WO1992003434A1 - Agents therapeutiques - Google Patents

Agents therapeutiques Download PDF

Info

Publication number
WO1992003434A1
WO1992003434A1 PCT/EP1991/001491 EP9101491W WO9203434A1 WO 1992003434 A1 WO1992003434 A1 WO 1992003434A1 EP 9101491 W EP9101491 W EP 9101491W WO 9203434 A1 WO9203434 A1 WO 9203434A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
formula
alkyl
pyrid
group
Prior art date
Application number
PCT/EP1991/001491
Other languages
English (en)
Inventor
Michael Jonathan Fray
Original Assignee
Pfizer Limited
Pfizer Inc.
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 Pfizer Limited, Pfizer Inc. filed Critical Pfizer Limited
Publication of WO1992003434A1 publication Critical patent/WO1992003434A1/fr
Priority to FI930674A priority Critical patent/FI930674A0/fi

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors

Definitions

  • This invention relates to indane and
  • cyclopentanothiophene derivatives which are potent, orally active antagonists of platelet activating factor and as such have clinical utility for treating allergic and inflammatory conditions such as asthma and
  • Platelet activating factor (PAF, 1-0-alkyl-2- acetyl-sn-glyceryl-3-phosphorylcholine) is an ether phospholipid whose structure was first elucidated in 1979. It is produced by, released from and interacts with many pro-inflammatory cells, platelets and the kidney. In addition to potent platelet aggregating activity, PAF exhibits a wide spectrum of biological activities elicited either directly or via the release of other powerful mediators such as thromboxane A 2 or the leukotrienes. In vitro, PAF stimulates the
  • both the acute broncho-constriction and chronic inflammatory reactions elicited by allergens in asthma can be mimicked by intratracheal administration of PAF.
  • agents which antagonise the actions of PAF and, consequently also prevent mediator release by PAF will have clinical utility in the treatment of a variety of allergic and inflammatory conditions such as asthma and arthritis, respectively.
  • Intravenous infusion of PAF at doses of 20-200 pmol kg -1 min -1 into rats results in the formation of extensive haemorrhagic erosions in the gastric mucosa and thus PAF is the most potent gastric ulcerogen yet described whose endogenous release may underlie or contribute to certain forms of gastric ulceration.
  • Psoriasis is an inflammatory and proliferative disease characterised by skin lesions.
  • PAF is pro-inflammatory and has been isolated from lesioned scale of psoriatic patients indicating PAF has a role in the disease of psoriasis.
  • increasing evidence supports a potential pathophysiological role for PAF in
  • R 1 is -COOR 3 , -CN, -CONR 4 R 5 or -NR 6 COR 3 where R 3 is H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, or
  • R 4 and R 5 are each independently H, C 1 -C 6 , alkyl which may optionally be substituted by a hydroxyl or C 1 -C 4 alkoxy group, C 3 -C 7 cycloalkyl, phenyl or pyridyl, said phenyl and pyridyl groups being optionally substituted by up to three groups independently selected from halo, hydroxy, -CF 3 , C 1 -C 4 alkyl and C 1 -C 4 alkoxy, or R4 and R 5 together with the nitrogen atom to which they are attached represent a pyrrolidine, piperidine or morpholine ring; R 6 is H or
  • R 2 is H, halo, or C 1 -C 4 alkyl; and their pharmaceutically acceptable salts.
  • halo means fluoro, chloro, bromo or iodo.
  • Alkyl and alkoxy groups of 3 or more carbon atoms may be straight or branched-chain.
  • R 5 when present, is preferably H and R 1 is preferably at the 2-position of the indane nucleus
  • R 1 groups are cyano, carboxy, ethoxycarbonyl, t-butylcarbonylammo and group -CONR 4 R 5 where R 4 and R 5 together form a piperidino or
