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WO1998029405A1 - Benzo[1,4]dioxannes substitues utilises comme agents anti-obesite - Google Patents

Benzo[1,4]dioxannes substitues utilises comme agents anti-obesite Download PDF

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Publication number
WO1998029405A1
WO1998029405A1 PCT/US1997/024019 US9724019W WO9829405A1 WO 1998029405 A1 WO1998029405 A1 WO 1998029405A1 US 9724019 W US9724019 W US 9724019W WO 9829405 A1 WO9829405 A1 WO 9829405A1
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WO
WIPO (PCT)
Prior art keywords
phenyl
alkyl
compound
benzo
formula
Prior art date
Application number
PCT/US1997/024019
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English (en)
Inventor
Aranapakam Mudumbai Venkatesan
Original Assignee
American Home Products 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 American Home Products Corporation filed Critical American Home Products Corporation
Priority to IL12971597A priority Critical patent/IL129715A0/xx
Priority to NZ336235A priority patent/NZ336235A/xx
Priority to JP53026098A priority patent/JP2001507704A/ja
Priority to BR9714109A priority patent/BR9714109A/pt
Priority to AU57230/98A priority patent/AU5723098A/en
Priority to HU0000768A priority patent/HUP0000768A2/hu
Priority to EP97953494A priority patent/EP0948494A1/fr
Priority to CA002271885A priority patent/CA2271885A1/fr
Publication of WO1998029405A1 publication Critical patent/WO1998029405A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
    • C07D319/14—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems
    • C07D319/16—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D319/20—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring with substituents attached to the hetero ring

