Pharmaceutical for treatment of neurological and neuropsychiatric disorders

Pharmaceutical for treatment of neurological and neuropsychiatric disorders

  • CN 1,327,383 A
  • Filed: 05/29/1997
  • Published: 12/19/2001
  • Est. Priority Date: 05/31/1996
  • Status: Abandoned Application
First Claim
Patent Images

1. following formula divides chemical compound or its pharmaceutically acceptable salt:

  • Wherein;

    (1) X is nitrogen or carbon, R when X is nitrogen 2Do not exist;

    (2) R 2(a) be hydrogen, (C1-C6) alkyl, (C1-C6) alkoxyl, cyano group, (C2-C7) alkanoyl, amino carbonyl, (C1-C6) alkyl amino-carbonyl or wherein each alkyl arrive the dialkyl amino carbonyl of C6 respectively independently for C1, (b) comprise (R wherein 1Be not amino ethylidene ,-O-R 8Or-S-R 8*) hydroxyl, fluorine, chlorine, bromine or (C2-C7) alkanoyloxy, (c) with adjacent from R 1, R XbOr R YbOne of carbon or nitrogen forms two keys or (d) for by R 2bBe connected to the R on the X 2a(2 i) R xBe R XbBe connected to the R on the X Xa(2 Ii) R yBe R YbBe connected to the R on the X Ya(2 Iii) R Xa, R YaAnd R 2aBe selected from the heteroatomic 5-7 of 0-2 of comprising oxygen, sulfur and nitrogen unit non-aromatic ring for aryl, heteroaryl, adamantyl or have independently.Wherein;

    (a) aryl is a phenyl or naphthyl,(b) heteroaryl comprise five-membered ring, hexatomic ring, with the condensed hexatomic ring of five-membered ring, with the condensed five-membered ring of hexatomic ring or with the condensed hexatomic ring of hexatomic ring, wherein said heteroaryl for fragrance and contain and be selected from the hetero atom that comprises oxygen, sulfur and nitrogen, and remaining annular atoms is a carbon(c) R Xa, R YaAnd R 2aEach can be R independently q, R rO-or R sOne of them replaces S-, wherein R q, R rAnd R sIn each be aryl, heteroaryl, adamantyl or 5-7 unit non-aromatic ring independently, the structure of above-mentioned ring such as R XaDefine and (d) R Xa, R Ya, R 2a, R q, R rAnd R sCan be replaced by being selected from following one or more substituent groups in addition;

    fluorine;

    chlorine;

    bromine;

    nitro;

    hydroxyl;

    cyano group;

    trifluoromethyl;

    has the independently amino-sulfonyl of (C1-C6) N-alkyl substituent of two of as many as;

    adamantyl;

    (C1-C12) alkyl;

    (C1-C12) alkenyl;

    amino;

    (C1-C6) alkyl amino;

    wherein each alkyl is the dialkyl amido of C1-C6 independently;

    (C1-C6) alkoxyl;

    (C2-C7) alkanoyl;

    (C2-C7) alkanoyl oxygen base;

    trifluoromethoxy;

    hydroxycarbonyl group;

    (C2-C7) alkoxy carbonyl;

    two of available as many as independently (C1-C6) alkyl replace the amino carbonyl of hydrogen;

    (C1-C6) alkyl sulphonyl;

    the amidino groups that independently replaces with three (C1-C6) alkyl of as many as;

    or with the methylene-dioxy or the ethylenedioxy of adjacent position bonding on two oxygen and described aromatic ring or the hetero-aromatic ring structure;

    this methylene-dioxy or ethylenedioxy can be used two independently (C1-C6) alkyl replacements of as many as, wherein;

