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WO1993014086A1 - Derives d'isoquinolone-1 substitues, utilises comme antagonistes de l'angiotensine ii - Google Patents

Derives d'isoquinolone-1 substitues, utilises comme antagonistes de l'angiotensine ii Download PDF

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Publication number
WO1993014086A1
WO1993014086A1 PCT/US1993/000188 US9300188W WO9314086A1 WO 1993014086 A1 WO1993014086 A1 WO 1993014086A1 US 9300188 W US9300188 W US 9300188W WO 9314086 A1 WO9314086 A1 WO 9314086A1
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Prior art keywords
compound
lower alkyl
biphenyl
spiro
salt
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PCT/US1993/000188
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English (en)
Inventor
Lawrence E. Fisher
Joan M. Caroon
Stephen R. Stabler
Robin D. Clark
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Syntex (U.S.A.) Inc.
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Publication of WO1993014086A1 publication Critical patent/WO1993014086A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/20—Spiro-condensed ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
    • C07D217/24—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings

Definitions

  • the present invention relates to pharmaceutical compounds, particularly to 1-isoguinolone compounds and derivatives thereof, and to their use as angiotensin II receptor ligands useful in the control of smooth and cardiac muscle contraction, particularly in the field of
  • cardiovascular disorders such as hypertension and congestive heart failure.
  • the invention also relates to
  • the invention also relates to processes for making the compounds of the
  • the renin-angiotensin system is a fundamental
  • the primary event in this system is the secretion into the blood of angiotensinogen by the liver. Angiotensinogen is then cleaved by the protease renin to yield the
  • Al decapeptide angiotensin I (Al). Al in turn is hydrolyzed by angiotensin converting enzyme (ACE) to the octapeptide angiotensin II (All). Angiotensin II may lose one amino acid to yield angiotensin III (AIII). Al is inactive in the cardiovascular system, but All has numerous cardiovascular- renal activities. It stimulates the adrenal cortex to secrete aldosterone, which causes the kidneys to retain sodium and water, increasing blood pressure. It causes vasoconstriction. It also facilitates neurotransmission in the sympathetic nervous system. Many of the effects of All, such as arteriolar
  • vasoconstriction aldosterone secretion, glycogenolysis and alteration of renal function, are mediated by the activation of specific All receptors on the vasculature, adrenal medulla, brain, liver and kidney.
  • All receptors may exhibit different preferences for All and AIII in terms of binding affinity, agonist potency and other characteristics. All receptors are therefore
  • Wong et al. further report (Wong et al., J. Pharmacol. Exp. Ther. 256:211 (1990)) that a major metabolite of DuP 753, EXP3174, possesses high affinity for All-specific binding sites.
  • the authors found that its affinity as a competitive antagonist of All is greater than that of DuP 753 and that the affinity of both compounds is greater than that of molecules reported earlier.
  • Lambert Company discloses 4,5,6,7-tetrahydro-1H- imidazo[4,5-C]pyridine compounds which antagonize the binding of All to rat adrenal receptor preparations.
  • One aspect of the present invention concerns certain substituted isoguinolones according to the following Formula (I):
  • Y is selected from the group consisting of H, OH, lower alkoxy, and halo;
  • X is selected from the group consisting of H, lower alkyl acid, lower alkyl ester, and lower alkyl;
  • R 1 is selected from the group consisting of H, alkenyl, lower alkyl, lower cycloalkyl, unsubstituted or substituted 3-spiro-1H-indane of the structure wherein R 2 is H, OH, lower alkyl, lower alkoxy or halo, and
  • n is an integer from zero to six
  • R 1 when R 1 is spiro-, X is H, and when R 1 is H, alkenyl, lower alkyl or lower cycloalkyl substituted at the 3-position of the isoquinolone moiety and X is H or lower alkyl, the (2"-1H-tetrazol-5-yl)biphenyl-4'-ylmethyl group cannot be at the 2(N) position.
  • the invention relates to
  • receptor-related disorders including a therapeutically effective amount of a compound of Formula (I) or a
  • the invention further comprises synthetic methods for the preparation of the compounds of Formula (I) :
  • R 1 , X, and Y are as defined in connection with Formula (I) above, which process comprises contacting a corresponding cyano intermediate compound of the following formula:
  • the invention further comprises cyano intermediate compounds as shown and defined above.
  • the invention further comprises synthetic methods useful in the preparation of the compounds of Formula (I), wherein R 1 is selected from the group consisting of H, alkenyl, lower alkyl; and X, and Y are as defined above, comprising the steps of:
  • alkyl means a fully saturated monovalent radical containing only carbon and hydrogen, and which may be a branched, straight chain, or cyclic alkyl radical. It includes up to 12 carbon atoms, for example, radicals such as methyl, ethyl, t-butyl, n-butyl, pentyl, pivalyl, cyclohexyl, heptyl and adamantyl.
  • lower alkyl means an alkyl radical, as defined above, of 1-6 carbon atoms.
  • lower cycloalkyl means a cyclic saturated hydrocarbon radical having from 3 to 7 carbon atoms.
  • lower alkyl acid means a lower alkyl radical as defined above further containing a carboxylic acid group, i.e., -(CH 2 ) m COOH, where m is an integer between 0 and 5.
  • lower alkyl ester means a lower alkyl acid as defined above esterified with a lower alkanol, i.e., -(CH 2 ) m COOR b , where m is as defined above and R b is lower alkyl.
  • lower alkoxy means a lower alkyl radical as defined above which further is a conjugate base of an alcohol functionality, i.e., -O-R, where R is lower alkyl, e.g., methoxy, ethoxy, n-propoxy, 1-methylethoxy, n-butoxy, and the like.
  • lower alkylene means a straight chain alkyl radical as defined above which is divalent and of one to five carbon atoms, e.g., methylene, ethylene, n-propylene, n-butylene, and n-pentylene.
  • alkenyl means both a straight-chain and branched-chain mono- or poly-olefinically-unsaturated hydrocarbonyl monovalent radical containing only carbon and hydrogen, having one or more double bonds (preferably not more than two) and having no triple bonds.
  • This term is further exemplified by radicals such as allyl; 2-methyl allyl; buten-2-yl; penten-2-,3- or 4-yl; hexen-2-, 3-, 4- or 5-yl; hepten-2-, 3-, 4-, 5- or 6-yl; and pentadien-2-, 4-yl.
  • halo means fluoro, bromo, chloro or iodo.
  • 3-spiro-cycloalkyl means a substituent illustrated as follows:
  • n is an integer from zero to six, denoting a total number of carbon atoms in the ring (including the spiro carbon) from three to nine, e.g., spiro-cyclopropyl and spiro-cyclononyl.
  • the unsubstituted and substituted "3-spiro-1H-indane" substituent has the following structure:
  • a wavy line (-) is used in a conventional manner to indicate a mixture of stereoisomeric forms for the bond so indicated, i.e., the bond may be oriented upwardly or downwardly-relative to the plane of the paper.
