CN1921856A

CN1921856A - Dpp-iv inhibitors for treating neurodegeneration and cognitive disorders

Info

Publication number: CN1921856A
Application number: CN 200580005568
Authority: CN
Inventors: T·E·休斯
Original assignee: Novartis AG
Current assignee: Novartis AG
Priority date: 2004-02-20
Filing date: 2005-02-18
Publication date: 2007-02-28

Abstract

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

Description

The DPP-IV inhibitor that is used for the treatment of neurodegenerative disease and cognitive disorder

The present invention relates to the purposes that inhibitors of dipeptidyl IV (DPP-IV inhibitor) or its officinal salt are used for prevention, delay of progression or treatment neurodegenerative disease, cognitive disorder and are used for improving memory (short-term and long-term) and learning capacity.

Term " DPP-IV inhibitor " means enzymatic activity to DPP-IV and function relevant enzyme and for example shows 1-100% or 20-80% and suppress and keep the molecule of substrate molecule effect especially, includes but not limited to glucagon-like peptide, gastric inhibitory polypeptide, histidine MET peptides, P material, Y neuropeptide and general at aminoterminal second molecule that comprises alanine or proline residue.Treat the persistent period that has prolonged the peptide substrates effect and improved its level complete, that do not degrade form with the DPP-IV inhibitor, cause the relevant biologic activity of a series of and disclosed the present invention.

Because the substrate of DPP-IV comprises insulinotropic hormone-glucagon-like-peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP), so available DPP-IV control glucose metabolism.GLP-1 and GIP only just have activity when its complete form; Remove then inactivation of two aminoacid of its N-terminal.Use synthetic property DPP-IV inhibitor in the body and stop the N-terminal degraded of GLP-1 and GIP, cause the plasma concentration of these hormones higher, insulin secretion increases and therefore improve glucose tolerance.For this purpose, tested the ability of the CD26/DPP-IV enzymatic activity of chemical compound inhibition purification.In brief, measure its activity by the ability of the synthetic property substrate Gly-Pro-paranitroanilinum (Gly-Pro-pNA) of CD26/DPP-IV cutting at external (in vitro).DPP-IV is to the cutting releasing product paranitroanilinum (pNA) of Gly-Pro-pNA, and it speed occurs and is directly proportional with enzymatic activity.By specific enzyme inhibitor inhibitory enzyme activity, the generation that slows down pNA.Between inhibitor and the enzyme effect strong more, the generation speed of pNA is slow more.Therefore the inhibition degree to the pNA accumulation rate is the direct tolerance of enzyme inhibition strength.Accumulation with spectrophotometer measurement PNA.Enzyme and the inhibitor of several variable concentrations and the inhibition constant K i that the substrate incubation is measured each chemical compound by fixed amount.

In this article, " DPP-IV inhibitor " also is intended to comprise its active metabolite and prodrug, the for example active metabolite of DPP-IV inhibitor and prodrug, the reactive derivative of the DPP-IV inhibitor that " metabolite " produced when being the metabolism of DPP-IV inhibitor." prodrug " is to produce the DPP-IV inhibitor or become the chemical compound of the metabolite that is the DPP-IV inhibitor equally through metabolism through metabolism.

The DPP-IV inhibitor is known in the art.Hereinafter, mention the representative of DPP-IV inhibitor.

Preferred DPP-IV inhibitor is described in following patent application: WO 02053548, especially chemical compound 1001 to 1293 and embodiment 1 to 124; WO 02067918, especially chemical compound 1000 to 1278 and 2001 to 2159; WO 02066627, especially described embodiment; WO02/068420, especially in example I concrete listed whole chemical compounds and described corresponding analogs to the LXIII, preferred chemical compound is at 2 (28), 2 (88), 2 (119), 2 (136) described in the form of report IC50; WO 02083128, as claim 1 to 5, and the chemical compound described in embodiment 1 to 13 and the claim 6 to 10 especially; US 2003096846, especially specifically described chemical compound; WO 2004/037181, and especially embodiment 1 to 33, and most preferably is the chemical compound described in the claim 3 to 5; WO 0168603, especially the chemical compound of embodiment 1 to 109; EP1258480, the especially chemical compound of embodiment 1 to 60; WO 0181337, and especially embodiment 1 to 118; WO 02083109, especially embodiment 1A to 1D; WO 030003250, especially the chemical compound of embodiment 1 to 166, most preferred embodiment 1 to 8; WO 03035067, especially the chemical compound described in the embodiment; WO 03035057, especially the chemical compound described in the embodiment; US2003216450, especially embodiment 1 to 450; WO 99/46272, especially claim 12,14,15 and 17 chemical compound; WO 0197808, especially the chemical compound of claim 2; WO 03002553, the chemical compound of embodiment 1 to 33 especially, and WO 01/34594, especially the chemical compound described in the embodiment 1 to 4; WO 02051836, and especially embodiment 1 to 712; EP1245568, especially embodiment 1 to 7; EP1258476, especially embodiment 1 to 32; US 2003087950, especially described embodiment; WO 02/076450, and especially embodiment 1 to 128; WO 03000180, and especially embodiment 1 to 162; WO 03000181, and especially embodiment 1 to 66; WO 03004498, and especially embodiment 1 to 33; WO 0302942, and especially embodiment 1 to 68; US 6482844, especially described embodiment; WO 0155105, especially listed chemical compound among the embodiment 1 and 2; WO 0202560, and especially embodiment 1 to 166; WO 03004496, and especially embodiment 1 to 103; WO 03/024965, and especially embodiment 1 to 54; WO 0303727, and especially embodiment 1 to 209; WO 0368757, and especially embodiment 1 to 88; WO 03074500, especially embodiment 1 to 72, embodiment 4.1 to 4.23, embodiment 5.1 to 5.10, embodiment 6.1 to 6.30, embodiment 7.1 to 7.23, embodiment 8.1 to 8.10, embodiment 9.1 to 9.30; WO 02038541, and especially embodiment 1 to 53; WO 02062764, and especially embodiment 1 to 293, preferably the chemical compound of embodiment 95 (2-{{3-(aminomethyl)-4-butoxy-2-neopentyl-1-oxo-1,2 dihydro-6-isoquinolyl } oxygen } acetamide hydrochloride); WO02308090, especially embodiment 1-1 to 1-109, embodiment 2-1 to 2-9, embodiment 3, embodiment 4-1 to 4-19, embodiment 5-1 to 5-39, embodiment 6-1 to 6-4, embodiment 7-1 to 7-10, embodiment 8-1 to 8-8, the embodiment 7-1 to 7-7 in the 90th page, embodiment 8-1 to 8-59, embodiment 9-1 to 9-33, embodiment 10-1 to 10-20 in the 91st to 95 page; US 2003225102, especially the chemical compound of chemical compound 1 to 115, embodiment 1 to 121, preferably compound a) to z), aa) to az), ba) to bz), ca) to cz) and da) to dk); WO 0214271, and especially embodiment 1 to 320; And US 2003096857; WO 2004/052850, and especially specifically described chemical compound is as the chemical compound of embodiment 1 to 42 and claim 1; DE102 56 264 A1, especially described chemical compound is as the chemical compound of embodiment 1 to 181 and claim 5; WO04/076433, especially specifically described chemical compound as chemical compound listed in the Table A, is preferably shown chemical compound listed among the B, and preferably Compound I is to the chemical compound of XXXXVII or claim 6 to 49; WO 04/071454, especially specifically described chemical compound, for example chemical compound of chemical compound 1 to 53 or Table I a to If or the chemical compound of claim 2 to 55; WO 02/068420, especially specifically described chemical compound, for example Compound I is to LXIII or Beispiele 1 and analog 1 to 140 or Beispiele 2 and analog 1 to 174 or Beispiele 3 and analog 1 or Beispiele 4 to 5 or Beispiele 6 and analog 1 to 5 or Beispiele7 and analog 1-3 or Beispiele 8 and analog 1 or Beispiele 9 or Beispiele10 and analog 1 to 531, the more preferably chemical compound of claim 13; WO 03/000250, especially specifically described chemical compound, and as chemical compound 1 to 166, the chemical compound of embodiment 1 to 9 preferably; WO 03/024942, and especially specifically described chemical compound is as the chemical compound (1 to 68) of chemical compound 1 to 59, table 1, claim 6,7,8,9 chemical compound; WO 03024965024942, and especially specifically described chemical compound is as chemical compound 1 to 54; WO03002593, especially specifically described chemical compound is as the chemical compound of table 1 or claim 2 to 15; WO03037327, especially specifically described chemical compound, as the chemical compound of embodiment 1 to 209, WO 03/000250, especially specifically described chemical compound, as chemical compound 1 to 166, the chemical compound of embodiment 1 to 9 preferably; WO 03/024942, and especially specifically described chemical compound is as the chemical compound (1 to 68) of chemical compound 1 to 59, table 1, claim 6,7,8,9 chemical compound; WO 03024965024942, and especially specifically described chemical compound is as chemical compound 1 to 54; WO03002593, especially specifically described chemical compound is as the chemical compound of table 1 or claim 2 to 15; WO03037327, especially specifically described chemical compound is as the chemical compound of embodiment 1 to 209; WO0238541; WO0230890; WO 03/000250, especially specifically described chemical compound, and as chemical compound 1 to 166, the chemical compound of embodiment 1 to 9 preferably; WO 03/024942, and especially specifically described chemical compound is as the chemical compound (1 to 68) of chemical compound 1 to 59, table 1, claim 6,7,8,9 chemical compound; WO 03024965, and especially specifically described chemical compound is as chemical compound 1 to 54; WO03002593, especially specifically described chemical compound is as the chemical compound of table 1 or claim 2 to 15; WO03037327, especially specifically described chemical compound is as the chemical compound of embodiment 1 to 209; WO0238541, especially specifically described chemical compound is as the chemical compound of embodiment 1 to 53; WO 03/002531, especially specifically described chemical compound, and preferably listed chemical compound in the 9th page to 13 pages most preferably is the chemical compound of embodiment 1 to 46, and more preferably is the chemical compound of embodiment 9; U.S. Patent number 6,395,767, preferably embodiment 1 to 109 chemical compound most preferably is the chemical compound of embodiment 60; The U. S. application serial number 09/788,173 (agent applies for LA50) that propose February 16 calendar year 2001, especially described embodiment; WO99/38501, especially described embodiment; WO99/46272, the fumarate of especially described embodiment and DE19616 486 A1, especially val-pyr, val-Thiazolidine, isoleucyl--Thiazolidine, isoleucyl--pyrrolidine and isoleucyl--Thiazolidine and isoleucyl--pyrrolidine (fumar salt).

Preferred DPP-IV inhibitor comprises the instantiation that is disclosed among U.S. Patent number 6124305 and US6107317, international application published WO 95,153 09 and the WO 9818763.

The patent application WO 9819998 that has announced discloses N-(N '-substituted glycyl)-2-Cyanopyrolidine; 1-[2-[5-cyanopyridine-2-yl particularly] amino]-ethylamino] acetyl group-2-cyano group-(S)-pyrrolidine (NVP-DPP728) and (2S)-I-[(2S)-2 amino-3,3-diformazan bytyry]-2-pyrrolidine nitrile.

