Derivatives of tryptophan as CCK antagonists

Claim 2

A compound of the formula: wherein R₁ and R₂ are independently selected from i) hydrogen, ii) loweralkyl, iii) cycloalkyl, iv) loweralkenyl, v) adamantyl, vi) aryl, vii) substituted aryl, viii) heterocyclic group, ix) substituted alkyl, x) substituted amide, xi) functionalized carbonyl, and xii) nitrogen containing ring wherein R₁, R₂ and the adjacent nitrogen atom form a ring; R₁₁ is i) hydrogen, ii) loweralkyl, or iii) loweralkenyl; R₂₀ is i) hydrogen, ii) loweralkyl, or iii) loweralkenyl; B is i) -(CH₂) m -, ii) substituted alkenylene, iii) -QCH₂- wherein Q is 0, S, or -N(R₈)- wherein R₈ is selected from hydrogen, -(C=O) r (C₁-C₆loweralkyl), -(C=O) r , cycloalkyl, -(C=O) r loweralkenyl, -(C=O) r (CH₂) m aryl, -(C=O) r (CH₂) m (substituted aryl) wherein substituted aryl is as defined above, -(CH₂) m SR₄ and -(CH₂) m OR₄ wherein R₄ is hydrogen, -(C=O) r loweralkyl, -(C=O) r loweralkenyl, -(C=O) r cycloalkyl, -(C=O) r (CH₂) m aryl or -(C=O) r (CH₂) m (substituted aryl), iv) -CH₂Q- wherein Q is as defined above, or v) NH; Z is i) C=O, ii) S(O)₂ or iii) C=S; Ar is a heterocyclic group, aryl or substituted aryl; D is unsubstituted or substituted indol-3-yl, indolin-3-yl or oxindol-3-yl; and m is 0 to 4 and r is 0 or 1; or a pharmaceutically acceptable salt thereof; with the proviso that when the compound is of the formula: wherein Ar is phenyl or phenyl substituted with one or two substituents independently selected from hydrogen, loweralkyl, hydroxy substituted alkyl, alkoxy substituted alkyl, alkoxy, halogen, amino, hydroxy, nitro, cyano, carboxy, ethoxycarbonyl and trihalomethyl; and R₁ is -(CH₂) a phenyl wherein a is 1 to 4; then R₂ is not loweralkyl, cycloalkyl, -(CH₂) b aryl wherein b is 0 to 4, -(CH₂) b (substituted aryl) wherein b is 0 to 4 and substituted aryl is as defined above, or -(CH₂) c (CO)R₃ wherein c is 1 to 4 and R₃ is hydroxy, alkoxy, -O(CH₂) c aryl, -O(CH₂) c (substituted aryl) wherein c is 1 to 4, or -NR₆R₇ wherein R₆ and R₇ are independently selected from hydrogen and loweralkyl.

Claim 3

The compound of Claim 1 wherein R₁ and R₂ are independently selected from loweralkyl; Z is C=O; B is absent; R₁₁ is hydrogen or loweralkyl; D is indol-3-yl, hydroxy-substituted indol-3-yl or halo-substituted indol-3-yl; and Ar is a heterocyclic group selected from indolyl, quinolyl, naphthyl and substituted derivatives thereof.

Claim 4

The compound of Claim 1 wherein R₁ is loweralkyl; R₂ is -(CH₂) s O(loweralkyl) wherein s is 1 to 4; Z is C=O; B is absent; R₁₁ is hydrogen or loweralkyl; D is indol-3-yl, hydroxy-substituted indol-3-yl or halo-substituted indol-3-yl; and Ar is a heterocyclic group selected from indolyl, quinolyl, naphthyl and substituted derivatives thereof

Claim 5

The compound of Claim 1 wherein R₁ is hydrogen or -(CH₂) s (C=O)O(loweralkyl) wherein s is 1 to 4; R₂ is benzyl or -CHR′R˝ wherein R′ is carboalkoxy or loweralkyl and R˝is phenyl; Z is C=O; B is absent; R₁₁ is hydrogen or loweralkyl; D is indol-3-yl, hydroxy-substituted indol-3-yl or halo-substituted indol-3-yl; and Ar is indolyl, quinolyl or naphthyl.

Claim 6

A compound selected from the group consisting of: N-(2′-Indolylcarbonyl)-R-Tryptophan-di-n-pentylamide, N-(3′-Quinolylcarbonyl)-R-Tryptophan-di-n-pentylamide, N-(3′-Quinolylcarbonyl)-R-(beta-Oxindolyl)Alanine-di-­n-pentylamide N(alpha)-(3′-Quinolylcarbonyl)-R-5-Hydroxytryptophan-di-­n-pentylamide, N-(4′,8′-Dihydroxy-2′-quinolylcarbonyl)-R-Tryptophan-di-n-­pentylamide, and N(alpha)-(4′,8′-Dihydroxy-2′-quinolylcarbonyl)-R-5-­Hydroxytryptophan-di-n-pentylamide.

