Dpp-iv inhibitors for treatment of neurodegeneration and cognitive disorders

FIELD: medicine.

SUBSTANCE: there is claimed application of dipeptidyl peptidase IV inhibitor (DPP-IV inhibitor), vildagliptin or its salt for production of medication for prevention, retardation of progress or treatment of peripheral diseases such as peripheral neuropatia, neurodegenerative disorders, cognitive disorders, as well as for improvement of memory and ability to learn, and pharmaceutical composition for the same purpose. It is demonstrated: vildagliptin increases stage of wakefulness and response to external stimuli, increases REM sleep phase.

EFFECT: combination of vildagliptin with donepezil considerably improves disturbed ability to learn.

23 cl, 5 ex

 

The invention relates to the use of inhibitor dipeptidylpeptidase IV (an inhibitor of DPP-IV) or its pharmaceutically acceptable salts for the prevention, delay of progression or treatment of neurodegenerative disorders, cognitive disorders and for improving memory (short-term and long-term) and learning ability.

The term "inhibitor of DPP-IV" refers to a molecule that inhibits the enzymatic activity of DPP-IV and functionally related enzymes, for example, 1-100% or 20-80% suppression, and especially keeps the activity of molecules of substrates, which include, but not limited to, the like peptide-1, gastric inhibitory polypeptide, peptide histidine methionine, substance P, neuropeptide Y and other molecules, usually containing residues of alanine or Proline in the second position with aminocore. Treatment with inhibitors of DPP-IV prolongs the duration of action of peptide substrates and increases the levels of intact saved forms, which leads to the spectrum of biological activities that are important for describing the invention.

DPP-IV can be used to control glucose metabolism, since the substrates of this enzyme are insulinotropic hormones the like peptide-1 (GLP-1) and gastric inhibitory peptide (GIP). GLP-1 and GIP active only in intact forms; the destruction of the Vuh N-terminal amino acids leads to their inactivation. In vivo introduction of synthetic inhibitors of DPP-IV prevents N-terminal destruction of GLP-1 and GIP, which leads to higher concentrations of these hormones in plasma, insulin secretion and, consequently, to increased glucose tolerance. For this purpose examine the ability of chemical compounds to inhibit the enzymatic activity of the purified CD26/DPP-IV. Briefly, the activity of CD26/DPP-IV is measured in vitro by the ability of this enzyme to cleave the synthetic substrate Gly-Pro-p - nitroanilide (Gly-Pro-pHA). As a result we DPP-IV cleavage of Gly-Pro-pHA released product p-nitroanilide (NSS), the degree of occurrence of which is directly proportional to the activity of the enzyme. Inhibition of enzyme activity by specific inhibitors of the enzyme reduces the destruction of the RNA. More strict interaction between the inhibitor and the enzyme leads to a slower rate of destruction of the RNA. Thus, the degree of suppression of the rate of accumulation of RNA is a direct indicator of the intensity of enzyme inhibition. The accumulation of RNA was measured by spectrophotometer. The inhibition constant, Ki, for each connection is determined by incubation of certain quantities of the enzyme with several different concentrations of inhibitor and substrate.

In the context of the present invention the term "inhibit the DPP-IV" also refers to the active metabolites and prodrugs, for example, the current metabolites and prodrugs of inhibitors of DPP-IV. The term "metabolite" means a valid derived inhibitor of DPP-IV, formed as a result of metabolism of the inhibitor of DPP-IV. The term "prodrug" means a compound, which as a result of metabolism becomes inhibitor of DPP-IV or the same metabolites (metabolites), which is converted inhibitor of DPP-IV.

Inhibitors of DPP-IV are known in the art. In subsequent references are examples of inhibitors of DPP-IV.

Preferred inhibitors of DPP-IV described is shown in the following patent applications: WO 02053548, especially compounds 1001-1293 and examples 1-124, WO 02067918, especially compounds 1000-1278 and 2001-2159, WO 02066627, especially the described examples, WO 02/068420, especially all compounds specifically listed in examples I-LXIII, and described their respective counterparts, also preferred are compounds 2(28), 2(88), 2(119), 2(136), described in the table that lists the values of IC50, WO 02083128, for example, in the claims 1-5, especially the compounds described in examples 1-13 and the claims 6-10, US 2003096846, especially the specifically described compounds, WO 2004/037181, especially examples 1-33, and most preferably the compounds described in the claims 3-5, WO 0168603, especially compounds of examples 1-109, IR, especially compounds of examples 1-60, WO 0181337, is particularly examples 1-118, WO 02083109, especially examples 1A-1G, WO 030003250, especially compounds of examples 1-166, most preferably 1-8, WO 03035067, especially the compounds described in the examples, WO 03/035057, especially the compounds described in the examples, US 2003216450, especially examples 1-450, WO 99/46272, especially compounds of claims 12, 14, 15 and 17, WO 0197808, especially compounds of claim 2, WO 03002553, especially compounds of examples 1-33, WO 01/34594, especially the compounds described in examples 1-4, WO 02051836, especially examples 1-712, ER, especially examples 1-7, ER, especially examples 1-32, US 2003087950, especially the described examples, WO 02/076450, especially examples 1-128, WO 03000180, especially examples 1-162, WO 03000181, especially examples 1-66, WO 03004498, especially examples 1-33, WO 0302942, especially examples 1-68, US 6482844, especially the described examples, WO 0155105, especially the compounds listed in examples 1 and 2, WO 0202560, especially examples 1-166, WO 03004496, especially examples 1-103, WO 03/024965, especially examples 1-54, WO 0303727, especially examples 1-209, WO 0368757, especially examples 1-88, WO 03074500, especially examples 1-72, examples 4.1-4.23, examples 5.1-5.10, examples 6.1-6.30, examples 7.1-7.23, examples 8.1-8.10, examples 9.1-9.30, WO 02038541, especially examples 1-53, WO 02062764, especially examples 1-293, preferably the compound of example 95 (2-{{3-(aminomethyl)-4-butoxy-2-neopentyl-1-oxo-1,2-dihydro-6-ethenolysis}oxy} acetamidomalonate), WO 02308090, especially examples 1-1 through 1-109, examples 2-1 to 2-9, example 3, examples C4-1 4-19, examples 5-1 through 5-39, examples 6-1 through 6-4, examples 7-1 through 7-10, examples 8-1 through 8-8, examples 7-1 through 7-7 on s, examples 8-1 on 8-59 on SS. 91-95, examples 9-1 on 9-33, examples 10-1 10-20, US 2003225102, especially compound 1-115, the compounds of examples 1-121, preferably compounds from a) to z), AA) to az), from ba to bz)from CA to cz) and da) to dk), WO 0214271, especially examples 1-320, and US 2003096857, WO 2004/052850, especially the specifically described compounds, for example, 1-42, and the connection of claim 1, DE 10256264 A1, especially the described connections, for example, 1-181 and connection of claim 5, WO 04/076433, especially the compounds specifically described, for example, listed in table, preferably compounds listed in TableB, preferred compounds I-XXXXVII, or connection points have 6 to 49, WO 04/071454, especially the specifically described compounds, for example compounds 1-53 or connection tables Ia no If, or compounds of claims 2-55, WO 02/068420, especially the compounds specifically described, for example, compounds I-LXIII, or product Beispiele I and analogues 1-140, or product Beispiele 2 and analogues 1-174, or product Beispiele 3 and alternative 1, or products Beispiele 4 and 5, or product Beispiele 6 and analogues 1-5, or product Beispiele 7 and analogues 1-3, or product Beispiele 8 and 1 analogue, or product Beispiele 9, or product Beispiele 10 and analogues 1-531, as well as the preferred connection of claim 13, WO 03/000250, especially specifically describe the connections, for example, compounds 1-166, preferably compounds of examples 1-9, WO 03/024942, especially the specifically described compounds, for example, 1-59, the compounds in table 1 (1-68), compounds of claims 6, 7, 8, 9, WO 03024965024942, especially the specifically described compounds, for example, 1-54, WO 03002593, especially the specifically described compounds, for example, compounds in table 1 or in the claims 2-15, WO 03037327, especially the compounds specifically described, for example, compounds in examples 1-209 WO 03/000250, especially compounds, for example specifically described compounds 1-166, preferably the compounds in examples 1-9, WO 03/024942, especially compounds, for example specifically described compounds 1-59, the compounds of table 1 (1-68), compounds of claims 6, 7, 8, 9, WO 03024965024942, especially the compounds specifically described, for example, compound 1-54, WO 03002593, especially the compounds specifically described, for example, compounds table 1 or of claims 2-15, WO 03037327, especially the compounds specifically described, for example, the compounds of examples 1-209, WO 0238541, WO 0230890, WO 03/000250, especially the compounds specifically described, for example, the compounds 1-166, preferably compounds of examples 1-9, WO 03/024942, especially the compounds specifically described, for example, compound 1-59, the compounds of table 1 (1-68), compounds of claims 6, 7, 8, 9, WO 03024965, especially connections, Conques is described to maintain, for example, compound 1-54, WO 03002593, especially the compounds specifically described, for example, compounds table 1 or of claims 2-15, WO 03037327, especially the compounds specifically described, for example, the compounds of examples 1-209, WO 0238541, especially the compounds specifically described, for example, the compounds of examples 1-53, WO 03/002531, especially the compounds specifically described, preferably the compounds listed in SS-13, most preferably compounds of examples 1-46, as well as the preferred compound of example 9, the patent US 6395767, preferably compounds of the examples 1-109, more preferably the compound of example 60, patent application US 09/788173, registered on February 16, 2001 (registration number LA50), especially the described examples, WO 99/38501, especially the described examples, WO 99/46272, especially the described examples, and DE 19616 486 A1, especially val-pyr, val-thiazolidin, isoleucyl-thiazolidin, isoleucyl-pyrrolidide and fumaric salt isoleucyl-thiazolidine and isoleucyl-pyrrolidide.

For your preferred inhibitors of DPP-IV also includes specific inhibitors described in US 6124305, US 6107317, WO 95153 09 and WO 9818763.

Published patent application WO 9819998 describes N-(N'-substituted glycyl)-2-cyanopyrrolidine, in particular 1-[2-[5-cyano-2-yl]amino]-ethylamino]acetyl-2-cyano-(S)-pyrrolidine (NVP-DPP728) and (2S)-I-[(2S)-2-amino-3,3-dimethylbutanol]-2-pyrrolidinecarbonyl.

Even on the nom preferred embodiment of the present invention the inhibitor of DPP-IV is N-peptidyl-O-aroylhydrazines or its pharmaceutically acceptable salt. Arola is, for example, afterburner; or benzoyl, which is unsubstituted, or mono - or disubstituted, for example lower CNS group, a lower alkyl group, halogen or preferably nitrogroup. Piptadenia part preferably contains two α-amino acids such as glycine, alanine, leucine, phenylalanine, lysine, or Proline, one of which is attached directly to the nitrogen atom of the hydroxylamine, preferably is a Proline.

Inhibitors of DPP-IV in each case in General and specifically described, for example, in WO 98/19998, DE 19616 486 A1, WO 00/34241, WO 95/15309, WO 01/72290, WO 01/52825, WO 03/002553, WO 9310127, WO 99/61431, WO 9925719, WO 9938501, WO 9946272, WO 9967278 and WO 9967279.

In each case, in particular in the present connection, and in the final products example, the nature of the final products, the pharmaceutical compositions and claims included in the present invention by reference to these publications.

Published patent application WO 9819998 describes N-(N'-substituted glycyl)-2-cyanopyrrolidine, in particular 1-[2-[5-cyano-2-yl]amino]- ethylamino]acetyl-2-cyano-(S)-pyrrolidin.

The preferred compounds described in WO 03/002553 are listed on the SS. 9-11 and included in the present invention by reference.

Patent DE19616 486 A1 describes val-pyr, val-thiazolidin, isoleucyl-thiazolidin, isoleucyl-pyrrolidide and fumaric with is whether isoleucyl-thiazolidine and isoleucyl-pyrrolidide.

Published patent application WO 0034241 and published patent US 6110949 describe N-substituted substituted-amino-acetyl-2-cyanopyrrolidine and N-(substituted glycyl)-4-cyanopyrrolidine, respectively. Interest inhibitors of DPP-IV are specifically those referred to in the claims 1-4. In particular, these applications describe the connection 1-[[(3-hydroxy-1-substituted)amino]acetyl]-2-cyano-(S)-pyrrolidin (also known under the designation LAF237 or called vildagliptin).

In WO 9515309 describes amino acid 2-cyanopyrrolidine amides as inhibitors of DPP-IV, and in WO 9529691 describes peptidyl double derivative esters of alpha-aminoalkylphosphonic acids, particularly Proline or related structures. Interest inhibitors of DPP-IV are specifically those referred to in tables 1-8.

In WO 01/72290 interest inhibitors of DPP-IV are specifically those referred to in example 1, and claims 1, 4 and 6.

In WO 01/52825 specifically describes the (S)-1-{2-[5-cyano-2-yl)amino]ethyl-aminoacetyl)-2-cyanopyrrolidine or (S)-1-[(3-hydroxy-1-substituted)amino]acetyl-2-cyanopyrrolidine.

In WO 9310127 describes esters of Proline and Baranovich acids that can be used as inhibitors of DPP-IV. Interest inhibitor and DPP-IV are exactly those referred to in examples 1-19.

