HK1053266B - Pharmaceutical combinations and their use in treating gastrointestinal disorders - Google Patents

Description

Pharmaceutical combination and its use in the treatment of gastrointestinal disorders

The present invention relates to a pharmaceutical combination comprising at least one compound of formula (I) and 5-HT and to its use in the treatment of gastrointestinal disorders₃Or 5-HT₄A receptor interacting drug.

5-hydroxytryptamine (5-hydroxytryptamine; 5-HT) plays a neurotransmitter role in the mammalian Central Nervous System (CNS) and in peripheral nerves. 5-hydroxytryptamine is a transmitter whose physiological importance is well recognized, and the current research on drugs interacting with 5-HT receptors is the focus (P. Bonate, Clinical Neuropharmacology, 1991, Vol.14(1), pp.1-16). To date, the 5-hydroxytryptamine receptor subtypes that have been identified have reached tens of species, including the major several, namely 5-HT₁、5-HT₂、5-HT₃、5-HT₄、5-HT₅、5-HT₆And 5-HT₇. Due to the diversity of the 5-hydroxytryptamine receptor subtypes, the identification of the 5-hydroxytryptamine receptor subtypes associated with various physiological/pharmacological effects is complicated.

It has been known for many years that 5-hydroxytryptamine can modulate the Gastrointestinal (GI) tract in various mammalian modelsThe peristalsis of (2). In the mid-80's of the 20 th century, several specific 5-HT have been identified₃Antagonists of the receptor subtype, and these antagonists are currently used as antiemetic/antiemetic agents in the treatment of cancer. Recently, 5-HT has also been investigated₃Treatment of irritable bowel syndrome ("IBS") with antagonists.

Many gastrointestinal syndromes are associated with the production and action of 5-hydroxytryptamine and are prevalent in a very large population worldwide. Some of the more well known gastrointestinal symptoms, syndromes or diseases are IBS, gastro-esophageal reflux disease ("GERD") and dyspepsia.

IBS is a chronic symptom associated with abdominal pain, flatulence and altered bowel function, estimated to affect up to 10-20% of the population. Sometimes these diseases are referred to as irritable colon, spastic colitis or mucous colitis. The latter two statements are almost certainly misnomers, since colitis implies inflammation of the colon, whereas no inflammation is a definite observation in the diagnosis of IBS. The cause of IBS is unknown, but involves many factors, including diet, lifestyle, depression, anxiety, infection, and unrelated inflammatory symptoms, including central neuron sensitization and enteric neuron sensitization resulting from previous injury. Almost all current medications used for IBS treatment do not produce significant therapeutic effects.

GERD is a condition associated with reflux of stomach contents into the esophagus through the lower esophageal sphincter. GERD is characterized by heartburn, bloating, abdominal pain, epigastric pain, early satiety, nausea, regurgitation, flatulence and vomiting. Reflux is thought to occur as a result of the increased number of transient lower esophageal sphincter relaxations that can cause stomach contents to enter the esophagus.

Dyspepsia is also an important health problem. The most common symptoms associated with patients with chronic dyspepsia symptoms are GERD, duodenal ulcer or gastric ulcer, and other diagnoses (e.g. functional/non-ulcer dyspepsia, gallbladder or liver disease).

These symptoms or diseases are characterized by altered motility, sensitivity, secretion and/or infection by Helicobacter pylori (Helicobacter pylori) and possibly mental (usually subconscious) overload. Currently, only a few drug therapies show clinically significant efficacy for the treatment of e.g. functional dyspepsia, some of which also have different side effects on the human body.

Therefore, there is a need for drugs that can modulate and normalize altered GI motility, sensitivity and secretion, interact with 5-HT receptors involved in various physiological processes, and have broad clinical applicability to the treatment of many gastrointestinal diseases affecting millions of people each year. More particularly, there is a need for pharmaceutical combinations comprising 5-HT effective in the treatment of altered gastrointestinal motility, sensitivity and/or secretion and/or abdominal disorders, including functional and organic disorders₄Receptor agonists or antagonists, 5-HT₄Partial agonists of receptors or 5-HT₃Receptor antagonists and coagents.

It has now been found that a composition comprising at least one compound of formula I and 5-HT₃Or 5-HT₄The combination of a receptor-interacting drug (e.g. as defined below) and a co-agent (e.g. as defined below) has good results and is suitable for the treatment of altered gastrointestinal motility, sensitivity and/or secretion and/or abdominal disorders. The combination product can also be used to regulate, stabilize and normalize altered gastrointestinal motility, sensitivity and/or secretion and/or abdominal disorders.

Definition of

Unless otherwise indicated herein, the words and terms used herein are to be given their ordinary definition. For example, the term "pharmaceutical combination product" as used herein refers to a product obtained by mixing or combining more than one active ingredient and includes both fixed and non-fixed combinations of active ingredients.

The term "fixed combination" as used herein means that the active ingredients, e.g. tegaserod and a co-agent, are co-administered to a patient simultaneously in the form of a single entity or dose. For example, the fixed combination may be a capsule containing two active ingredients.

The term "non-fixed combination" as used herein means that the active ingredients, e.g. tegaserod and a co-agent, are co-administered to a patient simultaneously, concurrently or sequentially and without specific time constraints in separate entities, wherein such administration provides a therapeutically effective level of both compounds in vivo (preferably simultaneously). For example, the non-fixed combination may be two capsules each containing one active ingredient, the purpose of which is to allow the patient to be treated with both active ingredients together in vivo.

The term "altered gastrointestinal motility, sensitivity and/or secretion disorder" as used herein includes one or more symptoms and conditions affecting the gastrointestinal tract from the mouth to the anus, including, but not limited to, heartburn, flatulence, postoperative ileus, abdominal pain and discomfort, early satiety, epigastric pain, nausea, vomiting, flatulence, regurgitation, intestinal pseudo-obstruction, anal incontinence, GERD, IBS, dyspepsia, chronic constipation or diarrhea, gastroparesis, e.g., diabetic gastroparesis, ulcerative colitis, Crohn's disease, ulcers and visceral pain associated therewith.

The term "abdominal disorder" as used herein includes conditions affecting the lower abdomen and includes, but is not limited to, those treated by modulating, stabilizing and normalizing enterochromaffin cell function, GI secretion, motility, afferent and efferent fiber activity, and/or abdominal smooth muscle cell activity.

The terms "gastro-esophageal reflux disease" and "GERD" as used herein refer to the syndrome and pathogenesis of those symptoms caused by reflux of components in the stomach into the esophagus. It includes all forms and/or manifestations of GERD (including, but not limited to, erosive and non-erosive GERD, heartburn, and other GERD-related symptoms).

The terms "irritable bowel syndrome" and "IBS" as used herein refer to functional disorders involving primarily altered motility, sensitivity and secretion of the small and large intestine, which are associated with varying degrees of abdominal pain, bloating, constipation or diarrhea without significant enteritis.