Claim 7

A compound selected from the group consisting of: N-(2′-Indolylcarbonyl)-R-Tryptophan-di-n-pentylamide, N-(3′-Quinolylcarbonyl)-R-Tryptophan-di-n-pentylamide, N-(3′-Quinolylcarbonyl)-R-(beta-Oxindolyl)Alanine-di-­n-pentylamide N(alpha)-(3′-Quinolylcarbonyl)-R-5-Hydroxytryptophan-di-­n-pentylamide, N-(4′,8′-Dihydroxy-2′-quinolylcarbonyl)-R-Tryptophan-di-n-­pentylamide, and N(alpha)-(4′,8′-Dihydroxy-2′-quinolylcarbonyl)-R-5-­Hydroxytryptophan-di-n-pentylamide.

Claim 8

A pharmaceutical composition for antagonizing CCK, comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of Claim 1.

Claim 9

A method for antagonizing CCK comprising administering to a host in need of such treatment a therapeutically effective amount of a compound of Claim 1.

Claim 10

A method for the treatment and prevention of gastrointestinal ulcers, cancers of the gall bladder and pancreas, pancreatitis, Zollinger-Ellison syndrome, central G cell hyperplasia, irritable bowel syndrome, the treatment or prevention of neuroleptic disorders, tardive dyskinesia, Parkinson's disease, psychosis, Gilles de la Tourette syndrome, disorders of appetite regulatory systems, the treatment of pain and the treatment of substance abuse comprising administering to a host in need of such treatment a therapeutically effective amount of a compound of Claim 1.

Claim 11

A pharmaceutical composition for the treatment and prevention of gastrointestinal ulcers, cancers of the gall bladder and pancreas, pancreatitis, Zollinger-Ellison syndrome, central G cell hyperplasia, irritable bowel syndrome, the treatment or prevention of neuroleptic disorders, tardive dyskinesia, Parkinson's disease, psychosis, Gilles de la Tourette syndrome, disorders of appetite regulatory systems, the treatment of pain and the treatment of substance abuse comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of Claim 1.

Claim 12

A process for the preparation of a compound of the formula: wherein R₁ and R₂ are independently selected from i) hydrogen, ii) loweralkyl, iii) cycloalkyl, iv) loweralkenyl, v) adamantyl, vi) aryl, vii) substituted aryl, viii) heterocyclic group, ix) substituted alkyl, x) substituted amide, xi) functionalized carbonyl, and xii) nitrogen containing ring wherein R₁ R₂ and the adjacent nitrogen atom form a ring; R₁₁ is i) hydrogen, ii) loweralkyl, or iii) loweralkenyl; R₂₀ is i) hydrogen, ii) loweralkyl, or iii) loweralkenyl; B is i) -(CH₂) m -, ii) substituted alkenylene, iii) -QCH₂- wherein Q is O, S, or -N(R₈)- wherein R₈ is selected from hydrogen, -(C=O) r (C₁-C₆loweralkyl), -(C=O) r -, cycloalkyl, -(C=O) r loweralkenyl, -(C=O) r (CH₂) m aryl, -(C=O) r (CH₂) m (substituted aryl) wherein substituted aryl is as defined above, -(CH₂) m SR₄ and -(CH₂) m OR₄ wherein R₄ is hydrogen, -(C=O) r loweralkyl, -(C=O) r loweralkenyl, -(C=O) r cycloalkyl, -(C=O) r (CH₂) m aryl or -(C=O) r (CH₂) m (substituted aryl), iv) -CH₂Q wherein Q is as defined above, or v) NH; Z is i) C=O, ii) S(O)₂ , or iii) C=S; Ar is a heterocyclic group, aryl or substituted aryl; D is unsubstituted or substituted indol-3-yl, indolin-3-yl or oxindol 3-yl; and m is 0 to 4 and r is 0 ro 1; or a pharmaceutically acceptable salt thereof; comprising coupling an amine of the formula wherein P₃ is hydrogen with a compound of the formula Ar-B-Z-Z′ wherein Z′ is an activating group; or -B-Z-Z′ taken together represent -N=C=O, -N=C=S, -CH₂-N=C=O or CH₂-N=C=S.

