR9R10, -NR8C(=S)NR9R10, -CO2R12, -C(=O)R12, -
C(=O)NR9R10, -C(=S)NR9R10, -CH=NOR12, -CH=NR7, -(CH2)pNR9R10, -
(CH2)pNHR11, or -CH=NNR12R12A, where R12 and R12A are the same or
different and each are independently selected from H, alkyl of 1 to 4
carbons, -OH, alkoxy of 1 to 4 carbons, -OC(=O)R7, -OC(=O)NR9R10, -
OC(=S)NR9R10, -O(CH2)pNR9R10, -O(CH2)pOR8, substituted or
unsubstituted arylalkyl having from 6 to 10 carbons, and substituted or
unsubstituted heterocyclylalkyl;
d) -S(O)yR12, -(CH2)pS(O)yR7, -CH2S(O)yR11 where y is 0,1 or 2; and
e) alkyl of 1 to 8 carbons, alkenyl of 2 to 8 carbons, or alkynyl of 2 to 8
carbons, where:
1) each alkyl, alkenyl, or alkynyl group is unsubstituted; or
2) each alkyl, alkenyl or alkynyl group is substituted with 1 to 3
groups selected from aryl of 6 to 10 carbons, heterocyclyl,
arylalkoxy, heterocycloalkoxy, hydroxylalkoxy, alkyloxy-alkoxy,
hydroxyalkylthio, alkoxy-alkylthio, F, Cl, Br, I, -CN, -NO2, -OH, -
OR7, - X2(CH2)pNR9R10, -X2(CH2)pC(=O)NR9R10, -
X2(CH2)pC(=S)NR9R10, -X2(CH2)pOC(=O)NR9R10, -
X2(CH2)PCO2R7, -X2(CH2)pS(O)yR7, -X2(CH2)pNR8C(=0)NR9R10,
-OC(=O)R7, -OC(=O)NHR12, O-tetrahydropyranyl, -NR9R10, -
NR8CO2R7, -NR8C(=0)NR9R10, -NR8C(=S)NR9R10, -
NHC(=NH)NH2, -NR8C(=O)R7, -NR8C(=S)R7, -NR8S(=O)2R7, -
S(O)yR7, -CO2R12, -C(=0)NR9R10, -C(=S)NR9R10, -C(=O)R12, -
CH2OR8, -CH=NNR12R12A, -CH=NOR12, -CH=NR7, -
CH=NNHCH(N=NH)NH2, -S(CO)2NR12R12a, -P(=OXOR8)2, -
OR11, and a monosaccharide of 5 to 7 carbons where each
hydroxyl group of the monosaccharide is independently either
unsubstituted or is replaced by H, alkyl of 1 to 4 carbons,
alkylcarbonyloxy of 2 to 5 carbons, or alkoxy of 1 to 4 carbons,
where X2 is O, S, or NR8; where
R7 is substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or
substituted or unsubstituted heterocyclyl;
Rs is H or alkyl having from 1 to 4 carbons;
p is from 1 to 4; and where either
1) R9 and R10 are each independently H, unsubstituted alkyl of 1 to 4
carbons, or substituted alkyl; or
2) R9 and R10 together form a linking group of the formula -(CH2)2
X1-(CH2)2-, wherein X1 is selected from -O-, -S-, and -CH2-;
and the stereoisomeric forms, mixtures of stereoisomeric forms, or pharmaceuticalry
acceptable salt and ester forms thereof.
In a preferred embodiment of the invention, there are provided compounds of
formula (I) wherein Ar1 and Ar2 are the same or different and are each selected from
thiophene, isothiazole, phenyl, oxazole, isoxazole, thiazole, imidazole, or other five or
six membered heterocycles comprising 1-3 atoms of-N-, -O-, or -S-, provided that Ar1
and Ar2 are not both phenyl; R1-R4 are the same or different and are each selected from
H, lower alkyl, -OH, -CH(R6)-CONR6aR6b, or any of RI-R4 can be taken together to
form a 3-7 member carbocyclic or heterocyclic ring, provided that R3 and R4 are not both
OH; R6A and R6B are independently H or lower alkyl; and n is 0,1, or 2; and in addition,
each of Ar1 or Ar2 may be independently optionally substituted with one or more
substituents independently selected from:
a) H, aryl, heterocyclyl, F, Cl, Br, I, -CN, -CF3, -NO2, -OH, -OR7, -
0(CH2)pNR9R10, -OC(=O)R7, -OC(=O)NR9R10, -O(CH2)POR8, -CH2OR8,
-NR2R10, -NR8S(=O)2R7, -NRgC(=O)R7, or -NR8C(=S)R7;
b) -CH2OR11, where R11 is the residue of an amino acid after the hydroxyl
group of the carboxyl group is removed;
c) NR8C(=0)NR9R10, -NR8C(=S)NR9R10, -CO2R12, -C(=O)R12, -
C(=0)NR9R10, -C(=S)NR9R10, -CH=NOR12, -CH=NR7, -(CH2)pNR9R10, -
(CH2)pNHR11, or -CH=NNR12R12A, where Ri2 and R12a are the same or
different and each are independently selected from H, alkyl of 1 to 4
carbons, -OH, alkoxy of 1 to 4 carbons, -OC(=O)R7, -OC(=O)NR9R10, -
OC(=S)NR9R10, -0(CH2)pNR9R10, -O(CH2)pOR8, substituted or
unsubstituted arylalkyl having from 6 to 10 carbons, and substituted or
unsubstituted heterocyclylalkyl;
d) -S(O)yR12, -(CH2)pS(O)yR7, -CH2S(O)yRn where y is 0,1 or 2; and
e) alkyl of 1 to 8 carbons, alkenyl of 2 to 8 carbons, or alkynyl of 2 to 8
carbons, where:
1) each alkyl, alkenyl, or alkynyl group is unsubstituted; or
2) each alkyl, alkenyl or alkynyl group is substituted with 1 to 3
groups selected from aryl of 6 to 10 carbons, heterocyclyl,
arylalkoxy, heterocycloalkoxy, hydroxylalkoxy, alkyloxy-alkoxy,
hydroxyalkylthio, alkoxy-alkylthio, F, Cl, Br, I, -CN, -NO2, -OH, -
OR7, - X2(CH2)pNR9R,0, -X2(CH2)pC(=O)NR9R10, -
X2(CH2)pC(=S)NR9Rio, -X2(CH2)pOC(=O)NR9R10, -
X2(CH2)pCO2R7, -X2(CH2)pS(O)yR7, -X2(CH2)pNR8C(=O)NR9R10,
-OC(=O)R7, -OC(=O)NHRi2,0-tetrahydropyranyl, -NR9R10, -
NR8CO2R7, -NR8C(=0)NR9R10, -NR8C(=S)NR9R10, -
NHC(=NH)NH2, -NR8C(=O)R7, -NR8C(=S)R7, -NR8S(=O)2R7, -
S(O)yR7, -CO2R,2, -C(=0)NR9R10, -C(=S)NR9R10, -C(=O)R12, -
CH2OR8, -CH=NNR12R12A, -CH=NOR12, -CH=NR7, -
CH=NNHCH(N=NH)NH2, -S(=O)2NR,2R12A, -P(=O)(ORs)2, -
OR11, and a monosaccharide of 5 to 7 carbons where each
hydroxyl group of the monosaccharide is independently either
unsubstituted or is replaced by H, alkyl of 1 to 4 carbons,
alkylcsrbonyloxy of 2 to 5 carbons, or alkoxy of 1 to 4 carbons,
where X2 is O, S, or NR8; where
R7 is substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or
substituted or unsubstituted heterocyclyl;
Rg is H or alkyl having from 1 to 4 carbons;
p is from 1 to 4; and where either
1) R9 and R10 are each independently H, unsubstituted alkyl of 1 to 4
carbons, or substituted alkyl; or
2) R9 and R10 together form a Unking group of the formula -(CH2)2
X1-(CH2)2-, wherein X1 is selected from -O-, -S-, and -CH2-;
and the stereoisomeric forms, mixtures of stereoisomeric forms, or pharmaceutically
acceptable salt and ester forms thereof.
In another embodiment of the invention, there is provided novel compounds of
the formula (11-A):
wherein
X is a bond, -CH2CH2-, -O-, -S(O)y-, -N(R8)-, -CHNORg)-, -CH=CH-, -CH2-CH=CH-,
C(=O), -C(R8)=N-, -N=C(R8)-, -C(=O)-N(R8)-, or -NR8-C(=O)-;
Rings A and B, together with the carbon atoms to which they are attached, are each
independently selected from:
a) a 6-membered aromatic carbocyclic ring in which from 1 to 3 carbon
atoms may be replaced by hetero atoms selected from oxygen, nitrogen
and sulfur; and
b) a 5-membered aromatic carbocyclic ring in which either:
i) one carbon atom may be replaced with an oxygen, nitrogen, or
sulfur atom;
ii) two carbon atoms may be replaced with a sulfur and a nitrogen
atom, an oxygen and a nitrogen atom, or two nitrogen atoms; or
iii) three carbon atoms may be replaced with three nitrogen atoms,
one oxygen and two nitrogen atoms, or one sulfur and two nitrogen
atoms;
R1 and R2 are each independently selected from:
a) H, C6-C10 aryl, heteroaryl, F, Cl, Br, I, -CN, -CF3, -NO2, -OH, -OR7, -
0(CH2)pNR9R10, -OC(=O)R7, -OC(=0)NR9R10, -O(CH2)POR8, -CH2OR8,
-NR9R10, -NR8S(=O)2R7, -NR8C(=O)R7, or-NR8C(=S)R7;
b) -CH2ORn;
c) -NRsC(=0)NR9Rio, -NR8C(=S)NR9R10, -CO2R12, -C(=O)Rl3, -
C(=O)NR9R10, -C(=S)NR9R10, -CH=NORI2, -CH=NR7, -(CH-OpNR8R10, -
(CH2)pNHRn, -CH=NNR12R12A, -C(=NR8)NR8AR8B -NR8C(=NH)R8a, -
d) -S(O)yR7, -(CHa^SCOJyR,, -CH2S(O)yR7; and
e) C1-C8 alkyl, C2-C8 alkenyl, or C2-C8 alkynyl, where:
1) each alkyl, alkenyl, or alkynyl group is unsubstituted; or
2) each alkyl, alkenyl or alkynyl group is independently substituted
with 1 to 3 groups independently selected from C6-C10 aryl,
heteroaryl, F, Cl, Br, I, CF3, -CN, -NO2, -OH, -OR7, -CH2OR8, -
NR9R1Of -O-(CH2)p-OH, -S-(CH2)P-OH, - Xi(CH2)pOR7,
Xi(CH2)pNR9R10, -Xi(CH2)pC(=O)NR9R10, -
Xi(CH2)pC(=S)NR9R10, -X,(CH2)pOC(=0)NR9Rio, -
Xi(CH2)pCO2R8, -Xi(CH2)pS(O)yR7, -Xi(CH2)pNR8C(=O)NR9R10,
-C(=O)R13, -CO2Rl2, -OC(=O)R7, -C(=0)NR9Rio, -
OC(=O)NR12Ri2a, O-tetrahydropyranyl, -C(=S)NR9Rio, -
CH=NNRi2Rl2A, -CH=NORl2, -CH=NR7, -
CH=NNHCH(N=NH)NH2, -NRgCO2R7, -NR8C(=O)NR9Ri0, -
NRgC(=S)NR10R10, -NHC(=NH)NH2, -NRgC(=O)R7, -
NR8C(=S)R7, -NRsSCOkR7, -S(O)yR7, -S(=O)2NR12R12A, -
P(=OXOR8)2, -OR11, and a C5-C7 monosaccharide where each
hydroxyl group of the monosaccharide is independently either
unsubstituted or is replaced by H, C1-C4 alkyl, C1-C4 alkoxy, or -
O-C(=O)R7;
R3 and R4 are the same or different and are each selected from H, C1-C4 alkyl, -OH, -
CH(R6)-CONR8AR8B, provided that R3 and R4 are not both OH, or R3 and R4,
together with the nitrogen to which they are attached, form a 3-7 member
heterocyclyl ring;
Rg is H, C1-C4 alkyl or the side chain of an ct-amino acid;
R7 is C1-C6 alkyl, C6-C10 aryl, or heteroaryl;
R8, R8A and R8B are each independently H, C1-C4 alkyl, or C6-C10 aryl;
R9 and R10 are independently selected from H, C1-C4 alkyl, and C6-C10 aryl; or R9 and
R10 together with the nitrogen to which they are attached, form a 3-7 member
heterocyclyl ring;
Rn is the residue of an amino acid after the hydroxyl group of the carboxyl group is
removed;
R12 and R12A are each independently selected from H, C1-C6 alkyl, cycloalkyl, C6-C10
aryl, and heteroaryl; or R12 and R12A, together with the nitrogen to which they are
attached, form a 5-7 member heterocyclyl ring;
R13 is H, C1-C6 alkyl, cycloalkyl, C6-C10 aryl, heteroaryl, -C(=O)R7, -C(=O)NR9R10, or -
C(=S)NR9R10;
X1 is-O-,-S-,-N(R8)-;
Y is selected from C1-C4 alkylene, C6-C10 arylene, heteroarylene, C3-C8 cycloalkylene,
heterocyclylene, -O-, -N(R8)-, -S(O)y, -CR8aCR8b-, -CH=CH-CH(R8)-, -
CH(R8)-CH=CH-, or -OC-; with the proviso that when Y is -O-, -N(R8)-, or -
S(O)y, m and n cannot be 0;
mis 0,1, 2 or 3;
nisO, 1,2 or 3;
p is from 1 to 4;
q is 0,1,2;
r is 0,1,2, or 3;
sisO, 1,2, or 3;
t is 2,3, or 4;
y is 0,1 or 2;
and the stereoisomcric forms, mixtures of stereoisomeric forms, or pharmaceutically
acceptable salt and ester forms thereof.
