Derivatives of triaryl-containing acids as of ppar receptor ligands

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new compounds of the following formulae:

and , and to a pharmaceutical composition possessing the PPAR-ligand binding activity and comprising the indicated compound, and a pharmaceutically acceptable vehicle. Also, invention relates to a method for treatment of patient suffering with physiological disorder that can be modulated with the compound possessing the PPAR-ligand binding activity. Method involves administration to the patient the pharmaceutically effective dose of indicated compound or its pharmaceutically acceptable salt.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

10 cl, 1 tbl, 104 ex

 

Prior art

This invention relates to the use of derivatives trailway acid and pharmaceutical compositions based on them as ligands of the receptor PPAR (PPAR). The ligands of the receptor PPAR according to this invention is used as agonists or antagonists of the receptor PPAR.

The technical field

Activated proliferation peroxisome receptor (PPAR) can be subdivided into three subtypes, namely: PPARα, PPARδ and PPARγ. They are encoded by different genes (Motojima, Cell Structure and Function, 18: 267-277, 1993). In addition, there are 2 isoforms of PPARγ, PARγ1and γ2. These two proteins differ NH2-terminal region of 30 amino acids and are the result of the use of alternative promoters and splicing of different mRNA (Vidal-Puig, Jimenez, Linan, Lowell, Hamann, Hu, Spiegelman, Flier, Moller, J. Clin. Invest., 97: 2553-2561, 1996).

The biological processes modulated PPAR represent a process modulated by receptors or combinations of receptors that are sensitive to the described ligands of the receptor PPAR. These processes include, for example, transport of lipid in the plasma and the catabolism of fatty acids, regulation of insulin sensitivity and glucose levels in the blood that are associated with hypoglyce-MIA/hyperinsulinemia (resulting, for example, animal the aqueous functioning pancreatic beta cells insulin secreting tumors and/or autoimmune hypoglycemia due to autoantibodies to insulin, the insulin receptor, or autoantibodies that are stimulatory to pancreatic beta cells), differentiation of macrophages, which leads to the formation of atherosclerotic plaques, inflammatory response, carcinogenesis, hyperplasia or differentiation of adipocytes.

Obesity is an excessive accumulation of adipose tissue. Recent work in this area indicates that PPARγ plays a Central role in the expression and differentiation of adipocyte gene. Excess adipose tissue is associated with development of serious medical conditions, such as insulin-independent diabetes mellitus (NIDDM), hypertension, coronary heart disease, hyperlipemia and some malignant tumors. Adipocyte may also affect glucose homeostasis by producing factor α tumor necrosis (TNFαand other molecules.

Insulin-independent diabetes mellitus (NIDDM, NIDDM) or Type II diabetes represents a particularly common form of diabetes, with 90-95% of patients with hyperglycemia are affected by this form of the disease. In NIDDM, probably, there is a decrease in the mass of pancreatic β-cells, some expressed the breach is in insulin secretion or decreased sensitivity of the tissues to insulin. The symptoms of this form of diabetes include fatigue, frequent urination, thirst, blurred vision, frequent infections and slow healing of open wounds on the skin, diabetic nerve disorder, and kidney disease.

The metabolic insulin (insulin resistance) is one of the main features of insulin-independent diabetes mellitus (NIDDM). Insulin resistance is characterized by impaired absorption and utilization of glucose in insulin-sensitive organs-the target of, for example, adipocytes and skeletal muscle and impaired inhibition of glucose release by the liver. The lack of functional insulin and lack of insulin to suppress the production of glucose by the liver leads to hyperglycemia with fasting. Pancreatic β-cells compensate for insulin resistance by enhancing insulin secretion. However, β-cells are not able to maintain this high production of insulin, and, ultimately, the insulin secretion induced by glucose, decreases, resulting in deterioration of glucose homeostasis and to the subsequent development of overt diabetes.

Hyperinsulinemia is also associated with insulin resistance, hypertriglyceridaemia and increased concentration of plasma low-density lipoprotein. The relationship of insulin resistance and hyperinsulinemia is these metabolic disorders is called "Syndrome X" and is associated with an increased risk of developing hypertension and ischemic heart disease.

It is known that Metformin is used to treat diabetes in humans (U.S. Patent No. 3174901). Metformin acts primarily by reducing the production of glucose by the liver. Troglitazone®as you know, basically, works to enhance the ability of skeletal muscle to respond to insulin and absorb glucose. It is known that for the treatment of abnormalities associated with diabetes, you can use combination therapy, including Metformin and troglitazone (DDT 3: 79-88 [in Russian], 1998).

Activators PPARγin particular Troglitazone®as it was found, convert cancerous tissue in normal cells when liposarcoma, tumors of fat. (PNAS 96: 3951-3956, 1999). In addition, it was confirmed that the activators PPARγ can be used to treat breast cancer and colon cancer (PNAS 95: 8806-8811, 1998, Nature Medicine 4: 1046-1052, 1998).

In addition, activators PPARγsuch as Troglitazone®were used for the treatment of polycystic ovarian syndrome (PCO). This syndrome in women is characterized by chronic anovulation and giperandrogenii. Women with this syndrome often have insulin resistance and increased risk for development of insulin-independent diabetes mellitus (Dunaif, Scott, Finegood, Quintana, Whitcomb, J. Clin. EndoGrinol. Metab., 81: 3299, 1996).

In addition, activators PPARγas was recently discovered, enhance the production of progesterone and ing berout the steroidogeneza in granular cell cultures and can therefore be used to treat menopause. (United States Patent 5814647 Urban et al. September 29, 1998; B. Lohrke et al. Journal of Endocrinology, 159, 429-39, 1998). Menopause is defined as a syndrome of endocrine, somatic and physiological changes that occur when the end of the reproductive period of a woman.

Peroxisomes are cellular organelles that play a role in the regulation of redox potential and oxidative stress of cells, metaboliser a number of substrates, such as hydrogen peroxide. There are a number of disorders associated with oxidative stress. For example, inflammatory response to tissue injury, pathogenesis of emphysema associated with ischemia damage to the body (shock), doxorubicin-induced disturbance of cardiac activity, induced drug-induced hepatotoxicity, atherosclerosis, and caused by hyperoxia lung damage, each of them associated with the formation of reactive oxygen and changes in the regenerative capacity of the cell. Therefore, it is assumed that the activators PPARαthat, among other things, regulate the redox potential and oxidative stress in cells, can be effective for the treatment of these disorders (Poynter et al, J. Biol. Chem. 273, 32833-41, 1998).

In addition, it was found that agonists of PPARα inhibit transcription-mediated NFκB, module is the ROI thus the processes of the inflammatory response on the way inducible synthase nitric oxide (NOS) and cyclooxygenase-2 (SOH-2) (Pineda-Torra, I. T al, 1999, Curr. Opinion in Lipidology, 10, 151-9), and therefore can be used for therapeutic intervention in a wide range of inflammatory diseases and other pathologies (Colville-Nash et al., Journal of Immunology, 161, 978-84, 1998; Staels et al, Nature, 393, 790-3, 1998).

Proliferatory peroxisome activate PPAR, which in turn, acts as a transcription factor and induces differentiation, cell growth and proliferation peroxisome. In addition, suppose that the activators PAR play a role in hyperplasia and carcinogenesis, as well as in changing the enzymatic ability of animal cells, such as cells of rodents, but these activators PAR, apparently, have minimal adverse action in human cells (Green, Biochem. Pharm. 43(3): 393, 1992). Activation PPAR leads to a rapid increase in gamma glutamyltranspeptidase and catalase.

PPARα activate a number of medium - and long-chain fatty acids and is involved in stimulating β-oxidation of fatty acids in tissues such as liver, heart, skeletal muscle and brown adipose tissue (Isseman and Green, supra; Beck et al., Proc. R. Soc. Lond. 247: 83-87, 1992; Gottlicher et al., Proc. Natl. Acad. Sci. USA 89: 4653-4657, 1992). In addition, pharmacological activators of PPARα, for example, fenofibrate, clofibrate, gemfibrozil and bezafibrat, participate in a significant reduction in plasma triglycerides, along with a moderate decrease in NPL (LDL) cholesterol, and the use in particular, for the treatment of hypertriglyceridemia, hyperlipemia and obesity. Furthermore, it is known that PPARα involved in the processes of inflammatory diseases (Schoonjans, K., Current Opionion in Lipidology, 8, 159-66, 1997).

PPARδ nuclear receptor human was cloned from a cDNA library of the cell osteosarcoma human and fully described in A. Schmidt et al., Molecular Endocrinology, 6: 1634-1641 (1992), the contents of which are used here as a reference. It should be borne in mind that PPARδ in the literature also referred to as PPARβ and as NUC1, and each of these names refers to the same receptor. For example, in A. Schmidt et al., Molecular. Endocrinology, 6: pp.1634-1641, 1992, receptor called NUC1. PPARδ detected in the tissues of the embryo and in adult tissues. It is reported that this receptor is involved in regulation of expression of some fat-specific genes and plays a role in lipolase. (Amri, E. et al., J. Biol. Cbem. 270, 2367-71, 1995).

It is known that atherosclerosis is caused by a number of factors, such as hypertension, diabetes, low levels of high density lipoprotein (IDPs HDL), and high levels of low density lipoprotein (NPL, LDL). In addition to reducing risk through effects on concentrations of lipids in plasma and other risk factors, the agonists of PPARα show direct terazosine actions (Frick, M.N., et al. 1997., Circulation 96: 2137-2143, de Faire, et al. 1997. Cardlovasc. Drugs Ther. 11 Suppi 1:257-63:257-263).

Not avno was detected, that agonists are useful for increasing levels of IDPs (HDL) and therefore can be used for the treatment of atherosclerotic diseases (Leibowitz et al.; WO/9728149). Atherosclerosis involves vascular disease, coronary heart disease, cerebrovascular disease and peripheral vascular disease. Coronary heart disease includes death from congenital heart disease, myocardial infarction and coronary revascularization. Areasmore disease includes ischemic or hemorrhagic stroke and transient disturbances of cerebral circulation.

Subtypes PPARγ involved in the activation of the differentiation of adipocytes and are not involved in the stimulation of peroxisome proliferation in the liver. Activation PPARγ involved in the differentiation of adipocytes through activation of expression of adipocyte-specific genes (Lehmann, Moore, Smith-Oliver, Wilkison, Willson, Kliewer, J. Blol. Chem., 270: 12953-12956, 1995). DNA sequences for the receptor PPARγ described Elbrecht et al., BBRC 224: 431-437 (1996). Although proliferatory peroxisome, including the fibrates and fatty acids, activate the transcriptional activity PER s, only the derivatives of prostaglandin J2such as arachidonic acid metabolite 15-deoxy-Delta12, 14-prostaglandin J2(15d-PGJ2), have been identified as natural ligands specific for subtype PPARγ, which is also vyzyvaet preparations of thiazolidinediones. This prostaglandin activates PPARγ-dependent adipogenic and PPARα activates only at high concentrations (Forman, Tontonoz, Chen; Brun, Spiegelman, Evans, Cell, 83: 803-812, 1995; Kliewer, Lenhard, Wilson, Patel, Morris, Lehman, Cell 83: 813-819, 1995). This is proof that the subtypes family PPAR differ from each other in their pharmacological response to ligands.

It has been suggested that compounds that activate as PPARαand PPARγmust be strong hypotriglyceridemic medicines that could be used for the treatment of dyslipidemia associated with atherosclerosis, insulin-independent diabetes mellitus, Syndrome X (Staels, B. et al., Curr. Pharm. Des., 3 (1), 1-14 (1997)) and hereditary combined hyperlipidemia (FCH). Syndrome X is a syndrome characterized insulinorezistentne state, generating hyperinsulinemia, dyslipidemia and impaired glucose tolerance, which may progress to insulin-independent diabetes mellitus (Type II diabetes)is characterized by hyperglycemia. FCH is characterized by hypercholesterinemia and hypertriglyceridemia within the same patient and family.

The present invention relates to a group of compounds that can be used to modulate receptor PPAR, and a number of other pharmaceutical is ramineni, related.

The invention

This invention relates to new aromatic compounds and pharmaceutical compositions obtained on their basis, which are ligands of the receptor PPAR and which may be used as agonists or antagonists of the receptors PPAR. In addition, the invention includes the discovery of new uses for previously known compounds.

Compounds for use in accordance with the invention, including the new compounds of the present invention, have the formula I

where:

andrepresent, independently, aryl, condensed arylchloroalkanes, condensed aristically, condensed arylheteroacetic, condensed arylheteroacetic, heteroaryl, condensed heteroarylboronic, condensed heteroalicyclic, condensed heterooligomerization or condensed heteroalicyclic;

And represents-O-, -S-, -SO-, -SO2-, -NR13-, -C(O)-, -N(R14)C(O)-, -C(O)N(R15)-, -N(R14)C(O)N(R15)-, -C(R14)=N-,

chemical bond,

or

In represents-O-, -S-, -SO-, -SO2-, -NR17-, chemical bond, ethynylene, -C (O)-, -N(R18)C(O)- or-C(O)NR18-;

D represents-O-, -S-, -NR19-, chemical bond, ethynylene, -C(O)-, -N(R20)C(O)- or-C(O)N(R20)-;

E represents a chemical bond or an ethylene group;

and is 0-4;

b is 0-4;

C is 0-4;

d is 0-5;

e is 0-4;

f is 0-6;

g is 1-4;

h is 1-4;

R1, R3, R5, R7, R9and R11are independently hydrogen, halogen, alkyl, carboxyl, alkoxycarbonyl or aralkyl;

R2, R4, R6, R8, R10and R12are independently -(CH2)q-X;

q is 0-3;

X represents hydrogen, halogen, alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, heteroalkyl, hydroxy, alkoxy, Alcoxy, hetero-Alcoxy, carboxyl, alkoxycarbonyl, tetrazolyl, acyl, HNSO2-, -SR23, Y1Y2N or Y3Y4NCO-;

Y1and Y2are independently hydrogen, alkyl, aryl, aralkyl or heteroalkyl, or one of the Y1and Y2represents hydrogen or alkyl and the other of Y1and Y2represents acyl or aroyl;

Y3and Y4are illegal is isimo hydrogen, alkyl, aryl, aralkyl or heteroalkyl;

Z is an R21O2C-, R21OC-, cycloid, -CN, R21O2SHNCO-, R21O2SHN-, (R21)2NCO-, R21O-2,4-thiazolidinedione or tetrazolyl and

R19and R21are independently hydrogen, alkyl, aryl, cycloalkyl or aralkyl;

R13, R17, R19and R23are independently R22OC-, R22NHOC-, hydrogen, alkyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, heteroalkyl or aralkyl;

R14, R15, R16, R18and R20are independently hydrogen, alkyl, aralkyl, carbonyl or alkoxycarbonyl;

or R14and R15taken together with the carbon atoms and nitrogen through which they are linked, form a 5 - or 6-membered azaheterocyclic group; or

when and equals 2-4, then adjacent radicals R1taken together with the carbon atoms, which radicals R1are bound, form an ethylene group; or

when b equals 2-4, then adjacent radicals R3taken together with the carbon atoms, which radicals R3are bound, form an ethylene group; or

when equals 2-4, then adjacent radicals R5taken together with the carbon atoms, which radicals R5are bound, form an ethylene group; or

when d is equal to 2-5, then adjacent adically R 7taken together with the carbon atoms, which radicals R7are bound, form an ethylene group; or

when e equals 2-4, then adjacent radicals R9taken together with the carbon atoms, which radicals R9are bound, form an ethylene group; or

when f is equal to 2-6, then adjacent radicals R11taken together with the carbon atoms, which radicals are bound R11, form an ethylene group; or

R22represents hydrogen, alkyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, heteroalkyl or aralkyl; or a pharmaceutically acceptable salt them, N-oxide thereof, the hydrate or MES.

Detailed description of the invention

Note that used above and hereinafter in the description, the following terms have the following meanings:

Definition

In the present description predpolagaetsya that the term "compounds for use in accordance with the invention", and equivalent expressions encompasses compounds of General formula (I)as described above, and the expression includes the prodrugs, pharmaceutically acceptable salts and salt wool, e.g. hydrates, where the context so admits. Similarly, relatively intermediate compounds, regardless of whether claimed or not, it is assumed that this expression covers their salts and solvate, where the context so admits. For the sake of clarity, the text sometimes refers to specific cases, when the context so admits, however, these cases are purely illustrative and it is understood that this does not exclude other cases, if the context so admits.

"Prodrug" means a compound that can be converted in vivo by metabolic means (e.g. by hydrolysis) to a compound of formula (I), including N-oxides. For example, ester compounds of formula (I)containing a hydroxy-group, can be converted by hydrolysis in vivo to the original molecule. Alternatively, the ester compounds of formula (I)containing carboxypropyl, can be converted by hydrolysis in vivo to the original molecule.

The term "patient" includes both human and other mammal.

The term "chemical bond" means a direct single bond between the atoms.

"Acyl" means an H-CO - or alkyl-CO - group, where the alkyl group is as herein described. Preferred atilov contain lower alkyl. Illustrative acyl groups include formyl, acetyl, propanol, 2-methylpropanol, butanoyl, which.

"Alkenyl" means an aliphatic hydrocarbon group containing a carbon-carbon double bond, and which may be straight or branched chain, having from about 2 to about 15 carbon atoms in the chain. Preferred alkeneamine groups have from 2 to about 12 carbon atoms in the chain and more preferably from about 2 to about 4 carbon atoms in the chain. The term "branched" means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to linear alkenylphenol chain. "Lower alkenyl" means from about 2 to about 4 carbon atoms in the chain which may be straight or branched. Alchemilla group optionally substituted by one or more halogen groups. Illustrative alkeneamine groups include ethynyl, propenyl, n-butenyl, Isobutanol, 3-methylbut-2-enyl, n-pentenyl, heptenyl, octenyl and decenyl.

"Alkoxy" means alkyl-O - group, where the alkyl group is as herein described. Illustrative alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, heptox.

"Alkoxycarbonyl" means alkyl-O-CO - group, where the alkyl group is as herein described. Illustrative alkoxycarbonyl group include methoxycarbonyl, etoxycarbonyl or t-butoxycarbonyl.

"Alkyl" means an aliphatic hydrocarbon group which may have a straight or branched chain, having from about 1 to about 20 carbon atoms in the chain. Preferred alkyl groups have from 1 to about 13 carbon atoms in the chain. The term branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are associated with a linear alkyl chain of Lower alkyl" means, that chain has from about 1 to about 4 carbon atoms, and this chain can be straight or branched. Alkyl optionally substituted by one or more "substituents alkyl groups, which may be the same or different and include halogen, carboxy, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclyl, aryl, alkoxy, alkoxycarbonyl, arelaxation, heteroarylboronic, Y1Y2NCO-, where Y1and Y2are independently hydrogen, alkyl, aryl, aralkyl or heteroalkyl, or Y1and Y2taken together with the nitrogen atom to which Y1and Y2attached, form heterocyclyl. Illustrative alkyl groups include methyl, trifluoromethyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl and 3-pentyl. Preferably, Deputy alkyl group selected from acyl, halogen, carboxy, carboxymethyl, methoxycarbonylmethyl, benzyloxycarbonylamino and pyridinedicarboxylate and alkoxycarbonyl.

"Alkylsulfonyl" means alkyl-SO - group, where the alkyl group such as defined above. Preferred are groups, where the alkyl group is a lower alkyl.

"Alkylsulfonyl" means an alkyl-SO2group, an alkyl group such as defined above. Preferred are groups, where the alkyl gr is the PAP is a lower alkyl.

"Alkylthio" means alkyl-S - group, where the alkyl group such as defined above. Illustrative of alkylthio groups include methylthio, ethylthio, isopropylthio, reptillia.

"Arakaki" means aralkyl-O - group, where kalkilya group is the same as here defined. Illustrative of Alcoxy groups include benzyloxy and 1 - and 2-naphthalene-methoxy.

"Arelaxation" means aralkyl-O-CO - group, where kalkilya group is the same as defined here. Typical arelatively group is benzyloxycarbonyl.

"Aralkyl" means an aryl-alkyl group, where the aryl and alkyl groups are as defined here. Preferred aralkyl contain lower alkyl part. Illustrative kalkilya groups include benzyl, 2-phenethyl and naphthalenethiol.

"Aralkylamines" means aralkyl-SO2group, kalkilya group such as defined here.

"Aralkylamines" means aralkyl-SO - group, where kalkilya group such as defined here.

"Uralkali" means aralkyl-S - group, where kalkilya group such as defined here. Typical Uralkali group is benzylthio.

"Aroyl" means an aryl-CO - group, where aryl group such as defined here. Illustrative aroline groups include benzoyl and 1 - and 2-naphtol.

"Aryl" means an aromatic monocyclic or polycyclic ring system from about 6 to about 14 carbon atoms, preferably from about 6 to about 10 carbon atoms.

Aryl optionally substituted by one or more "ring system substituents"which may be the same or different and are as defined here. Illustrative aryl groups include phenyl, naphthyl, substituted phenyl and substituted naphthyl.

"Araldit" means aryl-diazo - group, where aryl and diazo groups are as defined here.

"Condensed arylchloroalkanes" means a condensed aryl and cycloalkenyl, as defined here. The preferred condensed arylcyclohexylamine are those in which the aryl it represents phenyl and cycloalkenyl consists of about 5 to about 6 ring atoms. Condensed arylcyclohexylamine group can be connected with the remainder of the compound via any atom from a condensed matter system, capable of such bonding. Condensed arylchloroalkanes may be optionally substituted by one or more substituents of the ring system, where the Deputy ring system" as defined here. Illustrative condensed ar is cycloalkenyl groups include 1,2-dihydronaphthalene; indenyl; 1,4-naphtohinone etc.

"Condensed aristically" means a condensed aryl and cycloalkyl defined here. The preferred arylcyclohexylamine are, where aryl represents a phenyl and cycloalkyl consists of about 5 to about 6 ring atoms. Condensed arylcyclohexylamine group can be connected with the remainder of the compound via any atom in the condensed system, capable of forming such an Association. Condensed aristically may be optionally substituted by one or more substituents of the ring system, where the Deputy ring system" as defined here. Illustrative condensed arylcyclohexylamine and substituted condensed arylcyclohexylamine groups include 1,2,3,4-tetrahydronaphthyl; 1,4-dimethyl-2,3-dihydronaphtho; 2,3-dihydro-1,4-naphtohinone, α-tetralinyl, β-tetralone etc.

"Condensed arylheteroacetic" means a condensed aryl and heterocyclyl, where aryl and heterocyclyl groups such as here defined. The preferred condensed arylethanolamine groups are those in which the aryl represents a phenyl and heterocyclyl consists of about 5 to about 6 ring atoms. Condensed arylheteroacetic is supplemented flax group can be connected with the remainder of the compound via any atom in the condensed system, able to form such a link. The designation of Aza, oxa or thia as a prefix before heterocyclyl part of the condensed arylheteroacetic means that the atom is nitrogen, oxygen or sulfur, respectively, present as atom rings. Condensed arylheteroacetic may be optionally substituted by one or more substituents of the ring system, where the Deputy ring system" as defined here. The nitrogen atom condensed arylheteroacetic can be an atom of basic nitrogen. In addition, nitrogen atom or sulfur heterocyclyl part of the condensed arylheteroacetic optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Illustrative condensed arylheteroacetic and substituted condensed arylheteroacetic groups include 3H-indolinyl, 2(1H)hyalinosis, 4-oxo-1,4-dihydroquinoline, 2H-1-occaisonaly, 1,2-dihydroquinoline, (2H)chinoline N-oxide, 3,4-dihydroquinoline, 1,2-dihydroisoquinolyl, 3,4-dihydroisoquinoline, chromones, 3,4-dihydroisoquinoline, 4-(3H)chinazolinei, 4H-chromen-Il etc. Preferably, 2(1H)hyalinosis, 1,2-dihydroquinoline, (2N)chinoline N-oxide or 4-(3H)chinazolinei.

"Condensed arylheteroacetic" means a condensed aryl and heterocyclyl, where aryl and heterocycle is global groups such as defined here. The preferred condensed allheterocou are, where aryl represents a phenyl and heterocyclyl consists of about 5 to about 6 ring atoms. Condensed arylheteroacetic can be associated with the remainder of the compound via any atom in the condensed system, capable of forming such an Association. The designation of Aza, oxa or thia as a prefix before heterocyclyl part of the condensed allheterocou means that the atom is nitrogen, oxygen or sulfur, respectively, present as atom rings. Condensed arishamarishkina group may be optionally substituted by one or more substituents of the ring system, where the Deputy ring system" as defined here. The nitrogen atom condensed allheterocou can be an atom of basic nitrogen. In addition, nitrogen atom or sulfur heterocyclyl part of the condensed allheterocou optionally is oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Illustrative condensed analgeticalkie and substituted condensed analgeticalkie group include indolinyl, benzosulfimide, 4-chromanone, oxindol, 1,2,3,4-tetrahydroisoquinoline, 1,2,3,4-tetrahydroquinoline, 1H-2,3-digidroid is indol-2-yl, 2,3-dihydrobenzo[f]isoindole-2-yl, 1,2,3,4-tetrahydrobenzo[g]isoquinoline-2-yl, bromanil, isopropanol, 2,3-dihydrobromide, 1,4-benzodioxan, 1,2,3,4-tetrahydro-honokalani etc. Preferably 1,2,3,4-tetrahydroisoquinoline, 1,2,3,4-tetrahydroquinoxaline and 1,2,3,4-tetrahydroquinoline.

"Aryloxy" means aryl-O - group, where aryl group such as defined here. Illustrative groups include phenoxy and 2 naphthyloxy.

"Aryloxyalkyl" means aryl-O-CO - group, where aryl group such as defined here. Illustrative aryloxyalkyl group include phenoxycarbonyl and mattoxicator.

"Arylsulfonyl" means aryl-SO2group, aryl group such as defined here.

"Arylsulfonyl" means aryl-SO - group, where aryl group such as defined here.

"Aristeo" means an aryl-S - group, where aryl group such as defined here. Illustrative of aaltio groups include phenylthio, naphthylthio.

"Carbarnoyl represents NH2-CO - group.

"Carboxy" means(A)WITH-(carboxylic acid) group.

It is intended that the compounds of the invention", and equivalent expressions, cover the previously described compounds of General formula (I), and this expression includes the prodrugs, pharmaceutically acceptable salt and solvate such as a hydrate, if the context so the stage is producing. For the sake of clarity, in the text sometimes refers to specific cases where the context so admits, however, these cases are purely illustrative and it is understood that this does not exclude other cases, if the context so admits.

"Cycloalkane" means cycloalkyl-O - group, where cycloalkyl group such as defined here. Illustrative of cycloalkane groups include cyclopentyloxy, cyclohexyloxy.

"Cycloalkenyl" means a non-aromatic mono - or polycyclic ring system of about 3 to about 10 carbon atoms, preferably from about 5 to about 10 carbon atoms, and which contains at least one carbon-carbon double bond. Preferred sizes (types) of rings included in the ring system include about 5 to about 6 ring atoms. Cycloalkenyl optionally substituted by one or more "ring system substituents"which may be the same or different and are as defined here. Illustrative monocyclic cycloalkenyl include cyclopentenyl, cyclohexenyl, cycloheptenyl etc. Typical polycyclic by cycloalkenyl is norbornylene.

"Cycloalkyl" means a non-aromatic mono - or polycyclic ring system of about 3 to when listello 10 carbon atoms, preferably from about 5 to about 10 carbon atoms. Preferred sizes (types) of rings included in the ring system include about 5 to about 6 ring atoms. Cycloalkyl optionally substituted by one or more "ring system substituents"which may be the same or different and are as defined here. Illustrative monocyclic cycloalkyl include cyclopentyl, cyclohexyl, cycloheptyl etc. Illustrative polycyclic cycloalkyl include 1-decalin, norbornyl, adamant-(1 - or 2-)yl, etc.

"Cycloalkyl" means a bivalent, saturated of carbocyclic group having about 3 to about 6 carbon atoms. Preferred cycloalkene groups include 1,1-, 1,2-, 1,3 - and 1,4-CIS - or TRANS-cyclohexyl; and 1,1-, 1,2 - and 1,3-cyclopentane.

"Cycloid" means a compound of formula

Distribution part may be related to the parent (original) molecule through any carbon atom or nitrogen atom carbamoyl part. Typical kidney group is N-phthalimide.

"Diazo" means a bivalent radical-N=N-.

"Halogen" means fluorine, chlorine, bromine or iodine. Preferred are fluorine, chlorine and bromine, more preferably fluorine and chlorine.

"Heteroalkyl" about the means heteroaryl-alkyl - group, where heteroaryl and alkyl groups are as defined here. Preferred heteroalkyl contain lower alkyl part. Illustrative heteroalkyl group include thienylmethyl, pyridylmethyl, imidazolidinyl and personality.

"Heteroalkyl" means heteroaryl-S - group, where heteroalkyl group such as defined here. Typical heteroalkyl group is 3-pyridine-propandiol.

"Heteroaromatic" means heteroaryl-O - group, where heteroalkyl group is the same as defined here. Typical heteroaromatic group is 4-pyridylmethylene.

"Heteroaryl" means heteroaryl-CO - group, where the heteroaryl group such as defined here. Illustrative heteroaryl groups include thiophenol, nicotinoyl, pyrrol-2-ylcarbonyl and 1 - and 2-naphtol and pyridinoyl.

"Heteroaromatics" means heteroaryl-diazo - group, where the heteroaryl and diazo groups such as defined here.

"Heteroaryl" means an aromatic monocyclic or polycyclic ring system of about 5 to about 14 carbon atoms, preferably about 5 to about 10 carbon atoms, in which at least one of the carbon atoms in the ring system is replaced by a heteroatom, i.e. the other, che is carbon, for example nitrogen, oxygen or sulfur. Preferred sizes (types) of rings included in the ring system include about 5 to about 6 ring atoms. Heteroaryl ring optionally substituted by one or more "ring system substituents"which may be the same or different and are as defined here. The designation of Aza, oxa or thia as a prefix before heteroaryl means that the atom is nitrogen, oxygen or sulfur is present respectively as a ring atom. The nitrogen atom of heteroaryl can be an atom of basic nitrogen and, in addition, may be optionally oxidized to the corresponding N-oxide. Illustrative heteroaryl and substituted heteroaryl groups include pyrazinyl, thienyl, isothiazolin, oxazolyl, pyrazolyl, cinnoline, pteridine, benzofuran, furutani, pyrrolyl, 1,2,4-oxadiazolyl, benzoxazole, 1,2,4-thiadiazolyl, pyridazinyl, indazoles, honokalani, phthalazine, imidazo[1,2-a]pyridine, imidazo[2,1-b]thiazolyl, benzofurazanyl, isoindolyl, benzimidazolyl, Bastiani, cyanopyridyl, thienopyrimidine, pyrrolopyridine, imidazopyridine, naphthyridine, benzoxazines, 1,2,4-triazinyl, benzothiazolyl, furyl, imidazolyl, indolyl, isoindolyl, indolizinyl, isoxazolyl, ethenolysis, isothiazolin, oxadiazolyl, pyrazinyl, pyridazinyl, pyrazolyl, pyrid is l, pyrimidinyl, pyrrolyl, hintline, chinoline, 1,3,4-thiadiazolyl, thiazolyl, thienyl and triazolyl. Preferred heteroaryl and substituted heteroaryl groups include chinoline, indazoles, indolyl, hintline, pyridyl, pyrimidinyl, furyl, benzothiazolyl, benzoxazol, benzofuran, honokalani, benzimidazolyl, 1,2,4-oxadiazolyl, Bastiani and ethenolysis.

"Condensed heteroarylboronic" means a condensed heteroaryl and cycloalkenyl, where heteroaryl and cycloalkenyl group such as defined here. The preferred condensed heteroarylboronic are those in which heteroaryl them represents phenyl and cycloalkenyl consists of about 5 to about 6 ring atoms. Condensed heteroarylboronic can be associated with the remainder of the compound via any atom in the condensed system, capable of forming such an Association. The designation of Aza, oxa or thia as a prefix before the heteroaryl part of the condensed heteroarylboronic means that the atom is nitrogen, oxygen or sulfur is present respectively as a ring atom. Condensed heteroarylboronic may be optionally substituted by one or more substituents of the ring system, where the Deputy ring systems such as C is defined, return. The nitrogen atom condensed heteroarylboronic can be an atom of basic nitrogen. In addition, the nitrogen atom of the heteroaryl part of the condensed heteroarylboronic may be optionally oxidized to the corresponding N-oxide. Illustrative condensed heteroarylboronic groups include 5,6-dihydro-chinolin; 5,6-dihydroisoquinolyl; 5,6-dihydroquinoxaline; 5,6-dihydroquinazolin; 4, 5-dihydro-1H-benzimidazolyl; 4,5-dihydroisoxazole; 1,4-naphthenyl etc.

"Condensed heteroalicyclic" means a condensed heteroaryl and cycloalkyl, where heteroaryl and cycloalkyl groups are as defined here. The preferred condensed heteroarylboronic are those in which heteroaryl them consists of about 5 to about 6 ring atoms, and cycloalkyl consists of about 5 to about 6 ring atoms. Condensed heteroalicyclic can be associated with the remainder of the compound via any atom in the condensed system, capable of forming such an Association. The designation of Aza, oxa or thia as a prefix before the heteroaryl part of the condensed heteroalicyclic means that the atom is nitrogen, oxygen or sulfur is present respectively as a ring atom. Condensers the config heteroalicyclic may be optionally substituted by one or more substituents of the ring system, where "Deputy ring system" as defined here. The nitrogen atom condensed heteroalicyclic can be an atom of basic nitrogen. In addition, the nitrogen atom of the heteroaryl part of the condensed heteroalicyclic may be optionally oxidized to the corresponding N-oxide. Illustrative condensed heteroalicyclic include 5,6,7,8-tetrahydroquinoline; 5,6,7,8-tetrahydroisoquinoline; 5,6,7,8-tetrahydroquinoxaline; 5,6,7,8-tetrahydroquinazolin; 4,5,6,7-tetrahydro-1H-benzimidazolyl; 4,5,6,7-tetrahydrooxazolo; 1H-4-oxa-1,5-diazonaphthalene-2-IMT; 1,3-dihydroimidazo-[4,5]-pyridin-2-IMT; 2,3-dihydro-1,4-dinaphthyl and the like, preferably, 5,6,7,8-tetrahydroquinoline or 5,6,7,8-tetrahydroisoquinoline.

"Condensed heterooligomerization" means a condensed heteroaryl and heterocyclyl, where heteroaryl and heterocyclyl group such as defined here. The preferred condensed heterooligomerization are those in which heteroaryl them consists of about 5 to about 6 ring atoms and heterocyclyl consists of about 5 to about 6 ring atoms. Condensed heterooligomerization can be associated with the remainder of the compound via any atom in the condensed system, capable of forming t is some connection. The designation of Aza, oxa or thia as a prefix before the heteroaryl or heterocyclyl part of the condensed heterooligomerization means that the atom is nitrogen, oxygen or sulfur is present respectively as a ring atom. Condensed heterooligomerization may be optionally substituted by one or more substituents of the ring system, where the Deputy ring system" as defined here. The nitrogen atom condensed heterokedasticity can be an atom of basic nitrogen. In addition, nitrogen atom or sulfur or heteroaryl heterocyclyl part of the condensed heterooligomerization may be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Illustrative condensed heterooligomerization groups include 7,8-dihydro[1,7]naphthyridine; 1,2-dihydro[2,7]naphthyridine; 6,7-dihydro-3H-imidazo[4,5-C]pyridyl; 1,2-dihydro-1,5-naphthyridine; 1,2-dihydro-1,6-naphthyridine; 1,2-dihydro-1,7-naphthyridine; 1,2-dihydro-1, 8-naphthyridine; 1,2-dihydro-2,6-naphthyridine etc.

"Condensed heteroalicyclic" means a condensed heteroaryl and heterocyclyl, where heteroaryl and heterocyclyl groups are as defined here. The preferred condensed heteroalicyclic and are such where heteroaryl them consists of about 5 to about 6 ring atoms and heterocyclyl them consists of about 5 to about 6 ring atoms. Condensed heteroalicyclic can be associated with the remainder of the compound via any atom in the condensed system, capable of forming such an Association. The designation of Aza, oxa or thia as a prefix before the heteroaryl or heterocyclyl part of the condensed heteroalicyclic means that the atom is nitrogen, oxygen or sulfur is present respectively as a ring atom. Condensed heteroalicyclic may be optionally substituted by one or more substituents of the ring system, where the Deputy ring system" as defined here. The nitrogen atom condensed heteroalicyclic can be an atom of basic nitrogen.

In addition, nitrogen atom or sulfur or heteroaryl heterocyclyl part of the condensed heteroalicyclic may be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-oxide. Illustrative condensed heterooligomerization groups include 2,3-dihydro-1H-pyrrole[3,4-b]quinoline-2-yl; 1,2,3,4-Tetra-hydrobenzo[b][1,7]naphthiridine-2-yl; 1,2,3,4-tetrahydrobenzo-[b][1,6]naphthiridine-2-yl; 1,2,3,4-tetrahydro-N-pyrido[3,4-b]indole-2-is l; 1,2,3,4-tetrahydro-N-pyrido[4,3-b]indol-2-yl, 2,3-dihydro-1H-pyrrolo[3,4-b]indol-2-yl; 1H-2,3,4,5-Tetra-hydrazidine[3,4-b]indol-2-yl; 1H-2,3,4,5-tetrahydro-azepino[4,3-b]indol-3-yl; 1H-2,3,4,5-tetrahydroazepine[4,5-b]indol-2-yl, 5,6,7,8-tetrahydro[1,7]naphthyridine; 1,2,3,4-tetrahydro[2,7]naphthyridin; 2,3-dihydro[1,4]like[2,3-b]pyridyl; 2,3-dihydro[1,4]like[2,3-b]pyridyl; 3,4-dihydro-2H-1-oxa[4,6]diazonaphthalene; 4,5,6,7-tetrahydro-3H-imidazo[4,5-C]pyridyl; 6,7-dihydro[5,8]diazonaphthalene; 1,2,3,4-tetrahydro[1,5]naphthyridine; 1,2,3,4-tetrahydro-[1,6]naphthyridine; 1,2,3,4-tetrahydro[1,7]naphthyridine; 1,2,3,4-tetrahydro[1,8]naphthyridine; 1,2,3,4-tetrahydro-[2,6]naphthyridine etc.

"Heteroarylboronic" means heteroaryl-SO2group, heteroaryl group such as defined here. Typical heteroarylboronic group is a 3-pyridinemethanol.

"Heteroarylboronic" means heteroaryl-SO - group, a heteroaryl group such as defined here.

"Heteroaromatic" means heteroaryl-S - group, where the heteroaryl group such as defined here. Illustrative of heteroaromatic groups include pyridylthio, hyalinella.

"Heterocyclyl" means a non-aromatic monocyclic or polycyclic hydrocarbon ring system of about 3 to about 10 carbon atoms, preferably from approximately 5 to approximately the compulsory 10 carbon atoms, in which at least one or more of the carbon atoms in the ring system is replaced by a heteroatom such as nitrogen atom, oxygen or sulfur, and which contains at least one carbon-carbon double bond or carbon-nitrogen double bond. Preferred sizes (types) of rings included in the ring system include about 5 to about 6 ring atoms. The designation of Aza, oxa or thia as a prefix before heterocyclyl means that the atom is nitrogen, oxygen or sulfur is present respectively as a ring atom. Heterocyclyl may be optionally substituted by one or more substituents of the ring system, where the Deputy ring system" as defined here. The nitrogen atom heterocyclyl can be an atom of basic nitrogen. In addition, nitrogen atom or sulfur heterocyclyl may be optionally oxidized to the corresponding N-oxide, S-oxide or s-oxide. Illustrative monocyclic azaheterocycle and substituted monocyclic azaheterocycle groups include 1,2,3,4-tetrahydropyridine, 1,2-dihydropyridine, 1,4-dihydropyridin, 1,2,3,6-tetrahydropyridine, 4(3H)-pyrimidone, 1,4,5,6-tetrahydropyrimidine, 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 2-pyrazoline etc. Illustrative exegetically groups include 3,4-dihydro-2 is-Piran, dihydrofuran and ferrihydrite. Typical polycyclic exegetically group is 7-oxabicyclo-[2.2.1]heptenyl. Illustrative monocyclic togetherranitidine group include dihydrothiophene and dihydrothiophene.

"Heterocyclyl" means a non-aromatic saturated monocyclic or polycyclic ring system of about 3 to about 10 carbon atoms, preferably from about 5 to about 10 carbon atoms, in which at least one of the carbon atoms in the ring system is replaced by a heteroatom, for example nitrogen, oxygen or sulfur. Preferred sizes (types) of rings included in the ring system include about 5 to about 6 ring atoms. The designation of Aza, oxa or thia as a prefix before heterocyclyl means that the atom is nitrogen, oxygen or sulfur is present respectively as a ring atom. The heterocycle may be optionally substituted by one or more "ring system substituents"which may be the same or different and are as defined here. The nitrogen atom heterocyclyl can be an atom of basic nitrogen. In addition, nitrogen atom or sulfur heterocyclyl optionally oxidized to the corresponding N-oxide, S-oxide or S,S-oxide. Illustrative m is noticecookie geterotsiklicheskikh rings include piperidyl, pyrrolidinyl, piperazinil, morpholinyl, thiomorpholine, thiazolidine, 1,3-DIOXOLANYL, 1,4-dioxane, tetrahydrofuran, tetrahydrothiophene, tetrahydrothiopyran etc. Illustrative of polycyclic geterotsiklicheskikh rings include 1,4-diazabicyclo[2.2.2]octane and the anhydride 1,2-cyclohexanedicarboxylic acid.

"Deputy ring system" includes hydrogen, alkyl, cycloalkyl, heterocyclyl, the aryl heteroaryl, aralkyl, heteroalkyl, hydroxy, alkoxy, aryloxy, Alcoxy, acyl, aroyl, halogen, nitro, cyano, carboxy, alkoxycarbonyl, aryloxyalkyl, arelaxation, alkylsulfonyl, arylsulfonyl, heteroarylboronic, alkylsulfonyl, arylsulfonyl, heteroarylboronic, alkylthio, aaltio, heteroaromatic, Uralkali, heteroalkyl, condensed cycloalkyl, condensed cycloalkenyl, condensed heterocyclyl, condensed heterocyclyl, arylazo, heteroaryl, RaRbN-, RcRdNCO-, RcO2CN and RcRdNSO2-where Raand Rbare independently hydrogen, alkyl, aryl, aralkyl or heteroalkyl or one of Raand Rbrepresents hydrogen or alkyl and the other of Raand Rbis aroyl or heteroaryl. Rcand Rdare independently hydrogen, alkyl, aryl, heteroaryl, C is cloaker, cycloalkenyl, heterocyclyl, heterocyclyl, aralkyl or heteroalkyl. In the case where the ring is cycloalkyl, cycloalkenyl, heterocyclyl or heterocyclyl, Deputy ring system may also include a methylene (H2C=), oxo (O=), thioxo (S=) at its carbon atom(s). Preferably, the ring substituents selected from oxo (O=) (lower)alkyl, aryl, alkoxy, Alcoxy, halogen, trifloromethyl, carboxy, alkoxycarbonyl, optionally substituted phenyl, optionally substituted benzyloxy, optionally substituted cyclohexyl, optionally substituted cyclobutyl, optionally substituted heteroaryl and ReO2CN-, where Reis cycloalkyl.

"Tetrazolyl" means a group of the formula

where the hydrogen atom it is not necessarily replaced by alkyl, carboxylation or alkoxycarbonylmethyl.

The ligand of the receptor PPAR" means a ligand that binds with the receptor PPAR. The ligands of the receptor PPAR of the present invention is used as agonists or antagonists of the receptor PPAR-α, PPAR-β or PPAR-y.

The term "pharmaceutically acceptable salt" refers to a relatively non-toxic, additive salts of inorganic or organic acid compounds of the present invention. Salt can be obtained in siu during the final isolation and purification of the compounds, or by reacting the purified compound in the form of its free base with a suitable organic or inorganic acid and the allocation thus obtained the salt. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naftilan, mesilate, glucoheptonate, lactobionate, laurylsulfate and the like (See, for example, S.M.Berge, et al., "Pharmaceutical Salts." J. Pharm. Sci., 66: 1-19, 1977, the contents of which are here referred to).

"Treatment" means a partial or complete exemption from, or preventing one or more physiological or biochemical parameters associated with PPAR activity.

The term "modulate" refers to the ability of the compound either directly (by binding to the receptor as a ligand)or indirectly (as a precursor of the ligand or the inductor, which promotiom producing the ligand of the precursor) to induce the expression of gene(s)supported hormonal control, or suppress the expression of gene(s)supported by this control.

The term "obesity" refers, generally, to the individuals, the bulk of which at least 20-30% higher than the average weight for a person of a given age, gender and height. Technically, "fat" is defined for men as individuals whose body mass index is greater than 27,3 kg/m2. For specialists in this on the region of the obvious, that the inventive method is not limited to those that are within the above-mentioned criteria. Indeed, the inventive method can also be extended to individuals who are outside of these traditional criteria, such as those who have a propensity to obesity.

The expression "amount effective to reduce the levels of glucose in the blood" refers to levels of compound sufficient to provide circulating concentrations high enough to achieve the desired action. This concentration is typically in the range from about 10 nm up to 2 μm, and the concentration in the range from about 100 nm up to 500 nm is preferable.

The expression "amount effective to reduce the levels of triglycerides" refers to levels of compound sufficient to provide circulating concentrations high enough to achieve the desired action. This concentration is typically in the range from about 10 nm up to 2 μm, and the concentration in the range from about 100 nm up to 500 nm is preferable.

Preferred embodiments of the

Preferred embodiments of in accordance with the invention include the use of compounds of the formula I and their pharmaceutical compositions as binders for the of eception PAR.

In particular, the use of compounds of formula I that bind to the receptor PPAR-α,

compounds of formula I that bind to the receptor PPAR-δ,

compounds of formula I that bind to the receptor PPAR-γ,

compounds of formula I that bind to the receptor PPAR-α and PPAR-γ,

compounds of formula I that bind to the receptor PPAR-α and PPAR-δ,

compounds of formula I that bind to the receptor PPAR-γ and PPAR-δ,

compounds of formula I that act as agonists of the receptors PPAR,

compounds of formula I that act as agonists of the receptors PPAR-α,

compounds of formula I that act as agonists of the receptors PPAR-δ,

compounds of formula I that act as agonists of the receptors PPAR-γ,

compounds of formula I that act as agonists of the receptors as PPAR-αand PPAR-γ,

compounds of formula I that act as agonists of the receptors as PPAR-αand PPAR-δ,

compounds of formula I that act as agonists of the receptors as PPAR-γand PPAR-δ,

compounds of formula I that act as receptor antagonists PPAR-αand agonists of the receptors PPAR-γ,

compounds of formula I that act as the AK receptor antagonists PPAR-α and agonists of the receptors PPAR-δ,

compounds of formula I that act as receptor antagonists PPAR-γand agonists of the receptors PPAR-δ,

compounds of formula I that act as agonists of the receptors PPAR-αand antagonists of the receptors PPAR-γ,

compounds of formula I that act as agonists of the receptors PPAR-αand antagonists of the receptors PPAR-δ,

compounds of formula I that act as agonists of the receptors PPAR-γand antagonists of the receptors PPAR-δ,

compounds of formula I that act as receptor antagonists PAR,

compounds of formula I that act as receptor antagonists PPAR-α,

compounds of formula I that act as receptor antagonists PPAR-δ,

compounds of formula I that act as receptor antagonists PPAR-γ,

compounds of formula I that act as receptor antagonists as PPAR-αand PPAR-γ,

compounds of formula I that act as receptor antagonists as PPAR-αand PPAR-δ and

compounds of formula I that act as receptor antagonists as PPAR-γand PPAR-δ.

We offer you the option of carrying out the invention relates to the treatment of PA is rate, suffering from a physiological disorder capable of being subjected to modulation by the compound of formula I, having PPAR-ligand binding activity, comprising the administration to a patient pharmaceutically effective amount of a compound, or pharmaceutically acceptable salt it. Physiological disorders that can undergo such modulation include, for example, cell differentiation to obtain lipid-accumulating cells, regulation of insulin sensitivity and glucose levels in the blood, which include hypoglycemia/hyperinsulinism (resulting, for example, abnormal functioning pancreatic beta cells, tumors secreting insulin, and/or autoimmune hypoglycemia due to autoantibodies to insulin, autoantibodies to the insulin receptor, or autoantibodies that are stimulatory to pancreatic beta cells), differentiation of macrophages, which leads to the formation of atherosclerotic plaques, inflammatory response, carcinogenesis, hyperplasia, adipocyte gene expression, differentiation of adipocytes, decreased pancreatic masses β-cells, insulin secretion, tissue sensitivity to insulin, growth cell liposarcomas, chronic anovulation, giperandrogenii, the production of progesterone, steroidogeneza, an oxide is sustained fashion-reduction potential and oxidative stress (tension) in the cells, production synthase nitric oxide (NOS), increased levels of gamma glutamyltranspeptidase, catalase, triglycerides in plasma cholesterol IDPs and NPL etc.

Another proposed option implementation relates to a method of treatment of a disease state in a patient pharmaceutically effective amount of the compounds of formula I, or its pharmaceutically acceptable salt, where the disease is associated with a physiologically detrimental blood levels of insulin, glucose, free fatty acids (FFA, FFA) or triglycerides.