  • Stereoisomeric forms about a double bond are named in a conventional manner using the terms "Z”, from the German word “zusammen” (together) or “E”, from the German word “entalle” (opposite) to indicate cis-trans isomerism about a double bond.
  • a dashed line (--) indicates a bond which is optionally present between two carbon atoms in a structure when the structure can chemically accommodate such bond.
  • the bond is absent.
  • a “pharmaceutically acceptable salt” may be any salt derived from an inorganic or organic base.
  • pharmaceutically acceptable cation means the cation of such base addition salts.
  • the salt, and the cation are chosen not to be biologically or otherwise undesirable.
  • the cations derived from inorganic bases include sodium, potassium, lithium, ammonium, calcium, magnesium and the like.
  • Cations derived from organic bases include those formed from primary, secondary and tertiary amines, such as isopropylamine, diethylamine, trimethylamine, pyridine, cyclohexylamine, ethylene diamine, monoethanolamine, diethanolamine, triethanolamine and the like.
  • treatment or “treating” means any treatment of a disease in a mammal, including:
  • (iii) relieving the disease, that is, causing the regression of clinical symptoms.
  • the term "q.s.” means adding a quantity sufficient to achieve a stated function, e.g., to bring a solution to the desired volume (i.e., 100%).
  • the term "effective amount” means a dosage sufficient to provide treatment for the disease state being treated. This will vary depending on the patient, the disease and the treatment being effected.
  • inert organic solvent or “inert solvent” mean a solvent inert under the conditions of the reaction being described in conjunction therewith [including, for example, benzene, toluene, acetonitrile, tetrahydrofuran (“THF”), dimethylformamide (“DMF”), chloroform, methylene chloride (or dichloromethane), diethyl ether, methanol, pyridine and the like].
  • the solvents used in the reactions of the present invention are inert organic solvents. Unless specified to the contrary, the reactions
  • M.P melting point
  • the exemplary compound shown above is named (1R,1S)-8'-methoxy-1',4',2,3- tetrahydrospiro[1H-indane-1,3'(2'- ⁇ 2"'-1H-tetrazol-5- yl ⁇ biphenyl-4"-ylmethyl)-isoquinolin]-1'(2H)-one.
  • the designation "(1R,1S)” indicates a mixture of 1R and 1S stereoisomers.
  • these designations (1R, 1S, and 1R, 1S) are omitted from the names of compounds described herein, although it is to be
  • R 1S represents R 1 in the compounds and precursors thereof where R 1 is spiro, i.e., either 3-spiro- 1H-indane or 3-spiro cycloalkyl.
  • Y' represents precursors to compounds where Y is H, halo, or lower alkoxy; when Y' is methoxy, it is also a precursor to Y when Y is hydroxy. The use of R 1S and Y' is described further in connection with Reaction Scheme I.
  • Reaction Scheme I illustrates the preparation of the isoquinolin-1(2H)-one compounds of Formula (I) which
  • Reaction Scheme II illustrates the preparation of the isoquinolin-1(2H)-one compounds of Formula (I) which comprise a 2-biphenylmethyl group and a 3-R 1 group of H, alkenyl, or lower alkyl.
  • Reaction Scheme III illustrates the preparation of the isoquinolin-1(2H)-one compounds of Formula (I) which comprise a 3-biphenylmethyl group and a 2- R 1 group of H, alkenyl, or lower alkyl.
  • Reaction Scheme I illustrates the synthesis of the spiro compounds of Formula (I), designated below as Formula (Ia).
  • the spiro R 1 substituent, designated R 1S is illustrated as exemplified by the following precursor compound:
  • Steps 1 and 2 of Reaction Scheme I illustrate the preparation of ethyl 2-methoxy-6-methyl benzoate, a
  • step 7 additional reaction (step 7) is carried out on a compound of Formula (H) where Y' is methoxy; the methoxy is thus
  • step 8 When preparing the compounds of Formula (Ia) where Y is not hydroxy, a cyclization step 7a is carried out after step 6, bypassing step 7.
  • Y' is equivalent to Y and is treated the same as Y in Reaction Scheme I in all cases except where Y is hydroxy; in this case a Y' methoxy is converted to hydroxy in the penultimate step, step 7.
  • R 1 is 3-spiro-1H-indane, since a racemic mixture of R and S enantiomers is obtained.
  • a racemic mixture of Formula (F), (G), (H), (J), or (Ia) may be separated into its two enantiomers by conventional resolution means. For example, these compounds can be complexed with a chiral reagent, the complexed diastereoisomers separated by liquid
  • the cyclohexenone ester starting material of Formula (A) is prepared as described in F. Hauser and S. Pogany, Synthesis 1980; 814 (1980).
  • ethyl 3-methoxy-6-methyl benzoate and ethyl 4- ethoxy-6-methyl benzoate are available commercially, e.g., from Aldrich Chemical Co., Milwaukee WI, or may be prepared by conventional means, for example as follows: A benzoic acid substituted with the desired Y' group is converted to a benzoic diethyl amide by amidation with a molar excess of diethyl amine, in order to form an ortho-directing group at the acid functionality.
  • the benzoic diethyl amide is then reacted with t-butyllithium and quenched with an equimolar amount of methyl iodide, followed by acidic hydrolysis to remove the diethyl group and produce the o-methyl benzoic acid, which is then reacted with sodium acetate to form the corresponding ethyl o-methyl benzoate.
  • An indane carboxylic acid of Formula (E), used in step 4, may be prepared essentially as described in Meth-Cohn and Gronowitz, Chem. Comm. 1966:81 (1966). Also, carboxylic acids of Formula (E), where R 1 is 1-H-indane or cycloalkyl may be prepared according to Jahangir et al., J.Org. Chem. 54:2992-2996 (1989), the disclosure of which is hereby incorporated by reference. Various cycloalkyl carboxylic acid compounds may also be obtained from Aldrich Chemical Co., Milwaukee, WI.
  • Formula (P) may be prepared by a number of known methods, most preferably as follows: Equimolar amounts of 2- bromobenzylnitrile and 4-methyl-benzylboronic acid are combined with tetrakis[triphenylphosphine] palladium, toluene, 2M sodium carbonate in aqueous solution and ethanol and refluxed vigorously, with stirring for 6 to 12 hours; preferably overnight. The mixture is allowed to cool to 10 to 30°C; preferably ambient temperature and hydrogen
  • 4-Aminomethyl-2'-cyano-biphenyl may be prepared from the 4-bromomethyl-2'-cyano-biphenyl by conventional means, e.g., as follows: 4-Bromomethyl-2'-cyano-biphenyl is treated with a molar excess of sodium azide to produce the azomethyl-2'-cyano-biphenyl; this is catalytically reduced with Pdo, H 2 , and methanol to yield the 4-aminomethyl-2'- cyano-biphenyl.
  • the trialkyl tin azide used in step 8 (and in step 6 of Reaction Scheme II and step 5 of Reaction Scheme III) is prepared as described in Kricheldorf and Leppert, Synthesis 1976:329-330 (1976), for example, as follows: To an ice cold solution of sodium azide in water is added an equimolar amount of tributyl tin chloride, dropwise. The solution is stirred for two hours, extracted with methylene chloride, dried over sodium sulfate, stripped, and used as is.
