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WO1993003040A1 - Derive de thienopyrimidin-4-one - Google Patents

Derive de thienopyrimidin-4-one Download PDF

Info

Publication number
WO1993003040A1
WO1993003040A1 PCT/JP1992/000990 JP9200990W WO9303040A1 WO 1993003040 A1 WO1993003040 A1 WO 1993003040A1 JP 9200990 W JP9200990 W JP 9200990W WO 9303040 A1 WO9303040 A1 WO 9303040A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
nmr
group
methyl
added
Prior art date
Application number
PCT/JP1992/000990
Other languages
English (en)
Japanese (ja)
Inventor
Minoru Taguchi
Tomomi Ota
Katsuo Hatayama
Original Assignee
Taisho Pharmaceutical Co., Ltd.
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 Taisho Pharmaceutical Co., Ltd. filed Critical Taisho Pharmaceutical Co., Ltd.
Publication of WO1993003040A1 publication Critical patent/WO1993003040A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the present invention relates to a thienovirimidine-141 derivative having angiotensin II receptor blocking activity.
  • an angiotensin II antagonist having a pyrimidine skeleton Japanese Patent Application Laid-Open (JP-A) No. 3-115,711, European Patent Application Publication Nos. 407,342, and 419,048
  • JP-A No. 4-45811 Japanese Patent Application Laid-Open (JP-A) No. 3-115,711
  • European Patent Application Publication Nos. 407,342 European Patent Application Publication Nos. 407,342, and 419,048
  • JP-A No. 4-45811 is known, but the compound having a chenovirimidine skeleton is not known.
  • An object of the present invention is to provide a new compound having angiotensin ⁇ receptor blocker action of evening eve, which is useful for treating hypertension, heart failure and high intraocular pressure.
  • the invention relates to the formula
  • R 1 and R 2 are the same or different and each represent a hydrogen atom, an alkyl group having 1 to 7 carbon atoms or a furyl group, or R 1 and R 2 are adjacent to each other.
  • R 1 and R 2 come together to represent an alkylene group having 3 to 5 carbon atoms.
  • R 3 represents an alkyl group having 1 to 7 carbon atoms or an alkylthio group having 1 to 7 carbon atoms
  • B represents a carbon-carbon single bond or a formula—NHCO—.
  • R 4 represents a carboxyl group, a sulfoxyl group or a tetrazole-5-yl group, and X represents a hydrogen atom or a halogen atom.
  • an alkyl group having 1 to 7 carbon atoms means a straight-chain or branched alkyl group such as a methyl group, a methyl group, a propyl group, an isopropyl group, a butyl group and an isobutyl group.
  • the alkylthio group having 1 to 7 carbon atoms means a straight-chain or branched-chain alkylthio group such as methylthio group, ethylthio group, propylthio group, isopropylthio group, butylthio group, and isobutylthio group.
  • Halogen atoms refer to fluorine, chlorine, bromine and iodine.
  • the salt of the compound of the formula (I) means a metal salt such as a sodium salt and a potassium salt.
  • the compound of the present invention can be produced, for example, by the following method. That is, a compound which is known or can be obtained by a conventional method from a known compound,
  • R 5 represents a nitro group or a 2- (N-triphenylmethyl-tetrazol-1-yl) phenyl group
  • X ⁇ represents a halogen atom
  • R 3 and R 5 are as defined above.
  • a chlorine atom, a bromine atom or an iodine atom can be used as the halogen atom.
  • bases include metal hydrides such as sodium hydride, organic bases such as lithium lithium and lithium diisopropylamide, alcoholates such as sodium methoxide, and potassium hydroxide. Hydroxide or carbonate such as lime carbonate.
  • organic solvent N, N-dimethylformamide, dimethylsulfoxide, tetrahydrofuran, acetate, and the like can be used.
  • the reaction temperature is from 178 to the reflux temperature of the solvent.
  • Hydrochloric acid, hydrochloric acid, p-toluenesulfonic acid and the like can be used as an acid in this reaction, and methanol, ethanol, tetrahydrofuran and the like can be used as a solvent.
  • the reaction temperature is from room temperature to the reflux temperature of the solvent.
  • the reducing agent iron Z drunk acid, tin dichloride Z hydrochloric acid, nickel chloride Z hydrogenation Sodium boron, palladium / carbon hydrogen, and the like can be used.
  • the solvent an alcohol such as methanol, ethyl sulphate, water or the like can be used.
  • the reaction temperature is from room temperature to the reflux temperature of the solvent.
