Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/08—Bridged systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
  • A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
  • A61P25/16—Anti-Parkinson drugs
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/16—Otologicals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
  • C07C57/52—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing halogen
  • C07C57/58—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing halogen containing six-membered aromatic rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
  • C07C59/40—Unsaturated compounds
  • C07C59/58—Unsaturated compounds containing ether groups, groups, groups, or groups
  • C07C59/64—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings

Definitions

• the present invention relates to compounds of Formula (H):
• the invention relates to a method of treating a neurological disorder in an animal, comprising administering to the animal a therapeutically effective amount of a compound of Formula (I) or (II), or pharmaceutically acceptable salt, solvate, prodrug, pharmacologically active metabolite thereof, or pharmaceutically acceptable salt of said metabolite.
• a therapeutically effective amount of a neurotrophic factor selected from nerve growth factor, insulin growth factor and its active truncated derivatives, acidic and basic fibroblast growth factor, platelet-derived growth factors, brain-derived neurotrophic factor, ciliary neurotrophic factors, glial cell line-derived neurotrophic factor, neurotrophin-3, and neurotrophin 4/5 may be coadministered, separately or in a single pharmaceutical composition also containing an agent of the invention, to a patient in need of such treatment.
• cycloalkyl is intended to mean a non-aromatic monovalent monocyclic, bicyclic, or tricyclic radical containing from 3 to 14 carbon ring atoms, each of which may be saturated or unsaturated.
• Illustrative examples of cycloalkyl groups include the following moieties:
• aryl is intended to mean an aromatic monovalent monocyclic, bicyclic, or tricyclic radical containing 6, 10, 14, or 18 carbon ring atoms.
• aromatic ring structures include phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, furyl, thienyl, pyrrolyl, pyridyl, pyridinyl, pyrazolyl, imidazolyl, pyrazinyl, pyridazinyl, 1,2,3- triazinyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, l-H-tetrazol-5-yl, indolyl, quinolinyl, benzofuranyl, benzothiophenyl (thianaphthenyl), and the like.
• aryl groups include the following moieties:
• heterocycle is intended to mean a heteroaryl or heterocycloalkyl group.
• carbonyl refers to the -C (O)-R radical, where R is as defined below.
• sulfonyl refers to the -SO 2 -R radical, where R is as defined below.
• compositions according to the invention comprise, as an active ingredient, a compound of the Formula I or II, or a pharmaceutically acceptable salt, prodrug, solvate, or a pharmaceutically active metabolite of such compound, or a pharmaceutically acceptable salt of such a metabolite.
• Such compounds, salts, prodrugs, solvates and metabolites are sometimes referred to herein collectively as "neurotrophic agents”.
• a “pharmaceutically acceptable salt” is intended to mean a salt that retains substantially the biological effectiveness of the free acid or base form of the specified compound and that is biologically suitable for pharmaceutical use.
• a compound of the invention may possess a sufficiently acidic group, a sufficiently basic group, or both functional groups, and accordingly react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form pharmaceutically acceptable salts.
• Exemplary pharmaceutically acceptable salts include those salts prepared by reaction of the compounds of the present invention with a mineral or organic acid or an inorganic base, such as salts including sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1,4- dioates, hexyne-l,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates
• a pharmaceutically acceptable prodrug is intended to mean a compound that may be converted under physiological conditions or by solvolysis in the body to the specified compound.
• a pharmaceutically active metabolite is intended to mean a pharmacologically active product of a specified compound produced through metabolism in the body.
• inventive compounds having one or more chiral centers may exist as single stereoisomers (i.e., essentially free of other stereoisomers), racemates, and/or mixtures of enantiomers and/or diastereomers. All such single stereoisomers, racemates and mixtures thereof are intended to be within the scope of the present invention.
• an optically pure compound having one chiral center is one that consists essentially of one of the two possible enantiomers (i.e., is enantiomerically pure), and an optically pure compound having more than one chiral center is one that is both diastereomerically pure and enantiomerically pure.
