Indian Patents. 209754:"BICYCLIC COMPOUNDS, PREPARATION THEREOF "

Title of Invention	"BICYCLIC COMPOUNDS, PREPARATION THEREOF "
Abstract	This invention relates to novel compounds of general formula (1):

Full Text	- 1A- Bicyclic compounds, preparation thereof and use in pharmaceutical compositions Field of the Invention This invention relates to novel bi-cyclic compounds useful in pharmaceutical compositions as tachykinins antagonists, and to pharmaceutical compositions containing them • Background of the invention The receptor NK2 of tachykinins is widely expressed in the peripheral nervous system of Mammalia. One of the several effects caused by the selective stimulation of the receptor NK2 is the contraction of the smooth muscles. Therefore, antagonists of the receptor NK2 can be considered agents able to control the hypercontraction of the smooth muscles in any patological condition in which the release of the tachykinins contributes to the rise of the corrispondent disorder. In particular, the bronchospastic component of asthma, cough, pulmonary irritations and local spasms of the urinary bladder and of the ureter during cystitis, infections and renal colics can be considered conditions in which the administration of receptor NK2 antagonists can be effective (A.L. Magnan et al. Neuvopeptides, 1993. 24, 199)- Compounds which act as antagonists of the tachykinins, and in particular of the neurokinin A, are well-known in Literature. Among them, the cyclic compounds (B. J. Williams et al. J. Med. Chem. , 1993. 36, 2) are of particular interest. Lipophily has been defined as an essential requirement in order to have an intensive antagonist activity to the receptor NK2 of the tachykinins of a series of cyclic pseudopeptides (L. Quartara et al. J. Med. Chem. , 1994. 27) and - 2 - particularly in case of bicyclic hexapeptides. WO/93/21227). Surprisingly it has been now found that products structurally similar to those described above, but in which, however, at least one hydrophilic group is present, not only keep their high affinity in vitro, but also show an increase in the pharmacological activity in vivo if compared to the corrispondent compounds which do not contain any hydrophilic group. This is even more surprising if it is taken into account that monocyclic peptides having antagonist properties which are similar to those of the tachykinins do not show any increase in the pharmacological activity when hydrophilic groups are introduced onto the structure of the cycle [Int. J. Peptide Protein Res. (1984), 44:2, 105-111]. Summary This invention relates to novel compounds of the general formula (I): wherein: xl, X2 , X3 , X4, X5, and X6, same or different from one another, represent a - NR'CO- or a -CONR'- group, wherein R' is H or C1-3 alkyl; - 3 - Y represents a group selected from -NRCO-, -CONR-, or -SS- wherein R is H or C1-3 alkyl; at least one of the R1, R2 R3 and R4 groups, same or different from one another, is hydrophilic and the remaining groups are hydrophobic; and n, same or different from one another, are each an integer number from 1 to 4; and to pharmaceutical compositions containing them. Detailed description of the Invention The present invention relates to novel compounds having the general formula (I) wherein Xl, X2 , X3, X4 ,X5 ,X6, Y, Rl, R2 ,R3, R4, m and n goups are as defined above; processes for the preparation thereof and pharmaceutical compositions containing them. The formula (I) as reported above is considered the one giving the best representation of the real spatial structure of the bicyclic peptide according to the invention. However also the following Formula (Ia) (which chemically speaking is identical to Formula (I)) is given - 4 - in order to simplify the understanding of the compounds described hereinafter and in the Examples with their chemical name in particular in so far as the groups X1-6 and Y are concerned. The groups X1-6 and Y are in fact defined according to the aminoacid- sequence from the formal N- to the C-terminus of the peptide as they are represented in the linear structure, therefore reading Formula (Ia) no problem arises in the understanding of the linear structure as reported in the Examples. As it can be seen, the compounds of formula (I) as described above present chiral centers: it is understood that this invention relates also to the several enantiomers. More particularly the hydrophobic groups can be separately selected from the following: a) groups CnH2n+1 wherein n= 0, 1-4 b) linear- or branched alkyl groups corresponding to CnH2n-U-W wherein n= 1-4; U= 0, COO, CONH, S and W= alkyl-, aryl or alkylaryl-group containing from 1 to 15 carbon atoms c) (CH2)n -C6H3-A-B wherein n= 0, 1-3; A and B, placed in any of the ortho, meta or para positions, same or different from one another, represent H, halogen, OR, NHR, NR2, CH3, SR wherein R is an alkyl-, aryl- or alkyl aryl-group with less than 10 C atoms d) (CH2)n -CgH10 R', wherein n= 0, 1-3 and R'= H, C1-3 alkyl - 5 - e) (CH2)n -heterocycle, wherein n= 0, 1-3 and for heterocycle it is meant: imidazolyl-2-yl, indolyl-3-yl. furanyl-3-yl, pyridyl-3-yl, imidazoly1-3-y1 f) a -(CH2)S- group, wherein s= 3, 4, eventually OH-substituted or condensed with an aromatic group, which cyclizes with one of the two adjacent X1-6 groups in order to produce the side chain of proline, hydroxyproline, octahydroindol-2-carboxylic acid, tetrahydroisoquinolinic acid g) the side chain of a natural hydrophobic amino acid h) the side chain of a natural hydrophilic amino acid, suitably substituted in order to render it hydrophobic i) the side chain of non-natural hydrophobic amino acids selected from the group consisting of: norleucine, norvaline, alloisoleucine, cyclohexylglycine (Chg), a-amino-n-butyric acid (Aba), cyclohexylalanine (Cha), aminophenylbutyric acid (Pba), phenylalanines mono- and di- substituted in the ortho, meta and para positions of the benzene ring with one or more of the following groups: C1-10 alkyl, C1-10 alkoxy halogen, ?-2-thienylalanine, ?-3-thienylalanine, ?-2-furanylalanine, ?-3-furanylalanine, ?-2-piridylalanine, ????piridylalanine, ?-4-piridylalanine, ?-(1-naphtyl)alanine, ?-(2-naphtyl)alanine, O-alkylated serine- threonine- tyrosine-derivatives, S-alkyl cysteine, S-alkyl homocysteine, N-alkyl lysine, N-alkyl ornithine, N-alkyl 2,3 diaminopropionic acid. More particularly, the side chain of a hydrophobic amino acid according to paragraph (g) is the side chain of an amino acid selected from the group consisting of: glycine, alanine, valine, isoleucine, methionine, phenylalanine. tyrosine, tryptophan, proline, histidine. - 6 - aspargine, glutamine. The side chain of a hydrophilic amino acid, suitably substituted in order to render it hydrophobic according to paragraph (h) is the chain of an amino acid selected from the group consisting of: serine, threonine, cysteine, aspartic acid, glutamic acid, t-carboxyglutamic acid, arginine, ornithine, lysine. Preferably, the hydrophilic groups are selected from L-Q group, wherein L is a chemical bond or a linear or branched C1-6-alkyl residue and Q is a hydrophilic group. Preferably Q is selected from the group consisting of: guanidine, amine, M, OM, -CO-NH-M, -NH-CO-M, an aromatic group which has been mono-, di- or tri-substituted in ortho, meta, para positions with M or OM groups, wherein M is a hydrophilic group. With the term "hydrophilic group", for Q and M, it is preferably meant: i) eventually substituted mono-, di-, tri-glycosidic residues; ii) C1-6 linear o cyclic alkyl chains comprising one or more polar groups; iii) hydroxyl, amine, guanidine, carboxyl, sulfate, phosphonate, phosphate; iv) residues bearing substituted hydrophilic groups which in biologic environment are hydrolysated, re-establishing the hydrophilic function. As far as the definition according to paragraph (i) hereinabove is concerned, the following structures are preferably meant: hexoses or pentoses of the D or L series in a or ? configuration, selected from the group wherein: all C atoms bear a free or protected - 7 - hydroxylic group; one or more hydroxyls are substituted by: hydrogen, an amino or acylamino group; C6 of hexoses and C5 of pentoses are part of a carboxylic group; and wherein the eventually present 2 or 3 glycosidic units are linked by a glycosidic bond of a or ??configuration. Specific examples of glycosidic groups as defined above are: D or L ribose, D or L arabinose, D or L xylose, D or L lyxose, D or L allose, D or L altrose, D or L glucose, D or L mannose, D or L gulose, D or L idose, D or L galactose, D or L talose, D or L allulose, D or L fructose, D or L sorbose, D or L tagatose; 5-deoxy-D or L-arabinose, 2-deoxy-D or L-glucose, 2-deoxy-D or L-galactoset 2-deoxy-D or L-arabinose, 2-deoxy-D or L-ribose, D or L fucose, D or L ramnose; D-glucosamine, D-mannosamine, D-galactosamine, daunosamine, acosamine and N-acylate derivates thereof with lower fatty acids, i.e. having a N-formylic, acetylic, propionilic, butyric residue; glucuronic acid, galacturonic acid, cellobiose, lactose, maltose, D-lactosamine, cellotriose, maltotriose and protected derivates thereof. The definition according to paragraph (ii) hereinabove applies to chains deriving from a polyol-residue, such as tris(hydroxymethyl)methyl, D or L arabitol, D or L erythrol, D or L galactytol, meso-inositol, D or L mannitol, D or L perseitol, D or L ribitol, D or L sorbitol, D or L xylitol; or those deriving from the residue of tartaric acid, glucaric acid, gluconic acid, bycine, quinic acid, mucic acid, glucosaminic acid. Among the products of formula (I) as above indicated, the products wherein if one or both R1 and R4 groups are hydrophilic, both R2 and R3 groups are hydrophobic and viceversa, are particularly preferred. - 8 - Compounds of formula (I) object of the present invention can be synthetized by the various techniques known in Literature, see e.g. M. Bodansky, "Peptide Chemistry", Springer-Verlag, 1988. For example by means of in solution synthesis of the linear peptidic chain through subsequent coupling of suitably activated N-protected amino acids to an amino acid or to a C-protected peptidic chain, with isolation of the intermediates, subsequent selective de-protection of the C- and N-terminal chains, cyclization in polar organic solvents in diluted solution, hence selective de-protection of the side chains and at last cyclization of the same in polar organic solvents in diluted solution. The hydrophilic residue can be introduced both as protected amino acid derivative during the peptidic chain synthesis and by means of conjugation to the already formed peptide, as widely disclosed in Literature. Similarly a synthesis in solid phase of the peptidic chain from the C-terminal end to the N-terminal one on a insoluble polymeric support, the cyclization in solid phase between the previously de-protected side chains, the subsequent detachment from the polymeric support by means of hydrolysys in anhydrous hydrofluoric acid containing the suitable scavengers or in trifluoracetic acid containing the suitable scavengers or in aqueous bases and the cyclization of the raonocyclic peptide in polar organic solvents in diluted solution, can be used for the preparation. The hydrophilic residue being introduced according to the above disclosed indications. According to a particular preparation method, the desired product can be obtained in solid phase using the 2-chlorotrytil resin (Barlos et al.. Int. J.Peptide Protein Res., 37. 513-520, 1991) substituted with a protected amino acid having the Fmoc group at the N-terminal end; - 9 - preferably the amino acid directly bond to the resin is the one having the R1 or R3 side chain. After the other amino acids being introduced in the sequence, the peptide is detached from the resin with diluted acetic acid and a first cyclization is performed between the free C-terminal and N-terminal end by means of the conventional classic synthesis methods. Subsequently, the amino acid side chains are de-protected in position 5 and 6, for example with trifluoracetic acid, and way is given to the second cyclization. Other synthetic ways are anyway possible and largely described in Literature as above mentioned. The compounds of formula (I) as above indicated have revealed to be powerful antagonists of the receptor NK2 of the tachykinins, and hence may be administered in doses which are not higher than those required for the known products. They can be therefore indicated for the treatment of arthritis, asthma, inflammations, tumoral growth, gastro-intestinal hypermotility, Huntington's desease, neurites, neuralgia, hemicrania, hypertension, urinary incontinence, urticaria, symptoms from carcinoid desease, flu and colds. The compounds of formula (I) object of the present invention are suitable for the parenteral, oral, inhalatory and sublingual administration for therapeutical purposes to the superior animals and to the humans, achieving pharmacological effects according to the above described features. For parenteral administrations {endovenous, intramuscular and intradermic) sterile solutions or lyophilized chemical preparations are used. For nasal, inhalatory and sublinqual administrations, according to the particular instance, - 10 - aqueous solutions, aereosol preparations or capsules are used. The doses of active principle in the above compositions can be comprised between 0,1 and 10 mg/kg of body weight. EXAMPLE 1. Preparation of cyclo([Asn(?