Definitions

  • This invention relates to novel substituted 1,4-benzodioxane compounds which have antidiabetic, antihyperglycemic, and antiobesity properties.
  • the present invention also relates to pharmaceutical compositions comprising these compounds, methods for the preparation of these compounds, and methods for the use of these compounds in treating diabetes and/or hyperglycemia and/or obesity in mammals.
  • the antiobesity compounds may find further use in reducing the fat content in domestic edible animals.
  • the compounds of the present invention achieve their antidiabetic, antihyperglycemic, and antiobesity effects by acting as selective agonists at ⁇ 3 adrenergic receptors.
  • the stimulation of these receptors on white and brown adipocytes promotes both lipolysis (breakdown of fat) and energy expenditure.
  • Selective stimulation of ⁇ 3 adrenergic receptors is important for chronic treatment. Stimulation of other ⁇ -receptors could cause side effects such as increased heart rate ( ⁇ i effect) and/or muscle tremor ( ⁇ 2 effect).
  • the compounds of the present invention show high selectivity for ⁇ 3 adrenergic receptors.
  • R 1 and R 4 may be one or more groups which may be the same or different and are selected from the group consisting of hydrogen, Ci to C4 alkyl, Ci to C4 alkoxy, hydroxy, halogen, trifluoromethyl, carboxy, hydroxyalkyl, alkoxycarbonyl, Ci to C4 thioalkyl, sulfonyl and sulfinyl;
  • X is a divalent radical consisting of
  • R' is selected from the group consisting of hydrogen, Ci to C4 alkyl and Ci to C4 acyl and Y is selected from the group consisting of carbonyl and thiocarbonyl;
  • R 2 and R 3 may be the same or different and are selected from the group consisting of hydrogen and Cl to C4 alkyl;
  • R 5 and R 6 are selected from the group consisting of hydrogen, carboxy, alkoxycarbonyl, hydroxymethyl, -CH2OCH2COOR7 and -CH2OCH2CH2OR7, where R 7 is hydrogen or Cl to C4 alkyl; with the provision that R 5 and R 6 may not both be hydrogen; which have antihyperglycemic and antiobesity activity.
  • the compounds of the present invention contain a 1,4-benzodioxane ring, whereas the compounds in Bloom, et al., U.S. Patent 5,061,727 contain a 1,3-benzodioxole. They retain high selectivity for the ⁇ 3 receptor and show much higher antiobesity and antihyperglycemic activity in animal models. Therefore, the compounds of this invention are useful in treating diabetes, hyperglycemia, and obesity, exhibiting minimal side effects such as heart rate increase and/or muscle tremor in humans and animals, when formulated into pharmaceutical compositions. Health-conscious individuals today are making an effort to reduce body fat through exercise and low fat diet. An invention compound can help a human reduce body fat and through treatment of domestic edible animals such as cattle, swine, sheep, goats, turkeys and chickens can provide leaner meats for human consumption.
  • This invention provides new compounds of formula (II):
  • R 1 and R 6 are independently hydrogen, Q to C 6 alkyl, trifluoromethyl, cyano, Cj to alkoxy, or halogen;
  • R 2 is hydrogen or to C 6 trialkylsilyl
  • R 3 is hydrogen or to alkoxycarbonyl
  • R 2 and R 3 are joined to form the oxazolidinone ring
  • R 4 and R 5 are independently hydrogen or to alkyl
  • R 7 and R 8 are independently OR 9 or NR 10 R U ;
  • R 9 is hydrogen, to C 12 alkyl, Ci to C 12 cycloalkyl, to C ⁇ 2 silylalkyl, phenyl, naphthyl, phenyl to alkyl, Ci to alkoxy to C 6 alkyl, pyridyl, thiophenyl, furanyl, imidazolyl, oxazolyl, -CHR 12 COOR 13 , -
  • R 10 and R 11 are independently hydrogen, to C 12 alkyl, phenyl, naphthyl, phenyl-Q to alkyl, furanylalkyl, or alkoxycarbonylalkyl;
  • R 12 and R 13 are independently hydrogen, Q to C 12 alkyl, phenyl, naphthyl, or phenyl-Q to C 6 alkyl; and the pharmaceutically acceptable salts thereof, the salts thereof; the enantiomers thereof, the racemic mixtures thereof, and the diastereomeric mixtures thereof.
  • R 1 is preferably a halogen, more preferably chlorine and is preferably located at the meta-position of the benzene ring.
  • R 2 and R 3 are each independently preferably hydrogen or are joined to form the oxazolidinone ring.
  • R 4 and R 5 are each independently preferably hydrogen or Ci to C 6 alkyl; more preferably hydrogen or methyl. In particularly preferred embodiments one of R 4 and R 5 is hydrogen and the other is methyl.
  • R 6 is preferably hydrogen.
  • R 9 is preferably hydrogen, d to Q 2 alkyl, Q to C 12 cycloalkyl, phenyl, phenyl Ci to alkyl or Q to C 6 alkoxy Q to alkyl; more preferably hydrogen, methyl, ethyl, isopropyl, isobutyl, octyl, cyclopropyl, cyclohexyl, benzyl or 2-ethyloxyethyl.
  • alkyl includes both straight and branched chain alkyl groups, e.g. methyl, ethyl, propyl, isopropyl, n- butyl, isobutyl, s-butyl, pentyl and hexyl.
  • halogen includes chlorine, bromine, fluorine and iodine.
  • cycloalkyl includes cyclopropyl, cyclobutyl, cycopentyl and cycolohexyl.
  • Acid addition salts on an invention compound where a basic nitrogen is present can be prepared using a pharmaceutically acceptable inorganic or organic acid such as, but not limited to, hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, fumaric, maleic, succinic, benzoic, methanesulfonic or toluenesulfonic acid.
  • Base addition salts can be prepared where the invention compound has a carboxylic acid group from an alkali metal oxide or hyrdoxide or alkaline earth metal oxide or hydroxide such as NaOH, KOH, Ca(OH) 2 .
  • ⁇ 3 selective compounds of this invention are useful for the treatment of non- insulin dependent diabetes mellitus, hyperglycemia and obesity in mammals
  • ⁇ adrenergic receptors can be divided into ⁇ i, ⁇ 2 , and ⁇ 3 subtypes.
  • Activation of ⁇ i receptors invokes increase in heart rate while activation of ⁇ 2 receptors stimulates glycogen breakdown in muscle and therefore prevents glycogen synthesis.
