KR100802864B1 - Pyrazolyl indolyl derivatives as ppar activators - Google Patents

Abstract

The present invention relates to compounds of formula (I), all enantiomers and pharmaceutically acceptable salts and / or esters thereof:

Formula I

Where

이고, R¹ 내지 R¹⁵ 및 n은 설명에서 정의된 바와 같다.One of R ⁶ and R ⁷ , R ⁷ and R ⁸

And R ¹ to R ¹⁵ and n are as defined in the description.

The present invention also relates to pharmaceutical compositions containing said compounds, methods for their preparation and their use for the treatment and / or prevention of diseases controlled by PPARδ and / or PPARα agonists.

Description

Pyrazolyl INDOLYL DERIVATIVES AS PPAR ACTIVATORS}

The present invention relates to compounds of formula (I), all enantiomers, pharmaceutically acceptable salts and / or esters thereof:

Where

R ¹ is hydrogen or C _1-7 -alkyl;

R ² and R ³ are independently of each other hydrogen, C _1-7 -alkyl or C _1-7 -alkoxy;

R ⁴ and R ⁵ independently of one another are hydrogen, C _1-7 -alkyl, C _3-7 -cycloalkyl, halogen, C _1-7 -alkoxy-C _1-7 -alkyl, C _2-7 -alkenyl, C _2-7 -alkynyl, fluoro-C _1-7 -alkyl, cyano-C _1-7 -alkyl or cyano;

R ⁶ , R ⁷ , R ⁸ and R ⁹ independently of one another are hydrogen, C _1-7 -alkyl, C _3-7 -cycloalkyl, halogen, C _1-7 -alkoxy-C _1-7 -alkyl, C _{2 -7} -alkenyl, C _2-7 -alkynyl, fluoro-C _1-7 -alkyl, cyano-C _1-7 -alkyl or cyano;

이고,One of R ⁶ , R ⁷ and R ⁸

ego,

Then R ¹⁰ is hydrogen, C _1-7 -alkyl, C _3-7 -cycloalkyl or fluoro-C _1-7 -alkyl;

R ¹¹ is hydrogen, C _1-7 -alkyl or C _1-7 -alkoxy-C _1-7 -alkyl;

One of R ¹² or R ¹³ is hydrogen, C _1-7 -alkyl, C _3-7 -cycloalkyl, C _2-7 -alkoxy-C _1-7 -alkyl, C _2-7 -alkenyl, C _{2- 7} -alkynyl or fluor-C _1-7 -alkyl; The other is an isolation pair;

R ¹⁴ is hydrogen, C _1-7 -alkyl, C _3-7 -cycloalkyl, halogen, C _1-7 -alkoxy-C _1-7 -alkyl, C _2-7 -alkenyl, C _2-7 -alky Nil or fluoro-Ci_ ₇ -alkyl;

R ¹⁵ is aryl or heteroaryl;

n is 1, 2 or 3.

Compounds of formula (I) are useful as lipid modulators and insulin sensitizers. In particular, the compound of formula I is a PPAR activator.

Peroxysome Proliferator Activated Receptor (PPAR) is a member of the nuclear hormone receptor superfamily. PPARs are ligand-activated transcription factors that regulate gene expression and control multiple metabolic pathways. Three subtypes of PPARα, PPARδ (also known as PPARβ) and PPARγ have been described. PPARδ is ubiquitously expressed. PPARα is mainly expressed in the liver, kidneys and heart. There are two or more major isoforms of PPARγ. PPARγ1 is expressed in most tissues, and the longer isoform PPARγ2 is almost expressed only in adipose tissue. PPARs regulate a variety of physiological responses, including glucose- and lipid-continence and metabolism, energy balance, cell differentiation, inflammation, and cardiovascular abnormalities.

Approximately half of all patients with coronary artery disease have low levels of plasma HDL cholesterol. The atheroprotective function of HDL was first emphasized nearly 25 years ago and stimulated the exploration of genetic and environmental factors affecting HDL levels. The protective function of HDL stems from its role in a process called reverse cholesterol transport. HDL mediates the removal of cholesterol from cells of peripheral tissues, including cells of atherosclerotic lesions of the arterial walls. HDL then delivers its cholesterol to the liver and sterol-metabolic organs for conversion and excretion. The data from the Framingham study showed that HDL-C levels indicate a risk of coronary artery disease regardless of LDL-C levels. Age-adjusted assessed incidences of HDL-C levels below 35 mg / dL among Americans 20 years of age and older are 16% (male) and 5.7% (female). Substantial increases in HDL-C are generally achieved by treatment with niacin in various formulations. However, substantial side effects limit the therapeutic potential of this approach.

As many as 90% of the 14 million diagnosed type 2 diabetes in the United States are overweight or obese, and a high proportion of type 2 diabetes have abnormal concentrations of lipoproteins. The prevalence of total cholesterol higher than 240 mg / dL is 37% in diabetic men and 44% in women. The respective ratios for LDL-C higher than 160 mg / dL are 31% and 44%, respectively, and for HDL-C below 35 mg / dL, 28% and 11%, respectively. Diabetes is a disease in which the patient's ability to control blood glucose levels is reduced due to partial impairment of insulin action. Type II diabetes (T2D) is also called non-insulin dependent diabetes mellitus (NIDDM), and 80-90% of all diabetic patients in developed countries suffer. In T2D, the pancreatic islets continue to produce insulin. However, target organs, mainly muscle, liver and adipose tissue, to insulin action show great resistance to insulin stimulation. The human body produces and continues to supplement nonphysiologically high levels of insulin, which are ultimately reduced in later stages of the disease due to the depletion and lack of pancreatic insulin-producing ability. Thus, T2D is a cardiovascular-metabolic syndrome associated with several dual diagnoses, including insulin resistance, dyslipidemia, hypertension, endothelial dysfunction and inflammatory atherosclerosis.

The most important treatments for dyslipidemia and diabetes generally include low fat and low-glucose diet, exercise and weight loss. However, compliance may be moderate, and as the disease progresses, treatment of various metabolic deficiencies, for example, lipid-modulating agents such as statins and fibrates for dyslipidemia, and hypoglycemic drugs, such as insulin resistance There is a need for treatment with sulfonylureas or metformin. By resensitizing their own insulin to patients (insulin sensitizers), a promising new class of drugs has recently been found to restore blood sugar and triglyceride levels to normal, and in many cases to exclude or reduce the need for exogenous insulin. Was introduced. Pioglitazone (Actos®) and rosiglitazone (Avandia®) belong to the thiazolidinediones (TZD) class of PPARγ-agonists, the first of which is for NIDDM in several countries. Approved. However, these compounds are rare but suffer from side effects, including severe hepatotoxicity (as seen in troglitazone). They also increase the weight of the patients. Therefore, there is an urgent need for new and more effective drugs with higher safety and lower frequency of side effects. Recent studies have provided evidence that the competition of PPARδ provides compounds with increased therapeutic potential, i.e., the compounds have a superior effect on HDL-C elevation and normalization of insulin-levels compared to current therapies. With a positive effect, lipid profiles should be improved [Oliver et al, Proc. Nat. Acad. Sci. USA , 98 : 5306-5311, 2001]. Recent observations also suggest that there is an independent PPARα mediated effect on insulin-sensitization in addition to its known role in reducing triglycerides [Guerre-Millo et al., J. Biol. Chem. 275 : 16638-16642, 2000]. Thus, PPARδ agonists with selective PPARδ agonists or with additional PPARα activity may exhibit excellent therapeutic effects without side effects such as weight gain seen with PPARγ agonists.

The novel compounds of the present invention outperform those known in the art because they have much improved pharmacokinetic properties and bind to and selectively activate PPARδ or co-activate PPARδ and PPARα very effectively simultaneously. . Therefore, these compounds combine the anti-dyslipidemic and anti-glycemic effects of PPARδ and PPARα activation without affecting PPARγ. As a result, HDL cholesterol is increased, triglycerides are lowered (ie, lipid profile is improved), and plasma glucose and insulin are reduced (ie, insulin sensitization). In addition, the compounds also lower LDL cholesterol, lower blood pressure and counteract inflammatory atherosclerosis. In addition, the compounds may also be useful for treating inflammatory diseases such as rheumatoid arthritis, osteoarthritis and psoriasis. Since many aspects of combined dyslipidemia and T2D disease syndrome are addressed by PPARδ-selective agonists and PPARδ and α agonists, they are expected to have increased therapeutic potential over compounds already known in the art.

In addition, the compounds of the present invention exhibit improved pharmacological properties compared to known compounds.

Unless stated otherwise, the following definitions are presented to illustrate and define the meaning and scope of the various terms used to describe the invention herein.

The term "alkyl", alone or in combination with other groups, is a branched or straight-chain monovalent saturated aliphatic hydrocarbon having 1 to 20 carbon atoms, preferably 1 to 16 carbon atoms, more preferably 1 to 10 carbon atoms. Refers to radicals.

The term "lower alkyl" or "C _1-7 -alkyl", alone or in combination with other groups, refers to a branched or straight chain monovalent alkyl radical having 1 to 7 carbon atoms, preferably 1 to 4 carbon atoms. . The term is further exemplified by radicals such as methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, t-butyl and the groups specifically illustrated herein.

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

The term “fluoro-lower alkyl” or “fluoro-C _1-7 -alkyl” refers to lower alkyl groups mono- or polysubstituted with fluorine. Examples of fluoro-lower alkyl groups are, for example, -CF ₃ , -CH ₂ CF ₃ and -CH (CF ₃ ) ₂ and groups specifically exemplified herein.

The term "alkoxy" refers to the group R'-O, wherein R 'is alkyl. The term "lower alkoxy" or "C _1-7 -alkoxy" refers to the group R'-O, wherein R 'is lower-alkyl. Examples of lower-alkoxy groups are, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy and hexyloxy. Preference is given to lower-alkoxy groups specifically exemplified herein.

The term "lower fluoroalkoxy" or "fluoro-C _1-7 -alkoxy" refers to a lower alkoxy group as defined above, which is mono- or polysubstituted with fluorine. Examples of lower fluoroalkoxy groups are, for example, -OCH ₃ and -OCH ₂ CF ₃ .

The term "lower alkenyl" or "C _2-7 -alkenyl", alone or in combination, may be a straight chain comprising olefin bonds and up to 7, preferably up to 6, particularly preferably up to 4 carbon atoms or Branched hydrocarbon residues. Examples of alkenyl groups are ethenyl, 1-propenyl, 2-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl and isobutenyl. Preferred example is 2-propenyl.

The term "lower alkynyl" or "C _2-7 -alkynyl", alone or together, is a straight chain comprising triple bonds and up to 7, preferably up to 6, particularly preferably up to 4 carbon atoms or Branched hydrocarbon residues. Examples of alkynyl groups are ethynyl, 1-propynyl or 2-propynyl.

The term "cycloalkyl" or "C _3-7 -cycloalkyl" means a saturated carbocyclic group containing 3 to 7 carbon atoms, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl do.

The term "aryl" refers to halogen, hydroxy, CN, CF ₃ , NO ₂ , NH ₂ , N (H, lower-alkyl), N (lower-alkyl) ₂ , carboxy, aminocarbonyl, lower-alkyl, lower Phenyl or naphthyl groups, preferably phenyl groups, which may or may not be mono- or multi-substituted, in particular mono- or di-substituted, with fluoroalkyl, lower-alkoxy, lower fluoroalkoxy, aryl and / or aryloxy will be. Preferred substituents are halogen, CF ₃ , OCF ₃ , lower-alkyl and / or lower-alkoxy. Specifically exemplified aryl groups are preferred.

The term “heteroaryl” refers to an aromatic 5- or 6-membered ring, such as furyl, pyridyl, 1,2-, which may contain 1, 2 or 3 atoms selected from nitrogen, oxygen and / or sulfur. 1,3- and 1,4-diazinyl, thienyl, isoxazolyl, oxazolyl, imidazolyl or pyrrolyl. The term “heteroaryl” also refers to a bicyclic aromatic group comprising two 5- or 6-membered rings in which one or two rings may contain 1, 2 or 3 atoms selected from nitrogen, oxygen or sulfur, For example, indole or quinoline, or partially hydrogenated bicyclic aromatic groups such as indolinyl. Heteroaryl groups may have a substitution pattern as described above in connection with the term “aryl”. Preferred heteroaryl groups are, for example, thienyl and furyl, which may or may not be substituted with halogen, CF ₃ , lower-alkyl and / or lower-alkoxy, as described above.

An "isolated pair" is the electron phase of the outermost shell of atoms which are not used for bonding, especially nitrogen atoms.

The term "protecting group" refers to a group used to temporarily block the reactivity of a functional group, such as acyl, alkoxycarbonyl, aryloxycarbonyl, silyl or imine-derivative. Known protecting groups can be used, for example, for the protection of t-butyloxycarbonyl, benzyloxycarbonyl, fluorenylmethyloxycarbonyl or diphenylmethylene, or carboxy groups which can be used for the protection of amino groups. Lower-alkyl-, β-trimethylsilylethyl- and β-trichloroethyl-ester.

"Isomers" are compounds that have the same molecular formula but differ in their nature or in the arrangement of atoms or their arrangement in space. Isomers that differ in atomic arrangement in space are referred to as "stereoisomers". Stereoisomers that are not mirror images of one another are referred to as "diastereomers", and stereoisomers that are non-redundant mirror images are referred to as "enantiomers" or sometimes optical isomers. Carbon atoms bonded to four nonidentical substituents are referred to as "chiral centers".

The term "pharmaceutically acceptable salts" refers to salts of the compounds of formula I with pharmaceutically acceptable bases, such as alkali metal salts such as Na- and K- salts, alkaline earth metal salts such as , Ca- and Mg-salts, and ammonium or substituted ammonium salts such as trimethylammonium salts. The term "pharmaceutically acceptable salts" is also related to such salts.

The compounds of formula (I) can also be solvated, eg hydrated. Solvation can be carried out in the course of the preparation process or can occur, for example, as a result of hygroscopicity (hydration) of the initial anhydrous compound of formula (I). The term pharmaceutically acceptable salts also includes pharmaceutically acceptable solvates.

The term "pharmaceutically acceptable ester" includes derivatives of compounds of Formula I in which the carboxyl group is converted to an ester. Lower-alkyl, hydroxy-lower-alkyl, lower-alkoxy-lower-alkyl, amino-lower-alkyl, mono- or di-lower-alkyl-amino-lower-alkyl, morpholino-lower-alkyl, pyrroli Dino-lower-alkyl, piperidino-lower-alkyl, piperazino-lower-alkyl, lower-alkyl-piperazino-lower-alkyl and aralkyl esters are examples of suitable esters. Methyl, ethyl, propyl, butyl and benzyl esters are preferred esters. Methyl and ethyl esters are particularly preferred. The term " pharmaceutically acceptable esters " also refers to inorganic or organic acids where the hydroxy group is nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulfonic acid, p-toluenesulfonic acid, and the like. A compound of formula (I) which is nontoxic to living organisms, which is converted into the corresponding esters.

In particular, the present invention relates to compounds of formula (I), enantiomers, pharmaceutically acceptable salts and esters thereof:

Formula I

Where

R ¹ is hydrogen or C _1-7 -alkyl;

R ² and R ³ are independently of each other hydrogen, C _1-7 -alkyl or C _1-7 -alkoxy;

R ⁴ and R ⁵ independently of one another are hydrogen, C _1-7 -alkyl, C _3-7 -cycloalkyl, halogen, C _1-7 -alkoxy-C _1-7 -alkyl, C _2-7 -alkenyl, C _2-7 -alkynyl, fluoro-C _1-7 -alkyl, cyano-C _1-7 -alkyl or cyano;

R ⁶ , R ⁷ , R ⁸ and R ⁹ independently of one another are hydrogen, C _1-7 -alkyl, C _3-7 -cycloalkyl, halogen, C _1-7 -alkoxy-C _1-7 -alkyl, C _{2 -7} -alkenyl, C _2-7 -alkynyl, fluoro-C _1-7 -alkyl, cyano-C _1-7 -alkyl or cyano;

이고,One of R ⁶ , R ⁷ and R ⁸

ego,

Then R ¹⁰ is hydrogen, C _1-7 -alkyl, C _3-7 -cycloalkyl or fluoro-C _1-7 -alkyl;

R ¹¹ is hydrogen, C _1-7 -alkyl or C _1-7 -alkoxy-C _1-7 -alkyl;

One of R ¹² or R ¹³ is hydrogen, C _1-7 -alkyl, C _3-7 -cycloalkyl, C _2-7 -alkoxy-C _1-7 -alkyl, C _2-7 -alkenyl, C _{2- 7} -alkynyl or fluor-C _1-7 -alkyl; The other is an isolation pair;

R ¹⁴ is hydrogen, C _1-7 -alkyl, C _3-7 -cycloalkyl, halogen, C _1-7 -alkoxy-C _1-7 -alkyl, C _2-7 -alkenyl, C _2-7 -alky Nil or fluoro-Ci_ ₇ -alkyl;

R ¹⁵ is aryl or heteroaryl;

n is 1, 2 or 3.

Preferred compounds of formula (I) of the present invention are compounds of formula (I) having the formula (I-A), all enantiomers, pharmaceutically acceptable salts and / or esters thereof:

Where

R ¹ to R ⁵ , R ¹⁰ to R ¹⁵ and n are as defined above;

R ⁶ , R ⁷ and R ⁹ independently of one another are hydrogen, C _1-7 -alkyl, C _3-7 -cycloalkyl, halogen, C _1-7 -alkoxy-C _1-7 -alkyl, C _2-7- Alkenyl, C _2-7 -alkynyl, fluoro-C _1-7 -alkyl, cyano-C _1-7 -alkyl or cyano.

Particular preference is given to compounds of the formula IA according to the invention wherein R ⁶ , R ⁷ and R ⁹ are hydrogen.

Also preferred are compounds of formula I, all enantiomers, pharmaceutically acceptable salts and / or esters thereof, having the formulas I-B:

Where

R ¹ to R ⁵ , R ¹⁰ to R ¹⁵ and n are as defined above;

R ⁶ , R ⁸ and R ⁹ independently of one another are hydrogen, C _1-7 -alkyl, C _3-7 -cycloalkyl, halogen, C _1-7 -alkoxy-C _1-7 -alkyl, C _2-7- Alkenyl, C _2-7 -alkynyl, fluoro-C _1-7 -alkyl, cyano-C _1-7 -alkyl or cyano.

Particular preference is given to compounds of the formula (IB) in which R ⁶ , R ⁸ and R ⁹ are hydrogen.

Further preferred compounds of formula (I) have compounds of formula (I) having the formula (I-C), all enantiomers, pharmaceutically acceptable salts and / or esters thereof:

Where

R ¹ to R ⁵ , R ¹⁰ to R ¹⁵ and n are as defined above;

R ⁷ , R ⁸ and R ⁹ independently of one another are hydrogen, C _1-7 -alkyl, C _3-7 -cycloalkyl, halogen, C _1-7 -alkoxy-C _1-7 -alkyl, C _2-7- Alkenyl, C _2-7 -alkynyl, fluoro-C _1-7 -alkyl, cyano-C _1-7 -alkyl or cyano.

More preferred are compounds of formula IC, wherein R ⁷ , R ⁸ and R ⁹ are hydrogen.

Also preferred are compounds of formula I, wherein R ¹ is hydrogen.

Preference is also given to compounds of the formula (I) in which R ² and R ³ are independently of each other hydrogen or methyl.

Preference is also given to compounds of the formula (I) in which at least one R ² and R ³ is methyl.

Preference is further given to compounds of the formula (I) in which R ⁴ is hydrogen.

Preference is also given to compounds of the formula (I) in which R ⁵ is hydrogen, C _1-7 -alkyl or halogen.

The integer n is 1, 2 or 3. Preferred are compounds of formula I, wherein n is 1. Further preferred are compounds of formula I, wherein n is 2.

Also preferred are compounds of formula I, wherein n is 3.

이고, R¹⁰ 내지 R¹², R¹⁴, R¹⁵ 및 n이 상기에서 정의된 바와 같은 화학식 I의 화합물이다.Further preferred compounds are those in which R ⁶ , R ⁷ and R ⁸ are

And R ¹⁰ to R ¹² , R ¹⁴ , R ¹⁵ and n are compounds of formula I as defined above.

