Pyrrolidine derivatives as oxytocin antagonists

1. A pyrrolidine derivative of Formula I:

its optically active forms as enantiomers, diastereomers, mixtures of these and its racemate forms, as well as salts thereof, wherein:

R 1 is selected from the group consisting of H and C 1 -C 6 -alkyl;

B is selected from the group consisting of —COO, —CONR 4 , oxadiazole, thiadiazole or benzimidazole;

R 2 is selected from the group consisting of hydrogen, C 1 -C 6 -alkyl, aryl, C 1 -C 6 -alkyl aryl, heteroaryl, C 1 -C 6 -alkyl heteroaryl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkenyl aryl, C 2 -C 6 -alkenyl heteroaryl, C 2 -C 6 -alkynyl, C 2 -C 6 -alkynyl aryl, C 2 -C 6 -alkynyl heteroaryl, C 3 -C 8 -cycloalkyl, heterocycloalkyl, C 1 -C 6 -alkyl cycloalkyl, C 1 -C 6 -alkyl heterocycloalkyl, C 1 -C 6 -alkyl carboxy, acyl, C 1 -C 6 -alkyl acyl, C 1 -C 6 -alkyl acyloxy, C 1 -C 6 -alkyl alkoxy, alkoxycarbonyl, C 1 -C 6 -alkyl alkoxycarbonyl, aminocarbonyl, C 1 -C 6 -alkyl aminocarbonyl, C 1 -C 6 -alkyl acylamino, C 1 -C 6 -alkyl ureido, amino, C 1 -C 6 -alkyl amino, sulfonyloxy, C 1 -C 6 -alkyl sulfonyloxy, sulfonyl, C 1 -C 6 -alkyl sulfonyl, sulfinyl, C 1 -C 6 -alkyl sulfinyl, C 1 -C 6 -alkyl sulfanyl, and C 1 -C 6 -alkyl sulfonylamino;

R 3 is selected from the group consisting of aryl and heteroaryl;

R 4 is selected from the group consisting of H, C 1 -C 6 -alkyl, C 1 -C 6 -alkyl aryl, C 1 -C 6 -alkyl heteroaryl, aryl, and heteroaryl; or

R 2 and R 4 can form together with the N atom to which they are linked to, a 5-8 membered saturated or unsaturated heterocycloalkyl ring; and

n is an integer from 1 to 3.

2. A pyrrolidine derivative according to claim 1 , wherein R 1 is methyl.

3. A pyrrolidine derivative according to claim 1 , wherein R 3 is a biphenyl.

4. A pyrrolidine derivative according to claim 1 , wherein n is an integer 1 or 2.

5. A pyrrolidine derivative according to claim 1 , wherein B is —COO, CONR 4 or an oxadiazole.

6. A pyrrolidine derivative according to claim 1 , wherein R 2 is selected from the group consisting of H, C 1 -C 6 alkyl, and 3-8 membered cycloalkyl.

7. A pyrrolidine derivative according to claim 1 , wherein R 2 and R 4 form together with the N atom to which they are linked, a piperidinyl, piperazinyl or morpholino moiety.

8. A pyrrolidine derivative according to claim 1 , wherein wherein R 1 is methyl, R 3 is a biphenyl moiety, B is —COO, CONR 4 or a 1,2,4 oxadiazole moiety.

9. A pyrrolidine derivative according to claim 1 selected from the group consisting of:

3-[(2R, 4EZ)-1-(biphenyl-4-ylcarbonyl)-4-(methoxyimino)pyrrolidin-2-yl] propanoic acid,

methyl 3-[(2R,4EZ)-1-(biphenyl-4-ylcarbonyl)-4-(methoxyimino)pyrrolidin-2-yl] propanoate,

cyclopentyl [(2S,4EZ)-1-(biphenyl-4-ylcarbonyl)-4-(methoxyimino)pyrrolidin-2-yl] acetate,

cyclopentyl 3-[(2R,4EZ)-1-(biphenyl-4-ylcarbonyl)-4-(methoxyimino)pyrrolidin-2-yl] propanoate,

2-[(2S,4EZ)-1-(biphenyl-4-ylcarbonyl)-4-(methoxyimino)pyrrolidin-2-yl]-N-[(2S)-2-hydroxy-2-phenylethyl] acetamide,

3-[(2R,4EZ)-1-(biphenyl-4-ylcarbonyl)-4-(methoxyimino)pyrrolidin-2-yl]-N-[(2S)-2-hydroxy-2-phenylethyl] propanamide,

2-[(2S,4EZ)-1-(biphenyl-4-ylcarbonyl)-4-(methoxyimino)pyrrolidin-2-yl] acetamide,

3-[(2R,4EZ)-1-(biphenyl-4-ylcarbonyl)-4-(methoxyimino)pyrrolidin-2-yl] propanamide,

(3EZ,5S)-1-(biphenyl-4-ylcarbonyl)-5-(2-morpholin-4-yl-2-oxoethyl)pyrrolidin-3-one O-methyloxime,

(3EZ,5R)-1-(biphenyl-4-ylcarbonyl)-5-(3-morpholin-4-yl-3-oxopropyl)pyrrolidin-3-one O-methyloxime,

N-(2-aminophenyl)-2-[(2S,4EZ)-1-(biphenyl-4-ylcarbonyl)-4-(methoxyimino) pyrrolidin-2-yl] acetamide,

N-(2-aminophenyl)-3-[(2R,4EZ)-1-(biphenyl-4-ylcarbonyl)-4-(methoxyimino) pyrrolidin-2-yl] propanamide,

(3EZ,5S)-5-(1H-benzimidazol-2-ylmethyl)-1-(biphenyl-4-ylcarbonyl)pyrrolidin-3-one O-methyloxime.

(3EZ,5R)-5-[2-(1H-benzimidazol-2-yl)ethyl]-1-(biphenyl-4-ylcarbonyl)pyrrolidin-3-one O-methyloxime,

(3EZ,5S)-1-(biphenyl-4-ylcarbonyl)-5-[(3-methyl-1,2,4-oxadiazol-5-yl)methyl] pyrrolidin-3-one O-methyloxime,

(3EZ,5R)-1-(biphenyl-4-ylcarbonyl)-5-[2-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl] pyrrolidin-3-one O-methyloxime,

(3EZ,5S)-1-(biphenyl-4-ylcarbonyl)-5-{[3-(2-hydroxyethyl)-1,2,4-oxadiazol-5-yl] methyl}pyrrolidin-3-one O-methyloxime, and

(3EZ,5R)-1-(biphenyl-4-ylcarbonyl)-5-{2-[3-(2-hydroxyethyl)-1,2,4-oxadiazol-5-yl] ethyl}pyrrolidin-3-one O-methyloxime.

10. A medicament comprising a pyrrolidine according to claim 1 .

11. A method of treating preterm labor, premature birth or dysmenorrheal in a patient in need thereof comprising administering an effective dose of a medicament comprising a pyrrolidine according to claim 1 as well as optically active forms as enantiomers, diastereomers and mixtures of the same.

12. A pharmaceutical composition containing a pyrrolidine derivative according to claim 1 and a pharmaceutically acceptable carrier, diluent or excipient thereof.

13. A method of preparing a pyrrolidine derivative according to claim 1 comprising

reacting a carboxylic acid (II) with an alcohol (III)

14. A method of preparing a pyrrolidine derivative according to claim 1 comprising

reacting the carboxylic acid (II) with an amine (XIII)

15. A method of preparing a pyrrolidine derivative according to claim 1 comprising

reacting the carboxylic acid (II) with an amidoxime (XIV)