WO1994015926A1 - Inhibiteurs de l'angiotensine ii - Google Patents

Inhibiteurs de l'angiotensine ii Download PDF

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Publication number
WO1994015926A1
WO1994015926A1 PCT/US1994/000639 US9400639W WO9415926A1 WO 1994015926 A1 WO1994015926 A1 WO 1994015926A1 US 9400639 W US9400639 W US 9400639W WO 9415926 A1 WO9415926 A1 WO 9415926A1
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Prior art keywords
compound
cis
different
same
βalkyl
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English (en)
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Jeffrey D. Hsi
William V. Murray
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Ortho Pharmaceutical Corp
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Ortho Pharmaceutical Corp
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Priority to AU60905/94A priority Critical patent/AU6090594A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings

Definitions

  • the present invention relates to angiotensin II inhibitors for the treatment of hypertension. More particularly, the present invention relates to the use of certain tetrazolyl biphenyl compounds for the treatment of hypertension.
  • renin-angiotensin system has an established role in the regulation of blood pressure.
  • RAS renin-angiotensin system
  • ACE angiotensin converting enzyme
  • Angiotensin II receptor antagonists provide a novel approach to the treatment of hypertension.
  • the present invention provides angiotensin II receptor antagonists of the general structure (I):
  • X is CH 2 , O, S, N-R 4 , NH, NCHO, NCOCH 3 or NC0 2 R 4 ;
  • R 1 and R 2 are the same or different and are Ci- ⁇ alkyl; and
  • R 4 is Ci- ⁇ alkyl; including the pharmaceutically acceptable salts thereof.
  • the invention also provides novel intermediates of the general structure:
  • X 2 is CH 2 , O, S, N-R 4 or N-Si(R5)(R6)(R7 );
  • R 1 and R 2 are the same or different and are Ci- ⁇ alkyl
  • R 4 is C ⁇ . 6 alkyl
  • R 5 , R 6 , and R 7 are the same or different and are methyl, ethyl, t-butyl, or phenyl; and Z is selected from the group consisting of Li, MgCI, MgBr and Mgl. Also provided is a novel process to produce compounds of formula
  • X 1 is CH 2l O, S, N-R 4 or NH
  • R 1 and R 2 are the same or different and are Ci- ⁇ alkyl
  • R 4 is Ci- ⁇ alkyl; which comprises the steps:
  • X 2 is CH 2> O, S, N-R 4 or N-Si(R5)(R6)(R7) ;
  • R 1 and R 2 are the same or different and are C-j-ealkyl
  • R 4 is C ⁇ - ⁇ alkyl
  • R 5 , R 6 , and R 7 are the same or different and are methyl, ethyl, t-butyl, or phenyl; and Z is selected from the group consisting of Li, MgCI, MgBr and Mgl; and an oxazolinyl starting material of the formula:
  • Y is OMe or F; to produce an oxazolinyl intermediate of the formula:
  • R 1 , R 2 and X 1 are defined above;
  • X 2 is CH 2 , O, S, N-R 4 , N-Si(R5)(R6)(R7 );
  • R 1 and R 2 are the same or different and are C ⁇ - 6 alkyl
  • R 4 is C ⁇ - 6 alkyl
  • R 5 , R 6 , and R 7 are the same or different and are methyl, ethyl, t-butyl, or phenyl. Further provided are intermediates of the formula:
  • X 2 is CH 2 , O, S, N-R 4 , N-Si(R5)(R6)(R7); R 1 and R 2 are the same or different and are C-i- ⁇ alkyl; R 4 is Ci- ⁇ alkyl, and
  • R 5 , R 6 , and R 7 are the same or different and are methyl, ethyl, t-butyl, or phenyl.
  • Active compounds of the present invention may be produced by appropriately utilizing one of three suggested schemes. As seen therein, the various desired substituents are obtained concurrently with the manufacture of the core ring structure.
  • certain compounds of Formula I i. e., those in which X 1 is CH 2 , O, S, N-C-i- ⁇ alkyl or NH, may be produced by addition of fluorotetrazole Al and the organometallic compound Q2.
  • Z is Li or Z ⁇ Mg (where Z1 is CI, Br or I), X 2 is CH 2) O, S, N-R 4 or N-Si(R5)(R6)(R7) (where R 4 is Ci- ⁇ alkyl, and R 5 , R 6 , and R 7 are the same or different and are methyl, ethyl, t-butyl, or phenyl) and R 1 and R 2 are the same or different and are Ci- ⁇ alkyl.
  • Z is Li or Z ⁇ Mg (where Z1 is CI, Br or I)