-D-Glc)-Asp-Trp-Phe-Dap-Leu]cyclo(2?-5?)) (SEQ ID No. 1) compound of formula (I) wherein Y=X1=X2=X3=X4-X5=X6= C0-NH-; R1= -CH2-CH(CH3)2; R2= -CH2-C6H5, R3=-CH2indolyl-3-yl, R4=- CH2-C0-NH-(?-D-Glc) ; m=n=l and the carbon atoms C1, C2, C3, C4, C5, C6 have L configuration]. a) synthesis of the linear peptide H-Asn[{Acit0)-p'-D-Glc]-Asp{0tBu)- Trp-Phe-Dap(Boc)-Leu-OH. 1 g of 2-chlor trityl resin (1,6 mmol/g, Novabiochem) is functionalized with Fmoc-Leu~0H (0,6 eqs.) as described by Barlos et al.. Int. J. Peptide Protein Res., 1991, 37. 513-520. The substitution degree of the resin is determined by dosing the group Fmoc, and it is equal to 0,364 meq/g. The subsequent 4 amino acids are coupled as free acids using an excess 3 of amino acid and HOBt (4 eqs.) and DCC (3 eqs.) as activators with reaction times of 1 hour. In the following order: Fmoc-Dap{Boc)-0H. Fmoc-Phe-OH, Frnoc-Trp-OH. Fmoc-Asp(0tBu)-0H are added. The last amino acid is coupled as Fmoc-Asn[ (Ac4O)-?-D-Glc]- OPfp (Christiansen-Brams et al., J.Chem.Soc. Perkin Trans. I. 1993, 1461-1471), 2 eqs., with HOBt (2 eqs.) as activator, for 3h. After the de-protection of the group Fmoc, the detachment from the resin is performed, suspending it in 10 mL of a mixture of AcOH, TFE, DCM (1/1/8, v/v) at room temperature for 0,5 h. Thereafter the solvent is evaporated under vacuum at 30°C, it is again mixed with water and it is lyophilized. Yield in raw product: 405 mg (90 %) . Title HPLC: 70 - 11 - %. FAB-MS: [M+H]+ = 1266; tr: 14,7 min. b) Synthesis of the bicyclic product cyclo([Asn((AchO)-p-D- Glc)-Asp-Trp-Phe-Dap-Leu]cyclo(2ft-5p)) (compound 2). The linear raw product is cyclized in 1 mM solution in DMF, at 4°C, with 1 eq. of PyBOP and 1,2 eqs. of DIEA for 1 h. The mixture is dried and purified in HPLC obtaining 156 mg of the pure product (yield 39 %). Title HPLC:>99 %. FAB-MS: [M+H]+=1248; tr: 18.4 min. The monocyclic product is de-protected by solving it in 15 ml of TFA containing water at 10 %. After 0.5 h, the mixture is diluted in water and it is lyophilized. The residue is dissolved in 1 mM solution in DMF, the solution is brought to 0°C and 1 eq. of PyBOP and 1.2 eqs. of DIEA are added. After 5 h, it is dried and purified in HPLC. Yield 45 % (70 mg). Title HPLO 99 %. FAB-MS: [M+H]+= 1074; tr: 13-5 min. c) Synthesis of the bicyclic product cyclo ([Asn(?-D-Glc)-Asp-Trp- Phe-Dap-Leu]cyclo(2?-5?)) 70 mg of tetraacetylate product are dissolved in anhydrous methanol in 5 mM solution. The solution is brought to -20°C and a 1 mM solution of sodium methylate in methanol is added to achieve pH = 11. After 10' acetic acid is added to achieve neutral pH, high diluition with water and lyophilization follow. Yield 60 %. Title HPLC: 98 %. FAB-MS: [M+H]+= 906; tr: 9-3 min. EXAMPLE 2 Preparation of cyclo{[Ser(?-D-Glc)-Asp-Trp-Phe-Dap-Leu]cyclo(2P-5P)) (SEQ ID No. 2) [compound of Formula (I) wherein: Y=X1=X2=X3=X4=X5=X6=-C0-NH-; R1= -CH2-CH(CH3)2; R2= -CH2-C6H5; R3= -CH2-indolyl-3-yl; R4=-CH2-O-(P-D-Glc); m = n = 1 and C1, C2, C3. C4, C5, C6 carbon atoms have L configuration]. - 12 - a) synthesis of linear peptide H-Ser[{Bz4O)-?-D-Glc]-Asp(OtBu)-Trp- Phe-Dap{Boc)-Leu-OH. The same procedure which has been used for Example 1), paragraph a), is utilized here till the addition of the last amino acid, which is coupled as Fmoc-Ser[(Bz^O)-p-D-Glc]-OPfp (obtained by the procedure which has been described by Vargas-Berenguel et al., J. Chem. Soc. Perkin Trans. I, 1994, 2615, 2619). The detachment occurs as described above,in Example 1). Yield in raw product: 450 mg (83 %) . Title HPLC: 93 %. FAB-MS: [M+H]+= 1487; tr: 20.8 min. b) Synthesis of bicyclic product cyclo{[Ser[(Bz4O)-?-D-Glc]-Asp-Trp- Phe-Dap-Leu]cyclo(2?-5?)). The linear raw product is cyclized in lmM solution in DMF, at 4°C, with 1 eq. of PyBOP and 1.2 eqs. of DIEA for 1 h. The mixture is dried and purified in HPLC, obtaining 0.16 g of pure product (yield 35 %) . Title HPLC: >99 %. FAB-MS: [M+H]+= 1469; tr: 25-3 min. The monocyclic product is de-protected by liquefying it in 10 mL of TFA containing water at 10 %, After 0.5 h the mixture is diluted in water and it is lyophilized. The residue is dissolved in lmM solution in DMF, the solution is brought to 0°C and 1 eq. of PyBOP and 1.2 eqs. of DIEA are added. After 24 h it is dried and purified in HPLC. Yield 63 mg (45 %). Title HPLC: >99 %. FAB-MS: [M+H]+= 1295; tr: 21.6 min. c) Synthesis of bicyclic product cyclo([Ser(p-D-Glc)-Asp-Trp-Phe-Dap- Leu]cyclo(2p-5P))- 20 mg of tetrabenzoylate product are dissolved in anhydrous methanol in 5mM solution. The solution is brought to -20°C and a lmM solution of sodium methylate in methanol is added to achieve pH = 11. After 1.5 - 13 - h acetic acid is added to achieve neutral pH, high dilution with water and lyophilization follow. Yield: 6.5 mg (48 %). Title HPLC: > 99 %. FAB-MS: [M+H]+= 878; tr: 9-6 min. By similar procedures, the following compounds have been obtained: EXAMPLE 3 cyclo ([Asn(?-D-2-deoxy-2-amino-Glc)-Asp-Trp-Phe-Dap-Leu] cyclo {2?- 5P)) {SEQ ID No. 3) [compound of Formula I) wherein R4 -CH2-C0-NH-(?- D-2-deoxy-2-amino-Glc) and the other substituents are as defined in Example 1]. EXAMPLE 4 cyclo ([Asn (?-D-2-deoxy-2-acetamido-Glc)-Asp-Trp-Phe-Dap-Leu] cyclo(2?-5?)} (SEQ ID No. 4) [compound of Formula I) wherein R4= -CH2- C0-NH-((?-D-2-deoxy-2-acetamido-Glc) and the other substituents are as defined in Example 1]. EXAMPLE 5 cyclo {[Nle-Asp-Trp-Phe-Dap-Asn(?-D-2-deoxy-2-acetamido-Glc] cyclo(2?-5?)) (SEQ ID No. 5) [compound of Formula I) wherein R1= -CH2- C0-NH-(?-D-2-deoxy-2-acetamido-Glc) , R4 = -(CH2)3-CH3] and the other substituents are as defined in Example 1], EXAMPLE 6 cyclo ([Asn (?-D-ribofuranosyl)-Asp-Trp-Phe-Dap-Leu]cyclo(2?-5?)) (SEQ ID No. 6) [compound of Formula I) wherein R4= -CH2-C0-NH- (?-D- ribofuranosyl) and the other substituents are as defined in Example 1]. EXAMPLE 7 cyclo ( [Ser (?-D-ribofuranosyl) -Asp-Trp-Phe-Dap-Leu]cyclo (2?-5?)) (SEQ ID No. 7) [compound of Formula I) wherein R4 -CH2-0-(?-D- - 14 - ribofuranosyl), and the other substituents are as defined in Example 1]. EXAMPLE 8 cyclo ([Asn (?-L-arabinofuranosyl)-Asp-Trp-Phe-Dap-Leu]cyclo (2?-5??? (SEQ ID No. 8) [compound of Formula I) wherein R4= -CH2-C0- NH-((?-L-arabinofuranosyl) and the other substituents are as defined in Example 1]. EXAMPLE 9 cyclo ([Ser (?-L-arabinofuranosyl)-Asp-Trp-Phe-Dap-Leu]cyclo (2?-5?)) (SEQ ID No. 9) [compound of Formula I) wherein R4= -CH2-0-(?- L-arabinofuranosyl) and the other substituents are as defined in Example 1]. EXAMPLE 10 cyclo ( [ Asn((?-D-mannopyranosyl) -Asp-Trp-Phe-Dap-Leu]cyclo(2?-5?)) (SEQ ID 10) [compound of Formula I) wherein R4= -CH2-C0-NH-(?-D- mannopyranosyl) and the other substituents are as defined in Example 1]. EXAMPLE 11 cyclo ([Ser (?-D-mannopyranosyl)-Asp-Trp-Phe-Dap-Leu]cyclo (2?-5?)) (SEQ ID No. 11) [compound of Formula I) wherein: R4= -CH2-0-(?-D- mannopiranosyl) and the other substituents are ad defined in Example 1]. EXAMPLE 12 cyclo ([Asn (?-D-galactopyranosyl)-Asp-Trp-Phe-Dap-Leu]cyclo (2?-5?)) (SEQ ID No. 12) [compound of Formula I) wherein R4= -CH2-C0- NH-(?-D-galactopyranosyl) and the other substituents are as defined in Example 1]. - 15 - EXAMPLE 13 cyclo([Ser(?-D-galactopyranosyl)-Asp-Trp-Phe-Dap-Leu]cyclo(2?-5?) (SEQ ID No. 13) [compound of Formula I) wherein R4 = -CH2-0-(?-D-galactopyranosyl) and the other substituents are as defined in Example 1]. EXAMPLE 14 cyclo ([Asn(?-D-glucuronopyranosyl) -Asp-Trp-Phe-Dap-Leu]cyclo (2?-5?)) (SEQ ID No. 14) [compound of Formula I) wherein R4= -CH2-C0- NH-(?-D-glucuronopyranosyl) and the other substituents are as defined in Example 1]. EXAMPLE 15 cyclo( [Ser(?-D-glucuronopyranosyl) -Asp-Trp-Phe-Dap-Leu] cyclo (2?-5?)) (SEQ ID No. 15) [compound of Formula I) wherein R4= -CH2-0- (?-D-glucuronopyranosyl) and the other substituents are as defined in Example 1]. EXAMPLE 16 cyclo ([Asn(l-deoxy-sorbitol-l-yl)-Asp-Trp-Phe-Dap-Leu] cyclo (2?-5?)) (SEQ ID 16) [compound of Formula I) wherein R4 -CH2-C0-NH- (1-deoxy-sorbitol-l-yl) and the other substituents are as defined in Example 1]. EXAMPLE 17 cyclo ([Asn[4-0-(?-D-Glc)-?-D-Glc)]-Asp-Trp-Phe-Dap-Leu]cyclo- (2?-5?)) (SEQ ID No. 17) [compound of Formula I) wherein R4= -CH2-C0- NH_[4-0-(?-D-Glc)-?-D-Glc)] and the other substituents are as defined in Example 1], EXAMPLE 18 cyclo([Asn[4-0-(?-D-galactopyranosyl)-?-D-Glc]-Asp-Trp-Phe-Dap- - 16 - Leu]cyclo(2?-5?)) (SEQ ID No. 18) [compound of Formula I) wherein R4= -CH2-C0-NH-[4-0(?-D-galactopyranosyl)-?-D-Glc)] and the other substituents are as defined in Example 1], EXAMPLE 19 cyclo ([ Asn [ O-?-D-Glc-( 1-4 )-0-?-D-Glc-(l-4)-?-D-Glc]-Asp-Trp- Phe-Dap-Leu] cyclo(2?-5?)) (SEQ ID No. 19) [compound of Formula I) wherein: R4= -CH2-C0-NH-[0-?-D-Glc-(l-4)-O-?-D-Glc-(l-4)-?-D-Glc) and the other substituents are as defined in Example 1]. EXAMPLE 20 cyclo([Asn(D-2-deoxy-glucopyranos-2-yl)-Asp-Trp-Phe-Dap-Leu]cyclo (2?-5?)) (SEQ ID No. 20) [compound of Formula I) wherein R4= -CH2-C0- NH-(D-2-deoxy-gluco-pyranos-2-yl) and the other substituents are as defined in Example 1]. EXAMPLE 21 cyclo {[Dap[D(-)-quinyl]-Asp-Trp-Phe-Dap-Leu]cyclo(2?-5?)) (SEQ ID No. 21) [compound of Formula 1) wherein: R4= -CH2-NH-[D(-)-quinyl], and the other substituents are as defined in Example 1], EXAMPLE 22 cyclo ([Dap[D-gluconyl]-Asp-Trp-Phe-Dap-Leu] cyclo(2?-5?)) (SEQ ID No. 22) [compound of Formula I) wherein: R4= -CH2-NH-(D- gluconyl) and the other substituents are as defined in Example 1]. EXAMPLE 23 cyclo ([Dap[D-glucuryl]-Asp-Trp-Phe-Dap-Leu]cyclo(2?-5?)) (SEQ ID No. 23) [compound of Formula I) wherein R4 -CH2-NH-(D- glucuryl) and the other substituents are as defined in Example 1]. EXAMPLE 24 cyclo ([Dap(2-sulfo-benzoyl)-Asp-Trp-Phe-Dap-Leu] cyclo (2?-5?)) - 17 - (SEQ ID No. 24) [compound of Formula I) wherein: R4= -CH2-NH-CO-C6H4,- SO3H and the other substituents are as defined in Example 1]. EXAMPLE 25 cyclo ([Asn (4-sulfo-phenyl)-Asp-Trp-Phe-Dap-Leu] cyclo (2??5?)) (SEQ ID No. 25) [compound of Formula I) wherein R4= CH2-CO-NH-C6H4, SO3H and the other substituents are as defined in Example 1]. EXAMPLE 26 cyclo([Asn(?-L-Glc)-Asp-Trp-Phe-Dap-Leu]cyclo(2^-5P)) (SEQ ID No. 26) [compound of Formula I) wherein R4= -CH2-C0-NH(?-L-Glc) and the other substituents are as defined in Example 1], EXAMPLE 27 cyclo ([Asn (?-D-2-deoxy-glttcopyranos-2-yl) -Asp-Trp-Phe-Dap- Leu]cyclo(2?-5?)} (SEQ ID No. 27) [compound of formula I) wherein R4 = -CH2-C0-NH-(D-2-deoxy-glucopyranos-2-yl) and the other substituents are as defined in Example 1]. EXAMPLE 28 cyclo ([Asn(D-2-deoxy-mannopyranos-2-yl)-Asp-Trp-Phe-Dap-Leu]- cyclo(2?-5?)) (SEQ ID No. 28) [compound of formula I) wherein R4 = - CH2-C0-NH-(D-2-deoxy-niannopyranos-2-yl} and the other substituents are as defined in Example 1]. EXAMPLE 29 cyclo ([Asn(D-2-deoxy-galactopyranos-2-yl)-Asp-Trp-Phe-Dap-Leu]- cyclo(2?-5?) ) (SEQ ID No. 29) [compound of formula I) wherein R4 = - CH2-C0-NH-(D-2-deoxy-galactopyranos-2-yl) and the other substituents are as defined in Example 1]. EXAMPLE 30 cyclo ([Asn(?-D-xylopyranosyl)-Asp-Trp-Phe-Dap-Leu]cyclo(2??5?) ) - 18 - (SEQ ID No. 30} [compound of formula I) wherein R4 = -CH2-C0-NH-(?-D- xylo-pyranosyl) and the other substituents are as defined in Example 1]. EXAMPLE 31 cyclo ([Asn(3-sulfo-propionyl)-Asp-Trp-Phe-Dap-Leu]cyclo-(2p-5p) ) (SEQ ID 31) [compound of formula I) wherein R4 = -CH2-CO-NH-(3-sulfo- propionyl) and the other substituents are as defined in Example 1]. EXAMPLE 32 cyclo ([Dap{Lysyl)-Asp-Trp-Phe-Dap-Leu]cyclo(2$-5£)) (SEQ ID No. 32) [compound of formula I) wherein R4 = -CH2-C0-NH-(Lysyl) and the other substituents are as defined in Example 1]. EXAMPLE 33 cyclo ([Dap(Arginyl)-Asp-Trp-Phe-Dap-Leu]cyclo(2?-5?)} (SEQ ID No. 33) [compound of formula I) wherein R4 = -CH2-C0-NH-(Arginyl) and the other substituents are as defined in Example 1]. EXAMPLE 34 cyclo ([Dap(4-0-?-D-galactopyranosyl)-Asp-Trp-Phe-Dap-Leu]cyclo- (2?-5?)) (SEQ ID No. 34) [compound of formula I) wherein R4 = -CH2-C0- NH-(4-0-?-D-galactopyranosyl) and the other substituents are as defined in Example 1]. EXAMPLE 35 cyclo ([Asn(2-deoxy-2-trifluoroacetamido-£-D-Glc)-Asp-Trp-Phe-Dap- Leu]cyclo(2?-5?)) (SEQ ID No. 35) [compound of formula I) wherein R4 = -CH2-C0-NH-(2-deoxy-2-trifluoroacetamido-?-D-Glc) and the other substituents are as defined in Example 1]. BIOLOGICAL ACTIVITY The capability of the compounds of the present invention to interact - 19 - as agonists or antagonists with the neurokynin A (NKA) receptor has been valued in a in vitro test using the pulmonary artery of a rabbit (RPA) (Rovero et al., Neuropeptides, 1989, 13, 263-270) and their activity was determined as pKB (antilogarythm of the dissociation constant), as described in Jenkinson et al., TiPS, 12, 53-56, 1991- For example, compound 2 has shown a pKB = 8.67. The capability of the products of the present invention to interact as agonists or antagonists with NKA receptor has been valued in vivo as capability, after intravenous administration,to inhibit the agonist [betaAla8 ] NKA (4-10)-induced contractions of the urinary bladder in the anaesthetized mouse, as described in Maggi et al., J. Pharmacol. Exp. Ther., 1991, 257. 