  • the compounds of formula (I) contain at least one asymmetric centre and will therefore exist as one or more pairs of enantiomers, and such pairs of individual isomers may be separable by physical methods, e.g. by fractional crystallisation or chromatography of the parent compounds or of a suitable salt or derivative thereof. Alternatively, particular isomers may be prepared using the corresponding optical isomers of the precursors used in preparation of compounds of the invention.
  • the invention includes all the enantiomers of the compounds of formula (I) whether separated or not.
  • the pharmaceutically acceptable acid addition salts of the compounds of formula (I) are those formed from acids which form non-toxic acid addition salts, for example the hydrochloride, hydrobromide, sulphate or bisulphate, phosphate or acid phosphate, acetate, citrate, fumarate, gluconate, lactate, maleate, succinate, tartrate, methanesulphonate,
  • This reaction may be carried out by heating the compound (II) with acetic anhydride and glacial acetic acid, followed by separation of the product by
  • Compound (III) may be esterified by conventional methods to produce corresponding compounds in which R 3 is C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl or C 1 -C 4 alkyl substituted by phenyl.
  • the compound of formula (I) may be prepared from the acid (III) by converting the latter to the corresponding carbonyl chloride, for example by treatment with oxalyl
  • the acid (III) may first be converted to a corresponding compound (IV) in which R 1 is NH 2 , for example by treatment with
  • the amine (IV) may then be converted to the carbonylamino compound (V) in which R 6 is H by reaction with the appropriate carbonyl chloride:
  • R 6 is alkyl
  • compounds of formula (V) may be made by alkylating compounds of formula (V) in known manner.
  • novel intermediates (IV) constitute a further aspect of the present invention.
  • the compounds of formula (II) may be prepared from the corresponding cyanoindanes by the synthesis shown in Scheme 1. This synthesis entails nitration of the cyanoindane, for example with fuming nitric acid in acetic anhydride, followed by reduction of the nitro group, suitably with hydrogen in the presence of a palladium/carbon catalyst. The amine so formed may then be reacted with the appropriate
  • [b]thiophenes of formula (I) may be made firstly by reacting a 3-cyclopentanone carboxylic ester with sulphur and a cyanoacetate to form a cyclopentano [b] thiophene substituted by amino and carboxylate groups of formula (VI):
  • R 7 is an optionally substituted alkyl group such as ethyl or t-butyl.
  • the reaction may be conducted by heating the reagents together in the presence of a solvent such as
  • dimethylformamide and a base such as triethylamine.
  • a base such as sodium bicarbonate
  • the corresponding compounds of formula (I) in which R 3 is H may be obtained by hydrolysing the ester produced by the synthesis of Scheme 2 by conventional methods.
  • the CO 2 R 3 group may be attached to the cyclopentane ring of compound (VI) at either the 4- or the 5-position of the cyclopentano[b]thiophene and in practice a mixture of both isomers is produced. These isomers may be
  • the activity of the compounds of the invention is shown by their ability to inhibit the platelet
  • Blood samples are taken from either rabbit or man into 0.1 vol disodium ethylenediamine tetraacetic acid buffer and the samples centrifuged for 15 minutes to obtain platelet rich plasma. The plasma is further centrifuged to give a platelet pellet which is washed with a buffer solution (4mM KH 2 PO , 6mM Na 2 HPO 4 , 100 mM NaCl, 0.1% glucose and 0.1% bovine serum albumin, pH 7.25) and finally resuspended in buffer solution to a concentration of 2 ⁇ 10 8 platelets/ml. A sample (0.5 ml) is pre-incubated for two minutes at 37oC in a Paton aggregometer with stirring, either with vehicle alone, or with vehicle containing the particular compound under test.
  • a buffer solution 4mM KH 2 PO , 6mM Na 2 HPO 4 , 100 mM NaCl, 0.1% glucose and 0.1% bovine serum albumin, pH 7.25