  • Activation of ⁇ 3 receptors stimulates lipolysis or the breakdown of brown adipose tissue triglycerides to glycerol and free fatty acids, and therby promotes the loss of fat mass.
  • Compounds that stimulate ⁇ 3 receptors will have anti-obesity activity. Brown adipose tissue may also play a role in glucose homeostasis and ⁇ 3 adrenergic agonist may therefore also have hypoglycemic or anti- diabetic activity.
  • this invention provides for a method of treating obesity, hyperglycemia, and diabetes in mammals as well as a pharmaceutical composition.
  • the invention compounds may offer further health benefit in humans by use in reducing fat in meat of animals raised for human consumption such as cattle, poultry, swine, sheep and goats.
  • the compounds of the present invention may be prepared according to one of the general processes outlined below.
  • a catechol 1 is treated with a base and a dibromosuccinate ester 2 to afford an oxazolidinone 3, which is hydrolyzed to yield a 1,4-benzodioxane dicarboxylic acid 4, wherein R 1 , R 4 , R 5 , and R 6 , are as defined above.
  • Syntheses of the starting catechol 1 is described in U. S. patent 5,061,727 and U. S. patent 5,420,291.
  • a disodium carboxylate 4 is converted to a disilver carboxylate and treated with an iodo derivative 5 to yield the diester compounds 6 wherein R 1 , R 4 , R 5 , R 6 , R 12 , and R 13 are as defined above.
  • Scheme HI illustrates an alternative procedure for diester preparation wherein a dicarboxylic acid 4 is treated with an alcohol R 9 OH and an acid catalyst to yield the diester compounds 7 wherein R 1 , R 4 , R 5 , R 6 , and R 9 are as defined above.
  • the diester compounds 7 can be hydrolyzed under basic conditions to a monoester 8a and/or 8b, wherein R 1 , R 4 , R 5 , R 6 , and R 9 are as defined above.
  • R 1 , R 4 , R 5 , R 6 , and R 9 are as defined above.
  • One or both of the regioisomers 8a and 8b may be produced in the hydrolysis reaction.
  • a mono ester compound 8a or 8b may be suitably converted to a mono ester/mono acid halide derivative, e.g., the conversion to the corresponding acid chloride may conveniently be achieved with oxalyl chloride in dimethylforrnamide and methylene chloride.
  • the mono ester/mono acid halide derivative 10a or 10b may then be converted to the corresponding formula II mono ester/mono amide, e.g., by reaction with an amine of the formula HNR ⁇ R 11 .
  • reaction mixture was stirred for 8 hrs at room temperature.
  • the reaction mixture was then concentrated and dissolved in water (100 ml).
  • Concentrated hydrochloric acid was added and the separated compound was extracted with chloroform; washed well with water, dried over anhydrous magnesium sulfate; filtered and concentrated.
  • the product was purified by silica-gel column chromatography by eluting it with chloroform. Yield: 2.0 g solid; mp 198°C; M + H 476.
  • Hydrogen chloride gas was passed through isopropanol (100 ml) at 0°C for fifteen minutes and the (2,3-cis)-6- ⁇ (2R)-2-[(2R)-2-(3-chloro-phenyl)-2-hydroxy-ethylamino]- propyl)2,3-dihydro-benzo[l,4] dioxane-2,3-dicarboxylic acid (2.15 g, 5 mmol) was added. The reaction mixture was refluxed for twenty-four hours and it was concentrated. The residue obtained was neutralized with sodium bicarbonate solution and extracted with chloroform. It was dried over anhydrous sodium sulfate; filtered and concentrated. The product obtained was purified by silica-gel column chromatography by eluting it initially with chloroform and then with chloroform:methanol (9:1). The diester eluted out first and was followed by the monoester.
  • Hydrogen chloride gas was passed through the appropriate alcohol (100 ml) at 0°C for fifteen minutes and the (2,3-cis)-6- ⁇ (2R)-2-[(2R)-2-(3-chloro-phenyl)-2-hydroxy- ethylamino]-propyl ⁇ 2,3-dihydro-benzo[l,4] dioxane-2,3-dicarboxylic acid (2.15 g, 5 mmol) was added. The reaction mixture was heated to 100°C for forty-eight hours. At the end, excess alcohol was removed under reduced pressure and the residue was neutralized with sodium bicarbonate solution.
  • the product obtained was extracted with chloroform; washed well with water, dried over anhydrous magnesium sulfate; filtered and concentrated.
  • the products were purified by silica-gel column chromatography. Initially the column was eluted with chloroform and later with 9: 1 chlorofornrmethanol.
  • the title compound was prepared from from (2,3-cis)-6- ⁇ (2R)-2-[(2R)-2-(3-chloro- phenyl)-2-hydroxy-ethylamino]-propyl ⁇ 2,3-dihydro-benzo[l,4] dioxane-2,3-dicarboxylic acid (2.15 g, 5 mmol) and cyclopentanol according to the General Procedure above to yield an amorphous solid: 1.4g (49%); M + H 572.
  • test compounds on human ⁇ -adrenergic receptors were determined with Chinese hamster ovary (CHO) cells transfected with human ⁇ 3, ⁇ 2, or ⁇ i adrenergic receptors.
  • Chinese hamster ovary (CHO) cells transfected with human ⁇ 3, ⁇ 2, or ⁇ i adrenergic receptors.
  • the preparation of these cells has been described in Emorine, L.J., Marullo, S., Briend-Sutren, M., Patey, G., Tate, K., Delavier-Klutchko, C, Strosberg, A.D.
  • Agonist activity is indicated by increased cAMP levels in the CHO cells.
  • Selectivity of the test compounds for the ⁇ 3 receptor was assessed by comparison with results in ⁇ 2 and ⁇ i adrenergic receptor transfected cells.
  • Rats respond to a single oral dose of ⁇ 3 agonist by increasing plasma free fatty acids (FFA) in response to ⁇ 3 receptor stimulation on the plasma membrane of the fat cell.
  • FFA plasma free fatty acids
  • 5- ⁇ 2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino] -propyl ⁇ -benzo[ 1 ,3]dioxole-2,2- dicarboxylic acid diisopropyl ester (Standard 2) was used as a standard compound. All test compounds were dosed at 0.1 mg/kg and compared to the response by Standard 2.
  • Methyl cellulose:tween-80 drug suspension was given via gavage (1 mL/200g body weight; or 0.1 mg kg) to rats and blood was collected 50 min later. 4). Plasma was analyzed for free fatty acids using a kit supplied by Biochemical