In another preferred embodiment, the DPP-IV inhibitor is N-peptidyl-O-aroyl azanol or its officinal salt.Aroyl is a naphthyl carbonyl for example; Perhaps unsubstituted benzoyl or for example replace or disubstituted benzoyl by lower alkoxy, low alkyl group, halogen or preferred nitro list.The peptide base section preferably comprises 2 a-amino acids, as glycine, alanine, leucine, phenylalanine, lysine or proline, wherein with direct-connected that aminoacid of the nitrogen-atoms of azanol proline preferably.

DPP-IV inhibitor under each situation usually and clearly is disclosed in for example WO98/19998, DE19616 486 A1; WO 00/34241; WO 95/15309; WO 01/72290, WO01/52825, WO03/002553; WO 9310127; WO 99/61431; WO 9925719; WO 9938501; WO 9946272; WO 9967278 and WO 9967279.

Under each situation, especially under the situation of the finished product of compound claim and practical application embodiment, the purport of finished product, pharmaceutical preparation and claim is introduced the application herein as the reference to these announcements.

WO 9819998 discloses N-(N '-substituted glycyl)-2-Cyanopyrolidine, especially 1-[2-[5-Cyanopyrolidine-2-yl] amino l-ethylamino] acetyl group-2-cyano group-(S)-pyrrolidine.

Preferred compound described in the WO03/002553 is listed in the 9th to 11 page and introduce the application as a reference.

DE19616 486 A1 disclose the fumarate (fumar salt) of val-pyr, val-Thiazolidine, isoleucyl--Thiazolidine, isoleucyl--pyrrolidine and isoleucyl--Thiazolidine and isoleucyl--pyrrolidine.

Patent application WO 0034241 that has announced and the patent US 6110949 that has announced disclose N-respectively and have replaced adamantyl-amino-acetyl group-2-Cyanopyrolidine and N-(substituted glycyl)-4-Cyanopyrolidine.Purpose DPP-IV inhibitor is mentioned DPP-IV inhibitor in the claim 1 to 4 especially.Particularly, chemical compound 1-[[(3-hydroxyl-1-adamantyl has been described in these applications) amino] acetyl group]-2-cyano group-(S)-pyrrolidine (being also referred to as LAF237 or vildagliptin).

WO 9515309 discloses the aminoacid 2-Cyanopyrolidine amide as the DPP-IV inhibitor, and WO 9529691 discloses the peptide radical derivative of alpha-aminoalkyl phosphonic acid diester, especially has those peptide radical derivatives of proline or dependency structure.Those DPP-IV inhibitor that purpose DPP-IV inhibitor is especially mentioned in to 8 at table 1.

In WO 01/72290, those DPP-IV inhibitor that purpose DPP-IV inhibitor is especially mentioned in embodiment 1 and claim 1,4 and 6.

WO01/52825 discloses (S)-1-{2-[5-cyanopyridine-2-yl especially] amino } ethyl-ammonia acetyl group)-2-cyano group-pyrrolidine or (S)-1-[(3-hydroxyl-1-adamantyl) amino] acetyl group-2-cyano group-pyrrolidine.

WO 9310127 discloses the borate proline as the DPP-IV inhibitor.Those DPP-IV inhibitor that purpose DPP-IV inhibitor is especially mentioned in embodiment 1 to 19.

The patent application WO 9925719 that has announced discloses by cultivating the DPP-IV inhibitor sulphostin of streptomycete (Streptomyces) microorganism preparation.

WO 9938501 discloses the heterocycle of 4 to 8 atomic numbeies of N-replacement.Those DPP-IV inhibitor that purpose DPP-IV inhibitor is especially mentioned in embodiment 15 to 20.

WO 9946272 discloses the phosphorus-containing compound as the DPP-IV inhibitor.Those DPP-IV inhibitor that purpose DPP-IV inhibitor is especially mentioned in claim 1 to 23.

Other preferred DPP-IV inhibitor are formula I, II or the III chemical compounds that are disclosed among the 14th to 27 page of the patent application WO 03/057200.Most preferred DPP-IV inhibitor is specifically described those chemical compounds in the 28th and 29 page.

Patent application WO 9967278 that has announced and WO 9967279 disclose the DPP-IV prodrug and form is the inhibitor of A-B-C, and wherein C is stable or unsettled DPP-IV inhibitor.

Preferably, N-peptidyl-O-aroyl azanol is as shown in the formula the VIII compound or pharmaceutically acceptable salt thereof,

Wherein j is 0,1 or 2;

R ε ₁Represent the natural amino acid side chain; And

R ε ₂Represent lower alkoxy, low alkyl group, halogen or nitro.

In utmost point embodiment preferred of the present invention, N-peptidyl-O-aroyl azanol is as shown in the formula the VIIa compound or pharmaceutically acceptable salt thereof:

For example the N-of formula VII or VIIa peptidyl-O-aroyl azanol and preparation thereof by H.U.Demuth etc. at J.Enzyme Inhibition, 1988, the 2 volumes, the 129-142 page or leaf is particularly described in the 130-132 page or leaf.

Preferred DPP-IV inhibitor is adamantyl-amino-acetyl group-2-Cyanopyrolidine of replacing of N-, N (substituted glycyl)-4-Cyanopyrolidine, N-(N '-substituted glycyl)-2-Cyanopyrolidine, N-aminoacyl Thiazolidine, N-aminoacyl pyrrolidine, the other isoleucyl-thiazolidine of L-, L-threo form-isoleucyl-pyrrolidine and the other isoleucyl-pyrrolidine of L-, 1-[2-[(5-cyanopyridine-2-yl) amino] ethylamino] acetyl group-2-cyano group-(S)-pyrrolidine and pharmaceutical salts thereof.

Preferred DPP-IV inhibitor is at Expert OpinionInvestig Drugs.2003 Apr by Mona Patel and partner thereof; 12 (4): those DPP-IV inhibitor of describing in the 5th section of 623-33, especially P32/98, K-364, FE-999011, BDPX, NVP-DDP-728 and other DPP-IV inhibitor, especially described DPP-IV inhibitor is quoted as a reference in its announcement herein.

FE-999011 is described in the 14th page of patent application WO 95/15309 as compound number 18.

Another preferred inhibitors is to be disclosed in WO 2001068603 or U.S. Patent number 6,395, compd B MS-477118 in 767 (chemical compounds of embodiment 60), also be known as the illustrated (1S of patent application WO 2004/052850 page 2 formula M, 3S, 5S)-2-[(2S)-2-amino-2-(3-hydroxyl three ring [3.3.1.1 ^3,7] last of the ten Heavenly stems-the 1-yl)]-the 1-oxoethyl]]-2-azabicyclic [3.1.0] hexane-3-nitrile benzoate (1: 1) and patent application WO 2004/052850 page 3 formula M in illustrated corresponding free alkali (1S, 3S, 5S)-2-[(2S)-2-amino-2-(3 hydroxyls, three ring [3.3.1.1 ^3,7] last of the ten Heavenly stems-the 1-yl)-the 1-oxoethyl]-2-azabicyclic-[3.1.0] hexane-3-nitrile (M ') and monohydrate (M ") thereof.Compd B MS-477118 is called saxagliptin again.

Another preferred inhibitors is the chemical compound GSK23A that is disclosed among the WO 03/002531 (embodiment 9), be called again (2S, 4S)-1-((2R)-2-amino-3-[(4-methoxybenzyl) sulphonyl]-3-methylbutyryl base)-4-pyrrolidines-2-nitrile hydrochlorate.

P32/98 (CAS numbering: 251572-86-8) be called 3-[(2S again, 3S)-and 2-amino-3-methyl isophthalic acid-oxo amyl group] Thiazolidine, it can be used as 3-[(2S, 3S)-and 2-amino-3-methyl isophthalic acid-oxo amyl group] (2: 1) mixture of Thiazolidine and (2E)-2-butylene two acid esters, and be described in WO 99/61431, and following formula: compound is described in the WO 99/61431 and the Diabetes1998 of Probiodrug company, 47,1253-1258

And Compound P 93/01 has also been described by the said firm.

Other extremely preferred DPP-IV inhibitor are the chemical compounds in for example claim 1 to 5 that is disclosed among the patent application WO 02/083128.Most preferred DPP-IV inhibitor is by embodiment 1 to 13 and the specifically described chemical compound of claim 6 to 10.

Other extremely preferred DPP-IV inhibitor are by disclosed chemical compound of Bristol-Myers Squibb such as Saxagliptin (BMS477118).

Other extremely preferred DPP-IV inhibitor of the present invention are in International Patent Application WO 02/076450 (especially embodiment 1 to 128) and by Wallace T.Ashton (Bioorganic﹠amp; Medicinal Chemistry Letters 14 (2004) 859-863) describe, especially chemical compound 1 and the chemical compound of listing in table 1 and 2.Preferred chemical compound is as shown in the formula chemical compound 21e (table 1):

Other preferred DPP-IV inhibitor are described in patent application WO 2004/037169 (especially described in the embodiment 1 to 48 those) and WO 02/062764 (those that describe especially in embodiment 1 to 293, more preferably at the chemical compound 3-of the 7th page of description (aminomethyl)-2-isobutyl group-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolin carboxylic acid amides and 2-{[3-(aminomethyl)-2-isobutyl group-4-phenyl-1-oxo-1,2-dihydro-6-isoquinolyl] oxygen acetamide) and patent application WO2004/024184 in (especially in reference example 1 to 4).

Other preferred DPP-IV inhibitor are described in patent application WO 03/004498, especially among the embodiment 1 to 33, and most preferably be by embodiment 7 describe as shown in the formula chemical compound, be also referred to as MK-0431:

MK-0431

Preferred DPP-IV inhibitor also is described in patent application WO 2004/037181, especially among the embodiment 1 to 33, and most preferably is the chemical compound described in the claim 3 to 5.

Preferred DPP-IV inhibitor is that N-replaces adamantyl-amino-acetyl group-2-Cyanopyrolidine; N (substituted glycyl)-4-Cyanopyrolidine; N-(N '-substituted glycyl)-the 2-Cyanopyrolidine; N-aminoacyl Thiazolidine; N-aminoacyl pyrrolidine; the other isoleucyl-thiazolidine of L-; the other isoleucyl-pyrrolidine of L-threo form-isoleucyl-pyrrolidine and L-; 1-[2-[(5-cyanopyridine-2-yl) amino] ethylamino] acetyl group-2-cyano group-(S)-pyrrolidine; MK-431 and pharmaceutical salts thereof.

