HK1092089A - Combinations comprising alpha-2-delta ligands and serotonin/noradrenaline re-uptake inhibitors - Google Patents

Description

Compositions comprising alpha-2-delta ligands and 5-hydroxytryptamine/norepinephrine reuptake inhibitors

Technical Field

The present invention relates to synergistic combinations of an alpha-2-delta ligand and either or both of a binary 5-hydroxytryptamine-norepinephrine reuptake inhibitor (DSNRI) or a selective 5-hydroxytryptamine reuptake inhibitor (SSRI) and a Selective Norepinephrine Reuptake Inhibitor (SNRI) for the treatment of pain. Also relates to methods of treating pain by using an effective amount of a synergistic combination of an alpha-2-delta ligand and DSNRI or one or both of SSRI and SNRI.

Background

An alpha-2-delta receptor ligand is any molecule that is capable of binding to any subtype of the human calcium channel alpha-2-delta subunit. The calcium channel α -2- δ subunit contains many receptor subtypes, which have been documented in the literature: for example n.s.gee, j.p.brown, v.u.disananayake, j.offord, r.thurlow, and g.n.woodruff, J-Biol-Chem 271 (10): 5768-76, 1996, (type 1); gong, j.hang, w.kohler, z.li, 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 GABA analogs.

A number of alpha-2-delta ligands have been described in the literature. The best known alpha-2-delta ligand, gabapentin (Neurontin)^®) 1- (aminomethyl) -cyclohexylacetic acid is described for the first time in patent documents of the same family including U.S. Pat. No. 8, 4024175. The compounds are demonstrated to be useful in the treatment of epilepsy and neuropathic pain.

A second α -2- δ ligand, pregabalin, (S) - (+) -4-amino-3- (2-methylpropyl) butanoic acid, described in european patent application publication No. EP641330, as an anticonvulsant treatment for the treatment of epilepsy and in EP 0934061 for the treatment of pain.

Further, international patent application publication No. WO 0128978 describes a series of novel bicyclic amino acids represented by the following formula, pharmaceutically acceptable salts thereof and prodrugs thereof:

wherein n is an integer from 1 to 4, and when stereocenters are present, each can be R or S independently of the other, preferred compounds are those of formulae I-IV above wherein n is an integer from 2 to 4.

More recently, international patent application publication No. WO02/85839 describes an α -2- δ ligand having the following structural formula:

wherein R is¹And R²Independently of one another, from H, straight-chain or branched alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, phenyl and benzyl, with the proviso that, in addition to the tricyclic octane compound of the formula (XVII), R¹And R²Not hydrogen at the same time; in combination with a selective 5-hydroxytryptamine reuptake inhibitor such as fluoxetine, paroxetine, citalopram and sertraline, a mixed 5-hydroxytryptamine-norepinephrine reuptake inhibitor such as milnacipran, venlafaxine and duloxetine, and a selective norepinephrine reuptake inhibitor such as reboxetine, for the treatment of a number of indications including pain.

International patent application No. PCT/IB03/00976, not published on the filing date of the present application, describes a compound of formula I:

wherein R is₁Is hydrogen or optionally substituted by one to five fluorine atoms (C)₁-C₆) An alkyl group;

R₂is hydrogen or optionally substituted by one to five fluorine atoms (C)₁-C₆) Alkyl radical

R₁And R₂Together with the carbon atom to which they are attached form a three-to six-membered cycloalkyl ring;

R₃is (C)₁-C₆) Alkyl, (C)₃-C₆) Cycloalkyl group, (C)₃-C₆) Cycloalkyl- (C)₁-C₃) Alkyl, phenyl- (C)₁-C₃) Alkyl, pyridyl- (C)₁-C₃) Alkyl, phenyl-N (H) -or pyridyl-N (H) -wherein each of the above alkyl moieties can be optionally substituted with one to five fluorine atoms, preferably zero to three fluorine atoms, wherein said phenyl and said pyridyl and said phenyl- (C)₁-C₃) Alkyl and said pyridyl- (C)₁-C₃) The phenyl and pyridyl moieties of the alkyl groups, each independently, can be optionally substituted with one to three substituents, preferably zero to two substituents, independently selected from the group consisting of chloro, fluoro, amino, nitro, cyano, (C)₁-C₃) Alkylamino, optionally substituted by one to three fluorine atoms (C)₁-C₃) Alkyl and optionally substituted by one to three fluorine atoms (C)₁-C₃) An alkoxy group.

R₄Is hydrogen or optionally substituted by one to five fluorine atoms (C)₁-C₆) An alkyl group;

R₅is hydrogen or optionally substituted by one to five fluorine atoms (C)₁-C₆) An alkyl group;

R₄is hydrogen or (C)₁-C₆) An alkyl group.

Many types of neurological diseases stem from disturbances of the electrical brain circuit that use certain monoamine neurotransmitters to transmit signals. Monoamine neurotransmitters include, for example, 5-hydroxytryptamine (5-HT), norepinephrine (norepinephrine), and dopamine. These neurotransmitters travel from the end of a neuron into a small gap (e.g., the synaptic cleft) and bind to surface receptor molecules of a second neuron. This binding causes an intracellular change, i.e., a response or change that triggers or activates a post-synaptic neuron. Inactivation occurs primarily by transport (i.e., reuptake) of neurotransmitters back to presynaptic neurons.

Selective 5-hydroxytryptamine reuptake inhibitors (SSRIs) act by inhibiting the reuptake of 5-hydroxytryptamine by afferent neurons. SSRI's are known in the art and include, but are not limited to, sertraline (levofloxacin)^®) The sertraline metabolite desmethylsertraline, fluoxetine (Debaryol)^®) Norfluoxetine (fluoxetine nor-metabolite), fluvoxamine (Lanzhou-release)^®) Paroxetine (celecoxib)^®，Paxil^®) And other forms thereof, Paxil-CR^®Citalopram (Celexa)^®) Citalopram metabolite norcitalopram,Escitalopram (Lexapro)^®) D, 1-fenfluramine (Pondimin)^®) Non-moxidectin, efletin, cyanodithiazepine (cyanodothiepin), ritoxetine, dapoxetine, nefazodone (Serxone)^®) Western chloramine and trazodone (Desyrel)^®)。

Selective norepinephrine (or norepinephrine) uptake inhibitors (SNRIs) act by increasing the level of norepinephrine. SNRI's are known in the art and include, but are not limited to, reboxetine (Edronax)^®) And all enantiomers of reboxetine, i.e., (R/R, S/S, R/S, S/R), desipramine (Norpramin)^®) Maprotiline (Ludimei)^®) Lofepramine (Gamanil)^®) Mirtazepine (Remeturon)^®) Oxaprotiline, fezolamine, tomoxetine, mianserin (Bolvidon)^®)、buproprion(Wellbutrin^®) The buproprion metabolites, hydroxy buproprion and nomifensine (Merital)^®) And viloxazine (Vivalan)^®)。

Binary 5-hydroxytryptamine-norepinephrine reuptake inhibitors (DSNRIs) that inhibit reuptake of 5-hydroxytryptamine and norepinephrine, including venlafaxine (stasis-stretching)^®) Venlafaxine metabolites O-desmethylvenlafaxine, clomipramine (Ananafenib)^®) The clomipramine metabolite norclomipramine, duloxetine (cymbalata)^®) Milnacipran and imipramine (Tofranil)^®Or Janimine^®)。

The contents of all patents and publications cited in this application are hereby incorporated by reference.

Summary of The Invention

It has now been found that combination therapy of an alpha-2-delta ligand and either or both of a binary 5-hydroxytryptamine-norepinephrine reuptake inhibitor (DSNRI) or a selective 5-hydroxytryptamine reuptake inhibitor (SSRI) and a Selective Norepinephrine Reuptake Inhibitor (SNRI) can improve the treatment of headache. Furthermore, when administered simultaneously, sequentially or separately, the α -2- δ ligand and the DSNRI or one or both of the SSRI and SNRI may interact in a synergistic manner to control pain. This synergistic effect can reduce the required dose of each compound, thus reducing side effects and enhancing the clinical efficacy of the compound.

Accordingly, the present invention provides, as a first aspect, a combination product comprising an alpha-2-delta ligand and one or both of a binary 5-hydroxytryptamine-norepinephrine reuptake inhibitor (DSNRI) or a selective 5-hydroxytryptamine reuptake inhibitor (SSRI) and a Selective Norepinephrine Reuptake Inhibitor (SNRI), or a pharmaceutically acceptable salt thereof, with the proviso that 5-hydroxytryptamine-norepinephrine reuptake inhibitors, especially milnacipran, venlafaxine and duloxetine, in admixture with 5-hydroxytryptamine reuptake inhibitors, especially fluoxetine, paroxetine, citalopram and sertraline, are excluded, and norepinephrine reuptake inhibitors, particularly reboxetine-conjugated WO02/85839 compounds (i) - (xxv).

As another or other aspect, the invention provides a synergistic composition product comprising an alpha-2-delta ligand and either or both of DANRI or SSRI and SNRI, or a pharmaceutically acceptable salt thereof.

The cyclic alpha-2-delta ligands useful in the present invention are illustrated by the following formula (I):

wherein X is a carboxylic acid or carboxylic acid bioisostere;

n is 0, 1 or 2; and

R¹、R^1a、R²、R^2a、R³、R^3a、R⁴and R^4aIndependently selected from H and C₁-C₆Alkyl, or R¹And R²Or R²And R³Together form C₃-C₇A cycloalkyl ring, optionally selected from C₁-C₆One or two substituents of the alkyl group, or a pharmaceutically acceptable salt thereof.

In the formula (I), R is suitably¹、R^1a、R^2a、R^3a、R⁴And R^4aIs H and R²And R³Independently selected from H and methyl, or R^1a、R^2a、R^3aAnd R^4aIs H and R¹And R²Or R²And R³Together form C₃-C₇A cycloalkyl ring, optionally substituted with one or two methyl substituents. Suitable carboxylic acid bioisosteres are selected from tetrazolyl and oxadiazolonyl (oxadiazolonyl). X is preferably a carboxylic acid.

In the formula (I), preferably, R¹、R^1a、R^2a、R^3a、R⁴And R^4aIs H and R²And R³Independently selected from H and methyl, or R^1a、R^2a、R^3aAnd R^4aIs H and R¹And R²Or R²And R³Together form C₄-C₅Cycloalkyl ring, R when n is 0¹、R^1a、R^2a、R^3a、R⁴And R^4aIs H and R²And R³Form a cyclopentyl ring, or, when n is 1, R¹、R^1a、R^2a、R^3a、R⁴And R^4aIs H and R²And R³Are both methyl or R¹、R^1a、R^2a、R^3a、R⁴And R^4aIs H and R²And R³Form a cyclobutyl ring, or, when n is 2, R¹、R^1a、R²、R^2a、R³、R^3a、R⁴And R^4aIs H, or n is 0, R¹、R^1a、R^2a、R^3a、R⁴And R^4aIs H and R²And R³Form cyclopentyl groupAnd (4) a ring.

The cyclic alpha-2-delta ligands useful in the present invention are illustrated by the following formula (II):

wherein:

n is 0 or 1, R¹Is hydrogen or (C)₁-C₆) An alkyl group; r²Is hydrogen or (C)₁-C₆) An alkyl group; r³Is hydrogen or (C)₁-C₆) An alkyl group; r⁴Is hydrogen or (C)₁-C₆) An alkyl group; r⁵Is hydrogen or (C)₁-C₆) Alkyl radical, R²Is hydrogen or (C)₁-C₆) Alkyl, or a pharmaceutically acceptable salt thereof.

According to formula (II), suitably R¹Is C₁-C₆Alkyl radical, R²Is methyl, R³-R⁶Is hydrogen and n is 0 or 1. More suitably, R is¹Is methyl, ethyl, n-propyl or n-butyl, R²Is methyl, R³-R⁶Is hydrogen and n is 0 or 1. When R is²When it is methyl, R³-R⁶Is hydrogen and n is 0, R¹Suitably ethyl, n-propyl or n-butyl. When R is²When it is methyl, R³-R⁶Is hydrogen and n is 1, R¹Suitably methyl or n-propyl. Suitably, the compound of formula (II) is in the 3S, 5R configuration.

Examples of α -2- δ ligands used in the present invention are those compounds described generally or specifically in the following documents: US 4024175, in particular gabapentin, EP641330, in particular pregabalin, US 5563175, WO 9733858, WO 9733859, WO 9931057, WO 9931074, WO 9729101, WO 02085839, in particular [ (1R, 5R, 6S) -6- (aminomethyl) bicyclo [3.2.0] hept-6-yl ] acetic acid, WO 9931075, in particular 3- (1-aminomethyl) -cyclohexylmethyl-4H- [1, 2, 4] oxadiazol-5-one and C- [1- (1H-tetrazol-5-ylmethyl) -cycloheptyl ] -methylamine, WO9921824, in particular (3S, 4S) - (1-aminomethyl-3, 4-dimethyl-cyclopentyl) -acetic acid, WO 0190052, WO 0128978, in particular (1 α,3 α,5 α) (3-amino-methyl-bicyclo [3.2.0] hept-3-yl) -acetic acid, EP 0641330, WO 9817627, WO 0076958, especially (3S, 5R) -3-aminomethyl-5-methyl-octanoic acid, PCT/IB03/00976, especially (3S, 5R) -3-amino-5-methyl-heptanoic acid, (3S, 5R) -3-amino-5-methyl-nonanoic acid and (3S, 5R) -3-amino-5-methyl-octanoic acid, EP 1178034, EP 1201240, WO 9931074, WO 03000642, WO 0222568, WO 0230871, WO 0230881, WO 02100392, WO 02100347, WO 0242414, WO 0232736 and WO 0228881 or a pharmaceutically acceptable salt thereof, all of which are incorporated by reference.

