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  • 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
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  • 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 methods and pharmaceutical compounds and compositions for stimulating neurite outgrowth in nerve cells leading to nerve regeneration.
• the compositions comprise compounds that inhibit the peptidyl-prolyl isomerase (rotamase) enzyme activity associated with the FK-506 binding proteins (FKBP), such as FKBP- 12 and FKBP-52.
• the methods comprise treating nerve cells with compositions comprising the rotamase-inhibiting compound.
• the methods of the invention can be used to promote repair of neuronal damage caused by disease or physical trauma.
• BACKGROUND ART Immunophilins are a family of soluble proteins that serve as receptors for important immunosuppressant drugs such as cyclosporin A, FK-506 and rapamycin.
• FK-506 binding proteins FKBP
• FKBP-12 The 12-kiloDalton FK-506 binding protein, FKBP-12, binds FK-506 with high affinity.
• FK-506, e.g., [ 3 H]dihydro-FK-506 see Siekierka et al., Nature, 341, 755- 57 (1989); and U.S. Patent No.
• Binding affinity of other compounds for FKBP can be determined directly by microcalorimetry or from competitive binding assays using either tritiated or 14 C-labelled FK-506, as described by Siekierka et al. or Harding et al.
• FK-506-binding protein FKBP-12 participates in a variety of significant cellular functions.
• FKBP-12 catalyzes cis-trans isomerization of peptidyl-prolyl linkages.
• This peptidyl-prolyl isomerase enzyme activity is also referred to as rotamase activity.
• Such activity is readily assayed by methods known in the art (see Fischer et al., Biochim. Biophys. Acta, 791, 87 (1984); Fischer et al., Biomed. Biochim. Acta, 43, 1101 (1984); and Fischer et al., Nature, 337, 476-478 (1989)).
• U.S. Patent Nos. 5,192,773 and 5,330,993 to Armistead et al. report FKBP binding affinities that were correlated with rotamase-inhibiting activities for many compounds.
• FK-506 and compounds that bind FKBP competitively with FKBP stimulate outgrowth of neurites (axons) in nerve cells (see U.S. Patent No. 5,696,135 to Steiner et al.). Lyons et al. (Proc. Natl. Acad, Sci, USA, 91, 3191-95 (1994)) demonstrated that FK-506 acts to enhance or potentiate the effectiveness of nerve growth factor (NGF) in stimulating neurite outgrowth in a rat pheochromocytoma cell line. The mechanism of stimulation of such neurite outgrowth appears to be 10- to 100-fold potentiation of the action of nerve growth factor.
• NGF nerve growth factor
• rotamase peptidyl-prolyl isomerase
• the rotamase may convert a protein substrate into a form that promotes neural growth (see U.S. Patent No. 5,696,135).
• FKBP-12 forms bound complexes with the intracellular calcium ion channels — the ryanodine receptor (RyR) and the inositol 1,4,5-triphosphate receptor (IP 3 R) (Jayaraman et al., J. Biol. Chern., 267, 9474-9477 (1992); Cameron et al., Proc. Natl. Acad. Sci, USA, 92, 1784-1788 (1995)), helping to stabilize calcium release.
• RyR ryanodine receptor
• IP 3 R inositol 1,4,5-triphosphate receptor
• FK-506--FKBP bound complexes bind to and inhibit calcineurin, a cytoplasmic phosphatase.
• the phosphatase activity of calcineurin is necessary for dephosphorylation and subsequent translocation into the nucleus of nuclear factor of activated T-cells (NF-AT) (see Flanagan et al., Nature, 352, 803-807 (1991)).
• NF-AT nuclear factor of activated T-cells
• Calcineurin-inhibiting activity is correlated with the immunosuppressant activity of FK-506 and related compounds.
• Calcineurin inhibition does not correlate with the stimulation of neurite outgrowth. Therefore, compounds that are potent inhibitors of rotamase but not strong inhibitors of calcineurin are desired since they should be neurotrophic but non- immunosuppressive.