Particularly preferred are those compounds of formula I, wherein R ¹² is C _1-7 -alkyl or fluoro-C _1-7 -alkyl.

이고, R¹⁰ , R¹¹, R¹³ 내지 R¹⁵ 및 n이 상기에서 정의된 바와 같은 화학식 I의 화합물이 또한 바람직하다.R ⁶ , R ⁷ and R ⁸ are

Preference is also given to compounds of the formula I in which R ¹⁰ , R ¹¹ , R ¹³ to R ¹⁵ and n are as defined above.

Preferred are compounds of formula I, wherein R ¹⁵ is aryl. R ¹⁵ is unsubstituted phenyl or ₁ selected from C _1-7 -alkyl, C _1-7 -alkoxy, halogen, fluoro-C _1-7 -alkyl, fluoro-C _1-7 -alkoxy and cyano Preference is given to compounds of the formula (I) which are phenyl substituted with from to three groups, with phenyl substituted with R ¹⁵ being halogen, fluoro-C _1-7 -alkyl or fluoro-C _1-7 -alkoxy.

Examples of preferred compounds of formula (I) are:

{6- [5- (4-Trifluoromethyl-phenyl) -1 H-pyrazol-3-ylmethoxy] -indol-1-yl} -acetic acid,

{6- [5- (4-Chloro-phenyl) -2,4-dimethyl-2H-pyrazol-3-ylmethoxy] -indol-1-yl} -acetic acid,

{6- [2-Methyl-5- (4-trifluoromethyl-phenyl) -2H-pyrazol-3-ylmethoxy] -indol-1-yl} -acetic acid,

{6- [5- (4-Chloro-phenyl) -4-ethyl-2-methyl-2H-pyrazol-3-ylmethoxy] -indol-1-yl} -acetic acid,

{6- [5- (4-Chloro-phenyl) -2-methyl-2H-pyrazol-3-ylmethoxy] -indol-1-yl} -acetic acid,

{6- [5- (4-Chloro-phenyl) -1-methyl-2H-pyrazol-3-ylmethoxy] -indol-1-yl} -acetic acid,

{6- [2-ethyl-5- (4-trifluoromethyl-phenyl) -2H-pyrazol-3-ylmethoxy] -indol-1-yl} -acetic acid,

{6- [4-Bromo-2-methyl-5- (4-trifluoromethyl-phenyl) -2H-pyrazol-3-ylmethoxy] -indol-1-yl} -acetic acid,

(5- {2- [2-Methyl-5- (4-trifluoromethyl-phenyl) -2H-pyrazol-3-yl] -ethoxy} -indol-1-yl) -acetic acid,

{6- [2,4-Dimethyl-5- (4-trifluoromethyl-phenyl) -2H-pyrazol-3-ylmethoxy] -indol-1-yl} -acetic acid,

{6- [2-Methyl-5- (4-trifluoromethoxy-phenyl) -2H-pyrazol-3-ylmethoxy] -indol-1-yl} -acetic acid,

{5- [2-Methyl-5- (4-trifluoromethoxy-phenyl) -2H-pyrazol-3-ylmethoxy] -indol-1-yl} -acetic acid,

{6- [2- (2,2,2-Trifluoro-ethyl) -5- (4-trifluoromethyl-phenyl) -2H-pyrazol-3-ylmethoxy] -indol-1-yl} Acetic acid,

{4-Methyl-6- [2-methyl-5- (4-trifluoromethoxy-phenyl) -2H-pyrazol-3-ylmethoxy] -indol-1-yl} -acetic acid quaternary-butyl ester,

{6- [2- (2,2,2-Trifluoro-ethyl) -5- (4-trifluoromethoxy-phenyl) -2H-pyrazol-3-ylmethoxy] -indol-1-yl} Acetic acid,

{6- [1-Methyl-5- (4-trifluoromethoxy-phenyl) -1H-pyrazol-3-ylmethoxy] -indol-1-yl} -acetic acid,

{6- [5- (3,4-Dichloro-phenyl) -2-methyl-2H-pyrazol-3-ylmethoxy] -indol-1-yl} -acetic acid,

{6- [5- (4-Fluoro-3-trifluoromethyl-phenyl) -2-methyl-2H-pyrazol-3-ylmethoxy] -indol-1-yl} -acetic acid,

(6- {2- [2-Methyl-5- (4-trifluoromethyl-phenyl) -2H-pyrazol-3-yl] -ethoxy} -indol-1-yl) -acetic acid,

(6- {3- [2-Methyl-5- (4-trifluoromethoxy-phenyl) -2H-pyrazol-3-yl] -propoxy} -indol-1-yl) -acetic acid,

(6- {2- [2- (2,2,2-Trifluoro-ethyl) -5- (4-trifluoromethoxy-phenyl) -2H-pyrazol-3-yl] -ethoxy}- Indol-1-yl) -acetic acid,

Racemic-2- {6- [2- (2,2,2-trifluoro-ethyl) -5- (4-trifluoromethoxy-phenyl) -2H-pyrazol-3-ylmethoxy] -indole -1-yl} -propionic acid,

{6- [2-Difluoromethyl-5- (4-trifluoromethoxy-phenyl) -2H-pyrazol-3-ylmethoxy] -indol-1-yl} -acetic acid,

Racemic-2- {6- [2-methyl-5- (4-trifluoromethoxy-phenyl) -2H-pyrazol-3-ylmethoxy] -indol-1-yl} -propionic acid and

(6- {3- [2-Methyl-5- (4-trifluoromethyl-phenyl) -2H-pyrazol-3-yl] -propoxy} -indol-1-yl) -acetic acid.

Particularly preferred compounds of formula (I) of the invention are:

{6- [2-Methyl-5- (4-fluoromethyl-phenyl) -2H-pyrazol-3-ylmethoxy] -indol-1-yl} -acetic acid,

(5- {2- [2-Methyl-5- (4-trifluoromethyl-phenyl) -2H-pyrazol-3-yl] -ethoxy} -indol-1-yl) -acetic acid,

{6- [2,4-Dimethyl-5- (4-trifluoromethyl-phenyl) -2H-pyrazol-3-ylmethoxy] -indol-1-yl} -acetic acid,

{6- [2-Methyl-5- (4-trifluoromethoxy-phenyl) -2H-pyrazol-3-ylmethoxy] -indol-1-yl} -acetic acid,

{6- [2- (2,2,2-Trifluoro-ethyl) -5- (4-trifluoromethyl-phenyl) -2H-pyrazol-3-ylmethoxy] -indol-1-yl} Acetic acid,

(6- {2- [2-Methyl-5- (4-trifluoromethoxy-phenyl) -2H-pyrazol-3-yl] -ethoxy} -indol-1-yl) -acetic acid,

(6- {3- [2-Methyl-5- (4-trifluoromethoxy-phenyl) -2H-pyrazol-3-yl] -propoxy} -indol- 1-yl) -acetic acid,

{6- [2-Difluoromethyl-5- (4-trifluoromethoxy-phenyl) -2H-pyrazol-3-ylmethoxy] -indol-1-yl} -acetic acid and

(6- {3- [2-Methyl-5- (4-trifluoromethyl-phenyl) -2H-pyrazol-3-yl] -propoxy} -indol-1-yl) -acetic acid.

Particularly preferred compounds of formula I of the present invention are

{6- [2-Methyl-5- (4-trifluoromethoxy-phenyl) -2H-pyrazol-3-ylmethoxy] -indol-1-yl} -acetic acid,

{6- [2- (2,2,2-Trifluoro-ethyl) -5- (4-trifluoromethyl-phenyl) -2H-pyrazol-3-ylmethoxy] -indol-1-yl} Acetic acid,

(6- {3- [2-Methyl-5- (4-trifluoromethoxy-phenyl) -2H-pyrazol-3-yl] -propoxy} -indol-1-yl) -acetic acid and

(6- {3- [2-Methyl-5- (4-trifluoromethoxy-phenyl) -2H-pyrazol-3-yl] -propoxy} -indol-1-yl) -acetic acid.

In addition, the pharmaceutically acceptable salts of the compounds of formula (I) and the pharmaceutically acceptable esters of compounds of formula (I) individually constitute a preferred aspect of the invention.

Compounds of formula (I) may have one or more asymmetric carbon atoms and are optically pure enantiomers, mixtures of enantiomers such as racemates, optically pure diastereomers, diastereomeric mixtures, diastereomeric racemates It may be present in the form of a mixture of stereo or diastereomeric racemates. Optically active forms can be obtained, for example, by separation of racemates, asymmetric synthesis or asymmetric chromatography (chromatography with chiral adsorbents or eluents). The present invention includes all of the above forms.

It will be appreciated that the compounds of formula (I) in the present invention may provide derivatives that can be derivatized at the functional group and converted back to the parent compound in vivo. Physiologically acceptable and metabolically labile derivatives that can produce the parent compound of formula (I) in vivo are also within the scope of the present invention.

Further aspects of the invention, (a) a compound of a compound of formula II to give the compound of formula (I) is reacted with a Formula III compound, and selectively hydrolyzing ester group as R ¹ is hydrogen the formula I Obtaining a; Or alternatively (b) reacting a compound of formula IV with a compound of formula V to yield a compound of formula I, optionally hydrolyzing an ester group to obtain a compound of formula I wherein R ¹ is hydrogen The manufacturing method includes:

[Wherein,

R ¹ is C _1-7 -alkyl;

R ² , R ³ , R ⁴ and R ⁵ are as defined above;

R ⁶ , R ⁷ , R ⁸ and R ⁹ are hydrogen, C _1-7 -alkyl, C _3-7 -cycloalkyl, halogen, C _1-7 -alkoxy-C _1-7 -alkyl, C _2-7- Alkenyl, C _2-7 -alkynyl, fluoro-C _1-7 -alkyl, cyano-C _1-7 -alkyl and cyano, provided that R ⁶ , R ⁷ or R ⁸ One is -OH]

[Wherein,

X, Y, R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ and n are as defined above;

R ¹⁶ is —OH, —Cl, —Br, —I or another leaving group]

Formula I

[Wherein,

R ¹ is C _1-7 -alkyl;

R ² to R ⁹ are as defined above]

[Wherein,

R ⁴ to R ⁹ are as defined above]

[Wherein,

R ¹ is C _1-7 -alkyl;

R ² and R ³ are as defined above;

R ¹⁷ is halogen, triflate or another leaving group.

As mentioned above, the compounds of formula (I) of the present invention may be used as medicaments for the treatment and / or prevention of diseases regulated by PPARδ and / or PPARα agonists. Examples of such diseases are diabetes, in particular non-insulin dependent diabetes mellitus, increased lipid and cholesterol levels, in particular low HDL-cholesterol, high LDL-cholesterol, or high triglyceride levels, atherosclerosis disease, metabolic syndrome (syndrome X) , Elevated blood pressure, endothelial dysfunction, coagulopathy, dyslipidemia, polycystic ovary syndrome, inflammatory diseases (e.g. Crohn's disease, inflammatory bowel disease, colitis, pancreatitis, bile secretion of liver / fibrosis, rheumatoid arthritis, osteoarthritis, psoriasis And other skin diseases, and diseases with inflammatory components, such as, for example, Alzheimer's disease or impaired / improveable cognitive function), and proliferative diseases (cancers such as liposarcoma, colon cancer, prostate cancer, pancreatic cancer and breast cancer) Such as cancer). Preference is given to use as a medicament for the treatment of low HDL cholesterol levels, high LDL cholesterol levels, high triglyceride levels and metabolic syndrome (syndrome X).

The present invention therefore also relates to a pharmaceutical composition comprising a compound as defined above and a pharmaceutically acceptable carrier and / or adjuvant.

The invention also relates to compounds as defined above for use as therapeutically active substances, in particular as therapeutically active substances for the treatment and / or prophylaxis of diseases regulated by PPARδ and / or PPARα agonists. Examples of such diseases are diabetes, in particular non-insulin dependent diabetes mellitus, increased lipid and cholesterol levels, in particular low HDL-cholesterol, high LDL-cholesterol, or high triglyceride levels, atherosclerosis disease, metabolic syndrome (syndrome X) , Elevated blood pressure, endothelial dysfunction, coagulation conditions, dyslipidemia, polycystic ovary syndrome, inflammatory diseases such as rheumatoid arthritis, osteoarthritis, psoriasis and other skin diseases, and proliferative diseases.

In another aspect, the invention relates to a method of treating and / or preventing a disease modulated by a PPARδ and / or PPARα agonist comprising administering a compound of Formula I to a human or animal. Preferred examples of such diseases are diabetes, in particular non-insulin dependent diabetes mellitus, increased lipid and cholesterol levels, especially low HDL-cholesterol, high LDL-cholesterol, or high triglyceride levels, atherosclerosis disease, metabolic syndrome (syndrome X) ), Elevated blood pressure, endothelial dysfunction, coagulation state, dyslipidemia, polycystic ovary syndrome, inflammatory diseases such as rheumatoid arthritis, osteoarthritis, psoriasis and other skin diseases, and proliferative diseases.

The present invention also relates to the use of a compound as defined above for the treatment and / or prevention of diseases regulated by PPARδ and / or PPARα agonists. Preferred examples of such diseases are diabetes, in particular non-insulin dependent diabetes mellitus, increased lipid and cholesterol levels, especially low HDL-cholesterol, high LDL-cholesterol, or high triglyceride levels, atherosclerosis disease, metabolic syndrome (syndrome X) ), Elevated blood pressure, endothelial dysfunction, coagulation state, dyslipidemia, polycystic ovary syndrome, inflammatory diseases such as rheumatoid arthritis, osteoarthritis, psoriasis and other skin diseases, and proliferative diseases.

The present invention also relates to the use of a compound as defined above for the manufacture of a medicament for the treatment and / or prophylaxis of diseases regulated by PPARδ and / or PPARα agonists. Preferred examples of such diseases are diabetes, in particular non-insulin dependent diabetes mellitus, increased lipid and cholesterol levels, in particular low HDL-cholesterol, high LDL-cholesterol, or high triglyceride levels, atherosclerosis disease, metabolic syndrome (syndrome X), obesity, elevated blood pressure, endothelial dysfunction, coagulation state, dyslipidemia, polycystic ovary syndrome, inflammatory diseases such as rheumatoid arthritis, osteoarthritis, psoriasis and other skin diseases, and proliferative diseases. The medicament comprises a compound as defined above.

Compounds of formula (I) can be prepared by the methods given below, by the methods given in the examples or by analogous methods. Appropriate reaction conditions for the individual reaction steps are known to those skilled in the art. Starting materials are commercially available or may be prepared by methods analogous to those shown below, by the methods described in the references cited in the text or examples, or by methods known in the art.

와 같고, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵ 및 n이 상기에서 정의된 바와 같은, 반응식 1에서 설명된 방법에 따라 합성할 수 있다. Compound (compound (7) or compound (8) in Scheme 1) of formula I R ⁸ is

And R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ and n can be synthesized according to the method described in Scheme 1, as defined above.

와 같은 화학식 I의 화합물의 합성에 적용할 수 있다.The same reaction sequence with R ⁶ or R ⁷

It can be applied to the synthesis of the compound of formula (I).

6-hydroxyindole (1) and regioisomers 4- and 5-hydroxyindole are commercially available and known or can be synthesized by methods known in the art. The hydroxy functional groups of compound (1) are prepared by methods described in the literature, for example, in the presence of quaternary-butyldimethylsilyl chloride and imidazole, preferably at room temperature, such as N, N-dimethylformamide. Treatment in a solvent can give the corresponding quaternary-butyldimethylsilyl ether 2 (step a) to protect. N-alkylation of the intermediate 2 and the carboxylic acid ester 3 (R ¹⁷ may be for example chlorine, bromine, triflate or another leaving group) to prepare the indole 4 and by standard techniques, for example For example N, N-dimethylform in a solvent such as acetonitrile or acetone at a reflux temperature of the solvent in the presence of K ₂ CO ₃ or CsCO ₃ or at a temperature of -10 ° C. to 50 ° C. in the presence of sodium hydride. It may be carried out in a solvent such as amide (step b). The ester derivative (3) is commercially available or can be synthesized by methods known in the art. Deprotection of the indole 4 (however the protecting group is a silyl ester) by the method described in the literature is, for example, treated with quaternary-butyl ammonium fluoride in a solvent such as tetrahydrofuran at -15 ° C to ambient temperature. By doing so, hydroxyindole 5 is obtained. The pyrazole compound (6) (prepared as outlined in Schemes 3 to 6) is condensed with hydroxyindole (5) according to well known procedures: when R ¹⁶ represents a hydroxy group, for example as a reagent With triphenylphosphine and di-tert-butyl-, diisopropyl- or diethyl-azodicarboxylate or by tributylphosphine and N, N, N ', N by Mitsunobu-reaction By using '-tetramethyl azodicarboxamide; The conversion is preferably carried out at ambient temperature in a solvent such as toluene, dichloromethane or tetrahydrofuran. Alternatively, when R ¹⁶ represents a halide, mesylate or tosylate moiety, the pyrazole compound (6) is substituted with hydroxyindole (5) and N, N-dimethylformamide, acetonitrile, acetone or methyl- The ether compound 7 can be obtained by reacting ethyl ketone with a weak base such as cesium or potassium carbonate in a temperature range of room temperature to 140 ° C., preferably at about 50 ° C. The compound may be hydrolyzed selectively by standard methods, for example by treating the alkali hydroxides such as LiOH or NaOH in polar solvent mixtures such as tetrahydrofuran / ethanol / water, resulting in carboxylic acid (8). Can be. When the pyrazole compound (6) (prepared as described in Schemes 3 to 6) and / or hydroxyindole (5) contains chiral centers, the ester compound (7) and the carboxylic acid (8) are diastereomers Or obtained as a mixture of enantiomers and can be separated by methods well known in the art, for example by (chiral) HPLC or crystallization.

The carboxylic ester (7), alternatively the pyrazole (6) and the hydroxyindole (1) are subjected to regioselective condensation (step f) under the conditions given in step d and the ester (4) in the ether (9) and step b obtained Synthesis is followed by alkylation reagent (3) followed by alkylation (step g).

6-hydroxyindole (1) (Scheme 1) and O-protected 6-hydroxyindole (2) (Scheme 1) as well as their regioisomers 4- and 5-hydroxyindole analogues are known or known in the art It can be synthesized by known methods. Examples of possible syntheses of the above key intermediates (compounds (6) and (7) in Scheme 2) are shown in Scheme 2, where R ⁸ in Formula I is the same as hydroxy or protected hydroxy. Hydroxy, such as hydroxy or having a protecting group, can be subjected to the same reaction procedure to synthesize similar key intermediates wherein R ⁶ or R ⁷ is hydroxy.

The introduction of a protecting group to the nitrogen atom of indole (1) is carried out under standard conditions, for example by dehydrogenation with a base such as n-butyllithium, preferably at -78 ° C, for example quaternary-butyldimethylsilyl chloride Can be carried out by adding in a solvent such as tetrahydrofuran at −78 ° C. to room temperature (step a). Halogenation of the protected indole 2, for example by reaction with N-bromosuccinimide in a solvent such as tetrahydrofuran at −78 ° C. to ambient temperature, affords 3-halo indole 3 (step b). ). Compound (3)-the halogen metal is exchanged with quaternary-butyllithium in a solvent such as tetrahydrofuran, preferably at -78 ° C-alkylation reagent (4) and X (e.g. chlorine, bromine or iodine atoms) ) May preferably be reacted with alkyl iodide in a solvent such as tetrahydrofuran at −78 ° C. to ambient temperature to form indole 5 (with a substituent at position 3) (step c). N-deprotection or at the same time N- and O-deprotection of compound (5) resulting in building block (6) is carried out by the methods described in the literature when the protecting group is silyl ether and / or silylated indole, for example. For example by treatment with tetrabutyl ammonium fluoride in a solvent such as tetrahydrofuran at −15 ° C. to ambient temperature (step d).

Building blocks (7) with chlorine, bromine or iodine substituents at position 3 are optionally subjected to halogenation of indole (1) with protecting groups on hydroxy functional groups, for example with N-chlorosuccinimide and -15 ° C to solvent It can be synthesized in a solvent such as dichloromethane or chloroform at the reflux temperature of (step e). Alternatively, the same halo-indole 7 can be obtained by N-deprotection or N- and O-deprotection of indole 3 as described in step d (step f).