1172. Compound 1, e.g., causes, at dose of 10 nmol/Kg i.v., an inhibitory effect of 50-70 %, as it has been valued at different times. The effect lasts over a period of more than 3 hours. ABBREVIATIONS: AsnO-D-Glc) : Ng-(-D-glucopiranosyl)-L-asparagine Asn[(Ac4O)-?-D-Glc]: Ng-(2,3.4,6-tetra-0-acetyl-^-D-glucopiranosyl)-L- asparagine Fmoc-Asn[ (Ac4O) -?-D-Glc]-OPfp: Ng-(2,3 , 4 , 6-tetra-0-acetyl-?-D- glucopiranosyl)Na-(fluoren-9-ylmethoxycarbonyl)-L-asparagine pentafluorophenyl esthere Ser(?-D-Glc): 0g- (?-D-glucopiranosyl) L-asparagine Ser[(Bz4,0)-?-D-Glc]: 0g-(2,3,4,6-tetra-0-benzoyl-?-D-glucopiranosyl)L- asparagine Fmoc-Ser[(Bz4O)-?-D-Glc]-OPfp: 0&-(2, 3, 4 ,6- tetra-o-benzoyl-?-D- - 20 - glucopiranosyl)Na-(fluoren-9-ylmethoxycarbonyl)-L-serine pentafluorophenyl esther. Glc: glucopyranosyl - 21- MASS - SPECTRUM DATA EXAMPLE 3 Synthesized following the procedure described in example 1 [M+H]+- 906 tr= 9.4 min EXAMPLE 4 Synthesized following the procedure described in example 1 [M+H]+= 948 tr= 4.9 min EXAMPLE 5 Synthesized following the procedure described in example 1 [M+H]+= 948 tr= 10.3 min EXAMPLE 6 Synthesized following the procedure described in example 1 [M+H]+= 877 tr= 9.5 min EXAMPLE 7 Synthesized following the procedure described in example 2 [M+H]+= 850 -22- tr= 9.0 min EXAMPLE 8 Synthesized following the procedure described in example 1 [M+H]+= 877 tr= 8.5 min EXAMPLE 9 Synthesized following the procedure described in example 2 [M+H]+= 850 tr= 9.2 min EXAMPLE 10 Synthesized following the procedure described in example 1 [M+H]+= 907 V= 6.95 min EXAMPLE 11 Synthesized following the procedure described in example 2 [M+H]+= 878 tr= 10.1 min EXAMPLE 12 Synthesized following the procedure described in example 1 [M+H]+= 906 tr= 3.8 min EXAMPLE 13 Synthesized following the procedure described in example 2 [M+H]+= 878 tr= 10.5 min EXAMPLE 14 Synthesized following the procedure described in example 1 [M+H]+= 921 tr= 9.2 min EXAMPLE 15 Synthesized following the procedure described in example 2 [M+H]+= 894 tr= 8.7 min EXAMPLE 16 Synthesized following the procedure described in example 1 [M+H]+= 909 tr= 3.7 min EXAMPLE 17 Synthesized following the procedure described in example 1 [M+H]+=1069 tr= 9.2 min EXAMPLE 18 24 Synthesized following the procedure described in example 1 [M+H]+=1116 tr= 8.0 min EXAMPLE 19 Syntliesized following the procedure described in example 1 [M+H]+= 1261 tr= 7.8 min EXAMPLE 20 Synthesized following the procedure described in example 1 [M+H]+= 906 tr= 9.3 min EXAMPLE 21 Synthesized following the procedure described in example 1 [M+H]+- 890 tr= 8.4 min EXAMPLE 22 Synthesized following the procedure described in example 1 [M+H]+= 895 tr= 9.0 min EXAMPLE 23 Synthesized following the procedure described in example 1 -25- [M+H]+= 892 tr= 7.45 min EXAMPLE 24 Synthesized following the procedure described in example 1 [M+H]+= 900.2 tr= 6.5 min EXAMPLE 25 Synthesized following the procedure described in example 1 [M+H]+= 900.2 tr= 7.0 min EXAMPLE 26 Synthesized following the procedure described in example 1 [M+H]+- 906.7 tr- 4.4 min EXAMPLE 28 Synthesized following the procedure described in example 1 [M+H]+= 906.5 tr= 11 min EXAMPLE 29 Synthesized following the procedure described in example 1 [M+H]+= 906.5 tr= 10.5 min EXAMPLE 30 Synthesized following the procedure described in example 1 [M+H+= 876.5 tr- 11.3 min EXAMPLE 31 Synthesized following the procedure described in example 1 [M+Hf- 897 tr 7.5 min EXAMPLE 32 Synthesized following the procedure described in example 1 [M+H]+= 845 tr=3.8min EXAMPLE 33 Synthesized following the procedure described in example 1 [M+H]+= 873 tr= 4.3 min EXAMPLE 35 Synthetized following the procedure described in example 1 [M+H]+= 1001 tr=10.55 min - 27-WE CLAIMS- 1. Bicycyiccompounds of general Formula wherein X1, X2, X3, X4, X5 and X6, same or different from one another, represent a -NR'CO- or a -CONR'- group, where R' is H or C1-3 alkyl; Y represents a group selected from -NRCO-, -CONR- or -SS- wherein R is H or C1-3 alkyl; at least one of R1, R2, R3 and R4. groups, same or different from one another, is hydrophilic and the remaining groups are hydrophobic; m and n, same or different from one another, are each an integer number from 1 to 4. 2. Compounds as claimed in claim 1, wherein the hydrophobic groups can be separately selected from the following: a) groups corresponding to CnH2n+1 wherein n= 0, 1-4; b) linear or branched-alkyl groups corresponding to CnH2n-U-W wherein n= 1-4; U= 0, COO, CONH, S and W= alkyl-, aryl- or alkylaryl-group containing from 1 to 15 C atoms; c) (CH2)n-C6H3-A-B wherein n= 0, 1-3; A and B, placed in any of the ortho, meta or para positions, same or different from one another, represent H, halogen, OR, NHR, NR2, CH3, SR wherein R is an alkyl-, aryl- or alkyl aryl-group with less than 10 C atoms; - 23 - d) (CH2)n-C6H10R', wherein n= 0, 1-3 and R'= H, C1-3 alkyl e) (CH2)n-heterocycle, wherein n= 0, 1-3 and by the term heterocyclic imidazolyl-2-yl, indolyl-3-yl, furanyl-3-yl, piridyl-3-yl, imidazolyl- 3-yl are meant; f) a -(CH2)S- group wherein s = 3, 4, eventually 0H-substituted or condensed with an aromatic group, which cyclizes with one of the two adjacent X1-6 groups in order to produce the side chain of proline, hydroxyproline, octahydroindol-2-carboxylic acid, tetrahydroiso- quinolinic acid; g) the side chain of a natural hydrophobic amino acid; h) the side chain of a natural hydrophilic amino acid, suitably substituted in order to render it hydrophobic; i) the side chain of non-natural hydrophobic amino acids selected from the group consisting of: norleucine, norvaline, alloisoleucine, ciclohexylglycine (Chg) , ?-amino-n-butyric-acid (Aba) . ciclohexylalanine (Cha), aminophenylbutyric acid (Pba), mono- and di-substituted phenylalonines in ortho, meta and para positions of the benzene ring with one or more of the following groups: C1-10 alkyl, Cl-10 alkoxy, halogen, ?-2-thienylalanine, ?-3-thienylalanine, ?-2-furanylalanine, ?-3-furanylalanine , ?-2-pi ridyl alanine , ?-3-piridylalanine, ?-4-piridylalanine , ?- (1-naphtyl) alanine, ?-(2-naphtyl)alanine, 0-alkylated serine-threonine- tyrosine-derivatives, S-alkyl cysteine, S-alkyl homocysteine, N-alkyl lysine, N-alkyl ornithine, N-alkyl 2,3 diaminopropionic acid. 3. Compounds as claimed in claim 2 wherein the side chain of a hydrophobic amino acid according to paragraph g) is the side chain of an amino acid selected from the group consisting of: glycine, alanine, - 23 - valine, leucine, isoleucine, methionine, phenylalanine, tyrosine, tryptophan, proline, histidine, aspargine, glutamine. 4. Compounds as claimed in claim 2, wherein, "the side chain of an hydrophilic amino acid suitably substituted according to paragraph (h) is the side chain of an amino acid selected from the group consisting of: serine, threonine, cysteine, aspartic acid, glutamic acid, carboxyglutamic acid, arginine, ornythine, lysine. 5. Compounds according to Claim 2 wherein the hydrophilic groups are chosen in the group L-Q wherein L is a chemical bond of a linear or branched C1-6 alkyl-group and Q is chosen in the group consisting of: i) hydroxyl, amine, guanidine, carboxyl, sulfate, phosphonate, phosphate; ii) linear, branched or cyclic C1-6 alkyl chain containing one or more hydroxyl, amine, guanidine, carboxyl, sulfate, phosphate; iii) an aromatic group mono-, di- or tri-substituted ortho-, meta-, para-position with hydroxyl, amino, guanidine, carboxyl, sulfate, phosphate; iv) a group M, OM, CONHM, NHCOM wherein M is an hydrophilic group v) an hydrophilic group according to points i)-iv) protected with groups which are biologically hydrolized reforming an hydrophilic group. 6 Compounds according to Claim 5 wherein the group M is chosen in the group consisting of: i) eventually substituted mono-, di-, tri-glycosidic residues; ii) linear, branched or cyclic C1-6 alkyl-chains, containing one or more groups hydroxyl, amine, guanidine, carboxyl, sulfate, phosphonate, phosphate. 30 7. Compounds of Formula (I) as claimed in claim 6, wherein the glycosidic residues are selected from the group consisting of: hexoses'or, pentoses of D or L series in a or fi configuration, selected from the group wherein: all C atoms bear a tree or protected hydroxylic group; one or more hydroxyls are substituted by: hydrogen; an amino or acylamino group; C6 of hexoses and C5 of pentoses are part of a carboxylic group; and wherein the eventually present 2 or 3 glycosidic units are linked by a glycosidic bond of a or ? configuration. 8. Compounds of general Formula (I) according to claim 7 selected from the group consisting of: D or L ribose, D or L arabinose, D or L xylose, D or L lyxose, D or L allose, D or L altrose, D or L glucose, D or L mannose, D or L gulose, D or L idose, D or L galactose,D or L talose, D or L allulose, D or L fructose, D or L sorbose, D or L tagatose; 5-deoxy-D or L-arabinose, 2-deoxy-D or L-glucose, 2-deoxy-D or L-galactose, 2-deoxy-D or L-arabinose, 2-deoxy-D or L-ribose, D or L fucose, D or L ramnose; D-glucosamine, D-mannosamine, D- galaotosamine, daunosamine, acosamine and N-acylate derivates thereof with lower fat acids, i.e. containing a N-formylic, acetylic, propionilic, butyric residue; glucuronic acid, galacturonic acid; cellobiose, lactose, maltose, D-lactosamine, cellotriose, maltotriose; tris(hydroxymethyl)methyl, D or L arabitol, D or L erythrol, D or L perseitol, D or L ribitol, D or L sorbitol, D or L xylitol; or those from the residue of tartaric acid, glucaric acid, gluconic acid, bycine, quinic acid, mucic acid, glucosaminic acid. 9. Compounds of general Formula (I) according to claim 1, wherein if one or both R1 and R4 groups are hydrophilic, both R2 and R3 groups -31- are hydrophobic or viceversa. 10. Compounds as claimed in claim 1, as hereinafter indicated: i) cyclo([Asn(?-D-Glc)-Asp-Trp-Phe-Dap-Leu]cyclo(2£-5£)) (SEQ ID No. 1 ii) cyclo([Ser(?-D-Glc)-Asp-Trp-Phe-Dap-Leu]cyclo(2?-5?)) (SEQ ID No. 2) iii) cyclo ([Asn (?-D-2-deoxy-2-amino-Glc)-Asp-Trp-Phe-Dap-Leu] cyclo (2?-5?)) (SEQ ID No. 3) iv) cyclo ( [Asn(?-D-2-deoxy-2-acetamido-Glc)-Asp-Trp-Phe-Dap- Leu]cyclo(2?-5?)) (SEQ ID No. 4) v) cyclo([Nle-Asp-Trp-Phe-Dap-Asn(?-D-2-deoxy-2-acetamido-Glc)] cyclo(2?-5?)) (SEQ ID 5) vi) cyclo ([Asn((?-D-ribofuranosyl)-Asp-Trp-Phe-Dap-Leu]cyclo (2?-5?)) (SEQ ID 6) vii) cyclo ( [ Ser(?-D-ribofuranosyl )-Asp-Trp-Phe-Dap-Leu] cyclo (2?-5?)) (SEQ ID No. 7) viii) cyclo([Asn((5-L-arabinofuranosyl)-Asp-Trp-Phe-Dap-Leu]cyclo (2?-5?)) (SEQ ID No. 8) ix) cyclo([Ser(?-L-arabinofuranosyl)-Asp-Trp-Phe-Dap-Leu]cyclo (2?-5?)) (SEQ ID No. 9) x) cyclo ( [Asn (?-D-mannopyranosyl) -Asp-Trp-Phe-Dap-Leu] cyclo (2?-5?)) (SEQ ID No. 10) xi) cyclo ( [Ser (?-D-mannopyranosyl) -Asp-Trp-Phe-Dap-Leu] cyclo (2?-5?)) (SEQ ID No. 11) xii) cyclo ([Asn (?-D-galactopyranosyl) -Asp-Trp-Phe-Dap-Leu]cyclo (2?- 5?)) (SEQ ID No. 12) xiii) cyclo([Ser(?-D-galactopyranosyl)-Asp-Trp-Phe-Dap-Leu]cyclo (2?- 5?)) (SEQ ID No. 13) -3 2- xiv) cyclo ([ Asn (?-D-glucuronopyranosyl) -Asp-Trp-Phe-Dap- Leu]cyclo{2?-5?)) (SEQ ID No. 14) xv) cyclo ([Ser(?-D-glucuronopyranosyl) -Asp-Trp-Phe-Dap-Leu] cyclo(2?-5?)) (SEQ ID No. 15) xvi) cyclo ([Asn(l-deoxy-sorbitol-l-yl)-Asp-Trp-Phe-Dap-Leu]cyclo (2?-5?)) (SEQ ID No. 16) xvii) cyclo { [Asn [(4-0-(?-D-Glc)-?-D-Glc)]-Asp-Trp-Phe-Dap- Leu]cyclo(2?-5?)) (SEQ ID No. 17) xviii) cyclo ([Asn[(4-0-(?-D-galactopyranosyl)-?-D-Glc)]-Asp-Trp-Phe- Dap-Leu]cyclo(2?--5?)) (SEQ ID No. 18) xix) cyclo ( [ Asn [O-?-D-Glc-(1-4)-O-?-D-Glc-(l-4)-?-D-Glc]-Asp-Trp- Phe-Dap-Leu] cyclo(2?-5?)) (SEQ ID No. 19) xx) cyclo ([Asn(D-2-deoxy-glucopyranos-2-yl)-Asp-Trp-Phe-Dap- Leu]cyclo(2?-5?)) (SEQ ID No. 20) xxi) cyclo ([Dap[D(-)-quinyl]-Asp-Trp-Phe-Dap-Leu]cyclo(2?-5?)) (SEQ ID No. 21) xxii) cyclo ([Dap[D-gluconyl]-Asp-Trp-Phe-Dap-Leu] cyclo (2?-5?)) (SEQ ID No. 22) xxiii)cyclo ([Dap[D-glucuryl]-Asp-Trp-Phe-Dap-Leu]cyclo(2£-5&)) (SEQ ID No. 23) xxiv) cyclo ([Dap (2-sulfo-benzoyl)-Asp-Trp-Phe-Dap-Leu] cyclo (2?-5?)) (SEQ ID No. 24) xxv) cyclo ([Asn(4-sulfo-phenyl)-Asp~Trp-Phe-Dap-Leu]cyclo(2p"-5£)) (SEQ ID No. 25) xxvi) cyclo ( [Asn(?-L-Glc) -Asp-Trp-Phe-Dap-Leu]cyclo(2?-5?)) (SEQ ID No. 26) xxvii) cyclo ([Asn(?-D-2-deoxy-glucopyranos-2-yl) -Asp-Trp-Phe-Dap- -33- Leu]cyclo(2?-5?)) (SEQ 1D No. 27) xxviii) cyelo ([ Asn(?-D- 2 -deoxy-mannopyranos- 2 -y1 )-As- Trp-Phe-Dap-Leu] cyclo( 2?- 5P)) (SEQ ID No. 28) xxix) cyelo ([Asn( D- 2 -deoxy-galaetopyranos- 2 -yl )-Asp- Trp-Phe-Dap-Leu]cyclo( 2?-5?)) (SEQ 10 No. 29) xxx) cyclo([Asn(?-D-xylopyranosyl)-Asp-Trp-Phe-Dap-Leu]cyclo(2?-5?)) (SEQ 1D No. 30) xxxi) cyelo ([Asn(3-sulfo-propionyl)-Asp-Trp-Phe-Dap-Lue)cyclo(2?-5?)) (SEQ 1D No. 31) xxxii) cyelo ([Dap(Lysyl)-Asp-Trp-Phe-Dap-Lue]cyclo(2?-5?)) (SEQ 1D No. 32) xxxiii) cyclo([Dap(Arginyl)-Asp-Trp-Phe-Dap-Lue]cyclo(2?-5?)) (SEQ 1D No.33) xxxiv) cyelo ([Dap( 4-0- ?-D-gaalactopyranosyl)-Asp- Trp-Phe-Dap-Leu] cyclo(2?-5?)) (SEQ IDNo.34) xxxv) cyelo (Asn(2-deoxy- 2-trifluoroaeetamido-?-D-Glc )-Asp- Trp-Phe-Dap-Leu]cyclo( 2?- 5?))(SEQ1DNo.35). This invention relates to novel compounds of general formula (1):

