RU2001111812A - TRICYCLIC delta 3-PIPERIDINES AS alpha <Mv> 2 <D> - ANTAGONISTS - Google Patents

Claims (11)

1. The compound of the formula

its N-oxide form, a pharmaceutically acceptable addition salt or a stereochemically isomeric form, where Alk is C _1-6 alkanediyl; n is 1 or 2; X ₁ represents —O—, —S—, —S (= O) - or —S (= O) ₂ -; each R ¹ independently represents hydrogen, halogen, C _1-6 alkyl, nitro, hydroxy or C _1-4 alkyloxy; D represents a radical of the formula

in which each m is independently 0, 1 or 2; X ₂ represents —O— or —NR ¹¹ -; each X ₃ independently represents —O—, —S— or —NR ¹¹ -; X ₄ represents —O—, —S—, —CH ₂ —S— or —NR ¹² -; X ₅ and X ₆ each independently represents —CH ₂ -, —O—, —S — or —NR ¹¹ -; R ² represents hydrogen, C _1-6 alkyl, aryl or aryl C _1-6 alkyl; R ³ represents hydrogen, C _1-6 alkyl, C _1-6 alkyloxy, C _1-6 alkylthio, amino, or mono- or di (C _1-6 alkyl) amino; R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and R ¹⁵ each independently represents hydrogen or C _1-6 alkyl; R ¹² represents hydrogen, C _1-6 alkyl, C _1-6 alkyloxyC _1-6 alkyl or pyridinyl C _1-6 alkyl; R ¹³ , R ¹⁴ and R ¹⁶ each independently represents halogen or C _1-6 alkyl; R ³ and R ⁴ taken together can form a bivalent radical —R ³ —R ⁴ - formulas -CH ₂ -CH ₂ -CH ₂ - (a-1) -CH ₂ -CH ₂ -CH ₂ -CH ₂ - (a-2) -CH = CH-CH ₂ - (a-3) -CH ₂ -CH = CH- (a-4) or -CH = CH-CH = CH- (a-5) in which one or two hydrogen atoms of the aforementioned radicals (a-1) to (a-5) each independently can be substituted with halogen, C _1-6 alkyl, aryl C _1-6 alkyl, trifluoromethyl, amino, hydroxy, C _1-6 alkyloxy or C _1-10 alkylcarbonyloxy, or, when possible, two geminal hydrogen atoms may be substituted with C _1-6 alkylidene or aryl C _1-6 alkylidene; or R ³ -R ⁴ may also represent -S-CH ₂ -CH ₂ - (a-6) -S-CH ₂ -CH ₂ -CH ₂ - (a-7) -S-CH = CH- (a-8) -NH-CH ₂ -CH ₂ - (a-9) -NH-CH ₂ -CH ₂ -CH ₂ - (a-10) -NH-CH = CH- (a-11) -NH-CH = N- (a-12) -S-CH = N- (a-13) or -CH = CH-O- (a-14) in which one or possibly two or three hydrogen atoms of said radicals (a-6) to (a-14) each independently may be substituted with C _1-6 alkyl or aryl, and the aryl is phenyl or phenyl substituted with one, two or three substituents selected from halogen, hydroxy, nitro, cyano, trifluoromethyl, C _1-6 alkyl, C _1-6 alkyloxy, C _1-6 alkylthio, mercapto, amino, mono and di (C _1-6 alkyl) amino, carboxyl, C _1-6 alkyloxycarbonyl and C _1-6 alkylcarbonyl. 2. The compound according to claim 1, in which D represents a radical of the formula (a), (b), (c), (d), (e), (f), (g), (h), (i), (j), (k) or (l); in which m = 0; and aryl is phenyl or phenyl substituted with halogen or C _1-6 alkyl. 3. The compound according to claim 1 or 2, in which n = 1, a R ¹ represents hydrogen, chlorine, fluorine, methyl, methoxy or nitro. 4. The compound according to any one of claims 1 to 3, in which X is —O— or —S—. 5. The compound according to any one of claims 1 to 4, in which Alk is methylene, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl or 1,5-pentanediyl. 6. The compound according to any one of claims 1 to 5, in which D represents a radical of formula (a), in which R ² represents aryl or methyl, and R ³ and R ⁴ taken together form a bivalent radical of formula (a-5) or (a-8); or D represents a radical of formula (b) in which R ⁵ and R ⁶ are C _1-6 alkyl; or D represents a radical of formula (c) in which R ⁷ represents hydrogen; or D represents a radical of formula (d) in which X ₂ represents —NR ¹¹ - and R ¹¹ represents hydrogen; or D represents a radical of formula (e); or D represents a radical of formula (f) in which X ₃ is —S— and R ⁸ is hydrogen or C _1-6 alkyl; or D is a radical of formula (g) in which X ₄ is —CH ₂ —S— or —NR ¹² - and R ¹² is C _1-6 alkyloxyC _1-6 alkyl or pyridinyl C _1-6 alkyl; or D represents a radical of formula (h) in which X ₅ is —O— or —S— and R ¹⁰ is hydrogen; or D represents a radical of formula (j); or D represents a radical of formula (k) in which m = 1, and R ¹³ represents halogen. 7. The compound according to claim 1, which represents

or its N-oxide form, a pharmaceutically acceptable addition salt, or a stereochemically isomeric form. 8. The compound according to any one of claims 1 to 7, useful as a medicine. 9. The compound according to any one of claims 1 to 7, suitable in the manufacture of drugs for the treatment of depression or Parkinson's disease. 10. A composition for treating depression or Parkinson's disease, comprising a pharmaceutically acceptable carrier and, as an active ingredient, a therapeutically effective amount of a compound according to any one of claims 1 to 7. 11. The method of producing the compound according to claim 1, characterized in that it includes: a) N-alkylation of an intermediate of formula (II) with an alkylating reagent of formula (III)

where W ¹ represents a suitable leaving group; D, Alk, X ₁ , n and R ¹ have the meanings defined in claim 1, in a reaction inert solvent, in the presence of a base and optionally in the presence of a catalyst; b) N-alkylation of an amine of formula (IV) with an intermediate of formula (V)

where W ² represents a suitable leaving group; D, Alk, X ₁ , X ₃ , n, R ¹ and R ⁸ are as defined in claim 1; thus forming a compound of formula (I-f); c) reductive N-alkylation of an intermediate of formula (II) with an aldehyde derivative of formula (IV)

in which Alk 'represents C _1-5 alkanediyl; p is 0 or 1; X ₁ , n and R ¹ have the meanings defined in claim 1, recovering the reactant mixture in a suitable reaction inert solvent in accordance with techniques known in the art for reductive N-alkylation to form a compound of formula (I-f); d) and, if desired, converting the compounds of formula (I) into each other using transformations known in the art, and then, if desired, converting the compounds of formula (I) into a therapeutically active non-toxic acid addition salt by treatment with an acid, or into a therapeutically active non-toxic base addition salt by treatment with a base, or, conversely, converting an acid addition salt form into a free base by treatment with alkali, or converting a base addition salt of a base into a free acid by treatment with an acid and, if desired, preparing stereochemically isomeric forms or N-oxides.