• Such neurotrophic agents desirably find use in augmenting neurite outgrowth, and hence in promoting neuronal growth and regeneration in various pathological situations where neuronal repair can be facilitated, including peripheral nerve damage caused by injury or diseases such as diabetes, brain damage associated with stroke, and for the treatment of neurological disorders related to neurodegeneration, including Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis (ALS).
• Such neurotrophic agents should also be useful for the treatment of memory impairment, for the treatment of hair loss, for the treatment of hearing loss, and for the treatment of vision disorder. See International Publication Nos. WO 00/16603 and WO 00/32588. Further, such use is preferably without the associated effect of immunosuppression, since long-term use of immunosuppressants is associated with side effects such as kidney toxicity, neurological deficits, and vascular hypertension.
• neurotropic agents that are potent inhibitors of the enzyme activity and especially of the cis-trans propyl isomerase (rotamase) activity of the FKBP-type immunophilins, particularly the immunophilin FKBP-12.
• Such compounds will preferably have physical and chemical properties suitable for use in pharmaceutical preparations, e.g., bioavailability, half-life, and efficient delivery to the active site.
• small organic molecules are preferred over proteins.
• such compounds will not significantly inhibit the protein phosphatase calcineurin and therefore lack any significant immunosuppressive activity.
• the invention relates to certain small-molecule neurotrophic compounds, such as those having affinity for FKBP-type immunophilins. Once bound to these proteins, the neurotrophic compounds are inhibitors of the enzyme activity associated with immunophilin proteins, preferably rotamase enzyme activity. Preferably the inhibitor compounds do not exert any significant immunosuppressive activity in addition to their neurotrophic activity.
• the invention also relates to effective processes for synthesizing such compounds as well as useful intermediates therefor.
• the invention further relates to methods for treating patients having neurological trauma or disorders as a result of, or associated with, conditions that include (but are not limited to) neuralgias, muscular dystrophy, Bell's palsy, myasthenia gravis, Parkinson's disease, Alzheimer's disease, multiple sclerosis, ALS, stroke and ischemia associated with stroke, neural parapathy, other neural degenerative diseases, motor neuron diseases, and nerve injuries including spinal cord injuries.
• the invention also relates to methods for treating patients with hair loss, vision disorder, memory impairment, or hearing loss.
• the neurotrophic compounds of the present invention may be used to stimulate the growth and regeneration of neurons.
• the administration of these compounds to individuals requiring therapeutic stimulation of neuronal growth and regeneration provides effective therapies for treating various pathological situations where neuronal repair can be facilitated, including peripheral nerve damage caused by injury or disease such as diabetes, brain damage associated with stroke, and for the treatment of neurological disorders related to neurodegeneration, including Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis.
• the present invention relates to compounds of Formula (I):
• R ⁇ is hydrogen; substituted or unsubstituted alkyl, alkenyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, or cycloalkenyl; or C (R ⁇ )(R 12 )(R 13 ), wherein R 11 and 12 each independently is substituted or unsubstituted alkyl, or R 11 and R 12 together with the atom to which they are bound form a substituted or unsubstituted cycloalkyl, and R 13 is H, OH, substituted or unsubstituted alkyl, aryl, heteroaryl, or heterocycloalkyl, or (CH ⁇ n -O-L 1 , where n is 0, 1, 2, or 3, L 1 is R 2 or C(O)R 2 , and R 2 is substituted or unsubstituted alkyl; R' is hydrogen; or substituted or unsubstituted alkyl, hydroxyl or amino; or Ri and R' taken together
• R" is hydrogen or substituted or unsubstituted alkyl; or Ri and R" taken together with the adjacent nitrogen atom form a substituted or unsubstituted heterocycle (e.g., heterocycloalkyl, heteroaryl, etc.);
• A', B', C, and D" are independently carbon, oxygen, sulfur, or nitrogen;
• E ⁇ F', G', and H' are independently carbon or nitrogen;
• I' is hydrogen, a halide, alkyl, alkoxy, acyl, or amine; wherein there can be 1, 2, or 3 F groups, where F can be attached to one or more of E' , H' , F' , or G' ;
• J is hydrogen or substituted or unsubstituted alkyl, alkenyl, cycloalkyl, aryl, or heteroaryl; and
• X is hydrogen, cyano, alkoxy, dimethoxymethyl, or oxygen, where when X is oxygen, the C-X bond is a double bond; or
• the present invention relates to compounds of Formula (H):
• R is hydrogen, or substituted or unsubstituted alkyl
• D' is C, O, or N; each X' is independently halogen, methoxy, amine wherein there can be 1, 2, or 3 X' groups, where X' can be attached to one or more of A, D, E, or the carbon atom of the ring; A, D, and E are each independently carbon, oxygen, or nitrogen; and
• the invention in another general aspect, relates to pharmaceutical compositions comprising each: a therapeutically effective amount of a compound of Formula (I) or (II), or a pharmaceutically acceptable salt, solvate, prodrug, pharmacologically active metabolite thereof, or pharmaceutically acceptable salt of said metabolite; and a pharmaceutically acceptable carrier.
