WO1987003807A1 - Derives d'oxazole et leur utilisation en tant qu'agents anti-hyperglycemiques - Google Patents

Derives d'oxazole et leur utilisation en tant qu'agents anti-hyperglycemiques Download PDF

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Publication number
WO1987003807A1
WO1987003807A1 PCT/GB1986/000789 GB8600789W WO8703807A1 WO 1987003807 A1 WO1987003807 A1 WO 1987003807A1 GB 8600789 W GB8600789 W GB 8600789W WO 8703807 A1 WO8703807 A1 WO 8703807A1
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WO
WIPO (PCT)
Prior art keywords
methyl
compound
formula
oxazolyl
chlorophenyl
Prior art date
Application number
PCT/GB1986/000789
Other languages
English (en)
Inventor
Richard Mark Hindley
Original Assignee
Beecham Group P.L.C.
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 Beecham Group P.L.C. filed Critical Beecham Group P.L.C.
Publication of WO1987003807A1 publication Critical patent/WO1987003807A1/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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms

Definitions

  • Oxazole derivatives and their use as anti-hyperglycaemic are examples of Oxazole derivatives and their use as anti-hyperglycaemic.
  • the invention relates to a method for the treatment and/or prophylaxis of hyperglycaemia and compounds for use in such method.
  • R a lower alkyl
  • R b H or lower alkyl
  • R c H or halogen
  • the oxazoles of formula (A) and salts thereof are disclosed as having good serum-cholesterol and serum-triglyceride level lowering activity and good platelet-agglutination inhibitory activity, being useful as anti-lipaemic agents.
  • the present invention provides a method for the treatment and/or prophylaxis of hyperglycaemia in humans or non-human mammals, which method comprises the administration of an effective, non-toxic amount of a compound of formula (I):
  • R 1 represents a C 1-6 alkyl, C 1-6 arylalkyl or aryl group
  • R 2 represents a hydrogen atom or a C 1-6 alkyl group
  • R 3 represents a substituted or unsubstituted aryl group
  • n represents an integer of from 1 to 6.
  • R 1 represents an aryl group it is suitably a phenyl group.
  • R 3 represents an aryl group it is suitably a phenyl group, preferably substituted with up to two halogen atoms.
  • n represents an integer of from 1 to 4, preferably 1, 2 or 3.
  • the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, ester or amide thereof, for use in the manufacture of a medicament for the treatment and/or prophylaxis of hyperglycaemia in humans or non-human mammals.
  • the present invention also provides a pharmaceutical composition for use in the treatment and/or prophylaxis of hyperglycaemia in humans or non-human mammals which comprises an effective, non-toxic amount of a compound of formula (I), or a pharmaceutically acceptable salt, ester or amide thereof, and a pharmaceutically acceptable carrier therefor.
  • R 4 represents a C 1-6 alkyl, C 1 -6 arylalkyl or aryl group
  • R 5 represents a hydrogen atom or a C 1-6 alkyl group
  • R 6 represents a substituted or unsubstituted aryl group; and m represents an integer of from 1 to 6; providing that when R 4 represents lower alkyl, R 5 represents a hydrogen atom or lower alkyl and m represents 1; then R 6 does not represent a phenyl group or a phenyl group substituted with a halogen atom.
  • R 4 represents an aryl group it is suitably a phenyl group.
  • R 6 represents an aryl group it is suitably a phenyl group substituted with up to two halogen atoms.
  • R 3 or R 6 represent 4-chlorophenyl or 2,4-dichlorophenyl.
  • R 1 or R 4 represents a group selected from the group consisting of: methyl, ethyl, n-propyl or phenyl.
  • R 2 or R 5 represent a methyl group.
  • Suitable aryl groups, or aryl moieties as for example in the C 1-6 alkylaryl group, include substituted or unsubstituted phenyl or naphthyl groups.
  • the aryl group when substituted the aryl group may be substituted with up to five, favourably up to three, groups selected from halogen, C 1-6 alkyl, phenyl, C 1-6 alkoxy, halo C 1-6 alkyl, hydroxy, amino, nitro, carboxy C 1-6 alkoxycarbonyl, C 1-6 alkylcarbonyloxy or C 1-6 alkylcarbonyl groups.
  • lower alkyl' relates to C 1-6 alkyl groups.
