MXPA06010225A - Oxadiazolone derivatives as ppar delta agonists - Google Patents
Oxadiazolone derivatives as ppar delta agonistsInfo
- Publication number
- MXPA06010225A MXPA06010225A MXPA/A/2006/010225A MXPA06010225A MXPA06010225A MX PA06010225 A MXPA06010225 A MX PA06010225A MX PA06010225 A MXPA06010225 A MX PA06010225A MX PA06010225 A MXPA06010225 A MX PA06010225A
- Authority
- MX
- Mexico
- Prior art keywords
- phenyl
- compounds
- formula
- alkylene
- alkyl
- Prior art date
Links
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Abstract
The invention relates to oxadiazolones and to their physiologically acceptable salts and physiologically functional derivatives showing PPAR delta agonist activity. What is described are compounds of the formula (I) in which the radicals are as defined, and their physiologically acceptable salts and processes for their preparations. The compounds are suitable for the treatment and/or prevention of disorders of fatty acid metabolism and glucose utilization disorders as well as of disorders in which insulin resistance is involved;neurodegenerative diseases and/or demyelinating disorders of the central and peripheral nervous systems and/or neurological diseases involving neuroinflammatory processes and/or other peripheral neuropathies.
Description
DERIVATIVES OF OXADIAZOLONA AS AGONISTS OF PPAR DELTA
The invention relates to oxadiazolones and their physiologically acceptable salts and physiologically functional derivatives which exhibit PPAR-delta agonist activity.
PPAR-delia agonists have been considered in the prior art (eg WO 03/043997, WO 01/00603 and WO 02/092590). Compounds comprising a characteristic oxadiazolone as inhibitors of factor Xa were described in DE 10112768 A1, and hypoglycemic agents in WO 96/13264.
The invention is based on the objective of providing compounds that allow the lepraeulic use of the modulation of the lipid and / or carbohydrates metabolism, and are therefore suitable for preventing and / or bringing about diseases such as type 2 diabetes and Atherosclerosis and its various sequelae. Another purpose of the invention is to bring neurodegenerative diseases and / or demyelinating disorders of the central and peripheral nervous systems and / or neurological diseases that involve neuroinflammatory processes and / or hear peripheral neuropalias.
A series of compounds has been found that modulate the activity of PPA receptors. The compounds are suitable, in particular, to activate the PPAR-delta and PPAR-alpha, however the degree of relative activation may vary depending on the compounds.
The compounds of the present invention are described with the formula I:
formula in which
X is CH2 or a bond;
R1, R2, R3, R4 are independently H, F, Cl, Br, CF3, (C1-C4) alkyl, (C0-C4) alkylene-O-alkylene (C0-C4) -H, SCH3, S (O) CH3, S (O) 2CH3, CN, OCF3, OCHF2, OCH2F;
it is a bond or CH2;
And it is O, S, S (O) or S (O) 2;
W is CH2 or CH2CH2;
one of U and V is N, the other is S or O;
R5 is selected from the group consisting of (C1-C8) alkyl, alk (C1-C6) -O-alkylene (C0-C4) -H, (C0-C6) alkylene-phenyl, alkylene (C1-C6) ) -O- (C0-C4) alkylene-phenylene, (C3-C6) cycloalkyl, (C2-C8) alkenyl, and wherein the alkyl or (C1-C8) alkylene can be substituted 1-2 times with OH or O- (C 1 -C 4) alkyl;
R6, R7 are independently H, F, Br, CF3, OCF3, (C1-C6) alkyl, (C0-C4) alkylene-Oa! Quylene (C0-C4) -H, SCF3, SF5, OCF2-CHF2, OCHF2, OCH2F, O-phenyl, phenyl, NO2; or
thus, its physiologically acceptable salts and physiological forms are incorporated.
Another embodiment of this invention is a compound of formula I wherein X is a bond.
Another embodiment of this invention is a compound of formula I in which one or more substituents have the following meaning:
U is S and V is N or U is N and V is S or u is O and V is N or u is N and V is O; and / or U is S, V is N, z is a bond; and / or U is N, V is O, Z is a bond, X is a bond; and / or X is a link, z is a link; and / or R6 is in the para position; and / or R7 is H or F, preferably H;
and / or R2, R3, R4 are H, R1 is H, F, Cl, Br, CF3, (C1-C4) alkyl, (C0-C4) alkylene-O-alkylene (C0-C4) -H, SCH3, S (O) CH3, S (O) 2CH3, CN; and / or Y is O u S, preferably O; and / or W is CH2 and / or R5 is (C1-C4) alkyl, (C1-C4) alkylene-O-alkylene (C0-C4) -H or alkylene (C1-C4) -O-alkylan (C0-C4) ) -phenyl, wherein alkylene can be substituted by O-alkylan (C0-C4) -H.
Another embodiment of this invention is a compound of formula I wherein X is a bond or CH2, preferably a bond;
R1 is H, F, Cl, Br, CF3, (C1-C4) alkyl, O-C1-C4 alkyl, SCH3, S (O) CH3, S (O) 2CH3, CN;
R2 is H, F;
R3 is H, Br, O-(C1-C4) alkyl;
R4 is H;
Z is a bond or CH2, preferably a bond;
And it is O, S, S (0) or S (O) 2; preferably O;
W is CH2 or CH2CH2, preferably CH2;
U is S and V is N or U is N and V is S or U is N and V is O;
R5 is (C1-C6) alkyl or (C2-C6) alkenyl, where the (C1-C6) alkyl may be substituted 1 or 2 times with OH;
R6 is in position for and is CF3, SF5, OCH3, phenyl;
R7 is H or F.
Another embodiment of this invention is a compound of formula I wherein X is a bond;
R1 is Cl or CH3;
R2, R3, R4 are H;
it is a link;
Cast;
w is CH2;
- u is S and V is N or u is N and V is O u u is O and V is N;
R 5 is (C 1 -C 4) alkylene-O-(C 1 -C 4) alkylene -H, preferably CH 2 -O- (C 1 -C 3) alkylene -H, or (C 1 -C 4) alkylene-O-alkylene (C 1 -C 4) -phenyl, wherein alkylene can be substituted by O-C 1 -C 4 alkyl, preferably methoxy or ethoxy;
R6 is in position for and CF3 or OCH3;
R7 is H.
Another embodiment of this invention is a compound of formula I in which
R1, R2 are independently H, F, Cl, Br, OCH3, SCH3, CF3, CH3,
CN, S (O) CH 3, S (O) 2 CH 3;
X is a link and Z is a link; or X is CH2, Z is a bond and W is CH2; or X is a bond and W is CH2;
R3, R4 are independently H, OCH3;
R6 is in position for and is H, F, CF3, CH3, SF5, OCH3, phenyl;
R7 is H. Another embodiment of this invention is a compound of formula I wherein
X is a link; R1 is OCH3 or F; R2, R3, R4 are H; it is a link; And it is O or S; W is CH2 or CH2CH2;
u is S and V is N or u is N and V is S or u is O and V is N or U is N and V is O;
R5 is (C1-C4) alkyl, (C1-C4) alkylene-O-(C1-C4) alkylene, or a (C1-C4) -O-(C1-C4) alkylene-phenyl ester, wherein alkylene may be replaced by
O-C 1 -C 4 alkyl.
R6 is in position for and is CF3 or OCH3;
R7 is H.
Another embodiment of this invention is a compound of formula I in which
X is a bond or CH2;
R1 is H, F, Cl, Br, OCH3, SCH3, CF3, CH3, CN, S (O) CH3, S (O) 2CH3;
R2 is H, F;
R3 is H, OCH3, Br;
R4 is H;
Z is a bond or CH2;
And it is O, S, S (O) or S (O) 2;
W is CH2 or CH2CH2;
U is S and V is N or U is N and V is S;
R5 is (C1-C4) alkyl or (C2-C4) alkenyl, where the (C1-C4) alkyl may be substituted 1-2 times with OH, eg CH2CH2CH (OH) CH2OH or
CH2CH2CH2CH2OH or R5 is (C1-C4) alkylene-O-alkylene (C1-C4) -H or (C1-C4) alkylene-O- (C1-C4) alkylene-phenyl, where alkylene may be substituted by O-a! (C 1 -C 4) alkyl, preferably methoxy or ethoxy; R6 is p-CF3 or p-SF5; Y
R7 is H.
Another embodiment of this invention is a compound of formula I wherein X is a bond;
R1 is Cl, CH3;
R2 is H;
R3 is H;
R4 is H;
it is a link;
Cast;
W is CH2;
U is N and V is O u U is O and V is N;
R5 is (C1-C4) alkyl, (C1-C4) alkylene-O-(C1-C4) alkylene-H or! (C1-C4) -O-alkylene (C1-C4) -phenyl ester, wherein alkylene may be substituted by O-alkylene (C1-C4), preferably methoxy or ethoxy.
R6 is p-OCH3 or p-phenyl; Y
R7 is H.
Another form of this invention is a compound of formula I in which
R1 is F, Cl, CH3, OCH3, preferably F, Cl.
Another aspect of this invention is a compound of formula I in which
R5 is (C1-C4) alkyl.
Another embodiment of this invention is a compound of formula I in which
R6 is CF3, SF5, phenyl, OCH3, preferably CF3.
The most preferred compounds are:
3-. { 2-Fluoro-4- [4-methyI-2- (4-trifluoromethyl-1-phenyl) -thiazo-5-ylmethoxy] -phenyl} -4H- [1, 2,4] oxadiazol-5-one 3-. { 4- [4-Met.l-2- (4-trifluoromethyl-phenyl) -thiazol-5-ylmeyoxy] -pheni} -4H- [1, 2,4] oxadiazol-5-one
3-. { 3-Methoxy-4- [4-methyl-2- (4-ylfluoromethyl-phenyl) -thiazo-5-ylmethoxy] -phenyl} -4H- [1, 2,4] oxadiazol-5-one
3-. { 2-Chloro-4- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-ylmethoxy] -phenyl} -4H- [1, 2,4] oxadiazol-5-one
3-. { 4- [4-Methyl-2- (4-trifluoromethyl-phenyl) -yiazol-5-ylmelylsulfanyl] -phenyl} -4H- [1, 2,4] oxadiazol-5-one
3-. { 4- [4-Buyyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-ylmethoxy] -2-chloro-phenyl} -4H- [1, 2,4] oxadiazol-5-one
3-. { 4- [4-Butyl-2- (4-pentafluorosulfanyl-phenyl) -thiazol-5-ylmethoxy] -2-chloro-phenyl} -4H- [1, 2,4] oxadiazol-5-one
3-. { 2-Chloro-4- [4-methyl-2- (4-penlafluorosu-phanyl-phenyl) -iazol-5-ylmeyoxy] -phenyl} -4H- [1, 2,4] oxadiazoI-5-one
3- (4- { 2- [4-ButiI-2- (4-ylfluoromethyl-phenyI) -iazole-5-yl] -eloxy} -2-chloro-phenyl) -4H- [1, 2 , 43 -oxadiazol-5-one 3-. { 4- [4-Butyl-2- (4-ylfluoromethyl-phenyl) -thiazol-5-ylmethoxy] -2-chloro-benzyl} -4 - [1, 2,4] oxadiazol-5-one
3-. { 2-Methoxy-4- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-ylmethoxy] -phenyl} -4H- [1, 2,4] oxadiazol-5-one
3-. { 4- [4-Butyl-2- (4-trifluoromethyl-phenyl) -iazol-5-ylmethoxy] -2-fluoro-phenyl} -4H- [1, 2,4] oxadiazoI-5-one
3. . { 4- [4-Butyl-2- (4-ylfluoromethyl] -phenyl) -thiazol-5-ylmethoxy] -2,6-difluoro-phenyl} -4H- [1, 2,4] oxadiazol-5-one
3-. { 4- [4-Butyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-ylmethylsulfanyl] -phenyl} -4H- [1, 2,4] oxadiazol-5-one
3-. { 4- [4-Butyl-2- (4-ylfluoromethyl-phenyl) -thiazol-5-ylmethoxy] -2-trifluoromethyl-phenyl} -4r - [1, 2,4] oxadiazoI-5-one
3-. { 4- [4-Butyl-2- (4-trifluoromethyl-phenyl] -thiazol-5-ylmethoxy] -2-methyl-phenyl} -4H- [1, 2,4] oxadiazol-5-one
3-. { 2-.Bromo-4- [4-butyl-2- (4-trifluoromethyl-phenyl) -thiazole-5-ylmethoxy] -pheni} -4 - / - [1, 2,4] oxadiazol-5-one
3-. { 4- [4-Butyl-2- (4-trifluoromethyl-phenyl) -thiazoI-5-ylmethyloxy] -2-methoxy-phenyl} -4H- [1, 2,4] oxadiazol-5-one
3-. { 4- [4-But-3-enyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-ylmeyoxy] -2-chloro-phenyl} -4H- [1, 2,4] oxadiazoI-5-one 3-. { 2-Chloro-4- [4- (4-hydroxybutyl) -2- (4-trifluoromethyl-phenyl) -thiazol-5-ylmethoxy] -phenyl} -4H- [1, 2,4] oxadiazoI-5-one
3-. { 2-Chloro-4- [4- (3,4-dihydroxy-butyl) -2- (4-trifluoromethyl-phenyl) -thiazol-5-ylmethoxy] -pheni} -4 - / - [1,2,4] oxadiazol-5-one
- [4-Butyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-ylmethoxy] -2- (5-oxo-4,5-dihydro- [1, 2,4] oxadiazol-3-yl) -benzonitrile
3-. { 4- [4-Butyl-2- (4-trifluoromethyl-phenyl) -thiazole-5-ylmethoxy] -2-methylsulfanyl-phenyl} -4H- [1, 2,4] oxadiazol-5-one
3-. { 4- [4-Butyl-2- (4-trifluoromethyl-phenyl) -liazol-5-ylmethoxy] -2-methylsulfinyl-phenyl} -4H- [1, 2,4] oxadiazol-5-one
3-. { 4- [4-Butyl-2- (4-ylfluoromethyl-phenyl) -thiazol-5-ylmethoxy] -2-methanesulfonyl-phenyl} - 4H- [1, 2,4] oxadiazol-5-one
3-. { 4- [4-Builyl 2- (4-trifluoromethyl-phenyl) -thiazol-5-ylmethanesulfinyl] -pheni} -4 - [1, 2,4] oxadiazol-5-one
3-. { 4- [4-ButiI-2- (4-trifluoromethyl-phenyl) -thiazol-5-ylmethylsulfonyl] -phenyl} -4A - [1, 2,4] oxadiazol-5-one
3-. { 4- [4-Buiyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-ylmeoxymethyl] -2-fluoro-phenyl} -4H- [1, 2,4] oxadiazol-5-one
3-. { 4- [4-Methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-ylmethoxymethyl] -phenyl} -4H- [1, 2,4] oxadiazol-5-one
3- [4- (2-Biphenyl-4-yl-5-yl-oxazol-4-yl-loxy) -2-cioro-phenyl] -4 - / - [1,4] oxadiazoI-5-one
3-. { 2-Chloro-4- [2- (4-meioxy-phenyl) -5-methyl-oxazoI-4-ylmeyoxy] -pheni} -4 - / - [1, 2,4] oxadiazol-5-one
3- (2-Chloro-4-. {-2- [5-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-4-yl] -ioxy}. Phenyl) -4r - [1, 2 , 4] oxadiazol-5-one 3-. { 2-Chloro-4- [4-methoxymethyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-ylmethoxy] -phenyl} -4H- [1, 2,43-oxadiazol-5-one
3-. { 2-Chloro-4- [4- (2-methoxy-efioxymethyl) -2- (4-trifluoromethyl-phenyl) -thiazol-5-ylmethoxy] -phenyl} -4f / - [1, 2,4] oxadiazol-5-one
3-. { 2-Chloro-4- [4- (2-ethoxy-ethoxymethyl) -2- (4-trifluoromethyl-phenyl) -thiazol-5-ylmethoxy] -phenyl} -4H- [1, 2,4] oxadiazol-5-one
3-. { 2-Chloro-4- [4- (3-methoxy-propoxymethyl) -2- (4-l-trifluoromethyi-phenyl) -thiazol-5-ylmethoxy] -phenyl} -4H- [1, 2,4] oxadiazol-5-one
3-. { 4- [5-Methoxymethyl-2- (4-meioxy-phenyl) -oxazol-4-ylmeyoxy] -2-mephi-phenyl} -4 / V- [1, 2,4] oxadiazoI-5-one
3-. { 4- [5- (2-Methoxy-ethoxymethyl) -2- (4-meioxy-phenyl) -oxazol-4-ylmeyoxy] -2-meityl-phenyl} -4H- [1, 2,4] oxadiazoI-5-one
3-. { 4- [4-Methoxymethyl-2- (4-methoxy-phenyl] -oxazol-5-ylmethoxy] -2-methyl-phenyl} -4H- [1,2,4] oxadiazol-5-one
3-. { 4- [4- (2-Methoxy-eioxymethyl) -2- (4-meloxy-phenyl) -oxazol-5-ylmethoxy] -2-methyl-phenyl} -4H- [1, 2,4] oxadiazol-5-one 3-. { 4- [4- (2-Eioxy-eloximeiii) -2- (4-meioxy-phenyl) -oxazol-5-ylmeloxy] -2-meityl-phenyl} -4H- [1, 2,4] oxadiazol-5-one
3-. { 4- [2- (4-Meioxy-phenyI) -4- (3-methoxy-propoxymethyl) -oxazol-5-ylmeyoxy] -2-meityl-phenyl} -4H- [1, 2,4] oxadiazoI-5-one
3-. { 4- [4-Eioxymethyl-2- (4-meioxy-phenyl) -oxazol-5-ylmeyoxy] -2-meityl-phenyl} -4H- [1, 2,4] oxadiazol-5-one
3-. { 4- [4-Benzyloxymethyl-2- (4-meioxy-phenyl) -oxazol-5-imethoxy] -2-methyl-phenyl} -4ry- [1, 2,4] oxadiazoI-5-one
3-. { 2-Chloro-4- [5-methoxymethyl-2- (4-methoxy-phenyl) -oxazoI-4-ylmethoxy] -phenyl} -4 / - ('- [1, 2,4] oxadiazol-5-one
3-. { 2-Chloro-4- [5- (2-methoxy-ethoxymethyl) -2- (4-meloxy-phenyl) -oxazoI-4-ylmethoxy] -phenyl} -4A - [1, 2,4] oxadiazol-5-one
3-. { 2-Chloro-4- [4-meloxymethyl-2- (4-meioxy-phenyl) -oxazol-5-ylmethoxy] -phenyl} -4r7- [1, 2,4] oxadiazoI-5-one
3-. { 2-Chloro-4- [2- (4-meloxy-phenyl) -4- (3-meioxy-propoxymethyl) -oxazol-5-ylmethoxy] -phenyl} -4 - / - [1,2,4] oxadiazoi-5-one
3-. { 5-Bromo-2-methoxy-4- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazole-5-ylmeyoxy] -pheni} -4H- [1, 2,4] oxadiazol-5-one
3-. { 4- [4- (3-Benzyloxy-propyl) -2- (4-trifluoromethyi-phenyl) -iaz; o-5-methylhexy] -2-chloro-phenyl} -4 / - / - [1, 2,4] oxadiazol-5-one
3-. { 2-Chloro-4- [4- (3-hydroxy-propyl) -2- (4-ylfluoromethyl-phenyl) -thiazole-5-ylmeyoxy] -phenyl} -4H- [1, 2,4] oxadiazol-5-one
This invention also encompasses all combinations of preferred aspects of the invention described herein.
Alkyl and alkenyl radicals in substituents R1, R2, R3,
R4, R5, R6 and R7 can be straight-chain or branched.
The compounds of formula I can exist in the form of their racemates, racemic mixtures, pure enaniomers, diastereoisomers and mixtures of diastereomers as well as in their iauomeric forms. The present invention encompasses all such isomeric and tautomeric forms of the compounds of formula I. These isomeric forms can be obtained by known methods although they are not specifically described in some cases.
Because their solubility in water is greater than that of the initial or basic compounds, the pharmaceutically acceptable salts are particularly suitable for medical applications. These salts must have a pharmaceutically acceptable anion or cation. Pharmaceutically acceptable acid addition salts which are acceptable from suitable compounds of the invention are salts of inorganic acids such as hydrochloric, hydrobromic, phosphoric, mephaphosphoric, nitric and sulfuric acid, and organic acids such as, for example, acetic acid. , benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic, isotonic, lactic, lactobionic, maleic, malic, methanesulfonic, succinic, p-toluenesulfonic and tartaric acid. Suitable pharmaceutically acceptable basic salts are ammonium salts, alkali metal salts (such as sodium and potassium salts), alkaline earth metal salts (such as magnesium and calcium salts), and salts of fromethanol (2-amino-2). -hydroxymethyl-1,3-propanediol), diethanolamine, lysine or ethylenediamine.
Salts with a pharmaceutically unacceptable anion, such as, for example, trifluoroacety also belong to the framework of this invention as useful intermediates for preparing or purifying pharmaceutically acceptable salts and / or for use in non-therapeutic applications, for example, in vitro.
The term "physiologically functional derivative" used herein refers to any physiologically tolerated derivative of a compound of the formula I of the invention, for example an ester, which when administered to a mammal, for example, a human being, can forming (directly or indirectly) a compound of formula I or one of its active metabolites.
Physiologically functional derivatives also include prodrugs of the compounds of the invention, as described, for example, in H. Okada et al., Chem. Pharm. Buil.1994, 42, 57-61. Said prodrugs can be metabolized in vivo to a compound of the invention.
These prodrugs can be themselves acfivos or not.
Compounds of the invention may also exist in different polymorphic forms, for example, as crystalline and amorphous polymorphic forms. All polymorphic forms of the compounds of the invention belong to the framework of the invention and are a further aspect of the invention.
All references to the "compound (s) of formula (I)" hereinafter refer to the compound (s) of formula I as described above, and their salts, solvates, and physiologically functional derivatives as described herein.
Use
This invention also relates to the use of compounds of formula I and their pharmaceutical compositions as PPAR ligands. The PPAR ligands of the invention are suitable as modulators of PPAR activity.
Peroxisome Proliferator Activated Receptors (PPAR) are transcription factors that can be activated by ligands and belong to the class of nuclear hormone receptors. There are three isoforms of PPAR, PPAR-alpha, PPAR-gamma and PPAR-delta (identical to PPAR-beta), which are encoded by different genes (Peroxisome proliferalor-acíivated receptor (PPAR): struclure, mechanisms of acíivaíion and diverse funcíions: Moiojima K., Cell Síruct, Funct, 1993, 18 (5), 267-77).
