WO1999029697A1 - Pharmaceuticals - Google Patents
Pharmaceuticals Download PDFInfo
- Publication number
- WO1999029697A1 WO1999029697A1 PCT/EP1998/007764 EP9807764W WO9929697A1 WO 1999029697 A1 WO1999029697 A1 WO 1999029697A1 EP 9807764 W EP9807764 W EP 9807764W WO 9929697 A1 WO9929697 A1 WO 9929697A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compound
- indole
- formula
- methyl
- pharmaceutically acceptable
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/06—Antimigraine agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/06—Antiarrhythmics
Definitions
- This invention relates to novel compounds having pharmacological activity, to a process for their preparation and to their use as pharmaceuticals.
- EP-A-429984 (Nisshin Flour Milling Co., Ltd.) describes indole derivatives having 5- HT3 receptor antagonist activity.
- WO 91/16045 (SmithKline and French Laboratories Limited) describes the use of cardiac 5-HT4 receptor antagonists in the treatment of atrial arrhythmias and stroke.
- EP-A-501322 (Glaxo Group Limited) describes indole derivatives having 5-HT4 antagonist activity.
- WO93/18036 (SmithKline Beecham pic) describes certain condensed indole derivatives having 5-HT4 receptor antagonist activity.
- the compound N-[( l- n butyl-4-piperidyl)methyl]-3,4-dihydro-2H-[ 1, 3]oxazino[3,2- a] indole- 10-carboxamide has been found to have potent 5-HT4 receptor antagonist activity and to be of therapeutic value in the treatment of irritable bowel syndrome.
- one of its metabolites namely the compound of formula (I) below, itself has potent 5-HT4 receptor antagonist activity.
- the present invention provides ( ⁇ )-N-[(l-butyl-4-piperidinyl)methyl]-
- the pharmaceutically acceptable salts of the compound of the formula (I) include acid addition salts with conventional acids such as hydrochloric, hydrobromic, boric, phosphoric, sulphuric acids and pharmaceutically acceptable organic acids such as acetic, tartaric. maleic, citric, succinic, benzoic. ascorbic, methanesulphonic. ⁇ -keto glutaric, ⁇ -glycerophosphoric. and glucose- 1 -phosphoric acids.
- Examples of pharmaceutically acceptable salts include quaternary derivatives of the compound of formula (I) such as the compounds quaternised by compounds R x -T wherein R x is C j.g alkyl, phenyl-C ⁇ .g alkyl or C5.7 cycloalkyl, and T is a radical corresponding to an anion of an acid.
- R x include methyl, ethyl and n- and w ⁇ -propyl; and benzyl and phenethyl.
- Suitable examples of T include halide such as chloride, bromide and iodide.
- Examples of pharmaceutically acceptable salts also include internal salts such as N-oxides.
- the compound of the formula (I) and its pharmaceutically acceptable salts, (including quaternary derivatives and N-oxides) may also form pharmaceutically acceptable solvates, such as hydrates, which are included wherever the compound of formula (I) or a salt thereof is herein referred to.
- the compound of formula (I) is a racemate.
- the present invention also covers the corresponding individual (+) and (-) enantiomers.
- the compound of formula (I) may be prepared as described in the Example below or by other conventional coupling of the indole moiety with Z, for example by reacting l-n-butyl-4-piperidinyl methylamine with (+/-)-methyl 3,4-dihydro-4-
- Aza(bi)cyclic side chain intermediates are known compounds or may be prepared according to the methods described in PCT/GB92/01519 and /01612 (SmithKline Beecham p.l.c).
- the compounds of the present invention are 5-HT4 receptor antagonists and it is thus believed may generally be used in the treatment or prophylaxis of gastrointestinal disorders, cardiovascular disorders and CNS disorders.
- EBS irritable bowel syndrome
- these compounds block the ability of 5- HT to stimulate gut motility via activation of enteric neurones. In animal models of IBS, this can be conveniently measured as a reduction of the rate of defaecation. They are also of potential use in the treatment of urinary incontinence which is often associated with IBS.