  • R 6 represents a carbonyl group or a sulfonyl group c) by reacting with an acid anhydride represented by the following formula (I):
  • the compound of the present invention can be produced wherein NHC is 0 and R 4 is a carbonyl group or a sulfoxyl group.
  • This reaction can be performed in the presence of a base or in the absence of a base.
  • a base an organic base such as pyridine, triethylamine, diisobu ⁇ -viramine or the like can be used.
  • the solvent chloroform, dichloromethane, N, N-dimethylformamide or the like can be used. The reaction temperature is from room temperature to the reflux temperature of the solvent.
  • the compound of the present invention can be prepared orally or nonperiodically (for example, intravenously, rectally, or ocular mucosa) in the form of various dosage forms by conventional formulation techniques and administered.
  • the dosage form of the microbial preparation solid preparations such as tablets, granules and capsules, or liquid preparations such as solutions, fat emulsions and ribosome preparations can be used.
  • an aqueous or non-aqueous solution, an emulsifier, a suspension, or a solid preparation to be dissolved immediately before use can be used.
  • Suppositories and the like can be used as the dosage form of the preparation for rectal administration.
  • a solution, an emulsifier, a suspending agent, an ointment and the like can be used as the dosage form of the ophthalmic mucosal administration preparation.
  • the dose of the compound of the present invention in these administration methods varies depending on the patient's condition, disease type, age, body weight, etc., but when administered for hypertension or heart failure, it is usually from l to 100 per 1 B. 0 mg, given once or several times a day.
  • the compounds of the present invention have an excellent angiotensin II receptor blocking effect and can be useful for treating hypertension, heart failure and high intraocular pressure.
  • the compound obtained here was dissolved in 210 ml of methanol, a solution of 9.2 g (1.3 equivalents) of hydroxide hydroxide in 50 ml of methanol was added, and the mixture was heated under reflux for 5 hours. After the solvent was distilled off, water was added, and the pH was adjusted to 5 to 6 with 10% hydrochloric acid. The precipitated crystals were washed with water and ethyl acetate to obtain 2-1.3 g of 2-butyl-5-methylthieno [2,3-d] pyrimidine-4 (3H) -crystal. The crystals were recrystallized from methanol to obtain colorless crystals.
  • the mixture obtained here was dissolved in 70 ml of methanol, added with 1.19 ⁇ (1.2 equivalents) of a hydroxide, and stirred at room temperature at room temperature. After the reaction, add 10% hydrochloric acid The precipitated crystals were washed with water to obtain 2.79 g of crystals of 2-butylthieno [3,2-d] pyrimidine-14 (3H) -one. The crystals were recrystallized from methanol to obtain colorless crystals.
  • Example 7 (1) Substantially the same as Example 7 (2) using 2-bromothiothieno [3,2-d] pyrimidin-14 (3H) one obtained in Example 1 2 (1). Thus, 2-propylthio-3- (4-nitrobenzyl) thieno [3,2-d] birimidine-14 (3H) -one was obtained.
  • Example 15 (3) Using the compound obtained in Example 15 (2), the title compound was obtained in substantially the same manner as in Example 15 (3).
  • the compound 2.Og obtained here was dissolved in 40 ml of methanol, 0.70 g (1.2 equivalents) of a hydrating power was added, and the mixture was heated and refluxed for 10 hours.
  • % Hydrochloric acid was added to adjust the pH to 7-8, and the precipitated crystals were washed with water and crystallized with 2-butylethyleno [3,4-1C!] Birimidine-1 4 (3H) -one 1,71 g This crystal was meta- It was recrystallized from an aqueous solution of ethanol to obtain colorless crystals.
  • the measurement of the angiotensin ⁇ receptor binding reaction of the compound of the present invention can be carried out by the method described in J. Pharmacoco 1. Ex. Ther., Pp. 247, pp. 1 (1988, PC ong et al.) in the following manner.
  • the adrenal gland was removed and the cortex was separated. 50 times the adrenal cortex
  • the filter was washed three times with 3 ml of 50 mM Tris-HCl buffer ( ⁇ ⁇ 7.5) The radioactivity on the filter was determined by liquid scintillation with 10 ml of Aquasol 2 scintillation overnight Non-specific binding was 100 nM.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Abstract

