WO1988007858A1 - Benzazepines substituees en position 3 par un groupe sulfinyle et sulfonyle - Google Patents

Benzazepines substituees en position 3 par un groupe sulfinyle et sulfonyle Download PDF

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Publication number
WO1988007858A1
WO1988007858A1 PCT/US1988/001169 US8801169W WO8807858A1 WO 1988007858 A1 WO1988007858 A1 WO 1988007858A1 US 8801169 W US8801169 W US 8801169W WO 8807858 A1 WO8807858 A1 WO 8807858A1
Authority
WO
WIPO (PCT)
Prior art keywords
benzazepine
tetrahydro
methoxy
compound
methylsulfonyl
Prior art date
Application number
PCT/US1988/001169
Other languages
English (en)
Inventor
William Edward Bondinell
Herbert Stowel Ormsbee, Iii
Original Assignee
Smithkline Beckman Corporation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US07/167,663 external-priority patent/US4824839A/en
Application filed by Smithkline Beckman Corporation filed Critical Smithkline Beckman Corporation
Publication of WO1988007858A1 publication Critical patent/WO1988007858A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole

Definitions

  • This invention relates to sulfinyl and sulfonyl substituted benzazepine compounds for use in treating emesis.
  • These compounds are known in the art and may be prepared as shown in European Patent Application 86309846.3. They have been reported as having utility in the treatment of gastrointestinal diseases. It has now been found that the sulfinyl. and sulfonyl substituted benzazepine compounds are useful therapeutically for treating or preventing emesis.
  • R is hydrogen, C 1 -C 6 alkyl or C 3 -C 5 alkenyl
  • R 1 is SOR 3 , SO 2 R 3 or SO 2 NR 4 R 5 ;
  • R 2 is hydrogen, halogen, CF 3 , C 1 -C 6 alkyl or R 6 O-;
  • R 3 is C 1 -C 6 alkyl or CF 3 ;
  • R 4 and R 5 are hydrogen or C 1 -C 6 alkyl; and R 6 is hydrogen, C 1 -C 6 alkyl or C 1 -C 6 alkanoyl, provided that when R 1 is SO 2 NH 2 , R 2 is R 6 O-, halogen,
  • Particular compounds of formula (I) are those in which R 1 is in the 7-position. Further particular compounds of formula (I) axe those in which R 1 is in the
  • R 2 is in the 8-position.
  • a group of compounds of formula (I) is that in which R 1 is SO 2 R 3 or SO 2 NR 4 R 5 , R 2 is hydrogen, alkoxy or hydroxy, R 3 is methyl and R is hydrogen and, in addition, R 1 may be in the 7-position and R 2 may be in the 8-position.
  • the compounds of formula (I) form pharmaceutically acceptable acid addition salts with organic or inorganic acids.
  • these acids are hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, tartaric, citric, maleic, lactic, oxalic, succinic, methanesulfonic, and benzenesulfonic acids.
  • the salts are formed according to methods known to the art.
  • the product may be treated with an inorganic or organic base, such as aqueous sodium hydroxide, sodium carbonate, triethylamine, etc., and converted to the corresponding free base.
  • the base can then be treated with an appropriate acid, for example in an aqueous miscible solvent, such as a lower alkanol preferably methanol or ethanol, to give the desired salt.
  • an aqueous miscible solvent such as a lower alkanol preferably methanol or ethanol
  • the control group of dogs also apomorphine-sensitive, receive the test vehicle and apomorphine hydrochloride (0.1 mg/kg, s.c.) Emesis is recorded as with the test animals.
  • the mean frequency of emesis for the control and test groups is calculated. A value for each test group is then obtained which expresses the percentage increase or decrease in frequency of emesis relative to controls. An effective dose-50% is calculated.
  • the ED 50 refers to the dose that decreases emesis induced by apomorphine by 50%.
  • the pharmacologically active compounds of formula (I) can be administered orally or parenterally. Preferably, these compounds are administered in conventional dosage unit forms prepared by combining an appropriate dose of the compound with standard pharmaceutical carriers.
  • the dosage units will contain the active ingredient in an effective amount selected from about 1 mg. to about 250 mg., preferably 10 mg. to 100 mg.
  • the pharmaceutical carrier employed may be, for example, either a solid or liquid. Exemplary of solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like. Exemplary of liquid carriers are syrup, peanut oil, olive oil, water and the like.
  • the carrier or diluent can include any time delay material well known to the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax.
  • a wide variety of pharmaceutical forms can be employed.
  • a solid carrier the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form or in the form of a trouche or lozenge.
  • the amount of solid carrier will vary widely but preferably will be from about 25 mg. to about 1 g.
  • a liquid carrier the preparation will be in the form of a syrup, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampul or an aqueous or nonaqueous liquid suspension.
  • compositions are prepared by conventional techniques involving procedures such as mixing, granulating and compressing when necessary or variously mixing and dissolving the ingredients as appropriate to the desired composition.
  • the method of treating and preventing emesis in accordance with this invention comprises administering internally to a subject in need of said treatment an effective amount of a compound of formula (I), in particular, 7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3- benzazepine, 6-sulfamoyl-2,3,4,5-tetrahydro-1H-3-benzazepine, 7-sulfamoyl-2,3,4,5-tetrahydro-1H-3-benzazepine, or 8-methoxy-7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine or a pharmaceutically acceptable acid addition salt thereof.
  • the compound will preferably be administered in a dosage unit form orally or parenterally.
  • Advantageously equal doses will be administered one to four times daily with the daily dosage regimen being from about 1 mg. to about 1000 mg., preferably from 10 mg. to 400 mg.
  • 3-Acetyl-7-chlorosulfonyl-8-methoxy-2,3,4,5- tetrahydro-1H-3-benzazepine (3 g, 0.007 m) was treated with concentrated ammonium hydroxide (10 ml), stirred for 2 hours and filtered to give 3-acetyl-8-methoxy-7-sulfamoyl-2,3,4,5-tetrahydro-1H-3-benzazepine, m.p. 260-263°.
  • the sulfonamide (2.3 g, 0.007 m) was suspended in 3N hydrochloric acid and heated to reflux for 16 hours. The mixture was concentrated in vacuo and the residue crystallized from methanol to give 8-methoxy-7-sulfamoyl- 2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride, m.p. 270-274°.
  • 3-acetyl-8-methoxy-7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine was treated with 3N hydrochloric acid to give 8-methoxy-7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride, m.p. 228.5-229.5°. Refluxing this compound with 48% hydrobromic acid gave 8-hydroxy-7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

