9-chloro-15-deoxyprostaglandin derivatives, process for their preparation and their use as medicaments

1. A compound of formula I

where

R 1 is CH 2 OH, —COOR 2 , —CONHR 2 or —CONHR 3 ;

R 2 is hydrogen, linear or branched C 1 -C 10 -alkyl which is optionally mono- to polyunsaturated and optionally mono- to polysubstituted by halogen, C 1 -C 4 -alkoxy, substituted C 3 -C 10 -aryl, optionally substituted C 3 -C 10 -aroyl, optionally substituted di-C 1 -C 5 -alkylamino, or tri- C 1 -C 5 -alkylamino, C 3 -C 10 -cycloalkyl which is optionally substituted by C 1 -C 4 -alkyl, C 3 -C 10 -aryl which is optionally substituted by phenyl, 1-naphthyl, 2-naphthyl which in turn is optionally substituted in position 3 and in position 4 by fluorine, chlorine, alkoxy or trifluoromethyl or in position 4 by hydroxy, halogen, phenyl, one or more C 1 -C 4 -alkyl groups, chloromethyl, fluoromethyl, trifluoromethyl, carboxy, hydroxy or C 1 -C 4 -alkoxy, or C 3 -C 7 -heterocycloalkyl;

R 3 is C 1 -C 15 -carboxylic acid or C 1 -C 15 -sulphonic acid;

A is cis-CH═CH— or —CH 2 —CH 2 —;

B is trans-CH═CH— or —CH 2 —CH 2 —;

W is C 2 -C 6 -alkylene;

R 4 is hydroxy, —O—R 6 or —O—R 7

R 6 is tetrahydropyranyl, tetrahydrofuranyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or tribenzylsilyl;

R 7 is C 1 -C 15 -carboxylic acid;

R 5 is hydrogen, C 1 -C 10 -alkyl or C 1 -C 10 -alkenyl; and

n is the number 1-4; or

a salt thereof or a cyclodextrin clathrate thereof with a physiologically tolerated base.

2. A compound according to claim 1 , where

R 1 is CH 2 OH, —COOR 2 , —CONHR 2 or —CONHR 3 ;

R 2 is hydrogen, linear or branched C 1 -C 10 -alkyl which is optionally mono- to polyunsaturated and optionally monosubstituted by fluorine, chlorine, bromine, C 1 -C 4 -alkoxy, C 3 -C 10 -aryl, C 3 -C 10 -aroyl, di-C 1 -C 5 -alkylamino, or tri- C 1 -C 5 -alkylamino, C 5 -C 6 -cycloalkyl which is optionally substituted by C 1 -C 4 -alkyl, C 3 -C 10 -aryl which is optionally substituted by phenyl which is optionally substituted in position 3 or 4 by fluorine, chlorine, alkoxy or trifluoromethyl or in position 4 by hydroxyl, or C 5 -C 6 -heterocycloalkyl which is interrupted one or more times by nitrogen, oxygen or sulphur;

R 3 is C 1 -C 10 -carboxylic acid or C 1 -C 10 -sulphonic acid;

A is cis-CH═CH— or —CH 2 —CH 2 —;

B is trans-CH═CH— or —CH 2 —CH 2 —;

W is C 2 -C 6 -alkylene;

R 4 is hydroxy;

R 5 is hydrogen, C 1 -C 6 -alkyl or C 1 -C 10 -alkenyl; and

n is the number 1-4.

3. A compound according to claim 1 , where

R 1 is CH 2 OH, —COOR 2 , —CONHR 2 or —CONHR 3 ;

R 2 is hydrogen, C 1 -C 4 -alkyl which is optionally substituted by phenyl, C 5 -C 6 -cycloalkyl, or C 3 -C 6 -aryl which is optionally substituted by phenyl;

R 3 is C 1 -C 6 -carboxylic acid or a C 1 -C 6 -sulphonic acid;

A is cis-CH═CH— or —CH 2 —CH 2 —;

B is trans-CH═CH— or —CH 2 —CH 2 —;

W is C 2 -alkylene;

R 4 is hydroxy;

R 5 is hydrogen, saturated C 1 -C 4 -alkyl or C 1 -C 5 -alkenyl; and

n is the number 1-4.

4. A pharmaceutical composition comprising of at least one compound according to claim 1 .

5. A pharmaceutical composition according to claim 4 , further comprising one or more suitable formulating substances and/or carriers.

6. A pharmaceutical composition according to claim 4 , wherein said composition is in a form suitable for enteral, parenteral, vaginal or oral administration.

7. A method of reducing the release of Th-1 cytokines in a patient comprising administering to said patient an effective amount of a compound according to claim 1 .

8. A method of promoting fertility in a patient comprising administering to said patient an effective amount of a compound according to claim 1 .

9. A method of promoting in vitro fertilization in a patient comprising administering to said patient an effective amount of a compound according to claim 1 .

10. A method of promoting ovulation in a patient comprising administering to said patient an effective amount of a compound according to claim 1 .

