N-BENZOCYCLOALKYL-AMIDE DERIVATIVES AND THEIR USE AS MEDICAMENTS

Abstract: A compound of formula (I) or a pharmaceutically acceptable salt thereof; or an enantiomer thereof. Compounds of formula (I) are useful as inhibitors or microsomal triglyceride transfer protein (MTP) and apolipoprotein B (ApoB) secretion and accordingly for the prevention and treatment of MTP and Apo B dependent conditions.

Description: N-BENZOCYCLOALKYL-AMIDE DERIVATIVES AND THEIR USE AS MEDICAMENTS The invention relates to the compounds of formula wherein R 2 -C, R 3 -C, R -C or R 5 -C may be replaced by N; and wherein n is 1 , 2 or 3; R, is aryl, cycloalkyl or heterocyclyl; R 2 , R 3 , R 4 and R 5 are independently hydrogen, optionally substituted alkyl, halo, amino, substituted amino, trifluoromethyl, cyano, carboxyl, alkoxycarbonyl, aralkoxycarbonyl, (alkyl, aryl or aralkyl)-thio, (alkyl, aryl or aralkyl)-oxy, acyloxy, (alkyl, aryl or aralkyl)-aminocarbonyloxy; or any two of R 2 , R 3 , R 4 and R 5 at adjacent positions are alkylenedioxy; R 6 is hydrogen, optionally substituted alkyl, amino, substituted amino, acylamino, wherein R a is hydrogen or optionally substituted alkyl, R b and R c are independently hydrogen, optionally substituted alkyl, cycloalkyl, aryl or heterocyclyl; or R b and R c together represent lower alkylene or lower alkylene interrupted by O, S, or N-(H, alkyl or aralkyl); R d is optionally substituted alkyl, cycloalkyl, aryl or heterocyclyl; and R β is optionally substituted alkyl, aryl, heterocyclyl, cycloalkyl, amino or substituted amino; 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 prevention and treatment of MTP and Apo B dependent conditions. A particular embodiment of the invention relates to the compounds of formula I' wherein R 2 -C, R 3 -C, R 4 -C or R 5 -C may be replaced by N; and wherein n, and RrR 6 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 R -C or N; and n, and RrR 6 have meaning as defined above. Particular embodiments of the invention relate to the compounds of formula la wherein: (a) Ri represents aryl; (b) Ri represents heterocyclyl, in particular aromatic heterocyclyl (heteroaryl); (c) n is one; (d) X is R 2 -C; (e) X is N; (f) R 6 is amino, substituted amino or acyiamino; (g) R 6 is (h) R 6 is (i) Re is R_ -N- ■ SO 2 R θ Preferred are the compounds of formula la wherein n is 1 ; R<, is monocyciic aryl or heteroaryl; X is R 2 -C or N; R 2 , R 3l R 4 and R 5 are independently hydrogen, lower alkyl, halo, trifluoromethyl, lower alkoxy or amino; and R 6 is amino, substituted amino, acylamino, wherein R a is hydrogen; R and R c are independently hydrogen, lower alkyl, aralkyl, aryl, heteroaryl or heteroaralkyl; or R b and R c together with the nitrogen represent piperidino, morpholino, pyrrolidino, or N-lower alkylpiperazino; R d and R e are lower alkyl, aralkyl, aryl, heteroaryl or heteroaralkyl; and pharmaceutically acceptable salts thereof. Preferred are the compounds of formula I, I' or la wherein R 6 is located on the 5-, 6- or 7- membered saturated ring (n=1 , 2, or 3) at a position not directly adjacent to the ring junction (non-benzylic position). A particular aspect of the invention relates to the compounds of formula I wherein R 2 -C, R 3 -C, R 4 -C or R 5 -C may be replaced by N; wherein n is 1 , 2 or 3; Ri is phenyl or thienyl which in each case is unsubstituted or substituted by a substituent selected from the group consisting of lower alkyl, lower alkoxy, halo, trifluoromethyl, cyano, and trifluoromethoxy; R 2 , R 3 , R 4 and R 5 are independently hydrogen, lower alkyl, lower alkoxy, halo, trifluoromethyl, amino, lower alkyiamino, di-lower aikyl amino, or lower alkanoyl-amino; R 6 is amino, phenyl-lower alkyl-amino, lower alkanoyl-amino, lower alkanoyl-amino in which the alkyl group of the alkanoyl group is substituted by phenyl, by lower alkoxy, by phenoxy, by lower alkylthio, by phenylthio, by di-lower aI.kylamino, by morpholino, by thiomoφholino, by piperazino, or by 4-lower alkyl-piperazino, or is N-methyl-N'-lower alkanoyl-amino, benzoyl-amino, or isoxazolylcarbonyl-amino in which isoxazoyl is unsubstituted or substituted by lower alkyl, or is wherein R a is hydrogen or alkyl, R and R c are independently hydrogen, lower alkyl, 5- to 7-membered cycloalkyl, or phenyl; or R and R c together are morpholino, thiomoφhoiino or lower alkylene; R d is lower alkyl, lower alkyl substituted by lower alkoxy, by lower alkoxy-lower alkoxy, by moφholino, by thiomoφholino, by 2-oxo-1 -pyrrolidino, by pyridyl, by phenyl, or by phenyl which is substituted by a substituent selected from halo, trifluoromethyl, lower alkyl, and lower alkoxy, or is phenyl, phenyl substituted by substituent selected from halo, trifluoromethyl, lower alkyl, and lower alkoxy, or is 5- to 7-membered cycloalkyl, or pyranyl; and R β is lower alkyl, phenyl-lower alkyl, phenyl which is unsubstituted or substituted by a group selected from lower alkyl, lower alkoxy, halo, trifluoromethyl, and lower alkane- sulphonyl, or is naphthyl, thienyl, furyl, isoxazolyl, imidazolyi or quinolinyl each of which is unsubstituted or substituted by a group selected from lower alkyl, halo and trifluoromethyl, or is lower alkyl-amino, di-lower alkyl-amino or 5- to 7-membered cycloalkyl-amino; and pharmaceutically acceptable salts thereof; and enantiomers thereof. A particular aspect of the invention relates to the indane derivatives of formula lb wherein Ar is monocyclic aryl or heteroaryl; X is R 2 -C or N; R 2 , R 3 , R 4 and R 5 are independently hydrogen, lower alkyl, halo, trifluoromethyl, cyano, or lower alkoxy; and R 6 has meaning as defined above in each case. Preferred are the said compounds of formula lb wherein Ar is phenyl or phenyl substituted by fluoro, chloro, trifluoromethyl, cyano or lower alkyl; X is N or R 2 -C; R 2) R 3 , R 4 and R 5 are independently hydrogen, lower alkyl, lower alkoxy, halo or trifluoromethyl; and R 6 has meaning as defined above in each case. Further preferred are the compounds of formula lc wherein R 2 , R 3 and R are independently hydrogen, CrC 4 -alkyl, CrC 4 alkoxy, trifluoromethyl, chloro or fluoro; R 7 is trifluoromethyl, chloro or cyano; and R 6 is wherein R d is Cι-C 4 -alkyl; and R e is Cι-C 4 -alkyl, monocyclic carbocyclic aryl or heterocyclic aryl. Further preferred are the compounds of formula lc wherein R 2 is methyl; R 3 is hydrogen; R 4 is hydrogen or methyl; R 7 is trifluoromethyl or chloro; R d is C C 4 -alkyl; and R β is C C -alkyl or thienyl. A particular embodiment relates to the compounds of formula ic wherein R 2 is methyl; R 3 is hydrogen; R 4 is hydrogen or methyl; R 6 is -NHSO 2 R β wherein R β is methyl or thienyl; and R 7 is trifluoromethyl. Another embodiment relates to the compounds of formula Ic wherein R 2 is methyl; R 3 is hydrogen; R 4 is hydrogen or methyl; R 6 is wherein R d is methyl; and R7 is trifluoromethyl. Also preferred in all of the above, is the more active enantiomer in which the carbon atom bearing the substituent R 6 (if Re is not hydrogen) has either the (R) or the (S)- configuration. 