Combinations containing alpha-2-delta ligands and serotonin/noradrenaline reuptake inhibitors

FIELD: medicine, pharmacy.

SUBSTANCE: invention describes a combination used in therapeutic, prophylactic or palliative treatment of pain. Proposed combination consists of the following components: (a) alpha-2-delta ligand chosen from habapentine, prehabaline, [(1R,5R,6S)-6-(aminomethyl)bicyclo[3.2.0]hept-6-yl]acetic acid, 3-(1-aminomethylcyclohezylmethyl)-4H-[1.2.4]oxadiazol-5-one, C-[1-(1H-tetrazol-5-ylmethyl)cycloheptyl]methylamine, (3S,4S)-(1-aminomethyl-3,4-dimethylcyclopentyl)acetic acid, (1α,3α,5α)-(3-aminomethylbicyclo[3.2.0]hept-3-yl)acetic acid, (3S,5R)-3-aminomethyl-5-methyloctanoic acid, (3S,5R)-3-methylheptanoic acid, (3S,5R)-3-amino-5-methylnonanoic acid and (3S,5R)-3-amino-5-methyloctanoic acid, or pharmaceutically acceptable salts of any of them, and (b) S,S-reboxetine or its pharmaceutically acceptable salt wherein alpha-2-delta ligand and S,S-reboxetine are taken in the range of ratio from 1:10 to 10:1 of mass parts. Proposed combination provides decreasing the dose of each substance that results to declining adverse effects and enhancing clinical utility of compounds. Also, invention describes using this combination and a set comprising this combination.

EFFECT: improved, enhanced and valuable properties of combinations.

8 cl, 3 ex

 

The scope of the invention

The present invention relates to a synergistic combination of alpha-2-Delta ligand and inhibitor reuptake of serotonin-norepinephrine dual action (DSNRI) or one or both of the selective inhibitor of serotonin reuptake (SSRI) and selective inhibitor reuptake noradrenaline (SNRI) for the treatment of pain. It relates also to a method of treating pain by applying effective amounts of the synergistic combinations of alpha-2-Delta ligand and DSNRI or one or both of a SSRI and SNRI.

The level of technology

Ligand receptor alpha-2-Delta is any molecule that is associated with any subtype subunit alpha-2-Delta calcium channel man. Subunit alpha-2-Delta calcium channel includes a number of receptor subtypes, which are described in the literature: for example, N.S.Gee, J.P.Brown, V.U.Dissanayake, J.Offord, R.Thurlow, and G.N.Woodruff, J-Biol-Chem 271 (10):5768-76, 1996, (type 1); Gong, J.Hang, W.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); 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 can also be known as GABA analogues.

The ligands of alpha-2-Delta described for a number of indications. The most well-known ligand alpha-2-Delta, gabapentin (Neurontin®), 1-(aminomethyl)cyclohexyloxy acid, was first described in atento literature in the patent family, including US 4024175. The connection is allowed for the treatment of epilepsy and neuropathic pain.

The second ligand alpha-2-Delta, pregabalin, (S)-(+)-4-amino-3-(2-methylpropyl)batanouny acid described in the published European patent application number EP 641330 as anticonvulsant drugs suitable for the treatment of epilepsy, and EP 0934061 for the treatment of pain.

In addition, international patent application publication WO 0128978 describes a number of new bicyclic amino acids, their pharmaceutically acceptable salts and prodrugs of the formula:

where n is an integer from 1 to 4, in which there are stereocenter, each center independently can represent R or S; the preferred compounds are the compounds of formulas I-IV above, in which n is an integer from 2 to 4.

Later, international patent application publication WO 02/85839 describes the ligands of alpha-2-Delta following formulas:

where R1and R2each independently selected from H, linear or branched alkyl of 1-6 carbon atoms, cycloalkyl from 3 to 6 atoms of carbon is a, phenyl and benzyl, provided that, except in the case tricyclodecane the compounds of formula (XVII), R1and R2are not both hydrogen; for use in therapy for a number of indications, including pain, together with combinations: selective inhibitors of serotonin reuptake, such as fluoxetine, paroxetine, citalopram and sertraline; mixed reuptake inhibitors serotonin-norepinephrine, for example, milnacipram, venlafaxine and DULOXETINE, and selective inhibitors of reuptake of norepinephrine, such as reboxetine.

International patent application number PCT/IB03/00976, unpublished at the filing date of the present invention describes compounds of formula I, below:

where R1represents hydrogen or (C1-C6)alkyl, optionally substituted from one to five fluorine atoms;

R2represents hydrogen or (C1-C6)alkyl, optionally substituted from one to five fluorine atoms; or

R1and R2together with the carbon atom to which they are attached, form a three to six-membered cycloalkyl ring;

R3is a (C1-C6)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl-(C1-C3)alkyl, phenyl, phenyl-(C -C3)alkyl, pyridyl, pyridyl-(C1-C3)alkyl, phenyl-N(H)- or pyridyl-N(H)-, where each of the above alkyl may be optionally substituted by one to five fluorine atoms, preferably with from zero to three fluorine atoms, and where specified phenyl and the pyridyl and phenyl and Peregrina portions of the said phenyl-(C1-C3)alkyl and specified pyridyl-(C1-C3)alkyl may be optionally substituted by substituents from one to three, preferably one, substituents from zero to two, independently selected from chlorine, fluorine, amino, nitro, ceanography, (C1-C3)alkylamino, (C1-C3)alkyl, optionally substituted from one to three fluorine atoms, and (C1-C3)alkoxy, optionally substituted from one to three fluorine atoms;

R4represents hydrogen or (C1-C6)alkyl, optionally substituted from one to five fluorine atoms;

R5represents hydrogen or (C1-C6)alkyl, optionally substituted from one to five fluorine atoms;

R6represents hydrogen or (C1-C6)alkyl;

or its pharmaceutically acceptable salt.

Many types of neurological disorders occur due to disturbances in the supply chain of the brain, which is s transmit signals using specific monoaminergic neurotransmitters. Monoamine neurotransmitters include, for example, serotonin (5-HT), norepinephrine (noradrenaline) and dopamine. These neurotransmitters are moved from the terminal part of the neuron through the small gap (synaptic gap and bind to receptor molecules on the surface of the second neuron. The specified binding causes intracellular changes that initiate or activate a response or a change in the postsynaptic neuron. Inactivation occurs primarily due to transport (i.e. reuptake) of the neurotransmitter back into the presynaptic neuron.

Selective inhibitors of serotonin reuptake (SSRI) act by inhibiting serotonin reuptake afferent neurons. SSRI, well known in the art include, without limitation, sertraline (Zoloft®), a metabolite of sertraline desmethylsertraline, fluoxetine (Prozac®), noruoxetine demetrova metabolite of fluoxetine), fluvoxamine (Luvox®), paroxetine (Seroxat®, Paxil®) and its alternative composition Paxil-CR®, citalopram (Celexa®), a metabolite of citalopram to demethylcitalopram, ESCITALOPRAM (Lexapro®), d,l-fenfluramine (Pondimin®), femoxetine, ifoxetine, cyanidation, litoxetine, priligy generic, nefazodone (Serxone®), cericlamine and trazodone (Dsyrel ®).

Selective inhibitors of reuptake of noradrenaline (or norepinephrine) (SNRI) act by increasing levels of norepinephrine. SNRI, well known in the art include, without limitation, reboxetine (Edronax®and all enantiomers of reboxetine, ie (R/R, S/S, R/S, S/R), desipramine (Norpramin®), maprotiline (Ludiomil®), lofepramine (Gamanil®), mirtazepine (Remeron®), oxaprotiline, Ptolemy, tomoxetin, mianserin (Bolvidon®), buproprion (Wellbutrin®), a metabolite of bupropion hydroxybupropion, nomifensine (Merital®and viloxazine (Vivalan®).

Serotonin reuptake inhibitors serotonin-norepinephrine dual action (DSNRI), which inhibit the reuptake of serotonin and norepinephrine include venlafaxine (Effexor®), a metabolite of venlafaxine On-desmethylvenlafaxine, clomipramine (Anafranil®), a metabolite of clomipramine desmethylclomipramine, DULOXETINE (Cymbalta®), milnacipran and imipramine (Tofranil®or Janimine®).

The contents of all patents and publications cited in this application are incorporated herein as references.

The invention

It is now established that the combination therapy of alpha-2-Delta ligand and inhibitor of serotonin reuptake-Nora is renaline double action (DSNRI) or one or both of the selective inhibitor of serotonin reuptake (SSRI) and selective inhibitor reuptake noradrenaline (SNRI) leads to improvement in the treatment of pain. In addition, while the introduction, sequentially or separately, alpha-2-Delta ligand and DSNRI or one or both of a SSRI and SNRI may act synergistically to combat the pain. The specified synergy allows to reduce the required dose of each compound, reducing side effects and enhancing clinical fitness connection.

Accordingly, the present invention relates, in a first aspect, to the combined product containing alpha-2-Delta ligand and an inhibitor of the reuptake of serotonin-norepinephrine dual action (DSNRI) or one or both of the selective inhibitor of serotonin reuptake (SSRI) and selective inhibitor reuptake noradrenaline (SNRI) or their pharmaceutically acceptable salts, provided that the excluded compounds (i)to(xxv) WO 02/85839 in combination with an inhibitor of serotonin reuptake, especially fluoxetine, paroxetine, citalopram and sertraline, a mixed inhibitor of serotonin reuptake-noradrenaline, especially, milnacipram, venlafaxine and DULOXETINE, and inhibitor reuptake noradrenaline, especially reboxetine.

Alternatively, or in another aspect, the present invention relates to a synergistic combination product containing alpha-2-Delta ligand and DSNRI or one or both of the SSRI SNRI or their pharmaceutically acceptable salts.

Suitable cyclic alpha-2-Delta ligands of the present invention are illustrated by the following formula (I):

where X represents a carboxylic acid or bioisostere carboxylic acids;

n is 0, 1 or 2; and

R1, R1A, R2, R2A, R3, R3A, R4and R4Aindependently selected from H and C1-C6the alkyl, or

R1and R2or R2and R3taken together, form With the3-C7cycloalkyl ring, which is optionally substituted by one or two substituents selected from C1-C6the alkyl, or its pharmaceutically acceptable salt.

In the formula (I), respectively, R1, R1A, R2A, R3A, R4and R4Aare H, and R2and R3independently selected from H and methyl, or R1A, R2A, R3Aand R4Aare H, and R1and R2or R2and R3taken together, form With the3-C7cycloalkyl ring, which is optionally substituted by one or two methyl substituents. Suitable bioisostere carboxylic acid selected from tetrazolyl and oxadiazolyl. X preferably represents a carboxylic acid.

In the formula (I), preferably, R1, R1A, R2A, R3A, R4and R4A are H, and R2and R3independently selected from H and methyl, or R1A, R2A, R3Aand R4Aare H, and R1and R2or R2and R3taken together, form With the4-C5cycloalkyl ring, or, when n is 0, R1, R1A, R2A, R3A, R4and R4Aare H, and R2and R3form cyclopentene ring, or, when n is 1, R1, R1A, R2A, R3A, R4and R4Aare H, and R2and R3both represent methyl, or R1, R1A, R2A, R3A, R4and R4Aare H, and R2and R3form CYCLOBUTANE ring, or, when n is 2, R1, R1A, R2, R2A, R3, R3A, R4and R4Arepresent N, or n is 0, R1, R1A, R2A, R3A, R4and R4Aare H, and R2and R3form cyclopentene ring.

Suitable acyclic alpha-2-Delta ligands of the present invention are illustrated by the following formula (II):

where n is 0 or 1, R1represents hydrogen or (C1-C6)alkyl; R2represents hydrogen or (C1-C6)alkyl; R3represents the waters of the genus or (C 1-C6)alkyl; R4represents hydrogen or (C1-C6)alkyl; R5represents hydrogen or (C1-C6)alkyl and R6represents hydrogen or (C1-C6)alkyl, or its pharmaceutically acceptable salt.

According to the formula (II), respectively, R1represents a C1-C6alkyl, R2represents methyl, R3-R6represent hydrogen, and n is 0 or 1. More suitably, if R1represents methyl, ethyl, n-propyl or n-butyl, R2represents methyl, R3-R6represent hydrogen, and n is 0 or 1. When R2represents methyl, R3-R6represent hydrogen and n is 0, R1accordingly represents ethyl, n-propyl or n-butyl. When R2represents methyl, R3-R6represent hydrogen and n is 1, R1accordingly represents a methyl or n-propyl. The compounds of formula (II) are, respectively, 3S,5R configuration.

Examples of alpha-2-Delta ligands for use in the present invention are compounds, in General or specifically described in US 4024175, particularly gabapentin, EP 641330, especially pregabalin, US 5563175, WO 9733858, WO 9733859, WO 9931057, WO 9931074, WO 9729101, WO 02085839, especially [(1R,5R,6S)-6-(aminomethyl)bizi the lo[3.2.0]hept-6-yl]acetic acid, WO 9931075, especially 3-(1-aminoethylthiomethyl)-4H-[1,2,4]oxadiazol-5-it and C-[1-(1H-tetrazol-5-ylmethyl)cycloheptyl]methylamine, WO 9921824, particularly (3S,4S)-(1-aminomethyl-3,4-dimethylcyclopentene)acetic acid, WO 0190052, WO 0128978, particularly, (1α,3α,5α)(3-aminomethylbenzoic[3.2.0]hept-3-yl)acetic acid, EP 0641330, WO 9817627, WO 0076958, particularly (3S,5R)-3-aminomethyl-5-methyloctanoic acid, PCT/IB03/00976, particularly (3S,5R)-3-amino-5-methylheptanoic acid, (3S,5R)-3-amino-5-methylnonanoic acid and (3S,5R)-3-amino-5-methyloctanoic 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 their pharmaceutically acceptable salts, which are incorporated herein as references.

Preferred alpha-2-Delta ligands of the present invention include gabapentin, pregabalin, [(1R,5R,6S)-6-(aminomethyl)bicyclo[3.2.0]hept-6-yl]acetic acid, 3-(1-aminoethylthiomethyl)-4H-[1,2,4]oxadiazol-on, C-[1-(1H-tetrazol-5-ylmethyl)cycloheptyl]methylamine, (3S,4S)-(1-aminomethyl-3,4-dimethylcyclopentene)acetic acid, (1α,3α,5α)(3-aminomethylbenzoic[3.2.0]hept-3-yl)acetic acid, (3S,5R)-3-aminomethyl-5-methyloctanoic acid, (3S,5R)-3-amino-5-methylheptanoic acid, (3S,5R)-3-amino-5-methylnonanoic acid and (3S,5R)-3-amino-5-methyloctanoic acid or their pharmaceutically acceptable salts. Particularly preferred alpha-2-Delta ligands p the present invention is selected from gabapentin, pregabalin, [(1R,5R,6S)-6-(aminomethyl)bicyclo[3.2.0]hept-6-yl]acetic acid and (1α,3α,5α)(3-aminomethylbenzoic[3.2.0]hept-3-yl)acetic acid or their pharmaceutically acceptable salts.

SSRI suitable for the present invention include an SSRI, is described in US 4536518, i.e. CIS-isomeric compounds of the formula (III):

where R1selected from the group consisting of hydrogen and normal alkyl of 1-3 carbon atoms, R2represents a normal alkyl of 1-3 carbon atoms, Z represents a

X and Y are each selected from the group consisting of hydrogen, fluorine, chlorine, bromine, trifloromethyl, alkoxy of 1-3 carbon atoms and cyano, at least one of X and Y is not hydrogen, and W is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, trifloromethyl and alkoxy of 1-3 carbon atoms, and where the term "CIS-isomer" refers to the relative orientation NR1R2and Z parts on cyclohexenone ring, the specified connection is a (1S)-enantiomer or racemic mixture of (1S)-enantiomer and the corresponding (1R)-enantiomer, or prodrug or pharmaceutically acceptable salt of the specified prodrugs. Especially preferred compound of formula (III) is sertraline.