In a further embodiment, there are provided compounds of formula (II):
where X is -(CH2)-, -O-, -S(O)n-, -N(R5)-, -CH=CH-, or -CH2-CH=CH-; m is 0,
1,2 or 3; n is 0,1 or 2; R1-R4 are the same or different and are each selected from H,
lower alkyl, -OH, -CH(R6)-CONR7R8. or any of R1-R4 can be taken together to form a 3-
7 member carbocyclic or heterocyclic ring; R5 is H, lower alkyl, or -OH; R6, R7 and R8 is
H or lower alkyl; and ring A, together with the carbon atoms to which it is attached is
selected from:
a) a 6-membered carbocyclic ring in which from 1 to 3 carbon atoms may be
replaced by hetero atoms selected from oxygen, nitrogen and sulfur; and
b) a 5-membered carbocyclic ring in which either:
i) one carbon atom may be replaced with an oxygen, nitrogen, or sulfur
atom;
ii) two carbon atoms may be replaced with a sulfur and a nitrogen atom,
an oxygen and a nitrogen atom, or two nitrogen atoms; or
iii) three carbon atoms may be replaced with three nitrogen atoms, one
oxygen and two nitrogen atoms, or one sulfur and two nitrogen atoms;
and the stereoisomeric forms, mixtures of stereoisomeric forms, or pharmaceutically
acceptable salt and ester forms thereof.
As with any group of structurally related compounds which possess a particular
utility, certain groups and configurations are preferred for the compounds of the present
invention in their end-use application.
In some embodiments of formula (I-A) or (II-A), Y= -C(RiXR2), wherein Ri and
R2 are each independently selected from H or CpC* alkyl; and optionally, either Ri or R2
can combine with either R3 or R4 to form a 5-7 membered heterocyclic ring. Preferably,
either Ri combines with R3 or R4 to form
respectively.
In certain embodiments of formula (I-A), Ari and Ar2 are each independently
selected ftom a five or six membered heteroaryl comprising 1-3 atoms of-N-, -O-, or -S-
. Preferably, q=l. In preferred embodiments, Ari and Ar2 are each independently
selected from thienyl, isothiazolyl, pyridyl, oxazolyl, isoxazolyl, thiazolyl, and
imidazolyl, and more preferably, Ari and Ar2 are thienyl, and particularly Ari and Ar2
are 3-thienyl. In other preferred embodiments, Y is -O-, -S(O)y-» or -N(Rg)-. In another
preferred embodiment, Y is C1-C4 alkylene. In an additional embodiment, Y is -
CR8a=CR8b-, -CH=CH-CH(Rs)-, - CH(R8)-CH=CH-, or -O=C-. In certain preferred
embodiments, Y is C6-C 10 arylene or heteroarylene, and preferably, m=0 or 1 and n=0 or
1. More preferably, Y is
wherein X2 is -CH2-, -0-, -S(O)y. or -N(Rg)-; and X3, X4, and X5 are each independently
selected from -CH-, or -N-. Most preferably, Y is phenylene. In another more preferred
embodiment, Y is
In yet another embodiment, Y is furanylene. In further preferred embodiments, Y is C3-
Cg cycloalkylene or heterocyclylene. Preferably, Y is
In other embodiments of formula (I-A), Ari is phenyl and A12 is a five or six
membered heteroaryl comprising 1-3 atoms of-N-, -O-, or -S-. Preferably, q=l. In other
preferred embodiments, Ari and At? are each independently phenyl, thienyl, isothiazolyl,
pyridyl, oxazolyl, isoxazolyl, thiazolyl, and imidazolyl. In further preferred
embodiments, Arj is phenyl and Ar2 is thienyl, isothiazolyl, pyridyl, oxazolyl, isoxazolyl,
thiazolyl, and imidazolyl, and more preferably, Ari is phenyl and Ar2 is thienyl, and
particularly, Ar2 is 3-thienyl. In other preferred embodiments, Y is -O-, -S(O)y-, or -
N(R«)-. In another preferred embodiment, Y is Ci-C4alkylene. In an additional
embodiment, Y is -CR8a=CR8b-, -CH8=CH-CH(R8)-, - CH(R8)-CH=CH-, or -OC-. In
certain preferred embodiments, Y is Q-C10 arylene or heteroarylene, and preferably,
m=0 or 1 and n=0 or 1. More preferably, Y is
wherein X2 is -CH2, -O-, -S(O)y-, or -N(R8)-; and X3, X4, and X5 are each independently
selected from -CH-, or -N-. Most preferably, Y is phenylene. In another more preferred
embodiment, Y is
In yet another embodiment, Y is furanylene. In further preferred embodiments, Y is C3-
Cg cycloalkylene or heterocydylene. Preferably, Y is
In another embodiment of formula (I-A), Ar1 and Ax2 is phenyl. Preferably, q=l.
In other preferred embodiments, Y is -O-, -S(O)y, or -N(Rg)-. In another preferred
embodiment, Y is C1-C4 alkylene. In an additional embodiment, Y is -CRsa=CR«b-, -
CH=CH-CH(R«>, - CH(R«)-CH=CH-, or -OC-. In certain preferred embodiments, Y is
C6-C10 arylene or heteroarylene, and preferably, nrK) or 1 and n=0 or 1. More
preferably, Y is
wherein X2 is -CH2-, -O-, -S(O)y-, or -N(Rs)-; and X3, X4, and X5 are each independently
selected from -CH-, or -N-. Most preferably, Y is phenylene. In another more preferred
embodiment, Y is
In yet another embodiment, Y is furanylene. In further preferred embodiments, Y is C3-
C8 cycloalkylene or heterocyclylene. Preferably, Y is
In an additional embodiment of formula (I-A), Y is -O-, -S(0)r, -N(R8)-, C1-C4
alkylene, -CR8A=CR8B-, -CH=CH-CH(R8)-, - CH(R8)-CH=CH-, -OC-,
wherein X2 is -CH2-, -O-, -S(O)y-, or -N(Rs)-; and X3, X4, and X5 are each independently
selected from -CH-, or -N-. In other preferred embodiments, Y is -O-, -S(O)y-, or -
N(Rg)-. In another preferred embodiment, Y is C1-C4 alkylene. In an additional
embodiment, Y is -CR8ACR8B-, -CH=CH-CH(R8)-, - CH(R8>CH=CH-, or -OC-. In
certain preferred embodiments, Y is C6-Cioarylene or heteroarylene, and preferably,
m=0 or 1 and n=0 or 1. More preferably, Y is
wherein X2 is -CH2-, -O-, -S(O)y-, or -N(R8)-; and X3, X4, and X5 are each independently
selected from -CH-, or -N-. Most preferably, Y is phenylene. In another more preferred
embodiment, Y is
In yet another embodiment, Y is furanylene. In further preferred embodiments, Y is C3-
Cg cycloalkylene or heterocyclylene. Preferably, Y is
In yet another embodiment of formula (I-A), q=l.
In a further embodiment of formula (I-A), Ari and A12 are each independently
selected from phenyl and thienyl, and q=l. Preferably An and A12 are each
independently selected from phenyl and 3-thienyl, and q=l. In other preferred
embodiments, Y is -O-, -S(O)y-, or -N(R8)-. In another preferred embodiment, Y is Ci-
C4 alkylene. In an additional embodiment, Y is -CR8ARw, -CH=CH-CH(R8)-, -
CH(R8)-CH=CH-, or -O=C-. In certain preferred embodiments, Y is Q-C10 arylene or
heteroarylene, and preferably, m=0 or 1 and n=0 or 1 • More preferably, Y is
wherein X2 is -CH2-, -O-, -S(O)y, or -N(Rg)-; and X3, X4, and X5 are each independently
selected from -CH-, or -N-. Most preferably, Y is phenylene. In another more preferred
embodiment, Y is
In yet another embodiment, Y is furanylene. In further preferred embodiments, Y is C3-
Cg cycloalkylene or heterocyclylene. Preferably, Y is
Preferred embodiments of formula (I-A) are compounds wherein Ari and Ar2 are
the same or different and are each selected from thiophene, isothiazole, phenyl, pyridyl,
oxazole, isoxazole, thiazole, imidazole, provided that Art and Ar2 are both not phenyl
and when Ari is phenyl, Ar2 is not pyridyl.
Preferred embodiments of formula (I) are compounds wherein Arj and Ar2 are
the same or different and are each selected from thiophene, isothiazole, phenyl, oxazole,
isoxazole, thiazole, imidazole, provided that Ari and Ar2 are both not phenyl. Other
preferred embodiments are those where Ari and A12 are each independently substituted.
Additional preferred embodiments of formula (I) are given below:
1) Compounds in which Ari, Ar2 or both are thiophene;
2) Compounds in which Ari, Ar2 or both are isothiazole;
3) Compounds in which An, Ar2 or both are pyridyl;
4) Compounds in which Ari, Ar2 or both are oxazole;
5) Compounds in which Ar1, Ar2 or both are isoxazole;
6) Compounds in which Ar1, Ar2 or both are thiazole;
7) Compounds in which Ari, Ar2 or both are imidazole,
8) Compounds in which Ar1 is phenyl and Ar2 is thiophene.
In a preferred embodiment of the of formula (I-A), there are provided compounds
as represented in Table 1:
In certain preferred embodiments of the present invention, there are provided
compounds of formula (II) or (II-A) where q=l.
In another embodiment of formula (II-A), X is a bond, -CH2CH2-, -O-, -N(CH3)-,
or -CH=CH-, and preferably X is a bond.
In certain embodiments of formula (II-A), Y is -O-, -S(O)y. -N(R*>, C1-C4
alkylene, -CR«a=CR«b-, -CH=CH-CH(R«)-, - CH(R«)-CH=CH-, -OC-,
wherein X2 is -CH2-, -O-, -S(O)y-, or -N(R«>; and X3, X4, and X5 are each independently
selected from -CH-, or -N-. In other preferred embodiments, Y is -O-, -S(O)y-» °* -
N(R8>. In another preferred embodiment, Y is C1-C4 alkylene. In an additional
embodiment, Y is -CR8a=CR«b-, -CH=CH-CH(R«>, - CH(R«)-CH<:h- or in> certain preferred embodiments, Y is Q-Cio arylene or heteroarylene, and preferably,
m=0 or 1 and n=0 or 1. More preferably, Y is
wherein X2 is -CH2-, -O-, -S(O)y, or -NCRg)-; and X3, X4, and X5 are each independently
selected from -CH-, or -N-. Most preferably, Y is phenylene. In another more preferred
embodiment, Y is
In farther preferred embodiments, Y is C3-C8 cycloalkylene or heterocyclylene.
Preferably, Y is
In additional embodiments of formula (II-A), rings A and B, together with the
carbon atoms to which they are attached, are each independently selected from
phenylene, thienylene, isothiazolylene, pyridylene, oxazolylene, isoxazolylene,
thiazolylene, imidazolylene. In a preferred embodiment, ring A is phenylene, and more
preferably, rings A and B are phenylene. In another preferred embodiment, rings A and
B are thienylene, and more preferably, rings A and B are 2,3-thienylene. In preferred
embodiments, q=l. In further preferred embodiments, ring A is phenylene and ring B is
2,3-thienylene. In other preferred embodiments, X is a bond, -CH2CH2-, -O-, -N(CH3)-,
or -CH=CH-. In a more preferred embodiment, Y is -O-, -S(O)y-, -N(R8), C1-C4
alkylene, -CR8A=CR8B-, -CH=CH-CH(R8)-, - CH(R8)-CH=CH-, -OC-,
wherein X2 is -CH2-, -O-, -S(O)y-, or -N(R8)-, and X3, X4, and X5 are each independently
selected from -CH-, or -N-. In other preferred embodiments, Y is -O-, -S(O)y-, or -N(R8)-
. In another preferred embodiment, Y is C1-C4 alkylene. In an additional embodiment,
Y is -CR8a=CR8b-, -CH=CH-CH(R8)-, - CH(R8)-CH=CH-, or -OC-. In certain
preferred embodiments, Y is C6-C10 arylene or heteroarylene, and preferably, m=0 or 1
and n=0 or 1. More preferably, Y is
wherein X2 is -CH2-, -0-, -S(O)y, or -N(Rs)s and X3, X4, and X5 are each independently
selected from-CH-, or-N-. Most preferably, Y is phenyiene. In another more preferred
embodiment, Y is
In further preferred embodiments, Y is C3-C8 cycloalkylene or heterocyclylene.
Preferably, Y is
In an especially preferred embodiment, X is a bond, and Y is -CH2- and n=0.
Preferred embodiments of formula (II) are compounds wherein ring A is selected
from thiophene, isothiazole, phenyl, pxazole, isoxazole, thiazole, and imidazole. Other
preferred embodiments are those where the benzo ring and ring A are each independently
substituted.
Other preferred embodiments of formula (II) are given below:
1) Compounds in which A is benzo and X is a bond, Le. -(CH2)m, where m=0;
2) Compounds in which A is benzo and X is -O-;
3) Compounds in which A is benzo and X is -NCH3;
4) Compounds in which A is benzo and X is -S-; and
5) Compounds in which R3 and R4 are taken together with the nitrogen to which
they are attached to form a morpholine ring.
In a particularly preferred embodiment of formula (II-A), there are provided
compounds as represented in Table 2:
For example, compounds H-l and 11-22 have the following structures:
Definitions
As used herein, the term "alkyl" refers to a substituted or unsubstituted, branched
or straight hydrocarbon chain of 1 to 8 carbon atoms, which is formed by the removal of
one hydrogen atom. In certain preferred embodiments, the alkyl group contains from 1 to
6 carbon atoms. In other preferred embodiments, the alkyl group contains from 1 to 4
carbon atoms. A designation such as "C1-C4 alkyl" refers to an alkyl radical containing
from 1 to 4 carbon atoms. Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl,
isobutyl, sec-butyl, t-butyl, pentyl, 2-methylpentyl, hexyl, 2-memylhexyl, 2,3-
dimethylhexyl, heptyl, octyl, etc.
As used herein, the term "lower alkyl," refers to a d to Qs saturated straight
chain, branched, or cyclic hydrocarbon, which are optionally substituted. Lower alkyl
groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl,
isobutyl, t-butyl, n-pentyl, cyciopentyi, isopentyl, neopentyl, n-hexyl, isohexyl,
cyclohexyl, 3-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl and the like.
As used herein, "alkenyl" refers to a substituted or unsubstituted, straight or
branched hydrocarbon chain containing from 2 to 8 carbon atoms having one or more
carbon-carbon double bonds which may occur in any stable point along the chain, and
which is formed by removal of one hydrogen atom. A designation "C2-C8 alkenyl" refers
to an alkenyl radical containing from 2 to 8 carbon atoms. Examples include ethenyl,
propenyl, isopropenyl, 2,4-pentadienyli etc.
