KR20070032375A - Combination of DPP-IV Inhibitors and Compounds Modulating 5-HT3 and/or 5-HT4 Receptors - Google Patents

Abstract

The present invention comprises a DPP-IV inhibitor or a pharmaceutically acceptable salt thereof, each of which interacts with the 5-HT ₃ receptor and / or an agent that interacts with the 5-HT ₄ receptor, or their pharmaceutically acceptable A combination, such as a combination formulation or pharmaceutical composition, comprising one or more therapeutic agents selected from possible salts. The invention also relates to insulin resistance, impaired glucose metabolism, impaired glucose endogenous status, impaired fasting plasma glucose status, diabetes, especially type 2 diabetes, obesity, diabetic retinopathy, macular degeneration, cataracts, diabetic nephropathy, glomerulosclerosis, diabetes Sexual neuropathy, erectile dysfunction, premenstrual syndrome, coronary heart disease, hypertension, angina pectoris, myocardial infarction, stroke, vascular restenosis, skin and connective tissue disorders, foot ulcers and ulcerative colitis, endothelial dysfunction and impaired vascular compliance, Heartburn, abdominal swelling, postoperative ileus, abdominal pain and anxiety, premature satiety, epigastric pain, nausea, vomiting, bloating, reflux, intestinal obstruction, anal bowel incontinence, GERD, IBS, indigestion, chronic constipation or diarrhea, diabetic Gastroparesis, gastric palsy such as diabetic gastric palsy, ulcerative colitis, Crohn's disease, ulcers and associated visceral pain It does not have altered gastrointestinal motility, sensitivity and / or prevention of diseases and disorders selected from the secretion disorder (s), to a combination of applications such as for the treatment or delay in progress.

 DPI-Iv inhibitors, 5-HTH3 receptors, 5-HTH4 receptors.

Description

Combination of DPP-IV Inhibitors and Compounds Modulating 5-HT3 and / or 5-HT4 Receptors}

Serotonin has been known for many years to regulate peristalsis in the gastrointestinal (GI) tract in various mammalian models. During the mid-1980s, several specific antagonists for the 5-HT ₃ receptor subtype have been identified and are currently used as anti-emesis / vomiting in cancer treatment. 5-HT ₃ antagonists have also been recently studied for the treatment of irritable bowel syndrome (“IBS”).

Numerous gastrointestinal syndromes are associated with the production and action of serotonin, which occurs very frequently in so many people around the world. Some of the more well known gastrointestinal conditions, syndromes or diseases are IBS, gastro-esophageal reflux disease ("GERD") and dyspepsia.

IBS is a chronic condition associated with abdominal pain, abdominal swelling and colorectal dysfunction and is believed to affect 10-20% of the entire population. In some cases, the disease is called irritable colon, ankylosing colon, ankylosing colitis or mucus colitis. The latter two are almost certainly misleading because colitis involves inflammation of the colon and the absence of inflammation is one of the critical observational factors in the diagnosis of IBS. The cause of IBS is unknown, but a number of factors have been entangled, including diet, lifestyle, depression, anxiety, infections, and unrelated inflammatory conditions such as early onset that lead to central nerve sensitization and sensitization of the stomach nerves. Almost all drugs currently used for the treatment of IBS have not achieved significant therapeutic effects.

GERD is a condition associated with the reflux of gastric contents entering the esophagus through the lower esophageal sphincter. GERD is characterized by symptoms of heartburn, swelling, abdominal pain, epigastric pain, premature satiety, nausea, reflux, bloating and vomiting. Reflux may be due to the fact that gastric contents enter the esophagus due to an increased incidence of transient relaxation of the lower esophageal sphincter.

Indigestion is also an important health problem. The most common conditions associated with patients with chronic indigestion symptoms are GERD, duodenal ulcer or gastric ulcer and other diagnostic symptoms (eg functional / non-ulcer dyspepsia, gallbladder or liver disease).

These conditions or diseases are characterized by altered motility, sensitivity, secretion and / or Helicobacter pylori infection, and potentially a physiological (mostly subliminal) overlay. At present, only a few drugs have been clinically significant for the treatment of functional dyspepsia, for example, some of which have various side effects in humans.

GLP-1 derivatives are also described in the patent application US 2003216292 as potentially effective in treating gastrointestinal disorders.

Thus, there is a need for agents or therapies that control and normalize altered GI motility, sensitivity and secretion, and which have extensive clinical utility for the treatment of numerous gastrointestinal disorders that also affect millions of people each year.

Now, combinations comprising one or more agents that interact with 5-HT ₃ or 5-HT ₄ receptors, such as those defined below, and DPP-IV inhibitors, such as co-agents, defined below, for example, have altered gastrointestinal motility. It has been found to be beneficial and useful in the treatment of abdominal disorder states / disorders that can be treated by sensitization and / or secretion, and / or DPP-IV inhibition. This combination may also be used for the control, stabilization and normalization of altered gastrointestinal motility, sensitivity and / or secretion and / or abdominal disorders.

Therefore, the present invention,

i) a DPP-IV inhibitor or a pharmaceutically acceptable salt thereof, and

ii) one or more therapeutic agents selected from agents that interact with the 5-HT ₃ receptor and / or agents that interact with the 5-HT ₄ receptor, or pharmaceutically acceptable salts thereof

It relates to a combination comprising a.

Preferably, the present invention is a DPP-IV inhibitor or a pharmaceutically acceptable salt thereof, respectively, and

a) an agent or a pharmaceutically acceptable salt thereof that interacts with the 5-HT ₃ receptor,

b) one or more therapeutic agents selected from agents that interact with the 5-HT ₄ receptor or pharmaceutically acceptable salts thereof, and

A combination, such as a combination formulation or pharmaceutical composition, comprising one or more additional pharmaceutically acceptable carriers.

Preferably the combination is a pharmaceutical composition or a combined pharmaceutical formulation.

In this pharmaceutical composition, the combination partners (i) and (ii) may be administered in one combined unit dosage form or in two separate unit dosage forms, together, sequentially or separately. The unit dosage form can also be a fixed combination.

The term "one or more therapeutic agents" means that in addition to the DPP-IV inhibitor, one or more, for example two, or three active ingredients specified in accordance with the invention can be combined. Preferably, the combination partner a) or b), or a combination partner selected from a), is a combination partner selected from b).

The term "DPP-IV" as used herein is intended to mean dipeptidyl peptidase IV, also known as CD26. DPP-IV, a serine protease belonging to the group of proline / post alanine cleavage amino-dipeptidase, specifically removes two N-terminal amino acids from a protein with proline or alanine at position 2. DPP-IV can be used to regulate glucose metabolism because its substrate includes glucagon-like peptide-1 (GLP-1) and gastric inhibitory peptide (GIP), an insulin secretion hormone. GLP-1 and GIP are only active in their unmodified form, which is inactivated by removing their two N-terminal amino acids.

In vivo administration of inhibitors of synthesis of DPP-IV prevents N-terminal degradation of GLP-1 and GIP, thereby increasing plasma concentrations of this hormone, increasing insulin secretion and thus improving glucose endogenous.

The term “DPP-IV inhibitor” refers to the inhibition of enzymatic activity of DPP-IV and functionally related enzymes, such as 1-100% or 20-80% inhibition, in particular GLP-1, GIP, peptide histidine methionine, substance P, neuro It is intended to refer to a molecule that preserves the action of a substrate molecule, including but not limited to peptide Y, and other molecules that typically include an alanine or proline residue at the second amino terminal position. Treatment with a DPP-IV inhibitor prolongs the time of action of the peptide substrate and increases the level of its unmodified undegraded form, thereby obtaining a spectrum of biological activity related to the disclosed invention.

For that purpose, chemical compounds are tested for their ability to inhibit the enzymatic activity of purified CD26 / DPP-IV. In short, the activity of CD26 / DPP-IV is measured in vitro by its ability to cleave the synthetic substrate Gly-Pro-p-nitroanilide (Gly-Pro-pNA). Cleavage of Gly-Pro-Pna by DPP-IV liberates the product p-nitroanilide (pNA) and its production rate is directly proportional to the enzyme activity. Inhibition of enzyme activity by specific enzyme inhibitors slows down the development of pNA. The stronger the correlation between the inhibitor and the enzyme, the slower the development of pNA. Thus, the degree of inhibition of the rate of accumulation of pNA is a direct measure of the intensity of enzyme inhibition. The accumulation of pNA is measured spectrophotometrically. The inhibition constant, Ki, for each compound is determined by incubating a fixed amount of enzyme with several different concentrations of inhibitor and substrate.

In the text, “DPP-IV inhibitors” are also intended to encompass active metabolites and prodrugs thereof, such as active metabolites and prodrugs of DPP-IV inhibitors. An active "metabolite" is an active derivative of a DPP-IV inhibitor that is produced when the DPP-IV inhibitor is metabolized. A “prodrug” is a compound that is metabolized to a DPP-IV inhibitor or to the same metabolite (s) as the DPP-IV inhibitor.

DPP-IV inhibitors are known in the art. For example, DPP-IV inhibitors are collectively and specifically in each case, for example, WO 98/19998, DE 19616486 A1, WO 00/34241, WO 95/15309, WO 01/72290, WO 01/52825, WO 9310127 , WO 9925719, WO 9938501, WO 9946272, WO 9967278 and WO 9967279.