Examples of an SSRI for use in the present image the structure are compounds in General or specifically described in U.S. 4536518, especially, sertraline, U.S. 4943590 [RE 34712], U.S. 4650884, especially, citalopram, U.S. 3198834, especially d,l-fenfluramine, U.S. 3912743, 4571424, especially femoxetine, U.S. 4314081, 4626549, especially fluoxetine, U.S. 4085225, especially fluoxetine, U.S. 3912743, 4007196, especially paroxetine, ifoxetine, cyanidation and litoxetine, or their pharmaceutically acceptable salts, which are incorporated herein as references.

Suitable SSRI for use in the present invention include sertraline, a metabolite of sertraline desmethylsertraline, fluoxetine, noruoxetine demetrova metabolite of fluoxetine, fluvoxamine, paroxetine and alternative composition Paxil-CR®, citalopram, a metabolite of citalopram to demethylcitalopram, ESCITALOPRAM, d,l-fenfluramine, femoxetine, ifoxetine, cyanidation, litoxetine, priligy generic, nefazodon, cericlamine and trazodone or their pharmaceutically acceptable salts. Preferably, an SSRI is a sertraline or its pharmaceutically acceptable salt.

SNRI suitable for the present invention include compounds described in US 4229449, i.e. the racemates and optical isomers, corresponding to the compound of formula (IV)

preferably, substituted propanolamine and morpholine derivatives corresponding to formula (IV), where

n and n1RA is t, independently 1, 2 or 3;

each of the groups R and R1that may be the same or different, represents hydrogen; halogen; halogen-C1-C6alkyl; hydroxy; C1-C6alkoxy; C1-C6alkyl optionally substituted; aryl-C1-C6alkyl optionally substituted; aryl-C1-C6alkoxy optionally substituted; -NO2;

where R5and R6represent, independently, hydrogen or C1-C6alkyl, or two adjacent groups R or two adjacent groups R1taken together form a radical-O-CH2-O-;

R2represents hydrogen; C1-C12alkyl optionally substituted, or aryl-C1-C6alkyl;

each of the groups R3and R4that may be the same or different, represents hydrogen, C1-C6alkyl optionally substituted With2-C4alkenyl,2-C4quinil, aryl-C2-C4alkyl optionally substituted With3-C7cycloalkyl optionally substituted, or R3and R4together with the nitrogen atom to which they are bound, form pentatomidae or exatamente, saturated or unsaturated, optionally substituted, heterophilically radical, optionally containing d is ot heteroatoms, belonging to the class of O, S and N; or R2and R4taken together form a radical-CH2-CH2-. A preferred compound of formula (IV) is represented by reboxetine.

Examples SNRI for use in the present invention are compounds generically or specifically described in U.S. 4229449, 5068433, 5391735, especially, reboxetine, BP 908788980231, U.S. 3454554, especially desipramine, U.S. 3399201, especially, maprotiline, BP 1177525, U.S. 3637660, especially lofepramine, in the patent application of the Netherlands 6603256, U.S. 3534041, especially, mianserin, U.S. 4062843, especially mirtazapin; U.S. 4314081, 4018895, 4194009, especially tomoxetin, U.S. 4535186, 4611078, especially, venlafaxine, and U.S. 3819706, 3885046, especially, buproprion, and oxaprotiline and Ptolemy, or their pharmaceutically acceptable salts, which are incorporated herein as references.

Specific examples SNRI of the present invention include reboxetine and all enantiomers of reboxetine, ie (R/R, S/S, R/S, S/R), desipramine, maprotiline, lofepramine, mirtazepine, venlafaxine (described in U.S. patent No. 4761501), oxaprotiline, Ptolemy, tomoxetin, mianserin and buproprion, metabolite bupropion hydroxybupropion, nomifensine or viloxazine or their pharmaceutically acceptable salts. Preferably, SNRI is selected from maprotiline, desipramine, bupropion, reboxetine and S,S-reboxetine, or their pharmaceutically acceptable salts.

DSNRI, brightneedle of the present invention, can be illustrated by compounds of formula (V)

where the phenyl ring a and phenyl ring may each be, independently, replaced by naftalina group, and where, when the phenyl ring And is replaced by naftalina group, the ether oxygen of structure I and the carbon atom that is attached to R3, R4and NR1R2attached to adjacent ring carbon atoms naftilos group, and none of these adjacent ring carbon atoms is also adjacent to the carbon atom fused rings specified naftilos group;

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

R1and R2selected, independently, from hydrogen, (C1-C4)alkyl, (C2-C4)alkenyl and (C2-C4)quinil, 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, including the nitrogen atom is attached to R1and R2where the second heteroatom, when present, is selected from oxygen, nitrogen and sulfur, provided that said ring cannot contain two adjacent oxygen atoms or two adjacent sulfur atom, and where the specified ring may be optionally substituted at available binding sites substituents in the number of the one to three, selected, independently, from hydroxy and (C1-C6)alkyl;

R3and R4selected, independently, from hydrogen, (C1-C4)alkyl, optionally substituted from one to three fluorine atoms, or R3and R4together with the carbon atom to which they are attached, form a four to eight-membered saturated carbocyclic ring, where the specified ring may be optionally substituted at available binding sites substituents in the amount of from one to three, selected, independently, from hydroxy and (C1-C6)alkyl;

or R2and R3together with the nitrogen atom that is attached to R2and the carbon atom that is attached to R3form a four to eight-membered saturated ring containing one or two heteroatoms, including the nitrogen atom is attached to R2where the second heteroatom, when present, is selected from oxygen, nitrogen and sulfur, provided that said ring cannot contain two adjacent oxygen atoms or two adjacent sulfur atom, and where the specified ring may be optionally substituted at available binding sites substituents in the amount of from one to three, selected, independently, from hydroxy and (C1-C6)alkyl;

each X is selected, independently, from hydrogen, halogen (i.e. chlorine, fluorine, bromine or iodine), (the 1-C4)alkyl, optionally substituted from one to three fluorine atoms, (C1-C4)alkoxy, optionally substituted from one to three fluorine atoms, cyano, nitro, amino, (C1-C4)alkylamino, di-[(C1-C4)alkyl]amino, NR5(C=O)(C1-C4)alkyl, SO2NR5R6and SOp(C1-C6)alkyl, where R5and R6selected, independently, from hydrogen and (C1-C6)alkyl, and p is zero, one or two; and

each Y is selected, independently, from hydrogen, (C1-C6)alkyl and halogen;

provided that: (a) not more than one NR1R2, CR3R4and R2NCR3may form a ring; and (b) at least one X must not represent hydrogen when (i) R3and R4both represent hydrogen, (ii) R1and R2selected, independently, from hydrogen and (C1-C4)alkyl, and (iii) the ring is In one - or disubstituted, respectively, one or two halogen groups; and their pharmaceutically acceptable salts. The compounds of formula V are described in WO 00/50380.

Suitable DSNRI of the present invention is selected from the venlafaxine metabolite of venlafaxine On-desmethylvenlafaxine, clomipramine, a metabolite of clomipramine desmethylclomipramine, DULOXETINE, milnacipran and imipramine, or their pharmaceutical the ski acceptable salts. Preferred DSNRI of the present invention is selected from milnacipran, DULOXETINE, and venlafaxine, or their pharmaceutically acceptable salts.

The suitability of any particular DSNRI, an SSRI or SNRI can be easily determined by evaluating its effectiveness and selectivity using the methods described in the literature, followed by evaluation of its toxicity, absorption, metabolism, pharmacokinetics, etc. in accordance with conventional pharmaceutical practice.

Alternatively, or in another aspect, the present invention relates to combinations containing gabapentin or its pharmaceutically acceptable salt and DSNRI selected from the venlafaxine metabolite of venlafaxine On-desmethylvenlafaxine, clomipramine, a metabolite of clomipramine desmethylclomipramine, DULOXETINE, milnacipran and imipramine, or one or both of an SSRI selected from sertraline, fluoxetine, fluvoxamine, paroxetine, citalopram, d,l-fenfluramine, femoxetine, trazodone, cericlamine, ifoxetine, cyanidation and litoxetine or their pharmaceutically acceptable salts, and SNRI selected from reboxetine, S,S-reboxetine, desipramine, maprotiline, lofepramine, mianserin, mirtazepine, oxaprotiline, phetolamine, tomoxetine or buproprion or their pharmaceutically acceptable salts, and their pharmaceutically acceptable salts. Especially prefer the other combination includes gabapentin and one of the sertraline, milnacipran, DULOXETINE, venlafaxine, maprotiline, desipramine, bupropion, reboxetine or S,S-reboxetine, and their pharmaceutically acceptable salts.

Alternatively, or in another aspect, the present invention relates to combinations containing pregabalin and DSNRI selected from the venlafaxine metabolite of venlafaxine On-desmethylvenlafaxine, clomipramine, a metabolite of clomipramine desmethylclomipramine, DULOXETINE, milnacipran and imipramine, or in combination with one or both of an SSRI selected from sertraline, fluoxetine, fluvoxamine, paroxetine, citalopram, d,l-fenfluramine, femoxetine, trazodone, cericlamine, ifoxetine, cyanidation and litoxetine or their pharmaceutically acceptable salts, and SNRI selected from reboxetine, S,S-reboxetine, desipramine, maprotiline, lofepramine, mianserin, mirtazepine, oxaprotiline, phetolamine, tomoxetine or buproprion or their pharmaceutically acceptable salts, and their pharmaceutically acceptable salts. Especially preferred combination includes pregabalin and one of the sertraline, milnacipran, DULOXETINE, venlafaxine, maprotiline, desipramine, bupropion, reboxetine or S,S-reboxetine, and their pharmaceutically acceptable salts.

As another alternative, or in another aspect, the present invention relates to the combination, the content is soup (1α ,3α,5α)(3-aminomethylbenzoic[3.2.0]hept-3-yl)acetic acid or its pharmaceutically acceptable salt and DSNRI or one or both of a SSRI and SNRI. Accordingly, the invention relates to combinations containing (1α,3α,5α)(3-aminomethylbenzoic[3.2.0]hept-3-yl)acetic acid or its pharmaceutically acceptable salt and DSNRI selected from the venlafaxine metabolite of venlafaxine On-desmethylvenlafaxine, clomipramine, a metabolite of clomipramine desmethylclomipramine, DULOXETINE, milnacipran and imipramine, or one or both of an SSRI selected from sertraline, fluoxetine, fluvoxamine, paroxetine, citalopram, d,l-fenfluramine, femoxetine, trazodone, cericlamine, ifoxetine, cyanidation and litoxetine or their pharmaceutically acceptable salts, and SNRI selected from reboxetine, S,S-reboxetine, desipramine, maprotiline, lofepramine, mianserin, mirtazepine, oxaprotiline, phetolamine, tomoxetine or buproprion or their pharmaceutically acceptable salts, and their pharmaceutically acceptable salts. A particularly preferred combination comprises (1α,3α,5α)(3-aminomethylbenzoic[3.2.0]hept-3-yl)acetic acid and one of the sertraline, milnacipran, DULOXETINE, venlafaxine, maprotiline, desipramine, bupropion, reboxetine or S,S-reboxetine, and their pharmaceutically acceptable salts.

As one predpochtitelno what about the aspect of the present invention, the selected combination of:

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;

(1α,3α,5α)(3-aminomethylbenzoic[3.2.0]the EPT-3-yl)acetic acid and sertraline;

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

(1α,3α,5α)(3-aminomethylbenzoic[3.2.0]hept-3-yl)acetic acid and DULOXETINE;

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

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

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

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

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

(1α,3α,5α)(3-aminomethylbenzoic[3.2.0]hept-3-yl)acetic acid S,S-reboxetine;

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

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

(3S,4S)-(1-aminomethyl-3,4-dimethylcyclopentene)acetic acid and DULOXETINE;

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

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

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

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

(3S,4S)-(1-aminomethyl-3,4-dimethylcyclopentene)acetic acid and Reba the intranet; and

(3S,4S)-(1-aminomethyl-3,4-dimethylcyclopentene)acetic acid S,S-reboxetine;

or their pharmaceutically acceptable salts.

The combination of the present invention in the form of a single dosage form is suitable for administration to any mammal, preferably human. The introduction can be done once daily (o.d.), twice a day (b.i.d.) or three times a day (t.i.d.), eligible b.i.d. or t.i.d., more suitably, b.i.d., most suitably, o.d.

Thus, in another aspect the present invention relates to the use of a combination, especially a synergistic, alpha-2-Delta ligand and DSNRI or one or both of a SSRI and SNRI for the manufacture of a medicinal product that is administered one, two, or three, suitably, two or three, more suitably, the two most eligible, once a day, for therapeutic, prophylactic or palliative treatment of pain.

Alternatively, the present invention relates to a method of therapeutic, prophylactic or palliative treatment of pain in a mammal, comprising introducing one, two, or three, suitably, two or three, more suitably, the two most eligible, once per day, effective, particularly synergistic combination of alpha-2-Delta ligand and DSNRI or one or both of a SSRI and SNRI.

To determine the synergistic interaction between one and the and more components, you can finally measure the optimal limits to achieve the effect and the absolute limits of doses of each component to achieve the effect through the introduction of components in various limits mass ratios and doses to patients who need treatment. For people complexity and high cost of conducting clinical trials on patients makes impractical the use of the above forms of testing as the primary model of synergism. However, the observation of synergy on a single form may have prognostic significance in effect for other species, and there are models in animals, as described herein, for measuring a synergistic effect, and the results of such studies can also be used to predict the effective limits of the ratios of doses and concentrations in plasma, as well as the absolute doses and concentrations in plasma, which require other types, through the use of pharmacokinetic/pharmacodynamic methods. The established correlation between animal models and effects observed in humans, suggest that the synergism for animals best demonstrated using static and dynamic measurements allodynia on rodents, which made surgical (for example, damage to chronic compression) and the chemical treatments (e.g., streptozocin) to induce allodynia. Due to the effects of the plateau on the specified models of their value better evaluate from the point of view of the synergistic interactions that patients with neuropathic pain will be transformed into the advantages of reducing the dose. Other models that existing agents used to treat neuropathic pain, give only a partial answer, more suitable for prediction of potential combinations, acting synergistically, to obtain high maximum efficiency at the maximum-tolerated doses of the two components.

Thus, in another aspect the present invention relates to a synergistic combination for administration to humans comprising an alpha-2-Delta ligand and one of the DSNRI, an SSRI or SNRI, or their pharmaceutically acceptable salts, within mass combinations, which correspond to the absolute limits observed on the model, not a person, preferably a rat model, which is mainly used for the identification of synergies. Accordingly, the limits of the ratios for the person comply with the limits for animals that are not human, selected from: from 1:50 to 50:1 mass parts, from 1:50 to 20:1, from 1:50 to 10:1 from 1:50 to 1:1, from 1:20 to 50:1, from 1:20 to 20:1, from 1:20 to 10:1 from 1:20 to 1:1, from 1:10 to 50:1, from 1:10 to 20:1, from :10 to 10:1, from 1:10 to 1:1, from 1:1 to 50:1, from 1:1 to 20:1 and 1:1 to 10:1. More suitably, if the limits for a person comply with the limits for a model, not a man, from 1:10 to 20:1 mass parts. Preferably, the limits for human synergistic match with the limits for a model, not a person, on the order of from 1:1 to 10:1 mass parts.

