Patent EA-000607-B1 (EA)
Title: Tricyclic benzazepine vasopressin antagonists
Inventor: ALBRIGHT JAY DONALD
IPC: C07D471/14
Filed: 1996-01-16
Abstract: selected from hydrogen, (C1-C3) alkyl, (C1-C3) alk1. Tricyclic benzazepine of general formula I:   wC1-C3) alkyl, (C1-C3) alkoxy and halogen; R<6> is selected from (a) moieties of the formulae:     alkyl (C3-C8) straight or branched,   alkyl (C3-C8)  -CHOCO-alkyl((C1-C6), -CHNH(CH2)mNH2; -CHNH(CH2)mbranched,   alkenyl (C3-C8) straight or branched, )]2; -CHNH(CH2)m-S-alkyl ((C1-C6), -CHNH(CH2)m-O-alkyl((C1-C6),   S. O. -NH, -N-alkyl((C1-C6), -NCO-alkyl((C1-C6), m is an integer of 2 to 6; A-B is a cyclopentenyl; and Ra is independently selected for 2 provided that when Y is a bond, n is 2; and the moiety:   represents: (1) an unsaturated 6-membered heterocyclic aromatic ring containing one nit, (b) a moiety of the formula:   wherein J is Ra, ubstitutents 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, or S; and the moiety:   represents: (1) an unsaturated 6C3) - alkoxy, halogen, tetrahydrofuran, tetrahydroe or two nitrogen atoms, optionally substituted byin D, E, P and G are selected from carbon or nitrogen and wherein the carbon atorns may be optionalllamino; (2) a 5-membered aromatic (unsaturated) he, -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 isatoms; (4) 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 optional (C3-C8), alkenyl (C3-C8), -(CH2)p-cycloalkyl (C33) alkoxy; R<3> is -COAr, wherein Ar is a moiety sd wherein-Rd is selected from the moieties:   wherein p is zero to four and M is a bond or M is sele> is selected from hydrogen, alkyl (C1-C3) -CO-alka are as hereinbefore defined; wherein Ar' is selected from moieties of the formula:   wherein W' is selected from O, S, NH, N- alkyl (C1-C3) NHCO- al-C3) alkoxy and halogen; R<6> is selected from (a) moieties of the formulae:     alkyl(C1-C8) straig (C1-C3) and CF3; R<8> and R<9> are independently d,   alkyl(C1-C8) straight or branched,   alkenyl(C1-C8) straight or branched,   alkenyl(C1-C8) stra-C3)]2, -OCF3, -OH,. -CN, -S-CF3, -NO2, -NH2, O- alkyl (C1-C3), NHCO alkyl (C1-C3), -O-CO- alkyl (C1-C3) and CF3 and; R<10> is selected from hydrogen,is independently selected from hydrogen, -CH3 or -C2H5   -(CH2)q-O-alkyl(C1-C3), -CH2CH20H, q is oneN(Rb)2; and the pharmaceutically acceptable salts thereof. 21. A compound according to Claim 1 of the formula:   wherein Y is a bond, -CH2-, O, S, NH,ranched, alkenyl(C1-C8) branched or unhranched, O-herein n is an integer 1 or 2 with the proviso tha-C8) branched or unbranched, tetrahydrofuran, tetrahydrothiophene and 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 cn, amino, (C1-C3) alkoxy or (C1-C3) alkylamino; (2 be optionally substituted with halogen, (C1-C3),  ring having one heteroacom selected from O, N or S; (3) a 5-membered aromatic (unsaturated) heterocnbefore defined; (c) a moiety of the formula:   wherein Rc is selected from halogen, (C1-C3) alkyl, ring having one nitrogen atom together with eitherC3),   wherein Ra and Rb are as hereinbefore defin-membered heterocyclic rings are optionally substituted by (C1-C3) alkyl, halogen, or (C1-C3) alkoxy; R<3> is COAr, wherein Ar is a moiecy selected frM-Rd wherein Rd is selected from the moieties:   wd from O, S,.-NH, -NCH3 and -NCOCH3; R<4> is selecelected from O. S, NH, NCH3; wherein R<1>, R<2> and Ra are as hereinbefore defined; wherein Ar is seyl, (C1-C3) alkoxy and halogen; R<5> is selected f is selected from O. S, NH, N-alkyl(C1-C3) NHCO-allogen; R<6> is selected from (a) moieties of the formulae:     alkyl (C3-C8) straight or branched,  (C1-C3) and CF3; R<8> and R<9> are independently s8) straight or branched,   alkenyl (C3-C8) straight or branched,   alkenyl (C3-C8) straight or branc]2. -OCF3, -OH, -CN, -S-CF3, -N02, -NH2, O-alkyl(C1-C3), NHCO alkyl (C1-C3),. -O-CO-alkyl (C1-C3) and CF3 and; R<10>-is selected from hydrogen, halogen, alkyl (C1-C3), -NH-alkyl (C1-C3), -N-[alkyl (C1-C3)]2., -O-alkyl (C1-C3), -N(Rb) (CH2)q-N(Rb)2. athree, Rb is independently selected from hydrogen, -CH3 or -C2H5, (b) a moiety of the formula:   wherein J is Ra alkyl (C3-C8) branched or unbranched,or 2 and R<3> is as defined in Claim 1. 3. A compo(C3-C8) branched or unbranched, -O- alkenyl (C3-C8) branched or unbranched, tetrahydrofuran, tetrahyis as defined in Claim 1. 