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WO2000031071A1 - Derives d'acetal 2-alkyl-5-halo-3-[2'-(tetrazol-5-yl)-biphenyl-4-ylmethyl]-3h-imidazole-4-carboxaldehyde, preparation et utilisation de ceux-ci - Google Patents

Derives d'acetal 2-alkyl-5-halo-3-[2'-(tetrazol-5-yl)-biphenyl-4-ylmethyl]-3h-imidazole-4-carboxaldehyde, preparation et utilisation de ceux-ci Download PDF

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Publication number
WO2000031071A1
WO2000031071A1 PCT/EP1999/008991 EP9908991W WO0031071A1 WO 2000031071 A1 WO2000031071 A1 WO 2000031071A1 EP 9908991 W EP9908991 W EP 9908991W WO 0031071 A1 WO0031071 A1 WO 0031071A1
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WO
WIPO (PCT)
Prior art keywords
alkyl
tetrazol
biphenyl
ylmethyl
imidazole
Prior art date
Application number
PCT/EP1999/008991
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English (en)
Inventor
Rafael Foguet
Lluis Anglada
Aurelio Sacristán
Josep M. Castelló
José A. Ortiz
Original Assignee
Ferrer Internacional, S.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 Ferrer Internacional, S.A. filed Critical Ferrer Internacional, S.A.
Priority to AU12728/00A priority Critical patent/AU1272800A/en
Publication of WO2000031071A1 publication Critical patent/WO2000031071A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the present invention relates to new 2-alkyl-5-halo-3- [2 ' ⁇ (tetrazol-5-yl) -biphenyl-4-ylmethyl] -3H-imidazole-4- carboxaldehyde acetal derivatives which are useful for the management of hypertension.
  • US Patent 5,138,069 discloses the preparation and antihypertensive properties of 2-butyl-4-chloro-l- [ [2 ' - (1H- tetrazol-5-yl) [1,1' -biphenyl] -4-yl] methyl-lH-imidazole-5- methanol (Losartan, WHO-INN) on the basis of its capacity of blocking angiotensin II receptors.
  • the present invention relates to 2-Alkyl-5-halo-3- [2 ' - (tetrazol-5-yl) -biphenyl-4-ylmethyl] -3H-imidazole-4- carboxaldehyde acetal derivatives of general formula (I) :
  • R is an alkyl radical having 1 to 6 carbon atoms
  • X is a halogen atom
  • R x and R 2 are either alkyl radicals having 1 to 4 carbon atoms or form in conjunction with the carbon atom to which they are bound a 3- to 6-membered cycle
  • n is 0 or 1, as well as pharmaceutically acceptable salts thereof.
  • alkyl radical designates a lower alkyl radical having 1 to 6 and preferably up to 4 carbon atoms .
  • Said radical may be a straight chain or branched radical .
  • Preferred examples include methyl, ethyl, n-propyl, i- propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, etc.
  • halogen atom includes a fluorine, chlorine, bromine and iodine atom, a chlorine atom being preferred.
  • 3- to 6-membered cycle designates cycloalkyl radicals having 3 to 6 and preferably up to 4 carbon atoms in the ring moiety.
  • the cycle may be unsaturated or preferably saturated.
  • Preferred examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl. Particularly preferred is cyclobutyl.
  • cyclobutyl Together with the [1, 3] dioxan-2-yl moiety to which said cycles are attached, they form spiro units.
  • a preferred example of said spiro unit is 6,8- dioxaspiro [3 , 5] -non-7-yl .
  • pharmaceutically acceptable salt designates substitution salts of the present derivatives which can be obtained with pharmaceutically acceptable inorganic bases, in particular hydroxides.
  • inorganic salts include metal salts such as sodium, potassium, calcium, magnesium salts etc.
  • Particularly preferred examples include alkali metal salts, in particular potassium salts.
  • Preferred embodiments of the present invention are compounds wherein R is butyl, in particular n-butyl; X is chlorine; n is 0; and/or n is 1 and R x and R 2 are both methyl or R x and R 2 form in conjunction with the carbon atom to which they are bound a 4-membered saturated cycle; R is an alkyl radical having 4 carbon atoms at most, X is a halogen atom and R x and R 2 are either alkyl radicals having 4 carbon atoms at most or form in conjunction with the carbon atom to which they are bound a 4-link cycle at most, and n is 0 or 1.
  • the present invention also relates to a process for preparing the compounds of formula (I) as defined above, which comprises reacting an intermediate of the formula (ID :
  • R 1# R 2 and n are as defined for (I) , in the presence of a trialkyl chlorosilane, optionally followed by a salification with the corresponding base in order to obtain the pharmaceutically acceptable salt .
  • the trialkyl chlorosilane is trimethyl chlorosilane; and/or the base is the hydroxide.
