WO1995022543A1 - Derives heterocycliques diazotes possedant une activite dirigee contre l'angiotensine ii - Google Patents

Derives heterocycliques diazotes possedant une activite dirigee contre l'angiotensine ii Download PDF

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Publication number
WO1995022543A1
WO1995022543A1 PCT/EP1995/000468 EP9500468W WO9522543A1 WO 1995022543 A1 WO1995022543 A1 WO 1995022543A1 EP 9500468 W EP9500468 W EP 9500468W WO 9522543 A1 WO9522543 A1 WO 9522543A1
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WO
WIPO (PCT)
Prior art keywords
methyl
butyl
imidazole
biphenyl
oxide
Prior art date
Application number
PCT/EP1995/000468
Other languages
English (en)
Inventor
Fabrizio Bonaccorsi
Guido Cerbai
Nicholas J. S. Harmat
Raffaello Giorgi
Rocco Cirillo
Anna Rita Renzetti
Original Assignee
Laboratori Guidotti S.P.A.
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 Laboratori Guidotti S.P.A. filed Critical Laboratori Guidotti S.P.A.
Priority to AU17062/95A priority Critical patent/AU1706295A/en
Publication of WO1995022543A1 publication Critical patent/WO1995022543A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings

Definitions

  • the present invention relates to imidazole derivatives with All-antagonistic activity , a process for the preparation thereof and pharmaceutical compos itions containing them as the active principles .
  • the invention relates to compounds of formula ( I )
  • R is a C 1 -C 5 alkyl or a C 2 -C 5 alkenyl group
  • R 1 is a COOR 3 , CN, -SO 3 H group or a tetrazole group of formula (IIa) or (IIb)
  • R 2 is a pyrazine, pyrimidine or pyridazine ring, optionally substituted with one or more C 1 -C 5 alkyl groups , carboxy groups or C 1 -C 5 alkoxycarbonyl groups or the N-oxides thereof ;
  • R 3 is hydrogen, C 1 -C 5 alkyl or benzyl;
  • R 4 is hydrogen, C 1 -C 5 alkyl or triphenylmethyl and salts thereof with pharmaceutically acceptable acids or bases.
  • C 1 -C 5 alkyl means straight, branched or cyclic alkyl groups. Examples of said groups comprise methyl, ethyl, n-propyl, cyclopropyl, n-butyl, isobutyl, tert- butyl, n-pentyl, isoamyl, cyclopentyl.
  • C 2 -C 5 alkenyl groups are vinyl, allyl, isoprenyl, 2-butenyl, 3-pentenyl.
  • Examples of C 1 -C 5 alkoxycarbonyl groups comprise methoxycarbonyl, ethoxycarbonyl.
  • R is preferably a C 1 -C 5 alkyl group; R 1 is preferably a tetrazole group of formulae (IIa) or (IIb) wherein R 4 is as defined above and preferably hydrogen; R 2 is a 2-pyrimidinyl; 5-pyrimidinyl; 2-methyl-4-methoxycarbonyl-5-pyrimidinyl; 1-oxide-5-pyrimidinyl; 1-oxide-2-pyrimidinyl; 2-pyrazinyl; 2-pyrazinyl-4-oxide; 3-methoxycarbonyl-2-pyrazinyl; 3 , 6-dimethyl-2-pyrazinyl; 3-pyridazinyl; 3-methyl-6-pyridazinyl; 6-methoxycarbonyl-3-pyridazinyl;2-oxide-3-methyl-6-pyridazinyl; 1-oxide-3-methyl-6-pyridazinyl, 1-oxide-3,6-dimethyl-2-
  • Compounds of formula (I) have antagonistic activity on angiotensin II (AII) and therefore are useful in the pharmacological treatment of such cardiovascular diseases as hypertension, cardiac decompensation, intraocular hypertension, glaucoma, hyperaldosteronism, renal diseases, myocardial infarction.
  • cardiovascular diseases as hypertension, cardiac decompensation, intraocular hypertension, glaucoma, hyperaldosteronism, renal diseases, myocardial infarction.
  • Compounds with All-antagonistic activity characterized by a totally substituted imidazole ring were described in EP 253310, EP 324377, WO 91/00277, WO 91/00281, WO 91/14367, WO 91/15206 and WO 92/00977.
  • R 1 has the same meanings as R 1 or is a group which can be converted into R 1 by removing the protecting groups and X is a leaving group such as halogen, mesyloxy, acetyloxy
  • R and R 2 are as defined above and M is H, acetyl, p-methoxybenzyl, trityl.
  • the alkylation reaction can be carried out forming the salt of imidazole (IV), in which M is H, in an aprotic dipolar solvent such as DMF or DMSO by treatment with alkali and alkaline-earth metal (Na, K, Ca ) hydrides or alternatively in lower alcohols (MeOH, EtOH, t-BuOH) in the presence of the corresponding Na or K alcoholate at temperatures ranging from 20°C to 100°C.
  • an aprotic dipolar solvent such as DMF or DMSO
  • R is as defined above
  • Y is ZnCl, Bu..Sn, Me 3 Sn, B(OH) 2 and Z is a protecting group, with the suitable halogen- pyrimidines, pyridazines or pyrazines.
  • the reaction is carried out in a solvent, such as dioxane, at the reflux temperature, in the presence of transition metal complexes as catalysts, such as palladium complexes, for example palladium tetrakistriphenylphosphine, platinum, nickel (as described for example by M. Peyreyre et al., Tin in organic synthesis, ButterWorks, London, 1987; R.F. Heck, Palladium reagents in organic chemistry, Academic Press, Orlando, Florida, 1985).
