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COMPOSITIONS FOR THE TREATMENT OF PARKINSON'S DISEASE CONTAINING A CB1 RECEPTOR ANTAGONIST AND A PRODUCT THAT ACTIVATES DOPAMINERGIC NEUROTRANSMISSION IN THE BRAIN
COMPOSITIONS FOR THE TREATMENT OF PARKINSON'S DISEASE CONTAINING A CB1 RECEPTOR ANTAGONIST AND A PRODUCT THAT ACTIVATES DOPAMINERGIC NEUROTRANSMISSION IN THE BRAIN
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机译：包含CB1受体拮抗剂和能激活脑中多巴胺能神经传导的产品的帕金森氏病治疗组合物
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摘要
Composition comprise: (a) products that activate dopaminergic neurotransmission in the brain; and (b) azetidine CB1 antagonist (I) - (IV), their optical isomers or salts. Composition comprise: (a) products that activate dopaminergic neurotransmission in the brain; and (b) azetidine CB1 antagonist of formula (I) - (IV), their optical isomers or salts. [Image] In (I) and (II): R 1H, alkyl, -NH-R 1 5, CN, -S-alk-NR 1 6R 1 7, -CH 2-NR 1 8R 1 9 or -NR 2 0R 2 1; R 2-C(R 8)(R 9)(R 1 0), -C(R 8)(R 1 1)(R 1 2), -CO-NR 1 3R 1 4, -CH 2-CO-R 6, -COR 6, -CO-cycloalkyl, -SOR 6, -C(OH)(R 6)(alkyl), -C(=NOalk)R 6, -C(=NO-CH 2-CH=CH 2)R 6, -CH 2-CH(R 6)NR 3 1R 3 2, -CH(R 6)NHSO 2-alk, -CH(R 6)NHCONH-alk or -CH(R 6)NHCO-alk; R 3, R 4(cyclo)alkyl, phenyl, naphthyl, indenyl (optionally substituted os by T 1, formyl, -CO-alk, -COOH, -CONR 2 2R 2 3 -CONH-NR 2 4R 2 5 or alk-NR 2 4R 2 5), or heteroaromatic (os by T 1, -COOH or -CONHNR 2 4R 2 5); T 1halogen, (hydroxy)alkyl, alkoxy, OH, CF 3, CF 3O-, CN, -COOalkyl, alkylsulfanyl(alkyl), alkylsulfinyl(alkyl) or alkylsulfonyl(alkyl); R 5, R 8, R 13, R 18H or alkyl; R 6, R 10Ar 1 or Het 1; R 7(hetero)cycloalkyl, or heterocyclalkenyl os by -CSO-phenyl; R 9-CO-NR 2 6R 2 7, -COOH, -COOalk, -CH 2OH, -NH-CO-NH-alk, -CH 2-NHR 2 8, or -NHCOOalk; R 1 1-SO 2-alk, -SO 2-Ar 1, or -SO 2-Het 1; R 1 2H, Ar 1 or Het 1; R 1 4Ar 1, Het 1, -alk-Ar 1 or -alk-Het 1; R 1 5(cyclo)alkyl, or alk-NR 2 9R 3 0; R 1 6, R 1 7H or alkyl; or NR 1 6R 1 7T 2; T 2mono or bicyclic (un)saturated 3 - 10 membered heterocycle which may contain heteroatoms (O, N, S) and may be os by alkyl; R 1 9H, (cycloalkyl), cycloalkylalkyl, cycloalkylcarbonyl, -SO 2-alk, -CONH-alk, or -COO-alk; or NR 1 8R 1 9, NR 2 2R 2 3T 2; NR 2 0R 2 1T 3; T 3= a monocyclic (un)saturated 3 - 8 