MXPA06010258A - Combinations comprising alpha-2-delta ligands - Google Patents

Abstract

The instant invention relates to a combination, particularly a synergistic combination, of an alpha-2-delta ligand and an atypical antipsychotic, and pharmaceutically acceptable salts thereof, pharmaceutical compositions thereof and their use in the treatment of pain, particularly neuropathic pain.

Description

COMBINATIONS THAT INCLUDE LIGANDS ALFA-2-DELTA FIELD OF THE INVENTION The invention relates to a combination of an alpha-2-delta ligand and an atypical antipsychotic. The invention further relates to a combination of an aifa-2-delta ligand and an atypical antipsychotic for the treatment of pain. It also refers to a method of treating pain through the use of effective amounts of a combination of an alpha-2-delta ligand and an atypical antipsychotic. The invention further relates to a synergistic combination of an aifa-2-delta ligand and an atypical antipsychotic and the use of said for the treatment of pain.

BACKGROUND OF THE INVENTION An alpha-2-delta receptor ligand is any molecule that binds any sub-type of alpha-2-delta subunit of the human calcium channel. The alpha-2-delta subunit of the calcium channel comprises a number of receptor subtypes that have been described in the literature: for example N.S. Gee, J.P. Brown, V.U. Dissanayake, J. Offord, R. Thurlow and G.N. Woodruff, J-Biol-Chem 271/10): 5768-76, 1996 (type 1); Gong, J. Hang, W. Kohier, Z. L¡, and T-Z. Su, J. Membr. Biol .. 184 (1): 35-43, 2001, (types 2 and 3); E. Marais, N. Klugbauer and F. Hofmann, Mol. Pharmacol. 59 (5): 1243-1248, 2001. (types 2 and 3); and N. Qin, S. Yagel, M. L. Momplaisir, E. E. Codd and M. R. D'Andrea. Mol. Pharmacol. 62 (3): 485-496, 2002, (type 4). They are also known as GABA analogs.

The aIfa-2-delta ligands have been described for the treatment of a number of indications.

The best known alpha-2-delta ligand, gabapentin (Neurotin®, l- (aminomethyl) -cyclohexylacetic acid was first described in the patent literature in the patent family comprising US4024175. The compound was approved for the treatment of epilepsy and neuropathic pain.

A second alpha-2-delta ligand, pregabalin, (S) - (+) - 4-amino-3- (2-methylpropyl) butonic acid, is described in European Patent Application Publication No. EP641330 as an anti-aging treatment. seizures useful in the treatment of epilepsy and in EP0934061 in the treatment of pain.

The additional aifa-2-delta ligands are described in the following documents.

International Patent Application Publication No. WO0128978 describes a series of novel bicyclic amino acids, their pharmaceutically acceptable salts and their prodrugs of the formula: wherein n is an integer from 1 to 4, where there are stereocenters, each center can be independently R or S, the preferred compounds being those of Formula I-IV above in which n is an integer from 2 to 4 .

International Patent Application No. WO2004 / 039367 describes compounds of formula (I), below; wherein X is O, S, NH or CH2 and Y is CH2 or a direct bond or Y is O, S or NH and X is CH2 and R is a 3-12 membered cycloalkyl, 4-12 membered heterocycloalkyl, aryl or heteroaryl, wherein any ring may be optionally substituted with one or more substituents independently selected from Halogen, hydroxy, cyano, nitro, amino, hydroxycarbonyl, C 1 -C 6 alkyl, C 6 alkenyl, C 6 alkynyl, C 1 alkoxy, hydroxy alkyl C6-alkoxy, C6-C6-C6-alkyl, C-C6 perfluoro-C6-alkoxy, C-C6-alkylamino, C-C6-di-alkylamino, CrCe-aminoalkyl, C-C-alkylaminoC-C-alkyl, di-C-C6-alkylamino C6 alkyl, C, C acyl, C, C6 acyloxy, C, C6 acyloxy, C-rC6 alkyl, C-pCy acylamino, C, C, alkylthiocarbonyl, C, C6 alkylthioxo, alkoxycarbonyl, alkylsulfonyl, C, C6 alkylsulfonylamino, aminosulfonyl, alkylaminosulfonyl di-alkylaminosulfonyl CrC6, 3-8 membered cycloalkyl, 4-8 membered heterocycloalkyl, phenyl and heteroaryl or monocyclic or a pharmaceutically acceptable salt thereof.

Conventional antipsychotics are antagonists of (D2) dopamine receptors. Atypical antipsychotics also have antagonistic D2 properties but possess different binding kinetics for these receptors and activity in other receptors, particularly 5-HTZA, 5-HT2C and 5-HT2D (Schmidt B al, Soc. Neurosci. Abstr. 24: 2177, 1998).

The class of atypical antipsychotics includes clozapine (clozaril®, 8-chloro-11- (4-methyl-1-piperazinyl) -5H-dibenzo [b, e] [1,4] diazepine (U.S. Patent No. 3,539,573); risperidone; (risperdal®, 3- [2- [4- (6-fluoro-1, 2-benzisoxazol-3-yl) piperidino] ethyl] -2-methyl-6,7,8,9-tetrahydro-4H-pyrido- [1, 2-a] p-hm-id-4-one (U.S. Patent No. 4,804,663); olanzapine (zyprexa®), 2-methyl-4- (4-methyl-1-piperazinyl) -10H-thieno [ 2,3-b] [1,5] benzodiazepine (US Patent No. 5,229,382), quetiapine (seroquel®), 5- [2- (4-dibenzo [b, f] [1,4] thiazepin-11-yl) -1-piperazinyl) ethoxy] ethane (U.S. Patent No. 4,879,288); aripiprazole (abílify®), 7-. {4- [4- (2,3-dichlorophenyl) -1-piperazinyl] -butoxy.] - 3,4-dihydro carbostyril and 7-. {4- [4- (2,3-dichlorophenyl) -1-piperazinyl] -butoxy.] - 3,4-dihydro-2 (1 H) -quinoline (Patents North American nos. 4,734,416 and 5,006,528), sertindola, 1- [2- [4- [5-chloro-1- (4-fluorophenyl) -1 H -indol-3-yl] -1-piperidinyl] imidazolidin-2-one (North American Patent No. 4,710,500); amilsulpride (U.S. Patent No. 4,410,822); ziprasidone (geodon®), 5- [2- [4- (1, 2-benzisothiazol-3-yl) pieprazin-3-yl] ethyl] -6-chloroindolin-2-one hydrochloride hydrate (US Patent No. 4,831, 031), asenapine, trans-5-Chloro-2,3,3a, 12b-tetrahydro-2-methyl-1H-dibenz [2,3: 6,7] oxepino [4,5-c] pirola maleate; (3R, 4R, 5R) -3-amino-4,5-dimethyl-heptanoic acid and (3R, 4R, 5R) -3-amino-4,5-dimethyl-octanoic acid (PCT Application No. PCT / IB2004 / 002985, not yet published at the filing date).

The contents of all patents and publications cited within the present application are incorporated herein by reference.

SUMMARY OF THE INVENTION It has now been found that combination therapy with an alpha-2-delta ligand and an atypical antipsychotic results in improvement in the treatment of pain. Therefore, when administered simultaneously, sequentially or separately, the alpha-2-delta ligand and the atypical antipsychotic can interact in a synergistic manner to control pain. This synergy allows a reduction in the required dose of each compound, leading to a reduction in side effects and improvement of the clinical usefulness of the compounds.

Accordingly, the invention provides as a first aspect, a combination product comprising an alpha-2-delta ligand and an atypical antipsychotic.

As an alternative or additional aspect, the invention provides a synergistic combination product comprising an alpha-2-delta ligand and an atypical antipsychotic.

The useful cyclic alpha-2-delta ligands of the present invention are illustrated by the following formula (I): wherein X is a carboxylic acid or bioisostere of the carboxylic acid; n is 0, 1 or 2 and R1, R1a, R2, R2a, R3, R3a, R4 and R4a are independently selected from H and C6 alkyl or R1 and R2 or R2 and R3 are taken together to form a C3- cycloalkyl ring C7, which is optionally substituted with one or two substituents selected from C? -C6 alkyl or a pharmaceutically acceptable salt thereof.

In Formula (I) appropriately R1, R1a, R2a, R3a, R4 and R4a are H and R2 and R3 are independently selected from H and methyl or R1a, R2a, R3a and R4a are H and R1 and R2 or R2 and R3 are taken together to form a C3-C7 cycloalkyl ring, which is optionally substituted with one or two methyl substituents. A bioisostere of the appropriate carboxylic acid is selected from tetrazolyl and oxadiazolonyl. X is preferably a carboxylic acid.

In the formula (I), preferably R1, R1a, R2a, R3a, R4 and R4a are H and R2 and R3 are independently selected from H and methyl or R1a, R2a, R3a and R4a are H and R1 and R2 or R2 and R3 are taken together to form a C4-C5 cycloalkyl ring or when n is 0, R1, R1a, R2a, R3a, R4 and R4a are H and R2 and R3 form a cyclopenty ring or when n is 1, R1, R1a, R2a , R3a, R4 and R4a are H and R2 and R3 are both methyl or R1, R1a, R2a, R3a, R4 and R a are H and R2 and R3 form a cyclobutyl ring or when n is 2, R1, R1a, R2, R2a, R3, R3a, R4 and R4a are H, on is 0, R1, R1a, R2a, R3a, R4 are H and R2 and R3 form a cyclopentyl ring.

The useful acyclic alpha-2-delta ligands of the present invention are illustrated by the following formula (II): wherein: n is 0 or 1, R1 is hydrogen or alkyl (C? -C6); R2 is hydrogen or alkyl (C Ce); R3 is hydrogen or (C6C) alkyl; R 4 is hydrogen or alkyl (CrC 6); R5 is hydrogen or alkyl (C6) and R2 is hydrogen or (C6) alkyl or a pharmaceutically acceptable salt thereof.

According to formula (II), R1 is suitably CrC6 alkyl, R2 is methyl, R3-R6 is hydrogen and n is 0 or 1. More suitably R1 is methyl, ethyl, n-propyl or n-butyl, R2 is methyl, R3-R6 are hydrogen and n is 0 or 1. When R2 is methyl, R3-R6 is hydrogen and n is 0, R1 is suitably ethyl, n-propyl or n-butyl. When R2 is methyl, R3-R6 is hydrogen and n is 1, R1 is appropriately methyl or n-propyl. The compounds of Formula (II) are appropriately in the 3S.5R configuration.

Examples of the alpha-2-delta ligands for use with the present invention are those compounds generally or specifically described in US4024175, particularly gabapentin, EP641330, particularly pregabalin, US5563175, W09733858, W09733859, WO9931057, WO9931074, WO9729101, WO02085839, particularly acid [(1 R, 5R, 6S) -6- (aminomethyl) bicyclo [3.2.0] hept-6-yl] acetic acid, WO9931075, particularly 3- (1-Aminomethyl-cyclohexylmethyl) -4H- [1, 2.4 ] oxadiazol-5-one and C- [1- (1 H-Tetrazol-5-ylmethyl) -cycloheptyl] -methylamine, W09921824, particularly (3S, 4S) - (1-Aminomethyl-3,4-dimethyl-cyclopentyl) acid ) -acetic, WO0190052, WO0128978, particularly (1a, 3a, 5a) (3-amino-methyl-bicyclo [3.2.0] hept-3-yl) -acetic acid, EP0641330, W09817627, WO0076958, particularly acid (3S, 5R) -3-aminomethyl-5-methyl-octanoic, PCT / IB03 / 00976, particularly (3S, 5R) -3-amino-methyl-heptanoic acid, (3S, 5R) -3-amino-5 acid -methyl-nonanoic acid and (3S, 5R) -3-Amino-5-methyl-octanoic acid, WO2004 / 039367 , particularly (2S, 4S) -4- (3-fluoro-phenoxymethyl) -pyrrolidine-2-carboxylic acid, (2S, 4S) -4- (2,3-difluoro-benzyl) -pyrrolidine-2-carboxylic acid, (2S, 4S) -4- (3-chlorophenoxy) proline and (2S, 4S) -4- (3-fluorobenzyl) proline, EP1178034, WO9931074, WO03000642, WO0222568, WO0230871, WO0230881, WO02100392, WO02100347, WO0242414, WO0232736 and WO0228881 or the pharmaceutically acceptable salts thereof, all of which are incorporated herein by reference.

Preferred alpha-2-delta ligands of the present invention include: gabapentin, pregabalin, [(1 R, 5R, 6S) -6- (Aminomethyl) bicyclo [3.2.0] hept-6-yl-acetic acid, 3- ( 1-Aminomethyl-cyclohexylmethyl) -4 H- [1, 2,4] oxadiazol-5-one, (3S, 4S) - (1-Aminomethyl-3,4-dimethyl-cyclopentyl) -acetic acid, acid (1a, 3a , 5a) (3-amino-methyl-bicyclo [3.2.0] hept-3-yl) -acetic acid (3S, 5R) -3-Aminomethyl-5-methyl-octanoic acid, (3S, 5R) -3 acid -amino-5-methyl-heptanoic acid, (3S, 5R) -3-amino-5-methyl-nonanoic acid, (3S, 5R) -3-Amino-5-methyl-octanoic acid, (2S, 4S) - 4- (3-Fluoro-phenoxymethyl) -pyridine-2-carboxylic acid, (2S, 4S) -4- (2,3-difluoro-benzyl) -pyrrolidine-2-carboxylic acid, (2S, 4S) -4- ( 3-chlorophenoxy) proline and (2S, 4S) -4- (3-fluorobenzyl) proline or pharmaceutically acceptable salts thereof. Particularly preferred alpha-2-delta ligands of the present invention are selected from gabapentin, pregabalin, (1a, 3a, 5a) (3-amino-methyl-bicyclo [3.2.0] hept-3-yl) -acetic acid, ((2S, 4S) -4- (3-chlorophenoxy) proline and (2S, 4S) -4- (3-fluorobenzyl) proline or the pharmaceutically acceptable salts thereof.

Atypical antipsychotics useful in accordance with the present invention include those comprised within the description of US 4,831,031, ie the compounds of the formula (I): (Wherein Ar is naphthyl optionally substituted by fluorine, chlorine, trifluoromethyl, methoxy, cyano or nitro, quinolyl, isoquinolyl, 6-hydroxy-8-quinolyl, benzoisothiazolyl or an oxide or dioxide thereof, each optionally substituted by fluorine, chloro, trifluoromethyl, methoxy, cyano or nitro, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzoxazolyl, benzoxazolonyl, indolyl, indanyl optionally substituted by one or two fluoro, 3-indazolii optionally substituted by 1-trifluoromethylphenyl or phthalazinyl; n is 1 or 2 and X and Y together with the phenyl to which they are attached form quinolyl, 2-hydroxyquinolyl, benzothiazolyl, 2-aminobenzothiazolyl, benzoisothiazolyl, indazolyl, 3-hydroxyindazolyl, indolyl, spiro [cyclopentane-1,3'-indolinyl] ]; oxindolyl optionally substituted by one to three of alkyl (CrC) or one of chloro, fluoro or phenyl, said phenyl being optionally substituted by a chloro or fluoro; benzoxazolyl, 2-aminobenzoxazolyl, benzoxazolonil, 2-aminobenzoxazolinil, benzothiazolonil, benzoimidazolonil or benzotriazolyl.