In humans, PPAR-gamma exists in three variants, PPAR-gamma1, gamma2 and gamma3, which are the result of the alternative use of promoters and different religation of mRNA. Different PPARs have different tissue distributions and modulate different physiological functions.
PPARs have a major role in different aspects of the regulation of a large number of genes, and the products of these genes are directly or indirectly involved in the metabolism of lipids and carbohydrates. Thus, for example, the PPAR-alpha receptor plays an important role in the regulation of fatty acid catabolism or lipoprotein metabolism in the liver, while PPAR-gamma is crucially involved, for example, in the regulation of the differentiation of fat cells. However, in addition, PPARs are also involved in the regulation of many other physiological processes, including those that are not directly connected to the metabolism of carbohydrates or lipids. The activity of different PPARs can be modulated by different fatty acids and fatty acid derivatives and syn thetic compounds in different degrees. For relevant reviews on functions, physiological effects and pathophysiology, see: Berger, J. et al., Annu. Rev. Med., 2002, 53, 409-435; Wilson, T. et al., J. Med. Chem., 2000, 43 (4), 527-550; Kliewer, S. et al., Recent Prog. Horm. Res., 2001, 56, 239-63; Moller, D.E. and Berger, J.P., Int. J. Obes. Relat. Metab. Disord., 2003, 27 Suppl 3, 17-21; Ram, V. J., Drugs Today, 2003, 39 (8), 609-32).
Of the three isoforms of PPAR, for a long time the physiological functions of PPAR-delía have been an enigma. The first pharmacological role proposed for PPAR-delta, has been the regulation of choleslerol homeostasis. It was shown that the ligand of PPAR-delia to some selective extent L-165041 raises plasma cholesterol in a diabetic animal model (Berger J. et al., J. Biol. Chem., 1999, 274, 6718-6725; Leibowitz MD et al., FEBS Lett., 2000, 473 (3), 333-336). In rhesus and insulin-resistant rhesus monkeys, the potent and selective PPARdelta ligand GW501516 increases HDL-cholesterol, and lowers the levels of LDL-cholesterol, glycerides and insulin in the plasma (Oliver, W. et al., Proc. Naíl, Acad. Sci., 2001, 98, 5306-5311). The PPAR-delta / PPAR-alpha double agonist YM-16638 significantly decreases lipids in plasma in rhesus and cynomologus monkeys (Goto, S. et al., Br. J. Pharm., 1996, 118, 174-178) and acts similarly in two-week clinical trials in healthy volunteers (Shimokawa, T. et al., Drug Dev. Res., 1996, 38, 86-92). The most recent publications emphasize that PPAR-delta is an important target for the treatment of dyslipidemia, insulin resistance, type 2 diabetes, arteriosclerosis and syndrome X (Wang, YX et al., Cell, 2003, 113, 159-170; Luquet, S. et al., FASEB J., 2003, 17, 209-226; Tanaka, T. ei al., PNAS, 2003, 100, 15924-15929; Holsí, D. et al., BioChem, Biophys, Acta, 2003, 1633, 43-50, Dressel, U. et al., Mol.Endocrin., 2003, 17, 2477-2493; Lee, CH et al., Science, 2003, 302, 453- 457). In addition to its actions as a regulator of lipid, glucose and cholesterol metabolism, it is known that PPAR-delta has a role in embryonic bone development, implantation and formation (Lim, H. and Dey, SK, Trends Endocrinol, Metab. , 2000, 11 (4), 137-42; Ding, NZ et al., Mol Reprod Dev., 2003, 66 (3), 218-24; Mano, H. ei al., J. Biol. Chem., 2000,
275 (11), 8126-32). Numerous publications show that PPAR-delta causes the proliferation and differentiation of keratinocytes, which indicates its role in skin disorders and wound healing (Di-Poi, N. et al., J. Steroid, Biochem. Mol. Biol., 2003, 85 (2-5), 257-65; Tan, NS ei al., Am. J. Clin. Dermatol., 2003,4 (8), 523-30; Wahli, W., Swiss Med Wkly., 2002, 132 (7-8), 83-91). It seems that the PPAR-delta is expressed significantly in the
SNC; however, most of its function in this one remains undiscovered. However, the discovery that PPARdelta was expressed in rodent oligodendrocytes, the main lipid-producing cells of the CNS (J. Granneman, et al., J. Neurosci Res., 1998, 51, 563-) is of particular interest. 573). In addition, it was also found that a selective agonist of
PPAR-delta significantly increased the gene expression of oligodendroglial myelin and the diameter of the myelin sheath in mouse cultures (I. Saluja et al., Glia, 2001, 33, 194-204). Therefore, PPARdelta activators can be used for the treatment of demyelination and demyelination diseases.
The demyelination pathways are revealed by the loss of myelin, the multiple dense layers of lipids and protein that cover many nerve fibers. These layers are provided by oligodendroglia in the central nervous system (CNS), and Schwann cells in the peripheral nervous system (PNS). In patients with demyelination states, demyelination may be irreversible; it is usually accompanied or followed by axonal degeneration, and often of cellular degeneration. Demyelination can occur as a result of neuronal damage or damage to the myelin itself, whether due to aberrant immune responses, local injury, ischemia, melabolic transitions, toxic agents, or viral infections (Prineas and McDonald, Demyelinating Diseases., Greenfield's Neuropathology, 6.sup.th ed. (Edward Arnold: New York, 1997)
813-811, Beers and Berkow, eds., The Merck Manual of Diagnosis and Therapy, 17.sup.th ed. (Whitehouse Station, N.J .: Merck Research Laboratories, 1999) 1299, 1437, 1473-76, 1483).
Central demyelination (demyelination of the CNS) occurs in different states, often of undetermined etiology, which have been known as primary demyelinating diseases. Of these, multiple sclerosis (MS) is the most widespread. Other primary demyelinating diseases include adrenoleukodystrophy (ALD), adrenomyeloneuropathy, vacuolar myelopathy associated with AIDS, HTLV-associated myelopathy, Lebe's hereditary optic atrophy, progressive multifocal leukoencephalopathy (PML), subacute sclerosing panencephalitis, Guillian-Barre syndrome, and tropical spastic paraparesis. In addition, there are acute states in which demyelination can occur in the CNS, p. eg, in acute disseminated encephalomyelitis (ADEM) and acute viral encephalitis.
In addition, acute transverse myelitis, which is a syndrome in which an acute spinal cord transection of unknown cause affects both gray and white mays in one or more adjacent thoracic segments, may result in demyelination. Also, disorders in which myelin-forming glial cells are damaged, including spinal cord injuries, neuropathies and nerve injury.
The present invention relates to compounds of formula I suitable for modulating the activity of PPARs, especially the activity of PPAR-delta and PPAR-alpha. Depending on the modulation profile, the compounds of formula I are suitable for the handling, control and prophylaxis of the indications described hereinafter, and for a number of different pharmaceutical applications related thereto (see, for example, Berger, J., et al., Annu., Rev. Med., 2002, 53, 409-435; Wilson, T. eí al., J. Med. Chem., 2000, 43 (4), 527-550; Kliewer, S. eí al., Receni Prog. Horm. Res., 2001, 56, 239-63; Fruchart, JC et al., 2001, Pharmacological Research, 44 (5), 345-52; Kersten, S. et al., Nature, 2000, 405, 421-424; Torra, IP et al., Curr Opin Lipidol, 2001, 12, 245-254). Compounds of this type are particularly suitable for the treatment and / or prevention of: 1. - Disorders of fatty acid metabolism and disorders of glucose use. - Disorders in which insulin resistance is involved
2. Diabetes mellitus, especially type 2 diabetes, including the prevention of sequelae associated with it.
There are particular aspects related to this: - hypergiucemia, - improvement of insulin resistance, - improvement of glucose tolerance - protection of pancreatic β cells - prevention of macro and microvascular disorders
3. Dyslipidemias and their sequelae such as, for example, atherosclerosis, coronary heart disease, cerebrovascular disorders eic, especially (but not limited to) those characterized by one or more of the following factors: - high concentrations of glyceride in the plasma, alias concentrations of triglycerides in the postprandial plasma is, - low concentrations of HDL cholesterol - low concentrations of lipoproiein ApoA - high concentrations of LDL cholesterol - particles of low density LDL cholesterol - high concentrations of lipoprotein ApoB
4. Several different states that can be associated with the metabolic syndrome, such as: - obesity (excess weight), including central obesity - thrombosis, hypercoagulable and prothrombotic states (arterial and venous) - arterial hypertension - heart failure, such as for example ( but not limited to these), after myocardial infarction, hypertensive heart disease or cardiomyopathy
. Disorders or conditions in which inflammatory reactions are involved:
- atherosclerosis such as, for example (but not limited to), coronary sclerosis including angina pectoris or myocardial infarction, stroke - restenosis or vascular reocclusion - chronic inflammatory bowel diseases, eg, Crohn's disease and ulcerative colitis - asthma - lupus erythematosus (LE) or inflammatory rheumatic disorders, such as, for example, rheumatoid arthritis - other inflammatory conditions
6. Cell cycle disorders or cell differentiation processes - adipose cell tumors - lipomatous carcinomas such as, for example, liposarcomas - solid tumors and neoplasms toles such as, for example (but not limited to) gastric carcinoma of the liver , biliary and pancreatic abnormalities, endocrine lumens, carcinomas of the lungs, kidneys and urinary tract, genital tract, prostatic carcinomas, etc. - acute and chronic myeloproliferative disorders and lymphomas - angiogenesis
7. Neurodegenerative changes and / or demyelinating disorders of the central and peripheral nervous systems and / or neurological disorders involving neuroinflammatory processes and / or other peripheral neuropathies: - Alzheimer's disease - multiple sclerosis - Parkinson's disease - adrenoleukodystrophy (ALD) - adrenomyeloneuropathy - myelopathy Vacuolar associated with AIDS - myelopathy associated with HTLV - Leber's hereditary optic atrophy - Progressive multifocal leukoencephalopathy (PML) - Subacute sclerosing panencephalitis - Guillian-Barre syndrome - Tropical spastic paraparesis - Acute disseminated encephalomyelitis (EMDA) - Acute viral encephalitis - Myelitis acute transverse - spinal cord and brain trauma - Charcot-Marie-Toofh disease
Skin disorders and / or disorders of wound healing processes:
- erythematoscamosis dermatoses, such as, for example, psoriasis
- acne vulgaris - other skin disorders and dermatological conditions that are modulated by PPAR - eczema and neurodermatitis - dermatitis such as, for example, seborrheic dermatitis or foiodermayitis - keraphitis and keratosis, such as, for example, seborrheic keratosis, senile keratosis, Actinic keratosis, photoinduced keratosis or follicular keratosis - keloids and keloid prophylaxis - warts, including condylotoma or condyloma acuminata - human papilloma virus (HPV) infections such as, for example, venereal papillomatosis, viral warts, such as, for example, molluscum contagiosum, leukoplakia - papular dermatosis, eg, lichen planus - skin cancer such as, for example, basal cell carcinomas, cutaneous melanomas or T-cell lymphomas - localized benign epidermal lumens such as, for example, keraioderma, epidermal nevus - chilblains - wound healing
9. Other disorders - hypertension - pancreatitis - syndrome X - polycystic ovarian syndrome (PCOS) - asthma - osteoarthritis - lupus erythematosus (LE) or inflammatory rheumatic diseases, such as, for example, rheumatoid arthritis - vasculitis - Wasting syndrome (cachexia) k - gout - ischemia / reperfusion syndrome - acute respiratory distress syndrome (ARDS)
Formulations
The amount of a compound of formula I necessary to achieve the desired biological effect depends on a number of factors, for example, the specific compound chosen, the intended use, the mode of administration and the clinical condition of the patient. Generally the daily dose is in the range of 0.001 mg to 100 mg (typically 0.01 mg to 50 mg) per day and per kilogram of body weight, eg, 0.1-10 mg / kg / day. An intravenous dose can be, for example, in the range of 0.001 mg to 1.0 mg / kg, which can be suitably administered in the form of an infusion of 10 ng to 100 ng per kilogram and per minute. Suitable solutions for infusion for these purposes may contain, for example, 0.1 ng to 10 mg, typically 1 ng to 10 mg, per milliliter. The single doses may contain, for example, from 1 mg to 10 g of the active ingredient. Thus, ampoules for injection may contain, for example, 1 mg to 100 mg, and orally administrable single-dose formulations, such as, for example, capsules or tablets, may contain, for example, example, from 0.05 to 1000 mg, typically from 0.5 to 600 mg. For the therapy of the aforementioned states, the compounds of formula I can be used as the compound itself, but preferably they are in the form of a pharmaceutical composition with an acceptable carrier. Of course, the vehicle must be acceptable, in the sense of being compatible with the other ingredients of the composition, and not be harmful to the patient's health. The carrier may be a solid or a liquid, or both, and is preferably formulated with the compound in the form of a single dose, for example, in the form of a tablet, which may contain from 0.05% to 95% by weight of the acive ingredient. Other pharmaceutically active substances may also be present, including other compounds of formula 1. The pharmaceutical compositions of the invention can be prepared by one of the known pharmaceutical methods, which essentially consist of mixing the ingredients with pharmacologically acceptable carriers and / or excipients.
The pharmaceutical compositions of the invention are suitable for oral, rectal, topical, peroral (eg, sublingual) and parenteral (eg, subcutaneous, intramuscular, intradermal or intravenous) administration, although the most suitable mode of administration depends on each individual case of the nature and severity of the condition to be treated, and of the nature of the compound of formula I used in each case. Coated formulations and slow release coated formulations are also within the scope of the invention. Acid-resistant formulations and gastric juice are preferred. Suitable coatings resistant to gastric juice comprise cellulose acetate phthalate, poly (vinyl acetate-phylate), hydroxypropylmethyl cellulose phthalate, and anionic polymers of methacrylic acid and methylacrylate.
Pharmaceutical preparations suitable for oral administration may be in the form of separate, individual units, such as, for example, capsules, seals, lozenges or tablets, each of which confers a defined quality of the compound of formula 1; in the form of powders or granules, in the form of a solution or suspension in an aqueous or non-aqueous liquid; or in the form of an oil in water or water in oil emulsion. These compositions, as already mentioned, can be prepared by any suitable pharmaceutical method which includes a step in which the active ingredient and the vehicle (which can consist of one or more additional ingredients) are brought into contact. In general, the compositions are produced by uniform and homogeneous mixing of the active ingredient with a liquid and / or finely divided solid carrier, after which the product is molded if necessary. Therefore, a tablet can be prepared, for example, by compression or molding a powder or granules of the compound, as appropriate with one or more additional ingredients. The tablets can be produced by compressing the compound in fluid form such as, for example, a powder or granules, when appropriate, mixed with a binder, glidant, inert diluent and / or one (or more) insensitivity agent (s) ( s) / dispersant (s), in a suitable machine. Molded tablets may be prepared by molding the compound, which is in powder form and moistened with an inert liquid diluent, in a suitable machine.
Pharmaceutical compositions which are suitable for peroral (sublingual) administration comprise lozenges containing a compound of formula I with a flavor, typically sucrose and gum arabic or tragacanth, and lozenges comprising the compound in an inert base such as gelatin and glycerol or sucrose and gum arabic.
Pharmaceutical compositions suitable for parenteral administration preferably comprise sterile aqueous preparations of a compound of formula I, which are preferably isotonic with the blood of the recipient to which they are directed. These preparations are preferably administered in an intravenous manner, although the administration can also be by subcutaneous, inframuscular or inradramic injection. These preparations can preferably be prepared by mixing the compound with water and making the solution sterile and isotonic with the blood. The injectable compositions of the invention generally contain from 0.1 to 5% by weight of the active compound.
Pharmaceutical compositions suitable for rectal administration, preferably are in the form of single-dose suppositories. These may be prepared by mixing a compound of formula I with one or more conventional solid carriers, for example, cocoa butter, and shaping the resulting mixture.
Pharmaceutical compositions suitable for topical use in the skin, preferably are in the form of an ointment, cream, lotion, paste, spray, aerosol or oil. The vehicles that can be used are petrolatum, lanolin, polyethylene glycols, alcohols and combinations of two or more of these substrates. The active ingredient is generally present at a concentration of 0.1 to 15% by weight of the composition, for example, from 0.5 to 2%.
Transdermal administration is also possible. Pharmaceutical compositions suitable for transdermal uses may be in the form of a plaster which is suitable for long-term contact with the epidermis of the patient. Said castings adequately contain the active ingredient in an aqueous solution which is buffered, when appropriate, dissolved and / or dispersed in an adhesive or dispersed in a polymer. A suitable concentration of active ingredient is from about 1% to 35%, preferably from 3% to 15%. One possibility is that the active ingredient is released by elecrotransport or iontophoresis, as described, for example, in Pharmaceulical Research,
2 (6): 318 (1986).
The compounds of formula I are distinguished by favorable effects on metabolic transitions. They influence in a beneficial way in the lipid and sugar melabolism, in particular they decrease the level of triglycerides and are suitable for the prevention and travail of the type II diabei and atherosclerosis and its various sequelae.
Combinations with other medications
The compounds of the invention can be administered alone or in combination with one or more pharmacologically active substances having, for example, favorable effects in metabolic disorders or disorders frequently associated therewith. Examples of such medicines are
1. medicines that lower blood glucose, antidiabetics,
2. active ingredients for the treatment of dyslipidemias, 3. antialerosclerotic drugs, 4. aniiobesity agents, 5. anti-inflammatory active ingredients 6. active ingredients for the treatment of malignant tumors 7. anti-inflammatory active ingredients 8. ingredients for the hypertension of arterial hypertension, 9. Active ingredients for the eradication of heart failure and
. active ingredieníes for the traisamiento and / or prevention of complications caused by diabetes or associated with diabetes.
They can be combined with the compounds of the invention of formula I, in particular for a synergistic improvement of the effect. The administration of the combination of the active ingredient can be produced by separate administration of the ingredients that are active in the patient, or in the form of combination products, in which in a pharmaceutical preparation there is a plurality of active ingredients.
Examples that can be mentioned are:
Antidiabetics
Suitable antidoteletics are described, for example, in the Roie Liste 2001, chapter 12, or in the USP Dictionary of USAN and International Drug
Yams, US Pharmacopoeia, Rockville 2001. Antidiabetics include all insulins and insulin derivatives, such as, for example, Lanius D (see www.lantus.com) or Apidra, and other fast-acting insulins (see US 6,221. 633), GLP-1 receptor modulators as described in WO 01/04146, or for example those described in WO 98/08871 of Novo Nordisk A / S.
Orally effective hypoglycemic acive ingredients include, preferably, sulfonylureas, biguanides, megiitinides, oxadiazoli-dindiones, thiazolidinediones, glucosidase inhibitors, glucagon antagonisms, GLP-1 agonies, DPP-IV inhibitors, channel opening agents. potassium, such as, for example, those described in the documents
WO 97/26265 and WO 99/03861, insulin sensitizers, hepatic enzyme inhibitors involved in the stimulation of gluconeogenesis and / or glycogenolysis, modulators of glucose uptake, compounds that alter the metabolism of lipids and lead to a change in the lipid composition of blood, compounds that reduce food intake, modulators of PPAR and PXR, and active ingredients that act on the ATP-dependent potassium channel of beta cells.
In one embodiment of the invention, the compounds of formula I are administered in combination with insulin
In one embodiment of the invention, the compounds of formula I are administered in combination with substances that influence the production of hepatic glucose, for example, inhibitors of glycogen phosphorylase (see documents: WO 01/94300, WO 02/096864, WO 03/084923, WO
03/084922, WO 03/104188)
In one embodiment, the compounds of formula I are administered in combination with a sulfonylurea, such as, for example, tolbutamide, glibenclamide, glipizide or glimepiride.
In one embodiment, the compounds of formula I are administered in combination with an active ingredient that acylates in the ATP-dependent potassium channel of the beta cells, eg, íolbumamide, glibenclamide, glipizide, glimepiride or repaglinide.
In one embodiment, the compounds of formula I will be administered in combination with a biguanide, eg as metformin.
In a further embodiment, the compounds of formula I are administered in combination with a meglitinide, eg as repaglinide.
In one embodiment, the compounds of formula I are administered in combination with a thiazolidinedione, such as, for example, zylliazone, pioglifazone, rosiglitazone or the compounds described in WO
97/41097 from Dr. Reddy's Research Foundation, in particular 5 - [[4 - [(3,4-dihydro-3-methyl-4-oxo-2-quinazolinylmethoxy] -phenyl] methylj-2,4-yiazoIidinedione.
In one embodiment, the compounds of formula I are administered in combination with a DPPIV inhibitor as described, for example, in WO 98/19998, WO 99/61431, WO 99/67278, WO 99/67279, WO 01 / 72290, WO 02/38541, WO 03/040174, in particular P 93/01 (1-cyclopentyl-3-methyl-1-oxo-2-penanammonium chloride), P-31/98, LAF237 (1- [2- [3-hydroxiadamant-1-ylamino) acetyl] pyrroidin-2- (S) -carbonitrile), TS021 (monobenzenesulfonate of (2S, 4S) -4-fluoro-1 - [[(2- hydroxy-1, 1-dimethyletyl) amino) -acetyl] pyrrolidine-2-carbonyiyl).
In one embodiment of the invention, the compounds of formula I are administered in combination with a PPAR-gamma agonist, such as, for example, rosiglitazone, pioglitazone.
In one embodiment, the compounds of formula i will be administered in combination with compounds with an SGLT-1 and / or 2 inhibitory efflux, as described directly or indirectly, for example in PCT / EP03 / 06841, PCT / EP03 / 13454 and PCT / EP03 / 13455.
In one embodiment, the compounds of formula I are administered in combination with an α-glucosidase inhibitor, such as, for example, miglitol or acarbose.
In one embodiment, the compounds of formula I are administered in combination with more than one of the aforementioned compounds, for example, combined with a sulphonylurea and metformin, a sulfonylurea and acarbose, repaglinide and metformin, insulin and a sulfonylurea, insulin and metformin, insulin and troglitazone, insulin and lovastatin, etc.
Lipid modulators
In one embodiment of the invention, the compounds of formula I are administered in combination with an inhibitor of HMGCoA-reductase, such as lovastatin, fluvastatin, pravastatin, simvastatin, ivastatin, itavastatin, atorvastatin, rosuvastatin.
In one embodiment of the invention, the compounds of formula I are administered in combination with an inhibitor of bile acid reabsorption (see, for example, US 6,245,744, US 6,221,897, US Pat.
6. 277,831, EP 0683773, EP 0683774).
In one embodiment of the invention, the compounds of formula I are administered in combination with a polymeric bile acid adsorbent, such as, for example, cholestyramine, colesevelam.