An implementation option according to the invention relates to the treatment of a patient suffering from a physiological disorder associated with physiologically harmful levels of triglycerides in the blood, by introducing the patient pharmaceutically effective amount of a compound, or its pharmaceutically acceptable salt.

An implementation option according to the invention is the use of compounds of formula I and pharmaceutical compositions based on them as antidiabetic, protivoepidemicheskih, anti-hypertensive or anti-arteriosclerotic funds, or for the treatment of obesity.

Another variant of implementation according to the invention relates to a method of treating hyperglycemia in a patient by entering the patient a pharmaceutically effective amount for lowering the level of the glucose in the blood) of compound I or its pharmaceutically acceptable salt. Preferably, the shape of hyperglycemia, subject to treatment in accordance with the invention, is Type II diabetes.

Another variant embodiment of the invention relates to a method of reducing triglyceride levels in a patient, comprising the administration to a patient a therapeutically effective amount (for lowering levels of triglycerides) the compounds of formula I or its pharmaceutically acceptable salt.

Another variant embodiment of the invention relates to a method of treatment of hyperinsulinism in a patient, comprising the administration to a patient a therapeutically effective amount of the compounds of formula I or its pharmaceutically acceptable salt.

Another variant embodiment of the invention relates to a method of treating insulin resistance in a patient comprising the administration to a patient a therapeutically effective amount of the compounds of formula I or its pharmaceutically acceptable salt.

Another variant embodiment of the invention relates to a method for treatment of cardiovascular diseases such as atherosclerosis, in a patient, comprising the administration to a patient a therapeutically effective amount of the compounds of formula I or its pharmaceutically acceptable salt.

Another variant embodiment of the invention relates to the treatment of hyperlipidemia in a patient, comprising the administration to a patient a therapeutically effective the sector number of the compounds of formula I or its pharmaceutically acceptable salt.

Another variant of the invention consists in treating hypertension in a patient, comprising the administration to a patient a therapeutically effective amount of the compounds of formula I or its pharmaceutically acceptable salt.

Another variant embodiment of the invention relates to the treatment of disorders associated with eating in a patient, comprising the administration to a patient a therapeutically effective amount of the compounds of formula I or its pharmaceutically acceptable salt. Treatment of disorders associated with eating, includes the regulation of appetite during food uptake in patients suffering from disorders associated with excessive aversion to food, such as anorexia nervosa, as well as suffering from disorders associated with eating, such as obesity and bulimia (sharply increased hunger).

Another variant embodiment of the invention relates to the treatment of painful conditions associated with low levels (IDPs HDL), including introduction to the patient a therapeutically effective amount of the compounds of formula I or its pharmaceutically acceptable salt. Diseases associated with low levels of IDPs include atherosclerotic disease.

Another variant of the invention consists in the treatment of polycystic ovary syndrome, comprising the administration to the patient therapeutic the ski effective amount of the compounds of formula I or its pharmaceutically acceptable salt.

Another variant implementation is in the treatment of menopause, including introduction to the patient a therapeutically effective amount of the compounds of formula I or its pharmaceutically acceptable salt.

Another variant implementation of the invention consists in the treatment of inflammatory diseases such as rheumatoid arthritis, chronic obstructive pulmonary disease (emphysema or chronic bronchitis or asthma, comprising the administration to a patient a therapeutically effective amount of the compounds of formula I or its pharmaceutically acceptable salt.

Another aspect of the present invention is to develop a new pharmaceutical composition, which is effective, in part or in itself, for use in a beneficial combination therapy, as it contains many active ingredients that can be used in accordance with the invention.

In another aspect, the present invention relates to a method for the treatment of painful conditions in patients where the disease is associated with a physiologically detrimental level of insulin, glucose, free fatty acids (FFA) or triglycerides in the blood, including the introduction to the patient a therapeutically effective amount of the compounds of formula I and, in addition, the introduction of a therapeutically effective amount of extra hypoglycemic what someone means.

In another aspect, the present invention relates to a method for the treatment of painful conditions in patients where the disease is associated with a physiologically detrimental level of insulin, glucose, free fatty acids (FFA) or triglycerides in the blood, including the introduction to the patient a therapeutically effective amount of the compounds of formula I and, in addition, the introduction of a therapeutically effective amount of a compound biguanidine.

In another aspect, the present invention relates to a method for the treatment of painful conditions in patients where the disease is associated with a physiologically detrimental level of insulin, glucose, free fatty acids (FFA) or triglycerides in the blood, including the introduction to the patient a therapeutically effective amount of the compounds of formula I and, in addition, the introduction of a therapeutically effective amount of Metformin.

In addition, the invention relates to kits or single packages, which is a combination of two or more active ingredients used to treat the disease. The set can include one or in combination with a pharmaceutically acceptable diluent or carrier), the compound of formula (I) and additional hypoglycemic agent (by itself or in combination with diluent or carrier).

In this area there are many well-known hypoglycemic agents, e.g. the measures insulin; biguanides, such as Metformin and buformin; sulfonylureas, such as

acetohexamide, hlorpropamid, tolazamide, tolbutamide, gliburid, glipizide and gliclazide; preparations of thiazolidinediones, such as troglitazone; inhibitors α-glycosidase, such as acarbose and miglitol; and agonists In3-adrenergic receptors, such as CL-316, 243.

Because, as you know, sulfonylureas are capable of stimulating the release of insulin, but is unable to have an effect on insulin resistance, and the compounds of formula I are able to influence insulin resistance, it is assumed that the combination of these drugs could be used as a therapeutic agent for conditions associated with a deficiency of insulin secretion and insulin resistance.

In this regard, this invention relates also to a method of treatment of diabetes mellitus Type II in a patient, comprising introducing the compound of the formula I and one or more additional hypoglycemic agents selected from the group consisting of sulfonylation, biguanidines, preparations of thiazolidinediones, agonists3-receptor, inhibitors α-glycosidase and insulin.

In addition, this invention relates to a method of treatment of diabetes mellitus Type II in a patient, comprising introducing the compound of the formula I and sulfonylurea selected from the group consisting of acetohexamide, chlorpropamide, tolazamide, tolbutamide, gliburida, glipizide and gliklazida.

In addition, this invention relates to a method of treatment of diabetes mellitus Type II in a patient, comprising introducing the compound of the formula I and biguanidine selected from the group consisting of Metformin and buformin.

In addition, this invention relates to a method of treatment of diabetes mellitus Type II in a patient, comprising introducing the compound of the formula I and inhibitor α-glycosidase selected from the group consisting of acarbose and miglitol.

In addition, this invention relates to a method of treatment of diabetes mellitus Type II in a patient, comprising introducing the compound of the formula I and thiazolidinedione, for example, troglitazone.

As mentioned above, the compound of the formula I can be used in pure form or in combination with one or more additional hypoglycemic agents. Combination therapy includes the introduction of a single pharmaceutical dosage formulation (dosage form), which contains a compound of the formula I and one or more additional hypoglycemic agents, and the introduction of the compounds of formula I and each of the additional hypoglycemic agents in their own separate pharmaceutical dosage formulation (dosage form). For example, the compound of formula I and hypoglycemic means you can take the patient together, in a single oral dosage form such as tablet or capsule, or each agent can be administered in separate oral dosage formulations (dosage forms). If you use separate dosage formulations, the compound of formula I and one or more additional hypoglycemic agents can be taken essentially at the same time, i.e. simultaneously or separately in offset relation to each other times, i.e. sequentially.

For example, the compound of the formula I can be used in combination with one or more of the following additional hypoglycemic agents: insulin; biguanides, such as Metformin or buformin; sulfonylureas, such as acetohexamide, hlorpropamid, tolazamide, tolbutamide, gliburid, glipizide and gliclazide; preparations of thiazolidinediones, such as troglitazone; inhibitors α-glycosidase, such as acarbose and miglitol; and agonists In3-adrenergic receptors, such as CL-316, 243.

The compound of the formula I are preferably used with biguanidines, in particular, Metformin.

The compounds of formula I contain at least three aromatic or heteroaromatic ring, which can be labeled as shown in formula II below, and for which the picture replacing them along the chain relative to each other are also presented below.

Preferred compounds of formula II are compounds whereselected from hineline, benzothiophene, benzoimidazole, heatline, benzothiazolyl, khinoksalinona, naphthyl, pyridyl, 1H-indazole, 1,2,3,4-tetrahydroquinoline, benzofuranyl, tanila or indolyl, and one end of the linker, the linker I attached topreferably in 2-position of the ring part.

Other preferred compounds of formula II are compounds whererepresents a 6-membered aryl or heteroaryl group, and the Linker I and II Linker attached toin positions 1,2-, 1,3 - or 1,4 - to each other.

Other preferred compounds of formula II are compounds whererepresents naftalina group, the Linker I and II Linker attached toin positions 1,4 - or 2,4 - together on naftilos part.

Other preferred compounds of formula II are compounds whererepresents a 6-membered aryl or heteroaryl, and has a preferred position of attachment of the Linker II and Linker III to the ring III in positions 1,2 - each other.

Other preferred compounds of formula II are the HSIA connection, whererepresents a 6-membered aryl or heteroaryl, and has a preferred position of attachment of the Linker II and Linker III to the ring III in positions 1,2-, 1,3 - to each other.

Other preferred compounds of formula II are compounds whererepresents a 6-membered aryl or heteroaryl, and has a preferred position of attachment of the Linker II and Linker III to the ring III in positions 1,4 - to each other.

Other preferred compounds of formula II are compounds represented by formula V below:

where R1, R2, C, d, e, f, D, E and Z are such as defined above, c+d=1-3, and R' and R" are substituents of the ring system.

Another aspect of the present invention is a compound of the invention, whererepresents an optionally substituted aryl, optionally substituted azaheterocycle or optionally substituted condensed arylheteroacetic;represents an optionally substituted aryl, optionally substituted heteroaryl or optionally substituted condensed arylheteroacetic; andrepresents an optionally substituted aryl, optionally someseni heteroaryl, optionally substituted condensed arylheteroacetic or optionally substituted condensed arylheteroacetic.

Another aspect of the present invention is a compound of the invention where a=1 or 2; R1and R2represent hydrogen; a represents a chemical bond; and b=0.

Another aspect of the present invention is a compound of the invention, where a=0; a represents a

R15and R16represent hydrogen; g is 1, 2 or 3; and b=0.

Another aspect of the present invention is a compound of the invention, where a=0; a represents a-NR13-, b=1, R3and R4represent hydrogen.

Another aspect of the present invention is a compound of the invention where a=2; adjacent radicals R1together with the carbon atoms that are associated with the radicals R1, form an ethylene group; R2represents hydrogen; a represents a chemical bond; and b=0.

Another aspect of the present invention is a compound of the invention where a=1, 2, or 3; R1and R2represent hydrogen; And a represents-O-; and b=0.

Another aspect of the present invention is a compound of the invention where a=1; R1, R2, R3and R4represent hydrogen; a is the Wallpaper-O-; and b=1.

Another aspect of the present invention is a compound of the invention, where C=1 or 2; R5and R6represent hydrogen or alkyl; a represents a chemical bond, and d=0.

Another aspect of the present invention is a compound of the invention, where C=2; adjacent radicals R5taken together with the carbon atoms that are associated with the radicals R5, form an ethylene group; R6represents hydrogen; represents a chemical bond; and d=0.

Another aspect of the present invention is a compound of the invention, where C=0 or 1; R5and R6represent hydrogen; represents-O-; and d=0 or 1.

Another aspect of the present invention is a compound of the invention, where C=0; represents-C(O)- or-S(O)2-; d=1 and R7and R8are independently hydrogen or alkyl.

Another aspect of the present invention is a compound of the invention, where e=0; f=0; D and E are a chemical bond; Z is an R21O2SHNCO and R21represents phenyl.

Another aspect of the present invention is a compound of the invention, where e=0; f=0 or 1; D and E are a chemical bond; Z represents tetrazolyl, NH2CO - or-CO2R21and R21represents hydrogen or lower alkyl./p>

Another aspect of the present invention is a compound of the invention, where e=0; f=0 or 1; D represents-O - or a chemical bond; E is a chemical bond; and Z represents tetrazolyl, NH2CO - or-CO2R21; and R21represents hydrogen or lower alkyl.

Another aspect of the present invention is a compound of the invention, where e=0; f=1; D represents-O - or a chemical bond; E is a chemical bond; R11and R12represent hydrogen or alkyl; and Z represents tetrazolyl, NH2CO - or-CO2R21; and R21represents hydrogen or lower alkyl.

Another aspect of the present invention is a compound of the invention, where e=2, then adjacent radicals R9taken together with the carbon atoms that are associated with the radicals R9, form an ethylene group; f=0; D and E are a chemical bond; and Z represents-CO2R21; and R21represents hydrogen.

Another aspect of the present invention is a compound of the invention, where e=0; f=3; D represents-O-; E is a chemical bond; R11and R12represent hydrogen or alkyl, or, at least one of R11is carboxyl or alkoxycarbonyl; Z represents a Tetra is alil or-CO 2R21; and R21represents hydrogen or lower alkyl.

Another aspect of the present invention is a compound of the invention, where e=0; f=1, 2, or 3; D represents-C(O)-; E is a chemical bond; R11and R12represent hydrogen or alkyl; Z represents tetrazolyl or-CO2R21; and R21represents hydrogen or lower alkyl.

A preferred aspect of this invention is the compound according to the invention, whererepresents an optionally substituted chinoline, honokalani, enoxaparin, ethenolysis. N-ALKYLPHENOLS-4-IMT, hinzelin-4-IMT, benzoxazolyl, benzimidazolyl, benzothiazolyl, benzofuranyl, benzothiophene, indolyl, oxazolyl, thiazolyl, oxadiazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiadiazolyl, triazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, phenyl or naphthalenyl group where the Deputy is the Deputy ring system, defined herein, more preferably Deputy selected from the group consisting of phenyl, substituted phenyl, teinila, substituted tanila, cycloalkyl, lower alkyl, branched alkyl, fluorine, chlorine, alkoxy, aralkylated, trifloromethyl, cryptometrics.

More preferred aspect of this image is etenia is the connection according to the invention, whererepresents an unsubstituted quinoline-2-yl, 3-substituted quinoline-2-yl, 4-substituted quinoline-2-yl, 6-substituted quinoline-2-yl or 7-substituted quinoline-2-yl; unsubstituted of kynoselen-2-yl, 3-substituted of kynoselen-2-yl, 6-substituted of kynoselen-2-yl or 3,6-disubstituted of kynoselen-2-yl; unsubstituted hinzelin-2-yl, 4-substituted hinzelin-2-yl or 6-substituted hinzelin-2-yl; unsubstituted isoquinoline-3-yl, 6-substituted isoquinoline-3-yl or 7-substituted isoquinoline-3-yl; 3-substituted hinzelin-4-one-2-yl; N-substituted quinoline-4-one-2-yl; 2-substituted oxazol-4-yl or 2,5-disubstituted oxazole-4-yl; 4-substituted oxazol-2-yl or 4,5-disubstituted oxazol-2-yl; 2-substituted thiazol-4-yl or 2,5-disubstituted thiazol-4-yl; 4-substituted thiazol-2-yl or 4,5-disubstituted thiazol-2-yl; 5-substituted[1,2,4]oxadiazol-3-yl; 3-substituted[1,2,4]oxadiazol-5-yl; 5-substituted imidazol-2-yl or 3,5-disubstituted imidazol-2-yl; 2-substituted imidazol-5-yl or 2,3-disubstituted imidazol-5-yl; 3-substituted isoxazol-5-yl; 5-substituted isoxazol-3-yl; 5-substituted[1,2,4]thiadiazole-3-yl; 3-substituted[1,2,4]thiadiazole-5-yl; 2-substituted[1,3,4]thiadiazole-5-yl; 2-substituted[1,3,4]oxadiazol-5-yl; 1-substituted pyrazole-3-yl; 3-substituted pyrazole-5-yl; 3-substituted[1,2,4]triazole-5-yl; 1-substituted[1,2,4]-triazole-3-yl; 3-substituted pyridine-2-yl, 5-substituted pyridine-2-yl, 6-substituted pyridine-2-yl or 3,5-diz is displaced pyridine-2-yl; 3-substituted pyrazin-2-yl, 5-substituted pyrazin-2-yl, 6-substituted pyrazin-2-yl or 3,5-disubstituted pyrazin-2-yl; 5-substituted pyrimidine-2-yl or 6-substituted pyrimidine-2-yl; 6-substituted pyridazin-3-yl or 4,6-disubstituted pyridin-3-yl; unsubstituted naphthalene-2-yl,3-substituted naphthalene-2-yl, 4-substituted naphthalene-2-yl, 6-substituted naphthalene-2-yl or 7-substituted naphthalene-2-yl; 2-substituted phenyl, 4-substituted phenyl or 2,4-disubstituted phenyl; unsubstituted benzothiazol-2-yl or 5-substituted benzothiazole-2-yl; unsubstituted benzoxazol-2-yl or 5-substituted benzoxazol-2-yl; an unsubstituted benzimidazole-2-yl or 5-substituted benzimidazole-2-yl; unsubstituted thiophene-2-yl, 3-substituted thiophene-2-yl, 6-substituted thiophene-2-yl or 3,6-disubstituted thiophene-2-yl; unsubstituted benzofuran-2-yl, 3-substituted benzofuran-2-yl, 6-substituted benzofuran-2-yl or 3,6-disubstituted benzofuran-2-yl; 3-substituted benzofuran-6-yl or 3,7-disubstituted benzofuran-6-yl, where the Deputy is the Deputy ring system, defined herein, more preferably Deputy selected from the group consisting of phenyl, substituted phenyl, teinila, substituted tanila, cycloalkyl, lower alkyl, branched alkyl, fluorine, chlorine, alkoxy, aralkylated, trifloromethyl, cryptometrics.

Another preferred aspect of the present invention I have is the connection according to the invention, where R1and R2are both N, a=1 And a represents-O - and b=0.

Another preferred aspect of this invention is the compound according to the invention, where R1and R2are both H, a=2, a represents-O - and b=0.

Another preferred aspect of this invention is the compound according to the invention, where a=0 And represents-O - or-NR13-; R13represents hydrogen or alkyl; R3and R4are both independently hydrogen; and b=1.

Another preferred aspect of this invention is the compound according to the invention, where a=0 And represents-O - or-NR13-; R13represents hydrogen or alkyl; R3and R4are both independently hydrogen; b=1; and ArI is a 3-substituted quinoline-2-yl, 4-substituted quinoline-2-yl, 6-substituted quinoline-2-yl, 7-substituted quinoline-2-yl, unsubstituted cinoxacin-2-yl, 3-substituted cinoxacin-2-yl, 6-substituted cinoxacin-2-yl, 3,6-disubstituted cinoxacin-2-yl, unsubstituted hinzelin-2-yl, 4-substituted hinzelin-2-yl, 6-substituted hinzelin-2-yl, unsubstituted isoquinoline-3-yl, 6-substituted isoquinoline-3-yl, 7-substituted isoquinoline-3-yl, 4-substituted oxazol-2-yl, 4,5-disubstituted oxazol-2-yl, 4-substituted thiazol-2-yl, 4,5-disubstituted thiazol-2-yl, 5-replace the military imidazol-2-yl, 3,5-disubstituted imidazol-2-yl, 1-substituted pyrazole-3-yl, 3-substituted pyrazole-5-yl, 3-substituted pyridine-2-yl, 5-substituted pyridine-2-yl, 6-substituted pyridine-2-yl or 3,5-disubstituted pyridine-2-yl, 3-substituted pyrazin-2-yl, 5-substituted pyrazin-2-yl, 6-substituted pyrazin-2-yl, 3,5-disubstituted pyrazin-2-yl, 5-substituted pyrimidine-2-yl, 6-substituted pyrimidine-2-yl, 6-substituted pyridazin-3-yl, 4,6-disubstituted pyridin-3-yl, unsubstituted benzothiazol-2-yl, 5-substituted benzothiazole-2-yl, unsubstituted benzoxazol-2-yl, 5-substituted benzoxazol-2-yl, an unsubstituted benzimidazole-2-yl, 5-substituted benzimidazole-2-yl, 3-substituted benzofuran-6-yl or 3,7-disubstituted benzofuran-6-yl.

Another aspect of the present invention is a compound of formula I, represented by formula (Ia) below:

where

andrepresent independently aryl, condensed arylchloroalkanes, condensed aristically, condensed arylheteroacetic, condensed arylheteroacetic, heteroaryl, condensed heteroarylboronic, condensed heteroalicyclic, condensed heterooligomerization or condensed heteroalicyclic;

c+d=1 or 2;

In represents-O-;

R5, R6, R7, R 8are independently hydrogen;

e=0;

f=0;

D and E are a chemical bond;

Z is an R21O2C-, R21OC-, cycloid, -CN, R21O2SHNCO-, R21O2SHN-, (R21)2NCO-, R21O-2,4-thiazolidinedione or tetrazolyl;

R' and R" are substituents of the ring system, as defined here, more preferably, R' represents lower alkyl, halogen, alkoxy, aryloxy or aralkyl; and R" represents lower alkyl or halogen.

Another aspect of the present invention is a compound of formula I, represented by formula (Ia) below:

where:

a=0-2;

b=0-1;

And represents-O - or-NR13-;

c+d=1 or 2;

In represents-O-;

R1, R2, R3, R4, R5, R6, R7and R8are independently hydrogen;

R13represents hydrogen, R22OC - or alkyl;

e=0;

f=0;

D and E are a chemical bond;

Z represents-CO2H;

R' and R" are substituents of the ring system, as defined here, more preferably, R' represents lower alkyl, halogen, alkoxy, aryloxy or aralkyl; and R" represents lower alkyl or halogen.

More preferred aspect given to the CSOs of the invention is a compound of formula I, represented by formula (Ia)where:

a=1 or 2;

And represents-O-;

b=0;

R1, R2, R7and R8are independently hydrogen;

represents optionally substituted phenyl;

C=0;

In represents-O-;

d=1;

e=0;

f=0;

D and E are a chemical bond;

R' represents hydrogen, halogen or benzyloxy;

R" represents lower alkyl, preferably methyl;

Z represents-CO2N.

More preferred aspect of the present invention is a compound of formula I, represented by formula (Ia)where:

a=1 or 2;

And represents-O-;

b=0;

R1, R2, R5and R6are independently hydrogen;

represents optionally substituted phenyl;

C=1;

In represents-O-;

d=0;

e=0;

f=0;

D and E are a chemical bond;

R' represents hydrogen, halogen or benzyloxy;

R" represents lower alkyl, preferably methyl;

Z represents-CO2N.

More preferred aspect of the present invention is a compound of formula I, represented by formula (Ia)where:

a=1 or 2;

And represents-O-;

b=0;

R1, R2, R7, R8, R11and R12are independently hydrogen;

represents optionally substituted phenyl;

C=0;

In represents-O-;

d=1;

e=0;

f=1;

D and E are a chemical bond;

R' represents a halogen;

R" represents lower alkyl, preferably methyl;

Z represents-CO2N.

More preferred aspect of the present invention is a compound of formula I, represented by formula (Ia)where:

a=1;

And represents-O-;

b=0;

C=0-1;

In represents-O-;

d=0 or 1, where c+d=1 or 2;

e=0;

f=0;

D and E are a chemical bond;

R' represents hydrogen, Alcoxy or halogen;

R" represents lower alkyl, preferably methyl;

Z represents-CO2N.

More preferred aspect of the present invention is a compound of formula I, represented by formula (Ia)where:

a=1;

And represents-O-;

b=0;

C=0;

In represents-O-;

d=1;

e=0;

f=0;

D and E are a chemical bond;

R' represents hydrogen;

R" represents lower alkyl;

Z represents-CO2H.

More preferred aspect of this invention is the compound of formula 1, the image is Agen formula (Ia), where:

andrepresent aryl or heteroaryl;

a=1;

And represents-O-;

b=0;

C=0;

In represents-O-;

d=1;

e=0;

f=0;

D and E are a chemical bond;

R' represents hydrogen;

R" represents lower alkyl;

Z represents-CO2N.

More preferred aspect of the present invention is a compound of formula I, represented by formula (Ia)where:

represents an optionally substituted azaheterocycle;

represents optionally substituted phenyl;

a=1;

And represents-O-;

b=0;

C=0;

In represents-O-;

d=1;

e=0;

f=0;

D and E are a chemical bond;

R' represents hydrogen;

R" represents lower alkyl;

Z represents CO2H.

More preferred aspect of the present invention is a compound of formula I, represented by formula (Ia)where:

represents an optionally substituted hyalinella or 5-membered heteroaryl group, where the heteroaryl group is substituted by an optionally substituted phenyl or optionally substituted cyclohexyl;

represents optionally substituted phenyl;

a=1;

And represents-O-;

b=0;

C=0;

In represents-O-;

d=1;

e=0;

f=0;

D and E are a chemical bond;

R' represents hydrogen;

R" represents lower alkyl;

Z represents CO2N.

The proposed compounds selected from the group consisting of

Preferably compounds selected from the group consisting of

The most preferred compounds selected from the group consisting of

A preferred compound according to the invention that is selective for PPARα, is a

The preferred compounds are

This invention covers all combinations of the mentioned preferred aspects of the invention.

The compounds used according to the invention, can be obtained by segments, as is common for long-chain molecules. In line with this, it is convenient to synthesize these molecules, using the condensation reaction at a, b and D positions (sites) of the molecule. The compounds of formula I can be obtained by using known methods or adapting known methods that were used before or described in the literature. The compounds of formula I can be obtained generally accepted methods from known compounds or readily derived intermediates. Thus, to obtain a connection below formula, where Z is a normally CN or CO2R,

you can use the following reaction, or a combination of these reactions:

In the above schemes (1-3), you can use the substitution reaction, when a, b and D represent O, S or NR, and L represents a removable group, such as halogen, tosylate or mesilate. When a, b or D represents O or S, can be used a base such as sodium hydride, sodium hydroxide, potassium carbonate or triethylamine.

Alternative binding reaction is the Mitsunobu reaction (diethylazodicarboxylate/triphenylphosphine, see Synthesis, 1981, 1). This chemistry can be used for condensation of fragments when the functionality prone to this reaction. An example of this may be linking compounds of scheme I, where the formula VI (L=OH, a>0) and formula VII (A=Oh, b=0).

The temperature of reaction can range from about -78°C to 80°and reaction times range from about 1 to 48 hours. The reaction is usually carried out in an inert solvent, which usually dissolves the reagents. Solvents include, but are not limited to, N,N-dimethylformamide, acetone, acetonitrile, tetrahydrofuran.

Alternatively, the reaction indicated in schemes 1-3, can be performed using the fragment depicted in the formula. For example, as shown in scheme 4, the compound of formula (VI) (Scheme I) may be combined with the compound of the formula (VII), where the formula VII contains optional ArIII and Z. the notation used on the I formula VII in scheme 4, used throughout this document and are used to represent generalized described reaction. Therefore, all of the reaction schemes 1-3 can be carried out, as shown, or by using the fragment depicted in the formula. In some cases, when using a fragment of the formula may require the use of protective groups.

One way of preparing compounds where Z=tetrazol, lies in the interaction of intermediate compounds where Z=CN, with sodium azide and ammonium chloride at elevated temperature.

One way of preparing compounds where Z=CO2H is the hydrolysis of intermediate compounds where Z represents CN or CO2H. the Hydrolysis can be conducted under acidic or basic conditions, and the preferred method of carrying out in the presence of sodium hydroxide or potassium proton solvent such as aqueous ethanol, at a temperature of about 20°to 100°C.

An alternative method of conversion of nitrile to carboxylic acid is in the restoration of the nitrile to the corresponding aldehyde using a reducing agent such as diisobutylaluminium, with subsequent oxidation of aldehyde to carboxylic acid using a reagent, such as sodium chlorite, sodium dihydrophosphate, isobutene (see JACS 1980, 4, 1176) or other standard conditions.

Another alternative method of preparing compounds where Z=CO2H is the oxidation of the primary alcohol using a suitable oxidant, such as PDC in DMF (DMF), RuCl3/NaIO4in a mixture of water/acetonitrile/CCl4(3:2:2), or Swern system (for intermediate aldehyde, then the oxidation of this functionality to carboxylic acid as described above).

Some other ways to produce compounds where Z=CO2H, is shown in scheme 5. Carboxylic acid (2) can be generated directly halogen-metal exchange of the corresponding aromatic halide (1) with alkyllithium reagent, such as n-utility, followed by quenching of the resulting anion with carbon dioxide. Alternatively, you can implement alkoxy-carbonylation of aromatic bromide, iodide or triflate in an atmosphere of carbon monoxide in the presence of a suitable alcohol (usually methanol)using a catalyst such as Pd(PPh3)2Cl2/Et2NH, Pd(Ph2P(CH2)3PPh2/Et3N or alternatively, the catalyst of cobalt, i.e. With(SLA)2plus the base (NaH or2CO3). Received benzoate (3) is then converted into benzoic acid by hydrolysis, as described above.

Deriving fanily what usnei acid can be made from the corresponding helgaleena or triflate, as illustrated in scheme 6. Such linking of this type of connection vinylstyrene using a palladium catalyst such as Pd(OAc)2, P(o-tolyl)3gives the olefin, (5). Hydroporinae this derived vinylbenzene with subsequent oxidation of the resulting primary alcohol oxidizing agent such as Jones reagent (Jones'), provides phenylacetic acid (6).

In one embodiment of the present invention, ArI can represent a five-membered ring heterocycle, thereby giving rise to a structure of the General formula shown in figure 1.

In particular, the heterocycle may represent substituted thiazole, oxazole, oxadiazole, imidazole, isoxazol, pyrazole, thiadiazole, or triazole. These systems can be obtained using methods known in the chemical literature (see reviews Katritzky, A.R.; Rees, C.W., Eds. Comprehensive Heterocyclic Chemistry, Vol. 5; Pergamon Press (1984); Katritzky, A.R.; Rees, C.W.; Scriven, E.F.V. Eds. Comprehensive Heterocyclic Chemistry II; Vols 3&4, Pergamon Press (1996) ). More specifically, the oksazolov, imidazoles and thiazole can be obtained by merging amide, amidine or thioamide, respectively, with α-halogenatom at temperatures in the range from about 40°to 150°With (Scheme 7).

These reactions can be performed in the undiluted state,or in a solvent, such as toluene, dichlorobenzene or ethanol. Substituted oksazolov can also be obtained from diazoketone and nitrile using BF3-Ateret (Scheme 8), Ibata, T.; Isogami, Y. Bull. Chem. Soc. Jpn. 1989, 62, 618).

1,2,4-Oxadiazole can be obtained by the interaction of nitrile with hydroxylamine and subsequent condensation of the resulting hydroxyamide with acid chloride in the presence of a base and heating the adduct in a solvent such as toluene or dichlorobenzene, to carry out the ring closure. (Scheme 9, Banavara, L.M.; Beyer, T.A.; Scott, P.J.; Aldinger, C.E.; Dee, M.F.; Siegel, T.W.; Zembrowsky, W.J. J. Med. Chem., 1992, 35, 457).

1,3,4-oxadiazole get (Scheme 10) condensation acylhydrazides with syntheway acid (such as an ester, acid chloride of carboxylic acid, acylated), followed by cyclization of the obtained diacyl-hydrazide are heated in a solvent such as benzene or ethanol, with or without an acid catalyst such as sulfuric acid (examples see Weidinger, H.; Kranz, J. Cheia. Ber., 1963, 96, 1049 and Vakula, T.R.; Srinivarsan, V.R. Indian J. Chem., 1973, 11, 732).

Substituted 1,2,4-thiadiazole can be obtained by condensation thioamide derived from N,N-dimethylamide of dimethylacetal in a solvent such as benzene (Scheme 11, MacLeod, A.; Baker, R.; Freedman, S.F.; Patel, S.; Merchant, K.J.; Roe, M. Saunders, J. Med. Chem., 1990, 33, 2052, and Patzel, M. Liebscher, J.; Siegfried, A. Schitz, E. Synthesis, 1990, 1071), followed by reaction with electrophilic aminimum agent such as mesitylsulfonylhydroxylamine, in methanol, or dialkylanilines in a solvent such as toluene.

In another embodiment of the present invention, the ArI can be 1,3,4-thiadiazole. This system collects condensation of deciever salt imitator ether in a solvent such as ethanol, at a temperature between room temperature and the temperature of education phlegmy (Scheme 12, Stillings, M.R.; Welbourn, A.P.; Walter, D.S. J. Med. Cheia., 1986, 29, 2280). The predecessor of deciever obtained from the corresponding Grignard reagent and carbon disulfide/MeI. Imidatly ether is obtained from the corresponding nitrile by reaction with HCl gas in the presence of the corresponding alcohol.

Pyrazoles can be obtained by condensation of 1,3-diketone (Scheme 13) or a synthetic equivalent with substituted hydrazine (for example, (3-aminoindan. Alberola, A.; Calvo, L.; Ortega, A.G.; Sadaba, M.L.; Sanudo, M.C.; Granda, S.G.; Rodriguez, E.G., Heterocycles, 1999, 51, 2675).

Similarly, iaocati can be obtained by the interaction of 1,3-dicarbonyl compounds with hydroxylamine (Scheme 14. Pei, Y.; Wickham, B.O.S.; Tetrahedron Letts, 1993, 34, 7509) in a solvent such as ethanol, at temperatures from 22°With up to a temperature of education phlegmy.

Alternatively, isoxazoles can be obtained by condensation of hydrocapillary with Alcina (Scheme 15, Kano, H.; Adachi, I.; Kido, R.; Hirose, K.J. Med. Chem. 1967, 10, 411) in the presence of a base such as triethylamine. Link hydrocapillary can, in turn, be obtained from the corresponding oxime by oxidation of gas-chlorine at low temperature (such as -60° (C) in a solvent such as simple ether (Casanti, G. Ricca, A. Tetrahedron Lett., 1967, 4, 327).

Triazole is obtained by reaction Einhorn-Bruner or its variant (Scheme 16)

In addition, 5-hydroxymethylcytosine 1,2,4-triazole can be obtained by condensation imitator ether with link 2-hydroxyethylhydrazine (Scheme 17, Browne, E.J.; Nunn, E.E.; Polya, J.B. J. Chem. Soc., Since 1970, 1515).

Thus obtained five-membered heterocycles can, in some cases, to link directly with the fragment containing ArII, using standard methodology, described in detail elsewhere in the description of the present invention (Scheme 1-4). These methods include alkylation metalloconcentrate ArII hlormetilsilatran a heterocycle, or Vice versa, the alkylation of the heterocycle attached to a hydroxyl (in the presence of base) chloromethylene reagent containing ArII.

In another approach to condensation fra the cops, the substituents on the prior heterocycle first modify to include appropriate reactive functionality, then this system is associated with the fragment containing the ArII. For example (Scheme 18), processing 1,4-disubstituted imidazole base, such as n-utility, at a temperature of about -78°C, followed by alkylation of the resulting anion with the electrophile, such as ethylene oxide, provides the hydroxyethyl-substituted imidazole (used by other electrophiles are DMF) or formaldehyde). For example, see Manoharan, T.S.; Brown, R. S. J. Org. Cheia. 1989, 54, 1439). This intermediate compound can then be associated with ArII fragment containing aromatic alcohol by Mitsunobu reaction.

Another example of such a General approach is presented in figure 19. The substituents on the ring, such as an ester, can be restored to the corresponding alcohol using a reagent, such as sociallyengaged or litebrite, in a solvent such as THF or ether. This is followed by halogenoalkane obtained alcohol system reagents, such as NCS/Ph3P, Ph3R/Br2or PBr3(Pei, Y.; Wickham, .O.S.; Tetrahedron Lett., 1993, 34, 7509). Obtained in this way alkylhalogenide can be linked nucleophilic Deputy attached to ArIl, use what I base, such as2CO3in the case of aromatic alcohol, (thiol) or NaH in the case of aliphatic alcohol (thiol).

When the third General approach to condensation of fragments, ArII can be included in the predecessor of the five-membered heterocycle. For example (Scheme 20), amination of 3-aryl-propionate, acarnania obtained amide provides a suitable functionalized system for the synthesis of the thiazole ring. Similarly, the receipt of thiourea from arylmethylidene (path) provides a suitable precursor for the merge ?halogenatom, resulting in 2-aminosilanes thiazole (Collins, J.L.; Blanchard, S.G.; Boswell, G.E.; Charifson, P.S.; Cobb, J.E.; Henke, B.R.; Hull-Ryde, E.A.; Kazmierski, W.M.; Lake, D. H.; Leesnitzer, L.M.; Lehmann, J.; Lenhard, J.M.; Orband-Miller L.A.; Gray-Nunez, Y.; Parks, D.J.; Plunkett, K.D.; Tong, Wei-Qin. J. Med. Chem. 1998, 41, 5037).

In another variant embodiment of the present invention, ArI represents the five-membered heterocycle of the General formula shown in Figure 2.

In particular, this heterocycle may be a pyrazole, imidazole or triazole. These systems can be obtained by alkylation of N-unsubstituted heterocycle, using a base such as sodium hydride, in a solvent such as DMF, THF, DMPU or combinations of these solvents, at or near 0°and electrofilm the e connection such as alkylhalogenide, cyclic carbonate, or epoxide (Scheme 21).

These electrophiles can include ArII or products of alkylation can be further modified and associated with a fragment containing ArII, at a later stage, as described above. For example (Scheme 22), 3,5-disubstituted pyrazole is obtained by interaction of aldehyde β-dailyprincetonian.com using published methodology (Almirante, N.; Benicchio, A.; Cerri, A.; Fedrizzi, G.; Marazzi, G.; Santagostino, M. Synlett 1999, 299). This intermediate compound can then be alkylated with sodium hydride/ethylene carbonate resulting in DMF (as a concrete example, see Collins, J.L.; Blanchard, S.G.; Boswell, G.E.; Charifson, P.S.; Cobb, J.E.; Henke, B.R.; Hull-Ryde, E.A.; Kazmierski, W.M.; Lake, D. H.; Leesnitzer, L.M.; Lehmann, J.; Lenhard, J.M.; Orband-Miller L.A.; Gray-Nunez, Y.; Parks, D.J.; Plunkett, K.D.; Tong, Wei-Qin. J. Med. Chem. 1998, 41, 5037). This intermediate compound can be, in turn, is associated with a fragment containing ArII, a Mitsunobu reaction as described above.

In another embodiment of the present invention, ArI is a substituted benzene, pyridine, pyrimidine, pyrazin or pyridazin (Figure 3). These systems can be obtained by applying some of the General synthetic methods are discussed elsewhere in the description of this invention.

More specifically (Schemes is 23), processing the famous 5-bromo-2-methylpyridine (Graf. J. Prakt. Chem. 1932, 133, 19) LDA, then formaldehyde in THF at low temperature (usually about -78° (C) with subsequent linking by Mitsunobu of the resulting alcohol with an aromatic alcohol containing ArII, gives the derivative of bromopyridine, which then can be modified to produce different alkyl - and aryl-substituted pyridines cross-linking with the appropriate alkyl - or allergologicheskimi compound in the conditions of catalysis by palladium or Nickel (total reviews see Knight, D.W. and Billington, D.C. in Comprehensive Organic Synthesis Vol. 3, p.413, and 481, Trost, B.M. and Fleming, I. Eds. Pergamon Press 1993).

A similar method using the appropriate 5-bromo-2-methylpyrimidine (Kosolapoff, G.M.; Roy, C.H. J. Org. Chem. 1961, 26, 1895), 2-iodine-5-methylpyrazine (PR, A.; Spoerr, P.E.; J. Org. Chem., 1961, 26, 1907) and 3-bromo-6-methylpyridazine (Counotte-Potman, A.; van der Plas, H.C.; J. Heterocycllc Chem., 1983, 20, 1259) provide an approach to obtaining appropriate pyrimidines, pyrazines and pyridazines, respectively.

In other variations of this General class, ArI is a 3-heteroatom-substituted pyridazin. For example (Scheme 24), processing known 3,6-dibromopyridine the metal alkoxide (containing ArII, and obtained from the corresponding alcohol and sodium hydride) in a solvent such as DMSO, provides alkoxy-substituted bromine is irydzin. Bromide can be converted into the number of the substituents as described above for pyridines. In particular, linking by Suzuki with Bronevoy acid in the presence of a base and a palladium catalyst provides appropriate arylsubstituted pyridazine.

In another variant embodiment of the present invention, the ArI can be replaced by kinocilium (Figure 4). These systems are constructed by condensation of 1,2-dicarbonyl compounds with 1,2-diaminobenzene (for review see Katritzky, A.R.; Rees, C.W.; Scriven, E.F.V. Eds. Comprehensive Heterocyclic Chemistry II; Vol 6 Pergamon Press (1966).

The functionalization (introduction of functional groups) of these systems and linking ArII can be performed using the methods described for related pyrazino. For example (Scheme 25), the condensation of 1,2-diaminobenzene with 2,3-butadiene provides 2,3-dimethylquinoxaline. N-oxidation of this intermediate compound peroxycarbonates acid and treatment of the product by acetylchloride give 2-chloromethyl-3-methylphenoxy (Ahmed, Y.; Habib, M.S.; Bakhtiari, B. Bakhtiari, Z. J. Org. Chem., 1996, 31, 2613). Then this intermediate connection associated with the fragment containing ArII, under standard conditions.

In another variant embodiment of the present invention, the ArI can be hinazolinam (Scheme 26). Such systems usually receive the Ute condensation derived o-aminobenzaldehyde or o-aminoacylation with the acid chloride of the carboxylic acid followed by heating with ammonia. For example, the condensation of o-aminobenzaldehyde with chloroacetylation in the presence of pyridine, followed by the interaction of the product with ammonia in ethanol at room temperature (Armarego, W.L.F.; Smith, J.I.. J. Chem. Soc., With, 1966, 234) gives 2-chloromethyl-substituted hinzelin that can be associated with a fragment containing ArII, as described above.

Related ring systems hinzelin-4-it (Scheme 27) can be obtained by condensation of o-aminobenzonitrile and acid chloride of the carboxylic acid with the subsequent closure of the ring, using a reagent such as urea-hydrogen peroxide in the presence of a base such as potassium carbonate (Bavetsias, V. Synth. Coiamun. 1998, 28, 4547). In other varieties khinazolinov system, 4-heteroatom-substituted hintline can be obtained by condensation of aminobenzonitrile with chloroacetonitrile in the presence of acid, such as HCl or HBr (Chhabria, M.L.; Shishoo, C. J. Heterocycles 1999, 51, 2723). The resulting system can be associated with ArII, as described above. 4-Halogen-Deputy then you can modify the nucleophilic substitution of a metal alkoxide in a solvent such as DMSO.

The overall reaction of obtaining reagents, such as compounds of formulas VI, IX, X, XIII and XIV (scheme 1-3), presented in figure 28. Halogenoalkane methyl-substituted aromatic compounds reagent is m, such as N-bromosuccinimide, in the presence of free radicals provides obtaining halogenmethyl-substituted aromatic reactants.

Alternative getting some alkylating reagents presented in figure 29. For example, substituted derivatives of 2-chloromethylpyridine can be obtained by using the two-stage method (See, J. Med. Chem. 1991, 34, 3224). Oxidation of nitrogen to obtain N-oxide can be achieved by using an oxidant such as m-chlormadinone acid or hydrogen peroxide. The reaction of N-oxide with a reagent, such as toluensulfonate, at elevated temperatures can provide the specified chloromethylene derived. This chemistry can also be extended to derivatives of 2-picoline, where the 6-position Deputy is not hydrogen.

Obtaining reagents that can be used as alkylating agents of the formula VI (scheme I) is shown in figure 30. In the case of systems hinoksolinov rings, use trichloroisocyanurate acid (TCC) can provide the appropriate CHLOROTHALONIL similar (see, Cheia. Ber. 1987, 120, 649).

In a particular variant embodiment of the present invention, In formula I can represent amide linker of one of two forms, as the x on the Figure 5. Compounds of this formula can be obtained from a slice of carboxylic acid and amine fragment using standard reagents for the formation of the peptide bond. They can also be obtained by reaction with activated carboxylic acid derivative, such as, but not limited to, the acid chloride or anhydride in combination with aminoven fragment in the presence of a suitable base, such as triethylamine. It should be obvious that, essentially, the same methods can be used when group a of formula I is an amide linker, using the appropriate carboxylic acid and amine fragments.

In particular, the system (7) 2-aminomethyl-6-substituted benzoic acid can be obtained by using the reaction scheme presented in figure 31. Selective reduction of a substituted phthalic anhydride of the acid (9) steric difficult litigationrelated, such as L-selectride, provide the lactone (10), regioselective (See Krishnamurthy, Heterocycles, 1982, 18, 4525). The interaction of this lactone with phthalimide potassium gives a protected amine in accordance with the method of Bornstein, Org. Syn. Collective Vol IV, 1963, 810. Remove phthalimides protective group using standard conditions unprotect hydrazine, can give the amino acid (7).

Poluate the s 1,2-carboxylic acid, such as 12 (Scheme 32) are precursors for structures, linked by an amide bond (Figure 5), in which a fragment containing ArIII, is the acyl donor. These systems can be obtained in several ways: Alcoholysis of phthalic anhydride (9) can be selectively isomer (11) plus fewer isomer (12). Esterification getting diapir (13) can be performed using different conditions, such as esterification Fisher. Hydrolysis of diapir can give regioisomer (12) as the major isomer in addition to the isomer (11).

Derivatives of phthalic anhydride, such as (9)can, in turn, be obtained from the corresponding dibasic acid (decollate) (14)as shown in scheme 33, using dehydrating conditions, such as, but not limited to, hot acetic anhydride.

In one embodiment of the present invention, ArIII-(CR9R10)e-D-(CR11R12)f-E-Z, taken together, form a substituted benzoic acid. Used the sequence of reactions for designing this type of system is shown in scheme 34. The lactone (obtained as described in scheme 31) can be heated with Hydrobromic acid to obtain biometerorology acid. The carboxylate can es arificial, getting the acid chloride of the acid, followed by interaction with alcohol, to obtain the intermediate bromide, which can be used as described in scheme 2, formula XIII.

Alternative pattern substitution benzoate can be accessed using the reaction of alder-Rickert, as shown in figure 35 (See, J. Org. Chem. 1995, 60, 560). 2-Celloxide can be obtained from the northward, using a strong base such as LDA and trapping enolate silylium reagent. The heat of this diene with acetylenedicarboxylate at elevated temperatures may give further product of alder-Rickert. Alkylation of phenolic hydroxyl in standard conditions (using an alkylating agent R'-L, where L is the deleted group) followed by saponification of diapir can give the intermediate compound dibasic acid (decollate), manipulating whom in accordance with the chemistry shown in figures 31-34, you can get a useful intermediate for preparing compounds of formula I.

Another particular variant embodiment of the present invention appears to be one in which the substituted portion of benzoic acid, described above, has a 6-alkyl-2-alkoxy Deputy. Obtaining this type of system iilustrated, using 6-methyl-what proizvodnje, specified in scheme 36 (See Hamada, Tetrahedron, 1991, 47, 8635). Ethylacetoacetate and CROTONALDEHYDE can be condensed with obtaining cyclic β-keeeper. Subsequent aromatization, mediated by a combination of a lithium chloride/chloride copper(II), this intermediate compound can be carried out at elevated temperatures with obtaining the specified salicylates of ester. Next phenolic hydroxyl of this system can be derivatization alkylation, as described elsewhere in the description of this invention.

In addition, system 6-alkyl-2-alkoxybenzyl can be obtained aromatic nucleophilic substitution of 2-fluoro-benzaldehyde, at elevated temperatures, alkoxide (scheme 37) to obtain 2-alkoxybenzenes. Can then be carried out the oxidation of the aldehyde to the acid using conditions, such as sodium chlorite, sodium dihydrophosphate, isobutene (See JACS 1980, 45, 1176).

In another variant embodiment of the present invention, In formula I may represent a sulfur atom, forming a thioester bond (Scheme 2, Formula (XI and XII). This type of system can be obtained by standard tiruchelvam, using a suitable base (such as carbonate, hydroxide or hydride, sodium or potassium, or amine, such as triethylamine) to obtain the thiol anion, and then the interaction of this species with an appropriate electrophile, such as alkylhalogenide or sulphonate ester. Similarly, groups a and D of the formula I can also represent, independently, a sulfur atom. It should be obvious that the same transformation, as shown in the diagrams below can be applied to compounds of formula (VII, VIII, XI, XII, and XVI; schemes 1-3).

Aromatic thiols can be obtained from the corresponding phenols. For example, obtaining 2-thiobenzoate (10) from salicylate (7) may be made as shown in scheme 38. (see. Guise J. Chem. Soc., Perkin Trans. 1, 1982, 8, 1637). Thionocarbamate (8) can be obtained from the corresponding phenol (7), using thiocarbamoylation. Pyrolysis (8) (>300° (C) may give the product of the rearrangement (9), which after hydrolysis can give thiol (10).

Another used the transformation Deputy ring is in the conversion of aniline in an aromatic thiol. As shown in scheme 39, diazotization of aniline, such as (11), followed by conversion of the diazonium salt (12) disulfide (13), using sodium sulfide. Restore disulfide combination of zinc/acetic acid can give the thiol (14) (See, Guise J. Chem. Soc., Perkin Trans. I, 1982, 8, 1637).

