JP2002521360A - N-benzocycloalkylamide derivatives and their use as medicaments - Google Patents

Abstract

(57) [Summary] Formula I: Or a pharmaceutically acceptable salt thereof; or an enantiomer thereof. The compounds of formula (I) are useful as inhibitors of microsomal triglyceride transfer protein (MTP) and apolipoprotein B (ApoB) secretion, and are therefore useful for the prevention and treatment of MTP and ApoB dependent conditions.

Description

DETAILED DESCRIPTION OF THE INVENTION

DISCLOSURE OF THE INVENTION [Technical Solution] The present invention relates to a compound of the formula I:

Embedded image Wherein R ₂ -C, R ₃ -C, R ₄ -C or R ₅ -C may be substituted by N; n is 1, 2, or 3; R ₁ 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 in adjacent positions Is alkylenedioxy; R ₆ is hydrogen, optionally substituted alkyl, amino, substituted amino, acylamino;

Embedded image Wherein R _a is hydrogen or optionally substituted alkyl; R _b and R _c are independently hydrogen, optionally substituted alkyl, cycloalkyl,
Aryl or heterocyclyl, R or _b and R _c represents a lower alkylene together, or O, S, or N-(H, alkyl or aralkyl) represents a lower alkylene interrupted by; is R _d Is optionally substituted alkyl, cycloalkyl, aryl or heterocyclyl; and R _e is optionally substituted alkyl, aryl, heterocyclyl, cycloalkyl, amino or substituted amino]. And a pharmaceutically acceptable salt thereof; and an enantiomer thereof.

(Possibility of Industrial Use) / (Technical Problems to be Solved by the Invention) The compound represented by the formula I is a microsomal triglyceride transfer protein (MT
It is useful as an inhibitor of P) and apolipoprotein B (ApoB) secretion, and is therefore useful for the prevention and treatment of MTP and ApoB dependent conditions.

DETAILED DESCRIPTION OF THE INVENTION A particular embodiment of the present invention is a compound of formula I ′:

Embedded image Wherein R ₂ -C, R ₃ -C, R ₄ -C or R ₅ -C may be substituted by N; and n and R _{1 to} R ₆ have the meanings as defined above. And pharmaceutically acceptable salts thereof; and enantiomers thereof.

[0004] A specific aspect of the invention is a compound of formula Ia:

Embedded image Wherein X is R ₂ -C or N; and n and R _{1 to} R ₆ have the meanings as defined above.

[0005] A particular aspect of the invention relates to compounds of formula Ia. Wherein (a) R ₁ represents aryl; (b) R ₁ represents heterocyclyl, especially aromatic heterocyclyl (heteroaryl); (c) n is 1; (d) X is R ₂ -C (E) X is N; (f) R ₆ is amino, substituted amino or acylamino; (g) R ₆ is of the following formula:

Embedded image Is a group represented by (h) R ₆ is the following formula:

Embedded image Or (i) R ₆ is a group represented by the following formula:

Embedded image Is a group represented by

Preferred are those of the formula Ia wherein n is 1; R ₁ is monocyclic aryl or heteroaryl; X is R ₂ —C or N; R ₂ , R ₃ , R ₄ and R ₅ is independently hydrogen, lower alkyl, halo, trifluoromethyl, lower alkoxy or amino; and R ₆ is amino, substituted amino, acylamino or

Embedded image Wherein R _a is hydrogen and R _b and R _c are independently hydrogen, lower alkyl, aralkyl, aryl, heteroaryl or heteroaralkyl; or R _b and R _c together with nitrogen are piperidino, morpholino, pyrrolidino there or N- lower alkyl piperazino,; R _d and R _e is a lower alkyl, aralkyl, aryl, a compound represented by a group represented by heteroaryl or heteroaralkyl]]; and the pharmaceutically It is a salt acceptable for.

Preferred are those of the formula I, I ′ or Ia wherein R ₆ is a 5-membered, 6-membered or 7-membered ring
On the saturated ring of the membered ring (n = 1, 2, or 3), but not directly adjacent to the ring bond (non-benzylic position)].

[0008] A particular aspect of the invention relates to compounds of formula I. Wherein R ₂ -C, R ₃ -C, R ₄ -C or R ₅ -C may be substituted with N; n is 1, 2, or 3; R ₁ is phenyl or thienyl Wherein each is unsubstituted or substituted with 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 alkylamino,
Or lower alkanoylamino;

R ₆ is amino; phenyl lower alkylamino; lower alkanoylamino; lower alkanoyl-amino, wherein the alkyl group of the alkanoyl group is phenyl, alkoxy, phenoxy, lower alkylthio, phenylthio, Substituted by lower alkylamino, by morpholino, by thiomorpholino, by piperazino, or by 4-lower alkylpiperazino; or N-methyl-N′-lower alkanoylamino;
Benzoylamino or isoxazolylcarbonylamino, wherein the isoxazolyl is unsubstituted or substituted with lower alkyl, or has the formula:

Embedded image Wherein R _a is hydrogen or alkyl; R _b and R _c are independently hydrogen, lower alkyl, 5- to 7-membered cycloalkyl, or phenyl; R _b and R _c together Represents morpholino, thiomorpholino or lower alkylene;

R _d is optionally lower alkyl, or by lower alkoxy, lower alkoxy-lower alkoxy, morpholino, thiomorpholino,
Lower alkyl substituted by 2-oxo-1-pyrrolidino, by pyridyl, by phenyl, or by phenyl substituted with a substituent selected from the group consisting of halo, trifluoromethyl, lower alkyl, and lower alkoxy. Or phenyl, phenyl substituted by a substituent selected from halo, trifluoromethyl, lower alkyl and lower alkoxy, or 5- to 7-membered cycloalkyl or pyranyl; and

R _e is lower alkyl, phenyl-lower alkyl, unsubstituted phenyl,
Or phenyl substituted with a group selected from lower alkyl, lower alkoxy, halo, trifluoromethyl and lower alkanesulfonyl, or naphthyl, thienyl, furyl, isoxazolyl, imidazolyl, or quinolinyl, whichever Is also unsubstituted or substituted by a group selected from lower alkyl, halo, and trifluoromethyl, or is a lower alkylamino, di-lower alkylamino, or 5- to 7-membered ring. And a pharmaceutically acceptable salt thereof; and an enantiomer thereof.

A specific aspect of the invention is a compound of formula Ib:

Embedded image Wherein Ar is a 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, trifluoro And R ₆ has any of the meanings given above.].

Preferred are the above compounds of formula Ib, 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 any of the above meanings.

Further preferred are compounds of formula Ic:

Embedded image Wherein R ₂ , R ₃ and R ₄ are independently hydrogen, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, trifluoromethyl, chloro or fluoro; R ₇ is trifluoromethyl, And chloro or cyano; and R ₆ is of the formula:

Embedded image [Wherein R _d is C ₁ -C ₄ -alkyl; _Re is C ₁ -C ₄ -alkyl, monocyclic carbocyclic aryl or heterocyclic aryl]]. Compound.

Further preferred are compounds of formula Ic, 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 ₁ -C ₄ -alkyl; and _Re is C ₁ -C ₄ -alkyl or thienyl.

One particular aspect relates to compounds of formula Ic, wherein R_TwoIs methyl
And R_ThreeIs hydrogen; R_FourIs hydrogen or methyl; R₆Is -NHSO_TwoR _e But this R_eIs methyl or thienyl; and R₇Is trifluoro
Methyl.

Another aspect relates to compounds of formula Ic, wherein R ₂ is methyl; R ₃ is hydrogen; R ₄ is hydrogen or methyl; R ₆ is

Embedded image Wherein R _d is methyl; R ₇ is trifluoromethyl.

Preferred among all of the above are those wherein the carbon atom having the substituent R ₆ (when R ₆ is not hydrogen) has the (R)-or (S) -configuration, Is the stronger enantiomer.

The definitions of various terms used to describe the compounds of the present invention are listed below.
These definitions apply to the terms used throughout the specification (unless otherwise limited in specific instances individually or as part of a larger group). The term "lower" as referred to for each of the organic groups or compounds generally defined herein, unless otherwise defined, for example, including 7, up to 7, preferably including 4, It shows up to 4, preferably 1 or 2, carbon atoms. Such may be straight or branched.

The term “optionally substituted alkyl” refers to straight or branched unsubstituted or substituted carbons having from 1 to 20 carbon atoms, preferably from 1 to 7 carbon atoms. Shows a hydrogen group. Examples of unsubstituted alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl,
Includes isohexyl, heptyl, 4,4-dimethylpentyl, octyl, and others.

The term “substituted alkyl” refers to an alkyl group substituted with one or more of the following groups: halo (such as CCl ₃ or CF ₃ ), hydroxy,
Alkoxy, alkoxyalkoxy, aryloxy, cycloalkyl, alkanoyl, alkanoyloxy, amino, substituted amino, alkanoylamino, thiol, alkylthio, arylthio, alkylthiono, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aminosulfonyl, nitro, cyano, Carboxy, carbamyl, alkoxycarbonyl, aryl, aralkoxy, guanidino, heterocyclyl (eg, indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl, and the like) and others.

The term “lower alkyl” refers to an alkyl group as described above having one to seven carbon atoms, preferably one to four carbon atoms. The terms "halogen" or "halo" refer to fluorine, chlorine, bromine and iodine.

The term “haloalkyl” refers to an alkyl mono- or polysubstituted by halo, for example, trifluoromethoxy. The term "alkylene" straight chain bridge linked by single bonds of from one to six carbon atoms (e.g., - (CH _{2) x} -; where x is a is from 1 to 6) indicates, these lower It may be substituted with 1 to 3 alkyl groups.

The term “alkylene interrupted by O, S, N- (H, alkyl, or aralkyl)” includes, for example, methylene (or ethylene) oxymethylene (or ethylene),
2 to 6 carbon atoms interrupted by O, S, N- (H, alkyl or aralkyl), such as methylene (or ethylene) thiomethylene (or ethylene), or methylene (or ethylene) iminomethylene (or ethylene) Up to a linear chain.

The term “cycloalkyl” denotes a cyclic hydrocarbon group of 3 to 8 carbon atoms, for example, cyclopentyl, cyclohexyl or cycloheptyl. The terms "alkoxy" or "alkyloxy" refer 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" each refer to (alkyl) N
H- and (alkyl) ₂ N- are shown.

The term “alkanoylamino” refers to alkyl-C (O) —NH—. The term "alkylthio" refers to alkyl-S-. The term "alkylthiono" refers to alkyl-S (O)-. The term "alkylsulfonyl" refers to alkyl-S (O) _2- .

The term “carbamyl” refers to —C (O) -amino or —C (O) -substituted amino. The term "alkoxycarbonyl" refers to alkyl-OC (O)-. The term "acyl" refers to alkanoyl, aroyl, heteroaryloyl, arylalkanoyl, heteroarylalkanoyl, and the like.

The term “aryl” or “Ar” is a mono- or bicyclic aromatic hydrocarbon group having from 6 to 12 carbon atoms in the ring portion, for example, phenyl, naphthyl, tetrahydronaphthyl and biphenyl groups Is shown. Any of these may be, for example, alkyl, halo, trifluoromethyl, hydroxy, alkoxy, halo-alkyl, alkanoyl, alkanoyloxy, amino, substituted amino, alkanoylamino, thiol, alkylthio, nitro, cyano, carboxy, carboxyalkyl. , Carbamyl, alkoxycarbonyl, alkylthiono, alkylsulfonyl, aminosulfonyl, heterocyclyl, and the like, and may be substituted with 1 to 4 substituents.

The term “aralkyl” refers to an aryl group attached to an alkyl group, for example, benzyl. The term "aralkoxy" refers to an aryl group attached to an alkoxy group, for example, benzyloxy. The term "arylsulfonyl" aryl -SO ₂ - shows a. The term "aroyl" refers to aryl-CO-.