  • the compounds of the present invention may be obtained by acetalization of the aldehyde function which is present in 2-alkyl-5-halo-3- [2 ' - (tetrazol-5-yl) -biphenyl- 4-ylmethyl] -3H-imidazole-4-carboxaldehyde intermediates of general formula (II) according to the process shown in Scheme 1 :
  • the present invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising as active ingredient (s) at least one compound as defined above and a pharmaceutically acceptable carrier.
  • active ingredient (s) at least one compound as defined above
  • a pharmaceutically acceptable carrier optionally, other therapeutic ingredient (s) may be present .
  • compositions include those in a form suitable for oral, rectal, parenteral (including subcutaneous, intramuscular, intravenous and intraperitoneal) administration.
  • compositions suitable for oral administration are advantageous and may be in the form of descret units such as capsules, sachets, tablets or lozenges; in the form of a powder or granules; in the form of a solution or a suspension in an aqueous liquid or non-aqueous liquid; or in the form of an oil-in-water emulsion or water-in-oil emulsion.
  • compositions may conveniently be presented in dosage unit form and may be prepared by any of the methods well known in the art of pharmacy. Commonly, said preparation includes a step of bringing the active ingredient into association with the carrier.
  • the compounds of the present invention are angiotensin II antagonists and they are useful for the management of hypertension in man and mammals.
  • the present invention also relates to the use of at least one compound as defined above for preparing a pharmaceutical composition for the treatment of hypertension.
  • Treatment means treating patients, in particular mammals and preferably humans in need of such a treatment by administering to said patients an effective amount of at least one compound as defined above, if necessary together or concomitantly with one or more other therapeutically active components.
  • the present compounds have advantages over Losartan as evidenced in the following pharmacological tests: a) Effect on arterial blood pressure in furosemide- pretreated conscious rats after oral administration Following activation of the renin-angiotensin system, endogenous angiotensin II is the substrate responsible for the generation of hypertension, mostly because of vasoconstriction by AT X vasoreceptor stimulation.
  • the assessment of antihypertensive agents inhibiting the endogenous stimulation of AT., receptors is performed in experimental models. Normotensive animals are administered with repeated subcutaneous injection of furosemide provoking the release of renin by renal juxtaglomerular cells, which results in the formation of angiotensin I from its angiotensinogen.
  • Angiotensin I is converted by its conversion enzyme in angiotensin II, which is a substrate of potent vasoconstrictive action and is responsible for the generation of hypertension.
  • Losartan at an oral dose of 3 mg/kg decreased remarkably the MABP after 1 h of the administration down to a maximum of 14.8 mmHg at 5 h, the baseline value being 126 ⁇ 10.3 mmHg, which corresponds to an 11.7% reduction in comparison with baseline value.
  • losartan potassium decreased the MABP down to a maximum of 26 mmHg at 5 h, the baseline value being 119.3 ⁇ 9.77 mmHg, which corresponds to a 21.8% reduction in comparison with baseline value.
  • Example 6 The compound of Example 6 at an oral dose of 3 mg/kg produced a significant continual reduction to the MABP in comparison with baseline value already since 1 h and down to 21.0 mmHg at 5 h, which corresponds to a 17.3% reduction versus baseline value of 121.3 ⁇ 3.72 mmHg.
  • the compound of Example 6 reduced significantly the MABP in comparison with baseline value already since 1 h and down to 29.3 mmHg at 5 h. This reduction corresponds to 25.38% versus baseline value of 118.2 ⁇ 7.24 mmHg.
  • MABP 0 mean arterial blood pressure
  • the MABP 0 17.6.0 ⁇ 23.05 and 174.0 ⁇ 18.2 mmHg, respectively
  • the MABP 0 17.6 ⁇ 23.05 and 174.0 ⁇ 18.2 mmHg, respectively
  • the MABP 0 169.1 ⁇ 15.65 and 163.6 ⁇ 29.9 mmHg respectively
  • the MABP 0 was reduced to a mean value of 49.4 mmHg (29.2% decrease) and 59.1 mmHg (36.1% decrease) respectively at 5 h.
  • the compound of Example 6 showed a similar profile to that of losartan potassium. However, the antihypertensive effect of the compound of Example 2 was reached 1 h more rapidly and more significantly than with losartan potassium (p ⁇ 0.05) at single oral doses of 10 mg/kg.
  • Example 7 Coated tablet formulation

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Cardiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Heart & Thoracic Surgery (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)
  • Plural Heterocyclic Compounds (AREA)

