Patent EA-000380-B1 (EA)
Title: 4-aminotetrahydrobenzisoxazole or isothiazole compounds, use thereof and pharmaceutical composition on their base
Inventor: FALCH ERIK
IPC: A61K31/428
Filed: 1996-02-28
Abstract: 1. An 4-aminotetrahydrobenzisoxazole or -isothiazole compounds having general formula I:   wherein R<1> and R<2> are independently selected from the group consisting of: A) hydrogen, C1-4 cycloalkyl, phenyl, or a group   where R<7>, R<8> and R<9> are independently selected, from the group consisting of hydrogen, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 alkoxy-C1-4 alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl-C1-4 alkyl, phenyl, phenyl-C1-4 alkyl, phenoxy-C1-4 alkyl and heteroaryl selected from 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, imidazolyl, oxazolyl, pyrazolyl, pyrimidinyl, pyrrolyl, thiazolyl, 1,2,4-triazolyl, 2-pyridyl, 3-pyridyl or 4-pyridyl, any phenyl or heteroaryl group present optionally being substituted with one or two substituents selected from halogen, C1-4 alkyl, C1-4 alkoxy, hydroxy, nitro, C1-4 alkylthio, C1-4 alkylsulfonyl, C1-4 alkyl- or di(C1-4) alkylamino, cyano, trifluoromethyl, tritluoromethylthio, trifluoro-methylsulfonyloxy and phenyl which again may be substituted with halogen, methyl, methoxy or trifluoromethyl; and any alkyl group present being optionally substituted with one to three hydroxy groups which again are optionally esterified with a C2-C18 carboxylic acid; B) a group of general formula Y-(CH2)r-(CHR<11> )s-(CH2)t- wherein Y is selected from the following groups (1) - (5):   wherein U is CHR<10b>, NR<10b>, O or S, U<1> is NR<10b>. Oor S; p is 0 or 1; q is 0 or 1; V is C or N and the dotted line repressents a bond when V is C and no bond when V is N; A is O, S, CH2, (CH2)2, CH=CH-CH2, (CH2)3, CH=CH or O-CH2; R<a> and R<b> each represent one or more substituents selected from halogen, C1-4 alkyl, C1-4 alkoxy, hydroxy, nitro, C1-4 alkylthio, C1-4 alkylsulfonyl, C1-4 alkyl- or di(C1-4 alkyl)amino, cyano, trifluoromethyl, trifluoromethylsulfonyloxy and trifluoromethylthio; r and t are independently 0, 1, 2 or 3, s is 0 or 1, provided that when Y is a group (1) wherein U is NR<10b> O or S or a group (4), then r + s +t is at least 2; and when Y is a group (3) or a group (5) where V is N, then r + s +t is at least 1; R<7b>, R<8b> and R<b> are as defined for R<7>, R<8> and R<9> in A) provided that they are not at the same time selected from hydrogen, C1-4 alkyl, C2-4 alkenyl and C2-4 alkynyl; R<10b> and R<11> are independently hydrogen, C1-4 alkyl, C2-4 alkenyl or C2-4 alkynyl; and C) a group of general formula Y<c>-(CH2)n-W-(CH2)m- wherein n is 1, 2 or 3, m is 2 or 2; W is O or S; and Y<c> is a group (1) - (5) as defined in B) provided that n may not be 1, when Y is a group (1) or (4) wherein U or U<1>, respectively, is NR<10b>, S or O; D) a group of general formula   wherein k is 0, 1, 2 or 3; i is 0,1,2 or 3; R<11d> is as defined for R<11> in B) above; and Y is selected from the groups (2) and (5) as defined in B) above and the following groups (6) - (10):   wherein p, q, R<a>, R<b>, and A are as defined in B) and R<7d> - R<11d> are as defined for R<7b> - R<10b> and R<11>, respectively, under B) or R<1> and R<2> together designate alkylene thereby forming a 4-8 membered nitrogen containing ring; or one of R<1> and R<2> is a group R<2>'OCO wherein R<2>' is phenyl, or heteroaryl as defined in A) above or phenyl or such heteroaryl substituted with one or more substituents selected from halogen, C1-4 alkyl. C1-4 alkoxy, hydroxy, nitro, C1-4 alkylthio, C1-4 alkylsulfonyl, C1-4 alkyl- or di(C1-4)alkylamino, cyano, trifluoromethyl, trifluo-romethylthio, trifluoromethylsulfonyloxy, phenyl and phenyl substituted with halogen, methyl, methoxy or trifluoromethyl; R<3>-R<6> are independently selected from hydrogen, hydroxy and lower alkyl, any alkyl group optionally being substituted with one or two hydroxy groups; X is oxygen or