A particular preferred compound of the formula (I) is ziprasidone.

Examples of atypical antipsychotics for use in the present invention are the compounds generically and specifically described in US Pat. No. 4,831,301, particularly ziprasidone; US 5,229,382, particularly olanzapine, US 3,539,573, particularly clozapine, US 4,804,663, particularly risperidone; US 4,710,500 particularly sertindola; US 4,879,288, particularly quetiapine, US 4,734,416, particularly aripiprazole, US 4,401, 822, particularly amisulpride; PCT Application No. PCT / IB2004 / 002985, particularly (3R, 4R, 5R) -3-amino-4,5-dimethyl-heptanoic acid and (3R, 4R, 5R) -3-amino-4,5- dimethyl-octanoic and asenapine or pharmaceutically acceptable salts thereof, all of which are incorporated herein by reference.

Atypical antipsychotics suitable for use in the present invention include ziprasidone, olanzapine, clozapine, risperidone, sertindole, quetiapine, aripiprazole, asenapine, amisulpride, (3R, 4R, 5R) -3-amino-4,5-dimethyl-heptanoic acid and (3R, 4R, 5R) -3-amino-4,5-dimethyl-octanoic acid or pharmaceutically acceptable salts thereof. Preferably the atypical antipsychotic is ziprasidone or a pharmaceutically acceptable salt thereof.

The adequacy of any particular atypical antipsychotic can be determined quickly by evaluating its potency and selectivity using the methods of the literature followed by the evaluation of its toxicity, absorption, metabolism, pharmacokinetics, etc. in accordance with standard pharmaceutical practices.

As an additional or alternate aspect of the present invention, there is provided a combination comprising gabapentin or a pharmaceutically acceptable salt thereof and an atypical antipsychotic selected from ziprasidone, olanzapine, clozapine, risperidone, sertindola, quetiapine, aripiprazole, asenapine, amisulpride, acid. (3R, 4R, 5R) -3-amino-4,5-dimethyl-heptanoic and (3R, 4R, 5R) -3-amino-4,5-dimethyl-octanoic acid or a pharmaceutically acceptable salt thereof. A particularly preferred combination comprises gabapentin and ziprasidone and their pharmaceutically acceptable salts.

As an additional or alternate aspect of the present invention, a combination comprising pregabalin and an atypical antipsychotic selected from ziprasidone, olanzapine, clozapine, risperidone, sertindola, quetiapine, aripiprazole, asenapine, amisulpride, acid (3R, 4R, 5R) is provided. -3-amino-4,5-dimethyl-heptanoic acid and (3R, 4R, 5R) -3-amino-4,5-dimethyl-octanoic acid and its pharmaceutically acceptable salts. A particularly preferred combination comprises pregabalin and ziprasidone and their pharmaceutically acceptable salts.

As an additional or alternate aspect of the present invention there is provided a combination comprising (1a, 3a, 5a) (3-amino-methyl-bicyclo [3.2.0] hept-3-yl) -acetic acid or a salt pharmaceutically acceptable thereof, and an atypical antipsychotic. Suitably, a combination comprising (1a, 3a, 5a) (3-amino-methyl-bicyclo [3.2.0] hept-3-yl) -acetic acid or a pharmaceutically acceptable salt thereof and an atypical antipsychotic selected from ziprasidone, olanzapine, clozapine, risperidone, sertindola, quetiapine, aripiprazole, asenapine, amisulpride, (3R, 4R, 5R) -3-amino-4,5-dimethyl-heptanoic acid and (3R, 4R, 5R) -3- acid amino-4,5-dimethyl-octanoic or a pharmaceutically acceptable salt thereof. A particularly preferred combination comprises (1a, 3a, 5) (3-amino-methyl-bicyclo [3.2.0] hept-3-yl) -acetic acid and ziprasidone and their pharmaceutically acceptable salts.

As an additional or alternate aspect of the present invention, there is provided a combination comprising (2S, 4S) -4- (3-chlorophenoxy) proline or a pharmaceutically acceptable salt thereof and an atypical antipsychotic. Suitably, a combination comprising (2S, 4S) -4- (3-chlorophenoxy) proline or a pharmaceutically acceptable salt thereof and an atypical antipsychotic selected from ziprasidone, olanzapine, clozapine, risperidone, sertindola, quetiapine, aripiprazole, asenapine is provided. , amisulpride, (3R, 4R, 5R) -3-amino-4,5-dimethyl-heptanoic acid and (3R, 4R, 5R) -3-amino-4,5-dimethyl-octanoic acid or a pharmaceutically acceptable salt of the same. A particularly preferred combination comprises (2S, 4S) -4- (3-chlorophenoxy) proline and ziprasidone and their pharmaceutically acceptable salts.

As an additional or alternate aspect of the present invention, there is provided a combination comprising (2S, 4S) -4- (3-fluorobenzyl) proline or a pharmaceutically acceptable salt thereof and an atypical antipsychotic. Suitably, a combination comprising (2S, 4S) -4- (3-fluorobenzyl) proin or a pharmaceutically acceptable salt thereof and an atypical antipsychotic selected from ziprasidone, olanzapine, clozapine, risperidone, sertindole, quetiapine, aripiprazole, is provided. asenapine, amisulpride, (3R, 4R, 5R) -3-amino-4,5-dimethyl-heptanoic acid and (3R, 4R, 5R) -3-amino-4,5-dimethyl-octanoic acid or a pharmaceutically acceptable salt thereof. A preferred combination comprises (2S, 4S) -4- (3-fluorobenzyl) proinin and ziprasidone and their pharmaceutically acceptable salts.

As a further preferred aspect of the present invention, the combination is selected from: gabapentin and ziprasidone; gabapentin and olanzapine; gabapentin and clozapine; gabapentin and risperidone; gabapentin and sertindola; gabapentin and quetiapine; gabapentin and aripiprazole; gabapentin and asenapine; gabapentin and amisulpride; gabapentin and (3R, 4R, 5R) -3-amino-4,5-dimethyl-heptanoic acid; gabapentin and (3R, 4R, 5R) -3-amino-4,5-dimethyl-octanoic acid; pregabalin and ziprasidone; pregabalin and olanzapine; pregabalin and clozapine; pregabalin and risperidone; pregabalin and sertindola; pregabalin and quetiapine; pregabalin and aripiprazole; pregabalin and asenapine; pregabalin and amisulpride; pregabalin and (3R, 4R, 5R) -3-amino-4,5-dimethyl-heptanoic acid; pregabalin and (3R, 4R, 5R) -3-amino-4,5-dimethyl-octanoic acid; [(1 R, 5R, 6S) -6- (Aminomethyl) bicyclo [3.2.0] hept-6-yl] acetic acid and ziprasidone; [(1 R, 5R, 6S) -6- (Aminomethyl) bicyclo [3.2.0] hept-6-yl] acetic acid and olanzapine; [(1 R, 5R, 6S) -6- (Aminomethyl) bicyclo [3.2.0] hept-6-yl] acetic acid and clozapine; [(1 R, 5R, 6S) -6- (Aminomethyl) bicyclo [3.2.0] hept-6-yl] acetic acid and risperidone; [(1 R, 5R, 6S) -6- (Aminomethyl) bicyclo [3.2.0] hept-6-yl] acetic acid and sertindole; [(1 R, 5R, 6S) -6- (Aminomethyl) bicyclo [3.2.0] hept-6-yl] acetic acid and quetiapine; [(1R, 5R, 6S) -6- (Aminomethyl) bicyclo [3.2.0] hept-6-yl] acetic acid and aripiprazole; [(1 R, 5R, 6S) -6- (Aminomethyl) bicyclo [3.2.0] hept-6-yl] acetic acid and asenapine; [(1 R, 5R, 6S) -6- (Aminomethyl) bicyclo [3.2.0] hept-6-yl] acetic acid and amisulpride; [(1 R, 5R, 6S) -6- (Aminomethyl) bicyclo [3.2.0jhept-6-yl] acetic acid and (3R, 4R, 5R) -3-amino-4,5-dimethyl-heptanoic acid; [(1R, 5R, 6S) -6- (Aminomethyl) bicyclo [3.2.0] hept-6-yl] acetic acid and (3R, 4R, 5R) -3-amino-4,5-dimethyl-octanoic acid; (1 a, 3, 5 a) (3-amino-methyl-b-cyclo [3.2.0] hept-3-yl) -acetic acid and ziprasidone; (1a, 3, 5a) (3-Amino-methyl-bicyclo [3.2.0] hept-3-yl) -acetic acid and olanzapine; acid (1a, 3a, 5a) (3-amino-methyl-bicyclo [3.2.0] hept-3-yl) -acetic acid and clozapine; (1a, 3, 5a) (3-Amino-methyl-bicyclo [3.2.0] hept-3-yl) -acetic acid and risperidone; acid (1a, 3a, 5a) (3-amino-methyl-bicyclo [3.2.0] hept-3-yl) -acetic acid and sertindole; (1 a, 3a, 5) (3-Amino-methyl-bicyclo [3.2.0] hept-3-yl) -acetic acid and quetiapine; (1a, 3, 5a) (3-Amino-methyl-bicyclo [3.2.0] hept-3-yl) -acetic acid and aripiprazole; (1, 3a, 5) (3-Amino-methyl-bicyclo [3.2.0] hept-3-yl) -acetic acid and asenapine; acid (1, 3a, 5a) (3-amino-methyl-bicyclo [3.2.0] hept-3-yl) -acetic acid and amisulpride; acid (1a, 3, 5a) (3-amino-methyl-bicyclo [3.2.0] hept-3-yl) -acetic acid and (3R, 4R, 5R) -3-amino-4,5-dimethyl-heptanoic acid; acid (1a, 3a, 5a) (3-amino-methyl-bicyclo [3.2.0] hept-3-yl) -acetic acid and (3R, 4R, 5R) -3-amino-4,5-dimethyl-octanoic acid; (3S, 4S) - (1-Aminomethyl-3,4-dimethyl-cyclopentyl) -acetic acid and ziprasidone; (3S, 4S) - (1-Aminomethyl-3,4-dimethyl-cyclopentyl) -acetic acid and olanzapine; (3S, 4S) - (1-Aminomethyl-3,4-dimethyl-cyclopentyl) -acetic acid and clozapine; (3S, 4S) - (1-Aminomethyl-3,4-dimethyl-cyclopentyl) -acetic acid and risperidone; (3S, 4S) - (1-Aminomethyl-3,4-dimethyl-cyclopentyl) -acetic acid and sertindole; (3S, 4S) - (1-Aminomethyl-3,4-dimethyl-cyclopentyl) -acetic acid and quetiapine; (3S, 4S) - (1-Aminomethyl-3,4-dimethyl-cyclopentyl) -acetic acid and aripiprazole; (3S, 4S) - (1-Aminomethyl-3,4-dimethyl-cyclopentyl) -acetic acid and asenapine; (3S, 4S) - (1-Aminomethyl-3,4-dimethyl-cyclopentyl) -acetic acid and amisulpride; (3S, 4S) - (1-Aminomethyl-3,4-dimethyl-cyclopentyl) -acetic acid and (3R, 4R, 5R) -3-amino-4,5-dimethyl-heptanoic acid; (3S, 4S) - (1-Aminomethyl-3,4-dimethyl-cyclopentyl) -acetic acid and (3R, 4R, 5R) -3-amino-4,5-dimethyI-octanoic acid; (2S, 4S) -4- (3-chlorophenoxy) proline and ziprasidone; (2S, 4S) -4- (3-chlorophenoxy) proline and olanzapine; (2S, 4S) -4- (3-chlorophenoxy) proline and clozapine; (2S, 4S) -4- (3-chlorophenoxy) proline and risperidone; (2S, 4S) -4- (3-chlorophenoxy) proline and sertindole; (2S, 4S) -4- (3-chlorophenoxy) proin and quetiapine; (2S, 4S) -4- (3-chlorophenoxy) proline and aripiprazole; (2S, 4S) -4- (3-chlorophenoxy) proline and asenapine; (2S, 4S) -4- (3-chlorophenoxy) proline and amisulpride; (2S, 4S) -4- (3-chlorophenoxy) proline and (3R, 4R, 5R) -3-amino-4,5-dimethyl-heptanoic acid; (2S, 4S) -4- (3-chlorophenoxy) proline and (3R, 4R, 5R) -3-amino-4,5-dimethyl-octanoic acid; (2S, 4S) -4- (3-fluorobenzyl) proline and ziprasidone; (2S, 4S) -4- (3-fluorobenzyl) proline and olanzapine; (2S, 4S) -4- (3-fluorobenzyl) proline and clozapine; (2S, 4S) -4- (3-fluorobenzyl) proline and risperidone; (2S, 4S) -4- (3-fluorobenzyl) proline and sertindole; (2S, 4S) -4- (3-fluorobenzyl) proline and quetiapine; (2S, 4S) -4- (3-fluorobenzyl) proline and aripiprazole; (2S, 4S) -4- (3-fluorobenzyl) proline and asenapine; (2S, 4S) -4- (3-fluorobenzyl) proline and amisulpride; (2S, 4S) -4- (3-fluorobenzyl) proline and (3R, 4R, 5R) -3-amino-4,5-dimethyl-heptanoic acid; (2S, 4S) -4- (3-fluorobenzyl) proline and (3R, 4R, 5R) -3-amino-4,5-dimethyl-octanoic acid; or pharmaceutically acceptable salts or solvates of one or both components of any of said combinations.

Particularly preferred combinations of the invention include those in which each variable of the combination is selected from the appropriate parameters for each variable. Even the most preferred combinations of the invention include those in which each variable of the combination is selected from the most appropriate, most appropriate, preferred and most preferred parameters of each variable.

The combination of the present invention in a single dose form is suitable for administration to any mammalian subject, preferably human. The administration may be once (or.d.), twice (b.i.d.) or three times (t.i.d) daily, appropriately b.i.d. or t.i.d. more appropriately b.i.d. most appropriately o.d ..

Furthermore, as a further aspect of the present invention, there is provided the use of a combination, particularly synergistic, of an alpha-2-delta ligand and an atypical antipsychotic in the manufacture once, twice or three times, appropriately twice to three times, more appropriately twice, most appropriately a daily administration of the drug for the curative, prophylactic or palliative treatment of pain.

By determining a synergistic interaction between one or more components, the optimal range of effect and the absolute dose ranges of each component for the effect can be measured definitively by administering the components over different weight / weight radio ranges and doses to patients in need of such treatment. For humans, the complexity and cost of clinical studies in patients makes impractical the use of this form of testing as a primary model of synergy. However, the observation of synergy in a species may be predictive of the effect in other species and in existing animal models, as described in this document, to measure a synergistic effect and the results of such studies can also be used to predict the dose effective and radio ranges of plasma concentration and absolute doses and plasma concentrations required for other species through the application of pharmacokinetic / pharmacodynamic methods. The correlations established between animal models and the effects observed in man suggest that synergy in animals is best demonstrated using dynamic and static allodynia measurements in rodents rather than chemical (i.e., streptozocin) or surgical procedures (i.e. chronic constriction lesion) to induce allodynia. Due to the effects of high plateau in these models, its value is estimated better in terms of synergistic actions than in patients with neuropathic pain that would result in advantages of low dose. Other models in which existing agents used for the treatment of neuropathic pain give only a partial response are more appropriate for predicting the potential of combinations that act synergistically to produce maximum efficiency increased in maximally tolerated doses of the two components.