The term “heterocyclyl” refers to an optionally substituted, fully saturated or unsaturated, aromatic or non-aromatic cyclic group, for example a monocyclic from 4 to 7 membered ring A 7- to 11-membered bicyclic or 10- to 15-membered tricyclic ring system comprising at least one heteroatom and at least one carbon atom . Each ring of the heterocyclic group containing a hetero atom may have one, two or three hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and the nitrogen atom and the sulfur hetero atom are If necessary, it may be oxidized, and its nitrogen atom may also be quaternized, if necessary. The heterocyclic group may be attached at any heteroatom or carbon atom.

Exemplary monocyclic heterocyclic groups include pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl,
Oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl , 2-oxopyrrolidine, 2-oxoazepinyl, azepinyl, 4-piperidonyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3- Including dioxolane and tetrahydro-1,1-dioxothienyl, and others.

Exemplary bicyclic heterocyclic groups include indolyl, benzothiazolyl, benzoxazolyl, benzothienyl, quinuclidinyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, chromonyl, coumarinyl, Benzopyranyl, cinnolinyl,
Quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl (eg, furo [2,3-c] pyridinyl, furo [3,2-b] pyridinyl, furo [2,3-b] pyridinyl), dihydroisoindolyl, dihydroquinazolinyl ( For example, 3,4-dihydro-4-oxoquinazolinyl) and others. Exemplary tricyclic heterocyclic groups include carbazolyl, benzindolyl, phenanthrolinyl, acridinyl, phenanthridinyl, xanthenyl, and the like.

The term “heterocyclyl” also includes substituted heterocyclic groups. The substituted heterocyclic group is a heterocyclic group substituted with one, two or three of the following. (b) hydroxy (or protected hydroxy); (c) halo; (d) oxo (ie, ＝ O); (e) amino or substituted amino; (f) alkoxy; (g) cycloalkyl; (j) alkoxycarbonyl, such as unsubstituted lower alkoxycarbonyl; (k) carbamyl, alkylcarbamyl, arylcarbamyl, dialkylcarbamyl; (l) mercapto; (m) nitro (N) cyano; (o) sulfonamide, sulfonamidoalkyl or sulfonamidodialkyl; (p) aryl; (q) alkylcarbonyloxy; (r) arylcarbonyloxy; (s) arylthio; (v) formyl; (w) arylalkyl; or (x) alkyl, cycloalkyl, alkoxy, hydride Alkoxy, amino, alkylamino, aryl substituted by dialkylamino or halo.

The term “heterocyclooxy” refers to a heterocyclic group attached through an oxygen bridge. The term "heteroaryl" or "heteroAr" refers to an aromatic heterocycle group, e.g., a monocyclic or bicyclic aryl, e.g., pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furyl, thienyl. , Pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, benzothiazolyl, benzoxazolyl, benzothienyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzofuryl, and the like, if necessary, for example, lower alkyl, lower alkoxy or halo. And the like.

The term “heteroarylsulfonyl” refers to heteroaryl-SO ₂ —. The term "heteroaroyl" refers to heteroaryl-CO-. The term "acylamino" refers to acyl-NH-. The term "substituted amino" denotes amino mono- or independently disubstituted by alkyl, aralkyl, aryl, heteroaryl, cycloalkyl, cycloalkylalkyl, heteroaralkyl, or lower alkylene or O, S, N
-Represents amino di-substituted by lower alkylene interrupted by (H, alkyl, aralkyl), and the like.

The pharmaceutically acceptable salts of the acidic compounds according to the present invention are, for example, cationic salts such as alkali metal or alkaline earth metal salts such as, for example, sodium, lithium, potassium, calcium, magnesium, and for example ammonium. And ammonium salts such as trimethylammonium, diethylammonium, and tris (hydroxymethyl) methylammonium salts and the like.

Similarly, if a basic group, such as amino or pyridyl, forms part of the structure, mineral acids such as hydrochloric acid, methanesulfonic acid, maleic acid, organic carboxylic acids, and organic sulfonic acids Addition salts of acids are also possible. Since the compounds of the present invention have asymmetric carbons depending on the nature of the substituents, they exist as their racemates and (R) and (S) enantiomers. These are all within the scope of the present invention.

The compounds of the present invention may be exemplified by certain compounds of formula Ia, wherein n is 1, for example of formula II:

Embedded image Wherein BOC is a t-butoxycarbonyl protecting group, for example, an activated carboxyl derivative such as Formula III:

Embedded image [Wherein R _{1 to} R ₅ and X have the meanings described above] and a compound represented by the formula IV, for example, in the presence of a base such as N-methylmorpholine, diisopropylethylamine or pyridine.

Embedded image Can be produced by providing a compound represented by the formula:

The compound of formula IV is then reacted with an acid such as, for example, HCO ₂ H to form a compound of formula V
:

Embedded image Is formed.

The compound of formula V is then converted, for example, to an appropriately substituted sulfonyl chloride
(E.g. phenylsulfonyl chloride), chloroformate (e.g. methyl chloroformate), acid chlorides (e.g. acetyl chloride), an isocyanate (e.g. phenyl isocyanate), isothiocyanate (e.g. phenyl isothiocyanate), other such as the R ₆ Treatment with an electrophile corresponding to the amino substituent, if necessary in the presence of a base such as, for example, sodium hydroxide or triethylamine, forms a compound of formula Ia. The compound 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 can be prepared by acid hydrolysis such as, for example, N- (5-nitroindan-2-yl) acetamide and subsequent protection of the resulting amine with BOC anhydride and subsequent catalytic reduction. Produced by reduction of the nitro group with

Compounds of formula III wherein R ₁ is aryl or heteroaryl are shown in the following reaction scheme and aryl boronic acids of formula VI and VII (bromo, iodo Or trifluoromethyl) methanesulfonyloxy-substituted arylcarboxylic acid esters by palladium-catalyzed aryl-aryl coupling reaction. The ester group of the resulting compound of formula VIII is subsequently hydrolyzed with sodium hydroxide and subsequently reacted with a chlorinating agent such as oxalyl chloride to give the acid chloride of formula III.

Embedded image

Compounds of formula V wherein R ₁ is aryl or heteroaryl may be prepared using alternative synthetic methods of the formula:

Embedded image

As described above, an amine of formula II can be acylated with a compound of formula IX in the presence of a base such as, for example, N-methylmorpholine, diisopropylethylamine or pyridine, to give a compound of formula X Is obtained. The formula (R ₁ -B (
A palladium catalyzed aryl-aryl coupling reaction of an arylboronic acid of formula OH) ₂ ) with an aryl bromide of formula X (or iodide or triflate) gives a compound of formula IV. For example, treatment with an acid such as formic acid readily removes the nitrogen to give a compound of formula V.

Compounds of formula I wherein R ₆ is disubstituted amino may be prepared by a separate synthesis of the formula:

Embedded image The 2- (ethoxycarbonylamino) indane of formula XI is reduced with a reducing agent such as, for example, lithium aluminum hydride to produce N-methylamine of formula XII. Acylation, for example with a sulfonyl chloride, gives the compound of formula XIII. Nitration followed by catalytic reduction gives (via intermediate XIV) an amine of formula XV. Acylation of a compound of formula XV with a compound of formula III in the presence of diisopropylethylamine gives a compound of formula I, wherein R ₆ has the formula:

Embedded image Is a group represented by

A compound of the formula I wherein R ₆ is of the formula:

Embedded image The group represented by is also produced in the same manner.

The chiral compounds of the present invention can be prepared as follows: (a) (1S-trans)-or (1R-trans) -hydroxy-2-amino-6
-Reduction of nitroindane, in which the amino group is protected, gives 2-amino
The (R) or (S) -enane of the corresponding 2,6-diaminoindan in which the amino group is protected
(B) converting the (R) or (S) enantiomer to a compound of formula III, for example,
Condensed with any reactive derivative of a carboxylic acid, and removal of the amino protecting group is shown by Formula V
(R) or (S) -enantiomers are obtained; and (c) the enantiomers are subsequently N-derivatized in sequence to have the formula Ia ₆ Is a derivatized amino, which is R₆As defined herein for
A compound is obtained.

For example, a chiral compound of the present invention has the formula XVI:

Embedded image By acylating the protected amine of formula XVII with acetyl chloride:

Embedded image Can be produced.

The compound of formula XVII is nitrated with nitric acid, trifluoroacetic acid and trifluoroacetic anhydride to form a compound of formula XVIII:

Embedded image Is formed. The compound of formula XVIII is saponified with sodium hydroxide to form a compound of formula XIX:

Embedded image Is formed.

The compound of formula XIX is reduced with hydrogen in the presence of a Pd / C catalyst to give a compound of formula XX:

Embedded image Is formed.

A compound of formula XX is coupled to a compound of formula III in the presence of a base such as, for example, N-methylmorpholine, diisopropylethylamine or pyridine,

Embedded image Is formed.

The compound of formula XX is treated with, for example, trimethylsilyl iodide and the like to give a compound of formula V ′:

Embedded image To form a chiral compound represented by

The amine of formula V ′ is then treated with an electrophile as described above to give a compound of formula Ia
To form another N-substituted chiral compound. The opposite enantiomer is similarly prepared from diastereoisomers of the compound of formula XVI.

In the starting compounds and intermediates that are converted to the compounds of the present invention by the methods described herein, functional groups such as amino, thiol, carboxy, and hydroxy groups may be optionally synthesized It is protected by the usual protecting groups commonly used in organic chemistry. Protected amino, thiol, carboxy, and hydroxy groups are those that can be converted to free amino and hydroxy groups under mild conditions without disrupting the molecular structure or causing other undesirable side reactions.

The purpose of introducing the protecting group is to protect the functional group from undesired reactions by the reactive species under the conditions for effecting the desired chemical transformation. The need and choice of protecting groups for a particular reaction are known to those skilled in the art, and the nature of the functional group to be protected (hydroxy, amino, etc.) It depends on the structure and stability of the molecules forming the part and on the reaction conditions.

Well-known protecting groups which meet these conditions, their methods of introduction and removal are described, for example, by JFW McOmie, "Protective Groups in Organic Chemistry", Plenu
m Press, London, New York, 1973; TW Greene, "Protective Groups in
Organic Synthesis ", Wiley, New York, 1991.

In the methods described herein, reactive functional derivatives of carboxylic acids are represented by, for example, acid anhydrides (especially mixed acid anhydrides), acid halides, acid azides, lower alkyl esters and active esters. You. For example, the mixed anhydride is preferably from a lower alkyl (ethyl, isobutyl) hemiester of pivalic acid or carbonic acid; the acid halide is, for example, chloride or bromide; the active ester is, for example, succinimide, phthalimide, or 4-nitrophenyl ester; And lower alkyl esters are, for example, methyl or ethyl esters;

Depending on the choice of starting materials and methods, the novel compounds may be in one form or a mixture of the possible isomers, for example the substantially pure geometric isomers (cis or trans ) May be an optical isomer (enantiomer), a racemate or a mixture thereof. Said possible isomers or mixtures thereof are within the scope of the present invention.

The resulting mixture of isomers can be separated into pure geometric or optical isomers, diastereomers, racemates based on the physicochemical differences of the components, for example by chromatography and / or fractional crystallization. .

Any of the intermediate racemates obtained can be obtained by known methods such as, for example, by separation of diastereoisomeric salts obtained with an optically active acid or base and liberation of an optically active acidic or basic compound. Can be divided into target enantiomers.
The amine intermediate may be, for example, a d- or l-carboxylic acid (e.g., d- or l-
The salt can be separated into optical antipodes by fractional crystallization of a salt such as tartaric acid). Racemates can also be resolved by chiral chromatography, eg, high performance liquid chromatography using a chiral adsorbent.

