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    • 专利摘要:
    The present invention relates to pharmaceutical compositions and formulations comprising mixtures and mixtures of first agents and adjuvant agents comprising a 5-HT 4 receptor agonist or antagonist or a 5-HT 3 receptor antagonist. Pharmaceutical combinations can be used for the treatment of altered gastrointestinal motility, sensitivity, secretion or abdominal disease. Preferably orally administered. Preferred first agent is tegacerod.
    公开号:KR20030016208A
    申请号:KR1020027007332
    申请日:2000-12-08
    公开日:2003-02-26
    发明作者:스티븐 안토니 빌스테인；피터 두모빅；니콜라 프랑코；마크 토마스 이비키；한스-위르겐 판쿠헤；에드워드 죠셉 쥬니어 윌루즈
    申请人:노파르티스 아게；
    IPC主号:
    专利说明:

    Pharmaceutical Combinations and Their Use in Treating Gastrointestinal Disorders}
    [1] The present invention relates to pharmaceutical combinations comprising at least one of the agents which interact with the 5-HT 3 or 5-HT 4 receptors and their use for treating gastrointestinal diseases.
    [2] Serotonin (5-hydroxytryptamine; 5-HT) acts as a neurotransmitter in the mammalian central nervous system (CNS) and in the periphery. Serotonin is one of its recognized physiological significance, and drugs that interact with the 5-HT receptor have recently become the focus of many studies (P. Bonate, et al., Clinical Neuropharmacology, 1991, Vol. 14 (1), pp. 1-16]. The number of serotonin receptor subtypes identified to date includes major classes, namely 5-HT 1 , 5-HT 2 , 5-HT 3 , 5-HT 4 , 5-HT 5 , 5-HT 6 and 5-HT 7 That's about 10. Because of the redundancy of the serotonin receptor subtypes, it is complicated to confirm that the serotonin receptor subtypes are interrelated to several physiological / pharmacological actions.
    [3] Serotonin has been known for many years to modulate peristalsis in the gastrointestinal (GI) tract of various mammalian models. In the mid-1980s, several specific antagonists for the 5-HT 3 receptor subtype have been identified and are currently used as antiemetic agents during cancer treatment. 5-HT 3 antagonists have also recently been studied for the treatment of irritable bowel symptoms (“IBS”).
    [4] Many gastrointestinal symptoms are involved in the production and action of serotonin and are very common among the majority of people worldwide. Some of the better known gastrointestinal conditions, symptoms or diseases are IBS, gastro-esophageal reflux disease ("GERD") and dyspepsia.
    [5] IBS is a chronic condition associated with abdominal pain, dysfunction and altered bowel function, and it is estimated that about 10-20% of the population has this condition. This disease is sometimes referred to as irritable colon, spastic colon, spastic colitis and mucus colitis. The latter two are almost certainly wrong names because colitis means inflammation of the colon and no inflammation is observed when diagnosing IBS. The cause of IBS is unknown, but it is associated with a number of factors, such as diet, lifestyle, depression, anxiety, infection and inflammatory irrelevant conditions, including early seizures leading to central nervous sensitization and neuronal sensitization in the digestive tract.
    [6] Almost all drugs currently used to treat IBS have failed to achieve definite therapeutic effects.
    [7] GERD is a condition associated with the reflux of gastric contents into the esophagus through the lower esophageal sphincter. GERD is characterized by symptoms of heartburn, hypertension, abdominal pain, epigastric pain, premature satiety, nausea, reflux, burbulence and vomiting. Reflux is thought to be caused by gastric contents entering the esophagus due to an increased incidence of transient relaxation of the lower esophageal sphincter.
    [8] Indigestion is also an important health problem. The most common conditions associated with patients giving chronic symptoms of dyspepsia are GERD, duodenal ulcers or gastric ulcers and other causes (eg functional / non-ulcer dyspepsia, gallbladder or liver disease).
    [9] These conditions or diseases are characterized by altered motility, responsiveness, secretion and / or Helicobacter pylori infection and potential mental (usually conscious) additions. In the treatment of various adverse effects in humans, for example functional dyspepsia, only a few drugs have now been demonstrated to have clinically definite efficacy.
    [10] Therefore, there is a need for a medicinal agent that modulates and normalizes altered GI motility, sensitivity and secretion, interacts with 5-HT receptors involved in various physiological processes, and has extensive clinical utility for the treatment of multiple gastrointestinal disorders, which affect millions of people each year. It is becoming. More specifically, 5-HT 4 receptor agonists or antagonists, 5-HT 4 receptor partial agonists or 5 effective for the treatment of altered gastrointestinal motility, sensitivity and / or secretion and / or abdominal disease, including both functional and long term diseases. There is a need for pharmaceutical combinations comprising -HT 3 receptor antagonists and adjuvant agents.
    [11] Now in the present invention, a mixture comprising, for example, at least one agent which interacts with a 5-HT 3 or 5-HT 4 receptor as described below and an auxiliary agent as described below, for example, has a beneficial effect. And have been found useful in the treatment of altered gastrointestinal motility, sensitivity and / or secretion and / or abdominal disease. The mixture can also be used to modulate, stabilize and normalize altered gastrointestinal motility, sensitivity and / or secretion and / or abdominal disease.
    [12] Justice
    [13] Unless otherwise noted, the terms and terms used herein are commonly defined. For example, the term "pharmaceutical combination" as used herein is a product made by mixing or combining one or more active ingredients and includes both fixed and unfixed mixtures of the active ingredients.
    [14] As used herein, the term "fixed mixture" means that both the active ingredient, eg, tegaserod and adjuvant agents, are administered to the patient simultaneously in the form of a single unit or dosage. For example, the fixative mixture will be one capsule containing two active ingredients.
    [15] As used herein, the term "unfixed mixture" means that both the active ingredient, eg, tegaserod and adjuvant agents, are administered to the patient simultaneously, together or in sequence without specific time limits, as separate units, wherein The administration provides a therapeutically effective amount of the two compounds in the body, preferably simultaneously. As one example, the unfixed mixture would be two capsules each containing one active ingredient, with the purpose of allowing treatment by both active ingredients to be achieved in the body of the patient.
    [16] As used herein, the term “modified gastrointestinal motility, irritability and / or secretory disease (s)” includes one or more symptoms and conditions that affect the gastrointestinal tract from the mouth to the anus, including heartburn, dysfunction, Postoperative intestinal obstruction, abdominal pain and discomfort, early satiety, epigastric pain, nausea, vomiting, bourbon, reflux, intestinal gastric obstruction, anal incontinence, GERD, IBS, dyspepsia, chronic constipation or diarrhea, mild stomach Diabetic mild gastrotoni, ulcerative colitis, Crohn's disease, ulcers and associated visceral pain, but are not limited to this.
    [17] As used herein, the term “abdominal disease (s)” includes conditions affecting the lower abdomen and includes enterochrome affinity cellular function, GI secretion, motility, afferent and centrifugal fibrous activity, and / or abdominal smooth muscle cells. Conditions include, but are not limited to, conditions treated by modulation, stabilization and normalization of activity.
    [18] 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 the stomach contents into the esophagus. This includes, but is not limited to, GERD in all forms / expression, erosive and non-erosive GERD, heartburn and other symptoms associated with GERD.
    [19] As used herein, the terms “irritable bowel symptoms” and “IBS” refer to dysfunction, including altered motility, responsiveness and secretion of the small and large intestine, mainly associated with varying degrees of abdominal pain, hyperplasia, constipation or diarrhea without apparent bowel inflammation. Means.
    [20] As used herein, the term “digestive disorder” refers to upper abdominal pain as a complication, including, but not limited to, primary gastrointestinal dysfunction or diseases such as ulcer disease, appendicitis, gallbladder disorder or malnutrition, Refers to a condition characterized by abdominal pain, failure, early satiety, nausea, heartburn and vomiting.
    [21] As used herein, the term "mild gastrotoni" refers to gastric paralysis caused by motor muscle abnormalities in the stomach, often manifested by delayed gastric emptying. It may also be a complication of a disease such as diabetes, progressive systemic sclerosis, anorexia nervosa or myotonic dystrophy.
    [22] As used herein, the term "constipation" refers to a condition characterized by the discharge of rare and / or difficult feces caused by conditions such as altered GI motility, altered sensory or ventilatory function, altered secretion or resorption of electrolytes and water. do.
    [23] As used herein, the term "diarrhea" refers to a condition characterized by frequent discharge of feces of frequent and emergency due to conditions such as altered GI motility, altered sensation and secretion or reabsorption of electrolytes and water.
    [24] The term “treat” or “treatment” encompasses all ranges of therapeutically beneficial effects associated with pharmaceutical drugs, including alleviation, alleviation, and alleviation of symptoms or diseases affecting the organism.