In a particular variant embodiment of the present invention, ArIII may be halogen-substituted aromatic compound. The synthesis is particularly relevant systems is depicted in scheme 40. Regioselective halogenoalkane 2,6-disubstituted phenol with the aim of obtaining 4-halogenfrei system can be implemented with a halogenation reagent such as sulfurylchloride (See J. Het. Chem. 1989, 26, 1547). Phenolic hydroxyl group can then be subjected to transformation, as described elsewhere in the description of this invention.

An alternative way of obtaining halogen (or alkoxy)-substituted benzoate presented in figure 41. First aniline converted into its diazonium salt using nitrous acid, followed by conversion into the corresponding nitrile using a reagent such as copper cyanide (II) (See, Chem. Ber. 1983, 116, 1183). Then the cyano hydrolyzing the acid (see Fuson, JACS 1941, 63, 1679). Then the acid can simetite in the form of ester, in order to prevent further conversion system, as described elsewhere in the description of this invention.

Ortho-halogenated can be obtained similarly, by diazotization of o-carboxyaniline, with subsequent interaction with the copper halide (Scheme 42).

In another variant embodiment of the present invention, ArIII is benzofuranyl or dihydrobenzofuranyl carboxylic acid, as shown in Figure 6

Benzofuran-2-carboxylate derivatives can be obtained as shown in scheme 43, by cyclization of an appropriately substituted 2-carbonintensity in basic conditions. The recovery obtained benzofuran in the corresponding 2,3-dihydrobenzofuran can be carried out using sodium mercury amalgam in basic conditions (See, J. Med. Chem. 1984, 27, 570).

Alternative synthesis system 2,3-dihydrobenzofuran-2-carboxylate ring system presented in figure 44 (See, J. Med. Chem. 1981, 865). The klaisen rearrangement of substituted allylanisole ether at an elevated temperature, such as 250°or in undiluted state or in a solvent such as dimethylaniline, can give o-allylphenol. Oxidation nagkalat this intermediate compound 2-hydroxymethyl-2,3-dihydro-benzofuran, which might be further oxidized to carboxylic acid using a number of oxidizing agent such as Jones reagent.

In another variant embodiment of the present invention, "A" may represent imidazolidin-2-it, tetrahydropyrimidin-2-it, imidazolin-2,4-dione or tetrahydropyrimidine-2,4-Denon (Figure 7).

These systems are derived from amine containing ArI, serial acelero what W, aminolysis, shorting rings and recovery, as illustrated in scheme 45 (see for Example, Kitazaki, T.; Asaka, A.; Tamura, N.; Matsushita, Y.; Hosono, H.; Hayashi, R.; Okonogi, K.; Itoh, K. Chem. Pharm. Bull., 1999, 47, 351 and Basha, A.; Tetrahedron Lett., 1988, 29, 2525). Linking ArIl can be done by converting the cyclic urea N by treatment with base, such as NaH in THF at about 0°C, followed by alkylation of the resulting anion with the electrophile, such as allylbromide/triplet containing ArII.

In another variant embodiment of the present invention, ArII is a six-membered aromatic ring substitution, presented in Figure 8. In particular, ArII is a substituted benzene, pyridine, pyrimidine, pyridazine or pyrazin.

In principle, accordingly functionalityand ring system of this type can be obtained by functionalization of specific precursors with subsequent synthesis of the rings or through the conversion of previously received the ring system. There are many approaches to the synthesis and functionalization of the above-mentioned cyclic skeletons in the chemical literature (for example, see (a) Katritzky, A.R.; Rees, C.W.; Scriven, E.F.V. Eds. Comprehensive Heterocyclic Chemistry II, Vol 5 and Vol 6. Elsevier Science 1996 and references therein). For example (Scheme 46) alkylation of methylglucose alkyl what logarithm, containing ArI, using a base such as sodium hydride, in a solvent such as THF or DMSO, provides ester. Condensation of Clausena this complex ether and t-butyl acetate at low temperatures (usually below -15° (C)using a base such as LDA in THF provides an intermediate connection keeeper. It is subjected to interaction with formamidine in the presence of a base such as sodium methoxide, in methanol, receiving pyrimidine (Butters, M.J. Heterocyclic Chem., 1992, 29, 1369). This type of substituted aromatic system in the future can be functionalitywith to include ArI, as described elsewhere in the description of this invention.

In some cases, ArII (Figure 8) can be constructed by transformation of the rings other heterocycle, for example, the processing of the known 4-bromo-2-methoxyfuran (Scheme 47, Marini-Bettolo, R.; Flecker, P.; Tsai, T.Y.R.; Wiesner, K. Can. J. Chem. 1981, 59, 1403) alkyllithium at low temperature and the interaction of this anion with an electrophile containing ArIII (such as chloride, aldehyde, epoxide), provides 4-substituted furan. Oxidative cleavage of this intermediate connection dioxiranes followed by treatment with hydrazine provides pyridazine, which can later be modified to include ArI, as illustrated in Draganesti description of the present invention.

Especially the Protocol used in relation to the functionalization of heterocycles include esterification by Mitsunobu hydroxyl-substituted heterocycles (or ketonaemia), such as described in scheme 48. Processing the known 6-bromopyridin-2-it (Wibaut, J.P.; Waayman, P.W.; Vandijk, J. Rec. Trav. Chim. Pays-VAZ. 1940, 59, 202) alcohol containing ArI (or ArIII), Mitsunobu conditions provides the corresponding bromo-substituted pyridyloxy ether (as conventional methods see Mitsunobu. O., Synthesis, 1981, 1).

Heterocyclic bromide, thus obtained, can then be functionalized by a number of ways. For example, to get a system with alkenylamine the linkers (scheme 49) can bind with vinylstyrene using catalytic palladium(0) (Scheme 49).

The choice of catalyst and reaction temperature for the conversion depends on the substrate used, but most often it is tetranitroaniline palladium, bis(tri-phenylphosphine)palladium chloride, 1,1'-bis(diphenylphosphino)ferrocene/bis-dibenzylideneacetone palladium or 1,2-bis(diphenyl-phosphino)ethane/bis(acetonitrile)dichloropalladium at a temperature between 50°150°C. Suitable solvents include DMF, DMPU, NMR, DMSO, toluene and dimethyl ether (for example, see Farina, V. Krishnamurthy, V.; Scott, W.J. Organic Reactions, 1997, 50, 1). In Stanovlenie of olefin, using, for example, the catalyst of Wilkinson in a solvent such as toluene, THF or an alcohol, at a temperature between about 20°s and 80°provides appropriate alkane-linked system.

In some heterocyclic systems, where the bromide or chloride is in the ortho - or para-position relative to the nitrogen of the ring, the halogen can be replaced easily on alcohol (in the presence of a base such as sodium hydride in a solvent such as toluene, DMSO, THF, DMPU or NMR) at room temperature or above (as examples, see Kelly, T.R. et al. J. Amer. Chem. Soc., 1994, 116, 3657 and Newcome, G.R. et al. J. Org. Chem., 1977, 42, 1500). For example, alcoholysis 2,4-dichloropyrimidine (Scheme 50), using a controlled stoichiometric amount of alcohol reagent containing ArI (or ArIII), provides alkoxy-substituted bromopyrimidine. The subsequent interaction of this product (usually above room temperature) with an additional equivalent of another alcohol containing ArIII (or ArI) provides the asymmetrically dialkoxy-substituted heterocycle. Since the 4-position of dichloropyrimidine usually replaced first, the order in which the alkoxy substituents type will dictate their orientation in the product.

Similar methods using 2,6-dibromopyridin or 2,6-dibromopyridin, provide for the possibility of dialkoxy-substituted pyridine and pyridazine.

Simple alkoxy group, located in the ortho (up) position to the nitrogen in these heterocyclic systems can be hydrolyzed to the corresponding hydroxy Deputy, using aqueous hydrochloric acid at a temperature usually between room temperature and the boiling temperature under reflux. (Scheme 51).

For example (Scheme 51), processing the derived 2-methoxy-6-alkyl-substituted pyridine hydrochloric acid gives 6-alkyl-substituted pyridine-2-it. This is an intermediate connection, in turn, can then be converted to the corresponding 2-alkoxy - or 2-alkenyl-substituted system, as more fully described elsewhere in the description of this invention.

Methyl, methylene or methine group, located in the ortho (up) position to the nitrogen of the ring in these heterocyclic systems can be deprotoniruya base, such as alkylate or LDA in a solvent such as THF, a simple ester or NMRA, usually at low temperature (below 0° (C) and the resulting anion can be subjected to interaction with electrophiles, such as aldehydes, epoxides, alkyl halides or α,β-unsaturated carbonyl compounds, obtaining a number of functionalized heterocycles.

For example (Scheme 52), 2 is coxi-4-methylpyrimidin process, consistently, LDA and aldehyde at -78°receiving the replacement product. Subsequent dehydration of this intermediate compound Martin sulfureum in a solvent such as dichloromethane, at ambient temperature, followed by hydrogenation of the resulting olefin has a 4-ArI-containing-alkyl-2-alkoxy-pyrimidine. Similar techniques applied to 2-chloro-6-methylpyrazine (Karmas, G.; Spoerri, R.E.; J. Amer. Chem. Soc., 1952, 74, 1580) lead to the receipt of pyrazine.

In another variant embodiment of the present invention And may represent amide, thereby generating compounds of the formulae presented in Figure 9.

Getting an illustrative example within this series are presented in figure 53. Hydroxyaldehyde may be subjected to interaction with romancelatina with the intermediate connection of aldehidelor. Reductive amination of aldehyde and subsequent acylation can give amide.

In addition, the compounds of this invention can be easily synthesized by solid-phase methods, as illustrated by the Circuits 54 and 55, using load (XII)-(XVII), are shown in Table I.

z

Additional illustrative example of amide linker presented in figure 56. The interaction of activated carboxylic acid derivative, such as, but not limited to, the acid chloride or anhydride with an amine of General formula (15) and a suitable base, such as triethylamine, provides amide (16). A more detailed illustrative example presented in figure 57. Carboxylic acid (17) to activate oxalylamino, receiving the acid chloride of the carboxylic acid and then add 2-amino-6-methylbenzoic acid (18), receiving amide (19). Alternatively, 2-amino-methyl-6-methylbenzoic acid (20) can be used to obtain the amide (21).

Getting 2-aminomethyl-6-methylbenzoic acid, (20), can be carried out using the reaction scheme in scheme 31 (X=Me, R'=H).

The compounds used in accordance with the invention, can also be obtained by applying or adapting known methods, which are methods used before or described in the literature, for example the methods described R.C.Larock in Comprehensive Organic Transformations, VCH publishers, 1989.

In the reactions described hereinafter, may be necessary to protect reactive functional groups, for example hydroxy, amino, imino, thio or carboxy groups, to avoid their unwanted uchastiem reactions, if these groups are required in the final product. Can be used conventional protective groups in accordance with standard practice, for example see T.W.Green and P.G.M. Wuts in "Protective Groups in Organic Chemistry" John Wiley and Sons, 1991; J.F.W. McOmie in "Protective Groups in Organic Chemistry" Plenum Press, 1973.

In accordance with another feature of the present invention, the compounds used according to the invention, can be obtained by vzaimoperesechenie other compounds of the invention.

The connection according to the invention, including a group containing one or more ring nitrogen atom, preferably Imin (=N-), can be converted into the corresponding compound where one or more ring nitrogen atoms of the group oxidized to N-oxide, preferably by interaction with nagkalat, for example peracetic acid in acetic acid or m-chlormadinone acid in an inert solvent, such as dichloromethane, at a temperature from about room temperature up to temperatures of formation of phlegmy, preferably at elevated temperature.

The products of this invention can be obtained as racemic mixtures of their right - and levogyrate isomers, because they may contain at least one asymmetric carbon atom. In the case where there are two asymmetric carbon atom, the product may exist as mixtures of dieste is easemera, on the basis of SYN - and anticonspiracy. These diastereoisomers can be separated by fractionated crystallization. Then, each diastereoisomer can be divided into right - and levogyrate optical isomers by conventional methods.

For professionals in this field should be obvious that some of the compounds of formula I can exhibit geometrical isomerism. Geometrical isomers include CIS - and transforms compounds of the invention having alkenylphenol part. The present invention encompasses the individual geometrical isomers and stereometry and a mixture of them.

Such isomers can be distinguished from their mixtures by applying or adapting known methods, for example chromatographic methods and techniques recrystallization, or they may separately be obtained from the appropriate isomers of their intermediates, for example using the methods described here or adapting them to each specific case.

The division can best be implemented at an intermediate stage, where it is convenient to connect the racemic compound with an optically active compound by formation of a salt, the formation of ester or formation of amide to obtain the two diastereomeric product. If optically active base to add the acid, you can get two diastereomeric salts, which have a variety of the properties and different solubility and then they can be fractionated crystallization. After complete separation of the salts by repeated crystallization, the base is separated by acid hydrolysis and get purified enantiomeric acid.

The compounds used according to the invention, used in free base form or acid or in the form of their pharmaceutically acceptable salts. All forms are included in the scope of this invention.

When the connection is used according to the invention, replaces the main part, get additive salts of acids and they are simply a more convenient form for use; in practice, the use of salt forms, in essence, is equivalent to using the form of the free base. Acids which can be used to obtain additive acid salts include preferably acid, which give, when combined with the free base, pharmaceutically acceptable salt, that is, salts whose anions are non-toxic to the patient in pharmaceutical doses of the salts so that the beneficial pharmaceutical effect of these compounds in the free base are not particularly limited side effects attributed to the anions. Although pharmaceutically acceptable salts of these basic compounds are preferred, all of the additive salt of the acid used as sources of the free base form even if the particular salt, per se, is required tol is to as an intermediate product as, for example, when salt only get to clean and identification, or when it is used as intermediate compounds for obtaining a pharmaceutically acceptable salt by means of ion exchange. Pharmaceutically acceptable salts, are used within the scope of this invention are salts derived from the following acids: mineral acids such as hydrochloric acid, triperoxonane acid, sulfuric acid, phosphoric acid and sulfamic acid; and organic acids such as acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonate acid, econsultancy acid, benzolsulfonat acid, p-toluensulfonate acid, cyclohexylsulfamic acid, Hinn acid, etc. Corresponding additive salt of the acid include the following: hydrogen halides, e.g., hydrochloride and hydrobromide, triptorelin, sulfate phosphate, nitrate, sulpham, acetate, citrate, lactate, tartrate, malonate, oxalate, salicylate, propionate, succinate, fumarate, maleate, methylene-bis-β-hydroxynaphthoate, gentisate, mesylates, isocyanate, di-p-toluoyltartaric, methansulfonate, econsultancy, benzene-sulfonates, p-toluensulfonate, cyclohexylsulfamate and hint, respectively.

Additive salts of acid compounds used is according to the invention, obtained by reaction of the free base with the appropriate acid, by applying or adapting known techniques. For example, the additive salts of acid compounds of this invention are produced either by dissolving the free base in aqueous or aqueous-alcohol solution or other suitable solvents containing the appropriate acid and the release of salt by evaporating the solution, or by the interaction of the free base and acid in an organic solvent, and in this case, salt is produced directly or can be obtained by concentration of the solution.

The compounds used in accordance with the invention can be regenerated from the additive salts of acids, using known methods or adapting them. For example, the source compounds used according to the invention, can be regenerated from their additive salts of acids by treatment with alkali, for example aqueous sodium bicarbonate solution or aqueous ammonia solution.

When the connection is used according to the invention, the substituted acid part, you can get additive salts of the bases and they are simply a more convenient form for use; in practice, the use of salt forms, in essence, is equivalent to using the form of the free base. The Foundation, which can be used to obtain addit the main base salts, include preferably those which give, when combined with the free acid, pharmaceutically acceptable salt, that is, salts whose cations are non-toxic to the animal organism in pharmaceutical doses of the salts, so that the healing of the pharmaceutical activity of the compounds of the present invention in the form of the free acid (in terms of their activity) is not particularly limited side effects attributed to cations. Pharmaceutically acceptable salts used according to the invention, include, for example, salts of alkali and alkaline earth metals, including salts derived from the following bases: sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminum hydroxide, lithium hydroxide, magnesium hydroxide, zinc hydroxide, AMIC, Ethylenediamine, N-methylglucamine, lysine, arginine, ornithine, choline, N,N'-dibenziletilendiaminom, chloroprocaine, diethanolamine, procaine, diethylamine, N-benzylpenicillin, piperazine, Tris(hydroxymethyl)aminomethan, the hydroxide of Tetramethylammonium etc.

Metal salts of the compounds used according to the present invention can be obtained by contacting hydride, hydroxide, carbonate or similar reactive compound of the selected metal compound in the form of the free acid in water or an organic solvent. As water is astorias may be water or it may represent a mixture of water with an organic solvent, preferably an alcohol such as methanol or ethanol, a ketone such as acetone, simple aliphatic ether, such as tetrahydrofuran, or a complex ester, such as ethyl acetate. Such reactions are usually carried out at room temperature, but if necessary, they may be conducted under heating.

Amine-containing salt compounds used according to the present invention can be obtained by contacting an amine with the compound in the form of the free acid in water or an organic solvent. Suitable aqueous solvents include water and mixtures of water with alcohols, such as methanol or ethanol, ethers, such as tetrahydrofuran, NITRILES, such as acetonitrile, or ketones, such as acetone. It is similarly possible to obtain salts of amino acids.

Additive salts of the bases of the compounds used according to the invention can be regenerated from the salts by applying known methods or adapting them. For example, the source compounds used according to the invention, can be regenerated from their additive salts of the bases by treatment with an acid, for example hydrochloric acid.

In addition, the salt form used according to the invention include compounds having quaternionic nitrogen. Quaternion salt is produced by methods such as alkylation of nitrogen, is Tamagawa connections in state sp 3or sp2-hybridization.

As self-evident for specialists of medium qualification in this field, some of the compounds used according to the invention, do not form stable salts. However, it is most likely that additive salts of acids derived from compounds used according to the invention having a nitrogen-containing heteroaryl group, and/or where the compounds contain an amino group as a substituent. The preferred additive salts of acid compounds used according to the invention are those salts having no acid-labile group.

Along with, as such, as active compounds, salts of the compounds used according to the invention, used for the purposes of cleaning compounds, for example by methods known to experts in this field, using the differences in the solubilities of salts and related compounds, by-products and/or starting materials.

Different substituents in the compounds used according to the invention, such as defined for the substituents R, R1and R2may be present in the source compounds can be introduced into any one of the intermediates or introduced after the formation of the final products by known methods of substitution reactions or transformations. If estately, in themselves, are reactive, in accordance with the invention, the substituents may be subject to protection. You can use a number of protective groups. Examples of many of these groups, which can be used can be found in "Protective Groups in Organic Synthesis" by T.W.Green, John Wiley and Sons, 1981. For example, the nitro group can be introduced into the aromatic ring nitration, and then the nitro-group can be converted into other groups, such as amino, recovery, or halogen, by diazotization of the amino group and replacement of the diazo group. Acyl groups may be substituted on the aryl group by acylation according to the Friedel-Crafts. Acyl groups can then be converted into the corresponding alkyl groups in a variety of ways, including the restoration of wolf-Kizaru and recovery Clemmenson. Amino groups can be alkylated to obtain mono - and dialkylamino groups; and mercapto and hydroxy groups can be alkylated with the corresponding ethers. Primary alcohols can be oxidized by oxidizing agents known in the field, obtaining carboxylic acids or aldehydes and secondary alcohols can be oxidized to obtain ketones. Thus, substitution reactions or reaction conversion can be used to obtain a number of deputies during the synthesis of the, starting from the molecules of the source materials, intermediates, or the final product.

Source materials, intermediate compounds and some compounds of the invention receive, using known methods or adapting them, for example, by methods described in U.S. patent No. 4920132; 4920131; and 5059610; publications Huang, Fu Chih et al, J. Med. Chem. (1991), 34(5), 1704-7; and Huang, Fu Chih et al, J. Med. Chem. (1990), 33(4), 1194-200; and the reference examples and their obvious chemical equivalents.

The present invention is illustrated in more detail by examples, but it is not limited to the following examples, which illustrate the formation of compounds according to the invention.

Example 1

Methyl 2, 6-dimethylbenzoic

To a cooled (0° (C) to a solution of 2,6-dimethylbenzoic acid (20.2 g, 134 mmol) in dichloromethane (200 ml) is added DMF (1 ml) and then oxalicacid (14 ml, 162 mmol). After completion of the addition, the bath for cooling is removed and continue stirring for 3 hours. The resulting solution was concentrated in vacuo and the residue is added slowly to a cooled (0° (C) the solution containing methanol (200 ml) and triethylamine (40 ml). Upon completion of addition the reaction mixture was stirred for 30 min, then poured into a solution of hydrochloric acid (400 ml, 2 ad), which is then extracted with simple ether. The ether extract is washed with hydrochloric acid (1 n), a sodium bicarbonate solution and saturated salt solution and then dried over MgSO4and concentrate, getting mentioned in the title compound which is used without further purification. MS (EI) [MS (EI)] 164 (M)+.

Example 2

Methyl 2-methyl bromide-6-methylbenzoate

To a solution of methyl 2,6-dimethylbenzoic (22,0 g, 134 mmol, example 1) in CCl4(250 ml) is added N-bromosuccinimide (19 g, 107 mmol) and then benzoyl peroxide (1.0 g, 4.0 mmol). The resulting solution was heated at the boil under reflux and stirred at this temperature for 20 minutes. Then the reaction mixture allow to cool, then diluted with ether (200 ml), filtered and concentrated. The residue is purified flash chromatography (silica gel, 4% acetone in hexane)to give specified in the header connection. This product (approximately 85% purity, the remainder represents methyl 2, 6-dimethylbenzoyl) used without further purification. MS (EI) 242, 244 (M+the structure responsible Br).

Example 3

3-(Quinoline-2-ylethoxy)phenol

Hydrochloride of 2-chloromethylpyridine (25,0 g, 117 mmol) and monobenzoate of resorcinol (37,5 g, 175 mmol) suspended in dimethyl sulfoxide (180 ml) and stirred using an outboard mixer. The mixture is cooled to 15°and slowly for 10 minutes add 50% sodium hydroxide solution (25 ml) with slight warming. Reaction the th mixture is allowed to cool to room temperature and left to mix overnight. Then the reaction mixture is heated to 95°and add 50% sodium hydroxide solution (25 ml) for 10 minutes. After 20 min the reaction mixture was added hot water (300 ml) and stirred for 15 minutes. The reaction mixture is filtered while hot and the filtrate cooled, getting a brick-red solid, which is dried in vacuum, obtaining the sodium salt pentahydrate. Part of salt (15.6 g, 43,0 mmol) is neutralized when heated in water (30 ml) 1 N. HCl (43 ml), then cooled, getting a brown solid. The solid is dissolved in dichloromethane (550 ml) and methanol (14 ml), dried over magnesium sulfate, filtered and concentrated in vacuo, obtaining mentioned in the title compound as a yellowish brown solid. A portion is recrystallized from ethyl acetate, obtaining analytically pure sample; TPL 152-153°S, MS (EPI, ESI) 252 (M+N)+.

Example 4

Methyl 2-methyl-6-[3-(quinoline-2-ylethoxy)phenoxymethyl]-benzoate

3-(Quinoline-2-ylethoxy)phenol (5,2 g, 21 mmol, example 3), methyl 2-methyl bromide-6-methylbenzoate (example 2) (5.0 g, 21 mmol) and potassium carbonate (4.4 g, 32 mmol) are combined in DMF (50 ml) and heated at 85°C for 3 hours. The reaction mixture was poured into ethyl acetate (500 ml) and washed with water (4×20 ml) and saturated salt solution (100 ml). The solution is dried over magnesium sulfate, filtered and concentrated in HAC the mind, receiving the remnant that purify by chromatography on a column (silica gel, 10 to 20% ethyl acetate in hexane)to give specified in the header connection. MS (EPI) 414 (M+N)+.

The following connections will be received, using essentially the same method used in example 4, except using the specified phenol instead of 3-(quinoline-2-ylethoxy)phenol with either methyl-or isobutylbenzene (example 2).

Example 4A

Methyl{2-methyl-6-[3-(2-quinoline-2-elwenil)phenoxymethyl]}-benzoate

MS (EPI) 410 (M+N)+. Obtained from 3-(2-quinoline-2-elwenil)-phenol (example 15).

Example 4b

Methyl(2-methyl-6-{3-[2-(pyridine-2-yloxy)ethoxy]phenoxy-methyl})benzoate

1H NMR (300 MHz, CDCl3) δ 8,15 (m, 1H), 7,60 (t, 1H), 7,1-7,38 (m, 4H), 6.89 in (DD, 1H), for 6.81 (d, 1H), 6,56 (m, 3H), to 5.08 (s, 2H), 4,70 (t, 2H), 4,32 (t, 2H), 3,85 (s, 3H), of 2.36 (s, 3H). Obtained from 3-[2-(pyridine-2-yloxy)ethoxy]phenol (example 15A).

Example 4C

Methyl 2-{3-[(benzoxazol-2-ylmethylamino)methyl]phenoxy-methyl}-6-methylbenzoic

MS (EPI) 417 (M+N)+. Obtained from 3-[(N-benzoxazol-2-yl-N-methylamino)methyl]phenol (example 10A).

Example 4d

Methyl 2-methyl-6-{3-[(medicinalis-2-ylamino)methyl]-phenoxymethyl}benzoate

MS (EPI) 427 (M+H)+. Obtained from 3-[(N-methyl-N-quinoline-2-ylamino)methyl]phenol (example 10b).

Example 4E

Isobutyl 2-methyl-6-[3-(quinoline-2-intoximeter)phenoxymethyl]benzoate

MS (EPI) 456 (M+N)+. Recip is n from 3-(quinoline-2-yloxy-methyl)phenol (example 15b).

Example 4f

Methyl 2-{3-[2-(5-ethylpyridine-2-yl)ethoxy]phenoxymethyl}-6-methylbenzoic

1H NMR (300 MHz, CDCl3) δ 8,39 (SHS, 1H), 7,46 (d, 1H), 7,28 (m, 2H), 7,16 (m, 3H), of 6.52 (m, 3H), of 5.06 (s, 2H), or 4.31 (t, 2H), 3,82 (s, 3H), up 3.22 (t, 2H), 2.63 in (K, 2N), of 2.38 (s, 3H), of 1.24 (t, 3H). MS (EPI) 406 (M+N)+. Obtained from 3-[2-(5-ethylpyridine-2-yl)ethoxy]phenol (example 71).

Example 4g

Methyl 2-methyl-6-[3-(2-pyridin-2-ylethoxy)phenoxymethyl]-benzoate

1H NMR (300 MHz, CDCl3) δ 8,56 (d, IH), a 7.62 (m, 1H), 7,28 (m, 2H), 7,16 (m, 3H), of 6.52 (m, 4H), of 5.06 (s, 2H), 4,34 (t, 2H), 3,82 (s, 3H), of 3.25 (t, 2H), of 2.38 (s, 3H). MS (EPI) 378 (M+N)+. Obtained from 3-(2-pyridin-2-ylethoxy) phenol (example 71A).

Example 4h

Methyl 2-[3-(benzooxazol-2-iluminati)phenoxymethyl]-6-methylbenzoate

1H NMR (300 MHz, CDCl3) δ 7,54 (m, 1H), 7,38 (d, 1H), 7,26 (m, 3H), 7,18 (m, 2H), 7,05 (m, 1H), 6,98 (m, 2H), to 6.88 (DD, 1H), 5,10 (s, 2H), with 4.64 (CL, 2H), 3,80 (s, 3H), is 2.37 (s, 3H). MS (EPI) 403 (M+N)+. Obtained from 3-(benzooxazol-2-iluminati)phenol (example 10C).

Example 4i

Methyl 2-methyl-6-[3-(pyridine-2-ileocecal)phenoxy-methyl]benzoate

1H NMR (300 MHz, CDCl3) δ 8,56 (d, 1H), 7,71 (m, 1H), of 7.48 (d, 1H), 7,25 (m, 5H), of 6.99 (m, 2H), 6.87 in (DD, 1H), 5,11 (s, 2H), 4,69 (s, 2H), 4,63 (s, 2H), 3,82 (s, 3H), of 2.38 (s, 3H). MS (EPI) 378 (M+H)+. Obtained from 3-(pyridine-2-ileocecal)phenol (example 74).

Example 4j

Methyl 2-methyl-6-[3-(quinoline-2-ileocecal)phenoxy-methyl]benzoate

1H NMR (300 MHz, CDCl3) δ 8,19 (d, 1H), ,06 (d, 1H), 7,82 (d, 1H), 7,69 (m, 2H), 7,53 (m, 1H), 7,24 (m, 4H), 7,01 (m, 2H), to 6.88 (DD, 1H), 5,12 (s, 2H), a 4.86 (s, 2H), of 4.66 (s, 2H), 3,82 (s, 3H), of 2.38 (s, 3H). MS (EPI) (M+N)+. Obtained from 3-(quinoline-2-ileocecal)phenol (example a).

Example 5

Methyl 2-methyl-6-[(3-hydroxyphenoxy)methyl]benzoate

To a solution of 3-hydroxyphenol (1.5 g, of 13.6 mmol) in acetonitrile (50 ml) is added methyl 2-(methyl bromide)-6-methyl-benzoate (0,82 g, 3.4 mmol, example 2), and then To2CO3(3,76 g of 27.2 mmol). The resulting mixture was heated to 50°C and stirred at this temperature for 90 min, then cooled, filtered and the filtrate concentrated in vacuo. The residue is purified flaming (flash) chromatography (silica gel, 5% ethyl acetate in dichloromethane)to give specified in the title compound as a white solid. MS (EI) 272 (M)+.

Example 6

Methyl 2-methyl-6-[3-(2-phenyloxazol-4-ylethoxy)phenoxy-methyl]benzoate

To a solution of 4-chloromethyl-2-phenyloxazole (100 mg, 0.5 mmol, example 19) in DMF (2 ml) is added methyl 2-methyl-6-[(3-hydroxyphenoxy)methyl]benzoate (136 mg, 0.5 mmol, example 5), and then To2CO3(75 mg, 0.54 mmol). The resulting mixture was heated to 60°C and stirred at this temperature for 8 hours. Then the mixture is cooled to room temperature, diluted with simple ether, washed with water and saturated salt solution, dried over MgSO4and concentrate. The remainder acisoutver-chromatography (silica gel, 20% ethyl acetate in hexane)to give specified in the header connection. MS (EPI) 429 (M+N)+.

The following connections will be received, using basically the same method used in example 6, except using the specified alkylhalogenide instead of 4-chloromethyl-2-phenyloxazole with either methyl (ethyl or isobutyl)-2-methyl-6-[(3-hydroxyphenoxy)methyl]benzoate (example 5).

Example 6A

Methyl 2-methyl-6[3-(2-phenylthiazol-4-ylethoxy)phenoxy-methyl]benzoate

MS (EPI) 446 (M+N)+. Obtained from 4-chloromethyl-2-phenyl-thiazole (example 20).

Example 6b

Methyl 2-[3-(3,5-dimethylisoxazol-4-ylethoxy)phenoxy-methyl]-6-methylbenzoate

MS (EPI) 382 (M+N)+. Obtained from 3,5-dimethylisoxazol-4-iletileri.

Example 6C

Methyl 2-methyl-6-[3-(5-phenyl[1,2,4]oxadiazol-3-ylethoxy)phenoxymethyl]benzoate

MS (EPI) 431 (M+H)+. Obtained from 5-phenyl[1,1,4]oxa-diazol-3-iletileri.

Example 6d

Methyl 2-[3-(2,5-dimethylbenzylamine)phenoxymethyl]-6-methylbenzoate

MS (EPI) 391 (M+N)+. Obtained from 2,5-dimethylbenzyl-chloride.

Example 6E

Methyl 2-[3-(2,4-dichloraniline)phenoxymethyl]-6-methylbenzoate

MS (EPI) 431 (M+N, the structure responsible Cl2)+. Derived from 2,4-dichlorobenzaldehyde.

Example 6f

Methyl 2-[3-(5-tert-butyl[1,2,4]oxadiazol-3-ylethoxy)-phenoxymethyl]-6-methylbenzoate

MS (EPI) 411 (M+N)+. Obtained from 5-tert-butyl-[1,,4]oxadiazol-3-iletileri.

Example 6g

Methyl 2-{3-[3-(2,6-dichlorophenyl)-5-methylisoxazol-4-ylethoxy]phenoxymethyl}-6-methylbenzoic

MS (EPI) 512 (M+N)+. Obtained from (3-(2,6-dichlorophenyl)-5-methylisoxazol-4-yl)methyl chloride.

Example 6h

Methyl 2-methyl-6-[3-(2,4,5-trimethylaniline)phenoxy-methyl]benzoate

MS (EI) 405 (M+N)+. Derived from 2,4,5-trimethylbenzaldehyde.

Example 6i

Methyl 2-methyl-6-[3-(3-methylnaphthalene-2-ylethoxy)-phenoxymethyl]benzoate

MS (EPI) 427 (M+N)+. Obtained from (3-methylnaphthalene-2-yl)methyl bromide.

Example 6j

Methyl 2-[3-(5-acetyl-2-methoxybenzyloxy)phenoxymethyl]-6-methylbenzoate

MS (EPI) 435 (M+N)+. Obtained from 5-acetyl-2-methoxy-benzylchloride.

Example 6k

Methyl 2-[3-(6-ftorhinolon-2-ylethoxy)phenoxymethyl]-6-methylbenzoate

MS (EPI) 432 (M+N)+. Obtained from 6-ftorhinolon-2-ylmethyl-bromide (example 27b).

Example 6l

Methyl 2[3-(4-tert-butylbenzoate)phenoxymethyl]-6-methylbenzoate

MS (EPI) 419 (M+N)+. Obtained from 4-(tert-butyl) benzylbromide.

Example 6m

Methyl 2-[3-(4-isopropylbenzylamine)phenoxymethyl]-6-methylbenzoate

MS (EPI) 405 (M+N)+. Obtained from 4-isopropylbenzyl-chloride.

Example 6n

Methyl 2-methyl-6-[3-(3-phenoxybenzyl)phenoxymethyl]-benzoate

MS (EPI) 455 (M+N)+. Obtained from 3-phenoxybenzaldehyde.

Example 6o

Methyl 2[3-(4-tert-butylcyclohexylamine)phenoxymethyl]-6-m is Telesot

MS 425 (M+N)+. Obtained from 4-tert-butylcyclohexylamine-bromide (example 29A).

Example 6

Methyl 2-methyl-6-[3-(quinoline-2-ylethoxy)phenoxymethyl]-benzoate

MS 415 (M+N)+. Obtained from cinoxacin-2-iletileri (See Chem. Ber. 1987, 120, 649-651).

Example 6q

Methyl 2-methyl-6-[3-(2-methylbenzylamino)phenoxymethyl]-benzoate

MS 377 (M+N)+. Retrieved from α-bromo-o-xylene.

Example 6r

Methyl 2-methyl-6-{3-[2-(5-methylthiophene-2-yl)oxazol-4-ylethoxy]phenoxymethyl}benzoate

MS (EPI) 450 (M+N)+. Obtained from 2-(5-methylthiophene-2-yl) oxazol-4-iletileri (example 19a).

Example 6s

Methyl 2-[3-(2-cyclohexyloxy-4-ylethoxy)phenoxy-methyl]-6-methylbenzoate

MS (EPI) 436 (M+N)+. Obtained from 2-cyclohexyloxy-4-iletileri (example 19b).

Example 6t

Methyl 2-{3-[2-(3-forfinal)oxazol-4-ylethoxy]phenoxy-methyl}-6-methylbenzoic

MS (EPI) 448 (M+N)+. Obtained from 2-(3-fluoro-phenyl)oxazol-4-iletileri (example 19 (C)).

Example 6u

Methyl 2-{3-[2-(4-forfinal)oxazol-4-ylethoxy]phenoxy-methyl}-6-methylbenzoic

MS (EPI) 448 (M+N)+. Obtained from 2-(4-forfinal)oxazol-4-iletileri (example 19d).

Example 6v

Ethyl 2-[3-(6-chloropyridin-2-ylethoxy)phenoxymethyl]-6-methylbenzoate

MS (EPI) 412, 414 (M+N)+the structure complying with Cl. Obtained from 2-chloromethyl-6-chloropyridine (example 27C).

Example 6w

Ethyl 2-methyl-6-[3-(5-what ethyl-2-phenyloxazol-4-ylethoxy)-phenoxymethyl]benzoate

MS (EPI) 458 (M+N)+. Obtained from 4-chloromethyl-5-methyl-2-phenyloxazole.

Example 6x

Methyl 2-(3-benzyloxyphenyl)-6-methylbenzoate

MS (EI) 362 (M)+. Obtained from benzylbromide.

Example 6y

Methyl 2-methyl-6-[3-(pyridine-2-ylethoxy)phenoxymethyl]-benzoate.

Obtained from 2-chloromethylpyridine.

Example 6z

Methyl 2-[3-(7-chlorhydrin-2-ylethoxy)phenoxymethyl]-6-methylbenzoate

MS (EPI) 447 (M+N)+the structure complying with Cl. Obtained from 7-chlorhydrin-2-ylmethylboronic (example 46a).

Example a

Methyl 2-[3-(6-methoxyquinoline-2-ylethoxy)phenoxymethyl]-6-methylbenzoate

MS (EPI) 443 (M+N)+. Obtained from 6-methoxyquinoline-2-ylmethylboronic (example 46b).

Example 6b

Ethyl 2-[3-(2,4-aminobutiramida 5-methylbenzoate)phenoxymethyl]-6-methylbenzoate

1H NMR (300 MHz, CDCl3) δ 7,14 (m, 6N), 6,62 (m, 3H), 5,10 (s, 2H), 5,00 (s, 2H), 4,32 (m, 2H), 3,20 (m, 1H), 2,86 (m, 1H), 2.40 a (CL, 6N), of 1.28 (m, 15 NM). MS (EI) 484 (M)+. Obtained from 1-chloromethyl-2,4-aminobutiramida 5-methylbenzene.

Example 6 ° C

Ethyl 2-[3-(2,4-bis-triftormetilfosfinov)phenoxymethyl]-6-methylbenzoate

1H NMR (300 MHz, CDCl3) δ a 7.92 (m, 2H), 7,82 (m, 1H), 7,30 (m, 2H), 7,18 (m, 2H), to 6.57 (m, 3H), from 5.29 (s, 2H), 5,10 (s, 2H), or 4.31 (q, 2H), 2,39 (s, 3H), of 1.29 (t, 3H). MS (EI) 512 (M)+. Derived from 2,4-bis(trifluoromethyl)benzylbromide.

Example 6ad

Ethyl 2-[3-(biphenyl-4-ylethoxy)phenoxymethyl]-6-methylbenzoate

1H NMR(300 MHz, CDCl3) δ of 7.60 (m, 4H), 7,40 (m, 7H), 7,18 (m, 2H), return of 6.58 (m, 3H), 5,09 (s, 2H), 5,07 (s, 2H), 4,30 (kV, 2H), 2,39 (s, 3H), of 1.28 (t, 3H). MS (EI) 452 (M)+. Obtained from 4-phenylbenzoate.

Example AE

Ethyl 2-methyl-6-[3-(naphthalene-1-ylethoxy)phenoxymethyl]-benzoate

1H NMR (300 MHz, CDCl3) δ 8,04 (m, 1H), 7,88 (m, 2H), 7,52 (m, 4H), from 7.24 (m, 4H), to 6.67 (m, 2H), 6,59 (m, 1H), 5,46 (s, 2H), 5,10 (s, 2H), 4,30 (K, 2N), 2,39 (s, 3H), of 1.28 (t, 3H). MS (EI) 426 (M)+. Obtained from 1-chloromethylketone.

Example 6af

Methyl 2-[3-(5-ethylpyridine-2-ylethoxy)phenoxymethyl]-6-methylbenzoate

1H NMR (300 MHz, CDCl3) δ 8,44 (SHS, 1H), 7,54 (DD, 1H), 7,42 (d, 1H), 7,32 (m, 2H), 7,17 (m, 2H), return of 6.58 (m, 2H), further 5.15 (s, 2H), to 5.08 (s, 2H), 3,82 (s, 3H), 2,67 (K, 2N), of 2.38 (s, 3H), of 1.26 (t, 3H). MS (EPI) 392 (M+N)+. Obtained from 5-ethyl-2-chloromethylpyridine (example 68).

Example ad

Methyl 2-[3-(4-ethylbenzylamine)phenoxymethyl]-6-methylbenzoate

1H NMR (300 MHz, CDCl3) δ 7,28 (m, 8H), to 6.58 (m, 3H), 5,08 (d, 2H), 5,00 (d, 2H), 3,81 (d, 3H), 2,68 (m, 2H), of 2.38 (s, 3H), 1,24 (m, 3H). MS (EI) 390 (M)+. Obtained from 1-chlormethyl-4-ethylbenzene.

Example 6ah

Methyl 2[3-(3-bromobenzylamine)phenoxymethyl]-6-methylbenzoate

1H NMR (300 MHz, CDCl3) δ 7,58 (s, 1H), 7,44 (d, 1H), 7,25 (m, 6N), to 6.57 (m, 3H), to 5.08 (s, 2H), 5,00 (s, 2H), 3,81 (s, 3H), of 2.38 (s, 3H). MS (EI) 440 (M)+. Obtained from 3-bromobenzylamine.

Example 6ai

Ethyl-2-methyl-6-[3-(quinoline-2-ylethoxy)phenylethynyl]-benzoate

Specified in the header of the connection get is using, basically, the same method used in example 6, except using ethyl 2-(3-hydroxyphenylethyl)-6-methylbenzoate (example 15C) instead of methyl 2-methyl-6-[(3-hydroxyphenoxy)methyl]benzoate and 2-chloromethylpyridine instead of 4-chloromethyl-2-phenyloxazole. MS (EPI) 422 (M+N)+.

Example 6aj

Methyl 2-methyl-6-[3-(5-vinylpyridin-2-metoxy)phenoxy-methyl]benzoate

MS (EPI) 440 (M+N)+. Obtained from 5-vinylpyridin-2-iletileri (example 27g).

Example 6ak

Methyl 2-[3-(2-chlorobenzoyloxy)phenoxymethyl]-6-methylbenzoate

1H NMR (300 MHz, CDCl3) δ at 7.55 (m, 1H), 7,40 (m, 1H), 7,30 (m, 4H), 7,20 (m, 2H), 6,60 (m, 3H), 5,14 (s, 2H), 5,09 (s, 2H), 3,82 (s, 3H), of 2.38 (s, 3H). MS (EI) 396 (M)+the structure complying with Cl. Obtained from 2-chlorobenzylchloride.

Example 6l

Methyl 2-[3-(4-chlorobenzoyloxy)phenoxymethyl]-6-methylbenzoate

1H NMR (300 MHz, CDCl3) δ 7,32 (m, 6N), 7,18 (m, 2H), 6,56 (m, 3H), to 5.08 (s, 2H), 5,00 (s, 2H), 3,81 (s, 3H), of 2.38 (s, 3H). MS (EI) 396 (M+), the structure complying with Cl. Obtained from 4-chlorobenzylchloride.

Example 6am

Methyl ester of 2-methyl-6-[3-(3-methylphenoxy-2-ylethoxy)phenoxymethyl]benzoic acid

MS (EPI) 429 (M+N)+. Obtained from 2-methyl-3-chloromethyl-finokalia (See Chem. Ber. 1987, 120, 649).

Example 6an

Methyl ester of 2-methyl-6-[3-(naphthalene-2-ylethoxy)-phenoxymethyl]benzoic acid

MS (EI) 412 (M)+.

Example 7

2-Methyl-6-[3-(quinoline-2-ilma is hydroxy)phenoxymethyl]benzoic acid

A solution of methyl 2-methyl-6-[3-(quinoline-2-ylethoxy)phenoxymethyl]benzoate (1.6 g, 3.8 mmol, example 4) in ethanol (25 ml) is heated with 10 N. solution of sodium hydroxide (4.0 ml, 40 mmol) at 70°C for 14 h, the Reaction mixture is cooled, neutralized 2 N. HCl solution (20 ml) and concentrated by removing the ethanol. Add ethyl acetate and washed with water. The aqueous layer was saturated with sodium chloride and re-extracted with ethyl acetate. The organic layers are combined, dried over magnesium sulfate, filtered and concentrated, obtaining the crude solid. The solid is purified column chromatography (silica gel, 5% to 10% methanol in dichloromethane)to give specified in the header connection. Analytically pure sample is obtained by recrystallization from methanol: TPL 167-168°,1H NMR (300 MHz, CDCl3) δ 5,15 (d, 2H), 7,80 (d, 1H), 7,71 (t, 1H), to 7.61-7,51 (m, 2H), 7,26-7,10 (m, 3H), of 7.00 (t, 1H), 6,66 (s, 1H), of 6.52 (d, 1H), 6,46 (d, 1H), 5,26 (s, 2H), further 5.15 (s, 2H), 2,44 (s, 3H); MS (EPI) 400 (M+N)+.

Alternative a number of conditions that can be used for hydrolysis properties of ester is heated with 0.1 M solution of ester in a mixture of THF (THF)/methanol (1:1) with 10 equivalents of sodium hydroxide solution (10 BC) at 60°C for 3 hours or until the starting material disappears, as monitored by TLC (TLC) analysis.

The following connections get using mainly the same technique as in example 7, except using the specified complex ester instead of methyl 2-methyl-6-[3-(quinoline-2-ylethoxy)phenoxymethyl]benzoate.

Example 7a

2-Methyl-6-[3-(2-quinoline-2-elwenil)phenoxymethyl]-benzoic acid

1H NMR (300 MHz, DMSO) d 8,87 (sm, 1H), 8,14-at 8.36 (m, 4H), 8,00 (t, 1H), 7,81 (d, 1H), 7,71 (m, 1H), 7,34-of 7.48 (m, 5H), 7,29 (sm, 1H), was 7.08 (m, 1H), 5,22 (s, 2H), 2,35 (s, 3H). MS (EPI) 396 (M+N)+. Obtained from methyl {2-methyl-6-[3-(2-quinoline-2-elwenil)phenoxymethyl]benzoate (example 4A).

Example 7b

2-Methyl-6-{3-[2-(pyridine-2-yloxy)ethoxy]phenoxymethyl}-benzoic acid

1H NMR (300 MHz, DMSO) d 8,17 (d, 1H), 7,71 (m, 1H), 7,22 (d, 1H),? 7.04 baby mortality-7,19 (m, 3H), of 6.99 (DD, 1H), 6,86 (d, 1H), 6,55 (m, 3H), 5,13 (s, 2H), 4.53-in (CL, 2H), 4,28 (CL, 2H), 2,25 (CL, 3H). MS (EPI) 380 (M+N)+. Obtained from methyl (2-methyl-6-{3-[2-(pyridine-2-yloxy)ethoxy]phenoxymethyl})-benzoate (example 4b).

Example 7C

2-{3-[(Benzoxazol-2-ylmethylamino)methyl]phenoxymethyl}-6-methylbenzoic acid

1H NMR (300 MHz, CDCl3) δ 7,27 (sm, 1H), 7,07 of 7.3 (m, 5H), 7,03 (t, 1H), to 6.80 (m, 3H), 5,10 (CL, 2H), br4.61 (CL, 2H), 3,03 (s, 3H), 2,38 (CL, 3H). MS (EPI) 403 (M+N)+. Obtained from methyl 2-{3-[(benzoxazol-2-ylmethylamino)methyl]-phenoxymethyl}-6-methylbenzoate (example 4C).

Example 7d

2-Methyl-6-{3-[(medicinalis-2-ylamino)methyl]phenoxymethyl}benzoic acid

1H NMR (300 MHz, CDCl3) δ of 8.09 (d, 1H), 7,74 (d, 1H), 7,50 (m, 3H), 7,20 (m, 4H), 6,85 (m, 3H), of 6.65 (d, 1H), 5,20 (s, 2H), and 4.75 (s,2H), 3,29 (s, 3H), of 2.05 (s, 3H). MS (EPI) 413 (M+N)+. Obtained from methyl 2-methyl-6-{3-[(medicinalis-2-ylamino)methyl]phenoxymethyl}benzoate (example 4d).

Example 7E

2-Methyl-6-[3-(2-phenyloxazol-4-ylethoxy)phenoxymethyl]-benzoic acid

1H NMR (300 MHz, DMSO) δ 8,30 (s, 1H), 8,00 (m, 2H), 7,55 (m, 3H), 7,30 (m, 2H), 7,22 (m, 2H), 6,66 (m, 2H), 6,60 (d, 1H), 5,10 (s, 2H), is 5.06 (s, 2H), 2,34 (s, 3H). MS (EPI) 416 (M+N)+. Obtained from methyl 2-methyl-6-[3-(2-phenyloxazol-4-ylethoxy)phenoxymethyl]benzoate (example 6).

Example 7f

2-Methyl-6-[3-(2-phenylthiazol-4-ylethoxy)phenoxymethyl]-benzoic acid

1H NMR (300 MHz, CDCl3) δ to 7.95 (m, 2H), 7,43 (m, 3H), 1,32 (m, 2H), 7,24 (d, 1H), 7,20 (m, 1H), 7,14 (t, 1H), 6,66 (m, 1H), 6,56 (m, 1H), 5,20 (s, 2H), further 5.15 (s, 2H), 2,41 (s, 3H). MS (EPI) 432 (M+N)+. Obtained from methyl 2-methyl-6-[3-{2-phenylthiazol-4-ylethoxy)phenoxymethyl]benzoate (example 6A).