Finally, the compounds according to the invention are obtained in free form, if salt-forming groups are present,
Or as a salt thereof.

The acidic compounds of the invention are advantageously converted into the salts with a pharmaceutically acceptable base such as, for example, aqueous alkali metal hydroxides, in the presence of an ethereal or alcoholic solvent such as, for example, a lower alkanol. You may. From the latter solution, for example, a salt such as diethyl ether may be precipitated with ether. The resulting salt may be converted to the free compound by treatment with an acid. These or other salts can also be used for purification of the resulting compound.

The compounds of the invention having a basic group can be converted into acid addition salts, especially pharmaceutically acceptable salts. These are (C1-C4) -alkanecarboxylic acids, e.g. by inorganic acids such as, for example, mineral acids such as sulfuric acid, phosphoric acid, hydrohalic acid or the like, e.g. acetic acid unsubstituted or substituted by halogen, for example; For example, oxalic acid, succinic acid,
By an organic carboxylic acid such as a saturated or unsaturated dicarboxylic acid such as maleic acid or fumaric acid; a hydroxycarboxylic acid such as glycolic acid, lactic acid, malic acid, tartaric acid or citric acid; an amino acid such as aspartic acid or glutamic acid; Formed by C1 -C4) -alkylsulfonic acids (e.g. methanesulfonic acid) or e.g. unsubstituted or substituted (e.g. halogen) arylsulfonic acids. Preferred are salts formed with hydrochloric acid, methanesulfonic acid and maleic acid.

With reference to the close relationship between the free compound and the compound in its salt form, if a compound is described in the text it will correspond as long as salt formation is possible and appropriate Salt is also intended. The compounds, including their salts, are also obtained in the form of their hydrates. Alternatively, other solvents used for crystallization can be included.

The pharmaceutical compositions of the present invention are suitable for enteral, transdermal, and parenteral administration, such as oral or rectal administration to mammals, including humans, including, for example, microsomes. An effective amount of the pharmacologically active compound of the present invention is used alone for the purpose of inhibiting the secretion of triglyceride transfer protein (MTP) and apolipoprotein B (ApoB), and for treating a disease responsive thereto, for example. Or in combination with one or more pharmaceutically acceptable carriers.

The pharmacologically active compounds of the present invention are useful for the manufacture of pharmaceutical compositions containing an effective amount of the compounds as a combination or mixture with excipients or carriers suitable for oral or parenteral administration. Preferred are the active ingredients a) diluents such as, for example, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine; b), for example, silica, talc, stearic acid, its magnesium or calcium salts and / or polyethylene glycol. Lubricating agents such as; c) for example, magnesium aluminum silicate, starch paste, gelatin,
A binder such as tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone; d) a disintegrating or foaming agent such as starch, agar, alginic acid or its sodium salt if desired; and / or e) an absorbent; Tablets and gelatin capsules to include with coloring, flavoring and sweetening agents. Injectable compositions are preferably aqueous isotonic solutions or suspensions, and suppositories are advantageously made from emulsions or suspensions in fat. The composition may be sterile and / or contain adjuvants such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, osmoregulating salts and / or buffers. Good. In addition, these compositions may contain other therapeutically valuable substances. The composition is prepared according to the usual mixing, granulating or coating methods, and may contain from about 0.1% to 100% of the active ingredient.
%, Especially from about 0.1% to 75%, preferably from about 1% to 50%.

Formulations suitable for transdermal administration include a carrier with an effective amount of a compound of the present invention. Advantageous carriers include solvents that are absorbable and pharmaceutically acceptable and that aid movement through the skin of the host. Characteristically, the transdermal agent has a backing layer, a reservoir containing the compound, if necessary, together with a carrier, and, if necessary, a rate controlling layer for delivering the compound to the skin of the host at a controlled and designed rate for an extended period of time. And a patch containing a means for placing the transdermal dosage form on the skin.

Formulations suitable for topical administration, such as to the skin and eyes, are preferably aqueous solutions, ointments, creams, or gels well known in the art.

The present pharmaceutical formulations contain an inhibitory amount of a compound of the present invention described above, alone or in combination with, for example, each of the other therapeutic agents at an effective dose as each reported. Such therapeutic agents are well-known in the art.

In connection with the other active ingredients, the compounds of the present invention may be used simultaneously with the other active ingredients,
It may be administered before or after and may be administered separately by the same or different routes of administration or simultaneously as the same or different pharmaceutical preparations.

The dose of the active compound to be administered depends on the species, body weight, age and individual medical condition of the warm-blooded animal (mammal) and on the mode of administration. A unit dose for oral administration to mammals weighing about 50 kg to 70 kg may contain between about 10 mg and 1000 mg of active ingredient, preferably between about 25 mg and 50 mg.
It may contain between 0 mg.

The present invention also provides the use of a compound of the present invention and a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof for preventing or treating elevated levels of MTP and elevated levels of ApoB in a mammal, and pathologies associated therewith. Provide a way to The present invention also relates to the use of a compound of the present invention or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for use in the prophylaxis or treatment of elevated levels of MTP and ApoB and associated conditions.

The compounds of the present invention are inhibitors of microsomal triglyceride transfer protein (MTP) and also inhibitors of apolipoprotein B (ApoB) secretion, and blood lipid levels, including blood triglyceride and cholesterol levels. Useful for lowering This compound is useful for hyperlipidemia, hypercholesterolemia, and hypertriglyceridemia and diseases related thereto, such as cardiovascular diseases including cardiac ischemia, arteriosclerosis and its clinical sequelae, and obesity, pancreatitis. And for the treatment and prevention of diabetes.

The above properties can advantageously be demonstrated in in vitro and in vivo tests using mammals such as rats, mice, dogs, monkeys and isolated cell or enzyme preparations. The compounds are applied in vitro in the form of a solution, such as an aqueous solution, and in vivo preferably applied orally, topically, or parenterally, for example, intravascularly. Dosages in vitro may range from about 10 ^-5 to 10 ^-9 molar. In vivo dosages may range between about 1 mg / kg and 100 mg / kg, depending on the route of administration. These test methods are generally known in the art. For evaluation in vivo, the compounds are generally administered as a solution or suspension, for example, a 3% comb starch suspension.

The activity of the compound of the present invention can be evaluated by the following methods. The inhibition of cellular secretion of ApoB is measured as follows. Hep G2 cells were placed in a T-75 culture flask (Corning) in humidified air containing 5% carbon dioxide.
Dulbecco's modified Eagle's medium (DMEM; Gibco-BR) supplemented with 0% fetal bovine serum (Gibco-BRL)
L) Keep in. Hep G2 cells from T-75 maintenance flasks are harvested to test compounds, inoculated into 96-well culture plates (Corning) and cultured for 72 hours (approximately 80% confluence). Test compound (1 mg) was added to dimethyl sulfoxide (DMSO; Sigma) at 1 mg / mL (w /
v; 1-5 mM) to make a stock solution. Before use, stock solution of compound is 133μ with DMSO
M, and further diluted with growth medium (DMEM containing 10% fetal bovine serum) to grow
1 μM of compound in μM. 100 μL of growth medium containing the test compound is added to separate wells of a 96-well culture plate containing Hep G2 cells. To determine the dose-response curve of a compound, a stock solution of the test compound in DMSO was made 665 μM, and various dilutions from this solution were made in growth medium to give a compound concentration of 0.01 μM to 5 μM in 100 μL of growth medium.
Ranges up to μM were obtained. 100 μL of growth medium containing various concentrations of the test compound was added to Hep G2
Add to separate wells containing cells. Twenty-four hours later, growth media is collected and assayed in a specific ELISA for apolipoprotein B (ApoB). At the same time, Hep G2 cells obtained from the 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 reduce ApoB secretion into the medium without reducing total cell protein and / or cell viability. To perform an ApoB ELISA, an antiserum to human ApoB is made by immunizing rabbits with purified human ApoB. This antiserum was prepared using an affinity column (Pharmacia) containing human LDL as a ligand.
a; further purified using CNBr activated Sepharose 4B) and used as primary antibody against human ApoB. A secondary antibody against ApoB is prepared by combining a human ApoB antibody and alkaline phosphatase (Sigma). E for ApoB
LISA is performed as follows. Dilute 15 μL of primary antibody solution prepared for ApoB to a final volume of 10 mL with coating buffer (15 mM sodium carbonate, 35 mM sodium bicarbonate, 3 mM sodium azide, pH 9.6). Add 200 μL of the diluted antibody solution to each well of a 96-well plate (Maxisorb; Nunc, cat # 439454). Four
After overnight incubation at 0 ° C, the antibody solution is removed. Non-specific sites in plastic wells in phosphate buffered saline (PBS), 1% fetal bovine albumin (Sigma), pH
Block by adding 300 μL of blocking solution containing 7.4). After removing the blocking solution, a dilution buffer (PBS / 0.05% Tween 20/5 mM-sodium decyl sulfate (PBS / 0.05% Tween 20) was added with 20 μL of growth medium from Hep G2 cells or 1-30 ng of ApoB standard (prepared with dilution buffer). Add 200 μL (Acros Organics) / 2% BSA, pH 7.4) to each well. After 2 hours incubation at 37 ° C., the solution from each well was removed,
Wash 5 times with washing buffer (containing PBS and 0.05% Tween 20, pH 7.4). ApoB
Dilution of conjugated secondary antibody to (dilute 15 μL with dilution buffer to a final volume of 10 mL) 2
Add 00 μL to each well. After 2 hours incubation at 37 ° C., the solution is removed and each well is washed 5 times with wash buffer. Phosphate p- nitrophenyl ester disodium salt hexahydrate solution (Sigma; cat # 104-0) substrate buffer (0.95M- diethanolamine /0.5mM-MgCl ₂ / 3mM- sodium azide, pH 9.5) in the Prepare at a concentration of 1 mg / mL, add 200 μL of substrate solution to each well, and incubate for 45-60 minutes. The absorbance of each well is measured at 405 nm using a Beckman Biomek Workstation. ApoB concentration is calculated from a standard curve with a purified LDL standard prepared in parallel with the assay. Secreted ApoB values are normalized by whole cell protein assays and / or cell viability assays.

The inhibition of MTP is measured as follows. The inhibition of lipid transfer activity of MTP can be quantified by measuring the inhibition of transfer of radiolabeled triglyceride from donor vesicle to acceptor vesicle in the presence of soluble rat MTP. MTP is manufactured by Wetterau and Zilversmit (Biochim.
Based on the method of Biophys. Acta (1986) 875: 610). Briefly, rats are anesthetized with ether and decapitated. Livers are placed in ice-cold sucrose buffer (0.25 M-sucrose / 50 mM-Tris-HCl / 1 mM-EDTA / 0.02% sodium azide / pH 7.4) and washed several times with sucrose buffer.

The following processes are all performed on ice. Rat liver 57% homogenate (120 g / 210 mL) in 0.25 M sucrose buffer is prepared using a Potter-Elvehjem homogenizer. The homogenate is then centrifuged at 13000 × g for 30 minutes at 4 ° C. to remove large organelles. The supernatant is then centrifuged at 105000 × g for 90 minutes to pellet the microsomes. The pellet was resuspended in 10 mM Tris-HCl buffer pH 8.6,
Centrifuge at 000 xg. Next, the washed pellet was washed with 1 mM Tris-HCl buffer (pH 8.
Resuspend in 6) and centrifuge for 2 hours. The pellet was added to a 0.25 M-sucrose solution 28.5 m
Resuspend in 1 L and freeze 1 mL volume containing 4.2 g of liver and store at -80 ° C until use.
Before performing the assay, the thawed pellet was chilled with Tris HCl, 50 mM KCl, 5 mM MgCl,
Suspend in 12 mL of pH 7.4 and gently mix 0.54% deoxycholic acid solution (pH
7.4) is added slowly. The suspension is placed on ice for 30 minutes and then centrifuged at 105000 xg for 75 minutes. Supernatant containing soluble MTP was assayed in assay buffer (150 mM Tris HC).
1/40 mM-NaCl / 0.02% NaN ₃ / pH 7.4). The protein content is determined using the Sigma Lowry micro total protein method and reagents (Sigma; cat # 690A). Rat MTP is diluted with assay buffer to contain 15 μg protein per 50 μL and stored at 4 ° C.