    (i) R Xa, R YaAnd R 2aReplacement can be at R Xa, R YaAnd R 2aTwo between in conjunction with forming second bridge joint, comprise (1) (C1-C2) alkyl or alkenyl, its available one or more (C1-C6) alkyl replaces independently, (2) sulfur, (3) oxygen, (4) amino, its available (C1-C6) alkyl replaces hydrogen, (5) carbonyl, (6)-CH 2C (=O)-, two of its available as many as independently (C1-C6) alkyl replace hydrogen, (7)-C (=O)-and O-, (8)-CH 2-O-, two of its available as many as independently (C1-C6) alkyl replace hydrogen, (9)-C (=O) N (R 24), R wherein 24Be hydrogen or (C1-C6) alkyl, (10)-CH 2-NH-, three (C1-C6) alkyl of its available as many as replace hydrogen, or (11)-CH=N-, and its available (C1-C6) alkyl replaces hydrogen, or R wherein Xa, R YaAnd R 2aIn two directly connect with singly-bound;

    (2 Iv) R XbAnd R 2bBe singly-bound or (C1-C2) alkylidene independently;

    (2 v) R YbFor singly-bound, oxa-, (C1-C2) alkylidene, ethylidene or-CH=(wherein said pair of key is connected with X), thia, inferior methoxyl group or methylene sulfenyl or-N (R 6) or-CH 2-N (R 6*)-, be R wherein 6And R 6*Be hydrogen or (C1-C6) alkyl, wherein when X was nitrogen, X did not link to each other with other hetero atom;

    (3) R 1Comprise;

    straight chain (C2-C3) aliphatic group;

    When X is carbon, for=N-O-(ethylidene), wherein the two keys of pairing are not connected with X;

    (when X is a carbon, R YbWhen not comprising with hetero atom that X is connected), R wherein 8Or R 8*For ethylidene or ethenylidene-O-R 8Or-S-R 8*And O or S are connected with X;

    (when X is a carbon, R YbWhen not comprising with hetero atom that X is connected), the amino ethylidene that wherein said amino is connected with X;

    R wherein 1Can by hydroxyl at the most, at the most (C1-C6) alkoxyl or at the most (C2-C7) alkanoyloxy, to too many by two independently (C1-C6) alkyl, at the most oxo base, (C1-C6) alkylidene replaces at the most, prerequisite is that described hydroxyl, alkoxyl, alkanoyloxy or oxo substituent group do not link to each other with the carbon that links to each other with nitrogen or oxygen;

    R wherein 1Alkyl or alkylidene substituent group can be connected to form 3-7 unit non-aromatic ring;

    With If wherein X is a nitrogen, X is with singly-bound and R 1Be connected, connect R 1R with nitrogen 1End group carbon be saturated;

    (4) R 3(a) be that phenylalkyl and this phenyl of C1-C6 can be used above-mentioned R for hydrogen, (C1-C6) alkyl or phenyl or wherein said alkyl XaAryl or the defined identical substituent group of heteroaryl replace.(b) be-R 12Z (R Xx) (R Yy) (R 11), R wherein 12Combine with N, Z is identical with X independently, R XxIndependently with R xIdentical, R YyIndependently with R yIdentical, R 11Independently with R 2Identical, R 12Independently with R 1Identical, or (c) and R 4The following C ring of common formation;

    Wherein when C ring exists, R 4*Be hydrogen;

    (5) n is 0 or 1, and when n is 1, R 3*Be (C1-C6) alkyl (it is positively charged to be attached thereto the nitrogen that connects) or oxygen (forming the N-oxide), X is a carbon;

    Nitrogen and have a R on (5 '"'"') Q and the described ring 5Ring on carbon form C ring jointly, wherein C encircles to 3-8 unit ring, encircles the first ring of condensed 3-8 by the 3-8 unit ring of the first volution replacement of 3-6 or with 5-6 unit, the fused rings that wherein lacks nitrogen on the described ring can be aromatic ring or hetero-aromatic ring, wherein for the makeup ring of each C ring, have two hetero atoms of as many as that are selected from oxygen, sulfur or nitrogen, comprise described nitrogen and all the other carbon, its prerequisite is that ring atom comprises described nitrogen quaternary nitrogen just, its prerequisite is in saturated rings, and at least two insertion carbon atoms will encircle nitrogen-atoms and separate with last other hetero atom of ring;