Preferred DPP-IV inhibitors are described in the following patent applications: WO 02053548, in particular compounds 1001 to 1293, and Examples 1 to 124, WO 02067918, especially compounds 1000 to 1278 and 2001 to 2159, WO 02066627, examples described particularly , All compounds specifically described in WO 02/068420, in particular Examples I to LXIII, and the corresponding analogs described, more preferred compounds are described in the IC50 report table 2 (28), 2 (88), 2 (119). , 2 (136), WO 02083128, in particular Examples 1 to 13, US 2003096846, in particular the compounds described in particular, WO 2004/037181, in particular Examples 1 to 33, WO 0168603, in particular the compounds of Examples 1 to 109 , EP1258480, in particular the compounds of Examples 1 to 60, WO 0181337, in particular Examples 1 to 118, WO 02083109, in particular Examples 1A to 1D, WO 030003250, in particular the compounds of Examples 1 to 166, most preferably Examples 1 to 8, WO 03035067, especially described in the examples Compounds, WO 03/035057, especially the compounds described in the examples, US 2003216450, in particular the compounds of Examples 1 to 450, WO 99/46272, in particular the compounds of claims 12, 14, 15 and 17, WO 0197808 , In particular the compounds of claim 2, WO 03002553, in particular the compounds of Examples 1 to 33, WO 01/34594, in particular the compounds of Examples 1 to 4, WO 02051836, especially the compounds of Examples 1 to 712, EP1245568 , In particular Examples 1 to 7, EP1258476, in particular Examples 1 to 32, US 2003087950, in particular described embodiments, WO 02/076450, in particular Examples 1 to 128, WO 03000180, in particular Examples 1 to 162, WO 03000181 , In particular Examples 1 to 66, WO 03004498, in particular Examples 1 to 33, WO 0302942, in particular Examples 1 to 68, US 6482844, in particular the examples described, WO 0155105, in particular the compounds listed in Examples 1 and 2 , WO 0202560, in particular Examples 1 to 166, WO 03004496, in particular Examples 1 to 103, WO 03/024965, in particular Example 1 To 54, WO 0303727, especially Examples 1 to 209, WO 0368757, especially Examples 1 to 88, WO 03074500, especially Examples 1 to 72, Examples 4.1 to 4.23, Examples 5.1 to 5.10, Examples 6.1 to 6.30 , Examples 7.1 to 7.23, Examples 8.1 to 8.10, Examples 9.1 to 9.30, WO 02038541, in particular Examples 1 to 53, WO 02062764, in particular Examples 1 to 293, preferably the compounds of Examples 95 (2- {{3- (aminomethyl) -4-butoxy-2-neopentyl-1-oxo-1,2-dihydro-6-isoquinolinyl} oxy} acetamide hydrochloride), WO 02308090, in particular practice Examples 1-1 to 1-109, Examples 2-1 to 2-9, Example 3, Examples 4-1 to 4-19, Examples 5-1 to 5-39, and Examples 6-1 to 6 -4, Examples 7-1 to 7-10, Examples 8-1 to 8-8, Examples 7-1 to 7-7 on page 90, Examples 8-1 to 8 on pages 91 to 95 -59, Examples 9-1 to 9-33, Examples 10-1 to 10-20, US 2003225102, in particular Compounds 1 to 115, Practice The compounds of Examples 1 to 121, preferably compounds a) to z), aa) to az), ba) to bz), ca) to cz), and da) to dk), WO 0214271, in particular Examples 1 to 320 and US 2003096857 and WO 2004/052850, in particular the compounds specifically described in Examples 1 to 42 and the like, and the compounds of claim 1, the compounds described in DE 102 56 264 A1, in particular Examples 1 to 181 and the like, and the compounds of claim 5, Compounds specifically described, such as those listed in WO 04/076433, in particular Table A, etc., preferably compounds listed in Table B, preferably compounds I to XXXXVII, or compounds of claims 6 to 49, WO 04/071454, in particular Compounds, such as compounds 1 to 53, or compounds of Tables Ia to If, or compounds of claims 2 to 55, WO 02/068420, in particular compounds described in particular such as compounds I to LXIII or Beispiele I and Analog 1 to 140 or bar Ispieel 2 and Analogs 1-174, or Bispiel 3 and Analog 1, or Bispiel 4-5, or Bispiel 6 and Analogs 1-5, or Bispiel 7 and Analog 1-3, or Bispiel 8 and Analog 1, or Bispiel 9, or Bispiel 10 and analogs 1 to 531, more preferably the compound of claim 13, WO 03/000250, in particular the compounds described in particular such as compounds 1 to 166, preferably Examples 1 to 9 Of compounds, WO 03/024942, in particular the compounds described in particular, compounds 1 to 59, the compounds of Table 1 (1 to 68), the compounds of claims 6, 7, 8, 9, WO 03024965024942, especially the compounds described in particular Compounds 1 to 54, WO 03002593, in particular the compounds described in particular such as Table 1 or the compounds of claims 2 to 15, WO 03037327, especially the compounds described in particular such as the compounds of Examples 1 to 209, WO 03/000250, in particular the compounds described in particular such as compounds 1 to 166, preferably the compounds of Examples 1 to 9, WO 03/024942, especially the compounds described in particular such as compounds 1 to 59, the compounds of Table 1 (1 to 68), the compounds of claims 6, 7, 8, 9, WO 03024965024942, especially the specifically described compounds, such as the compounds of Compounds 1 to 54, WO 03002593, the particularly specifically described compounds, such as the compounds of Table 1 or 2 to 15 , WO 03037327, in particular the compounds described in particular, for example the compounds of Examples 1 to 209, WO 0238541, WO 0230890, WO 03/000250, in particular the compounds described in particular such as the compounds 1 to 166, preferably Examples 1 to 9 Of compounds, WO 03/024942, especially specifically described compounds such as compounds 1 to 59, compounds of Table 1 (1 to 68), compounds of claims 6, 7, 8, 9, WO 03024965, particularly specifically Compounds, such as compounds 1 to 54, WO 03002593, especially specifically described compounds, such as the compounds of Table 1 or 2 to 15, WO 03037327, particularly specifically described compounds, such as the compounds of Examples 1 to 209, WO 0238541 , In particular the compounds described in particular, for example the compounds of Examples 1 to 53, WO 03/002531, especially the compounds described in particular, preferably the compounds listed in pages 9 to 13, most preferably of Examples 1 to 46 Compound, even more preferably the compound of Example 9, US Patent No. 6,395,767, preferably the compounds of Examples 1-109, most preferably the compounds of Example 60, U.S. Application link No. 09 / 788,173 (filed February 16, 2001) (agent file LA50), in particular the examples described, WO 99/38501, especially the examples described, WO 99/46272, the examples particularly described, DE19616 486 A1, in particular val-pyr, fumar salts of val-thiazolidide, isoleucyl-thiazolidide, isoleucyl-pyrrolidide, and isoleucyl-thiazolidide and isoleucyl-pyrrolidide.

More preferred DPP-IV inhibitors are described in US Pat. 6124305 and US 6107317, International Patent Application Publication Nos. Specific examples disclosed in WO 9515309 and WO 9818763 are included.

In each case, in particular in the final products of the compounds and working examples of the claims, the final products, pharmaceutical preparations and the subject matter of the claims are hereby incorporated by reference by reference to these publications.

Published patent application WO 9819998 discloses N- (N'-substituted glycyl) -2-cyano pyrrolidines, in particular 1- [2- [5-cyanopyridin-2-yl] amino] -ethylamino] acetyl- 2-cyano- (S) -pyrrolidine (NVP-DPP728) is disclosed.

Published patent application WO 0034241 and published patent US 6110949 disclose N-substituted adamantyl-amino-acetyl-2-cyano pyrrolidine and W (substituted glycyl) -4-cyano pyrrolidine, respectively. The DPP-IV inhibitors of interest are those specifically recited in claims 1-4. In particular these applications are compounds of 1-[[(3-hydroxy-1-adamantyl) amino] acetyl] -2-cyano- (S) -pyrrolidine (also known as LAF237 or vildagliptin) It is described.

Published patent application WO 9515309 discloses the amino acid 2-cyanopyrrolidine amide as an inhibitor of DPP-IV. Published patent application WO 9529691 discloses peptidyl derivatives of alpha-aminoalkylphosphonic acid diesters, in particular those having proline or related structures. The DPP-IV inhibitors of interest are those specifically cited in Tables 1-8.

In WO 01/72290, the DPP-IV inhibitors of interest are specifically those mentioned in Example 1 and claims 1, 4 and 6.

WO 01/52825 specifically describes (S) -1- {2- [5-cyanopyridin-2-yl) amino] ethyl-aminoacetyl) -2-cyano-pyrrolidine or (S) -1- [(3-hydroxy-1-adamantyl) amino] acetyl-2-cyano-pyrrolidine is disclosed.

Published patent application WO 9310127 discloses proline boronic acid esters useful as DPP-IV inhibitors. The DPP-IV inhibitors of interest are those specifically mentioned in Examples 1-19.

Published patent application WO 9925719 discloses sulfostin, a DPP-IV inhibitor prepared by culturing Streptomyces microorganisms.

Published patent application WO 9938501 discloses N-substituted 4- to 8-membered heterocyclic rings. The DPP-IV inhibitors of interest are those specifically mentioned in claims 15-20.

Published patent application WO 9946272 discloses phosphorus compounds as inhibitors of DPP-IV. The DPP-IV inhibitors of interest are those specifically mentioned in claims 1-23.

Published patent applications WO 9967278 and WO 9967279 disclose inhibitors of DPP-IV prodrugs and Forms A-B-C, wherein C is a stable or labile inhibitor of DPP-IV.

Other preferred DPP-IV inhibitors are the compounds of formula (I), (II) or (III) disclosed in pages 14 to 27 of patent application WO 03/057200. Most preferred DPP-IV inhibitors are the compounds specifically described on pages 28 and 29.

Any material disclosed in these patent documents cited herein by reference is considered to be potentially useful as a DPP-IV inhibitor for use in carrying out the present invention.

In another preferred embodiment, the DPP-IV inhibitor is N-peptidyl-O-aroyl hydroxyamine or a pharmaceutically acceptable salt thereof. Aroyl is, for example, naphthylcarbonyl; Or unsubstituted or mono- or di-substituted benzoyl, for example by lower alkoxy, lower alkyl, halogen, or preferably nitro. The peptidyl moiety preferably comprises two α-amino acids such as glycine, alanine, leucine, phenylalanine, lysine or proline, of which directly bonded to the hydroxyamine nitrogen atom is preferably proline.

Preferably, the N-peptidyl-O-aroyl hydroxyamine is of formula VII:

Wherein j is 0, 1 or 2;

Rε ₁ represents the side chain of a natural amino acid;

Rε ₂ is lower alkoxy, lower alkyl, halogen or nitro)

Compound of; Or a pharmaceutically acceptable salt thereof.

In one very preferred embodiment of the invention, the N-peptidyl-O-aroyl hydroxyamine is of formula VIIa:

Compound, or a pharmaceutically acceptable salt thereof.

N-peptidyl-O-aroyl hydroxyamines, such as N-peptidyl-O-aroyl hydroxyamines of Formula VII or VIIa, and their preparation are described in HU Demuth, Enzyme Inhibition 1988, Volume 2, volume Pp. 129-142, particularly pp. 130-132).