Most preferred DPP-IV inhibitor is selected from [S]-1-[2-(5-cyano group-2-pyridine amino) ethylamino] acetyl group-2-pyrrolidine nitrile mono-hydrochloric salts; (S)-and 1-[(3-hydroxyl-1-adamantyl) amino] acetyl group-2-cyano group-pyrrolidine and L-threo form isoleucyl-thiazolidine be (according to the chemical compound code of Probiodrug: aforesaid P32/98); MK-0431; 3-(aminomethyl)-2-isobutyl group-1-oxo-4-phenyl-1; 2-dihydro-6-isoquinolin carboxylic acid amides and 2-{[3-(aminomethyl)-2-isobutyl group-4-phenyl-1-oxo-1,2-dihydro-6-isoquinolyl] oxygen } acetamide and its optional pharmaceutical salts.

[S]-1-[2-(5-cyano group-2-pyridine amino) ethylamino] acetyl group-2-pyrrolidine nitrile mono-hydrochloric salts and (S)-1-[(3-hydroxyl-1-adamantyl) amino] acetyl group-2-cyano group-pyrrolidine is disclosed in respectively among the embodiment 1 of the embodiment 3 of WO 98/19998 and WO 00/34241 particularly.DPP-IV inhibitor P32/98 (on seeing) specifically describes in Diabetes, and 1998,47,1253-1258.[S]-1-[2-(5-cyano group-2-pyridine amino) ethylamino] acetyl group-2-pyrrolidine nitrile mono-hydrochloric salts and (S)-1-[(3-hydroxyl-1-adamantyl) amino] acetyl group-2-cyano group-pyrrolidine can be as among the 20th page of the WO 98/19998 or prepare described in WO 00/34241.

Particularly preferably be the 1-{2-[(5-cyanopyridine-2-yl of following formula) amino] ethylamino } acetyl group-2-(S)-cyano group-pyrrolidine (be also referred to as [S]-1-[2-(5-cyano group-2-pyridine amino) ethylamino] acetyl group-2-pyrrolidine nitrile mono-hydrochloric salts):

Particularly its dihydrochloride and mono-hydrochloric salts; As shown in the formula pyrrolidine, 1-[(3-hydroxyl-1-adamantyl) amino] acetyl group-2-cyano group-, the amino that (S) (is called (S)-1-[(3-hydroxyl-1-adamantyl again)] acetyl group-2-cyano group-pyrrolidine, LAF237 or vildagliptin):

And L-threo form isoleucyl-thiazolidine (according to the chemical compound code of Probiodrug: as above-mentioned P32/98), MK-0431, GSK23A, saxagliptin, 3-(aminomethyl)-2-isobutyl group-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolin carboxylic acid amides and 2-{[3-(aminomethyl)-2-isobutyl group-4-phenyl-1-oxo-1,2-dihydro-6-isoquinolyl] oxygen } acetamide and the pharmaceutical salts of arbitrary example randomly.

DPP728 and LAF237 are disclosed in respectively among the embodiment 1 of the embodiment 3 of WO 98/19998 and WO 00/34241 particularly.DPP-IV inhibitor P32/98 (on seeing) is specifically at Diabetes1998, and 47, describe among the 1253-1258.DPP728 and LAF237 can prepare described in the 20th page of WO 98/19998 or WO 00/34241 or international patent application no EP2005/000400 (application number).

Disclosed any material in above-mentioned patent document or the scientific publication thing (herein quoting as a reference) is considered as effective DPP-IV inhibitor to be used for using in the embodiment of this invention.

According to the present invention, treat that the DPP-IV inhibitor that uses separately can be used in combination with carrier.

Carrier herein is a kind of (natural, synthetic, peptide, non-peptide) instrument, for example a kind of protein, and it passes through the embedded cell membrane of this protein with specific substance transportation and enters cell.That the transhipment of different material needs is different (natural, synthetic, peptide, non-peptide) carrier, therefore with every kind of carrier design for only discerning material like an a kind of material or the category.

Any detection method known to those skilled in the art can be used for detecting combining of DPP-IV and carrier, for example passes through labeled vector.

The DPP-IV inhibitor can be DPP-IV inhibitor peptide or that preferably be non-peptide.

The DPP-IV inhibitor and the pharmaceutical salts thereof that most preferably have Orally active.

Active component of the present invention or its officinal salt can also use with the form of solvate, and solvate is hydrate or comprise and be used for crystalline other solvents for example.The also any crystal form of active component.

Now be surprised to find, the DPP-IV inhibitor can be used for prevention, delay of progression or treatment neurodegenerative disease, cognitive disorder and improvement memory (short-term and long-term) and learning capacity.

Preferably, neurodegenerative disease is selected from following situation and disease: as dull-witted (as alzheimer disease, presenile dementia (being also referred to as mild cognitive impairment), Alzheimer dependency dementia (dementia of the Alzheimer type)), Huntington Chorea, tardive dyskinesia, unusual high power, mania, parkinson disease, Si-Li syndrome (steel-Richard syndrome), mongolism, myasthenia gravis, nerve and brain trauma, the blood vessel amyloidosis, follow the cerebral hemorrhage of amyloidosis, encephalitis, Friedreich ataxia, acute confusional disease, and those diseases of in disease, playing a role of apoptosis sexual cell necrosis especially, as amyotrophic lateral sclerosis, glaucoma, and Alzheimer especially.

More preferably, neurodegenerative disease is selected from Alzheimer and dementia, preferably alzheimer disease, mild cognitive impairment or dementia of the Alzheimer type.

More preferably, neurodegenerative disease is an Alzheimer.

The DPP-IV inhibitor is described in patent application WO 03/002596 to treatment multiple sclerosis, migraine, apoplexy, cerebral ischemia and Parkinsonian purposes, yet when using DPP-IV inhibitor vildagliptin, obtained the result of beat all advantage and improvement.Effect to multiple sclerosis can be assessed by the operational approach among WO 03/002596 (the quoting as a reference) embodiment 13 herein.

Therefore, the invention still further relates to vildagliptin or its pharmaceutical salts be used to make be used for preventing, the purposes of delay of progression or treatment multiple sclerosis, migraine, apoplexy, ischemia, cerebral ischemia, ischemic injury and Parkinsonian medicine.

The invention still further relates to and be used for prevention, delay of progression or treatment multiple sclerosis, migraine, apoplexy, ischemia, cerebral ischemia, ischemic injury and Parkinsonian method, comprise to needs its, vildagliptin or its pharmaceutical salts of the homoiothermic animal administering therapeutic effective dose that comprises the people.

The invention still further relates to vildagliptin or its pharmaceutical salts be used to make be used for preventing, the purposes of the medicine of delay of progression or treatment general peripheral neurophaty or diabetic peripheral neurophaty.The invention still further relates to be used to prevent, the method for delay of progression or treatment general peripheral neurophaty or diabetic peripheral neurophaty, comprise to needs its, vildagliptin or its pharmaceutical salts of the homoiothermic animal administering therapeutic effective dose that comprises the people.

The present invention also is provided for treating the purposes or the method for age related cognitive decline or mild cognitive impairment, comprise to needs its, the inhibitor of DPP-IV as defined above (preferably vildagliptin) of the homoiothermic animal administering therapeutic effective dose that comprises the people.In specific embodiments, the present invention also is provided for preventing, delay or stagnates any other the age related cognitive decline or the method for mild cognitive impairment progress, comprises to its patient of needs using DPP-IV inhibitor (preferably vildagliptin) or its officinal salt for the treatment of effective dose as defined above.

In a particular, the invention provides the purposes or the method that are used for preventing or delaying age related cognitive decline patient or mild cognitive impairment patient Alzheimer dependency dementia onset.

In a particularly preferred scheme, neurodegenerative disease is selected from Alzheimer.Be preferably used for preventing or delay to suffer from Alzheimer (AD) outbreak among the patient of age related cognitive decline or mild cognitive impairment.In a particular of the present invention, use the DPP-INV inhibitor to the patient who suffers from age related cognitive decline or mild cognitive impairment, wherein this patient also has following one or more risk factor that can develop into AD in addition: the disease family history; The genetic predisposition of disease; The serum cholesterol that raises; Adult outbreak type diabetes; The CSF level of the total tan that raises; The CSF level of the CSF level of the phosphoric acid taurine that raises and the A β 42 of reduction.

Cognitive disorder preferably is selected from following situation and disease, for example schizophrenia dependency cognitive defect, age inductivity memory impairment, psychosis dependency cognitive defect, diabetes dependency cognitive impairment, dependency cognitive defect after the apoplexy, anoxia dependency memory impairment, cognition of alzheimer disease dependency and attention deficit, attention deficit disorder, mild cognitive impairment dependency dysmnesia, dull-witted dependency cognitive function is impaired, Alzheimer dependency cognitive function is impaired, parkinson disease dependency cognitive function is impaired, vascular dementia dependency cognitive function is impaired, the cognitive disorder of cerebral tumor dependency, Pick disease, because of the cognitive defect due to the autism, cognitive defect after the electroconvulsive therapy, traumatic brain injury dependency cognitive defect, amnesia, delirium, dull-witted.Cognitive disorder also includes but not limited to learn acquistion sexual disorders (learning disorder), memory is consolidated obstacle, refresh memory obstacle and kept obstacle.

More preferably, cognitive disorder is selected from diabetes dependency cognitive impairment, Alzheimer dependency cognitive function is impaired, parkinson disease dependency cognitive function is impaired, dependency cognitive defect, the cognition of alzheimer disease dependency and attention deficit, mild cognitive impairment dependency dysmnesia after the apoplexy.

In an especially preferred embodiment, cognitive disorder is selected from the relevant cognitive disorder of diabetes and Alzheimer dependency cognitive function is impaired, dependency cognitive defect after the apoplexy.

In an especially preferred embodiment, cognitive disorder is selected from the age related cognitive decline." age related " refers to that preferably the age is 55 years old or bigger, 65 years old or bigger, 75 years old or bigger patient.

The DPP-IV inhibitor also can be used to improve substantially memory (short-term and long-term) and learning capacity, as treating substantially and/or stoping memory impairment.For example, the DPP-IV inhibitor can be used for improving pace of learning and potentiality in education and rehabilitation environment especially.One preferred aspect, the DPP-IV inhibitor can be used for treating be the age relevant, as the electroconvulsive therapy consequence or by for example apoplexy, anesthetic accident, injury of head, hypoglycemia, carbon monoxide poisoning, lithium poison or vitamin deficiency due to the memory that causes of brain injury or learn impaired.

Therefore, the present invention relates to DPP-IV inhibitor or its officinal salt and be used for making the purposes that is used for prevention, delay of progression or treatment neurodegenerative disease, cognitive disorder and is used for improving the medicine of remembering (short-term and long-term) and learning capacity.

Especially, the present invention relates to (S)-1-[(3-hydroxyl-1-adamantyl) amino] acetyl group-2-cyano group-pyrrolidine (LAF237 or vildagliptin) or its officinal salt be used for making and be used for prevention, delay of progression or treatment neurodegenerative disease, cognitive disorder and being used for and improve the new purposes of the medicine of memory (short-term and long-term) and learning capacity.

In addition, the invention still further relates to the method that is used for prevention, delay of progression or treatment neurodegenerative disease, cognitive disorder and is used for improving memory (short-term and long-term) and learning capacity, comprise to needs its, the DPP-IV inhibitor of the homoiothermic animal administering therapeutic effective dose that comprises the people, preferably vildagliptin.