For a person, you can use several experimental models of pain in humans to demonstrate that agents with confirmed synergism on animals also have an effect on people, consistent with the specified synergies. Examples of models on the people who may be suitable for this purpose include the model of the heat/capsaicin (Petersen K.L. & M.C. Rowbotham (1999) NeuroReport 10, 1511-1516), model capsaicin i.d. (Andersen O. L., Felsby s, Nicolaisen L., Bjerring P., Jsesn T.C. & Arendt-Nielsen L. (1996) Pain 66, 51-62), including the use of re-injury by capsaicin (Witting N., Svesson P., Arendt-Nielsen L. & Jensen T.S. (2000) Somatosensory Motor Res. 17, 5-12) and the summation of the reactions of the nervous excitation (Curatolo M. et al. (2000) Anesthesiology 93, 1517-1530). When using these models can be used as the final results of the subjective assessment of pain intensity or areas of hyperalgesia or you can use a more objective outcomes, based on electrophysiological or imaging technologies such as functional magnetic resonator is SNA visualization) (Bornhovd K, Quante m, Glauche V, Bromm b, Weiller C. & Buchel C. (2002) Brain 125, 1326-1336). All such models require data about objective correctness before you can conclude that they provide data in humans, confirming the synergistic action of the combination, which was observed in animal studies.

To use the present invention for a person appropriate limits of the ratios of alpha-2-Delta ligand:DSNRI, an SSRI or SNRI choose from the following ratio: from 1:50 to 50:1 mass parts, from 1:50 to 20:1, from 1:50 to 10:1 from 1:50 to 1:1, from 1:20 to 50:1, from 1:20 to 20:1, from 1:20 to 10:1 from 1:20 to 1:1, from 1:10 to 50:1, from 1:10 to 20:1, from 1:10 to 10:1 from 1:10 to 1:1, from 1:1 to 50:1, from 1:1 to 20:1 and 1:1 to 10:1, more suitably from 1:10 to 20:1, preferably from 1:1 to 10:1.

The optimal dose for each component for synergism can be defined using published procedures on experimental animals. However, for people (even in experimental models of pain) cost studies to determine the full extent of the relationship of exposure-response for all therapeutically relevant doses of each component of the combination can be very high. It may be necessary, at least initially, to assess whether it is possible to observe the effects that correspond to the synergies, in doses that were extrapolated on the basis of doses, provided that the protected area is maximum synergies in animals. In terms of doses to animals at doses to humans must take into account such factors as the relative measure of body weight/surface area, the relative absorption, distribution, metabolism and excretion of each component and the relative binding plasma proteins, and, for these reasons, the optimal dose ratio predicted for a man (and patients), is unlikely to be the same as the ratio of doses, optimal for animals. However, the relationship between the two indicators can understand and calculate a specialist in the field of pharmacokinetics in animals and humans. To establish links between effects in animals and humans are important in plasma concentrations obtained for each component used in experiments on animals, as these parameters are associated with the plasma concentration of each component, which, as should be expected to be effective for the individual. Pharmacokinetic/pharmacodynamic modeling (including such techniques as isobologram, the index of interaction and modeling of the response surface) and simulation can help in predicting synergistic ratios of doses in humans, especially in the case when one of these components, or both have already been studied in humans.

It is important to find out, p is oshodi whether any synergies, observed in animals or in humans, only due to pharmacokinetic interactions. For example, inhibition of the metabolism of one connection to others can create a false impression of pharmacodynamic synergism.

Thus, according to another feature, the present invention relates to a synergistic combination for administration to humans, containing alpha-2-Delta ligand and DSNRI and one or both of a SSRI and SNRI or their pharmaceutically acceptable salts in which the ratio of doses of each component corresponds to the absolute limits, which are observed on the model, not a person, preferably a rat model, which is primarily used for the identification of synergies.

Accordingly, the dose of alpha-2-Delta ligand for use in humans is in the range selected from 1-1200 mg, 1-500 mg, 1-100 mg, 1-50 mg, 1-25 mg, 500-1200 mg, 100-1200 mg 100-500 mg, 50-1200 mg 50-500 mg, or 50 to 100 mg; suitably, 50-100 mg, b.i.d. or t.i.d., suitably, t.i.d., as the dose of an SSRI and/or SNRI is within selected from 1-200 mg, 1-100 mg, 1-50 mg, 1-25 mg, 10-100 mg, 10-50 mg or 10-25 mg, suitably, 10-100 mg, b.i.d. or t.i.d., suitably, t.i.d.

The specialist will be clear that the limits of the concentrations in plasma of combinations of alpha-2-Delta ligand and DSNRI and one or both of a SSRI and SNRI in the present invention, which are required for therapeu the practical effect, depends on the species, which is treated and used components. For example, for gabapentin in the rat Cmax values ranged from 0,520 μg/ml to 10.5 µg/ml.

It is possible, using conventional PK/PD and allometric methods to extrapolate values in plasma concentrations that are observed in experimental animals to predict values in other species, especially humans.

Thus, according to another aspect, the present invention relates to a synergistic combination for administration to humans, containing alpha-2-Delta ligand and DSNRI and one or both of a SSRI and SNRI, in which the limits of the concentrations in plasma of each component corresponds to the absolute limits, which are observed on the model, not a person, preferably a rat model, which is primarily used for the identification of synergies. Accordingly, the limits of the concentrations in plasma to humans are within the limits of 0.05 μg/ml to 10.5 µg/ml for alpha-2-Delta ligand for rat model.

Particularly preferred combinations of the present invention include combinations in which each variable combination selected from the right settings for each variable. Even more preferred combinations of the present invention include combinations in which each variable is I the combination selected from more appropriate, most suitable, preferred or more preferred options for each variable.

Detailed description of the invention

Compounds of the present invention is produced by methods well known in the art. Specifically, patents, patent applications and publications mentioned in this document, each of which is incorporated herein by reference, provide examples of compounds that can be used in the combinations, pharmaceutical compositions, methods and kits in accordance with the present invention, and refer to methods of producing such compounds.

Compounds in combination according to the present invention may exist in resolutiony forms, as well as in solvated forms, including hydrated forms. In General, the solvated forms, including hydrated forms, which may contain isotopic substitution (e.g., D2O, d6-acetone, d6-DMSO)are equivalent nonsolvated forms and are included in the scope of the present invention.

Some of the compounds of the present invention have one or more chiral centers and each center may exist in the R - or S-configuration. The present invention includes all enantiomeric and epimeria forms, as well as their inherent mixture. Division of diastereoisomers or CIS - Frans-isomers can be accomplished using conventional techniques, for example, by fractional crystallization, chromatography or HPLC stereoisomeric mixtures of compounds of the present invention or a suitable salt or derivative.

The number of alpha-2-Delta ligands of the present invention are amino acids. Since amino acids are amphoteric, pharmacologically compatible salts can be salts of suitable non-toxic inorganic or organic acids or bases. Suitable acid additive salts are salts of acetate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulfate, camsylate, citrate, Etisalat, Eilat, fumarate, gluceptate, gluconate, glucuronate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, phosphate, isetionate, D - and L-lactate, malate, maleate, malonate, mesilate, methyl sulfate, 2-napsylate, nicotinate, nitrate, orotate, palmoate, phosphate, saharat, stearate, succinate, sulfate, D - and L-tartrate and toilet. Suitable basic salts are formed from bases which form non-toxic salts and examples are the salts of sodium, potassium, aluminum, calcium, magnesium, zinc, choline, diolamine, alumina, arginine, glycine, tromethamine, benzathine, lysine, meglumine and diethylamine. Salt with Quaternary ammonium ions can also be obtained, for example, ion of Tetramethylammonium. Compounds of the present invention also m which may be formed as zwitterion.

Suitable salts of amino acid compounds of the present invention is the hydrochloride salt. An overview of suitable salts, see Stahl and Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection, and Use, Wiley-VCH, Weinheim, Germany (2000).

Also in the scope of the present invention includes clathrates, connections enable drug-recipient, in which, unlike the above-mentioned solvate, medicine and the recipient is present in non-stoichiometric amounts. An overview of these connections, see J. Pharm. Sci., 64(8), 1269-1288, Haleblian (August 1975).

In this document, all references to compounds of the present invention include links to their salts and solvate and clathrate compounds of the present invention and their salts.

Also in the scope of the present invention included polymorphs of the compounds of the present invention.

Prodrugs of the compounds of the present invention is included in the scope of the present invention. Chemically modified drug or prodrug should have other than the parent compounds pharmacokinetic profile, allowing for easier absorption across the epithelium of the mucous membranes, the best education salts and/or solubility, improved system stability (for example, to increase half-life existence in the plasma). These chemical modifications which may be represented as:

(1) Ester or amide derivative, which can be split, for example, esterases or lipases. In the case of ester derivatives, ester obtained from part of the carboxylic acid molecule drugs known methods. In the case of amide derivatives, amide can be obtained from part of the carboxylic acid or amine portion of the molecule drugs known methods.

(2) Peptides that can be recognized by specific or nonspecific proteases. The peptide can be attached to the molecule drugs through the formation of amide bond with the amine part or a part of the carboxylic acid molecule drugs known methods.

(3) Derivatives that accumulate at the site of action through membrane selection proletarienne form or modified proletarienne form.

(4) Any combination of from 1 to 3.

The aminoacyl-glycolic and dairy esters known as prodrugs of amino acids (C.G. Wermuth, Chemistry and Industry, 1980:433-435). The carbonyl group of amino acids can be esterified by known methods. Prodrugs and soft drugs known to specialists (E. Palomino, Drugs of the Future, 1990; 15(4):361-368). The last two source incorporated herein by reference.

The combination of this image is the shadow is suitable for General treatment of pain, especially neuropathic pain. Physiological pain is an important protective mechanism aimed at warning about the danger of potentially damaging stimuli coming from the external environment. The system operates through a specific number of primary sensitive neurons and is activated by noxious stimuli through peripheral transformative mechanisms (review Millan, 1999 Prog. Neuribio. 57:1-164). These sensory fibers known as nociceptors and are characterized by the presence of axons of small diameter low speeds. The nociceptors encode the intensity, duration and quality of harmful irritant and, through their topographically organized projections to the spinal cord, the localization of the stimulus. The nociceptors are found in nociceptive nerve fibers that exist in two main types, A-Delta fibers (moulinsiana) and fiber (demyelination). The activity generated nociceptor input is transferred after complex processing in the dorsal horn, directly or through relay nuclei of the brain stem, in ventro-basal thalamus, and then to the cortex, where it generates the sensation of pain.

Intense acute pain and chronic pain may involve the same way, managed pathophysiologic processes, and, as ekovich, to cancel the provision of protective mechanism and, instead, to contribute to obessolivanie symptoms associated with a wide range of painful conditions. Pain is a symptom of many traumatic and painful conditions. With significant damage to tissues in the body through disease or injury characteristics nociceptor activation change. Is sensitization on the periphery, locally around damage and Central, where the nociceptors end. This leads to hypersensitivity to the injury site and in nearby normal tissue. Acute pain of these mechanisms can be useful and allow you to happen to the processes of recovery and hypersensitivity returns to normal after healing the damage. However, many chronic pain hypersensitivity lasts much longer than the healing process, and it usually occurs as a result of damage to the nervous system. The specified damage often leads to poor adaptation of afferent fibers (Woolf &Salter 2000 Science 288:1765-1768). Clinical pain occurs when the discomfort and abnormal sensitivity are the hallmark of the patient's symptoms. The composition of patients is quite diverse, and they can be a variety of pain symptoms. There are a number of obecnych subtypes of pain: 1) spontaneous pain, which may be dull, burning, or pricking; 2) pain response to noxious stimuli are excessive (hyperalgesia); 3) pain is caused by stimuli that normally are harmless (allodynia) (Meyer et al., 1994 Textbook of Pain 13-44). Although patients with back pain, arthritic pain, CNS injury or neuropathic pain can have similar symptoms, underlying pain mechanisms may vary and, therefore, may require different treatment strategies. Thus, pain can be divided into a number of different areas due to differing pathophysiology, including nociceptive, inflammatory, neuropathic pain, etc. it Should be noted that some types of pain have multiple etiology and, therefore, can be classified in more than one area, for example, back pain, pain in malignant tumors have both nociceptive and neuropathic components.

Nociceptive pain causes tissue damage or intense stimulus, which could potentially cause damage. Afferent paths of pain are activated by the conversion of stimuli by nociceptors at the site of injury and sensibiliser the spinal cord at the level of its end. It is then passed up through spinal pathways in the brain where pain is perceived (Meyer et al., 1994 Textbook of Pain 13-44). The act is vazia of nociceptors activates two types of afferent nerve fibers. Moulinsiana fiber And a-Delta carry out fast and are responsible for sensations of sharp and pricking pain, while demyelination fibers perform slower conduct and are responsible for the feeling dull or aching pain. Acute nociceptive pain from moderate to severe is the visible sign, but without limiting the pain from strain/sprains, post-operative pain (pain after surgical procedures of any type), post-traumatic pain, burns, myocardial infarction, acute pancreatitis, and renal colic. Also associated with malignant tumors acute pain syndromes usually occur as a result of therapeutic interactions, such as chemotherapeutic toxicity, immunotherapy, hormonal therapy and radiation therapy. Acute nociceptive pain from moderate to severe is the visible sign, but without limitation, pain in malignant tumors, which can be a pain associated with the tumor (for example, bone pain, headache and facial pain, visceral pain)or pain associated with therapy of malignant tumors (e.g., paschimotanasana syndromes, syndromes of chronic postsurgical pain syndromes after irradiation), back pain, which may appear as a result of a hernia or damage Meepo vanocni drive or pathology of the joints of the lumbar, the sacroiliac joints, paraspinal muscles or the posterior longitudinal ligament.

Neuropathic pain is defined as pain initiated or caused by a primary lesion or dysfunction of the nervous system (IASP definition). Nerve damage can be caused by injury and disease, and, thus, the term "neuropathic pain" covers many disorders of different etiology. They include, without limitation, diabetic neuropathy, post herpetic neuralgia, back pain, neuropathy in malignant tumors, the neuropathy in HIV infection, phantom pain in extremities, carpal tunnel syndrome, chronic alcoholism, hypothyroidism, trigeminal neuralgia, uremia or deficits of vitamins. Neuropathic pain is pathological, since it does not play a protective role. She often takes place after the disappearance of its cause, usually lasts for years, significantly impairing the quality of life of patients (Woolf and Mannion 1999 Lancet 353:1959-1964). Symptoms of neuropathic pain are difficult to treat because they are often heterogeneous even in patients with the same disease (Woolf & Decosterd 1999 Pain Supp.6:S141-S147; Woolf and Mannion 1999 Lancet 353:1959-1964). They include spontaneous pain, which may be continuous or paroxysmal, and pain caused by an unusual way, such as the guy who analgesia (increased sensitivity to a noxious stimulus) and allodynia (sensitivity to stimulus, harmless in normal).

The inflammatory process is a complex series of biochemical and cellular events that are activated in response to tissue damage or presence of foreign substances, which leads to swelling and pain (Levine and 1994 by Taiwo on: Textbook of Pain 45-56). Arthritic pain is a major part of the population of inflammatory pain. Rheumatoid disease is one of the most common chronic inflammatory conditions in developed countries, while rheumatoid arthritis is a common cause of disability. The exact etiology of RA is unknown, but the current hypotheses suggest that an important role can play both genetic and microbiological factors (Grennan & Jayson 1994 Textbook of Pain 397-407). It has been estimated that almost 16 million Americans have clinically significant osteoarthritis (OA) or degenerative joint disease, the age of most of them over 60 years, and it is expected that this number will increase to 40 million due to aging of the population, making this a public health problem of enormous magnitude (Houge & Mersfelder 2002 Ann. Pharmacother. 36:679-686; McCarthy et al., 1994 Textbook of Pain 387-395). The majority of patients with OA seek medical assistance in connection with the pain. Arthritis has a significant impact on the physiological and physical function and is known to be the leading being the Noah disability in later life. Other types of inflammatory pain include, without limitation, inflammatory bowel disease (IBD).