As used herein, "alkynyl" refers to a substituted or unsubstituted, straight or
branched hydrocarbon radical containing from 2 to 8 carbon atoms, having one or more
carbon-carbon triple bonds which may occur in any stable point along the chain, and
which is formed by removal of one hydrogen atom. A designation "C2-C8 alkynyl" refers
to an alkynyl radical containing from 2 to 8 carbon atoms. Examples include ethynyl,
propynyl, isopropynyl, 3,5-hexadiynyl, etc.
As used herein, "carbocycle" or "carbocyclic" refer to a substituted or
unsubstituted, stable monocyclic or bicyclic hydrocarbon ring which is saturated,
partially unsaturated or unsaturated, and contains from 3 to 10 carbon atoms.
Accordingly the carbocyclic group may be aromatic or non-aromatic. The bonds
connecting the endocychc carbon atoms of a carbocyclic group may be single, double,
triple, or part of a fused aromatic moiety. Carbocycles are intended to include the
"cycloalkyl" and "aryl" compounds defined herein.
As used herein, the term "cycloalkyl" refers to a substituted or unsubstituted
hydrocarbon ring of 3 to 7 carbon atoms fonned by the removal of one hydrogen atom.
A designation such as "C5-C7 cycloalkyl" refers to a cycloalkyl radical containing from 5
to 7 carbon atoms. Examples include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl,
etc.
As used herein, the terms "heterocycle" or "heterocyclic" refer to a substituted or
unsubstituted, saturated, partially unsaturated or unsaturated, stable 3 to 10 membered
monocyclic or bicyclic ring wherein at least one member of the ring is a hetero atom.
Accordingly die heterocyclic group may be aromatic or non-aromatic. Typically,
heteroatoms include, but are not limited to, oxygen, nitrogen, sulfur, selenium, and
phosphorus atoms. Preferable heteroatoms are oxygen, nitrogen and sulfur. The
nitrogen and sulfur heteroatoms may be optionally oxidized, and the nitrogen may be
optionally substituted in non-aromatic rings. The bonds connecting the endocyclic atoms
of a heterocyclic group may be single, double, triple, or part of a fused aromatic moiety.
Heterocycles are intended to include "heterocyclyl" and "heteroaryl" compounds defined
herein.
As used herein, "heterocyclyl" refers to a substituted or unsubstituted, saturated,
or partially unsaturated, stable 3 to 7 membered heterocyclic ring which is formed by
removal of one hydrogen atom. Examples include epoxyethyl, pyrrolidyl, pyrazolidinyl,
piperidyl, pyranyl, oxazolinyl, morpholino, morpholinyl, piperazinyl, etc.
Examples of heterocycles include, but are not limited to, 2-pyrrolidinyl, 2H-
pyrrolyl, 4-piperidinyl, 6H- 1,2,5-thiadiazinyl, 2H,6H- 1,5,2-dithiazinyl, furanyl,
furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, isoxazolyl, morpholinyl,
oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl,
oxazolidinyl., oxazolyl, piperazinyl, piperidinyl, pteridinyl, piperidonyl, 4-piperidinyl,
purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridinyl,
pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, tetrahydrofuranyl, 6H-\,2,5-
thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl,
thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, triazinyl, 1.2,3-
triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and tetrazole. Suitable
heterocycles are also disclosed in The Handbook of Chemistry and Physics, 76th Edition,
CRC Press, Inc., 1995-1996, pages 2-25 to 2-26, the disclosure of which is hereby
incorporated by reference.
Preferred heterocyclic groups formed with a nitrogen atom include, but are not
limited to, pyrrolidinyl, piperidinyl, piperidino, morpholinyl, morpholino,
thiomorpholino, N-methylpiperazinyl, indolyl, isoindolyl, imidazole, imidazoline,
oxazoline, oxazole, triazole, thiazoline, thiazole, isothiazole, thiadiazoles, triazines,
isoxazole, oxindole, indoxyl, pyrazole, pyrazolone, pyrimidine, pyrazine, quinoline,
iosquinoline, and tetrazole groups.
Preferred heterocyclic groups formed with an oxygen atom include, but are not
limited to, furan, tetrahydroraran, pyran, benzofurans, isobenzofurans, and
tetrahydropyran groups. Preferred heterocyclic groups formed with a sulfur atom
include, but are not limited to, thiophene, thianaphthene, tetrahydrothiophene,
tetrahydrothiapyran, and benzothiophenes.
Preferred aromatic heterocyclic groups include, but are not limited to, pyridyl,
pyrimidyl, pyrrolyl, furyl, thienyl, imidazolyl, triazolyl, tetrazolyl, quinolyl, isoquinolyl,
benzoimidazolyl, thiazolyl, pyrazolyl, and benzothiazolyl groups.
As used herein, the term "substituted" refers to replacement of one or more
hydrogen atoms on an indicated group with a selected group referred to herein as a
"substituent", provided that the substituted atom's valency is not exceeded, and that the
substitution results in a stable compound. A substituted group has 1 to 5, preferably 1 to
3, and more preferably 1, independently selected substituents. Preferred substituents
include, but are not limited to F, Cl, Br, I, OH, OR, NH2, NR2, NHOH, NO2, CN, CF3,
CF2CF3, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, CrC6 alkoxy, C3-C7 cycloalkyl,
heterocyclyl, C6-C10 aryl, heteroaryl, arylalkyl, C(=O)R, COOH, CO2R, O-C(=O)R,
C(=O)NRR,, NRC(=O)R\ NRCW, OC(=O)NRR, -NRC(=O)NRR\ -NRC(=S)NRR,
and -SQ2NRR1, wherein R and R' are each independently hydrogen, C1-C6 alkyl, or C6-
C10 aryl.
As used herein, the term "aryl" refers to a substituted or unsubstituted, aromatic
carbocyclic ring containing from 6 to 10 carbon atoms, which is formed by removal of
one hydrogen atom. Examples include phenyl, naphthyl, indenyl, etc.
As used herein, the term "heteroaryl" refers to a substituted or unsubstituted 5 to
10 membered aromatic heterocyclic ring, which is formed by removal of one hydrogen
atom. Examples include pyrrolyl, pyridyl, pyrimidinyl, pyrazinyl, tetrazolyl, indolyl,
quinolinyl, purinyl, imidazolyl, thienyl, tbiazolyl, benzothiazolyl, furanyl, benzofuranyl,
1,2,4-tbiadiazolyl, isotbiazolyl, triazoyl, tetrazolyl, isoquinolyl, benzothienyl,
isobenzofuryl, pyrazolyl, carbazolyl, benzimidazolyl, isoxazolyl, etc.
As used herein, the term "alkylene" refers to a substituted or unsubstituted,
branched or straight chained hydrocarbon of 1 to 8 carbon atoms, which is formed by the
removal of two hydrogen atoms. A designation such as "C1-C4 alkylene" refers to an
alkylene radical containing from 1 to 4 carbon atoms. Examples include methylene (-
CH2-), propylidene (CH3CH2CH=), 1,2-ethandiyl (-CH2CH2-), etc.
As used herein, the term "cycloalkylene" refers to substituted or unsubstituted
carbocyclic ring of 3 to 8 carbon atoms, which is formed by removal of two hydrogen
atoms. A designation such as "C3-C8 cycloaUcylene" refers to an cycloalkylene radical
containing from 3 to 8 carbon atoms. Examples include cyclopropylene (-C3H4-),
cyclopenrylene (-C5H8-), cyclohexylene (-C6H10-), etc.
As used herein, the term "heterocyclylene" refers to a substituted or
unsubstituted, saturated, or partially unsaturated, stable 3 to 7 membered heterocyclic
ring, which is formed by removal of two hydrogen atoms. Examples include
epoxyethylene, pyrrolidylene, pyrrolidylidene, pyrazolidinylene, piperidylene,
pyranylene, morpholinylidene, etc.
As used herein, the term "arylene" refers to a substituted or unsubstituted
aromatic carbocyclic ring containing from 6 to 10 carbon atoms, which is formed by
removal of two hydrogen atoms. Examples include phenylene (-C6H4-), naphthylene (-
C10H6-), etc. The "phenylene" group has the following structure:
As used herein, the term "heteroarylene" refers to a substituted or unsubstituted 5
to 10 membered aromatic heterocyclic ring formed by removal of two hydrogen atoms.
Examples include the heteroarylene groups which correspond to the respective heteroaryl
compounds described above, and in particular, include thienylene (-C4H2S-) , pyridylene
(-C5H3N-), pyrimidinylene (-C3H2N2-), quinolinylene (-C9H5N-), thiazolylene (-C3HNS-
), etc. The "thienylene" group has the following structure:
The "pyridylene" group has the following structure:
As used herein, the term "alkoxy" refers to an oxygen radical substituted with an
alkyl group. Preferably, the alkoxy group contains from 1 to 6 carbon atoms. A
designation such as "C1-C4 alkoxy" refers to an alkoxy containing from 1 to 4 carbon
atoms. Examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy,
sec-butoxy, t-butoxy, etc.
As used herein, the term "arylalkyl" refers to an aryl-substituted alkyl group and
includes benzyl, bromobenzyl, diphenylmethyl, triphenylmethyl, phenylethyl,
diphenylethyl, etc.
As used herein, "C5-C7monosaccharide" refers to simple sugars of the formula
(CH2O)n wherein n=5-7. The monosaccharides can be straight-chain or ring systems,
and can include a saccharose unit of the formula -CH(0H)-C(=O)-. Examples include
erythrose, threose, ribose, arabinose, xylose, lyxose, allose, altrose, glucose, mannose,
gulose, idose, galactose, talose, erythulose, ribulose, xyulose, psicose, fructose, sorbose,
tagatose, erythropentulose, threopentulose, glycerotetrulose, glucopyranose,
fructofuranose, etc.
As used herein, the term "amino acid" refers to a molecule containing both an
amino group and a carboxyl group. Embodiments of amino acids include cc-amino, ß-
amino, y-amino acids. The a-amino acids have a general formula HOOC-CH(side
chain)-NH2. The amino acids can be in their D, L or racemic configurations. Amino
acids include naturally-occurring and non-naturally occurring moieties. The naturally-
occurring amino acids include the standard 20 a-amino acids found in proteins, such as
glycine, serine, tyrosine, proline, histidine, glutamine, etc. Naturally-occurring amino
acids can also include non-a-amino acids (such as P-alanine, y-aminobutyric acid,
homocysteine, etc.), rare (such as 4-hydroxyproline, 5-hydroxylysine, 3-methylhistidine,
etc.) and non-protein (such as citrulline, omithine, canavanine, etc.) amino acids. Non-
naturally occurring amino acids are well-known in the art, and include analogs of natural
amino acids. See Lehninger, A. L. Biochemistry, 2nd ed.; Worth Publishers: New York,
1975; 71-77', me disclosure of which is incorporated herein by reference. Non-naturally
occurring amino acids also include a-amino acids wherein the side chains are replaced
with synthetic derivatives. Representative side chains of naturally occurring and non-
naturally occurring a-amino acids are shown below in Table A.
As used herein, the tenn "subject" refers to a warm blooded animal such as a
mammal, preferably a human, or a human child, which is afflicted with, or has the
potential to be afflicted with one or more diseases and conditions described herein.
As used herein, a "therapeutically effective amount" refers to an amount of a
compound of the present invention which is effective in reducing, eliminating, treating or
controlling the symptoms of the herein-described diseases and conditions. The term
"controlling" is intended to refer to all processes wherein there may be a slowing,
interrupting, arresting, or stopping of the progression of the diseases and conditions
described herein, but does not necessarily indicate a total elimination of all disease and
condition symptoms, and is intended to include prophylactic treatment
As used herein, the term "pharmaceutically acceptable" refers to those
compounds, materials, compositions, and/or dosage forms which are, within the scope of
sound medical judgment, suitable for contact with the tissues of human beings and
animals without excessive toxicity, irritation, allergic response, or other problem
complications commensurate with a reasonable benefit/risk ratio.
As used herein, "pharmaceutically acceptable salts" refer to derivatives of the
disclosed compounds wherein the parent compound is modified by making acid or base
salts thereof. The pharmaceutically acceptable salts include the conventional non-toxic
salts or the quaternary ammonium salts of the parent compound formed, for example,
from non-toxic inorganic or organic acids. For example, such conventional non-toxic
salts include those derived from inorganic acids such as hydrochloric, sulfuric, sulfamic,
phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic,
propionic, succinic, tartaric, citric, glutamic, benzoic, salicylic, toluenesulfonic, oxalic,
and the like.
The pharmaceutically acceptable salts of the present invention can be synthesized
from the parent compound which contains a basic or acidic moiety by conventional
chemical methods. Generally, such salts can be prepared by reacting the free acid or
base forms of these compounds with a stoichiometric amount of the appropriate base or
acid in water or in an organic solvent, or in a mixture of the two. Generally, nonaqueous
media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists
of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack
Publishing Company, Easton, PA, 1985, p. 1418, the disclosure of which is hereby
incorporated by reference.
As used herein, "prodrug" is intended to include any covalently bonded carriers
which release the active parent drug according to the compounds of the present invention
in vivo when such prodrug is administered to a mammalian subject. Since prodrugs are
known to enhance numerous desirable qualities of Pharmaceuticals (e.g., solubility,
bioavailability, manufacturing, etc.), the compounds of the present invention may be
delivered in prodrug form. Thus, the present invention contemplates prodrugs of the
claimed compounds, compositions containing the same, and methods of delivering the
same. Prodrugs of a compound of the present invention may be prepared by modifying
functional groups present in the compound in such a way that the modifications are
cleaved, either in routine manipulation or in vivo, to the parent compound. Accordingly,
prodrugs include, for example, compounds of the present invention wherein a hydroxy,
amino, or carboxy group is bonded to any group that, when the prodrug is administered
to a mammalian subject, cleaves to form a free hydroxyl, free amino, or carboxylic acid,
respectively. Examples include, but are not limited to, acetate, formate and benzoate
derivatives of alcohol and amine functional groups; and alkyl, cycloalkyl, aryl, and
alkylaryl esters such as methyl, ethyl, cyclopropyl, phenyl, benzyl, and phenethyl esters,
etc.