Published patent application WO 9925719 describes surfactin, an inhibitor of DPP-IV, obtained by cultivation of a microorganism of the genus Streptomyces.

In WO 9938501 describes N-substituted 4-8 membered heterocycles. Interest inhibitors of DPP-IV are specifically those referred to in the claims 15-20.

In WO 9946272 described phosphorus compounds as inhibitors of DPP-IV. Interest inhibitors of DPP-IV are specifically those referred to in the claims 1-23.

Other preferred inhibitors of DPP-IV are compounds of formulas I, II or III described in patent application WO 03/057200 on SS. 14-27. The most preferred inhibitors of DPP-IV are compounds specifically described in SS. 28 and 29.

In yet another preferred embodiment of the present invention the inhibitor of DPP-IV is N-peptidyl-O-aroylhydrazines or its pharmaceutically acceptable salt. Arola is, for example, afterburner; or benzoyl, which is unsubstituted, or mono - or disubstituted, for example lower CNS group, a lower alkyl group, halogen or preferably nitrogroup. Piptadenia part preferably contains two α-amino acids such as glycine, alanine, leucine, phenylalanine, lysine, or p is Olin, one of them is attached directly to the nitrogen atom of the hydroxylamine, preferably is a Proline.

Published patent applications WO 9967278 and WO 9967279 describe prodrugs of DPP-IV inhibitors of the form a-b-C, where C is either stable or unstable inhibitor of DPP-IV.

Preferably N-peptidyl-O-aroylhydrazines is a compound of formula VII

where j denotes 0, 1 or 2;

1represents a side chain of natural amino acids; and

2represents a lower alkoxy group, lower alkyl group, halogen or a nitro-group;

or its pharmaceutically acceptable salt.

In a highly preferred embodiment, the present

the invention N-peptidyl-O-aroylhydrazines is a compound of formula VIIa

or its pharmaceutically acceptable salt.

N-peptidyl-O-aroylhydrazines, for example, of formula VII or VIIa, and obtaining them are described H.U. Demuth, etc. in J. Enzyme Inhibition 2, 1988, SS. 129-142, especially on the SS. 130-132.

Preferably inhibitors of DPP-IV are N-substituted adamantylamine-2-cyanopyrrolidines, N-(substituted glycyl)-4-cyanopyrrolidine, N-(N'-substituted glycyl)-2-cyanopyrrolidines, N-aminoethylethanolamine, N-AMINOETHYLPIPERAZINE, L-ALLO-solicitation, L-reasonally is lidin, and L-ALLO-isolatin1encoding, 1-[2-[(5-cyano-2-yl)amino]ethylamino]acetyl-2-cyano-(S)-pyrrolidin and their pharmaceutically acceptable salts.

Preferred are inhibitors of DPP-IV, described Mona Patel and others (Expert Opinion Investig Drugs. 12, 2003, SS. 623-633) in paragraph 5, specifically inhibitors R/98, 364, FE-999011, BDPX, NVP-DDP-728 and others, this publication is referred to in the present invention in the form of links, namely the described inhibitors of DPP-IV.

Connection FE-999011 described in patent application WO 95/15309, p.14, at number 18.

Another preferred inhibitor is a compound BMS-477118, described in WO 2001068603 or US 6395767 (compound in example 60), also known as (1S,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxytriazine[3.3.1.13,7]Dec-1-yl)-1-oxoethyl]-2-azabicyclo [3.1.0]hexane-3-carbonitrile, benzoate (1:1), which is shown in the formula M patent application WO 2004/052850 on page 2, and the corresponding free base (1S,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxytriazine[3.3.1.13,7]Dec-1-yl)-1-oxoethyl]-2-azabicyclo-[3.1.0]hexane-3-carbonitrile (M'), as well as its monohydrate (M), which is shown in the formula M patent application WO 2004/052850 on p.3. The compound BMS-477118 also known as saxagliptin.

Another preferred inhibitor is a compound GSK23A described in WO 03/002531 (example 9), also known as (2S,4S)-1-((2R)-2-amino-3-[(4-methoxybenzyl)sulfonyl]-3-methylbutanoyl)-4-ftorpirimidinu-2-carbonitrile the chloride.

Connection R/98 (CAS number: 251572-86-8), also known as 3-[(2S,3S)-2-amino-3-methyl-1-oxobutyl]thiazolidin, can be used in the form of a mixture of 3-[(2S,3S)-2-amino-3-methyl-1-oxobutyl]thiazolidine and (2E)-2-butenedioate (2:1), it is described in WO 99/61431, and here is the formula

described in WO 99/61431 and Diabetes 47, 1998, SS-1258, under the name of Probiodrug and called connection R/01, is described by the same company.

Other highly preferred inhibitors of DPP-IV are compounds described in the patent application WO 02/083128, for example, in claims 1-5. The most preferred inhibitors of DPP-IV are compounds specifically described in examples 1-13 and in the claims 6-10.

Other highly preferred inhibitors of DPP-IV are compounds described by Bristol-Myers Squibb, for example, saxagliptin (BMS477118).

Other highly preferred inhibitors of DPP-IV of the present invention described in the application for international patent WO 02/076450 (especially examples 1-128), as well as in the work of Wallace T. Ashton (Bioorganic & Medicinal Chemistry Letters 14, 2004, s-863), especially compound 1 and compounds listed in tables 1 and 2. The preferred connection is the connection a (table 1) formula

Other preferred inhibitors of DPP-IV are described in patent applications WO 2004/037169, the person is but in examples 1-48, and WO 02/062764, particularly described in the examples 1-293, also preferred are the compounds 3-(aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-ethanolinduced and 2-{[3-(aminomethyl)-2-isobutyl-4-phenyl-1-oxo-1,2-dihydro-6-ethanolic]oxy}acetamide", she described on p.7, as well as in patent application WO 2004/024184, especially in the examples 1-4.

Other preferred inhibitors of DPP-IV are described in the patent application WO 03/004498, especially in examples 1-33, most preferably the compound of the formula

described in example 7, and is also known under the designation MK-0431.

In each case, in particular, the compounds in the claims and the final products in the above examples, the essence of the final products, the pharmaceutical preparations and the claims are included in the present invention by reference to these publications.

Preferred inhibitors of DPP-IV is also described in the patent application WO 2004/037181, especially in examples 1-33, the most preferred are the compounds described in the claims 3-5.

Preferred inhibitors of DPP-IV are N-substituted adamantylamine-2-cyanopyrrolidine, N(substituted glycyl)-4-cyanopyrrolidine, N-(N'-substituted glycyl)-2-cyanopyrrolidines, N-aminoethylethanolamine, N-AMINOETHYLPIPERAZINE, L-ALLO-solicitation, L-threo-isoleucyl Raiden and L-ALLO-isolatin1encoding, 1-[2-[(5-cyano-2-yl)amino]ethylamino]acetyl-2-cyano-(S)-pyrrolidin, MK-431 and their pharmaceutical salts.

The most preferred inhibitors of DPP-IV is selected from [S]-1-[2-[(5-cyano-2-pyridinylamino)ethylamino]acetyl-2-pyridylacetonitrile, (S)-1-[(3-hydroxy-1-substituted)amino]acetyl-2-cyanopyrrolidine, L-threo-isoleucyl-thiazolidine (code connection Probiodrug: P32/98 as described above), MK-0431, 3-(aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-ethanolinduced and 2-{[3-(aminomethyl)-2-isobutyl-4-phenyl-1-oxo-1,2-dihydro-6-ethanolic]oxy}ndimethylacetamide and not necessarily their pharmaceutical salts.

[S]-1-[2-(5-cyano-2-pyridinylamino)ethylamino]acetyl-2-pyridylacetonitrile and (S)-1-[(3-hydroxy-1-substituted)amino]acetyl-2-cyanopyrrolidine specifically described in example 3 in WO 98/19998 in example 1 in WO 00/34241, respectively. Inhibitor of DPP-IV R/98 (see above) specifically described in Diabetes 47, 1998, SS-1258. [S]-1-[2-(5-cyano-2-pyridinylamino)ethylamino]acetyl-2-pyridylacetonitrile and (S)-1-[(3-hydroxy-1-substituted)amino]acetyl-2-cyanopyrrolidine can be recycled as described on p.20 in WO 98/19998 or in WO 00/34241.

Especially preferred are 1-{2-[(5-cyano-2-yl)amino] ethylamino}acetyl-2-(S)-cyanopyrrolidine (also called [S]-1-[2-(5-cyano-2-pyridinylamino)ethylamino]acetyl-2-pyrrolidinecarboxamido the reed) formulas N

especially in the form of its dihydrochloride and monohydrochloride, pyrrolidine, 1-[(3-hydroxy-1-substituted)amino]acetyl-2-cyano-, (S)(also called (S)-1-[(3-hydroxy-1-substituted)amino]acetyl-2-cyanopyrrolidine, LAF237 or vildagliptin) formula

,

and L-threo-solicitation (above designation of the compound according to Probiodrug: R/98), MK-0431, GSK23A, saxagliptin, 3-(aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-ethanolinduced and 2-{[3-(aminomethyl)-2-isobutyl-4-phenyl-1-oxo-1,2-dihydro-6-ethanolic]oxy}ndimethylacetamide and optional in each case, their pharmaceutical salts.

DPP728 and LAF237 specifically described in example 3 of patent WO 98/19998 in example 1 of patent application WO 00/34241, respectively. Inhibitor of DPP-IV P32/98 (see above) specifically described in Diabetes 47, 1998, SS-1258. Connection DPP728 and LAF237 can be processed according to the description on p.20 patent WO 98/19998, or in the patent WO 00/34241, or in international patent application EP 2005/000400 (application number).

Each of the substances described in the above patent documents and scientific publications cited in the present invention in the form of links and presumably is evaluated as an inhibitor of DPP-IV, which is applicable in the present invention.

Inhibitor of DPP-IV applied according to the present invention as the sole agent can note the change together with the carrier.

The media in the context of the present invention is a tool (natural, synthetic, peptide, ones), such as a protein, which transfers certain substances across the cell membrane, in which he is immersed, and delivers them in a cage. Different carriers (natural, synthetic, peptide, ones) are required for the transport of various substances, as each is designed to recognize only one substance or group of related substances.

Any detection methods known to experts in this field can be used to identify the Association of DPP-IV with a carrier, for example, application of a label on the media.

Inhibitor of DPP-IV can be a peptide or, preferably, ones nature.

Most preferred are inhibitors of DPP-IV oral administration and their pharmaceutically acceptable salts.

Active ingredients or pharmaceutically acceptable salt according to the present invention can also be applied in the form of MES, for example hydrates, or include other solvents used for crystallization. Active ingredients can also be in any crystalline form.

Unexpectedly, it was found that inhibitors of DPP-IV is applicable for the prevention, delay of progression or treatment of neurodegenerative disorders, cognit the main disorders to improve memory (short-term and long-term) and learning ability.

Preferably, the neurodegenerative disorder is selected from the following conditions and diseases: dementia (e.g., senile dementia, presenilny dementia (also called mild cognitive failure), associated with Alzheimer's disease (dementia of the Alzheimer's type)), horei of Hantington, tardive dyskinesia, hyperkinesias, mania, Parkinson's disease, syndrome of iron Richard, down syndrome, asthenic bulbar palsy, injuries of nerves and brain, vascular amyloidosis, cerebral haemorrhage with amyloidosis, inflammation of the brain, hereditary ataxia ataxia, acute disorders of consciousness, especially those who have partially observed apoptotic mikrocytos, for example amyotrophic lateral sclerosis, glaucoma, and especially Alzheimer's disease.

More preferably, the neurodegenerative disorder is selected from Alzheimer's disease and dementia, preferably senile dementia, mild cognitive failure, or dementia of the Alzheimer's type.

More preferably, the neurodegenerative disorder is Alzheimer's disease.

The use of an inhibitor of DPP-IV for the treatment of multiple sclerosis, migraine, stroke, cerebral ischemia, and disease Parkinson had already been described in patent application WO 03/002596, but the unexpected advantages and improved results were obtained when using as an inhibitor of DPP-IV vildagliptin. Impact on multiple sclerosis can be analyzed according to the Protocol of example 13 in the patent application WO 03/002596 referred to in the present invention by reference.

Thus, the present invention also relates to the use of vildagliptin or its pharmaceutical salts to obtain drugs for the prevention, delay of progression or treatment of multiple sclerosis, migraine, stroke, cerebral ischemia, ischemic lesions and Parkinson's disease.

The present invention also relates to a method of prevention, delay of progression or treatment of multiple sclerosis, migraine, stroke, ischemia, cerebral ischemia, ischemic lesions and Parkinson's disease involving the introduction of a warm-blooded animal, including man, in need, a therapeutically effective amount vildagliptin or its pharmaceutical salts.

The present invention also relates to the use of vildagliptin or its pharmaceutical salts to obtain drugs for the prevention, delay of progression or treatment of nonspecific peripheral neuropathy or diabetic peripheral is such neuropathy. The present invention also relates to a method of prevention, delay of progression or treatment of nonspecific peripheral neuropathy or diabetic peripheral neuropathy, involving the introduction of a warm-blooded animal, including man, in need, a therapeutically effective amount vildagliptin or its pharmaceutical salts.