Des composés de benzazépine substituée en 3 par un groupe sulfinyle et sulfonyle se révèlent utiles dans le traitement et la prévention des vomissements. Des composés selon l'invention comprennent notamment la méthyl-7-sulfonyl-tétrahydro-2,3,4,5-1H-3-benzazépine et la méthoxy-8-méthylsulfonyl-7-tétrahydro-2,3,4,5-1H-3-benzazépine.
PCT/US1988/001169 1987-04-09 1988-04-04 Benzazepines substituees en position 3 par un groupe sulfinyle et sulfonyle WO1988007858A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US3640387A 1987-04-09 1987-04-09
US036,403 1987-04-09
US07/167,663 US4824839A (en) 1985-12-20 1988-03-14 Sulfinyl and sulfonyl substituted 2,3,4,5 tetrahydro-1H-3-benzazepines and their use in treating gastrointestinal motility disorders
US167,663 1988-03-14

Publications (1)

Publication Number Publication Date
WO1988007858A1 true WO1988007858A1 (fr) 1988-10-20

Family

ID=26713145

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1988/001169 WO1988007858A1 (fr) 1987-04-09 1988-04-04 Benzazepines substituees en position 3 par un groupe sulfinyle et sulfonyle

Country Status (2)

Country Link
AU (1) AU1700688A (fr)
WO (1) WO1988007858A1 (fr)