  • mice Male, db/db (C57BL/KsJ), Jackson Laboratories, 2 to 7 months of age and 35 to 60 g
  • a baseline blood sample was collected from the tail-tip of each mouse without anesthesia, placed directly into a fluoride-containing tube, mixed, and maintained on ice. Food was then returned to the mice.
  • the plasma was seperated and the levels of glucose in the plasma were dertermined by an Abbot VP Analyzer.
  • test compounds were administered (p.o.) to the ad libitum fed mice.
  • the food was removed from the cages for 3 h, a blood sample was collected, and the mice were then given the fourth administration of test compound or vehicle. Additional blood samples were collected at 2 and 4 h after test compound administration. Plasma glucose levels were determined.
  • the percent change of an animal's plasma glucose level on Day 4 (mean of 2 and 4 h values) from its level before test compound administration (Day 1 baseline sample) was determined as follows:
  • a 50-60% reduction of plasma glucose levels in the hyperglycemic db/db mice represents a normalization of glucose levels.
  • Compounds of this invention may be administered neat or with a pharmaceutical carrier to a patient in need thereof.
  • the pharmaceutical carrier may be solid or liquid.
  • Applicable solid carriers can include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents or an encapsulating material.
  • the carrier is a finely divided solid which is in admixture with the finely divided active ingredient.
  • the active ingredient is mixed with a carrier having the necessary compression properties n suitable proportions and compacted in the shape and size desired.
  • the powders and tablets preferably contain up to 99% of the active ingredient.
  • Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.
  • Liquid carriers may be used in preparing solutions, suspensions, emulsions, syrups and elixirs.
  • the active ingredient of this invention can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fat.
  • the liquid carrier can contain other suitable pharmaceutical additives such a solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators.
  • suitable pharmaceutical additives such as a solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators.
  • suitable examples of liquid carriers for oral and parenteral administration include water (particularly containing additives as above, e.g., cellulose derivatives, preferable sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, e.g., glycols) and their derivatives, and oils (e.g., fractionated coconut oil and arachis oil).
  • the carrier can also be an oily ester such as
  • Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. Oral administration may be either liquid or solid composition form.
  • the compounds of this invention may be administered rectally in the form of a conventional suppository.
  • the compounds of this invention may be formulated into an aqueous or partrially aqueous solution, which can then be utilized in the form of an aerosol.
  • the compounds of this invention may also be administered transdermally through the use of a transdermal patch containing the active compound and a carrier that is inert to the active compound, is non-toxic to the skin, and allows delivery of the agent for systemic absorption into the blood stream via the skin.
  • the carrier may take any number of forms such as creams and ointments, pastes, gels, and occlusive devices.
  • the creams and ointments may be viscous liquid or semi-solid emulsions of either the oil in water or water in oil type.
  • Pastes comprised of absorptive powders dispersed in petroleum or hydrophilic petroleum containing the active ingredient may also be suitable.
  • a variety of occlusive devices may be used to release the active ingredient into the blood stream such as a semipermeable membrane covering a reservoir containing the active ingredient with or without a carrier, or a matrix containing the active ingredient. Other occlusive devices are known in the literature. Further, an invention compound may be incorporated into a controlled release subcutaneous implant for gradual release over a period of time eliminating the necessity of frequent dosing.
  • An antiobesity invention compound may also be incorporated into animal feed for the use with livestock as a means of oral dosing.
  • the dosage to be used in the treatment of a specific patient suffering obesity and/or diabetes and/or hyperglycemia must be subjectively determined by the attending physician. The variables involved include the severity of the dysfunction, and the size, age, and response pattern of the patient. Treatment will generally be initiated with small dosages less than the optimum dose of the compound. Thereafter the dosage is increased until the optimum effect under the circumstances is reached. Precise dosages for oral, parenteral, nasal, or intrabronchial administration will be determined by the administering physician based on experience with the individual subject treated and standerd madical principles.
  • the pharmaceutical composition is in unit dosage form, e.g., as tablets or capsules.
  • the composition is sub-divided in unit dose containing appropriate quantities of the active ingredient;
  • the unit dosage form can be packaged compositions, for example packed powders, vials, ampoules, prefilled syringes or sachets containing liquids.
  • the unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Diabetes (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Child & Adolescent Psychology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Heterocyclic Compounds That Contain Two Or More Ring Oxygen Atoms (AREA)
  • Addition Polymer Or Copolymer, Post-Treatments, Or Chemical Modifications (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