  • heteroaryl imidazole compounds (IV) subjected to acidic hydrolysis (both with methanol HCl and with aqueous HCl), to remove the protecting group Z, are subsequently transformed into the corresponding sodium salts by reaction with alkali and alkaline-earth metal (Na, K, Ca) hydrides in aprotic polar (DMF, DMSO), then are reacted with the bromomethyl diphenyl tetrazole derivative (III).
  • Compound ⁇ (I), wherein R 3 is a corresponding N-oxide can be prepared by oxidation with conventional reagents and subsequent deprotection, again by heating with methanol.
  • Conventional oxidation reagents are organic or inorganic peracids. Hydrogen peroxide in 20-30% aqueous solution in the presence of variable amounts of glacial acetic acid, or perbenzoic or m-chloroperbenzoic acids in solvents which are preferably dichloromethane or chloroform, at temperatures from 0°C to 60°C, preferably from 0oC to 30°C, can be used.
  • the compounds of the present invention act as antagonists on All-receptors.
  • i n vitro tests such as the inhibition of the contraction induced by All in rabbit aorta and the displacement of 125 I-Sar 1 -Ile 8 -AT II in rat adrenal cortex
  • an in vivo test the inhibition of the pressory response induced by All in the ganglioblocked normotensive rat
  • the compounds of the invention proved active in the above tests; for example in the in vitro test on rabbit aorta, a number of compounds turned out to have pA 2 values higher than 6.5, whereas in the receptor binding they showed to have a Ki ⁇ 1 ⁇ M.
  • Compounds of general formula (I) or the pharmaceutically acceptable salts thereof can be used in pharmaceutical preparations, alone or in admixture with pharmaceutically acceptable excipients, for the oral or parenteral administrations.
  • suitable excipients are for example starch, lactose, glucose, arabic gum, stearic acid and the like.
  • the pharmaceutical preparations can be in solid form such as tablets, capsules or suppositories or in liquid form, such as solutions, suspensions or emulsions.
  • the pharmaceutical preparations can be in the form of sterile solutions.
  • Compounds of general formula (I) can be administered in unitary doses ranging from 1 to 100 mg, to patients suffering from cardiac and vascular diseases such as hypertension, acute and chronic cardiac decompensation, intraocular hypertension
  • cardiac and vascular diseases such as hypertension, acute and chronic cardiac decompensation, intraocular hypertension
  • other diseases such as secondary hyperaldosteronism, pulmonary hypertension, renal diseases (glomerulonephritis, diabetic nephropathy) or vascular diseases (hemicrania, Raynaud's disease).
  • the following examples further illustrate the invention.
  • reaction mixture was added with ethyl ether (180 ml) and 75 ml of a sodium fluoride saturated aqueous solution, then it was stirred at room temperature for 20 hours, was filtered on Celite and the filtrate was washed with a NaCl saturated solution (3 times), dried over MgSO 4 and evaporated under reduced pressure.
  • reaction mixture was stirred always at room temperature overnight, then was added with 180 ml of water and ice and repeatedly extracted with ethyl acetate. The combined organic extracts were washed with a NaCl saturated solution, dried over MgSO 4 and evaporated under reduced pressure.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention se rapporte aux dérivés imidazole de la formule générale (I) ainsi qu'à leurs sels à acides ou bases pharmaceutiquement acceptables, possédant une activité dirigée contre l'angiotensine II. Dans cette formule, R représente alkyle C1-C5 ou un groupe alcényle C2-C5; R1 représente COOR3, CN, un groupe -SO3H ou un groupe tétrazole de formule (IIa) ou (IIb); R2 représente un noyau pyrazine, pyrimidine ou pyridazine, éventuellement substitué par un ou plusieurs groupes alkyle C1-C5, carboxy, ou alcoxycarbonyle C1-C5 ou par les N-oxydes de ceux-ci; R3 représente hydrogène, alcoyle C1-C5, ou benzyle; R4 représente hydrogène, alkyle C1-C5 ou triphénylméthyle. L'invention se rapporte également au procédé de préparation de ces dérivés ainsi qu'aux compositions pharmaceutiques contenant ceux-ci en tant que principes actifs.
PCT/EP1995/000468 1994-02-18 1995-02-09 Derives heterocycliques diazotes possedant une activite dirigee contre l'angiotensine ii WO1995022543A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU17062/95A AU1706295A (en) 1994-02-18 1995-02-09 Dinitrogenated heterocyclic derivatives having aii-antagonistic activity