The present invention provides a method of treating diseases and conditions in a
subject in need thereof comprising administering to said subject a therapeutically
effective amount of a compound of formula (I), (I-A), (II), or (II-A). For example, the
compounds of formula (I), (I-A), (II), or (II-A) can be used in the treatment of sleepiness,
preferably sleepiness associated with narcolepsy, promotion of wakefulness, treatment of
Parkinson's disease, cerebral ischemia, stroke, sleep apneas, eating disorders, preferably
eating disorders associated with a disease, in particular, wherein the disease is anorexia
nervosa, stimulation of appetite and weight gain, treatment of attention deficit
hyperactivity disorder, enhancing function in disorders associated with hypofunctionality
of the cerebral cortex, including, but not limited to, depression, schizophrenia, fatigue, in
particular, fatigue associated with neurologic disease, such as multiple sclerosis, chronic
fatigue syndrome, and improvement of cognitive dysfunction.
The identification of those subjects who are in need of treatment of herein-
described diseases and conditions is well within the ability and knowledge of one skilled
in the art A clinician skilled in the art can readily identify, by the use of clinical tests,
physical examination and medical/family history, those subjects who are in need of such
treatment.
A therapeutically effective amount can be readily determined by the attending
diagnostician, as one skilled in the art, by the use of conventional techniques and by
observing results obtained under analogous circumstances. In determining the
therapeutically effective amount, a number of factors are considered by the attending
diagnostician, including, but not limited to: the species of subject; its size, age, and
general health; the specific disease involved; the degree of involvement or the severity of
the disease; the response of the individual subject; the particular compound administered;
the mode of administration; the bioavailabiliry characteristic of the preparation
administered; the dose regimen selected; the use of concomitant medication; and other
relevant circumstances.
The amount of a compound of formula (I), (I-A), (II), or (II-A) which is required
to achieve the desired biological effect will vary depending upon a number of factors,
including the dosage of the drug to be administered, the chemical characteristics (e.g.,
hydrophobicity) of the compounds employed, the potency of the compounds, the type of
disease, the diseased state of the patient, and the route of administration, hi general
terms, the compounds of this invention may be provided in an aqueous physiological
buffer solution containing about 0.1 to 10% w/v compound for parenteral administration.
Typical dose ranges are from about 1 ug/kg to about 1 g/kg of body weight per day; a
preferred dose range is from about 0.01 mg/kg to 100 mg/kg of body weight per day.. A
preferred daily dose for adult humans includes about 25,50,100 and 200 mg, and an
equivalent dose in a human child. The preferred dosage of drug to be administered is
likely to depend on such variables as the type and extent of progression of the disease or
disorder, the overall health status of the particular patient, the relative biological efficacy
of the compound selected, and formulation of fee compound excipient, and its route of
administration.
The compounds of the present invention are capable of being administered in unit
dose forms, wherein the term "unit dose" means a single dose which is capable of being
administered to a patient, and which can be readily handled and packaged, remaining as a
physically and chemically stable unit dose comprising either the active compound itself,
or as a pharmaceutically acceptable composition, as described hereinafter. As such,
typical daily dose ranges are from about 0.1 to 100 mg/kg of body weight By way of
general guidance, unit doses for humans range from about 0.1 mg to about 1000 mg per
day. Preferably the unit dose range is from about 1 to about 500 mg administered one to
four times a day, and even more preferably from about 10 mg to about 300 mg, two
times a day. In an alternate method of describing an effective dose, a preferred oral unit
dose is one that is necessary to achieve a blood serum level of about 0.05 to 20 µg/ml,
and more preferably, of about 1 to about 20 µg/ml in a subject.
Compounds provided herein can be formulated into pharmaceutical compositions
by admixture with one or more pharmaceutically acceptable excipients. Such
compositions may be prepared for use in oral administration, particularly in the form of
tablets or capsules; or parenteral administration, particularly in the form of liquid
solutions, suspensions or emulsions; or intranasally, particularly in the form of powders,
nasal drops, or aerosols; or dermally, for example, topically or via trans-dermal patches.
The compositions may conveniently be administered in unit dosage form and
may be prepared by any of the methods well known in the pharmaceutical art, for
example, as described in Remington: The Science and Practice of Pharmacy, 20th ed.;
Gennaro, A. R., Ed.; Lippincott Williams & Wilkins: Philadelphia, PA, 2000.
Pharmaceutically compatible binding agents, and/or adjuvant materials can be included
as part of the composition. Oral compositions will generally include an inert diluent
carrier or an edible carrier.
The tablets, pills, powders, capsules, troches and the like can contain one or more
of any of the following ingredients, or compounds of a similar nature: a binder such as
microcrystalline cellulose, or gum tragacanth; a diluent such as starch or lactose; a
disintegrants such as starch and cellulose derivatives; a lubricant such as magnesium
stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or
saccharin; or a flavoring agent such as peppermint, or methyl salicylate. Capsules can be
in the form of a hard capsule or soft capsule, which are generally made from gelatin
blends optionally blended with plasticizers, as well as a starch capsule. In addition,
dosage unit forms can contain various other materials that modify the physical form of
the dosage unit, for example, coatings of sugar, shellac, or enteric agents. Other oral
dosage forms syrup or elixir may contain sweetening agents, preservatives, dyes,
colorings, and flavorings. In addition, the active compounds may be incorporated into
fast dissolve, modified-release or sustained-release preparations and formulations, and
wherein such sustained-release formulations are preferably bi-modal.
Preferred formulations include pharmaceutical compositions in which a
compound of the present invention is formulated for oral or parenteral administration, or
more preferably those in which a compound of the present invention is formulated as a
tablet Preferred tablets contain lactose, cornstarch, magnesium silicate, croscarmellose
sodium, povidone, magnesium stearate, or talc in any combination. It is also an aspect of
the present disclosure mat a compound of the present invention may be incorporated into
a food product or a liquid.
Liquid preparations for administration include sterile aqueous or nonaqueous
solutions, suspensions, and emulsions. The liquid compositions may also include
binders, buffers, preservatives, chelating agents, sweetening, flavoring and coloring
agents, and the like. Nonaqueous solvents include alcohols, propylene glycol,
polyethylene glycol, vegetable oils such as olive oil, and organic esters such as ethyl
oleate. Aqueous carriers include mixtures of alcohols and water, buffered media, and
saline. In particular, biocompatible, biodegradable lactide polymer, lactide/glycolide
copolymer, or polyoxyethylene-polyoxypropylene copolymers may be useful excipients
to control the release of the active compounds. Intravenous vehicles can include fluid
and nutrient replenishers, electrolyte replenishers, such as those based on Ringer's
dextrose, and the like. Other potentially useful parenteral delivery systems for these
active compounds include ethylene-vinyl acetate copolymer particles, osmotic pumps,
implantable infusion systems, and liposomes.
Alternative modes of administration include formulations for inhalation, which
include such means as dry powder, aerosol, or drops. They may be aqueous solutions
containing, for example, polyoxyethylene-9-lauryl ether, glycocholate and deoxycholate,
or oily solutions for administration in the form of nasal drops, or as a gel to be applied
intranasally. Formulations for buccal administration include, for example lozenges or
pastilles and may also include a flavored base, such as sucrose or acacia, and other
excipients such as glycocholate. Formulations suitable for rectal administration are
preferably presented as unit-dose suppositories, with a solid based carrier, such as cocoa
butter, and may include a salicylate. Formulations for topical application to the skin
preferably take the form of an ointment, cream, lotion, paste, gel, spray, aerosol, or oil.
Carriers which can be used include petroleum jelly, lanolin, polyethylene glycols,
alcohols, or their combinations. Formulations suitable for transdermal administration
can be presented as discrete patches and can be lipophilic emulsions or buffered, aqueous
solutions, dissolved and/or dispersed in a polymer or an adhesive.
The compounds of the current invention can be employed as the sole active
ingredient in a pharmaceutical composition. Alternatively, they can be used in
combination or combined with other pharmaceutical agents associated with other disease
states. In particular, the compounds of formula (I), (I-A), (II), or (Q-A) can be combined
with agents that are useful for the treatment of impaired cognition associated with
various disease states including, but not limited to, age, trauma, stress or transient
impairment due to chemical imbalance or toxicity, hypersornnia, depression, Alzheimer's
Disease, non-Alzheimer's dementias, including Lewy body dementia, vascular dementia
and Binswanger's dementia, schizophrenia, and the like. The present invention would
encompass, therefore, combinations of the compounds of the current invention with
ebumane analogs, heterocyclic inducers of tyrosine hydroxylase, 3,4-diphenyl chromans,
tacrine metabolites, aza-cyclic compounds, polyamine compounds, or thiamine;
nonanticholinergic antidepressants such as benzodiazepines; phenothiazines aliphatic
such as chlorpromazine; piperidines such as thioridazine; piperazines such as
trifluoperazine, fluphenazine and perphenazine; dibenzoxazepines such as loxapine;
dihydroindolones such as molindone; thioxanthenes such as thiothixene; butyrophenones
such as haloperidol; diphenylbutyl-piperidines such as pimozide; dibenzodiazepine such
as clozapine; benztsoxazole such as risperidone; thienobenzodiazepine such as
olanzapine; dibenzothiazepine such as quetiapine; imidazolidinone such as sertindole,
benzisothiazoryl-piperazine such as ziprasidone, and the like.
Synthesis
The compounds of the present invention may be prepared in a number of ways
well known to those skilled in the art The compounds can be synthesized, for example,
by the methods described below, or variations thereon as appreciated by the skilled
artisan. The appropriate modifications and substitutions being readily apparent and well
known or readily obtainable from the scientific literature to those skilled in the art.
It will be appreciated that the compounds of the present invention may contain
one or more asymmetrically substituted carbon atoms, and may be isolated in optically
active or racemic forms. Thus, all chiral, diastereomeric, racemic forms and all
geometric isomeric forms of a structure are intended, unless the specific stereochemistry
or isomeric form is specifically indicated. It is well known in the art how to prepare and
isolate such optically active forms. For example, mixtures of stereoisomers may be
separated by standard techniques including, but not limited to, resolution of racemic
forms, normal, reverse-phase, and chiral chromatography, preferential salt formation,
recrystallization, and the like, or by chiral synthesis either from chiral starting materials
or by deliberate synthesis of target cbiral centers. ,
As will be readily understood, functional groups present on the compounds of the
present invention may contain protecting groups during the course of synthesis. For
example, the amino acid side chain substituents of the compounds of formula (I), (I-A),
(II), or (II-A) can be substituted with protecting groups such as benzyloxycarbonyl or t-
butoxycarbonyl groups. Protecting groups are known per se as chemical functional
groups that can be selectively appended to and removed from functionalities, such as
hydroxyl groups and carboxyl groups. These groups are present in a chemical compound
to render such functionality inert to chemical reaction conditions to which the compound
is exposed. Any of a variety of protecting groups may be employed with the present
invention. Preferred protecting groups include the benzyloxycarbonyl ("Cbz") group, the
tert-butyloxycarbonyl ("Boc") group, and the tosyl (p-toluensulfonyl, "Tos") group.
Other preferred protecting groups according to the invention may be found in Greene,
T.W. and Wuts, P.G.M., Protective Groups in Organic Synthesis 2d. Ed., Wiley & Sons,
1991.
Compounds of the present invention may be prepared as outlined in the following
schemes. The reagents and starting materials are commercially available, or readily
synthesized by well-known techniques by one of ordinary skill in the arts. All
substituents, unless otherwise indicated, are as previously defined.
A general synthetic procedure is set forth, in Scheme A for preparing the
compounds of formula (I) [wherein Y=C(R1)(R2) and m, n=0] or (I-A):
Scheme A, step 1: Synthesis of compounds of general structure c:
In step la, the appropriate aryl halide a undergoes a metal exchange reaction with
an organometallic compound to give the corresponding metalloaryl compound. For
example, an appropriate haloaromatic or haloheteroaromatic (compound a) is reacted
with an appropriate alkyl lithium compound in an aprotic solvent at a temperature -78 °C.
An appropriate haloaromatic or haloheteroaromatic compound is one where Ari is as
defined in the final product. An appropriate alkyl lithium compound is one that effects a
metal-halogen exchange.
In step lb, an appropriate aryl aldehyde b is added to the previously formed
metalloaryl compound to give desired di-aryl alcohol c. For example, an appropriate
aromatic aldehyde or heteroaromatic aldehyde (compound b) in an aprotic solvent is
added to reaction product of step la. An appropriate heteroaromatic aldehyde is one
where Ar2 is as defined in the final product Upon completion, the reaction mixture is
quenched by an appropriate quenching agent and the product, compound c, is isolated by
conventional methods commonly employed by those skilled in the art.
For example, a cooled (-70 °C to -78 °C) solution of an appropriate haloaromatic
or haloheteroaromatic (compound a) in dry ether is reacted with n-butyllithium (1.1 eqv).
After stirring for an additional period of time to allow the completion of halogen-metal
exchange reaction, the next reactant, an appropriate heteroaromatic aldehyde (compound
b) in ether is slowly be added to the reaction flask. Stirring is continued for an additional
2-3 h at the low temperature. The cooling bath is removed and the reaction mixture is
slowly allowed to come to ambient temperature, followed by quenching, preferably by a
saturated NH4CI solution. The mixture is extracted into an organic solvent (ether or
ethyl acetate). The organic layer is washed with brine, dried (MgSCU or NaaSCk) and
concentrated to give a crude product Purification is achieved by employing known
purification techniques (preferably by column chromatography and/or recrystallization)
to provide pure compounds c. The method is an adaptation from a procedure previously
described by Gronowitz, S.; Eriksson, B. Arkiv Kemi 1963,335, incorporated herein by
reference in its entirety. Alternatively, this class of compounds wherein Ari is the same
as Ar2 may be generated by treatment of two equivalents of an appropriate
haloheteroaromatic with two equivalents of n-butyllithium, followed by one equivalent
of ethyl formate as described by Nenajdenko, V. G.; Baraznenok, I. L.; Balenkova, E. S.
J. Org. Chem. 1998,6132, incorporated herein by reference in its entirety.
Scheme A, step 2: Synthesis of compounds of general structure d:
In step 2a, the alcohol moiety of compound c is converted to the corresponding
thiol. The thiol, in step 2b, undergoes a substitution reaction with an appropriate
halogen-substituted alkylcarboxylic acid of structure Br-(CH2VY-(CH2)n-COOH, to
generate compound d. For example, di-aryl alcohol c is reacted with thiourea in
presence of an acid to convert it to a thiouronium moiety that is subsequently hydrolyzed
in the presence of an alkaline base and reacted with the appropriate halogen-substituted
alkylcarboxylic acid to generate compound d (step 2b). An appropriate acid derivative is
one in which m, n, Y are as defined in the final product
For example, in step 2a, an appropriate amount of thiourea is taken into 48% HBr
and water. The mixture is wanned (preferably to 60 - 70 °C), followed by addition of
compound c. The temperature of the reaction mixture is elevated (preferably to 90—95
°C) and the stirring is continued for an additional period of time for completion of the
reaction. The reaction mixture is cooled to room temperature (in some cases, an ice-bath
might be needed) and the precipitated solid should be filtered and thoroughly washed
with water.