    Wherein the carbon of C ring and azo-cycle atom can replace with being selected from following substituent group;

    (C1-C6) alkyl, (C2-C6) alkylene group, cyano group, nitro, trifluoromethyl, (C2-C7) alkoxy carbonyl, (C1-C6) alkylidene, hydroxyl, (C1-C6) alkoxyl, oxo base, hydroxycarbonyl group, as R XaDefined aryl or as R XaDefined heteroaryl, its prerequisite is a carbon for the ring atom that is replaced by alkylidene, hydroxycarbonyl group or oxo base, and further prerequisite is separated by at least two insertion carbon atoms for being gone up other hetero atom by the ring atom that hydroxyl or alkoxyl replaced with ring;

    (6) R 4And R 4*Independent is hydrogen or (C1-C6) alkyl or R 4And R 4*One of can be (C1-C6) hydroxy alkyl;

    With (7) R 5Be (CO) NR 13R 14, (CO) OR 15, (CO) SR 16, (SO 2) NR 17R 18, (PO) (OR 19) (OR 20), (CR 22) (OR 23) (OR 24), CN or tetrazolium-5-base, wherein R 13, R 14, R 15, R 16, R 17, R 18, R 19And R 20Be hydrogen independently respectively, can comprise that (C1-C8) alkyl of (C3-C8) cycloalkyl is (wherein with R 15Oxygen or and R 16The carbon that connects of sulfur surpass the secondary side chain), (C2-C6) hydroxy alkyl, (wherein alkyl is C2-C6 to aminoalkyl, amino can by two of as many as independently (C1-C6) alkyl replace), aryl alkyl (wherein alkyl is C1-C6), heteroaryl alkyl (wherein alkyl is C1-C6), aryl or heteroaryl, R 22Be hydrogen or OR 25, R 23, R 24And R 25For (C1-C6) alkyl, phenyl, benzyl, acetyl group or, work as R 22During for hydrogen, R 23And R 24Alkyl can be combined into and comprise 1,3-dioxolanes or 1, the 3-dioxane;

    Wherein said aryl is a phenyl or naphthyl, described heteroaryl be five-membered ring, hexatomic ring, with the condensed hexatomic ring of five-membered ring, with the condensed five-membered ring of hexatomic ring or with the condensed hexatomic ring of hexatomic ring, wherein said heteroaryl is aromatic radical and contains and be selected from the hetero atom that comprises oxygen, sulfur and nitrogen, and the residue ring atom is a carbon;

    Wherein said aryl, heteroaryl, the aryl of aryl alkyl or the heteroaryl of heteroaryl alkyl can be selected from following substituent group and be replaced;

    fluorine, chlorine, bromine, nitro, cyano group, hydroxyl, trifluoromethyl, the independently amino-sulfonyl of (C1-C6) N-alkyl substituent of two of as many as can be arranged, (C1-C6) alkyl, (C2-C6) alkenyl, (C1-C6) alkylamine, each alkyl is the dialkylamine of C1-C6 independently, amino, (C1-C6) alkoxyl, (C2-C7) alkanoyl, (C2-C7) alkanoyl oxygen base, trifluoromethoxy, hydroxycarbonyl group, (C2-C7) alkoxy carbonyl, can be by two of the as many as amino carbonyl that replaces of (C1-C6) alkyl N-independently, (C1-C6) alkyl sulphonyl, the amidino groups that can be replaced by three (C1-C6) alkyl of as many as or with the methylene-dioxy or the ethylenedioxy of adjacent position bonding on two oxygen and aromatic ring or the hetero-aromatic ring structure, this methylene-dioxy or ethylenedioxy can be used two independently (C1-C6) alkyl replacements of as many as;

    R wherein 13And R 14Can form with nitrogen and contain the heteroatomic 5-7 of the another one that is selected from oxygen and sulfur unit ring, If R wherein 15Be hydrogen, R 1Be propylidene, one of following so at least situation is suitable for;

