HK1137011B - Mtp inhibiting tetrahydro-naphthalene-1-carboxylic acid derivatives - Google Patents

Description

MTP inhibiting tetrahydro-naphthalene-1-carboxylic acid derivatives

The present invention relates to novel tetrahydro-naphthalene-1-carboxylic acid derivatives having apoB secretion/MTP inhibiting activity and concomitant lipid lowering activity. The invention further relates to processes for the preparation of such compounds, pharmaceutical compositions comprising said compounds and the use of said compounds as a medicament for the treatment of atherosclerosis, pancreatitis, obesity, hypertriglyceridemia, hypercholesterolemia, hyperlipidemia, diabetes and type II diabetes.

Obesity is the cause of a number of serious health problems, such as adult onset diabetes and heart disease. Furthermore, weight loss is becoming an obsessive compulsive in an ever increasing proportion of the population.

Now, the causal relationship between hypercholesterolemia, particularly that accompanied by elevated plasma concentrations of low density lipoproteins (hereinafter LDL) and very low density lipoproteins (hereinafter VLDL), and premature atherosclerosis and/or cardiovascular disease is well established. However, the number of drugs currently available for the treatment of hyperlipidemia is limited.

The drugs mainly used for treating hyperlipidemia include: bile acid sequestrant resins such as cholestyramine (cholestyramine) and colestipol (colestipol); fibric acid derivatives such as bezafibrate, clofibrate, fenofibrate, ciprofibrate and gemfibrozil; nicotinic acid; and cholesterol synthesis inhibitors, such as HMG-coa reductase inhibitors. There remains a need for new lipid lowering agents with improved efficiency and/or acting via other mechanisms than the above mentioned drugs.

Plasma lipoproteins are high molecular weight water-soluble complexes formed from lipids (cholesterol, triglycerides, phospholipids) and apolipoproteins. The five major classes of lipoproteins, which differ in lipid proportion and type of apolipoprotein, are derived from the liver and/or intestine and have been defined in terms of their density (measured by ultracentrifugation). They include LDL, VLDL, medium density lipoprotein (hereinafter referred to as IDL), high density lipoprotein (hereinafter referred to as HDL) and chylomicron. Ten major human plasma apolipoproteins have been identified. VLDL secreted by the liver and containing apolipoprotein B (hereinafter referred to as Apo-B) is degraded to produce LDL, which transports 60 to 70% of the total serum cholesterol. Apo-B is also the major protein component of LDL. Increased serum LDL-cholesterol due to over-synthesis or reduced metabolism has a causal relationship with atherosclerosis. In contrast, high density lipoprotein (hereinafter referred to as HDL) containing apolipoprotein a1 has a protective effect and is negatively associated with coronary heart disease risk. Thus, the HDL/LDL ratio is a convenient method for assessing the atherogenic potential of an individual's plasma lipid profile.

Two isoforms of apolipoprotein (apo) B, apo B-48 and apo B-100, are important proteins in human lipoprotein metabolism. According to the sodium dodecyl sulfate-polyacrylamide gel, Apo B-48, which is about 48% of Apo B-100 in size, is synthesized by the human intestine. Apo B-48 is essential for chylomicron assembly and therefore has a necessary role in intestinal absorption of dietary fat. Apo B-100 is produced in the human liver and is required for the synthesis and secretion of VLDL. LDL contains about 2/3 of cholesterol in human plasma and is a metabolite of VLDL. Apo B-100 is almost the only protein component of LDL. Elevated plasma concentrations of apo B-100 and LDL cholesterol are recognized risk factors for developing atherosclerotic coronary heart disease.

Many genetic and acquired diseases can lead to hyperlipidemia. They can be classified into primary and secondary hyperlipidemic states. The most common causes of secondary hyperlipidemia are diabetes, alcohol abuse, medications, hypothyroidism, chronic renal failure, nephrotic syndrome, cholestasis, and bulimia. Primary hyperlipidemia has also been classified into general hypercholesterolemia, familial combined hyperlipidemia, familial hypercholesterolemia, residual hyperlipidemia (remnants hyperlipidaemia), chylomicronemia syndrome, and familial hypertriglyceridemia.

Microsomal triglyceride transfer protein (hereinafter MTP) is known to catalyze the transport of triglycerides, cholesterol esters, and phospholipids (e.g., phosphatidylcholine). This indicates that MTP is necessary for the synthesis of ApoB-containing lipoproteins (e.g., chylomicrons and LDL precursor VLDL). It follows that MTP inhibitors will inhibit the synthesis of VLDL and LDL, thereby lowering the levels of VLDL, LDL, cholesterol and triglycerides in humans. It is believed that compounds capable of inhibiting MTP are useful in treating conditions such as obesity, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, type II diabetes, atherosclerosis and lowering plasma levels of serum triglycerides after meals.

The present invention is based on the unexpected findings: a group of tetrahydro-naphthalene-1-carboxylic acid derivatives have apoB secretion/MTP inhibiting activity. These compounds of formula (I) may act systemically and/or as selective MTP inhibitors, i.e. capable of selectively blocking MTP at the level of the intestinal wall (gut wall) in mammals.

The present invention relates to a novel class of compounds of formula (I), the pharmaceutically acceptable acid addition salts thereof, the N-oxides thereof and the stereochemically isomeric forms thereof

Wherein

A is-CH₂-or- (C ═ O) -;

x represents

n is an integer of 2 or 3;

R⁵is hydrogen or C_1-4An alkyl group;

R⁶is hydrogen or C_1-4An alkyl group;

R¹is NR⁷R⁸OR OR⁹；

Wherein R is⁷And R⁸Each independently selected from

The presence of hydrogen in the presence of hydrogen,

C_1-8an alkyl group, a carboxyl group,

c substituted by 1, 2 or 3 substituents_1-8Alkyl, each substituent being independently selected from halo, cyano, C_3-8Cycloalkyl radical, C_1-4Alkylcarbonyl group, C_1-4Alkoxycarbonyl, polyhaloC_1-4Alkyl, hydroxycarbonyl, -OR¹⁰、-NR¹⁰R¹¹、-CONR¹²R¹³Aryl, polycyclic aryl or heteroaryl;

C_3-8a cycloalkyl group;

C_3-8a cycloalkenyl group;

C_3-8an alkenyl group;

C_3-8an alkynyl group;

an aryl group;

a polycyclic aryl group;

a heteroaryl group;

or with a carrier carrying R⁷And R⁸R bound to the nitrogen atom of⁷And R⁸Azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, azepanyl or azocinyl (azocanyl) rings may be formed, wherein each of these rings may be optionally substituted with one or two substituents, each substituent independently selected from C_1-4Alkyl radical, C_1-4Alkoxy, hydroxy, hydroxycarbonyl or C_1-4An alkoxycarbonyl group;

wherein R is¹⁰Is hydrogen, C_1-4Alkyl radical, C_1-4Alkylcarbonyl group, C_1-4Alkoxycarbonyl, aryl, polycyclic aryl or heteroaryl;

R¹¹is hydrogen or C_1-4An alkyl group;

R¹²is hydrogen, C_1-4Alkyl or phenyl;

R¹³is hydrogen, C_1-4Alkyl or phenyl;

R⁹is C_1-8An alkyl group, a carboxyl group,

c substituted by 1, 2 or 3 substituents_1-8Alkyl, each substituent being independently selected from halo, cyano, C_3-8Cycloalkyl radical, C_1-4Alkylcarbonyl group, C_1-4Alkoxycarbonyl, polyhaloC_1-4Alkyl, hydroxycarbonyl, -OR¹⁰、-NR¹⁰R¹¹、-CONR¹²R¹³Aryl, polycyclic aryl or heteroaryl;

C_3-8a cycloalkyl group;

C_3-8a cycloalkenyl group;

C_3-8an alkenyl group;

C_3-8an alkynyl group;

an aryl group;

a polycyclic aryl group;

a heteroaryl group;

wherein

Aryl is phenyl; phenyl substituted with 1 to 5 substituents, each substituent independently selected from C_1-4Alkyl radical, C_1-4Alkoxy, halo, hydroxy, trifluoromethyl, cyano, C_1-4Alkoxycarbonyl group, C_1-4Alkoxycarbonyl radical C_1-4Alkyl, methylsulfonylamino, methylsulfonyl, NR¹⁰R¹¹、C_1-4Alkyl radical NR¹⁰R¹¹、CONR¹²R¹³Or C_1-4Alkyl CONR¹²R¹³；

Polycyclic aryl is naphthyl, indanyl, fluorenyl or 1, 2, 3, 4-tetrahydronaphthyl, and said polycyclic aryl is optionally substituted with one or two substituents, each substituentSubstituents are independently selected from C_1-6Alkyl radical, C_1-6Alkoxy, phenyl, halo, cyano, C_1-4Alkylcarbonyl group, C_1-4Alkoxycarbonyl group, C_1-4Alkoxycarbonyl radical C_1-4Alkyl, NR¹⁰R¹¹、C_1-4Alkyl radical NR¹⁰R¹¹、CONR¹²R¹³、C_1-4Alkyl CONR¹²R¹³Or C_1-4Alkoxycarbonylamino group, and

heteroaryl is pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, pyrrolyl, furanyl, thienyl; a quinolyl group; an isoquinolinyl group; 1, 2, 3, 4-tetrahydro-isoquinolinyl; a benzothiazolyl group; benzo [1, 3 ]]Dioxolyl; 2, 3-dihydro-benzo [1, 4 ]]A dioxinyl group; an indolyl group; 2, 3-dihydro-1H-indolyl; 1H-benzimidazolyl; and said heteroaryl is optionally substituted with one or two substituents, each substituent independently selected from C_1-6Alkyl radical, C_1-6Alkoxy, phenyl, halo, cyano, C_1-4Alkylcarbonyl group, C_1-4Alkoxycarbonyl group, C_1-4Alkoxycarbonyl radical C_1-4Alkyl, NR¹⁰R¹¹、C_1-4Alkyl radical NR¹⁰R¹¹、CONR¹²R¹³Or C_1-4Alkyl CONR¹²R¹³；