Abstract

La présente invention concerne des dérivés d'acétal 2-Alkyl-5-halo-3-[2'-(tétrazol-5-yl)-biphényl-4-ylméthyl]-3H-imidazole-4-carboxaldéhyde représentés par la formule générale (I), dans laquelle R représente un radical alkyle ayant entre 1 et 6 atomes de carbone, X représente un atome d'halogène et R1 et R2 soit représentent des radicaux alkyle ayant entre 1 et 4 atome de carbone, soit forment an association avec l'atome de carbone auquel ils sont liés un cycle ayant entre 3 et 6 éléments, n représentant 0 ou 1; cette invention concernant également des sels des dérivés précités acceptables sur le plan pharmaceutique. En l'occurrence, ces composés sont utilisés pour lutter contre l'hypertension.
PCT/EP1999/008991 1998-11-24 1999-11-22 Derives d'acetal 2-alkyl-5-halo-3-[2'-(tetrazol-5-yl)-biphenyl-4-ylmethyl]-3h-imidazole-4-carboxaldehyde, preparation et utilisation de ceux-ci WO2000031071A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU12728/00A AU1272800A (en) 1998-11-24 1999-11-22 2-alkyl-5-halo-3-(2'-(tetrazol-5-YL)-biphenyl-4-ylmethyl)-3H imidazole-4-carboxaldehyde acetal derivatives, their preparation and use

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ES009802460A ES2154191B1 (es) 1998-11-24 1998-11-24 Nuevos acetales derivados de los 2-alquil-5-halo-3-(2'-(tetrazol-5-il)-bifenil-4-ilmetil)-3h-imidazol-4-carbaldehidos.
ESP9802460 1998-11-24

Publications (1)

Publication Number Publication Date
WO2000031071A1 true WO2000031071A1 (fr) 2000-06-02

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Country Status (5)

Country Link
AR (1) AR021343A1 (fr)
AU (1) AU1272800A (fr)
ES (1) ES2154191B1 (fr)
PA (1) PA8485801A1 (fr)
WO (1) WO2000031071A1 (fr)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BR0102252B1 (pt) 2001-04-10 2013-10-22 Sistema de liberação controlada para antagonista do receptor AT1 da angiotensina II, composição farmacêutica e seu uso
ES2242543B1 (es) * 2004-04-30 2006-12-01 Universidad De Alcala Derivados de losartan con propiedades antioxidantes.

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0492105A2 (fr) * 1990-11-17 1992-07-01 Hoechst Aktiengesellschaft Traitement de l'hypertrophie cardiaque par des bloqueurs des récepteurs de l'angiotensine II
US5138069A (en) * 1986-07-11 1992-08-11 E. I. Du Pont De Nemours And Company Angiotensin II receptor blocking imidazoles
US5264581A (en) * 1992-05-29 1993-11-23 E. I. Du Pont De Nemours And Company Radioiodinated angiotensin receptor antagonists
WO1994003435A1 (fr) * 1992-08-06 1994-02-17 E.I. Du Pont De Nemours And Company Promedicaments d'acides carboxyliques d'imidazole en tant qu'antagonistes des recepteurs de l'angiotensine ii
WO1998034922A1 (fr) * 1997-02-05 1998-08-13 Sankyo Company, Limited Agent destine a la prophylaxie ou la therapie des complications diabetiques

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE4132633A1 (de) * 1991-10-01 1993-04-08 Bayer Ag Cyclisch substituierte imidazolyl-propensaeurederivate
EP0577023A3 (en) * 1992-07-01 1996-12-18 Hoechst Ag Angiotensin-ii receptor-antagonists for the treatment of arrhythmices
KR0132001B1 (ko) * 1994-05-21 1998-04-17 강박광 신규한 치환된 이미다졸 유도체

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5138069A (en) * 1986-07-11 1992-08-11 E. I. Du Pont De Nemours And Company Angiotensin II receptor blocking imidazoles
EP0492105A2 (fr) * 1990-11-17 1992-07-01 Hoechst Aktiengesellschaft Traitement de l'hypertrophie cardiaque par des bloqueurs des récepteurs de l'angiotensine II
US5264581A (en) * 1992-05-29 1993-11-23 E. I. Du Pont De Nemours And Company Radioiodinated angiotensin receptor antagonists
WO1994003435A1 (fr) * 1992-08-06 1994-02-17 E.I. Du Pont De Nemours And Company Promedicaments d'acides carboxyliques d'imidazole en tant qu'antagonistes des recepteurs de l'angiotensine ii
WO1998034922A1 (fr) * 1997-02-05 1998-08-13 Sankyo Company, Limited Agent destine a la prophylaxie ou la therapie des complications diabetiques

Also Published As

Publication number Publication date
AR021343A1 (es) 2002-07-17
ES2154191B1 (es) 2001-10-16
PA8485801A1 (es) 2000-09-29
AU1272800A (en) 2000-06-13
ES2154191A1 (es) 2001-03-16

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