    (1) R xAnd R yNot right-fluoro phenyl, (2) R xAnd R yOne of comprise heteroaryl, (3) R yBe aralkyl, heteroarylalkyl, aryloxy group, heteroaryloxy, aryl methoxy, heteroaryl methoxyl group, arylthio, heteroarylthio, fragrant methyl mercapto, heteroaryl methyl mercapto, Ar-N (R 6)-or Ar-CH 2-N (R 6*)-, (4) R 2Be R XaR Xb-, (5) R 2*Not hydrogen, (6) R 3Be not hydrogen, (7) n is 1, or (8) R 3And R 4Form ring Q;

    If R 15Be hydrogen, R 1Be ethylidene or X-R 1Be inferior third-1-thiazolinyl, one of following so at least situation is suitable for;

    (1) is R at least xAnd R yOne of the aryl group that is different from hydrogen replace (2) R xAnd R yOne of comprise heteroaryl, (3) R yBe aralkyl, heteroarylalkyl, aryloxy group, heteroaryloxy, aryl methoxy, heteroaryl methoxyl group, arylthio, heteroarylthio, fragrant methyl mercapto, heteroaryl methyl mercapto, Ar-N (R 6)-or Ar-CH 2-N (R 6*)-, (4) R 2Be R XaR Xb-, (5) R 2*Not hydrogen, (6) R 3Be not hydrogen, (7) n is 1, or (8) R 3And R 4Form ring Q;

    If R 5Be C (O) NH 2, one of following so at least situation is suitable for;

    (1) is R at least xAnd R yOne of the aryl group that is different from hydrogen replace (2) R xAnd R yOne of comprise heteroaryl, (3) R yBe aralkyl, heteroarylalkyl, aryloxy group, heteroaryloxy, aryl methoxy, heteroaryl methoxyl group, arylthio, heteroarylthio, fragrant methyl mercapto, heteroaryl methyl mercapto, Ar-N (R 6)-or Ar-CH 2-N (R 6*)-, (4) R 2Be R XaR Xb-, (5) R 2*Not hydrogen, (6) R 3Be not hydrogen, (7) n is 1, (8) R 1Not ethylidene, or (9) R 3And R 4Form ring Q;

    If R 13Be hydrogen, R 14Be (3,4-dihydro-2H-1-.alpha.-5;

    6-benzopyran-4-yl) methylene, so at least a situation [preferably at least two kinds of situations, more preferably at least three kinds of situations] is suitable for;

    (1) is R at least xAnd R yOne of the aryl group that is different from hydrogen replace (2) R xAnd R yOne of comprise heteroaryl, (3) R yBe aralkyl, heteroarylalkyl, aryloxy group, heteroaryloxy, aryl methoxy, heteroaryl methoxyl group, arylthio, heteroarylthio, fragrant methyl mercapto, heteroaryl methyl mercapto, Ar-N (R 6)-or Ar-CH 2-N (R 6*)-, (4) R 2Be R XaR Xb-, (5) R 2*Not hydrogen, (6) R 3Be not ethyl, (7) n is 1, or (8) R 3And R 4Form ring Q;

    With If R 2Be phenyl, right-aminomethyl phenyl or right-methoxyphenyl, following so at least a kind of situation is suitable for;

    (1) R xAnd R yAryl do not replaced by right-aminomethyl phenyl or right-methoxyphenyl, (2) are R at least xAnd R yOne of the aryl group that is different from hydrogen replace (3) R xAnd R yOne of comprise heteroaryl, (4) R yBe aralkyl, heteroarylalkyl, aryloxy group, heteroaryloxy, aryl methoxy, heteroaryl methoxyl group, arylthio, heteroarylthio, fragrant methyl mercapto, heteroaryl methyl mercapto, Ar-N (R 6)-or Ar-CH 2-N (R 6*)-, (5) R 1Not amino ethylidene, OR 8Or SR 8*, (6) n is 1, or (7) R 3And R 4Form ring Q.

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