R^2a、R^2bAnd R^2cIndependently of one another, selected from hydrogen, C_1-4Alkyl radical, C_1-4Alkoxy, halo, hydroxy, cyano, nitro, polyhaloC_1-4Alkyl, polyhalo C_1-4Alkoxy or C_1-4An alkoxycarbonyl group;

R^3a、R^3band R^3cIndependently of one another, selected from hydrogen, C_1-4Alkyl radical, C_1-4Alkoxy, halo, hydroxy, cyano, nitro, polyhaloC_1-4Alkyl, polyhalo C_1-4Alkoxy or C_1-4An alkoxycarbonyl group;

R⁴is phenyl; phenyl substituted with 1, 2, 3 or 5 substituents, each substituent independently selected from C_1-4Alkyl, halo, hydroxy, C_1-4Alkoxy, cyano, nitro, polyhaloC_1-4Alkyl, polyhalo C_1-4Alkoxy radical, C_1-4Alkylcarbonyl, sulfamoyl, heterocyclyl or phenyl optionally substituted with 1, 2 or 3 substituents, each substituent independently selected from C_1-4Alkyl, halo, C_1-4Alkoxy or trifluoromethyl;

or a heteroaryl group selected from pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, furanyl and thienyl, wherein each of these heteroaryl groups may be optionally substituted with one or two substituents, each substituent independently selected from C_1-4Alkyl, halo, hydroxy, C_1-4Alkoxy, oxo, cyano, polyhaloC_1-4Alkyl radical, C_1-4Alkylcarbonyl group, C_1-4Alkoxycarbonyl or heterocyclyl;

wherein

Heterocyclyl is selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azepanyl and azacyclooctyl, which may be optionally substituted with one or two substituents, each substituent independently selected from C_1-4Alkyl or halo.

As used in the foregoing definitions:

halo includes fluoro, chloro, bromo and iodo

-C_1-4Alkyl is defined as straight and branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms, e.g., methyl, ethyl, propyl, butyl, 1-methylethyl, 2-methylpropyl and the like

-C_1-6Alkyl means including C_1-4Alkyl groups and higher homologues thereof having 5 or 6 carbon atoms, such as 2-methylbutyl, pentyl, hexyl, and the like;

-C_1-8alkyl means including C_1-6Alkyl radicals and higher homologues thereof having 7 to 8 carbon atoms, e.g. heptanesAlkyl, ethylhexyl, octyl, etc.;

-polyhalo C_1-4Alkyl is defined as polyhalo-substituted C_1-4Alkyl, especially C, substituted by 1 to 4 halogen atoms_1-4Alkyl (as defined above) such as fluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, and the like;

-C_3-8cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl;

-C_3-8cycloalkenyl groups include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl;

-C_3-8alkenyl defines straight and branched chain hydrocarbon radicals containing one double bond and having 3 to 8 carbon atoms, such as 2-propenyl, 3-butenyl, 2-pentenyl, 3-methyl-2-butenyl, 3-hexenyl, 2-pentenyl, 2-octenyl and the like;

C_3-8alkynyl defines straight and branched chain hydrocarbon radicals containing one triple bond and having from 3 to 8 carbon atoms, such as 2-propynyl, 3-butynyl, 2-pentynyl, 3-methyl-2-butynyl, 3-hexynyl, 2-pentynyl, 2-octynyl and the like.

The pharmaceutically acceptable acid addition salts mentioned above are meant to include the therapeutically effective non-toxic acid addition salt forms which may be formed from the compounds of formula (I). These pharmaceutically acceptable acid addition salts are conveniently obtained by treating the base form with a suitable acid. Suitable acids include, for example: inorganic acids such as hydrohalic acids (e.g., hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid, phosphoric acid, and the like; or organic acids such as acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid (i.e., oxalic acid), malonic acid, succinic acid (i.e., succinic acid), maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclamic acid, salicylic acid, p-aminosalicylic acid, pamoic acid, and the like.

In turn, the salt form can be converted to the free base form by treatment with a suitable base.

The compounds of formula (I) may exist in both unsolvated and solvated forms. The term "solvate" is used herein to describe a molecular complex comprising a compound of the invention and one or more pharmaceutically acceptable solvent molecules (e.g., ethanol). The term "hydrate" is used when the solvent is water.

The N-oxide forms of the compounds of formula (I) are meant to include compounds of formula (I) wherein one or several nitrogen atoms are oxidized to the so-called N-oxides, in particular those wherein one or more tertiary nitrogens (e.g. of piperazinyl or piperidinyl groups) are N-oxidized. Such N-oxides are readily available to the skilled person without any inventive skill and are obvious alternatives to the compounds of formula (I) as they are metabolites produced by oxidation in the human body after ingestion. It is well known that oxidation is generally the first step involved in drug metabolism (Textbook of Organic Medicinal and pharmaceutical chemical textbooks, 1977, pages 70-75). It is also well known that metabolite forms of a compound can also be administered to humans in place of the compound itself, with almost the same effect.

The compounds of formula (I) may be converted to the corresponding N-oxide form according to methods known in the art for converting a trivalent nitrogen to its N-oxide form. The N-oxidation reaction may generally be carried out by reacting a compound of formula (I) with a suitable organic or inorganic peroxide. Suitable inorganic peroxides include, for example, hydrogen peroxide, alkali or alkaline earth metal peroxides, such as sodium peroxide, potassium peroxide; suitable organic peroxides may include peroxy acids such as benzoperoxybenzoic acid (benzazaperoxoic acid) or halogen substituted peroxybenzoic acids (e.g. 3-chloroperoxybenzoic acid), peroxy alkanoic acids (e.g. peroxyacetic acid), alkyl hydroperoxides (e.g. t-butyl hydroperoxide). Suitable solvents are, for example, water, lower alkanols (e.g. ethanol, etc.), hydrocarbons (e.g. toluene), ketones (e.g. 2-butanone), halogenated hydrocarbons (e.g. dichloromethane) and mixtures of these solvents.

The term "stereochemically isomeric forms" as used hereinbefore defines all the possible isomeric forms which the compounds of formula (I) may possess. Unless otherwise stated or indicated, the chemical names of the compounds indicate mixtures of all possible stereochemically isomeric forms, said mixtures containing all diastereomers and enantiomers of the basic molecular structure. More particularly, the stereogenic center (stereogenic center) may have the R or S configuration; the substituents on the divalent cyclic (partially) saturated groups may have either the cis or trans configuration. Compounds containing a double bond may have E or Z stereochemistry at the double bond. Obviously, stereochemically isomeric forms of the compounds of formula (I) are intended to be included within the scope of the present invention.

The absolute stereochemical configuration of the compounds of formula (I) and intermediates used in their preparation can be readily determined by those skilled in the art using well-known methods such as X-ray diffraction.

The compounds of formula (I) have at least two asymmetric carbon atoms, as shown below, wherein the asymmetric carbon atoms are represented by x.

Due to the presence of at least two asymmetric carbon atoms, in general, the term "compound of formula (I)" comprises a mixture of four stereoisomers. Most of the compounds of the present invention are prepared in either the trans or cis configuration:

cis form

Trans form

Each of the above "cis" or "trans" compounds consists of a racemic mixture of two enantiomers, and bold or cleaved bonds (hashed bonds) have been used to indicate this relative stereochemical configuration.

Where a "cis" or "trans" compound is separated into two respective single enantiomers, the bold and cleavage bonds are replaced by wedge bonds to indicate that the compound is a single enantiomer. If the absolute stereochemistry of a particular chiral carbon atom in a single enantiomer is unknown, its stereochemical configuration is designated as R, which indicates the relative stereochemistry^*Or S^*。

Further, some compounds of formula (I) and some intermediates used in their preparation may exhibit polymorphism. It is to be understood that the present invention encompasses any polymorphic form having properties useful for treating the conditions described above.

Some of the compounds of formula (I) may also exist in their tautomeric form. Although not explicitly shown in the above formula, such forms are intended to be included within the scope of the present invention. For example, when an aromatic heterocycle is substituted with a hydroxyl group, the keto form may be the predominant tautomer present.

In the framework of the present application, the expression "compounds of the invention" is also meant to include compounds of general formula (I) and prodrugs thereof or isotopically labelled compounds thereof.

So-called "prodrugs" of the compounds of formula (I) are also within the scope of the present invention. Prodrugs are certain derivatives of pharmaceutically active compounds which may themselves have little or no pharmacological activity, but which, when administered to or in the human body, are converted, e.g. by hydrolytic cleavage, into compounds of formula (I) having the desired pharmaceutical activity. Such derivatives are referred to as "prodrugs".

Within the framework of the present application, the compounds of the invention will naturally include all isotopic combinations of their chemical elements. In the framework of the present application, a chemical element, in particular when referred to a compound of formula (I), includes all isotopes and isotopic mixtures of this element, whether naturally occurring or synthetically prepared, and whether in naturally abundant or isotopically enriched form. In particular, when hydrogen is mentioned, this is understood to mean¹H、²H、³H and mixtures thereof; when carbon is mentioned, this is understood to mean¹¹C、¹²C、¹³C、¹⁴C and mixtures thereof; when nitrogen is mentioned, this is understood to mean¹³N、¹⁴N、¹⁵N and mixtures thereof; when referring to oxygen, it is understood to mean¹⁴O、¹⁵O、¹⁶O、¹⁷O、¹⁸O and mixtures thereof; when fluorine is mentioned, this is understood to mean¹⁸F、¹⁹F and mixtures thereof.