• the compounds of the present invention are used in a form that is at least 90% optically pure, that is, a form that contains at least 90% of a single isomer (80% enantiomeric excess ("e.e.") or diastereomeric excess (“d.e.”)), more preferably at least 95% (90% e.e. or d.e.), even more preferably at least 97.5% (95% e.e. or d.e.), and even more preferably at least 99% (98% e.e. or d.e.).
• Formula (I) or (II) includes compounds of the indicated structure in both hydrated and non-hydrated forms.
• Other examples of solvates include the structures in combination with isopropanol, ethanol, methanol, DMSO.
• Neurotrophic compounds of the invention are represented by the general structural Formulae (I) and (II) defined above.
• these compounds inhibit the rotamase (peptidyl-prolyl isomerase) enzyme activity of FKBP, in particular, FKBP-12.
• Particularly preferred are compounds of the Formula (Ila):
• Q is phenylmethyl, 3-methylphenyl, 1-naphthalenyl, 4-(4- pyridinyloxy)-phenyl, 4-methylphenyl, 4-(l,l-dimethylethyl)phenyl, 4-(l- methylethyl)phenyl, 4-ethylphenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2,4-dinitro ⁇ henyl, 2-(l-naphthalenyl)ethyl, l,l'-biphenyl, 3-[(3,4,5- trimethoxyphenyl)amino]phenyl, 3',4'-dichloro[l,l'-biphenyl]-4-yl, 3',4'- dichloro[l,l'-biphenyl]-3-yl, 4-cyanophenyl, 6-chloro-3-pyridinyl, cis-2,6-
• Q' is l-lH-indozol-3-yl-methanoyl, difluoro(3,4,5- trimethoxyphenyl), difluoro(4-chlorophenyl), 3,4-dimethoxybenzoyl, or NHR 4 , where R 4 is phenyl, 3-methoxyphenyl, phenylmethyl, 3-methylphenyl, or 4-nitrophenyl.
• D' is carbon
• R is hydrogen
• R, D', X', A, D, E, and Q" are as previously defined for the compound of Formula (II).
• D' is carbon
• EDC is l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
• DCC is 1,3-dicyclohexylcarbodiimide
• DMAP is 4-dimethylaminopyridine
• DMF is N, N-dimethylformamide
• HATU is O-(7-azabenzotriazol-l-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate
• HRMS is high resolution mass spectrum
• DEAD is diethyl azodicarboxylate
• MS is mass spectrum
• THF is tetrahydrofuran
• DIEA is diisopropylethylamine
• HOBt is 1-hydroxybenzotiazole hydrate
• Pd-C is palladium on carbon; atm is (atmosphere);
• MOPS is (4
• the compounds of the present invention may be readily prepared by standard techniques of organic chemistry, utilizing the following synthetic pathways depicted below. Unless otherwise indicated, the starting materials are either commercially available or can be prepared by conventional techniques.
• Z is benzyloxycarbonyl.
• other moieties suitable for use as protecting groups for the bridgehead nitrogen may be employed, such as FMOC and BOC.
• 2,6-Pyridine dicarboxylic acid 25 g, 0.15 mol was dissolved in 2.0M NaOH (154 mL) and H2O (30 mL) at room temperature, and placed in a 500-mL Parr bottle. Rhodium on alumina powder (5%, 1.87 g) was added and the mixture was purged with argon for 15 minutes. The reaction mixture was shaken under 55 psi of hydrogen for 48 hours. The suspension was filtered through compacted Celite, and the clear filtrate was cooled to 0°C.
• Piperidine-1, 2, 6-tricarboxylic acid 1-benzyl ester (Compound 1, 19.7 g, 64.11 mmol) was suspended in acetic anhydride (80 mL, 848 mmol) in a dry 250-mL round- bottom flask. The mixture was stirred at 70°C for 30 minutes until a clear solution formed. The remaining acetic anhydride was removed in vacuo, to afford Compound 2 (18.5 g, 100%) as a clear oil. The material was of sufficiently good quality to be used in the next reaction without purification. The product was sensitive to water, so it was prepared for immediate use in the next step.
