JP2006510687A - Novel compounds, their preparation and use - Google Patents

Abstract

Novel classes of dicarboxylic acid derivatives, use of the compounds as pharmaceutical compositions, pharmaceutical compositions containing the compounds, and methods of treatment using the compounds and compositions. The compounds of the present invention may be useful for the treatment and / or prevention of conditions mediated by peroxisome proliferator activated receptors (PPARs).

Description

Field of Invention

  The present invention relates to novel dimeric dicarboxylic acid derivatives, the use of the compounds as pharmaceutical compositions, pharmaceutical compositions containing the compounds, and methods of treatment using the compounds and compositions. More particularly, the compounds of the present invention are used for the treatment and / or prevention of conditions mediated by Peroxisome Proliferator-Activated Receptors (PPARs), particularly PPARδ subtypes. Can do.

Background of the Invention

  Coronary artery disease (CAD) is the leading cause of death in patients with type II diabetes and metabolic syndrome (ie, patients who enter the “lethal quartet” of impaired glucose tolerance, insulin resistance, hypertriglyceridemia and / or obesity) .

  Although hypolipidaemic fibrates and anti-diabetic thiazolidinediones separately exhibit mild triglyceride-lowering activity, they are abnormal lipemia often found in patients with type II diabetes or metabolic syndrome It is not powerful enough or effective to choose as a monotherapy for the disease. Thiazolidinediones also strongly reduce circulating glucose levels in animal models of type II diabetes and humans. However, fibrates do not have a beneficial effect on glycemia. Studies on the molecular action of these compounds have shown that thiazolidinediones and fibrates exert their actions by activating different transcription factors of the peroxisome proliferator-activated receptor (PPAR) family to select specific enzymes and It has been shown to result in increased or decreased expression of apolipoproteins, both of which are key players in the regulation of plasma triglyceride content. On the other hand, fibrates are PPARα activators that act primarily in the liver. On the other hand, thiazolidinediones are high affinity ligands for PPARγ that act primarily on adipose tissue.

  Adipose tissue plays a central role in lipid homeostasis and energy balance maintenance in vertebrates. Adipocytes store energy in the form of triglycerides during nutrient rich periods and release it in the form of free fatty acids during nutrient deficiencies. The development of white adipose tissue is the result of a continuous differentiation process throughout life. Much evidence points to a central role for PPARγ activation in the initiation and regulation of this cell differentiation. During the differentiation of adipocytes, several highly specialized proteins are induced, most of which are involved in lipid accumulation and metabolism. The exact link from activation of PPARγ to changes in glucose metabolism (most notably insulin resistance in muscle) has not yet been elucidated. A possible link is that free fatty acids so that PPARγ activation induces lipoprotein lipase (LPL), fatty acid transport protein (FATP) and acyl-CoA synthase (ACS) in adipose tissue but not muscle tissue. Is going through. This then dramatically reduces the concentration of free fatty acids in the plasma, and due to substrate competition at the cellular level, skeletal muscle and other tissues with high metabolic rates eventually switch from fatty acid oxidation to glucose oxidation. Instead, insulin resistance decreases as a result.

  PPARα is involved in stimulating β-oxidation of fatty acids. In rodents, PPARα-mediated changes in the expression of genes involved in fatty acid metabolism are the basis of peroxisome proliferation, pleiotropic cellular responses confined primarily to the liver and kidneys, which are rodents May lead to liver cancer formation. The phenomenon of peroxisome proliferation is not seen in humans. In addition to its role in rodent peroxisome proliferation, PPARα is also involved in the regulation of HDL cholesterol in rodents and humans. This effect is based, at least in part, on PPARα-mediated transcriptional regulation of the major HDL apolipoproteins (ApoA-I and ApoA-II). The blood triglyceride lowering effects of fibrates and fatty acids also include PPARα and can be summarized as follows: (I) Lipid degradation and residuals due to changes in lipoprotein lipase and apo C-III levels. Increased particle clearance, (II) Stimulation of cellular fatty acid uptake and subsequent conversion to acyl-CoA derivatives by induction of fatty acid binding protein and acyl-CoA synthase, (III) Induction of fatty acid β-oxidation pathway, (IV) A decrease in fatty acid and triglyceride synthesis, and finally a decrease in (V) VLDL production. Thus, increased catabolism of triglyceride-rich particles and decreased secretion of VLDL particles constitute a mechanism that contributes to blood lipid lowering effects of fibrates.

  Activation of PPARδ was initially reported not to be involved in the regulation of glucose or triglyceride levels (Berger et al., J. Biol. Chem., 1999, Vol 274, pp. 6718-6725). Subsequently, activation of PPARδ was shown to lead to increased levels of HDL cholesterol in db / db mice (Leibowitz et al. FEBS letters 2000, 473, 333-336). In addition, PPARδ agonists produce a dose-dependent dramatic increase in serum HDL cholesterol when administered to insulin-resistant middle-aged obese rhesus monkeys, while low-density LDL, fasting triglycerides, and fasting insulin The level was reduced (Oliver et al. PNAS 2001, 98, 5306-5311). The same paper also showed that activation of PPARδ increased the reverse cholesterol transporter ATP-binding cassette A1 and also induced apoprotein A1-specific cholesterol efflux. The involvement of PPARδ in fatty acid oxidation in muscle was further demonstrated in PPARα knockout mice. Muoio et al. (J. Biol. Chem. 2002, 277, 26089-26097) showed that high levels of PPARδ in skeletal muscle can compensate for PPARα deficiency. Taken together, these findings suggest that PPARδ activation is useful in the treatment and prevention of cardiovascular diseases and conditions including atherosclerosis, hypertriglyceride plasma and mixed dyslipidemia ( WO 01/00603).

  Many PPARδ compounds have been reported as being useful for the treatment of hyperglycemia, hyperlipidemia and hypercholesterolemia (US 5,306,726, WO 91/19702, WO 95/03038, WO 96/04260, WO 94/13650, WO 94/01420, WO 97/36579, WO 97/25042, WO 95/17394, WO 99/08501, WO 99/19313, WO 99/16758 and WO 01/00603).

  The following documents disclose various compounds with PPARγ activity: US 5,063,240, EP 0597102, EP 0696585, WO 94/25448, JP 09291031, JP 08217766, WO 99/63983.

  Glucose reduction as a single approach does not overcome macrovascular complications associated with type II diabetes and metabolic syndrome. Therefore, novel treatments for type II diabetes and metabolic syndrome must both aim to reduce overt hyperglyceridemia associated with these syndromes, as well as to alleviate hyperglycemia.

  This is due to the search for compounds that exhibit varying degrees of activation of PPARα, PPARγ and PPARδ, and type II diabetes, dyslipidemia, syndrome X (metabolic syndrome, ie impaired glucose tolerance, insulin resistance, high triglycerides Discovery of effective triglycerides and / or cholesterol and / or glucose-lowering drugs with great potential in the treatment of cardiovascular disease (atherosclerosis) and hypercholesterolemia Indicates that will be guided.

Definition

  In the structural description set forth throughout the following description and throughout this specification, the following terms have the indicated meanings.

As used herein, the term “C _{1-n ′} -alkyl” _{where n ′} may be 2-6 represents a straight or branched saturated hydrocarbon chain having the specified number of carbon atoms. Examples of such groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl and the like.

As used herein, the term “C _{3-n ′} -cycloalkyl”, where n ′ may be 2-6, alone or in combination, is a monocyclic saturated hydrocarbon group having the specified number of carbon atoms. Is expressed. Examples of such groups are, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.

As used herein, the terms “divalent C _{1-n ′} saturated carbon chain” and “C _{1-n ′} -alkylene” where n ′ may be 2 to 6 have the specified number of carbon atoms. Represents a divalent straight or branched saturated hydrocarbon chain. Examples of such groups include, but are not limited to, methylene, ethylene, trimethylene, tetramethylene, propylene, ethylethylene, methylpropylene, ethylpropylene, and the like.

As used herein, the term “C _{4-n ′} -cycloalkylene” where n ′ may be 5-6 represents a divalent monocyclic saturated hydrocarbon group having the specified number of carbon atoms. Examples of such groups include, but are not limited to, cyclopentylene, cyclohexylene and the like.

As used herein, the term “C _{2-n ′} -alkenyl” _{where n ′} may be 3-6 is olefinic unsaturation having from 2 to the specified number of carbon atoms and at least one double bond. Represents a linear or branched hydrocarbon group. Examples of such groups include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, allyl, iso-propenyl, 1,3-butadienyl, 1-butenyl, hexenyl, pentenyl, and the like.

As used herein, the term “C _{2-n ′} -alkenylene”, _{where n ′} may be 3-6, is an olefinic unsaturation having from 2 to the specified number of carbon atoms and at least one double bond. Represents a linear or branched divalent hydrocarbon group. Examples of such groups include ethylene (—CH═CH—),
Propenylene isomers (eg, —CH ₂ CH═CH— and —C (CH ₃ ) ═CH—), butenylene isomers (eg, —CH ₂ CH═C (CH ₃ ) — and —CH ₂ CH ₂ CH═ CH-), but not limited to.

As used herein, the term “C _{4-n ′} -alkeneinyl” refers to a straight or branched chain having from 4 to the specified number of carbon atoms and both at least one double bond and at least one triple bond. Represents an unsaturated hydrocarbon group of the chain. Examples of such groups include 1-penten-4-yne, 3-penten-1-yne, 1,3-hexadiene-5-yne, and the like, particularly preferably 1-penten-4-yne. Although there is, it is not limited to these.

As used herein, the term “C _{4-n ′} -cycloalkenylene” where n ′ may be 5-6 is a divalent having from 4 to the specified number of carbon atoms and at least one double bond. Represents a monocyclic illegal hydrocarbon group. Examples of such groups include, but are not limited to, cyclohexenylene and the like.

As used herein, the term “C _{3-n ′} -alkynyl” _{where n ′} may be 4-6 is a straight or branched chain having 3 to the specified number of carbon atoms and at least one triple bond. Represents an unsaturated hydrocarbon group. Examples of such trees include, but are not limited to, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl and the like.

As used herein, the term “C _{2-n ′} -alkynylene” _{where n ′} may be 3-6 is a straight or branched chain having 2 to the specified number of carbon atoms and at least one triple bond Represents a divalent unsaturated hydrocarbon group. Examples of such groups include propynylene (—CH ₂ C≡C—), butynylene isomers (eg, —CH ₂ CH ₂ C≡C—, —CH ₂ C≡C—CH ₂ —), etc. However, it is not limited to these.

As used herein, the term “C _{4-n ′} -alkeneinylene”, where n ′ may be 5-9, is 4 to the specified number of carbon atoms, as well as at least one double bond and at least one A linear or branched divalent unsaturated hydrocarbon group having both triple bonds is represented. Examples of such groups include, but are not limited to, 1-pentene-4-inylene, 3-penten-1-inylene, 1,3-hexadiene-5-inylene, and the like.

As used herein, the term “divalent C _{3-n ′} -unsaturated carbon chain” where n ′ may be 4-9 is 3 to the specified number of carbon atoms, and at least one double bond A linear or branched divalent unsaturated hydrocarbon group having (alkenylene) or at least one triple bond (alkynylene) or a combination thereof (alkeneinylene). Examples of such groups include ethenylene (—CH═CH—), propenylene isomers (eg, —CH ₂ CH═CH— and —C (CH ₃ ) ═CH—), butenylene isomers (eg, — CH ₂ CH═C (CH ₃ )-and —CH ₂ CH ₂ CH═CH—), propynylene (—CH ₂ C≡C—), butynylene isomers (eg, —CH ₂ CH ₂ C≡C—, — CH ₂ C≡C—CH ₂ —), 1-pentene-4-inylene, 3-penten-1-inylene, 1,3-hexadiene-5-inylene, and the like, but are not limited thereto.

As used herein, the term “C _{1-n ′} -alkoxy”, _{where n ′} may be 2-6, alone or in combination, is bonded through an ether oxygen and removes its free valence bond from the ether oxygen. It means a linear or branched structure. Examples of such linear alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy and the like. Examples of such branched alkoxy include, but are not limited to, isopropoxy, sec-butoxy, tert-butoxy, isopentyloxy, isohexyloxy, and the like.

As used herein, the term “C _{3 -n′-} cycloalkoxy”, where n ′ may be 4-6, is linked, alone or in combination, via an ether oxygen and its free valence bond. And represents a monocyclic saturated hydrocarbon group having a specified number of carbon atoms. Such a position of the cycloalkoxy group includes, but is not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and the like.

As used herein, the term “C _{1-n ′} -alkylthio”, _{where n ′} may be 2-6, alone or in combination, is bonded through a divalent sulfur atom and is free from the sulfur atom. Means a monovalent substituent of straight or branched chain comprising C _1-6 -alkyl having 1 to 6 carbon atoms having a valence bond. Examples of such groups include, but are not limited to, methylthio, ethylthio, propylthio, butylthio, pentylthio, and the like.
As used herein, the term “C ₃ -n′-cycloalkylthio”, where n ′ may be 4-6, alone or in combination, is linked via a divalent sulfur atom and is free from that sulfur atom. A monocyclic saturated hydrocarbon group having a specified number of carbon atoms having a valence bond. Examples of such cycloalkoxy groups include, but are not limited to, cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio, and the like.

  The term “aryl” as used herein means an aromatic monocyclic or bicyclic or tricyclic condensed aromatic hydrocarbon group. Examples of such include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthrenyl, azulenyl, fluorenyl and the like.

  As used herein, the term “arylene” refers to a monocyclic divalent aromatic hydrocarbon group or a bicyclic or tricyclic divalent condensed aromatic hydrocarbon group (derived from aryl). means. Examples of such groups include, but are not limited to, phenylene, naphthylene, fluorenylene and the like.

  The term “heteroaryl” as used herein, alone or in combination, is a 5-7 membered monocyclic aromatic system or 8-10 membered containing one or more heteroatoms selected from nitrogen, oxygen and sulfur. Divalent substituents containing bicyclic fused aromatic systems or 10 to 16 membered tricyclic fused aromatic systems containing one or more heteroatoms selected from nitrogen, oxygen and sulfur, such as furyl , Thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, isothiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, indolyl, benzoimidazolyl, β -Carborinyl, acridin Means phenanthrolinyl, phenazinyl, phenoxazinyl, a phenothiazinyl like.

  The term “heteroarylene” as used herein, alone or in combination, is a 5- to 7-membered monocyclic aromatic system or 8- to 10-membered aromatic system containing one or more heteroatoms selected from nitrogen oxygen and sulfur. A divalent substituent comprising a cyclic manner system or a 10-16 membered tricyclic fused-ring aromatic system containing one or more heteroatoms selected from nitrogen, oxygen and sulfur (from heteroaryl Derived), e.g., furylene, thienylene, pyrrolylene, imidazolylene, pyrazolylene, triazolylene, pyrazinylene, pyrimidinylene, pyridazinylene, isothiazolylene, isoxazolylene, oxazolylene, oxadiazolylene, thiadiazolylene, quinolylene, quinolylene, quinolylene, quinolylene, quinolylene, quinolylene, , Benzimidazolylene, benzofurani Emissions, Puterijiniren means purinylene, carbazolylene, beta-Karuboriniren, Akurijiniren, phenanthrolinyl two Ren, Fenajiniren, phenoxazine Gini Ren, a phenol thia Gini Ren like.

  As used herein, the term “bivalent polycyclic ring system” refers to a bicyclic ring system formed from two to four aryl or heteroaryl ring systems, independently of each other, connected by a single bond. Means a valent group. Examples of such di-, tri-, and tetra-arylenes having 2-4 identical aryl ring systems include, but are not limited to, biphenylene, binaphthylene, terphenylene, ternaphthylene, quarterphenylene, quarternaphthylene, and the like. Not. Examples of such 2, 3, and 4 heteroarylenes having 2-4 identical heteroaryl ring systems include bipyridylylene, biindrylylene, terpyridylylene, terindylylene, quarterpyridylylene, quarterindolylene, and the like. Including, but not limited to. Examples of such polycyclic ring systems having non-identical ring systems include, but are not limited to, diphenylpyridine and the like.

As used herein, the term “aralkoxy” refers to a C _1-6 -alkoxy group substituted with an aromatic hydrocarbon, such as benzyloxy, phenoxy, 3-phenylpropoxy, 1-naphthylmethoxy, 2- (1-naphthyl) ethoxy. Etc.

  The term “aralkyl” as used herein refers to a straight or branched saturated carbon chain containing 1 to 6 carbons substituted with an aromatic hydrocarbon, such as benzyl, phenethyl, 3-phenylpropyl, 1-naphthyl. Methyl, 2- (1-naphthyl) ethyl and the like are meant.

  The term “halogen” means fluorine, chlorine, bromine or iodine.

  As used herein, the term “treatment” includes treatment, prevention and management of symptoms mediated by peroxisome proliferator-activated receptor (PPAR).

  Certain terms defined above may appear more than once in the structural formula, and in such cases, each term should be defined independently of the others.

  The term “optionally substituted” as used herein means that the group in question is substituted or unsubstituted with one or more specified substituents. When the group in question is substituted with two or more substituents, these substituents may be the same or different.

Description of the invention

The present invention relates to a compound comprising the following general formula (I), a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate thereof, any tautomer, stereoisomer, and racemic mixture. For mixtures of isomers, or polymorphs:

here,
A is C _1-3 -alkylene optionally substituted with one or more substituents selected from:
·halogen;
• C _1-3 -alkyl, C _1-6 -alkoxy, C _3-6 -cycloalkoxy, C _1-6 -alkylthio, C _3-6 -cycloalkylthio, each optionally substituted with one or more halogens Or aralkoxy;
NR ₁ R ₂ ; where R ₁ represents hydrogen or C _1-3 -alkyl, and R ₂ represents —R ₃ — (C═O) —R ₄
Represents;
here,
* R ₃ is C _1-6 -alkylene, C _2-6 -alkenylene, C _4-6 -cycloalkylene,
Optionally substituted with C _4-6 -cycloalkenylene, or one or more halogens
Represents arylene;
* R ₄ represents aryl optionally substituted with one or more halogens;
Or
A is -O-A 'or -S-A', wherein -O- or -S- is linked to X in formula (I), and A 'is one or more selected from C _1-3 -alkylene optionally substituted with substituents;
·halogen;
• C _1-3 -alkyl, C _1-6 -alkoxy, C _3-6 -cycloalkoxy, C _1-6 -alkylthio, C _3-6 -cycloalkylthio, each optionally substituted with one or more halogens Or aralkoxy;
NR ₁ R ₂ ; where R ₁ represents hydrogen or C _1-3 -alkyl, and R ₂ represents —R ₃ — (C═O) —R ₄
Represents;
here,
* R ₃ is C _1-6 -alkylene, C _2-6 -alkenylene, C _4-6 -cycloalkylene,
Optionally substituted with C _4-6 -cycloalkenylene, or one or more halogens
Represents arylene;
* R ₄ represents aryl optionally substituted with one or more halogens;
B is C _1-3 -alkylene optionally substituted with one or more substituents selected from:
·halogen;
• C _1-3 -alkyl, C _1-6 -alkoxy, C _3-6 -cycloalkoxy, C _1-6 -alkylthio, C _3-6 -cycloalkylthio, each optionally substituted with one or more halogens Or aralkoxy;
NR ₁ R ₂ ; where R ₁ represents hydrogen or C _1-3 -alkyl, and R ₂ represents —R ₃ — (C═O) —R ₄
Represents;
here,
* R ₃ is C _1-6 -alkylene, C _2-6 -alkenylene, C _4-6 -cycloalkylene,
Optionally substituted with C _4-6 -cycloalkenylene, or one or more halogens
Represents arylene;
* R ₄ represents aryl optionally substituted with one or more halogens;
Or
B is is -OB 'or -S-B', wherein -O- or -S- is linked to Y in formula (I), and B 'is one or more substitutions selected from C _1-3 -alkylene optionally substituted with groups;
·halogen;
• C _1-3 -alkyl, C _1-6 -alkoxy, C _3-6 -cycloalkoxy, C _1-6 -alkylthio, C _3-6 -cycloalkylthio, each optionally substituted with one or more halogens Or aralkoxy;
NR ₁ R ₂ ; where R ₁ represents hydrogen or C _1-3 -alkyl, and R ₂ represents —R ₃ — (C═O) —R ₄
Represents;
here,
* R ₃ is C _1-6 -alkylene, C _2-6 -alkenylene, C _4-6 -cycloalkylene,
Optionally substituted with C _4-6 -cycloalkenylene, or one or more halogens
Represents arylene;
* R ₄ represents aryl optionally substituted with one or more halogens;
D is H, C _1-6 -alkyl, or C _3-6 -cycloalkyl;
E is H, C _1-6 -alkyl, or C _3-6 -cycloalkyl;
L and M are independently -O- or -S-;
T is a divalent C _1-6 saturated carbon chain optionally substituted with one or more substituents selected from:
Halogen or hydroxy;
Aryl, aralkoxy, or C _1-3 -alkoxy optionally substituted with halogen;
Or
T is —NR ₁ —T ′; where —NR ₁ — is bonded to Z in formula (I) and T ′ is C _1-6 alkylene optionally substituted with one or more halogens. And R ₁ represents hydrogen or C _1-3 alkyl;
U is a divalent C _1-6 saturated carbon chain optionally substituted with one or more substituents selected from:
Halogen or hydroxy;
Aryl, aralkoxy, or C _1-3 -alkoxy optionally substituted with halogen;
Or
U is —NR ₁ —U ′; where —NR ₁ — is bonded to Z in formula (I) and U ′ is C _1-6 alkylene optionally substituted with one or more halogens And R ₁ represents hydrogen or C _1-3 alkyl;
X is arylene or heteroarylene, each optionally substituted with one or more substituents selected from
Halogen or hydroxy;
C _1-6 -alkyl, C _3-6 -cycloalkyl, C _1-6 -alkoxy, C _3-6 -cycloalkoxy, C _1-6 -alkylthio, each optionally substituted with one or more halogens C _3-6 -cycloalkylthio, aryl, aralkyl;
Y is an arylene or heteroarylene, each optionally substituted with one or more substituents selected from
Halogen or hydroxy;
C _1-6 -alkyl, C _3-6 -cycloalkyl, C _1-6 -alkoxy, C _3-6 -cycloalkoxy, C _1-6 -alkylthio, each optionally substituted with one or more halogens C _3-6 -cycloalkylthio, aryl, aralkyl;
Z is an arylene, heteroarylene, or divalent polycyclic ring system, each optionally substituted with one or more substituents selected from:
Halogen or hydroxy;
C _1-6 -alkyl, C _3-6 -cycloalkyl, C _1-6 -alkoxy, C _3-6 -cycloalkoxy, C _1-6 -alkylthio, each optionally substituted with one or more halogens C _3-6 -Cycloalkylthio.

In one embodiment, the invention relates to compounds of formula (I), wherein A is C _1-3 -alkylene optionally substituted with one or more substituents selected from:
• methyl, C _1-3 -alkoxy, C _3-6 -cycloalkoxy, or benzyloxy, each optionally substituted with one or more halogens; or NR ₁ R ₂ : where R ₁ represents hydrogen, R ₂ represents -R _3- (C = O) -R ₄
here,
* R ₃ is C _1-6 -alkylene, C _2-6 -alkenylene, C _4-6 -cycloalkylene,
Optionally substituted with C _4-6 -cycloalkenylene, or one or more halogens
Represents phenylene;
* R ₄ represents phenyl optionally substituted with one or more halogens.

In another embodiment, the present invention is concerned with compounds of formula (I) wherein A is methylene or ethylene, each of which is optionally substituted with one or more substituents selected from:
Methoxy or ethoxy; or NR ₁ R ₂ where R ₁ represents hydrogen, R ₂ represents —R ₃ — (C═O) —R ₄ ,
Here, R ₃ and R ₄ represent phenyl.

  In another embodiment, the present invention is concerned with compounds of formula (I) wherein A is ethylene optionally substituted with ethoxy.

In another embodiment, the invention provides that A is -O-A 'or -S-A', -O- or -S- is attached to X in formula (I), and A 'is Relates to compounds of formula (I) that are C _1-3 -alkylene optionally substituted with one or more substituents selected from:
• halogen; or • C _1-3 -alkyl, C _1-6 -alkoxy, C _3-6 -cycloalkoxy, or aralkoxy, each optionally substituted with one or more halogens.

  In another embodiment, the invention provides that A is —O—A ′ or —S—A ′, —O— or —S— is attached to X in formula (I), and A ′ is methylene Or ethylene, each of which is optionally substituted with one or more substituents selected from methyl, methoxy or ethoxy.

  In another embodiment, the present invention provides a compound of formula (I) wherein A is —O—A ′, —O— is bonded to X in formula (I), and A ′ is methylene or ethylene. About.

In another embodiment, the present invention is concerned with compounds of formula (I) wherein B is C _1-3 -alkylene, optionally substituted with one or more substituents selected from:
• methyl, C _1-3 -alkoxy, C _3-6 -cycloalkoxy, or benzyloxy, each optionally substituted with one or more halogens;
NR ₁ R _2, where R ₁ represents hydrogen and R ₂ represents —R ₃ — (C═O) —R ₄ ;
here,
* R ₃ is C _1-6 -alkylene, C _2-6 -alkenylene, C _4-6 -cycloalkylene,
Optionally substituted with C _4-6 -cycloalkenylene, or one or more halogens
Represents phenylene;
* R ₄ represents phenyl optionally substituted with one or more halogens.

In another embodiment, the present invention is concerned with compounds of formula (I) wherein B is methylene or ethylene, each of which is optionally substituted with one or more substituents selected from:
Methoxy or ethoxy; or NR ₁ R ₂ ; where R ₁ represents hydrogen, R ₂ represents —R ₃ — (C═O) —R ₄ , and R ₃ and R ₄ represent phenyl .

  In another embodiment, the present invention is concerned with compounds of formula (I) wherein B is ethylene optionally substituted with ethoxy.

In another embodiment, the invention provides that B is —O—B ′ or —S—B ′, wherein —O— or —S— is bound to Y in formula (I) and B 'Relates to a compound of formula (I) which is C _1-3 -alkylene optionally substituted with one or more substituents selected from:
• halogen; or • C _1-3 -alkyl, C _1-6 -alkoxy, C _3-6 -cycloalkoxy or aralkoxy, each optionally substituted with halogen.

  In another embodiment, the invention provides that B is —O—B ′ or —S—B ′, wherein —O— or —S— is bound to Y in formula (I) and B 'Is methylene or ethylene, each of which is optionally substituted with one or more substituents selected from methyl, methoxy or ethoxy (formula I).

  In another embodiment, the present invention provides a compound of formula (I) wherein B is -O-B ', wherein -O- is attached to Y in formula (I) and B' is methylene or ethylene. ).

  In another embodiment, the present invention is concerned with compounds of formula (I) wherein D is H.

  In another embodiment, the present invention is concerned with compounds of formula (I) wherein D is methyl.

  In another embodiment, the present invention is concerned with compounds of formula (I) wherein D is ethyl.

  In another embodiment, the present invention is concerned with compounds of formula (I) wherein D is isopropyl.

  In another embodiment, the present invention is concerned with compounds of formula (I) wherein E is H.

  In another embodiment, the present invention is concerned with compounds of formula (I) wherein E is methyl.

  In another embodiment, the present invention is concerned with compounds of formula (I) wherein E is ethyl.

  In another embodiment, the present invention is concerned with compounds of formula (I) wherein E is isopropyl.

  In another embodiment, the present invention is concerned with compounds of formula (I) wherein L is —O—.

  In another embodiment, the present invention is concerned with compounds of formula (I) wherein L is —S—.

  In another embodiment, the present invention is concerned with compounds of formula (I) wherein M is —O—.

  In another embodiment, the present invention is concerned with compounds of formula (I) wherein M is —S—.

In another embodiment, the present invention is a divalent C _1-6 saturated carbon chain in which T is optionally substituted with one or more substituents, wherein the substituents are optionally phenyl, benzyloxy, or halogen. It relates to compounds of formula (I) selected from substituted C _1-3 -alkoxy.

In another embodiment, the present invention is concerned with compounds of formula (I) wherein T is a divalent unsubstituted C _1-6 saturated carbon chain.

  In another embodiment, the present invention is concerned with compounds of formula (I) wherein T is methylene.

  In another embodiment, the present invention is concerned with compounds of formula (I) wherein T is ethylene.

  In another embodiment, the present invention is concerned with compounds of formula (I) wherein T is propylene.

In another embodiment, the invention provides that T is —NR ₁ —T ′, wherein —NR ₁ — is bonded to Z in formula (I), T ′ optionally being one or more halogens It relates to compounds of formula (I) which are substituted C _1-6 alkylene and R ₁ represents hydrogen or C _1-3 alkyl.

In another embodiment, the invention relates to wherein T is —NR ₁ —T ′, wherein —NR ₁ — is attached to Z in formula (I) and T ′ is C _1-3 alkylene. And R ₁ is hydrogen or C _1-3 alkyl.

In another embodiment, the present invention provides that T is —NR ₁ —T ′, wherein —NR ₁ — is bonded to Z in formula (I), and T ′ is ethylene, R ₁ Relates to a compound of formula (I) which is methyl.

In another embodiment, the invention is a divalent C _1-6 saturated carbon chain in which U is optionally substituted with one or more substituents, wherein the substituents are optionally phenyl, benzyloxy, or halogen. It relates to compounds of formula (I) which are substituted C _1-3 -alkoxy.

In another embodiment, the present invention is concerned with compounds of formula (I) wherein U is a divalent unsubstituted C _1-6 saturated carbon chain.

  In another embodiment, the present invention is concerned with compounds of formula (I) wherein U is methylene.

  In another embodiment, the present invention is concerned with compounds of formula (I) wherein U is ethylene.

  In another embodiment, the present invention is concerned with compounds of formula (I) wherein U is propylene.

In another embodiment, the invention provides that U is —NR ₁ —U ′, wherein —NR ₁ — is bonded to Z in formula (I), U ′ optionally represents one or more halogens It relates to compounds of formula (I) which are substituted C _1-6 alkylene and R ₁ represents hydrogen or C _1-3 alkyl.

In another embodiment, the invention provides that U is —NR ₁ —U ′, wherein —NR ₁ — is bonded to Z in formula (I), and U ′ is C _1-3 alkylene And R ₁ is hydrogen or C _1-3 alkyl.

In another embodiment, the invention provides that U is —NR ₁ —U ′, wherein —NR ₁ — is bonded to Z in formula (I), U ′ is ethylene, and R ₁ Relates to a compound of formula (I) which is methyl.

In another embodiment, the present invention is concerned with compounds of formula (I) wherein X is arylene or heteroarylene, each of which is optionally substituted with one or more substituents selected from:
• Halogen; or • C _1-6 -alkyl, aryl, each optionally substituted with one or more halogens.

In another embodiment, the present invention is concerned with compounds of formula (I) wherein X is arylene optionally substituted with one or more substituents selected from:
• Halogen; or • C _1-6 -alkyl, aryl, each optionally substituted with one or more halogens.

In another embodiment, the present invention is concerned with compounds of formula (I) wherein X is phenylene optionally substituted with one or more substituents selected from:
Halogens; or
C _1-3 -alkyl, phenyl, each optionally substituted with one or more halogens.

  In another embodiment, the present invention is concerned with compounds of formula (I) wherein X is phenylene optionally substituted with one or more halogen, methyl or phenyl.

  In another embodiment, the present invention is concerned with compounds of formula (I) wherein X is phenylene optionally substituted with one or more trifluoromethyl or methoxy.

In another embodiment, the present invention is concerned with compounds of formula (I) wherein Y is arylene or heteroarylene optionally substituted with one or more substituents selected from:
• Halogen; or • C _1-6 -alkyl, aryl, each optionally substituted with one or more halogens.

In another embodiment, the present invention is concerned with compounds of formula (I) wherein Y is arylene optionally substituted with one or more substituents selected from:
• Halogen; or • C _1-6 -alkyl, aryl, each optionally substituted with one or more halogens.

In another embodiment, the present invention is concerned with compounds of formula (I) wherein Y is phenylene optionally substituted with one or more substituents selected from:
• Halogen; or • C _1-3 -alkyl, phenyl, each optionally substituted with one or more halogens.

  In another embodiment, the present invention is concerned with compounds of formula (I) wherein Y is phenylene optionally substituted with one or more halogen, methyl or phenyl.

  In another embodiment, the present invention is concerned with compounds of formula (I) wherein Y is phenylene optionally substituted with one or more trifluoromethyl or methoxy.

In another embodiment, the present invention provides compounds of formula (I) wherein Z is arylene, heteroarylene, or a divalent polycyclic system, each of which is optionally substituted with one or more substituents selected from For the compound:
Halogen, oxo; or
C _1-6 -alkyl, C _1-6 -alkoxy, each optionally substituted with one or more halogens.

In another embodiment, the present invention is concerned with compounds of formula (I) wherein Z 1 is selected from the following groups:

However, each of the above groups is optionally substituted with one or more substituents selected from:
Halogens; or
C _1-6 -alkyl or C _1-6 -alkoxy, each optionally substituted with one or more halogens.

In another embodiment, the present invention is concerned with compounds of formula (I) wherein Z 1 is selected from the following groups:

However, each of the above groups is optionally substituted with one or more substituents selected from:
• halogen; or • C _1-6 -alkyl or C _1-6 -alkoxy, each optionally substituted with one or more halogens.

In another embodiment, the present invention is concerned with compounds of formula (I) wherein Z 1 is selected from the following groups:

However, each of the above groups is optionally substituted with one or more substituents selected from:
• halogen; or • C _1-6 -alkyl or C _1-6 -alkoxy, each optionally substituted with one or more halogens.
In another embodiment, the present invention is concerned with compounds of formula (I) wherein Z 1 is selected from the following groups:

However, each of the above groups is optionally substituted with one or more substituents selected from:
• halogen; or • C _1-6 -alkyl or C _1-6 -alkoxy, each optionally substituted with one or more halogens.
In another embodiment, the present invention provides that Z is

Relates to compounds of formula (I):
In another embodiment, the present invention provides that Z is

Which relates to compounds of formula (I) optionally substituted with one or more trifluoromethyl.

In another embodiment, the present invention provides that Z is

Relates to a compound of formula (I)

In another embodiment, the present invention provides that Z is

Relates to a compound of formula (I)

In another embodiment, the present invention provides that Z is

Relates to a compound of formula (I)

  In another embodiment, the present invention is concerned with compounds of the present invention having (S) -configuration where possible.

  In another embodiment, the present invention is concerned with compounds of the present invention which are mixed PPARα / PPARγ profiles.

  In another embodiment, the present invention is directed to compounds of the present invention that are mixed PPARα / PPARδ profiles.

  In another embodiment, the present invention is concerned with compounds of the present invention which are mixed PPARγ / PPARδ profiles.

  In another embodiment, the present invention is concerned with compounds of the present invention which are mixed PPARα / PPARγ / PPARδ profiles.

  In another embodiment, the present invention is directed to compounds of the present invention that are selective PPARα profiles.

  In another embodiment, the present invention is directed to compounds of the present invention that are selective PPARγ profiles.

  In another embodiment, the present invention is directed to compounds of the present invention that are selective PPARδ profiles.

