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US 7,078,410 B2Granted
2-arylamino-pyrimidines for the treatment of GSK3-related disorders
AssigneeAstraZeneca AB
InventorsStefan Berg, Ratan Bhat, Sven Hellberg
Life of this patent
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Abstract
An aqueous solution for prophylactic treatment of teats of lactating mammals, comprising as a first component at least partially deacetylated chitosan, or an acid addition salt thereof, in a concentration of up to about 2% by weight of chitosan, the solution having a pH of from about 4 to about 6.8, and said first component having a molecular weight such that the viscosity of the solution is less than about 50 mPas; and a method of prophylactic treatment of teats of lactating mammals.
Claims10
A method of treatment of conditions associated with glycogen synthase kinase-3 activity selected from the group consisting of dementia, Alzheimer's disease, Parkinsons disease, Frontotemporal dementia Parkinson's type, Parkinson's dementia complex of Guam, HIV dementia, mayotropic lateral sclerosis, corticobasal degeneration, dementia puglistica, postencephalitic Parkinsonism, progressive supranuclear palsy, Pick's disease, Nieman Pick's disease, Bipolar disease, depression, cognitive disorders, Type I and Type II diabetes, diabetic retinopathy and hairloss comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of formula (I)
- or a pharmaceutically acceptable salt thereof wherein:
- Ring A is imidazo[1,2a]pyrid-3-yl or pyrazolo[2,3a]pyrid-3-yl,
- R2 is attached to a ring carbon and is selected from halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C1-6alkoxy, C1-6alkanoyl, C1-6alkanoyloxy, N-(C1-6alkyl)amino, N,N-(C1-6alkyl)2amino, C1-6alkanoylamino, N-(C1-6alkyl)carbamoyl, N,N-(C1-6alkyl)2carbamoyl, C1-6alkylS(O)a wherein a is 0, 1, or 2, C1-6alkoxycarbonyl, N-(C1-6alkyl)sulphamoyl, N,N-(C1-6alkyl)2sulphamoyl, phenyl, heterocyclic group, phenylthio and, (heterocyclic group)thio;
- wherein any C1-6alkyl, C2-6alkenyl, C2-6alkynyl, phenyl or heterocyclic group may be optionally substituted on carbon by one or more G;
- and wherein if said heterocyclic group contains an —NH— moiety that nitrogen may be optionally substituted by a group selected from Q;
- m is 0, 1, 2, 3, 4 or 5;
- wherein the values of R2 may be the same or different;
- R1 is halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C1-3alkyl, C2-3alkenyl, C2-3alkynyl, C1-3alkoxy, C1-3alkanoyl, N-(C1-3alkyl)amino, N,N-(C1-2alkyl)2amino, C1-3alkanoylamino, N-(C1-3alkyl)carbamoyl, N,N-(C1-2alkyl)2carbamoyl, C1-3alkylS(O)a wherein a is 0, 1 or 2, N-(C1-3alkyl)sulphamoyl or N,N-(C1-3alkyl)2sulphamoyl;
- wherein any C1-2alkyl, C1-3alkyl, C2-3alkenyl or C2-3alkynyl may be optionally substituted on carbon by one or more J;
- n is 0, 1 or 2, wherein the values of R1 may be the same or different;
- Ring B is phenyl or phenyl fused to a C5-7cycloalkyl ring;
- R3 is halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl or C1-6alkoxy;