In one embodiment of the invention, the compounds of formula I are administered in combination with a cholesterol absorption inhibitor, as described, for example, in WO 0250027, or ezetimibe, tiqueside, pamaqueside.
In one embodiment, the compounds of formula I are administered in combination with an inducer of the LDL receptor (see, for example, US 6,342,512).
In one embodiment of the invention, the compounds of formula I are administered in combination with bulking agents, preferably insoluble bulking agents (see, for example, carob / Caromax® (Zunft HJ; et al., Carob pulp preparation for treatment of hypercholesterolemia , ADVANCES IN THERAPY (2001 Sep-Oct), 18 (5), 230-6.) Caromax is a product containing carob from Nutrinova, Nutrition Specialties &Food Ingredients GmbH, Industriepark Hóechst, 65926 Frankfurí / Main)). It can be combined with Caromax® in one preparation, or the compounds of formula I and Caromax® can be administered separately. In connection with this, Caromax® can be administered in the form of food products, such as, for example, in bakery products or muesli bars.
In one embodiment of the invention, the compounds of formula I are administered in combination with a PPAR-alpha agonist.
In one embodiment of the invention, the compounds of formula I are administered in combination with a mixed PPAR-alpha / gamma agonist, such as, for example, AZ 242 (Tesaglitazar, (S) -3- (4- [2- ( 4-methylsulfonyloxyphenyl) eloxyl] phenyl) -2-ethoxypropionic acid), BMS 298585 (N - [(4-methoxyphenoxy) carbonyl] -N - [[4- [2- (5-methyl-2-phenol- 4-oxazolyl) ethoxy] phenyI] methyl] glycine) or as described in WO 99/62872, WO 99/62871, WO 01/40171, WO 01/40169, WO96 / 38428, WO 01/81327, WO 01/21602, WO 03/020269, WO 00/64888 or WO 00/64876.
In one embodiment of the invention, the compounds of formula I are administered in combination with a fibrate, such as, for example, fenofibrate, gemfibrozil, clofibrate, bezafibrate.
In one embodiment of the invention, the compounds of formula I are administered in combination with nicotinic acid or niacin.
In one embodiment of the invention, the compounds of formula I are administered in combination with a CETP inhibitor. p. eg, CP-529.414 (torcetrapib).
In one embodiment of the invention, the compounds of formula I are administered in combination with an ACAT inhibitor.
In one embodiment of the invention, the compounds of formula I are administered in combination with an MTP inhibitor, such as, for example, implitapide.
In one embodiment of the invention, the compounds of formula I are administered in combination with an antioxidant.
In one embodiment of the invention, the compounds of formula I will be administered in combination with a lipoprotein lipase inhibitor.
In one embodiment of the invention, the compounds of formula I are administered in combination with an inhibitor of ATP-citrate-iiasa.
In one embodiment of the invention, the compounds of formula I will be administered in combination with an inhibitor of squalene synthetase.
In one embodiment of the invention, the compounds of formula I will be administered in combination with an anolygonism of lipoprolein (a).
Agencies aníiobesity
In one embodiment of the invention, the compounds of formula I are administered in combination with a lipase inhibitor, such as, for example, orlistai.
In one embodiment, the additional active ingredient is fenfluramine or dexfenfluramine.
In another embodiment, the additional active ingredient is sibutramine.
In a further embodiment, the compounds of formula I are administered in combination with CART modulators (see "Cocaine-amphetamine-regulated transcript influences energy metabolism, anxiety and gastric emptying in mice" Asakawa, A, et al., M .: Hormone and Metabolic Research (2001), 33 (9), 554-558), antagonisms of NPY, p. ex. hydrochloride. { 4 - [(4-aminoquinazoin-2-ylamino) meily] -cyclohexylmethyl} Naphthalene-1-sulfonic acid amide (CGP 71683A)), MC4 agonists (eg [2- (3a-benzyl-2-methyl-3-oxo-2,3,3a, 4,6J-hexahydropyrazolo [ 4-C-pyridin-5-yl) -1- (4-chlorophenyl) -2-oxoxy] -amide of 1-amino-1,2,3,4-eeryhydronaphthalene-2-carboxylic acid; (WO 01 / 91752)), orexin antagonisms (eg 1- (2-methylbenzoxazol-6-yl) -3- [1,5] naphthyridin-4-iiurea hydrochloride (SB-334867-A)) , H3 agonists (salt of oxalic acid and 3-cyclohexyl-1- (4,4-dimethyl-1, 4,6,7-tetrahydroimidazo [4,5-c] pyridin-5-yl) propan-1- ona (WO 00/63208)); TNF agonisias, CRF antagonists (e.g. [2-methyl-9- (2,4,6-trimethylphenyl) -9H-1, 3,9-triazafluoren-4-yl] dipropylamine (WO 00/66585) ), CRF BP antagonists (eg urocortin), urocortin agonists, ß3 agonists (eg 1- (4-chloro-3-methanesulfonylmethylphenyl) -2- [2- (2,3-dimefil -1H-indoI-6-yloxy) ethylamino] -ethanol (WO 01/83451)), agonists of MSH (melanocyte stimulating hormone), agonists of CCK-A (eg, trifluoroacetic acid salt and acid. 2- [4- (4-Chloro-2,5-dimethoxy-phenyl) -5- (2-cyclohexylethyl) thiazo-2-ylcarbamoyl] -5,7-dimethyl-indol-1-yl} -acetic acid ( WO 99/15525)), serotonin reuptake inhibitors (eg dexfenfluramine), mixed sero-ioninergic and noradrenergic compounds (eg WO 00/71549), 5HT agonists eg oxalic acid salt and 1- (3-efilbenzofuran-7-yl) piperazine (WO 01/09111), bombesin agonists, galanin antagonisms, growth hormone (eg human growth hormone), free compounds of the growth hormone (tertiary butyl ester of 6-benzyloxy-1- (2-diisopropylaminoethylcarbamoyl) -3,4-dihydro-1H-isoquinoline-2-carboxylic acid (WO 01/85695)), agonisías of TRH ( see, for example, EP 0462884), modulators of decoupling protein 2 or 3, leptin agonists (see, for example, Lee, Daniel W .; Leinung, Matfhew C; Rozhavskaya- Arena, Marina; Grasso, Patricia. "Leptin agonists as a potential approach to the treatment of obesity". Drugs of íhe Fuíure (2001), 26 (9), 873-881), agonisias of DA (bromocriptine, Doprexin), lipase / amylase inhibitors (eg WO 00/40569), PPAR modulators (eg. WO 00/78312), RXR modulators or TR-β agonists.
In one embodiment of the invention, the additional active ingredient is leptin.
In one embodiment, the additional active ingredient is dexamfetamine, amphetamine, mazindol or phentermine.
In one embodiment, the compounds of formula I are administered in combination with drugs that have effects on the coronary circulation and the vascular system, such as, for example, ACE inhibitors (eg ramipril), drugs that act on the angiogenesis system -renine, calcium anijagonisías, befa blockers, eic.
In one embodiment, the compounds of formula I are administered in combination with drugs that have an anti-inflammatory effect.
In one embodiment, the compounds of formula I are administered in combination with drugs that are used in cancer therapy or cancer prevention.
It will be noted that each suitable combination of the compounds of the invention with one or more of the aforementioned compounds, and optionally one or more pharmacologically active substances, is considered to be within the protection of the present invention.
The activity of the compounds was tested as follows:
Determination of the EC50 values of PPAR agonisias in the assay of PPAR-alpha cell
Beginning
The potency of the substrates that bind to the human PPAR-alpha and activate it agonistically, is analyzed using a stable transfected HEK cell line (HEK = human embryonic kidney), here called PPAR-alpha indicator cell line. It contains two genetic elements, a luciferase indicator element (pdeltaM-GAL4-Luc-Zeo) and a fusion protein of PPAR-alpha (GR-GAL4-PPARalpha-human-LBD) that mediates the expression of the luciferase indicator element that depends on a ligand of PPAR-alpha. The fusion protein GR-GAL4-PPARaIfa-human-LBD expressed constitutively and stably, binds in the cell nucleus of the PPAR-alpha indicator cell line by the GAL4 protein part to the GAL4 DNA binding patterns , 5 'upstream of the luciferase reporter element which is stably integrated into the genome of the cell line. In the absence of a PPAR-alpha ligand there is only weak expression of the luciferase reporter gene, if fetal calf serum with fatty acid reduction (cs-FCS) is used in the assay. Ligands of PPAR-alpha bind to and activate the PPAR-alpha fusion protein, and thus stimulate the expression of the luciferase reporter gene. The luciferase that forms can be detected by chemiluminescence using a suitable substrate.
Construction of PPAR-alpha indicator cell line
The PPAR-alpha indicator cell line was prepared in two stages. First, the luciferase reporter element was constructed and transfected stably into HEK cells. For this purpose, five binding sites of the yeast transcription factor GAL4 (accession number AF264724) 5 'upstream of a MMTV minimum promoter of 68 bp length (accession number V01175) were cloned. The minimum promoter section of MMTV contains a CCAAT box and a TATA element in order to allow efficient transcription by RNA polymerase II. Cloning and sequencing of the GAL4-MMTV construct occurs in a manner analogous to that described by Sambrook J. et. to the. (Molecular cloning, Cold Spring
Harbor Laboratory Press, 1989). The Photinus pyralis gene (Accession No. M15077) 3 'downstream of the GAL4-MMTV element was then cloned. After sequencing, the luciferase reporter element consisting of five GAL4 binding sites, MMTV promoter and luciferase gene, was cloned back into a plasmid conferring zeocin resistance in order to obtain the plasmid pdeltaM- GAL4-Luc-Zeo. This vector was transfected into HEK cells according to what was stated by Ausubel, F.M. et al. (Current protocols in molecular biology, Vol. 1-3, John Wiley &Sons, Inc., 1995). Then medium containing zeocin (0.5 mg / ml) was used to select a suitable stable cell clone that showed very little basal expression of the luciferase gene.
In a second step, the fusion protein of PPAR-alpha (GR-GAL4-PPARalpha-human-LBD) was introduced into the described stable cell clone. For this purpose, the cDNA encoding the N-terminal 76 amino acids of the glucocorticoid receptor (accession P04150) was originally linked to the cDNA section encoding amino acids 1-147 of the yeast transcription factor GAL4 (n Access point P04386). The cDNA of the ligand binding domain of the primary PPAR-alpha receptor (amino acids S167-Y468; accession number S74349) was cloned at the 3 'end of this construct GR-GAL4. The fusion construct prepared in this way (GR-GAL4-PPAR-a! Fa-human-LBD) was re-cloned into the plasmid pcDNA3 (Invitrogen) in order to allow constitutive expression in it by the cytomegalovirus promoter. This plasmid was linearized with a restriction endonuclease and stably transfected into the previously described cell clone containing the luciferase reporter element. The finished PPAR-alpha receptor cell line containing a luciferase reporter element and constiuously expresses the fusion protein of
PPAR-alpha (GR-GAL4-PPAR-alpha-human-LBD) was isolated by selection with zeocin (0.5 mg / ml) and G418 (0.5 mg / ml).
Test procedure
The activity of PPAR-alpha agonists is determined in a 3-day trial described below:
Dia l The PPAR-alpha indicator cell line is cultured up to 80% confluence in DMEM (No. 41965-039, Invitrogen) which is mixed with the following additions: cs-10% FCS (fetal calf serum; ° SH-30068.03,
Hyclone), zeocin 0.5 mg / ml (No. R250-01, Invitrogen), G418 0.5 mg / ml (No. 10131-027, Inviirogen), 1% penicillin-esreptomycin solution (No. 122, Invifrogen) and 2mM L-glulamine (n ° 25030-024, Inviirogen). The culture is carried out in standard cell culture bottles (No. 353112, Becfon Dickinson) in a cell culture incubator at 37 ° C in the presence of 5% CO2. Cells at 80% confluence are washed once with 15 ml of PBS
(n ° 14190-094, Invitrogen), were brought with 3 ml of trypsin solution (n ° 25300-054, Invitrogen) at 37 ° C for 2 min, collected in 5 ml of the described DMEM medium and counted in a cell counter After diluting to 500,000 cells / ml, 35,000 cells are seeded in each well of a 96-well microtiter plate with a transparent plasmid base
(n ° 3610, Corning Costar). The plates are incubated in the cell culture incubator at 37 ° C and with 5% CO2 for 24 h.
Day 2 The PPAR-alpha agonists to be tested are dissolved in DMSO at a concentration of 10 mM. This stock solution is diluted in DMEM (No. 41965-039, Invitrogen) which is mixed with cs-5% FCS (No. SH-30068.03, Hyclone), 2mM L-glutamine (No. 25030-024, Inviirogen) and the previously described antibiotics (zeocin, G418, penicillin and streptomycin).
The test substances are tested at 11 different concentrations in the range of 10 μM to 100 pM. The most potent compounds are tested at concentrations in the range of 1 μM to 10 pM or between 100 nM and 1 pM.
The medium of the PPAR-alpha indicator cell line seeded on day 1 is completely removed by aspiration, and test substances diluted in medium are immediately added to the cells. The dilution and addition of the substances is carried out by means of a robot (Beckman FX). The final volume of test substances diluted in medium is 100 μl per well of a 96-well microtiter plate. The concentration of DMSO in the assay is less than 0.1% vol / vol in order to avoid cytotoxic effects of the solvent.
Each plate was loaded with a standard PPAR-alpha agonist, which was also diluted in 11 different concentrations, in order to demonstrate the performance of the assay in each individual plate. The test plates are incubated in a 37 ° C incubator and 5% CO2 for 24 h.
Day 3 Cells with PPAR-alpha indicator treated with the test substances are removed from the incubator and the medium is aspirated. The cells are lysed by pipetting 50 μl of Bright Glo reagent (from Promega) into each well of a 96-well microtiter plate. After incubation at ambient lemperairia in the dark for 10 minutes, microtiter plates are measured in the luminometer (Wallac's Triiux). The measurement time for each well of the microtiter plate is 1 second.
Evaluation The raw data of the luminometer is transferred to a Microsoft Excel file. The graphs of the effect of the dose and the EC50 values of the PPAR agonists are calculated, using the XL.Fit program as specified by the manufacturer (I DBS).
The EC50 values of the PPAR-alpha for the compounds of the
Examples 1 to 32 in this assay are in the range of 100 nM to > 10 μM. The compounds of the invention of formula I activate the PPAR-alpha receptor.
Determination of EC50 values of PPAR agonists in the PPAR-cell delta assay
Beginning
The potency of the substances that bind to the human PPAR-delta and activate it agonistically, is analyzed using a cell line
Stable transfected HEK (HEK = human embryonic kidney), which is called the PPAR-delta indicator cell line here. Analogous to the assay described for PPAR-alpha, the PPAR-alpha indicator cell line also contains two genetic elements, a luciferase indicator element (pdeltaM-GAL4-Luc-Zeo) and a PPAR-delta fusion protein (GR -GAL4-PPARdelía-humana-LBD) that mediates the expression of the elemenios indicator of luciferase that depends on a ligand of PPAR-delía. The GR-GAL4-PPARdetata-human-LBD fusion protein, constitutively and stably expressed, binds in the cell nucleus of the PPAR-delía indicator cell line through the GAL4 protein pair to the GAL4 DNA binding pads. , 5 'upstream of the luciferase indicator element which is stably integrated into the genome of the cell line. In the absence of a PPAR-delta ligand there is only a little expression of the luciferase reporter gene, if fetal calf serum with fatty acid reduction (cs-FCS) is used in this assay. The PPAR-delta ligands bind to and activate the PPAR-delta fusion protein, and thus stimulate the expression of the luciferase reporter gene. The luciferase that forms can be detected by chemiluminescence using a suitable substrate.
Construction of the PPAR-delta indicator cell line
The production of the stable PPAR-delta indicator cell line is based on a stable HEK cell clone that was essentially transfected with a luciferase reporter element. This stage has already been described anfes, in the section "construction of the indicator cell line
PPAR-delta. "In a second step, the PPAR-delía fusion protein (GR-GAL4-PPARdeita-human-LBD) was stably introduced into this cell clone, for this purpose, the cDNA encoding the 76 amino acids N- of the glucocorficoid receptor (Accession No. P04150) was linked to the cDNA section encoding amino acids 1-147 of the yeast transcription factor GAL4 (accession no.P04386) The cDNA of the ligand binding domain of the ligand PPAR-delta receptor (amino acids S139-Y411; accession number L07592) was cloned at the 3 'end of this GR-GAL4 construct The fusion construct prepared in this way (GR-GAL4-PPAR-delta-human-LBD ) was re-cloned into plasmid pcDNA3 (Invitrogen) in order to allow constitutive expression by the cytomegalovirus promoter.
This plasmid was linearized with a restriction endonuclease and stably transfected into the previously described cell clone containing the luciferase reporter element. The PPAR-delia indicator cell line containing a luciferase reporter element and constitutively expressing the PPAR-delta fusion protein (GR-GAL4-PPAR-de-human-LBD) was isolated by selection with zeocin (0.5 mg / ml) and G418 (0.5 mg / ml).
Testing and evaluation procedure
The activity of the PPAR-delta agonists is determined in a 3-day assay analogously to the procedure described above for the PPAR-alpha indicator cell line, except that the PPAR-delta indicator cell line and a specific agonist for PPAR-delta, as a pairo to confirm the efficacy of the assay.
The EC50 values for the PPAR-delta in the range of 0.2 nM a > 10 μM for the PPAR agonists of Examples 1 to 51 described in this application. The compounds of formula I of the invention activate the PPAR-delta receptor.
The examples given in Table II serve to illustrate the invention, but without limiting it.
Table I 10
fifteen
WHAT IS CN CO
LO LO 10
fifteen
fifteen
LO In the next. The table indicates the power of some of the described examples.
Procedures
The compounds of the general formula I according to the invention can be obtained as indicated in the following reaction schemes.
Procedure A
A compound of general formula A-1 in which Y is -OH or -SH and X, Z, R1, R2, R3 and R4 are as defined, reacted with a halide of general formula A-2 in which R = halide and U, V, W, R5, R6 and R7 are as defined, in the presence of a base such as cesium carbonate or sodium hydride in a solvent such as dimethylformamide or with an alcohol of general formula A-2 in which R = OH and U, V, W, R5, R6 and R7 are as defined, under the reaction conditions of Mitsunobu (triphenylphosphine, diethyl azodicarboxylate, for example) in an apolar solvent such as dichloromethane, to give a compound of general formula A-5.
Alternately, the compound of general formula A-5 can be obtained by reacting a compound of general formula A-3 in which R = halide, Z = -CH2 and X, R1, R2, R3 and R4 are as defined, with a compound of general formula A-4 wherein Y is -OH and U, V, W, R5, R6 and R7 are as defined, in the presence of a base such as sodium hydride in a solvent such as dimethylformamide. If Y = S in the compound of general formula A-5, the sulfur atom can be oxidized (Y = SO or Y = SO2) by methods known in the art, for example, with an oxidizing agent tol such as metachloroperbenzoic acid in a apolar solvent such as dichloromethane. The compound of general formula A-5 is reacted with hydroxylamine hydrochloride in the presence of a base such as triethylamine, in a solvent such as tetrahydrofuran and methanol to obtain a compound of general formula A-6. A compound of general formula A-6 is converted into the product of general formula AJ, by reaction with phenyl chloroformate in the presence of a base such as pyridine, and treatment of this intermediate product with a base such as 1,8-diazabicyclo [ 5.4.0] undec-7-ene in a solvent such as acetonitrile.
Examples 1-9, 12-14, 28-32 and 45-48 were obtained according to procedure A.
Other compounds can be obtained according to, or by known methods.
Procedure B
A compound of general formula B-1 in which Y is -OH or -SH and Z, R1, R2, R3 and R4 are as defined, is reacted with a halide of general formula B-2 in which R = halide and U, V, W, R5, R6 and R7 are as defined, in the presence of a base such as cesium carbonate or sodium hydride in a solvent such as dimethylformamide or with an alcohol of general formula B-2 in wherein R = OH and U, V, W, R5, R6 and R7 are as defined, under the reaction conditions of Mitsunobu (triphenylphosphine, diethylazodicarboxylate) in an apolar solvent such as dichloromethane, to give a compound of general formula B-3. The compound of general formula B-3 is converted to the alcohol of general formula B-4, by treatment with a reducing agent such as sodium borohydride in a solvent such as tetrahydrofuran. The alcohol of general formula B-4 is reacted with methanesulfonyl chloride in the presence of a base such as triethylamine, in a solvent such as dichloromethane, to obtain the compound of general formula B-5. The compound of general formula B-5 is reacted with tetrabutylammonium cyanide in a solvent such as acetonitrile, to obtain a compound of general formula B-6. A compound of general formula B-6 is reacted with hydroxylamine hydrochloride in the presence of a base such as triethylamine, in a solvent such as tetrahydrofuran and methanol to obtain a compound of general formula B-7. A compound of general formula B-7 is converted to the product of general formula B-8, by reaction with phenyl chloroformate in the presence of a base such as pyridine, and treatment of this intermediate product with a base such as 1,8- diazabicyclo [5.4.0] undec-7-ene in a solvent such as aceionifril.
Example 10 was made according to procedure B.
Other compounds can be obtained according to, or by known procedures.
Procedure C
A compound of general formula C-1 in which R1 = F and U, V, W, Y, Z, R2, R3, R4, R5, R6 and R7 are as defined, reacted with a nucleophile, p . g., sodium methylate, to obtain a compound of general formula C-2. A compound of general formula C-2 is reacted with hydroxylamine hydrochloride in the presence of a base such as erytylamine, in a solvent such as leihydrofuran and methanol to obtain a compound of general formula C-3. A compound of general formula C-3 is converted to the production of general formula C-4, by reaction with phenyl chloroformate in the presence of a base such as pyridine, and treatment of this intermediate product with a base such as
1,8-diazabicyclo [5.4.0] undec-7-ene in a solvent such as acetoniiryl.
Examples 11, 22 and 23 were made according to procedure C.
Other compounds can be obtained according to, or by known methods.