Pyrazole 6 (Scheme 1) is commercially available and can be synthesized by methods known or known in the art. Representative examples of possible synthesis of these key intermediates are shown in Schemes 3-6.

Substituted acetophenones and heteroaryl ketones (1) are commercially known and can be prepared by methods known in the art. Acylation of compound (1) with oxalate derivatives is carried out under standard conditions, for example in a solvent such as ethanol or at a temperature of -78 ° C to 50 ° C in the presence of a base such as diethyl oxalate and sodium ethoxide or lithium hexa Methyldisilazide was carried out in a solvent such as ether at −78 ° C. to ambient temperature to form ethyl pyruvate 2 of glass after subsequent acidification (step a). Alternatively, pyruvate (2) can be converted to (i) ketone (1) with the corresponding silyl enol ether (3) in the presence of a base such as trimethylsilyl chloride and triethylamine, for example, from 0 ° C to 40 ° C. Converting via treatment in a solvent such as acetonitrile at temperature (step b); (ii) subsequent acylation of metal enol ethers, for example zinc chloride and in situ formation and acylation reagents such as enol oxali in a solvent such as toluene or dichloromethane at 0 ° C. to 50 ° C. (step c) It can synthesize | combine by. Pyruvate (2) can be converted via condensation with hydrazine H ₂ NNHR ^12/13 monosubstituted with regioisomeric pyrazoles (4) and (5), which is either commercially known or known in the art. By way of example, in a solvent such as ethanol at ambient temperature to the reflux temperature of the solvent (step d). Alternatively, pyrazoles (4) and (5) are reacted with (i) pyruvate (2) and hydrazine in ethanol at reflux (step e); (ii) the obtained pyrazole (6) was subjected to regioisomers (4) and (5) under standard conditions, for example ethanol at -78 ° C to reflux temperature of the solvent in the presence of a base such as alkyl halonide and potassium hydroxide. It can be synthesized by the conversion step through alkylation in a solvent such as (step f). The regioisomers pyrazoles (4) and (5) can be easily separated by techniques well known in the art, for example via column chromatography on silica. By methods well known in the art, for example, reduction of esters (4) and (5) can be carried out in a solvent such as tetrahydrofuran or diethyl ether at a reflux temperature of lithium aluminum hydride and the solvent at 0 ° C. (Step g).

The alcohol compounds (7) and (8) correspond to the general compound of general formula (Scheme 1) or in the presence of a base such as triethylamine in methanesulfonyl chloride and dichloromethane, preferably at -20 ° C to room temperature. By treating in a temperature range or in a solvent such as carbon tetrahydrochloride or carbon tetrabromide and triphenylphosphine and tetrahydrofuran, preferably at room temperature to the reflux temperature of the solvent Can be switched to 1).

Reduction of the pyrazole ester (1) (compounds (4), (5) and (6) in Scheme 3), preferably in a solvent such as ether or tetrahydrofuran, preferably lithium hydride aluminum at 0 ° C. to room temperature To obtain a primary alcohol (2) (step a), for example in the presence of 2,6-lutidine in dichloromethane, preferably at -20 ° C to the reflux temperature of dichloromethane By treatment with methanesulfonyl chloride, in a solvent such as dichloromethane or chloroform, preferably by treatment with thionyl chloride at a temperature of -20 ° C to + 50 ° C or in a solvent such as tetrahydrofuran Treatment with tetrabromomethane and triphenylphosphine at the reflux temperature of tetrahydrofuran can be used as such or converted to the corresponding halide (3) ( Type b). Through the reaction with an alkyl organometallic reagent, the ester (1) is further added R ¹⁰ and R in a solvent such as tetrahydrofuran or ether, preferably using an alkyl Grignard compound, preferably at -15 ° C to the reflux temperature of the solvent. ¹¹ can be converted to this quaternary alcohol (4) (step c). Sensitizing an alcohol (4) wherein R ¹⁰ and R ¹¹ are not equal to the following procedure (i) with acid; (ii) optionally treating with R ¹⁰ Li in ether or tetrahydrofuran in the presence of a Cu (I) salt to obtain an alkyl ketone-COR ¹⁰ ; (iii) by subsequent reaction with R ¹¹ Li or lithium aluminum hydride in ether or tetrahydrofuran. Preferred as manganese dioxide in a solvent such as dichloromethane by methods known in the art, for example by treatment with pyridinium chlorochromate in dichloromethane, preferably at room temperature to the reflux temperature of dichloromethane. Preferably, the primary alcohol (2) can be oxidized to aldehyde (5) by treatment at room temperature (step d). The aldehyde (5) can be converted to the corresponding secondary alcohol (6) under the conditions given for converting the alkyl organometallic compound and the ester (1) to a quaternary alcohol (4) (step e). Ketones (7) by treatment by methods known to those skilled in the art, for example by treatment with Cr (VI) reagents (Jones et al. J. Chem. Soc. 1953, 2548.), such as Jones reagent . Can be obtained from the secondary alcohol (6) (step f). Reduction of ketone (7) with the corresponding secondary alcohol (6) of Scheme 4 can also be carried out in an optically selective manner, for example by Corey et al. [EJ Corey, RK Bakshi, S. Shibata, J. Am. Chem. Soc ., 109 , 5551-5553, 1987 and borane-dimethylsulfide complexes and (S)-or (R) -2 with chiral catalysts in tetrahydrofuran, preferably at temperatures from -78 ° C to ambient temperature. Treatment with -methyl-CBS-oxazaborolidin or according to Brown et al. (PV Ramachandran, B. Gong, AV Teodorovic, HC Brown, Tetrahedron: Asymmetry , 5 , 1061-1074, 1994) (R)-or (S) -alcohol (6) can be obtained by treatment with)-or (-)-B-chlorodiisofinocamphorylborate (DIP-Cl) (step g). Preferably, ketone (7) is further converted to the corresponding quaternary alcohol (4) by reaction with an alkyl organometallic compound under the conditions given for converting the ester (1) to a quaternary alcohol (4) in step c. Can be. If the alcohol compounds (2), (4) or (6) contain one or more chiral centers and are not optically pure, they are prepared by methods known in the art, for example by chromatography on a chiral HPLC column or By derivatization with optically pure acids and derivatives, it can be selectively separated into optically pure counterparts which form esters, which can then be separated by conventional HPLC chromatography and inverted back to the original alcohol. .

Alcohol compounds (2), (4) and (6) and halide compounds (3) correspond to the compounds of general formula 6 (Scheme 1), preferably in the presence of a base, for example triethylamine. Treatment of methanesulfonyl chloride in dichloromethane at a temperature of -20 ° C to room temperature or carbon tetrachloride or carbon tetrabromide and triphenylphosphine in a solvent such as tetrahydrofuran, preferably at room temperature to the reflux temperature of the solvent. It can be converted to the compound of formula 6 (Scheme 1) by reacting in the temperature range.

Converting pyrazole alkanol (1) of chain length n of carbon atoms, by methods known in the art, for example to primary alcohol functionalities into suitable leaving groups such as halides (step b), Chain length of the carbon atom by the step of sensitization (step c), followed by the reduction of the acid (compound 4) formed subsequently with primary alcohol (5), for example using diborane in tetrahydrofuran (step d) Can be converted to an analog of +1. To introduce hydrogen and other substituents R ¹⁰ and / or R ¹¹ , the cyano intermediate (3) of the extension process is subjected to alkyl Grignard reagent R ¹⁰ in a solvent such as ether or tetrahydrofuran at 0 ° C. to the reflux temperature of the solvent. Reaction with MgX forms the corresponding R ¹⁰ CO-alkyl ketone and the treatment of alkyllithium reagent R ¹¹ Li or lithium aluminum hydride in a solvent such as ether or tetrahydrane yields alcohol (5). R ¹⁰ CO-alkyl ketones may also be reduced by treatment with sodium borohydride in alcohol, preferably at a temperature of −15 ° C. to 40 ° C. The reaction can also be carried out in an optically selective manner, for example, in Korei et al . Chem. Soc ., 109 , 5551-5553, 1987 and borane-dimethylsulfide complexes and (S)-or (R) -2 with chiral catalysts in tetrahydrofuran, preferably at temperatures from -78 ° C to ambient temperature. (+)-Or by treatment with methyl-CBS-oxazaborolidine or according to Brown et al. (PV Ramachandran, B. Gong, AV Teodorovic, HC Brown, Tetrahedron: Asymmetry , 5 , 1061-1074, 1994) (R)-or (S) -alcohol (5) can be obtained by treatment with (-)-B-chlorodiisofinocampayl borane (DIP-Cl). Alternatively, the ester is formed by an alcohol compound (5) containing at least one chiral center by methods known in the art, for example by chromatography on a chiral HPLC column or by derivatization with optically pure acids and derivatives. Can be selectively separated into optically pure counterparts, which can then be separated by conventional HPLC chromatography and converted back to the original alcohol. The alcohol compound (5) corresponds to the compound of the general compound of formula 6 (Scheme 1), or in the presence of a base such as, for example, triethylamine, in dichloromethane, preferably at a temperature of -20 ° C to room temperature. By treatment with insulfonyl chloride or by reacting carbon tetrachloride or carbon tetrabromide with triphenylphosphine in a solvent such as tetrahydrofuran, preferably at room temperature to the reflux temperature of the solvent (Scheme 1 Can be converted to).

Alcohol (1) (compound (6) wherein R ¹⁴ = H and R ¹⁶ = OH in Scheme 1, R14 = H compounds (7) and (8) in Scheme 3, compound (2) wherein R ¹⁴ = H in Scheme 4) , (4) and (6), compounds (1) and (5), wherein R ¹⁴ = H in Scheme 5, can be prepared by methods known in the literature, for example, with quaternary-butyldimethylsilyl chloride. Protection can be achieved by obtaining the corresponding quaternary-tetradimethylsilyl ether (2) by treatment in a solvent such as N, N-dimethylformamide at room temperature, preferably at room temperature (step a). Halogenation of the protected pyrazole 2 yields 4-halo pyrazole 3 via reaction in, for example, bromine and dichloromethane, preferably at temperatures between 0 ° C. and ambient (step b). Compound (3) is replaced with a halogen metal, preferably quaternary-butyllithium, in a solvent such as tetrahydrofuran at -78 ° C. X, for example alkylating reagents having chlorine, bromine or iodine atoms (4) ), Preferably with alkyl iodide in a solvent such as tetrahydrofuran at a temperature of -78 ° C. to caution, to form pyrazole 5 having a substituent at position 4 (step c). Alternatively, a reaction catalyzed transition metal is used to convert 4-halo pyrazole (3) to compound (5) to form Pd such as stanine (X is trialkyl stanyl) [Pd ₂ (dba) ₃ ] (0) by treatment in a solvent such as dioxane at 0 ° C. to the reflux temperature of the solvent in the presence of a catalyst and triphenyl arsine. The residue R ¹⁴ is further added to (i) phosphorus oxychloride and N, N-dimethylformamide by methods well known in the art, for example, of pyrazole (2) at preferably 0 ° C. to 100 ° C. By formylation; (ii) Intermediate formyl pyrazole with 4-substituted pyrazole (5), for example a solvent such as diethyl ether at reflux temperature of -78 ° C to the solvent in the presence of sodium cyanoborohydride and zinc iodide Can be introduced by subsequent conversion via reduction (step d). O-deprotection of the compound (5) resulting in the building block (6) by methods known in the literature, for example, when the protecting group is silyl ether, at temperatures between −15 ° C. and ambient with tetrabutyl ammonium fluoride By treatment in a solvent such as tetrahydrofuran (step e). The alcohol compound (6) corresponds generally to the compound of formula (6) and is a compound of formula (6), for example methanesulfonyl chloride and dichloromethene in the presence of a base such as triethylamine, preferably from -20 ° C to room temperature By treatment at or by reaction in, for example, carbon tetrachloride or carbon tetrabromide with tetrahydrofuran, preferably at room temperature to the reflux temperature of the solvent (Scheme 1).

The following tests were performed to determine the activity of the compounds of formula (I).

For background information on the assays performed, see Nichols JS et al., “Development of a scintillation proximity assay for peroxisome proliferator-activated receptor gamma ligand binding domain”, Anal. Biochem ., 257 : 112-119, 1998.

Full-length cDNA clones for human PPARδ and PPARα and mouse PPARγ were obtained by RT-PCR from each of human fat and mouse liver cRNA cloned into plasmid vectors and confirmed by DNA sequencing. Glutathione-s-transferase (GST) and Gal4 DNA binding regions fused to ligand binding regions (LBD) of PPARδ (amino acids 139-442), PPARγ (amino acids 174-476) and PAPRα (amino acids 167-469) Bacterial and mammalian expression vectors were constructed to produce proteins. To accomplish this, cloned sequence portions encoding LBD were amplified by PCR from full-length clones and then subcloned into plasmid vectors. Final clones were confirmed by DNA sequence analysis.

Induction, expression and purification of GST-LBD fusion proteins were performed by standard methods . Coli were carried out in (E. coli) strain BL21 (pLysS) cells (see the literature [Current Protocols in Molecular Biology, Wiley Press, edited by Ausubel et al.]).

Radioligand binding assay

PPARδ receptor binding was analyzed in HNM10 (50 mM Hepes, pH 7.4, 10 mM NaCl, 5 mM MgCl ₂ , 0.15 mg / ml fatty acid-free BSA and 15 mM DTT). For each 96 well reaction, 500 ng equivalents of GST-PPARδ-LBD fusion protein and radioligand, e.g., 20000 dpm of {2-methyl-4- [4-methyl-2- (4-trifluoro) Methyl-phenyl) -thiazol-5-yl-ditrithiomethylsulfanyl] -phenoxy} -acetic acid is bound to 10 μg SPA beads (Pharmacia Amersham) by shaking to a final volume of 50 μl. I was. The resulting slurry was incubated at room temperature for 1 hour and centrifuged at 1300 g for 2 minutes. The supernatant containing unbound protein was removed and the semi-dried pellets containing the receptor-coated beads were resuspended in 50 μl of HNM. Radioligand was added and the reaction was incubated for 1 hour at room temperature and the scintillation approximation coefficients performed in the presence of the test compound were measured. All binding assays were performed in 96 well plates, and the amount of bound ligand was measured on Packard TopCount using OptiPaltes (Packard). Dose response curves were performed in triplicates within the concentration range of 10 ⁻¹⁰ to 10 ⁻⁴ M.

PPARα receptor binding was analyzed in TKE50 (50 mM Tris-HCl, pH 8, 50 mM KCl, 2 mM EDTA, 0.1 mg / ml fatty acid-free BSA and 10 mM DTT). For each 96 well reaction, 140 ng equivalent of GST-PPARδ-LBD fusion protein was bound to 10 μg SPA beads (Pharmacia Amersham) by shaking to a final volume of 50 μl. The resulting slurry was incubated at room temperature for 1 hour and centrifuged at 1300 g for 2 minutes. Supernatants containing unbound protein were removed and semi-dried pellets containing receptor-coated beads were dissolved in 50 μl of TKE. For radioligand binding, for example, 10000 dpm of 2 (S)-(2-benzoyl-phenylamino) -3- {4- [1,1-ditrithio-2- (5-methyl) in 50 μl -2-phenyl-oxazol-4-yl) -ethoxy] -phenyl} -propionic acid or 2,3-ditrithio-2 (S) -methoxy-3- {4- [2- (5-methyl 2-phenyl-oxazol-4-yl) -ethoxy] -benzo [b] thiophen-7-yl} -propionic acid was added, the reaction was incubated at room temperature for 1 hour and a scintillation approximation count was performed. All binding assays were performed in 96 well plates and the amount of bound ligand was measured on Packard topcount using Optiplate (Packard). Nonspecific binding was measured in the presence of ^10-4 M unlabelled compound. Dose response curves were performed in triplicates within the concentration range of 10 ⁻¹⁰ to 10 ⁻⁴ M.

PPARγ receptor binding was analyzed in TKE50 (50 mM Tris-HCl, pH 8, 50 mM KCl, 2 mM EDTA, 0.1 mg / ml fatty acid-free BSA and 10 mM DTT). For each 96 well reaction, 140 ng equivalent of GST-PPARγ-LBD fusion protein was bound to 10 μg SPA beads (Pharmacia Amersham) by shaking to a final volume of 50 μl. The resulting slurry was incubated at room temperature for 1 hour and centrifuged at 1300 g for 2 minutes. Supernatants containing unbound protein were removed and semi-dried pellets containing receptor-coated beads were dissolved in 50 μl of TKE. For radioligand binding, for example, 10000 dpm of 2 (S)-(2-benzoyl-phenylamino) -3- {4- [1,1-ditrithio-2- (5-methyl) in 50 μl 2-phenyl-oxazol-4-yl) -ethoxy] -phenyl} -propionic acid was added and the reaction was incubated for 1 hour at room temperature and scintillation approximation coefficients were performed. All binding assays were performed in 96 well plates and the amount of bound ligand was measured on Packard topcount using Optiplate (Packard). Nonspecific binding was measured in the presence of ^10-4 M unlabelled compound. Dose response curves were performed in triplicates within the concentration range of 10 ⁻¹⁰ to 10 ⁻⁴ M.

Luciferase Transcription Receptor Gene Analysis

Baby hamster kidney cells (BHK21 ATCC CCL10) were grown in DMEM medium containing 10% FBS at 37 ° C. under a 95% O ₂ : 5% CO ₂ atmosphere. Cells were seeded into 6-well plates at a density of 10 ⁵ cells / well and then batch-transfected with pFA-PPARδ-LBD, pFA-PPARγ-LBD or pFA-PPARα-LBD expression plasmids and receptor plasmids. Transfection was performed using Fugene 6 reagent (Roche Molecular Biochemicals) according to the presented protocol. Six hours after transfection, cells were harvested by trypsinization and seeded in 96 well plates at a density of 10 ⁴ cells / well. After 24 hours the cells were bound and the medium was removed and replaced with 100 μl of phenol red-free medium containing the test substance or control ligand (final DMSO concentration: 0.1%). After 24 hours of incubation of the cells with the material, 50 μl of the supernatant was discarded and then 50 μl of Luciferase Constant-Light Reagent (Roche Mole) to lyse the cells and initiate the luciferase reaction. Kula Biochemicals) was added. Luminescence for luciferase was measured on a Packard top count. Transcriptional activation in the presence of test substance was indicated as embryo-activation for cells cultured in the absence of substance. EC50 values were calculated using the XL compliance program (ID Business Solutions Ltd., UK).

The free acid of the compounds of the invention (R ¹ is hydrogen) has an IC ₅₀ value of 0.1 nM to 10 μM, preferably 1 nM to 500 nM for PPARδ, and 1 nM to 10 μM, preferably 10 for PPARα. IC ₅₀ values between nM and 5 μM are shown. R Compound ¹ is not hydrogen are converted to the compounds R ¹ is hydrogen. The table below shows the values measured for some selected compounds of the invention.

The compounds of formula (I) and their pharmaceutically acceptable salts and esters can be used as medicaments, for example in the form of pharmaceutical preparations for enteral, parenteral or topical administration. These can be, for example, orally, e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions, or rectally, e.g. in the form of suppositories, or parenterals. Alternatively, it may be administered, for example, in the form of an injection or infusion, or topically, for example in the form of an ointment, cream or oil.

The preparation of pharmaceutical preparations is carried out in the form of the galenose dosage form with the desired compound of formula (I) and its pharmaceutically acceptable salts in combination with a suitable nontoxic inert therapeutically compatible solid or liquid carrier material, and, where appropriate, conventional pharmaceutical auxiliaries. This can be done in a manner familiar to those skilled in the art.

Suitable carrier materials are organic carrier materials as well as inorganic carrier materials. Thus, for example, lactose, corn starch or derivatives thereof, talc, stearic acid or its salts can be used as carrier materials for tablets, coated tablets, dragees and hard gelatin capsules. Suitable carrier materials for soft gelatin capsules are, for example, vegetable oils, waxes, fats and semi-solid and liquid polyols (but depending on the nature of the active ingredient, no carrier is required for soft gelatin capsules). Suitable carrier materials for the production of solutions and syrups are, for example, water, polyols, sucrose, invert sugar and the like. Suitable carrier materials for injection are, for example, water, alcohols, polyols, glycerol and vegetable oils. Suitable carrier materials for suppositories are, for example, natural or hardened oils, waxes, fats and semi-liquid or liquid polyols. Suitable carrier materials for topical preparations are glycerides, semi-synthetic and synthetic glycerides, hydrogenated oils, liquid waxes, liquid paraffins, liquid fatty alcohols, sterols, polyethylene glycols and cellulose derivatives.