- p is 0, 1, 2, 3 or 4;
- wherein the values of R3 may be the same or different;
- R4 is a group A-E-;
- wherein
- A is selected from hydrogen, C1-6alkyl, phenyl, a heterocyclic group, C3-8cycloalkyl, phenylC1-6alkyl, (heterocyclic group)C1-6alkyl or C3-8cycloalkylC1-6cycloalkyl;
- which C1-6alkyl, phenyl, a heterocyclic group, C3-8cycloalkyl, phenylC1-6alkyl, (heterocyclic group)C1-6alkyl or C3-8cycloalkylC1-6cycloalkyl may be optionally substituted on carbon by one or more D;
- and wherein if said heterocyclic group contains an —NH— moiety, that nitrogen may be optionally substituted by a group selected from R;
- E is a direct bond or —O—, —C(O)—, —OC(O)—, —C(O)O—, —N(Ra)C(O)—, —C(O)N(Ra)—, —N(Ra)—, —S(O)r—, —SO2N(Ra)— or —N(Ra)SO2—;
- wherein Ra is hydrogen or C1-6alkyl optionally substituted by one or more D and r is 0, 1 or 2;
- D is independently selected from oxo, halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, C1-6alkanoyl, C1-6alkanoyloxy, N-(C1-6alkyl)amino, N,N-(C1-6alkyl)2amino, C1-6alkanoylamino, N-(C1-6alkyl)carbamoyl, N,N-(C1-6alkyl)2carbamoyl, C1 alkylS(O)a wherein a is 0 to 2, C1-6alkoxycarbonyl, C1-6alkoxycarbonylamino, benzyloxycarbonylamino, N-(C1-6alkyl)sulphamoyl and N,N-(C1-6 alkyl)2sulphamoyl;
- wherein any C1-6alkyl, C2-6alkenyl, C2-6alkynyl or phenyl may be optionally substituted on carbon by one or more K;
- q is 0, 1 or 2;
- wherein the values of R4 maybe the same or different;
- and wherein p+q≦5;
- G, J and K are independently selected from halo, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, carboxy, carbamoyl, mercapto, sulphamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, mesyl, ethylsulphonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulphamoyl, N-ethylsulphamoyl, N,N-dimethylsulphamoyl, N,N-diethylsulphamoyl and N-methyl-N-ethylsulphamoyl;
- and
- Q and R are independently selected from C1-4alkyl, C1-4alkanoyl, C1-4alkylsulphonyl, C1-4alkoxycarbonyl, carbamoyl, N-(C1-4alkyl)carbamoyl, N,N-(C1-4alkyl)carbamoyl, benzyl, benzyloxycarbonyl, benzoyl and phenylsulphonyl.
26 more elements
A compounds selected from the group consisting of
- 2-(4-Fluoro-3-methylanilino)-4-(imidazo[1,2a]pyrid-3-yl)pyrimidine,
- 2-(4-Cyanoanilino)-4-(imidazo[1,2a]pyrid-3-yl)pyrimidin,
- 2-(4-Chloroanilino)-4-(imidazo[1,2a]pyrid-3-yl)pyrimidine,
- 2-Anilino-4-(2-methylimidazo[1,2a]pyrid-3-yl)pyrimidine,
- 2-[4-(Pyrimid-2-ylaminosulphonyl)anilino]-4-(imidazo[1,2a]pyrid-3-yl)pyrimidine,
- 2-(4-Carbamoylanilino)-4-(imidazo[1,2a]pyrid-3-yl)pyrimidine,
- 2-(3-Cyanoanilino)-4-(imidazo[1,2a]pyrid-3-yl)pyrimidine,
- 2-(3,5-Difluoroanilino)-4-(imidazo[1,2a]pyrid-3-yl)pyrimidine,
- 2-(3-Chloroanilino)-4-(imidazo[1,2a]pyrid-3-yl)pyrimidine,
- 2-[4-(N,N-Dimethyl-carbamoyl)anilino]4-(imidazo[1,2a]pyrid-3-yl)primidine,
- 2-(4-Mesylanilino)-4-(imidazo[1,2a]pyrid-3-yl)pyrimidine and
- 2-(3-Sulphamoylanilino)-4-(imidazo[1,2a]pyrid-3-yl)pyrimidine,
- and a pharmaceutically acceptable salt of any one of said compounds.
