Patent EA-004247-B1 (EA)
Title: Methods and compositions for stimulating neurite growth
Inventor: ZELLE ROBERT E
IPC: A61K31/44
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: RI, B and D are independently: hydrogen, Ar, (C1-C6) straight or branched alkyl, (C2-C6) straight or branched alkenyl or alkynyl, (C5-C7) cycloalkyl substituted (C1-C6) straight or branched alkyl, (C5-C7) cycloalkyl substituted (C3-C6) straight or branched alkenyl or alkynyl, (C5-C7) cycloalkenyl substituted (C1-C6) straight or branched alkyl, (C5-C7) cycloalkenyl substituted (C3-C6) straight or branched alkenyl of alkynyl, Ar-substituted (C1-C6) straight or branched alkyl, Ar-substituted (C3-C6) straight or branched alkenyl or alkynyl; provided that RI is not hydrogen or (C1-C6) straight or branched alkyl, and; wherein any one of the CH2 groups of said alkyl chains in RI, B and D is optionally replaced by O, S, SO, SO2 or NR; wherein R is hydrogen, (C1-C6) straight or branched alkyl, (C3-C4) straight or branched alkenyl or alkynyl, or (C1-C4) bridging-alkyl wherein a bridge is formed between the nitrogen and a carbon atom of said alkyl chain to form a ring, and wherein said ring is optionally fused to Ar; wherein each Ar is independently selected from phenyl, 1-naphthyl, 2-naphthyl, indenyl, azulenyl, fluorenyl, anthracenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyraxolyl, 2-pyrazolinyl, pyrazolidinyl, isoxazolyl, isotriazolyl, 1,2,3-oxadiazolyl, 1,2,3-triazolyl, 1,3,4-thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, 1,3,5-trithianyl, indolizinyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo[b]furanyl, benzo[b]thiophenyl, 1H-indazolyl, benzimidazolyl, benzthiazolyl, purinyl, 4H-quinolizinyl, quinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, isoquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl and phenoxazinyl; and wherein each Ar is optionally and independently substituted with one to three substituents independently selected from hydrogen, halogen, hydroxyl, nitro, -SO3H, trifluoromethyl, trifluoromethoxy, (C1-C6) straight or branched alkyl, O-((C1-C6) straight or branched alkyl), O-benzyl, O-phenyl, 1,2-methylenedioxy, -NR5R6, carboxyl, N-(C1-C6 straight or branched alkyl or C3-C5 straight or branched alkenyl) carboxamides, N,N-di-((C1-C6) straight or branched alkyl or (C3-C5) straight or branched alkenyl), carboxamides, morpholinyl, piperidinyl, O-M, CH2-(CH2)q-M, O-(CH2)q-M, (CH2)q-O-M, and CH=CH-M; wherein R5 and R6 are independently selected from the group consisting of hydrogen, (C1-C6) straight or branched alkyl, (C2-C6) straight or branched alkenyl or alkynyl, and benzyl or R5 and R6 are taken together to form a 5-7 membered heterocyclic ring; M is selected from the group consisting of 4-methoxyphenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrazyl, quinolyl, 3,5-dimethylisoxazoyl, 2-methylthioazoyl, thiazoyl, 2-thienyl, 3-thienyl, 4-thienyl and pyrimidyl; and q is 0-2; J is selected from the group consisting of (C1-C6) straight or branched alkyl, (C3-C6) straight or branched alkenyl or alkynyl, Ar-substituted (C1-C6) straight or branched alkyl, and Ar-substituted (C3-C6) straight or branched alkenyl of alkynyl, and cyclohexylmethyl; K is selected from the group consisting of (C1-C6) straight or branched alkyl, Ar-substituted (C1-C6) straight or branched alkyl, (C2-C6) straight or branched alkenyl or alkynyl, and Ar-substituted (C3-C6) straight or branched alkenyl or alkynyl; J and K together with nitrogen and carbon atoms, that they are correspondingly bonded with, forms 5-7-membered heterocyclic ring, which can contain an heteroatom, selected from O, S, SO and SO2; X is selected from the group consisting of Ar, -OR2, and -N(R3)R4; wherein R2 has the same definition as R1; R3 and R4 independently have the same definitions as B and D; or R3 and R4 are taken together to form a 5-7 membered heterocyclic aliphatic or aromatic ring; and m is 0 or 1; b) a neurotrophic factor; and c) a pharmaceutically suitable carrier. 2. The pharmaceutically acceptable composition according to claim 1, wherein said compound has the formula: wherein: J and K are independently (C1-C6) straight or branched alkyl, or Ar-substituted (C1-C6) straight or branched alkyl; and w is 1 or 2. 3. The pharmaceutically acceptable composition according to claim 1, wherein at least one of B or D is independently represented by the formula -(CH2)r-(Z)-(CH2)s-Ar, wherein: r is 1-4; s is 0-1; and each Z is independently selected from the group consisting of O, S, SO, SO2 and NR; wherein R is selected from the group consisting of hydrogen, (C1-C4) straight or branched alkyl, (C3-C4) straight or branched alkenyl or alkynyl, and (C1-C4) bridging alkyl wherein a bridge if formed between the nitrogen and the Ar group. 