  • dehydrogenation e.g., with a palladium catalyst, or, preferably, as is described below, by bromine, for further conversion into the precursor of the isoquinolin-1(2H)-one.
  • Ethyl 6-methyl cyclohexene-2-one carboxylate (Formula (A)) is dissolved in a nonpolar solvent (such as ether, cyclohexane, or carbon tetrachloride; preferably carbon tetrachloride) and placed under an inert atmosphere (such as argon, helium, or nitrogen; preferably nitrogen) at -5 to 5°C; preferably 0°C.
  • a molar equivalent of a halogenating agent such as iodine,
  • step 2 of Reaction Scheme I the hydroxy group of ethyl 2-hydroxy-6-methyl-benzoate (B) is next converted to methoxy by means of an alkylhalo compound, such as methyl chloride, methyl bromide, or methyl iodide;
  • an alkylhalo compound such as methyl chloride, methyl bromide, or methyl iodide
  • a base such as potassium carbonate potassium hydroxide, or t-butoxide; preferably t-butoxide
  • a polar solvent such as DMF, acetonitrile, or THF; preferably THF
  • B ethyl 2-hydroxy-6- methyl benzoate
  • bromomethane, chloromethane, or iodomethane; preferably iodomethane) is added, and the mixture is stirred for 1 to 6 hours; preferably 2 hours.
  • the mixture is poured into an aqueous solvent and extracted with a polar solvent (such as ether, ethyl acetate, or water; preferably water), to afford ethyl 2-methoxy-6-methyl benzoate, which is a preferred starting material, and also a compound according to Formula (C).
  • a polar solvent such as ether, ethyl acetate, or water; preferably water
  • the ethyl optionally substituted 6-methyl benzoate (C) is added to an equimolar amount of a halogen compound (such as N-bromosuccinimide, N-chlorosuccinimide, or N- iodosuccinimide; preferably N-bromosuccinimide) and a nonpolar solvent (such as carbon tetrachloride, ether, or cyclohexane; preferably carbon tetrachloride) and heated to 70°C to reflux; preferably reflux for 1 to 4 hours;
  • a halogen compound such as N-bromosuccinimide, N-chlorosuccinimide, or N- iodosuccinimide; preferably N-bromosuccinimide
  • a nonpolar solvent such as carbon tetrachloride, ether, or cyclohexane; preferably carbon tetrachloride
  • a nonpolar hydrocarbon solvent such as cyclohexane, heptane, or hexane; preferably hexane
  • D optionally substituted halomethyl benzoate
  • a cyclic carboxylic acid compound of Formula (E) is added to the halomethyl group of the optionally substituted halomethyl benzoate (D), to attach the precursor of the spiro group, R 1S .
  • An alkyl lithium base such as n-, tert-, or sec- butyllithium; preferably sec-butyllithium
  • a cyclic carboxylic acid compound (E) such as cyclobutyl carboxylic acid, cyclopentyl carboxylic acid, or 1H-indane-1-carboxylic acid; preferably 1H-indane-1-carboxylic acid, is added.
  • the reaction mixture is then heated to 35 to 50°C; preferably 40 to 45°C for 10 to 40 minutes; preferably 30 minutes.
  • the solution is then cooled to -25 to 5°C; preferably 15°C and the optionally substituted halomethyl benzoate (D) is added.
  • the mixture is allowed to come to ambient temperature and quenched with an acid (such as H 2 SO 4 , CH 3 COOH, or aqueous HCl; preferably aqueous HCl).
  • an acid such as H 2 SO 4 , CH 3 COOH, or aqueous HCl; preferably aqueous HCl.
  • the resultant optionally substituted cyclic-carboxy-benzoate (F) is recovered, e.g. by extraction with ethereal solvent, washing, extraction, and drying.
  • step 5 of Reaction Scheme I optionally substituted cyclic-carboxy-benzoate (F) is converted to a 1- isoquinoline ring structure, namely a spiro[ (cycloalkyl or 1H-indane)-1,3'(2'-H)-isoquiolin]-1'(2H)-one, by conversion, through an azide, to an isocyanate intermediate (not
  • An optionally substituted cyclic-carboxy-benzoate (F) is cooled to -5 to 5°C; preferably 0°C in a polar solvent (such as THF, MEK or acetone; preferably acetone) and combined with a molar excess of an amine (such as
  • a mixed anhydride such as benzylchloroformate, methylchloroformate, or ethylchloroformate; preferably ethylchloroformate
  • the acid is added and the mixture is stirred for 0.5 to 2 hours; preferably 1 hour.
  • An azide (such as potassium azide, lithium azide, or sodium azide; preferably sodium azide) for displacing the activating group in an acyl azide rearrangement is then added, and the mixture is stirred at -5 to 5°C; preferably 0°C for 0.5 to 2 hours;
  • benzene xylene, or toluene; preferably toluene) and an alcohol (such as ethanol, t-butanol, or benzyl alcohol;
  • a 4-methyl-2'- cyano-biphenyl group wherein the methyl is substituted with a leaving group such as halo (preferably Br) is next
  • a strong base such as potassium carbonate, lithium hydride, or sodium hydride; preferably sodium hydride
  • a 4-halomethyl-2'-cyano-biphenyl compound (such as 4- iodomethyl-2'-cyano-biphenyl, 4-chloromethyl-2'-cyano- biphenyl, or 4-bromomethyl-2'-cyano-biphenyl; preferably 4- bromomethyl-2'-cyano-biphenyl) is added and the mixture is stirred for 4 to 24 hours; preferably 14-16 hours, coming to ambient temperature.
  • a methoxy (Y') of a previously prepared methoxy 1',4',2,3- tetrahydrospiro[cycloalkyl or 1H-indane-1,3'(2'- ⁇ 2"'- cyano ⁇ biphenyl-4"-ylmethyl)-isoquinolin]-1'(2H)-one (H) may be next converted to -OH (Y). Nucleophilic attack (for removing the methyl group from Y') is facilitated by
  • a molar excess of a bromide compound (such as aluminum tribromide or boron tribromide; preferably boron tribromide) is added to a solution of a 5'-, 6'-, 7'- or 8'-methoxy- 1',4',2,3-tetrahydrospiro[cycloalkyl or 1H-indane-1,3'(2'- ⁇ 2"'-cyano ⁇ biphenyl-4"-ylmethyl)-isoquinolin]-1'(2H)-one (H) under an inert gas (such as nitrogen, helium, or argon;
  • a bromide compound such as aluminum tribromide or boron tribromide; preferably boron tribromide
  • reaction mixture is allowed to reach room temperature and stirred for 0.5 to 4 hours; preferably 1.5 hours. It is then poured onto an ice/base (such as sodium or potassium carbonate, or sodium bicarbonate; preferably sodium
  • a polar organic solvent such as ethyl acetate, chloroform, or methylene chloride; preferably methylene chloride
  • the mixture is cooled to ambient temperature, mixed with acid (such as H 2 SO 4 , CH 3 COOH, or aqueous HCl; preferably aqueous HCl), and the precipitated solid is recovered, e.g., by washing and recrystallization to afford the corresponding optionally substituted- 1',4',2,3-tetrahydrospiro[cycloalkyl or 1H-indane-1,3'(2'- ⁇ 2"'-H-tetrazol-5-yl ⁇ biphenyl-4"-ylmethyl)-isoquinolin]- 1'(2H)-one (Ia).