In step 2b, the wet solid from the previous step is taken into additional water and
treated with an aqueous base, preferably sodium hydroxide solution. The mixture is
wanned (preferably to 70 - 80 °C, but in some cases a higher temperature might be
needed) and to it an appropriate amount of halogen-substituted alkylcarboxylic acid
derivative in water ( or in some cases, an alcoholic solvent) is added. The reaction
mixture is maintained at an elevated temperature (preferably 100 — 110 °C) for an
appropriate period of time, cooled, taken into water and washed with an organic solvent
(preferably ether). The basic aqueous layer is acidified with an inorganic acid solution
(e.g. aqueous HC1 solution). The aqueous (acidic) solution is then extracted several
times into an organic solvent (e.g. ether or ethyl acetate). The combined organic layer is
washed with brine, dried (MgSO4 or Na2SO4) and concentrated to give the crude product
that may be used directly in the next step. However, purification could be achieved by
employing known purification techniques (e.g. recrystallization) to provide pure
compound d.
The method is an adaptation from a procedure previously described in U.S. Pat
No. 4,177,290, incorporated by reference herein in its entirety.
Scheme A, step 3: Synthesis of compounds of general structure e:
In step 3a, the carboxylic acid is converted into appropriate acid derivative, which
is then reacted with an appropriate amine to give compound e. For example in step 3a,
compound d can be converted to the corresponding acid chloride, or the corresponding
activated ester. The acid chloride can be obtained by reacting compound d with thionyl
chloride in an aromatic hydrocarbon solvent in refluxing condition. Alternatively, the
activated ester can be obtained by use of various agents known in the art, such as 2-(lH-
Benzotriazol-l-yl)-l,l,3,3-tetramethyluronium tetrafluoroborate ("TBTU"), N-
methylmorpholine ("NMM") and dimethyl formamide ("DMF"). In step 3b, the product
of step 3a is reacted with an appropriate amine of structure NHR3R4 to give the desired
compound e. An appropriate amine is one which correlates to R3 and R4 as defined in
the final product
For example, a solution of an appropriate carboxylic acid (compound d) in either
benzene or toluene is brought to reflux temperature and to it is slowly added an
appropriate amount of thionyl chloride. The mixture is refluxed until the disappearance
of starting material (as evidenced by analytical techniques), cooled and solvent removed.
The resulting residue is taken into an appropriate organic solvent (preferably
tetrahydrofuran or methylene chloride) and treated with ammonia gas (or 28% aqueous
ammonia hydroxide solution) or an appropriate amine. The reaction mixture is then
partitioned between water and an organic solvent (preferably ethyl acetate). The
separated organic layer is washed with water, dilute acid, dilute base and brine, dried
over a drying agent (e.g. MgSC>4 or Na2SC>4) and concentrated to give the crude product
that may be purified by column chromatography and/or recrystallization to produce
compound e.
Scheme A, optional step 4: Synthesis of compounds of general structure f:
Compounds of structure e may optionally be oxidized to generate compounds of
structure f. Thus, compound f is prepared by reacting compound e in an appropriate
solvent with an appropriate oxidizing agent. An appropriate oxidizing agent is one that
oxidizes the sulfide group of compound e. The corresponding product is isolated and
purified by methods well known in the art
For example, to a cooled (-15 °C to -25 °C) solution of compound e in an organic
solvent (preferably methylene chloride or chloroform), an appropriate oxidizing agent
(e.g. m-chloroperoxybenzoic acid ["w-CPBA"], 1 equivalent) in the same solvent is
slowly added. Stirring is continued at low temperature until the disappearance of the
starting material, as evidenced by various analytical techniques. The reaction mixture is
then thoroughly washed with a saturated sodium bicarbonate solution, water and brine,
respectively, dried over a drying agent (e.g. MgSO4 or Na2SO4) and concentrated. The
desired product (compound f) is purified, if needed, by employing known purification
techniques (preferably by column chromatography and/or recrystallization). In some
cases, the oxidation is performed by employing 50% H2O2 in glacial acetic acid solvent
A general synthetic procedure is set forth in Scheme B for preparing the
compounds of formula (II) [wherein ring A is phenylene; Y=C(Ri)(R2) and m, n, r, s=0]
and (H-A):
Scheme B, steps 1,2, and 3: Synthesis of compounds of general structure dd, ee and ff.
The synthetic steps in Scheme B involve the same multistep general method
described in Scheme A, wherein Scheme B, steps 1-3 corresponds to Scheme A, steps 2
4, respectively.
A general synthetic procedure is set forth in Scheme C for preparing the
compounds of formula (I-A), wherein n=0 and Y is
Scheme C, steps 1 and 2: Synthesis of compounds of general structure ddd and eee.
The synthetic steps in Scheme C, steps 1 and 2 involve the same multistep
general method described in Scheme A, steps 2-3, respectively to give compounds of
structure eee.
Scheme C, step 3: Synthesis of compounds of general structure fit
The amide moiety in compound eee is converted to corresponding thioamide
moiety iff with an appropriate sulfur-transfer reagent. For example, a mixture of
compound eee and Lawesson's reagent (1.05 eqv) in a suitable solvent (dimethoxyethane
or tetrahydroniran) is heated to reflux until the disappearance of the starting material.
After cooling, the'desired product (compound ffi) is obtained by employing known
purification techniques (preferably by column chromatography and/or recrystallization).
Scheme C, step 4: Synthesis of compounds of general structure ggg.
The thioamide moiety in compound flffis cyclized to the corresponding thiazole
moiety. For example, a mixture of compound fiff and an appropriate bromomethyl
ketone (1.1 eqv) in a suitable solvent (e.g. ethanol) is heated to reflux until the
disappearance of the starting material. After cooling, the desired product (compound
ggg) is obtained by employing known purification techniques (preferably by column
chromatography and/or recrystallization).
Scheme C, steps 5-6: Synthesis of compounds of general structure hhh and iii.
The synthetic steps in Scheme C, steps 5 and 6 involve the same multistep
general method described in Scheme A, steps 3 and 4, respectively to give compounds of
structure hhh and iii.
A general synthetic procedure is set forth in Scheme D for preparing the
compounds of formula (II- A), wherein n=0 and Y is
Scheme D, steps 1-6: Synthesis of compounds of general structure hhhh and iiii. The
synthetic steps in Scheme D involve the same multistep general method described in
Scheme C to give compounds of structure hhhh and optionally, iiii.
A synthetic procedure is set forth in Reaction Scheme E for preparing compounds
of formula Q) or (I-A) wherein R1 or R2 can be taken together with either R3 or R4 to
form a 3-7 member heterocyclic ring. The subsequently formed ring is represented in
Scheme E by "G". In the present scheme, R1 is taken together with R3 to form
heterocyclic ring MG'\ It is understood that Ri may be also be taken with R4 to form ring
"G", or R2 may be also be taken with R3 to form ring "G", or R2 may be also be taken
with R4 to form ring "G". The reagents and starting materials are commercially
available, or readily synthesized by well-known techniques by one of ordinary skill in
the arts. In Reaction Scheme E, all substituents, unless otherwise indicated, are as
previously defined.
Scheme E, steps 1 and 2: Synthesis of compounds of general structure 60,
containing compounds of formula (I) wherein either Ri or Ra are taken together with
either R3 or R» to form a 3-7 member heterocyclic ring "G'In the first step, an appropriate mercaptolactam 59 is reacted with an appropriate
diarylmethanol, compound 27, in the presence of a weak acid, in order to affect
nucleophilic displacement at the methanol carbon to form the corresponding thioether.
The appropriate mercaptolactam 59 and appropriate diaryl- or diheteroarylmethanol, 27
are ones in which Ari, Ar2, R2 and R4 are as defined in the final product.
In the second step, the thioether formed in the first step is optionally oxidized
with an appropriate oxidizing agent to provide compound 60. An appropriate oxidizing
agent is one that oxidizes the thioether to its corresponding sulfoxide or sulfone.
A synthetic procedure is set forth in Reaction Scheme F for preparing compounds
of formula (II-A), wherein Ri or R2 can be taken together with either R3 or R4 to form a
3-7 member heterocyclic ring. A similar procedure may be utilized to prepare the
corresponding compounds of formula (II-A). The subsequently formed ring is
represented in Scheme E by "G". In the present scheme, K\ is taken together with R3 to
form heterocyclic ring "G". It is understood that Ri may be also be taken with R4 to
form ring "G", or R3 may be also be taken with R3 to form ring "G", or Rj may be also
be taken with R4 to form ring "G". The reagents and starting materials are commercially
available, or readily synthesized by well-known techniques by one of ordinary skill in
the arts. In Reaction Scheme F, all substituents, unless otherwise indicated, are as
previously defined.
Scheme F, steps 1 and 2: Synthesis of compounds of general structure 62,
containing compounds of formula (II-A) wherein either Ri or R2 are taken together with
either R3 or R4 to form a 3-7 member heterocyclic ring "G"In the first step, an appropriate mercaptolactam 59 is reacted with an appropriate
diaryl- or diheteroarylmethanol, 27a, in the presence of a weak acid, in order to affect
nucleophilic displacement at the methanol carbon to form the corresponding tbioether.
The appropriate mercaptolactam 61 and appropriate diaryl- or diheteroarylmethanol, 27a
are ones in which A, X, R2 and R4 are as defined in the final product.
In the second step, the thioether formed in the first step is optionally oxidized
with an appropriate oxidizing agent to provide compound 62. An appropriate oxidizing
agent is one that oxidizes the thioether to its corresponding sulfoxide or sulfone.
Examples
> Other features of the invention will become apparent in the course of the
following descriptions of exemplary embodiments. These examples are given for
illustration of the invention and are not intended to be limiting thereof. The following
Examples 1-6 were synthesized according to Scheme 1.
Preparation of compound C:
To a vigorously stirred mixture of thiourea (compound B, 5 g, 0.066 mol), 48%
HBr (30 mL) and water (5 mL) at 70-75 °C was added 9-hydroxyfluorene (compound A,
9.28 g, 0.051 mol) in small portions, followed by additional amount of water (30 mL).
The reaction mixture was then heated to 100-105 °C (bath temperature), maintained there
for another 30 min and cooled to room temperature. The precipitated solid was filtered,
washed with water and ether, successively and dried under vacuum to generate 14 g of
the corresponding thiouronium salt that was used in the next step without any further
purification.
To a vigorously stirred mixture of the above-mentioned thiouronium salt (10.47
g,) in 10 N NaOH (10.26 mL) and water (25 mL) at 60-65 °C was slowly added 3-
bromopropionic acid (5.24 g, 0.034 mol) in water (20 mL). The reaction mixture was
then heated to 105-110 °C (bam temperature), maintained there for another 30 min,
cooled to room temperature, diluted with water (25 mL), and washed with ether (3 x 50
mL). The basic aqueous layer was acidified (pH 2~3) with cone. HC1 and extracted into
ethyl acetate (3 x 100 mL). The combined organic layer was dried (MgSC>4) and
concentrated to generate 7.80 g of compound C that was used in the next step without
any further purification; 'H-NMR (CDC13) 5 7.80 (m, 4H), 7.30 (m, 4H), 4.90 (s, 1H),
2.10 (m, 4H).
Preparation of compound D:
This compound was prepared from compound A, following the same procedure
as described above for the synthesis of compound D, except that 4-bromobutyric acid
was used in place of 3-bromopropionic acid in the alkylation step; ^-NMR (CDCI3) 5
7.70 (m, 4H), 7.40 (m, 4H), 4.80 (s, 1H), 2.20 (t, 2H), 2.00 (t, 2H), 1.40 (m, 2H).
Preparation of compound £:
To a refluxing solution of compound C (7.8 g, 0.029 mol) in benzene (40 mL)
was slowly added thionyl chloride (5.3 mL). The mixture was refluxed for another 2 h,
cooled, filtered and concentrated under reduced pressure to generate 8 g of compound E
that was immediately taken into next step without any further purification.
Preparation of compound F:
This compound was prepared from compound D, following the same procedure
as described above for the synthesis of compound E from compound C.
Example 1: Synthesis of compound G.
Compound £ (8 g) from previous step was dissolved in methylene chloride (20
mL) and added to a vigorously stirred, cooled (0 °C) 28% NH4OH solution (50 mL).
The ice-bath was removed and stirring was continued for another hour. The reaction
mixture was diluted with water (30 mL) and extracted into methylene chloride (2 x 30
mL). The combined organic layer was washed with water (2 x 20 mL), 3% NaHCCb
solution (2 x 30 mL), brine (1 x 30 mL), dried (Na2SO4) and concentrated to give a
residue that was triturated with ether to generate 6.30 g of compound G; 'H-NMR
(DMSO-dg) 6 7.90 (d, 2H), 7.70 (d, 2H), 7.40 (m, 4H), 7.30 (broad, 1H), 6.80 (broad,
1H), 5.20 (s, 1H), 2.30 (t, 2H), 2.10 (t, 2H).
Example 2: Synthesis of compound H.
This compound was prepared from compound E, following the same procedure
as described above for the synthesis of compound G, except that dimethylamine was
used in placeof 28% NH4OH in the animation step; 'H-NMR (DIVISOR) 8 7.90 (d, 2H),
7.60 (d, 2H), 7.40 (m, 4H), 5.20 (s, 1H), 2.70 (2 singlets, 6H), 2.20 (m, 4H).
Example 3: Synthesis of compound I.
This compound was prepared from compound F, following the same procedure
as described above for the synthesis of compound G from compound E; 'H-NMR
(DMSO-de) 6 7.80 (d, 2H), 7.60 (d, 2H), 7.40 (m, 4H), 7.10 (broad, 1H), 6.70 (broad,
1H), 5.10 (s, 1H), 2.10 (t, 2H), 2.00 (t, 2H), 1.50 (m, 2H).
Example 4: Synthesis of compound II-l.