10 more elements
A method for inhibition of glycogen synthase kinase-3 comprising administering to a mammal a therapeutically effective amount of a compound of formula (I)
- or a pharmaceutically acceptable salt thereof wherein:
- Ring A is imidazo[1,2a]pyrid-3-yl or pyrazolo[2,3a]pyrid-3-yl,
- R2 is attached to a ring carbon and is selected from halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C1-6alkoxy, C1-6alkanoyl, C1-6alkanoyloxy, N-(C1-6alkyl)amino, N,N-(C1-6alkyl)2amino, C1-6alkanoylamino, N-(C1-6alkyl)carbamoyl, N,N-(C1-6alkyl)2carbamoyl, C1-6alkylS(O)a wherein a is 0, 1, or 2, C1-6alkoxycarbonyl, N-(C1-6alkyl)sulphamoyl, N,N-(C1-6alkyl)2sulphamoyl, phenyl, heterocyclic group, phenylthio and, (heterocyclic group)thio;
- wherein any C1-6alkyl, C2-6alkenyl, C2-6alkynyl, phenyl or heterocyclic group may be optionally substituted on carbon by one or more G;
- and wherein if said heterocyclic group contains an —NH— moiety that nitrogen may be optionally substituted by a group selected from Q;
- m is 0, 1, 2, 3, 4 or 5;
- wherein the values of R2 may be the same or different;
- R1 is halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C1-3alkyl, C2-3alkenyl, C2-3alkynyl, C1-3alkoxy, C1-3alkanoyl, N-(C1-3alkyl)amino, N,N-(C1-2alkyl)2amino, C1-3alkanoylamino, N-(C1-3alkyl)carbamoyl, N,N-(C1-2alkyl)2carbamoyl, C1-3alkylS(O)a wherein a is 0, 1 or 2, N-(C1-3alkyl)sulphamoyl or N,N-(C1-3alkyl)2sulphamoyl;
- wherein any C1-2alkyl, C1-3alkyl, C2-3alkenyl or C2-3alkynyl may be optionally substituted on carbon by one or more J;
- n is 0, 1 or 2, wherein the values of R1 may be the same or different;
- Ring B is phenyl or phenyl fused to a C5-7cycloalkyl ring;
- R3 is halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl or C1-6alkoxy;
- p is 0, 1 2, 3 or 4;
- wherein the values of R3 may be the same or different;
- R4 is a group A-E-;
- wherein
- A is selected from hydrogen, C1-6alkyl, phenyl, a heterocyclic group, C3-8cycloalkyl, phenylC1-6alkyl, (heterocyclic group)C1-6alkyl or C3-8cycloalkylC1-6cycloalkyl;
- which C1-6alkyl, phenyl, a heterocyclic group, C3-8cycloalkyl, phenylC1-6alkyl, (heterocyclic group)C1-6alkyl or C3-8cycloalkylC1-6cycloalkyl may be optionally substituted on carbon by one or more D;
- and wherein if said heterocyclic group contains an —NH— moiety, that nitrogen may be optionally substituted by a group selected from R;
- E is a direct bond or —O—, —C(O)—, —OC(O)—, —C(O)O—, —N(Ra)C(O)—, —C(O)N(Ra)—, —N(Ra)—, —S(O)r—, —SO2N(Ra)— or —N(Ra)SO2—;
- wherein Ra is hydrogen or C1-6alkyl optionally substituted by one or more D and r is 0, 1 or 2;
- D is independently selected from oxo, halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, C1-6alkanoyl, C1-6alkanoyloxy, N-(C1-6alkyl)amino, N,N-(C1-6alkyl)2amino, C1-6alkanoylamino, N-(C1-6alkyl)carbamoyl, N,N-(C1-6alkyl)2carbamoyl, C1 alkylS(O)a wherein a is 0 to 2, C1-6alkoxycarbonyl, C1-6alkoxycarbonylamino, benzyloxycarbonylamino, N-(C1-6alkyl)sulphamoyl and N,N-(C1-6 alkyl)2sulphamoyl;
- wherein any C1-6alkyl, C2-6alkenyl, C2-6alkynyl or phenyl may be optionally substituted on carbon by one or more K;
- q is 0, 1 or 2;
- wherein the values of R4 maybe the same or different;
- and wherein p+q≦5;
- G, J and K are independently selected from halo, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, carboxy, carbamoyl, mercapto, sulphamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, mesyl, ethylsulphonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulphamoyl, N-ethylsulphamoyl, N,N-dimethylsulphamoyl, N,N-diethylsulphamoyl and N-methyl-N-ethylsulphamoyl;
- and
- Q and R are independently selected from C1-4alkyl, C1-4alkanoyl, C1-4alkylsulphonyl, C1-4alkoxycarbonyl, carbamoyl, N-(C1-4alkyl)carbamoyl, N,N-(C1-4alkyl)carbamoyl, benzyl, benzyloxycarbonyl, benzoyl and phenylsulphonyl.
