WO1993014086A1 - Substituted 1-isoquinolone derivatives as angiotensin ii antagonists - Google Patents

Abstract

1-Isoquinolone derivatives and related compounds according to formula (I) wherein, 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; and R1 is selected from the group consisting of H, alkenyl, lower alkyl, lower cycloalkyl, unsubstituted or substituted 3-spiro-1H-indane of structure (II) wherein R2 is H, OH, lower alkyl, lower alkoxy or halo, and 3-spiro-cycloalkyl of structure (III) wherein n is an integer from zero to six, provided that when R1 is spiro- X is H, or a pharmaceutically acceptable salt thereof, with the proviso that when R1 is spiro-, X is H, and when R1 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, are useful as angiotensin II receptor antagonists. Also disclosed are methods of synthesis, intermediates, pharmaceutical formulations and methods of treatment.

Description

SUBSTITUTED 1-ISOQUINOLONE DERIVATIVES AS ANGIOTENSIN

II ANTAGONISTS

Background of the Invention

Field of the Invention 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

pharmaceutically acceptable compositions containing an effective amount of at least one of the compounds in

combination with a suitable excipient. The invention also relates to processes for making the compounds of the

invention and the use of the compounds of the invention in the treatment of cardiovascular disorders such as

hypertension and congestive heart failure, chronic renal failure, cognitive disorders and inflammatory bowel disease.

Description of Related Art

The renin-angiotensin system is a fundamental

physiological mechanism for maintaining proper blood

pressure in mammals. 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

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

categorized into subtypes. Various All receptor antagonists are known, as discussed below.

Carini et al. EP 0 323 841, assigned to E.I. Dupont De Nemours and Company, discloses substituted pyrrole, pyrazole and triazole All receptor antagonists. A related

application, Carini et al. EP 0 253 310, discloses

substituted imidazoles as All receptor antagonists. One such imidazole receptor antagonist is DuP 753, discussed below. The preparation of biphenyl tetrazole intermediates of the compounds referred to above is disclosed in another related application, Aldrich et al. EP 0 291 969.

The substituted imidazole DuP 753, as disclosed in Wong et al., Hypertension 15:459, (1990), is disclosed as being an orally active, highly selective, competitive All receptor antagonist. 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. These experiments also demonstrated that the All receptor subtype AII-1 is sensitive to EXP3174, as well as DuP 753.

Chiu et al., Biochem. Biophys. Res. Comm. 165:196-203 (1989), reported that the All receptor subtype AII-2 is highly sensitive to EXP 655, but not DuP 753. Conversely, All receptor subtype AII-1 is sensitive to DuP 753, but not EXP 655.

Blankley et al. EP 0 245 637, assigned to Warner

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.

Chakravarty, EP 0 400 974-A, assigned to Merck and Co., discloses imidazo-fused 6 membered heterocycles for use in angiotensin inhibition.

Narr et al. EP 392,317, assigned to Dr. Karl Thomae GmbH, discloses substituted benzimidazole All antagonists. EP 0 399 732, assigned to Imperial Chemical Industries, also discloses benzimidazole derivatives which antagonize the actions of angiotensin II. Chakravarty et al. EP 0 400 835, assigned to Merck & Co., also discloses substituted benzimidazole compounds useful as angiotensin antagonists.

Carini et al. U.S. 4,880,804, assigned to E.I. Dupont De Nemours and Company, also discloses All blocking

benzimidazole compounds.

Substituted 1-isoguinolones are disclosed in Jahangir et al. Syntheses and Rearrangements of Spiro-Fused

Dihydroisoquinolones, J. org. Chem. 54:2992-2996 (1989).

SUMMARY OF THE INVENTION

One aspect of the present invention concerns certain substituted isoguinolones according to the following Formula (I):

wherein,

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; and

R¹ is selected from the group consisting of H, alkenyl, lower alkyl, lower cycloalkyl, unsubstituted or substituted 3-spiro-1H-indane of the structure

wherein R² is H, OH, lower alkyl, lower alkoxy or halo, and

3-spiro-cycloalkyl of the structure

wherein n is an integer from zero to six,

or a pharmaceutically acceptable salt thereof, with the proviso that when R¹ is spiro-, X is H, and when R¹ 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.

In another aspect, the invention relates to

pharmaceutical compositions for the treatment of All

receptor-related disorders, including a therapeutically effective amount of a compound of Formula (I) or a

pharmaceutically acceptable salt thereof admixed with at least one pharmaceutically acceptable excipient.

The invention further comprises synthetic methods for the preparation of the compounds of Formula (I) :

wherein R¹, 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:

with a trialkyl tin azide to form the compound of Formula (I). 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 R¹ is selected from the group consisting of H, alkenyl, lower alkyl; and X, and Y are as defined above, comprising the steps of:

(a) treating an optionally substituted N-(prop-1- enyl)benzamide of Formula (M) :

with a compound of the formula H₃CN(OCH₃)C(O)R¹ to form an optionally substituted N-(prop-1-enyl)-isoquinolin-1(2H)-one of Formula (N):

(b) treating the compound of Formula (N) with an acid to form an optionally substituted isoquinolin-1(2H)-one of Formula (0)

(c) coupling the compound of Formula (0) with a 4- halomethyl-2 -cyano-biphenyl compound to produce an

optionally substituted 2-[(2"-cyano)biphenyl-4'ylmethyl]' isoquinolin-1(2H)-one of Formula (P) :

( P)

; and

(d) treating the compound of Formula (P) with a trialkyl tin azide to form the compound of Formula (I)

DESCRIPTION OF THE PREFERRED EMBODIMENT

DEFINITIONS AND GENERAL PARAMETERS

The following definitions and general parameters are set forth to illustrate and define the meaning and scope of the various terms used to describe the present invention. The term "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.

The term "lower alkyl" means an alkyl radical, as defined above, of 1-6 carbon atoms. The term "lower cycloalkyl" means a cyclic saturated hydrocarbon radical having from 3 to 7 carbon atoms.

The term "lower alkyl acid" means a lower alkyl radical as defined above further containing a carboxylic acid group, i.e., -(CH₂)_mCOOH, where m is an integer between 0 and 5.

The term "lower alkyl ester" means a lower alkyl acid as defined above esterified with a lower alkanol, i.e., -(CH₂)_mCOOR^b, where m is as defined above and R^b is lower alkyl.

The term "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.

The term "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.

The term "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.

The term "halo" means fluoro, bromo, chloro or iodo. The term "3-spiro-cycloalkyl" means a substituent illustrated as follows:

representing a cyclic alkyl radical as defined above sharing a common carbon (the spiro carbon) indicated by the asterisk (*) with the 1-isoquinolone to which it is attached; "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:

with the spiro carbon indicated by the asterisk (*). Either or both R- and S- stereoisomers which result from the spiro attachment are included in this definition, as is indicated by a wavy line (-).

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 "entgegen" (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. When the structure cannot accommodate such bond, e.g., when one of the carbon atoms is a spiro carbon, or one of the carbon atoms contains a substituent double bonded thereto, the bond is absent.

A "pharmaceutically acceptable salt" may be any salt derived from an inorganic or organic base. The term

"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. The term "treatment" or "treating" means any treatment of a disease in a mammal, including:

(i) preventing the disease, that is, causing the

clinical symptoms of the disease not to develop; (ii) inhibiting the disease, that is, arresting the

development of clinical symptoms; and/or

(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. The terms "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]. Unless specified to the contrary, the solvents used in the reactions of the present invention are inert organic solvents. Unless specified to the contrary, the reactions

described herein take place at atmospheric pressure over a temperature range from about 10°C to about 100°C, more preferably from about 10°C to about 50°C, and most

preferably at about room (or "ambient") temperature, e.g., about 20°C. Unless specified to the contrary, the ranges of time and temperature described herein are approximate, e.g., "from 8 to 24 hours at from 10°C to 100°C" means "from about 8 to about 24 hours at about 10°C to about 100°C". Isolation and purification of the compounds and

intermediates described herein can be effected, if desired, by any suitable separation or purification procedure such as, for example, filtration, extraction, crystallization, column chromatography, thin-layer chromatography or thick-layer chromatography, or a combination of these procedures. Specific illustrations of suitable separation and isolation procedures can be had by reference to the examples hereinbelow. However, other equivalent separation or isolation procedures can, of course, also be used.

"M.P." refers to melting point. All temperatures are given in degrees Celsius.

The naming and numbering of the compounds of the present invention in which the biphenyl tetrazole group is at the 2 (N) position is illustrated with reference to the following structure:

Following the illustrated numbering system, the exemplary compound shown above is named 3-n-butyl-2-[(2"-1H-tetrazol- 5-yl)biphenyl-4'-ylmethyl]-isoquinolin-1(2H)-one-4- carboxylie acid.

The position numbering on each ring is consistent in the different embodiments of Formula (I) (although different prime designations are used for the spiro compounds), and applies throughout the specification and the claims, even though position numbering may not be specifically set forth.

As a further example of the naming and numbering of the compounds of the present invention, a compound according to Formula (I) which contains a biphenyl tetrazole group at the 3 position is illustrated below:

Following the illustrated numbering system, the exemplary compound shown above is named 2-n-butyl-3-[(2"-1H-tetrazol- 5-yl)biphenyl-4'-ylmethyl]-isoquinolin-1(2H)-one-4- carboxylic acid.

As a further example of the naming and numbering of the compounds of the present invention, a compound according to Formula (I) in which R¹ is 3-spiro-1H-indane is shown below:

Following the illustrated numbering system, 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. For purposes of this disclosure, these designations (1R, 1S, and 1R, 1S) are omitted from the names of compounds described herein, although it is to be

understood that the present invention encompasses single isomers, racemic and non-racemic mixtures thereof. SYNTHESIS OF THE COMPOUNDS OF FORMULA (I)

The compounds of Formula (I) are prepared as

illustrated in Reaction Schemes I to III, in which Y, X, and R¹ have the same meanings as used in the Summary of the Invention. Z represents a leaving group, such as tosylate, sulfonate or halo. R^1S represents R¹ in the compounds and precursors thereof where R¹ 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

comprise a 2-biphenylmethyl group and a 3-spiro substitution as R¹. 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-R¹ 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- R¹ group of H, alkenyl, or lower alkyl.

Reaction Scheme I

Reaction Scheme I, below, illustrates the synthesis of the spiro compounds of Formula (I), designated below as Formula (Ia). The spiro R¹ substituent, designated R^1S, is illustrated as exemplified by the following precursor compound:

wherein a carboxyl group is shown attached to a cyclic carbon which will become the spiro carbon. Steps 1 and 2 of Reaction Scheme I illustrate the preparation of ethyl 2-methoxy-6-methyl benzoate, a

preferred starting material within the scope of Formula (C) wherein Y' is 2-methoxy. The preparation of other starting materials of Formula (C) is described below. When preparing the compounds of Formula (Ia) where Y is hydroxy, an

additional reaction (step 7) is carried out on a compound of Formula (H) where Y' is methoxy; the methoxy is thus

converted to hydroxy. A cyclization is then carried out in 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. Thus, 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. R¹ 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

chromatography, and the separate R and S enantiomers recovered from their respective complexes.

Reaction Scheme I

Reaction Scheme I (continued)

C

Starting Materials

The cyclohexenone ester starting material of Formula (A) is prepared as described in F. Hauser and S. Pogany, Synthesis 1980; 814 (1980).

The compounds of Formula (C) where Y' is H or halo (e.g. ethyl 6-methyl benzoate, ethyl 5-fluoro-6-methyl- benzoate, and ethyl 5-iodo-6-methyl-benzoate) or where Y' is alkoxy (other than illustrated in Reaction Scheme I steps 1 and 2, e.g. 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 R¹ 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.

The 4-halomethyl-2'-cyano-biphenyl or 4-aminomethyl-2'- cyano-biphenyl compounds used in step 6 in the preparation of the compounds of Formula (H) , as well as in step 5 of Reaction Scheme II in the preparation of compounds of

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

peroxide is added. The mixture is stirred, extracted with ether, washed with water, and dried over magnesium sulphate to produce an oil, 4-methyl-2'-cyano-biphenyl. To this oil is added an equimolar amount of N-bromosuccinimide and a catalytic amount of azaisobutylnitrile, in a nonpolar solvent (such as ether, cyclohexane, or carbon

tetrachloride; preferably carbon tetrachloride), and the mixture is heated under reflux for 1 to 4 hours; preferably 2 hours. The mixture is cooled and filtered, and the solvent is extracted to yield 4-bromomethyl-2'-cyano- biphenyl. 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, H₂, 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.

Preparation of a Preferred Starting Material As shown in step 1 of Reaction Scheme I, ethyl 6-methyl cyclohexene-2-one carboxylate according to Formula (A) is first reduced to the corresponding phenol by

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. To this solution is added a molar equivalent of a halogenating agent (such as iodine,

chlorine, or bromine; preferably bromine) and the mixture is heated at 100°C to reflux; preferably reflux for 8 to 24 hours; preferably 12 hours. To this mixture is added one or more polar solvents (such as ether, ethyl acetate, water, and methylene chloride; preferably water and methylene chloride) and the corresponding ethyl 2-hydroxy-6-methyl- benzoate product of Formula (B) is recovered from the organic phase, e.g., extracted, dried and solvent distilled.