The donor and acceptor liposomes are prepared as follows. Egg phosphatidylcholine (Sigma; cat # P-3556) 12.4 mg, cardiolipin (Sigma; cat # C-0563) 5.2 mg and hydroxybutyrate toluene for donor vesicle production
Dissolve 8 mg in 4 mL of chloroform. To this solution was added ³ H-labeled triolein (Amersha
m; cat # TRA 191, added glycerol tri [1,9- ³ H] oleate) 34.8 [mu] L, and mixed. Transfer 200 μL of this mixture to a screw cap glass vial, dry in nitrogen and reconstitute into 2 mL of assay medium. Put this lipid suspension in a water bath with ice
Sonicate for 30 minutes using a Branson 450 sonicator set at 1.5 with pulse 75.

For the production of acceptor vesicles, 18 mg of egg phosphatidylcholine and 4 mg of hydroxybutylated toluene are added to 1 mL of chloroform. 200 μL of this mixture
Transfer volume to screw cap glass vial. Add triolein (0
.92 mg / mL chloroform) 10 μL and ¹⁴ C-labeled phosphatidylcholine (Amersham;
cat # CFA 695, 2 μL of L-3-phosphatidylcholine 1,2-di [1- ¹⁴ C] oleyl), dry in nitrogen and reconstitute in 2 mL of assay buffer. Add this lipid suspension to Branson
Sonicate as above with a 450 sonicator. The donor and acceptor liposomes were placed in a Ti50 rotor using a Beckman Ultracentrifuge at 7 ° C for 2 hours.
Centrifuge at 46000 rpm. Carefully collect the upper 75% of the supernatant and store at 4 ° C. until use in the MTP transfer assay.

[0080] MTP activity is measured using an MTP transfer assay. In this assay, donor and acceptor vesicles are mixed with soluble MTP and a test compound to measure the transfer of triglycerides from donor vesicles to acceptor vesicles. Donor vesicle 50 μL, acceptor vesicle 50 μL, bovine serum albumin (10
20 μL of 20% (w / v) and 50 μL of MTP (15 μg of protein) are added along with various concentrations of the test compound, and the final volume is made up to 450 μL with assay buffer.

After incubation at 37 ° C. for 45 minutes, the DEAE cellulose suspension (50% w / v
) Add 300 μL to terminate the triglyceride transfer reaction. After shaking for 4 minutes, the donor vesicle bound to DEAE cellulose is separated from the acceptor vesicle by centrifugation at 14,00 rpm for 7 minutes. Supernatant containing acceptor vesicles 250
Measure μL with 5.5 mL of Ready safe scintillation solution (Beckman; cat # 158735). ^The acceptor liposome recovery percentage is calculated using the ¹⁴ C and ³ H counts and the triglyceride transfer percentage is calculated using the primary reaction mechanism. The reduction of ^{the 3 H-labeled} triglycerides present in the acceptor vesicles as compared to the test compound the absence of control measurements to calculate the inhibition of triglyceride transfer by test compound.

[0082] The compound of Example 13b as illustrative of the present invention the IC ₅₀ of about 1.8 nM in ApoB assay
And the MTP assay shows an IC _{50 of} about 60 nM. The compound of Example 13 (i) was Apo
The B test shows an IC _{50 of} about 0.7 nM, and the MTP assay shows an IC _{50 of} about 70 nM. The compound of Example 13 (al) shows an IC ₅₀ of about 3 nM in the ApoB assay. The compound of Example 13 (ey) shows an IC ₅₀ of about 1 nM in ApoB assay.

The effect of the compounds of the present invention in lowering serum triglyceride in vivo can be determined by measuring the effect of triglyceride levels in mice, rats or dogs according to methods well known in the art, for example, in hypertriglyceride blood in rats fed fructose. The disease can be determined by measuring in a pre-established model or in blood lipid-normal rats.

The effect of the compounds of the present invention in lowering serum triglycerides in vivo can be determined by measuring the effect on cholesterol levels in mice, rats or dogs according to methods well known in the art, for example, in blood lipid-normal rats. Can decide.

As an illustration of the present invention, the compound of Example 13 (i) lowers both blood triglycerides and cholesterol at a dose of 10 mg / kg administered orally.

The following examples are intended to illustrate the present invention and should not be construed as limiting the invention. Temperatures are given in degrees Celsius. Unless stated otherwise, all evaporations are carried out under reduced pressure, preferably between about 15 and 100 mmHg (= 20-133 mbar). The structures of the final products, intermediates, and starting materials are confirmed by standard analytical methods such as, for example, microanalytical and spectral analytical properties (eg, MS, IR, NMR). The abbreviations used are those conventional in the art. [α] _D measurement concentration is mg / m
Shown by L. Each compound is purified by standard methods, such as recrystallization and high performance liquid chromatography (HPLC).

The following examples illustrate the invention. Example 1 4'-trifluoromethylbiphenyl-2-carboxylic acid (2-benzenesulfonyl
Amino-indan-5-yl) amide

Embedded image A. To 2-amino-5-nitroindan hydrochloride N- (5-nitroindan-2-yl) acetamide (23.5 g, 107 mmol) is added 500 mL of 2N hydrochloric acid. The mixture is heated at reflux for 24 hours and then concentrated in vacuo. 100 mL of methanol is added to the residue and the mixture is concentrated in vacuo. 100 mL of toluene are added and the mixture is concentrated again. A solution of the residue in 100 mL of methanol is warmed, 500 mL of diethyl ether is added and the mixture is left overnight. The solid is collected by filtration and air-dried to give a white solid.

B. To a solution of the compound of (5-nitro-indan-2-yl) carbamic acid t-butyl ester A (20.4 g, 95 mmol) in 500 mL of methylene chloride is added diisopropylethylamine (14.7 g, 114 mmol) under nitrogen. To this is added a solution of di-tert-butyl dicarbonate (22.8 g, 105 mmol) in methylene chloride. The mixture is stirred for 16 hours, washed with brine, 1N hydrochloric acid and brine, 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. A solution of (5-amino-indan-2-yl) carbamic acid t-butyl ester B compound (3.52 g, 12.6 mmol) in 100 mL of ethanol is degassed and 10% palladium on carbon is added. The reaction is evacuated and placed under 1 atmosphere of hydrogen gas for 2 hours. The reaction mixture was filtered through celite and the filtrate was concentrated in vacuo (5.
-Amino-indan-2-yl) carbamic acid tert-butyl ester is obtained as an oil which is used directly without further purification.

D. 4'-trifluoromethyl-2-biphenylcarboxylic acid chloride 4'-trifluoromethyl-2-biphenylcarboxylic acid (5.15 g, 19.35
Oxalyl chloride (5.06 mL, 58.04) in 100 mL of methylene chloride.
Mmol) followed by two drops of DMF. Addition of DMF causes severe gas evolution. After 1.5 hours, the reaction mixture was concentrated in vacuo to give an oil, which was used without further purification.

E. {5-[(4'-trifluoromethylbiphenyl-2-carbonyl) amino] in
To a solution of the compound of dan-2-yl} carbamic acid t-butyl ester C ((5-amino-indan-2-yl) carbamic acid t-butyl ester; 12.5 mmol) in methylene chloride (75 mL) was added diisopropylethylamine (3. (3 g, 25 mmol) were added, followed by a 0.5 M solution of the compound of D (4'-trifluoromethyl-2-biphenylcarboxylic acid chloride) in methylene chloride (25.3).
mL, 12.6 mmol). After stirring for 16 hours, the reaction mixture is poured into ethyl acetate and washed with 1N HCl, 8% NaHCO ₃ solution, and brine. The organic layer is dried (MgSO ₄ ) and concentrated under reduced pressure to give a solid. By recrystallization from toluene {5-
[(4'-trifluoromethylbiphenyl-2-carbonyl) amino] indane-2
-Ill} carbamic acid t-butyl ester is obtained as two crops. mp.198
~ 201 ° C. MS (ES +) m / z 514 (M + NH + 4).

F. 4'-trifluoromethylbiphenyl-2-carboxylic acid (2-amino-indane
Compound of ( n-5-yl) amide hydrochloride E ({5-[(4′-trifluoromethylbiphenyl-2-carbonyl) amino] indan-2-yl} carbamic acid t-butyl ester; 5.19 g, 10 .
A solution of 5 mmol) of formic acid in 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 is dissolved in ethyl acetate. When the organic layer is washed with an 8% NaHCO ₃ solution until the aqueous layer is basic, 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 (MgSO ₄ ) and concentrated under reduced pressure to give a solid. This solid is stirred with diethyl ether to give additional 4'-trifluoromethylbiphenyl-2-carboxylic acid (2-amino-indan-5-yl) amide.

A portion of the free amine (0.580 mmol) is dissolved in ethyl acetate and saturated with HCl gas to give the hydrochloride as a white solid. ¹ H-NMR (MeOH-d4; 250 MHz) δ: 7.70-7.48 (7h, M), 7.16 (4H, q), 4.06 (1H, m
), 3.38 (2H, dd), 2.97 (2H, d). MS (ES +) m / z 397 (M + H).

G. 4'-trifluoromethylbiphenyl-2-carboxylic acid (2-benzenesulfo
Nylamino-indan-5-yl) amide F Compound (4'-trifluoromethylbiphenyl-2-carboxylic acid (2-amino-indan-5-yl) amide; 0.100 g, 0.250 mmol) in methylene chloride To the 10 mL solution is added diisopropylethylamine (0.036 g, 0.280 mmol) followed by benzenesulfonyl chloride (0.046 g, 0.260 mmol). After 1 hour, the reaction mixture was poured into ethyl acetate and 1N HCl, 8% N
Wash with aHCO ₃ solution, water and brine. The organic layer was dried (MgSO ₄ ) and concentrated in vacuo to give an oil, which was purified by silica gel chromatography. 60 ° C
To give 4'-trifluoromethylbiphenyl-2-carboxylic acid (2-benzenesulfonylamino-indan-5-yl) amide as an amorphous solid. mp. 96 ° C (decomposition point). MS (ES +) m / z 537 (M + l); 554 (M + NH4 +).

Example 2 The following compound was prepared in the same manner as in Example 1 to obtain the F compound of Example 1 (4'-trifluoromethylbiphenyl-2-carboxylic acid (2-amino-indan-5-yl) amide).
And a suitable N-derivatizing reagent (eg, sulfonyl chloride, acid chloride, isocyanate, sulfamoyl chloride, etc.).

