WO1993003015A1 - Heteroalcoxy benzazepines - Google Patents

Heteroalcoxy benzazepines Download PDF

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Publication number
WO1993003015A1
WO1993003015A1 PCT/US1992/006538 US9206538W WO9303015A1 WO 1993003015 A1 WO1993003015 A1 WO 1993003015A1 US 9206538 W US9206538 W US 9206538W WO 9303015 A1 WO9303015 A1 WO 9303015A1
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WIPO (PCT)
Prior art keywords
chloro
methyl
tetrahydro
benzazepine
pyrazol
Prior art date
Application number
PCT/US1992/006538
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English (en)
Inventor
Robert Michael Demarinis
Francis Richard Pfeiffer
Original Assignee
Smithkline Beecham 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
Application filed by Smithkline Beecham Corporation filed Critical Smithkline Beecham Corporation
Priority to JP5503834A priority Critical patent/JPH06511239A/ja
Priority to EP92917522A priority patent/EP0630372A1/fr
Priority to US08/193,075 priority patent/US5639748A/en
Publication of WO1993003015A1 publication Critical patent/WO1993003015A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • 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
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • 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
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • This invention relates to novel substituted 2,3,4,5- tetrahydro-1H-3-benzazepine compounds having ⁇ -adrenergic receptor antagonist activity.
  • the autonomic nervous system is separated into the cholinergic and adrenergic nervous systems.
  • Norepinephrine the neurotransmitter of the adrenergic nervous system, exerts its activity by interaction with receptors, (adrenoceptors) on the effector organs or on the nerve endings.
  • the adrenoceptors are of two primary types : ⁇ and ⁇ . Based upon selectivity of the receptors for a series of agonists and antagonists, the a adrenoceptors have been subdivided into ⁇ 1 and ⁇ 2 subtypes.
  • SK&F 104078- insensitive SK&F 104078-sensitive ⁇ 2 adrenoceptors.
  • ⁇ 2 adrenoceptors variously are referred to as postjunctional ⁇ 2 adrenoceptors or, preferably, ⁇ 3 adrenoceptors.
  • ⁇ adrenoceptors long have been the targets of efforts to develop agents effective in changing vascular tone for use in treating diseases, such as hypertension, in which alterations in vascular resistance produce
  • Antihypertensive compounds presently in clinical use that function via interaction with a adrenoceptors include methyldopa, clonidine, and prazosin. Efforts to modulate sympathetic tone through interactions with a adrenoceptors have resulted in several compounds that interact somewhat selectively with ⁇ 1 or ⁇ 2
  • adrenoreceptors include phenylephrine and methoxamine which preferentially activate ⁇ 1 receptors; and clonidine, ⁇ -methyl-norepinephrine, and tramazoline which preferentially activate ⁇ 2 adrenoceptors.
  • selective ⁇ -adrenoceptor antagonists include prazosin which has high selectivity for ⁇ 1 adrenoceptors; and the ⁇ 2 -selective blockers yohimbine and rauwolscine.
  • the present invention resides in the discovery that certain substituted-2,3,4,5,-tetrahydro-1H-3-benzazepine compounds are ⁇ -adrenoceptor antagonists.
  • preferred compounds of the invention include:
  • the most preferred compound of the invention is 6- chloro-9-(3-furanylmethoxy)-2,3,4,5-tetrahydro-3-methyl- lH-3-benzazepine or a pharmaceutically acceptable salt thereof.
  • compositions comprising compounds useful in the method of the invention and a suitable pharmaceutical carrier.
  • compositions are used to produce a adrenoceptor antagonism and contain an effective amount of compounds useful in the methods of the invention.
  • X is H, Cl, Br, F, I, CF 3 , C 1-6 alkyl, COR 1 , CO2R 2 , CONR 2 R 2 , CN, NO 2 , NR 3 R 4 , OR 3 , SR 1 , SCF 3 , or any
  • R is H, C 1-6 alkyl, or C 3-5 alkenyl
  • Z is O oo S
  • each R 1 independently is C 1-6 alkyl or
  • each R 2 independently is H, C 1-6 alkyl, or
  • R 3 is H, C 1-6 alkyl, CHO, COR 1 , or SO 2 R 1 ;
  • R 4 is H or C 1-6 alkyl
  • Het is a heteroaryl group selected from thienyl, furanyl, pyrazolyl, imidazolyl, pyrrolyl, triazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl,