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 "lower" referred to herein in connection with organic radicals or compounds respectively generally defines, if not defined differently, such with up to and including 7, preferably up and including 4 and advantageously one or two carbon atoms. Such may be straight chain or branched. The term "optionally substituted alkyl" refers to unsubstituted or substituted straight or branched chain hydrocarbon groups having 1 to 20 carbon atoms, preferably lower alkyl of 1 to 7 carbon atoms. Exemplary unsubstituted alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl and the like. The term "substituted alkyl" refers to alkyl groups substituted by one or more of the following groups: halo (such as CCI 3 or CF 3 ), hydroxy, alkoxy, alkoxyalkoxy, aryloxy, cyclo- Ikyl, alkanoyl, alkanoyloxy, amino, substituted amino, alkanoylamino, thiol, alkylthio, arylthio, alkylthiono, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aminosulfonyl, nitro, cyano, carboxy, carbamyl, alkoxycarbonyl, aryl, aralkoxy, guanidino, heterocyclyl {e.g., indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl), and the like. 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 "haloalkyl" refers to alkyl which mono- or poiysubstituted by halo, such as trifluoromethoxy. The term "alkylene" refers to a straight chain bridge of 1 to 6 carbon atoms connected by single bonds (e.g., -(CH 2 )χ- wherein x is 1 to 6) which may be substituted with 1 to 3 lower alkyl groups. The term "alkylene interrupted by O, S, N-(H, alkyl or aralkyl)" refers to a straight chain of 2 to 6 carbon atoms which is interrupted by O, S, N-(H, alkyl or aralkyl), such as (m)ethyleneoxy(m)ethylene, (m)ethylenethio(m)ethylene, or (m)ethyieneimino(m)ethylene. The term "cycloalkyl" refers to cyclic hydrocarbon groups of 3 to 8 carbon atoms such as cyclopentyl, cyclohexyl or cycloheptyi. The term "alkoxy" or "alkyloxy" refers to alkyl-O-. The term "alkanoyl" refers to alkyl-C(O)-. The term "alkanoyloxy" refers to alkyl-C(O)-O-. The terms "alkylamino" and "dialkylamino" refer to (alkyl)NH- and (alkyl)2N-, respectively. The term "alkanoylamino" refers to alkyl-C(O)-NH-. The term "alkylthio" refers to alkyl-S-. The term "alkylt iono" refers to alkyl-S(O)-. The term "alkylsulfonyl" refers to al yl-S(0) 2 -. The term "carbamyl" refers to -C(O)-amino or -C(O)-substituted am o. The term "alkoxycarbonyl" refers to alkyl-O-C(O)-. The term "acyl" refers to alkanoyl, aroyl, heteroaryol, aryl-alkanoyl, heteroarylalkanoyl, and the like. The term "aryl" or "ar", refers to monocyciic or bicyclic aromatic hydrocarbon groups having 6 to 12 carbon atoms in the πng portion, such as phenyl, naphthyl, tetrahydronaphthyl, and biphenyl groups, each of which may optionally be substituted by one to four substituents such as alkyl, halo, trifluoromethyl, hydroxy, alkoxy, halo-alkyl, alkanoyl, alkanoyloxy, ammo, substituted amino, alkanoylamino, thiol, alkylthio, nitro, cyano, carboxy, carboxyalkyl, carbamyl, alkoxycarbonyl, alkylthiono, alkylsulfonyl, aminosulfonyl, heterocyclyl and the like. The term "aralkyl" refers to an aryl group linked to an alkyl group, such as benzyl. The term "aralkoxy" refers to an aryl group linked to an alkoxy group, such as locozyloxy. The term "arylsulfonyl" refers to aryl-SO 2 -. The term "aroyl" refers to aryl-CO-. The term "heterocyclyl" refers to an optionally substituted, fully saturated or unsaturated, aromatic or nonaromatic cyclic group, for example, which is a 4 to 7 membered monocyciic, 7 to 11 membered bicyclic, or 10 to 15 membered tricyciic ring system, which has at least one heteroatom in at least one carbon atom-containing ring. Each ring of the heterocyclic group containing a heteroatom may have 1 , 2 or 3 heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms, where the nitrogen and sulfur heteroatoms may also optionally be oxidized and the nitrogen heteroatoms may also optionally be quaternized. The heterocyclic group may be attached at any heteroatom or carbon atom. Exemplary monocyciic heterocyclic groups include pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazoiidinyl, oxazolyl, oxazoiidinyl, isoxazohnyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazoiidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, pipendinyl, piperaz yl, 2-oxopιperazιnyl, 2-oxopιpeπdιnyl, 2-oxopyrrolodιnyl, 2-oxoazepinyl, azepinyl, 4-piperidonyl, pyridyl, pyrazinyl, pyrimidinyl, pyndazinyl, tetrahydropyranyl, moφholmyl, thiamoφholinyl, thiamoφholinyl suifoxide, thiamoφholinyl sulfone, 1 ,3-dιoxolane and tetrahydro-1 ,1-dιoxothienyl, and the like. Exemplary bicyclic heterocyclic groups include indolyl, benzothiazolyl, benzoxazolyl, benzothienyl, quinuclidinyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, chromonyl, coumaπnyl, benzopyranyl, cinnolinyl, quinoxaiinyl, indazolyl, pyrrolopyndyl, furopyridinyl (such as furo[2,3-c]pyridinyl, furo[3,2-b]pyridinyl] or furo[2,3-b]pyndinyl), dihydroisoindolyl, dihydroqumazolinyl (such as 3,4-dihydro-4-oxo-quιnazolinyl) and the like. Exemplary tricyciic heterocyclic groups include carbazolyl, benzidolyl, phenanthrolinyl, acπdinyl, phenanthridinyl, xanthenyl and the like. The term "heterocyclyl" also includes substituted heterocyclic groups. Substituted heterocyclic groups refer to heterocyclic groups substituted with 1 , 2 or 3 of the following: (a) alkyl; (b) hydroxy (or protected hydroxy); (c) halo; (e) ammo or substituted am o; (f) alkoxy; (g) cycloalkyl; (h) carboxy; (i) heterocyciooxy; (l) alkoxycarbonyl, such as unsubstituted lower alkoxycarbonyl; (k) carbamyl, alkylcarbamyl, arylcarbamyl, dialkylcarbamyl; (I) mercapto; (m) nitro; (n) cyano, (o) sutfonamido, sulfonamidoalkyl or sulfonamidodialkyl; (P) aryl; (q) alkylcarbonyloxy; (r) arylcarbonyloxy; (s) arylthio; (t) aryloxy; (u) alkylthio; (v) formyl; (w) arylalkyl; or (x) aryl substituted with alkyl, cycloalkyl, alkoxy, hydroxy, ammo, alkylammo, dialkylamino or halo. The term "heterocyciooxy" denotes a heterocyclic group bonded through an oxygen bridge. The term "heteroaryl" "or heteroar" refers to an aromatic heterocycle, for example monocyciic or bicyclic aryl, such as pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furyl, thienyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, benzothiazolyl, benzoxazolyl, benzothienyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzofuryl, and the like, optionally substituted by e.g., lower alkyl, lower alkoxy or halo. The term "heteroarylsulfonyl" refers to heteroaryl-SO 2 -. The term "heteroaroyl" refers to heteroaryl-CO-. The term "acylamino" refer to acyl-NH-. The term "substituted amino" refers to amino mono- or, independently, disubstituted by alkyl, aralkyl, aryl, heteroaryl, cycloalkyl, cycloalkylaikyl, heteroaralkyl, or disubstituted by lower alkylene or lower alkylene interrupted by O, S, N-(H, alkyl, aralkyl) and the like. Pharmaceutically acceptable salts of any acidic compounds of the invention are salts formed with bases, namely cationic salts such as alkali and alkaline earth metal salts, such as sodium, lithium, potassium, calcium, magnesium, as well as ammonium salts, such as ammonium, trimethyiammonium, diethylammonium, and tris-(hydroxymethyl)- methylammonium salts. Similarly acid addition salts, such as of mineral acids, organic carboxylic, and organic sulfonic acids e.g., hydrochloric acid, methanesulfonic acid, maieic acid, are possible provided a basic group, such as amino or 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. 