    [25] More specifically, the present invention is:
    [26] 1.1 a) a first agent that is a 5-HT 4 receptor partial agonist; And
    [27] b) providing a pharmaceutical combination comprising an adjuvant agent.
    [28] The 5-HT 4 receptor partial agonist as the first agent in mixture 1.1 includes any compound capable of partially activating the 5-HT 4 receptor (intrinsic activity lower than that of serotonin, ie <1.00. Non-electrical or electrical stimulation guinea pig ileum or striatum analysis or as described in, for example, EP-A1-0 505 322, Br. J. Pharmacol., 115, 1387, 1995. J. Pharm., 1593-1599, 1993, which may be measured by the guinea pig terminal colon test disclosed in the literature).
    [29] In another embodiment of the invention, the invention is:
    [30] 1.2 a) A compound of formula (I) which is in free or salt form, preferably in the form of a pharmaceutically acceptable salt and wherein R 5 is hydroxy, a physiologically hydrolyzable and acceptable ether or ester thereof 1 pharmaceutical and
    [31] b) providing a pharmaceutical combination comprising an adjuvant agent.
    [32]
    [33] In the above formula,
    [34] R 1 is hydrogen; C 1-6 alkyl; (C 1-6 alkyl) carbonyl; Benzoyl; Or phenylC 1-4 alkyl-carbonyl;
    [35] R 5 is hydrogen; halogen; C 1-6 alkyl; Hydroxy; Nitro; Amino; C 1-6 alkylamino; C 1-10 alkyl-carbonylamino; C 2-6 alkoxycarbonyl; SO 2 NR a R b , wherein each R a and R b are independently hydrogen or C 1-6 alkyl; Cyano; Or trimethylsilyl; -SO 2 -C 1-6 alkyl, -SO 2 NR a R b , -CONR a R b , -NH-SO 2 -C 1-6 alkyl, -N (C 1-6 alkyl) -SO 2- ( C 1-6 alkyl), -NR a R b ', wherein R b ' is hydrogen or C 1-6 alkyl, C 2-6 alkoxycarbonyl or -PO (C 1-4 alkyl) 2 C 1-6 alkyl substituted by; Carboxy; CONR a R b ; -PO (Ci_ 6 alkyl) 2 ; OCONR c R d , wherein each R c and R d are independently C 1-6 alkyl;
    [36] R 6 is hydrogen or when R 5 is OH, R 6 is hydrogen or halogen,
    [37] Z is -CR 4 = (wherein R 4 is hydrogen, halogen, hydroxy or C 1-6 alkyl) or when R 5 is hydrogen or hydroxy, Z is also -N =,
    [38] R 7 is hydrogen, halogen, C 1-6 alkyl or C 1-6 alkoxy,
    [39] XY is -CR 8 = N- or -CH (R 8 ) -NH-, wherein R 8 is hydrogen or C 1-6 alkyl,
    [40] B is a radical of the formula (a) or (b).
    [41]
    [42]
    [43] In the above formulas,
    [44] n is 1 or 2,
    [45] A 1 is C═O or CH 2 ,
    [46] X 1 is S; NR 11 , wherein R 11 is hydrogen, (C 1-6 alkyl) carbonyl, benzoyl or phenylC 1-4 alkyl-carbonyl; Or CR 12 R 13 , wherein each R 12 and R 13 is independently hydrogen or C 1-4 alkyl;
    [47] R 10 is hydrogen; C 1-12 alkyl; C 1-6 alkyl substituted by hydroxy, aryl, aryloxy, adamantyl, heterocyclic radical, -NR 15 -CO-R 16 or-NH-SO 2 -aryl; C 5-7 cycloalkyl; Adamantyl; (C 1-10 alkyl) carbonyl; Benzoyl; Phenyl (C 1-4 alkyl) carbonyl; Or -CONHR 14 , wherein R 14 is C 1-10 alkyl or C 5-7 cycloalkyl, R 15 is hydrogen or C 1-4 alkyl, R 16 is C 1-6 alkyl, C 5- 7 cycloalkyl, C 5-7 cycloalkyl-C 1-4 alkyl, aryl or arylC 1-4 alkyl,
    [48] Whether aryl is itself or "aryl" in "aryloxy", "-NH-SO 2 -aryl" or "aryl (C 1-4 alkyl)" above, it is phenyl; Or phenyl substituted by halogen, C 1-4 alkyl or C 1-6 alkoxy,
    [49] When a "heterocyclic radical" is described in the above definition, it is pyridyl, imidazolyl, benzimidazolyl, pyrrolidinyl, pyrrolidoneyl, piperidino, pyrazinyl, perhydroindolyl or A radical of formula (c), (d) or (e),
    [50]
    [51]
    [52]
    [53] (In the above formula,
    [54] R 22 is hydrogen or C 1-4 alkyl,
    [55] B 1 is -CH 2 CH 2- , -COCH 2 -or-(CH 2 ) 3- , wherein one or two H thereof is substituted by C 1-4 alkyl or 1,2-phenylene Can be,
    [56] E is -CH 2 CH 2- , -CH 2 N (R 17 )-or-(CH 2 ) 3- , wherein one or two H thereof is C 1-6 alkyl or 1,2-phenyl May be substituted by lene,
    [57] E 1 is CO or CH 2 ,
    [58] R 17 is hydrogen or C 1-4 alkyl,
    [59] G is CO, -CHCOOR 18 , -CHCOR 19 , 5,5-dimethyl-1,3-dioxane-2-ylidene or 1,3-dioxolan-2-ylidene, wherein R 18 is hydrogen Or C 1-6 alkyl and R 19 is C 1-6 alkyl,
    [60] n 'is 0 or 1)
    [61] X 2 is —SR 20 or —NR 3 R 10 ′, wherein R 20 is C 1-6 alkyl, R 3 is hydrogen or C 1-6 alkyl and R ′ 10 is defined in R 10 above One of them, or R 3 and R ′ 10 together with the nitrogen atom to which they are attached form a heterocyclic radical as described above;
    [62] Provided that when B is a radical of formula (b), only one of R 10 and R 10 ′ may not be hydrogen and X 2 may be —SR 20 only when R 10 is hydrogen.
    [63] Compounds of formula (I) and their physiologically hydrolyzable and acceptable ethers or esters are disclosed, for example, in EP-A1-0 505 322. Suitable pharmaceutically acceptable salts are, for example, salts obtained with inorganic or organic acids, for example pharmaceutically acceptable acid addition salts such as hydrochloride, sulfate, acetate, oxalate, malate and fumarate salts. to be.
    [64] When R 5 is hydroxy, the term “physiologically hydrolyzable and acceptable ether or ester” applied to a compound of formula (I) means that R 5 is (eg by optionally substituted C 1-6 alkyl) ether By esterified ether and R 5 is esterified ester, which is hydrolyzed under physiological conditions to produce an alcohol or acid which is physiologically acceptable, ie nontoxic at the desired dosage level. Specific examples are described in EP-A1-0 505 322.
    [65] Representative 5-HT 4 receptor partial agonists include, but are not limited to, compounds of formula (I) having intrinsic activity lower than the intrinsic activity of serotonin. Preferred compounds of formula (I) as 5-HT 4 receptor partial agonists are, for example, R 1 is H, Z is -CH = and R 5 is OH or C 1-6 alkoxy.
    [66] Other examples for 5-HT 4 receptor partial agonists are described, for example, in 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- Propaneone).
    [67] Preference is given to compounds of the formula (I) above. Particularly preferred compounds of formula (I) are compounds of the formula which are in free form or in pharmaceutically acceptable salt form.
    [68]
    [69] This compound has the chemical name 3- (5-methoxy-1H-indol-3-yl-methylene) -N-pentylcarbazimidamide and is also known as tegacerod. It is disclosed as a 5-HT 4 receptor partial agonist. It may also exist in the form of the following tautomers and is included in the present invention. Preferred salt form is hydrogen maleate.