Full Text

- 1A-
Bicyclic compounds, preparation thereof and use in pharmaceutical compositions Field of the Invention
This invention relates to novel bi-cyclic compounds useful in pharmaceutical compositions as tachykinins antagonists, and to pharmaceutical compositions containing them • Background of the invention
The receptor NK2 of tachykinins is widely expressed in the peripheral nervous system of Mammalia. One of the several effects caused by the selective stimulation of the receptor NK2 is the contraction of the smooth muscles. Therefore, antagonists of the receptor NK2 can be considered agents able to control the hypercontraction of the smooth muscles in any patological condition in which the release of the tachykinins contributes to the rise of the corrispondent disorder. In particular, the bronchospastic component of asthma, cough, pulmonary irritations and local spasms of the urinary bladder and of the ureter during cystitis, infections and renal colics can be considered conditions in which the administration of receptor NK2 antagonists can be effective (A.L. Magnan et al. Neuvopeptides, 1993. 24, 199)- Compounds which act as antagonists of the tachykinins, and in particular of the neurokinin A, are well-known in Literature. Among them, the cyclic compounds (B. J. Williams et al. J. Med. Chem. , 1993. 36, 2) are of particular interest. Lipophily has been defined as an essential requirement in order to have an intensive antagonist activity to the receptor NK2 of the tachykinins of a series of cyclic pseudopeptides (L. Quartara et al. J. Med. Chem. , 1994. 27) and