In addition, as a further aspect of the present invention, a synergistic combination for administration to humans comprising an alpha-2-delta ligand and an atypical antipsychotic or pharmaceutically acceptable salts or solvates thereof in a weight / weight combination range is provided. corresponds to the absolute ranges observed in a non-human animal model, preferably a rat model, primarily used to identify a synergistic interaction. Appropriately, the ratio range in humans corresponds to a non-human range selected from 1: 50 to 50: 1 parts by weight, 1: 50 to 20: 1, 1: 50 to 10: 1, 1: 50 to 1: 1, 1:20 to 50: 1, 1:20 to 20: 1, 1:20 to 10: 1, to: 20 to 1: 1, 1:10 to 50: 1, 1:10 to 20: 1, 1:10 to 10: 1, 1:10 to 1: 1, 1: 1 to 50: 1, 1.1 to 20: 1 and 1: 1 to 10: 1. More appropriately, the human range corresponds to a non-human range of 1: 10 to 20: 1 parts by weight. Preferably, the human range corresponds to a non-human synergistic range of the order of 1: 1 to 10: 1 parts by weight.

For humans, several experimental models for pain can be used in humans to show that agents with synergy tested in animals also have effects on humans compatible with that synergy. Examples of human models that can be adjusted for this purpose include the capsaicin / heat model (Petersen, KL &Rowbotham, MC (1999) NeuroReport 10, 1511-1516), ie the capsaicin model (Andersen, OL, Felsby, S ., Nicolaisen, L., Bjerring, P., Jsesn, TS &Arendt-Nielsen, L. (1996) pain 66, 51-62), including the use of repeated capsaicin traumas (Witting, N., Svensson, P., Arendt-Nielsen, L. &Jensen, TS (2000) Somatosensory Motors Res. 17, 5-12) and summary or concluding answers (Curatolo, M. et al. (2000) Anesthesiology 93, 1517-1530 ). With these models, the subjective assessment of pain intensity or areas of hyperalgesia can be used as end points or more objective endpoints dependent on imaging or electrophysical technologies (such as functional magnetic resonance imaging) can be used (Bornhovd, K., Quante, M., Glauche, V., Bromm, B. Weiller, C. &Buchel, C. (2002) Brain 125, 1326-1336). All of these models require evidence of objective validation before it can be concluded that they provide evidence of objective validation in men to support the synergistic actions of a combination that has been observed in animal studies.

For the present invention in humans, a range of atypical antipsychotic: appropriate alpha-2-delta ligand ratio is selected from 1: 50 to 50: 1 parts by weight, 1: 50 to 20: 1, 1: 50 to 10 : 1, 1: 50 to 1: 1, 1: 20 to 50: 1, 1: 20 to 20: 1, 1: 20 to 10: 1, 1: 20 to 1: 1, 1: 10 to 50: 1 , 1: 10 a : 1, 1: 10 to 20: 1, 1: 10 to 10: 1, 1: 10 to 1: 1, 1: 1 to 50: 1, 1: 1 to 20: 1 and 1: 1 to 10: 1, more appropriately 1: 10 to 20: 1, preferably 1: 1 to 10: 1.

The optimal doses of each component for synergy can be determined in accordance with the procedures published in the animal models. However, in humans (even in experimental pain models) the cost can be too high for studies to determine the full exposure-response relationship at all the therapeutically relevant doses of each component of a combination. It may be necessary, at least initially, to estimate whether the effects can be observed that are consistent with synergy in doses that have been extrapolated from those that give optimal synergy in animals. In descending doses of animals to humans, factors such as body surface area / relative body weight, relative absorption, distribution, metabolism and excretion of each component and the protein binding in relative plasma need to be considered and for these reasons, the proportion of Optimal dose predicted for humans (and also for patients) is unlikely the same as the proportion of doses known to be optimal in animals. However, the relationship between the two can be understood and calculated by a person skilled in the art of pharmacokinetics in humans and animals. The plasma concentrations obtained for each component used in animal studies is important in establishing the bridge between human and animal effects, as these relate to the plasma concentration of each component that would be expected to provide efficiency in humans. The pharmacokinetic / pharmacodynamic model (including methods such as isobolograms, the interaction index and the response surface model) and stimulations can help predict the proportions of synergistic doses in humans, particularly where one or both of these components It has already been studied in men.

It is important to check if any concluded synergy observed in animals or humans is due only to pharmacokinetic interactions. For example, inhibiting the metabolism of one compound by another could give a false impression of pharmacodynamic synergy.

Further, in accordance with a further aspect of the present invention, there is provided a synergistic combination for administration to humans comprising an aIfa-2-deta ligand and an atypical antipsychotic or pharmaceutically acceptable salts or solvates thereof, wherein the dose range of each component corresponds to the absolute ranges observed in a non-human animal model, preferably the rat model, first used to identify a synergistic interaction.

Suitably, the dose of the alpha-2-delta ligand for use in humans is in a selected range of 1-1200 mg, 1-500 mg, 1-100mg, 1-50mg, 1-25mg, 500-1200mg, 100-1200mg , 100-500mg, 50-1200mg, 50-500mg or 50-1 OOmg, appropriately 50-500mg, bid or t.i.d., appropriately t.i.d. and the dose of atypical antipsychotic is in a selected range of 1-200mg, 1-1 OOmg, 0.25-25mg, 1-50mg, 1-25mg, 10-1OOmg, 10-50mg or 10-25mg, appropriately 10-100mg , bid or t.i.d., appropriately t.i.d.

It will be apparent to that reader that the plasma concentration ranges of the combinations of the alpha-2-delta ligand and the atypical antipsychotic of the present invention required to provide a therapeutic effect depend on the species to be treated and the components used. For example, for gabapentin in rats, the range of Cmax values of 0. 520 μg / ml to 10.5 μg / ml.

It is possible, using standard PK / PD and allometric methods, to extrapolate the plasma concentration values observed in an animal model to predict values in a different species, particularly humans. Furthermore, as a further aspect of the present invention, a synergistic combination for administration to humans comprising an alpha-2-delta ligand and an atypical antipsychotic is provided, wherein the range of the plasma concentration of each component corresponds to the ranges Absolutes observed in a non-human animal model, preferably the rat model, first used to identify a synergistic interaction. Appropriately, the human plasma concentration range corresponds to a range of 0.05 μg / ml to 10.5 μg / ml for an alpha-2-delta ligand in the rat model.

Particularly preferred combinations of the invention include those in which each variable of the combination is selected from the appropriate parameters for each variable. Even those where each variable of the combination is selected from most appropriate, most appropriate, preferred or most preferred parameters for each variable.

DETAILED DESCRIPTION OF THE INVENTION The compounds of the present invention are prepared by methods well known to those skilled in the art. Specifically, the patents, patent applications and publications mentioned hereinabove, each of which by means of this document is incorporated by reference, the exemplary compounds can be used in combinations, pharmaceutical compositions, methods and equipment in accordance with the present invention and with reference to the methods of preparation of those compounds.

The compounds of the present combination invention can exist in unsolvated forms as well as in solvated forms, including hydrated forms. In general, solvated forms including hydrated forms, which may contain isotopic substitutions (ie D20, d6-acetone, d6-DMSO) are equivalent to unsolvated forms and are within the scope of the present invention.

Certain of the compounds of the present invention possess one or more chiral centers and each center may exist in the R or S configuration. The present invention includes all enantiomeric and epimeric forms as well as appropriate mixtures thereof. The separation of diastereoisomers or the cis and trans isomers can be achieved by conventional techniques, i.e., by fractional crystallization, chromatography or H.P.L.C. of a stereoisomeric mixture of a compound of the invention or an appropriate salt or derivative thereof.

A number of alpha-2-delta ligands of the present invention are amino acids. Since the amino acids are amphoteric, pharmacologically compatible salts can be salts of appropriate non-toxic organic or inorganic acids or bases. Suitable acid addition salts are acetate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate, camsylate, citrate, edisilate, esylate, fumarate, gluceptate, gluconate, glucuronate, hybienate, chloride / hydrochloride, hydrobromide / bromide, hydroiodide / iodide , hydrogen phosphate, isethionate, DL-lactate, malate, maleate, malonate, mesylate, methylsulfate, 2-nafsylate, nicotinate, nitrate, orotrate, palmoate, phosphate, saccharate, stearate, sulfate succinate, D- and L-tartrate and salts of tosylate. The basic addition salts are formed from bases which form non-toxic salts and examples are sodium, potassium, aluminum, calcium, magnesium, zinc, choline, diolamine, olamine, arginine, glycine, tromethamine, benzathine, lysine, meglumine and salts of diethylamine. Salts with quaternary ammonium ions can also be prepared with, for example, the tetramethyl ammonium ion. The compounds of the invention can also be formed as an amphoteric ion.

A suitable salt for the amino acid compounds of the present invention is the hydrochloride salt. For a review of the appropriate salts see Stahl and Vermuth, Handbook of Pharmaceutical Salts: Properties, Selection and Use, Wiley-VCH, Weinheim, Germany (2002).

Also within the scope of the invention are clathrates, drug inclusion complexes in the host, wherein, in contrast to the aforementioned solvates, the drug and the host are present in non-stoichiometric amounts. For a review of such complexes, see J Pharm Sci, 64 (8), 1269-1288 by Haleblian (August 1975).

Hereinafter all references to the compounds of the invention include those references to the salts thereof and to the solvates and clathrates of the compounds of the invention and the salts thereof.

Also included within the scope of the compounds of the present invention are the polymorphs thereof.

The prodrugs of the above compounds of the invention are included within the scope of the present invention. The drug chemically modified or prodrug, should have a pharmacokinetic profile different from the mother, allowing to facilitate the absorption through the mucosal epithelium, the best formulation of the salt and / or solubility, the improved systemic stability (for example an increase in the half life of the plasma). These chemical modifications can be (1) Ester or amide derivatives that can be penetrated by, for example, esterases or lipases. By ester derivatives, the ester is derived from the carboxylic acid moiety of the drug molecule by known means. For the amide derivatives, the amide can be derived from the carboxylic acid portion or the amide portion of the drug molecule by known means. (2) Peptides that can be recognized by non-specific or specific proteinases. A peptide can be coupled to the drug molecule via the formation of the amide bond with the amide or the carboxylic acid moiety of the drug molecule by known means. (3) Derivatives that accumulate in a site of action through the selection of the membrane of a prodrug form or modified prodrug form. (4) Any combination of 1 to 3.

Aminoacyl-glycolic and lactic esters are known as amino acid prodrugs (Wermuth C.G., Chemistry and Industry, 1980: 433-435). The carbonyl group of the amino acids can be esterified by known means. Prodrugs and mild drugs are known in the art (Palomino E., Drugs of the Future, 1990; 15 (4): 361-368). The last two citations are incorporated in this document as a reference.

The combination of the present invention is useful for the general treatment of pain, particularly neuropathic pain. Physiological pain is an important protective mechanism designed to prevent damage from potentially harmful stimuli from the external environment. The system operates through a specific set of primary sensory neurons and is activated exclusively by the noxious stimulus via the peripheral translation mechanisms (Millan 1999 Prog. Neurobio 57: 1-164 for a comprehensive review). These sensory fibers are known as nociceptors and are characterized by small diameter axons with slow conduction velocities. Nociceptors modify the intensity, duration and quality of the noxious stimulus and by virtue of its topographically organized projection for the spine, the location of the stimulus. Nociceptors are found in the fibers of the nociceptive nerve, of which there are two main types, the A-delta fibers (myelinated) and the C fibers (non-myelinated). The activity generated by the entrance of the nociceptor is transferred after the processing of the complex in the dorsal horn, directly or via the nucleus of relief of the brainstem to the ventrobasal thalamus and then in the cortex, where the pain sensation is generated.

Severe acute pain and chronic pain may involve the same pathways driven by the pathophysiological processes and such cease to provide a protective mechanism and instead contribute to weaken the symptoms associated with a wide range of disease states. Pain is a feature of many states of trauma and disease. When a substantial injury, via disease or trauma, occurs to the body tissue, the activation characteristics of the nociceptor are altered. There is sensitivity in the periphery, locally around the lesion and centrally where the nociceptors end. This leads to hypersensitivity at the site of damage and near normal tissue. In acute pain, these mechanisms can be useful and are allowed for the repair processes to take place and the hypersensitivity returns to normal once the lesion has healed. However, in many chronic pain states, hypersensitivity lasts throughout the healing process and is normal due to damage to the nervous system. This injury commonly leads to poor adaptation of the afferent fibers (Woolf &Salter 2000 Series Science 288: 1765-1768). Clinical pain is present when there is discomfort and abnormal sensitivity characteristics among the patient's symptoms. Patients tend to be very heterogeneous and may present various symptoms of pain. There are a number of typical pain subtypes: 1) spontaneous pain, which can be constant, burning or acute; 2) pain responses to noxious stimuli are exaggerated (hyperalgesia); 3) the pain is produced by normally innocuous stimuli (allodynia) (Meyer et al., Textbook of Pain 13-44). Although patients with return pain, arthritis pain, CNS trauma or neuropathic pain may have similar symptoms, the underlying mechanisms are different and therefore may require different treatment strategies. Therefore pain can be divided into a different number of areas due to different pathophysiology, these include nociceptive, inflammatory, neuropathic pain, etc. It should be noted that some types of pain have multiple etiologies and can also be classified in more than one area, ie back pain, cancer pain has both neuropathic and nociceptive components.

Nociceptive pain is induced by tissue injury or intense stimulation with the potential to cause injury. The afferent pains are activated by the transduction of the stimulus by the nociceptors at the site of the lesion and sensitize the spine at the level of its termination. This is subsequently released above the spinal tract to the brain where the pain is perceived (Meyer et al., 1994 Textbook of Pain 13-44). The activation of the nociceptors activates two types of afferent nerve fibers. A-delta honeydew fibers transmit rapidly and are responsible for the sensations of sharp and cutting pain, while non-honeydew C fibers transmit at a slower rate and lead to complete or constant pain. Moderate to severe severe nociceptive pain is a prominent feature of, but not limited to, nerve tension pain / sprains, post-operative pain (pain following any type of surgical procedure), post-traumatic pain, burns, myocardial infarction, acute pancreatitis and renal colic. Also acute pain syndromes related to cancer commonly due to therapeutic interactions such as chemotherapy toxicity, immunotherapy, hormone therapy and radiotherapy. Moderate to severe acute nociceptive pain is a prominent feature of, but is not limited to, pain from cancer, which may be pain related to tumors (ie, bone pain, headache and facial pain, visceral pain) or associated with cancer therapy (ie, post-chemotherapy syndromes, post-surgical pain syndromes, post-radiation syndromes), back pain that may be due to abnormalities or ruptured intervertebral discs of the lumbar junctions, sacral junctions iliac, paraspinal muscles or the posterior longitudinal ligament.

