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 PDFInfo
- 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
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- 230000000694 effects Effects 0.000 title claims abstract description 6
- 125000000623 heterocyclic group Chemical group 0.000 title description 2
- 150000002460 imidazoles Chemical class 0.000 claims abstract description 23
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 claims abstract description 11
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 11
- 239000001257 hydrogen Substances 0.000 claims abstract description 10
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- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical group C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims abstract description 6
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical group C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 claims abstract description 5
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- 150000003536 tetrazoles Chemical group 0.000 claims abstract description 5
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- 208000002815 pulmonary hypertension Diseases 0.000 description 1
- 150000003216 pyrazines Chemical class 0.000 description 1
- 150000004892 pyridazines Chemical class 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000011775 sodium fluoride Substances 0.000 description 1
- 235000013024 sodium fluoride Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
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.
Landscapes
- 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.
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 |
Family
ID=11367906
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)
| 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 |
| 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 |
| 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)
| 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 |
-
1994
- 1994-02-18 IT ITMI940296A patent/IT1273790B/it active IP Right Grant
-
1995
- 1995-02-09 WO PCT/EP1995/000468 patent/WO1995022543A1/fr active Application Filing
- 1995-02-09 AU AU17062/95A patent/AU1706295A/en not_active Abandoned
Patent Citations (2)
| 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 (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| US8481037B2 (en) | 2003-04-11 | 2013-07-09 | Medimmune, Llc | Recombinant IL-9 antibodies and uses thereof |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
|---|---|
| ITMI940296A1 (it) | 1995-08-19 |
| AU1706295A (en) | 1995-09-04 |
| ITMI940296A0 (it) | 1994-02-18 |
| IT1273790B (it) | 1997-07-10 |
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