To a solution of compound G (5.15 g, 0.019 mol) in glacial acetic acid (20 mL) at
room temperature was slowly added 50% H2O2 (1.2 eqv). The mixture was stirred for 1
h, poured into ice-water and filtered. The precipitated solid was thoroughly washed with
water, followed by ether and dried under high vacuum to generate 4.42 g of compound
II-l; white solid; mp 163-164 °C; R, 7.57 min. !H-NMR (DMSO-dg) 5 8.10-7.50 (a
series of m, 8H), 7.40 (broad, 1H), 6.90 (broad, 1H), 5.70 (s, 1H), 2.30 (m, 4H).
Example 5: Synthesis of compound II-2.
This compound was prepared from compound H, following the same procedure
as described above for the synthesis of compound II-l from compound G; white solid;
mp 110-112 °C; R, 8.64 min. 'H-NMR (DMSO-d6) 5 8.00 (t, 2H), 7.70 (d, 1H), 7.60 (d,
1H), 7.50 (m, 2H), 7.40 (q, 2HQ, 5.60 (s, 1H), 2.80 (s, 3H), 2.70 (s, 3H), 2.60-2.20 (a
series of m, 4H).
Example 6: Synthesis of compound II-3.
This compound was prepared from compound I, following the same procedure as
described above for the synthesis of compound II-l from compound G; white solid; mp
161-162 °C; R, 7.61 min. JH-NMR (DMSO-d6) 5 8.20-7.60 (a series of m, 8H), 7.40
(broad, 1H), 6.90 (broad, 1H), 5.80 (s, 1H), 2.30 (m, 4H), 1.80 (m, 2H).
The following Examples 7-8 were synthesized according to Scheme 2.
Example 7: Synthesis of compound J.
To a stirred solution of compound C (1.9 g, 0.007 mol) in dry DMF (20 mL) at 0
°C was added iST-methylmoipholine ("NMM")(1.92 mL), followed by 2-(lH-
Besnzotriazol-l-yl>1433-tetrametiiyluroniumtetiafluoroborate ("TBTU")(3.38 g.
0.0105 mol). The mixture was stirred for 10 min and to it added (L)alaninamide (as
hydrochloride salt) (1.3 g, 0.0105 mol) in dry DMF (5 mL). The cooling bath was
removed and the mixture was stirred for another 2 h. It was then poured into cold water
(25 mL) and extracted into ethyl acetate (3 x 50 mL). The combined organic layer was
washed with water, 2% citric acid, 3% sodium bicarbonate, water and brine,
successively. Drying (MgSO4) and solvent evaporation produced a residue that on
trituration with cold ether generated 1.93 g of compound J; 'H-NMR (DMSO-d6) 5 770
(m, 3H), 7.50 (d, 2H), 7.20 (m, 4H), 7.10 (broad, 1H), 6.80 (broad, 1H), 5.00 (s, 1H),
4.00 (m, 1H), 2.10 (m, 2H), 2.00 (m, 2H), 0.90 (d, 3H).
Example 8: Synthesis of compound II-4.
This compound was prepared from compound J, following the same procedure as
described above for the synthesis of compound II-1 from compound G (Scheme 1);
white solid (diastereomeric mixture); R, 7.16 min. 'H-NMR (DMSO-de) 5 8.30 (2
overlapping d, 1H), 8.20-7.60 (a series of m, 8H), 7.50 (d, 1H), 7.10 (d, 1H), 5.80 (s,
1H), 4.20 (m 1H), 2.60-2.40 (2 sets of m, 4H), 1.30 (2 overlapping d, 3H).
The following Examples 9-18 were synthesized according to Scheme 3.
Preparation of compound 33:
Scheme 3, step 1: In step la, 3-bromothiophene (10.22 g)(compound 31) in
dry ether at a temperature -70° C to -78° C was reacted with n-butyllithium (25 ml of 2.5
M, 1.1 equivalents). After stirring for an additional period of time to allow for the
completion of the halogen-metal exchange reaction, 3-thiophenecarboxaldehyde (6.39
gXcompound 32) in ether was slowly added to the reaction flask. Stirring was continued
for an additional 2-3 h at the low temperature. The cooling bath was removed and the
reaction mixture was slowly allowed to come to ambient temperature, followed by
quenching, preferably by 50% aqueous NH4CI solution. The mixture was extracted into
an organic solvent (ether or ethyl acetate). The organic layer was washed with brine,
dried (MgSO4 or Na2SO4) and concentrated to give a crude product Purification may be
achieved by employing known purification techniques (preferably by column
chromatography and/or recrystallization) to provide pure compound 33; 'H-NMR
(CDCI3) 5 7.40 (d, 2H), 7.30 (s, 2H), 7.10 (d, 2H), 6.00 (d, 1H), 2.20 (d, 2H). The
method was an adaptation from a procedure previously described by Gronowitz, S.;
Eriksson, B. Arkiv Kemi 1963,335, incorporated herein by reference in its entirety.
Preparation of compound 34:
Scheme 3, step 2: In the first step, thiourea (5 g, 1.3 equivalents) was taken into
48% HBr and water. The mixture was warmed (preferably to 60° - 70° C), followed by
addition of compound 33 (10 g). The temperature of the reaction mixture was elevated
(preferably to 90° -95° C) and stirring was continued for an additional period of time for
completion of the reaction. The reaction mixture was then cooled to room temperature
(in some cases, an ice-bath might be needed) and the precipitated solid was filtered and
thoroughly washed with water.
The wet solid was then taken into additional water and treated with an aqueous
base, preferably sodium hydroxide solution. The mixture was warmed (preferably to 70°
— 80° C, but in some cases, a higher temperature might be needed) and to it chloroacetic
acid (4.8 g, 1.1 equivalents) in water was added. The reaction mixture was maintained at
an elevated temperature (preferably 100° - 110° C) for an appropriate period of time,
cooled, taken into water and washed with an organic solvent (preferably ether). The
basic aqueous layer was acidified with an inorganic acid solution (e.g. aqueous HC1
solution). The aqueous (acidic) solution was then extracted several times into an organic
solvent (e.g. ether or ethyl acetate). The combined organic layer was washed with brine,
dried (MgSO4 or Na&SC^) and concentrated to give the crude product 34 that may be
used directly in the next step. However, purification may also be achieved by employing
known purification techniques (e.g. recrystallization) to provide pure compound 34; 1H-
NMR (CDCI3) 6 7.30 (d, 2H), 7.20 (s, 2H), 7.10 (d, 2H), 5.40 (s, 1H), 3.10 (s, 2H).
The method is an adaptation from a procedure previously described in US Patent
No. 4,177,290 (issued on December 4,1979) that is incorporated by reference herein in
its entirety.
Preparation of compound 35:
Scheme 3, step 3: A solution of the thioacid 34 (9.0 g) in benzene was brought to
reflux temperature and to it was slowly added 1.1 equivalents of thionyl chloride. The
mixture was refluxed until the disappearance of the starting material (as evidenced by
analytical techniques), cooled and the solvent removed to give the crude product 35 that
may be used directly in the next step. However, purification may also be achieved by
employing known purification techniques (e.g. recrystallization) to provide pure
compound 35.
Example 9: Synthesis of compound 36.
Scheme 3, step 4: The resulting thioacid chloride 35 (9.5 g) from the previous
step was taken into an appropriate organic solvent (preferably tetrahydrofuran or
methylene chloride) and treated with ammonia gas (or 28% aqueous solution). The
reaction mixture is then partitioned between water and ethyl acetate. The separated
organic layer is washed with water, dilute acid, and brine, dried over a drying agent (e.g.
MgSO4 or Na2SO4) and concentrated to produce 6.40 g of compound 36. Analytical
Data: white solid; mp 88.5-89.5° C; R» 9.61 min. 'H-NMR (CDCI3) 5 7.40 (d, 2H), 7.30
(s, 2H), 7.20 (d, 2H), 6.40 (broad, 1H), 5.50 (broad, 1H), 5.40 (s, 1H), 3.10 (s, 2H).
Example 10: Synthesis of compound 37.
In a procedure similar to that of Example 9, treatment of 2.15 g of freshly
prepared compound 35 with 2.2 g of n-propylamine generated a crude material that was
purified by flash column chromatography (eluent: 30% ethyl acetate in hexanes) to
generate 1.71 g of compound 37. Analytical Data: viscous oil, Rt 12.30 min. 'H-NMR.
(DMSO-d6) 5 7.90 (t, 1H), 7.50 (d, 2H), 7.40 (s, 2H), 7.10 (d, 2H), 5.60 (s, 1H), 3.30 (d,
1H), 3.10 (m, 3H), 1.30 (m, 2H), 0.80 (t, 3H).
Example 11: Synthesis of compound 38.
In a procedure similar to that of Example 9, treatment of 2.56 g of freshly
prepared compound 35 with dimethylamine gas generated a crude material that was
purified by flash column chromatography (eluent: 30% ethyl acetate in hexanes) to
produce 1.96 g of compound 38. Analytical Data: white solid; mp 71-72° C; Rt 11.08
min. 'H-NMR (CDC13) 5 7.30-7.10 (m, 6H), 5.50 (s, 1H), 3.20 (s, 2H), 3.00 and 2.90 (2
sets of s, 6H).
Example 12: Synthesis of compound 39.
In a procedure similar to that of Example 9, treatment of 2.15 g of freshly
prepared compound 35 with 2.74 g of diethylamine generated a crude product that was
purified by flash column chromatography (eluent: 25% ethyl acetate in hexanes) to
generate 1.56 g of compound 39. Analytical Data: white solid; mp 83-84° C; Rt 13.37
min. 'H-NMR (CDC13) 8 7.30-7.10 (m, 6H), 5.60 (s, 1H), 3.40 (q, 2H), 3.30 (q, 2H),
3.20 (s, 2H), 1.10 (2 overlapping 16H).
Example 13: Synthesis of compound 40.
In a procedure similar to that of Example 9, treatment of 2.15 g of freshly
prepared compound 35 with 4 g of morpholine generated a crude product that was
purified by flash column chromatography (eluent: 50% ethyl acetate in hexanes) to
generate 2.02 g of compound 40. Analytical Data: white solid; mp 75.5-78° C; Rt 11.21
min. 'H-NMR (CDC13) 6 7.40-7.20 (2 sets of m, 6H), 5.50 (s, 1H), 3.70 (m, 4H), 3.60
(m, 2H), 3.40 (m, 2H), 3.20 (s, 2H).
Example 14: Synthesis of compound 1-9.
To a cooled (-15° C to -25° C) solution of compound 36 (5.50 g) in either
methylene chloride or chloroform, 1 equivalent of the oxidizing agent m-
chloroperoxybenzoic acid (m-CPBA) in the same solvent was slowly added. Stirring
was continued at the low temperature until the disappearance of the starting material, as
evidenced by various analytical techniques. The reaction mixture was then thoroughly
washed with a saturated sodium bicarbonate solution, water and brine, respectively, dried
over a drying agent (e.g. MgSO4 or Na2SO4) and concentrated. The resulting material
was then purified by column chromatography and/or recrystallization to give compound
1-9 (5.50 g). Analytical Data: white solid, mp 131-132° C. *H-NMR (CDC13) 6 7.40 (m,
4H), 7.25 (d, 1H), 7.15 (d, 1H), 6.90 (broad, 1H), 5.60 (broad, 1H), 5.45 (s, 1H), 3.45 (d,
1H), 3.10 (d, 1H).
Example 15: Synthesis of compound 1-10.
In a procedure similar to that of Example 14, compound 37 (1.67 g) was oxidized
with 1 equivalent of the oxidizing agent m-chloroperoxybenzoic acid (m-CPBA), and
then purified to give compound 1-10 (1.40 g). Analytical Data: semi-solid; Rt 8.95 min.
'H-NMR (DMSO-de) 5 8.00 (t, 1H), 7.40 (m, 4H), 7.10 (m, 2H), 5.30 (s, 1H), 3.20 (d,
1H), 3.10 (m, 1H), 3.00 (d, 1H), 2.90 (m, 1H), 1.20 (m, 2H), 0.80 (t, 3H).
Example 16: Synthesis of compound 1-11.
In a procedure similar to that of Example 14, compound 38 (1.91 g) was oxidized
with 1 equivalent of the oxidizing agent m-chloroperoxybenzoic acid (m-CPBA), and
then purified to give compound 1-11 (1.63 g). Analytical Data: white solid; mp 93-96°
C; R, 7.79 min. lH-NMR (CDCI3) 5 7.50-7.30 (m, 6H), 5.70 (s, 1H), 3.60 (d, 1H), 3.40
(d, 1H), 3.10 and 2.90 (2 sets of s, 6H).
Example 17: Synthesis of compound 1-12.
In a procedure similar to that of Example 14, compound 39 (1.53 g) was oxidized
with 1 equivalent of the oxidizing agent m-chloroperoxybenzoic acid (m-CPBA), and
then purified to give compound 1-12 (1.35 g). Analytical Data: white solid; mp 93-95°
C; Rt 9.70 min. 'H-NMR (CDCI3) 8 7.40-7.20 (m, 6H), 5.70 (s, 1H), 3.60 (d, 1H), 3.40
(m, 2H), 3.30 (d, 1H), 3.20 (m, 2H), 1.20 (t, 3H), 1.10 (t, 3H).
Example 18: Synthesis of compound 1-13.
In a procedure similar to that of Example 14, compound 40 (2.00 g) was oxidized
with 1 equivalent of the oxidizing agent m-chloroperoxybenzoic add (m-CPBA), and
then purified to give compound 1-13 (1.60 g). Analytical Data: white solid; mp 59-73°
C; Rt 8.03 min. 'H-NMR (CDCh) 8 7.40-7.20 (2 sets of m, 6H), 5.60 (s, 1H), 3.80-3.20
(a series of m, 10H).
Example 19: Synthesis of compound 1-22.
Compound 1-22 was prepared following the same multistep general method as
described in Scheme A, utilizing 3-bromothiophene and benzaldehye in step 1. (M + H)
= 280.
i
Examples 20-39: Synthesis of compounds 1-1 through 1-7 and 1-26 through 1-38.
Compounds 1-1 through 1-7 and 1-26 through 1-38 were prepared following the
same multistep general method as described in Scheme A utilizing the appropriately
substituted amine NHR3R4 in step 3b. The analytical data is represented by each
compound's mass spectrum (M+H) as shown in the following Table 3.
The following Examples 40-41 were synthesized according to Scheme 4.+
Preparation of Compound 43:
A mixture of compound 41 (0.75 g)(Dondoni, A. et. al. J. Org. Chem. 1988, pp.