  • acid such as H 2 SO 4 , CH 3 COOH, or aqueous HCl; preferably aqueous HCl
  • racemic mixture of Formula (F) may be separated into its two stereoisomers at this stage of the synthesis. This may be accomplished by conventional
  • resolution means for example by separation (e.g. fractional crystallization) of the diastereomeric salts formed by the reaction of these compounds with optically active bases, at temperatures between 0°C and the reflux temperature of the solvent employed for fractional crystallization.
  • optically active bases are the optically active form of cinchonidine, cinchonine and the like.
  • the separated pure diastereomeric salts may then be cleaved by standard means, such as treatment with a acid, to afford the
  • Racemic mixtures may also be separated by
  • Formula (Ia) may be prepared via an appropriate stereoisomer of a compound of Formula (G).
  • the compound of Formula (G) is reacted with a chiral isocyanate to form a mixture of two diastereoisoraeric ureas.
  • Formula (G) is dissolved in an inert solvent such as
  • stereoisomer of a compound of Formula (Ia) may be carried out according to Reaction Scheme I.
  • Reaction Scheme II illustrates the synthesis of the compounds of Formula (I) in which the biphenylmethyl moiety is attached to the N- (i.e. 2-) position of the isoquinolinone ring, i.e. R 1 is at position 3, and, further, in which R 1 does not form a spiro structure; these compounds are designated below as Formula (lb).
  • a halomethyl-cyano- biphenyl (or aminomethyl-cyano-biphenyl) compound is used in the coupling, as in Reaction Scheme I.
  • Z is again used to represent halo.
  • Compounds (M) and (N) are mixtures of Z and E stereoisomers.
  • the substituted o-toluoyl chlorides of Formula (K) are commercially available, e.g. from Aldrich Chemical Company, Inc., Milwaukee, WI, or may be prepared by conventional methods generally involving the treatment of a methyl methoxy benzoic acid with oxalyl chloride.
  • 3- methoxy-2-methylbenzoyl chloride may be prepared by the treatment of 2-methyl-3-methoxy-benzoic acid with oxalyl chloride in dichloromethane;
  • 4-methoxy-2-methylbenzoyl chloride may be prepared by the treatment of 2-methyl-4- methoxy-benzoic acid with oxalyl chloride in
  • dichloromethane and 4-fluoro-2-methylbenzoyl chloride may be prepared by the treatment of 2-methyl-4-fluoro-benzoic acid with oxalyl chloride in dichloromethane.
  • N-methoxy-N-methylcarboxyamides (“Weinreb amides") of the formula H 3 CN(OCH 3 )C(O)R 1 (wherein R 1 is H, alkenyl, lower alkyl or cycloalkyl) used in step 3 in the preparation of optionally substituted N-(prop-1-enyl)-isoquinolin-1(2H)- one (N) may be prepared according to the procedure described in Nairn, S. and Weinreb, S.M., Tetrahedron Lett. 22:3815 (1981).
  • halomethyl-cyano-biphenyl compound used in step 5 and the trialkyl tin azide used in step 6 are obtained as described in connection with Reaction Scheme I.
  • a reactant of Formula (0) may be prepared from homophthalic anhydride, commercially available, e.g., from Aldrich Chemical Company, Inc., Milwaukee, WI. This
  • the 3,4-dihydro-1(2H)-isoquinolinone produced as described in this reference may be dehydrogenated to produce the corresponding 1(2H)-isoquinolone by conventional means, e.g., bromination followed by basic dehydrohalogenation.
  • an optionally substituted N-allyl methyl benzamide (L) is first prepared, so that the appropriate N-substitution may be present at the time of cyclization, by treatment of a benzoic acid ester with trimethylaluminum and allylamine, or, preferably, as is described below, by addition of an allylamine to an acid halide.
  • a solution of an o-toluoyl chloride (K) in a polar aprotic solvent such as ether, THF, or methylene chloride; preferably methylene chloride
  • a polar aprotic solvent such as ether, THF, or methylene chloride; preferably methylene chloride
  • a trialkylamine such as tri-n-butylamine, tri-n-propylamine, or triethylamine; preferably triethylamine
  • allylamine allylamine.
  • the mixture is allowed to warm to ambient temperature and shaken with an acid (such as H 2 SO 4 , CH 3 COOH, or aqueous HCl; preferably aqueous HCl) in order to remove excess base.
  • the product in the organic layer is recovered, e.g., separated, dried, filtered, solvent removed, and triturated, to yield the corresponding optionally substituted N-allyl methyl benzamide (L).
  • step 2 of Reaction Scheme II an optionally substituted N-allyl methyl benzamide (L) is then converted to an N-propenyl derivative as a further step in the
  • a solution of diisopropylamine in an ethereal aprotic solvent such as ether, dioxane, or THF; preferably THF
  • an ethereal aprotic solvent such as ether, dioxane, or THF; preferably THF
  • an alkyl lithium base such as n-, tert-, or sec- butyllithium; preferably n-butyllithium
  • LDA lithium diisopropyl amide
  • the mixture is stirred for 5 to 20 minutes; preferably 10 minutes and allowed to warm to -5 to 5°C; preferably 0°C.
  • the mixture is treated with a buffered acid (such as aqueous ammonium chloride or aqueous ammonium sulfate; preferably aqueous ammonium chloride, diluted with a polar aprotic solvent such as ethyl acetate, THF, or ether; preferably ether), and the product in the organic layer is recovered, e.g., separated, dried, filtered, and concentrated, to yield the corresponding optionally
  • a buffered acid such as aqueous ammonium chloride or aqueous ammonium sulfate; preferably aqueous ammonium chloride
  • a polar aprotic solvent such as ethyl acetate, THF, or ether; preferably ether
  • an optionally substituted 1(2H)-isoquinolone ring with an N-prop-1-enyl substituent is then formed in a ring closure reaction of an optionally substituted N-(prop-1-enyl) benzamide (M) in the presence of a base with the appropriate (according to R 1 ) N- methoxy-N-methylcarboxyamide (Weinreb amide).
  • a solution of optionally substituted N-(prop-1-enyl)- benzamide (M) in an ethereal aprotic solvent such as ether, dioxane, or THF; preferably THF
  • an ethereal aprotic solvent such as ether, dioxane, or THF; preferably THF
  • a molar excess of an alkyl lithium base such as n- , tert-, or sec-butyllithium; preferably sec-butyllithium.