The present invention also provides a use or a method of treating age-related cognitive impairment or mild cognitive deficiency, which includes the introduction of a patient in need, a therapeutically effective amount of an inhibitor of DPP-IV (preferably vildagliptin) as described above. In one of the embodiments of the present invention also provides a method of prevention, delay or cessation of any further age-related cognitive deterioration or progression of mild cognitive deficiency, comprising the administration to a patient in need, a therapeutically effective amount of an inhibitor of DPP-IV (preferably vildagliptin) as described above or its pharmaceutically acceptable salt.

In one of the embodiments of the present invention provides a use or a method of preventing or delaying began the development of dementia, associated with Alzheimer's disease, in a patient with age-related cognitive impairment or in patients with mild cognitive impairment.

In a particularly preferred embodiment of the present invention is selected neurodegenerative disorder is Alzheimer's disease (ad). It is preferable to prevent or delay the development of ad in a patient with age-related cognitive impairment or mild cognitive impairment. In a specific embodiment of the present invention, the inhibitor of DPP-IV is administered to a patient with age-related cognitive impairment or mild cognitive deficiency, which also has one or more risk factors for BA, selected from: family medical history; genetic predisposition to this disease; elevated serum cholesterol; non-insulin dependent diabetes mellitus; elevated levels in the cerebrospinal fluid (CSF) amount of tannins; elevated levels in CSF phospho-Tau protein; and low levels in CSF Ar.

Preferably, the cognitive disorder is selected from the following conditions and diseases: cognitive complications associated with schizophrenia, age-related memory impairments, cognitive impairments associated with what sihota, cognitive impairments associated with diabetes, cognitive impairment associated with ischaemic stroke, defects of memory, associated with hypoxia, cognitive disorders, and disorders of attention, associated with senile dementia, disorders of attention, memory impairment associated with mild cognitive deficiency, impaired cognitive function associated with dementia, impaired cognitive function associated with Alzheimer's disease, impaired cognitive function associated with Parkinson's disease, impaired cognitive function associated with vascular dementia, cognitive impairment associated with brain tumors, diseases of the Peak, cognitive impairment associated with autism, cognitive impairment after electroshock treatment, cognitive impairment associated with brain injury, memory impairment, dementia. Cognitive disorders include, but are not limited to, violations of learning abilities (skills), consolidation of memory, recovering memory and retention disorders.

More preferably cognitive disorder selected from cognitive impairment associated with diabetes, impaired cognitive function associated with Alzheimer's disease, violated cognition the second function, associated with Parkinson's disease, cognitive impairment associated with ischaemic stroke, cognitive disorders, and disorders of attention, associated with senile dementia, memory impairment associated with mild cognitive impairment.

In a particularly preferred embodiment of the present invention cognitive disorder selected from cognitive impairment associated with diabetes, impaired cognitive function associated with Alzheimer's disease and cognitive impairment associated with ischaemic stroke.

In a particularly preferred embodiment of the present invention cognitive disorder is selected from age-related cognitive deterioration. Preferably, the notion of "age" refers to the patient at the age of 55 years or older, 65 years or older, 75 years old or older.

Inhibitors of DPP-IV can also be used to improve memory (short-term and long-term) and learning ability in General, for example, for treating and/or preventing memory impairment in General. For example, inhibitors of DPP-IV can be particularly useful for improving the speed of skill acquisition and effective in the context of training and rehabilitation. In a preferred embodiment, the inhibitors of DPP-IV can be useful for the treatment violated the first memory or the ability to acquire the skills associated with age, resulting electroconvulsive therapy, or resulting from brain damage caused, for example, stroke, accident, head trauma, hypoglycemia, carbon monoxide poisoning, lithium intoxication or beriberi.

The present invention relates to the use of an inhibitor of DPP-IV or its pharmaceutically acceptable salt for a medicinal product for the prevention, delay of progression or treatment of neurodegenerative disorders, cognitive disorders and for improving memory (short-term and long-term) and learning ability.

In particular, the present invention relates to a new use (S)-1-[(3-hydroxy-1-substituted)amino]acetyl-2-cyanopyrrolidine (LAF237 or vildagliptin) or its pharmaceutically acceptable salt for a medicinal product for the prevention, delay of progression or treatment of neurodegenerative disorders, cognitive disorders and for improving memory (short-term and long-term) and learning ability.

The present invention also relates to a method of prevention, delay of progression or treatment of neurodegenerative disorders, cognitive disorders and for improving memory (short-term and long-term is) and the ability to learn, involving the introduction of a warm-blooded animal, including man, in need, a therapeutically effective amount of an inhibitor of DPP-IV, preferably vildagliptin.

In another embodiment, the present invention relates to the use of an inhibitor of DPP-IV, preferably (S)-1-[(3-hydroxy-1-substituted)amino]acetyl-2-cyanopyrrolidine (LAF237 or vildagliptin) of the formula (I) for the prevention and/or preventing memory impairment or learning ability, for example, due to the action of a toxic agent, brain injury, brain aneurysm, age-related memory loss, mild cognitive deficiency, epilepsy, mental retardation in children and dementia, which is a consequence of the disease, such as Parkinson's disease, Alzheimer's disease, AIDS, head injuries, diseases Hantington, disease Peak, disease of Creutzfeldt-Jakob disease and stroke. In addition, the compounds of the present invention can be applied to improve memory in normal individuals.

In another embodiment, the present invention relates to pharmaceutical compositions comprising a therapeutically effective amount of an inhibitor of DPP-IV in combination with one or more pharmaceutically acceptable carriers for the prevention, delay of progression or treatment neurodegenerative what's disorders cognitive disorders and for improving memory (short-term and long-term) and learning ability.

Unexpectedly, it was found that inhibitors of DPP-IV affect the growth of neuritis in neurodegenerative diseases, especially Alzheimer's disease and Parkinson's disease.

The term "prevention" refers to prophylactic administration of the combination to healthy patients to prevent the development referred to in the present invention States. Moreover, the term "prevention" refers to prophylactic administration of this combination in patients who are at a preliminary stage conditions being treated.

The term "delay of progression"as used in the present invention, refers to the introduction of combination, such as a combined preparation or pharmaceutical composition, the patients who are at the preliminary stage of the condition being treated, which is diagnosed in the initial stage of the corresponding state.

The term "treatment" refers to treatment and patient care for the treatment of the disease, condition or disorder.

Even though causes may be different, usually in patients with neurodegenerative disorders observed atrophy of brain cells, from localized to generalized, leading to the violation IU the orbital and physical function.

A condition mediated by DPP-IV, preferably selected from the group consisting of dementia, Alzheimer's disease, amyotrophic lateral sclerosis and glaucoma.

The most preferred condition mediated by DPP-IV, is dementia, Alzheimer's or Parkinson's disease.

The term "dementia" in the context of the present invention includes dementia type Alzheimer's type, Parkinson's disease, type of disease Hantington, type of disease Peak, the type of disease of Creutzfeldt-Jakob disease, and senile dementia, presenilny dementia, dementia of unknown origin associated with trauma dementia associated with stroke, dementia associated with cerebral hemorrhage dementia, vascular dementia, and includes acute, chronic or recurrent forms.

Alzheimer's disease is the most common form of dementia. It is a neurological disorder affects the brain and cause cognitive problems such as memory loss, impaired thinking, difficulty in performing familiar actions, disorientation in time and space, limited or reduced ability to form opinions, problems with language, changes in mood or behavior and personality. Old age is the main risk factor for Alzheimer's disease for whom Alemania, which affects 10% of the population aged 65 years and 50% to 85 years. Partially increased risk is related to the fact that with age, the vulnerability of brain cells to stress increases.

In Alzheimer's disease fragments of beta-amyloid protein (β) are accumulated with the formation of abnormal structures called amyloid plaques. To create effective treatments for Alzheimer's disease should be clear why in this disease as a result of violations of the chemical composition and cellular communications are killed brain cells. Many experts believe that the key point of cell death in Alzheimer's disease is the abnormal processing of amyloid precursor protein (PUB).

Parkinson's disease is a progressive disease of the Central nervous system, in the US hurts more than a million people. Typical clinical manifestations of this disease are loss of spontaneous movements, gait disturbance, impaired posture, rigidity and tremor. Parkinson's disease results from degeneration of pigmented neurons in the black substance of the brain, resulting in reduced availability of dopamine.

Parkinson's hurt both men and women. The frequency of occurrence of the disease is significantly higher in the age group of people over the age of 50 years, although it appears revona growth trend in the number of diseases among younger people. Because in this country and worldwide life expectancy has increased, the number of people with Parkinson's disease will increase.

Genetically programmed death of neurons in certain areas of the brain leads to the development of disease Hantington. The first symptoms of Hantington are mood swings, difficulty in acquiring new knowledge or memorization. Most drugs used to treat symptoms of Hantington cause side effects, such as fatigue, anxiety or hyperactivity. Currently there is no way to stop or reverse the disease progression of Hantington. Therefore, there is a need in the pharmaceutical agent for the treatment of manifestations of the disease with less severe side effects.

Diabetes, which is the cognitive disorder is associated with age-related condition. In the United States among people older than 65 years, diabetes is distributed approximately four times more often than among younger members of the community. In the U.S. more than 3 million seniors was identified diabetes; another 6 million have undiagnosed diabetes or increased resistance to glucose (Kenny and others, 1995). Because of the concomitant high prevalence of diabetes and dementia among older people is even moderate the relationship between diabetes and lower cognitive abilities may be of great importance for public health. In addition, diabetes, and dementia are complex clinical diagnoses, the treatment of which can be a challenge for physicians. Experimental evidence increasingly confirms that diabetes is associated with cognitive impairment. In addition, cognitive disorders may affect the ability of self-help and thus complicate therapy of diabetes. The impact of diabetes on cognitive function is supposed to be connected with factors, inseparable from diabetes (glycemia and insulin resistance), diabetic complications (stroke) or unwanted side effects from diabetes (hypoglycemia). Thus, there is a need for new medicines, which can provide improved treatment and prevention of cognitive lesions in patients with diabetes.

Alzheimer's disease is characterized by many symptoms, including cognitive lesions and impaired attention. Diagnostic signs of this disease are described in the book: "Diagnostic and Statistical Manual of Mental Disorders", 4th ed. American Psychiatric Association SM-T, cc. 139-143. To the diagnostic criteria of Alzheimer's disease is the development of a large number of patients with cognitive disorders, which manifest in the form of (1) non-persistent memory (reduced ability to learn new information or to reproduce previously usborn the th information) and (2) one (or more) of the following cognitive disturbances: (a) aphasia (disorder of the ability to speak and articulate thoughts), (b) apraxia (reduced ability to carry motor activities despite intact motor function) (C) agnosia (failure to recognize or identify objects despite intact sensory function), and (g) disorders of Executive activities (i.e. planning, organizing, sequencing, implementation actions, the ability to draw conclusions). Currently, these disorders are treated with cholinesterase inhibitors. These inhibitors reduce the breakdown of acetylcholine and provide a non-specific increase in the activity of cholinergic nervous system. Since these medicines are nonspecific, they are characterized by a wide range of side effects. Hence the need for new drugs that can improve impaired cognitive activity and attention associated with Alzheimer's disease, but without the side effects resulting from non-specific stimulation of the cholinergic pathways.

Musculoskeletal disorder associated with conventional antipsychotics. This disease is characterized by involuntary movements, which in most cases appear as utter lips and tongue and/or involuntary jerking of the arms and legs. The frequency of occurrence of musculoskeletal Rosstroy the VA is approximately 5% per year among patients receiving conventional antipsychotics. Approximately 2% of patients with musculoskeletal disorders are severely disfigured. Currently there is not a generalized treatment of movement disorders. Moreover, the abolition of causing musculoskeletal disorder medicines is not always a choice due to underlying problems. Therefore, there is a need for pharmaceutical agents aimed at treating the symptoms of movement disorders.

Presenilny dementia (mild cognitive disorder) refers to memory impairment in more than disorders of attention, and, on the other hand, does not violate cognitive function. Moderate cognitive disturbance is different from senile dementia that moderate cognitive disturbance is more persistent and difficult problem of memory loss over the life of the patient. There are currently no drugs intended for the treatment of moderately pronounced cognitive disorders, possibly because of the novelty identification of this disease. There is therefore a need in medicine to treat problems of memory impairment associated with mild cognitive impairment.

Age-related decline in cognitive ability and reasonable cognitiv the th failure (Chis) are States, when less memory is observed, but other diagnostic criteria for dementia are absent (Santacruz, Swagerty, American Family Physician, 63, 2001, s-713. (See also the book: "The ICD-10 Classification of Mental and Behavioural Disorders", Geneva, world health organization, 1992, SS-65). In the context of the present invention age-related decline in cognitive abilities is characterized by a decline, at least for four months, preferably for six months, at least one of the indicators: memory and learning abilities; attention and concentration, thinking; speech; ability to comprehend and conceptualize visual images and spatial relationships in teaching and performing tasks and the ability to mark more than one standard deviation from the standardized neuropsychological testing, for example, MEMS (inexpertise mental status). In particular, can be a progressive decline in memory. In more severe state of moderate cognitive impairment (Chis) the degree of memory impairment is outside the limit range, assessed as normal for the patient to be certain, but in the absence of Alzheimer's disease (AD). Differential diagnosis Chis and moderate BA described Petersen and others, Arch. Neurol., 56, 1999, SS-308. In this article, Petersen and Dr. who. describe that patients with Chis usually experience a progressive impairment in cognitive abilities and, in many cases, they develop AD. For more information on differential diagnosis Chis proposed Knopman and others in the Mayo Clinic Proceedings, 78, 2003, s-1308. In older subjects TuokLo and others (Arch. Neurol., 60, 2003, SS-582) found that those who showed Chis in the beginning of the study, the risk of developing dementia within 5 years was three times higher.

