Patent ID: 6051578
Filing Date: 2000-04-18
Classification: A61K

Abstract:
A method of treating, preventing or inhibiting a disorder selected from head trauma, spinal cord trauma, muscular spasms, urinary incontinence, multiinfarct dementia, and hypoglycemia in a mammal, comprising administering to said mammal in need thereof an amount of a compound of the formula ##STR12## wherein X is nitrogen or --CR.sup.6 ;A is --NR.sup.1 R.sup.2, --CR.sup.1 R.sup.2 R.sup.11, --C(.dbd.CR.sup.2 R.sup.12)R.sup.1, --NHCR.sup.1 R.sup.2 R.sup.11, --OCR.sup.1 R.sup.2 R.sup.11, --SCR.sup.1 R.sup.2 R.sup.11, --NHNR.sup.1 R.sup.2, --CR.sup.2 R.sup.11 NHR.sup.1, --CR.sup.2 R.sup.11 OR.sup.1, --CR.sup.2 R.sup.11 SR.sup.1, or --C(O)R.sup.2 ;R.sup.1 is hydrogen, or C.sub.1 -C.sub.6 alkyl which may optionally be substituted with from one to two substituents independently selected from the group consisting of hydroxy, fluoro, chloro, bromo, iodo, C.sub.1 -C.sub.8 alkoxy, --O--(C.sub.1 -C.sub.6 alkyl), --O--NH(C.sub.1 -C.sub.4 alkyl), --O--N(C.sub.1 -C.sub.4 alkyl)(C.sub.1 -C.sub.2 alkyl), amino, --NH(C.sub.1 -C.sub.4 alkyl), --N(C.sub.1 -C.sub.2 alkyl)(C.sub.1 -C.sub.4 alkyl), --S(C.sub.1 -C.sub.6 alkyl), --N(C.sub.1 -C.sub.4 alkyl)(C.sub.1 -C.sub.4 alkyl), --NH(C.sub.1 -C.sub.4 alkyl), --COOH, --O(C.sub.1 -C.sub.4 alkyl), --NH(C.sub.1 -C.sub.4 alkyl), --N(C.sub.1 -C.sub.4 alkyl)(C.sub.1 -C.sub.2 alkyl), --SH, --CN, --NO.sub.2, --SO(C.sub.1 -C.sub.4 alkyl), --SO.sub.2 (C.sub.1 -C.sub.4 alkyl), --SO.sub.2 NH(C.sub.1 -C.sub.4 alkyl), --SO.sub.2 (C.sub.1 -C.sub.4 alkyl)(C.sub.1 -C.sub.2 alkyl), and wherein each of the foregoing C.sub.1 -C.sub.6 alkyl moieties in the definition of R.sup.1 may contain one or two double or triple bonds;R.sup.2 is C.sub.1 -C.sub.12 alkyl, aryl or --(C.sub.1 -C.sub.10 alkylene)aryl wherein said aryl is phenyl, naphthyl, thienyl, benzothienyl, pyridyl, quinolyl, pyrazinyl, pyrimidyl, imidazolyl, furanyl, benzofuranyl, benzothiazolyl, isothiazolyl, benzisothiazolyl, thiazolyl, isoxazolyl, benzisoxazolyl, benzimidazolyl, triazolyl, pyrazolyl, pyrrolyl, indolyl, pyrrolopyridyl, oxazolyl, or benzoxazolyl; 3- to 8-membered cycloalkyl or --(C.sub.1 -C.sub.6 alkylene) cycloalkyl, wherein one or two of the carbon atoms of any of said cycloalkyl moieties may optionally be replaced, independently, by O, S or N-Z wherein Z is hydrogen, C.sub.1 -C.sub.4 alkyl or C.sub.1 -C.sub.4 alkanoyl, and wherein R.sup.2 may optionally be substituted with from one to three substituents independently selected from chloro, fluoro and C.sub.1 -C.sub.4 alkyl, or by one substituent selected from hydroxy, bromo, iodo, C.sub.1 -C.sub.6 alkoxy, --O--(C.sub.1 -C.sub.6 alkyl), --O--N(C.sub.1 -C.sub.4 alkyl)(C.sub.1 -C.sub.2 alkyl), --S(C.sub.1 -C.sub.6 alkyl), --NH.sub.2, --NH(C.sub.1 -C.sub.2 alkyl), --N(C.sub.1 -C.sub.2 alkyl) (C.sub.1 -C.sub.4 alkyl), --N(C.sub.1 -C.sub.4 alkyl)-(C.sub.1 -C.sub.4 alkyl), --NH(C.sub.1 -C.sub.4 alkyl), --COOH, --O(C.sub.1 -C.sub.4 alkyl), --NH(C.sub.1 -C.sub.4 alkyl), --N(C.sub.1 -C.sub.4 alkyl)(C.sub.1 -C.sub.2 alkyl), --SH, --CN, --NO.sub.2, --SO(C.sub.1 -C.sub.4 alkyl), --SO.sub.2 (C.sub.1 -C.sub.4 alkyl), --SO.sub.2 NH(C.sub.1 -C.sub.4 alkyl), and --SO.sub.2 N(C.sub.1 -C.sub.4 alkyl)(C.sub.1 -C.sub.2 alkyl), and wherein each of the foregoing C.sub.1 -C.sub.12 alkyl and C.sub.1 -C.sub.10 alkylene moieties in the definition may optionally contain one to three double or triple bonds; or R.sup.1 and R.sup.2, taken together with the atom to which they are attached, may form a saturated 3- to 8-membered ring which, if it is a 5- to 8-membered ring, may optionally contain one to two double bonds, and wherein one or two of the carbon atoms of said 5- to 8- membered ring may optionally be replaced, independently, by O, S or N-Z wherein Z is hydrogen, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkanoyl or benzyl;R.sup.3 is hydrogen, C.sub.1 -C.sub.6 alkyl, fluoro, chloro, bromo, iodo, hydroxy, amino, --O(C.sub.1 -C.sub.6 alkyl), --NH(C.sub.1 -C.sub.6 alkyl), --N(C.sub.1 -C.sub.4 alkyl)(C.sub.1 -C.sub.2 alkyl), --SH, --S(C.sub.1 -C.sub.4 alkyl), --SO(C.sub.1 -C.sub.4 alkyl), or --SO.sub.2 (C.sub.1 -C.sub.4 alkyl), wherein each of the foregoing C.sub.1 -C.sub.4 alkyl and C.sub.1 -C.sub.6 alkyl moieties in the definition of R.sup.3 may contain one double or triple bond and may optionally be substituted with from 1 to 3 substituents independently selected from the group consisting of hydroxy, C.sub.1 -C.sub.3 alkoxy, fluoro, chloro and C.sub.1 -C.sub.3 thioalkyl;R.sup.4 is hydrogen, C.sub.1 -C.sub.6 alkyl, fluoro, chloro, bromo, iodo, C.sub.1 -C.sub.6 alkoxy, formyl, --NH(C.sub.1 -C.sub.6 alkyl), --N(C.sub.1 -C.sub.6 alkyl)(C.sub.1 -C.sub.2 alkyl), --SO.sub.n (C.sub.1 -C.sub.6 alkyl), wherein n is 0, 1 or 2, cyano, hydroxy, carboxy, or amido, wherein each of the foregoing C.sub.1 -C.sub.6 alkyl moieties in the definition of R.sup.4 may optionally be substituted with one substituent selected from hydroxy, trifluoromethyl, amino, carboxy, amido, --NH(C.sub.1 -C.sub.4 alkyl), --NH(C.sub.1 -C.sub.4 alkyl), --N(C.sub.1 -C.sub.4 alkyl)(C.sub.1 -C.sub.2 alkyl), --O(C.sub.1 -C.sub.4 alkyl), C.sub.1 -C.sub.3 alkoxy, C.sub.1 -C.sub.3 thioalkyl, fluoro, bromo, chloro, iodo, cyano and nitro;R.sup.5 is phenyl, naphthyl, thienyl, benzothienyl, pyridyl, quinolyl, pyrazinyl, pyrimidyl, imidazolyl, furanyl, benzofuranyl, benzothiazolyl, isothiazolyl, benzoisothiazolyl, thiazolyl, isoxazolyl, benzisoxazolyl, benzimidazolyl, triazolyl, pyrazolyl, pyrrolyl, indolyl, pyrrolopyridyl, benzoxazolyl, oxazolyl, pyrrolidinyl, thiazolindinyl, morpholinyl, piperidinyl, piperazinyl, tetrazolyl, or