Preferred alpha-2-delta ligands of the invention include: gabapentin, pregabalin, [ (1R, 5R, 6S) -6- (aminomethyl) bicyclo [3.2.0] hept-6-yl ] acetic acid, 3- (1-aminomethyl-cyclohexylmethyl) -4H- [1, 2, 4] oxadiazol-5-one, C- [1- (1H-tetrazol-5-ylmethyl) -cycloheptyl ] -methylamine, (3S, 4S) - (1-aminomethyl-3, 4-dimethyl-cyclopentyl) -acetic acid, (1 α,3 α,5 α) (3-amino-methyl-bicyclo [3.2.0] hept-3-yl) -acetic acid, (3S, 5R) -3-aminomethyl-5-methyl-octanoic acid, (3S, 5R) -3-amino-5-methyl-heptanoic acid, (3S, 5R) -3-amino-5-methyl-nonanoic acid, and (3S, 5R) -3-amino-5-methyl-octanoic acid, or a pharmaceutically acceptable salt thereof. Particularly preferred alpha-2-delta ligands of the invention are selected from gabapentin, pregabalin, [ (1R, 5R, 6S) -6- (aminomethyl) bicyclo [3.2.0] hept-6-yl ] acetic acid and (1 alpha, 3 alpha, 5 alpha) (3-amino-methyl-bicyclo [3.2.0] hept-3-yl) -acetic acid, or pharmaceutically acceptable salts thereof.

SSRIs useful according to the present invention include those contained in the disclosure of US 4536518, namely the cis-isomer compounds of formula (III):

wherein R is₁Selected from the group consisting of hydrogen and conventional alkyl groups of 1 to 3 carbon atoms, R₂Is a conventional alkyl radical of 1 to 3 carbon atoms, Z is

X and Y are each selected from the group consisting of hydrogen, fluorine, chlorine, bromine, trifluoromethyl, alkoxy of 1 to 3 carbon atoms and cyano, at least one of X and Y is other than hydrogen, W is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, trifluoromethyl and alkoxy of 1 to 3 carbon atoms, wherein the term "cis-isomer" refers to NR on the cyclohexene ring₁R₂And the relative orientation of the Z moiety, the compound may be the (1S) -enantiomer or a racemic mixture of the (1S) -enantiomer and the corresponding (1R) -enantiomer, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, or the prodrug. A particularly preferred compound of formula (III) is sertraline.

Examples of SSRIs used in the present invention are the compounds generally and specifically disclosed in the following documents: U.S.4,536,518, especially sertraline, U.S.4,943,590[ RE 34,712], U.S.4,650,884, especially citalopram, U.S.3,198,834, especially d, 1-fenfluramine, U.S.3,912,743, 4,571,424, especially non-moxidetin, U.S.4,314,081, 4,626,549, especially fluoxetine, U.S.4,085,225, especially fluoxetine, U.S.3,912,743, 4,007,196, especially paroxetine, ifoxetine, cyanodibenzothiepine and ritoxetine, or pharmaceutically acceptable salts thereof, all of which are incorporated herein by reference.

Suitable SSRIs for use in the invention include sertraline, the sertraline metabolite norsertraline, fluoxetine, norfluoxetine (fluoxetine nor metabolite), fluvoxamine, paroxetine and other forms thereof, Paxil-CR^®Citalopram, a citalopram metabolite norcitalopram, escitalopram, d, 1-fenfluramine, femoxetine, efoxetine, cyanodithiazepine, ritoxetine, dapoxetine, nefazodone, cilansam and trazodone, or a pharmaceutically acceptable salt thereof. A preferred SSRI is sertraline, or a pharmaceutically acceptable salt thereof.

SNRI's useful according to the present invention include the compounds disclosed in US 4229449, i.e. the racemic and optical isomers corresponding to the compounds of formula (IV):

preference is given to substituted propanolamine and morpholine derivatives corresponding to the formula IV, where

n and n1 are independently 1, 2 or 3;

r and R₁Which may be identical or different, are each hydrogen, halogen, halogeno C₁-C₆Alkyl, hydroxy, C₁-C₆Alkoxy, optionally substituted C₁-C₆Alkyl, optionally substituted aryl-C₁-C₆Alkyl, optionally substituted aryl-C₁-C₆Alkoxy, -NO₂；

Wherein R is₅And R₆Independently is hydrogen or (C)₁-C₆) Alkyl, or two adjacent R groups or two adjacent R₁Groups, taken together, forming-O-CH₂-an O-group;

R₂is hydrogen, optionally substituted C₁-C₁₂Alkyl or aryl-C₁-C₆An alkyl group;

R₃and R₄Which may be the same or different, are each hydrogen, optionally substituted C₁-C₆Alkyl radical, C₂-C₄Alkenyl radical, C₂-C₄Alkynyl, optionally substituted aryl-C₂-C₄Alkyl, optionally substituted C₃-C₇Cycloalkyl, or R₃And R₄Form, together with the nitrogen atom to which they are bound, a five-or six-membered saturated or unsaturated, optionally substituted, heteromonocyclic group optionally containing other heteroatoms O, S and NGroup, or R₂And R₄Together form-CH₂-CH₂-a group. Preferred compounds of formula (IV) are represented by reboxetine.

Examples of SNRIs for use in the present invention are compounds disclosed generally and specifically in the following references: U.S.4,229,449, 5,068,433, 5,391,735, especially reboxetine, BP908,788, 980,231, U.S.3,454,554, especially desipramine, U.S.3,399,201, especially maprotiline, BP 1,177,525, U.S.3,637,660, especially lofepramine, neth. Pat. appl.6,603,256, U.S.3,534,041, especially mianserin, U.S.4,062,843, especially mirtazepine, U.S.4,314,081, 4,018,895, 4,194,041, especially tomoxetine, U.S.4,535,186, 4,611,078, especially venlafaxine, and U.S.3,819, 3,885,046, especially butraline, and propiconazole, and all pharmaceutically acceptable salts thereof are incorporated herein by reference.

Specific examples of SNRIs according to the invention include reboxetine and all enantiomers of reboxetine, i.e. (R/R, S/S, R/S, S/R), desipramine, maprotiline, lofepramine, mirtazepine, venlafaxine (described in U.S. Pat. No. 4,761,501), oxaprotiline, fezolamide, tomoxetine, mianserin and buprpion, the buprpion metabolite hydroxybuprpion, nomifensine or viloxazine, or pharmaceutically acceptable salts thereof. Preferably, the SNRI is selected from maprotiline, desipramine, bupropion, reboxetine and S, S-reboxetine, or a pharmaceutically acceptable salt thereof.

The DSNRIs useful according to the present invention can be illustrated by the compounds of formula (V):

wherein the phenyl ring A and the phenyl ring B can be substituted independently of one another by naphthyl, wherein the ether oxygen-containing radical of the formula I and R are³、R⁴And NR¹R²Linked carbon atomsA ring attached to a ring carbon atom of an adjacent naphthyl group, neither of which is adjacent to a fused ring carbon atom of the naphthyl group;

n and m are independently selected from one, two and three;

R¹and R²Independently selected from hydrogen, (C)₁-C₄) Alkyl, (C)₂-C₄) Alkenyl and (C)₂-C₄) Alkynyl, or R¹And R²Together with the nitrogen atom to which they are attached form a four-to eight-membered saturated ring containing one or two heteroatoms including¹And R²A linking nitrogen wherein the second heteroatom, when present, is selected from oxygen, nitrogen and sulfur, with the proviso that the ring cannot contain two adjacent oxygen atoms or two adjacent sulfur atoms, wherein the ring may optionally be substituted at the available bonding positions with one to three substituents independently selected from hydroxy and (C)₁-C₆) An alkyl group;

R³and R⁴Independently selected from hydrogen and optionally substituted by one to three fluorine atoms (C)₁-C₄) Alkyl, or R³And R⁴Together with the carbon to which they are attached form a four to eight membered saturated carbocyclic ring wherein said ring may optionally be substituted at the available bonding positions with one to three substituents independently selected from hydroxy and (C)₁-C₆) An alkyl group;

or R²And R³And R²To the nitrogen and R³The attached carbons, taken together, form a four to eight membered saturated ring containing one or two heteroatoms including R²A linking nitrogen wherein the second heteroatom, when present, is selected from oxygen, nitrogen and sulfur, with the proviso that the ring does not contain two adjacent oxygen atoms or two adjacent sulfur atoms, wherein the ring may optionally be substituted at the available bonding positions with one to three substituents independently selected from hydroxy and (C)₁-C₆) An alkyl group;

each X is independently selected from hydrogen, halogen (i.e., chlorine, fluorine, bromine or iodine), optionally substituted with one to three fluorine atoms (C)₁-C₄) Alkyl, optionally substituted by one to three fluorine atoms (C)₁-C₄) Alkoxy, cyano, nitro, amino, (C)₁-C₄) Alkylamino, di- [ (C)₁-C₄) Alkyl radical]Amino group, NR⁵(C＝O)(C₁-C₄) Alkyl, SO₂NR⁵R⁶And SO_p(C₁-C₆) Alkyl radical, wherein R⁵And R⁶Independently selected from hydrogen and (C)₁-C₆) Alkyl, p is zero, one or two; and

each Y is independently selected from hydrogen, (C)₁-C₆) Alkyl and halogen;

with the additional condition that: (a) NR (nitrogen to noise ratio)¹R²、CR³R⁴And R²NCR³Only one of which can form a ring; and (b) at least one X must not be hydrogen when (i) R³And R⁴Are both hydrogen, (ii) R¹And R²Independently selected from hydrogen and (C)₁-C₄) (ii) alkyl, and (iii) when ring B is mono-or disubstituted with one or two halo groups, respectively; and pharmaceutically acceptable salts thereof. Compounds according to formula V are described in WO 00/50380.

Suitable DSNRIs according to the present invention are selected from venlafaxine, venlafaxine metabolite O-desmethylvenlafaxine, clomipramine metabolite desmethylclomipramine, duloxetine, milnacipran and imipramine, or a pharmaceutically acceptable salt thereof. Preferred DSNRIs according to the present invention are selected from milnacipran, duloxetine and venlafaxine, or pharmaceutically acceptable salts thereof.

The suitability of any particular DSNRIs, SSRIs or SNRIs can be readily determined by assessing their potency and selectivity using literature-documented methods, and then assessing their toxicity, absorption, metabolism, pharmacokinetics, etc. in accordance with standard pharmaceutical guidelines.

As a further or alternative aspect of the invention, there is provided a composition comprising gabapentin or a pharmaceutically acceptable salt thereof, and a DSNRI selected from venlafaxine, venlafaxine metabolite O-desmethylvenlafaxine, clomipramine metabolite norclomipramine, duloxetine, milnacipran, and imipramine, or one or both of SSRI and SNRI, wherein SSRI is selected from sertraline, fluoxetine, fluvoxamine, paroxetine, citalopram, d, 1-fenfluramine, femoxetine, trazodone, cilazachloramine, ifoxetine, cyano benzothiepin, and ritoxetine, or a pharmaceutically acceptable salt thereof, SNRI is selected from reboxetine, S-reboxetine, desipramine, maprotiline, lofepramine, mianserin, mirtazepine, oxaprotiline, oxaprozaline, non-prouzole, or prion, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable salt thereof. Particularly preferred compositions contain gabapentin and one of the following: sertraline, milnacipran, duloxetine, venalfaxine, maprotiline, desipramine, buproprion, reboxetine or S, S-reboxetine, and pharmaceutically acceptable salts thereof.

As a further or alternative aspect of the invention, there is provided a composition comprising pregabalin and a DSNRI selected from venlafaxine, venlafaxine metabolite O-desmethylvenlafaxine, clomipramine metabolite desmethylclomipramine, duloxetine, milnacipran and imipramine, or in combination with one or both of an SSRI selected from sertraline, fluoxetine, fluvoxamine, paroxetine, citalopram, d, 1-fenfluramine, non-moxidetin, trazodone, cilazaloamine, efoxetine, cyanobenzothiepin and ritoxetine, or a pharmaceutically acceptable salt thereof, and an SNRI selected from reboxetine, S-reboxetine, desipramine, maprotiline, lofepramine, mianserin, mirtapine, mirtazapine, oxaprotiline, non-propiconazole, atomoxetine or probucon, a pharmaceutically acceptable salt thereof, and pharmaceutically acceptable salts thereof. Particularly preferred compositions comprise pregabalin and one of the following: sertraline, milnacipran, duloxetine, venalfaxine, maprotiline, desipramine, buproprion, reboxetine or S, S-reboxetine, or a pharmaceutically acceptable salt thereof.

As a further or another aspect of the present invention, there is provided a composition comprising (1 α,3 α,5 α) (3-amino-methyl-bicyclo [3.2.0] hept-3-yl) -acetic acid or a pharmaceutically acceptable salt thereof, and one or both of DSNRI or SSRI and SNRI. Suitably, the compositions provided herein comprise (1 α,3 α,5 α) (3-amino-methyl-bicyclo [3.2.0] hept-3-yl) -acetic acid, or a pharmaceutically acceptable salt thereof, and a DSNRI selected from venlafaxine, venlafaxine metabolite O-desmethylvenlafaxine, clomipramine metabolite norclomipramine, duloxetine, milnacipran, and imipramine, or one or both of an SSRI and an SNRI, wherein the SSRI is selected from sertraline, fluoxetine, fluvoxamine, paroxetine, citalopram, d, 1-fenfluramine, fexidectin, trazodone, cilazalomine, ifoxetine, cyanobiphilzepine, and ritoxetine, or a pharmaceutically acceptable salt thereof, and the SNRI is selected from reboxetine, S-reboxetine, desipramine, maprotiline, lofexofenadine, and a pharmaceutically acceptable salt thereof, Mianserin, mirtazepine, oxaprotiline, fezolamine, tomoxetine, or buproprion, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable salt thereof. Particularly preferred compositions contain (1 α,3 α,5 α) (3-amino-methyl-bicyclo [3.2.0] hept-3-yl) -acetic acid and one of the following: sertraline, milnacipran, duloxetine, venalfaxine, maprotiline, desipramine, buproprion, reboxetine or S, S-reboxetine, and pharmaceutically acceptable salts thereof.

