Patent EA-001143-B1 (EA)
Title: Tricyclic benzazepine vasopressin antagonists
Inventor: ALBRIGHT JAY DONALD
IPC: A61P9/00
Filed: 1996-01-16
Abstract: 1. Tricyclic benzazepine of the general formula:   wherein Y is a moiety selected from -(CH2)n- wherein n is an integer from 0 to 2,  alkyl(C1-C3) and   A-B is a moiety selected from    and   wherein m is an integer from 1 to 2 provided that when Y is -(CH2)n- and n is 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 be two; 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 or (C1-C3)alkylamino; (2) a 5-membered aromatic  (unsaturated) heterocyclic ring having one heteroatom selected from O, N or 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 atom or one sulfur atom; wherein the 5- or 6-membered heterocyclic rings are optionally substituted by (C1-C3)alkyl, halogen or (C1-C3)alkoxy; the moiety:    is a five membered aromatic (unsaturated) nitrogen containing heterocyclic ring wherein D, E and F are selected from carbon and nitrogen and wherein the carbon atoms may be optionally substituted by substituents, selected from halogen, (C1-C3)alkyl, hydroxy, -COCl3, -COCF3,  , alkyl (C1-C3),  ,   -CHO, amino, (C1-C3) alkoxy, (C1-C3) alkylamino, CONH-alkyl(C1-C3), and CON-[alkyl(C1-C3)]2; q is one or two; Rb is independently selected from hydrogen, -CH3 or C2H5; R<3> is a moiety of the formula:    wherein Ar is a moiety selected from the group consisting of    R<4> is selected from hydrogen, alkyl(C1-C3); -COalkyl(C1-C3); R<1> and R<2> are independently selected from hydrogen, (C1-C3) alkyl, (C1-C3)alkoxy and halogen; R<5> is selected from hydrogen, (C1-C3) alkyl, (C1-C3) alkoxy and halogen; R<6> is selected from (a) moieties of the formulas:    alkyl(C3-C8) straight or branched,  alkyl (C3-C8) straight or branched,  -NHSO2-alkyl (C3-C8) straight or branched,  alkenyl(C3-C8) straight or branched,   alkenyl(C3-C8) straight or branched,  -NHSO2-alkenyl(C3-C8) straight or branched, wherein cycloalkyl is defined as C3-C6cycloalkyl, cyclohexyl or cyclopentenyl; Ra is independently selected from hydrogen, -CH3, -C2H5,   -(CH2)q-O-alkyl(C1-C3) and -CH2CH2OH, q is one or two, and R1, R2 and Rb are as hereinbefore defined;  (b) moieties of the formula:   wherein R<7> is alkyl(C3-C8), alkenyl(C3-C8), -(CH2)p-cycloalkyl (C3-C6),   wherein p is one to five and X is selected from O, S, NH, NCH3; wherein R<1> and R<2> are as hereinbefore defined;  (c) a moiety of the formula:   wherein J is Ra, alkyl(C3-C8) branched or unbranched, alkenyl (C3-C8) branched or unbranched, O-alkyl (C3-C8) branched or unbranched, -O-alkenyl (C3-C8) branched or unbranched, tetrahydrofuran, tetrahydrothiophene, the moieties:   or -CH2-K', wherein K' is (C1-C3)alkoxy, halogen, 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-alkyl(C1-C3), CHO, (C1-C3)alkoxy, -CO2-alkyl(C1-C3), and Ra and Rb are as hereinbefore defined;  (d) a moiety of the formula:   wherein Rc is selected from halogen, (C1-C3) alkyl, -O-alkyl (C1-C3), OH,  alkyl (C1-C3), -S-alkyl (C1-C3),   wherein Ra and Rb are as hereinbefore defined, and Ar' is selected from moieties of the formula:   wherein W' is selected from O, S, NH, N-alkyl(C1-C3), NHCO-alkyl(C1-C3), and NSO2 alkyl(C1-C3); R8 and R9 are independently selected from hydrogen, alkyl(C1-C3), -S-alkyl(C1-C3), halogen,  -NH-alkyl(C1-C3), -N-[alkyl(C1-C3)]2, -OCF3, -OH, -CN, -S-CF3, -NO2, -NH2, O-alkyl(C1-C3),   -N(Rb)(CH2)vN(Rb)2, and CF3 wherein v is one to three and; R<10> is selected from hydrogen, halogen and alkyl(C1-C3); R<14> is -O-alkyl (C1-C3) branched or unbranched,    -NH-alkyl (C3- C8) branched or unbranched,      wherein n is O or 1; Ra is hydrogen, -CH3 or -C2H5; R' is hydrogen, (C1-C3)alkyl, (C1-C3)alkoxy or halogen; R<20> is hydrogen, halogen, (C1-C3) alkyl,  (C1-C3) alkoxy, NH2, -NH-(C1-C3) alkyl, -N-[(C1-C3)alkyl]2,   and the pharmaceutically acceptable salts thereof.  2. A compound according to Claim 1 wherein R<3> is the moiety:   and Ar is selected from the moiety:   wherein R<6> is selected from the moieties of the formulas:   wherein R<1>, R<2>, R<7>, R<14>, Ra, Rb, X and Ar are as defined in Claim 1. 3. A compound according to Claim 1 wherein R<3> is the moiety:   and Ar is selected from the moiety:   wherein R<6> is selected from the moieties of the formulas:   wherein R<1>, R<2>, Ra and Rb, R<7>, R<14>, X and cycloalkyl are as defined in Claim 1 and Ar' is selected from the moieties:   wherein R<5>, R<8>, R<9> and W' are as defined in Claim 1.  