Claims
- 1. A compound of the formula ##STR10## wherein one of U and V is --CHR.sup.2 --, and the other of U and V is selected from the group consisting of --N(COR.sup.4)--, --CH(COR.sup.4)--, --N(SO.sub.2 R.sup.4)-- and --CH(SO.sub.2 R.sup.4)--, in which:
- R.sup.2 is H, --COOR.sup.5 wherein R.sup.5 is H or C.sub.1 to C.sub.4 hydrocarbyl, --CONR.sup.6 R.sup.7 wherein R.sup.6 is H or methyl and R.sup.7 is aryl, substituted aryl, or a group of the formula --(C.sub.1 to C.sub.4)alkylene-W, in which W is amidino, hydroxy, acyloxy, sulphamoyl, hydroxysulphonyl, carboxy, esterified carboxy, amidated carboxy, tetrazolyl, hydroxamyl, R.sup.14 --SO.sub.2 --NH--, R.sup.14 --SO.sub.2 --NH--CO--, R.sup.14 --SO.sub.2 --, R.sup.14 --SO--, R.sup.14 --CO--, R.sup.14 --CO--NH--, R.sup.14 --CO--NH--SO--, R.sup.14 --CO--NH--SO.sub.2 --, or R.sup.15 --NH--SO.sub.2 -- wherein R.sup.14 is selected from the group consisting of H, C.sub.1 to C.sub.6 alkyl, C.sub.1 to C.sub.6 haloalkyl, aryl and substituted aryl, except that R.sup.14 may not be H when attached to a sulphur atom, and R.sup.15 is H, C.sub.1 to C.sub.6 alkyl, C.sub.1 to C.sub.6 haloalkyl, aryl, substituted aryl, --OH or --CN; or R.sup.6 and R.sup.7 together form a carboxy-substituted propylene, butylene or pentylene group or --COR.sup.7 ; and R.sup.4 is H, C.sub.1 to C.sub.6 hydrocarbyl in which up to three of the carbon atoms may be replaced by a nitrogen, oxygen or sulphur atom, provided that R.sup.4 does not contain a --O--O-- group, or R.sup.4 is a group of the formula --Q--R.sup.16 wherein Q is selected from the group consisting of a bond, --NR.sup.7 -- in which R.sup.17 is H or C.sub.1 to C.sub.3 alkyl and --O--, and R.sup.16 is aryl, substituted aryl, arylalkyl or (substituted aryl)alkyl;
- R is independently C.sub.1 to C.sub.3 alkyl,
- R.sup.1 is H or C.sub.1 to C.sub.15 hydrocarbyl wherein one or more hydrogen atoms may be replaced by halogen atoms, and one carbon atom may be replaced by a nitrogen, oxygen or sulphur atom;
- R.sup.3 is independently halo, alkyl, --NO.sub.2, --NH.sub.2 or --NHCOR.sup.5 ;
- X is H, and Y is H or C.sub.1 to C.sub.10 hydrocarbyl wherein one or more hydrogen atoms may be replaced by halogen atoms, and one carbon atom may be replaced by a nitrogen, oxygen or sulphur atom; or X and Y together are .dbd.O or .dbd.CH.sub.2 ;
- Z is: H; C.sub.1 to C.sub.15 hydrocarbyl, in which one or more hydrogen atoms may be replaced by a halogen atom, and up to three of the carbon atoms may be replaced by a nitrogen, oxygen or sulphur atom, provided that Z does not contain a --O--O-- group; or --(CHR.sup.18).sub.m --R.sup.8, wherein R.sup.18 is H or C.sub.1 to C.sub.3 alkyl and R.sup.8 is phenyl, substituted phenyl or a group of the formula --COOR.sup.9 or --CONR.sup.9 R.sup.10, in which R.sup.9 and R.sup.10 are independently H or C.sub.1 to C.sub.6 alkyl, or R.sup.9 and R.sup.10 together form a propylene, butylene, pentylene or hexylene group; m is 1, 2 or 3; and
- n and p are independently from 0, 1, 2, or 3,
- or a pharmaceutically acceptable salt thereof.