Examples of specific compounds of the invention are as follows:
2-ethoxy-3- [4- (2-{[6-({2- [4- (2-ethoxy-2-methoxycarbonyl-ethyl) -phenylsulfanyl] -ethyl} -methyl-amino) -pyridine -2-yl] -methyl-amino} -ethylsulfanyl) -phenyl] -propionic acid;
3- [4- (2-{[6-({2- [4- (2-carboxy-2-ethoxy-ethyl) -2-chloro-phenylsulfanyl] -ethyl} -methyl-amino) -pyridine- 2-yl] -methyl-amino} -ethylsulfanyl) -3-chloro-phenyl] -2-ethoxy-propionic acid;
(5 '-{2-[(6-{[2- (2'-ethoxycarbonylmethoxy- [1,1'; 3 ', 1'']terphenyl-5'-yloxy) -ethyl] -methyl -Amino} -pyridin-2-yl) -methyl-amino] -ethoxy}-[1,1 ′; 3 ′, 1 ″] terphenyl-2′-yloxy) -acetic acid;
(5 '-{2-[(6-{[2- (2'-Carboxymethoxy- [1,1'; 3 ', 1'']terphenyl-5'-yloxy) -ethyl] -methyl- Amino} -pyridin-2-yl) -methyl-amino] -ethoxy}-[1,1 ′; 3 ′, 1 ″] terphenyl-2′-yloxy) -acetic acid;
・ (S, S) -2- (2-Benzoyl-phenylamino) -3- {4- [2-({6-[(2- {4- [2- (2-benzoyl-phenylamino) -2 -Methoxycarbonyl-ethyl] -phenoxy} -ethyl) -methyl-amino] -pyridin-2-yl} -methyl-amino) -ethoxy] -phenyl} -propionic acid;
・ (S, S) -2- (2-Benzoyl-phenylamino) -3- {4- [2-({6-[(2- {4- [2- (2-benzoyl-phenylamino) -2 -Carboxy-ethyl] -phenoxy} -ethyl) -methyl-amino] -pyridin-2-yl} -methyl-amino) -ethoxy] -phenyl} -propionic acid;
(3-Chloro-4- {2-[(6-{[2- (2-Chloro-4-ethoxycarbonylmethyl-phenoxy) -ethyl] -methyl-amino} -pyridin-2-yl) -methyl- Amino] -ethoxy} -phenyl) -acetic acid;
(4- {2-[(6-{[2- (4-Carboxymethyl-2-chloro-phenoxy) -ethyl] -methyl-amino} -pyridin-2-yl) -methyl-amino] -ethoxy} -3-chloro-phenyl) -acetic acid;
・ (3- {2-[(6-{[2- (3-Ethoxycarbonylmethyl-phenoxy) -ethyl] -methyl-amino} -pyridin-2-yl) -methyl-amino] -ethoxy} -phenyl) -Acetic acid;
(3- {2-[(6-{[2- (3-Carboxymethyl-phenoxy) -ethyl] -methyl-amino} -pyridin-2-yl) -methyl-amino] -ethoxy} -phenyl)- Acetic acid;
(S, S) -2-ethoxy-3- [4- (2-{[6-({2- [4- (2-ethoxy-2-ethoxycarbonyl-ethyl) -phenoxy] -ethyl} -methyl -Amino) -pyridin-2-yl] -methyl-amino} -ethoxy) -phenyl] -propionic acid;
(S, S) -3- [4- (2-{[6-({2- [4- (2-carboxy-2-ethoxy-ethyl) -phenoxy] -ethyl} -methyl-amino) -pyridine -2-yl] -methyl-amino} -ethoxy) -phenyl] -2-ethoxy-propionic acid;
(S, S) -2-Ethoxy-3- {4- [3- (4 '-{3- [4- (2-Ethoxy-2-isopropoxycarbonyl-ethyl) -phenoxy] -propyl} -2 , 2'-bis-trifluoromethyl-biphenyl-4-yl) -propoxy] -phenyl} -propionic acid;
(S, S) -3- {4- [3- (4 '-{3- [4- (2-carboxy-2-ethoxy-ethyl) -phenoxy] -propyl} -2,2'-bis- Trifluoromethyl-biphenyl-4-yl) -propoxy] -phenyl} -2-ethoxy-propionic acid;
(S, S) -2-ethoxy-3- {4- [3- (4 '-{3- [4- (2-ethoxy-2-isopropoxycarbonyl-ethyl) -phenoxy] -propyl} -3 , 3'-bis-trifluoromethyl-biphenyl-4-yl) -propoxy] -phenyl} -propionic acid;
(S, S) -3- {4- [3- (4 '-{3- [4- (2-carboxy-2-ethoxy-ethyl) -phenoxy] -propyl} -3,3'-bis- Trifluoromethyl-biphenyl-4-yl) -propoxy] -phenyl} -2-ethoxy-propionic acid;
(S, S) -3- {3-Bromo-4- [3- (4 '-{3- [2-Bromo-4- (2-ethoxy-2-isopropoxycarbonyl-ethyl) -phenoxy]- Propyl} -2,2′-bis-trifluoromethyl-biphenyl-4-yl) -propoxy] -phenyl} -2-ethoxy-propionic acid;
(S, S) -3- {3-bromo-4- [3- (4 '-{3- [2-bromo-4- (2-carboxy-2-ethoxy-ethyl) -phenoxy] -propyl} -2,2'-bis-trifluoromethyl-biphenyl-4-yl) -propoxy] -phenyl} -2-ethoxy-propionic acid;
(S, S) -3- {3-Bromo-4- [3- (4 '-{3- [2-Bromo-4- (2-ethoxy-2-isopropoxycarbonyl-ethyl) -phenoxy]- Propyl} -3,3′-bis-trifluoromethyl-biphen-4-yl) -propoxy] -phenyl} -2-ethoxy-propionic acid;
(S, S) -3- {3-bromo-4- [3- (4 '-{3- [2-bromo-4- (2-carboxy-2-ethoxy-ethyl) -phenoxy] -propyl} -3,3'-bis-trifluoromethyl-biphenyl-4-yl) -propoxy] -phenyl} -2-ethoxy-propionic acid;
(S, S) -3- {3-Bromo-4- [3- (7- {3- [2-bromo-4- (2-ethoxy-2-isopropoxycarbonyl-ethyl) -phenoxy] -propyl } -9H-Fluoren-2-yl) -propoxy] -phenyl} -2-ethoxy-propionic acid isopropyl ester;
(S, S) -3- {3-bromo-4- [3- (7- {3- [2-bromo-4- (2-carboxy-2-ethoxy-ethyl) -phenoxy] -propyl}- 9H-Fluoren-2-yl) -propoxy] -phenyl} -2-ethoxy-propionic acid;
(S, S) -2-ethoxy-3- {4- [3- (7- {3- [4- (2-ethoxy-2-isopropoxycarbonyl-ethyl) -phenoxy] -propyl} -9H- Fluoren-2-yl) -propoxy] -phenyl} -propionic acid isopropyl ester;
(S, S) -3- {4- [3- (7- {3- [4- (2-carboxy-2-ethoxy-ethyl) -phenoxy] -propyl} -9H-fluoren-2-yl) -Propoxy] -phenyl} -2-ethoxy-propionic acid;
-[4- (3- {4 '-[3- (4-Methoxycarbonylmethoxy-3-methyl-phenylsulfanyl) -propyl] -2,2'-bis-trifluoromethyl-biphenyl-4-yl}- Propylsulfanyl) -2-methyl-phenoxy] -acetic acid;
・ [4- (3- {4 '-[3- (4-Methoxycarbonylmethoxy-3-methyl-phenylsulfanyl) -propyl] -3,3'-bis-trifluoromethyl-biphenyl-4-yl}- Propylsulfanyl) -2-methyl-phenoxy] -acetic acid;
[4- (3- {4 '-[3- (4-Carboxymethoxy-3-methyl-phenylsulfanyl) -propyl] -3,3'-bis-trifluoromethyl-biphenyl-4-yl} -propyl Sulfanyl) -2-methyl-phenoxy] -acetic acid;
・ [4- (3- {7- [3- (4-Methoxycarbonylmethoxy-3-methyl-phenylsulfanyl) -propyl] -9H-fluoren-2-yl} -propylsulfanyl) -2-methyl-phenoxy] -Acetic acid;
[4- (3- {7- [3- (4-Carboxymethoxy-3-methyl-phenylsulfanyl) -propyl] -9H-fluoren-2-yl} -propylsulfanyl) -2-methyl-phenoxy]- Acetic acid;
・ (4- {2- [2- (3- {4- [2- (4-Methoxycarbonylmethoxy-3-methyl-phenylsulfanyl) -ethyl] -5-methyl-oxazol-2-yl} -phenyl) -5-methyl-oxazol-4-yl] -ethylsulfanyl} -2-methyl-phenoxy) -acetic acid;
・ (4- {2- [2- (3- {4- [2- (4-Carboxymethoxy-3-methyl-phenylsulfanyl) -ethyl] -5-methyl-oxazol-2-yl} -phenyl)- 5-methyl-oxazol-4-yl] -ethylsulfanyl} -2-methyl-phenoxy) -acetic acid;
・ (S, S) -2-Ethoxy-3- [4- (2- {2- [4 '-(4- {2- [4- (2-Ethoxy-2-isopropoxycarbonyl-ethyl) -phenoxy] ] -Ethyl} -5-methyl-oxazol-2-yl) -biphenyl-4-yl] -5-methyl-oxazol-4-yl} -ethoxy) -phenyl] -propionic acid;
(S, S) -3- [4- (2- {2- [4 '-(4- {2- [4- (2-carboxy-2-ethoxy-ethyl) -phenoxy] -ethyl} -5 -Methyl-oxazol-2-yl) -biphenyl-4-yl] -5-methyl-oxazol-4-yl} -ethoxy) -phenyl] -2-ethoxy-propionic acid;
(S, S) -2-Ethoxy-3- [4- (2- {2- [3- (4- {2- [4- (2-Ethoxy-2-isopropoxycarbonyl-ethyl) -phenoxy] -Ethyl} -5-methyl-oxazol-2-yl) -phenyl] -5-methyl-oxazol-4-yl} -ethoxy) -phenyl] -propionic acid;
(S, S) -3- [4- (2- {2- [3- (4- {2- [4- (2-carboxy-2-ethoxy-ethyl) -phenoxy] -ethyl} -5- Methyl-oxazol-2-yl) -phenyl] -5-methyl-oxazol-4-yl} -ethoxy) -phenyl] -2-ethoxy-propionic acid.

  A salt thereof with a pharmaceutically acceptable acid or base, a mixture of optical isomers including any optical isomer or racemic mixture, or any tautomer.

Other examples of specific compounds of the invention are as follows:
-[4- (3- {4 '-[3- (4-Carboxymethylsulfanyl-3-chloro-phenylsulfanyl) -propyl] -3,3'-bis-trifluoromethyl-biphenyl-4-yl}- Propylsulfanyl) -2-chloro-phenylsulfanyl] -acetic acid;
[4- [3- [4 '-[3- (4-carboxymethoxy-3-trifluoromethylphenylsulfanyl) propyl] biphenyl-4-yl] -propylsulfanyl] -2-trifluoromethylphenoxy] acetic acid;
[4- [3- [4 '-[3- (4-Carboxymethoxy-3-chlorophenylsulfanyl) propyl] -3,3'-bis-trifluoromethylbiphenyl-4-yl] propylsulfanyl] -2- Chlorophenoxy] acetic acid;
[4- (3- {4 '-[3- (4-Carboxymethoxy-3-chloro-phenylsulfanyl) -propyl] -biphenyl-4-yl} -propylsulfanyl) -2-chloro-phenoxy]- Acetic acid;
[4- (3- {4 '-[3- (4-Carboxymethoxy-3-methoxy-phenylsulfanyl) -propyl] -biphenyl-4-yl} -propylsulfanyl) -2-methoxy-phenoxy] -acetic acid ;
・ {4- [3- (4- {4- [3- (4-Carboxymethoxy-3-trifluoromethyl-phenylsulfanyl) -propyl] -2-trifluoromethyl-phenylsulfanyl} -3-trifluoromethyl -Phenyl) -propylsulfanyl] -2-trifluoromethyl-phenoxy} -acetic acid; or a salt thereof with a pharmaceutically acceptable acid or base, any optical isomer or racemic mixture Or any tautomer.

Other examples of specific compounds of the invention are as follows:
3- [4- (2-{[6-({2- [4- (2-carboxy-2-ethoxy-ethyl) -phenoxy] -ethyl} -methyl-amino) -pyridin-2-yl]- Methyl-amino} -ethoxy) -phenyl] -2-ethoxy-propionic acid;
(3- {2-[(6-{[2- (3-Carboxymethyl-phenoxy) -ethyl] -methyl-amino} -pyridin-2-yl) -methyl-amino] -ethoxy} -phenyl)- Acetic acid;
2- (2-benzoyl-phenylamino) -3- {4- [2-({6-[(2- {4- [2- (2-benzoyl-phenylamino) -2-carboxy-ethyl]- Phenoxy} -ethyl) -methyl-amino] -pyridin-2-yl} -methyl-amino) -ethoxy] -phenyl} -propionic acid;
(5 '-{2-[(6-{[2- (2'-Carboxymethoxy- [1,1'; 3 ', 1'']terphenyl-5'-yloxy) -ethyl] -methyl- Amino} -pyridin-2-yl) -methyl-amino] -ethoxy}-[1,1 ′; 3 ′, 1 ″] terphenyl-2′-yloxy) -acetic acid;
3- [4- (2-{[6-({2- [4- (2-carboxy-2-ethoxy-ethyl) -phenylsulfanyl] -ethyl} -methyl-amino) -pyridin-2-yl] -Methyl-amino} -ethylsulfanyl) -phenyl] -2-ethoxy-propionic acid;
(4- {2-[(6-{[2- (4-Carboxymethyl-2-chloro-phenoxy) -ethyl] -methyl-amino} -pyridin-2-yl) -methyl-amino] -ethoxy} -3-chloro-phenyl) -acetic acid;
(4- {2-[(6-{[2- (4-Carboxymethyl-2-bromo-phenoxy) -ethyl] -methyl-amino} -pyridin-2-yl) -methyl-amino] -ethoxy} -3-bromo-phenyl) -acetic acid;
(4- {2-[(6-{[2- (4-Carboxymethoxy-3-methyl-phenylsulfanyl) -ethyl] -methyl-amino} -pyridin-2-yl) -methyl-amino] -ethyl Sulfanyl} -2-methyl-phenoxy) -acetic acid;
(4- {2-[(6-{[2- (4-Carboxymethoxy-phenylsulfanyl) -ethyl] -methyl-amino} -pyridin-2-yl) -methyl-amino] -ethylsulfanyl} -phenoxy ) -Acetic acid;
(3- {2-[(6-{[2- (3-Carboxymethyl-phenylsulfanyl) -ethyl] -methyl-amino} -pyridin-2-yl) -methyl-amino] -ethylsulfanyl} -phenyl ) -Acetic acid;
・ (4- {2-[(6-{[2- (4-Carboxymethyl-phenylsulfanyl) -ethyl] -methyl-amino} -pyridin-2-yl) -methyl-amino] -ethylsulfanyl} -phenyl ) -Acetic acid;
2- (2-benzoyl-phenylamino) -3- {4- [2-({6-[(2- {4- [2- (2-benzoyl-phenylamino) -2-carboxy-ethyl]- Phenylsulfanyl} -ethyl) -methyl-amino] -pyridin-2-yl} -methyl-amino) -ethylsulfanyl] -phenyl} -propionic acid;
3- {4- [2-({6-[(2- {4- [2-carboxy-2- (1-methyl-3-oxo-3-phenyl-propenylamino) -ethyl] -phenylsulfanyl} -Ethyl) -methyl-amino] -pyridin-2-yl} -methyl-amino) -ethylsulfanyl] -phenyl} -2- (1-methyl-3-oxo-3-phenyl-propenylamino) -propionic acid;
3- {4- [2-({6-[(2- {4- [2-carboxy-2- (1-methyl-3-oxo-3-phenyl-propenylamino) -ethyl] -phenoxy}- Ethyl) -methyl-amino] -pyridin-2-yl} -methyl-amino) -ethoxy] -phenyl} -2- (1-methyl-3-oxo-3-phenyl-propenylamino) -propionic acid;
(4- {2-[(6-{[2- (4-Carboxymethyl-2-chloro-phenylsulfanyl) -ethyl] -methyl-amino} -pyridin-2-yl) -methyl-amino] -ethyl Sulfanyl} -3-chloro-phenyl) -acetic acid;
(4- {2-[(6-{[2- (4-Carboxymethyl-2-bromo-phenylsulfanyl) -ethyl] -methyl-amino} -pyridin-2-yl) -methyl-amino] -ethyl Sulfanyl} -3-bromo-phenyl) -acetic acid;

3- [4- (2- {2- [3- (4- {2- [4- (2-carboxy-2-ethoxy-ethyl) -phenoxy] -ethyl} -5-methyl-oxazole-2- Yl) -phenyl] -5-methyl-oxazol-4-yl} -ethoxy) -phenyl] -2-ethoxy-propionic acid;
・ (4- {2- [2- (3- {4- [2- (4-Carboxymethoxy-3-methyl-phenylsulfanyl) -ethyl] -5-methyl-oxazol-2-yl} -phenyl)- 5-methyl-oxazol-4-yl] -ethylsulfanyl} -2-methyl-phenoxy) -acetic acid;
(4- {2- [2- (3- {4- [2- (4-Carboxymethoxy-3-methyl-phenoxy) -ethyl] -5-methyl-oxazol-2-yl} -phenyl) -5 -Methyl-oxazol-4-yl] -ethoxy} -2-methyl-phenoxy) -acetic acid;
・ (4- {2- [2- (3- {4- [2- (4-Carboxymethoxy-phenoxy) -ethyl] -5-methyl-oxazol-2-yl} -phenyl) -5-methyl-oxazole -4-yl] -ethoxy} -phenoxy) -acetic acid;
・ (4- {2- [2- (3- {4- [2- (4-Carboxymethoxy-phenylsulfanyl) -ethyl] -5-methyl-oxazol-2-yl} -phenyl) -5-methyl- Oxazol-4-yl] -ethylsulfanyl} -phenoxy) -acetic acid;
3- [4- (2- {2- [3- (4- {2- [4- (2-carboxy-2-ethoxy-ethyl) -phenylsulfanyl] -ethyl} -5-methyl-oxazole-2 -Yl) -phenyl] -5-methyl-oxazol-4-yl} -ethylsulfanyl) -phenyl] -2-ethoxy-propionic acid;

3- {4- [3- (7- {3- [4- (2-carboxy-2-ethoxy-ethyl) -phenoxy] -propyl} -9H-fluoren-2-yl) -propoxy] -phenyl} -2-ethoxy-propionic acid;
3- {4- [3- (7- {3- [4- (2-carboxy-2-ethoxy-ethyl) -phenylsulfanyl] -propyl} -9H-fluoren-2-yl) -propylsulfanyl]- Phenyl} -2-ethoxy-propionic acid;
[4- (3- {7- [3- (4-Carboxymethoxy-3-methyl-phenylsulfanyl) -propyl] -9H-fluoren-2-yl} -propylsulfanyl) -2-methyl-phenoxy]- Acetic acid;
[4- (3- {7- [3- (4-carboxymethoxy-phenylsulfanyl) -propyl] -9H-fluoren-2-yl} -propylsulfanyl) -phenoxy] -acetic acid;
3- {3-bromo-4- [3- (7- {3- [2-bromo-4- (2-carboxy-2-ethoxy-ethyl) -phenoxy] -propyl} -9H-fluorene-2- Yl) -propoxy] -phenyl} -2-ethoxy-propionic acid;
3- {3-bromo-4- [3- (7- {3- [2-bromo-4- (2-carboxy-2-ethoxy-ethyl) -phenylsulfanyl] -propyl} -9H-fluorene-2 -Yl) -propylsulfanyl] -phenyl} -2-ethoxy-propionic acid;

3- {4- [3- (4 '-{3- [4- (2-carboxy-2-ethoxy-ethyl) -phenoxy] -propyl} -2,2'-bis-trifluoromethyl-biphenyl- 4-yl) -propoxy] -phenyl} -2-ethoxy-propionic acid;
3- {4- [3- (4 '-{3- [4- (2-carboxy-2-ethoxy-ethyl) -phenoxy] -propyl} -3,3'-bis-trifluoromethyl-biphenyl- 4-yl) -propoxy] -phenyl} -2-ethoxy-propionic acid;
3- {3-bromo-4- [3- (4 '-{3- [2-bromo-4- (2-carboxy-2-ethoxy-ethyl) -phenoxy] -propyl} -2,2'- bis-trifluoromethyl-biphenyl-4-yl) -propoxy] -phenyl} -2-ethoxy-propionic acid;
3- {3-bromo-4- [3- (4 '-{3- [2-bromo-4- (2-carboxy-2-ethoxy-ethyl) -phenoxy] -propyl} -3,3'- bis-trifluoromethyl-biphenyl-4-yl) -propoxy] -phenyl} -2-ethoxy-propionic acid;
[4- (3- {4 '-[3- (4-Carboxymethoxy-3-methyl-phenylsulfanyl) -propyl] -3,3'-bis-trifluoromethyl-biphenyl-4-yl} -propyl Sulfanyl) -2-methyl-phenoxy] -acetic acid;
[4- (3- {4 '-[3- (4-Carboxymethoxy-phenylsulfanyl) -propyl] -3,3'-bis-trifluoromethyl-biphenyl-4-yl} -propylsulfanyl) -phenoxy ] -Acetic acid;
[4- (3- {4 '-[3- (4-Carboxymethoxy-phenoxy) -propyl] -3,3'-bis-trifluoromethyl-biphenyl-4-yl} -propoxy) -phenoxy]- Acetic acid;
・ [4- (3- {4 '-[3- (4-Carboxymethoxy-3-methyl-phenoxy) -propyl] -3,3'-bis-trifluoromethyl-biphenyl-4-yl} -propoxy) -2-methyl-phenoxy] -acetic acid;
[4- (3- {4 '-[3- (4-Carboxymethoxy-3-methyl-phenylsulfanyl) -propyl] -2,2'-bis-trifluoromethyl-biphenyl-4-yl} -propyl Sulfanyl) -2-methyl-phenoxy] -acetic acid;
・ [4- (3- {4 '-[3- (4-Carboxymethoxy-3-methyl-phenoxy) -propyl] -2,2'-bis-trifluoromethyl-biphenyl-4-yl} -propoxy) -2-methyl-phenoxy] -acetic acid;
3- [4- (2- {2- [4 '-(4- {2- [4- (2-carboxy-2-ethoxy-ethyl) -phenoxy] -ethyl} -5-methyl-oxazole-2) -Yl) -biphenyl-4-yl] -5-methyl-oxazol-4-yl} -ethoxy) -phenyl] -2-ethoxy-propionic acid; or • with their pharmaceutically acceptable acids or bases Salts, mixtures of optical isomers including any optical isomer or racemic mixture, or any tautomer.

  The present invention also includes pharmaceutically acceptable salts of the compounds of the present invention. Such salts include pharmaceutically acceptable acid addition salts, pharmaceutically acceptable base addition salts, pharmaceutically acceptable metal salts, ammonium and alkylated ammonium salts. Acid addition salts include inorganic and organic acid salts. Representative examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, sulfuric acid, nitric acid and the like. Representative examples of suitable organic acids include formic acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, propionic acid, benzoic acid, cinnamic acid, citric acid, fumaric acid, glycolic acid, lactic acid, maleic acid, malic acid, malon Acid, mandelic acid, succinic acid, picric acid, pyruvic acid, salicylic acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, tartaric acid, ascorbic acid, pamoic acid, bismethylenesalicylic acid, ethanedisulfonic acid, gluconic acid, citracone Acid, aspartic acid, stearic acid, palmitic acid, EDTA, glycolic acid, p-aminobenzoic acid, glutamic acid, benzenesulfonic acid, p-toluenesulfonic acid, sulfate, nitrate, phosphate, perchlorate, borate, acetate, benzoate, Hydroxy naphthoate, glycerophosphate , Ketoglutarate and the like. Additional examples of pharmaceutically acceptable inorganic or organic acid addition salts include those pharmaceutically acceptable listed in J. Pharm. Sci., 1977, 66, 2, which is incorporated herein by reference. Salt. Examples of the metal salt include lithium salt, sodium salt, potassium salt, magnesium salt, zinc salt, calcium salt and the like. Examples of amines and organic amines include ammonium, methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, propylamine, butylamine, tetramethylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, ethylenediamine, choline, N, N Examples include '-dibenzylethylenediamine, N-benzylphenylethylamine, N-methyl-D-glucamine, and guanidine. Examples of cationic amino acids include lysine, arginine, histidine and the like.

  Pharmaceutically acceptable salts include a compound of the invention and 1 to 4 equivalents of a base such as sodium hydroxide, sodium methoxide, sodium hydride, potassium t-butoxide, calcium hydroxide, magnesium hydroxide and the like. Is reacted in a solvent such as ether, THF, methanol, t-butanol, dioxane, isopropanol, ethanol and the like. A mixture of solvents may be used. Organic bases such as lysine, arginine, diethanolamine, choline, guanidine, and derivatives thereof may also be used. Alternatively, where applicable, the acid addition salts can be prepared in a solvent such as ethyl acetate, ether, alcohol, acetone, THF, dioxane, etc., with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, p It is prepared by treating with toluenesulfonic acid, methanesulfonic acid, acetic acid, citric acid, maleic acid, salicylic acid, hydroxynaphthoic acid, ascorbic acid, palmitic acid, succinic acid, benzoic acid, benzenesulfonic acid, tartaric acid and the like. A mixture of solvents may also be used.

  Stereoisomers of compounds that form part of the present invention are used whenever possible in the process by using their single enantiomeric forms of reactants or in a single enantiomeric form of a reagent or catalyst. It may be prepared by reacting in the presence or by resolving a mixture of stereoisomers by conventional methods. Some preferred methods include microbial resolution, enzymatic resolution, and whenever applicable, chiral acids such as mandelic acid, camphoric acid, tartaric acid and lactic acid, or brucine, (R)-or (S) -Resolving diastereomeric salts formed with chiral bases such as phenylethylamine, quinaalkaloids and their derivatives. A commonly used method is compiled by Jaques et al in “Enantiomers, Racemates and Resolution” (Wiley Interscience, 1981). More particularly, the compound of formula (I) may be converted to a 1: 1 mixture of diastereomeric amides by treatment with chiral amines, amino acids, amino alcohols derived from amino acids. In order to convert the acid into an amine, conventional reaction conditions may be used. These diastereomers can be separated by fractional crystallization or chromatography, and stereoisomers of the compounds of the invention can be prepared by hydrolyzing the pure diastereomeric amides. .

  Various polymorphs of the compounds of the invention that form part of the invention can be prepared by crystallizing the compounds of the invention under different conditions. For example, various solvents or mixtures thereof commonly used for recrystallization; crystallization at different temperatures; various cooling modes are used ranging from very fast cooling to very slow cooling during crystallization. Polymorphs can also be obtained by heating or melting a compound followed by slow cooling or rapid cooling. The presence of the polymorph can be determined by solid probe NMR spectral analysis, IR spectral analysis, scanning differential thermal analysis, powder X-ray diffraction or other techniques.

  The present invention also encompasses prodrugs of the compounds of the present invention which, when administered, undergo chemical transformation by metabolic processes before becoming active pharmacological agents. In general, such prodrugs are functional derivatives of the compounds of the invention that are readily convertible in vivo into the required compounds of the invention. Conventional methods for the selection and preparation of suitable prodrug derivatives are described, for example, in “Design of Prodrugs”, H. Bundgaard, Elsevier, 1985.

  The present invention also includes active metabolites of the compounds of the present invention.

  The present invention also includes at least one compound of the present invention, or any optical isomer, geometric isomer, tautomer or active ingredient as an active ingredient together with one or more pharmaceutically acceptable carriers or diluents. The present invention relates to a pharmaceutical composition containing a mixture thereof or a pharmaceutically acceptable salt thereof.

  The present invention further provides for the treatment and / or prevention of conditions mediated by nuclear receptors, particularly Peroxisome Proliferator-Activated Receptors (PPAR), such as those described above. A compound of the present invention, or a tautomer, stereoisomer, polymorph, pharmaceutically acceptable salt, or pharmaceutically acceptable solvent thereof for the manufacture of a pharmaceutical composition Regarding the use of Japanese products.

  In another aspect, the present invention relates to a method for treating and / or preventing type I diabetes or type II diabetes.

  In a further aspect, the invention provides the use of a compound of the invention or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical composition for treating and / or preventing type I diabetes or type II diabetes. About.

  In a further aspect, the compounds of the present invention are useful for the treatment and / or prevention of IGT.

  In a further aspect, the compounds of the present invention are useful for the treatment and / or prevention of type II diabetes.

  In a further aspect, the compounds of the invention are useful for delaying or preventing progression from IGT to type II diabetes.

  In a further aspect, the compounds of the invention are useful for delaying or preventing the progression from non-insulin-requiring Type II diabetes to insulin-requiring Type II diabetes.

  In another aspect, the compounds of the invention lower blood glucose and triglyceride levels and are therefore useful for treating and / or preventing diseases and disorders such as diabetes and / or obesity.

  In yet another aspect, the compounds of the present invention comprise insulin resistance (type II diabetes), impaired glucose tolerance, dyslipidemia, and hypertension, obesity, insulin resistance, hyperglycemia, atherosclerosis, hyperlipidemia. It is useful for treating and / or preventing disorders related to Syndrome X, such as infectious diseases, coronary artery disease, myocardial ischemia and other cardiovascular disorders.

  In yet another aspect, the compounds of the present invention are effective in reducing apoptosis in mammalian cells such as β cells of the islets of Langerhans.

  In yet another aspect, the compounds of the present invention are useful for the treatment of certain renal diseases including glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis.

  In yet another aspect, the compounds of the present invention may also be used for improving cognitive function in dementia, treating diabetic complications, psoriasis, polycystic ovary syndrome (PCOS), and preventing bone loss (eg, osteoporosis). Useful.

  In yet another aspect, the present invention also provides compounds of the invention that reduce atherosclerotic biomarkers (including but not limited to c-reactive protein (CRP), TNFα and IL-6) after administration. About the use of.

  The compounds of the present invention are also, for example, anti-obesity agents, anti-diabetic agents, antihypertensive agents, therapeutic and / or preventive agents for complications derived from or associated with diabetes, and derived from or associated with obesity. May be administered in combination with one or more additional pharmacologically active substances, such as therapeutic and / or prophylactic agents for complications and diseases.

  Thus, in a further aspect of the invention the present compounds may be administered in combination with one or more antiobesity agents or appetite regulating agents.

  Such drugs include CART (cocaine amphetamine-regulated transcript) agonists, NPY (neuropeptide Y) antagonists, MC4 (melanocortin 4) agonists, aurexin antagonists, TNF (tumor necrosis factor) agonists, CRF (corticotropin release) Factor) agonist, CRF BP (corticotropin releasing factor binding protein) antagonist, urocortin agonist, β3 agonist, MSH (melanocyte stimulating hormone) agonist, MCH (melanocyte condensing hormone) antagonist, CCK (cholecystokinin) agonist, serotonin reactivation Uptake inhibitors, serotonin and noradrenaline reuptake inhibitors, mixed serotonin and noradrenergic compounds, 5HT (serotonin) agonists, bombesin agonists, galanin antagonists , Growth hormone, growth hormone releasing compound, TRH (thyroid stimulating hormone releasing hormone) agonist, UCP 2 or 3 (binding dissociated protein 2 or 3) modulator, leptin agonist, DA agonist (bromocriptine, doplexin), lipase / amylase inhibition Selected from the group consisting of agents, RXR (retinoid X receptor) modulators, and TRβ agonists.

  In one embodiment of the invention, the antiobesity agent is leptin.

  In another embodiment, the antiobesity agent is dexamphetamine or amphetamine.

  In another embodiment, the antiobesity agent is fenfluramine or dexfenfluramine.

  In yet another embodiment, the antiobesity agent is sibutramine.

  In yet another embodiment, the antiobesity agent is orlistat.

  In another embodiment, the antiobesity agent is mazindol or phentermine.

  Suitable anti-diabetic drugs include insulin, GLP-1 (glucagon-like peptide-1) derivatives disclosed in WO 98/08871 of Novonordisk A / S, which is incorporated herein by reference, and oral Active hypoglycemic agents are included.

  Orally active hypoglycemic agents are preferably sulfonylureas, biguanides, meglitinides, glucosidase inhibitors, Novo Nordisk A / S and WO 99/01423 of Agouron Pharmaceuticals, Inc. Glucagon antagonists as disclosed, GLP-1 agonists, potassium channel openers disclosed in WO 97/26265 and WO 99/03861 of Novo Nordisk A / S, incorporated herein by reference, DPP Anti-hyperlipidemia such as -IV (dipeptidyl peptidase-IV) inhibitors, inhibitors of liver enzymes involved in the stimulation of gluconeogenesis and / or glycogenolysis, glucose uptake regulators, HMG CoA inhibitors (statins) Compounds that modify lipid metabolism, such as drugs and antilipidemic agents, compounds that reduce food intake, RXR agonists, and ATP-dependent potassium thiamine in beta cells It contains drugs that act on the channel.

  In one embodiment of the invention, the compounds of the invention are administered in combination with insulin.

  In a further embodiment, the compounds of the invention are administered in combination with a sulfonylurea such as tolbutamide, glibencamide, glipizide, or glicazide.

  In another embodiment, the compounds of the invention are administered in combination with a biguanide (eg, metformin).

  In yet another embodiment, the compounds of the invention are administered in combination with a meglitinide (eg, repaglinide or senaglinide).

  In further embodiments, the compounds of the invention are administered in combination with an alpha glucosidase inhibitor (eg, miglitol or acarbose).

  In another embodiment, the compounds of the invention are administered in combination with an agent that acts on β-cell ATP-dependent potassium channels, such as tolbutamide, glibenclamide, glipizide, glicazide or repaglinide.

  Furthermore, the compounds of the present invention may be administered in combination with nateglinide.

  In yet another embodiment, the compound of the invention comprises an antihyperlipidemic or antilipidemic agent such as cholestyramine, colestipol, clofibrate, gemfibrozil ( gemfibrozil), fenofibrate, benzafibrate, tesaglitazar, EML-4156, LY-518674, LY-519818, MK-767, atorvastatin, fluvastatin, lovastatin, pravastatin ( Administered in combination with pravastatin, simvastatin, cerivastatin, acipimox, ezetimibe, probucol, dextrothyroxine, or nicotinic acid.

  In yet another embodiment, the compounds of the invention are administered in combination with a thiazolidinedione, such as troglitazone, ciglitazone, pioglitazone, or rosiglitazone.

  In further embodiments, a compound of the present invention is combined with one or more of the compounds described above, eg, sulfonylurea and metformin, sulfonylurea and acarbose, repaglinide and metformin, insulin and sulfonylurea, insulin and metformin, insulin And administered in combination with lovastatin and the like.

Furthermore, the compounds of the present invention may be administered in combination with one or more antihypertensive agents. Examples of antihypertensive agents are β-blockers such as alprenolol, atenolol, timolol, tidolol, pindolol, propranolol and metoprolol; benazepril, captopril ), Enalapril, fosinopril, fosinopril, lisinopril, quinapril and ramipril, ACE (angiotensin converting enzyme) inhibitors; nifedipine, felodipine, icardipine, icardipine ), Calcium channel blockers such as isradipine, nimodipine, diltiazem and verapamil; and doxazosin, urapidil, prazosin (p α blockers such as razosin and terazosin. Further reference may be made to Remington's “The Science and Practice of Pharmacy” (19 ^th Edition, Gennaro, Ed., Mack Publishing Co., Easton, PA, 1995).

  It is understood that suitable combinations of a compound according to the invention with one or more of the compounds mentioned above and optionally one or more further pharmacologically active substances are considered to be within the scope of the invention. Should be.

  The present invention also provides the above novel compound, derivative thereof, analog thereof, tautomer thereof, stereoisomer, polymorph thereof, pharmaceutically acceptable salt thereof, or pharmaceutically acceptable solvent. It also relates to a method for preparing a Japanese product.

<Pharmaceutical composition>
The compounds of the present invention may be administered alone or in combination with a pharmaceutically acceptable carrier or excipient in a single dose or multiple doses. The pharmaceutical compositions according to the present invention can be prepared using Remington: The Science and Practice of Pharmacy, 19th Edition, Gennaro, Ed., Using pharmaceutically acceptable carriers or diluents and other known adjuvants and excipients. , Mack Publishing Co., Easton, PA, 1995. The composition may be in conventional form, for example in the form of capsules, tablets, aerosols, solutions, suspensions or topical coatings.

  A typical composition is combined with or diluted with a pharmaceutically acceptable excipient (which may be a carrier or diluent) or in the form of a capsule, sachet, paper or other container. A compound of the present invention or a pharmaceutically acceptable acid addition salt thereof is encapsulated in a carrier. In producing the composition, conventional techniques for the preparation of pharmaceutical compositions may be used. For example, typically the active compound will be mixed with or diluted with a carrier or enclosed in a carrier in the form of an ampoule, capsule, sachet, paper or other container. When the carrier acts as a diluent, it can be a solid, semi-solid, or liquid material that acts as a carrier, excipient, or medium for the active compound. The active compound may be adsorbed on a granular solid container, for example a sachet. Some examples of suitable carriers are water, salt solution, alcohol, polyethylene glycol, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, clay, sucrose, cyclodextrin, amylose, magnesium stearate, talc, Gelatin, agar, pectin, acacia, stearic acid or lower alkyl ether of cellulose, silicic acid, fatty acid, fatty acid amine, fatty acid monoglyceride and diglyceride, pentaerythritol fatty acid ester, polyoxyethylene, hydroxymethylcellulose, and polyvinylpyrrolidone. Similarly, the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax. The formulations may also contain wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents and flavoring agents. The formulations of the present invention may be formulated to provide rapid, sustained or delayed release of the active ingredient after administration to a patient by using methods well known in the art.

  The pharmaceutical compositions can be sterilized and, if desired, admixtures such as adjuvants, emulsifiers, salts that affect osmotic pressure, buffers and / or colorants that do not adversely react with the active compound. Good.

  The route of administration is oral, nasal, pulmonary, transdermal, or parenteral (e.g. rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic solution or ointment), Any route that effectively transports the active compound to the appropriate or desired site of action may be used, with the oral route being preferred.