[0096]

[Table 1]

[0097]

[Table 2]

[0098]

[Table 3]

[0099]

[Table 4]

[0100]

[Table 5]

[0101]

[Table 6]

[0102]

[Table 7]

[0103]

[Table 8]

[0104]

[Table 9]

[0105]

[Table 10]

[0106]

[Table 11]

[0107]

[Table 12]

[0108]

[Table 13]

[0109]

[Table 14]

[0110]

[Table 15]

[0111]

[Table 16]

[0112]

[Table 17]

[0113]

[Table 18]

[0114]

[Table 19]

[0115]

[Table 20]

[0116]

[Table 21]

[0117]

[Table 22]

[0118]

[Table 23]

[0119]

[Table 24]

[0120]

[Table 25]

[0121]

[Table 26]

[0122]

[Table 27]

[0123]

[Table 28]

[0124]

[Table 29]

[0125]

[Table 30]

[0126]

[Table 31]

[0127]

[Table 32]

[0128]

[Table 33]

[0129]

[Table 34]

[0130]

[Table 35]

[0131]

[Table 36]

[0132]

[Table 37]

[0133]

[Table 38]

[0134]

[Table 39]

Example 3 4'-Fluorobiphenyl-2-carboxylic acid (2-acetylamino-indane-5
-Yl) amide

Embedded image A. N- (5-amino-indan-2-yl) acetamide N- (5-nitroindan-2-yl) acetamide (Bigge, CF; Retz, D.
M., WO 9617832 A1) (0.37 g, 1.68 mmol) in 10 mL of ethanol was degassed and 10% palladium on charcoal (0.05 g) was added. The reaction mixture is depressurized and placed under 1 atm of hydrogen gas for 2 hours. The reaction mixture is filtered through celite, and the filtrate is then concentrated under reduced pressure to give N- (5-aminoindan-2-yl) acetamide as a white solid, which is used directly without further purification. ¹ H-NMR (DMSO-d6; 300 MHz) δ: 8.05 (1H, d), 6.82 (1H, d), 6.40 (1H, d), 6
.35 (1H, 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 converted to 4-trifluoromethyl-2-biphenyl-
Prepared as described for the carboxylic acid chloride (Compound D of Example 1) and used without further purification.

C. N- (2-acetylaminoindan-5-yl) -2-bromobenzamide The title compound is {5-[(4'-trifluoromethylbiphenyl-2-carbonyl)
Amino] indan-2-yl} carbamic acid t-butyl ester (Compound E of Example 1) as described for N- (5-aminoindan-2-yl) acetamide (Compound A; 1.05 g; The product is obtained and prepared using 5.55 mmol) and 2-bromobenzoyl chloride (compound of B; 1.21 g, 5.50 mmol). 216-217 ° C. MS (ES +) m / z: 373 (M + H), 375 (M
+ H).

D. N- (2-acetylaminoindan-5-yl) -2-bromobenzamide (
C compound; 0.150 g, 0.40 mmol) and 4-fluorobenzeneboronic acid (
0.084 g (0.60 mmol) in DME (7 mL) was added to PdCl ₂ (dppf) (
0.010 g, 0.012 mmol), followed by K ₃ PO ₄ (0.25 g, 1.20 mmol). The reaction mixture is degassed and heated at reflux for 16 hours under nitrogen. After cooling to room temperature, the reaction mixture is diluted with water and extracted with ethyl acetate. Dry the organic layer (M
gSO ₄ ) and concentrate under reduced pressure to give a tan solid. Stir with ethyl acetate and mix with 4'-fluorobiphenyl-2-carboxylic acid (2-acetylamino-indan-5-yl)
The amide is obtained as a gray solid. mp. MS (ES +) m / z
: 389 (M + 1).

Example 4 The following compounds were prepared in the same manner as in Example 1 or 3.

[Table 40]

[0140]

[Table 41]

[0141]

[Table 42]

[0142]

[Table 43]

Example 5 5-Amino-2- (thiophen-2-yl) -N- (indan-5-yl) benzure
Mid

Embedded image A. 2-Bromo-5-nitrobenzoyl chloride A solution of 2-bromo-5-nitrobenzoic acid (1.00 g, 4.06 mmol) in 15 mL methylene chloride is oxalyl chloride (1.42 mL, 16.24 mmol) followed by DMF
Add one drop. Addition of DMF causes severe gas evolution. After 1.5 hours, the reaction mixture was concentrated in vacuo to give an oil which was used without further purification.

B. 2-Bromo-N- (indan-5-yl) -5-nitrobenzamide 2-bromo-N- (indan-5-yl) -5-nitrobenzamide was prepared in Example 1.
Compound A, 2-bromo-5-nitrobenzoyl chloride (1.07 g, 4.06 mmol) and 5-aminoindane (0.540 g, 4.06
It is prepared using mmol. ¹ H-NMR (DMSO-d6; 300 MHz) δ: 10.52 (1H, s), 8.34 (1H, d), 8.21 (1H, dd), 8
.03 (1H, d), 7.60 (1H, s), 7.38 (1H, d), 7.19 (1H, d), 2.85 (4H, m), 2.0
2 (2H, m).

C. N- (indan-5-yl) -5-nitro-2- (thiophen-2-yl) ben
Zuamido N- (indan-5-yl) -5-nitro-2- (thiophen-2-yl) benzamide was prepared in the same manner as the title compound of Example 3, the compound of B, 2-bromo-N- (indan-5 -Yl) -5-nitrobenzamide (0.137 g, 0.380 mmol
) And 2-thiophenboronic acid (0.073 g, 0.570 mmol). ¹ H-NMR (DMSO-d6; 300 MHz) δ: 10.59 (1H, s), 8.38 (1H, dd) 8.30 (1H, d), 7
.81 (1H, d), 7.73 (1H, d), 7.06 (1H, s), 7.46 (1H, d), 7.30 (1H, d), 7.1
8 (2H, m), 2.83 (4H, q), 2.01 (2H, m).

D. 5-amino-2- (thiophen-2-yl)-(N-indan-5-yl) ben
Zuamide The compound of Example 5, N- (indan-5-yl) -5-nitro-2-thiophen-2-ylbenzamide (0.083 g, 0.228 mmol) in 10 mL of ethyl acetate
The solution is degassed and 10% palladium on charcoal is added. The reaction mixture is depressurized and placed under 1 atm of hydrogen gas for 16 hours. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to give 5-amino-N- (indan-5-yl) -2- (thiophen-2-yl) benzamide as an oil, which was treated with diethyl ether. To a solid from a foam. mp. 62-67 ° C. MS (ES +) m / z: 3
35 (M + 1).

Example 6 The following compounds are prepared in analogy to the compounds of Example 5 by reduction of the corresponding nitro compounds.

[Table 44]

Example 7 N- (Indan-5-yl) -2- (4-trifluoromethylphenyl) nicotinia
Mido hydrochloride

Embedded image A. 2- Chloronicotinic acid methyl ester A solution of 2-chloronicotinic acid (2.00 g, 12.69 mmol) in 40 mL of DMF at 0 ° C. with cesium carbonate (4.96 g, 15.23 mmol) followed by iodomethane (0.25 g).
95 mL, 15.23 mmol). The reaction mixture is warmed to room temperature and stirred for 16 hours. Dilute with ethyl acetate, then wash with water, 8% NaHCO ₃ solution and brine. The organic layer is dried (MgSO ₄ ) and concentrated in vacuo to give 2-chloronicotinic acid methyl ester as an oil. ^{1 H-NMR (CDCl3; 300} MHz) δ: 8.55 (1H, dd), 8.18 (1H, dd) 7.33 (1H, dd), 3.
97 (3H, s).

B. 2- (4-trifluoromethyl-phenyl) nicotinic acid methyl ester 2- (4-trifluoromethyl-phenyl) nicotinic acid methyl ester was prepared in the same manner as in the title compound of Example 3 to give 2-chloronicotinic acid methyl ester (1 .45g,
8.45 mmol) and 4-trifluoromethylbenzeneboronic acid (2.41 g, 12
.68 mmol) to give the product as an oil. ^{1 H-NMR (CDCl3; 300} MHz) δ: 8.80 (1H, dd), 8.19 (1H, dd), 7.67 (4H, q), 7.4
0 (1H, dd), 3.70 (3H, s). MS (ES +) m / z: 282 (M + 1).

C. Compound of 2- (4-trifluoromethylphenyl ) nicotinoyl chloride B, 2- (4-trifluoromethyl-phenyl) nicotinic acid methyl ester (0.626 g, 2.228 mmol) in THF: water (1: 1) , 10 mL)
iOH.H ₂ O (0.187 g, 4.456 mmol) was added. After 3.5 hours, the reaction mixture is concentrated to dryness under reduced pressure. Oxalyl chloride (0.78 mL, 8.91 mmol) and a few drops of DMF are added to a 10 mL slurry of the crude lithium salt in methylene chloride. After stirring for 16 hours, the reaction mixture is concentrated to dryness under reduced pressure and used without purification.

D. N- (indan-5-yl) -2- (4-trifluoromethylphenyl) nicoti
Amide hydrochloride The title compound was prepared in the same manner as described for the compound E in Example 1 as 2- (4
-Trifluoromethylphenyl) nicotinoyl chloride (2.228 mmol) and 5
Prepared with aminoindane (0.296 g, 2.228 mmol). The hydrochloride is prepared by passing HCl gas through a solution of the free base in ethyl acetate and stirring the salt with diethyl ether. mp. 190-205 ° C. MS (ES +) m / z: 383 (M + 1).

Example 8 The following compound was prepared in the same manner as in Example 7.

[Table 45]

[0153]

[Table 46]

Example 9 The following compound was prepared according to the method of Abdel-Magid, AF et al. (J. Org. Chem., 1996, 61: 3849), the compound of Example 1 (4'-trifluoromethylbiphenyl-2). -Carboxylic acid (2-aminoindan-5-yl) amide hydrochloride) and a suitable aldehyde.

[Table 47]

Example 10 N- [2- (N-methyl-N-methanesulfonylamino) indan-5-yl] -4
'-Trifluoromethylbiphenyl-2-carboxamide

Embedded image A. N-methyl-2-aminoindan carbamate 2- (ethoxycarbonylamino) indane (6.07 g,
A solution of 29.6 mmol) in 100 mL Et ₂ O was cooled to 0 ° C. with LiAlH 4 (1.70 mmol).
g, is added slowly to a mixture of 44.7 mmol) and Et ₂ O100mL. The resulting mixture is stirred for 18 hours and warmed to 20 ° C. The reaction mixture was again cooled to 0 ° C.
Note that _{H 2 O (1.7mL), 15} % NaOH (1.7mL) and again H ₂ O (5.1mL)
To process. The mixture is stirred for 20 minutes and gradually warmed to 20 ° C. The precipitate is vacuum filtered and the filtrate is extracted with 1N HCl. The acidic solution is washed with fresh Et ₂ O and then made basic with cold 1N NaOH. The cloudy mixture was extracted with Et ₂ O, washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to an oil.

B. N- (Indan-2-yl) -N-methylmethanesulfonamide In a nitrogen atmosphere, methanesulfonyl chloride (1.08 g, 9.5 mmol) in CH ₂ Cl ₂ (1
0 mL) solution was slowly added to a solution of compound A (1.35 g, 9.2 mmol) and ethyldiisopropylamine (4.75 g, 36.8 mmol) in CH ₂ Cl ₂ (50 mL) at 20 ° C. Stir for 18 hours. The reaction mixture was concentrated to dryness, redissolved the residue in Et ₂ O. This solution was sequentially added to 8% NaHCO ₃ , H ₂ O, 1N HCl, H ₂ O,
And finally washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to dryness to give the product.

C. N- (5-nitroindan-2-yl) -N-methylmethanesulfonamide fuming nitric acid (2.0 mL, 50.4 mmol) was very slowly cooled to 0 ° C. to give compound B (1.80 g, 8 (0.0 mmol) in a solution of 25 mL of TFA. The reaction mixture is stirred at 0 ° C. for 3 hours, then the solvent is evaporated at 20 ° C. The residue was treated with ice,
Extract to tOAc. The EtOAc solution is washed with 8% NaHCO ₃ , H ₂ O and brine, then dried over Na ₂ SO ₄ . The solution is filtered and the solvent is evaporated to give a solid product, which is recrystallized from cold EtOAc.