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ITMI940296A IT1273790B (it) 1994-02-18 1994-02-18 Derivati eterociclici diazotati aventi attivita' aii antagonista
ITMI94A000296 1994-02-18

Publications (1)

Publication Number Publication Date
WO1995022543A1 true WO1995022543A1 (fr) 1995-08-24

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1995/000468 WO1995022543A1 (fr) 1994-02-18 1995-02-09 Derives heterocycliques diazotes possedant une activite dirigee contre l'angiotensine ii

Country Status (3)

Country Link
AU (1) AU1706295A (fr)
IT (1) IT1273790B (fr)
WO (1) WO1995022543A1 (fr)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008021237A1 (fr) 2006-08-10 2008-02-21 Arubor Corporation Thérapie locale de troubles inflammatoires des voies aériennes inférieures avec des inhibiteurs de cytokine proinflammatoire
US7351739B2 (en) 2004-04-30 2008-04-01 Wellgen, Inc. Bioactive compounds and methods of uses thereof
US7354584B2 (en) 2003-04-11 2008-04-08 Medimmune, Inc. Recombinant IL-9 antibodies
WO2009158309A2 (fr) * 2008-06-25 2009-12-30 Ligand Pharmaceuticals Inc. Biphényle sulfonamides en tant que doubles antagonistes du récepteur d'angiotensine et d'endothéline
WO2010095462A1 (fr) * 2009-02-23 2010-08-26 興和株式会社 Nouveaux composés comprenant une structure de 3-(5-alcoxypyrimidin-2-yl) pyrimidin-4(3h)-one et médicaments les comprenant
EP2422811A2 (fr) 2004-10-27 2012-02-29 MedImmune, LLC Modulation d'une spécificité d'anticorps par adaptation sur mesure de son affinité a une antigène apparente
US8273738B2 (en) 2006-09-05 2012-09-25 Kyowa Hakko Kirin Co., Ltd. Imidazole derivatives
US8664226B2 (en) 2009-04-17 2014-03-04 Kowa Company, Ltd. Compound having 3-heteroarylpyrimidin-4-(3H)-one structure and pharmaceutical preparation containing same
EP2851064A2 (fr) 2006-07-11 2015-03-25 Roy C. Levitt Prévention de la rhinosinusite et thérapie avec des inhibiteurs de cytokine proinflammatoires
US9315493B2 (en) 2011-03-14 2016-04-19 Kowa Company, Ltd. Phenylpyridine derivative and drug containing same