  When a solid carrier is used for oral administration, the preparation may be tableted, placed in a hard gelatin capsule in the form of a powder or pellets, or in the form of a troche or lozenge Good. When a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatin capsule, or sterile injectable solution such as an aqueous or non-aqueous liquid suspension or solution.

  For nasal administration, the formulation can include a compound of the invention dissolved or suspended in a liquid carrier, particularly an aqueous carrier for aerosol application. The carrier may contain additives such as solubilizers (eg, polyethylene glycol), surfactants, eg, absorption enhancers such as lecithin (phosphatidylcholine) or cyclodextrins, or preservatives such as parabens.

  For parenteral application, injectable solutions or suspensions, preferably aqueous solutions in which the active ingredient is dissolved in polyhydroxylated castor oil are particularly preferred.

  For oral application, tablets, dragees or capsules with talc and / or carbohydrate carriers or binders are particularly preferred. Preferred carriers for tablets, dragees or capsules include lactose, corn starch, and / or potato starch. Syrups or elixirs can be used when a sweetened carrier can be used.

Typical tablets that can be prepared by conventional tableting techniques include:
<Core>:
Active compound (as free compound or its salt) 5 mg
Colloidal silicon dioxide (Aerosil) 1.5 mg
Microcrystalline cellulose (Avicel) 70 mg
Modified cellulose gum (Ac-Di-Sol) 7.5 mg
Magnesium stearate Ad.
<Coating>:
HPMC approx. 9 mg
^* Mywacett 9-40 T approx. 0.9 mg
^* Used as a plasticizer for film coating
Acylated monoglycerides If desired, the pharmaceutical compositions of the invention may contain a compound of the invention together with further pharmacologically active substances as described above.

  The compounds of the present invention can be administered to mammals, particularly humans, in need of treatment, prevention, elimination, alleviation, or amelioration of diseases associated with blood glucose regulation.

  Such mammals include both domestic animals such as domestic pets and non-domestic animals such as wild animals.

  The compounds of the present invention are effective over a wide dosage range. A typical oral dosage is about 0.001 to about 100 mg / kg body weight per day, preferably about 0.01 to about 50 mg / kg body weight per day administered in one or more doses, such as 1 to 3 doses, and more Preferably, it is about 0.05 to about 10 mg / kg body weight per day. The exact dosage will depend on the frequency and mode of administration, the gender of the patient to be treated, age, weight and general symptoms, the nature and severity of the symptoms to be treated, and the concomitant diseases to be treated and others apparent to those skilled in the art Will depend on other factors.

  The formulation is conveniently provided in unit dosage form by methods known to those skilled in the art. A typical unit dosage form for oral administration of one or more times per day, for example 1-3 times a day, is 0.05 to about 1000 mg, preferably about 0.1 to about 500 mg, more preferably 0.5 mg to about 200 mg. May be included.

  Any novel feature or combination of features described herein is considered essential to this invention.

  The present invention is illustrated in the following representative examples, which are not intended to limit the scope of the invention in any way.

  The following examples and general procedures refer to intermediate compounds and final products identified herein and in the synthetic schemes. The preparation of the compounds according to the invention is illustrated in detail using the following examples. In some cases, reactions may not be applicable as described for each compound included within the disclosed scope of the invention. Such compounds will be readily recognized by those skilled in the art. In these cases, the reaction can be successfully carried out by conventional changes known to those skilled in the art, i.e., appropriate protection of interfering alkyl groups, changes to other conventional reagents, or routine modification of reaction conditions. Can do. Alternatively, other reactions disclosed herein and other conventional reactions may be applicable to the preparation of the corresponding compounds of the invention. In all preparation methods, all starting materials are known or can be easily prepared from known starting materials. The structure of the compound was confirmed by nuclear magnetic resonance (NMR). The NMR shift (δ) is expressed in parts per million (ppm). Mp is the melting point and is indicated in “° C.”.

Abbreviations used in the examples have the following meanings:
THF: Tetrahydrofuran
DMSO: Dimethyl sulfoxide
CDCl ₃ : Deuterated chloroform
DMF: N, N-dimethylformamide
min: minutes
h: Time.

（式中、Zは上記で定義した通りであり、Hlgは臭素またはヨウ素である）
適切な化合物P（ここでPは不飽和アルコールまたは不飽和エステルである）とを、Pd(PPh₃)₂ またはPdCl₂(PPh₃)₂ のようなPd触媒、および触媒量の例えばヨウ化銅(I)および有機アミン塩基、さらに必要であれば共溶媒を用いた交叉カップリング反応により反応させて、次式(b)の化合物

（式中、ZおよびPは上記で定義した通りであり、Hlgは臭素またはヨウ素である）
を得る。 <General procedure (A)>
Step A:
A compound of the following formula (a):

Where Z is as defined above and Hlg is bromine or iodine.
A suitable compound P (where P is an unsaturated alcohol or unsaturated ester), a Pd catalyst such as Pd (PPh ₃ ) ₂ or PdCl ₂ (PPh ₃ ) ₂ , and a catalytic amount of eg copper iodide; The compound of the following formula (b) is reacted by a cross-coupling reaction using (I) and an organic amine base and, if necessary, a co-solvent.

Where Z and P are as defined above, and Hlg is bromine or iodine.
Get.

（式中、Z, P およびP'は上記で定義した通りである）
を得る。 Step B:
A compound of formula (b) wherein Z and P are as defined above and Hlg is bromine or iodine, and a suitable compound of formula P ′ where P ′ is an unsaturated alcohol. Or an unsaturated ester), a Pd catalyst such as d (PPh ₃ ) ₂ or PdCl ₂ (PPh ₃ ) ₂ , and a catalytic amount of eg copper (I) iodide and an organic amine base, For example, a compound of the following formula (c) is reacted by a cross-coupling reaction using a co-solvent.

(Wherein Z, P and P ′ are as defined above)
Get.

（式中、T, ZおよびUは上記で定義した通りである）
を得る。 Step C:
The compound of formula (c) (wherein P, Z and P ′ are as defined above) is reacted with a reducing agent such as NaBH ₄ or LiBH ₄ to give a compound of formula (d)

(Wherein T, Z and U are as defined above)
Get.

（式中、A, X およびDは上記で定義した通り；但しDは水素ではない）
トリフェニルホスフィン／アゾジカルボン酸ジエチル等のような試薬を使用してMitsunobu条件下で反応させて、次式(f)の化合物：

（式中、A, D, L, T, U, X, およびZは上記で定義した通り；但しDは水素ではない）
を得る。 Step D:
A compound of the above formula (d) (wherein T, Z and U are as defined above) and a compound of the following formula (e):

(Wherein A, X and D are as defined above; however, D is not hydrogen)
A compound of the following formula (f) is reacted under Mitsunobu conditions using a reagent such as triphenylphosphine / diethyl azodicarboxylate and the like:

(Where A, D, L, T, U, X, and Z are as defined above; provided that D is not hydrogen)
Get.

（式中、B, M, YおよびEは上記で定義した通り；但しEは水素ではない）
トリフェニルホスフィン／アゾジカルボン酸ジエチル等のような試薬を使用してMitsunobu条件下で反応させて、前記式(I)の化合物（式中、A, B, D, E, L, M, T, U, X, YおよびZは上記で定義した通り；但しDおよびEは水素ではない）を得る。 Step E:
A compound of the formula (f) (wherein A, D, L, T, U, X, and Z are as defined above; D is not hydrogen) and a compound of the following formula (g):

(Wherein B, M, Y and E are as defined above; however, E is not hydrogen)
The reaction is carried out under Mitsunobu conditions using a reagent such as triphenylphosphine / diethyl azodicarboxylate and the like to form a compound of the above formula (I) wherein A, B, D, E, L, M, T, U, X, Y and Z are as defined above; provided that D and E are not hydrogen.

  Steps D and E are carried out in one step, wherein said compound of formula (I) wherein A and B are the same, D and E are the same, L and M are the same and X and Y May be the same).

（式中、Q, T, U およびZは上記で定義した通りである）
を得る。 <General procedure (B)>
Step A:
The —OH function of the compound of formula (d) (wherein T, Z and U are as defined above) is replaced with p-toluenesulfonate, methanesulfonate, halogen (eg by the following method: Houben- Weyl, Methoden der organischen Chemie, Alkohole III, 6 / 1b, Thieme-Verlag 1984, 4th Ed., Pp. 927-939; Comprehensive Organic Transformations. Aguide to functionalgroup preparations, VCH Publishers 1989, 1 ^st Ed., Pp. 353 -363 and J. Org. Chem., Vol. 36 (20), 3044-3045, 1971), converted to a suitable leaving group (Q) such as triflate, etc. :

(Where Q, T, U and Z are as defined above)
Get.

（式中、A, D, L, Q, T, U, X, およびZは上記で定義した通り；
但しDは水素ではない）
を得る。 Step B:
Said formula (h) wherein Q is a leaving group such as p-toluenesulfonate, methanesulfonate, halogen, triflate and the like, T, U and Z are as defined above, Reacting with a compound of formula (e) (wherein A, L, X and D are as defined above; where D is not hydrogen);

Where A, D, L, Q, T, U, X, and Z are as defined above;
D is not hydrogen)
Get.

Step C:
A compound of formula (i) wherein Q is a leaving group such as p-toluenesulfonate, methanesulfonate, halogen, triflate and the like, and A, D, L, Q, T, U, X, and Z is as defined above) and is reacted with a compound of formula (g) wherein B, M, Y and E are as defined above; provided that E is not hydrogen. A compound of formula (I) is obtained, wherein A, B, D, E, L, M, T, U, X, Y and Z are as defined above; provided that D and E are not hydrogen.

  Steps B and C are carried out in one step, wherein said compound of formula (I) wherein A and B are the same, D and E are the same, L and M are the same, X and Y are May be obtained).

<General procedure (C)>
Step A:
A compound of formula (I) wherein A, B, D, E, L, M, T, U, X, Y and Z are as defined above; provided that D and E are not hydrogen; After saponification by chemical action or enzymatic action, the compound of the above formula (I) (wherein A, B, L, M, T, U, X, Y and Z are as defined above, D and E Is hydrogen).

<General procedure (D)>
Step A:
A compound of formula (I) wherein A, B, D, E, L, M, T, U, X, Y and Z are as defined above; provided that D and E are not hydrogen; Hydrolysis using an aqueous NaOH solution or the like, the compound of formula (I) (wherein A, B, L, M, T, U, X, Y and Z are as defined above, D and E is hydrogen).

（式中、T', R₁ およびZは上記で定義した通りであり、Hlgは臭素または
ヨウ素である）
を得る。 <General procedure (E)>
Step A:
The compound of formula (a) (wherein Z is as defined above and Hlg is bromine or iodine) is converted to a compound of formula HO-T′-HNR ₁ (wherein T ′ and R ₁ Is as defined above) and a compound of formula (j):

Where T ′, R ₁ and Z are as defined above, and Hlg is bromine or iodine.
Get.

（式中、T', R_1, U', Z は上記で定義した通りである）
を得る。 Step B:
The compound of formula (j) (wherein T ′, R ₁ and Z are as defined above and Hlg is bromine or iodine) is converted to the compound of formula HO—U′-HNR ₁ (wherein , U ′ and R ₁ are as defined above) and a compound of formula (k):

(Where T ', R _1, U', and Z are as defined above)
Get.

（式中、A, D, L, R_1, T', U', X, およびZは上記で定義した通り；
但しDは水素ではない）
を得る。 Step C:
The compound of formula (k) (wherein T ′, Z and U ′ are as defined above) and the compound of formula (e) (where A, X and D are as defined above) And D is not hydrogen) using a reagent such as triphenylphosphine / diethyl azodicarboxylate and the like under Mitsunobu conditions to give a compound of formula (m):

Wherein A, D, L, R _1, T ′, U ′, X, and Z are as defined above;
D is not hydrogen)
Get.

（式中、A, B, D, E, L, M, T', R₁, U', X, YおよびZは上記で定義した通り；
但しDおよびEは水素ではない）
を得る。 Step D:
A compound of formula (m) wherein A, D, L, T ′, R ₁ , U ′, X, and Z are as defined above; provided that D is not hydrogen; (Wherein B, M, Y and E are as defined above; where E is not hydrogen) using a reagent such as triphenylphosphine / diethyl azodicarboxylate under Mitsunobu conditions The compound of the following formula (n):

Wherein A, B, D, E, L, M, T ′, R ₁ , U ′, X, Y and Z are as defined above;
D and E are not hydrogen)
Get.

  Steps D and E are carried out in one step and a compound of formula (n) wherein A and B are the same, D and E are the same, L and M are the same, and X and Y are the same May be obtained).

ステップ１：
o-クレゾール(100g, 0.925mol)を2-ブタノン(1200mL)中に溶解させ、炭酸カリウム(191.7g, 1.5mol)およびブロモ酢酸エチル(162.2g, 0.971mol)を添加し、該混合物を撹拌しながら24ｈ還流させ、次いで一晩静置した。固体を濾過除去し、濾液を蒸発させ、ベンゼン(400mL)中に溶解させた。該溶液を水(200mL)、炭酸ナトリウム(100mL)の5％溶液で洗浄し、MgSO₄上で乾燥させた。残渣(ca 200g)を真空下で蒸留させた。これにより161.9g(90.1％)の(2-メチル-フェノキシ)-酢酸 エチルエステル, 沸点 120-130℃／2kPaを得た。 Intermediate 1:
(4-Mercapto-2-methyl-phenoxy) -acetic acid methyl ester

Step 1:
o-Cresol (100 g, 0.925 mol) is dissolved in 2-butanone (1200 mL), potassium carbonate (191.7 g, 1.5 mol) and ethyl bromoacetate (162.2 g, 0.971 mol) are added and the mixture is stirred. The mixture was refluxed for 24 hours, and then allowed to stand overnight. The solid was filtered off and the filtrate was evaporated and dissolved in benzene (400 mL). The solution was washed with 5% solution of water (200 mL), sodium carbonate (100 mL) and dried over MgSO ₄ . The residue (ca 200g) was distilled under vacuum. This gave 161.9 g (90.1%) of (2-methyl-phenoxy) -acetic acid ethyl ester, boiling point 120-130 ° C./2 kPa.

Step 2:
Chlorosulfonic acid (180.9 g, 104 mL, 1.553 mol) was cooled to −2 to 0 ° C., then the above (2-methyl-phenoxy) -acetic acid ethyl ester (75.35 g, 0.388 mol) was stirred and reacted. The mixture was added dropwise (20 minutes) at a rate such that the temperature did not exceed 0 ° C. The mixture was allowed to warm to ambient temperature (1 h) and then poured onto crushed ice (1 kg). The crystalline product was filtered off, washed with water (500 mL) and dried in air until the weight was constant. This gave 108.4 g (95.5%) of crude (4-chlorosulfonyl-2-methylphenoxy) -acetic acid ethyl ester. The product was crystallized from cyclohexane (500 mL) to give 73.3 g (64.6%) pure product. Melting point 86-89 ° C.

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.84 (m, 2H); 6.80 (m, 1H); 4.76 (s, 2H); 4.29 (q, J = 7.1 Hz); 2.37 (s, 3H); 1.31 (s, 3H).

Step 3:
To the above mixture, the above-mentioned sulfochloride (97.7 g, 0.333 mol), tin (189.9 g, 1.59 mol) and methanol (170 mL) were added dropwise for 20 minutes with vigorous stirring. The reaction exothermed and began to reflux spontaneously. The reaction mixture was further heated to reflux for 3 hours, then cooled and poured onto crushed ice (1 kg). The mixture was extracted with diethyl ether (3 × 200 mL) and the ether solution was washed with water (2 × 80 mL), dried over MgSO ₄ and evaporated under vacuum. The residue (97.7 g) was dissolved in benzene (300 mL), passed through a column of silica gel (Fluka 60, 800 g), and the column was washed with benzene (2500 mL). The collected benzene solution was evaporated and the residue was distilled under vacuum. This gave 41.3 g (58.4%) of (4-mercapto-2-methylphenoxy) -acetic acid methyl ester as an oil, boiling point 136.5-137 ° C./133 Pa.

¹ H NMR (250 MHz, CDCl ₃ ): δ 7.04 (m) +7.04 (m), Σ 2 H; 6.54 (m, 1H); 2.20 (m, 3H); 4.56 (s, 2H); 3.73 ( s, 3H); 3.34 (s, 1H).

方法Ａ：
ステップ１：
ジオキサン(640mL)中の3-(4-ヒドロキシフェニル)-2-エトキシプロパンエチル(100.8g, 0.423mol)、トリエチルアミン(83.4g, 115mL, 0.824mol)、4-ジメチルアミノピリジン(5.2g, 42.3mmol)および塩化ジメチルチオカルバモイル(62.6g, 0.507mol)の混合物を撹拌し、100℃で10h窒素雰囲気下にて雰囲気下で加熱した。固体を濾過除去し、ジオキサンで洗浄し、濾液を真空下で蒸発させた。残渣をジクロロメタン(600mL)中に溶解させ、この溶液を水で洗浄し(3×250mL)、乾燥させ(MgSO₄)、シリカゲル(Fluka 60, 500g)のカラムを通過させた。該カラムを500mLジクロロメタンで洗浄し、回収したジクロロメタン溶液を蒸発させて140.1g(~100％)の 3-(4-ジメチルチオカルバモイルオキシ-フェニル)-2-エトキシ-プロピオン酸エチルエステルを油状物として得、これを次の工程に用いた。 Intermediate 2
2-Ethoxy-3- (4-mercapto-phenyl) -propionic acid methyl ester

Method A:
Step 1:
3- (4-hydroxyphenyl) -2-ethoxypropaneethyl (100.8 g, 0.423 mol), triethylamine (83.4 g, 115 mL, 0.824 mol), 4-dimethylaminopyridine (5.2 g, 42.3 mmol) in dioxane (640 mL) ) And dimethylthiocarbamoyl chloride (62.6 g, 0.507 mol) were stirred and heated at 100 ° C. under a nitrogen atmosphere for 10 h under an atmosphere. The solid was filtered off and washed with dioxane and the filtrate was evaporated under vacuum. The residue was dissolved in dichloromethane (600 mL) and the solution was washed with water (3 × 250 mL), dried (MgSO ₄ ) and passed through a column of silica gel (Fluka 60, 500 g). The column was washed with 500 mL dichloromethane and the collected dichloromethane solution was evaporated to give 140.1 g (~ 100%) of 3- (4-dimethylthiocarbamoyloxy-phenyl) -2-ethoxy-propionic acid ethyl ester as an oil. This was used in the next step.

Step 2:
A mixture of the above compound (140 g, 0.423 mol) and tetradecane (1000 mL) was vigorously stirred at 230-245 ° C. for 8 h under an argon atmosphere. The reaction mixture was cooled, the tetradecane phase was separated, and the residue was decanted using n-hexane (2 × 150 mL). This residue was dissolved in benzene (150 mL) and passed through a silica gel column (Fluka 60, 600 g). The column was washed with benzene (4000 mL) and the collected benzene solution was evaporated under vacuum. This gave 90.2 g (65.5%) of 3- (4-dimethylcarbamoylsulfanyl-phenyl) -2-ethoxypropionic acid ethyl ester as a solid.

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.41 (d, J = 4.5 Hz, 2H); 7.26 (d, J = 4.5 Hz, 2H); 4.15 (q, J = 7.2 Hz, 2H); 3.99 ( 3.59 (quint, 1H); 3.33 (quint, 1H); 2.99 (m, 6H); 1.23 (t, J = 7.1Hz, 3H); 1.17 (t, J = 7.1 Hz, 3H).

Step 3:
A solution of the above ester (90.0 g, 0.2765) in tetrahydrofuran (370 mL) was cooled to 10 ° C. An 85% solution of potassium hydroxide (58.4 g, 0.885 mol) in methanol (150 mL) was added dropwise and the reaction mixture was stirred at ambient temperature for 15 h. Diethyl ether (250 mL) and water (250 mL) were added and the mixture was acidified with stirring with 15% hydrochloric acid (pH = 1) while cooling. The ether phase was separated and the aqueous phase was extracted with diethyl ether (3 × 250 mL). The collected organic solution was washed with water (2 × 100 mL), brine (80 mL), dried (MgSO ₄ ) and evaporated under vacuum. The residue was purified by chromatography (silica gel Fluka 60, 600 g). Elute with chloroform (2000 mL), then elute with a mixture of chloroform / methanol 95: 5 (1000 mL) to give 64 g (~ 100%) of 2-ethoxy-3- (4-mercapto-phenyl)- Propionic acid was obtained as a solid.

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.17 (m, 2H); 7.11 (m, 2H); 4.01 (dd, 1H); 3.62 (dq, 1H); 3.38 (dq, 1H); 3.42 (s , 1H); 2.98 (m, 2H); 1.15 (t, 3H).

Step 4:
A gas stream of hydrogen chloride was introduced into a solution of the above acid (56.1 g, 0.248 mol) in methanol (450 mL) and benzene (90 mL) at 30-35 ° C. for 6 h. The reaction mixture was left overnight, diluted with benzene (400 mL) and poured onto crushed ice (500 g). The benzene phase was separated and the aqueous phase was extracted with diethyl ether (2 × 200 m). The collected organic phase was washed with water (4 × 150 mL), dried over MgSO ₄ , filtered through silica gel (60 g) and evaporated. The residue was distilled under vacuum to give 48.4 g (81.2%) of the title compound. Boiling point 130 ° C / 200Pa.

¹ H NMR (250 MHz, CDCl ₃ ): δ 7.18 (m, 2H); 7.09 (m, 2H); 3.43 (s, 1H); 2.94 (m, 2H); 3.99 (dd, J = 5.6 and 7.4 Hz 3.68 (s, 3H); 3.32 (dqua, J = 7.0 and 9.10Hz, 1H); 3.59 (dqua, J = 7.0 and 9.14Hz, 1H); 1.14 (t, J = 7.0Hz, 3H) .

Method B:
Step 1:
A solution of ethyl 2-ethoxycinnamate (53.9 g, 0.267 mol; prepared as described in Justus Liebigs Ann. Chem. 699, 53 (1966)) in ethanol (500 mL) at ambient temperature is activated carbon (5.0 g) Hydrogenation was carried out in the presence of 5% palladium above under a pressure of 10 atm until hydrogen absorption ceased. The catalyst was removed by filtration and the filtrate was evaporated to give 52.8 g (97%) of ethyl 2-ethoxy-3-phenylpropionate as a solid.

Step 2:
Chlorosulfonic acid (110.8 g, 0.95 mol) was cooled to −2 to 0 ° C., and then this was the rate at which the temperature of the reaction mixture did not exceed 0 ° C. while stirring the ester (52.8 g, 0.238 mol). Was added dropwise (20 minutes). The mixture was stirred for 1 h, poured into crushed ice (1 kg) and extracted with dichloromethane (300 mL). The organic phase was dried (MgSO ₄ ) and evaporated. This gave 36.6 g (43.7%) of crude 3- (4-chlorosulfonylphenyl) -2-ethoxypropionic acid ethyl ester, which was used in the next step without purification.

Step 3:
Concentrated hydrochloric acid was added dropwise thereto over 20 minutes while vigorously stirring the above mixture of sulfochloride (36.6 g, 0.114 mol), tin (65.4 g, 0.55 gat) and methanol (60 mL). The reaction became exothermic and began to reflux spontaneously. The reaction mixture was heated to reflux for an additional 3 hours, then cooled and poured onto crushed ice (1 kg). The mixture was extracted with dichloromethane (2 × 200 mL) and the organic phase was washed with water (2 × 80 mL), dried over MgSO ₄ and evaporated under vacuum. The residue was dissolved in benzene (100 mL), passed through a column of silica gel (Fluka 60, 300 g) and the column was washed with benzene (750 mL). The collected benzene solution was evaporated and the residue was evaporated under vacuum. This gave 14 g (51%) of the title compound as an oil. Boiling point 136.5-137 ° C / 133Pa.

ステップ１：
4-アセトキシ-2,6-ジフェニルフェノール(6.1g, 20mmol；Ber. 101, 2519(1968)に記載の通りに調製)、ブロモ酢酸エチル(4.0g, 24mmol)、炭酸カリウム(3.3g, 24mmol)および2-ブタノン(150mL)の混合物を24ｈ還流させ、次いで濾過し、溶媒を蒸発させた。残渣をシリカゲル(120g, 溶出剤 ベンゼン)上のクロマトグラフィにより精製して、7.2g(92％)の油状の4-アセトキシ-2,6-ジフェニルフェノキシ酢酸エチルを得た。 Intermediate 3
2,6-diphenyl-4-hydroxyphenoxyacetic acid ethyl ester

Step 1:
4-acetoxy-2,6-diphenylphenol (6.1 g, 20 mmol; prepared as described in Ber. 101, 2519 (1968)), ethyl bromoacetate (4.0 g, 24 mmol), potassium carbonate (3.3 g, 24 mmol) And a mixture of 2-butanone (150 mL) was refluxed for 24 h, then filtered and the solvent was evaporated. The residue was purified by chromatography on silica gel (120 g, eluent benzene) to give 7.2 g (92%) of oily 4-acetoxy-2,6-diphenylphenoxyethyl acetate.

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.64 (m, 4H); 7.37 (m, 6H); 7.08 (s, 2H); 3.93 (q, J = 7.1, 2H); 3.79 (s, 2H) 1.07 (t, J = 7.1, 3H).

Step 2:
The above ester (7.2 g, 18.5 mmol) was dissolved in wet toluene (400 mL) and the catalyst (25 g SiO ₂ was treated with a solution of 2 g 4-toluenesulfonic acid in 10 mL acetone and evaporated under vacuum. ) Was added. The mixture was stirred and heated at 100 ° C. for 6 h, cooled and filtered through a silica gel column (50 g). Elution with benzene gave 3.6 g (56%) of the title compound as white crystals, which were recrystallized from benzene / petroleum ether. Melting point 91-93 ° C.

¹ H NMR (250 MHz, CDCl ₃ ): δ 1.05 (t, J = 7.2 Hz, 3H); 3.92 (q, J = 7.2 Hz, 2H); 3.73 (s, 2H); 6.82 (s, 2H); 7.60 (m, 4H); 7.35 (m, 6H).

ステップＡ-Ｂ：
2,6-ジブロモピリジン(82.9g, 0.35mol)および2-(メチルアミノ)エタノール(525.8g, 7mol)の混合物を、120-140℃で20ｈ撹拌した。酢酸エチル(900mL)および水(600mL)を撹拌しながら添加し、有機相を分離し、水相を酢酸エチルで抽出した(5×250mL)。回収した有機相を塩水(80mL)で洗浄し、MgSO₄上で乾燥させ、蒸発させて500mLの体積にし、シリカゲル(Fluka 60, 600g)のカラムを通過させた。該カラムを酢酸エチル(2.5L)で洗浄し、回収した溶液を蒸発させ、真空下で乾燥させた。これにより68.6g(86.2％)の標題化合物を固体で得た。 Intermediate 4 (General Procedure E)
2-({6-[(2-hydroxy-ethyl) -methyl-amino] -pyridin-2-yl} -methyl-amino) -ethanol

Step AB:
A mixture of 2,6-dibromopyridine (82.9 g, 0.35 mol) and 2- (methylamino) ethanol (525.8 g, 7 mol) was stirred at 120-140 ° C. for 20 h. Ethyl acetate (900 mL) and water (600 mL) were added with stirring, the organic phase was separated and the aqueous phase was extracted with ethyl acetate (5 × 250 mL). The collected organic phase was washed with brine (80 mL), dried over MgSO ₄ , evaporated to a volume of 500 mL and passed through a column of silica gel (Fluka 60, 600 g). The column was washed with ethyl acetate (2.5 L) and the collected solution was evaporated and dried under vacuum. This gave 68.6 g (86.2%) of the title compound as a solid.

¹ H NMR (250 MHz, CDCl ₃ ): δ 7.26 (t, J = 8.0 Hz, 1H); 5.79 (d, J = 8.1 Hz, 2H); 4.49 (bs, 2H); 3.74 (m, 4H); 3.61 (m, 4H); 2.97 (s, 6H).

ステップ１：
2,2'-Bisトリフルオロメチル-4,4'-ジアミノビフェニル(42,6g, 133mmol；J. Chem. Soc.で 1951, 3459に記載の通りに調製)を、酢酸(300mL)中に溶解させ、濃硫酸(50mL)を添加した。得られた懸濁物を、50mLの水中において5℃で1h、NaNO₂(20.2g, 293mmol)を用いてジアアゾ化し、次いで濾過し、800mL水中のKI(220g, 1.35mol)の溶液に注いだ。この混合物を３ｈ撹拌し、ベンゼン(300mL)で抽出し、5％ NaHSO₃で洗浄し、乾燥させ(MgSO₄)、ベンゼンを真空下で蒸発させた。残渣をシリカゲル上でのクロマトグラフィにより精製し、56.5g(78.4％)の2,2'-bisトリフルオロメチル-4,4'-ジヨードビフェニルを得た。融点 119-120℃。 Intermediate 5 (General Procedure A)
3- [4 '-(3-Hydroxy-propyl) -2,2'-bis-trifluoromethyl-biphenyl-4-yl] -propan-1-ol

Step 1:
2,2′-Bis trifluoromethyl-4,4′-diaminobiphenyl (42,6 g, 133 mmol; prepared as described in J. Chem. Soc. As 1951, 3459) dissolved in acetic acid (300 mL) And concentrated sulfuric acid (50 mL) was added. The resulting suspension was diazotized with NaNO ₂ (20.2 g, 293 mmol) in 50 mL water at 5 ° C. for 1 h, then filtered and poured into a solution of KI (220 g, 1.35 mol) in 800 mL water. . The mixture was stirred for 3 h, extracted with benzene (300 mL), washed with 5% NaHSO ₃ , dried (MgSO ₄ ) and the benzene evaporated in vacuo. The residue was purified by chromatography on silica gel to give 56.5 g (78.4%) of 2,2′-bistrifluoromethyl-4,4′-diiodobiphenyl. Melting point 119-120 ° C.

Step AB:
The above diiodo derivative (56.5 g, 104.3 mmol), palladium (II) acetate (0.7 g, 3.1 mmol), triphenylphosphine (2.1 g, 8 mmol), triethylamine (20 g, 198 mmol) and methyl acrylate (120 mL) in 120 mL dimethylformamide 28 g, 325 mmol) was heated at 110 ° C. for 5 h. The reaction mixture was poured into water, extracted with benzene, dried (MgSO ₄ ) and evaporated under vacuum. The residue was chromatographed on silica gel (benzene / chloroform). In the first fraction, 10.7 g (27.4%) of 3- (2,2′-bistrifluoromethylbiphenyl-4-yl) acrylic acid was obtained. Melting point 97-98 ° C. (cyclohexane). In the next fraction, 18.3 g (38.3%) of 2,2′-bistrifluoromethylbiphenyl-4,4′-diacrylic acid dimethyl ester was obtained. Melting point 158-161 ° C (cyclohexane).

Step C:
2,2′-Bis trifluoromethylbiphenyl-4,4′-diacrylic acid dimethyl ester (11.5 g, 25.1 mmol) was dissolved in 200 mL polyethylene glycol (PEG 400) and sodium borohydride (6.5 g, 172 mmol). ) Was gradually added at 130 ° C for 30 minutes. The mixture was heated at this temperature for 6 h. After cooling, water was added and the mixture was extracted with chloroform, dried (MgSO ₄ ) and evaporated to give a residue that was chromatographed on silica gel. Elution with ethyl acetate gave 3.57 g (35%) of the title compound as a solid.

¹ H NMR (250 MHz, CDCl ₃ ): δ 7.55 (d, J = 1.4 Hz, 2H); 7.35 (dd, J = 1.4 and 7.7 Hz, 2H); 7.18 (d, J = 7.7 Hz, 2H); 3.72 (t, J = 6.3 Hz, 4H); 2.83 (t, J = 7.8 Hz, 4H); 1.96 (m, 4H); 1.65 (bs, 2H).

ステップＣ：
3,3'-Bisトリフルオロメチルビフェニル-4,4'-ジアクリル酸ジメチルエステル(12.3g, 26.8mmol；中間体５, ステップＡ−Ｂの2,2'-異性体と同様に調製)を、200mL ポリエチレングリコール(PEG 400)中に溶解させ、ホウ水素化ナトリウム(7.4g, 196mmol)を、30分 130℃で徐々に添加した。該混合物をこの温度で６ｈ加熱し、冷却後に水を添加し、該混合物をクロロホルムで抽出した。クロロホルム抽出物を乾燥させ(MgSO₄)、蒸発させて残渣を得、これをシリカゲル上でのクロマトグラフィに供した。酢酸エチルを用いた溶出により、1.85gの標題化合物を白色の結晶で得た。融点 87.5-90℃(シクロヘキサン)。 Intermediate 6 (General Procedure A)
3- [4 '-(3-Hydroxy-propyl) -3,3'-bis-trifluoromethyl-biphenyl-4-yl] -propan-1-ol

Step C:
3,3′-Bis trifluoromethylbiphenyl-4,4′-diacrylic acid dimethyl ester (12.3 g, 26.8 mmol; prepared in the same manner as the 2,2′-isomer of Intermediate 5, Step AB), Dissolved in 200 mL polyethylene glycol (PEG 400) and sodium borohydride (7.4 g, 196 mmol) was added slowly at 130 ° C. for 30 minutes. The mixture was heated at this temperature for 6 h, after cooling water was added and the mixture was extracted with chloroform. The chloroform extract was dried (MgSO ₄ ) and evaporated to give a residue that was chromatographed on silica gel. Elution with ethyl acetate gave 1.85 g of the title compound as white crystals. Melting point 87.5-90 ° C. (cyclohexane).

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.78 (s, 2H); 7.63 (d, J = 8.2 Hz, 2H); 7.42 (d, J = 8.2 Hz, 2H); 3.75 (t, J = 6.4 Hz, 4H); 2.92 (t, J = 7.9 Hz, 4H); 2.17 (bs, 2H); 1.93 (m, 4H).

塩化メチレン(75mL)中の(S)-2-エトキシ-3-(4-ヒドロキシ-フェニル)-プロピオン酸イソプロピルエステル(7.56g, 30mmol)の溶液に、塩化メチレン(30mL)中のBr₂ の溶液を、窒素下において室温で滴下添加した。該反応物を60分撹拌した後、Na₂SO₃飽和水溶液(50mL)を添加した。塩化メチレン(100mL)を添加し、メチレン相を分離した。有機相を塩水(50mL)で洗浄し、乾燥させて蒸発させた。残渣を、ヘプタン：酢酸エチル(3：1)を溶出剤として用いたカラムクロマトグラフィにより精製した。標題化合物を8.91g(90％)の収量で単離した。 Intermediate 7
(S) -3- (3-Bromo-4-hydroxy-phenyl) -2-ethoxy-propionic acid isopropyl ester

To a solution of (S) -2-ethoxy-3- (4-hydroxy-phenyl) -propionic acid isopropyl ester (7.56 g, 30 mmol) in methylene chloride (75 mL), a solution of Br _{2 in} methylene chloride (30 mL) Was added dropwise at room temperature under nitrogen. The reaction was stirred for 60 minutes before adding saturated aqueous Na ₂ SO ₃ (50 mL). Methylene chloride (100 mL) was added and the methylene phase was separated. The organic phase was washed with brine (50 mL), dried and evaporated. The residue was purified by column chromatography using heptane: ethyl acetate (3: 1) as eluent. The title compound was isolated in a yield of 8.91 g (90%).

ステップＡ−Ｂ：
2,7-ジブロモフルオレン(48.6g, 0.15mol, Ber. 53, 1236(1920))、酢酸パラジウム(II)(1.0g, 4.45mmol)、トリフェニルホスフィン(3.0g, 11.4mmol)、トリエチルアミン(30.3g, 0.3mol)、アクリル酸メチル(38.7g, 0.45mol)およびジメチルホルムアミド(150mL)の混合物を撹拌し、110℃で７ｈ加熱した。この混合物を水(1000mL)中に注ぎ、得られた固体を濾過除去し、クロロホルムから再結晶化させて、36.8g(73.9％)の フルオレン-2,7-ジアクリル酸ジメチルエステルを得た。融点 206-209℃。 ¹ H NMR (300 MHz, CDCl ₃ ): δ 7.37 (s, 1H); 7.10 (d, J = 8 Hz, 1H); 6.93 (d, J = 8 Hz, 1H); 5.05 (m, 1H); 3.93 ( t, J = 6 Hz, 1H); 3.63 (m, 1H); 3.35 (m, 1H); 2.92 (d, J = 6 Hz, 2H); 1.30-1.14 (m, 9H).
Intermediate 8 (General Procedure A)
3- [7- (3-Hydroxy-propyl) -9H-fluoren-2-yl] -propan-1-ol

Step AB:
2,7-dibromofluorene (48.6 g, 0.15 mol, Ber. 53, 1236 (1920)), palladium (II) acetate (1.0 g, 4.45 mmol), triphenylphosphine (3.0 g, 11.4 mmol), triethylamine (30.3 g, 0.3 mol), methyl acrylate (38.7 g, 0.45 mol) and dimethylformamide (150 mL) were stirred and heated at 110 ° C. for 7 h. The mixture was poured into water (1000 mL) and the resulting solid was filtered off and recrystallized from chloroform to give 36.8 g (73.9%) of fluorene-2,7-diacrylic acid dimethyl ester. Melting point 206-209 ° C.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.96 (m, 4H); 7.75 (m, 2H); 7.73 (d, J = 15.9 Hz, 2H); 6.69 (d, J = 15.9 Hz, 2H) 3.98 (s, 2H); 3.73 (s, 6H).