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 H 2 N OO NHBOC wherein BOC is the protecting group t-butoxycarbonyl, with e.g, an activated carboxyl derivative, e.g. a compound of formula III wherein R R 5 and X have meaning as defined above, in the presence of a base such as N-methylmoφholine, diisopropylethylamine or pyridine to provide compounds of the formula IV J T NHBOC IV Compounds of formula IV are then reacted with an acid such as HCO 2 H, to form compounds of formula V Compounds of formula V are then treated with an electrophile corresponding to the amino substituent in R 6 , such as an appropriately substituted sulfonyl chloride (e.g., phenylsulfonyl chloride), a chloroformate (e.g., methyl chloroformate), an acid chloride (e.g., acetyl chloride), an isocyanate (e.g., phenyl isocyanate), an isothiocyanate (e.g., phenyl isothiocyanate) and the like, optionally in the presence of a base such as sodium hydroxide or triethylamine to form compounds of formula la. Compounds of formula V may be N- alkylated according to methods well known in the art prior to treatment with an electrophile. 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 BOC-anhydride and subsequent reduction, e.g., by catalytic hydrogenation, of the nitro group. Compounds of formula III wherein Ri is aryl or heteroaryl are prepared as shown 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 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 oxaiyl chloride gives acid chlorides of formula III. Compounds of formula V wherein Ri is aryl or heteroaryl may also be prepared using the alternative synthesis below: IX PdCI2(dppf) R1-B(0H)2 K3P0 As shown above, amines of formula II are acylated with compounds of formula IX in the presence of a base such as N- methylmoφholine, diisopropylethylamine or pyridine to give compounds of the formula X. Palladium catalyzed aryl-aryl coupling of aryl boronic acids of formula (R B(OH)2) with aryl bromides of the formula X (or iodides or triflates) gives compounds of formula IV. Acid, e.g., formic acid, treatment readily deprotects the nitrogen to give compounds of formula V. Compounds of formula I wherein R 6 is disubstituted amino may also be prepared by the alternative synthesis illustrated below: C - NHCO = E _ 2-(Ethoxycarbonylamino)- indanes of formula XI are reduced with a reducing agent such as lithium aluminum hydride to give the N-methylamine of formula XII. Acylation, e.g., with sulfonyl chlorides, gives compounds of the formula XIII. Nitration followed by catalytic hydrogenatioπ gives amines of the formula XV (via intermediate XIV). Acylation of compounds of formula XV with compounds of the formula III in the presence of diisopropylethyl amine gives compounds of formula I where R 6 is [ Compounds of formula I wherein R 6 is are similarly prepared. Chiral compounds of the invention can be prepared as follows: (a) reducing (1 S-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 formula la wherein R 6 is derivatized amino as defined herein for R 6 . For example, chiral compounds of the invention, can be prepared e.g., by acylating a protected amine of e.g., formula XVI with acetyl chloride to form compounds of formula XVII Compounds of formula XVII are nitrated with nitric acid, trifluoroacetic acid and trifluoroacefic anhydride to form compounds of formula XVIII O I XVIII CCOCH, Compounds of formula XVIII are saponified with sodium hydroxide to form compounds of formula XIX Compounds of formula XIX are reduced with hydrogen in the presence of Pd/C catalyst to form compounds of formula XX „, D - XX Compounds of the formula XX are coupled with compounds of formula III in the presence of a base such as N-methylmorphoiine, diisopropylethylamine or pyridine to provide compounds of formula XXI Compounds of formula XXI are treated with e.g., trimethylsilyl iodide to form the chiral compounds of the formula V Amines of formula V are then treated with an electrophile as previously described to form other N-substituted chiral compounds of formula la. The opposite enantiomer is similarly prepared from the diastereoisomer of the compound of formula XVI. 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, thiol, carboxyl, and hydroxy groups, are optionally protected by conventional protecting groups that are common in preparative organic chemistry. Protected amino, thiol, carboxyl, and hydroxy groups are those that can be converted under mild conditions into free amino 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", Wiley, New York, 1991. 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 exampie chlorides or bromides; activated esters for example succinimido, phthalimido or 4- nitrophenyi 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. 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). Racemic products can also be resolved by chiral chromatography, e.g., high-pressure liquid chromatography using a chiral adsorbent. Finally, compounds of the invention are either obtained in the free form, or as a salt thereof if salt forming groups are present. Acidic compounds of the invention may be converted into salts with pharmaceutically acceptable bases, e.g., an aqueous alkali metal hydroxide, advantageously in the presence of an ethereal or alcoholic solvent, such as a lower alkanol. From the solutions of the latter, the salts may be precipitated with ethers, e.g., diethyl ether. Resulting salts may be converted into the free compounds by treatment with acids. These or other salts can also be used for purification of the compounds obtained. 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 (Cι-C 4 )-alkanecarboxyiic 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 (C C 4 )-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, e.g. to inhibit microsomal triglyceride transfer protein (MTP) and apolipoprotein B (Apo B) secretion, and e.g. 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 polyv ylpyrrolidone; if desired d) dis tegrants, 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% to 100%, especially 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 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 for the prevention or treatment of elevated levels of MTP and of Apo B and conditions related thereto. The present invention also relates to the use of a compound according to the instant invention or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the prevention or treatment of diseases or conditions associated with elevated levels of MTP and of Apo B. The compounds of the invention are inhibitors of microsomal tπglyceπde 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 hyperlipedemia, hypercholesterolemia and hypertriglyceπdemia 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, 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% cornstarch 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 follows: Hep G2 ceils are maintained in T-75 culture flasks (Corning) in Dulbecco's modified Eagles Medium (DMEM; Gibco-BRL) supplemented with 10% fetal calf serum Gibco-BRL) in a humidified atmosphere containing 5% carbon dioxide until they are confluent. For testing compounds, Hep G2 cells from the T-75 maintenance flasks are harvested and seeded in 96-well culture plates (Corning) and are grown for 72 hours (approximately 80% confluent). Test compound is dissolved at 1 mg/ml (w/v;1-5 mM) in dimethyl sulfoxide DMSO; Sigma) as stock solution. Prior to use, the stock solution of compound is diluted to 133 μM with DMSO and diluted further with growth medium (DMEM containing 10% fetal calf serum) to obtain 1 μM of compound in 100 μl of growth medium. 