- They may also be of potential use in other gastrointestinal disorders, such as those associated with upper gut motility, and as antiemetics. In particular, they are of potential use in the treatment of the nausea and gastric symptoms of gastro- oesophageal reflux disease and dyspepsia. Antiemetic activity is determined in known animal models of cytotoxic-agent/radiation induced emesis.
- platelet-derived 5-HT induces atrial arrhythmias which encourage atrial fibrillation and atrial disorders are associated with symptomatic cerebral and sytemic embolism.
- Cerebral embolism is the most common cause of ischaemic stroke and the heart the most common source of embolic material. Of particular concern is the frequency of embolism associated with atrial fibrillation.
- Anxiolytic activity is likely to be effected via the hippocampus (Dumuis et al 1988, Mol Pharmacol., 34, 880-887). Activity may be demonstrated in standard animal models, the social interaction test and the X-maze test.
- the invention also provides a pharmaceutical composition comprising the compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
- compositions are prepared by admixture and are usually adapted for enteral such as oral, nasal or rectal, or parenteral administration, and as such may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, nasal sprays, suppositories, injectable and infusable solutions or suspensions. Sublingual or transdermal administration is also envisaged. Orally administrable compositions are preferred, since they are more convenient for general use.
- Tablets and capsules for oral administration are usually presented in a unit dose, and contain conventional excipients such as binding agents, fillers, diluents, tabletting agents, lubricants, disintegrants, colourants, flavourings, and wetting agents.
- the tablets may be coated according to well known methods in the art, for example with an enteric coating.
- Suitable fillers for use include cellulose, mannitol, lactose and other similar agents.
- Suitable disintegrants include starch, polyvinylpolypyrrolidone and starch derivatives such as sodium starch glycollate.
- Suitable lubricants include, for example, magnesium stearate.
- Suitable pharmaceutically acceptable wetting agents include sodium lauryl sulphate.
- Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
- Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example, almond oil, fractionated coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and if desired conventional flavourin ⁇ g or colouring agents.
- suspending agents for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monoole
- Oral liquid preparations are usually in the form of aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs or are presented as a dry product for reconstitution with water or other suitable vehicle before use.
- Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), preservatives, and flavouring or colouring agents.
- the oral compositions may be prepared by conventional methods of blending, filling or tabletting. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are, of course, conventional in the art.
- fluid unit dose forms are prepared containing a compound of the present invention and a sterile vehicle.
- the compound depending on the vehicle and the concentration, can be either suspended or dissolved.
- Parenteral solutions are normally prepared by dissolving the compound in a vehicle and filter sterilising before filling into a suitable vial or ampoule and sealing.
- adjuvants such as a local anaesthetic, preservatives and buffering agents are also dissolved in the vehicle.
- the composition can be frozen after filling into the vial and the water removed under vacuum.
- Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilised by exposure of ethylene oxide before suspending in the sterile vehicle.
- a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound of the invention.
- the invention further provides a method of treatment of irritable bowel syndrome, gastro-oesophagal reflux disease, dyspepsia, atrial arrhythmias and stroke, anxiety and/or migraine in mammals, such as humans, which comprises the administration of an effective amount of the compound of the formula (I) or a pharmaceutically acceptable salt thereof.
- the method comprises treatment of IBS or atrial arrhythmias and stroke.
- a unit dose for a 70 kg adult will normally contain 0.05 to 1000 mg for example 0.5 to 500 mg, of the compound of the invention.
- Unit doses may be administered once or more than once a day, for example, 2. 3 or 4 times a day, more usually 1 to 3 times a day. that is in the range of approximately 0.0001 to 50 mg/kg/day, more usually 0.0002 to 25 mg/kg/day.
- the invention also provides the compound of formula (I) or a pharmaceutically acceptable salt thereof for use as an active therapeutic substance, in particular for use as a 5-HT4 receptor antagonist in the treatment of the disorders hereinbefore described.
- the invention also provides the use of the compound of formula (I) in the manufacture of a medicament for use as a 5-HT4 receptor antagonist in the treatment of the disorders hereinbefore described.
- the metabolite (10) was prepared a) as a mixture and b) as a pure compound:
- N- chlorosuccinimide (3.53g, 0.026 mol). After 30 min, 1 ,3-propanediol (18.5g, 0.24 mol) was added, followed by methanesulphonic acid (0.5g, 0.005 mol). The solution was stirred for a further 30 min, then washed with aqueous sodium carbonate solution (10% w/v, 50 ml). The chloroform layer was cooled to 0°C, the precipitate collected by filtration, obtaining 7.52g (80%) (2).