As a further aspect of the invention, the composition is selected from:

gabapentin and sertraline;

gabapentin and milnacipran;

gabapentin and duloxetine;

gabapentin and venlafaxine;

gabapentin and maprotiline;

gabapentin and desipramine;

gabapentin and bupropion;

gabapentin and reboxetine;

gabapentin and S, S-reboxetine;

pregabalin and sertraline;

pregabalin and milnacipran;

pregabalin and duloxetine;

pregabalin and venlafaxine;

pregabalin and maprotiline;

pregabalin and desipramine;

pregabalin and bupropion;

pregabalin and reboxetine;

pregabalin and S, S-reboxetine;

[ (1R, 5R, 6S) -6- (aminomethyl) bicyclo [3.2.0] hept-6-yl ] acetic acid and sertraline;

[ (1R, 5R, 6S) -6- (aminomethyl) bicyclo [3.2.0] hept-6-yl ] acetic acid and milnacipran;

[ (1R, 5R, 6S) -6- (aminomethyl) bicyclo [3.2.0] hept-6-yl ] acetic acid and duloxetine;

[ (1R, 5R, 6S) -6- (aminomethyl) bicyclo [3.2.0] hept-6-yl ] acetic acid and venlafaxine;

[ (1R, 5R, 6S) -6- (aminomethyl) bicyclo [3.2.0] hept-6-yl ] acetic acid and maprotiline;

[ (1R, 5R, 6S) -6- (aminomethyl) bicyclo [3.2.0] hept-6-yl ] acetic acid and desipramine;

[ (1R, 5R, 6S) -6- (aminomethyl) bicyclo [3.2.0] hept-6-yl ] acetic acid and bupropion;

[ (1R, 5R, 6S) -6- (aminomethyl) bicyclo [3.2.0] hept-6-yl ] acetic acid and reboxetine;

[ (1R, 5R, 6S) -6- (aminomethyl) bicyclo [3.2.0] hept-6-yl ] acetic acid and S, S-reboxetine;

(1 α,3 α,5 α) (3-amino-methyl-bicyclo [3.2.0] hept-3-yl) -acetic acid and sertraline;

(1 α,3 α,5 α) (3-amino-methyl-bicyclo [3.2.0] hept-3-yl) -acetic acid and milnacipran;

(1 α,3 α,5 α) (3-amino-methyl-bicyclo [3.2.0] hept-3-yl) -acetic acid and duloxetine;

(1 α,3 α,5 α) (3-amino-methyl-bicyclo [3.2.0] hept-3-yl) -acetic acid and venlafaxine;

(1 α,3 α,5 α) (3-amino-methyl-bicyclo [3.2.0] hept-3-yl) -acetic acid and maprotiline;

(1 α,3 α,5 α) (3-amino-methyl-bicyclo [3.2.0] hept-3-yl) -acetic acid and desipramine;

(1 α,3 α,5 α) (3-amino-methyl-bicyclo [3.2.0] hept-3-yl) -acetic acid and bupropion;

(1 α,3 α,5 α) (3-amino-methyl-bicyclo [3.2.0] hept-3-yl) -acetic acid and reboxetine;

(1 α,3 α,5 α) (3-amino-methyl-bicyclo [3.2.0] hept-3-yl) -acetic acid and S, S-reboxetine;

(3S, 4S) - (1-aminomethyl-3, 4-dimethyl-cyclopentyl) -acetic acid and sertraline;

(3S, 4S) - (1-aminomethyl-3, 4-dimethyl-cyclopentyl) -acetic acid and milnacipran;

(3S, 4S) - (1-aminomethyl-3, 4-dimethyl-cyclopentyl) -acetic acid and duloxetine;

(3S, 4S) - (1-aminomethyl-3, 4-dimethyl-cyclopentyl) -acetic acid and venlafaxine;

(3S, 4S) - (1-aminomethyl-3, 4-dimethyl-cyclopentyl) -acetic acid and maprotiline;

(3S, 4S) - (1-aminomethyl-3, 4-dimethyl-cyclopentyl) -acetic acid and desipramine;

(3S, 4S) - (1-aminomethyl-3, 4-dimethyl-cyclopentyl) -acetic acid and bupropion;

(3S, 4S) - (1-aminomethyl-3, 4-dimethyl-cyclopentyl) -acetic acid and reboxetine; and

(3S, 4S) - (1-aminomethyl-3, 4-dimethyl-cyclopentyl) -acetic acid and S, S-reboxetine;

or a pharmaceutically acceptable salt thereof.

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

Thus, as a further aspect of the invention, there is provided the use of a combination, especially a synergistic combination, of an α -2- δ ligand and a DSNRI or one or both of a SSRI and SNRI in the manufacture of a medicament for administration once, twice or three times, suitably twice or three times, more suitably twice, most suitably once daily, for the therapeutic, prophylactic or palliative treatment of pain.

Further provided herein is a method for the therapeutic, prophylactic or palliative treatment of pain in a mammalian subject comprising administering once, twice or three times daily, suitably twice or three times daily, more suitably twice daily, most suitably once effective, especially synergistic, combination of an alpha-2-delta ligand and a DSNRI or one or both of a SSRI and SNRI.

The synergistic interaction between one or more of the components, the optimum range for this effect and the absolute dose of each component for this effect can be determined unambiguously by administering the components in different ranges of w/w ratios and dosages to a patient in need of treatment. The complexity and cost of clinical studies on patients in humans suggest that it is not practical to use this test format as a primary model of synergy. However, observation of synergy in one species can predict the effect in other species, and there are animal models for determining synergy, and the results of such studies can also be used to predict the effective dose and plasma concentration ratio ranges and absolute doses and plasma concentrations required for other species by using pharmacokinetic/pharmacodynamic methods, as described herein. The established correlation between the effects observed in animal models and in humans suggests that animal synergy using static and dynamic allodynia assays (surgical (e.g. chronic constrictive injury) or chemical (e.g. streptozocin) treatments to induce allodynia) in rodents is the best proof. Because of the isocurve effect of this model, the values are best assessed for synergy, and thus neuropathic pain patients will be able to shift to the advantage of lower doses. Other models, in which the agents present for the treatment of neuropathic pain only partially respond, are more suitable for predicting the potential of a composition to act synergistically to increase the maximum efficacy of the two components at the maximum tolerated dose.

Thus, as a further aspect of the invention, there is provided a synergistic composition for administration to a human comprising an α -2- δ ligand and one of DSNRI, SSRI or SNRI, or a pharmaceutically acceptable salt thereof, in a w/w combination in a range corresponding to the absolute range observed in a non-human animal model, preferably a rat model, primarily for use in determining synergistic interactions. Suitably, the human ratio range corresponding to the non-human range 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 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. Preferably, the human range corresponds to the non-human range of 1: 10 to 20: 1 parts by weight. Preferably, the human range corresponds to the synergistic non-human range of 1: 1 to 10: 1 parts by weight.

In humans, there are experimental pain models that can be used in humans to demonstrate that agents that prove synergistic in animals also have effects in humans that are comparable to that synergy. Examples of human models suitable for this purpose include the heat/capsaicin model (Petersen, K.L. & Rowbotham, M.C. (1999) neuro report 10, 1511-. With these models, subjective assessment of pain intensity or hyperalgesia area can be used as endpoints, or more target endpoints (objectiveendipins) can be used, relying on electrophysiology or imaging techniques (e.g., magnetic resonance machine-enabled imaging) (Bornhovd, k., Quante, m., Glauche, v., broomm, b., weiler, C. & Buchel, C. (2002) Brain 125, 1326-. All of these models require objectively determined evidence before they can be concluded that they provide evidence that supports composition synergy (an effect that has been observed in animal studies) in humans.

For the purposes of the present invention, in humans, the α -2- δ ligand: suitable ratios of DSNRI, SSRI or SNRI are selected from the group consisting of 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 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 suitably 1: 10 to 20: 1, preferably 1: 1 to 10: 1.

The optimal dosage of each component of the synergy can be determined according to the procedures disclosed in the animal model. However, in humans (even in experimental models of pain), the cost for studies to determine the overall exposure-response relationship of each component of the composition at all therapeutically relevant doses is very high. It may be desirable, at least initially, to assess whether a consistent synergistic effect is observed at doses extrapolated from the optimum synergy obtained from the animal. At the converted dose from animal to human, factors such as relative body weight/body surface area, relative absorption, distribution, metabolism and excretion of each component, and relative plasma protein binding need to be considered, for which reason the predicted optimal proportion of humans (also for patients) is unlikely to be the same as the optimal dose proportion for animals. However, the relationship between the two is understood and can be calculated by those skilled in the art of animal and human pharmacokinetics. The key to bridging the effects of animals and humans is the blood concentration obtained from each component used in animal studies, which relates to the blood concentration of each component that is expected to provide efficacy in humans. Pharmacokinetic/pharmacodynamic modeling (including methods such as isobolograms, interaction indices and response surface modeling) and simulations may also help predict synergistic dose ratios in humans, particularly where one or both of these components have been studied.

It is important to determine whether any inferred synergy observed in animals or humans is solely due to pharmacokinetic interactions. For example, inhibition of the metabolism of one compound by another may result in a false pharmacokinetic synergistic effect.

Thus, according to a further aspect of the present invention there is provided a synergistic composition for administration to a human comprising an α -2- δ ligand and either DSNRI or one or both of SSRI and SNRI, or a pharmaceutically acceptable salt thereof, wherein the dosage range of each component is equal to the absolute range observed in a non-human animal model, preferably a rat model (primarily for determining synergy).

Suitably, the dose of alpha-2-delta ligand for use in humans is selected from the following ranges: 1-1200mg, 1-500mg, 1-100mg, 1-50mg, 1-25mg, 500-1200mg, 100-500mg, 50-1200mg, 50-500mg or 50-100mg, suitably 50-100mg, b.i.d. or t.i.d., suitably t.i.d., the amount of SSRI and/or SNRI being selected from the following ranges: 1-200mg, 1-100mg, 1-50mg, 1-25mg, 10-100mg, 10-50mg or 10-25mg, suitably 10-100mg, b.i.d or t.i.d, suitably t.i.d.

It will be apparent to the skilled person that the range of blood levels of the compositions of the invention which provide a therapeutic effect of the alpha-2-delta ligand and either or both of the DSNRI or SSRI and SNRI will depend on the species being treated and the ingredients used. For example, in rats, gabapentin has a Cmax value of 0.520. mu.g/ml to 10.5. mu.g/ml.

Plasma concentration values observed in animal models can be extrapolated using standard PK/PD and allometric growth methods to predict values in different species, especially humans.

Thus, as a further aspect of the invention, there is provided a synergistic composition for administration to humans comprising an α -2- δ ligand and either DSNRI or SSRI and SNRI, wherein the concentration range of each active ingredient corresponds to the absolute range observed in a non-human animal experiment, preferably a rat experiment, primarily for determining synergistic interactions. Suitably, the plasma concentration range in humans corresponds to the range of 0.05. mu.g/ml to 10.5. mu.g/ml of alpha-2-delta ligand in the rat model.

Particularly preferred compositions of the present invention include those wherein each variable of the composition is selected from the appropriate parameters for each variable. Even more preferred compositions of the present invention include those wherein each variable of the composition is selected from the more suitable, most suitable, preferred or more preferred parameters of each variable.

Detailed Description

The compositions of the present invention are prepared by methods well known to those skilled in the art. In particular, the above patents, patent applications and publications, all of which are incorporated herein by reference, exemplify compounds that can be used in the compositions, pharmaceutical compositions, methods and kits according to the present invention and indicate methods for preparing such compounds.

The compounds of the present combination invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. Typically, solvated forms, including hydrate forms, may contain isotopic substitutions (e.g., D)₂O, d 6-acetone, d6-DMSO), equivalent to the unsolvated form and are included within the scope of the present invention.

Certain compounds of the invention have one or more chiral centers, each of which may exist in either the R or S configuration. The present invention includes all enantiomeric and epimeric forms and suitable mixtures thereof. Resolution of the diastereomers or cis and trans isomers may be achieved by conventional methods, for example fractional crystallization, chromatography or h.p.l.c. of a stereoisomeric mixture of a compound of the invention or a suitable salt or derivative thereof.

Many of the α -2- δ ligands of the present invention are amino acids. Since the amino acids are amphoteric, the pharmaceutically compatible salts may be those of suitable non-toxic inorganic or organic acids or bases. Suitable acid addition salts are acetate, aspartate, benzoate, benzenesulfonate, bicarbonate/carbonate, bisulfate, camphorsulfonate, citrate, edisylate, ethanesulfonate, fumarate, glucoheptonate, gluconate, glucuronate, oxybenzoate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, biphosphate, isethionate, D-and L-lactate, malate, maleate, malonate, methanesulfonate, methylsulfate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, palmoate, phosphate, saccharate, stearate, succinate sulfate, D-and L-tartrate and tosylate. Suitable base salts are formed from bases which form non-toxic salts, examples being sodium, potassium, aluminium, calcium, magnesium, zinc, choline, diethanolamine, ethanolamine, arginine, glycine, tromethamine, benzathine (benzathine), lysine, meglumine and diethylamine salts. Salts with quaternary ammonium ions can also be prepared, for example with tetramethylammonium ions. The compounds of the present invention can also be formed in zwitterionic form.