  • the mixture is stirred at the above temperature for 5 to 20 minutes; preferably 10
  • R 1 is H, alkenyl, lower alkyl or lower cycloalkyl
  • a molar equivalent of a Wienreb amide selected on the basis of the desired identity of R 1 (where R 1 is H, alkenyl, lower alkyl or lower cycloalkyl), preferably N- methyl-N-methoxyvaleramide, is added.
  • the reaction is immediately quenched at -5 to 5°C; preferably 0°C with an acid (such as H 2 SO 4 , CH 3 COOH, or aqueous HCl; preferably
  • the suspension is heated at 70°C to reflux; preferably reflux for 10 minutes to 2 hours; preferably 20 minutes, cooled to ambient temperature, diluted with an ethereal solvent (such as THF, ethyl acetate, or ether;
  • an ethereal solvent such as THF, ethyl acetate, or ether
  • step 4 of Reaction Scheme II the prop-1- enyl substituent on the heterocyclic nitrogen of the optionally substituted N-(prop-1-enyl)-isoquinolin-1(2H)-one (N) is next removed by hydrolysis.
  • a solution of optionally substituted N- (prop-1-enyl)- isoquin-12(H)-one (N) in a solvent resistant to acid (such as diglyme, THF, or dioxane; preferably dioxane) and an acid (such as H 2 SO 4 , CH 3 COOH, or aqueous HCl; preferably aqueous HCl) is heated under reflux for 2 to 10 hours; preferably 6 hours.
  • the mixture is cooled to ambient temperature, diluted with a polar solvent (such as ether,
  • a 4-methyl- 2'-cyano-biphenyl group wherein the methyl is substituted with a leaving group, such as halo (preferably Br),
  • sulfonate, or tosylate is next attached at the N position of the optionally substituted isoquinolin-1(2H)-one (0) by a nucleophilic displacement reaction.
  • Optionally substituted isoquinolin-1(2H)-one (O) in a polar, aprotic solvent such as THF, ether, or DMF;
  • a base such as potassium hydride, lithium hydride, or sodium hydride; preferably sodium hydride
  • a base such as potassium hydride, lithium hydride, or sodium hydride; preferably sodium hydride
  • a molar equivalent of a 4-aminomethyl-2'-cyano-biphenyl or 4- halomethyl-2'-cyano-biphenyl compound (such as 4-iodomethyl- 2'-cyano-biphenyl, 4-chloromethyl-2'-cyano-biphenyl, or 4- bromomethyl-2'-cyano-biphenyl; preferably 4-bromomethyl-2'- cyano-biphenyl) is added, and stirring is continued for 4-24 hours; preferably 14-16 hours at ambient temperature, after which the mixture is poured onto ice, and extracted with a polar organic solvent (such as ethyl acetate,
  • step 6 of Reaction Scheme II the cyano group of optionally substituted 2-[ (2"-cyano) biphenyl- 4'ylmethyl]-isoquinolin-1(2H)-one (P) is next converted to the 1H-tetrazol-5-yl group in a cycloaddition reaction mediated by a trialkyl tin azide, as in step 8 of Reaction Scheme I.
  • 4'ylmethyl]-isoquinolin-1(2H)-one (P) is combined with a molar excess of a trialkyl tin azide (such as trimethyl tin azide, triethyl tin azide, or tributyl tin azide; preferably tributyl tin azide) in a high boiling aromatic solvent (such as benzene, toluene, or xylene; preferably xylene) and heated at 100°C to 200°C; preferably reflux for 8-48 hours; preferably 10 hours.
  • a trialkyl tin azide such as trimethyl tin azide, triethyl tin azide, or tributyl tin azide; preferably tributyl tin azide
  • a high boiling aromatic solvent such as benzene, toluene, or xylene; preferably xylene
  • the mixture is cooled to ambient temperature, mixed with acid (such as H 2 SO 4 , CH 3 COOH, or aqueous HCl; preferably aqueous HCl),- and the precipitated solid is recovered, e.g., by washing and recrystallization to afford the corresponding optionally substituted 2-[(2"- 1H-tetrazol-5-yl)biphenyl-4'ylmethyl]-isoquinolin-1(2H)-one (lb).
  • acid such as H 2 SO 4 , CH 3 COOH, or aqueous HCl; preferably aqueous HCl
  • Reaction Scheme III illustrates the synthesis of the compounds of Formula (I) in which the biphenyImethyl moiety is attached to the 3 position of the 1-isoquinolone ring, designated below as Formula (lc).
  • N-allyl methyl benzamide (L) is prepared as described in step 1 of Reaction Scheme II.
  • the N-methoxy-N-methyl amide (“Wienreb amide”) used in step 1 of Reaction Scheme III, N,0-dimethyl-4-bromophenylacetamide, is prepared according to conventional methods, as described in connection with the Reaction Scheme II Weinreb amide
  • the 2-bromobenzylnitrile and the trialkyl borane used in step 4 are commercially available from Aldrich Chemical Co., Milwaukee, WI, or from Lancaster Laboratories, Inc., Lancaster, PA, or may be prepared by conventional means.
  • step 5 The trialkyl tin azide used in step 5 is obtained as described in connection with Reaction Scheme I.
  • a 1- isoquinolone with a 4'-bromo-3-phenyImethyl substitution is first formed by coupling of a parabromobenzyl compound (the Wienreb amide) to an N-allyl methyl benzamide (L) prepared, e.g., in accordance with Reaction Scheme II.
  • N-allyl methyl benzamide (L) in a polar aprotic solvent (such as ether, glyme, or THF; preferably THF) at -40 to -100°C; preferably -70°C is combined with a molar excess of an alkyl lithium base (such as n-, tert-, or sec-butyllithium; preferably t- butyllithium).
  • a molar equivalent of N,O-dimethyl-4-bromophenylacetamide is added to this solution.
  • the reaction mixture is allowed to warm to -5 to 5°C; preferably 0°C and treated with an aqueous acid (such as hydrochloric acid, sulfuric acid, or acetic acid; preferably acetic acid).
  • an aqueous acid such as hydrochloric acid, sulfuric acid, or acetic acid; preferably acetic acid.
  • the mixture is then heated to 70°C to reflux; preferably reflux for 15 minutes to 2 hours; preferably 1 hour, cooled to ambient temperature, and extracted with a polar aprotic solvent (such as ethyl acetate, THF, or ether; preferably ether).
  • a polar aprotic solvent such as ethyl acetate, THF, or ether; preferably ether.
  • the product in the organic layer is recovered, e.g., dried, filtered, concentrated and crystallized, to yield the corresponding optionally substituted 2-(prop-1- enyl)-3-(4'-bromophenylmethyl)-1-isoquinolone (R).
  • the 2-prop- 1-enyl group is next removed from the optionally substituted 2-(prop-1-enyl)-3-(4'-bromophenyImethyl)-1-isoquinolone (R) by acidic hydrolysis .