• Step 5 Synthesis of 9,13-Imino-8H-azocino[2,l-a]isoquinolin-8- one,5,6,9,10,ll,12,13,13a-octahydro-6-methyl-,(6S,9S,13R,13aR)-(9Cl) (Compound
• Step 3 Synthesis of 9,13-Imino-8H-azocino [2,1-a] isoquinolin-8-one, 5,6,9,10,11, 12,13, 13a-octahydro-6-methyl-, (6R, 9R, 13S, 13aS)-(9Cl) (Compound 10):
• the imide (Compound 15, 1.42 g, 3.34 mmol) was reduced and cyclized according to a procedure similar to the Compound 5 synthesis (Example l ⁇ Step 4).
• the title Compound (0.63 g) was obtained as a mixture of enantiomers in 46% yield.
• the basic aqueous layer was acidified with concentrated hydrochloric acid prior to extraction with ethyl acetate and drying over magnesium sulfate.
• R a is selected from substituted or unsubstituted aryl, alkyl, heteroaryl, and heterocycloalkyl .
• This compound was prepared similar to Example 1 A, using Compound A (0.0326 g, 0.1189 mmol), which was synthesized according to a published procedure (Katoh, S. and et al. WO0004020), DMF (1 mL), p-tolylsulfonyl chloride (0.0256 g, 0.1342 mmol) and ethyl diisopropyl amine (0.0205 mL, 0.116 mmol). Filtration of the final precipitate gave 0.0248 g of Compound 36 (49% yield).
• This compound was prepared similar to Example 1 A, using Compound B (0.0339 g, 0.126 mmol, synthesized according to a published procedure [Katoh, S. and et al. WO 00/04020]), DMF (1 mL), p-tolylsulfonyl chloride (0.0237 g, 0.126 mmol) and ethyl diisopropyl amine (0.021 mL, 0.126 mmol). Filtration of the final precipitate gave 0.0255 g of Compound 37 (47% yield).
• This compound was prepared similar to Example 1 A, using Compound B (0.0532 g, 0.1954 mmol, synthesized according to a published procedure [Katoh, S. and et al. WO 0004020]), DMF (1 mL), p-t-butyl phenylsulfonyl chloride (0.0680 g, 0.293 mmol) and ethyl diisopropyl amine (0.0339 mL, 0.195 mmol). Filtration of the final precipitate gave 0.0691 g of Compound 38 (75% yield).
• This compound was prepared similar to Example 1 A using Compound C (0.1021 g, 0.337 mmol), DMF (1 mL), p-t-butylphenylsulfonyl chloride (0.2303 g, 0.993 mmol) and ethyl diisopropyl amine (0.058 mL, 0.337 mmol). Filtration of the final precipitate gave the product which was dissolved in CH 2 C1 2 , concentrated onto silica and purified by MPLC (hexane/ethyl acetate gradient 90:10 to 40:60). Concentration of the fractions containing the desired product gave 0.1396 g of Compound 42 (83% yield).
• This compound was prepared similar to Example 1 A using Compound C (0.1056 g, 0.349 mmol), DMF (1 mL), p-i-propylphenylsulfonyl chloride (0.2171 g, 0.993 mmol) and ethyl diisopropyl amine (0.0576 L, 0.369 mmol). Filtration of the final precipitate gave the product which was dissolved in CE ⁇ 2C1 2 , concentrated onto silica and purified by MPLC (hexane/ethyl acetate gradient 90:10 to 40:60). Concentration of the fractions containing the desired product gave 0.142 g of Compound 43 (84% yield).
• This compound was prepared similar to Example 1 A, using Compound C (0.1053 g, 0.348 mmol), DMF (1 mL), m-bromophenylsulfonyl chloride (0.2739 g, 1.07 mmol) and ethyl diisopropyl amine (0.057 mL, 0.348 mmol). Filtration of the final precipitate gave very little product so the water layer was extracted with 3x10 mL CH 2 Cl 2 . The organic layers were combined, dried over MgSO , filtered and concentrated onto silica and purified by MPLC (hexane/ethyl acetate gradient 90:10 to 40:60). Concentration of the fractions containing the desired product gave 0.1472 g of Compound 48 (81% yield).
