Pyrrolidine derivatives as oxytocin antagonists

1. A pyrrolidine derivative of Formula I:

a geometrical isomer thereof, an optically active form thereof, an enantiomer thereof, a diastereomer thereof, one or more mixtures thereof, a racemate form thereof, or a salt thereof, wherein:

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

R 2 is selected from the group consisting of hydrogen, C 1 –C 6 -alkyl, 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;

X is selected from the group consisting of O and NR 4 ;

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; wherein

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 phenyl.

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 R 2 and R 4 form together with the N atom to which they are linked, a 5 or 6 membered cycloalkyl or heterocycloalkyl ring.

6. A pyrrolidine derivative according to claim 1 wherein X is O or NH.

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

(3EZ,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one O-methyloxime;

(3EZ,5S)-1-(1,1′-biphenyl-4-ylcarbonyl)-5-(hydroxymethyl)pyrrolidin-3-one O-methyloxime;

(3E,5S)-1-(1,1′-biphenyl-4-ylcarbonyl)-5-(hydroxymethyl)pyrrolidin-3-one O-methyloxime;

(3Z,5S)-1-(1,1′-biphenyl-4-ylcarbonyl)-5-[(4-methylpiperazin-1-yl)methyl]pyrro-lidin-3-one O-methyloxime;

tert-butyl {[(2S,4EZ)-1-(1,1′-biphenyl-4-ylcarbonyl)-4-(methoxyimino)pyrrolidin-2-yl]methoxy}acetate;

{[(2S,4EZ)-1-(1,1′-biphenyl-4-ylcarbonyl)-4-(methoxyimino)pyrrolidin-2-yl]methoxy}acetic acid;

2-{[(2S,4EZ)-1-(1,1′-biphenyl-4-ylcarbonyl)-4-(methoxyimino)pyrrolidin-2-yl]methoxy}-N-(2-pyrrolidin-1-ylethyl)acetamide;

(3EZ,5S)-1-(1,1′-biphenyl-4-ylcarbonyl)-5-(methoxymethyl)pyrrolidin-3-one O-methyloxime;

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

(3EZ,5S)-1-(1,1′-biphenyl-4-ylcarbonyl)-5-{[(4-methoxyphenyl)amino]methyl}-pyrrolidin-3-one O-methyloxime;

(3EZ,5S)-1-(1,1′-biphenyl-4-ylcarbonyl)-5-({[2-(1H-pyrazol-1-yl)ethyl]amino)methyl)-pyrrolidin-3-one O-methyloxime;

2-{[(2S,4EZ)-1-(1,1′-biphenyl-4-ylcarbonyl)-4-(methoxyimino)pyrrolidin-2-yl]methyl}-1H-isoindole-1,3(2H)-dione;

(3EZ,5S)-5-(aminomethyl)-1-(1,1′-biphenyl-4-ylcarbonyl)pyrrolidin-3-one O-methyloxime;

N-{[(2S,4EZ)-1-(1,1′-biphenyl-4-ylcarbonyl)-4-(methoxyimino)pyrrolidin-2-yl]methyl}acetamide;

(3EZ,5S)-1-(1,1′-biphenyl-4-ylcarbonyl)-5-(piperidin-1-ylmethyl)pyrrolidin-3-one O-methyloxime; and

(3EZ,5S)-1-(1,1′-biphenyl-4-ylcarbonyl)-5-(2-hydroxyethyl)pyrrolidin-3-one O-methyloxime.

8. A method of treating preterm labor, premature birth or dysmenorrhea, said method comprising administering said pyrrolidine derivative according to claim 1 to a patient in need thereof in an amount sufficient to treat said preterm labor, said premature birth or said dysmenorrhea.

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

10. A process for the preparation of said pyrrolidine derivative according to claim 1 wherein X is O, comprising O-alkylating an alcohol derivative of formula (II) with an alkylating agent R 2 -LG wherein LG is a leaving group

to obtain said pyrrolidine derivative.

11. A process for the preparation of said pyrrolidine derivative according to claim 1 wherein X is NR 4 , comprising reductively aminating an aldehyde derivative of formula (XI) with an amine HNR 2 R 4

to obtain said pyrrolidine derivative.