Preferred DPP-IV inhibitors are N-substituted adamantyl-amino-acetyl-2-cyano pyrrolidine, N- (substituted glycyl) -4-cyano pyrrolidine, N- (N'-substituted glycyl ) -2-cyanopyrrolidine, N-aminoacyl thiazolidine, N-aminoacyl pyrrolidine, L-allo-isorusilyl thiazolidine, L-threo-isorusilyl pyrrolidine, and L- Allo-isorusilyl pyrrolidine, 1- [2-[(5-cyanopyridin-2-yl) amino] ethylamino] acetyl-2-cyano- (S) -pyrrolidine and pharmaceutical salts thereof to be.

Preferred DPP-IV inhibitors are those described in paragraph 5 of Mona Patel and colleagues, Expert Opinion Investig Drugs. 2003 Apr; 12 (4): 623-33, in particular P32 / 98, K-364, FE-999011 , BDPX, NVP-DDP-728 and the like, which are incorporated herein by reference, in particular, the DPP-IV inhibitors described.

Another preferred inhibitor is WO 2001068603 or US Pat. Compound BMS-477118 ((1S, 3S, 5S) -2-[(2S) -2-amino-2- (3-hydroxytricyclo [3.3.1.1 ^3] , disclosed in 6,395,767 (compound of Example 60) ^{, 7} ] des-1-yl) -1-oxoethyl] -2-azabicyclo [3.1.0] hexane-3-carbonitrile), as formula M on page 2 of the patent application WO 2004/052850 Benzoate (1: 1) and the corresponding free base, (1S, 3S, 5S) -2-[(2S) -2-amino, represented by formula M on page 3 of patent application WO 2004/052850 -2- (3-hydroxy-tricyclo [3.3.1.1 ^3,7 ] dec-1-yl) -1-oxoethyl] -2-azabicyclo- [3.1.0] hexane-3-carbonitrile (M ') And its monohydrate (M "). Compound BMS-477118 is also known as saxagliptin.

Another preferred inhibitor is (2S, 4S) -1-((2R) -2-amino-3-[(4-methoxybenzyl) sulfonyl] -3-methylbutanoyl) -4-fluoropyrroli Compound GSK23A disclosed in WO 03/002531 (Example 9), also known as din-2-carbonitrile hydrochloride.

FE-999011 discloses compound No. 1 on page 14 of patent application WO 95/15309. 18.

P32 / 98 or P3298 (CAS No .: 251572-86-8), also known as 3-[(2S, 3S) -2-amino-3-methyl-1-oxopentyl] thiazolidine, (2: 1) mixture of 3-[(2S, 3S) -2-amino-3-methyl-1-oxopentyl] thiazolidine and (2E) -2-butenedioate:

It may be used as WO 99/61431 and in Diabetes 1998, 47, 1253-1258, which is described by the name Probiodrug, and is also described as compound P93 / 01 by the same company.

Other highly preferred DPP-IV inhibitors of the present invention are described in International Patent Applications WO 02/076450 (especially Examples 1-128), and Wallace T. Ashton, in Bioorganic & Medicinal Chemistry Letters 14 (2004) 859-863. And the compounds listed in Table 1 and 2, in particular. Preferred compounds are represented by the formula:

Compound 21e (Table 1).

Other preferred DPP-IV inhibitors are described in patent applications WO 2004/037169, in particular Examples 1 to 48, and also in WO 02/062764, in particular Examples 1 to 293, more preferably on page 7, and Compound 3- (aminomethyl) -2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinecarboxamide, as described in patent application WO2004 / 024184, in particular Reference Examples 1 to 4, And 2-{[3- (aminomethyl) -2-isobutyl-4-phenyl-1-oxo-1,2-dihydro-6-isoquinolyl] oxy} acetamide.

Other preferred DPP-IV inhibitors are described in patent application WO 03/004498, in particular Examples 1 to 33, most preferably described in Example 7, and also known as MK-0431 or Sitagliptin. Formula:

Compound.

Preferred DPP-IV inhibitors are also the compounds described in patent application WO 2004/037181, in particular examples 1 to 33, most preferably the compounds as described in claims 3 to 5.

Preferred DPP-IV inhibitors are N-substituted adamantyl-amino-acetyl-2-cyano pyrrolidine, N (substituted glycyl) -4-cyano pyrrolidine, N- (N'-substituted glycyl) 2-cyanopyrrolidine, N-aminoacyl thiazolidine, N-aminoacyl pyrrolidine, L-allo-isorusilyl thiazolidine, L-threo-isorusilyl pyrrolidine, and L-allo Isoleucyl pyrrolidine, 1- [2-[(5-cyanopyridin-2-yl) amino] ethylamino] acetyl-2-cyano- (S) -pyrrolidine, MK-431 and its Pharmaceutical salts.

Most preferred DPP-IV inhibitors are [S] -1- [2- (5-cyano-2-pyridinylamino) ethylamino] acetyl-2-pyrrolidine carbonitrile monohydrochloride, (S) -1- [(3-hydroxy-1-adamantyl) amino] acetyl-2-cyano-pyrrolidine and L-threo-isorusilyl thiazolidine (Compound code according to probiodrug: P32 as described above / 98), MK-0431, 3- (aminomethyl) -2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinecarboxamide and 2-{[3- ( Aminomethyl) -2-isobutyl-4-phenyl-1-oxo-1,2-dihydro-6-isoquinolyl] oxy} acetamide and optionally pharmaceutical salts thereof.

[S] -1- [2- (5-cyano-2-pyridinylamino) ethylamino] acetyl-2-pyrrolidine carbonitrile monohydrochloride and (S) -1-[(3-hydroxy- 1-adamantyl) amino] acetyl-2-cyano-pyrrolidine is specifically disclosed in Example 3 of WO 98/19998 and Example 1 of WO 00/34241, respectively. DPP-IV inhibitor P32 / 98 (see above) is described in detail in Diabetes 1998, 47, 1253-1258. [S] -1- [2- (5-cyano-2-pyridinylamino) ethylamino] acetyl-2-pyrrolidine carbonitrile monohydrochloride and (S) -1-[(3-hydroxy- 1-adamantyl) amino] acetyl-2-cyano-pyrrolidine may be formulated as described in page 20 of WO 98/19998 or WO 00/34241.

Particularly preferred is the formula:

1- {2-[(5-cyanopyridin-2-yl) amino] ethylamino} acetyl-2, (S) -cyano-pyrrolidine dihydrochloride (DPP728) ([S] -1- [2- (5-cyano-2-pyridinylamino) ethylamino] acetyl-2-pyrrolidine carbonitrile monohydrochloride) compound,

In particular their dihydrochloride and monohydrochloride, and the formula:

1-[(3-hydroxy-1-adamantyl) amino] acetyl-2-cyano- (S) ((S) -1-[(3-hydroxy-1-adamantyl) amino] Also referred to as acetyl-2-cyano-pyrrolidine, LAF237 or vildagliptin), and L-threo-isorusilyl thiazolidine (Compound code according to probiodrug: P32 / 98 as described above) , MK-0431, GSK23A, saxagliptin, 3- (aminomethyl) -2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinecarboxamide and 2-{[ 3- (aminomethyl) -2-isobutyl-4-phenyl-1-oxo-1,2-dihydro-6-isoquinolyl] oxy} acetamide and optionally pharmaceutical salts thereof.

DPP728 and LAF237 are specifically disclosed in Example 3 of WO 98/19998 and Example 1 of WO 00/34241, respectively. DPP-IV inhibitor P32 / 98 (see above) is described in detail in Diabetes 1998, 47, 1253-1258. DPP728 and LAF237 are on page 20 of WO 98/19998 or WO 00/34241, or in International Patent Application No. It may be formulated as described in EP2005 / 000400 (application number).

Especially preferred are orally active DPP-IV inhibitors.

Any material disclosed in the above-mentioned patent documents or scientific publications, which is incorporated herein by reference, is considered to be potentially useful as a DPP-IV inhibitor for use in carrying out the present invention.

In each case, in particular in the final products of the compounds and working examples of the claims, the final products, pharmaceutical preparations and the subject matter of the claims are hereby incorporated by reference by reference to these publications.

5-HT ₄ agonists that interact with the receptor, the 5-HT ₄ receptor partial agonists (agonist), 5-HT ₄ receptor agonists, 5-HT ₄ receptor antagonist, or a dual 5-HT ₃ and 5-HT ₄ agonist A varnish is included.

Representative 5-HT ₄ receptor partial agonists include US Pat. 5510353, especially the compounds described in Examples 1-117, are included, but not limited to (the corresponding gist of this document is incorporated herein by reference).

5-HT ₄ are those described in a preferred compound as a receptor partial agonist is, for example, US 5510353 (herein, R ₁ is H, Z is -CH = and, R ₅ is OH or C _{1 -6} alkoxy).

Further examples of 5-HT ₄ receptor partial agonists include, for example, RS 67333 (1- (4-amino-5-chloro-2-methoxyphenyl) -3- [1-butyl-4-piperidinyl] -1 -Propanone), or RS 67506 (1- (4-amino-5-chloro-2-methoxyphenyl) -3- [1-methylsulfonylamino) ethyl-4-piperidinyl] -1-propanone ) Is included.

Particularly preferred compounds described in US 5510353 are formulated in free form or in pharmaceutically acceptable salt form:

Compound. This compound has the chemical name of 3- (5-methoxy-1H-indol-3-yl-methylene) -N-pentylcarbazide, also known as tegaserod, and the trade name is ZELMAC. And ZELNORM. It is US Patent No. 5510353 and European Patent No. 505322 is described in Example 13 and disclosed as a 5-HT ₄ receptor moiety agonist. It is also a tautomer:

, 프레풀시드(PREPULSID)

, 리사몰(RISAMOL)

, 펄사르(PULSAR)

및 프로펄신(PROPULSIN)

과 같은 상표명들로 시판된다.It may exist in the form of, which is included in the present invention. One preferred salt form is hydrozin maleate. 5-HT ₄ receptor agonists as co-agents in combination include any compound capable of activating the 5-HT ₄ receptor under stationary / rest state. Examples of this compound include compounds of the formula (I) disclosed in EP-B1-0 505 322, cisapride, norsis aprid, renzapride, zacopride, mosapride, Prucalopride, buspirone, norsisapride; 4-amino-5-chloro-2-methoxy-N- (1-substituted piperidin-4-yl) benzamide (also known as Y-34959; SB 205149, SC 53116, RS 67333, RS 67506, BIMU -1, BIMU-8 and (S) -RS 56532), US patent application no. 20040127514, in particular Examples 1 to 22, or US patent application no. 20040122043, in particular Examples 1 to 9, or US Patent Application No. US20040034226, in particular Examples 1 to 30, or US Patent No. 6624162, in particular, but not limited to, the compounds described in Examples 1-30. Various imiazopyridine 5-HT ₄ receptor modulator compounds are disclosed in US Application No. 60 / 343,371, filed Oct. 22, 2001. Cisaprid, cis-4-amino-5-chloro-N- [1- [3- (4-fluorophenoxy) propyl] -3-methoxy-4-piperidinyl] -2-methoxy- Benzamide is used as a gastrointestinal motility promoter (see A. Reyntjens et al., Drug Div. Res., 8, 251 (1986) and Curr. Ther. Res., 36, 1029-1070 (1984)). The compound is ACENALIN worldwide

, PREPULSID

, Lisa Mall

, PULSAR

And propulsine

Available under trade names such as

Preferred groups of the 5-HT ₄ receptor agonist or partial agonist are optional; By selective is meant a compound that substantially does not bind or stimulate 5-HT ₃ receptor subtypes. Tegase rods do not bind to or stimulate the 5-HT ₃ receptor subtype, for example.