• 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.
• the invention further relates to methods of treating neurological trauma or disorders as a result of, or associated with, conditions mediated by FKBP binding by administering a therapeutically effective amount of a compound of Formula (I) or (II), including neuralgias, muscular dystrophy, Bell's palsy, myasthenia gravis, Parkinson's disease, Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis (ALS), stroke and ischemia associated with stroke, neural parapathy, other neural degenerative diseases, motor neuron diseases, and nerve injuries including spinal cord injuries
• the invention relates to a method of treating hair loss, memory impairment, vision disorder, or hearing loss in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of Formula (I), or pharmaceutically acceptable salt, solvate, prodrug, or pharmacologically active metabolite thereof, or pharmaceutically acceptable salt of said metabolite.
• inventive methods comprise administering a therapeutically effective amount of a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt, prodrug, or solvate, or pharmacologically active metabolite thereof, or a pharmaceutically acceptable salt of said metabolite, to a patient in need of such treatment.
• 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.
• the invention also relates to intermediates of Formulae (6), (10), (13), (17), L, and K which are described below and are useful for preparing the FKBP-modulating compounds of general structural Formula (I) and (II).
• the invention further relates to processes of making the compounds using such intermediates.
• alkyl is intended to mean a straight- or branched-chain onovalent radical of saturated and/or unsaturated carbon and hydrogen atoms having one to twelve carbon atoms.
• a "lower alkyl” is intended to mean an alkyl group having from 1 to 4 carbon atoms in its chain.
• Illustrative alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, ethenyl, pentenyl, butenyl, propenyl, ethynyl, butynyl, propynyl, pentynl, hexynyl, and the like.
• the alkyl can be unsubstituted (i.e., containing only carbon and hydrogen) or substituted as specified.
• Suitable substituted alkyls include fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 3- fluoropropyl, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, and the like.
• 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:
• heterocycloalkyl is intended to mean a non-aromatic monovalent monocyclic, bicyclic, or tricyclic radical, which is saturated or unsaturated, containing from 3 to 18 ring atoms, and which includes from 1 to 5 heteroatoms selected from nitrogen, oxygen, and sulfur.
• heterocycloalkyl 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:
• heteroaryl is intended to mean an aromatic monovalent monocyclic, bicyclic, or tricyclic radical containing from 4 to 18 ring atoms, including from 1 to 5 heteroatoms selected from nitrogen, oxygen, and sulfur.
• heteroaryl 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.
• amide refers to the - C (O)NR radical, where R is as defined below.
• sulfonyl refers to the -SO 2 -R radical, where R is as defined below.
• nitro refers to the - C (NO 2 )-R radical, where R is as defined below.
• R is hydrogen or substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl or heteroaryl.
• an “amino” group is intended to mean the radical -NH 2 .