In another embodiment; the present invention relates to the DPP-IV inhibitor; (the S)-1-[(3-hydroxyl-1-adamantyl of formula (I) preferably) amino] purposes of acetyl group-2-cyano group-pyrrolidine (LAF237 or vildagliptin); it is used for the treatment of and/or prevents memory or learning disorder, for example because the poisonous substance contact; brain injury; cerebral aneurysm; the age related memory impairment; mild cognitive impairment; epilepsy; children ' s intelligence development postpones and is derived from disease such as parkinson disease; Alzheimer; AIDS; injury of head; Huntington Chorea; Pick disease; obstacle due to the dementia of Creutzfeldt-Jakob disease and apoplexy.In addition, The compounds of this invention also can be used for strengthening the memory of normal individual.

In another embodiment, the present invention relates to be used for prevention, delay of progression or treatment neurodegenerative disease, cognitive disorder and be used for improving the pharmaceutical composition of memory (short-term and long-term) and learning capacity, it comprises the DPP-IV inhibitor with the treatment effective dose of one or more pharmaceutically suitable carrier combinations.

Also be surprised to find the axon growth in DPP-IV inhibitor preferably effected neurodegenerative disease, especially the Alzheimer parkinson disease.

Term " prevention " means to healthy person is preventative and uses this combination, with the outburst of the mentioned disease of prevention this paper.In addition, term " prevention " means to the patient to be treated who is in the disease preliminary stage is preventative and uses this kind combination.

Term used herein " delay of progression " means to being in the patient to be treated disease preliminary stage, that made a definite diagnosis corresponding disease omen form and uses this combination, as the preparation or the pharmaceutical composition of combination.

Term " treatment " is understood as for the purpose of resisting disease, situation or disease the patient is handled and looks after.

Although reason may be different, the patient with neurodegenerative disease might show extremely general the brain cell atrophy from the part that causes endangering intelligence and body function.

The disease of DPP-IV mediation preferably is selected from dementia, Alzheimer, amyotrophic lateral sclerosis and glaucoma.

More preferably, the disease of DPP-IV mediation is dementia, Alzheimer or parkinson disease.

Term " dementia " as used in this article " comprise dementia of the Alzheimer type, parkinson type dementia, Huntingdon type dementia, pik type dementia, the refined type dementia of gram, alzheimer disease, presenile dementia, sudden relevant dementia, wound dependency dementia, apoplexy dependency dementia, the hemorrhage dependency dementia of cranium, vascular dementia, and comprise acute, chronic or recurrence form.

Alzheimer is dull-witted modal form.This neurological disorder involves brain, and causes cognitive disorder, for example the loss of memory, thinking impaired, be difficult to carry out the change of being familiar with task, time and orientation for place obstacle, judgment difference or decline, aphasis, emotion or behavior and personality.Increasing age is unique greateset risk factor of Alzheimer, and the age reaches and has 10% individuality to suffer from this disease age in 65 years old the individuality to reach 85 years old individuality and then have up to 50% individuality and suffer from this disease.The risk of this increase in part because brain cell it more and more is subject to and stress damages when old and feeble.

In Alzheimer, amyloid-beta fragment (A β) accumulation is so that form the anomalous structure that is called the amyloid speckle.Developing effective treatment of alzheimer method needs thorough this disease of understanding how to kill brain cell by destroying cytochemistry and communication effect.Many experts believe, cause a key of cell death in the Alzheimer to be the abnormal processing of amyloid precursor protein (APP).

Parkinson disease are PDs of central nervous system, and involve above 1 million people in the U.S..Clinically, this sick feature be that autonomy motion descends, walks with difficulty, position shakiness, stiff and tremble.Parkinson disease cause the reduction of dopamine utilizability to cause by the pigmentation neuronal degeneration in the substantia nigra.

Parkinson disease had both been involved the male, also involved the women.Sickness rate is high in organizing above 50 years old, even alarming growth also occurs in less patient of age.Consider the prolongation of life expectancy in this country and the world wide, suffering from Parkinsonian number will increase.

Neuronic genetic program degeneration in brain in some zone causes Huntington Chorea.The early symptom of Huntington Chorea comprises the difficulty that takes the fling or learn the new things or the memory fact.The medicine that major part is used for the treatment of the Huntington chorea disease symptoms has side effect, as tired, uneasy or be overexcited.At present do not stop or reversing the therapy of Huntington chorea disease progression.Therefore, need to solve symptom and have the pharmaceutical preparation of less side effect.

As cognitive disorder, diabetes are relevant diseases of a kind of age.In the U.S., the onset diabetes rate almost is four times of onset diabetes rate among the young crowd among the over-65s crowd.Surpassing 300 ten thousand old peoples in the U.S. has made a definite diagnosis and has suffered from diabetes; Other 600 ten thousand old adults suffer from not yet diagnosed diabetes or carbohydrate tolerance impaired (nineteen ninety-five Kenny etc.).In view of diabetes among the old people and the dull-witted high prevalence of merging, even if the moderate associating between diabetes and the cognitive decline also may have important public health influence.In addition, diabetes and dementia all are complicated clinically diagnosed cases, and its control and management is a kind of challenge for the clinicist.More and more evidences show that diabetes are relevant with cognitive impairment.In addition, cognitive impairment may influence oneself's cooking, and this will make the diabetes control and management complicated.Diabetes to the influence of cognitive function as if owing to the intrinsic factor (glucemia and insulin resistant) of diabetes, diabetes associated complication (apoplexy) or from the harmful side effect (hypoglycemia) for the treatment of diabetes.Therefore, need to improve the novel drugs of treatment and prevent diabetes patient cognitive impairment.

Alzheimer has many-sided the embodiment, comprises cognition and attention deficit.Its diagnosis is described in the Diagnostic and Statistical Manual ofMental Disorders that the SM-T of APA,American Psychiatric Association is published, the 4th edition (for example 139-143 page or leaf).The diagnostic criteria of Alzheimer comprises the multiple cognitive decline that takes place among the patient, its performance is as follows: (1) temporary memory impaired (study fresh information or recall the ability of institute's learning information recently impaired), (2) one of following (or multiple) cognitive disorder: (a) aphasia (aphasis), (b) apraxia are (although have complete motor function, but it is impaired that motor activity is finished ability), (c) agnosia (, still can not discern or differentiate object) and (d) carry out function difficulty (for example plan, organize, ordering, abstract) although have complete sensory function.These defectives are treated with acetylcholinesteraseinhibitors inhibitors at present.This class inhibitor slows down acetylcholine degraded, the activity of non-specific increase cholinergic nerve system.Because this type of medicine is non-specific, so have multiple side effect.Therefore need to improve the cognitive and attention deficit of Alzheimer dependency and less than the novel drugs of side effect due to nonspecific stimulation cholinergic approach.

Tardive dyskinesia is relevant with using of conventional antipsychotic drug.The primary disease feature is usually to show as lip and tongue is tight and/or the autonomic movement of arm or lower limb distortion.Sickness rate because of the tardive dyskinesia due to the medicine contact in taking the patient of conventional antipsychotic drug is annual about 5%.In about 2% patient, tardive dyskinesia has disfeaturing property of severe.Do not treat at present the universal method of tardive dyskinesia.In addition, the medicine that can not abandon having effect because there being potential problems usually.Therefore need to solve the medicament of tardive dyskinesia symptom.

Presenile dementia (mild cognitive impairment) relates to memory impairment, and does not relate to attention deficit problem and int cognitive function.The difference of mild cognitive impairment and alzheimer disease is that mild cognitive impairment relates to because of the more lasting and thorny loss of memory problem due to the patient age.Be not used in the medicine of clearly identifying of treatment mild cognitive impairment at present, partly cause is the evaluation of primary disease not familiar.Therefore, need the amnemonic medicine of treatment mild cognitive impairment dependency.

Age related cognitive decline and mild cognitive impairment (MCI) are to have memory defects but the disease (Santacruz and the Swagerty that lack other diagnosis of dementias standard, American FamilyPhysician, 63 (2001), 703-13) (also referring to " The ICD-10 Classification of Mentaland Behavioural Disorders ", Geneva, World Health Organization (WHO), 1992,64-5).When using in this article, the feature of age related cognitive decline is to occur decline at least 4 months, preferred six months period one of aspect following at least: memory and study; Attention and absorbed, thinking; Language and visual space function, and the score value that in standardized neuropsychological test such as MMSE, is lower than normal (noun) above standard deviation.Especially, may there be the carrying out property decline of memory.In more serious mild cognitive impairment (MCI), the degree of memory impairment has exceeded be normal scope for patient age, but Alzheimer (AD) do not occur.Petersen etc. are at Arch.Neuro., and 56 (1999), the differential diagnosis of MCI and moderate AD has been described among the 303-8.In same article, the carrying out property that disclosure MCI patients such as Petersen generally experience cognitive impairment increases the weight of and in many cases AD takes place.About other information of the differential diagnosis of MCI by Knopman etc., Mayo Clinic Proceedings, 78 (2003) 1290-1308 provide.In older experimenter's research, TuokLo etc. (Arch, Neurol., 60 (2003) 577-82) find, the experimenter who shows the MCI outbreak dull-witted risk takes place in 5 years increases by 3 times.

According to Grundman etc. (J.Mol.Neurosci., 19 (2002), 23-28) report, baseline Hippocampus volume lower among the MCI patient is the prognostic indicator of concurrent AD.

Similarly, Andreasen etc. (Aeta Neurol.Scand, 107 (2003) 47-51) have reported that the phosphoric acid taurine of total taurine of high CSF level, high CSF level is all relevant with the increase that develops into the AD risk from MCI with the A β 42 of low CSF level.

The age related cognitive decline with mild cognitive impairment with some the time because of brain or systemic disease and wound such as the serious dialysis of apoplexy, concussion or hypophysis due to obvious cognitive decline different.

The people who suffers from mongolism has chromosomal extra and crucial part at it No. 21 in all or at least some cell.The known adult who suffers from mongolism has the risk of suffering from dementia of the Alzheimer type.At present, the therapy that does not have success for mongolism.Therefore need to solve the medicine of mongolism dependency dementia.

Alzheimer disease is not an independent morbid state.Yet the disease that is classified as alzheimer disease often comprises cognition and attention deficit.Usually, these defectives can not be treated.Therefore, need improve the medicine of cognition of alzheimer disease dependency and attention deficit.

Pick disease is degenerated by carrying out property interpersonal skill slowly and personality changes causes, the symptom of cause having intelligence, memory and language damaging.Common sympton comprises the loss of memory, spontaneous shortage, thinking and absorbed difficulty and aphasis.The specific treatment method and the medicament that do not have Pick disease at present, but some symptom can be with cholinergic and increase the anti-depressant therapy of 5-hydroxy tryptamine.In addition, antipsychotic drug can alleviate FTD patient's symptom of experience vain hope or hallucination.Therefore, the medicament that needs to treat the interpersonal skill's degeneration of carrying out property and personality changes and solution Pick disease symptom and have less side effect.

