WO2001005767A1 - Organic compounds - Google Patents

Abstract

Compounds of formula (I) wherein R2-C, R3-C, R4-C or R5-C may be replaced by N; and wherein n is 1, 2 or 3; R1 is carbocyclic aryl or heteroaryl; R2, R3, R4 and R5 are independently hydrogen, lower alkyl, lower alkoxy, halo, trifluoromethyl or cyano; R6 is heteroaryl or heteroaryl-lower alkyl; R7 is hydrogen, lower alkyl or carbocyclic or heterocyclic aryl-lower alkyl; and pharmaceutically acceptable salts thereof; and enantiomers thereof; which are useful as inhibitors of microsomal triglyceride transfer protein (MTP) and of apolipoprotein B (ApoB) secretion and accordingly for the treatment of MTP and Apo B dependent conditions.

Description

Organic Compounds

The invention is directed to heteroar(alkyl)amino-benzocycloalkane substituted amide derivatives of formula I

wherein R₂-C, R₃-C, R»-C or R₅-C may be replaced by N; and wherein n is 1 , 2 or 3;

Ri is carbocyclic aryl or heteroaryl;

R₂, R3, R4 and R₅ are independently hydrogen, lower alkyl, lower alkoxy, halo, trifluoromethyl or cyano;

R₆ is heteroaryl or heteroaryl-lower alkyl; R₇ is hydrogen, lower alkyl, or carbocyclic or heterocyciic aryl-lower alkyl; and pharmaceutically acceptable salts thereof; and enantiomers thereof.

Compounds of formula I are useful as inhibitors of microsomal triglyceride transfer protein (MTP) and of apolipoprotein B (ApoB) secretion and accordingly for the treatment of MTP and Apo B dependent conditions.

A particular embodiment of the invention relates to the compounds of formula I'

wherein R₂-C, R₃-C, R₄-C or R₅-C may be replaced by N; and wherein n, and R₁-R₇ have meaning as defined above; pharmaceutically acceptable salts thereof; and enantiomers thereof.

A specific embodiment of the invention relates to the compounds of formula la

wherein X is R₂-C or N; and n, and RrR have meaning as defined above; pharmaceutically acceptable salts thereof; and enantiomers thereof.

Preferred are the compounds of formula la wherein n is 1 ; R₁ is monocyclic carbocyclic aryl or heteroaryl; X is R₂-C or N; R₂, R₃, R4 and R₅ are independently hydrogen, lower alkyl, halo, trifluoromethyl, lower alkoxy or cyano; R₆ is heteroaryl or heteroaryl-lower alkyl; R₇ is hydrogen or lower alkyl; pharmaceutically acceptable salts thereof; and enantiomers thereof.

Further preferred are the compounds of formula la wherein n is 1 or 3; X is R₂-C and R₂ is hydrogen or C₁-C₄-alkyl, such as methyl; R₃ is hydrogen; R₄ is hydrogen or Cι-C₄-alky|, such as methyl; R₆ is Cι-C₄-alkyl,such as methyl, substituted by pyrrolyl, thienyl, imidazolyl, thiazolyl, pyridyl, or quinolyl, each of which is unsubstituted or substituted by a substituent selected from the group consisiting of Cι-C-4-alkyl, CrC₄-alkoxy, trifluoromethyl, halo, or cyano; or is pyrrolyl, thienyl, imidazolyl, thiazolyl, pyridyl, or quinolyl, each of which is unsubstituted or substituted by a substituent selected from the group consisiting of C_rC₄- alkyl, C_rC -alkoxy, trifluoromethyl, halo, or cyano; R is hydrogen, Cι-C₄-alkyl, or d-C-₄-alkyl substituted by pyrrolyl, thienyl, imidazolyl, thiazolyl, or pyridyl, each of which is unsubstituted or substituted by a substituent selected from the group consisiting of d-C -alkyl, Cι-C₄- alkoxy, trifluoromethyl, halo, or cyano; such as thienylmethyl; pharmaceutically acceptable salts thereof; and enantiomers thereof. A particular aspect of the invention relates to the indane derivatives of formula lb

wherein Ri is monocyclic carbocyclic aryl or heteroaryl;

X is R₂-C or N;

R₂, R₃, R₄ and R₅ are independently hydrogen, lower alkyl, halo, trifluoromethyl, cyano, or lower alkoxy; and R₆ and R₇ have meaning as defined above; and pharmaceutically acceptable salts thereof; and enantiomers thereof.

Preferred are the said compounds of formula lb wherein Ri is phenyl or phenyl substituted by fluoro, chloro, trifluoromethyl, cyano or lower alkyl; X is N or R₂-C; R₂, R₃, R₄ and R₅ are independently hydrogen, lower alkyl, halo or trifluoromethyl; and R₆ and R₇ have meaning as defined above; and pharmaceutically acceptable salts thereof; and enantiomers thereof.

Further preferred are the compounds of formula lc

wherein R₂, R₃ and R₄ are independently hydrogen, Cι-C₄-alkyl, Cι-C₄-alkoxy, trifluoromethyl, chloro or fluoro; R₇ is hydrogen or methyl; R₈ is trifluoromethyl, chloro or cyano; m is zero or one; and Het is heteroaryl; pharmaceutically acceptable salts thereof; and enantiomers thereof.

Further preferred are the compounds of formula lc wherein R₂ is methyl; R₃ is hydrogen; FU is hydrogen or methyl; R₇ is hydrogen; R₈ is trifluoromethyl or chloro; m is zero or one; and Het is optionally substituted pyridyl, pyrimidinyl, imidazolyl, thienyl, thiazolyl or quinolyl; pharmaceutically acceptable salts thereof; and enantiomers thereof.

A particular embodiment relates to the compounds of formula lc wherein R₂ is methyl; R₃ is hydrogen; R₄ is hydrogen or methyl; Het is pyridyl, thiazolyl or imidazolyl; R₇ is hydrogen; R₈ is trifluoromethyl; and m is zero or one; pharmaceutically acceptable salts thereof; and enantiomers thereof.

Particular embodiments relate to said compounds of formula lc wherein m is one; wherein m is zero; and R₇ is hydrogen.

Listed below are definitions of various terms used to describe the compounds of the instant invention. These definitions apply to the terms as they are used throughout the specification (unless they are otherwise limited in specific instances either individually or as part of a larger group).

The term "alkyl" refers to straight or branched chain hydrocarbon groups having 1 to 20 carbon atoms, preferably lower alkyl of 1 to 7 carbon atoms. Exemplary alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl and the like. Preferred is Cι-C₄-alkyl.

The term "lower alkyl" refers to those alkyl groups as described above having 1 to 7, preferably 1 to 4 carbon atoms.

The term "halogen" or "halo" refers to fluorine, chlorine, bromine and iodine.

The term "alkoxy" or "aikyloxy" refers to alkyl-O-. The term "aryl" or "ar", refers to carbocyclic monocyclic or bicyclic aromatic hydrocarbon groups having 6 to 12 carbon atoms in the ring portion, such as phenyl, naphthyl, tetrahydronaphthyl, and biphenyl groups, each of which may optionally be substituted by one to four, e.g. one or two, substituents such as alkyl, halo, trifluoromethyl, hydroxy, alkoxy, alkanoyl, alkanoyloxy, amino, substituted amino, alkanoylamino, thiol, alkylthio, nitro, cyano, carboxy, carboxyalkyl, carbamyl, alkoxycarbonyl, alkylthiono, alkylsulfonyl, aminosulfonyl, and the like.

The term "aralkyl" refers to an aryl group linked to an alkyl group, such as benzyl.

The term "heteroaryl" "or heteroar" refers to an aromatic heterocycle, for example monocyclic or bicyclic heterocyclic aryl, such as pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, triazolyl, isoxazolyl, thiazolyl, isothiazolyl, furyl, thienyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, benzothiazolyl, benzoxazolyl, benzothienyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzofuryl, and the like, optionally substituted by one to four, e.g. one or two, substituents, such as lower alkyl, lower alkoxy or halo, the point of attachment of said heterocycle being at a carbon atom of the heterocyclic ring. Preferred heteroaryl residues are 1 -methyl-2-pyrrolyl, 2-, 3-thienyl, 2-thiazolyl, 2-imidazolyl, 1-methyl-2-imidazolyl, 2-,3-,4- pyridyl, or 2-quinolyl.

The term "alkanoyl" refers, for example, to C₂-C₇-alkanoyl, especially C₂-C₅-alkanoyl, such as acetyl, propionyl or pivaloyl.

The term "substituted amino" refers to amino mono- or, independently, disubstituted by alkyl, aralkyl, aryl, heteroaryl, cycloalkyl, cycloalkylalkyl, heteroaralkyl, or disubstituted by lower alkylene or lower alkylene interrupted by O, S, N-(H, alkyl, aralkyl) and the like.