A suitable salt of the amino acid compound of the invention is the hydrochloride salt. For a review of suitable Salts see Stahl and Wermuth, Handbook of Pharmaceutical Salts: properties, Selection, and Use, Wiley-VCH, Weinheim, Germany (2002).

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

All references hereinafter to compounds of the invention include references to salts thereof and to solvates and clathrates of the compounds of the invention and salts thereof.

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

The above prodrugs of the compounds of the present invention are included within the scope of the present invention. The chemically modified drug, or prodrug, should have a different pharmacokinetic profile than the parent, be readily absorbed through mucosal epithelial cells, better salt form and/or solubility, improved systemic stability (e.g., increased plasma half-life). These chemical modifications may be

(1) Ester or amide derivatives which can be cleaved by, for example, esterases or lipases. For ester derivatives, the ester is derived from the carboxylic acid moiety of the drug molecule by known methods. For amide derivatives, the amide may be derived from the carboxylic acid moiety or the amine moiety of the drug molecule by known methods.

(2) A peptide, which can be recognized by a specific or non-specific protease. The peptide may be coupled to the drug molecule by amide bond formation with an amine or carboxylic acid moiety of the drug molecule by known methods.

(3) A derivative which is accumulated at the site of action by a prodrug form or a modified prodrug form.

(4)1 to 3 in any combination.

Aminoacyl-glycolides and-lactates are known amino acid prodrugs (Wermuth C.G., Chemistry and Industry, 1980: 433-. The carbonyl group of the amino acid can be esterified by known methods. Prodrugs and soft Drugs are known in the art (Palomino E., Drugs soft fire, 1990; 15 (4): 361-. The latter two references are incorporated herein by reference.

The compositions of the invention are useful in the general treatment of pain, in particular neuropathic pain. Physiological pain is an important protective mechanism for danger warning from potentially damaging stimuli from the external environment. This system functions through a specific set of major sensory neurons and is activated exclusively by noxious stimuli of peripheral transduction mechanisms (Millan 1999 prog. neurobio.57: 1-164 for an integral Review)). These sensory fibers are known as nociceptors and are characterized by small diameter axons with slower conduction rates. Nociceptors encode the intensity, duration, and nature of the noxious stimulus and rely on projection of their local anatomy to the spinal cord, localizing the stimulus. Nociceptors are found in nociceptive nerve fibers, of two major types, a-delta fibers (with myelin sheath) and C fibers (without myelin sheath). The activity produced by nociceptor input is transferred after a complex process (complexprocessing) through the dorsal horn, directly or through the brainstem relay nuclei to the ventral basal thalamus and then to the cortex where pain sensation is produced.

Acute pain and chronic pain can involve the same pathways driven by pathophysiological processes, as such stopping the provision of protective mechanisms and instead contributing to debilitating symptoms associated with a wide range of disease states. Pain is a characteristic of many trauma and disease conditions. When a substantial injury, through disease or trauma, reaches human tissue, the nociceptor activation profile that occurs is altered. The periphery of the lesion and its surrounding local and central nociceptor termination have a sensitizing effect. This can lead to hypersensitivity at the site of injury and adjacent normal tissue. These mechanisms can be used in acute pain and a reparative process can occur, returning to a normal state once the injury heals from hypersensitivity. However, in many chronic pain conditions, hypersensitivity reactions take longer than the healing process, which is often attributed to damage to the nervous system. Such damage often leads to maladaptation of afferent fibers (Woolf & Salter 2000 Science 288: 1765-. Clinical pain occurs when discomfort and abnormally sensitive features are present in the patient's symptoms. Patients tend to be completely heterogeneous and may present with various pain symptoms. There are many typical pain subtypes: 1) spontaneous pain, which may be dull, burning or stinging; 2) pain in response to a noxious stimulus is exaggerated (hyperalgesia); 3) pain (allodynia) produced by normal, non-noxious stimulation (Meyer et al, 1994Textbook of Pain 13-44). Although patients with back pain, arthritic pain, CNS injury, or neuropathic pain may have similar symptoms, their underlying mechanisms are different and, therefore, different treatment strategies may be required. Therefore, pain can be divided into many different areas, including nociceptive pain, inflammatory pain, neuropathic pain, etc., in view of different pathophysiology. It should be noted that some types of pain have multiple etiologies and therefore can be divided into more than one aspect, such as back pain. Cancer pain has nociceptive and neuropathic components.

Nociceptive pain is induced by tissue damage or damage caused by intense stimulation of electrical potentials. Pain afferents are activated by stimulation transduction of nociceptors at the site of injury and sensitize the spinal cord at its endpoint level. Then from the spinal cord to the brain where Pain is perceived (Meyer et al, 1994Textbook of Pain 13-44). Activation of nociceptors activates two types of afferent nerve fibers. The myelinated a-delta fibers transmit rapidly and are responsible for the sharp and stinging sensations, while the unmyelinated C fibers transmit at a slower rate and convey dull or sore pain. Moderate to severe acute nociceptive pain is a prominent feature of, but not limited to: pain from strain/sprain, post-operative pain (pain after any type of surgical procedure), post-traumatic pain, burns, myocardial infarction, acute pancreatitis and renal colic. Cancers involving acute pain symptoms are also generally therapeutic interactions such as chemotherapy toxicity, immunotherapy, hormonal therapy, and radiation therapy. Moderate to severe acute nociceptive pain is a prominent feature of, but not limited to: cancer pain which may be pain-related tumours (e.g. bone pain, headache and facial pain, visceral pain), or cancer pain associated with cancer therapy (e.g. postchemotherapy syndromes, chronic post-operative pain syndromes, post-radiation syndromes), back pain which may be due to abnormal conditions of a herniated or ruptured intervertebral disc or lumbar (lumbo) articular surface, sacroiliac joint, paraspinal muscles or posterior longitudinal ligaments.

Neuropathic pain is defined as pain initiated or caused by a primary injury or dysfunction of the nervous system (IASP definition). Nerve damage can result from trauma and disease, and thus the term "neuropathic pain" encompasses many diseases with different etiologies. These include, but are not limited to, diabetic neuropathy, post herpetic neuralgia, back pain, cancerous neuropathy, HIV neuropathy, pseudolimb pain, carpal tunnel syndrome, chronic alcoholism, hypothyroidism, trigeminal neuralgia, uremia, or vitamin deficiency. Neuropathic pain is pathological in that it has no protective effect. It usually occurs after the original cause has dissipated, typically for some years, which severely reduces the quality of life for the patient (Woolf and Mannion 1999Lancet 353: 1959-. Symptoms of neuropathic Pain are difficult to treat because they are often heterogeneous even among patients with the same disease (Woolf & Decosterd 1999 Pain supp.6: S141-S147; Woolf and Mannion 1999Lancet 353: 1959-1964). They include spontaneous pain, which can be persistent or paroxysmal and abnormally induced pain, such as hyperalgesia (increased sensitivity to noxious stimuli) and allodynia (sensitivity to normally innocuous stimuli).

The inflammatory process is a complex series of biochemical and cellular events that are activated in response to tissue damage or the presence of foreign bodies, which can lead to swelling and Pain (Levine and Taiwo 1994: Textbook of Pain 45-56). Arthritic pain accounts for the majority of the total inflammatory pain. Rheumatoid disease is one of the most common chronic inflammatory diseases in developed countries, and rheumatoid arthritis is a common cause of disability. The exact etiology of RA is unknown, but current assumptions suggest that genetic and microbiological factors may be critical (Grennan & Jayson 1994Textbook of Pain 397-407). Almost sixteen million Americans are estimated to have symptomatic Osteoarthritis (OA) or degenerative joint disease, most of which are over the age of 60, and are expected to increase to 4 million with increasing population age, which becomes a huge number of public health problems (Houge & Mersfelder 2002 Ann Pharmacother.36: 679-. Most patients with OA seek medical attention due to pain. Arthritis has significantly affected psychosocial and physical functions and is known to cause semi-half disability. Other types of inflammatory pain include, but are not limited to, Inflammatory Bowel Disease (IBD).

Other types of pain include, but are not limited to:

-musculo-skeletal diseases including, but not limited to, myalgia, fibromyalgia, spondylitis, seronegative (non-rheumatoid) arthropathy, non-articular rheumatism, dysphophenopathgy, glycogenolysis, polymyositis, pyomyositis.

Central pain or "thalamic pain", defined as pain caused by injury or dysfunction of the nervous system, including but not limited to central post-stroke pain, multiple sclerosis, spinal cord injury, parkinson's disease and epilepsy.

Cardiac and vascular pain including, but not limited to, angina, myocardical infarction, mitral stenosis, pericarditis, raynaud's phenomenon, stone cells (scleredoma), stone cells, skeletal muscle ischemia.

-visceral pain and gastrointestinal disorders. The viscera includes the organs of the abdominal cavity. These organs include the sexual organs, spleen and part of the digestive system. Visceral associated pain is divided into digestive visceral pain and non-digestive visceral pain. Commonly encountered Gastrointestinal (GI) diseases include Functional Bowel Disorders (FBD) and Inflammatory Bowel Disease (IBD). These GI disorders include a number of disease conditions that are currently only moderately controlled, including gastroesophageal reflux, dyspepsia, Irritable Bowel Syndrome (IBS) and Functional Abdominal Pain Syndrome (FAPS) for FBD and crohn's disease, ileitis and ulcerative colitis for IBD, all of which are regularly-occurring visceral pain. Other types of visceral pain include pain associated with dysmenorrhea, pelvic pain, cystitis and pancreatitis.

-headache, including but not limited to migraine, migraine with aura, migraine without aura, cluster headache, tension type headache.

Orofacial pain, including but not limited to dental pain, temporomandibular myofascial pain.

The compositions of the invention are also useful in the treatment of urinary incontinence, such as genuine stress urinary incontinence (GSI), Stress Urinary Incontinence (SUI) or senile urinary incontinence; overactive bladder (OAB), including idiopathic detrusor instability, detrusor overactivity secondary to neurological diseases (e.g., parkinson's disease, multiple sclerosis, spinal cord injury, and stroke), and detrusor overactivity secondary to bladder outflow obstruction (e.g., Benign Prostatic Hyperplasia (BPH), urethral stricture, or stenosis); nocturnal enuresis; urinary incontinence resulting from a combination of the above diseases (e.g., true stress urinary incontinence associated with overactive bladder); urinary symptoms such as frequency and urgency.

The composition can also be used for treating fecal incontinence.

As another aspect, provided herein is the use of an α -2- δ ligand and a DSNRI or one or both of an SSRI and SNRI in the manufacture of a medicament for the therapeutic, prophylactic or palliative treatment of pain, particularly neuropathic pain, with the proviso that combinations of compounds (i) - (xxv) of WO02/85839 with 5-hydroxytryptamine reuptake inhibitors, particularly fluoxetine, paroxetine, citalopram and sertraline, mixed 5-hydroxytryptamine-norepinephrine reuptake inhibitors, particularly milnacipran, venlafaxine and duloxetine, and norepinephrine reuptake inhibitors, particularly reboxetine, are excluded.

As a further feature, the present invention provides the use of a synergistically effective amount of an alpha-2-delta ligand and a DSNRI or one or both of a SSRI and SNRI in the manufacture of a medicament for the therapeutic, prophylactic or palliative treatment of pain, in particular neuropathic pain.

As a further aspect, there is provided a method of therapeutic, prophylactic or palliative treatment of pain, especially neuropathic pain, comprising the simultaneous, sequential or separate administration of a therapeutically effective amount of an α -2- δ ligand and a DSNRI or one or both of a SSRI and SNRI to a mammal in need of such treatment, with the proviso that the composition described in WO02/85839, i.e. the composition of a compound of formulae (i) - (xxv) with: 5-hydroxytryptamine reuptake inhibitors such as fluoxetine, paroxetine, citalopram and sertraline, mixed 5-hydroxytryptamine-norepinephrine reuptake inhibitors such as milnacipran, venlafaxine and duloxetine, or norepinephrine reuptake inhibitors such as reboxetine.

As a further aspect, provided herein is a method of therapeutic, prophylactic or palliative treatment of pain, particularly neuropathic pain, comprising administering simultaneously, sequentially or separately to a mammal in need of such treatment a therapeutically effective amount of an alpha-2-delta ligand and a DSNRI or one or both of a SSRI and SNRI.

The biological activity of the alpha-2-delta ligand of the present invention can be measured in a radioligand binding assay using the term³H]Gabapentin and alpha from porcine brain tissue₂Delta subunits (Gee N.S., Brown J.P., Dissanayake V.U.K., Offord J.S., Thurlow R., Woodruff G.N., J.biol.Chez., 1996; 271: 5879-. The results can be in terms of μ M or nM α₂Delta binding affinity.

The ability of the compounds of the invention to act as selective reuptake inhibitors can be determined in vivo according to established methods, for example according to example 68 of US 4536518.

The ability of the compounds of the present invention to act as binary 5-hydroxytryptamine-norepinephrine or selective norepinephrine reuptake inhibitors can be determined according to established methods, especially those described in the literature cited above.