D. A mixture of N- (5-aminoindan-2-yl) -N-methylmethanesulfonamide compound C (1.10 g, 4.1 mmol) and 0.11 g of 10% palladium on carbon was treated with hydrogen (1 atm.) In 50 mL of EtOAc. ) At 20 ° C. for 3 hours. The catalyst is removed by filtration and the filtrate is concentrated to give the title product as a solid.

E. N- {2- (N-methyl-N-methanesulfonylamino) indan-5-yl}
-(4'-trifluoromethylbiphenyl-2-yl) carboxamide 4'-trifluoromethyl-2-biphenylcarboxylic acid chloride (0.2
3 g (0.80 mmol) of CH ₂ Cl _{2 in} 5 mL of compound D (0.18 g, 0.7
4 mmol) and ethyldiisopropylamine (0.38 g, is added to CH ₂ Cl ₂ 10 mL solution of 2.94 mmol). The mixture is stirred at room temperature for 18 hours, concentrated in vacuo, and the residue is dissolved in EtOAc. The solution was washed with 8% NaHCO ₃ (twice), water, 1N
-HCl, then with saturated brine, dried over Na ₂ SO _4. The solution is filtered and concentrated in vacuo to dryness. Dry the residue to obtain the product. mp.163-165 ° C.

Example 11 In the same manner as in Example 10, N- [2- (N-methyl-N-acetylamino)
Indan-5-yl] -2-4'-trifluoromethylbiphenyl-2-carboxamide is prepared.

Embedded image mp. MS: 453 (M + 1).

Example 12 (a) (S) -4'-trifluoromethylbiphenyl-2-carboxylic acid (2-methoxy
Carbonylamino-indan-5-yl) amide

Embedded image A. Prepared from L-phenylalanine (18.7 g, 0.09 mol) (J. Org. Che
m., 1983, 48: 2675-2679) The alcohol, (1-hydroxyindan-2-yl) carbamic acid methyl ester (1S-trans), is suspended in methylene chloride and cooled to 0 ° C. Pyridine (10.7 g, 0.135 mol) followed by acetyl chloride (10.5 g)
, 0.135 mol). The mixture is stirred for 1 hour, then sodium bicarbonate, 1N
-Wash with HCl and saturated sodium chloride. Drying the organic layer over Na ₂ SO ₄ ,
Filter and evaporate under reduced pressure to give (1-acetyloxyindan-2-yl) -carbamic acid methyl ester (1S-trans).

B. 90% nitric acid (55.1, 0.8 mol) in nitrogen at -30 ° C in trifluoroacetic acid 1
00 mL followed by trifluoroacetic anhydride (100 g, 0.476 mol) are added over 5 minutes. The carbamate (1-acetyloxyindan-2-yl)
To a solution of carbamic acid methyl ester (1S-trans)) (20.0 g, 0.08 mol) in 34 mL of methylene chloride slowly (over 90 minutes) while maintaining the temperature gradually between -30 ° C and -35 ° C. Added. Add 100 mL of water to the reaction, warm to 0 ° C. and work up to give two layers. Separate both layers and extract the aqueous layer with methylene chloride. The combined organic extracts are washed with 100 mL of water (pH adjusted to 8.5 with sodium bicarbonate) and cold water. Dry the organic layer over MgSO ₄ , filter and evaporate to give the crude product. The crude product is recrystallized from ethyl acetate and precipitated by further addition of heptane to give (1-acetyloxy-6-nitroindan-2-yl) carbamic acid methyl ester (1S-trans). mp.164-167 ° C.

C. The above acetate (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. Dilute the reaction with water and collect the solid. The solid is reslurried in 250 mL of ice water and adjusted to pH 6.5-7.0 with 1N HCl. The solution was filtered, washed with water, the product was collected and dried in vacuo to give (1-hydroxy-6-nitroindan-2-yl) carbamic acid methyl ester (1S-trans).
). mp.

D. The nitro alcohol (6.0 g, 0.023 mol) was added to acetic acid 3 containing 3 mL of water.
Dissolve in 50 mL at 00 ° C. The mixture was cooled to room temperature and HClO ₄ (6 g, 0
.042 mL) and 10% palladium on charcoal (6 g) are added and the mixture is hydrogenated at 50 psi for 2 days. Two additional portions of fresh catalyst (3 g) are added within the reaction time. The reaction mixture was filtered through celite and the filtrate was concentrated and the residue washed with ice water, dried over MgSO _4.
The solution is filtered and the solvent is removed under reduced pressure to give (S)-(5-aminoindan-2-yl) carbamic acid methyl ester. mp.

(R)-(5-aminoindan-2-yl) carbamic acid methyl ester is obtained in the same manner as (1-acetyloxyindan-2-yl) carbamic acid methyl ester (1
R-trans), starting from D-phenylalanine instead of L-phenylalanine.

E. (S)-(5-aminoindan-2-yl) carbamic acid methyl ester (50
0 mg, 2.43 mmol) in 20 mL methylene chloride and 0.236 mL pyridine (0.236 mL).
(0.9 mmol) at 0 ° C. is added a solution of 4′-trifluoromethyl-2-biphenylcarboxylic acid chloride (0.076 g, 2.6 mmol) in 5 mL of methylene chloride.
The reaction is warmed to room temperature and stirred for 1 hour. The mixture is washed with 1N HCl, sodium bicarbonate and brine. The organic layer was dried over MgSO ₄ , filtered, concentrated and chromatographed on silica gel using ethyl acetate / hexane (1: 1) to give (S)-{5-[(4′-trifluoromethylbiphenyl). ) -2-carbonyl) amino} indan-2-yl] carbamic acid methyl ester. This is Example 13
(d).

(B) (S) -4′-trifluoromethylbiphenyl-2-carboxylic acid (2-benzene
Sulfonylamino-indan-5-yl) amide

Embedded image A. To a solution of the carbamate of Example 12 (a) (0.96 g, 2.1 mmol) in 75 mL of acetonitrile at 0 ° C. is added trimethylsilyl iodide. The mixture is stirred for 16 hours. The reaction is quenched with 2 mL of methanol and stirred for 1 hour. Concentrate the mixture and redissolve the residue in ethyl acetate. This solution is washed with sodium bicarbonate and saturated sodium chloride solution. The organic layer was dried over MgSO _4, filtered, and concentrated under reduced pressure (S) -
N- (2-aminoindan-5-yl) -4'-trifluoromethylbiphenyl-
Obtain 2-carboxamide.

B. (S) -4'-Trifluoromethylbiphenyl-2-carboxylic acid (2-benzenesulfonylaminoindan-5-yl) -amide is prepared from the above amine as described in Example 1. 152-153 ° C. [α] _D -7.304 (c = 1
0.152 mg / mL, methanol).

Example 13 In the same manner as in Example 12, (1S-trans)-or (1R-trans)-(1-
The following compound is prepared from any of acetyloxyindan-2-yl) carbamic acid methyl esters.

[Table 48]

[0170]

[Table 49]

[0171]

[Table 50]

[0172]

[Table 51]

[0173]

[Table 52]

[0174]

[Table 53]

Example 14 (R) -6-methyl-4'-trifluoromethylbiphenyl-2-carboxylic acid (2-
Methoxycarbonylamino-indan-5-yl) amide

Embedded image A. 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 heated at reflux overnight. The methanol was removed in vacuo, the residue taken up in ether, washed with sodium bicarbonate, brine, dried over magnesium sulfate, filtered and evaporated under reduced pressure to give methyl 2-bromo-3-methylbenzoate as an oil. .

B. Methyl 2-bromo-3-methylbenzoate (22.33 g, 97.5 mmol), potassium phosphate (82.8 g, 390 mmol), [1,1-bis (diphenylphosphino) ferrocene] dichloropalladium (II) Complex with dichloromethane (
A mixture of 1: 1) (3.98 g, 4.87 mmol) and p-trifluoromethylphenylboronic acid (22.2 g, 117 mmol) in 500 mL of DME was degassed and heated to reflux overnight in a stream of argon. . The mixture is concentrated, poured into water,
Extract with ethyl acetate. The combined organic extracts are washed with brine, dried over magnesium sulfate, 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'-trifluoromethylbiphenyl-2-carboxylate.

C. 6-Methyl-4'-trifluoromethylbiphenyl-2-carboxylic acid methyl ester (13.6 g, 46.3 mmol) and 1N NaOH (92.5 mL, 92.5
(Mmol) in 225 mL ethanol at reflux for 5 hours. Water is added to the mixture and the aqueous layer is washed with ether. The aqueous layer is acidified with 1N HCl, extracted with ethyl acetate, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The product is purified by crystallization from ethyl acetate / hexane to give 6-methyl-4'-trifluoromethylbiphenyl-2-carboxylic acid. mp. 202-203 ° C. MS m /
z: 279 (M-1).

D. 6-methyl-4'-trifluoromethylbiphenyl-2-carboxylic acid (17.
Oxalyl chloride (22.1 mL, 253 mmol) is added to a cold suspension of 7 g (63.2 mmol) of methylene chloride in 500 mL of ice bath, followed by 4 drops of DMF. The reaction is stirred for 2 hours and another 22 mL of oxalyl chloride and 4 drops of DMF are added. Stirring is continued for a further 2 hours. The mixture is concentrated under reduced pressure. Add 100 mL of methylene chloride,
The acid chloride is used as is in the next reaction.

E. (R)-(5-aminoindan-2 prepared as described in Example 12.
-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.
To a 200 mL ice bath cooled suspension of methylene chloride with 48 mL, 55.5 mmol) was added 6-methyl-4'-trifluoromethylbiphenyl-2-carboxylic acid chloride (80.5 mL, 55.5 mmol).
0.63M solution in methylene chloride, 50.7 mmol) is added. The reaction is stirred at room temperature for 15 minutes. Wash the mixture with 1N HCl, bicarbonate, and brine. Dry the organic layer over magnesium sulfate, filter, and concentrate under reduced pressure. The product was crystallized from ethyl acetate / hexane (1: 2) to give (R) -6-methyl-4'-trifluoromethylbiphenyl-2-carboxylic acid (2-methoxycarbonylaminoindan-5-yl) amide (Compound of Example 13 (i)) is obtained as a crystalline solid. m
112-114 ° C. MS (ES +) m / z: 469 (M + 1).

Example 15 6-methyl-4'-trifluoromethylbiphenyl-2-carboxylic acid (7-methoxy
Cicarbonylamino-6,7,8,9-tetrahydro-5H-benzocyclohepte
N-2-yl) amide

Embedded image A. 6,7,8,9-Tetrahydro-5H-benzocyclohepten-7-one (2.
To a solution of 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-5.
H-benzocyclohepten-7-amine is obtained as a white solid.

B. NaBH4 (1.98 g, 52.3 mmol) DME40mL suspension was cooled in an ice bath, to which is added TiCl _4. Compound A (2.3 g, 13.1) was added to this mixture.
(Mmol) in 28 mL of DME. The mixture was stirred overnight and ice water 13
Pour into 5 mL, basify with 20 mL of 28% ammonia, and extract with ethyl acetate. The organic extract was dried over magnesium sulfate, filtered, and concentrated under reduced pressure to 6,7,8,9.
-Tetrahydro-5H-benzocyclohepten-7-amine is obtained as an oil.

C. Treating the compound of B with methyl chloroformate, nitrating, reducing,
Acylation with 6-methyl-4'-trifluoromethylbiphenyl-2-carboxylic acid chloride according to the method described in Example 12 gives the title compound. mp. 190
~ 193 ° C.

Example 16 The compound of Example 15 was treated with trimethylsilyl iodide and the resulting amine was then reacted with a suitable N-derivatizing reagent (as described in the preceding Examples) to give the following compound: :

Embedded image Are obtained in the following table.