The term "dyspepsia" as used herein refers to a condition characterized by the above symptoms of abdominal pain, flatulence, early satiety, nausea, heartburn and vomiting as major gastrointestinal dysfunction or as a complication, but does not exclude conditions such as ulcerative diseases, appendicitis, gallbladder disturbances or malnutrition.

The term "gastroparesis" as used herein refers to gastric paralysis resulting from an abnormality in the motility of the stomach, which is often manifested as a delay in gastric emptying. This may be, for example, a complication of diabetes, progressive systemic scleroderma, anorexia nervosa or myotonic dystrophy.

As used herein, the term "constipation" refers to a condition characterized by infrequent and/or difficult fecal excretion resulting from symptoms such as altered GI motility, altered sensory or excretory function, altered secretion or reabsorption of electrolytes and water.

The term "diarrhea" as used herein refers to a condition characterized by massive and urgent frequent fecal excretion usually resulting from symptoms such as altered GI motility, altered sensation and secretion, or reabsorption of electrolytes and water.

The term "treatment" includes the full range of therapeutically positive effects associated with drug treatment, including reduction, alleviation and alleviation of symptoms or diseases affecting an organism.

Description of the invention

More specifically, the present invention provides:

1.1 a pharmaceutical combination comprising:

a) as 5-HT₄A first agent that is a receptor moiety agonist; and

b) a co-agent.

5-HT as the first drug in combination 1.1₄Receptor moiety agonists include any moiety that can partially activate 5-HT₄A compound of the receptor (which compound has an intrinsic activity less than 5-hydroxytryptamine activity, i.e. < 1.00. intrinsic activity can be determined by non-electrical or electrical stimulation of guinea pig ileum or striatal assays, e.g. as disclosed in EP-a 1-0505322 and british journal of pharmacology, 115, 1387, 1995, or by a guinea pig distal colon assay, e.g. as disclosed in br.j.pharm., 1593-1599, 1993).

In another embodiment, the present invention provides:

1.2 a pharmaceutical combination comprising:

a) a first drug represented by a compound of formula I

Wherein

R₁Is hydrogen; c_1-6An alkyl group; (C)_1-6Alkyl) carbonyl; benzoyl or phenyl C_1-4Alkyl-carbonyl;

R₅is hydrogen; halogen; c_1-6An alkyl group; a hydroxyl group; a nitro group; an amino group; c_1-6An alkylamino group; c_1-10Alkyl-carbonylamino; c_2-6An alkoxycarbonyl group; SO (SO)₂NR_aR_bWherein R is_aAnd R_bEach of which is independently hydrogen or C_1-6An alkyl group; cyano or trimethylsilyl; c substituted by_1-6Alkyl groups: -SO₂-C_1-6Alkyl, -SO₂NR_aR_b、-CONR_aR_b、-NH-SO₂-C_1-6Alkyl, -N (C)_1-6Alkyl) -SO₂-(C_1-6Alkyl) wherein R'_bIs hydrogen or C_1-6Of alkyl radicals-NR_aR’_b、C_2-6Alkoxycarbonyl or-PO (C)_1-4Alkyl radical)₂(ii) a A carboxyl group; CONR_aR_b；-PO(C_1-6Alkyl radical)₂；OCONR_cR_dWherein R is_cAnd R_dEach of which is independently C_1-6An alkyl group;

R₆is hydrogen, or, when R is₅When is OH, R₆Is a hydrogen or a halogen, and the halogen,

z is-CR₄Wherein R is₄Is hydrogen, halogen, hydroxy or C_1-6Alkyl, or, when R is₅When hydrogen or hydroxy, Z is also-N ═ N,

R₇is hydrogen, halogen, C_1-6Alkyl or C_1-6An alkoxy group,

X-Y is-CR₈N-or-CH (R)₈) -NH-, wherein R₈Is hydrogen or C_1-6Alkyl radical, and

b is a group of formula (a) or (B),

wherein

n is a number of 1 or 2,

A₁is C ═ O or CH₂，

X₁Is S; NR (nitrogen to noise ratio)₁₁Wherein R is₁₁Is hydrogen, (C)_1-6Alkyl) carbonyl, benzoyl or phenyl C_1-4Alkyl-carbonyl; or CR₁₂R₁₃Wherein R is₁₂And R₁₃Each of which is independently hydrogen or C_1-4An alkyl group, a carboxyl group,

R₁₀is hydrogen; c_1-12An alkyl group; c substituted by_1-6Alkyl groups: hydroxy, aryl, aryloxy, adamantyl, heterocyclyl, -NR₁₅-CO-R₁₆or-NH-SO₂-aryl radicalA group; c_5-7A cycloalkyl group; an adamantyl group; (C)_1-10Alkyl) carbonyl; a benzoyl group; phenyl (C)_1-4Alkyl) carbonyl; or-CONHR₁₄，

Wherein

R₁₄Is C_1-10Alkyl or C_5-7A cycloalkyl group,

R₁₅is hydrogen or C_1-4Alkyl radical, and

R₁₆is C_1-6Alkyl radical, C_5-7Cycloalkyl radical, C_5-7cycloalkyl-C_1-4Alkyl, aryl or aryl C_1-4An alkyl group, a carboxyl group,

"aryl" group, wherever it appears, whether by itself or in the above-defined "aryloxy", "-NH-SO₂-aryl "or" aryl (C)_1-4Alkyl) "which is phenyl or substituted by halogen, C_1-4Alkyl or C_1-6Alkoxy-substituted phenyl; and is

"Heterocyclyl" is, wherever it appears in the above definition, pyridyl, imidazolyl, benzimidazolyl, pyrrolidinyl, pyrrolidinonyl, piperidino, pyrazinyl, perhydroindolyl or a group of formula (c), (d) or (e)

Wherein

R₂₂Is hydrogen or C_1-4An alkyl group, a carboxyl group,

B₁is-CH₂CH₂-、-COCH₂-or- (CH)₂)₃-, where one or two H may be replaced by C_1-4Alkyl or 1, 2-phenylene substituted,

e is-CH₂-CH₂-、-CH₂N(R₁₇) -or- (CH)₂)₃-, where one or two H may be replaced by C_1-6Alkyl or 1, 2-phenylene substituted,

E₁is CO or CH₂，

R₁₇Is hydrogen or C_1-4An alkyl group, a carboxyl group,

g is CO, -CHCOOR₁₈、-CHCOR₁₉5, 5-dimethyl-1, 3-dioxane-2-yl subunit or 1, 3-dioxolan-2-yl subunit, wherein R is₁₈Is hydrogen or C_1-6Alkyl and R₁₉Is C_1-6Alkyl radical, and

n' is 0 or 1, and

X₂is-SR₂₀or-NR₃R’₁₀Wherein R is₂₀Is C_1-6Alkyl radical, R₃Is hydrogen or C_1-6Alkyl and R'₁₀Having the above pair R₁₀One of the meanings given, or R₃And R'₁₀Together with the nitrogen atom to which they are attached form a heterocyclic group as defined above;

with the proviso that, where B is a radical of the formula (B), R₁₀And R'₁₀May not be hydrogen, and only when R is₁₀When is hydrogen, X₂Can be-SR₂₀，

And when R is₅A physiologically hydrolyzable and physiologically acceptable ether or ester thereof when it is a hydroxyl group,

these drugs are in free form or in salt form, preferably in the form of a pharmaceutically acceptable salt,

and

b) a co-agent.