• An “alkoxy” group is intended to mean the radical -OR a , where R a is an alkyl group. Exemplary alkoxy group include methoxy, ethoxy, propoxy, and the like.
• a "hydroxy” group is intended to mean the radical -OH. Where indicated, the various moieties or functional groups for variables in the formulae may be substituted by one or more substituents.
• Such moieties may also be optionally substituted by a fused-ring structure or bridge, for example OCH -O. These substituents may optionally be further substituted with a substituent selected from such groups. Other examples of substituents are those reflected in the exemplary compounds that follow.
• 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
• the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, by treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyrovic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha-hydroxy acid, such as citric acid or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid or cinnamic acid, a sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic acid, or the like.
• an inorganic acid such as hydrochloric acid
• the desired pharmaceutically acceptable salt may be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), an alkali metal hydroxide or alkaline earth metal hydroxide, or the like.
• suitable salts include organic salts derived from amino acids, such as glycine and arginine, ammonia, primary, secondary, and tertiary amines, and cyclic amines, such as piperidine, morpholine and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.
• 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.
• Prodrugs and active metabolites of a compound may be identified using routine techniques known in the art. See, e.g., Bertolini et al., J. Med. Chern., 40, 2011-2016
• 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.
• the inventive compounds that are optically active are used in optically pure form.
• 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):
• R, D', X', A, D, E, and Q are as previously defined for the compound of Formula (II).
• 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-
• X' is 3-methoxy, 1,3-dimethoxy, 4-methoxy, or l,3-dimethoxy-4- chloro.
• D' is carbon.
• R is preferably hydrogen.
• R, D', X', A, D, E, and Q' are as previously defined for the compound of Formula (II).
• 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.
• X' is 4-methoxy, 3-methoxy, or 1,3-dimethoxy.
• D' is carbon
• R is hydrogen
• R, D', X', A, D, E, and Q" are as previously defined for the compound of Formula (II).
• Q" is (2,5-dihydro-lH-pyrrol-l-yl)-oxo, or oxo-1-piperidinyl.
• X' is 3-methoxy.
• D' is carbon
• R is preferably hydrogen.
• 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.
• Benzyl chloroformate (30.62 g, 0.18 mol) was added from the top to the cooled filtrate in three portions during a period of 30 minutes, and the solution was allowed to reach room temperature and stirred for an additional 5 hours. The remaining benzyl chloroformate was extracted from the mixture with diethyl ether. The aqueous layer was acidified with 2N HCI and extracted with ethyl acetate (EtOAc). The EtOAc was passed over a short plug of Na2SO4 and evaporated.
• 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):
• Compound 11 was prepared from piperidine-1, 2, 6-tricarboxylic acid 1-benzyl ester (2.11 g, 6.86 mmol) and 3,5-dimethoxyphenethyl amine (1.16 mL, 6.9 mmol) according to a procedure similar to the Compound 3 synthesis (Example l ⁇ Step 3). The title compound (11, 2.29 g) was obtained in 74% yield.
• the imide (Compound 11, 2.24 g, 4.95 mmol) was reduced and cyclized according to a procedure similar to the Compound 5 synthesis (Example l ⁇ Step 4).
• the title compound (12, 1.51 g) was obtained as a mixture of enantiomers in 70% yield.
• Step 3 Synthesis of 9,13-Irnino-8H-azocino [2,1-a] isoquinolin-8-one, 5,6,9,10,11, 12,13,13a-octahydro-l, 3-dimethoxy- (9C1) (Compound 13):
• 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.
• Step 4 Synthesis of 9,13-Imino-oxa-6-8H-azocino [2,1-a] isoquinolin-8-one, 5,9,10,ll,12,13,13a-heptahydro-3-methoxy-(9Cl) (Compound 17):
• Step 1 Synthesis of the precursors 3K-3L:
• the N-z protected 2,6-dicarboxylic acid 1 (1.0 eq) was suspended in acetic anhydride (0.08 M) and heated at 65 °C for 30 minutes, during which time the solution became clear and colorless. The mixture was cooled to room temperature and concentrated to an oil which was dissolved in 20 ml toluene and concentrated again. The toluene treatment was repeated 3 additional times to remove all traces of acetic anhydride. The residual oil was dissolved in toluene (0.45 M) and the desired phenethyl amine (1.1 eq.) was added and the mixture was stirred for 1.5 hours at room temperature.