Other types of pain include, without limitation:

muscular-skeletal disorders, including, without limitation, myalgia, fibromyalgia, spondylitis, seronegative (primatine) arthropathies, sustavnoi rheumatism, dystrophinopathy, glycogenolysis, polymyositis, pyomyositis;

Central pain or thalamic pain"that determines the pain caused by damage to or dysfunction of the nervous system, including, without limitation, Central post-stroke pain, multiple sclerosis, spinal cord injury, Parkinson's disease and epilepsy;

- heart and vascular pain, including, without limitation, angina, myocardial infarction, phenomenon, Raynaud's disease, scleredema, ischemia of skeletal muscles;

- visceral pain and gastrointestinal disorders. Internal organs include the abdominal organs. These bodies include the genitals, spleen and part of the digestive system. The pain associated with internal organs, can be divided into a pain in the digestive organs and sore bodies, not related to the digestive system. Common gastrointestinal (GI) disorders include functional bowel disorders (FBD) and inflammatory bowel disease (IBD). These GI disorders include a broad range over the United States, currently only partly controlled, including - in the case of FBD, gastro-esophageal reflux, dyspepsia, irritable bowel syndrome (IBS) syndrome and functional abdominal pain (FAPS), and, in the case of IBD, Crohn's disease, REIT and ulcerative colitis, which regularly cause visceral pain. Other types of visceral pain include the pain associated with dysmenorrhea, pelvic pain, cystitis and pancreatitis;

headache, including, without limitation, migraine, migraine with aura, migraine without aura, headaches, headache type voltage;

the Oro - facial pain, including, without limitation, dental pain, temporomandibular myofascial pain.

The combination of the present invention is also suitable for the treatment of urinary incontinence, such as genuine stress incontinence (GSI), stress urinary incontinence (SUI) or urinary incontinence in older individuals; an overactive bladder (OAB), including idiopathic detrusor instability, hyperactivity of the detrusor, secondary to neurological diseases (such as Parkinson's disease, multiple sclerosis, spinal cord injury and stroke), and hyperactivity of the detrusor, secondary to obstruction of the outflow from the bladder (for example, benign prostatic hyperplasia (national Department of standardization, stricture or stenosis of the urethra); nocturnal enuresis; incontinence of urine due to a combination of the above conditions (for example, the true stress incontinence associated with overactive bladder and urinary symptoms such as frequency and urgentely.

The combination is also suitable for the treatment of fecal incontinence.

In another aspect the present invention relates to the use of alpha-2-Delta ligand and DSNRI or one or both of a SSRI and SNRI, provided that the excluded compounds (i)to(xxv) WO 02/85839 in combination with an inhibitor of serotonin reuptake, especially fluoxetine, paroxetine, citalopram and sertraline, a mixed inhibitor of the reuptake of serotonin, norepinephrine, especially, milnacipram, venlafaxine and DULOXETINE, and inhibitor reuptake noradrenaline, especially, reboxetine, for the production of medicinal products for therapeutic, prophylactic or palliative treatment of pain, especially neuropathic pain.

As an alternative feature, the invention relates to the use of a synergistic effective amount of alpha-2-Delta ligand and DSNRI or one or both of a SSRI and SNRI for the production of medicinal products for therapeutic, prophylactic or palliative treatment of pain, especially neuropathic pain.

In quality the ve alternative features of the invention relates to a method of therapeutic, prophylactic or palliative treatment of pain, particularly neuropathic pain, comprising simultaneous, sequential or separate introduction of a therapeutically effective amount of alpha-2-Delta ligand and DSNRI or one or both of the SSRI and the SNRI mammal that needs specific treatment, provided that excluded combinations described in WO 02/85839, i.e. the compound of formula (i)to(xxv) in combination with an inhibitor of serotonin reuptake, especially fluoxetine, paroxetine, citalopram and sertraline, a mixed inhibitor of the reuptake of serotonin, norepinephrine, especially, milnacipram, venlafaxine and DULOXETINE, and inhibitor reuptake noradrenaline, especially reboxetine.

As an alternative particularly the invention relates to a method of therapeutic, prophylactic or palliative treatment of pain, particularly neuropathic pain, comprising simultaneous, sequential or separate introduction therapeutically synergistic amount of alpha-2-Delta ligand and DSNRI or one or both of the SSRI and the SNRI mammal that needs specific treatment.

The biological activity of alpha-2-Delta ligands of the present invention can be measured by analyzing the binding of radioligand with the use of [3H]gabapentin and subjeci the Itza α 2δobtained from brain tissue of pigs (Gee N.S., Brown JP, Dissanayake V.U.K., Offord j, Thurlow R, G.N. Woodruff, J. Biol. Chem., 1996; 271:5879-5776). The results can be expressed as µm or nm α2δ binding affinity.

The ability of the compounds of the present invention to act as selective inhibitors of serotonin reuptake can be measured in vivo in accordance with established procedures, for example, according to example 68 US 4536518.

The ability of the compounds of the present invention to act as inhibitors of reuptake of serotonin-norepinephrine dual action or selective inhibitors of reuptake of norepinephrine can be measured in accordance with established procedures, especially in accordance with the documents mentioned above in this document.

The elements of a combination according to the present invention can be entered separately, simultaneously or sequentially, for the treatment of pain. A combination is also possible, optionally, to enter with one or more other pharmacologically active agents. Suitable optional agents include:

(i) opioid analgesics, such as morphine, heroin, hydromorphone, Oxymorphone, Levorphanol, levallorphan, methadone, meperidine, fentanyl, cocaine, codeine, Dihydrocodeine, oxycodone, hydrocodone, propoksifen, nalmefene, nalor is in, naloxone, naltrexone, buprenorphine, butorphanol, nalbuphine and pentazocine;

(ii) non-steroidal anti-inflammatory drug (NSAID)such as aspirin, diclofenac, diflunisal, etodolac, fenbufen, fenoprofen, flufenisal, flurbiprofen, ibuprofen, indometacin, Ketoprofen, Ketorolac, meclofenamic acid, mefenamico acid, nabumetone, naproxen, oxaprozin, phenylbutazone, piroxicam, sulindac, tolmetin, zomepirac and their pharmaceutically acceptable salts;

(iii) barbiturate sedatives, for example, amobarbital, aprobarbital, butabarbital, butalbital, mephobarbital, metharbital, methohexital, pentobarbital, phenobarbital, secobarbital, talbutal, SEAMILL, thiopental and their pharmaceutically acceptable salts;

(iv) benzodiazepines possess sedative action, such as chlordiazepoxide, clorazepate, diazepam, flurazepam, lorazepam, oxazepam, temazepam, triazolam and their pharmaceutically acceptable salts;

(v) H1antagonists having a sedative action, e.g. diphenhydramine, pyrilamine, promethazine, chlorpheniramine, chlorcyclizine and their pharmaceutically acceptable salts;

(vi) mixed sedatives, such as glutethimide, meprobamate, methaqualone, dichloralphenazone and their pharmaceutically acceptable salts;

(vii) skeletal muscle relaxants, such as baclofen, carisop is odol, chlorzoxazone, cyclobenzaprine, Methocarbamol, Grenadin and their pharmaceutically acceptable salts;

(viii) the NMDA receptor antagonists, such as dextromethorphan ((+)-3-hydroxy-N-methylmorphinan) and its metabolite dextrorphan ((+)-3-hydroxy-N-methylmorphinan), ketamine, memantine, pyrroloquinoline and CIS-4-(phosphonomethyl)-2-piperidinecarbonitrile acid and their pharmaceutically acceptable salts;

(ix) alpha-adrenergic active compounds, for example, doxazosin, tamsulosin, clonidine and 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydrothieno-2-yl)-5-(2-pyridyl)hinzelin;

(x) tricyclic antidepressants, such as desipramine, imipramine, amitriptyline, and nortriptyline;

(xi) anticonvulsants, such as carbamazepine and valproate;

(xii) antagonists tachykinin (NK), particularly NK-3, NK-2 and NK-1, for example, antagonists, (αR,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9,10,11-tetrahydro-9-methyl-5-(4-were)-7H-[1,4]thiazocine[2,1-g][1,7]nightrider-6-13-dione (TAK-637), 5-[[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy-3-(4-forfinal)-4-morpholinyl]methyl]-1,2-dihydro-3H-1,2,4-triazole-3-one (MK-869), lapitan, dapitan and 3-[[2-methoxy-5-(triptoreline)phenyl]methylamino]-2-phenylpiperidine (2S,3S);

(xiii) muscarinic antagonists, for example, oxybutin, tolterodine, propiverine, Tropea chloride, darifenacin;

(xiv) inhibitors SOH-2, for example, celecoxib, rofecoxib and valdecoxib;

(xv) non-selective inhibitors MOR (preferably with protection GI), for example, nitroprussiate (HCT-1026);

(xvi) coal analgesics, in particular, paracetamol;

(xvii) a neuroleptic such as droperidol;

(xviii) agonists vanilloid receptors, for example, resiniferatoxin;

(xix) beta-adrenergic compounds such as propranolol;

(XX) local anesthetics, such as meksiletin;

(xxi) corticosteroids, such as dexamethasone;

(xxii) agonists and antagonists of serotonin receptors;

(xxiii) cholinergic (nicotinic) analgesics;

(xxiv) mixed agents such as Tramadol®;

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

The present invention relates to a product comprising an alpha-2-Delta ligand, DSNRI or one or both of a SSRI and SNRI and one or more other therapeutic agents, such as listed above, for simultaneous, separate or sequential use for therapeutic, prophylactic treatment of pain, especially neuropathic pain.

The combination of the present invention can be entered separately, but one or both will usually enter into the mixture with a suitable pharmaceutical excipient (fillers), diluent (solvent) or carrier (s)selected taking into account the planned put the administration and standard pharmaceutical practice. If you want, you can add auxiliary substances. Excipients are preservatives, antioxidants, corrigentov or dyes. Compounds of the present invention can be released for immediate, delayed, modified, weak pulse or controlled type.

The elements of a combination according to the present invention can be entered, for example, without limitation, in the following way: oral, transbuccal or sublingually in the form of tablets, capsules, multi - and nanoparticles, gels, films (including mucoadhesive), powder, oval, elixirs, cakes (including fluid-filled), chewable tablets, solutions, suspensions and sprays. Compounds of the present invention can also be entered in the form of an osmotic dosage form, or in the form of high-energy dispersion or particles with a coating or in the form of quick-dissolving, fast-disintegrating dosage forms, as described in Ashley Publications, 2001, Liang and Chen. Compounds of the present invention can be introduced in the form of crystalline or amorphous products, freeze-dried or dried using spray drying products. Suitable compositions of the compounds of the present invention can be hydrophilic or hydrophobic matrix, the complex ion-exchange resin, in the form of coating is or uncoated and other types as described in US 6106864, if desired. 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 starch or tapioca starch), mannitol, disintegrating agents, such as glycolate, sodium starch, sodium croscarmellose, and certain complex silicates, and a binder for granulating agents, such as polyvinylpyrrolidone, hypromellose (receiver array), triglycerides, hydroxypropylcellulose (LDCs), bentonite, sucrose, sorbitol, gelatin and Arabic gum. In addition, the solid compositions can be added lubricating agents such as magnesium stearate, stearic acid, glycerinated, PEG and talc, or moisturizing agents, such as sodium lauryl sulfate. In addition, you can include polymers, such as carbohydrates, phospholipids and proteins.

Dosage forms with fast dispersing or fast-dissolving (FDDF) may contain the following ingredients: aspartame, Acesulfame potassium, citric acid, sodium-croscarmellose, crosspovidone, desorbing acid, acrylate, ethylcellulose, gelatin, hypromellose, magnesium stearate, mannitol, methyl methacrylate, mint corrigent, polietilenglikol the ü, fine silicon dioxide, silicon dioxide, glycolate, sodium starch, sodium fumarate, sorbitol or xylitol. The terms "dispersion" or "dissolution"as used herein to describe FDDF depend on the solubility of the used medicinal substances, i.e. when the medicinal substance is insoluble, it is possible to manufacture the dosage form with the rapid dispersion, and when the medicinal substance is soluble, it is possible to produce a formulation with rapid dissolution.

Solid dosage forms such as tablets, manufactured using a standard process, for example, direct compression or wet, dry granulation or pelletization of the melt, freeze and melt extrusion. At the core of the tablets, which can be single - or multilayer, can apply a suitable coating, known to specialists.

Solid compositions of a similar type may also be used for filling capsules, such as gelatin, starch or receiver array capsules. Preferred excipients in this regard include lactose, starch, cellulose, milk sugar or high molecular weight polyethylene glycols. Liquid compositions can be used for filling soft or hard capsules, such as gelatin capsules. For water or wt is anyh suspensions, solutions, syrups and/or elixirs, the compounds of the present invention can be combined with various sweetening or korrigentami, colouring matter or dyes, with emulsifying and/or suspendresume 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, compositions containing these compounds and fillers, can be presented as a dry product for reconstitution with water or other suitable media before use.

Liquid preparations include solutions, suspensions and emulsions, for example, solutions in water or in water and propylene glycol. For parenteral injection, liquid preparations can be produced in an aqueous solution of polyethylene glycol. Aqueous solutions suitable for oral administration, can be produced by dissolving the active component in water and adding suitable colorants, corrigentov, stabilizing and thickening agents as desired. Aqueous suspensions suitable for oral administration, can be produced by dispersing finely ground active component in water with viscous material such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose others well known suspendresume agents.

The elements of a combination according to the present invention can also be administered by injection, i.e. intravenously, intramuscularly, intradermally, intraduodenal or IPR, intraarterial, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intraspinal or subcutaneously, or they can be administered by infusion, the needleless injectors or with use of methods of injection of the implant. For the specified injecting them best used in the form of a sterile aqueous solution, suspension or emulsion (or system, which may include micelles), which may contain other substances known in the art, for example, salt or carbohydrates such as glucose, in a quantity sufficient to give the solution isotonicity with respect to blood. Aqueous solutions should contain an appropriate amount of buffer (preferably to a pH of from 3 to 9), if necessary. For some forms of parenteral administration, they can be used in the form of a sterile non-aqueous systems, such as non-volatile oils, including mono - or diglycerides, and fatty acids, including oleic acid. Fabrication of suitable compositions for parenteral administration in sterile conditions, for example, lyophilization, it is easy to implement using standard pharmaceutical techniques well known in the art. Alternatively, the active ingredient may be in powder form for reconstitution with a suitable carrier (e.g. sterile pyrogen-free water) before use.

Also the elements of a combination according to the present invention it is possible to enter intranasally or by inhalation. Them conveniently delivered in the form of a dry powder (either individually or as a mixture, for example in the form of a dry blend with lactose, or as a mixed multi-component particle, for example, with phospholipids) from a nebulizer for a dry powder or in the form of an aerosol spray from a pressurized container, pump, spray, atomizer (preferably, atomizer using electrohydrodynamics to obtain a fine mist) or a nebulizer, with or without the use of a suitable propellant, e.g. DICHLORODIFLUOROMETHANE, trichloromethane, dichlorotetrafluoroethane, hydrofluroalkane, such as 1,1,1,2-Tetrafluoroethane (HFA 134A [trade mark] or 1,1,1,2,3,3,3-Heptafluoropropane (HFA 227EA [trade mark]), carbon dioxide, optionally perfluorinated hydrocarbon, such as Perflubron (trademark), or other suitable gas. In the case of an aerosol under pressure, the standard dose can be determined by using the valve for delivering metered quantities. Container, pump, spray, atomizer, or nebulizer pressure may contain the solution is whether the suspension of the active compound, for example, using a mixture of ethanol (optional, aqueous ethanol) or a suitable agent for dispersion, solubilization, or release the extension and the propellant as the solvent, which may additionally contain a lubricating agent, for example, triolein sorbitan. Capsules, blisters and cartridges (made, for example, from gelatin or a receiver array for use in an inhaler or insufflator may contain a powder mix of the compound of the present invention, a suitable powder base, such as lactose or starch, and modifier actions, such as 1-leucine, mannitol, or magnesium stearate.