When the unexpected physical impact of head was destroyed brain, traumatic brain injury took place.The symptom of traumatic brain injury comprises mental disorder and other awareness difficulties.Therefore, need to solve the symptom of mental disorder and other awareness difficulties.

The cerebral tumor is abnormal structure's growth of intracranial.The symptom of the cerebral tumor comprises behavior and cognitive difficulties.Available surgical operation, radiation and chemotherapy are treated this tumor, but need to solve other preparations of related symptom.Therefore, the symptom that needs solution behavior and cognitive difficulties.

For example can confirm to use the pharmaceutically active that representative DPP-IV inhibitor kind is produced according to the present invention by known corresponding pharmacology model in the field under using.The technical staff can select relevant animal model to prove before this and treatment indication and the beneficial effect after this pointed out fully in the affiliated field.

For example following definite chemical compound of the present invention and the pharmacological activity that is combined in the neurodegenerative disease:

A) in the viewing test in mice, 0.01 to 100mg/kg, more preferably the chemical compound of 0.1 to 50mg/kg p.o. dosage causes the reactivity that stimulates to external world of clear-headed stage of prolongation and increase,

B) in the sleep of chronic transplanting rat/clear-headed periodic test, scope from about 0.01 to 100mg/kg, more preferably the chemical compound from 0.1 to 50mg/kg p.o. dosage has prolonged REM sleep phase, and

C) in carbon-14 deoxyglucose rat test (according to L:Sokoloff journal ofcerebral Blood flow and metabolism 1981,1,7-36, H.E Savaki etc., Brainresearch 1982,233,347 and J.Mc Culloch etc., Journal of cerebral BloodFlow and Metabolism 1981,1, the principle of 133-136), from about 0.01 to 100mg/kg, more preferably the chemical compound from 0.1 to 50mg/kg p.o. dosage has increased brain, especially the picked-up of the carbon-14 deoxyglucose in the specific region of limbic system.

In the sleep of long-term transplanting rat/in the clear-headed cycle (for method referring to J-M Vigouret etc., J.pharmacology 10,503 (1978)), when with 0.01 to 100mg/kg, more preferably 0.1 to 50mg/kgp.o. (oral) can realize vigilant increase by prolonging the clear-headed stage when dosage is used The compounds of this invention.

And, with 0.01 to 100mg/kg, more preferably from the dosage of 0.1 to 50mg/kg p.o. after the rat of the both sides damage that has locus coeruleus (LC) and nbM (NBM) is used The compounds of this invention, can significantly improve the cognitive behavior performance, as measured by the ability of avoiding electric shock in the shuttle box.

The method is similar to the methods described in Bran Research 507 (1990) 261-266 such as V.Haroutunian.Male OFA rat (300g) is with pentobarbital anesthesia and be fixed in the stereotaxic instrument, and will go up the front tooth bar and be placed in the position that is lower than biauricular line 5mm (LC) or 3.3mm (NBM).Use radio frequency infringement generator to cause damage in 10 seconds at 60c.After 5 week of damage, as A.R.Dravid, A-L.Jaton and E.B.Van Deusen are at experimental Brain Research, and Suppl.13 described in the 249th page (1986), carries out performance testing with the active avoidance test in shuttle box.

The present invention is also based on wonderful discovery, it is The compounds of this invention and combination present the necrosis of significant anti-apoptosis sexual cell to facial motor neuron protective effect, and can be according to Ausari etc., J.Neuroscience 13, and the experimental technique of 4042-4053 (1993) is assessed being applied on 0.01 to 100mg/kg, more preferably 0.1 to 50mg/kg and the following s.c. dosage of neonate rat; And continue 4 days to hippocampal pyramidal cell present significant anti-kainic acid use due to the protective effect of necrocytosis; it can be according to Golowitz and Paterson; Soc.Neurosc.Abstr.20; 246; 113.2 experimental technique (1994), to give birth to fully year rat use 0.01 to 100mg/kg, more preferably 0.1 to 50mg/kg and following s.c. dosage after assess.

Main rat model in the Alzheimer helps to understand neuropathy, and provides new method likely for treatment.

Sudden change in amyloid precursor protein (APP) gene causes early onset familial Alzheimer (AD) by the formation of influence as the amyloid-beta peptide (A β) of AD speckle main component.Use to drive several neuronal specificity promoteres that people APP cDNA expresses, produced and expressed transgenic mice with 717 and 670/671 codon mutation APP.Lesion degree depends on expression and concrete sudden change.In the transgenic mice at 18 monthly ages, the people APP with 670/671 dual sudden change of Swede and V717I sudden change crosses and expresses 2 times cause that A β deposits in neopallium and Hippocampus.

The APP23 transgenic mice is crossed people's amyloid precursor protein of expressing a kind of sudden change, and show a sign of Alzheimer disease pathologic, be the extracellular deposition (Calhoun etc. of amyloid speckle, Proceedings of the National Academy of Sciences of theUnited States of America (on December 23rd, 1999), the 96th volume, the 24th phase, the 14088-14093 page or leaf).

Except that the amyloid speckle, the accumulation of amyloid-beta in cerebrovascular also takes place in this APP23 mouse model.Brain amyloid angiopathy in this mice and related pathologies show with and AD patient individual at advanced age in viewed brain amyloid angiopathy and the surprising similarity of related pathologies.The accumulation of amyloid-beta in the APP23 mice (CAA) in cerebrovascular causes local neuron's forfeiture, property synaptic button malnutrition and microglia activation, and this provides CAA to cause neurodegenerative evidence.

This APP23 mouse model is particularly useful to the pharmacological activity that confirms chemical compound of the present invention and combination.

Embodiment 2-4 described in the patent application WO2005009349 has described assessment The compounds of this invention and combined therapy or has prevented X syndrome, AD, Parkinsonian active additive method.

The compounds of this invention and be combined in the pharmacological activity that improves in the cognitive function and can use test assessment known to those skilled in the art for example, as standardized psychometry test (as Wechsler Memory Scale, Wechsler Adult Intelligence Scale, Raven Standard Progressive Matrices Test, the test of Schaie-Thurstone adult [), Five neuropsychological tests (as Luria-Nebraska), metacognition self evaluation (as Metamemory Questionnaire), vision-space screening test (is schemed as Poppelreuter, clock identification, Nidus Vespae is drawn and is eliminated), cognitive screening test (as the simple and easy mental status test of Folstein) and response time test.This type of standardized test as listed above is described in Ruoppila, l. and Suutama, and T. (1997) Scand.J.Soc.Med.Suppl.53, among the 44-65 and serve as example, described list of references is complete herein to be quoted as a reference.Term " cognitive function " comprises the function of being assessed by any this type of test.

Prove DPP-4 inhibitor of the present invention or make up forward that the clinical method that influences the AD disease is described in the 31-37 page or leaf (quoting as a reference) among the patent application WO 2004/082706 herein.

The degree of patient's cognitive decline or infringement also advantageously before with DPP-IV inhibitor or its officinal salt therapeutic process, among and/or assess during regular intervals of time afterwards so that detect the variation that therefore takes place, for example cognitive decline slows down or stops.It is known in the art to be used for the multiple Five neuropsychological tests of this purpose, as has simple and clear mental status scale (MMSE) (Folstein etc., J.Psych.Res., 12 (1975), the 196-198 of the standard that is subjected to age and education degree adjustment; Anthony etc., Psychological Med.12 (1982), 397-408; Cockrell etc., Psychopharmacology, 24 (1988), 689-692; Crum etc., J.Am.Med.Assoc.18 (1993), 2386-2391).MMSE is used to be grown up the succinct quantitatively property measurement of cognitive state.The cognitive change procedure that it also can be used for screening cognitive decline or infringement, the order of severity, the track individual of assessment cognitive decline or infringement takes place in time on particular point in time, and recording individual is to the reaction of treatment.

Other standard tests that are used for cognitive behavior performance for example Alzheimer assessment scale (ADAS-cog) by Doraiswamy (Neurology.1997 June; 48 (6): 1511-7) describe and in patent US20040024043 and US 6369046, describe.ADAS-cog is the multinomial order instrument that is used to measure the cognitive behavior performance that comprises memory, location, maintenance, reasoning, language and practical matter.US20040024043 has also described in embodiment 5 in the body of Rodents and has test model, has described clinical study design in embodiment 9.Another clinical study design is described among the US6369046 (embodiment 1).

Another can be used for proving that the DPP-IV inhibitor improves that method is described in the european patent number 1310258 (embodiment 5-8) in the useful body of cognitive function.

The method that can be used to assess the vildagliptin treatment or prevent the advantage of ischemia or ischemic injury has been described among the embodiment 3 of WO2004004664, WO2004004702, WO2003101276 (embodiment 1-9) or WO2004096225.

WO0110867 has described the method for the advantage that can be used to assess vildagliptin treatment or prevention of stroke.

WO 2004006911 (experimental section), WO 0162277 (embodiment 2) provide and can be used to assess vildagliptin treatment or prevention peripheral neurophaty, the especially method of the advantage of diabetic peripheral neurophaty.Orally administered alternative its local application of Vildagliptin.The peripheral sensory neuropathy is the diabetic complication (Greene etc., 1990) that takes place frequently relatively and often cause weakness, but the nosetiology of diabetes and basic pathology physiology also uncertain (Ward, 1992).

Above-mentioned file, especially described test model are quoted as a reference herein.

Another aspect of the present invention relates to the combination of at least a DPP-IV inhibitor or its officinal salt and at least a COMBINATION OF THE INVENTION of the present invention, this combination can be used for prevention, delay of progression or treatment neurodegenerative disease, cognitive disorder and is used for improving memory (short-term and long-term) and learning capacity, so that treatment suffers from or easily suffers from neurodegenerative disease, especially Alzheimer or the Parkinsonian homoiothermic animal that comprises mammal, especially people.

More surprisingly following experiment is found: combined administration DPP-IV inhibitor; especially (S)-1-{2-[5-cyanopyridine-2-yl] amino } ethyl-ammonia acetyl group }-2-cyano group-pyrrolidine (DPP728) or (S)-1-[(3-hydroxyl-1-adamantyl) amino] acetyl group-2-cyano group-pyrrolidine (LAF237) not only produces useful therapeutic effect with at least a other COMBINATION OF THE INVENTION of the present invention; especially strengthen or collaborative therapeutic effect; but also generation is from the additional benefit of combined therapy, for example surprised prolongation of effect; therapeutic treatment and to the surprised beneficial effect of neurodegenerative disease and disease and cognitive disorder (for example having described obstacle herein) widely.

COMBINATION OF THE INVENTION of the present invention comprises the medicine of other pharmacology's kinds that for example belong to relevant with the central degenerative disease with periphery; as the anti-inflammatory agent under peripheral neurophaty and the neurodegenerative disease situation; antioxidant and neuroprotective (as the glutamine receptor antagonist); the MAO inhibitor; the COMT inhibitor; and acetyl cholinesterase enzyme inhibitor (for example thunder department is for bright (Exelon)); the BuCh inhibitor; γ and beta-secretase inhibitors; the amyloid peptide aggregation inhibitor; dopamine agonist or antagonist and the active immunity in the Alzheimer situation (amyloid beta of adjuvant is puted together or do not puted together in use) and passive immunity (using the specific antibody of anti-amyloid beta); be used for the treatment of the medicine of cognitive disorder such as the selective depressant of acetylcholinesterase, as donepezil.