    [70]
    [71] Adjuvants in the mixture 1.1 or 1.2 are selected from the group of compounds: the properties of the 5-HT 3 receptor antagonist, the 5-HT 4 receptor antagonist or antagonist, the 5-HT 3 receptor antagonist and the 5-HT 4 receptor antagonist or antagonist PPI, including an irreversible, reversible drug and prodrug of a compound that represents, a somatostatin receptor agonist, a histamine H 2 receptor antagonist, a proton pump inhibitor (“PPI”), anxiolytics, such as chlorodiazepoxide, benzodiazepine compound, anti Convulsive / anti-muscarinic agents, selective serotonin reuptake inhibitors (“SSRIs”), tricyclic antidepressants, selegelin, muscarinic 1 (“M 1 ”) receptor agonists or antagonists, cholecystokinin (“CCK”) receptor antagonists, opioid receptors Agonists or antagonists, motilin receptor agonists or antagonists, nitric oxide synthase inhibitors, GABA B receptor agonists or modulators, neurokinin (“NK”) Receptor agonists or antagonists, calcitonin gene related peptide receptors ("CGRP") or corticotropin secretion factor ("CRF") receptor agonists or antagonists, anti-inflammatory compounds, stimulating laxatives, osmotic diarrhea, stool softeners, absorbents and fiber supplements , Antacids, GI relaxants, diphenoxylates, antigas compounds, bismuth-comprising preparations, pentosan polysulfates, hydroxyzin, mammary cell stabilizers, and antipothodopamine D 2 antagonists.
    [72] In an alternative embodiment, the present invention also provides:
    [73] 1.3. a) a first agent selected from the group consisting of 5-HT 4 receptor agonists or antagonists and 5-HT 3 receptor antagonists; And
    [74] b) somatostatin receptor agonists, anxiolytics such as chlordiazepoxide, benzodiazepine compounds, anticonvulsant / antimuscarinic agents, tricyclic antidepressants, selegelin, M 1 receptor agonists or antagonists, CCK receptor antagonists, opioid receptor agonists Or antagonists, motilin receptor agonists or antagonists, nitric oxide synthase inhibitors, GABA B receptor agonists or modulators, NK receptor agonists or antagonists, CGRP or CRF receptor agonists or antagonists, anti-inflammatory compounds, stimulating diarrhea, osmotic diarrhea, Adjuvant agents selected from the group consisting of stool softeners, absorbents and fiber supplements, antacids, GI relaxants, diphenoxylates, antigas compounds, bismuth containing preparations, pentosan polysulfates, hydroxyzin and mammary cell stabilizers; , provided a medicament a) is when the 5-HT 3 receptor antagonist, an auxiliary agent b) is anticonvulsant / anti Karin's agent, provides a M 1 receptor antagonists, opioid receptor agonists or antagonists, NK receptor antagonists, laxatives stimulation, the osmotic laxative or an anti-inflammatory pharmaceutical combination is other than a corticosteroid.
    [75] In another embodiment, the present invention also provides:
    [76] 1.4. a) a first agent that is a 5-HT 4 receptor antagonist; And
    [77] b) a pharmaceutical composition comprising an adjuvant agent selected from the group consisting of somatostatin receptor agonists, histamine H 2 receptor antagonists, PPI, metoclopramide, and anti-dopamine D 2 antagonists.
    [78] 5-HT 4 receptor agonists as adjuvant agents in mixtures 1.1 or 1.2 or as first agents in mixture 1.3 include any compound capable of activating the 5-HT 4 receptor under stationary / dwelling conditions. These compounds are compounds of the formula (I) disclosed in EP-B1-0 505 322, cisaprides, nor-cisaprids, lenzafrieds, jacobrides, mosafrieds, frucalofrieds, SB 205149, SC 53116, RS 67333 , RS 67506, BIMU-1, BIMU-8 and (S) -RS 56532, but are not limited thereto. Cisaprid, cis-4-amino-5-chloro-N- [1- [3- (4-fluorophenoxy) propyl] -3-methoxy-4-piperidinyl] -2-methoxy- Benzamide is used as a gastric prokinetic agent (A. Reyntjens et al., Drug Div. Res., 8, 251 (1986)) and Curr. Ther. Res., 36, 1029-1070 (1984). This compound is marketed worldwide under trade names such as ACENALIN®, PREPULSID®, RISAMOL®, PULSAR® and PROPULSIN®.
    [79] Preferred groups of 5-HT 4 receptor agonists or partial agonists are those that are selective; Selectivity herein means compounds that do not substantially bind or stimulate 5-HT 3 receptor subtypes. For example, tegaserod does not bind to or stimulate 5-HT 3 receptor subtypes.
    [80] 5-HT 4 antagonists for use as auxiliary agents in mixtures 1.1 or 1.2 or as first agents in mixtures 1.3 or 1.4 are defined by IUPHAR (Pharmacological Reviews, Vol. 44, p. 157-213, 1994). bonded to the 5-HT 4 receptors as described and includes any of the compounds to antagonize the effects of serotonin without activating the 5-HT 4 receptor. 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 terminal colon test or Arch. Pharmacol., Vol. 343, p. 439-446 (1991). Representative 5-HT 4 receptor antagonists include, for example, picoserods; A-85830 (Abbot Laboratories) (WO 94/08994); SB204070 (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 205800 (Drug Data Report, 15 (10): 949, 1993); SB 203 186 (Br. J. Pharmacol., 110: 1023-1030, 1993); N 3389 (Nishin 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 (Scher / Monsanto) (J. Pharmacol. Exp. Ther. 226: 1339, 1993); DAU 6285 (Boerhinger Ingelheim) (Br. J. Pharmacol., 105: 973, 1992); GR 125487 (Glaxo) (Br. J. Pharmacol., 113 suppl. 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 (Eli Lilly Co., Ltd.) (J. Pharmacol. Exp. Ther., 277 (1), 97-104, 1996); And R59595 (Eur. J. Pharmacol., 212, 51-59, 1992).
    [81] The mixture 5-HT as a first agent in or mixture 1.3 as a secondary drug in the 1.1 or 1.2 3 receptor antagonists are 5-HT 3 compounds that bind to the receptor and antagonize the effects of 5-HT 3 receptor agonist, for example, the EP 29761 Silanesetrons described in US Pat. Allosetron described in WO 99/17755; Lamosetron; Azasetron; Ondansetron; Dolacetron; Lamosetron; Granistron; And trophysetron.
    [82] Compounds that characterize the 5-HT 3 receptor antagonist and 5-HT 4 receptor agonist or antagonist for use as an adjuvant in a mixture 1.1 or 1.2 or as a first agent in a mixture 1.3 are for example cisaprid and nor- Cisapride; BIMU compounds, such as Dumuis A. et al., Naunyn Schmiedeber's Arch. Pharmacol., Vol. 343 (3), pp. 245-251 (1991), BIMU1, BIMU8, and DAU 6215 (also known as itacetron); Ricci, mr. Rizza, CA et al., J. Pharmacol. Exp. Ther., Vol. 261, pp. 412-419 (1992); and DAU-6236; and DAU-6258, Turconi M. et al. Med. Chem., Vol. 33 (8), pg. 2101-2108 (1990); SDZ 205-557, Eglen Egg, a benzoic acid derivative (ester). Eglen RM et al., Proc. Br. Pharmacol. Soc., Vol. 149 (1992); Lenzaprid; Jacobride; SB 205149; SC 53116; RS 67333; RS 67506; Or (S) -RS 56532, lintofried.
    [83] Further examples of adjuvant agents that may be combined with the first agent according to the present invention include, but are not limited to:
    [84] i) compounds that inhibit the action of histamine at the histamine H 2 receptor on gastric cells, such as pamotidine, sold under the trademark PEPCID®; Cimetitin sold under the trade name TAGAMET®; Ranitidine sold under the trade name ZANTAC®; And histamine H 2 receptor antagonists, including nizatidine sold under the trade name AXID®.
    [85] ii) compounds which inhibit gastric acid secretion by inhibition of the H + / K + ATPase enzyme system of gastric outer wall cells, such as omeprazole sold under the trademarks PRILOSEC® and LOSEC®; Lansoprazole sold under the trade name PREVACID®; Rabeprazole sold under the trade names PARIET (R) and ACIPHEX (R); Pantroprazole sold under the trade name PROTIUM®; And an irreversible proton pump inhibitor (PPI) comprising esomeprazole sold under the trademark NEXIUM®. Reversible PPIs are described, for example, in BY 841, SKF 97574, SKF 96067, H 40502 and YH1238 and in WO 98/43968, YH1885, Kim et al., Korean Journal of Physiology and Pharmacology, 1997 , Vol 1 (3), pp. 337-343].
    [86] iii) Benzodiazepines compounds and analogs that act to inhibit seizures by interacting with γ-aminobutyric acid (GABA) receptors of type A (GABA A ), such as DIASTAT® and VALIUM® ); LIBRIUM®; And ZANAX®.
    [87] iv) anticonvulsant / antimuscarinic agents, for example dicyclomine sold under the trademark BENTYL®; Hydroxysamine, sold under the tradename LEVSIN®; And Darfenacin, (S) -1- [2- (2,3-dihydro-5-benzofuranyl) ethyl] -α, described in US Pat. No. 5,837,724 and a selective muscarinic M 3 receptor antagonist α-diphenyl-3-pyrrolidineacetamide.