Conventional stabilizers, preservatives, wetting and emulsifying agents, consistency-improving agents, fragrance-enhancing agents, osmotic pressure adjusting salts, buffering materials, solubilizers, colorants and masking agents and antioxidants are contemplated as pharmaceutical aids.

The dosage of the compound of formula (I) can vary within wide limits depending on the disease to be controlled, the age and individual condition of the patient and the mode of administration, and will of course be tailored to the individual needs in each particular case. For adult patients a daily dosage of about 1 to about 1000 mg, especially about 1 to about 100 mg, comes into consideration. Depending on the dosage it is convenient to administer the daily dosage in several dosage units.

The pharmaceutical preparations conveniently contain about 0.1 to 500 mg, preferably 0.5 to 100 mg of the compound of formula (I).

The following examples are intended to illustrate the invention in more detail. However, these examples do not limit the scope in any way.

Abbreviation

AcOEt = ethyl acetate, DMF = N, N-dimethylformamide, DMPU = 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H) -pyrimidinone, LDA = lithium diiso Propylamide, MeOH = methanol, quant. = Quantitative value, THF = tetrahydrofuran.

Example 1

a) [5- (4-Trifluoromethyl-phenyl) -1 H-pyrazol-3-yl] -methanol

5- (4-Trifluoromethyl-phenyl) -1H-pyrazole-3-carboxylic acid ethyl ester (160 mg, 0.56 mmol; International Patent Application Publication No. WO 2004000785 A2) in tetrahydrofuran (2.5 ml) The solution was added in 5 minutes to a suspension of lithium aluminum hydride (43 mg, 1.13 mmol) in tetrahydrofuran (2.5 ml) at ambient temperature under an argon atmosphere. The mixture was heated to reflux for 12 hours, cooled to 0 ° C. and carefully treated with water (2 ml) and 10% aqueous NaOH solution (0.5 ml). The reaction mixture was filtered over celite, ice water / ethyl acetate 1/1 was added and the layers separated. The aqueous layer was extracted one or more times with ethyl acetate and the combined organic layers were washed with ice water / brine 1/1 and dried over sodium sulfate. The solvent was removed under reduced pressure to yield 81 mg (0.33 mmol, 59%) of the title compound as a white solid.

MS: 243.1 (M + H) ⁺ .

b) 3-chloromethyl-5- (4-trifluoromethyl-phenyl) -1 H-pyrazole

Thionyl chloride (0.34 ml) in a solution of [5- (4-trifluoromethyl-phenyl) -1 H-pyrazol-3-yl] -methanol (40 mg, 0.17 mmol) in chloroform (4 ml) at 0 ° C. under argon atmosphere. , 4.7 mmol) was added. The solution was stirred at 40 ° C. for 2 hours and at 60 ° C. for 10 minutes. The mixture was poured into 1/1 of ice water / NaHCO ₃ aqueous solution, extracted twice with dichloromethane and the combined extracts were dried over sodium sulfate. Evaporation of the solvent under reduced pressure gave 43 mg (0.165 mmol, 97%) of the title compound as white crystals.

c) [6- (tert-butyl-dimethyl-silanyloxy) -indol-1-yl] -acetic acid tert-butyl ester

Bromo- in an ice-cold solution of 6- (tert-butyl-dimethyl-silanyloxy) -1H-indole (13 g, 52.5 mmol) and cesium carbonate (18.8 g, 57.8 mmol) in DMF (130 ml) under argon atmosphere. Acetic acid tert-butyl ester (8.5 ml, 57.8 mmol) was added. The mixture was naturally warmed to rt, stirred for 14 h, poured into 2N HCl / ice water 1/1 and extracted twice with ethyl acetate. The combined organic layers were washed with water and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by column chromatography (silica gel, heptane / AcOEt) to give 14.3 g (39.6 mmol, 75%) of the title compound as a yellow oil.

MS: 362.4 (M + H) ⁺ .

d) (6-hydroxy-indol-1-yl) -acetic acid tert-butyl ester

THF (11.6 ml) in an ice-cold solution of [6- (tert-butyl-dimethyl-silanyloxy) -indol-1-yl] -tertiary-butyl ester (4.2 g, 11.6 mmol) in THF (24 ml) 11.6 mmol) tetrabutylammonium fluoride 1M solution was added within 15 minutes. The reaction mixture was stirred at ambient temperature for 1 hour, poured into 1N HCl / ice water 1/1 and extracted twice with ethyl acetate. The combined organic layers were washed with brine / ice water 1/1 and dried over sodium sulfate. The solvent was removed under reduced pressure to give 3.4 g (quant.) Of the title compound as a brown oil which was used in the next step without further purification.

MS: 265.5 (M + NH ₄ ) ⁺ , 248.4 (M + H) ⁺ .

e) tert-butyl ester

(6-Hydroxy-indol-1-yl) -acetic acid tert-butyl ester (37 mg, 0.15 mmol), 3-chloromethyl-5- (4-trifluoromethyl-phenyl) -1 H-pyrazole (43 mg , 0.16 mmol), cesium carbonate (54 mg, 0.16 mmol) and a mixture of traces of potassium iodide were suspended in N, N-dimethylformamide (4 ml). The suspension was stirred at ambient temperature for 14 hours and at 80 ° C. for 4 hours. The solvent was evaporated under reduced pressure and the residue was dissolved in 1N HCl / ice water 1/1 and ethyl acetate. The layers were separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed twice with brine and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by column chromatography (silica gel, heptane / AcOEt) to give 5 mg (10 μmol, 7%) of the title compound as an orange oil.

f) {6- [5- (4-Trifluoromethyl-phenyl) -1 H-pyrazol-3-ylmethoxy] -indol-1-yl} -acetic acid

{6- [5- (4-Trifluoromethyl-phenyl) -1H-pyrazol-3-ylmethoxy] -indol-1-yl} -acetic acid tertiary- in THF / methanol 2/1 (750 μl) To a solution of butyl ester (5 mg, 10 μmol) was added 1N LiOH aqueous solution (600 μl). The reaction mixture was stirred at ambient temperature for 14 hours and concentrated under reduced pressure. The residue was dissolved in 1N HCl / ice water 1/1 and ethyl acetate, the layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with ice water / brine 1/1, dried over sodium sulfate and the solvent was evaporated in vacuo to afford the title compound (3 mg, 7 μmol, 68%) as brown crystals.

MS: 412.2 (MH) ^- .

Example 2

a) 5- (4-chloro-phenyl) -2,4-dimethyl-2H-pyrazole-3-carboxylic acid ethyl ester and 5- (4-chloro-phenyl) -1,4-dimethyl-1H-pyra Sol-3-carboxylic acid ethyl ester

5- (4-Chloro-phenyl) -4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (58 mg, 0.22 mmol; International Patent Application Publication No. WO 9721692 A1) was dissolved in anhydrous ethanol (1.6 ml). To a solution of KOH (15 mg, 0.27 mmol) in water. The solution was stirred at ambient temperature for 15 minutes. Methane iodide (30 μl, 0.44 mmol) was added and the reaction mixture was heated to reflux for 2 hours. The solvent was removed under reduced pressure and the residue was dissolved in brine / waterproof 1/1 and ethyl acetate. The layers were separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by column chromatography (silica gel, heptane / AcOEt) to give 29 mg of 5- (4-chloro-phenyl) -2,4-dimethyl-2H-pyrazole-3-carboxylic acid ethyl ester (0.1 mmol, 47%) was obtained as colorless crystals and 22 mg (0.08 mmol, 36%) of 5- (4-chloro-phenyl) -1,4-dimethyl-1H-pyrazole-3-carboxylic acid ethyl ester was colorless. Obtained by crystals.

5- (4-Chloro-phenyl) -2,4-dimethyl-2H-pyrazole-3-carboxylic acid ethyl ester: MS: 279.0 (M + H) ⁺ .

5- (4-Chloro-phenyl) -1,4-dimethyl-1H-pyrazole-3-carboxylic acid ethyl ester: MS: 279.0 (M + H) ⁺ .

b) [5- (4-Chloro-phenyl) -2,4-dimethyl-2H-pyrazol-3-yl] -methanol

Similar to the process described in Example 1 a), 5- (4-chloro-phenyl) -2,4-dimethyl-2H-pyrazole-3-carboxylic acid ethyl ester was reduced with lithium ammonium hydride [5 -(4-Chloro-phenyl) -2,4-dimethyl-2H-pyrazol-3-yl] -methanol was obtained as colorless crystals.

MS: 236.9 (M + H) ⁺ .

c) 5-chloromethyl-3- (4-chloro-phenyl) -1,4-dimethyl-1H-pyrazole

Similar to the process described in Example 1 b), [5- (4-Chloro-phenyl) -2,4-dimethyl-2H-pyrazol-3-yl] -methanol was reacted with thionyl chloride at 0 ° C. Reaction for 20 minutes gave 5-chloromethyl-3- (4-chloro-phenyl) -1,4-dimethyl-1H-pyrazole as a yellow oil.

MS: 255.1 (M + H) ⁺ .

d) [6- (tert-butyl-dimethyl-silanyloxy) -indol-1-yl] -acetic acid ethyl ester

Bromo- in an ice-cold solution of 6- (tert-butyl-dimethyl-silanyloxy) -1H-indole (1 g, 4.04 mmol) and cesium carbonate (1.45 g, 4.45 mmol) in DMF (10 ml) under argon atmosphere. Ethyl acetate (490 μl, 4.45 mmol) was added. The mixture was naturally warmed to room temperature, stirred for 14 h, poured into 1N HCl / ice water 1/1 and extracted twice with ethyl acetate. The combined organic layers were washed with water and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by column chromatography (silica gel, heptane / AcOEt) to give 1.2 g (3.6 mmol, 89%) of the title compound as a yellow oil.

MS: 334.3 (M + H) ⁺ .

e) (6-hydroxy-indol-1-yl) -acetic acid ethyl ester

Tetrabutylammonium Fluoride in THF in an ice cold solution of [6- (tert-butyl-dimethyl-silanyloxy) -indol-1-yl] -ethyl acetate (1.15 g, 3.45 mmol) in THF (11.5 ml) Ride 1M solution (3.45 ml, 3.45 mmol) was added within 15 minutes. The reaction mixture was stirred at ambient temperature for 1 hour, poured into 1N HCl / ice water 1/1 and extracted twice with ethyl acetate. The combined organic layers were washed with brine / ice water 1/1 and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by column chromatography (silica gel, heptane / AcOEt) to give 590 mg (2.7 mmol, 78%) of the title compound as colorless crystals.

MS: 291.0 (M) ⁺ , 146.0.

f) {6- [5- (4-Chloro-phenyl) -2,4-dimethyl-2H-pyrazol-3-ylmethoxy] -indol-1-yl} -acetic acid ethyl ester

Similar to the process described in Example 1 e), (6-hydroxy-indol-1-yl) -acetic acid ethyl ester was added to 5-chloromethyl-3- (4- in the presence of cesium carbonate and potassium iodide in acetone. By reaction with chloro-phenyl) -1,4-dimethyl-1H-pyrazole {6- [5- (4-chloro-phenyl) -2,4-dimethyl-2H-pyrazol-3-ylmethoxy] -Indol-1-yl} -acetic acid ethyl ester was obtained as a yellow crystal.

MS: 438.1 (M + H) ⁺ .

g) {6- [5- (4-Chloro-phenyl) -2,4-dimethyl-2H-pyrazol-3-ylmethoxy] -indol-1-yl} -acetic acid

Similar to the process described in Example 1 f), {6- [5- (4-chloro-phenyl) -2,4-dimethyl-2H-pyrazol-3-ylmethoxy] -indol-1-yl } -Acetic acid ethyl ester was treated with LiOH to give {6- [5- (4-chloro-phenyl) -2,4-dimethyl-2H-pyrazol-3-ylmethoxy] -indol-1-yl} -acetic acid Was obtained as colorless crystals.

MS: 410.3 (M + H) ⁺ .

Example 3

a) 2-methyl-5- (4-trifluoromethyl-phenyl) -2H-pyrazole-3-carboxylic acid ethyl ester and 1-methyl-5- (4-trifluoromethyl-phenyl) -1H-pyra Sol-3-carboxylic acid ethyl ester

Similar to the process described in Example 2 a), 5- (4-trifluoromethyl-phenyl) -1H-pyrazole-3-carboxylic acid ethyl ester (Wo 20040007885 A2) Is reacted with methane iodide in the presence of potassium hydroxide to yield 2-methyl-5- (4-trifluoromethyl-phenyl) -2H-pyrazole-3-carboxylic acid ethyl ester and 1-methyl-5- (4-trifluoro Both rommethyl-phenyl) -1H-pyrazole-3-carboxylic acid ethyl ester was obtained as colorless crystals.

2-Methyl-5- (4-trifluoromethyl-phenyl) -2H-pyrazole-3-carboxylic acid ethyl ester: MS: 299.2 (M + H) ⁺ .

1-Methyl-5- (4-trifluoromethyl-phenyl) -2H-pyrazole-3-carboxylic acid ethyl ester: MS: 299.2 (M + H) ⁺ .

b) [2-methyl-5- (4-trifluoromethyl-phenyl) -2H-pyrazol-3-yl] -methanol

Similar to the process described in Example 1 a), 2-methyl-5- (4-trifluoromethyl-phenyl) -2H-pyrazole-3-carboxylic acid ethyl ester is reduced to lithium ammonium hydride [2 -Methyl-5- (4-trifluoromethyl-phenyl) -2H-pyrazol-3-yl] -methanol was obtained as white crystals.

MS: 243.1 (M + H) ⁺ .

c) {6- (2-Methyl-5- (4-trifluoromethyl-phenyl) -2H-pyrazol-3-ylmethoxy] -indol-1-yl} -acetic acid ethyl ester

(6-hydroxy-indol-1-yl) -acetic acid ethyl ester (35 mg, 160 μmol; Example 2 e)) in tetrahydrofuran (3.5 ml), [2-methyl-5- (4-trifluoromethyl -Phenyl) -2H-pyrazol-3-yl] -methanol (41 mg, 160 μmol) and tributylphosphine (50 μl, 19 μmol) in an ice-cold solution of N, N, N ′, N′-tetramethyl azodica Radiamide (33 mg, 19 μmol) was added. The cold bath was removed and stirring continued for 14 h. The mixture was filtered over celite and the solvent was removed under reduced pressure to give a brown oil which was purified by column chromatography (silica gel, heptane / AcOEt) to give 22 mg (50 μmol, 30%) of the title compound as a colorless oil.

MS: 458.3 (M + H) ⁺ .

d) {6- (2-Methyl-5- (4-trifluoromethyl-phenyl) -2H-pyrazol-3-ylmethoxy] -indol-1-yl} -acetic acid

Similar to the process described in Example 1 f), {6- (2-methyl-5- (4-trifluoromethyl-phenyl) -2H-pyrazol-3-ylmethoxy] -indol-1-yl } -Acetic acid ethyl ester was treated with LiOH to give {6- (2-methyl-5- (4-trifluoromethyl-phenyl) -2H-pyrazol-3-ylmethoxy] -indol-1-yl} -acetic acid Was obtained as brown crystals.

MS: 428.5 (MH) ^- .

Example 4

a) 3- (4-chloro-benzoyl) -2-oxo-pentanoic acid ethyl ester

Under anhydrous conditions, a solution of tert-butoxy potassium (292 mg, 2.6 mmol) in diethyl ether (100 ml) was cooled to -78 ° C and stirred for 10 minutes under argon atmosphere. 2M LDA in commercial heptane / THF / ethyl benzene (13 ml, 26 mmol) was added by syringe and the mixture was stirred for 15 minutes. 4-chlorobutyrophenone (5 g, 26 mmol) in diethyl ether (35 ml) was added dropwise with stirring for 30 minutes. After an additional 30 minutes, some diethyl oxalate (3.53 ml, 26 mmol) was added. The cold bath was removed and the reaction stirred for 2.5 hours after reaching ambient temperature. After standing for 3 days, the precipitated brown solid was filtered off. The solid was partitioned between 1M HCl and ethyl acetate. The aqueous layer was extracted twice with ethyl acetate and the combined extracts were washed with brine and dried over sodium sulfate. Evaporation of the solid gave 740 mg (4.6 mmol, 18%) of the title compound as an orange oil.

b) 5- (4-chloro-phenyl) -4-ethyl-1 H-pyrazole-3-carboxylic acid ethyl ester

Hydrazine monohydrate (0.13 ml, 3 mmol) was added to a solution of 3- (4-chloro-benzoyl) -2-oxo-pentanoic acid ethyl ester (740 mg, 3 mmol) in ethanol (4 ml) at ambient temperature under argon. The solution was stirred for 8 h at reflux, the solvent was removed under reduced pressure and the residue partitioned between 1M HCl / ice water and ethyl acetate. The aqueous layer was extracted twice with ethyl acetate and the combined extracts were washed with brine (three times) and dried over sodium sulfate. The orange oil obtained by removing the solvent under reduced pressure was purified by column chromatography (silica gel, heptane / AcOEt) to give 355 mg (1.27 mmol, 49%) of the title compound as yellow crystals.

MS: 278.1 (M + H) ⁺ .

c) 5- (4-chloro-phenyl) -4-ethyl-2-methyl-2H-pyrazole-3-carboxylic acid ethyl ester and 5- (4-chloro-phenyl) -4-ethyl-1-methyl-1H -Pyrazole-3-carboxylic acid ethyl ester

Similar to the process described in Example 2 a), 5- (4-chloro-phenyl) -4-ethyl-1H-pyrazole-3-carboxylic acid ethyl ester was reacted with methane iodide in the presence of potassium hydroxide to give 5 -(4-Chloro-phenyl) -4-ethyl-2-methyl-2H-pyrazole-3-carboxylic acid ethyl ester was obtained as yellow crystals and 5- (4-chloro-phenyl) -4-ethyl-1-methyl -1H-pyrazole-3-carboxylic acid ethyl ester was obtained as a yellow oil.

5- (4-Chloro-phenyl) -4-ethyl-2-methyl-2H-pyrazole-3-carboxylic acid ethyl ester: MS: 293.0 (M + H) ⁺ .

5- (4-Chloro-phenyl) -4-ethyl-1-methyl-1 H-pyrazole-3-carboxylic acid ethyl ester: MS: 332.3 (M + K) ⁺ .

d) [5- (4-Chloro-phenyl) -4-ethyl-2-methyl-2H-pyrazol-3-yl] -methanol

Similar to the process described in Example 1 a), 5- (4-chloro-phenyl) -4-ethyl-2-methyl-2H-pyrazole-3-carboxylic acid ethyl ester was reduced with lithium aluminum hydride [ 5- (4-Chloro-phenyl) -4-ethyl-2-methyl-2H-pyrazol-3-yl] -methanol was obtained as colorless crystals.

MS: 251.0 (M + H) ⁺ .

e) {6- [5- (4-Chloro-phenyl) -4-ethyl-2-methyl-2H-pyrazol-3-ylmethoxy] -indol-1-yl} -acetic acid tert-butyl ester

Similar to the process described in Example 3 c), (6-hydroxy-indol-1-yl) -acetic acid tert-butyl ester (Example 1 d)) was replaced by N, N, N ', N'- Reacted with [5- (4-chloro-phenyl) -4-ethyl-2-methyl-2H-pyrazol-3-yl] -methanol in the presence of tetramethyl azodicarboxamide and tributylphosphine {6 -[5- (4-Chloro-phenyl) -4-ethyl-2-methyl-2H-pyrazol-3-ylmethoxy] -indol-1-yl} -acetic acid tert-butyl ester was obtained as a colorless oil. .

MS: 480.3 (M + H) ⁺ .

f) {6- [5- (4-Chloro-phenyl) -4-ethyl-2-methyl-2H-pyrazol-3-ylmethoxy] -indol-1-yl} -acetic acid

Similar to the process described in Example 1 f), {6- [5- (4-chloro-phenyl) -4-ethyl-2-methyl-2H-pyrazol-3-ylmethoxy] -indole-1- Mono-acetic acid tert-butyl ester was treated with LiOH to give {6- [5- (4-chloro-phenyl) -4-ethyl-2-methyl-2H-pyrazol-3-ylmethoxy] -indole- 1-yl} -acetic acid was obtained as brown crystals.