membered heterocycle which may contain heteroatoms (O, N, S); R 2 4, R 2 5= H, -COO-alk, (cyclo)alkyl, alkylcycloalkyl, -alk-O-alk, hydroxyalkyl; or NR 2 4R 2 5T 3 (os by (hydroxy)alkyl, -CO-alk, -COO-alk, -CO-NH-alk, -CS-NH-alk, oxo, -alk-O-alk-, or -CONH 2); R 2 6, R 2 7H, (hydroxy)alkyl, cycloalkyl(alkyl), -alk-COOalk, -alk-Ar 1, alk-het 1, Het 1, -alk-N(alk) 2; or NR 2 6R 2 7T 3 (os by alkyl, alkoxy or halogen); R 2 8-CH 2-alk, benzyl, -SO 2-alk, -CONH-alk, -CO-alk, cycloalkyl(alkyl)carbonyl, or -CO-(CH 2) n-OH; n : 1 - 3; R 2 9, R 3 0H or alkyl; or NR 2 9R 3 0T 2; R 3 1, R 3 2H, alkyl, Ar 1, or alk-Ar 1; or NR 3 1R 3 2aziridinyl, pyrrolidinyl or piperidinyl; Ar 1= phenyl or naphthyl, os by halogen, (hydroxy)alkyl, alkoxy, -CO-alk, CN, -COOH, -COO-alk, -CONR 2 2R 2 3, -CONH-NR 2 4R 2 5, alkylsulfanyl(alkyl), alkylsulfinyl(alkyl), alkylsulfonyl(alkyl), -alk-NR 2 4, -NR 2 4R 2 5, alkylthioalkyl, formyl, OH, CF 3, OCF 3, Het 1, -O-alk-NH-cycloalkyl or -SO 2NH 2; Het 1T 3 os by (hydroxy)alkyl, halogen, alkoxy(carbonyl), -CONR 2 2R 2 3, O, oxo or -SO 2NH 2; alk : alkyl or alkylene; and provided that when R 1 is H, then R 2 is -C(R 8)(R 9)(R 1 0), -C(R 8)(R 1 1)(R 1 2), -CO-NR 1 3R 1 4, -CH 2-CO-R 6, -COR 6, -CO-cycloalkyl, -SOR 6, -C(OH)(R 6)(alkyl), -C(=NOalk)R 6, -C(=NO-CH 2-CH=CH 2)R 6, -CH 2-CH(R 6)NR 3 1R 3 2, -CH(R 6)NHSO 2-alk, -CH(R 6)NHCONH-alk, or -CH(R 6)NHCO-alk, or when R 1 is alkyl, -NH-R 1 5, CN, -S-alk-NR 1 6R 1 7, -CH 2-NR 1 8R 1 9 or -NR 2 0R 2 1, then R 2 is -C(R 8)(R 1 1)(R 1 2). N.B. R 7 is defined but does not appear in formulae or list of definitions. In (III): R 3 3-NHCOR 3 4, or -N(R 3 5)-Y-R 3 6; Y : CO or SO 2; R 3, R 4phenyl, naphthyl, indenyl (os by T 1 (except halogen), formyl, -CO-alk, -COOH, -CONR 3 7R 3 8, -CONHR 3 9R 4 0 or alk-NR 3 7R 3 8), heteroaromatic os by T 1 (except halogen) -COOH or -CONHNR 2 4R 2 5; R 3 4-alk-SO 2-R 4 1, alk-SO 2-CH=CH-R 4 1, Het 2 substituted by -SO 2-R 4 1 or -alk-SO 2-R 4 1; R 3 5H or alkyl; R 3 6phenylalkyl, Ar 2 or Het 2; R 3 7, R 3 8H or alkyl; or NR 3 7R 3 8T 2; R 3 9, R 4 0H, -COOalk, (cyclo)alkyl, alkylcycloalkyl, alk-O-alk or hydroxyalkyl; or NR 3 9R 4 0T 3 os by (hydroxy)alkyl, -CO-alk, -COO-alk, -CONH-alk, -CS-NH-alk, oxo, -alk-O-alk, or CONH 2; R 4 1alkyl, Ar 2, or Het 2; Ar 2phenyl, naphthyl or indenyl, os