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991000277A1 (fr) * 1989-06-30 1991-01-10 E.I. Du Pont De Nemours And Company Imidazoles substitues
WO1994003449A1 (fr) * 1992-08-07 1994-02-17 Istituto Luso Farmaco D'italia S.P.A. Derives d'imidazole a activite antagoniste de l'angiotensine ii

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991000277A1 (fr) * 1989-06-30 1991-01-10 E.I. Du Pont De Nemours And Company Imidazoles substitues
WO1994003449A1 (fr) * 1992-08-07 1994-02-17 Istituto Luso Farmaco D'italia S.P.A. Derives d'imidazole a activite antagoniste de l'angiotensine ii

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8481037B2 (en) 2003-04-11 2013-07-09 Medimmune, Llc Recombinant IL-9 antibodies and uses thereof
US7354584B2 (en) 2003-04-11 2008-04-08 Medimmune, Inc. Recombinant IL-9 antibodies
EP2316487A1 (fr) 2003-04-11 2011-05-04 MedImmune, LLC Anticorps IL-9 recombinants et leurs utilisations
US7351739B2 (en) 2004-04-30 2008-04-01 Wellgen, Inc. Bioactive compounds and methods of uses thereof
EP2422811A2 (fr) 2004-10-27 2012-02-29 MedImmune, LLC Modulation d'une spécificité d'anticorps par adaptation sur mesure de son affinité a une antigène apparente
EP2851064A2 (fr) 2006-07-11 2015-03-25 Roy C. Levitt Prévention de la rhinosinusite et thérapie avec des inhibiteurs de cytokine proinflammatoires
US11718853B2 (en) 2006-08-10 2023-08-08 Onspira Therapeutics, Inc. Localized therapy of lower airways inflammatory disorders with proinflammatory cytokine inhibitors
EP3669878A1 (fr) 2006-08-10 2020-06-24 Roy C. Levitt Thérapie localisée des troubles inflammatoires des voies respiratoires inférieures avec des inhibiteurs de cytokines inflammatoires
WO2008021237A1 (fr) 2006-08-10 2008-02-21 Arubor Corporation Thérapie locale de troubles inflammatoires des voies aériennes inférieures avec des inhibiteurs de cytokine proinflammatoire
US8273738B2 (en) 2006-09-05 2012-09-25 Kyowa Hakko Kirin Co., Ltd. Imidazole derivatives
WO2009158309A3 (fr) * 2008-06-25 2010-04-22 Ligand Pharmaceuticals Inc. Biphényle sulfonamides en tant que doubles antagonistes du récepteur d'angiotensine et d'endothéline
WO2009158309A2 (fr) * 2008-06-25 2009-12-30 Ligand Pharmaceuticals Inc. Biphényle sulfonamides en tant que doubles antagonistes du récepteur d'angiotensine et d'endothéline
WO2010095462A1 (fr) * 2009-02-23 2010-08-26 興和株式会社 Nouveaux composés comprenant une structure de 3-(5-alcoxypyrimidin-2-yl) pyrimidin-4(3h)-one et médicaments les comprenant
US8664226B2 (en) 2009-04-17 2014-03-04 Kowa Company, Ltd. Compound having 3-heteroarylpyrimidin-4-(3H)-one structure and pharmaceutical preparation containing same
US9315493B2 (en) 2011-03-14 2016-04-19 Kowa Company, Ltd. Phenylpyridine derivative and drug containing same

Also Published As

Publication number Publication date
IT1273790B (it) 1997-07-10
ITMI940296A0 (it) 1994-02-18
ITMI940296A1 (it) 1995-08-19
AU1706295A (en) 1995-09-04

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