  • 'C 1-6 alkyl' or the term 'C 1-6 alk' relate to the groups or moieties comprising straight and branched chain alkyl groups containing from 1 to 6 carbon atoms, such as methyl, ethyl, propyl and butyl.
  • 'halogen' refers to fluorine, chlorine, bromine and iodine, preferably chlorine.
  • Suitable pharmaceutically acceptable salts of carboxy groups include metal salts, such as for example aluminium, alkali metal salts such as sodium or potassium, alkaline earth metal salts such as calcium or magnesium and ammonium or substituted ammonium salts, for example those with lower alkylamines such as triethylamine, hydroxy-lower alkylamines such as 2-hydroxyethylamine, bis-(2-hydroxyethyl)-amine or tri-(2-hydroxyethyl) -amine, eyeloaIkylamines such as bicyclohexylamine, or with procaine, dibenzylpiperidine, N-benzyl- ⁇ -phenethylamine, dehydroabietylamine, N,N'-bisdehydroabietylamine, glucamine, N-methylglucamine or bases of the pyridine type such as pyridine, collidine or quinoline.
  • metal salts such as for example aluminium, alkali metal salts such as sodium or potassium
  • Suitable pharmaceutically acceptable esters of carboxy groups are in-vivo hydrolysable esters.
  • Suitable pharmaceutically acceptable in vivo hydrolysable ester groups include those which break down readily in the human body to leave the parent acid or its salt.
  • Suitable ester groups of this type include those of part formula (i), (ii) and (iii):
  • R a is hydrogen, methyl, or phenyl
  • R b is C 1-6 alkyl, C 1-6 alkoxy or phenyl; or R a and R b together form a 1,2-phenylene group optionally substituted by one or two methoxy groups; R c represents C 1-6 alkylene optionally substituted with a methyl or ethyl group - R d and R e independently represent C 1-6 alkyl; R f represents C 1-6 alkyl.
  • Suitable in vivo hydrolysable ester group include for example acyloxyalkyl groups such as acetoxymethyl, pivaloyloxy-methyl, ⁇ -acetoxyethyl and ⁇ -pivaloyloxyethyl groups; alkoxycarbonyloxyalkyl groups, such as ethoxycarbonyl-oxymethyl and ⁇ -ethoxycarbonyloxyethyl; dialkylamino-alkyl especially di-loweralkylamino alkyl groups such as dimethylaminomethyl, dimethylaminoethyl, diethyl-aminomethyl or diethylaminoethyl and lactone groups such as phthalidyl and dimethoxyphthalidyl.
  • acyloxyalkyl groups such as acetoxymethyl, pivaloyloxy-methyl, ⁇ -acetoxyethyl and ⁇ -pivaloyloxyethyl groups
  • Suitable acid addition salts of compound (I) or (II),when comprising an amino group include pharmaceutically acceptable inorganic salts such as the sulphate, nitrate, phosphate, borate, hydrochloride and hydrobromide and pharmaceutically acceptable organic acid addition salts such as acetate, tartrate, maleate, citrate, succinate, benzoate, ascorbate, methane-sulphonate, ⁇ -keto glutarate, ⁇ -glycerophosphate, and glucose-1-phosphate.
  • the acid addition salt is a hemisuccinate, hydrochloride, ⁇ -ketoglutarate, ⁇ -glycerophosphate or glucose-1-phosphate, in particular the hydrochloride salt.
  • Suitable pharmaceutically acceptable amides are amides of formula CO.NR S R t wherein R s and R t each independently represent hydrogen or C 1-6 alkyl or R s and R t together with the nitrogen atom to which they are attached form a 5- or 6- membered ring.
  • the present invention also provides a process for the preparation of compounds of formula (II), or a pharmaceutically acceptable salt, ester or amide thereof, which process comprises cyclising a compound of formula (III):
  • R 4 , R 5 , R 6 and m are as defined in relation to formula (II); and thereafter if necessary carrying out one or more of the following steps:
  • the cyclisation of the compound of formula (II) is carried out in the presence of a dehydrating agent, such as phosphoryl chloride.
  • the compounds of formula (I) may be prepared by an analogous process to that used to prepare compounds of formula (II).
  • reaction is suitably carried out in toluene, or any other suitable solvent, at any convenient temperature, preferably at an elevated temperature such as the refluxing temperature of the chosen solvent.
  • the compounds of formula (III) are either known compounds or may be prepared using processes analogous to those used to prepare known compounds, for example by using the processes disclosed in Japanese Published Application No. 51111. The methods disclosed therein may also be used to prepare compounds of formula (I) or (II).