Before use in a dry powder composition or suspension for inhalation elements of the combination of the present invention should be mikronizirovanny to a size suitable for delivery by inhalation (typically less than 5 microns). Micronisation can be achieved using several methods, for example grinding in a jet mill, grinding fluidized bed on the jet mill, the use of supercritical crystallization of liquid or spray drying.

Suitable solution for use in the spray, using electrohydrodynamics to obtain a fine mist may contain from 1 μg to 10 m in the compounds of the present invention in one click, and the amount of operation can be varied from 1 to 100 μl. A typical composition may contain combinations of the present invention, propylene glycol, sterile water, ethanol and sodium chloride. Alternative solvents can be used instead of propylene glycol, for example, glycerol or polyethylene glycol.

Alternatively, the elements of a combination according to the present invention can be entered locally on the skin, mucous membranes, dermal or transdermal, for example, in the form of a gel, hydrogel, lotion, solution, cream, ointment, spray powders, dressings, foams, films, skin patches, plates, implants, sponges, fibers, bandage, microemulsions and their combinations. For such applications, the compounds of the present invention can be suspended or dissolved, for example, in a mixture with one or more of the following agents: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylenesorbitan compound, emulsifying wax, non-volatile oils, including mono - or diglycerides, and fatty acids, including oleic acid, water, monostearate sorbitan, polyethylene glycol, liquid paraffin, Polysorbate 60, wax atilovykh esters, clearily alcohol, 2-octyldodecanol, benzyl alcohol, alcohols, such as ethanol. Alternatively, you can use the penetration enhancers. You can also use polymers, carbohydrates, proteins, phospholipids in the form of nanoparticles (such as Nozomi or liposomes) or in suspended or dissolved form. In addition, they can be delivered using iontophoresis, electroporation, phonophoresis or sonophoresis.

Alternatively, the elements of a combination according to the present invention it is possible to enter rectally, e.g. in the form of a suppository or pessary. They can also enter the vaginal way. For example, these compositions can be produced mixing the drug with a suitable non-irritating fillers, such as cocoa butter, synthetic esters of glycerol or polyethylene glycols, which are solid at ordinary temperatures, but the process of dissolving and/or dissolve in the cavity and release the drug.

The elements of a combination according to the present invention can also enter by ocular. For ophthalmic use, the compounds can be produced in the form of micronized suspensions in isotonic, with a selected pH, sterile saline, or, preferably, as solutions in isotonic, with a selected pH, sterile physiological solution. You can add a polymer, such as cross-linked polyacrylic acid, polyvinyl alcohol, Gulu is about acid, cellulose polymer (e.g., hypromellose, hydroxyethylcellulose, methylcellulose) or heteropolysaccharide polymer (for example, Galanova gum). Alternatively, they can be made in the form of ointments, such as ointment on the basis of vaseline or mineral oil incorporated in a biodegradable (e.g., absorbable gel sponges, collagen) or nonbiodegradable (e.g., silicone) implants, plates, drops, lenses, or delivered by a particle or bubble systems, such as Nozomi or liposomes. The composition can, optionally, be combined with a preservative, such as benzalkonium chloride. In addition, they can be delivered using iontophoresis. They can also enter in the ear, using, for example, without limitation, drops.

The elements of a combination according to the present invention can also be used in combination with a cyclodextrin. Cyclodextrins known to form inclusion complexes with and without the inclusion with the molecules of the drug. Complex formation of the drug-cyclodextrin can modify the solubility, dissolution rate, taste masking, bioavailability and/or stability of the molecule drugs. Complexes of drug-cyclodextrin are usually suitable for most Lekarstvo the x forms and routes of administration. Alternatively, direct integration with drug cyclodextrin can be used as an auxiliary additive, for example, as a carrier, diluent or solubilizing agent. Most commonly used alpha-, beta - and gamma-cyclodextrins, and suitable examples are described in WO-A-91/11172, WO-A-94/02518 and WO-A-98/55148.

The term "input" includes delivery using viral and non-viral methods. Viral delivery mechanisms include, without limitation, adenovirus vectors, adeno-associated viral (AAV) vectors, herpesvirus vectors, retroviral vectors, lentiviral transfer vector and baculovirus vectors. Non-viral delivery mechanisms include transfection mediated by lipids, liposomes, immunoliposomes, lipofectin, cationic facial amphiphilic substances (CFA) and their combinations. The path for the specified delivery mechanisms include, without limitation, delivery via the mucous membranes, nasal, oral, parenteral, gastrointestinal, local or sublingual route.

Thus, in another feature, the present invention relates to pharmaceutical compositions containing alpha-2-Delta ligand, DSNRI or one or both of a SSRI and SNRI or their pharmaceutically acceptable salts, provided that the excluded compounds (i)to(xxv) WO 02/85839 in combination the inhibitor of serotonin reuptake, especially, fluoxetine, paroxetine, citalopram and sertraline, a mixed inhibitor of the reuptake of serotonin, norepinephrine, especially, milnacipram, venlafaxine and DULOXETINE, and inhibitor reuptake noradrenaline, especially, reboxetine, and a suitable excipient, diluent or carrier. Accordingly, the composition is suitable for use for the treatment of pain, especially neuropathic pain.

As an alternative particularly, the present invention relates to pharmaceutical compositions containing a synergistic combination of alpha-2-Delta ligand, DSNRI or one or both of a SSRI and SNRI or their pharmaceutically acceptable salts and a suitable excipient, diluent or carrier. Accordingly, the composition is suitable for use for the treatment of pain, especially neuropathic pain.

For the introduction of an animal that is not a person, the term "pharmaceutical"as used herein can be replaced by "veterinary".

The pharmaceutical preparation is preferably in the form of a standard dosage forms. In this form of the drug is divided into standard doses containing appropriate quantities of the active component. Standard dosage form can be a packaged preparation, UE is forging contains a specific quantity of the drug, such as packaged tablets, capsules, and powders in vials or ampoules. Standard dosage form may present themselves capsule, tablet, wafer or wafer, or it can be an adequate amount of, any of the above forms in Packed form. The number of active component in the preparation of standard dosage forms can be varied or brought to a quantity of from 0.1 mg to 1 g, in accordance with the specific application and the effectiveness of active ingredients. When the medical use of the drug can be injected three times a day in the form of, for example, capsules containing 100 or 300 mg therapeutic application of compounds that are used in the pharmaceutical method of the present invention, administered at the initial dosage of about 0.01 mg to 100 mg/kg / day. The preferred limits of daily doses of approximately from 0.01 mg to 100 mg/kg Dose, however, may vary depending on the needs of the patient, severity of condition, about which medical treatment and used connections. Determining the correct dosage for a particular situation is within the competence of the specialist. Usually begin treatment with lower doses that are less than the optimum dose of the compounds. Then the dosage is gradually increased to achieve the op is kalinago in the circumstances of the effect. For convenience, the total daily dose can be divided and enter the parts during the day, if this is desirable.

For veterinary use combination of the present invention or veterinary-acceptable salt or solvate injected into a suitable acceptable composition, in accordance with normal veterinary practice and the veterinary doctor will determine the dosage and route of administration that are most appropriate for a particular animal.

Biological examples

Methods

Animals

Male rats Sprague Dawley (200-250 g)obtained from Charles River (Margate, Kent, U.K.)contain groups of 6 animals each. All animals were kept under a 12-hour cycle of light/dark (light included in 07 h 00 min), with free access to food and water. All experiments were carried out by the observer was not informed about drug treatment.

CCI surgery on rats

Animals were obezbolivatmi by isoflurane. Sciatic nerve ligated as previously described (Bennett and Xie, 1988. Animals were placed on homeothermic a blanket for the whole duration of the procedure. After surgical treatment were exposed common sciatic nerve at mid-thigh by blunt dissection through the biceps muscle of the thigh. Proximal to the division of the sciatic nerve into three branches, about 7 mm of nerve was freed from surrounding tissue and around the his loosely tied 4 ligatures (4-0 silk), with the distance between them is about 1 mm Incision sutured in layers, and the wound was treated with local antibiotics.

The effect of combinations on the preservation of CCI-induced static and dynamic-allodynia

The definition of the relationship of the dose-responses to gabapentin, DSNRI, SSRI and SNRI first carried out separately on the model of the CCI. The combination was studied in accordance with a fixed scheme of correlation. Was carried out by determination of the relationship of the dose-response for each fixed ratio of doses. In each experimental day before drug exposure was determined by the source thresholds otdergivanija feet (PWT) from threads von Frey and latent periods before otdergivanija feet (PWL) from irritation cotton swab.

Evaluation of allodynia

Static allodynia was measured using threads Semmes-Weinstein von Frey (Stoelting, Illinois, USA). Animals were placed in cages with wire bottoms, which provide access to the lower surface of their paws. Before the start of the experiment the animals were accustomed to the specified environment. Static allodynia was studied by touching the plantar surface of right hind paws of the animals yarns von Frey with increasing order of effort(0,7, 1,2, 1,5, 2, 3,6, 5,5, 8,5, 11,8, 15,1 and 29 g). After establishing the reaction otdergivanija paw re-tested, starting with the next descending series of threads von Frey, until the disappearance is eacli. The cut-off point was the largest effort, 29 g, which lifted a paw, and had caused the reaction. The small effort required to obtain reactions were noted as PWT in grams.

Dynamic allodynia was assessed by a slight blow on the plantar surface of the hind legs with a cotton swab. Had taken all measures to ensure that this procedure made the fully accustomed to this environment, the rats that did not show activity in order to avoid the entry of General motor activity. At least three measurements were carried out in each moment of time; the average value from these measurements represented the latent period otdergivanija feet (PWL). If within 15 seconds of the reaction was not observed, the procedure was stopped and the animals were set specified time otdergivanija. Thus, the period of time of 15 sec was effectively presented no otdergivanija. The reaction straightening was often accompanied by re-indexed or licking of the paws. It was believed that the dynamic allodynia occurs when animals responded to stimulation with cotton wool before the expiration of 8 seconds after impact.

Study combination

The definition of the relationship of dose-responses were first carried out with the use of alpha-2-Delta ligand (p/o) DSNRI or SSRI and SNRI (p/C or p/o) separately. Then the study shall be the number fixed ratio of doses in combination. Was carried out by determination of the relationship of the dose-response for each fixed ratio of doses over time for each experiment, a certain duration intelligencesm the actions of each individual ratio. You can explore different fixed ratio of doses of the combinations on the mass.

Suitable DSNRI or SSRI and/or SNRI compounds of the present invention can be obtained, as described in the reference, or as it is obvious to the specialist on the basis of these documents.

Suitable alpha-2-Delta ligands of the present invention can be obtained, as described later in this document, or in the above referenced patent literature, which are illustrated in the following non-limiting examples and intermediate substances.

Chemical examples

Example 1

Hydrochloride, (3S,5R)-3-amino-5-methyloctanoic acid

(R)-2,6-dimethylene-2-ene. To (S)citronellate (50 g, 0,228 mol) in THF (800 ml) at 0°With added LiCl (4.3 g), and then CuCl2(6.8 g). After 30 minutes of added chloride Metalmania (152 ml of 3 M solution in THF, Aldrich) and the solution was heated to room temperature. After 10 hours the solution was cooled to 0°and was carefully added to saturated aqueous solution of ammonium chloride. Resulting two layers were separated and the aqueous phase was extracted with ether. The combined organic phase is dried (MgSO 4) and concentrated to obtain (R)-2,6-dimethylene-2-ene. 32,6 g; 93%. Used without additional purification.1H NMR (400 MHz; CDCl3) δ 5,1 (m, 1H), 1,95 (m, 2H), 1,62 (s, 3H), and 1.6 (s, 3H)and 1.3 (m, 4H), 1,2 (m, 2H), 0,8 (s, 6H).

(R)-4-methylheptanoic acid. To (R)-2,6-dimethylene-2-ENU (20 g, 0.13 mol) in acetone (433 ml) was added a solution of CrO3(39 g, to 0.39 mol) in H2SO4(33 ml)/N2(146 ml) for 50 minutes. After 6 hours was added an additional amount CrO3(26 g, 0.26 mol) in H2SO4(22 ml)/N2O (100 ml). After 12 hours the solution was diluted with saturated salt solution and the solution was extracted with ether. The combined organic phases were dried (MgSO4) and concentrated. Flash chromatography (gradient from 6:1 to 2:1 hexane/EtOAc) gave (R)-4-methylheptanoic acid in the form of oil, 12,1 g; 65%. MS, m/z (relative intensity): 143 [M-H, 100%].

(4R,5S)-4-methyl-3-((R)-4-methylheptanoic)-5-phenyloxazolidine-2-it. To (R)-4-methylheptanoic acid (19 g, 0,132 mol) and triethylamine (to 49.9 g, 0,494 mol) in THF (500 ml) at 0°With added trimethylacetylchloride (20 g, to 0.17 mol). After 1 hour was added LiCl (7,1 g to 0.17 mol), and then (4R,5S)-(+)-4-methyl-5-phenyl-2-oxazolidinone) 3 (30 g, to 0.17 mol). The mixture then was heated to room temperature and after 16 hours the filtrate was removed by filtration and the solution was concentrated under reduced pressure. Flash chromatography (7:1 hexane/EtOAc) gave (4R,5S)-4-methyl-3-((R)4-methylheptanoic)-5-phenyloxazolidine-2-it is in the form of oil, 31,5 g; 79%. [α]D=+5,5 (1 in CHCl3). MS, m/z (relative intensity): 304 [M+H, 100%].

Tert-butyl ether (3S,5R)-5-methyl-3-((4R,5S)-4-methyl-2-oxo-5-phenyloxazolidine-3-carbonyl)octanoic acid. (4R,5S)-4-methyl-3-((R)-4-methylheptanoic)-5-phenyloxazolidine-2-ONU (12.1 g, 0.04 mol) in THF (200 ml) at -50°With added bis(trimethylsilyl)amide, sodium (48 ml of 1 M solution in THF). After 30 min was added tert-butylbromide (15.6 g, 0.08 mol). The solution was stirred for 4 hours at -50°and then was heated to room temperature. After 16 hours was added a saturated aqueous solution of ammonium chloride, and the two layers were separated. The aqueous phase was extracted with ether, and the combined organic phases were dried (MgSO4) and concentrated. Flash chromatography (9:1 hexane/EtOAc) gave tert-butyl ether (3S,5R)-5-methyl-3-((4R,5S)-4-methyl-2-oxo-5-phenyloxazolidine-3-carbonyl)octanoic acid in a solid white color, 12 g; 72%. [α]D=+30,2 (1 in CHCl3).13With NMR (100 MHz; CDCl3) δ 176,47, 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.