Grundman and others (J. Mol. Neurosi., 19, 2002, SS-28) reported that a lower initial level of hippocampal volume in patients with Chis is a prognostic indicator for the subsequent development of ad.

Similarly just dragging and others (Aeta Neurol. Scand, 107, 2003, SS-51) reported that in General, high levels of CSF Tau protein, phospho-Tau protein and decreased levels in CSF And,W all associated with an increased risk of progression from Chis to BA.

Age-related decline in cognitive ability and moderate cognitive disturbance differ from severe cognitive deficiency that may occur due to cerebral or systemic diseases and injuries, such as stroke, concussion or large separation of the pituitary gland.

People with down syndrome have in all cells, or at least in some cells an extra chromosome in the 21st pair of chromosomes. It is known that adults with down syndrome overview the wife's risk of developing dementia of Alzheimer's type. There is currently no effective treatment for down syndrome. Therefore, there is a need to treat dementia associated with down syndrome.

Senile dementia is not a uniform disease. However, the state classified under this name often include insufficient cognitive abilities and attention. Usually such failure is not cured. Accordingly, there is a need in the remedy capable of improvement with the lack of cognitive abilities and attention associated with senile dementia.

The disease peaks occurs as a result of slowly progressive deterioration of social skills and personality changes with symptoms that worsen the intellect, memory and speech. Usual symptoms include memory loss, loss of natural behavior, difficulty thinking or concentrating, and impaired speech. There is currently no specific treatment for the disease peaks, but some symptoms can be treated with cholinergic, serotonin-enhancing antidepressants. In addition, antipsychotic drugs can alleviate the symptoms of patients with FTD, which are subject to the delusional ideas and hallucinations. Thus, there is a need in the pharmaceutical agent for the treatment prog is esteroideo deterioration of social behavior and personality changes, which would be designed to treat symptoms, but with less manifestation of side effects.

Traumatic brain injury occurs when an accidental physical injury to the head. The symptoms of traumatic brain injury include confusion, and other cognitive disorders. Thus, there is a need in the treatment of symptoms of mental confusion and other cognitive disorders.

Brain tumors are abnormal tissue growth, developing inside the skull. Symptoms of brain tumors are disorders of behavior and cognitive abilities. For the treatment of tumors use surgery, radiation and chemotherapy, but also requires agents to treat accompanying symptoms. Thus, there is a need in the treatment of symptoms of behavior disorders and cognitive disorders.

Pharmaceutical action caused by the introduction of the representatives of the class of inhibitors of DPP-IV applied according to the present invention, can be shown, for example, through the use of appropriate pharmacological models known in the art. Specialist in the art is fully capable to choose the appropriate model experimental animal for confirmation described in the present invention these therapeutic indications Leche and the service effects.

Pharmacological action of the compounds and combinations according to the present invention when the neurodegenerative disease can be established, for example, as follows:

A) in experiments on mice compounds in doses of 0.01 to 100 mg/kg, more preferably in doses from 0.1 to 50 mg/kg, when administered orally cause a prolonged stage of wakefulness and increased responsiveness to external stimuli,

B) when studying the cycle of sleep/wakefulness in rats with implanted electrodes compounds in doses of 0.01 to 100 mg/kg, more preferably in doses from 0.1 to 50 mg/kg, when administered orally to increase REM sleep, and

(B) in experiments on rats using labeled14With deoxyglucose (experiments are based on the publications: Sokoloff, Journal of cerebral Blood flow and metabolism 1, 1981, cc.7-36, H.E Savaki, etc., Brain research 233, 1982, s; J. Mc Culloch and others, Journal of cerebral Blood Flow and Metabolism 1, 1981, 133-136), compounds in doses of from about 0.01 to 100 mg/kg, more preferably in doses from 0.1 to 50 mg/kg, when administered orally to increase the consumption of labeled14With deoxyglucose in certain areas of the brain, especially the limbic system.

In the cycle of sleep/wakefulness in rats with prolonged implantation method described J-M Vigouret etc., J. pharmacology 10, 1978, s) compounds according to the present invention when the doses from 0.01 to 10 mg/kg, more preferably in doses from 0.1 to 50 mg/kg (oral introduction) can increase wakefulness due to prolongation of the phase of the excitation.

In addition, after oral administration of doses from 0.01 to 100 mg/kg, more preferably doses from 0.1 to 50 mg/kg, rats with bilateral lesions of blue spots (SE) and basal core Meinert (BAM), the connection according to the present invention can significantly improve cognitive action, which is measured by the ability to avoid electric shock, while in the Shuttle box.

This method resembles other methods described V.Haroutunian etc. in Brain Research 507, 1990, SS-266. Male rats OFA (weight 300 g) were anestesiologi pentobarbital and placed in a stereotaxic instrument with the top strap, mounted on 5 mm above the incisors (SE) or 3.3 mm (BAM) below the inner ear line. Damage inflicted by a generator of radio frequency damage at 60 C for 10 sec. After 5 weeks of training studied the behavior of animals, using the method based on the ability to avoid electric shock, while in the Shuttle box; the method described A.R.Dravid, A-L. Jaton and ..Van Deusen in Experimental Brain Research, Appendix 13, 1986, s.

The present invention is also based on the surprising discovery that compounds and combinations according to the present izobreteny who show clear protective effect of facial motor neurons from apoptotic macrocytosis; they can be used in doses of 0.01 to 100 mg/kg, more preferably in doses from 0.1 to 50 mg/kg (subcutaneous injection) and below, put a newborn rats according to the scheme of the experiment described Ausari etc. in J. Neuroscience 13, 1993, SS-4053, and show a pronounced protective effect of pyramidal cells of the hippocampus during 4 days from macrocytosis, caused by injection of kainic acid, which can be achieved after administration of doses from 0.01 to 100 mg/kg, more preferably doses from 0.1 to 50 mg/kg (after subcutaneous administration) and below under the age of full adulthood in rats according to the scheme of the experiment described Golowitz and Paterson, Soc, Neurosc. Abstr. 20, 1994, 246, 113.2.

Experimental rat model of Alzheimer's disease was important for understanding neurodegenerative diseases and have yielded promising new approaches to treatment.

Mutations of the amyloid precursor protein (PUB) cause early start family Alzheimer's disease (ad) by the defeat of the formation of amyloid β-peptide (β) - principal Deputy plaques in ad. Were obtained from transgenic mice expressing the PUB with mutations at codon 717 and 670/671 using multiple neuron-specific promoters to run the expression of a PUB person with cDNA molecules. The degree of pathological lesions depends on the levels of expression of specific mutations. DV is a multiple of the excess of the expression of a PUB person with the Swedish double mutation at position 670/671, combined with V717I mutation causes deposition β in the neocortex and hippocampus of 18-month-old transgenic mice.

Transgenic mouse lines AR with increased expression of one mutant predshestvennika amyloid protein are one pathological feature of Alzheimer's disease, namely the extracellular deposition of amyloid plaques (Calhoun and other Proceedings of the National Academy of Sciences of The United States of America 96, 1999, SS-14093).

These experimental mice ARR in addition to amyloid plaques developing cerebrovascular accumulation of amyloid β. Cerebral amyloid angiopathy and associated pathology in these mice show a striking resemblance to similar pathologies observed in elderly individuals and in patients with Alzheimer's disease. Cerebrovascular accumulation of amyloid β (CNA) in mice lines ARR leads to the loss of focal neuronal degeneration of synaptic vesicles and the activation of microglia, suggesting that the CNA leads to neurodegeneration.

Transgenic mouse lines ARR especially useful for demonstrating the pharmacological action of the compounds and combinations according to the present invention.

Examples 2-4, described in patent application WO 2005009349 describe other protocols to evaluate the activity of compounds and combinations of the present invention for treating or preventing Shin the Roma X, BA, Parkinson's disease.

Pharmacological action of the compounds and combinations according to the present invention for improving cognitive function can be assessed using tests known to specialists in this field, such as standardized psychometric tests (e.g., scale memory Wesley, scale Wesley to assess intelligence in adults, standard serial matrix Ravena, test the mental capacity of adults Shaie-thurstone), neuropsychological tests (for example, test Luria-Nebraska), metacognitive self-assessments (e.g., questionnaires assessing memory), tests of visual-spatial filtering (e.g., figures of Poppelreiter, recognition of hours drawing and Erasure hundred), tests of cognitive filtering (for example, mini-tests of mental status Folstein) and test response times. The above standardized tests described in Ruoppila, I. and Suutama, T., Scand. J. Soc. Med. Suppl. 53, 1997, SS. 44-65 and examples, this reference incorporated the present invention in its entirety. The term "cognitive function" includes functions, evaluated any of these tests.

Clinical Protocol for the demonstration of a positive effect of the inhibitor of DPP-4, or combinations of the present invention on for BA is described in patent application WO 2004/082706 on SS-37, which is incorporated into this invention by reference.

The degree of reduction or damage to the cognitive abilities of the patient effectively assess at regular intervals before, during, or after treatment with the inhibitor of DPP-IV or pharmaceutically acceptable salt so that this can be fixed changes, such as reduction or distortion of cognitive decline. Various neuropsychological tests used for this purpose are known in this field, such as inexpertise mental status (MEMS), they take into account the norms for their age and education (Folstein, etc., J. Psych. Res., 12, 1975, SS-198, Anthony and other Psychological Med., 12, 1982, SS-408; Cockrell and others, Psychopharmacology, 24, 1988, SS-692; Crum and others, J. Am. Med. Assoc., 18, 1993, SC-2391. MEMS is a brief quantitative measure of cognitive status in adults. It can be used to search for reduction or damage to cognitive abilities, to assess the severity of reduction or damage to cognitive ability at this time to assess cognitive changes in an individual over time and to identify individual treatment response.

Other standard tests to assess cognitive status, such as the scale for the assessment of Alzheimer's disease (ADAS - cog), described Doraiswamy (Neurology, 48, 1997,

SS-1517) and in patents US 20040024043 and US 6369046. Test ADAS-cg is a multi-component tool to measure cognitive status, consisting of elements of memory, orientation, retention, relevance, language and praxis. US 20040024043 also describes in vivo test model in rodents in example 5, and the schema of the clinical studies in example 9. Another clinical study design described in US 6369046 (example 1).

Another Protocol that can be applied in vivo to show that inhibitors of DPP-IV can improve cognitive function, described in EP 1310258 (examples 5-8).

Patents WO 2004004664, WO 2004004702, WO 2003101276 (examples 1-9) or WO 2004096225 in example 3 describe the protocols that can be applied to evaluate the strengths vildagliptin for the treatment or prevention of ischemia or ischemic damage.

Patent WO 0110867 describes the protocols that can be used to evaluate the strengths vildagliptin for the treatment or prevention of stroke.

In WO 2004006911 (experimental part), WO 0162277 (example 2) provided by the protocols, according to which one can evaluate the benefits vildagliptin for treating or preventing peripheral neuropathies, especially diabetic peripheral neuropathies. Topical application can be replaced by oral administration vildagliptin. Peripheral sensory neuropathy is a relatively common and often debilitating complication of diabetes mellitus (Greene and others, 1990,but its etiology and leg is based on the basis of the pathophysiology has not been elucidated (Ward, 1992).

The above-mentioned documents, especially the described test-models are provided in the present invention by reference.

The present invention also relates to the combination of at least one inhibitor of DPP-IV or its farmatsevticheskii acceptable salt, and at least one COMBINABLE COMPONENT of the PRESENT INVENTION, which can be applied for the prevention, delay of progression or treatment of neurodegenerative disorders, cognitive disorders and for improving memory (short-term and long-term) and learning ability, for the treatment of warm-blooded animals including mammals, especially humans with neurodegenerative disease or is susceptible to neurodegenerative diseases, especially Alzheimer disease or Parkinson's disease.

Most surprising is the experimental result, showing that the combined introduction of the inhibitor of DPP-IV, especially (S)-1-{2[5-cyano-2-yl)amino]acylaminoacyl}-2-cyanopyrrolidine (DPP728) or (S)-1-[(3-hydroxy-1-substituted)amino]acetyl-2-cyanopyrrolidine (LAF237), and at least one additional combine partner present invention not only leads to healing, especially potentiating or cinergena therapeutic effect, but also to complement the d advantages resulting from combined treatment such as unexpected prolongation of efficacy, a broader variety of therapeutic treatment and surprising therapeutic effects against neurodegenerative diseases and conditions, as well as cognitive disorders, such as already described above.

Combinable component of the present invention includes, for example, drugs belonging to different pharmacological classes, important for Central and peripheral degenerative diseases, such as anti-inflammatory drugs, anti-oxidant agents and neuroprotective agents (e.g., antagonists of glutamate receptor), is effective against and peripheral neuropathy and neurodegenerative diseases, MAO inhibitors, inhibitors of COMT, as well as acetylcholinesterase inhibitors (e.g., rivastigmine (Exelon)), inhibitors butyrylcholinesterase, inhibitors of gamma - and beta-secretase, inhibitors of amyloid aggregation, agonists or antagonists of dopamine and immunization, and active (amyloid beta-peptide, paired or not paired with adjuvants), and passive (specific antibodies to amyloid beta peptide), in the case of Alzheimer's disease, drugs for treatment of cognitive disorders, such as selective inhibitor and miljoministern, for example donepezil.