100 μl of growth medium containing the test compound is added to separate wells of a 96-well culture plate containing Hep G2 cells. For testing dose response of compound, a stock solution of test compound in DMSO is made at 665 μM and various dilutions from this solution are made in growth medium to obtain range of concentration of compound from 0.01 μM to 5 μM in 100 μl of growth medium. 100 μl of the growth medium containing different concentrations of test compound is added to separate wells containing Hep G2 cells. Twenty-four hours later, growth medium is collected and assayed by specific ELISA for apolipoprotein B (Apo B). At the same time Hep G2 cells from wells are assayed for protein (BioRad ; cat# 500-0006 ) and / or cell viability (Promega; CellTiter 96 Aqueous, cat # G3581 ). Inhibitors are identified as compounds that decrease Apo B secretion into the medium without decreasing the total cellular protein and/or cell viability. For performing Apo B ELISA, an antisera for human Apo B is made by immunizing rabbit with purified human Apo B. The antisera is further purified by using an affinity column (CNBr activated Sepharose 4B, Pharmacia) with human LDL as ligand and used as primary antibody for human Apo B. A secondary antibody for Apo B is prepared by conjugating the human Apo B antibody with alkaline phosphatase (Sigma). The ELISA for Apo B is performed as follows. 15 μl of primary antibody solution prepared against Apo B is diluted to a final volume of 10 ml with coating buffer (containing 15 mM sodium carbonate, 35 mM sodium bicarbonate, 3 mM sodium azide, pH 9.6). 200 μl of diluted antibody solution is added to each well of a 96 well plate (Maxisorb, Nunc , cat # 439454). After an overnight incubation at 4 ° C, the antibody solution is removed. Nonspecific sites on the plastic well are blocked by adding 300 μl of blocking solution containing phosphate buffered saline (PBS) , 1% (w/v) bovine serum albumin (Sigma), pH 7.4) and incubated for 45 minutes at room temperature. After removing blocking solution, 200 μl of dilution buffer (containing PBS/ 0.05% Tween 20 / 5 mM decyl sodium sulfate (Acros Organics) / 2% BSA, pH 7.4) containing 20 μl of growth medium from Hep G2 cells or 1 - 30 ng of Apo B standards (prepared in dilution buffer) is added to each well. After 2 hours incubation at 37 ° C, solution from each well is removed and washed five times with washing buffer (containing PBS and 0.05% Tween 20, pH 7.4). 200 μl of diluted conjugated secondary antibody for Apo B (15 μl diluted to a final volume of 10 ml in dilution buffer) is added to each well. After 2 hours incubation at 37°C, the solution is removed and the well is washed five times with washing buffer, p-nitrophenyl phosphate disodium hexahydrate solution (Sigma, cat # 104-0) is prepared in substrate buffer (containing 0.95M diethanoiamine / 0.5mM MgCI2 / 3 mM sodium azide, pH 9.5) at a concentration of 1 mg/ml and 200 μl of substrate solution is added to each well and incubated for 45-60 minutes. Absorbance of each well is read at 405 nm using a Beckman Biomek workstation. Apo B concentration is calculated from a standard curve generated from purified LDL standards that are run in parallel in the same assay. Secreted Apo B values are normalized with the total cellular protein assay and/or cell viability assay. The inhibition of MTP is measured as follows: Inhibition of the lipid transfer activity of MTP can be quantitated by measuring the inhibition of transfer of radiolabeled triglyceride from donor vesicles to acceptor vesicles in presence of soluble rat MTP. The procedure for preparing MTP is based on the method of Wetterau and Zilversmit (Biochim. Biophys. Acta (1986) 875:610). Briefly rats are decapitated under ether anesthesia. The liver is placed in ice cold sucrose buffer (contains 0.25M sucrose, 50 mM Tris Hcl, 1 mM EDTA, 0.02% sodium azide, pH 7.4) rinsed several times with the sucrose buffer. All subsequent steps are performed on ice. A 57% homogenate (120g/210 ml) of rat liver in 0.25M sucrose buffer is prepared by using a Potter-Elvehjem homogenizer. The homogenate is then centrifuged at 4°C for 30 min at 13,000 x g to remove large cellular organells. The supernatant is then centrifuged for 90 min at 105,000 x g to pellet the microsomes. The pellet is resuspended in 10mM Tris-HCI buffer pH 8.6. and centrifuged for 90 min at 105,000 x g. The washed pellet is then resuspended in 1mM Tris buffer (pH 8.6) and centrifuged for 2 hrs. The pellet is resuspended in 28.5 ml of 0.25M sucrose solution and 1 ml aliquotes containing 4.2 g of liver are stored frozen at -80 ° C until needed. Prior to performing the assay, the thawed pellet is suspended in 12 ml of cold Tris-HCI, 50 mM KCI, 5 mM MgCI, pH 7.4 and 1.2 ml of a 0.54% deoxycholate solution (pH 7.4) is added slowly with gentle mixing. The suspension is kept on ice for 30 min and then centrifuged at 105,000g for 75 min. The supernatant containing soluble MTP is dialyzed against assay buffer (150 mM Tris-HCI, 40 mM NaCI, 1 mM EDTA, 0.02% Na N3, pH 7.4). The protein content is measured using the Sigma Lowry micro total protein method and reagents (Sigma Cat # 690A). The rat MTP is diluted with assay buffer to contain 15 μg protein per 50 μl and stored at 4°C. Donor and acceptor liposomes are prepared as follows. For preparation of donor vesicles, 12.4 mgs of egg phosphatidylcholine (Sigma, cat# P-3556), 5.2 mgs of cardiolipin (Sigma, Cat# C-0563) and 8 mgs of hydroxybutylate toluene are dissolved in 4 ml of chloroform. To this solution, 34.8 μl of 3 H labeled Triolein (Amersham, Cat# TRA 191 , glycerol tri[1 ,9- 3 H]oleate) is added and mixed. 200 μl of this mixture is transferred into a screw cap glass vial, dried under nitrogen and reconstituted in 2 ml of assay buffer. The lipid suspension is sonicated for 30 min at 1.5 setting with pulse at 75 using Branson 450 sonifier in a water bath with ice. For preparation of acceptor vesicles, 18 mgs of egg phophatidylcholine and 4 mgs of hydroxybutylated toluene is added in 1 ml of chloroform. A 200 μl aliquot from this mixture is transferred into a screw cap glass vial. To this vial, 10 μl of Triolein ( 0.92 mg/ml in chloroform) and 2 μl of U C labeled phosphotidylchoiine (Amersham, cat# CFA 695, L-3-phosphatidylcholine,1 ,2-di[1- 1 C]oleoyl) are added and dried under nitrogen and reconstituted in 2 ml of assay buffer. The lipid suspension is sonicated using Branson 450 sonifier as described above. The donor and acceptor liposomes are centrifuged for 2 hours at 7 ° C at 46,000 φm in Ti50 rotor using Beckman Ultracentrifuge. The upper 75% of the supernatant is carefully removed and stored at 4°C until used for MTP transfer assay . MTP activity is measured using a MTP transfer assay. In this assay, donor and acceptor vesicles are mixed together with soluble MTP and test compound to measure the transfer of triglycerides from donor vesicles to acceptor vesicles. 