4-tert-butyl ether (S)-2-((R)-2-methylpentyl)succinic acid. To tert-butyl ether (3S,5R)-5-methyl-3-((4R,5S)-4-methyl-2-oxo-5-phenyloxazolidine-3-carbonyl)octanoic acid (10.8 g, 0,025 mol) in N2(73 ml) and THF (244 ml) at 0°With added pre-mixed solution of LiOH (51,2 ml of 0.8 M races the thief) and H 2About2(14,6 ml of 30% solution). After 4 hours was added to 12.8 ml of LiOH (0.8 M solution) and the 3.65 ml of N2About2(30% solution). After 30 minutes, was added sodium bisulfite (7 g), sodium sulfite (13 g) and water (60 ml)and then hexane (100 ml) and ether (100 ml). Two layers were separated, and the aqueous layer was extracted with ether. The combined organic phase was concentrated to an oil, which was dissolved in heptane (300 ml). The obtained solid was filtered and the filtrate was dried (MgSO4) and concentrated to obtain 4-tert-butyl ether (S)-2-((R)-2-methylpentyl)succinic acid (6 g, 93%)which was used immediately without further purification. MS, m/z (relative intensity): 257 [M+H, 100%].

Tert-butyl ether (3S,5R)-3-antioxidansvitamine-5-methyloctanoic acid. To a solution of 4-tert-butyl ether (S)-2-((R)-2-methylpentyl)succinic acid (6.0 g, 23,22 mmol) and triethylamine (of 3.64 ml, 26,19 mmol) in toluene (200 ml) were diphenylphosphorylacetate (5.0 ml, 23,22 ml) and stirred at room temperature for 0.5 hours. After the reaction mixture was heated under reflux for 3 hours and rapidly cooled, was added benzyl alcohol (7.2 ml, was 69.7 mmol) and the solution was heated for another 3 hours. After cooling, the reaction mixture was diluted with ethyl ether (200 ml) and the combined organic layer was washed sequentially us is on NaHCO 3and saturated saline and dried (Na2SO4). Concentrated organic component was purified by chromatography (MPLC) with elution 8:1 hexane: ethyl acetate, to obtain tert-butyl ether (3S,5R)-3-antioxidansvitamine-5-methyloctanoic acid (6.4 g, 75.8 per cent). MS: M+1: 364,2, 308,2.

Tert-butyl ether (3S,5R)-3-amino-5-methyloctanoic acid. To a solution of tert-butyl methyl ether (3S,5R)-3-antioxidansvitamine-5-methyloctanoic acid (2.14 g, 5,88 mmol) in THF (50 ml) acted Pd/C (0.2 g) and N2at 50 pounds per square inch for 2 hours. The reaction mixture was then filtered and concentrated to an oil under vacuum, to obtain tert-butyl ether (3S,5R)-3-amino-5-methyloctanoic acid with a quantitative yield. MS: M+1: 230,2, 174,1.

Hydrochloride, (3S,5R)-3-amino-5-methyloctanoic acid. A suspension of tert-butyl methyl ether (3S,5R)-3-amino-5-methyloctanoic acid (2,59 g, 11.3 mmol) in 6 BC HCl (100 ml) was heated under reflux for 18 hours, cooled and filtered through celite. The filtrate was concentrated in vacuo to 25 ml and the obtained crystals were collected and dried, to obtain the hydrochloride of (3S,5R)-3-amino-5-methyloctanoic acid, TPL 142,5-142,7°With (1.2 g, 50,56%). The second part (of 0.91 g) was obtained from the filtrate. Analytically calculated for C9H19NO2·HCl: C: 51,55, H: being 9.61, N: 6,68, Cl: 16,91. Found: C: 51,69, H: 9,72, N: 6,56, Cl: 16,63.

Salt chlorine is stevedorage acid (3S,5R)-3-amino-5-methyloctanoic acid. to 5.3 g of 4-tert-butyl ether 2S-(2R-methylpentyl)succinic acid contained in 30 ml tert-butyl methyl ether, interacted at room temperature with 3.5 ml of triethylamine, and then 6.4 g diphenylphosphinite. After reaching the reaction mixture ectotherm to 45°and mixing for at least 4 hours, the reaction mixture was left to cool to room temperature and to stand until phase separation. The bottom layer was decanted and the upper layer was washed with water and then dilute aqueous HCl. The top layer was then combined with 10 ml of 6 N. aqueous HCl and was stirred at 45-65°C. the Reaction mixture was concentrated by vacuum distillation until about 10-14 ml and allowed to crystallize by cooling to approximately 5°C. After collecting the product by filtration the product was washed with toluene and re-suspended in toluene. The product was dried by heating under vacuum, to obtain 2.9 g (67%) of crystalline white product. The product can be recrystallized from aqueous HCl. TPL 137°C.

Example 2

(3S,5R)-amino-5-methylheptanoic acid

(S)was 3.7-dimethylocta-6-enjoy ether methanesulfonate acid. To (S)-(-)citronellol (42.8 g, 0,274 mol) and triethylamine (91 ml, 0,657 mol) in CH2Cl2(800 ml) at 0°With added methanesulfonamide (26 ml, 0,329 mol) in CH2Cl2(200 ml). After 2 hours at 0&x000B0; With the solution washed with 1 N. HCl and then with saturated saline. The organic phase was dried (MgSO4) and concentrated, obtaining specified in the connection header in the form of oil (of 60.5 g, 94%)which was used without further purification. MS, m/z (relative intensity): 139 [100%], 143 [100%].

(R)-2,6-dimethylocta-2-ene. To (S)was 3.7-dimethylocta-6-enjoy ether methanesulfonate acid (60 g, 0,256 mol) in THF (1 l) at 0°With added hydride lithium aluminium (3.8 g, 0,128 mol). After 7 hours was added 3.8 g of lithium hydride-aluminum and the solution was heated to room temperature. After 18 hours was added 3.8 g of lithium hydride-aluminum. After 21 hours the reaction was carefully marked 1 N. citric acid and the solution was further diluted with a saturated saline solution. Received two phases were separated, and the organic phase was dried (MgSO4) and concentrated, obtaining specified in the connection header in the form of oil, which was used without further purification. MS, m/z (relative intensity): 139 [100%].

(R)-4-methylhexanoic acid. Used a procedure similar to the procedure for the synthesis of (R)-4-methylheptanoic acid, to obtain the acid in the form of oil (9.3 g, 56%). MS, m/z (relative intensity): 129 [M-H -, 100%].

(4R,5S)-4-methyl-3-((R)-4-methylhexanoic)-5-phenyloxazolidine-2-it. Used a procedure similar to the procedure for the synthesis of (4R,5S)-4-ethyl-3-((R)-4-methylheptanoic)-5-phenyloxazolidine-2-it, obtaining specified in the title compound as oil (35,7 g, 95%). MS, m/z (relative intensity): 290 [M+H, 100%].

Tert-butyl ether (3S,5R)-5-methyl-3-[1-((4R,5S)-4-methyl-2-oxo-5-phenyloxazolidine-3-yl)methanol]heptane acid. Used a procedure similar to the procedure for the synthesis of tert-butyl methyl ether (3S,5R)-5-methyl-3-((4R,5S)-4-methyl-2-oxo-5-phenyloxazolidine-3-carbonyl)octanoic acid with obtaining specified in the connection header in the form of oil (of 7.48 g, 31%). MS, m/z (relative intensity): 178 [100%], 169 [100%], [α]D=+21,6 (c 1 in CHCl3).

4-tert-butyl ether (S)-2-((R)-2-methylbutyl)succinic acid. To tert-butyl ether (3S,5R)-5-methyl-3-[1-((4R,5S)-4-methyl-2-oxo-5-phenyloxazolidine-3-yl)methanol]heptane acid (7,26 g, 0.018 mol) in N2(53 ml) and THF (176 ml) at 0°With added pre-mixed solution of LiOH (37 ml of a 0.8 M solution) and N2About2(10,57 ml of 30% solution) and the solution was heated to room temperature. After 2 hours, was added sodium bisulfite (7 g), sodium sulfite (13 g) and water (60 ml), and the two layers were separated, and the aqueous layer was extracted with ether. The combined organic phase was concentrated to an oil, which was dissolved in heptane (200 ml). The obtained solid was filtered and the filtrate was dried (MgSO4) and concentrated, obtaining specified in the title compound as oil (4.4 g), which COI is litovali without additional purification. MS, m/z (relative intensity): 243 [100%].

Tert-butyl ether (3S,5R)-3-antioxidansvitamine-5-methylheptanoic acid. The specified connection was received, as described above, starting from 4-tert-butyl ether (S)-2-((R)-2-methylbutyl)succinic acid, to obtain tert-butyl ether (3S,5R)-3-antioxidansvitamine-5-methylheptanoic acid in the form of an oil (yield 73,3%).1H NMR (400 MHz; CDCl3) δ from 0.84 (t, 3H, J=7,33 Hz)to 0.89 (d, 3H, J=6,60 Hz), 1,12-to 1.38 (m, 4H), of 1.41 (s, 9H), 1,43-to 1.59 (m, 2H), 2,42 (m, 2H), of 4.05 (m, 1H), 5,07 (t, 2H, J=12,95 Hz) and 7,28-7,34 (m, 5H).

Tert-butyl ether (3S,5R)-amino-5-methylheptanoic acid. The specified connection was received, as described above, starting from tert-butyl ether (3S,5R)-3-antioxidansvitamine-5-methylheptanoic acid instead of tert-butyl methyl ether (3S,5R)-3-antioxidansvitamine-5-methyloctanoic acid, obtaining specified in the connection header.1H NMR (400 MHz; CDCl3) δ 0,84 (overlapping t and d, 6H), 1,08 is 1.16 (m, 2H), 1,27-of 1.30 (m, 2H), of 1.42 (s, 9H), 1,62 (users, 2H), 2,15 (DD, 1H, J=8,54 and 15.62 wide Hz)to 2.29 (DD, 1H, J=4,15 and shed 15.37 Hz) and 3,20 (users, 2H).

Hydrochloride, (3S,5R)-amino-5-methylheptanoic acid. A suspension of tert-butyl methyl ether (3S,5R)-amino-5-methylheptanoic acid (1.44 g, 6,69 mmol) in 3 BC HCl was heated under reflux for 3 hours, filtered hot through celite and concentrated to dryness. Rubbing the obtained solids in ethyl EF the re gave hydrochloride (3S,5R)-3-amino-5-methylheptanoic acid (0.95 g, 85%), TPL 126,3-128,3°C.

Example 3

(3S,5R)-3-amino-5-methylnonanoic acid

(R)-4-methyloctanoic acid. The lithium chloride (0.39 g, 9,12 mmol) and copper chloride (I) (0,61 g, 4,56 mmol) were combined in 45 ml of THF at room temperature and was stirred for 15 minutes, then was cooled to 0°and at this point was added to the bromide of etermine (1 M solution in THF, 45 ml, 45 mmol). Was added dropwise (S)-citronellal (5.0 g, of 22.8 mmol) and the solution was allowed to slowly warm to room temperature with stirring overnight. The reaction was suppressed by careful addition of saturated NH4Cl (aqueous) and stirred with Et2O and saturated NH4Cl (water) for 30 minutes. The phases were separated and the organic phase was dried (MgSO4) and concentrated. Crude (R)-2,6-timeteller-2-ene was used without purification. To a solution of (R)-2,6-timeteller-2-ene (3.8 g, of 22.8 mmol) in 50 ml of acetone at 0°With added Jones reagent (2.7 M in H2SO4(water), 40 ml, 108 mmol) and the solution was allowed to slowly warm to room temperature with stirring overnight. The mixture was distributed between Et2O and H2Oh, the phases were separated and the organic phase is washed with saturated salt solution, dried (MgSO4) and concentrated. The residue was purified flash chromatography (8:1 hexane: EtOAc), to obtain 2.14 g (59%) indicated in the title compound in the form of the be the color of oil: LRMS: m/z 156,9 (M+). The Jones reagent was made as a 2.7 M solution of Association 26.7 g CrO3, 23 ml of H2SO4and dilution to 100 ml of N2O.

(4R,5S)-4-methyl-3-((R)-4-methyloctanoic)-5-phenyloxazolidine-2-it. To (R)-4-methyloctanoic acid (2.14 g, 13.5 mmol) in 25 ml of CH2Cl2when 0°added 3 drops of DMF, and then oxalicacid (1,42 ml, 16.2 mmol), followed by rapid gas evolution. The solution is then directly heated to room temperature, was stirred for 30 minutes and concentrated. Meanwhile, to a solution of oxazolidinone (2.64 g, 14.9 mmol) in 40 ml THF at -78°C was added n-utility (1.6 M solution in hexano, and 9.3 ml, 14.9 mmol) dropwise. The mixture was stirred for 10 minutes, after which was added the acid chloride of the acid in 10 ml of THF dropwise. The reaction mixture was stirred for 30 minutes at -78°With, then directly heated to room temperature and extinguished saturated NH4Cl. The mixture was distributed between Et2O and saturated NH4Cl (water), the phases were separated and the organic phase was dried (MgSO4) and concentrated, to obtain 3.2 g specified in the title compounds as colorless oils. LRMS: m/z 318,2 (M+).

Tert-butyl ether (3S,5R)-5-methyl-3-((4R,5S)-4-methyl-2-oxo-5-phenyloxazolidine-3-carbonyl)nonanalog acid. To a solution of Diisopropylamine (1.8 ml, 12.6 mmol) in 30 ml THF at -78°C was added n-butyl the Tille (1.6 M solution in hexano, of 7.6 ml, 12.1 mmol) and the mixture was stirred for 10 minutes, after which was added (4R,5S)-4-methyl-3-((R)-4-methyloctanoic)-5-phenyloxazolidine-2-he (3.2 g, 10.1 mmol) in 10 ml of THF dropwise. The solution was stirred for 30 minutes, quickly was added dropwise tert-bromoacetate (1.8 ml, 12.1 mmol) at -50°C, and the mixture was allowed to slowly warm to 10°C for 3 hours. The mixture was distributed between Et2O and saturated NH4Cl (water), the phases were separated and the organic phase was dried (MgSO4) and concentrated. The residue was purified flash chromatography (16:1 to 8:1 hexane:EtOAc), to obtain 2.65 g (61%) indicated in the title compound as a colourless solid, TPL=84-86°C. [δ]D23+17,1 (c=1.00, it CHCl3).

4-tert-butyl ether (S)-2-((R)-2-etylhexyl)succinic acid. To a solution of tert-butyl methyl ether (3S,5R)-5-methyl-3-((4R,5S)-4-methyl-2-oxo-5-phenyloxazolidine-3-carbonyl)nonanalog acid (2.65 g, 6,14 mmol) in 20 ml THF at 0°With added pre-cooled (0° (C) a solution of LiOH monohydrate (1.0 g, to 23.8 mmol) and hydrogen peroxide (30 wt.% aqueous solution, 5.0 ml) in 10 ml of N2O. the Mixture was intensively stirred for 90 minutes, then was heated to room temperature and was stirred for 90 minutes. The reaction was suppressed at 0°by adding 100 ml of 10% NaHSO3(water), then was extracted with Et2O. the Phases were separated and organic the action phase was washed with saturated saline solution, dried (MgSO4) and concentrated. Specified in the title compound was used without purification.

Tert-butyl ether (3S,5R)-3-antioxidansvitamine-5-methylnonanoic acid. The specified connection was received, as described above, starting from 4-tert-butyl ether (S)-2-((R)-2-etylhexyl)succinic acid instead of 4-tert-butyl ether (S)-2-((R)-2-methylpentyl)of succinic acid with obtaining specified in the title compound as oil (yield 71.6 per cent).1H NMR (400 MHz; CDCl3) δ 0,81 (t, 3H, J=4,40 Hz)to 0.85 (d, 3H, J=6,55 Hz), 1.06 a-1,20 (m, 7H), of 1.36 (s, 9H), 1,38 of 1.50 (m, 2H), a 2.36 (m, 2H), 3,99 (m, 1H), 5,02 (m+s, 3H) and 7,28-7,28 (m, 5H).