The components of the compositions of the present invention may be administered separately, simultaneously or sequentially to treat pain. The composition may also optionally be administered with one or more other pharmaceutically active agents. Suitable optional agents include:

(i) opioid analgesics such as morphine, heroin, oxymorphone, levorphanol, methadone, meperidine, fentanyl, cocaine, codeine, dihydrocodeine, oxycodone, hydrocodone, propoxyphene, nalmefene, nalorphine, naloxone, naltrexone, buprenorphine, butorphanol, nalbuphine and pentazocine;

(ii) non-steroidal anti-inflammatory drugs (NSAIDs), such as aspirin, diclofenac, diflusinal, etodolac, fenbufen, fenoprofen, flufenisal, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, meclofenamic acid, mefenamic acid, nabumetone, naproxen, oxaprozin, phenylbutazone, piroxicam, sulindac, tolmetin, zomepirac, and pharmaceutically acceptable salts thereof;

(iii) barbiturate sedatives such as amobarbital, alprenol, sec-butyl barbital, butabital, mebendal, methamphetal, methohexital, pentobarbital, phenobarbital, secobarbital, talbarbital, theamylal, thiopental, and pharmaceutically acceptable salts thereof;

(iv) benzodiazepines * with sedative effect, such as clonazene *, potassium chloride *, diazepam, flurazepam, lorazepam, oxazepam, temazepam, triazolam and their pharmaceutically acceptable salts,

(v) h1 antagonists with sedative effects such as diphenhydramine, pyrilamine, promethazine, chlorpheniramine, clorox and their pharmaceutically acceptable salts;

(vi) miscellaneous sedatives such as glutethimide, meprobamate, methaqualone, dichlophenazone, and pharmaceutically acceptable salts thereof;

(vii) muscle relaxants, such as baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, methocarbamol, orphradine and pharmaceutically acceptable salts thereof,

(viii) NMDA receptor antagonists such as dextromethorphan ((+) -3-hydroxy-N-methyl morphinan) and its metabolite dextrorphan (dextrorphan) (+) -3-hydroxy-N-methyl morphinan), ketamine, memantine (memantine), pyrroloquinoline quinone, and cis-4- (phosphonomethyl) -2-piperidinecarboxylic acid and pharmaceutically acceptable salts thereof;

(ix) α -adrenergic active compounds, such as doxazosin, tamsulosin, clonidine and 4-amino-6, 7-dimethoxy-2- (5-methanesulfonamido-1, 2, 3, 4-tetrahydroisoquinol-2-yl) -5- (2-pyridine) quinazoline;

(x) Tricyclic antidepressants, such as desipramine, imipramine, amytriptiline and nortriptyline;

(xi) Anticonvulsants such as carbamazepine and valproate;

(xii) Tachykinin (NK) antagonists, in particular NK-3, NK-2 and NK-1, e.g., (α R, 9R) -7- [3, 5-bis (trifluoromethyl) benzyl ] -8, 9, 10, 11-tetrahydro-9-methyl-5- (4-tolyl) -7H- [1, 4] diazocino (diazocino) [2, 1-g ] [1, 7] naphthridine-6-13-dione (TAK-637), 5- [ [ (2R, 3S) -2- [ (1R) -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), lanopiptan, dapitaptan and 3- [ [ 2-methoxy-5- (trifluoromethoxy) phenyl ] methylamino ] -2-phenyl-piperidine (2S, 3S)

(xiii) Muscarinic antagonists such as oxybutynin, tolterodine, propiverine, tropium chloride and darifenacin;

(xiv) COX-2 inhibitors, such as celecoxib, rofecoxib, and valdecoxib;

(xv) Non-selective COX inhibitors (preferably with GI protection), such as nitrocyanopyrafen (HCT-1026);

(xvi) Coal tar analgesics, especially acetaminophen;

(xvii) Antipsychotics, such as droperidol;

(xviii) vanilloid receptor agonists, e.g. resinferoxin

(xix) Beta-adrenergic compounds, such as propranolol;

(xx) Local anesthetics, such as mexiletine;

(xxi) Corticosteroids, such as dexamethasone;

(xxii) 5-hydroxytryptamine receptor agonists and antagonists;

(xxiii) A cholinergic (nicotinic) analgesic;

(xxiv) Miscellaneous agents, such as tramadol ®;

(xxv) PDEV inhibitors, such as sildenafil, vardenafil or taladafil.

The invention extends to a product containing an alpha-2-delta ligand, one or both of a DSNRI or SSRI and SNRI, and one or more other therapeutic agents, such as those listed above, for simultaneous, separate or sequential use in the therapeutic, prophylactic treatment of pain, particularly neuropathic pain.

The compositions of the invention can be administered alone, but one or both of the ingredients will generally be administered in admixture with a suitable pharmaceutical excipient, diluent or carrier selected with regard to the intended route of administration and standard pharmaceutical practice. If appropriate, auxiliaries can be added. The adjuvant comprises antiseptic, antioxidant, correctant and colorant. The compounds of the invention may be of the direct, delayed, limited, sustained, pulsed or controlled release type.

The components of the composition of the present invention can be administered, for example, by the following routes, but are not limited thereto: oral, buccal or sublingual administration in the form of tablets, capsules, multiparticulates and nanoparticles, gels, films (incl. mucoadhesives), powders, pellets (ovules), elixirs, lozenges (incl. liquid filled), chews, solutions, suspensions and syrups. The compounds of the invention can also be administered in osmotic dosage forms, or in highly dispersible form or as coated granules or in fast dissolving, fast dispersing dosage forms, as described by Ashley Publications, 2001 by Liang and Chen. The compounds of the invention may be administered as crystalline or amorphous products, lyophilized or spray dried products. Suitable formulations of the compounds of the invention may be in hydrophilic or hydrophobic matrices, ion exchange resin complexes, coated or uncoated forms and other forms, as desired from the description of US6,106,864. Such 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 such as sodium starch glycolate, croscarmellose sodium and certain complex silicates, and granulation binders such as polyvinylpyrrolidone, Hypromellose (HPMC), triglycerides, Hydroxypropylcellulose (HPC), bentonite sucrose, sorbitol, gelatin and acacia. Additionally, lubricants may be added to the solid composition, such as magnesium stearate, stearic acid, glyceryl behenate, PEG, and talc, or wetting agents such as sodium lauryl sulfate. In addition, polymers such as carbohydrates, phospholipids (phospholipids) and proteins may be included.

Fast dispersing or dissolving dosage formulations (FDDFs) may comprise the following ingredients: aspartame, potassium acesulfame, citric acid, croscarmellose sodium, crospovidone, ascorbic acid (diaascorbic acid), ethyl acrylate, ethylcellulose, gelatin, hypromellose, magnesium stearate, mannitol, methyl methacrylate, mint flavors, polyethylene glycol, fumed silica, silicon dioxide, sodium starch glycolate, sodium stearyl fumarate, sorbitol, or xylitol. The terms dispersion and dissolution used herein to describe FDDFs depend on the solubility of the drug used, i.e., when the drug is insoluble, a fast dispersing dosage form can be prepared, and when the drug is soluble, a fast dissolving dosage form can be prepared.

Solid dosage forms, such as tablets, are prepared by standard procedures, such as direct compression or wet, dry or melt granulation, melt congealing, and extrusion. The core, which may be single or multi-layered, may be coated with a suitable outer coating as is known in the art.

Solid compositions of a similar type may also be used as fillers in capsules, for example gelatin, starch or HPMC capsules. Preferred excipients in this context include lactose, starch, cellulose, milk sugar or high molecular weight polyethylene glycols. Liquid compositions may also be used as fillers in soft or hard capsules, such as gelatin capsules. For aqueous and oily suspensions, solutions, syrups and/or elixirs, the compounds of the invention may be combined with various sweetening or flavouring agents, colouring matter or dyes, with emulsifying agents and/or suspending agents and with diluents such as water, ethanol, propylene glycol, methylcellulose, alginic acid or sodium alginate, glycerol, oils, hydrocolloid agents and combinations thereof. In addition, formulations containing these compounds and excipients may be presented as a dry product for constitution with water or other suitable vehicle before use.

Liquid form preparations include solutions, suspensions and emulsions, for example, water or water propylene glycol solutions. For parenteral injection, liquid formulations can be formulated in aqueous polyethylene glycol solutions. Aqueous solutions suitable for oral use can be prepared by dissolving the active ingredient in water and adding suitable colorants, flavors, stabilizers, and thickening agents, as desired. Aqueous suspensions suitable for oral use can be prepared by dispersing the finely divided active ingredient in water with viscous material, such as natural or synthetic gums, methylcellulose, sodium carboxymethylcellulose, and other known suspending agents.

The components of the compositions of the present invention can also be administered by injection, i.e., intravenously, intramuscularly, intradermally, intraduodenally or intraperitoneally, intraarterially, intrathecally, intraventricularly, intraurethrally, intrasternally, intracranially, intraspinally or subcutaneously, or they can be administered by infusion, needleless syringe or implanted injection techniques. For such parenteral administration, they are best used in the form of a sterile aqueous solution, suspension or emulsion (or so as to be capable of containing micellar systems), which may contain other substances known in the art, such as sufficient salts or carbohydrates such as glucose to render the solution isotonic with blood. The aqueous solution should be suitably buffered (preferably at a pH of 3 to 9), if desired. For some forms of parenteral administration, they may be used in the form of a sterile non-aqueous system, for example, fixed oils, which include mono-or diglycerides, and fatty acids, which include oleic acid. Preparation of suitable parenteral formulations under sterile conditions, e.g., by lyophilization, can be readily accomplished by standard pharmaceutical techniques known to those skilled in the art. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile, pyrogen-free water, before use.

Likewise, the components of the compositions of the present invention can be administered intranasally or by inhalation. They can conveniently be administered in the form of a dry powder (alone, as a mixture, for example with a lactose dry mixture, or particles of a mixed ingredient, for example mixed with a phospholipid) from a dry powder inhalation device, or as an aerosol spray from a pressurised container, pump, nozzle, nebuliser (preferably a nebuliser using electronic fluidics to produce a fine mist) or nebuliser, with or without the use of a suitable propellant, for example difluorodichloromethane, trichlorofluoromethane, difluorotetrachloroethane, a hydrofluoroalkane such as 1,1, 1, 2-tetrafluoroethane (HFA 134A trademark) or 1,1, 1, 2, 3,3, 3-heptafluoropropane (HFA 227EA trademark), carbon dioxide, other perfluorinated hydrocarbons such as perfluororon (trademark) or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by a valve capable of delivering a metered amount. The pressurised container, pump, spray, nebuliser or nebuliser may comprise a solution or suspension of the active compound, for example using a mixture of ethanol (optionally an aqueous alcohol) or a suitable agent for dispersion, dissolution or extended release and a propellant as a solvent, which may additionally comprise a lubricant such as sorbitan trioleate. Capsules, blisters and cartridges (made of, for example, gelatin or HPMC) for use in an inhaler or insufflator may be formulated to contain a powder mix of a compound of the invention, a suitable powder base such as lactose or starch, and a performance modifying agent such as 1-leucine, mannitol or magnesium stearate.

Prior to use in a dry powder formulation or suspension formulation for inhalation, the components of the composition of the present invention should be micronized to a size suitable for administration by inhalation (generally considered to be less than 5 microns). Micronization can be achieved by several methods, such as spiral gas-flow dynamic milling, fluidized bed gas-flow dynamic milling, crystallization using supercritical fluids, or spray drying.

Suitable solution formulations for use in nebulizers using electrohydrodynamic to produce fine mist may contain 1. mu.g to 10mg of the compound of the invention per press stroke, and may be 1 to 100. mu.l per press stroke. A typical formulation may contain the ingredients of the composition of the present invention, propylene glycol, sterile water, ethanol and sodium chloride. Other solvents may also be substituted for propylene glycol, such as glycerol or polyethylene glycol.

In addition, the ingredients of the composition of the invention may be administered topically to the skin, mucosa, on the epidermis or transdermally, for example in the form of: gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, 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 of one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax, fixed oils including synthetic mono or diglycerides, and fatty acids including oleic acid, water, sorbitan monostearate, polyethylene glycol, liquid paraffin, polysorbate 60, cetyl esters wax, cetyl alcohol, 2-octyldodecanol, benzyl alcohol, alcohols such as ethanol. In addition, penetration enhancers may be used. The following can also be used in nanoparticle form (e.g., niosomes or liposomes) or in suspended or dissolved form: polymers, carbohydrates, proteins, phospholipids (phospholipides). In addition, iontophoresis, electroporation, sonophoresis, and sonophoresis may be used to deliver them.

In addition, the components of the compositions of the present invention can be administered rectally, for example, in the form of suppositories or pessaries. They may also be administered via the vaginal route. For example, these compositions may be prepared by mixing the drug with a suitable non-irritating excipient, such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at room temperature but liquefy and/or dissolve in the cavities to release the drug.

The components of the compositions of the present invention may also be administered by ocular route. For ophthalmic use, the compounds can be formulated as micronized suspensions in isotonic, pH-adjusted sterile saline, or preferably as solutions in isotonic, pH-adjusted sterile saline. Polymers such as cross-linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, fibrous polymers (e.g. hypromellose, hydroxyethyl cellulose, methyl cellulose) or heteropolysaccharide polymers (e.g. agarose) may be added. Alternatively, they may be formulated as ointments, such as petrolatum or mineral oil, incorporated into biodegradable (e.g. absorbable gel sponges, collagen) or non-biodegradable (e.g. silicone) implants, wafers, drops, lenses or administered by microparticle or vesicular systems such as niosomes or liposomes. The formulation may optionally be combined with a preservative such as benzalkonium chloride. In addition, they can be delivered using iontophoresis. They may also be administered in the ear by using, for example, but not limited to, drops.