As shown in 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;

preferably methyl iodide. A molar excess of a base (such as potassium carbonate potassium hydroxide, or t-butoxide; preferably t-butoxide) is added in a polar solvent (such as DMF, acetonitrile, or THF; preferably THF) to a solution of ethyl 2-hydroxy-6- methyl benzoate (B) in a polar solvent (such as DMF,

acetonitrile, or THF; preferably THF) at ambient

temperature. The mixture is stirred for 5 to 60 minutes; preferably 20 minutes, then a methyl halide (such as

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).

Preparation of Compounds of Formula (D)

As shown in step 3 of Reaction Scheme I, a 6-methyl substituent of a compound according to Formula (C) (either prepared as described above when Y' is 2-methoxy, or

prepared as described under "Starting Materials" when Y' is H, halo or alkoxy other than 2-methoxy) is next converted into a halomethyl substituent by halogenation.

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;

preferably 1.5 hours. A nonpolar hydrocarbon solvent (such as cyclohexane, heptane, or hexane; preferably hexane) is added and the resultant optionally substituted halomethyl benzoate (D) is recovered, e.g., by filtration.

Preparation of Compounds of Formula (F)

As shown in step 4 of Reaction Scheme I, 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) is added to a cold (-25 to 5°C; preferably 0°C) stirring solution of a molar excess of a secondary amine (such as diethylamine, ethylisopropylamine, or diisopropylamine; preferably

diisopropylamine) under an inert gas (such as argon, nitrogen, or helium; preferably argon). After stirring for 2 to 20 minutes; preferably 10 minutes, 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 H₂SO₄, CH₃COOH, 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.

Preparation of Compounds of Formula (G)

As shown in 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

illustrated) that is cyclized to give the spiro compound.

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

diethylisopropylamine, N-methylmorpholine, or triethylamine; preferably triethylamine), and the mixture is stirred for 5 to 30 minutes; preferably 15 minutes. A mixed anhydride (such as benzylchloroformate, methylchloroformate, or ethylchloroformate; preferably ethylchloroformate) for activating 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;

preferably 1 hour. The resultant optionally substituted cyclic-azide-benzoate compound is worked up in a

conventional manner (e.g. extraction, washing, drying, and filtration) and immediately converted to the corresponding optionally substituted cyclic-isocyanate-benzoate by heating the filtrate under an inert gas (such as argon, helium, or nitrogen; preferably nitrogen) for 1 to 10 hours; preferably 2 hours. The optionally substituted cyclic-isocyanate- benzoate is dissolved in an organic solvent (such as

benzene, xylene, or toluene; preferably toluene) and an alcohol (such as ethanol, t-butanol, or benzyl alcohol;

preferably benzyl alcohol) is added. A molar equivalent of a hydride (such as sodium hydride, lithium hydride, or potassium hydride; preferably sodium hydride) is added and the reaction mixture is heated at 70°C to reflux; preferably reflux, for 1 to 6 hours; preferably 2 hours. The product in the organic layer is recovered, e.g., separated solvent distilled, and chromatographed on silica gel, to yield the corresponding optionally substituted spiro[ (cycloalkyl or 1H-indane)-1,3'(2'-H)-isoquiolin]-1'(2H)-one (G). Preparation of Compounds of Formula (H)

As shown in step 6 of Reaction Scheme I, a 4-methyl-2'- cyano-biphenyl group, wherein the methyl is substituted with a leaving group such as halo (preferably Br) is next

attached at the N position of an optionally substituted spiro[ (cycloalkyl or 1H-indane)-1,3 '(2'-H)-isoquiolin]- 1'(2H)-one (G).

An optionally substituted spiro[ (cycloalkyl or 1H- indane)-1,3'(2'-H)-isoquiolin]-1'(2H)-one (G) in a polar organic solvent (such as ethyl acetate, ether, or DMF;

preferably DMF) is combined with a molar excess of a strong base (such as potassium carbonate, lithium hydride, or sodium hydride; preferably sodium hydride) and stirred for 0.5 to 2 hours; preferably 1 hour at -5 to 5°C; preferably 0°C. 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. The mixture is then poured into an aqueous solvent, extracted with a polar organic solvent (such as THF, ether, or ethyl acetate; preferably ethyl acetate), and the product in the organic layer is recovered, e.g., extracted, washed, dried, and solvent removed, to yield the corresponding optionally substituted 1',4',2,3- tetrahydrospiro[cycloalkyl or 1H-indane-1,3'(2'-{2"'- cyano}biphenyl-4"-ylmethyl)-isoquinolin]-1'(2H)-one (H). Preparation of Compounds of Formula (J)

As shown in step 7 of Reaction Scheme I, 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

refluxing with HI or, preferably, as is described below, by the addition of a bromide compound.

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;

preferably argon) at -100 to -40°C; preferably -70°C. The 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

bicarbonate) solution and extracted with a polar organic solvent (such as ethyl acetate, chloroform, or methylene chloride; preferably methylene chloride) to yield a

corresponding 5'-, 6'-, 7'- or 8'-hydroxy-1',4',2,3- tetrahydrospiro[cycloalkyl or 1H-indane-1,3'(2'-{2"'- cyano}biphenyl-4"-ylmethyl)-isoquinolin]-1'(2H)-one (J).

Preparation of Compounds of Formula fla)

As shown in step 7a and 8 of Reaction Scheme I, the cyano group of the 5 ' -, 6 '-, 7 ' - or 8'-hydroxy-1',4',2,3- tetrahydrospiro[cycloalkyl or 1H-indane-1,3'(2'-{2'"- cyano}biphenyl-4"-ylmethyl)-isoquinolin]-1'(2H)-one (J) or of the optionally substituted l',4',2,3- tetrahydrospiro[cycloalkyl or 1H-indane-1,3'(2'-{2"'- cyano}biphenyl-4"-ylmethyl)-isoquinolin]-1'(2H)-one (H) is next converted to a corresponding 1H tetrazol-5-yl group by cycloaddition with a trialkyl tin azide. A 5'-, 6'-, 7'- or 8'-hydroxy-1',4',2,3- tetrahydrospiro[cycloalkyl or 1H-indane-1,3'(2'-{2"'- cyano}biphenyl-4"-ylmethyl)-isoquinolin]-1'(2H)-one (J) or optionally substituted 1',4',2,3-tetrahydrospiro[cycloalkyl or 1H-indane-1,3'(2'-{2"'-cyano}biphenyl-4"-ylmethyl)- isoquinolin]-1'(2H)-one (H) 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. The mixture is cooled to ambient temperature, mixed with acid (such as H₂SO₄, CH₃COOH, 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).

Preparation of Stereoisomers of Compounds of Formula (Ia)

If desired, 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. Exemplary of such 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

respective stereoisomers of the compound of Formula (F). Conversion of the appropriate stereoisomer of Formula (F) to the corresponding stereoisomer of a compound of Formula (Ia) may be carried out according to Reaction Scheme I.

Racemic mixtures may also be separated by

chromatography on a chiral column, for example, HPLC-CSP Type I supplied by Baker, with (R)-N-3,5-dinitrobenzoyl- (phenylglycine) as the chiral agent.

Alternatively, the stereoisomers of a compound of

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. For example, the compound of

Formula (G) is dissolved in an inert solvent such as

benzene, toluene, ethyl acetate, tetrahydrofuran, diethyl ether, chloroform or dichloromethane, containing about l molar equivalent of a chiral isocyanate such as (R)-(+)-α- methylbenzylisocyanate. The reaction is conducted at a temperature of about 0°C to 50°C for about 5 minutes to 4 hours. When the reaction is substantially complete, the mixture of the two diastereomeric urea compounds may then be separated by chromatography on silica gel, especially medium pressure chromatography. Conversion of an appropriate stereoisomer of Formula (G) to the corresponding

stereoisomer of a compound of Formula (Ia) may be carried out according to Reaction Scheme I.

REACTION SCHEME II

Reaction Scheme II, below, 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. R¹ is at position 3, and, further, in which R¹ 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.

REACTION SCHEME II

- 32 -

Starting Materials

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. For example, 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.

The N-methoxy-N-methylcarboxyamides ("Weinreb amides") of the formula H₃CN(OCH₃)C(O)R¹ (wherein R¹ 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).

The 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.

In cases where X is lower alkyl acid or lower alkyl ester, a reactant of Formula (0) may be prepared from homophthalic anhydride, commercially available, e.g., from Aldrich Chemical Company, Inc., Milwaukee, WI. This

preparation may be carried out essentially as described in Haimova et al., Tetrahedron 33:331-336 (1977), the

disclosure of which is hereby incorporated by reference.

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.

Preparation of Compounds of Formula (L)

As shown in step 1 of Reaction Scheme II, 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) is added to a mixture of a trialkylamine (such as tri-n-butylamine, tri-n-propylamine, or triethylamine; preferably triethylamine) and allylamine. The mixture is allowed to warm to ambient temperature and shaken with an acid (such as H₂SO₄, CH₃COOH, 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).

Preparation of Compounds of Formula (M)

As shown in 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

synthesis of the heterocycle by means of an isomerization reaction mediated by a strong base.

A solution of diisopropylamine in an ethereal aprotic solvent (such as ether, dioxane, or THF; preferably THF) at 0 to -70°C; preferably -20°C is combined with an equimolar amount of an alkyl lithium base (such as n-, tert-, or sec- butyllithium; preferably n-butyllithium) to form the lithium diisopropyl amide (LDA) base. This mixture is cooled to -40 to -100°C; preferably -70°C and a molar excess of the previously prepared optionally substituted N-allyl methyl benzamide (L) is added. 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

substituted N-(prop-1-enyl) benzamide (M).

Preparation of Compounds of Formula (N)

As shown in step 3 of Reaction Scheme II, 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 R¹) 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) is cooled to -40 to -100°C; preferably -70°C. To this is added 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

minutes, and a molar equivalent of a Wienreb amide, selected on the basis of the desired identity of R¹ (where R¹ 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 H₂SO₄, CH₃COOH, or aqueous HCl; preferably

CH₃COOH). 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;

preferably ether), shaken, and the product in the organic layer is recovered, e.g., separated, dried, filtered, concentrated, and flash chromatographed, to yield the corresponding optionally substituted N-(prop-1-enyl)- isoquinolin-1(2H)-one (N). Preparation of Compounds of Formula (O)

As shown in 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 H₂SO₄, CH₃COOH, 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,

dichloromethane, or THF; preferably ether), shaken, and the product in the organic layer is separated, dried, filtered, and concentrated to yield the corresponding optionally substituted isoquinolin-1(2H)-one (O).

Preparation of Compounds of Formula (P)

As shown in step 5 of Reaction Scheme II, 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;

preferably DMF) is combined with a molar excess of a base (such as potassium hydride, lithium hydride, or sodium hydride; preferably sodium hydride), is warmed to ambient temperature, then cooled to -5 to 5°C; preferably 0°C. 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,

dichloromethane, or ether; preferably ether). The product in the solution is recovered, e.g., dried, filtered, and flash chromatographed, to yield the corresponding

optionally substituted 2-[(2"-cyano)biphenyl-4'ylmethyl]- isoquinolin-1(2H)-one (P).

Preparation of Compounds of Formula (Ib)

As shown in 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. Optionally substituted 2-[(2"-cyano)biphenyl-

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. The mixture is cooled to ambient temperature, mixed with acid (such as H₂SO₄, CH₃COOH, 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).

REACTION SCHEME III

Reaction Scheme III, below, 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).

Starting Materials

Optionally substituted 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

starting materials.

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.

The trialkyl tin azide used in step 5 is obtained as described in connection with Reaction Scheme I.

Preparation of Compounds of Formula (R)

As shown in step 1 of Reaction Scheme III, a 1- isoquinolone with a 4'-bromo-3-phenyImethyl substitution (R) 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.

An optionally substituted 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). To this solution is added a molar equivalent of N,O-dimethyl-4-bromophenylacetamide. 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). 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). 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).

Preparation of Compounds of Formula (S)

As shown in step 2 of Reaction Scheme III, 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;

preferably dioxane) and an acid (such as H₂SO₄, CH₃COOH, or aqueous HCl; preferably aqueous HCl) and heated under reflux for 12-36 hours; preferably 24 hours. The mixture is cooled to ambient temperature, poured onto ice, extracted with a polar aprotic solvent (such as ether, dichloromethane, or ethyl acetate; preferably ethyl acetate), and the product in the organic layer is recovered, e.g., recrystallized, to yield a corresponding optionally substituted 3-(4'- bromophenyImethyl)-1-isoquinolone (S).

Preparation of Compounds of Formula (T)

As shown in step 3 of Reaction Scheme III, an N- substituent (i.e., R¹, where R¹ is H, alkenyl, lower alkyl or lower cycloalkyl) is next added to the optionally

substituted 3-(4'-bromophenyImethyl)-1-isoquinolone (S) by treatment with base and nucleophilic displacement with the appropriate R'-halo compound.

An optionally substituted 3-(4'-bromophenyImethyl)-1- isoquinolone (S) in a polar solvent (such as THF, ether, or DMF; preferably DMF) at -5 to 5°C; preferably 0°C is

combined with a metal hydride (such as lithium hydride, potassium hydride, or sodium hydride; preferably sodium hydride) and allowed to warm to ambient temperature. A molar equivalent of the desired R¹-halo substituent, e.g. 1- iodobutane 2-chloropentane, or 1-bromobutane, preferably 1- iodobutane is added to the mixture at ambient temperature. After 18 to 40 hours; preferably 26 hours, 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;

preferably ether), and further purified, e.g. by flash chromatography to yield the corresponding optionally

substituted 3-(4'-bromophenylmethyl)-2-(lower alkyl or alkenyl)-1-isoquinolone (T).