The COMT inhibitor is such as but not limited to tolcapone and entacapone.

Antiinflammatory includes but not limited to naproxen sodium, diclofenac sodium, diclofenac potassium, match comes former times cloth, sulindac Evil promazine, diflunisal, etodolac, meloxicam, ibuprofen, ketoprofen, nabumetone, rofecoxib, methotrexate, take fluorine Lip river rice, sulfasalazine, gold salt, the RHo-D immunoglobulin, Mycophenolic Acid morpholine ethyl ester (mycophenylate mofetil), ciclosporin, azathioprine, tacrolimus, basiliximab, Dary pearl monoclonal antibody (daclizumab), salicylic acid, aspirin, methyl salicylate, diflunisal, salsalate, Olsalazine, sulfasalazine, acetaminophen, indomethacin, sulindac, mefenamic acid, meclofenamate sodium, Tolmetin, ketorolac, diclofenac (dichlofenac), flurbiprofen Evil promazine, piroxicam, meloxicam, ampiroxicam, Droxicam, piroxicam, tenoxicam, Phenylbutazone, Offitril, phenazone, aminophenazone, azapropazone, Zileuton, aurothioglucose, sodium aurothiomalate, auranofin, methotrexate, colchicine, allopurinol, probenecid, sulfinpyrazone and benzbromarone or betamethasone and other sugared cortical hormones.

Preferably, chemical compound with inhibiting activity of acetylcholinesterase, is selected from 3-[1-(benzyl)-4-piperidyl]-1-(2,3,4,5-tetrahydrochysene-1H-1-benzazepine-8-yl)-1-acetone fumarate, 2,3-dihydro-5,6-dimethoxy-2-[[1-(benzyl)-4-piperidyl] methyl l-1H-indeno-1-one hydrochloric acid is (with trade mark ARICEPT ^The donepezil of selling), (S)-3-[1-(dimethylamino) ethyl] phenyl-N-ethyl-N-methyl carbamate (thunder department replaces bright), 9-amino-2,3,5,6,7,8-six hydrogen-1H-Pentamethylene. [b] quinoline (ipidacrine), hydrochloric acid 1,2,3,4-tetrahydrochysene-9-aminoacridine amine is (with trade mark COGNEX ^The tacrine of being sold); hydrochloric acid 8-[3-[4-(diethylamino formoxyl) piperazine-1-yl] propyl group]-1; 3; 7-trimethyl xanthine (stacofylline); 4a; 5; 9; 10; 11; 12-six hydrogen-3-methoxyl group-11-methyl-6-H-benzofuran [3a; 3; 2-ef] [2] benzazepine-6-alcohol (galantamine); and dimethyl (2; 2; 2-three chloro-1-ethoxys) phosphate ester (metrifonate); Yi Si's is bright; tie up that crin; physostigmine; icozepil; A Miruiding; Minaprine; huperzine (huperzine); huprine; the amino acridine (bis-THA) of two-tetrahydrochysene; imidazoles; 1; 2; 4-Thiadiazoline diketone (1; 2; 4-thiadiazolidinone); benzazepine; 4; 4 '-bipyridyl; indeno quinolinamine (indenoquinolinylamine); decamethonium; rise the happiness dragon; third pyridine (propidium); fasciculins; organophosphorus ester; carbamate; imido grpup 1; 2; 3; 4-tetrahydro cyclopentyl diene is [b] indole carbamates also; N-pyrimidine-4-acetanilide; 7-aryloxy group coumarin; propargyl amino-carbamic acid ester; Zifrosilone; nos inhibitor; ACh precursor such as choline and pyrrolidine choline (pyrrolidinedholine) or cholinergic agonist (for example nicotine type nicotinic cry especially, and muscarinic type) and its can treat with and officinal salt.

Antioxidant preferably is selected from vitamin C and E, and the NMDA instrumentality is a Memantine hydrochloride, and the MAO inhibitor is selected from rasagiline, selegiline, tranylcypromine, iproniazid, CGL, phenelzine and isocarboxazid.

In the AD treatment, the standard dose of present used tacrine is 10mg, four times a day, and recommending maximum is 40mg/ day.At present, tacrine capsule oral administration.For donepezil, standard dose is 5mg/ day, and recommending maximum is 10mg/ day.At present, tacrine tablet oral administration.

For bright, standard dose is 1.5mg for thunder department, every day twice, recommends maximum 6mg, twice of every day.At present, thunder department is for gelatin wafer oral administration.For galantamine, used standard dose is 4mg at present, twice of every day.At present, galantamine tablet oral administration.

In a preferred embodiment, tacrine about 0.1 to mg with everyone every day, preferably everyone every day about 10 to 150mg, more preferably everyone every day about 20 to 60mg or everyone every day about dosage of 60 to 100mg use.

In another preferred embodiment, donepezil about 0.1 to 200mg with everyone every day, preferably everyone every day about 1 to 100mg, more preferably everyone every day about 2 to 30mg or everyone every day about dosage of 30 to 60mg use.

In another preferred embodiment, thunder department for bright about 0.1 to 200mg with everyone every day, preferably everyone every day about 0.3 to 50mg, more preferably everyone every day about 0.5 to 20mg or everyone every day about dosage of 20 to 40mg use.

In another preferred embodiment, galantamine about 0.1 to 200mg with everyone every day, preferably everyone every day about 0.5 to 1O0mg, more preferably be everyone every day about 1 to 30mg or everyone every day about dosage of 30 to 60mg use.

Can change applied actual dose according to the order of severity of the needs of patients and the disease for the treatment of.Determine that the suitable dosage under the particular case is those skilled in the art's capabilities.For simplicity, total dosage every day can be divided into aliquot and as required the same day by part using.

An embodiment preferred, cholinesterase inhibitor is preferably Orally administered.

Dopamine agonist or antagonist are such as but not limited to levodopa, the combination of L-DOPA/ carbidopa, cocaine, O-methyl-tyrosine, reserpine, tetrabenazine, benzatropine, pargyline, Fenoldopam Mesylate (fenodolpam mesylate), cabergoline, two hydrochloric acid pramipexoles, Ropinrole, amantadine hydrochloride, SelegilineHydrochloride, carlbidopa, pergolide mesylate, Sinemet CR or amantadine (Symmekel).

COMBINATION OF THE INVENTION of the present invention comprises the other drug that for example improves cognitive function, as relates to the preparation of regulating GABA, NMDA, cannabinoid, AMPA, kainate, phosphodiesterase (PDE), PKA, PKC, CREB or intelligence-developing system.

Result of study shows, combination of the present invention can prevention, delay of progression or treatment neurodegenerative disease, cognitive disorder and is used for improving memory (short-term and long-term) and learning capacity, the disease of having mentioned more than especially.

Term " collaborative " meaning is meant the effect summation of the overall combined effect that produces when using medicine simultaneously every kind of medicine when using separately.

Term " enhancing " meaning is meant that corresponding pharmacological activity or therapeutic effect increase respectively.By using the effect that effect that the effect meaning that another kind of composition of the present invention strengthens a kind of composition in the present invention's combination is meant that institute is obtained approximately is used alone into the branch acquisition jointly.

Can for example obtain structure in the international monopoly (for example IMS World Publications) from " Merck index " standard compilation of current version or from the data base by Code Number, attribute or the determined active ingredient of trade mark.Their corresponding contents is quoted as a reference herein.Any those skilled in the art can identify this type of active ingredient based on these lists of references fully, equally also can make medicine and check medicine indication and characteristic in vivo with in the external code test model.

Another aspect of the present invention is that pharmaceutical composition is used for preparing the purposes that is used for prevention, delay of progression or treatment neurodegenerative disease, cognitive disorder and is used for improving the pharmaceutical composition of remembering (short-term is with for a long time) and learning capacity, especially the above preferred disease, wherein this pharmaceutical composition comprise independent or with the DPP-IV inhibitor as active component of another kind of at least COMBINATION OF THE INVENTION combination of the present invention, under each situation, this DPP-IV inhibitor is free form or its pharmaceutical acceptable salt.

The invention still further relates to pharmaceutical composition, its comprise independent or with the DPP-IV inhibitor as active component of another kind of at least COMBINATION OF THE INVENTION combination of the present invention, this DPP-IV inhibitor is free form or its pharmaceutical acceptable salt under each situation.

The invention still further relates to the method that is used for prevention, delay of progression or treatment neurodegenerative disease, cognitive disorder and is used for improving memory (short-term and long-term) and learning capacity, comprise to needs its, the homoiothermic animal that comprises the people compositions of administering therapeutic effective dose jointly, wherein said compositions comprise independent or with the DPP-IV inhibitor as active component of another kind of at least COMBINATION OF THE INVENTION combination of the present invention, this DPP-IV inhibitor is free form or its pharmaceutical acceptable salt under each situation.

These pharmaceutical preparatioies can be used (as Orally administered and rectal administration) or parenteral administration through intestinal to Homoiotherm, preparation comprise independent or with common drug auxiliary material pharmaceutically active compounds together.For example, this type of pharmaceutical preparation is formed to about 80% reactive compound by about 0.1% to 90%, preferably approximately 1%.Be used for using or parenteral administration and be for example unit dosage forms, as coated tablet, tablet, capsule or suppository or ampulla through the pharmaceutical preparation that eye is used through intestinal.These preparations prepare in a manner known way, for example use conventional mixing, granulation, coating, solubilising or freeze-drying process.Therefore, if can by reactive compound is mixed with solid excipient granulating mixture that expectation will obtain and if desired or must after adding suitable auxiliary material, mixture or granule are processed into the tablet or the coated tablet sheet heart, obtain the pharmaceutical preparation that orally uses.

The dosage of reactive compound depends on multiple factor, as method of application, homoiothermic animal kind, age and/or individual state.

In the neurodegenerative disease field, the preferred patient colony age is more than 50 years old, most preferably over-65s.

For those active component in can the commercial drug regimen of the present invention that obtains, preferred dosage is especially treated effectively can the commercial dosage that obtains.

Corresponding active component or its officinal salt can also hydrate the form use or comprise and be used for crystalline other solvents.

For these indications, precise dosage can change according to the chemical compound that is adopted, mode of administration and conceivable treatment certainly.Chemical compound can be used by any conventional route, not dosage forms for oral administration or preferred dosage forms for oral administration.

Generally speaking, when can obtain satisfied result when using with about daily dose of 0.01 to 100mg/kg, preferred 0.1 to 50mg/kg daily dose.

For bigger mammal, total dosage range every day of needed chemical compound is about 0.01 to 100mg, for simplicity, with every day 2 to 4 times dosage, for example to comprise from about 0.1 to about 50mg or the unit dosage form separate administration of the chemical compound of 100mg slow release form.