Compounds of the formula I and their physiologically hydrolyzable and physiologically acceptable ethers or esters are, for example, those disclosed in EP-A1-0505322. Suitable pharmaceutically acceptable salts are, for example, pharmaceutically acceptable acid addition salts, for example salts with inorganic or organic acids, such as the hydrochloride, sulfate, acetate, oxalate, maleate and fumarate salts.

When R is₅The term "physiologically hydrolyzable and physiologically acceptable ether or ester" as applied to a compound of formula I when it is hydroxy refers to a compound wherein R is₅By etherification (e.g. by optionally substituted C_1-6Alkyl etherification) and wherein R₅Esters that are esterified and which can be hydrolyzed under physiological conditions to produce physiologically acceptable alcohols or acids, i.e., which are non-toxic at the dosage levels required. Specific examples are shown in EP-A1-0505322.

Typical 5-HT₄Receptor moiety agonists include, but are not limited to, compounds of formula I in which the intrinsic activity is less than 5-hydroxytryptamine activity. Preferred as 5-HT₄Compounds of formula I which are agonists of the receptor moiety are, for example, those in which R₁Is H, Z is-CH ═ and R₅Is OH or C_1-6Those of alkoxy.

5-HT₄Other examples of receptor moiety agonists include, for example, RS67333 (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-methanesulfonylamino group]Ethyl-4-piperidinyl) -1-propanone).

The compounds of formula I above are preferred; particularly preferred compounds of the formula I are those of the formula

The chemical name of this compound is 3- (5-methoxy-1H-indol-3-ylmethylene) -N-pentylcarbazimidamide, also known as tegaserod. The substance is as 5-HT₄Receptor partial agonists are disclosed. It may also exist in tautomeric forms

These tautomeric forms are included in the present invention. The preferred salt form is hydrogen maleate.

The coagent in the combination 1.1 or 1.2 is selected from the following groups of compounds: 5-HT₃Receptor antagonists, 5-HT₄Receptor agonists or antagonists exhibiting 5-HT₃Receptor antagonists and 5-HT₄Compounds with receptor agonist or antagonist properties, somatostatin receptor agonists, histamine H₂Receptor antagonists, proton pump inhibitors ("PPIs") including irreversible PPIs, reversible PPIs and prodrugs of PPIs, anxiolytics such as chlordiazepoxide, benzodiazepine * compounds, antispasmodic/antimuscarinic agents, selective 5-hydroxytryptamine reuptake inhibitors ("SSRIs"), tricyclic antidepressants, selegiline, muscarinic agents₁(“M₁") receptor agonists or antagonists, cholecystokinin (" CCK ") receptor antagonists, opioid receptor agonists or antagonists, motilin receptor agonists or antagonists, nitric oxide synthase inhibitors, GABA_BReceptor agonists or modulators, neurokinin ("NK") receptor agonists or antagonists, calcitonin gene-related peptide receptor ("CGRP") or corticotropin releasing factor ("CRF") receptor agonists or antagonists, anti-inflammatory compounds, stimulant laxatives, osmotic laxatives, stool softeners, absorbents and fiber supplements, antacids, GI relaxants, diphenoxylate, anti-gasification compounds, bismuth-containing preparations, pentosan polysulfate, hydroxyzine, mast cell stabilizers and anti-emetic dopamine D₂An antagonist.

In another embodiment, the present invention also provides:

1.3. a pharmaceutical combination comprising

a) Selected from 5-HT₄Receptor agonists or antagonists and 5-HT₃A first agent that is a receptor antagonist; and

b) a coagent selected from the group consisting of: somatostatin receptor agonists, anxiolytics such as chlordiazepoxide, benzodiazepine * compounds, antispasmodic/antimuscarinic agents, tricyclic antidepressants, celecoxib, M₁Receptor agonists or antagonistsAgents, CCK receptor antagonists, opioid receptor agonists or antagonists, motilin receptor agonists or antagonists, nitric oxide synthase inhibitors, GABA_BReceptor agonists or modulators, NK receptor agonists or antagonists, CGRP or CRF receptor agonists or antagonists, anti-inflammatory compounds, stimulant laxatives, osmotic laxatives, stool softeners, absorbents and fiber supplements, antacids, GI relaxants, diphenoxylate, anti-gasification compounds, bismuth-containing preparations, pentosans polysulfate, hydroxyzine, mast cell stabilizers,

with the proviso that when the drug a) is 5-HT₃In the case of receptor antagonists, the coagent b) is not an antispasmodic/antimuscarinic agent, M₁Receptor antagonists, opioid receptor agonists or antagonists, NK receptor antagonists, stimulant laxatives, osmotic laxatives, or anti-inflammatory corticosteroids.

In another embodiment, the present invention also provides:

1.4. a pharmaceutical combination comprising

a) As 5-HT₄A first agent that is a receptor antagonist; and

b) selected from somatostatin receptor agonists, histamine H₂Receptor antagonists, PPIs, metoclopramide and antiemetic dopamine D₂A coagent for the antagonist.

5-HT as a co-agent in combination 1.1 or 1.2 or as a first drug in combination 1.3₄Receptor agonists include any agonist capable of inducing 5-HT under resting/resting conditions₄A receptor-activating compound. These compounds include, but are not limited to, the compounds of formula I disclosed in EP-B1-0505322, cisapride, nor-cisapride, rezapride, zacopride, mosapride, clenbaride (prucalopride), SB 205149, SC 53116, RS67333, RS 67506, BIMU-1, BIMU-8 and (S) -RS 56532. Cisapride, cis-4-amino-5-chloro-N- [1- [3- (4-fluorophenoxy) propyl]-3-methoxy-4-piperidinyl]-2-methoxy-benzamides as gastric-motility drugs (see a. reyntjens et al, Drug div. re)s., 8, 251(1986) and current therapeutic studies, 36, 1029-. The compounds are sold in the international market under the trade names, for example, acealin ®, PREPULSID ®, RISAMOL ®, pulser ® and prepulsin ®.

Preferred group of 5-HT₄Receptor agonists or partial agonists are those which are selective; the term selective means substantially free of 5-HT₃Receptor subtype binding or stimulation of 5-HT₃A compound of the receptor subtype. For example, Tegaserod is not compatible with 5-HT₃Receptor subtype binding nor stimulation of 5-HT₃The receptor subtype.