Preparation of Compounds of Formula (U)

As shown in step 4 of Reaction Scheme III, a

benzylnitrile compound is next added to the phenyl

substituent on the previously prepared optionally

substituted 3-(4'-bromophenyImethyl)-2-(lower alkyl or alkenyl)-1-isoquinolone (T), by nucleophilic substitution of the 4'-bromo group to form a biphenyImethyl moiety.

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.

An optionally substituted 3-(4'-bromophenyImethyl)-2- (lower alkyl or alkenyl)-1-isoquinolone (T) in a polar aprotic solvent (such as ether, glyme, or THF; preferably THF) at -40 to -100°C; preferably -70°C is combined, with stirring, with a molar excess of an alkyl lithium base (such as sec-butyllithium, tert-butyllithium, or n-butyllithium; preferably n-butyllithium) and stirring is continued for 5 to 35 minutes; preferably 15 minutes. 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 H₂SO₄, CH₃COOH, or aqueous HCl; preferably aqueous HCl) and stirred for 10 to 50 minutes; preferably 15 minutes at ambient temperature. 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. The resultant oil is dissolved in a high boiling aromatic solvent (such as benzene, toluene, or xylene;

preferably toluene), ethanol, and aqueous sodium carbonate and added to a molar equivalent of 2-bromobenzylnitrile and a transition metal catalyst (such as di-[triphenyl phosphine] palladium chloride palladium or

tetrakis[triphenylphosphine] palladium; preferably

tetrakis[triphenylphosphine] palladium) and heated at 100°C to reflux; preferably reflux with vigorous stirring for 18 to 36 hours; preferably 24 hours. The reaction mixture is then poured into water and the layers are separated. The organic layer is dried, and the solvent is removed to yield the corresponding optionally substituted 3-[2"- (cyano)biphenyl-4'-ylmethyl]-2-(lower alkyl or alkenyl)- isoquinolin-1(2H)-one (U).

Preparation of Compounds of Formula (lc)

As shown in step 5 of Reaction Scheme III, 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. The mixture is cooled to ambient temperature, mixed with acid (such as H₂SO₄, CH₃COOH, or HCl; preferably HCl in ether), and the precipitated solid is recovered, e.g., by washing and recrystallization to afford the corresponding optionally substituted 3-[(2"-1H-tetrazol-5-yl)biphenyl-4'-ylmethyl]-2- (lower alkyl or alkenyl)-isoquinolin-1(2H)-one (lc). SALTS OF COMPOUNDS OF FORMULA (I)

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

tetrazole. 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) in an inert organic solvent (such as ether, methanol, or THF; preferably methanol) at a temperature of about 0°- 50°C; preferably ambient temperature. The

resulting salt may be brought out of solution with a less polar solvent or by lyophilization of the solution.

PREFERRED COMPOUNDS

Preferred are the compounds where R¹ is 3-spiro-1H- indane or 3-spiro-1H-cycloalkyl, particularly those where R¹ 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. PREFERRED PROCESSES

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

substituted)-3-[(2"-cyano)biphenyl-4'-ylmethyl]-isoquinolin- 1(2H)-one with tributyl tin azide followed by treatment with acid to yield the corresponding 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 substituted)-3-[(2"-1H-tetrazol-5yl)biphenyl-4'-ylmethyl]- isoquinolin-1(2H)-one; contacting a 3-(optionally lower alkyl, alkenyl or lower cycloalkyl substituted)-4-(lower alkyl acid or lower alkyl ester substituted) -5-, 6- , 1- , or 8-(optionally hydroxy, lower alkoxy or halo substituted)-2-[(2"- cyano)biphenyl-4'-ylmethyl]-isoquinolin-1(2H)-one with tributyl tin azide followed by treatment with acid to yield the corresponding 3-(optionally lower alkyl, alkenyl or lower cycloalkyl substituted)-4-(lower alkyl acid or lower alkyl ester substituted)-5-, 6-, 7-, or 8- (optionally hydroxy, lower alkoxy or halo substituted)-2-[(2"-1H- tetrazol-5yl)biphenyl-4'-ylmethyl]-isoquinolin-1(2H) -one; contacting a 5'-, 6'-, 7'-, or 8'-(optionally hydroxy, lower alkoxy or halo substituted)-1',4',2,3- tetrahydrospiro[cycloalkyl or 1H-indane-1,3'(2'- {2"'cyano}biphenyl-4"-yImethyl)-isoquinolin]-1'(2H)-one with tributyl tin azide followed by treatment with acid to yield the corresponding 5'-, 6'-, 7'-, or 8'-(optionally hydroxy, lower alkoxy or halo substituted)-1',4',2,3- tetrahydrospiro[cycloalkyl or 1H-indane-1,3'(2'-{2"'-H- tetrazol-5-yiybiphenyl-4"-yImethyl)-isoquinolin]-1'(2H)-one; contacting a 3-n-butyl-5-, 6-, 7-, or 8-(optionally hydroxy, methoxy or halo substituted)-2-[(2"-cyano)biphenyl- 4'-yImethyl]-ihoquinolin-1(2H)-one with tributyl tin azide followed by treatment with acid to yield the corresponding 3-n-butyl-5-, 6-, 7-, or 8- (optionally hydroxy, methoxy or halo substituted)-2-[(2"-1H-tetrazol-5yl)biphenyl-4'- ylmethyl]-isoquinolin-1(2H)-one; contacting a 3-n-butyl-6-methoxy-4- (lower alkyl acid or lower alkyl ester substituted)-2-[(2"-cyano)biphenyl-4'- ylmethyl]isoquinolin-1(2H)-one with tributyl tin azide followed by treatment with acid to yield the corresponding 3-n-butyl-6-methoxy-4-(lower alkyl acid or lower alkyl ester substituted)-2-[(2"-1H-tetrazol-5yl)biphenyl-4'- ylmethyl]isoquinolin-1(2H)-one; contacting a free 2-(optionally lower alkyl or alkenyl substituted)-4-(optionally lower alkyl, lower alkyl acid or lower alkyl ester substituted) -5-, 6-, 7-, or 8-(optionally hydroxy, lower alkoxy or halo substituted)-3-[(2"-1H- tetrazol-5yl)biphenyl-4'-ylmethyl]-isoquinolin-1(2H)-one with an appropriate base to yield the corresponding base salt; contacting a free 3- (optionally lower alkyl, alkenyl or lower cycloalkyl substituted)-4-(lower alkyl acid or lower alkyl ester substituted) -5-, 6-, 7-, or 8-(optionally hydroxy, lower alkoxy or halo substituted)-2-[(2"-1H- tetrazol-5yl)biphenyl-4'-ylmethyl]-isoquinolin-1(2H)-one with an appropriate base to yield the corresponding base salt; and contacting a free 5'-, 6'-, 7'-, or 8'-(optionally hydroxy, lower alkoxy or halo substituted)-1',4',2,3- tetrahydrospiro[cycloalkyl or 1H-indane-1,3'(2'-{2'"-H- tetrazol-5-yl}biphenyl-4"-yImethyl)-isoquinolin]-1'(2H)-one with an appropriate base to yield the corresponding base salt. UTILITY AND ADMINISTRATION

Utility

The compounds of the present invention, including the pharmaceutically acceptable salts thereof and the

compositions containing them, are useful as cardiovascular agents, such as anti-hypertensives and in the treatment of congestive heart failure and chronic renal disease. In view of the local role of 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

cognitive and affective disorders, mood disorders and alcoholism, as well as disorders of the alimentary tract, including motility and secretory disorders and inflammatory bowel disease. The compounds of the present invention may also be used to treat chronic renal failure, glaucoma, as well as neuroblastoma and other growth disorders.

The ability of the compounds of Formula (I) to

effectively inhibit the binding of All to its receptors can be determined by a variety of in vitro and in vivo assays that are known to those of ordinary skill in the art. In particular, assays which inhibit the response of isolated smooth muscle and cardiac muscle to All, and assays which inhibit hypertensive responses to All in animal models are predictive of therapeutic utility.

Assays

In vitro assays for determining binding of the present compounds to angiotensin receptors AII-1 and AII-2 follow a method which is essentially that described by Gunther, J. Biol. Chem. 259:7622 (1984) and Whitebread et al., Biochem. Biophvs. Res. Comm. 163:284 (1989). This method employs

[¹²⁵I]-Sar¹ lle⁸ All in membrane preparations from rat liver (AII-1 binding sites) and bovine cerebellum (AII-2 binding sites). Binding affinity of a test compound to an All receptor site is considered predictive of in vivo potency as a receptor antagonist.

In vitro functional assays for determining antagonist activity of the present compounds at All receptors follow a method essentially as described previously by Chiu et al., J. Pharmacol. Exp. Ther. 252:711 (1990) and Kamikawa et al., Gastroenterology 88:706 (1985). Isolated rings segments of rabbit thoracic aorta and isolated guinea pig esophagus are used these assays. These tissues are exposed to All with and without test compounds, and a contractile response is evoked. Inhibition of contraction demonstrates All receptor antagonist activity of the test compound.

In order to evaluate the in vivo anti-hypertensive activity of the present compounds, male normotensive rats are subjected to complete left renal artery ligation

essentially as described by Wong et al., J. Pharmacol. Exp. Ther. 252:726-732 (1990), and a test compound is

administered. Lowering of blood pressure demonstrates in vivo hypotensive activity of the test compound. In

addition, 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

inhibition of the pressor response to All by the test compound. GENERAL ADMINISTRATION

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 of agents for serving similar utilities. Thus, 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

administration of precise dosages. 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.

Generally, depending on the intended mode of

administration, the pharmaceutically acceptable composition will contain about 0.1% to 90%, preferably about 0.5% to

50%, by weight of a pharmaceutically active compound of this invention, the remainder being suitable pharmaceutical excipients, carriers, etc. The preferred manner of administration for the

conditions detailed above is oral, using a convenient daily dosage regimen which can be adjusted according to the degree of affliction. For such oral administration, a

pharmaceutically acceptable, non-toxic 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. Such compositions take the form of solutions,

suspensions, tablets, pills, capsules, powders, sustained release formulations and the like.

Preferably the 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.

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

pharmaceutical adjuvants in a carrier, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol or the like.

If desired, 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.

For example, see Remington's Pharmaceutical Sciences. 18th edition. Mack Publishing Co., Easton Pa., A. Gennaro, ed., 1990.

The compounds of the present invention are administered in a therapeutically effective amount, which will vary on the condition being treated. Typically, 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. Thus, for an average human of 70 kg body weight, a therapeutic dose is about 210 mg. EXAMPLES

The following preparations and examples are given to enable those skilled in the art to more clearly understand and practice the present invention. They should not be considered as a limitation on the scope of the invention, but merely as being illustrative and representative of the preferred embodiments of the present invention.

PREPARATION 1

Ethyl 2-hydroxy-6-methylbenzoate

A. Formula (B).

Ethyl 6-methyl cyclohexene-2-one carboxylate (60 g, 0.33 mol), was dissolved in carbon tetrachloride (200 ml) and placed in a stirred solution under nitrogen and cooled in an ice bath. To this solution was added bromine (53 g, 0.33 mol) in acetic acid (200 ml) rapidly, dropwise. The mixture was heated under refluxing conditions overnight, venting the hydrogen bromide which evolved. Then, to this mixture, was added H₂O (400 ml) and methylene chloride (300 ml), and the organic phase was extracted and washed twice with dilute sodium carbonate. The extract was dried over magnesium sulfate. The solvent was removed and the residue was steam distilled to produce a crystalline solid, ethyl 2- hydroxy-6-methylbenzoate (25 g, 0.14 mol), having a melting point of 44°C.

PREPARATION 2

Ethyl 2-methoxy-6-methylbenzoate

A. Formula (C) where Y' = 2-methoxy. Potassium t-Butoxide (6.5 g, 0.0566 mol) was added in THF solution dropwise to ethyl 2-hydroxy-6-methyl-benzoate (.5 g, 0.047 mol), prepared, e.g., as described in

Preparation 1, in acetonitrile (100 ml) at 25° C. The mixture was stirred for 20 minutes, then iodomethane

(3.6 ml, 0.0566 mol) was added dropwise, and the mixture was stirred for 2 hours. It was then poured onto water and extracted with ether. The solvent was removed to afford an oil, ethyl 2-methoxy-6-methylbenzoate (9.0 g, 0.046 mol).

PREPARATION 3

Ethyl 2-methoxy-6-bromomethylbenzoate A. Formula (D) where Y' = 2-methoxy

Ethyl 2-methoxy-6-methylbenzoate (6.0 g, 0.03 mol), prepared e.g., as described in Preparation 2,

N-bromosuccinimide (6.6 g, 0.036 mol), and carbon

tetrachloride (100 ml) were combined and heated under reflux while exposing the mixture to a 200 watt bulb for 1.5 hours. Hexane (100 ml) was added, the mixture was filtered, and the filtrate was isolated as a solid, ethyl 2-methoxy-6- bromomethylbenzoate (10.0 g, 0.03 mol), having a melting point of 67°C.