Especially to the suitable day oral dose of vildagliptin between 1 to 500mg, preferably between 10 to 100mg, 10mg for example, perhaps between 25 to 100mg, most preferably 50 to 100mg, 25mg or 40 or 50 or 70 or 100mg for example.

Especially the suitable for oral administration administration of unit doses to vildagliptin comprises for example about 10 to about 100mg chemical compound, preferably comprises 25mg or 50mg or 100mg.

Especially the suitable parenteral administration dosage to vildagliptin comprises for example about 10 to about 50mg or 25 to about 100mg chemical compound, for example 25mg, 50mg, 75mg or 100mg.

Be particularly useful for preventative-therapeuticly being suitable for Orally administered unit dose and comprising for example about chemical compound of 0.5 to about 15mg, for example from 1 to 10mg.The suitable dose that is used for parenteral administration comprises for example about chemical compound of 0.2 to about 30mg, for example from 0.3 to 10mg.

This compounds can the mode similar to the known standard that uses in these purposes be used.Suitable daily dose for specific compound can depend on numerous factors, for example its relative effective active.One of ordinary skill in the art can determine to treat effective dose fully.

Chemical compound of the present invention can free alkali form or is used as pharmaceutically acceptable acid addition salts or quaternary ammonium salt.This type of salt can prepare and show the activity with its free form same levels in a usual manner.

If these chemical compounds have for example at least one basic center, then they can form acid-addition salts.Can also form the respective acids addition salts that has an extra basic center that exists as required.Chemical compound with acid group (for example COOH) also can form salt with alkali.For example the chemical compound of pending combination can be used as sodium salt, maleate or dihydrochloride existence.Active component or its officinal salt also may use or comprise and be used for crystalline other solvents with hydrate forms.

One of target of the present invention provides pharmaceutical composition (fixed combination), and it comprises (i) DPP-IV inhibitor or its officinal salt and (ii) at least a other COMBINATION OF THE INVENTION of the present invention and at least a pharmaceutically suitable carrier.

Pharmaceutical composition of the present invention can prepare in a manner known way, and be to be suitable for using the pharmaceutical composition of (as Orally administered or rectal administration) and parenteral administration to the mammal that comprises the people (homoiothermic animal) through intestinal, it comprises independent or with one or more pharmaceutically suitable carrier, especially be suitable for pharmaceutically active compounds through the treatment effective dose of pharmaceutically suitable carrier combination of intestinal or parenteral applications.

In said composition, composition (i) and (ii) can use jointly, use successively or use respectively with a composite unit dosage form or two unit dosage forms that separate.In an embodiment preferred of the present invention, unit dosage form is a fixed combination.In fixed combination, composition composition (i) and (ii) using with the form of single Galenic formula is as single tablet or single preserved material.

As before this or after this described drug regimen of the present invention can use simultaneously or use successively with any order, use separately or use as fixed combination.

In some cases, the medicine with different mechanism of action can make up.Yet, only consider to have different model of action but any combination of the similar medicine of sphere of action is not the combination that must cause favourable effect.

Other benefits are, can use single medicine than the pending combination of the present invention of low dosage to reduce dosage, and for example needed dosage is not only usually less, and frequency of utilization is lower, perhaps uses in order to reduce the side effect incidence rate.This is with patient's to be treated serious hope and require consistent.

Drug regimen of the present invention comprises " component bag (kit of parts) " in some sense, promptly composition can use independently or different time points by with the different fixing combined administration of not commensurability composition.After this, the part in " component bag " can for example use simultaneously or sequence alternate is used, and promptly uses in different time points and with the interval that equates or do not wait for the arbitrary portion in this " component bag ".Preferably, interval is selected, made to be used in combination the effect that each several part is obtained when only using arbitrary composition the effect of treatment disease or situation.

In addition, the invention still further relates to commercial packing material, it comprises combination of the present invention and for the description of using simultaneously, using or use successively separately.

Each composition in the present invention's combination of treatment effective dose can be used or use successively according to random order simultaneously, and composition can be used separately or use as fixed combination.Therapeutic Method for example of the present invention can comprise (i) use the DPP-IV inhibitor of free form or pharmaceutical acceptable salt and (ii) simultaneously or with any order in turn with the therapeutic alliance effective dose, preferably with cooperative effective quantity for example corresponding to the daily dose of ratio described herein, use at least a other COMBINATION OF THE INVENTION of the present invention.

The dosage range that DPP-IV inhibitor and at least a other COMBINATION OF THE INVENTION of the present invention to be used make up depends on the factor known to those skilled in the art, comprises character and the order of severity, method of application and the predetermined substance to be used of homoiothermic animal kind, body weight and age, situation to be treated.Unless this paper declares especially, with DPP-IV inhibitor and at least a other COMBINATION OF THE INVENTION of the present invention preferably with 1 time to 4 times separate administration every day.

Below, still one skilled in the art will recognize that many increases, omission and modification all may be in the scope of following claim by having described the present invention with reference to embodiment preferred.

All patents quoted in this description and list of references are complete herein to be quoted as a reference.Under inconsistent situation, be as the criterion to comprise definition and this description of explaining.

Experimental section:

Embodiment 1-is used to prevent or delay the therapy of Alzheimer onste

Water is used the vildagliptin tablet of a 25mg or 50mg every day to the experimenter of this treatment of needs.

Embodiment 2-is used for preventing or delaying the experimenter of performance mild cognitive impairment the therapy of Alzheimer onste

Use MMSE or similar diagnostic tool to identify the experimenter who suffers from mild cognitive impairment.

Water is used the vildagliptin tablet of a 25mg or 50mg every day to this experimenter.

Use MMSE or similar tool periodic monitoring experimenter's cognitive state, and monitoring experimenter's dull-witted clinical symptoms.

Embodiment 3-treats, prevents or delays diabetes dependency cognitive impairment

Water is used the vildagliptin tablet of a 50mg every day to the experimenter such as the diabetics of this treatment of needs.Use MMSE or similar tool periodic monitoring experimenter's cognitive state.

Embodiment 4

Research vildagliptin or vildagliptin are used in combination learning the effect of improving of defective with the chemical compound with cholinesterase inhibition in the advanced age rat.Following method has been described one group of experiment of the combination of the vildagliptin that uses monotherapy or vildagliptin and cholinesterase inhibitor such as donepezil.

Method: use transgenic lines male (3 to 27 monthly age) rat.Following with advanced age rat be divided into 4 groups (active component dosage can be adjusted by those skilled in the art).

1) matched group: repetitive administration placebo ball.

2) Vildagliptin group: the vildagliptin that repeats Orally administered 3mg/kg.

3) cholinesterase inhibitor group: the donepezil that repeats Orally administered 0.3mg/kg.

4) combination group: repeat the vildagliptin of Orally administered 3mg/kg and the donepezil of 0.3mg/kg.

In the combination group, use donepezil and use vildagliptin after 30 minutes.

At treatment beginning on the 14th passive avoidance learning test, and at treatment beginning on the 20th Maurice water maze learning test.

In every day of test, used vildagliptin and/or cholinesterase inhibitor respectively at preceding 30 minutes and 1 hour on-test.

1. passive avoidance study:

The room that use is made up of bright chamber and darkroom carries out the passive avoidance learning test.With young rat (pill, 10 animals) and advanced age rat (matched group, 10 animals; The vildagliptin group, 10 animals; The donepezil group, 10 animals; Combination group, 10 animals) individually place bright indoorly, and open slide after 10 seconds.After Mus moves to the darkroom, close slide Mus was stopped in the darkroom about 10 seconds.After 1 to 2 hour, carry out the acquistion test at adequacy test.

In acquistion test, treat that Mus moves to the darkroom after, give foot electric shock (0.4mA, 3 seconds) by the grid floor.Keep test after 24 hours in the acquistion test.

In each experiment, measure and be open into the incubation period (stepping into incubation period) that animal moves to the darkroom from slide.

2. Maurice's water maze study:

To in the passive avoidance test, used same animals carry out the water maze test.Yet some rats can not well be swum in water tank, therefore their are got rid of beyond the water maze task.Young rat (saline, 10 animals) and advanced age rat (matched group, 9 animals; The vildagliptin group, 9 animals; The donepezil group, 8 animals; Combination group, 8 animals) carry out the water maze learning test in.

In the pre-training that the escape stimulation is carried out in for swimming instruction and water, use the water vat of diameter 80cm to carry out the experiment of four groups, condition is to see platform.After this, use the platform that in the water vat of diameter 120cm, places under water, carry out once (experiments of four groups) learning test every day.

1. passive avoidance study

Compare with young group, matched group shows that the avoidance time significantly reduces.Therefore, this test can be assessed the remarkable improvement of advanced age that vildagliptin group and donepezil group shown learning defective in the rat.Therefore this test can assess the improvement of the experimenter's cognitive state for the treatment of.

This test also illustrates, the combination of vildagliptin and donepezil has improved the study defective in the rat at advanced age, and this effect viewed better effects if when using arbitrary medicine separately.Therefore, can prove that the effect during with the arbitrary medicine of independent use is compared, this kind combination has the result or the advantage of improvement.

2. water maze study

In the water maze task, to compare with young rat, matched group finds to be immersed in significant prolongation incubation period of the platform in the water.Therefore, this test can be assessed the remarkable improvement to water maze study defective that vildagliptin organizes and the donepezil group is shown.Therefore this test can assess the improvement of the experimenter's cognitive state for the treatment of.

This test also illustrates, the combination of vildagliptin and donepezil has improved the water maze study defective of rat at advanced age, and this effect viewed better effects if when using arbitrary medicine separately.Therefore, can prove that the effect during with the arbitrary medicine of independent use is compared, this kind combination has the result or the advantage of improvement.

For example can use dementia animal model to carry out other tests, such as below with reference to described in or some dementia animal model of being summarized: Higgins L.S., Vol.Med Today1999,5 (6): 274-6; Borchelt D.R. etc., Brain Pathol.1998,8 (4): 735-57 and Genette S.Y. etc., Neurobiol.Aging 1999,20 (2): 201-11.

Embodiment 5:

Research vildagliptin and the effect that is combined in the Parkinson disease model described herein in mice.Every day, (30mg/kg, i.p.) the male C57/BL6 mice of injection continued 7 with MPTP.Use Vildagliptin every day 1 time or 2 times, continue 14.On 28th, take out striatum, homogenate and centrifugal in perchloric acid.Shift out supernatant, and analyze dopamine and other monoamines, as 5-hydroxy tryptamine by reversed-phase HPLC and Electrochemical Detection.By compare assessment anti-Parkinson activity with reference compound such as selegiline.

Claims

1. be used to prevent, delay of progression or treatment neurodegenerative disease, cognitive disorder and be used to improve the method for memory and learning capacity, comprise to needs its, the DPP-IV inhibitor of the homoiothermic animal administering therapeutic effective dose that comprises the people.

2.DPP-IV the purposes of inhibitor or its officinal salt, it is used for making the medicine that is used for prevention, delay of progression or treats neurodegenerative disease, cognitive disorder and improvement memory (short-term and long-term) and learning capacity.