Step C:
To a mixture of sodium borohydride (3.7 g, 98 mmol) and lithium chloride (4.2 g, 101 mmol) in ethanol (70 mL) with stirring at 5 ° C. for 15 min, 9H-fluorene in diglyme (150 mL) -2,7-Diacrylic acid dimethyl ester (5.0 g, 15 mmol) was added in several portions at 20-50 ° C. and the mixture was refluxed for 18 h. After cooling, diluted hydrochloric acid was added dropwise and the mixture was extracted with diethyl ether. The organic phase was separated, dried (MgSO ₄ ) and evaporated to give a residue that was purified by chromatography on silica gel. Elution with ethyl acetate gave 1.85 g (44%) of the title compound as white crystals. Melting point 160-180 ° C.

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.65 (d, J = 7.0 Hz, 2H); 7.35 (s, 2H); 7.18 d, J = 7.7 Hz, 2H); 3.84 (s, 2H); 3.71 (t, J = 6.3 Hz, 4H); 2.78 (t, J = 7.6 Hz, 4H); 1.95 (m, 4H); 1.59 (bs, 2H).

ステップ１：
水(1 500mL)中のカルボン酸ナトリウム(62.8g, 0.592mol)の溶液を、ジオキサン(600mL)中の4-ベンジル-L-アスパラギン酸塩(89.6g, 0.4mol)の懸濁液に添加し、該混合物を、透明な溶液が得られるまで撹拌した(30分)。ジオキサン(400mL)中の塩化テレフタロイル(40.4g, 0.199mol)の溶液を周囲温度で２ｈ滴下添加し、該反応混合物を周囲温度でさらに３ｈ撹拌し、次いで一晩静置した。溶液をジエチルエーテルで洗浄し(2×500mL)、10％ 塩酸を用いてpH＝2にまで酸性にし、生成物をジクロロメタンで抽出した(3×500mL)。回収した濾液を水(200mL)、塩水(100mL)で洗浄し、MgSO₄で乾燥させ、真空下で蒸発させて、128.8g(56.7％)の 2-[3-(2-ベンジルオキシカルボニル-1-カルボキシ-エチルカルバモイル)-ベンゾイルアミノ]-スクシン酸 4-ベンジルエステルを白色の固体として得た。 Intermediate 9
2- (2- {3- [4- (2-hydroxy-ethyl) -5-methyl-oxazol-2-yl] -phenyl} -5-methyl-oxazol-4-yl) -ethanol

Step 1:
A solution of sodium carboxylate (62.8 g, 0.592 mol) in water (1 500 mL) is added to a suspension of 4-benzyl-L-aspartate (89.6 g, 0.4 mol) in dioxane (600 mL). The mixture was stirred until a clear solution was obtained (30 minutes). A solution of terephthaloyl chloride (40.4 g, 0.199 mol) in dioxane (400 mL) was added dropwise at ambient temperature for 2 h and the reaction mixture was stirred at ambient temperature for an additional 3 h and then allowed to stand overnight. The solution was washed with diethyl ether (2 × 500 mL), acidified with 10% hydrochloric acid to pH = 2 and the product was extracted with dichloromethane (3 × 500 mL). The collected filtrate was washed with water (200 mL), brine (100 mL), dried over MgSO ₄ and evaporated in vacuo to give 128.8 g (56.7%) of 2- [3- (2-benzyloxycarbonyl-1 -Carboxy-ethylcarbamoyl) -benzoylamino] -succinic acid 4-benzyl ester was obtained as a white solid.

¹ H NMR (250 MHz, DMSO-d ₆ ): δ 9.03 (d, J = 8.0 Hz, 2H); 8.37 (m, 1H); 8.00 (dd, J = 1.6 and 7.8 Hz, 2H); 7.63 (m 5.14 (s, 4H); 4.89 (m, 2H); 3.05 (dd, J = 5.7 and 16.2 Hz, 2H); 2.9 (dd, J = 8.4 and 16.2 Hz, 2H).

Step 2:
Acetic anhydride (600 mL) was added dropwise over 1.5 h to a solution of the above diester (110.5 g, 0.191 mol) in pyridine (600 mL) and the reaction mixture was stirred at 95 ° C. for 2 h. The dark solution was cooled to 80 ° C., and water (325 mL) was added dropwise (30 minutes) at a rate that allowed the mixture to vigorously reflux, then warmed to reflux for an additional 30 minutes and allowed to stand overnight. The reaction mixture was acidified with 10% hydrochloric acid (1800 mL), extracted with ethyl acetate (1000 mL, 2 × 500 mL), the collected extracts were washed with water (200 mL), dried, MgSO ₄ , under vacuum Evaporate 97.1 g (88.8%) of crude 3- [3- (1-benzyloxycarbonylmethyl-2-oxo-propylcarbamoyl) -benzoylamino] -4-oxo-pentanoic acid benzyl ester as an oil Which was used directly in the next step.

Step 3:
The above compound (95.0 g, 0.166 mol) was dissolved in toluene (1000 mL), phosphorus oxychloride (320 mL) was added and the mixture was stirred at reflux for 4 h. After standing overnight, the mixture was poured into ice (3 kg) and neutralized with solid potassium carbonate (1.6 kg) with stirring. The mixture was extracted with diethyl ether (3 × 600 mL) and the extract was washed with brine (2 × 200 mL), dried (MgSO ₄ ) and evaporated under vacuum. The residue (106 g) was subjected to chromatography on a column of SiO ₂ (Fluka 60, 1000 g).

  By-product (10.5g) was obtained by elution with benzene, and 22.8g (25.6%) of {2- [3- (4-benzyloxycarbonylmethyl-5] was obtained by elution with benzene / ethyl acetate (9: 1). -Methyl-oxazol-2-yl) -phenyl] -5-methyl-oxazol-4-yl} -acetic acid benzyl ester was obtained. Melting point 98-100 ° C.

Step 4:
A solution of the above diester (21.4 g, 39.8 mmol) in tetrahydrofuran (800 mL) was added dropwise to a suspension of lithium aluminum hydride (3.0 g, 79.7 mmol) in diethyl ether (200 mL) at 0 ° C. for 60 min. did. The mixture was stirred for 30 minutes at the same temperature, stirred for 4 h at ambient temperature and then allowed to stand overnight. The reaction mixture was destroyed by sequential addition of water (3 mL), 15% sodium hydroxide solution (3 mL), and water (10 mL). The suspension was stirred at ambient temperature for 3 h, the solid was filtered off and washed with tetrahydrofuran (100 mL) and ethyl acetate (300 mL). The collected filtrate was dried (MgSO ₄ ) and evaporated. The residue was subjected to (23 g) chromatography (silica gel Fluka 60, 500 g). Elution with ethyl acetate and ethanol (95: 5) gave the title product (10.1 g, 77.2%), mp 134-135 ° C.

¹ H NMR (250 MHz, DMSO-d ₆ ): δ 8.41 (s, 1H); 7.98 (d, J = 7.8 Hz, 2H); 7.67 (t, J = 7.7 Hz, 1H); 4.68 (t, J = 5.4 Hz, 2H); 3.67 (q, J = 6.6 Hz, 4H); 2.64 (t, J = 6.7 Hz, 4H); 2.38 (s, 6H).

ステップ１：
L-アスパラギン酸 4-ベンジルエステル(78.1g, 0.35mol)をジオキサン(1000mL)中に懸濁させ、水(1200mL)中の炭酸ナトリウム(56g, 0.52mol)の溶液および該混合物を１ｈ撹拌した。この混合物に、ビフェニル-4,4'-ジカルボニル二塩化物 (48.9g, 0.175mol)を数回に分けて２ｈ添加し、該反応混合物を周囲温度で３ｈ撹拌した。水を添加し(350mL)、該混合物を一晩静置し、次いで、ジエチルエーテルで洗浄した(3×350mL)。水相を10％ 塩酸で酸性にし、沈殿した固体を濾過し、水で洗浄して乾燥させた。粗製の2-{[4'-(2-ベンジルオキシカルボニル-1-カルボキシ-エチルカルバモイル)-ビフェニル-4-カルボニル]-アミノ}-スクシン酸 4-ベンジルエステルの収量は69.5g(60.8％)であった。融点 204-207℃。 Intermediate 10
2- (2- {4 '-[4- (2-hydroxy-ethyl) -5-methyl-oxazol-2-yl] -biphenyl-4-yl} -5-methyl-oxazol-4-yl) -ethanol

Step 1:
L-aspartic acid 4-benzyl ester (78.1 g, 0.35 mol) was suspended in dioxane (1000 mL) and a solution of sodium carbonate (56 g, 0.52 mol) in water (1200 mL) and the mixture was stirred for 1 h. To this mixture was added biphenyl-4,4′-dicarbonyl dichloride (48.9 g, 0.175 mol) in several portions over 2 h and the reaction mixture was stirred at ambient temperature for 3 h. Water was added (350 mL) and the mixture was allowed to stand overnight and then washed with diethyl ether (3 × 350 mL). The aqueous phase was acidified with 10% hydrochloric acid and the precipitated solid was filtered, washed with water and dried. The yield of crude 2-{[4 '-(2-benzyloxycarbonyl-1-carboxy-ethylcarbamoyl) -biphenyl-4-carbonyl] -amino} -succinic acid 4-benzyl ester was 69.5 g (60.8%) there were. Melting point 204-207 ° C.

¹ H NMR (250 MHz, DMSO-d ₆ ): δ 8.97 (d, 2H); 7.99 (m, 4H); 7.90 (m, 4H); 7.36 (m, 10H); 5.15 (s, 4H); 4.90 (m, 2H); 3.20 (bs); 2.99 (m, Σ 4H).

Step 2:
The above compound (68.9 g, 0.145 mol) was dissolved in anhydrous pyridine (300 mL) and then acetic anhydride (300 mL) was added dropwise. The reaction mixture was warmed to 95 ° C., stirred for 3.5 h, and cooled to 80 ° C. Water (160 mL) was added (temperature of 100-120 ° C.) and then the reaction mixture was stirred at 90 ° C. for 1 h and allowed to stand overnight. Hydrochloric acid (10%, 900 mL) was added with ice cooling and the precipitated solid was filtered off and washed with water (3 × 250 mL). This allowed 58.5 g (85.5%) crude 3-{[4 '-(1-benzyloxycarbonylmethyl-2-oxo-propylcarbamoyl) -biphenyl-4-carbonyl]-after drying in air. Amino} -4-oxo-pentanoic acid benzyl ester was obtained. Melting point 165-168 ° C.

¹ H NMR (250 MHz, DMSO-d ₆ ): δ 9.25 (d, 2H); 8.03 (m, 4H); 7.91 (m, 4H); 7.35 (m, 10H); 5.14 (s, 4H); 4.82 (m, 2H); 3.12 and 3.78 (m, Σ 4H); 2.20 (s, 6H).

Step 3:
A mixture of the above compound (57.4 g, 0.123 mol), toluene (600 mL) and phosphorus oxychloride (160 mL) was stirred at reflux temperature for 4 h. The mixture was cooled to 50 ° C., poured into ice (1 500 g) and neutralized with potassium carbonate solid (600 g) with stirring. The mixture is extracted with diethyl ether (3 × 500 mL) and chloroform (3 × 200), the extracts are combined, the powdered polymer is filtered off and the filtrate is washed with water (100 mL), brine (80 mL). , Dried (MgSO ₄ ) and evaporated in vacuo. The residue (41 g) was chromatographed on a column of SiO ₂ (Fluka 60, 800 g). Elution with benzene / ethyl acetate (9: 1) gave 6.2 g (12.5%) of {2- [4 '-(4-benzyloxycarbonylmethyl-5-methyl-oxazol-2-yl) -biphenyl-4 -Yl] -5-methyl-oxazol-4-yl} -acetic acid benzyl ester was obtained. Mp 162-168 ° C.

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 7.98 (m, 4H); 7.88 (m, 4H); 7.35 (m, 10H); 5.14 (s, 4H); 3.71 (s, 4H); 2.36 (s, 6H).

Step 4:
A solution of the above diester (6.0 g, 14.8 mmol) in tetrahydrofuran (500 mL) was added dropwise to a suspension of lithium aluminum hydride (1.12 g, 29.7 mmol) in diethyl ether (150 mL) at 5 ° C. over 60 minutes. Added. The mixture was stirred for an additional 2 h at the same temperature and an additional 2 h at ambient temperature. The reaction mixture was destroyed by sequential addition of water (1.1 mL), 15% sodium hydroxide solution (1.1 mL), and water (3.5 mL). The suspension was stirred at ambient temperature for 1.5 h, the solid was filtered off and washed with tetrahydrofuran (50 mL) and chloroform (100 mL). The collected filtrate was dried (MgSO ₄ ) and evaporated. The residue (2.9g) was subjected to chromatography (silica gel Fluka 60, 200g). Elution with ethyl acetate and ethanol (95: 5 and then 40:60) gave the title compound (0.95 g, 15.8%). Melting point 134-135 ° C.

¹ H NMR (250 MHz, DMSO-d ₆ ): δ 8.01 (m, 4H); 7.87 (m, 4H); 4.70 (bt, 2H); 3.69 (m, 4H); 2.65 (t, J = 7.7 Hz , 4H); 2.36 (s, 6H).

ステップ１：
2-トリフルオロメチル-4-ニトロフェノール(73.4g, 0.354mol)、ブロモ酢酸エチル(65.2g, 0.39mol)、炭酸カリウム(58.7g, 0.425mol)および2-ブタノン(400mL)の混合物を撹拌しながら10ｈ還流させた。固体を濾過除去し、濾液を蒸発させ、残渣を分画して、97.8g(95％)の2-トリフルオロメチル-4-ニトロフェノキシ酢酸 エチルエステルを得た。沸点 126℃/40Pa。 Intermediate 11
(4-Mercapto-2-trifluoromethyl-phenoxy) -acetic acid ethyl ester

Step 1:
Stir a mixture of 2-trifluoromethyl-4-nitrophenol (73.4 g, 0.354 mol), ethyl bromoacetate (65.2 g, 0.39 mol), potassium carbonate (58.7 g, 0.425 mol) and 2-butanone (400 mL). The mixture was refluxed for 10 hours. The solid was filtered off, the filtrate was evaporated and the residue was fractionated to give 97.8 g (95%) of 2-trifluoromethyl-4-nitrophenoxyacetic acid ethyl ester. Boiling point 126 ° C / 40Pa.

Step 2:
The above ester (97.8 g, 0.334 mol) was dissolved in ethanol (450 mL), 5% Pd / C (6.0 g) was added and the mixture was hydrogenated at normal pressure and ambient temperature for 3 h. The catalyst was removed by filtration, the ethanol was evaporated, and the residue 4-amino-2-trifluoromethyl-phenoxyacetic acid ethyl ester (87.6 g, 0.334 mol) was added to a mixture of concentrated hydrochloric acid (65 mL) and water (170 mL). Added. The mixture was cooled to 5 ° C., then a solution of sodium nitrite (23.0 g, 0.334 mol) in water (90 mL) was added dropwise with crushed ice to maintain the temperature below 5 ° C. This takes about 5 minutes. In another beaker, heat 100 mL water to reflux, then dissolve Na ₂ S.3H ₂ O (46.5 g, 0.367 mol) and powdered sulfur (11.7 g, 0.367 mol) by heating and stirring. It was. A solution of sodium hydroxide (13.3 g, 0.334) in water (30 mL) was then added and the mixture was cooled below 5 ° C. The diazonium salt solution was added with ice to prevent temperature rise. When the addition was complete, the mixture was warmed to experimental temperature overnight and filtered. The filtrate was acidified with concentrated hydrochloric acid and extracted with ethyl acetate. To remove excess sulfur, the solution was extracted with sodium carbonate solution, filtered, acidified and extracted again with ethyl acetate. The extract was dried (MgSO ₄ ) and the solvent was evaporated.

  The residual 4,4′-dithiobis- (2-trifluoromethylphenoxyacetic acid) was refluxed with ethanol (1500 mL) and concentrated sulfuric acid (30 mL) for 8 h, then the ethanol was evaporated. The residue was dissolved in benzene, the solution was washed with water and the solvent was evaporated. The residue was purified by chromatography on silica gel (250 g, benzene / chloroform) to give 42.0 g (45%) of diethyl ester. Melting point 118-120 ° C.

Step 3:
The above ethyl ester (20.0 g, 358 mmol) was dissolved in dimethylacetamide (100 mL), sodium borohydride (3.5 g, 926 mmol) was added in several portions at 5 ° C., and the mixture was stirred for 60 minutes. did. Acetone (20 mL) and benzene (300 mL) were added, the mixture was washed with water and the organic phase was evaporated. The residue was fractionated under reduced pressure to give the title compound (7.5 g, 37%). Boiling point 72 ℃ / 5Pa. A large amount of high boiling material (starting diethyl ester) remained.

R _F (SiO ₂ , chloroform / methanol 9: 1): 0.69.

¹ H NMR spectrum (300 MHz, CDCl ₃ ): 7.56 (d, J = 2.2 Hz, 1H); 7.41 (dd, J = 2.2 and 8.5 Hz, 1H); 6.78 (d, J = 8.5 Hz, 1H); 4.68 (s, 2H); 4.25 (q, J = 7.15 Hz, 2H); 3.46 (s, 1H); 1.27 (t, J = 7.15 Hz, 3H).

ステップ１：
2-クロロ-4-ニトロフェノール(63.6g, 0.367mol)、ブロモ酢酸エチル(67.0g, 0.4mol)、炭酸カリウム(60.7g, 0.44mol)および2-ブタノン(400mL)の混合物を、撹拌しながら10ｈ還流させ、次いで濾過し、溶媒を蒸発させた。残渣を分画して、61.1g(64％)の 2-クロロ-4-ニトロフェノキシ酢酸 エチルエステルを得た。沸点 150^o C/40Pa。 Intermediate 12
(2-Chloro-4-mercapto-phenoxy) -acetic acid ethyl ester

Step 1:
While stirring, a mixture of 2-chloro-4-nitrophenol (63.6 g, 0.367 mol), ethyl bromoacetate (67.0 g, 0.4 mol), potassium carbonate (60.7 g, 0.44 mol) and 2-butanone (400 mL) was stirred. Reflux for 10 h, then filter and evaporate the solvent. The residue was fractionated to give 61.1 g (64%) of 2-chloro-4-nitrophenoxyacetic acid ethyl ester. Boiling point 150 ^o C / 40Pa.

Step 2:
The above ester (61.1 g, 0.236 mol) was dissolved in ethanol (300 mL), 5% Pd / C (4.0 g) was added and the mixture was hydrogenated at atmospheric pressure and laboratory temperature for 3 h. The catalyst was removed by filtration, the ethanol was evaporated, and the residue 4-amino-2-chloro-phenoxyacetic acid ethyl ester (54.1 g, 0.236 mol) was added to a mixture of concentrated hydrochloric acid (50 mL) and water (125 mL). The mixture was cooled to 5 ° C. A solution of sodium nitrite (16.3 g, 0.236 mol) in 70 mL of water was added dropwise with crushed ice to maintain the temperature below 5 ° C. This takes about 5 minutes.

Heat (75 mL) water to reflux with another beaker, add Na ₂ S.3H ₂ O (33.0 g, 0.26 mol) and powdered sulfur (8.3 g, 0.26 mol) and dissolve by heating and stirring. It was. A solution of sodium hydroxide (9.5 g, 0.236 mol) in water (25 mL) was then added and the mixture was cooled to below 5 ° C. To this solution was added a solution of diazonium salt along with crushed ice to avoid temperature rise. When the addition was complete, the mixture was allowed to warm to temperature overnight and filtered. The filtrate was acidified with concentrated hydrochloric acid and extracted with ethyl acetate. To remove excess sulfur, the solution was extracted with sodium carbonate solution, filtered and acidified again with ethyl acetate. The extract was dried (MgSO ₄ ) and the solvent was evaporated.

  The residue 4,4′-dithiobis- (2-chlorophenoxyacetic acid) (41.5 g) was refluxed with ethanol (1000 mL) and sulfuric acid (25 mL) for 8 h, and the ethanol was evaporated. Benzene was added, the mixture was washed with water and the solvent was evaporated. The residue was purified by chromatography on silica gel (250 g, benzene / chloroform) and 17.7 g (40%) of 2-chloro-4- (3-chloro-4-ethoxycarbonylmethoxy-phenyldisulfanyl) -phenoxy]- Acetic acid diethyl ester was obtained.

Step 3:
The above diethyl ester (13.4 g, 273 mmol) was dissolved in 70 mL dimethylacetamide, sodium borohydride (3.1 g, 820 mmol) was added in several portions at 5 ° C. and the mixture was stirred for 30 minutes. Acetone (15 mL) and benzene (200 mL) were added, the solution was washed with water, the organic phase was evaporated and the residue was fractionated under reduced pressure. This gave the title compound (2.5 g, 19%). Boiling point 120 ℃ / 10Pa. A large amount of high boiling material (starting diethyl ester) remained.

R _F (SiO ₂ , chloroform / methanol 9: 1): 0.73.

¹ H NMR spectrum (300 MHz, CDCl ₃ ): 7.35 (d, J = 2.2 Hz, 1H); 7.12 (dd, J = 2.2 and 8.5 Hz, 1H); 6.72 (d, J = 8.5 Hz, 1H); 4.65 (s, 2H); 4.24 (q, J = 7.15 Hz, 2H); 3.41 (s, 1H); 1.27 (t, J = 7.15 Hz, 3H).

ステップ１：
4-アミノ-2-クロロ-フェニルチオ酢酸水和物(109.3g, 0.49mol, FR Pat. 1489916に従って調製した)を、濃塩酸(100mL)および水(200mL)の混合物に添加し、該混合物を5℃にまで冷却した。水(150mL)中の亜硝酸ナトリウム(34.5g, 0.5mol)の溶液を、温度5℃未満に保つために砕いた氷と共に滴下添加した。これには約５分かかる。他のビーカーで、200mL 水を加熱して沸騰させ、Na₂S.9H₂O(72.6g, 0.55mol)および粉末硫黄(17.0g, 0.53mol)を加熱および撹拌により溶解させた。次いで、水(50mL)中の水酸化ナトリウム(20g, 0.5モル)の溶液を添加し、混合物を５℃未満に冷却した。この溶液に、温度上昇を防ぐために砕いた氷と共に、ジアゾニウム塩の溶液を添加した。添加が完了したら、該混合物を一晩室温にまで加温させ、濾過した。濾液を濃塩酸で酸性にし、酢酸エチルで抽出した。過剰の硫黄を除去するために、この溶液を炭酸ナトリウム溶液で抽出し、濾過し、酸性にし、再び酢酸エチルで抽出した。抽出物を乾燥させ(MgSO₄)、溶媒を蒸発させた。この残渣の粗製4,4'-ジチオbis-(2-クロロフェニルチオ酢酸)(49g)、エタノール(500mL)および濃硫酸(30mL)の混合物を８ｈ還流させた。エタノールを蒸発させ、残渣をジエチルエーテル中に溶解させ、この溶液を水、丹さん水素ナトリウムの5％溶液で洗浄し、溶媒を真空下で蒸発させた。残渣を、シリカゲル上でのクロマトグラフィ (250g, ベンゼン／クロロホルム) により精製した。ジエチルエステルの収量は29g(23％)であった。 Intermediate 13
(2-Chloro-4-mercapto-phenylsulfanyl) -acetic acid ethyl ester

Step 1:
4-Amino-2-chloro-phenylthioacetic acid hydrate (109.3 g, 0.49 mol, prepared according to FR Pat. 1489916) was added to a mixture of concentrated hydrochloric acid (100 mL) and water (200 mL) and the mixture was added to 5 Cooled to 0C. A solution of sodium nitrite (34.5 g, 0.5 mol) in water (150 mL) was added dropwise with crushed ice to keep the temperature below 5 ° C. This takes about 5 minutes. In another beaker, 200 mL water was heated to boiling and Na ₂ S.9H ₂ O (72.6 g, 0.55 mol) and powdered sulfur (17.0 g, 0.53 mol) were dissolved by heating and stirring. A solution of sodium hydroxide (20 g, 0.5 mol) in water (50 mL) was then added and the mixture was cooled to below 5 ° C. To this solution was added a solution of diazonium salt along with crushed ice to prevent temperature rise. When the addition was complete, the mixture was allowed to warm to room temperature overnight and filtered. The filtrate was acidified with concentrated hydrochloric acid and extracted with ethyl acetate. To remove excess sulfur, the solution was extracted with sodium carbonate solution, filtered, acidified and extracted again with ethyl acetate. The extract was dried (MgSO ₄ ) and the solvent was evaporated. A crude 4,4′-dithiobis- (2-chlorophenylthioacetic acid) (49 g), ethanol (500 mL) and concentrated sulfuric acid (30 mL) of this residue was refluxed for 8 h. Ethanol was evaporated, the residue was dissolved in diethyl ether, the solution was washed with water, 5% solution of sodium hydride, and the solvent was evaporated under vacuum. The residue was purified by chromatography on silica gel (250 g, benzene / chloroform). The yield of diethyl ester was 29 g (23%).

ステップＡ−Ｂ：
N,N-ジメチルホルムアミド(90mL)中の3,3'-ジクロロ-4,4'-ジヨードビフェニル(44.5g, 95mmol；J.Chem. Soc 85, 7(1904)に従い調製)、トリフェニルホスフィン(2.0g, 7.6mmol)、酢酸パラジウム(II)(0.67g, 3mmol)、アクリル酸メチル(25.8g, 300mmol)およびトリエチルアミン(18.0g, 178mmol)の混合物を撹拌し、110℃にまで９ｈ加熱し、次いで一晩静置した。3,3'-ジクロロビフェニル-4,4'-ジアクリル酸ジメチルエステルが混ざった結晶を濾過し、水およびベンゼンで洗浄し、乾燥させた。粗生成物収量：22.5g。 Intermediate 14 (General Procedure A)
3- [4 '-(3-Hydroxy-propyl) -biphenyl-4-yl] -propan-1-ol

Step AB:
3,3′-dichloro-4,4′-diiodobiphenyl (44.5 g, 95 mmol; prepared according to J. Chem. Soc 85, 7 (1904)), triphenylphosphine in N, N-dimethylformamide (90 mL) (2.0 g, 7.6 mmol), a mixture of palladium (II) acetate (0.67 g, 3 mmol), methyl acrylate (25.8 g, 300 mmol) and triethylamine (18.0 g, 178 mmol) was stirred and heated to 110 ° C. for 9 h. And then left overnight. Crystals mixed with 3,3′-dichlorobiphenyl-4,4′-diacrylic acid dimethyl ester were filtered, washed with water and benzene, and dried. Crude product yield: 22.5 g.

Step C:
A mixture of the above crude diester (22.5 g), dioxane (300 mL) and 5% aqueous sodium hydroxide (150 mL) was refluxed for 4 h. Dioxane was evaporated and the residue was dissolved in water (900 mL). Palladium (5% on charcoal, 4.3 g) was added and the mixture was hydrogenated at atmospheric pressure and ambient temperature for 6 h. The catalyst was removed by filtration, and the contaminated biphenyl-4,4′-dipropionic acid was precipitated by the addition of concentrated hydrochloric acid, filtered, washed with water and dried. Crude product yield: 15.0 g.

  The above crude acid (14.1 g) was dissolved in tetrahydrofuran (150 mL) and sodium borohydride (4.35 g, 115 mmol) was added in several portions over 30 minutes followed by etherified trifluoride. Boron (22.0 g, 155 mmol) was added dropwise. The mixture was refluxed for 8 h, quenched with a 5% aqueous solution of sodium hydroxide (100 mL) and extracted with ether (4 × 25 mL). The organic phase was dried using anhydrous potassium carbonate, evaporated and the residue was crystallized from methanol to give pure 4,4′-biphenyldipropanol. Yield: 5.1 g (calculated with 20%, 3,3′-dichloro-4,4′-diiodobiphenyl). Melting point 154-158 ° C.

¹ H NMR spectrum (CDCl ₃ ) 7.51 (d, J = 8.1 Hz, 4H); 7.26 (d, J = 8.1 Hz, 4H); 3.71 (t, J = 6.5 Hz, 4H); 2.75 (t, J = 8.0Hz, 4H); 1.95 (m, 4H).

ステップ１：
エタノール(800mL)中の(2-メトキシ-4-ニトロフェノキシ)酢酸エチルエステル(107.0g, 0.42mol, J. Chem. Soc. 1955, 3681に記載の通りに調製)の溶液に、エタノール(50mL)中の炭素上5％パラジウム(5.0g)のスラリを添加した。この混合物を、Parr装置中で３ｈ水素添加した。触媒および溶媒を除去し、油状の粗製(4-アミノ-2-メトキシフェノキシ)酢酸 エチルエステルを得た。収量：93.7g, 99％。 Intermediate 15
(4-Mercapto-2-methoxyphenoxy) acetic acid methyl ester

Step 1:
To a solution of (2-methoxy-4-nitrophenoxy) acetic acid ethyl ester (107.0 g, 0.42 mol, prepared as described in J. Chem. Soc. 1955, 3681) in ethanol (800 mL), ethanol (50 mL) A slurry of 5% palladium on carbon (5.0 g) in was added. This mixture was hydrogenated in a Parr apparatus for 3 h. The catalyst and solvent were removed to give an oily crude (4-amino-2-methoxyphenoxy) acetic acid ethyl ester. Yield: 93.7g, 99%.

Step 2:
The above crude ester (91.7 g, 0.405 mol) was added to a mixture of concentrated hydrochloric acid (78 mL) and water (195 mL) and the resulting mixture was cooled to 5 ° C. A solution of sodium nitrite (27.0 g, 0.391 mol) in water (100 mL) was added dropwise with crushed ice (5 minutes) to maintain the reaction temperature below 5 ° C. The diazo compound solution was stirred for 30 minutes and then a solution of ethyl potassium xanthate (90 g, 0.56 mol) in water (100 mL) was added dropwise while maintaining the reaction temperature at 45-50 ° C. The mixture was stirred for 2 h, cooled and extracted with ether (4 × 50 mL). The combined organic phase was evaporated and the residue was dissolved in ethanol (300 mL). To this warm solution was added potassium hydroxide pellets (100 g, 1.79 mol) quickly so that reflux was maintained, and then reflux was continued for 8 h. Ethanol was evaporated and the residue was dissolved in water, acidified with concentrated hydrochloric acid and extracted with ethyl acetate (3 × 75 mL). The collected extract was dried over anhydrous magnesium sulfate and evaporated under vacuum. The resulting residue was crystallized from chloroform to give hemihydrate of 4-mercapto-2-methoxyphenoxyacetic acid. Yield: 22.5 g (25%). Melting point 138-140 ° C.

¹ H NMR spectrum (CDCl ₃ ): 6.86 (m, 2H); 6.78 (d, J = 8.8 Hz, 1H); 4.66 (s, 2H); 3.87 (s, 3H); 3.45 (s, 1H).

Step 3:
A solution of the above acid (20 g, 0.09 mol) in methanol (200 mL) was saturated with gaseous hydrogen chloride for 1 h. The resulting mixture was refluxed for 8 h and then evaporated under vacuum. Ether (100 mL) was added and the solution was washed with water (2 × 20 mL) and 5% aqueous sodium bicarbonate (2 × 20 mL). The collected organic phase was dried over anhydrous sodium sulfate, evaporated under vacuum and the residue was distilled under reduced pressure to give the title compound. Yield: 10 g (49%).

R _F (SiO ₂ , hexane / ethyl acetate, 70:30) 0.45.

¹ H NMR spectrum (300 MHz, CDCl ₃ ): 6.83 (m, 2H); 6.71 (d, J = 8.0 Hz, 1H); 4.65 (s, 2H); 3.85 (s, 3H); 3.78 (s, 3H) 3.42 (s, 1H).

ステップ１：
水(300mL)中の硫化ナトリウム九水和物(300g, 1.25mol)の溶液を、4-クロロ-3-トリフルオロメチルニトロベンゼン(113g, 0.5mol)および250mL の水の混合物に100℃で滴下添加した。次いで、該反応混合物を撹拌しながら６ｈ加熱した。油相をデカントし、ベンゼン中に溶解させ、溶媒を真空下で蒸発させて75.6gの油状残渣を得た。この油状物(66.4g)をエタノール(300mL)中に溶解させ、ヒドラジン水和物(25g)、活性炭(5g)および塩化第２鉄六水化物(1.0g)を添加し、該混合物を32ｈ還流させ、次いで濾過し、蒸発させた。残渣をシリカゲル(Fluka 60, 400g)上のクロマトグラフィに供した。ベンゼン用いた溶出により、22.6gの4-アミノ-2-トリフルオロメチルベンゼンチオールを得た。融点35-36.5℃。 Intermediate 16
3- {4- [4- (3-hydroxy-propyl) -2-trifluoromethyl-phenylsulfanyl] -3-trifluoromethyl-phenyl} -propan-1-ol

Step 1:
Add a solution of sodium sulfide nonahydrate (300 g, 1.25 mol) in water (300 mL) dropwise to a mixture of 4-chloro-3-trifluoromethylnitrobenzene (113 g, 0.5 mol) and 250 mL water at 100 ° C. did. The reaction mixture was then heated with stirring for 6 h. The oil phase was decanted, dissolved in benzene and the solvent was evaporated under vacuum to give 75.6 g of an oily residue. This oil (66.4 g) was dissolved in ethanol (300 mL), hydrazine hydrate (25 g), activated carbon (5 g) and ferric chloride hexahydrate (1.0 g) were added and the mixture was refluxed for 32 h. Then filtered and evaporated. The residue was chromatographed on silica gel (Fluka 60, 400 g). Elution with benzene gave 22.6 g of 4-amino-2-trifluoromethylbenzenethiol. Melting point 35-36.5 ° C.

¹ H NMR spectrum (300 MHz, CDCl ₃ ): 7.22 (d, J = 8.5 Hz, 1H); 6.95 (d, J = 2.75 Hz, 1H); 6.72 (dd, J = 2.75 and 8.5 Hz, 1H); 3.83 (bs, 3H).

  Chromatography was continued using chloroform to obtain 35.4 g of 4,4′-diamino-2,2′-bis (trifluoromethyl) diphenyl sulfide. Melting point 65-70 ° C.

¹ H NMR spectrum (300 MHz, CDCl ₃ ): 7.05 (m, 4H); 6.72 (d, J = 8.5 Hz, 2H); 4.25 (bs, 4H).

Step 2:
A solution of sodium nitrite (12.2 g, 177 mmol) in 30 mL of water was added dropwise to the above mixture of sulfide (33.5 g, 95 mmol), concentrated hydrochloric acid (100 mL) and crushed ice (150 g) with stirring at 0 ° C. did. The resulting cold bis-diazonium salt solution was slowly added to a stirred solution of potassium iodide (90 g, 338 mmol) in 300 mL of water. Benzene (300 mL) was added and the mixture was stirred at ambient temperature for 3 h before the phases were separated. The organic phase was washed with 5% sodium bisulfite, dried and evaporated to give 50 g (91%) of 4,4′-diiodo-2,2′-bis (trifluoromethyl) diphenyl sulfide. Melting point 75-87 ° C. This product was used in the next step without purification.

General procedure A:
Step AB:
The above sulfide (49.7 g, 86.6 mmol), triphenylphosphine (1.8 g, 6.9 mmol), palladium (II) acetate (0.6 g, 2.67 mmol), methyl acrylate (22.1 g, 257 mmol) in 80 mL dimethylformamide and A mixture of triethylamine (17 g, 168 mmol) was stirred and heated to 110 ° C. for 9 h. After standing overnight, water and benzene were added, the organic phase was separated, washed with water, evaporated and the residue was purified by chromatography on silica gel (Fluka, 300 g, benzene and chloroform). The yield of 3- {4- [4- (2-carboxyvinyl) -2-trifluoromethyl-phenylsulfanyl] -3-trifluoromethyl-phenyl} -acrylic acid dimethyl ester was 20.1 g (47%). . Melting point 169-174 ° C.

¹ H NMR spectrum (300 MHz, CDCl ₃ ): 7.86 (d, J = 1.6 Hz, 2H); 7.65 (d, J = 16.2 Hz, 2H); 7.54 (dd, J = 1.6 and 8.25 Hz, 2H); 7.24 (d, J = 8.25 Hz, 2H); 6.48 (d, J = 16.2 Hz, 2H); 3.82 (s, 6H).