MS: 422.1 (MH) ^- .

Example 5

a) 5- (4-Chloro-phenyl) -2-methyl-2H-pyrazole-3-carboxylic acid ethyl ester and 5- (4-chloro-phenyl) -1-methyl-1 H-pyrazole-3-carboxylic acid ethyl Ester

Similar to the process described in Example 2 a), 5- (4-chloro-phenyl) -1H-pyrazole-3-carboxylic acid ethyl ester (T. van Herk et al. , J. Med. Chem. 2003, 46, 3945-3951)) is reacted with methane iodide in the presence of potassium hydroxide to give 5- (4-chloro-phenyl) -2-methyl-2H-pyrazole-3-carboxylic acid ethyl ester as colorless crystals. -(4-Chloro-phenyl) -1-methyl-1H-pyrazole-3-carboxylic acid ethyl ester was obtained as a colorless oil.

5- (4-Chloro-phenyl) -2-methyl-2H-pyrazole-3-carboxylic acid ethyl ester: MS: 265.0 (M + H) ⁺ .

5- (4-Chloro-phenyl) -1-methyl-1H-pyrazole-3-carboxylic acid ethyl ester: MS: 265.0 (M + H) ⁺ .

b) [5- (4-Chloro-phenyl) -2-methyl-2H-pyrazol-3-yl] -methanol

Similar to the process described in Example 1 a), 5- (4-chloro-phenyl) -2-methyl-2H-pyrazole-3-carboxylic acid ethyl ester was reduced to lithium aluminum hydride [5- (4 -Chloro-phenyl) -2-methyl-2H-pyrazol-3-yl] -methanol was obtained as colorless crystals.

MS: 223.2 (M + H) ⁺ .

c) {6- [5- (4-Chloro-phenyl) -2-methyl-2H-pyrazol-3-ylmethoxy] -indol-1-yl} -acetic acid tert-butyl ester

Similar to the process described in Example 3 c), (6-hydroxy-indol-1-yl) -acetic acid tert-butyl ester (Example 1 d)) was replaced by N, N, N ', N'- Reaction with [5- (4-chloro-phenyl) -2-methyl-2H-pyrazol-3-yl] -methanol in the presence of tetramethyl azodicarboxamide and tributylphosphine {6- [5- (4-Chloro-phenyl) -2-methyl-2H-pyrazol-3-ylmethoxy] -indol-1-yl} -acetic acid tert-butyl ester was obtained as a colorless oil.

MS: 452.3 (M + H) ⁺ .

d) {6- [5- (4-Chloro-phenyl) -2-methyl-2H-pyrazol-3-ylmethoxy] -indol-1-yl} -acetic acid

Similar to the process described in Example 1 f), {6- [5- (4-chloro-phenyl) -2-methyl-2H-pyrazol-3-ylmethoxy] -indol-1-yl} -acetic acid Treatment of tert-butyl ester with LiOH gave {6- [5- (4-chloro-phenyl) -2-methyl-2H-pyrazol-3-ylmethoxy] -indol-1-yl} -acetic acid as an off-white crystal Obtained.

MS: 394.1 (MH) ^- .

Example 6

a) [5- (4-Chloro-phenyl) -1-methyl-1 H-pyrazol-3-yl] -methanol

Similar to the process described in Example 1 a), 5- (4-chloro-phenyl) -1-methyl-1H-pyrazole-3-carboxylic acid ethyl ester was reduced to lithium aluminum hydride [5- (4 -Chloro-phenyl) -1-methyl-1H-pyrazol-3-yl] -methanol was obtained as a white solid.

b) {5- [5- (4-chloro-phenyl) -1-methyl-1H-pyrazol-3-ylmethoxy] -indol-1-yl} -acetic acid tert-butyl ester

Similar to the process described in Example 3 c), (6-hydroxy-indol-1-yl) -acetic acid tert-butyl ester (Example 1 d)) was replaced by N, N, N ', N'- Reacted with [5- (4-chloro-phenyl) -1-methyl-1H-pyrazol-3-yl] -methanol in the presence of tetramethyl azodicarboxamide and tributylphosphine to yield {5- [5- (4-Chloro-phenyl) -1-methyl-1H-pyrazol-3-ylmethoxy] -indol-1-yl} -acetic acid tert-butyl ester was obtained as a colorless solid.

MS: 452.3 (M + H) ⁺ .

c) {5- [5- (4-chloro-phenyl) -1-methyl-1H-pyrazol-3-ylmethoxy] -indol-1-yl} -acetic acid

Similar to the process described in Example 1 f), {5- [5- (4-chloro-phenyl) -1-methyl-1H-pyrazol-3-ylmethoxy] -indol-1-yl} -acetic acid Treatment of tert-butyl ester with LiOH gave {5- [5- (4-chloro-phenyl) -1-methyl-1H-pyrazol-3-ylmethoxy] -indol-1-yl} -acetic acid as a colorless solid Obtained.

MS: 396.1 (M + H) ⁺ .

Example 7

a) 2-ethyl-5- (4-trifluoromethyl-phenyl) -2H-pyrazole-3-carboxylic acid ethyl ester

Similar to the process described in Example 2 a), 5- (4-trifluoromethyl-phenyl) -1H-pyrazole-3-carboxylic acid ethyl ester (WO 2004000785 A2) Was reacted with ether iodide in the presence of potassium hydroxide to give 2-ethyl-5- (4-trifluoromethyl-phenyl) -2H-pyrazole-3-carboxylic acid ethyl ester as colorless crystals.

b) [2-ethyl-5- (4-trifluoromethyl-phenyl) -2H-pyrazol-3-yl] -methanol

Similar to the process described in example 1 a), 2-ethyl-5- (4-trifluoromethyl-phenyl) -2H-pyrazole-3-carboxylic acid ethyl ester was reduced to lithium aluminum hydride [2 -Ethyl-5- (4-trifluoromethyl-phenyl) -2H-pyrazol-3-yl] -methanol was obtained as colorless crystals.

MS: 271.1 (M + H) ⁺ .

c) {6- [2-ethyl-5- (4-trifluoromethyl-phenyl) -2H-pyrazol-3-ylmethoxy] -indol-1-yl} -acetic acid tert-butyl ester

Similar to the process described in Example 3 c), (6-hydroxy-indol-1-yl) -acetic acid tert-butyl ester (Example 1 d)) was replaced by N, N, N ', N'- Reaction with [2-ethyl-5- (4-trifluoromenyl-phenyl) -2H-pyrazol-3-yl] -methanol in the presence of tetramethyl azodicarboxamide and tributylphosphine {6- [2-Ethyl-5- (4-trifluoromethyl-phenyl) -2H-pyrazol-3-ylmethoxy] -indol-1-yl} -acetic acid tert-butyl ester was obtained as a colorless oil.

MS: 500.4 (M + H) ⁺ .

d) {6- [2-ethyl-5- (4-trifluoromethyl-phenyl) -2H-pyrazol-3-ylmethoxy] -indol-1-yl} -acetic acid

Similar to the process described in Example 1 f), {6- [2-ethyl-5- (4-trifluoromethyl-phenyl) -2H-pyrazol-3-ylmethoxy] -indol-1-yl } -Acetic acid tert-butyl ester was treated with LiOH to give {6- [2-ethyl-5- (4-trifluoromethyl-phenyl) -2H-pyrazol-3-ylmethoxy] -indol-1-yl } -Acetic acid was obtained as yellow crystals.

MS: 442.3 (MH) ^- .

Example 8

a) 5- (tert-butyl-dimethyl-silanyloxymethyl) -1-methyl-3- (4-trifluoromethyl-phenyl) -1 H-pyrazole

Tert-butylchlorodimethylsilane (32 mg, 0.21 mmol) in [2-methyl-5- (4-trifluoromethyl-phenyl) -2h-pyrazol-3-yl in DMF (0.5 ml) under argon atmosphere ] -Methanol (50 mg, 0.2 mmol; Example 3 b)) and imidazole (15 mg, 0.22 mmol) were added to an ice cold solution. After stirring for 14 h at ambient temperature, the mixture was quenched with ice water (5 ml) and extracted twice with ethyl acetate. The combined extracts were washed with ice water and brine and dried over sodium sulfate. The yellow crystals obtained by removing the solvent under reduced pressure were purified by column chromatography (silica gel, heptane / AcOEt) to give 55 mg (0.15 mmol, 76%) of the title compound as colorless crystals.

MS: 371.3 (M + H) ⁺ .

b) 4-bromo-5- (tert-butyl-dimethyl-silanyloxymethyl) -1-methyl-3- (4-trifluoromethyl-phenyl) -1 H-pyrazole

Argonon 5- (tert-butyl-dimethyl-silanyloxymethyl) -1-methyl-3- (4-trifluoromethyl-phenyl) -1 H-pyrazole solution in dichloromethane (1.7 ml) To a mixture of bromine (20 μl, 480 μmol) and sodium carbonate (93 mg, 880 μmol) in dichloromethane (4.3 ml) at 0 ° C. in air was added within 10 minutes. After stirring for 1 h at 0-5 ° C. and 1 h at ambient temperature, the mixture was quenched with water (5 ml) and extracted twice with dichloromethane. The combined extracts were washed with saturated aqueous NaHSO ₃ and brine / ice water 1/1 and dried over sodium sulfate. The off-white crystals obtained by removing the solvent under reduced pressure were purified by column chromatography (silica gel, heptane / AcOEt) to yield 90 mg (0.2 mmol, 46%) of the title compound as colorless crystals.

c) [4-bromo-2-methyl-5- (4-trifluoromethyl-phenyl) -2H-pyrazol-3-yl] -methanol

Similar to the process described in Example 2 e), 4-bromo-5- (tert-butyl-dimethyl-silanyloxymethyl) -1-methyl-3- (4-trifluoromethyl-phenyl ) -1H-pyrazole was treated with tetrabutylammonium fluoride in THF to [4-bromo-2-methyl-5- (4-trifluoromethyl-phenyl) -2H-pyrazol-3-yl]- Methanol was obtained as a yellow oil.

MS: 335.1 (M + H) ⁺ .

d) {6- [4-Bromo-2-methyl-5- (4-trifluoromethyl-phenyl) -2H-pyrazol-3-ylmethoxy] -indol-1-yl} -acetic acid ethyl ester

Similar to the process described in Example 3c), (6-hydroxy-indol-1-yl) -ethyl acetate (Example 2 e)) was added N, N, N ', N'-tetramethyl azo. Reaction with [4-bromo-2-methyl-5- (4-trifluoromethyl-phenyl) -2H-pyrazol-3-yl] -methanol in the presence of dicarboxamide and tributylphosphine { 6- [4-Bromo-2-methyl-5- (4-trifluoromethyl-phenyl) -2H-pyrazol-3-ylmethoxy] -indol-1-yl} -acetic acid ethyl ester as colorless crystals Obtained.

MS: 536.3 (M + H) ⁺ .

e) {6- [4-Bromo-2-methyl-5- (4-trifluoromethyl-phenyl) -2H-pyrazol-3-ylmethoxy] -indol-1-yl} -acetic acid

Similar to the process described in Example 1 f), {6- [4-bromo-2-methyl-5- (4-trifluoromethyl-phenyl) -2H-pyrazol-3-ylmethoxy]- Indol-1-yl} -acetic acid ethyl ester was treated with LiOH to give {6- [4-bromo-2-methyl-5- (4-trifluoromethyl-phenyl) -2H-pyrazol-3-ylmethoxy ] -Indol-1-yl} -acetic acid was obtained as colorless crystals.

MS: 508.2 (MH) ^- .

Example 9

a) 5-chloromethyl-1-methyl-3- (4-trifluoromethyl-phenyl) -1H-pyrazole

Similar to the process described in Example 1 b), [2-methyl-5- (4-trifluoromethyl-phenyl) -2H-pyrazol-3-yl] -methanol (Example 3 b)) Reaction with thionyl chloride in chloroform gave 5-chloromethyl-1-methyl-3- (4-trifluoromethyl-phenyl) -1H-pyrazole as a yellow oil.

b) [2-methyl-5- (4-trifluoromethyl-phenyl) -2H-pyrazol-3-yl] -acetonitrile

Tetrabutylammonium cyanide (1.96 g, 7 mmol) was added to 5-chloromethyl-1-methyl-3- (4-trifluoromethyl-phenyl) -1H-pyrazole (1,54 g, in acetonitrile (35 ml). 6 mmol) was added to the solution. The solution was stirred for 16 h at ambient temperature, saturated aqueous sodium bicarbonate solution / ice water 1/1 and ethyl acetate were added and the layers separated. The aqueous layer was extracted with ethyl acetate, the combined organic layers were washed with ice water / brine 1/1, dried over sodium sulfate and the solvent was evaporated in vacuo to yield an orange oil which was titled by column chromatography (silica gel, n-heptane / AcOEt). 267 mg (1 mmol, 18%) of compound were obtained as yellow crystals.

MS: 266.0 (M + H) ⁺ .

c) [2-methyl-5- (4-trifluoromethyl-phenyl) -2H-pyrazol-3-yl] -acetic acid

[2-Methyl-5- (4-trifluoromethyl-phenyl) -2H-pyrazol-3-yl] -acetonitrile (267 mg, 1 mmol), sodium hydroxide (403 mg, 10 mmol), water (4 ml) and ethanol (4 ml) was stirred vigorously at 85 ° C. for 14 h. The reaction mixture was poured into crushed ice and aqueous HCl solution and extracted three times with ethyl acetate. The combined extracts were washed with water and brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give 286 mg (1 mmol, quant.) Of the title compound as off-white crystals.

MS: 283.1 (MH) ^- .

d) 2- [2-methyl-5- (4-trifluoromethyl-phenyl) -2H-pyrazol-3-yl] -ethanol

A solution of [2-methyl-5- (4-trifluoromethyl-phenyl) -2H-pyrazol-3-yl] -acetic acid (286 mg, 1 mmol) in tetrahydrofuran (4 ml) was added with tetrahydrofuran (2.5 ml, ₃ mmol) was treated with 1M solution of BH ₃ * THF at 0 ° C. The cold bath was removed and the reaction mixture was stirred at ambient temperature for 16 hours. Carefully quench with MeOH and ice water, extract twice with AcOEt, wash with ice water / brine 1/1, dry over magnesium sulfate, evaporate the solvent and reflux the crude product for 30 minutes in MeOH to free alcohol. It was released quantitatively. The solvent was evaporated in vacuo to give 273 mg (1 mmol, quant.) Of the title compound as colorless crystals.

MS: 271.1 (M + H) ⁺ .

e) (6- {2- [2-methyl-5- (4-trifluoromethyl-phenyl) -2H-pyrazol-3-yl] -ethoxy} -indol-1-yl) -acetic acid ethyl ester

Similar to the process described in Example 3 c), (6-hydroxy-indol-1-yl) -ethyl acetate (Example 2 e)) was converted to di-tert-butyl azodicarboxylate and triphenyl Reacted with 2- [2-methyl-5- (4-trifluoromethyl-phenyl) -2H-pyrazol-3-yl] -ethanol in the presence of phosphine (6- {2- [2-methyl- 5- (4-Trifluoromethyl-phenyl) -2H-pyrazol-3-yl] -ethoxy} -indol-1-yl) -acetic acid ethyl ester was obtained as colorless crystals.

MS: 472.1 (M + H) ⁺ .

f) (6- {2- [2-Methyl-5- (4-trifluoromethyl-phenyl) -2H-pyrazol-3-yl] -ethoxy} -indol-1-yl) -acetic acid

Similar to the process described in Example 1 f), (6- {2- [2-methyl-5- (4-trifluoromethyl-phenyl) -2H-pyrazol-3-yl] -ethoxy} Indol-1-yl) -acetic acid ethyl ester was treated with LiOH to give (6- {2- [2-methyl-5- (4-trifluoromethyl-phenyl) -2H-pyrazol-3-yl]- Ethoxy} -indol-1-yl) -acetic acid was obtained as yellow crystals.

MS: 442.4 (MH) ^- .

Example 10

a) 5- (tert-butyl-dimethyl-silanyloxymethyl) -1,4-dimethyl-3- (4-trifluoromethyl-phenyl) -1 H-pyrazole

A 1.5 M solution of tert-butyllithium in pentane (0.5 ml, 748 μmol) was added to 4-bromo-5- (tert-butyl-dimethyl-silanyloxymethyl in THF (2 ml) at -78 ° C under an argon atmosphere. ) -1-methyl-3- (4-trifluoromethyl-phenyl) -1H-pyrazole (280 mg, 623 μmol; Example 8 b)) was added dropwise. After 15 minutes methane iodide (177 gm, 1.2 mmol) was added at -78 ° C. The reaction mixture was stirred for an additional 30 minutes at -78 ° C and then for 2 hours at RT. After quenching with saturated aqueous NaHCO ₃ solution, the reaction mixture was partitioned between tert-butyl methyl ether and water. The ether phase was dried over sodium sulfate and concentrated in vacuo to afford 5- (tert-butyl-dimethyl-silanyloxymethyl) -1,4-dimethyl-3- (4-trifluoromethyl-phenyl) -1 H-pyra 240 mg (620 μmol, quant.) Sol was obtained as a yellow oil which was used in the next step without further purification.

b) [2,4-dimethyl-5- (4-trifluoromethyl-phenyl) -2H-pyrazol-3-yl] -methanol

Similar to the process described in Example 2 e), 5- (tert-butyl-dimethyl-silanyloxymethyl) -1,4-dimethyl-3- (4-trifluoromethyl-phenyl)- Treatment of 1H-pyrazole with tetrabutylammonium fluoride in THF gave [2,4-dimethyl-5- (4-trifluoromethyl-phenyl) -2H-pyrazol-3-yl] -methanol yellow Obtained as an oil.

MS: 271.1 (M + H) ⁺ .

c) {6- [2,4-dimethyl-5- (4-trifluoromethyl-phenyl) -2H-pyrazol-3-ylmethoxy] -indol-1-yl} -acetic acid ethyl ester

Similar to the process described in Example 3c), (6-hydroxy-indol-1-yl) -ethyl acetate (Example 2 e)) was added N, N, N ', N'-tetramethyl azo. Reaction with [2,4-dimethyl-5- (4-trifluoromethyl-phenyl) -2H-pyrazol-3-yl] -methanol in the presence of dicarboxamide and tributylphosphine {6- [2,4-Dimethyl-5- (4-trifluoromethyl-phenyl) -2H-pyrazol-3-ylmethoxy] -indol-1-yl} -acetic acid ethyl ester was obtained as a yellow oil.

d) {6- [2,4-Dimethyl-5- (4-trifluoromethyl-phenyl) -2H-pyrazol-3-ylmethoxy] -indol-1-yl} -acetic acid

Similar to the process described in Example 1 f), {6- [2,4-dimethyl-5- (4-trifluoromethyl-phenyl) -2H-pyrazol-3-ylmethoxy] -indole- 1-yl} -acetic acid ethyl ester was treated with LiOH to give {6- [2,4-dimethyl-5- (4-trifluoromethyl-phenyl) -2H-pyrazol-3-ylmethoxy] -indole- 1-yl} -acetic acid was obtained as a yellow solid.

MS: 442.2 (MH) ^- .

Example 11

a) (Z) -2-hydroxy-4-oxo-4- (4-trifluoromethoxy-phenyl) -but-2-enoic acid ethyl ester

A solution of 1- (4-trifluoromethoxy-phenyl) -ethanone (5 g, 24 mmol) and diethyl oxalate (3.25 ml, 24 mmol) in ethanol (5 ml) was dissolved in metallic argon (552 ml) in ethanol (15 ml) under argon. , 24 mmol) in an ice-cold solution within 20 minutes. The ice bath was removed and the reaction stirred for 30 minutes after reaching ambient temperature. After standing for 14 hours, the precipitated yellow solid was filtered off. The solid was partitioned between 1M HCl / ice water 1/1 and tertiary butyl methyl ether. The aqueous layer was extracted twice with tertiary butyl methyl ether and the combined extracts were washed with brine / ice water 1/1 and dried over sodium sulphate. Evaporation of the solid gave 7.2 g (23.8 mmol, 99%) of the title compound as orange crystals.