Thus, the compounds of the present invention inherently include compounds having one or more isotopes of one or more elements and mixtures thereof, including radioactive compounds, also known as radiolabeled compounds, in which one or more non-radioactive atoms are replaced by one of its radioactive isotopes. The term "radiolabeled compound" refers to any compound of formula (I), a pharmaceutically acceptable acid or base addition salt thereof, an N-oxide form thereof or a quaternary ammonium salt thereof, which contains at least one radioactive atom. For example, the compound may be labelled with a positron or gamma emitting radioisotope. For radioligand binding techniques (membrane receptor assays),³h-atom or¹²⁵An I-atom is an atom that is selected for substitution. For imaging, the most commonly used Positron Emitting (PET) radioisotope is¹¹C、¹⁸F、¹⁵O and¹³n, all of which are accelerator produced (accelerated) and have half-lives of 20, 100, 2 and 10 minutes, respectively. Because the half-life of these radioisotopes is so short, it is only possible to have accelerators in the field for the facilities that generate them to use them, thus limiting their application. The most widely used of these radioisotopesIs that¹⁸F、^99mTc、²⁰¹Tl and¹²³I. the handling, generation, separation and incorporation of these radioisotopes into molecules is known to those skilled in the art.

In particular, the radioactive atoms are selected from hydrogen, carbon, nitrogen, sulfur, oxygen and halogens. Preferably, the radioactive atom is selected from hydrogen, carbon and halogen.

In particular, the radioisotope is selected from³H、¹¹C、¹⁸F、¹²²I、¹²³I、¹²⁵I、¹³¹I、⁷⁵Br、⁷⁶Br、⁷⁷Br and⁸²br is added. Preferably, the radioisotope is selected from³H、¹¹C and¹⁸F。

in one embodiment, the present invention relates to those compounds of formula (I) wherein a represents- (C ═ O) -; r¹Is OR⁹Wherein R is⁹Is C_1-6Alkyl or C_3-8An alkenyl group; r^2a、R^3a、R^2b、R^3b、R^2cAnd R^3cIs hydrogen; r⁴Represents phenyl, Via C_1-4Phenyl substituted by alkoxy, phenyl substituted by halogen, pyridyl substituted by hydroxy or C_1-4An alkoxy-substituted pyridyl group; and X represents a group (a-1) in which R is⁵Is hydrogen, and R⁶Is hydrogen or C_1-4An alkyl group.

Interesting compounds of formula (I) are those wherein one or more of the following limitations apply:

a) x represents a group (a-1) wherein n is 2; or

b) X represents a group (a-1) wherein n is 3; or

c) X represents a group (a-2); or

d) X represents a group (a-4); or

e) X represents a group (a-5); or

f)R^2a＝R^3a，R^2b＝R^3bAnd R is^2c＝R^3c(ii) a In particular, R^2a＝R^3a＝H，R^2b＝R^3bIs H, and R^2c＝R^3cH, or

g) A is- (C ═ O) -; or

h) A is-CH₂-; or

i)R¹Is NR⁷R⁸Wherein R is⁷And R⁸Each independently selected from hydrogen; c_1-8An alkyl group; c substituted by one or two substituents_1-8Alkyl, the substituents are independently selected from hydroxyl and C_1-4Alkoxy radical, C_1-4Alkoxycarbonyl, hydroxycarbonyl, NR¹⁰R¹¹、CONR¹²R¹³Aryl or heteroaryl; or an aryl group; or

j)R¹Is NR⁷R⁸Wherein R is⁷And R⁸And carry R⁷And R⁸Wherein each of these rings may be optionally substituted with one or two substituents each independently selected from C_1-4Alkyl radical, C_1-4Alkoxy, hydroxy, hydroxycarbonyl or C_1-4An alkoxycarbonyl group; or

k)R¹Is OR⁹Wherein R is⁹Is C_1-8Alkyl or C_3-8An alkenyl group; or

l)R⁴Is phenyl; phenyl substituted with 1, 2 or 3 substituents, each substituent independently selected from C_1-4Alkyl, halo, hydroxy, C_1-4Alkoxy or polyhalo C_1-4An alkoxy group; or heteroaryl selected from pyridyl or pyridazinyl, each optionally via hydroxy or C_1-4Alkoxy substitution.

In general, the compounds of formula (I) may be prepared by N-alkylating an intermediate of formula (II) with a carboxylic acid intermediate of formula (III) in at least one reaction-inert solvent and optionally in the presence of at least one suitable coupling reagent and/or a suitable base, said process further optionally comprising converting a compound of formula (I) into an addition salt thereof, and/or preparing a stereochemically isomeric form thereof.

The carboxylic acid of formula (III) may conveniently be activated by the addition of an effective amount of a reaction promoter. Non-limiting examples of such reaction promoters include carbonyldiimidazole, diimides (e.g., N' -dicyclohexyl-carbodiimide or 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide), and functional derivatives thereof. The reaction may be further carried out in the presence of an effective amount of a compound such as Hydroxybenzotriazole (HOBT), benzotriazolyloxytris (dimethylamino) -phosphonium hexafluorophosphate, tetrapyrrolidinophosphonium hexafluorophosphate, bromotripyrrolidinophosphonium hexafluorophosphate or a functional derivative thereof.

Compounds of formula (I-a), defined as compounds of formula (I) wherein the group a represents- (C ═ O) -, may be prepared by reacting an intermediate of formula (V) with an intermediate of formula (IV) in at least one reaction-inert solvent and optionally in the presence of at least one suitable coupling reagent and/or a suitable base, said process further optionally comprising converting a compound of formula (I) into an addition salt thereof, and/or preparing a stereochemically isomeric form thereof.

The carboxylic acid of formula (IV) may conveniently be activated by the addition of an effective amount of a reaction promoter. Non-limiting examples of such reaction promoters include carbonyldiimidazole, diimides (e.g., N' -dicyclohexyl-carbodiimide or 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide), and functional derivatives thereof. When using chirally pure reactants of formula (IV), the rapid and enantiospecific free reaction of an intermediate of formula (IV) with said intermediate (V) may further be carried out in the presence of an effective amount of a compound such as Hydroxybenzotriazole (HOBT), benzotriazolyloxytris (dimethylamino) -phosphonium hexafluorophosphate, tetrapyrrolidinophosphonium hexafluorophosphate, bromotripyrrolidinophosphonium hexafluorophosphate or a functional derivative thereof, e.g. d.hudson, j.org.chem. (1988), 53: 617.

The compound of formula (I-b) is defined in that the group A represents-CH₂Compounds of formula (I) of (la) may be prepared by N-alkylating an intermediate of formula (V) with an intermediate of formula (IV-b), wherein W is a suitable leaving group such as halo, e.g. chloro, bromo, iodo, or in some cases W may also be a sulfonyloxy group such as methanesulfonyloxy, benzenesulfonyloxy, trifluoromethane-sulfonyloxy and similar reactive leaving groups. The reaction may be carried out in a reaction-inert solvent such as acetonitrile, 2-pentanol, isobutanol, dimethylacetamide or DMF and optionally in the presence of a suitable base such as sodium carbonate, potassium carbonate or triethylamine. Agitation can increase the reaction rate. The reaction may conveniently be carried out at a temperature between room temperature and the reflux temperature of the reaction mixture.

The intermediate of formula (II) may be prepared as follows: reacting an intermediate of formula (IV) or an intermediate of formula (IV-b) with an intermediate of formula (VI) (wherein PG is a protecting group, such as tert-butyloxycarbonyl or benzyl), a carboxylic acid intermediate of formula (IV) in at least one reaction inert solvent, and optionally in the presence of at least one suitable coupling reagent and/or a suitable base; the protecting group PG is subsequently removed.

The intermediate of formula (V) may be prepared as follows: reacting an intermediate of formula (VII) (wherein PG is a protecting group, such as tert-butyloxycarbonyl or benzyl) with a carboxylic acid intermediate of formula (III) in at least one reaction-inert solvent and optionally in the presence of at least one suitable coupling reagent and/or a suitable base; the protecting group PG is subsequently removed.

Intermediates of formula (XIII) are defined wherein R¹Represents OR⁹、R^2a＝R^3a、R^2b＝R^3bAnd R is^2c＝R^3cThe intermediate of formula (IV) may be prepared as follows.

The intermediate of formula (XV) can be prepared as follows. The intermediate of formula (XV) is wherein R¹Represents NR⁷R⁸An intermediate of formula (IV).

The intermediates of formula (IV-b) can be prepared as follows. The intermediate of formula (IV-b-1) is defined as wherein R¹Represents NR⁷R⁸The intermediate of formula (IV-b-2) is defined as wherein R¹Represents OR⁹An intermediate of formula (IV-b).

H-NR can be used by N-acylation methods known in the art⁷R⁸As a reagent, an intermediate of formula (XVII) (wherein the substituent R^2a、R^2b、R^2c、R^3a、R^3b、R^3c、R⁴、R⁵、A¹、A²And X is as defined for the compound of formula (I)) to a compound of formula (I-c) (defined as wherein R is¹Represents NR⁷R⁸A compound of formula (I) of (1).

The compounds of formula (I) prepared in the above-described processes may be synthesized as racemic mixtures of enantiomers which can be separated from each other according to resolution methods known in the art. Those compounds of formula (I) obtained in racemic form can be converted into the corresponding diastereomeric salt forms by reaction with a suitable chiral acid. The diastereomeric salt forms are then separated, for example, by selective or fractional crystallization, from which the enantiomers are liberated by a base. An alternative way of separating the enantiomeric forms of the compounds of formula (I) comprises liquid chromatography using a chiral stationary phase. The pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms suitable as starting materials, provided that the reaction occurs stereospecifically. Preferably, if a particular stereoisomer is desired, the compound will be synthesized by stereospecific methods of preparation. These processes advantageously employ enantiomerically pure starting materials.

The compounds of formula (I), their N-oxide forms, pharmaceutically acceptable salts and stereoisomeric forms have good apoB secretion and MTP inhibitory activity and concomitant lipid lowering activity. The compounds of formula (I) according to the invention can therefore be used as medicaments, in particular in a method for treating patients suffering from hyperlipidemia, obesity, atherosclerosis or type II diabetes. The compounds of the invention can therefore be used for the manufacture of a medicament for the treatment of conditions caused by excess Very Low Density Lipoprotein (VLDL) or Low Density Lipoprotein (LDL), and in particular such conditions caused by VLDL and LDL-related cholesterol. In particular, the compounds of the invention can be used for the production of medicaments for the treatment of hyperlipidemia, obesity, atherosclerosis or type II diabetes.

