Patent EA-003530-B1 (EA)
Title: Methods and compositions for stimulating neurite growth using compounds with affinity for fkbp12 in combination with neurotrophic factors
Inventor: ZELLE ROBERT E
IPC: A61K38/18
Filed: 1997-11-13
Abstract: 1. A pharmaceutically acceptable composition comprising: a) a neurotrophic amount of a compound having the formula (I): and pharmaceutically acceptable derivatives thereof, wherein: A is oxygen; wherein B and D are independently: Ar-(C1-C6) straight or branched alkyl, or Ar-substituted (C3-C6) straight or branched alkenyl or alkynyl; wherein any one of the CH2 groups of said alkyl chain in B and D is optionally replaced by O; J is selected from hydrogen or (C1-C6)-straight or branched alkyl; K is selected from (C1-C4)-straight or branched alkyl or -CH2Ar, or J and K are taken together with the nitrogen and carbon atoms to which they are respectively bound to form a 5-7 membered heterocyclic ring; Z is OS; Y is O or N; wherein when Y is O, then R1 is alone pair and R2 is Ar; when Y is N, then R1 and R2 are independently selected from the group consisting of Ar and (C1-C6)-straight or branched alkyl; or R1 and R2 are taken together to form a heterocyclic 5-6 membered ring selected from the group consisting of pyrrolidine and piperidine; wherein Ar is selected from the group consisting of phenyl, 1-naphthyl, 2-naphthyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, quinolinyl, isoquinolinyl, 1,2,3,4-tetrahydro-quinolinyl, 1,2,3,4-tetrahydro-isoquinolinyl; wherein Ar is optionally substituted with one to three substituents which are independently selected from hydrogen, halogen, hydroxyl, nitro, -SO3H, trifluoromethyl, trifluoromethoxy, (C1-C6)-straight or branched alkyl, (C2-C6)-straight or branched alkenyl, O-[(C1-C6)-straight or branched alkyl], O-[(C3-C4)-straight or branched alkenyl], O-benzyl, O-phenyl, 1,2-methylenedioxy, -NR3R4, carboxyl, N- (C1-C5-straight or branched alkyl or C3-C5-straight or branched alkenyl) carboxamides, N,N-di-(C1-C5-straight or branched alkyl or C3-C5-straight or branched alkenyl) carboxamides, morpholinyl, piperidinyl, O-Z, CH2- (CH2) q-Z, O-(CH2) q-Z, (CH2) q-Z-O-Z, or CH=CH-Z; wherein R3 and R4 are independently selected from (C1-C6)-straight or branched alkyl, (C3-C6) straight or branched alkenyl or alkynyl, hydrogen or benzyl; or wherein R3 and R4 are taken together to form a 5-6 membered heterocyclic ring; Z is selected from 4-methoxyphenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrazyl, quinolyl, 3,5-dimethylisoxazoyl, isoxazoyl, 2-methylthiazoyl, thiazoyl, 2-thienyl, 3-thienyl, or pyrimidyl; wherein q is 0-2; and n is 0 or 1; b) a neurotropic factor; and c) a pharmaceutically suitable carrier. 2. The pharmaceutically acceptable composition according to claim 1, wherein, in compound of formula (I), at least one of B or D is independently represented by the formula - (CH2) r-(X) - (CH2) s-Ar, wherein r is 1-4; s is 0-1: and each X is independently selected from CH2, and O. 3. The pharmaceutically acceptable composition according to claim 1, wherein said compound has formula (II) or formula (III):   Formula (II)   Formula (III) wherein: Y, R1, R2, and Ar are as defined in claim 1, and w is 1 or 2. 4. The pharmaceutically acceptable composition according to claim 1, wherein said compound has formula   Formula (IV)    Formula (V): wherein: Y, R1, R2, and Ar are as defined in claim 1, and w is 1 or 2. 