- 2. A compound according to claim 1 in which U is --CHR.sup.2 -- and V is --N(COR.sup.4)--.
- 3. A compound according to claim 1, wherein R.sup.1 is H, C.sub.1 to C.sub.6 alkyl- or cycloalkyl-(C.sub.1 to C.sub.6)alkyl.
- 4. A compound according to claim 3 wherein R.sup.1 is t-butyl or (1-adamantyl)methyl.
- 5. A compound according to claim 1, wherein R.sup.4 is selected from the group consisting of H, methyl, methoxy, carboxymethyl, carboxyethyl, benzyloxy and a group of the formula --NH--Ar, wherein Ar is an aromatic group selected from the group consisting of methylphenyl, carboxyphenyl, dicarboxyphenyl, dichlorophenyl, naphthyl and indolyl.
- 6. A compound according to claim 1, wherein R.sup.8 is selected from the group consisting of t-butyloxycarbonyl, ethoxycarbonyl, pyrrolidinyl, phenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-chlorophenyl, 4-chlorophenyl and 3-aminophenyl.
- 7. A compound according to claim 1, wherein X and Y together form a .dbd.O group.
- 8. A compound according to claim 1, wherein n is 0.
- 9. A compound according to claim 1, wherein p is 0.
- 10. A pharmaceutical composition comprising a compound according to claim 1, together with a pharmaceutically acceptable excipient or carrier.
- 11. A method of preparing a compound according to claim 1, comprising the step of oxidising a compound of the formula ##STR11## wherein U.sup.1 and V.sup.1 are U and V, respectively, or protected derivatives thereof, with an oxidant to form a compound of the formula ##STR12##
- 12. A method of preparing a compound according to claim 1, in which X is H and Y is --OH, said method comprising reducing a compound of the formula wherein U.sup.1 and V.sup.1 are U and V, respectively, or protected derivatives thereof.
- 13. A method of preparing a compound according to claim 1, in which X is H and Y is --CH.sub.3, said method comprising reducing a compound of the formula ##STR13## wherein U.sup.1 and V.sup.1 are U and V, respectively, or suitably protected derivatives thereof.
- 14. A method of preparing a compound according to formula I above, said method comprising the step of reacting a compound of the formula ##STR14## with an isocyanate of the formula R.sup.16 NCO or a carboxyfic acid of the formula
- R.sup.1 COOH, wherein R.sup.1', R.sup.2', R.sup.3', R', and Z' are R.sup.1, R.sup.2, R.sup.3, R, and Z, respectively, or protected derivatives thereof, and U.sup.1 and V.sup.1 are U and V, respectively, or suitably protected derivatives thereof.
- 15. A method of preparing a compound according to claim 1, said method comprising the step of ring closure of a compound of the formula ##STR15## with a base, wherein Q.sup.1 is H or a protecting group, and OL is a suitable leaving group.
- 16. A method of lowering gastrin or cholecystokinin activity in a patient, comprising administering to said patient an effective amount of a compound according to claim 1.
- 17. A method of preparing a compound according to claim 1, wherein X and Y together form a methylene group, said method comprising the step of reacting a compound of formula ##STR16## wherein U.sup.1 and V.sup.1 represent any of the groups recited in claim 1 for U and V, respectively, or protected derivatives thereof, with .mu.-chloro-.mu.-methylene-{bis(cyclopentadienyl)titanium}- dimethylaluminium.