Procedure D:
A compound of general formula D-2 in which R is -OH or -SH and U, V, W, R5, R6 and R7 are as defined above, is reacted with a fluoronitrile of general formula D-1 in wherein R1, R2, R3 and R4 are as defined above, in the presence of a base such as cesium carbonate or sodium hydride, in a solvent such as dimethylformamide, to give a compound of general formula D-3 wherein U, V, W, R1, R2, R3, R4, R5, R6 and R7 are as defined. If Y = S in the compound of general formula D-3, the sulfur atom can be oxidized (Y = SO or Y = SO2) by methods known in the art, for example, an oxidizing agent such as meiachloroperbenzoic acid in a solvent apolar such as dichloromethane. As described in process A, the compound D-3 is reacted with hydroxylamine hydrochloride in the presence of an alkaline base such as triethylamine, in a solvent such as tetrahydrofuran and methanol to obtain a compound of general formula D-4. Compound D-4 is converted to the product of general formula D-5 by reaction with phenyl chloroformia in the presence of an alkaline base such as pyridine, and treatment of this is carried out in the middle with a base such as 1,8-diazabicyclo [5.4. 0] undec-7-ene in a solvent such as acetylonitrile.
Examples 15-19, 37-44 and 50 were obtained according to procedure D.
Other compounds can be obtained according to, or by known methods.
Method E: This procedure is used to synthesize the structural unit E-4 in which U, V, R5, R6 and R7 are as defined above.
A halide of general formula E-1 in which U, V, R5, R6 and R7 are as defined above, is reacted with tetrabutylammonium cyanide in a solvent such as acetonitrile, to obtain a compound of general formula E- 2. This compound of general formula E-2 is hydrolyzed with a base such as sodium hydroxide to obtain the carboxylic acid of general formula E-3. The carboxylic acid of general formula E-3 is reduced with a reducing agent, e.g. eg, borane, to alcohol of general formula E-4.
Other compounds can be obtained according to, or by known methods.
Procedure F: This procedure is used to synthesize the structural units F-5 and F-6 in which R5, R6 and R7 are as defined above and U is S or O.
F-1 R '= methyl or ethyl F-2
A methyl or ethyl ester of 3-oxo-butyric acid of general formula F-1 in which R 5 is as defined above, is reacted with sulfuryl chloride to give a chloro substituted compound of general formula F-2. This compound of general formula F-2 is reacted with a benzamide or thiobenzamide of general formula F-3, wherein U is S or O and
R7 and R8 are as defined, to obtain a phenylthiazole phenylthiazole ester of general formula F-4. The ester of the general formula F-4 is reduced with a reducing agent, e.g. eg, lithium aluminum hydride, alcohol of general formula F-5. The alcohol of the general formula F-5 is reacted with methanesulfonyl chloride in the presence of a base such as erytylamine, in a solvent such as dichloromethane to obtain a structural unit of formula F-6, in which R5, R6 and R7 are as they have been defined before.
Other compounds can be obtained according to, or by known methods.
Procedure G: This procedure is used to synthesize the spherical units G-4, where V = S or O and R5, R6 and R7 are as defined above.
R '= methyl or ethyl Hal = Cl, Br
A halide of general formula G-1 in which Hal = chlorine or bromine, R '= methyl or ethyl and R 5 is as defined above, is reacted with a benzamide or thiobenzamide of general formula G-2 in which V = O or S and R6 and R7 are as defined above, to obtain an ester of general formula G-3. The ester of the general formula G-3 is reduced with a reducing agent, e.g. eg, lithium aluminum hydride, alcohol of general formula G-4.
Other compounds can be obtained according to, or by known methods.
Method H1: This procedure is used to synthesize the structural units H-4 and H-5 in which R5, R6 and R7 as defined above.
The compound H-1 wherein R5 is as defined above, is reacted with the aldehyde H-2 wherein R6 and R7 are as defined above, in ethanol and using hydrogen chloride, to give the compound H-3.
Compound H-3 is refluxed in phosphoryl chloride to give compound H-4. This is heated to reflux with sodium iodide in acetone. This gives the compound H-5.
You can compose them according to, or by known procedures.
US 10 / 788,997; US 10 / 788,996 US 10 / 789,017 Procedure
A compound of general formula 1-1 (which can be synthesized according to procedures A, B and D, where the substitution of R5 of the structural units A-2, B-2 and D-2 is -CH2-OGP; these structural units are described in processes J and K) where X, Y, Z, W R1, R2, R3, R4, R6 and R7 are as defined and GP means a protective group such as a terahydropyranyl ether. The procyclic group of the compound of general formula 1-1 is eliminated, in case GP is tetrahydropyranyl ether, for example, by fractionation with an acid in a polar solvent such as methanol to obtain a compound of general formula 1-2. The hydroxyl group of the compound of general formula 1-2 is converted to a leaving group (GS) for example a mesylate by trapping with methanesulfonyl chloride in the presence of a base such as triethylamine in a solvent such as dichloromethane to obtain a compound of general formula 1 -3. The compound of general formula 1-3 is reacted with an alcohol in the presence of a base such as sodium hydride to obtain a compound of general formula 1-4, where the definition of -CH 2 -O-R 8 is included in the definition of R 5 as described. The compound of general formula I-4 is reacted with hydroxylamine hydrochloride in the presence of a base such as triethylamine, in a solvent such as tetrahydrofuran and methanol to obtain a compound of general formula I-5. A compound of general formula I-5 is converted into the product of general formula I-6, by reaction with phenyl chloroformate in the presence of a base such as pyridine, and treatment of this in-center product with an alkaline base such as 1, 8- diazabicyclo [5.4.0] undec-7-ene in a solvent such as acetylonitrile.
Examples 33-36 were obtained according to procedure I.
Other compounds can be obtained according to, or by known procedures.
Procedure J: This procedure is used to synthesize the structural units A-2, B-2 and D-2 where R5 = -CH2-OGP (GP = protection group), U is S or O, W = -CH2, R = -OH or -Cl and R6 and R7 are as defined above.
A compound of general formula J-1 (which can be synthesized according to the process F (J-1 is part of F-4)) where U is S or O, R 'is alkyl as me yyl or ethyl, and R6 and R7 are as defined above, a joke is treated by treatment with N-bromosuccinimide in an apolar solvent as the tetraioromean to obtain a compound of general formula J-2. The bromide of general formula J-2 is converted to the alcohol of general formula J-3 by treatment with silver trifluoroacetate in a solvent such as dimethylformamide and subsequent heating of the trifluoroacetate resulting in a solvent such as ethanol. The hydroxyl group of the compound of general formula J-2 is for example prepared as tetrahydropyranyl ether by treatment with 3,4-dihydro-2H-pyran in a solvent such as dichloromethane in the presence of acid such as pyridinium para-toluenesulfonate to obtain a compound of general formula J-4. The ester of the compound of general formula J-4 is reduced with an agent such as lithium aluminum hydride in a solvent such as tetrahydrofuran to obtain the compound of general formula A-2, B-2 or D-2, where R is OH. The hydroxy group can be converted to a chlorine by irradiation with measosulfonyl chloride in the presence of a base such as triethylamine in a solvent such as dichloromethane to obtain a compound of general formula A-2, B-2 or D-2, where R is Cl .
Other compounds may be obtained according to, or by known procedures.
Procedure K: This procedure is used to synthesize the structural units A-2, B-2 and D-2 where R5 = -CH2-OGP (GP = protective group), V is N and U is O, W = -CH2- , R = -OH or -Cl and R6 and R7 are as defined above.
t3
Methyl 2-diazo-3-oxobutanoate (R '= Me) or 2-diazo-3-oxobutanoate elly (R' = Ei) is reacted with a benzamide of general formula K-1, where R6 and R7 are as it was previously defined in the presence of dirodium epifacetate in an apolar solvent such as 1,2-dichloroethane to obtain a compound of general formula K-2. The compound of general formula K-2 is cyclized to obtain a compound of general formula K-3 by treatment with triphenylphosphine and iodine in an apolar solvent such as dichloromethane.
The compound of general formula K-3 is brominated by treatment with N-bromosuccinimide in an apolar solvent such as tetrachloromethane to obtain a compound of general formula K-4. The bromide of the general formula K-4 is converted to the alcohol of the general formula K-5 by treatment with silver urea trifluoroacetal in a solvent such as dimethylformamide and after heating the trifluoroacetal resulting in a solvent such as ethanol. The hydroxyl group of the compound of general formula K-5 is prepared, for example, as a hydropyranilic ether by branching with 3,4-dihydro-2H-pyran in a solvent such as dichloromean in the presence of acid such as pyridinium para-toluenesulfonate to obtain a compound of general formula K- 6. The ester of the compound of general formula K-6 is reduced with a reducing agent such as lithium aluminum hydride in a solvent such as hydro-hydrofuran to obtain the compound of general formula A-2, B-2 or D- 2, where R is OH. The hydroxyl group can be converted to a chlorine by treatment with methanesulfonyl chloride in the presence of a base such as triethylamine in a solvent such as dichloromelan to obtain a compound of general formula A-2, B-2 or D-2, where R is Cl .
List of abbreviations: Ac acetyl Bn Benzyl Ibu Isobutyl Tbu tere-Butyl BuLi n-butyl lithium Bz benzoyl Cy ciciohexyl DCI Direct chemical ionization (EM) DCM dichloromethane DMAP N, N-dimethylaminopyridine DMF NN-dimethylarformamide DMSO dimethisulfoxide EE acetate ethyl eq equivalents ESI Electrospray ionization (EM)
FG Halogen group Hal halogen HPLC High efficiency liquid chromatography LC-MS coupled liquid chromatography with GS mass spectrometry Labile group Melyl EM EM mass spectrometry MsCI methanesulfonyl chloride NBS N-bromosuccinimide NMR Nuclear magnetic resonance P for Pd / C palladium on Coal GP Protector group iPr isopropyl nPr n-propyl Rf retention time (TLC) tere tertiary TLC Thin layer chromatography Additional compounds of formula I can be prepared correspondingly or by known procedures.
The experimental procedures for preparing the aforementioned examples are described below.
Synthesis of the structural units according to procedure F:
4-Butyl-5-chloromethyl-2- (4-trifluoromethyl-phenyl) -iazole
LÍAIH4
4-Butyl-2- (4-trifluoromethyl-phenyl) -thiazole-5-carboxylic acid methyl ester
.0 g of 3-oxo-heptanoic acid methyl ester were dissolved in 80 ml of dry dichloromelane and 2.82 ml of sulfuryl chloride were added. The reaction mixture was stirred at room temperature for 30 minutes. 20 ml of water was added and the reaction mixture was extracted five times with 30 ml portions of dichloromethane. The combined organic extracts were washed with water and saturated NaHCO3 solution and brine, and dried over MgSO4. The solvent was removed under reduced pressure to obtain 6.0 g of methyl 2-doro-3-oxo-hepanoic acid ester as crude material. This material was used without further purification. 6.0 g of 2-chloro-3-oxo-heptanoic acid methyl ester were dissolved in 50 ml of ethanol and 6.4 g of 4- (if-fluoromethyl) thiobenzamide were added. The reaction mixture was heated to reflux overnight. The solvent was removed under reduced pressure, and the residue was purified by chromatography with the eluent n-heptane: ethyl acetate = 100: 1 = >; 60: 1 This yields 7.4 g of 4-butyl-2- (4-trifluoromethyl-phenyl) -thiazole-5-carboxylic acid methyl ester in the form of a yellow oil. C 16 H 16 F 3 NO 2 S (343.37), MS (ESI): 344.1 (M + H +), Rf (n-heptane: ethyl acetate = 4: 1) = 0.62.
[4-Butyl-2- (4-trifluoromethyl-phenyl) -thiazole-5-p-methanol
1.2 g of lithium aluminum hydride were dissolved in 100 ml of dry tetrahydrofuran. 5.3 g of 4-butyl-2- (4-trifluoromethyl-phenyl) -thiazole-5-carboxylic acid methyl ester, dissolved in 100 ml of tetrahydrofuran, were added. The reaction mixture was stirred at room temperature over a period of one hour, and then 50 ml of saturated ammonium chloride solution and 50 ml of a 1 molar hydrochloric acid solution were added. The reaction mixture was extracted five times with 60 ml portions of ethyl acetate. The combined organic layers were dried over MgSO4 and the solvent was removed under reduced pressure to provide 4.6 g of [4-butyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -methanol as a yellow oil, which solidified after standing at room temperature. C15H16F3NOS (315.36), MS (ESI): 316.4 (M + H +).
4-Butyl-5-chloromethyl-2- (4-trifluoromethyl-phenyl) -thiazole
1.Og of [4-butyl-2- (4-trifluoromethyl-phenyl) -thiazoI-5-yl-methanol was dissolved in 50 ml of dichloromethane, and 0.88 ml of triethylamine and 0.39 ml were added. ml of methanesulfonyl chloride. The reaction mixture was stirred at room temperature for a period of three hours, and then 100 ml of dichloromethane was added, and the reaction mixture was washed with 50 ml of saturated NaHCO3 solution, water and brine. The organic layer was dried over MgSO4 and the solvent was removed under reduced pressure. This gave 1.0 g of 4-butyl-5-chloromethyl-2- (4-trifluoromethyl-phenyl) -thiazole as a yellow oil. C15H15CIF3NS (333.81), MS (ESI): 334.3 (M + H +).
| "4-But-3-enyl-2- (4-trifluoromethyl-phenyl) -thiazoyl-5-yl] -methanol
According to the method described for [4-butyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -melanol, the [4-but-3-eniI-2- (4 -trifluoromethy1-pheny1) -thiazol-5-yl] -methanol from the ethyl ester of 3-oxo-hept-6-enoic acid and 4- (trifluoro) thiobenzamide. C15H14F3NOS (313.34), MS (ESI): 312 (M-H +).
["4- (3-Benzyloxy-propy-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -methanol
According to the method described for [4-butyI-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -methanol, [4- (3-benzyloxy-propyl) -2- (4 -trifluoromethyl-phenyl) -thiazol-5-yl] -methanol from the known 6-benzyloxy-3-oxo-hexanoic acid methyl ester and 4- (trifluoro) thiobenzamide. C 21 H 20 F 3 NO 2 S (407.45), MS (ESI): 408 (M + H +).
4-Butyl-5-chloromethyl-2- (4-pentafluorosulfanyl-phenyl) -thiazole
According to the method described for 4-butyI-5-chloromethyl-2- (4-trifluoromethyl-phenyl) -iazole, 4-butyl-5-chloromethyl-2- (4-pentafUuorosu-phenyl) -thiazole was obtained. from the methyl ester of 3-oxo-heptanoic acid and 4- (rentafluorosulfanyl) thiobenzamide commercially available. C 14 H 15 ClF 5 NS 2 (391, 86), MS (ESI): 392.3 (M + H +).
-Chloromethyl-4-methyl-2- (4-pentafluorosulfanyl-phenyl) -thiazole
According to the method described for 4-butyI-5-chloromethyl-2- (4-trifluoromethyl-phenyl) -thiazole, 5-cyoromethyl-4-methyl-2- (4-pentafluorosulfanyl-phenyl) -thiazole was obtained. from ethyl 2-chloroacetoacetate and 4- (pentafluorosulfanyl) thiobenzamide commercially available. C11H9CIF5NS2 (349.77), MS (ESI): 350.4 (M + H +).
2- (4-Methoxy-phenyl-4-methyl-oxazole-5-carboxylic acid ethyl ester
40.0 g of 4-methoxybenzamide were dissolved in 400 ml of ethanol. The mixture was heated to 50 ° C and 48.8 ml of ethyl 2-chloroacetoacetate were added in one portion. The resulting mixture was refluxed for four days. The reaction mixture was cooled and the solvent was removed under reduced pressure. The resulting residue was purified by flash chromatography on silica gel to obtain 23.5 g of 2- (4-methoxy-phenyl) -4-methyl-oxazole-5-carboxylic acid ethyl ester as a solid. C 14 H 15 NO 4 (261.28), MS (ESI): 262.1 (M + H +).
Synthesis of the structural units according to the procedure E:
2- [4-Butyl-2- (4-trifluoromethyl-phenyl) -thiazole-5-ip-ethanol
4-Buyyl-2- (4-ír-trifluoromethyl-phenyl) -thiazole-5-ip-acetonitrile
3.0 g of 4-butyl-5-chloromethyl-2- (4-trifluoromethyl-1-phenyl) -thiazo I were dissolved in 50 ml of acetonitrile. To this solution was added 2.89 g of tetrabuylammonium cyanide. The reaction mixture was stirred at ambient temperature for 30 minutes. Then a mixture of saturated NaHCO3 solution, ice and ethyl acetate was added. The aqueous phase was separated and extracted three times in 30 ml portions of ethyl acetate. The combined organic layers were washed with ice water and brine, and dried over MgSO4. The solvent was removed in vacuo. The residue was purified by flash chromatography with the eluent n-heptane: ethyl acetate = 5: 1 to provide 1.1 g of [4-butyl-2- (4-trifluoromethyl-phenyl) -thiazole-5-i0-acetonitrile in the form of aceife C 16 H 15 F 3 N 2 S (324.37), MS (ESI): 325.3 (M + H +), Rf (n-heptane: ethyl acetate = 4: 1) = 0.32.
F4-Butyl-2- (4-if-trifluoromethyl-phenyl) -thiazol-5-yl] -acetic acid
1.1 g of [4-butyl-2- (4-yl-1-fluoromethyl-phenyl) -thiazol-5-yl] -acetonitrile was dissolved in a mixture of 1 ml of water and 6 ml of isopropanol. 1.36 g of sodium hydroxide were added, and the mixture was heated to 100 ° C. After three hours, the cooled reaction mixture was neutralized with concentrated hydrochloric acid and extracted three times with 50 ml portions of ethyl acetate. The combined organic extracts were dried over MgSO 4 and the solvent was removed to provide 1.15 g of crude [4-butyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -acetic acid in the form of a brown oil. This material was used without purification. C 16 H 16 F 3 NO 2 S (343.37), MS (ESI): 344.4 (M + H +).
2 - ["4-Butyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -ethanol
1.15 g of crude [4-butyl-2- (4-trifluoromethyl-phenyl) -thiazole-5-yl] -acetic acid was dissolved in 50 ml of tetrahydrofuran and cooled in an ice bath at 0 ° C. At 0 ° C, 9.3 ml of borane complex solution and 1 M tetrahydrofuran were added. The reaction mixture was heated to 55 ° C and stirred for one hour at this temperature. The reaction mixture was cooled in an ice bath and 50 ml of water was added. The organic layer was added.
The tetrahydrofuran was removed in vacuo, and the residue was extracted three times with 80 ml portions of ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, and the solvent was removed in vacuo to provide 1.1 g of 2- [4-butyl-2- (4-trifluoromethyl-phenyl) -thiazoI-5. -iI] - crude ethanol in the form of a brown oil. This material was used without purification. C 16 H 18 F 3 NOS (329.39), MS (ESI): 330.4 (M + H +).
Synthesis of the structural units according to the G procedure:
2- [5-methyl-2- (4-pentafluorosulfanyl-phenyl) -thiazole-4-p-ethanol
4-Pentafluorosulfanyl-benzamide
g of 4-pentafluorosulfanylbenzoic acid in 300 ml of thionyl chloride were heated to reflux for three hours. The thionyl chloride was removed under reduced pressure, and the resulting residue was dissolved in 100 ml of tetrahydrofuran. This solution was added dropwise to 80 ml of a concentrated solution of ammonia. The solvent was removed in vacuo and the resulting residue was dissolved in 300 ml of water and extracted three times with 250 ml portions of ethyl acetate. The combined organic layers were dried over MgSO 4, and the solvent was removed in vacuo to provide 24.5 g of 4-penfafluorosu-phenyl-benzamide as a yellow solid. This material was used without purification. C7H6F5NOS (247.19), MS (ESI): 248 (M + H +).
4-Pentafluorosulfanyl-thiobenzamide
9 g of phosphorus pentasulfide were dissolved in 300 ml of toluene. 16.8 g of NaHCO3 were added and the mixture was heated to reflux for thirty minutes. Then, 25.2 g of 4-pentafluorosulfanyl-benzamide dissolved in 200 ml of uenole was added, and the reaction mixture was stirred at 90 ° C for three hours. The solvent was removed in vacuo and the resulting residue was dissolved in 300 ml of brine and extracted three times with 250 ml portions of dichloromean. The combined organic layers were dried over MgSO 4, and the solvent was removed in vacuo to provide 17.4 g of 4-penyafluorosu-phenyl-thiobenzamide as a yellow solid. C7H6F5NS2 (263.25), MS (ESI): 264 (M + H +).
[5-Methyl-2- (4-penyfluorosulfanyl-phenyl) -thiazole-4-p-acylic acid ethyl ester
g of 4-pentafluorosulfanyl-thiobenzamide and 9.93 g of 4-bromo-3-oxo-pentanoic acid methyl ester were dissolved in 30 ml of acetone and heated to reflux for one hour. The cooled reaction mixture was diluted by adding 250 ml of ethyl acetate and washed three times with saturated NaHCO3 solution. The organic layer was dried over MgSO4 and the solvent was removed in vacuo. The residue was purified by flash chromatography with the eluent n-heptane: ethyl acetoto = 5: 1 to give 4.5 g of [5-mephyl-2- (4-penyafUuorosulfani-phenyl) -thiazole-4-ethyl ester. -iI] - acetic in the form of an oil that solidified upon standing. C 13 H 12 F 5 NO 2 S 2 (373.37), MS (ESI): 374 (M + H +).
2- [5-Methyl-2- (4-pentefluorosulfanyl-phenyl) -thiazole-4-ip-ethanol
458 mg of lithium aluminum hydride were suspended in 100 ml of dry teirahydrofuran and cooled in an ice bath. To this ice-cooled suspension was added 4.5 g of [5-methyl-2- (4-pentafluorosu-phenyl) -thiazol-4-yl] -acetic acid ethyl ester, dissolved in 50 ml of tetrahydrofuran. The reaction mixture was stirred for one hour. Then 300 ml of effel acetate and 20 ml of saturated solution of NH4Cl were added. The organic layer was separated. The aqueous phase was extracted three times with 50 ml portions of ethyl acetate. The combined organic layers were dried over MgSO4, and the solvent was removed in vacuo. The residue was purified by flash chromatography with the eluent n-heptane: ethyl acetate = 2: 1 to provide 1.44 g of 2- [5-methyl-2- (4-penyafluorosuIfaniI-phenyI) -thiazoI-4-ylj -ethanol in the form of an oil that solidified upon standing. C12H12F5NOS2 (345.36), MS (ESI): 346 (M + H +).
Synthesis of the structural units according to the procedure H: 4-Yodomethyl-2- (4-mexoxyphenyl) -5-methyloxazole
3-2- (4-methoxy-pheno-4,5-dimethyl-oxazole oxide)
50.6 g of diacetyl monooxime and 66J ml of 4-meioxy-benzaldehyde are added to 100 ml of glacial acetic acid, and gaseous HCl is ingested for 30 minutes, with cooling with ice. The product is precipitated in the form of the hydrochloride, by the addition of methyl tertiary-buffyl ether and filtered with suction, and the precipitate is washed with methyl ether-bulyl ether. The precipitate is suspended in water and the pH is made alkaline using ammonia.