  • Optionally substituted 2-(prop-1-enyl)-3-(4'- bromophenyImethyl)-1-isoquinolone (R) is added to a solvent resistant to acid (such as diglyme, THF, or dioxane;
  • an N- substituent i.e., R 1 , where R 1 is H, alkenyl, lower alkyl or lower cycloalkyl
  • R 1 is H, alkenyl, lower alkyl or lower cycloalkyl
  • a metal hydride such as lithium hydride, potassium hydride, or sodium hydride; preferably sodium hydride
  • a molar equivalent of the desired R 1 -halo substituent e.g. 1- iodobutane 2-chloropentane, or 1-bromobutane, preferably 1- iodobutane is added to the mixture at ambient temperature.
  • the mixture is cooled to -5 to 5°C; preferably 0°C, extracted with a polar aprotic solvent (such as ethyl acetate, DME, or ether;
  • a boronic acid intermediate (3-(4'- diethoxyborophenylmethyl)-2-(lower alkyl or alkenyl)-1- isoquinolone) is formed; this is carried forward without further isolation to react with the bromo group on 2- bromobenzylnitrile to form a complex for a transition metal catalyzed coupling of the benzylnitrile to the phenylmethyl group of the 3-(phenylmethyl)-2-(lower alkyl or alkenyl)-1- isoquinolone.
  • a polar aprotic solvent such as ether, glyme, or THF; preferably THF
  • a molar excess of a trialkyl borane (such as triethyl borane, tri-n-propyl borane, or tributyl borane; preferably tributyl borane) is then added dropwise, and the mixture is allowed to warm to -5 to 5°C; preferably 0°C.
  • the reaction is quenched with an acid (such as H 2 SO 4 , CH 3 COOH, or aqueous HCl; preferably aqueous HCl) and stirred for 10 to 50 minutes; preferably 15 minutes at ambient temperature.
  • an acid such as H 2 SO 4 , CH 3 COOH, or aqueous HCl; preferably aqueous HCl
  • the reaction mixture is extracted with a polar aprotic solvent (such as ethyl acetate, DME, or ether; preferably ether), and the product in the organic phase is recovered, e.g., washed, dried, and the solvent evaporated to produce an oil, which is the corresponding boronic acid intermediate.
  • a polar aprotic solvent such as ethyl acetate, DME, or ether; preferably ether
  • the product in the organic phase is recovered, e.g., washed, dried, and the solvent evaporated to produce an oil, which is the corresponding boronic acid intermediate.
  • the resultant oil is dissolved in a high boiling aromatic solvent (such as benzene, toluene, or xylene;
  • a cyano group of optionally substituted 3-[2"-(cyano)biphenyl-4'- ylmethyl]-2-(lower alkyl or alkenyl)-isoquinolin-1(2H)-one (U) is next cyclized to form the 1H-tetrazol-5-yl group by means of a trialkyl tin azide, as in step 8 of Reaction Scheme I.
  • An optionally substituted 3-[2"-(cyano)biphenyl-4'- ylmethyl]-2-(lower alkyl or alkenyl)-isoquinolin-1(2H)-one (U) is combined with a molar excess of a trialkyl tin azide (such as trimethyl tin azide, triethyl tin azide, or tributyl tin azide; preferably tributyl tin azide) in a high boiling aromatic solvent (such as benzene, toluene, or xylene; preferably xylene) and heated at 100°C to 200°C; preferably reflux for 8-48 hours; preferably 10 hours.
  • a trialkyl tin azide such as trimethyl tin azide, triethyl tin azide, or tributyl tin azide; preferably tributyl tin azide
  • a high boiling aromatic solvent such as benzene
  • Some of the compounds of Formula (I) may be converted to corresponding salts. These will generally be base salts, particularly where the compound contains an acid or
  • the conversion is accomplished by treatment of the free compound with a stoichiometric amount of an
  • appropriate base such as KOH, NaOH or potassium t-butoxide; preferably KOH
  • an inert organic solvent such as ether, methanol, or THF; preferably methanol
  • resulting salt may be brought out of solution with a less polar solvent or by lyophilization of the solution.
  • R 1 is 3-spiro-1H- indane or 3-spiro-1H-cycloalkyl, particularly those where R 1 is 3-spiro-1H-indane or 3-spiro-1H-cycloalkyl, X is H and the biphenyl substituent is at the 2 (N) position. Further preferred are those of the above-described compounds where Y is H, OH, lower alkoxy (particularly methoxy) or halo, at the 5-, 6-, 7- or 8-position.
  • the salts of Formula (I) are also preferred, particularly the Na and K salts.
  • the compounds of the present invention can be prepared according to the following last steps: contacting a 2- (optionally lower alkyl, alkenyl or lower cycloalkyl substituted)-4-(optionally lower alkyl, lower alkyl acid or lower alkyl ester substituted) -5-, 6-, 7-, or 8-(optionally hydroxy, lower alkoxy or halo
  • compositions containing them are useful as cardiovascular agents, such as anti-hypertensives and in the treatment of congestive heart failure and chronic renal disease.
  • cardiovascular agents such as anti-hypertensives and in the treatment of congestive heart failure and chronic renal disease.
  • angiotensin in smooth muscle in the Gl tract and in the brain, the compounds are also considered useful in therapy of disorders of the brain such as
  • the compounds of the present invention may also be used to treat chronic renal failure, glaucoma, as well as neuroblastoma and other growth disorders.
  • male normotensive rats are subjected to complete left renal artery ligation
  • in vivo testing can be conducted on conscious normotensive rats to which All and a test compound are administered. In vivo activity is demonstrated by
  • Administration of active compounds of Formula (I), in pure form or in an appropriate pharmaceutical composition can be carried out via any of the accepted modes of
  • administration can be, for example, orally, nasally, parentally or topically, in the form of solid, semi-solid or liquid dosage forms, such as for example, tablets,
  • suppositories capsules, powders, solutions, suspensions, emulsions, creams, lotions, aerosols, ointments or the like; preferably in unit dosage forms suitable for the
  • compositions will include a conventional pharmaceutical carrier or excipient and an active compound of Formula (I) and, in addition, may include other medicinal agents, pharmaceutical agents, carriers, adjuvants, etc.
  • the pharmaceutically acceptable composition will contain about 0.1% to 90%, preferably about 0.5% to
  • composition is formed by the incorporation of any of the normally employed
  • excipients such as, for example, mannitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, glucose, gelatin, sucrose, magnesium carbonate, and the like.
  • excipients such as, for example, mannitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, glucose, gelatin, sucrose, magnesium carbonate, and the like.
  • Such compositions take the form of solutions,
  • compositions will take the form of a pill or tablet and thus the composition will contain, along with the active ingredient, a diluent such as lactose, sucrose, dicalcium phosphate, or the like; a lubricant such as magnesium stearate or the like; and a binder such as starch, gum acacia, polyvinylpyrrolidine, gelatin, cellulose and derivatives thereof, and the like.
  • a diluent such as lactose, sucrose, dicalcium phosphate, or the like
  • a lubricant such as magnesium stearate or the like
  • binder such as starch, gum acacia, polyvinylpyrrolidine, gelatin, cellulose and derivatives thereof, and the like.