[Table 54]

Formulation Examples : For example, 4'-trifluoromethylbiphenyl-2-carboxylic acid (2-
100 mg of active substance such as benzenesulfonylaminoindan-5-yl) amide
Can be produced, 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 through a sieve with a mesh size of 0.2 mm. Mix both components thoroughly. Then first lactose with mesh size 0
Add through a 0.6 mm sieve, then add microcrystalline cellulose through a sieve with a mesh size of 0.9 mm. The components are then thoroughly mixed for 10 minutes. Finally, magnesium stearate is added through a sieve with a mesh size of 0.8 mm. After mixing for an additional 3 minutes, 390 mg of each composition are filled into size 0 hard gelatin capsules.

[Procedure amendment]

[Submission date] November 13, 2001 (2001.11.13)

[Procedure amendment 1]

[Document name to be amended] Statement

[Correction target item name] Claims

[Correction method] Change

[Correction contents]

[Claims]

Embedded image Wherein R ₂ -C, R ₃ -C, R ₄ -C or R ₅ -C may be substituted by N; n is 1, 2 or 3; R ₁ is aryl, cycloalkyl Or heterocyclyl; R ₂ , 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 ₄ and R ₅ in adjacent positions are alkylenedioxy; R ₆ is amino, substituted amino, acylamino Or has the following formula:

Embedded image 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 And R _e is an optionally substituted alkyl, aryl, heterocyclyl, cycloalkyl, amino or substituted amino]. The variable group R ₆ is a group represented by the following formula: A 5-membered ring, a 6-membered ring or a 7-membered saturated ring at a position not directly adjacent to the compound]; or a pharmaceutically acceptable compound thereof. Salt; or an enantiomer.

Embedded image Wherein n is 1, 2 or 3; R 1 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), or an amino carbonyloxy; any two of or in adjacent positions R _2, R _3, R ₄ and R ₅ are alkylenedioxy; R ₆ is amino , Substituted amino, acylamino, or

Embedded image 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 are lower alkylene or lower alkylene interrupted by O, S or N- (H, alkyl or aralkyl); R _d is optionally substituted alkyl, cycloalkyl, aryl or And R _e is an optionally substituted alkyl, aryl, heterocyclyl, cycloalkyl, amino or substituted amino]. The variable group R ₆ is a group represented by the following formula: A 5-membered ring, a 6-membered ring or a 7-membered saturated ring at a position that is not directly adjacent to the compound]. Acceptable salt thereof; or an enantiomer.

Embedded image Wherein Ar is monocyclic 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, tri And R ₆ has the meaning defined in claim 2], or a pharmaceutically acceptable salt thereof; or an enantiomer thereof.

Embedded image 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 are Taken together is morpholino, thiomorpholino, or lower alkylene; R _d is lower alkyl, lower alkyl but lower alkoxy, lower alkoxy-lower alkoxy, morpholino, thiomorpholino, 2-oxo-1-- Substituted by pyrrolidino, by pyridyl, by phenyl, or by phenyl substituted by a substituent selected from halo, trifluoromethyl, lower alkyl and lower alkoxy; or phenyl, phenyl but halo , Trifluoromethyl, lower alkyl, and Or those substituted by selected substituents from grade alkoxy, or are cycloalkyl or pyranyl from 5-membered ring to 7-membered ring; and R _e is a lower alkyl, phenyl lower alkyl, phenyl Or unsubstituted or substituted with a group selected from lower alkyl, lower alkoxy, halo, trifluoromethyl and lower alkanesulfonyl; or naphthyl, thienyl, furyl, isoxazolyl, imidazolyl or Quinolyl, either unsubstituted or substituted by a group selected from lower alkyl, halo and trifluoromethyl; or lower alkylamino, di-lower alkylamino, or 5 A cycloalkylamino having from 7 to 7 membered rings Shall be]

Embedded image Wherein R ₂ , R ₃ and R ₄ are independently hydrogen, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, trifluoromethyl, chloro or fluoro; R ₇ is trifluoromethyl, And R ₆ is chloro or cyano;

Embedded image [Wherein, R _d is C ₁ -C ₄ -alkyl; R _e is C ₁ -C ₄ -alkyl, monocyclic carbocyclic aryl or heterocyclic aryl]]. 4. The compound of claim 3; or an enantiomer thereof.

Embedded image Wherein R _d is methyl; and R ₇ is trifluoromethyl; the compound of claim 5, or an enantiomer thereof.

10. (i) reduced apolipoprotein B secretion in mammals; (ii) treatment of microsomal triglyceride transfer protein or lipoprotein B dependent conditions in mammals; (iii) arteriosclerosis, hypertriglyceridemia. Or the use of any of claims 8 or 9 for the treatment of hypercholesterolemia.

[Procedure amendment]

[Submission date] November 13, 2001 (2001.11.13)

[Procedure amendment 1]

[Document name to be amended] Statement

[Correction target item name] 0006

[Correction method] Change

[Correction contents]

Preferred are those of the formula Ia wherein n is 1; R ₁ is a monocyclic aryl or heteroaryl.
It is a reel; X is located at R ₂ -C or _{N; R 2, R 3,} R 4 and R ₅ are independently hydrogen, lower alkyl, halo, trifluoromethyl, lower alkoxy or amino; and R ₆ Is amino, substituted amino, acylamino or the following formula:

Embedded image Wherein R _a is hydrogen and R _b and R _c are independently hydrogen, lower alkyl, aralkyl, aryl, heteroaryl or heteroaralkyl; or R _b and R _c together with nitrogen Piperidino, morpholino, pyrrolidino, or N
- a lower alkylpiperazino; R _d and R _e is a lower alkyl, aralkyl,
Aryl, heteroaryl or heteroaralkyl]
And a pharmaceutically acceptable salt thereof.

[Procedure amendment 2]

[Document name to be amended] Statement

[Correction target item name] 0008

[Correction method] Change

[Correction contents]

[0008] A particular aspect of the invention is a compound of formula I wherein R ₂ -C, R ₃ -C, R ₄ -C or R ₅ -C may be substituted with N; Or 3; R ₁ is phenyl or thienyl, in each case unsubstituted or 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 Alkylamino,
Or lower alkanoylamino;

[Procedure amendment 3]

[Document name to be amended] Statement

[Correction target item name] 0009

[Correction method] Change

[Correction contents]

R ₆ is amino; phenyl lower alkylamino; lower alkanoylamino; lower alkanoyl-amino, wherein the alkyl group of the alkanoyl group is phenyl, lower alkoxy, phenoxy, lower alkylthio,
Substituted by phenylthio, di-lower alkylamino, morpholino, thiomorpholino, piperazino, or 4-lower alkylpiperazino; or N-methyl-N′-lower alkanoylamino, benzoyl An amino or isoxazolylcarbonylamino, wherein the isoxazolyl is unsubstituted or substituted with lower alkyl, or

Embedded image Wherein R _a is hydrogen or alkyl; R _b and R _c are independently hydrogen, lower alkyl, 5- to 7-membered cycloalkyl, or phenyl; R _b and R _c together Represents morpholino, thiomorpholino or lower alkylene;

[Procedure amendment 4]

[Document name to be amended] Statement

[Correction target item name] 0010

[Correction method] Change

[Correction contents]

R _d is lower alkyl or lower alkoxy, lower alkoxy-lower alkoxy, morpholino, thiomorpholino, 2-oxo-1-pyrrolidino, pyridyl, phenyl, or halo, tri. Lower alkyl substituted by phenyl substituted with a substituent selected from the group consisting of fluoromethyl, lower alkyl, and lower alkoxy, or phenyl, halo, trifluoromethyl, lower alkyl and lower alkoxy Phenyl substituted by a substituent selected from or a 5- to 7-membered cycloalkyl or pyranyl; and

[Procedure amendment 5]

[Document name to be amended] Statement

[Correction target item name] 0020

[Correction method] Change

[Correction contents]

The term “optionally substituted alkyl” is a lower alkyl having 1 to 20 carbon atoms, preferably 1 to 7 carbon atoms, linear or branched non-alkyl. Indicates a substituted or substituted hydrocarbon group. Examples of unsubstituted alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, and others.

[Procedure amendment 6]

[Document name to be amended] Statement

[Correction target item name] 0030

[Correction method] Change

[Correction contents]

The term “heterocyclyl” refers to an optionally substituted, fully saturated or unsaturated, aromatic or non-aromatic cyclic group, for example a monocyclic from 4 to 7 membered ring A 7-membered to 11-membered bicyclic or 10-membered to 15-membered tricyclic ring system, wherein at least one ring is contained in at least one carbon atom-containing ring.
Having a hetero atom of Each ring of the heterocyclic group containing a hetero atom may have one, two or three hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and the nitrogen atom and the sulfur hetero atom are If necessary, it may be oxidized, and its nitrogen atom may also be quaternized, if necessary. The heterocyclic group may be attached at any heteroatom or carbon atom.

[Procedure amendment 7]

[Document name to be amended] Statement

[Correction target item name] 0037

[Correction method] Change

[Correction contents]

Similarly, if a basic group, such as amino or pyridyl, forms part of the structure, mineral acids such as hydrochloric acid, methanesulfonic acid, maleic acid, organic carboxylic acids, and organic sulfonic acids Addition salts of acids are also possible. Since the compounds of the present invention have one or more asymmetric carbon atoms depending on the nature of the substituents, they exist as their racemates and (R) and (S) enantiomers. These are all within the scope of the present invention.

[Procedure amendment 8]

[Document name to be amended] Statement

[Correction target item name] 0063

[Correction method] Change

[Correction contents]

The compounds of the invention having a basic group can be converted into acid addition salts, especially pharmaceutically acceptable salts. These may be inorganic acids such as, for example, mineral acids such as sulfuric acid, phosphoric acid, hydrohalic acid, or (C ₁ -C ₄ ) -alkanecarboxylic acids such as, for example, acetic acid unsubstituted or substituted by halogen, for example. Acids; saturated or unsaturated dicarboxylic acids such as oxalic acid , succinic acid, maleic acid or fumaric acid; hydroxycarboxylic acids such as glycolic acid, lactic acid, malic acid, tartaric acid or citric acid;
By an organic carboxylic acid, such as an amino acid such as aspartic acid or glutamic acid; or by, for example, a (C ₁ -C ₄ ) -alkylsulfonic acid (eg, methanesulfonic acid) or, for example, an unsubstituted or substituted (eg, halogen) arylsulfonic acid. It is formed. Preferred are salts formed with hydrochloric acid, methanesulfonic acid and maleic acid.

[Procedure amendment 9]

[Document name to be amended] Statement

[Correction target item name]

[Correction method] Change

[Correction contents]

The above properties can advantageously be demonstrated in in vitro and in vivo tests using mammals such as rats, mice, dogs, monkeys and isolated cell or enzyme preparations. The compounds are applied in vitro in the form of a solution, such as an aqueous solution, and in vivo preferably applied orally, topically, or parenterally, for example, intravascularly. Dosages in vitro may range from about 10 ^-5 to 10 ^-9 molar. In vivo dosages may range between about 1 mg / kg and 100 mg / kg, depending on the route of administration. These test methods are generally known in the art. For evaluation in vivo, the compounds are generally administered as a solution or suspension, for example, a 3% corn starch suspension.