• This compound was prepared similar to Example 1 A, using Compound C (0.1024 g, 0.338 mmol), DMF (1 mL), 2,4-Dinitrophenylsulfonyl chloride (0.271 g, 1.02 mmol) and ethyl diisopropyl amine (0.059 mL, 0.338 mmol). Filtration of the final precipitate gave very little product so the water layer was extracted with 3x10 mL CH 2 Ci 2 . The organic layers were combined, dried over MgSO 4 , filtered and concentrated onto silica and purified by MPLC (hexane/ethyl acetate gradient 90:10 to 40:60). Concentration of the fractions containing the desired product gave 0.0481 g of Compound 50 (27% yield).
• This compound was prepared similar to Example 24A from Compound E (54 mg, 0.2 mmol), m-toluenesulphonylchloride (45 mg, 0.24 mmol), and N- methylmorpholine (0.03 mL, 0.28 mmol) to give 15 mg of the title compound (18% yield).
• the racemic dimethoxyisoquinoline compound (502 mg, 1.66 mmol) was reacted with (R)-Mandelic acid (190 mg, 1.25 mmol), HATU (1.49 g, 3.92 mmol), and N-methylmorpholine (0.5 mL, 4.5 mmol) in 10 mL DMF at room temperature for 2 hours.
• the mixture was dropped into a cold solution of aqueous sodium bicarbonate.
• the resulting precipitate was collected by filtration.
• the filtrate was extracted with ethyl acetate (2x).
• the extracts and the solid were combined and set aside.
• the aqueous layer was basified with IN NaOH to ⁇ pH 11 and extracted with ethyl acetate (2x).
• the extracts were combined with the earlier organics and were washed with 0.5N HCI (3x), brine (lx), dried over sodium sulfate, concentrated to dryness and set aside.
• the acidic aqueous washings were basified with ION NaOH to ⁇ pH 11 and extracted with ethyl acetate (3x). These extracts were washed with brine, dried over sodium sulfate and concentrated to dryness to yield recovered isoquinoline compound (140 mg, 0.46 mmol, 28%) as predominantly one enantiomer( ⁇ 80ee approx).
• Sulfamoyl chloride B was prepared from Compound C by a synthetic method analogous to sulfamoyl chloride A synthesis.
• the title compound was obtained in 35% yield which contains -25% (mol/mol) of inseparable chloride as a side product (sulfamoyl chloride C).
• This compound was prepared from Compound D (Compound 6) by synthetic method analogous to sulfamoyl chloride A. synthesis. The title compound was obtained in 42% yield.
• This compound was prepared from sulfamoyl chloride A by a synthetic method analogous to Example 4B. A 49% yield was obtained.
• This compound was prepared from sulfamoyl chloride A by a synthetic method analogous to Example 4B. A 59% yield was obtained.
• This compound was prepared from sulfamoyl chloride A by a synthetic method analogous to Example 4B. A 31% yield was obtained.
• This compound was prepared from sulfamoyl chloride A by a synthetic method analogous to Example 5B. A 50% yield was obtained.
• This compound was prepared from sulfamoyl chloride A by a synthetic method analogous to Example 4B. An 80% yield was obtained.
• This compound was prepared from sulfamoyl chloride A by a synthetic method analogous to Example 4B. A 55% yield was obtained.
• This compound was prepared from sulfamoyl chloride A by a synthetic method analogous to Example 5B. A 68% yield was obtained.
• This compound was prepared from sulfamoyl chloride A by a synthetic method analogous to Example 5B. A 7% yield was obtained.
