Patent IL-106142-A (IL)
Title: Morpholine and thiomorpholine tachykinin receptor antagonists, their preparation and pharmaceutical compositions containing them
IPC: C01B15/013
Filed: 1993-06-25
Abstract: Compounds of the formula R3XR4 R2NR5 R1 or pharmaceutically acceptable salts thereof, wherein: R1 is selected from the group consisting of: (1) hydrogen; (2) C1-6 alkyl, unsubstituted or substituted with one or more of the substituents selected from: (a) hydroxy, (b) oxo, (c) C1-6 alkoxy, (d) phenyl-C1-3 alkoxy, (e) phenyl, (f) -CN, (g) halo, (h) -NR9R10, wherein R9 and R10 are independently selected from: (i) hydrogen, (ii) C1-6 alkyl, (iii) hydroxy-C1-6 alkyl, and (iv) phenyl, (i) -NR9COR10, (j) -NR9CO2R10, (k) -CONR9R10, (l) -COR9, (m) -CO2R9, (n) optionally substituted heterocycle, selected from (A) benzimidazolyl, (B) benzofuranyl, (C) benzothiophenyl, (D) benzoxazolyl, (E) furanyl, (F) imidazolyl, (G) indolyl, (H) isooxazolyl, (I) isothiazolyl, (J) oxadiazolyl, (K) oxazolyl, (L) pyrazinyl, (M) pyrazolyl, (N) pyridyl, (O) pyrimidyl, (P) pyrrolyl, (Q) quinolyl, (R) tetrazolyl, (S) thiadiazolyl, (T) thiazolyl, (U) thienyl, (V) triazolyl, (W) azetidinyl, (X) 1, 4-dioxanyl, (Y) hexahydroazepinyl, (Z) oxanyl, (AA) piperazinyl, (AB) piperidinyl, (AC) pyrrolidinyl, (AD) tetrahydrofuranyl, and (AE) tetrahydrothienyl, and wherein the heterocycle substituents are defined in the specification; (3) C2-6 alkenyl, optionally substituted with one or more of the substituent(s) defined in the specification (4) C2-6 alkynyl; (5) phenyl, optionally substituted with one or more of the substituent(s) defined in the specification R2 and R3 are independently selected from the group consisting of: (1) hydrogen, (2) C1-6 alkyl, optionally substituted with one or more of the substituents defined in the specification (3) C2-6 alkenyl, optionally substituted with one or more of the substituent(s) as defined in the specification; (4) C2-6 alkynyl; (5) phenyl, optionally substituted with one or more of the substituent(s) defined in the specification; and the groups R1 and R2 may be joined together to form a heterocyclic ring selected from the group consisting of: (a) pyrrolidinyl, (b) piperidinyl, (c) pyrrolyl, (d) pyridinyl, (e) imidazolyl, (f) oxazolyl, and (g) thiazolyl, and wherein the heterocyclic ring is unsubstituted or substitued with one or more substituent(s) selected from: (i) C1-6 alkyl, (ii) oxo, (iii) C1-6 alkoxy, (iv) -NR9R10, wherein R9 and R10 are as defined above, (v) halo, and (vi) trifluoromethyl; and the groups R2 and R3 may be joined together to form a carbocyclic ring selected from the group consisting of: (a) cyclopentyl, (b) cyclohexyl, (c) phenyl, ane wherein the carbocyclic ring is optionally substituted with one or more substituents defined in the specification and the groups R2 and R3 may be joined together to form a heterocyclic ring selected from the group consisting of: (a) pyrrolidinyl, (b) piperidinyl, (c) pyrrolyl, (d) pyridinyl, (e) imidazolyl, (f) furanyl, (g) oxazolyl, (h) thienyl, and (i) thiazolyl, and wherein the heterocyclic ring is optionally substituted with one or more substituents as defined in the specification; X is selected from the group consisting of: (1) -O-, (2) -S-, (3) -SO-, and (4) -SO2-; R4 is selected from the group consisting of: R6 (1)R7 ZR8 (2) -Y-C1-8 alkyl, wherein the alkyl is optionally substituted with one or more of the substituents; as defined in the specification (3) -Y-C2-6 alkenyl, wherein the alkenyl is optionally substituted with one or more of the substituent(s) defined in the specification; (4) -O(CO)-phenyl, wherein the phenyl is unsubstituted or substituted with one or more of R6, R7 and R8; R5 is selected from the group consisting of: (1) phenyl, unsubstituted or substituted with one or more of R11, R12 and R13, (2) C3-7 cycloalkyl, (3) heterocycle, wherein the heterocycle is as defined above; R6, R7 and R8 are independently selected from the group consisting of: (1) hydrogen; (2) alkyl, (3) alkenyl, (4) phenyl, the groups (2), (3) and (4) being optionally substituted; (5) C2-6 alkynyl, (6) halo, (7) -CN, (8) -CF3, (9) -NO2, (10) -SR14, wherein R14 is hydrogen or C1-6 alkyl, (11) -SOR14, (12) -SO2R14, (13) NR9COR10, (14) CONR9COR10, (15) NR9R10, (16) NR9CO2R10, (17) hydroxy, (18) C1-6 alkoxy, (19) COR9, (20) CO2R9, R11, R12 and R13 are independently selected from the definitions of R6, R7 and R8; Y is selected from the group consisting of: (1) a single bond, (2) -O-, (3) -S-, (4) -CO-, (5) -CH2-, (6) -CHR15-, and (7) -CR15R16-, wherein R15 and R16 are independently selected from the group consisting of: (a) C1-6 alkyl, which is optionally substituted, (b) phenyl, which is optionally substituted Z is selected from: (1) hydrogen, (2) C1-4 alkyl, and (3) hydroxy, with the proviso that if Y is -O-, Z is other than hydroxy, or if Y is -CHR15-, then Z and R15 may be joined together to form a double bond. The compounds are tachykinin receptor antagonists and are useful in the treatment of inflammatory diseases, pain or migraine and asthma. Also, some of these compounds are calcium channel blockers and are useful in the treatment of cardiovascular disorders such as angina, hypertension or ischemia.