- 18. A compound of the formula ##STR17## wherein U is --CHR.sup.2 --, V is selected from the group consisting of --N(COR.sup.4)--, --CH(COR.sup.4)--, --N(SO.sub.2 R.sup.4)-- and --CH(SO.sub.2 R.sup.4)--, in which:
- R.sup.2 is H, --COOR.sup.5 wherein R.sup.5 is H or C.sub.1 to C.sub.4 hydrocarbyl, --CONR.sup.6 R.sup.7 wherein R.sup.6 is H or methyl and R.sup.7 is aryl, substituted aryl, or a group of the formula --(C.sub.1 to C.sub.4)alkylene-W, in which W is amidino, hydroxy, acyloxy, sulphamoyl, hydroxysulphonyl, carboxy, esterified carboxy, amidated carboxy, tetrazolyl, hydroxamyl, R.sup.14 --SO.sub.2 --NH--, R.sup.14 --SO.sub.2 --NH--CO--, R.sup.14 --SO.sub.2 --, R.sup.14 --SO--, R.sup.14 --CO--, R.sup.14 --CO--NH--, R.sup.14 --CO--NH--SO--, R.sup.14 --CO--NH--SO.sub.2 --, or R.sup.15 --NH--SO.sub.2 -- wherein R.sup.14 is selected from the group consisting of H, C.sub.1 to C.sub.6 alkyl, C.sub.1 to C.sub.6 haloalkyl, aryl and substituted aryl, except that R.sup.14 may not be H when attached to a sulphur atom, and R.sup.15 is H, C.sub.1 to C.sub.6 alkyl, C.sub.1 to C.sub.6 haloalkyl, aryl, substituted aryl, --OH or --CN; or R.sup.6 and R.sup.7 together form a carboxy-substituted propylene, butylene or pentylene group or --COR.sup.7 ; and
- R.sup.4 is H, C.sub.1 to C.sub.6 hydrocarbyl in which up to three of the carbon atoms may be replaced by a nitrogen, oxygen or sulphur atom, provided that R.sup.4 does not contain a --O-- group, or R.sup.4 is a group of the formula --Q--R.sup.16 wherein Q is selected from the group consisting of a bond, --NR.sup.7 -- in which R.sup.17 is H or C.sub.1 to C.sub.3 alkyl and --O--, and R.sup.16 is aryl, substituted aryl, arylalkyl or (substituted aryl)alkyl;
- R is independently C.sub.1 to C.sub.3 alkyl,
- R.sup.1 is H or C.sub.1 to C.sub.15 hydrocarbyl wherein one or more hydrogen atoms may be replaced by halogen atoms, and one carbon atom may be replaced by a nitrogen, oxygen or sulphur atom;
- R.sup.3 is independently halo, alkyl, alkoxy, --NO.sub.2, --NH.sub.2 or --NHCOR.sup.5 ;
- X is H, and Y is H or C.sub.1 to C.sub.10 hydrocarbyl wherein one or more hydrogen atoms may be replaced by halogen atoms, and one carbon atom may be replaced by a nitrogen, oxygen or sulphur atom; or X and Y together are .dbd.O or .dbd.CH.sub.2 ;
- Z is: H; C.sub.1 to C.sub.15 hydrocarbyl, in which one or more hydrogen atoms may be replaced by a halogen atom, and up to three of the carbon atoms may be replaced by a nitrogen, oxygen or sulphur atom, provided that Z does not contain a --O--O-- group; or --(CHR.sup.18).sub.m --R.sup.8, wherein R.sup.18 is H or C.sub.1 to C.sub.3 alkyl and R.sup.8 is phenyl, substituted phenyl or a group of the formula --COOR.sup.9 or --CONR.sup.9 R.sup.10, in which R.sup.9 and R.sup.10 are independently H or C.sub.1 to C.sub.6 alkyl, or R.sup.9 and R.sup.10 together form a propylene, butylene, pentylene or hexylene group;
- m is 1, 2 or 3; and
- n and p are independently from 0, 1, 2, or 3,
- or a pharmaceutically acceptable salt thereof.
- 19. A compound according to claim 18, wherein V is --N(COR.sup.4)--.
- 20. A compound according to claim 18, wherein R.sup.1 is H, C.sub.1 to C.sub.6 alkyl- or cycloalkyl-(C.sub.1 to C.sub.6)alkyl-.