5-HT ₄ receptor antagonists for use as coagents in combinations 1.1 or 1.2 or as first agents in combinations 1.3 or 1.4 include IUPHAR (Pharmacological Reviews, Vol. 44, pp. 157-213, 1994). Any compound that binds to the 5-HT ₄ receptor as defined by and antagonizes the effects of serotonin without activating the 5-HT ₄ receptor is included. Relevant tests to determine whether a compound is a 5-HT ₄ receptor antagonist are described in Br. J. Pharm., P. 1593-1599 (1993)], the guinea pig distal colon test, or Arch. Pharmacol., Vol. 343, pp. 439-446 (1991). Representative 5-HT ₄ receptor antagonists include, for example, piboserods; A-85380 from Abbott Laboratories (WO 94/08994); SB 204070 from SmithKline Beecham (Drugs Fut., 19: 1109-1121, 1994); SB 207058 (Exp. Opin. Invest. Drugs, 3 (7): 767, 1994); SB 207710 (Drug Data Report, 15 (10): 949, 1993); SB 205 800 (Drug Data Report, 15 (10): 949, 1993); SB 203 186 (Br. J. Pharmacol., 110: 1023-1030, 1993); N 3389 from Nisshin Flour Milling (Eur. J. Pharmacol., 271: 159, 1994); FK 1052 (Fujisawa) (J. Pharmacol. Exp. Ther, 265: 752, 1993); SC 56184 (Searle) (R & D Focus, 2 (37) 10, 1993); SC 53606 (Searle / Monsanto) (J. Pharmacol. Exp. Ther. 226: 1339, 1993); DAU 6285 from Boerhinger Ingelheim (Br. J. Pharmacol., 105: 973, 1992); GR 125487 (Glaxo) (Br. J. Pharmacol., 113 Appendix 119P & 120P, 1994); GR 113808 (Br. J. Pharmacol. 110: 1172, 1993); RS 23597 (Syntex) (Bioorg Med. Chem. Lett., 4 (20): 2477, 1994); RS 39604 (Br. J. Pharmacol., 115, 1087-1095, 1995); LY0353433 (EIi Lilly Co. Ltd.) (J. Pharmacol. Exp. Ther, 277 (1), 97-104, 1996); And R59595 (Eur. J. Pharmacol., 212, 51-59, 1992). 5-HT ₄ receptor antagonist fiboserod or SB-207266A has also been shown for the treatment of IBS.

Among these 5-HT ₃ and 5-HT ₄ agonists include Lenzafried (SmithKline Beecham) and E3620 (Eisai). 5-HTIa agonists are known, such as LY315535 (Elli Lilly).

5-HT ₃ agonists that interact with receptors include 5-HT ₃ receptor antagonists and dual 5-HT ₃ and 5-HT ₄ agonists.

5-HT ₃ receptor antagonists include, for example, cilansetron described in EP 29761; Allosetrons described in WO 99/17755; Ramosetron; Azasettron; Ondansetron; Dolasetron; Lamosetron; Granisetron; Mirtazapine; Insetetron; Leristron; Ro-93777; YM-114; Talipexole; N-3389, jacoboprid, silanesetron, E-3620, lintopride, KAE-393, itasetron, mosaprid; Dolasetron and tropisetron, or US patent application no. Compounds described in US 20030158221, in particular Examples 1 to 30, are included.

UK patent no. 2209335 specifically includes compound 2,3,4,5-tetrahydro-5-methyl-2-[(5-methyl-1H-imidazol-4-yl) methyl] -1H-pyrido [4,3-b] Indole-1-ones (now known as allosetrons), and pharmaceutically acceptable salts, solvates and pharmaceutically acceptable equivalents thereof, in particular hydrochloride salts thereof, are disclosed.

Compounds that characterize 5-HT ₃ receptor antagonists, and 5-HT ₄ receptor agonists or antagonists for use as coagents in combination 1.1 or 1.2 or as first agents in combination 1.3, are for example cisaprid and nore. Cisapride; Dumuis A. et al., Naunyn Schmiedeber's Arch. Pharmacol., Vol. 343 (3), pp. 245-251 (1991)], for example BIMU compounds, such as BIMU1, BIMU8 and DAU 6215 (also known as itacetron); Rizza, CA et al., J. Pharmacol. Exp. Ther., Vol. 261, pp. 412-419 (1992), DAU-6236; And Turconi M. et al., J. Med. Chem., Vol. 33 (8), pp. 2101-2108 (1990), DAU-6258, Eglen RM et al., Proc. Br. Pharmacol. Soc, Vol. 149 (1992); SDZ 205-557 which is a benzoic acid derivative (ester); Lenzaprid; Jacobride; SB 205149; SC 53116; RS 67333; RS 67506; Or (S) -RS 56532, lintofried.

The dose of an agent that interacts with the 5-HT ₃ receptor or the agent that interacts with the 5-HT ₄ receptor is generally also determined by the health of the subject being treated, the desired degree of gastrointestinal treatment, and, where there is a combination treatment, It may depend on the nature and type, and the frequency of treatment desired and the nature of the treatment. In general, the dosage of the agent is usually in the range of about 0.1 to about 10 mg per kg of body weight per day of subject, preferably from about 0.1 to about 10 mg per kg body weight of daily subject when administered in single or divided doses. . However, depending on the age, weight and species of the patient, the intended route of administration, and the progress and severity of the disease or condition being treated, some possibility of change in dosage ranges may also be generally needed.

The daily dose of an agent that interacts with the 5-HT ₃ receptor or an agent that interacts with the 5-HT ₄ receptor required in carrying out the methods of the present invention will vary depending on, for example, the mode of administration and the severity of the condition being treated. will be. The daily doses indicated are in the range of about 1 to about 200 mg, such as 2 to 30 mg or 2 to 24 mg, or 2 to 12 mg of the oral active agent, conveniently administered in single or divided doses.

DPP-IV inhibitors, preferably LAF237 or a pharmaceutically acceptable salt thereof, and tegacerod, cisapride, norsisaprid, renzafried, jacobride, mosafried, frucaloprid, busch as second active agents Preference is given to an active agent selected from the group consisting of pyrones and norsisaprids, or in each case a combination, such as a combination formulation or pharmaceutical composition, each comprising their pharmaceutically acceptable salts, in particular tegaserod hydrozinmaleate Do.

Also DPP-IV inhibitors, preferably LAF237 or a pharmaceutically acceptable salt thereof, and silanesetron, lamosetron, azasetron, ondansetron, dolasetron, lamosetron, granistron, mirtazapine , Indisetron, lerisetron, Ro-93777, YM-114, thalipexole, N-3389, jacobride, silanesetron, E-3620, lintofried, KAE-393, itacetron, mosaprid; Preference is given to combinations, such as combination preparations or pharmaceutical compositions, each comprising one active agent selected from the group consisting of dolasetron and trophetrone, or in each case their pharmaceutically acceptable salts.

Corresponding active ingredients or pharmaceutically acceptable salts thereof may also be used in the form of solvates, including solvates such as hydrates or other solvents used for crystallization.

The compound to be combined may exist as a pharmaceutically acceptable salt. If this compound has, for example, one or more base centers, it may form acid addition salts. Also, if desired, corresponding acid addition salts with additionally present base centers may be formed. Compounds with acid groups (eg COOH) can also form salts with bases.

All of these commercial products can be used as products for combination therapy in accordance with the present invention.

The structure of the active agent, identified by the generic name or trade name, can be obtained from an actual edition of the standard list "The Merck Index" or from a database, such as an international patent (eg, an IMS World Publication). Its corresponding contents are incorporated herein by reference. One skilled in the art can fully identify active agents and, based on this reference, can similarly produce and test pharmaceutical labels and properties in in vitro and in vivo standard test models.

More surprisingly, the combined administration of a DPP-IV inhibitor or a salt thereof and at least one therapeutic agent selected from (i) to (ii) not only results in a beneficial effect, in particular a synergistic therapeutic effect, but also an additional benefit from the combination treatment. It is also an experimental finding that results in more surprising beneficial effects compared to monotherapy applying only one of the pharmaceutically active compounds used in the combinations disclosed herein.

With established test models, and in particular the experimental models described herein, the combination of a DPP-IV inhibitor with one or more therapeutic agents selected from (i) to (ii) provides more effective prevention, or preferably treatment, of the diseases specified below. It may appear. In particular, with established test models, and in particular the models described herein, it can be seen that the combinations of the present invention result in more effective prophylaxis, or preferably treatment, of the diseases specified below.

When co-aggregated, this not only results in a further enhanced beneficial effect, in particular a synergistic therapeutic effect, but in the numerous combinations described herein, surprisingly prolonged efficacy, wider variety of therapeutic treatments, and irritable bowel syndrome, gastric- It also results in additional benefits resulting from concurrent treatment such as esophageal reflux disease, dyspepsia, diabetes, especially type II diabetes, IGT, and the surprising beneficial effects on diabetes, IGT, obesity related diseases and conditions.

The term "potentiation" means an increase in the corresponding pharmacological activity or therapeutic effect, respectively. The potentiation of one component of the combination according to the invention by the co-administration of another component according to the invention means that a greater effect is achieved than the effect achieved with one component alone.