5-HT as a co-agent in combination 1.1 or 1.2 or as a first drug in combination 1.3 or 1.4₄Receptor antagonists include any of those defined by IUPHAR (for pharmacological review, Vol.44, p.157-213, 1994) and 5-HT₄Receptor binding without 5-HT₄Compounds that activate receptors and antagonize the action of 5-hydroxytryptamine. Determining whether a compound is 5-HT₄Relevant tests for receptor antagonists are the guinea pig distal colon test described in br.j.pharm., p.1593-1599(1993), or the test described in the pharmaceutical literature, vol.343, p.439-446 (1991). Typical 5-HT₄Receptor antagonists include, for example, picoserod; a-85380(Abbott laboratory) (WO 94/08994); SB 204070(SmithKline Beecham) (future pharmacy, 19: 1109-; SB 207058(exp. Opin. invest. drugs, 3 (7): 767, 1994); SB 207710 (pharmaceutical data report, 15 (10): 949, 1993); SB 205800 (pharmaceutical data report, 15 (10): 949, 1993); SB 203186 (J.British Pharmacology, 110: 1023-1030, 1993); n3389 (Nisshin flow Milling) (J.Eur.Pharmacology, 271: 159, 1994); FK 1052(Fujisawa) (J. Pharmacology & Experimental therapeutics, 265: 752, 1993); SC 56184(Searle) (R)&D Focus, 2(37)10, 1993); SC 53606(Searle/Monsanto) (J. Pharmacology & Experimental therapeutics 226: 1339, 1993); DAU 6285(Boerhinger Ingelheim) (journal of british pharmacology, 105: 973, 1992); GR 125487(Glaxo) (J.England Pharmacology, 113 appendix 119P&120P, 1994); GR 113808 (British Pharmacology Heterota)Log 110: 1172, 1993); RS23597(Syntex) (Bioorg med. chem. lett., 4 (20): 2477, 1994); RS 39604 (journal of British pharmacology, 115, 1087-; LY0353433(Eli Lilly co. ltd.) (journal of pharmacology and experimental therapeutics, 277(1), 97-104, 1996); and R59595 (european journal of pharmacology, 212, 51-59, 1992).

5-HT as a co-agent in combination 1.1 or 1.2 or as a first drug in combination 1.3₃Receptor antagonists include those that react with 5-HT₃Receptor binding and antagonism of 5-HT₃Compounds which act as receptor agonists, such as cilansetron, as described in EP 29761; alosetron as described in WO 99/17755; ramosetron; azasetron; ondansetron; dolasetron; ramosetron; glanesilone; and trapixone.

Having 5-HT as a co-agent in combination 1.1 or 1.2 or as a first agent in combination 1.3₃Receptor antagonists and 5-HT₄Compounds which are characteristic of receptor agonists or antagonists are, for example, cisapride and nor-cisapride; BIMU compounds such as BIMU1, BIMU8 and DAU 6215 (also known as itasetron) disclosed in the Wansterin-Schmidberg pharmacology literature, Vol.343(3), pp.245-251(1991), by Dumuis A. et al; DAU-6236, disclosed in Rizzi, c.a., et al, journal of pharmacology and experimental therapeutics, vol.261, pp.412-419 (1992); and DAU-6258, Turconi M et al, J.Med., Vol.33(8), pg.2101-2108(1990), benzoic acid derivatives (esters) SDZ 205-; renzapride; zacopride; SB 205149; SC 53116; RS 67333; RS 67506 or (S) -RS 56532, lintopride.

Examples of other co-agents that may be combined with the first medicament of the invention include, but are not limited to, the following:

i) histamine H₂Receptor antagonists comprising histamine H inhibition on gastric cells₂Compounds that act on histamine at receptors, such as famotidine sold under the trade name PEPCID ®; west sold under the trade name TAGAME ®Mizidine; ranitidine sold under the trade name ZANTAC ®; and nizatidine sold under the trade name AXID ®.

ii) irreversible Proton Pump Inhibitors (PPIs), including by inhibiting H of parietal cells⁺/K⁺Compounds of the ATPase enzyme system which inhibit gastric acid secretion, e.g. under the trade name PRILOSEC^®And omeprazole sold by LOSEC ®; lansoprazole sold under the trade name PREVACID ®; rabeprazole sold under the tradenames PARIET ® and acipex ®; pantoprazole sold under the trade name PROTIUM ®; and esomeprazole sold under the trade name NEXIUM ®. Reversible PPIs include, for example, BY 841, SKF 97574, SKF 96067, H40502 and YH1238 and YH1885 disclosed in WO 98/43968, Kim H. et al, Korean journal of physiology and pharmacology, 1997, Vol1(3), pp.337-343.

iii) benzodiazepine * compounds and their use as inhibitors of the enzyme_A) Analogues of gamma-aminobutyric acid (GABA) receptor interaction exerting an inhibitory effect, e.g. DIASTAT^®And VALIUM^®；LIBRIUM^®(ii) a And ZANAX^®。

iv) antispasmodics/antimuscarinics, such as the bicyclic amine sold under the trade name BENTYL ®; hyoscyamine sold under the trade name LEVSIN ®; and darifenacin, (S) -1- [2- (2, 3-dihydro-5-benzofuranyl) ethyl]-alpha, alpha-diphenyl-3-pyrrolidineacetamide, described in U.S. Pat. No. 5,837,724, is a selective muscarinic M₃A receptor antagonist.

v) SSRIs, such as fluvoxamine; fluoxetine; paroxetine; sertraline; citalopram; venlafaxine; cericlamine; duloxetine; milnacipran; nefazodone; and cyanodothiepin (see The Yeast Drugs News, 1995Edition, pp.47-48, author Prous J.R.) and WO 97/29739.

vi) tricyclic antidepressants, such as amitriptyline sold under the tradenames ELAVIL ®, ETRAFON ®, LIMBITROL ® and TRIAVIL ®; bupropion (buproprion); and more so.

vii) SerligiForest, e.g. under the trade name ELDEPRYL^®、ATAPRYL^®And DEPRENYL^®And (4) selling.

viii) CCK receptor antagonists, such as devazepide; a clomipide; dexloxyglumide; cloglumine, D' Amato, M. et al, journal of British Pharmacology Vol.102(2), pp.391-395 (1991); CI 988; l364,718; l363,260; l740,093 and LY288,513; CCK receptor antagonists, disclosed in U.S. Pat. No. 5, 5,220,017, Bruley-Des-Varannes, S et al, Gastroenterol, Clin, biol, Vol.15: (10) pp.744-757(1991), and Worker C: EUPHAR' 99-the second European Pharmacology conference (fourth part) Budapest, Hungarian Iddb conference report on days 7, 3-7, 1999.

ix) opioid receptor agonists or antagonists may be, for example, ADL8-2698, fedotozine, dextromethorphan, loperamide (e.g., IMODIUM ®), diphenoxylate (e.g., LOMOTIL)^®) Belladonna alkaloids, endorphins/enkephalins analogues.

