Patent EA-000752-B1 (EA)
Title: Tricyclic benzazepine vasopressin antagonists, process for preparing thereof pharmaceutical composition based on them and method of treating diseases
Inventor: ALBBRIGHT JAY DONALD
IPC: C07D267/16
Filed: 1996-01-16
Abstract: 1. A compound selected from those of Formula I:    wherein Y is selected from (CH2)n, O, S, NH, NCOCH3, N-(C1-C3)alkyl, CH-(C1-C3)alkyl, CHNH-(C1-C3)alkyl, CHNH2, CHN[(C1-C3)alkyl], CHO-(C1-C3)alkyl, CHS-(C1-C3)alkyl, wherein n is an integer from 0-2; A-B is     or    m is an integer from 1-2, provided that when Y is -(CH2)n- and n=2, m may also be zero and when n is zero, m may also be three, provided also that when Y is -(CH2)n- and n is 2, m may not also be two; R1 is hydrogen, halogen (chlorine, bromine, fluorine, iodine), OH, -S-(C1-C3)alkyl, -SH, -SO (C1-C3)alkyl, -SO2-(C1-C3)alkyl, -CO-(C1-C3)alkyl, -CF3, (C1-C3)alkyl, O-(C1-C3)alkyl, -NO2, -NH2, -NHCO (C1-C3)alkyl, -N[(C1-C3)alkyl]2, -SO2NH2, -SO2NH (C1-C3)alkyl, or -SO2N[(C1-C3)alkyl]2; R2 is hydrogen, Cl, Br, F, I, -OH, (C1-C3)alkyl, O-(C1-C3)alkyl, or R1 and R2 taken together are methylenedioxy or ethylenedioxy;  R3 is the moiety     wherein Ar is a moiety selected from the group    and X is O, S, -NCH3 or -NH; R4 is selected from hydrogen, (C1-C3)alkyl, -CO-(C1-C3)alkyl; R5 and R7 are selected from hydrogen, (C1-C3)alkyl, (C1-C3)alkoxy and halogen; R6 is selected from (a) moieties of the formula:  cycloalkyl    (C3-C8)alkyl,    (C3-C8)alkenyl,   (C3-C8)alkyl, straight or branched,   (C3-C8)alkyl, straight or branched,   (C3-C8)alkenyl, straight or branched,   (C3-C8)alkenyl, straight or branched, wherein cycloalkyl is defined as C3-C6-cycloalkyl, cyclohexenyl or cyclopentenyl; Ra is hydrogen, CH3, C2H5, moieties of the formulae:   -(CH2)2O-(C1-C3)alkyl or -CH2CH2OH; q is one, two or three; Rb is hydrogen, -CH3 or -C2H5; (b) a moiety of the formula: -X-R10, wherein R10 is (C3-C8)alkyl, (C3-C8)alkenyl, -(CH2)p-(C3-C6)cycloalkyl,     and p is zero to three; X is O, S, NH, NCH3,  or a bond and R5 and R7 are as previously defined.  (c) a moiety of the formula:   wherein J is Ra, (C3-C8)alkyl, branched or unbranched, (C3-C8)alkenyl, branched or unbranched, -O-(C3-C8)alkyl, branched or unbranched, -O-(C3-C8)alkenyl, branched or unbranched, tetrahydrofuran, tetrahydrothiophene, the moieties    or -CH2-K' wherein K' is halogen, -OH, tetrahydrofuran, tetrahydrothiophene or the heterocyclic ring moiety:   wherein D, E, F and G are selected from carbon or nitrogen and wherein the carbon atoms may be optionally substituted with halogen, (C1-C3)alkyl, hydroxy, -CO-lower alkyl(C1-C3), CHO, (C1-C3)alkoxy, -CO2-(C1-C3)alkyl, and Ra and Rb are as hereinbefore defined;  (d) a moiety selected from those of the formulae:    (C1-C3)alkyl, -S-(C1-C3)alkyl   wherein Rc is selected from halogen, (C1-C3)alkyl, -O-(C1-C3)alkyl and OH; Rb is as hereinbefore defined; wherein Ar' is selected from the group:   R8 and R9 are independently hydrogen, (C1-C3)alkyl, O-(C1-C3)alkyl, S-(C1-C3)alkyl, -CF3, -CN, -OH, -SCF3, -OCF3, halogen, NO2, amino, or -NH-(C1-C3)alkyl; -N-[(C1-C3)alkyl], -N(Rb)(CH2)q-N(Rb)2; W' is selected from O, S, NH, N-(C1-C3)alkyl, -NCO-(C1-C3)alkyl or NSO2-(C1-C3)alkyl R25 is selected from the moieties:   and the moiety    represents: (1) phenyl or substituted phenyl optionally substituted by one or two substituents selected from (C1-C3)alkyl, halogen, amino, (C1-C3)alkoxy, and (C1-C3)alkylamino; (2) a 5-membered aromatic (unsaturated) heterocyclic ring having one heteroatom selected from O, N and S; (3) a 6-membered aromatic (unsaturated) heterocyclic ring having one nitrogen atom; (4) a 5 or 6-membered aromatic (unsaturated) heterocyclic ring having two nitrogen atoms; (5) a 5-membered aromatic (unsaturated) heterocyclic ring having one nitrogen atom together with either one oxygen or one sulfur atom; wherein the 5 or 6-membered heterocyclic rings are optionally substituted by (C1-C3)alkyl, formyl, a moiety of the formula:   halogen or (C1-C3)alkoxy; and the pharmaceutically acceptable salts, esters and pro-drug forms thereof. 2. A compound according to claim 1 wherein  the moiety    is selected from the group comprising a phenyl ring optionally substituted by one or two substituents selected from (C1-C3)alkyl, halogen, amino, (C1-C3)alkoxy; and (C1-C3)alkylamino; a 6-membered aromatic (unsaturated) heterocyclic ring having one nitrogen atom; a 6-membered aromatic (unsaturated) heterocyclic ring having two nitrogen atoms; a 5-membered aromatic (unsaturated) heterocyclic ring having one sulfur atom; a 5-membered aromatic (unsaturated) heterocyclic ring having one oxygen atom; a 5-membered aromatic (unsaturated) heterocyclic ring having one nitrogen atom; a 5-membered aromatic (unsaturated) heterocyclic ring having two nitrogen atoms; a 5-membered aromatic (unsaturated) heterocyclic ring having one nitrogen atom and one sulfur atom; a 5-membered aromatic (unsaturated) heterocyclic ring having one nitrogen atom and one oxygen atom; a 6-membered aromatic (unsaturated) heterocyclic ring having one nitrogen atom;, where a 6-membered aromatic (unsaturated) heterocyclic ring having one nitrogen atom is optionally substituted by (C1-C3)alkyl, formyl, a moiety of the formula:   halogen or (C1-C3)alkoxy; or  a 5-membered aromatic (unsaturated) heterocyclic ring having one sulfur atom; where a 5-membered aromatic (unsaturated) heterocyclic ring is optionally substituted by (C1-C3)alkyl; and the pharmaceutically acceptable salts, esters and pro-drug forms thereof. 3. A compound according to claim 1 wherein Y is selected from -CH2-,   (C1-C3)alkyl,   (C1-C3)alkyl,   (C1-C3)alkyl,  (C1-C3)alkyl, 4. A compound according to claim 1 wherein Y is -(CH2)n-, wherein n is an integer zero. 5. A compound according to claim 1 wherein Y is selected from O, S, NH, NCOCH3 and N-(C1-C3)alkyl. 6. A compound according to claim 1, wherein Y is selected from -(CH2)n-, wherein n is an integer zero and   (C1-C3)alkyl,   (C1-C3)alkyl,   (C1-C3)alkyl,  (C1-C3)alkyl,    wherein n is an integer zero or one; and R6 is selected from the group   cycloalkyl,   wherein Ar' is selected from the group:   W' is O or S. 7. A compound according to claim 6, wherein n is an integer one. 8. A compound according to claim 7, wherein  the moiety   represents: a phenyl ring optionally substituted by one or two substituents selected from (C1-C3)alkyl, halogen, amino, (C1-C3)alkoxy, and (C1-C3)alkylamino. 9. A compound according to claim 6 wherein Y is -(CH2)n-,and n is an integer zero. the moiety   represents: a phenyl ring optionally substituted by one or two substituents selected from (C1-C3)alkyl, halogen, amino, (C1-C3)alkylamino. 