• the precursor (3K-3L) was dissolved in THF (0.2 M) and the solution was cooled to -78 °C for the addition of Li(HBEt 3 ) (1.7 eq.). After 30 minutes at -78 °C, methanol was added and the reaction mixture was warmed to O °C. After 10 minutes, NaHCO 3 (saturated aqueous) and 30% H 2 O 2 were added and the mixture was stirred for 30 minutes at room temperature. The solution was then concentrated, diluted with water, extracted with CH 2 C1 2 , organics combined, dried over MgSO 4 /Na 2 SO 4 , filtered and concentrated. The residual oil was taken up in dry CH 2 C1 and TFA (0.02 M) was added.
• 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 B (0.0521 g, 0.191 mmol), DMF (1 mL), p-i-propyl phenylsulfonyl chloride (0.0626 g, 0.286 mmol) and ethyl diisopropyl amine (0.033 mL, 0.191 mmol). Filtration of the final precipitate gave 0.0539 g of Compound 39 (62% yield).
• This compound was prepared similar to Example 1 A using Compound C (0.1060 g, 0.350 mmol), DMF (2 mL), p-tolyl sulfonyl chloride (0.200 g, 1.05 mmol), and ethyl diisopropyl amine (0.060 mL, 0.350 mmol). Filtration of the final precipitate gave the product in the water layer. The water layer was extracted with CH 2 C1 2 (3 10 mL). The organic layers were combined, dried over MgSO 4 , filtered, 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 0.1409 g of Compound 40 (88% 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 1 A, using Compound C (0.1028 g, 0.340 mmol), DMF (1 mL), 2-(l-naphthyl)ethanesulfonyl chloride (0.259 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 C1 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 0.0203 g of Compound 51 (17% yield).
• Compound 48 (0.050 g, 0.0985 mmol) was combined with 3,5,5-trimethoxy aniline (0.0189 g, 0.114 mmol), Pd 2 (dba) 3 (0.0024 g, 0.00249 mmol), Cs 2 CO 3 (0.0436 g, 0.134 mmol), and (S)-tol-BINAP (0.0072 g, 0.0105 mmol) in toluene (0.5 mL) at room temperature. The mixture was heated at reflux for 18 hours, and then allowed to cool to room temperature.
• Compound 48 (0.050 g, 0.0985 mmol) was combined with anthranilic acid ethyl ester (0.0189 g, 0.114 mmol), Pd 2 (dba) 3 (0.0023 g, 0.00249 mmol), Cs 2 CO 3 (0.0436 g, 0.134 mmol), and (S)-tol-BINAP (0.0072 g, 0.0105 mmol) in toluene (0.5 mL) at room temperature. The mixture was heated at reflux for 18 hours, and then allowed to cool to room temperature.
• This compound was prepared similar to Example 1 A, using Compound C (0.103 g, 0.340 mmol), DMF (2 mL), m-tolyl sulfonyl chloride (0.194 g, 1.02 mmol), and ethyl diisopropyl amine (0.059 mL, 0.340 mmol). Filtration of the final precipitate gave the product in the water layer. The water layer was extracted with 3x10 mL CH 2 CI 2 . The organic layers were combined, dried over MgSO 4 , filtered, 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 0.1244 g of Compound 64 (80% yield).
• This compound was prepared by a synthetic method analogous to Example 23A from Compound B and 2-chloro-pyridin-5 -sulfonyl chloride, which was synthesized according to a published procedure (Naegeli, C. and et al. Helv. Chim. Acta. 1939, 21,
• 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).