a 3- or 8-membered cycloalkyl or 9- or 12-membered bicycloalkyl ring, wherein one or two of the carbon atoms in said ring may optionally be replaced, independently, by O, S or N-Z wherein Z is hydrogen, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkanoyl, phenyl or benzyl, and wherein each of the above R.sup.5 groups may optionally be substituted with one or more substituents, preferably with two or three substituents, independently selected from fluoro, chloro, bromo, formyl, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy and trifluoromethyl, or with one substituent selected from hydroxy, iodo, cyano, nitro, amino, --NH(C.sub.1 -C.sub.4 alkyl), --N(C.sub.1 -C.sub.4 alkyl)(C.sub.1 -C.sub.2 alkyl), --COO(C.sub.1 -C.sub.4 alkyl), --CO(C.sub.1 -C.sub.4 alkyl), --SO.sub.2 NH(C.sub.1 -C.sub.4 alkyl), --SO.sub.2 N(C.sub.1 -C.sub.4 alkyl)(C.sub.1 -C.sub.2 alkyl), --SO.sub.2 NH.sub.2, --NHSO.sub.2 (C.sub.1 -C.sub.4 alkyl), --S(C.sub.1 -C.sub.6 alkyl), --SO.sub.2 (C.sub.1 -C.sub.6 alkyl), and wherein each of the foregoing C.sub.1 -C.sub.4 alkyl and C.sub.1 -C.sub.6 alkyl moieties in the definition of R.sup.5 may optionally be substituted with from one to two substituents independently selected from fluoro, chloro, hydroxy, C.sub.1 -C.sub.4 alkoxy, amino, methylamino, dimethylamino and acetyl, and wherein each of the foregoing C.sub.1 -C.sub.4 alkyl and C.sub.1 -C.sub.6 alkyl moieties in the definition of R.sup.5 may optionally contain one double or triple bond; with the proviso that R.sup.5 is not unsubstituted phenyl;R.sup.6 is hydrogen, C.sub.1 -C.sub.6 alkyl, fluoro, chloro, bromo, iodo, C.sub.1 -C.sub.6 alkoxy, formyl, amino, --NH(C.sub.1 -C.sub.6 alkyl), N(C.sub.1 -C.sub.6 alkyl)(C.sub.1 -C.sub.2 alkyl), --SO.sub.n (C.sub.1 -C.sub.6 alkyl), wherein n is 0, 1 or 2, cyano, carboxy, or amido, and wherein each of the foregoing (C.sub.1 -C.sub.6)alkyl moieties in the definition of R.sup.6 may be optionally substituted with one substituent selected from hydroxy, trifluoromethyl, amino, carboxy, amido, --NH(C.sub.1 -C.sub.4 alkyl), --NH(C.sub.1 -C.sub.4 alkyl), --N(C.sub.1 -C.sub.4 alkyl)(C.sub.1 -C.sub.2 alkyl), --O(C.sub.1 -C.sub.4 alkyl), C.sub.1 -C.sub.3 alkoxy, C.sub.1 -C.sub.3 thioalkyl, fluoro, bromo, chloro, iodo, cyano and nitro;R.sup.11 is hydrogen, hydroxy, fluoro, chloro, --COO(C.sub.1 -C.sub.2 alkyl), cyano, or --CO(C.sub.1 -C.sub.2 alkyl); andR.sup.12 is hydrogen or C.sub.1 -C.sub.4 alkyl;with the proviso that:(1) when X is --CR.sup.6, A is not straight chain alkyl;(2) when X is CR.sup.6 and R.sup.5 is unsubstituted cycloalkyl and R.sup.3 and R.sup.4 are both hydrogen and R.sup.6 is hydrogen or methyl, then A is not NHR.sup.2 wherein R.sup.2 is benzyl or thienylmethyl, and(3) when X is --CR.sup.6 and R.sup.5 is p-bromophenyl and R.sup.3, R.sup.4 