x) motilin receptor agonists or antagonists, including, for example, motilin agonist ABT-269, (erythromycin, 8, 9-didehydro-N-dimethyl-9-deoxo-4 ", 6, 12-trideoxy-6, 9-epoxy-N-ethyl), des (N-methyl-N-ethyl-8, 9-anhydroerythromycin a) and des (N-methyl) -N-isopropyl (isoprop) -8, 9-anhydroerythromycin a), Sunazika t. et al, reports on chemistry and pharmacy, vol.37(10), pp.2687-2700 (1989); a-173508(Abbot laboratories); motilin antagonists (Phe3, Leu13) porcine motilin, 214^thAmerican Chemical Society (ACS) meeting (part V); high heights from Medicinal Chemistry Poster Session, Wednesday10 September, Las Vegas, Nevada, (1997), Iddb Meeting Report September7-11 (1997); and ANQ-11125, Peeters T.L., et al, Biochemical and biophysical research Command, Vol.198(2), pp.411-416 (1994).

xi)GABA_BReceptor agonists or modulators, e.g., (+ -) -baclofen, S (-) -baclofen, R (+) -baclofen, CGP44532, CGP47656, CGP7930, SK&F97541。

xii) NK receptor antagonists including, for example, FK 888 (Fujisawa); GR 205171 (GlaxoWellcome); LY 303870 (Lilly); MK 869 (Merck); GR82334 (GlaxoWellcome); l758298 (Merck); l733060 (Merck); l741671 (Merck); l742694 (Merck); PD 154075 (Parke-Davis); s18523 (Servier); s19752 (Servier); OT 7100 (Otsuka); WIN 51708(Sterling Winthrop); NKP-608A; TKA 457; DNK 333; CP-96345; CP-99994; CP 122721; l-733060; l-741671; l-742694; l-758298; l-754030; GR-203040; GR-205171; RP-67580; RPR-100893 (dapitant); RPR-107880; RPR-111905; FK-888; SDZ-NKT-343; MEN-10930; MEN-11149; s-18523; s-19752; PD-154075 (CAM-4261); SR-140333; LY-303870 (lanepitant); EP-00652218; EP-00585913; l-737488; CGP-49823; WIN-51708; SR-48968 (saredutant); SR-144190; YM-383336; ZD-7944; MEN-10627; GR-159897; RPR-106145; PD-147714 (CAM-2291); ZM-253270; FK-224; MDL-105212A; MDL-105172A; l-743986; an L-743986 analog; s-16474; SR-142801 (osanetant); PD-161182; SB-223412; and SB-222200.

xiii) calcitonin gene-related peptide (CGRP) receptor agonists or antagonists, including, for example, CGRP- (8-37), Onodera S et al, J.Pharmacology, Vol.68(2), pg.161-173(1995) and Daines R.A. et al, Bioorganic Med.Chem., Vol.7 (20), pg.2673-2676 (1997).

xiv) CRF receptor agonists or antagonists, such as those disclosed in WO 99/40089, AXC 2219, Antalarmin, NGD-98-1, CRA 0165, CRA 1000, CRA 1001.

xv) somatostatin receptor agonists such as octreotide, vapreotide, lanreotide.

xvi) anti-inflammatory compounds, especially those of the immunomodulatory type, such as NSAIDS; inhibitors of tumor necrosis factor (TNF, TNF α); basiliximab (e.g., SIMULECT ®); daclizumab (e.g., ZENAPAX ®); infliximab (e.g., REMICADE ®); mycophenolatetofetil (e.g., CELLCEPT ®); azathioprine (e.g., IMURAN ®); tacrolimus (e.g., PROGRAF ®); a steroid compound; and GI anti-inflammatory agents, such as sulfasalazine (e.g., AZULFIDINE ®); olsalazine (e.g., DIPENTUM ®); and aminosalicylic acids (e.g., ASACOL ®, PENTASA ®, ROWASA ®).

xvii) stimulant laxatives, such as bisacodyl sold under the tradenames DULCOLAX ®, FLEET ®, and EVAC-Q-KWIK ®; EX-LAX ®; and senna leaf concentrates sold under the trade names X-PREP ® and senkot ®.

xviii) osmotic purgative, such as lactulose, PEG, sorbitol activated charcoal sold under the trade name ACTIDOSE with sorbitol ®; and phosphate buffered saline.

xix) absorbents and fiber supplements including stool softeners, such as fibers such as bulk fiber laxatives sold under the trade name PERDIEM ® plus natural plant stimulants; and natural therapeutic fibers formed in large numbers, such as METAMUCIL ® and FIBERCON ®.

xx) antacids, such as aluminum and magnesium antacids; and calcium hydroxide such as MAALOX ®.

xxi) GI relaxants, such as cholestyramine resins sold under the trade names LOCHOLEST ® and QUESTRAN ®.

xxii) anti-gassing compounds such as dimethicone sold under the trade names MYLANTA ® and MYLICON ®; and the enzyme preparation comprises PHAZYME^®And BEANO^®。

xxiii) bismuth-containing formulations, such as bismuth subsalicylate, also known as PEPTO-BISMOL ®.

xxiv) pentosans polysulfate, sold under the trade name ELMIRON^®Heparin-like macromolecular carbohydrate derivatives are sold, chemically and structurally similar to glycosaminoglycans.

xxv) hydroxyzine, for example hydroxyzine HCl, sold under the trade name ATARAX ®, 1- (p-chlorobenzhydryl) 4- [2- (2-hydroxyethoxy) -ethyl ] piperazine dihydrochloride.

xxvi) mast cell stabilizers including, for example, ketotifen, sold under the tradename ZADITEN ®.

xxvii) antiemetic dopamine D₂Antagonists, including for example domperidone.

Also included are pharmaceutically acceptable salts, hydrates, polymorphs, tautomers, racemates, diastereomers or enantiomers of all of the above-identified first pharmaceutical agent or co-agent.

Combinations of two or more of the individual active ingredients listed above are also included within the scope of the invention, i.e. a pharmaceutical combination within the scope of the invention may comprise three or more active ingredients. In addition, both the first agent and the coagent are not the same active ingredient.

One of the preferred combinations of the present invention is to include tegaserod (e.g. in the form of the hydrogen maleate salt) formulated into a solid oral pharmaceutical composition such as a tablet as the first medicament. Typical tegaserod tablets contain 20 to 60%, e.g. 30 to 50% by weight of disintegrant based on the total weight of the tablet; for example superdisintegrants such as crospovidone, as described in WO 00/10526. An example is a tablet containing, for example, 8.31mg tegaserod in the form of its hydrogen maleate salt (or 6mg base), 50.00mg polyplasdone XL, 12.50mg glycerol monostearate, 2.50mg poloxamkol, 37.94mg lactose, 6.25mg HPCM, 7.50mg PEG 4000 and 3.00mg adsorbed water.

In another aspect, the present invention provides a pharmaceutical composition comprising a compound as described in 1.1 above; 1.2; 1.3 or 1.4 with a co-agent as active ingredient, or a pharmaceutically acceptable salt, racemate or enantiomer thereof. In a preferred embodiment, the first agent in 1-1 is 5-HT₄Receptor partial agonists, e.g. compounds of formula I with an internal activity < 1.00 as defined above, e.g. wherein R₁Is H, Z is-CH ═ and R₅Is OH or C_1-6Alkoxy compounds of formula I; in a more preferred embodiment the first agent is tegaserod, preferably in the form of the hydrogen maleate salt.