• This compound was prepared similar to Example 24A, using Compound D (68 mg, 0.26 mmol), 1-naphthalenelsulfonylchloride (70 mg, 0.31 mmol), and N- methylmorpholine (0.04 mL, 0.38 mmol) in 5 mL dichloromethane.
• the crude product was purified on silica gel using ethyl acetate/hexanes (1:1) as eluent to give 25mg of the title compound (21% 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).
• This compound was prepared similar to Example 25 A, using Compound A (145 mg, 0.37 mmol), Palladium on Carbon (10%, 50 mg) in 5 mL ethyl acetate/ethanol, then 4'-pyridyloxy-4-phenylsulfonylchloride hydrochloride (100 mg, 0.33 mmol), and N-methylmorpholine (100 mg, 0.99 mmol) in 5 mL dichloromethane.
• Compound was purified by flash column chromatography (0-5% methanol in chloroform) to give 65 mg of the title compound (36% yield).
• R' and R" are selected from hydrogen, substituted or unsubstituted alkyl, aryl, heteroaryl, or R' and R" together taken with an adjacent nitrogen atom form a substituted or unsubstituted heterocycle.
• R is selected from hydrogen, substituted or unsubstituted alkyl and aryl.
• 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 B (containing 25% mol/mol sulfamoyl chloride C) by a synthetic method analogous to Example 4B. A 53% yield was obtained.
• This compound was prepared from sulfamoyl chloride A by a synthetic method analogous to Example 4B. A 51% yield was obtained.
• This compound was prepared from sulfamoyl chloride A by a synthetic method analogous to Example 4B. A 58% 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 from sulfamoyl chloride D by a synthetic method analogous to Example 5B. A 72% yield was obtained.
• This compound was prepared from sulfamoyl chloride A by a synthetic method analogous to Example lC. A 61% yield was obtained.
• ureas compounds of the present invention may be prepared in the manner depicted in Scheme D below:
• R c is selected from hydrogen, substituted or unsubstituted aryl, alkyl, heteroaryl or heterocycloalkyl.
• This compound was prepared similar to Example ID, using Compound B (0.0549 g, 0.2017 mmol), DMF (1.0 mL), 2-methylphenyl isocyanate (0.062 mL, 0.504 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 0.0369 g of Compound 71 (45% yield).
• This compound was prepared similar to Example ID, using Compound A (0.0705 g, 0.2509 mmol), DMF (1.0 mL), 4-methylphenyl isocyanate (0.065 mL, 0.518 mmol). After stirring for 12 hours at room temperature, an additional 0.065 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 .
• 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 (0.0569 g, 0.201 mmol), DMF (1.0 mL), 2,6-dimethylphenyl isocyanate (0.09 mL, 0.646 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 0.100 g of Compound 77 (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 B (0.0818 g, 0.300 mmol), DMF (1.0 mL), benzyl isocyanate (0.0737 mL, 0.601 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 , 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 0.0676 g of Compound 81 (56% yield).
• This compound was prepared similar to Example ID, using Compound C (0.0822 g, 0.272 mmol), DMF (1.0 mL), benzyl isocyanate (0.0667 mL, 0.544 mmol). The reaction was quenched with 3 mL 1.0 M HCI, and the solution was extracted with 3x5 mL CH2CI2. 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 82 (72% 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).
• This compound was prepared similar to Example ID, using Compound B (0.0866 g, 0.318 mmol), DMF (1.0 mL), 3 -methylphenyl isocyanate (0.1197 mL, 0.954 mmol). The reaction was added to 5 mL brine, filtered and the solids were 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 0.0785 g of Compound 85 (60% yield). Spectral analysis of the product was consistent with Compound 85: MS (APCI) 406.1 (M+H 4 ).
• This compound was prepared similar to Example ID, using Compound A (0.0816 g, 0.299 mmol), DMF (1.0 mL), t-butyl isocyanate (0.1056 mL, 0.899 mmol). The reaction was added to 5 mL brine, filtered and the solids were dissolved in CH 2 CI 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 0.0619 g of Compound 87 (56% yield).