MS: 305.0 (M + H) ⁺ .

b) 5- (4-trifluoromethoxy-phenyl) -1 H-pyrazole-3-carboxylic acid ethyl ester

Similar to the process described in Example 4 b), (Z) -2-hydroxy-4-oxo-4- (4-trifluoromethoxy-phenyl) -but-2-enoic acid ethyl ester was subjected to reflux conditions. Reaction with hydrazine monohydrate in ethanol gave 5- (4-trifluoromethoxy-phenyl) -1H-pyrazole-3-carboxylic acid ethyl ester as yellow crystals.

MS: 301.0 (M + H) ⁺ .

c) 2-methyl-5- (4-trifluoromethoxy-phenyl) -2H-pyrazole-3-carboxylic acid ethyl ester and 1-methyl-5- (4-trifluoromethoxy-phenyl) -1H-pyra Sol-3-carboxylic acid ethyl ester

Similar to the process described in Example 2 a), 2- (4-trifluoromethoxy-phenyl) -1H-pyrazole-3-carboxylic acid ethyl ester was reacted with methane iodide in the presence of potassium hydroxide to give 2- Methyl-5- (4-trifluoromethoxy-phenyl) -2H-pyrazole-3-carboxylic acid ethyl ester was obtained as white crystals and 1-methyl-5- (4-trifluoromethoxy-phenyl) -1H- Pyrazole-3-carboxylic acid ethyl ester was obtained as a yellow oil.

2-Methyl-5- (4-trifluoromethoxy-phenyl) -2H-pyrazole-3-carboxylic acid ethyl ester: MS: 315.0 (M + H) ⁺ .

d) [2-methyl-5- (4-trifluoromethoxy-phenyl) -2H-pyrazol-3-yl] -methanol

Similar to the process described in Example 1 a), 2-methyl-5- (4-trifluoromethoxy-phenyl) -2H-pyrazole-3-carboxylic acid ethyl ester is reduced to lithium aluminum hydride [2 -Methyl-5- (4-trifluoromethoxy-phenyl) -2H-pyrazol-3-yl] -methanol was obtained as white crystals.

MS: 273.1 (M + H) ⁺ .

e) {6- [2-methyl-5- (4-trifluoromethoxy-phenyl) -2H-pyrazol-3-ylmethoxy] -indol-1-yl} -acetic acid ethyl ester

Similar to the process described in Example 3 c), (6-hydroxy-indol1-yl) -acetic acid ethyl ester (Example 2 e)) was added N, N, N ', N'-tetramethyl azodi Reacted with [2-methyl-5- (4-trifluoromethoxy-phenyl) -2H-pyrazol-3-yl] -methanol in the presence of carboxamide and tributylphosphine {6- [2-methyl -5- (4-Trifluoromethoxy-phenyl) -2H-pyrazol-3-ylmethoxy] -indol-1-yl} -acetic acid ethyl ester was obtained as yellow crystals.

MS: 474.0 (M + H) ⁺ .

f) {6- [2-methyl-5- (4-trifluoromethoxy-phenyl) -2H-pyrazol-3-ylmethoxy] -indol-1-yl} -acetic acid

Similar to the process described in Example 1 f), {6- [2-methyl-5- (4-trifluoromethoxy-phenyl) -2H-pyrazol-3-ylmethoxy] -indol-1-yl } -Acetic acid ethyl ester was treated with LiOH to give {6- [2-methyl-5- (4-trifluoromethoxy-phenyl) -2H-pyrazol-3-ylmethoxy] -indol-1-yl} -acetic acid Was obtained as off-white crystals.

MS: 495.3 (M + H) ⁺ .

Example 12

a) 5- (tert-butyl-dimethyl-silanyloxy) -1 H-indole

A solution of 5-hydroxy-indole (5 g, 38 mmol), tert-butyldimethylsilyl chloride (6.13 g, 39.4 mmol) and imidazole (5.37 g, 68.1 mmol) in DMF (50 mL) was added at RT for 20 h. Stirred. Diethyl ether was added and the mixture was washed with 1N HCl and water. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to yield 9.4 g (389 mmol, quant.) Of 5- (tert-butyl-dimethyl-silanyloxy) -1H-indole.

MS: 248.1 (M + H) ⁺ .

b) [5- (tert-butyl-dimethyl-silanyloxy) -indol-1-yl] -acetic acid ethyl ester

5- (tert-butyl-dimethyl-silanyloxy) -1H-indole (9.2 g, 37.2 mmol), ethyl bromoacetate (4.79 ml, 40.9 mmol) and cesium carbonate (36.4 g, in DMF (140 ml) 111.5 mmol) was stirred at RT for 3 h. Diethyl ether was added and the mixture was washed with 1N HCl and water and dried over sodium sulfate. The ether phase was concentrated under reduced pressure to give 12.9 g (quant.) Of [5- (tert-butyl-dimethyl-silanyloxy) -indol-1-yl] -acetic acid ethyl ester, which was used in the next step without further purification. It was.

MS: 334.1 (M + H) ⁺ .

c) 5- (hydroxy-indol-1-yl) -acetic acid ethyl ester

Tetrabutylammonium fluoride hydrate in an ice-cold solution of [5- (tert-butyl-dimethyl-silanyloxy) -indol-1-yl] -ethyl acetate (12.9 g, 39.7 mmol) in THF (130 ml) 12.5 g, 38.7 mmol) was added. The reaction mixture was stirred at RT for 1 h, diluted with diethyl ether and washed with 1N HCl and water. Evaporation of the solvent under reduced pressure gave 7.07 g (32.2 mmol, 83%) of 5- (hydroxy-indol-1-yl) -acetic acid ethyl ester.

MS: 220.1 (M + H) ⁺ .

d) {5- [2-Methyl-5- (4-trifluoromethoxy-phenyl) -2H-pyrazol-3-ylmethoxy] -indol-1-yl} -acetic acid ethyl ester

Similar to the process described in Example 3 c), (5-hydroxy-indol-1-yl) -acetic acid ethyl ester was added with N, N, N ', N'-tetramethyl azodicarboxamide and tributyl Reaction with [2-methyl-5- (4-trifluoromethoxy-phenyl) -2H-pyrazol-3-yl] -methanol in the presence of phosphine {5- [2-methyl-5- (4- Trifluoromethoxy-phenyl) -2H-pyrazol-3-ylmethoxy] -indol-l-yl} -acetic acid ethyl ester was obtained as a colorless oil.

MS: 474.0 (M + H) ⁺ .

e) {5- [2-methyl-5- (4-trifluoromethoxy-phenyl) -2H-pyrazol-3-ylmethoxy] -indole-1-acetic acid

Similar to the process described in Example 1 f), {5- [2-methyl-5- (4-trifluoromethoxy-phenyl) -2H-pyrazol-3-ylmethoxy] -indol-1-yl } -Acetic acid ethyl ester was treated with LiOH to give {5- [2-methyl-5- (4-trifluoromethoxy-phenyl) -2H-pyrazol-3-ylmethoxy] -indol-1-yl} -acetic acid Was obtained as a yellow foam.

MS: 446.0 (M + H) ⁺ .

Example 13

a) 2- (2,2,2-trifluoro-ethyl) -5- (4-trifluoromethyl-phenyl) -2H-pyrazole-3-carboxylic acid ethyl ester

Sodium hydride (55% dispersion in mineral oil, 203 mg, 5 mmol) in 5- (4-trifluoromethyl-phenyl) -1 H-pyrazole-3-carboxylic acid ethyl ester (1 g, 4 mmol) in DMF (60 ml) under argon atmosphere It was added to the ice-cooled solution of WO2004000785 A2). The solution was stirred at 0 ° C. for 10 minutes and at ambient temperature for 40 minutes. Trifluoroethyltriplate (1.07 g, 5 mmol) was added and the mixture was stirred at ambient temperature for 3 hours. The solution was cooled to 0 ° C. and 1N HCl / ice water 1/2 and dichloromethane were added. The aqueous phase was extracted twice with dichloromethane and the combined extracts were washed with brine / ice water 1/1 and dried over sodium sulfate. The yellow crystals obtained by evaporation of the solvent under reduced pressure were purified by column chromatography (silica gel, n-heptane.AcOEt) to give 833 mg (2.27 mmol, 65%) of the title compound as colorless crystals.

b) [2- (2,2,2-Trifluoro-ethyl) -5- (4-trifluoromethyl-phenyl) -2H-pyrazol-3-yl] -methanol

Similar to the process described in example 1 a), 2- (2,2,2-trifluoro-ethyl) -5- (4-trifluoromethyl-phenyl) -2H-pyrazole-3-carboxylic acid Reduction of the ethyl ester with lithium aluminum hydride [2- (2,2,2-trifluoro-ethyl) -5- (4-trifluoromethyl-phenyl) -2H-pyrazol-3-yl]- Methanol was obtained as colorless crystals.

MS: 324.0 (M) ⁺ .

c) {6- [2- (2,2,2-trifluoro-ethyl) -5- (4-trifluoromethyl-phenyl) -2H-pyrazol-3-ylmethoxy] -indole-1- Japanese} -ethyl acetate

Similar to the process described in Example 3c), (6-hydroxy-indol-1-yl) -ethyl acetate (Example 2 e)) was added N, N, N ', N'-tetramethyl azo. [2- (2,2,2-trifluoro-ethyl) -5- (4-trifluoromethyl-phenyl) -2H-pyrazol-3-yl in the presence of dicarboxamide and tributylphosphine ]-To react with methanol {6- [2- (2,2,2-trifluoro-ethyl) -5- (4-trifluoromethyl-phenyl) -2H-pyrazol-3-ylmethoxy]- Indol-1-yl} -acetic acid ethyl ester was obtained as a colorless oil.

MS: 526.0 (M + H) ⁺ .

d) {6- [2- (2,2,2-Trifluoro-ethyl) -5- (4-trifluoromethyl-phenyl) -2H-pyrazol-3-ylmethoxy] -indole-1- Japanese} -acetic acid

Similar to the process described in Example 1 f), {6- [2- (2,2,2-trifluoro-ethyl) -5- (4-trifluoromethyl-phenyl) -2H-pyrazole 3-ylmethoxy] -indol-1-yl} -acetic acid ethyl ester was treated with LiOH to give {6- [2- (2,2,2-trifluoro-ethyl) -5- (4-trifluoro Methyl-phenyl) -2H-pyrazol-3-ylmethoxy] -indol-1-yl} -acetic acid was obtained as off-white crystals.

MS: 498.3 (M + H) ⁺ .

Example 14

a) 6-benzyloxy-4-methyl-1H-indole-2-carboxylic acid

A solution of potassium hydroxide 2M in ethanol (0.48 ml, 0.97 mmol) was added to 6-benzyloxy-4-methyl-1H-indole-2-carboxylic acid ethyl ester in ethanol (1 ml) (100 mg, 0.32 mmol; International Patent Application Publication (2001) WO 2001044186 A1) was added to the solution. The mixture was heated to reflux for 1.5 h, acidified with 1N HCl and extracted twice with ethyl acetate. The combined extracts were washed with brine and dried over sodium sulfate. Evaporation of the solvent under reduced pressure gave 90 mg (0.32 mmol, 99%) of the title compound as yellow crystals.

b) 6-benzyloxy-4-methyl-1 H-indole

A suspension of 6-benzyloxy-4-methyl-1H-indole-2-carboxylic acid (28 mg, 0.95 mmol) and copper chromite (19 mg, 0.06 mmol) in quinoline (1.4 ml) was heated at 230 ° C. (water bath temperature) for 1.5 hours. Heated during. The mixture was poured into 2N HCl / ice water 1/1 and extracted three times with ethyl acetate. The combined extracts were washed with saturated aqueous NaHCO ₃ and brine and dried over sodium sulfate. The black oil remaining by evaporation of the solvent under reduced pressure was purified by column chromatography (silica gel, n-heptane / AcOEt) to give 90 mg (0.32 mmol, 34%) of the title compound as a brown oil.

MS: 252.4 (M + H) ⁺ .

c) (6-benzyloxy-4-methyl-1H-indole) -acetic acid tert-butyl ester

Similar to the process described in Example 1 c), 6-benzyloxy-4-methyl-1H-indole is reacted with bromo-acetic acid tert-butyl ester in the presence of cesium carbonate in DMF (6-benzyloxy 4-Methyl-1H-indole) -acetic acid tert-butyl ester was obtained as a yellow oil.

MS: 352.1 (M + H) ⁺ .

d) (6-hydroxy-4-methyl-indol-1-yl) -acetic acid tert-butyl ester

A solution of (6-benzyloxy-4-methyl-1H-indole) -acetic acid tert-butyl ester (140 mg, 0.4 mmol) in ethanol (14 ml) was hydrogenated over 10% palladium on activated carbon (14 mg) at ambient temperature for 3 hours. It was. The catalyst was filtered off and the solvent was evaporated under reduced pressure to yield 100 mg (0.38 mmol, 96%) of the title compound as a brown oil which was used in the next step without further purification.

MS: 279.3 (M + NH ₄ ) ⁺ .

e) {4-methyl-6- [2-methyl-5- (4-trifluoromethoxy-phenyl) -2H-pyrazol-3-ylmethoxy] -indol-1-yl} -acetic acid tert-butyl Ester

Similar to the process described in Example 3c), (6-hydroxy-4-methyl-indol-1-yl) -acetic acid tert-butyl ester was added with N, N, N ', N'-tetramethyl azo. By reaction with [2-methyl-5- (4-trifluoromethoxy-phenyl) -2H-pyrazol-3-yl] -methanol in the presence of dicarboxamide and tributylphosphine {4-methyl-6 -[2-Methyl-5- (4-trifluoromethoxy-phenyl) -2H-pyrazol-3-ylmethoxy] -indol-1-yl} -acetic acid tert-butyl ester was obtained as a colorless liquid.

MS: 516.5 (M + H) ⁺ .

f) {4-methyl-6- [2-methyl-5- (4-trifluoromethoxy-phenyl) -2H-pyrazol-3-ylmethoxy] -indol-1-yl} -acetic acid

Similar to the process described in Example 1 f), {4-methyl-6- [2-methyl-5- (4-trifluoromethoxy-phenyl) -2H-pyrazol-3-ylmethoxy] -indole -1-yl} -Acetic acid tert-butyl ester was treated with LiOH to produce {4-methyl-6- [2-methyl-5- (4-trifluoromethoxy-phenyl) -2H-pyrazol-3-ylmeth Oxy] -indol-1-yl} -acetic acid was obtained as a colorless solid.

MS: 460.4 (M + H) ⁺ .

Example 15

a) 2- (2,2,2-trifluoro-ethyl) -5- (4-trifluoromethoxy-phenyl) -2H-pyrazole-3-carboxylic acid ethyl ester

Similar to the process described in Example 13a), 5- (4-trifluoromethoxy-phenyl) -1H-pyrazole-3-carboxylic acid ethyl ester (Example 11b)) was added to trifluoroethyltriplate. Reaction with gave 2- (2,2,2-trifluoro-ethyl) -5- (4-trifluoromethoxy-phenyl) -2H-pyrazole-3-carboxylic acid ethyl ester as a colorless solid.

MS: 382.1 (M) ⁺ .

b) [2- (2,2,2-Trifluoro-ethyl) -5- (4-trifluoromethoxy-phenyl) -2H-pyrazol-3-yl] -methanol

Similar to the process described in Example 1 a), 2- (2,2,2-trifluoro-ethyl) -5- (4-trifluoromethoxy-phenyl) -2H-pyrazole-3-carboxylic acid Reduction of ethyl ester with lithium aluminum hydride [2- (2,2,2-trifluoro-ethyl) -5- (4-trifluoromethoxy-phenyl) -2H-pyrazol-3-yl]- Methanol was obtained as a colorless solid.

MS: 341.0 (M + H) ⁺ .

c) {6- [2- (2,2,2-trifluoro-ethyl) -5- (4-trifluoromethoxy-phenyl) -2H-pyrazol-3-ylmethoxy] -indole-1- Japanese} -ethyl acetate

Similar to the process described in Example 3 c), (6-hydroxy-indol-1-yl) -ethyl acetate (Example 2e)) was added N, N, N ', N'-tetramethyl azodi [2- (2,2,2-trifluoro-ethyl) -5- (4-trifluoromethoxy-phenyl) -2H-pyrazol-3-yl] in the presence of carboxamide and tributylphosphine Reacted with methanol to produce {6- [2- (2,2,2-trifluoro-ethyl) -5- (4-trifluoromethoxy-phenyl) -2H-pyrazol-3-ylmethoxy] -indole -1-yl} -acetic acid ethyl ester was obtained as a yellow oil.

MS: 542.2 (M + H) ⁺ .

d) {6- [2- (2,2,2-Trifluoro-ethyl) -5- (4-trifluoromethoxy-phenyl) -2H-pyrazol-3-ylmethoxy] -indole-1- Japanese} -acetic acid

Similar to the process described in Example 1 f), {6- [2- (2,2,2-trifluoro-ethyl) -5- (4-trifluoromethoxy-phenyl) -2H-pyrazole 3-ylmethoxy] -indol-1-yl} -acetic acid ethyl ester was treated with LiOH to give {6- [2- (2,2,2-trifluoro-ethyl) -5- (4-trifluorometh Toxy-phenyl) -2H-pyrazol-3-ylmethoxy] -indol-1-yl} -acetic acid was obtained as a brown oil.

MS: 514.2 (M + H) ⁺ .

Example 16

a) [1-Methyl-5- (4-trifluoromethoxy-phenyl) -1 H-pyrazol-3-yl] -methanol

Similar to the process described in Example 1 a), 1-methyl-5- (4-trifluoromethoxy-phenyl) -1H-pyrazole-3-carboxylic acid ethyl ester (Example 11 c)) Reduction with hydride gave [1-methyl-5- (4-trifluoromethoxy-phenyl) -1H-pyrazol-3-yl] -methanol as a brown solid.

MS: 273.0 (M + H) ⁺ .

b) {6- [1-methyl-5- (4-trifluoromethoxy-phenyl) -1H-pyrazol-3-ylmethoxy] -indol-1-yl} -acetic acid ethyl ester

Similar to the process described in Example 3c), (6-hydroxy-indol-1-yl) -ethyl acetate (Example 2 e)) was added N, N, N ', N'-tetramethyl azo. Reacted with [1-methyl-5- (4-trifluoromethoxy-phenyl) -1H-pyrazol-3-yl] -methanol in the presence of dicarboxamide and tributylphosphine {6- [1- Methyl-5- (4-trifluoromethoxy-phenyl) -1H-pyrazol-3-ylmethoxy] -indol-1-yl} -acetic acid ethyl ester was obtained as a colorless solid.

MS: 474.4 (M + H) ⁺ .

c) {6- [1-methyl-5- (4-trifluoromethoxy-phenyl) -1H-pyrazol-3-ylmethoxy] -indol-1-yl} -acetic acid

Similar to the process described in Example 1 f), {6- [1-methyl-5- (4-trifluoromethoxy-phenyl) -1H-pyrazol-3-ylmethoxy] -indol-1-yl } -Acetic acid ethyl ester was treated with LiOH to give {6- [1-methyl-5- (4-trifluoromethoxy-phenyl) -1H-pyrazol-3-ylmethoxy] -indol-1-yl} -acetic acid Was obtained as a colorless solid.

MS: 446.0 (M + H) ⁺ .

Example 17

a) (Z) -4- (3,4-dichloro-phenyl) -2-hydroxy-4-oxo-but-2-enoic acid ethyl ester

Similar to the process described in Example 11 a), 1- (3,4-dichloro-phenyl) -ethanone was reacted with diethyl oxalate in the presence of metal sodium to give 4-Dichloro-phenyl) -2-hydroxy-4-oxo-but-2-enoic acid ethyl ester was obtained as an off-white solid.

MS: 289.0 (M + H) ⁺ .

b) 5- (3,4-dichloro-phenyl) -2-methyl-2H-pyrazole-3-carboxylic acid ethyl ester and 5- (3,4-dichloro-phenyl) -1-methyl-1H-pyra Sol-3-carboxylic acid ethyl ester

Similar to the process described in Example 4 b), (Z) -4- (3,4-dichloro-phenyl) -2-hydroxy-4-oxo-but-2-enoic acid ethyl ester was subjected to reflux conditions. Reaction with methylhydrazine in ethanol yields 5- (3,4-dichloro-phenyl) -2-methyl-2H-pyrazole-3-carboxylic acid ethyl ester as colorless crystals and 5- (3,4-dichloro- Phenyl) -1-methyl-1H-pyrazole-3-carboxylic acid ethyl ester was obtained as colorless crystals.