  • the active compounds of Formula (I) may be formulated into a liquid by dissolving, dispersing etc. an active compound (about 0.5% to about 10.0%) and optional
  • a carrier such as, for example, water, saline, aqueous dextrose, glycerol, ethanol or the like.
  • the pharmaceutical composition to be administered may also contain non-toxic amounts of auxiliary substances such as wetting agents, emulsifying agents, pH buffering agents or the like, such as, for example, sodium acetate, sorbitan monolaurate, triethanolamine oleate, etc. Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in the art.
  • auxiliary substances such as wetting agents, emulsifying agents, pH buffering agents or the like, such as, for example, sodium acetate, sorbitan monolaurate, triethanolamine oleate, etc.
  • a therapeutically effective daily dose of active ingredient is between about 0.5 and 4.0 mg per kg body weight, preferably about 3 mg per kg of body weight.
  • a therapeutic dose is about 210 mg.
  • N-Butyllithium was added dropwise to a cold (-15°C) stirring solution of diisopropylamine (4.1 ml, 0.029 mol) in THF (125 ml) under argon. After stirring for ten minutes, 1H-indane-1-carboxylic acid (1.9 g, 0.013 mol) in THF (25 ml) was added dropwise. After complete addition, the reaction was heated to 40° to 45°C for 30 minutes. The reddish solution was cooled to -15°C and to this was added ethyl 2-methoxy-6-bromomethylbenzoate (4.0 g, 0.015 mol) prepared, e.g., as described in Preparation 3, in THF (25 ml). The mixture was allowed to come to room temperature over one hour and quenched with HCl (10%). The mixture was extracted with a mixture of ether and THF three times. It was washed with cold water and the organic phase was
  • Triethylamine (1.2 ml, 0.0084 mol) was added, and the mixture was stirred for fifteen minutes.
  • Ethylchloroformate (0.8 ml, 0.0084 mol) in acetone was added and the mixture was stirred for one hour.
  • Sodium azide (0.85 g, 0.013 mol) in water was added dropwise and the reaction was stirred cold for one hour. It was then poured onto ice water and extracted twice with toluene, washed, dried over magnesium sulfate, and filtered.
  • N-(prop-1-enyl)-2- methylbenzamide (1.65 g, 9.4 mmol) as a 1:1 mixture of E- and Z-isomers (as determined by NMR) which needed no further purification.
  • N-(prop-1-enyl)-2-(3,3-dimethylpropyl)-3-methoxy- benzamide N-(prop-1-enyl)-benzamido-4-chloro-2-n-butylcarboxylic acid, and
  • N-(prop-1-enyl)-2-methylbenzamide (1.1 g, 6.3 mmol) prepared, e.g., as described in Preparation 9, in THF (25 ml) was cooled to -70°C. To this was added 1.3M sec-butyllithium (10.6 ml, 13.78 mmol) in cyclohexane at such a rate as to maintain the reaction mixture below -65°C. The resulting purple-red solution was stirred for 10 minutes at this temperature. To this mixture was added N-methyl-N- methoxyvaleramide (1.0 g 6.9 mmol) in 10 ml THF.
  • Tributyl borane (12.5 ml, 0.046 mol) in THF was then added dropwise and the reaction was allowed to warm to 0°C. It was then quenched with 10% HCl (to bring the mixture to pH 2-3) and stirred for 15 minutes at room temperature. The reaction mixture was extracted three times with ether, washed with water, dried, and the solvent was removed to produce an oil.
  • This example describes the preparation of a
  • a solid dose form (capsule or tablet) may be prepared as follows:
  • the compounds of the present invention may also be formulated in a solution for oral administration as follows:
  • This example describes the preparation of a
  • Membranes of rat liver cells were homogenized (using a Polytron P10 tissue disrupter, setting 10 for 5 or 10 sec bursts) in 10 volumes (w/v) Tris buffer (pH 7.4 at 4°C) of the following composition: Tris HCl (50 mM) and Na 2 EDTA (5 mM). The homogenate was centrifuged at 500 x g and the supernatant retained. This procedure was repeated. The supernatant was rehomogenized and centrifuged at 30,000 to 48,000 x g, and the pellet resuspended in homogenizing buffer. Non-specific binding was determined using human angiotensin II (1.0 ⁇ M). AII-1 binding sites were labelled with [ 125 I]-Sar 1 lle 8 All (0.01 nM; New England Nuclear).
  • test compound producing 50% inhibition of specific radioligand binding was determined by iterative curve fitting and its inhibition dissociation constant (K i ) calculated.
  • test compounds were preincubated with the tissue and a second concentration-effect curve to All was constructed. A shift in the concentration-effect curve to All showed agonistic or antagonistic activity of the test compound.
  • the compounds of Formula (I) were active as antagonists of All-mediated contraction in this assay.
  • the rats were divided into test and control groups.
  • test group received the test compound (10 mg/ml, in a vehicle of Tween®80
  • test group received only a single dose of the test compound (3, 10, 30 or 100 mg/kg), whereas the control group received the appropriate volume of vehicle. Blood pressure and heart rate were monitored for 4 hours, at which time captopril (3 mg/kg, iv) was administered.
  • the compounds of Formula (I) significantly lowered mean blood pressure when given by both the intravenous and oral routes.
  • Normotensive rats were set-up for recording systemic blood pressure and heart rate as described for renal hypertensive rats in (a) above. All (0.1 ⁇ g/kg, iv) was administered intravenously to both control and test groups at 15 and 30 minutes prior to administration of vehicle or test compound, which was administered by bolus injection or infusion. All (0.1 ⁇ g/kg, iv) was then
  • the Morris Water Maze consists of a circular pool made from black perspex (122 cm diameter, 46 cm in height, with a 15 cm rim), filled with opaque water to a height of 35 cm. A hidden platform consisting of black plexiglass was placed 1-2 cm below the surface of the water. The pool was divided into four quadrants, arbitrarily corresponding to north, south, east and west. The platform was located in the south quadrant, about 24 cm from the side. Objects of high contrast were placed about the room to serve as spatial cues.
  • Test trials were initiated by placing a rat into one of the four quadrants, facing the wall. Testing consisted of a block of six trials (starting first in the north quadrant, then east, south, west, north, and finally east) on each of two consecutive days. During each trial the rat was allowed 90 seconds to find the platform. When the rat successfully found the platform, it was given 30 seconds to "study" the spatial cues. When the rat failed to find the platform within 90 seconds, it was given a score of 90 seconds, and placed on the platform for 30 seconds.