The term "synergistic" means that the total binding effect when taken together is greater than the sum of the effects when each drug is taken alone.

In addition, for human patients, especially older people, taking two tablets simultaneously, eg before meals, is more convenient and easier than taking them staggered according to more complex treatment schedules. More preferably, both active ingredients are administered as fixed combinations, ie as single tablets, in all cases described herein. Taking a single tablet is easier to handle than taking two tablets at the same time. In addition, packaging can be achieved with less effort.

One skilled in the art can fully select relevant and standard animal test models to demonstrate the indicated therapeutic indications and beneficial effects shown before or after.

Pharmaceutical activity exerted by the administration of a combination of active agents used in accordance with the present invention can be demonstrated, for example, by using corresponding pharmacological models known in the art.

The insulin secretion enhancing properties of the combinations according to the invention are described, for example, in publications [T. Ikenoue et al., Biol. Pharm. Bull. 29 (4), 354-359 (1997).

Corresponding gist of this reference is incorporated herein by reference.

Thus, the combinations according to the invention can be used for the prophylaxis, retardation or treatment of diseases and disorders that can be inhibited, for example, by DPP-IV inhibition and / or interaction with 5-HT ₃ or 5-HT ₄ receptors. Can be used.

Thus, in one further aspect, the invention

i) a DPP-IV inhibitor or a pharmaceutically acceptable salt thereof, and

ii) one or more therapeutic agents selected from agents that interact with the 5-HT ₃ receptor and / or agents that interact with the 5-HT ₄ receptor, or pharmaceutically acceptable salts thereof

Use for the manufacture of a medicament for the prevention, delay of progression or treatment of diseases and disorders which can be inhibited by a combination comprising a DPP-IV inhibition and / or interaction with a 5-HT ₃ or 5-HT ₄ receptor It is about.

The invention also provides a DPP-IV inhibitor or a pharmaceutically acceptable salt thereof, an agent that interacts with the 5-HT ₃ receptor and / or an agent that interacts with the 5-HT ₄ receptor, or a pharmaceutically acceptable salt thereof. One or more therapeutic agents selected from; And

One or more additional pharmaceutically acceptable carriers

A method for inhibiting DPP-IV and / or interacting with a 5-HT ₃ or 5-HT ₄ receptor, comprising administering a binding effective amount of a combination comprising to a warm blooded animal, including a human in need thereof. It relates to a method of preventing, delaying the progression or treating diseases and disorders that can be inhibited by.

The invention also provides a DPP-IV inhibitor or a pharmaceutically acceptable salt thereof, an agent that interacts with the 5-HT ₃ receptor and / or an agent that interacts with the 5-HT ₄ receptor, or a pharmaceutically acceptable salt thereof. One or more therapeutic agents selected from; And prevention of DPP-IV inhibition and / or interaction with 5-HT ₃ or 5-HT ₄ receptors, comprising a combination of one or more additional pharmaceutically acceptable carriers. , Pharmaceutical compositions for delaying progression or treatment.

In one additional embodiment, the present invention relates to the following:

1. Heartburn, abdominal swelling, postoperative ileus, abdominal pain and anxiety, premature satiety, epigastric pain, nausea, vomiting, swelling, reflux, intestinal obstruction, anal bowel incontinence, GERD, IBS, indigestion, chronic constipation or diarrhea, Selected from altered gastrointestinal motility, sensitivity and / or secretion disorder (s), including but not limited to diabetic gastroparesis, gastric palsy, such as diabetic gastric palsy, ulcerative colitis, Crohn's disease, ulcers and associated visceral pain The use of a DPP-IV inhibitor or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the prevention, delay of progression or treatment of the resulting disease and disorder;

2. DPP, comprising administering an effective amount of a DPP-IV inhibitor, or a pharmaceutically acceptable salt thereof, and one or more additional pharmaceutically acceptable carriers to a warm blooded animal, including a human in need of such treatment. Methods of preventing, delaying or treating disease and disorders that may be inhibited by -IV inhibition and / or interaction with 5-HT ₃ or 5-HT ₄ receptors;

3. Heartburn, abdominal swelling, postoperative ileus, abdominal pain and anxiety, comprising administering an effective amount of a DPP-IV inhibitor or a pharmaceutically acceptable salt thereof to a warm blooded animal, including a human in need thereof Premature satiety, epigastric pain, nausea, vomiting, bloating, reflux, intestinal obstruction, anal bowel incontinence, GERD, IBS, indigestion, chronic constipation or diarrhea, diabetic gastrointestinal disorder, gastric palsy, such as diabetic gastric palsy, ulcer A method of preventing, delaying or treating disease and disorders selected from altered gastrointestinal motility, sensitivity and / or secretory disorder (s), including but not limited to colitis, Crohn's disease, ulcers and visceral pain associated therewith.

In the methods or uses described above, the disease or condition may be insulin resistance, impaired glucose metabolism, impaired glucose endogenous status, impaired fasting plasma glucose status, diabetes, especially type 2 diabetes, obesity, diabetic retinopathy, macular degeneration, cataracts, diabetes Sexual nephropathy, glomerulosclerosis, diabetic neuropathy, erectile dysfunction, premenstrual syndrome, coronary heart disease, hypertension, angina pectoris, myocardial infarction, stroke, vascular restenosis, skin and connective tissue disorders, foot ulcers and ulcerative colitis, endothelial Cellular dysfunction and impaired vascular compliance, heartburn, abdominal swelling, postoperative ileus, abdominal pain and anxiety, early satiety, epigastric pain, nausea, vomiting, swelling, reflux, intestinal obstruction, anal bowel incontinence, GERD, IBS , Indigestion, chronic constipation or diarrhea, diabetic gastropathy, gastric palsy such as diabetic gastric palsy, ulcerative colitis, Crohn's disease, ulcers The internal include, but pain is associated, is selected from is not limited to these altered gastrointestinal motility that is, sensitivity and / or secretion disorder (s).

Most preferably, the disease or condition is selected from diabetes, type 2 diabetes, IGT and diseases or conditions associated with diabetes.

Most preferably, the disease or condition is selected from irritable bowel syndrome (IBS), gastro-esophageal reflux disease (GERD), diabetic gastroparesis, diabetic gastric palsy, chronic constipation and dyspepsia.

Preferred combinations for the described uses or methods are described herein.

"Diseases or conditions that can be inhibited by DPP-IV inhibitors" as defined herein include insulin resistance, impaired glucose metabolism, impaired glucose endogenous status, impaired fasting plasma glucose status, diabetes, especially type 2 diabetes, obesity, diabetes Sex retinopathy, macular degeneration, cataracts, diabetic nephropathy, glomerulosclerosis, diabetic neuropathy, erectile dysfunction, premenstrual syndrome, coronary heart disease, hypertension, angina pectoris, myocardial infarction, stroke, vascular restenosis, skin and connective tissue Disorders, foot ulcers and ulcerative colitis, endothelial dysfunction and impaired vascular compliance. Preferably, the "disease or condition that can be inhibited by a DPP-IV inhibitor" includes impaired glucose metabolism, impaired glucose endogenous status, impaired fasting plasma glucose status, diabetes, especially type 2 diabetes, obesity, diabetic retinopathy, diabetic Nephropathy, diabetic neuropathy and foot ulcers.

As used herein, the term "therapeutic" means efficacy in the treatment of an ongoing disease, disorder or condition.

The term "prophylactic" means the prevention of the occurrence or recurrence of a disease, disorder or condition being treated.

As used herein, the term “delayed progression” means administration of the combination to a patient in a prophylactic or early stage of the disease to be treated, for example in which the preliminary form of the corresponding disease is diagnosed, The patient is, for example, under medical treatment or under conditions such as those resulting from an accident that causes the corresponding disease to be prone to development.

As used herein, the term “combined pharmaceutical preparation” means that the active ingredient, such as tegaserod or tegaserod hydrozyl maleate, and the DPP-IV inhibitor, preferably LAF237, are separated simultaneously, together or sequentially without particular time limit. It means that both are administered to the patient as an established entity, wherein the administration provides two compounds, preferably simultaneously, of therapeutically effective levels in the body. As an example, an unfixed combination will be two capsules each containing one active ingredient, the purpose of which is to achieve treatment with both active ingredients in the body together.

“Diseases or conditions that can be inhibited by interacting with 5-HT ₃ or 5-HT ₄ receptors” are preferably altered gastrointestinal motility, emotional and / or secretory disorder (s).

In this description, the term “treatment” includes both prophylactic or prophylactic treatments, as well as therapeutic or disease inhibiting treatments, including treatment of patients suffering from or suspected of having a disease or disorder, and treatment of sick patients. do. The term also includes treatments for delaying the progression of the disease.

As used herein, the term “changed gastrointestinal motility, emotional and / or secretory disorder (s)” includes heartburn, abdominal swelling, postoperative ileus, abdominal pain and anxiety, premature satiety, epigastric pain, nausea, vomiting, bloating, reflux, Intestinal obstruction, anal bowel incontinence, GERD, IBS, dyspepsia, chronic constipation or diarrhea, diabetic gastrointestinal disorder, gastric palsy such as diabetic gastric palsy, ulcerative colitis, Crohn's disease, ulcers and associated visceral pain And one or more of the symptoms and conditions affecting the gastrointestinal tract from mouth to anus, including but not limited to.

As used herein, the term “abdominal disorder (s)” includes conditions affecting the lower abdomen, including intestinal chromaffin cell function, GI secretion, motility, centripetal and centrifugal fibers, active and / or abdominal smooth muscle cells Conditions include, but are not limited to, conditions treated by control, stabilization and normalization of activity.

As used herein, the terms "gastro-esophageal reflux disease" and "GERD" refer to the occurrence and symptoms of a condition caused by the reflux of gastric contents into the esophagus. This includes all forms / signs of GERD, including but not limited to erosive and non-erosive GERD, heartburn and other symptoms associated with GERD.

As used herein, the terms "irritable bowel syndrome" and "IBS" refer to changes in function associated with altered motility, sensitivity, and secretion primarily associated with the small and large intestine associated with varying degrees of abdominal pain, swelling, constipation or diarrhea, without apparent bowel infection. It means disability.

As used herein, the term “digestion” refers to epigastric pain, abdominal pain, abdominal swelling, premature as a complication or as primary gastrointestinal dysfunction due to disorders such as ulcer disease, appendicitis, gallbladder disorder or malnutrition Refers to a condition characterized by satiety, nausea, heartburn and vomiting.