- LMMP Longitudinal muscle-myenteric plexus
- DMPP 1, 1 -dimethy 1-4-pheny 1-piperazinium iodide
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Pain & Pain Management (AREA)
- Hospice & Palliative Care (AREA)
- Otolaryngology (AREA)
- Nutrition Science (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
Description
Claims
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2000524290A JP2001525415A (en) | 1997-12-05 | 1998-12-01 | Medicine |
EP98965209A EP1037894A1 (en) | 1997-12-05 | 1998-12-01 | Pharmaceuticals |
CA002312844A CA2312844A1 (en) | 1997-12-05 | 1998-12-01 | Pharmaceuticals |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB9725933.7 | 1997-12-05 | ||
GBGB9725933.7A GB9725933D0 (en) | 1997-12-05 | 1997-12-05 | Pharmaceuticals |
Related Child Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US09555851 A-371-Of-International | 2000-07-13 | ||
US09/845,884 Continuation US20010031751A1 (en) | 1997-12-05 | 2001-04-30 | Pharmaceuticals |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1999029697A1 true WO1999029697A1 (en) | 1999-06-17 |
Family
ID=10823280
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP1998/007764 WO1999029697A1 (en) | 1997-12-05 | 1998-12-01 | Pharmaceuticals |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP1037894A1 (en) |
JP (1) | JP2001525415A (en) |
CA (1) | CA2312844A1 (en) |
GB (1) | GB9725933D0 (en) |
WO (1) | WO1999029697A1 (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6583294B2 (en) | 1998-07-16 | 2003-06-24 | Smithkline Beecham P.L.C. | Process for the preparation of an indole derivative |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0501322A1 (en) * | 1991-02-25 | 1992-09-02 | Glaxo Group Limited | 3-Piperidinylmethylcarboxylate substituted indoles |
WO1993018036A1 (en) * | 1992-03-12 | 1993-09-16 | Smithkline Beecham Plc | Condensed indole derivatives as 5ht4-receptor antagonists |
-
1997
- 1997-12-05 GB GBGB9725933.7A patent/GB9725933D0/en not_active Ceased
-
1998
- 1998-12-01 CA CA002312844A patent/CA2312844A1/en not_active Abandoned
- 1998-12-01 JP JP2000524290A patent/JP2001525415A/en active Pending
- 1998-12-01 WO PCT/EP1998/007764 patent/WO1999029697A1/en not_active Application Discontinuation
- 1998-12-01 EP EP98965209A patent/EP1037894A1/en not_active Withdrawn
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0501322A1 (en) * | 1991-02-25 | 1992-09-02 | Glaxo Group Limited | 3-Piperidinylmethylcarboxylate substituted indoles |
WO1993018036A1 (en) * | 1992-03-12 | 1993-09-16 | Smithkline Beecham Plc | Condensed indole derivatives as 5ht4-receptor antagonists |
Non-Patent Citations (3)
Title |
---|
G. A. KENNETT ET AL., NEUROPHARMACOLOGY, vol. 35, no. 4/5, 1997, pages 707 - 12, XP002099387 * |
L. GASTER, DRUGS OF THE FUTURE, vol. 22, no. 12, 1997, pages 1325 - 32, XP002099385 * |
L. M. GASTER ET AL., JOURNAL OF MEDICINAL CHEMISTRY, vol. 38, no. 24, 1995, pages 4760 - 3, XP002099386 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6583294B2 (en) | 1998-07-16 | 2003-06-24 | Smithkline Beecham P.L.C. | Process for the preparation of an indole derivative |
US6946565B2 (en) | 1998-07-16 | 2005-09-20 | Smithkline Beecham Plc | Process for the preparation of an indole derivative |
Also Published As
Publication number | Publication date |
---|---|
GB9725933D0 (en) | 1998-02-04 |
CA2312844A1 (en) | 1999-06-17 |
EP1037894A1 (en) | 2000-09-27 |
JP2001525415A (en) | 2001-12-11 |
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