  • PAF is added at a sufficient concentration to give a maximum aggregating response in the absence of test compound (10 -8 to 10 -9 molar), and the platelet aggregation is measured by following the increase in light transmission of the solution.
  • the experiment is repeated in the presence of test compound at a range of concentrations and the concentration of compound required to reduce the response to 50% of its maxiumum value is recorded as the IC 50 value.
  • the activity of the compounds of formula (I) is also demonstrated in vivo by their ability to protect mice from the lethal effect of an injection of PAF.
  • a mixture of PAF (50 ⁇ g/kg) and DL-propranolol (5 mg/kg) in 0.9% w/v sodium chloride is injected (0.2 ml) via a tail vein immediately prior to the PAF/propranolol injection or administered orally by gavage two hours earlier.
  • the compounds are tested at several doses in groups of 5 mice and the dose which reduces mortality to 50% is recorded as the PD 50 value.
  • the compounds of the formula (I) will generally be administered in admixture with a pharmaceutical carrier selected with regard to the intended route of administration and standard
  • compositions may be administered orally in the form of tablets containing such excipients as starch or lactose, or in capsules or ovules either alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavouring or colouring agents. They may be injected parenterally, for example, intravenously,
  • a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood.
  • oral dosage of the compounds will generally be in the range of from 2-1000 mg daily for an average adult patient (70 kg).
  • individual tablets or capsules contain from 1 to 500 mg of active compound, in a suitable pharmaceutically acceptable vehicle or carrier.
  • Dosages for intravenous administration would typically be within the range 1 to 10 mg per single dose as required.
  • inhalation via a nebuliser or aerosol may be the preferred route of drug
  • Dose levels by this route would be within the range 0.1 to 50 mg per single dose as required.
  • the physician will determine the actual dosage which will be most suitable for an individual patient and it will vary with age, weight and response of the particular patient.
  • the above dosages are exemplary of the average case but there can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the formula (I) or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable diluent or carrier.
  • the invention also includes a compound of the formula (I) or a pharmaceutically acceptable salt thereof, for use in medicine, in particular in the treatment of allergic and inflammatory conditions in a human being.
  • Oxalyl chloride (1.3ml, 14.9mmol) was added dropwise over 5 min to a stirred suspension of
  • the foam obtained (210 mg) was dissolved in methanol (5 ml), fvunaric acid (70 mg) added and the solvent removed in vacuo.
  • the white solid was filtered off and dried, yielding the title compound as the fumarate salt (92 mg, 20%), m.p. 110-120°C.
  • the hydrochloride salt had m.p. 210-220°C. Analysis % :
  • 6-ethoxycarbonyl-2-(2-methylimidazo[4,5-c]pyrid-1-yl)-cyclopentano[b]thiophene (Example 18, 350 mg, 1.07 mmoles) was dissolved in a mixture of ethanol (3 ml) and sodium hydroxide (80 mg, 2.0 mmole) in water (2 ml) was added. The mixture was stirred for 3 hours at room temperature then evaporated to low volume in vacuo and acidified to pH 4.5 with acetic acid. Continuous extraction with CH 2 Cl 2 gave the product (300 mg, 93%), m.p. 320°C.
  • N 4 O 2 S.C 4 H 4 O 4 requires C,57.02; H,4.96; N,11.57.
  • the compounds of Table 2 were made by the method of Example 21 using diethylamine and 2-aminopyridine instead of morpholine.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (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