Claim 13

A process for the preparation of a compound of the formula: wherein R₁ and R₂ are independently selected from i) hydrogen, ii) loweralkyl, iii) cycloalkyl, iv) loweralkenyl, v) adamantyl, vi) aryl, vii) substituted aryl, viii) heterocyclic group, ix) substituted alkyl, x) substituted amide, xi) functionalized carbonyl, and xii) nitrogen containing ring wherein R₁ R₂ and the adjacent nitrogen atom form a ring; R₁₁ is i) hydrogen, ii) loweralkyl, or iii) loweralkenyl; R₂₀ is i) hydrogen, ii) loweralkyl, or iii) loweralkenyl; B is i) -(CH₂) m -, ii) substituted alkenylene, iii) -QCH₂- wherein Q is O, S, or -N(R₈)- wherein R₈ is selected from hydrogen, -(C=O) r (C₁-C₆loweralkyl), -(C=O) r -, cycloalkyl, -(C=O) r loweralkenyl, -(C=O) r (CH₂) m aryl, -(C=O) r (CH₂) m (substituted aryl) wherein substituted aryl is as defined above, -(CH₂) m SR₄ and -(CH₂) m OR₄ wherein R₄ is hydrogen, -(C=O) r loweralkyl, -(C=O) r loweralkenyl, -(C=O) r cycloalkyl, -(C=O) r (CH₂) m aryl or -(C=O) r (CH₂) m (substituted aryl), iv) -CH₂Q wherein Q is as defined above, or v) NH; Z is i) C=O, ii) S(O)₂ , or iii) C=S; Ar is a heterocyclic group, aryl or substituted aryl; D is unsubstituted or substituted indol-3-yl, indolin-3-yl or oxindol 3-yl; and m is 0 to 4 and r is 0 ro 1; or a pharmaceutically acceptable salt thereof; comprising coupling an amine of the formula wherein P₃ is hydrogen with a compound of the formula Ar-B-Z-Z′ wherein Z′ is an activating group; or -B-Z-Z′ taken together represent -N=C=O, -N=C=S, -CH₂-N=C=O or CH₂-N=C=S.

Claim 14

A process for the preparation of a compound of the formula wherein R₁ and R₂ are independently selected from i) hydrogen, ii) loweralkyl, iii) cycloalkyl, iv) loweralkenyl, v) adamantyl, vi) aryl, vii) substituted aryl, viii) heterocyclic group, ix) substituted alkyl, x) substituted amide, xi) functionalized carbonyl, and xii) nitrogen containing ring wherein R₁, R₂ and the adjacent nitrogen atom form a ring; R₅ is hydrogen or R₅ is one, two or three of the substituents independently selected from the group -(C₁-C₆loweralkyl), loweralkenyl, -(O) t (CH₂) m carboxyl, -(O) t (CH₂) m carboalkoxy, -(O) t (CH₂) m carboaryloxy, haloalkyl, nitro, alkoxy, cyano, -N₃, -NHP₄ wherein P₄ is an N-protecting group, -OP₅ wherein P₅ is an O-protecting group, alkylaminocarbonyl, dialkylaminocarbonyl, aryloxy, thioalkoxy, thioaryloxy, halogen, CN, -OH, -NH₂ -NR₆R₇ wherein R₆ and R₇ are independently selected from hydrogen, loweralkyl, cycloalkyl, loweralkenyl, -(CH₂) m aryl, -(CH₂) m (substituted aryl) wherein the aryl group is substituted with one, two or three substituents independently selected from loweralkyl, alkoxy, thioalkoxy, carboxy, carboalkoxy, cyano, haloalkyl, -N₃ -NHP₄ wherein P₄ is an N-protecting group, -OP₅ wherein P₅ is an O-protecting group, nitro, halogen, hydroxy, amino and -NH(loweralkyl); -(CH₂) m OR₄ wherein R₄ is hydrogen, -(C=O) r loweralkyl. -(C=O) r loweralkenyl, -(C=O) r cycloalkyl, -(C=O) r (CH₂) m aryl or -(C=O) r (CH₂) m (substituted aryl), and -(CH₂) m SR₄ wherein R₄ is independently as defined above; R₁₁ is i) hydrogen, ii) loweralkyl, or iii) loweralkenyl; R₂₀ is i) hydrogen, ii) loweralkyl, or iii) loweralkenyl; B is i) -(CH₂) m -, ii) substituted alkenylene, iii) -QCH₂- wherein Q is 0, S, or -N(R₈)- wherein R₈ is selected from hydrogen, -(C=O) r (C₁-C₆loweralkyl), -(C=O) r -, cycloalkyl, -(C=O) r loweralkenyl, -(C=O) r (CH₂) m aryl, -(C=O) r (CH₂) m (substituted aryl) wherein substituted aryl is as defined above, -(CH₂) m SR₄ and -(CH₂) m OR₄ wherein R₄ is hydrogen, -(C=O) r loweralkyl, -(C=O) r loweralkenyl, -(C=O) r cycloalkyl, -(C=O) r (CH₂) m aryl or -(C=O) r (CH₂) m (substituted aryl), iv) -CH₂Q- wherein Q is as defined above, or v) NH; Z is i) C=O, ii) S(O)₂ , or iii) C=S; Ar is a heterocyclic group, aryl or substituted aryl; R₃₀ is hydrogen, loweralkyl, arylalkyl, (substituted aryl)alkyl or an N-protecting group; R₃₁ is loweralkyl, aryl or substituted aryl; and m, t and r are independently selected at each occurrence from the values m is 0 to 4, t is 0 or and r is 0 or 1; or a pharmaceutically acceptable salt thereof; comprising reacting a compound of the formula wherein P₆ is an N-protecting group; and R₁, R₂, R₅, R₁₁ and R₃₀ are independently as defined above, with a compound of the formula R₃₁SH wherein R₃₁ is loweralkyl, aryl or substituted aryl.