• This compound was prepared similar to Example ID, using Compound B (0.0867 g, 0.318 mmol), DMF (1.0 mL), t-butyl isocyanate (0.112 mL, 0.955 mmol). The reaction was added to 5 mL brine, filtered. The water layer was extracted with 3x10 mL CH2CI2. The organic layers were combined, and the filtered product was added and dissolved. The mixture was dried over MgSO 4 , filtered and concentrated onto silica and the solids were 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 0.0978 g of Compound 88 (83% yield).
• This compound was prepared similar to in Example ID, using Compound A (0.0871 g, 0.320 mmol), DMF (1.0 mL), 3-methylphenyl isocyanate (0.121 mL, 0.960 mmol). The mixture was added to 5 mL brine and filtered. The mixture 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 0.0463 g of Compound 90 (36% yield).
• This compound was prepared similar to Example ID, using Compound C (0.0744 g, 0.246 mmol), DMF (1.0 mL), 4-nitrophenyl isocyanate (0.0806 g, 0.960 mmol). The mixture was added to 1 mL HCI (1.0 M) and the mixture was extracted with 3x5 mL CH2CI2. 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 0.0245 g of Compound 91 (22% 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:
• This compound was prepared in a manner analogous to Example 24E, using appropriate starting materials. A white solid with melting point of 198-200 °C was made.
• This compound was prepared similar to Example IF, using Compound A (0.080 g, 0.294 mmol, synthesized according to a published procedure [Katoh, S. and et al. WO 0004020]), ⁇ , ⁇ -difluoro-3,4,5-trimethoxy-phenylacetic acid (18, 0.092 g, 0.352 mmol), CH 3 CN (9 mL), EDC (0.070 g, 0.367 mmol) and DMAP (0.036 g, 0.294 mmol). Purification afforded 0.017 g of Compound 103 (12% yield).
• This compound was prepared similar to Example IF, using Compound C (0.080 g, 0.264 mmol), ⁇ , -difluoro-4-chloro-phenylacetic acid (20, 0.066 g, 0.317 mmol), CH 3 CN (9 mL), EDC (0.063 g, 0.330 mmol) and DMAP (0.032 g, 0.264 mmol). Purification afforded 0.027 g of Compound 104 (21% yield).
• oxalyl diamides compounds of the present invention may be prepared in the manner depicted in Scheme G below:
• R e and R f are selected from alkoxy, heterocycloalkyl, heteroaryl, hydrogen, aryl, alkyl, or R e and R f together taken with an adjacent nitrogen atom form a heterocycle.
• 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.
• efficacious levels of non-peptide rotamase-inhibiting compounds are provided so as to provide therapeutic benefits involving regulation of FKBP.
• efficacious levels of compounds is meant levels in which the FKBP binding of FKBP-12 is, at a minimum, regulated.
• the compounds may be administered in the form of a prodrug which, in general, is designed to enhance absorption and is cleaved in vivo to form the active component. Efficacious levels may also be achieved by administration of pharmaceutically active metabolites (products of metabolic conversions) of the compound.
• 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.
• the carrier or diluent may include time-delay or time-release material known in the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax, ethylcellulose, hydroxypropylmethylcellulose, methylmethacrylate and the like.
• time-delay or time-release material known in the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax, ethylcellulose, hydroxypropylmethylcellulose, methylmethacrylate and the like.
• a variety of pharmaceutical forms can be employed.
• the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form or in the form of a troche or lozenge.
• the amount of solid carrier may vary, but generally will be from about 25 mg to about 1 g.

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• 2002
  • 2002-05-10 MX MXPA03010255A patent/MXPA03010255A/es unknown
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  • 2002-05-10 CA CA002446795A patent/CA2446795A1/en not_active Abandoned
  • 2002-05-10 WO PCT/US2002/014966 patent/WO2002089806A1/en active Application Filing
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