L'objet de la présente invention est la production d'un nouveau type de composé possédant une action de blocage du récepteur d'angiotensine II, ce qui contribue à la thérapie de l'hypertension et des insuffisances cardiaques. Ce composé est constitué d'un dérivé de thiénopyrimidin-4-one représenté par la formule générale (I) et d'un sel du dérivé. Dans la formule, (a) représente (b), (c) ou (d), où R1 et R2 représentent chacun hydrogène, alkyle ou phényle, ou alternativement lorsque R1 est adjacent à R?2, R1 et R2¿ sont combinés entre eux pour représenter alkylène; R3 représente alkyle ou alkylthio; B représente une liaison simple carbone-carbone ou -NHCO-; R4 représente carboxyle, sulfoxyle ou tétrazol-5-yle; et X représente hydrogène ou halogène.
PCT/JP1992/000990 1991-08-05 1992-08-04 Derive de thienopyrimidin-4-one WO1993003040A1 (fr)

Applications Claiming Priority (8)

Application Number Priority Date Filing Date Title
JP3/284248 1991-08-05
JP28424891 1991-08-05
JP29610691 1991-11-13
JP3/296106 1991-11-13
JP135992 1992-01-08
JP4/1359 1992-01-08
JP1286892 1992-01-28
JP4/12868 1992-01-28

Publications (1)

Publication Number Publication Date
WO1993003040A1 true WO1993003040A1 (fr) 1993-02-18

Family

ID=27453386

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1992/000990 WO1993003040A1 (fr) 1991-08-05 1992-08-04 Derive de thienopyrimidin-4-one

Country Status (2)

Country Link
AU (1) AU2390792A (fr)
WO (1) WO1993003040A1 (fr)

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001098290A3 (fr) * 2000-06-19 2002-05-16 Pharmacia Italia Spa Derives de thiophene actifs en tant qu'inhibiteurs de kinase, leur procede de preparation, et compositions pharmaceutiques les contenant
EP1925303A2 (fr) 1999-08-27 2008-05-28 Sanofi-Aventis Deutschland GmbH Utilisation d'antagonistes du récepteur Angiotensin II Type 1 pour prévenir l'accident cérébrovasculaire, le diabète et/ou l'insuffisance cardiaque globale
WO2011069038A2 (fr) 2009-12-03 2011-06-09 Synergy Pharmaceuticals, Inc. Agonistes de la guanylate cyclase utiles dans le traitement de l'hypercholestérolémie, de l'athérosclérose, d'une coronaropathie, des calculs biliaires, de l'obésité et d'autres maladies cardiovasculaires
WO2013138352A1 (fr) 2012-03-15 2013-09-19 Synergy Pharmaceuticals Inc. Formulations d'agonistes de la guanylate cyclase c et procédés d'utilisation
WO2014151206A1 (fr) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Agonistes de la guanylate cyclase et leurs utilisations
WO2014151200A2 (fr) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Compositions utiles pour le traitement de troubles gastro-intestinaux
EP2810951A2 (fr) 2008-06-04 2014-12-10 Synergy Pharmaceuticals Inc. Agonistes de guanylate cyclase utile dans le traitement de troubles gastro-intestinaux, d'une inflammation, d'un cancer et d'autres troubles
WO2014197720A2 (fr) 2013-06-05 2014-12-11 Synergy Pharmaceuticals, Inc. Agonistes ultra-purs de guanylate cyclase c, leur procédé de production et d'utilisation
EP2998314A1 (fr) 2007-06-04 2016-03-23 Synergy Pharmaceuticals Inc. Agonistes de guanylase cyclase utiles pour le traitement de troubles gastro-intestinaux, d'inflammation, de cancer et d'autres troubles
EP3241839A1 (fr) 2008-07-16 2017-11-08 Synergy Pharmaceuticals Inc. Agonistes de guanylate cyclase utiles pour le traitement de troubles gastro-intestinaux, inflammatoires, cancéreux et autres
US10588894B2 (en) 2017-06-21 2020-03-17 SHY Therapeutics LLC Compounds that interact with the Ras superfamily for the treatment of cancers, inflammatory diseases, rasopathies, and fibrotic disease
US10870657B2 (en) 2015-12-22 2020-12-22 SHY Therapeutics LLC Compounds for the treatment of cancer and inflammatory disease