Pharmaceutically acceptable salts of the compounds of the invention are particularly acid addition salts, such as of mineral acids, organic carboxylic, and organic sulfonic acids e.g., hydrochloric acid, methanesulfonic acid, maleic acid, and the like provided a basic group, such as pyridyl, constitutes part of the structure.

The compounds of the invention depending on the nature of the substituents, possess one or more asymmetric carbon atoms, and therefore exist as racemates and the (R) and (S) enantiomers thereof. All are within the scope of the invention. Preferred is the more active enantiomer typically assigned the R-configuration (at the carbon being the NR₆R₇ substituent).

The compounds of the invention, as illustrated for certain compounds of formula la wherein n is 1 , can be prepared by coupling a protected compound of e.g. formula II

H₂N /C >^NHcooR- wherein R_a is lower alkyl,

with a reactive functional carboxyiic acid derivative, e.g, a compound of formula III

wherein R₁-R5 and X have meaning as defined above,

in the presence of a base such as N-methylmorpholine, diisopropylethylamine, triethylamine or pyridine to provide compounds of the formula IV

Compounds of formula IV are then deprotected with an acid such as HCO₂H or with trimethylsilyl iodide, to form compounds of formula V

Compounds of formula V are then reacted with an electrophile corresponding to the amino substituent R₆ and/or R₇, optionally in the presence of a base such as pyridine, triethylamine or polymer supported morpholine to form compounds of the invention. A palladium catalyzed (Buchwald) condensation can be used for compounds wherein R₆ is heteroaryl, e.g. as illustrated in the examples.

Alternatively, for the preparation of compounds wherein R₆ is not heteroaryl, compounds of formula V are treated with the aldehyde or ketone corresponding to the amino substituents R₆ and/or R₇ under conditions of reductive amination well-known in the art, in the presence of e.g. sodium borohydnde, sodium triacetoxyborohydride or polymer supported borohydride.

Compounds of formula II are prepared by acid hydrolysis of e.g., N-(5-nitro-indan-2- yl)acetamide followed by protection of the resulting amine with e.g. BOC-anhydride and subsequent reduction, e.g., by catalytic hydrogenation, of the nitro group.

The biarylcarboxylic acids corresponding to the compounds of formula III can be prepared e.g. as described in Bioorg. Med. Chem. Lett. 7 (13), 1595 (1997).

Compounds of formula III wherein Ri is aryl or heteroaryl can be prepared as illustrated in the scheme below by palladium catalyzed aryl-aryl coupling of aryl boronic acids of formula VI with bromo, iodo or trifluomethylmethanesulfonyloxy-substituted arylcarboxylic acid esters of e.g. formula VII. Subsequent hydrolysis of the ester group of resulting compounds of formula VIII with sodium hydroxide followed by reaction with a chlorinating agent such as oxalyl chloride gives acid chlorides of formula III.

VI VII VIII

Compounds of formula V may also be prepared using t e alternative synthesis below:

NHCOOFL

As shown above, amines of formula II are acylated with compounds of formula IX in the presence of a base such as N- methylmorpholine, diisopropylethylamine or pyridine to give compounds of the formula X. Palladium catalyzed aryl-aryl coupling of aryl boronic acids of formula (Rι-B(OH)₂) with aryl bromides of the formula X (or iodides or triflates) gives compounds of formula IV. Treatment with e.g. formic acid or trimethylsilyl iodide readily deprotects the nitrogen to give compounds of formula V.

Chiral compounds of the invention can be prepared as follows: (a) reducing (1S-trans)- or (1 R-trans)-hydroxy-2-amino-6-nitroindane wherein the amino group is in protected form to the corresponding (R) or (S)- enantiomer of 2,6- diaminoindane in which the 2-amino group is in protected form;

(b) condensing said (R) or (S) enantiomer with a reactive derivative of a carboxylic acid, e.g., a compound of formula III, and removing the amino protecting group to obtain the (R) or (S) enantiomer of a compound of formula V; and

(c) subsequently N-derivatizing a said enantiomer to a compound of the invention.

For example, chiral compounds of the invention, can be prepared e.g., by acylating a protected amine of e.g., formula XI

with acetyl chloride to form compounds of formula XII

Compounds of formula XII are nitrated with nitric acid, trifluoroacetic acid and trifluoroacetic anhydride to form compounds of formula XIII

Compounds of formula XIII are saponified with sodium hydroxide to form compounds of formula XIV

Compounds of formula XIV are reduced with hydrogen in the presence of Pd/C catalyst to form compounds of formula XV

A compound of the formula XV is then coupled with a compound of formula III in the presence of a base such as N-methylmorpholine, diisopropylethylamine, triethylamine, or pyridine to provide e.g. a compound of formula XVI

Compounds of formula XVI are then treated with e.g., trimethylsilyl iodide to form the chiral compounds of the formula V

Amines of formula V are then reacted as previously described to obtain the enantiomers corresponding to the compounds of formula lb.

The opposite enantiomers are similarly prepared.

Alternatively, e.g. 5-bromo-2-aminoindane is resolved with D- or L-camphorsulfonic acid, and the resulting chiral amine is protected as e.g. the N-methoxycarbonyl derivative. Reaction with benzophenone imine (in a Buchwald condensation, Tetrahedron Letters 36, 6367, 1997) yields the corresponding chiral compound of formula XV (or its enantiomer).

A method for the preparation of enantiomers of the compounds of the invention, e.g. of formula lb, thus comprises:

(a) resolving 5-bromo-2-aminoindane with either (R) or (S)-10-camphorsulfonic acid to obtain either chiral (R)- or (S)-5-bromo-2-aminoindane;

(b) protecting the resulting (R)- or (S)-5-bromo-2-aminoindane with e.g. an N- alkoxycarboxyl protecting group;

(c) reacting a said N-alkoxycarbonyl-5-bromo-2-aminoindane with benzophenone imine under conditions of a Buchwald condensation;

(d) cleaving the resulting 5-benzophenoneimine derivative by catalytic hydrogenation or treatment with acid;

(e) condensing the resulting 2-protected amino-5-aminoindane with a reactive derivative of a carboxyiic acid, e.g. of the formula III wherein R_1f R₃-R₅ and X have meaning as defined herein, and optionally removing the amino protecting group to obtain the corresponding (R) or (S) enantiomer of a compound of formula V; and

(f) N-derivatizing a said compound to obtain a compound of formula lb wherein R₆ is derivatized amine as defined herein.

Illustrative of step (a), R-2-amino-5-bromoindane can be prepared e.g. by treating racemic 2-amino-5-bromoindane with 1 (S)-10-camphorsulfonic acid, selectively crystallizing and purifying the resulting (R,S) diastereomeric salt, and then liberating, by treatment with a base, (R)-2-amino-5-bromoindane which is substantially free of the (S)-isomer.

In turn, racemic 2-amino-5-bromoindane is prepared by bromination of 2-aminoindane which is commercially available or can be prepared by converting ninhydrin to 1 ,3-dioxo-2- hydroxyiminoindane followed by catalytic hydrogenation. The Buchwald amination by condensation of e.g. 5-bromo-2- carbomethoxyaminoindane with benzophenone imine can be carried out similarly to the procedures described in Tetrahedron Letters 38, 6367 (1997). The amination is carried out in the presence of a palladium catalyst, a ligand and a base in an inert solvent such as toluene. Palladium catalysts include tris(dibenzyiideneacetone)dipalladium (O), bis(dibenzylideneacetone)palladium (O) and palladium acetate. Preferred ligands include 2,2'-bis(diphenylphosphino-1 ,1'-binaphthyl, bis(2-diphenylphosphinophenyl)ether and 1 ,1'- bis(diphenylphosphino)ferrocene.

Preferred bases include sodium methoxide and sodium isopropoxide, the use of which is not disclosed in Tetrahedron Letters 38, 6367 (1997).

The resulting benzophenone imines are cleaved to the free amines, e.g. by treatment with dilute acid, such as 2N hydrochloric acid.

The other steps are carried out as described herein.

In starting compounds and intermediates which are converted to the compounds of the invention in a manner described herein, functional groups present, such as amino, carboxyl, and hydroxy groups, are optionally protected by conventional protecting groups that are common in preparative organic chemistry. Protected amino, carboxyl, and hydroxy groups are those that can be converted under mild conditions into free amino, carboxyl and hydroxy groups without the molecular framework being destroyed or other undesired side reactions taking place.

The purpose of introducing protecting groups is to protect the functional groups from undesired reactions with reaction components under the conditions used for carrying out a desired chemical transformation. The need and choice of protecting groups for a particular reaction is known to those skilled in the art and depends on the nature of the functional group to be protected (hydroxy group, amino group, etc.), the structure and stability of the molecule of which the substituent is a part and the reaction conditions.