3. be used for prevention, delay of progression or treatment neurodegenerative disease, cognitive disorder and be used for improving the pharmaceutical composition of remembering (short-term and long-term) and learning capacity, it comprises the DPP-IV inhibitor with the bonded treatment effective dose of one or more pharmaceutically suitable carrier.

4. the described method of claim 1, the described purposes of claim 2, the described compositions of claim 3, wherein neurodegenerative disease is selected from dementia, alzheimer disease, mild cognitive impairment, Alzheimer dependency dementia, Huntington Chorea, tardive dyskinesia, unusual high power, mania, parkinson disease, Si-Li syndrome, mongolism, myasthenia gravis, nerve and brain trauma, the blood vessel amyloidosis, follow the cerebral hemorrhage of amyloidosis, encephalitis disease, Friedreich ataxia, acute confusional disease, the acute confusional disease that the necrosis of apoptosis sexual cell is worked therein, amyotrophic lateral sclerosis, glaucoma and Alzheimer.

5. the described method of claim 1, the described purposes of claim 2, the described compositions of claim 3, wherein neurodegenerative disease is selected from Alzheimer and dementia, preferably alzheimer disease, mild cognitive impairment or dementia of the Alzheimer type.

6. the described method of claim 1, the described purposes of claim 2, the described compositions of claim 3 are used for suffering from the age related cognitive decline or suffering from patient's prevention of mild cognitive impairment or delay the outbreak of Alzheimer dependency dementia.

7. the described method of claim 1, the described purposes of claim 2, the described compositions of claim 3 are used in patient's prevention of suffering from age related cognitive decline or mild cognitive impairment or delay the Alzheimer onste.

8. the described method of claim 1, the described purposes of claim 2, the described compositions of claim 3, wherein cognitive disorder is selected from schizophrenia dependency cognitive defect, age inductivity memory impairment, psychosis dependency cognitive defect, diabetes dependency cognitive impairment, dependency cognitive defect after the apoplexy, anoxia dependency memory impairment, cognition of alzheimer disease dependency and attention deficit, attention deficit disorder, mild cognitive impairment dependency dysmnesia, dull-witted dependency cognitive function is impaired, Alzheimer dependency cognitive function is impaired, parkinson disease dependency cognitive function is impaired, vascular dementia dependency cognitive function is impaired, the cognitive disorder of cerebral tumor dependency, Pick disease, because of the cognitive defect due to the autism, cognitive defect after the electroconvulsive therapy, traumatic brain injury dependency cognitive defect, amnesia, delirium, dull-witted.

9. the described method of claim 1, the described purposes of claim 2, the described compositions of claim 3, wherein cognitive disorder is selected from study acquistion sexual disorders (learning disorder), memory is consolidated obstacle, refresh memory obstacle and kept obstacle.

10. the described method of claim 1, the described purposes of claim 2, the described compositions of claim 3, wherein cognitive disorder is selected from diabetes dependency cognitive impairment, Alzheimer dependency cognitive function is impaired, parkinson disease dependency cognitive function is impaired, dependency cognitive defect, the cognition of alzheimer disease dependency and attention deficit, mild cognitive impairment dependency dysmnesia after the apoplexy.

11. the described method of claim 1, the described purposes of claim 2, the described compositions of claim 3, wherein cognitive disorder be selected from that diabetes dependency cognitive impairment, Alzheimer dependency cognitive function are impaired, dependency cognitive defect after the apoplexy.

12. the described method of claim 1, the described purposes of claim 2, the described compositions of claim 3, it is used for improving pace of learning and potentiality in education and rehabilitation environment.

13. the described method of claim 1, the described purposes of claim 2, the described compositions of claim 3, its be used for the treatment of the memory or learn impaired, wherein said memory or learn impaired be age related, be the result of electroconvulsive therapy or the consequence of brain injury.

14. the described method of claim 1, the described purposes of claim 2, the described compositions of claim 3, it is used to prevent, delay or stop the progress of any other age related cognitive decline or mild cognitive impairment.

15. the described method of claim 1, the described purposes of claim 2, the described compositions of claim 3, its be used for the treatment of the memory due to the brain injury or learn impaired, wherein said brain injury be by apoplexy, anesthetic accident, injury of head, hypoglycemia, carbon monoxide poisoning, lithium poison or vitamin deficiency due to.

16. the described method of claim 1, the described purposes of claim 2, the described compositions of claim 3, it is used for the treatment of and/or prevents memory impaired.

17. the described method of claim 1, the described purposes of claim 2, the described compositions of claim 3, its be used for the treatment of and/or prevent because relevant memory impairment, mild cognitive impairment, epilepsy, the children ' s intelligence development of poisonous substance contact, brain injury, cerebral aneurysm, age postpones and dementia due to memory impaired, wherein said dementia is derived from for example disease of parkinson disease, Alzheimer, AIDS, injury of head, Huntington Chorea, Pick disease, creutzfeldt-jakob disease and apoplexy.

18. each described method in the claim 1 to 17; each described purposes in the claim 1 to 17; each described compositions in the claim 1 to 17; wherein the DPP-IV inhibitor is selected from 1-{2-[(5-cyanopyridine-2-yl) amino] ethylamino } acetyl group-2-(S)-cyano group-pyrrolidine; vildagliptin; L-threo form-isoleucyl-thiazolidine; MK-0431; GSK23A; saxagliptin; 3-(aminomethyl)-2-isobutyl group-1-oxo-4-phenyl-1; 2-dihydro-6-isoquinolin carboxylic acid amides and 2-{[3-(aminomethyl)-2-isobutyl group-4-phenyl-1-oxo-1,2-dihydro-6-isoquinolyl) oxygen } acetamide and its pharmaceutical salts under the situation arbitrarily randomly.

19. each described compositions in each described purposes, the claim 1 to 17 in each described method, the claim 1 to 17 in the claim 1 to 17, wherein the DPP-IV inhibitor is vildagliptin or its officinal salt.

20. each described compositions in each described purposes, the claim 1 to 19 in each described method, the claim 1 to 19 in the claim 1 to 19, wherein the DPP-IV inhibitor and at least aly can be used for preventing, drug regimen that the medicine of delay of progression or treatment neurodegenerative disease, cognitive disorder or be used to improves memory uses.

21. pharmaceutical composition, it comprises

A) DPP-IV inhibitor or its officinal salt and

B) at least aly can be used for preventing, the medicine of delay of progression or treatment neurodegenerative disease, cognitive disorder or be used to improve the medicine of memory; And

C) at least a pharmaceutically suitable carrier.

22. pharmaceutical composition according to claim 21; wherein the DPP-IV inhibitor is selected from 1-{2-[(5-cyanopyridine-2-yl) amino] ethylamino } acetyl group-2-(S)-cyano group-pyrrolidine, vildagliptin, L-threo form isoleucyl-thiazolidine, MK-0431, GSK23A, saxagliptin, 3-(aminomethyl)-2-isobutyl group-1-oxo-4-phenyl-1; 2-dihydro-6-isoquinolin carboxylic acid amides and 2-{[3-(aminomethyl)-2-isobutyl group-4-phenyl-1-oxo-1,2-dihydro-6-isoquinolyl] oxygen } acetamide and in any case its pharmaceutical salts randomly.

23. pharmaceutical composition according to claim 21, wherein the DPP-IV inhibitor is vildagliptin or its officinal salt.

24. according to each described pharmaceutical composition in the claim 21 to 23; purposes according to claim 20; method according to claim 20; wherein be used for prevention; delay of progression or treatment neurodegenerative disease; the medicine that the medicine of cognitive disorder or be used to improves memory is selected from anti-inflammatory agent; antioxidant; neuroprotective; glutamate receptor antagonists; acetylcholinesteraseinhibitors inhibitors; butyrylcholinesterase inhibitor; the MAO inhibitor; dopamine agonist or antagonist; the inhibitor of γ and beta-secretase, the amyloid peptide aggregation inhibitor; amyloid beta; the antibody of anti-amyloid beta; the inhibitor of acetylcholinesterase; relate to and regulate GABA; NMDA; cannabinoid; AMPA; kainate; phosphodiesterase (PDE); PKA; PKC; the preparation of CREB or nootropics system.

25. according to each described pharmaceutical composition in the claim 21 to 23, purposes according to claim 20, method according to claim 20, wherein be used for prevention, delay of progression or treatment neurodegenerative disease, the medicine that the medicine of cognitive disorder or be used to improves memory is selected from donepezil, thunder department is for bright, ipidacrine, tacrine, stacofylline, galantamine, metrifonate, Yi Si's is bright, tie up that crin, physostigmine, icozepil, A Miruiding, Minaprine, huperzine, huprine, two-tetrahydroaminoacridine (bis-THA), imidazoles, 1,2,4-Thiadiazoline diketone, benzazepine, 4,4 '-bipyridyl, the indeno quinolinamine, decamethonium, rise the happiness dragon, third pyridine, fasciculins, organophosphorus ester, carbamate, imido grpup 1,2,3,4-tetrahydro cyclopentyl diene is [b] indole carbamates also, N-pyrimidine 4-acetanilide, 7-aryloxy group coumarin, propargyl amine carbaminate, Zifrosilone, nos inhibitor, the ACh precursor, choline pyrrolidinedholine, cholinergic agonist, vitamin C and E, Memantine hydrochloride, rasagiline, selegiline, tranylcypromine, iproniazid, CGL, phenelzine, isocarboxazid, tolcapone and entacapone, naproxen sodium, diclofenac sodium, diclofenac potassium, match comes former times cloth, sulindac Evil promazine, diflunisal, etodolac, meloxicam, ibuprofen, ketoprofen, nabumetone, rofecoxib, methotrexate, take fluorine Lip river rice, sulfasalazine, gold salt, the RHo-D immunoglobulin, the Mycophenolic Acid morpholine ethyl ester, ciclosporin, azathioprine, tacrolimus, basiliximab, Dary pearl monoclonal antibody, salicylic acid, aspirin, methyl salicylate, diflunisal, salsalate, Olsalazine, sulfasalazine, acetaminophen, indomethacin, sulindac, mefenamic acid, meclofenamate sodium, Tolmetin, ketorolac, diclofenac, flurbiprofen Evil promazine, piroxicam, meloxicam, ampiroxicam, Droxicam, piroxicam, tenoxicam, Phenylbutazone, Offitril, phenazone, aminophenazone, azapropazone, Zileuton, aurothioglucose, sodium aurothiomalate, auranofin, methotrexate, colchicine, allopurinol, probenecid, sulfinpyrazone and benzbromarone or betamethasone and other glucocorticoids and officinal salt thereof.

26. the medicine that according to each described pharmaceutical composition, purposes according to claim 20, method according to claim 20 in the claim 21 to 23, wherein can be used for preventing, the medicine of delay of progression or treatment neurodegenerative disease, cognitive disorder or be used to improves memory is selected from donepezil, tacrine, thunder department and replaces bright, galantamine, vitamin C, vitamin E, Memantine hydrochloride, rasagiline, selegiline, tranylcypromine, iproniazid, CGL, phenelzine and isocarboxazid.