- 21. A compound according to claim 20, wherein R.sup.1 is t-butyl or (1-adamantyl)methyl.
- 22. A compound according to claim 18, wherein R.sup.4 is selected from the group consisting of H, methyl, methoxy, carboxymethyl, carboxyethyl, benzyloxy and a group of the formula --NH--Ar, wherein Ar is an aromatic group selected from the group consisting of methylphenyl, carboxyphenyl, dicarboxyphenyl, dichlorophenyl, naphthyl and indolyl.
- 23. A compound according to claim 18, wherein R.sup.8 is selected from the group consisting of t-butyloxycarbonyl, ethoxycarbonyl, pyrrolidinyl, phenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-chlorophenyl, 4-chlorophenyl and 3-aminophenyl.
- 24. A compound according to claim 18, wherein X and Y together form a .dbd.O group.
- 25. A compound according to claim 18, wherein n is 0.
- 26. A compound according to claim 18, wherein p is 0.
- 27. A pharmaceutical composition comprising a compound according to claim 18, together with a pharmaceutically acceptable excipient or carrier.
- 28. A method of preparing a compound according to claim 18, comprising the step of oxidising a compound of the formula ##STR18## wherein U.sup.1 and V.sup.1 are U and V, respectively, or protected derivatives thereof with an oxidant to form a compound of the formula ##STR19##
- 29. A method of preparing a compound according to claim 18, in which X is H and Y is --OH, said method comprising reducing a compound of the formula wherein U.sup.1 and V.sup.1 and U and V, respectively, or protected derivatives thereof.
- 30. A method of preparing a compound according to claim 18, in which X is H and Y is --CH.sub.3, said method comprising reducing a compound of the formula ##STR20## wherein U.sup.1 and V.sup.1 are U and V, respectively, or protected derivatives thereof.
- 31. A method of preparing a compound according to claim 18, said method comprising the step of reacting a compound of the formula ##STR21## with an isocyanate of the formula R.sup.16 NCO or a carboxylic acid of the formula
- R.sup.1 COOH, wherein R.sup.1', R.sup.2', R.sup.3', R', and Z' are R.sup.1, R.sup.2, R.sup.3, R, and Z, respectively, or protected derivatives thereof, and U.sup.1 and V.sup.1 are U and V, respectively, or suitably protected derivatives thereof.
- 32. A method of preparing a compound according to claim 18, said method comprising the step of ring closure of a compound of the formula ##STR22## with a base, wherein Q.sup.1 is H or a protecting group, and OL is a leaving group.
- 33. A method of treating a patient suffering from a condition in which lowered gastrin or cholecystokinin activity is desirable, comprising administering to said patient an effective amount of a compound according to claim 18.
- 34. A method of preparing a compound according to claim 18, wherein X and Y together form a methylene group, said method comprising the step of reacting a compound of formula ##STR23## wherein U.sup.1 and V.sup.1 represents any of the groups recited in claim 18 for U and V, respectively, or protected derivatives thereof, with .mu.-chloro-.mu.-methylene-{bis(cyclopentadienyl)titanium}-dimethylaluminium.
Priority Claims (1)
Number |
Date |
Country |
Kind |
9604996 |
Mar 1996 |
GBX |
|
Parent Case Info
This application is a 371 of PCT/GB97/00632, filed Mar. 7, 1997.
PCT Information
Filing Document |
Filing Date |
Country |
Kind |
102e Date |
371c Date |
PCT/GB97/00632 |
3/7/1997 |
|
|
10/26/1998 |
10/26/1998 |
Publishing Document |
Publishing Date |
Country |
Kind |
WO97/32860 |
9/12/1997 |
|
|
US Referenced Citations (1)
Number |
Name |
Date |
Kind |
5206234 |
Bock et al. |
Apr 1993 |
|
Non-Patent Literature Citations (1)
Entry |
Kikugawa et al. (J. Chem. Soc., Chem. Commun. (1991), (19), 1354-5), 1991. |