11. A method of inducing cumulus expansion in a patient comprising administering to said patient an effective amount of a compound according to claim 1 .

12. A method of reducing elevated intraocular pressure in a patient comprising administering to said patient an effective amount of a compound according to claim 1 .

13. A process for preparing a compound according to claim 1 , said process comprising:

reacting an aldehyde of formula II with a carbanion of a sulphone of formula III

wherein R 1 is —COOR 2 or —CONHR 3 , and where the free OH group in R 4 is protected;

acetylating the resulting hydroxysulphone;

subjecting the resultant compound to reductive elimination to give the resulting olefin;

and, where appropriate;

deprotecting hydroxy groups which are protected in any sequence;

and, where appropriate,

esterifying, etherifying, and/or hydrogenating double bonds and/or esterifying an esterified carboxy group and/or a free carboxy group and/or converting a free carboxy group into an amide and/or reducing a free or esterified carboxy group.

14. A compound according to claim 1 , wherein R 2 is hydrogen,

linear or branched C 1 -C 10 -alkyl which is optionally mono- to polyunsaturated and optionally mono- to polysubstituted by halogen, C 1 -C 4 -alkoxy, C 3 -C 10 -aryl substituted by halogen, phenyl, C 1 -C 4 -alkyl, chloromethyl, fluoromethyl, trifluoromethyl, carboxy, hydroxy or C 1 -C 4 -alkoxy, C 3 -C 10 -aroyl which is optionally substituted by halogen, phenyl, C 1 -C 4 -alkyl, chloromethyl, fluoromethyl, trifluoromethyl, carboxy, hydroxy or C 1 -C 4 -alkoxy, di-C 1 -C 5 -alkylamino which is optionally substituted by halogen, methoxy, ethoxy, phenyl, dimethylamino, diethylamino, or dimethylaminopropyl, or tri- C 1 -C 5 -alkylamino,

C 3 -C 10 -cycloalkyl which is optionally substituted by C 1 -C 4 -alkyl,

C 3 -C 10 -aryl which is optionally substituted by phenyl, 1-naphthyl, 2-naphthyl which in turn is optionally substituted in position 3 and in position 4 by fluorine, chlorine, alkoxy or trifluoromethyl or in position 4 by hydroxy, halogen, phenyl, one or more C 1 -C 4 -alkyl groups, chloromethyl, fluoromethyl, trifluoromethyl, carboxy, hydroxy or C 1 -C 4 -alkoxy, or

C 3 -C 7 -heterocycloalkyl.

15. A compound according to claim 2 , wherein before R 2 is hydrogen,

linear or branched C 1 -C 10 -alkyl which is optionally mono- to polyunsaturated and optionally monosubstituted by fluorine, chlorine, bromine, C 1 -C 4 -alkoxy, C 3 -C 10 -aryl substituted by halogen, phenyl, C 1 -C 4 -alkyl, chloromethyl, fluoromethyl, trifluoromethyl, carboxy, hydroxy or C 1 -C 4 -alkoxy, C 3 -C 10 -aroyl which is optionally substituted by halogen, phenyl, C 1 -C 4 -alkyl, chloromethyl, fluoromethyl, trifluoromethyl, carboxy, hydroxy or C 1 -C 4 -alkoxy, di-C 1 -C 5 -alkylamino which is optionally substituted by halogen, methoxy, ethoxy, phenyl, dimethylamino, diethylamino, or dimethylaminopropyl, or tri- C 1 -C 5 -alkylamino,

C 5 -C 6 -cycloalkyl which is optionally substituted by C 1 -C 4 -alkyl,

C 3 -C 10 -aryl which is optionally substituted by phenyl which is optionally substituted in position 3 or 4 by fluorine, chlorine, alkoxy or trifluoromethyl or in position 4 by hydroxyl, or

C 5 -C 6 -heterocycloalkyl which is interrupted one or more times by nitrogen, oxygen or sulphur.

16. A compound according to claim 1 , wherein before R 2 is methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, hexyl, heptyl, octyl, decyl, butenyl, isobutenyl, propenyl, pentenyl, benzyl, m-chlorobenzyl or p-chlorobenzyl.

17. A compound according to claim 2 , wherein n is 2-3.

18. A compound according to claim 15 , wherein n is 2-3.

19. A compound according to claim 3 , wherein n is 2-3.

20. A compound according to claim 3 , wherein n is 2.

21. A compound according to claim 1 , wherein said compound is methyl (5Z,13E)-(9R,11R)-9-chloro-11-[(2H)-tetrahydropyran-2-yloxy]-17,17-tetramethylene-20-nor-5,13-prostadienoate.

22. A compound according to claim 1 , wherein said compound is methyl (5Z,13E)-(9R,11R)-9-chloro-11-hydroxy-17,17-tetramethylene-20-nor-5,13-prostadienoate.

23. A compound according to claim 1 , wherein said compound is (5Z,13E)-(9R,11R)-9-Chloro-11-hydroxy-17,17-tetramethylene-20-nor-5,13-prostadienoic acid.