Carbamate/urea derivatives
AssigneeNovartis AG
InventorsYves AUBERSON, Mark Gary BOCK, Dario BRAGA, Marco CURZI, Stephanie Kay DODD, Stefano Luca GIAFFREDA, Hayang JIANG, Piotr KARPINSKI, Thomas J. TROXLER, Tie-Lin WANG, Xiaoyang WANG, Xuechun ZHANG
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Abstract
The invention relates to compound of the formula I or a salt thereof, wherein the substituents are as defined in the specification; to its preparation, to its use as medicament and to medicaments comprising it.
Claims17
A compound of the formula I
- or a salt thereof, wherein
- R1 is C1-6alkyl, C2-6alkenyl, C2-6alkinyl, C3-6cycloalkyl, C5-6cycloalkenyl or C3-6cycloalkyl-C1-4alkyl;
- wherein said C1-6alkyl, C2-6alkenyl, C2-6alkinyl or C3-6cycloalkyl-C1-4alkyl may be substituted once or more than once by halogen;
- and wherein said C3-6cycloalkyl or C5-6cycloalkenyl may be substituted once or more than once by halogen, C1-4alkyl or C1-4halogenalkyl;
- m is 1 or 2;
- n is 0, 1, 2, 3 or 4;
- each R2 independently is halogen, hydroxyl, amino, cyano, nitro, C1-6alkyl, C1-6halogenalkyl, C1-6hydroxyalkyl, C1-4alkoxy-C1-6alkyl, amino-C1-6alkyl, C1-4alkyl-amino-C1-6alkyl, di(C1-4alkyl)-amino-C1-6alkyl, C1-6alkoxy, C1-6halogenalkoxy, C1-6alkylamino, di(C1-6alkyl)amino, C2-6alkenyl, C2-6halogenalkenyl, C2-6alkinyl or C2-6halogenalkinyl;
- or C3-6cycloalkyl, wherein one carbon atom may be replaced by an oxygen atom, wherein the C3-6cycloalkyl may be attached directly to the methylene or via a C1-2alkylene, and wherein the C3-6cycloalkyl may be substituted once or more than once by halogen;
- or two R2 at the same carbon atom form together with said carbon atom a C3-6cycloalkyl;
- X1 is oxygen or —N(R4)—;
- R4 is hydrogen, C1-6alkyl, C3-6cycloalkyl, or C3-6cycloalkyl-C1-2alkyl;
- p is 1 and q is 1;
- p is 0 and q is 1;
- or
- p is 0 and q is 0;
- r is 0, 1, 2, 3 or 4;
- each R3 independently is halogen, hydroxyl, amino, cyano, nitro, C1-6alkyl, C1-6halogenalkyl, C1-6hydroxyalkyl, C1-4alkoxy-C1-6alkyl, amino-C1-6alkyl, C1-4alkyl-amino-C1-6alkyl, di(C1-4alkyl)-amino-C1-6alkyl, C1-6alkoxy, C1-6halogenalkoxy, C1-6alkylamino, di(C1-6alkyl)amino, C2-6alkenyl, C2-6halogenalkenyl, C2-6alkinyl or C2-6halogenalkinyl;
- or C3-6cycloalkyl, wherein one carbon atom may be replaced by an oxygen atom, wherein the C3-6cycloalkyl may be attached directly to the methylene or via a C1-2alkylene, and wherein the C3-6cycloalkyl may be substituted once or more than once by halogen;
- or two R3 at the same carbon atom form together with said carbon atom a C3-6cycloalkyl;
- A is
- wherein the bond marked with the asterisk is attached to the nitrogen atom;
- R5 is hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkinyl, C3-6cycloalkyl, C5-6cycloalkenyl or C3-6cycloalkyl-C1-4alkyl;
- wherein said C1-6alkyl, C2-6alkenyl, C2-6alkinyl or C3-6cycloalkyl-C1-4alkyl may be substituted once or more than once by halogen, hydroxyl or C1-6alkoxy;
- and wherein said C3-6cycloalkyl or C5-6cycloalkenyl may be substituted once or more than once by halogen, C1-4alkyl or C1-4halogenalkyl;
- X2 is nitrogen or carbon;
- s is 0, 1, 2 or 3;
- each R6 independently is halogen, hydroxyl, amino, cyano, nitro, C1-6alkyl, C1-6halogenalkyl, C1-6hydroxyalkyl, C1-4alkoxy-C1-6alkyl, amino-C1-6alkyl, C1-4alkyl-amino-C1-6alkyl, di(C1-4alkyl)-amino-C1-6alkyl, C1-6alkoxy, C1-6halogenalkoxy, C1-6alkylamino, di(C1-6alkyl)amino, C2-6alkenyl, C2-6halogenalkenyl, C2-6alkinyl or C2-6halogenalkinyl;
- or C3-6cycloalkyl, wherein one carbon atom may be replaced by an oxygen atom, wherein the C3-6cycloalkyl may be attached directly to the methylene or via a C1-2alkylene, and wherein the C3-6cycloalkyl may be substituted once or more than once by halogen.
A compound of formula II-1
- or a salt thereof;
- in which p, q, r, R3 and A are as defined under formula I;
- and Ra is a leaving group.
A free form of 1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate in solid form;
- or a salt of 1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate in solid form, wherein said salt is the citrate, hydrochloride, fumarate, adipate, maleate or sebacate of 1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate.
A method of preparing a citrate salt of 1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate in crystalline form comprising the steps of
- (a) preparing a solution of 1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate and citric acid in acetone, wherein the 1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate:citric acid ratio is about 1:2;
- (b) adding to the solution of step (a) an ether antisolvent, e.g. diethyl ether, until an acetone:ether antisolvent volume ratio from 1:1 to 1:5 is reached;
- and
- (e) isolate the solids by filtration to obtain the citrate salt of 1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate in crystalline form.
Dependencies are inferred from the claim text.