Neuropathic pain is defined as pain initiated or caused by a primary lesion or dysfunction in the nervous system (IASP definition). Damage to the nerve can be caused by trauma or disease and also the term "neuropathic pain" encompasses many diseases with various etiologies. These include, but are not limited to, diabetic neuropathy, post-herpetic neuralgia, back pain, cancer neuropathy, HIV neuropathy, phantom leg pain, carpal tunnel syndrome, chronic alcoholism, hypothyroidism, trigeminal neuralgia, uremia or deficiencies of vitamin. Neuropathic pain is pathological as it does not have a protective role. It commonly occurs after the original cause has dissipated, commonly lasting for years, significantly decreasing the quality of life of patients (Woolf and Mannion 1999 Lancet 353: 1959-1964). Symptoms of neuropathic pain are difficult to treat, as they are commonly heterogeneous even among patients with the same disease (Woolf &Decosterd 1999 Pain Supp 6: S141-S147; Woolf and Mannion 1999 Lancet 353: 1959-1964) . They include spontaneous pain, which may be continuous or paroxysmal and abnormally provoked pain, such as hyperalgesia (increased sensitivity to a noxious stimulus) and allodynia (sensitivity to a normally innocuous stimulus).

The inflammatory process is a complex series of cellular and biochemical events activated in response to tissue injury or the presence of foreign substances, resulting in pain and swelling (Levine and Taiwo 1994: Textbook of Pain 45-56). Arthritic pain constitutes the majority of the population with inflammatory pain. Rheumatoid disease is one of the most common chronic inflammatory conditions in developed countries and rheumatoid arthritis is a common cause of disability. The exact etiology of RA is unknown, but real hypotheses suggest that both microbiological and genetic factors may be important (Grennan & Jayson 1994 Textbook of Pain 397-407). It has been estimated that almost 16 million Americans have sympathetic osteoarthritis (OA) or degenerative joint disease, most of them are over 60 years of age and are expected to increase to 40 million as age increases. of the population increases, making this a public health problem of enormous magnitude (Houge &Mersfelder 2002 Ann Pharmacother 36: 679-686; McCarthy et al., 1994 Textbook of Pain 387-395). The majority of patients with OA observe medical attention due to pain. Arthritis has a significant impact on psychosocial and physical function and is known to be the cause that leads to disability in the last stage of life. Other types of inflammatory pain include but are not limited to inflammatory bowel diseases (IBD).

Other types of pain include but are not limited to: -Skeletal muscle diseases including but not limited to myalgia, fibromyalgia, spondylitis, arthropathies will be negative (not rheumatoid), non-articular rheumatism, dystrophinopathy, glycogenolysis, polymyositis, pyomyositis. Central pain or "thalamic pain" as defined by pain caused by injury or dysfunction of the nervous system including but not limited to central post-stroke, multiple sclerosis, spinal cord damage, Parkinson's disease and epilepsy. Vascular and cardiac pain including but not limited to angina, myocardial infarction, mitral stenosis, pericarditis, Raynaud's phenomenon, scleredoma, skeletal muscle ischemia.

- Visceral pain and gastrointestinal diseases. The viscera encompass the organs of the abdominal cavity. These organs include the sexual organs, the spleen and the part of the digestive system. The pain associated with the viscera can be divided into visceral digestive pain and non-digestive visceral pain. Gastrointestinal diseases commonly found (Gl) include functional bowel diseases (FBD) and inflammatory bowel diseases (IBD). These Gl diseases include a wide range of disease states that are commonly only moderately controlled, including for -FBD, gastro esophageal reflux, dyspepsia, irritable bowel syndrome (IBS) and functional abdominal pain syndrome (FAPS) and -for IBD, Crohn's disease, ileitis and ulcerative colitis, which all regularly produce visceral pain. Other types of visceral pain include pain associated with dysmenorrhea, pelvic pain, cystitis, and pancreatitis. - Head pain including but not limited to migraine, migraine with aura, headache in cluster of migraine without aura, tension headache. - Orofacial pain including but not limited to dental pain, temporomandibular myofacial pain.

As a still further aspect, the use of an alpha-2-delta ligand and an atypical antipsychotic is provided in the manufacture of a medicament for the curative, prophylactic or palliative treatment of pain, particularly neuropathic pain.

As an alternate feature, the invention provides the use of an effective synergistic amount of an alpha-2-delta ligand and an atypical antipsychotic in the manufacture of a medicament for the palliative, curative or prophylactic treatment of pain, particularly neuropathic pain.

As an alternate aspect, a method is provided for the curative, prophylactic or palliative treatment of pain, particularly neuropathic pain, comprising the simultaneous, sequential or separate administration of a therapeutically effective amount of an alpha-2-delta ligand and an atypical antipsychotic to a mammal in need of such treatment.

As an alternate feature, a method is provided for the curative, prophylactic or palliative treatment of pain, particularly neuropathic pain, comprising the simultaneous, sequential or separate administration of a therapeutically synergistic amount of an alpha-2-delta ligand and an atypical antipsychotic to a mammal in need of such treatment.

The biological activity of the alpha-2-delta ligands of the invention can be measured in a radioligand binding test using [3 H] gabapentin and the a2d subunit derived from porcine brain tissue (Gee NS Brown JP Dissanayake VUK Offord J., Thurlow R ., Woodruff GNJ Biol. Chem., 1996; 271: 5879-5776). The results can be expressed in terms of μM or nM 2d for the binding affinity.

The ability of the compounds of the invention to act as atypical antipsychotics can be measured in accordance with established procedures, particularly those described in the aforementioned documents herein.

The elements of the combination of the present invention can be administered separately, simultaneously or sequentially for the treatment of pain. The combination can also optionally be administered with one or more other pharmacologically active agents. Suitable optional agents include: (i) opioid analgesics, ie morphine, heroin, hydromorphone, oxymorphone, levorphanol, levalorfan, methadone, meperidine, fentanyl, cocaine, codeine, dihydrocodeine, oxycodone, hydrocodone, propoxyphene, nalmefene, nalorphine, naloxone , naltrexone, buprenorphine, butorphanol, malbuphine and pentazocine; (ii) non-steroidal anti-inflammatory drugs (NSAIDs), ie, aspirin, diclofenac, diflusinal, etodolac, fenbufen, fenoprofen, flufenisal, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, meclofenamic acid, mefenamic acid, nabumetone, naproxen, ozaprozin, phenylbutazone, piroxicam, sulindac, tolmetin, zomepirac and their pharmaceutically acceptable salts; (iii) barbiturate sedatives, ie amobarbital, aprobarbital, butabarbital, butabital, mephobarbital, metharbital, methohexital, pentobarbital, phenobarbital, secobarbital, talbutal, teamilal, thiopental and their pharmaceutically acceptable salts; (iv) benzodiazepines having a sedative action, ie chlordiazepoxide, clorazepate, diazepam, flurazepan, lorazepam, oxazepan, temazepam, triazolam and their pharmaceutically acceptable salts, (v) antagonists Hi having a sedative action, ie diphenylhydramine, pyrilamine, promethazine, chlorpheniramine, chlorcyclizine and their pharmaceutically acceptable salts; (vi) miscellaneous sedatives such as glutethimide, meprobamate, methaqualone, dichloralphenazone and their pharmaceutically acceptable salts; (vii) Skeletal muscle relaxants, ie, baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, methocarbamol, orfrenadine and their pharmaceutically acceptable salts; (viii) NMDA receptor antagonists, ie, dextromethorphan ((+) - 3-hydroxy-N-methylmorphinan) and its metabolite dextrorphan ((+) - 3-hydroxy-N-methylmorphinan), ketamine, memantine, pyrroloquinoline quinone and ei cis-4- (phosphonomethyl) -2-piperidinecarboxylic acid and its pharmaceutically acceptable salts; (ix) alpha-adrenergic active compounds, ie doxazosin, tamsulosin, clonidine and 4-amino-6,7-dimethoxy-2- (5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl) -5 - (2-pyridyl) quinazoline; (x) tricyclic antidepressants, ie, desipramine, imipramine, amitriptyline and nortriptyline; (xi) anticonvulsants, ie carbamazepine and valproate; (xii) antagonists (NK) tachikinin particularly Mk-3, NK-2 and NK-1, ie the antagonists (aR, 9R) -7- [3,5-bis (trifluoromethyl) benzyl] -8,9,10 , 11-tetrahydro-9-methyl-5- (4-methylphenyl) -7H- [1,4] diazocyne [2,1g] [1,7] naphthridine-6-13-dione (TAK-637), 5- [[(2R, 3S) -2 - [(1 R) -1- [3,5-bis (trifluoromethyl) phenyl] ethoxy-3- (4-fluorophenyl) -4-morpholinyl] methyl] -1, 2- dihydro-3H-1, 2,4-triazol-3-one (MK-869), lanepitant, dapitant and 3 - [[2-methoxy-5- (trifluoromethoxy) phenyl] methylamino] -2-phenyl-piperidine [2S .3S) (xiii) muscarinic antagonists, i.e. oxybutyn, tolterodine, propiverine, tropsium chloride and darifenacin; (xiv) COX-2 inhibitors, that is, celecoxib, rofecoxib and valdecoxib; (xv) non-selective COX inhibitors (preferably with Gl protection), ie nitroflurbiprofen (HCT-1026); (xvi) analgesics of coal tar, in particular, paracetamol; (xvii) neuroleptics, such as droperidol; (xviii) vanilloid receptor agonists, ie, resinferatoxin; (xix) beta-adrenergic compounds such as propranolol; (xx) local anesthetics, such as mexiletine; (xxi) corticosteroids, such as dexamethasone; (xxii) serotonin receptor agonists and antagonists; (xxiii) cholinergic (nicotinic) analgesics; (xxiv) miscellaneous agents such as Tramadol®; (xxv) PDEV inhibitors, such as sildelnafil, vardenafil or taladafil; (xxvi) inhibitors of serotonin re-uptake, ie, fluoxetine, paroxetine, citalopram and sertraline; (xxvii) mixed serotonin-noradrenaline re-uptake inhibitors, ie milnacipran, venlafaxine and duloxetine; (xxviii) inhibitors of norepinephrine re-uptake, ie reboxetine.

The present invention extends to a product comprising an alpha-2-delta ligand, an atypical antipsychotic and one or more therapeutic agents such as those listed above, for simultaneous, sequential or separate use in the curative, prophylactic treatment of the pain, particularly neuropathic pain.

The combination of the invention can be administered alone but one or both of the elements will generally be administered in a mixture with appropriate pharmaceutical excipient (s), diluent (s) or carrier (s) selected with respect to the attempted route of administration and standard pharmaceutical practice. If appropriate, auxiliaries can be added. The auxiliaries are preservatives, anti-oxidants, flavorings or colorants. The compounds of the invention may be of the immediate, delayed, modified, sustained, pulsed or controlled release type.

The elements of the combination of the present invention can be administered, for example but not limited to, the following route, orally, buccally or sublingually in the form of tablets, capsules, multi and nanoparticles, gels, films (including muco-adhesive) , dust, ovule elixirs, pills (including liquid fillers), gums, solutions, suspensions and sprays. The compounds of the invention can also be administered as an osmotic dose form or in the form of a high energy dispersion or as rapidly dissolving or covered particles, in the form of easily disintegrated doses as described in Ashley Publications, 2001 by Liang and Chen. The compounds of the invention can be administered as amorphous or crystalline, dry frozen or spray dried products. Suitable formulations of the compounds of the invention may be in hydrophilic or hydrophobic matrix, ion exchange resin complex, coated or uncoated forms and other types as described in US Patent No. US 6,106,864 as desired.

Said pharmaceutical compositions, for example tablets, may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate, glycine and starch (preferably corn, potato or tapioca starch), mannitol, disintegrants as sodium starch glycolate, croscarmellose sodium and certain complex silicates and granulation binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), triglycerides, hydroxypropylcellulose (HPC), bentonite sucrose, sorbitol, gelatin and acacia. Additionally, lubricating agents can be added to solid compositions such as magnesium stearate, stearic acid, glyceryl behenate, PEG and talc or wetting agents such as sodium lauryl sulfate. Additionally, polymers such as carbohydrates, phospholipids and proteins may be included.

Fast dissolving or dispersing dose formulations (FDDFs) may contain the following ingredients: aspartame, acesulfame potassium, citric acid, croscarmellose sodium, crospovidone, diascorbic acid, ethyl acrylate, ethyl cellulose, gelatin, hydroxypropylmethyl cellulose, stearate magnesium, mannitol, methyl methacrylate, peppermint flavors, polyethylene glycol, exhaled silica, silicon dioxide, sodium starch glycolonate, sodium stearyl fumarate, sorbitol and xylitol. The terms dispersion or dissolution as used herein to describe FDDFs are dependent on the solubility of the drug substance used, i.e., wherein the drug substance is insoluble, a rapidly dispersing dose form can be prepared and Where the drug substance is soluble, a rapidly dissolving dose form can be prepared.

The solid dose form, such as tablets are manufactured by a standard process, for example, direct or wet compression processes, melt or dry granulation, mixing freezing and extrusion. Tablet centers that can be mono-multi-layers can be covered with appropriate coverages known in the art.

Solid compositions of a similar type can also be used as filling agents in capsules such as gelatin, starch or HPMC capsules. Preferred excipients in this regard include lactose, starch, a cellulose, milk sugar or high molecular weight polyethylene glycols. The liquid compositions can be used as fillers in hard or soft capsules such as gelatin capsules. For suspensions, solutions, "aqueous and oily syrups and / or elixirs, the compounds of the invention may be combined with various sweetening or flavoring agents, dyes or coloring material, with emulsifying and / or suspending agents and with diluents such as water. , ethanol, polyethylene glycol, methylcellulose, alginic acid or sodium alginate, glycerin, oils, hydrocolloid agents and combinations thereof In addition, the formulations containing these compounds and excipients can be presented as a dry product for constitution with water or other suitable vehicles before use Liquid form preparations include solutions, suspensions and emulsions, for example, water or propylene glycol solutions in water. For parenteral injection, the liquid preparations can be formulated in aqueous polyethylene glycol solution. Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding appropriate dyes, stabilizing and thickening agents as desired. Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as synthetic or natural gums, resins, methylcellulose, sodium carboxymethylcellulose and other well-known suspending agents.

The elements of the combination of the present invention can also be administered by injection, this is intravenous, intramuscular, intracutaneous, intraduodenal or intraperitoneal, intraarterial, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intraspinal or subcutaneous or can be administered by infusion, implant injection techniques or needle-free injectors. For such parenteral administration, they are best used in the form of a sterile aqueous solution, suspension or emulsion (or system that includes micelles) which may contain other substances known in the art, for example sufficient salts or carbohydrates such as glucose to make the isotonic solution with blood. The aqueous solutions should be appropriately stabilized (preferably at a pH of from 3 to 9), if necessary. For some forms of parenteral administration, they can be used in the form of a non-aqueous sterile system such as fixed oils, including mono or diglycerides and fatty acids, including oleic acid. The preparation of the appropriate parenteral formulations under sterile conditions for example lyophilization is carried out rapidly by standard pharmaceutical techniques well known to those skilled in the art. Alternatively, the active ingredient may be in powder form for constitution with an appropriate vehicle before use (i.e., sterile, water-free pyrogen).