B. Formula (D), varying Y'.

By following the procedure described in part A of this preparation and substituting ethyl 2-methoxy-6-methyl- benzoate with the following:

(1) ethyl 3-methoxy-6-methylbenzoate,

(2) ethyl 4-ethoxy-6-methylbenzoate,

(3) ethyl 5-fluoro-6-methylbenzoate,

(4) ethyl 5-iodo-6-methylbenzoate, and (5) ethyl 6-methylbenzoate; there were obtained the following respective compounds:

(1) ethyl 3-methoxy-6-bromomethylbenzoate,

(2) ethyl 4-ethoxy-6-bromomethylbenzoate,

(3) ethyl 5-fluoro-6-bromomethylbenzoate,

(4) ethyl 5-iodo-6-bromomethylbenzoate, and

(5) ethyl 6-bromomethylbenzoate.

PREPARATION 4

1-[1-[2-Ethoxycarbonyl-3-methoxy)benzyl]-1H-indane-1- carboxylic acid

A. Formula (F) where Y' = 3-methoxy and R¹ = 1H-indane.

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

extracted with dilute (2%) cold sodium hydroxide solution. The extract was acidified and extracted twice with ethyl acetate, washed with brine (saturated saline solution), and dried over magnesium sulfate. The solvent was removed to yield a red oil, which was further purified using silica gel chromatography, to produce 1-[1-(2-ethoxycarbonyl-3- methoxy)benzyl]-1H-indane-1-carboxylic acid (2.4 g,

0.0068 mol).

B. Formula (F), varying Y' and R¹.

By following the procedure described in part A of this preparation and substituting 1H-indane-1-carboxylic acid and/or ethyl 2-methoxy-6-bromomethyl-benzoate with the following:

(1) cyclopentylcarboxylic acid and ethyl 3-methoxy-6- bromomethylbenzoate,

(2) cyclobutylcarboxylic acid and ethyl 4-ethoxy-6- bromomethylbenzoate,

(3) cyclopentylcarboxylic acid and ethyl 5-fluoro-6- bromomethylbenzoate,

(4) cyclopropylcarboxylic acid and ethyl 5-iodo-6- bromomethylbenzoate,

(5) ethyl 6-bromomethyl benzoate,

(6) cyclobutylcarboxylic acid and ethyl 6-bromomethyl- benzoate, and

(7) cyclopentylcarboxylic acid and ethyl 2-methoxy-6- bromomethylbenzoate; there were obtained the following respective compounds:

(1) 1-[1-(2-ethoxycarbonyl-4-methoxy)benzyl]cyclopentyl-1- carboxylic acid,

(2) 1-[1-(2-ethoxycarbonyl-5-ethoxy)benzyl]cyclobutyl-1- carboxylic acid,

(3) 1-[1-(2-ethoxycarbonyl-6-fluoro)benzyl]cyclopentyl-1- carboxylic acid,

(4) 1-[1-(2-ethoxycarbonyl-6-iodo)benzyl]cyclopropyl-1- carboxylic acid. (5) 1-[1-(2-ethoxycarbonyl)benzyl]-1H-indane-1-carboxylic acid,

(6) 1-[1-(2-ethoxycarbonyl)benzyl]cyclobutyl-1-carboxylic acid, and

(7) 1-[1-(2-ethoxycarbonyl-3-methoxy)benzyl]cyclopentyl-1- carboxylic acid.

PREPARATION 5

8'-Methoxy-1',4',2,3-tetrahydrospiro[1H-indane-1,3'-(2'H)- isoquinolin]-1'(2H)-one

A. Formula (G) where Y' = 8'-methoxy and R¹ = spiro-1H- indane.

A 250 ml round bottomed flask was charged with 1-[1-(2- ethoxycarbonyl-3-methoxy)benzyl]-1H-indane-1-carboxylic acid (2.3 g, 0.0065 mol), prepared, e.g. as described in

Preparation A , in acetone and cooled in an ice bath.

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.

Next, to the filtrate was added magnesium sulfate

(3-4 g) in toluene solution and the mixture was heated on a steam bath under nitrogen for two hours. The mixture was filtered and the solvent was extracted to afford a reddish oil. This reddish oil (the corresponding isocyanate of the carboxylic acid) was dissolved in toluene and benzyl alcohol was added. Sodium hydride (0.8 q, 0.0195 mol) was added cautiously and the reaction mixture was heated under reflux for two hours. The reaction mixture was poured into cold, dilute hydrochloric acid. The layers were separated and the organic layer, containing the benzyl alcohol was distilled out. The residue was further purified by silica gel

chromatography to yield a reddish oil, 8'-methoxy-1',4',2,3- tetrahydrospiro[1H-indane-1,3'-(2Η)-isoquinolin]-1'(2H)-one (1 g, 0.0036 mol), which crystallized on standing to a solid having a melting point of 146-149°C. B. Formula (G), varying Y' and R¹.

By following the procedure described in part A of this preparation and substituting 1-[1-(2-ethoxycarbonyl-3- methoxy)benzyl]-1H-indane-1-carboxylic acid with the

following:

(1) 1-[1-(2-ethoxycarbonyl-4-methoxy)benzyl]cyclopentyl-1- carboxylic acid,

(2) 1-[1-(2-ethoxycarbonyl-5-ethoxy)benzyl]cyclobutyl-1- carboxylic acid,

(3) 1-[1-(2-ethoxycarbonyl-6-fluoro)benzyl]cyclopentyl-1- carboxylic acid,

(4) 1-[1-(2-ethoxycarbonyl-6-iodo)benzyl]cyclopropyl-1- carboxylic acid,

(5) 1-[1-(2-ethoxycarbonyl)benzyl]-1H-indane-1-carboxylic acid,

(6) 1-[1-(2-ethoxycarbonyl)benzyl]cyclobutyl-1-carboxylic acid, and

(7) 1-[1-(2-ethoxycarbonyl-3-methoxy)benzyl]cyclopentyl-1- carboxylic acid; there were obtained the following respective compounds:

(1) 7'-methoxy-1',4',2,3-tetrahydrospiro[cyclopentyl-1,3'- (2'H)-isoquinolin]-1'(2H)-one, (2) 6'-ethoxy-1',4',2,3-tetrahydrospiro[cyclobutyl-1,3'- (2'H)-isoquinolin]-1'(2H)-one,

(3) 5'-fluoro-1',4',2,3-tetrahydrospiro[cyclopentyl-1,3'- (2'H)-isoquinolin]-1'(2H)-one,

(4) 5'-iodo-1',4',2,3-tetrahydrospiro[cyclopropyl-1,3'- (2'H )-isoquinolin]-1'(2H)-one,

(5) 1',4',2,3-tetrahydrospiro[1H-indane-1,3'-(2'H)- isoquinolin]-1'(2H)-one,

(6) 1',4',2,3-tetrahydrospiro[cyclobutyl-1,3'-(2Η)- isooquinolin]-1'(2H)-one, and

(7) 8'-methoxy-1',4', 2 ,3-tetrahydrospiro[cyclopentyl-1,3'- (2'H)-isoquinolin]-1'(2H)-one.

PREPARATION 6

8'-Methoxy-1',4',2,3-tetrahydrospiro[1H-indane-1,3' - (2'-{2"'- cyano}biphenyl-4"-ylmethyl)isoquinolin]-1'(2H)-one

A. Formula (H), where Y' = 8'-methoxy and R¹ = spiro-1H- indane.

Sodium hydride (0.09 g, 2.2 mol) was added under nitrogen to a cold stirring solution of 8'-methoxy- 1',4',2,3-tetrahydrospiro[1H-indane-1,3'-(2Η)-isoquinolin]- 1'(2H)-one (0.5 g, 1.8 mmol), prepared, e.g., as described in Preparation 5, in DMF. After stirring for one hour, 4- bromomethyl-2'-cyanobiphenyl (0.5 g, 1.8 mmol) in DMF was added and the mixture was stirred overnight, coming to room temperature. The mixture was poured into ice water

extracted with ethyl acetate three times, washed with cold water, dried over magnesium sulfate, and the solvent was removed to afford an oil. This oil was further purified by silica gel chromatography to produce 8'-methoxy-1',4',2,3- tetrahydrospiro[1H-indane-1,3'-(2'-{2"'-cyano}biphenyl-4"- ylmethyl)isoquinolin]-1'(2H)-one (0.6 g, 1.1 mmol) as an oil .

B. Formula (H), varying Y' and R¹. By following the procedure described in part A of this preparation and substituting 8'-methoxy-1',4',2,3- tetrahydrospiro[1H-indane-1,3'(2'-H)-isoquinolin]-1'(2H)-one with the following: (1) 7'-methoxy-1',4',2,3-tetrahydrospiro[cyclopentyl- 1,3'(2'-H)-isoquinolin]-1'(2H)-one,

(2) 6'-ethoxy-1',4',2,3-tetrahydrospiro[cyclobutyl-1,3'(2'- H)-isoquinolin]-1'(2H)-one,

(3) 5'-fluoro-1',4',2,3-tetrahydrospiro[cyclopentyl-1,3'(2'- H)-isoquinolin]-1'(2H)-one,

(4) 5'-iodo-1',4',2,3-tetrahydrospiro[cyclopropyl-1,3'(2'- H)-isoguinolin]-1'(2H)-one,

(5) 1',4',2,3-tetrahydrospiro[1H-indane-1,3'(2'-H)- isoquinolin]-1'(2H)-one,

(6) 1',4',2,3-tetrahydrospiro[cyclobutyl-1,3'(2'-H)- isooquinolin]-1'(2H)-one, and

(7) 8'-methoxy-1',4',2,3-tetrahydrospiro[cyclopentyl- 1,3'(2'-H)-isoquinolin]-1'(2H)-one; there were obtained the following respective compounds:

(1) 7'-methoxy-1',4',2,3-tetrahydrospiro[cyclopentyl- 1,3'(2'-{2"'-cyano}biphenyl-4"-yImethyl)-isoquinolin]-1'(2H)- one,

(2) 6'-ethoxy-1',4',2,3-tetrahydrospiro[cyclobutyl-1,3'(2'- {2"'-cyano}biphenyl-4"-yImethyl)-isoquinolin]-1'(2H)-one,

(3) 5'-fluoro-1',4',2,3-tetrahydrospiro[cyclopentyl-1,3'(2'- {2"'-cyano}biphenyl-4"-yImethyl)-isoquinolin]-1'(2H)-one,

(4) 5'-iodo-1',4',2,3-tetrahydrospiro[cyclopropyl-1,3'(2'- {2"'-cyano}biphenyl-4"-yImethyl)-isoquinolin]-1'(2H)-one,

(5) 1',4',2,3-tetrahydrospiro[1H-indane-1,3'(2'-{2"'- cyano}biphenyl-4"-ylmethyl)-isoquinolin]-1'(2H)-one,

(6) 1',4',2,3-tetrahydrospiro[cyclobutyl-1,3'(2'-{2'"- cyano}biphenyl-4"-ylmethyl)-isoquinolin]-1'(2H)-one, and

(7) 8'-methoxy-1',4',2,3-tetrahydrospiro[cyclopentyl-

1,3'(2'-{2"'-cyano}biphenyl-4"-yImethyl)-isoquinolin]-1'(2H)- one.

PREPARATION 7

8'-Hydroxy-1',4',2,3-tetrahydrospiro[1H-indane-1,3'(2'-{2'"- cyano}biphenyl-4"-yImethyl)-isoquinolin]-1'(2H)-one A. Formula (J) where Y = 8' hydroxy and R¹ = spiro-1H- indane.

Boron tribromide (5 ml, 5.0 mmol) was added to a solution of 8'-methoxy-1',4',2,3-tetrahydrospiro[1H-indane- 1,3'(2'-{2"'-cyano}biphenyl-4"-ylmethyl)isoquinolin]-1'(2H)- one (0.55 g, 1.0 mmol) prepared, e.g. as described in

Preparation 6, under argon at -70°. The reaction mixture was allowed to reach room temperature and stirred for 1.5 hours. It was poured onto an ice-sodium bicarbonate

solution and extracted twice with methylene chloride, washed with water and dried over sodium sulfate. The solvent was extracted to yield an oil, 8'-hydroxy-1',4',2,3- tetrahydrospiro[1H-indane-1,3'(2'-{2"'-cyano}biphenyl-4"- ylmethylisoquinolin]-1'(2H)-one (0.4 g, 0.75 mol). B. Formula (J), varying Y' and R¹.

By following the procedure described in part A of this preparation and substituting 8'-methoxy-1',4',2,3- tetrahydrospiro[1H-indane-1,3'(2'-{2"'-cyano}biphenyl-4"- ylmethyl)isoquinolin]-1'(2H)-one with the following: 7'-methoxy-1',4',2,3-tetrahydrospiro[cyclopentyl-1,3'(2'- {2"'-cyano}biphenyl-4"-ylmethyl)isoquinolin]-1'(2H)-one, there was obtained the following compound:

7'-hydroxy-1',4', 2 ,3-tetrahydrospiro[cyclopentyl-1,3'(2' {2"'-cyano}biphenyl-4"-ylmethyl)isoquinolin]-1'(2H)-one.