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6953787B2 (en) 2002-04-12 2005-10-11 Arena Pharmaceuticals, Inc. 5HT2C receptor modulators
US7704993B2 (en) 2003-06-17 2010-04-27 Arena Pharmaceuticals, Inc. Benzazepine derivatives and methods of prophylaxis or treatment of 5ht2c receptor associated diseases
US8168782B2 (en) 2006-04-03 2012-05-01 Arena Pharmaceuticals, Inc. Processes for the preparation of 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine and intermediates related thereto
US8168624B2 (en) 2004-12-21 2012-05-01 Arena Pharmaceuticals, Inc. Crystalline forms of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride
US8299241B2 (en) 2006-12-05 2012-10-30 Arena Pharmaceuticals, Inc. Processes for preparing (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine and intermediates thereof
US8367657B2 (en) 2003-06-17 2013-02-05 Arena Pharmaceuticals, Inc. Processes for preparing 3-benzazepines
US8546378B2 (en) 2004-12-23 2013-10-01 Arena Pharmaceuticals, Inc. 5HT2C receptor modulator compositions and methods of use
US8822727B2 (en) 2008-03-04 2014-09-02 Arena Pharmaceuticals, Inc. Processes for the preparation of intermediates related to the 5-HT2C agonist (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
US8952197B2 (en) 2009-06-18 2015-02-10 Arena Pharmaceuticals, Inc. Processes for the preparation of 5-HT2C receptor agonists
US8999970B2 (en) 2010-09-01 2015-04-07 Arena Pharmaceuticals, Inc. Administration of an anti-obesity compound to individuals with renal impairment
US9045431B2 (en) 2010-06-02 2015-06-02 Arena Pharmaceuticals, Inc. Processes for the preparation of 5-HT2C receptor agonists
US9169213B2 (en) 2012-10-09 2015-10-27 Arena Pharmaceuticals, Inc. Method of weight management
US9248133B2 (en) 2010-09-01 2016-02-02 Arena Pharmaceuticals, Inc. Salts of lorcaserin with optically active acids
US9365521B2 (en) 2010-09-01 2016-06-14 Arena Pharmaceuticals, Inc. Non-hygroscopic salts of 5-HT2C agonists
US10226471B2 (en) 2010-09-01 2019-03-12 Arena Pharmaceuticals, Inc. Modified-release dosage forms of 5-HT2C agonists useful for weight management

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3689649A (en) * 1970-07-16 1972-09-05 Henri Dietrich N-substituted n-arylsulfonyl ureas for producing a hypoglycaemic effect
US4024128A (en) * 1974-02-22 1977-05-17 Hoffmann-La Roche Inc. Benzazepinyl sulfonylureas and intermediates therefore

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3689649A (en) * 1970-07-16 1972-09-05 Henri Dietrich N-substituted n-arylsulfonyl ureas for producing a hypoglycaemic effect
US4024128A (en) * 1974-02-22 1977-05-17 Hoffmann-La Roche Inc. Benzazepinyl sulfonylureas and intermediates therefore