Also, the elements of the combination of the present invention can be administered intranasally or by inhalation. They are conveniently sent in the form of a dry powder (i.e., alone, as a mixture, for example a dry lactose mixture or a mixed component particle, for example with phospholipids) of a dry powder inhaler or a presentation of aerosol spray from a pressurized container, pump, spray, atomizer (preferably an atomizer using electrohydrodynamics to produce a fine mist) or nebulizer, with or without the use of an appropriate propellant, i.e., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane or hydrofluoroalkane such as 1, 1, 1, 2-tetraf luoroethane (HFA 134A [registered trademark] or 1,1,1,3,3,3-heptafluoropropane (HFA 227EA [registered trademark]), carbon dioxide, an additional perfluorinated hydrocarbon such as Perflubron (registered trademark) or other appropriate gases In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to send a measured quantity. The pressurized enerator, pump, spray, atomizer or nebulizer may contain a solution or suspension of the active compound, that is, using a mixture of ethanol (optionally, aqueous ethanol) or an appropriate agent for dispersion, solubilization or extended release and the propellant as the solvent, which may additionally contain a lubricant, ie, sorbitan trioleate. Capsules, packets of pills and cartridges (made for example of gelatin or HPMC) for use in an inhaler or insufflator can be formulated to contain a powder mixture of the compound of the invention, an appropriate powder base such as lactose or starch and a performance modifier such as l-leucine, mannitol or magnesium stearate.

Before being used in a dry powder formulation or suspension formulation for the inhalation of the elements of the combination of the invention, they will be micronized to an appropriate size for release by inhalation (typically considered to be less than 5 microns). Micronization could be carried out by a range of methods, for example spiral-jet milling, corro-milling in fluid bed, the use of critical fluid crystallization or by spray drying.

A solution formulation suitable for use in an atomizer using electrohydrodynamics to produce a fine mist may contain 1 μg of the compound of the invention per actuation and the actuation volume may vary from 1 to 100 μl. A typical formulation may comprise the elements of the combination of the invention, propylene glycol, sterile water, ethanol and sodium chloride. Alternate solvents can be used in place of propylene glycol, for example glycerol or polyethylene glycol.

Alternatively, the elements of the combination of the invention can be administered topically to the skin, mucosa, dermally or transdermally, for example, in the form of a gel, hydrogel, lotion, solution, cream, ointment, powder, bandages, foam, films , patches for the skin, wafers, implants, sponges, fibers, bandages, microemulsions and combinations thereof. For such applications, the compounds of the invention can be suspended or dissolved in, for example, a mixture with one or more of the following: mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax, fixed oils , including synthetic mono- or diglycerides and fatty acids, including oleic oil, water, sorbitan monostearate, a polyethylene glycol, liquid paraffin, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, alcohols such as ethanol. Alternatively, penetration enhancers can be used. The following may also be used, polymers, carbohydrates, proteins, phospholipids in the form of nanoparticles (such as niosomes or liposomes) or suspended or dissolved. In addition, they can be released using iontophoresis, electroporation, phonophoresis and sonophoresis.

Alternatively, the elements of the combination of the invention can be administered rectally, for example in the form of a suppository pessary. They can also be administered through the vaginal route. For example, these compositions can be prepared by mixing the drug with appropriate non-irritating excipients, such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ordinary temperatures, but can liquefy and / or dissolve in the cavity to release the drug .

The elements of the combination of the invention can also be administered by the ocular route. For ophthalmic use, the compounds can be formulated as micronized suspensions in isotonic solutions, adjusted pH, sterile saline or preferably, as solutions in isotonic solutions, adjusted pH, sterile saline. A polymer can be added such as crosslinked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, a cellulosic polymer (ie, hydroxypropylmethylcellulose, hydroxyethylcellulose, methyl cellulose) or a heteropolysaccharide polymer (ie, gelan gum). Alternatively, they can be formulated into an ointment such as petroleum or mineral oil, incorporated into biodegradable (ie absorbing gel sponges, collagen) or non-biodegradable (ie silicone) implants, wafers, drops, lenses or released via particles or vesicular systems such as as niosomes or liposomes. The formulations may optionally be combined with a condom, such as benzalkonium chloride. In addition, they can be released using iontophoresis. They can also be administered in the ear, using for example but not limited to drops.

The elements of the combination of the invention can also be used in combination with a cyclodextrin. Cyclodextrins are known to form inclusion and non-inclusion complexes with drug molecules. The formation of a cyclodextrin complex in the drug can modify the solubility, the rate of dissolution, the taste masking, the bioavailability and / or the stability property of a drug molecule. The cyclodextrin complexes in the drug are generally useful for most dosage forms and routes of administration. As an alternative to the direct complex with the drug, the cyclodextrin can be used as an auxiliary additive, i.e., a carrier, diluent or solubilizer. Alpha, beta and gamma cyclodextrins are most commonly used and appropriate examples are described in WO-A-91/11172, WO-A-94/02518 and WO-A-98/55148.

The term "administered" includes the release by viral or non-viral techniques. Viral delivery mechanisms include but are not limited to adenoviral vectors, adeno-associated viral vectors (AAV), viral vectors of herpes, retroviral vectors, lentiviral vectors and baculoviral vectors. Non-viral delivery mechanisms include lipid-mediated transfection, liposomes, immunoliposomes, lipofectin, cationic facial amphiphiles (CFAs), and combinations thereof. Routes for such release mechanisms include but are not limited to mucosal, oral, nasal, parenteral, gastrointestinal, topical or sublingual routes.

In addition, as a further aspect of the present invention, there is provided a pharmaceutical composition comprising a combination comprising an alpha-2-delta ligand, an atypical antipsychotic or pharmaceutically acceptable salts thereof and an appropriate excipient, carrier or diluent. Suitably, the composition is suitable for use in the treatment of pain, particularly neuropathic pain.

As an alternate aspect of the present invention, there is provided a pharmaceutical composition comprising a synergistic combination comprising an alpha-2-delta ligand, an atypical antipsychotic or pharmaceutically acceptable salts thereof and an appropriate excipient, carrier or diluent. Suitably, the composition is suitable for use in the treatment of pain, particularly neuropathic pain.

For administration to non-human animals, the term "pharmaceutical" as used herein may be replaced by "veterinarian".

The element of the pharmaceutical preparation is preferably in the unit dose form. In such form the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package contains discrete quantities of the preparation, such as packed tablets, capsules and powders in ampoules and injections. Also, the unit dosage form can be in a capsule, tablet, pill or pill or it can be the appropriate number of any of these in package form. The amount of the active component in a unit dose preparation can be varied or adjusted from 0.1 mg to 1 g in accordance with the particular application and potency of the active components. In medical use, the drug can be administered three times a day, for example, capsules of 100 or 300 mg. In therapeutic use, the compounds used in the pharmaceutical method of this invention are administered in the initial dose of about 0.01 mg to about 100 mg / kg daily. A daily dose range of about 0.01 mg to about 100 mg / kg is preferred. The doses, however, can be varied depending on the requirements of the patient, the severity of the condition being treated and the compounds being used. The determination of the appropriate dose for a particular situation is within the skill of the art. Generally, treatment starts with smaller doses that are less than the optimal dose of the compounds. Therefore, the dose is increased by small increments until the optimal effect under the circumstances is reached. For convenience, the total daily dose can be divided and administered in portions during the day, if desired.

For veterinary use, a combination according to the present invention or veterinarily used salts or solvates thereof, are administered as an appropriately acceptable formulation with normal veterinary practice and the veterinarian will determine the dosage regimen and the route of administration which will be the most appropriate for a particular animal.

BIOLOGICAL EXAMPLES METHODS Animals Male Sprague Dawley rats (200-250 g), obtained from Charles River, (Margato, Kent, U.K.) were housed in groups of 6. All animals were kept under a 12-hour light / dark cycle (the lights were switched on at 7:00 hrs.) With food and water ad libitum. All the experiments were carried out by an unconscious observer of the drug treatments.

ICC surgery in the rat Animals were anesthetized with isoflurane. The sciatic nerve was ligated as previously described in Bennett and Xie, 1988. The animals were placed in a homeothermic blanket for the duration of the procedure. After the surgical preparation, the preparation of the common sciatic nerve was exposed in the middle of the thigh by blunt dissection through the femoris of the biceps. Near the sciatic trifurcation, approximately 7 mm of the nerve was released from the adhesion tissue and 4 ligatures (4-0 silk) were loosely secured around it with approximately 1 mm of space. The incision was closed in layers and the wound was treated with topical antibiotics.

Effect of combinations in the maintenance of static and dynamic allodynia induced CCI The responses to the dose of gabapentin and an atypical antipsychotic were first performed alone in the CCI model. The combinations were examined following a fixed proportion design. A dose response was made for each fixed dose proportion of the combination. On each test day, the beginnings of the back leg withdrawal in the baseline (PWT) for the withdrawal latencies of the hind legs and the von Frey wires (PWL) were determined to a cotton graft stimulus before the treatment with the drug.

Evaluation of allodynia Static allodynia was measured using Semmes-Weinstein von Frey wires (Stoelting, Illinois USA). The animals were placed in boxes with wire mesh bottom allowing access to the bottom of their legs. The animals became accustomed to this environment before starting the experiment. Static allodynia was tested by touching the plantar surface of the right hind leg of the animals with von Frey wires in ascending order of force (0.7, 1.2, 1.5, 2, 3.6, 5.5, 8.5, 11.8, 15.1 and 29 g) by more than 6 seconds. Once the withdrawal response was established, the leg was retested, starting with the next downward force of Von Frey cramp until no response occurred. The force majeure required to raise the para and to provoke response, also represents the cutoff point. The lower amount of force required to elicit a response is recorded as the PWT in grams.

Dynamic allodynia is assessed by tapping the plantar surface of the hind paw with a cotton graft. This procedure is carefully performed on fully habituated rats that are not active to avoid recording general motor activity. At least three measurements are taken in each time interval, the average of which represents the leg withdrawal latency (PWL). If no reaction is shown within 15s of the procedure, it is terminated and the animals are assigned to this withdrawal time. In addition, the 15s effectively represent non-retirement. A withdrawal response is commonly accompanied by chills or repeated licking of the leg. Dynamic allodynia is considered to be present if the animals respond to cotton stimulation before cotton before touch 8s.

Combination Studies The first dose responses were made for both the alpha-2-delta ligand (p.o.) and the atypical antipsychotic (s.c. or p.o.) alone. A number of fixed dose proportions of the combination can then be examined. The dose responses for each fixed dose ratio are made over time for each experiment determined by the duration of the anti-allodynic action of each separate proportion. Various proportions of fixed doses of the weight combinations can be examined.

The appropriate atypical antipsychotic compounds of the present invention can be prepared as described in the references or are obvious to those skilled in the art based on these documents.

The appropriate alpha-2-delta ligand compounds of the present invention can be prepared as described below or in the aforementioned patent literature references, which are illustrated by the following non-limiting and intermediate examples.