10. A compound according to claim 5 wherein R6 is selected from the group:   wherein Ar' is selected from the group:   W' is O or S and. the moiety   represents: a phenyl ring optionally substituted by one or two substituents selected from (C1-C3)alkyl, halogen, amino, (C1-C3)alkoxy, and (C1-C3)alkylamino. 11. A compound according to claim 6 wherein Y is -(CH2)n-,and n is an integer zero; and the moiety   represents a 6-membered aromatic (unsaturated) heterocyclic ring having one nitrogen atom. 12. A compound according to claim 7 wherein Y is selected from -CH2-, and the moiety   represents a 6-membered aromatic (unsaturated) heterocyclic ring having one nitrogen atom. 13. A compound according to claim 6 wherein Y is -(CH2)n-,and n is an integer zero; and the moiety   represents a 5-membered aromatic (unsaturated) heterocyclic ring having one sulfur atom; 14. A compound according to claim 7 wherein Y is selected from -CH2-, and the moiety   represents a 5-membered aromatic (unsaturated) heterocyclic ring having one sulfur atom. 15. A compound according to claim 5 wherein R6 is selected from the group:   wherein Ar' is selected from the group:   W' is O or S and the moiety   represents a 5-membered aromatic (unsaturated) heterocyclic ring having one sulfur atom. 16. A compound of claim 1, wherein has the formula:   wherein R1' and R2' are independently hydrogen, (C1-C3)alkyl, halogen, amino, (C1-C3)alkoxy, or (C1-C3)alkylamino; and m is integer zero or two and pharmaceutically acceptable salts thereof. 17. A compound of claim 1, wherein has the formula:   and pharmaceutically acceptable salts thereof. 18. A compound selected from those of the formula:   wherein Y is selected from O, S. NH, and N-(C1-C3)alkyl; R1 is hydrogen, halogen (chlorine, bromine, fluorine, iodine), OH, S-(C1-C3)alkyl, -SH, -SO(C1-C3)alkyl, -SO2-(C1-C3)alkyl, -CO-(C1-C3)alkyl, -CF3, (C1-C3)alkyl, O-(C1-C3)alkyl, -NO2, -NH2, -NHCO (C1-C3)alkyl, -N-[(C1-C3)alkyl]2, -NH-(C1-C3)alkyl, -SO2NH2; -SO2NH (C1-C3)alkyl,or -SO2N[(C1-C3)alkyl]2; R2 is hydrogen, Cl, Br, F, I, -OH, (C1-C3)alkyl, O-(C1-C3)alkyl or R1 and R2 taken together are methylenedioxy or ethylenedioxy; R3 is the moiety:    wherein Ar is selected from moieties of the formula:    (C3-C8)alkyl,  (C3-C8)alkenyl,  (C3-C8)alkyl, straight or branched,  (C3-C8)alkyl, straight or branched,  (C3-C8)alkenyl, straight or branched,  (C3-C8)alkenyl, straight or branched, wherein cycloalkyl is defined as C3-C6 cycloalkyl, cyclohexenyl or cyclopentenyl; Ra is hydrogen, CH3, C2H5, moieties of the formulae:   -(CH2)-O-(C1-C3)alkyl or -CH2CH2OH; q is one, two or three; Rb is hydrogen, -CH3 or -C2H5; and  (b) a moiety of the formula: -X-R10, wherein R10 is (C3-C8)alkyl, (C3-C8)alkenyl, -(CH2)p-(C3-C6)cycloalkyl,   and p is zero or three; X is O, S, NH, NCH3,  or a bond and R5 and R7 are as previously defined.  (c) a moiety of the formula:   wherein J is Ra, (C3-C8)alkyl, branched or unbranched, (C3-C8)alkenyl branched or unbranched,  -O-(C3-C8)alkyl, branched or unbranched, -O-(C3-C8), branched or unbranched, tetrahydrofuran, tetrahydrothiophene, the moieties    or -CH2-K' wherein K' is halogen, -OH, tetrahydrofuran, tetrahydrothiophene or the heterocyclic ring moiety:   wherein D, E, F and G are selected from carbon or nitrogen and wherein the carbon atoms may be optionally substituted with halogen, (C1-C3)alkyl, hydroxy, -CO-(C1-C3)alkyl, CHO, (C1-C3)alkoxy, -CO2-(C1-C3)alkyl, and Ra and Rb are as hereinbefore defined;  (d) a moiety selected from those of the formulae:    (