We have surprisingly found that the pharmaceutical combination products and compositions of the present invention provide enhanced therapeutic response to such altered gastrointestinal motility, sensitivity and/or secretion and/or abdominal disorders. For example, the combination of tegaserod and PPI not only provides motility modulating effect in the upper gastrointestinal tract, but also inhibits gastric acid secretion, which is also of great benefit to patients suffering from GERD. Furthermore, we have surprisingly found that the pharmaceutical combination products and compositions of the present invention enhance the relief of gastrointestinal pain and other symptoms commonly associated with disturbed/altered gastrointestinal motility, sensitivity and/or secretion.

The term "pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases, including inorganic acids and bases. Suitable pharmaceutically acceptable acid addition salts of the first pharmaceutical agent of the invention with a co-agent include acetate, benzenesulfonate, benzoate, camphorsulfonate, citrate, ethenesulfonate (ethanesulfonic acid), fumarate, gluconate, glutamate, hydrobromide, hydrochloride, isethionate, lactate, maleate, malate, mandelic acid, methanesulfonate, mucate, nitrate, pamoate, pantothenate, phosphate, succinate, sulfate, tartrate and p-toluenesulfonate, and the like.

To prepare the pharmaceutical compositions of the present invention, the first agent of the present invention and the co-agent, or a pharmaceutically acceptable salt, racemate or enantiomer thereof, are intimately mixed with a pharmaceutically acceptable carrier, by mixing, blending or combining in any manner known to those skilled in the art. Pharmaceutically acceptable carriers can take a wide variety of forms depending on the form of preparation desired for administration.

Any suitable route of administration may be employed for mammals to provide a therapeutically effective amount of the pharmaceutical combinations and compositions of the present invention. For example, oral, rectal, vaginal, topical, parenteral (subcutaneous, intramuscular, intravenous, transdermal) and the like forms of administration may be employed. Dosage formulations include ointments, foams, gels, transdermal patches, tablets (both divisible and non-divisible), caplets, inhalation powders, gelcaps, capsules, elixirs, syrups, chewable tablets, lozenges, troches, dispersions, aerosols, solutions, instant wafers, suppositories or suspensions or other known effective methods of administration.

In addition to the dosage formulations listed above, the pharmaceutical combination products and compositions of the present invention may be administered by controlled release methods and/or delivery methods (such as those described in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123 and 4,008,719) as well as by "fast melt" methods, including delivery methods that dissolve rapidly in the oral cavity. Rapid dissolution is meant to include dissolution occurring in the oral cavity of a patient in less than 3 minutes. Delivery techniques for this type of formulation include, but are not limited to, tablets and capsules. An example of a fast-melt process used in the present invention is described in U.S. Pat. No. 5,178,878, which discloses an effervescent dosage form having microparticles to allow rapid dissolution of a tablet or capsule.

Oral administration is preferred. In the preparation of compositions for oral administration, any of the usual pharmaceutically acceptable carriers may be employed, including any substance, composition or vehicle, such as liquid or solid fillers, diluents, excipients, solvents or encapsulating materials involved in the transport, formulation or transport of a chemical drug. For oral liquid preparations, specific examples are water, glycols, oils and alcohols, and the like. In oral solid forms, solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like may be employed. Oral solid preparations are preferred over oral liquid preparations. Preferred oral solid preparations are capsules and tablets because of their ease of administration.

For parenteral compositions, the carrier will typically comprise sterile water, at least in large part, although other ingredients may also be included to help solve, for example, solubility problems. For example, injectable solutions may be prepared in which the carrier comprises PEG, saline solution, glucose solution or a mixture of saline and glucose solution. Injectable suspensions may also be prepared in which case appropriate liquid carriers and suspending agents and the like may be employed. In compositions suitable for transdermal administration, the carrier may optionally contain penetration enhancers and/or suitable wetting agents, which may optionally be combined in minimal proportions with additives of any nature that do not cause significant deleterious effects on the skin. It is particularly advantageous to formulate the above pharmaceutical compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.

Another embodiment of the present invention provides:

2. a pharmaceutical combination of a first drug with a co-agent or a pharmaceutically acceptable salt, racemate or enantiomer thereof, or a pharmaceutical composition comprising such a combination, as defined above, in the presence of a pharmaceutically acceptable carrier, for use in the treatment of altered gastrointestinal motility, sensitivity and/or secretion and/or abdominal disorders.

3. Use of a pharmaceutical combination of a first agent as defined above and a co-agent or a pharmaceutically acceptable salt, racemate or enantiomer thereof, in the manufacture of a medicament for the treatment of altered gastrointestinal motility, sensitivity and/or secretion and/or abdominal disorders.

4. Use of a first medicament as defined above together with a co-agent or a pharmaceutically acceptable salt, racemate or enantiomer thereof in the manufacture of a pharmaceutical composition for the treatment of altered gastrointestinal motility, sensitivity and/or secretion and/or abdominal disorders.

5. A method of treating a patient suffering from altered gastrointestinal motility, sensitivity and/or secretion and/or abdominal disorders, which comprises administering to said patient a therapeutically effective amount of a pharmaceutical combination of a first agent as defined above and a co-agent or a pharmaceutically acceptable salt, racemate or enantiomer thereof, or a pharmaceutical composition comprising such a combination in the presence of a pharmaceutically acceptable carrier.

The pharmaceutical combination or composition of the invention is typically used to treat altered gastrointestinal motility, sensitivity and/or secretion and/or abdominal disorders, including, but not limited to: heartburn, flatulence, postoperative ileus, abdominal pain and discomfort, early satiety, epigastric pain, nausea, vomiting, flatulence, regurgitation, intestinal pseudo-obstruction, anal incontinence, GERD, IBS, dyspepsia, chronic constipation or diarrhea, gastroparesis (e.g. diabetic gastroparesis), ulcerative colitis, Crohn's disease, ulcers or visceral pain associated therewith. Furthermore, the pharmaceutical combinations and compositions of the present invention may also be used as laxatives, as preparations for colonoscopy patients, or as a means of regulating, stabilizing or normalizing gastrointestinal disorders, for example, by regulating, stabilizing or normalizing gut pheochromocyte function, GI secretion, afferent and efferent fibre activity or abdominal smooth muscle cell activity. The pharmaceutical combinations and compositions of the invention are also suitable for the treatment of menstrual cramps or spastic or interstitial cystitis.