  • the present invention further provides a compound of the general formula (II), or pharmaceutically acceptable salt, ester or amide thereof, for use in the treatment of hyperglycaemia in human or non-human mammals.
  • a compound of the general formula (I) or (II), or a pharmaceutically acceptable salt thereof may be administered per se or, preferably, as a pharmaceutical composition also comprising a pharmaceutically acceptable carrier.
  • a pharmaceutical composition comprising a compound of the general formula (II), or a pharmaceutically acceptable salt, ester or amide thereof, and a pharmaceutically acceptable carrier therefor.
  • the term ''pharmaceutically acceptable'' embraces compounds, compositions and ingredients for both human and veterinary uses for example the term ''pharmaceutically acceptable salt'' embraces a veterinarily acceptable salt.
  • the composition may, if desired, be in the form of a pack accompanied by written or printed instructions for use.
  • the administration to the human or non-human mammal may be by way of oral administration or parenteral administration.
  • the compound of formula (I) or (II) (hereinafter called ''the drug'') is administered in the form of a unit-dose composition, such as a unit dose oral or parenteral composition.
  • a unit dose composition such as a unit dose oral or parenteral composition.
  • unit doses will normally comprise 0.1 to 1000 mg of the drug, more usually 0.1 to 550 mg.
  • compositions are prepared by admixture and are suitably adapted for oral or parenteral administration, and as such may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable and infusable solutions or suspensions.
  • Orally administrable compositions are preferred, in particular shaped oral compositions, 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.
  • Suitable fillers for use include cellulose, mannitol, lactose and other similar agents.
  • Suitable disintegrants include starch, polyvinylpyrrolidone and starch derivatives such as sodium starch glycollate.
  • Suitable lubricants include, for example, magnesium stearate.
  • Suitable pharmaceutically acceptable wetting agents include sodium lauryl sulphate.
  • solid oral compositions may be prepared by conventional methods of blending, filling, tabletting or the like. 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.
  • 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, carboxymethyl cellulose, 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 flavouring or colouring agents.
  • suspending agents for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate
  • Oral formulations also include conventional sustained release formulations, such as tablets or granules having an enteric coating.
  • fluid unit dose forms are prepared containing the drug 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 to 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.
  • the drug may be taken in doses, such as those described above, one to six times a day in a manner such that the total daily dose for a 70 kg adult will generally be about 0.1 to 6000 mg, and more usually about 1 to 1500 mg.
  • the drug may be administered by mouth, usually once or twice a day and at about 0.025 mg/kg to 25 mg/kg, for example 0.1 mg/kg to 20 mg/kg.
  • C57Bl/KsJ diabetic (db/db) female mice 5-6 weeks old, were housed 5 per cage and fed on a powdered rat and mouse breeders diet (H.C. Styles, Bewdley, Worcs.) for one week. At the end of this period, blood samples were obtained at mid-day for the determination of blood glucose in all mice. The animals then continued to receive the powdered diet or were given the powdered diet supplemented with the test compound. After 7 days, the blood glucose concentration at mid-day were again determined.
  • mice The results of the determination of mid-day blood glucose concentrations taken at the end of each treatment are shown below as the mean (mM). The comparable values for animals fed on the powdered diet alone are also shown as controls. Five mice (i.e. one cage of mice) were used on each treatment.