The main mechanism of action of the compounds of formula (I) has been shown to involve inhibition of MTP (microsomal triglyceride transfer protein) activity in hepatocytes and intestinal epithelial cells, resulting in reduced VLDL and chylomicron production, respectively. This is a novel and inventive approach to hyperlipidemia and is expected to lower LDL-cholesterol and triglycerides by reducing hepatic production of VLDL and intestinal production of chylomicrons.

Many genetic and acquired diseases can lead to hyperlipidemia. They can be classified into primary and secondary hyperlipidemic states. The most common causes of secondary hyperlipidemia are diabetes, alcohol abuse, medications, hypothyroidism, chronic renal failure, nephrotic syndrome, cholestasis, and bulimia. The primary hyperlipidemia includes common hypercholesterolemia, familial combined hyperlipidemia, familial hypercholesterolemia, residual hyperlipidemia, chylomicronemia syndrome, and familial hypertriglyceridemia. The compounds of the invention may also be used for the prevention or treatment of patients suffering from obesity or atherosclerosis, in particular coronary atherosclerosis, and more generally conditions associated with atherosclerosis, such as ischemic heart disease, peripheral vascular disease, cerebrovascular disease. The compounds of the invention can cause regression of atherosclerosis and inhibit the clinical consequences of atherosclerosis, particularly morbidity and mortality.

In view of the utility of the compounds of formula (I), the present invention also provides a method of treating warm-blooded animals, collectively referred to herein as patients, including humans, suffering from conditions caused by excess Very Low Density Lipoprotein (VLDL) or Low Density Lipoprotein (LDL), and in particular such VLDL-and LDL-related cholesterol. Accordingly, methods of treating patients suffering from conditions such as hyperlipidemia, obesity, atherosclerosis, or type II diabetes are provided.

Apo B-48 synthesized by the intestine is essential for chylomicron assembly and therefore plays an essential role in intestinal absorption of dietary fat. The present invention provides compounds that act as selective MTP inhibitors at the level of the intestinal wall.

In addition, the present invention provides pharmaceutical compositions comprising at least one pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula (I).

To prepare the pharmaceutical compositions of this invention, an effective amount of the particular compound, in base or acid addition salt form, as the active ingredient is combined in intimate admixture with at least one pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirably in single dosage form suitable for preferred use in oral, rectal, transdermal or parenteral injection.

For example, in preparing the compositions in oral dosage form, any of the usual liquid pharmaceutical carriers may be employed in the case of oral liquid preparations (e.g., suspensions, syrups, elixirs and solutions), such as the use of water, glycols, oils, alcohols and the like; or in the case of powders, pills, capsules and tablets, solid pharmaceutical carriers may be employed, for example, starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. For parenteral injection compositions, the pharmaceutical carrier consists essentially of sterile water, although other ingredients may be added to improve the solubility of the active ingredient. Injectable solutions can be prepared, for example, using a pharmaceutical carrier comprising saline solution, dextrose solution, or a mixture of the two. Injectable suspensions may be prepared using suitable liquid carriers, suspending agents and the like. In compositions suitable for transdermal administration, the pharmaceutical carrier may optionally include a penetration enhancer and/or a suitable wetting agent, optionally in combination with a small proportion of suitable additives that do not produce a significant deleterious effect on the skin. The additives may be selected to facilitate application of the active ingredient to the skin and/or to aid in the preparation of the desired composition. These topical compositions may be administered in various ways, for example as a transdermal patch, a patch (spot-on) or an ointment. Addition salts of the compounds of formula (I) are significantly more suitable for the preparation of aqueous compositions due to their increased water solubility relative to the corresponding base forms.

It is particularly advantageous to formulate the pharmaceutical compositions of the present invention in dosage unit form for ease of administration and uniformity of dosage. As used herein, "dosage unit form" refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such dosage unit forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions, teaspoonfuls, tablespoonfuls, and the like, as well as segregated multiples thereof.

For oral administration, the pharmaceutical compositions of the present invention may take the form of solid dosage forms, such as tablets (swallowable and chewable forms), capsules or gelcaps, prepared by conventional means with pharmaceutically acceptable excipients and carriers such as binders (e.g., pregelatinized corn starch, polyvinylpyrrolidone, hydroxypropylmethylcellulose and the like), fillers (e.g., lactose, microcrystalline cellulose, calcium phosphate and the like), lubricants (e.g., magnesium stearate, talc, silicon dioxide and the like), disintegrants (e.g., potato starch, sodium starch glycolate and the like), wetting agents (e.g., sodium lauryl sulfate) and the like. Such tablets may be coated by methods well known in the art.

Liquid preparations for oral administration may take the form of, for example, solutions, syrups, suspensions, or they may be formulated as a dry product for constitution with water and/or another suitable liquid carrier before use. Such liquid preparations may be prepared in a conventional manner, optionally using other pharmaceutically acceptable additives such as suspending agents (e.g. sorbitol syrup, methyl cellulose, hydroxypropyl methyl cellulose or hydrogenated edible fats), emulsifying agents (e.g. lecithin or acacia), non-aqueous carriers (e.g. almond oil, oily esters or ethyl alcohol), sweetening agents, flavouring agents, masking agents and preservatives (e.g. methyl or propyl p-hydroxybenzoates or sorbic acid).

The pharmaceutically acceptable sweeteners used in the pharmaceutical compositions of the present invention preferably comprise at least one intense (intense) sweetener such as aspartame, acesulfame potassium, sodium cyclamate, alitame, dihydrochalcone sweeteners, monellin, stevioside sucralose (4, 1 ', 6' -trichloro-4, 1 ', 6' -trideoxygalactosucrose) or preferably saccharin, sodium saccharin or calcium saccharin, and optionally at least one bulk (bulk) sweetener such as sorbitol, mannitol, fructose, sucrose, maltose, isomaltose, glucose, hydrogenated caramel, xylitol, honey. Intense sweeteners are conveniently used in low concentrations. For example, in the case of sodium saccharin, the concentration may be about 0.04% to 0.1% (weight/volume) of the final formulation. High amounts of sweeteners may be usefully employed in greater concentrations ranging from about 10% to about 35%, preferably about 10% to 15% (weight/volume).

The pharmaceutically acceptable flavours that mask the bitter tasting ingredients of the low dosage formulations are preferably fruit flavours such as cherry, raspberry, blackcurrant or strawberry flavours. The combination of the two fragrances can produce very good results. In high dose formulations, stronger pharmaceutically acceptable flavours may be required, such as Caramel Chocolate (carame Chocolate), Mint (Mint Cool), Fantasy, etc. Each fragrance may be present in the final composition at a concentration of about 0.05% to 1% (weight/volume). Combinations of said strong fragrances are advantageously used. It is preferred to use a perfume that does not undergo any change or loss of taste and/or color in the case of formulation.

The compounds of formula (I) may be formulated for parenteral administration by injection, conveniently by intravenous, intramuscular or subcutaneous injection, for example by bolus (bolus) injection or continuous intravenous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. They may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as isotonic agents, suspending agents, stabilizing agents and/or dispersing agents. Alternatively, the active ingredient may be presented in powder form for constitution with a suitable vehicle, e.g., sterile, pyrogen-free water, before use.

The compounds of formula (I) may also be formulated in rectal compositions such as suppositories or retention enemas containing conventional suppository bases such as cocoa butter and/or other glycerides.

The compounds of formula (I) may be used in combination with other drugs, in particular, the pharmaceutical compositions of the invention may further comprise at least one other lipid lowering agent, resulting in a so-called combined lipid lowering therapy. The other lipid lowering agent may be, for example, a known drug conventionally used for the treatment of hyperlipidemia, such as bile acid sequestrant resins, fibric acid derivatives or nicotinic acid as mentioned previously in the background of the invention. Suitable additional lipid lowering agents may also include other cholesterol biosynthesis inhibitors and cholesterol absorption inhibitors, particularly HMG-CoA reductase inhibitors and HMG-CoA synthase inhibitors, HMG-CoA reductase gene expression inhibitors, CETP inhibitors, ACAT inhibitors, squalene synthetase inhibitors, CB-1 antagonists, cholesterol absorption inhibitors (e.g., ezetimibe), and the like.

Any HMG-CoA reductase inhibitor may be used as the second compound in the combination therapy aspect of the invention. The term "HMG-CoA reductase inhibitor" as used herein, unless otherwise indicated, refers to a compound that inhibits the bioconversion of hydroxymethylglutaryl-coenzyme a to mevalonic acid catalyzed by the enzyme HMG-CoA reductase. Such "HMG-CoA reductase inhibitors" are, for example, lovastatin, simvastatin, fluvastatin, pravastatin, rivastatin and atorvastatin.

Any HMG-CoA synthase inhibitor may be used as the second compound in the combination therapy aspect of the invention. The term "HMG-CoA synthase inhibitor" as used herein, unless otherwise specified, refers to a compound that inhibits the biosynthesis of hydroxymethylglutaryl-coenzyme a from acetyl-coenzyme a and acetoacetyl-coenzyme a catalyzed by the enzyme HMG-CoA synthase.

Any HMG-CoA reductase gene expression inhibitor may be used as the second compound in the combination therapy aspect of the invention. These substances may be HMG-CoA reductase transcription inhibitors which block DNA transcription or translation inhibitors which prevent translation of mRNA encoding HMG-CoA reductase into protein. Such inhibitors may directly affect transcription or translation, or may be bioconverted to a compound having the above properties by one or more enzymes in the cholesterol biosynthesis cascade, or may result in the accumulation of metabolites having the above activities.

Any CETP inhibitor may be used as the second compound in the combination therapy aspect of the invention. The term "CETP inhibitor" as used herein, unless otherwise indicated, refers to compounds that inhibit Cholesteryl Ester Transfer Protein (CETP) -mediated transport of various cholesteryl esters and triglycerides from HDL to LDL and VLDL.

Any ACAT inhibitor may be used as the second compound in the combination therapy aspect of the invention. The term "ACAT inhibitor" as used herein, unless otherwise indicated, refers to an inhibitor of the activity of an acyl CoA: a compound which is the intracellular esterification of dietary cholesterol by cholesterol acyltransferase.