Step C:
Step 1:
A mixture of 100 mL of methanol and the above ester (14.1 g, 28.8 mmol) in 20% sodium hydroxide (25 mL) was heated to reflux and then stirred without heating for 4 h. Methanol was evaporated, the residue was dissolved in water, acidified with concentrated hydrochloric acid, and the precipitate was filtered and dried. The yield of 3- {4- [4- (2-carboxyvinyl) -2-trifluoromethyl-phenylsulfanyl] -3-trifluoromethyl-phenyl} -acrylic acid was 13.3 g (quant.). Melting point 227-247 ° C.

¹ H NMR spectrum (300 MHz, DMSO): 12.25 (bs, 2H); 8.17 (s, 2H); 7.96 (d, J = 8.0 Hz, 2H); 7.66 (d, J = 16.2 Hz, 2H); 7.28 ( d, J = 8.0 Hz, 2H); 6.68 (d, J = 16.2 Hz, 2H).

Step 2:
The acid (7.2 g, 156 mmol) is dissolved in 200 mL of ethanol, hydrazine hydrate (40 mL) is added, and then a solution of sodium (meth) periodate (15.0 g, 70 mmol) in 80 mL of water is added over 5 h. Add dropwise at room temperature. The mixture was filtered, diluted with water, acidified with concentrated hydrochloric acid and extracted with chloroform. The organic extract was dried (MgSO ₄ ) and evaporated, the residue was purified by chromatography on silica gel (Fluka 60, 85 g, chloroform / diethyl ether) and 4.5 g (62%) of 3- {4- [4 -(2-Carboxy-ethyl) -2-trifluoromethyl-phenylsulfanyl] -3-trifluoromethyl-phenyl} -propionic acid was obtained. Melting point 175-178 ° C.

¹ H NMR spectrum (300 MHz, DMSO-d ₆ ): 12.20 (s, 2H); 7.71 (s, 2H); 7.48 (d, J = 8.2 Hz, 2H); 7.13 (d, J = 8.2 Hz, 2H) 2.87 (t, J = 7.4 Hz, 4H); 2.56 (t, J = 7.4 Hz, 4H).

Step 3:
The above acid (4.4 g, 9.4 mmol)) was dissolved in 50 mL tetrahydrofuran and sodium borohydride (0.80 g, 21.1 mmol) was added dropwise over 30 minutes, followed by etherified boron trifluoride (4.9 g, 34.5 mmol) was added dropwise. The mixture was diluted with diethyl ether (100 mL) and then stirred at lab temperature for 48 h. The reaction mixture was quenched with 10% hydrochloric acid and the organic phase was dried (K ₂ CO ₃ ) and evaporated to give 4.1 g (99%) of 3- {4- [4- (3-hydroxy-propyl)- 2-Trifluoromethyl-phenylsulfanyl] -3-trifluoromethyl-phenyl} -propan-1-ol was obtained. Melting point 96-102 ° C.

¹ H NMR spectrum (300 MHz, CDCl ₃ ): 7.55 (s, 2H); 7.24 (dd, 2H); 7.13 (d, J = 8.0 Hz, 2H); 3.68 (t, 4H); 2.75 (t, J = 7.8 Hz, 4H); 1.89 (m, 4H); 1.60 (bs, 1H); 1.38 (bs, 1H).

ステップＣ−Ｄ：
乾燥THF(3.5mL)中の2-({6-[(2-ヒドロキシ-エチル)-メチル-アミノ]-ピリジン-2-イル}-メチル-アミノ)-エタノール(中間4)(38mg, 0.17mmol)の撹拌した溶液に、０℃で窒素下にてトリブチルホスフィン(100mg, 0.50mmol)および2-エトキシ-3-(4-メルカプト-フェニル)-プロピオン酸メチルエステル（中間体２）(98mg, 0.41mmol)を添加した。該反応混合物を15分撹拌し、アゾジカルボキンジピペリジン(126mg, 0.50mmol)を添加した。該反応物を６ｈ撹拌した後、水(5mL)を添加し、該混合物を塩化メチレンで抽出した(3×20mL)。合体した有機相を乾燥させ(MgSO₄)、濾過し、蒸発させた。粗生成物を、ヘプタン：酢酸エチル(3：1)を溶出剤に用いたカラムクロマトグラフィ上で精製し、標題化合物を85mg(75％)の収量で得た。 Example 1 (general procedure E)
2-Ethoxy-3- [4- (2-{[6-({2- [4- (2-ethoxy-2-methoxycarbonyl-ethyl) -phenylsulfanyl] -ethyl} -methyl-amino) -pyridine- 2-yl] -methyl-amino} -ethylsulfanyl) -phenyl] -propionic acid methyl ester

Step CD:
2-({6-[(2-Hydroxy-ethyl) -methyl-amino] -pyridin-2-yl} -methyl-amino) -ethanol (intermediate 4) (38 mg, 0.17 mmol) in dry THF (3.5 mL) To a stirred solution of tributylphosphine (100 mg, 0.50 mmol) and 2-ethoxy-3- (4-mercapto-phenyl) -propionic acid methyl ester (intermediate 2) (98 mg, 0.41) mmol) was added. The reaction mixture was stirred for 15 minutes and azodicarboquinedipiperidine (126 mg, 0.50 mmol) was added. After the reaction was stirred for 6 h, water (5 mL) was added and the mixture was extracted with methylene chloride (3 × 20 mL). The combined organic phase was dried (MgSO ₄ ), filtered and evaporated. The crude product was purified on column chromatography using heptane: ethyl acetate (3: 1) as eluent to give the title compound in 85 mg (75%) yield.

¹ H NMR (300 MHz, CDCl ₃ ): δ7.3-7.2 (m, 5H); 7.15 (d, J = 8 Hz, 4H); 5.72 (d, J = 8 Hz, 2H); 4.01 (t, J = 6 Hz) 3.71 (s, 6H); 3.7-3.55 (m, 6H); 3.40-3.27 (m, 2H); 3.10 (t, J = 7Hz, 4H); 2.98 (m, 4H); 2.95 (s , 6H); 1.15 (t, J = 6 Hz, 6H).

ステップＡ：
2-エトキシ-3-[4-(2-{[6-({2-[4-(2-エトキシ-2-メトキシカルボニル-エチル)-フェニルスルファニル]-エチル}-メチル-アミノ)-ピリジン-2-イル]-メチル-アミノ}-エチルスルファニル)-フェニル]-プロピオン酸メチルエステル（例１）(85mg, 0.13mmol)を、エタノール(5mL)中で60℃にまで加熱することにより溶解させた。この温溶液に1N NaOH水溶液を添加し、該反応混合物を60℃で５ｈ撹拌した。該反応混合物を蒸発させ、残渣を水(2mL)中に懸濁させた。該懸濁物を塩化メチレンで抽出し(2×25mL)、合体した有機相を乾燥させ、濾過し、蒸発させて標題化合物を71mg(86％)の収量で得た。 Example 2 (General Procedure D)
3- [4- (2-{[6-({2- [4- (2-carboxy-2-ethoxy-ethyl) -2-chloro-phenylsulfanyl] -ethyl} -methyl-amino) -pyridine-2 -Yl] -Methyl-amino} -ethylsulfanyl) -3-chloro-phenyl] -2-ethoxy-propionic acid

Step A:
2-Ethoxy-3- [4- (2-{[6-({2- [4- (2-ethoxy-2-methoxycarbonyl-ethyl) -phenylsulfanyl] -ethyl} -methyl-amino) -pyridine- 2-yl] -methyl-amino} -ethylsulfanyl) -phenyl] -propionic acid methyl ester (Example 1) (85 mg, 0.13 mmol) was dissolved by heating to 60 ° C. in ethanol (5 mL). . To this warm solution was added 1N aqueous NaOH and the reaction mixture was stirred at 60 ° C. for 5 h. The reaction mixture was evaporated and the residue was suspended in water (2 mL). The suspension was extracted with methylene chloride (2 × 25 mL) and the combined organic phases were dried, filtered and evaporated to give the title compound in 71 mg (86%) yield.

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.26 (m, 5H); 7.15 (d, J = 8 Hz, 4H); 5.73 (d, J = 8 Hz, 2H); 4.05 (m, 2H); 3.74 3.55 (m, 6H); 3.46-3.34 (m, 2H); 3.12-2.94 (m, 8H); 2.93 (s, 6H); 1.15 (t, J = 6Hz, 6H).

ステップＣ−Ｄ：
2-エトキシ-3-(4-メルカプト-フェニル)-プロピオン酸メチルエステルの代わりに、2,6-ジフェニル-4-ヒドロキシフェノキシ酢酸エチル（中間体３）(143mg, 0.41mmol)を用いて、例１の ステップＣ−Ｄに記載の通りに合成し、標題化合物を26mg(17％)の収量で得た。 Example 3 (general procedure E)
(5 '-{2-[(6-{[2- (2'-Ethoxycarbonylmethoxy- [1,1'; 3 ', 1'']terphenyl-5'-yloxy) -ethyl] -methyl- Amino} -pyridin-2-yl) -methyl-amino] -ethoxy}-[1,1 ′; 3 ′, 1 ″] terphenyl-2′-yloxy) -acetic acid ethyl ester

Step CD:
Example using ethyl 2,6-diphenyl-4-hydroxyphenoxyacetate (intermediate 3) (143 mg, 0.41 mmol) instead of methyl 2-ethoxy-3- (4-mercapto-phenyl) -propionic acid Synthesized as described in Step C-D in Step 1 to give the title compound in 26 mg (17%) yield.

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.58 (m, 8H); 7.43-7.27 (m, 13H); 6.85 (s, 4H); 5.83 (d, J = 8 Hz, 2H); 4.20 (t, J = 6Hz, 4H); 5.93 (m, 8H); 5.73 (s, 4H); 3.07 (s, 6H); 1.06 (t, J = 7Hz).

ステップＡ：
(5'-{2-[(6-{[2-(2'-エトキシカルボニルメトキシ-[1,1'；3',1'']ターフェニル-5'-イルオキシ)-エチル]-メチル-アミノ}-ピリジン-2-イル)-メチル-アミノ]-エトキシ}-[1,1'；3',1'']ターフェニル-2'-イルオキシ)-酢酸エチルエステル（例３）から、例２のステップＡのもとで記載した通りに合成し、15mg(60％)の収量で得た。 Example 4 (general procedure D)
(5 '-{2-[(6-{[2- (2'-carboxymethyl- [1,1'; 3 ', 1'']terphenyl-5'-yloxy) -ethyl] -methyl-amino } -Pyridin-2-yl) -methyl-amino] -ethoxy}-[1,1 ′; 3 ′, 1 ″] terphenyl-2′-yloxy) -acetic acid

Step A:
(5 '-{2-[(6-{[2- (2'-Ethoxycarbonylmethoxy- [1,1'; 3 ', 1'']terphenyl-5'-yloxy) -ethyl] -methyl- Amino} -pyridin-2-yl) -methyl-amino] -ethoxy}-[1,1 ′; 3 ′, 1 ″] terphenyl-2′-yloxy) -acetic acid ethyl ester (Example 3) Synthesized as described under step A in step 2 to give a yield of 15 mg (60%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.60-7.25 (m, 21H); 6.84 (s, 4H); 5.86 (d, J = 8 Hz, 2H); 4.19 (t, J = 6 Hz, 4H); 3.92 (t, J = 6 Hz, 4H); 3.72 (s, 4H); 3.10 (s, 6H).

ステップＣ−Ｄ：
2-エトキシ-3-(4-メルカプト-フェニル)-プロピオン酸メチルエステルの代わりに、(S)-2-(2-ベンゾイル-フェニルアミノ)-3-(4-ヒドロキシ-フェニル)-プロピオン酸メチルエステル(J. Med. Chem. 1998, 41, 5020-5036)(154mg, 0.41mmol)を用いて、例１のステップＣ−Ｄのもとでの記載した通りに合成し、標題化合物を46mg(29％)の収量で得た。 Example 5 (general procedure E)
(S, S) -2- (2-Benzoyl-phenylamino) -3- {4- [2-({6-[(2- {4- [2- (2-benzoyl-phenylamino) -2- Methoxycarbonyl-ethyl] -phenoxy} -ethyl) -methyl-amino] -pyridin-2-yl} -methyl-amino) -ethoxy] -phenyl} -propionic acid methyl ester

Step CD:
Instead of 2-ethoxy-3- (4-mercapto-phenyl) -propionic acid methyl ester, methyl (S) -2- (2-benzoyl-phenylamino) -3- (4-hydroxy-phenyl) -propionic acid Ester (J. Med. Chem. 1998, 41, 5020-5036) (154 mg, 0.41 mmol) was synthesized as described under Example 1, Steps C-D to give 46 mg ( 29%) yield.

¹ H NMR (300 MHz, CDCl ₃ ): δ 8.91 (d, J = 7 Hz, 2H); 7.60 (d, J = 7 Hz, 4H); 7.55-7.25 (m, 11H); 7.15 (d, J = 8 Hz) , 4H); 6.76 (d, J = 8Hz, 4H); 6.56-6.53 (m, 4H); 5.80 (d, J = 8Hz, 2H); 4.37 (q, J = 6Hz, 2H); 4.08 (t, 3.87 (t, J = 6 Hz, 4H); 3.67 (s, 6H); 3.24-3.06 (m, 4H); 3.05 (s, 6H).

ステップＡ：
(S,S)-2-(2-ベンゾイル-フェニルアミノ)-3-{4-[2-({6-[(2-{4-[2-(2-ベンゾイル-フェニルアミノ)-2-メトキシカルボニル-エチル]-フェノキシ}-エチル)-メチル-アミノ]-ピリジン-2-イル}-メチル-アミノ)-エトキシ]-フェニル}-プロピオン酸メチルエステル（例５）から、例２のステップＡのもとで記載した通りに合成し、42mg(93％)の収量で得た。 Example 6 (General Procedure D)
(S, S) -2- (2-Benzoyl-phenylamino) -3- {4- [2-({6-[(2- {4- [2- (2-benzoyl-phenylamino) -2- Carboxy-ethyl] -phenoxy} -ethyl) -methyl-amino] -pyridin-2-yl} -methyl-amino) -ethoxy] -phenyl} -propionic acid

Step A:
(S, S) -2- (2-Benzoyl-phenylamino) -3- {4- [2-({6-[(2- {4- [2- (2-benzoyl-phenylamino) -2- Methoxycarbonyl-ethyl] -phenoxy} -ethyl) -methyl-amino] -pyridin-2-yl} -methyl-amino) -ethoxy] -phenyl} -propionic acid methyl ester (Example 5) from Example 2 Step A And was obtained in a yield of 42 mg (93%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 8.80 (br. S, 2H); 7.62-7.27 (m, 15H); 7.10 (t, J = 7 Hz, 4H); 6.72 (d, J = 8 Hz, 6H 6.60 (q, J = 7Hz, 2H); 5.84 (d, J = 8Hz, 2H); 4.48 (br s, 2H); 4.08 (t, J = 6Hz, 4H); 3.95 (t, J = 6Hz) , 4H); 3.30-3.12 (m, 4H); 3.04 (d, J = 5 Hz, 6H).

ステップＣ−Ｄ：
2-エトキシ-3-(4-メルカプト-フェニル)-プロピオン酸メチルエステルの代わりに、(3-クロロ-4-ヒドロキシ-フェニル)-酢酸 エチルエステル(US 6,090,836)(88mg, 0.41mmol)を用いて例１のステップＣ−Ｄのもとで記載した通りに合成し、標題化合物を45mg(43％)の収量で得た。 Example 7 (general procedure E)
(3-Chloro-4- {2-[(6-{[2- (2-chloro-4-ethoxycarbonylmethyl-phenoxy) -ethyl] -methyl-amino} -pyridin-2-yl) -methyl-amino ] -Ethoxy} -phenyl) -acetic acid ethyl ester

Step CD:
Instead of 2-ethoxy-3- (4-mercapto-phenyl) -propionic acid methyl ester, using (3-chloro-4-hydroxy-phenyl) -acetic acid ethyl ester (US 6,090,836) (88 mg, 0.41 mmol) Synthesized as described under Example 1, Steps C-D, to give the title compound in 45 mg (43%) yield.

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.32-7.00 (m, 5H); 6.75 (d, J = 8 Hz, 2H); 5.83 (d, J = 8 Hz, 2H); 4.15 (m, 8H); 3.97 (t, J = 6 Hz); 5.50 (s, 4H); 3.14 (s, 6H); 1.24 (t, J = 6 Hz, 6H).

ステップＡ：
(3-クロロ-4-{2-[(6-{[2-(2-クロロ-4-エトキシカルボニルメチル-フェノキシ)-エチル]-メチル-アミノ}-ピリジン-2-イル)-メチル-アミノ]-エトキシ}-フェニル)-酢酸エチルエステル（例７）から、例２のステップＡに記載したようにして合成し、90mg(73％)の収量で得た。 Example 8 (General Procedure D)
(4- {2-[(6-{[2- (4-Carboxymethyl-2-chloro-phenoxy) -ethyl] -methyl-amino} -pyridin-2-yl) -methyl-amino] -ethoxy}- 3-Chloro-phenyl) -acetic acid

Step A:
(3-Chloro-4- {2-[(6-{[2- (2-chloro-4-ethoxycarbonylmethyl-phenoxy) -ethyl] -methyl-amino} -pyridin-2-yl) -methyl-amino ] -Ethoxy} -phenyl) -acetic acid ethyl ester (Example 7) was synthesized as described in Step 2 of Example 2 and was obtained in 90 mg (73%) yield.

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.25 (m, 2H); 7.10-6.93 (m, 5H); 6.68 (d, J = 8 Hz, 2H); 5.82 (d, J = 8 Hz, 2H); 4.15 (t, J = 6 Hz, 4H); 3.98 (t, J = 6 Hz, 4H); 3.50 (s, 4H); 3.13 (s, 6H).

ステップＣ−Ｄ：
2-エトキシ-3-(4-メルカプト-フェニル)-プロピオン酸メチルエステルの代わりに、(3-ヒドロキシ-フェニル)-酢酸エチルエステル(US6,090,836)(74mg, 0.41mmol)を用いて、例１のステップＣ−Ｄのもとでの記載した通りに合成し、標題化合物を30mg(32％)の収量で得た。 Example 9 (general procedure E)
(3- {2-[(6-{[2- (3-Ethoxycarbonylmethyl-phenoxy) -ethyl] -methyl-amino} -pyridin-2-yl) -methyl-amino] -ethoxy} -phenyl)- Acetic acid ethyl ester

Step CD:
Example 1 using (3-hydroxy-phenyl) -acetic acid ethyl ester (US 6,090,836) (74 mg, 0.41 mmol) instead of 2-ethoxy-3- (4-mercapto-phenyl) -propionic acid methyl ester And was synthesized as described under Steps C to D in 30% (32%) yield of the title compound.

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.34–7.14 (m, 3H); 6.87-6.70 (m, 6H); 5.84 (d, J = 8 Hz, 2H); 4.15 (m, 8H); 3.93 ( t, J = 6 Hz, 4H); 3.54 (s, 4H); 3.10 (s, 6H); 1.24 (t, J = 7 Hz, 6H).

ステップＡ：
(3-{2-[(6-{[2-(3-エトキシカルボニルメチル-フェノキシ)-エチル]-メチル-アミノ}-ピリジン-2-イル)-メチル-アミノ]-エトキシ}-フェニル)-酢酸 エチルエステル（例９）を用いて、例２の ステップＡのもとで記載した通りに合成し、26mg(88％)の収量で得た。 Example 10 (General Procedure D)
(3- {2-[(6-{[2- (3-Carboxymethyl-phenoxy) -ethyl] -methyl-amino} -pyridin-2-yl) -methyl-amino] -ethoxy} -phenyl) -acetic acid

Step A:
(3- {2-[(6-{[2- (3-Ethoxycarbonylmethyl-phenoxy) -ethyl] -methyl-amino} -pyridin-2-yl) -methyl-amino] -ethoxy} -phenyl)- Synthesized as described under Step A of Example 2 using ethyl acetate (Example 9) to give 26 mg (88%) yield.

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.28-1.14 (m, 3H); 6.80 (m, 6H); 5.82 (d, J = 8 Hz, 2H); 4.12 (t, J = 6 Hz, 4H); 3.93 (t, J = 6 Hz, 4H); 3.57 (s, 4H); 3.13 (s, 6H).

ステップＣ−Ｄ：
2-エトキシ-3-(4-メルカプト-フェニル)-プロピオン酸メチルエステルの代わりに、(S)-2-エトキシ-3-(4-ヒドロキシ-フェニル)-プロピオン酸メチルエステル(501mg, 2.11mmol)を用いて、例１のステップＣ−Ｄのもとで記載した通りに合成し、標題化合物を106mg(30％)の収量で得た。 Example 11 (general procedure E)
(S, S) -2-Ethoxy-3- [4- (2-{[6-({2- [4- (2-Ethoxy-2-ethoxycarbonyl-ethyl) -phenoxy] -ethyl} -methyl- Amino) -pyridin-2-yl] -methyl-amino} -ethoxy) -phenyl] -propionic acid ethyl ester

Step CD:
Instead of 2-ethoxy-3- (4-mercapto-phenyl) -propionic acid methyl ester, (S) -2-ethoxy-3- (4-hydroxy-phenyl) -propionic acid methyl ester (501 mg, 2.11 mmol) Was used as described under Step C-D of Example 1 to give the title compound in 106 mg (30%) yield.

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.29 (t, J = 8 Hz, 1H); 7.12 (d, J = 8 Hz, 4H); 6.77 (d, J = 8 Hz, 4H); 5.82 (d, J = 8Hz, 2H); 4.14 (m, 8H); 5.93 (m, 6H); 3.60 (m, 2H); 3.35 (m, 2H); 3.07 (s, 6H); 2.94 (d, J = 7Hz, 4H ); 1.22 (t, J = 7 Hz, 6H); 1.14 (t, J = 7 Hz, 6H).

ステップＡ：
(S,S)-2-エトキシ-3-[4-(2-{[6-({2-[4-(2-エトキシ-2-エトキシカルボニル-エチル)-フェノキシ]-エチル}-メチル-アミノ)-ピリジン-2-イル]-メチル-アミノ}-エトキシ)-フェニル]-プロピオン酸エチルエステル(例11)を用いて、例２のステップＡのもとで記載した通りに合成し、91mg(93％)の収量で得た。 Example 12 (General Procedure D)
(S, S) -3- [4- (2-{[6-({2- [4- (2-carboxy-2-ethoxy-ethyl) -phenoxy] -ethyl} -methyl-amino) -pyridine- 2-yl] -methyl-amino} -ethoxy) -phenyl] -2-ethoxy-propionic acid

Step A:
(S, S) -2-Ethoxy-3- [4- (2-{[6-({2- [4- (2-Ethoxy-2-ethoxycarbonyl-ethyl) -phenoxy] -ethyl} -methyl- Amino) -pyridin-2-yl] -methyl-amino} -ethoxy) -phenyl] -propionic acid ethyl ester (Example 11) was synthesized as described under Step A of Example 2 to yield 91 mg Obtained in a yield of (93%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.29 (t, J = 7 Hz, 1H); 7.09 (d, J = 8 Hz, 4H); 6.75 (d, J = 8 Hz, 4H); 5.80 (d, J = 7Hz, 2H); 4.12 (t, J = 6Hz, 4H); 4.04 (t, J = 7Hz, 2H); 3.94 (t, J = 7Hz, 4H); 3.62 (m, 2H); 3.42 (m, 2H); 3.07 (s, 6H); 3.05-2.92 (m, 4H); 1.17 (t, J = 7 Hz, 6H).

ステップＤ−Ｅ：
乾燥THF(10mL)中の3-[4'-(3-ヒドロキシ-プロピル)-2,2'-bis-トリフルオロメチル-ビフェニル-4-イル]-プロパン-1-オール（中間体５）(102mg, 0.25mmol)の撹拌した溶液に、０℃で窒素下にて、トリフェニルホスフィン(252mg, 1.0mmol)および(S)-2-エトキシ-3-(4-ヒドロキシ-フェニル)-プロピオン酸イソプロピルエステル(252mg, 1.0mmol)を添加した。該反応混合物を15分撹拌し、アゾジカルボン酸ジエチル(174mg, 1.0mmol)を添加した。該反応物を６ｈ撹拌した後、水(10mL)を添加し、該混合物を塩化メチレンで抽出した(3×20mL)。合体した有機相を乾燥させ(MgSO₄)、濾過し、蒸発させた。粗生成物を、塩化メチレン：THF(100：1)を溶出剤として用いたカラムクロマトグラフィ上で精製して、標題化合物を150mg(69％)の収量で得た。 Example 13 (general procedure A)
(S, S) -2-ethoxy-3- {4- [3- (4 '-{3- [4- (2-ethoxy-2-isopropoxycarbonyl-ethyl) -phenoxy] -propyl} -2, 2'-bis-trifluoromethyl-biphenyl-4-yl) -propoxy] -phenyl} -propionic acid isopropyl ester

Step DE:
3- [4 '-(3-hydroxy-propyl) -2,2'-bis-trifluoromethyl-biphenyl-4-yl] -propan-1-ol (intermediate 5) in dry THF (10 mL) ( 102 mg, 0.25 mmol) to a stirred solution at 0 ° C. under nitrogen, triphenylphosphine (252 mg, 1.0 mmol) and isopropyl (S) -2-ethoxy-3- (4-hydroxy-phenyl) -propionate Ester (252 mg, 1.0 mmol) was added. The reaction mixture was stirred for 15 minutes and diethyl azodicarboxylate (174 mg, 1.0 mmol) was added. After the reaction was stirred for 6 h, water (10 mL) was added and the mixture was extracted with methylene chloride (3 × 20 mL). The combined organic phase was dried (MgSO ₄ ), filtered and evaporated. The crude product was purified on column chromatography using methylene chloride: THF (100: 1) as eluent to give the title compound in 150 mg (69%) yield.

¹ H NMR (400 MHz, CDCl ₃ ): δ 7.57 (s, 2H); 7.37 (d, J = 8 Hz, 2H); 7.18 (m, 6H); 6.83 (d, J = 8 Hz, 4H); 5.04 ( m, 2H); 3.98 (m, 6H); 3.61 (m, 2H); 3.36 (m, 2H); 2.93 (m, 8H); 2.15 (m, 4H); 1.25 (d, J = 6Hz, 12H) 1.17 (t, J = 6Hz, 6H).

ステップＡ：
エタノール(4mL)中の(S,S)-2-エトキシ-3-{4-[3-(4'-{3-[4-(2-エトキシ-2-イソプロポキシカルボニル-エチル)-フェノキシ]-プロピル}-2,2'-bis-トリフルオロメチル-ビフェニル-4-イル)-プロポキシ]-フェニル}-プロピオン酸イソプロピルエステル(例13)の溶液に、1N NaOH(0.6mL)を室温で添加した。該反応物を48時間室温で撹拌し、蒸発させた。残渣を1N HClで処理し、塩化メチレンで抽出した(2×15mL)。合体した有機相を乾燥させ、蒸発させて、標題化合物を105mg(78％)の収量で得た。 Example 14 (General Procedure D)
(S, S) -3- {4- [3- (4 '-{3- [4- (2-carboxy-2-ethoxy-ethyl) -phenoxy] -propyl} -2,2'-bis-tri Fluoromethyl-biphenyl-4-yl) -propoxy] -phenyl} -2-ethoxy-propionic acid

Step A:
(S, S) -2-ethoxy-3- {4- [3- (4 '-{3- [4- (2-ethoxy-2-isopropoxycarbonyl-ethyl) -phenoxy] in ethanol (4 mL) -Propyl} -2,2'-bis-trifluoromethyl-biphenyl-4-yl) -propoxy] -phenyl} -propionic acid isopropyl ester (Example 13) in solution with 1N NaOH (0.6 mL) at room temperature did. The reaction was stirred for 48 hours at room temperature and evaporated. The residue was treated with 1N HCl and extracted with methylene chloride (2 × 15 mL). The combined organic phases were dried and evaporated to give the title compound in 105 mg (78%) yield.

¹ H NMR (400 MHz, CDCl ₃ ): δ 7.56 (s, 2H); 7.47 (d, J = 8 Hz; 2H); 7.18 (m, 6H); 6.84 (d, J = 8 Hz, 4H); 4.05 ( 4.00 (t, J = 6 Hz, 4H); 3.63 (m, 2H); 3.41 (m, 2H); 3.07 (m, 2H); 2.96 (m, 2H); 2.91 (t, J = 6 Hz, 4H); 2.15 (m, 4H); 1.17 (t, J = 6 Hz, 6H).

ステップＤ−Ｅ：
3-[4'-(3-ヒドロキシ-プロピル)-2,2'-bis-トリフルオロメチル-ビフェニル-4-イル]-プロパン-1-オールの代わりに、3-[4'-(3-ヒドロキシ-プロピル)-3,3'-bis-トリフルオロメチル-ビフェニル-4-イル]-プロパン-1-オール（中間体６）(102mg, 0.25mmol)を用いて、例13 のステップＣ−Ａのもとで記載した通りに合成し、標題化合物を205mg(93％)の収量で得た。 Example 15 (general procedure A)
(S, S) -2-ethoxy-3- {4- [3- (4 '-{3- [4- (2-ethoxy-2-isopropoxycarbonyl-ethyl) -phenoxy] -propyl} -3, 3'-bis-trifluoromethyl-biphenyl-4-yl) -propoxy] -phenyl} -propionic acid isopropyl ester

Step DE:
Instead of 3- [4 '-(3-hydroxy-propyl) -2,2'-bis-trifluoromethyl-biphenyl-4-yl] -propan-1-ol, 3- [4'-(3- Hydroxypropyl) -3,3′-bis-trifluoromethyl-biphenyl-4-yl] -propan-1-ol (intermediate 6) (102 mg, 0.25 mmol) was used to prepare Step CA of Example 13 And the title compound was obtained in a yield of 205 mg (93%).

¹ H NMR (400 MHz, CDCl ₃ ): δ 7.82 (s, 2H); 7.67 (d, J = 8 Hz, 2H); 7.45 (d, J = 8 Hz, 2H); 7.16 (d, J = 8 Hz, 4H) 6.84 (d, J = 8 Hz, 4H); 5.04 (m, 2H); 4.01 (t, J = 6 Hz, 4H); 3.96 (t, J = 6 Hz, 2H); 3.61 (m, 2H); 3.37 (m, 2H); 3.04 (t, J = 6 Hz, 4H); 2.95 (d, J = 6 Hz, 4H); 2.14 (m, 4H); 1.28-1.13 (m, 18H).

ステップＡ：
(S,S)-2-エトキシ-3-{4-[3-(4'-{3-[4-(2-エトキシ-2-イソプロポキシカルボニル-エチル)-フェノキシ]-プロピル}-3,3'-bis-トリフルオロメチル-ビフェニル-4-イル)-プロポキシ]-フェニル}-プロピオン酸イソプロピルエステル(例15)を用いて、例14 ステップＡのもとで記載した通りに合成して、標題化合物を167mg(90％)の収量で得た。 Example 16 (General Procedure D)
(S, S) -3- {4- [3- (4 '-{3- [4- (2-carboxy-2-ethoxy-ethyl) -phenoxy] -propyl} -3,3'-bis-tri Fluoromethyl-biphenyl-4-yl) -propoxy] -phenyl} -2-ethoxy-propionic acid

Step A:
(S, S) -2-ethoxy-3- {4- [3- (4 '-{3- [4- (2-ethoxy-2-isopropoxycarbonyl-ethyl) -phenoxy] -propyl} -3, Synthesized as described under Example 14 Step A using 3′-bis-trifluoromethyl-biphenyl-4-yl) -propoxy] -phenyl} -propionic acid isopropyl ester (Example 15) The title compound was obtained in a yield of 167 mg (90%).

¹ H NMR (400 MHz, CDCl ₃ ): δ 7.83 (s, 2H); 7.67 (d, J = 8 Hz, 2H); 7.45 (d, J = 8 Hz, 2H); 7.18 (d, J = 8 Hz, 4H) 6.85 (d, J = 8 Hz, 4H); 4.04 (m, 6H); 3.64 (m, 2H); 3.44 (m, 2H); 3.12-2.93 (m, 8H); 2.14 (m, 4H); 1.19 (t, J = 6Hz, 6H).

ステップＤ−Ｅ：
2-エトキシ-3-(4-ヒドロキシ-フェニル)-プロピオン酸イソプロピルエステルの代わりに、(S)-3-(3-ブロモ-4-ヒドロキシ-フェニル)-2-エトキシ-プロピオン酸イソプロピルエステル（中間体７）(331mg, 1.0mmol)を用いて、例13 のステップＤ−Ｅのもとで記載した通りに合成し、標題化合物を160mg(62％)の収量で得た。 Example 17 (general procedure A)
(S, S) -3- {3-Bromo-4- [3- (4 '-{3- [2-Bromo-4- (2-ethoxy-2-isopropoxycarbonyl-ethyl) -phenoxy] -propyl } -2,2'-bis-trifluoromethyl-biphenyl-4-yl) -propoxy] -phenyl} -2-ethoxy-propionic acid isopropyl ester

Step DE:
Instead of 2-ethoxy-3- (4-hydroxy-phenyl) -propionic acid isopropyl ester, (S) -3- (3-bromo-4-hydroxy-phenyl) -2-ethoxy-propionic acid isopropyl ester (intermediate) Compound 7) (331 mg, 1.0 mmol) was synthesized as described under Example 13, Step DE, to give the title compound in 160 mg (62%) yield.

¹ H NMR (400 MHz, CDCl ₃ ): δ 7.58 (s, 2H); 7.45 (s, 2H); 7.40 (d, J = 8 Hz, 2H); 7.19 (d, J = 8 Hz, 2H); 7.14 ( d, J = 8Hz, 2H); 6.78 (d, J = 8Hz, 2H); 5.05 (m, 2H); 4.04 (t, J = 6Hz, 4H); 3.94 (t, J = 6Hz, 2H); 3.63 (m, 2H); 3.37 (m, 2H); 2.99 (t, J = 6Hz, 4H); 2.93 (d, J = 6Hz, 4H); 2.20 (m, 4H); 1.27-1-14 (m, 18H).

ステップＡ：
(S,S)-3-{3-ブロモ-4-[3-(4'-{3-[2-ブロモ-4-(2-エトキシ-2-イソプロポキシカルボニル-エチル)-フェノキシ]-プロピル}-2,2'-bis-トリフルオロメチル-ビフェニル-4-イル)-プロポキシ]-フェニル}-2-エトキシ-プロピオン酸イソプロピルエステル(例17)を用いて、例14のステップＡのもとで記載した通りに合成し、標題化合物を112mg(76％)の収量で得た。 Example 18 (general procedure D)
(S, S) -3- {3-bromo-4- [3- (4 '-{3- [2-bromo-4- (2-carboxy-2-ethoxy-ethyl) -phenoxy] -propyl}- 2,2'-bis-trifluoromethyl-biphenyl-4-yl) -propoxy] -phenyl} -2-ethoxy-propionic acid

Step A:
(S, S) -3- {3-Bromo-4- [3- (4 '-{3- [2-Bromo-4- (2-ethoxy-2-isopropoxycarbonyl-ethyl) -phenoxy] -propyl } -2,2'-bis-trifluoromethyl-biphenyl-4-yl) -propoxy] -phenyl} -2-ethoxy-propionic acid isopropyl ester (Example 17) under Example 14 Step A To give 112 mg (76%) of the title compound.

¹ H NMR (400 MHz, CDCl ₃ ): δ 7.58 (s, 2H); 7.47 (s, 2H); 7.39 (d, J = 8 Hz, 2H); 7.20 (d, J = 8 Hz, 2H); 7.15 ( d, J = 8Hz, 2H); 6.78 (d, J = 8Hz, 2H); 4.02 (m, 6H); 3.65 (m, 2H); 3.40 (m, 2H); 3.08-2.90 (m, 8H); 2.20 (m, 4H); 1.19 (t, J = 6Hz, 6H).

ステップＤ−Ｅ：
3-[4'-(3-ヒドロキシ-プロピル)-2,2'-bis-トリフルオロメチル-ビフェニル-4-イル]-プロパン-1-オールの代わりに、3-[4'-(3-ヒドロキシ-プロピル)-3,3'-bis-トリフルオロメチル-ビフェニル-4-イル]-プロパン-1-オール（中間体６）(102mg, 0.25mmol)を用いて、例17のステップＤ−Ｅのもとで記載した通りに合成し、標題化合物を132mg(51％)の収量で得た。 Example 19 (general procedure A)
(S, S) -3- {3-Bromo-4- [3- (4 '-{3- [2-Bromo-4- (2-ethoxy-2-isopropoxycarbonyl-ethyl) -phenoxy] -propyl } -3,3'-bis-trifluoromethyl-biphenyl-4-yl) -propoxy] -phenyl} -2-ethoxy-propionic acid isopropyl ester

Step DE:
Instead of 3- [4 '-(3-hydroxy-propyl) -2,2'-bis-trifluoromethyl-biphenyl-4-yl] -propan-1-ol, 3- [4'-(3- Hydroxypropyl) -3,3′-bis-trifluoromethyl-biphenyl-4-yl] -propan-1-ol (Intermediate 6) (102 mg, 0.25 mmol) was used to prepare Step DE of Example 17 And the title compound was obtained in a yield of 132 mg (51%).