1748-1761), acetic anhydride (3 equivalents) and anhydrous pyridine (2-3 mL/mmol of
alcohol) was stirred overnight at room temperature, or until the reaction was complete by
thin layer chromatography. The reaction mixture was then poured into cold water and
extracted into ethyl acetate (3 x 25 mL). The combined organic phase was successively
washed with saturated sodium bicarbonate solution, water, brine, dried (sodium sulfate)
and concentrated to generate the desired product compound 43 (0.84 g). Analytical
Data: %= 0.6 (2.5% methanol/ethyi acetate); JH-NMR (CDC13) 5 7.72 (s, 1H), 7.47 (m,
1H), 7.38-7.22 (m, 5H), 7.11 (s, 1H), 2.17 (s, 3H).
Preparation of Compound 44:
Compound 42 (0.92 g) was reacted in a manner similar to that described above in
the preparation of compound 41. The resulting crude ester was purified by flash
chromatography (eluant: 4:1 hexane/ethyl acetate) to give 0.41 g of compound 44.
Analytical Data: R/ = 0.32 (4:1 hexane/ethyl acetate); 'H-NMR (CDC13) 5 7.83 (s, 1H),
7.42 (s, 1H), 7.36 (m, 1H), 7.17 (m, 1H), 7.00 (m, 1H), 2.19 (s, 3H).
Preparation of Compound 45:
To a stirring solution of compound 43 (0.84 g) and methyl thioglycolate (1.2
equivalents) in anhydrous dichloromethane (4-5 mL/mmol) at 0 °C under argon was
added trimethylsilyl trifluoromethane (TMS-triflate, 1 equivalent). The reaction mixture
was allowed to warm to room temperature and stirred until complete (2-6 h). It was then
diluted with dichloromethane, washed with saturated sodium bicarbonate solution, dried
(sodium sulfate), concentrated and dried under high vacuum to give compound 45 (1.01
g) that was used directly in the next step without any further purification. Analytical
Data: R/= 0.62 (2.5% methaool/ethyl acetate);1H-NMR (CDC13) § 7.75 (s, 1H), 7.5 (d,
1H), 7.38-7.27 (m, 5H), 5.72 (s, 1H), 3.69 (s, 3H), 3.25 (q, 2H).
Preparation of Compound 46:
Compound 44 (0.41 g) was reacted in a manner similar to that described above in
the preparation of compound 45 to give compound 46 (0.30 g). Analytical Data: R/=
0.62 (2.5% methanol/ethyl acetate); *H NMR (CDC13) S. 7.75 (s, 1H), 7.39 (s, 1H), 7.36
(m, 1H), 7.17 (broad, 1H), 6.94 (m, 1H), 6.07 (s, 1H), 3.72 (s, 3H), 3.30 (q, 2H).
Preparation of Compound 47:
Anhydrous ammonia was bubbled into a stirring solution of compound 45 (1.0 g)
in methanol (10 mL/mmol) at 0 °C for 5-10 minutes. The reaction mixture was allowed to
warm to room temperature, stirred for additional 5-7 h, concentrated under reduced
pressure and dried under vacuum. The crude product was purified by flash
chromatrography (eluant: 5% methanol/ethyl acetate) to give 0.48 g of compound 47.
Analytical Data: R/= 0.20 (5% methanol/ethyl acetate); !H-NMR (CDC13) 8 7.77 (s, 1H),
7.47 (d, 1H), 7.44-7.27 (m, 5H), 5.53 (broad, 1H), 3.22 (q, 2H).
Preparation of Compound 48:
Compound 46 (0.30 g) was reacted in a manner similar to that described above in
the preparation of compound 47 to give compound 48 (0.25 g). Analytical Data: R/ =
0.20 (5% methanoVethyl acetate); 'H-NMR (CDC13): § 7.72, (s, 1H), 7.31 (s, 1H), 7.28
(m, 1H), 7.17 (s, 1H), 6.97 (m, 1H), 6.84 (broad, 1H), 6.11 (broad, 1H), 5.86 (s, 1H),
3.25 (q,2H).
Example 40: Synthesis of compound 1-39.
To a stirring solution of compound 47 (0.48) in anhydrous dichloromethane (10
mL/mmol) at -78 °C was added a solution of m-CPBA (1.0 equivalent) in
dichloromethane (5-8 mL/mmol). After an additional stirring for 1 h, the reaction
mixture was allowed to warm to —30 to -40°C and quenched with 10% aqueous Na2S2Cb
solution. Separated organic phase was successively washed with saturated sodium
bicarbonate solution, water and brine, dried (sodium sulfate), and concentrated to
generate compound 1-37 (0.31 g). Analytical Data: fy= 0.13 (5% methanol/ethyl
acetate); 'H-NMR (CDCI3) major diastereomer: Q7.92 (s, 1H), 7.61 (m, 2H), 7.44-7.36
(m, 5H), 7.00 (broad, 1H), 5.61 (s, 1H), 3.42 (q, 2H); minor diastereomer: 5 7.86 (s, 1H),
7.55 (m, 2H), 7.44-7.36 (m, 5H), 6.83 (broad, 1H), 5.55 (s, 1H), 3.61 (q, 2H).
Example 41: Synthesis of compound 1-40.
Compound 48 (0.25 g) was reacted in a manner similar to that described above in
the preparation of compound 47 to give compound 1-39 (0.105 g) (diastereomeric
mixture). Analytical Data: !H-NMR (DMSO-6> major diastereomer: 5. 8.03 (s, 1H),
7.92 (s, 1H), 7.78 (broad, 1H), 7.68 (s, 1H), 7.36 (broad, 1H)), 7.17 (m, 1H), 6.50 (s,
1H), 3.47 (q, 2H); minor diastereomer: 5 7.97 (s, 1H), 7.86 (s, 1H), 7.78 (broad, 1H),
7,72 (s, 1H), 7.36 (broad, 1H), 7.22 (m, 1H), 6.39 (s, 1H), 3.36 (q, 2H).
Example 42: Synthesis of compound II-9.
Starting with 9-hydroxyfluorene, this compound was prepared following
the same multistep general method as described in Scheme 3 above, and utilizing L-
Alanine-NH2 in the amination step. Analytical Data: white solid (diastereomeric
mixture); Rt 7.27 min and 7.41 min. 'H-NMR (DMSO-d6) 6 8.40-7.00 (a series of m
and d, 11H), 5.60 and 5.70 (2 sets of s, 1H), 4.20 (m, 1H), 3.20 and 3.00 (2 sets of dd,
2H), 1.20 (2 overlapping doublets, 3H).
Example 43: Synthesis of compound 11-23.
Starting with 9-hydroxyfluorene, this compound was prepared following the
same multistep general method as described in Scheme 3 above, and utilizing 28%
aqueous ammonia in the amination step. Analytical Data: white solid; mp 178.5-180° C;
Rt 7.48 min. 'H-NMR (CDC13) 5 7.90-7.40 (a series of m, 8H), 6.60 (broad, 1H), 5.40 (s,
1H), 5.30 (broad, 1H), 2.80 (d, 1H), 2.60 (d, 1H).
Example 44: Synthesis of compound 11-25.
Starting with dibenzosuberol, this compound was prepared following the same.
multistep general method as described in Scheme.3 above, and utilizing 28% aqueous
ammonia in the amination step. Analytical Data: white solid; mp 182-190° C; Rt 8.43
min. ^-NMRODMSO-de) 8 7.80 (d, 1H), 7.60 (d, 1H), 7,40 (m, 8H), 5.50 (s, 1H), 3.60
(m, 2H), 3.50 (d, 1H), 3.40 (d, 1H), 2.90 (m, 2H).
Example 45: Synthesis of compound 11-26.
Starting with dibenzosuberol, this compound was prepared following the same
multistep general method as described in Scheme 3 above, utilizing dimethylamine in the
amination step. Analytical Data: white solid; mp 112.5-115° C; Rt 10.36 min. *H-NMR
(DMSO-d«) 8 7.60 (d, 1H), 7.40 (m, 7H), 5.50 (s, 1H), 4.00 (d, 1H), 3.60 (d, 1H), 3.50
(m, 2H), 2.90 (s, 3H), 2.80 (m, 2H), 2.70 (s, 3H).
Examples 46-91: Synthesis of compounds U-6 through H-8,11-10 through 11-15,11-24,
11-27, n-30 through n-54, n-56 through 11-91.
Compounds II-6 through US, II-10 through II-15,11-24,11-27,11-30 through II-
54,11-56 through 11-91 were prepared following the same multistep general method as
described in Scheme B incorporating the appropriate reactants to form the desired
product. The analytical data is represented by each compound's mass spectrum (M + H)
as shown in the following Table 4.
The following Example 92 was synthesized according to Scheme 5.
Preparation of Compound M:
A mixture of dimethyl phthalate (compound K, 10 g, 0.51 mol), 3,4-
dimethoxyacetophenonc (compound L, 9.74 g, 0.054 mol), and powdered sodium
methoxide (2.76 g, 0.051 mol) was heated at reflux overnight, cooled to room
temperature, and concentrated in vacuo. The yellow slurry was suspended in water (100
mL), stirred for 10 min, acidified with 6N HC1 (pH ~ 1-2), and filtered. The residue was
placed in ethanol (200 mL), heated to reflux for 30 min, cooled to room temperature, and
filtered. The residue was washed with cold ethanol and dried in vacuo to generate
compound M as a bright yellow fluffy solid (4.1 g) that was used without any further
purification. Analytical Data: !H-NMR (CDC13) 5 3.99 (s, 3H), 4.02 (s, 3H), 6.99 (d,
1H), 7.68-7.75 (m, 2H), 7.85 (m, 2H), 8.07 (d, 1H), 8.09 (s, 1H); MS: (M+H)+ = 311.
Preparation of Compound N:
A mixture of compound M (3.37 g, 0.011 mol), hydrazine (0.41 mL, 0.013 mol)
and ethanol (250 mL) under nitrogen was heated to reflux for 6 h, cooled to room
temperature and filtered. The residue was washed with ethanol and dried to give
compound N as a yellow solid (2.0 g). Analytical Data: lH NMR (CDCI3) 5 3.85 (s,
3H), 3.89 (s, 3H), 7.17 (d, 1H), 7.38-7.43 (m, 1H), 7.55 (m, 2H), 7.60 (d, 1H), 7.85 (d,
1H), 7.95 (s, 1H); MS: (M+H)+ = 307.
Preparation of Compound O:
To a stirred solution of compound N (0.084 g, 0.27 mmol) in THF/ H2O (3:1,8
mL) at room temperature under nhrogen was added solid sodium borohydride (0.029 g,
0.63 mmol) in one portion. The reaction mixture was cooled to 0 °C, stirred for 1 h,
warmed to room temperature, diluted with ethyl acetate and washed with water. The
organic phase was dried (magnesium sulfate) and concentrated in vacua. The residue, on
trituration with ether, generated compound O (0.077 g) as a yellow solid that was used
without further purification. Analytical Data: lK NMR (CDCI3) 5 3.86 (s, 3H), 3.87 (s,
3H), 5.53 (s, 1H), 6.79 (d, 1H), 7.29 (t, 2H), 7.46 (d, 1H), 7.50 (s, 2H), 7.58 (t, 1H); MS:
(M+H)+ = 309.
Preparation of Compound P:
To a stirred solution of compound O (1.55 g, 0.005 mol) in CH2C12 (40 mL)
under nitrogen at 0 °C was added methyl thioglycolate (0.54 mL, 0.006 mmol). Next,
trifluoroacetic anhydride (1.42 mL, 0.01 mol) was added dropwise to the reaction
mixture. The reaction mixture was stirred at 0 °C for 0.5 h, wanned to room
temperature, stirred overnight, quenched with saturated aqueous sodium bicarbonate and
extracted into ethyl acetate (3 x 25 mL). The organic layer was washed with water,
brine, dried (magnesium sulfate), and concentrated in vacuo to generate compound P as a
yellow solid (1.75 g) that was used without any further purification. Analytical Data: 1H
NMR (CDCI3) 5 2.77 (q, 2H), 3.33 (s, 3H), 3.93 (s, 3H), 4.00 3H), 4.99 (s, 1H), 6.96 (d,
1H), 7.23-7.42 (m, 2H), 7.47 (d, ltf), 7.49 (d, 1H), 7.64 (d, 1H), 7.69 (d, 1H), 7.72 (d,
lH);MS:(M+H)+ = 397.
Example 92: Synthesis of compound 11-66.
Starting from compound P, this compound was generated following the
procedure as described above for the preparation of compound 47, and in Example 35 for
the synthesis of compound 1-37. Thus, 0.050 mg of compound P, on treatment with
ammonia in the first step, followed by oxidation with w-CPB A in the next step,
generated 0.011 g of compound 11-66. Analytical Data: *H-NMR (CDC13) 8 2.75 (d,
1H), 2.88 (d, 1H), 3.92 (s, 3H), 3.96 (s, 3H), 5.67 (s, 1H),6.8O (s, 1H), 6.94 (d, 1H), 7.37
(t, 1H), 7.45-7.52 (m, 2H), 7.58 (d, 1H), 7.64 (s, 1H), 7.79 (d, 1H); MS: (M+H)+ - 420.
Example 93: Demonstration of Wake-promoting activity of compound 1-9.
The methodology utilized is as described by Edgar and Seidel, Journal of
Pharmacology and Experimental Therapeutics, 283:757-769,1997, incorporated herein
in its entirety by reference.
Animal Surgery. Adult, male Wistar rats (275-320g from Charles River
Laboratories, Wilmington, MA) were anesthetized (Nembutal, 60mg/kg, ip) and
surgically prepared with implants for recording of chronic EEG and EMG recording. The
EEG implants consisted of stainless steel screws (2 frontal (+3.9 AP from bregma,
±2.0ML) and 3 occipital (-6.4 AP, ± 5.5ML). Two Teflon-coated stainless steel wires
were positioned under the nuchal trapezoid muscles for EMG recording. All leads were
soldered to a miniature connector (Microtech, Boothwyn, PA) and gas sterilized with
ethylene oxide before surgery. The implant assembly was affixed to the skull by the
combined adhesion of the EEG recording screws, cyanoacrylate applied between the
hermetically sealed implant connector and skull and dental acrylic. An antibiotic
(Gentamycin) was administered for 3 to 5 days postsurgery. At least 3 weeks were
allowed for postsurgical recovery.