PREPARATION 8

N-Allyl-2-methylbenzamide

A. Formula (L) where Y = H and X = H.

A cold (0°C) solution of o-toluoyl chloride (61.8 g, 0.4 mol) in CH₂Cl₂ (500 ml) was added to a mixture of triethylamine (61.8 ml, 0.44 mol) and allylamine (33.0 ml, 0.44 mol) at such a rate that the reaction temperature did not exceed 5°C. After addition was complete, the reaction mixture was allowed to warm to ambient temperature and shaken with 1M HCl (400 ml). The organic layer was

separated, dried with Na₂SO₄, filtered, and the solvent removed in vacuo to give a solid. This solid was triturated with pentane, taken up in ether, and crystallized from the ethereal solution to yield N-allyl-2-methylbenzamide (76.5 g, 437 mmol), having a melting point of 121-124°C.

B. Formula (L), varying Y and X.

By following the procedure described in part A of this preparation and substituting o-toluoyl chloride with the following:

(1) 2-methyl-3-methoxy-benzoyl chloride,

(2) 2-methyl-4-methoxy-benzoyl chloride,

(3) 2-chlorocarbonylphenylethanoic acid, (4) 2-methyl-4-fluoro-benzoyl chloride,

(5) 2-(3,3-dimethylpropyl)-3-methoxy-benzoyl chloride,

(6) 2-chlorocarbonyl-4-chloro-phenylpentanoic acid,

(7) methyl 2-chlorocarbonyl-5-methoxyphenyl propionate,

(8) 2-n-propyl-3-hydroxy-benzoyl chloride,

(9) methyl 2-chlorocarbonyl-4-methoxy-benzoate, and

(10) 2-chlorocarbonyl-5-bromo-phenylpropanoic acid; there are obtained the following respective compounds:

(1) N-allyl-2-methyl-3-methoxybenzamide,

(2) N-allyl-2-methyl-4-methoxybenzamide,

(3) 2-(N-allyl-carboxamido)phenylethanoic acid,

(4) N-allyl-2-methyl-4-fluorobenzamide,

(5) N-allyl-2- (3 , 3-dimethylpropyl) -3-methoxybenzamide,

(6) 2-(N-allyl-carboxamido)-4-chloro-phenylpentanoic acid,

(7) methyl 2-(N-allyl-propionamido)-5-methoxybenzoate,

(8) N-allyl-2-n-propyl-3-hydroxybenzamide,

(9) methyl 2-(N-allyl-carboxamido)-4-methoxybenzoate, and (10) 2-(N-allyl-carboxamido)-5-bromo-phenylpropanoic acid.

PREPARATION 9

N-(Prop-1-enyl)-2-methylbenzamide

A. Formula (M) where Y and X = H.

To a solution of diisopropylamine (3.2 ml, 22.6 mmol) in THF (100 ml) maintained at -20°C was added 2.5 M n-BuLi (9.0 ml, 22.6 mmol) in hexanes. This mixture was cooled to -70°C and a solution of N-allyl-2-methylbenzamide (1.79 g

10.3 mmol), prepared, e.g. as described in Preparation 8, in THF (25 ml) was added dropwise. The dark red solution was stirred at this temperature for 10 minutes and then allowed to warm to 0°C, whereupon the color largely disappeared. The mixture was treated with an excess of saturated aqueous NH₄Cl, diluted with ether, shaken, and the organic layer was separated and dried with Na₂SO₄. Filtration and

concentration in vacuo gave 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.

B. Formula (M), varying Y and X.

By following the procedure described in part A of this preparation and substituting N-allyl-2-methylbenzamide with the following:

(1) N-allyl-2-methyl-3-methoxybenzamide,

(2) N-allyl-2-methyl-4-methoxybenzamide,

(3) 2-(N-allyl-carboxamido)phenylethanoic acid,

(4) N-allyl-2-methyl-4-fluorobenzamide,

(5) N-allyl-2-(3,3-dimethylpropyl)-3-methoxybenzamide,

(6) 2-(N-allyl-carboxamido)-4-chloro-phenylpentanoic acid, and

(7) methyl 2-(N-allyl-propionamido)-5-methoxybenzoate; there were obtained the following respective compounds: (1) N-(prop-1-enyl)-2-methyl-3-methoxybenzamide, having a melting point of 127-129°C,

(2) N-(prop-1-enyl)-2-methyl-4-methoxybenzamide, having a melting point of 117-120°C,

(3) N-(prop-1-enyl)carboxamidophenylethanoic acid, having a melting point of 141-145°C,

(4) N-(prop-1-enyl)-2-methyl-4-fluorobenzamide, having a melting point of 171-173°C,

(5) N-(prop-1-enyl)-2-(3,3-dimethylpropyl)-3-methoxy- benzamide. (6) N-(prop-1-enyl)-benzamido-4-chloro-2-n-butylcarboxylic acid, and

(7) methyl N-(prop-1-enyl)-benzamido-5-methoxy-2-propionate.

PREPARATION 10

2-(Prop-1-enyl)-3-n-butyl-isoquinolin-1(2H)-one

A. Formula (N) where Y = H, R¹ = 3-n-butyl, and X = H.

A solution of 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. The color disappeared immediately and the reaction was quenched at 0°C with 50% aqueous acetic acid (25 ml). The suspension was heated under reflux for 20 minutes. The mixture was cooled to room temperature, diluted with ether, shaken, and the organic layer was separated and dried with MgSO₄.

Filtration and concentration in vacuo gave a solid which was purified by flash chromatography on silica gel (hexane-ethyl acetate 3:1) to yield 2-(prop-1-enyl)-3-n-butyl-isoquinolin- 1(2H)-one (1.3 g, 5.4 mmol), having a melting point of 112- 114°C.

B. Formula (N), varying Y and R¹ and X.

By following the procedure described in part A of this preparation and substituting 2-(prop-1-enyl)-2- methylbenzamide and/or N-methyl-N-methoxyvaleramide with the following: (I) N- (prop-1-enyl) -2-methyl-3-methoxybenzamide,

(2) N- (prop-1-enyl) -2-methyl-4-methoxybenzamide,

(3) N-(prop-1-enyl)carboxamidophenylethanoic acid and

N-methyl-N-methoxy(n-penten-2-ylamide),

(4) N-(prop-1-enyl)-2-methyl-4-methoxybenzamide and

N-methyl-N-methoxy(n-hexylamide),

(5) N-(prop-1-enyl)-2-methyl-4-methoxybenzamide and

N-methyl-N-methoxy(cyclohexylformamide),

(6) N-(prop-1-enyl)carboxamidophenylethanoic acid and

N-methyl-N-methoxy(n-penten-1-ylamide),

(7) N-(prop-1-enyl)-2-methyl-4-fluorobenzamide,

(8) N-methyl-N-methoxy(n-propionamide),

(9) N-methyl-N-methoxy-(2,2-dimethyl)acetamide,

(10) N-(prop-1-enyl)-2-(3,3-dimethylpropyl)-3-methoxy- benzamide,

(II) N-(prop-1-enyl)-benzamido-4-chloro-2-n-butylcarboxylic acid and N-methyl-N-methoxy(cyclopentylformamide),

(12) methyl N-(prop-1-enyl) benzamido-5-methoxy-2-propionate and N-methyl-N-methoxy(n-hex-3-ylamide); there were obtained the following respective compounds:

(1) 2-(prop-1-enyl)-3-n-butyl-5-methoxyisoquinolin-1(2H)- one, having a melting point of 104-107°C,

(2) 2-(prop-1-enyl)-3-n-butyl-6-methoxyisoquinolin-1(2H)- one, having a melting point of 119-121°C,

(3) 2-(prop-1-enyl)-3-(n-buten-1-yl)isoquinolin-1(2H)-one-4- carboxylic acid, having a melting point of 119-123°C,

(4) 2-(prop-1-enyl)-6-methoxy-3-n-pentylisoquinolin-1(2H)- one, having a melting point of 115-117°C,

(5) 2-(prop-1-enyl)-6-methoxy-3-cyclohexylisoquinolin-1(2H)- one, having a melting point of 110-113°C,

(6) 2-(prop-1-enyl)-3-n-butylidineisoquinolin-1(2,4H)-one-4- carboxylic acid, having a melting point of 147-149°C, (7) 2-(prop-1-enyl)-3-n-butyl-6-fluoroisoquinolin-1(2H)-one, having a melting point of 131-132°C,

(8) 2-(prop-1-enyl)-3-ethylisoquinolin-1(2H)-one, having a melting point of 129-133°C,

(9) 2-(prop-1-enyl)-3-isopropylisoquinolin-1(2H)-one, having a melting point of 124-125°C,

(10) 2-(prop-1-enyl)-4-t-butyl-5-methoxyisoquinolin-1(2H)- one,

(11) 2-(prop-1-enyl)-6-chloro-3-cyclopentylisoquinolin- 1(2H)-one-4-butanoic acid, and

(12) methyl 2-(prop-1-enyl)-7-methoxy-3-(n-penten-2-yl)- isoquinolin-1(2H)-one-4-methylcarboxylate.

PREPARATION 11

3-n-Butyl-isoguinolin-1(2H)-one

A. Formula (O) where Y = H, R¹ = 3-n-butyl, and X = H.

A solution of 2-(prop-1-enyl)-3-n-butyl-isoquinolin- 1(2H)-one (0.45 g, 1.7 mmol), prepared, e.g., as described in Preparation 10, in 1:1 v/v dioxane and 6M HCl (25 ml) was heated under reflux for 6 hours. The mixture was cooled to room temperature, diluted with ether, shaken, and the organic layer was separated and dried with Na₂SO₄.

Filtration and concentration in vacuo gave a solid which was purified by flash chromatography on silica gel (hexane-ethyl acetate 3:1) to yield 3-n-butylisoquinolin-1(2H)-one

(0.40 g, 2.0 mmol) having a melting point of 140-141°C.

B. Formula (O), varying Y and R¹ and X.

By following the procedure described in part A of this preparation and substituting 2-(prop-1-enyl)-3-n- butylisoquinolin-1(2H)-one with the following:

(1) 2-(prop-1-enyl)-3-n-butyl-5-methoxyisoquinolin-1(2H)- one,

(2) 2-(prop-1-enyl)-3-n-butyl-6-methoxyisoquinolin-1(2H)- one,

(3) 2-(prop-1-enyl)-3-(n-buten-1-yl)isoquinolin-1(2H)-one-4- carboxylic acid,

(4) 2-(prop-1-enyl)-6-methoxy-3-n-pentylisoquinolin-1(2H)- one,

(5) 2-(prop-1-enyl)-6-methoxy-3-cyclohexylisoquinolin-1(2H)- one,

(6) 2-(prop-1-enyl)-3-n-butylidineisoquinolin-1(2,4H)-one-4- carboxylic acid,

(7) 2-(prop-1-enyl)-3-n-butyl-6-fluoroisoquinolin-1(2H)-one,

(8) 2-(prop-1-enyl)-3-ethylisoquinolin-1(2H)-one,

(9) 2-(prop-1-enyl)-3-isopropylisoquinolin-1(2H)-one,

(10) 2-(prop-1-enyl)-4-t-butyl-5-methoxyisoquinolin-1(2H)- one,

(11) 2-(prop-1-enyl)-6-chloro-3-cyclopentylisoquinolin- 1(2H)-one-4-butanoic acid, and

(12) methyl 2-(prop-1-enyl)-7-methoxy-3-(n-penten-2-yl)- isoquinolin-1(2H)-one-4-methylcarboxylate; there were obtained the following respective compounds:

(1) 3-n-butyl-5-methoxyisoquinolin-1(2H)-one, having a melting point of 119-121°C,

(2) 3-n-butyl-6-methoxyisoquinolin-1(2H)-one, having a melting point of 143-145°C,

(3) 3-(n-buten-1-yl)-isoquinolin-1(2H)-one-4-carboxylic acid,

(4) 6-methoxy-3-n-pentylisoquinolin-1(2H)-one, having a melting point of 127-129°C,

(5) 6-methoxy-3-cyclohexylisoquinolin-1(2H)-one, having a melting point of 114-117°C,

(6) 3-n-butylidineisoquinolin-1(2,4H)-one-4-carboxylic acid, having a melting point of 123-127°C,

(7) 3-n-butyl-6-fluoroisoquinolin-1(2H)-one, having a melting point of 125-127°C,

(8) 3-ethylisoquinolin-1(2H)-one, having a melting point of 104-107°C,

(9) 3-isopropylisoquinolin-1(2H) -one, having a melting point of 100-103°C,

(10) 4-t-butyl-5-methoxyisoquinolin-1(2H)-one,

(11) 6-chloro-3-cyclopentylisoquinolin-1(2H)-one-4-butanoic acid, and

(12) methyl 7-methoxy-3-(n-penten-2-yl)-isoquinolin-1(2H)- one-4-methylcarboxylate.