Claim 15

A process for the preparation of a compound of the formula wherein R₁ and R₂ are independently selected from i) hydrogen, ii) loweralkyl, iii) cycloalkyl, iv) loweralkenyl, v) adamantyl, vi) aryl, vii) substituted aryl, viii) heterocyclic group, ix) substituted alkyl, x) substituted amide, xi) functionalized carbonyl, and xii) nitrogen containing ring wherein R₁, R₂ and the adjacent nitrogen atom form a ring; R₅ is hydrogen or R₅ is one, two or three of the substituents independently selected from the group -(C₁-C₆loweralkyl), loweralkenyl, -(O) t (CH₂) m carboxyl, -(O) t (CH₂) m carboalkoxy, -(O) t (CH₂) m carboaryloxy, haloalkyl, nitro, alkoxy, cyano, -N₃, -NHP₄ wherein P₄ is an N-protecting group, -OP₅ wherein P₅ is an O-protecting group, alkylaminocarbonyl, dialkylaminocarbonyl, aryloxy, thioalkoxy, thioaryloxy, halogen, CN, -OH, -NH₂ -NR₆R₇ wherein R₆ and R₇ are independently selected from hydrogen, loweralkyl, cycloalkyl, loweralkenyl, -(CH₂) m aryl, -(CH₂) m (substituted aryl) wherein the aryl group is substituted with one, two or three substituents independently selected from loweralkyl, alkoxy, thioalkoxy, carboxy, carboalkoxy, cyano, haloalkyl, -N₃ -NHP₄ wherein P₄ is an N-protecting group, -OP₅ wherein P₅ is an O-protecting group, nitro, halogen, hydroxy, amino and -NH(loweralkyl); -(CH₂) m OR₄ wherein R₄ is hydrogen, -(C=O) r loweralkyl. -(C=O) r loweralkenyl, -(C=O) r cycloalkyl, -(C=O) r (CH₂) m aryl or -(C=O) r (CH₂) m (substituted aryl), and -(CH₂) m SR₄ wherein R₄ is independently as defined above; R₁₁ is i) hydrogen, ii) loweralkyl, or iii) loweralkenyl; R₂₀ is i) hydrogen, ii) loweralkyl, or iii) loweralkenyl; B is i) -(CH₂) m -, ii) substituted alkenylene, iii) -QCH₂- wherein Q is 0, S, or -N(R₈)- wherein R₈ is selected from hydrogen, -(C=O) r (C₁-C₆loweralkyl), -(C=O) r -, cycloalkyl, -(C=O) r loweralkenyl, -(C=O) r (CH₂) m aryl, -(C=O) r (CH₂) m (substituted aryl) wherein substituted aryl is as defined above, -(CH₂) m SR₄ and -(CH₂) m OR₄ wherein R₄ is hydrogen, -(C=O) r loweralkyl, -(C=O) r loweralkenyl, -(C=O) r cycloalkyl, -(C=O) r (CH₂) m aryl or -(C=O) r (CH₂) m (substituted aryl), iv) -CH₂Q- wherein Q is as defined above, or v) NH; Z is i) C=O, ii) S(O)₂ , or iii) C=S; Ar is a heterocyclic group, aryl or substituted aryl; R₃₀ is hydrogen, loweralkyl, arylalkyl, (substituted aryl)alkyl or an N-protecting group; R₃₁ is loweralkyl, aryl or substituted aryl; and m, t and r are independently selected at each occurrence from the values m is 0 to 4, t is 0 or and r is 0 or 1; or a pharmaceutically acceptable salt thereof; comprising reacting a compound of the formula wherein P₆ is an N-protecting group; and R₁, R₂, R₅, R₁₁ and R₃₀ are independently as defined above, with a compound of the formula R₃₁SH wherein R₃₁ is loweralkyl, aryl or substituted aryl.