Any squalene synthetase inhibitor can be used as the second compound in the combination therapy aspect of the invention. The term "squalene synthetase inhibitor" as used herein, unless otherwise specified, refers to a compound that inhibits the condensation of two molecules of farnesyl pyrophosphate to squalene, catalyzed by the enzyme squalene synthetase.

The therapeutically effective amount of a compound of formula (I) will be readily determined by those skilled in the art of hyperlipidemia treatment based on the test results provided below. In general, a therapeutically effective dose is contemplated to be from about 0.001mg/kg to about 50mg/kg body weight, more preferably from about 0.01mg/kg to about 5mg/kg body weight of the patient to be treated. It may be appropriate to administer the therapeutically effective dose in two or more sub-dose forms at suitable intervals throughout the day. The sub-doses may be formulated in unit dosage forms, for example each containing from about 0.1mg to about 350mg, more particularly from about 1 to about 200mg, of the active ingredient per unit dosage form.

It is well known to those skilled in the art that the exact dose and frequency of administration will depend on the particular compound of formula (I) used, the particular condition being treated, the severity of the condition being treated, the age, weight and general physical state of the particular patient and other medications that the patient may be taking (including other lipid lowering agents described above). Moreover, the effective daily amount may be decreased or increased based on the response of the patient being treated and/or based on the evaluation of the physician prescribing the compounds of the instant invention. Thus, the effective daily amount ranges described above are merely guidelines.

Experimental part

The following abbreviations are used in the methods described below: "ACN" represents acetonitrile; "DCM" means dichloromethane; "DMF" refers to N, N-dimethyl-formamide; "THF" represents tetrahydrofuran; and "DIPE" represents diisopropyl ether.

N-cyclohexylcarbodiimide N-methyl polystyrene HL resin (1.90mmol/g) is Novabiochem 01-64-021 resin; polymer-supported carbonate base [ polystyrene-methyl ] -trimethylammonium bicarbonate resin (5.8mmol/g) is Novabiochem 01-64-041 resin; the polystyrene-carbodiimide resin (1.90mmol/g) was Novabiochem 01-64-024 resin; polystyrene-N-methylmorpholine HL (3.80mmol/g) resin is Novabiochem 01-64-0211 resin; the polystyrene-bicarbonate (5.8mmol/g) resin was Novabiochem-01-064-.

Novabiochem resins are available from Calbiochem-Novabiochem AG, Weidenmattweg 4, CH-4448Switzerland。

A. Synthesis of intermediates

Example A.1

Benzoic acid (0.00012mol, 1.2 equiv.) was dissolved in DMF (0.5ml) and mixed with N-cyclohexylcarbodiimide N-methyl polystyrene HL resin (1.90mmol/g) (0.10526g, 0.0002mol, 2 equiv.). 1-Hydroxybenzotriazole (HOBT) (0.02027g, 0.00015mol, 1.5 equiv)/DMF (0.5ml) was added. The mixture was stirred for 15 min, then N- (tert-butoxycarbonyl) -1, 2-ethane-diamine (0.0001mol)/DCM (3ml) was added. After the reaction was complete, polymer supported carbonate [ polystyrylmethyl ] trimethylammonium bicarbonate resin (5.8mmol/g) (0.076g, 0.00045mol, 4.5 equivalents) was added and the mixture stirred for 3 hours. Finally, the resin was removed by filtration, washed three times with a mixture of DCM/DMF (3/1 v/v, 1.0ml), followed by evaporation of the solvent under reduced pressure, thereby yielding intermediate (1) (quantitative yield; used in the next reaction step without further purification).

Intermediate (1) (0.0001mol) was dissolved in a mixture of 6N HCl in isopropanol (2ml), stirred and heated at 65 ℃ for 5 hours. The reaction mixture was concentrated under reduced pressure, thereby yielding intermediate (2) as a hydrochloric acid addition salt thereof.

In a similar manner, intermediates (3) to (8) were prepared as hydrochloride salts. To this effect, in reaction step a), benzoic acid is replaced by 2-methoxybenzoic acid or 4' - (trifluoromethyl) -2-biphenylcarboxylic acid; and N- (tert-butoxycarbonyl) -1, 2-ethanediamine is replaced by N- (tert-butoxycarbonyl) -1, 3-propanediamine, N-methyl-N- (tert-butoxycarbonyl) -1, 2-ethanediamine or N-methyl-N- (tert-butoxycarbonyl) -1, 3-propanediamine.

Example A.2

Methyl 2-hydroxy-2-phenyl-propionate (0.1mol) was added to a solution of sulfuric acid (300ml) in water (250ml) and the reaction mixture was stirred at 100 ℃ for 20 h. The precipitate was filtered off and dissolved in DCM (600 ml). The organic layer was separated, dried, filtered and the solvent was evaporated until the volume was 100 ml. The precipitate was filtered off and dried, yielding 9g of intermediate (14).

Example A.3

A mixture of intermediate (14) (1.327mol) in absolute ethanol (2360ml) was stirred and concentrated sulphuric acid (4ml) was added. The reaction mixture was refluxed for 22 hours under nitrogen and then allowed to cool to room temperature overnight. The resulting precipitate was filtered off, washed with absolute ethanol and dried, yielding 120g of intermediate (15) (mp.186-187 ℃ C.).

The ethanol layers were combined and evaporated, and the resulting residue was dissolved in DCM (1450ml) and washed with NaHCO₃The aqueous solution was washed (twice, 500ml), dried and the solvent was evaporated. The residue was stirred in DIPE (680ml) at 50-55 ℃ and the residual DCM was distilled off, leaving the concentrate to stand at room temperature for more than 2 hours. The resulting solid was filtered off, washed with DIPE (120ml) and pentane and then dried at 40 ℃ to give a further 103.2g of intermediate (15) (mp.187-188 ℃).

The previous DIPE/pentane layer was evaporated and the residue was dissolved in anhydrous ACN (200ml) and the solvent was evaporated again yielding 166.3g of intermediate (16) (mp.75 ℃).

Example A.4

Intermediate (15) (0.03mol) was stirred in chloroform (50 ml). Thionyl chloride (0.06mol) was added and the reaction mixture was stirred and refluxed for 4 hours until the venting stopped. The reaction mixture was concentrated by evaporation of the solvent. Chloroform (200ml) was added, the solvent was again evaporated, and the resulting residue was slowly added to anhydrous ethanol (100ml), which was cooled on an ice-water bath at ± 5 ℃. The ice bath was removed and the reaction mixture was allowed to warm to room temperature. The reaction mixture was stirred at room temperature for 4 hours. Evaporation of the solvent gave intermediate (17) (mp: 78-80 ℃ C.).

Intermediate (18) was prepared similarly starting from intermediate (16).

Example A.5

Mixture of intermediate (17) (0.0567mol) and p-toluenesulfonic acid (1g)In a mixture of formic acid (500ml) and concentrated hydrochloric acid (125ml) was stirred and refluxed for 3 hours. The reaction mixture was concentrated by evaporation of the solvent, the residue was dissolved in DCM and NaHCO was used₃The aqueous solution is washed and dried. The solvent was evaporated and the residue was purified by column chromatography over silica (eluent: ethyl acetate/hexane 1/9) to give intermediate (19) (mp.115-118 ℃ C.).

Intermediate (20) was prepared similarly starting from intermediate (18) (mp.133-135 ℃ C.).

Example A.6

2-methoxy-benzoic acid (0.028mol) was dissolved in DCM (150 ml). Thionyl chloride (8.2ml) was added dropwise to the mixture, and the mixture was refluxed for 2 hours and 30 minutes. The reaction mixture was cooled and the solvent was evaporated. DCM (150ml) was then added and the solvent was evaporated again. The crude compound was dissolved in DCM (150 ml). 1- (Phenylmethyl) -3-pyrrolidinamine (0.028mol) was added first, followed by saturated NaHCO₃Aqueous solution (75 ml). The mixture was reacted for 2 hours. And then the layers were separated. The separated organic layer was dried (MgSO)₄) Filtered and the solvent evaporated. The residue was treated with diisopropyl ether and the crude compound was purified by column chromatography (eluent: 100% CH)₂Cl₂To 3% CH₃OH/CH₂Cl₂). The product fractions were collected and the solvent was evaporated, yielding 7.14g of intermediate (21).

Intermediate (21) (0.023mol) in CH₃A mixture in OH (150ml) was hydrogenated with 10% (1g) palladium on carbon as catalyst. After hydrogen (1 equivalent) uptake, the catalyst was filtered off and the filtrate was evaporated. The residue was purified by reverse phase high performance liquid chromatography (Shandon)C18BDS (base-deactivated silica) 8 μm, 250g, I.D.5 cm). Using a gradient of two or three mobile phases (phase A: 0.25% NH)₄HCO₃An aqueous solution; phase B: CH (CH)₃OH (optional); phase C: CH (CH)₃CN). The product fractions were collected and the solvent was evaporated, yielding 2.56g of intermediate (22).

Example A.7

2-methoxy-3-pyridinecarboxylic acid (0.028mol) was dissolved in DCM (150 ml). Thionyl chloride (8.2 ml; 0.112mol)) was added dropwise to the mixture and the mixture was refluxed for 2 hours 30 minutes. The solvent was evaporated. DCM (150ml) was then added and the solvent was evaporated again. The crude compound was dissolved in DCM (150 ml). 1- (Phenylmethyl) -3-pyrrolidinamine (0.028mol) was added first, followed by saturated NaHCO₃Aqueous solution (75 ml). The mixture was reacted for 2 hours. And then the layers were separated. The separated organic layer was dried (MgSO)₄) Filtered and the solvent evaporated. The residue was purified by column chromatography (eluent: 100% CH)₂Cl₂To 3% CH₃OH/CH₂Cl₂1/100). The product fractions were collected and the solvent was evaporated, yielding 7.97g of intermediate (23).