The reaction mixture is extracted twice with 200 ml of dichloromethane in each case, the combined organic phases are dried over MgSO 4 and then the solvent is removed under reduced pressure. This produces 82.1 g of the 2- (4-methoxy-phenyl) -4,5-dimethyl-oxazole-3-oxide in the form of a white solid. C12H13NO3 (219.24), MS (ESI) = 220 (M + H +).
4-Chloromethyl-2- (4-methioxy-phenyl) -5-methyl-1-oxazole
82 g of 2- (4-methoxy-phenyl) -4,5-dιmethyl-oxazole 3-oxide are dissolved in 400 ml of chloroform, 37.4 ml of phosphorus oxychloride are added, and the mixture it was heated to reflux for 30 minutes. The reaction mixture is cooled to 0 ° C, the pH is made slightly alkaline using ammonia, and the mixture is extracted three times with 100 ml of ethyl acetate in each case. The combined organic phases are washed with water and dried over MgSO 4, and then the solvent is removed under reduced pressure. The residue is purified on silica gel using as the mobile phase n-heptane: ethyl acetate = 80: 1 = > 5: 1 This yields 46.3 g of 4-chloromethyI-2- (4-methoxy-phenyl) -5-methyl-oxazole as a yellow solid. C12H12CINO2 (237.69), MS (ESI) = 238 (M + H +), Rf (n-heptane: ethyl acetate) = 7: 3) = 0.45.
4-Yodomethyl-2- (4-methoxy-phenyl) -5-methyl-oxazole
19.9 g of 4-chloromethyl-2- (4-methoxy-phenyl) -5-methyl-oxazole were heated together with 37 J g of sodium iodide in 300 ml of acetone at reflux temperature for 2 hours . After cooling the reaction mixture, the solvent was removed under reduced pressure, and the residue was dissolved in 300 ml of methyl tert-butyl-ether, the mixture washed with saturated Na 2 S 2 O 3 solution, and dried over MgSO 4, and then the solvent is removed under reduced pressure. This yields 49.8 g of 4-iodoxy-2- (4-methoxyphenyl) -5-meityloxazole in the form of a light brown solid. C12H12INO2 (329.14), MS (ESI): 330 (M + H +).
4-Yodomethyl-5-methyl-2-p-biphenyloxazole
In a manner analogous to the synthesis of the structural unit of 4-iodomido-2- (4-mephoxyphenyl) -5-methyloxazole, the monooxime of diacetyl and the p-biphenylcarbaldehyde gave 4-iodoxy-5-methyl-2- p-bifenoxazole. C12H121NO (375.21), MS (ESI): 376 (M + H +).
Synthesis of the sírucíurales units according to the procedure J:
[2- (4-methoxy-phenyl) -4- (tetrahydro-pyrn-2-yloxymethyl) -oxazol-5-yl] -methanol and 5-cyoromethyl-2- (4-methoxy-phenyl) -4- (tetrahydro-pyran-2-yloxymethyl) -oxazole
4-bromomethyl-2- (4-methoxy-phenyl) -oxazole-5-carboxylic acid ethyl ester
To a boiling solution of 23.5 g of 2- (4-methoxy-phenyl) -4-methyl-oxazoI-5-carboxylic acid ethyl ester in 250 ml of telracloromethane was added, little by little, a mixture of 5-methoxy-5-methoxy-5-carboxylic acid. , 92 g of 2,2'-azobis (2-methypropionitrile) and 19.3 g of N-bromosuccinimide. The reaction mixture was refluxed for seven hours. The cooled reaction mixture was filtered on a Celite bed and the solvent was removed in vacuo to obtain 30 Jg of the crude 4-bromomethyl-2- (4-meioxy-phenyl) -oxazole-5-carboxylic acid ethyl ester. The material was used in the next step without further purification. C14H14BrNO4 (340.18), MS (ESI): 340.0 and 342.0 (M + H +), Rf (ethyl acetate: n-heptane = 7: 3) = 0.43).
Elylyl ester of 4-hydroxymethyl-2- (4-methoxy-phenoxy-5-carboxylic acid)
30Jg of the crude 4-bromomethyl-2- (4-methoxy-phenyl) -oxazoI-5-carboxylic acid ethyl ester was dissolved in 170 ml of dry dimethyloxyformamide. 29.95 g of silver urea trifluoroacetate was added and the mixture was stirred at room temperature overnight. 100 ml of brine was added and the mixture was stirred for one hour. The reaction mixture was filtered with a celiac bed, the solvent was removed in vacuo and the resulting residue was dissolved in 200 ml of ethanol. The mixture was refluxed for three hours. The solvent was then removed in vacuo and the residue dissolved in water and extracted five times with ethyl acetate. The combined organic layers were dried over MgSO 4, the solution was removed in vacuo and the residue was purified by flash chromatography on silica gel (eluting with n-heptane: ethyl acetate = 5: 1 => ethyl acetate) to obtain 17.8 g of 4-hydroxymethyl-2- (4-methoxy-phenyl) -oxazole-5-carboxylic acid ethyl ester as a solid. C 14 H 15 NO 5 (277.28), MS (ESI): 278.1 (M + H +), Rf (ethyl acetate: n-heptane =
1: 2) = 0.11).
2- (4-Methioxy-phenyl) -4- (tetrahydro-pyran-2-yloxymethyl) -oxazole-5-carboxylic acid ethyl ester
.0 g of the 4-hydroxymethyl-2- (4-methoxy-phenyl) -oxazole-5-carboxylic acid ethyl ester were dissolved in 85 ml of dichloromethane. 4.0 ml of 3,4-dihydro-2H-pyran and 1.85 mg of pyridinium p-toluenesulfonate were added and the reaction mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel (eluting with n-heptane: ethyl acetate = 4: 1 => 1: 1) to obtain 12.3 g of the ethyl ester. of 2- (4-methoxy-phenyl) -4- (teirahydro-pyran-2-yloxymethyl) -oxazoI-5-carboxylic acid as an oil. C19H23NO6 (361, 40), MS (ESl): 362.2 (M + H +), 278.2 (M-THP + H +), Rf (ethyl acetate: n-heptane = 1: 1) = 0, 56).
[2- (4-Methoxy-phenyl) -4- (1-yrahydro-pyran-2-yloxymethyl-p-oxazole-5-ill-methanol
To a cooled suspension of 2J3 g of lithium aluminum hydride in 180 ml of tetrahydrofuran was added a solution of 12.3 g of 2- (4-methoxy-phenyl) -4- (tephrahydro-pyran) ethyl ester. 2-yloxymethyl) -oxazole-5-carboxylic acid in 120 ml of tetrahydrofuran at 0 ° C. The ice bath was removed, and the reaction mixture was stirred at room temperature for one hour. The reaction mixture was again cooled in an ice bath and 100 ml of ethyl acetate was added followed by the addition of 300 ml of methyl ether-builyl ether. Then a solution of 10.92 g of sodium hydroxide in 12.3 ml of water was added. The solid precipitate was filtered off through a pad of celite. The filtrate was dried over MgSO4 and then the solvent was removed in vacuo to obtain 11.8 g of [2- (4-trioxy-phenol) -4- (teirahydro-pyran-2-yloxymethyl) -oxazol-5-yl. ] -methanol as a solid. C17H21NO5 (319.36), MS (ESI): 320.2 (M + H +), Rf (ethyl acetate: n-heptane = 1: 1) = 0.18).
-Chloromethyl-2- (4-meioxy-phenyl) -4- (tetrahydro-pyran-2-yloxymethyl) -oxazole
2.0 g of [2- (4-methoxy-phenyl) -4 ~ (terahydro-pyran-2-yloxymethyl) -oxazol-5-yl] -methanol were dissolved in 30 ml of dichloromethane and cooled in a water bath. ice. 0.88 ml of triethylamine was added, followed by the addition of 0.49 ml of methanesulfonyl chloride. The ice bath was removed, and the resulting mixture was stirred at room temperature overnight. The reaction mixture was then washed with water and brine, dried over MgSO 4 and the solvent was removed in vacuo to obtain 2.5 g of 5-chloromene-2- (4-methoxy-phenol) -4- (terahydroxy) -piran-2-yloxymethyl) -oxazole as an oil that was used without further purification. C17H20CINO4 (337.81), MS (ESI): 338.2 (M + H +), Rf (ethyl acetate.n-heptane = 1: 1) = 0.42).
Synthesis of the structural units according to the procedure K:
[2- (4-Meioxy-phenyl) -5- (toirahrodro-pyran-2-yloxymethyl) -oxazol-4-yl] -methanol and ester 2- (4-meioxy-phenyl) -5- ( tetrahydro-pyran-2-yloxymethip-oxazol-4-ylmethylic acid methane sulphonic acid
2- (4-methoxy-benzoyl! Amino) -3-oxo-buiric acid efflic ester
A solution of 12.1 g of ethyl 2-diazo-3-oxobutanoate2 in 100 ml of 1,2-dichloroethane was added dropwise to a boiling solution of 9.0 g of 4-methoxybenzamide and 1 g. , 05 g of rhodium acetate dimer (ll) in 200 ml of dry 1,2-dichloroethane. The mixture was refluxed for thirty minutes, allowed to cool, evaporated in vacuo and purified by flash chromatography on silica gel to obtain 11.3 g of 2- (4-meloxy-benzoyl) ethyl ester. Iamino) -3-oxo-buir. C 14 H 17 NO 5 (279.30), MS (ESI): 280.2 (M + H +), Rf (ethyl acetate: n-heptane = 1: 1) = 0.32).
2- (4-Methoxy-phenyl-5-methyl-oxazole-4-carboxylic acid ethyl ester
Sequentially 23.2 ml of triethylamine and one
! J.Chem.Soc, Perkin Trans. 1, 1998, 591-600.
Solution of 11.3 g of the 2- (4-mephoxy-benzoylamino) -3-oxo-butyric acid ethyl ester in 200 ml of dichloromethane was added to a stirred solution of 20.5 g of iodine and 21.2 g of phenylphenylphosphine in 500 ml of dry dichloromethane. The reaction mixture was stirred at ambient temperature overnight. The solvent was evaporated in vacuo and the resulting residue was purified by flash chromatography on silica gel to obtain 6.0 g of ethyl 2- (4-methoxy-phenyl) -5-methyl-oxazoI-4- ethyl ester. carboxylic acid as a light yellow solid. C 14 H 15 NO 4 (261, 28), MS (ESI): 262.2 (M + H +), Rf (ethyl acetate: n-hepiene = 2: 1) = 0.31).
-Bromometyl-2- (4-meioxy-phenyl) -oxazole-4-carboxylic acid eylyl ester
To a boiling solution of 6.0 g of the 2- (4-meioxy-phenyl) -5-methyl-oxazole-4-carboxylic acid eyl ester in 100 ml of tetrarchlor-methane a mixture of 1 , 51 g of 2,2'-azobis (2-methylpropionitrile) and 4.9 g of N-bromosuccinimide. The reaction mixture was refluxed for hours. The cooled reaction mixture was filtered on a celite bed and the solvent was removed in vacuo to obtain 10.6 g of the crude 5-bromomeyyl-2- (4-meioxy-phenyl) -oxazole-4-carboxylic acid ethyl ester. , which contained some of the dibrominated byproduct. The material was used in the next step without further purification. C14H14BrNO4 (340.18), MS (ESI): 340.0 and 342.0 (M + H +), Rf (ethyl cell-heptane = 2: 1) = 0.27).
-hydroxymethyl-2- (4-meioxy-phenyl) -oxazole-4-carboxylic acid eylyl ester
8.0 g of the 5-bromomethyl-2- (4-meioxy-phenyl) -oxazole-4-carboxylic acid ethyl ester were dissolved in 50 ml of dry dimethylformamide. 7.8 g of silver trifluoroacetate were added and the mixture was stirred at room temperature for two hours. 30 ml of brine was added and the mixture was stirred for two hours. The reaction mixture was filtered with a pad of celite, the solvent was removed in vacuo and the residue was dissolved in 200 ml of elanol. The mixture was refluxed for three hours. The solvent was then removed in vacuo and the residue dissolved in water and extracted five times with ethyl acetate. The combined organic layers were dried over MgSO 4, the solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel (eluting with n-heptane: ethyl acetate = 2: 3 = >; ethyl acetate) to obtain 4.8 g of the 5-hydroxymethyl-2- (4-methoxy-phenyl) -oxazole-4-carboxylic acid ethyl ester as a solid. C 14 H 15 NO 5 (277.28), MS (ESl): 278.1 (M + H +), Rf (ethyl acetate: n-heptane = 1: 2) = 0.09).
2- (4-methoxy-phenyl) -5- (teirahydro-pyran-2-yloxymethyl) -oxazole-4-carboxylic acid eylyl ester
4.8 g of the 5-hydroxymethyl-2- (4-methoxy-phenyl) -oxazole-4-carboxylic acid eylyl ester were dissolved in 75 ml of dichloromethane. 1.9 ml of 3,4-dihydro-2H-pyran and 870 mg of pyridinium p-toluenesulfonate were added and the reaction mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel (eluting with n-heptane: ethyl acetate = 3: 1 => 1: 1) to obtain 5.3 g of the ethyl ester. of 2- (4-methoxy-phenyl) -5- (teirahydro-pyrn-2-yloxymethyl) -oxazole-4-carboxylic acid. C19H23NO6 (361, 40), MS (ESI): 362.2 (M + H +), 278.1 (M-THP + H +).
| "2- (4-Methoxy-phen-p-5- (teirahydro-pyran-2-yloxymethyl) -oxazole-4-ill-methanol
.3 g of the 2- (4-methoxy-phenyl) -5- (leirahydro-pyran-2-yloxymethyl) -oxazoI-4-carboxylic acid ethyl ester were dissolved in 100 ml of teirahydrofuran and cooled in a water bath. ice. 21.8 ml of a one molar solution of lithium aluminum hydride in tetrahydrofuran was added. The ice bath was removed, and the reaction mixture was stirred at ambient temperature for several minutes. Again the reaction mixture was cooled in an ice bath and 6 ml of water, 12 ml of 15% NaOH and 18 ml of water were added sequentially. After stirring for one hour at room temperature, the reaction mixture was filtered on a pad of celite and washed with ethyl acetate. The filtrate was dried over MgSO 4 and the solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel (eluting with n-heptane: ethyl acetate = 6: 4 => 9: 1; ethyl) to obtain 3.0 g of [2- (4-methoxy-phenyl) -5- (tetrahydro-pyran-2-yloxymethyl) -oxazol-4-yl] -methanol. C17H21NO5 (319.36), MS (ESI): 320.2 (M + H +).
Ester 2-f4-meioxy-fenip-5- (1-ehydro-pyran-2-yloxymethyl) -oxazol-4-ylmethylic acid of methanesulfonic acid
0.44 g of [2- (4-methoxy-phenyl) -5- (tetrahydro-pyran-2-yloxymethyl) -oxazol-4-yl] -melanol was dissolved in 30 ml of dichloromethane and cooled in a bath of ice. 0.29 ml of triethylamine was added, followed by the addition of
0.13 ml of methanesulfonyl chloride. The reaction mixture was stirred at 0 ° C for one hour, then the ice bath was removed and the resulting mixture was stirred at room temperature for an additional hour. After the reaction mixture was washed with water and brine, dried over MgSO 4 and the solvent removed in vacuo to obtain 0.55 mg of the ester 2- (4-methoxy-phenyl) -5- (tetrahydro-pyran-2-yl) yloxymethyl) -oxazole-4-ylmethylic acid methane sulphonic acid as an oil that was used without further purification. C 18 H 23 NO 7 S (397.45), MS (ESI): 398.2 (M + H +).
Example 1
3-. { 2-Fluoro-4- 4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-ylmethoxy-phenyl} -4H- [1.2.41-Oxadiazol-5-one Example 1
[4-Methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl-1-mei-anol
.0 g of 4-mefyl-2- (4-yltrluoromethyl-phenyl) -thiazole-5-carboxylic acid were dissolved in 50 ml of hydrofuran in the argon atmosphere. 69J ml of borane-teirahydrofuran complex (1 molar solution in tetrahydrofuran) was added and the mixture was heated to reflux for three hours. To the cooled reaction mixture was added water and the solvent was removed in vacuo. The residue was extracted five times with 50 ml portions of ethyl acetate.
The combined exiphases were dried over MgSO4. The solvent was removed under vacuum to obtain 9.3 g of [4-mephi-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -methanol as a yellow solid. C12H10F3NOS (273.28), MS (ESI): 274.2 (M + H +), Rf = 0.21 (n -heptane: acetyl ether = 2: 1).
-Chloroxy-4-meityl-2- (4-yltrluoromethyl-phenyl) -iazole
3.0 g of [4-methyl-2- (4-trifluoromethyl-phenyI) -thiazoI-5-yl] -methanol was dissolved in 50 ml of dichloromethane, and 3.0 ml of amyrylamine was added followed by the addition of 1.36 ml of methanesulfonyl chloride. The reaction mixture was stirred at ambient temperature for two hours. They were added100 ml of dichloromethane and the mixture was washed with saturated sodium hydrogen carbonate solution, water and brine. The organic layer was dried over MgSO4. The solvent was removed in vacuo to obtain 3.3 g of 5-coryloyl-4-meityl-2- (4-trifluoromethyl-phenyl) -iiazole as a brown oil. C12H9CIF3NS (291, 72), MS (ESI): 292.2 (M + H +).
2-Fluoro-4-f4-methyl-2- (4-trifluoromethyl-phenoxyazol-5-ylmethoxy-benzonitrile
560 mg of 5-chloromethyl-4-methyl-2- (4-trifluoromethyl-phenyl) -thiazole was dissolved in 10 ml of dimethylformamide. 1.2 g of cesium carbonate and 395 mg of 2-fluoro-4-hydroxybenzonitrile were added and the mixture was stirred at room temperature for three hours. Then, 50 ml of methyl tert-buffyl ether was added, the mixture was washed with brine and dried over MgSO 4. The solvent was removed in vacuo. The resulting crude material was purified by reverse phase HPLC, to obtain 153 mg of 2-fluoro-4- [4-methyl-2- (4-frifluoromethyl-phenyl) -thiazol-5-ylmeyoxy] -benzontromyl in the form of amorphous lyophilisate. C19H12F4N2OS (392.38), MS (ESI): 393.1 (M + H +).
2-Fluoro-N-hydroxy-4-r4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-ylmethoxy-benzamidine
153 mg of 2-fluoro-4- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazoI-5-ylmethoxy] -benzonitrile was dissolved in a mixture of 1 ml of irrahydrofuran and 2 ml of methanol. 265 mg of hydroxylamine hydrochloride was added followed by the addition of 0.5 ml of triefylamine. The reaction mixture was stirred at 60 ° C for twenty hours. The solvents were removed in vacuo and the resulting residue was poured into water and extracted five times with ethyl acetate. The combined organic extractions were washed with brine, dried over MgSO 4, and the solvent was evaporated in vacuo to obtain 138 mg of 2-fluoro-N-hydroxy-4- [4-meityl-2- (4-trifluoromethyl-phenyl) -thiazo I-5-ylmeyoxy] -benz-amidine in the form of a crude material. C 19 H 15 F 4 N 3 O 2 S (425.41), MS (ESI): 426.1 (M + H +).
3-. { 2-Fluoro-4-r 4 -methyl-2- (4-yltrluoromethyl-pheno-thiazol-5-ylmethoxy] -phenyl} -4 H- [1, 2,4"loxa-diazol-5-one]
Example 1 138 mg of 2-fluoro-N-hydroxy-4- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-ylmethoxy] -benzamidine were dissolved in 2 ml of dichloromethane. 35 μl of pyridine and 53 μl of phenyl chloroformate were added, and the mixture was stirred at ambient temperature for thirty minutes. The reaction mixture was diluted by addition of 20 ml of ethyl acetate, washed with brine, and dried over MgSO4. The solvent was evaporated in vacuo. The resulting residue was dissolved in 2 ml of acetylonil and 105 μl of 1,8-diazabicyclo [5.4.0] undec-7-ene was added. The reaction mixture was stirred at room temperature for 10 minutes. The mixture was evaporated in vacuo and the resulting crude material was purified by reverse phase HPLC to obtain 70 mg of 3-. { 2-fIuoro-4- [4-methyI-2- (4-ylfluoromethyl-phenyl) -yiazol-5-ylmeyoxy] -phenyl} -4H- [1, 2,4] oxadiazol-5-one in the form of an amorphous lyophilizate. C 20 H 13 F 4 N 3 O 3 S (451, 40), MS (ESI): 452.1 (M + H +).
EXAMPLE 2 3- (4-R4-Methyl-2- (4-trifluoromethyl-phenyl-V-thiazol-5-ylmethoxy-phenyl) -4 H-p, 2,41-oxadiazol-5-one
In accordance with the method described in Example 1, the
3-. { 4- [4-methyl-2- (4-ylfluoromethyl-phenyl) -thiazol-5-ylmethoxy] -phenyl} -4H- [1, 2,4] oxadiazol-5-one from 5-cymoremethyl-4-methyl-2- (4-trifluoromethyl-phenol) -thiazole and 4-hydroxy-benzonitrile commercially available . C 20 H 14 F 3 N 3 O 3 S (433.41), MS (ESI): 434.3 (M + H +).
EXAMPLE 3 3- (3-Methoxy-4 - ["4-methyl-2- (4-trifluoromethyl-phenyl) -thiazole-5-methylmethyl-phenyl} -4H- [1.2.41oxa] -diazol-5-one
According to the method described in Example 1, 3- was obtained. { 3-Methioxy-4- [4-methyl-2- (4-yl-Ivoromethyl-phenyl) -iazoyl-5-ylmethoxy] -phenyl} -4H- [1, 2,4] oxadiazol-5-one from 5-chloromethyl-4-methyl-2- (4-trifluoromethyl-phenyl) -thiazole and the 4-hydroxy-3-methoxy-benzonaryl available on trade. C 21 H 16 F 3 N 3 O 4 S (463.44), MS (ESI): 464.2 (M + H +).
Example 4 3-. { 2-Chloro-4-r4-meityl-2- (4-fluoro-methyl-phenyl) -i-azole-5-methylmethyl] -phenyl} -4H- [1,2,41oxa-diazol-5-one
According to the method described in Example 1, the 3- was obtained. { 2-Chloro-4- [4-meityl-2- (4-trifluoromethyl-phenyl) -liazol-5-ylmethoxy] -phenyl} -4H- [1, 2,4] oxadiazoI-5-one from 5-chloromethyl-4-methyl-2- (4-frifluoromethyl-phenyl) -thiazole and 2-chloro-4-hydroxy-benzonitrile available in the trade. C20H13CIF3N3O3S (467.86), MS (ESI): 468.2 (M + H +).