  • pyridinyl, or tetrazolyl which are unsubstituted or substituted by C 1-6 alkyl, C 1-6 alkoxy, Cl, Br, F, I,
  • A-Het is not -S (CH 2 ) o-l"thienyl or
  • C 1-6 alkyl means straight or branched alkyl of one to six carbon atoms
  • C 3-5 alkenyl means a straight or branched chain alkenyl having from 3 to 5 carbon atoms
  • any accessible combination thereof means any combination of up to three substituents on the phenyl moiety that is available by chemical synthesis and is stable.
  • Formula (la) includes presently preferred Formula (I) compounds:
  • X is H, Cl, Br, F, I, CF 3 , C 1-6 alkyl, COR 1 , CO 2 R 2 , CONR 2 R 2 , CN, NO 2 , NR 3 R 4 , OR 3 , or SCF 3 ;
  • R is H, C 1-6 alkyl, or C 3-5 alkenyl
  • each R 1 independently is C 1-6 alkyl or
  • each R 2 independently is H, C 1-6 alkyl, or
  • R 3 is H, C 1-6 alkyl, CHO, COR 1 , or SO 2 R 1 ;
  • R 4 is H or C 1-6 alkyl
  • Het is a heteroaryl group selected from thienyl, furanyl, pyrazolyl, imidazolyl, pyrrolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, or
  • tetrazolyl which are unsubstituted or substituted by C 1-6 alkyl, C 1-6 alkoxy, Cl, Br, F, I, NR 3 R 4 , CO 2 R 2 , CONR 2 R 2 , CN, or NO 2 ;
  • A-Het is not -S (CH 2 ) o-1 -thienyl or
  • Preferred compounds are represented by Formula (la) when:
  • X is Cl, Br, F, or I
  • R is CH 3 ;
  • Het is pyrazolyl, furanyl, thienyl, triazolyl, pyridinyl, or pyrrolyl with each heteroaryl group being unsubstituted or substituted by Cl or CH 3 .
  • a suitable base such as an alkali metal hydride, for example, sodium hydride
  • a suitable organic solvent such as
  • Formula (I) compounds wherein A is -O(CH 2 ) 2 - are prepared by reacting the formula (1) benzazepine compounds with a suitable base, such as an alkali metal hydride, in a suitable solvent, such as dimethylformamide, followed by reaction with an ester of a haloacetate, such as ethyl bromoacetate. The resulting (benzazepinyl)oxy acetate ester is reduced to the formula (1) benzazepine compounds with a suitable base, such as an alkali metal hydride, in a suitable solvent, such as dimethylformamide, followed by reaction with an ester of a haloacetate, such as ethyl bromoacetate. The resulting (benzazepinyl)oxy acetate ester is reduced to the formula (1) benzazepine compounds with a suitable base, such as an alkali metal hydride, in a suitable solvent, such as dimethylformamide, followed by reaction with an ester of a
  • the benzazepines of formula (2) are known to the art (J . Med. Chem., 27:918-921 (1984)) or are synthesized by known procedures.
  • the primary amine of formula (2) compounds is diazotized using, for example, sodium nitrite in acetic acid, water, and sulfuric acid.
  • Conversion to the corresponding cyano compounds of formula (3) is accomplished by reacting the diazonium salt with cyanide, for example, potassium cyanide.
  • the carboxylic acid compounds of formula (4) are prepared by reacting the cyano of the formula (3) compounds in the presence of barium hydroxide, in a suitable solvent, such as a mixture of ethanol and water.
  • the resulting acids are reacted with a suitable base, such as an alkali metal hydride, such as sodium hydride, in an appropriate solvent, such as dimethylformamide.
  • benzazepine nucleus may be prepared from Formula (2) amine compounds.
  • the amine-substituted benzazepine compounds are reacted with 2,5-hexane-dione or 2,5-dimethoxytetrahydrofuran in a suitable solvent, such as acetic acid or a mixture of acetic acid and toluene, at a temperature of about 80°C to about 120°C, preferably at about 110°C, to give pyrrole-substituted Formula (I) compounds.
  • Formula (I) compounds wherein A is a methylene group may be prepared from formula (3) cyano compounds.
  • benzazepines is reduced, for example, using lithium aluminum hydride, in an inert solvent, such as
  • Scheme III illustrates the preparation of additional Formula (I) compounds.
  • formula (3) cyano compounds are converted to the corresponding aldehyde derivatives of formula (6), for example using Raney® nickel in a suitable solvent, such as formic acid, at a temperature of about 35°C to about 100°C, preferably at about 100°C.