Well-known protecting groups that meet these conditions and their introduction and removal are described, for example, in J.F.W. McOmie, "Protective Groups in Organic Chemistry", Plenum Press, London, New York, 1973, T. W. Greene, "Protective Groups in Organic Synthesis", third edition, Wiley, New York, 1999.

In the processes cited herein, reactive functional derivatives of carboxylic acids represent, for example, anhydrides (especially mixed anhydrides), acid halides, acid azides, lower alkyl esters, and activated esters thereof. Mixed anhydrides are preferably such from pivalic acid, or a lower alkyl (ethyl, isobutyl) hemiester of carbonic acid; acid halides are for example chlorides or bromides; activated esters for example succinimido, phthalimido or 4- nitrophenyl esters; lower alkyl esters are for example the methyl or ethyl esters.

Depending on the choice of starting materials and methods, the new compounds may be in the form of one of the possible isomers or mixtures thereof, for example, as substantially pure geometric (cis or trans) isomers, optical isomers (antipodes), racemates, or mixtures thereof. The aforesaid possible isomers or mixtures thereof are within the purview of this invention.

Any resulting mixtures of isomers can be separated on the basis of the physico- chemical differences of the constituents, into the pure geometric or optical isomers, diastereoisomers, racemates, for example by chromatography and/or fractional crystallization, or resolved by enzymatic resolution.

Any resulting racemates of intermediates can be resolved into the optical antipodes by known methods, e.g., by separation of the diastereoisomeric salts thereof, obtained with an optically active acid or base, and liberating the optically active acidic or basic compound. The amine intermediates can thus be resolved into their optical antipodes e.g., by fractional crystallization of salts of d- or l-carboxylic acids (e.g., d-or l-tartaric acid or d- or I- camphorsulfonic acid). Racemic products can also be resolved by chiral chromatography, e.g., high-pressure liquid chromatography using a chiral absorbent.

Finally, compounds of the invention are either obtained in the free form, or as a salt thereof if salt forming groups are present.

Compounds of the invention having basic groups can be converted into acid addition salts, especially pharmaceutically acceptable salts. These are formed, for example, with inorganic acids, such as mineral acids, for example sulfuric acid, a phosphoric or hydrohalic acid, or with organic carboxylic acids, such as (C C₄)-alkanecarboxylic acids which, for example, are unsubstituted or substituted by halogen, for example acetic acid, such as saturated or unsaturated dicarboxylic acids, for example oxalic, succinic, maleic or fumaric acid, such as hydroxycarboxylic acids, for example glycolic, lactic, malic, tartaric or citric acid, such as amino acids, for example aspartic or glutamic acid, or with organic sulfonic acids, such as (CrC₄)-alkylsulfonic acids (for example methanesulfonic acid) or arylsulfonic acids which are unsubstituted or substituted (for example by halogen). Preferred are salts formed with hydrochloric acid, methanesulfonic acid and maleic acid.

In view of the close relationship between the free compounds and the compounds in the form of their salts, whenever a compound is referred to in this context, a corresponding salt is also intended, provided such is possible or appropriate under the circumstances.

The compounds, including their salts, can also be obtained in the form of their hydrates, or include other solvents used for their crystallization.

The pharmaceutical compositions according to the invention are those suitable for enteral, such as oral or rectal, transdermal and parenteral administration to mammals, including man, to inhibit microsomal triglyceride transfer protein (MTP) and apolipoprotein B (Apo B) secretion, and for the treatment of disorders responsive thereto, comprising an effective amount of a pharmacologically active compound of the invention, alone or in combination, with one or more pharmaceutically acceptable carriers.

The pharmacologically active compounds of the invention are useful in the manufacture of pharmaceutical compositions comprising an effective amount thereof in conjunction or admixture with excipients or carriers suitable for either enteral or parenteral application. Preferred are tablets and gelatin capsules comprising the active ingredient together with a) diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine; b) lubricants, e.g., silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol; for tablets also c) binders e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and or polyvinylpyrrolidone; if desired d) disintegrants, e.g., starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and/or e) absorbants, colorants, flavors and sweeteners. Injectable compositions are preferably aqueous isotonic solutions or suspensions, and suppositories are advantageously prepared from fatty emulsions or suspensions. Said compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. In addition, they may also contain other therapeutically valuable substances. Said compositions are prepared according to conventional mixing, granulating or coating methods, respectively, and contain about 0.1 to75%, preferably about 1 to 50%, of the active ingredient.

Suitable formulations for transdermal application include an effective amount of a compound of the invention with carrier. Advantageous carriers include absorbable pharmacologically acceptable solvents to assist passage through the skin of the host. Characteristically, transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with carriers, optionally a rate controlling barrier to deliver the compound of the skin of the host at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin.

Suitable formulations for topical application, e.g., to the skin and eyes, are preferably aqueous solutions, ointments, creams or gels well known in the art.

The pharmaceutical formulations contain an inhibiting amount of a compound of the invention as defined above, either alone or in combination with another therapeutic agent, e.g., each at an effective therapeutic dose as reported in the art. Such therapeutic agents are well known in the art.

In conjunction with another active ingredient, a compound of the invention may be administered either simultaneously, before or after the other active ingredient, either separately by the same or different route of administration or together in the same pharmaceutical formulation.

The dosage of active compound administered is dependent on the species of warmblooded animal (mammal), the body weight, age and individual condition, and on the form of administration. A unit dosage for oral administration to a mammal of about 50 to 70 kg may contain between about 10 and 1000 mg, advantageously between about 25 and 500 mg of the active ingredient.

The present invention also relates to methods of using the compounds of the invention and their pharmaceutically acceptable salts, or pharmaceutical compositions thereof, in mammals, e.g. for the treatment of elevated levels of MTP and of Apo B and conditions related thereto.

The compounds of the invention are inhibitors of microsomal triglyceride transfer protein (MTP) and of apolipoprotein B (Apo B) secretion and are thus useful for lowering serum lipid levels, including serum triglyceride and serum cholesterol levels. Such compounds are therefore useful for the treatment and prevention of hyperiipedemia, hypercholesterolemia and hypertriglyceridemia and diseases associated therewith, e.g., cardiovascular diseases including cardiac ischemia, atherosclerosis and its clinical sequelae, as well as obesity, pancreatitis and diabetes.

The invention also relates to the use of a compound of the invention and a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the prevention and treatment of of elevated levels of MTP and of Apo B and conditions related thereto, such as hyperiipedemia, hypercholesterolemia and hypertriglyceridemia and diseases associated therewith, e.g., cardiovascular diseases including cardiac ischemia, atherosclerosis and its clinical sequelae, as well as obesity, pancreatitis and diabetes.

The above-cited properties are demonstrable in vitro and in vivo tests using advantageously mammals, e.g., rats, hamsters, mice, dogs, monkeys, and isolated cells or enzyme preparations. Said compounds can be applied in vitro in the form of solutions, e.g., aqueous solutions, and in vivo advantageously orally, topically or parenterally, e.g., intravenously. The dosage in vitro may range from about 10^'5 to 10^'9 molar concentrations. The dosage in vivo may range, depending on the route of administration, between about 1 and 100 mg kg. The tests are generally known in the art. For in vivo evaluation, the compounds are generally administered as a solution or suspension, e.g., as a suspension in 3% comstarch. The activity of a compound according to the invention can be assessed by the following methods:

The inhibition of the cellular secretion of Apo B is determined as described in International application WO 00/05201 published February 3, 2000.

The inhibition of MTP is measured as described in International application WO00/05201 , published February 3, 2000.

Illustrative of the invention the compound of Example 1 (a) demonstrates an inhibition of about 86% at 0.1 μM in the Apo B assay and an IC50 of about 120 nM in the MTP assay. The compound of Example 2 demonstrates an inhibition of about 70% at 0.1 μM in the Apo B assay and an IC₅0 of about 160 nM in the MTP assay. Similarly, the compound of example 7(a) demonstrates an inhibition of about 93% at 0.1 μM in the Apo B assay and an IC50 of about 50 nM in the MTP assay.

The in vivo serum triglyceride lowering effect of the compounds of the invention can be determined by measuring their effect on triglyceride levels in mice, rats or dogs according to methodology well known in the art, e.g., in a model of pre-established hypertriglyceridemia in fructose fed rats or in normolipidemic rats.

The in vivo serum cholesterol lowering effect of the compounds of the invention can be determined by measuring their effect on cholesterol levels in mice, rats, or dogs according to methodology well known in the art, e.g., in normolipidemic rats.

Illustrative of the invention, the compound of example 1 (a) lowers both plasma triglycerides and cholesterol at a dose of 5 mg/kg. p.o.