4. The pharmaceutically acceptable composition according to claim 3, wherein said compound has the formula: wherein: J and K are independently (C1-C6) straight or branched alkyl, or Ar-substituted (C1-C6) straight or branched alkyl; and w is 1 or 2. 5. The pharmaceutically acceptable composition according to claim 1, wherein: each Ar is independently selected from phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, imidazolyl, indolyl, isoindoyl, quinolinyl, isoquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, and 1,2,3,4-tetrahydroquinolinyl; and each Ar optionally and independently contains one to three substituents independently selected from hydroxyl, nitro, trifluoromethyl, (C1-C6) straight or branched alkyl, O-((C1-C6) straight or branched alkyl), halogen, SO3H, and -NR3R4. 6. The pharmaceutical composition according to claim 2, wherein said compound is selected from compounds 6-10, 12, 16-19, 21 or 23 of the Table I below: Table I Compound B D K R1 6 4-Pyr-(CH2)2- 4-Pyr-(CH2)2- PhCH2- 4-F-PhCH2- 7 4-Pyr-(CH2)2- 4-Pyr-(CH2)2- PhCH2- PhCH2- 8 4-Pyr-(CH2)2- 4-Pyr-(CH2)2- PhCH2- 4-Cl-PhCH2- 9 4-Pyr-(CH2)2- 4-Pyr-(CH2)2- 4-Cl-PhCH2- PhCH2- 10 H Ph-(CH2)3- PhCH2- 4-PyCH2- 12 4-Pyr-(CH2)3- 4-Pyr-(CH2)3- PhCH2- PhCH2- 16 4-Pyr-(CH2)2- 4-Pyr-(CH2)2- (CH3)2CH-CH2- PhCH2- 17 4-Pyr-(CH2)2- 4-Pyr-(CH2)2- (CH3)2CH-CH2- 4-F-PhCH2- 18 4-Pyr-(CH2)2- 4-Pyr-(CH2)2- (CH3)2CH-CH2- 4-Cl-PhCH2- 19 4-Pyr-(CH2)2- 4-Pyr-(CH2)2- 4-Cl-PhCH2- 4-F-PhCH2- 21 H 3-Im-(CH2)2- PhCH2- PhCH2- 23 Ph-(CH2)2- Ph-(CH2)2- PhCH2- 1H-Im-CH2- 7. The pharmaceutical composition according to claim 6, selected from (S)-N-Methyl-2-(methyl-(2-oxo-2-(3,4,5-trimethoxyphenyl)acetyl)amino)-3-phenyl-N-(3-(pyridin-4-yl)-1-(2-(pyridin-4-yl)-ethyl)propyl)propionamide (Compound 7); (S)-N-Methyl-2-(methyl-(2-oxo-2-(3,4,5-trimethoxyphenyl)acetyl)amino)-3-phenyl-N-(3-(pyridin-3-yl)-1-(2-(pyridin-3-ylpropyl)butyl)propionamide (Compound 8); (S)-N-Methyl-2-(methyl-(2-oxo-2-(3,4,5-trimethoxyphenyl)acetyl)amino)-(4-chlorophenyl)-N-(3-(pyridin-4-yl)-1-(2-(pyridin-4-yl)-ethyl)propyl)propionamide, and; (S)-N-Methyl-2-(methyl-(2-oxo-2-(3,4,5-trimethoxyphenyl)acetyl)amino)-(4-chlorophenyl)-N-(3-(pyridin-4-yl)-1-(2-(pyridin-3-yl-propyl)butyl)propionamide. 8. 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 neurotrophic factors (CNTF), glial cell-derived neurotrophic factor (GDNF), neurotrophin-3 (NT-3) and neurotrophin 4/5 (NT-4/5). 9. The pharmaceutically acceptable composition according to claim 8, wherein said neurotrophic factor is nerve growth factor (NGF). 10. 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): and pharmaceutically acceptable derivatives thereof, wherein: R1, B, D, J, K, X and m are defined as in claim 1. 11. The method according to claim 10, wherein said compound has the formula: wherein: J, K and w are such as defined in claim 2. 12. The method according to claim 10, wherein at least one of B or D is independently represented by the formula -(CH2)r-(Z)-(CH2)s-Ar, wherein r and s are such as defined in claim 3. 13. The method according to claim 12, wherein said compound has the formula: wherein: J and K are such as defined in claim 4. 14. The method according to claim 10, wherein: each Ar is independently selected from phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, imidazolyl, indolyl, isoindoyl, quinolinyl, isoquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, and 1,2,3,4-tetrahydroquinolinyl; and each Ar optionally and independently contains one to three substituents independently selected from hydroxyl, nitro, trifluoromethyl, (C1-C6) straight or branched alkyl, O-((C1-C6) straight or branched alkyl), halogen, SO3H, and -NR3R4. 15. The method according to claim 11, wherein said compound is selected from compounds 6-10, 12, 16-19, 21 or 23 Table I. 16. The method according to claim 15, wherein said compound is selected from a group comprising (S)-N-Methyl-2-(methyl-(2-oxo-2-(3,4,5-trimethoxyphenyl)acetyl)amino)-3-phenyl-N-(3-(pyridin-4-yl)-1-(2-(pyridin-4-yl)-ethyl)propyl)propionamide (Compound 7); (S)-N-Methyl-2-(methyl-(2-oxo-2-(3,4,5-trimethoxyphenyl)acetyl)amino)-3-phenyl-N-(3-(pyridin-3-yl)-1-(2-(pyridin-3-ylpropyl)butyl)propionamide (Compound 8); (S)-N-Methyl-2-(methyl-(2-oxo-2-(3,4,5-trimethoxyphenyl)acetyl)amino)-(4-chlorophenyl)-N-(3-(pyridin-4-yl)-1-(2-(pyridin-4-yl)-ethyl)propyl)propionamide, and; (S)-N-Methyl-2-(methyl-(2-oxo-2-(3,4,5-trimethoxyphenyl)acetyl)amino)-(4-chlorophenyl)-N-(3-(pyridin-4-yl)-1-(2-(pyridin-3-yl-propyl)butyl)propionamide. 17. The method according to any one of claims 10-16, wherein said