by T 1 (except OH) -CO-alk, -COOH, -CONR 4 2R 4 3, -CONH-NR 4 4R 4 5, Het 2, -O-alk-NH-cycloalkyl, -NH-CO-alk, -SO 2-NH 2, -NH-COCH 3, -NH-COO-alk, or two adjacent C atoms may be linked by dioxymethylene; Het 2T 3 os by alkyl, vinyl, halogen, alkoxy(carbonyl), oxo, OH, OCF 3 or CF 3, and their N-oxides; R 4 2, R 4 3H or alkyl; or NR 4 2R 4 3T 2; R 4 4, R 4 5H, -COO-alk, (cyclo)alkyl, alkylcycloalkyl, -alk-O-alk or hydroxyalkyl; or NR 4 4R 4 5T 3 os by (hydroxy)alkyl, -CO-alk, -COO-alk, -CONH-alk, -CS-NH-alk, oxo, -alk-O-alk, or CONH 2. In (IV): R 4 6-N(R 4 7)(R 4 8), -N(R 4 7)CO(R 4 8), or -N(R 4 7)-SO 2(R 4 9); R 3, R 4phenyl, naphthyl, indenyl (os by T 1, formyl, -CO-alk, -COOH, -CONR 3 7R 3 8, -CONHR 3 9R 4 0 or alk-NR 3 7R 3 8), heteroaromatic os by -COOH, -CONHNR 5 2R 5 3, -CONR 5 0R 5 1 or -alk-NR 5 2R 5 3; R 4 7-C(R 5 4)(R 5 5)-Het 3, Het 3, - C(R 5 4)(R 5 5)-Ar 3, Ar 3, cycloalkyl or norbornyl; R 4 8, R 4 9H, hydroxyalkyl, -alk-COO-alk, -alk-CONR 5 0R 5 1, alkoxy, Ar 3, Het 3, -CH 2-Het 3 or (halo)alkyl; R 5 0, R 5 1H or alkyl; or NR 5 0R 5 1T 2; R 5 2, R 5 3H, -COOalk, (cyclo)alkyl, alkylcycloalkyl, -alk-O-alk or hydroxyalkyl; or NR 5 2R 5 3T 3 os by (hydroxy)alkyl, -CO-alk, -COO-alk, -CONH-alk, -CS-NH-alk, oxo, -alk-O-alk, or CONH 2; R 5 4H, hydroxyalkyl, -alk-COO-alk, -alk-CONR 5 0R 5 1, alk-NR 5 0R 5 1, alkoxyalkyl, Ar 3, Het 3, -CH 2Ar 3, -CH 2-Het 3 or (halo)alkyl; R 5 5H, hydroxyalkyl, -alk-COO-alk, -alk-CONR 5 0R 5 1, -alk-NR 5 0R 5 1, alkoxyalkyl, alkyl (os by halogens), or T 2; Ar 3phenyl, naphthyl or indenyl, os by halogen, (hydroxy)alkyl, alkoxy, -CO-alk, CN, -COOH, -COO-alk, -CONR 5 6R 5 7, -CONH-NR 5 8R 5 9, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, alk-NR 5 8R 5 9, NR 5 8R 5 9, alkylthioalkyl, formyl, OCF 3, CF 3, Het 3, -O-alk-NH-cycloalkyl, SO 2NH 2, OH, -NH-CO-alk, -NH-COO-alk, or two adjacent C atoms may be linked by dioxymethylene; Het 3T 3 os by alkyl, halogen, alkoxy(carbonyl), oxo, or OH, and their N-oxides; and R 5 6, R 5 7, or R 5 8, R 5 9H; or NR 5 6R 5 7, NR 5 8R 5 9T 2; Alkyl, alkoxy and alkylene groups have 1-6C atoms, and cycloalkyl groups have 3-10C atoms. ACTIVITY : Antiparkinsonian. MECHANISM OF ACTION : CB1 receptor antagonist; Dopaminergic neurotransmission activator.
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