The following examples are intended to illustrate the invention and are not to be construed as being limitations thereon. Temperatures are given in degrees Centrigrade. If not mentioned otherwise, all evaporations are performed under reduced pressure, preferably between about 15 and 100mm Hg (= 20-133 mbar). The structure of final products, intermediates and starting materials is confirmed by standard analytical methods, e.g., microanalysis and spectroscopic characteristics (e.g., MS, IR, NMR). Abbreviations used are those conventional in the art. The concentration for [α]_D determinations is expressed in mg/mL. Compounds are purified by standard methods, e.g., recrystallization or flash chromatography.

Examples

Preparation of Starting Materials

Preparation of optically active 5-aminoindan-2-yl-carbamic acid methyl ester

Method (a)

The alcohol, (1-hydroxy-indan-2-yl)-carbamic acid methyl ester (IS-trans) prepared from L-phenylalanine (18.7g, 0.09mol) (J. Org. Chem. 1983, 48, 2675-2679) is suspended in methylene chloride and cooled to 0°C. Pyridine (10.7 g, 0.135 mol) is added followed by acetyl chloride (10.5 g, 0.135 mol). The mixture is stirred for 1 hour and then washed with sodium bicarbonate, 1 HCI and saturated sodium chloride. The organic layer is dried over Na₂SO₄, filtered and evaporated under reduced pressure to give (1-acetyloxy-indan-2-yl)- carbamic acid methyl ester (1 S-trans).

To 90% HNO₃ (55.1 mL, 0.8 mol) under nitrogen at -30°C is added 100mL of trifluoroacetic acid followed by the addition of trifluoroacetic anhydride (100 g, 0.476 mol) over 5 minutes. The above carbamate (1 -acetyloxy-indan-2-yl)-carbamic acid methyl ester (1 S-frans)) (20.0g, O.Oδmol) in 34 mL of methylene chloride is added slowly (over 90 min.) keeping the temperature between -30 and -35°C. The reaction is worked up by adding 100 mL of water and warmed to 0°C to give two layers. The layers are separated and the aqueous layer extracted with methylene chloride. The combined organic extracts are washed with 100 mL of water (pH is adjusted to 8.5 with sodium bicarbonate), and with cold water. The organic layer is dried over MgSO₄, filtered and evaporated to give crude product. The crude product is crystallized from ethyl acetate and further precipitated by the addition of heptane to give (1-acetyioxy-6-nitro-indan-2-yl)-carbamic acid methyl ester (1S- fraπs); mp 164-167°C.

The above ester (16.5 g, 0.056 mol) is suspended in 275 mL of methanol at room temperature. 1 N Sodium hydroxide solution (112 mL, 0.112 mol) is added and the mixture is stirred at room temperature for 15 minutes. The reaction is diluted with water and the solid is collected. The solid is reslurried in 250 mL of ice-water and pH is adjusted to 6.5- 7.0 with 1 N HCI. The solution is filtered and washed with water, and the product is collected and dried under vacuum to give (1-hydroxy-6-nitro-indan-2-yl)-carbamic acid methyl ester (1S-fraπs); mp 201-203°C.

The above nitro alcohol (6.0 g, 0.023 mol) is dissolved in 300 mL of acetic acid containing 3mL of water at 50°C. The mixture is cooled to room temperature and HCIO₄ (6 g, 0.042 mol) and 10% Pd/C (6 g) are added and the mixture is hydrogenated at 50 psi for two days. Fresh catalyst (3 g) is added twice during the reaction period. The reaction mixture is filtered through celite, the filtrate is concentrated and the residue is washed with ice-water, dried over MgSO₄. The solution is filtered and solvent removed under reduced pressure to give (S)-(5-amino-indan-2-yl)-carbamic acid methyl ester; mp 140-142°C.

(R)-(5-aminoindan-2-yl)-carbamic acid methyl ester, m.p. 144-145⁹C, is similarly prepared from (1-acetyloxyindan-2-yl)-carbamic acid methyl ester (1R-trans), starting with D-phenylalanine instead of L-phenylalanine.

Method b)

Alternately, (R)-(5-aminoindan-2-yl)-carbamic acid methyl ester is prepared as follows:

A mixture of ninhydrin (33 g, 0.185 mol) and acetic acid (554 g) is stirrred at room temperature (rt) under N₂ until complete dissolution of ninhydrin. Sulfuric acid is then added (54.42 g, 0.555 mol) followed by hydroxylamine sulfate (31.63 g, 0.193 mol). The mixture is heated to 55⁹C for 30 minutes and is then allowed to cool to room temperature. 10% Pd/C (2.64 g, 8% w/w) is added to the resulting yellow suspension and the mixture is hydrogenated at a pressure of H₂ of 20 psi. After stirring for 1 hour at rt, the H₂ pressure is increased to 40 psi and the temperature increased to 35²C. After stirring for 8 hours, the reaction is allowed to cool before filtration on a pad of Celite (20 g). The Celite cake is washed with acetic acid (70 g). The filtrate is concentrated, xylene (250 g) is added to the resulting slurry and the mixture concentrated again. Xylene (170 g) is added followed by slow addition of 20% NaOH (367 g) until a basic pH and a clear separation of the organic and aqueous layers is obtained. The xylene layer is then separated and filtered. The HCI salt is then precipitated out by slow addition of a 4 N HCI solution in 1-pentanol (51 g). The suspension is cooled to 0⁹C and filtered. The cake is rinsed with heptane (100 g) and dried under vacuum to yield 2-aminoindane hydrochloride as a white powder.

A solution of 118.8 g of 2-aminoindane hydrochloride in 594 mL of water is heated to a temperature of 58-60^gC and 120.0 g of bromine is added over a period of 50 minutes while maintaining an internal temperature at 58 to 62⁹C. The mixture is stirred at 60-62⁹C for 1 hour and 107 mL of hydrobromic (48%) is added over a period of 5 minutes while maintaining the internal temperature of 60-62⁹C. The mixture is stirred for an additional 10 minutes. The reaction mixture is cooled to an internal temperature of 20-23⁹C over a period of 1 hour. The resulting solid is collected by filtration, washed with 3 x 133 mL of 2- propanol and dried at 58-60⁹C under vacuum (10-30 torr) to obtain crude (±)-5-bromo-2- aminoindan hydrobromide. A suspension of 156.0 g of crude (±)-5-bromo-2-aminoindane hydrobromide in 390 mL of deionized water is heated to a temperature at 95-100°C to obtain a clear solution. The solution is cooled to an internal temperature at 20-23°C over a period of 2.5 hours and stirred at 20-23°C for an additional 30 minutes. The resulting solid is collected by filtration and washed with 3 x 20 mL of water (precooled to 0-5°C), and dried at 60-65°C under vacuum (10-30 torr) with nitrogen bleeding to obtain (±)-5-bromo-2- aminoindane hydrobromide. A mixture of 130.0 g of (±)-5-bromo-2-aminoindane hydrobromide and 1500 mL of isopropyl acetate is stirred at 20-25°C under nitrogen. A solution (precooled to 20-25°C) of 26.62 g of sodium hydroxide and 186.35 g of sodium chloride in 750 mL of water is added over a period of 5 minutes while maintaining an internal temperature at 20-25°C. The suspension is stirred efficiently until all the solid dissolves (30 minutes). The organic layer is separated and the aqueous layer is extracted with 750 mL of isopropyl acetate. The organic layers are combined to afford -2330 mL of a solution of (±)-5-bromo-2-aminoindane free base.

To the above solution is added 1300 mL of isopropyl acetate and 930 mL of methanol. The solution is stirred under nitrogen and heated to an internal temperature of 65^CC to achieve a gentle refluxing, over a period of 15 minutes. A solution of 103.1 g of (1S)-(+)-10-camphorsulfonic acid in 660 mL of methanol is added over a period of 15 minutes while maintaining an internal temperature of 60-65°C to obtain a clear solution followed by 185 mL of methanol to achieve a v v ratio of isopropyl acetate : methanol of about 2 : 1. The reaction mixture is cooled to 20-23°C over a period of 2 hours. The mixture is stirred at room temperature (20-23°C) for an additional 2 hours. The solid is collected, washed with 500 mL of precooled (to 0-2°C) mixture of isopropyl acetate and methanol (2:1 ; v/v) in two equal portions of 250 mL each, and dried at 50-55°C (100 mm Hg) to obtain crude (R)-5-bromo-2-aminoindane (1 S)-(+)-10-camphorsulfonate salt as a white solid.