PREPARATION 12

3-n-Butyl-2-[(2"-cyano)biphenyl-4'-ylmethyl]-isoguinolin-

1(2H)-one

A. Formula (P) where Y = H, X = H, and R¹ = 3-n-butyl.

To a solution of 3-n-butylisoquinolin-1(2H)-one (1.3 g, 6.9 mmol), prepared, e.g., as described in Preparation 11, in DMF (25 ml) was added 60% NaH dispersion in oil (605.3 mg, 15.1 mmol). The mixture was warmed to room temperature, recooled to 0°C and 4-bromomethyl-2'-cyanobiphenyl (2.06 g, 7.6 mmol) was added. Stirring was continued for 14 hours at room temperature, and the mixture was poured onto ice, diluted with 1M HCl and shaken with ether (150 ml X 3). The solution was dried with magnesium sulfate, filtered, and the residue was chromatographed on silica gel with 3:1

hexane:ethyl acetate to yield 3-n-butyl-2-[(2"- cyano)biphenyl-4'-ylmethyl]-isoquinolin-1(2H)-one (2 g, 5.1 mmol), having a melting point of 192-194°C.

B. Formula (P), varying Y and X and R^1.

By following the procedure described in part A of this preparation and substituting 3-n-butylisoquinolin-1(2H)-one with the following:

(1) 3-n-butyl-5-methoxyisoquinolin-1(2H)-one,

(2) 3-n-butyl-6-methoxyisoquinolin-1(2H)-one,

(3) 3-(n-buten-1-yl)-isoquinolin-1(2H)-one-4-carboxylic acid,

(4) 6-methoxy-3-n-pentylisoquinolin-1(2H)-one,

(5) 6-methoxy-3-cyclohexylisoquinolin-1(2H)-one,

(6) 3-n-butylidineisoquinolin-1(2,4H)-one-4-carboxylic acid,

(7) 3-n-butyl-6-fluoroisoquinolin-1(2H)-one,

(8) 3-ethylisoquinolin-1(2H)-one,

(9) 3-isopropylisoquinolin-1(2H)-one,

(10) 4-t-butyl-5-methoxyisoquinolin-1(2H)-one,

(11) 6-chloro-3-cyclopentylisoquinolin-1(2H)-one-4-butanoic acid, and

(12) methyl 7-methoxy-3-(n-penten-2-yl)-isoquinolin-1(2H)- one-4-methylcarboxylate; there were obtained the following respective compounds:

(1) 3-n-butyl-5-methoxy-2-[(2"-cyano)biphenyl-4'-ylmethyl]- isoquinolin-1(2H)-one, having a melting point of 165-167°C,

(2) 3-n-butyl-6-methoxy-2-[(2"-cyano)biphenyl-4'-ylmethyl]- isoquinolin-1(2H)-one, having a melting point of 163-165°C,

(3) 3-(n-buten-1-yl)-2-[(2"-cyano)biphenyl-4'-ylmethyl]- isoquinolin-1(2H)-one-4-carboxylic acid, having a melting point of 82-86°C,

(4) 6-methoxy-3-n-pentyl-2-[(2"-cyano)biphenyl-4'-ylmethyl]- isoquinolin-1(2H)-one, having a melting point of 151-153°C, (5) 6-methoxy-3-cyclohexyl-2-[(2"-cyano)biphenyl-4'- ylmethyl]-isoquinolin-1(2H)-one, having a melting point of 159-162°C,

(6) 3-n-butylidine-2-[(2"-cyano)biphenyl-4'-ylmethyl]- isoquinolin-1(2,4H)-one-4-carboxylic acid, having a melting point of 109-110°C,

(7) 3-n-butyl-6-fluoro-2-[(2"-cyano)biphenyl-4'-ylmethyl]- isoquinolin-1(2H)-one, having a melting point of 117-120°C, (8) 3-ethyl-2-[(2"-cyano)biphenyl-4'-ylmethyl]-isoquinolin- 1(2H)-one, having a melting point of 114-116°C,

(9) 3-isopropyl-2-[(2"-cyano)biphenyl-4'-ylmethyl]- isoquinolin-1(2H)-one, having a melting point of 171-174°C,

(10) 4-t-butyl-5-methoxy-2-[(2"-cyano)biphenyl-4'-ylmethyl]- isoquinolin-1(2H)-one,

(11) 6-chloro-3-cyclopentyl-2-[(2"-cyano)biphenyl-4'- ylmethyl]-isoquinolin-1(2H)-one-4-butanoic acid, and

(12) methyl 7-methoxy-3-(n-penten-2-yl)-2-[(2"- cyano)biphenyl-4'-ylmethyl]-isoquinolin-1(2H)-one-4- methylcarboxylate.

PREPARATION 13

2-(Prop-1-enyl)-3-(4'-bromophenylmethyl)isoquinolin- 1(2H)-one

A. Formula (R) where Y = H and X = H.

To a solution of N-allyl-2-methylbenzamide (5.7 g, 32.6 mmol), prepared, e.g, as described in Preparation 8, in 100 ml THF at -70°C, was added sec-BuLi (55.1 ml, 71.7 mmol,

1.3M solution in cyclohexanes). To this solution was added N-methyl-N-methoxy-4-bromophenylacetamide (8.4 g, 32.6 mmol) in THF (30 ml). The reaction mixture was allowed to warm to 0°C and treated with glacial acetic acid (30 ml) and H₂O (30 ml). This mixture was heated to 70°C for 1 hour, cooled, and extracted (3X) with ether. The organic layers were combined and dried with magnesium sulfate. Filtration, concentration in vacuo and crystallization in hexane / ethylacetate gave 2-(prop-1-enyl)-3-(4'- bromophenylmethyl)isoquinolin-1(2H)-one (9.3 g, 26.3 mmol), as yellow crystals, having a melting point of 165-169°C.

B. Formula (R), varying Y and X.

By following the procedure described in part A of this preparation and substituting N-allyl-2-methylbenzamide with the following:

(1) 2-(N-allylcarboxamido)-phenylethanoic acid,

(2) N-allyl-2-n-propyl-3-hydroxybenzamide,

(3) methyl 2-(N-allylcarboxamido)-4-methoxy-benzoate, and

(4) 2-(N-allylcarboxamido)-5-bromo-phenylpropanoic acid; there were obtained the following respective compounds:

(1) 2-(prop-1-enyl)-3-(4'-bromophenylmethyl)-isoquinolin- 1(2H)-one-4-carboxylic acid,

(2) 2-(prop-1-enyl)-4-ethyl-5-hydroxy-3-(4'- bromophenylmethyl)-isoquinolin-1(2H)-one,

(3) methyl 2-(prop-1-enyl)-6-methoxy-3-(4'- bromophenylmethyl)-isoquinolin-1(2H)-one-4-carboxylate; and (4) 2-(prop-1-enyl)-7-bromo-3-(4'-bromophenylmethyl)- isoquinolin-1 (2H) -one-4-ethylcarboxylic acid.

PREPARATION 14

3- (A'-Bromophenylmethyl)isoquinolin-1(2H)-one

A. Formula (S) where Y = H and X = H. To a solution of dioxane (50 ml) and concentrated HCl (10 ml) was added 2-(prop-1-enyl)-3-(4'-bromophenylmethyl) isoquinolin-1(2H)-one (4.1 g, 11.6 mmol), prepared, e.g., as described in Preparation 13. The solution was heated under reflux for 24 hours, cooled to room temperature and poured onto ice. Extraction with ethyl acetate (100 ml X 3) gave 3-(4'-bromophenylmethyl)isoquinolin-1(2H)-one as a tan solid. Recrystallization from ethyl acetate gave the 3-(4'- bromophenyImethyl)isoquinolin-1(2H)-one as a white solid (3.1 g, 9.9 mmol), M.P. 197-201°C.

B. Formula (S), varying Y and X.

By following the procedure described in part A of this preparation and substituting 2-(prop-1-enyl)-3-(4'- bromophenyImethyl)isoquinolin-1(2H)-one with the following:

(1) 2-(prop-1-enyl)-3-(4'-bromophenylmethyl)-isoquinolin- 1(2H)-one-4-carboxylic acid,

(2) 2-(prop-1-enyl)-4-ethyl-5-hydroxy-3-(4'- bromophenylmethyl)-isoquinolin-1(2H)-one,

(3) methyl 2-(prop-1-enyl)-6-methoxy-3-(4'- bromophenylmethyl)-isoquinolin-1(2H)-one-4-carboxylate; and

(4) 2-(prop-1-enyl)-7-bromo-3-(4'-bromophenylmethyl)- isoquinolin-1(2H)-one-4-ethylcarboxylic acid; there were obtained the following respective compounds:

(1) 3-(4'-bromophenylmethyl)-isoquinolin-1(2H)-one-4- carboxylic acid,

(2) 4-ethyl-5-hydroxy-3-(4'-bromophenylmethyl)-isoquinolin- 1(2H)-one,

(3) methyl 6-methoxy-3-(4'-bromophenylmethyl)-isoquinolin- 1(2H)-one-4-carboxylate; and (4) 7-bromo-3-(4'-bromophenylmethyl)-isoquinolin-1(2H)-one- 4-ethylcarboxylic acid.

PREPARATION 15

2-n-Propyl-3-(4'-bromophenylmethyl)-isoquinolin-1(2H)-one

A. Formula (T) where Y = H, X = H, and R¹ = n-propyl.

3-(4'-Bromophenylmethyl)-isoquinolin-1(2H)-one (1.7 g, 5.4 mmol), prepared, e.g, as described in Preparation 14, was treated at 0°C in DMF (40 ml) with NaH (476 mg of 60% dispersion in mineral oil) and allowed to warm to room temperature. To this mixture at room temperature was added 1-iodopropane (816 mg, 4.8 mmol). The mixture was poured onto ice after 26 hours at room temperature. Extraction with ether and purification with silica gel gave 2-n-propyl- 3-(4'-bromophenylmethyl)-isoquinolin-1(2H)-one (1.2 g, 3.2 mmol) as a foam. B. Formula (T), varying Y and X and R¹.

By following the procedure described in part A of this preparation and substituting 3-(4'-bromophenylmethyl)- isoquinolin-1(2H)-one and/or 1-iodopropane with the

following:

(1) 3-(4'-bromophenylmethyl)-isoquinolin-1(2H)-one-4- carboxylic acid and 1-iodobutane,

(2) methyl 6-methoxy-3-(4'-bromophenylmethyl)-isoquinolin- 1(2H)-one-4-carboxylate and 1-iodoprop-2-ene

(3) 7-bromo-3-(4'-bromophenylmethyl)-isoquinolin-1(2H)-one- 4-ethylcarboxylic acid and iodocyclobutane; there were obtained the following respective compounds:

(1) 2-n-butyl-3-(4'-bromophenylmethyl)-isoquinolin-1(2H)- one-4-carboxylic acid,

(2) methyl 6-methoxy-2-(prop-2-enyl)-3-(4'- bromophenylmethyl)-isoquinolin-1(2H)-one-4-carboxylate; and

(3) 7-bromo-2-cyclobutyl-3-(4'-bromophenylmethyl)- isoquinolin-1(2H)-one-4-ethylcarboxylic acid.

PREPARATION 16

2-n-propyl-3-[(2"-cyano)biphenyl-4'-ylmethyl]- isoquinolin-1(2H)-one A. Formula (U) where Y = H, X = H, and R¹ = n-propyl.

To a cold (-70°C) stirring solution of 2-n-propyl-3- (4'-bromophenylmethyl)-isoquinolin-1(2H)-one (1.9 g, 0.029 mol), prepared, e.g., as described in Preparation 15, in THF (150 ml) was added dropwise n-butyllithium (18 ml, 2.5 M, 0.044 mol), and stirring was continued for 15 minutes.

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.

The resultant oil was dissolved in toluene (200 ml), ethanol (40 ml) and 2M sodium carbonate (40 ml) and added to 2-bromobenzylnitrile (5.8 g, 0.32 mol) and

tetrakis[triphenylphosphine] palladium (0.6 g) and heated under reflux with vigorous stirring for 24 hours. The reaction mixture was then poured into water, and the layers were separated. The organic layer was dried over magnesium sulphate, and the solvent was removed to afford an oil, which was further purified by silica gel chromatography to yield 2-n-propyl-3-[(2"-cyano)biphenyl-4'-ylmethyl]- isoquinolin-1(2H)-one (1.95 g, 5 mol), having a melting point of 210-204°C.