The inhibitors of COMT, for example, include, but are not limited to, tolkapon and entacapone.

To anti-inflammatory agents include, but are not limited to, naproxen sodium, diclofenac sodium, diclofenac potassium, celecoxib, sulindac, oxaprozin, diflunisal, etodolac, meloxicam, ibuprofen, Ketoprofen, nabumetone, rofecoxib, methotrexate, Leflunomide, sulfasalazin, gold salts, RHo-D immune globulin, mycophenolate mofetil, cyclosporine, azathioprine, tacrolimus, basiliximab, daclizumab, salicylic acid, acetylsalicylic acid, methyl salicylate, diflunisal, salsalate, alazarin, sulfasalazin, acetaminophen, indomethacin, sulindac, mefenamovaya acid, meclofenamate sodium, tolmetin, Ketorolac, diclofenac, flurbiprofen, oxaprozin, piroxicam, meloxicam, ampiroxicam, droxicam, pivoxil, tenoxicam, phenylbutazone, oxyphenbutazone, antipyrine, aminopyrine, Amazon, Smeaton, aurothioglucose, thiomalate sodium, auranofin, methotrexate, colchicine, allopurinol, probenecid, sulfinpirazon and benzobromarone or betamethasone and other glucocorticoids.

Preferably the compounds having inhibitory activity against acetylcholinesterase selected from the group comprising 3-[1-(phenylmethyl)-4-piperidinyl]-1-(2,3,4,5-tetrahydro-1H-1-benzazepin-8-yl)-1-propanolamine, 2,3-dihydro-5,6-d is methoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-inden-1-he hydrochloride (donepezil, sold under the trade name ARICEPT®), (S)-3-[1-(dimethylamino)ethyl]phenyl N-ethyl-N-methylcarbamate (rivastigmine), 9-amino-2,3,5,6,7,8-hexahydro-1H-cyclopent[b]quinoline (ipidacrine), 1,2,3,4-tetrahydro-9-aminoacridine hydrochloride (taken sold under the brand name COGNEX®,), 8-[3-[4-(diethylcarbamoyl)piperazine-1-yl]propyl]-1,3,7-trimethylxanthine hydrochloride (stackopolis), 4A,5,9,10,11,12-hexahydro-3-methoxy-11-methyl-6-N-benzofuro[3A,3,2-ef][2]benzazepin-6-ol (galantamine), and dimethyl(2.2.2-trichloro-1-hydroxyethyl)phosphonate (metrifonate), eptastigmine, velnacrine, fototermin, iksemel, amiridin, minupren, huperzine, Kuprin, bis-tetrahydroaminoacridine (bis-TGA), imidazoles, 1,2,4-thiadiazolidine, benzazepin, 4,4'-bipyridine, indenopyrene, decamethonium, eiroforum, propidium, fasciculi, organophosphates, carbamates, imino-1,2,3,4-tetrahydrocyclopent[b]intolerability, N-pyrimidine-4-acetylenyl, 7-aryloxyalkyl, propargylamine, ziprasidon NOS inhibitors, precursors of acetylcholine, such as choline and pyrrolidinedione, or agonists cholinergic receptor (e.g., nicotine, especially meaningful, and muscarinic) and their therapeutically and pharmaceutically acceptable salts.

Preferably the antioxidant is selected from vitamin C and E, the modulator of the NMDA (N-methyl--aspartate) is memantine, an MAO inhibitor selected from rasagiline, selegiline is, tranylcypromine, iproniazida, clorgyline, phenelzine and isocarboxazid.

In the treatment of BA used in the present standard dose of tacrine is 10 mg a four-time use per day, 40 mg per day is the maximum recommended number. At the present time capsule of tacrine used orally. The standard dose of donepezil is 5 mg/day at the recommended maximum of 10 mg/day. Currently, tablets donepezil is used for oral administration.

The standard dose of rivastigmine 1.5 mg twice a day when the recommended maximum of 6 mg twice a day. Currently capsules rivastigmine is used orally. For galantamine currently used standard dose is 4 mg twice a day. Currently pills galantamine are used for oral administration.

In a preferred embodiment of the present invention, taken injected at a dose of about 0.1 mg per individual per day, preferably about 10-150 mg per individual per day, more preferably about 20-60 mg per individual per day, or approximately 60-100 mg per individual per day.

In another preferred embodiment of the present invention donepezil is administered at a dose of about 0.1-200 mg per individual per day, preferably about 1-100 mg per individual per day, more predpochtite is) about 2-30 mg per individual per day, or approximately 30-60 mg per individual per day.

In another preferred embodiment of the present invention rivastigmine administered at a dose of about 0.1-200 mg per individual per day, preferably about 0.3-50 mg per individual per day, more preferably about 0.5-20 mg per individual per day, or about 20-40 mg per individual per day.

In another preferred embodiment of the present invention galantamine is administered at a dose of about 0.1-200 mg per individual per day, preferably about 0.5 to 100 mg per individual per day, more preferably about 1-30 mg per individual per day, or approximately 30-60 mg per individual per day.

Actually applied dose may vary depending on the needs of the patient and severity exposed to the treatment condition. Choosing the right dose regime in a particular situation is determined by the person skilled in the art. For convenience, the total daily dose may be divided and put the parts in a day as needed.

In a preferred embodiment of the present invention cholinesterase inhibitors preferably introduced orally.

Agonists or antagonists of dopamine, such as, but not limited to, levodopa, combination of L-DOPA/carbidopa, cocaine-methyltyrosine, reserpine, tetrabenazine, benzotropine, pargyline, mesilate of pentalpha, the Kaba is Golin, pramipexol the dihydrochloride, ropinerole, amantadine hydrochloride, selegiline hydrochloride, carbidopa, mesilate of pergolid, sinemet CR or simecal.

Combinable component of the present invention includes, for example, other medicines, improving cognitive function, such as agents, aimed at regulating GABA (gamma-aminobutyric acid), NMDA (N-methyl-D-aspartate), cannabinoid, AMPA ((S)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolidinone acid), kainate, phosphodiesterase (PDE), PKA (protein kinase A), RKS (protein kinase C), CREB (camp-response element-binding protein) or nootropic systems.

The results of these studies show that the combination according to the present invention can be used for the prevention, delay of progression or treatment of neurodegenerative disorders, cognitive disorders and for improving memory (short-term and long-term) and learning ability, in particular the aforementioned diseases.

The concept of "synergenic" means that a drug used together, give a joint effect that is greater than the sum of effects of each drug taken separately.

The term "potentiation" means a corresponding increase pharmacological activity or therapeutic effect, the respectively. Potentiation of one component of the combination according to the present invention by combining the introduction of another component according to the present invention means that the achieved action more action, achieved only by the introduction of a single component.

The structure of the active agents determined code numbers, generic or trade names may be gleaned from the latest edition of the standard reference book "The Merck Index" or from databases, for example. Patents International (e.g. IMS World Publications). Corresponding information is provided in the present invention in the form of links. Any person skilled in the art are fully capable of identifying active agents and, on the basis of data sources may also receive and test pharmaceutical indications and properties using standard test models and in vitro and in vivo.

Another object of the present invention is the use of pharmaceutical compositions comprising as active ingredients only one inhibitor of DPP-IV, or in combination, at least one combinable component of the present invention, in each case in free form or in the form of its pharmaceutically acceptable salts, for the preparation of pharmaceutical compositions for the prevention, delay of progression or treatment of n is rodegenerative disorders, cognitive disorders and for improving memory (short-term and long-term) and learning ability, particularly preferred of the above-described conditions.

The present invention also relates to pharmaceutical compositions comprising as active ingredients only one inhibitor of DPP-IV, or in combination, at least one combinable component of the present invention, in each case in free form or in the form of its pharmaceutically acceptable salts.

It is also an object of the present invention is the use of pharmaceutical compositions comprising as active ingredients only one inhibitor of DPP-IV, or in combination, at least one combinable component of the present invention, in each case in free form or in the form of its pharmaceutically acceptable salts, for the preparation of pharmaceutical compositions for the prevention, delay of progression or treatment of neurodegenerative disorders, cognitive disorders and for improving memory (short-term and long-term) and learning ability, particularly preferred of the above-described conditions.

The present invention also relates to a method of prevention, delay of progression or treatment of neurodegenerative resstr ist, cognitive disorders and for improving memory (short-term and long-term) and learning ability, including the introduction of a warm-blooded animal, including man, in need of this, simultaneously therapeutically effective amounts of compositions containing as active ingredients only one inhibitor of DPP-IV, or in combination, at least one combinable component of the present invention, in each case in free form or in the form of its pharmaceutically acceptable salts.

Such pharmaceutical preparations intended for oral administration, for example oral or rectal, or parenteral administration warm-blooded animals with drugs, including either only one pharmaceutical active compound or together with customary pharmaceutical additional substances. For example, pharmaceutical preparations made from about 0.1 to 90%, preferably about 1-80% of the active compound. Pharmaceutical preparations for oral administration or parenteral administration, as well as for ocular injection, there are, for example, in unit dosage forms such as tablets, coated tablets, capsules or suppositories, and also ampoules. They are prepared by a method, the essence of which is known, for example, using tra the investment processes of mixing, granulating, coating, dissolving or lyophilization. Thus, pharmaceutical preparations for oral use can be obtained by combining the active compound with solid excipients, optionally granulare the resulting mixture, and, if desired or if necessary, processing the mixture or granulate into tablets or core tablets are coated after adding suitable additional substances.

The dose of active compound may depend on various factors such as method of administration, the species of warm-blooded animal, age and/or individual condition.

Mainly neurodegenerative diseases common among patients 50 years and older, most often among patients 65 years and older.

Preferred doses for those active ingredients of the pharmaceutical combinations according to the present invention, are commercially available, are specifically therapeutically effective commercially available dose.

The dose of active compound may depend on various factors, for example, the method of administration, species of warm-blooded animal, age and/or individual condition.

The corresponding active ingredient or its pharmaceutically acceptable salt can also be used in the form of a hydrate or on the part of other solvents, used for crystallization.

For these indications the exact dose can certainly vary depending on the compound, the route of administration and desired treatment. The connection may be entered in any traditional way, mostly oral or different way.

Generally satisfactory results are obtained with the introduction of a daily dose of approximately 0.01 to 100 mg/kg, more preferably a dose in the range 0.1-50 mg/kg

For larger mammals shows the total daily dose of a compound is in the range of about 0.01 to 100 mg/kg and normally divided 2-4 intake per day in unit dosage form containing, for example, from about 0.1 to about 50 mg or 100 mg of the compound in the form of a stable release.

Proper daily oral dose specifically for vildagliptin is 1-500 mg, preferably 10-100 mg, for example 10 mg or 25-100 mg, most preferably 50-10, for example, 25 mg, or 40, or 50, or 70, or 100 mg.

Suitable single dose for oral administration specifically for vildagliptin contain, for example, about 10-100 mg compounds, preferably 25 mg, or 50 mg, or 100 mg of the Appropriate dose for parenteral administration specifically for vildagliptin contain, for example, about 10-50 mg or 25-100 mg compounds, such as 25 mg, 5 mg, 75 mg or 100 mg

Suitable single dose for oral administration specifically for preventive treatment include, for example, about 0.5-15 mg compounds, such as 1-10 mg Appropriate dose for parenteral administration include, for example, approximately 0.2-30 mg compounds, e.g. 0.3-10 mg

Connections can be introduced in a way that is close to standard methods used for such purposes. Suitable daily dose of a particular compound can depend on a number of factors, for example, the relative power of action. Specialist in the art is fully capable to determine a therapeutically effective dose.

The compound of the present invention may be in the form of a free base or as farmatsevticheskii acceptable acid additive salt or Quaternary ammonium salt. Such salts can be prepared in the traditional way, and they are of the same order effect, and unbound forms. If these compounds are, for example, at least one basic center, they can form acid additive salt. The corresponding acid additive salts may also be formed in the presence of, if necessary, additional present the main center. Compounds having an acid group (for example COOH)can also form salts with bases. For example, combine the compounds may be in the form of sodium salt, as maleate or dihydrochloride. The active ingredient or its pharmaceutically acceptable salt can also be used in the form of hydrates or include other solvents used for crystallization.

One of the objectives of the present invention is to develop a pharmaceutical composition (fixed combination), including (i) an inhibitor of DPP-IV or its pharmaceutically acceptable salt and (ii)at least one additional combine component of the present invention and at least one pharmaceutically acceptable carrier.

The pharmaceutical compositions according to the present invention can be prepared in a known manner, and those that are applicable for oral administration, for example oral or rectal, and parenteral administration mammals (warm-blooded animals), including humans, contain a therapeutically effective amount of the pharmacologically active compound, one or in combination with one or more pharmaceutically acceptable carriers, especially suitable for oral administration or for parenteral use.

In such compositions the components (i) and (ii) can be put together, one after the other or separately in one combined unit dosage form or in two separate unit dosage forms. Water is the preferred embodiment of the present invention, the unit dosage form is a fixed combination. In fixed combination of components (i) and (ii) are introduced in the form of a herbal composition, for example a tablet or one of infusions.

The pharmaceutical combination according to the present invention described above and below, can be used for simultaneous or sequential use, in any order, for separate use or as a fixed combination.