A mixture of 90.0 g of crude (R)-5-bromo-2-aminoindane (1 S)-(+)-10- camphorsulfonate salt and 900 mL of methanol is heated to a temperature of 65°C to achieve a gentle refluxing. This suspension is stirred at 65°C for 1 hour and the reaction mixture is cooled to 20-23°C over a period of 2 hours and stirred at 20-23°C for an additional 2 hours. The resulting solid is collected, washed with 190 mL of precooled (to 0- 2°C) mixture of isopropyl acetate and methanol (1 :1 ; v/v) in two equal protions of 95 mL each. The solid is dried at 50-55^cC (100 mm Hg) to obtain (R)-5-bromo-2-aminoindane (1S)-(+)-10-camphorsulfonate salt as a white solid (98.7% optical purity).

A suspension of 111.1 g of (R)-5-bromo-2-aminoindane (1S)-(+)-10- camphorsulfonate salt and 300 mL of isopropyl acetate is stirred at 20-25°C and a solution of 15.0 g of sodium hydroxide and 75.0 g of sodium chloride in 300 mL of water is added over a period of 10 minutes while maintaining an internal temperature at 20 to 25°C. The suspension is stirred for 30 minutes or until all the solids dissolve. The organic layer is separated and the aqueous layer is extracted with 100 mL of isopropyl acetate. The organic layers containing (R)-5-bromo-2-aminoindane free base are combined. A solution of 60 g of sodium bicarbonate in 600 mL of water is added and the resulting white slurry is stirred under nitrogen and cooled to a temperature of 0-5°C over a period of 15 minutes. A solution of 35.4 g of methyl chloroformate in 200 mL of isopropyl acetate is added over a period of 45 minutes while maintaining an internal temperature of 0-5°C and the mixture is stirred at this temperature for an additional 1 hour. The organic layer is separated and washed with 150 mL of 1 N sulfuric acid is added, then with a solution of 10 g of sodium bicarbonate in 100 mL of deionized water and finally with 150 mL of deionized water. The organic layer is concentrated under vacuum (100-300 torr) at a temperature of 40-50°C to -150 mL of a slurry. Heptane (500 mL) is added and the mixture is again concentrated under vacuum (100-200 torr) at a temperature of 40-50°C to about 300 mL of a slurry. Heptane (500 mL) is again added and the mixture is cooled to an intemal temperature of 0- 5°C. The solid is collected and washed with 40 mL of heptane in two equal portions of 20 mL each. The solid is dried at 60-65°C under vacuum (10-30 torr) to obtain (R)-(5- bromoindan 2-yl)-carbamic acid methyl ester as a crystalline white solid. A mixture of 94.55 g of (R)-(5-bromo-indan-2-yl)-carbamic acid methyl ester, 69.78 g of benzophenone imine, 2.32 g of (±)-2,2'-bis(diphenylphosphino)-1 ,1'-binaphthyl, 26.47 g of sodium methoxide, and 1.60 g of tris(dibenzylideneacetone)dipalladium(0) in 875 mL of deoxygenated and dry toluene is stirred under nitrogen and heated to an internal temperature of 70-75°C over a period of 15 minutes. The mixture is stirred at this temperature for 16 hours, and cooled to 30-35°C over a period of 30 minutes. Isopropyl acetate (875 mL) is added over a period of about 15 minutes and the mixture is further cooled to 20-25°C. Water (875 mL) is added over a period of about 15 minutes and the suspension is stirred for an additional 10 minutes. The solid is collected and washed with 175 mL of toluene followed by 263 mL of water to obtain crude (R)-[5-(diphenylmethylene)- amino-indan-2-yl]-carbamic acid methyl ester as a yellow solid. The reaction flask, Buchner funnel, and filtration flask are washed with about 400 mL of isopropyl acetate and this is combined with the filtrate. The organic layer is separated and washed with a solution of 43.75 g of citric acid in 831 mL of water to afford a solution of additional crude (R)-[5- (diphenylmethylene)amino-indan-2-yl]-carbamic acid methyl ester which is added to the above crude product. 2 N Hydrochloric acid (170 mL) is added and the mixture is stirred at an intemal temperature of 20-25°C for 16 hours. Water (350 mL) is then added and the biphasic solution is stirred for an additional 10 minutes. The mixture is filtered, the aqueous layer is separated and washed with a total of 1750 mL of isopropyl acetate in two equal portions to yield about 2200 mL of a solution of (R)-(5-amino-indan-2-yl)-carbamic acid methyl ester hydrochloride. The solution is cooled to 0-5°C over a period of 15 minutes. 2 N sodium hydroxide (2175 mL) is added to adjust the pH to 8-9 in 45 minutes while maintaining an internal temperature below 18°C. A solution of 93.5 g of sodium chloride in 267 mL of water is added and the resulting suspension is stirred at this temperature for an additional 30 minutes. The solid is collected by filtration and washed with 438 mL of water in two equal portions. The solid is dried at 55-60°C under vacuum (10-30 torr) with nitrogen bleeding to obtain crude (R)-(5-amino-indan-2-yl)-carbamic acid methyl ester as a solid.

A mixture of crude (R)-(5-amino-indan-2-yl)-carbamic acid methyl ester, activated carbon (about 0.15 times weight of the weight of crude material) and methanol (about 20 times volume of the weight of crude material) is stirred and heated to an internal temperature at 65°C to achieve a gentle refluxing over a period of 15 minutes. The mixture is stirred at this temperature for an additional 2 hours and filtered through celite to afford a solution of (R)-(5-aminoindan-2-yl)-carbamic acid methyl ester. The solution is concentrated under vacuum (200-400 torr) at an internal temperature of 45-55°C to a small volume. Water is added (the ratio of methanol and water should be about 1 :1). The mixture is cooled to an internal temperature of 0-5°C. The resulting suspension is filtered, the solid is washed with a precooled mixture of methanol and water (1 :1 ; v/v) and dried at 55-60°C under vacuum (10-30 torr) under nitrogen to yield (R)-(5-amino-indan-2-yl)-carbamic acid methyl ester.

Preparation of (R)-6-Methyl-4'-trifluoromethylbiphenyl-2-carboxylic acid [2- methoxycarbonylaminoindan-5-yll-amide:

A solution of 2.5 g of 6-methyl-4'-trifluoromethyl-biphenyl-2-carboxyiic acid in 8mL of tetrahydrofuran is added to a solution of 1.2 g of oxalyl chloride and 0.06 g of dimethylformamide in 16 mL of tetrahydrofuran at 0-5⁹C over 20 minutes and the temperature is maintained at 0-5°C for 1 hour to obtain the solution of the acid chloride.

To a solution of 1.6 g of (R)-(5-aminoindan-2-yl)-carbamic acid methyl ester in 32 mL of tetrahydrofuran cooled to 0 to 5⁹C is added 3.2 g of triethylamine.

The above acid chloride solution is then added over about 25 minutes at a temperature below 8⁹C. The reaction mixture is warmed to 0-5⁹C and stirred for 2 hours.

The solvent is exchanged to ethyl acetate by concentrating to a volume of 20 mL at ca. 70mbar/40⁹C, adding 40 mL of ethyl acetate, concentrating to a volume of 30 mL and adding a further 20 mL of ethyl acetate.

The ethyl acetate solution is sequentially washed with 20 mL of water, 10 mL of 2N HCI, 3x15 mL of 5% sodium tetraborate decahydrate and 20 mL of water, and then evaporated to dryness. The crude foam is then crystallized from ethyl acetate/heptane to yield title compound (see Example 1 ).

Preparation of 6-Methyl-4'-trifluoromethylbiphenyl-2-carboxylic acid

3-Methylsalicyiic acid is esterified to methyl 3-methylsalicylate by reaction under reflux for about 48 hours with methanol in the presence of trimethyl orthoformate (4.0 moles) and concentrated sulfuric acid (1.1 moles) while removing by distillation the generated methyl formate and replacing the methanol which is lost by distillation. The reaciton mixture is then evaporated to dryness at 40⁹ under vacuum and toluene is added. The toluene solution is washed with water, then 20% aqueous potassium bicarbonate solution and saturated sodium chloride solution. The toluene solution is filtered through neutral activated aluminum oxide and evaporated to dryness to yield methyl 3-methylsalicylate as a liquid.

To a solution of 1.0 mole of methyl 3-methylsalicylate in toluene are added 2.33 moles of 4-methylmorpholine and 0.022 moles of 4-dimethylaminopyridine. The resulting solution is then treated with 1.07 moles of trifluoromethanesulfonic acid anhydride (triflic anhydride) at -15⁹C. The reaction mixture is stirred overnight at -3 to -4⁹C and washed consecutively with 3.7% aqueous HCI, 20% potassium bicarbonate solution and saturated sodium chloride solution. The toluene solution is then filtered through alumina and evaporated to dryness at less than 50^SC and about 40 tnmHg pressure. The residue is distilled at 50⁹C and 5 mmHg pressure to obtain methyl 3-methyl-2-trifluoromethanesulfonyloxybenzoate as an oil.