• This compound was prepared similar to Example ID, using Compound A (0.0912 g, 0.335 mmol), DMF (1.0 mL), 2,4-difluorophenyl isocyanate (0.0796 mL, 0.670 mmol). After stirring for 12 hours at room temperature, an additional 0.07 mL isocyanate was added and stirring was continued for 48 hours. The reaction was quenched with 3 mL 1.0 M HCI, and the solution was extracted with 3x5 mL CH 2 CI 2 . The organic layers were combined, dried over MgSO 4 , filtered and concentrated onto silica. The crude material was purified by MPLC (hexane/ethyl acetate gradient 90:10 to 40:60). Concentration of the fractions containing the desired product gave 0.0464 g of Compound 74 (32% yield).
• This compound was prepared similar to Example ID, using Compound A (0.0573 g, 0.210 mmol), DMF (1.0 mL), phenyl isocyanate (1.2 mL, 1.1 mmol). The reaction was quenched with 3 mL 1.0 M HCI, and the solution was extracted with 3x5 mL CH 2 C1 2 . The organic layers were combined, dried over MgSO 4 , filtered and concentrated onto silica. The crude material was purified by MPLC (hexane/ethyl acetate gradient 90:10 to 40:60). Concentration of the fractions containing the desired product gave 0.0222 g of Compound 75 (27% yield).
• This compound was prepared similar to Example ID, using Compound B (0.0576 g, 0.211 mmol), DMF (1.0 mL), phenyl isocyanate (O.lmL, 0.920 mmol). The reaction was quenched with 3 mL 1.0 M HCI, and the solution was extracted with 3x5 mL CH2C1 2 . The organic layers were combined, dried over MgSO , filtered and concentrated onto silica. The crude material was purified by MPLC (hexane/ethyl acetate gradient 90:10 to 40:60). Concentration of the fractions containing the desired product gave 0.0864 g of Compound 76 (100% yield).
• This compound was prepared similar to Example ID, using Compound B (0.0829 g, 0.304 mmol), DMF (1.0 mL), 2-methoxyphenyl isocyanate (0.079 mL, 0.609 mmol). The reaction was quenched with 3 mL 1.0 M HCI, and the solution was extracted with 3x5 mL CH 2 ⁇ 2 . The organic layers were combined, dried over MgSO 4 , filtered and concentrated onto silica. The crude material was purified by MPLC (hexane/ethyl acetate gradient 90:10 to 40:60). Concentration of the fractions containing the desired product gave 0.1138 g of Compound 78 (89% yield).
• This compound was prepared similar to Example ID, using Compound C (0.0867 g, 0.286 mmol), DMF (1.0 mL), 3-methoxyphenyl isocyanate (0.074 mL, 0.573 mmol). The reaction was quenched with 3 mL 1.0 M HCI, and the solution was extracted with 3x5 mL CH 2 C1 2 . The organic layers were combined, dried over MgSO 4 , filtered and concentrated onto silica. The crude material was purified by MPLC (hexane/ethyl acetate gradient 90:10 to 40:60). Concentration of the fractions containing the desired product gave 0.0418 g of Compound 79 (32% yield). Spectral analysis of the product was consistent with Compound 79: MS (APCI) 452.2 (M+H + ).
• This compound was prepared similar to Example ID, using Compound A (0.0893 g, 0.328 mmol), DMF (1.0 mL), benzyl isocyanate (0.0804 mL, 0.656 mmol). The reaction was quenched with 3 mL 1.0 M HCI, and the solution was extracted with 3x5 mL CH 2 CI 2 . The organic layers were combined, dried over MgSO 4 , filtered and concentrated onto silica. The crude material was purified by MPLC (hexane/ethyl acetate gradient 90:10 to 40:60). Concentration of the fractions containing the desired product gave 0.085 g of Compound 80 (64% yield).
• This compound was prepared similar to Example ID, using Compound A (0.0823 g, 0.302 mmol), DMF (1.0 mL), 4-nitrophenyl isocyanate (0.1093 g, 0.604 mmol). The reaction was quenched with 3 mL 1.0 M HCI, and the solution was extracted with 3x5 mL CH 2 CI2. The organic layers were combined, dried over MgSO 4 , filtered and concentrated onto silica. The crude material was purified by MPLC (hexane/ethyl acetate gradient 90:10 to 40:60). Concentration of the fractions containing the desired product gave 0.0568 g of Compound 83 (56% yield).
