Central cholecystokinin antagonists for treatment of psychiatric disorders

Claim 1

A pharmaceutical composition for use in the treatment of psychoses and/or anxiety or in the treatment of the withdrawal response produced by chronic treatment followed by withdrawal of diazepam, nicotine, alcohol or cocaine in a mammal said composition comprising an antipsychotically or anxiolytically effective amount of at least one of the following CCK-ligands: pharmaceutically active derivatives of D,L-glutamic acid and D,L-aspartic acid of formula: wherein n is 1 or 2; R₁ is a phenyl group mono-, di, or tri-substituted with linear or branched C₁-C₄ alkyl groups, which may be the same or different, or with halogens, with a cyano group or with a trifluoromethyl group; and R₂ is selected from the group consisting of morpholino, piperidino and amino with one or two linear, branched or cyclic alkyl group substituents containing from 1 to 8 carbon atoms which may be the same or different; or wherein R¹ is H, C₁-C₆ linear or branched alkyl, loweralkenyl, lower alkynyl, -X¹²COOR⁶, -X¹¹cycloloweralkyl, -X¹²NR⁴R⁵, X¹²CONR⁴R⁵, -X¹²CN, or -X¹¹CX₃¹⁰; R² is H, loweralkyl, substituted or unsubsti­tuted phenyl (wherein the substituents may be 1 or 2 of halo, loweralkyl, loweralkoxy, loweralkylthio, carboxyl, carboxyloweralkyl, nitro, -CF₃, or hydroxy), 2-, 3-, 4-pyridyl, wherein R₄ and R₅ are independently R⁶ or in combination the N of the NR⁴R⁵ group form an unsubstituted or mono or disubstituted, saturated or unsaturated, 4-7 membered heterocyclic ring or benzofused 4-7 membered heterocyclic ring, or said heterocyclic ring or said benzofused heterocyclic ring which further comprises a second heteroatom selected from O and NCH₃ and the substituents(s) is/are independently selected from C₁₋₄ alkyl; R⁶ is H, loweralkyl, cycloloweralkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted phenylloweralkyl wherein the phenyl or phenylloweralkyl substituents may be 1 or 2 of halo, loweralkyl, loweralkoxy, nitro, or CF₃; R₇ and R a ⁷ are independently α- or β-naphthyl, substituted or unsubstituted phenyl (wherein the substituents may be 1 or 2 of halo -NO₂, -OH, -X¹¹NR₄R₅, loweralkyl, CF₃, CN, SCF₃, C=CH, CH₂SCF₃, O CH₃, OCHF₂, SH, SPh, PO₃H-loweralkoxy, or loweralkyl­ thio, COOH), 2-, 3-, 4- pyridyl, R⁸ is H, loweralkyl, cycloloweralkyl, -X¹²CONH₂, -X¹²COOR⁶, -X¹²-cycloloweralkyl, -X¹²NR⁴R⁵, R⁹ and R¹⁰ are independently H, -OH, or -CH₃; R¹¹ and R¹² are independently loweralkyl or cycloloweralkyl; R¹³ is H, loweralkyl, acyl, O, or cycloloweralkyl; R¹⁴ is loweralkyl or phenylloweralkyl; R¹⁵ is H, loweralkyl, or -NH₂; R¹⁸ is H, loweralkyl, or acyl; p is 0 when its adjacent==is unsaturated and 1 when its adjacent==is saturated except that when R¹³ is O, p=1 and ==is unsaturated; q is 0-4; r is 1 or 2; X¹ is H, -NO₂, CF₃, CN, OH, loweralkyl, halo, loweralkylthio, loweralkoxy, -X¹¹COOR⁶, or -X¹¹NR⁴R⁵-; X² and X³ are independently H, -OH, -NO², halo, loweralkylthio, loweralkyl, or loweralkoxy; X⁴ is S, O, CH₂, or NR¹⁸ or NR⁸; X⁵ is H, CF₃, CN, -COOR⁶, NO₂, or halo; X⁶ is O or HH; X⁷ is O, S, HH, or NR¹⁵; X⁸ is H, loweralkyl; X⁹ and X a ⁹ are independently NR¹⁸ or O; X¹⁰ is F, Cl, or Br; X¹¹ is absent or C₁₋₄ linear or branched alkylidene; X¹² is C₁₋₄ linear or branched alkylidene; --is a saturated or unsaturated bond; or wherein R¹, R², R⁴, R⁵, R⁶, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, p, q, r, X¹, X², X³, X⁵, X⁶, X⁷, X⁸, X⁹, X¹⁰, X¹¹ and X¹² are as defined above, R⁷ is α- or β-naphthyl, substituted or unsubstituted phenyl (wherein the substituents may be 1 to 2 of halo, -NO², -OH,-X¹¹NR⁴R⁵, loweralkyl, CF₃, CN, SCF₃, C=CH, CH₂SCF₃, O CH₃, OCHF₂, SH, SPh, PO₃H, loweralkoxy, loweralkylthio or COOH), 2-, 3-, 4- pyridyl, R¹⁶ is alpha or beta naphthyl or 2-indolyl; R¹⁸ is H or loweralkyl; and = is a saturated or unsaturated bond; or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable carrier.

Claim 6

A method of use of a compound as described in Claims 1 to 3 for the manufacturing of pharmaceuticals for treating psychoses in a mammal.

Claim 7

A method of use of a compound as described in Claims 1 to 3 for the manufacturing of pharmaceuticals for treating anxiety in a mammal.

Claim 8

A method of use of a compound as described in Claims 1 to 3 for the manufacturing of pharmaceuticals for treating or preventing the withdrawal response produced by withdrawal of chronic treatment with diazepam in a mammal.

Claim 9

A method of use of a compound as described in Claims 1 to 3 for the manufacturing of pharmaceuticals for treating or preventing the withdrawal response produced by withdrawal from chronic use of cocaine in a mammal.

Claim 10

A method of use of a compound as described in Claims 1 to 3 for the manufacturing of pharmaceuticals for treating or preventing the withdrawal response produced by withdrawal from chronic use of alcohol in a mammal.

Claim 11

A method of use of a compound as described in Claims 1 to 3 for the manufacturing of pharmaceuticals for treating or preventing the withdrawal response produced by withdrawal from chronic use of nicotine in a mammal.