Antagonistes du facteur d'activation des plaquettes de formule (I), dans laquelle X représente -CH=CH- ou S, R1 représente un ester carboxylique, cyano, carboxy ou un groupe amido ou carbamoyle éventuellement substitué et R2 représente H, halogène ou C¿1?-C4 alkyle.
PCT/EP1991/001491 1990-08-17 1991-08-05 Agents therapeutiques WO1992003434A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
FI930674A FI930674A0 (fi) 1990-08-17 1993-02-16 Terapeutiska aemnen

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB909018139A GB9018139D0 (en) 1990-08-17 1990-08-17 Therapeutic agents
GB9018139.7 1990-08-17

Publications (1)

Publication Number Publication Date
WO1992003434A1 true WO1992003434A1 (fr) 1992-03-05

Family

ID=10680861

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1991/001491 WO1992003434A1 (fr) 1990-08-17 1991-08-05 Agents therapeutiques

Country Status (8)

Country Link
EP (1) EP0549598A1 (fr)
JP (1) JPH05509314A (fr)
CA (1) CA2087710A1 (fr)
FI (1) FI930674A0 (fr)
GB (1) GB9018139D0 (fr)
IE (1) IE912905A1 (fr)
PT (1) PT98677A (fr)
WO (1) WO1992003434A1 (fr)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7592461B2 (en) 2005-12-21 2009-09-22 Bristol-Myers Squibb Company Indane modulators of glucocorticoid receptor, AP-1, and/or NF-κB activity and use thereof
WO2009158380A1 (fr) * 2008-06-24 2009-12-30 Bristol-Myers Squibb Company Modulateurs de cyclopentathiopène du récepteur glucocorticoïde, ap-1, et/ou activité nf-kappa b et utilisation de ceux-ci
US10780074B2 (en) 2017-08-02 2020-09-22 Sunovion Pharmaceuticals Inc. Compounds and uses thereof
US10815249B2 (en) 2018-02-16 2020-10-27 Sunovion Pharmaceuticals Inc. Salts, crystal forms, and production methods thereof
US10894033B2 (en) 2009-12-04 2021-01-19 Sunovion Pharmaceuticals Inc. Multicyclic compounds and methods of use thereof
US10927124B2 (en) 2016-07-29 2021-02-23 Sunovion Pharmaceuticals Inc. Compounds and compositions and uses thereof
US11077090B2 (en) 2016-07-29 2021-08-03 Sunovion Pharmaceuticals Inc. Compounds and compositions and uses thereof
US11129807B2 (en) 2017-02-16 2021-09-28 Sunovion Pharmaceuticals Inc. Methods of treating schizophrenia
US11136304B2 (en) 2019-03-14 2021-10-05 Sunovion Pharmaceuticals Inc. Salts of a heterocyclic compound and crystalline forms, processes for preparing, therapeutic uses, and pharmaceutical compositions thereof
US11738002B2 (en) 2020-04-14 2023-08-29 Sunovion Pharmaceuticals Inc. Methods of treating neurological and psychiatric disorders

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1989008653A1 (fr) * 1988-03-15 1989-09-21 G.D. Searle & Co. 1H/3H-[4-(N,N-DICYCLOALKYLE/ALKYLCARBOXAMIDO RAMIFIE)-BENZYLE]IMIDAZO[4,5-c]PYRIDINES EN TANT QU'ANTAGONISTES DE PAF (FACTEUR D'ACTIVATION DES PLAQUETTES)

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1989008653A1 (fr) * 1988-03-15 1989-09-21 G.D. Searle & Co. 1H/3H-[4-(N,N-DICYCLOALKYLE/ALKYLCARBOXAMIDO RAMIFIE)-BENZYLE]IMIDAZO[4,5-c]PYRIDINES EN TANT QU'ANTAGONISTES DE PAF (FACTEUR D'ACTIVATION DES PLAQUETTES)