    [88] v) SSRIs such as fluvoxamine; Fluoxetine; Paroxetine; Sertraline; Citalopram; Venlafaxine; Cericamine; Duloxetine; Milnacipran; Nefazodone; And cyanodotiepine (see The Year Drugs News, 1995 Edition, pp. 47-48 by Prous J. R.).
    [89] vi) tricyclic antidepressants such as amitriptyline sold under the trademarks ELAVIL®, ETRAFON®, LIMBITROL® and TRIAVIL®; Bupropion; And Cinequan.
    [90] vii) Selegelin, for example sold under the trade names ELDEPRYL®, ATAPRYL® and DEPRENYL®.
    [91] viii) CCK receptor antagonists such as devazefeed; Lorglumid; Dexyloxyglumid; Roxyglumid, damato, D'Amato, M. et al., Br. J. Pharmacol. Vol. 102 (2), pp. 391-395 (1991); CI 988; L 364,718; L363,260; L740,093 and LY288,513; CCK receptor antagonists, Bruley-Des-Varannes, S, et al., Described in US Pat. No. 5,220,017, Gastroenterol. Clin. Biol. Vol. 15: (10), pp. 744-757 (1991) and Worker C: EUPHAR'99-Second European Congress of Pharmacology (Part IV) Budapest Hungary Hungary 3-7 July 1999.
    [92] ix) Opioid receptor agonists or antagonists include, for example, ADL8-2698, Fedotozin, Dextromethorphan, Loperamide (e.g. IMODIUM®), Diphenoxylate (e.g. LOMOTIL ( Trademarks)), belladonna alkaloids, endorphins / enkephalin analogs.
    [93] x) motilin receptor agonists or antagonists, for example motiline agonists ABT-269, (erythromycin, 8,9-didehydro-N-dimethyl-9-deoxo-4 ", 6,12-trideoxy- 6,9-epoxy-N-ethyl), de (N-methyl-N-ethyl-8,9-anhydroerythromycin A) and de (N-methyl) -N-isoprop-8,9-anhydro Erythromycin A), Sunazika T. et al., Chem. Pharm. Bull., Vol. 37 (10), pp. 2687-2700 (1989); A-173508 (Abbott Labo) Latoriz); motilin antagonist (Phe3, Leu13) forcin motilin, 214 th American Chemical Society (ACS) Meeting (Part V); Highlights from Medicinal ChemistryPoster Session, Wednesday, September 10, Las Vegas, NV, ( 1997), Iddb Meeting Report Sept. 7-11 (1997); and ANQ-11125, Peters TL, et al., Biochem. Biophys. Res. Commun., Vol. 198 (2) , pp. 411-416 (1994).
    [94] xi) GABA B receptor agonists or modulators, for example ( + )-baclopene, S (−)-baclopene, R (+)-baclopene, CGP44532, CGP47656, CGP7930, SK & F97541.
    [95] xii) NK receptor antagonists such as FK888 (Fujisawa); GR 205171 (Glaxo Wellcome); LY303870 (Lily); MK 869 (Merck); GR82334 (Glaxo Welcome); L758298 (Merck); L733060 (Merck); L741671 (Merck); L742694 (Merck); PD 154075 (Parke-Davis); S18523 (Sevier); S19752 (Servier); OT 7100 (Otsuka); WIN51708 (Sterling Winthrop); NKP-608A; TKA457; DNK333; CP-96345; CP-99994; CP122721; 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 (Ranepitant); EP-00652218; EP-00585913; L-737488; CGP-49823; WIN-51708; SR-48968 (sareditant); SR-144190; YM-383336; ZD-7944; MEN-10627; GR-159897; RPR-106145; PD-144714 (CAM-2291); ZM-253270; FK-224; MDL-105212A; MDL-105172A; L-743986; L-743986 analogs; S-16474; SR-142801 (osanetant); PD-161182; SB-223412; And SB-222200.
    [96] xiii) calcitonin gene related peptide (CGRP) receptor agonists or antagonists such as CGRP- (8-37), Onodera S et al., Jpn. J. Pharmacol., Vol. 68 (2), pg. 161-173 (1995) and Daines R. A. et al. Bioorganic Med. Chem. Lett., Vol. 7 (20), pg. 2673-2676 (1997).
    [97] xiv) CRF receptor agonists or antagonists, for example AXC 2219, antalamine, NGD-98-1, CRA 0165, CRA 1000, CRA 1001, as disclosed in WO 99/40089.
    [98] xv) somatostatin receptor agonists such as occreotide, vapreotide, lanreotide.
    [99] xvi) anti-inflammatory compounds, especially those of the immune modulation type, for example NSAIDS; Tumor necrosis factor (TNF, TNFα) inhibitors; Basiliximab (eg, SIMULECT®); Daclizumab (eg, ZENEPAX®); Infliximab (eg, REMICADE®); Mycophenolate mofetil (eg, CELLCEPT®); Azathioprine (eg, IMURAN®); Tacrolimus (eg, PROGRAF®); steroid; And GI anti-inflammatory agents such as sulfasalazine (eg, AZULFIDINE®); Olsalazine (eg, DIPENTUM®); And mesalamine (eg, ASACOL®, PENTASA®, ROWASA®).
    [100] xvii) irritant diarrhea, for example bisacryl sold under the trademarks DULCOLAX®, FLEET® and EVAC-Q-KWIC®; EX-LAX®; And Senna concentrates sold under the trade names X-PREP® and SENEKOT®.
    [101] xviii) activated carbon with osmotic laxatives such as lactulose, PEG, sorbitol commercially available as ACTIDOSE with SORBITOL®; Phosphate buffered saline.
    [102] xix) absorbents and fiber supplements, including stool softeners, such as fiber, such as bulk fiber laxatives sold under the tradename PERDIEM® and natural vegetable irritants; And bulk forming natural therapeutic fibers, such as METAMUCIL® and FIBERCON®.
    [103] xx) antacids such as aluminum and magnesium antacids; And calcium hydroxides such as MAALOX®.
    [104] xxi) GI relaxants such as cholestyramine resin sold under the trademarks LOCHOLEST® and QUESTRAN®.
    [105] xxii) antigas compounds such as simethicone sold under the trademarks MYLANTA® and MYLICON®; And an enzyme preparation comprising PHAZYME® and BEANO®.
    [106] xxiii) Bismuth containing preparations, for example bismuth subsalicylate, also known as PEPTO-BISMOL®.
    [107] xxiv) Pentosan polysulfate, heparin-like macromolecular carbohydrate derivatives chemically and structurally similar to glycosaminoglycans sold under the trade name ELMIRON®.
    [108] xxv) hydroxyzine, for example hydroxyzine HCl, marketed under the trade name ATRAX®, 1- (p-chlorobenzhydryl) 4- [2- (2-hydroxyethoxy) -ethyl] pipe Lysine dihydrochloride.
    [109] xxvi) mammary cell stabilizers, eg ketotifen, sold under the trade name ZADITEN®.
    [110] xxvii) Antifreeze dopamine D 2 antagonists such as domperidone.
    [111] Also included are pharmaceutically acceptable salts, hydrates, polymorphs, tautomers, racemates, diastereomers or enantiomers of the first agent or auxiliary agent.
    [112] Mixtures of two or more separate active ingredients as described above are also within the scope of the invention, ie pharmaceutical combinations within the scope of the invention may comprise three or more active ingredients. In addition, the first agent and the auxiliary agent are not the same active ingredient.
    [113] Preferred mixtures of the present invention are those which comprise tegacerod in the form of, for example, hydrogen maleate, formulated as a solid oral pharmaceutical composition, eg a tablet, as the first agent. Representative tegaserod tablets include 20 to 60%, such as 30 to 50% by weight of disintegrant, based on the total weight of the tablet, as disclosed in WO 00/10526; Super-disintegrants such as, for example, crospovidone. 8.31 mg tetacerod (or 6 mg base) in hydrogen-maleate form, 50.00 mg polyplastone XL, 12.50 mg glyceryl monostearate, 2.50 mg poloxalchol, 37.94 mg lactose, 6.25 mg HPCM One example would be a tablet comprising 7.50 mg PEG 4000 and 3.00 mg absorbed water.
    [114] According to another aspect of the invention 1.1; 1.2; As defined above in 1.3 or 1.4, the active ingredient comprises a first agent and an adjuvant, or a pharmaceutically acceptable salt, racemate or enantiomer thereof, and a pharmaceutically acceptable carrier is present, optionally Pharmaceutical compositions comprising other therapeutic ingredients are provided. In a preferred embodiment, the first agent according to 1.1 is a 5-HT 4 receptor partial agonist, for example a compound of formula I as described above having intrinsic activity <1.00, for example R 1 is H and Z is -CH = and R 5 is a compound of Formula I wherein OH or C 1-6 alkoxy; In an even more preferred embodiment, the first agent is tegacerod, preferably in the form of a hydrogen maleate salt.