  • a suitable solvent such as formic acid
  • benzazepines are prepared from the formula (6) aldehyde compounds by reductive methods, for example, using sodium borohydride in a suitable solvent, such as methanol, at a temperature from about 0°C to about 35°C, preferably from about 5°C to about 24°C.
  • Formula (8) benzazepines, which are Formula (I) compounds, are prepared from formula (7) benzazepines, using the methods described in Scheme I.
  • Scheme III also shows the preparation of Formula (I) compounds wherein A is -(CH 2 ) 3-5 -.
  • formula (6) aldehyde compounds are reacted with a phosphorus ylide, such as triphenylphosphoranylideneacetaldehyde, in a suitable solvent, such as toluene, at a temperature of about 80°C to about 110°C, preferably at 110°C, or with an
  • Formula (I) are formed with inorganic or organic acids, by methods well known in the art.
  • suitable acids are maleic, fumaric, benzoic, ascorbic, pamoic, succinic, bismethylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, hydrochloric, hydrobromic, sulfuric, cyclohexylsulfamic, phosphoric and nitric acids.
  • the compounds of Formula (I) are ⁇ - adrenoceptor antagonists they are useful in treating cardiovascular diseases in which changes in vascular resistance are desirable, including hypertension, pulmonary hypertension, congestive heart failure, myocardial
  • Formula (I) compounds also are useful in treating peripheral vascular disease, benign prostatic hypertrophy, diabetes, glaucoma, ocular
  • hypertension obesity, disorders of gastrointestinal motility, including colonic spasm, irritable bowel
  • the invented compounds are useful in treating diseases resulting from inappropriate platelet aggregation.
  • ⁇ -adrenoceptor activity of certain compounds of the present invention was determined using the following in vitro systems.
  • Alphas adrenoceptor antagonist activity was determined using the rabbit aorta.
  • Male New Zealand White rabbits (2-4 Kg) were euthanized by cervical concussion.
  • a 4 cm portion of the thoracic aorta was removed and placed in a dish of cold (10°C) Krebs-Hensleit solution.
  • the tissue was cleaned of fat and connective tissue and cut into segments of approximately 3 mm in length. These segments were suspended in 10 ml tissue baths via hangers
  • Tissues were washed at 30 minute intervals during this equilibration period.
  • the Krebs- Hensleit solution contained cocaine (6mM) to block neuronal uptake and propranolol (1mM) to block beta-adrenoceptors .
  • Tissues were usually challenged once with norepinephrine (0.1mM) during the equilibration period to check for viability.
  • norepinephrine was obtained in each aortic segment.
  • the a adrenoceptor antagonist to be tested was added to the bath. After the tissue had been in contact with the antagonist for 30-60 minutes, the norepinephrine concentration response-curve was repeated in the presence of antagonist. The tissue was then washed again, and a tenfold higher concentration of antagonist added. Following equilibration (30-60 minutes), a third norepinephrine concentration-response curve was determined in the presence of the antagonist.
  • the receptor dissociation constant (K ⁇ ) for the antagonist was determined using the relationship
  • the left atrium is removed from a pentobarbital-anesthetized male guinea pig.
  • the left atrium is separated, dissected free of extraneous tissue and mounted in a 2 ml superfusion chamber.
  • the tissue is paced at 30 pulse/minute and the sympathetic nerves excited at 6 minute intervals by field stimulation.
  • the response to nerve stimulation is measured as the difference in contractile force between the basal
  • a concentration-response curve for B-HT 920 (a known ⁇ 2 agonist) is prepared by administering
  • Alpha 3 adrenoceptor antagonist receptor activity was determined using the dog saphenous vein (DSV) as the test system. This test system has been shown a suitable
  • Solid or liquid pharmaceutical carriers can be employed.
  • Solid carriers include, starch, lactose, calcium sulfate dihydrate, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid.
  • Liquid carriers include syrup, peanut oil, olive oil, saline, and water.