4. A compound according to Claim 1 wherein Y is -(CH2)n- and n is zero or one; A-B is   or   wherein R<3> is a moiety of the formula:   wherein Ar, R<1>, R<2>, R<4>, R<5>, R<6>, R<7>, R<8>, R<9>, R<10> and R<14> are as defined in Claim 1 and m is an integer from 1-2.  5. A compound according to Claim 1 wherein Y is -(CH2)n- and n is one; A-B is      or    R<3> is the moiety of the formula:    Ar is the moiety:    R<6> is selected from (a) moieties of the formulas:      alkyl (C3- C8) straight or branched,    alkyl(C3-C8) straight or branched,  -NHSO2-alkyl(C3-C8) straight or branched,    alkenyl(C3-C8) straight or branched,    alkenyl(C3-C8) straight or branched,  - NHSO2-alkenyl (C3- C8) straight or branched, wherein cycloalkyl is defined as C3-C6 cycloalkyl, cyclohexenyl, or cyclopentenyl; Ra is independently selected from hydrogen, -CH3, -C2H5,    -(CH2)q-O-alkyl(C1-C3), -CH2CH2OH; q is one or two;  Rb is independently selected from hydrogen, -CH3, and -C2H5; or (b) a moiety of the formula:     wherein J is Ra, alkyl(C3-C8) branched or unbranched, alkenyl(C3-C8) branched or unbranched, O-alkyl(C3-C8) branched or unbranched, -O-alkenyl(C3-C8) branched or unbranched, tetrahydrofuran, tetrahydrothiophene, the moieties:   or -CH2-K', wherein K' is (C1-C3)alkoxy, halogen, 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-alkyl (C1-C3), CHO, (C1-C2)alkoxy, -CO2-alkyl(C1-C3), and Ra, Rb and R<8> are as herein-before defined;  (c) a moiety of the formula:     wherein Rc is selected from halogen, (C1-C3)alkyl, -O-alkyl (C1- C3), OH,    wherein Ra, Rb are as hereinbefore defined;  Ar' is     wherein R<1>, R<2>, R<5>, R<7>, R<8>, R<9>, R<14>, and X are as previously defined in Claim 1.  6. A compound according to Claim 1 wherein Y is -(CH2)n- and n is zero or one; the moiety:    is a phenyl ring optionally substituted with one or two substituents selected from (C1-C3)alkyl, halogen, amino, (C1-C3)alkoxy and (C1-C3)alkylamino, or a thiophene, furan, pyrrole or pyridine ring; A-B is    or    m is one, when n is one, and m is one or two when n is zero; R<3> is the moiety of the formula:     wherein Ar is the moiety:    R<6> is selected from (a) moieties of the formulas:        alkyl(C3-C8) straight or branched,    alkyl (C3-C8) straight or branched,  - NHSO2-alkyl (C3-C8) straight or branched,    alkenyl(C3-C8) straight or branched,    alkenyl (C3-C8) straight or branched,  - NHSO2-alkenyl (C3-C8) straight or branched, wherein cycloalkyl is defined as C3-C6 cycloalkyl, cyclohexyl or cyclopentenyl; Ra is independently selected from hydrogen, -CH3, -C2H5,     -(CH2)qO-alkyl(C1-C3), -CH2CH2OH; q is one or two; Rb is independently selected from hydrogen, -CH3, and -C2H5; or  (b) a moiety of the formula:   wherein J is Ra, alkyl(C3-C8) branched or unbranched, alkenyl(C3-C8) branched or unbranched, O-alkyl(C3-C8) branched or unbranched, O-alkenyl(C3-C8) branched or unbranched, tetrahydrofuran, tetrahydrothiophene, the moieties:     or -CH2-K', wherein K' is (C1-C3)alkoxy, halogen, 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-alkyl(C1-C3), CHO, (C1-C3)alkoxy, -CO2-alkyl(C1-C3), and Ra and Rb are as hereinbefore defined;  (c) a moiety of the formula:    wherein Rc is selected from halogen, (C1-C3) alkyl, -O-alkyl (C1- C3), OH,  alkyl (C1-C3), -S-alkyl(C1-C3),      wherein Ra  and Rb are as hereinbefore defined; Ar' is selected from the group    wherein D, E, F, Ra, Rb, R<1>, R<2>, R<4>, R<5>, R<7>, R<8>, R<9>, R<10>, R<14>, X, cycloalkyl and W' are as defined in Claim 1. 7. A compound in accordance with Claim 1 represented with the formula:     wherein the moiety:    is selected from a phenyl, thiophene, furan, pyrrole, or a pyridine ring; R<3> is the moiety of the formula:     wherein Ar is selected from the moieties:    R<6> is selected from (a) moieties of the formulas:      alkyl(C3-C8) straight or branched,    alkyl (C3-C8) straight or branched,  -NHSO2-alkyl(C3-C8) straight or branched,    alkenyl (C3-C8) straight or branched,    alkenyl (C3-C8) straight or branched,  - NHSO2-alkenyl (C3-C8) straight or branched, wherein cycloalkyl is defined as C3-C6cycloalkyl, cyclohexenyl or cyclopentenyl; Ra is independently selected from hydrogen, -CH3, -C2H5,    -(CH2)q-O-alkyl(C1-C3), -CH2CH2OH; q is one or two; Rb is independently selected from hydrogen, -CH3, and -C2H5;  (b) a moiety of the formula:    wherein J is Ra, alkyl(C3-C8) branched or unbranched, alkenyl(C3-C8) branched or unbranched, O-alkyl(C3-C8) branched or unbranched, -O-alkenyl(C3-C8) branched or unbranched, tetrahydrofuran, tetrahydrothiophene, the moieties:    or -CH2-K', wherein K' is (C1-C3)alkoxy, halogen, tetrahydrofuran, tetrahydrothiophene o