    [115] The pharmaceutical combinations and compositions of the present invention have surprisingly been found to provide improved treatment of the altered gastrointestinal motility, sensitivity and / or secretion and / or response to abdominal disease as mentioned herein. For example, a mixture of tegaserod and PPI not only regulates motility in the upper GI tract but also inhibits gastric acid secretion, which is very beneficial for patients suffering from GERD. In addition, the pharmaceutical combinations and compositions of the present invention have been found to surprisingly provide improved relief of gastrointestinal pain and gastrointestinal pain and other symptoms commonly associated with disrupted / modified gastrointestinal motility, sensitivity and / or secretion.
    [116] The term “pharmaceutically acceptable salts” or “pharmaceutically acceptable salts thereof” refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases, including inorganic acids and bases. Pharmaceutically acceptable acid addition salts for the first and adjuvant agents of the invention include acetates, benzenesulfonates (vesylates), benzoates, camphorsulfonates, citrates, ethenesulfonates, fumarates, Gluconate, Glutamate, Hydrobromite, Hydrochloride, Isethionate, Lactate, Maleate, Malate, Mandelate, Methanesulfonate, Muxate, Nitrate, Palmate, Pantothenate, Phosphate, Succinate, Sulfate, Tartarate, p-toluenesulfonate, and the like.
    [117] To prepare a pharmaceutical composition of the present invention, the first agent and the adjuvant or pharmaceutically acceptable salts, racemates or enantiomers thereof are pharmaceutically acceptable by any method known to those skilled in the art. Mix, blend or combine with the carrier to combine into an intimate mixture. Pharmaceutically acceptable carriers will take a wide variety of forms depending on the dosage form desired.
    [118] Any suitable route of administration will be used to provide the mammal with a therapeutically effective amount of the pharmaceutical combinations and compositions of the invention. For example, dosage forms of oral, rectal, vaginal, topical, parenteral (subcutaneous, intramuscular, intravenous, transdermal) and the like will be used. Dosage formulations may include ointments, foams, gels, transdermal patches, tablets (cleavable and non-cleavable), caplets, inhalable powders, gelcaps, capsules, elixirs, syrups, chewable tablets, lozenges, prescribed agents, dispersions, aerosols, solutions , Fast dissolving wafers, suppositories or suspensions or other known and effective delivery methods.
    [119] In addition to the above dosage formulations, the pharmaceutical combinations and compositions of the present invention are described in US Pat. 3,916,899; 3,563,809; 3,563,809; 3,598,123; 3,598,123; And sustained-release means and / or delivery devices as described in US Pat. No. 4,008,719 and by "quick-dissolving" means including delivery devices that dissolve rapidly in the mouth. Rapid dissolution includes dissolution in the patient's mouth within 3 minutes. Delivery devices for this type of formulation include, but are not limited to, tablets and capsules. One example of a quick-dissolving means used herein is described in US Pat. No. 5,178,878, which discloses a bubbling dosage form of microparticles for rapid dissolution of a tablet or capsule.
    [120] Oral administration is preferred. When preparing a composition in oral dosage form, any conventional materials, compositions or excipients, such as liquid or solid fillers, diluents, excipients, solvents or encapsulating materials, which are involved in transporting, formulating or transporting a chemical agent, Phosphorus pharmaceutical carriers can be used. Specific examples are water, glycols, oils, alcohols and the like in the case of oral liquid formulations. In oral solid forms, solid carriers such as starch, sugars, kaolin, lubricants, binders, disintegrants and the like can be used. Oral solid formulations are preferred over oral liquid formulations. Preferred oral dosage formulations are capsules and tablets due to their ease of administration.
    [121] In parenteral compositions, the carrier may typically comprise mostly sterile water, although other components may be included to aid solubility, for example. Injectable solutions can be prepared, for example, in which the carrier comprises PEG, saline solution, glucose solution or a mixture of saline and glucose solution. Injection suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. In a composition suitable for transdermal administration, the carrier optionally comprises a penetration enhancer and / or an appropriate wetting agent, optionally combined with a suitable minor amount of any additive that does not cause significant adverse effects on the skin. It is particularly advantageous to formulate the pharmaceutical composition in dosage unit form for easy administration and uniform dosage. Dosage unit forms, as used herein, are physically suitable for a single administration, wherein each unit comprises a predetermined amount of active ingredient (s) calculated to produce the desired therapeutic effect with the required pharmaceutical carrier. Refers to an individual unit.
    [122] In another embodiment of the present invention, the following is provided:
    [123] 2. A first agent and an adjuvant as described above, or a pharmaceutically acceptable salt, racemate or enantiomer thereof, for use in the treatment of altered gastrointestinal motility, sensitivity and / or secretion and / or abdominal disease. A pharmaceutical composition comprising said mixture in the presence of a pharmaceutical combination of isomers, or a pharmaceutically acceptable carrier.
    [124] 3. For the treatment of altered gastrointestinal motility, sensitivity and / or secretion and / or abdominal disease, of a mixture of a first agent and an adjuvant as described above, or a pharmaceutically acceptable salt, racemate or enantiomer thereof Use for the manufacture of drugs.
    [125] 4. Used in the treatment of altered gastrointestinal motility, sensitivity and / or secretion and / or abdominal disease of the first agent and the adjuvant as described above, or a pharmaceutically acceptable salt, racemate or enantiomer thereof. Use for the manufacture of pharmaceutical compositions.
    [126] 5. A pharmaceutical comprising said mixture in the presence of a first and an adjuvant or a pharmaceutically acceptable salt, racemate or enantiomer thereof, or a pharmaceutically acceptable carrier as described above, for example. A method of treating a patient suffering from altered gastrointestinal motility, sensitivity and / or secretion, and / or abdominal disease, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition.
    [127] In general, the pharmaceutical combinations or compositions of the present invention are heartburn, hypertension, postoperative ileus, abdominal pain and discomfort, premature satiety, epigastric pain, nausea, vomiting, bourbon, reflux, intestinal gastric obstruction, anal incontinence, GERD, IBS Altered gastrointestinal motility, irritability, including, but not limited to, dyspepsia, chronic constipation or diarrhea, mild gastrione, for example diabetic mild gastric tony, ulcerative colitis, Crohn's disease, ulcers, or related visceral pain. And / or for secretion and / or abdominal disease treatment. In addition, the pharmaceutical combinations and compositions of the present invention may also be used as laxatives, as preparations for patients for colonoscopy, such as enterochrome affinity cell function, GI secretion, afferent and centrifugal fibrotic activity or abdominal smooth muscle. It can be used as a method of control, stabilization or normalization of gastrointestinal diseases through the regulation, stabilization or normalization of cell activity. Pharmaceutical combinations and compositions of the invention may also be useful in the treatment of dysmenorrhea or convulsive or recurrent cystitis.
    [128] More specifically, the first agent (s) may be combined with the following adjuvant agents in accordance with the present invention:
    [129] Histamine H 2 receptor antagonists, PPIs, antacids, bismuth containing agents, GABA B agonists or antagonists to treat GERD, dyspepsia, IBS, visceral pain and other abdominal diseases;
    [130] Anxiolytics to treat IBS, dyspepsia, visceral pain, hyperplasia and anal incontinence and other abdominal diseases, SSRIs, tricyclic antidepressants, somatostatin agonists;
    [131] Opioid agonists or antagonists, motilin receptor agonists or antagonists, CRF or CGRP receptor agonists to treat IBS, dyspepsia, visceral pain, hypertonia, anal incontinence, mild gastrotonicity, chronic constipation, chronic diarrhea, postoperative ileus and other abdominal diseases Or antagonists, NK or CCK receptor agonists or antagonists, muscarinic M1 receptor agonists or antagonists, anticonvulsants, NO synthetase inhibitors;
    [132] Irritant laxatives, osmotic diarrhea, stool softeners, absorbents or fiber supplements, GI relaxants, antigas compounds to treat chronic constipation, chronic diarrhea, hyperplasia, postoperative ileus and other abdominal diseases.
    [133] The therapeutically effective dosage of the pharmaceutical composition of the present invention will vary depending on the extent of the condition being treated and the route of administration. Dosage and possibly frequency of administration will also vary depending on the age, weight and response of the individual patient. Generally, the mixture of the first agent and the adjuvant will be administered in a molar ratio of the first agent from about 0.01 to about 2 to the adjuvant from about 0.01 to 1000. As one example, the molar ratio of the first agent to the auxiliary agent is about 1: 1000 (first agent to the auxiliary agent). As a more specific example, the molar ratio of the first agent to the auxiliary agent may be about 1: 1000, 1: 500, 1: 200, 1: 100, 1:20, 1: 5, 1: 1 or 1: 0.1. . Preferred molar ratios are about 1:20, even more preferably about 1: 5, and most preferably about 1: 1.