Example 7g

2-[3-(3,5-Dimethylisoxazol-4-ylethoxy)phenoxymethyl]-6-methylbenzoic acid

1H NMR (300 MHz, CDCl3) δ 7,34 (m, 2H), 7,20 (m, 1H), 7,15 (t, 1H), 6,56 (m, 3H), 5,19 (s, 2H), 4,71 (s, 2H), 2,43 (s, 3H), of 2.34 (s, 3H), 2,22 (s, 3H). MS (EPI) 368 (M+N)+. Obtained from methyl 2-[3-(3,5-dimethylisoxazol-4-ylethoxy)-phenoxymethyl]-6-methylbenzoate (example 6b).

Example 7h

2-Methyl-6-[3-(5-phenyl-[1,2,4]oxadiazol-3-ylethoxy)-phenoxymethyl]benzoic acid

1H NMR (300 MHz, CDCl3) δ 8,15 (m, 2H), to 7.59 (m, 1H), 7,50 (m, 2H), 7,33 (m, 2H), 7,20 (m, 1H), 7,14 (t, 1H), 6,70 (m, 1H), 6,61 (m,2H), 5,19 (s, 2H), 2,44 (s, 3H). MS (EPI) 417 (M+N)+. Obtained from methyl 2-methyl-6-[3-(5-phenyl-[1,2,4]oxadiazol-3-ylethoxy)phenoxymethyl]benzoate (example 6C).

Example 7i

2-[3-(2,5-Dimethylbenzylamine)phenoxymethyl]-6-methylbenzoic acid

1H NMR (300 MHz, CDCl3) δ 7,35 (m, 2H), 7,13-7,24 (m, 3H), to 7.09 (d, 1H),? 7.04 baby mortality (d, 1H), 6,60 (m, 3H), of 5.17 (s, 2H), 4,90 (s, 2H), 2,44 (s, 3H), of 2.30 (s, 3H), and 2.26 (s, 3H).

MS (EPI) 375 (M-N)+. Obtained from methyl 2-[3-(2,5-dimethylbenzylamine)phenoxymethyl]-6-methylbenzoate (example 6d).

Example 7j

2-[3-(2,4-Dichloraniline)phenoxymethyl]-6-methylbenzoic acid

1H NMR (300 MHz, CDCl3) δ 7,40 (m, 2H), 7,34 (m, 2H), 7,24 (m, 2H), 7,17 (t, 1H), 6,59 (m, 3H), 5,19 (s, 2H), to 5.03 (s, 2H), of 2.45 (s, 3H). MS (EPI) 415 (M-H, structure, corresponding Cl2. Obtained from methyl 2-[3-(2,4-dichloro-benzyloxy)phenoxymethyl]-6-methylbenzoate (example 6E).

Example 7k

2-[3-(5-tert-Butyl[1,2,4]oxadiazol-3-ylethoxy)-phenoxymethyl]-6-methylbenzoic acid

1H NMR (300 MHz, CDCl3) δ 7,32 (m, 2H), 7,19 (m, 1H), 7,15 (t, 1H), 6,66 (d, 1H), 6,60 (d, 1H), 6,59 (d/ 1H), 5,17 (s, 2H), 5,10 (s, 2H), 1,45 (s, N). MS (EPI) 395 (M-N)-. Obtained from methyl 2-[3-(5-tert-butyl[1,2,4]oxadiazol-3-ylethoxy)phenoxymethyl]-6-methylbenzoate (example 6f).

Example 7l

2-{3-[3-(2,6-Dichlorophenyl)-5-methylisoxazol-4-ylethoxy]phenoxymethyl}-6-methylbenzoic acid

1H NMR (300 MHz, CDCl3) δ 7,24-7,41 (m, 5H), 7,21 (m, 1H), was 7.08 (t, 1H), 6,53 (m, 1H), 6,40 (m, 2H), 511 (, 2H)and 4.65 (s, 2H), 2,48 (s, 3H), 2,41 (s, 3H). MS (EPI) 496 (M-N)-. Obtained from methyl 2-{3-[3-(2,6-dichlorophenyl)-5-methyl-isoxazol-4-ylethoxy]phenoxymethyl}-6-methylbenzoate (example 6g).

Example 7m

2-Methyl-6-[3-(2,4,5-trimethylaniline)phenoxymethyl]-benzoic acid

1H NMR (300 MHz, CDCl3) δ 7,35 (m, 2H), 7,20 (m, 1H), 7,15 (t, 1H), 7,10 (s, 1H), 6,97 (s, 1H), 6,60 (m, 3H), 5,16 (s, 2H), to 4.87 (s, 2H), 2,42 (s, 3H), of 2.25 (s, 3H), of 2.21 (s, 3H), of 2.20 (s, 3H). MS (EPI) 389 (M-N)-. Obtained from methyl 2-methyl-6-[3-(2,4,5-trimethylaniline)phenoxymethyl]benzoate (example 6h).

Example 7n

2-Methyl-6-[3-(Z-methylnaphthalene-2-ylethoxy)phenoxymethyl]-benzoic acid

1H NMR (300 MHz, CDCl3) δ to 7.77 (m, 3H), of 7.64 (s, 1H), 7,41 (m, 2H), 7,33 (m, 2H), 7,19 (m, 2H), is 6.61 (m, 3H), of 5.17 (s, 2H), 5,09 (s, 2H), 2,47 (s, 3H), 2,43 (s, 3H). MS (EPI) 411 (M-N)-. Obtained from methyl 2-methyl-6-[3-(3-methylnaphthalene-2-ylethoxy) phenoxymethyl] benzoate (example 6i).

Example a

2-[3-(5-Acetyl-2-methoxybenzyloxy)phenoxymethyl]-6-methylbenzoic acid

1H NMR (300 MHz, CDCl3) δ 8,05 (SHS, 1H), 7,93 (sm, 1H), 7,33 (m, 2H), 7,20 (m, 1H), 7,13 (t, 1H), 6,91 (d, 1H), 6,60 (m, 3H), 5,16 (s, 2H), to 5.03 (s, 2H), with 3.89 (s, 3H), of 2.53 (s, 3H), 2,43 (s, 3H). MS (EPI) 419 (M-N)-. Obtained from methyl 2-[3-(5-acetyl-2-methoxybenzyloxy)phenoxymethyl]-6-methylbenzoate (example 6j).

Example 7đ

2-[3-(6-Ftorhinolon-2-ylethoxy)phenoxymethyl]-6-methylbenzoic acid

so 153-154°C.1H NMR (300 MHz, CDCl3): B4; to 8.12 (m, 2H), to 7.61 (d, 1H), 7,43 (m, 2H), 7,28 (m, 2H), 7,17 (m, 1H), 7,05 (m, 1H), 6,66 (s, 1H), 6,51 (m, 2H), 5,26 (s, 2H), 5,14 (s, 2H), of 2.45 (s, 3H). MS (EPI) 418 (M+N)+. Obtained from methyl 2-[3-(6-ftorhinolon-2-ylethoxy)phenoxymethyl]-6-methylbenzoate (example 6k).

Example 7q

2-[3-(4-tert-Butylbenzoate)phenoxymethyl]-6-methylbenzoic acid

TPL 122-123°C.1H NMR (300 MHz, CDCl3) δ 7,41-7,28 (m, 5H), 7.23 percent for 7.12 (m, 3H), 6,61-6,55 (m, 3H), 5,16 (s, 2H), 4.95 points (s, 2H), of 2.45 (s, 3H), 1,32 (s, N). MS (EPI) 405 (M+N)+. Obtained from methyl 2-[3-(4-tert-butylbenzoate)phenoxymethyl]-6-methylbenzoate (example 61).

Example 7r

2-[3-(4-Isopropylbenzylamine)phenoxymethyl]-6-methylbenzoic acid

TPL 132-133°C.1H NMR (300 MHz, CDCl3): δ 7,35 (m, 5H), 7,22 (m, 2H), 7,17 (m, 1H), return of 6.58 (m, 3H), of 5.15 (s, 2H), equal to 4.97 (s, 2H), 2,92 (m, 1H), 2,46 (s, 3H), 1,25 (d, 6N). MS (EPI) 391 (M+N)+. Poluchena of methyl 2-[3-(4-isopropyl-benzyloxy)phenoxymethyl]-6-methylbenzoate (example 6m).

Example 7s

2-Methyl-6-[3-(3-phenoxybenzyl)phenoxymethyl]benzoic acid

1H NMR (300 MHz, CDCl3): δ 7,31 (m, 5H), to 7.15 (m, 1H), 7,12-6,98 (m, 6N), 6,93 (m, 1H), 6,54 (m, 3H), 5,13 (s, 2H), 4,94 (s, 2H), 2,43 (s, 3H). MS (EPI) 441 (M+N)+. Obtained from methyl 2-methyl-6-[3-(3-phenoxybenzyl)phenoxymethyl]benzoate (example 6n).

Example 7t

2-[3-(4-tert-Butylcyclohexylamine)phenoxymethyl]-6-methylbenzoic acid

1H NMR (300 MHz, CDCl3): δ 7,34 (m, 2H), 7,21 (m, 1H), 7,12 (m, 1H), 6,50 (m, 3H) 5,16 (s, 2N), to 3.67 (d, 2H), of 2.45 (s, 3H), 1,92 is 1.75 (m, 4H), of 1.64 (m, 2H), and 0.98 (m, 4H), 0,84 (s, N). MS 411 (M+N)+. Obtained from methyl 2-[3-(4-tert-butylcyclohexylamine)phenoxymethyl]-6-methylbenzoate (example 6o).

Example 7u

2-Methyl-6-[3-(hicklin-2-ylethoxy)phenoxymethyl]-benzoic acid

TPL 57-60°C.1H NMR (300 MHz, CDCl3): δ 8,96 (s, 1H), 8,08 (m, 2H), 7,74 (m, 2H), 7,24 (m, 2H), 7,12 (m, 1H), 7,00 (m, 1H), only 6.64 (s, 1H), of 6.49 (m, 2H), 5,24 (s, 2H), 5,14 (s, 2H), 2,39 (s, 3H). MS 401 (M+N)+. Obtained from methyl 2-methyl-6-[3-(cinoxacin-2-ylethoxy)phenoxymethyl]benzoate(example 6).

Example 7v

2-Methyl-6-[3-(2-methylbenzylamino)phenoxymethyl]benzoic acid

1H NMR (300 MHz, CDCl3): δ 7,35 (m, 3H), 7,20 (m, 5H), 6,59 (m, 3H), of 5.17 (s, 2H), 4.95 points (s, 2H), 2,44 (s, 3H), 2,32 (s, 3H). MS(APcI) 385 (M+H+Na)+. Obtained from methyl 2-methyl-6-[3-(2-methylbenzylamino)phenoxymethyl]benzoate (example 6q).

Example 7w

2-Methyl-6-{3-[2-(5-methylthiophene-2-yl)oxazol-4-ylethoxy]phenoxymethyl}benzoic acid

TPL 129-130°C.1H NMR (300 MHz, CDCl3): δ 7,54 (s, 1H), of 7.48 (d, 1H), 7,27 (m, 2H), 7,11 (m, 2H), 6,74 (m, 1H), 6,66 (s, 1H), 6,53 (m, 2H), 5,12 (s, 2H), 4.95 points (s, 2H), of 2.51 (s, 3H), 2,39 (s, 3H). MS (EPI) 436 (M+N)+. Obtained from methyl 2-methyl-6-{3-[2-(5-methylthiophene-2-yl)oxazol-4-ylethoxy]-phenoxymethyl}benzoate (example 6r).

Example 7

2-[3-(2-Cyclohexyloxy-4-ylethoxy)phenoxymethyl]-6-methylbenzoic acid

TPL 158-159°C.1H NMR (300 MHz, CDCl3): δEUR 7.57 (s, 1H), 7,30 (m, 2H), 7,20 (m, 1H), 7,12 (m, 1H), 6,72 (m, 1H), 6,53 (m, 2H), 5,13 (s, 2H), 4.95 points (s, 2H), 2,84 (m, 1H), of 2.45 (s, 3H), of 2.06 (m, 2H), is 1.81 (m, 2H), 1,73-1,20 (m, 6N). Obtained from methyl 2-[3-(2-cyclohexyloxy-4-ylethoxy)-phenoxymethyl]-6-methylbenzoate (example 6s).

Example 7y

2-{3-[2-(3-Forfinal)oxazol-4-ylethoxy]phenoxymethyl}-6-methylbenzoic acid

TPL 152-154°C.1H NMR (300 MHz, 5:1 CDCl3:CD3OD): δ to 7.84 (d, 1H), 7,80(c, 1H), 7,74 (d, 1H), 7,46 (m, 1H), 7,31 (m, 2H), 7,19 (m, 3H), only 6.64 (m, 3H), of 5.17 (s, 2H), 5,04 (s, 2H), 2,44 (s, 3H). MS (EPI) 434 (M+N)+. Obtained from methyl 2-{3-[2-(3-forfinal)oxazol-4-ylethoxy]phenoxymethyl}-6-methylbenzoate (example 6t).

Example 7z

2-{3-[2-(4-Forfinal)oxazol-4-ylethoxy]phenoxymethyl}-6-methylbenzoic acid

TPL 159-160°C.1H NMR (300 MHz, CDCl3): δ 8,03 (m, 2H), of 7.70 (s, 1H), 7,32 (d, 2H), 7,16 (m, 3H), 6,93 (m, 1H), 6,69 (m, 1H), 6,55 (m, 2H), 5,16 (s, 2H), to 5.03 (s, 2H), 2,44 (s, 3H). MS (EPI) 434 (M+N)+. Obtained from methyl 2-{3-[2-(4-forfinal)oxazol-4-ylethoxy]phenoxymethyl}-6-methylbenzoate (example 6u).

Example a

2-[3-(6-Chloropyridin-2-ylethoxy)phenoxymethyl]-6-methylbenzoic acid

TPL 97-98°C.1H NMR (300 MHz, 5:1 CDCl3:CD3OD): δ 7,73 (m, 1H), 7,47 (m, 1H), 7,28 (m, 3H), 7,16 (m, 2H), 6,60 (m, 3H), 5,16 (s, 2H), 5,12 (s, 2H), 2,42 (s, 3H). MS (EPI) 384, 386 (M+N)+the structure responsible C1. Obtained from ethyl 2-[3-(6-chloropyridin-2-ylethoxy)phenoxymethyl]-6-methylbenzoate (example 6v).

Example 7ab

2-Methyl-6-3-(5-methyl-2-phenyloxazol-4-ylethoxy)-phenoxymethyl]benzoic acid

TPL 144-145°C.1H NMR (300 MHz, 3:1 CDCl3:CD3OD): δ 7,99 (m, 2H), 7,42 (m, 3H), 7,30 (m, 2H), 7,19 (m, 2H), 6,63 (m, 3H), of 5.17 (s, 2H), 4.95 points (s, 2H), of 2.45 (s, 3H), 2,43 (s, 3H). MS (EPI) 430 (M+N)+. Obtained from ethyl 2-methyl-6-[3-(5-methyl-2-phenyloxazol-4-ylethoxy)phenoxymethyl]benzoate (example 6w).

Example as

2-(3-Benzyloxyphenyl)-6-methylbenzoic acid

1H NMR (300 MHz, CD3OD) d 7,40-7,19 (m, 8H), 7,14 (t, 1H), 6,61-6,51 (m, 3H), 5,07 (s, 2H), to 5.03 (s, 2H), 2.40 a (s, 3H); MS (EI) 348 (M)+. Obtained from methyl 2-(3-benzyloxy-phenoxymethyl)-6-methylbenzoate (example 6).

Example 7ad

2-Methyl-6-[3-(pyridine-2-ylethoxy)phenoxymethyl]benzoic acid

1H NMR (300 MHz, CD3OD) d 8,53 (d, 1H), 7,87 (t, 1H), 7,60 (d, 1H), 7,37-7,13 (m, 5H), 6,64-6,59 (m, 3H), 5,15 (d, 4H), 2.40 a (s, 3H); MS (EPI) 350 (M+N)+. Obtained from methyl 2-methyl-6-[3-(pyridine-2-ylethoxy)phenoxymethyl]benzoate (example 6y).

Example AE

2-[3-(7-Chlorhydrin-2-ylethoxy)phenoxymethyl]-6-methyl-benzoic acid

TPL 188-193°;1H NMR (300 MHz, DMSO-d6d of 8.47 (d, 1H), of 8.09 (s, 1H), 8,08 (d, 1H), 7,69 (DD, 2H), 7,29-7,14 (m, 4H), 6,68-6,56 (m, 3H), of 5.34 (s, 2H), 5,10 (s, 2H), 2,31 (s, 3H); MS (EPI) 434, 436 (M+H; Cl)+. Obtained from methyl 2-[3-(7-chlorhydrin-2-ylethoxy)phenoxymethyl]-6-methylbenzoate (example 4bc).

Example 7af

2-[3-(6-Methoxyquinoline-2-ylethoxy)phenoxymethyl]-6-methylbenzoic acid

TPL 176-179°;1H NMR (300 MHz, DMSO-d6d 8,29 (d, 1H), to $ 7.91 (d, 1H), ,60 (d, 1H), 7,42-7,39 (m, 2H), 7,28-7,14 (m, 4H), 6,67-6,55 (m, 3H), at 5.27 (s, 2H), 5,09 (s, 2H), 3,90 (s, 3H), 2,31 (s, 3H); MS (EPI) 430 (M+H)+. Obtained from methyl 2-[3-(6-methoxyquinoline-2-ylethoxy)phenoxymethyl]-6-methylbenzoate (example a).

Example ad

2-Methyl-6-[3-(quinoline-2-intoximeter)phenoxymethyl]-benzoic acid

TPL 68-72°;1H NMR (300 MHz, DMSO-d6d of 8.25 (d, 1H), 7,88 (d, 1H), 7,78 (d, 1H), to 7.67 (DD, 1H), 7,43 (DD, 1H), 7,30-7,05 (m, 7H), 6.89 in (d, 1H), the 5.45 (s, 2H), 5,11 (s, 2H), 2,30 (s, 3H); MS (EPI) 400 (M+N)+. Derived from isobutyl 2-methyl-6-[3-(quinoline-2-intoximeter)phenoxymethyl]benzoate (example 4E).

Example 7ah

2-Methyl-6-[3-(quinoline-2-ylethoxy)benzoyloxymethyl]-benzoic acid

TPL 39-65°;1H NMR (300 MHz, CDCl3) δ 8,44 (d, 1H), compared to 8.26 (d, 1H), 7,85 to 7.75 (m, 3H), to 7.59 (DD, 1H), 7,38 (s, 1H), 7.23 percent (OSS, 2H), 7,15-7,10 (m, 2H), to 6.88 (DD, 1H), of 6.71 (d, 1H), 5,59 (s, 2H), 4,67 (s, 2H), of 4.44 (s, 2H), 2,64 (s, 3H); MS (EPI) 414 (M+N)+. Obtained from methyl 2-methyl-6-[3-(quinoline-2-ylethoxy)benzoyloxymethyl]benzoate (example 53).

Example 7ai

2-[3-(Quinoline-2-ylethoxy)benzyloxy]benzoic acid

TPL 149-154°;1H NMR (300 MHz, CDCl3) δ 8,19 (d, 1H), 8,15 (DD, 1H), 8,11 (d, 1H), 7,83 (DD, 1H), to 7.77-7,71 (m, 1H), 7,66 (d, 1H), 7,58-7,53 (m, 1H), 7,52-7,46 (m, 1H), 7,33 (t, 1H), 7.18 in-7,17 (m, 1H), 7,11 (t, 1H), 7,07-7,00 (m, 3H), 5,41 (s, 2H), 5,24 (s, 2H); MS (EPI) 386 (M+N)+. Obtained from methyl 2-[3-(quinoline-2-ylethoxy)benzyloxy]benzoate (example 60).

Example 7aj

3-Methoxy-2-[3-(quinoline-2-ylethoxy)benzyl) - Rev. XI]benzoic acid

1H NMR (300 MHz, CDCl3) δ to 8.20 (d, 1H), 8,10 (d, 1H), to 7.84 (d, 1H), 7,74 (t, 1H), 7,69-the 7.65 (m, 2H), 7,56 (t, 1H), 7,30 (m, 1H), 7,20 for 7.12 (m, 3H), 7,02 (d, 1H), 5,41 (s, 2H), with 5.22 (s, 2H), 3,93 (s, 3H); MS (EPI) 416 (M+H)+. Obtained from methyl 3-methoxy-2-[3-(quinoline-2-ylethoxy)benzyloxy]benzoate (example 60A).

Example 7ak

4-Methoxy-2-[3-(quinoline-2-ylethoxy)benzyloxy]benzoic acid

TPL 117-118°;1H NMR (300 MHz, CDCl3) δ to 8.20 (d, 1H), 8,14 (d, 1H), of 8.09 (d, 1H), 7,83 (d, 1H), 7,74 (DDD, 1H), 7,65 (d, 1H), 7,56 (DDD, 1H), 7,34 (t, 1H), 7,14-7,13 (m, 1H), 7,06-7,01 (m, 2H), only 6.64 (DD, 1H), 6,56 (d, 1H), 5,41 (s, 2H), to 5.21 (s, 2H), of 3.84 (s, 3H); MS (EPI) 416 (M+N)+. Obtained from methyl 4-Methoxy-2-[3-(quinoline-2-ylethoxy)-benzyloxy]benzoate (example 60b).

Example 7l

5-methoxy-2-[3-(quinoline-2-ylethoxy)benzyloxy]benzoic acid

TPL 248-249°;1H NMR (300 MHz, DMSO-d6d to 8.40 (d, 1H), 8,01 (t, 2H), 7,78 (t, 1H), 7,68 (d, 1H), to 7.61 (t, 1H), 7,28-7,21 (m, 2H),? 7.04 baby mortality (d, 1H), 6,94 (DD, 1H), 6,78-of 6.71 (m, 2H), 6,56 (DD, 1H), are 5.36 (s, 2H), to 4.98 (s, 2H), to 3.64 (s, 3H); MS (EPI) 416 (M+N)+. Obtained from methyl 5-methoxy-2-[3-(quinoline-2-ylethoxy)benzyloxy]benzoate (example 60C).

Example 7am

2-Methoxy-6-[3-(quinoline-2-ylethoxy)benzyloxy]benzoic acid

TPL 149-152°;1H NMR (300 MHz, CDCl3) δ a 8.34 (d, 1H), 8,16 (d, 1H), 7,80 (d, 1H), of 7.75 (DDD, 1H), 7,69 (d, 1H), 7,55 (t, 1H), 7,40 (S, 1H), 7,27 (t, 1H), 7,18 (t, 1H), 6,91-87 (m, 2H), 6,60 (d, 2H), of 5.45 (s, 2H), to 5.08 (s, 2H), 3,89 (s, 3H); MS (EPI) 416 (M+N)+. Obtained from methyl 2-methoxy-6-[(quinoline-2-ylethoxy)benzyloxy]benzoate (example 60d).

Example 7an

2-Methyl-6-[3-(quinoline-2-ylethoxy)benzyloxy]benzoic acid

TPL 154-156°,1H NMR (300 MHz, CD3OD) d of 8.37 (d, 1H), with 8.05 (d, 1H), 7,95(d, 1H), 7,81-7,71 (m, 2H), 7,63-to 7.59 (t, 1H), 7,31-to 7.15 (m, 3H), 7,06-6,97 (m, 2H), 6.87 in (d, 1H), PC 6.82 (d, 1H), to 5.35 (s, 2H), 5,12 (s, 2H), 2,31 (s, 3H); MS (EPI) 400 (M+N)+. Obtained from ethyl-2-methyl-6-[3-(quinoline-2-ylethoxy) benzyloxy]benzoate (example ' 60s).

Example a

5-[3-(Quinoline-2-ylethoxy)benzyloxy]nicotinic acid

1H NMR (300 MHz, CDCl3) δ of 8.90 (s, 1H), charged 8.52 (s, 1H), 8,19 (d, 1H), 8,12 (d, 1H), 7,87-of 7.70 (m, 4H), at 7.55 (t, 1H), 7,30 (m, 1H), 7,13 (s, 1H), 7,01 (t, 2H), 5,44 (s, 2H), 5,10 (s, 2H); MS (EPI) 387 (M+N)+. Obtained from methyl 5-[3-(quinoline-2-ylethoxy)benzyloxy]nicotinate (example 62).

Example ar

2-[3-(2,4-Aminobutiramida 5-methylbenzoate)phenoxymethyl]-6-methylbenzoic acid

1H NMR (300 MHz, CDCl3) δ 7,35 (m, 2H); was 7.08 (m, 4H); 6,60 (m, 3H); by 5.18 (s, 2H); to 4.98 (s, 2H); 3,19 (m, 1H); of 2.86 (m, 1H); of 2.44 (s, 3H); to 2.35 (s, 3H); 1,22 (m, N). MS (EI) 484 (M)+. Obtained from ethyl 2-[3-(2,4-aminobutiramida 5-methylbenzoate)phenoxymethyl]-6-methylbenzoate (example 6ab).

Example 7aq

2-[3-(2,4-bis-Triftormetilfosfinov)phenoxymethyl]-6-methylbenzoic acid

1H NMR (300 MHz, CDCl3) δ to $ 7.91 (s, 1H), 7,80 (m, 2H), 7,33 (d, 2H), 7,18 (m, 2H), 6,60 (m, 2H), of 6.52 (DD, 1H), 5,24 (S, 2H), 5,17 (s, 2H), of 2.45 (s, 3H). MS (EI) 484 (M)+. Obtained from ethyl 2-[3-(2,4-bis-triftormetilfosfinov)-phenoxymethyl]-6-methylbenzoate (example 6 is (C).

Example AG

2-[3-(Biphenyl-4-ylethoxy)phenoxymethyl]-6-methylbenzoic acid

1H NMR (300 MHz, CDCl3) δ 7,58 (m, 4H), 7,44 (m, 4H), 7,35 (m, 3H), 7,18 (m, 2H), 6,60 (m, 3H), of 5.17 (s, 2H), 5,02 (s, 2H), 2,44 (s, 3H). MS (EI) 424 (M+H)+. Obtained from ethyl 2-[3-(biphenyl-4-ylethoxy)phenoxymethyl]-6-methylbenzoate (example 6d).

Example 7as

2-Methyl-6-[3-(naphthalene-1-ylethoxy)phenoxymethyl]-benzoic acid

1H NMR (300 MHz, CDCl3) δ 8,00 (m, 1H), a 7.85 (m, 2H), 7,47 (m, 4H), 7,34 (m, 2H), 7,17 (m, 2H), 6,62 (m, 3H), of 5.40 (s, 2H), 5,16 (s, 2H), 2,43 (s, 3H). MS (EI) 398 (M)+. Obtained from ethyl 2-methyl-6-[3-(naphthalene-1-ylethoxy)phenoxymethyl]benzoate (example e).

Example 7at

2-[3-(5-Ethylpyridine-2-ylethoxy)phenoxymethyl]-6-methylbenzoic acid

1H NMR (300 MHz, DMSO) δ 8,42 (SHS, 1H), 7,65 (d, 1H), 7,39 (d, 1H), 6,63 (SHS, 1H), 6,56 (m, 2H), 2,60 (K, 2N), to 2.29 (s, 3H), of 1.21 (t, 3H). MS (EPI) 378 (M+N)+. Obtained from methyl 2-[3-(5-Ethylpyridine-2-ylethoxy)phenoxymethyl]-6-methylbenzoate (example 6af).

Example II

2-[3-(4-Ethylbenzylamine)phenoxymethyl]-6-methylbenzoic acid

1H NMR (300 MHz, DMSO) δ to 7.2 (m, 8H), and 6.6 (m, 3H), 5,13 (s, 2H), of 5.05 (d, 2H), 2,64 (m, 2H), 2,28 (s, 3H), of 1.17 (t, 3H). MS (EPI) 375 (M-N)-. Obtained from methyl 2-[3-(4-ethylbenzylamine)phenoxymethyl]-6-methylbenzoate (example ad).

Example 7av

2-[3-(3-Bromobenzylamine)phenoxymethyl]-6-methylbenzoic acid

1H NMR (300 MHz, DMSO) δ 7,62 (SHS, 1H), 7,50 (d, 1H), 7,42 (d, 1H, 7,33 (d, 1H), was 7.08 (m, 4H), 6,67 (SHS, 1H), 6,54 (m, 2H), 5,13 (s, 2H), to 5.08 (s, 2H), 2,28 (s, 3H). MS (EPI) 425 (M-N)-. Obtained from methyl 2-[3-(3-bromobenzylamine)phenoxymethyl]-6-methylbenzoate (example 6ah).

Example 7aw

2-{3-[2-(5-Ethylpyridine-2-yl)ethoxy]phenoxymethyl}-6-methylbenzoic acid

1H NMR (300 MHz, DMSO) δ at 8.36 (SHS, 1H), 7,56 (d, 1H), 7,14 (m, 5H), of 6.49 (m, 3H), 5,11 (CL, 2H), 4,27 (t, 2H), to 3.09 (t, 2H), 2,56 (K, 2N), to 2.29 (s, 3H), of 1.17 (t, 3H). MS (EPI) 392 (M+N)+. Obtained from methyl 2-{3-[2-(5-ethylpyridine-2-yl)ethoxy]phenoxymethyl}-6-methylbenzoate (example 4f).

Example ach

2-Methyl-6-[3-(2-quinoline-2-ylethoxy)phenoxymethyl]-benzoic acid

1H NMR (300 MHz, CD3OD) δ of 8.28 (d, 1H), of 7.97 (d, 1H), 7,88 (d, 1H), 7,74 (t, 1H), 7,51 (m, 1H), 7,26 (d, 2H), 7,16 (m, 2H), 7,02 (m, 1H), 6,38 (m, 3H), 5,10 (s, 2H), 3,83 (t, 2H), up 3.22 (t, 2H), 2,39 (s, 3H). Obtained from methyl 2-methyl-b-[3-(2-quinoline-2-ylethoxy)phenoxymethyl]benzoate (example 21b).

Example AU

2-Methyl-6-[3-(2-pyridin-2-ylethoxy)phenoxymethyl]-benzoic acid

1H NMR (300 MHz, DMSO) δ 8,49 (d, 1H), 7,69 (m, 1H), 7,26 (m, 3H),? 7.04 baby mortality (m, 2H), 6,38 (m, 4H), to 5.03 (s, 2H), to 3.67 (t, 2H), equal to 2.94 (t, 2H), 2,31 (s, 3H). MS (EPI) 364 (M+N)+. Obtained from methyl 2-methyl-6-[3-(2-pyridin-2-ylethoxy)phenoxymethyl] benzoate (example 4g).

Example 7az

2-[3-(Benzooxazol-2-illuminometer)phenoxymethyl]-6-methylbenzoic acid

1H NMR (300 MHz, DMSO) δ 8,61 (PCs, 1H), 7,34 (d, 1H),? 7.04 baby mortality (m, 10H), 5,12 (s, 2H), 4,47 (sm, 2N), TO 2.29 (3H). MS (EPI) 389 (M+N)+. Get the from methyl 2-[3-(benzooxazol-2-illuminometer)phenoxymethyl]-6-methylbenzoate (example 4h).

Example 7b

2-Methyl-6-[3-(pyridine-2-ileocecal)phenoxymethyl]-benzoic acid

1H NMR (300 MHz, DMSO) δ charged 8.52 (sm, 1H), 7,81 (m, 1H), 7,47 (d, 1H), 7,20 (m, 5H), 6,94 (m, 3H), 5,12 (s, 2H), 4,59 (s, 2H), 4,56 (s, 2H), 2,30 (s, 3H). MS (EPI) 364 (M+N)+. Obtained from methyl 2-methyl-6-[3-(pyridine-2-ileocecal)-phenoxymethyl]benzoate (example 4i).

Example 7bb

2-Methyl-6-[3-(quinoline-2-ileocecal)phenoxymethyl]-benzoic acid

1H NMR (300 MHz, DMSO) δ to 8.40 (d, 1H), 7,98 (d, 2H), 7,76 (m, 1H), to 7.64 (m, 1H), 7,31 (m, 5H), 7,00 (m, 2H), 6,92 (DD, 1H), 5,12 (s, 2H), 4,79 (s, 2H), to 4.62 (s, 2H), 2,32 (s, 3H). MS (EPI) 414 (M+N)+. Obtained from methyl 2-methyl-6-[3-(quinoline-2-ileocecal)phenoxymethyl]benzoate (example 4j).

Example 7b

2-Methyl-6-{3-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-phenoxymethyl}benzoic acid

1H NMR (300 MHz, CDCl3): δ 8,03 (m, 2H), 7,43 (m, 3H), 7,26 (m, 2H), 7,17 (m, 1H), 7,10 (m, 1H), of 6.68 (s, 1H), 6,51 (m, 2H), by 5.18 (s, 2H), 4,22 (m, 2H), 2,96 (m, 2H), 2,41 (s, 3H), of 2.36 (s, 3H). MS (EPI) 444 (M+N)+. Obtained from methyl 2-methyl-6-{3-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenoxymethyl}benzoate (example 21A).

Example 7bd

2-Methyl-6-[3-(6-vinylpyridin-2-ylethoxy)phenoxymethyl]-benzoic acid

1H NMR (300 MHz, CDCl3): δ 7,88 (m, 2H), 7,63 (m, 1H), 7,52 (m, 1H), 7,37 (m, 4H), 7,18 (m, 2H), 6,99 (m, 2H), 6,60-6,36 (m, 3H), 5,14 (s, 2H), 5,00 (s, 2H), of 2.23 (s, 3H). MS (EPI) 426 (M+N)+. Obtained from ethyl 2-methyl-6-[3-(6-vinylpyridin-2-ylethoxy)phenoxymethyl]Ben is oate (example 33).

Example 7 be

2-Methyl-6-[3-(quinoline-2-ylethoxy)phenylsulfanyl]-benzoic acid

1H NMR (300 MHz, DMSO-d6d to 8.40 (d, 1H), 7,99 (t, 2H), 7,78 (t, 1H), 7,65-EUR 7.57 (m, 2H), 7,20-7,01 (m, 6N), 6,85 (t, 1H), 5,33 (s, 2H), 4,25 (s, 2H), and 2.26 (s, 3H); MS (EPI) 415 (M+N)+. Derived from isobutyl 2-methyl-6-[3-(quinoline-2-ylethoxy) phenylsulfanyl] benzoate (example 84).

Example 7bf

2-Methyl-6-[3-(quinoline-2-ylethoxy)phenylsulfinyl]-benzoic acid

1H NMR (300 MHz, DMSO-d6d 8,43 (d, 1H), 8,01 (t, 2H), 7,78 (t, 1H), 7,68 (d, 1H), 7.62mm (t, 1H), of 7.48 (t, 1H), 7,25-7,22 (m, 4H), 7,10 (d, 1H), 6,94 (t, 1H), 5,41 (s, 2H), 4,22 (d, 1H), 4,11 (d, 1H), 2,33 (s, 3H); MS (EPI) 432 (M+N)+. Derived from isobutyl 2-methyl-6-[3-(quinoline-2-ylethoxy) phenylsulfinyl] benzoate (example 85).

Example 7bg

2-Methyl-6-[3-(quinoline-2-ylethoxy)phenylsulfonyl]-benzoic acid

1H NMR (300 MHz, DMSO-d6d 8,43 (d, 1H), 8,05-7,98 (m, 2H), to 7.77 (t, 1H), to 7.67 (d, 1H), 7,60 (t, 1H), 7,51 (t, 1H), 7,43-7,35 (m, 2H), 7,26-7,20 (m, 3H), 6,95-6,92 (m, 1H), 5,42 (s, 2H), to 4.81 (s, 2H), 2,32 (s, 3H); MS (EPI) 448 (M+N)+. Derived from isobutyl 2-methyl-6-[3-(quinoline-2-ylethoxy)phenylsulfonyl]benzoate (example 86).

Example 7bh

2-Methyl-6-[3-(quinoline-2-ylethoxy)phenylethynyl]benzoic acid

1H NMR (300 MHz, CDCl3d 8,19 (d, 1H), 8,04 (d, 1H), 7,89 (d, 1H), 7,82 (d, 1H), 7,73 (dt, 2H), to 7.64 (t, 2H), 7,54 (t, 1H), 7,26 (t, 1H), 6,94 (DD, 1H), for 6.81-6,85 (m, 2H), of 5.34 (s, 2H), was 2.76 (s, 3H); MS (EPI) 394 (M+H)+. Derived from ethyl-2-m is Teal-6-[3-(quinoline-2-ylethoxy)phenylethynyl]benzoate (example 6ai).

Example 7bi

2-Methyl-6-[3-(5-vinylpyridin-2-ylethoxy)phenoxymethyl]-benzoic acid

TPL 80-83°C.1H NMR (300 MHz, 5:1 CDCl3:CD3OD): δ 8,76 (s, 1H), of 7.97 (d, 1H), 7.62mm (m, 3H), of 7.48 (m, 3H), 7,30 (m, 2H), 7,19 (m, 2H), of 6.68 (s, 1H), 6,62 (d, 2H), total of 5.21 (s, 2H), 5,17 (s, 2H), 2,44 (s, 3H). MS (EPI) 426 (M+N)+. Obtained from methyl 2-methyl-6-[3-(5-vinylpyridin-2-ylethoxy)phenoxymethyl]-benzoate (example 6aj).

Example 7bj

2-[3-(2-Chlorobenzoyloxy)phenoxymethyl]-6-methylbenzoic acid

1H NMR (300 MHz, DMSO) δ 7,56 (m, 1H), 7,50 (m, 1H), 7,38 (m, 2H), 7,14 (m, 2H), 7,06 (m, 2H), to 6.67 (s, 1H), return of 6.58 (m, 2H), 5,13 (sm, 4H), of 2.28 (s, 3H). MS (EI) (M)+. the structure complying with Cl. Is obtained from 2-[3-(2-Chlorobenzyl-hydroxy)phenoxymethyl]-6-methylbenzoate (example 6ak).

Example 7bk

2-[3-(4-Chlorobenzoyloxy)phenoxymethyl]-6-methylbenzoic acid

1H NMR (300 MHz, DMSO) δ 7,42 (m, 3H), was 7.08 (m, 5H), of 6.66 (s, 1H), 6,54 (m, 2H), 5,13 (s, 2H), 5,07 (s, 2H), 2,28 (s, 3H). MS (EI) 382 (M)+the structure complying with Cl. Is obtained from 2-[3-(4-chlorobenzoyloxy)phenoxymethyl]-6-methylbenzoate (example 6l).

Example 7bl

2-Methyl-6-[3-(3-methylphenoxy-2-ylethoxy)phenoxymethyl]benzoic acid

1H NMR (300 MHz, DMSO) δ with 8.05 (m, 2H), 7,82 (m, 2H), 7,14 (m, 4H), 6.75 IN (S, 1H), 6,61 (m, 2H), 5,41 (s, 2H), 5,11 (s, 2H), was 2.76 (s, 3H), and 2.27 (s, 3H). MS (EPI) 415 (M+H)+. Obtained from the methyl ester of 2-methyl-6-[3-(3-methylphenoxy-2-ylethoxy) phenoxymethyl]benzoic acid (example 6am).

Example 7m

2-Methyl-6-[3-(naphthalene-2-ylethoxy)phenoxymethyl]-benzoic acid

1H NMR (300 MHz, DMSO) δ 7,94 (m, 4H), 7,54 (m, 3H), 7,16 (m, 4H), 6,69 (s, 1H), return of 6.58 (m, 2H), 5,24 (s, 2H), 5,11 (s, 2H), to 2.29 (s, 3H). Obtained from the methyl ester of 2-methyl-6-[3-(naphthalene-2-ylethoxy)phenoxymethyl]benzoic acid (example 6an).

Example 8

3-[(2-Methoxyethoxy)methoxy]benzonitrile

To a cooled suspension (0° (C) sodium hydride (840 mg, 60% dispersion in mineral oil, 21 mmol) in THF (20 ml) add a solution containing 3-hydroxybenzonitrile (2.4 g, 20 mmol), MEM chloride (2.25 ml, 20 mmol) and DMPU (2 ml) in THF (20 ml). Upon completion of the addition, the bath for cooling is removed and continue stirring for 3 hours. Then the reaction mixture was diluted with simple ether, washed with water and saturated salt solution, dried over MgSO4and concentrate. The residue is purified flaming (flash) chromatography (silica gel, 30% ethyl acetate, 10% dichloromethane in hexane)to give specified in the title compound in the form of oil. MS (EPI) 207 (M+N)+.

Example 8A

3-[(2-Methoxyethoxy)methoxy]benzaldehyde

Specified in the header of the get connection using basically the same technique as in example 8, except using 3-hydroxybenzaldehyde instead of 3-hydroxy-benzonitrile. MS (EI) 210 (M)+.

Example 9

3-[(2-Methoxyethoxy)methoxy]benzylamine

To a cooled (0° (C) a solution of the 3-[(2-methoxyethoxy)-methoxy]benzonitrile (3,9 g, for 18.8 mmol, example 8) in THF (40 ml) was added LAH (40 ml, 1 M in THF). The resulting solution was stirred for 10 minutes, then the cold bath is removed and continue stirring for 2 hours. The resulting mixture was cooled to 0°With, then add dropwise water (1.5 ml), and then a solution of NaOH (1.5 ml, 5 M) and water (1.5 ml). The resulting suspension was diluted with simple ether, then filtered through celite. The filtrate is concentrated, getting mentioned in the title compound which is used without further purification. MS (EPI) 211 (M+N)+.

Example 10

3-(Quinoline-2-illuminometer)phenol

To a solution of 3-[(2-methoxyethoxy)methoxy]benzylamine (422 mg, 2 mmol, example 9) in DMSO (4 ml) is added 2-chloro-quinoline (328 mg, 2 mmol). The resulting solution was heated to 140°C and stirred at this temperature for 3 hours. The mixture is cooled, diluted with water, then extracted with ethyl acetate. The organic extract was washed with saturated salt solution, dried over MgSO4and concentrate. The remainder absorb methanol (10 ml), then add monohydrate p-toluenesulfonic acid (190 mg, 1 mmol). This mixture is heated to 60°C and stirred at this temperature for 2 hours. Then the reaction mixture is cooled, concentrated under reduced pressure and the residue purified flash chromatography (silica gel, 30% ethyl acetate in dichloromethane)to give the criminal code is mentioned in the header connection. MS (EPI) 251 (M+N)+.

The following connections will be received, using basically the same technique as in example 10, except using the specified chloride and amine instead of 2-chloro-quinoline and 3-[(2-methoxyethoxy)methoxy]benzylamine.

Example 10A

3-[(N-Benzoxazol-2-yl-N-methylamino)methyl]phenol

MS (EPI) 255 (M+N)+. Obtained from 3-[(methylamino)methyl]-(2-methoxyethoxyethoxy)benzene (example 28) and 2-chloro-benzoxazole. In addition, without heating to 140°C. the Reaction mixture was stirred at room temperature.

Example 10b

3-[(N-Methyl-N-quinoline-2-ylamino)methyl]phenol

MS (EPI) 265 (M+N)+. Obtained from 3-[(methylamino)methyl]-(2-methoxyethoxyethoxy)benzene (example 28) and 2-chlorhydrin.

Example 10C

3-(Benzooxazol-2-illuminometer)phenol

Specified in the header of the get connection using basically the same procedure as in example 10 except using 2-chlorobenzoxazol instead of 2-chlorhydrin. In addition, without heating to 140°C. the Reaction mixture was stirred at room temperature. MS (EPI) 241 (M+N)+.

Example 11

2-(3-([2-Methoxyethoxy]methoxy)phenoxy]ethanol

To a cooled (0° (C) a solution of t-butyl (3-([2-methoxyethoxy]methoxy)phenoxy])acetate (1.2 g, 3.8 mmol, example 12) in THF (10 ml) add a solution of sociallyengaged (5 ml, 1 M in THF). The resulting solution paramesh who live within 10 min, then added dropwise water (0.2 ml), followed by the addition of NaOH solution (0.2 ml, 5 M) and water (0.2 ml). The resulting mixture was diluted with simple ether, filtered through celite and the filtrate is concentrated, getting mentioned in the title compound in the form of oil, which is used without further purification. MS (EI) 242 (M)+.

Example 11a

2-(5-Methyl-2-phenyloxazol-4-yl)ethanol

Specified in the header of the get connection using basically the same procedure as in example 11, except using methyl 2-(5-Methyl-2-phenyloxazol-4-yl)acetate (example 32) instead of t-butyl (3-([2-methoxyethoxy]methoxy)-phenoxy])acetate. MS (EPI) 204 (M+H)+.

Example 12

t-Butyl(3-([2-methoxyethoxy]methoxy)phenoxy])acetate

Specified in the header of the get connection using basically the same procedure as in example 4, except using 3-([2-methoxyethoxy]methoxy)phenol (example 13) instead of 3-(quinoline-2-ylethoxy)phenol and t-butyl bromoacetate instead of methyl 2-methyl bromide-6-methylbenzoate. MS (EI) 312 (M)+.

Example 13

3-[(2-Methoxyethoxy)methoxy]phenol

To a cooled (0° (C) suspension of NaH (440 mg, 60% dispersion in oil, 11 mmol) in THF (10 ml) is added slowly a solution containing 3-benzylphenol (2.14 g, 10 mmol), MEM chloride (1,28 ml, 10.5 mmol) and DMPU (3 ml) in THF (20 ml). After adding the cold bath is removed and continue stirring to use the e 2.5 hours. Add a saturated solution of NH4Cl and the mixture is diluted with simple ether, washed with water and saturated salt solution, dried over MgSO4and concentrate. The remainder absorb methanol (10 ml) and THF (10 ml), add THF (10 ml), then add a solution of sodium hydroxide (10 ml, 2 BC). This mixture is stirred for 20 min, then add hydrochloric acid (10 ml, 2 BC). The mixture is then diluted with simple ether, washed with saturated solution of NaHCO3and saturated salt solution, dried over MgSO4and concentrate. The residue is purified flaming (flash) chromatography (silica gel, 30% ethyl acetate in hexane)to give specified in the title compound in the form of oil.1H NMR (300 MHz, CDCl3) δ 7,00 (t, 1H), 6,52 (sm, 1H), 6.48 in (SHS, 1H), 6,38 (sm, 1H), 5,14 (s, 2H), 3,71 (m, 2H), 3,47 (m, 2H), 3,30 (s, 3H).

Example 14

[(2-Methoxyethoxy)methoxy]-3-[2-(pyridine-2-yloxy)-ethoxy]benzene

To a solution of 2-(3-([2-methoxyethoxy]methoxy)phenoxy])-ethanol (242 mg, 1 mmol, example 11) in DMSO (1.5 ml) is added sodium hydride (44 mg, 60% dispersion in mineral oil, 1.1 mmol) followed by addition of 2-herperidin (176 ml, 2 mmol). The resulting solution was heated to 60°C and stirred at this temperature for 3 hours, cooled, diluted with simple ether, washed with water, saturated salt solution, dried over MgSO4and concentrate. The residue is purified flash chromatography (with lycogel, 30% ethyl acetate in hexane)to give specified in the header connection. MS (EPI) 320 (M+N)+.

Example 15

3-(2-Quinoline-2-elwenil)phenol

To a solution of 1-(2-methoxyethoxy)methoxy-3-(2-Quinoline-2-elwenil) benzene (120 mg, 0.35 mmol, example 16) add monohydrate p-toluenesulfonic acid (74 mg, 0,39 mmol). The resulting solution was heated to 60°C and stirred at this temperature for 4 hours. Then the reaction mixture is cooled, concentrated and the residue absorb dichloromethane. This solution was washed with a saturated solution of NaHCO3, dried over MgSO4then concentrate receiving specified in the title compound in the form of solids. MS (EPI) 248 (M+N)+.

The following connections will be received, using basically the same procedure as in example 15, except using the specified MEM simple ester instead of 1-(2-methoxyethoxy)methoxy-3-(2-quinoline-2-elwenil)benzene.

Example 15a

3-[2-(pyridine-2-yloxy)ethoxy]phenol

MS (EPI) 232 (M+N)+. Derived from [(2-methoxyethoxy)-methoxy]-3-[2-(pyridine-2-yloxy)ethoxy]benzene (example 14).

Example 15b

3-(Quinoline-2-intoximeter)phenol

MS (EPI) 252 (M+N)+. Is obtained from 2-[3-(2-methoxyethoxy-methoxy)benzyloxy]quinoline (example 81).

Example 15C

Ethyl 2-(3-hydroxyphenylethyl)-6-methylbenzoate

MS (EI) 280 (M)+. Derived from ethyl-2-[3-(2-methoxy-ethoxyethoxy)phenylethynyl]-6-m is diventata (example 98).

Example 16

1-(2-Methoxyethoxy)methoxy-3-(2-quinoline-2-elwenil)benzene

To a cooled (-78° (C) suspension of triphenyl(quinoline-2-ylmethyl)phosphorylated (1,76 g, 4 mmol, example 17) in THF (24 ml) is added, dropwise, a solution of n-utility (1.7 ml, 2.5 M in hexane). The resulting mixture was stirred for 30 min, then add a solution of 3-[(2-methoxyethoxy)-methoxy]benzaldehyde (756 mg, 3.6 mmol, example 8A) in THF (3 ml). This mixture is stirred for 30 minutes, then the cold bath is removed and continue stirring for 2 hours. Then the reaction mixture was diluted with ethyl acetate, washed with saturated solution of ammonium acetate and a saturated salt solution, dried over MgSO4and concentrate. The residue is purified flash chromatography (silica gel, 40% ethyl acetate in hexane)to give specified in the title compound in the form of oil. MS (EPI) 336 (M+N)+.