The ingredients of the composition of the present invention may also be used in combination with a cyclodextrin. Cyclodextrins are known to form inclusion and non-inclusion complexes with drug molecules. The drug-cyclodextrin complex formulation can modify the solubility, dissolution rate, taste masking, bioavailability, and/or stability of the drug molecule. Drug-cyclodextrin complexes are generally used in most dosage forms and routes of administration. In addition to being directly complexed with the drug, cyclodextrins may also act as auxiliary additives, for example as carriers, diluents or co-solvents. alphA-, betA-and gammA-cyclodextrins are the most commonly used, suitable examples being described in WO-A-91/11172, WO-A-94/02518 and WO-A-98/55148.

The term "administering" includes delivery by viral or non-viral techniques. Viral delivery mechanisms include, but are not limited to, adenoviral vectors (vectors), adeno-associated viral (AAV) vectors, herpes viral vectors, retroviral vectors, lentiviral (lentivirus) vectors, and baculovirus vectors. Non-viral delivery mechanisms include lipid-mediated transfection, liposomes, immunoliposomes, lipofectins, Cationic Facial Amphiphiles (CFAs), and combinations thereof. Routes of such delivery mechanisms include, but are not limited to, mucosal, nasal, oral, parenteral, gastrointestinal, topical, or sublingual routes.

Thus, as a further aspect of the invention, there is provided a pharmaceutical composition comprising an α -2- δ ligand, DSNRI or one or both of SSRI and SNRI, or a pharmaceutically acceptable salt thereof, together with a suitable excipient, diluent or carrier, with the proviso that combinations of compounds (i) - (xxv) of WO02/85839 with 5-hydroxytryptamine reuptake inhibitors, especially fluoxetine, paroxetine, citalopram and sertraline, mixed 5-hydroxytryptamine-norepinephrine reuptake inhibitors, especially milnacipran, venlafaxine and duloxetine, and norepinephrine reuptake inhibitors, especially reboxetine, are excluded. Suitably, the composition is suitable for the treatment of pain, in particular neuropathic pain.

As a further aspect of the invention there is provided a pharmaceutical composition comprising a synergistic composition comprising an alpha-2-delta ligand, a DSNRI or one or both of a SSRI and SNRI, or a pharmaceutically acceptable salt thereof, together with a suitable adjuvant, diluent or carrier. Suitably, the composition is suitable for the treatment of pain, in particular neuropathic pain.

For administration to a non-human animal, the term "pharmaceutically" may be substituted herein for "veterinarily".

The components of the pharmaceutical formulation are preferably in unit dosage form. In this form, the formulation is subdivided into unit dosage forms containing appropriate quantities of the active ingredient. The unit dosage form may be a packaged preparation, the package containing a plurality of discrete formulations, for example, packaged tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form itself can be a capsule, tablet, cachet, or lozenge, or it can be the appropriate number of any of these packaged forms. The amount of active ingredient in a unit dosage form may vary or be adjusted from 0.1mg to 1g depending on the particular application and the potency of the active ingredient. In pharmaceutical applications, the drug may be administered three times daily, for example in 100 or 300mg capsules. In therapeutic use, the compounds used in the pharmaceutical methods of the present invention are initially administered in a dose of about 0.01mg to about 100mg/kg per day. A preferred daily dosage is from about 0.01mg to about 100 mg/kg. However, the dosage may vary depending on the requirements of the patient, the severity of the condition being treated and the compound being used. It is within the skill of the art to determine the correct dosage for a particular situation. Typically, treatment is first administered at a lower dose, which is less than the optimal dose of the compound. Subsequently, the dosage is increased in smaller increments until the optimum effect is achieved in the environment. For convenience, the total daily dose may be divided and administered in portions throughout the day, if desired.

In veterinary use, the compositions according to the invention, or a veterinarily acceptable salt or solvate thereof, are administered as a suitable acceptable formulation according to conventional veterinary practice and the veterinarian will determine the most appropriate dosing regimen and route of administration for the particular animal.

Biological examples

Method

Animal(s) production

Male Sprague Dawley rats (200-250g) obtained from Charles River, (Margate, Kent, U.K.) were housed in 6 groups. All animals were kept on a 12 hour day/night cycle (0 min. light at 7 am) with free access to food and water. All experiments were performed by unknown drug treatment observers.

CCI surgery in rats

Animals were anesthetized with isoflurane. The sciatic nerve was ligated as described previously by Bennett and Xie, 1988. During this procedure the animals were placed on a constant temperature blanket. After surgery, the common sciatic nerve was exposed in the middle of the thigh by blunt dissection and through the biceps femoris. Adherent tissue on approximately 7mm nerves was removed adjacent to the sciatic trigeminal site and 4 ligatures (4-0 silk) were loosely tied around them at approximately 1mm intervals. The incision was closed layer by layer and the wound treated with topical antibiotics.

Effect of compositions on CCI-induced maintenance of static and dynamic allodynia

Doses in response to (responses to) gabapentin, DSNRI, SSRI and SNRI were first applied alone on the CCI model. The composition was tested after a fixed ratio was designed. Doses responsive to each fixed ratio of the composition were administered. On each day of the experiment, baseline Paw Withdrawal Thresholds (PWT) for von Frey haires (baselinew with swab threshold) and swab-stimulated Paw Withdrawal Latencies (PWL) (paw with swab latencies) were determined prior to drug treatment.

Evaluation of allodynia

Static allodynia was measured using Semmes-Weinstein von Freyhairs (Stoelting, Illinois, u.s.a.). The animal was placed on the bottom of the metal mesh cage to reach the paw underneath. Animals were familiarized with this environment prior to starting the experiment. Static allodynia was measured by palpating the plantar surface of the right hind paw with von Frey hairs, with increasing palpation force (0.7, 1.2, 1.5, 2, 3.6, 5.5, 8.5, 11.8, 15.1 and 29g) until 6sec was reached. Once the withdrawal response is established, the paw is measured again, starting with the next decreasing von Frey haires until no response occurs. The maximum force of 29g lifts the paw and causes a reaction, which is the cut-off point. The minimum force required to produce a response is recorded as PWT in grams.

Dynamic allodynia was assessed by tapping the plantar surface of the hind paw with a cotton swab. This procedure was carefully performed in rats that were completely accustomed to this environment and were not active, to avoid recording general motor activity. At least three measurements were made at each time point, the average of which represents the latency Period (PWL) for paw withdrawal. If no response occurred within 15 seconds, the procedure was terminated and the time was designated as the retraction time for the animal. Thus 15 seconds effectively indicates no retraction. The withdrawal reaction is usually accompanied by repeated paw withdrawal or licking of the paw. If the animal responded to cotton stimuli 8 seconds before tapping, then dynamic allodynia was considered to have occurred.

Investigation of the composition

Dose responses (dose responses) were first performed on α -2- δ ligands (p o.), DSNRI or SSRI and/or SNRI alone (s.c. or p.o.). Some fixed dose ratio of the composition can then be tested. The dose response to each fixed dose ratio was performed in each experiment and was determined by the duration of the anti-allodynic effect of each individual ratio. Various weight fixed dose ratios of the composition can be determined.

Suitable DSNRI or SSRI and/or SNRI compounds of the invention may be prepared according to or based on the literature by methods which are obvious to a person skilled in the art.

Suitable α -2- δ ligand compounds of the present invention can be prepared as described below or in the aforementioned patent references, which are illustrated by the following non-limiting examples and intermediates.

Chemical examples

Example 1: (3S, 5R) -3-amino-5-methyl-octanoic acid hydrochloride (R) -2, 6-dimethyl-non-2-ene. To (S) -citronellyl bromide in THF (800mL) (50g, 0.228mol) at 0 deg.C was added LiCl (4.3g) followed by CuCl₂(6.8 g). After 30 minutes, methylmagnesium chloride (152mL, 3M in THF, Aldrich) was added and the solution warmed to room temperature. After 10 hours the solution was cooled to 0 ℃ and a saturated aqueous solution of ammonium chloride was carefully added. The two resulting layers were separated and the aqueous phase was extracted with ether. The combined organic phases were dried (MgSO)₄) And concentrating to obtain (R) -2, 6-dimethyl-non-2-alkene. 32.6 g; 93% and used without further purification.¹H NMR(400MHz；CDCl₃)δ5.1(m，1H)，1.95(m，2H)，1.62(s，3H)，1.6(s，3H)，1.3(m，4H)，1.2(m，2H)，0.8(s，6H)。

(R) -4-methyl-heptanoic acid. To (R) -2, 6-dimethyl-non-2-ene (20g, 0.13mol) in acetone (433mL) was added CrO₃(39g, 0.39mol) in H₂SO₄(33mL)/H₂Solution in O (146mL) was continued for 50 minutes. After 6 hours, the solution is added again at H₂SO₄(22mL)/H₂CrO in O (100mL)₃(26g, 0.26 mol). After 12 hours the solution was diluted with brine and extracted with ether. Drying (MgSO)₄) And the combined organic phases were concentrated. Flash chromatography (gradient 6: 1 to 2: 1 hexanes/EtOAc) afforded (R) -4-methyl-heptanoic acid as an oil. 12.1 g; MS, m/z (relative intensity): 143[ M-H, 100%]。

(4R, 5S) -4-methyl-3- ((R) -4-methyl-heptanoyl) -5-phenyl-oxazolidin-2-one. To (R) -4-methyl-heptanoic acid (19g, 0.132mol) and triethylamine (49.9g, 0.494mol) in THF (500mL) was added trimethylacetyl chloride (20g, 0.17mol) at 0 deg.C. After 1 hour LiCl (7.1g, 0.17mol) was added followed by (4R,5S) - (+) -4-methyl-5-phenyl-2-oxazolidinone) 3(30g, 0.17 mol). The mixture was warmed to room temperature, after 16 hours the filtrate was removed by filtration and the solution was concentrated under reduced pressure. Flash chromatography (7: 1 hexanes/EtOAc) afforded (4R, 5S) -4-methyl-3- ((R) -4-methyl-heptanoyl) -5-phenyl-oxazolidin-2-one as an oil. 31.5 g; 79% [ alpha ]]_D(iii) 5.5(c1 in CHCl)₃MS, m/z (relative intensity): 304[ M + H, 100%]。

(3S, 5R) -5-methyl-3- ((4R, 5S) -4-methyl-2-oxo-5-phenyl-oxazolidine-3-carbonyl) -octanoic acid tert-butyl ester. To (4R, 5S) -4-methyl-3- ((R) -4-methyl-heptanoyl) -5-phenyl-oxazolidin-2-one (12.1g, 0.04mol) in THF (200mL) was added sodium bis (trimethylsilyl) amide (48mL of a 1M solution in THF) at-50 ℃. After 30 minutes, tert-butyl bromoacetate (15.6g, 0.08mol) was added. The solution was stirred at-50 ℃ for 4 hours and then warmed to room temperature. After 16 hours, saturated aqueous ammonium chloride solution was added and the two layers were separated. The aqueous phase was extracted with ether and dried (MgSO)₄) And the combined organic phases were concentrated. Flash chromatography (9: 1 hexanes/EtOAc) afforded (3S, 5R) -5-methyl-3- ((4R, 5S) -4-methyl-2-oxo-5-phenyl-oxazolidine-3-carbonyl) -octanoic acid tert-butyl ester as a white solid. 12g of a mixture; 72% [ alpha ]]_D+30.2(c1 in CHCl)₃In (1).¹³C NMR(100MHz；CDCl₃)δ176.47，171.24，152.72，133.63，128.87，125.86，80.85，78.88，55.34，39.98，38.77，38.15，37.58，30.60，28.23，20.38，20.13，14.50，14.28。

(S) -2- ((R) -2-methyl-pentyl) -succinic acid 4-tert-butyl ester. At 0 ℃ in the direction of H₂O (73mL) and (3S, 5R) -5-methyl-3- ((4R, 5S) -4-methyl-2-oxo-5-phenyl-oxazolidine-3-carbonyl) -octanoic acid tert-butyl ester (10.8g, 0.025mol) in THF (244mL) LiOH (51.2mL of a 0.8M solution) and H₂O₂(14.6mL of 30% solution) in a pre-mixed solution. After 4 hours, an additional 12.8mL of LLIOH (0.8M solution) and 3.65mL of H were added₂O₂(30% solution). After 30 minutes, sodium bisulfite (7g), sodium sulfite (13g) and water (60mL) were added followed by hexane (100mL) and ether (100 mL). The two layers were separated and the aqueous phase was extracted with ether.The combined organic phases were concentrated to an oil dissolved in heptane (300 mL). The resulting solid was filtered off, the filtrate was dried and concentrated to give (S) -2- ((R) -2-methyl-pentyl) -succinic acid 4-tert-butyl ester (6g, 93%), which was used immediately without further purification. MS m/z (relative intensity): 257[ M + H, 100%]。

(3S, 5R) -3-benzyloxycarbonylamino-5-methyl-octanoic acid tert-butyl ester. A solution of (S) -2- ((R) -2-methyl-pentyl) -succinic acid 4-tert-butyl ester (6.0g, 23.22mmol) and triethylamine (3.64mL, 26.19mmol) in toluene (200mL) was treated with diphenylphosphoryl azide (5.0mL, 23.22mL) and stirred at room temperature for 0.5 h. After the reaction the mixture was heated at reflux for 3 hours then briefly cooled, benzyl alcohol (7.2rnL, 69.7mmol) was added and the solution was heated for an additional 3 hours. After reaction the mixture was cooled, diluted with ether (200mL) and the combined organic layers were washed with saturated NaHCO₃Washed successively with brine and then dried (Na)₂SO₄). The concentrated organic fractions were purified by chromatography eluting with 8: 1 hexane: ethyl acetate to give (3S, 5R) -3-benzyloxycarbonylamino-5-methyl-octanoic acid tert-butyl ester (6.4g, 75.8%). MS: m + 1: 364.2, 308.2.