sulfur; P is hydrogen or a group ZR wherein Z is CO, CS, SO2 or CR<t>R<u>, wherein R<t> and R<u> being hydrogen, hydroxy or C1-4 alkyl, and if Z is CO or CS, then R is selected from the groups consisting of: i) hydrogen, C1-C18 alkyl, C2-C18 alkenyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl or C4-C26 cycloalk(en)yl-alk(en)yl, optionally substituted with one or two hydroxy groups, or phenyl optionally substituted with one or more substituents selected from the group consisting of halogen, trifluoromethyl, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, C1-C5 acyloxy, or cyano;or ii) QR<v>, wherein Q is 0 or S and R<v> is selected from the substituents defined under i) above; and iii) NR<x>R<y>, wherein R<x> and R<y> independently are selected from the substituents under i) above or R<x> and R<y> are combined to form a four to eight membered heterocyclic ring containing from one to three nitrogen atoms and from zero to three oxygen or sulfur atoms; or if Z is CR<t>R<u>, R is selected from the groups consisting of: iv) a group QR<v> as defined in ii); v) a group NR<x> R<y> as defined in iii); or vi) a group OC(O)R<z>, SC(0)R<z>, OC(S)R<z> or SC(S)R<z> wherein R<z> is selected from the substituents defined for R under i) above; if Z is SO2, R is selected from group i) defined above; provided that P may not be hydrogen, when R<1> to R<6> are all hydrogen, X is oxygen and the compound exists as a racemic mixture; or a pharmaceutically acceptable salts thereof. 2. A compound of Claim 1, characterised in that X is oxygen. 3. A compound of Claim 2, characterised in that R<1> is C1-4 alk(en/yn)yl optionally substituted with hydroxy which may be esterified with a C2-C22 carboxylic acid, or phenyl or phenyl- C1-4 alkyl, optionally substituted with halogen, C1-4 alkyl, C1-4 alkoxy or trifluoromethyl, R<1> being preferably methyl, ethyl or phenylbutyl. 4. A compound of Claim 3 or 4, characterized in that P is not hydrogen, P preferably being a group ZR as defined in Claim 1, wherein Z is CH2 and R is a group OC(O)R<z>. as defined in vi) in Claim 1. 5. A compound of Claim 4, characterized in that it is a compound of formula Ia. 6. A compound of Claim 2, characterized in that R<1> is a group as defined under B), C) or D). 7. A compound of Claim 8, characterized in that R<1> is a group as defined in B) wherein Y is a group of formula (1), (2) or (3) wherein R<7b> and R<8b> are phenyl, heteroaryl or substituted phenyl or heteroaryl, as defined in Claim 1 for R<7> and R<8> preferably a group of formula (1) or (2) wherein U is CH2 or O 8. A compound of Claim 8, characterized in that R<1> is a group as defined in B) wherein Y is a group of formula (4), (5) 9. A compound of Claim 6, characterized in that R<1> is a group as defined in C), preferably such a group wherein Y<c> is a group of formula (1) where U is CH2, or a group of formula (2) in which formulas R<7b> and R<8b> are phenyl, heteroaryl or substituted phenyl or heteroaryl as defined in Claim 1 for R<7> and R. 10. A compound of Claim 6, characterized in that R<1> is a group as defined in D) wherein Y<d> is a group of formula (2), (5),(6), (7), (8), (9) or (10). 11. A compound of any of Claims 2-10, characterized in that R<2> is hydrogen, C1-4 alkyl or a group R<2>'-O-CO- wherein R<2>' is as defined in Claim 1. 12. A compound of any of Claims 6-11, characterized In that P is hydrogen. 13. A pharmaceutical composition comprising at least one novel 4-amino-tetrahydro-benzisoxazoles or -isothiazole of any of Claims 1 -12 in a therapeutically effective amount together with a phamnaceutically acceptable carrier and or diluent. 14. Use of a 4-aminotetrahydrobenzisoxazole or -isothiazole of any of Claims 1-27 for the manufacture of a pharmaceutical preparation for the treatment of analgesia, psychosis, convulsions, epilepsy, anxiety, muscular and movement disorders, spastic disorders or symptoms of Huntington's or Parkinsons disease, preferably convulsions.