[Procedure amendment 10]

[Document name to be amended] Statement

[Correction target item name] 0077

[Correction method] Change

[Correction contents]

The following processes are all performed on ice. Rat liver 57% homogenate (120 g / 210 mL) in 0.25 M sucrose buffer is prepared using a Potter-Elvehjem homogenizer. The homogenate is then centrifuged at 13000 × g for 30 minutes at 4 ° C. to remove large organelles. The supernatant is then centrifuged at 105000 × g for 90 minutes to pellet the microsomes. The pellet was resuspended in 10 mM Tris-HCl buffer pH 8.6,
Centrifuge at 000 xg. Next, the washed pellet was washed with 1 mM Tris-HCl buffer (pH 8.
Resuspend in 6) and centrifuge for 2 hours. The pellet was added to a 0.25 M-sucrose solution 28.5 m
Resuspend in 1 L and freeze 1 mL volume containing 4.2 g of liver and store at -80 ° C until use.
Before performing the assay, the thawed pellet was chilled with Tris HCl, 50 mM KCl, 5 mM MgCl,
Suspend in 12 mL of pH 7.4 and gently mix 0.54% deoxycholic acid solution (pH
Gradually add 1.2 mL of 7.4). Place the suspension on ice for 30 minutes, then 105000 for 75 minutes
Centrifuge at xg. The supernatant containing the soluble MTP is dialyzed against assay buffer (150 mM Tris HCl / 40 mM NaCl / 1 mM EDTA / 0.02% NaN ₃ / pH 7.4). Sigma Low
The protein content is determined using the ry micro-total protein method and reagents (Sigma; cat # 690A). Rat MTP is diluted with assay buffer to contain 15 μg protein per 50 μL and stored at 4 ° C.

[Procedure amendment 11]

[Document name to be amended] Statement

[Correction target item name]

[Correction method] Change

[Correction contents]

The effect of the compounds of the present invention to lower serum cholesterol in vivo is determined by measuring the effect on cholesterol levels in mice, rats or dogs according to methods well known in the art, for example, in lipoprotein normal rats. it can.

[Procedure amendment 12]

[Document name to be amended] Statement

[Correction target item name] 0093

[Correction method] Change

[Correction contents]

A portion of the free amine (0.580 mmol) is dissolved in ethyl acetate and saturated with HCl gas to give the hydrochloride 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 (1H,
m), 3.38 (2H, dd), 2.97 (2H, d). MS (ES +) m / z 397 (M + H).

[Procedure amendment]

[Submission date] November 13, 2001 (2001.11.13)

[Procedure amendment 13]

[Document name to be amended] Statement

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[0155] Example 10 N- [2- (N- methyl -N- methanesulfonylamino) indan-5-yl] - 2
- 4'-trifluoromethyl-biphenyl-2-carboxamide

Embedded image A. N-methyl-2-aminoindane Carbamate 2- (ethoxycarbonylamino) indane (6.07 g,
Et ₂ O100mL LiAlH ₄ the solution was cooled to 0 ℃ to 29.6 mmol) (1.70
g, is added slowly to a mixture of 44.7 mmol) and Et ₂ O100mL. The resulting mixture is stirred for 18 hours and warmed to 20 ° C. The reaction mixture was again cooled to 0 ° C.
Note that _{H 2 O (1.7mL), 15} % NaOH (1.7mL) and again H ₂ O (5.1mL)
To process. The mixture is stirred for 20 minutes and gradually warmed to 20 ° C. The precipitate is vacuum filtered and the filtrate is extracted with 1N HCl. The acidic solution is washed with fresh Et ₂ O and then made basic with cold 1N NaOH. The cloudy mixture was extracted with Et ₂ O, washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to an oil.

[Procedure amendment 14]

[Document name to be amended] Statement

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E. N- {2- (N-methyl-N-methanesulfonylamino) indan-5-yl}
-2- (4'-trifluoromethylbiphenyl-2-yl) carboxamide 4'-trifluoromethyl-2-biphenylcarboxylic acid chloride (0.2
3 g (0.80 mmol) of CH ₂ Cl _{2 in} 5 mL of compound D (0.18 g, 0.7
4 mmol) and ethyldiisopropylamine (0.38 g, is added to CH ₂ Cl ₂ 10 mL solution of 2.94 mmol). The mixture is stirred at room temperature for 18 hours, concentrated in vacuo, and the residue is dissolved in EtOAc. The solution was washed with 8% NaHCO ₃ (twice), water, 1N
-HCl, then with saturated brine, dried over Na ₂ SO _4. The solution is filtered and concentrated in vacuo to dryness. Dry the residue to obtain the product. mp.163-165 ° C.

[Procedure amendment 15]

[Document name to be amended] Statement

[Correction target item name] 0176

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B. Methyl 2-bromo-3-methylbenzoate (22.33 g, 97.5 mmol), potassium phosphate (82.8 g, 390 mmol), [1, 1 '- bis (diphenylphosphino) ferrocene] dichloropalladium (II Complex with dichloromethane (
1: 1) (3.98 g, 4.87 mmol) and a solution of p-trifluoromethylphenylboronic acid (22.2 g, 117 mmol) in 500 mL of DME were degassed and heated to reflux overnight in a stream of argon. . The mixture is concentrated, poured into water,
Extract with ethyl acetate. The combined organic extracts are washed with brine, dried over magnesium sulfate, 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'-trifluoromethylbiphenyl-2-carboxylate.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI theme coat ゛ (Reference) A61K 31/381 A61K 31/381 4C206 31/40 31/40 31/4164 31/4164 31/42 31/42 31/4402 31/4402 31/4418 31/4418 31/5375 31/5375 A61P 3/06 A61P 3/06 9/10 101 9/10 101 43/00 111 43/00 111 C07D 213/82 C07D 213/82 233/84 233/84 261/10 261/10 261/18 261/18 295/14 295/14 AZ 295/20 295/20 Z 309/12 309/12 333/24 333/24 333/34 333 / 34 (81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP ( GH, GM, KE, LS, MW, SD, SL, SZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU , ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, UA, UG, US, UZ, VN, YU, ZA, ZW (72) Invention Paiva Yana Kokkola 08889 New Jersey White House Station Ishon, Bulley Place No. 6 (72) Inventor Eli Melville Wallace, United States 27516 North Carolina, Chapel Hill, Tremont Circle 125 F-term (reference) 4C023 EA11 4C055 AA01 BA01 BA02 BA08 BA13 BA17 CA02 CA46 CA58 CB10 CB17 DA01 4C056 AA01 AB01 AC01 AD01 AE03 BA01 BA03 BB09 BB14 BC01 FB18 FC01 4C062 AA17 4C086 AA01 AA02 AA03 BA07 BB02 BC07 BC17 BC38 BC50 BC72 BC77 4C206 AA01 AA02 AA03 GA07 GA19 GA31 HA21 HA24 ZA31 MA21

Claims (10)

[Claims] 1. Formula I: ## STR1 ## Wherein R ₂ -C, R ₃ -C, R ₄ -C or R ₅ -C may be substituted by N; n is 1, 2 or 3; R ₁ is aryl, cycloalkyl Or heterocyclyl; R ₂ , 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 ₄ and R ₅ in adjacent positions are alkylenedioxy; R ₆ is amino, substituted amino, acylamino Or has the following formula: 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 And R _e is an optionally substituted alkyl, aryl, heterocyclyl, cycloalkyl, amino or substituted amino]. The variable group R ₆ is a group represented by the following formula: A 5-membered ring, a 6-membered ring or a 7-membered saturated ring at a position not directly adjacent to the compound]; or a pharmaceutically acceptable compound thereof. Salt; or an enantiomer. 2. Formula Ia: Wherein n is 1, 2 or 3; R 1 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), or an amino carbonyloxy; any two of or in adjacent positions R _2, R _3, R ₄ and R ₅ are alkylenedioxy; R ₆ is amino Or a substituted amino, acylamino, or a compound of the following formula: 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 are lower alkylene or lower alkylene interrupted by O, S or N- (H, alkyl or aralkyl); R _d is optionally substituted alkyl, cycloalkyl, aryl or And R _e is an optionally substituted alkyl, aryl, heterocyclyl, cycloalkyl, amino or substituted amino]. The variable group R ₆ is a group represented by the following formula: A 5-membered ring, a 6-membered ring or a 7-membered saturated ring at a position that is not directly adjacent to the compound]. Acceptable salt thereof; or an enantiomer. 3. A compound of formula Ib: Wherein Ar is monocyclic 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, tri And R ₆ has the meaning defined in claim 2], or a pharmaceutically acceptable salt thereof; or an enantiomer thereof. 4. A compound of formula I, or a pharmaceutically acceptable salt thereof,
Or an enantiomer thereof, wherein R ₂ -C, R ₃ -C, R ₄ -C or R ₅ -C may be substituted by N; n is 1, 2 or 3 R ₁ is phenyl or thienyl, either unsubstituted or 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 alkylamino,
Or R ₆ is amino, phenyl lower alkylamino, lower alkanoylamino, or lower alkanoylamino, wherein the alkyl group of the alkanoyl group is phenyl, lower alkoxy, phenoxy, lower alkylthio. Phenylthio, di-lower alkylamino, morpholino, thiomorpholino, piperazino, or 4-lower alkylpiperazino, or N-methyl-N′-lower alkanoylamino, Benzoylamino or isoxazolylcarbonylamino, wherein the isoxazolyl is unsubstituted or substituted with lower alkyl; or 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 are Taken together is morpholino, thiomorpholino, or lower alkylene; R _d is lower alkyl, lower alkyl but lower alkoxy, lower alkoxy-lower alkoxy, morpholino, thiomorpholino, 2-oxo-1-- Substituted by pyrrolidino, by pyridyl, by phenyl, or by phenyl substituted by a substituent selected from halo, trifluoromethyl, lower alkyl and lower alkoxy; or phenyl, phenyl but halo , Trifluoromethyl, lower alkyl, and Or those substituted by selected substituents from grade alkoxy, or are cycloalkyl or pyranyl from 5-membered ring to 7-membered ring; and R _e is a lower alkyl, phenyl lower alkyl, phenyl Or unsubstituted or substituted with a group selected from lower alkyl, lower alkoxy, halo, trifluoromethyl and lower alkanesulfonyl; or naphthyl, thienyl, furyl, isoxazolyl, imidazolyl or Quinolyl, either unsubstituted or substituted by a group selected from lower alkyl, halo and trifluoromethyl; or lower alkylamino, di-lower alkylamino, or 5 A cycloalkylamino having from 7 to 7 membered rings Shall be] 5. A compound of formula Ic: Wherein R ₂ , R ₃ and R ₄ are independently hydrogen, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, trifluoromethyl, chloro or fluoro; R ₇ is trifluoromethyl, And chloro or cyano; and R ₆ is of the following formula: [Wherein, R _d is C ₁ -C ₄ -alkyl; R _e is C ₁ -C ₄ -alkyl, monocyclic carbocyclic aryl or heterocyclic aryl]]. 4. The compound of claim 3; or an enantiomer thereof. 6. R ₂ is methyl; R ₃ is hydrogen; R ₄ is hydrogen or methyl; R ₆ is of the following formula: Wherein R _d is methyl; and R ₇ is trifluoromethyl; the compound of claim 5, or an enantiomer thereof. 7. (S) -enantiomers wherein R ₂ is methyl; R ₃ and R ₄ are hydrogen; _Re is methyl; and R ₇ is trifluoromethyl; (S) - a enantiomers, R ₂ is methyl; R ₃ and R ₄ are hydrogen, R _e is 2-thienyl; those and R ₇ is trifluoromethyl;
(S) - a enantiomers, methyl R ₂ and R _4; R ₃ is hydrogen, R _e is 2-thienyl; those and R ₇ is trifluoromethyl; and (R A) wherein R ₂ is methyl; R ₃ and R ₄ are hydrogen; R _d is methyl; and R ₇ is trifluoromethyl. Compound. 8. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier. 9. A method for inhibiting microsomal triglyceride transfer protein in a mammal comprising administering to the mammal in need thereof an effective microsomal triglyceride transfer protein inhibitory amount of a compound according to any one of claims 1 to 8. 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. The method of claim 9, wherein (i) reducing apolipoprotein B secretion in the mammal; (ii) treating a microsomal triglyceride transfer protein or lipoprotein B dependent condition in the mammal. (Iii) for treating arteriosclerosis, hypertriglyceridemia, or hypercholesterolemia.