A solution of 140.75 g of 4-bromobenzotrifluoride and 117.6 g of triisopropylborate in 1050 mL of dry and peroxide-free THF is cooled to -72± 3⁹C. 275 mL of 2.5 M n-BuLi solution in hexane are slowly added over a period of 90 minutes at such a rate that the internal temperature of the reaction mixture remains below -60⁹C. The mixture is stirred at - 65 to -70⁹C for 30 minutes after the addition and warmed to 0⁹C over 90 minutes. This solution of diisopropyl 4-trifluoromethylphenylboronate is used as is in the next step.

A solution of 155 g of methyl 3-methyl-2-trifluoromethylmethanesulfonyloxybenzoate, 107.8 g of potassium carbonate in 467.5 mL of THF and 935 g of deionized water is stirred under nitrogen for 20 minutes. 15.0 g of Tetrakis(triphenylphosphine)pailadium (0) and -1610 mL of boronate solution from step above are added and the reaction mixture is heated under gentle reflux (~64⁹C) for 16 hours. The reaction mixture is cooled to room temperature and filtered through a pad of 40 g of the filter agent Celite^® 521. The filter cake is washed with 100 mL of THF and the total filtrate is partially evaporated under reduced pressure (110-120 mbar/40⁹C) to remove about 1500 mL of distillate and obtain a three phase mixture (about 1250 mL). 500 mL of f-Butyl methyl ether and 200 mL of 2% sodium chloride solution are added. The mixture is stirred for 5 minutes and filtered through a pad of 40 g of Filter agent, Celite^® 521 and the filter cake is washed with 100 mL of f-butyl methyl ether. The top organic layer (1100 mL) is separated from the bottom aqueous layer (950 mL). The bottom aqueous layer (950 mL) is extracted with 300 mL of f-butyi methyl ether. The combined upper organic phases are washed with 300 mL of 2% sodium chloride solution and evaporated under reduced pressure (28 mbar/40⁹C) to obtain methyl 6-methyl- 4'-trifluoromethyl-biphenyl-2-carboxylate.

6N Sodium hydroxide (260 mL) is added slowly at room temperature to a solution of 183 g of methyl 6-methyl-4'-trifluoromethyl-biphenyl-2-carboxylate in 1200 mL of methanol. The reaction mixture is heated under gentle reflux for 2.5 hours, cooled to room temperature and diluted with 300 mL of water. The reaction mixture is evaporated under reduced pressure (110-120 mbar/40⁹C) to a suspension of about 750 mL which is filtered through the filter agent Celite^® 521 , and the filter cake is washed sequentially with 250 mL of water and 250 mL of heptane. The organic layer is separated and the aqueous layer is washed with 250 mL of heptane. The aqueous layer is acidified with 500 mL of 4N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate extract is washed with water and filtered through the filter agent Celite^® 521. The ethyl acetate solution (ca.1000 mL) is evaporated under reduced pressure (110-120 mbar/40⁹C) to a volume of 600 mL to which is added heptane (3125 mL). The suspension is then heated to reflux until a clear solution is obtained, the solution is cooled to 0⁹C and the resulting solid is filtered off to yield 6-methyl-4'-trifluoromethyl-biphenyl-2-carboxylic acid (See Example 1).

Example 1

(a) (R)-6-Methyl-4'-trifluoromethylbiphenyl-2-carboxylic acid r2-(2-pyridylmethylaminol- indan-5-yl -amide

A solution of 2-bromo-3-methylbenzoic acid (21.5 g, 100 mmol) in 500 mL of methanol and 8 mL of concentrated sulfuric acid is refluxed overnight. Methanol is removed under reduced pressure, the residue is taken up in ether, washed with sodium bicarbonate, brine, and dried over magnesium sulfate, filtered, and evaporated under reduced pressure to give methyl 2-bromo-3-methylbenzoate as an oil.

A mixture of methyl 2-bromo-3-methylbenzoate (22.33 g, 97.5 mmol), potassium phosphate (82.8 g, 390 mmol), [1 ,1'-bis(diphenylphosphino)-ferrocene]dichloro palladium (II), complex with dichloromethane (1 :1) (3.98 g, 4.87 mmol), and p- trifluoromethylphenylboronic acid (22.2 g, 117 mmol) in 500 mL of DME is degassed and refluxed under an atmosphere of argon overnight. The mixture is concentrated, poured into water and extracted with ethyl acetate. The combined organic extracts are washed with brine, dried over magnesium sulphate, filtered and evaporated under reduced pressure. The residue is purified by silica gel chromatography eluting with ethyl acetate / toluene (1:9) to give methyl 6-methyl-4'-trifluoromethyl-biphenyl-2-carboxylate.

Alternatively, methyl 6-methyl-4'-trifluoromethyl-biphenyl-2-carboxylate can be prepared as follows:

To a slurry of 3-methylsalicylic acid (200 g) in 600 mL of methanol at -15⁹ is added 65.7 g of concentrated sulfuric acid. The mixture is treated at reflux temperature for 5 days. The reaction mixture is concentrated, and methyl-t-butyl ether (500 mL) and water (250 mL) are added. The ether layer is separated, washed with bicarbonate solution and evaporated to dryness to give methyl 3-methylsalicylate an oil.

A mixture of methyl 3-methylsalicylate (150 g), pyridine (178.5 g) and methylene chloride (1500 mL) is cooled to -5^s. Triflic anhydride (305.6 g) is added over 30 minutes. 4- Dimethylaminopyridine (3.31 g) is then added, the reaction mixture is stirred at room temperature overnight, washed with 1 N HCI, then with saturated sodium bicarbonate solution and finally with brine. The solution is dried over magnesium sulfate, and evaporated to dryness in the presence of toluene. The residual oil is disoived in toluene to obtain a volume of 3000 mL and the solution of methyl 2-trifluoromethanesulfonyloxy-3- methylbenzoate is used as is in the next step. A solution of p-trifluoromethylbromobenzene (814.8 g) and triisopropoxyborane (681.0 g) in tetrahydrofuran (6300 mL) is cooled to -78^s and n-butyllithium (2.5 m in hexanes, 1448 mL) is added over 30 minutes at a temperature below -60⁹ to yield p- trifluoromethylphenylboronic acid. To a solution of methyl 2-trifluoromethanesulfonyloxy-3- methylbenzoate (900 g, in toluene), potassium carbonate (629.6 g), tetrahydrofuran (2700 mL) and deionized water (5400 mL) under nitrogen is added tetrakis (triphenylphosphine) palladium (0) (104.6 g). To this is added the above solution of p- trifluoromethylphenylboronic acid and the mixture is heated at reflux for 2 days. The reaction mixture is filtered and evaporated to dryness. The residue is partitioned between water and ethyl acetate. The ethyl acetate layer is separated and evaporated to dryness. The residue is taken up in heptane-ethyl acetate (9:1), the mixture is filtered and the filtrate is evaporated to dryness to give methyl 6-methyl-4'-trifiuoromethylbiphenyl-2-carboxylate as an oil.

A mixture of methyl 6-methyl-4'-trifluoromethyl-biphenyl-2-carboxylate (13.6 g, 46.3 mmol), and 1 N NaOH (92.5 mL, 92.5 mmol) in 225 mL of ethanol is refluxed for 5 h. Water is added to the mixture and the aqueous layer is washed with ether. The aqueous layer is acidified with 1 N HCI and extracted with ethyl acetate, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The product is purified by crystallization from ethyl acetate / hexanes to yield 6-methyl-4'-trifluoromethyl-biphenyl-2-carboxylic acid melting at 202-203°C. ¹HNMR CDCI₃: 300 MHz): δ 7.87 (1H, d),7.65(2H, d), 7.47(1 H, d),7.35 (1 H, t), 7.25 (2H, d), 2.05(3H, s). MS m/z 279 (M -1 ).

To an ice bath cooled suspension of 6-methyl-4'-trifluoromethyl-biphenyl-2-carboxylic acid (17.7 g, 63.2 mmol) in 500mL of methylene chloride is added oxalyl chloride (22.1 mL, 253 mmol) followed by 4 drops of DMF. The reaction is stirred for 2 h and another 22 mL of oxalyl chloride and 4 drops of DMF is added. Stirring is continued another 2 h. The mixture is concentrated under reduced pressure. Methylene chloride (100 mL) is added and the acid chloride is used as is in subsequent reactions.

To an ice bath cooled solution of (R)-(5-aminoindan-2-yl)-carbamic acid methyl ester (9.5 g, 46.1 mmol), ([α] _D = -26.29° (c = 9.87 mg/mL, DMSO); mp 144-145°C) and pyridine (4.48 mL, 55.5 mmol) in 200 mL of methylene chloride is added 6-methyl-4'-trifiuoromethyl- biphenyl-2-carboxylic acid chloride ( 80.5 mL of a 0.63 M solution in methylene chloride, 50.7 mmol). The reaction is stirred for 15 minutes at room temperature. The mixture is washed with 1 N HCI, bicarbonate and brine. The organic layer is dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The product is purified by crystallization from ethyl acetate / hexanes (1:2) to give (R)-6-methyl-4'- trtfluoromethylbiphenyl-2-carboxylic acid (2-methoxycarbonylaminoindan-5-yl)-amide as a crystalline solid, mp 112-114°C. [α]_D = -12.85°, c=11.36 mg/mL DMS0.