In particular, the first agent mentioned above can be combined according to the invention with the following coagents:

histamine H₂Receptor antagonists, PPIs, antacids, bismuth-containing preparations, GABA_BAgonists or antagonists to treat GERD, dyspepsia, IBS, visceral pain and other abdominal disorders;

anxiolytics, SSRIs, tricyclic inhibitors, somatostatin agonists to treat IBS, dyspepsia, visceral pain, flatulence, anal incontinence and other abdominal disorders;

opioid receptor agonists or antagonists, motilin receptor agonists or antagonists, CRF or CGRP receptor agonists or antagonists, NK or CCK receptor agonists or antagonists, muscarinic M1 receptor agonists or antagonists, spasmolytics, NO synthase inhibitors, for the treatment of IBS, dyspepsia, visceral pain, flatulence, anal incontinence, gastroparesis, chronic constipation, chronic diarrhea, post-operative ileus, and other abdominal disorders;

stimulant laxatives, osmotic laxatives, stool softeners, absorbent or fiber supplements, GI relaxants, anti-gas compounds to treat chronic constipation, chronic diarrhea, flatulence, post-operative ileus, and other abdominal conditions.

The therapeutically effective dose of the pharmaceutical composition of the present invention will vary depending on the severity of the condition to be treated and the route of administration. The dosage or frequency of administration will also vary depending on the age, weight and response of the particular patient. Generally, the combination of the first agent and the co-agent may be formulated in accordance with a ratio of about 0.01 to about 2 of the first agent: in a molar ratio ranging from about 0.01 to 1000 coagent. For example, the molar ratio of first drug to co-agent is about 1: 1000 (first drug: co-agent). As a more specific example, the molar ratio of the first agent to the co-agent may be about 1: 1000, 1: 500, 1: 200, 1: 100, 1: 20, 1: 5, 1: 1, or 1: 0.01. The preferred molar ratio is about 1: 20, even more preferably about 1: 5, and most preferably about 1: 1.

The total daily dose for the conditions described herein, which contains the above molar ratios, ranges from about 0.01mg to about 1000 mg. The daily dose range may be about 800mg, 600mg, 400mg, 200mg, 100mg, 50mg, 20mg, 10mg, 5mg, 1mg, 0.1mg or 0.01 mg. A preferred daily dosage range should be between about 0.5mg to about 100mg, and a most preferred daily dosage range should be between about 5mg to about 75 mg. Preferably Once Daily (OD) or twice daily (BID) administration. In patient management, treatment should be initiated at lower doses, ranging from about 5mg to about 10mg, and increased to about 50mg or higher depending on patient response. It will be apparent to those skilled in the art that dosages outside these ranges may be necessary in some cases. Further, it should be noted that the clinician or treating physician knows how and when to discontinue, adjust or terminate therapy depending on the individual patient's response. The term "therapeutically effective amount" is included in the above molar ratios and dosages and dosing frequency regimen. A "therapeutically effective amount" may be administered by a fixed or non-fixed combination of a first agent (e.g., tegaserod) and a co-agent.

Examples

The invention will be further described by the following examples. The present invention is illustrated by reference to specific embodiments only. While these examples illustrate certain aspects of the invention, they are not intended to limit or delimit the scope of the disclosed invention.

Example 1

Pharmacodynamic effects of tegaserod and coagents on gastrointestinal and colonic motility

Animal preparation: these experiments were performed with beagle dogs. Under halothane anesthesia, four strain gauge sensors were sutured at the sinus serosa 5cm from the pylorus, at the duodenum 10cm from the pylorus, at the jejunum 50cm from the ligament of Terretz, and at the proximal colon 10cm from the ileocolic junction, as described by Pascauld et al (journal of physiology, 1978, 235: E532-E538). Each sensor was sutured with a recording axis parallel to the transverse axis of the intestine to record the force of contraction of the annular muscle layer. The ends of the strain gauge wires were pulled out subcutaneously and exposed between the shoulder blades of the back.

Recording: each strain gauge was calibrated prior to implantation. Mechanical activity is recorded by a sensor. The motility indices of the sinuses, duodenum, jejunum and colon were determined according to the technique of Hachet et al (J.Pharmacology methods (1986) 16: 171-180). The calculated motility index corresponds to the area between the baseline and the contraction curve during the 30 minute interval.

Experiment design: the dogs were grouped. Each group received one of the following protocols: 1) placebo, 2) tegaserod, 3) staccaride, 4) ADL8-2698 (LY246736), 5) fluoxetine, 6) tegaserod + staccaride, 7) tegaserod + ADL8-2698, 8) tegaserod + fluoxetine. Different doses of compound or placebo were administered orally to fasted dogs 30 minutes prior to feeding (free water intake). Different doses of compound or placebo were infused intravenously into fasted dogs 30 minutes prior to feeding (free water intake). Gastrointestinal and colonic motility was recorded starting after feeding and for a total of 6 hours.

And (3) data analysis: the change in motility index over a 6 hour period after eating associated with different compounds/doses at the sinus, duodenum, jejunum and colon levels was determined.

The combination of tegaserod co-active agent significantly improved gastrointestinal and colonic motility compared to placebo and any compound administered alone.

Example 2

Tegaserod and coagent's effects on the sensitivity of the stomach and colon to distension and on the use of barometric pressure to compensate for the effects of distended muscularis intestinalis tone

Stomach sensitivity and tone

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

The animals were placed in a supine position, and after an xypho-ombicial laparotomy, the stomach was equipped with a permanent balloon connected to a tube inserted into the upper part of the rumen (at 1cm from the maximum curvature of the gastro-esophageal junction). After abdominal closure, the rats were placed in a supine position using a mounting system described in ruckbucch and Fioramonti, gastroenterology 68: the technique described in 1500-. The free ends of the electrodes and the catheter of the balloon were externally placed on the back of the neck and protected by a glass tube that was hung on the skin.

Gastric dilatation was performed at constant pressure using an air pressure compensator (Hachet et al, clinical gastroenterology and biology, 1993, 17, 347-. Balloons (5.0-5.5 cm long) were made of a condom without a groove and sutured to polyethylene tubes (1.0 and 1.8mm inner and outer diameter, respectively, 80cm long). The ends of the tube are drilled to facilitate evacuation of the bladder.

10 days after surgery, stock market scans were recorded with a brain electrograph (Reega VIII, Alvar, Paris, France) at a paper speed of 2.4 cm/min. The spike burst (0.03s) was selectively recorded using a short-term amplification constant. The stock market motion scan activity was summed once every 20 seconds by the integrator loop and automatically plotted on the computer.

Under noxious gastric distension, the rat stretches his body and raises his head and/or turns his head side to view his flank. The neck muscles contract and the motor tracing signal is recorded. In addition, a barometric pressure compensator was attached to the potentiometer recorder to continuously record the intra-gastric pressure. The animals were grouped.

After a control recording of 30 minutes, the animals received one of the following protocols: 1) placebo, 2) tegaserod, 3) non-polytozazine, 4) baclofen, 5) octreotide, 6) fluoxetine, 7) tegaserod + non-polytozine, 8) tegaserod + baclofen, 9) tegaserod + octreotide, 10) tegaserod + fluoxetine.

After 30 minutes gastric dilatation started.

Neck musculoskeletal scanning activity (easm) is associated with postural changes and is proportional to pain caused by gastric distension. The integrated values every 20 seconds add up to continuous 10 minute values. For each expansion phase, neck activity is determined using the following formula:

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

The stomach volume was determined on a potentiometer recorder as the maximum volume for each expansion phase. Pain thresholds and stomach volumes are given as mean ± SEM and for unpaired values, compared with Student's "t" test.

