Pyrrolidine ester derivatives with oxytocin modulating activity

1. A pharmaceutical composition comprising a pyrrolidine ester according to formula (I), or a pharmaceutically acceptable salt thereof,

as well as its geometrical isomers, its optically active forms as enantiomers, diastereomers and its racemate forms, as well as pharmaceutically acceptable salts thereof, wherein

X is selected from the group consisting of CR 6 R 7 , NOR 6 , NNR 6 R 7 ;

R is selected from the group consisting of C 1 –C 6 alkyl, C 2 –C 6 alkenyl, C 2 –C 6 alkynyl, aryl, C 1 –C 6 -alkyl aryl, C 1 –C 6 -alkyl-saturated 3–8-membered cycloalkyl, and C 1 –C 6 -alkyl-unsaturated 3–8-membered cycloalkyl;

R 1 is selected from the group consisting of C 1 –C 6 -alkyl, aryl, saturated or unsaturated 3–8-membered cycloalkyl, acyl, and C 1 –C 6 -alkyl aryl, wherein said cycloalkyl or aryl groups may be fused with 1–2 further cycloalkyl groups or aryl groups;

R 2 , R 3 , R 4 and R 5 are independently from each other selected from the group consisting of hydrogen, halogen, C 1 –C 6 -alkyl;

R 6 and R 7 are independently selected from the group consisting of hydrogen, C 1 –C 6 alkyl, C 2 –C 6 alkenyl, C 2 –C 6 alkynyl, C 1 –C 6 alkoxy, C 1 –C 6 thioalkoxy, halogen, cyano, nitro, acyl, alkoxycarbonyl, aminocarbonyl, aryl, C 1 –C 6 -alkyl aryl, C 1 –C 6 -alkyl-saturated 3–8-membered cycloalkyl, and C 1 –C 6 -alkyl-unsaturated 3–8-membered cycloalkyl.

2. The pharmaceutical composition according to claim 1 , wherein X is NOR 6 and R 6 is selected from the group consisting of H, C 1 –C 6 alkyl, C 2 –C 6 alkenyl, C 2 –C 6 alkynyl, acyl, aryl, saturated or unsaturated 3–8-membered cycloalkyl, and C 1 –C 6 -alkyl aryl, wherein said cycloalkyl or aryl groups may be fused with 1–2 cycloalkyl or aryl groups.

3. The pharmaceutical composition according to claim 2 , wherein R 6 is H or CH 3 .

4. The pharmaceutical composition according to any claim 1 , wherein R 1 is a C 1 –C 6 -alkyl, C 2 –C 6 -alkenyl, C 2 –C 6 -alkynyl, aryl, saturated or unsaturated 3–8-membered cycloalkyl.

5. The pharmaceutical composition according to claim 4 , wherein R 1 is a biphenyl.

6. The pharmaceutical composition according to claim 1 , wherein X is NOR 6 , R 6 is H, a C 1 –C 6 -alkyl, or aryl or C 1 –C 6 -alkyl aryl group and R 1 is selected from C 1 –C 6 -alkyl; aryl or C 1 –C 6 -alkyl aryl.

7. The pharmaceutical composition according to claim 6 , wherein R 6 is methyl, R is a C 1 –C 6 -alkyl group and R 1 is a biphenyl.

8. A method of modulating an oxytocin receptor in vitro comprising administering to one or more cells having an oxytocin receptor the pharmaceutical composition according to claim 1 .

9. The method according to claim 8 , wherein said modulating comprises blocking the oxytocin receptor or in antagonising the binding of oxytocin to its receptor.

10. A method of treating premature labor, premature birth or dysmenorrheal comprising administering to a patient in need thereof an effective amount of the pharmaceutical composition of claim 1 .

11. A pyrrolidine ester compound of formula (I′), or a pharmaceutically acceptable salt thereof,

wherein R is selected from C 1 –C 6 alkyl, C 1 –C 6 alkyl aryl, and 3–8-membered cycloalkyl and R 1 is selected from the group consisting of a 1,1′-biphenyl, a pyridinyl-phenyl and a pyrimidinyl-phenyl group.

12. A pyrrolidine ester compound according to claim 11 , wherein R is a methyl group.

13. A pyrrolidine ester compound according to claim 11 , wherein R 1 is a 1,1′-biphenyl group.

14. A pyrrolidine ester compound according to claim 11 , wherein R 1 is a 1,1′-biphenyl group which is substituted by 1 or 2 substituents selected from the group consisting of C 1 –C 6 alkyl, C 1 –C 6 alkoxy, halogen, CN.

15. A pyrrolidine derivative according to claim 11 , selected from the group consisting of:

Methyl (2S,4EZ)-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxylate,

Methyl (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylate,

Methyl (2S,4E)-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxylate,

Methyl (2S,4Z)-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxylate,

Methyl (2S,4EZ)-1-[(2′-fluoro[1,1′-biphenyl]-4-yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxylate,

Methyl (2S,4Z)-1-[(2′-fluoro[1,1′-biphenyl]-4-yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxylate,

Methyl (2S,4EZ)-1-[(2′-chloro[1,1′-biphenyl]-4-yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxylate,

Methyl (2S,4EZ)-1-[(2′-cyano[1,1′-biphenyl]-4-yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxylate,

Methyl (2S,4EZ)-4-(methoxyimino)-1 {[2′-(trifluoromethyl)[1,1′-biphenyl]-4-yl]carbonyl}-2-pyrrolidinecarboxylate,

Methyl (2S,4EZ)-1-[(2′-methoxy[1,1′-biphenyl]4-yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxylate,

Methyl (2S,4EZ)-1-[(2′,6′-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-4-(methoxy-imino)-2-pyrrolidinecarboxylate,

Methyl (2S,4EZ)-1-[(2′,3-dimethyl[1,1′-biphenyl]4-yl)carbonyl]-4-(methoxy-imino)-2-pyrrolidinecarboxylate,

Methyl (2S,4EZ)-1-[(3-methyl[1,1′-biphenyl]-4-yl)carbonyl]4-(methoxyimino)-2-pyrrolidinecarboxylate,

Methyl (2S,4EZ)-1-[(3′,4′-dichloro[1,1′-biphenyl]-4-yl)carbonyl]-4-(methoxy-imino)-2-pyrrolidinecarboxylate,

Ethyl (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylate,

sec-butyl (2S,4EZ)-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]2-pyrrolidinecarboxylate,

Cyclopentyl (2S,4EZ)-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxylate, and

Methyl (2S,4EZ)-1-[(4′-fluoro[1,1′-biphenyl]-4-yl)carbonyl]4-(methoxyimino)-2-pyrrolidinecarboxylate.

16. A pharmaceutical composition comprising at least one pyrrolidine derivative according to claim 11 , and a pharmaceutically acceptable carrier, diluent or excipient thereof.

17. A process of preparing a compound according to claim 11 , comprising:

reacting a compound of formula (III)

wherein X, R 2 –R 5 are H,

with a carboxylic acid or acyl chloride of formulae (IVa) or (IVb)

18. The pharmaceutical composition of claim 11 , wherein R is a methyl group.

19. A method of treating and/or preventing premature labor, premature birth or dysmenorrheal, comprising administering to a patient in need thereof an effective amount of the pharmaceutical composition of claim 1 .