Intermediate (23) (0.026mol) in CH₃A mixture in OH (150ml) was hydrogenated with 10% (1g) palladium on carbon as catalyst. After hydrogen (1 equivalent) uptake, the catalyst was filtered off and the filtrate was evaporated. The residue was purified by reverse phase high performance liquid chromatography (Shandon)C18BDS (Base Deactivated Silica) 8 μm, 250g, I.D.5 cm). Using a gradient of two or three mobile phases (phase A: 0.25% NH)₄HCO₃An aqueous solution; phase B: CH (CH)₃OH (optional); phase C: CH (CH)₃CN). The product fractions were collected and the solvent was evaporated, yielding 3.01g of intermediate (24).

Example A.8

NaHCO of 4-Ethyl trans-1-phenyl-1, 2, 3, 4-tetrahydro-naphthalene-1, 4-dicarboxylate (0.15mol)₃(0.15M, 200ml of water) solution was stirred and Aliquat was added^TM(0.15mol) (tri-C_8-10A mixture of alkylmethylquaternary ammonium chlorides) and 3-bromo-1-propene (0.75mol)/DCM (200ml), and the reaction mixture was stirred at 20 ℃ for 4 days, and the organic layer was separated. The aqueous layer was extracted with DCM (300ml) and dried (MgSO)₄) Combined organic layers. The solvent was evaporated and the residue stirred in hexane (500ml) and then cooled to 0 ℃. The resulting precipitate was filtered off, washed with hexane and dried at 60 ℃ overnight to yield 46g of intermediate (25).

Concentrated hydrochloric acid (28%) (100ml) and 4-methyl-benzenesulfonic acid (0.7)g) To a solution of intermediate (25) (0.13mol) in formic acid (400ml) was added, then the reaction mixture was stirred and refluxed for 6 hours. The solvent was evaporated and the residue was taken up in DCM (300ml) and saturated NaHCO₃The mixture was partitioned in an aqueous solution (200 ml). DCM-layer was separated and dried (MgSO)₄) And the solvent was evaporated. The residue was triturated with ether to give solid (I), the mother liquor layer was concentrated, then crystallized from an ethyl acetate/hexane mixture to give solid (II). The solids (I) and (II) were combined and purified by flash column chromatography (eluent: DCM/CH)₃OH 95/5). The product fractions were collected, the solvent was evaporated and the residue was triturated with hexane. The residue was then triturated with ether and filtered off to give a solid, yielding 7g of intermediate (26) (mp.138-139 ℃).

Example A.9

2-methoxy-3-pyridinecarboxylic acid (0.028mol) was dissolved in DCM (150 ml). Thionyl chloride (8 ml; 0.112mol) was added dropwise to the mixture, which was refluxed for 2 hours 30 minutes. The solvent was evaporated. DCM (150ml) was then added and the solvent was evaporated again. The crude compound was dissolved in DCM (150 ml). N-methyl-N- (phenylmethyl) -1, 3-propanediamine (0.028mol) was added first, followed by saturated NaHCO₃Aqueous solution (75 ml). The mixture was reacted for 2 hours. And then the layers were separated. The separated organic layer was dried (MgSO)₄) Filtered and the solvent evaporated. The residue was purified by column chromatography (eluent: 100% CH)₂Cl₂To CH₃OH/CH₂Cl₂1/100). The product fractions were collected and the solvent was evaporated, yielding 8.71g of intermediate (27).

Intermediates(27) (0.028mol) in CH₃A mixture in OH (150ml) was hydrogenated with 10% (2g) palladium on carbon as catalyst. After hydrogen (1 equivalent) uptake, the catalyst was filtered off and the filtrate was evaporated. The residue was crystallized from 2-propanol by addition of a solution of HCl (6N) in 2-propanol. The residue was purified by reverse phase high performance liquid chromatography (Shandon)C18BDS (base-deactivated silica) 8 μm, 250g, I.D.5 cm). Using a gradient of two or three mobile phases (phase A: 0.25% NH)₄HCO₃An aqueous solution; phase B: CH (CH)₃OH (optional); phase C: CH (CH)₃CN). The product fractions were collected and the solvent was evaporated, yielding 2.65g of intermediate (28).

Example A.10

2-methoxy-3-pyridinecarboxylic acid (0.00485mol) was dissolved in DCM (50 ml). Thionyl chloride (1.4ml) was added dropwise to the mixture, and the mixture was refluxed for 2 hours and 30 minutes. The solvent was evaporated. DCM (50ml) was then added and the solvent was evaporated again. The crude compound was dissolved in DCM (50 ml). 4- (Phenylmethyl) -2-morpholinomethylamine (0.00485mol) was added first, followed by saturated NaHCO₃Aqueous solution (25 ml). The mixture was reacted for 2 hours. And then the layers were separated. The separated organic layer was dried (MgSO)₄) Filtered and the solvent evaporated. The residue was purified by column chromatography (eluent: 100% CH)₂Cl₂To CH₃OH/CH₂Cl₂1/100). The product fractions were collected and the solvent was evaporated, yielding 1.6g of intermediate (29).

Intermediate (29) (0.0049mol) in CH₃A mixture in OH (50ml) was hydrogenated with palladium on carbon (0.4g) as a catalyst. After hydrogen (1 equivalent) uptake, the catalyst was filtered off and the filtrate was evaporated. The residue was crystallized from 2-propanol by addition of a solution of HCl (6N) in 2-propanol. The product was filtered off and dried, yielding 0.8g of intermediate (30) isolated as the hydrochloride salt.

Example A.11

2-methoxy-3-pyridinecarboxylic acid (0.0269mol) was dissolved in DCM (150 ml). Thionyl chloride (8ml) was added dropwise to the mixture, and the mixture was refluxed for 2 hours and 30 minutes. The solvent was evaporated. DCM (150ml) was then added and the solvent was evaporated again. The crude compound was dissolved in DCM (150 ml). First adding 4-amino hexahydro-1H-aza-1-Carboxylic acid ethyl ester (0.0269mol) and then saturated NaHCO was added₃Aqueous solution (75 ml). The mixture was reacted for 2 hours. And then the layers were separated. The separated organic layer was dried (MgSO)₄) Filtered and the solvent evaporated. The residue was purified by column chromatography (eluent: 100% CH)₂Cl₂To CH₃OH/CH₂Cl₂1/100). The product fractions were collected and the solvent was evaporated, yielding 8.63 intermediate (31).

Intermediate (31) (0.026mol) was dissolved in CH₃OH (60 ml). Potassium hydroxide (7g) was added and the reaction mixture refluxed for 5 hours. DCM was added to the reaction mixture and the organic layer was washed twice with water. Separation ofDried (MgSO 4)₄) Filtered and the solvent evaporated. The residue was purified by reverse phase high performance liquid chromatography (Shandon)C18BDS (base-deactivated silica) 8 μm, 250g, I.D.5 cm). Using a gradient of two or three mobile phases (phase A: 0.25% NH)₄HCO₃An aqueous solution; phase B: CH (CH)₃OH (optional); phase C: CH (CH)₃CN). The product fractions were collected and the solvent was evaporated, yielding 2.01g of intermediate (32).

Example A.12

2-methoxy-benzoic acid (0.0269mol) was dissolved in DCM (150 ml). Thionyl chloride (8ml) was added dropwise to the mixture, and the mixture was refluxed for 2 hours and 30 minutes. The solvent was evaporated. DCM (150ml) was then added and the solvent was evaporated again. The crude compound was dissolved in DCM (150 ml). First adding 4-amino hexahydro-1H-aza-1-Carboxylic acid ethyl ester (0.0269mol) and then saturated NaHCO was added₃Aqueous solution (75 ml). The mixture was reacted for 2 hours. And then the layers were separated. The separated organic layer was dried (MgSO)₄) Filtered and the solvent evaporated. The residue was purified by column chromatography (eluent: 100% CH)₂Cl₂To CH₃OH/CH₂Cl₂1/100). The product fractions were collected and the solvent was evaporated, yielding 8.5g of intermediate (33).

Intermediates(33) (0.0262mol) in CH₃OH (120ml) and water (1ml) was added. Sodium hydroxide (7g) was added and the reaction mixture was refluxed for 72 hours. The solvent was evaporated and water and DCM were added. The organic layer was washed with water. The separated organic layer was dried (MgSO)₄) Filtered and the solvent evaporated. The residue was purified by reverse phase high performance liquid chromatography (Shandon)C18BDS (base-deactivated silica) 8 μm, 250g, I.D.5 cm). Using a gradient of two or three mobile phases (phase A: 0.25% NH)₄HCO₃An aqueous solution; phase B: CH (CH)₃OH (optional); phase C: CH (CH)₃CN). The product fractions were collected and the solvent was evaporated, yielding 4.02g of intermediate (34).

B. Preparation of the Final Compounds

Example B.1

A mixture of intermediate (2) (0.0001mol), polystyrene-carbodiimide (1.90mmol/g) resin (0.0002mol, 0.105g), polystyrene-N-methylmorpholine HL (3.80mmol/g) resin (0.0005mol, 0.132g), intermediate (19) (0.00015mol) in DCM (1ml) and 1-Hydroxybenzotriazole (HOBT) (0.0015mol, 0.020g)/THF (1ml) was shaken overnight at room temperature. Polystyrene-bicarbonate (5.8mmol/g) resin (0.0005mol, 0.086g) was added as a scavenger to remove excess HOBT. The reaction mixture was shaken for 2 hours, filtered and the filtrate was evaporated to give compound (1).

Example B.2

DMF (3 drops) was added to a solution of intermediate (19) (0.025mol) in DCM (100ml) followed by thionyl chloride (0.1 mol). The reaction mixture was stirred, refluxed for 1 hour, and then the solvent was evaporated. DCM was added and the solvent was evaporated. The resulting residue was dissolved in DCM (100ml) and then intermediate (7) (0.025mol) was added followed byAddition of NaHCO₃Aqueous solution (50 ml). The reaction mixture was stirred at room temperature for 4 hours and the layers were separated. The organic layer was dried and the solvent was evaporated. The residue was separated into its enantiomers by high performance liquid chromatography (Chiralpak AD) (eluent: hexane/ethanol 80/20). Two product fractions were collected and the solvent was evaporated. The residues were each triturated with DIPE and then the desired product was collected, yielding 4.84g of compound (25) and 4.72g of compound (26).