• amides and , ⁇ -difluoro amides of the present invention may be prepared in the manner depicted in Schemes E and F respectively shown below:
• R is selected from substituted or unsubstituted aryl, alkoxy aryl, and hydroxy aryl.
• This compound was prepared similar to Example IE, using Compound C (0.080 g, 0.264 mmol), bis-(4-chlorophenyl)acetic acid (0.093, 0.330 mmol), THF (3.3 mL), EDC (0.080 g, 0.417 mmol), HOBt (0.05g, 0.370 mmol) and TEA (0.06mL, 0.430 mmol). Purification afforded 0.111 g of Compound 105 (74% yield).
• This compound was prepared similar to Example IE, using Compound C (0.080 g, 0.264 mmol), 2-oxo-3,4-dimethoxyphenyl acetic acid (0.055, 0.264 mmol), THF (3.3 mL), EDC (0.080 g, 0.417 mmol), HOBt (0.05 g, 0.370 mmol) and TEA (0.06 mL, 0.430 mmol). Purification afforded 0.012 g of Compound 107 (10% yield) as a byproduct.
• This compound was prepared similar to Example IE, using Compound A (0.200 g, 0.734 mmol), 2-oxo-3,4-dichlorophenyl acetic acid (0.193, 0.881 mmol), CH 2 C1 2 instead of THF (8 mL), EDC (0.170 g, 0.881 mmol), HOBt (0.120 g, 0.881 mmol) and TEA (0.13 mL, 0.881 mmol). Purification afforded 0.072 g of Compound 100 (22% yield) as a byproduct.
• This compound was prepared similar to Example IE, using Compound B (0.200 g, 0.734 mmol, synthesized according to a published procedure [Katoh, S. and et al. WO 0004020]), 2-oxo-3,4-dichlorophenyl acetic acid (0.190, 0.881 mmol), CH 2 C1 2 instead of THF (8 mL), EDC (0.170 g, 0.881 mmol), HOBt (0.120g, 0.881 mmol) and TEA (0.13mL, 0.881 mmol). Purification afforded 0.049g of Compound 101 (15% yield) as a byproduct.
• This compound was prepared similar to Example 6E from the amine (Compound G, 90 mg, 0.33 mmol), 3-indazole carboxylic acid (53 mg, 0.33 mmol), HATU (125 mg, 0.33 mmol) and N-methylmorpholine (0.044 mL, 0.4 mmol) to afford 103 mg of the title compound (74% yield).
• This compound was prepared similar to Example 9E from the amine (Compound E, 45 mg, 0.17 mmol), 1-naphthoyl chloride (0.03 mL, 0.2 mmol) and Hunig's base (0.04 mL, 0.23 mmol).
• the compound was purified by flash chromatography on silica gel using gradient elution of ethyl acetate/hexanes (25-50%) to give 30 mg of the title compound (43% yield).
• This compound was prepared similar to Example IE, using Compound C (0.101 g, 0.330 mmol), 2-oxo-N-[(benzyloxy) carbonyl]-2-aminophenyl acetic acid (0.120 g, 0.530 mmol), THF (4 mL), EDC HCI (0.096 g, 0.500 mmol), HOBt (0.067 g, 0.500 mmol) and TEA (0.08 mL, 0.530 mmol). Purification afforded 0.015 g of Compound 109 (8% yield).
• This compound was prepared similar to Example IE, using Compound C (0.100 g, 0.330 mmol), 2,4-Dichlorophenyl acetic acid (0.088 g, 0.396 mmol), THF (6 mL), EDCHC1 (0.095 g, 0.500 mmol), HOBt (0.067 g, 0.500 mmol) and TEA (0.05 mL, 0.530 mmol). Purification afforded 0.030 g of Compound 108 (19% yield). Spectral analysis of the product was consistent with Compound 108:
• heterobicycles compounds of the present invention may be prepared in the manner depicted in Scheme H below:
• A', B' are nitrogen, sulfur, or oxygen.
• Example IH
• Compound C (Compound 13). An off-white solid, mp 207-209 °C.