The following examples and preparations illustrate the preparation of the atypical antipsychotics described in PCT / IB2004 / 002985: Example 1 (S) -3 - ((E) -2-methyl-pent-2-enoyl) -4-phenyl-oxazolidin-2-one A covered reactor of 20 L was fitted with a reflux condenser and an inlet of nitrogen. To the flask was charged 1006 g (8.81 mol) of (E) -2-methyl-2-pentenoic acid, 1250 g (7.661 mol) of (S) - (+) - 4-phenyl-oxazolidin-2-one, 2179 g (8.81 mol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ), 81 g (1915 mol) of lithium chloride and 12.5 L of ethyl acetate (EtOAc). The reaction was heated to 75 ° C for 20 hours and then cooled to room temperature. The reaction solution was extracted with 3x with 4 L of aliquots of 1N HCl and 1x with 4L of 0.2N of NaOH. The 20 L reactor was adjusted with a distillation head. The organic layer was distilled to remove, in succession: 6.5 I of EtOAc, after which 8 I of heptane was added to the reactor, 41 of EtOAc / heptane, after which 4 I of heptane were added to the reactor and 4 I of EtOAc / heptane, after which 5 I of heptane were added to the reactor. After an additional 2 I of EtOAc / heptane, it was removed by distillation, the reaction mixture was cooled to an internal temperature of 40 ° C and the contents of the reactor were charged to a filter and filtered under 5 psig of nitrogen washed with 8 I of heptane. The solids were dried under 5 psig of nitrogen overnight to give 1772 g of the title compound: 1 H-NMR (DMSO) 7363-7.243 (m, 5H), 6.137-6.096 (m, 1 H), 5.434-5.394 (m , 1 H), 4,721-4,678 (t, 1 H, J = 8,578), 4,109-4,069 (m, 1H), 2,119-2,044 (m, 2H), 1,703-1,700 (d, 3H, J = 1,364), 0.945-0.907 (t, 3H, J = 7.603); Anal. Cale, for C ^ H ^ Os: C, 69.48; H, 6.61; N, 5.40. Found: C, 68.66; H, 6.60; N, 5.60; MS (Ion Mode: APCl) m / z = 260 [M + 1] 0 (4S, 5R) -3 - ((E) -2-Methyl-penti-2-enoyl) -4,5-diphenyl-oxazolidin-2-one To a solution of (E) -2-methyl-2- acid Pentenoic acid (5.3 g, 47 mmol) in 250 ml of THF at 0 ° C was added 16.3 ml (117 mmol) of triethylamine, then 5.8 ml (47 mmol) of pivaloyl chloride in a slurry. The mixture was stirred for 1 hour at 0 ° C at which time 2.0 g (47 mmol) of lithium chloride was added in one portion followed by 10 g (42 mmol) of (4S, 5R) -4,5-diphenyl- 2-oxazolidinone in four batches. Agitation was maintained through the solid additions. The reaction mixture was stirred for 1 hour at 0 ° C and for 1 hour at room temperature and filtered under vacuum through a rough frit and concentrated. The residue was partitioned between EtOAc / water and the organics were dried over MgSO4 and concentrated. To the residue was added 200 ml of MTBE and the mixture was heated carefully with stirring. The warm suspension is filtered to provide 13.0 g (83% yield) of the title compound as a colorless solid: 1 H NMR (CDCl 3) d 7.12 (m, 3 H), 7.08 (m, 3 H), 6.93 (m, 2 H), 6.86 (m, 2H), 6.147 (m, 1H), 5.90 (d, J = 7.8 Hz, 1H), 5.69 (d, J = 7.8 Hz, 1 H), 2.23 (pent, J = 7.6 Hz, 2H) , 1.92 (s, 3H), 1.07 (t, J = 7.6 Hz, 3H). The title acylated oxazolidinone can be used in the next step in place of (S) -3 - ((E) -2-methyl-pent-2-enoyl) -4-phenyl-oxazolidin-2-one. (2R, 3R, 4S) -3- (2,3-Dimethyl-pentanoyl) -4-phenyl-oxazolidin-2-one A covered 20 L reactor was fitted with a gas inlet and a 2 I instillation oven A nitrogen sweep was started on the reactor and maintained throughout the process. The reactor was charged with 329 g (9.26 mol) of lithium chloride, 1332 f (6479 mol) of dimethyl sulphide complex of copper bromide and 11 L of tetrahydrofuran. The reaction was stirred for 30 minutes at room temperature and then cooled to -15 ° C. To the reaction mixture was added 4.268 L (12.80 mol) of 3.0 M methyl magnesium chloride in a proportion such as the reaction temperature which did not exceed -10 ° C. At the end of the addition, the cuprate solution was allowed to stir at -5 ° C overnight. To the cuprate solution was added 500 g (3.09 mol) of (S) -3 - ((E) -2-methyl-pent-2-enoyl) -4-phenyl-oxazolidin-2-one as a solid. The reaction was stirred at -3 ° C for 2 hours. The reaction solution was charged to a 22 L round bottom flask containing 800 ml of acetic acid and 2 L of tetrahydrofuran in a proportion such that the temperature of the warm solution did not exceed 25 ° C. To the warm solution, 6 L of water were added. The resulting emulsion was filtered and the layers separated. The organic layer was extracted with 9 L of 4.8 M NH 4 OH followed by 9 L of saturated NH CI. The organic layer was clarified through a magnesol plug. The organic layer was concentrated to give 822 g of a crude solid. The crude solid was recrystallized from 8 L of 20% H20 in MeOH, filtered and dried in a vacuum oven to give 550 g of a white solid. The white solid was recrystallized from 5 L of 20% H20 in MeOH, filtered and dried in a vacuum oven to give 475 g of the title compound: H NMR (DMSO) 7.338-7.224 (m, 5H), 5.413- 5,399 (q, 1 H, J = 4,288), 4,696-4,652 (t, 1 H, J = 8,773), 4,120-4,087 (m, 1 H), 3,622-3,556 (m, 1 H), 1,648-1,584 ( m, 1 H), 1.047-0.968 (m, 1 H), 0.900-0.883 (d, 3H, J = 6.823), 0.738-0.721 (d, 3H, J = 6.628), 0.693-0.656 (t, 3H, J = 7.408); Anal. Cale, for C1ßH2? N103: C, 69.79; H, 7.69; N, 5.09. Found: C, 69.81; H, 7.61; N, 5.07; MS (Ion Mode: APCl) m / z = 276 [M + 1] 0 Acid (2R, 3R) -2,3-Dimethyl-pentanoic A 20 L covered flask was fitted with a gas inlet. A nitrogen purge was started on the reactor and was maintained throughout the process. To the flask was charged 450 g (1634 mol) of (2R, 3R, 4S) -3- (2,3-dimethyl-pentanoyl) -4-phenyl-oxazolidin-2-one and 3.375 L of tetrahydrofuran. The contents of the reactor were stirred at 15 ° C. In a separate 3 L round bottom flask, placed in an ice bath, 500 ml of water was charged, 137 g (3.269 mol) of LiOH-H20 and 942 ml (9.81 mol) of 30% weight / weight of H202. The contents of the 3 L round bottom flask were stirred for 3 minutes and poured into the covered 20 L reactor in a proportion such that the temperature did not exceed 25 ° C. The reaction was stirred at 15 ° C for 2 hours and subsequently raised to 25 ° C and stirred for an additional 2 hours. The temperature of the covered reactor was set at -20 ° C. To the reaction was added 1.66 L of saturated NaHS03 in a proportion such that the reaction temperature did not exceed 25 ° C. The layers separated. The aqueous layer was extracted 2x with 1 L aliquots of MTBE. The organic phases were combined and concentrated to give an oil / solid mixture. The oil / solid mixture was suspended in 1.7 L of hexane. The suspension was filtered and the collected solids were washed with 1.7 L of hexane. The hexane filtrates were extracted with 2x with aliquots of 1.35 L of 1 N NaOH. The aqueous extracts were combined and extracted with 800 ml of dichloromethane. The aqueous layer was subsequently acidified with 240 ml of concentrated hydrochloric acid. The aqueous solution was extracted with 2x with 1L of aliquots of dichloromethane. The organic extracts were combined, dried over MgSO4 and concentrated to give 201 g of the title compound: 1 H NMR (DMSO) 11,925 (bs, 1 H), 2,204-2,135 (m, 1 H), 1556-1.490 (m, 1 H), 1382-1.300 (m, 1 H), 1111-1000 (m, 1 H), 0.952-0.934 (d, 3H, J = 7.018), 0.809-0.767 (m, 6H); Gas chromatogram 9.308 minutes, 98.91% of the area. Anal. Cale, for C7H1402: C, 64.58; H, 10.84; N, 0. Found: C, 64.39; H, 10.77; N, 0.18; MS (Ion Mode: APCl) m / z = 131 [M + 1] +, Ethyl (4R, 5R) -4,5-Dimethyl-3-oxo-heptanoic acid ester To a 1 L round bottom flask equipped with a nitrogen inlet was charged 22 g (230 mmol) of magnesium chloride, 39 g (230 mmol) of potassium ethyl malonate and 200 ml of dimethylformamide. The contents of the flask were stirred at 50 ° C for 1 hour and then cooled to 35 ° C. In a separate 500 ml flask, 200 ml of dimethylformamide, 28.6 g (177 mmol) of diimidazole carbonyl and 20 g of (2R, 3R) -2,3-dimethyl-pentanoic acid were instilled for 30 minutes were added to the inert nitrogen. . When the evolution of the gas had ceased, the contents of the 500 ml flask were added to the 1 L flask. The reaction was stirred for 2 days at 35 ° C. The reaction was cooled to room temperature and diluted with 800 mL of 1 N HCl. The aqueous solution was extracted with 3x with aliquots of 1 L of MTBE. The organic extracts were combined and extracted with 200 mL of saturated NaHCO 3. The organic layer was dried over MgSO4 and concentrated to give 31.74 g of the title compound: 1 H NMR (CDCl 3) 4,180-4,120 (m, 2H), 3.454 (s, 2H), 2.522-2.453 (q, 1 H, J = 7,018), 1,738-1,673 (m, 1 H), 1,418-1,328 (m, 1 H), 1,270-1,217 (m, 3H), 1,113-1,010 (m, 4H), 0.889-0.815 (m, 5H), MS (Ion Mode: APCl) m / z = 201 [M + 1] 0 (4R, 5R) -3-Methoxyimino-4,5-dimethyl-heptanoic acid ethyl ester (4R, 5R) -4,5-Dimethyl-3-oxo-heptanoic acid ethyl ester (21.33 g, 106 mmol) dissolved in 200 ml of EtOH and added to 10.6 g (127 mmol) of methoxylamine-HCl and 10.6 g (127 mmol) of sodium acetate solids. The suspension was stirred at room temperature for 48 hours. MTBE (200 ml) and 100 ml of water were added and the resulting phases were separated. The organic phase was washed with 100 ml of water and evaporated to produce a two-phase mixture. Hexanes (100 ml) were added and the phases separated. The aqueous phase was extracted with 50 ml of hexanes and the combined organic phases were washed with 50 ml of water, dried over magnesium sulfate and evaporated to give 21.24 g (87.4% of the production) of the title compound as a yellow oil. clear: 1H NMR (CDCl3, 399.77 MHz) d 0.84-0.88 (m, 6H), 1.07 (d, J = 7.1 Hz, 3H), 1.24 (t, J = 7.1 Hz, 3H), 1.4-1.6 (m, 2H), 2.24 (m, 1 H), 3.08 (d, J = 15.8 Hz, 1 H), 3.19 (d, J = 15.8 Hz, 1 H), 3.80 (s, 3H), 4.10-4.2 (m, 3H). Spec. of low resolution mass: nominal m / e calculated for C12H23N03 (M + H) +: 230. Found: m / e 230. (4R, 5R) -3-Amino-4,5-dimethyl-hept-2- (Z) -enoic acid methyl ester A solution of 21.1 g (92 mmol) of heptanoic acid ethyl ester (200 ml) was treated with Sponge nickel (10 g, Johnson Matthey A7000). The resulting suspension was hydrogen on a Parr type hydrogenator stirrer at 50 psig and at room temperature for 20 hours. At this time an additional 10 g of the nickel catalyst was added and the hydrogenation was continued for a total of 42.0 hours. The suspension was filtered, the solids were washed with fresh methanol and the combined filtrate was evaporated to give 17.75 g (96.8% yield) of the title compound as a colorless oil: 1 H NMR (CDCl 3, 399.77 MHZ) d 0.83-0.89 (m , 6H), 1.1 (d, J = 6.8 Hz, 3H), 1.25 (t, J = 7.1 Hz, 2H), 1.35-1.6 (m, 4H), 1.85-1.93 (m, 1 H), 4.1 (q , J = 7.0 Hz, 2H), 4.5 (s, 1 H). Esp. Low resolution mass: nominal m / e calculated for C11H2- | N02 (M + H) +: 200. Found: m / e 200.

Ethyl ester of (4R, 5R) -3-Acetylamino-4,5-dimethyl-hept-2- (Z) -enoic acid A solution of 15.84 g (79.84 mmol) of the ethyl ester of the acid (79.84 mmol) of (4R) .5R) -3-amino-4,5-dimethyl-hept-2- (Z) -enoic acid and 6.89 g (7.04 ml, 87.82 ml) of pyridine was stirred in 200 ml of methylene chloride and cooled to 0 °. C. A solution of 6.85 g (6.21 ml, 87.82 ml) of acetyl chloride in 20 ml of methylene chloride was added dropwise over 1 hour. The solution was warmed to room temperature and stirred for two hours. 1M hydrochloric acid (100 ml) was added and the phases were separated. The organic phase was washed with saturated aqueous NaHCO3 solution and dried briefly over Na2SO4. The solvent was evaporated and subsequently the resulting oil was passed through a short column of silica (200 g of silica, 230-400 mesh) with 8: 1 (v / v) hexane / EtOAc. The fractions contained in the product were evaporated to give 13.75 g (71.7% of the production) of the title compound as an almost colorless, clear oil: 1H NMR (CDCl3, 399.77 MHz) d 0.84 (t, J = 7.1 Hz, 3H) , 0.95 (d, J = 6.8 Hz, 3H), 1.0 (d, J = 7.0 Hz, 3H), 1.29 (t, J = 7.2 Hz, 3H), 1.30-1.45 (m, 3H), 2.13 (s, 3H), 3.79-3.82 (m, 1 H), 4.11-4.18 (m, 2H), 5.01 (s, 1 H). Spec. of low resolution mass: nominal m / e cale, for C13H23N03 (M + H) +: 242. Found: m / e 242.

Ethyl ester of (3R, 4R, 5R) -3-Acetylamino-4,5-dimethyl-heptanoic acid A solution containing 13.75 g (57 mmol) of ethyl ester of (4R, 5R) -3-acetylamino-4,5-ethyl ester -dimethyl-hept-2- (Z) -enoic acid in 200 ml of methanol was treated with 5% Pd / Al203 (1.5 g, Johnson Matthey # 2127, lot 13449). The resulting suspension was hydrogen in a Parr type hydrogenator stirrer at 40 psig. For 50 psig. and at room temperature for a total of 3.8 hours. The suspension was filtered and the solids were washed with fresh methanol. The combined filtrate was evaporated to give 13.63 g (98.6% of yield) of the title compound as a colorless oil: 1 H NMR (CDCl 3, 399.77 MHz) d 0.82 (d, J = 7.0 Hz, 3H), 0.86 (t, J = 7.3 Hz, 3H), 0.90 (d, J = 6.5 Hz, 3H), 0.98-1.1 (m, 2H), 1.25 (t, J = 7.2 Hz, 2H), 1.3-1.6 (m, 2H), 1.96 (s, 3H), 2.48 (dd, J = 16, 5.65 Hz, 1 H), 2.53 (dd, J = 16, 5.2 Hz, 1 H), 4.08-4.19 (m, 2H), 4.27-4.34 (m , 1 H), 5.86 (br, d, J = 8.9 Hz, 1 H). Spec. of low resolution mass: nominal m / e cale, for C13H25N03 (M + H) +: 244. Found: m / e 244. (3R, 4R, 5R) -3-Amino-4,5-dimethyl-heptanoic acid hydrochloride (3R, 4R, 5R) -3-Acetylamino-4,5-dimethyl-heptanoic acid ethyl ester (13.63 g, 56.0 mmol) was heated under reflux with 200 ml of 1 M hydrochloric acid for 72 hours. The solution was cooled and extracted 2x with 50 ml aliquots of MTBE. The aqueous phase was evaporated to a semi-solid. Acetonitrile (4 x 100 ml) was added and evaporated to give 10.75 g (89% yield) of the title compound as a white crystalline solid: 1 H NMR (CDCl 3, 399.77 MHz) 0.87 (t, J = 7.3 Hz, 3H ), 0.94 (t, J = 6.6 Hz, 6H), 1.02-1.15 (m, 1 H), 1.37-1.53 (m, 2H), 1.58-1.68 (m, 1 H), 2.64 (dd, J = 17.5 , 7.4 Hz, 1 H), 2.73 (dd, J + 17.5, 4.8 Hz, 1 H), 3.54-3.61 (m, 1 H). Spec. of low resolution mass: nominal m / e cale, for C9H20CINO2 (M + H) +: 174. Found: m / e 174. (3r, 4R, 5R) -3-Amino-4,5-dimethyl-hepanoic acid The (3R, 4R, 5R) -3-Amino-4,5-dimethyl-heptanoic acid hydrochloride (10.8 g, 51.5 mmol) it was dissolved in 50 ml of methanol. To this solution was added triethylamine (5.2 g, 7.2 ml, 51.5 mmol). The solution was stirred for 10 minutes and then evaporated to a flocculent solid. Dichloromethane (376 ml) was added and the resulting suspension was stirred at room temperature for 45 minutes.

Then 188 ml of acetonitrile was added and the suspension was stirred for 30 minutes and subsequently filtered. The solids were washed with 20 ml of 2: 1 (v / v) dichloromethane-acetonitrile and dried in a nitrogen press to give 7.64 g (85.6% yield) of the title compound as a white solid: 1H NMR (CD3OD , 399.77 MHz) 0.88 (t, J = 7.5 Hz, 3H), 0.91 (d, J = 7.0 Hz, 3H), 0.94 (d, J = 6.6 Hz, 3H), 0.98-1.12 (m, 1 H), 1.32-1.43 (m, 1 H), 1.43-1.64 (m, 2H), 2.26 (dd, J = 16.5, 9.9 Hz, 1 H), 2.47 (dd, J = 19.5, 3.7 Hz, 1 H), 3.28 -3.36 (m, 1 H), Spec. of low resolution mass: nominal m / e cale, for C9H19N02 (M + H) +: 174. Found: m / e 174.

