Patent DE-4325254-A1 (DE)
Title: New asymmetrically substd. xanthine derivs. - useful as adenosine antagonist(s), cholinomimetic(s) and diuretic(s), in treatment of Parkinsonism, depression, dyslexia, cystic fibrosis, etc.
Inventor: KUEFNER-MUEHL ULRIKE DR
IPC: C07D473/06
Filed: 1993-07-28
Abstract: A symmetrically substd. xanthine deriv. of formula (I) (including racemates, enantiomers, diastereomers and mixts.) and their salts are new. R1 , R2 are different; R1 = H, 1-6C alkyl, allyl, 3-6C alkenyl or 3-6C alkynyl; R2 = (i) H; (ii) a 1-8C alkyl, 2-8C alkenyl or 2-8C alkynyl gp. substd. by CN, CH2NR6R7, OH (where multiple substitution is possible), OR8, NR6R7, NHCOR8, NHCONR6R7, halogen, OCOR8, OCH2COOH, OCH2COOR8, SO2R5, SR5, NHCONHPh, OCH2CONR6R7, OCH2CH2OH, SO2CH2CH2OCOR8, OCH2CH2NR6R7, SO2CH2CH2CONHSO2R8, CH2CONHSO2R8, OCH2CH2OR8, COOH, COOR8, CONR6R7, CHO, SR8, SOR8, SO2R8, SO3H, SO2NR6R7, OCH2CH2OCOR8, CH=NOH, CH=NOR8, COR9, CH(OH)R9, CH(OR8)2, CH=CHR10, OCONR6R7, -CH=N-NHR11, etc.. R3 = (ii) 3-7C cycloalkyl (pref. cyclopentyl) opt. substd. by O, OH, OR9 or OCOR8; (ii) phenyl opt. substd. by OH, halogen, OR8, 1-4C alkyl (pref. Me), NH2, COOH, SO3H, COOR8, OCH2COOR8, CN or OCH2CONR6R7; (iii) norbornane, norbornene, 3-6C dicycloalkylmethyl, etc.. R4 = H, Me, benzyl (opt. substd. by 1-3 OMe gps.), MeOCH2, MeSCH2, PhCH2OCH2, pivaloyloxymethyl or CH2CH=CH2; R5 = 1-4C alkyl (opt. substd. by OH, OCOR8, NH2, NR6R7 or NHCOR8), pref. CH2CH2OH, CH2CH2OCOR8, CH2CH2CH2OH or CH2CH2CH2OCOR8; R6, R7 = H, opt. substd. 3-6C cycloalkyl; 1-10C alkyl, 2-10C alkenyl, etc.. OR NR6R7 = opt. unsatd. 5- or 6-membered heterocycle, opt. contg. an O, N or S hetero atom, and opt. monosubstd. by 1-4C alkyl, -(CH2)n-NH2, O, ketol gp., -(CH2)n-NH-(1-4C alkyl), etc.. n = 2-4; R8 = H, 1-4C alkyl, 2-4C alkenyl, 2-4C alkynyl or phenyl or benzyl (both opt. substd. by OMe); R9 = 1-4C alkyl, 2-4C alkenyl, 2-4C alkynyl, opt. substd. phenyl, opt. substd. benzyl or 3-6C cycloalkyl; R10 = COOR8, CH2OR8, CONR6R7, H, 1-3C alkyl, opt. substd. phenyl or CH2NR6R7; R11 = H, opt. substd. phenyl or OMe. USE/ADVANTAGE - (I) are adenosine antagonists (claimed). They have high adenosine-A, receptor affinity and are useful as cholinomimetic, esp. for treating degenerative CNS diseases such as senile dementia or Alzheimer's disease. As well as this use as geronto-psychopharmaceuticals and nootropics, (I) can be used for treatment of cardiovascular disorders or respiratory tract disorders (esp. bronchial asthma) or as diuretics (e.g. for treating renal disorders and hypertension). (I) may also be used for treatment of organic brain syndrome, parkinsonism, depression, traumatic CNS damage, post-stroke neurological deficiency, respiratory depression (post-operative or due to intoxication, cerebral trauma in premature babies, dyslexia, hyperactivity and cystic fibrosis (mucoviscidosis). (I) may be used by inhalation for treatment of pulmonary disorders e.g. asthma and other allergic or chronic obstructive lung disorders. They are esp. used for treatment of degenerative geriatric disorders in combination with cholinomimetic agents such as 3-(2-propynyloxy)-1-azabicyclo (2.2.2) octane (Wal 801). (I) have high receptor affinity, allowing therapeutic use at low doses which do not cause side-effects. Daily dose for adults is 1-80 (pref. 10-300) mg, orally or parenterally.