Under certain circumstances, drugs with different mechanisms of action can be combined. However, an objective evaluation of any combination of drugs with different mechanisms of action, but acting on similar sites, does not necessarily lead to combinations with improved properties.

Other advantages are that lower doses of the individual combined medicines according to the present invention can be used to reduce the dosage, for example, not only the required dose may be lower, but they can also be applied less frequently, or can be used to reduce the frequency of side effects. This is consistent with the wishes and needs of the affected patients.

The pharmaceutical combination according to the present invention includes a "kit of parts"; this means that components can be dosed independent is, or by use of different fixed combinations with varying amounts of compounds at different times. Part of the "kit of parts" can then, for example, be administered simultaneously or at certain intervals, at different times and with equal or different time intervals for any part of the "kit of parts". Preferably the time intervals are chosen so that the impact on the disease or condition on the combined use of the parts is greater than the effect that would be obtained by applying any one of the components.

The present invention also relates to a commercial package comprising a combination according to the present invention together with instructions for simultaneous, separate or sequential use.

A therapeutically effective amount of each of the components of the combination of the present invention may be administered simultaneously or sequentially and in any order, and the components can be introduced separately or as a fixed combination. For example, described in the present invention the method of treatment may include (i) the introduction of an inhibitor of DPP-IV in free form or in the form of a pharmaceutically acceptable salt and (ii) introducing at least one additional combine component of this image is the shadow, at the same time or sequentially in any order, simultaneously in an effective therapeutic amounts, preferably in an efficient resulting in synergistic amounts, e.g. in daily doses corresponding to the ratios described in this invention.

Additional advantages are that lower doses of the individual combined medicines according to the present invention can be applied to lowering the dose, which, for example, can not only be smaller but are also applied less frequently, or can be used to reduce the frequency of side effects. This corresponds to the wishes and needs of the affected patients.

Dose range combination of an inhibitor of DPP-IV and at least one applicable additional combinable component of the present invention depends on factors known to specialists in this area, including species of warm-blooded animal, body weight and age, the nature and severity exposed to the treatment condition, the route of administration and specific applicable substances. If the present invention is not specified otherwise, the inhibitor of DPP-IV and at least one additional combine component of the present invention preferably divided and administered from 1 to 4 times per day.

Despite the fact that this is completed with the invention described above with the preferred options for its implementation, for specialists in this area it is obvious that in these options, you can make various changes and improvements in the scope of the following claims.

All the patents and articles cited in the present description, given in reference to their essence. In the event of any inconsistency present description, including definitions and interpretation prevails.

Experimental part

Example 1. Therapy to prevent or delay the development of Alzheimer's disease

One tablet vildagliptin mass of 25 or 50 mg administered daily with water to subjects in need of such therapy.

Example 2. Therapy to prevent or delay the development of Alzheimer's disease in a subject exhibiting mild cognitive disorder

Subject with mild cognitive disorder, identify using MEMS (inexpertise mental status) or similar diagnostic examination.

One tablet vildagliptin mass of 25 or 50 mg enter the specified subject daily with water. The cognitive status of the subject is subjected to periodic monitoring using MEMS or similar expertise, as well as monitor the subject has clinical symptoms of dementia.

Example 3. Treatment, prevention or delay cognitive impairment associated with Diab is the fact

One tablet vildagliptin mass of 50 mg administered daily with water to subjects in need of such therapy, such as patients with diabetes. The cognitive status of the subject is subjected to periodic monitoring using MEMS or similar expertise

Example 4

Improved effect vildagliptin or combined use vildagliptin connections, any abscopal cholinesterase, when learning disabilities are exploring in old rats. The following methods describe a set of experiments using vildagliptin as monotherapy, or vildagliptin with a cholinesterase inhibitor such as donepezil.

Methods

Use of male rats (aged 3-27 months) transgenic line. Old rats distributed into the following four groups (dose of active ingredient can be adapted by the person skilled in the art).

1) Control group: repeated administration of placebo pills.

2) Group vildagliptin: repeated oral administration of vildagliptin dose of 3 mg/kg

3) the Group of cholinesterase inhibitor: repeated oral administration of donepezil at a dose of 0.3 mg/kg

4) application Group combinations: repeated oral administration of vildagliptin dose of 3 mg/kg) and donepezil at a dose of 0.3 mg/kg

In the group use a combination vildagliptin injected 30 min after in the edenia donepezil.

Test learning passive avoidance begin a 14 day treatment, and test learning the water maze Morris start to spend on the 20th day of treatment.

On each day of the experiment vildagliptin and/or the cholinesterase inhibitor is administered for 30 min or 1 h before the start of the study, respectively.

1. Learning passive avoidance test learning passive avoidance is done using the camera, consisting of light and dark compartments. Young rats (tablets, 10 animals) and old rats (control group, 10 animals; group vildagliptin, 10 animals; group donepezil, 10 animals; application group combinations, 10 animals) separately placed in the bright compartment and after 10 sec open sliding door. After moving rats in the dark compartment leave her there for about 10 seconds behind the closed door. 1-2 hours after getting used to investigate the ability to learn.

In the study of learning ability after moving the mouse in a dark compartment through the slatted floor serves current (0.4 milliampere, 3 sec) and through paws cause a shock. The study of delay performed 24 h after the studies of learning.

In each study measured the duration of the delay period since the opening of the sliding door up until the animal will not move into the dark compartment (step-through latency).

2. Test training is possible water maze Morris: the same animal, which is used in the test learning passive avoidance, are learning the water maze. However, some rats are not able to swim well in water containers, so they are excluded from learning the water maze. Test learning the water maze spend on young rats (saline, 10 animals) and old rats (control group, 9 animals; group vildagliptin, 9 animals: a group of donepezil, 8 animals; application group combination, 8 animals).

During preliminary training, which is conducted for teaching swimming and motivation to escape from the water, spend four studies using a water bath of 80 cm in diameter, at which visible platform. The next day conduct daily session (four studies) research training with the use of a water bath with a diameter of 120 cm and a platform that is lowered into the water.

1. Learning passive avoidance

The control group may show a significant reduction in time to Dodge compared with a group of young animals. Accordingly, the test allows us to estimate that in old rats in group vildagliptin and group donepezil improves significantly impaired learning ability. This experiment can, respectively, to evaluate the improvement in the cognitive status of the exposed treatment of the subject.

A real experience is iment can also show the combination vildagliptin and donepezil improves reduced learning ability in aged rats and that this effect is more effect observed when using only one of the drugs. It can also show that the combination has improved the results or advantages in comparison with the results or benefits from the use of only one drug.

2. Learning the water maze

When solving the task in the water maze, animals in the control group can show significant prolongation lamentoso period detection platform, submerged in water, compared with young rats. This test could therefore estimate that the rats in group vildagliptin and group donepezil show significant improvement in impaired learning ability in the water maze. Thus, this test can evaluate the improvement in the cognitive status of the exposed treatment of the subject.

This test can also show that the combination of vildagliptin and donepezil improves insufficient capacity for learning in the water maze in aged rats and that this effect is greater than when using only one drug. It also shows that the combination results in improved outcomes or benefits compared with the results of the AMI or benefits from the use of only one drug.

Other tests can be performed using experimental animal models, for example, dementia, for example, described and generalized in the following publications: L.S. Higgins, Vol.Med Today 5, 1999, SS-276; Borchelt D.R., etc., Brain Pathol. 8, 1998, SS-757 and Guenette S.Y. and others, Neurobiol. Aging 20, 1999, SS-211.

Example 5

Studying the effects vildagliptin and described in the present invention combinations on the model of Parkinson's disease in mice. Male mice of C57/BL6 by injection daily for 7 days enter MRTR (30 mg/kg, intraperitoneally). Vildagliptin injected once or twice a day for 14 days. At 28 days the cerebral cortex is removed, homogenized perchloro acid and centrifuged. The supernatant is taken and examined for the presence of dopamine and other monoamines, such as serotonin, using back-phase HPLC and electrochemical detection. Effect against Parkinson's disease assessed by comparison with a particular connection, such as selegiline.

1. Application vildagliptin or its pharmaceutically acceptable salt for a medicinal product for the prevention, delay of progression or treatment of peripheral diseases such as peripheral neuropathy, neurodegenerative disorders, cognitive disorders and for improving memory (and kratkofil is Noah, and long-term) and learning ability.

2. The use according to claim 1, in which the neurodegenerative disorder is selected from dementia, senile dementia, mild cognitive damage, dementia associated with Alzheimer's disease, horei of Hantington, late dyskinesia, hyperkineses, mania, Parkinson's disease, syndrome "iron" Richard, down syndrome, asthenic bulbar paralysis, injury to the nerves and brain, vascular amyloidosis, cerebral haemorrhage with amyloidosis, inflammation of the brain, genetic Friedrich's ataxia, acute disorders of consciousness, acute disorders of consciousness with the apoptotic necroticism, amyotrophic lateral sclerosis, glaucoma and Alzheimer's disease.

3. The use according to claim 1, in which the neurodegenerative disorder is selected from the group comprising Alzheimer's disease and dementia, preferably senile dementia, mild cognitive disorder or dementia type Alzheimer's disease.

4. The use according to claim 1 for the prevention or delay the symptoms of dementia associated with Alzheimer's disease, in a patient with age-related decline in cognitive abilities or in patients with mild cognitive impairment.

5. The use of claim 1 for preventing or delaying the early manifestations of Alzheimer's disease in a patient suffering from age the aqueous reducing cognitive abilities or moderate cognitive impairment.

6. The use of claim 1, wherein the cognitive disorder selected from cognitive impairment associated with schizophrenia, age-related memory impairments, cognitive disorders associated with psychosis, cognitive impairment associated with diabetes, cognitive impairment associated with the ported blow, defects of memory associated with hypoxia, cognitive disorders, and disorders of attention, associated with senile dementia, disorders associated with lack of attention, memory impairment associated with mild cognitive deficiency, impaired cognitive function associated with dementia, impaired cognitive function associated with Alzheimer's disease, impaired cognitive function associated with Parkinson's disease, impaired cognitive function associated with vascular dementia, cognitive impairment associated with brain tumors, diseases of the Peak, cognitive impairment due to autism, cognitive impairment after electroshock treatment, cognitive impairment associated with brain injury, amazing disorders, delusional States, dementia.

7. The use of claim 1, wherein the cognitive disorder is selected from disorders associated with the acquisition of skills (learning disabilities), memory consolidation, disorders recovery memory and retention.

8. The use according to claim 1, in cat the rum cognitive disorder selected from cognitive impairment, associated with diabetes, impaired cognitive function associated with Alzheimer's disease, impaired cognitive function associated with Parkinson's disease, cognitive impairment associated with the ported stroke, cognitive disorders, and disorders of attention, associated with senile dementia, memory impairment associated with mild cognitive impairment.

9. The use of claim 1, wherein the cognitive disorder selected from cognitive impairment associated with diabetes, impaired cognitive function associated with Alzheimer's disease, cognitive impairment associated with the ported blow.

10. The use according to claim 1 to improve the speed and capacity of learning in the context of education and rehabilitation.

11. The use according to claim 1 for the treatment of impaired memory or learning ability associated with age, resulting electroshock treatment or the result of brain damage.

12. The use according to claim 1, for the prevention, slowing or cessation of any further age-related cognitive deterioration or progression of mild cognitive failure.

13. The use according to claim 1 for the treatment of degraded memory or ability to learn, which is the result of brain damage caused by stroke, accident, head trauma, hypoglycemia, poisoning wharn the m gas intoxication lithium or beriberi.

14. The use according to claim 1 for the treatment and/or prevention of memory loss.

15. The use according to claim 1 for the treatment and/or prevention of memory loss because of the action of the toxic agent, brain injury, brain aneurysm, age-related memory loss, mild cognitive deficiency, epilepsy, mental retardation in children and dementia resulting from diseases such as Parkinson's disease, Alzheimer's disease, AIDS, head injuries, diseases Hantington, disease Peak, disease of Creutzfeldt-Jakob disease and stroke.

16. Use according to one of claims 1 to 15, in which vildagliptin or its pharmaceutically acceptable salt is administered in combination with at least one additional drug, which can be used for the prevention, delay of progression or treatment of neuro-degenerative disorders, cognitive disorders, or drug to improve memory.

17. The application of article 16, in which the medicinal product, which can be applied for the prevention, delay of progression or treatment of neurodegenerative disorders, cognitive disorders, or drug to improve memory, selected from anti-inflammatory drugs, antioxidants, neuroprotectors, anti the revisionists receptor glutamate, the acetylcholinesterase inhibitors, inhibitors butyrylcholinesterase, MAO inhibitors (monoamine oxidase), agonists or antagonists of dopamine, inhibitors of gamma - and beta-secretase, inhibitors of amyloid aggregation, amyloid beta-peptide antibodies to amyloid beta peptide, acetylcholinesterase inhibitors, agents, aimed at the regulation of GABA (gamma-aminobutyric acid), NMDA (N-methyl-D-aspartate), cannabinoid, AMPA ((S)-alpha-amino-3-hydroxy-5-methyl-4-ISO-cisalpino acid), kainate, PDE (phosphodiesterase), PKA (protein kinase A), RKS (protein kinase C), CREB (camp-response element-binding protein) or nootropic systems.