5. The pharmaceutically acceptable composition according to any one of claims 1-4, wherein Ar is selected from phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, quinolinyl, isoquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, and 1,2,3,4tetrahydroquinolinyl, and wherein Ar optionally contains one to three substituents which are independently selected from hydrogen, hydroxyl, nitro, trifluoromethyl, (C1-C6)-straight or branched alkyl, O-[(C1-C6)-straight or branched alkyl], halogen, SO3H, or NR3R4. 6. The pharmaceutically acceptable composition according to claim 1, wherein said compound is selected from the group consisting of: (S)-1-((3,4,5-trimethoxyphenyl)-methyl-carbamoyl)-piperidine-2-carboxylic acid 4-pyridin-3-yl-1-(3-pyridin-3-yl-propyl)-butyl ester; (S)-1-((3-trifluoromethylphenyl)-methyl-carbamoyl)-piperidine-2-carboxylic acid 4-pyridin-3-yl-1-(3-pyridin-3-yl-propyl)-butyl ester; (S)-1-((4-tert-butylphenyl)-methyl-carbamoyl)-piperidine-2-carboxylic acid 4-pyridin-3-yl-1-(3-pyridin-3-yl-propyl)-butyl ester; (S)-1-((9-isopropylphenyl)-methyl-carbamoyl)-piperidine-2-carboxylic acid 4-pyridin-3-yl-1-(3-pyridin-3-yl-propyl)-butyl ester; (S)-1-(piperidine-1-carbonyl)-piperidine-2-carboxylic acid 4-pyridin-3-yl-1-(3-pyridin-3-yl-propyl)-butyl ester; (S)-1-((3,4,5-trimethoxyphenyl)-methyl-carbamoyl)-piperidine-2-carboxylic acid 4-pyridin-1-yl-1-(3-pyridin-1-yl-propyl)-butyl ester: (S)-piperidine-1,2-dicarboxylic acid 1-(3,4,5-trimethoxyphenyl)ester-2-(4-pyridin-3-yl-1-(3-pyridin-3-yl-propyl)-butyl)ester; (S)-1-((3,4,5-trimethoxyphenyl)-methyl-carbamoyl)-piperidine-2-carboxylic acid 1-(2-phenyl-ethyl)-3-phenyl-propyl ester; (S)-piperidine-2-carboxylic acid 2-1-(2-phenyl- ethyl)-3-phenyl-propyl ester; 4-(methyl-(2-(1-phenethyl-3-phenyl-propoxycarbonyl)-piperidine-1-carbonyl)-amino)-benzenesulfonic acid; (S)-piperidine-2-carboxylic acid 1-benzyloxy-methyl-2-benzyloxyethyl ester; (S)-1-(methyl-(4-morpholin-1-yl-phenyl)-carbamoyl)-piperidine-2-carboxylic acid 2-benzyloxy-1-(benzyloxy-methyl)-ethyl ester; (S)-1-(methyl-(4-piperidin-1-yl-phenyl)-carbamoyl)-piperidine-2-carboxylic acid 2-benzyloxy-1-(benzyloxy-methyl)-ethyl ester; (S)-piperidine-1,2-dicarboxylic acid 2-(2-benzyloxy-1-(benzyloxymethyl)-ethyl)ester-1-quinolin-5-yl ester; (S)-piperidine-1,2-dicarboxylic acid 2-(2-benzyloxy-1-(benzyloxymethyl)-ethyl)ester-1-pyridin-3-yl ester; 2-(1,3-dimethyl-3(3,4,5-trimethoxyphenyl)ureido)-3 phenyl-propanoic acid 4-pyridin-3-yl-1-(3-pyridin-3-yl-propyl)-butyl ester; 2-(1,3-dimethyl-3-(3,4,5-trimethoxyphenyl)ureido)-3-(phenyl)-propanoic acid 3-pyridin-3-yl-1-(2-pyridin-3-yl-ethyl)-propyl ester; N-methyl-2-phenylethylamine-1,2-dicarboxylic acid 1-(3,4,5-trimethoxyphenyl)ester; 2-(4-pyridin-3-yl-1-(3-pyridin-3-yl-propyl)butyl) ester; N-Methyl-2-phenylethylamine-1,2-dicarboxylic acid 1-(3,4,5-trimethoxyphenyl)ester; or 2-(3-pyridin-3-yl-1-(2-pyridin-3-yl-ethyl)propyl) ester; and pharmaceutically acceptable derivatives thereof. 7. The pharmaceutically acceptable composition according to claim 1, wherein said neurotrophic factor is selected from nerve growth factor (NGF), insulin growth factor (IGF) and active truncated derivatives thereof, acidic fibroblast growth factor (aFGF), basic fibroblast growth factor (bFGF), platelet-derived growth factors (PDGF), brain-derived neurotrophic factor (BDNF), ciliary neurotropic factors (CNTF), glial cell-derived neurotropic factor (GDNF), neurotrophin-3 (NT-3) or neurotrophin 4/5 (NT-4/5). 