Example B.3

A solution of intermediate (19) (0.025mol) in DCM (100ml) was stirred and refluxed with thionyl chloride (0.1mol) for 1h, then the solvent was evaporated. Fresh DCM was added and excess thionyl chloride was removed by evaporation. The residue was dissolved in DCM (50ml) and the resulting solution was added to a mixture of intermediate (9) (0.025mol) in DCM (50 ml). Addition of NaHCO₃Aqueous solution (50ml) and the reaction mixture was stirred at room temperature for 2 hours. The layers were separated and the organic layer was washed with dilute hydrochloric acid, dried and the solvent was evaporated. The resulting residue was separated into its enantiomers by HPLC purification (Chiral phase AD) (eluent: hexane/ethanol 60/40), yielding 5.02g of compound (27) and 5.05g of compound (28).

Example B.4

Intermediate (26) (1 g; 0.0030mol) was dissolved in DCM (15 ml). To this solution was added thionyl chloride (0.54 ml; 0.0075mol) dropwise, followed by a few drops of DMF. The reaction was refluxed for 1 hour. The solvent was evaporated. DCM (15ml) was added to the residue and the solvent was evaporated again. The crude mixture was dissolved in DCM (15ml) and intermediate (9) (0.003mol) was added first followed by NaHCO₃Saturated aqueous solution (15 ml). The reaction mixture was stirred at room temperature for 2 hours. And (5) layering. The separated organic layer was dried (MgSO)₄) Filtration and evaporation of the solvent gave 1.6g of compound (34).

Practice ofExample B.5

Compound (38) (0.00297mol) was dissolved in THF (20 ml). The reaction was bubbled through nitrogen and tetrakis (triphenylphosphine) palladium (0.070g) was added. The mixture was cooled to 0 ℃ with an ice bath, and then sodium borohydride (0.00297mol) was added. Cooling was continued for 4 hours and the mixture was allowed to react at room temperature overnight. The reaction was then quenched with HCl (1N) and extracted with DCM. The separated organic layer was dried (MgSO)₄) Filtered and the solvent evaporated. The product is purified by column chromatography (eluent: (CH)₂Cl₂/CH₃OH) from 99/1 to 90/10). The product fractions were collected and the solvent was evaporated in vacuo. The residue is redissolved in CH₂Cl₂/CH₃OH, treating with activated carbon. The mixture was filtered over decalite and the solvent was evaporated. The residue was purified by reverse phase high performance liquid chromatography (Shandon)C18BDS (base-deactivated silica) 8 μm, 250g, I.D.5 cm). Using a gradient of two or three mobile phases (phase A: 0.25% NH)₄HCO₃An aqueous solution; phase B: CH (CH)₃OH (optional); phase C: CH (CH)₃CN). The pure fractions were collected and the solvent was evaporated. The residue was redissolved in DCM and the solution was added to diisopropyl ether. The precipitate was filtered off and the solid was dried to yield 0.016g of compound (29).

Example b.6.

a) Compound (34) (0.0030mol) was dissolved in THF (20 ml). The reaction was bubbled with nitrogen, then tetrakis (triphenylphosphine) palladium (0.00006mol) was added. The mixture was cooled to 0 ℃ with an ice bath, and then sodium borohydride (0.003mol) was added. Cooling was continued for 4 hours and the mixture was allowed to react at room temperature overnight. The reaction was then quenched with HCl (1N) and extracted with DCM. The separated organic layer was dried (MgSO)₄) Filtered and the solvent evaporated. The product was purified by column chromatography (eluent (DCM/MeOH) from 99/1 to 90/10). The product fractions were collected and the solvent was evaporated in vacuo. The residue is redissolved in CH₂Cl₂/CH₃OH, treating with activated carbon. The mixture was filtered over decalite and the solvent was evaporated. The residue was purified by reverse phase high performance liquid chromatography (Shandon)C18BDS (base-deactivated silica) 8 μm, 250g, I.D.5 cm). Using a gradient of two or three mobile phases (phase A: 0.25% NH)₄HCO₃An aqueous solution; phase B: CH (CH)₃OH (optional); phase C: CH (CH)₃CN). The product fractions were collected and the solvent was evaporated. The residue was dissolved in DCM and the solution was added to diisopropyl ether. The precipitate was filtered off and the white solid was dried to give trans-4- { [3- (2-methoxy-benzoylamino) -propyl]-methyl-carbamoyl } -1-phenyl-1, 2, 3, 4-tetrahydro-naphthalene-1-carboxylic acid (intermediate (35)).

b) Intermediate (35) (0.000199mol, 0.100g) was dissolved in dry DCM (2 ml). To the mixture was then added 1-hydroxy-1H-benzotriazole (1.2 eq, 0.032g), N '- (ethylcarbodiimide) -N, N-dimethyl-1, 3-propanediamine (N' - (ethylcarbodiimide) -N, N-dimethyl-1, 3-propandiamine) monohydrochloride (1.2 eq, 0.046g) and methyl 3-aminopropionate hydrochloride (3 eq, 0.083g) and N-ethyl-N- (1-methyl-ethyl) -2-propylamine (10 eq, 0.329 ml). The reaction mixture was stirred at room temperature overnight. Additional methyl 3-amino-propionate hydrochloride (3 eq, 0.083g) was added and the mixture was saturated with NaHCO₃The aqueous solution was washed 3 times. The separated organic layer was dried (MgSO)₄) Filtered and the solvent evaporated. The residue was then purified by column chromatography (100% CH)₂Cl₂To 2% CH₃OH/CH₂Cl₂). The desired fractions were collected and the solvent was evaporated to yield compound (31).

Example B.7

Intermediate (19(0.00376mol, 1.22g) was dissolved in anhydrous DCM (20ml) then HOBt (0.00451mol, 0.733g), 1-ethyl-3- (3' -dimethyl-aminopropyl) carbodiimide hydrochloride (EDCI) (0.00451mol, 1.04g) and intermediate (24) (0.00451mol) and DIPEA (0.0376mol, 7.4ml) were added to the mixture the reaction mixture was stirred overnight at room temperature additional intermediate (24) (0.00451mol) was added, the mixture was washed 3 times with saturated aqueous NaHCO3 solution the separated organic layer was dried, filtered, the solvent evaporated, the residue was then purified by flash column chromatography (100% CH2Cl2 to CH3OH/CH2Cl 21/20) the desired product fraction was collected, the solvent evaporated yielding compound (45).

Table F-1 lists compounds prepared according to one of the above examples. The stereochemical configuration of some compounds has been indicated as R^*Or S^*Relative stereochemistry is indicated without knowledge of absolute stereochemistry, although the compounds themselves have been isolated as single stereoisomers and are therefore enantiomerically pure. For some compounds, the melting point (m.p.) is included.

TABLE F-1

Compound identification

General procedure A

HPLC measurements were performed using an Alliance HT 2790(Waters) system comprising a quaternary pump with air displacement, autosampler, column oven (set at 40 ℃ unless otherwise specified), Diode Array Detector (DAD) and columns specified in the respective methods below. The fluid from the column was split to the MS spectrometer. The MS detector was equipped with an electrospray ionization source. Mass spectra were acquired by scanning 100 to 1000 in 1 second using a dwell time of 0.1 second. The capillary tip voltage was 3kV and the source temperature was maintained at 140 ℃. Nitrogen was used as the nebulizer gas. Data acquisition was performed using a Waters-Micromass MassLynx-Openlynx data System.

General procedure B

LC measurements were performed using the Acquity UPLC (Waters) system comprising a binary pump, sample organizer, column heater (set at 55 ℃), Diode Array Detector (DAD) and columns specified in the respective methods below. The fluid from the column was split to the MS spectrometer. The MS detector was equipped with an electrospray ionization source. Mass spectra were acquired using a dwell time of 0.02 seconds to scan 100 to 1000 in 0.18 seconds. The capillary tip voltage was 3.5kV and the source temperature was maintained at 140 ℃. Nitrogen was used as the nebulizer gas. Data acquisition was performed using a Waters-Micromass MassLynx-Openlynx data System.

Method 1In addition to general procedure a: reverse phase HPLC was performed on a Xterra MS C18 column (3.5 μm, 4.6X100mm) at a flow rate of 1.6 ml/min. Gradient conditions were run using three mobile phases (mobile phase a: 95% 25mM ammonium acetate + 5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol): 100% A to 1% A, 49% B and 50% C in 6.5 min, 1% A and 99% B in 1 min and maintaining these conditions for 1 min, equilibrate for 1.5 min with 100% A. An injection volume of 10 μ l was used. The cone (cone) voltage is 10V for positive ionization mode and 20V for negative ionization mode.

Method 2

In addition to general procedure B: on a bridged ethylsiloxane/silica mixture (BEH) C18 column (1.7 μm, 2.1X50 mm; Waters Acquity)Reversed phase UPLC (ultra high performance liquid chromatography) was performed at a flow rate of 0.8 ml/min. Two mobile phases were used (mobile phase A: 0.1% formic acid in H)₂O medium/methanol 95/5; mobile phase B: methanol) gradient conditions were run: from 95% a and 5% B to 5% a and 95% B in 1.3 minutes and held for 0.2 minutes. An injection volume of 0.5 μ l was used. The cone voltage was 10V for positive ionization mode and 20V for negative ionization mode.

Method 3

In addition to general procedure a: reverse phase HPLC was performed on Chromolith (4.6X25mm) with a flow rate of 3 ml/min. Gradient conditions were run using three mobile phases (mobile phase a: 95% 25mM ammonium acetate + 5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol): from 96% a, 2% B and 2% C to 49% B and 49% C in 0.9 minutes, to 100% B in 0.3 minutes and held for 0.2 minutes. Injection volumes of 2 μ l were used. The cone voltage was 10V for positive ionization mode and 20V for negative ionization mode.