18. The application of article 16, in which the medicinal product, which can be applied for the prevention, delay of progression or treatment of neurodegenerative disorders, cognitive disorders, or drug to improve memory, selected from donepezil, rivastigmine, ipidacrine, tacrine, stacofylline, galantamine, metrifonate, eptastigmine, velnacrine, fototermin, casefile, Americana, minaprine, huperzine, suprina, bis-tetrahydroaminoacridine (bis-TGA), imidazoles, 1,2,4-thiadiazolidine, benzazepine, 4,4'-bipyridine, indenopyrene, decamethonium, edrophonium, propidium, fascicules, organophosphates, carbamates, imino-1,2,3,4-tetrahydro clopant[b]intolernace, N-pyrimidine-4-acetilcolina, 7 aryloxyalkyl, propargylamine, ziprasidone, NOS inhibitors, precursors of acetylcholine, choline, pyrrolidinedione, agonists cholinergic receptor, vitamins C and E, memantine, rasagiline, selegilina, tranylcypromine, iproniazida, clorgyline, phenelzine, isocarboxazid, tolcapone and entacapone, naproxen sodium, diclofenac sodium, diclofenac potassium, celecoxib, sulindaka, oxaprozin, diflunisal, etodolac, meloxicam, ibuprofen, Ketoprofen, nabumetone, rofecoxib, methotrexate, Leflunomide, sulfasalazin, gold salts, immunoglobulin RHo-D, mycophenylate, cyclosporine, azathioprine, tacrolimus, basiliximab, daclizumab, salicylic acid, acetylsalicylic acid, methyl salicylate, diflunisal, salsalate, OLS-latina, sulfasalazine, acetaminophen, indomethacin, sulindaka, mefenamovoy acid, meclofenamate sodium, tolmetin, Ketorolac, diclofenac, flurbiprofen, oxaprozin, piroxicam, meloxicam, ampiroxicam, droxicam, pivoxil, tenoxicam, phenylbutazone, oxyphenbutazone, antipyrine, aminopyrine, Upasana, zolatone, aurothioglucose, thiomalate gold sodium, auranofin, methotrexate, colchicine, allopurinol, probenecid, sulfinpirazon and benzobromarone or betamethasone and other glucocorticoids and the x pharmaceutically acceptable salts.

19. The application of article 16, in which the medicinal product, which can be applied for the prevention, delay of progression or treatment of neurodegenerative disorders, cognitive disorders, or drug to improve memory, selected from donepezil, tacrine, rivastigmine, galantamine, vitamin C, vitamin E, memantine, rasagiline, selegilina, tranylcypromine, iproniazida, clorgyline, phenelzine and isocarboxazid.

20. Pharmaceutical composition for the prevention, delay of progression or treatment of peripheral diseases such as peripheral neuropathy, neurodegenerative disorders, cognitive disorders and for improving memory (short-term and long-term) and learning ability, including
a) vildagliptin or its pharmaceutically acceptable salt in a therapeutically effective amount and
b) at least one drug that can be used for the prevention, delay of progression or treatment of neurodegenerative disorders, cognitive disorders, or drug to improve memory, in therapeutically effective amounts, and C) at least one pharmaceutically acceptable carrier.

21. The pharmaceutical composition according to claim 20, in which the drug, which is th can be applied to prevent, delay of progression or treatment of neurodegenerative disorders, cognitive disorders, or drug to improve memory, selected from anti-inflammatory drugs, antioxidants, neuroprotective agents, antagonists of glutamate receptor, acetylcholinesterase inhibitors, inhibitors butyrylcholinesterase, MAO inhibitors, agonists or antagonists of dopamine, inhibitors of gamma - and beta-secretase, inhibitors of amyloid aggregation, amyloid beta-peptide antibodies to amyloid beta peptide, acetylcholinesterase inhibitors, agents, aimed at the regulation of GABA, NMDA, cannabinoid, AMR, kainate, PDE, RCA, CSWs, CREB or nootropic systems.

22. The pharmaceutical composition according to claim 20, in which the medicinal product, which can be applied for the prevention, delay of progression or treatment of neurodegenerative disorders, cognitive disorders, or drug to improve memory, selected from donepezil, rivastigmine, ipidacrine, tacrine, stacofylline, galantamine, metrifonate, eptastigmine, velnacrine, fototermin, casefile, Americana, minaprine, huperzine, suprina, bis-tetrahydroaminoacridine (bis-TGA), imidazoles, 1,2,4-thiadiazolidine, benzazepine, 4,4'-bipyridine, indenopyrene, decamethonium, edrophonium, propecia is a, fascicules, organophosphates, carbamates, imino-1,2,3,4-tetrahydrocyclopent[b]intolernace, N-pyrimidine-4-acetilcolina, 7 aryloxyalkyl, propargylamine, ziprasidone, inhibitors of NOS (NO synthase), precursors of acetylcholine, choline, pyrrolidinedione, agonists cholinergic receptor, vitamins C and E, memantine, rasagiline, selegilina, tranylcypromine, iproniazida, clorgyline, phenelzine, isocarboxazid, tolcapone and entacapone, naproxen sodium, diclofenac sodium, diclofenac potassium, celecoxib, sulindaka, oxaprozin, diflunisal, etodolac, meloxicam, ibuprofen, Ketoprofen, nabumetone, rofecoxib, methotrexate, Leflunomide, sulfasalazin, gold salts, immunoglobulin RHo-D, mycophenylate, cyclosporine, azathioprine, tacrolimus, basiliximab, daclizumab, salicylic acid, acetylsalicylic acid, methyl salicylate, diflunisal, salsalate, olsalazine, sulfasalazine, acetaminophen, indomethacin, sulindaka, mefenamovoy acid, meclofenamate sodium, tolmetin, Ketorolac, diclofenac, flurbiprofen, oxaprozin, piroxicam, meloxicam, ampiroxicam, droxicam, pivoxil, tenoxicam, phenylbutazone, oxyphenbutazone, antipyrine, aminopyrine, Upasana, zolatone, aurothioglucose, thiomalate gold sodium, auranofin, methotrexate, colchicine, al is apurina, probenecid, sulfinpirazon and benzobromarone or betamethasone and other glucocorticoids and their pharmaceutically acceptable salts.

23. The pharmaceutical composition according to claim 20, in which the medicinal product, which can be used for the prevention, delay of progression or treatment of neurodegenerative disorders, cognitive disorders, or drug to improve memory, selected from donepezil, tacrine, rivastigmine, galantamine, vitamin C, vitamin E, memantine, rasagiline, selegilina, tranylcypromine, iproniazida, clorgyline, phenelzine and isocarboxazid.



 

Same patents:

FIELD: chemistry; pharmaceutics.

SUBSTANCE: present invention relates to novel cyclohexane derivatives of formula (I) or their pharmaceutically acceptable salts having inhibitory effect on Na+-glucose cotranspoter (SGLT2), as well as to pharmaceutical compositions based on the said compounds and their use in preventing or treating diabetes, diabetic complications caused by hyperglycaemia or obesity. , where A is -O-; n is an equal to 0 or 1; R6 and R7 each independently represents a hydrogen atom or a C1-C6alkyl group, m is an integer selected from 1-3; Q is selected from Q1 - Q5, given in formula 2.

EFFECT: obtaining novel cyclohexane derivatives or their pharmaceutically acceptable salts and preparation of a pharmaceutical composition based on the said compounds.

15 cl, 19 dwg, 11 tbl, 86 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a complex containing an insulin conjugate which contains native insulin or its polypeptide analogue conjugated with a modifying group, where the polypeptide analogue exhibits similar activity relative native insulin and where the modifying group contains a polyalkylene gycol component (PAG) and an alkyl component and a cation, where the insulin conjugate forms a complex with a divalent cation of a group II metal or transition metal. The invention also relates to pharmaceutical compositions containing such complexes and their preparation methods. The invention also relates to fatty acid compositions for administration of complexes of conjugates of disclosed insulin compounds.

EFFECT: design of an efficient method of preparing pharmaceutical compositions containing an insulin conjugate.

60 cl, 42 dwg, 100 ex

FIELD: chemistry.

SUBSTANCE: in the formula (I) , R1 is metoxymethyl; R2 is selected out of -C(O)NR4R5, -SO2NR4R5, -S(O)PR4 and HET-2; R3 is selected out of halogeno, fluoromethyl, metoxy and cyano; HET-1 is 5- or 6-member heteroaryl ring linked by C atom and containing nitrogen atom in 2 position and possibly 1 or 2 additional ring heteroatoms selected independently out of O, N and S, which is possible substituted at available carbon atom or at ring nitrogen atom by 1 substitute selected independently out of R6, provided that it would not cause ring quaternisation. The other radicals are indicated in the invention claim. Also invention refers to pharmaceutical composition containing claimed compound as active component, and methods of obtaining compound of the formula (I).

EFFECT: compounds with glucokinase inhibition effect.

19 cl, 2 tbl, 61 ex

FIELD: chemistry.

SUBSTANCE: claimed compounds show effect on receptor activated by peroxysome proliferate δ (PPARδ). In formula I: [Formula I] , [Formula VII] , [Formula VI] , A is R1 is C1-4alkyl group; R3 groups are different and denote halogen atom or C1-4alkyl group substituted or unsubstituted by halogen; R4 is R5 is hydrogen atom or hydroxyl group; the other radicals are as defined in the invention claim. Also invention refers to methods of compound I obtainment, to intermediary compounds VI, VII and methods of their obtainment, to medicines of diabetes, obesity, atherosclerosis, hyperlipidemia treatment and prevention, containing thiazole derivative of the formula I as active component.

EFFECT: enhanced activity of derivatives.

21 cl, 10 tbl, 102 ex

FIELD: chemistry.

SUBSTANCE: invention refers to compounds of the formula (I) and pharmaceutically acceptable salts, where R1-R7 mean the same as provided in the invention description and claim. Compounds of the formula (I) are specific inhibitors of 11b-HSD1. They can be applied in treatment and/or prevention of diseases caused by dysfunctions related to 11b-HSD1 enzyme, particularly in treatment and/or prevention of metabolic diseases, obesity, dyslipidemia, hypertension and/or diabetes, especially diabetes type "П". Additionally subject matter includes pharmaceutical composition for treatment and/or prevention of the said diseases.

EFFECT: improved efficiency of derivatives.

21 cl, 1 tbl, 146 ex

FIELD: medicine.

SUBSTANCE: invention belongs to medicine, notably to biguanid compounds, namely Siofor 500, Delagil and 0.5 acetylsalicylic acid administration 1 tablet 3 times a day for diabetes mellitus tipe I treatment.

EFFECT: there is offered diabetes mellitus type I treatment method.

1 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to cyclic derivatives of aminobenzoic acid and to their pharmaceutically acceptable salts of general formula , in which ring Ar is a phenyl group, a 5-member aromatic heterocyclic group containing 1-2 heteroatoms selected from nitrogen, sulphur and oxygen, or a benzothiazolyl group; where the said groups can have 1-2 substitutes selected from a group comprising lower alkyl; a phenyl group; a phenyl group substituted with 1-2 halogens; a phenyl group substituted with a lower alkoxy group; a phenyl group substituted with a halogen-substituted lower alkyl group; a phenoxy group substituted with a halogen; a halogen; Z is an oxygen atom or -(CH2)-n (where n equals 0, 1 or 2); Y is C1-C4 alkylene, C2-C4 alkenylene or general formula (2) -T-A-U- (2) in which T is a single bond, C1-C4 alkylene or C2-C4 alkenylene; U is single bond, C1-C4 alkylene; values of the rest of radicals are given in the formula of invention.

EFFECT: obtaining a PPARα, agonist which contains an active ingredient in form of at least one cyclic derivative of aminobenzoic acid, and an agent which reduces the level of lipids which contains an active ingredient in form of at least one cyclic derivative of aminobenzoic acid.

12 cl, 16 tbl, 184 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to phenylalanine derivatives and their pharmaceutically acceptable salts. In formula (1) R11 is a hydroxyl group, an alkoxyl group having 1-6 carbon atoms, which can be substituted with a methoxy group, cycloalkoxyl group having 3-6 carbon atoms, or a benzyloxy group; R12 and R13 each independently represents a hydrogen atom, alkyl group having 1-6 carbon atoms, cycloalkyl group having 3-6 carbon atoms, acetyl group or methyloxycarbonyl group, or N(R12)R13 is a 1-pyrrolidinyl group, 1-piperidinyl group, 4-morpholinyl group; R14 is a methyl group; R1' is a hydrogen atom, fluorine atom; X1 is -CH(R1a)-, -CH(R1a)CH(R1b)-, -CH(R1a)CH(R1b)CH(R1c)-, -N(R1a)CH(R1b)CH(R1c)-, -OCH(R1a)CH(R1b)-, -OCH(R1a)CH(R1b)CH(R1c)- or 1,3-pyrrolidinylene, where R1a, R1b, each independently represents a hydrogen atom or a methyl group, and R1c is a hydrogen atom; Y11 and Y12 represent any of the combinations (CI, Cl), (CI, Me), (CI, F). Invention also relates to phenylalanine derivatives of formulae (2)-(14), given in the formula of invention.

EFFECT: obtaining a pharmaceutical composition having antagonistic effect on α4-integrin, containing a phenylalanine derivative as an active ingredient, a α4-integrin antagonist and a therapeutic agent.