¹ H NMR (400 MHz, CDCl ₃ ): δ 7.82 (s, 2H); 7.67 (d, J = 8 Hz, 2H); 7.47 (m, 4H); 7.15 (d, J = 8 Hz, 2H); 6.80 ( d, J = 8Hz, 2H); 5.05 (m, 2H); 4.05 (t, J = 6Hz, 4H); 3.93 (t, J = 6Hz, 2H); 3.63 (m, 2H); 3.37 (m, 2H) 3.10 (t, J = 7 Hz, 4H); 2.94 (d, J = 6 Hz, 4H); 2.17 (m, 4H); 1.28-1.14 (m, 18H).

ステップＡ：
(S,S)-3-{3-ブロモ-4-[3-(4'-{3-[2-ブロモ-4-(2-エトキシ-2-イソプロポキシカルボニル-エチル)-フェノキシ]-プロピル}-3,3'-bis-トリフルオロメチル-ビフェニル-4-イル)-プロポキシ]-フェニル}-2-エトキシ-プロピオン酸イソプロピルエステル(例19)を用いて、例14のステップＡのもとで記載した通りに合成し、標題化合物を95mg(78％)の収量で得た。 Example 20 (general procedure D)
(S, S) -3- {3-bromo-4- [3- (4 '-{3- [2-bromo-4- (2-carboxy-2-ethoxy-ethyl) -phenoxy] -propyl}- 3,3'-bis-trifluoromethyl-biphenyl-4-yl) -propoxy] -phenyl} -2-ethoxy-propionic acid

Step A:
(S, S) -3- {3-Bromo-4- [3- (4 '-{3- [2-Bromo-4- (2-ethoxy-2-isopropoxycarbonyl-ethyl) -phenoxy] -propyl } -3,3'-bis-trifluoromethyl-biphenyl-4-yl) -propoxy] -phenyl} -2-ethoxy-propionic acid isopropyl ester (Example 19) under Example 14 Step A And the title compound was obtained in a yield of 95 mg (78%).

¹ H NMR (400 MHz, CDCl ₃ ): δ 7.82 (s, 2H); 7.67 (d, J = 8 Hz, 2H); 7.49 (m, 4H); 7.15 (d, J = 8 Hz, 2H); 6.82 ( d, J = 8 Hz, 2H); 4.05 (m, 6H); 3.66 (m, 2H); 3.42 (m, 2H); 3.14-2.90 (m, 8H); 2.16 (m, 4H); 1.19 (t, J = 6Hz, 6H).

ステップＤ−Ｅ：
3-[4'-(3-ヒドロキシ-プロピル)-2,2'-bis-トリフルオロメチル-ビフェニル-4-イル]-プロパン-1-オールの代わりに、3-[7-(3-ヒドロキシ-プロピル)-9H-フルオレン-2-イル]-プロパン-1-オール(中間体8)(85mg, 0.30mmol)を用いて、例17のステップＤ−Ｅのもとで記載した通りに合成し、標題化合物を100mg(37％)の収量で得た。
¹H NMR(400MHz, CDCl₃)：δ7.64(d, J＝8Hz, 2H)；7.44(s, 2H)；7.36(s, 2H)；7.22(d, J＝8Hz, 2H)；7.10(d, J＝8Hz, 2H)；6.75(d, J＝8Hz, 2H)；5.50(m, 2H)；3.99(t, J＝6Hz, 4H)；3.94(t, J＝6Hz, 2H)；3.82(s, 2H)；3.62(m, 2H)；3.55(m, 2H)；2.90(m, 8H)；2.17(m, 4H)；1.27-1.14(m, 18H)。 Example 21 (general procedure A)
(S, S) -3- {3-bromo-4- [3- (7- {3- [2-bromo-4- (2-ethoxy-2-isopropoxycarbonyl-ethyl) -phenoxy] -propyl} -9H-Fluoren-2-yl) -propoxy] -phenyl} -2-ethoxy-propionic acid isopropyl ester

Step DE:
Instead of 3- [4 '-(3-hydroxy-propyl) -2,2'-bis-trifluoromethyl-biphenyl-4-yl] -propan-1-ol, 3- [7- (3-hydroxy -Propyl) -9H-fluoren-2-yl] -propan-1-ol (Intermediate 8) (85 mg, 0.30 mmol) was synthesized as described under Example 17, Step DE. The title compound was obtained in a yield of 100 mg (37%).
¹ H NMR (400 MHz, CDCl ₃ ): δ 7.64 (d, J = 8 Hz, 2H); 7.44 (s, 2H); 7.36 (s, 2H); 7.22 (d, J = 8 Hz, 2H); 7.10 ( d, J = 8Hz, 2H); 6.75 (d, J = 8Hz, 2H); 5.50 (m, 2H); 3.99 (t, J = 6Hz, 4H); 3.94 (t, J = 6Hz, 2H); 3.82 (s, 2H); 3.62 (m, 2H); 3.55 (m, 2H); 2.90 (m, 8H); 2.17 (m, 4H); 1.27-1.14 (m, 18H).

ステップＡ：
(S,S)-3-{3-ブロモ-4-[3-(7-{3-[2-ブロモ-4-(2-エトキシ-2-イソプロポキシカルボニル-エチル)-フェノキシ]-プロピル}-9H-フルオレン-2-イル)-プロポキシ]-フェニル}-2-エトキシ-プロピオン酸イソプロピルエステル(例21)を用いて、例14のステップＡのもとで記載した通りに合成し、標題化合物を51mg(56％)の収量で得た。 Example 22 (general procedure D)
(S, S) -3- {3-bromo-4- [3- (7- {3- [2-bromo-4- (2-carboxy-2-ethoxy-ethyl) -phenoxy] -propyl} -9H -Fluoren-2-yl) -propoxy] -phenyl} -2-ethoxy-propionic acid

Step A:
(S, S) -3- {3-bromo-4- [3- (7- {3- [2-bromo-4- (2-ethoxy-2-isopropoxycarbonyl-ethyl) -phenoxy] -propyl} -9H-Fluoren-2-yl) -propoxy] -phenyl} -2-ethoxy-propionic acid isopropyl ester (Example 21) was synthesized as described under Step A of Example 14 to give the title compound Was obtained in a yield of 51 mg (56%).

¹ H NMR (400 MHz, CDCl ₃ ): δ 7.57 (s, 2H); 7.47 (s, 2H); 7.38 (d, J = 8 Hz, 2H); 7.18 (d, J = 8 Hz, 2H); 7.14 ( d, J = 8Hz, 2H); 6.80 (d, J = 8Hz, 2H); 4.03 (t, J = 6Hz, 6H); 3.65 (m, 2H); 3.40 (m, 2H); 3.07-2.88 (m , 8H); 2.19 (m, 4H); 1.19 (t, J = 6 Hz, 6H).

ステップＤ−Ｅ：
3-[4'-(3-ヒドロキシ-プロピル)-2,2'-bis-トリフルオロメチル-ビフェニル-4-イル]-プロパン-1-オールの代わりに、3-[7-(3-ヒドロキシ-プロピル)-9H-フルオレン-2-イル]-プロパン-1-オール（中間体８）(102mg, 0.25mmol)を用いて、例13のステップＤ−Ｅのもとで記載した通りに合成し、標題化合物を100mg(45％)の収量で得た。 Example 23 (general procedure A)
(S, S) -2-Ethoxy-3- {4- [3- (7- {3- [4- (2-Ethoxy-2-isopropoxycarbonyl-ethyl) -phenoxy] -propyl} -9H-fluorene -2-yl) -propoxy] -phenyl} -propionic acid isopropyl ester

Step DE:
Instead of 3- [4 '-(3-hydroxy-propyl) -2,2'-bis-trifluoromethyl-biphenyl-4-yl] -propan-1-ol, 3- [7- (3-hydroxy -Propyl) -9H-fluoren-2-yl] -propan-1-ol (intermediate 8) (102 mg, 0.25 mmol) was synthesized as described under Example 13 Step DE. The title compound was obtained in a yield of 100 mg (45%).

¹ H NMR (400 MHz, CDCl ₃ ): δ 7.64 (d, J = 8 Hz, 2H); 7.35 (s, 2H); 7.18 (d, J = 8 Hz, 2H); 7.15 (d, J = 8 Hz, 4H) 6.80 (d, J = 8 Hz, 4H); 5.02 (m, 2H); 3.95 (m, 6H); 3.82 (s, 2H); 3.60 (m, 2H); 3.35 (m, 2H); 2.94 ( d, J = 7 Hz, 4H); 2.86 (t, J = 7 Hz, 4H); 2.12 (m, 4H); 1.25-1.14 (m, 18H).

ステップＡ：
(S,S)-2-エトキシ-3-{4-[3-(7-{3-[4-(2-エトキシ-2-イソプロポキシカルボニル-エチル)-フェノキシ]-プロピル}-9H-フルオレン-2-イル)-プロポキシ]-フェニル}-プロピオン酸イソプロピルエステル(例23)を用いて、例14のステップＡのもとで記載した通りに合成し、標題化合物を65mg(73％)の収量で得た。 Example 24 (general procedure D)
(S, S) -3- {4- [3- (7- {3- [4- (2-carboxy-2-ethoxy-ethyl) -phenoxy] -propyl} -9H-fluoren-2-yl)- Propoxy] -phenyl} -2-ethoxy-propionic acid

Step A:
(S, S) -2-Ethoxy-3- {4- [3- (7- {3- [4- (2-Ethoxy-2-isopropoxycarbonyl-ethyl) -phenoxy] -propyl} -9H-fluorene 2-yl) -propoxy] -phenyl} -propionic acid isopropyl ester (Example 23) was synthesized as described under Example 14, Step A, yielding 65 mg (73%) of the title compound. I got it.

¹ H NMR (400 MHz, CDCl ₃ ): δ 7.65 (d, J = 8 Hz, 2H); 7.36 (s, 2H); 7.18 (d, J = 8 Hz, 2H); 7.16 (d, J = 8 Hz, 4H) 6.83 (d, J = 8 Hz, 4H); 4.04 (m, 2H); 3.96 (t, J = 6 Hz, 4H); 3,82 (s, 2H); 3.63 (m, 2H); 3.44 (m 3.06 (m, 2H); 2.96 (m, 2H); 2.86 (t, J = 7Hz, 4H); 2.12 (m, 4H); 1.17 (t, J = 6Hz, 6H).

ステップＤ−Ｅ：
窒素下において、THF(10mL)中の3-[4'-(3-ヒドロキシ-プロピル)-2,2'-bis-トリフルオロメチル-ビフェニル-4-イル]-プロパン-1-オール（中間体５）(102mg, 0,25mmol)およびトリブチルホスフィン(203mg, 1.0mmol)の溶液に、アゾジカルボキシジピペリジン(253mg, 1.0mmol)を０℃で添加した。該反応混合物を10分撹拌した後、(4-メルカプト-2-メチル-フェノキシ)-酢酸メチルエステル（中間体１）(213mg, 1.0mmol)を数回に分けて5分間に亘り添加した。該反応混合物を０℃で２ｈ、および室温で１ｈ撹拌した。水(20mL)を添加し、該反応混合物を塩化メチレンで抽出した(3×25mL)。合体した有機相を乾燥させ(MgSO₄)、濾過し、蒸発させ、粗生成物を得た。残渣を、塩化メチレン：THF(100：1)を溶出剤として用いたカラムクロマトグラフィ上で精製し、標題化合物を102mg(51％)の収量で得た。 Example 25 (general procedure A)
[4- (3- {4 '-[3- (4-Methoxycarbonylmethoxy-3-methyl-phenylsulfanyl) -propyl] -2,2'-bis-trifluoromethyl-biphenyl-4-yl} -propyl Sulfanyl) -2-methyl-phenoxy] -acetic acid methyl ester

Step DE:
Under nitrogen, 3- [4 '-(3-hydroxy-propyl) -2,2'-bis-trifluoromethyl-biphenyl-4-yl] -propan-1-ol (intermediate) in THF (10 mL) 5) To a solution of (102 mg, 0,25 mmol) and tributylphosphine (203 mg, 1.0 mmol), azodicarboxydipiperidine (253 mg, 1.0 mmol) was added at 0 ° C. After the reaction mixture was stirred for 10 minutes, (4-mercapto-2-methyl-phenoxy) -acetic acid methyl ester (Intermediate 1) (213 mg, 1.0 mmol) was added in several portions over 5 minutes. The reaction mixture was stirred at 0 ° C. for 2 h and at room temperature for 1 h. Water (20 mL) was added and the reaction mixture was extracted with methylene chloride (3 × 25 mL). The combined organic phases were dried (MgSO ₄ ), filtered and evaporated to give the crude product. The residue was purified on column chromatography using methylene chloride: THF (100: 1) as eluent to give the title compound in 102 mg (51%) yield.

¹ H NMR (400 MHz, CDCl ₃ ): δ 7.51 (s, 2H); 7.35-7.14 (m, 8H); 6.64 (d, J = 8 Hz, 2H); 4.63 (s, 4H); 3.79 (s, 6H); 2.86 (m, 8H); 2.26 (s, 6H); 1.95 (m, 4H).

ステップＡ：
エタノール(5mL)中の[4-(3-{4'-[3-(4-メトキシカルボニルメトキシ-3-メチル-フェニルスルファニル)-プロピル]-2,2'-bis-トリフルオロメチル-ビフェニル-4-イル}-プロピルスルファニル)-2-メチル-フェノキシ]-酢酸メチルエステル(例25)(102mg, 0.12mmol)の溶液に、1N NaOH水溶液(0.5mL)を添加した。該反応混合物を３時間室温で撹拌し、蒸発させた。残渣に水(10mL)および1N HCl(0.6mL)を添加し、該混合物を塩化メチレンで抽出した(2×30mL)。合体した有機相を乾燥させ(MgSO₄)、濾過し、蒸発させて、標題化合物を96mg(98％)の収量で得た。 Example 26 (General Procedure D)
[4- (3- {4 '-[3- (4-Carboxymethyl-3-methyl-phenylsulfanyl) -propyl] -2,2'-bis-trifluoromethyl-biphenyl-4-yl} -propylsulfanyl ) -2-Methyl-phenoxy] -acetic acid

Step A:
[4- (3- {4 '-[3- (4-Methoxycarbonylmethoxy-3-methyl-phenylsulfanyl) -propyl] -2,2'-bis-trifluoromethyl-biphenyl- in ethanol (5 mL) To a solution of 4-yl} -propylsulfanyl) -2-methyl-phenoxy] -acetic acid methyl ester (Example 25) (102 mg, 0.12 mmol) was added 1N aqueous NaOH (0.5 mL). The reaction mixture was stirred for 3 hours at room temperature and evaporated. To the residue was added water (10 mL) and 1N HCl (0.6 mL) and the mixture was extracted with methylene chloride (2 × 30 mL). The combined organic phases were dried (MgSO ₄ ), filtered and evaporated to give the title compound in 96 mg (98%) yield.

¹ H NMR (400 MHz, CDCl ₃ ): δ 7.51 (s, 2H); 7.32 (d, J = 8 Hz, 2H); 7.15 (m, 6H); 6.65 (d, J = 8 Hz, 2H); 4.64 ( s, 4H); 2.85 (m, 8H); 2.25 (s, 6H); 1.95 (m, 4H).

ステップＤ−Ｅ：
3-[4'-(3-ヒドロキシ-プロピル)-2,2'-bis-トリフルオロメチル-ビフェニル-4-イル]-プロパン-1-オールの代わりに、3-[4'-(3-ヒドロキシ-プロピル)-3,3'-bis-トリフルオロメチル-ビフェニル-4-イル]-プロパン-1-オール（中間体６）(102mg, 0.25mmol)を用いて、例25のステップＤ−Ｅ のもとで記載した通りに合成し、標題化合物を130mg(65％)の収量で得た。 Example 27 (general procedure A)
[4- (3- {4 '-[3- (4-methoxycarbonylmethoxy-3-methyl-phenylsulfanyl) -propyl] -3,3'-bis-trifluoromethyl-biphenyl-4-yl} -propyl Sulfanyl) -2-methyl-phenoxy] -acetic acid methyl ester

Step DE:
Instead of 3- [4 '-(3-hydroxy-propyl) -2,2'-bis-trifluoromethyl-biphenyl-4-yl] -propan-1-ol, 3- [4'-(3- Hydroxypropyl) -3,3′-bis-trifluoromethyl-biphenyl-4-yl] -propan-1-ol (Intermediate 6) (102 mg, 0.25 mmol) was used to prepare Step DE of Example 25. And the title compound was obtained in a yield of 130 mg (65%).

¹ H NMR (400 MHz, CDCl ₃ ): δ 7.77 (s, 2H); 7.65 (d, J = 8 Hz, 2H); 7.37 (d, J = 8 Hz, 2H); 7.22 (m, 4H); 6.64 ( d, J = 8 Hz, 2H); 4.64 (s, 4H); 3.81 (s, 6H); 2.93 (m, 8H); 2.26 (s, 6H); 1.93 (m, 4H).

ステップＡ：
[4-(3-{4'-[3-(4-メトキシカルボニルメトキシ-3-メチル-フェニルスルファニル)-プロピル]-3,3'-bis-トリフルオロメチル-ビフェニル-4-イル}-プロピルスルファニル)-2-メチル-フェノキシ]-酢酸メチルエステル(例27)を用いて、例26のステップＡのもとで記載した通りに合成し、標題化合物を130mg(96％)の収量で得た。 Example 28 (General Procedure D)
[4- (3- {4 '-[3- (4-Carboxymethyl-3-methyl-phenylsulfanyl) -propyl] -3,3'-bis-trifluoromethyl-biphenyl-4-yl} -propylsulfanyl ) -2-Methyl-phenoxy] -acetic acid

Step A:
[4- (3- {4 '-[3- (4-methoxycarbonylmethoxy-3-methyl-phenylsulfanyl) -propyl] -3,3'-bis-trifluoromethyl-biphenyl-4-yl} -propyl Sulfanyl) -2-methyl-phenoxy] -acetic acid methyl ester (Example 27) was synthesized as described under Example 26, Step A to give the title compound in 130 mg (96%) yield. .

¹ H NMR (400 MHz, MeOD): δ 7.81 (s, 2H); 7.75 (d, J = 8 Hz, 2H); 7.43 (J = 8 Hz, 2H); 7.17 (m, 4H); 6.75 (d, J = 8 Hz, 2H); 4.64 (s, 4H); 2.90 (m, 8H); 2.24 (s, 6H); 1.87 (m, 4H).

ステップＤ−Ｅ：
3-[4'-(3-ヒドロキシ-プロピル)-2,2'-bis-トリフルオロメチル-ビフェニル-4-イル]-プロパン-1-オールの代わりに、3-[7-(3-ヒドロキシ-プロピル)-9H-フルオレン-2-イル]-プロパン-1-オール（中間体８）(85mg, 0.3mmol)を用いて、例25 ステップＤ−Ｅのもとで記載した通りに合成し、ヘプタン：酢酸エチル(5：2)を溶出剤として使用した第２のカラム精製後に標題化合物を34mg(17％)で得た。 Example 29 (general procedure A)
[4- (3- {7- [3- (4-methoxycarbonylmethoxy-3-methyl-phenylsulfanyl) -propyl] -9H-fluoren-2-yl} -propylsulfanyl) -2-methyl-phenoxy]- Acetic acid methyl ester

Step DE:
Instead of 3- [4 '-(3-hydroxy-propyl) -2,2'-bis-trifluoromethyl-biphenyl-4-yl] -propan-1-ol, 3- [7- (3-hydroxy -Propyl) -9H-fluoren-2-yl] -propan-1-ol (intermediate 8) (85 mg, 0.3 mmol) was synthesized as described under Example 25 Step DE. After a second column purification using heptane: ethyl acetate (5: 2) as eluent, the title compound was obtained in 34 mg (17%).

¹ H NMR (400 MHz, CDCl ₃ ): δ 7.64 (d, J = 8 Hz, 2H); 7.33 (s, 2H); 7.15 (m, 6H); 6.70 (d, J = 8 Hz, 2H); 4.63 ( 3.82 (s, 6H); 2.85 (t, J = 6Hz, 4H); 2.79 (t, J = 6Hz, 4H); 2.26 (s, 6H); 1.94 (s, 4H); m, 4H).

ステップＡ：
[4-(3-{7-[3-(4-メトキシカルボニルメトキシ-3-メチル-フェニルスルファニル)-プロピル]-9H-フルオレン-2-イル}-プロピルスルファニル)-2-メチル-フェノキシ]-酢酸メチルエステル(例29)を用いて、例26のステップＡのもとで記載した通りに合成し、標題化合物を27mg(73％)の収量で得た。 Example 30 (general procedure D)
[4- (3- {7- [3- (4-Carboxymethyl-3-methyl-phenylsulfanyl) -propyl] -9H-fluoren-2-yl} -propylsulfanyl) -2-methyl-phenoxy] -acetic acid

Step A:
[4- (3- {7- [3- (4-methoxycarbonylmethoxy-3-methyl-phenylsulfanyl) -propyl] -9H-fluoren-2-yl} -propylsulfanyl) -2-methyl-phenoxy]- Synthesis using acetic acid methyl ester (Example 29) as described under Step A of Example 26 gave the title compound in 27 mg (73%) yield.

¹ H NMR (400 MHz, DMSO): δ 7.73 (d, J = 8 Hz, 2H); 7.35 (s, 2H); 7.16 (m, 6H); 6.78 (d, J = 8 Hz, 2H); 4.67 (s 3.83 (s, 2H); 2.87 (t, J = 6 Hz, 4H); 2.75 (t, J = 6 Hz, 4H); 2.16 (s, 6H); 1.84 (m, 4H).

ステップＤ−Ｅ：
3-[4'-(3-ヒドロキシ-プロピル)-2,2'-bis-トリフルオロメチル-ビフェニル-4-イル]-プロパン-1-オールの代わりに、2-(2-{3-[4-(2-ヒドロキシ-エチル)-5-メチル-オキサゾール-2-イル]-フェニル}-5-メチル-オキサゾール-4-イル)-エタノール（中間体９）(99mg, 0.3mmol)を用いて、例25のステップＤ−Ｅのもとで記載した通りに合成し、塩化メチレン：THF(50：1)を溶出剤として使用した第２のカラム精製後に、標題化合物を123mg(57％)の収量で得た。 Example 31 (general procedure A)
(4- {2- [2- (3- {4- [2- (4-methoxycarbonylmethoxy-3-methyl-phenylsulfanyl) -ethyl] -5-methyl-oxazol-2-yl} -phenyl)- 5-Methyl-oxazol-4-yl] -ethylsulfanyl} -2-methyl-phenoxy) -acetic acid methyl ester

Step DE:
Instead of 3- [4 '-(3-hydroxy-propyl) -2,2'-bis-trifluoromethyl-biphenyl-4-yl] -propan-1-ol, 2- (2- {3- [ With 4- (2-hydroxy-ethyl) -5-methyl-oxazol-2-yl] -phenyl} -5-methyl-oxazol-4-yl) -ethanol (intermediate 9) (99 mg, 0.3 mmol) , Synthesized as described under Example 25, Step DE, and after a second column purification using methylene chloride: THF (50: 1) as the eluent, the title compound was 123 mg (57%) Obtained in yield.

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.49 (s, 1H); 7.99 (d, J = 8 Hz, 2H); 7.48 (t, J = 8 Hz, 1H); 7.23 (s, 2H); 7.17 ( d, J = 8Hz, 2H); 6.61 (d, J = 8Hz, 2H); 4.58 (s, 4H); 3.80 (s, 6H); 3.17 (t, J = 7Hz, 4H); 2.78 (t, J = 7 Hz, 4H); 2.32 (s, 6H); 2.24 (s, 6H).

ステップＡ：
(4-{2-[2-(3-{4-[2-(4-メトキシカルボニルメトキシ-3-メチル-フェニルスルファニル)-エチル]-5-メチル-オキサゾール-2-イル}-フェニル)-5-メチル-オキサゾール-4-イル]-エチルスルファニル}-2-メチル-フェノキシ)-酢酸メチルエステル(例31)を用いて、例26 ステップＡのもとで記載した通りに合成し、標題化合物を108mg(92％)の収量で得た。 Example 32 (General Procedure D)
(4- {2- [2- (3- {4- [2- (4-carboxymethyl-3-methyl-phenylsulfanyl) -ethyl] -5-methyl-oxazol-2-yl} -phenyl) -5 -Methyl-oxazol-4-yl] -ethylsulfanyl} -2-methyl-phenoxy) -acetic acid

Step A:
(4- {2- [2- (3- {4- [2- (4-methoxycarbonylmethoxy-3-methyl-phenylsulfanyl) -ethyl] -5-methyl-oxazol-2-yl} -phenyl)- 5-methyl-oxazol-4-yl] -ethylsulfanyl} -2-methyl-phenoxy) -acetic acid methyl ester (Example 31) was synthesized as described under Example 26 Step A to give the title compound Was obtained in a yield of 108 mg (92%).

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.37 (s, 1H); 7.95 (d, J = 8 Hz, 2H); 7.47 (t, J = 8 Hz, 1H); 7.16 (s, 2H); 7.06 ( d, J = 8Hz, 2H); 6.54 (d, J = 8Hz, 2H); 4.52 (s, 4H); 3.15 (t, J = 7Hz, 4H); 2.82 (t, J = 7Hz, 4H); 2.24 (s, 6H); 2.19 (s, 6H).

ステップＤ−Ｅ：
3-[4'-(3-ヒドロキシ-プロピル)-2,2'-bis-トリフルオロメチル-ビフェニル-4-イル]-プロパン-1-オールの代わりに、2-(2-{4'-[4-(2-ヒドロキシ-エチル)-5-メチル-オキサゾール-2-イル]-ビフェニル-4-イル}-5-メチル-オキサゾール-4-イル)-エタノール（中間体１０）(101mg, 0.25mmol)を用いて、例13 ステップＤ−Ｅのもとで記載した通りに合成し、標題化合物を5mg(2％)の収量で得た。 Example 33 (General Procedure A)
(S, S) -2-ethoxy-3- [4- (2- {2- [4 '-(4- {2- [4- (2-ethoxy-2-isopropoxycarbonyl-ethyl) -phenoxy] -Ethyl} -5-methyl-oxazol-2-yl) -biphenyl-4-yl] -5-methyl-oxazol-4-yl} -ethoxy) -phenyl] -propionic acid isopropyl ester

Step DE:
Instead of 3- [4 '-(3-hydroxy-propyl) -2,2'-bis-trifluoromethyl-biphenyl-4-yl] -propan-1-ol, 2- (2- {4'- [4- (2-Hydroxy-ethyl) -5-methyl-oxazol-2-yl] -biphenyl-4-yl} -5-methyl-oxazol-4-yl) -ethanol (intermediate 10) (101 mg, 0.25 The title compound was obtained in a yield of 5 mg (2%) as described under Example 13 Step DE.

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.05 (d, J = 8 Hz, 4H); 7.70 (d, J = 8 Hz, 4H); 7.15 (d, J = 8 Hz, 4H); 6.83 (d, J = 8Hz, 4H); 5.02 (m, 2H); 4.23 (t, J = 6Hz, 4H); 3.94 (t, J = 6Hz, 2H); 3,58 (m, 2H); 3.35 (m, 2H) 2,99 (t, J = 6 Hz, 4H); 2.94 (d, J = 6 Hz, 4H); 2.39 (s, 6H); 1.24-1.13 (m, 18H).

ステップＡ：
(S,S)-2-エトキシ-3-[4-(2-{2-[4'-(4-{2-[4-(2-エトキシ-2-イソプロポキシカルボニル-エチル)-フェノキシ]-エチル}-5-メチル-オキサゾール-2-イル)-ビフェニル-4-イル]-5-メチル-オキサゾール-4-イル}-エトキシ)-フェニル]-プロピオン酸イソプロピルエステル(例33)を使用して、例26 のステップＡのもとで記載した通りに合成し、標題化合物を4mg(100％)の収量で得た。 Example 34 (General Procedure D)
(S, S) -3- [4- (2- {2- [4 '-(4- {2- [4- (2-carboxy-2-ethoxy-ethyl) -phenoxy] -ethyl} -5- Methyl-oxazol-2-yl) -biphenyl-4-yl] -5-methyl-oxazol-4-yl} -ethoxy) -phenyl] -2-ethoxy-propionic acid

Step A:
(S, S) -2-ethoxy-3- [4- (2- {2- [4 '-(4- {2- [4- (2-ethoxy-2-isopropoxycarbonyl-ethyl) -phenoxy] -Ethyl} -5-methyl-oxazol-2-yl) -biphenyl-4-yl] -5-methyl-oxazol-4-yl} -ethoxy) -phenyl] -propionic acid isopropyl ester (Example 33) Was synthesized as described under Example 26, Step A to give the title compound in 4 mg (100%) yield.

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.05 (d, J = 8 Hz, 4H); 7.68 (d, J = 8 Hz, 4H); 7.12 (m, 4H); 6.83 (d, J = 8 Hz, 2H) 6.77 (d, J = 8 Hz, 2H); 4.24 (t, J = 6 Hz, 4H); 4.05 (m, 2H); 3.58 (m, 2H); 3.48 (m, 2H); 3.12-2.95 (m) , 4H); 1.16 (t, J = 6 Hz, 6H).

ステップＤ−Ｅ：
3-[4'-(3-ヒドロキシ-プロピル)-2,2'-bis-トリフルオロメチル-ビフェニル-4-イル]-プロパン-1-オールの代わりに、2-(2-{3-[4-(2-ヒドロキシ-エチル)-5-メチル-オキサゾール-2-イル]-フェニル}-5-メチル-オキサゾール-4-イル)-エタノール（中間体９）(164mg, 0.5mmol)を用いて、例13のステップＤ−Ｅのもとで記載した通りに合成し、標題化合物を313mg(84％)の収量で得た。 Example 35 (General Procedure A)
(S, S) -2-ethoxy-3- [4- (2- {2- [3- (4- {2- [4- (2-ethoxy-2-isopropoxycarbonyl-ethyl) -phenoxy]- Ethyl} -5-methyl-oxazol-2-yl) -phenyl] -5-methyl-oxazol-4-yl} -ethoxy) -phenyl] -propionic acid isopropyl ester

Step DE:
Instead of 3- [4 '-(3-hydroxy-propyl) -2,2'-bis-trifluoromethyl-biphenyl-4-yl] -propan-1-ol, 2- (2- {3- [ Using 4- (2-hydroxy-ethyl) -5-methyl-oxazol-2-yl] -phenyl} -5-methyl-oxazol-4-yl) -ethanol (intermediate 9) (164 mg, 0.5 mmol) Synthesized as described under Example 13, Step D-E, to give the title compound in 313 mg (84%) yield.

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.57 (s, 1H); 8.03 (d, J = 8 Hz, 2H); 7.47 (t, J = 8 Hz, 1H); 7.14 (d, J = 8 Hz, 4H 6.82 (d, J = 8Hz, 4H); 5.02 (m, 2H); 4.23 (t, J = 6Hz, 4H); 3.93 (t, J = 7Hz, 2H); 3.58 (m, 2H); 3.34 (m, 2H); 2.98 (t, J = 6Hz, 4H); 2.93 (d, J = 6Hz, 4H); 2.38 (s, 6H); 1.30-1.12 (m, 18H).

ステップＡ：
(S,S)-2-エトキシ-3-[4-(2-{2-[3-(4-{2-[4-(2-エトキシ-2-イソプロポキシカルボニル-エチル)-フェノキシ]-エチル}-5-メチル-オキサゾール-2-イル)-フェニル]-5-メチル-オキサゾール-4-イル}-エトキシ)-フェニル]-プロピオン酸イソプロピルエステル(例35)を用いて、例26のステップＡのもとで記載した通りに合成し、標題化合物を150mg(44％)の収量で得た。 Example 36 (General Procedure D)
(S, S) -3- [4- (2- {2- [3- (4- {2- [4- (2-carboxy-2-ethoxy-ethyl) -phenoxy] -ethyl} -5-methyl -Oxazol-2-yl) -phenyl] -5-methyl-oxazol-4-yl} -ethoxy) -phenyl] -2-ethoxy-propionic acid

Step A:
(S, S) -2-ethoxy-3- [4- (2- {2- [3- (4- {2- [4- (2-ethoxy-2-isopropoxycarbonyl-ethyl) -phenoxy]- Ethyl} -5-methyl-oxazol-2-yl) -phenyl] -5-methyl-oxazol-4-yl} -ethoxy) -phenyl] -propionic acid isopropyl ester (Example 35) Synthesized as described under A to give the title compound in 150 mg (44%) yield.

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.45 (s, 1H); 7.94 (d, J = 8 Hz, 2H); 7.42 (t, J = 8 Hz, 1H); 7.06 (d, J = 8 Hz, 4H) 6.72 (d, J = 8 Hz, 4H); 4.14 (t, J = 6 Hz, 4H); 3.94 (m, 2H); 3.52 (m, 2H); 3.32 (m, 2H); 3.02-2.81 (m) , 8H); 2.26 (s, 6H); 1.06 (t, J = 6 Hz, 6H).

ステップＡ−Ｂ：
(2-クロロ-4-メルカプト-フェニルスルファニル)-酢酸エチルエステル(中間体13)(3.7g, 7mmol)をジメチルアセトアミド(20mL)中に溶解させた。ホウ水素化ナトリウム(0.5g, 13.2mmol)を５℃で数回に分けて添加し、該混合物を30分撹拌した。2-ブタノン(35mL)に溶解させた3,3'-ビストリフルオロメチル-4,4'-ビフェニルジプロパノール（中間体６）ビスメタンスルホネート(3.25g, 5.8mmol)、および炭酸カリウム(1.4g, 10mmol)を添加し、該混合物を48ｈ実験室温度で撹拌した。水およびベンゼンを添加し、有機相を分離し、乾燥させ(K₂CO₃)、濾過し、蒸発させて残渣を得、これをシリカゲル上でのクロマトグラフィ(100g, ベンゼン)により精製した。これにより3.05g(59％)の標題化合物のジエチルエステルを得た。 Example 37 (general procedure B)
[4- (3- {4 '-[3- (4-Carboxymethylsulfanyl-3-chloro-phenylsulfanyl) -propyl] -3,3'-bis-trifluoromethyl-biphenyl-4-yl} -propyl Sulfanyl) -2-chloro-phenylsulfanyl] -acetic acid

Step AB:
(2-Chloro-4-mercapto-phenylsulfanyl) -acetic acid ethyl ester (intermediate 13) (3.7 g, 7 mmol) was dissolved in dimethylacetamide (20 mL). Sodium borohydride (0.5 g, 13.2 mmol) was added in several portions at 5 ° C. and the mixture was stirred for 30 minutes. 3,3′-bistrifluoromethyl-4,4′-biphenyldipropanol (intermediate 6) bismethanesulfonate (3.25 g, 5.8 mmol) dissolved in 2-butanone (35 mL), and potassium carbonate (1.4 g, 10 mmol) was added and the mixture was stirred for 48 h at laboratory temperature. Water and benzene were added, the organic phase was separated, dried (K ₂ CO ₃ ), filtered and evaporated to give a residue that was purified by chromatography on silica gel (100 g, benzene). This gave 3.05 g (59%) of the diethyl ester of the title compound.

¹ H-NMR spectrum (CDCl ₃ ): 7.80 (d, J = 1.65 Hz, 2H); 7.66 (dd, J = 1.65 and 8.2 Hz, 2H); 7.38 (d, J = 8.2 Hz, 2H); 7.34 ( m, 4H); 7.16 (dd, J = 2.2 and 8.25 2H); 4.15 (q, J = 7.15 Hz, 4H); 3.63 (s, 4H); 2.97 (m, 8H); 1.99 (pent, 4H); 1.22 (t, J = 7.15Hz, 6H).

General procedure D:
Step A:
The above diethyl ester (3.0 g, 3.35 mmol) was dissolved in a mixture of ethanol (30 mL) and tetrahydrofuran (30 mL), 20% sodium hydroxide (7 mL) was added and the mixture was allowed to stand for 48 h. The solvent was evaporated, the residue was dissolved in water, the mixture was acidified with hydrochloric acid and the product was extracted with chloroform. The organic phase was dried (MgSO ₄ ), evaporated and the residue was triturated with methanol to give 2.17 g (72%) of the title compound as the trihydrate.

Melting point 108-112 ° C. R _F (SiO ₂ , chloroform / ethanol 10: 1) 0.40.