Table: analyzing data

When the compound is an isomeric mixture that gives different peaks in the LCMS process, only the retention times of the major components are provided in the LCMS table (Rt: retention time in minutes).

Co.No.	Rt	(MH)+	Proc.	Co.No.	Rt	(MH)+	Proc.	Co.No.	Rt	(MH)+	Proc.
												1	5.93	471	1	15	6.72	615	1	29	1.34	541	2
2	6.06	501	1	16	6.13	485	1	30	1.36	542	2
												3	6.65	615	1	17	6.23	515	1	31	1.20	586	2
4	6.06	485	1	18	6.76	629	1	32	1.18	587	2
												5	6.19	515	1	19	6.15	485	1	33	1.19	613	2
6	6.72	629	1	20	6.16	515	1	36	1.08	527	3
												7	6.05	485	1	21	6.79	629	1	37	5.61	556	1
8	6.16	515	1	22	6.22	499	1	38	6.20	539	1
												9	6.76	629	1	23	6.32	529	1	39	6.14	540	1
10	6.19	499	1	24	6.82	643	1	40	6.40	568	1
												11	6.32	529	1	25	5.68	515	1	41	6.42	567	1
12	6.79	643	1	26	5.68	515	1	42	1.43	569	2
												13	6.06	471	1	27	5.81	529	1	43	1.03	601	2
14	6.16	501	1	28	5.82	529	1	44	1.20	612	2

Optical rotation:

the optical rotation was measured using a polarimeter. [ alpha ] to]_D ²⁰The optical rotation measured at a temperature of 20 ℃ using light having a sodium D line wavelength (589nm) is shown. After the actual values, the solution concentration and the solvent used to measure the optical rotation are mentioned.

C. Pharmacological examples

C.1.quantification of ApoB secretion

HepG2 cells were cultured in MEM Rega 3 containing 10% fetal bovine serum in 24-well plates. At 70% confluence, the medium was changed and test compound or vehicle (DMSO, 0.4% final concentration) was added. After 24 hours of incubation, the medium was transferred to Eppendorf tubes and cleaned by centrifugation. Sheep antibodies to either apoB were added to the supernatant and the mixture was held at 8 ℃ for 24 hours. Then, rabbit anti-sheep antibody was added and the immunocomplexes were precipitated at 8 ℃ for 24 hours. Exempt fromThe pellet was pelleted by centrifugation at 1320g for 25 minutes and pelleted with 40mM Mops, 40mM NaH₂PO₄100mM NaF, 0.2mM DTT, 5mM EDTA, 5mM EGTA, 1% Triton-X-100, 0.5% sodium Deoxycholate (DOC), 0.1% SDS, 0.2. mu.M leupeptin, and 0.2. mu.M PMSF. Radioactivity in the pellet was quantified by liquid scintillation counting. IC (integrated circuit)₅₀Values are usually converted to pIC50 values (═ log IC₅₀Values) for ease of use and are summarized in table C-1.

TABLE C-1: pIC50 value

Co.No.	pIC50	Co.No.	pIC50	Co.No.	pIC50
						4	6.499	16	6.102	25	7.761
5	6.716	17	6.382	26	6.252
						6	7.37	18	6.51	28	7.018
7	＜6	19	6.642	29	6.985
						8	＜6	20	＜6	30	7.115
9	6.893	21	6.62	31	＜6
						10	6.127	22	6.179	32	＜6
11	6.177	23	6.224	33	＜6
						12	7.634	24	7.635	42	6.544

C.2.MTP assay

MTP activity was measured using a similar assay described in Chemistry and Physics of Lipids, 38, 205-222(1985) by J.R.Wetterau and D.B.Zilversmit. To prepare donor and recipient vesicles (vesicles), the appropriate lipid/chloroform was placed in glass tubes and incubated at N₂And (4) drying under flowing. Containing 15mM Tris-HCl pH 7.5, 1mM EDTA, 40mM NaCl, 0.02% NaN₃To the dried lipid (assay buffer). The mixture was briefly vortexed, and then the lipids were hydrated on ice for 20 minutes. The vesicles were then prepared by bath sonication (Branson 2200) at room temperature for up to 15 minutes. Butylated hydroxytoluene was included in all vesicle formulations at a concentration of 0.1%. The lipid transfer assay mixture contained donor vesicles (40nmol phosphatidylcholine, 7.5 mol% cardiolipin, and 0.25 mol% glycerotris [1-¹⁴C]Oleate), receptor vesicles (240nmol phosphatidylcholine) and 5mg BSA in a total volume of 675. mu.l in a 1.5ml microcentrifuge tube. Test compounds were dissolved in DMSO (0.13% final concentration)Degree) is added. After a 5 min pre-incubation at 37 ℃, the reaction was initiated by adding 100 μ l MTP in dialysis buffer. By addition of 1mM EDTA, 0.02% NaN at 15mM Tris-HCl pH 7.5₃The reaction was stopped with pre-equilibrated 400. mu.l DEAE-52 cellulose (1: 1, vol/vol). The mixture was stirred for 4 minutes and centrifuged at maximum speed in an Eppendorf centrifuge tube for 2 minutes (4 ℃) to precipitate DEAE-52 bound donor vesicles. The supernatant fraction containing the acceptor liposome is counted, and the use of [ alpha ], [ alpha ]¹⁴C]The percentage of triglycerides transferred from the donor vesicles to the recipient vesicles was counted.

TABLE C-2: pIC50 value

Co.No.	pIC50	Co.No.	pIC50	Co.No.	pIC50
						1	5.902	13	5.269	25	8.186
2	6.391	14	5.604	26	6.761
						3	6.681	15	5.56	27	6.112
4	7.654	16	＜7	28	8.144
						5	8.028	17	7.428	29	7.398
6	8.018	18	7.209	30	7.633
						7	7.068	19	6.883	31	7.186
8	7.568	20	7.151	32	6.78
						9	7.718	21	7.317	33	7.097
10	8	22	7.785	42	7.639
						11	8.245	23	7.935	43	＜6
12	8.198	24	8.214	44	7.277

Claims (11)

1.A compound of formula (I), pharmaceutically acceptable acid addition salts thereof, and stereochemically isomeric forms thereof:

wherein

A is- (C ═ O) -;

x represents

n is an integer of 2 or 3;

R⁵is hydrogen;

R⁶is hydrogen or C_1-4An alkyl group;

R¹is NR⁷R⁸OR OR⁹；

Wherein R is⁷And R⁸Each of which is independently selected from the group consisting of hydrogen,

c substituted by 1, 2 or 3 substituents_1-8Alkyl, each substituent being independently selected from C_1-4An alkoxycarbonyl group;

R⁹is C_1-8An alkyl group, a carboxyl group,

C_3-8an alkenyl group;

R^2a、R^2band R^2cIs hydrogen;

R^3a、R^3band R^3cIs hydrogen;

R⁴is phenyl; phenyl substituted with 1, 2, 3 or 5 substituents, each substituent independently selected from C_1-4Alkoxy or phenyl optionally substituted with 1, 2 or 3 substituents, each substituent independently selected from halo or trifluoromethyl;

or pyridyl optionally substituted with one or two substituents, each substituent independently selected from hydroxy or C_1-4An alkoxy group.

2. The compound of claim 1, wherein R¹Is NR⁷R⁸。

3. The compound of claim 1, wherein R¹Is OR⁹。

4. A compound as claimed in claim 1, wherein a represents- (C ═ O) -; r¹Is OR⁹Which isIn R⁹Is C_1-6Alkyl or C_3-8An alkenyl group; r^2a、R^3a、R^2b、R^3b、R^2cAnd R^3cIs hydrogen; r⁴Represents phenyl, Via C_1-4Phenyl substituted by alkoxy, phenyl substituted by halogen, pyridyl substituted by hydroxy or C_1-4An alkoxy-substituted pyridyl group; and X represents a group (a-1) in which R is⁵Is hydrogen, and R⁶Is hydrogen or C_1-4An alkyl group.

5. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically active amount of a compound according to any one of claims 1 to 4.

6. A process for preparing a pharmaceutical composition as claimed in claim 5, wherein a therapeutically active amount of a compound as claimed in any one of claims 1 to 4 is intimately mixed with a pharmaceutically acceptable carrier.

7. Use of a compound according to any one of claims 1 to 4 in the manufacture of a medicament.

8. A compound of formula (II) wherein A, X, R¹、R^2a、R^2b、R^2c、R^3a、R^3b、R^3cAnd R⁵As defined in claim 1

9. A compound of formula (XVII) wherein the substituent R^2a、R^2b、R^2c、R^3a、R^3b、R^3c、R⁴、R⁵A and X are as defined in claim 1

10. A process for the preparation of a compound of formula (I), wherein

a) The intermediate of formula (II) is reacted with the intermediate of formula (III) in a reaction-inert solvent and optionally in the presence of a suitable coupling reagent and/or a suitable base

b) Alternatively, compounds of formula (I) are interconverted; or if desired; the compound of formula (I) is converted into a pharmaceutically acceptable acid addition salt or, conversely, the acid addition salt of the compound of formula (I) is converted into the free base form with a base; and, if desired, preparing stereochemically isomeric forms thereof,

wherein R is¹、R^2a、R^2b、R^2c、R^3a、R^3b、R^3c、R⁴、R⁵A and X are as defined in claim 1.

11. A process for the preparation of a compound of formula (I-a) defined as a compound of formula (I) wherein the group A represents- (C ═ O) -,

a) wherein an intermediate of formula (V) is reacted with an intermediate of formula (IV) in a reaction-inert solvent and optionally in the presence of a suitable coupling reagent and/or a suitable base

b) Alternatively, compounds of formula (I-a) are interconverted; or if desired; the compound of formula (I-a) is converted into a pharmaceutically acceptable acid addition salt or, conversely, the acid addition salt of the compound of formula (I-a) is converted into the free base form with a base; and, if desired, preparing stereochemically isomeric forms thereof,

wherein R is¹、R^2a、R^2b、R^2c、R^3a、R^3b、R^3c、R⁴、R⁵And X is as defined in claim 1.