  • X 2 is CH 2) O, S, N-R 4 or N-Si(R5)(R6)(R7) (where R 4 is Ci- ⁇ alkyl, and R 5 , R 6 , and R 7 are the same or different and are methyl, ethyl, t-butyl, or phenyl) and R 1 and R 2 are the same or different and are Ci- ⁇ alkyl.
  • Z 1 Mg the addition
  • Grignard reaction and may be carried out in a solvent, such as, diethyl ether, THF, 1 ,2-dimethoxyethane or dioxane at from -78 °C to reflux, preferably for about 6 to 24 hours.
  • a solvent such as, diethyl ether, THF, 1 ,2-dimethoxyethane or dioxane at from -78 °C to reflux, preferably for about 6 to 24 hours.
  • the addition is an organolithium addition which may be carried out under conditions similar to those of the Grignard reaction. Protection of the tetrazolyl moiety is optional if a molar excess of the organometallic compound is employed.
  • those compounds in which X 2 are N-Si(R 5 )(R 6 )(R 7 ) are deprotected to NH.
  • the fluorotetrazole Al may be prepared by techniques well known in the art, such as, those described in Herbst, R. M., and Wilson, K. R., J. Org. Chem. 1957, 22, 1142.
  • the preparation generally comprises reacting 2-fluoro benzonitrile with NaN3 and glacial acetic acid in a solvent, such as, n-butanol.
  • the preparation of the organometallic compound C_3_ is discussed below.
  • certain compounds of Formula I i. e., those in which X 1 is CH 2) O, S, N-C-i- ⁇ alkyl or NH, may be produced by a direct displacement reaction between tetrazolyl biphenyl compound f L and heterocycle QZ-
  • the direct displacement reaction is carried out by simply refluxing the two reactants in a suitable solvent, such as, CH3CN, with a base, such as, K 2 C ⁇ 3 , and, subsequently, deprotecting the tetrazolyl to the desired product in aq. HCI and THF.
  • a suitable solvent such as, CH3CN
  • K 2 C ⁇ 3 a base
  • those compounds in which X 2 are N-Si(R 5 )(R 6 )(R 7 ) are deprotected to NH.
  • the tetrazolyl biphenyl BJ_ may be prepared by known methods, such as, a modification of the method disclosed in U. S. Pat. Appl. 786,666 filed November 1 , 1992, to Russell, et al., hereby incorporated by reference, where £ might be obtained from the simple bromination of the protected ⁇ - tolylphenyl tetrazole.
  • fluorotetrazole Al is added in a Grignard reaction with a p_-Z 1 Mg-toluene where Z 1 is bromo, chioro or iodo. Protection of the tetrazolyl moiety is optional if a molar excess of the organometallic compound is employed. Protection of the biphenyl tetrazole with an agent , such as, triphenyl methyl chloride and subsequent bromination affords B1.
  • organometallic compound Q2. is produced by the addition of an activated benzyl compound £ to heterocycle QZ by alkylation.
  • the alkylation might be carried out in a suitable solvent, such as, CH 3 CN, DMF or THF with a base, such as, K 2 C ⁇ 3, NaH or KH at temperatures from 0 °C to reflux.
  • the benzyl compound .01. wherein L 1 is bromo, chloro or iodo is activated with a leaving group, L, wherein L is bromo, chloro, iodo, O-mesylate or O-tosylate, by methods well known in the art.
  • the L 1 substituent on the alkylation product is subsequently converted to the organometallic moiety, Z, by one of two reactions.
  • L 1 is converted to Z as Li in a lithium-halogen exchange.
  • the lithium- halogen exchange is performed by treatment of the alkylation product with an alkyllithium reagent, such as, n-butyllithium, s-butyllithium or l-butyllithium in an ethereal solvent, such as, THF or diethyl ether.
  • L 1 is converted to Z as MgCI, MgBr or Mgl in a Grignard preparation reaction.
  • the alkylation product is reacted with magnesium turnings in an ethereal solvent, such as, THF or diethyl ether, with or without the presence of an activating reagent, such as, l 2 or ethylene dibromide.
  • an ethereal solvent such as, THF or diethyl ether
  • the biphenylyl oxazoline intermediate D2 is produced by the addition of an organometallic compound C_3_, wherein R 1 , R 2 , X 2 and Z are defined above, to p_-substituted phenyl oxazoline P_ wherein Y is OMe or F.
  • the addition may be accomplished by one of two well known reactions.
  • the addition is, of course, a Grignard reaction and may be carried out in a solvent, such as, diethyl ether, THF, 1 ,2-dimethoxyethane or dioxane at from -78 °C to reflux, preferably for about 6 to 24 hours.