¹ H NMR spectrum (300 MHz, DMSO-d ₆ ): 7.91 (m, 4H); 7.55 (d, J = 7.7 Hz, 2H); 7.40 (d, J = 1.65 Hz, 2H); 7.28 (m, 4H) 3.86 (s, 4H); 3.07 (t, J = 7.15Hz, 4H); 2.89 (t, J = 7.7Hz, 4H); 1.85 (m, 4H).

ステップＡ：
3-[4'-(3-ヒドロキシ-プロピル)-ビフェニル-4-イル]-プロパン-1-オール（中間体１４）(5.0g,18.5mmol)をジクロロメタン(100mL)中に溶解させ、トリエチルアミン(6.0g, 59mmol)と、その後に塩化メタンスルホニル(4.6g, 40mmol)を滴下添加した。この混合物を一晩撹拌し、水(30mL)で洗浄し、真空下で蒸発させ、残渣をベンゼンから結晶化させて4,4'-ビフェニルジプロパノール・ビスメタンスルホネートを得た。 Example 38 (general procedure B)
[4- [3- [4 '-[3- (4-Carboxymethyl-3-trifluoromethylphenylsulfanyl) propyl] biphenyl-4-yl] -propylsulfanyl] -2-trifluoromethylphenoxy] acetic acid

Step A:
3- [4 '-(3-hydroxy-propyl) -biphenyl-4-yl] -propan-1-ol (intermediate 14) (5.0 g, 18.5 mmol) was dissolved in dichloromethane (100 mL) and triethylamine ( 6.0 g, 59 mmol) followed by dropwise addition of methanesulfonyl chloride (4.6 g, 40 mmol). The mixture was stirred overnight, washed with water (30 mL), evaporated in vacuo and the residue crystallized from benzene to give 4,4′-biphenyldipropanol bismethanesulfonate.

Yield: 6.8 g (87%). Melting point 155.5-157 ° C.

¹ H NMR spectrum (CDCl ₃ ): 7.51 (d, J = 8.2 Hz, 4H); 7.25 (m, 4H); 4,26 (t, J = 6.3 Hz, 4H); 3.00 (s, 6H); 2.79 (t, J = 7.4 Hz, 4H); 2.11 (m, 4H).

Step B:
4,4′-dithiobis (2-trifluoromethylphenoxyacetic acid diethyl ester) (Intermediate 11) (4.5 g, 8 mmol) was dissolved in N, N-dimethylacetamide (20 mL) and sodium borohydride (0.6 g 15.9 mmol) was added in several portions at 5 ° C. and the mixture was stirred for 30 minutes. A solution of the above bismethanesulfonate (3.1 g, 7.3 mmol) in 2-butanone (30 mL) and potassium carbonate (1.4 g, 10 mmol) were added and the resulting mixture was stirred overnight at ambient temperature and then refluxed for 3 h. I let you. Water (250 mL) and benzene (150 mL) were added and the organic phase was separated, dried using anhydrous potassium carbonate, filtered and evaporated under vacuum. The residue was purified by column chromatography (silica gel Fluka 60, benzene). [4- [3- [4 '-[3- (4-carboxymethyl-3-trifluoromethylphenylsulfanyl) propyl] biphenyl-4-yl] -propylsulfanyl] -2-trifluoromethylphenoxy] acetic acid Diethyl ester was obtained.

Yield: 3.35 g (58%). Melting point 100.5-102.5 ° C. (benzene).

¹ H NMR spectrum (CDCl ₃ ): 7.61 (d, J = 2.2 Hz, 2H); 7.47 (m, 6H); 7.21 (d, J = 8.3 Hz, 4H); 6.80 (d, J = 8.8 Hz, 2H) 4.70 (s, 4H); 4.25 (q, J = 7.2Hz, 4H); 2.88 (t, J = 7.3Hz, 4H); 2.77 (t, J = 7.2Hz, 4H); 1.94 (m, 4H) ); 1.28 (t, J = 7.2 Hz, 6H).

General procedure D:
Step A:
The above diethyl ester (3.25 g, 4.1 mmol) was dissolved in a mixture of ethanol (30 mL) and tetrahydrofuran (50 mL), a 20% aqueous solution of sodium hydroxide (5 mL) was added, and the mixture was allowed to stand for 48 h. The solvent was evaporated and the residue was dissolved in water and precipitated with acetic acid. The title compound was filtered, washed with water and dried.

Yield: 2.9 g (96%). Melting point 208-218 ° C.

¹ H NMR spectrum (300 MHz, DMSO-d ₆ ): 7.48-7.58 (m, 8H); 7.21 (d, J = 8.0 Hz, 4H); 7.05 (d, J = 8.5 Hz, 2H); 4.76 (s, 4H); 2.90 (t, J = 7.2 Hz, 4H); 2.70 (t, J = 7.4 Hz, 4H); 1.81 (m, 4H).

ステップＡ：
ジクロロメタン(40mL)中の3-[4'-(3-ヒドロキシ-プロピル)-3,3'-bis-トリフルオロメチル-ビフェニル-4-イル]-プロパン-1-オール（中間体６）(5.4g, 13.3mmol)の溶液に、トリエチルアミン(2.5g, 24.7mmol)および塩化メタンスルホニル(2.7g, 23.6mmol)を滴下添加した。この混合物を一晩撹拌し、ジクロロメタン(50mL)で希釈し、水で洗浄した(2×15mL)。有機溶液を蒸発させて、3,3'-ビストリフルオロメチル-4,4'-ビフェニルジプロパノール・ビスメタンスルホネートを得た。収量：6.6g(88％)。 Example 39 (general procedure B)
[4- [3- [4 '-[3- (4-Carboxymethyl-3-chlorophenylsulfanyl) propyl] -3,3'-bis-trifluoromethylbiphenyl-4-yl] propylsulfanyl] -2-chloro Phenoxy] acetic acid

Step A:
3- [4 '-(3-Hydroxy-propyl) -3,3'-bis-trifluoromethyl-biphenyl-4-yl] -propan-1-ol (intermediate 6) (5.4) in dichloromethane (40 mL) g, 13.3 mmol), triethylamine (2.5 g, 24.7 mmol) and methanesulfonyl chloride (2.7 g, 23.6 mmol) were added dropwise. The mixture was stirred overnight, diluted with dichloromethane (50 mL) and washed with water (2 × 15 mL). The organic solution was evaporated to give 3,3′-bistrifluoromethyl-4,4′-biphenyldipropanol bismethanesulfonate. Yield: 6.6 g (88%).

¹ H NMR spectrum (CDCl ₃ ): 7.81 (s, 2H); 7.70 (d, J = 8.0 Hz, 2H); 7.44 (d, J = 8.0 Hz, 2H); 4.31 (t, J = 6.1 Hz, 4H) ); 3.04 (s, 6H); 2.96 (t, J = 7.8 Hz, 4H); 2.11 (m, 4H).

Step B:
4,4′-dithiobis (2-chlorophenoxyacetic acid diethyl ester) (intermediate 12) (3.7 g, 7.5 mmol) was dissolved in N, N-dimethylacetamide (50 mL) and sodium borohydride (0.55 g, 14.5 mmol) was added in several portions at 5 ° C. and the mixture was stirred for 30 minutes. To the mixture was added a solution of the above bismethanesulfonate (3.25 g, 5.8 mmol) in 2-butanone (15 mL) and potassium carbonate (1.4 g, 10 mmol) and the resulting suspension was stirred overnight at ambient temperature. And then refluxed for 3 h. Water (300 mL) and benzene (100 mL) were added and the organic phase was separated, dried over anhydrous potassium carbonate, filtered and evaporated under vacuum. The residue was purified by column chromatography (silica gel Fluka 60, benzene) to give [4- [3- [4 '-[3- (4-carboxymethyl-3-chlorophenylsulfanyl) propyl] -3,3'-bis-tri Fluoromethylbiphenyl-4-yl] propylsulfanyl] -2-chlorophenoxy] acetic acid diethyl ester was obtained. Yield: 2.86 g (60%).

¹ H NMR spectrum (CDCl ₃ ): 7.79 (d, J = 1.7 Hz, 2H); 7.65 (dd, J = 1.7 and 8.0 Hz, 2H); 7.42 (d, J = 2.2 Hz, 2H); 7.37 (d , J = 8.0Hz, 2H); 7.22 (dd, J = 2.2 and 8.5Hz, 2H); 6.78 (d, J = 8.5Hz, 2H); 4.68 (s, 4H); 4.26 (q, J = 7.2Hz , 4H); 2.93 (t, J = 7.2 Hz, 8H); 1.94 (m, 4H); 1.29 (t, J = 7.2 Hz, 6H).

General procedure D:
Step A:
The above diethyl ester (2.8 g, 3.5 mmol) was dissolved in ethanol (30 mL) and tetrahydrofuran (30 mL). A 20% aqueous solution of sodium hydroxide (7 mL) was added and the mixture was allowed to stand for 48 h and then evaporated under vacuum. The residue was dissolved in water and the title compound was precipitated using hydrochloric acid. The solid mass was filtered, washed with water and dried. Yield: 2.3 g (85%). Melting point 143-152 ° C.

¹ H NMR spectrum (300 MHz, DMSO-d ₆ ): 7.89 (m, 4H); 7.53 (d, J = 7.7 Hz, 2H); 7.43 (d, J = 2.2 Hz, 2H); 7.27 (dd, J = 2.2 and 8.5 Hz, 2H); 6.97 (d, J = 8.5 Hz, 2H); 4.77 (s, 4H); 3.00 (t, J = 7.1 Hz, 4H); 2.86 (m, 4H); 1.80 (m, 4H).

ステップＢ：
4,4'-ジチオビス-(2-クロロメチルフェノキシ酢酸ジエチルエステル)（中間体12）(2.5g, 5.1mmol)を20mL N,N-ジメチルアセトアミド中に溶解させ、ホウ水素化ナトリウム(0.50g, 13.2mmol)を数回に分けて５℃で添加し、該混合物を30分撹拌した。4,4'-ビフェニルジプロパノール・ビスメタンスルホネート(例38)(2.1g, 4.95mmol)を2-ブタノン(20mL)中に溶解させ、炭酸カリウム(1.4g, 10mmol)を添加し、該混合物を一晩周囲温度で撹拌し、次いで3ｈ還流させた。水およびベンゼンを添加し、有機相を乾燥させ(K₂CO₃)、濾過し、蒸発させて残渣を得、これをシリカゲル上のクロマトグラフィ(Fluka 60, 60g, ベンゼン)により精製した。これにより2.3g(64％)の標題化合物のジエチルエステルを得た。 Example 40 (general procedure B)
[4- (3- {4 '-[3- (4-Carboxymethyl-3-chloro-phenylsulfanyl) -propyl] -biphenyl-4-yl} -propylsulfanyl) -2-chloro-phenoxy] -acetic acid

Step B:
4,4′-dithiobis- (2-chloromethylphenoxyacetic acid diethyl ester) (intermediate 12) (2.5 g, 5.1 mmol) was dissolved in 20 mL N, N-dimethylacetamide and sodium borohydride (0.50 g, 13.2 mmol) was added in several portions at 5 ° C. and the mixture was stirred for 30 minutes. 4,4′-biphenyldipropanol bismethanesulfonate (Example 38) (2.1 g, 4.95 mmol) was dissolved in 2-butanone (20 mL), potassium carbonate (1.4 g, 10 mmol) was added and the mixture was added. Stir overnight at ambient temperature and then reflux for 3 h. Water and benzene were added and the organic phase was dried (K ₂ CO ₃ ), filtered and evaporated to give a residue that was purified by chromatography on silica gel (Fluka 60, 60 g, benzene). This gave 2.3 g (64%) of the diethyl ester of the title compound.

¹ H-NMR spectrum (CDCl ₃ ): 7.49 (d, 4H, J = 8.0); 7.40 (d, 2H, J = 2.2); 7.36 (m, 2H); 7.22 (m, 4H); 6.76 (d, 2H, J = 8.5); 4.67 (s, 4H); 4.26 (q, 4H, J = 7.15); 2.87 (t, 4H); 2.76 (t, 4H); 1.95 (pent, 4H); 1.29 (t, 6H, J = 7.15).

General procedure D:
Step A:
The above diethyl ester (2.2 g, 2.9 mmol) was dissolved in 50 mL ethanol, a 20% solution of sodium hydroxide (5 mL) was added and the mixture was allowed to stand for 48 h. The solvent was evaporated, the residue was dissolved in water and the product was precipitated with HCl: the solid was filtered off with suction, washed with water and dried to give 1.95 g (96%) of the title compound, which was dioxane. Recrystallization from water gave 1.44 g of a solvate with 1/2 mol of dioxane.

Melting point 181.5-184.5 ° C. R _F (free acid, SiO ₂ , ethyl acetate) 0.53.

¹ H NMR spectrum (300 MHz, DMSO-d ₆ ): 13.10 (s, 2H); 7.52 (d, J = 8.2 Hz, 4H); 7.41 (d, J = 2.2 Hz, 2H); 7.26 (dd, J = 2.2 and 8.8Hz, 2H); 7.22 (d, J = 8.2Hz, 4H); 6.97 (d, J = 8.8Hz, 2H); 4.79 (s, 4H); 2.88 (t, J = 7.15Hz, 4H) 2.69 (t, J = 7.15 Hz, 4H); 1.80 (p, 4H); dioxane 3.55 (s).

ステップＢ：
4-メルカプト-2-メトキシフェノキシ酢酸メチル（中間体15）（1.6g,7mmol)、4,4'-ビフェニルジプロパノール ・ビスメタンスルホネート(例38)(1.48g,3.5mmol)、炭酸カリウム(1.38g, 10mmol)および2-ブタノン(40mL)の混合物を、撹拌しながら８ｈ還流させた。水および酢酸エチルを添加し、有機相を分離し、乾燥させ(K₂CO₃)、蒸発させた。残渣をシリカゲル上でのクロマトグラフィ(25g, 酢酸エチル)により精製し、次いでジエチルエーテルから再結晶化させて、標題化合物のジメチルエステル1.60g(66％)を得た。融点108.5-110.5℃。 Example 41 (general procedure B)
[4- (3- {4 '-[3- (4-Carboxymethyl-3-methoxy-phenylsulfanyl) -propyl] -biphenyl-4-yl} -propylsulfanyl) -2-methoxy-phenoxy] -acetic acid

Step B:
4-Mercapto-2-methoxyphenoxyacetic acid methyl ester (intermediate 15) (1.6 g, 7 mmol), 4,4′-biphenyldipropanol bismethanesulfonate (Example 38) (1.48 g, 3.5 mmol), potassium carbonate (1.38 g, 10 mmol) and 2-butanone (40 mL) were refluxed for 8 h with stirring. Water and ethyl acetate were added and the organic phase was separated, dried (K ₂ CO ₃ ) and evaporated. The residue was purified by chromatography on silica gel (25 g, ethyl acetate) and then recrystallized from diethyl ether to give 1.60 g (66%) of the dimethyl ester of the title compound. Melting point 108.5-110.5 ° C.

¹ H-NMR spectrum (DMSO): 7.51 (d, J = 8.0 Hz, 4H); 7.22 (d, J = 8.0 Hz, 4H); 6.93 (s, 2H); 6.82 (m, 4H); 4.73 (s , 4H); 3.73 (s, 6H); 3.66 (s, 6H); 2.88 (t, 4H); 2.70 (t, 4H); 1.82 (m, 4H).

General procedure D:
Step A:
The dimethyl ester (1.52 g, 2.2 mmol) was dissolved in a mixture of ethanol (25 mL) and tetrahydrofuran (25 mL) under reflux, a 20% solution of sodium hydroxide (3 mL) was added, and the mixture was tested. Left at room temperature for 48 h. The solvent was evaporated, water was added to the residue and the product was precipitated with HCl. The solid was filtered off with suction, washed with water and dried to give 1.45 g (95%) of the title compound as a sesquihydrate.

Melting point 178-180 ℃. R _F (free acid, SiO ₂ , ethyl acetate) 0.50.

¹ H NMR spectrum (300 MHz, DMSO-d ₆ ): 13.0 (bs, 2H); 7.51 (d, J = 8.2 Hz, 4H); 7.22 (d, J = 8.2 Hz, 4H); 6.93 (d, J = 1.8 Hz, 2H); 6.85 (dd, J = 1.8 and 8.4 Hz, 2H); 6.78 (d, J = 8.4 Hz, 2H); 4.60 (s, 4H); 3.73 (s, 6H); 2.88 (t, J = 7.3 Hz, 4H); 2.70 (t, J = 7.3 Hz, 4H); 1.81 (p, 4H).

ステップＡ：
ジクロロメタン(50mL)中の3-{4-[4-(3-ヒドロキシ-プロピル)-2-トリフルオロメチル-フェニルスルファニル]-3-トリフルオロメチル-フェニル}-プロパン-1-オール（中間体16）(4.0g, 9.1mmol)およびトリエチルアミン(2.5g, 24.7mmol)の溶液に、塩化メタンスルホニル(2.5g, 21.8mmol)を滴下添加した。この混合物を一晩室温で撹拌し、次いで水で洗浄し、ジクロロメタンを蒸発させた。これにより5.4g(99.5％)のメタンスルホン酸3-{4-[4-(3-メタンスルホニルオキシ-プロピル)-2-トリフルオロメチル-フェニルスルファニル]-3-トリフルオロメチル-フェニル}-プロピルエステルを固体で得た。 Example 42 (general procedure B)
{4- [3- (4- {4- [3- (4-carboxymethyl-3-trifluoromethyl-phenylsulfanyl) -propyl] -2-trifluoromethyl-phenylsulfanyl} -3-trifluoromethyl- Phenyl) -propylsulfanyl] -2-trifluoromethyl-phenoxy} -acetic acid

Step A:
3- {4- [4- (3-hydroxy-propyl) -2-trifluoromethyl-phenylsulfanyl] -3-trifluoromethyl-phenyl} -propan-1-ol (intermediate 16) in dichloromethane (50 mL) ) (4.0 g, 9.1 mmol) and triethylamine (2.5 g, 24.7 mmol) in solution were added dropwise methanesulfonyl chloride (2.5 g, 21.8 mmol). The mixture was stirred overnight at room temperature, then washed with water and the dichloromethane was evaporated. This gives 5.4 g (99.5%) of 3- {4- [4- (3-methanesulfonyloxy-propyl) -2-trifluoromethyl-phenylsulfanyl] -3-trifluoromethyl-phenyl} -propyl methanesulfonate The ester was obtained as a solid.

¹ H NMR spectrum (300 MHz, CDCl ₃ ): 7.54 (s, 2H); 7.25 (dd, J = 1.1 and 7.15 Hz, 2H); 7.14 (d, J = 8.0 Hz, 2H); 4.23 (t, J = 6.2 Hz, 4H); 3.00 (s, 6H); 2.79 (t, J = 7.0 Hz, 4H); 2.07 (m, 4H).

Step B:
The 4,4′-dithiobis- (2-trifluoromethylphenoxyacetic acid diethyl ester) (intermediate 11) (2.6 g, 4.65 mmol) was dissolved in 15 mL of dimethylacetamide and sodium borohydride (0.4 g, 10.6 mmol). ) Was added in several portions at 5 ° C. and the mixture was stirred for 30 minutes. To a solution of the above methanesulfonate (2.3 g, 3.87 mmol) in acetone (30 mL) was added potassium carbonate (1.4 g, 10 mmol) and the mixture was stirred at ambient temperature overnight and then refluxed for 7 h. Water and benzene were added, the organic phase was dried (K ₂ CO ₃ ), filtered and evaporated to give a residue which was purified by chromatography on silica gel (100 g, benzene) which gave the title compound 3.1 g (85%) of diethyl ester was obtained.

¹ H NMR spectrum (3O 0 MHz, CDCl ₃ ): 7.59 (d, 2H, J = 2.2); 7.50 (d, 2H, J = 1.5); 7.45 (dd, 2H, J = 2.2; 8.5); 7.19 (dd, 2H, J = 1.5; 8.0); 7.11 (d, 2H, J = 8.0); 6.80 (d, 2H, J = 8.5); 4.70 (s, 4H); 4.25 (q, 4H, J = 7.15); 2.84 (t, 4H, J = 7.15); 2.76 (t, 4H, J = 7.15); 1.89 (pent, 4H); 1.27 (t, 6H, J = 7.15).

General procedure D:
Step A:
The above diethyl ester (3.0 g, 3.3 mmol) was dissolved in 100 mL of ethanol, 20% NaOH (5 mL) was added and the mixture was refluxed for 5 h. The solvent was evaporated, the residue was dissolved in water, the product was precipitated with concentrated hydrochloric acid and extracted with chloroform. The organic phase was dried (MgSO ₄ ), filtered and evaporated and the residue obtained was purified by chromatography on silica gel (30 g, chloroform / ethanol 95: 5). The yield of the title compound was 1.82 g (61%).

Melting point 58-64 ° C. R _F (SiO ₂ , ethyl acetate): 0.62.

¹ H NMR spectrum (300 MHz, DMSO-d ₆ ): 7.60 (d, J = 2.2 Hz, 2H); 7.50 (d, J = 1.6 Hz, 2H); 7.43 (dd, J = 8.5 and 2.2 Hz, 2H) 7.17 (dd, J = 8.0 and 1.6 Hz, 2H); 7.11 (d, J = 8.0 Hz, 2H); 6.81 (d, J = 8.5 Hz, 2H); 4.76 (s, 4H); 2.85 (t, J = 7.15 Hz, 4H); 2.76 (t, J = 7.15 Hz, 4H); 1.89 (m, 4H).

  By using a combination of the above methods or using similar methods, various compounds can be made within the scope of the present invention.

<Pharmacological method>
In vitro activation of PPAR alpha, PPAR gamma and PPAR delta:
The transient transactivation assay of PPAR is based on transient transfection of two plasmids encoding chimeric test protein and reporter protein, respectively, into human HEK293 cells. The chimeric test protein is obtained by fusing a DNA binding domain (DBD) derived from a yeast GAL4 transcription factor to a ligand binding domain (LBD) of human PPAR protein. In addition to the ligand binding pocket, PPAR-LBD also contains a natural activation domain (activation function 2 = AF2), allowing the fusion protein to function as a PPAR ligand-dependent transcription factor. . GAL4 DBD will direct the chimeric protein to bind only to Gal4 enhancers (those that are not present in HEK293 cells). The reporter plasmid contained a Gal4 enhancer that drives the expression of firefly luciferase protein. After transfection, HEK293 cells expressed GAL4-DBD-PPAR-LBD fusion protein. The fusion protein will then bind to the Gal4 enhancer to control the expression of luciferase and will do nothing in the absence of ligand. When PPAR ligand is added to the cells, luciferase protein will be produced in an amount corresponding to activation of the PPAR protein. The amount of luciferase protein is measured by luminescence after adding the appropriate substrate.

Cell culture and transfection:
HEK293 cells were grown in DMEM + 10% FCS. The day before transfection, cells were seeded in 96-well plates and gave 50-80% confluency at the time of transfection. A total of 0.8 μg of DNA containing 0.64 μg pM1α / γLBD, 0.1 μg pCMVβGal, 0.08 μg pGL2 (Gal4) ₅ and 0.02 μg pADVANTAGE was added to the wells using FuGene transfection reagent and following the manufacturer's instructions (Roche). Transfected every time. Cells were allowed to express protein for 48 hours, followed by addition of compounds.

Plasmid: Human PPARα, γ and δ were obtained by PCR amplification using cDNA synthesized by reverse transcription of mRNA derived from human liver, adipose tissue and placenta, respectively. The amplified cDNA was cloned into pCR2.1 and sequenced. The ligand binding domain (LBD) of each PPAR isoform was generated by PCR (PPARα: aa 167-C terminus; PPARγ: aa 165-C terminus; PPARδ: aa 128-C terminus) and this fragment was transformed into vector pM1 (Sadowski et al. (1992), Gene 118, 137) were subcloned in frame and fused to the DNA binding domain (DBD) of the yeast transcription factor GAL4 to generate plasmids pM1αLBD, pM1γLBD and pM1δ. Fusion was confirmed by sequencing. For the reporter, an oligonucleotide encoding 5 repeats of the GAL4 recognition sequence (5 × CGGAGTACTGTCCTCCG (AG)) (Webster et al. (1988), Nucleic Acids Res. 16, 8192) was placed in the vector pGL2 promoter (Promega). And constructed by constructing plasmid pGL2 (GAL4) ₅ . pCMVβGal was purchased from Clontech and pADVANTAGE was purchased from Promega.

In vitro transactivation assay:
Compounds: All compounds were dissolved in DMSO and diluted 1: 1000 when added to the cells. The compounds were tested four times at concentrations varying from 0.001 to 300 μM. Cells were treated with compounds for 24 hours followed by a luciferase assay. Each compound was tested in at least two separate experiments.

  Luciferase Assay: The medium containing the test compound was aspirated and 100 μl PBS containing 1 mM Mg ++ and Ca ++ was added to each well. The luciferase assay was performed using the LucLite kit according to the manufacturer's (Packard Instruments) instructions. Luminescence was quantified by counting on a Packard Lumi counter. To measure β-galactosidase activity, 25 μl of supernatant from each transfection lysate was transferred to a new microplate. The β-galactosidase assay was performed using a Promega kit and read with a Labsystems Ascent Multiscan reader. The β-galactosidase data was used to normalize the luciferase data (transfection efficiency, cell growth, etc.).

<Statistical method>
The activity of the compound is calculated as the fold induction compared to the untreated sample. The effect (maximum activity) for each compound is given as relative activity when compared to Wy14,643 for PPARα, Rosiglitazone for PPARγ, and Carbacyclin for PPARδ. Its EC ₅₀ is the concentration that gives 50% of the maximum activity observed. EC ₅₀ values were calculated by non-linear regression using GraphPad PRISM 3.02 (GraphPad software, San Diego, Ca). The results were expressed as mean ± SD.

Claims (79)

Compounds of general formula (I) below, pharmaceutically acceptable salts thereof, pharmaceutically acceptable solvates thereof, any tautomers, stereoisomers, mixtures of stereoisomers including racemic mixtures Or polymorphs:

here,
A is C _1-3 -alkylene optionally substituted with one or more substituents selected from:
·halogen;
• C _1-3 -alkyl, C _1-6 -alkoxy, C _3-6 -cycloalkoxy, C _1-6 -alkylthio, C _3-6 -cycloalkylthio, each optionally substituted with one or more halogens Or aralkoxy;
NR ₁ R ₂ ; where R ₁ represents hydrogen or C _1-3 -alkyl, and R ₂ represents —R ₃ — (C═O) —R ₄
Represents;
here,
* R ₃ is C _1-6 -alkylene, C _2-6 -alkenylene, C _4-6 -cycloalkylene,
Optionally substituted with C _4-6 -cycloalkenylene, or one or more halogens
Represents arylene;
* R ₄ represents aryl optionally substituted with one or more halogens;
Or
A is -O-A 'or -S-A', wherein -O- or -S- is linked to X in formula (I), and A 'is one or more selected from C _1-3 -alkylene optionally substituted with substituents;
·halogen;
• C _1-3 -alkyl, C _1-6 -alkoxy, C _3-6 -cycloalkoxy, C _1-6 -alkylthio, C _3-6 -cycloalkylthio, each optionally substituted with one or more halogens Or aralkoxy;
NR ₁ R ₂ ; where R ₁ represents hydrogen or C _1-3 -alkyl, and R ₂ represents —R ₃ — (C═O) —R ₄
Represents;
here,
* R ₃ is C _1-6 -alkylene, C _2-6 -alkenylene, C _4-6 -cycloalkylene,
Optionally substituted with C _4-6 -cycloalkenylene, or one or more halogens
Represents arylene;
* R ₄ represents aryl optionally substituted with one or more halogens;
B is C _1-3 -alkylene optionally substituted with one or more substituents selected from:
·halogen;
• C _1-3 -alkyl, C _1-6 -alkoxy, C _3-6 -cycloalkoxy, C _1-6 -alkylthio, C _3-6 -cycloalkylthio, each optionally substituted with one or more halogens Or aralkoxy;
NR ₁ R ₂ ; where R ₁ represents hydrogen or C _1-3 -alkyl, and R ₂ represents —R ₃ — (C═O) —R ₄
Represents;
here,
* R ₃ is C _1-6 -alkylene, C _2-6 -alkenylene, C _4-6 -cycloalkylene,
Optionally substituted with C _4-6 -cycloalkenylene, or one or more halogens
Represents arylene;
* R ₄ represents aryl optionally substituted with one or more halogens;
Or
B is is -OB 'or -S-B', wherein -O- or -S- is linked to Y in formula (I), and B 'is one or more substitutions selected from C _1-3 -alkylene optionally substituted with groups;
·halogen;
• C _1-3 -alkyl, C _1-6 -alkoxy, C _3-6 -cycloalkoxy, C _1-6 -alkylthio, C _3-6 -cycloalkylthio, each optionally substituted with one or more halogens Or aralkoxy;
NR ₁ R ₂ ; where R ₁ represents hydrogen or C _1-3 -alkyl, and R ₂ represents —R ₃ — (C═O) —R ₄
Represents;
here,
* R ₃ is C _1-6 -alkylene, C _2-6 -alkenylene, C _4-6 -cycloalkylene,
Optionally substituted with C _4-6 -cycloalkenylene, or one or more halogens
Represents arylene;
* R ₄ represents aryl optionally substituted with one or more halogens;
D is H, C _1-6 -alkyl, or C _3-6 -cycloalkyl;
E is H, C _1-6 -alkyl, or C _3-6 -cycloalkyl;
L and M are independently -O- or -S-;
T is a divalent C _1-6 saturated carbon chain optionally substituted with one or more substituents selected from:
Halogen or hydroxy;
Aryl, aralkoxy, or C _1-3 -alkoxy optionally substituted with halogen;
Or
T is —NR ₁ —T ′; where —NR ₁ — is bonded to Z in formula (I) and T ′ is C _1-6 alkylene optionally substituted with one or more halogens. And R ₁ represents hydrogen or C _1-3 alkyl;
U is a divalent C _1-6 saturated carbon chain optionally substituted with one or more substituents selected from:
Halogen or hydroxy;
Aryl, aralkoxy, or C _1-3 -alkoxy optionally substituted with halogen;
Or
U is —NR ₁ —U ′; where —NR ₁ — is bonded to Z in formula (I) and U ′ is C _1-6 alkylene optionally substituted with one or more halogens R ₁ represents hydrogen or C _1-3 alkyl;
X is arylene or heteroarylene, each optionally substituted with one or more substituents selected from
Halogen or hydroxy;
C _1-6 -alkyl, C _3-6 -cycloalkyl, C _1-6 -alkoxy, C _3-6 -cycloalkoxy, C _1-6 -alkylthio, each optionally substituted with one or more halogens C _3-6 -cycloalkylthio, aryl, aralkyl;
Y is an arylene or heteroarylene, each optionally substituted with one or more substituents selected from
Halogen or hydroxy;
C _1-6 -alkyl, C _3-6 -cycloalkyl, C _1-6 -alkoxy, C _3-6 -cycloalkoxy, C _1-6 -alkylthio, each optionally substituted with one or more halogens C _3-6 -cycloalkylthio, aryl, aralkyl;
Z is an arylene, heteroarylene, or divalent polycyclic ring system, each optionally substituted with one or more substituents selected from:
Halogen or hydroxy;
C _1-6 -alkyl, C _3-6 -cycloalkyl, C _1-6 -alkoxy, C _3-6 -cycloalkoxy, C _1-6 -alkylthio, each optionally substituted with one or more halogens C _3-6 -Cycloalkylthio. The compound of claim 1, wherein A is C _1-3 -alkylene optionally substituted with one or more substituents selected from:
• methyl, C _1-3 -alkoxy, C _3-6 -cycloalkoxy, or benzyloxy, each optionally substituted with one or more halogens; or NR ₁ R ₂ : where R ₁ represents hydrogen, R ₂ represents -R _3- (C = O) -R ₄
here,
* R ₃ is C _1-6 -alkylene, C _2-6 -alkenylene, C _4-6 -cycloalkylene,
Optionally substituted with C _4-6 -cycloalkenylene, or one or more halogens
Represents phenylene;
* R ₄ represents phenyl optionally substituted with one or more halogens. 3. A compound according to claim 2, wherein A is methylene or ethylene, each optionally substituted with one or more substituents selected from:
Methoxy or ethoxy; or NR ₁ R ₂ where R ₁ represents hydrogen, R ₂ represents —R ₃ — (C═O) —R ₄ ,
Here, R ₃ and R ₄ represent phenyl. 4. A compound according to any one of claims 2-3, wherein A is ethylene optionally substituted with ethoxy. The compound according to claim 1, wherein A is -O-A 'or -S-A', -O- or -S- is bonded to X in formula (I), and A 'is A compound that is C _1-3 -alkylene optionally substituted with one or more substituents selected from:
• halogen; or • C _1-3 -alkyl, C _1-6 -alkoxy, C _3-6 -cycloalkoxy, or aralkoxy, each optionally substituted with one or more halogens. The compound of claim 1, wherein A is -O-A 'or -S-A', -O- or -S- is bonded to X in formula (I), and A 'is methylene. Or ethylene, each of which is optionally substituted with one or more substituents selected from methyl, methoxy or ethoxy. 7. A compound according to claim 6, wherein A is -O-A ', -O- is bonded to X in formula (I) and A' is methylene or ethylene. 8. A compound according to claim 7, wherein A is -O-A ', -O- is bound to X in formula (I) and A' is methylene. 9. A compound according to any one of claims 1 to 8, wherein B is _C1-3 -alkylene optionally substituted with one or more substituents selected from:
• methyl, C _1-3 -alkoxy, C _3-6 -cycloalkoxy, or benzyloxy, each optionally substituted with one or more halogens;
NR ₁ R _2, where R ₁ represents hydrogen and R ₂ represents —R ₃ — (C═O) —R ₄ ;
here,
* R ₃ is C _1-6 -alkylene, C _2-6 -alkenylene, C _4-6 -cycloalkylene,
Optionally substituted with C _4-6 -cycloalkenylene, or one or more halogens
Represents phenylene;
* R ₄ represents phenyl optionally substituted with one or more halogens; 10. A compound according to claim 9, wherein B is methylene or ethylene, each of which is optionally substituted with one or more substituents selected from:
Methoxy or ethoxy; or NR ₁ R ₂ ; where R ₁ represents hydrogen, R ₂ represents —R ₃ — (C═O) —R ₄ , and R ₃ and R ₄ represent phenyl . 11. A compound according to any one of claims 9 to 10, wherein B is ethylene optionally substituted with ethoxy. The compound according to any one of claims 1 to 8, wherein B is -O-B 'or -S-B', wherein -O- or -S- is represented by formula (I): A compound bonded to Y and B ′ is C _1-3 -alkylene optionally substituted with one or more substituents selected from:
• halogen; or • C _1-3 -alkyl, C _1-6 -alkoxy, C _3-6 -cycloalkoxy or aralkoxy, each optionally substituted with halogen. 13. The compound according to claim 12, wherein B is -O-B 'or -S-B', wherein -O- or -S- is bound to Y in formula (I), and B 'Is methylene or ethylene, each of which is optionally substituted with one or more substituents selected from methyl, methoxy or ethoxy. 14. A compound according to claim 13, wherein B is -O-B ', wherein -O- is bonded to Y in formula (I) and B' is methylene or ethylene. 15. A compound according to claim 14, wherein B is -O-B ', wherein -O- is bonded to Y in formula (I) and B' is methylene. The compound according to any one of claims 1 to 15, wherein D is H. The compound according to any one of claims 1 to 15, wherein D is methyl or ethyl. The compound according to any one of claims 1 to 15, wherein D is isopropyl. The compound according to any one of claims 1 to 18, wherein E is H. 19. A compound according to any one of claims 1 to 18, wherein E is methyl or ethyl. The compound according to any one of claims 1 to 18, wherein E is isopropyl. The compound according to any one of claims 1 to 21, wherein L is -O-. 23. The compound according to any one of claims 1 to 22, wherein L is -S-. 24. The compound according to any one of claims 1 to 23, wherein M is -O-. 25. The compound according to any one of claims 1 to 24, wherein M is -S-. A compound according to any one of claims 1 to 25, T is a bivalent C _1-6 saturated carbon chain is optionally substituted with one or more substituents, the substituents phenyl , Benzyloxy, or a compound selected from C _1-3 -alkoxy optionally substituted with halogen. A compound according to claim 26, T is a compound which is a divalent unsubstituted C _1-6 saturated carbon chain. 28. The compound of claim 27, wherein T is ethylene or propylene. 26. The compound according to any one of claims 1 to 25, wherein T is —NR ₁ —T ′, wherein —NR ₁ — is bonded to Z in formula (I), and T ′ is A compound which is C _1-6 alkylene optionally substituted with one or more halogens, and wherein R ₁ represents hydrogen or C _1-3 alkyl. 30. The compound of claim 29, wherein T is —NR ₁ —T ′, wherein —NR ₁ — is bonded to Z in formula (I), and T ′ is C _1-3 alkylene. And R ₁ is hydrogen or C _1-3 alkyl. A compound according to claim 30, T is ', wherein -NR ₁ - is attached to Z In formula (I), also T' -NR ₁ -T is ethylene, R ₁ Is a methyl compound. 32. The compound of any one of claims 1-31, wherein U is a divalent C _1-6 saturated carbon chain optionally substituted with one or more substituents, the substituents being phenyl, A compound that is benzyloxy or C _1-3 -alkoxy optionally substituted with halogen. A compound according to claim 32, compound U is a divalent unsubstituted C _1-6 saturated carbon chain. 34. The compound of claim 33, wherein U is ethylene or propylene. The compound according to any one of claims 1 to 31, wherein U is -NR ₁ -U ', wherein -NR ₁ -is bonded to Z in formula (I), and U' is A compound which is C _1-6 alkylene optionally substituted with one or more halogens, and wherein R ₁ represents hydrogen or C _1-3 alkyl. 36. The compound of claim 35, wherein U is —NR ₁ —U ′, wherein —NR ₁ — is bonded to Z in formula (I), and U ′ is C _1-3 alkylene. And R ₁ is hydrogen or C _1-3 alkyl. A compound according to claim 36, U is ', wherein -NR ₁ - is attached to Z in formula (I), U' -NR ₁ -U is ethylene, and R ₁ Is a methyl compound. 38. The compound of any one of claims 1-37, wherein X is arylene or heteroarylene, each of which is optionally substituted with one or more substituents selected from:
• halogen; or • C _1-6 -alkyl, C _1-6 -alkoxy, each optionally substituted with one or more halogens
Aryl. 40. The compound of claim 38, wherein X is arylene optionally substituted with one or more substituents selected from:
• halogen; or • C _1-6 -alkyl, C _1-6 -alkoxy, each optionally substituted with one or more halogens
Aryl. 40. The compound of claim 39, wherein X is phenylene optionally substituted with one or more substituents selected from:
Halogens; or
C _1-3 -alkyl, C _1-3 -alkoxy, each optionally substituted with one or more halogens
Phenyl. 41. The compound of claim 40, wherein X is phenylene optionally substituted with one or more halogen, methyl or phenyl. 41. The compound of claim 40, wherein X is phenylene optionally substituted with one or more trifluoromethyl or methoxy. 43. The compound according to any one of claims 1-42, wherein Y is arylene or heteroarylene optionally substituted with one or more substituents selected from:
Halogen; or • C _1-6 -alkyl, C _1-6 -alkoxy, each optionally substituted with one or more halogens,
Aryl. 44. The compound of claim 43, wherein Y is arylene optionally substituted with one or more substituents selected from:
• halogen; or • C _1-6 -alkyl, C _1-6 -alkoxy, each optionally substituted with one or more halogens
Aryl. 45. The compound of claim 44, wherein Y is phenylene optionally substituted with one or more substituents selected from:
• halogen; or • C _1-3 -alkyl, C _1-3 -alkoxy, each optionally substituted with one or more halogens,
Phenyl. 46. The compound of claim 45, wherein Y is phenylene optionally substituted with one or more halogen, methyl or phenyl. 46. The compound of claim 45, wherein Y is phenylene optionally substituted with one or more trifluoromethyl or methoxy. 48. The compound of any one of claims 1-47, wherein Z is arylene, heteroarylene or a divalent polycyclic system, each of which is optionally one or more substituents selected from Replaced compounds:
Halogen, oxo; or
C _1-6 -alkyl, C _1-6 -alkoxy, each optionally substituted with one or more halogens. 49. The compound of claim 48, wherein Z is selected from the following groups:

