Claims
- 1. A compound of the formula (I): ##STR15## wherein X is a 5- or 6-membered C-linked heteroaromatic ring containing 1 to 4 nitrogen atoms and optionally containing in the ring one oxygen or sulphur atom;
- Y is a group of the formula --(CH.sub.2).sub.n NR.sup.6 R.sup.7, or a methylene- or ethylene-linked imidazolyl group;
- Z is hydrogen or C.sub.1-4 alkyl optionally substituted by a hydroxy group;
- R.sup.1 is hydrogen, halogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, CF.sub.3, NO.sub.2, CN, SR.sup.a, SOR.sup.a, SO.sub.2 R.sup.a, CO.sub.2 R.sup.a, CONR.sup.a R.sup.b, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl or C.sub.1-4 alkyl substituted by C.sub.1-4 alkoxy, wherein R.sup.a and R.sup.b each independently represent hydrogen or C.sub.1-4 alkyl;
- R.sup.2 is hydrogen, halogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy substituted by C.sub.1-4 alkoxy or CF.sub.3 ;
- R.sup.3 is hydrogen, halogen or CF.sub.3 ;
- R.sup.4 is hydrogen, halogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, hydroxy, CF.sub.3, NO.sub.2, CN, SR.sup.a, SOR.sup.a, SO.sub.2 R.sup.a, CO.sub.2 R.sup.a, CONR.sup.a R.sup.b, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl or C.sub.1-4 alkyl substituted by C.sub.1-4 alkoxy, wherein R.sup.a and R.sup.b are as previously defined;
- R.sup.5 is hydrogen, halogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy substituted by C.sub.1-4 alkoxy or CF.sub.3 ;
- R.sup.6 is hydrogen, C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, C.sub.3-7 cycloalkylC.sub.1-4 alkyl, phenyl, or C.sub.2-4 alkyl substituted by C.sub.1-4 alkoxy or hydroxy;
- R.sup.7 is hydrogen, C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, C.sub.3-7 cycloakylC.sub.1-4 alkyl, phenyl, or C.sub.2-4 alkyl substituted by one or two substituents selected from C.sub.1-4 alkoxy, hydroxy or a 4, 5 or 6 membered heteroaliphatic ring containing one or two heteroatoms selected from N, O and S;
- or R.sup.6 and R.sup.7, together with the nitrogen atom to which they are attached, form a saturated or partially saturated heterocyclic ring of 4 to 7 ring atoms, which ring may optionally contain in the ring one oxygen or sulphur atom or a group selected from NR.sup.8, S(O) or S(O).sub.2 and which ring may be optionally substituted by one or two groups selected from hydroxyC.sub.1-4 alkyl, C.sub.1-4 alkoxyC.sub.1-4 alkyl, oxo, COR.sup.a or CO.sub.2 R.sup.a where R.sup.a is as previously defined;
- or R.sup.6 and R.sup.7 together with the nitrogen atom to which they are attached, form a non-aromatic azabicyclic ring system of 6 to 12 ring atoms;
- R.sup.8 is hydrogen, C.sub.1-4 alkyl, hydroxyC.sub.1-4 alkyl or C.sub.1-4 alkoxyC.sub.1-4 alkyl;
- R.sup.9a and R.sup.9b are each independently hydrogen or C.sub.1-4 alkyl, or R.sup.9a and R.sup.9b are joined so, together with the carbon atoms to which they are attached, there is formed a C.sub.5-7 ring; and
- n is zero, 1 or 2;
- or a pharmaceutically acceptable salt thereof.
- 2. A compound as claimed in claim 1 wherein R.sup.1 is hydrogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, halogen or CF.sub.3.
- 3. A compound as claimed in claim 1 wherein R.sup.2 is hydrogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, halogen or CF.sub.3.
- 4. A compound as claimed in claim 1 wherein R.sup.3 is hydrogen, fluorine, chlorine or CF.sub.3.
- 5. A compound as claimed in claim 1 wherein R.sup.4 is hydrogen.
- 6. A compound as claimed in claim 1 wherein R.sup.5 is hydrogen, fluorine, chlorine or CF.sub.3.
- 7. A compound as claimed in claim 1 wherein R.sup.9a and R.sup.9b are each independently hydrogen or methyl.