As used herein, the term "gastric palsy" refers to gastric palsy caused by altered motility in the stomach, often indicated as delayed gastric emptying. It may also be a complication of diseases such as diabetes, progressive systemic sclerosis, anorexia nervosa, or myotonic dystrophy.

As used herein, the term “constipation” refers to a condition characterized by a decreased frequency and / or difficulty in defecation resulting from conditions such as altered GI motility, altered sensitization or excretion functions, altered secretion, or reabsorption of electrolytes and water. it means.

As used herein, the term "diarrhea" refers to a condition characterized by high GI motility, altered sensitization, and frequent release of bowel movements often associated with high volume and eruptions resulting from conditions such as secretion or reabsorption of electrolytes and water.

The term “treat” or “treatment” refers to the full range of therapeutically positive effects associated with pharmaceutical medicines, including reducing, alleviating, and relieving symptoms or conditions affecting an organism. Comprehensive

Preferably, the therapeutically effective amount of the combined therapeutic agent according to the invention may be administered simultaneously or in any order, such as separately (combined pharmaceutical formulation) or sequentially in a fixed combination.

Under certain circumstances, drugs with different mechanisms of action may be combined. However, merely considering any combination of drugs with different modes of action but acting in similar fields does not necessarily result in a beneficial effect on the combination.

Even more surprising is the experimental finding that the combination administration of the DPP-IV inhibitor according to the invention or in each case a pharmaceutically acceptable form thereof does not only result in a beneficial effect, in particular a potentiating or synergistic therapeutic effect. Regardless, additional benefits resulting from combinatorial treatment, such as surprising prolonged efficacy, more diverse therapeutic treatments, and surprising beneficial effects on diseases and conditions associated with diabetes (eg, reduced weight gain or reduced cardiovascular side effects) Profit can be achieved.

Diseases, disorders or conditions associated with diabetes, particularly type 2 diabetes, include diabetic nephropathy, diabetic retinopathy and diabetic neuropathy, macular degeneration, coronary heart disease, myocardial infarction, diabetic cardiomyopathy, cardiomyocyte death, coronary Arterial disease, peripheral artery disease, stroke, lower limb ischemia, vascular restenosis, foot ulcers, endothelial dysfunction and / or atherosclerosis.

A further benefit is that the doses can be reduced by using the lower doses of the individual drugs to be combined according to the invention, for example, while the doses are not only often smaller but need to be applied less frequently, It can be used to reduce the occurrence of side effects. This is in accordance with the desires and requirements of the patients to be treated.

For example, the combinations according to the invention are particularly useful in the treatment of diabetic patients, such as reducing the risk of negative cardiovascular development, reducing the risk of side effects, and reducing weight gain (in diabetic patients). , Or has been proven to provide benefits for patients suffering from altered gastrointestinal motility, emotional and / or secretory disorder (s).

In view of the dose reduction of DPP-IV inhibitors used in accordance with the present invention, or agents interacting with 5-HT ₃ or 5-HT ₄ receptors, there is a significant stability profile of the combination that makes it more suitable for first-line treatment.

Pharmaceutical compositions according to the invention as described herein before and after may be used for separate use, or as fixed combinations, for simultaneous use, or for sequential use in any order.

In the methods or uses described above, the agent (s) interacting with the DPP-IV inhibitor and the 5-HT ₃ or 5-HT ₄ receptor may be selected from the combinations of the invention, such as fixed combinations or kits of combination formulations or parts. Is administered in the form.

In the combinations, methods or uses described herein, the DPP-IV inhibitor is (S) -1-[(3-hydroxy-1-adamantyl) amino] acetyl-2-cyano-pyrrolidine, 5 Agents that interact with the -HT ₄ receptor are preferably tegase rods, cisaprids, nor-cisaprids, lenzafrieds, zacofrieds, mosafrieds, frucaloprids, buspyrones, norsisaprids or in each case It is selected from the group consisting of pharmaceutically acceptable salts thereof.

In the combinations, methods or uses described herein, the DPP-IV inhibitor is (S) -1- {2- [5-cyanopyridin-2-yl] amino] ethyl-aminoacetyl)}-2-cyano- Pyrrolidine, and the agent that interacts with the 5-HT ₄ receptor is tegaserod, or in each case its pharmaceutically acceptable salt, in particular tegaserod hydrozyl maleate.

In the combinations, methods or uses described herein, the DPP-IV inhibitor is (S) -1-[(3-hydroxy-1-adamantyl) amino] acetyl-2-cyano-pyrrolidine, 5 Agents that interact with the -HT ₃ receptor are preferably silanesetron, lamosetron, azasetron, ondansetron, dolasetron, lamosetron, granistron, mirtazapine, indiesetron, lerisetron , Ro-93777, YM-114, Talipexole, N-3389, Zacofried, Silanesetron, E-3620, Lintofried, KAE-393, Itasetron, Mosafried, Dolasetron, and Trocesetron or each If pharmaceutically acceptable salts thereof.

According to the present invention, the DPP-IV inhibitor and the agent (s) interacting with the 5-HT ₃ receptor and / or the 5-HT ₄ receptor can be administered together, such administration can be either sequentially or simultaneously in time and In general, the preferred method is the simultaneous method. For sequential administration, the DPP-IV inhibitor, and the agent (s) interacting with the 5-HT ₃ receptor and / or the 5-HT ₄ receptor, can be administered in any order. It is generally preferred that such administration is oral administration. Particularly preferably, the administration is oral and simultaneous administration. However, parenteral or transdermal administration will be suitable if the subject cannot be swallowed, or if oral absorption is impaired or otherwise undesirable. When the DPP-IV inhibitor and the agent (s) interacting with the 5-HT ₃ receptor and / or the 5-HT ₄ receptor are administered sequentially, each administration can be by the same method or by different methods.

Another aspect of the invention,

(a) an amount of a DPP-IV inhibitor, or a pharmaceutically acceptable salt thereof, in a first dosage form;

(b) one or more therapeutic agents selected from certain amounts of (i) to (ii), or in each case pharmaceutically acceptable salts thereof, in a second or other unit dosage form; And

(c) a container for containing said first, second or other unit dosage form

Comprising a kit for preventing, delaying or treating a disease or condition according to the present invention.

As a variant, the invention also relates to the sense that, for example, the components combined according to the invention can be administered independently, or by using different fixed combinations of components in different amounts, ie simultaneously or at different time points. "Kit-of-parts". The parts of the kit of parts can then be administered at different time points, eg simultaneously or at time staggered, ie at the same or different time intervals for any part of the kit of parts. Preferably, the time interval is chosen such that the effect on the disease or condition to be treated when using the combination of parts is greater than the effect obtained by the use of only any one of the components.

Accordingly, the present invention provides for the prevention, delay of progression or treatment of a disease or condition according to the invention,

(a) an amount of a DPP-IV inhibitor, or a pharmaceutically acceptable salt thereof, in a first dosage form; And

(b) agent (s) interacting with a quantity of 5-HT ₃ receptor and / or 5-HT ₄ receptor in the form of two or three or more discrete units of components (a) to (b), And, if appropriate, one or more therapeutic agents selected from pharmaceutically acceptable salts thereof.

It relates to a kit of parts comprising a.

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

In one preferred embodiment, the (commercial) product, together with instructions for simultaneous, separate or sequential use, or any combination thereof, in delaying or treating the disease referred to herein, comprises (component (a) Or a combination according to the invention (in the form of two or three or more separate units of (b)).

All preferences mentioned herein apply to combinations, compositions, uses, methods of treatment, "kits of parts" and commercial packages of the present invention.

This pharmaceutical preparation is intended for enteral, such as oral, and rectal or parenteral administration of a formulation comprising a pharmacologically active compound alone or in combination with a conventional pharmaceutical adjuvant. For example, the pharmaceutical formulation consists of about 0.1% to 90%, preferably about 1% to about 80% of the active compound. Pharmaceutical preparations for enteral or parenteral, and intraocular administrations are also in the form of unit dosage forms, such as coated tablets, tablets, capsules or suppositories, and ampoules. It is produced in a manner known so far, for example using conventional mixing, granulating, coating, solubilizing or lyophilization processes. Thus, pharmaceutical preparations for oral use combine the active compound (s) with solid excipients, granulate the mixture obtained if desired, and if necessary or necessary, add the appropriate auxiliary substance to the mixture or granules. Or by processing into coated tablets.

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

Preferred doses for the active ingredients of the pharmaceutical combinations according to the invention are therapeutically effective doses, in particular commercially available doses.

Normally, for oral administration, for example a patient weighing approximately 75 kg, a suitable daily dose of about 1 mg to about 360 mg is estimated.

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

The pharmaceutical formulation will be supplied in a suitable dosage unit form, eg, in the form of a capsule or tablet, including in combination with an amount such as 50 mg of LAF237 with bindingly active additional ingredient (s).

The pharmaceutical compositions according to the invention described above can be used for separate use or fixed combinations, for simultaneous use or for sequential use in any order.

Thus, according to one further embodiment, the DPP-IV inhibitor is preferably in the form of a fixed pharmaceutical composition comprising a pharmaceutically acceptable carrier, vehicle or diluent, 5-HT ₃ receptor and / or 5-HT ₄ It is administered with the agent (s) that interact with the receptor. Thus, the DPP-IV inhibitors of the invention, as fixed combinations, interact with the agent (s) and / or 5-HT ₄ receptors which interact with the 5-HT ₃ receptor in any conventional oral, parenteral or transdermal dosage form. It may be administered with an agent that acts.

For example, a dose of a DPP-IV inhibitor of formula (I) administered to a warm blooded animal, such as a human, of approximately 70 kg body weight, in particular a dose effective for inhibition of DPP-IV enzyme, may be from about 3 mg to about 3 per person per day. g, preferably about 10 mg to about 1 g, for example about 20 mg to 200 mg, which is preferably divided into 1 to 4 individual doses, which may for example be of the same size. Typically, children receive about half of the adult dose. The dose required for each individual can be monitored and adjusted to optimal levels, for example by measuring the serum concentration of the active ingredient. Single doses include, for example, 10, 40 or 100 mg per adult patient.