65 cl, 51 tbl, 244 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new compounds of formula , in which: Ra and Ra' denote hydrogen, R1 denotes cycloalkyl; R2 denotes a group of formula -(CH2)x-(CO)y-Y or -(CO)y-(CH2)x-Y, in which x=0, y=1, Y denotes -N-R11R12;- R11 and R12 denote alkyl; R3 denotes a halogen atom; R5 denotes a hydrogen atom; R4 is selected from: (1) a group of formula : in which each of the rings in formulae (a) and (b) can be substituted in any position with 1-4 R7 groups which are identical or different from each other, and in which: a=0; p=0, 1, 2 or 3; m=1; X is an oxygen or sulphur atom or a C(R6)(R7)- or -N(R10)- group; R6 is selected from: a hydrogen atom; a -(CH2)x-NR8R9 group in which x=0, aryl, alkylaryl; R7 is selected from hydrogen atoms; aryl, alkylaryl groups; -OR group; -NRR' groups; R8 and R9 are selected from a hydrogen atom; R10 is selected from: hydrogen atom; aryl, alkylaryl; R and R' denote a hydrogen atom; (2) a group of formula -A-R18, -A-CH=N-R19, in which A denotes a straight or branched alkyl; R18 denotes a halogen atom or a -NH2 group; R19 denotes hydroxyl; (3) a group of formula : in which r equals 1; s equals 1, and one of U, V and W denotes a nitrogen atom while the others denote a methylene group; or (4) -(CH2)r-heteroaryl, where r equals 1; where the heteroaryl denotes a 5-6-member aromatic group containing 1-2 heteroatoms such as nitrogen, oxygen, in form of a base or additive acid salt. The invention also relates to a method for synthesis of formula (I) compounds, to compounds of formulae (IV) and (V), to a medicinal agent, to a pharmaceutical composition, as well as to use of formula (I) compounds.

EFFECT: obtaining new biologically active compounds having melanocortin receptor agonist activity.

11 cl, 28 ex, 1 tbl

FIELD: medicine.

SUBSTANCE: invention concerns a composition obtained from a combination of vegetable oil or cod-liver oil with a compound which contains fatty acids analogues resistant to β-oxidation. The invention also concerns animals' fodder produced form a combination of vegetable oil and cod-liver oil containing fatty acids analogues resistant to β-oxidation, to application of the fodder with the purpose of improving the animal's body composition and to the product obtained from the above animals.

EFFECT: production of pharmaceutical or edible composition for prevention and/or treatment of insulin resistance, obesity, diabetes, fatty liver, hypercholesterinemia, dislipidemia, atherosclerosis, coronary heart disease, thrombosis, stenosis, myocardial infarction, apoplexy, hypertension, endothelial dysfunction, hypercoagulability, polycystic ovary syndrome, metabolic syndrome, malignant tumour, inflammatory disorder and poliferous skin lesions.

47 cl, 12 tbl, 2 ex, 4 dwg

FIELD: chemistry.

SUBSTANCE: present invention relates to a compound having the structural formula I , or its pharmaceutically acceptable salt, ester or amide, where A has the structure , where each bond in A, represented by a dotted and a solid line, represents a carbon-carbon single bond; each of a, b and c is a carbon atom; each of e, f, g and h is a carbon atom; X is nitrogen; X' is C; L is absent; each n equals 1; Y is nitrogen; W is nitrogen; R1 is hydrogen; each of R2, R3 and R4 is a hydrogen atom; each of R6, R8 and R9 is a hydrogen atom; R5 is selected from a group consisting of halogen, C1-6alkyl, optionally substituted with a hydroxy group, and C1-6alkoxy; R7 is selected from a group consisting of halogen, C1-6alkyl and perhalogenalkyl; Z is selected from a group consisting of NR11, oxygen and CH2; R11 is hydrogen; and each bond in formula I, represented by a dotted and a solid line, is a carbon-carbon double bond. The invention also relates to a method for synthesis of a formula V compound, a pharmaceutical composition based on a formula I compound, methods of treating psychoneurological disorders, a pharmaceutical composition containing a formula I compound and a psychoneurological agent.

EFFECT: obtaining novel compounds useful for modulating muscarine receptor activity.

37 cl, 1 tbl, 141 ex

FIELD: medicine.

SUBSTANCE: invention refers to psychoneurology, particularly to an agent for treating multiple sclerosis. A composition (solid or liquid dosage form) contains triiodide 1,3-diethylbenzimidazolium as an agent, low-molecular surgical polyvinylpyrrolidone, presented as a solubiliser, and an agent stabiliser, and in addition in the liquid dosage form - ethanol as a solvent.

EFFECT: composition under the invention exhibits high therapeutic effectiveness in treating multiple sclerosis, and is characterised by relieving undesirable by-effects.

2 cl, 4 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to novel substituted 2-alkylsulfanyl-3-arylsulfonyl-pyrazolo[1,5-a]pyrimidines of general formula 1, their pharmaceutically acceptable salts and/or hydrates having serotonin 5-HT6 receptor antagonist properties. In general formula 1 , R1 and R3 independently denote optionally identical C1-C3 alkyl, and R2 is a -(CH2)nX group or R1 and R3 independently denote different substitutes selected from C1-C3 alkyl or a -(CH2)nX group, and R2 is a hydrogen atom or C1-C3 alkyl; R4 is C1-C3 alkyl; Ri5 is a hydrogen atom, one or two identical or different halogen atoms, C1-C3 alkyl; equals 0, 1 or 2; n equals 0, 1, 2 or 3; X is a carboxyl CO2H, C1-C3 alkyloxycarbonyl, aminocarbonyl CONR6R7 or amino group NR6R7; except compounds in which R3 is a -(CH2)nX group, where X is an amino group NR6R7 and n equals 0; R6 and R7 are optionally identical and denote a hydrogen atom, optionally substituted C1-C5 alkyl or R6 and R7 together with the nitrogen atom with which they are bonded form an optionally substituted 6-member azaheterocyclyl containing 1-2 nitrogen atoms in the ring, where the substitute is selected from C1-C3 alkyl.

EFFECT: obtaining compounds which can be used in treating diseases of the central nervous system during prevention or treatment of cognitive disorders, neurodegenerative diseases, psychiatric disorders, have anxiolytic and nootropic effect and can be used to prevent and treat anxiety disorders and enhance mental capacity.

25 cl, 2 tbl, 12 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to novel substituted 3-arylsulfonyl-pyrazolo[1,5-a]pyrimidines of general formula 1, their pharmaceutically acceptable salts and/or hydrates having serotonin 5-HT6 receptor antagonist properties. The compounds can be used in treating and preventing various diseases of the central nervous system, pathogenesis of which is associated with 5-HT6 receptors, particularly cognitive disorders, neurodegenerative diseases and psychiatric disorders. The compounds have anxiolytic and nootropic effect and can also be used for preventing and treating anxiety disorder and for enhancing metal capacity. In formula 1 , R1 is a hydrogen atom, C1-C3 alkyl, (C1-C3)alkyloxy(C1-C3)alkyl, hydroxy(C1-C3)alkyl, pyridyl; R2 is a hydrogen atom, halogen atom, C1-C3 alkyl, phenyloxy or pyridyloxy; R3 is a hydrogen atom, C1-C3 alkyl, C1-C3 alkyloxy, (C1-C3)alkyloxy(C1-C3)alkyl, hydroxy(C1-C3)alkyl, pyridyl; R4 is C1-C3 alkyl; R5 is a hydrogen atom, one or two halogen atoms, C1-C3 alkyl, C1-C3 alkyloxy or hydroxyl; X is a sulphur atom or thionyl group (SO).

EFFECT: obtaining compounds which can be used in treating and preventing various diseases of the central nervous system.

24 cl, 9 dwg, 4 tbl, 19 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to novel 2-alkylamino-3-arylsulfonyl-pyrazolo[1,5-a]pyrimidines of general formula 1, their pharmaceutically acceptable salts and/or hydrates having serotonin 5-HT6 receptor antagonist properties. The compounds can be used to treat and prevent development of various diseases of the central nervous system, pathogenesis of which is associated with 5-HT6 receptors, particularly Alzheimer's disease, Parkinson's disease, Huntington disease, schizophrenia, other neurodegenerative diseases and cognitive disorders. In general formula 1 , R1 is a hydrogen atom, C1-C3alkyl, C1-C3alkyloxyC1-C3alkyl, hydroxyC1-C3alkyl, adamantyl, optionally substituted phenyl, 5-6-member heterocyclyl containing a nitrogen or oxygen heteroatom, possibly condensed with a benzene ring; R2 is a hydrogen atom, halogen atom, C1-C3alkyl, pyridyloxy; R3 is a hydrogen atom; C1-C3alkyl; optionally substituted amino group selected from amino, mono- or di(C1-C3alkyl)amino, di(C1-C3alkyl)aminoC2-C3alkylamino, N-[di(C1-C3alkyl)aminoC2-C3alkyl]-N-(C1-C3alkyl)-amino; C1-C3alkyloxy, C1-C3alkyloxyC1-C3alkyl, hydroxyC1-C3alkyl; 6-member azaheterocyclyl, possibly containing an extra nitrogen or oxygen atom, a -N(C1-C3alkyl) group; R4 is C1-C3alkyl; R5 is a hydrogen atom, one or two halogen atoms or C1-C3alkyl.

EFFECT: design of a method of obtaining compounds, a pharmaceutical composition and a medicinal agent for treating and preventing various diseases of the central nervous system.

25 cl, 12 dwg, 3 tbl, 20 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to medicine and aims at treating the conditions associated with amnesia and impaired cognition. A medically indigent patient is prescribed with the effective amount of a composition containing a mixed extract prepared of Scutellaria plants with high concentration of free V-ring flavonoids, including Baicalin, and an extract of Acacia plants with high concentration of flavanes, including catechine and epicatechin.

EFFECT: methods ensure restoration and preservation of cognition and memory.

44 cl, 15 ex, 2 tbl, 17 dwg

FIELD: chemistry.

SUBSTANCE: invention refers to novel compounds of the general formula (I) , where R1, R2 are independently H or C1-C6-alkyl; R3, R4 are independently H or C1-C6-alkyl; R5 is halogen, CN; n, m or o are 0, 1 or 2; and to pharmaceutically acceptable salts thereof.

EFFECT: compounds with monoaminooxidase B inhibition properties applicable in obtainment of pharmaceutical drugs with relevant effect.

14 cl, 3 dwg, 31 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to serotonin 5-HT6 receptor antagonists - new substituted 3-sulphonyl-6,7,8,9-tetrahydro-pyrazolo[1,5-a]pyrido[4,3-e]pyrimidines of formula and substituted 3-sulphonyl-5,6,7,8-tetrahydro-pyrazolo[1,5-a]pyrido[4,3-c1]pyrimidines of general formula 2, a medicinal base and pharmaceutical compositions containing the medicinal base in form of the said compounds, as well as to a method of treating and preventing development of different conditions and diseases of the central nervous system of humans and warm-blooded animals. In formulae and Ar is phenyl which is optionally substituted with halogen atoms, or a 6-member heteroaryl which contains a nitrogen atom in the ring; R1 is a hydrogen atom, C1-C3alkyl, hydroxy C1-C3alkyloxy group, C1-C3alkylsulphanyl group; R2 is a hydrogen atom or C1-C3alkyl, R3 is a hydrogen atom optionally substituted C1-C3alkyl or tert-butyloxycarbonyl.

EFFECT: obtaining compounds for preventing development of different conditions and diseases of the central nervous system of humans and warm-blooded animals.

16 cl, 3 tbl, 1 dwg, 10 ex

FIELD: medicine.

SUBSTANCE: invention relates to field of medicine and pharmaceutical industry and represents pharmaceutical combination for treatment of cerebral circulatory insufficiency and psychodependent form of erectile dysfunction, including choline alfoscetate in amount 50-600 mg per one intake and hopantenic acid or its pharmaceutically acceptable salt in amount 20-800 mg per one intake.

EFFECT: invention ensures reduction of frequency, duration and intensity of headache, dizziness, fatigability, irritability, improvement of memory for current events and sleep, as well as increase of erectile dysfunction (ED), reduction and fixation of stable positive motivation for quality erection and full orgasm in case of psychodependent form of ED; simultaneously, due to manifestation of synergic effect, which results from the use of claimed combination, it became possible to reduce day dose of hopantenic acid or its salt from 1,5 mg to 0,5 mg.

12 cl, 4 ex, 24 tbl, 4 dwg

FIELD: medicine.

SUBSTANCE: methods according to the invention consist in introducing an Aβ 16-23 fragment having an amino acid sequence KLVFFAED of 16-23 residues SEQ ID NO:1. Besides the invention concerns the Aβ 16-23 fragment and a pharmaceutical composition containing it.

EFFECT: feasible prevention and treatment of Alzheimer's disease ensured by inhibition of amyloid deposition in cerebrum.

72 cl, 2 dwg, 1 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to neurology and reflexotherapy and can be used for treating neurological manifestations of vertebral osteochondrosis. The method involves introduction of the medicine mixture in acupuncture points. The mixture contains 0.05% cyanocobalamin, 1% Lidocaine and Diprospan suspension. The relation of the medicines in the mixture is 1:1:1. And the mixture is introduced into the acupuncture points VB 25 (2), V 24 (2), V 52(2), T4 at a depth of 0.4 - 2.0 cm.

EFFECT: method provides prolonged remission.

1 ex

Up!