- 2 -
particularly in case of bicyclic hexapeptides. WO/93/21227).
Surprisingly it has been now found that products structurally similar
to those described above, but in which, however, at least one
hydrophilic group is present, not only keep their high affinity in
vitro, but also show an increase in the pharmacological activity in
vivo if compared to the corrispondent compounds which do not contain
any hydrophilic group.
This is even more surprising if it is taken into account that
monocyclic peptides having antagonist properties which are similar to
those of the tachykinins do not show any increase in the
pharmacological activity when hydrophilic groups are introduced onto
the structure of the cycle [Int. J. Peptide Protein Res. (1984), 44:2,
105-111].
Summary
This invention relates to novel compounds of the general formula (I):

wherein:
xl, X2 , X3 , X4, X5, and X6, same or different from one another,
represent a - NR'CO- or a -CONR'- group, wherein R' is H or C1-3
alkyl;

- 3 -
Y represents a group selected from -NRCO-, -CONR-, or -SS-
wherein R is H or C1-3 alkyl;
at least one of the R1, R2 R3 and R4 groups, same or different from
one another, is hydrophilic and the remaining groups are hydrophobic;
and n, same or different from one another, are each an integer
number from 1 to 4;
and to pharmaceutical compositions containing them.
Detailed description of the Invention
The present invention relates to novel compounds having the general
formula (I)

wherein
Xl, X2 , X3, X4 ,X5 ,X6, Y, Rl, R2 ,R3, R4, m and n goups are as
defined above;
processes for the preparation thereof and pharmaceutical compositions
containing them.
The formula (I) as reported above is considered the one giving the
best representation of the real spatial structure of the bicyclic
peptide according to the invention. However also the following Formula
(Ia) (which chemically speaking is identical to Formula (I)) is given

- 4 -
in order to simplify the understanding of the compounds described hereinafter and in the Examples with their chemical name in particular in so far as the groups X1-6 and Y are concerned.

The groups X1-6 and Y are in fact defined according to the aminoacid-
sequence from the formal N- to the C-terminus of the peptide as they
are represented in the linear structure, therefore reading Formula
(Ia) no problem arises in the understanding of the linear structure as
reported in the Examples.
As it can be seen, the compounds of formula (I) as described above
present chiral centers: it is understood that this invention relates
also to the several enantiomers.
More particularly the hydrophobic groups can be separately selected
from the following:
a) groups CnH2n+1 wherein n= 0, 1-4
b) linear- or branched alkyl groups corresponding to CnH2n-U-W wherein
n= 1-4; U= 0, COO, CONH, S and W= alkyl-, aryl or alkylaryl-group
containing from 1 to 15 carbon atoms
c) (CH2)n -C6H3-A-B wherein n= 0, 1-3; A and B, placed in any of the
ortho, meta or para positions, same or different from one another,
represent H, halogen, OR, NHR, NR2, CH3, SR wherein R is an alkyl-,
aryl- or alkyl aryl-group with less than 10 C atoms
d) (CH2)n -CgH10 R', wherein n= 0, 1-3 and R'= H, C1-3 alkyl

- 5 -
e) (CH2)n -heterocycle, wherein n= 0, 1-3 and for heterocycle it is
meant: imidazolyl-2-yl, indolyl-3-yl. furanyl-3-yl, pyridyl-3-yl,
imidazoly1-3-y1
f) a -(CH2)S- group, wherein s= 3, 4, eventually OH-substituted or
condensed with an aromatic group, which cyclizes with one of the two
adjacent X1-6 groups in order to produce the side chain of proline,
hydroxyproline, octahydroindol-2-carboxylic acid,
tetrahydroisoquinolinic acid
g) the side chain of a natural hydrophobic amino acid
h) the side chain of a natural hydrophilic amino acid, suitably substituted in order to render it hydrophobic
i) the side chain of non-natural hydrophobic amino acids selected from the group consisting of: norleucine, norvaline, alloisoleucine, cyclohexylglycine (Chg), a-amino-n-butyric acid (Aba), cyclohexylalanine (Cha), aminophenylbutyric acid (Pba), phenylalanines mono- and di- substituted in the ortho, meta and para positions of the benzene ring with one or more of the following groups: C1-10 alkyl, C1-10 alkoxy halogen, ?-2-thienylalanine, ?-3-thienylalanine, ?-2-furanylalanine, ?-3-furanylalanine, ?-2-piridylalanine, ????piridylalanine, ?-4-piridylalanine, ?-(1-naphtyl)alanine, ?-(2-naphtyl)alanine, O-alkylated serine- threonine- tyrosine-derivatives, S-alkyl cysteine, S-alkyl homocysteine, N-alkyl lysine, N-alkyl ornithine, N-alkyl 2,3 diaminopropionic acid.
More particularly, the side chain of a hydrophobic amino acid according to paragraph (g) is the side chain of an amino acid selected from the group consisting of: glycine, alanine, valine, isoleucine, methionine, phenylalanine. tyrosine, tryptophan, proline, histidine.

- 6 -
aspargine, glutamine.
The side chain of a hydrophilic amino acid, suitably substituted in
order to render it hydrophobic according to paragraph (h) is the chain
of an amino acid selected from the group consisting of: serine,
threonine, cysteine, aspartic acid, glutamic acid, t-carboxyglutamic
acid, arginine, ornithine, lysine.
Preferably, the hydrophilic groups are selected from L-Q group,
wherein L is a chemical bond or a linear or branched C1-6-alkyl
residue and Q is a hydrophilic group. Preferably Q is selected from
the group consisting of: guanidine, amine, M, OM, -CO-NH-M, -NH-CO-M,
an aromatic group which has been mono-, di- or tri-substituted in
ortho, meta, para positions with M or OM groups, wherein M is a
hydrophilic group.
With the term "hydrophilic group", for Q and M, it is preferably
meant:
i) eventually substituted mono-, di-, tri-glycosidic residues;
ii) C1-6 linear o cyclic alkyl chains comprising one or more polar
groups;
iii) hydroxyl, amine, guanidine, carboxyl, sulfate, phosphonate,
phosphate;
iv) residues bearing substituted hydrophilic groups which in biologic
environment are hydrolysated, re-establishing the hydrophilic
function.
As far as the definition according to paragraph (i) hereinabove is
concerned, the following structures are preferably meant:
hexoses or pentoses of the D or L series in a or ? configuration,
selected from the group wherein: all C atoms bear a free or protected

- 7 -
hydroxylic group; one or more hydroxyls are substituted by: hydrogen, an amino or acylamino group; C6 of hexoses and C5 of pentoses are part of a carboxylic group; and wherein the eventually present 2 or 3 glycosidic units are linked by a glycosidic bond of a or ??configuration.
Specific examples of glycosidic groups as defined above are: D or L ribose, D or L arabinose, D or L xylose, D or L lyxose, D or L allose, D or L altrose, D or L glucose, D or L mannose, D or L gulose, D or L idose, D or L galactose, D or L talose, D or L allulose, D or L fructose, D or L sorbose, D or L tagatose; 5-deoxy-D or L-arabinose, 2-deoxy-D or L-glucose, 2-deoxy-D or L-galactoset 2-deoxy-D or L-arabinose, 2-deoxy-D or L-ribose, D or L fucose, D or L ramnose; D-glucosamine, D-mannosamine, D-galactosamine, daunosamine, acosamine and N-acylate derivates thereof with lower fatty acids, i.e. having a N-formylic, acetylic, propionilic, butyric residue; glucuronic acid, galacturonic acid, cellobiose, lactose, maltose, D-lactosamine, cellotriose, maltotriose and protected derivates thereof. The definition according to paragraph (ii) hereinabove applies to chains deriving from a polyol-residue, such as tris(hydroxymethyl)methyl, D or L arabitol, D or L erythrol, D or L galactytol, meso-inositol, D or L mannitol, D or L perseitol, D or L ribitol, D or L sorbitol, D or L xylitol; or those deriving from the residue of tartaric acid, glucaric acid, gluconic acid, bycine, quinic acid, mucic acid, glucosaminic acid.
Among the products of formula (I) as above indicated, the products wherein if one or both R1 and R4 groups are hydrophilic, both R2 and R3 groups are hydrophobic and viceversa, are particularly preferred.

- 8 -
Compounds of formula (I) object of the present invention can be synthetized by the various techniques known in Literature, see e.g. M. Bodansky, "Peptide Chemistry", Springer-Verlag, 1988. For example by means of in solution synthesis of the linear peptidic chain through subsequent coupling of suitably activated N-protected amino acids to an amino acid or to a C-protected peptidic chain, with isolation of the intermediates, subsequent selective de-protection of the C- and N-terminal chains, cyclization in polar organic solvents in diluted solution, hence selective de-protection of the side chains and at last cyclization of the same in polar organic solvents in diluted solution. The hydrophilic residue can be introduced both as protected amino acid derivative during the peptidic chain synthesis and by means of conjugation to the already formed peptide, as widely disclosed in Literature. Similarly a synthesis in solid phase of the peptidic chain from the C-terminal end to the N-terminal one on a insoluble polymeric support, the cyclization in solid phase between the previously de-protected side chains, the subsequent detachment from the polymeric support by means of hydrolysys in anhydrous hydrofluoric acid containing the suitable scavengers or in trifluoracetic acid containing the suitable scavengers or in aqueous bases and the cyclization of the raonocyclic peptide in polar organic solvents in diluted solution, can be used for the preparation. The hydrophilic residue being introduced according to the above disclosed indications. According to a particular preparation method, the desired product can be obtained in solid phase using the 2-chlorotrytil resin (Barlos et al.. Int. J.Peptide Protein Res., 37. 513-520, 1991) substituted with a protected amino acid having the Fmoc group at the N-terminal end;

- 9 -
preferably the amino acid directly bond to the resin is the one having the R1 or R3 side chain. After the other amino acids being introduced in the sequence, the peptide is detached from the resin with diluted acetic acid and a first cyclization is performed between the free C-terminal and N-terminal end by means of the conventional classic synthesis methods. Subsequently, the amino acid side chains are de-protected in position 5 and 6, for example with trifluoracetic acid, and way is given to the second cyclization.
Other synthetic ways are anyway possible and largely described in Literature as above mentioned.
The compounds of formula (I) as above indicated have revealed to be powerful antagonists of the receptor NK2 of the tachykinins, and hence may be administered in doses which are not higher than those required for the known products.
They can be therefore indicated for the treatment of arthritis, asthma, inflammations, tumoral growth, gastro-intestinal hypermotility, Huntington's desease, neurites, neuralgia, hemicrania, hypertension, urinary incontinence, urticaria, symptoms from carcinoid desease, flu and colds.
The compounds of formula (I) object of the present invention are suitable for the parenteral, oral, inhalatory and sublingual administration for therapeutical purposes to the superior animals and to the humans, achieving pharmacological effects according to the above described features. For parenteral administrations {endovenous, intramuscular and intradermic) sterile solutions or
lyophilized chemical preparations are used. For nasal, inhalatory and sublinqual administrations, according to the particular instance,

- 10 -
aqueous solutions, aereosol preparations or capsules are used.
The doses of active principle in the above compositions can be
comprised between 0,1 and 10 mg/kg of body weight.
EXAMPLE 1.
Preparation of cyclo([Asn(?-D-Glc)-Asp-Trp-Phe-Dap-Leu]cyclo(2?-5?))
(SEQ ID No. 1) compound of formula (I) wherein Y=X1=X2=X3=X4-X5=X6=
C0-NH-; R1= -CH2-CH(CH3)2; R2= -CH2-C6H5, R3=-CH2indolyl-3-yl, R4=-
CH2-C0-NH-(?-D-Glc) ; m=n=l and the carbon atoms C1, C2, C3, C4, C5, C6
have L configuration].
a) synthesis of the linear peptide H-Asn[{Acit0)-p'-D-Glc]-Asp{0tBu)-
Trp-Phe-Dap(Boc)-Leu-OH.
1 g of 2-chlor trityl resin (1,6 mmol/g, Novabiochem) is
functionalized with Fmoc-Leu~0H (0,6 eqs.) as described by Barlos et
al.. Int. J. Peptide Protein Res., 1991, 37. 513-520. The substitution
degree of the resin is determined by dosing the group Fmoc, and it is
equal to 0,364 meq/g. The subsequent 4 amino acids are coupled as
free acids using an excess 3 of amino acid and HOBt (4 eqs.) and DCC
(3 eqs.) as activators with reaction times of 1 hour. In the following
order: Fmoc-Dap{Boc)-0H. Fmoc-Phe-OH, Frnoc-Trp-OH. Fmoc-Asp(0tBu)-0H
are added. The last amino acid is coupled as Fmoc-Asn[ (Ac4O)-?-D-Glc]-
OPfp (Christiansen-Brams et al., J.Chem.Soc. Perkin Trans. I. 1993,
1461-1471), 2 eqs., with HOBt (2 eqs.) as activator, for 3h.
After the de-protection of the group Fmoc, the detachment from the
resin is performed, suspending it in 10 mL of a mixture of AcOH, TFE,
DCM (1/1/8, v/v) at room temperature for 0,5 h. Thereafter the solvent
is evaporated under vacuum at 30°C, it is again mixed with water and
it is lyophilized. Yield in raw product: 405 mg (90 %) . Title HPLC: 70