However, each of the above groups is optionally substituted with one or more substituents selected from:
Halogens; or
C _1-6 -alkyl or C _1-6 -alkoxy, each optionally substituted with one or more halogens. 50. The compound of claim 49, wherein Z is selected from the following groups:

However, each of the above groups is optionally substituted with one or more substituents selected from:
• halogen; or • C _1-6 -alkyl or C _1-6 -alkoxy, each optionally substituted with one or more halogens. 51. The compound of claim 50, wherein Z is selected from the following groups:

However, each of the above groups is optionally substituted with one or more substituents selected from:
• halogen; or • C _1-6 -alkyl or C _1-6 -alkoxy, each optionally substituted with one or more halogens. 52. The compound of claim 51, wherein Z is selected from the following groups:

However, each of the above groups is optionally substituted with one or more substituents selected from:
• halogen; or • C _1-6 -alkyl or C _1-6 -alkoxy, each optionally substituted with one or more halogens. 53. The compound of claim 52, wherein Z is

Is a compound: 53. The compound of claim 52, wherein Z is

Which is optionally substituted with one or more trifluoromethyl. 53. The compound of claim 52, wherein Z is

A compound that is 52. The compound of claim 51, wherein Z is

A compound that is 52. The compound of claim 51, wherein Z is

A compound that is 58. The compound according to any one of claims 1 to 57, comprising any of the following compounds, a salt thereof with a pharmaceutically acceptable acid or base, any optical isomer or racemic mixture: A mixture of optical isomers, or any tautomer:
2-ethoxy-3- [4- (2-{[6-({2- [4- (2-ethoxy-2-methoxycarbonyl-ethyl) -phenylsulfanyl] -ethyl} -methyl-amino) -pyridine -2-yl] -methyl-amino} -ethylsulfanyl) -phenyl] -propionic acid;
3- [4- (2-{[6-({2- [4- (2-carboxy-2-ethoxy-ethyl) -2-chloro-phenylsulfanyl] -ethyl} -methyl-amino) -pyridine- 2-yl] -methyl-amino} -ethylsulfanyl) -3-chloro-phenyl] -2-ethoxy-propionic acid;
(5 '-{2-[(6-{[2- (2'-ethoxycarbonylmethoxy- [1,1'; 3 ', 1'']terphenyl-5'-yloxy) -ethyl] -methyl -Amino} -pyridin-2-yl) -methyl-amino] -ethoxy}-[1,1 ′; 3 ′, 1 ″] terphenyl-2′-yloxy) -acetic acid;
(5 '-{2-[(6-{[2- (2'-Carboxymethoxy- [1,1'; 3 ', 1'']terphenyl-5'-yloxy) -ethyl] -methyl- Amino} -pyridin-2-yl) -methyl-amino] -ethoxy}-[1,1 ′; 3 ′, 1 ″] terphenyl-2′-yloxy) -acetic acid;
・ (S, S) -2- (2-Benzoyl-phenylamino) -3- {4- [2-({6-[(2- {4- [2- (2-benzoyl-phenylamino) -2 -Methoxycarbonyl-ethyl] -phenoxy} -ethyl) -methyl-amino] -pyridin-2-yl} -methyl-amino) -ethoxy] -phenyl} -propionic acid;
・ (S, S) -2- (2-Benzoyl-phenylamino) -3- {4- [2-({6-[(2- {4- [2- (2-benzoyl-phenylamino) -2 -Carboxy-ethyl] -phenoxy} -ethyl) -methyl-amino] -pyridin-2-yl} -methyl-amino) -ethoxy] -phenyl} -propionic acid;
(3-Chloro-4- {2-[(6-{[2- (2-Chloro-4-ethoxycarbonylmethyl-phenoxy) -ethyl] -methyl-amino} -pyridin-2-yl) -methyl- Amino] -ethoxy} -phenyl) -acetic acid;
(4- {2-[(6-{[2- (4-Carboxymethyl-2-chloro-phenoxy) -ethyl] -methyl-amino} -pyridin-2-yl) -methyl-amino] -ethoxy} -3-chloro-phenyl) -acetic acid;
・ (3- {2-[(6-{[2- (3-Ethoxycarbonylmethyl-phenoxy) -ethyl] -methyl-amino} -pyridin-2-yl) -methyl-amino] -ethoxy} -phenyl) -Acetic acid;
(3- {2-[(6-{[2- (3-Carboxymethyl-phenoxy) -ethyl] -methyl-amino} -pyridin-2-yl) -methyl-amino] -ethoxy} -phenyl)- Acetic acid;
(S, S) -2-ethoxy-3- [4- (2-{[6-({2- [4- (2-ethoxy-2-ethoxycarbonyl-ethyl) -phenoxy] -ethyl} -methyl -Amino) -pyridin-2-yl] -methyl-amino} -ethoxy) -phenyl] -propionic acid;
(S, S) -3- [4- (2-{[6-({2- [4- (2-carboxy-2-ethoxy-ethyl) -phenoxy] -ethyl} -methyl-amino) -pyridine -2-yl] -methyl-amino} -ethoxy) -phenyl] -2-ethoxy-propionic acid;
(S, S) -2-Ethoxy-3- {4- [3- (4 '-{3- [4- (2-Ethoxy-2-isopropoxycarbonyl-ethyl) -phenoxy] -propyl} -2 , 2'-bis-trifluoromethyl-biphenyl-4-yl) -propoxy] -phenyl} -propionic acid;
(S, S) -3- {4- [3- (4 '-{3- [4- (2-carboxy-2-ethoxy-ethyl) -phenoxy] -propyl} -2,2'-bis- Trifluoromethyl-biphenyl-4-yl) -propoxy] -phenyl} -2-ethoxy-propionic acid;
(S, S) -2-ethoxy-3- {4- [3- (4 '-{3- [4- (2-ethoxy-2-isopropoxycarbonyl-ethyl) -phenoxy] -propyl} -3 , 3'-bis-trifluoromethyl-biphenyl-4-yl) -propoxy] -phenyl} -propionic acid;
(S, S) -3- {4- [3- (4 '-{3- [4- (2-carboxy-2-ethoxy-ethyl) -phenoxy] -propyl} -3,3'-bis- Trifluoromethyl-biphenyl-4-yl) -propoxy] -phenyl} -2-ethoxy-propionic acid;
(S, S) -3- {3-Bromo-4- [3- (4 '-{3- [2-Bromo-4- (2-ethoxy-2-isopropoxycarbonyl-ethyl) -phenoxy]- Propyl} -2,2′-bis-trifluoromethyl-biphenyl-4-yl) -propoxy] -phenyl} -2-ethoxy-propionic acid;
(S, S) -3- {3-bromo-4- [3- (4 '-{3- [2-bromo-4- (2-carboxy-2-ethoxy-ethyl) -phenoxy] -propyl} -2,2'-bis-trifluoromethyl-biphenyl-4-yl) -propoxy] -phenyl} -2-ethoxy-propionic acid;
(S, S) -3- {3-Bromo-4- [3- (4 '-{3- [2-Bromo-4- (2-ethoxy-2-isopropoxycarbonyl-ethyl) -phenoxy]- Propyl} -3,3′-bis-trifluoromethyl-biphen-4-yl) -propoxy] -phenyl} -2-ethoxy-propionic acid;
(S, S) -3- {3-bromo-4- [3- (4 '-{3- [2-bromo-4- (2-carboxy-2-ethoxy-ethyl) -phenoxy] -propyl} -3,3'-bis-trifluoromethyl-biphenyl-4-yl) -propoxy] -phenyl} -2-ethoxy-propionic acid;
(S, S) -3- {3-Bromo-4- [3- (7- {3- [2-bromo-4- (2-ethoxy-2-isopropoxycarbonyl-ethyl) -phenoxy] -propyl } -9H-Fluoren-2-yl) -propoxy] -phenyl} -2-ethoxy-propionic acid isopropyl ester;
(S, S) -3- {3-bromo-4- [3- (7- {3- [2-bromo-4- (2-carboxy-2-ethoxy-ethyl) -phenoxy] -propyl}- 9H-Fluoren-2-yl) -propoxy] -phenyl} -2-ethoxy-propionic acid;
(S, S) -2-ethoxy-3- {4- [3- (7- {3- [4- (2-ethoxy-2-isopropoxycarbonyl-ethyl) -phenoxy] -propyl} -9H- Fluoren-2-yl) -propoxy] -phenyl} -propionic acid isopropyl ester;
(S, S) -3- {4- [3- (7- {3- [4- (2-carboxy-2-ethoxy-ethyl) -phenoxy] -propyl} -9H-fluoren-2-yl) -Propoxy] -phenyl} -2-ethoxy-propionic acid;
-[4- (3- {4 '-[3- (4-Methoxycarbonylmethoxy-3-methyl-phenylsulfanyl) -propyl] -2,2'-bis-trifluoromethyl-biphenyl-4-yl}- Propylsulfanyl) -2-methyl-phenoxy] -acetic acid;
・ [4- (3- {4 '-[3- (4-Methoxycarbonylmethoxy-3-methyl-phenylsulfanyl) -propyl] -3,3'-bis-trifluoromethyl-biphenyl-4-yl}- Propylsulfanyl) -2-methyl-phenoxy] -acetic acid;
[4- (3- {4 '-[3- (4-Carboxymethoxy-3-methyl-phenylsulfanyl) -propyl] -3,3'-bis-trifluoromethyl-biphenyl-4-yl} -propyl Sulfanyl) -2-methyl-phenoxy] -acetic acid;
・ [4- (3- {7- [3- (4-Methoxycarbonylmethoxy-3-methyl-phenylsulfanyl) -propyl] -9H-fluoren-2-yl} -propylsulfanyl) -2-methyl-phenoxy] -Acetic acid;
[4- (3- {7- [3- (4-Carboxymethoxy-3-methyl-phenylsulfanyl) -propyl] -9H-fluoren-2-yl} -propylsulfanyl) -2-methyl-phenoxy]- Acetic acid;
・ (4- {2- [2- (3- {4- [2- (4-Methoxycarbonylmethoxy-3-methyl-phenylsulfanyl) -ethyl] -5-methyl-oxazol-2-yl} -phenyl) -5-methyl-oxazol-4-yl] -ethylsulfanyl} -2-methyl-phenoxy) -acetic acid;
・ (4- {2- [2- (3- {4- [2- (4-Carboxymethoxy-3-methyl-phenylsulfanyl) -ethyl] -5-methyl-oxazol-2-yl} -phenyl)- 5-methyl-oxazol-4-yl] -ethylsulfanyl} -2-methyl-phenoxy) -acetic acid;
・ (S, S) -2-Ethoxy-3- [4- (2- {2- [4 '-(4- {2- [4- (2-Ethoxy-2-isopropoxycarbonyl-ethyl) -phenoxy] ] -Ethyl} -5-methyl-oxazol-2-yl) -biphenyl-4-yl] -5-methyl-oxazol-4-yl} -ethoxy) -phenyl] -propionic acid;
(S, S) -3- [4- (2- {2- [4 '-(4- {2- [4- (2-carboxy-2-ethoxy-ethyl) -phenoxy] -ethyl} -5 -Methyl-oxazol-2-yl) -biphenyl-4-yl] -5-methyl-oxazol-4-yl} -ethoxy) -phenyl] -2-ethoxy-propionic acid;
(S, S) -2-Ethoxy-3- [4- (2- {2- [3- (4- {2- [4- (2-Ethoxy-2-isopropoxycarbonyl-ethyl) -phenoxy] -Ethyl} -5-methyl-oxazol-2-yl) -phenyl] -5-methyl-oxazol-4-yl} -ethoxy) -phenyl] -propionic acid;
(S, S) -3- [4- (2- {2- [3- (4- {2- [4- (2-carboxy-2-ethoxy-ethyl) -phenoxy] -ethyl} -5- Methyl-oxazol-2-yl) -phenyl] -5-methyl-oxazol-4-yl} -ethoxy) -phenyl] -2-ethoxy-propionic acid. 58. The compound according to any one of claims 1 to 57, comprising any of the following compounds, a salt thereof with a pharmaceutically acceptable acid or base, any optical isomer or racemic mixture: A mixture of optical isomers, or any tautomer:
2-ethoxy-3- [4- (2-{[6-({2- [4- (2-ethoxy-2-methoxycarbonyl-ethyl) -phenylsulfanyl] -ethyl} -methyl-amino) -pyridine -2-yl] -methyl-amino} -ethylsulfanyl) -phenyl] -propionic acid methyl ester;
(5 '-{2-[(6-{[2- (2'-ethoxycarbonylmethoxy- [1,1'; 3 ', 1'']terphenyl-5'-yloxy) -ethyl] -methyl -Amino} -pyridin-2-yl) -methyl-amino] -ethoxy}-[1,1 ′; 3 ′, 1 ″] terphenyl-2′-yloxy) -acetic acid ethyl ester;
・ (S, S) -2- (2-Benzoyl-phenylamino) -3- {4- [2-({6-[(2- {4- [2- (2-benzoyl-phenylamino) -2 -Methoxycarbonyl-ethyl] -phenoxy} -ethyl) -methyl-amino] -pyridin-2-yl} -methyl-amino) -ethoxy] -phenyl} -propionic acid methyl ester;
(3-Chloro-4- {2-[(6-{[2- (2-Chloro-4-ethoxycarbonylmethyl-phenoxy) -ethyl] -methyl-amino} -pyridin-2-yl) -methyl- Amino] -ethoxy} -phenyl) -acetic acid ethyl ester;
・ (3- {2-[(6-{[2- (3-Ethoxycarbonylmethyl-phenoxy) -ethyl] -methyl-amino} -pyridin-2-yl) -methyl-amino] -ethoxy} -phenyl) -Acetic acid ethyl ester;
(S, S) -2-Ethoxy-3- [4- (2-{[6-({2- [4- (2-Ethoxy-2-ethoxycarbonyl-ethyl) -phenoxy] -ethyl} -methyl- Amino) -pyridin-2-yl] -methyl-amino} -ethoxy) -phenyl] -propionic acid ethyl ester;
(S, S) -2-Ethoxy-3- {4- [3- (4 '-{3- [4- (2-Ethoxy-2-isopropoxycarbonyl-ethyl) -phenoxy] -propyl} -2 , 2'-bis-trifluoromethyl-biphenyl-4-yl) -propoxy] -phenyl} -propionic acid isopropyl ester;
(S, S) -2-ethoxy-3- {4- [3- (4 '-{3- [4- (2-ethoxy-2-isopropoxycarbonyl-ethyl) -phenoxy] -propyl} -3 , 3'-bis-trifluoromethyl-biphenyl-4-yl) -propoxy] -phenyl} -propionic acid isopropyl ester;
(S, S) -3- {3-Bromo-4- [3- (4 '-{3- [2-Bromo-4- (2-ethoxy-2-isopropoxycarbonyl-ethyl) -phenoxy]- Propyl} -2,2′-bis-trifluoromethyl-biphenyl-4-yl) -propoxy] -phenyl} -2-ethoxy-propionic acid isopropyl ester;
(S, S) -3- {3-Bromo-4- [3- (4 '-{3- [2-Bromo-4- (2-ethoxy-2-isopropoxycarbonyl-ethyl) -phenoxy]- Propyl} -3,3′-bis-trifluoromethyl-biphenyl-4-yl) -propoxy] -phenyl} -2-ethoxy-propionic acid isopropyl ester;
-[4- (3- {4 '-[3- (4-Methoxycarbonylmethoxy-3-methyl-phenylsulfanyl) -propyl] -2,2'-bis-trifluoromethyl-biphenyl-4-yl}- Propylsulfanyl) -2-methyl-phenoxy] -acetic acid methyl ester;
[4- (3- {4 '-[3- (4-Carboxymethoxy-3-methyl-phenylsulfanyl) -propyl] -2,2'-bis-trifluoromethyl-biphenyl-4-yl} -propyl Sulfanyl) -2-methyl-phenoxy] -acetic acid;
・ [4- (3- {4 '-[3- (4-Methoxycarbonylmethoxy-3-methyl-phenylsulfanyl) -propyl] -3,3'-bis-trifluoromethyl-biphenyl-4-yl}- Propylsulfanyl) -2-methyl-phenoxy] -acetic acid methyl ester;
・ [4- (3- {7- [3- (4-Methoxycarbonylmethoxy-3-methyl-phenylsulfanyl) -propyl] -9H-fluoren-2-yl} -propylsulfanyl) -2-methyl-phenoxy] -Acetic acid methyl ester;
・ (4- {2- [2- (3- {4- [2- (4-Methoxycarbonylmethoxy-3-methyl-phenylsulfanyl) -ethyl] -5-methyl-oxazol-2-yl} -phenyl) -5-methyl-oxazol-4-yl] -ethylsulfanyl} -2-methyl-phenoxy) -acetic acid methyl ester;
・ (S, S) -2-Ethoxy-3- [4- (2- {2- [4 '-(4- {2- [4- (2-Ethoxy-2-isopropoxycarbonyl-ethyl) -phenoxy] ] -Ethyl} -5-methyl-oxazol-2-yl) -biphenyl-4-yl] -5-methyl-oxazol-4-yl} -ethoxy) -phenyl] -propionic acid isopropyl ester;
(S, S) -2-Ethoxy-3- [4- (2- {2- [3- (4- {2- [4- (2-Ethoxy-2-isopropoxycarbonyl-ethyl) -phenoxy] -Ethyl} -5-methyl-oxazol-2-yl) -phenyl] -5-methyl-oxazol-4-yl} -ethoxy) -phenyl] -propionic acid isopropyl ester. 58. The compound according to any one of claims 1 to 57, comprising any of the following compounds, a salt thereof with a pharmaceutically acceptable acid or base, any optical isomer or racemic mixture: A mixture of optical isomers, or any tautomer:
-[4- (3- {4 '-[3- (4-Carboxymethylsulfanyl-3-chloro-phenylsulfanyl) -propyl] -3,3'-bis-trifluoromethyl-biphenyl-4-yl}- Propylsulfanyl) -2-chloro-phenylsulfanyl] -acetic acid;
[4- [3- [4 '-[3- (4-carboxymethoxy-3-trifluoromethylphenylsulfanyl) propyl] biphenyl-4-yl] -propylsulfanyl] -2-trifluoromethylphenoxy] acetic acid;
[4- [3- [4 '-[3- (4-Carboxymethoxy-3-chlorophenylsulfanyl) propyl] -3,3'-bis-trifluoromethylbiphenyl-4-yl] propylsulfanyl] -2- Chlorophenoxy] acetic acid;
[4- (3- {4 '-[3- (4-Carboxymethoxy-3-chloro-phenylsulfanyl) -propyl] -biphenyl-4-yl} -propylsulfanyl) -2-chloro-phenoxy]- Acetic acid;
[4- (3- {4 '-[3- (4-Carboxymethoxy-3-methoxy-phenylsulfanyl) -propyl] -biphenyl-4-yl} -propylsulfanyl) -2-methoxy-phenoxy] -acetic acid . 58. The compound according to any one of claims 1 to 57, comprising any of the following compounds, a salt thereof with a pharmaceutically acceptable acid or base, any optical isomer or racemic mixture: A mixture of optical isomers, or any tautomer:
3- [4- (2-{[6-({2- [4- (2-carboxy-2-ethoxy-ethyl) -phenoxy] -ethyl} -methyl-amino) -pyridin-2-yl]- Methyl-amino} -ethoxy) -phenyl] -2-ethoxy-propionic acid;
(3- {2-[(6-{[2- (3-Carboxymethyl-phenoxy) -ethyl] -methyl-amino} -pyridin-2-yl) -methyl-amino] -ethoxy} -phenyl)- Acetic acid;
2- (2-benzoyl-phenylamino) -3- {4- [2-({6-[(2- {4- [2- (2-benzoyl-phenylamino) -2-carboxy-ethyl]- Phenoxy} -ethyl) -methyl-amino] -pyridin-2-yl} -methyl-amino) -ethoxy] -phenyl} -propionic acid;
(5 '-{2-[(6-{[2- (2'-Carboxymethoxy- [1,1'; 3 ', 1'']terphenyl-5'-yloxy) -ethyl] -methyl- Amino} -pyridin-2-yl) -methyl-amino] -ethoxy}-[1,1 ′; 3 ′, 1 ″] terphenyl-2′-yloxy) -acetic acid;
3- [4- (2-{[6-({2- [4- (2-carboxy-2-ethoxy-ethyl) -phenylsulfanyl] -ethyl} -methyl-amino) -pyridin-2-yl] -Methyl-amino} -ethylsulfanyl) -phenyl] -2-ethoxy-propionic acid;
(4- {2-[(6-{[2- (4-Carboxymethyl-2-chloro-phenoxy) -ethyl] -methyl-amino} -pyridin-2-yl) -methyl-amino] -ethoxy} -3-chloro-phenyl) -acetic acid;
(4- {2-[(6-{[2- (4-Carboxymethyl-2-bromo-phenoxy) -ethyl] -methyl-amino} -pyridin-2-yl) -methyl-amino] -ethoxy} -3-bromo-phenyl) -acetic acid;
(4- {2-[(6-{[2- (4-Carboxymethoxy-3-methyl-phenylsulfanyl) -ethyl] -methyl-amino} -pyridin-2-yl) -methyl-amino] -ethyl Sulfanyl} -2-methyl-phenoxy) -acetic acid;
(4- {2-[(6-{[2- (4-Carboxymethoxy-phenylsulfanyl) -ethyl] -methyl-amino} -pyridin-2-yl) -methyl-amino] -ethylsulfanyl} -phenoxy ) -Acetic acid;
(3- {2-[(6-{[2- (3-Carboxymethyl-phenylsulfanyl) -ethyl] -methyl-amino} -pyridin-2-yl) -methyl-amino] -ethylsulfanyl} -phenyl ) -Acetic acid;
・ (4- {2-[(6-{[2- (4-Carboxymethyl-phenylsulfanyl) -ethyl] -methyl-amino} -pyridin-2-yl) -methyl-amino] -ethylsulfanyl} -phenyl ) -Acetic acid;
2- (2-benzoyl-phenylamino) -3- {4- [2-({6-[(2- {4- [2- (2-benzoyl-phenylamino) -2-carboxy-ethyl]- Phenylsulfanyl} -ethyl) -methyl-amino] -pyridin-2-yl} -methyl-amino) -ethylsulfanyl] -phenyl} -propionic acid;
3- {4- [2-({6-[(2- {4- [2-carboxy-2- (1-methyl-3-oxo-3-phenyl-propenylamino) -ethyl] -phenylsulfanyl} -Ethyl) -methyl-amino] -pyridin-2-yl} -methyl-amino) -ethylsulfanyl] -phenyl} -2- (1-methyl-3-oxo-3-phenyl-propenylamino) -propionic acid;
3- {4- [2-({6-[(2- {4- [2-carboxy-2- (1-methyl-3-oxo-3-phenyl-propenylamino) -ethyl] -phenoxy}- Ethyl) -methyl-amino] -pyridin-2-yl} -methyl-amino) -ethoxy] -phenyl} -2- (1-methyl-3-oxo-3-phenyl-propenylamino) -propionic acid;
(4- {2-[(6-{[2- (4-Carboxymethyl-2-chloro-phenylsulfanyl) -ethyl] -methyl-amino} -pyridin-2-yl) -methyl-amino] -ethyl Sulfanyl} -3-chloro-phenyl) -acetic acid;
(4- {2-[(6-{[2- (4-Carboxymethyl-2-bromo-phenylsulfanyl) -ethyl] -methyl-amino} -pyridin-2-yl) -methyl-amino] -ethyl Sulfanyl} -3-bromo-phenyl) -acetic acid;

3- [4- (2- {2- [3- (4- {2- [4- (2-carboxy-2-ethoxy-ethyl) -phenoxy] -ethyl} -5-methyl-oxazole-2- Yl) -phenyl] -5-methyl-oxazol-4-yl} -ethoxy) -phenyl] -2-ethoxy-propionic acid;
・ (4- {2- [2- (3- {4- [2- (4-Carboxymethoxy-3-methyl-phenylsulfanyl) -ethyl] -5-methyl-oxazol-2-yl} -phenyl)- 5-methyl-oxazol-4-yl] -ethylsulfanyl} -2-methyl-phenoxy) -acetic acid;
(4- {2- [2- (3- {4- [2- (4-Carboxymethoxy-3-methyl-phenoxy) -ethyl] -5-methyl-oxazol-2-yl} -phenyl) -5 -Methyl-oxazol-4-yl] -ethoxy} -2-methyl-phenoxy) -acetic acid;
・ (4- {2- [2- (3- {4- [2- (4-Carboxymethoxy-phenoxy) -ethyl] -5-methyl-oxazol-2-yl} -phenyl) -5-methyl-oxazole -4-yl] -ethoxy} -phenoxy) -acetic acid;
・ (4- {2- [2- (3- {4- [2- (4-Carboxymethoxy-phenylsulfanyl) -ethyl] -5-methyl-oxazol-2-yl} -phenyl) -5-methyl- Oxazol-4-yl] -ethylsulfanyl} -phenoxy) -acetic acid;
3- [4- (2- {2- [3- (4- {2- [4- (2-carboxy-2-ethoxy-ethyl) -phenylsulfanyl] -ethyl} -5-methyl-oxazole-2 -Yl) -phenyl] -5-methyl-oxazol-4-yl} -ethylsulfanyl) -phenyl] -2-ethoxy-propionic acid;

3- {4- [3- (7- {3- [4- (2-carboxy-2-ethoxy-ethyl) -phenoxy] -propyl} -9H-fluoren-2-yl) -propoxy] -phenyl} -2-ethoxy-propionic acid;
3- {4- [3- (7- {3- [4- (2-carboxy-2-ethoxy-ethyl) -phenylsulfanyl] -propyl} -9H-fluoren-2-yl) -propylsulfanyl]- Phenyl} -2-ethoxy-propionic acid;
[4- (3- {7- [3- (4-Carboxymethoxy-3-methyl-phenylsulfanyl) -propyl] -9H-fluoren-2-yl} -propylsulfanyl) -2-methyl-phenoxy]- Acetic acid;
[4- (3- {7- [3- (4-carboxymethoxy-phenylsulfanyl) -propyl] -9H-fluoren-2-yl} -propylsulfanyl) -phenoxy] -acetic acid;
3- {3-bromo-4- [3- (7- {3- [2-bromo-4- (2-carboxy-2-ethoxy-ethyl) -phenoxy] -propyl} -9H-fluorene-2- Yl) -propoxy] -phenyl} -2-ethoxy-propionic acid;
3- {3-bromo-4- [3- (7- {3- [2-bromo-4- (2-carboxy-2-ethoxy-ethyl) -phenylsulfanyl] -propyl} -9H-fluorene-2 -Yl) -propylsulfanyl] -phenyl} -2-ethoxy-propionic acid;

3- {4- [3- (4 '-{3- [4- (2-carboxy-2-ethoxy-ethyl) -phenoxy] -propyl} -2,2'-bis-trifluoromethyl-biphenyl- 4-yl) -propoxy] -phenyl} -2-ethoxy-propionic acid;
3- {4- [3- (4 '-{3- [4- (2-carboxy-2-ethoxy-ethyl) -phenoxy] -propyl} -3,3'-bis-trifluoromethyl-biphenyl- 4-yl) -propoxy] -phenyl} -2-ethoxy-propionic acid;
3- {3-bromo-4- [3- (4 '-{3- [2-bromo-4- (2-carboxy-2-ethoxy-ethyl) -phenoxy] -propyl} -2,2'- bis-trifluoromethyl-biphenyl-4-yl) -propoxy] -phenyl} -2-ethoxy-propionic acid;
3- {3-bromo-4- [3- (4 '-{3- [2-bromo-4- (2-carboxy-2-ethoxy-ethyl) -phenoxy] -propyl} -3,3'- bis-trifluoromethyl-biphenyl-4-yl) -propoxy] -phenyl} -2-ethoxy-propionic acid;
[4- (3- {4 '-[3- (4-Carboxymethoxy-3-methyl-phenylsulfanyl) -propyl] -3,3'-bis-trifluoromethyl-biphenyl-4-yl} -propyl Sulfanyl) -2-methyl-phenoxy] -acetic acid;
[4- (3- {4 '-[3- (4-Carboxymethoxy-phenylsulfanyl) -propyl] -3,3'-bis-trifluoromethyl-biphenyl-4-yl} -propylsulfanyl) -phenoxy ] -Acetic acid;
[4- (3- {4 '-[3- (4-Carboxymethoxy-phenoxy) -propyl] -3,3'-bis-trifluoromethyl-biphenyl-4-yl} -propoxy) -phenoxy]- Acetic acid;
・ [4- (3- {4 '-[3- (4-Carboxymethoxy-3-methyl-phenoxy) -propyl] -3,3'-bis-trifluoromethyl-biphenyl-4-yl} -propoxy) -2-methyl-phenoxy] -acetic acid;
[4- (3- {4 '-[3- (4-Carboxymethoxy-3-methyl-phenylsulfanyl) -propyl] -2,2'-bis-trifluoromethyl-biphenyl-4-yl} -propyl Sulfanyl) -2-methyl-phenoxy] -acetic acid;
・ [4- (3- {4 '-[3- (4-Carboxymethoxy-3-methyl-phenoxy) -propyl] -2,2'-bis-trifluoromethyl-biphenyl-4-yl} -propoxy) -2-methyl-phenoxy] -acetic acid;
3- [4- (2- {2- [4 '-(4- {2- [4- (2-carboxy-2-ethoxy-ethyl) -phenoxy] -ethyl} -5-methyl-oxazole-2) -Yl) -biphenyl-4-yl] -5-methyl-oxazol-4-yl} -ethoxy) -phenyl] -2-ethoxy-propionic acid. {4- [3- (4- {4- [3- (4-Carboxymethoxy-3-trifluoromethyl-phenylsulfanyl) -propyl] -2-trifluoromethyl-phenylsulfanyl} -3-trifluoromethyl- Phenyl) -propylsulfanyl] -2-trifluoromethyl-phenoxy} -acetic acid, salts thereof with pharmaceutically acceptable acids or bases, optical isomers including any optical isomers or racemic mixtures A mixture, or any tautomer. 63. A compound according to any one of claims 1 to 62 which is a PPARδ agonist. 64. The compound of claim 63, wherein the compound is a selective PPARδ agonist. 65. Use of a compound according to any one of claims 1 to 64 as a pharmaceutical composition. 65. A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 64 as an active ingredient together with one or more pharmaceutically acceptable carriers or excipients. 67. The pharmaceutical composition according to claim 66, wherein from about 0.05 mg to about 1000 mg, preferably from about 0.1 to about 500 mg, particularly preferably from about 0.5 mg to about 200 mg per day. A pharmaceutical composition in unit dosage form containing the compound according to any one of the above. A pharmaceutical composition for treating and / or preventing a condition mediated by a nuclear receptor, particularly a peroxisome proliferator activated receptor (PPAR), comprising one or more pharmaceutically acceptable carriers or supplements. A pharmaceutical composition comprising a compound according to any one of claims 1 to 64 together with a form. Type I diabetes, Type II diabetes, dyslipidemia, syndrome X (including metabolic syndrome, ie impaired glucose tolerance, insulin resistance, hypertriglyceridemia and / or obesity), cardiovascular disorders (including atherosclerosis) ), Or a pharmaceutical composition for treating and / or preventing hypercholesterolemia, together with one or more pharmaceutically acceptable carriers or excipients. A pharmaceutical composition comprising the compound described in 1. 70. A compound according to any one of claims 66 to 69 for oral, nasal, transdermal, pulmonary or parenteral administration. 65. Any one of claims 1 to 64 for preparing a pharmaceutical composition for treating and / or preventing a condition mediated by a nuclear receptor, in particular a peroxisome proliferator activated receptor (PPAR). Use of the compounds described in 1. 65. Use of a compound according to any one of claims 1 to 64 for the preparation of a pharmaceutical composition for treating type I diabetes or type II diabetes. 65. Use of a compound according to any one of claims 1 to 64 for the preparation of a pharmaceutical composition for the treatment of dyslipidemia. 65. Any one of claims 1 to 64 for preparing a pharmaceutical composition for treating metabolic syndrome, i.e. syndrome X including impaired glucose tolerance, insulin resistance, hypertriglyceridemia and / or obesity. Use of the compounds described in 1. 65. Use of a compound according to any one of claims 1 to 64 for the preparation of a pharmaceutical composition for the treatment of cardiovascular disorders including atherosclerosis. 65. Use of a compound according to any one of claims 1 to 64 for the preparation of a pharmaceutical composition for the treatment of hypercholesterolemia. A method for treating a condition mediated by a nuclear receptor, in particular a peroxisome proliferator activated receptor (PPAR), in an effective amount for a patient in need thereof. A method comprising administering the compound according to any one of the above or a pharmaceutical composition containing the compound. Type I diabetes, Type II diabetes, dyslipidemia, syndrome X (including metabolic syndrome, ie impaired glucose tolerance, insulin resistance, hypertriglyceridemia and / or obesity), cardiovascular disorders (including atherosclerosis) Or a method for treating hypercholesterolemia in an effective amount of the compound according to any one of claims 1 to 64 or a pharmaceutical comprising the same for a patient in need thereof Administering a pharmaceutical composition. 79. The method of claim 77 or 78, wherein an effective amount of the compound of any one of claims 1 to 64 is from about 0.05 mg to about 1000 mg, preferably from about 0.1 to about 500 mg, particularly preferably per day. Is about 0.5 mg to about 200 mg.