B. Formula (U), varying Y and X and R¹.

By following the procedure described in part A of this preparation and substituting 2-n-propyl-3-(4'- bromophenylmethyl)-isoquinolin-1(2H)-one with the following:

(1) 2-n-butyl-3-(4'-bromophenylmethyl)-isoquinolin-1(2H)- one-4-carboxylic acid,

(2) 4-ethyl-5-hydroxy-3-(4'-bromophenylmethyl)-isoquinolin- 1(2H)-one,

(3) methyl 6-methoxy-2-(prop-2-enyl)-3-(4'- bromophenylmethyl)-isoquinolin-1(2H)-one-4-carboxylate, and

(4) 7-bromo-2-cyclobutyl-3-(4'-bromophenylmethyl)- isoquinolin-1(2H)-one-4-ethylcarboxylic acid; there were obtained the following respective compounds:

(1) 2-n-butyl-3-[(2"-cyano)biphenyl-4'-ylmethyl]- isoquinolin-1(2H)-one-4-carboxylic acid, having a melting point of 109-110°C,

(2) 4-ethyl-5-hydroxy-3-[(2"-cyano)bipheny1-4'-ylmethyl]- isoquinolin-1(2H)-one,

(3) methyl 6-methoxy-2-(prop-2-enyl)-3-[(2"-cyano)biphenyl- 4'-ylmethyl]-isoquinolin-1(2H)-one-4-carboxylate, and

(4) 7-bromo-2-cyclobutyl-3-[(2"-cyano)biphenyl-4'-ylmethyl]- isoquinolin-1(2H)-one-4-ethylcarboxylic acid. EXAMPLE 1

8'-Hydroxy-1',4',2,3-tetrahydrospiro[1H-indane-1,3'(2'-{2"'- 1H-tetrazol-5-yl}biphenyl-4"-ylmethyl)-isoquinolin]-1'(2H)- one

A. Formula (I) where Y = 8'-hydroxy, X = H, and R¹ = spiro indane.

8'-Hydroxy-1', 4',2,3-tetrahydrospiro[1H-indane-1,3'(2'- {2"'-cyano}biphenyl-4"-yImethyl)-isoquinolin]-1'(2H)-one (400 mg, 0.75 mmol), prepared, e.g. as described in Preparation 7, tributyl tin azide (500 mg, 1.5 mmol) and xylene (10 ml) were combined and heated under reflux for 2 days. The mixture was cooled and a solution of ethereal HCl (5 ml) was added to the solution, which was then stirred overnight. Hexane was added to the solution to precipitate the product, which was filtered and washed with hexane. The product was dissolved in potassium hydroxide, washed twice with ether, reacidified, extracted with ethyl acetate and dried with sodium sulphate. After filtering away the drying agent, the solvent was removed and the product was crystallized with hexane to yield 8'-hydroxy-1',4', 2 ,3-tetrahydrospiro[1H- indane-1,3'(2'-{2"'-1H-tetrazol-5-yl}biphenyl-4"-yImethyl)- isoquinolin]-1'(2H)-one (82 mg, 0.16 mmol), having a melting point of 135-140°C. B. Formula (I), varying R¹ and Y.

By following the procedure described in part A of this example and substituting 8'-hydroxy-1',4',2,3- tetrahydrospiro[1H-indane-1,3'(2'-{2"'-cyano}biphenyl-4"- yImethyl)-isoquinolin]-1'(2H)-one with the following:

(1) 7'-hydroxy-1', 4', 2 ,3-tetrahydrospiro[cyclopentyl-

1,3'(2'-{2"'-cyano}biphenyl-4"-yImethyl)-isoquinolin]-1'(2H)- one,

(2) 6'-ethoxy-1',4',2,3-tetrahydrospiro[cyclobutyl-1,3'(2'- {2"'cyano}biphenyl-4"-yImethyl)-isoquinolin]-1'(2H)-one,

(3) 5'-fluoro-1',4',2,3-tetrahydrospiro[cyclopentyl-1,3'(2'- {2"'-cyano}biphenyl-4"-ylmethyl)-isoquinolin]-1'(2H)-one,

(4) 5'-iodo-1',4',2,3-tetrahydrospiro[cyclopropyl-1,3'(2'- {2"-cyano}bipheny1-4"-yImethyl)-isoquinolin]-1'(2H)-one,

(5) 1',4',2,3-tetrahydrospiro[1H-indane-1,3'(2'-

{2"'cyano}biphenyl-4"-yImethyl)-isoquinolin]-1'(2H)-one,

(6) 1',4',2,3-tetrahydrospiro[cyclobutyl-1,3'(2'-{2'"- cyano}biphenyl-4"-ylmethyl)-isoquinolin]-1'(2H)-one,

(7) 8'-methoxy-1',4',2,3-tetrahydrospiro[cyclopentyl-

1,3'(2'-{2"'-cyano}biphenyl-4"-yImethyl)-isoquinolin]-1'(2H)- one; and

(8) 8'-methoxy-1',4',2,3-tetrahydrospiro[1H-indane-1,3'(2'- {2"'-cyano}biphenyl-4"-ylmethyl)-isoquinolin]-1'(2H)-one; there were obtained the following respective compounds:

(1) 7'-hydroxy-1',4',2,3-tetrahydrospiro[cyclopentyl- 1,3'(2'-{2"'-1H-tetrazol-5-yl}biphenyl-4"-yImethyl)- isoquinolin]-1'(2H)-one,

(2) 6'-ethoxy-1',4',2,3-tetrahydrospiro[cyclobutyl-1,3'(2'- {2"'-1H-tetrazol-5-yl}biphenyl-4"-ylmethyl)-isoquinolin]-

1'(2H)-one,

(3) 5'-fluoro-1',4',2,3-tetrahydrospiro[cyclopentyl-1,3'(2'- {2"'-1H-tetrazol-5-yl}biphenyl-4"-ylmethyl)-isoquinolin]-

1'(2H)-one,

(4) 5'-iodo-1',4',2,3-tetrahydrospiro[cyclopropyl-1,3'(2'- {2"'-1H-tetrazol-5-yl}biphenyl-4"-yImethyl)-isoquinolin]- 1'(2H)-one,

(5) 1',4',2,3-tetrahydrospiro[1H-indane-1,3'(2'-{2'"-1H- tetrazol-5-yl}biphenyl-4"-ylmethyl)-isoquinolin]-1'(2H)-one, having a melting point of 159-162°C,

(6) 1',4',2,3-tetrahydrospiro[cyclobutyl-1,3'(2'-{2'"-1H- tetrazol-5-yl}biphenyl-4"-ylmethyl)-isoquinolin]-1'(2H)-one, having a melting point of 163-170°C,

(7) 8'-methoxy-1',4',2,3-tetrahydrospiro[cyclopentyl- 1,3'(2'-{2"'-1H-tetrazol-5-yl}biphenyl-4"-ylmethyl)- isoquinolin]-1'(2H)-one, having a melting point of 152- 154°C; and

(8) 8'-methoxy-1',4',2,3-tetrahydrospiro[1H-indane-1,3'(2'- {2"'-1H-tetrazol-5-yl}biphenyl-4"-ylmethyl)-isoquinolin]- 1'(2H)-one, having a melting point of >240°C.

EXAMPLE 2

3-n-Butγl-2-[(2"-1H-tetrazol-5-yl)biphenyl-4'-ylmethyl]- isoquinolin-1(2H)-one A. Formula (I) where Y = H, R¹ = n-buten-1-yl, and X = - COOH.

3-(n-buten-1-yl)-2-[(2"-cyano)biphenyl-4'-ylmethyl]- isoquinolin-1(2H)-one-4-carboxylic acid (2.8 mmol),

prepared, e.g. as described in Preparation 12, was dissolved in xylene (50 ml) containing tributyl tin azide (1 g, 3.0 mmol) and heated under reflux for 10 hours. The mixture was cooled to room temperature, diluted with anhydrous HCl in ether, and the precipitated solid was triturated repeatedly with hexane. Recrystallization in acetonitrile gave 3-(n- buten-1-yl)-2-[(2"-1H-tetrazol-5-yl)biphenyl-4'-ylmethyl]- isoquinolin-1(2H)-one-4-carboxylic acid, having a melting point of 152°C.

B. Formula (I), varying Y, R¹ and X.

By following the procedure described in part A of this example and substituting 3-(n-buten-1-yl)-2-[(2"- cya-o)biphenyl-4'-ylmethyl]-isoquinolin-1(2H)-one-4- carboxylic acid with the following: (1) 3-n-butylidine-2-[(2"-cyano)biphenyl-4'-ylmethyl]- isoquinolin-1(2,4H)-one-4-carboxylic acid,

(2) 6-chloro-3-cyclopentyl-2-[(2"-cyano)biphenyl-4'- ylmethyl]-isoquinolin-1(2H)-one-4-butanoic acid, and

(3) methyl 7-methoxy-3-(n-penten-2-yl)-2-[(2"- cyano)biphenyl-4'-ylmethyl]-isoquinolin-1(2H)-one-4- methylcarboxylate;

There were obtained the following respective compounds:

(1) 3-n-butylidine-2-[(2"-1H-tetrazol-5-yl)biphenyl-4'- ylmethyl]-isoquinolin-1(2,4H)-one-4-carboxylic acid, having a melting point of 154-156°C,

(2) 6-chloro-3-cyclopentyl-2-[(2"-1H-tetrazol-5-yl)biphenyl- 4'-ylmethyl]-isoguinolin-1(2H)-one-4-butanoic acid, and

(3) methyl 7-methoxy-3-(n-penten-2-yl)-2-[(2"-1H-tetrazol-5- yl)biphenyl-4'-ylmethyl]-isoquinolin-1(2H)-one-4- methylcarboxylate.

EXAMPLE 3

2-n-propyl-3-[(2"-1H-tetrazol-5-yl)biphenyl-4'-ylmethyl]- isoguinolin-1(2H)-one A. Formula (I) where Y = H, X = H, and R¹ = n-propyl.

2-n-Propyl-3-[(2"-cyano)biphenyl-4'-ylmethyl]- isoquinolin-1(2H)-one (757 mg, 2.0 mmol), prepared, e.g., as described in Preparation 16, was dissolved in xylene (50 ml) containing tributyl tin azide (1 g, 3.0 mmol) and heated under reflux for 10 hours. The mixture was cooled to room temperature, diluted with anhydrous HCl in ether, and the precipitated solid was triturated repeatedly with hexane. Recrystallization in acetonitrile gave 2-n-propyl-3-[(2"-1H- tetrazol-5-yl)biphenyl-4'-ylmethyl]-isoquinolin-1(2H)-one (420 mg, 1 mmol), 50% yield, having a melting point of 187-

190°C.

B. Formula (I), varying Y and X and R¹.

By following the procedure described in part A of this preparation and substituting 2-n-propyl-3-[(2"- cyano)biphenyl-4'-ylmethyl]-isoquinolin-1(2H)-one with the following: (1) 2-n-butyl-3-[(2"-cyano)biphenyl-4'-ylmethyl]- isoquinolin-1(2H)-one-4-carboxylie acid,

(2) 4-ethyl-5-hydroxy-3-[(2"-cyano)biphenyl-4'-ylmethyl]- isoquinolin-1(2H)-one,

(3) methyl 6-methoxy-2-(prop-2-enyl)-3-[(2"-cyano)biphenyl- 4'-ylmethyl]-isoquinolin-1(2H)-one-4-carboxylate, and

(4) 7-bromo-2-cyclobutyl-3-[(2"-cyano)biphenyl-4'-ylmethyl]- isoquinolin-1(2H)-one-4-ethylcarboxylic acid; there were obtained the following respective compounds:

(1) 2-n-butyl-3-[(2"-1H-tetrazol-5-yl)biphenyl-4'-ylmethyl]- isoquinolin-1(2H)-one-4-carboxylie acid, having a melting point of 154-156°C,

(2) 4-ethyl-5-hydroxy-3-[(2"-1H-tetrazol-5-yl)biphenyl-4'- ylmethyl]-isoquinolin-1(2H)-one,

(3) methyl 6-methoxy-2-(prop-2-enyl)-3-[(2"-1H-tetrazol-5- yl)biphenyl-4'-ylmethyl]-isoquinolin-1(2H)-one-4- carboxylate; and

(4) 7-bromo-2-cyclobutyl-3-[(2"-1H-tetrazol-5-yl)biphenyl- 4'-ylmethyl]-isoquinolin-1(2H)-one-4-ethylcarboxylic acid.

EXAMPLE 4

CONVERSION OF ACID OF FORMULA (I) TO SALT This example describes the preparation of a

pharmaceutically acceptable salt of a compound of Formula (I). A. Na Salt of Formula (I) where Y = 8'-hydroxy, R¹ =

spiroindane, and X = H.

To an aqueous solution of 8'-hydroxy-1',4',2,3- tetrahydrospiro[1H-indane-1,3'(2'-{2"'-1H-tetrazol-5- yl}biphenyl-4"-yImethyl)-isoquinolin]-1'(2H)-one (0.4 mmol), prepared, e.g., as described in Example 1, in water (5 ml) was added 0.1 M sodium hydroxide (3.94 ml, 0.4 mmol). The solution was freeze dried and the resultant salt was

collected to yield (95%) the sodium salt. B. Salt of Formula (I) varying base, Y, R¹ and Z.

By following the procedure described in part A of this example and substituting 8'-hydroxy-1',4',2,3- tetrahydrospiro[1H-indane-1,3'(2'-{2"'-1H-tetrazol-5- yl}biphenyl-4"-yImethyl)-isoquinolin]-1'(2H)-one and/or sodium hydroxide with the following:

(1) 8'-hydroxy-1',4',2,3-tetrahydrospiro[1H-indane-1,3'(2'- {2"'-1H-tetrazol-5-yl}biphenyl-4"-ylmethyl)-isoquinolin]- 1'(2H)-one and potassium hydroxide, and

(2) 2-n-propyl-3-[(2"-1H-tetrazol-5-yl)biphenyl-4'- ylmethyl]-isoquinolin-1(2H)-one; there were obtained the following respective salts: (1) potassium 8'-hydroxy-1',4',2,3-tetrahydrospiro[1H- indane-1,3'(2'-{2"'-1H-tetrazol-5-yl}biphenyl-4"-yImethyl)- isoquinolin]-1'(2H)-one, and

(2) sodium 2-n-propyl-3-[(2"-1H-tetrazol-5-yl)biphenyl-4'- ylmethyl]-isoquinolin-1(2H)-one. EXAMPLE 5

ORAL FORMULATIONS

This example describes the preparation of a

representative pharmaceutical formulation for oral

administration containing an active compound of Formula (I), e.g. 3-n-butyl-2-[(2"-1H-tetrazol-5-yl)biphenyl-4'- ylmethyl]-isoquinolin-1(2H)-one. A solid dose form (capsule or tablet) may be prepared as follows:

Compound of Formula (I) 10 mg

lactose 153 mg pregelatinized starch 10 mg corn starch 20 mg magnesium stearate 2 mg hydroxypropylmethyl cellulose 4 mg

TOTAL 200 mg

The compounds of the present invention may also be formulated in a solution for oral administration as follows:

Compound of Formula (I) 10 mg/ml sucrose 10 mg/ml sorbitol 100 mg/ml sodium benzoate 10 mg/ml

HCl or NaOH to adjust pH to 3 - 7; q.s. to 1 ml with H₂O.