50 μl of donor vesicles, 50 μl of acceptor vesicles, 20 μl of bovine serum albumin (10% w/v) and 50 μl of MTP (15 μg protein) are added along with various concentrations of test compound in a final volume 450 μl of assay buffer. After incubation at 37 °C for 45 min, the triglyceride transfer was terminated by addition of 300 μl of DEAE cellulose suspension (50%, w/v). After 4 min of vortexing, the donor vesicles bound to the DEAE cellulose are separated from acceptor vesicles by centrifuging at 14,00 φm for 7 min. 250 μl of supernatant containing acceptor vesicles are counted using 5.5 ml of Ready safe scintillation solution (Beckman, cat# 158735). The 14 C and 3 H counts are used to calculate the percent recovery of acceptor liposomes and the percent of triglyceride transfer using first order kinetics. Inhibition of triglyceride transfer by test compound is calculated by measuring the decrease in 3 H label of triglyceride present in the acceptor vesicles as compared to controls where no test compound is present. Illustrative of the invention the compound of example 13b demonstrates an IC 50 of about 1.8 nM in the Apo B assay and an IC 5 0 of about 60 nM in the MTP assay. The compound of example 13(i) demonstrates an IC 50 of about 0.7nM in the Apo B assay and an IC50 of about 70nM in the MTP assay. The compound of example 13(al) demonstrates an IC 50 of about 3 nM in the Apo B assay. The compound of example 13(ey) demonstrates an IC 50 of about 1 nM in the Apo B 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 normoiipidemic 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 normoiipidemic rats. lllustrative of the invention, the compound of example 13(i) lowers both plasma triglycerides and cholesterol at a dose of 10 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 [a] D determinations is expressed in mg/ml. Compounds are purified by standard methods, e.g., recrystallization and high pressure iiquid chromatography (HPLC). The following Examples serve to illustrate the invention. Example 1 4'-Trifluoromethylbiphenyl-2-carboxylic acid (2-benzenesulfonylamino-indan-5-yl)-amide A. 2-Amino-5-nitro-indane hydrochloride 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 24h 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 a white solid. B. (5-Nitro-indan-2-yl)-carbamic acid tert-butyl ester To a solution of the title A compound (20.4g, 95 mmol) in methylene chloride (500 mL) under nitrogen is added diisopropylethyl amine (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 16h, washed with brine, 1 N 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 a white solid. C. (5-Amιno-indan-2-yl)-carbamic acid tert-butyl ester A solution of the title B compound (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 2h. Filtration of the reaction mixture through Celite is followed by concentration of the filtrate under reduced pressure to give (5-amino-indan-2-yl)-carbamic acid tert-butyl ester as an oil which is used directly without further purification. D. 4'-Trifluoromethyl-2-biphenylcarboxylic acid chloride To a solution of 4'-trifluoromethyl-2-biphenyicarboxylic acid (5.15 g, 19.35 mmol) in methylene chloride (100 mL) is added oxalyl chloride (5.06 mL, 58.04 mmol) followed by 2 drops of DMF Addition of DMF results in vigorous gas evolution. After 1.5h, the reaction mixture is concentrated under reduced pressure to give an oil which is used as is without purification. E. (5-[(4'-Trιfluoromethylbιphenyl-2-carbonyl)-amιno1-ιndan-2-yl)-carbamιc acιd tert-butyl ester To a solution of the title C compound ((5-amιno-ιndan-2-yl)-carbamιc acid tert-butyl ester; 12.5 mmol) in methylene chloride (75 L) is added diisopropylethyl amine (3.3 g, 25 mmol) followed by a 0.5 M solution of the title D compound (4'-trifluoromethyl-2-biphenyl carboxylic acid chloride) in methylene chloride (25.3 mL, 12.6 mmol). After stirring 16h, the reaction mixture is poured into ethyl acetate and washed with 1 N HCI, 8% NaHCO3 solution, and brine. The organic layer is dried (MgSO4) and concentrated under reduced pressure to give a solid. Recrystallization from toluene gives (5-[(4'-trifluoromethylbiphenyl- 2-carbonyl)-amιno]-ιndan-2-yl}-carbamιc acid tert-butyl ester in two crops; mp 198-201 °C. MS (ES+), m/z 514 (M+NH+ 4 ). F. 4'-Tπfluoromethylbiphenyl-2-carboxylic acιd (2-arnιno-indan-5-yl)-amide hydrochloride A solution of the title E compound ({5-[(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 h, the reaction mixture is cooled to room temperature and stirring is continued for 16h. The reaction mixture is concentrated under reduced pressure and the resulting oil dissolved in ethyl acetate. The organic layer is washed with 8% NaHCθ3 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 4'- trifluoromethylbiphenyl-2-carboxylic acid (2-amino-indan-5-yl)-amide. The organic layer of the filtrate is dried (MgSO4) and concentrated under reduced pressure to give a solid. Trituation of the soiid with diethyl ether yields additional 4'-trifluoromethylbiphenyl-2- carboxylic acid (2-amino-indan-5-yl)-amide. A small portion of free amine (0.580 mmol) is dissolved in ethyl acetate and saturated with HCI (g) to give the HCI salt as a white solid. 1 H NMR (MeOH-d.4: 250 MHz): δ 7.70- 7.48 (7H, m), 7.16 (4H, q), 4.06 (1 H, m), 3.38 (2H, dd), 2.97 (2H, d). MS (ES+), m/z 397 (M+H). G. 4'-Trifluoromethylbiphenyl-2-carboxylic acid (2-benzenesulfonylamino-indan-5-yl)- amide To a solution of the title F compound (4'-trifluoromethylbiphenyl-2-carboxylic acid (2- amino-indan-5-yl)-amide; 0.100 g, 0.250 mmol) in methylene chloride (10 mL) is added diisopropylethyl amine (0.036 g, 0.280 mmol) followed by benzenesulfonyl chloride (0.046 g, 0.260 mmol). After 1 h, the reaction mixture is poured into ethyl acetate and washed with 1 N HCI, 8% NaHCθ3 solution, water, and brine. The organic layer is dried (MgSO4) and concentrated under reduced pressure to give an oil which is purified by silica gel chromatography. Drying under vacuum at 60 °C gives 4'-trifluoromethyl-biphenyl-2- carboxylic acid (2-benzenesulfonylamino-indan-5-yl)-amide as a non-crystalline solid; mp 96 °C sinters. MS (ES+), m/z 537 (M+1 , 554 (M+NH4 + ). Example 2 The following compounds are prepared similarly to Example 1 using the title F compound of Example 1 (4'-trifluoromethylbiphenyl-2-carboxylic acid (2-amino-indan-5-yl)- amide and the appropriate N-derivatizing agent (e.g., a sulfonyl chloride, an acid chloride, an isocyanate, a sulfamoyl chloride). 00/05201 43 00/05201 47 00/05201 51 Example 3 4'-Fluorobiphenyl-2-carboxylic acid (2-acetylamino-indan-5-yl)-amide A. N-(5-Amino-indan-2-yl)-acetamide A solution of N-(5-nitro-indan-2-yl)-acetamide (Bigge, C.F.; Retz, D. M. WO 9617832 A1 ) (0.37 g, 1.68 mmol) in ethanol (10 mL) is degassed and 10% palladium on carbon added (0.05 g). The reaction mixture is evacuated and placed under 1 atm H2(g) for 2h. Fitration of the reaction mixture through Celite is followed by concentration of the filtrate under reduced pressure to give N-(5-amino-indan-2-yl)-acetamide as a white solid which is used directly without further purification. 