- 11 -
%. FAB-MS: [M+H]+ = 1266; tr: 14,7 min.
b) Synthesis of the bicyclic product cyclo([Asn((AchO)-p-D-
Glc)-Asp-Trp-Phe-Dap-Leu]cyclo(2ft-5p)) (compound 2).
The linear raw product is cyclized in 1 mM solution in DMF, at 4°C, with 1 eq. of PyBOP and 1,2 eqs. of DIEA for 1 h. The mixture is dried and purified in HPLC obtaining 156 mg of the pure product (yield 39 %). Title HPLC:>99 %. FAB-MS: [M+H]+=1248; tr: 18.4 min. The monocyclic product is de-protected by solving it in 15 ml of TFA containing water at 10 %. After 0.5 h, the mixture is diluted in water and it is lyophilized. The residue is dissolved in 1 mM solution in DMF, the solution is brought to 0°C and 1 eq. of PyBOP and 1.2 eqs. of DIEA are added. After 5 h, it is dried and purified in HPLC. Yield 45 % (70 mg). Title HPLO 99 %. FAB-MS: [M+H]+= 1074; tr: 13-5 min.
c) Synthesis of the bicyclic product cyclo ([Asn(?-D-Glc)-Asp-Trp-
Phe-Dap-Leu]cyclo(2?-5?))
70 mg of tetraacetylate product are dissolved in anhydrous methanol in 5 mM solution. The solution is brought to -20°C and a 1 mM solution of sodium methylate in methanol is added to achieve pH = 11. After 10' acetic acid is added to achieve neutral pH, high diluition with water and lyophilization follow. Yield 60 %. Title HPLC: 98 %. FAB-MS: [M+H]+= 906; tr: 9-3 min. EXAMPLE 2
Preparation of cyclo{[Ser(?-D-Glc)-Asp-Trp-Phe-Dap-Leu]cyclo(2P-5P)) (SEQ ID No. 2) [compound of Formula (I) wherein: Y=X1=X2=X3=X4=X5=X6=-C0-NH-; R1= -CH2-CH(CH3)2; R2= -CH2-C6H5; R3= -CH2-indolyl-3-yl; R4=-CH2-O-(P-D-Glc); m = n = 1 and C1, C2, C3. C4, C5, C6 carbon atoms have L configuration].

- 12 -
a) synthesis of linear peptide H-Ser[{Bz4O)-?-D-Glc]-Asp(OtBu)-Trp-
Phe-Dap{Boc)-Leu-OH.
The same procedure which has been used for Example 1), paragraph a), is utilized here till the addition of the last amino acid, which is coupled as Fmoc-Ser[(Bz^O)-p-D-Glc]-OPfp (obtained by the procedure which has been described by Vargas-Berenguel et al., J. Chem. Soc. Perkin Trans. I, 1994, 2615, 2619).
The detachment occurs as described above,in Example 1). Yield in raw product: 450 mg (83 %) . Title HPLC: 93 %. FAB-MS: [M+H]+= 1487; tr: 20.8 min.
b) Synthesis of bicyclic product cyclo{[Ser[(Bz4O)-?-D-Glc]-Asp-Trp-
Phe-Dap-Leu]cyclo(2?-5?)).
The linear raw product is cyclized in lmM solution in DMF, at 4°C, with 1 eq. of PyBOP and 1.2 eqs. of DIEA for 1 h. The mixture is dried and purified in HPLC, obtaining 0.16 g of pure product (yield 35 %) . Title HPLC: >99 %. FAB-MS: [M+H]+= 1469; tr: 25-3 min. The monocyclic product is de-protected by liquefying it in 10 mL of TFA containing water at 10 %, After 0.5 h the mixture is diluted in water and it is lyophilized. The residue is dissolved in lmM solution in DMF, the solution is brought to 0°C and 1 eq. of PyBOP and 1.2 eqs. of DIEA are added. After 24 h it is dried and purified in HPLC. Yield 63 mg (45 %). Title HPLC: >99 %. FAB-MS: [M+H]+= 1295; tr: 21.6 min.
c) Synthesis of bicyclic product cyclo([Ser(p-D-Glc)-Asp-Trp-Phe-Dap-
Leu]cyclo(2p-5P))-
20 mg of tetrabenzoylate product are dissolved in anhydrous methanol in 5mM solution. The solution is brought to -20°C and a lmM solution of sodium methylate in methanol is added to achieve pH = 11. After 1.5

- 13 -
h acetic acid is added to achieve neutral pH, high dilution with water
and lyophilization follow. Yield: 6.5 mg (48 %). Title HPLC: > 99 %.
FAB-MS: [M+H]+= 878; tr: 9-6 min.
By similar procedures, the following compounds have been obtained:
EXAMPLE 3
cyclo ([Asn(?-D-2-deoxy-2-amino-Glc)-Asp-Trp-Phe-Dap-Leu] cyclo {2?-
5P)) {SEQ ID No. 3) [compound of Formula I) wherein R4 -CH2-C0-NH-(?-
D-2-deoxy-2-amino-Glc) and the other substituents are as defined in
Example 1].
EXAMPLE 4
cyclo ([Asn (?-D-2-deoxy-2-acetamido-Glc)-Asp-Trp-Phe-Dap-Leu]
cyclo(2?-5?)} (SEQ ID No. 4) [compound of Formula I) wherein R4= -CH2-
C0-NH-((?-D-2-deoxy-2-acetamido-Glc) and the other substituents are as
defined in Example 1].
EXAMPLE 5
cyclo {[Nle-Asp-Trp-Phe-Dap-Asn(?-D-2-deoxy-2-acetamido-Glc]
cyclo(2?-5?)) (SEQ ID No. 5) [compound of Formula I) wherein R1= -CH2-
C0-NH-(?-D-2-deoxy-2-acetamido-Glc) , R4 = -(CH2)3-CH3] and the other
substituents are as defined in Example 1],
EXAMPLE 6
cyclo ([Asn (?-D-ribofuranosyl)-Asp-Trp-Phe-Dap-Leu]cyclo(2?-5?))
(SEQ ID No. 6) [compound of Formula I) wherein R4= -CH2-C0-NH- (?-D-
ribofuranosyl) and the other substituents are as defined in Example
1].
EXAMPLE 7
cyclo ( [Ser (?-D-ribofuranosyl) -Asp-Trp-Phe-Dap-Leu]cyclo (2?-5?))
(SEQ ID No. 7) [compound of Formula I) wherein R4 -CH2-0-(?-D-

- 14 -
ribofuranosyl), and the other substituents are as defined in Example
1].
EXAMPLE 8
cyclo ([Asn (?-L-arabinofuranosyl)-Asp-Trp-Phe-Dap-Leu]cyclo
(2?-5??? (SEQ ID No. 8) [compound of Formula I) wherein R4= -CH2-C0-
NH-((?-L-arabinofuranosyl) and the other substituents are as defined in
Example 1].
EXAMPLE 9
cyclo ([Ser (?-L-arabinofuranosyl)-Asp-Trp-Phe-Dap-Leu]cyclo
(2?-5?)) (SEQ ID No. 9) [compound of Formula I) wherein R4= -CH2-0-(?-
L-arabinofuranosyl) and the other substituents are as defined in
Example 1].
EXAMPLE 10
cyclo ( [ Asn((?-D-mannopyranosyl) -Asp-Trp-Phe-Dap-Leu]cyclo(2?-5?))
(SEQ ID 10) [compound of Formula I) wherein R4= -CH2-C0-NH-(?-D-
mannopyranosyl) and the other substituents are as defined in Example
1].
EXAMPLE 11
cyclo ([Ser (?-D-mannopyranosyl)-Asp-Trp-Phe-Dap-Leu]cyclo (2?-5?))
(SEQ ID No. 11) [compound of Formula I) wherein: R4= -CH2-0-(?-D-
mannopiranosyl) and the other substituents are ad defined in Example
1].
EXAMPLE 12
cyclo ([Asn (?-D-galactopyranosyl)-Asp-Trp-Phe-Dap-Leu]cyclo
(2?-5?)) (SEQ ID No. 12) [compound of Formula I) wherein R4= -CH2-C0-
NH-(?-D-galactopyranosyl) and the other substituents are as defined in
Example 1].

- 15 -
EXAMPLE 13
cyclo([Ser(?-D-galactopyranosyl)-Asp-Trp-Phe-Dap-Leu]cyclo(2?-5?) (SEQ ID No. 13) [compound of Formula I) wherein R4 = -CH2-0-(?-D-galactopyranosyl) and the other substituents are as defined in Example 1]. EXAMPLE 14
cyclo ([Asn(?-D-glucuronopyranosyl) -Asp-Trp-Phe-Dap-Leu]cyclo
(2?-5?)) (SEQ ID No. 14) [compound of Formula I) wherein R4= -CH2-C0-
NH-(?-D-glucuronopyranosyl) and the other substituents are as defined
in Example 1].
EXAMPLE 15
cyclo( [Ser(?-D-glucuronopyranosyl) -Asp-Trp-Phe-Dap-Leu] cyclo
(2?-5?)) (SEQ ID No. 15) [compound of Formula I) wherein R4= -CH2-0-
(?-D-glucuronopyranosyl) and the other substituents are as defined in
Example 1].
EXAMPLE 16
cyclo ([Asn(l-deoxy-sorbitol-l-yl)-Asp-Trp-Phe-Dap-Leu] cyclo
(2?-5?)) (SEQ ID 16) [compound of Formula I) wherein R4 -CH2-C0-NH-
(1-deoxy-sorbitol-l-yl) and the other substituents are as defined in
Example 1].
EXAMPLE 17
cyclo ([Asn[4-0-(?-D-Glc)-?-D-Glc)]-Asp-Trp-Phe-Dap-Leu]cyclo-
(2?-5?)) (SEQ ID No. 17) [compound of Formula I) wherein R4= -CH2-C0-
NH_[4-0-(?-D-Glc)-?-D-Glc)] and the other substituents are as defined
in Example 1],
EXAMPLE 18
cyclo([Asn[4-0-(?-D-galactopyranosyl)-?-D-Glc]-Asp-Trp-Phe-Dap-

- 16 -
Leu]cyclo(2?-5?)) (SEQ ID No. 18) [compound of Formula I) wherein R4=
-CH2-C0-NH-[4-0(?-D-galactopyranosyl)-?-D-Glc)] and the other
substituents are as defined in Example 1],
EXAMPLE 19
cyclo ([ Asn [ O-?-D-Glc-( 1-4 )-0-?-D-Glc-(l-4)-?-D-Glc]-Asp-Trp-
Phe-Dap-Leu] cyclo(2?-5?)) (SEQ ID No. 19) [compound of Formula I)
wherein: R4= -CH2-C0-NH-[0-?-D-Glc-(l-4)-O-?-D-Glc-(l-4)-?-D-Glc) and
the other substituents are as defined in Example 1].
EXAMPLE 20
cyclo([Asn(D-2-deoxy-glucopyranos-2-yl)-Asp-Trp-Phe-Dap-Leu]cyclo
(2?-5?)) (SEQ ID No. 20) [compound of Formula I) wherein R4= -CH2-C0-
NH-(D-2-deoxy-gluco-pyranos-2-yl) and the other substituents are as
defined in Example 1].
EXAMPLE 21
cyclo {[Dap[D(-)-quinyl]-Asp-Trp-Phe-Dap-Leu]cyclo(2?-5?)) (SEQ ID No.
21) [compound of Formula 1) wherein: R4= -CH2-NH-[D(-)-quinyl], and
the other substituents are as defined in Example 1],
EXAMPLE 22
cyclo ([Dap[D-gluconyl]-Asp-Trp-Phe-Dap-Leu] cyclo(2?-5?))
(SEQ ID No. 22) [compound of Formula I) wherein: R4= -CH2-NH-(D-
gluconyl) and the other substituents are as defined in Example 1].
EXAMPLE 23
cyclo ([Dap[D-glucuryl]-Asp-Trp-Phe-Dap-Leu]cyclo(2?-5?))
(SEQ ID No. 23) [compound of Formula I) wherein R4 -CH2-NH-(D-
glucuryl) and the other substituents are as defined in Example 1].
EXAMPLE 24
cyclo ([Dap(2-sulfo-benzoyl)-Asp-Trp-Phe-Dap-Leu] cyclo (2?-5?))