Example 5 3- (4-f4-Methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-ylmethylsulfanyl-1-phenyl} -4H-f1, 2,4] oxadiazol-5-one
According to the method described in Example 1, 3- was obtained. { 4- [4-methyl-2- (4-ylfluoromethyl-phenyl) -iazol-5-ylmethylsulfanyl] -pheni} -4H- [1, 2,4] oxadiazoI-5-one from 5-chloromethyl-4-meityl-2- (4-trifluoromethyl-phenyl) -thiazole and 4-mercaplo-benzoniiryl commercially available . C 20 H 14 F 3 N 3 O 2 S 2 (449.48), MS (ESI): 450.2 (M + H +).
Example 6 3- (4-R4-Butyl-2 -? / 4-trifluoromethyl-phenyl) -thiazol-5-ylmethoxy-1-2-chloro-phenyl} -4H-1, 2,4 '] oxadiazol-5-one
According to the method described in Example 1, 3- was obtained. { 4- [4-bujyl-2- (4-ylfluoromethyl-phenyl] -thiazole-5-ylmefoxy] -2-chloro-phenyl} -4H- [1, 2,4] oxadiazol-5-one from 4-buyl-5-chloromethyl-2- (4-urea) -l-phenyl) -thiazole and 2-chloro-4-hydroxy-benzonitrile available in the trade. C23H19CIF3N3O3S (509.94), MS (ESI): 510.3 (M + H +)
Example 7 3-. { 4- [4-Butyl-2- (4-penfafluorosulfanyl-phen-p-thiazol-5-ylmeyoxy] -2-chloro-phenyl} -4H-1, 2.41-oxadiazol-5-one
According to the method described in Example 1, 3- was obtained. { 4- [4-Butyl-2- (4-penlafluorosulfanyl-phenyI) -thiazol-5-ylmethoxy] -2-chloro-phenyl} -4H- [1, 2,4] oxadiazol-5-one from 4-butyl-5-chloromethyl-2- (4-pentafluorosulfanyl-phenyl) -iazole and the 2-chloro-4-hydroxy-benzonyl-ryl available in trade. C22H19CIF5N3O3S2 (567.4), MS (ESI): 568.1 (M + H +)
EXAMPLE 8 3- (2-Chloro-4 - ("4-meityl-2- (4-peniafluorosulfanyl-phenyl) -thiazol-5-ylmefoxp-phenol.} -4H- [1,2,4" | oxadiazol-5-one
According to the method described in Example 1, 3- was obtained. { 2-Chloro-4- [4-methyl-2- (4-pentafluorosulfanyl-phenyl) -thiazoI-5-methylmethyl] -phenyl} -4H- [1,2,4] oxadiazoI-5-one from 5-chloromethyl-4-mephyl-2- (4-penfafluorosulfanyl-phenyl) -thiazole and 2-chloro-4-hydroxy-benzonitrile available from trade. C19H13CIF5N3O3S2 (525.91), MS (ESI): 526.0 (M + H +).
EXAMPLE 9 3- (4- {2-R4-Butyl-2- (4-trifluoromethyl-phenin-thiazol-5-yn-eroxy > -2-chloro-phenyl) -4H - ["1.2.41-oxadiazole -5-one
4-. { 2-j "4-Butyl-2- (4-ylfluoromethyl-phenyl) -iazole-5-in-eoxy) -2-chloro-benzoniiryl
To an ice-cooled solution of 1.1 g of 2- [4-butyl-2- (4-trifluoromethyl-phenyl) -iazole-5-yl] -emphenol dissolved in 50 ml of dichloromethane, 0.56 was added. g of 2-cyclo-4-hydroxybenzonitrile and 0.95 g of triphenylphosphine commercially available. To this solution, 0.57 ml of diethyl azodicarboxylate was added dropwise. The cooling bath was removed, and the reaction mixture was agitated at ambient temperature for six hours. The solvent was removed in vacuo, and the residue was purified by RP-HPLC to give 400 mg of 4-. { 2- [4-Butyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -ethoxy} -2-chloro-benzonitrile in lyophilized form. C 23 H 20 ClF 3 N 2 OS (464.94), MS (ESI): 465.2 (M + H +).
3- (4- (2-r4-Butyl-2- (4-ylfluoromethyl-phenyl) -thiazol-5-yl-e-xyloxy-2-chloro-phenyl-4H- [1,4,4-loxadiazol-5-one]
According to the method described in Example 1, 3- (4-. {2- [4-butyl-2- (4-trifluoromethyl] -phenyl) -thiazol-5-yl] -ethoxy was obtained. -2-chloro-phenyl) -4H- [1, 2,4] oxadiazol-5-one from 4. { 2- [4-Butyl-2- (4-if-trifluoromethyl-phenyl) -thiazol-5-yl] -ethoxy} -2-cyclobenzonitrile. C 24 H 21 ClF 3 N 3 O 3 S (523.97), MS (ESI): 524.3 (M + H +).
Example 10 3- (4-l4-Butyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-ylmeyoxy-2-chloro-benzyl} -4 H- [1,2,4-oxadiazol-5-one
4- [4-Butyl-2- (4-ír-trifluoromethyl] -pheno-thiazol-5-ylmethoxy-1-2-chlorobenzaldehyde
3.2 g of 4-butyl-5-chloromethyl-2- (4-trifluoromethyl-phenyl) -thiazole and 1.5 g of 2-chloro-4-hydroxybenzaldehyde were dissolved in 150 ml of dimethylformamide. 4J g of cesium carbonate was added, and the reaction mixture was stirred at room temperature for four hours. AfterThe reaction mixture was diluted by adding 300 ml of ethyl acetate and washed three times with 50 ml of water, saturated NaHCO3 solution and brine. The organic layer was dried over MgSO4 and the solvent was removed in vacuo to provide 3.0 g of 4- [4-butyl-2- (4-trifluoromethyl-phenyI) -thiazoI-5-imethoxy] -2-chloro-benzaldehyde in the form of an oil. C22H19CIF3NO2S (453.91), MS (ESI): 454.4 (M + H +), Rf (n-heptane: ethyl acetate = 4: 1) = 0.63.. { 4- [4-Butyl-2- (4-trifluoromethyl-phenylHiazol-5-yl-methoxy-2-chloro-phenyl) -methanol
3.0 g of 4- [4-buyl-2- (4-trifluoromethyl-phenyl) -thiazole-5-ylmethoxy] -2-cyclobenzaldehyde were dissolved in 100 ml of methanol, and 300 mg of methanol was added. sodium borohydride. The reaction mixture was stirred at room temperature for two hours, and then the solvent was removed in vacuo and the residue was dissolved in 100 ml of ethyl acetate. This solution was washed three times with 30 ml of brine, dried over MgSO4 and the solvent removed in vacuo to give 3.0 g of. { 4- [4-butyl-2- (4-ylfluoromethyl-phenyl) -iazol-5-ylmeyoxy] -2-chloro-phenyl} -methanol in the form of a pale yellow solid. C 22 H 21 ClF 3 NO 2 S (455.93), MS (ESI): 456.4 (M + H +), Rf (n-heptane: ethyl acetate = 1: 1) = 0.44.
4-Bufyl-5- (3-chloro-4-chloromethyl-phenoxymethyl) -2- (4-ylfluoromethyl-pheno-yiazole)
3.0 g of. { 4- [4-Butyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-ylmeyoxy] -2-chloro-phenyl} -meanol and 1.84 ml of iarythylamine in 150 ml of dichloromethane. To this ice-cooled solution were added 0.82 g of methanesulfonyl chloride. The cooling bath was removed and the reaction mixture was stirred at room temperature for an additional three hours. The reaction mixture was washed three times with 50 ml of saturated NaHCO3 solution, dried over MgSO4, and the solvent was removed under vacuum to provide 3.1 g of 4-butyl-5- (3-chloro-4-chloromethyl). phenoxymethyl) -2- (4-trifluoromethyl-phenyl) -thiazole in the form of a hard material. This material was used without further purification. C 22 H 20 Cl 2 F 3 NOS (474.38), MS (ESI): 476.4 (M + H +).
. { 4-f4-Butyl-2- (4-ylluoromethyl-phenyl) -thiazol-5-ylmeyoxy-1-2-chloro-phenyl} - acetonitrile
3.1 g of 4-bufiI-5- (3-cyclo-4-chloromethyl-phenoxymethyl) -2- (4-trifluoromethyl-phenyl) -iiazoi were dissolved in 50 ml of acetonitrile. 2.0 g of tetrabutylammonium cyanide was added and the reaction mixture was stirred at room temperature for one hour. Then a mixture of saturated NaHCO3 solution, ice and ethyl acephella was added. The aqueous phase was separated and extracted three times in 30 ml portions of ethyl acetate. The combined organic layers were washed with ice water and brine, and dried over MgSO4. The solvent was removed in vacuo. The residue was purified by flash chromatography with the eluent n-heptane: ethyl acetate = 4: 1 to provide 2.2 g of. { 4- [4-Butyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-ylmethoxy] -2-chloro-phenyl} -acetonyryl in the form of an oil. C23H20CIF3N2OS (464.94), MS (ESI): 465.5 (M + H +), Rf (n-heptane: ethyl acetate = 4: 1) = 0.32.
2-. { 4-f4-Butyl-2- (4-ylfluoromethyl-phenyl) -yiazol-5-ylmeyoxy-1-2-chloro-phenyl} -N-hydroxy-acetamidine
2.2 g of. { 4- [4-butyl-2- (4-ylfluoromethyl-phenyl) -yiazol-5-ylmethoxy] -2-chloro-phenyl} -acetonitrile in a mixture of 6 ml of tetrahydrofuran and 12 ml of methanol. 3.3 g of hydroxylamine hydrochloride were added followed by the addition of 6.6 ml of triethylamine. The reaction mixture was stirred at 60 ° C for two hours. The solvents were removed in vacuo and the resulting residue was poured into water and extracted five times with 30 ml portions of ethyl acetate. The combined organic extracts were dried over MgSO 4 and the solvent was evaporated in vacuo to provide 2.3 g of 2-. { 4- [4-butyl-2- (4-trifluoromethyi-phenyl) -thiazo-5-ylmefoxy] -2-chloro-phenyl} -N-hydroxy-acetamidine in the form of crude material. C23H23CIF3N3O2S (497.97), MS (ESI): 498.5 (M + H +).
3-. { 4-j "4-Butyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-ylmethoxy-2-chlorobenzyl} -4H- [1,2,4] oxa-diazol-5-one
2.3 g of 2- were dissolved. { 4- [4-Butyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-ylmethoxy] -2-chloro-phenyl} Crude N-hydroxy-acetamidine in 30 ml of dichloromethane. 0.46 ml of pyridine and 0J1 ml of phenyl chloroformate were added, and the mixture was stirred at room temperature for ten minutes. The mixture was diluted by addition of 150 ml of ethyl acetate, washed with brine and dried over MgSO 4. The solvent was evaporated in vacuo. The resulting residue was dissolved in 20 ml of acetonitrile and OZO of 1 was added., 8-diazabicyclo [5.4.0] undec-7-ene. The reaction mixture was stirred at ambient temperature for 10 min. The mixture was evaporated in vacuo and the resulting brute material was purified by reverse phase HPLC to obtain 820 mg of 3-. { 4- [4-Butyl-2- (4-trifluoromethyI-phenyl) -thiazol-5-ylmeyoxy] -2-chloro-benzyl} -4H- [1, 2,4] oxadiazol-5-one in the form of an amorphous lyophilizate. C 24 H 21 ClF 3 N 3 O 3 S (523.97), MS (ESI): 524.3 (M + H +).
Example 11 3-. { 2-Methoxy-4- [4-methyl-2- (4-trifluoromethyl-phenyl-thiazol-5-ylmethoxp-phenyl) -4 H-f1.2.4-oxadiazole-5-one
dim
2-Methoxy-4- [4-methyl-2- (4-trifluoromethyl-phenylHiazol-5-methoxyfl-benzoniyl)
280 mg of 2-fluoro-4- [4-methyl-2- (4-trifluoromethyl-phenol) -thiazol-5-ylmethoxy] -benzonyryl (intermediate of Example 1) was dissolved in 10 ml of methanol . 390 mg of sodium methoxide was added and the reaction mixture was stirred at a 60 ° C lemperairy for two hours. The cooled reaction mixture was diluted by addition of 200 ml of ethyl acetate and washed three times with 50 ml portions of water. The organic layer was dried over MgSO4 and the solvent was removed under vacuum to provide 140 mg of 2-methoxy-4- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-ylmethoxy] -benzonitrile in the form of a pale yellow solid. C20H15F3N2O2S (404.41), MS (ESI): 405.4 (M + H +), Rf (n-heptane: ethyl acetate = 2: 1) = 0.32.
3-. { 2-Methoxy-4-r4-methyl-2-f4-trifluoromethyl-phenyl) -thiazole-5-methoxy-phenyl} -4H- [1.2.4loxadiazol-5-one
According to the method described in Example 1, the 3- was obtained. { 2-meioxy-4- [4-methyl-2- (4-frifluoromethyl-phenyl) -yiazol-5-ylmeyoxy] -phenyl} -4H- [1, 2,4] oxadiazoI-5-one from 2-methoxy-4- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-ylmethoxy] -benzonitrile. C 21 H 16 F 3 N 3 O 4 S (463.44), MS (ESI): 464.3 (M + H +).
Example 12 3-. { 4-R4-Butyl-2- (4-trifluoromethyl-phenin-1-yiazol-5-ylmeyoxy-2-fluoro-phenyl} -4 H-1,2.2-joxaadiazol-5-one
In accordance with the method described in Example 1, the
3-. { 4- [4-Bufyl-2- (4-ylluoromethyl-phenyl) -yiazol-5-ylmethoxy] -2-fluoro-phenyl} -4H- [1,2,4] oxadiazol-5-one from 4-butyl-5-chloromethyl-2- (4-trifluoromethyl-phenyl) -iazole and 2-fluoro-4-hydroxy-benzonitrile available on trade.
C23H19F4N3O3S (493.11), MS (ESI): 494.3 (M + H +)
Example 13 3-f4-f4-Butyl-2- (4-trifluoromethyl-phenyl ') -thiazol-5-ylmethoxy-1-2,6-difluoro-phenyl} -4H-f1.2.41oxadiazol-5-one
In accordance with the method described in Example 1, the
3-. { 4- [4-ButyI-2- (4-trifluoromethyl-phenyl) -liazol-5-ylmethoxy] -2,6-difluoro-phenyl} -4r7 '- [1, 2,4] oxadiazol-5-one from 4-butyl-5-chloromefil-2- (4-l-trifluoromethyl-phenyl) -iazole and 2,6-difluoro-4-hydroxy-benzonitrile available in the trade. C23H18F5N3O3S (511.10), MS (ESI): 512.2 (M + H +)
Example 14 3-f4-R4-Butyl-2 -? - 4-trifluoromethyl-pheny1) -iazol-5-ylmethylsulfanin-pheny1 > -4H-H, 2,41-oxadiazol-5-one
According to the method described in Example 1, the - was obtained. { 4- [4-butyl-2- (4-ylfluoromethyl-pheny] -thiazol-5-ylmethyl-sulphanyl] -phenyl} -4ry- [1, 2,4] oxadiazol-5-one from commercially available 4-butyl-5-chloromethyl-2- (4-trifluoromethyl-phenyl) -thiazole and 4-mercapto-benzoniiryl. C 23 H 20 F 3 N 3 O 2 S 2 (491.09), MS (ESI): 492.2 (M + H +)
Example 15 3- (4-f4-Butyl-2 -? / 4-trifluoromethyl-phenyl-thiazol-5-ylmethoxy-2-trifluoromethyl-phenyl} -4H-1, 2,41-oxadiazol-5-one
4- [4-Butyl-2- (4-frifluoromethyl-phenyl) -thiazole-5-methylmethoxy-2- trifluoromethyl-benzonyl)
To a solution of 100 mg of 4-fluoro-2-trifluoromethyl-benzonitrile in 5 ml of anhydrous dimethylformamide was added 200 mg of [4-butyI-2- (4-trifluoromethyl-phenyl) -iazole-5-yl] -meanol and 0.49 g of cesium carbonate. The resulting mixture was stirred at ambient temperature overnight, poured into water and extracted with heptane 1 / ethyl acetate 3. The organic extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (heptane 4 / ethyl acetate 1) to give 180 mg of 4- [4-butyl-2- (4-trifluoromethyl-phenyl) -iazoyl-5-yl); lmeioxy] -2-nifluoromethyl-benzonyl ether. C 23 H 18 F 6 N 2 OS (484.10), MS (ESI): 485 (M + H +).
4-R4-Butyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-ylmethoxy-1 -? / - hydroxy-2-trifluoromethyl-benzamidine
To a solution of 180 mg of 4- [4-butyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-ylmethoxy] -2-trifluoromethyl-benzonyryl in 5 ml of tetrahydrofuran and 10 ml of methanol, 267 were added. mg hydroxylamine hydrochloride followed by 0, 55 ml of triethylamine. The resulting mixture was heated at 60 ° C overnight. The solvents were removed in vacuo, and the resulting residue was poured into water and extracted with ethyl acetate. The organic exfracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (heptane 1 / ethyl acetate 1) to give 90 mg of 4- [4-butyl-2- (4-trifluoromethyl-phenol) -thiazole- 5-ylmethoxy] - / V-hydroxy-2-trifluoromethyl-benzamidine and 50 mg of 4- [4-butyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-ylmethoxy] -2-trifluoromethyl-benzamide . C 23 H 21 F 6 N 3 O 2 S (517.49), MS (ESI): 518 (M + H +).
3- (4-r4-Butyl-2 -? / 4-trifluoromethy1-pheno-thiazol-5-ylmeyoxy-1-2-trifluoromethyl-phenyl-4H-1,2,4-oxadiazol-5-one)
To a solution of 89.3 mg of 4- [4-butyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-ylmeyoxy] - / V-hydroxy-2-trifluoromethyl-benzamidine in 2 ml of anhydrous dichloromethane, 92 μl of pyridine followed by 21.6 μl of phenyl chloroformate were added dropwise. The resulting mixture was stirred at room temperature for 1 h. The solvent was removed in vacuo. To a solution of the resulting residue in 2.5 ml of acetonitrile, 88 μl of 1,8-diazabicyclo [5.4.0] undec-7-ene was added. The mixture was stirred by heating with microwave at 180 ° C for 10 minutes (or stirred at room temperature overnight). The solvent was removed in vacuo and the crude product was purified by column chromatography on silica gel (heptane 1 / ethyl acetate 1 and then dichloromethane 95 / methanol 5, followed by another column with dichloromean 90 / aceine 10) to give 65 mg of 3-. { 4- [4-buyyl-2- (4- urea-1-phenyl) -thiazole-5-ylmethyl] -2-trifluoromethyl-phenyl} -4H- [1, 2,4] oxadiazoI-5-one. C 24 H 19 F 6 N 3 O 3 S (543.10), MS (ESI): 544.4 (M + H +).
Example 16 3-. { 4-f4-Buyyl-2- (4-ylfluoromethyl-pheno-thiazol-5-ylmeyoxy-1-2-methyl-phenyl) -4 H- [1,2,4-oxadiazol-5-one]
According to the method described in Example 15, the 3- was obfuscated. { 4- [4-Butyl-2- (4-trifluoromethyl-phenyl) -thiazole-5-ylmex] -2-methyl-phenyl} -4f - [1, 2,4] oxadiazoI-5-one from [4-butyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -methanol and 4-fluoro-2-methyl- benzonifrile available in commerce. C 24 H 22 F 3 N 3 O 3 S (489.13), MS (ESI): 490.4 (M + H +)
Example 17 3-. { 2-Bromo-4- [4-butyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-ylmethoxy-1-phenyl} -4H- [1,2,4"l-Oxadiazol-5-one
According to the method described in Example 15, 3- was obtained. { 2-bromo-4- [4-butyl-2- (4-ylluoromethyl-phenyl) -iiazoI-5-ylmeyoxy] -phenyl} -4r7'- [1, 2,4] oxadiazol-5-one from [4-buyl-2- (4-urea) -methylol and 2-bromo-4-fluoro-4-trifluoromethyl-phenyl) -thiazole-5-yl] -benzonitriIo available in the trade. C23H19BrF3N3O3S (553.03), MS (ESI): 554.2 (M + H +)
Example 18 3-. { 4-f4-Builyl-2- (4-frifluoromethyl-phenyl) -thiazol-5-ylmexyl-1-2-methoxy-phenyl} -4H-1, 2,4"l-oxadiazol-5-one
According to the method described in Example 15, 3- was obtained. { 4- [4-Butyl-2- (4-ylluoromethyl-pheny] -thiazol-5-ylmethoxy] -2-methoxy-phenyl} -4H- [1, 2,4] oxadiazol-5-one from [4-bufiI-2- (4-trifluoromethyl-phenyI) -iiazoI-5-yl] -methanol and 4-fluoro-2-methoxy-benzon Trilo available in the trade. C 24 H 22 F 3 N 3 O 4 S (505.12), MS (ESI): 506.3 (M + H +) Example 19 3- (4-r 4 -Buy-3-enyl-2- (4-if-trifluoromethyl-phenin-iazol-5-methyl) 1-2-chloro-phenyl.} -4H- [1,2,4-loxanediazol-5-one
According to the method described in Example 15, 3- was obtained. { 4- [4-but-3-enyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-ylmeyoxy] -2-cioro-phenyl} -4r - [1, 2,4] oxadiazol-5-one from [4-but-3-enyl-2- (4-frifluoromethyl-1-phenyl) -thiazo-5-yl] -methanol and 4-Fluoro-2-chloro-benzonitrile commercially available. C 23 H 17 ClF 3 N 3 O 3 S (507.06), MS (ESI): 508 (M + H +).