Nouveaux composés 1,4-benzodioxannes substitués présentant des propriétés anti-diabétiques, antihyperglycémiques et anti-obésité, représentés par la formule (II) dans laquelle R1 et R6 représentent indépendamment hydrogène, alkyle C¿1? à C6, trifluorométhyle, cyano, alcoxy C1 à C6, ou halogène; R?2¿ représente hydrogène ou trialkylsilyle C¿1? à C6; R?3¿ représente hydrogène ou alcoxycarbonyle C¿1? à C6; ou R?2 et R3¿ sont liés pour former le cycle oxazolidinone (III); R4 et R5 représentent indépendamment hydrogène ou alkyle C¿1? à C6; R?7 et R8¿ sont indépendamment OR?9 ou NR10R11; R9¿ représente hydrogène, alkyle C¿1? à C12, cycloalkyle C1 à C12, silylalkyle C1 à C12, phényle, naphtyle, phényl-alkyle C1 à C6, alcoxy C1 à C6-alkyle C1 à C6, pyridyle, thiophényle, furanyle, imidazolyle, oxazolyle, -CHR?12COOR13, -CHR12C(O)R13, -CHR12CONR10R11, -CHR12OCOOR13¿, ou -CHR?12OC(O)R13; R10 et R11¿ représentent indépendamment hydrogène, alkyle C¿1? à C12, phényle, naphtyle, phényl-alkyle C1 à C6, furanylalkyle, ou alcoxycarbonylalkyle; R?12 et R13¿ représentent indépendamment hydrogène, alkyle C¿1? à C12, phényle, naphtyle ou phényl-alkyle C1 à C6; et les sels pharmaceutiquement acceptables de ces composés, un sel de ceux-ci; un énantiomère, les conglomérats racémiques et les mélanges diastéréoisomères de ces composés.
PCT/US1997/024019 1996-12-30 1997-12-18 Benzo[1,4]dioxannes substitues utilises comme agents anti-obesite WO1998029405A1 (fr)