Example 17

Triphenyl(quinoline-2-ylmethyl)phosphonylated

To a solution of 2-chloromethylpyridine (2,9 t, 20 mmol) in acetonitrile (32 ml) is added triphenylphosphine (4,49 g, 17 mmol). The resulting mixture was heated to 60°C and stirred at this temperature for 15 hours. This mixture is cooled, diluted with simple ether, then filtered. The solid is washed with simple ether, then dried in high vacuum, getting mentioned in the title compound as a solid substance.1H NMR (300 M is C, CDCl3) δ to 8.20 (d, 1H), of 8.06 (d, 1H), 7,95 (m, 6N), 7,42-to 7.8 (m, 13H), 6,10 (d, 2H).

Example 18

{2-Methyl-6-[3-(2-quinoline-2-retil)phenoxymethyl]phenoxy}-acetic acid

To a solution of {2-methyl-6-[3-(2-quinoline-2-elwenil)phenoxymethyl]phenoxy}acetic acid (94 mg, 0.23 mmol, example 41A) in DMF (1.5 ml) is added to chloride trascription rhodium (25 mg, or 0.027 mmol). The resulting solution was placed in an atmosphere of hydrogen, heated to 60°C and stirred at this temperature for 5 hours. The reaction mixture is cooled to room temperature and then the system is rinsed with nitrogen and concentrated in vacuo. The residue is purified HPLC (HPLC) with reversed phase, receiving specified in the title compound in the form of triptoreline salt.1H NMR (300 MHz, CDCl3) δ to 8.57 (d, 1H), 8,40 (d, 1H), 8.0 a (m, 2H), 7,80 (t, 1H), 7,52 (d, 1H), 7,24 (sm, 1H), 7,14 (m, 2H),? 7.04 baby mortality (t, 1H), 6,93 (SHS, 1H), 6,83 (d, 1H), 6,74 (d, 1H), 5,11 (s, 2H), 4,50 (s, 2H), 3,68 (t, 2H), 3,20 (t, 2H), 2,28 (s, 3H). MS (EPI) 428 (M+N)+.

The following connection receive, using basically the same procedure as in example 18 except using the specified acid instead of {2-methyl-6-[3-(2-quinoline-2-elwenil)phenoxymethyl]phenoxy}acetic acid.

Example 18a

2-Methyl-6-[3-(2-quinoline-2-retil)phenoxymethyl]benzoic acid

1H NMR (300 MHz, CDCl3) δ to 8.62 (d, 1H), 8,44 (d, 1H), 8.0 a (m, 2H), 7,80 (t, 1H), to 7.61 (d, 1H), 7,21 (d, 1H), 7,11 (d, 1H), 7,07 (t, 1H), 6,94 (SHS, 1H), 6,76 (sm, 1H), of 6.68 (d, 1 is), 5,09 (s, 2H), 3,70 (t, 2H), 3,18 (t, 2H), 2.40 a (s, 3H). MS (EPI) 398 (M+H)+. Derived from {2-methyl-6-[3-(2-quinoline-2-elwenil)phenoxymethyl]benzoic acid (example 4A).

Example 19

4-Chloromethyl-2-phenyloxazol

Benzamid (1,21 g, 10 mmol) is mixed with 1,3-dichloro-acetone (1.26 g, 10 mmol) and the mixture is heated to 130°C and stirred at this temperature for 1 hour. Then the mixture is cooled, diluted with ethyl acetate, washed with a solution To a2CO3(rich), then with saturated salt solution, dried over MgSO4and concentrate, getting mentioned in the title compound in the form of a solid substance, which is used without further purification. MS (EPI) 194 (M+N, the structure responsible Cl)+.

The following connections will be received, using basically the same procedure as in example 19 except using the specified amide instead of benzamide.

Example 19a

2-(5-Methylthiophene-2-yl)oxazol-4-ylmethylene

MS (EPI) 214, 216 (M+N)+the structure complying with Cl. Obtained from 5-methylthiophene-2-carboxamide.

Example 19b

2-Cyclohexyloxy-4-ylmethylene

MS (EPI) 200, 202 (M+N)+the structure complying with Cl. Receive from cyclohexanecarboxylic.

Example 19 (C)

2-(3-Forfinal)oxazol-4-ylmethylene

MS (EPI) 212, 214 (M+N)+the structure complying with Cl. Obtained from 3-foraminated.

Example 19d

2-(4-Forfinal)is xazal-4-ylmethylene

MS (EPI) 212, 214 (M+N)+the structure complying with Cl. Obtained from 4-foraminated.

Example 20

4-Chloromethyl-2-phenylthiazole

The solution thiobenzamide (of 1.37 g, 10 mmol) and 1,3-dichloro-acetone (1.27 g, 10 mmol) in ethanol (25 ml) is heated to 75°C and stirred at this temperature for 1 hour. The resulting solution is cooled, poured into ice, then brought to pH 8 (saturated) solution To2CO3. This mixture is extracted with ethyl acetate, dried over MgSO4and concentrate, receiving specified in the header connection. This product is used without further purification. MS (EPI) 210 (M+N)+.

Example 21

{2-methyl-6-[3-(2-pyridin-2-ylethoxy)phenoxymethyl]-phenoxy}acetonitrile

To a solution of [2-methyl-6-(3-hydroxyphenoxy)phenoxy]-acetonitrile (135 mg, 0.5 mmol, example 25) and 2-(pyridin-2-yl)ethanol (126 ml of 0.94 mmol) in THF (2 ml) is added triphenylphosphine (262 mg, 1 mmol) followed by addition of DEAD (118 ml, 0.75 mmol). The resulting solution was stirred for 2 h, then concentrated and the residue purified flash chromatography (silica gel, 50% ethyl acetate in hexane)to give specified in the title compound in the form of oil. MS (EPI) 375 (M+N)+.

The following connection receive, using basically the same procedure as in example 21 except using the specified alcohol and phenol instead of 2-(pyridin-2-yl)ethanol and [2-methyl-6-(3-hydro is nifenecker)phenoxy]-acetonitrile, respectively.

Example 21A

Methyl 2-methyl-6-{3-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenoxymethyl}benzoate

MS (EPI) 458 (M+N)+. Is obtained from 2-(5-methyl-2-phenyl-oxazol-4-yl) ethanol (example) and methyl 2-(3-hydroxy-phenoxymethyl)-6-methylbenzoate (example 5).

Example 21b

Methyl 2-methyl-6-[3-(2-quinoline-2-ylethoxy)phenoxymethyl]-benzoate

1H NMR (300 MHz, CDCl3) δ 8,08 (m, 2H), 7,80 (d, 1H), of 7.70 (t, 1H), 7,51 (t, 1H), 7,42 (d, 1H), 7,29 (m, 2H), 7,16 (m, 2H), 6,53 (m, 3H), of 5.06 (s, 2H), 4,46 (t, 2H), 3,81 (s, ZN), of 3.45 (t, 2H), 2,37 (s, ZN). MS (EPI) 428 (M+H)+. Is obtained from 2-quinoline-2-retinol (example 69A) and 2-(3-hydroxyphenoxy)-6-methylbenzoate (example 5).

Example 22

2 Cyanoethoxy-3-methylbenzaldehyde

A mixture of 2-hydroxy-3-methylbenzaldehyde (10.2 g, 75,0 mmol, Aldrich), bromoacetonitrile (5,70 ml of 82.5 mmol) and potassium carbonate (11.4 g, of 82.5 mmol) in DMF (150 ml) is heated to 55°C for 3 hours, cooled, then diluted with simple ether. The mixture is washed with distilled water, saturated NaCl solution, then the organic layer is dried over MgSO4and concentrate, getting mentioned in the title compound as a yellow solid.1H NMR (300 MHz, CDCl3): δ and 10.20 (s, 1H), of 7.70 (d, 1H), 7,53 (d, 1H), 7,29 (m, 1H), to 4.81 (s, 2H), 2,42 (s, 3H).

The following connections are getting, basically, using the same procedure as in example 22, except using the specified phenol pax is 2-hydroxy-3-methylbenzaldehyde.

Example 22A

2 Cyanoethoxy-3,5-dichlorobenzaldehyde

MS (EI) 229, 231 (M)+. Derived from 3,5-dichlorosalicylaldehyde.

Example 22b

2 Cyanoethoxy-5-chloro-3-methoxybenzaldehyde

MS (EI) 225 (M)+. Obtained from 5-chloro-2-hydroxy-3-methoxybenzaldehyde (example 44).

Example 22s

Methyl 2-(2-formyl-6-methylphenoxy)propionate

Specified in the header connection comes primarily using the same procedure as in example 22, except using methyl 2-bromopropionate instead of bromoacetonitrile.

Example 23

(2-Hydroxymethyl-6-methylphenoxy)acetonitrile

2 M trislim a solution of sodium borohydride (16.0 ml, 32.1 mmol) is added slowly to the cooled solution (-78° (C) 2-cyanoethoxy-3-methylbenzaldehyde (11,25 g, 64,2 mmol, example 22) in THF (180 ml). After stirring for one hour, the reaction mixture is heated to 0°C for two hours, then quenched with 2 N. HCl (16,8 ml) and diluted with simple ether. The organic layer is separated and washed twice with distilled water and saturated salt solution, then dried over MgSO4. The organic solution is concentrated and receiving specified in the title compound as a yellow oil.

The following connections are getting, basically, using the same procedure as in example 23, except using the specified aldehyde instead of 2-cyanoethoxy-3-methylbenzaldehyde

Example 23a

(2,4-Dichloro-6-hydroxymethylene)acetonitrile

Receive, using 2-cyanoethoxy-C,5-dichlorobenzaldehyde (example 22A).

Example 23b

(4-Chloro-2-hydroxymethyl-6-methoxyphenoxy)acetonitrile

MS (EI) 227 (M)+. Receive, using 2-cyanoethoxy-5-chloro-3-methoxybenzaldehyde (example 22b).

Example 23C

Methyl ester 2-(2-hydroxymethyl-6-methylphenoxy)-propionic acid

MS (EI) 194 (M)+. Receive, using methyl 2-(2-formyl-6-methylphenoxy)propionate (example 22 ° C).

Example 24

(2-methyl bromide-6-methylphenoxy)acetonitrile

Triphenylphosphine (15.2 g, of 57.8 mmol) are added to 2-cyanoethoxy-3-methylbenzylamine (9.3 g, is 52.5 mmol, example 23) in THF (175 ml). The mixture is stirred until then, until it becomes homogeneous and cooled to 0°S, and then adding three portions of N-bromosuccinimide (10/3 g of 57.8 mmol). After 90 minutes, the reaction mixture was concentrated and the residue purified column chromatography (silica gel, 5:1 Gex:EtOAc)to give specified in the title compound in the form of blignault crystalline solid. MS (EI) 239, 241 (M)+the structure Br.

The following connections are getting, basically, using the same procedure as in example 24, except using the specified alcohol instead of 2-cyanoethoxy-3-methylbenzylamine.

Example 24A

(2-methyl bromide-4,6-diclofe the oxy)acetonitrile

MS (EI) 277 (M-16)+. Get from (2,4-dichloro-6-hydroxymethylene)acetonitrile (example 23a).

Example 24b

(2-methyl bromide-4-chloro-6-methoxyphenoxy)acetonitrile

MS (EI) 289 (M)+. Is obtained from (4-chloro-2-hydroxymethyl-6-methoxyphenoxy)acetonitrile (example 23b).

Example 24C

Methyl 2-(2-methyl bromide-6-methylphenoxy)propionate

MS (EI) 286 (M)+the structure responsible to the bromine. Obtained from methyl 2-(2-hydroxymethyl-6-methylphenoxy)propionate (example 23C).

Example 25

(2-[3-Hydroxyphenoxy]-6-methylphenoxy)acetonitrile

Heated (60° (C) a mixture of 2-cyanoethoxy-3-methylbenzylamine (10.2 g, and 42.7 mmol, example 24), resorcinol (18,8 g, 171 mmol) and potassium carbonate (47,2 g, 342 mmol) in acetonitrile (140 ml) for two hours. The reaction mixture was diluted with simple ether and washed three times with distilled water, once with saturated salt solution and dried over MgSO4. The organic layer is separated and concentrated, and the obtained residue is purified column chromatography (silica gel, 5% EtOAc/CH2Cl2), getting mentioned in the title compound as a white crystalline solid. MS (EI) 269 (M)+.

The following connections are getting, basically, using the same procedure as in example 25 except using the specified bromide instead of 2-cyanoethoxy-3-methylbenzylamine.

Example 25A

[4-chlorine is-2-(3-hydroxyphenoxy)-6-methylphenoxy]-acetonitrile

Is obtained from (2-methyl bromide-4-chloro-6-methylphenoxy)acetonitrile (example 43).

Example 25b

[4,6-Dichloro-2-(3-hydroxyphenoxy)phenoxy]-acetonitrile

Is obtained from (2-methyl bromide-4,6-dichlorophenoxy)acetonitrile (example 24A).

Example 26

2-Methyl-6,7-divergingly

To boiling (under reflux) to a solution of 3,4-diferencia (2.30 ml, 23.2 mmol), tetrachloro-1,4-benzoquinone (5,70 g, 23.2 mmol) and concentrated hydrochloric acid (6 ml) in 2-butanol (40 ml) add CROTONALDEHYDE (1,92 ml, 23.2 mmol). After 2.5 hours, the reaction mixture was concentrated and the resulting residue is stirred in a warm (50° (C) THF (15 ml). This mixture is cooled (0° (C) and the solid is collected by filtration and washed with cold THF. The solid is stirred in distilled water (200 ml)and the resulting solution is alkalinized To a2CO3and extracted with EtOAc (3×100 ml). The organic extracts are combined and dried over sodium sulfate and then concentrated, receiving specified in the header connection. MS (EPI) 180 (M+H)+.

The following connections are getting, basically, using the same procedure as in example 26, except using the specified aniline instead of 3,4-diferencia.

Example 26a

2-Methyl-6,8-divergingly

MS (EPI) 180 (M+N)+. Receive, using 2,4-diptiranjan.

Example 27

6,8-Divergingly-2-iletileri

2Cl2:hexane, then CH2Cl2), getting mentioned in the title compound as a white solid. MS (EPI) 258, 260 (M+N)+the structure Br.

The following connections are getting, basically, using the same procedure as in example 27, except using the methyl-containing compounds instead of 6.8-debtor-2-methylinosine.

Example 27A

6,7-Divergingly-2-ylmethylene

MS (EPI) 214, 216 (M+N)+the structure complying with Cl. Receive from 6,7-divergingly (example 26) and NCS instead of NBS.

Example 27b

6-Ftorhinolon-2-iletileri

MS (EPI) 240, 242 (M+N)+the structure Br. Obtained from 6-fluoro-2-methylinosine.

Example 27C

2-Chloromethyl-6-chloropyridin

MS (EPI) 162, 164, 166 (M+N)+the structure responsible Cl2. Obtained from 6-chloro-2-picoline and NCS instead of NBS.

Example 27d

2-Bromomethylbiphenyl

MS (EI) 195 (M)+the structure Br. Derived from o-tolunitrile.

Example 27E

Methyl 3-brometalia-2-carboxylate

MS (EI) 234 (M)+art is ucture, meet Br. Obtained from methyl 3-methylthiophene-2-carboxylate.

Example 27f

6,7-Dichloro-2-chlormethine

MS (EPI) 246 (M+N)+. Receive from 6,7-dichloraniline and NCS instead of NBS.

Example 27g

5-Vinylpyridin-2-ylmethylene

MS (EPI) 204, 206 (M+N)+the structure complying with Cl. Obtained from 5-phenyl-2-methylpyridine (example 104) and NCS instead of NBS.

Example 28

3-[(Methylamino)methyl]-(2-methoxyethoxyethoxy)benzene

To a solution of 3-(2-methoxyethoxyethoxy)benzaldehyde (2.10 g, 10 mmol, example 8A) in THF (60 ml) is added methylamine (20 ml, 2M in THF) followed by addition of palladium on carbon (210 mg, 10% Pd). The resulting mixture is stirred for 24 hours in an atmosphere of hydrogen gas, then rinsed with nitrogen, filtered through celite and the filtrate concentrated. The residue is purified flash chromatography (silica gel, 10% methanol in dichloromethane)to give specified in the title compound in the form of oil.

Example 29

1-Methyl-4-oxo-1,4-dihydroquinoline-2-iletileri

A solution of 1-Methyl-4-oxo-1,4-dihydroquinoline-2-ylmethanol (112 mg, 0,592 mmol, Coppola, G.M. J. Heterocyclic Chem., 1986, 23 g 1717) and tribromide phosphorus (56,2 μl, 0,592 mmol) in a mixture of 3:1 CH2Cl2:DMF (20 ml) is stirred for 18 hours and add another portion (20 μl) tribromide phosphorus. After 24 hours, add distilled water (10 ml) and extracted with EtOAc. The organic layer is concentrated and the scientists residue purified column chromatography (silica gel, 20:1 CH2Cl2:MeOH)to give specified in the title compound as a white solid. MS (EPI) 252, 254 (M+N)+the structure Br.

The following connection comes primarily using the same procedure as in example 29 except using the specified alcohol instead of 1-methyl-4-oxo-1,4-dihydroquinoline-2-ylmethanol.

Example 29A

4-tert-Butylcyclohexylamine

1H NMR (300 MHz, CDCl3): δ of 3.27 (d, 2H), 1.93 and (m, 2H), is 1.81 (m, 2H), and 1.54 (m, 2H), and 0.98 (m, 4H), 0,84 (s, N). Obtained from 4-tert-butylcyclohexylamine (example 30).

Example 30

4-tert-Butylcyclohexylamine

To a cooled (0° (C) to a solution of 4-tert-butylcyclohexane-carboxylic acid (3.00 g, 16.3 mmol) in THF (30 ml) is added slowly a solution of a complex of borane-THF in THF (1.0 M, 21.2 ml of 21.2 mmol). The solution was stirred at room temperature for 18 hours, then quenched with a solution of 2 N. HCl solution (30 ml) and extracted with EtOAc. The organic layer is separated, washed with 1 N. NaOH, dried over sodium sulfate and concentrated, obtaining mentioned in the title compound as a clear oil.1H NMR (300 MHz, CDCl3): δ to 2.06 (d, 2H), equal to 1.82 (m, 4H), of 1.52 (m, 2H), 0.88 to (m, 4H), or 0.83 (s, N).

Example 31

Methyl 4-bromo-3-oxopentanoate

To a cooled (0° (C) to a solution of methyl 3-oxopentanoate (9,62 ml of 76.8 mmol, Acros) in carbon tetrachloride (60 ml) is added dropwise within a period of 45 minutes a solution of bromine (3,96 ml, of 76.8 mmol) in carbon tetrachloride (10 ml). After 30 minutes, allow stirring at room temperature for one hour. Bubbled N2through the reaction mixture for twenty minutes. Concentrate, getting mentioned in the title compound as a brown oil. MS (EI) 208, 210 (M)+the structure Br.

Example 32

Methyl 2-(5-methyl-2-phenyloxazol-4-yl)acetate

A solution of benzamide (0,606 g, 5.00 mmol) and methyl 4-bromo-3-oxopentanoate (of 1.05 g, 5.00 mmol, example 31) are heated in toluene (6 ml) to 120°C for 18 hours. Then the reaction mixture was purified column chromatography (silica gel, 4:1 Gex:EtOAc), getting mentioned in the title compound as a clear oil, MS (APcI) 232 (M+N)+.

Example 33

Ethyl 2-methyl-6-[3-(6-vinylpyridin-2-ylethoxy)phenoxymethyl]benzoate

A solution of phenylboronic acid (74,0 mg, 0,607 mmol), ethyl 2-[3-(6-chloropyridin-2-ylethoxy)phenoxymethyl]-6-methyl-benzoate (250 mg, 0,607 mmol, example, 6v) and sodium carbonate (77,8 mg of 1.21 mmol) in a mixture of 1:1 H2O:AcCN (8 ml) is stirred under vacuum for five minutes. The reaction mixture was placed in a nitrogen atmosphere and add tetrakis(triphenylphosphine)palladium(0) (60,7 mg) followed by heating to 90°C. two hours Later, add another portion (15 mg) phenylboronic acid. An hour later the heat stop. Add distiller annoy water (10 ml), followed by extraction with methylene chloride (twice 20 ml). The organic extracts are combined and concentrated and the resulting residue is purified column chromatography (silica gel, 6:1 Gex:EtOAc)to give specified in the header connection. MS (EPI) 454 (M+N)+.

Example 34

1-Oksihinolina-2-ylmethylene

2-(Chloromethyl)quinoline hydrochloride (1,00 g of 4.67 mmol) is distributed between methylene chloride (15 ml) and sodium hydroxide solution (1 M, 15 ml)to obtain the free base. The organic layer is separated and cooled (0°C), then adding 3-chlormadinone acid (57-86%, 1.13 g, ˜of 4.67 mmol). After stirring at room temperature for 18 hours, the reaction mixture is washed with diluted sodium hydroxide. The organic layer is separated and concentrated. The resulting residue is purified column chromatography (silica gel, 1:1 Gex:EtOAc), getting mentioned in the title compound as a white solid. MS (EPI) 194, 196 (M+N)+the structure complying with Cl.

Example 35

{2-[3-(Quinoline-2-ylethoxy)phenoxymethyl]-6-methyl-phenoxy}acetonitrile

3-(Quinoline-2-ylethoxy)phenol (1.3 g, 5.4 mmol, example 3), (2-methyl bromide-6-methylphenoxy)acetonitrile (1.56 g, 6.5 mmol, example 24), tetrabutylammonium iodide (99 mg, 0.27 mmol) and potassium carbonate (0.45 g, 3.3 mmol) is heated at boiling under reflux in acetone (20 ml) during the 16 hours. The reaction mixture is filtered, washed with dichloromethane, concentrated and purified column chromatography (silica gel, 1% ether in dichloromethane)to give specified in the header connection. MS (EPI) 411 (M+N)+.

The following connections are getting, basically, using the same procedure as in example 35 except using the specified phenol instead of 3-(quinoline-2-ylethoxy)phenol.

Example 35A

{2-Methyl-6-[3-(quinoline-2-illuminometer)phenoxymethyl]- phenoxy}acetonitrile

MS (EPI) 409 (M+N)+. Obtained from 3-(quinoline-2-illuminometer) phenol (example 10).

Example 35b

{2-Methyl-6-[3-(2-[quinoline-2-elwenil)phenoxymethyl]-phenoxy}acetonitrile

MS (EPI) 407 (M+N)+. Obtained from 3-(2-quinoline-2-elwenil)phenol (example 15).

Example 35C

(2-methyl-6-{3-[2-(pyridine-2-yloxy)ethoxy]phenoxymethyl}-phenoxy)acetonitrile

MS (EPI) 391 (M+N)+. Obtained from 3-[2-(pyridine-2-yloxy)-ethoxy]phenol (example 15A).

Example 35d

{2-[3-(Benzooxazol-2-illuminometer)phenoxymethyl]-6-methylphenoxy}acetonitrile

1H NMR (300 MHz, CDCl3) δ to 7.15 (m, 11N), are 5.36 (SHS, 1H), to 5.08 (s, 2H), 4,67 (s, 4H), is 2.37 (s, 3H). MS (EPI) 400 (M+N)+. Obtained from 3-(benzooxazol-2-illuminometer) phenol (example 10C).

Example a

{2-[3-(4-Chlorhydrin-2-ileocecal)phenoxymethyl]-6-methylphenoxy}acetonitrile

1H NMR (300 MHz, CDCl3) δ by 8.22 (d, 1H), of 8.06 (d, 1H), 7,76 (m, 2H, 7,63 (m, 1H), 7,32 (m, 2H), 7.23 percent (m, 1H), 7,13 (m, 1H),? 7.04 baby mortality (m, 2H), 6,94 (m, 1H), 5,09 (s, 2H), a 4.83 (s, 2H), 4.72 in (s, 2H), and 4.68 (s, 2H), 2,39 (s, 3H). MS (EPI) 459 (M+N)+. Obtained from 3-(4-chlorhydrin-2-ileocecal) phenol (example 74b).

Example 35f

{2-[3-(6-Methoxyquinoline-2-ileocecal)phenoxymethyl]-6-methylphenoxy}acetonitrile

1H NMR (300 MHz, CDCl3) δ 8,08 (d, 1H), of 7.96 (d, 1H), 7,60 (d, 1H), 7,19 (m, 8H), 6,92 (DD, 1H), 5,07 (s, 2H), 4,84 (s, 2H), 4,71 (s, 2H), of 4.66 (s, 2H), 3,93 (s, MN), 2,39 (s, 3H). MS (EPI) 455 (M+N)+. Obtained from 3-(6-methoxyquinoline-2-ileocecal)phenol (example s).

Example 35g

{2-Methyl-6-[3-(quinoline-2-ileocecal)phenoxymethyl]-phenoxy}acetonitrile

Obtained from 3-(quinoline-2-ileocecal)phenol (example a).

The following connections are getting, basically, using the same procedure as in example 35 except using the specified bromide instead of (2-methyl bromide-6-methylphenoxy)-acetonitrile.

Example 36A

Methyl ester 2-{2-methyl-6-[3-(quinoline-2-ylethoxy)-phenoxymethyl]phenoxy}propionic acid

MS (EPI) 457 (M+N)+. Receive, using methyl 2-(2-methyl bromide-6-methylphenoxy)propionate (example 24C).

Example 36b

{2,4-Dichloro-6-[3-(quinoline-2-ylethoxy)phenoxymethyl]-phenoxy}acetonitrile

MS (EPI) 465 (M+N)+the structure responsible Cl2. Is obtained from (2-methyl bromide-4,6-dichlorophenoxy)acetonitrile (example 24A).

Example 36C

{4-Chloro-2-methyl-6-[3-(quinoline-2-ILM is toxi}phenoxymethyl]-phenoxy}acetonitrile

MS (EPI) 445 (M+N)+. Is obtained from (2-methyl bromide-4-chloro-6-methylphenoxy)acetonitrile (example 43).

Example 36d

{2-tert-Butyl-6-[3-(quinoline-2-ylethoxy)phenoxymethyl]-phenoxy}acetonitrile

MS (EPI) 453 (M+N)+. Is obtained from (2-methyl bromide-6-tert-butylphenoxy)acetonitrile (example 43A).

Example a

{4-Chloro-2-methoxy-6-[3-(quinoline-2-ylethoxy)phenoxymethyl] phenoxy}acetonitrile

MS (EPI) 461 (M+N)+the structure complying with Cl. Is obtained from (2-methyl bromide-4-chloro-6-methoxyphenoxy)acetonitrile (example 24b).

Example 36f

2-[3-(Quinoline-2-ylethoxy)phenoxymethyl]benzonitrile

MS (EPI) 386 (M+N)+. Is obtained from 2-bromomethylbiphenyl (example 27d).

Example 36g

Methyl 2-[3-(quinoline-2-ylethoxy)phenoxymethyl]thiophene-2-carboxylate

MS (EPI) 406 (M+N)+. Obtained from methyl 3-methyl bromide-thiophene-2-carboxylate (example 27E).

Example 36h

Ethyl {2-methyl-6-[3-(quinoline-2-ylethoxy)phenoxymethyl]-phenoxy}acetate

MC (EPI) 457 (M+H)+. Obtained from ethyl (2-methyl bromide-6-methylphenoxy)acetate (example 43b).

Example 36i

Ethyl 7-[3-(quinoline-2-ylethoxy)phenoxymethyl]benzofuran-2-carboxylate

MC (EPI) 354 (M+N)+. Obtained from ethyl 7-bromeilles-furan-2-carboxylate (example 94).

Example 36j

Ethyl{2-methyl-6-[3-methyl-5-(quinoline-2-ylethoxy)phenoxymethyl]phenoxy}acetate

Specified in the header of the get connection using basically the same technique, as in example 35 except using 3-methyl-5-(quinoline-2-ylethoxy)phenol (example 55) instead of 3-(quinoline-2-ylethoxy)phenol and ethyl (2-methyl bromide-6-methylphenoxy)acetate (example 43b) instead of (2-methyl bromide-6-methylphenoxy)acetonitrile.

The following connections are getting, basically, using the same procedure as in example 35 except using the specified phenol instead of 3-(quinoline-2-ylethoxy)phenol and (2-methyl bromide-4-chloro-6-methylphenoxy)acetonitrile (example 43) instead of (2-methyl bromide-6-methylphenoxy)acetonitrile.

Example 36k

{4-Chloro-2-methyl-6-[3-(2-pyridin-2-ylethoxy)phenoxymethyl] phenoxy}acetonitrile

1H NMR (300 MHz, CDCl3) δ 8,56 (d, 1H), 7.62mm (m, 1H), 7,30 (m, 1H), 7,18 (m, 3H), to 6.57 (m, 4H), at 4.99 (s, 2H), 4,67 (s, 2H), 4,36 (t, 2H), 3.27 to (t, 2H), a 2.36 (s, 3H). MS (EPI) 409 (M+N)+. Obtained from 3-(2-pyridin-2-ylethoxy) phenol (example 71A).

Example 36l

{2-[3-(Benzoxazol-2-illuminometer)phenoxymethyl]-4-chloro-6-methylphenoxy}acetonitrile

1H NMR (300 MHz, CDCl3) δ 7,14 (m, 10H), 5,35 (SHS, 1H), 5,04 (s, 2H), 4,67 (d, 2H), 4,63 (s, 2H), 2,34 (s, 3H). MS (EPI) 434 (M+N)+. Obtained from 3-(benzoxazol-2-ylamino-methyl)phenol (example 10C).

Example 37

2-[3-(2-Chloromethylbenzene)phenoxymethyl]quinoline

Specified in the header of the get connection using basically the same procedure as in example 35, except for using an excess of 1,2-bis-chloromethylbenzene instead of (2-methyl bromide-6-methyl is enocsi)acetonitrile and tetrabutylammonium iodide. MS (EPI) 390 (M+N)+the structure complying with Cl.

Example 38

2-[3-(Quinoline-2-ylethoxy)phenoxymethyl]phenyl}acetonitrile

Sodium cyanide (14 mg, 0.28 mmol) is added to a solution of 2-[3-(2-chloromethylbenzene)phenoxymethyl]quinoline (110 mg, 0.28 mmol, example 37) in DMSO (5 ml) and the reaction mixture is stirred for 5 hours. The reaction mixture was partitioned between water and ethyl acetate, the organic phase is washed with water, dried and concentrated, obtaining mentioned in the title compound which is used without further purification. MS (EPI) 381 (M+N)+.

Example 39

{2-[3-(Cinoxacin-2-ylethoxy)phenoxymethyl]-6-methyl-phenoxy}acetonitrile

A solution of (2-[3-hydroxyphenoxy]-6-methylphenoxy)-acetonitrile (100 mg, of 0.37 mmol, example 25), cinoxacin-2-iletileri [72 mg, 0.40 mmol (See Chem. Ber. 1987, 120, 649-651)] in DMF (1 ml) is heated with potassium carbonate (105 mg, 0.75 mmol) at 60°C for 16 hours. The reaction mixture is filtered and concentrated distribution between ethyl acetate and water. The organic phase is washed with water, dried over magnesium sulfate, concentrated and purified column chromatography (silica gel, 30% ethyl acetate in hexane)to give specified in the header connection. MS (EPI) 412 (M+N)+.

The following connections are getting, basically, using the same procedure as in example 39, except using the specified halide VM is STO cinoxacin-2-iletileri.

Example 39A

{2-[3-(7-Chloroisoquinoline-3-ylethoxy)phenoxymethyl]-6-methylphenoxy}acetonitrile

MS (EPI) 445 (M+N, the structure responsible Cl)+. Derived from {2-methyl-6-[(3-hydroxyphenoxy)methyl]phenoxy}acetonitrile (example 25) and (7-chloroisoquinoline-3-yl)methyl bromide (see Ewing, William R.; Becker, Michael R.; Choi-Sledeski, Yong Mi; Pauls, Heinz W.; He, Wei; Condon, Stephen M.; Davis, Roderick S.; Hanney, Barbara A.; Spada, Alfred P.; Burns, Christopher J.; Jiang, John Z.; Li, Aiwen; Myers, Michael R.; Lau, Wan F.; Poli, Gregory B; Substituted piperazinone derivatives and other oxoazaheterocyclyl compounds useful as factor Xa inhibitors. PCT Int. Appl, (1999), WO 9937304.

Example 39b

{2-Methyl-6-[3-(naphthalene-2-ylethoxy)phenoxymethyl]-phenoxy}acetonitrile

MS (EPI) 410 (M+N)+. Derived from naphthalene-2-ylmethyl-chloride.

Example 39C

{2-[3-(4-tert-Butylbenzoate)phenoxymethyl]-6-methyl-

phenoxy}acetonitrile

MS (EPI) 416 (M+N)+. Obtained from 4-tert-butylbenzylamine.

Example 39d

{2-Methyl-6-[3-(2-phenoxyethoxy)phenoxymethyl]phenoxy}-acetonitrile

MS (EPI) 390 (M+N)+. Is obtained from 2-phenoxyethylamine.

Example 39e

{2-Methyl-6-[3-(3-phenylpropoxy)phenoxymethyl]phenoxy}-

acetonitrile

MS (EPI) 388 (M+N)+. Obtained from 3-phenylpropylamine.

Example 39f

{2-Methyl-6-[3-(3-phenoxybenzyl)phenoxymethyl]-phenoxy}acetonitrile

MC (EPI) 452 (M+N)+. Obtained from 3-phenoxybenzyl-chloride.

Example 39g

{2-[3-(3-Methoxybenzyloxy)phenoxymethyl-6-methylphenoxy}-acetonitril the

MC (EPI) 390 (M+H)+. Obtained from 3-methoxybenzylamine.

Example 39h

{2-[3-(3,4-Dichloraniline)phenoxymethyl-6-methyl-phenoxy}acetonitrile

MC (EPI) 428 (M+H)+. Derived from 3,4-dichlorobenzaldehyde.

Example 39i

{2-[3-(6,7-Divergingly-2-ylethoxy)phenoxymethyl]-6-methylphenoxy}acetonitrile

MC (EPI) 446 (M+N)+. Receive from 6,7-divergingly-2-iletileri (example 27).

Example 39j

{2-[3-(6,8-Divergingly-2-ylethoxy)phenoxymethyl]-6-methylphenoxy}acetonitrile

MC (EPI) 446 (M+N)+. Receive from 6,8-divergingly-2-ylmethylboronic (example 27A).

Example 39k

{2-Methyl-6-[3-(1-oksihinolina-2-ylethoxy)phenoxymethyl]-phenoxy}acetonitrile

MC (EPI) 427 (M+N)+. Obtained from 1-oksihinolina-2-ylmethyl-chloride (example 34).

Example 39 (l model

{2-[3-(6-Ftorhinolon-2-ylethoxy)phenoxymethyl]-6-methyl-phenoxy}acetonitrile

MS (EPI) 429 (M+N)+. Obtained from 6-ftorhinolon-2-ylmethylboronic (example 27b).

Example 39m

{2-Methyl-6-[3-(1-methyl-4-oxo-1,4-dihydroquinoline-2-ylethoxy)phenoxymethyl]phenoxy}acetonitrile

MS (EPI) 441 (M+N)+. Obtained from 1-methyl-4-oxo-1,4-dihydroquinoline-2-ylmethylboronic (example 29).

Example 39n

{2-[3-(4-Chlorhydrin-2-ylethoxy)phenoxymethyl]-6-methylphenoxy}acetonitrile

MS (EPI) 445 (M+N)+. Obtained from 4-chlorhydrin-2-iletileri (example 46).

Example 39

{2-[3-(7-Chlorhydrin-2-ylethoxy)hair dryer is kemetyl]-6-methylphenoxy}acetonitrile

MS (EPI) 445 (M+N)+. Obtained from 7-chlorhydrin-2-iletileri (example 46a).

Example R

{2-[3-(6-Methoxyquinoline-2-ylethoxy)phenoxymethyl]-6-methylphenoxy}acetonitrile

MS (EPI) 441 (M+N)+. Obtained from 6-methoxyquinoline-2-iletileri (example 46b).

Example 39q

{2-Methyl-6-[3-(pyridine-4-ylethoxy)phenoxymethyl]-phenoxy}acetonitrile

1H NMR (300 MHz, CDCl3) δ 8,62 (sm, 2H), 7,24 (m, 6N), 6,62 (m, 3H), to 5.08 (s, 2H), is 5.06 (s, 2H), 4,70 (s, 2H), 2,39 (s, 3H). MS (EPI) 361 (M+N)+. Obtained from 4-chloromethylpyridine.

Example 39r

{2-Methyl-6-[3-(pyridine-2-ylethoxy)phenoxymethyl]-phenoxy}acetonitrile

1H NMR (300 MHz, CDCl3) δ at 8.60 (d, 1H), 7,72 (m, 1H), 7,52 (d, 1H), 7,21 (m, 5H), 6,63 (m, 3H), 5,20 (s, 2H), 5,04 (S, 2H), 4,69 (s, 2H), 2,39 (s, 3H). MS (EPI) 361 (M+N)+. Is obtained from 2-chloromethylpyridine.

Example 39s

{2-Methyl-6-[3-(pyridine-3-ylethoxy)phenoxymethyl]-phenoxy}acetonitrile

1H NMR (300 MHz, CDCl3) δ 8,68 (SHS, 1H), 8,59 (sm, 1H), 7,78 (m, 1H), from 7.24 (m, 5H), 6,63 (m, 3H), 5,07 (s, 2H), is 5.06 (s, 2H), 4,70 (s, 2H), 2,39 (s, 3H). MS (EPI) 361 (M+H)+. Obtained from 3-chloromethylpyridine.

Example 39t

{2-[3-(6,7-Dichlorohydrin-2-ylethoxy)phenoxymethyl]-6-methylphenoxy}acetonitrile

1H NMR (300 MHz, CDCl3) δ to 8.20 (s, 1H), 8,10 (d, 1H), 7,94 (s, 1H), of 7.70 (d, 1H), 7,20 (m, 4H), of 6.65 (m, 3H), of 5.34 (s, 2H), of 5.05 (s, 2H), 4,69 (s, 2H), of 2.38 (s, 3H). MS (EPI) 479 (M+N)+. Receive from 6,7-dichlor-chloromethylpyridine (example 27f).

Example 39u

{2-Methyl-6-[3-(2-phenylthiazol-4-ylethoxy)phenoxymethyl]-phenoxy}acetonitrile

MS (EPI) 443 (M+N)+. Obtained from 4-chloromethyl-2-phenylthiazole (example 20).

The following connections are getting, basically, using the same procedure as in example 39, except for the use of the phenol instead of (2-[3-hydroxyphenoxy]-6-methylphenoxy)of acetonitrile and 6-ftorhinolon-2-ylmethylboronic (example 27b) instead of cinoxacin-2-iletileri.

Example 40A

{4-Chloro-2-[3-(b-ftorhinolon-2-ylethoxy)phenoxymethyl]-6-methylphenoxy}acetonitrile

MS (EPI) 463, 465 (M+N)+the structure complying with Cl. Is obtained from (2-[3-hydroxyphenoxy]-4-chloro-6-methyl-phenoxy)acetonitrile (example 25A).

Example 40b

{2,4-Dichloro-6-[3-(6-ftorhinolon-2-ylethoxy)phenoxymethyl] phenoxy}acetonitrile

MS (EPI) 483, 485, 487 (M+N)+the structure responsible Cl2. Derived from [4,6-dichloro-2-(3-hydroxyphenoxy)phenoxy]-acetonitrile (example 25b).

Example 41

{2-Methyl-6-[3-(quinoline-2-illuminometer)phenoxymethyl]-phenoxy}acetic acid

To a solution of {2-methyl-6-[3-(quinoline-2-illuminometer)-phenoxymethyl]phenoxy}acetonitrile (134 mg, 0.31 mmol, example 35A) in methanol (1 ml) is added THF (1 ml) followed by the addition of sodium hydroxide solution [0.2 ml, 10 BC). The resulting mixture was heated to 60°C and stirred at this temperature for 3 hours. Then implement the transition mixture is cooled to room temperature and acidified to approximately pH 5 with hydrochloric acid (1 ml, 2 N.), then extracted with ethyl acetate, washed with saturated salt solution, dried over MgSO4and concentrate. The residue is purified flash chromatography (silica gel, 10% methanol in dichloromethane)to give specified in the header of the connection.1H NMR (300 MHz, CDCl3) δ 8,10 (d, 1H), 7,80 (d, 1H), 7,68 (t, 2H), 7,40 (t, 1H), 7,25 (m, 2H),? 7.04 baby mortality (m, 3H), 6.90 to (m, 3H), 6,6 (SHS, 1H), further 5.15 (s, 2H), 4,60 (d, 2H), 4,50 (s, 2H), and 2.27 (s, 3H). MS (EPI) 429 (M+N)+.

The following connections are getting, basically, using the same procedure as in example 41, except for the use of the nitrile or complex ester instead of {2-methyl-6-[3-(quinoline-2-illuminometer)phenoxymethyl]phenoxy}acetonitrile.

Example 41A

{2-Methyl-6-[3-(2-quinoline-2-elwenil)phenoxymethyl]-phenoxy}acetic acid

1H NMR (300 MHz, DMSO) d scored 8.38 (d, 1H), 8,01 (d, 1H), of 7.97 (d, 1H), 7,89 (d, 1H), 7,83 (d, 1H), 7,78 (dt, 1H), to 7.59 (dt, 1H), 7,53 (d, 1H), 7,44 (sm, 1H), was 7.36 (m, MN), 7,25 (sm, 1H), 7,11 (t, 1H), 7,02 (dt, 1H), the 5.25 (s, 2H), of 4.54 (s, 2H), 2,32 (s, 3H). MS (EPI) 426 (M+N)+. Derived from {2-methyl-6-[3-(2-quinoline-2-elwenil)phenoxymethyl]phenoxy}acetonitrile (example 35b).

Example 41b

(2-Methyl-6-{3-[2-(pyridine-2-yloxy)ethoxy]phenoxymethyl}-phenoxy)acetic acid

1H NMR (300 MHz, DMSO) d 8,17 (DD, 1H), 7,72 (m, 1H), 7,29 (DD, 1H), 7,20 (m, 2H), 7,07 (t, 1H), 6,99 (m, 1H), 6,85 (d, 1H), 6,60 (m, 3H), 5,13 (s, 2H), 4,57 (t, 2H), 4,49 (s, 2H), 4,30 (t, 2H), 2,28 (s, 3H). MS (EPI) 410 (M+N)+. Is obtained from (2-methyl-6-{3-[2-(pyridine-2-yloxy)ethoxy]phenoxymethyl}phenoxy)acetonitrile (example 35C).

Example 41p

{2-[3-(7-Chloroisoquinoline-3-ylethoxy)phenoxymethyl]-6-methylphenoxy}acetic acid

1H NMR (300 MHz, CDCl3) δ 9,13 (d, 1H), of 7.96 (s, 1H), 7,79 (s, 1H), 7,74 (d, 1H), 7,65 (d, 1H), 7,30 (d, 1H), 7,20 (m, 1H), 7,10 (m, 2H), for 6.81 (s, 1H), 6,62 (d, 1H), of 6.49 (d, 1H), 5.25 in (s, 2H), 5,16 (s, 2H), 4,59 (s, 2N), is 2.37 (s, 3H). MS (PEM) 464 MS (EPI) (M+N, the structure responsible Cl)+. Derived from {2-[3-(7-chloroisoquinoline-3-ylethoxy)phenoxymethyl]-6-methylphenoxy}acetonitrile (example 39A).

Example 41d

{2-Methyl-6-[3-(naphthalene-2-ylethoxy)phenoxymethyl]-phenoxy}acetic acid

1H NMR (300 MHz, CDCl3) δ 8,00 (m, 3H), of 7.48 (DD, 1H), 7,43 (m, 2H), 7.23 percent (m, 2H), 7,16 (m, 2H), 7,05 (t, 1H), 6,62 (m, 1H), 6,55 (m, 2H). MS (EPI) 429 (M+N)+. Derived from {2-methyl-6-[3-(naphthalene-2-ylethoxy)phenoxymethyl]phenoxy}-acetonitrile (example 39b).

Example a

{2-[3-(4-tert-Butylbenzoate)phenoxymethyl]-6-methyl-phenoxy}acetic acid

1H NMR (300 MHz, CDCl3) δ 7,38 (m, 3H), 7,27 (m, 2H), 7,24 (d, 1H), 7,17 (d, 1H), 7,10 (d, 1H), 6,59 (m, 3H), 5,07 (s, 2H), to 4.98 (s, 2H), 4,57 (s, 2H), 2,33 (s, 3H), of 1.33 (s, N). MS (EPI) 435 (M+N)+. Derived from {2-[3-(4-tert-butylbenzoate)phenoxymethyl]-6-methylphenoxy}acetonitrile (example 39C).

Example 41f

{2-Methyl-6-[3-(2-phenoxyethoxy)phenoxymethyl]phenoxy}-acetic acid

1H NMR (300 MHz, CDCl3) δ 7,03-7,33 (m, 6N), to 6.95 (m, 3H), to 6.57 (m, 3H), 5,07 (s, 2H), 4,55 (s, 2H), 4,29 (m, 4H), of 2.33 (s, 3H). MS (EPI) 409 (M+N)+. Derived from {2-methyl-6-[-(2-phenoxyethoxy)phenoxymethyl]phenoxy}acetonitrile (example 39d).

Example 41g

{2-Methyl-6-[3-(3-phenylpropoxy)phenoxymethyl]phenoxy}-acetic acid

1H NMR (300 MHz, CDCl3) δ 7,07-7,41 (m, N), is 6.54 (m, 3H), to 5.08 (s, 2H), 4,58 (s, 2H), 3,94 (t, 2H), 2,80 (t, 2H), 2,34 (s, 3H), of 2.09 (Quint, 2H). MS (EPI) 407 (M+N)+. Derived from {2-methyl-6-[3-(3-phenylpropoxy)phenoxymethyl]phenoxy)acetonitrile (example 39e).

Example 41h

{2-Methyl-6-[3-(3-phenoxybenzyl)phenoxymethyl]-phenoxy}acetic acid

1H NMR (300 MHz, CDCl3) δ 7,31 (m, 4H), 7,06-7,25 (m, 6N), 7,01 (m, 2H), 6,94 (m, 1H), to 6.57 (m, 3H), of 5.06 (s, 2H), 4,99 (s, 2H), 4,56 (s, 2H), 2,33 (S, 3H). MS (EPI) 471 (M+N)+. Derived from {2-methyl-6-[3-(3-phenoxybenzyl)-phenoxymethyl]phenoxy}acetonitrile (example 39f).

Example 41i

{2-[3-(3-Methoxybenzyloxy)phenoxymethyl]-6-methyl-phenoxy}acetic acid

MS (EPI) 409 (M+N)+. Derived from {2-[3-(3-methoxy-benzyloxy)phenoxymethyl]-6-methylphenoxy}acetonitrile (example 39g).

Example 41j

(2-[3-(3,4-Dichloraniline)phenoxymethyl]-6-methylphenoxy}acetic acid

1H NMR (300 MHz, CDCl3) δ of 7.60 (d, 1H), 7,51 (d, 1H), 7,30-7,38 (m, 2H), 7,28 (d, 1H), 7.23 percent (d, 1H), 7,17 (d, 1H), 6,66 (m, 3H), 5,16 (s, 2H), of 5.05 (s, 2H)and 4.65 (s, 2H), 2,42 (s, 3H). MS (EPI) 447 (M+N)+. Derived from {2-[3-(3,4-dichloro-benzyloxy)phenoxymethyl]-6-methylphenoxy}acetonitrile (example 39h.

Example 41k

{2-[3-(6,7-Divergingly-2-ylethoxy)phenoxymethyl]-6-methylphenoxy}acetic acid

TPL 94-95°C.1H NMR (300 MG IS, CDCl3) δ 8,10 (d, 1H), 7,73 (m, 1H), 7,56 (d, 1H), 7,44 (d, 1H), 7,29 (s, 1H), 7,18 (m, 1H), was 7.08 (m, 2H), 6,79 (s, 1H), is 6.61 (d, 1H), 6,51 (m, 1H), 5,31 (s, 2H), further 5.15 (s, 2H), br4.61 (s, 2H), 2,35 (s, 3H). MS (EPI) 466 (M+N)+. Derived from {2-[3-(6,7-Divergingly-2-ylethoxy )phenoxymethyl]-6-methylphenoxy}acetonitrile (example 39i).

Example 41l

{2-[3-(6,8-Divergingly-2-ylethoxy)phenoxymethyl]-6-methylphenoxy}acetic acid

TPL 137-141°C.1H NMR (300 MHz, CDCl3): δ is 8.16 (d, 1H), 7,79 (d, 1H), 7,29-7,05 (m, 6N), of 6.71 (s, 1H), 6,61 (m, 2H), of 5.53 (s, 2H), 5,10 (s, 2H), 4,57 (s, 2H), 2,33 (s, 3H). MS (EPI) 466 (M+N)+. Derived from {2-[3-(6,8-Divergingly-2-ylethoxy) phenoxymethyl]-6-methylphenoxy}acetonitrile (example 39j).