• This compound was prepared in a process analogous to Example 3H, using Compound C (Compound 13). A white solid, mp 202-210 °C.
• BIOCHEMICAL AND BIOLOGICAL ASSAYS BIOCHEMICAL AND BIOLOGICAL ASSAYS :
• a variety of assays and techniques may be employed to determine the activities of the compounds of the present invention.
• the activity of a compound of the invention for stimulation of neurite outgrowth can be directly related to its binding affinity for FKBP-12 and its ability to inhibit FKBP-12 rotamase activity.
• assays known in the art for measuring ligand binding and enzyme activity may be employed.
• Rate constants were determined from the absorbance versus time plots generated.
• the compounds of the invention may be used to prepare pharmaceutical compositions, such as those described below.
• the pharmaceutical compositions of this invention comprise an effective neurite-outgrowth-stimulating compound of Formula (I) or (II) and an inert, pharmaceutically acceptable carrier or diluent.
• the pharmaceutical compositions may additionally comprise a neurotrophic factor.
• inventive agents may be administered by any of a variety of suitable routes, such as orally, rectally, transdermally, subcutaneously, intravenously, intramuscularly, or intranasally.
• suitable routes such as orally, rectally, transdermally, subcutaneously, intravenously, intramuscularly, or intranasally.
• the agents are preferably formulated into compositions suitable for the desired routes before being administered.
• An inventive agent is preferably administered in conventional dosage form prepared by combining a therapeutically effective amount of an agent (e.g., a compound of Formula I or LI) as an active ingredient with appropriate pharmaceutical carriers or diluents according to conventional procedures. These procedures may involve mixing, granulating and compressing or dissolving the ingredients as appropriate to the desired preparation.
• a pharmaceutical composition or preparation according to the invention comprises an effective amount of the neurotrophic agent and a pharmaceutically acceptable carrier, such as a diluent or excipient for the agent.
• a pharmaceutically acceptable carrier such as a diluent or excipient for the agent.
• the carrier serves as a diluent, it may be a solid, semi-solid, or liquid material acting as a vehicle, excipient, or medium for the active ingredient(s).
• compositions according to the invention may be made by admixing the active ingredient(s) with a carrier, or diluting it with a carrier, or enclosing or encapsulating it within a carrier, which may be in the form of a capsule, sachet, paper container, or the like.
• Exemplary ingredients in addition to one or more cell-cycle control agents and any other active ingredients, include Avicel (microcrystalline cellulose), starch, lactose, calcium sulfate dihydrate, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid, peanut oil, olive oil, glyceryl monostearate, Tween 80 (polysorbate 80), 1,3-butanediol, cocoa butter, beeswax, polyethylene glycol, propylene glycol, sorbitan monostearate, polysorbate 60, 2-octyldodecanol, benzyl alcohol, glycine, sorbic acid, potassium sorbate, disodium hydrogen phosphate, sodium chloride, and water.
• Avicel microcrystalline cellulose
• starch lactose
• calcium sulfate dihydrate terra alba
• sucrose talc
• gelatin agar
• compositions may be prepared in any of a variety of forms suitable for the desired mode of administration.
• pharmaceutical compositions may be prepared in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solids or in liquid media), ointments (e.g., containing up to 10% by weight of a cell-cycle control agent), soft-gel and hard-gel capsules, suppositories, sterile injectable solutions, sterile packaged powders, and the like.

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• 2002
  • 2002-05-10 BR BR0210060-6A patent/BR0210060A/pt not_active IP Right Cessation
  • 2002-05-10 JP JP2002586941A patent/JP2004532854A/ja not_active Abandoned
  • 2002-05-10 WO PCT/US2002/014966 patent/WO2002089806A1/en not_active Ceased
  • 2002-05-10 CA CA002446795A patent/CA2446795A1/en not_active Abandoned
  • 2002-05-10 MX MXPA03010255A patent/MXPA03010255A/es unknown
  • 2002-05-10 EP EP02731761A patent/EP1423119A4/en not_active Withdrawn

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