  • the carrier or diluent may include any prolonged release material, such as glyceryl monostearate or glyceryl distearate, alone or with a wax.
  • the amount of solid carrier varies widely but, preferably, will be from about 25 mg to about 1 g per dosage unit. When a liquid carrier is used, the
  • composition will be in the form of a syrup, elixir,
  • emulsion emulsion, soft gelatin capsule, sterile injectable liquid, or an aqueous or nonaqueous liquid suspension or solution.
  • the pharmaceutical preparations are made following conventional techniques of a pharmaceutical chemist
  • Doses of the present compounds in pharmaceutical dosage units will be an efficacious, nontoxic quantity selected from the range of 0.01-100 mg/kg of active
  • the selected dose is administered to a human patient in need of treatment from 1-6 times daily, orally, rectally, topically, by
  • Oral administration is preferred because it is more convenient for the patient.
  • Example 2 6-Chloro-2,3,4,5-t-etrahydro-3-methyl-9-(1H-pyrazol-1- ylmethoxy)-1H-3-bsnzazepine Using the general procedure of Example 1, replacing 4-chloro-1-(chloromethyl)-1H-pyrazole with 1-(chloromethyl)-1H-pyrazole gave, after chromatography on silica gel eluted with a methanol-methylene chloride gradient, 6-chloro-2,3,4,5-tetrahydro-3-methyl-9-(1H-pyrazol-1- ylmethoxy)-1H-3-benzazepine; mp 69-71.5°C .
  • Example 2 Using the general procedure of Example 2, replacing 1-(chloromethyl)-1H-pyrazole with 2-(chloromethyl)furan, 3-(bromomethyl)furan, 2-(3-chloro-1-propenyl)furan, 2- (bromomethyl)thiophene, 3-(bromomethyl)thiophene, 2-(1H- pyrazol-1-yl)ethyl 4-methylbenzenesulfonate, 1-(chloromethyl)-1H-1,2,4-triazole, and 4-(chloromethyl)pyridine hydrochloride gave:
  • Lithium aluminum hydride (1.53 g, 40 mmol) in ethyl ether (80 ml) was stirred, heated to reflux and treated with a solution of ethyl [(9-chloro-2,3,4,5-tetrahydro-3- methyl-1H-3-benzazepin-6-yl) oxy] acetate (4.0 g, 13.5 mmol) in ethyl ether (60 ml). The mixture was stirred at reflux for 3.5 hours, cooled, and carefully treated with water (1.5 ml), 10% sodium hydroxide (4.5 ml) and water (1.5 ml).
  • 6-Chloro-9-(2 ,5-dimethyl-1H-pyrrol-1-yl)-2,3,4,5- tetrahydro-3-methyl-1H-3-benzazepine Using the general procedure of Example 40, 9-chloro- 2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepin-6-amine (420 mg, 2.7 mmol) in acetic acid (6 ml) and toluene (6 ml) was treated with 2,5-hexanedione (300 mg, 2.7 mmol) and heated to reflux for 1 hour to give 6-chloro-9-(2,5- dimethyl-1H-pyrrol-1-yl)-2,3,4,5-tetrahydro-3-methyl-1H- 3-benzazepine (acetonitrile); mp 268-270°C.
  • Example 16 6 -Chloro-2 , 3, 4 , 5-tetrahydro-3-met h yl-9- (1H-pyrrol-1 - yl methyl ) -1 H-3-benzazepine
  • a suspension of lithium aluminum hydride (1.14 g, 30 mmol) in tetrahydrofuran (20 ml) was stirred and treated with a solution of 9-chloro-2, 3,4,5-tetrahydro-3-methyl- 1H-3-benzazepine-6-carbonitrile, prepared as in Example 12, (1.5 g, 6.8 mmol) in tetrahydrofuran (20 ml) and heated to reflux for 3 hours.
  • the aqueous phase was washed with ethyl ether, basified with aqueous sodium hydroxide and extracted with ethyl acetate-ethyl ether (2:1).
  • the organic phase was washed with water and brine, dried with magnesium sulfate and concentrated.
  • Example 43 Using the general procedure of Example 43, replacing 6-chloro-9-(3-chloropropyl)-2,3,4,5-tetrahydro-3-methyl- 1H-3-benzazepine with 6-chloro-9-(5-chloropentyl)- 2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepine gave 52 mg (13 %) of 6-chloro-9-[5-(4-chloro-1H-pyrazol-1- yl)pentyl]-2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepine hydrochloride; mp 158-161°C.
  • An oral dosage form for administering the presently invented compounds is produced by screening, mixing, and filling into a hard gelatin capsule ingredients in the proportions shown in Table II, below.
  • sucrose, calcium sulfate dihydrate and Formula (I) compound shown in Table III below are mixed and granulated with a 10% gelatin solution.
  • the wet granules are
  • 6-Chloro-9-(3-furanylmethoxy)2,3,4,5-tetrahydro-3- methyl-1H-3-benzazepine 75 mg, is dispersed in 25 ml of normal saline to prepare an injectable preparation.