Example 41 m

{2-Methyl-6-[3-(1-oksihinolina-2-ylethoxy)phenoxymethyl]-phenoxy}acetic acid

TPL 146-147°C.1H NMR (300 MHz, CDCl3) δ 8,73 (d, 1H), 8,01 (m, 1H), to 7.93 (m, 1H), 7,89 (m, 1H), of 7.70 (m, 1H), 7,55 (d, 1H), 7,26 (m, 2H), 7,01 (m, 2H), 6.75 in (m, 3H), 5,69 (s, 2H), 5,26 (s, 2H), 4,47 (s, 2H), 2,24 (s, 3H). MS (EPI) 446 (M+N)+. Derived from {2-methyl-6-[3-(1-oksihinolina-2-ylethoxy)phenoxymethyl]phenoxy}acetonitrile (example 39k).

Example 41n

{2-[3-(6-Ftorhinolon-2-ylethoxy)phenoxymethyl]-6-methyl-phenoxy}acetic acid

TPL 160-161°C.1H NMR (300 MHz, CDCl3): δ 8,17 (m, 2H), 7,72 (d, 1H), of 7.48 (m, 2H), 7,27 (m, 1H), 7,19 (d, 1H), was 7.08 (m, 2H), 6,63 (s, 1H), 6,62 (d, 1H), 6,53 (d, 1H), to 5.35 (s, 2H), 5,14 (s, 2H), br4.61 (s, 2H), 2,34 (s, 3H). MS (EPI) 448 (M+N)+. Derived from {2-[3-(6-Ftorhinolon-ylethoxy)-phenoxymethyl]-6-methylphenoxy}acetonitrile (example 391).

Example a

{2-Methyl-6-[3-(1-methyl-4-oxo-1,4-dihydroquinoline-2-ylethoxy)phenoxymethyl]phenoxy}acetic acid

TPL 192-194°C.1H NMR (300 MHz, 1:1 CDCl3:CD3OD): δ 8,29 (m, 1H), 7,76 (m, 2H), 7,41 (m, 1H), 7,25-6,92 (m, 4H), for 6.81-6,41 (m, 4H), 5,11 (m, 4H), 4,39 (s, 2H), 3,88 (s, 3H), and 2.27 (s, 3H). MS (EPI) 460 (M+N)+. Derived from {2-methyl-6-[3-(1-methyl-4-oxo-1,4-dihydroquinoline-2-ylethoxy)phenoxymethyl]phenoxy}acetonitrile (example 39m).

Example R

{4-Chloro-2-[3-(6-Ftorhinolon-2-ylethoxy)phenoxymethyl]-6-methylphenoxy}acetic acid

TPL 140-141°C.1H NMR (300 MHz, 5:1 CDCl3:CD3OD): δ to 8.20 (d, 1H), 8,07 (m, 1H), 7,69 (d, 1H), 7,50 (m, 2H), 7,25 (s, 1H), 7,16 (m, 1H), 7,11 (s, 1H), to 6.67 (s, 1H), 6,60 (m, 2H), and 5.30 (s, 2H), 5,07 (s, 2H), 4,24 (s, 2H), of 2.25 (s, 3H). MS (EPI) 482, 484 (M+N)+the structure complying with Cl. Derived from {4-chloro-2-[3-(6-ftorhinolon-2-ylethoxy)phenoxymethyl]-6-methylphenoxy}acetonitrile (example 40A).

Example 41q

{2,4-Dichloro-6-[3-(6-ftorhinolon-2-ylethoxy)phenoxymethyl]phenoxy}acetic acid

TPL 189-190°C.1H NMR (300 MHz, 5:1 CDCl3:CD3OD) δ by 8.22 (d, 1H), 8,07 (m, 1H), 7,73 (d, 1H), 7,52 (m, 2H), 7,35 (m, 2H), 7,21 (m, 1H), 6,72 (s, 1H), 6,65 (m, 2H), of 5.34 (s, 2H), with 5.22 (s, 2H), and 4.68 (s, 2H). MS (EPI) 502, 504, 506 (M+N)+the structure responsible Cl2. Derived from {2,4-dichloro-6-[3-(6-ftorhinolon-2-ylethoxy)phenoxymethyl]phenoxy}acetonitrile (example 40b).

Example 41r

{2-Methyl-6-[3-(2-pyridin-2-ylethoxy)phenoxymethyl]-f is noxy}acetic acid

1H NMR (300 MHz, DMSO) d of 8.50 (d, 1H), 7,73 (dt, 1H), was 7.36 (d, 1H), 7,20 (m, 4H),? 7.04 baby mortality (m, 1H), return of 6.58 (m, 2H), 6,50 (d, 1H), 5,77 (s, 2H), further 5.15 (s, 2H), 4,35 (m, 4H), 3,20 (t, 2H), of 2.25 (s, 3H). MS (EPI) 394 (M+N)+. Derived from {2-methyl-6-[3-(2-pyridin-2-ylethoxy)phenoxymethyl]phenoxy}acetonitrile (example 21).

Example 41s

{2-[3-(Quinoline-2-ylethoxy)phenoxymethyl]-6-methyl-phenoxy}acetic acid

TPL 154-157°;1H NMR (300 MHz, CDCl3) δ of 8.25 (d, 1H), 8,19 (d, 1H), 7,81 (d, 1H), to 7.77-of 7.70 (m, 2H), 7,60-of 7.55 (m, 1H), 7,27 (DD, 1H), 7,18 (d, 1H), 7,13? 7.04 baby mortality (m, 2H), 6,85 (t, 1H), is 6.61 (DD, 1H), 6,53 (DD, 1H), of 5.40 (s, 2H), by 5.18 (s, 2H), to 4.62 (s, 2H), 2,35 (s, 3H); MS (EPI) 430 (M+N)+. Derived from {2-[3-(quinoline-2-ylethoxy)phenoxymethyl]-6-methylphenoxy}acetonitrile (example 35).

Example 41t

{2-Methyl-6-[3-(cinoxacin-2-ylethoxy)phenoxymethyl]-phenoxy}acetic acid

1H NMR (300 MHz, DMSO-d6) δ 9,07 (s, 1H), 8,14-with 8.05 (m, 2H), 7,87-of 7.82 (m, 2H), 7,19-7,05 (m, 3H), 6,97-6,92 (m, 1H), 6,77 (s, 1H), 6,67-to 6.57 (m, 2H), 5,41 (s, 2H), 5,19 (s, 2H), 4,10 (s, 2H), of 2.21 (s, 3H); MS (EPI) 431 (M+N)+. Derived from {2-[3-(cinoxacin-2-ylethoxy)phenoxymethyl]-6-methylphenoxy}-acetonitrile (example 39).

Example 41u

2-{2-Methyl-6-[3-(quinoline-2-ylethoxy)phenoxymethyl]-phenoxy}propionic acid

1H NMR (300 MHz, DMSO-d6d to 8.40 (d, 1H), to 7.99 (DD, 2H), to 7.77 (DD, 1H), to 7.67-7,58 (m, 2H), 7,22-7,10 (m, 3H), 6,98 (DD, 1H), 6.73 x (s, 1H), 6,60 (DD, 2H), 5,33 (s, 2H), 5,19 (DD, 2H), 4,40-4,34 (m, 1H), 2,24 (s, 3H), of 1.35 (d, 3H); MS (EPI) 444 (M+N)+. Obtained from methyl 2-{2-METI the-6-[3-(quinoline-2-ylethoxy)phenoxymethyl]phenoxy}propionate (example 36A).

Example 41v

{2,4-Dichloro-6-[3-(quinoline-2-ylethoxy)phenoxymethyl]-phenoxy}acetic acid

TPL 201-203°;1H NMR (300 MHz, DMSO-d6d scored 8.38 (d, 1H), 7,98 (DD, 2H), 7,76 (DD, 1H), 7,66-EUR 7.57 (m, 2H), 7,54 (d, 1H), 7,39 (d, 1H), 7,18 (DD, 1H), 6.75 in (s, 1H), 6,66-of 6.61 (m, 2H), 5,33 (s, 2H), 5,28 (s, 2H), 4,48 (s, 2H); MS (EPI) 484, 486 (M+N; Cl2)+. Derived from {2,4-dichloro-6-[3-(quinoline-2-ylethoxy)phenoxymethyl]phenoxy}acetonitrile (example 36b).

Example 41w

(4-Chloro-2-methyl-6-[3-(quinoline-2-ylethoxy)phenoxymethyl]-phenoxy}acetic acid

1H NMR (300 MHz, CDCl3) δ of 8.37 (d, 1H), 8,02 (d, 1H), to 7.93 (d, 1H), 7,78-of 7.70 (m, 2H), 7,60 (t, 1H), 7.24 to to 7.15 (m, MN), was 6.73 (s, 1H), 6,66-of 6.61 (m, 2H), of 5.34 (s, 2H), 5,14 (s, 2H), 4,27 (s, 2H), to 2.29 (s, 3H); MS (EPI) 464 (M+N)+. Derived from {4-chloro-2-methyl-6-[3-(quinoline-2-ylethoxy)-phenoxymethyl]phenoxy}acetonitrile (example 36C).

Example h

{2-tert-Butyl-6-[3-(quinoline-2-ylethoxy)phenoxymethyl]-phenoxy}acetic acid

1H NMR (300 MHz, CD3OD) d with 8.33 (d, 1H), 8,01 (d, 1H), of 7.90 (d, 1H), 7,80-of 7.55 (m, 3H), 7,35-7,28 (m, 2H), 7,15-7,01 (m, 2H), of 6.71 (s, 1H), 6,60 (d, 2H), of 5.40 (s, 2H), 5,10 (s, 2H), and 4.40 (s, 2H), 1,41 (s, N); MS (EPI) 472 (M+N)+.

Derived from {2-tert-butyl-6-[3-(quinoline-2-ylethoxy)phenoxymethyl]phenoxy}acetonitrile (example 36d).

Example 41y

{4-Chloro-2-methoxy-6-[3-(quinoline-2-ylethoxy)phenoxymethyl] phenoxy} acetic acid

TPL 185-190°,1H NMR (300 MHz, DMSO) d to 8.45 (d, 1H), 8,04 (t, 2H), 7,82 (t, 1H), 7,71-7,76 (m, 2H), 7.23 percent (t, 1H), 7,13 (d, 1H, 7,02 (d, 1H), 6,77 (d, 1H), of 6.71 is 6.67 (m, 2H), 5,38 (s, 2H), 5,28 (s, 2H), to 4.62 (s, 2H), 3,86 (s, 3H); MS (EPI) 480 (M+N)+. Derived from {4-Chloro-2-methoxy-6-[3-(quinoline-2-ylethoxy)phenoxymethyl]phenoxy}acetonitrile (example e).

Example 41z

2-[3-(Quinoline-2-ylethoxy)phenoxymethyl]benzoic acid

1H NMR (300 MHz, CDCl3) δ 8,13 (d, 1H), 8,03 (d, 1H), 7,79 (d, 1H), 7,70-7,41 (m, 5H), 7,10 (t, 1H), to 6.67 (s, 1H), return of 6.58 (d, 2H), 5,51 (s, 2H), are 5.36 (s, 2H); MS (EPI) 386 (M+N)+. Is obtained from 2-[3-(quinoline-2-ylethoxy)phenoxymethyl]-benzonitrile (example 36f).

Example a

2-[3-(Quinoline-2-ylethoxy)phenoxymethyl]thiophene-2-carboxylic acid

1H NMR (300 MHz, CD3OD) d at 8.36 (d, 1H), 8,04 (d, 1H), 7,94 (d, 1H), 7,78 (t, 1H), of 7.70 (d, 1H), to 7.61 (t, 1H), of 7.48 (d, 1H), 7,13-7,19 (m, 2H), 6,70 (s, 1H), 6,61 (dt, 2H), 5,46 (s, 2H), 5,32 (s, 2H); MS (EPI) 392 (M+H)+. Obtained from methyl 2-[3-(quinoline-2-ylethoxy)phenoxymethyl]thiophene-2-carboxylate (example 36g).

Example 41ab

{2-[3-(Quinoline-2-ylethoxy)phenoxymethyl]phenyl}acetic acid

1H NMR (300 MHz, CDCl3) δ 8,20-8,11 (m, 2H), 7,83-7,52 (m, 4H), 7,40-7,27 (m, 4H), 7.18 in-7,10 (m, 1H), 6,67-6,46 (m, 3H), to 5.35 (s, 2H), 5,12 (s, 2H), 3,76 (s, 2H); MS 400 (M+N)+. Derived from {2-[3-(quinoline-2-ylethoxy)phenoxymethyl]phenyl}-acetonitrile (example 38).

Example 41ac

{4-Chloro-2-methyl-6-[3-(quinoline-2-ylethoxy)benzyloxy-methyl]phenoxy}acetic acid

1H NMR (300 MHz, CDCl3) δ 8,19 (d, 1H), of 8.09 (d, 1H), 7,82 (d, 1H), 7,78-the 7.65 (m, 2H), of 7.75 (DD, 1H), 7,31-26 (DD, 1H), 18th (DD, 1H), 7,05-6,92 (m, 4H), 5,20 (s, 2H), 4.26 deaths (s, 2H), 4,23 (s, 2H), 4,15 (s, 2H), 2,12 (s, 3H); MS (EPI) 478, 480 (M+H; Cl)+. Get from (example 52).

Example 41ad

{2-[3-(4-Chlorhydrin-2-ylethoxy)phenoxymethyl]-6-methylphenoxy}acetic acid

1H NMR (300 MHz, DMSO) δ to 8.20 (DD, 1H), 8,08 (d, 1H), to $ 7.91-7,74 (m, 3H), 7.24 to to 7.15 (m, 3H), 7,01 (t, 1H), 6,74 (t, 1H), 6,66-6,59 (m, 2H), 5,32 (s, 2H), 5,12 (s, 3H), 4,43 (s, 2H), 2,24 (s, 3H); MS (EPI) 464 (M+N)+. Derived from {2-[3-(4-chlorhydrin-2-ylethoxy)phenoxymethyl]-6-methylphenoxy}Aceto-nitrile (example 39n).

Example AE

{2-[3-(7-Chlorhydrin-2-ylethoxy)phenoxymethyl]-6-methyl-phenoxy}acetic acid

1H NMR (300 MHz, DMSO) δ 8,42 (d, 1H), 8,03-of 8.00 (m, 2H), 7.68 per-of 7.60 (m, 2H), 7,27-7,07 (m, 3H), 6,94 (t, 1H), 6,70 (d, 1H), 6,59 (DD, 2H), 5,31 (s, 2H), by 5.18 (s, 2H), measuring 2.20 (s, 3H); MS (EPI) 464 (M+N)+. Derived from {2-[3-(7-chlorhydrin-2-ylethoxy)phenoxymethyl]-6-methylphenoxy}acetonitrile (example 39).

Example 41af

{2-[3-(6-Methoxyquinoline-2-ylethoxy)phenoxymethyl]-6-methylphenoxy)acetic acid

1H NMR (300 MHz, CDCl3) δ 8,07 (t, 2H), 7,60 (d, 1H), was 7.36 (DD, 1H), 7,27-7,24 (m, 1H), 7,15 (d, 1H), 7,05-7,00 (m, MN), 6,79 (s, 1H), return of 6.58 (d, 1H), of 6.49 (DD, 1H), 5,31 (s, 2H), 5,14 (s, 2H), of 4.54 (s, 2H), 3,90 (s, 3H), of 2.30 (s, 3H); MS (EPI) 460 (M+N)+. Derived from {2-[3-(6-Methoxyquinoline-2-ylethoxy )phenoxymethyl]-6-methylphenoxy}acetonitrile (example R).

Example 41ag

{2-[4-Bromo-3-(quinoline-2-ylethoxy)phenoxymethyl]-6-methylphenoxy}acetic acid

1H NMR (300 MG IS, DMSO) δ 8,42 (d, 1H), 8,00-of 7.97 (m, 2H), 7,79-of 7.70 (m, 2H), 7,63-7,58 (m, 1H), 7,46 (d, 1H), 7,20-7,13 (m, 2H), 6,99-to 6.95 (m, 2H), 6,59 (DD, 1H), 5,42 (s, 2H), 5,17 (s, 2H), 4,30 (s, 2H), 2,22 (s, 3H); MS (ion spray) 508 (M+N)+. Obtained from ethyl {2-[4-bromo-3-(quinoline-2-ylethoxy)phenoxymethyl]-6-methylphenoxy}acetate (example 54).

Example 41ah

{2-[2-Bromo-5-(quinoline-2-ylethoxy)phenoxymethyl]-6-methylphenoxy}acetic acid

1H NMR (300 MHz, CDCl3) δ 8,18-of 8.15 (m, 2H), 7,81-7,72 (m, 2H), 7,63-7,53 (m, 2H), 7,37 (d, 1H), 7,28 (d, 1H), 7,17-7,13 (m, 1H), to 7.09-7.03 is (m, 1H), 6,91 (d, 1H), 6.42 per (DD, 2H), are 5.36 (s, 2H), 5,32 (s, 2H), 4,63 (s, 2H), 2,32 (s, 3H); MS (other spraying) 508 (M+N)+. Obtained from ethyl {2-[2-bromo-5-(quinoline-2-ylethoxy)phenoxymethyl]-6-methylphenoxy}-acetate (example 54).

Example 41ai

{2-Methyl-6-[3-methyl-5-(quinoline-2-ylethoxy)phenoxymethyl]phenoxy}acetic acid

1H NMR (300 MHz, CDCl3) δ 8,21-to 8.14 (m, 2H), 7,82-7,66 (m, 3H), 7,58 (t, 1H), 7,27-7,24 (m, 1H), 7,17 (d, 1H),? 7.04 baby mortality (t, 1H), 6,60 (s, 1H), gold 6.43 (s, 1H), 6,37 (s, 1H), 5,24 (s, 2H), 5,13 (s, 2H), 4,60 (s, 2H), 2,32 (s, 3H)), are 2.19 (s, 3H); MS (ion spray) 444 (M+N)+. Obtained from ethyl {2-methyl-6-[3-methyl-5-(quinoline-2-ylethoxy)phenoxymethyl]phenoxy}-acetate (example 36j).

Example 41aj

{2-[2-Acetyl-5-(quinoline-2-ylethoxy)phenoxymethyl]-6-methylphenoxy}acetic acid

1H NMR (300 MHz, DMSO) δ 8,39 (d, 1H), 8,00-of 7.96 (m, 2H), 7,76 (t, 1H), to 7.67-EUR 7.57 (m, 3H), 7,28 (d, 1H), 7,14 (d, 1H), 7,02-7,00 (m, 2H), 6,69 (d, 1H), 5,43 (s, 2H), to 5.35 (s, 2H), 4,27 (s, 2H), 2,39 (s, 3H)), of 2.23 (s, 3H); MS(ion spray) 472 (M+N) +. Obtained from ethyl {2-[2-acetyl-5-(quinoline-2-ylethoxy)phenoxymethyl]-6-methylphenoxy}acetate (example 59).

Example 41ak

{4-Chloro-2-methyl-6-[3-(2-pyridin-2-ylethoxy)phenoxymethyl]phenoxy}acetic acid

1H NMR (300 MHz, DMSO) δ charged 8.52 (d, 1H), 7,73 (m, 1H), 7,26 (m, 5H), 6,56 (m, 3H), 5,12 (s, 2H), 4,48 (s, 2H), 4,34 (t, 2H), 3,17 (t, 2H), and 2.26 (s, 3H). MS (EPI) 428 (M+N)+. Derived from {4-Chloro-2-methyl-6-[3-(2-pyridin-2-ylethoxy)-phenoxymethyl]phenoxy}acetonitrile (example 36k).

Example 41l

{2-[3-(Benzoxazol-2-illuminometer)phenoxymethyl]-6-methylphenoxy}acetic acid

1H NMR (300 MHz, DMSO) δ 8,48 (SHS, 1H), 7,12 (m, 11N), 5,14 (s, 2H), 4,46 (m, 4H), and 2.26 (s, 3H). MS (EPI) 419 (M+N)+. Derived from {2-[3-(benzoxazol-2-illuminometer)-phenoxymethyl]-6-methylphenoxy}acetonitrile (example 35d).

Example 41am

{2-[3-(Benzoxazol-2-illuminometer)phenoxymethyl]-4-chloro-6-methylphenoxy}acetic acid

1H NMR (300 MHz, DMSO) δ of 8.47 (PCs, 1H), 7,28 (m, 5H), 7,02 (m, 5H), 5,14 (s, 2H), 4,49 (d, 2H), 4,46 (s, 2H), and 2.26 (s, 3H). MS (EPI) 453 (M+N)+. Derived from {2-[3-(benzoxazol-2-illuminometer) phenoxymethyl]-4-chloro-6-methylphenoxy}Aceto-nitrile (example 361).

Example 41an

{2-[3-(4-Chlorhydrin-2-ileocecal)phenoxymethyl]-6-methylphenoxy}acetic acid

1H NMR (300 MHz, DMSO) δ to 8.20 (d, 1H), with 8.05 (d, 1H), 7,81 (m, 3H), 7,25 (m, 2H), 7,12 (m, 1H), 7,00 (m, 4H), TO 5.21 (S, 2H), of 4.77 (s, 2H), to 4.62 (s, 2H), 4,15 (s, 2H), 2,24 (s, 3H). MS (EPI) 478 (M+N)+. Get is from {2-[3-(4-chlorhydrin-2-ileocecal)phenoxymethyl]-6-methylphenoxy}acetonitrile (example e).

Example a

{2-[3-(6-Methoxyquinoline-2-ileocecal)phenoxymethyl]-6-methylphenoxy}acetic acid

1H NMR (300 MHz, CDCl3) δ 8,18 (d, 1H), 8,10 (d, 1H), to 7.64 (d, 1H), was 7.36 (m, 2H), 7,26 (m, 3H), 7,12 (m, 2H), 6,98 (m, 2H), 5,24 (s, 2H), to 4.73 (s, 2H), 4,69 (s, 2H), to 4.62 (s, 2H), 3,93 (s, 3H), of 2.38 (s, 3H). MS (EPI) 474 (M+N)+. Is obtained from (2-[3-(6-methoxyquinoline-2-ileocecal)phenoxymethyl]-6-methylphenoxy}acetonitrile (example 35f).

Example 41ap

{2-Methyl-6-[3-(quinoline-2-ileocecal)phenoxymethyl]-phenoxy}acetic acid

1H NMR (300 MHz, CDCl3) δ 8,30 (d, 1H), 8,18 (d, 1H), a 7.85 (d, 1H), 7,74 (m, 2H), 7,58 (m, 1H), 7,38 (d, 1H), 7,28 (m, 3H), 7,12 (m, 1H), 6,99 (m, 2H), 5,24 (s, 2H), 4,78 (s, 2H), 4,71 (s, 2H), 4,63 (s, 2H), 2,39 (s, 3H). MS (EPI) 444 (M+N)+. Derived from {2-methyl-6-[3-(quinoline-2-ylethoxy-methyl)phenoxymethyl]phenoxy}acetonitrile (example 35g).

Example 41aq

{2-Methyl-6-[3-(pyridine-4-ylethoxy)phenoxymethyl]-phenoxy}acetic acid

1H NMR (300 MHz, DMSO) δ 8,57 (CL, 2H), 7,44 (m, 2H), 7,22 (m, MN), 7,07 (m, 1H), 6,69 (m, 1H), 6,61 (m, 2H), further 5.15 (s, 2H), 5,13 (s, 2H), 4,47 (s, 2H), and 2.27 (s, 3H). MS (EPI) 380 (M+N)+. Derived from {2-methyl-6-[3-(pyridine-4-ylethoxy)-phenoxymethyl]phenoxy}acetonitrile (example 39q).

Example AG

{2-Methyl-6-[3-(pyridine-2-ylethoxy)phenoxymethyl]-phenoxy}acetic acid

1H NMR (300 MHz, DMSO) δ 8,58 (sm, 1H), 7,83 (m, 1H), 7,50 (d, 1H), 7,34 (m, 1H), 7,21 (m, 3H), 7,05 (m, 1H), only 6.64 (m, MN), 5,14 (s, 4H), to 4.38 (s, 2H), and 2.26 (s, 3H). MS (EPI) 380 (M+N) . Derived from {2-methyl-6-[3-(pyridine-2-ylethoxy)-phenoxymethyl]phenoxy}acetonitrile (example 39r).

Example 41as

{2-Methyl-6-[3-(pyridine-3-ylethoxy)phenoxymethyl]-phenoxy}acetic acid

1H NMR (300 MHz, DMSO) δ 8,67 (s, 1H), 8,55 (sm, 1H), 7,86 (d, 1H), 7,43 (m, 1H), 7,28 (m, 3H), 7,07 (m, 1H), 6,70 (s, 1H), 6,62 (m, 2H), 5,13 (s, 4H), 4,47 (s, 2H), and 2.27 (s, 3H). MS (EPI) 380 (M+N)+. Derived from {2-methyl-6-[3-(pyridine-3-ylethoxy)phenoxymethyl]phenoxy}acetonitrile (example 39s).

Example 41at

{2-[3-(6,7-Dichlorohydrin-2-ylethoxy)phenoxymethyl]-6-methylphenoxy}acetic acid

1H NMR (300 MHz, DMSO) δ 8,44 (m, 2H), 8,30 (s, 1H), 7,76 (d, 1H), 7,22 (m, 3H),? 7.04 baby mortality (m, 1H), 6,72 (m, 1H), 6,63 (m, 2H), to 5.35 (s, 2H), 5,13 (s, 2H), 4,46 (s, 2H), and 2.26 (s, 3H). MS (EPI) 498 (M+N)+. Derived from {2-[3-(6,7-Dichlorohydrin-2-ylethoxy) phenoxymethyl]-6-methylphenoxy}acetonitrile (example 39t).

Example II

Ethyl 4-benzyloxy-2-[3-(2-carboxymethoxy-3-methylbenzyl-oxy)-6-methylbenzoate

1H NMR (300 MHz, DMSO) δ 7,31 (m, 8H), 7,06 (m, 2H), of 6.96 (m, 2H), of 6.65 (d, 1H), is 6.54 (d, 1H), 5,12 (d, 6N), 4,48 (s, 2H), 4,22 (kV, 2H), 2,28 (s, 3H), 2,19 (s, 3H), of 1.21 (t, 3H). MS (EPI) 571 (M+N)+. Is obtained from ethyl 4-benzyloxy-2-[3-(2-cyanoethoxy-3-methylbenzylamino)benzyloxy]-6-methylbenzoate (example 64b).

Example 41av

4-Benzyloxy-2-[3-(2-carboxymethoxy-3-methylbenzylamino)-benzyloxy]-6-methylbenzoic acid

1H NMR (300 MHz, DMSO) δ 7,32 (m, 8H), 7,02 (m, 4H), only 6.64 (d, 1H), of 6.52 (d, 1H), 5,13 (m, 6N), 4,48(s, 2H), 2,28 (s, 3H), 2,22 (s, 3H). MS (EPI) 543 (M+N)+. Is obtained from ethyl 4-benzyloxy-2-[3-(2-carboxymethoxy-3-methylbenzylamino)-benzyloxy]-6-methylbenzoate (example 41au).

Example 41aw

{2-Methyl-6-[3-(1,3 .3m-trimethyl-2-oxo-2,3-dihydro-1H-indole-6-intoximeter)phenoxymethyl]phenoxy}acetic acid

1H NMR (300 MHz, DMSO) δ 7,21 (m, 5H), of 6.99 (m, 3H), 6.75 in (d, 1H), only 6.64 (DD, 1H), 5,24 (s, 2H), 5,07 (s, 2H), 4,12 (s, 2H), 3,10 (s, 3H), of 2.25 (s, 3H), 1,21 (C, 6N). MS (EPI) 476 (M+N)+. Derived from {2-methyl-6-[3-(1,3 .3m-trimethyl-2-oxo-2,3-dihydro-1H-indole-6-intoximeter)phenoxymethyl]phenoxy}-acetonitrile (example s).

Example 41ax

7-[3-(Quinoline-2-ylethoxy)phenoxymethyl]benzofuran-2-carboxylic acid

1H NMR (300 MHz, CD3OD) d at 8.36 (DD, 1H), 8,03 (DD, 1H), 7,94 (DD, 1H), to 7.61 for 7.78 (m, 4H), 7,45-7,49 (m, 2H), 7,16-7,29 (m, 2H), 6,77 (s, 1H), 6,67 (dt, 2H), 5,42 (s, 2H), 5,32 (s, 2H); MS (EPI) 426 (M+N)+. Obtained from ethyl 7-[3-(quinoline-2-ylethoxy)phenoxymethyl]benzofuran-2-carboxylate (example 36i).

Example 41ay

{2-Methyl-6-[3-(2-phenylthiazol-4-ylethoxy)phenoxymethyl]-phenoxy}acetic acid

1H NMR (300 MHz, DMSO): δ 5 a 7.92 (m, 2H), to 7.77 (s, 1H), 7,47 (m, 3H), 7,20 (m, 1H), 7,15 (m, 2H), 6,98 (t, 1H), 6,72 (t, 1H), 6,60 (m, 2H), further 5.15 (s, 2H), 5,14 (s, 2H), 4,15 (s, 2H), of 2.23 (s, 3H); MS (EPI) 462 (M+N)+. Derived from {2-methyl-6-[3-(2-phenylthiazol-4-ylethoxy)phenoxymethyl]phenoxy}Aceto-nitrile (example 39u).

Example 42

(4-Chloro-2,6-dimethylphenoxy)acetonitrile

4-Chloro-2,6-dimethylphenol (5,0g, 32 mmol), bromoacetonitrile (2.2 ml, 32 mmol) and potassium carbonate (6.6 g, 48 mmol) are combined with acetone (50 ml) and heated at the boil under reflux for 18 hours. The reaction mixture was filtered, concentrated and the residue is subjected to distribution between dichloromethane and water. The organic phase is washed with 1 N. hydrochloric acid and water and then dried over magnesium sulfate, concentrated and purified by chromatography on a column (silica gel, 10% ethyl acetate in hexane)to give specified in the header connection. MS (EI) 195 (M)+the structure complying with Cl.

Example 42A

(2-tert-Butyl-6-methylphenoxy)acetonitrile

Specified in the header connection comes primarily using the same procedure as in example 42, except using 2-tert-butyl-6-METHYLPHENOL instead of 4-chloro-2,6-dimethylphenol. MS (EI) 203 (M)+.

Example 42b

Ethyl (2,6-dimethylphenoxy)acetate

Specified in the header connection comes primarily using the same procedure as in example 42, except using 2, 6-dimethylphenol instead of 4-chloro-2,6-dimethylphenol and ethylbromoacetate instead of bromoacetonitrile.

Example 43

(2-methyl bromide-4-chloro-6-methylphenoxy)acetonitrile

(4-Chloro-2,6-dimethylphenoxy)acetonitrile (700 mg, 3.6 mmol, example 42), N-bromosuccinimide (510 mg, 2.9 mmol) and benzoyl peroxide (72 mg, 0.29 mmol) is heated at boiling under reflux in tetracha the ideal carbon (10 ml) for 16 hours. The reaction mixture is cooled, filtered and the filtrate is concentrated and purified by chromatography on a column (silica gel, 5% ethyl acetate in hexane)to give specified in the header connection. MS (EI) 273, 275 (M)+the structure Br.

The following connections are getting, basically, using the same procedure as in example 43, except for the use of the methyl analogue instead of (4-chloro-2,6-dimethylphenoxy)-acetonitrile.

Example 43A

2-methyl bromide-6-tert-butylphenoxy)acetonitrile

MS (EI) 281 (M+)+. Is obtained from (2-tert-butyl-6-methylphenoxy)acetonitrile (example 42A).

Example 43b

Ethyl (2-methyl bromide-6-methylphenoxy)acetate

Obtained from ethyl (2,6-dimethylphenoxy)acetate (example 42b).

Example 44

5-Chloro-2-hydroxy-3-methoxybenzaldehyde

The solution sulfurylchloride (15 ml, 190 mmol) in toluene (20 ml) is added dropwise over 1.5 hours a solution of o-vanillin (of 25.0 g, 164 mmol) in toluene (90 ml) and then the reaction mixture is stirred for 16 hours. Add water (30 ml) for 10 minutes while cooling bath with ice. The solid is filtered off, washed with water and dried, obtaining specified in the header connection. MS (EI) 186 (M)+.

Example 45

4-Chloro-2-methyl-1-exogenesis

mCPBA 70% purity (6,9 g, 29 mmol) is added to a solution of 4-chloraniline (5,1 g, 29 mmol) in dichloroethane and heated to 50°C for 4 h the owls. The reaction mixture was concentrated and subjected distribution between ethyl acetate and aqueous potassium carbonate. The organic phase is washed with additional aqueous potassium carbonate, water and then dried over magnesium sulfate. The solution is filtered and concentrated, obtaining mentioned in the title compound which is used without further purification. MS (EPI) 194 (M+N)+.

The following connections are getting, basically, using the same procedure as in example 45, except using the specified rinaldina instead of 4-chloraniline.

Example 45A

7-Chloro-2-methyl-1-exogenesis

MC (EPI) 194 (M+N)+. Obtained from 7-chloraniline.

Example 45b

6-Methoxy-2-methyl-1-exogenesis

MC (EPI) 190 (M+H)+. Obtained from 6-methoxyaniline.

Example 45C

5-Ethyl-2-methylpyridine 1-oxide

MC (EPI) 138 (M+N)+. Obtained from 5-ethyl-2-methylpyridine.

Example 46

4-Chlorhydrin-2-ylmethylene

4-Chloro-2-methyl-1-exogenesis (4.3 g, 22 mmol) dissolved in chloroform (200 ml) and add n-toluensulfonate (3.7 g, 20 mmol) and the reaction mixture is heated at 65°C for 24 hours. The reaction mixture allow to cool and then concentrated and subjected distribution between ethyl acetate and 10% aqueous potassium carbonate. The organic phase is dried over magnesium sulfate, concentrated and purified by chromatography nakaloke (silica gel, 60% dichloromethane in hexane)to give specified in the header connection. MC (EPI) 212 (M+N)+.

The following connections are getting, basically, using the same procedure as in example 45, except using the specified rinaldina instead of 4-chloraniline.

Example 46a

7-Chlorhydrin-2-ylmethylene

MC (EPI) 212 (M+N)+. Obtained from 7-chloro-2-methyl-1-oxo-quinoline (example 45A).

Example 4 6b

6-Methoxyquinoline-2-ylmethylene

MC (EPI) 208 (M+H)+. Obtained from 6-methoxy-2-methyl-1-oxacilin (example 45b).

Example 47

2-{3-[5-Chloro-3-methyl-2-(1H-tetrazol-5-ylethoxy)benzyl-oxy]phenoxymethyl}quinoline

Sodium azide (395 mg, 6.1 mmol) and ammonium chloride (325 mg, 6.1 mmol) is added to a solution of {4-chloro-2-methyl-6-[3-(quinoline-2-ylethoxy)phenoxymethyl]phenoxy}acetonitrile (300 mg, of 0.68 mmol, example 36C) in DMF (2 ml) and heated at 110°C for 2 hours. Then the reaction mixture is cooled and poured into 1 n sodium hydroxide solution (20 ml) to obtain a solid substance. Then this mixture is washed with simple ether (4×) and a simple ether drop. The remaining aqueous solution contains a solid substance is filtered off. This solid is dissolved in a mixture of 10% ethanol-water (250 ml) and the pH is reduced to about 5 by 2 N. HCl. Solid precipitates, it is filtered off, getting mentioned in the title compound, TPL 181-184�B0; ;1H NMR (300 MHz, DMSO-d6d to 8.40 (d, 1H), 8,01-of 7.97 (m, 2H), to 7.77 (DD, 1H), 7,66-of 7.60 (m, 2H), 7,33 (d, 2H), 7,18 (DD, 1H), 6,72 (DD, 1H), 6,65 (DD, 1H), 6,59 (DD, 1H), 5,33 (s, 2H), 5,27 (s, 2H), 5,07 (s, 2H), 2,24 (s, 3H); MC (EPI) 488, 490 (M+H; Cl)+.

Example 48

[3-(Quinoline-2-ylethoxy)phenyl]methanol

2-Chlormethine hydrochloride (11.6 g, 54 mmol), 3-hydroxybenzoyl alcohol (6.7 g, 54 mmol) and potassium carbonate (16 g, 116 mmol) are heated in DMF (45 ml) at 50°C for 14 hours. The temperature was raised to 80°and heated for another 24 hours. The reaction mixture is cooled and added to water, filtered and the solid is washed with water, getting a semifinished product. The residue is dissolved in ethyl acetate, dried over magnesium sulfate, filtered and concentrated. The sample was then recrystallized from ethyl acetate and hexane, obtaining specified in the header connection. MS (EPI) 266 (M+N)+.

Example 49

2-(3-Chloromethylphenoxyacetic)quinoline hydrochloride

Thionyl chloride (0.95 ml, 13 mmol) is added to a solution of [3-(quinoline-2-ylethoxy)phenyl]methanol (2.9 g, 11 mmol, example 48) in dichloromethane (30 ml) and allow to mix for 18 hours. The reaction mixture was concentrated in vacuo and subjected to azeotropic distillation twice from chloroform, getting mentioned in the title compound which is used without further purification.

Example 50

2-[3-(Quinoline-2-ylethoxy)benzyloxy]-6-thrift rmeil-benzaldehyde

[3-(Quinoline-2-ylethoxy)phenyl]methanol (300 mg, 1.13 mmol, example 48) was dissolved in DMF (6 ml), add sodium hydride (60%, 60 mg, 1.5 mmol) and allow to mix for 20 minutes. Add 2-fluoro-6-(trifluoromethyl)-benzaldehyde (of 0.30 ml, 2.2 mmol) and the reaction mixture is heated at 90°C for 5 hours. The reaction mixture is subjected to distribution between ethyl acetate (200 ml) and water (200 ml), dried over magnesium sulfate, filtered, concentrated in vacuo and purified by chromatography on a column (silica gel, 25% ethyl acetate in hexane)to give specified in the title compound, MS (EPI) 438 (M+N)+.

Example 51

2-[3-(Quinoline-2-ylethoxy)benzyloxy]-6-trifluoromethyl-benzoic acid

A solution of 2-[3-(quinoline-2-ylethoxy)benzyloxy]-6-Cryptor-methylbenzaldehyde (46 mg, 0.1 mmol, example 50) in 2-methyl-2-butene (1 ml), t-butanol (2 ml) and water (2 ml) was processed by the dihydrate of sodium dihydrophosphate (153 mg, 1.1 mmol) and sodium chlorite (198 mg, 2.2 mmol). After about 45 minutes the reaction mixture is subjected to distribution between dichloromethane (50 ml) and water (50 ml). The organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo, obtaining specified in the header connection: TPL 184-185°;1H NMR (300 MHz, CDCl3) δ of 8.28 (d, 1H), 8,12 (d, 1H), 7,82 to 7.75 (m, 2H), 7,66-of 7.55 (m, 2H), 7,42 (DD, 1H), 7,30-7,27 (m, 2H), 7,16 (d, 1H), 7,07 (DD, 1H), to 6.88 (d, 1H), 6,77 (DD, 1H), 5,44 (s, 2H, 5,07 (s, 2H); MS (EPI) 454 (M+N)+.

Example 52

{4-Chloro-2-methyl-6-[3-(quinoline-2-ylethoxy)benzyloxy-methyl]phenoxy}acetonitrile

[3-(Quinoline-2-ylethoxy)phenyl]methanol (190 mg, to 0.72 mmol, example 48) was dissolved in DMF (6 ml) and add sodium hydride (60%, 30 mg, 0.75 mmol) and allow to mix for 10 minutes. Add (2-methyl bromide-4-chloro-6-methylphenoxy)acetonitrile (210 mg, 0.78 mmol, example 43) and the reaction mixture allow to mix for 6 hours. The reaction mixture is subjected to distribution between ethyl acetate and water and the organic phase is washed with additional water. The organic phase is dried, concentrated and purified by chromatography on a column (silica gel, 25% ethyl acetate in hexane)to give specified in the header connection. MS (EPI) 458 (M+N)+the structure complying with Cl.

Example 53

Methyl 2-methyl-6-[3-(quinoline-2-ylethoxy)benzyloxy-methyl]benzoate

Specified in the header connection comes primarily using the same procedure as in example 52, except using methyl 2-methyl bromide-6-methylbenzoate (example 2) instead of (2-methyl bromide-4-chloro-6-methylphenoxy)acetonitrile. MS (EPI) 427 (M+N)+.

Example 54

Ethyl{2-[4-bromo-3-(quinoline-2-ylethoxy)phenoxymethyl]-6-methylphenoxy}acetate and ethyl{2-[2-bromo-5-(quinoline-2-ylethoxy)phenoxymethyl]-6-methylphenoxy}acetate

Ethyl{2-methyl-6-[3-(quinoline-2-ylethoxy)is taximeter]-phenoxy}acetate (350 mg, 0,76 mmol, example 36h), NBS (150 mg, 0,84) and benzoyl peroxide (20 mg, 0.08 mmol) was dissolved/suspended in chloroform (7 ml) and heated at the boil under reflux for 2 hours. The reaction mixture is cooled to room temperature, filtered, pre-adsorb on silica gel by rotary evaporation. The crude substance is purified flash chromatography (silica gel, 15% ethyl acetate in hexane), getting listed in the connection header in approximately 1:1 ratio. The regioisomers set according to NMR (NMR NOE). MS (ion spray) 537(M+N)+for both compounds.

Example 55

3-Methyl-5-(quinoline-2-ylethoxy)phenol

2-(Chloromethyl)quinoline hydrochloride (1.28 g, 6.0 mmol), ursin (568 mg, 4.0 mmol), K2CO3(1.68 g, 12,0 mmol) and a catalytic amount of tetrabutylammonium iodide (˜10 mg) was dissolved/suspended in anhydrous DMF (10 ml) and heated at 50°With during the night. The reaction mixture is cooled to room temperature and subjected to the distribution between water (100 ml) and ethyl ether (100 ml). the pH of the aqueous layer adjusted to ˜5 and additionally extracted with ethyl ether (100 ml). The organic fractions are combined and washed with a saturated solution of salt (2×100 ml), dried over MgSO4filter and pre-adsorb on silica gel. Untreated pre-adsorbed substances is about clean flash chromatography (silica gel, 20% ethyl acetate in hexane)to give specified in the header connection. This product (about 80% purity, the remainder is 2-methyl-quinoline) is used without additional purification. MS (EPI) 266 (M+N)+.

Example 56

2-[3-(Quinoline-2-ylethoxy)benzyloxy]benzaldehyde

2-(3-Chloromethylphenoxyacetic)quinoline (371 mg, 1.3 mmol, example 49) and salicylaldehyde (133 μl, 1.25 mmol) dissolved in acetone (10 ml). Add To2CO3(525 mg, 3.75 mmol) and the contents heated at the boil under reflux for 16 hours. The reaction mixture is cooled to room temperature, poured into water (100 ml) and extracted with simple ether (3×50 ml). The ether layers are combined and washed with saturated salt solution (Brine) (3×75 ml) and dried over MgSO4. The crude substance is pre-adsorb on silica gel and purified flash chromatography (silica gel, 20 to 25% ethyl acetate in hexane)to give specified in the header connection. MS (ion spray) 370 (M+N)+.

Example 57

3-{2-[3-(Quinoline-2-ylethoxy)benzyloxy]phenyl}acrylic acid

2-[3-(Quinoline-2-ylethoxy)benzyloxy]benzaldehyde (110 mg, 0.3 mmol, example 56) was dissolved in pyridine (1 ml). Added malonic acid (63 mg, 0.6 mmol) and piperidine (10 μl, 0.1 mmol) and the contents heated to 85°C for 2 hours, then at 110°C for another 2 hours. The reaction is th the mixture is cooled and rinsed with stream of nitrogen at 40° To remove the pyridine. Add a small amount of toluene and the contents again rinsed with stream of nitrogen at 40° (repeat). The crude substance is purified on silica gel flash chromatography (silica gel, 2.5% methanol in dichloromethane)to give specified in the header of the connection.1H NMR (300 MHz, CDCl3) δ with 8.33 (d, 1H), 8,21-8,16 (m, 2H), 7,81-of 7.70 (m, 3H), 7,56 is 7.50 (m, 2H), 7,37-7,25 (m, 3H), 7.03 is-6,93 (m, 4H), of 6.50 (d, 1H), 5,48 (s, 2H), 5,14 (s, 2H); MS (ion spray) 412 (M+N)+.

Example 58

1-[2-Hydroxy-4-(quinoline-2-ylethoxy)phenyl]alanon

2',4'-Dihydroxyacetophenone (912 mg, 6 mmol) and 2-chlormethine hydrochloride (856 mg, 4.0 mmol, example 49) was dissolved in acetonitrile (20 ml). Add To2CO3(1.12 g, 8.0 mmol) and the contents heated to 50°C for 16 hours. The reaction mixture is cooled to room temperature, and the solvent is removed by rotary evaporation. The contents are distributed between ethyl acetate (100 ml) and water (100 ml), the aqueous layer was acidified with 2 N. HCl to pH ˜2 and additionally extracted with ethyl acetate (2×50 ml). All organic fractions are combined and washed with a saturated solution of salt (3×150 ml), dried over MgSO4and concentrate. The crude substance is pre-adsorb on silica gel and purified flash chromatography (silica gel, 15% ethyl acetate in hexane)to give specified in the title compound;MS (ion spray) 294 (M+N) +.

Example 59

Ethyl{2-[2-acetyl-5-(quinoline-2-ylethoxy)phenoxymethyl]-6-methylphenoxy}acetate

1-[2-Hydroxy-4-(quinoline-2-ylethoxy)phenyl]alanon (185 mg, 0,63 mmol, example 58) was dissolved in a mixture of 2:1 DMF/acetonitrile (6 ml). Add ethyl (2-methyl bromide-6-methylphenoxy) acetate (272 mg, 0.95 mmol, example 43b) and K2CO3(177 mg, of 1.26 mmol) and the contents heated to 50°C for 2 days. The reaction mixture is cooled to room temperature and reduce the volume in a stream of nitrogen at 40°C. the Contents are distributed between ethyl acetate (50 ml) and water (50 ml). The aqueous layer was additionally extracted with ethyl acetate (2×50 ml). The organic fractions are combined and washed with a saturated solution of salt (3×75 ml), dried over MgSO4and concentrate. The crude substance was dissolved in a mixture of 1:1 dichloromethane/methanol, pre-adsorb on silica gel and purified flash chromatography (silica gel, 20% ethyl acetate in hexane)to give specified in the header connection. MS (ion spray) 500 (M+N)+.

Example 60

Methyl 2-[3-(quinoline-2-ylethoxy)benzyloxy]benzoate

The free base 2-(3-chloromethylphenoxyacetic)quinoline hydrochloride (540 mg, 1.7 mmol, example 49) is obtained by distribution of the substance between the simple ether and sodium bicarbonate and drying the organic phase with magnesium sulfate. Then this substance is dissolved by specilalities (260 mg, 1.7 mmol) in DMF (10 ml) at 0°and add sodium hydride (60%, 65 mg, 1.7 mmol). The reaction mixture is brought to room temperature for 15 min and then heated at 60°C for 6 hours. The reaction mixture is cooled and subjected distribution between ethyl acetate and a saturated solution of ammonium chloride. The organic phase is dried over magnesium sulfate, filtered, concentrated in vacuo and purified by chromatography on a column (silica gel, 50 to 80% ether in hexane)to give specified in the title compound, MS (EPI) 400 (M+N)+.

The following connections are getting, basically, using the same procedure as in example 60, except using the specified substituted salicylate instead of methyl salicylate.

Example 60A

Methyl 3-methoxy-2-[3-(quinoline-2-ylethoxy)benzyloxy]-benzoate

Obtained from methyl 3-metoxisalicilice.

Example 60b

Methyl 4-methoxy-2-[3-(quinoline-2-ylethoxy)benzyloxy]-benzoate

Obtained from methyl 4-metoxisalicilice.

Example 60C

Methyl 5-methoxy-2-[3-(quinoline-2-ylethoxy)benzyloxy]-benzoate

Is obtained from methyl 5-metoxisalicilice.

Example 60d

Methyl 2-methoxy-6-[3-(quinoline-2-ylethoxy)benzyloxy]-benzoate

Obtained from methyl 6-metoxisalicilice (example 61).

An example of 60s

Ethyl 2-methyl-6-[3-(quinoline-2-ylethoxy)benzyloxy]-benzoate

MS (EPI) 428 (M+N)+. Get and the ethyl 6-methyl salicylate (See, Hauser, Frank M., Synthesis 1980, 10, 814-15.

Example 61

Methyl 6-methoxysilyl

A mixture of 6-methoxysilanes acid (10.0 g, 59.5 mmol) in methanol (40 ml) and sulfuric acid (2 ml) are heated at the boil under reflux for 48 hours. Although some acid remains, the reaction mixture was concentrated to remove methanol, and subjected to distribution between ethyl acetate and a saturated solution of sodium carbonate. The organic phase is separated and washed with sodium carbonate until, while according to TLC analysis will not remain acid. The organic phase is dried and concentrated, obtaining mentioned in the title compound as a low melting solid.

Example 62

Methyl 5-[3-(quinoline-2-ylethoxy)benzyloxy]nicotinate

To a solution of methyl ester 5-hydroxynicotinic acid (200 mg, 1.3 mmol) in DMF (3 ml) is added 60% emulsion of sodium hydride (50 mg, 1.2 mmol) and the mixture stirred for 30 minutes. The free base of the hydrochloride of 2-(3-chloromethylphenoxyacetic)quinoline (350 mg, 1.2 mmol, example 49) is obtained by the matter distribution between ethyl ether and sodium bicarbonate and drying the organic phase with magnesium sulfate. The solution of this free base in DMF (2 ml) is added to the alcohol and the mixture is stirred at 25°C for 16 hours. The solvent is removed in vacuo, add dichloromethane (10 ml)and water (5 ml) and the mixture is acidified to pH 6 with acetic acid. The organic layer is dried over magnesium sulfate and the solvent is removed in vacuum. The residue is purified flash chromatography (silica gel, 4% methanol in dichloromethane)to give specified in the header connection. MS (EPI) 401 (M+N)+.