Recording environment Rats were housed individually within specially
modified Nalgene microisolator cages equipped with a low-torque slip-ring commutator
(Biella Engineering, Irvine, CA) and a custom polycarbonate filter-top riser. These
cages were isolated in separate, ventilated compartments of a stainless steel sleep-wake
recording chamber. Food and water were available ad libitum and ambient temperature
was 24 +_ 1°C. A 24-h light-dark cycle (light/dark 12-12-) was maintained throughout
the study by 4-watt fluorescent bulbs located approximately 5cm from the top of each
cage. Light intensity was 30 to 35 lux at midlevel inside the cage. Animals were
undisturbed for 3 days both before and after the treatments.
Automated data collection. Sleep and wake stages were determined with
SCORE, a microcomputer-based sleep-wake and physiological monitoring system.
SCORE™design features, validation in rodents and utility in preclinical drug evaluation
have been reported elsewhere (Van Gelder, et al., 1991; Edgar, et al., 1991,1997; Seidel,
et al, 1995, incorporated by reference herein in their entirety). In the present study, the
system monitored amplified (X 10,000) EEG (bandpass, 1-30 Hz; digitization rate, 100
Hz) and integrated EMG (bandpass, 10-100 Hz, root mean square integration). Arousal
states were classified on-line as NREM sleep, REM sleep, wake or theta-dominated
wake every 10s by use of EEG period and amplitude feature extraction and ranked
membership, algorithms. Individually taught EEG-arousal-state templates and EMG
criteria differentiated REM sleep from theta-dominated wakefulness (Welsh, et al, 1985,
incorporated by reference herein in its entirety). Data quality was assured by frequent on-
line inspection of the EEG and EMG signals. Raw data quality and sleep-wake scoring
was scrutinized further by a combination of graphical and statistical assessments of the
data as well as visual examination of the raw EEG wave forms and distribution of
integrated EMG values.
Drag administration and study design. Compound 1-9 was suspended in
sterile 0.25% methylcellulose (pH=6.2; Upjohn Co., Kalamazoo, MI) or methylcellulose
vehicle alone was injected intraperitoneally in a volume of lml/kg. Sample size (n) was
13 animals per treatment group.
EEG spectral analysis. Each 10-s epoch of raw EEG signal was digitized (100
Hz) for 24h and wakefulness was scored as described previously by Edgar and Seidel
(1996), incorporated by reference herein in its entirety.
Data analysis and statistics. The principal variable recorded was minutes per
hour of wake. Treatment groups were compared post-treatment by repeated-measures
ANOVA. In the presence of a significant main effect, Dunnett's contracts {a = 0.05)
assessed differences between active treatment groups and vehicle controls, unless
otherwise specified.
Results. Figure 1 illustrates degree of wakefulness in rats treated at time zero
with either 100 mg/kg, ip of compound 1-9 (solid line) or methylcellulose vehicle
(stippled line). Compound 1-9 produced wakefulness beyond that observed in vehicle-
treated animals that lasted until approximately 110 minutes following administration.
Example 94: Demonstration of Wake-promoting activity of compound 11-23.
The methodology utilized is based on that described by Edgar and Seidel, Journal
of Pharmacology and Experimental Therapeutics, 283:757-769,1997, and incorporated
herein in its entirety by reference.
Animal Surgery. Adult, male Wistar rats (275-320g from Charles River
Laboratories, Wilmington, MA) were anesthetized (NembutaL 4Smg/kg, ip) and surgically
prepared with implants for recording of chronic EEG and EMG recording. The EEG
implants were made from commercially available components (Plastics One, Roanoke, VA).
EEG's were recorded from stainless steel screw electrodes (2 frontal (+3.0 mm AP from
bregma, ±2.0 mm ML) and 2 occipital (-4.0 mm AP, ±2.0 mm ML)). Two Teflon-coated
stainless steel wires were positioned under the nuchal trapezoid muscles for EMG recording.
All electrode leads were inserted into a connector pedestal and the pedestal, screws, and
wires affixed to the skull by application dental acrylic. Antibiotic was administered post
surgically and antibiotic cream was applied to the wound edges to prevent infection. At
least 1 week elapsed between surgery and recording. Animals are tested for approximately
6-8 weeks and then sacrificed.
Recording environment. PostsurgicaUy, rats were housed individually in an
isolated room. At least 24 hrs. prior to recording, they were placed in Nalgene
containers (31x31x31 cm) with a wire-mesh top, and entry to the room was prohibited
until after recording had ended except for dosing. The containers were placed on a 2-
shelf rack, 4 per shelf. Food and water were available ad libitum, ambient temperature
was 21°C, and humidity was 55%. White-noise was provided in the background (68db
inside the containers) to mask ambient sounds. Fluorescent overhead room lights were
set to a 24 hr. light/dark cycle (on at 7 AM, off at 7 PM). Light levels inside the
containers were 38 and 25 lux for the top and bottom shelves respectively.
Data acquisition. EEG and EMG signals were led via cables to a commutator
(Plastics One) and then to pre-amplifiers (model 1700, A-M Systems, Carlsborg, WA).
EEG and EMG signals were amplified (10K and IK respectively) and bandpass filtered
between 0.3 and 500 Hz for EEG, and betweenlO and 500 Hz for EMG. These signals
were digitized at 128 samples per second using ICELUS sleep research software (M.
Opp, U. Texas; see Opp, Physiology and Behavior 63:67-74,1998, and Imeri, Mancia,
and Opp, Neuroscicnce 92:745-749,1999, incorporated by reference herein in their
entirety) running under Labview 5.1 software and data acquisition hardware (PCI-MIO-
16E-4; National Instruments, Austin, TX). On the day of dosing, data was recorded from
11 AM to 6PM.
Sleep./ wake scoring. Sleep and wake stages were determined manually using
ICELUS software. This program displays the EEG and EMG data in blocks of 6 sec.
along with the EEG-FFT. Arousal state was scored as awake (WAK), rapid eye-
movement (REM), or slow-wave or non-REM sleep (NREM) according to visual
analysis of EEG frequency and amplitude characteristics and EMG activity (Opp and
Krueger, American Journal of Physiology 266:R688-95,1994; Van Gelder, et al., 1991;
Edgar, et al., 1991,1997; Seidel, et al, 1995, incorporated by reference herein in their
entirety). Essentially, waking activity consists of relative low-amplitude EEG activity
with relatively lower power in the lower frequency bands from 0.5 - 6 Hz, accompanied
by moderate to high level EMG activity. In a particular waking state ("theta-waking"),
EEG power can be relatively focused in the 6-9 Hz (theta) range, but significant EMG
activity is always present NREM sleep is characterized by relative high-amplitude EEG
activity with relatively greater power in the low frequency bands from 0.5 - 6 Hz,
accompanied by little or no EMG activity. REM sleep is characterized by moderate and
constant amplitude EEG focused in the theta (6-9 Hz range), similar to waking theta, but
with no EMG activity.
Drug administration and study design. Compounds were evaluated on groups
of 4 or 8 rats which were tested in 2 sessions at least 2 days apart. Initial studies used a
crossover design, such that rats received either vehicle or test compound during each
session. Animals were pseudo-randomized so that they did not receive the same drug
twice. Compound 11-23 was suspended in sterile 0.25% methylcellulose (pH=6.2;
Upjohn Co., Kalamazoo, MI) at 30 mg/ml. This study was carried out on 8 rats which
were tested in 2 sessions 5 days apart (overall, 7 rats received compound 11-23 and 6
methylcellulose vehicle). Dosing was carried out at noon, while the rats were
predominantly asleep. Each rat was lifted out of its container, given an intrapcritoneal.
injection in a volume of 333 ml/kg, and replaced. Dosing required approximately 8
minutes*
Data analysis and statistics. The principal outcome measure was minutes per
hour of wakefulness. The pommy outcome measure for puipostt
in these experiments consists of the total integrated wake time for the first 3 hours post
dosing relative to vehicle control. Thus, vehicle treated animals typically average 20%
wake time during the recording period, or a total of 0.2 * 180 =36min. A2-tailed,
unpaired t-test (Statview 5.0, SAS Institute, Inc., Cary, NQ was performed on the wake
time values for drug and vehicle treated animals, and compounds with p deemed significantly wake-promoting. Waking activity was also evaluated for
successive half-hour periods beginning with the time of dosing, and individual t-tests
performed at each time point to establish the duration of significant wake-promoting
activity.
Results. Figure 2 illustrates degree of wakefulness in rats treated at noon with
either 100 mg/kg, ip. of compound 11-23 (solid triangles) or methylcellulose vehicle
(open circles). Each point represents the mean percent of time awake for the
succeeding half hour. The dosing procedure produced a transient (~20 min.) period of
elevated wakefulness in bom treatment groups compared to pre-dosing baseline activity.
Compound 11-23 produced significantly greater wakefulness than that observed in
vehicle-treated animals (p References. The following references, to the extent that they provide exemplary
procedural or other details supplementary to those set forth herein, are specifically
incorporated in their entirety herein by reference:
Touret, et al., Neuroscience Letters, 189:43-46,1995.
Van Gelder, ILN. etal., Sleep 14:48-55,1991.
Edgar, D.M., J. Pharmacol Exp.Ther. 282:420-429,1997.
Edgar and Seidei, J. Pharmacol Exp. Ther., 283:757-69,1997.
Hernant et al., Psychopharmacology, 103:28-32,1991.
Lin et al., Brain Research, 591:319-326,1992.
Opp and Krueger, American Journal of Physiology 266:R688-95,1994
Panckeri etal., Sleep, 19(8):626-631,1996.
Seidel, W.F.,etal.,J. Pharmacol. Exp. Ther. 275:263-273,1995.
Shelton et ai, Sleep 18(10):8f 7-826,1995.
Welsh, DjL,etd3PHysioL Behav. 35:533-538,1985.
Although the present invention has been described in considerable detail, those
skilled in the art will appreciate that numerous changes and modifications may be made
to the embodiments and preferred embodiments of the invention and that such changes
and modifications may be made without departing from the spirit of the invention. It is
therefore intended that the appended claims cover all equivalent variations as fall within
the scope of the invention.
WE CLAIM:
1. A compound of formula (I-A):
wherein:
An and Ar2 are each independently selected from phenyl, thienyl,
isothiazolyl, oxazolyl, isoxazolyl, and thiazolyl;
Y is selected from C1-C4 alkylene, -C(R1)(R2)-, phenylene, and
oxazolylene, wherein R1 and R2 are each independently H or C1-C6
alkyl;
R3 and R4 are the same or different and are each selected from H and C1-
C6 alkyl, wherein said alkyl is optionally substituted with OH or a
heterocyclyl ring selected from piperidyl, morpholinyl and pyridyl;
or R3 and R4, together with the nitrogen to which they are
attached, form an optionally substituted morpholinyl or pyrrolidyl
ring;
m is 0, 1 or 2;
n is 0, 1 or 2; and
qis 1;
with the proviso that when An and Ar2 are both phenyl, then Y cannot
be C1-C4 alkylene;
and the stereoisomeric forms, mixtures of stereoisomeric forms, or
pharmaceutically acceptable salt and ester forms thereof.
2. The compound as claimed in claim 1, wherein An and Arc
are each independently selected from thienyl, isothiazolyl, oxazolyl,
isoxazolyl, and thiazolyl.
3. The compound as claimed in claim 2, wherein An and Ar2
are 3-thienyl.
4. The compound as claimed in claim 1, wherein Ari is phenyl
and Ar2 is selected from thienyl, isothiazolyl, oxazolyl, isoxazolyl, and
thiazolyl
5. The compound as claimed in claim 1, wherein An and Ar2
are phenyl.
6. The compound as claimed in claim 1, wherein Y is
phenylene or thiazolylene.
7. The compound as claimed in claim 6, wherein Y is
phenylene.
8. The compound as claimed in claim 1, wherein Y is C1-C4
alkylene.
9. The compound as claimed in claim 1 wherein Y is C(R1)(R2),
wherein R1 and R2 are each independently H or C1-C6 alkyl; and m and n
= 0.
10. The compound as claimed in claim 1, wherein Ar1 and Ar2
are each independently selected from phenyl and 3-thienyl.
11. The compound as claimed in claim 1, selected in accordance
with the following table:
A compound of formula (I-A):
wherein:
Ar1 and Ar2 are each independently selected from phenyl, thienyl,
isothiazolyl, oxazolyl, isoxazolyl, and thiazolyl;
Y is selected from C1-C4 alkylene, -C(R1)(R2)-, phenylene, and
oxazolylene, wherein R1 and R2 are each independently H or C1-C6
alkyl;
R3 and R4 are the same or different and are each selected from H and C1-
C6 alkyl, wherein said alkyl is optionally substituted with OH or a
heterocyclyl ring selected from piperidyl, morpholinyl and pyridyl;
or R3 and R4, together with the nitrogen to which they are
attached, form an optionally substituted morpholinyl or pyrrolidyl
ring;
m is 0, 1 or 2;
n is 0, 1 or 2; and
q is 1;
with the proviso that when An and Ar2 are both phenyl, then Y cannot
be C1-C4 alkylene;
and the stereoisomeric forms, mixtures of stereoisomeric forms, or
pharmaceutically acceptable salt and ester forms thereof.

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Patent Number 223425
Indian Patent Application Number IN/PCT/2002/01385/KOL
PG Journal Number 37/2008
Publication Date 12-Sep-2008
Grant Date 10-Sep-2008
Date of Filing 11-Nov-2002
Name of Patentee CEPHALON INC.
Applicant Address 145 BRANDYWINE PARKWAY, WEST CHESTER, PA 19380
Inventors:
# Inventor's Name Inventor's Address
1 BACON, EDWARD R. 1006 SKYLINE CIRCLE AUDUBON, PA 19403
2 CHATTERJEE, SANKAR 1375 WEST INDIAN CREEK DRIVE WYNNEWOOD, PA 19096
3 DUNN, DEREK 122 AUTUMN TRAIL COATESVILLE, PA 19320
4 MALLAMO, JOHN P 98 MACLEOD POND ROAD GLENMOORE, PA 19343
5 MILLER, MATTHEW S 2120 DAWN LANE NEWTOWN, PA 18940
6 VAUGHT, JEFFREY L 206 KATHLEEN WAY GLENMOORE, PA 19343
PCT International Classification Number C07C 323/00
PCT International Application Number PCT/US01/15752
PCT International Filing date 2001-05-16
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 60/268,283 2001-02-13 U.S.A.
2 60/204,789 2000-05-16 U.S.A.
3 09,855,228 2001-05-15 U.S.A.