(3S, 5R) -3-amino-5-methyl-octanoic acid, tert-butyl ester. With Pd/C (0.2g) and H₂A solution of (3S, 5R) -3-benzyloxycarbonylamino-5-methyl-octanoic acid tert-butyl ester (2.14g, 5.88mmol) in THF (50mL) was treated at 50psi for 2 hours. The reaction mixture was then filtered and concentrated in vacuo to an oil to give a quantitative yield of (3S, 5R) -3-amino-5-methyl-octanoic acid tert-butyl ester. MS: m + 1: 230.2, 174.1.

(3S, 5R) -3-amino-5-methyl-octanoic acid hydrochloride. A slurry of (3S, 5R) -amino-5-methyl-octanoic acid tert-butyl ester (2.59g, 11.3mmol) in 6N HCl (100mL) was heated at reflux for 18 h, cooled, and filtered through celite. The filtrate was concentrated to 25mL under vacuum, the resulting crystals were collected and dried to give (3S, 5R) -3-amino-5-methyl-octanoic acid hydrochloride, m.p. 142.5-142.7 ℃ (1.2g, 50.56%). a second crop (0.91g) was obtained from the filtrate. Analytically calculated as C₉H₁₉NO₂HCl: c: 51.55, H: 9.61, N: 6.68, Cl: 16.91. measured in factComprises the following steps: c: 51.69, H: 9.72, N: 6.56, Cl: 16.63.

(3S, 5R) -3-amino-5-methyl-octanoic acid hydrochloride. 5.3g of 2S- (2R-methyl-pentyl) -succinic acid-4-tert-butyl ester contained in 30mL of methyl-tert-butyl ether are reacted at room temperature with 3.5mL of triethylamine and then with 6.4g of diphenylphosphoryl azide. After the reaction exothermed to 45 ℃ and stirred for at least 4 hours, the reaction mixture was cooled to room temperature and allowed to stand for stratification. The bottom layer was discarded and the upper layer was washed with water and then diluted aqueous HCl. The upper layer was then combined with 10mL of 6N aqueous HCl and stirred at 45-65 ℃. The reaction mixture was concentrated by vacuum distillation to about 10-14mL and crystallized upon cooling at about 5 ℃. After filtration of the collected product, the product was washed with toluene and reslurried in toluene. The product was dried by heating under vacuum to give 2.9g (67%) of the product as white crystals. The product can be recrystallized from aqueous HCl. Melting point 137 ℃.

EXAMPLE 2 (3S, 5R) -amino-5-methyl-heptanoic acid

(S) -3, 7-dimethyl-oct-6-enyl methanesulfonate. In the CH direction at 0 DEG C₂Cl₂(800mL) of S- (-) -citronellol (42.8g, 0.274mol) and triethylamine (91mL, 0.657mol) were added in the presence of CH₂Cl₂Methanesulfonyl chloride (26mL, 0.329mol) (200 mL). After 2 hours the solution was washed with 1N HCl at 0 ℃ and then brine. Drying (MgSO)₄) And the organic phase was concentrated to give the title compound as an oil (60.5g, 94%), which was used without further purification. MS, m/z (relative intensity): 139[ 100%]，143[100％]。

(R) -2, 6-dimethyl-oct-2-ene. To (S) -3, 7-dimethyl-oct-6-enyl methanesulfonate (60g, 0.256mol) in THF (1L) was added lithium aluminum hydride (3.8g, 0.128mol) at 0 ℃. After 7 hours, a further 3.8g of lithium aluminium hydride were added and the solution was warmed to room temperature. After 18 hours, a further 3.8g of lithium aluminium hydride are added. After another 21 hours, the reaction was carefully quenched with 1N citric acid and the solution was further diluted with brine. The two phases obtained are separated and dried (MgSO)₄) And concentrating the organic phase to give an oily targetThe title compound, which was used without further purification. MS, m/z (relative intensity): 139[ M + H, 100%]。

(R) -4-methyl-hexanoic acid. An analogous procedure to that used to synthesize (R) -4-methyl-heptanoic acid was used to give an oily acid (9.3g, 56%) MS, m/z (relative strength): 129[ M-H, 100% ].

(4R, 5S) -4-methyl-3- ((R) -4-methyl-hexanoyl) -5-phenyl-oxazolidin-2-one. In analogy to the synthesis of (4R, 5S) -4-methyl-3- ((R) -4-methyl-heptanoyl) -5-phenyl-oxazolidin-2-one was applied the title compound (35.7g, 95%) was obtained as oil. MS, m/z (relative intensity): 290[ M + H, 100.

(3S, 5R) -5-methyl-3- [1- ((4R, 5S) -4-methyl-2-oxo-5-phenyl-oxazolidin-3-yl) -formyloxy]-tert-butyl heptanoate. The title compound was obtained as an oil (7.48g, 31%) in analogy to the preparation of (3S, 5R) -5-methyl-3- ((4R, 5S) -4-methyl-2-oxo-5-phenyl-oxazolidine-3-carbonyl) -tert-butyl octanoate. MS, m/z (relative intensity): 178[ 100%]，169[100％]；[α]_D+21.6(c1 in CHCl)₃In (1).

(S) -2- ((R) -2-methyl-butyl) -succinic acid 4-tert-butyl ester. At 0 ℃ in the direction of H₂O (53mL) and (3S, 5R) -5-methyl-3- [1- ((4R, 5S) -4-methyl-2-oxo-5-phenyl-oxazolidin-3-yl) -formyloxy in THF (176mL)]Tert-butyl-heptanoate (7.26g, 0.018mol) to which LiOH (37mL of a 0.8M solution) and H were added₂O₂(10.57mL of 30% solution) and the solution was warmed to room temperature. After 2 hours, sodium bisulfite (7g), sodium sulfite (13g) and water (60mL) were added and the two layers were separated and the aqueous layer was extracted with ether. The combined organic phases were concentrated to an oil dissolved in heptane (200 mL). The resulting solid was filtered off and dried (MgSO)₄) And the filtrate was concentrated to give the title compound (4.4g) as an oil, which was used without further purification. MS, m/z (relative intensity): 243[ 100%].

(3S, 5R) -3-benzyloxycarbonylamino-5-methyl-heptanoic acid, tert-butyl ester. This compound was prepared as described above from (S) -2- ((R) -2-methyl-butyl) amber4-tert-butyl acid ester tert-butyl (3S, 5R) -3-benzyloxycarbonylamino-5-methyl-heptanoate was obtained as an oil (yield 73.3%).¹H NMR(400MHz；CDCl₃) δ 0.84(t, 3H, J ═ 7.33Hz), 0.89(d, 3H, J ═ 6.60Hz), 1.12-1.38(m, 4H), 1.41(s, 9H), 1.43-1.59(m, 2H), 2.42(m, 2H), 4.05(m, 1H), 5.07(t, 2H J ═ 12.95Hz), and 7.28-7.34(m, 5H).

(3S, 5R) -amino-5-methyl-heptanoic acid, tert-butyl ester. This compound was prepared as described above starting from (3S, 5R) -3-benzyloxycarbonylamino-5-methyl-heptylic acid tert-butyl ester and replacing it with (3S, 5R) -3-benzyloxycarbonylamino-5-methyloctanoic acid tert-butyl ester to give the title compound. 1H NMR (400 MHz; CDCl)₃) δ 0.84(t and d overlap, 6H), 1.08-1.16(m, 2H), 1.27-1.30(m, 2H), 1.42(s, 9H), 1.62(br s, 2H), 2.15(dd, 1H, J ═ 8.54 and 15.62Hz), 2.29(dd, 1H, J ═ 4.15 and 15.37Hz), and 3.20(br s, 2H).

(3S, 5R) -amino-5-methyl-heptanoic acid hydrochloride-A slurry of (3S, 5R) -amino-5-methyl-heptanoic acid tert-butyl ester (1.44g, 6.69mmol) in 3N HCl was heated under reflux for 3h, filtered hot through celite, and concentrated to dryness. The resulting solid was triturated in ether to give (3S, 5R) -3-amino-5-methyl-heptanoic acid hydrochloride, (0.95g, 85%) melting point 126.3-128.3 ℃.

Example 3 (3S, 5R) -3-amino-5-methyl-nonanoic acid

(R) -4-methyl-octanoic acid. Lithium chloride (0.39g, 9.12mmol) and copper (I) chloride (0.61g, 4.56mmol) were combined in 45mL THF at room temperature and stirred for 15 minutes, then cooled to 0 deg.C at which time ethyl magnesium bromide (1M in THF, 45mL, 45mmol) was added. (S) -citronellyl bromide (5.0g, 22.8mmol) was added dropwise and the solution was slowly warmed to room temperature and stirred overnight. Sat. nh was carefully added₄Cl (aq) and Et₂O and sat₄Cl (aq) was stirred for 30 minutes to terminate the reaction. The phases were separated and dried (MgSO)₄) And the organic phase was concentrated. The crude product (R) -2, 6-dimethyl-dec-2-ene was used without purification. At 0 ℃ in 50mL of propyleneTo a solution of (R) -2, 6-dimethyl-dec-2-ene (3.8g, 22.8mmol) in ketone was added Jones' reagent (2.7M in H)₂SO₄(aq, 40mL, 108mmol), the solution was slowly warmed to room temperature and stirred overnight. The mixture is dissolved in Et₂O and H₂The phases were separated, the organic phase was washed with brine and dried (MgSO)₄) And concentrated. The residue was purified by flash chromatography (8: 1 hexanes: EtOAc) to give 2.14g (59%) of the title compound as a colorless oil: LRMS: m/z 156.9(M +). Jones reagent was made as a 2.7M solution by combining 26.7g of CrO₃、23mLH₂SO₄And use of H in combination₂O was diluted to 100 mL.

(4R, 5S) -4-methyl-3- ((R) -4-methyl-octanoyl) -5-phenyl-oxazolidin-2-one. At 0 ℃ down to 25mLCH₂Cl₂To (R) -4-methyl-octanoic acid (2.14g, 13.5mmol) in 3 drops of DMF was added followed by oxalyl chloride (1.42mL, 16.2mmol) resulting in evolution of a powerful gas. The solution was warmed directly to room temperature, stirred for 30 minutes, and concentrated. At the same time, n-butyllithium (1.6M in hexane, 9.3mL, 14.9mmol) was added dropwise at-78 deg.C to a solution of oxazolidinone (2.64g, 14.9mmol) in 40mL THF. The mixture was stirred for 10 minutes at which time the acid chloride in 10mL THF was added dropwise. The reaction was stirred at-78 ℃ for 30 minutes, then warmed directly to room temperature and washed with sat₄The reaction was stopped with Cl. The mixture is in Et₂O and sat₄The layers were separated in Cl (aq), the phases were separated and dried (MgSO)₄) And the organic phase was concentrated to complete the preparation, yielding 3.2g of the title compound as a colorless oil. LRMS: m/z318.2(M +).

(3S, 5R) -5-methyl-3- ((4R, 5S) -4-methyl-2-oxo-5-phenyl-oxazolidine-3-carbonyl) -nonanoic acid tert-butyl ester. To a solution of diisopropylamine (1.8mL, 12.6mmol) in 30mL THF at-78 deg.C was added n-butyllithium (1.6M in hexane, 7.6mL, 12.1mmol), the mixture was stirred for 10 minutes at which time (4R, 5S) -4-methyl-3- ((R) -4-methyl-octanoyl) -5-phenyl-oxazolidin-2-one (3.2g, 10.1mmol) in 10mL THF was added dropwise. The solution was stirred for 30 minutes and t-butyl bromoacetate (1.8mL, 1) was added dropwise rapidly at-50 deg.C2.1mmol) and the mixture was slowly warmed to 10 ℃ over 3 hours. The mixture is in Et₂O and sat₄The phases were separated between Cl (aq), separated and dried (MgSO)₄) And the organic phase was concentrated. The residue was purified by flash chromatography (16: 1 to 8: 1 hexane: EtOAc) to give 2.65g (61%) of the title compound as a colorless crystalline solid having a melting point of 84-86 ℃, [ delta ]]_D ²³+17.1(c＝1.00，CHCl₃)。

(S) -2- ((R) -2-methyl-hexyl) -succinic acid 4-tert-butyl ester. To a solution of (3S, 5R) -5-methyl-3- ((4R, 5S) -4-methyl-2-oxo-5-phenyl-oxazolidine-3-carbonyl) -nonanoic acid tert-butyl ester (2.65g, 6.14mmol) in 20mL THF at 0 deg.C was added₂LiOH monohydrate in O (1.0g, 23.8mmol) and hydrogen peroxide (30 wt% aqueous, 5.0mL) in a pre-cooled (0 ℃ C.) solution. The mixture was stirred vigorously for 90 minutes, then warmed to room temperature and stirred for 90 minutes. The reaction was carried out by adding 100mL of 10% NaHSO at 0 deg.C₃(aq) to stop, then Et₂And (4) extracting. The phases were separated and the organic phase was washed with brine and dried (MgSO)₄) And concentrated. The title compound was used without purification.

(3s.sr) -3-benzyloxycarbonylamino-5-methylnonanoic acid, tert-butyl ester this compound was prepared analogously to the above description, starting from 4-tert-butyl (S) -2- ((R) -2-methylhexyl) succinate, replacing 4-tert-butyl (S) -2- ((R) -2-methylpentyl) succinate, to give the title compound as an oil (71.6% yield).¹H NMR(400MHz；CDCl₃) δ 0.81(t, 3H, J ═ 4.40Hz), 0.85(d, 3H, J ═ 6.55Hz), 1.06-1.20(m, 7H), 1.36(s, 9H), 1.38-1.50(m, 2H), 2.36(m, 2H), 3.99(m, 1H), 5.02(m + s, 3H), and 7.28-7.28(m, 5H).