Example 63

Ethyl 4-benzyloxy-2-hydroxy-6-methylbenzoate

To a solution of ethyl-2,4-dihydroxy-6-methylbenzoate (4,22 g, 22 mmol) in acetone (80 ml) is added potassium carbonate (3.0 g, 22 mmol) and benzylbromide (2.6 ml, 22 mmol) and the mixture is heated at the boil under reflux overnight. The cooled reaction mixture is diluted with ethyl acetate (100 ml) and water (100 ml) and the organic layer washed with water (2×80 ml) and saturated salt solution (2×80 ml). The organic layer is dried over magnesium sulfate and the solvent is removed, getting mentioned in the title compound without further purification. MS (EI) 286 (M)+.

Example 63A

Ethyl 2-hydroxy-4-methoxy-6-methylbenzoate

Specified in the header connection comes primarily using the same procedure as in example 63, except for the use of iodomethane instead of benzylbromide.

Example 64

Ethyl 4-benzyloxy-2-methyl-6-[3-(quinoline-2-ylethoxy)-benzyloxy]benzoate

To a solution of ethyl 4-benzyloxy-2-hydroxy-6-methylbenzoate (of 5.1 g, 16 mmol, example 63) in DMF (100 ml), while cooling bath of water at 25°add 60% emulsion of sodium hydride (1.3 g, 32 mo is ü) for 2 minutes. This mixture is stirred for 30 minutes after the cooling bath removed. Add a solution of the hydrochloride of 3-(quinoline-2-ylethoxy)benzyl chloride (5.1 g, 16 mmol, example 49) in DMF (55 ml) and the reaction mixture is heated at 60°C for 6 hours. The solvent is removed in vacuo and the residue purified flash chromatography (silica gel, 0.5 to 2% methanol in dichloromethane)to give specified in the header connection. MS (EPI) 534 (M+N)+.

Example 64A

Ethyl 4-methoxy-2-methyl-6-[3-(quinoline-2-ylethoxy)benzyloxy]benzoate

Specified in the header connection comes primarily using the same procedure as in example 64, except using ethyl 2-hydroxy-4-methoxy-6-methylbenzoate (example 63A) instead of ethyl 4-benzyloxy-2-hydroxy-6-methyl-benzoate. MS (EPI) 458 (M+N)+.

Example 64b

Ethyl 4-benzyloxy-2-[3-(2-cyanoethoxy-C-methylbenzyl-oxy)benzyloxy]-6-methylbenzoate

Specified in the header connection comes primarily using the same procedure as in example 64, except for the use of [2-(3-bromomethylphenyl)-6-methylphenoxy]-acetonitrile (example 76) instead of hydrochloride of 3-(quinoline-2-ylethoxy)benzylchloride.1H NMR (300 MHz, CDCl3) δ 7,30 (m, 8H), 7,12 (m, 1H), 7,06 (SHS, 1H), 6,99 (d, 1H), 6.90 to (DD, 1H), 6.42 per (s, 2H), 5,07 (s, 2H), 5,04 (s, 2H), 5,02 (s, 2H), 4,71 (s, 2H), 4,33 (K, 2N), 2,39 (s, 3H), of 2.30 (s, 3H), 1,31 (t, 3H). MS (EPI) 552 (M+N)+.

Example s

{2-Methyl-6-[3-(1,3 .3m-trimethyl-2-oxo-2,3-dihydro-1H-indole-6-intoximeter)phenoxymethyl]phenoxy}acetonitrile

Specified in the header connection comes primarily using the same procedure as in example 64, except that the use of [2-(3-bromomethylphenyl)-6-methylphenoxy] acetonitrile (example 76) instead of hydrochloride of 3-(quinoline-2-ylethoxy)benzylchloride and 6-hydroxy-1,3 .3m-trimethyl-1,3-dihydroindol-2-he (example 80) instead of ethyl 4-benzyloxy-2-hydroxy-6-methylbenzoate.

1H NMR (300 MHz, CDCl3) δ to 7.32 (DD, 2H), 7,24 (s, 1H), 7,11 (m, 4H), of 6.96 (DD, 1H), 6,62 (DD, 1H), is 6.54 (d, 1H), 5,10 (s, 2H), is 5.06 (s, 2H), 4.72 in (s, 2H), 3,18 (s, 3H), 2,39 (s, 3H), of 1.34 (s, 6N). MS (EPI) 457 (M+N)+.

Example 65

Ethyl 2-hydroxy-6-methyl-4-[3-(quinoline-2-ylethoxy)-benzyloxy]benzoate

Ethyl ester of 2,4-dihydroxy-6-methylbenzoic acid (315 mg, 1.6 mmol) in collaboration with the hydrochloride of 2-(3-chloromethylphenoxyacetic)quinoline (0.51 g, 1.6 mmol, example 49), tetrabutylammonium iodide (55 mg, 0.15 mmol) and potassium carbonate (0,48 g, 3.5 mmol) in acetone (9 ml). The reaction mixture is heated at the boil under reflux for 48 hours. The reaction mixture is subjected to distribution between ethyl acetate and a saturated solution of ammonium chloride. The organic phase is washed with saturated salt solution, dried over magnesium sulfate, filtered and concentrated, obtaining the crude product. This substance is purified by chromatography on a column (silica gel, 3% ether in dichloromethane)to give the decree is Noah in the title compound; TPL 127-128°S, MS (EPI) 444 (M+N)+.

Example 66

Ethyl 2-methoxy-6-methyl-4-[3-(quinoline-2-ylethoxy)benzyloxy]benzoate

To a solution of ethyl 2-hydroxy-6-methyl-4-[3-(quinoline-2-ylethoxy) benzyloxy]benzoate (150 mg, 0.34 mmol, example 65) in DMF (5 ml) is added sodium hydride (60%, 14 mg, 0.34 mmol) and the reaction mixture is stirred for 20 minutes. Add itmean one (0.03 ml, 0.5 mmol) and the reaction mixture is heated at 50°C for 7 hours. The reaction mixture was concentrated in vacuo and the residue is subjected to distribution between dichloromethane and aqueous ammonium chloride. The aqueous layer was again extracted with dichloromethane, the combined organic phases, dried over magnesium sulfate, filtered and concentrated, obtaining the crude product. The residue is purified by chromatography on a column (silica gel, 10 to 20% ethyl acetate in hexane)to give specified in the title compound, MS (EPI) 458 (M+N)+.

Example 66A

Ethyl 2-benzyloxy-6-methyl-4-[3-(quinoline-2-ylethoxy)-benzyloxy]benzoate

Specified in the header connection comes primarily using the same procedure as in example 66, except that the use of benzylbromide instead of iodomethane. MS (EPI) 534 (M+N)+.

Example 67

4-Benzyloxy-2-methyl-6-[3-(quinoline-2-ylethoxy)benzyloxy]benzoic acid

Ethyl 4-benzyloxy-2-methyl-6-[3-(quinoline-2-ylethoxy)-benzyloxy]benzoate 2.4 g, 4.5 mmol, example 64) are added to ethanol (50 ml) and 10 N. the sodium hydroxide (4.4 ml, 44 mmol) and refluxed for 8 hours. The solvent is removed in vacuum and the residue is dissolved in dichloromethane with a small amount of water and acidified to pH 6 1 N. HCl. The organic layer is dried over MgSO4and the solvent is removed in vacuum. The crude product is purified column chromatography (silica gel, 1% methanol in dichloromethane)to give specified in the title compound, TPL 146-149°;1H NMR (300 MHz, CD3OD) d a 8.34 (d, 1H), 8,04 (d, 1H), to $ 7.91 (d, 1H), 7,78-of 7.70 (m, 2H), to 7.61 (t, N), 7,37-7,20 (m, 7H), 7,05-6,91 (m, 2H), 6,51 (d, 1H), 6,47 (d, 1H), to 5.35 (s, 2H), 5,09 (s, 2H), to 5.03 (s, 2H), to 2.29 (s, 3H); MS (EPI) 506 (M+N)+.

The following connections are getting, basically, using the same procedure as in example 67, except that use the specified ester instead of ethyl 4-benzyloxy-2-methyl-6-[3-(quinoline-2-ylethoxy)benzyloxy]benzoate.

Example 67a

2-Methoxy-6-methyl-4-[3-(quinoline-2-ylethoxy)benzyloxy]-benzoic acid

1H NMR (300 MHz, CDCl3) δ scored 8.38 (d, 1H), 8,03 (d, 1H), 7,79 (d, N), 7,70-to 7.67 (m, 2H), to 7.61 (t, N), 7,28 (m, 1H), 7,14 (s, 1H), 7,01 (t, 2H), 6.35mm (t, 2H), lower than the 5.37 (s, 2H), to 5.03 (s, 2H), 3,71 (s, 3H), and 2.26 (s, 3H); MS (EPI) 430 (M+N)+. Obtained from ethyl 2-Methoxy-6-methyl-4-[3-(quinoline-2-ylethoxy)benzyloxy]benzoate (example 66).

Example 67b

2-Benzyloxy-6-methyl-4-[3-(quinoline-2-ylethoxy)benzyloxy]benzoic acid

125-127°;1H NMR (300 MHz, CDCl3) δ 8,18 (d, 1H), 7,83 (d, 1H), 7,74-of 7.55 (m, 3H), 7,40 (s, 5H), 7,39-7,29 (m, 1H), to 7.09 (s, 1H), 7,00 (m, 2H), 6,50 (s, 2H), 5,41 (s, 2H), 5,13 (s, 2H), 5,04 (s, 2H), 2,58 (s, 3H); MS (EPI) 506 (M+N)+. Obtained from ethyl 2-benzyloxy-6-methyl-4-[3-(quinoline-2-ylethoxy)benzyloxy]benzoate (example 66A).

Example s

4-Methoxy-2-methyl-6-[3-(quinoline-2-ylethoxy)benzyloxy]-benzoic acid

1H NMR (300 MHz, DMSO) δ 8,39 (d, 1H), 8,02-of 7.96 (m, 2H), 7,79-7,74 (m, 1H), to 7.67-EUR 7.57 (m, 2H), 7,31-7,25 (m, 1H), 7,16 (s, 1H), 7,02-of 6.96 (m, 2H), of 6.49 (s, 1H), to 6.39 (s, 1H), of 5.34 (s, 2H), 5,09 (s, 2H), 3,71 (s, 2H), measuring 2.20 (s, 3H); MS (EPI) 429 (M+N)+. Is obtained from ethyl 4-Methoxy-2-methyl-6-[3-(quinoline-2-ylethoxy)benzyloxy]benzoate (example 64A).

Example 68

5-Ethyl-2-chloromethylpyridine

To a solution of 5-ethyl-2-methylpyridine-1-oxide (427 mg, 3.11 mmol, example 45C) in CH2Cl2(2 ml) add a solution (0.2 ml) oxide trichloride phosphorus(V) (i.e., POCl3the acid chloride phosphoric acid) (327 μl) in CH2Cl2(2 ml). Add at the same time the remainder of the solution of the oxide trichloride phosphorus (V) and a solution of triethylamine (488 μl) in CH2Cl2(2 ml) at such a rate as to maintain the formation of phlegmy. After complete addition, the reaction mixture is allowed to cool to 20°and diluted with EtOAc. The organic layer was washed with a saturated solution of NaHCO3saturated salt solution, dried over MgSO4and concentrate. About who headed the remainder of the purified flash chromatography (silica gel, 10% ethyl acetate in dichloromethane)to give specified in the header connection. MS (EPI) 156 (M+N)+.

Example 69

2-(5-Ethylpyridine-2-yl)ethanol

To the cooled solution (-10° (C) Diisopropylamine (2,31 ml of 16.5 ml) in THF (45 ml) is added dropwise (2.5 M) n-utility (6,6 ml, 16.5 mmol), allowed to mix for 10 minutes, then cooled to -78°C. To this mixture is added dropwise a solution of 5-ethyl-2-methylpyridine (1,98 ml, 15 mmol) in THF (3 ml) and allowed to mix for 10 minutes at -78°C. To the reaction mixture are added paraformaldehyde (1.13 g, 37.5 mmol), bath to cool, remove and continue stirring for 1 hour. Quenched the reaction of H2O, diluted with EtOAc and the organic layer was washed with saturated salt solution, dried over MgSO4and concentrate. The residue is purified flash chromatography (silica gel, 0.5% ammonia/5% methanol/dichloromethane)to give specified in the title compound as a pale yellow oil. MS (EI) 151 (M)+.

Example 69A

2-Quinoline-2-retinol

Specified in the header connection comes primarily using the same procedure as in example 69, except that use 2-methylinosine instead of 5-ethyl-2-methylpyridine. MS (EPI) 174 (M+N)+.

Example 70

3-[2-(5-Ethylpyridine-2-yl)ethoxy]phenyl ester of benzoic acid

To a solution of 2-(5-ethylpyridine-2-yl)ethanol (480 mg, 3,17 mmol, etc which measures 69) in THF (10 ml) add resorcinarenes (630 mg, 2/94 mmol), triphenylphosphine (850 mg, 3,24 mmol) and diethylazodicarboxylate (510 μl, 3,24 mmol). The resulting mixture was stirred for 1 hour, then concentrated. The residue is purified flash chromatography (silica gel, 35% ethyl acetate in hexane)to give specified in the title compound as a yellow oil. MS (EPI) 348 (M+N)+.

Example 70A

3-(2-Pyridin-2-ylethoxy)phenyl ester of benzoic acid

Specified in the header connection comes primarily using the same procedure as in example 70, except that the use of 2-(2-hydroxyethyl)pyridine instead of 2-(5-ethylpyridine-2-yl)ethanol. MS (EPI) 320 (M+N)+.

Example 71

3-[2-(5-ethylpyridine-2-yl)ethoxy]phenol

To a solution of 3-[2-(5-ethylpyridine-2-yl)ethoxy]phenyl ester of benzoic acid (493 mg, of 1.42 mmol, example 70) in a mixture of 1:1 THF/CH3HE (5 ml) add 10 n NaOH solution (0.5 ml) and water (50 μl). The reaction mixture is stirred for 15 minutes, then cooled to 5°C, adjusted to pH 7 2 N. HCl solution and diluted with EtOAc. The organic layer is washed successively with a saturated solution of salt, a saturated solution of NaHCO3, then dried over MgSO4and concentrate. The residue is purified by several rubbing with hexane, getting mentioned in the title compound as crystalline solid. MS (EPI) 244 (M+N)+.

Example 71A

3-(2-Pyridin-2-and is ethoxy)phenol

Specified in the header connection comes primarily using the same procedure as in example 71, except using 3-(2-Pyridin-2-ylethoxy)phenyl ester of benzoic acid (example 70A) instead of 3-[2-(5-ethylpyridine-2-yl)ethoxy]phenyl ester. MS (EPI) 216 (M+N)+.

Example 72

[3-(2-Methoxyethoxyethoxy)phenyl]methanol

To a cooled suspension (0° (C) 60% NaH (660 mg, 16.5 mmol) in THF (35 ml) is added dropwise a solution of 3-hydroxybenzaldehyde (1.89 g, 15 mmol) in THF (15 ml) and the resulting mixture is stirred for 20 minutes. To this mixture 2-methoxyethoxymethyl (of 1.88 ml, 16.5 mmol) and DMPU (5 ml), bath for cooling is removed and stirred for 1 hour. The reaction mixture was cooled to 0°With, then slowly add 2 M NaBH4(triglyme) (3.75 ml, 7.5 mmol) and allowed to mix for 1 hour. Slowly quenched with 2 N. HCl solution (3.9 ml) and the reaction mixture is diluted with simple ether. The organic layer was washed with saturated salt solution, dried over MgSO4and concentrate. The residue is purified flash chromatography (silica gel, 60% ethyl acetate in hexane)to give specified in the title compound as a pale yellow oil. MS (EI) 212 (M)+.

Example 73

2-[3-(2-Methoxyethoxyethoxy)benzoyloxymethyl]pyridine

To the cooled solution (0° (C) [3-(2-methoxyethoxy-methoxy)phenyl]methanol (212 mg, 1 mmol, example 7) in THF (3 ml) is added 60% NaH (80 mg, 2 mmol) and the mixture is stirred for 10 minutes. Add 2-picolylamine hydrochloride (164 mg, 1 mmol) and DMPU (0.8 ml), remove bath for cooling and allow the reaction mixture to mix for 2 hours. The reaction mixture was quenched with saturated solution of NH4Cl and diluted with EtOAc. The organic layer was washed with saturated salt solution, dried over MgSO4and concentrate. The residue is purified flash chromatography (silica gel, 70% ethyl acetate in hexane)to give specified in the title compound as a pale yellow oil. MS (EPI) 304 (M+N)+.

The following connections are getting, basically, using the same procedure as in example 73, except that use the specified halide instead of 2-picolylamine hydrochloride.

Example 73a

2-[3-(2-Methoxyethoxyethoxy)benzoyloxymethyl]quinoline

MS (EPI) 354 (M+N)+. Is obtained from 2-(chloromethyl)quinoline hydrochloride.

Example 73b

4-Chloro-2-[3-(2-methoxyethoxyethoxy)benzoyloxymethyl]-quinoline

MS (EPI) 388 (M+H)+. Is obtained from 2-chloromethyl-4-chlorhydrin (example 46).

Example 73s

6-Methoxy-2-[3-(2-methoxyethoxyethoxy)benzoyloxymethyl]-quinoline

MS (EPI) 384 (M+N)+. Is obtained from 2-chloromethyl-6-methoxyquinoline (example 46b).

Example 74

3-(Pyridine-2-ileocecal)phenol

To a solution of 2-[3-(2-methoxyethoxyethoxy)benzoyloxymethyl] pyridine (171 mg, 0.56 to mo the R, example 73) in CH3HE (1.9 ml) is added monohydrate p-toluenesulfonic acid (148 mg, 0.78 mmol). The mixture is heated to 60°C and stirred for 1.5 hours, then cooled to room temperature and diluted with EtOAc. The organic layer was washed with a saturated solution of NaHCO3saturated salt solution, then dried over MgSO4and concentrate, getting mentioned in the title compound as a white crystalline solid. MS (EPI) 216 (M+N)+.

The following connections are getting, basically, using the same procedure as in example 74, except for the use of the MEM ether instead of 2-[3-(2-methoxyethoxyethoxy)-benzoyloxymethyl]pyridine.

Example a

3-(Quinoline-2-ileocecal)phenol

MS (EPI) 266 (M+N)+. Is obtained from 2-[3-(2-methoxy-ethoxyethoxy)benzoyloxymethyl]quinoline (example 73a).

Example 74b

3-(4-Chlorhydrin-2-ileocecal)phenol

MS (EPI) 300 (M+N)+. Obtained from 4-chloro-2-[3-(2-methoxy-ethoxyethoxy)benzoyloxymethyl]quinoline (example 73b).

Example s

3-(6-Methoxyquinoline-2-ileocecal)phenol

MS (EPI) 296 (M+N)+. Obtained from 6-methoxy-2-[3-(2-methoxyethoxyethoxy)benzoyloxymethyl]quinoline (example 73s).

Example 75

[2-(3-Hydroxyethylaminomethyl)-6-methylphenoxy]acetonitrile

To a solution of 3-hydroxybenzylated alcohol (202 mg, and 1.63 mmol) in DMF (5.4 ml) is added To a2/sub> CO3(247 mg, to 1.79 mmol) and (2-methyl bromide-6-methylphenoxy)acetonitrile (430 mg, to 1.79 mmol, example 24). The resulting mixture was heated to 60°C and stirred for 3 hours, then cooled to room temperature and diluted with simple ether. The organic layer is washed with water, saturated salt solution, dried over MgSO4and concentrate. The residue is purified flash chromatography (silica gel, 30% ethyl acetate in hexane)to give specified in the header connection. MS (EI) 283 (M)+.

Example 76

[2-(3-Bromomethylphenyl)-6-methylphenoxy]acetonitrile

To a solution of [2-(3-hydroxyethylaminomethyl)-6-methylphenoxy]acetonitrile (230 mg, 0.81 mmol, example 75) in THF (3 ml) add PHCR (233 mg, 0.89 mmol) and stirred until then, until it forms a homogeneous solution. The solution is cooled to 0°With, then add portions NBS (151 mg, 0.85 mmol) and allowed to mix for 45 minutes. The reaction mixture was concentrated under reduced pressure. The residue is purified flash chromatography (silica gel, 40% CH2Cl2in hexane), getting mentioned in the title compound as a white crystalline substance. MS (EI) 345, 347 (M)+the structure Br.

Example 77

6-Methoxy-3-methyl-1,3-dihydroindol-2-he

To the cooled solution (-78°C) 6-methoxy-1,3-dihydro-indol-2-it (840 mg, 5.2 mmol, See Quallich, Synthesis 1993, 51-53) in THF (20 ml)is added dropwise TMEDA (of 1.57 ml, 10.4 ml) followed by adding dropwise 2.5 M n-BuLi (4,16 ml, 10.4 mmol). The mixture allow to mix for 15 minutes, then warmed to -25°C. is Added dropwise itmean (405 μl, 6.5 mmol) and stirred for 20 minutes. The reaction mixture was quenched with saturated solution of NH4Cl, warmed to room temperature and diluted with EtOAc. The organic layer was washed with a saturated solution of NH4Cl, saturated salt solution, dried over MgSO4and concentrate. The residue is purified flash chromatography (silica gel, 45% ethyl acetate in hexane)to give specified in the header connection. MS (EPI) 178 (M+H)+.

Example 78

6-Methoxy-3,3-dimethyl-1,3-dihydroindol-2-he

To the cooled solution (-78°C) 6-methoxy-3-methyl-1,3-dihydroindol-2-it (679 mg, a 3.83 mmol, example 77) in THF (13 ml) was added TMEDA (1,16 ml, 7,66 mmol), followed by adding dropwise 2.5 M n-BuLi (of 3.06 ml, 7,66 mmol). The mixture is stirred for 15 minutes, then warmed to -25°C. added dropwise itmean (275 μl, 4.40 mmol) and stirred for 30 minutes. The reaction mixture was quenched with saturated solution of NH4Cl, warmed to room temperature and diluted with EtOAc. The organic layer was washed with a saturated solution of NH4Cl, saturated salt solution, dried over MgSO4and concentrate. The residue is purified flash chromatography (silica gel, 35% ethyl acetate in hexane), getting listed in the title compound as a white crystalline solid. MS (EPI) 192 (M+N)+.

Example 79

6-Methoxy-1,3 .3m-trimethyl-1,3-dihydroindol-2-he

To the cooled solution (-5°-0°C) 6-methoxy-3,3-dimethyl-1,3-dihydroindol-2-she (600 mg, 3.14 mmol, example 78) in THF (10.5 ml) is added 60% NaH (132 mg, 3,30 mmol) and stirred for 15 minutes. In the reaction mix add itmean (215 μl, of 3.45 mmol) and stirred for 2 hours. The reaction is quenched with saturated solution of NH4Cl and diluted with EtOAc. The organic layer was washed with a saturated solution of NH4Cl, saturated salt solution, dried over MgSO4and concentrate. The residue is purified flash chromatography (silica gel, 30% ethyl acetate in hexane)to give specified in the title compound as a white crystalline solid. MS (EPI) 206 (M+N)+.

Example 80

6-Hydroxy-1,3 .3m-trimethyl-1,3-dihydroindol-2-he

To a solution of 6-methoxy-1,3 .3m-trimethyl-1,3-dihydroindol-2-it (601 mg, at 2.93 mmol, example 79) in acetic acid (880 μl) is added Hydrobromic acid (48% in N2O) (8,8 ml). The resulting solution was heated at the boil under reflux (105-110°C), stirred for 2 hours, then cooled to room temperature and concentrate under reduced pressure. The residue is dissolved in EtOAc and the organic layer washed with water,saturated salt solution, dried over MgSO4and concentrate. The residue is purified by rubbing with a small amount of simple ether, getting mentioned in the title compound in the form of a whitish solid. MS (EPI) 192 (M+N)+.

Example 81

2-[3-(2-Methoxyethoxyethoxy)benzyloxy]quinoline

To a suspension of 60% NaH (44 mg, 1.1 mmol) in DMSO (2 ml) is added dropwise a solution of [3-(2-methoxyethoxyethoxy)-phenyl]methanol (212 mg, 1.0 mmol, example 72) in DMSO (1 ml). Allow to mix for 20 minutes, then add 2-chlorhydrin (180 mg, 1.1 mmol) and heated to 100°C for 1 hour. The reaction mixture is cooled to room temperature and diluted with EtOAc. The organic layer was washed with a saturated solution of NH4Cl, saturated salt solution, dried over MgSO4and concentrate. The residue is purified flash chromatography (silica gel, 25% ethyl acetate in hexane)to give specified in the title compound as a colourless oil. MS (EPI) 340 (M+N)+.

Example 82

Isobutyl 2-[3-(methoxy)phenylsulfanyl]-6-methyl-benzoate

10 n sodium hydroxide solution (0,32 ml, 3.2 mmol) is added slowly to a solution of 3-methoxybenzamide (0,42 g, 3.0 mmol) in isobutyl alcohol (2 ml) followed by a solution of isobutyl 2-methyl bromide-6-methylbenzoate (0.96 g, 3.3 mmol, example 2) in isobutyl alcohol (2 ml). The reaction mixture allow to mix for 15 min the t and then subjected distribution between ethyl acetate and dilute aqueous HCl. The organic phase is washed with water, dried over magnesium sulfate, concentrated and purified column chromatography (silica gel, 40% dichloromethane in hexane)to give specified in the header connection. MS (EI) 344 (M)+.

Example 83

Isobutyl 2-[3-(hydroxy)phenylsulfanyl]-6-methylbenzoate

Tribromide boron (1.3 ml, 1.0 M in dichloromethane, 1.3 mmol) is added to a solution of isobutyl 2-[3-(methoxy)phenylsulfanyl-methyl]-6-methylbenzoate (194 mg, 0,56 mmol, example 82) in dichloromethane (3 ml) at 0°and then the reaction mixture was stirred at room temperature for 3 hours. Then the reaction mixture is subjected to distribution between sodium bicarbonate solution and ethyl acetate. The organic phase is dried over magnesium sulfate, concentrated and purified by chromatography on a column (silica gel, 15% ethyl acetate in hexane)to give specified in the header connection. MS (EI) 330(M)+.

Example 84

Isobutyl 2-methyl-6-[3-(quinoline-2-ylethoxy)phenyl-sulfanilyl]benzoate

The free base of the hydrochloride of 2-(chloromethyl)quinoline (148 mg, 0.69 mmol) receive, exposing the substance distribution between ethyl ether and sodium bicarbonate and drying the organic phase with magnesium sulfate. This substance is then dissolved with isobutyl 2-[3-(hydroxy)phenylsulfanyl]-6-methylbenzoate (220 mg, 0.67 mmol, example 83) in DMF (2 ml) at 0°and add ghee is reed sodium (60%, 27 mg, 0.67 mmol). The reaction mixture allow to mix for 16 hours and then subjected distribution between ethyl acetate and water. The organic phase is washed with water (3×), dried over magnesium sulfate, concentrated and purified by chromatography on a column (silica gel, 10% ethyl acetate in hexane)to give specified in the header of the connection.1H NMR (300 MHz, CDCl3) δ 8,19 (d, 1H), 8,08 (d, 1H), 7,83 (d, 1H), 7,74 (t, 1H), 7,63 (d, 1H), 7,55 (t, 1H), 7.18 in-7,07 (m, 4H), of 6.99 (d, 1H), 6.89 in (d, 1H), PC 6.82 (DD, 1H), 5,33 (s, 2H), 4,18 (s, 2H), 4,10 (d, 2H), 2,36 (s, 3H), 2,07 is 2.01 (m, 1H), and 0.98 (d, 6N); MS (EPI) 472 (M+N)+.

Example 85

Isobutyl 2-methyl-6-[3-(quinoline-2-ylethoxy)phenyl-sulfanilyl]benzoate

m-Chlormadinone acid (<86%, 34 mg, 0,17 mmol) is added to a solution of isobutyl 2-methyl-6-[3-(quinoline-2-ylethoxy)phenylsulfanyl]benzoate (80 mg, 0,17 mmol, example 84) in dichloromethane (1 ml) and the reaction mixture was stirred over night. The reaction mixture is subjected to distribution between ethyl acetate and sodium bicarbonate and the organic phase is washed with additional bicarbonate solution, dried over magnesium sulfate, concentrated and purified by chromatography on a column (silica gel, 40% ethyl acetate in hexane)to give specified in the header connection. MS (EPI) 488 (M+N)+.

Example 86

Isobutyl 2-methyl-6-[3-(quinoline-2-ylethoxy)phenyl-sulfanilyl]benzoate

m-Horn benzoine acid (< 86%, 62 mg, 0.31 mmol) is added to a solution of isobutyl 2-methyl-6-[3-(quinoline-2-ylethoxy)phenylsulfanyl]benzoate (73 mg, 0.16 mmol, example 85) in dichloromethane (1 ml) and the reaction mixture was stirred over night. The reaction mixture is subjected to distribution between ethyl acetate and sodium bicarbonate and the organic phase is washed with additional bicarbonate solution, dried over magnesium sulfate, concentrated and purified by chromatography on a column (silica gel, 30% ethyl acetate in hexane)to give specified in the header connection. MS (EPI) 504 (M+N)+.

Example 87

(1-Quinoline-2-ylmethyl-1H-imidazol-4-yl)methanol and (3-quinoline-2-ylmethyl-3H-imidazol-4-yl)methanol

2-Chlormethine hydrochloride (2.24 g, 10.5 mmol), hydrochloride of 4-(hydroxymethyl)imidazole (1.35 g, 10 mmol) and K2CO3(to 4.2 g, 30 mmol) was dissolved/suspended in anhydrous DMF (20 ml) and heated to 100°With vigorous stirring over night. The reaction mixture is cooled to room temperature and poured into water (400 ml) and extracted with chloroform (3×150 ml). The organic fractions are combined and washed with a saturated solution of salt (2×200 ml), dried over MgSO4, filtered and concentrated in vacuo to an oil. The crude substance is purified flash chromatography (silica gel, 5% methanol in dichloromethane)to give (3-quinoline-2-ylmethyl-3H-imidazol-4-yl)methanol and (1-hee is Olin-2-ylmethyl-1H-imidazol-4-yl)methanol in the ratio 2:3. The authenticity of each set isomer by NMR NOE. MS (EPI) 240 (M+N)+established for both regioisomers.

Example 88

Isobutyl 2-methyl-6-(1-quinoline-2-ylmethyl-1H-imidazol-4-ileocecal)benzoate

(1-Quinoline-2-ylmethyl-1H-imidazol-4-yl)methanol (350 mg, of 1.46 mmol, example 87) was dissolved in 20% DMPU in THF (5 ml) and cooled to 0°C. Portions add sodium hydride (60%, 60 mg, 1.50 mmol) and the contents stirred for 15 minutes. Add isobutyl 2-methyl bromide-6-methylbenzoate (57%, 730 mg of 1.46 mmol, example 2), the reaction mixture allow to reach room temperature and stirred over night. The content was poured into water (200 ml) and extracted with dichloromethane (3×75 ml). The organic fractions are combined and washed with a saturated solution of salt (3×100 ml), dried over MgSO4, filtered and concentrated in vacuo to an oil. The crude substance is purified flash chromatography (silica gel, 3% methanol in dichloromethane)to give specified in the header connection. MS (EPI) 443 (M+H)+.

Example a

Isobutyl 2-methyl-6-(3-quinoline-2-ylmethyl-3H-imidazol-4-ileocecal)benzoate

Specified in the header connection comes primarily using the same procedure as in example 88, except for using (3-quinoline-2-ylmethyl-3H-imidazol-4-yl)methanol instead of (1-quinoline-2-ylmethyl-1H-imidazol-4-yl)methanol. MS (EPI) 443 (M+N)+ .

Example 89

2-Methyl-6-(1-quinoline-2-ylmethyl-1H-imidazol-4-ylethoxy-methyl)benzoic acid

Isobutyl 2-methyl-6-(1-quinoline-2-ylmethyl-1H-imidazol-4-ileocecal)benzoate (300 mg, of 0.68 mmol, example 88) dissolved in ethanol (5 ml). Add 10 N. NaOH (680 μl, 6.8 mmol) and the contents heated to 90°With during the night. The reaction mixture is cooled to room temperature, add 2 N. HCl (3.4 ml, 6.8 mmol) and adjusted the pH to ˜5-7. The content was poured into water (100 ml) and extracted with chloroform (3×75 ml). The organic fractions combined, washed with saturated salt solution (3×100 ml), dried over MgSO4, filtered and concentrated in vacuo, obtaining oil. The crude substance is purified HPLC (C-18, 25-50% acetonitrile in water over 15 minutes), getting mentioned in the title compound as TFA salt (TFA).1H NMR (300 MHz, CDCl3) δ 8,93 (s, 1H), 8,31 (d, 1H), 8,07 (d, 1H), 7,86 (d, 1H), 7,78 (t, 1H), 7,63 (t, 1H), 7,51 (d, 1H), 7,44 (s, 1H), 7,17 for 7.12 (m, 1H), 7,06-7,01 (m, 2H), 5,64 (s, 2H), of 4.66 (s, 2H), 4,48 (s, 2H), to 2.29 (s, 3H). MS (EPI) 388 (M+N)+.

Example 89a

2-Methyl-6-(3-quinoline-2-ylmethyl-3H-imidazol-4-ileocecal)benzoic acid

Specified in the header connection comes primarily using the same procedure as in example 89, except that the use of isobutyl 2-methyl-6-(3-quinoline-2-ylmethyl-3H-imidazol-4-ileocecal)benzoate instead of isobutyl 2-methyl-6-(1-henol is n-2-ylmethyl-1H-imidazol-4-ileocecal)benzoate. 1H NMR (300 MHz, CDCl3) δ of 8.95 (s, 1H), 8,27 (d, 1H), with 8.05 (d, 1H), 7,82-7,76 (m, 2H), of 7.64-to 7.59 (m, 1H), 7,46 (s, 1H), 7,38 (d, 1H), 7,10-of 6.99 (m, 2H), 6,92 (d, 1H), 5,91 (s, 2H), to 4.52 (s, 2H), 4,49 (s, 2H), of 2.23 (s, 3H)). MS (EPI) 388 (M+N)+.

Example 90

2-[3-(1H-Indol-3-ylmethyl)phenoxymethyl]quinoline

Indole (230 mg, 2.0 mmol) dissolved in tetrahydrofuran (3 ml) and add ethylaniline (1 M, 2.0 ml, 2.0 mmol) and the reaction mixture is heated for 2 hours at 65°C. the Free base to the hydrochloride of 2-(3-chloromethylene-methyl)quinoline (400 mg, 1.2 mmol, example 49) receive, exposing the substance distribution between ethyl ether and sodium bicarbonate and drying the organic phase with magnesium sulfate. This free base is dissolved in tetrahydrofuran (2 ml) and added dropwise to the cooled solution of the indole/a Grignard reagent, along with a catalytic amount of tetrabutylammonium iodide. This mixture is heated for 6 hours at 65°C. Then the reaction mixture is cooled and subjected distribution between ethyl ether and ammonium chloride. The organic phase is washed with saturated salt solution, dried over magnesium sulfate, concentrated and purified by chromatography on a column (silica gel, dichloromethane)to give specified in the header connection. MS (EPI) 365 (M+N)+.

Example 91

{3-[3-(Quinoline-2-ylethoxy)benzyl]indol-1-yl}acetic acid

Sodium hydride (60%, 22 mg, 0.55 mmol) is dobavlaut to a solution of 2-[3-(1H-indol-3-ylmethyl)phenoxymethyl]quinoline (90 mg, 0.25 mmol, example 90) in DMF (2.5 ml). After 5 min stirring ethylbromoacetate (0.1 ml, 0.9 mmol) and the reaction mixture allow to mix for 2 hours. The reaction mixture is subjected to distribution between ethyl acetate and ammonium chloride and the organic phase is washed with water. The organic phase is dried over magnesium sulfate, concentrated, and then the solid is triturated with ethyl ether and ethyl acetate, getting mentioned in the title compound in the form of solids. TPL 151-159°;1H NMR (300 MHz, CDC3) δ to 8.20 (t, 2H), 7,83-7,80 (m, 1H), to 7.77-7,71 (m, 1H), to 7.67 (d, 1H), to 7.61-7,53 (m, 1H), 7,45-7,42 (m, 1H), 7,29-7,14 (m, 3H), 7,05-of 6.99 (m, 2H), 6,94 (s, 1H), 6,85 (m, 2H), 5,16 (s, 2H), 4,84 (s, 2H), 4,11 (s, 2H); MS (EPI) 423 (M+N)+.

Example 92

Ethyl (2-formyl-6-methyl-2-phenoxy)acetate

Ethylbromoacetate (4.5 ml, 40 mmol), 2-hydroxy-Z-methyl-benzaldehyde (5 g, 37 mmol) and potassium carbonate (8.1 g, 59 mmol) are combined in acetone (60 ml) and refluxed overnight. The reaction mixture is filtered and the solvent removed from the filtrate under reduced pressure, obtaining specified in the header connection. MS (GC-MS) 222 (M)+.

Example 93

Ethyl 7-methylbenzofuran-2-carboxylate

Sodium (0.52 g, 23 mmol) is dissolved in ethanol (60 ml) and to this add ethyl (2-formyl-6-methyl-2-phenoxy)acetate (5 g, 23 mmol, example 92). This mixture is boiled with a back hall is dildocam for 3 hours and the solvent is removed in vacuum. The residue is dissolved in a mixture of dichloromethane/water and acidified with 1 N. HCl. The organic layer is washed with water and saturated salt solution and then dried over magnesium sulfate and the solvent is removed in vacuum. The residue is purified flash chromatography (silica gel, 1% methanol in dichloromethane)to give specified in the header connection. MS (GC-EI) 176 (M)+.

Example 94

Ethyl 7-bromomethylbiphenyl-2-carboxylate

Ethyl 7-methylbenzofuran-2-carboxylate (0.5 g, 2.4 mmol, example 93), N-bromosuccinimide (of 0.48 g, 2.7 mmol) and benzoyl peroxide (0.06 g, 2.4 mmol) are combined in carbon tetrachloride (10 ml) and heated on an oil bath at 90°With during the night. The reaction mixture is filtered and the solvent removed from the filtrate in vacuo. The residue is purified flash chromatography (silica gel, 5% to 10% ethyl acetate in hexane)to give specified in the header connection. MS (GC-EI) 360, 362 (M+the structure responsible Br).

Example 95

Ethyl 2-methyl-6-tripterocalyx benzoate

Ethyl 6-methyl salicylate (2.5 g, 14 mmol, see Hauser, Frank M., Synthesis 1980, 10, 814-15) dissolved in THF (20 ml) under nitrogen atmosphere and cooled in a bath with ice. Add sodium hydride (60%, 0.56 g, 14 mmol) and the mixture is stirred for 15 minutes. Then add DMPU (0,20 ml) and N-phenyltrichlorosilane (5.0 g, 14 mmol) and the reaction mixture was stirred under cooling for 2 hours. The solvent is removed the vacuum and add a simple ether and the organics washed with water, then dried over magnesium sulfate and concentrate under reduced pressure. The residue is purified flash chromatography (silica gel, dichloromethane)to give specified in the header of the connection.

Example 96

3-(2-Methoxyethoxyethoxy)periodic

To a suspension of 60% sodium hydride (of 1.76 g, 44 mmol) in THF (10 ml), cooled to 0°add 3-itfinal (8.8 g, 40 mmol) and methoxyethoxymethyl (5 ml, 44 mmol} in THF (50 ml). Then add DMPU (10 ml), the cooling bath removed and the reaction mixture is stirred for one hour. The reaction mixture was diluted with simple ether, washed with water and saturated salt solution and the organic layer is dried over magnesium sulfate. The solvent is removed in vacuum, obtaining specified in the header of the connection.

Example 97

[3-(2-methoxyethoxyethoxy) phenylethynyl] trimethylsilane

3-(2-Methoxyethoxyethoxy)periodic (12.1 g, 39 mmol, example 96) and tetrakis(triphenylphosphine)palladium (1.2 g, 1.0 mmol) and copper iodide(1) (0,096 g, 0.5 mmol) dissolved in THF (120 ml) and to it added piperidine (12 ml) and (trimethylsilyl) acetylene (8 ml, 57 mmol). This mixture Tegaserod and then stirred for 2 hours. Then the reaction mixture was diluted with simple ether and washed twice with water and saturated salt solution and the organic layer is dried over magnesium sulfate. The solvent is removed in vacuum, obtaining specified in the header connection is out. MS (EI) 206 (M)+.

Example 98

Ethyl 2-[3-(2-methoxyethoxyethoxy)phenylethynyl]-6-methyl-benzoate

[3-(2-methoxyethoxyethoxy)phenylethynyl]trimethylsilane (or 0.57 g, 2 mmol, example 97) and 1.0 M tetrabutylammonium fluoride (2.1 ml, 2 mmol) are added to THF (10 ml) and add acetic acid (0,13 g, 2 mmol) and the mixture stirred at 20°C in nitrogen atmosphere. After 15 minutes the solvent is removed in vacuum and the residue is subjected to azeotropic distillation with benzene and purified flash chromatography (silica gel, 20% ethyl acetate, 30% dichloromethane in hexane)to give 1-ethinyl-3-(2-methoxyethoxyethoxy)benzene (0.28 g, 1.4 mmol), dissolved in THF (8 ml), cooled to -78°C in an atmosphere of nitrogen and to this solution are added dropwise 2.5 M n-utility high (0.56 ml, 1.4 mmol) in 30 seconds. After stirring for 15 minutes, added dropwise 1.0 M zinc chloride in a simple ether (1.4 ml, 1.4 mmol) in 30 seconds and the mixture is stirred for 30 minutes. Add bis(dibenzylideneacetone)palladium (0.04 g, 0.07 mmol) and bis(diphenylphosphino)ferrocene (0.04 g, 0.07 mmol) and to this mixture is added ethyl-2-methyl-6-tripterocalyx-benzoate (of 0.44 g, 1.4 mmol, 95) in THF (2 ml). The cooling bath removed and the reaction mixture was allow to warm to room temperature. Then the reaction mixture is heated on an oil bath at 65°With during the night. Then implement the operating mixture is diluted with ethyl acetate (50 ml), washed with saturated ammonium chloride and saturated salt solution and then dried over magnesium sulfate. The solvent is removed in vacuo and the residue purified flash chromatography (silica gel, 10% ethyl acetate, 25% dichloromethane in hexane)to give specified in the header connection. MS (EPI) 369 (M+N)+.

Example 99

(3-Methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl chloride

To a suspension of the anhydride isatool (isatoic) acid (1.63 g, 10 mmol) in dioxane (40 ml) add a solution of methylamine (5 ml, 2 M in THF). The resulting solution was stirred for 1 hour, then concentrated in vacuo. The remainder of the absorbed toluene (30 ml), then added pyridine (5.5 ml), and then the solution chloroacetanilide (2.7 ml, 34 mmol) in toluene (15 ml). The resulting mixture is stirred for 15 hours. The solid product is filtered off, washed with water, then dried in vacuum, obtaining 2.1 g of a yellowish brown solid. Part of this product (452 mg, 2 mmol) is suspended in benzene (10 ml), then add monohydrate p-toluenesulfonic acid (394 mg, 2 mmol). This mixture is heated to 70°C and stirred at this temperature for 10 hours. The mixture is then cooled to room temperature and the benzene solution is decanted. The residual solid is mixed with (saturated) solution of sodium bicarbonate and the mixture extracted with a mixture of ethyl acetate/methanol/dichlor the Tang. The combined extracts washed with saturated salt solution, dried over MgSO4and concentrate, getting mentioned in the title compound as a yellowish brown solid.1H NMR (300 MHz, CDCl3): δ of 8.28 (d, 1H), of 7.75 (t, 1H), to 7.67 (d, 1H), 7,51 (t, 1H), 4,62 (s, 3H), 3,76 (s, 3H).

Example 100

3-(2-Hydroxymethyl-3-methylbenzylamino)phenol

To a cooled (0° (C) to a solution of methyl 2-methyl-6-[(3-hydroxyphenoxy)methyl]benzoate (220 mg, from 0.76 mmol, example 5) in THF (2 ml) add a solution of sociallyengaged (1.5 ml, 1 M in THF). The resulting solution was stirred for 10 minutes, then warmed to room temperature and stirred for 40 minutes. Then the solution is cooled to 0°and add water (75 ml)dropwise, followed by the addition of sodium hydroxide solution (75 ml, 5 BC) and water (75 ml). The resulting suspension was diluted with simple ether, filtered through celite and the solid is thoroughly washed with methanol (up until according to TLC analysis, the solid will not be released from the product). The combined filtrates concentrated in vacuo, obtaining mentioned in the title compound as a white solid. MS (EI) 244 (M)+.

Example 101

2-[3-(2-Hydroxymethyl-3-methylbenzylamino)phenoxymethyl]-3-methyl-3H-hinzelin-4-one

To a suspension of 3-(2-hydroxymethyl-3-methylbenzylamino)phenol (87 mg, 0.38 mmol,example 100) and (3-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl chloride (94 mg, 0.45 mmol, example 99) in DMF (1 ml) is added powdered To2CO3(78 mg, 0.5 mmol). The resulting mixture was heated to 60°C and stirred at this temperature for 5 hours. This mixture is cooled to room temperature, diluted with ethyl acetate, washed with water and saturated salt solution, dried over MgSO4and concentrate. The residue is purified flash chromatography (silica gel, 40% ethyl acetate/30% dichloromethane in hexane)to give specified in the title compound in the form of foam. MS (EPI) 417 (M+N)+.

Example 101A

{2-[3-(5-Cyclobutyl[1,2,4]oxadiazol-3-ylethoxy)-phenoxymethyl]-6-were}methanol

Specified in the header connection comes primarily using the same procedure as in example 101, except that the use of 3-chloromethyl-5-cyclobutyl-[1,2,4]oxadiazol instead of (3-methyl-4-oxo-3,4-dihydrogen-Zolin-2-yl)methyl chloride. MS (EPI) 381 (M+N)+.

Example 102

2-Methyl-6-[3-(3-methyl-4-oxo-3,4-dihydroquinazolin-2-ylethoxy)phenoxymethyl]benzaldehyde

To a cooled (-78° (C) the solution oxalicacid (2.5 ml, 1.75 M in CH2Cl2add, dropwise, DMSO (80 ml). After adding dropwise added a solution of 2-[3-(2-hydroxymethyl-3-methylbenzylamino)phenoxymethyl]-3-methyl-3H-hinzelin-4-it (120 mg, 0.28 mmol, example 101) in dichloromethane (1 ml). This solution is stirred for 5 minutes, then one the second portion add triethylamine (276 ml, 2 mmol). The cold bath is removed and continue stirring for 10 minutes. The mixture is then diluted with ethyl acetate, washed with water and saturated salt solution, dried over MgSO4and concentrate, getting mentioned in the title compound in the form of solids. MS (EPI) 415 (M+N)+.

Example 102A

2-[3-(5-Cyclobutyl[1,2,4]oxadiazol-3-ylethoxy)-phenoxymethyl]-6-methylbenzaldehyde

Specified in the header connection comes primarily using the same procedure as in example 102, except that the use of {2-[3-(5-cyclobutyl-[1,2,4]oxadiazol-3-ylethoxy)phenoxymethyl]-6-were}-methanol (example 101A) instead of 2-[3-(2-hydroxymethyl-3-methyl-benzyloxy)phenoxymethyl]-3-methyl-3H-hinzelin-4-it. MS (EPI) 379 (M+N)+.

Example 103

2-Methyl-6-[3-(3-methyl-4-oxo-3,4-dihydroquinazolin-2-ylethoxy)phenoxymethyl]benzoic acid

To a suspension of 2-methyl-6-[3-(3-methyl-4-oxo-3,4-dihydro-hinzelin-2-ylethoxy)phenoxymethyl]benzaldehyde (120 mg, 0.28 mmol, example 102) in t-butanol (1.5 ml) add isobutan (0.5 ml), and then NaClO2(220 mg, technical grade, 1.6 mmol) in water (1.5 ml) and NaH2PO4·H2O (220 mg, 1.6 mmol) in water (1.5 ml). This mixture is stirred for 1 hour (during this time, the solids dissolve), then diluted with ethyl acetate, washed with water and saturated salt solution, dried over MgSO 4and concentrate. The residue is purified flash chromatography (10% methanol in dichloromethane). This product is suspended in chloroform and filtered through celite. The filtrate is concentrated under reduced pressure, obtaining mentioned in the title compound as amorphous solid.1H NMR (300 MHz, CDCl3) δ to 8.41 (d, 1H), to 7.84 (m, 2H), 7.62mm (m, 1H), 7,33 (m, 2H), 7,20 (m, 1H), 7,14 (t, 1H), for 6.81 (m, 1H), 6,70 (m, 2H), from 5.29 (s, 2H), 5.25 in (s, 2H), 3,80 (s, 2H), 2,52 (s, 3H). MS (EPI) 430 (M+H)+.