- 17 -
(SEQ ID No. 24) [compound of Formula I) wherein: R4= -CH2-NH-CO-C6H4,-
SO3H and the other substituents are as defined in Example 1].
EXAMPLE 25
cyclo ([Asn (4-sulfo-phenyl)-Asp-Trp-Phe-Dap-Leu] cyclo (2??5?))
(SEQ ID No. 25) [compound of Formula I) wherein R4= CH2-CO-NH-C6H4,
SO3H and the other substituents are as defined in Example 1].
EXAMPLE 26
cyclo([Asn(?-L-Glc)-Asp-Trp-Phe-Dap-Leu]cyclo(2^-5P)) (SEQ ID No. 26)
[compound of Formula I) wherein R4= -CH2-C0-NH(?-L-Glc) and the other
substituents are as defined in Example 1],
EXAMPLE 27
cyclo ([Asn (?-D-2-deoxy-glttcopyranos-2-yl) -Asp-Trp-Phe-Dap-
Leu]cyclo(2?-5?)} (SEQ ID No. 27) [compound of formula I) wherein R4
= -CH2-C0-NH-(D-2-deoxy-glucopyranos-2-yl) and the other substituents
are as defined in Example 1].
EXAMPLE 28
cyclo ([Asn(D-2-deoxy-mannopyranos-2-yl)-Asp-Trp-Phe-Dap-Leu]-
cyclo(2?-5?)) (SEQ ID No. 28) [compound of formula I) wherein R4 = -
CH2-C0-NH-(D-2-deoxy-niannopyranos-2-yl} and the other substituents are
as defined in Example 1].
EXAMPLE 29
cyclo ([Asn(D-2-deoxy-galactopyranos-2-yl)-Asp-Trp-Phe-Dap-Leu]-
cyclo(2?-5?) ) (SEQ ID No. 29) [compound of formula I) wherein R4 = -
CH2-C0-NH-(D-2-deoxy-galactopyranos-2-yl) and the other substituents
are as defined in Example 1].
EXAMPLE 30
cyclo ([Asn(?-D-xylopyranosyl)-Asp-Trp-Phe-Dap-Leu]cyclo(2??5?) )

- 18 -
(SEQ ID No. 30} [compound of formula I) wherein R4 = -CH2-C0-NH-(?-D-
xylo-pyranosyl) and the other substituents are as defined in Example
1].
EXAMPLE 31
cyclo ([Asn(3-sulfo-propionyl)-Asp-Trp-Phe-Dap-Leu]cyclo-(2p-5p) )
(SEQ ID 31) [compound of formula I) wherein R4 = -CH2-CO-NH-(3-sulfo-
propionyl) and the other substituents are as defined in Example 1].
EXAMPLE 32
cyclo ([Dap{Lysyl)-Asp-Trp-Phe-Dap-Leu]cyclo(2$-5£)) (SEQ ID No. 32)
[compound of formula I) wherein R4 = -CH2-C0-NH-(Lysyl) and the other
substituents are as defined in Example 1].
EXAMPLE 33
cyclo ([Dap(Arginyl)-Asp-Trp-Phe-Dap-Leu]cyclo(2?-5?)} (SEQ ID No. 33)
[compound of formula I) wherein R4 = -CH2-C0-NH-(Arginyl) and the
other substituents are as defined in Example 1].
EXAMPLE 34
cyclo ([Dap(4-0-?-D-galactopyranosyl)-Asp-Trp-Phe-Dap-Leu]cyclo-
(2?-5?)) (SEQ ID No. 34) [compound of formula I) wherein R4 = -CH2-C0-
NH-(4-0-?-D-galactopyranosyl) and the other substituents are as
defined in Example 1].
EXAMPLE 35
cyclo ([Asn(2-deoxy-2-trifluoroacetamido-£-D-Glc)-Asp-Trp-Phe-Dap-
Leu]cyclo(2?-5?)) (SEQ ID No. 35) [compound of formula I) wherein R4 =
-CH2-C0-NH-(2-deoxy-2-trifluoroacetamido-?-D-Glc) and the other
substituents are as defined in Example 1].
BIOLOGICAL ACTIVITY
The capability of the compounds of the present invention to interact

- 19 -
as agonists or antagonists with the neurokynin A (NKA) receptor has been valued in a in vitro test using the pulmonary artery of a rabbit (RPA) (Rovero et al., Neuropeptides, 1989, 13, 263-270) and their activity was determined as pKB (antilogarythm of the dissociation constant), as described in Jenkinson et al., TiPS, 12, 53-56, 1991- For example, compound 2 has shown a pKB = 8.67. The capability of the products of the present invention to interact as agonists or antagonists with NKA receptor has been valued in vivo as capability, after intravenous administration,to inhibit the agonist

[betaAla8 ] NKA (4-10)-induced contractions of the urinary bladder in
the anaesthetized mouse, as described in Maggi et al., J. Pharmacol.
Exp. Ther., 1991, 257. 1172. Compound 1, e.g., causes, at dose of 10
nmol/Kg i.v., an inhibitory effect of 50-70 %, as it has been valued
at different times. The effect lasts over a period of more than 3
hours.
ABBREVIATIONS:
AsnO-D-Glc) : Ng-(-D-glucopiranosyl)-L-asparagine
Asn[(Ac4O)-?-D-Glc]: Ng-(2,3.4,6-tetra-0-acetyl-^-D-glucopiranosyl)-L-
asparagine
Fmoc-Asn[ (Ac4O) -?-D-Glc]-OPfp: Ng-(2,3 , 4 , 6-tetra-0-acetyl-?-D-
glucopiranosyl)Na-(fluoren-9-ylmethoxycarbonyl)-L-asparagine
pentafluorophenyl esthere
Ser(?-D-Glc): 0g- (?-D-glucopiranosyl) L-asparagine
Ser[(Bz4,0)-?-D-Glc]: 0g-(2,3,4,6-tetra-0-benzoyl-?-D-glucopiranosyl)L-
asparagine
Fmoc-Ser[(Bz4O)-?-D-Glc]-OPfp: 0&-(2, 3, 4 ,6- tetra-o-benzoyl-?-D-

- 20 -
glucopiranosyl)Na-(fluoren-9-ylmethoxycarbonyl)-L-serine pentafluorophenyl esther. Glc: glucopyranosyl

- 21-
MASS - SPECTRUM DATA
EXAMPLE 3
Synthesized following the procedure described in example 1
[M+H]+- 906
tr= 9.4 min
EXAMPLE 4
Synthesized following the procedure described in example 1
[M+H]+= 948
tr= 4.9 min
EXAMPLE 5
Synthesized following the procedure described in example 1
[M+H]+= 948
tr= 10.3 min
EXAMPLE 6
Synthesized following the procedure described in example 1
[M+H]+= 877
tr= 9.5 min
EXAMPLE 7
Synthesized following the procedure described in example 2
[M+H]+= 850

-22-
tr= 9.0 min
EXAMPLE 8
Synthesized following the procedure described in example 1
[M+H]+= 877
tr= 8.5 min
EXAMPLE 9
Synthesized following the procedure described in example 2
[M+H]+= 850
tr= 9.2 min
EXAMPLE 10
Synthesized following the procedure described in example 1
[M+H]+= 907
V= 6.95 min
EXAMPLE 11
Synthesized following the procedure described in example 2
[M+H]+= 878
tr= 10.1 min
EXAMPLE 12
Synthesized following the procedure described in example 1
[M+H]+= 906 tr= 3.8 min

EXAMPLE 13
Synthesized following the procedure described in example 2
[M+H]+= 878
tr= 10.5 min
EXAMPLE 14
Synthesized following the procedure described in example 1
[M+H]+= 921
tr= 9.2 min
EXAMPLE 15
Synthesized following the procedure described in example 2
[M+H]+= 894
tr= 8.7 min
EXAMPLE 16
Synthesized following the procedure described in example 1
[M+H]+= 909
tr= 3.7 min
EXAMPLE 17
Synthesized following the procedure described in example 1
[M+H]+=1069 tr= 9.2 min EXAMPLE 18

24
Synthesized following the procedure described in example 1
[M+H]+=1116
tr= 8.0 min
EXAMPLE 19
Syntliesized following the procedure described in example 1
[M+H]+= 1261
tr= 7.8 min
EXAMPLE 20
Synthesized following the procedure described in example 1
[M+H]+= 906
tr= 9.3 min
EXAMPLE 21
Synthesized following the procedure described in example 1
[M+H]+- 890
tr= 8.4 min
EXAMPLE 22
Synthesized following the procedure described in example 1
[M+H]+= 895
tr= 9.0 min
EXAMPLE 23
Synthesized following the procedure described in example 1

-25-
[M+H]+= 892
tr= 7.45 min
EXAMPLE 24
Synthesized following the procedure described in example 1
[M+H]+= 900.2
tr= 6.5 min
EXAMPLE 25
Synthesized following the procedure described in example 1
[M+H]+= 900.2
tr= 7.0 min
EXAMPLE 26
Synthesized following the procedure described in example 1
[M+H]+- 906.7
tr- 4.4 min
EXAMPLE 28
Synthesized following the procedure described in example 1
[M+H]+= 906.5
tr= 11 min
EXAMPLE 29
Synthesized following the procedure described in example 1
[M+H]+= 906.5

tr= 10.5 min
EXAMPLE 30
Synthesized following the procedure described in example 1
[M+H+= 876.5
tr- 11.3 min
EXAMPLE 31
Synthesized following the procedure described in example 1
[M+Hf- 897
tr 7.5 min
EXAMPLE 32
Synthesized following the procedure described in example 1
[M+H]+= 845
tr=3.8min
EXAMPLE 33
Synthesized following the procedure described in example 1
[M+H]+= 873
tr= 4.3 min
EXAMPLE 35
Synthetized following the procedure described in example 1
[M+H]+= 1001
tr=10.55 min

- 27-WE CLAIMS-
1. Bicycyiccompounds of general Formula

wherein X1, X2, X3, X4, X5 and X6, same or different from one another,
represent a -NR'CO- or a -CONR'- group, where R' is H or C1-3 alkyl;
Y represents a group selected from -NRCO-, -CONR- or -SS-
wherein R is H or C1-3 alkyl;
at least one of R1, R2, R3 and R4. groups, same or different from one
another, is hydrophilic and the remaining groups are hydrophobic;
m and n, same or different from one another, are each an integer
number from 1 to 4.
2. Compounds as claimed in claim 1, wherein the hydrophobic groups can
be separately selected from the following:
a) groups corresponding to CnH2n+1 wherein n= 0, 1-4;
b) linear or branched-alkyl groups corresponding to CnH2n-U-W wherein
n= 1-4; U= 0, COO, CONH, S and W= alkyl-, aryl- or alkylaryl-group
containing from 1 to 15 C atoms;
c) (CH2)n-C6H3-A-B wherein n= 0, 1-3; A and B, placed in any of the
ortho, meta or para positions, same or different from one another,
represent H, halogen, OR, NHR, NR2, CH3, SR wherein R is an alkyl-,
aryl- or alkyl aryl-group with less than 10 C atoms;