Priority Applications (8)

Application Number Priority Date Filing Date Title
IL12971597A IL129715A0 (en) 1996-12-30 1997-12-18 Substituted benzo (1,4) dioxanes as antiobesity agents
NZ336235A NZ336235A (en) 1996-12-30 1997-12-18 Compounds containing 1,4-benzodioxane ring as antiobesity agents with antidiabetic, antihyperglycemic and antiobesity properties
JP53026098A JP2001507704A (ja) 1996-12-30 1997-12-18 抗肥満薬としての置換ベンゾ［１，４］ジオキサン
BR9714109A BR9714109A (pt) 1996-12-30 1997-12-18 Benzo [1,4] dioxanos substituìdos como reagentes antiobesidades
AU57230/98A AU5723098A (en) 1996-12-30 1997-12-18 Substituted benzo{1,4}dioxanes as antiobesity agents
HU0000768A HUP0000768A2 (hu) 1996-12-30 1997-12-18 Szubsztituált benzo[1,4]dioxánok, eljárás előállításukra és ezeket tartalmazó gyógyszerkészítmények
EP97953494A EP0948494A1 (fr) 1996-12-30 1997-12-18 Benzo 1,4]dioxannes substitues utilises comme agents anti-obesite
CA002271885A CA2271885A1 (fr) 1996-12-30 1997-12-18 Benzo[1,4]dioxannes substitues utilises comme agents anti-obesite

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US77474996A 1996-12-30 1996-12-30
US08/774,749 1996-12-30

Publications (1)

Publication Number Publication Date
WO1998029405A1 true WO1998029405A1 (fr) 1998-07-09

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PCT/US1997/024019 WO1998029405A1 (fr) 1996-12-30 1997-12-18 Benzo[1,4]dioxannes substitues utilises comme agents anti-obesite