  • a solvent such as, diethyl ether, THF, 1 ,2-dimethoxyethane or dioxane at from -78 °C to reflux, preferably for about 6 to 24 hours.
  • the addition is an organolithium addition which may carried out under conditions similar to those of the Grignard reaction. Both the Grignard addition and the organolithium addition will function regardless of whether Y is OMe or F. However, Y as F is preferred to obtain higher yields.
  • biphenylyl nitrile D3_ is obtained by treatment of D2 with phosphorous oxychloride in pyridine at 0 °C to room temperature.
  • target compounds of formula (I) are obtained by treating biphenylyl nitrile p_3_ with sodium azide and tributyltin chloride in xylene.
  • those compounds in which X are N-Si(R 5 )(R 6 )(R 7 ) are deprotected to NH.
  • Each of Schemes A, B, and D produce compounds of Formula (I) wherein X 1 replaces X. More specifically, those procedures illustrated in Schemes A, B, and D may not be effective to produce those compounds in which X is NCHO, NCOCH 3 or NC0 2 R 4 (where R 4 is Ci- ⁇ alkyl), i.e. those in which X contains a carbonyl or carboxy. It is not surprising to those skilled in the art that the reason for this is that Schemes A, B, and D contain reaction steps that will degrade X containing carbonyl or carboxy substitution. Thus, compounds containing these X may not be produced or may not be obtained in high yield.
  • the acylating agent is dimethylformamide in the presence of a base , such as NaH or KH, and the solvent may be dimethylformamide itself or there may be additionally added an ethereal solvent.
  • a base such as NaH or KH
  • the acylating agent is acetyl chloride and the solvent might be pyridine or dichloromethane.
  • the acylating agent is R 4 -chloroformate and the solvent is pyridine or dichloromethane.
  • the pharmaceutically acceptable salts referred to above generally take the form of a salt with tetrazole, where tetrazole is associated with a metal or ammonium cation or tetrazole is reacted with an inorganic or organic acid to form an acid addition salt.
  • Further pharmaceutically acceptable acid addition salts may be formed where, in addition to the nitrogen of tetrazole, a nitrogen of the 6-membered heterocycle is protonated with an inorganic or organic acid.
  • Suitable metal or ammonium cations include sodium, potassium, calcium, magnesium, zinc, ammonium, or alkylammonium, where alkylammonium includes, tetramethylammonium, tetrabutylammonium, choline, triethylhydroammonium, meglumine, triethanolhydroammonium, etc.
  • Suitable salts derived from organic or inorganic acids are the following: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecyllsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2- hydroxyethanesulfonate, lactate, maieate, methanesulfonate, 2- naphthalene-sulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate,
  • the compounds described above are angiotensin II antagonists as demonstrated by their behavior in aortic rings and the salt depleted rat.
  • the compound of general structure (I) produced in the examples below i.e., the compound in which X is O and R 1 and R 2 are cis-dimethyl, displays a pA2 of 6.91 , as determined by test procedure 1 , below, and good oral activity with a maxirhum mean arterial pressure drop of 31 mm Hg and duration of 12 hours in the spontaneously hypertensive rat, as determined in test procedure 2, below.
  • compositions comprising a compound of the invention as the active ingredient in intimate admixture with a pharmaceutical carrier can be prepared according to conventional pharmaceutical compounding techniques.
  • the carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., intravenous, oral or parenteral.
  • the composition may also be administered by means of an aerosol.
  • any of the usual pharmaceutical media may be employed.
  • oral liquid preparations such as suspensions, elixirs and solutions
  • water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like may be used.
  • oral solid preparations such as, for example, powders, capsules and tablets
  • carriers such as starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like, may be used.
  • tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed.