- 23 -
d) (CH2)n-C6H10R', wherein n= 0, 1-3 and R'= H, C1-3 alkyl
e) (CH2)n-heterocycle, wherein n= 0, 1-3 and by the term heterocyclic
imidazolyl-2-yl, indolyl-3-yl, furanyl-3-yl, piridyl-3-yl, imidazolyl-
3-yl are meant;
f) a -(CH2)S- group wherein s = 3, 4, eventually 0H-substituted or
condensed with an aromatic group, which cyclizes with one of the two
adjacent X1-6 groups in order to produce the side chain of proline,
hydroxyproline, octahydroindol-2-carboxylic acid, tetrahydroiso-
quinolinic acid;
g) the side chain of a natural hydrophobic amino acid;
h) the side chain of a natural hydrophilic amino acid, suitably substituted in order to render it hydrophobic;
i) the side chain of non-natural hydrophobic amino acids selected from
the group consisting of: norleucine, norvaline, alloisoleucine,
ciclohexylglycine (Chg) , ?-amino-n-butyric-acid (Aba) .
ciclohexylalanine (Cha), aminophenylbutyric acid (Pba), mono- and di-substituted phenylalonines in ortho, meta and para positions of the benzene ring with one or more of the following groups: C1-10 alkyl, Cl-10 alkoxy, halogen, ?-2-thienylalanine, ?-3-thienylalanine, ?-2-furanylalanine, ?-3-furanylalanine , ?-2-pi ridyl alanine , ?-3-piridylalanine, ?-4-piridylalanine , ?- (1-naphtyl) alanine, ?-(2-naphtyl)alanine, 0-alkylated serine-threonine- tyrosine-derivatives, S-alkyl cysteine, S-alkyl homocysteine, N-alkyl lysine, N-alkyl ornithine, N-alkyl 2,3 diaminopropionic acid.
3. Compounds as claimed in claim 2 wherein the side chain of a hydrophobic amino acid according to paragraph g) is the side chain of an amino acid selected from the group consisting of: glycine, alanine,

- 23 -
valine, leucine, isoleucine, methionine, phenylalanine, tyrosine, tryptophan, proline, histidine, aspargine, glutamine.
4. Compounds as claimed in claim 2, wherein, "the side chain of an
hydrophilic amino acid suitably substituted according to paragraph (h)
is the side chain of an amino acid selected from the group consisting
of: serine, threonine, cysteine, aspartic acid, glutamic acid,
carboxyglutamic acid, arginine, ornythine, lysine.
5. Compounds according to Claim 2 wherein the hydrophilic groups are
chosen in the group L-Q wherein L is a chemical bond of a linear or
branched C1-6 alkyl-group and Q is chosen in the group consisting of:
i) hydroxyl, amine, guanidine, carboxyl, sulfate, phosphonate,
phosphate;
ii) linear, branched or cyclic C1-6 alkyl chain containing one or more
hydroxyl, amine, guanidine, carboxyl, sulfate, phosphate;
iii) an aromatic group mono-, di- or tri-substituted ortho-, meta-,
para-position with hydroxyl, amino, guanidine, carboxyl, sulfate,
phosphate;
iv) a group M, OM, CONHM, NHCOM wherein M is an hydrophilic group
v) an hydrophilic group according to points i)-iv) protected with
groups which are biologically hydrolized reforming an hydrophilic
group.
6 Compounds according to Claim 5 wherein the group M is chosen in the
group consisting of:
i) eventually substituted mono-, di-, tri-glycosidic residues;
ii) linear, branched or cyclic C1-6 alkyl-chains, containing one or
more groups hydroxyl, amine, guanidine, carboxyl, sulfate,
phosphonate, phosphate.

30
7. Compounds of Formula (I) as claimed in claim 6, wherein the
glycosidic residues are selected from the group consisting of:
hexoses'or, pentoses of D or L series in a or fi configuration, selected
from the group wherein: all C atoms bear a tree or protected
hydroxylic group; one or more hydroxyls are substituted by: hydrogen;
an amino or acylamino group; C6 of hexoses and C5 of pentoses are
part of a carboxylic group; and wherein the eventually present 2 or 3
glycosidic units are linked by a glycosidic bond of a or ?
configuration.
8. Compounds of general Formula (I) according to claim 7 selected from
the group consisting of: D or L ribose, D or L arabinose, D or L
xylose, D or L lyxose, D or L allose, D or L altrose, D or L glucose,
D or L mannose, D or L gulose, D or L idose, D or L galactose,D or L
talose, D or L allulose, D or L fructose, D or L sorbose, D or L
tagatose; 5-deoxy-D or L-arabinose, 2-deoxy-D or L-glucose, 2-deoxy-D
or L-galactose, 2-deoxy-D or L-arabinose, 2-deoxy-D or L-ribose, D or
L fucose, D or L ramnose; D-glucosamine, D-mannosamine, D-
galaotosamine, daunosamine, acosamine and N-acylate derivates thereof
with lower fat acids, i.e. containing a N-formylic, acetylic,
propionilic, butyric residue; glucuronic acid, galacturonic acid;
cellobiose, lactose, maltose, D-lactosamine, cellotriose, maltotriose;
tris(hydroxymethyl)methyl, D or L arabitol, D or L erythrol, D or L
perseitol, D or L ribitol, D or L sorbitol, D or L xylitol; or those
from the residue of tartaric acid, glucaric acid, gluconic acid,
bycine, quinic acid, mucic acid, glucosaminic acid.
9. Compounds of general Formula (I) according to claim 1, wherein if
one or both R1 and R4 groups are hydrophilic, both R2 and R3 groups

-31-
are hydrophobic or viceversa.
10. Compounds as claimed in claim 1, as hereinafter indicated:
i) cyclo([Asn(?-D-Glc)-Asp-Trp-Phe-Dap-Leu]cyclo(2£-5£)) (SEQ ID No. 1
ii) cyclo([Ser(?-D-Glc)-Asp-Trp-Phe-Dap-Leu]cyclo(2?-5?)) (SEQ ID No.
2)
iii) cyclo ([Asn (?-D-2-deoxy-2-amino-Glc)-Asp-Trp-Phe-Dap-Leu]
cyclo (2?-5?)) (SEQ ID No. 3)
iv) cyclo ( [Asn(?-D-2-deoxy-2-acetamido-Glc)-Asp-Trp-Phe-Dap-
Leu]cyclo(2?-5?)) (SEQ ID No. 4)
v) cyclo([Nle-Asp-Trp-Phe-Dap-Asn(?-D-2-deoxy-2-acetamido-Glc)]
cyclo(2?-5?)) (SEQ ID 5)
vi) cyclo ([Asn((?-D-ribofuranosyl)-Asp-Trp-Phe-Dap-Leu]cyclo
(2?-5?)) (SEQ ID 6)
vii) cyclo ( [ Ser(?-D-ribofuranosyl )-Asp-Trp-Phe-Dap-Leu] cyclo
(2?-5?)) (SEQ ID No. 7)
viii) cyclo([Asn((5-L-arabinofuranosyl)-Asp-Trp-Phe-Dap-Leu]cyclo
(2?-5?)) (SEQ ID No. 8)
ix) cyclo([Ser(?-L-arabinofuranosyl)-Asp-Trp-Phe-Dap-Leu]cyclo
(2?-5?)) (SEQ ID No. 9)
x) cyclo ( [Asn (?-D-mannopyranosyl) -Asp-Trp-Phe-Dap-Leu] cyclo (2?-5?))
(SEQ ID No. 10)
xi) cyclo ( [Ser (?-D-mannopyranosyl) -Asp-Trp-Phe-Dap-Leu] cyclo (2?-5?))
(SEQ ID No. 11)
xii) cyclo ([Asn (?-D-galactopyranosyl) -Asp-Trp-Phe-Dap-Leu]cyclo (2?-
5?)) (SEQ ID No. 12)
xiii) cyclo([Ser(?-D-galactopyranosyl)-Asp-Trp-Phe-Dap-Leu]cyclo (2?-
5?)) (SEQ ID No. 13)

-3 2-
xiv) cyclo ([ Asn (?-D-glucuronopyranosyl) -Asp-Trp-Phe-Dap-
Leu]cyclo{2?-5?)) (SEQ ID No. 14)
xv) cyclo ([Ser(?-D-glucuronopyranosyl) -Asp-Trp-Phe-Dap-Leu]
cyclo(2?-5?)) (SEQ ID No. 15)
xvi) cyclo ([Asn(l-deoxy-sorbitol-l-yl)-Asp-Trp-Phe-Dap-Leu]cyclo
(2?-5?)) (SEQ ID No. 16)
xvii) cyclo { [Asn [(4-0-(?-D-Glc)-?-D-Glc)]-Asp-Trp-Phe-Dap-
Leu]cyclo(2?-5?)) (SEQ ID No. 17)
xviii) cyclo ([Asn[(4-0-(?-D-galactopyranosyl)-?-D-Glc)]-Asp-Trp-Phe-
Dap-Leu]cyclo(2?--5?)) (SEQ ID No. 18)
xix) cyclo ( [ Asn [O-?-D-Glc-(1-4)-O-?-D-Glc-(l-4)-?-D-Glc]-Asp-Trp-
Phe-Dap-Leu] cyclo(2?-5?)) (SEQ ID No. 19)
xx) cyclo ([Asn(D-2-deoxy-glucopyranos-2-yl)-Asp-Trp-Phe-Dap-
Leu]cyclo(2?-5?)) (SEQ ID No. 20)
xxi) cyclo ([Dap[D(-)-quinyl]-Asp-Trp-Phe-Dap-Leu]cyclo(2?-5?)) (SEQ
ID No. 21)
xxii) cyclo ([Dap[D-gluconyl]-Asp-Trp-Phe-Dap-Leu] cyclo (2?-5?)) (SEQ
ID No. 22)
xxiii)cyclo ([Dap[D-glucuryl]-Asp-Trp-Phe-Dap-Leu]cyclo(2£-5&)) (SEQ
ID No. 23)
xxiv) cyclo ([Dap (2-sulfo-benzoyl)-Asp-Trp-Phe-Dap-Leu] cyclo (2?-5?))
(SEQ ID No. 24)
xxv) cyclo ([Asn(4-sulfo-phenyl)-Asp~Trp-Phe-Dap-Leu]cyclo(2p"-5£))
(SEQ ID No. 25)
xxvi) cyclo ( [Asn(?-L-Glc) -Asp-Trp-Phe-Dap-Leu]cyclo(2?-5?)) (SEQ ID
No. 26)
xxvii) cyclo ([Asn(?-D-2-deoxy-glucopyranos-2-yl) -Asp-Trp-Phe-Dap-

-33-
Leu]cyclo(2?-5?)) (SEQ 1D No. 27)
xxviii) cyelo ([ Asn(?-D- 2 -deoxy-mannopyranos- 2 -y1 )-As- Trp-Phe-Dap-Leu] cyclo( 2?-
5P)) (SEQ ID No. 28)
xxix) cyelo ([Asn( D- 2 -deoxy-galaetopyranos- 2 -yl )-Asp- Trp-Phe-Dap-Leu]cyclo( 2?-5?))
(SEQ 10 No. 29)
xxx) cyclo([Asn(?-D-xylopyranosyl)-Asp-Trp-Phe-Dap-Leu]cyclo(2?-5?)) (SEQ 1D No. 30) xxxi) cyelo ([Asn(3-sulfo-propionyl)-Asp-Trp-Phe-Dap-Lue)cyclo(2?-5?)) (SEQ 1D No. 31)
xxxii) cyelo ([Dap(Lysyl)-Asp-Trp-Phe-Dap-Lue]cyclo(2?-5?)) (SEQ 1D No. 32) xxxiii) cyclo([Dap(Arginyl)-Asp-Trp-Phe-Dap-Lue]cyclo(2?-5?)) (SEQ 1D No.33)
xxxiv) cyelo ([Dap( 4-0- ?-D-gaalactopyranosyl)-Asp- Trp-Phe-Dap-Leu] cyclo(2?-5?)) (SEQ
IDNo.34)
xxxv) cyelo (Asn(2-deoxy- 2-trifluoroaeetamido-?-D-Glc )-Asp- Trp-Phe-Dap-Leu]cyclo( 2?-
5?))(SEQ1DNo.35).
This invention relates to novel compounds of general formula (1):

Documents:

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Patent Number

209754

Indian Patent Application Number

00419/CAL/1996

PG Journal Number

36/2007

Publication Date

07-Sep-2007

Grant Date

06-Sep-2007

Date of Filing

08-Mar-1996

Name of Patentee

A. MENARINI INDUSTRIE FARMACEUTICHE RIUNITE S.R.L.

Applicant Address

VIA SETTE SANTI, 3, 50131 FLORENCE, ITALY

Inventors:

#	Inventor's Name	Inventor's Address
1	CARLO ALBERTO MAGGI	VIA MICHELAZZI, 43; 50100 FLORENCE, ITALY;
2	LAURA QUARTARA	VIALE OSIMO, 385; 52037 SANSEPOLCRO (PROV. OF AREZZO), ITALY;
3	DANILO GIANNOTTI	VIA ROMA, 128; 55011 ALTOPASCIO (PROV. OF LUCCA), ITALY;
4	FEDERICO ARCAMONE	VIA 4 NOVEMBRE, 20014 NERVIANO (PROV. OF MILAN), ITALY

PCT International Classification Number

C07K 7/22

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	FI95A000044	1995-03-13	Italy