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EP (1) EP0948494A1 (fr)
JP (1) JP2001507704A (fr)
KR (1) KR20000062404A (fr)
AU (1) AU5723098A (fr)
BR (1) BR9714109A (fr)
CA (1) CA2271885A1 (fr)
HU (1) HUP0000768A2 (fr)
IL (1) IL129715A0 (fr)
NZ (1) NZ336235A (fr)
WO (1) WO1998029405A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000006562A1 (fr) * 1998-07-31 2000-02-10 Nisshin Flour Milling Co., Ltd. Derives d'acide 1,4-benzodioxine-2-carboxylique optiquement actifs et procede de production
WO2004037807A3 (fr) * 2002-10-22 2004-06-24 Glaxo Group Ltd Composes medicinaux
WO2007078523A3 (fr) * 2005-12-15 2007-11-15 Astrazeneca Ab Composes d'oxazolidinone et leur utilisation en tant que potentialisateurs de recepteur de glutamate metabotropique
US7442839B2 (en) 2002-10-28 2008-10-28 Glaxo Group Limited Phenethanolamine derivative for the treatment of respiratory diseases

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US5061727A (en) * 1990-05-04 1991-10-29 American Cyanamid Company Substituted 5-(2-((2-aryl-2-hydroxyethyl)amino)propyl)-1,3-benzodioxoles
US5482971A (en) * 1993-10-01 1996-01-09 American Cyanamid Company Beta3 -adrenergic agents and their use in pharmaceutical compositions
WO1996035685A1 (fr) * 1995-05-12 1996-11-14 Nisshin Flour Milling Co., Ltd. Derives de 1,4-benzodioxine

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5061727A (en) * 1990-05-04 1991-10-29 American Cyanamid Company Substituted 5-(2-((2-aryl-2-hydroxyethyl)amino)propyl)-1,3-benzodioxoles
US5482971A (en) * 1993-10-01 1996-01-09 American Cyanamid Company Beta3 -adrenergic agents and their use in pharmaceutical compositions
WO1996035685A1 (fr) * 1995-05-12 1996-11-14 Nisshin Flour Milling Co., Ltd. Derives de 1,4-benzodioxine
EP0825189A1 (fr) * 1995-05-12 1998-02-25 Nisshin Flour Milling Co., Ltd. Derives de 1,4-benzodioxine

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000006562A1 (fr) * 1998-07-31 2000-02-10 Nisshin Flour Milling Co., Ltd. Derives d'acide 1,4-benzodioxine-2-carboxylique optiquement actifs et procede de production
US6222050B1 (en) 1998-07-31 2001-04-24 Nisshin Flour Milling Co., Ltd. Optically active 1,4-benzodioxine-2-carboxylic acid derivatives and process for producing the same
US6329533B2 (en) 1998-07-31 2001-12-11 Nisshin Pharma Inc. Optically active 1,4-benzodioxin-2-carboxylic acid derivatives and process for producing the same
US6509482B2 (en) 1998-07-31 2003-01-21 Nisshin Pharma Inc. Optically active 1,4-benzodioxin-2-carboxylic acid derivatives and process for producing the same
WO2004037807A3 (fr) * 2002-10-22 2004-06-24 Glaxo Group Ltd Composes medicinaux
JP2006506373A (ja) * 2002-10-22 2006-02-23 グラクソ　グループ　リミテッド 医薬アリールエタノールアミン化合物
US7442839B2 (en) 2002-10-28 2008-10-28 Glaxo Group Limited Phenethanolamine derivative for the treatment of respiratory diseases
WO2007078523A3 (fr) * 2005-12-15 2007-11-15 Astrazeneca Ab Composes d'oxazolidinone et leur utilisation en tant que potentialisateurs de recepteur de glutamate metabotropique
US7816354B2 (en) 2005-12-15 2010-10-19 Astrazeneca Ab Oxazolidinone compounds and their use as metabotropic glutamate receptor potentiators

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KR20000062404A (ko) 2000-10-25
CA2271885A1 (fr) 1998-07-09
HUP0000768A2 (hu) 2001-05-28
IL129715A0 (en) 2000-02-29
EP0948494A1 (fr) 1999-10-13
NZ336235A (en) 2000-11-24
AU5723098A (en) 1998-07-31
BR9714109A (pt) 2000-03-21
JP2001507704A (ja) 2001-06-12

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