    [134] The total daily dosage range of the molar ratios for the conditions described herein will be administered in the range of about 0.01 mg to 1000 mg. The daily dosage range will be about 800 mg, 600 mg, 400 mg, 200 mg, 100 mg, 50 mg, 20 mg, 10 mg, 5 mg, 1 mg, 0.1 mg or 0.01 mg. Preferably, the daily dosage range will be about 0.5 mg to 100 mg, but most preferably the daily dosage range should be about 5 mg to about 75 mg. The dosage is preferably administered in OD (once a day) or BID (twice a day). When administering a patient, treatment should begin with a lower dose, perhaps about 5 mg to about 10 mg, and rise to about 50 mg or more depending on the patient's response. It will be apparent to those skilled in the art that in some cases it may be necessary to use dosages outside these ranges. It is also noted that the clinician or the treating physician will know how to stop, adjust or terminate the treatment in relation to the individual patient's response. The term "therapeutically effective amount" is achieved by said molar ratio and dosage and dosing schedule. A "therapeutically effective amount" can be administered as a fixed and unfixed mixture of a first agent, such as tegacerod and auxiliary agents.
    [135] The invention is further illustrated by the following examples. The examples are only illustrative of the present invention with reference to specific embodiments. These examples illustrating particular aspects of the invention do not limit or limit the scope of the invention.
    [136] Example 1
    [137] Pharmacokinetic Effects of Tegaserod and Adjuvant on Gastrointestinal and Colon Motility
    [138] Animal Preparation: Beagle dogs were used for these experiments. Under Halotan anesthesia, Pascaud et al., Am. Four strain-gauge transducers constructed according to J. Physiol., 1978, 235: E532-E538], from the pylorus to the 5cm pyloric sinus, from the pylorus to 10cm duodenum, and the Triitz. Sew to 50 cm from the ligament and into the 10 cm proximal colon from the ileum-colon connection. Each transducer was stitched so that its recording axis was parallel to the transverse axis of the digestive tract to measure the contractile force of the annular muscle layer. The free ends of the strain-gauge wires were pulled subcutaneously to the dorsal side between the scapula.
    [139] Notes: Calibration of each strain-gauge was performed before implantation. The mechanical activity measured by the transducer was recorded. Motility indices of pyloric, duodenal, jejunum and colon were reviewed by Hachet et al. Pharmacol. Meth. (1986) 16: 171-180. The calculated motility index corresponded to the area during the 30 minute interval between the baseline and the contraction curve.
    [140] Research design; Dogs were divided into groups. Each group received one of the following prescriptions: 1) Placebo, 2) Tegaserod, 3) Frucaloprid, 4) ADL 8-2698 (LY246736), 5) Fluoxetine, 6) Tegaserod + Frucalo Fried, 7) Tegase Rod + ADL 8-2698, 8) Tegase Rod + Fluoxetine. Different doses of the compound or placebo were administered orally 30 minutes prior to feeding the dog (water ad libitum). Intravenous infusion into fasted dogs of various doses of the compound or placebo (excipient) began 30 minutes before feeding the water ad libitum. Recordings of gastrointestinal and colonic motility were performed for a total of six hours beginning with feeding.
    [141] Data Analysis: Changes in motility index associated with various compounds / administrations during 6 hours after feeding were measured at locations of pyloric, duodenum, jejunum and colon.
    [142] The mixture of tegaserod and adjuvant agents significantly increased gastrointestinal and colon motility compared to placebo and any compound administered alone.
    [143] Example 2
    [144] Effects of Tegaserod and Adjuvant Drugs on Gastric and Colon Sensitivity and Digestive Muscle Tension on Pressure-Inflated Manipulators
    [145] 1. stomach sensitivity and stress
    [146] A group of Wistar rats weighing 200-250 g were used. For surgery, animals were predosed with 0.3 ml of acepromazine (0.5 mg / kg) injected intraperitoneally and anesthetized with 0.3 ml of ketamine injected intraperitoneally.
    [147] After the animal was placed on the dorsal dorsum and after xypho-ombilical laparotomy, a permanent balloon connected to the tube introduced into the upper portion of the dislocation was mounted on the stomach at 1 cm of the gastro-esophageal junction of the Taiwanese song. After closing the abdomen, the rats were placed into the ventral stomach and a group of three stainless steel electrodes (1 m long-270 μm diameter) were placed on the neck muscles by Lucebusch and Fioramonti, Gastroenterol. . 68: 1500-1508, 1975] using the technique described. The free end of the electrode and the catheter of the balloon were taken out to the back of the neck and protected by a glass tube attached to the skin. Gastric dilatation at constant pressure was performed with an electronic pressure regulator (Gastroenterol Clin Biol, 1993, 17, 347-351). Balloons (5.0-5.5 cm long) were made of condoms without secretory reservoirs and sewn into polyethylene tubes (1.0 and 1.8 mm inner and outer diameters, 80 cm long, respectively). A hole was drilled in the end of the tube so that the balloon was easily emptied.
    [148] Ten days after surgery, EMG recordings were performed with an EEG recording machine (Reega VIII, Alba, Paris, France) at a paper speed of 2.4 cm / min. The spike burst (0.03 s) was selectively recorded using short time constant amplification. EMG activity was summed every 20 seconds by the integrated circuit and automatically plotted by computer.
    [149] Under virulent stomach swelling, the rat's flanks were observed by extending the body of the rat, lifting its head and / or turning its head left and right. The neck muscles contracted and EMG signals were recorded. A pressure regulator was also connected to the potentiometer recorder for permanent recording of intragastric pressure. Animals were divided into groups.
    [150] After 30 minutes of the control record, the animals were given one of the following regimens: 1) placebo, 2) tegacerod, 3) pedotozin, 4) baclofen, 5) okreotide, 6) fluoxetine, 7 A) Tegase rod + Fedotozin, 8) Tegase rod + baclofen, 9) Tegase rod + Oak Throated, 10) Tegase rod + Fluoxetine.
    [151] The protocol of gastric swelling started after 30 minutes.
    [152] EMG activity of the neck muscles (EANM) was correlated with postural changes and proportional to pain induced by gastric dilation. Every 20 seconds the treated values were combined for 10 consecutive minutes. For each stage of inflation, neck activity was calculated by the following equation:
    [153] [{(EANM at measured pressure)-(EANM at reference conditions)} / EANM at reference conditions] X 100
    [154] Pain thresholds were set to> 100% increase in the electrical activity of the neck muscles.
    [155] The volume was measured as the maximum volume obtained for each stage of expansion with a potentiometer recorder. Pain thresholds and gastric volumes are shown as compared values using Student's “t” test for mean + SEM and non-paired values.
    [156] The pharmaceutical combination of tegaserod and adjuvant agents significantly reduced gastric pain associated with gastric swelling and significantly increased gastric tension compared to placebo and any administered compound alone.
    [157] 2. Colorectal irritability and tension
    [158] The effect on rectal or colonic tension and pain of tegaserod and adjuvant medications is applied with elevated pressure in a stepwise manner for 5 consecutive minutes; Each pressure was performed using a pressure regulator inflation method by evaluating the change in tension by measuring the volume.
    [159] Individually housed 220-250 g of Wistar rats were used. Animals were anesthetized with predrug treatment with 0.5 mg / kg acepromazine injected intraperitoneally and intramuscularly administered with 100 mg / kg ketamine. These were prepared for EMG recording using the techniques described in Lucebush and Fioramonti, 1975. Pairs of nitrim wire electrodes (60 cm long and 80 μm in diameter) were implanted into the abdominal cavity rhabdom at 2 cm laterally from the white line. The free end of the electrode was removed from the back of the neck and protected by a plastic tube attached to the skin.
    [160] EMG drawing (time constant: 0.03 sec) was started 8 days after surgery. Bipolar recording of EMG activity was performed for 1 hour, starting 30 minutes before rectal dilation with an electroencephalogram.
    [161] To prevent false recordings due to movement during inflation, rats were acclimated to being placed in a tunnel of polypropylene where inflation and EMG recordings were performed three days prior to inflation. A balloon (4 cm) consisting of a condom was introduced 5 cm from the anus inside the rectum and fixed at the base of the tail. The balloon connected to the pressure regulator was inflated with air at pressures of 15, 30, 45 and 60 mmHg applied for 5 minutes each.