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (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)

Abstract

Procédé de traitement et/ou de prophylaxie de l'hyperglycémie chez l'homme ou chez l'animal, consistant à administrer une quantité non-toxique efficace d'un composé de formule (I), ou un sel, un ester ou un amide pharmaceutiquement acceptable de ce composé, où R1 représente un groupe alkyle C1-6, alkylaryle C1-6 ou aryle; R2 représente un atome d'hydrogène ou un groupe alkyle C1-6; R3 représente un groupe aryle substitué ou non-substitué; et n représente un nombre entier compris entre 1 et 6. Sont également décrits des composés et des compositions pharmaceutiques pouvant être utilisés dans ce procédé.
PCT/GB1986/000789 1985-12-23 1986-12-22 Derives d'oxazole et leur utilisation en tant qu'agents anti-hyperglycemiques WO1987003807A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB8531608 1985-12-23
GB858531608A GB8531608D0 (en) 1985-12-23 1985-12-23 Treatment

Publications (1)

Publication Number Publication Date
WO1987003807A1 true WO1987003807A1 (fr) 1987-07-02

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PCT/GB1986/000789 WO1987003807A1 (fr) 1985-12-23 1986-12-22 Derives d'oxazole et leur utilisation en tant qu'agents anti-hyperglycemiques

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EP (1) EP0250528A1 (fr)
GB (1) GB8531608D0 (fr)
WO (1) WO1987003807A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6156748A (en) * 1996-10-07 2000-12-05 Eli Lilly And Company Compounds useful as neuro-protective agents
WO2002083111A2 (fr) * 2001-04-16 2002-10-24 Tanabe Seiyaku Co., Ltd. Substance d'ouverture du canal k activee par le calcium a grande conductance
US6472387B1 (en) 1996-10-07 2002-10-29 Eli Lilly And Company Methods of using compounds as neuro-protective agents
US6767864B2 (en) 2000-06-13 2004-07-27 Bayer Cropscience Ag Heteroaryl-substituted heterocycles
US7420062B2 (en) 2003-07-14 2008-09-02 Bayer Cropscience, Ag Hetaryl-substituted pyrazolidindione derivatives with pesticidal characteristics

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0092239A2 (fr) * 1982-04-19 1983-10-26 Takeda Chemical Industries, Ltd. Dérivés d'oxazole, préparation et utilisation
EP0094612A2 (fr) * 1982-05-19 1983-11-23 Tanabe Seiyaku Co., Ltd. Dérivés d'acides alcoyloxazolyl acétiques, procédé de préparation et compositions pharmaceutiques les contenant
EP0096890A2 (fr) * 1982-06-15 1983-12-28 Takeda Chemical Industries, Ltd. Dérivés de l'acide oxazolacétique, procédé pour leur production et compositions contenant lesdits dérivés

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0092239A2 (fr) * 1982-04-19 1983-10-26 Takeda Chemical Industries, Ltd. Dérivés d'oxazole, préparation et utilisation
EP0094612A2 (fr) * 1982-05-19 1983-11-23 Tanabe Seiyaku Co., Ltd. Dérivés d'acides alcoyloxazolyl acétiques, procédé de préparation et compositions pharmaceutiques les contenant
EP0096890A2 (fr) * 1982-06-15 1983-12-28 Takeda Chemical Industries, Ltd. Dérivés de l'acide oxazolacétique, procédé pour leur production et compositions contenant lesdits dérivés

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6579871B2 (en) 1996-10-07 2003-06-17 Eli Lilly And Company Methods of using novel compounds as neuro-protective agents
US6166216A (en) * 1996-10-07 2000-12-26 Eli Lilly And Company Compounds useful as neuro-protective agents
US6380213B1 (en) 1996-10-07 2002-04-30 Eli Lilly And Company Compounds useful as neuro-protective agents
US6423709B1 (en) 1996-10-07 2002-07-23 Eli Lilly And Company Methods of using novel compounds as neuro-protective agents
US6472387B1 (en) 1996-10-07 2002-10-29 Eli Lilly And Company Methods of using compounds as neuro-protective agents
US6156748A (en) * 1996-10-07 2000-12-05 Eli Lilly And Company Compounds useful as neuro-protective agents
US6767864B2 (en) 2000-06-13 2004-07-27 Bayer Cropscience Ag Heteroaryl-substituted heterocycles
US7141533B2 (en) 2000-06-13 2006-11-28 Bayer Cropscience Ag Hetaryl-substituted heterocycles
WO2002083111A2 (fr) * 2001-04-16 2002-10-24 Tanabe Seiyaku Co., Ltd. Substance d'ouverture du canal k activee par le calcium a grande conductance
WO2002083111A3 (fr) * 2001-04-16 2004-04-15 Tanabe Seiyaku Co Substance d'ouverture du canal k activee par le calcium a grande conductance
KR100863659B1 (ko) * 2001-04-16 2008-10-15 미쓰비시 타나베 파마 코퍼레이션 질소-함유 헤테로시클릭 화합물 및 이를 포함하는 제약 조성물
US7759373B2 (en) 2001-04-16 2010-07-20 Mitsubishi Tanabe Pharma Corporation Large conductance calcium-activated K channel opener
US7420062B2 (en) 2003-07-14 2008-09-02 Bayer Cropscience, Ag Hetaryl-substituted pyrazolidindione derivatives with pesticidal characteristics

Also Published As

Publication number Publication date
EP0250528A1 (fr) 1988-01-07
GB8531608D0 (en) 1986-02-05

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