1 H NMR (DMSO-d6, 300 MHz) δ 8.05 (1 H, d), 6.82 (1H, d), 6.40 (1 H, s), 6.35 (1 H, d), 4.81 (2H, bs), 4.38 (1H, m), 2.98 (2H, m), 2.58 (2H, m), 1.81 (3H, s). B. 2-Bromobenzoyl Chloride 2-Bromobenzoyl chloride is prepared as described for 4-trifluoromethyl-2-biphenyl- carboxylic acid chloride (the title D compound of Example 1 ) and used as is without purification. C. N-(2-Acetylamino-indan-5-yl)-2-bromobenzamide The title compound is prepared as described for {5-[(4'-trifluoromethylbiphenyl-2- carbonyl)-amino]-indan-2-yl}-carbamic acid tert-butyl ester (the title E compound of Example 1) using N-(5-amino-indan-2-yl)-acetamide (the title A compound; 1.05 g, 5.50 mmol) and 2- bromo-benzoyl chloride (the title B compound; 1.21 g, 5.50 mmol) to give the product, mp 216-217 °C. MS (ES+), m/z 373 (M+H), 375 (M+H). D. To a solution of N-(2-acetylamino-indan-5-yl)-2-bromo-benzamide (the title C compound; 0.150 g, 0.40 mmol) and 4-fluorobenzeneboronic acid (0.0.84 g, 0.60 mmol) in DME (7 mL) is added PdCl2(dppf) (0.010 g, 0.012 mmol) followed by K3PO4 (0.25 g, 1.20 mmol). The reaction mixture is degassed and heated at reflux under N2 atmosphere for 16 h. After cooling to room temperature, the reaction mixture is diluted with water and extracted with ethyl acetate. The organic layer is dried (MgSO4) and concentrated under reduced pressure to give a tan solid. Trituration with ethyl acetate gives 4'-fluorobiphenyl-2- carboxylic acid (2-acetylamino-indan-5-yl)-amide as a grey solid, mp 218-220 °C. MS (ES+), m/z 389 (M+1 ). Example 4 The following compounds are prepared similarly to Examples 1 or 3. Example 5 5-Amino-2-(thiophen-2-vD-N-(indan-5-yl)-benzamide A. 2-Bromo-5-nitrobenzoyl chloride To a solution of 2-bromo-5-nitrobenzoic acid (1.00 g, 4.06 mmol) in methylene chloride (15 mL) is added oxalyl chloride (1.42 mL, 16.24 mmol) followed by 1 drop DMF. Addition of DMF results in vigrous gas evolution. After 1.5h, the reaction mixture is concentrated under reduced pressure to give an oil which is used as is without purification. B. 2-Bromo-N-(indan-5-yl)-5-nitro-benzamide 2-Bromo-N-indan-5-yl-5-nitro-benzamide is prepared similarly to the title E compound of Example 1 using the title A compound, 2-bromo-5-nitrobenzoyl chloride (1.07 g, 4.06 mmol) and 5-aminoindan (0.540 g, 4.06 mmol). 1 H NMR (DMSO-d6, 300 MHz): S 10.52 (1 H, s), 8.34 (1 H, d), 8.21 (1 H, dd), 8.03 (1 H, d), 7.60 (1 H, s), 7.38 (1 H, d), 7.19 (1 H, d), 2.85 (4H, m), 2.02 (2H, m). C. N-(lndan-5-yl)-5-nitro-2-(thiophen-2-yl)-benzamide N-(lndan-5-yl)-5-nitro-2-(thiophen-2-yl)-benzamide is prepared similarly to the title compound of Example 3 using the title B compound, 2-bromo-N-(indan-5-yl)-5-nitro- benzamide (0.137 g, 0.380 mmol) and 2-thiopheneboronic acid (0.073 g, 0.570 mmol). H NMR (DMSO-d6, 300 MHz): δ 10.59 (1 H, s), 8.38 (1 H, dd), 8.30 (1 H, d), 7.81 (1 H, d), 7.73 (1 H, d), 7.06 (1 H, s), 7.46 (1 H, d), 7.30 (1 H, d), 7.18 (2H, m), 2.83 (4H, q), 2.01 (2H, m). D. 5-Amino-2-(thiophen-2-yl)-(N-indan-5-yl)-benzamide A solution of the compound of Example 5, N-(indan-5-yl)-5-nitro-2-thiophen-2-yl- benzamide (0.083 g, 0.228 mmol) in ethyl acetate (10 mL) is degassed and 10% palladium on carbon added. The reaction mixture is evacuated and placed under 1 atm H2(g) for 16 h. Filtration of the reaction mixture through Celite is followed by concentration of the filtrate under reduced pressure to give 5-amino-N-(indan-5-yl)-2-(thiophen-2-yl)-benzamide as an oil which foams to a solid on treatment with diethyl ether, mp 62-67 °C. MS (ES+), m/z 335 (M+1). Example 6 The following compounds are prepared similarly to the compound of Example 5 by reduction of the corresponding nitro compounds. Example 7 N-(lndan-5-v0-2-(4-trifluoromethv!-phenyl)-nicotinamide hydrochloride A. 2-Chloronicotinic acid methyl ester To a solution of 2-chloronicotinic acid (2.00 g, 12.69 mmol) in DMF (40 mL) at 0 °C is added cesium carbonate (4.96 g, 15.23 mmol) followed by iodomethane (0.95 mL, 15.23 mmol). The reaction mixture is warmed to room temperature and stirred 16 h. Dilution with ethyl acetate is followed by washing with water, 8% NaHCO3 solution and brine. The organic layer is dried (MgSO4) and concentrated under reduced pressure to give 2- chloronicotinic acid methyl ester as an oil: 1 H NMR (CDCI3, 300 MHz): δ 8.55 (1 H, dd), 8.18 (1 H, dd), 7.33 (1 H, dd), 3.97 (3H, s). B. 2-(4-Trifluoromethyl-phenyl)-nicotinic acid methyl ester 2-(4-Trifluoromethyl-phenyl)-nicotinic acid methyl ester is prepared similarly to the title compound of Example 3 using 2-chloronicotinic acid methyl ester (1.45 g, 8.45 mmol) and 4-trifluoromethylbenzeneboronic acid (2.41 g, 12.68 mmol) to give the product as an oil: 1 H NMR (CDCI3, 300 MHz): δ 8.80 (1 H, dd), 8.19 (1 H, dd), 7.67 (4H, q), 7.40 (1 H, dd), 3.70 (3H, s). MS (ES+) m/z 282 (M+1). C. 2-(4-Trifluoromethyl-phenyl)-nicotinoyl chloride To a solution of the title B compound, 2-(4-trifluoromethyl-phenyl)-nicotinic acid methyl ester (0.626 g, 2.228 mmol) in 1 :1 THRH2O (10 mL) is added LiOH « H2θ (0.187 g, 4.456 mmol). After 3.5 h, the reaction mixture is concentrated to dryness under reduced pressure. To a slurry of the crude lithium salt in methylene chloride (10 mL) is added oxalyl chloride (0.78 mL, 8.91 mmol) followed by a few drops DMF. After stirring 16 h, the reaction mixture is concentrated to dryness under reduced pressure and used as is without purification. D. N-(lndan-5-yl)-2-(4-trifluoromethyl-phenyl)-nicotinamide hydrochloride The title compound is prepared in a manner similar to that described for the title E compound of Example 1 using 2-(4-trifluoromethyl-phenyl)-nicotinoyl chloride (2.228 mmol) and 5-aminoindan (0.296 g, 2.228 mmol) to give the product as the free base. The hydrochloride salt is prepared by bubbling HCI(g) through an ethyl acetate solution of the free base and trituation of the salt with diethyl ether; mp 190-205 °C. MS (ES+) m/z 383 (M+1 ). Example 8 The following compounds are prepared similarly to the compound of Example 7. Example 9 The following compounds are prepared by the method of Abdel-Magid, A.F. et al (J. Org. Chem. 1996, 61 , 3849) using the title F compound of Example 1 (4'-Trifluoromethyl- biphenyl-2-carboxylic acid (2-amino-indan-5-yl)-amide hydrochloride) and the appropriate aldehyde. Example 10 N-^-fN-methyl-N-methanesulfonylamiπo^indan-δ-yll^^'-trifluoromethylbiphenyl^- carboxamide A. N-Methyl-2-aminoindane Under a nitrogen atmosphere, a solution of the carbamate 2-(ethoxycarbonyl- amino)indane (6.07 g, 29.6 mmol) in Et 2 O (100 ml) is added slowly to a mixture of LiAIH 4 (1.70g, 44.7 mmol) in Et 2 O (100 ml) chilled at 0°. The resulting mixture is stirred for 18 hr and allowed to warm to 20°. The reaction mixture is re-chilled to 0° and treated cautiously with H O (1.7 ml), 15 %NaOH (1.7 ml) and again H 2 O (5.1 ml). The mixture is stirred for 20 minutes, warming slowly to 20°. The precipitate is vacuum filtered and the filtrate extracted into 1 N HCI. The acid solution is washed with fresh Et 2 O, then basified with cold 1 N NaOH. The cloudy mixture is extracted with Et 2 O, washed with saturated brine, dried over Na 2 SO , is filtered and concentrated to an oil. B. N-(lndan-2-yl)-N-methyl-methanesulfonamide Under a nitrogen atmosphere, a solution of methanesulfonyl chloride (1.08 g, 9.5 mmol) in CH 2 CI 2 (10 ml) is added slowly to a solution of the title A compound (1.35 g, 9.2 mmol) and ethyldiisopropylamine (4.75 g, 36.8 mmol) in CH 2 CI 2 (50 ml) and stirred at 20° for 18 hr. The reaction mixture is concentrated to dryness and the residue is re-dissolved into Et 2 O. The solution is washed sequentially with 8% NaHCO 3 , H 0, 1 N HCI, H 2 0 and finally saturated brine, and is dried over Na 2 SO 4 , filtered and concentrated to dryness to yield the product. C. N-(-5-Nitro-indan-2-yl)-N-methyl-methanesulfonamide Fuming HNO 3 (2.0 ml, 50.4 mmol) is added very slowly to a solution of the title B compound (1.80 g, 8.0 mmol) in TFA (25 ml) chilled at 0°. The reaction mixture is stirred at 0° for 3 hr., then the solvent evaporated at 20°. The residue is treated with ice and extracted into EtOAc. The EtOAc solution is washed with 8% NaHC0 3 , H 2 O and saturated brine and then dried over Na 2 S0 . The solution is filtered and the solvent evaporated to yield a solid product which is recrystalized from cold EtOAc. D. N-(5-Amino-indan-2-yl)-N-methyl-methanesulfonamide A mixture of the title C compound (1.10 g, 4.1 mmol) and 10% palladium on carbon (0.11g) are in EtOAc (50 ml) is stirred under hydrogen (1 atmosphere) at 20° for 3 hr. The catalyst is filtered off and the filtrate concentrated to yield the title product as a solid. E. N-f2-(N-methyl-N-methanesulfonylamino)-indan-5-yll-2-(4'-trifluoromethylbiphenyl-2- carboxamide Under a nitrogen atmosphere, a solution of 4'-trifluoromethyl-2-biphenylcarboxylic acid chloride (0.23 g, 0.80 mmol) in CH 2 CI 2 (5 ml) is slowly added to a solution of the title D compound (0.18 g, 0.74 mmol) and ethyldiisopropyl amine (0.38 g, 2.94 mmol) in CH 2 CI 2 (10 ml). The mixture is stirred at room temperature for 18 hrs, concentrated in vacuo and the residue is dissolved into EtOAc. The solution is washed with 8% NaHC0 3 (twice), then with water, and then with 1 N HCI, and then with saturated brine solution, and dried over Na 2 S0 . The solution is filtered and concentrated to dryness in vacuo. The residue is dried to yield the title product, mp 163-165°. Example 11 Prepared similarly to Example 10, is N-[2-(N-methyl-N-acetyiamino)indan-5-yl]-2-4'- trifluoromethylbiphenyl-2-carboxamide of the formula mp 195-198°; MS: 453 (M+1 ) Example 12 (a) (S)-4'-Trifluoromethylbiphenyl-2-carboxylic acid (2-methoxycarbonylamino-indan-5-yl)- amide A. The alcohol, (1 -hydroxy-indan-2-yl)-carbamic acid methyl ester (1 S-trans) prepared from L-phenyialanine (18.7g, 0.09mol) (J. Org. Chem. 1983, 48, 2675-2679) is suspended in methylene chloride and cooled to 0°C. Pyridine (10.7g, 0.135mol) is added followed by acetyl chloride (10.5g, 0.135mol). The mixture is stirred for 1h. and then washed with sodium bicarbonate, 1 HCI and saturated sodium chloride. The organic layer is dried over Na S0 , filtered and evaporated under reduced pressure to give (1 -acetyloxy-indan-2-yl)- carbamic acid methyl ester (1S-frans). B. To 90% HN0 3 (55.1 , O.βmol) under nitrogen at -30°C is added 100mL of trifluoroacetic acid followed by the addition of trifluoroacetic anhydride (100g, 0.476mol) over 5 minutes. The above carbamate (1-acetyloxy-indan-2-yl)-carbamic acid methyl ester (1S-frans)) (20. Og, O.Oδmol) in 34mL of methylene chloride is added slowly (over 90 min.) keeping the temperature between -30 and -35°C. The reaction is worked up by adding 100mL 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 100mL 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 -acetyloxy-6-nitro-indan-2-yl)-carbamic acid methyl ester (IS-trans); mp 164- 167°C. C. The above acetate (16.5g, 0.056mol) is suspended in 275mL of methanol at room temperature. 1 N Sodium hydroxide solution (112mL, 0.112mol) 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 250mL 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- frans); mp 201-203°C. D. The above nitro alcohol (6.0g, 0.023mol) is dissolved in 300mL of acetic acid containing 3mL of water at 50°C. The mixture is cooled to room temperature and HCIO 4 (6g, 0.042mol) and 10% Pd C (6g) are added and the mixture is hydrogenated at 50psi for two days. Fresh catalyst (3g) 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 is similarly prepared from (1- acetyloxyindan-2-yl)-carbamic acid methyl ester (1 R-trans), starting with D-phenylalanine instead of L-phenylaianine. E. To a 0°C solution of (S)-(5-aminoindan-2-yl)-carbamic acid methyl ester, (500mg, 2.43mmol) in 20mL of methylene chloride and pyridine (0.236mL, 2.9mmol) is added 4'- trifluoromethyl-2-biphenylcarboxylic acid chloride (.076g, 2.6mmol) in 5mL of methylene chloride. The reaction is warmed to room temperature and stirred for 1 h. The mixture is washed with 1 N HCI, sodium bicarbonate and brine. The organic layer is dried over MgS04, filtered, concentrated, and chromatographed on silica gel eluting with ethyl acetate/hexanes (1 :1) to give (S)-[5-[(4'-trifluoromethyl-biphenyl]-2-carbonyl)amino]-indan-2- yl]-carbamic acid methyl ester, the compound of example 13(d). (b) (S)-4'-Trifluoromethylbiphenyl-2-carboxylic acid (2-benzenesulfonylamino-indan-5-yl)- amide A. To a 0°C solution of the carbamate of example 12(a) (0.96g, 2.1 mmol) in 75mL of acetonitrile is added trimethylsilyl iodide. The mixture is stirred for 16h. The reaction is quenched with 2mL of methanol and stirred for 1 h. The mixture is concentrated and the residue is redissolved in ethyl acetate. The solution is washed with sodium bicarbonate and saturated sodium chloride solution. The organic layer is dried over MgSO , filtered and concentrated under reduced pressure to give (S)-N-(2-aminoindan-5-yl)-4'- trifluoromethylbiphenyl-2-carboxamide. B. (S)-4'-Trifluoromethylbiphenyl-2-carboxylic acid (2-benzenesulfonylaminoindan-5-yl)- amide is prepared from the amine as described in Example 1 , mp 152-153°C; [a] D -7.304 (c = 10.152mg/mL, methanol). Example 13 Prepared similarly to Example 12 from either (1 S-trans)- or (1 R-fraπs)-(1 -acetyloxy indan-2-yl) carbamic acid methyl ester are the following compounds. 00/05201 -81 00/05201 -83- Example 14 (R)-6-Methyl-4'-trifluoromethylbiphenyl-2-carboxylic acid (2-methoxycarbonylamino- indan-5-yl)-amide A. A solution of 2-bromo-3-methyl-benzoic 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. B. 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-trifluoromethylphenyl- boronic 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. C. 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 crystallisation from ethyl acetate / hexanes to yield 6-methyl-4'-trifluoromethyl-biphenyl-2-carboxylic acid melting at 202-203°C. MS m/z 279 (M -1 ). D. To a 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 (100mL) is added and the acid chloride is used as is in subsequent reactions. E. To an ice bath cooled solution of (R)-(5-aminoindan-2-yl)-carbamic acid methyl ester (9.5 g, 46.1 mmol) prepared as described in example 12 ([a] 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'-trifluoromethyl-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'-trifluoromethylbiphenyl-2-carboxylic acid (2-methoxycarbonylaminoindan-5-yl)-amide (the compound of example 13(i)) as a crystalline solid, mp 112-114°C. MS (ES+), m/z 469 (M+1). Example 15 6-Methyl-4'trifluoromethylbiphenyl-2-carboxylic acid (7-methoxycarbonylamino-6.7.8.9- tetrahvdro-5H-benzocvclohepten-2-yl)-amide A. 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-benzocyciohepten-7-amine as a white solid. B. To a suspension of NaBH (1.98 g, 52.3 mmol) in 40 mL of DME cooled in an ice-bath is added TiCI . To this mixture is added title compound A (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. C. The compound from step B is treated with methyl chloroformate, nitrated, reduced, and acylated with 6-methyl-4'-trifluoromethylbiphenyl-2-carboxylic acid chloride according to procedure described in example 12 to give the title compound; m.p. 190-193°C. Example 16 The compound of example 15 is treated with trimethylsilyl iodide and the resulting amine is then reacted with the appropriate N-derivatizing agent (as described in previous examples) to yield the following compounds of the formula Formulation example: Hard gelatin capsules, comprising 100 mg active substance, for example 4'-trifluoromethylbiphenyl-2-carboxylic acid (2-benzenesulfonylamino-indan-5-yl)- amide, can be prepared for example as follows: Composition (for 1000 capsules) Active ingredient 100.0 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 lyophilized 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, 390 mg each of the formulation obtained are filled into hard gelatin capsules of size 0.