    [162] Groups of rats were each subjected to a pressure regulator inflation protocol. 10 minutes prior to them intraperitoneally: 1) placebo, 2) tegase rod, 3) fedodozin, 4) baclofen, 5) octetide, 6) fluoxetine, 7) tegase rod + fedodozin, 8) te Gaserod + bacclofen, 9) tegaserod + octreotide, 10) tegaserod + fluoxetine. Statistical analysis of the number of abdominal spike bursts that occurred during each 5 minutes was performed by comparing the values, which were the student's "t" test pairs after 2-way ANOVA. P <0.05 was considered statistically significant. The colorectal volume is expressed as the value compared for non-paired values using the mean + SEM and Student's "t" test.
    [163] The pharmaceutical combination of tegaserod and adjuvant agents significantly reduced rectal and colon pain associated with rectal swelling and significantly increased colorectal tension as compared to placebo and any compound administered alone.
    [164] Example 3
    [165] Treatment of non-erosive GERD with a mixture of tegaserod and adjuvant agents
    [166] Patients selected for the study had heartburn, a target symptom of non-erosive GERD patients, with major upper gastrointestinal symptoms in the last three months prior to study, and had at least three days / week history of heartburn. Patients with GERD and no endoscopic signal of erosive esophagitis were included in this study. Among other factors, patients treated with a prescribed dose of histamine H 2 -receptor antagonist (H 2 RA) or PPI within one month before entering the study's baseline phase (Day-14) and three months before entering the study's baseline phase. Patients requiring continuous use of PPI within a day were excluded.
    [167] The study consisted of a 8 week double-blind, placebo-controlled treatment period after a 1 week screening period and a 2 week drug free baseline period. Endoscopy was performed during the screening period (-21 to -14 days) to exclude patients with erosive esophagitis. During the baseline period (-14 days to 1 day), the patient's GERD symptoms were recorded on a daily basis. At the beginning of this period, drugs for GERD, such as H 2 RA, PPI, prokinetics and other unacceptable drugs, were removed and the patient was instructed not to change their diet or lifestyle. Patients were asked to take Maalox tablets as a rescue drug to control their symptoms. Patients entering the double blind period had more than three days of heartburn in the last week of the baseline period.
    [168] Patients were randomly assigned to the same group during the double-blind, placebo-controlled period of the study. This period of study lasted eight weeks, with 12 treatment groups. Patients in each group were given one of the following regimens: 1) placebo, orally administered for 8 weeks, 2) 0.4 mg / day of tagaserod, 3) 1 mg / day of tagaserod, 4) 4 mg / day of tagaserod , 5) ranitidine 300 mg / day, 6) omeprazole 20 mg / day, 7) tegacerod 0.4 mg / day + ranitidine 300 mg / day, 8) tegacerod 1 mg / day + ranitidine 300 mg / day, 9) tegacerod 4 mg / Day + ranitidine 300mg / day, 10) tegaserod 0.4mg / day + omeprazole 20mg / day, 11) tegaserod 1mg / day + omeprazole 20mg / day and 12) tegaserod 4mg / day + omeprazole 20mg / day . Administration was performed within 30 minutes prior to breakfast and dinner for the 12 groups. For eight weeks, patients were recorded daily and only Maalox tablets were used as rescue drugs for the control of these symptoms.
    [169] Heartburn that occurs weekly during the 8-week, double-blind, placebo-controlled period of the study compared to any placebo, tegaserod, ranitidine, and omeprazole alone compared to any placebo, tegaserod, ranitidine, and omeprazole alone Significantly reduced the occurrence of The Tegaserod mixture also reduced other symptoms of GERD, including abdominal pain, hyperplasia and reflux. In addition, the patient showed a significant improvement in the quality of life elements as compared to any placebo, tegaserod, ranitidine and omeprazole alone.
    [170] Pharmaceutical combinations of the invention, for example 5-HT 4 agonists or partial agonists such as tegacerod, and PPIs such as omeprazole, or histamine H 2 receptor antagonists such as ranitidine, or antacids or GABA A receptor agonists or modulations Pharmaceutical compositions comprising substances such as baclofen are described by Talley NJ et al. Gastroenterol. Intl., 1993, 6 (4), 189: 211 or in Beldhuyzen van Zanten SJO et al., Gut 1999, 45 (Suppl. II), 1169: 1177. Can also be tested clinically. Administration is preferably administered orally and may be administered once or twice daily.
    [171] While the present invention has been described in detail with reference to certain preferred variations thereof, other variations will be possible without departing from the spirit and scope of the preferred variations contained herein. All references and patents cited herein (US, etc.) are incorporated by reference.
    权利要求:
    Claims (11)
    [1" claim-type="Currently amended] a) a first agent which is a 5-HT 4 receptor partial agonist or a pharmaceutically acceptable salt, racemate or enantiomer thereof; And
    b) Pharmaceutical combinations comprising an adjuvant or a pharmaceutically acceptable salt, racemate or enantiomer thereof.
    [2" claim-type="Currently amended] a) a first agent which is a compound of formula (I) in free or pharmaceutically acceptable salt form and its physiologically hydrolyzable and acceptable ether or ester when R 5 is hydroxy and
    b) Pharmaceutical combinations comprising an adjuvant or a pharmaceutically acceptable salt, racemate or enantiomer thereof.
    <Formula I>

    In the above formula,
    R 1 is hydrogen; C 1-6 alkyl; (C 1-6 alkyl) carbonyl; Benzoyl; Or phenylC 1-4 alkyl-carbonyl;
    R 5 is hydrogen; halogen; C 1-6 alkyl; Hydroxy; Nitro; Amino; C 1-6 alkylamino; C 1-10 alkyl-carbonylamino; C 2-6 alkoxycarbonyl; SO 2 NR a R b , wherein each R a and R b are independently hydrogen or C 1-6 alkyl; Cyano; Or trimethylsilyl; -SO 2 -C 1-6 alkyl, -SO 2 NR a R b , -CONR a R b , -NH-SO 2 -C 1-6 alkyl, -N (C 1-6 alkyl) -SO 2- ( C 1-6 alkyl), —NR a R b ′ (where R b ′ is hydrogen or C 1-6 alkyl), C 2-6 alkoxycarbonyl or —PO (C 1-4 alkyl) 2 C 1-6 alkyl substituted by; Carboxy; CONR a R b ; -PO (Ci_ 6 alkyl) 2 ; OCONR c R d , wherein each R c and R d are independently C 1-6 alkyl;
    R 6 is hydrogen or when R 5 is OH, R 6 is hydrogen or halogen,
    Z is -CR 4 = (wherein R 4 is hydrogen, halogen, hydroxy or C 1-6 alkyl) or when R 5 is hydrogen or hydroxy, Z is also -N =,
    R 7 is hydrogen, halogen, C 1-6 alkyl or C 1-6 alkoxy,
    XY is -CR 8 = N- or -CH (R 8 ) -NH-, wherein R 8 is hydrogen or C 1-6 alkyl,
    B is a radical of the formula (a) or (b).
    <Formula a>

    <Formula b>

    In the above formulas,
    n is 1 or 2,
    A 1 is C═O or CH 2 ,
    X 1 is S; NR 11 , wherein R 11 is hydrogen, (C 1-6 alkyl) carbonyl, benzoyl or phenylC 1-4 alkyl-carbonyl; Or CR 12 R 13 , wherein each R 12 and R 13 is independently hydrogen or C 1-4 alkyl;
    R 10 is hydrogen; C 1-12 alkyl; C 1-6 alkyl substituted by hydroxy, aryl, aryloxy, adamantyl, heterocyclic radical, -NR 15 -CO-R 16 or-NH-SO 2 -aryl; C 5-7 cycloalkyl; Adamantyl; (C 1-10 alkyl) carbonyl; Benzoyl; Phenyl (C 1-4 alkyl) carbonyl; Or -CONHR 14 , wherein R 14 is C 1-10 alkyl or C 5-7 cycloalkyl, R 15 is hydrogen or C 1-4 alkyl, R 16 is C 1-6 alkyl, C 5- 7 cycloalkyl, C 5-7 cycloalkyl-C 1-4 alkyl, aryl or arylC 1-4 alkyl;
    Whether “aryl” itself or “aryl” in the above definition, “-NH—SO 2 -aryl” or “aryl” (C 1-4 alkyl), it is phenyl; Or phenyl substituted by halogen, C 1-4 alkyl or C 1-6 alkoxy;
    When a "heterocyclic radical" is described in the above definition, it is pyridyl, imidazolyl, benzimidazolyl, pyrrolidinyl, pyrrolidoneyl, piperidino, pyrazinyl, perhydroindolyl or A radical of formula (c), (d) or (e),
    <Formula c>

    <Formula d>

    <Formula e>

    (In the above formula,
    R 22 is hydrogen or C 1-4 alkyl,
    B 1 is -CH 2 CH 2- , -COCH 2 -or-(CH 2 ) 3- , wherein one or two H thereof is substituted by C 1-4 alkyl or 1,2-phenylene Can be,
    E is -CH 2 CH 2- , -CH 2 N (R 17 )-or-(CH 2 ) 3- , wherein one or two H thereof is C 1-6 alkyl or 1,2-phenyl May be substituted by lene,
    E 1 is CO or CH 2 ,
    R 17 is hydrogen or C 1-4 alkyl,
    G is CO, -CHCOOR 18 , -CHCOR 19 , 5,5-dimethyl-1,3-dioxane-2-ylidene or 1,3-dioxolan-2-ylidene, wherein R 18 is hydrogen Or C 1-6 alkyl and R 19 is C 1-6 alkyl,
    n 'is 0 or 1)
    X 2 is —SR 20 or —NR 3 R 10 ′, wherein R 20 is C 1-6 alkyl, R 3 is hydrogen or C 1-6 alkyl and R ′ 10 is defined in R 10 above One of them, or R 3 and R ′ 10 together with the nitrogen atom to which they are attached form a heterocyclic radical as described above;
    Provided that when B is a radical of formula (b), only one of R 10 and R 10 ′ may not be hydrogen and X 2 may be —SR 20 only when R 10 is hydrogen.