The dose of (S) -1-[(3-hydroxy-1-adamantyl) amino] acetyl-2-cyano-pyrrolidine is preferably from 10 to 150 mg per day, most preferably from 25 to 150 per day mg, 25 to 100 mg, or 25 to 50 mg, or 50 to 100 mg. Preferred examples of daily oral doses are 25, 30, 35, 45, 50, 55, 60, 80 or 100 mg. Application of the active ingredient may occur no more than three times daily, preferably one or two times daily.

Preferred agent (s) that interact with the 5-HT ₃ receptor and / or agents that interact with the 5-HT ₄ receptor, as mentioned herein, are therapeutically effective amounts, such as about as described above and described in the prior art. It will be supplied in the form of a suitable dosage unit, eg, in the form of a capsule or tablet, including from 2 to about 200 mg. Application of the active ingredient may occur no more than three times daily, preferably one or two times daily. The same preferred dose is chosen for the fixed combination.

The daily tegaserod dose required to carry out the methods of the invention will vary depending on, for example, the mode of administration and the severity of the condition being treated. The daily doses indicated are in the range of about 1 to about 30 mg, such as 2 to 24 mg, or 2 to 12 mg of the oral active agent conveniently administered in single or divided doses. Preferred herbal formulations used to deliver tegaserod are described in international patent applications WO 2003053432, in particular Examples 1 to 3, and WO 00/10526, each of which is incorporated herein by reference.

Corresponding doses can be taken, for example, at breakfast, lunch or dinner.

In one preferred aspect, the present invention,

i) 25 to 150 mg, or 50 to 100 mg of vildagliptin, and

ii) 1 to 30 mg, or 2 to 12 mg of tegaserod, or

In any case, to a combination, use, or method described herein, comprising their pharmaceutically acceptable salts and administering them daily.

The present invention,

50 mg of vilagliptin and 2 mg of tegaserod or, in any case, their pharmaceutically acceptable salts;

50 mg of vilagliptin and 6 mg of tegacerod or, in any case, their pharmaceutically acceptable salts;

50 mg of vilagliptin and 12 mg of tegacerod or, in any case, their pharmaceutically acceptable salts;

-100 mg of vilagliptin and 2 mg of tegacerod or, in any case, their pharmaceutically acceptable salts;

-100 mg of vilagliptin and 6 mg of tegaserod or, in any case, their pharmaceutically acceptable salts;

A combination, use, or method described herein, comprising -100 mg of vilagliptin and 2 mg of tegaserod, or in any case their pharmaceutically acceptable salts, is administered daily.

Preferably, in the case of glass combinations, dosages for approved and marketed articles are preferred.

Low dose combinations are particularly preferred.

In order to further illustrate the invention without limitation, the following examples are provided.

Example 1

Tegasse Road  And LAF237 For stomach and colon motility in Pharmacodynamics  effect

Animal Preparation : Beagle dogs are used in these experiments. Under halotan anesthesia, four strain-gauge transducers constructed according to Pascaud et al., Am. J. Physiol., 1978, 235: E532-E538 were placed at 5 cm from the pylorus, 10 cm from the pylorus. Sewn into the duodenum, the jejunum 50 cm from the Tritz ligament, and the adjacent colon 10 cm from the ileum-colon connection. Each transducer is sutured to a recording axis parallel to the above abscissa, measuring the contractile force of the circular muscle layer. The glass end of the strain-gauge wire is pulled subcutaneously to appear dorsally between the scapula.

Notes : Titration of each strain-gauge is performed before implantation. Record the mechanical activity detected by the transducer. Motility indices of the sinus, duodenum, jejunum and colon are determined according to the technique of Hachet et al. (J. Pharmacol. Meth. (1986) 16: 171-180). The calculated motility index corresponds to the area between the baseline and the contraction curve for 30 minute intervals.

Study Design : Divide dogs into groups. Each group is given one of the following prescriptions: 1) placebo, 2) tegase rod, 3) LAF237, 4) tegase rod + LAF237. Different doses of compounds or placebos are administered orally to fasted dogs (unlimited water) 30 minutes before meals. Beginning intravenous infusion into fasted dogs (unlimited water) 30 minutes before meals of different doses of compounds or placebo. Records of gastrointestinal and colon motility recordings are taken at the time of eating, and are performed for a total of 6 hours.

Data Analysis : Changes in the motility index for 6 hours after meals associated with different compounds / administrations are obtained at the levels of sinus, duodenum, jejunum and colon.

The combination of Tegaserod + LAF237 can significantly increase gastrointestinal and colon motility compared to any of the placebo, and compounds administered alone.

Example 2

Sensitivity to gastric and colonic distension with barometric distension, and tegaserod for gastric muscle tension and LAF237 Influence

1.1. Stomach sensitivity and tension

Groups of Wistar rats weighing 200-250 g are used. For surgery, animals were pretreated by intraperitoneal injection (ip) of 0.3 ml of acepromazine (0.5 mg / kg) and anesthetized by intraperitoneal injection of 0.3 ml of ketamine.

The animal is placed horizontally, lying down, and after a xypho-ombilical laparotomy, the stomach is permanently connected to a tube introduced into the upper part of the rumen at 1 cm of the gastric-esophageal junction on the great curvature. Fit a balloon. After closing the abdomen, the rats were lying in the horizontal position, and the group of three stainless steel electrodes (length 1 m-diameter 270 μm) was prepared by Lucebusch and Fioramonti, Gastroenterol. 68: 1500-1508, 1975, to implant into the neck muscles. The free end of the electrode and the conduit of the balloon are taken out from behind the neck and protected by a glass tube attached to the skin.

Gastric distension at constant pressure is performed using an electronic pressure regulator (Hachet et al., Gastroenterol Clin Biol, 1993, 17, 347-351). Balloons (5.0-5.5 cm in length) are made using a cistern free condom and sutured into polyethylene tubes (1.0 mm and 1.8 mm in inner and outer diameters, 80 cm in length, respectively). Drill through the end of the tube to allow the balloon to empty easily.

EMG recording is performed 10 days after surgery using an EEG recorder (Reega VIII, Alba, Paris, France) at a paper speed of 2.4 cm / min. Using short-term amplification constants, spike bursts (0.03 seconds) are optionally recorded. EMG activity is summed every 20 seconds by the integrated circuit and automatically plotted to a computer.

Under toxic stomach bloating, the rat stretches his body, lifts his head and / or turns his head from side to side and observes his side. The neck muscles contract and record the EMG signal. In addition, a pressure regulator is connected to the potentiometer recorder to permanently record the intragastric pressure.

Divide the animals into groups.

After 30 minutes of control recording, the animal is given one of the following regimens:

1) Placebo, 2) Tegase Road, 3) LAF237, 4) Tegase Road + LAF237.

The protocol of gastric distension is initiated after 30 minutes. EMG activity of neck muscles correlates with postural changes and is proportional to pain induced by gastric distension. Every 20 seconds, the integrated values are summed for 10 consecutive minutes. For each distension step, the neck activity is determined according to the following formula:

[(EANM under predetermined pressure)-(EANM in base state)] / (EANM in base state) × 100

The pain threshold is determined as> 100% increase in the electrical activity of the neck muscles.

Obtain the volume in the potentiometer recorder as the maximum volume obtained for each bloating step. Pain thresholds and gastric volumes are given as mean ± SEM and the values are compared using Student's “ t ” test for unpaired values.

The pharmaceutical combination of Tegaserod and LAF237 can significantly reduce gastric pain associated with gastric distension and increase gastric tone compared to placebo and any compound administered alone.

2. Colon Sensitivity and Strain

Using the pressure regulator bloating procedure by applying increasing pressure in a stepwise manner over a 5 minute continuous period, the effects of tegaserod and LAF237 on rectal or colonic tension and pain, and volumetric measurements for each pressure Evaluate tension, change too.

Individual childish wister rats weighing 220-250 g are used. Animals are pretreated by intraperitoneal injection (ip) of 0.5 mg / kg of acepromazine and anesthetized by intramuscular administration of 100 mg / kg of ketamine. They are prepared for EMG recording using the technique described in Lucebusch and Fioramonti, 1975. A pair of nichrome wire electrodes (60 cm in length and 80 μm in diameter) is implanted into the abscissa of the abdomen at 2 cm laterally in a white string. The free end of the electrode is pulled out from behind the neck and protected by a plastic tube attached to the skin.

EMG recording (time constant: 0.03 sec) is started 8 days after surgery. Beginning 30 minutes before rectal distension, bipolar recording of electromyogenic activity is performed using a recorder of an EEG recorder for 1 hour.

To prevent the consequences of exercise during bloating, rats are acclimated 3 days before distension, staying in the tunnel of polypropylene, where bulging and EMG recordings are performed. A balloon consisting of a condom (4 cm) is introduced into the rectum 5 cm from the anus and fixed to the base of the tail. The balloon connected to the pressure regulator is gradually inflated with air at pressures of 15, 30, 45 and 60 mmHg, with each pressure being applied for 5 minutes.

Each group of rats is provided for a pressure-controlled distension protocol. Ten minutes prior, they were intraperitoneally injected with 1) placebo, 2) tegase rod, 3) LAF237, 4) tegase rod + LAF237 (ip). Statistical analysis of the number of abdominal spike bursts that occur during each 5 minutes is performed by Student's “ t ” test normal pair value comparison after two way ANOVA. P <0.05 is considered statistically significant. Colon volume is given as mean ± SEM and values are obtained using Student's “ t ” test for unpaired values.

The pharmaceutical combination of Tegaserod and LAF237 can significantly reduce rectal and colon pain associated with rectal distension and increase colonic tension as compared to placebo and any compound administered alone.

Example 3

Tegasse Road  And LAF237 of Combination  Used Non-erosive GERD Treatment of

Patients selected for the study have heartburn, a target symptom in patients with a non-erosive GERD as the predominant upper gastric symptom for at least 3 months before entering the study and a history of heartburn that occurs at least 3 days per week. Suffer from the disease. Patients with GERD but not endoscopic indications of erosive esophagitis are included in the study. Among other factors, patients treated with PPI or a prescribed dose of histamine H ₂ -receptor antagonist (H ₂ RA) within 1 month before entering the study baseline (14 days prior), and PPI within 3 months before entering the study baseline. Patients who require continuous use of are excluded.