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0344377A (ja) * 1989-07-06 1991-02-26 Ciba Geigy Ag 新規ピリミジン誘導体
JPH03115271A (ja) * 1989-07-03 1991-05-16 Merck & Co Inc アンギオテンシン２拮抗薬としての置換キナゾリノン類
EP0443568A1 (fr) * 1990-02-22 1991-08-28 Takeda Chemical Industries, Ltd. Dérivés fusés de thiophène, leur préparation et leur application

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH03115271A (ja) * 1989-07-03 1991-05-16 Merck & Co Inc アンギオテンシン２拮抗薬としての置換キナゾリノン類
JPH0344377A (ja) * 1989-07-06 1991-02-26 Ciba Geigy Ag 新規ピリミジン誘導体
EP0443568A1 (fr) * 1990-02-22 1991-08-28 Takeda Chemical Industries, Ltd. Dérivés fusés de thiophène, leur préparation et leur application

Cited By (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1925303A2 (fr) 1999-08-27 2008-05-28 Sanofi-Aventis Deutschland GmbH Utilisation d'antagonistes du récepteur Angiotensin II Type 1 pour prévenir l'accident cérébrovasculaire, le diabète et/ou l'insuffisance cardiaque globale
EP2277519A2 (fr) 1999-08-27 2011-01-26 Sanofi-Aventis Deutschland GmbH Utilisation d'antagonistes du récepteur Angiotensin II Type 1 pour prévenir l'accident cérébrovasculaire, le diabète et/ou l'insuffisance cardiaque globale
US6414013B1 (en) 2000-06-19 2002-07-02 Pharmacia & Upjohn S.P.A. Thiophene compounds, process for preparing the same, and pharmaceutical compositions containing the same background of the invention
AU2001285745B2 (en) * 2000-06-19 2007-03-22 Pharmacia Italia S.P.A. Thiophene derivatives active as kinase inhibitors, process for their preparation and pharmaceutical compositions comprising them
WO2001098290A3 (fr) * 2000-06-19 2002-05-16 Pharmacia Italia Spa Derives de thiophene actifs en tant qu'inhibiteurs de kinase, leur procede de preparation, et compositions pharmaceutiques les contenant
EP2998314A1 (fr) 2007-06-04 2016-03-23 Synergy Pharmaceuticals Inc. Agonistes de guanylase cyclase utiles pour le traitement de troubles gastro-intestinaux, d'inflammation, de cancer et d'autres troubles
EP2810951A2 (fr) 2008-06-04 2014-12-10 Synergy Pharmaceuticals Inc. Agonistes de guanylate cyclase utile dans le traitement de troubles gastro-intestinaux, d'une inflammation, d'un cancer et d'autres troubles
EP3241839A1 (fr) 2008-07-16 2017-11-08 Synergy Pharmaceuticals Inc. Agonistes de guanylate cyclase utiles pour le traitement de troubles gastro-intestinaux, inflammatoires, cancéreux et autres
EP2923706A1 (fr) 2009-12-03 2015-09-30 Synergy Pharmaceuticals Inc. Agonistes de guanylate cyclase utiles pour le traitement de l'hypercholestérolémie
WO2011069038A2 (fr) 2009-12-03 2011-06-09 Synergy Pharmaceuticals, Inc. Agonistes de la guanylate cyclase utiles dans le traitement de l'hypercholestérolémie, de l'athérosclérose, d'une coronaropathie, des calculs biliaires, de l'obésité et d'autres maladies cardiovasculaires