(3S, 5R) -3-amino-5-methyl-nonanoic acid, tert-butyl ester this compound is prepared analogously to the above description, starting from (3S, 5R) -benzyloxycarbonylamino-5-methyl-nonanoic acid tert-butyl ester, in place of (3S, 5R) -3-benzyloxycarbonylamino-5-methyl-octanoic acid tert-butyl ester. The yield was 97%.¹H NMR(400MHz；CDCl₃) δ 0.82(d and t overlap, 6H), 1.02-1.08(m, 1H), 1.09-1.36(m, 6H), 1.39(s, 9H), 1.47(br s, 1H), 1.80(s, 2H), 2.13(dd, 1H, J ═ 8.54 and 15.61Hz), and 2.27(dd, 1H, J ═ 4.15 and 15.38 Hz).

(3S, 5R) -3-amino-5-methyl-nonanoate-A mixture of tert-butyl (3S, 5R) -3-amino-5-methyl-nonanoate (1.50g, 6.16mmol) in 3N HCl (100mL) was heated under reflux, filtered hot through celite, and concentrated to 30mL under vacuum. The resulting crystals were collected, washed with additional 3N HCl and dried to give the title compound, m.p. 142.5-143.3 deg.C. Additional harvest from the filtrate yielded 1.03g (70.4%). Analytically calculated as C₁₀H₂₁NO₂HCl: c: 53.68, H: 9.91, N: 6.26, Cl: 15.85. actually measuring as follows: c: 53.89, H: 10.11, N: MS: m + 1: 188.1.

pharmaceutical composition examples

In the following examples, the term "active compound" or "active ingredient" refers to a suitable combination or single ingredient of an alpha-2-delta ligand and DSNRI or one or both of SSRI and SNRI and/or a pharmaceutically acceptable salt according to the invention.

(i) Tablet composition

The following compositions a and B can be made by wet granulation of a solution of ingredients (a) to (c) and (a) to (d) with povidone, followed by the addition of magnesium stearate and compression.

Composition A

mg/tablet

(a) Active ingredient 250250

(b) Lactose b.p. 21026

(c) Sodium starch glycolate 2012

(d) Povidone B.P.159

(e) Magnesium stearate 53

500 300

Composition B

mg/tablet

(a) Active ingredient 250250

(b) Lactose 150150-

(c)Avicel PH 101 60 26

(d) Sodium starch glycolate 2012

(e) Povidone B.P 159

(f) Magnesium stearate 53

500 300

Composition C

mg/tablet

Active ingredient 100

Lactose 200

Starch 50

Povidone 5

Magnesium stearate 4

359

The following compounds D and E can be prepared by direct compression of the combined ingredients. The lactose used in formulation E was of the direct compression type.

Composition D

mg/tablet

Active ingredient 250

Magnesium stearate 4

Pregelatinized starch NF 15146

400

Composition E

mg/tablet

Active ingredient 250

Magnesium stearate 5

Lactose 145

Avicel 100

500

Composition F (controlled Release composition)

mg/tablet

(a) Active ingredient 500

(b) Hydroxypropyl methylcellulose 112

(Methocel K4M Premium)

(c) Lactose B.P. 53

(d) Povidone B.P.C 28

(e) Magnesium stearate 7

700

The composition can be prepared by wet granulating ingredients (a) to (c) with a povidone solution, then adding magnesium stearate and tabletting.

Composition G (enteric-coated tablet)

Enteric-coated tablets of composition C can be prepared by coating 25 mg/tablet of an enteric polymer such as cellulose acetate phthalate, polyvinyl acetate phthalate, hypromellose phthalate, or methacrylic acid and methyl methacrylate (Eudragit L) anionic polymer. In addition to Eudragit L, these polymers should also include 10% (by weight of the amount of composition used) of a plasticizer to prevent film cracking during use or storage. Suitable plasticizers include diethyl phthalate, tributyl citrate and triacetin.

Composition H (enteric-coated controlled release tablet)

Enteric-coated tablets of composition F can be prepared by coating 50 mg/tablet of an enteric polymer such as cellulose acetate phthalate, polyvinyl acetate phthalate, hypromellose phthalate, or methacrylic acid and methyl methacrylate (Eudragit L) anionic polymer. In addition to Eudragit L, these polymers should also include 10% (by weight of the amount of composition used) of a plasticizer to prevent film cracking during use or storage. Suitable plasticizers include diethyl phthalate, tributyl citrate and triacetin.

(ii) Capsule composition

Composition A

Capsules can be prepared by mixing the ingredients of composition D above and filling the resulting mixture into hard gelatin capsules consisting of two parts. Composition B (infra) can be prepared in a similar manner.

Composition B

mg/capsule

(a) Active ingredient 250

(b) Lactose B.P. 143

(c) Sodium starch glycolate 25

(d) Magnesium stearate 2

420

Composition C

mg/capsule

(a) Active ingredient 250

(b)Macrogol 4000 BP 350

600

Capsules can be prepared by melting Macrogol 4000BP, dispersing the active ingredient in the melt and filling into hard gelatin capsules consisting of two parts.

Composition D

mg/capsule

Active ingredient 250

Lecithin 100

Peanut oil 100

450

Capsules can be prepared by dispersing the active ingredient in lecithin and peanut oil and encapsulating in soft, elastic gelatin capsules.

Composition E (controlled release capsule)

mg/capsule

(a) Active ingredient 250

(b) Microcrystalline cellulose 125

(c) Lactose BP 125

(d) Ethyl cellulose 13

513

The controlled-release capsule formulation can be prepared by extruding the mixed ingredients (a) to (c) with an extruder, followed by spheronization and drying of the extrudate. The dried pellets are coated with a controlled release film (d) and filled into a hard gelatin capsule consisting of two parts.

Composition F (enteric capsule)

mg/capsule

(a) Active ingredient 250

(b) Microcrystalline cellulose 125

(c) Lactose BP 125

(d) Cellulose acetate phthalate 50

(e) Phthalic acid diethyl ester 5

555

The enteric capsule composition can be prepared by extruding the mixed ingredients (a) to (c) with an extruder, followed by spheronization and drying of the extrudate. The dried pellets are coated with a controlled release film (d) containing a plasticizer (e) and filled into a hard gelatin capsule consisting of two parts.

Composition G (enteric-coated controlled release capsule)

Enteric capsules of composition E can be prepared by coating enteric polymers such as cellulose acetate phthalate, polyvinyl acetate phthalate, hypromellose phthalate, or methacrylic acid and methyl methacrylate (Eudragit L) anionic polymers onto 50 mg/capsule of controlled release pellets. In addition to Eudragit L, these polymers should also include 10% (by weight of the amount of composition used) of a plasticizer to prevent film cracking during use or storage. Suitable plasticizers include diethyl phthalate, tributyl citrate and triacetin.

(iii) Intravenous injection composition

Active ingredient 0.200g

Sterile pyrogen-free phosphate buffer (pH 9.0) to 10ml

The active ingredient is dissolved in most phosphate buffer at 35-40 ℃ then the volume is made up and filtered through a sterile microporous filter into sterile 10ml glass vials (type 1) which are sealed with sterile closures (closures) and closures (overheads).

(iv) Intramuscular injection composition

Active ingredient 0.20g

Benzyl alcohol 0.10g

Glycofurol 1.45g

Water for injection q.s. to 3.00ml

The active ingredient is dissolved in glycofurol. Then benzyl alcohol was added and dissolved, and water was added to 3 ml. The mixture was then filtered through a sterile microporous filter and sealed in a sterile 3ml glass vial (type 1).

(v) Syrup composition

Active ingredient 0.25g

Sorbitol solution 1.50g

Glycerol 1.00g

Sodium benzoate 0.005g

0.0125ml of flavoring agent

Pure water q.s. to 5.00ml

Sodium benzoate was dissolved in partially pure water and sorbitol solution was added. The active ingredient is added and dissolved. The resulting solution was mixed with glycerol and then made up to the desired volume with purified water.

(vi) Suppository composition

mg/suppository

Active ingredient 250

Stearin, BP (Witepsol H15-Dynamit NoBel) 1770

2020

One fifth of the Witepsol H15 was melted in a steam-jacketed pan (steam-jacked pan) to the maximum limit at 45 ℃. The active ingredient was sieved through a 2001m sieve and added to the molten matrix with stirring, using a Silverson equipped with a cutting head, until a smooth dispersion was formed. The mixture was maintained at 45 ℃ and Witepsol H15 was added to the suspension and stirred to ensure uniform mixing. The entire suspension was then passed through a 2501m stainless steel sieve, with constant stirring, and cooled to 40 ℃. 2.02g of the mixture are partly filled into suitable plastic moulds at a temperature of 38-40 ℃ and the suppositories are cooled to room temperature.

(vii) Vaginal suppository composition

mg/vaginal suppository

Active ingredient (631m) 250

Anhydrous dextrose 380

Potato starch 363

Magnesium stearate 7

1000

Pessaries are prepared by directly mixing the above ingredients and compressing the resulting mixture.

(viii) Transdermal composition

Active ingredient 200mg

Ethanol USP 0.1ml

Hydroxyethyl cellulose

The active ingredient and ethanol USP were gelled with hydroxyethylcellulose and packaged to a surface area of 10cm²The percutaneous device of (1).

Claims (19)

1. A composition for treating pain comprising a synergistically effective amount of an alpha-2-delta ligand and one or both of a binary 5-hydroxytryptamine-norepinephrine reuptake inhibitor (DSNRI) or a selective 5-hydroxytryptamine reuptake inhibitor (SSRI) and a Selective Norepinephrine Reuptake Inhibitor (SNRI), or a pharmaceutically acceptable salt thereof.

2. A composition according to claim 1 or 2, wherein the α -2- δ ligand is selected from gabapentin, pregabalin, [ (1R, 5R, 6S) -6- (aminomethyl) bicyclo [3.2.0] hept-6-yl ] acetic acid, 3- (1-aminomethyl-cyclohexylmethyl) -4H- [1, 2, 4] oxadiazol-5-one, C- [1- (1H-tetrazol-5-ylmethyl) -cycloheptyl ] -methylamine, (3S, 4S) - (1-aminomethyl-3, 4-dimethyl-cyclopentyl) -acetic acid, (1 α,3 α,5 α) (3-amino-methyl-bicyclo [3.2.0] hept-3-yl) -acetic acid, (3S, 5R) -3-aminomethyl-5-methyl-octanoic acid, (3S, 5R) -3-amino-5-methyl-heptanoic acid, (3S, 5R) -3-amino-5-methyl-nonanoic acid, and (3S, 5R) -3-amino-5-methyloctanoic acid, or a pharmaceutically acceptable salt thereof.

3. A composition according to claim 1 or 2, wherein the α -2- δ ligand is gabapentin.

4. A composition according to claim 1 or 2, wherein the α -2- δ ligand is pregabalin.

5. The composition according to any one of claims 1-4, wherein the α -2- δ ligand is combined with an SSRI or a pharmaceutically acceptable salt thereof.

6. The composition according to any one of claims 1 to 5, wherein the SSRI is selected from the group consisting of sertraline, fluoxetine, fluvoxamine, paroxetine, citalopram, d, 1-fenfluramine, femoxetine, trazodone, cilansylamine, ifenproxtine, cyanodithiazepine and ritoxetine, or a pharmaceutically acceptable salt thereof.

7. A composition according to any one of claims 1 to 6 wherein the SSRI is sertraline.

8. The composition according to any one of claims 1-4, wherein the α -2- δ ligand is combined with the SNRI or a pharmaceutically acceptable salt thereof.

9. The composition according to any one of claims 1-4 and 8, wherein the SNRI is selected from reboxetine, S-reboxetine, desipramine, maprotiline, lofepramine, mianserin, mirtazepine, oxaprotiline, fezolamide, tomoxetine, and buproprion, or a pharmaceutically acceptable salt thereof.

10. The composition according to any one of claims 1-4 and 8-9, wherein the SNRI is selected from maprotiline, desipramine, buproprion, reboxetine and S, S-reboxetine, or a pharmaceutically acceptable salt thereof.

11. The composition according to any one of claims 1-4 and 8-10, wherein the SNRI is S, S-reboxetine, or a pharmaceutically acceptable salt thereof.

12. The composition according to any one of claims 1 to 4, wherein the α -2- δ ligand is combined with DSNRI or a pharmaceutically acceptable salt thereof.

13. A composition according to any one of claims 1 to 4 and 12, wherein the DSNRI is selected from venlafaxine, venlafaxine metabolite O-desmethylvenlafaxine, clomipramine metabolite desmethylclomipramine, duloxetine, milnacipran and imipramine, or a pharmaceutically acceptable salt thereof.

14. A composition according to any one of claims 1-4 and 12-13, wherein the DSNRI is selected from milnacipran, duloxetine and venlafaxine, or a pharmaceutically acceptable salt thereof.

15. A pharmaceutical composition for the therapeutic, prophylactic or palliative treatment of pain, comprising a therapeutically effective amount of a composition according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, and a suitable carrier or excipient.

16. Use of a synergistically effective amount of an alpha-2-delta ligand and a DSNRI or one or both of a SSRI and SNRI, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the therapeutic, prophylactic or palliative treatment of pain.

17. Use according to claim 16, wherein the pain is neuropathic pain.

18. A method for the therapeutic, prophylactic or palliative treatment of pain, in particular neuropathic pain, comprising administering to a mammal in need of such treatment, simultaneously, sequentially or separately, therapeutically synergistically effective amounts of an alpha-2-delta ligand and a DSNRI or one or both of a SSRI and SNRI, or a pharmaceutically acceptable salt thereof.

19. The method according to claim 18, wherein the pain is neuropathic pain.