The pharmaceutical combination of tegaserod with an active ingredient significantly reduced gastric pain associated with gastric distention and improved gastric tone compared to placebo and any compound administered alone.

2. Colorectal sensitivity and tone

Determining the effect of tegaserod with the co-agent on rectal or colonic tone and pain using a barocompensator dilation method by applying increasing pressure in a stepwise manner over successive periods of 5 minutes; for each pressure, the change in tonicity is evaluated by measuring the volume.

Wistar rats weighing 220-250g were used in isolated pens. Animals were prodromal by Intraperitoneal (IP) injection of 0.5mg/kg of acepromazine and anesthetized by intraperitoneal injection of 100mg/kg of ketamine. The myoscan recordings were performed using the technique described in rugebusch and fire amonti, 1975. A pair of nichrome wire electrodes (60 cm in length and 80 μm in diameter) was implanted in the abdominal striated muscle 2cm outside the white line. The free end of the electrode was externally placed on the back of the neck and protected by a plastic tube that was hung on the skin.

The recording of the myoscan was started 8 days after the operation (time constant: 0.03 sec). Bipolar recordings of myoelectrical activity with a brain electrokinetic scanning recorder were started for one hour before rectal distension for 30 minutes.

To prevent recording of artifacts due to movement during distension, rats were acclimatized to the new environment 3 days prior to distension in polypropylene tubes for distension and EMG recording. A balloon consisting of a condom (4cm) was introduced into the rectum 5cm from the anus and fixed at the root of the tail. The balloon was connected to a barometric pressure compensator and was inflated incrementally with air at pressures of 15, 30, 45 and 60mmHg, each applied for 5 minutes.

Each group of rats was subjected to a barocompensator expansion protocol. Rats were injected Intraperitoneally (IP) with 1) placebo, 2) tegaserod, 3) non-doxazone, 4) baclofen, 5) octreotide, 6) fluoxetine, 7) tegaserod + non-doxazone, 8) tegaserod + baclofen, 9) tegaserod + octreotide, 10) tegaserod + fluoxetine after 10 minutes. Statistical analysis of the number of abdominal peak bursts occurring every 5 minutes was performed by comparison of student "t" test fair pair (fair paired) values after ANOVA by both methods. P < 0.05 was considered statistically significant. Colorectal volumes are given as mean ± SEM and unpaired values are compared using student "t" test.

The pharmaceutical combination of tegaserod co-agent significantly reduces rectal and colonic pain associated with rectal distension and improves colorectal tone compared to an anmural and any compound administered alone.

Example 3

Treatment of non-erosive GERD with the combination of tegaserod co-agent treatment chose heartburn patients for the study, which was the target symptom for non-erosive GERD patients, was primarily upper gastrointestinal symptoms within three months prior to entry into the study, and had a history of heartburn episodes of at least 3 days/week. The study included patients with GERD symptoms without signs of erosive esophagitis endoscopy. Among other factors, the prescribed dose of histamine H was received within one month prior to entry into the baseline phase of the study (14 days)₂-receptor antagonists (H)₂RAs) or PPI, as well as patients who must continue to use PPIs for three months prior to entering the baseline study.

The study consisted of a one week screening period and a 2 week drug-free baseline period, followed by an 8 week double-blind, placebo-controlled treatment period. During the screening period (days-21 to-14), endoscopy was performed to exclude the presence of erosive esophagitis. The patients' GERD symptoms were documented daily in a daily diary during the baseline period (days-14 to 1). At the beginning of this phase, drug treatment of GERD, such as H, is withdrawn₂Ras, PPIs, prokinetic (prokinetic) and other impermissible medications, and patients were instructed not to change their diet and lifestyle during the trial. Patients were allowed to take Maalox tablets as a rescue medication to control their symptoms. Patients who entered the double-blind phase had heartburn episodes on day 3 or more of the last week of the baseline period.

During the double-blind, placebo-controlled phase of the study, patients were randomized into equal groups. The study period lasted 8 weeks with 12 treatment arms. Each group of patients received one of the following regimens: 1) placebo, 2) tegaserod 0.4 mg/day, 3) tegaserod 1 mg/day, 4) tegaserod 4 mg/day, 5) ranitidine 300 mg/day, 6) omeprazole 20 mg/day, 7) tegaserod 0.4 mg/day plus ranitidine 300 mg/day, 8) tegaserod 1 mg/day plus ranitidine 300 mg/day, 9) tegaserod 4 mg/day plus ranitidine 300 mg/day, 10) tegaserod 0.4 mg/day plus omeprazole 20 mg/day, 11) tegaserod 1 mg/day plus omeprazole 20 mg/day and 12) tegaserod 4 mg/day plus omeprazole 20 mg/day, orally twice daily for a total of 8 weeks. Each of these 12 groups was administered within 30 minutes prior to the morning and evening meal. During 8 weeks, patients continued to complete daily diaries and used Maalox tablets only as a rescue medication to control their symptoms.

The combination of 1) tegaserod with omeprazole and 2) tegaserod with ranitidine significantly reduced the weekly-onset heartburn during the 8-week double-blind, placebo-controlled period of the study compared to any single placebo, tegaserod, ranitidine and omeprazole. The Tegaserod combination also reduces other symptoms of GERD, including abdominal pain, flatulence and regurgitation. In addition, the patient had a significant improvement in the quality of life factor compared to any single placebo, tegaserod, ranitidine and omeprazole.

Pharmaceutical combinations of the invention, e.g. comprising 5-HT₄Agonists or partial agonists such as tegaserod, and PPIs such as omeprazole, or histamine H₂Receptor antagonists such as ranitidine, or antacids or GABA_BReceptor agonists or modulators, such as baclofen, may also be tested clinically, for example using Talley NJ et al in International gastroenterology, 1993, 6(4), 189: 211 or Veldhuyzen van Zanten SJO et al in alimentary canal 1999, 45 (supplement. II), 1169: 1177. Oral administration is preferred, and once or twice daily administration is preferred.

Although the present invention has been described in detail with reference to certain preferred versions, other versions are possible without departing from the spirit and scope of the preferred versions of the present invention. All references and patents (U.S. and others) are incorporated herein by reference in their entirety.

Claims (5)

1. A pharmaceutical combination comprising:

a) tegaserod in free or pharmaceutically acceptable salt form, and

b) the omeprazole is used for preparing the omeprazole and the sodium benzoate,

as an active ingredient.

2. A combination according to claim 1 in the form of a pharmaceutical composition.

3. The combination of claim 2, further comprising a pharmaceutically acceptable carrier.

4. A combination product according to claim 2 or 3, wherein the combination product is in an oral dosage form.

5. Use of a pharmaceutical combination comprising:

a) tegaserod in free or pharmaceutically acceptable salt form, and

b) the omeprazole is used for preparing the omeprazole and the sodium benzoate,

as an active ingredient.