  • tablets may be sugar-coated or enteric-coated by standard techniques.
  • the carrier will usually comprise sterile water, though other ingredients, for example, to aid solubility or for preservative purposes, may be included.
  • injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed.
  • the pharmaceutical compositions will generally be in the form of a dosage unit, e.g., tablet, capsule, powder, injection, teaspoonful and the like, containing from 0.1 to about 1000 mg/kg, and preferably from about 1 to 200 mg/kg of the active ingredients.
  • angiotensin 11-1 activity i.e., angiotensin ll-induced vasoconstriction in in vitro aortic rings.
  • Krebs bicarbonate buffer The aorta is gently freed of clots and adventitia and cleanly cut with a scalpel into 5 mm segments. Each ring is suspended from a Gould isotonic force transducer in a tissue bath containing 15 mL oxygenated Krebs bicarbonate buffer regulated at 37 °C. Initial tension is adjusted to 4.0 g and equilibrated over three 20-min wash periods to achieve a baseline tension of 3.0 g. Graded angiotensin II doses are given cumulatively to achieve a maximal contraction. Three 20-min washes are performed to remove the initial angiotensin II effect. The test compound is then given at a screening concentration of 1.0 x 10 ⁇ 5 M. After observing any effects of the test compound alone, the angiotensin II cumulative dose- response is then repeated in the presence of the test compound.
  • Angiotensin II vasoconstrictor tension in grams is expressed as a percent of maximal contraction for the before and after test compound angiotensin II dose-responses.
  • Angiotensin II ED50 and ED90 values are determined from the angiotensin II dose-response curves generated before and after test compound.
  • This test is designed to detect hypotensive effects of a compound after oral dosing in normotensive animals made renin-dependent by salt depletion.
  • normotensive rats Prior to salt depletion, normotensive rats typically show a plasma renin activity (PRA, ng angiotensin l/mL plasma/h, RIA) of 0.7. After the salt-depletion protocol PRA values taken 3 h after the furosemide dose have risen to about 7.4. Whereas blood pressure of normotensive rats that have not been salt-depleted does not change in response to treatment with the nonpeptide angiotensin receptor antagonist, DuP-753, salt-depleted animals typically respond with a blood pressure decrease of about 35 mmHg (mean arterial pressure, MAP). PRA is increased by this DuP-753 treatment to about 41.4.
  • PRA plasma renin activity
  • MAP blood pressure 10 or more mmHg
  • Maximum possible response is about -35 mmHg.
  • Compounds that are not orally active are retested by giving a solution dose intra-arterially through the blood pressure cannula three hours after a furosemide dose.
  • Proton nuclear magnetic resonance ( 1 H NMR) spectra were recorded on a Bruker AC-300 (300 MHz) spectrometer in CDCI 3 unless otherwise indicated. The reported values are expressed in parts per million (ppm) downfield from tetramethylsilane (TMS) which was used as an internal standard. Infrared spectra (IR) were recorded on a Beckman Instruments IR- B spectrophotometer and are expressed in reciprocal centimeters (cm- 1) .
  • Mass spectra were obtained on a Finnigan MAT 8230 Double Focusing high resolution mass spectrometer. Melting points were obtained on a Thomas- Hoover apparatus and are uncorrected.
  • the fra ⁇ s-trityltetrazole (0.646 g, 20%) was also isolated.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention se rapporte à des biphénylyle tétrazoles de la formule (I), utilisés pour traiter l'hypertension chez les mammifères, formule dans laquelle X représente CH2, O, S, N-R4, NH, NCHO, NCOCH¿3? ou NCO2R?4; R1 et R2¿ sont identiques ou différents et représentent alkyle C¿1-6?, et R?4¿ représente alkyle C¿1-6?; l'invention se rapporte également à des procédés et à des intermédiaires de production de ces composés.
PCT/US1994/000639 1993-01-15 1994-01-13 Inhibiteurs de l'angiotensine ii Ceased WO1994015926A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU60905/94A AU6090594A (en) 1993-01-15 1994-01-13 Angiotensin ii inhibitors

