EP0549598A1 - 2-METHYLIMIDAZO[4,5-c]PYRIDIN-DERIVATE UND ANTIALLERGISCHE MITTEL - Google Patents
2-METHYLIMIDAZO[4,5-c]PYRIDIN-DERIVATE UND ANTIALLERGISCHE MITTELInfo
- Publication number
- EP0549598A1 EP0549598A1 EP91914266A EP91914266A EP0549598A1 EP 0549598 A1 EP0549598 A1 EP 0549598A1 EP 91914266 A EP91914266 A EP 91914266A EP 91914266 A EP91914266 A EP 91914266A EP 0549598 A1 EP0549598 A1 EP 0549598A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- compound
- formula
- alkyl
- pyrid
- group
- Prior art date
- Legal status (The legal status 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 status listed.)
- Ceased
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)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Diabetes (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Hematology (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)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB909018139A GB9018139D0 (en) | 1990-08-17 | 1990-08-17 | Therapeutic agents |
GB9018139 | 1990-08-17 |
Publications (1)
Publication Number | Publication Date |
---|---|
EP0549598A1 true EP0549598A1 (de) | 1993-07-07 |
Family
ID=10680861
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP91914266A Ceased EP0549598A1 (de) | 1990-08-17 | 1991-08-05 | 2-METHYLIMIDAZO[4,5-c]PYRIDIN-DERIVATE UND ANTIALLERGISCHE MITTEL |
Country Status (8)
Country | Link |
---|---|
EP (1) | EP0549598A1 (de) |
JP (1) | JPH05509314A (de) |
CA (1) | CA2087710A1 (de) |
FI (1) | FI930674A0 (de) |
GB (1) | GB9018139D0 (de) |
IE (1) | IE912905A1 (de) |
PT (1) | PT98677A (de) |
WO (1) | WO1992003434A1 (de) |
Families Citing this family (10)
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 |
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 |
AU2010325925B2 (en) | 2009-12-04 | 2016-02-25 | Pgi Drug Discovery Llc. | Multicyclic compounds and methods of use thereof |
MA45857A (fr) | 2016-07-29 | 2021-05-19 | Sunovion Pharmaceuticals Inc | Composés et compositions, et utilisations associées |
JP2019523279A (ja) | 2016-07-29 | 2019-08-22 | サノビオン ファーマシューティカルズ インクSunovion Pharmaceuticals Inc. | 化合物および組成物ならびにそれらの使用 |
AU2018220509B2 (en) | 2017-02-16 | 2022-04-28 | Sunovion Pharmaceuticials Inc. | Methods of treating schizophrenia |
CA3070993A1 (en) | 2017-08-02 | 2019-02-07 | Sunovion Pharmaceuticals Inc. | Isochroman compounds and uses thereof |
KR20200122345A (ko) | 2018-02-16 | 2020-10-27 | 선오비온 파마슈티컬스 인코포레이티드 | 염, 결정 형태 및 이들의 제조 방법 |
MX2021010880A (es) | 2019-03-14 | 2022-01-18 | Sunovion Pharmaceuticals Inc | Sales de un compuesto de isocromanilo y formas cristalinas, procesos de preparacion, usos terapeuticos y composiciones farmaceuticas de las mismas. |
CA3180115A1 (en) | 2020-04-14 | 2021-10-21 | Sunovion Pharmaceuticals Inc. | (s)-(4,5-dihydro-7h-thieno[2,3-c]pyran-7-yl)-n-methylmethanamine for treating neurological and psychiatric disorders |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE68920998T2 (de) * | 1988-03-15 | 1995-06-22 | Searle & Co | 1H/3H-[4-(N,N-CYCLOALKYL UND/ODER VERZWEIGTES ALKYLCARBOXAMIDO)-BENZYL]IMDAZO[4,5-c]PYRIDINE ALS PAF-ANTAGONISTEN. |
-
1990
- 1990-08-17 GB GB909018139A patent/GB9018139D0/en active Pending
-
1991
- 1991-08-05 JP JP3513164A patent/JPH05509314A/ja active Pending
- 1991-08-05 EP EP91914266A patent/EP0549598A1/de not_active Ceased
- 1991-08-05 CA CA002087710A patent/CA2087710A1/en not_active Abandoned
- 1991-08-05 WO PCT/EP1991/001491 patent/WO1992003434A1/en not_active Application Discontinuation
- 1991-08-14 PT PT98677A patent/PT98677A/pt not_active Application Discontinuation
- 1991-08-16 IE IE290591A patent/IE912905A1/en unknown
-
1993
- 1993-02-16 FI FI930674A patent/FI930674A0/fi unknown
Non-Patent Citations (1)
Title |
---|
See references of WO9203434A1 * |
Also Published As
Publication number | Publication date |
---|---|
JPH05509314A (ja) | 1993-12-22 |
WO1992003434A1 (en) | 1992-03-05 |
PT98677A (pt) | 1992-07-31 |
FI930674A (fi) | 1993-02-16 |
FI930674A0 (fi) | 1993-02-16 |
CA2087710A1 (en) | 1992-02-18 |
IE912905A1 (en) | 1992-02-26 |
GB9018139D0 (en) | 1990-10-03 |
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Legal Events
Date | Code | Title | Description |
---|---|---|---|
PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
17P | Request for examination filed |
Effective date: 19930118 |
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AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AT BE CH DE DK ES FR GB GR IT LI LU NL SE |
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17Q | First examination report despatched |
Effective date: 19931213 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE APPLICATION HAS BEEN REFUSED |
|
18R | Application refused |
Effective date: 19940605 |
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RTI1 | Title (correction) |
Free format text: 2-METHYLIMIDAZO??4,5-C PYRIDINE DERIVATIVES AND THERAPEUTIC AGENTS |