Hydrate 1/6 of the complex of 1/6 succinic acid of (3R, 4R, 5R) -3-Amino-4,5-dimethyl-heptanoic acid, ie 6 - ((3R, 4R, 5R) -3- amino-4,5-dimethyl-heptanoic acid): 1 - (succinic acid): 1- (H20) (3R, 4R, 5R) -3-Amino-4,5-dimethyl-heptanoic acid (7.6 g, 44 mmol) and succinic acid (2.6 g, 22 mmol) were suspended in 20.2 ml of water. The suspension was heated to 100 ° C to dissolve the solids. Acetonitrile (253 ml) was added to the hot solution. The mixture was stirred at 55 ° C for 1 hour and then gradually cooled to room temperature overnight. The resulting solids were filtered, washed with 10 ml of acetonitrile and dried in a nitrogen press to give 6.21 g (72% yield) of the title compound as hollow white crystals: H NMR (CD3OD, 399.77 MHz) 1H NMR ( CD3OD, 399.77 MHz) 0.88 (t, J = 7.5 Hz, 3H), 0.91 (d, J0 7.0 Hz, 3H), 0.94 (d, J = 6.6 Hz, 3H), 0.98-1.12 (m, 1 H) , 1.32-1.43 (m, 1H), 1.43-1.64 (m, 2H), 2.26 (dd, J = 16.5, 9.9 Hz, 1 H), 2.47 (dd, J = 19.5, 3.7 Hz, 1 H), 2.50 (s, 0.67H), 3.28-3.36 (m, 1 H). Spec. of low resolution mass: nominal m / e cale, for C9H 9? 2 (M + H) 0 174. Found: m / e 174. Anal. Cale, for 6 - ((3S, 4R, 5R-3-amino-4,5-dimethyl-heptanoic acid): 1 - (succinic acid): 1- (H20), C58H122N6013: C, 59.26; H, 10.46; N, 7.15 Found: C, 59.28; H, 10.58; N "7.09, KF cale, for C58H122N6013: H20, 1.43% by weight Found: H20, 1.50% by weight.

Example 2 (4S, 5R) -4,5-Diphenyl-oxazolidin-2-one To a 5 L round bottom flask equipped with an overhead stirrer, distillation head and thermocouple was charged 550 g (2579 mol) of (1 R, 2 S) -diphenyl-2-aminoethane, 457 g (3,868 mol, 1.5 eq) of diethyl carbonate, 18 g (0.258 mol, 0.1 eq) of NaOEt in 100 ml of EtOH and 3.5 L of toluene. The reaction was heated until an internal temperature of 90 ° C was reached and distillation of EtOH started. The reaction was refluxed until the internal temperature reached 110 ° C (7 hours). For each 500 ml of the solvent that was removed via the distillation head, 500 ml of toluene was added to the reaction. A total of approximately 1.6 L of the solvent was removed. The reaction was cooled to room temperature and subsequently filtered through a rough porous funnel with 2 psig of N2. Nitrogen was blown over the cake overnight to give 580 g (94% of the production) of the title compound: 1 H NMR (DMSO) 7,090-6.985 (m, 6H), 6,930-6,877 (m, 4H), 5,900 (d, 1 H, J = 8,301), 5,206 (d, 1 H, J = 8,301). (4S, 5R) -3 - ((E) -2-Methyl-hex-2-enoyl) -4,5-diphenyl-oxazolidin-2-one (Alternative A) A covered reactor of 20 L was fitted with a condenser of reflux. To the reactor was charged 1100 g (4.597 mol) of (4S, 5R) -4,5-diphenyl-oxazolidin-2-one, 884 g (6.896 mol) (E) -2-methyl-2-pentenoic acid 1705 g (6,896 mol) of EEDQ, 48 g (1149 mol) of LiCl and 16 L of EtOAc. The reaction mixture was heated to 65 ° C and maintained for 200 minutes. The reaction mixture was cooled to room temperature and c3x was extracted with 3.5 L aliquots of 1 N HCl. The combined aqueous extracts were filtered to give a white solid. The recovered white solid was added back to the organic layer. The 20 L reactor was adjusted with a distillation head and the organic layer was distilled to stir in succession: 13.5 L of EtOAc, after which 5 L of heptane was added to the reactor, 5 L of EtOAc / heptane, after 5 L of heptane were added to the reactor and 2.7 L of EtOAc / heptane, after which 2.7 L of heptane were added to the reactor. The contents of the reactor were cooled to 25 ° C and the resulting mixture was filtered under 5 psig of nitrogen while it was washed with 4 L of heptane. The wet cake was dried under nitrogen pressure overnight to give 1521 g of the title compound: 1 H NMR (DMSO) 7-12-6.94 (m, 8H), 6,834 (dd, 2H, J = 7,813, 1,709), 6,060 (d, 1 H, J = 8,057), 6,050 (td, 1 H, J = 7,447, 1,221), 5,795 (d, 1 H, J = 8,057), 2,119-2,064 (m, 2H), 1,778 (d, 3H, J = 0.997), 1394 (m, 2H), 0.874 (t, 3H, J = 7.324); Anal. Cale, for C ^ H ^ Oa: C, 75.62; H, 6.63; N, 4.01. Found: C, 75.26; H, 6.72; N, 3.95. (4S, 5R) -3- (2- (E) -Methyl-hex-2-enoyl) -4,5-diphenyl-oxazolidin-2-one (Alternative B) To a solution of (E) -2- acid methyl-2-hexenoic acid (6.0 g, 47 mmol) in 250 mL of THF at 0 ° C was added 16.3 mL (117 mmol) of triethylamine, then 5.8 mL (47 mmol) of pivaloyl chloride resulting in a slurry. The mixture was stirred for 1 hour at 0 ° C at that time, 2.0 g (47 mmol) of lithium chloride were added in one portion, followed by 10.0 g (42 mmol) of (4S, 5R) -4,5-diphenol. -2-oxazolidinone in four batches. Stirring was maintained through the solid additions. The resulting mixture was stirred for 1 hour at 0 ° C for 1 hour at room temperature and filtered under vacuum through a rough frit and concentrated. The residue was partitioned between EtOAc / water and the organics were dried over MgSO4 and concentrated. To the residue, 100 ml of MTBE was added and the mixture warmed cautiously with stirring. The heated suspension was filtered to provide 10.5 g (64% yield) of the title compound as a colorless solid: 1H NMR (CDCla) d 7.12 (m, 3H), 7.07 (m, 3H), 6.94 (m, 2H), 6.84 (m, 2H), 6.17 (m, 1H), 5.89 (d, J = 7.8 Hz, 1 H), 5.68 (d, J = 7.8 Hz, 1 H), 2.18 (m, 2H), 1.92 (s) , 3H), 1.50 (m, 2H), 0.96 (t, J = 7.6 Hz, 3H). (4S, 5R) -3 - ((2R, 3R) -2,3-Dimethyl-hexanoyl) -4,5-diphenyi-oxaIidin-2-one A 22-liter round bottom flask with 4 necks was equipped with a addition funnel, mechanical agitator and nitrogen inlet. The system was purged with nitrogen for 1 hour. THF (6 L) were charged to the flask followed by 1236 g (6.01 mol) of CuBrS (CH3) 2 and 364 g (8.59 mol) of LiCl. The reaction was stirred for 15 minutes at room temperature. The solution was cooled to -35 ° C and 3.96 L (11.88 mol) of a 3M solution of CH3MgCI in THF was charged in a proportion to keep the internal temperature of the reaction mixture below -25 ° C. The reaction was stirred for 1 hour after the addition of CH3MgCI was complete. The reaction was stirred for 1 hour after the addition of CH3MgCI and completed. S, 5R) -3 - ((E) -2-Methyl-hex-2-eneyl) -4,5-diphenyl-oxazolidin-2-one (1.00 Kg, 2.86 mmol) was added as a solid in one portion and the reaction was stirred at -30 ° C for 4 hours. The reaction mixture was transferred for a period of 2 hours in another 22 L flask equipped with a mechanical stirrer, transfer line, vacuum line and containing 4 L acetic acid 1 : 1: THF solution cooled in an ice-water bath. The warm solution was stirred for 30 minutes and then diluted with 4 L of 2 M NH 4 OH in saturated aqueous NH 4 Cl and 2 L of water. The biphasic mixture was stirred for 15 minutes and the phases were separated. The organic phase was washed 4x with 4 L aliquots of 2M NH OH solution. The blue color was no longer observed in the washes or the organic phase so that the organic phase was diluted with 8 L of water and the THF was distilled until the internal temperature of the distillation bowl reached 95 ° C. The suspension was cooled to room temperature and filtered. The solids were washed with 4 L of water and the suction was dried to give 868.2 g of a grayish solid. This material was recrystallized from 2 L of 95: 5 heptane: toluene with a cooling ratio of 5 ° C per hour to provide 317.25 g of the title compound as a clear solid: 1 H NMR (CDCl 3) 7.12-6.85 (m, 10H), 5.90 (d, 1 H, J = 8.06 Hz), 5.72 (d, 1 H, J = 7.81), 3.83-3.76 (m, 1 H), 1.95-1.89 (m, 1H), 1.35- 1.31 (m, 1 H), 1.11 (d, 3H, J = 6.84), 1.10-0.95 (m, 3H), 0.92 (d, 3H, J = 6.59), 0.76 (t, 3H, J = 7.20) MS (APCl) M + 1 = 366.2.

Acid (2R, 3R) -2,3-Dimethyl-hexanoic A 12-neck, 4-necked round bottom flask, equipped with a mechanical stirrer, 500 ml addition funnel, nitrogen inlet and thermometer, was charged with 4515 mL of THF and 330.g of (4S, 5R) -3 - ((2R, 3R) -2,3-dimethyl-hexanoyl) -4,5-diphenyl-oxazolidin-2-one. The resulting liquid mie (all solids were dissolved) was cooled to -5 ° C to 0 ° C using an acetone / ice bath. A solution of 60.6 g of UOH-H20 in 1800 mL of deionized water was cooled to 0 ° C to 5 ° C and combined with 512 g of 30% cold hydrogen peroxide (w / w) in an Erlenmeyer flask of 2 ml. L. The solution was kept cold using an ice / water bath. After the THF / oxazolidinone solution in the 12 L reaction flask reached -5 ° C to 0 ° C, the addition funnel was charged with about a quarter of cold LiOH / water / H202 solution. While the nitrogen sweep was maintained to minimize the concentration of oxygen in the head space of the reactor, the Li0H / water / H202 solution was added dropwise to the THF / oxazolidinone solution vigorously stirred in said proportion to maintain the reaction temperature at 0 ° C to 5 ° C. The addition funnel was recharged with approximately one quarter of the cold Li0H / water / H202 solution as required until all the solution had been added to the reaction mie (about 40 minutes on the 0.45 mole scale). After the addition was complete, the mie was stirred at 0 ° C to 5 ° C for 5 hours, during which the reaction mie loaded with a homogeneous solution for white suspension. A solution of 341 g of Na2S03 and 188 g of NaHS03 in 2998 ml of deionized water (15% by weight) was added dropwise to the reaction mie over about a period of 1.5 hours (the reaction was exothermic) via the funnel. addition, while maintaining the reaction temperature at 0 ° C to 10 ° C. Following the addition, the reaction mie was stirred at 0 ° C to 10 ° C for 1 hour. The reaction mie was tested with potassium iodide starch test paper to ensure the absence of peroxides. The reaction mie was charged with 2000 ml EtOAc and stirred for 5 minutes. The phases were separated and the aqueous phase was extracted with 2000 mL of EtOAc. The combined organic extract was washed with brine (2x1500 ml). The colorless organic solution was concentrated under vacuum (35 ° C-40 ° C) for a "wet" white solid. Heptane (1000 ml) was added and the suspension was concentrated under vacuum (35 ° C-40 ° C for a wet white solid) Heptane (5000 ml) was added and the suspension was kept at 0 ° C to 5 ° C for 16 minutes. hours and then at -10 ° C to -5 ° C for 1 hour.The cold suspension was filtered through a thin pad of celite and the filter cake was washed with 100 ml of heptane from -10 ° C to -5 C. The colorless filtrate was concentrated under vacuum (40 ° C-45 ° C) to give 130 g of the title compound as a pale yellow oil: 1 H NMR (400 MHz, CHLOROFORM-D) 0.89 (t, J = 7.00 Hz , 3H), 0.94 (d, J = 6.8 Hz, 3H), 1.13 (d, J = 7.0 Hz, 3H), 1.75-1.82 (m, 1 H), 2.34-2.41 (m, 1 H); GC purity chiral: 99.18% (with 0.82% diastereomer) (direct acid method) Chemical purity: 100% Anal Cal for C8H1602: C, 66.63; H, 11.18 Found: C, 66.15; H, 11.41.

Ethyl ester of (4R, 5R) -4,5-Dimethyl-3-oxo-octanoic acid (Alternative A) A 3-neck, 3-neck round bottom flask equipped with a reflux condenser, mechanical stirrer, nitrogen inlet and thermometer, was charged with 1390 mL of dry THF and 389.3 g of potassium ethyl malonate. MgCl 2 (217.8 g) was added in three equal portions so that the internal temperature was less than 50 ° C. The resulting gray suspension was heated to 55 ° C to 60 ° C using a temperature-controlled heating mantle. The mie was stirred at 55 ° C to 60 ° C for 5 hours. A 2-L 3-necked round bottom flask, equipped with a 500 mL addition funnel, mechanical stirrer, nitrogen inlet and thermometer, was charged with 680 ml of dry THF and 286.8 g of 1, 1'-carbonyldiimidazole (CDI). The addition funnel was charged a prudent portion with a solution of 219.9 g of (2R, 3R) -2,3-dimethyl-hexanoic acid in 350 ml of dry THF. A solution of complete dimethyl hexanoic acid / THF was added dropwise to the stirred CDI / THF suspension in said proportion so that the evolution of C02 was monitored and to maintain the reaction at a temperature of 20 ° C to 25 ° C. Following the addition, the reaction mixture was stirred at 20 ° C to 25 ° C for 1 hour. Following the addition, the reaction mixture was stirred at 20 ° C to 25 ° C for 1 hour, during which the suspension became a clear yellow solution. After a reaction time of 5 hours, the malonate / MgCl 2 reaction mixture was cooled to 20 ° C to 25 ° C and the condenser was replaced with a 1 L addition funnel. The addition funnel was charged with a prudent portion with the reaction mixture THF / dimethylhexanoic acid. This complete reaction mixture was added dropwise to the stirred THF / MgCl2 / malonate reaction mixture in about 10 minutes. After the addition was complete, the reaction mixture was heated to 35 ° C to 40 ° C. Some effervescence was noted. The reaction mixture was stirred at 35 ° C to 40 ° C for 16 hours. The reaction mixture was cooled to 20 ° C to 25 ° C. A 12 L round 3-necked flask, equipped with a mechanical stirrer and thermometer, was charged with 3060 mL of 2N aqueous HCl. The reaction mixture (a gray suspension) was added dropwise to the aqueous HCl solution while maintaining a temperature of 20 ° C-25 ° C. The reaction temperature was moderated with a water / ice bath, the pH of the reaction mixture was approximately 1. Following the addition, the reaction mixture was stirred at 20 ° C to 25 ° C for 2 hours. The reaction mixture was subsequently charged with 4000 mL of EtOAc and stirred for 5 minutes. The phases were separated and the aqueous phase was extracted with 2000 ml of EtOAc. The combined organic extract was washed sequentially with: 1 N aqueous HCl (2x1500 ml); 1000 ml of water (complete phase separation); half saturated aqueous Na2CO3 solution (2x1500 ml); 1000 ml of water and brine (2x1000 ml). (The water-based wash removed the acid from the unreacted malonate ester). The straw colored organic solution was concentrated under vacuum (35 ° C-40 ° C) to give a light yellow cloudy oil with some white solid present. The oil was redissolved in 1500 mL of n-heptane and filtered. The filtrate was concentrated under vacuum (40 ° C-45 ° C) to give 327 g of the title compound as a light yellow oil: 1 H NMR (400 MHz, CHLOROFORM-D) d ppm 0.82 (t, J = 7.1 Hz, 3 H ), 0.85 (d, J = 6.8 Hz, 3H), 0.99 (d, J = 7.1 Hz, 3H), 1.20 (t, J = 7.3 Hz, 3H), 2.42-2.49 (m, 1 H), 3.39 ( s, 2H), 4.12 (q, J = 7.16 Hz, 3H). Chemical purity GC: 96.24%.