(R)-6-methyl-4'-trifluoromethylbiphenyl-2-carboxylic acid (2- methoxycarbonylaminoindan-5-yl)-amide (6.5 g, 13.9 mmol) is dissolved in acetonitrile (325 mL) and cooled to 0°C under nitrogen, lodotrimethylsilane (11.1 g, 55.6 mmol) is added dropwise, the mixture is allowed to warm to room temperature and is stirred overnight. Methanol (100 mL) is added and the mixture is stirred for 1 hour and then concentrated in vacuo. The residue is dissolved in ethyl acetate (750 mL) and washed with saturated sodium bicarbonate (2x 125 mL), water (125 mL), 5% Na₂S₂O₃ solution (125 mL), water (125 mL), and brine (50 mL). The organic phase is dried over sodium sulfate and concentrated to afford (R)-N-(2-aminoindan-5-yl)-6-methyl-4'-trifluoromethylbiphenyl-2- carboxamide.

The amine is dissolved in methanol (160 mL), triethylamine (1.45 g, 14.4 mmol) and 2- pyridinecarboxaldehyde (1.59 g, 14.8 mmol) are added, and the mixture is stirred overnight. Polymer supported borohydride (Aldrich, borohydride on Amberiite IRA-400, 2.5 mmol g, 6.0 g, 14.8 mmol) is added and the mixture is stirred for an additional 24 hours. The resin is removed by filtration and the filtrate is concentrated in vacuo. The residue is dissolved in a small amount of ethyl acetate and triturated with hexane to yield (R)-6-methyl-4'- trifluoromethylbiphenyl-2-carboxylic acid [2-(2-pyridylmethyiamino)-indan-5-yl] amide as a solid. The solid is dissolved in ethanol (100 mL) and a saturated solution of HCI (g) in ethyl ether is added. The resulting solid is collected to yield (R)-6-methyl-4'- trifluoromethylbiphenyl-2-carboxylic acid [2-(2-pyridylmethylamino)-indan-5-yl] amide hydrochloride, m.p. 281-283°C.

(b) Similarity prepared is (S)-6-methyl-4'-trifiuoromethylbiphenyl-2-carboxylic acid [2-(2- pyridylmethylamino)-indan-5-yl] amide, m.p. 161 -162°C. Example 2

To N-(5-nitro-indan-2-yl)-acetamide (23.5 g, 107 mmol) is added 2N hydrochloric acid (500 mL). The mixture is heated to reflux for 24 h and then concentrated in vacuo. Methanol (100 mL) is added to the residue and the mixture is concentrated in vacuo. Toluene (100mL) is added and the mixture is again concentrated. A solution of the residue in methanol (100 mL) is warmed, diethyl ether (500 mL) is added and the mixture is let stand overnight. The solid is collected by filtration and air dried to yield 2-amino-5-nitro- indane hydrochloride as a white solid.

To a solution 2-amino-5-nitro-indane hydrochloride (20.4 g, 95 mmol) in methylene chloride (500 mL) under nitrogen is added diisopropylethylamine (14.7 g, 114 mmol). To this is added a solution of di-tert-butyldicarbonate (22.8 g, 105 mmol) in methylene chloride. The mixture is stirred for 16 h, washed with brine, 1N hydrochloric acid, brine, and then dried over sodium sulfate. The solution is concentrated in vacuo to give a solid residue which is triturated with diethyl ether to give (5-nitro-indan-2-yl)-carbamic acid tert-butyl ester as a white solid.

A solution of (5-nitro-indan-2-yl)-carbamic acid tert-butyl ester (3.52 g, 12.6 mmol) in ethanol (100 mL) is degassed and 10% palladium on carbon added. The reaction is evacuated and placed under 1 atm H₂(g) for 2 hours. Filtration of the reaction mixture through Celite is followed by concentration of the filtrate under reduced pressure to give (5- aminoindan-2-yl)-carbamic acid tert-butyl ester as an oil which is used directly without further purification. To a solution of 5-amino-indan-2-yl)-carbamic acid tert-butyl ester (12.5 mmol) in methylene chloride (75 mL) is added diisopropylethyl amine (3.3 g, 25 mmol) followed by a solution of 6-methyl-4'-trifluoromethyl-2-biphenylcarboxylic acid chloride in methylene chloride (See Example 1 , 12.6 mmol). After stirring 16 hours, the reaction mixture is poured into ethyl acetate and washed with 1 N HCI, NaHCO3 solution, and brine. The organic layer is dried (MgSO4) and concentrated under reduced pressure to give a solid.

Recrystallization from toluene gives {5-[(6-methyl-4'-trifluoromethylbiphenyl-2-carbonyl)- amino]-indan-2-yl}-carbamic acid tert-butyl ester.

A solution of {5-[(6-methyl-4'-trifluoromethylbiphenyl-2-carbonyl)-amino)-indan-2-yl}- carbamic acid tert-butyl ester (5.19 g, 10.5 mmol) in formic acid (40 mL) is heated to 40 °C with stirring. After 3 hours, the reaction mixture is cooled to room temperature and stirring is continued for 16 hours. The reaction mixture is concentrated under reduced pressure and the resulting oil dissolved in ethyl acetate. The organic layer is washed with 8% NaHCO3 solution until the aqueous layer remains basic at which point a precipitate forms in the organic layer. The precipitate is collected by filtration to give 6-methyl-4'- trifluoromethylbiphenyl-2-carboxylic acid (2-amino-indan-5-yl)-amide.

lmidazole-2-carboxaldehyde (2.45 g, 25.5mmol) is added to a solution of 6-methyl-4'- trifluoromethyl-biphenyl-2-carboxylic acid (2-amino-indan-5-yl)-amide hydrochloride (11.1 g, 24.9 mmol) and triethylamine (5.05 mL, 50.0 mmol) in methanol (500 mL). The mixture is stirred at room temperature for 16 hours. Polymer supported borohydride (Aldrich, borohydride on Ambelite IR-400, 2.5 mmol/g, 10.0 g, 25.0 mmol) is added, the mixture stirred for 2 hours, filtered and concentrated under reduced pressure. The residue is taken up in ethanol (100 mL) and a saturated solution of hydrochloric acid gas in diethyl ether (10 mL) is added. The white precipitate is collected to yield 6-methyl-4'-trifluoromethylbiphenyl- 2-carboxylic acid [2-(2-imidazolylmethyiamino)-indan-5-yl] amide hydrochloride, m.p. 240- 242°C. Free base has m.p. 169-170⁹C. Example 3

The following compounds are prepared similarly to the previous example, starting from racemic (5-aminoindan-2-yl)-carbamic acid methyl ester.

* = 2-naphthalenesulfonate salt

Example 4

6-Methyl-4'trifluoromethylbi^phenyl-2-carboxylic acid r7-(2-pyridylmethylaminoV6,7,8,9- tetrahydro-5H-benzocvclohepten-2-vπ-amide

To 6,7,8,9-tetrahydro-5H-benzocyclohepten-7-one (2.56 g, 16 mmol) and hydroxylamine hydrochloride (2.2 g, 32 mmol) in 27 mL of water is slowly added a solution of sodium carbonate (1.69 g, 16 mmol) in 14 mL of water. The mixture is stirred overnight. The solid is then filtered off, washed with water, and dried at 50 °C under reduced pressure to give 6,7,8, 9-tetrahydro-N-hydroxy-5H-benzocyclohepten-7-amine as a white solid.

To a suspension of NaBH₄ (1.98 g, 52.3 mmol) in 40 mL of DME cooled in an ice-bath is added TiCI₄. To this mixture is added the above compound (2.3 g, 13.1 mmol) in 28 mL of DME dropwise. The mixture is stirred overnight, poured into ice water (135 mL), basified with 28% ammonia (20 mL) and extracted with ethyl acetate. The organic extracts are dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 6,7,8,9- tetrahydro-5H-benzocyclohepten-7-amine as an oil.

The amine is treated with methyl chloroformate, nitrated, reduced, acylated with 6- methyl-4'-trifluoromethylbiphenyl-2-carboxylic acid chloride , then N-deprotected and treated with 2-pyridinecarboxaldehyde under conditions similar to those described above for indane derivatives to give the title compound; m.p. 145-148°C.