8. The pharmaceutically acceptable composition according to claim 8, wherein said neurotrophic factor is nerve growth factor (NGF). 9. A method for stimulating neurite growth in a patient or in an ex vivo nerve cell comprising the step of administering to said patient or said nerve a neurotrophic amount of a compound having the formula (I): Formula (I) and pharmaceutically acceptable derivatives thereof, wherein: R1, R2, B, D, J, K, A, Y, Z, and n are defined as in claim 1. 10. The method according to claim 9, wherein, in compound of formula (I), at least one of B or D is independently represented by the formula -(CH2) r-(X)-(CH2) s-Ar, wherein r, s, and X are as defined in claim 2. 11. The method according to claim 9, wherein said compound has formula (II) or formula (III):   Formula (II)   Formula (III) wherein: Y, R1, R2, and Ar are as defined in claim 1, and w is 1 or 2. 12. The method according to claim 9, wherein said compound has formula (IV) or formula (V):   Formula (IV)    Formula (V): wherein: Y, R1, R2, and Ar are as defined in claim 1, w is 1 or 2 and J is selected from hydrogen or (C1-C6)-straight or branched alkyl. 13. The method according to any one of claims 9-13, wherein Ar is selected from phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, quinolinyl, isoquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, or 1,2,3,4-tetrahydroquinolinyl, wherein Ar optionally contains one to three substituents which are independently selected from hydrogen, hydroxyl, nitro, trifluoromethyl, (C1-C6)-straight or branched alkyl, O-[(C1-C6)-straight or branched alkyl], halogen, SO3H, and NR3R4. 14. The method according to claim 9, wherein said compound is selected from: (S)-1-((3,4,5-trimethoxyphenyl)-methyl-carbamoyl)-piperidine-2-carboxylic acid 4-pyridin-3-yl-1-(3-pyridin-3-yl-propyl)-butyl ester; (S)-1-((3-trifluoromethylphenyl)-methyl-carbamoyl)-piperidine-2-carboxylic acid 4-pyridin-3-yl-1-(3-pyridin-3-yl-propyl)-butyl ester; (S)-1-((4-tert-butylphenyl)-methyl-carbamoyl)-piperidine-2-carboxylic acid 4-pyridin-3-yl-1-(3-pyridin-3-yl-propyl)-butyl ester; (S)-1-((4-isopropylphenyl)-methyl-carbamoyl)-piperidine-2-carboxylic acid 4-pyridin-3-yl-1-(3-pyridin-3-yl-propyl)-butyl ester; (S)-1-(piperidine-1-carbonyl)-piperidine-2-carboxylic acid 4-pyridin-3-yl-1-(3-pyridin-3-yl-propyl)-butyl ester; (S)-1-((3,4,5-trimethoxyphenyl)-methyl-carbamoyl)-piperidine-2-carboxylic acid 4-pyridin-1-yl-1-(3-pyridin-1-yl-propyl)-butyl ester; (S)-piperidine-1,2-dicarboxylic acid 1-(3,4,5-trimethoxyphenyl)ester-2-(4-pyridin-3-yl-1-(3-pyridin-3-yl-propyl)-butyl)ester; (S)-1-((3,4,5-trimethoxyphenyl)-methyl-carbamoyl)-piperidine-2-carboxylic acid 1-(2-phenyl-ethyl)-3-phenyl-propyl ester; (S)-piperidine-2-carboxylic acid 2-1-(2-phenyl- ethyl)-3-phenyl-propyl ester; 4-(methyl-(2-(1-phenethyl-3-phenyl-propoxycarbonyl)-piperidine-1-carbonyl)-amino)-benzenesulfonic acid; (S)-piperidine-2-carboxylic acid 1-benzyloxy-methyl-2-benzyloxyethyl ester; (S)-1-(methyl-(4-morpholin-1-yl-phenyl)-carbamoyl)-piperidine-2-carboxylic acid 2-benzyloxy-1-(benzyloxy-methyl)-ethyl ester; (S)-1-(methyl-(4-piperidin-1-yl-phenyl)-carbamoyl)-piperidine-2-carboxylic acid 2-benzyloxy-1-(benzyloxy-methyl)-ethyl ester; (S)-piperidine-1,2-dicarboxylic acid 2-(2-benzyloxy-1-(benzyloxymethyl)-ethyl)ester-1-quinolin-5-yl e