EXAMPLE 20 3- (2-Chloro-4-r4- (4-hydroxy-butyne-2 - (, 4-trifluoromethyl-phenin-thiazol-5-ylmethoxy] -phenyl} -4H-p .2.4] oxadiazol-5-one
To a solution of 50 mg of 3-. { 4- [4-but-3-enyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-ylmethoxy] -2-chloro-phenyl} 4H- [1, 2,4] oxadiazol-5-one in 2 ml of tetrahydrofuran at 0 ° C, 0.3 ml of a borane-methylsulfide complex solution in 2M hydroxyurea was added. it was stirred allowing it to warm to room temperature, and then it was stirred at ambient temperature for 30 minutes. After cooling to 0 ° C, 0.1 ml of a 5 M aqueous sodium hydroxide solution and 0.1 ml of 30% aqueous hydrogen peroxide solution were added. The mixture was stirred and allowed to warm to room temperature in 1 hour. It was then poured into water, extracted with ethyl acetate, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (gradient of dichloromean / mefanol from 100/0 to 95/5), followed by crystallization from dichloromethane / penan to give 28 mg of 3-. { 2-Chloro-4- [4- (4-hydroxy-builyl) -2- (4-ylluoromethyl-phenyl) -iazol-5-ylmeyoxy] -pheni} -4r7 '- [1, 2,4] oxadiazoi-5-one. C23H19CIF3N3O4S (525.07), MS (ESI): 526.2 (M + H +)
EXAMPLE 21 S ^ -Cloro ^^ - fS ^ -dihydroxy-butip ^ - ^ - urea-phenyl-thiazole-5-ylmethoxy-phen '* H- [1,4,4-oxadiazol-5-one]
To a mixture of 189 mg of 3-. { 4- [4-but-3-enyl-2- (4-ylluoromethyl-phenyl) -thiazol-5-ylmethoxy] -2-chloro-phenyl} -4H- [1,2,4] oxadiazol-5-one in 0.4 ml of tetrahydrofuran, 0.2 ml of water and 0.4 ml of tert-butanol, 0.05 ml of a tetraoxide solution was added. of osmium in 25% tert-butanol and 76 mg of N-methyl-morpholine oxide. The resulting mixture was stirred at room temperature for 24 hours. It was then poured into a saturated aqueous solution of sodium hydrogen carbonate, extracted with dichloromethane, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (gradient dichloromethane / meianol from 100/0 to 95/5) to give 32 mg of 3-. { 2-Chloro-4- [4- (3,4-d.hydroxy-buyl) -2- (4-trifluoromethyl-phenyl) -thiazol-5-ylmeyoxy] -phenyl} - 4H- [1, 2,4] oxadiazol-5-one. C23H19C1F3N3O5S (541, 06), MS (ESI): 542.2 (M + H +)
Example 22 d- -Butyl ^ - ^ - trifluoromethyl-phenin-thiazole-d-ylmethoxy ^ -Cd-oxo ^ .d-dihydro- [1,2,4-oxadiazol-3-yl] -benzoniiryl
To a solution of 100 mg of 3-. { 2-Bromo-4- [4-buyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-ylmethoxy] -phenyl} -4H- [1, 2,4] oxadiazoI-5-one in 4 ml of pyridine, 29 mg of copper cyanide was added. The resulting mixture was stirred by microwave heating at 210 ° C for 10 min., And then concentrated under reduced pressure. The residue was taken up in ethyl ether, washed with an aqueous solution of ammonia to pH 9, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel preparative thin layer chromatography (dichloromeanol 95 / meianol 5) and precipitated in ethyl acetate / diisopropyl ether / penanne to give 9.5 mg of 5- [4-buiyl-2- ( 4-nifluoromethyl-phenyl) -thiazol-5-ylmethoxy] -2- (5-oxo-4,5-dihydro- [1, 2,4] -oxadiazol-3-yl) -benzonyl chloride C24H19F3N4O3S (500.11 ), MS (ESI): 501.3 (M + H +)
Example 23 3-. { 4-r4-Bujyl-2- (4-ylfluoromethyl-phenyl) -thiazole-5-yl [methoxp-2-methylsulfanyl-phenyl) -4 H-p, 2.41-oxadiazol-5-one
To a solution of 50 mg of 4- [4-butyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-ylmethoxy] -2-fluoro-benzonyryl (prepared according to the method described in Example 1 ) in 10 ml of dimethylformamide, 121 mg of sodium thiomethoxide was added. The resulting mixture was stirred at room temperature overnight, then poured into water, and extracted with diisopropyl ether. The combined organic extractions were washed with water, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by crystallization from diisopropyl ether / heptane to give 350 mg of 4- [4-buffyl-2- (4-trifluoromethyl-phenyl) -fiazoI-5-ylmethoxy] -2-methylsulfanyl-benzonitrile , which became 3-. { 4- [4-Butyl-2- (4-trifluoromethyl-phenyl) -thiazole-5-ylme-toxy] -2-methylsuivane-phenyl} -4f7, - [1, 2I4] oxadiazol-5-one according to the method described in Example 1. C24H22F3N3O3S2 (521, 10), MS (ESI): 522.3 (M + H +)
Example 24 3- (4-R4-Butyl-2- (4-trifluoromethyl-phenin-1-yiazol-5-ylmethoxy-1-2-methylsulfinyl-phenyl) -4H- [1,4] oxadiazole-5 -one
To a solution of 200 mg of 4- [4-butyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-ylmethoxy] -2-methylsulfanyl-benzonitrile (prepared according to the method described in Example 23) in 4 ml of dichloromethane at 0 ° C, 74 mg of metachloroperbenzoic acid was added. The resulting mixture was stirred at 0 ° C for 2 hours and then kept in the freezer overnight. A saturated aqueous solution of sodium hydrogen carbonate was added and the organic layer was separated. The aqueous layer was extracted with dichloromethane. The combined extractions were dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 203 mg of 4- [4-buffyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-ylmethoxy] -2- methylsulfonylbenzonitrile, which was transformed into 3-. { 4- [4-butyI-2- (4-frifluoromethyl-phenyl) -thiazol-5-ylmethoxy] -2-methylsulfinyl-phenyl} -4r7 '- [1, 2,4] oxadiazoI-5-one according to the method described in Example 1. C24H22F3N3O4S2 (537.10), MS (ESI): 538.3 (M + H +)
Example 25 3-. { 4- | -4-Butyl-2- (4-trifluoromethyl-phenin-thiazol-5-ylmethoxy! -2-methanesulfonyl-phenyl} -4 H- [1,4,4-oxadiazole-5-] ona
To a solution of 200 mg of 4- [4-buliI-2- (4-trifluoromethyl-phenyl) -thiazole-5-methylmethyl] -2-methyl-benzonitrile (prepared in accordance with method described in Example 23) in 20 ml of dichloromethane at 0 ° C, 149 mg of metachloroperbenzoic acid was added. The resulting mixture was stirred at 0 ° C for 2 hours, and then 1 hour at room temperature. After adding another 75 mg of metachloroperbenzoic acid, the reaction mixture was stirred for 3 hours at room temperature. A saturated aqueous solution of sodium hydrogen carbonate was added and the organic layer was separated. The aqueous layer was extracted with dichloromethane. The combined organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 210 mg of 4- [4-butyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-ylmethoxy] -2-methanesulfonium. -benzonitriIo, which became the 3-. { 4- [4-Butyl-2- (4-l-trifluoromethyl-phenyl) -thiazol-5-ylmethoxy] -2-methandosulfonyl-phenyl} -4f7 '- [1) 2,4] oxadiazol-5-one according to the method described in Example 1. C24H22F3N3O5S2 (553.09), MS (ESI): 554.1 (M + H +)
EXAMPLE 26 4- [4-Builyl-2- (4-ylfluoromethyl-phenyl) -iazole-5-methylmerylsulfinyl-1-phenyl) -4 H-f1, 2,41-oxadiazol-5-one
To a solution of 200 mg of 4- [4-buffyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-ylmethylsulfanyl] -benzontrotyl (prepared according to the method described in Example 14) in 4 ml of dichloromethane at 0 ° C, 80 mg of metachloroperbenzoic acid was added. The resulting mixture was stirred at 0 ° C for 5 hours, at ambient temperature for 2 hours and then left in the refrigerator overnight. A saturated aqueous solution of sodium hydrogen carbonate was added and the organic layer was separated. The aqueous layer was extracted with dichloromethane. The combined extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (acetone / dichloromean gradient from 1 to 4%) to give 185 mg of 4- [4-bufiI-2- (4-trifluoromethyl-phenyl) -iazole-5 -ylmethylsulfonyl] -benzonitrile, which was transformed into 3-. { 4- [4-Butyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-ylmethanesulfinyl] -phenyl} -4r7 '- [1, 2,4] oxadiazol-5-one according to the method described in Example 1. C23H20F3N3O3S2 (507.09), MS (ESI): 508 (M + H +).
Example 27 3-f4-R4-Butyl-2- (4-trifluoromethyl-phenoxyazol-5-ylmethylsulfonin-phenyl} -4 H- [1,4] oxadiazol-5-one
To a solution of 200 mg of 4- [4-buffyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-ylmethyl-sulphani] -benzonitrile (prepared according to the method described in Example 14) in 4 ml of dichloromean at 0 ° C, 200 mg of metachloroperbenzoic acid was added. The reaction mixture was stirred at 0 ° C for 5 hours. A saturated aqueous solution of sodium hydrogencarbonate was added and the organic layer was separated. The aqueous layer was extracted with dichloromethane. The combined extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 225 mg of 4- [4-butyl-2- (4-trifluoromethyl-phenyl) -iazole-5-methylmethersulfonyl] -benzoniíriIo, which became the 3-. { 4- [4-Butyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-ylmelanosulfonyl] -phenyl} -4r / - [1,2,4] oxadiazoI-5-one according to the method described in Example 1. C23H20F3N3O4S2 (523.08), MS (ESI): 522 (M-H +).
EXAMPLE 28 3- (4-R4-Butyl-2- (4-trifluoromethyl-phenin-yl-azo-5-methylmethoxy-1-2-fluoro-phenyl) -4-7, -l1.2.4] oxadiazole-5 -one
To a solution of 2.255 g of [4-butyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -methane! in 25 ml of dimethylformamide, 0.286 g of a dispersion of sodium hydride in 60% mineral oil was added. After stirring for 15 minutes, 3 g of 4-bromomethyl-2-fluoro-benzonitrile was added. The resulting mixture was stirred at room temperature overnight, then poured into water, and extracted with diisopropyl ether. The combined organic extracts were washed with water, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (heptane 95 / ethyl acetate 5) to give 0.6 g of 4- [4-butyl-2- (4-trifluoromethyl-phenyl) -thiazole-5- ilmeloxymethyl] -2-fluoro-benzonitrile, which was transformed into 3-. { 4- [4-butyl-2- (4-trifluoromethyl-phenyl) -thiazoI-5-methylmethyl] -2-fluoro-phenyl} -4f - [1, 2,4] oxadiazoI-5-one according to the method described in Example 1. C24H21F4N3O3S (507.12), MS (ESI): 508.3 (M + H +)
Example 29 3-f4-f4-Methyl-2- (4-l-trifluoromethyl-phenyl) -thiazol-5-ylmethoxymethyl-phenyl} -4H-F1, 2,4] Oxadiazol-5-one
According to the method described in Example 28, 4- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazole-5-methoxymethyl] -benzonitrile was obtained from [4-methyl-2-methoxy] -benzonitrile. - (4-ylluoromethyl-phenyl) -thiazol-5-yl] -melanic acid and commercially available 4-bromomethyl-benzonifryl. 4- [4-MethyI-2- (4-trifluoromethyl-phenyl) -thiazol-5-ylmethyloxy] -benzonyl-trile was converted to 3-. { 4- [4-methyl-2- (4-trifluoromethyl-phenyl) -liazoI-5-ylmeioxymethyl] -phenyl} -4H- [1, 2,4] oxadiazol-5-one according to the method described in Example 1. C21 H16F3N3O3S (447.74), MS (ESI): 448 (M + H +).
EXAMPLE 30 3-r4- (2-Biphenyl-4-yl-5-methyl-oxazol-4-methylmethyl) -2-chloro-phenyl-4H- [1, 2,41-oxadiazol-5-one
According to the method described in Example 1, 3- [4- (2-biphenyl-4-yl-5-methyl-oxazol-4-ylmethoxy) -2-cyoro-phenol] -4H- was obtained [1,2,4] pxadiazol-5-one from commercially available 4-iodomethyl-5-methyl-2-p-biphenyloxazole and 2-chloro-4-hydroxy-benzonitrile. C25H18CIN3O4 (459.89), MS (ESI): 460 (M + H +).
Example 31 3-. { 2-cl-4-1'2-1'4-m-ethoxy-f in i 1) -5-methy1-oxazo l-4-i I methoxyl-phen i. -4H-f 1, 2.4] oxadiazol-5-one
In accordance with the method described in Example 1, the
3-. { 2-Chloro-4- [2- (4-mephoxy-phenyl) -5-methyl-oxazol-4-ylmeyoxy] -phenyl} -4H- [1, 2,4] oxadiazoI-5-one from commercially available 4-iodomy-2- (4-methoxyphenyl) -5-methyloxazole and 2-chloro-4-hydroxy-benzonitrile. C20H16CIN3O5 (413.82), MS (ESI): 414 (M + H +).
EXAMPLE 32 3- (2-Chloro-4-f2-r 5 -methyl-2- (4-trifluoromethyl-phenin-thiazol-4-yl-1-ethoxy) -phen4-4H- [1,2,4] -oxadirazole-5-one
According to the method described in Example 9, 2-chloro-4- was obtained. { 2- [5-methyl-2- (4-penfafluorosufanyl-phenyl) -thiazol-4-yl] -ioxyl} -benzonitrile from 2- [5-meityl-2- (4-pentafluorosulfanyl-phenyl) -iazol-4-yl] -ethanol and 2-doro-4-hydroxy-benzonyl ether available commercially. The 2-chloro ~ 4-. { 2- [5-methyl-2- (4-pentafluorosuIfaniI-phenyI) -thiazol-4-yl] -ethoxy} -benzo-nitrile was transformed into 3- (2-chloro-4-. {2- 2- [5-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-4-yl] -efoxy.} -pheni ) -4H- [1,4] oxadiazol-5-one according to the method described in Example 1. C20H15CIF5N3O3S2 (439.93), MS (ESI): 540 (M + H +)
Example 33 3-. { 2-Chloro-4-r4-meioxymethyl-2- (4-ylluoro-methyl-phenyl) -thiazol-5-ylmethoxy-1-phenyl} -4H- [1.2.41oxadirazole-5-one
2-Chloro-4- [4- (1-6-yl) pyro-pyran-2-yloxymethip-2- (4-trifluoromethyl-phenyl) -thiazol-5-ylmethoxyl-benzonitrile
3.0 g of 5- (Chloromethyl) -4 - [(1-hydroxy-2H-pyran-2-yloxy) meth] -2- [4- (trifluoromethyl) phenyl] -1,3-tiazole were dissolved. (its synthesis is described in WO2002 / 067912) in 100 ml of dimethylformamide. 5.0 g of cesium carbonate and 1.53 g of 2-chloro-4-hydroxybenzonitrile were added and the mixture was stirred at room temperature overnight. After 300 ml of ethyl acetate was added, the mixture was washed three times with saturated NaHCO3 solution and brine, then dried over MgSO4. The solvent was removed under vacuum to obtain 4.1 g of 2-chloro-4- [4- (tetrahydro-pyran-2-yloxymethyl) -2- (4-trifluoromethyl-phenyl) -thiazol-5-ylmethoxy] -benzoniyl gross in the form of yellow oil. This material was used without further purification. C 24 H 20 ClF 3 N 2 O 3 S (508.95), MS (ESI): 509.1 (M + H +), 425.1 (M-THP + H +).
2-Chloro-4-r4-hydroxymethyl-2- (4-trifluoromethyl-phenyl) -iazole-5-ylmethyl-benzonyldyl
4.1 g of 2-chloro-4- [4- (1-eryhydro-pyran-2-yloxy-ethyl) -2- (4-ylfluoromethyl-phenyl) -thiazol-5-ylmethoxy] -benzoniiryl were dissolved in 50 g. my methanol 320 mg of p-toluenesulfonic acid monohydrate was added and the mixture was stirred for one hour at room temperature. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate and washed twice with saturated NaHCO3 solution and brine, then dried over MgSO4. The solvent was removed in vacuo to obtain 3.4 g of 2-chloro-4- [4-hydroxymethyl-2- (4-ylfluoromethyl-phenyl) -thiazol-5-ylmethoxy] -benzoniiryl as a light yellow solid. C19H12CIF3N2O2S (424.83), MS (ESI): 425.1 (M + H +), Rf (n-hepyane: ethyl cell = 1: 1) = 0.27.
Ester 5- (3-chloro-4-cyano-phenoxymethyl) -2- (4-frifluoromethyl-phenyl) -thiazol-4-ylmethyl of methanesulfonic acid
1.8 g of 2-chloro-4- [4-hydroxymethyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-ylmehoxy] -benzoniyri in 50 ml of dichloromethane were suspended and cooled in a water bath. ice. 0.39 ml of methanesulfonyl chloride and 0.89 ml of triethylamine were added. The resulting mixture was agitated at 0 ° C for one hour, then washed with water and brine, dried over MgSO 4. The solvent was removed in vacuo to obtain 1.0 g of the 5- (3-chloro-4-cyano-phenoxymethyl) -2- (4-trifluoromethyl-phenyl) -thiazole-4-ylmethyl ester of the ester. menesulfonic acid as a light yellow solid. C20H14CIF3N2O4S2 (502.92), MS (ESI): 503.1 (M + H).
2-Chloro-4-f4-mexoxymethyl-2- (4-if-trifluoromethyl-phenyl) -thiazole-5-ylmethoxyfl-benzonitrile
120 mg of the 5- (3-chloro-4-cyano-phenoxymethyl) -2- (4-trifluoromethyl-phenyl) -thiazole-4-methylmethyl ester of methanesulfonic acid were dissolved in 5 ml of methanol. 12.9 mg of sodium methoxide was added and the mixture was stirred at 50 ° C for one hour. The reaction mixture was diluted by addition of 50 ml of ethyl acetate, washed with one molar hydrochloric acid and then dried over MgSO 4. The solvent was removed in vacuo, and the residue was purified by RP-HPLC to provide 30 mg of 2-chloro-4- [4-methoxymethyl-2- (4-yl-1-fluoromethyl-phenyl) -thiazole-5-ylmethoxy] -benzonitrile in the form of lyophilisate. C20H14CIF3N2O2S (438.86), MS (ESI): 439, .1 (M + H).
3-. { 2-Chloro-4- [4-methoxymethyl-2- (4-ylluoromethyl-phenyl) -thiazole-5-ylmethoxy-1-phenyl-4H-ri) -2,41-oxadiazol-5-one
According to the method described in Example 1, 3- was obtained. { 2-Chloro-4- [4-methoxymethyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-ylmethoxy] -phenyl} -4H- [1, 2,4] oxadiazol-5-one from 2-chloro-4- [4-methoxymethyl-2- (4-trifluoromethyl-phenyl) -thiazoI-5-ylmethoxy] -benzonifrile. C21H15C1F3N3O4S (497.88), MS (ESI): 498.3 (M + H +).
EXAMPLE 34 3- (2-Chloro-4 - ["4- (2-methoxy-ethoxymethyl) -2- (4-trifluoromethyl-phenyl) -thiazole-5-ylmethoxyethyl} -4H-yl, 2,41-oxadiazol-5-one
2-Chloro-4-f4- (2-methoxy-ethoxymethyl) -2- (4-trifluoromethyl-phenyl) -thiazole-5-ylmethoxyl-benzonylate
120 mg of the 5- (3-cyano-4-cyano-phenoxymethyl) -2- (4-trifluoromethyl-phenyl-thiazol-4-ylmethyl) methanesulfonic acid ester were dissolved in 5 ml of 2-methoxyethanol. 0 mg of sodium hydride and the mixture was stirred at 50 ° C for one hour The reaction mixture was diluted by addition of 50 ml of ethyl acetate, washed with brine, then dried over MgSO 4. vacuum, and the residue was purified by RP-HPLC to provide 30 mg of 2-chloro-4- [4- (2-methoxy-ethoxymethyl) -2- (4-trifluoromethyl-phenyl) -thiazol-5-ylmethoxy] - benzonifril in lyophilized form C22H18CIF3N2O3S (482.91), MS (ESI): 483.1 (M + H).
3- (2-Chloro-4-r4-f2-methoxy-ethoxymethip-2- (4-trifluoromethyl-phen-p-thiazol-5-ylmethoxy-1-phenyl} -4H-1, 2.41-oxadiazole-5 -one
According to the method described in Example 1, 3- was obtained. { 2-doro-4- [4- (2-methoxy-ethoxymethyl) -2- (4-ylfluoromethyl-phenyl) -iazole-5-ylmethoxy] -phenyl} -4H- [1, 2,4] oxadiazol-5-one from 2-chloro-4- [4- (2-methoxy-ethoxymethyl) -2- (4-trifluoromethyl-phenyl) -thiazole-5-ylmethoxy] ] -benzonitriIo. C 23 H 19 ClF 3 N 3 O 5 S (541, 94), MS (ESI): 542.2 (M + H +).
Example 35 3-. { 2-Chloro-4- [4- (2-ethoxy-ethyoxymethip-2- (4-yl) fluoride-phenyl-azol-5-ylmethoxy-1-phenyl} -4 H-F1.2,4] oxadiazol-5-one
According to the method described in Examples 1 and 34, 3- was obtained. { 2-Chloro-4- [4- (2-ethoxy-eioxymethyl) -2- (4-l-fluoomethyl-phenyl) -thiazol-5-ylmeyoxy] -phenyl} -4H- [1, 2,4] oxadiazol-5-one from the 5- (3-chloro-4-cyano-phenoxymethyl) -2- (4-trifluoromethyl-phenyl) -thiazole-4-ylmethyl acid ester of the acid methanesulfonic acid and 2-ethoxy-ethanol. C 24 H 21 ClF 3 N 3 O 5 S (555.96), MS (ESI): 556.3 (M + H +).
Example 36 3-. { 2-Chloro-4-r4- (3-meioxy-propoxymethyp-2- (4-ylfluoromethyl-phen-p-thiazol-5-ylmethoxy] -phenyl} -4H- [1.2.4 ] oxadiazol-5-one
According to the method described in Examples 1 and 34, 3- was obtained. { 2-Chloro-4- [4- (3-methoxy-propoxymethyl) -2- (4-trifluoromethyl-phenyl) -thiazole-5-methoxy] -phenyl} -4H- [1, 2,4] oxadiazol-5-one from the 5- (3-chloro-4-cyano-phenoxymethyl) -2- (4-trifluoromethyl-phenyl) -thiazole-4-ylmethyl ester of the acid methanesulfonic acid and 3-methoxy-1-propanol. C 24 H 21 ClF 3 N 3 O 5 S (555.96), MS (ESI): 556.3 (M + H +).