Ethyl ester of (4R, 5R) -4,5-Dimethyl-3-oxo-octanoic acid (Alternative B) To a solution containing 2.0 g (13.9 mmol) of (2R, 3R) -2,3-dimethyl-hexanoic acid in 20 mL of dichloromethane was added 2.1 g (16.6 mmol) of ammonium chloride-dimethyl chloromethylene. After stirring the resulting solution under nitrogen for 1.5 hours, the solvent was evaporated to give (2R, 3R) -2,3-dimethyl-hexanoyl chloride. Butyl lithium (32.7 ml, 52.4 mmol) was added to a solution of diisopropylamine (4.9 g, 48.5 mmol) in dry THF (20 ml) under nitrogen at 0 ° C and stirred for 20 minutes. The solution was cooled to -78 ° C and 4.3 g (48.5 mmol) of ethyl acetate were added. The solution was stirred at that temperature for 45 minutes. Chloride of (2R, 3R) -2,3-Dimethyl-hexanoyl in THF (20 mL) was added slowly to the ethyl acetate enolate at -78 ° C and the resulting reaction mixture was warmed to room temperature. The reaction mixture was stirred at room temperature for 2.5 hours and cooled to 0 ° C. The reaction was warmed with a saturated solution of ammonium chloride and extracted into ethyl acetate. The solution was washed with brine, dried over MgSO4 and concentrated. The resulting residue was filtered through a plug of silica, eluting with 60/40 ethyl acetate / hexane solution to yield 2.7 g (89.2% yield) of the title compound as an oil.

Ethyl ester of (4R, 5R) -4,5-Dimethyl-3-oxo-octanoic acid (Alternative C) To a solution containing 1.0 g (6.9 mmol) of (2R, 3R) -2,3-dimethyl-hexanoic acid in 10 ml of dichloromethane was added 1.1 g of dimethyl-ammonium chloromethylene chloride (8.3 mmol). The resulting solution was stirred under nitrogen for 1.5 hours. The solvent was subsequently evaporated to give (2R, 3R) -2,3-dimethyl-hexanoyl chloride. To a solution containing 2. 5 g (14.6 mmol) of potassium monoethylene malonate in 50 ml of acetonitrile was added 1.7 g (17.3 mmol) of magnesium chloride and 1.2 g (11.4 mmol) of triethylamine. The resulting mixture was stirred at room temperature for 2.5 hours. The reaction was cooled to 0 ° C and a solution of (2R, 3R) -2,3-dimethyl-hexanoyl chloride in acetonitrile (20 ml) was slowly added followed by the addition of triethylamine (0.4 g, 0.4 mmol). The reaction was heated to 40 ° C and stirred at that temperature for 6 hours. The reaction mixture was cooled to 25 ° C, warmed with a saturated solution of ammonium chloride and extracted with ethyl acetate. The solution was washed with brine, dried over MgSO4 and concentrated. The resulting residue was filtered through a plug of silica, eluting with a 60/40 solution of ethyl acetate / hexane to yield 1.3 g (87.8% of the production) of the title compound as an oil. (4R, 5R) -3-methoxyamino-4,5-dimethyl- (Z) -oct-2-enoic acid ethyl ester A 3-neck, 3-neck round bottom flask equipped with a magnetic stirrer and nitrogen inlet. charged with 153 g (0.71 mol) of (4R, 5R) -4,5-dimethyl-3-oxo-octanoic acid ethyl ester and 600 ml of anhydrous EtOH. The solution was cooled to 0 ° C-5 ° C with an ice bath and 65.6 g (0.79 mol) of methoxylamine hydrochloride was added, followed by 58.6 g (0.71 mol) of sodium acetate. These contents of the flask were heated slowly to room temperature (approximately 2 hours) and the reaction mixture was stirred at room temperature for another 24 hours. The solvent (EtOH) was removed under reduced pressure and the mixture was charged with CH 2 Cl 2 (2 x 300 ml) which were subsequently removed. The mixture was cooled to RT, diluted with CH2Cl2 (300 mL), stirred at room temperature for 0.5 hour and filtered under 5 psig of nitrogen. The filter cake was washed with CH2Cl2 (150 ml). The filtrate was concentrated under vacuum (50 ° C) to give 172 g (99% yield) of the title compound as a light yellow oil: 1 H NMR (400 MHz, CHLOROFORM-D) 0.87 (t, J = 3.5 Hz, 5H ), 0.89 (d, J = 7.2 Hz, 3H), 1.08 (d, J = 7.0 Hz, 3H), 1.24 (t, J = 7.2 Hz, 4H), 1.3-1.55 (m, 2H), 2.25 (m , 1H), 3.15 (q, J = 19.5 Hz, 2H), 3.81 (s, 3H), 4.14 (q, J = 7.0 Hz, 2H).

Ethyl ester of (4R, 5R) -3-Amino-4,5-dimethyl- (Z) -oct-2-enoic acid A reactor vessel loaded with 171 g of (4R, 5R) -3-methoxyamino acid ethyl ester 4,5-dimethyI- (Z) -oct-2-enoic, 1600 ml of MeOH and 65 g of Raney nickel catalyst (Ra-Ni). The methoxyamino ester was reacted with hydrogen at 50 psig at 55 psig. During hydrogenation, the additional Ra-Ni was added in reaction times of 8 hours (20 g), 21 hours (20 g) and 37 hours (8 g). After the reaction was complete (51 hours), the Ra-Ni was filtered and the filtrate was concentrated under reduced pressure to give 150 g (> 99% yield) of the title compound as an oil: 1 H NMR (400 MHz , CHLOROFORM-D): 0.86 (t, J = 4.5 Hz, 3H), 0.88 (d, J = 4.9 Hz, 3H), 1.05-1.50 (m, 6H), 1.10 (d, J = 7.0 Hz, 3H) , 1.24 (t, J = 7.2 Hz, 3H), 1.87 (m, 1H), 3.45 (s, 2H) 4.08 (q, J = 7.0 Hz, 2H). (4R, 5R) -3-Acetylamino-4,5-dlmethyl- (Z) -oct-2-enoic acid ethyl ester To a 1-liter 3-necked round neck flask equipped with overhead stirrer, thermocoupler, additional funnel and nitrogen inlet, was charged with 150 g (OJO mol) of (4R, 5R) -3-amino-4,5-dimethyl- (Z) -oct-2-enoic acid ethyl ester and 50 ml of dry CH2Cl2. . The reaction mixture was cooled to -20 ° C. To the mixture was added successively, acetyl chloride (60 ml, 0.84 mmol) and pyridine (66.8 g, 0.84 mol) in a time of 0.5 hour intervals. After the additions, the mixture was stirred at -20 ° C to 0 ° C for 2 hours and then filtered to remove the HCl.pyridine salt. The filtrate was diluted with 200 ml of CH 2 Cl 2 and washed 2x with aliquots of aqueous NH 4 Cl. The organic solution was treated with silica gel (50 g), MgSO 4 (20 g) and carbon (20 g) and stirred at room temperature for 0.5 hour. The solids are filtered and the filtrate is concentrated under reduced pressure to give 166.5 g (93% yield) of the title compound as an oil: 1 H NMR (400 MHz, CHLOROFORM-D) 0.85 (t, J = 7.4 Hz, 3H) , 0.95 (d, J = 6.8 Hz, 3H), 1.00 (d, j = 7.0 Hz, 3H), 1.11 (m, 1 H), 1.29 (t, j = 5.8 Hz, 3H), 1.40-1.25 (m , 2H), 1.65 (m, 1 H), 2.13 (s, 3H), 3.80 (m, 1 H), 4.2-4.14 (m, 3H), 5.01 (s, 1 H), 11.28 (s, 1 H) ).

Ethyl ester of (3R, 4R, 5R) -3-Acetylamino-4,5-dimethyl-octanoic acid One reactor was charged with 166 g of (4R, 5R) -3-acetylamino-4,5-dimethyl ethyl ester - (Z) -oct-2-enoic (substrate), 2650 ml of MeOH and 36 g of Pd / SrC03 catalyst (batch No. D25N17).

The substrate was reacted with H2 at a pressure of 50 psig at 51 psig. After the reaction was complete (90 hours), Pd / SrC03 was filtered and the filtrate was concentrated under reduced pressure to give 167 g (> 99% yield) of the title compound as an oil: 1 H NMR (400 MHz, CHLOROFORM-D): 0.82 (d, J = 6.8 Hz, 3H), 0.88 (t, J = 7.2 Hz, 3H), 0.90 (d, J = 6.6 Hz, 3H), 1.25 (t, J = 7.3 Hz, 3H), 1.00-1.58 (m, 6H), 1.96 (s, 3H), 2.52 (q, J = 5.2 Hz, 2H), 3.47 (s, 1 H), 4.10-1.30 (m, 2H), 4.12 ( t, J = 7.1 Hz, 1 H), 5.9 (d, 1 H). (3R, 4R, 5R) -3-Amino-4,5-dimethy1-octanoic acid hydrochloride Under nitrogen, 167 g of (3R, 4R, 5R) -3-acetylamino-4,5-dimethyl- ethyl ester Octanoic was diluted with 11000 ml of 6H HCl, stirred at room temperature for 16 hours and subsequently refluxed for another 24 hours. The reaction mixture was concentrated and recharged with 500 ml of isopropyl alcohol (IPA) which was subsequently removed. Acetonitrile (500 ml) was added to the crude white HCl salt and the mixture was stirred at 20 ° C to 25 ° C for 1 hour. The resulting suspension was filtered and the solids were isolated to give 97 g of the title compound (67% yield, 89.7% chemical purity, 90.7% chiral purity with two major diastereomers, 6.8% and 1.5%): 1H NMR (CD3OD ): d? .89 (t J = 7.0 Hz, 3H), 0.94 (t, J = 6.9 Hz, 6H), 1.65-1.0 (m, 4H), 2.61 (dd, J = 7.6 Hz, 1 H), 2J3 (dd, j = 4.6 Hz, 1 H), 3.27 (m, 1.6 Hz, 2H), 3.56 (m, 1 H), 4.82 (s, 3H). (3R, 4R, 5R) -3-Amino-4,5-dimethyl-octanoic acid (3R, 4R, 5R) -3-Amino-4,5-dimethyl-octanoic acid hydrochloride (92 g), 0.41 mol) was dissolved in 250 ml to 260 ml of dry MeOH in a 2-necked 3-necked round bottom flask. To this solution was added Et3N (0.45 mol, 45.8 g) per drop, which formed a white precipitate. The resulting suspension was stirred at room temperature for 15 minutes. The solvent was removed to dryness. The white solid was dispersed in 1L of CH2Cl2 (1L) and stirred for 1 hour. CH3CN (0.6 L) was added and the suspension was stirred for another 0.5 hour. The suspension was filtered and the solids were washed 2x with 50 ml aliquots of CH3CN, giving 71 g of the title compound as a white solid (92% of the production; 98.8% chiral purity; 99.7% chemical purity): 1 H NMR (400 MHz, CD30D): 0.89 (t, j = 7.2 Hz, 3 H), 0.91 (d, J = 5.1 Hz, 3 H), 0.93 (d, 6.6 Hz, 3 H), 1.02-1.65 (m, H), 2.26 (dd, J = 10.2 Hz, 1H), 2.50 (dd, J = 3J Hz, 1H), 3.27 (m, j = 1.6 Hz, 2H), 3.33-3.28 (m , H), 4.82 (s, 3H).

Claims (12)

1. A combination for the treatment of pain comprising an alpha-2-delta ligand and an atypical antipsychotic or pharmaceutically acceptable salts thereof.

2. A combination according to claim 1 or 2, wherein the alpha-2-delta ligand is selected from gabapentin, pregabalin, acid [(1R, 5R, 6S) -6- (AminometiI) bicyclo [3.2.0] hept -6-yl] acetic acid, 3- (1-Aminomethyl-cyclohexymethyl) -4 H- [1, 2,4] oxadiazol-5-one, C- [1- (1 H-Tetrazol-5-ylmethyl) -cycloheptyl] -methylamine, (3S, 4S) - (1-Aminomethyl-3,4-dimethyl-cidopentyl) -acetic acid, (1 a, 3, 5a) acid (3-amino-methyl-bicyclo [3.2.0] hept- 3-yl) -acetic, (3S, 5R) ~ 3-Aminomethyl-5-methyl-octanoic acid, (3S, 5R) -3-amino-5-methyl-heptanoic acid, (3S, 5R) -3- acid amino-5-methyl-nonanoic, (3S, 5R) -3-Amino-5-methyl-octanoic acid, (2S, 4S) -4- (3-chlorophenoxy) -proline and (2S, 4S) -4- ( 3-fluorobenzyl) proline or a pharmaceutically acceptable salt thereof.

3. A combination according to claim 1 or 2, wherein the alpha-2-delta ligand is gabapentin.

4. A combination according to claim 1 or 2, wherein the alpha-2-delta ligand is pregabalin.

5. A combination according to any one of claims 1-4, wherein the atypical antipsychotic is selected from ziprasidone, olanzapine, clozapine, risperidone, sertindola, quetiapine, aripiprazole, asenapine, amisulpride, acid (3R, 4R, 5R) - 3-amino-4,5-dimethyl-heptanoic and (3R, 4R, 5R) -3-amino-4,5-dimethyl-octanoic acid or a pharmaceutically acceptable salt thereof.

6. A combination according to any of claims 1-5, wherein the atypical antipsychotic is ziprasidone.

7. A pharmaceutical composition for the treatment of palliative, prophylactic or curative pain comprising a therapeutically effective amount of a combination according to any one of claims 1-6 or pharmaceutically acceptable salts thereof and a suitable carrier or excipient.

8. The use of an aIfa-2-delta ligand in combination with an atypical antipsychotic or pharmaceutically acceptable salts thereof in the manufacture of a medicament for the palliative, prophylactic or curative treatment of pain.

9. The use according to claim 8, wherein the pain is neuropathic pain.

10. A method for the treatment of palliative, prophylactic or curative pain comprising the simultaneous, sequential or separate administration of a therapeutic amount of an alpha-2-delta ligand and an atypical antipsychotic or pharmaceutically acceptable salts thereof to a mammal in need of said treatment.

11. The method according to claim 10, wherein the pain is neuropathic pain.

12. A product containing an alpha-2-delta ligand and an atypical antipsychotic or pharmaceutically acceptable salts thereof as a combined preparation for simultaneous, separate or sequential use in the treatment of pain.