Cited By (31)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8846906B2 (en) 2002-04-12 2014-09-30 Arena Pharmaceuticals, Inc. 5HT2C receptor modulators
US8546379B2 (en) 2002-04-12 2013-10-01 Arena Pharmaceuticals, Inc. 5HT2C receptor modulators
US7977329B2 (en) 2002-04-12 2011-07-12 Arena Pharmaceuticals, Inc. 5HT2C receptor modulators
US8575149B2 (en) 2002-04-12 2013-11-05 Arena Pharmaceuticals, Inc. 5HT2C receptor modulators
US8993750B2 (en) 2002-04-12 2015-03-31 Arena Pharmaceuticals, Inc. 5HT2C receptor modulators
US8207158B2 (en) 2002-04-12 2012-06-26 Arena Pharmaceuticals, Inc. 5HT2c receptor modulators
US8273734B1 (en) 2002-04-12 2012-09-25 Arena Pharmaceuticals, Inc. 5HT2C receptor modulators
US6953787B2 (en) 2002-04-12 2005-10-11 Arena Pharmaceuticals, Inc. 5HT2C receptor modulators
US9102627B2 (en) 2003-06-17 2015-08-11 Arena Pharmaceuticals, Inc. Processes for preparing 3-benzazepines
US8404675B2 (en) 2003-06-17 2013-03-26 Arena Pharmaceuticals, Inc. Benzazepine derivatives and methods of prophylaxis or treatment of 5HT2C receptor associated diseases
US8367657B2 (en) 2003-06-17 2013-02-05 Arena Pharmaceuticals, Inc. Processes for preparing 3-benzazepines
US8946207B2 (en) 2003-06-17 2015-02-03 Arena Pharmaceuticals, Inc. Processes for preparing 3-benzazepines
US7704993B2 (en) 2003-06-17 2010-04-27 Arena Pharmaceuticals, Inc. Benzazepine derivatives and methods of prophylaxis or treatment of 5ht2c receptor associated diseases
US8697686B2 (en) 2004-12-21 2014-04-15 Arena Pharmaceuticals, Inc. Crystalline forms of (R)-8-chloro-1-methyl-2,3,4,5-thtrahydro-1H-3-benzazepine hydrochloride
US8980881B2 (en) 2004-12-21 2015-03-17 Arena Pharmaceuticals, Inc. Crystalline forms of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride
US8168624B2 (en) 2004-12-21 2012-05-01 Arena Pharmaceuticals, Inc. Crystalline forms of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride
US8546378B2 (en) 2004-12-23 2013-10-01 Arena Pharmaceuticals, Inc. 5HT2C receptor modulator compositions and methods of use
US8168782B2 (en) 2006-04-03 2012-05-01 Arena Pharmaceuticals, Inc. Processes for the preparation of 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine and intermediates related thereto
US8802845B2 (en) 2006-04-03 2014-08-12 Arena Phamaceuticals, Inc. Processes for the preparation of 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine and intermediates related thereto
US8501935B2 (en) 2006-04-03 2013-08-06 Arena Pharmaceuticals, Inc. Processes for the preparation of 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine and intermediates related thereto
US8299241B2 (en) 2006-12-05 2012-10-30 Arena Pharmaceuticals, Inc. Processes for preparing (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine and intermediates thereof
US8822727B2 (en) 2008-03-04 2014-09-02 Arena Pharmaceuticals, Inc. Processes for the preparation of intermediates related to the 5-HT2C agonist (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
US8952197B2 (en) 2009-06-18 2015-02-10 Arena Pharmaceuticals, Inc. Processes for the preparation of 5-HT2C receptor agonists
US9045431B2 (en) 2010-06-02 2015-06-02 Arena Pharmaceuticals, Inc. Processes for the preparation of 5-HT2C receptor agonists
US8999970B2 (en) 2010-09-01 2015-04-07 Arena Pharmaceuticals, Inc. Administration of an anti-obesity compound to individuals with renal impairment
US9248133B2 (en) 2010-09-01 2016-02-02 Arena Pharmaceuticals, Inc. Salts of lorcaserin with optically active acids
US9365521B2 (en) 2010-09-01 2016-06-14 Arena Pharmaceuticals, Inc. Non-hygroscopic salts of 5-HT2C agonists
US9770455B2 (en) 2010-09-01 2017-09-26 Arena Pharmaceuticals, Inc. Administration of an anti-obesity compound to individuals with renal impairment
US10226471B2 (en) 2010-09-01 2019-03-12 Arena Pharmaceuticals, Inc. Modified-release dosage forms of 5-HT2C agonists useful for weight management
US10463676B2 (en) 2010-09-01 2019-11-05 Arena Pharmaceuticals, Inc. Modified-release dosage forms of 5-HT2C agonists useful for weight management
US9169213B2 (en) 2012-10-09 2015-10-27 Arena Pharmaceuticals, Inc. Method of weight management

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Publication number Publication date
AU1700688A (en) 1988-11-04

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