5- (3,4-Dichloro-phenyl) -2-methyl-2H-pyrazole-3-carboxylic acid ethyl ester: MS: 299.1 (M + H) ⁺ .

c) [5- (3,4-Dichloro-phenyl) -2-methyl-2H-pyrazol-3-yl] -methanol

Similar to the process described in Example 1 a), 5- (3,4-dichloro-phenyl) -2-methyl-2H-pyrazole-3-carboxylic acid ethyl ester was reduced with lithium aluminum hydride [5 -(3,4-Dichloro-phenyl) -2-methyl-2H-pyrazol-3-yl] -methanol was obtained as a white solid.

MS: 256.0 (M) ⁺ .

d) {6- [5- (3,4- Dichloro - Phenyl )-2- methyl -2H- Pyrazole -3- Ilmethoxy ] -Indol-1-yl} -acetic acid ethyl ester

Similar to the process described in Example 3c), (6-hydroxy-indol-1-yl) -ethyl acetate (Example 2 e)) was added N, N, N ', N'-tetramethyl azo. Reaction with [5- (3,4-Dichloro-phenyl) -2-methyl-2H-pyrazol-3-yl] -methanol in the presence of dicarboxamide and tributylphosphine {6- [5 -(3,4-Dichloro-phenyl) -2-methyl-2H-pyrazol-3-ylmethoxy] -indol-1-yl} -acetic acid ethyl ester was obtained as a colorless oil.

MS: 458.2 (M + H) ⁺ .

e) {6- [5- (3,4-Dichloro-phenyl) -2-methyl-2H-pyrazol-3-ylmethoxy] -indol-1-yl} -acetic acid

Similar to the process described in Example 1 f), {6- [5- (3,4-Dichloro-phenyl) -2-methyl-2H-pyrazol-3-ylmethoxy] -indol-1-yl } -Acetic acid ethyl ester was treated with LiOH to give {6- [5- (3,4-dichloro-phenyl) -2-methyl-2H-pyrazol-3-ylmethoxy] -indol-1-yl} -acetic acid Was obtained as brown crystals.

MS: 430.4 (M + H) ⁺ .

Example 18

a) (Z) -4- (4-fluoro-3-trifluoromethyl-phenyl) -2-hydroxy-4-oxo-but-2-enoic acid ethyl ester

Similar to the process described in Example 11 a), 1- (4-fluoro-3-trifluoromethyl-phenyl) -ethanone was reacted with diethyl oxalate in the presence of metal sodium (Z) -4 -(4-Fluoro-3-trifluoromethyl-phenyl) -2-hydroxy-4-oxo-but-2-enoic acid ethyl ester was obtained as a colorless solid.

MS: 307.1 (M + H) ⁺ .

b) 5- (4-fluoro-3-trifluoromethyl-phenyl) -2-methyl-2H-pyrazole-3-carboxylic acid ethyl ester and 5- (4-fluoro-3-trifluoromethyl- Phenyl) -1-methyl-1H-pyrazole-3-carboxylic acid ethyl ester

Similar to the process described in example 4 b), (Z) -4- (4-fluoro-3-trifluoromethyl-phenyl) -2-hydroxy-4-oxo-but-2-enoic acid ethyl The ester was reacted with methylhydrazine in ethanol under reflux conditions to give 5- (4-fluoro-3-trifluoromethyl-phenyl) -2-methyl-2H-pyrazole-3-carboxylic acid ethyl ester as colorless crystals 5- (4-Fluoro-3-trifluoromethyl-phenyl) -1-methyl-1H-pyrazole-3-carboxylic acid ethyl ester was obtained as colorless crystals.

5- (4-Fluoro-3-trifluoromethyl-phenyl) -2-methyl-2H-pyrazole-3-carboxylic acid ethyl ester: MS: 317.0 (M + H) ⁺ .

c) [5- (4-Fluoro-3-trifluoromethyl-phenyl) -2-methyl-2H-pyrazol-3-yl] -methanol

Similar to the process described in Example 1 a), 5- (4-fluoro-3-trifluoromethyl-phenyl) -2-methyl-2H-pyrazole-3-carboxylic acid ethyl ester was added to lithium aluminum hydride. Reduction with [5- (4-fluoro-3-trifluoromethyl-phenyl) -2-methyl-2H-pyrazol-3-yl] -methanol gave a white solid.

MS: 275.3 (M + H) ⁺ .

d) {6- [5- (4-Fluoro-3-trifluoromethyl-phenyl) -2-methyl-2H-pyrazol-3-ylmethoxy] -indol-1-yl} -acetic acid ethyl ester

Similar to the process described in Example 3c), (6-hydroxy-indol-1-yl) -ethyl acetate (Example 2 e)) was added N, N, N ', N'-tetramethyl azo. Reacted with [5- (4-fluoro-3-trifluoromethyl-phenyl) -2-methyl-2H-pyrazol-3-yl] -methanol in the presence of dicarboxamide and tributylphosphine { 6- [5- (4-Fluoro-3-trifluoromethyl-phenyl) -2-methyl-2H-pyrazol-3-ylmethoxy] -indol-1-yl} -acetic acid ethyl ester as white solid Obtained.

MS: 476.0 (M + H) ⁺ .

d) {6- [5- (4-Fluoro-3-trifluoromethyl-phenyl) -2-methyl-2H-pyrazol-3-ylmethoxy] -indol-1-yl} -acetic acid

Similar to the process described in Example 1 f), {6- [5- (4-fluoro-3-trifluoromethyl-phenyl) -2-methyl-2H-pyrazol-3-ylmethoxy]- Indol-1-yl} -acetic acid ethyl ester was treated with LiOH to give {6- [5- (4-fluoro-3-trifluoromethyl-phenyl) -2-methyl-2H-pyrazol-3-ylmethoxy ] -Indol-1-yl} -acetic acid was obtained as a brown solid.

MS: 448.1 (M + H) ⁺ .

Example 19

a) 5-chloromethyl-1-methyl-3- (4-trifluoromethoxy-phenyl) -1H-pyrazole

Similar to the process described in Example 1 b), [2-methyl-5- (4-trifluoromethoxy-phenyl) -2H-pyrazol-3-yl] -methanol (Example 11d)) was added chloroform. Reaction with heavy thionyl chloride afforded 5-chloromethyl-1-methyl-3- (4-trifluoromethoxy-phenyl) -1H-pyrazole as a colorless oil.

MS: 291.0 (M + H) ⁺ .

b) [2-methyl-5- (4-trifluoromethoxy-phenyl) -2H-pyrazol-3-yl] -acetonitrile

Similar to the process described in Example 9 b), 5-chloromethyl-1-methyl-3- (4-trifluoromethoxy-phenyl) -1H-pyrazole is reacted with tetrabutylammonium cyanide in acetonitrile To give [2-methyl-5- (4-trifluoromethoxy-phenyl) -2H-pyrazol-3-yl] -acetonitrile as a yellow solid.

MS: 300.4 (M + NH ₄ ) ⁺ .

c) [2-methyl-5- (4-trifluoromethoxy-phenyl) -2H-pyrazol-3-yl] -acetic acid

Similar to the process described in Example 9 c), [2-methyl-5- (4-trifluoromethoxy-phenyl) -2H-pyrazol-3-yl] -acetonitrile was water / ethanol at 85 ° C. Treatment with sodium hydroxide in 1/1 gave [2-methyl-5- (4-trifluoromethoxy-phenyl) -2H-pyrazol-3-yl] -acetic acid as an off-white solid.

MS: 301.0 (M + H) ⁺ .

d) 2- [2-methyl-5- (4-trifluoromethoxy-phenyl) -2H-pyrazol-3-yl] -ethanol

Similar to the process described in Example 9 c), [2-methyl-5- (4-trifluoromethoxy-phenyl) -2H-pyrazol-3-yl] -acetic acid was converted to BH ₃ * in tetrahydrofuran. Reduction with 1M solution of THF afforded 2- [2-methyl-5- (4-trifluoromethoxy-phenyl) -2H-pyrazol-3-yl] -ethanol as colorless crystals.

MS: 287.0 (M + H) ⁺ .

e) (6- {2- [2-methyl-5- (4-trifluoromethoxy-phenyl) -2H-pyrazol-3-yl] -ethoxy} -indol-1-yl) -acetic acid ethyl ester

Similar to the process described in Example 3 c), (6-hydroxy-indol-1-yl) -ethyl acetate (Example 2 e)) was converted to di-tert-butyl azodicarboxylate and triphenyl Reacted with 2- [2-methyl-5- (4-trifluoromethoxy-phenyl) -2H-pyrazol-3-yl] -ethanol in the presence of phosphine (6- {2- [2-methyl- 5- (4-Trifluoromethoxy-phenyl) -2H-pyrazol-3-yl] -ethoxy} -indol-1-yl) -acetic acid ethyl ester was obtained as colorless crystals.

MS: 488.1 (M + H) ⁺ .

f) (6- {2- [2-Methyl-5- (4-trifluoromethoxy-phenyl) -2H-pyrazol-3-yl] -ethoxy} -indol-1-yl) -acetic acid

Similar to the process described in Example 1 f), (6- {2- [2-methyl-5- (4-trifluoromethoxy-phenyl) -2H-pyrazol-3-yl] -ethoxy} -Indol-1-yl) -acetic acid ethyl ester was treated with LiOH to give (6- {2- [2-methyl-5- (4-trifluoromethoxy-phenyl) -2H-pyrazol-3-yl]- Ethoxy} -indol-1-yl) -acetic acid was obtained as colorless crystals.

MS: 460.4 (M + H) ⁺ .

Example 20

a) 5-iodomethyl-1-methyl-3- (4-trifluoromethoxy-phenyl) -1H-pyrazole

5-chloromethyl-1-methyl-3- (4-trifluoromethoxy-phenyl) -1H-pyrazole (3.2 g, 11 mmol; Example 19a) in acetone (56 ml) and sodium iodide (8.25 g, 55 mmol) ) Suspension was heated under reflux conditions for 30 minutes. Tertiary butyl methyl ether was added, the solids were filtered off and the filtrate was dried under reduced pressure. The residue was dissolved in tert butyl methyl ether, washed with ice water / brine 1/1 and the aqueous layer was extracted twice with tert butyl methyl ether. The combined extracts were washed with aqueous sodium thiosulfate solution and brine and dried over sodium sulfate. The solvent was removed under reduced pressure to give the title compound as a yellow oil which was used in the next step without further purification.

b) 3- [2-methyl-5- (4-trifluoromethoxy-phenyl) -2H-pyrazol-3-yl] -propionic acid ethyl ester

A solution of lithium diisopropylamide (16.5 ml of 2M solution in tetrahydrofuran / heptane / ethylbenzol, 33 mmol) in tetrahydrofuran (25 ml) was cooled to -78 ° C. A solution of ethyl acetate (3.77 ml, 38 mmol) in tetrahydrofuran (10 ml) was added within 30 minutes. The solution was stirred at −78 ° C. for 45 minutes, DMPU (6.63 ml, 55 mmol) was added within 20 minutes and the mixture was left at −78 ° C. for an additional 30 minutes. A solution of 5-iodomethyl-1-methyl-3- (4-trifluoromethoxy-phenyl) -1H-pyrazole (4.2 g, 11 mmol) in tetrahydrofuran (25 ml) was added within 20 minutes. The solution was stirred at −78 ° C. for 40 minutes, the cold bath was removed and stirring continued for 1 hour. The reaction mixture was poured into aqueous NH ₄ Cl / ice water and extracted twice with ethyl acetate. The combined extracts were washed three times with ice water / brine and dried over sodium sulfate. The orange oil obtained by removing the solvent under reduced pressure was purified by column chromatography (silica gel, heptane / AcOEt) to give 1.5 g (4.4 mmol, 40%) of the title compound as a yellow oil.

MS: 343.1 (M + H) ⁺ .

c) 3- [2-methyl-5- (4-trifluoromethoxy-phenyl) -2H-pyrazol-3-yl] -propan-1-ol

Similar to the process described in Example 1 a), 3- [2-methyl-5- (4-trifluoromethoxy-phenyl) -2H-pyrazol-3-yl] -propionic acid ethyl ester was converted to diethyl ether. Reduction with heavy lithium aluminum hydride gave 3- [2-methyl-5- (4-trifluoromethoxy-phenyl) -2H-pyrazol-3-yl] -propan-1-ol as a yellow oil.

MS: 300.2 (M) ⁺ .

d) (6- {3- [2-Methyl-5- (4-trifluoromethoxy-phenyl) -2H-pyrazol-3-yl] -propoxy} -indol-1-yl) -acetic acid ethyl ester

Similar to the process described in Example 3c), (6-hydroxy-indol-1-yl) -ethyl acetate (Example 2 e)) was added N, N, N ', N'-tetramethyl azo. Reacted with 3- [2-methyl-5- (4-trifluoromethoxy-phenyl) -2H-pyrazol-3-yl] -propan-1-ol in the presence of dicarboxamide and tributylphosphine Colorless (6- {3- [2-methyl-5- (4-trifluoromethoxy-phenyl) -2H-pyrazol-3-yl] -propoxy} -indol-1-yl) -acetic acid ethyl ester Obtained as an oil.

MS: 502.5 (M + H) ⁺ .

e) (6- {3- [2-Methyl-5- (4-trifluoromethoxy-phenyl) -2H-pyrazol-3-yl] -propoxy} -yndol-1-yl) -acetic acid

Similar to the process described in Example 1 f), (6- {3- [2-methyl-5- (4-trifluoromethoxy-phenyl) -2H-pyrazol-3-yl] -propoxy} -Indol-1-yl) -acetic acid ethyl ester was treated with LiOH (6- {3- [2-methyl-5- (4-trifluoromethoxy-phenyl) -2H-pyrazol-3-yl]- Propoxy} -indol-1-yl) -acetic acid was obtained as a yellow foam.

MS: 472.1 (MH) ^- .

Example 21

a) 5-chloromethyl-1- (2,2,2-trifluoro-ethyl) -3- (4-trifluoromethoxy-phenyl) -1H-pyrazole

Similar to the process described in Example 1 b), [2- (2,2,2-trifluoro-ethyl) -5- (4-trifluoromethoxy-phenyl) -2H-pyrazole-3- Il] -methanol (Example 15 b)) is reacted with thionyl chloride in chloroform to give 5-chloromethyl-1- (2,2,2-trifluoro-ethyl) -3- (4-trifluoromethoxy -Phenyl) -1H-pyrazole was obtained as a colorless oil.

MS: 359.0 (M + H) ⁺ .

b) [2- (2,2,2-Trifluoro-ethyl) -5- (4-trifluoromethoxy-phenyl) -2H-pyrazol-3-yl] -acetonitrile

Similar to the process described in Example 9 b), 5-chloromethyl-1- (2,2,2-trifluoro-ethyl) -3- (4-trifluoromethoxy-phenyl) -1H-pyra The sol is reacted with tetrabutylammonium cyanide in acetonitrile to give [2- (2,2,2-trifluoro-ethyl) -5- (4-trifluoromethoxy-phenyl) -2H-pyrazole-3 -Yl] -acetonitrile was obtained as a yellow oil.

MS: 350.3 (M + NH ₄ ) ⁺ .

c) [2- (2,2,2-Trifluoro-ethyl) -5- (4-trifluoromethoxy-phenyl) -2H-pyrazol-3-yl] -acetic acid

Similar to the process described in Example 9 c), [2- (2,2,2-trifluoro-ethyl) -5- (4-trifluoromethoxy-phenyl) -2H-pyrazole-3- Il] -acetonitrile was treated with sodium hydroxide in water / ethanol 1/1 at 85 ° C. to give [2- (2,2,2-trifluoro-ethyl) -5- (4-trifluoromethoxy-phenyl) -2H-pyrazol-3-yl] -acetic acid was obtained as brown crystals.

MS: 369.1 (M + H) ⁺ .

d) 2- [2- (2,2,2-trifluoro-ethyl) -5- (4-trifluoromethoxy-phenyl) -2H-pyrazol-3-yl] -ethanol

Similar to the process described in Example 9 c), [2- (2,2,2-trifluoro-ethyl) -5- (4-trifluoromethoxy-phenyl) -2H-pyrazole-3- Il] -acetic acid is reduced with a 1M solution of BH ₃ * THF in tetrahydrofuran to afford 2- [2- (2,2,2-trifluoro-ethyl) -5- (4-trifluoromethoxy-phenyl) -2H-pyrazol-3-yl] -ethanol was obtained as a colorless oil.

MS: 355.3 (M + H) ⁺ .

e) (6- {2- [2- (2,2,2-trifluoro-ethyl) -5- (4-trifluoromethoxy-phenyl) -2H-pyrazol-3-yl] -ethoxy } -Indol-1-yl) -acetic acid ethyl ester

Similar to the process described in Example 3c), (6-hydroxy-indol-1-yl) -ethyl acetate (Example 2 e)) was converted to di-tert-butyl azodicarboxylate and triphenyl Reaction with 2- [2- (2,2,2-trifluoro-ethyl) -5- (4-trifluoromethoxy-phenyl) -2H-pyrazol-3-yl] -ethanol in the presence of phosphine To (6- {2- [2- (2,2,2-trifluoro-ethyl) -5- (4-trifluoromethoxy-phenyl) -2H-pyrazol-3-yl] -ethoxy} -Indol-1-yl) -acetic acid ethyl ester was obtained as a colorless oil.

MS: 556.3 (M + H) ⁺ .

f) (6- {2- [2- (2,2,2-Trifluoro-ethyl) -5- (4-trifluoromethoxy-phenyl) -2H-pyrazol-3-yl] -ethoxy } -Indol-1-yl) -acetic acid

Similar to the process described in Example 1 f), (6- {2- [2- (2,2,2-trifluoro-ethyl) -5- (4-trifluoromethoxy-phenyl) -2H -Pyrazol-3-yl] -ethoxy} -indol-1-yl) -acetic acid ethyl ester was treated with LiOH (6- {2- [2- (2,2,2-trifluoro-ethyl) -5- (4-Trifluoromethoxy-phenyl) -2H-pyrazol-3-yl] -ethoxy} -indol-1-yl) -acetic acid was obtained as an off-white solid.

MS: 528.0 (M + H) ⁺ .

Example 22

a) racemic-2- {6- [2- (2,2,2-trifluoro-ethyl) -5- (4-trifluoromethoxy-phenyl) -2H-pyrazol-3-ylmethoxy] -Indol-1-yl} -ethyl propionate

Similar to the process described in Example 3 c), racemic-2- (6-hydroxy-indol-1-yl) -propionic acid ethyl ester (JED Barton, D. Cartwright (D. Cartwright), C. J. Mathews, GB 2253848 A1 (UK Patent Application No. 1992)), N, N, N ', N'-tetramethyl azodicarboxamide and tributylforce [2- (2,2,2-Trifluoro-ethyl) -5- (4-trifluoromethoxy-phenyl) -2H-pyrazol-3-yl] -methanol (Example 15 b) )) To react with racemic-2- {6- [2- (2,2,2-trifluoro-ethyl) -5- (4-trifluoromethoxy-phenyl) -2H-pyrazole-3- Ilmethoxy] -indol-1-yl} -propionic acid ethyl ester was obtained as a colorless oil.

MS: 556.5 (M + H) ⁺ .

b) racemic-2- {6- [2- (2,2,2-trifluoro-ethyl) -5- (4-trifluoromethoxy-phenyl) -2H-pyrazol-3-ylmethoxy] -Indol-1-yl} -propionic acid

Similar to the process described in Example 1 f), racemic-2- {6- [2- (2,2,2-trifluoro-ethyl) -5- (4-trifluoromethoxy-phenyl) -2H-pyrazol-3-ylmethoxy] -indol-1-yl} -propionic acid ethyl ester treated with LiOH to give racemic-2- {6- [2- (2,2,2-trifluoro-ethyl ) -5- (4-trifluoromethoxy-phenyl) -2H-pyrazol-3-ylmethoxy] -indol-1-yl} -propionic acid was obtained as a colorless foam.

MS: 528.3 (M + H) ⁺ .