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Abstract

Dérivés d'isoquinolone-1 et composés apparentés répondant à la formule (I) dans laquelle Y est choisi dans le groupe composé de H, OH, alcoxy inférieur et halo; X est choisi dans le groupe composé de H, acide d'alkyle inférieur, ester d'alkyle inférieur et alkyle inférieur; et R1 spiro-1H-indane substitué ou non substitué de la structure dans laquelle R2 représente H, OH, alkyle inférieur, alcoxy inférieur ou halo, et 3-spiro-cycloalkyle de la structure dans laquelle n représente un nombre entier compris entre zéro et six, à condition que, lorsque R1 représente spiro, X représente H, ou un sel pharmaceutiquement accepatble, à condition que, lorsque R1 représente spiro-, X représente H, et lorsque R1 représente H, alcényle, alkyle inférieur ou cycloalkyle inférieur substitué dans la position 3 de la fraction d'isoquinolone, et que X représente H ou alkyle inférieur, le groupe (2'-1H--tétrazol-5-yl)biphényl-4'-ylméthyle ne peut pas se trouver dans la position 2(N). Ces dérivés et composés sont utiles comme antagonistes du récepteur de l'angiotensine II. Des procédés de synthèse sont également décrits, ainsi que des intermédiaires, des formulations pharmaceutiques et des procédés de traitement.
PCT/US1993/000188 1992-01-17 1993-01-15 Derives d'isoquinolone-1 substitues, utilises comme antagonistes de l'angiotensine ii WO1993014086A1 (fr)

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EP1193257A3 (fr) * 1994-12-29 2002-06-26 The Regents Of The University Of California Composés pour la transduction de signaux à médiation par la céramide
WO2002090334A1 (fr) * 2001-05-08 2002-11-14 Kudos Pharmaceuticals Limited Derives d'isoquinolinone comme inhibiteurs de parp
US7196085B2 (en) 2002-04-30 2007-03-27 Kudos Pharmaceuticals Limited Phthalazinone derivatives
US7407957B2 (en) 2004-08-26 2008-08-05 Maybridge Limited Phthalazinone derivatives
US7449464B2 (en) 2003-03-12 2008-11-11 Kudos Pharmaceuticals Limited Phthalazinone derivatives
US7470688B2 (en) 2005-10-19 2008-12-30 Maybridge Limited Phthalazinone derivatives
US7981890B2 (en) 2007-09-14 2011-07-19 Astrazeneca Ab Phthalazinone derivatives
US8129380B2 (en) 2008-01-23 2012-03-06 Astrazeneca Ab Phthalazinone derivatives
US8475842B2 (en) 2008-10-07 2013-07-02 Astrazeneca Ab Immediate release pharmaceutical formulation of 4-[3-(4-cyclopropanecarbonyl-piperazine-1-carbonyl)-4-fluoro-benzyl]-2H-phthalazin-1-one
US8569528B2 (en) 2003-07-15 2013-10-29 Novartis Ag Process for the preparation of tetrazole derivatives from organo boron and organo aluminium azides
US8912187B2 (en) 2003-03-12 2014-12-16 Kudos Pharmaceuticals Limited Phthalazinone derivatives
CN105198810A (zh) * 2015-07-16 2015-12-30 西安交通大学 2-苄基-1-异喹啉酮类化合物及其合成方法和用途

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EP1193257A3 (fr) * 1994-12-29 2002-06-26 The Regents Of The University Of California Composés pour la transduction de signaux à médiation par la céramide
WO2002090334A1 (fr) * 2001-05-08 2002-11-14 Kudos Pharmaceuticals Limited Derives d'isoquinolinone comme inhibiteurs de parp
US6664269B2 (en) 2001-05-08 2003-12-16 Maybridge Plc Isoquinolinone derivatives
US7196085B2 (en) 2002-04-30 2007-03-27 Kudos Pharmaceuticals Limited Phthalazinone derivatives
US11160803B2 (en) 2003-03-12 2021-11-02 Kudos Pharmaceuticals Limited Phthalazinone derivatives
US7449464B2 (en) 2003-03-12 2008-11-11 Kudos Pharmaceuticals Limited Phthalazinone derivatives
US10449192B2 (en) 2003-03-12 2019-10-22 Kudo Pharmaceuticals Limited Phthalazinone derivatives
US7662818B2 (en) 2003-03-12 2010-02-16 Kudos Pharmaceuticals Limited Phthalazinone derivatives
US9566276B2 (en) 2003-03-12 2017-02-14 Kudos Pharmaceuticals Limited Phthalazinone derivatives
US9169235B2 (en) 2003-03-12 2015-10-27 Kudos Pharmaceuticals Limited Phthalazinone derivatives
US8912187B2 (en) 2003-03-12 2014-12-16 Kudos Pharmaceuticals Limited Phthalazinone derivatives
US8569528B2 (en) 2003-07-15 2013-10-29 Novartis Ag Process for the preparation of tetrazole derivatives from organo boron and organo aluminium azides
US7407957B2 (en) 2004-08-26 2008-08-05 Maybridge Limited Phthalazinone derivatives
US7902193B2 (en) 2005-10-19 2011-03-08 Maybridge Limited Phthalazinone derivatives
US7470688B2 (en) 2005-10-19 2008-12-30 Maybridge Limited Phthalazinone derivatives
US7981890B2 (en) 2007-09-14 2011-07-19 Astrazeneca Ab Phthalazinone derivatives
US8129380B2 (en) 2008-01-23 2012-03-06 Astrazeneca Ab Phthalazinone derivatives
US8475842B2 (en) 2008-10-07 2013-07-02 Astrazeneca Ab Immediate release pharmaceutical formulation of 4-[3-(4-cyclopropanecarbonyl-piperazine-1-carbonyl)-4-fluoro-benzyl]-2H-phthalazin-1-one
US11633396B2 (en) 2008-10-07 2023-04-25 Kudos Pharmaceuticals Limited Immediate release pharmaceutical formulation of 4-[3-(4- cyclopropanecarbonyl-piperazine-1-carbonyl)-4-fluoro-benzyl]-2H- phthalazin-1-one
US11975001B2 (en) 2008-10-07 2024-05-07 Kudos Pharmaceuticals Limited Immediate release pharmaceutical formulation of 4-[3-(4-cyclopropanecarbonyl-piperazine-1-carbonyl)-4-fluoro-benzyl]-2H-phthalazin-1-one
US12048695B2 (en) 2008-10-07 2024-07-30 Kudos Pharmaceuticals Limited Immediate release pharmaceutical formulation of 4-[3-(4-cyclopropanecarbonyl-piperazine-1-carbonyl)-4-fluoro-benzyl]-2H-phthalazin-1-one
US12144810B1 (en) 2008-10-07 2024-11-19 Kudos Pharmaceuticals Limited Immediate release pharmaceutical formulation of 4-[3-(4-cyclopropanecarbonyl-piperazine-1-carbonyl)-4-fluoro-benzyl]-2H-phthalazin-1-one
US12178816B2 (en) 2008-10-07 2024-12-31 Kudos Pharmaceuticals Limited Immediate release pharmaceutical formulation of 4-[3-(4-cyclopropanecarbonyl-piperazine-1-carbonyl)-4-fluoro-benzyl]-2H-phthalazin-1-one
CN105198810A (zh) * 2015-07-16 2015-12-30 西安交通大学 2-苄基-1-异喹啉酮类化合物及其合成方法和用途

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