26 more elements
A method for contraception comprising administering to a male mammal a therapeutically effective amount of a compound of formula (I)
- or a pharmaceutically acceptable salt thereof wherein:
- Ring A is imidazo[1,2a]pyrid-3-yl or pyrazolo[2,3a]pyrid-3-yl,
- R2 is attached to a ring carbon and is selected from halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C1-6alkoxy, C1-6alkanoyl, C1-6alkanoyloxy, N-(C1-6alkyl)amino, N,N-(C1-6alkyl)2amino, C1-6alkanoylamino, N-(C1-6alkyl)carbamoyl, N,N-(C1-6alkyl)2carbamoyl, C1-6alkylS(O)a wherein a is 0, 1, or 2, C1-6alkoxycarbonyl, N-(C1-6alkyl)sulphamoyl, N,N-(C1-6alkyl)2sulphamoyl, phenyl, heterocyclic group, phenylthio and, (heterocyclic group)thio;
- wherein any C1-6alkyl, C2-6alkenyl, C2-6alkynyl, phenyl or heterocyclic group may be optionally substituted on carbon by one or more G;
- and wherein if said heterocyclic group contains an —NH— moiety that nitrogen may be optionally substituted by a group selected from Q;
- m is 0, 1, 2, 3, 4 or 5;
- wherein the values of R2 may be the same or different;
- R1 is halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C1-3alkyl, C2-3alkenyl, C2-3alkynyl, C1-3alkoxy, C1-3alkanoyl, N-(C1-3alkyl)amino, N,N-(C1-2alkyl)2amino, C1-3alkanoylamino, N-(C1-3alkyl)carbamoyl, N,N-(C1-2alkyl)2carbamoyl, C1-3alkylS(O)a wherein a is 0, 1 or 2, N-(C1-3alkyl)sulphamoyl or N,N-(C1-3alkyl)2sulphamoyl;
- wherein any C1-2alkyl, C1-3alkyl, C2-3alkenyl or C2-3alkynyl may be optionally substituted on carbon by one or more J;
- n is 0, 1 or 2, wherein the values of R1 may be the same or different;
- Ring B is phenyl or phenyl fused to a C5-7cycloalkyl ring;
- R3 is halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl or C1-6alkoxy;
- p is 0, 1 2, 3 or 4;
- wherein the values of R3 may be the same or different;
- R4 is a group A-E-;
- wherein
- A is selected from hydrogen, C1-6alkyl, phenyl, a heterocyclic group, C3-8cycloalkyl, phenylC1-6alkyl, (heterocyclic group)C1-6alkyl or C3-8cycloalkylC1-6cycloalkyl;
- which C1-6alkyl, phenyl, a heterocyclic group, C3-8cycloalkyl, phenylC1-6alkyl, (heterocyclic group)C1-6alkyl or C3-8cycloalkylC1-6cycloalkyl may be optionally substituted on carbon by one or more D;
- and wherein if said heterocyclic group contains an —NH— moiety, that nitrogen may be optionally substituted by a group selected from R;
- E is a direct bond or —O—, —C(O)—, —OC(O)—, —C(O)O—, —N(Ra)C(O)—, —C(O)N(Ra)—, —N(Ra)—, —S(O)r—, —SO2N(Ra)— or —N(Ra)SO2—;
- wherein Ra is hydrogen or C1-6alkyl optionally substituted by one or more D and r is 0, 1 or 2;
- D is independently selected from oxo, halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, C1-6alkanoyl, C1-6alkanoyloxy, N-(C1-6alkyl)amino, N,N-(C1-6alkyl)2amino, C1-6alkanoylamino, N-(C1-6alkyl)carbamoyl, N,N-(C1-6alkyl)2carbamoyl, C1 alkylS(O)a wherein a is 0 to 2, C1-6alkoxycarbonyl, C1-6alkoxycarbonylamino, benzyloxycarbonylamino, N-(C1-6alkyl)sulphamoyl and N,N-(C1-6 alkyl)2sulphamoyl;
- wherein any C1-6alkyl, C2-6alkenyl, C2-6alkynyl or phenyl may be optionally substituted on carbon by one or more K;
- q is 0, 1 or 2;
- wherein the values of R4 maybe the same or different;
- and wherein p+q≦5;
- G, J and K are independently selected from halo, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, carboxy, carbamoyl, mercapto, sulphamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, mesyl, ethylsulphonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulphamoyl, N-ethylsulphamoyl, N,N-dimethylsulphamoyl, N,N-diethylsulphamoyl and N-methyl-N-ethylsulphamoyl;
- and
- Q and R are independently selected from C1-4alkyl, C1-4alkanoyl, C1-4alkylsulphonyl, C1-4alkoxycarbonyl, carbamoyl, N-(C1-4alkyl)carbamoyl, N,N-(C1-4alkyl)carbamoyl, benzyl, benzyloxycarbonyl, benzoyl and phenylsulphonyl.
26 more elements
Dependencies are inferred from the claim text.