Example 23

a) 2-difluoromethyl-5- (4-trifluoromethoxy-phenyl) -2H-pyrazole-3-carboxylic acid ethyl ester and 1-difluoromethyl-5- (4-trifluoromethoxy- Phenyl) -1H-pyrazole-3-carboxylic acid ethyl ester

Chlorodifluoromethane (28.6 g, 331 mmol) was added 5- (4-trifluoromethoxy-phenyl) -1H-pyrazole-3-carboxylic acid in 90 ° C. dry N, N-dimethylformamide (120 ml). It was introduced for 2 hours into a suspension of ethyl ester (2 g, 7 mmol; Example 11 b)) and anhydrous potassium carbonate (2.76 g, 20 mmol). After cooling, the mixture was poured into ice water (400 ml) and extracted four times with dichloromethane. The combined extracts were washed twice with ice water / brine and dried over sodium sulfate. The yellow solid obtained by removing the solvent under reduced pressure was purified by column chromatography (silica gel, heptane / AcOEt) to give 2-difluoromethyl-5- (4-trifluoromethoxy-phenyl) -2H-pyrazole-3- 281 mg (0.8 mmol, 12%) of carboxylic acid ethyl ester were obtained as a white solid and 1.29 g of 1-difluoromethyl-5- (4-trifluoromethoxy-phenyl) -1H-pyrazole-3-carboxylic acid ethyl ester 3.7 mmol, 55%) was obtained as a white solid.

2-Difluoromethyl-5- (4-trifluoromethoxy-phenyl) -2H-pyrazole-3-carboxylic acid ethyl ester: MS: 351.3 (M + H) ⁺ .

1-difluoromethyl-5- (4-trifluoromethoxy-phenyl) -1H-pyrazole-3-carboxylic acid ethyl ester: MS: 351.3 (M + H) ⁺ .

b) [2-Difluoromethyl-5- (4-trifluoromethoxy-phenyl) -2H-pyrazol-3-yl] -methanol

Similar to the process described in Example 1 a), 2-difluoromethyl-5- (4-trifluoromethoxy-phenyl) -2H-pyrazole-3-carboxylic acid ethyl ester is reduced with lithium aluminum hydride. To give [2-difluoromethyl-5- (4-trifluoromethoxy-phenyl) -2H-pyrazol-3-yl] -methanol as a white solid.

MS: 309.4 (M + H) ⁺ .

c) {6- [2-Difluoromethyl-5- (4-trifluoromethoxy-phenyl) -2H-pyrazol-3-ylmethoxy] -indol-1-yl} -acetic acid ethyl ester

Similar to the process described in Example 3c), (6-hydroxy-indol-1-yl) -ethyl acetate (Example 2 e)) was added N, N, N ', N'-tetramethyl azo. Reacted with [2-difluoromethyl-5- (4-trifluoromethoxy-phenyl) -2H-pyrazol-3-yl] -methanol in the presence of dicarboxamide and tributylphosphine {6- [2-Difluoromethyl-5- (4-trifluoromethoxy-phenyl) -2H-pyrazol-3-ylmethoxy] -indol-1-yl} -acetic acid ethyl ester was obtained as a white solid.

MS: 510.6 (M + H) ⁺ .

d) {6- [2-Difluoromethyl-5- (4-trifluoromethoxy-phenyl) -2H-pyrazol-3-ylmethoxy] -indol-1-yl} -acetic acid

Similar to the process described in example 1 f), {6- [2-difluoromethyl-5- (4-trifluoromethoxy-phenyl) -2H-pyrazol-3-ylmethoxy] -indole- 1-yl} -acetic acid ethyl ester was treated with LiOH to give {6- [2-difluoromethyl-5- (4-trifluoromethoxy-phenyl) -2H-pyrazol-3-ylmethoxy] -indole- 1-yl} -acetic acid was obtained as colorless crystals.

MS: 482.5 (M + H) ⁺ .

Example 24

a) racemic-2- {6- [2-methyl-5- (4-trifluoromethoxy-phenyl) -2H-pyrazol-3-ylmethoxy] -indol-1-yl} -propionic acid ethyl ester

Similar to the process described in Example 3 c), racemic-2- (6-hydroxy-indol-1-yl) -propionic acid ethyl ester (JED Barton, D. Cartwright (D. Cartwright), C. J. Mathews, GB 2253848 A1 (UK Patent Application No. 1992)), N, N, N ', N'-tetramethyl azodicarboxamide and tributylforce Racemic-2- {6 by reaction with [2-methyl-5- (4-trifluoromethoxy-phenyl) -2H-pyrazol-3-yl] -methanol (Example 11 d)) in the presence of a pin -[2-Methyl-5- (4-trifluoromethoxy-phenyl) -2H-pyrazol-3-ylmethoxy] -indol-1-yl} -propionic acid ethyl ester was obtained as a colorless oil.

MS: 488.5 (M + H) ⁺ .

b) racemic-2- {6- [2-methyl-5- (4-trifluoromethoxy-phenyl) -2H-pyrazol-3-ylmethoxy] -indol-1-yl} -propionic acid

Similar to the process described in Example 1 f), racemic-2- {6- [2-methyl-5- (4-trifluoromethoxy-phenyl) -2H-pyrazol-3-ylmethoxy]- Indol-1-yl} -propionic acid ethyl ester was treated with LiOH to give racemic-2- {6- [2-methyl-5- (4-trifluoromethoxy-phenyl) -2H-pyrazol-3-ylmethoxy ] -Indol-1-yl} -propionic acid was obtained as off-white crystals.

MS: 460.4 (M + H) ⁺ .

Example 25

a) 5-iodomethyl-1-methyl-3- (4-trifluoromethyl-phenyl) -1H-pyrazole

Similar to the process described in Example 20a), 5-chloromethyl-1-methyl-3- (4-trifluoromethyl-phenyl) -1H-pyrazole (Example 9a)) is iodide in acetone Treatment with sodium yielded 5-iodomethyl-1-methyl-3- (4-trifluoromethyl-phenyl) -1H-pyrazole as a yellow replacement and used in the next step without further purification.

b) 3- [2-methyl-5- (4-trifluoromethyl-phenyl) -2H-pyrazol-3-yl] -propionic acid ethyl ester

Similar to the process described in Example 20 b), 5-iodomethyl-1-methyl-3- (4-trifluoromethyl-phenyl) -1H-pyrazole was present in the presence of lithium diisopropylamide and DMPU. Reaction with ethyl acetate to afford 3- [2-methyl-5- (4-trifluoromethyl-phenyl) -2H-pyrazol-3-yl] -propionic acid ethyl ester as a yellow solid.

MS: 327.3 (M + H) ⁺ .

c) 3- [2-methyl-5- (4-trifluoromethyl-phenyl) -2H-pyrazol-3-yl] -propan-1-ol

Similar to the process described in Example 1 a), 3- [2-methyl-5- (4-trifluoromethyl-phenyl) -2H-pyrazol-3-yl] -propionic acid ethyl ester was converted to diethyl ether. Reduction with heavy lithium aluminum hydride gave 3- [2-methyl-5- (4-trifluoromethyl-phenyl) -2H-pyrazol-3-yl] -propan-1-ol as a yellow oil.

MS: 285.1 (M + H) ⁺ .

d) (6- {3- [2-Methyl-5- (4-trifluoromethyl-phenyl) -2H-pyrazol-3-yl] -propoxy} -indol-1-yl) -acetic acid ethyl ester

Similar to the process described in Example 3c), (6-hydroxy-indol-1-yl) -ethyl acetate (Example 2 e)) was added N, N, N ', N'-tetramethyl azo. Reacted with 3- [2-methyl-5- (4-trifluoromethyl-phenyl) -2H-pyrazol-3-yl] -propan-1-ol in the presence of dicarboxamide and tributylphosphine Colorless (6- {3- [2-methyl-5- (4-trifluoromethyl-phenyl) -2H-pyrazol-3-yl] -propoxy} -indol-1-yl) -acetic acid ethyl ester Obtained as an oil.

MS: 486.5 (M + H) ⁺ .

e) (6- {3- [2-Methyl-5- (4-trifluoromethyl-phenyl) -2H-pyrazol-3-yl] -propoxy} -indol-1-yl) -acetic acid

Similar to the process described in Example 1 f), (6- {3- [2-methyl-5- (4-trifluoromethyl-phenyl) -2H-pyrazol-3-yl] -propoxy} Indol-1-yl) -acetic acid ethyl ester was treated with LiOH to give (6- {3- [2-methyl-5- (4-trifluoromethyl-phenyl) -2H-pyrazol-3-yl]- Propoxy} -indol-1-yl) -acetic acid was obtained as colorless crystals.

MS: 458.5 (M + H) ⁺ .

Example A

Film coated tablets of the following composition were prepared in a conventional manner:

The active ingredient was sieved and mixed with microcrystalline cellulose and the mixture was granulated with aqueous polyvinylpyrrolidine solution. The granules were mixed with sodium starch glycolate and magnesium stearate and compressed to yield 120 or 350 mg of contents, respectively. The contents were coated with the aqueous solution / suspension of the coating.

Example B

Capsules of the following composition were prepared in a conventional manner:

The ingredients were sieved and mixed to fill a size 2 capsule.

Example C

Injection solutions may have the following composition:

Example  D

Soft gelatin capsules having the following composition were prepared in a conventional manner:

The active ingredient was dissolved in a warm melt of the other ingredients and the mixture was filled into soft gelatin capsules of appropriate size. Filled soft gelatin capsules were treated according to conventional procedures.

Example E

Sachets of the following composition were prepared in a conventional manner:

The active ingredient was mixed with lactose, microcrystalline cellulose and sodium carboxymethyl cellulose and granulated with a mixture of polyvinylpyrrolidone in water. The granules were mixed with magnesium stearate and the additive and filled into sachets.

Claims (31)

A compound of formula (I) or a pharmaceutically acceptable salt thereof: Formula I

Where R ¹ is hydrogen or C _1-7 -alkyl; R ² and R ³ are independently of each other hydrogen, C _1-7 -alkyl or C _1-7 -alkoxy; R ⁴ and R ⁵ independently of one another are hydrogen, C _1-7 -alkyl, C _3-7 -cycloalkyl, halogen, C _1-7 -alkoxy-C _1-7 -alkyl, C _2-7 -alkenyl, C _2-7 -alkynyl, fluoro-C _1-7 -alkyl, cyano-C _1-7 -alkyl or cyano; R ⁶ , R ⁷ , R ⁸ and R ⁹ independently of one another are hydrogen, C _1-7 -alkyl, C _3-7 -cycloalkyl, halogen, C _1-7 -alkoxy-C _1-7 -alkyl, C _{2 -7} -alkenyl, C _2-7 -alkynyl, fluoro-C _1-7 -alkyl, cyano-C _1-7 -alkyl or cyano; One of R ⁶ , R ⁷ and R ⁸

ego, Then R ¹⁰ is hydrogen, C _1-7 -alkyl, C _3-7 -cycloalkyl or fluoro-C _1-7 -alkyl; R ¹¹ is hydrogen, C _1-7 -alkyl or C _1-7 -alkoxy-C _1-7 -alkyl; One of R ¹² or R ¹³ is hydrogen, C _1-7 -alkyl, C _3-7 -cycloalkyl, C _2-7 -alkoxy-C _1-7 -alkyl, C _2-7 -alkenyl, C _{2- 7} -alkynyl or fluor-C _1-7 -alkyl; The other is an isolation pair; R ¹⁴ is hydrogen, C _1-7 -alkyl, C _3-7 -cycloalkyl, halogen, C _1-7 -alkoxy-C _1-7 -alkyl, C _2-7 -alkenyl, C _2-7 -alky Nil or fluoro-Ci_ ₇ -alkyl; R ¹⁵ is aryl or heteroaryl; n is 1, 2 or 3. The method of claim 1, A compound of formula (I) or a pharmaceutically acceptable salt thereof, having the formula (I-A) Formula I-A

Where R ¹ to R ⁵ , R ¹⁰ to R ¹⁵ and n are as defined in claim 1; R ⁶ , R ⁷ and R ⁹ independently of one another are hydrogen, C _1-7 -alkyl, C _3-7 -cycloalkyl, halogen, C _1-7 -alkoxy-C _1-7 -alkyl, C _2-7- Alkenyl, C _2-7 -alkynyl, fluoro-C _1-7 -alkyl, cyano-C _1-7 -alkyl or cyano. The method of claim 2, A compound of formula (IA) or a pharmaceutically acceptable salt thereof, wherein R ⁶ , R ⁷ and R ⁹ are hydrogen. The method of claim 1, A compound of formula (I) or a pharmaceutically acceptable salt thereof, having the formula (I-B) Formula I-B

Where R ¹ to R ⁵ , R ¹⁰ to R ¹⁵ and n are as defined in claim 1; R ⁶ , R ⁸ and R ⁹ independently of one another are hydrogen, C _1-7 -alkyl, C _3-7 -cycloalkyl, halogen, C _1-7 -alkoxy-C _1-7 -alkyl, C _2-7- Alkenyl, C _2-7 -alkynyl, fluoro-C _1-7 -alkyl, cyano-C _1-7 -alkyl or cyano. The method of claim 4, wherein A compound of formula (IB) or a pharmaceutically acceptable salt thereof, wherein R ⁶ , R ⁸ and R ⁹ are hydrogen. The method of claim 1, A compound of formula (I) or a pharmaceutically acceptable salt thereof, having the formula Formula I-C

Where R ¹ to R ⁵ , R ¹⁰ to R ¹⁵ and n are as defined in claim 1; R ⁷ , R ⁸ and R ⁹ independently of one another are hydrogen, C _1-7 -alkyl, C _3-7 -cycloalkyl, halogen, C _1-7 -alkoxy-C _1-7 -alkyl, C _2-7- Alkenyl, C _2-7 -alkynyl, fluoro-C _1-7 -alkyl, cyano-C _1-7 -alkyl or cyano. The method of claim 6, A compound of formula (IC) or a pharmaceutically acceptable salt thereof, wherein R ⁷ , R ⁸ and R ⁹ are hydrogen. The method of claim 1, A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R ¹ is hydrogen. The method of claim 1, A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R ² and R ³ are independently of each other hydrogen or methyl. The method of claim 1, A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein at least one R ² and R ³ is methyl. The method of claim 1, A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R ⁴ is hydrogen. The method of claim 1, A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R ⁵ is hydrogen, C _1-7 -alkyl or halogen. The method of claim 1, A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein n is 1 or 2. The method of claim 1, or a pharmaceutically acceptable salt thereof. The method of claim 1, R ⁶ , R ⁷ and R ⁸ are

ego; Or a pharmaceutically acceptable salt thereof, wherein R ¹⁰ to R ¹² , R ¹⁴ , R ¹⁵ and n are as defined in claim 1; The method of claim 15, A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R ¹² is C _1-7 -alkyl or fluoro-C _1-7 -alkyl. The method of claim 1, R ¹⁵ is unsubstituted phenyl or ₁ selected from C _1-7 -alkyl, C _1-7 -alkoxy, halogen, fluoro-C _1-7 -alkyl, fluoro-C _1-7 -alkoxy and cyano Or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is phenyl substituted with from to 3 groups; The method of claim 1, Or a pharmaceutically acceptable salt thereof, wherein R ¹⁵ is phenyl substituted with halogen, fluoro-C _1-7 -alkyl or fluoro-C _1-7 -alkoxy. The method of claim 1, A compound of formula (I) or a pharmaceutically acceptable salt thereof, selected from the group consisting of: {6- [2-Methyl-5- (4-fluoromethyl-phenyl) -2H-pyrazol-3-ylmethoxy] -indol-1-yl} -acetic acid, (5- {2- [2-Methyl-5- (4-trifluoromethyl-phenyl) -2H-pyrazol-3-yl] -ethoxy} -indol-1-yl) -acetic acid, {6- [2,4-Dimethyl-5- (4-trifluoromethyl-phenyl) -2H-pyrazol-3-ylmethoxy] -indol-1-yl} -acetic acid, {6- [2-Methyl-5- (4-trifluoromethoxy-phenyl) -2H-pyrazol-3-ylmethoxy] -indol-1-yl} -acetic acid, {6- [2- (2,2,2-Trifluoro-ethyl) -5- (4-trifluoromethyl-phenyl) -2H-pyrazol-3-ylmethoxy] -indol-1-yl} Acetic acid, (6- {2- [2-Methyl-5- (4-trifluoromethoxy-phenyl) -2H-pyrazol-3-yl] -ethoxy} -indol-1-yl) -acetic acid, (6- {3- [2-Methyl-5- (4-trifluoromethoxy-phenyl) -2H-pyrazol-3-yl] -propoxy} -indol-1-yl) -acetic acid, {6- [2-Difluoromethyl-5- (4-trifluoromethoxy-phenyl) -2H-pyrazol-3-ylmethoxy] -indol-1-yl} -acetic acid and (6- {3- [2-Methyl-5- (4-trifluoromethyl-phenyl) -2H-pyrazol-3-yl] -propoxy} -indol-1-yl) -acetic acid. The method of claim 1, A compound of formula (I) or a pharmaceutically acceptable salt thereof, selected from the group consisting of: {6- [2-Methyl-5- (4-trifluoromethoxy-phenyl) -2H-pyrazol-3-ylmethoxy] -indol-1-yl} -acetic acid, {6- [2- (2,2,2-Trifluoro-ethyl) -5- (4-trifluoromethyl-phenyl) -2H-pyrazol-3-ylmethoxy] -indol-1-yl} Acetic acid, (6- {3- [2-Methyl-5- (4-trifluoromethoxy-phenyl) -2H-pyrazol-3-yl] -propoxy} -indol-1-yl) -acetic acid and (6- {3- [2-Methyl-5- (4-trifluoromethoxy-phenyl) -2H-pyrazol-3-yl] -propoxy} -indol-1-yl) -acetic acid. (a) reacting a compound of formula II with a compound of formula III to yield a compound of formula I, optionally hydrolyzing an ester group to obtain a compound of formula I wherein R ¹ is hydrogen; Or otherwise (b) reacting a compound of formula IV with a compound of formula V to yield a compound of formula I, optionally hydrolyzing an ester group to yield a compound of formula I wherein R ¹ is hydrogen A method for preparing a compound according to any one of claims 1 to 20, comprising: Formula II

[Wherein, R ¹ is C _1-7 -alkyl; R ² , R ³ , R ⁴ and R ⁵ are as defined in claim 1; R ⁶ , R ⁷ , R ⁸ and R ⁹ are hydrogen, C _1-7 -alkyl, C _3-7 -cycloalkyl, halogen, C _1-7 -alkoxy-C _1-7 -alkyl, C _2-7- Alkenyl, C _2-7 -alkynyl, fluoro-C _1-7 -alkyl, cyano-C _1-7 -alkyl and cyano, provided that R ⁶ , R ⁷ or R ⁸ One is -OH] Formula III

[Wherein, X, Y, R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ and n are as defined in claim 1; R ¹⁶ is —OH, —Cl, —Br, —I or another leaving group] Formula I

[Wherein, R ¹ is C _1-7 -alkyl; R ² to R ⁹ are as defined in claim 1] Formula IV

[Wherein, R ⁴ to R ⁹ are as defined in claim 1] Formula V

[Wherein, R ¹ is C _1-7 -alkyl; R ² and R ³ are as defined in claim 1; R ¹⁷ is halogen, triflate or another leaving group] The method according to any one of claims 1 to 20, A compound prepared by the method according to claim 21. Diabetes, non-insulin dependent diabetes mellitus, increased lipid and cholesterol levels, atherosclerosis disease, metabolism, comprising the compound according to any one of claims 1 to 20 and a pharmaceutically acceptable carrier and / or adjuvant Pharmaceutical composition for the treatment or prevention of syndrome (syndrome X), obesity, elevated blood pressure, endothelial dysfunction, coagulation state, dyslipidemia, polycystic ovary syndrome, inflammatory disease or proliferative disease. delete The method according to any one of claims 1 to 20, Compounds for use as therapeutically active substances. The method according to any one of claims 1 to 20, A compound for use as a therapeutically active substance for the treatment or prevention of a disease regulated by a PPARδ or PPARα agonist. A method for treating or preventing a disease regulated by a PPARδ or PPARα agonist, comprising administering a compound according to any one of claims 1 to 20 to an animal other than a human. delete delete The method of claim 23, A pharmaceutical composition for the treatment or prevention of elevated lipid and cholesterol levels, or metabolic syndrome (syndrome X), selected from the group consisting of low HDL-cholesterol levels, high LDL-cholesterol levels and high triglyceride levels. delete