    [3" claim-type="Currently amended] A compound according to claim 1 or 2, wherein said adjuvant agent exhibits the properties of a 5-HT 3 receptor antagonist, a 5-HT 4 receptor agonist or antagonist, a 5-HT 3 receptor antagonist and a 5-HT 4 receptor agonist or antagonist. , Somatostatin receptor agonists, histamine H 2 receptor antagonists, PPIs including irreversible, reversible drugs and prodrugs of proton pump inhibitors (“PPIs”), anxiolytics, anticonvulsant / antimuscarinic agents, selective serotonin reuptake inhibitors, Tricyclic antidepressants, selegelin, muscarinic 1 receptor agonists or antagonists, cholecystokinin receptor antagonists, opioid receptor agonists or antagonists, motilin receptor agonists or antagonists, nitric oxide synthase inhibitors, GABA B receptor agonists or modulators, neurokinin receptors Acceptance of agonists or antagonists, calcitonin gene related peptide receptors or corticosteroid secretion factors Agonists or antagonists, anti-inflammatory compounds, stimulating laxatives, osmotic laxatives, stool softeners, absorbents and fiber supplements, antacids, GI relaxants, antigas compounds, bismuth-containing agents, pentosan polysulfates, hydroxyzin, mammary cell stabilizers And an antiemetic dopamine D 2 antagonist.
    [4" claim-type="Currently amended] The pharmaceutical combination according to claim 1 or 2, wherein the first agent a) is tegaserrod in free form or in a pharmaceutically acceptable salt form.
    [5" claim-type="Currently amended] a) a first agent selected from the group consisting of 5-HT 4 receptor agonists or antagonists and 5-HT 3 receptor antagonists or pharmaceutically acceptable salts, racemates or enantiomers thereof; And
    b) somatostatin receptor agonists, anxiolytics, benzodiazepine compounds, anticonvulsant / antimuscarinic agents, tricyclic antidepressants, selegelin, muscarinic receptor agonists or antagonists, cholecystokinin receptor antagonists, opioid receptor agonists or antagonists, motiline receptor agonists or Antagonists, nitric oxide synthase inhibitors, GABA B receptor agonists or modulators, neurokinin receptor agonists or antagonists, calcitonin gene related peptide receptor agonists or antagonists, corticotropin secretion factor receptor agonists or antagonists, anti-inflammatory compounds, stimulating diarrhea , Osmotic laxatives, fecal softeners, absorbents and fiber supplements, antacids, GI relaxants, antigas compounds, bismuth-containing preparations, pentosan polysulfate, hydroxyzine, dextromethorphan and mammary cell stabilizers or pharmaceutically thereof Acceptable salts, racemates Comprises an auxiliary agent selected one from the enantiomers, with the proviso that the medicament a) a 5-HT 3 receptor as antagonists days, the auxiliary agent b) is anticonvulsant / antimuscarinic agent, a muscarinic receptor antagonists, opioid receptor agonists Or a pharmaceutical combination that is not an antagonist, neurokinin receptor antagonist, stimulatory diarrhea, osmotic diarrhea or anti-inflammatory corticosteroid.
    [6" claim-type="Currently amended] a) a first agent which is a 5-HT 4 receptor antagonist or a pharmaceutically acceptable salt, racemate or enantiomer thereof; And
    b) an adjuvant comprising a somatostatin receptor agonist, a histamine H 2 receptor antagonist, a PPI, a metoclopramide and an anti-dopamine D 2 antagonist, or a pharmaceutically acceptable salt, racemate or enantiomer thereof. Pharmaceutical combinations.
    [7" claim-type="Currently amended] The method of claim 1,
    a) tegase rods in free or pharmaceutically acceptable salt form, and
    b) A pharmaceutical combination comprising an adjuvant that is a proton pump inhibitor or a histamine H 2 receptor antagonist.
    [8" claim-type="Currently amended] A pharmaceutical composition comprising a pharmaceutical combination according to any one of claims 1, 2, 5 and 6 and a pharmaceutically acceptable carrier.
    [9" claim-type="Currently amended] A pharmaceutical combination according to any one of claims 1, 2, 5 and 6 or 8 for use in treating altered gastrointestinal motility, sensitivity and / or secretion and / or abdominal disease. Pharmaceutical composition according to claim.
    [10" claim-type="Currently amended] Use for the manufacture of a medicament for the treatment of altered gastrointestinal motility, sensitivity and / or secretion and / or abdominal disease of the pharmaceutical combination according to claim 1.
    [11" claim-type="Currently amended] Altered gastrointestinal motility, sensitivity and / or secretion and / or abdomen, comprising administering to a patient a therapeutically effective amount of the pharmaceutical combination according to claim 1 or 2 or the pharmaceutical composition according to claim 8. How to treat a patient with a disease.
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    同族专利:
    公开号 | 公开日
    DE60019814D1|2005-06-02|
    AU2005200797A1|2005-03-17|
    PT1286668E|2005-08-31|
    IL149496A|2009-12-24|
    NO20022680D0|2002-06-06|
    RU2002118316A|2004-02-20|
    KR100765579B1|2007-10-09|
    CN1409634A|2003-04-09|
    PL202201B1|2009-06-30|
    DK1286668T3|2005-08-15|
    PE20011030A1|2001-10-31|
    IL149496D0|2002-11-10|
    EP1286668B1|2005-04-27|
    CZ300690B6|2009-07-15|
    AU2005200797B2|2008-01-24|
    PL355663A1|2004-05-04|
    EP1488788A1|2004-12-22|
    MXPA02005695A|2002-09-18|
    CA2388959A1|2001-06-14|
    AU2672801A|2001-06-18|
    CN1310644C|2007-04-18|
    HU0301122A2|2003-08-28|
    NO20022680L|2002-08-12|
    AT293971T|2005-05-15|
    NZ531489A|2005-09-30|
    CN1875966A|2006-12-13|
    CO5261535A1|2003-03-31|
    NZ566800A|2009-11-27|
    TWI263496B|2006-10-11|
    JP2003523324A|2003-08-05|
    SK8062002A3|2003-04-01|
    AU778869B2|2004-12-23|
    SG152025A1|2009-05-29|
    DE60019814T2|2006-03-02|
    ES2240229T3|2005-10-16|
    RU2264215C2|2005-11-20|
    EP1913944A1|2008-04-23|
    BR0016275A|2002-08-27|
    WO2001041748A3|2002-12-19|
    EP1286668A2|2003-03-05|
    TR200402293T2|2004-10-21|
    WO2001041748A2|2001-06-14|
    HU0301122A3|2005-03-29|
    ZA200204493B|2003-09-29|
    AR026916A1|2003-03-05|
    CZ20021967A3|2002-08-14|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    1999-12-10|Priority to US45838899A
    1999-12-10|Priority to US09/458,388
    2000-12-08|Application filed by 노파르티스 아게
    2000-12-08|Priority to PCT/EP2000/012420
    2003-02-26|Publication of KR20030016208A
    2007-10-09|Application granted
    2007-10-09|Publication of KR100765579B1
    优先权:
    申请号 | 申请日 | 专利标题
    US45838899A| true| 1999-12-10|1999-12-10|
    US09/458,388|1999-12-10|
    PCT/EP2000/012420|WO2001041748A2|1999-12-10|2000-12-08|Pharmaceutical combinations and their use in treating gastrointestinal disorders|
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