The study consisted of a 1 week screening period and a 2 week drug exclusion baseline period, followed by a 8 week double-blind placebo-controlled treatment period. During the screening period (21-14 days prior), an endoscope is performed to exclude the presence of erosive esophagitis. During baseline (day 14 to day 1), symptoms of patients with GERD are documented in the daily diary. At the beginning of the period, drugs for GERD, such as H ₂ RA, PPI, prokinetic and other unlicensed drugs, are withdrawn and the patient is instructed not to change diet or lifestyle during the trial. Patients are advised to take Maalox tablets as rescue medications to suppress the symptoms. Patients entering the double-blind period have onset of heartburn in a period of three days or more in the last week of the baseline period.

Patients are randomly divided into equal groups during the double blind, placebo-controlled study. The study period lasts eight weeks and has 12 treatment arms. Patients in each group are given one of the following regimens: 1) placebo, 2) tegaserod 0.4 mg / day, 3) tegaserod 1 mg / day, 4) tegaserod 4 mg / day, 5) LAF237 50 mg / day, 6) Tegaserod 0.4 mg / day + LAF237 50 mg / day, 7) Tegaserod 1 mg / day + LAF237 50 mg / day, 8) Tegaserod 4 mg / day + LAF237 50 mg / Day (they are injected by oral prescription for 8 weeks). Administration to the 12 groups takes place within 30 minutes before the morning and dinner time. For eight weeks, the patient continues to complete the daily diary and use only Maalox tablets as a rescue medication for the control of symptoms.

The combination of Tegaserod and LAF237 can significantly reduce the number of heartburn events that occur weekly for eight weeks, which is a double-blind placebo-controlled study period, compared to any of placebo, Tegaserod, and LAF237 alone. The Tegaserod combination also reduces other symptoms of GERD, including abdominal pain, swelling and reflux. In addition, the patient shows a significant improvement in quality of life factors compared to any of placebo, tegase rod and LAF237 alone.

Pharmaceutical combinations according to the invention, including, for example, 5-HT ₄ agonists or partial agonists such as tegaserod, and DPP-IV inhibitors such as LAF237, are also clinically exemplified by [Talley NJ et al., Gastroenterol]. . Intl., 1993, 6 (4), 189: 211 or Veldhuyzen van Zanten SJO et al., Gut 1999, 45 (Appendix II), 1169: 1177). Dosage is preferably oral, and may preferably be administered once or twice daily.

The above examples can be used to demonstrate the efficacy of the DPP-IV inhibitor alone for treating the diseases and conditions of the present invention. The doses and formulations described herein for combination therapy may also be applied when DPP-IV is used as a single therapy.

Although the invention has been described in considerable detail with respect to certain preferred embodiments of the invention, other aspects are possible without departing from the spirit and scope of the preferred embodiments contained herein. All references and patents (US and others) mentioned herein are incorporated herein by reference in their entirety, as if all were incorporated herein by reference.

Claims (21)

i) a DPP-IV inhibitor or a pharmaceutically acceptable salt thereof, and ii) one or more therapeutic agents selected from agents that interact with the 5-HT ₃ receptor and / or agents that interact with the 5-HT ₄ receptor, or their pharmaceutically acceptable salts Combination comprising a. The combination of claim 1, comprising one or more additional pharmaceutically acceptable carriers. The combination according to claim 1 or 2, which is in the form of a combination formulation or a fixed combination. i) a DPP-IV inhibitor or a pharmaceutically acceptable salt thereof, and ii) one or more therapeutic agents selected from agents that interact with the 5-HT ₃ receptor and / or agents that interact with the 5-HT ₄ receptor, or pharmaceutically acceptable salts thereof Of combinations comprising: Use for the manufacture of a medicament for the prevention, delay of progression or treatment of diseases and disorders that may be inhibited by DPP-IV inhibition and / or interaction with 5-HT ₃ receptor or 5-HT ₄ receptor. One selected from a DPP-IV inhibitor or a pharmaceutically acceptable salt thereof, an agent that interacts with the 5-HT ₃ receptor and / or an agent that interacts with the 5-HT ₄ receptor, or a pharmaceutically acceptable salt thereof Abnormal therapeutic agents; And One or more additional pharmaceutically acceptable carriers Comprising administering a combined effective amount of a combination comprising a to a warm blooded animal, including a human in need thereof, A method of preventing, delaying or treating a disease and disorder that may be inhibited by DPP-IV inhibition and / or interaction with a 5-HT ₃ receptor or 5-HT ₄ receptor. The disease or condition according to claim 5 or 6, wherein the disease or condition is insulin resistance, impaired glucose metabolism, impaired glucose endogenous condition, impaired fasting plasma glucose status, diabetes, in particular type 2 diabetes, obesity, diabetic retinopathy, macular degeneration, cataract , Diabetic nephropathy, glomerulosclerosis, diabetic neuropathy, erectile dysfunction, premenstrual syndrome, coronary heart disease, hypertension, angina pectoris, myocardial infarction, stroke, vascular restenosis, skin and connective tissue disorders, foot ulcers and ulcerative colitis , Endothelial dysfunction and impaired vascular compliance, heartburn, abdominal swelling, postoperative ileus, abdominal pain and anxiety, premature satiety, epigastric pain, nausea, vomiting, burbulence, reflux, intestinal obstruction, Anal bowel incontinence, GERD, IBS, dyspepsia, chronic constipation or diarrhea, diabetic gastroparesis, gastric palsy, such as diabetic gastric palsy, ulcerative colitis, Crohn's disease, ulcers The internal include, but pain is associated, is not limited to these altered gastrointestinal motility that, sensitivity and / or the method or use is selected from the secretion disorder (s). The DPP-IV inhibitor according to any one of claims 1 to 6, wherein the DPP-IV inhibitor is (S) -1- {2- [5-cyanopyridin-2-yl) amino] ethyl-aminoacetyl) -2-cya No-pyrrolidine, vilagliptin, MK-0431, GSK23A, saxagliptin, 3- (aminomethyl) -2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-iso Quinolinecarboxamide and 2-{[3- (aminomethyl) -2-isobutyl-4-phenyl-1-oxo-1,2-dihydro-6-isoquinolyl] oxy} acetamide, or in each case The combination, method or use of which is selected from pharmaceutically acceptable salts thereof. The combination, method or use according to any one of claims 1 to 7, wherein the DPP-IV inhibitor is bilagliptin or a pharmaceutically acceptable salt thereof. The agent according to any one of claims 1 to 8, wherein the agent which interacts with the 5-HT ₄ receptor is preferably tegacerod, cisaprid, norsisaprid, lenzafried, jacobridd, mosafrid, pruh. Combination, method or use selected from the group consisting of carloprid, buspyrone and norsisaprid or in each case a pharmaceutically acceptable salt thereof. The combination according to any one of the preceding claims, wherein the agent interacting with the 5-HT ₄ receptor is tegacerod or in each case a pharmaceutically acceptable salt thereof, in particular tegacerod hydrozin maleate. Water, methods or uses. The agent according to any one of claims 1 to 10, wherein the agent which interacts with the 5-HT ₃ receptor is preferably silanesetron, lamosetron, azasetron, ondansetron, dolasetron, lamosetron, Ranisetrone, mirtazapine, indysetron, lerisetron, Ro-93777, YM-114, talipexol, N-3389, jacobride, silansetron, E-3620, lintoprid, KAE-393, eta Setron, mosafried; Combination, method or use selected from the group consisting of dolacetron and trocecetron or in each case a pharmaceutically acceptable salt thereof. Heartburn, abdominal swelling, postoperative ileus, abdominal pain and anxiety, premature satiety, epigastric pain, nausea, vomiting, bloating, reflux, intestinal obstruction, anal bowel incontinence, GERD, IBS, indigestion, chronic constipation or diarrhea, diabetic Gastropathy, gastroparesis, such as diabetic gastric palsy, ulcerative colitis, Crohn's disease, ulcers and diseases selected from altered gastrointestinal motility, sensitivity and / or secretion disorder (s), including but not limited to these And the use of a DPP-IV inhibitor or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the prevention, delay of progression or treatment of a disorder. Heartburn, abdominal swelling, postoperative ileus, abdominal pain and anxiety, premature satiety, comprising administering an effective amount of a DPP-IV inhibitor or a pharmaceutically acceptable salt thereof to a warm blooded animal, including a human in need thereof Epigastric pain, nausea, vomiting, swelling, reflux, intestinal obstruction, anal bowel incontinence, GERD, IBS, indigestion, chronic constipation or diarrhea, diabetic gastrointestinal disorder, gastric palsy, such as diabetic gastric palsy, ulcerative colitis, Crohn's disease , Methods of preventing, delaying or treating disease and disorders selected from altered gastrointestinal motility, emotional and / or secretory disorder (s), including but not limited to ulcers and visceral pain associated therewith. The method according to claim 12 or 13, wherein the DPP-IV inhibitor is (S) -1- {2- [5-cyanopyridin-2-yl) amino] ethyl-aminoacetyl) -2-cyano-pyrroli Dean, Bildagliptin, MK-0431, GSK23A, Saxagliptin, 3- (aminomethyl) -2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinecarboxamide And 2-{[3- (aminomethyl) -2-isobutyl-4-phenyl-1-oxo-1,2-dihydro-6-isoquinolyl] oxy} acetamide, or in each case its pharmaceutical Or is selected from acceptable salts. Use or method according to claim 12 or 13, wherein the DPP-IV inhibitor is bilagliptin or a pharmaceutically acceptable salt thereof. The combination, method or use according to any one of claims 1 to 15, wherein the vildagliptin is administered in an amount of 25 to 150 mg, or 50 to 100 mg per day. The combination, method or use according to any one of claims 1 to 16, wherein tegacerod is administered in an amount of 1 to 30 mg, or 2 to 12 mg per day. The method of claim 3, i) 25 to 150 mg, or 50 to 100 mg of vildagliptin, and ii) 1 to 30 mg, or 2 to 12 mg of tegaserod, Or in any case their pharmaceutically acceptable salts Combination comprising a. The method of claim 18, i) 50 mg of vildagliptin, and ii) 2, 6 or 12 mg of tegase rod, Or in any case their pharmaceutically acceptable salts Combination comprising a. The method of claim 18, i) 100 mg of vildagliptin, and ii) 2, 6 or 12 mg of tegase rod, Or in any case their pharmaceutically acceptable salts Combination comprising a. The method according to claim 4 or 5, i) 25 to 150 mg, or 50 to 100 mg of vildagliptin, and ii) 1 to 30 mg, or 2 to 12 mg of tegaserod, Or in any case their pharmaceutically acceptable salts Or the method of daily administration.