Example 5

To a solution of N-(2-aminoindan-5-yl)-6-methyl-4'-trifluoromethylbiphenyl-2- carboxamide (0.3 g, 0.73mmol) in methylene chloride (3 mL) is added 3-thiophene carboxaldehyde (0.068 mL, 0.73 mmol) and sodium triacetoxyborohydride (0.2 g, 0.95 mmol). The mixture is stirred for 3 hours and then washed with brine. The organic phase is dried over magnesium sulfate and concentrated in vacuo. The residue is purified by flash chromatography (SiO₂; hexane/ethyl acetate) to give 6-methyl-4'-trifluoromethylbiphenyl-2- carboxylic acid [2-(2-di(thienylmethyl)amino)indan-5-yl]amide as a white foam, mp 58-64°C.

Example 6

To a solution of 6-methyl-4'-trifluoromethylbiphenyl-2-carboxylic acid [2-(2- pyridylmethylamino)-indan-5-yl] amide (the compound of Example 3(f), 0.4 g, 0.8 mmol) in methylene chloride (5 mL) is added triethylamine (0.12 g, 1.15 mmol) and paraformaldehyde (0.024 g, 0.8 mmol). The mixture is stirred for two hours and then sodium triacetoxyborohydride (0.24 g, 1.12 mmol) is added. The mixture is stirred overnight and then washed with dilute sodium bicarbonate, dried over sodium sulfate, and evaporated. The residue is purified by flash chromatography (SiO₂; ethyl acetate) to afford 6-methyl-4'-trifluoromethylbiphenyl-2-carboxylic acid [2[(2-pyridylmethyl)(methyl)amino]- indan-5-yl] amide as a white solid, mp 105-115^s.

Example 7

(a) 6-Methyl-4'-trifluoromethylbiphenyl-2-carboxylic acid [2-(2-pyridylamino)-indan-5-yπ amide

A solution of tiis(dibenzylideneacetone)dipalladium(0) (180) mg, 0.19 mmol), 1,3- biddiphenylphosphino)propane(80 mg, 0.19 mmol) and 32 mL of toluene in a pressure bottle is degassed and filled with argon. To this mixture is added 6-methyl-4'- trifluoromethylbiphenyl-2-carboxylic acid (2-aminoindan-5-yl)-amide (see example 2) (2.0 g, 4.87 mmol) and 2-bromopyridine (1.08 g, 6.82 mmol). This mixture is stirred at room temperature for 5 minutes. Sodium tert-butoxide (1.22 g, 12.7 mmol) is added and the mixture is stirred for 16 hours at 120°C. The reaction is cooled, extracted with ethyl acetate and the extract is washed with water, dried over MgSO4, filtered, concentrated, and the residue chromatographed on silica gel eluting with (1:1) hexane / ethyl acetate to give an oil. The oil is triturated with ether and the solid collected and dried to yield title compound, m.p. 169-172°C.

(b) Similarly prepared is (S)-6-methyl-4'-trifluoromethylbiphenyl-2-carboxylic acid [2-(2- pyrimidinylamino)-indan-5-yl] amide, m.p. 93-96°. Example 8

Hard gelatin capsules, comprising 50 mg active substance can be prepared for example as follows: Composition (for 1000 capsules) Active ingredient 50.0 g

Lactose 250.0 g

Microcrystalline cellulose 30.0 g Sodium Lauryl sulfate 2.0 g

Magnesium stearate 8.0 g

The sodium lauryl sulfate is added to the lyophiiized active ingredient via a sieve with a mesh size of 0.2 mm. Both components are intimately mixed. Then first the lactose is added via a sieve with a mesh size of 0.6 mm and then the microcrystalline cellulose via a sieve with a mesh size of 0.9 mm. Thereupon these components are intimately mixed for a further 10 minutes. Finally the magnesium stearate is added via a sieve with a mesh size of 0.8 mm. After 3 minutes of further mixing, the formulation is filled into hard gelatin capsules of size 0 (340 mg each).

Claims

What is claimed is:

1. A compound of formula

wherein R₂-C, R₃-C, R -C or R₅-C may be replaced by N; and wherein n is 1 , 2 or 3;

R_T is carbocyclic aryl or heteroaryl;

R₂, R₃, FU and R₅ are independently hydrogen, lower alkyl, lower alkoxy, halo, trifluoromethyl or cyano;

R₆ is heteroaryl or heteroaryl-lower alkyl; R₇ is hydrogen, lower alkyl or carbocyclic or heterocyclic aryl-lower alkyl; or a pharmaceutically acceptable salt thereof; or an enantiomer thereof.

2. A compound according to claim 1 of formula I'

wherein R₂-C, R₃-C, R₄-C or R₅-C may be replaced by N; and wherein n, and R R₇ have meaning as defined in claim 1 ; a pharmaceutically acceptable salt thereof; or an enantiomer thereof.

3. A compound according to claim 1 of formula la

wherein X is R₂-C or N; and n, and R1-R7 have meaning as defined in claim 1; a pharmaceutically acceptable salt thereof; or an enantiomer thereof.

4. A compound according to claim 3 of formula la wherein n is 1 or 3; X is R₂-C and R₂ is hydrogen or d-d-alkyl; R₃ is hydrogen; R₄ is hydrogen or Cι-C₄-alkyl; R₆ is d-d-alkyl substituted by pyrrolyl, thienyl, imidazolyl, thiazolyl, pyridyl, or quinolyl, each of which is unsubstituted or substituted by a substituent selected from the group consisiting of d-d- alkyl, Cι-d-alkoxy, trifluoromethyl, halo, or cyano; or is pyrrolyl, thienyl, imidazolyl, thiazolyl, pyridyl, or quinolyl, each of which is unsubstituted or substituted by a substituent selected from the group consisiting of d-C₄-alkyl, d-C₄-alkoxy, trifluoromethyl, halo, or cyano; R₇ is hydrogen, C C alkyl or d-d-alkyl substituted by pyrrolyl, thienyl, imidazolyl, thiazolyl, or pyridyl, each of which is unsubstituted or substituted by a substituent selected from the group consisiting of d-d-alkyl, d-C -alkoxy, trifluoromethyl, halo, or cyano; a pharmaceutically acceptable salt thereof; or an enantiomer thereof.

5. A compound according to claim 3 of formula lb

wherein Ri is monocyclic carbocyclic aryl or heteroaryl; X is R₂-C or N; R₂, R₃, FU, and R₅ are independently hydrogen, lower alkyl, halo, trifluoromethyl, cyano, or lower alkoxy; and R₆ and R₇ have meaning as defined in claim 1 ; or a pharmaceutically acceptable salt thereof; or an enantiomer thereof.

6. A compound according to claim 1 of formula lc

wherein R₂, R₃ and FU are independently hydrogen, d-d-alkyl, Cι-C -alkoxy, trifluoromethyl, chloro or fluoro; R₇ is hydrogen or methyl; R₈ is trifluoromethyl, chloro or cyano; m is zero or one; and Het is heteroaryl; a pharmaceutically acceptable salt thereof; or an enantiomer thereof.

7. A compound according to claim 6 of formula lc wherein m is one; R₂ is methyl; R₃ and R₄ are hydrogen; R₇ is hydrogen; R₈ is trifluoromethyl; Het is 2-pyridyl; a pharmaceutically acceptable salt thereof; or an enantiomer thereof.

8. A compound according to claim 1 selected from the group consisting of (R)-6-methyl-4'-trifluoromethylbiphenyl-2-carboxylic acid [2-(2-pyridylmethyiamino)-indan-5- yl] amide;

6-methyl-4'-trifluoromethylbiphenyl-2-carboxylic acid [2-(2-imidazolylmethylamino)-indan-5- ylj amide;

6-methyl-4'trifluoromethylbiphenyl-2-carboxylic acid [7-(2-pyridylmethylamino)-6,7,8,9- tetrahydro-5H-benzocyclohepten-2-yl]-amide; 6-methyl-4'-trifluoromethylbiphenyl-2-carboxylic acid [2-(2-di(thienyimethyl)amino)indan-5- yljamide;

6-methyl-4'-trifluoromethylbiphenyl-2-carboxylic acid [2[(2-pyridylmethyl)(methyl)amino]- indan-5-yl] amide; or

6-methyl-4'-trifluoromethylbiphenyl-2-carboxylic acid [2-(2-pyridylamino)-indan-5-yl] amide; or, in each case, a pharmaceutically acceptable salt thereof.

9. A pharmaceutical composition comprising a compound according to any one of claims 1 to 8 and one or more pharmaceutically acceptable carriers.

10. Use of a compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for inhibiting microsomal triglyceride transfer protein, for decreasing apolipoprotein B secretion, for treating microsomal triglyceride transfer protein or lipoprotein B dependent conditions, or for treating atherosclerosis, hypertriglyceridemia, or hypercholesteremia.