Example 37 3-. { 4- [5-Mefoximetyl-2- (4-meioxy-phenol) -oxazol-4-methyl-2-yl] -methyl-phenol} -4H-p .2,41-oxadiazol-5-one
According to the method described in Example 15 and Example 33, 3- was obtained. { 4- [5-methoxymethyl-2- (4-methoxy-pheny] -oxazoI-4-ylmethoxy] -2-methyl-phenyl} 4H- [1,2,4] oxadiazol-5-one from [2- (4-methoxy-phenyl) -5- (tetrahydro-pyran-2-yloxymethyl) -oxazol-4-yl] -methane and 4-Fluoro-2-methylbenzonitrile commercially available. C 22 H 21 N 3 O 6 (423.43), MS (ESI): 424.2 (M + H +).
Example 38 3- (4-5 5 - (2-Methoxy-ethoxymethyl) -2- (4-methoxy-phenyl) -oxazol-4-methylmethoxy-2- methyl-phenyl-4H-p .2.41-oxadiazol-5-one
According to the method described in Example 15 and Example 34, 3- was obtained. { 4- [5- (2-methoxy-ethoxymethyl) -2- (4-methoxy-phenyl) -oxazol-4-ylmethoxy] -2-methyl-phenyl} -4H- [1,2,4] oxadiazol-5-one from [2- (4-methoxy-phenyI) -5- (tetrahydro-pyran-2-yloxymethyl) -oxazol-4-yl] -methanol and Commercially available 4-fluoro-2-methylbenzonitrile and 2-methoxy-elanoI. C 24 H 25 N 3 O 7 (467.48), MS (ESI): 468.2 (M + H +).
Example 39 3-. { 4-f4-Methoxymethyl-2- (4-mephoxy-phenol) -oxazol-5-ylmethoxy] -2-meityl-phenyl} -4H- [1.2.4loxadiazol-5-one
According to the method described in Example 15 and Example
33, 3- was obtained. { 4- [4-methoxymethyl-2- (4-mephoxy-phenyl) -oxazol-5-ylmethoxy] -2-methyl-phenyl} -4H- [1, 2,4] oxadiazol-5-one from [2- (4-meioxy-phenyl) -4- (1-ehydro-pyran-2-yloxymethyl) -oxazol-5-yl] -methanol and 4-Fluoro-2-methylbenzonitrile commercially available. C22H21 3O6 (423.43), MS (ESI): 424.2 (M + H +).
Example 40 3-. { 4- [4- (2-Methoxy-ethoxymethyl) -2- (4-methoxy-phenyl) -oxazol-5-ylmethoxy] -2-methyl-phenyl} -4H-f1,2,41oxadiazol-5-one
According to the method described in Example 15 and Example 34, 3- was obtained. { 4- [4- (2-methoxy-eyloxymethyl) -2- (4-meloxy-phenyl) -oxazoI-5-ylmethoxy] -2-meityl-phenyl} -4H- [1, 2,4] oxadiazol-5-one from [2- (4-meioxy-phenyI) -4- (tetrahydro-pyrn-2-yloxymethyl) -oxazol-5-yl] -meanol and commercially available 4-fluoro-2-methyIbenzo-nitrile and 2-methoxy-ethane. C 24 H 25 N 3 O 7 (467.48), MS (ESl): 468.2 (M + H +).
Example 41 3-. { 4- [4- (2-Ethoxy-eyloxymethyl) -2- (4-methoxy-phenyl) -oxazol-5-ylmethoxy-2-methyl-phenyl} -4H- [1, 2.4"| oxadiazol-5-one
According to the method described in Example 15 and Example 34, 3- was obtained. { 4- [4- (2-ethoxy-ethoxymethyl) -2- (4-methoxy-phenyl) -oxazoI-5-ylmethoxy] -2-mephyl-phenyl} -4H- [1, 2,4] oxadiazol-5-one from [2- (4-methoxy-phenyl) -4- (tetrahydro-pyran-2-yloxymethyl) -oxazol-5-yl] - meianol and commercially available 4-fluoro-2-methylbenzonitrile and 2-ethoxy-ethanol. C 25 H 27 N 3 O 7 (481.51), MS (ESI): 482.2 (M + H +).
Example 42 3-. { 4-f2- (4-Methoxy-pheny1) -4- (3-methoxy-propoxymethyl) -oxazol-5-ylmeyoxy-2-methyl-phenyl} -4H- [1.2.41oxadiazol-5-one
According to the method described in Example 15 and Example 34, 3- was obtained. { 4- [2- (4-methoxy-phenyl) -4- (3-methoxy-propoxymethyl!) - oxazoI-5-ylmethoxy] -2-methyl-phenyl} -4H- [1,2,4] oxadiazol-5-one from [2- (4-methoxy-phenyl) -4- (tetrahydro-pyran-2-yloxymethyl) -oxazol-5-yl] -methane and Commercially available 4-fluoro-2-methylbenzonylryl and 3-methoxy-propan-1-ol. C 25 H 27 N 3 O 7 (481.51), MS (ESI): 482.2 (M + H +).
Example 43 3-. { 4- [4-Ethoxymethyl-2- (4-methoxy-phenyl) -oxazol-5-ylmeyoxy] -2-meityl-phenyl) -4H- [1,2,4-oxadiazol-5-one]
According to the method described in Example 15 and Example 34, 3- was obtained. { 4- [4-ethoxymethyl-2- (4-meioxy-phenyl) -oxazoI-5-ylmethoxy] -2-meityl-phenyl} -4H- [1,2,4] oxadiazol-5-one from 2- (4-methoxy-phenyl) -4- (iorahydro-pyran-2-yloxymethyl) -oxazole-5-yl] -methanol and commercially available 4-fluoro-2-methylbenzoniiryl and ethylene. C 23 H 23 N 3 O 6 (437.46), MS (ESI): 438.2 (M + H +).
Example 44 3-. { 4- [4-Benzyloxymethyl-2- (4-methoxy-phenyl) -oxazol-5-ylmethoxy "| -2-methyl-phenyl} -4H-f1,2.4-oxadiazole-5-one
According to the method described in Example 15 and Example 34, 3- was obtained. { 4- [4-benzyloxymethyl-2- (4-meloxy-phenyl) -oxazol-5-ylmethoxy] -2-methyl-phenyl} 4H- [1,2,4] oxadiazol-5-one from [2- (4-methoxy-phenyI) -4- (tetrahydro-pyran-2-yloxymethyl) -oxazol-5-yl] -melanol and Commercially available 4-fluoro-2-methylbenzonitrile and phenyl-methanol. C 28 H 25 N 3 O 6 (499.53), MS (ESI): 500.2 (M + H +).
Example 45 3-. { 2-Chloro-4-r5-methoxymethyl-2- (4-methoxy-phenyl) -oxazol-4-ylmethoxy-phenyl > -4H-p.2.4Toxadiazol-5-one
According to the method described in Example 1 and Example 33, 3- was obtained. { 2-Chloro-4- [5-methoxymethyl-2- (4-methoxy-phenyl) -oxazol-4-ylmethoxy] -phenyl} 4H- [1,2,4] oxadiazol-5-one from the 2- (4-mephoxy-phenyl) -5- (terahydro-pyran-2-yloxymethyl) -oxazoyl-4-ylmethyl ester of methanesulfonic acid and 2-chloro-4-hydroxy-benzoniiryl commercially available. C21 H18CIN3O6 (443.85), MS (ESI): 444.2 (M + H +).
Example 46 3-. { 2-Chloro-4- [5- (2-methoxy-ethoxymethyl-p-2- (4-methoxy-phenyl) -oxazol-4-ylmethoxy "j-phenyl} -4 H- [1, 2, 41oxadiazol-5-one
According to the method described in Example 1 and Example 34, it was obtained
3-. { 2-Chloro-4- [5- (2-methoxy-ethoxymethyl) -2- (4-methoxy-phenyl) -oxazoI-4-ylmethoxy] -phenyl} -4H- [1, 2,4] oxadiazol-5-one from the 2- (4-methioxy-phenyl) -5- (tetrahydro-pyran-2-yloxymethyl) -oxazol-4-ylmethylic acid ester of the acid methanesulfonic and 2-doro-4-hydroxy-benzonitrile commercially available and 2-methoxyethanol. C23H22CIN3O7 (487.90), MS (ESI): 488.2 (M + H +).
Example 47 3-. { 2-Chloro-4 - ["4-meioxymethyl-2- (4-methioxy-phep-p-oxazol-5-ylmethoxyl-phenyl] -4 H- [1, 2,41-oxadiazol-5-one]
According to the method described in Example 1 and Example
33, it was worked 3-. { 2-Chloro-4- [4-methoxymethyl-2- (4-methioxy-phenyl) -oxazol-5-ylmethoxy] -phenyl} -4H- [1, 2,4] oxadiazoI-5-one from 5-chloromethyl-2- (4-methioxy-phenyl) -4- (teirahydro-pyran-2-yloxymethyl) -oxazole and 2-chloro- Commercially available 4-hydroxy-benzonitrile. C21 H18C1N3O6 (443.85), MS (ESI): 444.2 (M + H +).
Example 48 3-. { 2-Chloro-4-r2- (4-methoxy-phenyl) -4- (3-methoxy-propoxymethyl) -oxazol-5-ylmethoxy] -phenyl} -4H- [1,2,4loxadiazol-5-one
According to the method described in Example 1 and Example 34, 3- was obtained. { 2-Chloro-4- [2- (4-methoxy-phenyl) -4- (3-methoxy-propoxymethyl) -oxazoI-5-ylmethoxy] -phenyl} -4H- [1, 2,4] oxadiazoI-5-one from 5-chlorometyl-2- (4-methoxy-phenyl) -4- (1-hydra-pyran-2-yloxymethyl) -oxazoI and 2 -chloro-4-hydroxy-benzonitrile commercially available and 3-meioxy-propan-1-ol. C 24 H 24 CIN 3 O 7 (501, 93), MS (ESI): 502.2 (M + H +).
Example 49 3-. { 5-Bromo-2-methoxy-4-f4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-ylmeyoxyfl-phenyl} -4 - - [1,2,4pxadiazol-5-one
To a solution of 100 mg of 3-. { 2-methoxy-4- [4-methyI-2- (4-trifluoromethyl-phenyl) -thiazoI-5-methoxy] -phenyl} -4H- [1,2,4] oxadiazol-5-one in 1 ml of acetonitrile was added 0.08 g of N-bromosuccinimide. The resulting mixture was heated to 70 ° C overnight, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (gradient dichloromethane / methanol 100/0 to 94/6) and washed with 94/6 dichloromethane / methanol to give 35 mg of 3-. { 5-Bromo-2-methoxy-4- [4-meityl-2- (4-trifluoromethyl-phenyl) -thiazo-5-ylmeyoxy] -pheni} -4 - [1, 2,4] oxadiazol-5-one. C21 H15BrF3N3O4S (542.33), MS (ESI): 542.0 (M + H +).
Example 50 3-. { 4- [4- (3-Benzyloxy-propyl) -2- (4-trifluoromethyl-pheny] -iiazol-5-lmetoxy-1-chloro-phenyl) -4H- [1, 2,41-oxadiazole-5 -one
According to the method described in Example 15, 3- was obtained. { 4- [4- (3-benzyloxy-propyl) -2- (4-trifluoromethyl-phenyl) -thiazoI-5-ylmethoxy] -2-chloro-phenyl} -4H- [1, 2,4] oxadiazol-5-one from [4- (3-benzyloxy-propyl) -2- (4-trifluoromethyl-phenyl) -thiazoI-5-yl] -methanol and 2- Commercially available cyclo-4-fluorobenzonitrile. C29H23CIF3N3O4S (602.03), MS (ESI): 602.2 (M + H +)
Example 51 3-. { 2-Chloro-4-r4- (3-hydroxy-propyn-2- (4-trifluoromethyl-phe n-thiazol-5-ylmeyoxy] -phenyl} -4-7, - ["1, 2.4] oxadiazole -5-one
To a solution of 200 mg of 3-. { 4- [4- (3-benzyloxy-propy) -2- (4-trifluoromethyl-pheny1) -iazole-5-methylmethyl] -2-chloro-phenyl} -4r7, - [1, 2,4] oxadiazol-5-one in 6 ml of dichloromethane cooled to -70 ° C was added 0.8 ml of a 1M solution of boron tribromide in dichloromethane. After stirring for 45 minutes at -60 ° C, the solution was poured into a mixture of meianol and a saline aqueous solution of sodium hydrogencarbonate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (gradient dichloromethane / methanol from 100/0 to 90/10), then crystallized from dichloromethane / diisopropylether to give 18 mg of 3-. { 2-Chloro-4- [4- (3-hydroxy-propyl) -2- (4-trifluoromethyl-phenyl) -thiazole-5-methoxy] -pheni} -4 - / - [1, 2,4] oxadiazoI-5-one. C22H17CIF3N3O4S (511, 91), MS (ESI): 512.1 (M + H +)
Claims (36)
1. - Compounds of the formula in you X is CH2 or a bond; R1, R2, R3, R4 are independently H, F, Cl, Br, CF3, (C1-C4) alkyl, (C0-C4) alkylene-O-alkylene (C0-C4) -H, SCH3, S (O) CH3, S (O) 2CH3, CN, OCF3, OCHF2, OCH2F; Z is a bond or CH2; And it is O, S, S (O) or S (0) 2; W is CH2 or CH2CH2; one of U and V is N, the other is S or O; R5 is selected from the group consisting of (C1-C8) alkyl, (C1-C6) alkylene-O-alkylene (C0-C4) -H, (C0-C6) alkyl-phenylene, (C1-C6) alkylene-O -alkylene (C0-C4) -phenyl, (C3-C6) cycloalkyl, (C2-C8) alkenyl, and wherein the alkyl or (C1-C8) alkylene can be substituted 1-2-fold with OH or O-alkyl (C1 -C4); R6, R7 are independently H, F, Br, CF3, OCF3, (C1-C6) alkyl, al-quiIen (C0-C4) -O-alkylene (C0-C4) -H, SCF3, SF5, OCF2-CHF2, OCHF2, OCH2F, O-phenyl, phenyl, NO2; or as well as their salts and physiologically acceptable tautomeric forms.
2. - Compounds of the formula I according to the claim 1, in which X is a link.
3. - Compounds of the formula I according to the claim 1, in which X is a bond or CH2; R1 is H, F, Cl, Br, CF3, (C1-C4) alkyl, O-alkyl (C1-C4), SCH3, S (O) CH3, S (O) 2CH3, CN; R2 is H, F; R3 is H, Br, O-(C1-C4) alkyl; R4 is H; it is a bond or CH2; And it is O, S, S (O) or S (O) 2; W is CH2 or CH2CH2; U is S and V is N or U is N and V is S or U is N and V is O; R5 is (C1-C6) alkyl or (C2-C6) alkenyl, wherein the (C1-C6) alkyl may be substituted 1-2 times with OH; R6 is in. position for y is CF3, SF5, OCH3, phenyl; R7 is H or F.
4. - Compounds of the formula I according to the claim 1, in which X is a link; R1 is H, F, Cl, Br, CF3, (C1-C4) alkyl, O-C1-C4 alkyl, SCH3, S (O) CH3, S (O) 2CH3, CN; R2 is H, F; R3 is H, Br, O-(C1-C4) alkyl; R4 is H; it is a bond or CH2; And it is O, S, S (O) or S (O) 2; W is CH2 or CH2CH2; U is S and V is N or U is N and V is S or U is N and V is O; R5 is (C1-C6) alkyl or (C2-C6) alkenyl, where the (C1-C6) alkyl may be substituted 1-2 times with OH; R6 is in position for and is CF3, SF5, OCH3, phenyl; R7 is H or F.
5. - Compounds of the formula I according to the claim 1, in which X is a link; R1 is Cl or CH3; R2, R3, R4 are H; it is a link; Cast; w is CH2; u is S and V is N or u is N and V is O u u is O and V is N; R5 is (C1-C4) alkylene-O-alkylene (C1-C4) -H or alkylene (C1-C4) -O-alkylene (C1-C4) -pheni, wherein alkylene can be substituted by O-alkyl ( C1- C4); R6 is in position for and is CF3 or OCH3; R7 is H.
6. - Compounds of the formula I according to the claim 1, where X is a link; R1 is OCH3 or F; R2, R3, R4 are H; Z is a link; And esOoS; W is CH2 or CH2CH2; u esS and V is N or u is N and V is S or u is O and V is N or u is N and V is O; R5 is (C1-C4) alkyl, (C1-C4) alkyl-O-(C1-C4) alkylene -H or (C1-C4) alkyl-O-(C1-C4) alkylene-phenyl, where alkylene may be substituted by Oa! quiIo (C1-C4). R6 is in position for and is CF3 or OCH3; R7 is H.
7 '.- Compounds of the formula I according to the claim 1 or 2, in which X is a bond or CH2; R1 is H, F, Cl, Br, OCH3, SCH3, CF3, CH3, CN, S (O) CH3, S (O) 2CH3; R2 is H, F; R3 is H, OCH3, Br; R4 is H; Z is a bond or CH2; And it is O, S, S (0) or S (O) 2; W is CH2 or CH2CH2; U is S and V is N or U is N and V is S; R5 is (C1-C4) alkyl or (C2-C4) alkenyl, where (C1-C4) alkyl may be substituted 1-2 times with OH or R5 is (C1-C4) alkylene-O-alkylene (C1-C4) ) -H or alkyl (C 1 -C 4) -O- (C 1 -C 4) alkylene-phenyl alkylene, where alkylene can be substituted by O-alkyl or (C 1 -C 4); R6 is p-CF3 or p-SF5; Y R7 is H.
8. - Compounds of the formula I according to the claim 1, in which X is a link; R1 is Cl, CH3; R2 is H; R3 is H; R4 is H; Z is a link; Cast; W is CH2; U is N and V is O u U is O and V is N; R5 is (C1-C4) alkyl, (C1-C4) alkyl-O-alkylene (C1-C4) -H or alkylene (C1-C4) -O-alkylene (C1-C4) -phenyl, where alkylene may be substituted by O-(C1-C4) alkyl. R6 is p-OCH3 or p-phenyl; Y R7 is H.
9. - Compounds of the formula I according to claims 1 to 8, wherein R1 R2, are independently H, F, Cl, Br, OCH3, SCH3, CF3, CH3, CN, S (O) CH 3, S (O) 2 CH 3; X is a link and Z is a link; R3, R4, are independently H, OCH3; R6 is in position for and is H, F, CF3, CH3, SF5, OCH3, phenyl; R7 is H.
10. - Compounds of the formula I according to claims 1 to 8, wherein R1, R2, are independently H, F, Cl, Br, OCH3, SCH3, CF3, CH3, CN, S (O) CH 3, S (O) 2 CH 3; X is a bond and W is CH2; R3, R4, are independently H, OCH3; R6 is in position for and is H, F, CF3, CH3, SF5, OCH3, phenyl; R7 is H.
11. - Compounds of the formula I according to claim 1, wherein u is S and V is N or u is N and V is S or u is O and V is N or u is N and V is O.
12. - Compounds of the formula I according to claims 1 to 11, wherein U is S, V is N, Z is a link.
13. - Compounds of the formula I according to claims 1 to 12, wherein u is N, V is O, z is a link, X is a link.
14. - Compounds of the formula I according to claims 1 to 13, wherein X is a link and Z is a link.
15. - Compounds of the formula I according to claims 1 to 14, wherein R6 is in the para position;
16. - Compounds of the formula I according to claims 1 to 15, wherein R7 is H or F.
17. - Compounds of the formula I according to claims 1 to 16, wherein R2, R3, R4 are H, R1 is H, F, Cl, Br, CF3, (C1-C4) alkyl, (C0-C4) -O- alkylene (C0-C4) -H, SCH3, S (O) CH3, S (O) 2CH3, CN.
18. - Compounds of the formula I according to claims 1 to 17, wherein And it's O or S.
19. - Compounds of the formula I according to claims 1 to 18, wherein W is CH2.
20. Compounds of the formula I according to claims 1 to 19, wherein R 5 is (C 1 -C 4) alkyl or (C 1 -C 4) alkylene-O-alkylene (C 0 -C 4) -H, wherein alkylene can be substituted by 0 -alkylene (C0-C4) -H or phenyl.
21. - Compounds of the formula I according to claims 1 to 20, wherein R1 is F, Cl, CH3, OCH3.
22. - Compounds of the formula I according to claims 1 to 21, wherein R 5 is (C 1 -C 4) alkyl.
23. - Compound of formula I according to claims 1 to 22, wherein R6 is CF3, SF5, phenyl, OCH3.
24. - A pharmaceutical product comprising one or more compounds of the formula I according to one or more of claims 1 to 23.
25. - A pharmaceutical product comprising one or more compounds of the formula I according to one or more of claims 1 to 23, and one or more active substances that have beneficial effects on the metabolic alterations or disorders frequently associated therewith.
26. - A pharmaceutical product comprising one or more compounds of the formula I according to one or more of claims 1 to 23, and one or more antidiabetics.
27. - A pharmaceutical product comprising one or more compounds of the formula I according to one or more of claims 1 to 23, and one or more lipid modulators.
28. Compounds of the formula I according to one or more of claims 1 to 23, for use in the treatment and / or prevention of disorders of fatty acid metabolism and glucose utilization disorders.
29. Compounds of the formula I according to one or more of claims 1 to 23, for use in the treatment and / or prevention of disorders in which insulin resistance is involved.
30. Compounds of the formula I according to one or more of claims 1 to 23, for use in the irradiation and / or prevention of diabetes mellitus, including the prevention of sequelae associated therewith.
31. - Compounds of the formula I according to one or more of claims 1 to 23, for use in the treatment and / or prevention of dyslipidemias and their sequelae.
32. - Compounds of the formula I according to one or more of claims 1 to 23, for use in the trafamiento and / or the prevention of states that may be associated with the metabolic syndrome.
33. - Compounds of the formula I according to one or more of claims 1 to 23, for use in the treatment and / or prevention of neurodegenerative diseases and / or demyelination disorders of the central and peripheral nervous systems, and / or neurological diseases that they involve neuroinflammatory processes and / or other peripheral neuropathies.
34. Compounds according to one or more of claims 1 to 23, combined with at least one additional active compound, for use in the treatment of disorders of fatty acid metabolism and disorders of glucose use.
35. Compounds according to one or more of claims 1 to 23, combined with at least one additional active compound, for use in the treatment of frasures in which insulin resistance is involved.
36. A process for preparing a pharmaceutical product comprising one or more of the compounds according to one or more of claims 1 to 23, comprising mixing the active compound with a pharmaceutically acceptable carrier, and putting this mixture in a suitable administration form.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP04007879 | 2004-04-01 |
Publications (1)
Publication Number | Publication Date |
---|---|
MXPA06010225A true MXPA06010225A (en) | 2007-04-20 |
Family
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