and R.sup.6 are methyl, then A is not methylamino or hydroxyethylamino;and when X is nitrogen, with the further proviso that:(a) A is not straight chain C.sub.1 -C.sub.12 alkyl;(b) R.sup.5 is not a sugar group;(c) when R.sup.3 and R.sup.4 are hydrogen and R.sup.5 is chlorophenyl, then A is not --NH--CH(CH.sub.3)--(CH.sub.2).sub.3 --(C.sub.2 H.sub.5).sub.2 ;(d) when R.sup.3 and R.sup.4 are hydrogen and A is --NR.sup.1 R.sup.2 wherein R.sup.1 is C.sub.3 -C.sub.7 cycloalkyl, and R.sup.2 is C.sub.2 -C.sub.6 alkenyl, phenyl-(C.sub.1 -C.sub.6 alkylene) or hetero-(C.sub.1 -C.sub.6 alkylene) wherein the hetero radical is furyl, thienyl or pyridinyl, and wherein said phenyl may be substituted by fluoro, chloro, bromo and iodo, then R.sup.5 is not tetrahydrofuranyl or tetrahydropyranyl;(e) when R.sup.3 is methoxy, methylthio, or methylsulfonyl, R.sup.4 is hydrogen, and R.sup.5 is tetrahydrofuranyl or tetrahydropyranyl, then A is not --NH(C.sub.1 -C.sub.2 alkyl), morpholinyl, hydrazino, or --NHC.sub.2 H.sub.4 C.sub.6 H.sub.5, the phenyl of which may be substituted by one methyl or two methoxy groups;(f) when R.sup.3 is hydrogen, C.sub.1 -C.sub.6 alkyl, chloro, bromo, --SH, or --S--(C.sub.1 -C.sub.4 alkyl), R.sup.4 is hydrogen and R.sup.5 is C.sub.3 -C.sub.8 cycloalkyl, then A is not hydrazino, --NH(C.sub.1 -C.sub.2 alkyl) or --N(C.sub.1 -C.sub.6 alkyl) (C.sub.1 -C.sub.12 alkyl);(g) when R.sup.3 and R.sup.4 are hydrogen and A is --NH(CH.sub.2).sub.m COOH wherein m is 1-12, then R.sup.5 is not phenyl substituted by one fluoro, chloro, bromo or iodo group;(h) when R.sup.3 is hydrogen, hydroxy, methylthio, chloro or --NHbenzyl, R.sup.4 is hydrogen, and R.sup.5 is chlorophenyl or bromophenyl, then A is not --NH(C.sub.1 -C.sub.12 alkyl), --NHallyl, or --N(C.sub.1 -C.sub.6 alkyl) (C.sub.1 -C.sub.12 alkyl), wherein said C.sub.1 -C.sub.12 alkyl may be substituted by --NC.sub.2 H.sub.5, or --NH benzyl which may be substituted by one or two bromo, chloro, fluoro, --NC.sub.2 H.sub.5 phenyl or morpholinopropyl groups;(i) when R.sup.3 and R.sup.4 are hydrogen and R.sup.5 is nitrophenyl, then A is not --NHR.sup.2 wherein R.sup.2 is phenyl, benzyl or C.sub.1 -C.sub.12 alkyl which may be substituted by one or two hydroxy groups;(j) when R.sup.3 is chloro or --O(C.sub.1 -C.sub.6 alkyl), R.sup.4 is hydrogen, and A is --NR.sup.1 R.sup.2 wherein R.sup.1 and R.sup.2 are independently hydrogen or C.sub.1 -C.sub.6 alkyl, then R.sup.5 is not chlorophenyl; and(k) when R.sup.3 is hydrogen, A is benzyl or phenethyl, and R.sup.4 is fluoro, chloro, bromo or iodo, then R.sup.5 is not 5'-deoxy-ribofuranosyl or 5'-amino-5'-deoxy-ribofuranosyl; or a pharmaceutically acceptable salt thereof, that is effecting in treating or preventing such disorder,wherein said compound does not substantially inhibit adenosine kinase.