Other compounds and salts of Formula (I), such as those prepared in accordance with Examples 1-4, can be used as the active compound in the preparation of the orally

administrable formulations of this example.

EXAMPLE 6 INJECTABLE FORMULATIONS

This example describes the preparation of a

representative pharmaceutical formulation for i.m. or i.v. administration containing an active compound of Formula (I), e.g. 3-n-butyl-2-[(2"-1H-tetrazol-5-yl)biphenyl-4'- ylmethyl]-isoquinolin-1(2H)-one.

Compound of Formula (I) 20 mg/ml ethanol 100 mg/ml

NaCl 60 mg/ml

HCl or NaOH to adjust pH to 3 - 7; q.s. to 1 ml with water for injection. Other compounds and salts of Formula (I), such as those prepared in accordance with Examples 1-4, can be used as the active compound in the preparation of the injectable

formulations of this example.

EXAMPLE 7

ACTIVITY ASSAYS

Angiotensin II binding assays

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 Na₂ 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 μM). AII-1 binding sites were labelled with [¹²⁵I]-Sar¹ lle⁸ All (0.01 nM; New England Nuclear).

Incubations of test compound, radiolabelled All, and AII-1 binding sites were terminated by vacuum filtration over Whatman GF/B glass fiber filters. After filtration, the filters were washed, dried and counted for radioactivity by liquid scintillation spectrometry with quench correction.

The concentration of test compound producing 50% inhibition of specific radioligand binding was determined by iterative curve fitting and its inhibition dissociation constant (K_i) calculated.

The compounds of Formula (I) were active in this assay.

EXAMPLE 8

ANGIOTENSIN RECEPTOR ANTAGONISM FUNCTIONAL ASSAYS

(a) Isolated ring segments of rabbit aorta were set up in Krebs' physiological salt solution at 37°C, pH 7.4, under 1 g resting tension. The segments were exposed to 50 mM KCl to evoke contraction. After thorough washing,

cumulative concentration-effect curves to All were

constructed. Then, 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.

(b) Isolated guinea pig esophagous was set up in Krebs' physiological salt solution at 37°C, pH 7.4, under 1 g resting tension. Cumulative concentration-effect curves to All were constructed using 0.5 log unit increases in concentration. Then, test compounds were pre-incubated 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.

EXAMPLE 9

IN VIVO ASSAYS

(a) Male normotensive rats were subjected to complete left renal artery ligation. Four to 8 days post ligation, systemic blood pressure and heart rate were recorded via the left femoral artery from conscious rats housed in Bollman restraint cages. Test and control compounds were

administered via the femoral vein. The rats were divided into test and control groups.

For intravenous administration, the test group received the test compound (10 mg/ml, in a vehicle of Tween®80

[polyoxyethylene sorbitan monooleate] and normal saline) in increasing doses (3, 10 and 30 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 to both groups as a positive control, and blood pressure and heart rate were recorded for a further 30 minutes.

For oral administration, the 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 to both groups as a positive control and the same parameters were recorded for a further 30 minutes.

The compounds of Formula (I) significantly lowered mean blood pressure when given by both the intravenous and oral routes.

(b) 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 μg/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 μg/kg, iv) was then

injected every 30 minutes for 4 hours. A final dose of All (1.0 μg/kg, iv) was given at the end of the experiment.

The compounds of Formula (I) inhibited significantly the pressor response to All without causing sustained hypotension, demonstrating that the compounds possess All blocking properties in vivo and that their hypotensive action is selective to All-dependent hypotension. (The systemic blood pressure of normotensive rats is not All- dependent.) EXAMPLE 10

COGNITIVE ENHANCEMENT ASSAY

The following describes a model to determine the cognitive enhancing effects of compounds of Formulae (I).

Sprague Dawley rats (240-260 g) were kept in the laboratory the night prior to testing, and remained there throughout the experiment. 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. A TV camera tracked the swim path of the rats, and the data thus obtained was examined to determine the time in seconds the rats took to find the platform (escape latency). 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.

The following groups of 8 rats each were used: 1) vehicle-treated controls; 2) atropine treated-controls; 3) atropine plus test drug. Thus the studies were designed to determine whether the test drug could alleviate the cognitive deficit induced by atropine (30 mg/kg, ip).

Statistical tests were applied to test for heterogeneity of the learning curves, and separation of the learning curves.

1', 4',2,3-tetrahydrospiro[1H-indane-1,3'(2'-{2"'-1H- tetrazol-5-yl}biphHnyl-4"-ylmethyl)-isoquinolin]-1'(2H)-one was active in this assay at 0.01 to 1 mg/Kg p.o.

While the present invention has been described with respect to specific embodiments thereof, it will be

understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the true spirit and scope of the invention. All such modifications are intended to be within the scope of the claims appended hereto.

Claims

WHAT IS CLAIMED IS:

1. A compound according to the following formula:

wherein,

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; and

R¹ is selected from the group consisting of H, alkenyl, lower alkyl, lower cycloalkyl, unsubstituted or substituted 3-spiro-1H-indane of the structure

wherein R² is H, OH, lower alkyl, lower alkoxy or halo, and

3-spiro-cycloalkyl of the structure

wherein n is an integer from zero to six,

or a pharmaceutically acceptable salt thereof, with the proviso that when R¹ is spiro-, X is H, and when R¹ 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.

2. A compound or salt of Claim 1 where R¹ is at position 3 of the isoquinolin-1(2H)-one.

3. A compound or salt of Claim 2 where R¹ is 3-spiro-1H- indane or 3-spiro-cycloalkyl.

4. A compound or salt of Claim 3 where R¹ is 3-spiro-1H- indane.

5. A compound or salt of Claim 4 where X is H.

6. A compound or salt of Claim 5 where Y is H, OH, halo, or lower alkoxy.

7. A compound or salt of Claim 6 where Y is OH or alkoxy preferably methoxy.

8. A compound or salt of Claim 6 where R¹ is 3-spiro-1H- indane, X is H, Y is H and the (2"-1H-tetrazol-5- yl)biphenyl-4'-ylmethyl group is at the 2 (N) position.

9. A compound or salt of Claim 7 where R¹ is 3-spiro-1H- indane, X is H, Y is 8'-OH and the (2"-1H-tetrazol-5- yl)biphenyl-4'-ylmethyl group is at the 2 (N) position.

10. A compound or salt of Claim 7 where where R¹ is 3- spiro-1H-indane, X is H, Y is 8'-methoxy and the (2"-1H- tetrazol-5-yl)biphenyl-4'-ylmethyl group is at the 2(N) position.

11. A compound or salt of Claim 3 where R¹ is 3-spiro- cycloalkyl.

12. A compound or salt of Claim 11 where X is H.

13. A compound or salt of Claim 12. where Y is H, OH, halo or lower alkoxy.

14. A compound or salt of Claim 13 where Y is OH or alkoxy preferably methoxy.

15. A compound or salt of Claim 13 where R¹ is 3-spiro- cyclobutyl, X is H, Y is H and the (2"-1H-tetrazol-5- yl)biphenyl-4'-ylmethyl group is at the 2 (N) position.

16. A compound or salt of Claim 14 where R¹ is 3-spiro- cyclopentyl, X is H, Y is 8'-methoxy and the (2"-1H- tetrazol-5-yl)biphenyl-4'-ylmethyl group is at the 2 (N) position.

17. A sodium or potassium salt of the compound of Claims 2- 16.

18. A compound or salt of Claim 2 where R¹ is 3-alkenyl.

19. A compound or salt of Claim 18 where X is -COOH.

20. A compound or salt of Claim 19 where Y is H, alkoxy, or halo.

21. A compound or salt of Claim 20 where R¹ is 3-n-buten-1- yl, X is -COOH, Y is H and the (2"-1H-tetrazol-5- yl)biphenyl-4'-ylmethyl group is at the 2 (N) position.

22. A compound or salt of Claim 20 where R¹ is 3-n- butylidine, X is -COOH, Y is H and the (2"-1H-tetrazol-5- yl)biphenyl-4'-ylmethyl group is at the 2 (N) position.

23. A compound or salt of Claim 1 where R¹ is at position 2 of the isoquinolin-1(2H) -one.

24. A compound or salt of Claim 23 where R¹ is a lower alkyl.

25. A compound or salt of Claim 24 where X is H or -COOH, and Y is H.

26. A compound or salt of Claim 25 where R¹ is 2-n-propyl, X is H, Y is H and the (2"-1H-tetrazol-5-yl)biphenyl-4'- ylmethyl group is at position 3 of the isoquinolin-1(2H)- one.

27. A compound or salt of Claim 25 where R¹ is 2-n-butyl, X is -COOH, Y is H and the (2"-1H-tetrazol-5-yl)biphenyl-4'- ylmethyl group is at position 3 of the isoquinolin-1(2H)- one.

28. A pharmaceutical composition comprising a

pharmaceutically acceptable non-toxic excipient and a therapeutically effective amount of a compound or salt of Claim 1.

29. A method for treating a mammal having a disease state which is alleviated by treatment with an angiotensin II receptor antagonist, which method comprises administering to a mammal in need thereof a therapeutically effective amount of a compound or pharmaceutically acceptable salt of the following formula:

wherein,

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; and

R¹ is selected from the group consisting of H, alkenyl, lower alkyl, lower cycloalkyl, unsubstituted or substituted 3-spiro-1H-indane of the structure

wherein R² is H, OH, lower alkyl, lower alkoxy or halo, and

3-spiro-cycloalkyl of the structure

wherein n is an integer from zero to six, or a pharmaceutically acceptable salt thereof, with the proviso that when R¹ is spiro-, X is H, and when R¹ is H, alkenyl, lower alkyl, 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.

30. The method of claim 29 wherein said disease state is hypertension.

31. The method of claim 29 wherein said disease state is inflammatory bowel disease.

32. A process for preparing a compound of Formula (I):

wherein,

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; and

R¹ is selected from the group consisting of H, alkenyl, lower alkyl, lower cycloalkyl, unsubstituted or substituted 3-spiro-1H-indane of the structure

wherein R² is H, OH, lower alkyl, lower alkoxy or halo, and

3-spiro-cycloalkyl of the structure

wherein n is an integer from zero to six, provided that when R¹ is spiro- X is H,

or a pharmaceutically acceptable salt thereof, with the proviso that when R¹ is spiro-, X is H, and when R¹ 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, said process comprising contacting a corresponding compound of the following

formula:

wherein X, Y and R¹ are as defined above, with a trialkyl tin azide, and optionally converting a compound of Formula (I) into a pharmaceutically acceptable salt thereof.

33. The process of Claim 32 wherein R¹ is H, alkenyl, lower alkyl or cycloalkyl, further comprising:

(a) treating an optionally substituted N-(prop-1- enyl) benzamide of Formula (M):

with a compound of the formula H₃CN(OCH₃)C(O)R¹ to form an optionally substituted N-(prop-1-enyl)-isoquinolin-1(2H)-one of Formula (N):

(b) treating the compound of Formula (N) with an acid to form an optionally substituted isoquinolin-1(2H)-one of Formula (O)

; and

(c) coupling the compound of Formula (O) with a 4-halo methyl-2'-cyano-biphenyl compound to produce an optionally substituted 2-[(2"-cyano)biphenyl-4'ylmethyl]-3-isoquinolin- 1(2H)-one of Formula (P):

34. The process of Claim 33 wherein said optionally substituted N-(prop-1-enyl)benzamide of Formula (M) is formed by treatment of the corresponding N-allyl-2- methylbenzamide with a strong base.

35. A compound useful in the synthesis of angiotensin II antagonists, according to the following formula:

wherein,

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; and

R¹ is selected from the group consisting of H, alkenyl, lower alkyl, lower cycloalkyl, unsubstituted or substituted 3-spiro-1H-indane of the structure

wherein R² is H, OH, lower alkyl, lower alkoxy or halo, and

3-spiro-cycloalkyl of the structure

wherein n is an integer from zero to six, provided that when R¹ is spiro- X is H,

or a pharmaceutically acceptable salt thereof, with the proviso that when R¹ is spiro-, X is H, and when R¹ 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"-cyano)biphenyl-4'-ylmethyl group cannot be at the 2 (N) position.

36. A compound of Claim 35 where R¹ is 3-spiro-1H-indane or 3-spiro-cycloalkyl.

37. A compound of Claim 36 where R¹ is 3-spiro-1H-indane, X is H and Y is H, OH, halo or lower alkyl and the (2"- cyano)biphenyl-4'-ylmethyl group is at the 2 (N) position.