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US08/006,093 1993-01-15
US08/006,093 US5256658A (en) 1993-01-15 1993-01-15 Angiotensin II inhibitors

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Families Citing this family (17)

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Publication number Priority date Publication date Assignee Title
US5256658A (en) * 1993-01-15 1993-10-26 Ortho Pharmaceutical Corporation Angiotensin II inhibitors
WO2000001389A1 (fr) 1998-07-06 2000-01-13 Bristol-Myers Squibb Co. Biphenyl sulfonamides en tant que doubles antagonistes de recepteurs d'angiotensine et d'endotheline
GB0316546D0 (en) 2003-07-15 2003-08-20 Novartis Ag Process for the manufacture of organic compounds
CA2632030A1 (fr) * 2005-12-15 2007-06-21 Boehringer Ingelheim International Gmbh Composes qui modulent le recepteur cb2
EP2081905B1 (fr) * 2006-07-28 2012-09-12 Boehringer Ingelheim International GmbH Composés sulfonyles modulant le récepteur cb2
CA2664310A1 (fr) * 2006-09-25 2008-04-03 Boehringer Ingelheim International Gmbh Composes modulant le recepteur cb2
JP5492092B2 (ja) * 2007-11-07 2014-05-14 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Ｃｂ２受容体を調節する化合物
EP2326629B1 (fr) * 2008-07-10 2013-10-02 Boehringer Ingelheim International GmbH Composés sulfones qui modulent le récepteur cb2
WO2010036630A2 (fr) 2008-09-25 2010-04-01 Boehringer Ingelheim International Gmbh Composés modulant sélectivement le récepteur cb2
CN102348684B (zh) * 2009-03-11 2014-11-12 拜尔农作物科学股份公司 被卤代烷基亚甲基氧基苯基取代的酮烯醇
US8299103B2 (en) 2009-06-15 2012-10-30 Boehringer Ingelheim International Gmbh Compounds which selectively modulate the CB2 receptor
JP5756800B2 (ja) 2009-06-16 2015-07-29 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Ｃｂ２受容体を調節するアゼチジン２−カルボキサミド誘導体
JP2013505295A (ja) * 2009-09-22 2013-02-14 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Ｃｂ２受容体を選択的に調節する化合物
US9315454B2 (en) 2010-01-15 2016-04-19 Boehringer Ingelheim International Gmbh Compounds which modulate the CB2 receptor
EP2542539B1 (fr) 2010-03-05 2014-02-26 Boehringer Ingelheim International GmbH Composés tétrazoles qui modulent sélectivement le récepteur cb2
JP5746764B2 (ja) 2010-07-22 2015-07-08 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Ｃｂ２受容体を調節する化合物
EP2803668A1 (fr) 2013-05-17 2014-11-19 Boehringer Ingelheim International Gmbh Nouveau (cyano-dimethyl-methyl)-isoxazoles et - [1,3,4] thiadiazoles

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EP0443983A1 (fr) * 1990-02-19 1991-08-28 Ciba-Geigy Ag Composés acylés
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AU6090594A (en) 1994-08-15
US5382666A (en) 1995-01-17

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