Tert-butyl ether (3S,5R)-3-amino-5-methylnonanoic acid. The specified connection was received, as described above, starting from tert-butyl ether (3S,5R)-antioxidansvitamine-5-methylnonanoic acid instead of tert-butyl methyl ether (3S,5R)-3-antioxidansvitamine-5-methyloctanoic acid. Yield=97%.1H NMR (400 MHz; CDCl3) δ 0,82 (overlapping d and t, 6H), 1,02-1,08 (m, 1H), 1,09-of 1.36 (m, 6H), of 1.39 (s, 9H), 1,47 (users, 1H), 1,80 (s, 2H), 2,13 (DD, 1H, J=8,54 and 15,61 Hz) and of 2.27 (DD, 1H, J=4,15 and 15,38 Hz).

Hydrochloride, (3S,5R)-3-amino-5-methylnonanoic acid. A mixture of tert-butyl methyl ether (3S,5R)-3-amino-5-methylnonanoic acid (1.50 g, 6,16 mmol) in 3 BC HCl (100 ml) was heated under reflux for 3 hours, filtered hot through celite and concentrated in vacuo to 30 ml of the Obtained crystal is s collected, washed an additional 3 N. HCl and dried, obtaining specified in the connection header, TPL 142,5-br143.3°C. Additional batch was obtained from the filtrate, of 1.03 g (70,4%). Anal. calculated for C10H21NO2·HCl: C: 53,68, H: to 9.91, N: 6,26, Cl: 15,85. Found: C: 53,89, H: 10,11, N: 6,13. MS: M+1: 188,1.

Examples of pharmaceutical compositions

In the following examples, the term "active compound" or "active ingredient" refers to a suitable combination or individual element of the alpha-2-Delta ligand and DSNRI or one or both of a SSRI and SNRI and/or their pharmaceutically acceptable salts, according to the present invention.

(i) Compositions tablets

The following compositions a and b can be manufactured by wet granulation of the ingredients (a) to (C) and (a) through (d) using a solution of povidone, followed by addition of magnesium stearate and pressed.

Composition And
mg tabletmg tablet
(a) Active ingredient250250
(b) Lactose V.R.21026
(C) Glycolate, sodium starch2012
(d) Povidone V.R.159
(e) tearin magnesium 53
500300
Composition
mg tabletmg tablet
(a) Active ingredient250250
(b) Lactose 150150-
(C) Avicel pH 1016026
(d) Glycolate, sodium starch2012
(e) Povidone V.R.159
(f) magnesium Stearate53
500300
Composition
mg tablet
The active ingredient100
Lactose200
Starch50
Povidone5
Magnesium stearate4
359

The following compositions D and E can be made by direct extrusion of the mixed ingredients. The lactose used in the composition E, which is the Wallpaper lactose type direct compression.

Composition D
mg tablet
The active ingredient250
Magnesium stearate4
Pregelatinization starch NF15146
400
Composition E
mg tablet
The active ingredient250
Magnesium stearate5
Lactose145
Avicel100
500

Composition F (composition with controlled-release)
mg tablet
(a) Active ingredient500
(b) Hypromellose (Methocel K4M Premium)112
(C) Lactose V.R.53
(d) Povidone VRS28
(e) magnesium Stearate7
700

The composition can be manufactured by wet granulation of the ingredients (a) through (C) using rest the RA povidone, with the subsequent addition of magnesium stearate and pressed.

Composition G (tablet with intersolubility the floor)

Tablets with intersolubility coating compositions can be made by drawing on a tablet coating in the amount of 25 mg per tablet of Intercollege polymer, such as acatitla cellulose, polyvinylacetate, phthalate of hydroxypropylmethylcellulose or anionic polymers of methacrylic acid and methyl ester of methacrylic acid (Eudragit L). Except for Eudragit L, these polymers should also include 10% (by weight of the used polymer) of a plasticizer to prevent the cracking of the shell during use or storage. Suitable plasticizers include diethylphthalate, tributyltin and triacetin.

Composition N (tablet with intersolubility coated, controlled-release)

Tablets with intersolubility coating composition F can be made by drawing on a tablet coating in the amount of 50 mg per tablet of Intercollege polymer, such as acatitla cellulose, polyvinylacetate, phthalate of hydroxypropylmethylcellulose or anionic polymers of methacrylic acid and methyl ester of methacrylic acid (Eudragit L). Except for Eudragit L, these polymers should also include 10% (by weight used is on polymer) of plasticizer, to prevent cracking of the membrane during application or storage. Suitable plasticizers include diethylphthalate, tributyltin and triacetin.

(ii) the Composition for capsules

Composition And

Capsules can be manufactured by mixing the ingredients of the composition D, above, and filling two-part hard gelatin capsules obtained mixture. Composition (below) can be manufactured in a similar manner.

Composition
mg/capsule
(a) Active ingredient250
(b) Lactose V.R.143
(C) Glycolate, sodium starch25
(d) magnesium Stearate2
420
Composition
mg/capsule
(a) Active ingredient250
(b) Macrogol 4000 BP350
600

Capsules can be manufactured by melting Macrogol 4000 BP, dispersing the active ingredient in the melt and filling them hard gelatin capsules.

Composition D&x0200A;
mg/capsule
The active ingredient250
Lecithin100
Peanut butter100
450

Capsules can be made by dispersing the active ingredient in the lecithin and peanut oil and filling the variance of the soft, elastic gelatin capsules.

Composition E (capsule with controlled-release)
mg/capsule
(a) Active ingredient250
(b) Microcrystalline cellulose125
(C) Lactose BP125
(d) Ethylcellulose13
513

Capsules can be manufactured by extruding the mixed ingredients from (a) to (C) using an extruder, then spheronization and drying the extrudate. The dried granules are covered with a shell that provides controlled release (d), and fill them two-part hard gelatin capsule.

Composition F (intersolubility capsule)
mg/capsule
(a) Active ingredient250
(b) Microcrystalline cellulose125
(C) Lactose BP125
(d) Acatitla cellulose50
(e) Diethylphthalate5
555

Composition for intersolubility capsules can be manufactured by extruding the mixed ingredients from (a) to (C) using an extruder, then spheronization and drying the extrudate. The dried granules cover intersolubility shell (d)containing the plasticizer (e), and fill them two-part hard gelatin capsule.

Composition G (intersolubility capsule with controlled-release)

Intersolubility capsules composition E can be produced by coating the pellets with a controlled release coating in the amount of 50 mg per capsule of Intercollege polymer, such as acatitla cellulose, polyvinylacetate, phthalate of hydroxypropylmethylcellulose or anionic polymers of methacrylic acid and methyl ester of methacrylic acid (Eudragit L). Except for Eudragit L, these polymers should also include 10% (by weight of the used polymer) of plasticizer, in order to prevent the ratite cracking the shell during application or storage. Suitable plasticizers include diethylphthalate, tributyltin and triacetin.

(iii) a Composition for intravenous injection

The active ingredient0,200 g
Sterile, pyrogen-free phosphate buffer (pH 9,0)10 ml

The active ingredient is dissolved in most of the phosphate buffer at 35-40°With, then brought to the desired volume and filtered through a sterile micropore filter into a sterile 10 ml glass vials (type 1), which is hermetically sealed with sterile closures and additional sealing means.

(iv) the Composition for intramuscular injection

The active ingredient0.20 g
Benzyl alcohol : 0.10 g
Glucotrol 751.45 g
Water for injection q.s. to3,00 ml

The active ingredient is dissolved in glucotrole. Then add benzyl alcohol and dissolve, and add water to 3 ml of the Mixture was then filtered through a sterile Millipore filter and hermetically sealed in a sterile 3 ml glass vials (type 1).

(v) the composition of the syrup

Active ingr dient 0.25 g
The solution of sorbitol1.50 g
Glycerin1,00 g
Sodium benzoate0.005 g
Corrigentof 0.0125 ml
Purified water q.s. to5.0 ml

Sodium benzoate is dissolved in parts of purified water and add a solution of sorbitol. Add the active ingredient and dissolve. The resulting solution was mixed with glycerol, and then brought to the desired volume of purified water.

(vi) the composition of the suppository

mg/suppository
The active ingredient250 g
Hard fat, BP (Witepsol H15 - Dynamit NoBel)1770
2020

One-fifth of the Witepsol H15 is melted in the pan with a steam jacket at a maximum temperature of 45°C. the Active ingredient is sifted through a sieve of 200 lm and added to the molten base with mixing, using a Silverson with a cutting head, until a homogeneous dispersion. Maintaining a temperature of 45°add the remaining Witepsol H15 to the suspension, which is stirred until a homogeneous mixture. The entire suspension is then passed through a stainless steel sieve of 250 lm and with stirring, p is help cool down to 40° C. At a temperature of 38-40°aliquot of the mixture on 2,02 g fill suitable plastic moulds and the suppositories allow to cool to room temperature.

(vii) the composition of the pessary

mg/pessary
Active ingredient (63 lm)250
Anhydrous dextrose380
Corn starch363
Magnesium stearate7
1000

The above ingredients directly mixed, and pessaries are made by extrusion of the mixture.

(viii) the Transdermal composition

The active ingredient200 mg
Alcohol USP0.1 ml
Hydroxyethylcellulose

The active ingredient and alcohol USP heliroute the hydroxyethyl cellulose and Packed into a transdermal device with a surface area of 10 cm2.

1. Combination for therapeutic, prophylactic or palliative treatment of pain, consisting essentially of (a) alpha-2-Delta ligand selected from gabapentin, pregabalin, [(1R,5R,6S)-6-(aminomethyl)bicyclo[3.2.0]hept-6-yl]acetic acid 3-(1-aminoethylthiomethyl)-4H-[1,2,4]oxadiazol-5-she S-[1-(1H-tetrazol-5-ylmethyl)cycloheptyl]methylamine, (3S,4S)-(1-aminomethyl-3,4-dimethylcyclopentene)acetic acid, (1α,3α,5α)(3-aminomethylbenzoic[3.2.0]hept-3-yl)acetic acid, (3S,5R)-3-aminomethyl-5-methyloctanoic acid, (3S,5R)-3-amino-5-methylheptanoic acid, (3S,5R)-3-amino-5-methylnonanoic acid and (3S,5R)-3-amino-5-methyloctanoic acid or pharmaceutically acceptable salt of any of them and (b) S,S-reboxetine, or its pharmaceutically acceptable salt, where the alpha-2-Delta ligand and S,S-reboxetine are present in the range of ratios from 1:10 to 10:1 wt. PM

2. The combination according to claim 1, in which the alpha-2-Delta ligand is a gabapentin.

3. The combination according to claim 1, in which the alpha-2-Delta ligand is pregabalin.

4. The combination according to claim 1, in which pain is a neuropathic pain.

5. Pharmaceutical composition for therapeutic, prophylactic or palliative treatment of pain comprising a therapeutically effective amount of a combination according to claim 1 and a suitable carrier or excipient.

6. The application of (a) alpha-2-Delta ligand selected from gabapentin, pregabalin, [(1R,5R,6S)-6-(aminomethyl)bicyclo[3.2.0]hept-6-yl]acetic acid, 3-(1-aminoethylthiomethyl)-4H-[1,2,4]oxadiazol-5-it, S-[1-(1H-tetrazol-5-ylmethyl)cycloheptyl]methylamine, (3S,4S)-(1-aminomethyl-3,4-dimethylcyclopentene)acetic acid is, (1α,3α,5α)(3-aminomethylbenzoic[3.2.0]hept-3-yl)acetic acid, (3S,5R)-3-aminomethyl-5-methyloctanoic acid, (3S,5R)-3-amino-5-methylheptanoic acid, (3S,5R)-3-amino-5-methylnonanoic acid and (3S,5R)-3-amino-5-methyloctanoic acid or pharmaceutically acceptable salt of any of them and (b) (S,S)-reboxetine, or its pharmaceutically acceptable salt for the manufacture of a medicine for treatment of pain, where the alpha-2-Delta ligand and S,S-reboxetine are present in the range of ratios from 1:10 to 10:1 wt. PM

7. The use according to claim 6, in which pain is a neuropathic pain.

8. Set includes

(a) alpha-2-Delta ligand selected from gabapentin, pregabalin, [(1R,5R,6S)-6-(aminomethyl)bicyclo[3.2.0]hept-6-yl]acetic acid, 3-(1-aminoethylthiomethyl)-4H-[1,2,4]oxadiazol-5-it, S-[1-(1H-tetrazol-5-ylmethyl)cycloheptyl]methylamine, (3S,4S)-(1-aminomethyl-3,4-dimethylcyclopentene)acetic acid, (1α,3α,5α)(3-aminomethylbenzoic[3.2.0]hept-3-yl)acetic acid, (3S,5R)-3-aminomethyl-5-methyloctanoic acid, (3S,5R)-3-amino-5-methylheptanoic acid, (3S,5R)-3-amino-5-methylnonanoic acid and (3S,5R)-3-amino-5-methyloctanoic acid or pharmaceutically acceptable salt of any of them;

(b) (S,S)-reboxetine, or its pharmaceutically acceptable salt; and

(c) the container

where type combination it is used for the treatment of pain, and where the alpha-2-Delta ligand and S,S-reboxetine are present in the range of ratios from 1:10 to 10:1 wt. PM



 

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12 cl, 19 ex

FIELD: medicine, pharmacology, pharmaceutical technology, pharmacy.

SUBSTANCE: invention relates to a solid pharmaceutical composition used in treatment of cyclooxygenase-2-dependent disorder or state that comprises from 200 mg to 400 mg of 5-methyl-2-(2'-chloro-6'-fluoroaniline)-phenylacetic acid and excipients wherein level of residual moisture in composition is from 1.5% to 5%. Also, invention relates to a method for stabilization of 5-methyl-2-(2'-chloro-6'-fluoroaniline)-phenylacetic acid as a component of the solid pharmaceutical composition that involves preparing the solid pharmaceutical composition comprising 5-methyl-2-(2'-chloro-6'-fluoroaniline)-phenylacetic acid wherein the composition comprises the level of residual moisture from 1.5% to 5%. The dried granulated preparation comprises 5-methyl-2-(2'-chloro-6'-fluoroaniline)-phenylacetic acid, microcrystalline cellulose, lactose monohydrate, croscarmellosa sodium wherein the level of residual moisture in the granulated preparation is from 2.5% to 4.5%. Solid pharmaceutical compositions comprise indicated dried granulated preparation. Invention provides enhancing stability of 5-methyl-2-(2'-chloro-6'-fluoroaniline)-phenylacetic acid as component of compositions and preparations.

EFFECT: improved and valuable properties of pharmaceutical compositions.

31 cl, 3 tbl, 1 ex

FIELD: organic chemistry, biochemistry.

SUBSTANCE: invention describes novel substituted pyrazoles of the general formula (I): wherein values of radicals Ar, Ar2, W, G, R5-R8, RZ and n are given in the invention claim. Also, invention relates to a pharmaceutical composition based on these compounds, using this pharmaceutical composition for manufacturing agent designated for treatment of asthma, and a method for inhibition of activity of cathepsin S. Compounds indicated above can be used in medicine.

EFFECT: valuable medicinal and biochemical properties of compounds and pharmaceutical composition.

27 cl, 3 tbl, 352 ex

FIELD: medicine, dermatology, pharmaceutical industry, pharmacy.

SUBSTANCE: invention relates to a composition used in treatment and prophylaxis of allergic diseases and non-allergic inflammatory diseases in mammals and containing winter-hardy kiwi extract. Also, invention relates to a method for preparing the composition containing winter-hardy kiwi extract and involving diluting milled and dried winter-hardy kiwi with water or lower alcohols, heating a diluted winter-hardy kiwi and extraction of product to obtain winter-hardy kiwi extract. Also, invention relates to a method for treatment, relive or prophylaxis of allergic diseases and non-allergic inflammatory diseases in mammals involving administration in a mammal winter-hardy kiwi extract for treatment or prophylaxis of at least one symptom of allergic disease or non-allergic inflammatory disease. Also, invention elates to a method for treatment and prophylaxis of allergic diseases and non-allergic inflammatory diseases in mammals involving prescription or administration in mammal winter-hardy kiwi extract for treatment or prophylaxis of at least one symptom of allergic disease or non-allergic inflammatory diseases in mammal. Also, invention relates to using winter-hardy kiwi extract for treatment, relieve or prophylaxis of allergic diseases or non-allergic inflammatory diseases in mammals. Above described winter-hardy kiwi extract and a composition based on thereof show effectiveness in treatment, relieve or prophylaxis of allergic diseases or non-allergic inflammatory diseases in mammals.