- 8. A compound of the formula (Ia): ##STR16## wherein A.sup.1 is fluorine or CF.sub.3 ;
- A.sup.2 is fluorine or CF.sub.3 ;
- A.sup.3 is fluorine or hydrogen;
- X is a 5- or 6-membered C-linked heteroaromatic ring containing 1 to 4 nitrogen atoms and optionally containing in the ring one oxygen or sulphur atom;
- Y is a group of the formula --(CH.sub.2).sub.n NR.sup.6 R.sup.7, or a methylene- or ethylene-linked imidazolyl group;
- Z is hydrogen or C.sub.1-4 alkyl optionally substituted by a hydroxy group;
- or a pharmaceutically acceptable salt thereof.
- 9. A compound as claimed in claim 1 wherein X is selected from imidazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, thiadiazolyl and oxadiazolyl.
- 10. A compound as claimed in claim 1 wherein Y is a group of the formula --(CH.sub.2).sub.n NR.sup.6 R.sup.7.
- 11. A compound as claimed in claim 1 wherein Z is a C.sub.1-2 alkyl group optionally substituted by a hydroxy group.
- 12. A compound selected from:
- 4-(5-amino-1,2,4-triazol-3-yl)-2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl) ethoxy)-3-(S)-phenylmorpholine;
- 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(2-N,N -dimethylaminoethyl-2H-tetrazol-5-yl)-3-(S)-(4-fluorophenyl)morpholine;
- 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(4-dimethylaminomethyl)thiazol-2-yl)-3-(S)-(4-fluorophenyl)morpholine;
- or a pharmaceutically acceptable salt thereof.
- 13. A process for the preparation of a compound as claimed in claim 1 which comprises:
- (A), reaction of formula (II) ##STR17## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.9a, R.sup.9b and Z are as defined in claim 1 and R.sup.20 is phenyl or C.sub.1-6 alkyl, with hydrazine; or
- (B), reaction of a compound of formula (III) ##STR18## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.9a, R.sup.9b, X and Z are as defined in claim 1, R.sup.21 is a leaving group, and m is 1 or 2, with an amine of the formula HNR.sup.6 R.sup.7 or imidazole; or
- (C), reaction of a compound of formula (IV) ##STR19## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.9a, R.sup.9b, X and Z are as defined claim 1 and Hal is a halogen atom and m is 1 or 2, with an amine of the formula HNR.sup.6 R.sup.7 or imidazole; or
- (D), interconversion of a compound of formula (I) in which the heteroaromatic ring represented by X is substituted by a group of the formula --(CH.sub.2).sub.n NH.sub.2, by reaction with alkyl halides of the formula R.sup.6 -Hal and R.sup.7 -Hal, or a suitable dihalide designed to form a saturated heterocyclic ring, wherein R.sup.6 and R.sup.7 are as defined in claim 1, and Hal is as previously defined, in the presence of a base;
- (E), reaction of a compound of formula (V) ##STR20## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.9a, R.sup.9b and Z are as defined in claim 1, with a compound of formula (XI)
- Hal--X--Y (XI)
- wherein Hal is a halogen atom;
- each process being followed, where necessary, by the removal of any protecting group where present;
- and when the compound of formula (I) is obtained as a mixture of enantiomers or diastereoisomers, optionally resolving the mixture to obtain the desired enantiomer;
- and/or, if desired, converting the resulting compound of formula (I) or a salt thereof, into a pharmaceutically acceptable salt or prodrug thereof.
- 14. A pharmaceutical composition comprising a compound as claimed in claim 1 in association with a pharmaceutically acceptable carrier or excipient.
- 15. A method for the treatment or prevention of physiological disorders associated with an excess of tachykinins, which method comprises administration to a patient in need thereof of a tachykinin reducing amount of a compound according to claim 1.
- 16. A method according to claim 15 for the treatment or prevention of pain or inflammation.
- 17. A method according to claim 15 for the treatment or prevention of migraine.
- 18. A method according to claim 15 for the treatment or prevention of emesis.
- 19. A method according to claim 15 for the treatment or prevention of postherpetic neuralgia.
Priority Claims (1)
Number |
Date |
Country |
Kind |
9523244 |
Nov 1995 |
GBX |
|
Parent Case Info
This application is a 371 of PCT/GB96/02766 filed Nov. 13, 1996.
PCT Information
Filing Document |
Filing Date |
Country |
Kind |
102e Date |
371c Date |
PCT/GB96/02766 |
11/13/1996 |
|
|
5/14/1998 |
5/14/1998 |
Publishing Document |
Publishing Date |
Country |
Kind |
WO97/18206 |
5/22/1997 |
|
|
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EPX |
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Jun 1995 |
WOX |
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Jul 1995 |
WOX |
WO 9523798 |
Sep 1995 |
WOX |
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Nov 1995 |
WOX |
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Sep 1996 |
WOX |