4-Aminoquinazolin compounds as prolyl hydroxylase inhibitors
AssigneeJanssen Pharmaceutica NV
InventorsMichael H. Rabinowitz, Mark D. Rosen, Kyle T. Tarantino, Hariharan Venkatesan
Life of this patent
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Abstract
Aminoquinazolinyl compounds of formula (I) are described, which are useful as prolyl hydroxylase inhibitors. Such compounds may be used in pharmaceutical compositions and methods for the treatment of disease states, disorders, and conditions mediated by prolyl hydroxylase activity. Thus, the compounds may be administered to treat, e.g., anemia, vascular disorders, metabolic disorders, and wound healing.
Claims22
A compound of the formula (I):
- wherein:
- n is 1 or 2;
- each R1 is a member independently selected from the group consisting of bromo, fluoro, cyclohexyl, cyclohexyloxy, phenyl, 2-methylphenyl, benzyl, phenoxy, 4-chlorophenoxy, 2,6-dimethyl-phenoxy, piperidinyl, and (2,6-dimethylbenzyl)amino;
- R2 is a member selected from the group consisting of —H, cyclopropyl, 2,6-dimethylbenzyl, and —C1-4alkyl;
- R3 is a member selected from the group consisting of —H, —C1-4alkyl optionally substituted with —OCH3 or —N(C1-4alkyl)2, cyano, —SO2CH3, tetrahydropyran, —(CH2)mC3-8cycloalkyl, and —(CH2)mphenyl optionally substituted with one or more halo;
- or —C1-4alkyl;
- wherein
- m is 0-1;
- or
- R2 and R3 can be taken together with the nitrogen to which they are attached to form a pyrrolidine, piperidine, 4-methyl-1,4-diazepane, thiomorpholine, 4-hydroxypiperidine, morpholine, 4-acetamidopiperidine, 4-cyanopiperidine, 4-fluoropiperidine, azepane, or 4-isopropylpiperidine;
- or an enantiomer, diastereomer, racemate, or a pharmaceutically acceptable salt thereof.
A pharmaceutical composition comprising a pharmaceutically acceptable excipient
- and an effective amount of the compound of formula (I):
- wherein:
- n is 1 or 2;
- each R1 is a member independently selected from the group consisting of bromo, fluoro, cyclohexyl, cyclohexyloxy, phenyl, 2-methylphenyl, benzyl, phenoxy, 4-chlorophenoxy, 2,6-dimethyl-phenoxy, piperidinyl, and (2,6-dimethylbenzyl)amino;
- R2 is a member selected from the group consisting of —H, cyclopropyl, 2,6-dimethylbenzyl, and —C1-4alkyl;
- R3 is a member selected from the group consisting of —H, —C1-4alkyl optionally substituted with —OCH3 or —N(C1-4alkyl)2, cyano, —SO2CH3, tetrahydropyran, —(CH2)mC3-8cycloalkyl, and —(CH2)mphenyl optionally substituted with one or more halo, or —C1-4alkyl;
- wherein
- m is 0-1;
- R2 and R3 can be taken together with the nitrogen to which they are attached to form a pyrrolidine, piperidine, 4-methyl-1,4-diazepane, thiomorpholine, 4-hydroxypiperidine, morpholine, 4-acetamidopiperidine, 4-cyanopiperidine, 4-fluoropiperidine, azepane, or 4-isopropylpiperidine;
- or an enantiomer, diastereomer, racemate, or a pharmaceutically acceptable salt thereof.
A method for the treatment of any one of the conditions selected from the group consisting of anemia, hypoxia, ischemia, peripheral vascular disease, myocardial infarction, stroke, diabetes, obesity, inflammatory bowel disease, ulcerative colitis, Crohn's disease, wounds, infection, burns and bone fracture comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I):
- wherein:
- n is 1 or 2;
- each R1 is a member independently selected from the group consisting of bromo, fluoro, cyclohexyl, cyclohexyloxy, phenyl, 2-methylphenyl, benzyl, phenoxy, 4-chlorophenoxy, 2,6-dimethyl-phenoxy, piperidinyl, and (2,6-dimethylbenzyl)amino;
- R2 is a member selected from the group consisting of -H, cyclopropyl, 2,6-dimethylbenzyl, and -C1-4alkyl;
- R3 is a member selected from the group consisting of -H, -C1-4alkyl optionally substituted with -OCH3 or -N(C1-4alkyl)2, cyano, -SO2CH3, tetrahydropyran, -(CH2)mC3-8cycloalkyl, and -(CH2)mphenyl optionally substituted with one or more halo, or -C1-4alkyl;
- wherein m is 0-1;
- or R2 and R3 can be taken together with the nitrogen to which they are attached to form a pyrrolidine, piperidine, 4-methyl-1,4-diazepane, thiomorpholine, 4-hydroxypeperidine, morpholine, 4-acetamidopoperidine, 4-cyanopiperidine, 4-fluoropiperidine, azepane, or 4-isopropylpiperidine;
- or an enantiomer, diastereomer, racemate, or pharmaceutically acceptable salt thereof.
A method for treating a hypoxic disorder comprising administering to a patient in need thereof a therepeutically effective amount of a compound of formula (I):
- wherein
- n is 1 or 2;
- each R1 is a member independently selected from the group consisting of bromo, fluoro, cyclohexyl, cyclohexyloxy, phenyl, 2-methylphenyl, benzyl, phenoxy, 4-chlorophenoxy, 2,6-dimethyl-phenoxy, piperidinyl, and (2,6-dimethylbenzyl)amino;
- R2 is a member selected from the group consisting of -H, cyclopropyl, 2,6-dimethylbenzyl, and -C1-4alkyl;
- R3 is a member selected from the group consisting of -H, -C1-4alkyl optionally substituted with -OCH3 or -N(C1-4alkyl)2, cyano, -SO2CH3, tetrahydropyranm -(CH2)mC3-8cycloalkyl, and -(CH2)mphenyl optionally substituted with one or more halo, or -C1-4alkyl;
- wherein
- m is 0-1;
- or
- R2 and R3 can be taken together with the nitrogen to which they are attached to form a pyrrolidine, piperidine, 4-methyl-1, 4-diazepane, thiomorpholine, 4-hydroxypiperidine, morpholine, 4-acetamidopiperidine, 4-cyanopiperidine, 4-fluoropiperidine, azepane, or 4-isopropylpiperidine;
- or -enantiomer, diasteromer, racemate, or pharmaceutically acceptable salt thereof.
Dependencies are inferred from the claim text.