EFFECT: valuable medicinal properties of composition.

58 cl, 5 dwg, 11 tbl, 11 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to a novel compound - ((1R,3S)-3-isopropyl-3-{[3-(trifluoromethyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl]carbonyl}cyclopentyl)[(3S,4S)-3-methoxytetrahydro-2H-pyran-4-yl]amine succinate of the formula: that possesses property of CCR-2 antagonist. Also, invention relates to a method for modulation of activity of chemokine receptors and a method for treatment, improvement, control and reducing risk of inflammatory and immunoregulatory disorder or disease, and to a method for improvement, control and reducing risk of rheumatic arthritis.

EFFECT: valuable medicinal properties of compound.

4 cl, 3 tbl, 5 ex

FIELD: pharmaceutical industry, medicine, pharmacy.

SUBSTANCE: invention relates to a medicinal agent possessing anti-migraine effect consisting of core and envelope. Agent comprises sumatriptan succinate as an active component and polyvinylpyrrolidone, calcium phosphate, hydroxypropylcellulose, polyethylene glycol, titanium dioxide, talc, magnesium stearate and lactose taken in the definite amounts. Also, invention relates to a method for preparing a medicinal agent possessing anti-migraine effect. Method involves mixing sifted powders of calcium phosphate and sumatriptan succinate followed by addition of lactose. The prepared mixture of powders is stirred, wetted with polyvinylpyrrolidone aqueous solution followed by successive steps of wetted granulation, drying the prepared granules, dry granulation, powdering with magnesium stearate, tabletting to obtain cores and applying a film envelope on core by spraying an aqueous suspension consisting of talc and titanium dioxide in hydroxypropylmethylcellulose solution and, if necessary, a dye. The medicinal agent prepared by above described method possesses the enhanced dissolving index, provides high bioavailability of active substances and provides high dosing degree. Invention can be used as anti-migraine agent.

EFFECT: improved preparing method.

3 cl, 3 tbl, 2 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to a method for prophylaxis or treatment of neuropathic pain and involves administration to a patient the therapeutically effective dose of compound of the formula (Ic): or enantiomeric mixture of wherein enantiomer of the formula (Ic) prevails. Proposed method provides prophylaxis or elimination of neuropathic pain distinct from that in trifacial nerve and based on the proved anti-allodinal activity of this enantiomer.

EFFECT: valuable medicinal properties of compounds.

2 cl, 2 tbl, 2 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to producing a medicinal agent that can be used in prophylaxis or treatment of the neuropathic pain. Invention proposes using as an active component of indicated agent an enantiomer of the formula (Ib): no containing other enantiomers, or enantiomer mixture wherein enantiomer of the formula (Ib) prevails. Invention expands assortment of medicinal agent used in treatment or prophylaxis of different kinds of neuropathic pain.

EFFECT: valuable medicinal property of compounds and agent.

5 cl, 1 tbl

FIELD: organic chemistry, heterocyclic compounds, medicine.

SUBSTANCE: invention relates to dihydropyrimidine compounds of the formula (I*): their enantiomers, diastereoisomers and pharmaceutically acceptable salts wherein X1, X2 and X3 in common with atoms to which they are added form ring of the formula: or ; R1 represents hydrogen atom; R2, R3*, R4, R5, R6 and R7 have values given in cl. 1 of the invention claim. Also, invention relates to separate dihydropyrimidine compounds. Proposed compounds are inhibitors of calcium channel function being especially inhibitors of Kv1 subfamily of potential-overlapping K+-channels and especially inhibitors of Kv 1.5 that associated with super-rapid activating delayed cleaning K+-flow of Ikur and can be used in treatment of arrhythmia and Ikur-associated diseases.

EFFECT: valuable medicinal properties of compounds.

15 cl, 589 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to a pharmaceutical composition used in migraine treatment as a solid dosed medicinal formulation for the peroral administration that comprises 5-HT1-agonist sumatriptan or its pharmaceutically active salt or solvate as an active component (in the amount 20-150 mg of sumatriptan as a base) and a main component of a carbonated pair, a loosening agent and an insoluble excipient wherein the amount of the main component id from about 5 to about 50%% by mass, the amount of a loosing component is from about 0.5 to about 10% by mass, and the amount of insoluble excipient is from about 35 to about 80% by mass. Also, invention relates to using the proposed composition in migraine treatment. The composition can be used orally as a whole and provides the curative effect after rapid absorption typical for carbonated compositions.

EFFECT: improved and valuable medicinal and pharmaceutical properties of composition.

8 cl, 6 tbl, 3 dwg, 16 ex

FIELD: organic chemistry of heterocyclic compounds, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of pyrimidine of the general formula (I) and their pharmaceutically acceptable acid-additive salts possessing properties of neurokinin-1 (NK) receptors antagonists. In the general formula (I): R1 means lower alkyl, lower alkoxyl, pyridinyl, pyrimidinyl, phenyl, -S-lower alkyl, -S(O2)-lower alkyl, -N(R)-(CH2)n-N(R)2, -O-(CH)n-N(R)2, -N(R)2 or cyclic tertiary amine as a group of the formula: R1 means lower alkyl, lower alkoxyl, pyridinyl, pyrimidinyl, phenyl, -S-lower alkyl, -S(O2)-lower alkyl, -N(R)-(CH2)n-N(R)2, -O-(CH)-N(R)2, -N(R)2 or cyclic tertiary amine of the formula: that can comprise additional heteroatom chosen from atoms N, O or S, and wherein this group can be bound with pyrimidine ring by bridge -O-(CH2)n-; R2 means hydrogen atom, lower alkyl, lower alkoxyl, halogen atom or trifluoromethyl group; R3/R3' mean independently of one another hydrogen atom or lower alkyl; R4 means independently of one another halogen atom, trifluoromethyl group or lower alkoxyl; R means hydrogen atom or lower alkyl; R means independently of one another hydrogen atom or lower alkyl; X means -C(OH)N(R)- or -N(R)C(O)-; Y means -O-; n = 1, 2, 3 or 4; m means 0, 1 or 2. Also, invention relates to a pharmaceutical composition comprising one or some compounds by any claim among claims 1-19 and pharmaceutically acceptable excipients. Proposed compounds can be used in treatment, for example, inflammatory diseases, rheumatic arthritis, asthma, benign prostate hyperplasia, Alzheimer's diseases and others.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

21 cl, 1 tbl, 76 ex

FIELD: organic chemistry, biochemistry.

SUBSTANCE: invention relates to novel coumarone derivatives of the general formula (1): wherein two OH-substitutes in phenyl moiety are in ortho-position with respect to one to another; R1 is in ortho-position with respect to one hydroxyl group; X means oxygen atom (O); R1 represents -NO2; R2 represents hydrogen atom or (C1-C6)-alkyl; R3 means -(Y)n-(B)m-COOH or -(Y)n-(B)m-R8 wherein m = 0 or 1; n = 0; Y represents -CO-; B represents (C1-C6)-alkylene; R8 represents phenyl or 5- or 6-membered heterocycle with one-four heteroatoms chosen from nitrogen atom (N) wherein indicated phenyl is substituted optionally with one substitute chosen from halogen atom, -NO2 or (C1-C6)-alkyl; or R2 and R3 form in common -(CH2)r- wherein r = 3, 4 or 5; R4 and R5 form in common -O; R6 means hydrogen atom (H), or to their pharmaceutically acceptable salts or pharmaceutically acceptable esters that are inhibitors of enzyme - catechol O-methyltransferase (COMT). Invention provides preparing novel coumarone derivatives possessing the valuable biologically active effect.

EFFECT: valuable biochemical property of derivatives.

9 cl, 1 tbl, 13 ex

FIELD: medicine, vitamins.

SUBSTANCE: invention proposes a composition of vitamins riboflavin and nicotinic acid (niacin) or nicotinamide for treatment of primary headaches representing usual migraine, classic migraine, migraine combined with "histamine" headache. The composition comprises the combination of 0.5-750 mg of nicotinic acid (niacin or nicotinamide) and 0.1-250 mg of riboflavin. Also, the invention involves the corresponding method for treatment. Proposed treatment provides body with necessary NAD/NADP and FAD/FMN in order to modulate activity of mast cells when changes in their secretion results to migraine. Method provides disappearance of all migraine symptoms during the next 20 months of dispensary observation.

EFFECT: enhanced medicinal effectiveness of vitamins.

13 cl

FIELD: medicine, pharmacy.

SUBSTANCE: invention represents a pharmaceutical tablet comprising a core and bound envelope wherein (a) core comprises solid particles of water-soluble dye dispersed in matrix, and (b) envelope comprises hellanic gum. Due to the presence of water-soluble dye in the tablet core it shows spotted shape that provides easy recognition of the tablet. The tablet is useful for peroral and intraoral administration.

EFFECT: improved and valuable properties of tablet.

30 cl, 6 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of cyanoaryl (or cyanoheteroaryl)-carbonylpiperazinyl-pyrimidines of the general formula and their physiologically acceptable salts that elicit the broad spectrum of biological activity exceeding activity of structurally related known compounds. In the general formula (I) R1 represents radical OR3 wherein R3 represents saturated hydrocarbon radical with linear or branched chain and comprising from 1 to 4 carbon atoms; R2 represents phenyl radical substituted with cyano-radical (-C≡N) or radical representing 5- or 6-membered heteroaromatic ring wherein heteroatom is taken among oxygen (O), nitrogen (N) or sulfur (S) atom and substituted with cyano-radical (-C≡N). Also, invention relates to methods for preparing compounds of the general formula (I) that involve incorporation of group of the formula:

into piperazinyl-pyrimidine compound or by the condensation reaction of corresponding pyrimidine with piperazine comprising group of the formula:

. Also, invention relates to pharmaceutical composition and applying these compounds. Compounds can be used for preparing medicinal agents useful in human therapy and/or for therapeutic applying in veterinary science as agents eliciting ant-convulsive and soporific effect or for the general anesthesia.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

13 cl, 7 sch, 8 tbl, 41 ex

FIELD: organic chemistry, medicine, pharmacology.

SUBSTANCE: invention relates to compounds of the formula: , wherein variable value Y in ring is not obligatory and represents heteroatom chosen from nitrogen (N), oxygen (O) and sulfur (S) atoms under condition that N atom is trivalent and O or S atoms are bivalent; k means a whole number from 0 to 1; n means a whole number 0, 1 or 2; p means a whole number 0, 1 or 2; X means O or S atom; dotted lines represent a bond or its absence under condition that ring comprises only a single double bond and two adjoining lines are not a bond; R1, R2, R3 and R represent independently hydrogen atom (H), phenyl wherein indicated phenyl group is substituted optionally with one, two or three substitutes represented by (C1-C6)-alkyl, -SO3H, -N3, halogen atom, -CN, -NO2, -NH2, (C1-C6)-alkoxy-, (C1-C6)-thioalkoxy-, (C1-C6)-alkylamino-, (C1-C6)-dialkylamino-group, (C2-C6)-alkynyl, (C2-C6)-alkenyl; 5- or 6-membered heteroaryl comprising from 1 to 3 heteroatoms chosen from O, S and N atoms wherein indicated heteroaryl groups are substituted optionally and independently with one, two or three substitutes represented by (C1-C6)-alkyl, -SO3H, -N3, halogen atom, -CN, -NO2, -NH2, (C1-C6)-alkoxy- (C1-C6)-thioalkoxy-, (C1-C6)-alkylamino-, (C1-C6)-dialkylamino-group, (C2-C6)-alkynyl, (C2-C6)-alkenyl, or indicated groups R1, R2, R3 and R4 represent independently alkyl comprising from 1 to 4 carbon atoms, cycloalkyl comprising from 3 to 5 carbon atoms, -CH2CN, -CH2SR5, -CH2NR6R6, -COR5, -CH2OR5, -OR6, -SR6, -NR6R6, alkenyl comprising from 1 to 4 carbon atoms, alkynyl comprising from 1 to 4 carbon atoms, cycloalkyl comprising from 3 to 6 carbon atoms, fluorine atom, chlorine atom, bromine atom, iodine atom, -CF3 or -CN, oxygen atom bound by a double bond with ring carbon under condition that adjoining dotted line inside of ring means absence of a bond; R5 means H, -OR7, alkyl comprising from 1 to 4 carbon atoms, -CF3, cycloalkyl comprising from 3 to 6 carbon atoms, phenyl, phenyl substituted with one or two alkyl groups comprising from 1 to 4 carbon atoms, fluorine atom, chlorine atom, bromine atom, iodine atom or -CF3, either R5 represents 5- or 6-membered heteroaryl comprising from 1 to 3 heteroatoms chosen from O, S and N atoms, and 5- or 6-membered heteroaryl comprising from 1 to 3 heteroatoms chosen from O, S and N atoms substituted with one or two alkyl groups comprising from 1 to 4 carbon atoms, fluorine atom, chlorine atoms, bromine atom, iodine atom or -CF3; R6 means H, alkyl comprising from 1 to 4 carbon atoms, allyl, cycloalkyl comprising from 3 to 6 carbon atoms, phenyl, phenyl substituted with one or two alkyl groups comprising from 1 to 4 carbon atoms, fluorine atom, chlorine atom, bromine atom, iodine atom or -CF3, either R6 represents 5- or 6-membered heteroaryl comprising from 1 to 3 heteroatoms chosen from O, S and N atoms, either 5- or 6-membered heteroaryl comprising from 1 to 3 heteroatoms chosen from O, S and N atoms substituted with one or two alkyl groups comprising from 1 to 4 carbon atoms, fluorine atom, chlorine atom, bromine atom, iodine atom or -CF3; R7 means H, alkyl comprising from 1 to 4 carbon atoms, allyl, cycloalkyl comprising from 3 to 6 carbon atoms, phenyl, phenyl substituted with one or two alkyl groups comprising from 1 to 4 carbon atoms, fluorine atom, chlorine atom, bromine atom, iodine atom or -CF3; R1 and R2 or R2 and R3, or R3 and R4 can form in common a ring with corresponding carbon atoms to which they are bound; fragments represented by substitutes R1 and R2 or R2 and R3, or R3 and R4 have the following formulae (i): , (ii): , (iii): , (iv): or (v): - wherein m means a whole number from 0 to 3; R8 represents independently H, alkyl comprising from 1 to 6 carbon atoms, alkenyl comprising from 2 to 6 carbon atoms, alkynyl comprising from 2 to 6 carbon atoms, -SO3H, -N3, -CN, - NO2, F, Cl, Br, J atoms, -CF3, -COR9, -CH2OR9, -OR10, -SR10, (C1-C)-alkylamino- or (C1-C6)-dialkylamino-group wherein R9 means H, alkyl comprising from 1 to 6 carbon atoms, or -OR10 wherein R10 represents independently H or alkyl comprising from 1 to 6 carbon atoms. Also, invention relates to compounds of the formula: and , and to a method for activation of alpha2B- or alpha2C-adrenergic receptors. Invention provides synthesis of novel biologically active compound possessing activity as agonists of alpha-2B and alpha-2C-adrenergic receptors.

EFFECT: valuable medicinal properties of compounds.

34 cl, 5 tbl, 33 ex

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