4. A compound according to Claim 1 wherein Y is O, S. NH, N-alkyl (C1-C6),n, tetrahydrothiophene or the heterocyclic ring mois an integer 1 or 2 and R<3> is as defined in Clarbon or nitrogen and wherein the carbon atorns 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 herN-alkyl (C1-C6), -NCO alkyl (C1-C6) and A-B is a moiety:   wherein n is an integer 1 and R<3> is as , -O- alkyl (C1-C3), OH,   alkyl (C1-C3), -S- alkyl (C1-C3),   wherein Ra and Rb are as hereinbefore defined; (d) a moiety of the formula: -M-Rd wherein Rd is alkyl (C3-C8), alkenyl (C3-C8), -(CH2)p-c; and the moiety:   represents: (1) an unsaturaced 6-membered heterocyclic aromatic ring containing eties:   wherein p is zero to four and M is a bondby 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 f-C3) NHCO- alkyl (C1-C3) and NSO2 alkyl (C1-C3); Rted) heterocyclic ring having two adjacent nitrogen atorns; (4) a 5-membered aromatic (unsaturated) ndependently selected from hydrogen, alkyl (C1-C3)r with either one oxygen or one sulfur atom; wherein the 5 or 6-membered heterocyclic rings are optionally substituted by (C1-C3) alkyl, halogen or (C1-C3) alkoxy; R<3> is -COAr, wherein Ar is a moiety selected from the group consisting of:   whereinC1-C3), -N-[alkyl (C1-C3)]2, -O- alkyl (C1-C3), -N(Rb) (CH2)q-N(Rb)2; and the pharmaceutically accepO-alkyl (C1-C3), R<1> and R<2> are selected from hydrogen. (C1-C3) alkyl (C1-C3) alkoxy and halogen; R<5> is selected from hydrogen, (C1-C3) alkyl, (Cthe proviso that when Y is a bond, n is 2; and the moiecy.   represents: (1) an unsaturated 6-membered heterocyclic aromatic ring containing one or two nitrogen atorns, 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) heterocy cycloalkyl, cyclohexenyl or cyclopentenyl; and Ra is independently selected from hydrogen. -CH3 or -C2H5,   -(CH2)q-O-alkyl (C1-C3), -CH2CH20H, q is one, two or three, Rb is independently selected from hydrogen, -CH3 or -C2H5, (b) a moiety of the formula:   wherein J is Ra. alkyl (C3-C8), branched or 6-membered heterocyclic rings are optionally suched. O-alkenyl (C3-C8), branched or unbranched, -oxy; R<3> is COAr, wherein Ar is a moiecy selected from the group consisting of:   wherein x is selected from O, S, -NH, -NCH3 and -NCOCH3; R<4> is setetrahydrofuran, tetrahydrothiophene or the heteroR<1> and R<2> are 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 formulae:     alkyl (C3-C8) straight or branched are as hereirbefore defined; (c) a moiety of the formula:   wherein Rc is selected from halogen, (Cight or branched,   alkenyl (C3-C8) straight or br, -S-alkyl (C1-C3),   wherein Ra and Rb-are as herwherein cycloalkyl is defined as (C3-C6) cycloalky-Rd wherein Rd is alkyl (C3-C8), alkenyl(C3-C8), -(CH2)p-cycloalkyl (C3-C6), when M is O, S, NH, NHCH3 and the moiety -M-Rd wherein Rd is selected from the moieties:   wherein p is zero to four and M is a bond or M is selected from O, S, NH, NCH3 wherein R<1>, R<2> and Ra are as hereinbefore defined; wherein 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); R<7> is selected from hydrogen, alkyl (C1-C3), halogen, O-alkyl (C1-C3) and CF3; R<8> and R<9> 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), NHCO alkyl (C1-C3), -O-CO-alkyl (C1-C3) and CF3 and; R<10> is selected from hydrogen, halogen, alkyl (C1-C3), -NH-alkyl (C1-C3), -N-[alkyl (C1-C3)]2, -O-alkyl (C1-C3), -N(Rb) (CH2)q-N(Rb)2; and the pharmaceutically acceptable salts thereof. 8. A compound according to Claim 1 of the formula:   wherein Y is a bond or -CH2-, A-B is   wherein n is an integer 1 or 2 with the proviso that when Y is a bond, n is an integer 2; and the moiety:   represents: an unsaturated 6-membered heterocyclic aromatic ring containing one or two nitrogen atoms, optionally substituted by one or two substituents selected from (C1-C3) alkyl, halogen, amino, (C1-C3) alkoxy or (C1-C3) alkylamino; R<3> is -COAr, wherein Ar is a moiety selected from the group consisting of:   wherein X is selected from O, S, -NH, -HCH3 and -NCOCH3; R<4> is selected from hydrogen, alkyl (C1-C3), -CO-alkyl (C1-C3), R<1> and R<2> are 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 formulae:     alkyl(C3-C8) straight or branched,   alkyl (C3-C8) straight or branched,   alkyl (C3-C8) straight or branched,   alkenyl (C3-C8) straight or branched,   alkenyl (C3-C8) straight or branched,   alkenyl (C3-C8) straight or branched,   wherein cycloalkyl is defined as (C3-C6) cycloalkyl, cyclohexenyl or cyclopentenyl; and Ra is