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Abstract

Antagonistes au récepteur alpha-adrénergique de la formule (I), utiles pour produire un antagonisme à l'α-adrénorécepteur, compositions pharmaceutiques comprenant ces antagonistes, et procédés d'utilisation desdits antagonistes afin de produire un antagonisme à l'α-adrénorécepteur chez des mammifères.
PCT/US1992/006538 1991-08-05 1992-08-05 Heteroalcoxy benzazepines WO1993003015A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
JP5503834A JPH06511239A (ja) 1991-08-05 1992-08-05 ヘテロアルコキシベンズアゼピン類
EP92917522A EP0630372A1 (fr) 1991-08-05 1992-08-05 Heteroalcoxy benzazepines
US08/193,075 US5639748A (en) 1991-08-05 1992-08-05 6,9-disubstituted benzazepines having α-adrenoceptor blocking activity

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB919116824A GB9116824D0 (en) 1991-08-05 1991-08-05 Chemical compounds
GB9116824.5 1991-08-05

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WO1993003015A1 true WO1993003015A1 (fr) 1993-02-18

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EP (1) EP0630372A1 (fr)
JP (1) JPH06511239A (fr)
AU (1) AU2433092A (fr)
GB (1) GB9116824D0 (fr)
WO (1) WO1993003015A1 (fr)

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* Cited by examiner, † Cited by third party
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US6303600B1 (en) * 1996-06-19 2001-10-16 Rhone-Poulenc Rorer Limited Substituted azabicyclic compounds
WO2004018432A1 (fr) * 2002-08-20 2004-03-04 Eli Lilly And Company Azepines substituees utilisees comme antagonistes des recepteurs h3 de l'histamine, leur preparation et leurs utilisations therapeutiques
WO2004035544A1 (fr) * 2002-10-16 2004-04-29 Glaxo Group Limited Derives de benzazepine pour le traitement de troubles neurologiques et psychiatriques
WO2005042491A1 (fr) * 2003-10-22 2005-05-12 Arena Pharmaceuticals, Inc. Derives de benzazepine et methodes de prophylaxie ou traitement de maladies associees au recepteur 5ht2c
WO2005082859A1 (fr) 2004-02-25 2005-09-09 Eli Lilly And Company 2,3,4,5-tetrahydro-1h-benzo[d]azepines substitues en position 6 en tant qu'agonistes de recepteur 5-ht2c
WO2007028132A2 (fr) 2005-09-01 2007-03-08 Eli Lilly And Company 2,3,4,5-TETRAHYDRO-1H-BENZO[d]AZEPINES SUBSTITUEES PAR UN HETEROCYCLE A LIAISON 6-N EN TANT QU'AGONISTES DE RECEPTEUR 5-HT2C
US7696193B2 (en) 2002-12-20 2010-04-13 Glaxo Group Limited Benzazepine derivatives for the treatment of neurological disorders
US7704993B2 (en) 2003-06-17 2010-04-27 Arena Pharmaceuticals, Inc. Benzazepine derivatives and methods of prophylaxis or treatment of 5ht2c receptor associated diseases
US7994163B2 (en) 2005-09-01 2011-08-09 Eli Lilly And Company 6-substituted-2,3,4,5-tetrahydro-1H-benzo[d]azepines as 5-HT2C receptor agonists
US8153621B2 (en) 2004-12-23 2012-04-10 Arena Pharmaceuticals, Inc. 5ht2C receptor modulator compositions
US8420631B2 (en) 2005-09-01 2013-04-16 Eli Lilly And Company 6-substituted-2,3,4,5-tetrahydro-1H-benzo[d]azepines as 5-HT2C receptor agonists
US8680091B2 (en) 2005-09-01 2014-03-25 Eli Lilly And Company 6-arylalkylamino-2,3,4,5-tetrahydro-1H-benzo[d]azepines as 5-HT2C receptor agonists
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US8999970B2 (en) 2010-09-01 2015-04-07 Arena Pharmaceuticals, Inc. Administration of an anti-obesity compound to individuals with renal impairment
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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

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US8153621B2 (en) 2004-12-23 2012-04-10 Arena Pharmaceuticals, Inc. 5ht2C receptor modulator compositions
US7981882B2 (en) 2005-09-01 2011-07-19 Eli Lilly And Company 6-N-linked heterocycle-substituted 2,3,4,5-tetrahydro-1H-benzo[d]azepines as 5-HT2C receptor agonists
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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
US9045431B2 (en) 2010-06-02 2015-06-02 Arena Pharmaceuticals, Inc. Processes for the preparation of 5-HT2C receptor agonists
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Also Published As

Publication number Publication date
JPH06511239A (ja) 1994-12-15
EP0630372A1 (fr) 1994-12-28
AU2433092A (en) 1993-03-02
GB9116824D0 (en) 1991-09-18
EP0630372A4 (fr) 1994-07-05

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