WO2013138352A1 (fr) 2012-03-15 2013-09-19 Synergy Pharmaceuticals Inc. Formulations d'agonistes de la guanylate cyclase c et procédés d'utilisation
EP3708179A1 (fr) 2012-03-15 2020-09-16 Bausch Health Ireland Limited Formulations d'agonistes de guanylate cyclase c et leurs procédés d'utilisation
EP4309673A2 (fr) 2012-03-15 2024-01-24 Bausch Health Ireland Limited Formulations d'agonistes de guanylate cyclase c et leurs procédés d'utilisation
WO2014151200A2 (fr) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Compositions utiles pour le traitement de troubles gastro-intestinaux
WO2014151206A1 (fr) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Agonistes de la guanylate cyclase et leurs utilisations
WO2014197720A2 (fr) 2013-06-05 2014-12-11 Synergy Pharmaceuticals, Inc. Agonistes ultra-purs de guanylate cyclase c, leur procédé de production et d'utilisation
EP4424697A2 (fr) 2013-06-05 2024-09-04 Bausch Health Ireland Limited Agonistes ultra-purs de guanylate cyclase c, leur procédé de fabrication et d'utilisation
US11560390B2 (en) 2015-12-22 2023-01-24 SHY Therapeutics LLC Compounds for the treatment of cancer and inflammatory disease
US10870657B2 (en) 2015-12-22 2020-12-22 SHY Therapeutics LLC Compounds for the treatment of cancer and inflammatory disease
US12168668B2 (en) 2015-12-22 2024-12-17 SHY Therapeutics LLC Compounds for the treatment of cancer and inflammatory disease
US10940139B2 (en) 2017-06-21 2021-03-09 SHY Therapeutics LLC Compounds that interact with the Ras superfamily for the treatment of cancers, inflammatory diseases, rasopathies, and fibrotic disease
US11000515B2 (en) 2017-06-21 2021-05-11 SHY Therapeutics LLC Compounds that interact with the Ras superfamily for the treatment of cancers, inflammatory diseases, rasopathies, and fibrotic disease
US11026930B1 (en) 2017-06-21 2021-06-08 SHY Therapeutics LLC Compounds that interact with the Ras superfamily for the treatment of cancers, inflammatory diseases, rasopathies, and fibrotic disease
US11213515B1 (en) 2017-06-21 2022-01-04 SHY Therapeutics LLC Compounds that interact with the Ras superfamily for the treatment of cancers, inflammatory diseases, rasopathies, and fibrotic disease
US11541041B1 (en) 2017-06-21 2023-01-03 SHY Therapeutics LLC Compounds that interact with the Ras superfamily for the treatment of cancers, inflammatory diseases, Rasopathies, and fibrotic disease
US10933054B2 (en) 2017-06-21 2021-03-02 SHY Therapeutics LLC Compounds that interact with the Ras superfamily for the treatment of cancers, inflammatory diseases, rasopathies, and fibrotic disease
US10588894B2 (en) 2017-06-21 2020-03-17 SHY Therapeutics LLC Compounds that interact with the Ras superfamily for the treatment of cancers, inflammatory diseases, rasopathies, and fibrotic disease

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