Example 103A

2-[3-(5-Cyclobutyl[1,2,4]oxadiazol-3-ylethoxy)-phenoxymethyl]-6-methylbenzoic acid

Specified in the header connection comes primarily using the same procedure as in example 103, except that the use of 2-[3-(5-cyclobutyl-[1,2,4]oxadiazol-3-ylethoxy)phenoxymethyl]-6-methylbenz-aldehyde (example 102A) instead of 2-methyl-6-[3-(3-methyl-4-oxo-3,4-dihydroquinazolin-2-ylethoxy)phenoxymethyl]benzaldehyde.1H NMR (300 MHz, DMSO) δ 7,10 (m, 4H), of 6.68 (s, 1H), 6,60 (m, 2H), 5,19 (s, 2H), 5,13 (s, 2H), 3,86 (m, 1H), a 2.36 (m, 4H), of 2.28 (s, 3H), of 2.08 (m, 1H), 1,96 (m, 1H). MS (EPI) 395 (M+N)+.

Example 104

5-Phenyl-2-methylpyridin

To a cooled (-70° (C) to a solution of 3-phenylpyridine (1,43 ml, 10.0 mmol) in diethyl ether (7.5 ml) added dropwise motility (LiBr complex, 1.5 M in diethyl ether, 7,33 ml, 11.0 mmol). After allowing to warm to room temperature for 16 hours, the reaction mixture was cooled (0° C) and quenched with distilled water (5 ml). Then the reaction mixture is extracted with methylene chloride, the organic layer is separated and concentrated, and the obtained residue is purified column chromatography (silica gel, mixture 3:1 hexane:EtOAc), getting mentioned in the title compound as a pale yellow oil. MS (EPI) 170 (M+H)+.

The synthesis of compounds of formula (VI)

The compound of formula (VI) are obtained by a multi-stage synthesis, illustrated below diagram. A key source of concern is hinanden. In the first stage of his glorious, receiving 2-chlormethine that, no highlighting, is subjected to the interaction with hydroquinone to obtain intermediate compound, 4-(quinoline-2-ylethoxy)phenol (VIII). Then this intermediate connection handle α,α'-dichloro-o-xylene, receiving 2-[4-quinoline-2-ylethoxy)-phenoxymethyl]benzylchloride, which makes in situ 2-[4-quinoline-2-ylethoxy)phenoxymethyl]phenylacetonitrile (IX), the penultimate precursor (VI).

(IX) transformed into a crude product (VI) by reaction with sodium azide and ammonium chloride, resulting nitrile group is transformed into tetrazole ring. Purification of the final product is carried out by recrystallization of the crude substance from methanol, obtaining the pure product (VI).

Solid state is inches compounds of the formula:

1. The acid load:

1-liter round-bottom flask is charged with 4-(methyl bromide)-benzoic acid (32,26 g, 150,0 mmol) and dichloromethane (650 ml). Gently bring the stirrer (stir bar) and the reaction flask is placed in a bath with a mixture of ice-water. After approximately 15 minutes, add oxalicacid (15.7 ml, 180 mol). After approximately 15 minutes, add N,N-dimethylformamide (500 ml, cat.). In the reaction mixture starts to separate bubbles. After stirring for 1.5 hours bath with a mixture of ice-water are removed. After stirring for 3 hours at ambient temperature, bubbling gas stops. At the end of this period of time, from the reaction mixture to remove the agitator and vacuum to remove the solvent from the reaction mixture. After the solvent is removed in the reaction flask add an additional amount of dichloromethane and again removed in vacuo.

Three-neck 3-liter round-bottom flask is charged with dry N,N-dimethylformamide (1.3 l), N,N-diisopropylamino-amine (39,19 ml, 225 mmol), 4-N,N-dimethylaminopyridine (3,67 g, 30 mmol) and MicroKANS [1456, 15 mg of Wang resin (1.7 mmol/g loading) on the MicroKANs, 25.5 micromol/microKAN, 37,1 mmol]. The flask supply outboard mixer. After stirring for approximately 15 minutes in reaction to the BU transfer the solution obtained above acid chloride in dry N,N-dimethylformamide (200 ml). After 14 hours, the solvent is removed from the reaction mixture. The reaction flask was added DMF (DMF) (1.5 liters). The flask and allow to mix for about 15 minutes and the solvent away. MicroKANs washed, stirred for 20 minutes and the solvent disperses in the following repeatedly: DMF (2×6 l), THF (3×6 l), dichloromethane (3×6 l) and a simple ether (2×6 l). After washing, the MicroKANs are dried, blowing nitrogen through the flask with periodic stirring. After sufficient drying, the MicroKANs are sorted for the next reaction.

2. Substitution of phenol:

Three-neck 3-liter round-bottom flask is charged with 3-chloro-4-hydroxybenzaldehyde (21,9 g, 140 mmol) and DMF (1.5 l). The reaction flask supply overhead stirrer and placed in a bath with a mixture of ice-water. After approximately 15 minutes, carefully add sodium hydride (60% dispersion in oil, 6,48 g, 180 mmol). After approximately 30 minutes, bath with a mixture of ice-water is removed and the reaction mixture is allowed the opportunity to mix at ambient temperature for 1 hour. At the end of this time the reaction mixture was added MicroKANs [1274, 25.5 micromol/microKAN, 32.5 mmol] and potassium iodide (1.0 g). The reaction flask is immersed in an oil bath, which is heated to 60°C. After 14 hours, the reaction flask is removed from the oil the bath and allow to cool to ambient temperature. Remove the solvent from the reaction mixture. The reaction flask was added DMF (1.2 l). The flask and allow to mix for about 15 minutes and the solvent away. In the reaction flask is added a mixture of DMF:water (1:1, 1.2 l). The flask and allow to mix for about 15 minutes and the solvent away. This sequence of operations is repeated at least three times or up until the drainage runoff from washing will not become transparent, the reaction flask is washed repeatedly in the following sequence: THF (2×4 l), dichloromethane (1×4 l)then methanol (1×4 l), dichloromethane (1×4 l)then methanol (1×4 l), dichloromethane (1×4 l)then methanol (1×4 l), dichloromethane (1×4 l) and a simple ether (1×4 l). After washing, the MicroKANs are dried, blowing a stream of nitrogen flask with periodic stirring. After sufficient drying, the microKANs are sorted for the next reaction.

3. Reductive amination:

Three-neck 2 l round bottom flask is charged with microKANs [784, 25.5 micromoles/microKAN, 20.0 mmol], triethylorthoformate (850 ml) and 2-(2-amino-ethyl)pyridine (20,79 g, 170 mmol). The reaction flask supply outboard mixer. After 2 hours add cyanoborohydride sodium (21,37 g, 340 mmol). After about 10 minutes add acetic acid (17,0 m is, 297 mmol). After stirring for an additional hour the reaction flask drain. Into the flask, add methanol (800 ml). After stirring for about 10 minutes, the flask is drained by the reaction flask is washed repeatedly in the following sequence: DMF (3×4 l), dichloromethane (1×4 l)then methanol (1×4 l), dichloromethane (1×4 l)then methanol (1×4 l), dichloromethane (1×4 l)then methanol (1×4 l), dichloromethane (1×4 l) and a simple ether (1×4 l). After washing the microKANs are dried by pulling a flask with a stream of nitrogen at periodic stirring. After sufficient drying, the microKANs are sorted for subsequent reactions.

4. Acylation:

Three-neck 2 l round bottom flask is charged with microKANs [784, 15 mg of resin (1.7 mmol/g loading) on the MicroKAN, 25.5 micromoles/microKAN, 20.0 mmol] and dichloromethane (800 ml). The reaction flask supply outboard mixer. Add N,N-diisopropylethylamine (20,9 ml, 120 mmol) and 4-N,N-dimethylaminopyridine (195 mg, 1.6 mmol). After approximately 15 minutes, add cyclopentanecarbonitrile (10.6 g, 80,0 mmol). The reaction mixture allow to mix for 61 hours, the reaction flask drain. In the reaction flask add dichloromethane (800 ml). After stirring for about 10 minutes, the flask drain. This operation .MicroKANs from all acylation reactions combine randomly in two separate large bulb and repeatedly washed in the following sequence: dichloromethane (1× 4 l), THF (2×4 l), dichloromethane (1×4 l)then methanol (1×4 l), dichloromethane (1×4 l)then methanol (1×4 l), dichloromethane (1×4 l)then methanol (1×4 l), dichloromethane (1×4 l) and a simple ether (1×4 l).

5. Removal:

MicroKAN distribute in individual wells IRORI AccuCleave 96-well station off. Well load dichloromethane (600 ml) and then with a mixture of TFA (TFA):dichloromethane (1:1, 600 ml). After stirring for about forty minutes, the reaction well is drained by a 2-ml microprobing in 96-well format. The reaction well again load dichloromethane (600 ml). After manual shaking well also drain in 2-ml microprobing in 96-well format. Cocktail removal removed in vacuo using a Savant Speedvac. Concentrated products with uterine tablets off restore THF and transferred to two children, a tablet, using a Packard liquid dispenser for multiple selection of microprobe. Child tablets, concentrated in vacuo, using GenieVac.

Analytical: MS: m/z 493 (M)+.

The methods described above, is used to obtain the following compounds of the invention.

5-[2-(4-(2-Hyalinella)phenoxymethyl)benzyl]tetrazol (TPL 108-111°)

The expect.: With, 59,87; N, 5,96; N, 13,96

Found: C, 59,67, 60,01; N, 5,62, 5,63; N, 13,73, 13,77

5-[4-Methoxy-3-(3-(2-hyalinella)phenoxymethyl)phenyl]-Tetris is l (TPL 184-87°)

The expect.: With, 67,63; N, 4,88; N, 15,78

Found: C, 67,18; N, 5,13; N, 15,40

5-[3-(4-(2-Inaliniulmice)phenoxymethyl)phenyl]tetrazole (TPL 176-177°)

The expect.: With, 69,63; N, Of 4.75; N, 16,92

Found: C, 69,58, 69,64; N, 5,00, To 4.98; N, 16,66, 16,63

5-[3-Methoxy-4-(4-(2-inaliniulmice)benzyloxy)phenyl]-tetrazol (TPL 195-97°)

The expect.: With, 67,63; N, 4,88; N, 15,77

Found: C, 67,27; N, 4,89; N, 15,41

5-[4-(3-(2-inaliniulmice)phenoxymethyl)-3-methoxyphenyl]-tetrazol (TPL 189-91°)

The expect.: With, 66,95; N, Of 4.95; N, 15,61

Found: C, 66,48; N, 5/14; N, 14,93

5-[3-(4-(2-Inaliniulmice)phenoxymethyl)benzyl]tetrazol (TPL 139-44°)

The expect.: With, 70,53; N, Of 5.03; N, 16,45

Found: C, 70,33, 70,54; H, 5.25-Inch, Are 5.36; N, 16,38, 16,41

5-[4-(4-(2-Inaliniulmice)phenoxymethyl)benzyl]tetrazol (TPL 167-71°)

The expect.: With, 67,33; N, 5,31; N, 15,70

Found: C, 67,54, 67,67; N, 5,33, 5,33; N, 15,48, 15,52

5-[4-Methoxy-3-(4-(2-inaliniulmice)phenylmethoxy)-phenyl]tetrazole (TPL 210-13°)

The expect.: With, 68,33: N, 4,82; N, 4,90

Found: C, 68,32: N, The 4.90; N, 14,79

4-[3-(2-Inaliniulmice)phenoxymethyl]venexiana acid (TPL 164°C (decomp.))

The expect.: With, 69,27; N, To 5.35; N, 3,23

Found: C, 69,53, 69,65; N, 5,11, Of 5.05; N, 3,21, 3,12

5-[2-(4-(2-Inaliniulmice)phenoxymethyl)phenoxymethyl]-tetrazol (TPL 183-85°)

The expect.: With, 65,63; N, To 5.08; N, 15,31

Found: C, 65,77, 65,52; N, 4,99, To 5.03; N, 14,92, 15,03

4-[4-(2-Inaliniulmice)phenoxymethyl]tenoxicam the traveler acid (176° C (decomp.))

The expect.: With, 71,50; N, 5,16; N, 3,34

Found: C, 71,10, 71,17; N, 5,27, 5,33; N, 3,37, 3,34

4-[3-(2-Inaliniulmice)phenoxymethyl]phenylacetic acid (TPL 158-60°)

The expect.: With, 75,17; N, And 5.30; N, 3,51

Found: C, 74,89; N, Are 5.36; N, 3,37

2-[3-(3-(2-Inaliniulmice)phenoxymethyl)phenoxy]-pentane acid (TPL 133-35°)

The expect.: With, 73,51; N, 5,95; N, 3,06

Found: C, 73,35, 73,60; N, 5,95, 5,98; N is 3.08, 3,05

2-[3-(2-Inaliniulmice)phenoxymethyl]venexiana acid (TPL 169-172°)

The expect.: With, 72,28; N, 5,10; N, 3,37

Found: C, 69,34, 69,69; N, 5,10, 5,13; N, 3,00, is 3.08

The expect.: With, 69,27; N, To 5.35; N, 3,23 (as hydrate)

2-[4-(2-Inaliniulmice)phenoxymethyl]cinnamic acid (TPL 175-178°)

The expect.: With, 75,90; N, 5,14; N, 3,40

Found: C, 73,92; N, 5,20; N, 3,01

The expect.: With, 74,27; N, At 5.27; N, 3.33 and (as hydrate)

6-Acetyl-2-propyl-3-[3-(2-inaliniulmice)benzyloxy]-venexiana acid (TPL 153-58°)

The expect.: With, 72,13; N, 5,85: N, 2,90

Found: C, 71,68, 72,08; N, 5,88, Of 5.83; N, 2,65, 2,70

2-[2-(4-(7-Chlorhydrin-2-ylmethylene)phenoxymethyl)phenoxy]-propionic acid (TPL 169-173°)

The expect.: With, 67,32; N, 4,78; N, 3,02; Cl, of 7.64

Found: C, 65,18; N, Of 4.90; N, 2,84; Cl, 8,33

The expect.: With, 65,41; N, 4,96; N, 2,93; Cl, 7,42 (as hydrate)

2-[4-(2-Inaliniulmice)phenoxymethyl]phenylacetic acid (TPL 181-83°)

The expect.: With, 75,17; N, And 5.30; N, 3,51

Found: C, 75,12, 74,96; N, 5,50, 5,49; N, 3,16, 3,16

3-[3-(2-Hyalinella the XI)phenoxymethyl]venexiana acid (TPL 146-51°)

The expect.: With, 72,28; N, 5,10; N, 3,37

Found: C, 71,82, 71,80; N, 5,24, 5,23; N, 2,98, 3,00

The expect.: With, 71,50; N, 5,16; N, 3,34 (as hydrate)

2-[4-(2-Hemolymphatic)phenoxymethyl]venexiana acid (TPL 153-57°)

The expect.: With, 72,28; N, 5,10; N, 3,37

Found: C, 72,30, 71,72; N, 5,39, And 5.30; N, 2,94, 2,89

5-[2-(4-(7-Chlorhydrin-2-ylmethylene)phenoxymethyl)benzyl]tetrazol (TPL 159-63°)

The expect.: With, 65,57; N, And 4.40; N, 15,29

Found: C, 64,16; N, 4,72; N, 14,98

The expect.: With, 64,30; N, A 4.53; N, 14,99 (as hydrate)

2 Carbomethoxy-5-[3-(2-inaliniulmice)phenoxymethyl]-venexiana acid (TPL 187-89°)

The expect.: With, 68,49; N, Of 4.90; N, 2,95

Found: C, 66,71; N, 4,96; N, 2,70

The expect.: With, 66,59; N, 5,07; N, 2,87 (as hydrate)

2-[3-(2-Inaliniulmice)phenoxymethyl]-6-methylphenoxy-acetic acid (TPL 149-53°)

The expect.: With, 72,71; N, Of 5.40; N, 3,26

Found: C, 71,23; N, 5,46; N is 3.08

The expect.: With, 71,22; N, The 5.51; N, 3,19 (as hydrate)

2-[3-(3-(2-Inaliniulmice)phenoxymethyl)phenoxy]-glutaric acid (TPL 129-30°)

The expect.: C 69,00: N, Of 5.17; N, 2,87

Found: C, 58,19; N, Is 4.93; N, 2,23

The expect.: With, 58,23; N, To 5.17; N, 2,43 (as hydrate)

2-[3-(2-Inaliniulmice)phenoxymethyl]benzylmalonate acid (TPL 164-65°)

The expect.: With, 70,89; N, 4,08; N, 3,06

Found: C, 70,51, 70,61; N, 5,03, Of 5.24; N, 3,03, 2,90

2-[2-(3-(2-Inaliniulmice)phenoxymethyl)phenoxy]-pentane acid (TPL 118-20°)

The expect.: With,73,51; N, 5,95; N, 3,06

Found: C, 73,26; N, 6,07; N, 2,79

2-[4-(2-Inaliniulmice)phenoxymethyl]-6-methylphenoxy-acetic acid (TPL 151-53°)

The expect.: With, 72,71; N, Of 5.40; N, 3,26

Found: C, 71,41; N, To 5.58; N, 3,03

The expect.: With, 71,22; N, The 5.51; N, 3,19 (as hydrate)

2-[2-(4-(2-Inaliniulmice)phenoxymethyl)phenoxy]-pentane acid (TPL 85-92°)

The expect.: With, 73,51; N, 5,95; N, 3,06

Found: C, 71,73, 71,79; N, 5,96, 5,91; N, 3,06, 2,83

The expect.: With, 72,09; N, equal to 6.05; N, 3,00 (as hydrate)

2 Carbomethoxy-5-[4-(2-inaliniulmice)phenoxymethyl]-venexiana acid (TPL 149-51°)

The expect.: With, 68,49; N, Of 4.90; N, 2,95

Found: C, 68,00, 68,08; N, 4,98, 5,04; N, 2,90, 2,90

2-[2-(4-(2-Inaliniulmice)phenoxymethylpenicillin]-propionic acid (TPL 161-64°)

The expect.: With, 72,71; N, Of 5.40; N, 3,26

Found: C, 70,96, 71,10; N, 5,51, To 5.58; N, is 3.08, 3,10

The expect.: With, 71,22; N, 5,52; N, 3,19 (as hydrate)

2-[2-(3-(2-Inaliniulmice)phenoxymethyl)phenoxy]-glutaric acid (TPL 83°decomp.)

The expect.: With, 68,98; N, To 5.17; N, 2,87

Found: C, 64,10, 63,75; N, 4,89, To 4.92; N, 2,64, 2,69

The expect.: With, 63,74; N, 5,63; N, 2,65 (as hydrate)

2-(3-[2-Inaliniulmice]benzyloxy)venexiana acid (TPL 153-55°)

The expect.: With, 72,28; N, 5,10; N, 3,37

Found: C, 71,75; N, 5,14; N, 3,38

The expect.: With, 71,50; N, 5,16; N, 3,34 (as hydrate)

2-(2-[4-(2-Inaliniulmice)phenoxymethyl]-4-chlorophenoxy) propionic acid (TPL 196-99°)

The expect.: With, 6732; N, 4,78; N, 3,02

Found: C, 67,40, 67,43; N, 4,89, 4,94; N, 3,01, 3,13

2-(2-[3-(2-Inaliniulmice)phenoxymethyl]-4-chlorophenoxy) propionic acid (TPL 169-71°)

The expect.: With, 67,32; N, 4,78; N, 3,02

Found: C, 65,47; N, 5,31; N, 2,78

The expect.: With, 65,41; N, 4,96; N, 2,93 (as hydrate)

2-(2-[3-(2-Inaliniulmice)phenoxymethyl]-4-chlorphenoxy) pentane acid (TPL 144-45°)

The expect.: With, 68,36; N, 5,33; N, 2,85

Found: C, 67,74, 67,86; N, 5,39, Vs. 5.47; N, 2.91 in, 2,84

The expect.: With, 67,74; N, 5,38; N, 2,82 (as hydrate)

2-(2-[4-(2-Inaliniulmice)phenoxymethyl]-4-chlorphenoxy) pentane acid (TPL 155-56°)

The expect.: With, 68,36; N, 5,33; N, 2,85

Found: C, 65,96; N, 5,59; N, 2,66

The expect.: With, 65,95; N, Of 5.53; N, 2,75 (as hydrate)

2-(2-[4-(2-Inaliniulmice)phenoxymethyl]-4-chlorphenoxy) pentane acid (TPL 155-56°)

The expect.: With, 68,36; N, 5,33; N, 2,85

Found: C, 66,15; N, To 5.58; N, 2,68

The expect.: With, 65,95; N, Of 5.53; N, 2,75 (as hydrate)

2-(2-[4-(2-Inaliniulmice)phenoxymethyl]-6-chlorphenoxy) pentane acid (TPL 161-62°)

The expect.: With, 68,36; N, 5,33; N, 2,85

Found: C, 68,15; N, Are 5.36; N, 2,72

2-(2-[3-(2-Inaliniulmice)phenoxymethyl]-6-chlorphenoxy)pentane acid (TPL 169-70°)

The expect.: With, 68,36; N, 5,33; N, 2,85

Found: C, 68,10; N, Of 5.39; N, 2,72

2-(2-[3-(2-Inaliniulmice)phenoxymethyl]-6-chlorophenoxy)-4-methylpentanoic acid (TPL 164-66°)

The expect.: With, 68,84; N, To 5.58; N, 2,77

Found: C, 68,84; N,5,70; N, 2,69

2-(2-[4-(2-Inaliniulmice)phenoxymethyl]-6-chlorophenoxy)-4-methylpentanoic acid (TPL 167-69°)

The expect.: With, 68,84; N, To 5.58; N, 2,77

Found: C, 68,78; N, 5,67; N, 2,68

5-[3-(3-(2-Inaliniulmice)benzyloxy)-4-methoxyphenyl]-tetrazol (TPL 204-07°)

The expect.: With, 67,63; N, 4,88; N, 15,78

Found: C, 67,11; N, 5,15; N, 15,86

N-[3-Methoxy-4-(3-(2-inaliniulmice)benzyloxy)benzoyl)-benzosulfimide hydrochloride (TPL rasl°)

The expect.: With, 62,99; N, 4,60; N, 4,74

Found: C, 63,88; N, 5,13; N, 4,80

5-Carboxy-2-(3-(2-Inaliniulmice)phenoxymethyl)phenoxy-acetic acid (TPL 226-28°)

The expect.: With, 61,90; N, 5,18; N, 2,77

Found: C, 61,62; N, 5,11; N, 2,67

5-[3-Methoxy-4-(3-(2-inaliniulmice)benzyloxy)phenyl]-tetrazol (TPL 204-05°)

The expect.: With, 67,67; N, 5,14; N $ 15.87 with

Found: C, 67,63; N, 4,88; N, 15,78

5-(4-(3-(2-Inaliniulmice)benzyloxy)phenyl)tetrazol (TPL 233-36°)

The expect.: With, 69,58; N, To 4.73; N, 16,91

Found: C, 69,59; N, 4,89; N, 16,91

Using a combination of the above examples, you can get a variety of compounds within the scope of this invention.

The proposed compounds provide significant pharmacological activity in accordance with the tests described in the literature, and the results of these tests are thought to be in accordance with pharmacological activity in humans and other animals. The results of the following pharmacological tests are typical features of the specific compounds according to this invention.

The compounds of this invention have a strong activity as ligands of the receptor PPAR and possess antidiabetic, antilipidemics, antihypertensive and antiarteriosclerotic activity and, as expected, are effective for the treatment of diabetes, obesity and other related diseases.

Test for binding CPARα.

The active compounds according to the invention as modulators of PPARα can be tested in several suitable in vitro and in vivo preclinical biological tests, such as benchmarking with a known modulator of PPARαfor example, [3H]-GW2331(2-(4-[2-(3-[2,4-differenl]-1-heptyl-ureido)ethyl]phenoxy)-2-methylmalonic acid). (S.Kliewer, et al. Proc. Natl. Acad. Sci. USA 94 (1997).

The ligand-binding domain of the receptor, activated by proliferation peroxisome person (CPARα-LSD, hPPARα-LBD):

The analysis of binding to PPARα can be carried out by the following procedure: cDNA encoding the presumed ligand-binding domain PPARα human (amino acids 167-468) (Sher.T., Yi, H.-F., McBride, OW & Gonzalez, F.J. (1993) Biochemistry 32, 5598-5604), amplified by PCR PCR (polymerase chain reaction) and inserted into the frame in the BamHI site of pGEX-2T plasmid (Pharmacia). Soluble fraction fused protein GST-CPARα or glutathione S-transferase (GST), one sverkhekspressiya in E. coli BL21(DE3)pLysS to ecah and purified from the extracts of bacteria, as described in (S.Kliewer, et al., Proc. Natl. Acad. Sci. USA 94 (1997), 4318-4323).

Gel-filtration of the sample 30 ml of 90 nm GST-hPPARα-LBD mixed with 20 ml of 50 nm3H-GW2331 with or without 5 ml of 10 mm of the test compounds in binding buffer containing 10 mm Tris, 50 mm KCl, 0.05% tween 20 and 10 mm DTT (DTT). The reaction mixture is incubated in 96-well tablets for 2 hours at room temperature. Then 50 ml reaction mixtures applied to 96-well gel filtration block (following the instructions received) (EdgeBioSystems). The unit placed on top of a clean 96-lunch-aqueous tablet, centrifuged at 1500 rpm for 2 minutes. The block is removed. In each well of 96-hole tablet add 100 ml of scintillation fluid. After equilibration during the night the tablet reads the counter microbeta particles (Wallac.).

Analysis of affinity for binding in a homogeneous scintillation environment. For Scarchard analysis, SPA granules loaded with glutathione (1.5 mg/ml) (Amersham) mixed with GST-hPPARα-LBD (10 mg/ml) in binding buffer. The resulting suspension is incubated at room temperature with stirring for 15 minutes. Then 20 ml of suspension added to 30 ml of binding buffer containing various amounts of3H-GW2331 (10-500 nm). The nonspecific binding determined in the presence of 100 mm GW2331. For analysis of competitive binding, 20 ml of the suspension were then added 30 ml swiatowej the buffer, containing 75 nm3H-GW2331 and 0.03-20 mm of the test compounds. For control experiments, loaded with glutathione SPA granules (1.5 mg/ml) cover the GST protein (10 mg/ml). 20 ml of the suspension is mixed with 30 ml of 75 nm3H-GW2331 with or without 10 mm GW2331. The above experiments, all performed in 96-well plates. Sealed tablets reaction mixtures give the opportunity to be balanced within 2 hours, and read the counter microbeta particles (Wallac.).

Analysis on linking CPARγ

The active compounds according to the invention as modulators of PPARγ can be tested in several suitable in vitro and in vivo preclinical biological tests, such as benchmarking with a known modulator of PPARγfor example, [3H]-BRL 49853 (Lehman L.J. et al, J. Biol. Chem. 270, 12953-12956; Lehman L.J. et al, J. Biol. Chem. 272, 3406-3410 (1997), and Nichols, J. S.; et al Analytical Biochemistry 257, 112-119 (1998)).

The ligand-binding domain of the receptor, activated by proliferation peroxisome person (CPARγ-LSD, hPPARγ-LBD)

Test link for PPARγ can be carried out by the following procedure: cDNA encoding the presumed ligand-binding domain of human PPARγ (PPARγ) (amino acids 176-477) (Green, M.E. et al. Gene expression 281-299 (1995)), amplified by PCR (polymerase chain reaction) and inserted into the frame in the BamHI site of pGEX-2T plasmid (Pharmacia). Soluble f the action fused protein GST-hPPARγ or glutathione S-transferase (GST), one sverkhekspressiya in E. coli BL21(DE3)pLysS cells and purified from the extracts of bacteria.

Sample link: Fused protein GST-PPARγ-LBD in SFR (PBS) (5 mg/100 ml/well) are incubated in 96-well tablets, coated glutathione, within 4 hours. Then the unbound proteins were removed and tablets washed twice with buffer flushing (10 mm Tris, 50 mm KCl and 0.05% tween-20). Then add 100 ml reaction mixtures containing 60 nm3H-BRL-49853 and 10 mm of the test compounds (10 ml of 0.1 mm of the compounds from each well of tablets) in binding buffer (10 mm Tris, 50 mm KCl and 10 mm DTT) and incubated at room temperature for 2.5 hours. The reaction mixture is removed and tablets washed twice with the buffer for washing. To each well was added 100 ml of scintillation liquid and tablets read on β-the counter.

Test for binding CPARδ (hPPARδ)

The active compounds according to the invention as modulators of PPARδ can be tested in several suitable in vitro and in vivo preclinical biological tests (see references WO 97/28149; Brown P. et al Chemistry & Biology, 4, 909-18, (1997)), for example benchmarking with a known modulator of PPARδfor example, [3H2]GW2433 or [3H2] Compound X

Analysis of the binding hPPARδ involves the following stages:

(a) the floor is giving multiple samples for testing by incubation separate aliquot of receptor hPPARδ with the test compound in TEGM containing 5-10% cytoplasmic lysate of COS-1 cells and 2.5 nm labeled ([3H] Compounds X, 17 CI/mmol) for at least 12 hours, and preferably for about 16 hours, at 4°where the concentration of the test compounds in each sample for various tests, and the reference sample by incubation an additional separate aliquots of the receptor hPPARδ in the same conditions but without the test compound; then

(b) removing unbound ligand by adding in each sample loaded dextran/gelatin coal dust while maintaining samples at 4°C for at least 10 minutes; then

(c) stage, in which each of the test samples and control sample from step (b) is subjected to centrifugation at 4°up until the coal dust will not be preformed; then

(d) counting part supernatant fraction of each of the test samples and the control sample from step (C) liquid scintillation counter, and analysis of results to determine IC50test the connection.

In the analysis of binding hPPARδto determine the IC50for each test compound preferably prepared at least four sample for testing with different concentrations.

p> The activity of the compounds tested, determining the concentration of the IC50the PPAR agonist in cell analysis of PPAR-alpha

The effectiveness of compounds that bind the human PPAR-alpha and act as agonists, is analyzed using a stably transformed cell line SOME (SOME kidney of a human embryo), which in this case is used as a cell line carrier PPAR-alpha. It contains two genetic elements: element vector luciferase (pdeltaM-GAL4-Luc-Zeo) and protein PPAR-alpha (GR-GAL4-human PPAR-alpha-LBD), which mediates the expression element vector luciferase depending on the ligand of PPAR-alpha. Stable and significantly expressed protein (GR-GL4-human PPAR-alpha-LBD) that binds the nuclei of cells of the cell line carrier PPAR-alpha through a portion of protein, GAL-4, GAL-4 DNA-binding motifs located after the 5' - position of the element vector luciferase, which integrates into the genome of the cell line. There is only a slight expression of a gene vector luciferase without added ligand of PPAR-alpha, if the analysis is used serum depleted fatty acids fetal calf (cs-FCS). Ligands of PPAR-alpha bind and activate protein PPAR-alpha and therefore induce gene expression of the luciferase vector. Luciferase, which is formed, can be the ü determined by chemical luminescence through a suitable substrate.

Cell line carrier PPAR-alpha was prepared in two stages. The first element of the vector luciferase was constructed and stably moved in SOME cells. For this purpose 5 binding sites of factor GAL-4 transcription of yeast (every fifth CGGAGTACTGTCCTCCGAG-3') was cloned after the 5'-position of the MMTV-promoter 68 bp minimum length (Genbank Accession # V01175). Part of the minimum MMTV-promoter contains a block SEAT and TATA-element for efficient transcription by RNA polymerase II. Cloning and sequencing of construction the combination of GAL-4-MMTV similar to the description Sambrook J and others, Molecular cloning, Cold Spring Harbor laboratory Press, 1989). Following is the complete gene of Photinus pyralis (Genbank Accession # M15077) was cloned after the 3' position of the GAL-4-MMTV. After sequencing element vector luciferase consisting of 5 sites linking GAL-4, MMTV-promoter and luciferase gene was re-cloned into a plasmid, which gives resistance against zeocin to obtain plasmids pdeltaM-GAL4-Luc-Zeo. This vector was transformed into SOME cells in accordance with the information provided in F.M. Ausubel, Current protocols in molecular biology, vol. 1-3, John Wiley&Sons, Inc.1995). Then socinstrasse medium (0.5 mg/ml) was used to select stable clone cells, which showed very low basal expression of luciferase gene.

In the second phase protein PPAR-alpha (R-GAL4-human PPAR-alpha-LBD) was introduced in the described stable clone cells. For this purpose, in the initial stage cDNA encoding a 76 N-terminal amino acids glucocorticoides receptor (Genbank Accession # P04150), was connected with a plot to DNA coding for amino acids 1-147 factor GAL-4 transcription of yeast (Genbank Accession # R). K-DNA ligand-binding domain of the human receptor PPAR-alpha (amino acids S167-Y468, Genbank Accession # S74349) was cloned in the 3'-end part of this design GR-GAL4. Fused design is obtained in this way (GR-GL4-human PPAR-alpha-LBD) was re-cloned in the plasmid PC-DNC (Invitrogen) in order to activate significant expression using the cytomegalovirus promoter. This plasmid was lineality using restriction endonuclease and stably transformed in the previously described cell clone containing an element of the carrier of luciferase. This derived cell line carrier PPAR-alpha containing element vector luciferase and largely expressing the protein PPAR-alpha (GR-GAL4-human PPAR-alpha-LBD) was isolated by selection with zeocin (0.5 mg/ml) and G418 (0.5 mg/ml).

Analysis

The activity of agonists of PPAR-alpha was determined for three days as follows.

Day 1 cell Line carrier PPAR-alpha

cultured until reaching 80%confluence in DMEM (# 41965-0,39, Invitrogen), which is mixed with the following additives: 10% cs-FCS (fetal calf serum, # SH-30068.03, hollon), 0.5 mg/ml zeocin (# R250-01, Invitrogen), 0.5 mg/ml G418 (# 10131-027,Invitrogen), 1%solution of penicillin-streptomycin (#15140-122, Invitrogen) and 2 mm L-glutamine (# 25030-024, Invitrogen).

Cultivation was carried out in tanks with standard cell culture (# 353112, Becton Dickinson) in the incubator for cell cultures at 37°in the presence of 5% CO2. Merged up to 80% of the cells were washed once with 15 ml of PBS ((# 14190-094, Invitrogen), was treated with 3 ml trypsin solution (#2 5300-054, Invitrogen) at 37°C for 2 minutes, and took 5 ml described DMEM and determined the number in the counter cell. After dilution to 500,000 cells/ml, 35,000 cells were seeded in each well of 96-well microtiter tablet (# 3610, Corning Costar). The plates were incubated in the incubator for cell cultures at 37°in the presence of 5% CO2within 24 hours.

Day 2 Agonists PPAR-alpha for testing was dissolved in DMF at a concentration of 10 mm. This basic solution was diluted in DMEM (# 41965-039, Invitrogen), which was mixed with 5% cs-FCS (# SH-30068.03, hollon), 2 mm L-glutamine (# 25030-024, Invitrogen) and the previously described antibiotics (zeocin, G418, penicillin and streptomycin). The test substance was investigated in 11 different concentrations ranging from 10 μm to 100 RMB. The most active compounds were tested in the concentration range from 1 μm to 10 RMB or from 100 nm to 1 RMB.

Wednesday is gunning culture carrier of PPAR-alpha, sowing which was carried out on day 1, were completely removed by sucking, subject substance, diluted medium was immediately added to the cells. Dilution and adding substance was carried out by the robot (Beckman FX). The final volume of the test substance diluted with medium, 100 μl per well 96-well microtiter tablet. The concentration of DMF was less than 0.1%.about. to exclude cytotoxic action of the solvent. Each plate was loaded with standard agonist of PPAR-alpha, which was diluted similarly in 11 different concentrations to demonstrate the results of the analysis in each tablet. The study tablets were incubated in the incubator at 37°C and 5% CO2within 24 hours.

Day 3 Cell carrier PPAR-alpha treated with the test substances were removed from the incubator, the medium was aspirated. Cells were literally by pipetting 50 ál Bright Glo (from the company Promega) to each well of 96-hole microtiter tablet. After incubation at room temperature in the dark for 10 minutes microtiter tablet investigated in a luminometer (Trilux from the company Wallac). The study of each well microtiter tablet was 1 sec.

The data obtained in the luminometer, transferred into a Microsoft Excel file. Influence diagrams doses and values is concentratie IC 50agonists of PPAR-alpha was determined using the program XL.Fit in accordance with the manufacturer's descriptions (IDBS).

The results of the activity of some compounds of formula 1 according to the invention are presented in the table below:

Table 1
Example No.IC50PPAR-alpha [µm]
7th0,06
7ab0,01
7z0,03
7y0,09

The compounds used in this invention, it is possible to enter the patient in the form of various dosage forms adapted to the chosen route of administration, i.e. oral or parenteral. Parenteral administration in this respect includes the introduction of the following routes: intravenous, intramuscular, subcutaneous, intraocular, intraarticular, transepithelial (transepthelially), including TRANS-dermal, opthalmic, sublingual and buccal; topically including opthalmic, dermal, ocular, rectal and nasal inhalation via insufflation and aerosol and rectal systemic approach.

The active compound can be administered orally, for example, with an inert diluent or with an assimilable edible carrier, or it can be enclosed in capsules with hard or soft gelatin is a shell, or it can be pressed into tablets, or it may be mixed with the food product directly when eating. For oral therapeutic use, the active compound can be mixed with excipient and used in the form of a swallow (taken orally) tablets, tablets for slow dissolution in the buccal pocket, pastilles, capsules, elixirs, suspensions, syrups, wafers and the like, Such compositions and preparations should contain at least 0.1% of active compound. The percentage of the compositions and preparations may, of course, be varied and useful when it is between 2% to about 6% by weight of units (dosage forms). The number of active compound in such therapeutically used in the compositions should be such that you could get appropriate dose. Preferred compositions or preparations according to the invention are the so that the oral dosage form contains from about 50 to 300 mg of active compound.

Tablets, lozenges, pills, capsules and the like can contain any of the following adjuvants: a binder, such as tragacanth gum, Arabia gum, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrator such as corn starch, potato starch, alginic acid and the like; MCA is ku, such as magnesium stearate; and can be added sweetener, such as sucrose, lactose or saccharin or a flavoring, such as peppermint, oil of Grushenka, or the perfume of cherries. In the case when the dosage form is a capsule, it may contain, in addition to the above substances, liquid media. Various other substances may be present as coatings or to otherwise modify the physical form of the dosage forms. For example, tablets, pills, or capsules may be coated with shellac, sugar or both. A syrup or elixir may contain the active compound, sucrose as a sweetening substance, methyl - and propylparaben as a preservative and dye and flavoring, such as odorant cherry or orange. Of course, any substance used for any dosage form, used in quantities should be pharmaceutically pure and mostly non-toxic. In addition, the active compound may be included in the compositions and preparations with prolonged action.

In addition, the active compound can be entered or parenteral administered intraperitoneally. Solutions of the active compounds in the form of a base or pharmaceutically acceptable salts can be obtained in water, appropriate education is mixed with a surface-active substance, such as hydroxypropylcellulose. In addition, you can obtain the variance in glycerol, liquid polyethylene glycols and their mixtures or in oils. Under normal conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

The pharmaceutical forms suitable for injection include sterile aqueous solutions or dispersions and sterile powders for the immediate preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid in the sense to be able to easily be injected with a syringe. It must be stable under the conditions of production and storage and must be protected from contaminating action of microorganisms (bacterial contamination), such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g. glycerol, propylene glycol and liquid polyethylene glycol and the like), suitable mixtures of them, and vegetable oil. The proper fluidity can be maintained, for example, by use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. To prevent the action of microorganisms can use the logging part antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal and the like In many cases, it is desirable to introduce into the composition isotonic agents, such as sugars or sodium chloride. Prolonged absorption of injectable compositions is achieved by introducing tools that slow down the absorption, for example, aluminum monostearate and gelatin.

Sterile injectable solutions prepared incorporating the active compounds in the required amount in the appropriate solvent with various other ingredients enumerated above, if required, with subsequent filtration sterilization. Typically, the dispersion is obtained by integrating various sterilized active ingredients into a sterile filler, which is a basic dispersion medium and contains the required other ingredients from those enumerated above. In the case of sterile powders for obtaining sterile injectable solutions, the preferred methods of obtaining are drying in the vacuum drying and freezing (freeze drying), which provide a powder of the active ingredient plus any additional desired component from a previously sterile-filtered solution, which includes these components.

Therapeutic compounds used in accordance with this invention, can enter the TB patient as such, or in combination with pharmaceutically acceptable carriers mentioned above, the composition of which is determined by the solubility and chemical nature of the compound, chosen route of administration and standard pharmaceutical practice.

The doctor determines the portion of the proposed therapeutic agents which will be most suitable for prophylaxis or treatment and it usually varies depending on the form of administration and the specific compound, and, in addition, it will change in relation to the particular patient to be treated. The doctor usually prefer to start treatment with low doses by small increases them, up until when the circumstances will not be achieved optimal action. therapeutic dose is usually from 0.1 to 100 mm/day or from about 0.1 mg to about 50 mg/kg of body weight per day, or 10 mg to about 50 mg/kg of body weight per day, or more preferably 30 mg to about 50 mg/kg of body weight per day and above, although it can be entered multiple separate dosage units. For oral administration require higher doses.

The compounds used in accordance with the invention, can be taken as often as necessary to obtain the desired therapeutic effect. Some patients may respond quickly to Bo is it higher or lower dose and for them can be much more adequate maintenance dose. For other patients may need prolonged treatment at the rate of 1 to 4 doses per day, in accordance with the physiological requirements of each individual patient. Usually, active product can be taken orally 1 to 4 times a day. Needless to say that other patients will need to register no more than one or two doses per day.

The person skilled in the art it is obvious that this invention is well adapted for carrying out the purposes of the invention, achieve them, and the implementation of the mentioned advantages, as well as the purpose and benefits inherent in it. Compounds, compositions and methods described herein are presented as illustrative of preferred embodiments of the invention, or, as is implied, they are illustrative and are not limitations of the present invention.

1. A compound selected from the group

2. The compound according to claim 1, selected from the group including

3. The compound according to claim 1 or 2, selected from the group including

4. The connection according to one of claims 1 to 3, representing

5. The connection according to one of claims 1 to 2, representing

6. The compound according to claim 1, which represents the

7. Pharmaceutical composition having PPAR-landscapemode activity, containing pharmaceutically acceptable amount of a compound according to one of claims 1 to 6 and a pharmaceutically acceptable carrier.

8. A method of treating a patient suffering from a physiological disorder capable modulated by a connection according to one of claims 1 to 6, with PPAR-landscapemode activity, including Vedenyapin pharmaceutically effective amount of the compounds or its pharmaceutically acceptable salt.

9. The method of claim 8, where the disease is a disease associated with a physiologically detrimental level of insulin, glucose, free fatty acids (FFA, FFA) or triglycerides in the blood, as well as hyperglycemia such as diabetes, in particular Type II diabetes, hyperinsulinism, such as Syndrome X, insulin resistance, cardiovascular disease, such as atherosclerosis, hyperlipemia, hypertension, a disorder associated with food intake.

10. The method according to claim 8 or 9, characterized in that the compound is a compound according to claim 3.



 

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The invention relates to new derivatives oksiminoalkil acid of the formula (I), where R1is oxazolyl, optionally substituted with 1-2 substituents selected from lower alkyl, phenyl, teinila, furil; thiazolyl, optionally substituted with 1-2 substituents selected from lower alkyl, phenyl; unsubstituted chinoline and so on; X represents a bond or the group-NR6- where R6represents hydrogen or C1-4alkyl; n represents an integer from 1 to 3; Y represents an oxygen atom or the group-NR7- where R7is hydrogen; ring a represents a benzene ring, optionally substituted by one or two1-4alkoxy; p is an integer from 1 to 3; R2represents phenyl, optionally substituted lower alkyl, halogen, and so on; unsubstituted furyl; unsubstituted pyridyl; pyridinyl-1-oxide; q is an integer from 0 to 6; m represents 0 or 1; R3represents a hydroxy-group, lower alkoxy or-NR9R10where R9and R10represent identical or different groups selected from hydrogen, lower alkyl and lower alkylsulfonyl; R4and R5represent identical or different groups selected from hydrogen or

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FIELD: organic chemistry, chemical technology, biochemistry, medicine, pharmacy.

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EFFECT: improved preparing method, valuable medicinal properties of compounds and compositions.

9 cl, 1 tbl, 41 ex

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EFFECT: valuable medicinal properties of compounds and agent.

21 cl, 15 tbl, 14 ex

FIELD: organic chemistry, medicine, pharmacy.

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EFFECT: valuable medicinal properties of compounds.

6 cl, 7 tbl, 109 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of azole of the formula:

wherein R1 represents (1) halogen atom; (2) nitrogen-containing 5- or 6-membered heterocyclic group comprising from 1 to 4 nitrogen atoms as atoms of ring system in addition to carbon atoms, and group with condensed rings comprising nitrogen-containing 5- or 6-membered heterocyclic group comprising 1-2 nitrogen atoms as atoms of ring system in addition to carbon atoms, and benzene ring wherein nitrogen-containing 5- or 6-membered heterocyclic group and group with condensed rings can comprise optionally from 1 to 3 substituted taken among group consisting of: (i) aliphatic hydrocarbon group comprising from 1 to 15 carbon atoms; (ii) (C6-C14)-aryl group, and (iii) carboxy-group that can be in form of group of (C1-C6)-alkyl ester wherein above indicated substitutes (i)-(iii) can have from 1 to 3 substituted additionally taken among group consisting of: (a) carboxyl group and (b) hydroxy-group; (3) (C1-C10)-alkylsulfanyl group that can be substituted with hydroxy-group; (4) heteroarylsulfanyl group taken among pyridylsulfanyl, imidazolylsulfanyl and pyrimidinylsulfanyl, or (5) amino-group that can be mono- or di-substituted optionally with substitutes(substitutes) among group consisting of: (i) (C1-C10)-alkyl group that can be substituted with hydroxy-group, and (ii) (C7-C10)-aralkyl group; Ab represents aryloxy-group that is substituted with alkyl group and can be substituted with halogen atom, (C1-C4)-alkoxy-group, (C1-C4)-alkyl group, hydroxy-group or (C1-C6)-alkylcarbonyloxy-group additionally; B represents (C6-C14)-aryl group or thienyl group each of that can has optionally from 1 to 4 substitutes taken among halogen atom, (C1-C6)-alkoxy-group and (C1-C6)-alkyl group that can has optionally from 1 to 3 halogen atoms; Y represents saturated aliphatic bivalent group with direct or branched chain and having from 1 to 7 carbon atoms, or to its salt. Also, invention relates to a pharmaceutical composition that elicits activity for promoting production/secretion of neurotrophine, and to methods for prophylaxis and treatment based on these compounds. Invention provides preparing new compounds and pharmaceutical composition based on thereof used for prophylaxis and treatment of neuropathy.

EFFECT: improved and valuable medicinal properties of agent, improved methods for treatment.

19 cl, 1 dwg, 5 tbl, 122 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a prophylactic or therapeutic agent used against hyperlipidemia and comprising as an active component the heterocyclic compound of the formula [1]:

or its pharmaceutically acceptable salt wherein R1 represents aryl optionally substituted with similar or different one-three groups taken among alkyl, halogenalkyl, trihalogen alkyl, alkoxy-group and halogen atom; Het represents bivalent aromatic heterocyclic group of the formula [5]:

wherein X represents oxygen, sulfur atom or NR6 wherein R6 represents hydrogen atom or alkyl; R2 represents hydrogen atom, alkyl or trihalogenalkyl; D represents alkylene and alkenylene; E represents group of the formulae [3] or [4] wherein Y represents oxygen or sulfur atom; R3 and R4 are similar or different and each represents hydrogen atom or alkyl; p = 1; Z represents carboxy-group, alkoxycarbonyl, cyano-group or 1H-5-tetrazolyl. Also, invention relates to new compounds belonging to group of above enumerated heterocyclic compounds of the formula [1] that show effect reducing blood triglycerides level, low density lipoprotein cholesterol, glucose and insulin or effect enhancing high density lipoprotein cholesterol and effect reducing the atherogenic effect. Therefore, these compounds can be used in prophylaxis or treatment of hyperlipidemia, arteriosclerosis, heart ischemic disease, brain infarction, rheocclusion after percutaneous intraluminal coronary angioplasty, diabetes mellitus and obesity.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

29 cl, 1 tbl, 170 ex

The invention relates to new derivatives oksiminoalkil acid of the formula (I), where R1is oxazolyl, optionally substituted with 1-2 substituents selected from lower alkyl, phenyl, teinila, furil; thiazolyl, optionally substituted with 1-2 substituents selected from lower alkyl, phenyl; unsubstituted chinoline and so on; X represents a bond or the group-NR6- where R6represents hydrogen or C1-4alkyl; n represents an integer from 1 to 3; Y represents an oxygen atom or the group-NR7- where R7is hydrogen; ring a represents a benzene ring, optionally substituted by one or two1-4alkoxy; p is an integer from 1 to 3; R2represents phenyl, optionally substituted lower alkyl, halogen, and so on; unsubstituted furyl; unsubstituted pyridyl; pyridinyl-1-oxide; q is an integer from 0 to 6; m represents 0 or 1; R3represents a hydroxy-group, lower alkoxy or-NR9R10where R9and R10represent identical or different groups selected from hydrogen, lower alkyl and lower alkylsulfonyl; R4and R5represent identical or different groups selected from hydrogen or
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