Claims: What is claimed is: 1. A compound of the formula wherein R 2 -C, R 3 -C, R 4 -C or R 5 -C may be replaced by N; and wherein n is 1 , 2 or 3; R, is aryl, cycloalkyl or heterocyclyl; R , R 3 , R 4 and R 5 are independently hydrogen, alkyl, substituted alkyl, halo, amino, substituted amino, trifluoromethyl, cyano, carboxyl, alkoxycarbonyl, aralkoxycarbonyl, (alkyl, aryl or aralkyl)-thio, (alkyl, aryl or aralkyl)-oxy, acyloxy, (alkyl, aryl or aralkyl)- aminocarbonyloxy; or any two of R 2 , R 3 , R and R 5 at adjacent positions are alkylenedioxy; R 6 is amino, substituted amino, acylamino, wherein R a is hydrogen or optionally substituted alkyl, R and R c are independently hydrogen, optionally substituted alkyl, cycloalkyl, aryl or heterocyclyl; or R and R c together represent lower alkylene or lower alkylene interrupted by O, S, or N-(H, alkyl or aralkyl); R d is optionally substituted alkyl, cycloalkyl, aryl or heterocyclyl; and R β is optionally substituted alkyl, aryl, heterocyclyl, cycloalkyl, amino or substituted amino; the variable R 6 being located on the 5-, 6- or 7- membered saturated ring at a position not directly adjacent to the ring junction; or a pharmaceutically acceptable salt thereof; or an enantiomer thereof. 2. A compound according to claim 1 of the formula wherein n is 1 , 2, or 3; R T is aryl, cycloalkyl or heterocyclyl; X is R 2 -C or N; R 2 , R 3 , R 4 and R 5 are independently hydrogen, optionally substituted alkyl, halo, amino, substituted amino, trifluoromethyl, cyano, carboxyl, alkoxycarbonyl, aralkoxycarbonyl, (alkyl, aryl or aralkyl)-thio, (alkyl, aryl or aralkyl)-oxy, acyloxy, (alkyl, aryl or aralkyl)-aminocarbonyloxy; or any two of R 2 , R 3 , R 4 and R 5 at adjacent positions are alkylenedioxy; R 6 is amino, substituted amino, acylamino, wherein R a is hydrogen or optionally substituted alkyl, R b and R c are independently hydrogen, optionally substituted alkyl, cycloalkyl, aryl or heterocyclyl; or R b and R c together represent lower alkylene or lower alkylene interrupted by O, S, or N-(H, alkyl or aralkyl); R d is optionally substituted alkyl, cycloalkyl, aryl or heterocyclyl; and R e is optionally substituted alkyl, aryl, heterocyclyl, cycloalkyl, amino or substituted amino; the variable R 6 being located on the 5-, 6- or 7- membered saturated ring at a position not directly adjacent to the ring junction; or a pharmaceutically acceptable salt thereof; or an enantiomer thereof. A compound according to claim 2 of the formula wherein Ar is monocyciic aryl or heteroaryl; X is R 2 -C or N; and R 2 , R 3 , R 4 and R 5 are independently hydrogen, lower alkyl, halo, trifluoromethyl, cyano, or lower alkoxy; and R 6 has meaning as defined in claim 2; or a pharmaceutically acceptable salt thereof; or an enantiomer thereof. 4. A compound of formula I wherein R ∑ -C, R 3 -C, FU-C or R 5 -C may be replaced by N; and wherein n is 1 , 2 or 3; Ri is phenyl or thienyl which in each case is unsubstituted or substituted by a substituent selected from the group consisting of lower alkyl, lower alkoxy, halo, trifluoromethyl, cyano, and trifluoromethoxy; R 2 , R 3 , R 4 and R 5 are independently hydrogen, lower alkyl, lower alkoxy, halo, trifluoromethyl, amino, lower alkylamino, di-lower alkyl amino, or lower alkanoyl-amino; R 6 is amino, phenyl-lower alkyl-amino, lower alkanoyl-amino, lower alkanoyl-amino in which the alkyl group of the alkanoyl group is substituted by phenyl, by lower alkoxy, by phenoxy, by lower alkylthio, by phenylthio, by di-lower alkylamino, by moφholino, by thiomoφholino, by piperazino, or by 4-iower alkyl-piperazino, or is N-methyl-N'-lower alkanoyl-amino, benzoyl-amino, or isoxazolylcarbonyl-amino in which isoxazoyl is unsubstituted or substituted by lower alkyl, or is wherein R a is hydrogen or alkyl, R b and R c are independently hydrogen, lower alkyl, 5- to 7-membered cycloalkyl, or phenyl; or R b and R c together are moφholino, thiomoφholino or lower alkylene; R d is lower alkyl, lower alkyl substituted by lower alkoxy, by lower alkoxy-lower alkoxy, by moφholino, by thiomoφholino, by 2-oxo-1 -pyrrolidino, by pyridyl, by phenyl, or by phenyl which is substituted by a substituent selected from halo, trifluoromethyl, lower alkyl, and lower alkoxy, or is phenyl, phenyl substituted by substituent selected from halo, trifluoromethyl, lower alkyl, and lower alkoxy, or is 5- to 7-membered cycloalkyl, or pyranyl; and R β is lower alkyl, phenyl-lower alkyl, phenyl which is unsubstituted or substituted by a group selected from lower alkyl, lower alkoxy, halo, trifluoromethyl, and lower alkane- sulphonyl, or is naphthyl, thienyl, furyl, isoxazolyl, imidazolyl or quinolinyl each of which is unsubstituted or substituted by a group selected from lower alkyl, halo and trifluoromethyl, or is lower alkyl-amino, di-lower alkyl-amino or 5- to 7-membered cycloalkyl-amino; and pharmaceutically acceptable salts thereof; and enantiomers thereof. 5. A compound according to claim 3 of the formula wherein R 2 , R 3 and R 4 are independently hydrogen, Cι-C -alkyl, d-C 4 -alkoxy, trifluoromethyl, chloro or fluoro; R 7 is trifluoromethyl, chloro or cyano; and R 6 is wherein R d is C,-C 4 -alkyl; and R β is Cι-C 4 -alkyl, monocyciic carbocyciic aryl or heterocyclic aryl; or an enantiomer thereof. 6. A compound according to claim 5 wherein R 2 is methyl; R 3 is hydrogen; R is hydrogen or methyl; R 6 is wherein R d is methyl; and R 7 is trifluoromethyl; or an enantiomer thereof. 7. A compound according to claim 5 which is selected from the (S)-enantiomer wherein R 2 is methyl; R 3 and FL are hydrogen; R β is methyl; and R 7 is trifluoromethyl; the (S)-enantiomer wherein R 2 is methyl; R 3 and ^ are hydrogen; R β is 2-thienyl; and R 7 is trifluoromethyl; the (S)-enantiomer wherein R 2 and R 4 are methyl; R 3 is hydrogen; R β is 2-thienyl; and R 7 is trifluoromethyl; and the (R)-enantiomer wherein R 2 is methyl; R 3 and R 4 are hydrogen; R d is methyl; and R 7 is trifluoromethyl. 8. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier. 9. A method of inhibiting microsomal triglyceride transfer protein in a mammal which comprises administering to a mammal in need thereof an effective microsomal triglyceride transfer protein inhibiting amount of a compound according to any one of claims 1 to 8; or the use of a compound according to any one of claims 1 to 8 for the manufacture of a medicament for inhibiting microsomal triglyceride transfer protein. 10. A method according to claim 9 of (i) decreasing apolipoprotein B secretion in a mammal; (ii) treating microsomal triglyceride transfer protein or lipoprotein B dependent conditions in mammals; (iii) treating atherosclerosis, hypertrigiyceridemia or hypercholesteremia.

Inventors: FINK CYNTHIA ANNE, KSANDER GARY MICHAEL, KUKKOLA PAIVI JAANA, WALLACE ELI MELVILLE, FINK, CYNTHIA, ANNE, KSANDER, GARY, MICHAEL, KUKKOLA, PAIVI, JAANA, WALLACE, ELI, MELVILLE
Applicants: FINK CYNTHIA ANNE, KSANDER GARY MICHAEL, KUKKOLA PAIVI JAANA, NOVARTIS AG, NOVARTIS ERFIND VERWALT GMBH, WALLACE ELI MELVILLE, FINK, CYNTHIA, ANNE, KSANDER, GARY, MICHAEL, KUKKOLA, PAIVI, JAANA, NOVARTIS-ERFINDUNGEN VERWALTUNGSGESELLSCHAFT MBH, WALLACE, ELI, MELVILLE
Application year: 1999
Main classification: C07C311
IPC codes: A61K31, A61P3, A61P9, A61P43, C07C233, C07C235, C07C237, C07C271, C07C275, C07C307, C07C311, C07C317, C07D213, C07D233, C07D261, C07D295, C07D309, C07D333