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8324401B2 (en) 2005-12-21 2012-12-04 Bristol-Myers Squibb Company Indane modulators of glucocorticoid receptor, AP-1, and/or NF-κB activity and use thereof
US7592461B2 (en) 2005-12-21 2009-09-22 Bristol-Myers Squibb Company Indane modulators of glucocorticoid receptor, AP-1, and/or NF-κB activity and use thereof
WO2009158380A1 (fr) * 2008-06-24 2009-12-30 Bristol-Myers Squibb Company Modulateurs de cyclopentathiopène du récepteur glucocorticoïde, ap-1, et/ou activité nf-kappa b et utilisation de ceux-ci
US8106046B2 (en) 2008-06-24 2012-01-31 Bristol-Myers Squibb Company Cyclopentathiophene modulators of the glucocorticoid receptor, AP-1, and/or NF-κB activity and use thereof
US10894033B2 (en) 2009-12-04 2021-01-19 Sunovion Pharmaceuticals Inc. Multicyclic compounds and methods of use thereof
US11958862B2 (en) 2016-07-29 2024-04-16 Sumitomo Pharma America, Inc. Compounds and compositions and uses thereof
US10927124B2 (en) 2016-07-29 2021-02-23 Sunovion Pharmaceuticals Inc. Compounds and compositions and uses thereof
US11077090B2 (en) 2016-07-29 2021-08-03 Sunovion Pharmaceuticals Inc. Compounds and compositions and uses thereof
US11129807B2 (en) 2017-02-16 2021-09-28 Sunovion Pharmaceuticals Inc. Methods of treating schizophrenia
US10780074B2 (en) 2017-08-02 2020-09-22 Sunovion Pharmaceuticals Inc. Compounds and uses thereof
US11491133B2 (en) 2017-08-02 2022-11-08 Sunovion Pharmaceuticals Inc. Heteroaryl-isochroman compounds and uses thereof
US11440921B2 (en) 2018-02-16 2022-09-13 Sunovion Pharmaceuticals Inc. Salts, crystal forms, and production methods thereof
US10815249B2 (en) 2018-02-16 2020-10-27 Sunovion Pharmaceuticals Inc. Salts, crystal forms, and production methods thereof
US11987591B2 (en) 2018-02-16 2024-05-21 Sumitomo Pharma America, Inc. Salts, crystal forms, and production methods thereof
US11136304B2 (en) 2019-03-14 2021-10-05 Sunovion Pharmaceuticals Inc. Salts of a heterocyclic compound and crystalline forms, processes for preparing, therapeutic uses, and pharmaceutical compositions thereof
US11738002B2 (en) 2020-04-14 2023-08-29 Sunovion Pharmaceuticals Inc. Methods of treating neurological and psychiatric disorders

Also Published As

Publication number Publication date
PT98677A (pt) 1992-07-31
FI930674A (fi) 1993-02-16
IE912905A1 (en) 1992-02-26
CA2087710A1 (fr) 1992-02-18
JPH05509314A (ja) 1993-12-22
EP0549598A1 (fr) 1993-07-07
FI930674A0 (fi) 1993-02-16
GB9018139D0 (en) 1990-10-03

Similar Documents

Publication Publication Date Title
EP0466711B1 (fr) Agents anti-allergiques a base de dihydropyrimidine
WO2007032466A1 (fr) Composé hétérocyclique et procédé de production et utilisation de celui-ci
US20080255110A1 (en) Imidazoquinoline derivatives as adenosine a3 receptor ligands
EP3144303B1 (fr) Dérivés d'acide carboxylique phenoxychroman substitués en position 6
JPH05230055A (ja) 三環式ヘテロ環化合物、その製法及びこれを含有する抗−痛覚過敏作用を有する医薬組成物
EP0294074B1 (fr) Agents dihydropyridiniques à activité antiallergique et anti-inflammatoire
EP0299727B1 (fr) Agents thérapeutiques
EP0258033A2 (fr) Dihydropyridines comme agents antiallergiques et antiinflammatoires
EP0266989B1 (fr) Dihydropyridines comme agents anti-allergiques et anti-inflammatoires
WO1992003434A1 (fr) Agents therapeutiques
US5248681A (en) Dihydropyridine antiallergy agents
IE882944L (en) Therapeutic agents
EP0329357B1 (fr) Dihydropyridines et leur utilisation comme agents antiallergiques et anti-inflammatoires
US4963560A (en) 1,4-dihydropyridine derivatives
IE913167A1 (en) Therapeutic agents
EP0462986B1 (fr) Agents d'imidazopyrimidine antiallergie
IE913102A1 (en) Therapeutic agents
US5214044A (en) 1,4-dihydropyridines useful as pharmaceuticals
JP2003516990A (ja) 経口で活性のあるエラスターゼ阻害剤としてのサッカリン誘導体

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): CA FI JP US

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IT LU NL SE

WWE Wipo information: entry into national phase

Ref document number: 1991914266

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 2087710

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 930674

Country of ref document: FI

WWP Wipo information: published in national office

Ref document number: 1991914266

Country of ref document: EP

WWR Wipo information: refused in national office

Ref document number: 1991914266

Country of ref document: EP

WWW Wipo information: withdrawn in national office

Ref document number: 1991914266

Country of ref document: EP