Patent Application
20050014812
The present invention relates to novel benzimidazole compounds. More particularly, the present invention relates to novel benzimidazole compounds, salts thereof and prodrugs thereof having a hypoglycemic activity. The present invention also relates to a method for producing the above-mentioned benzimidazole compounds, salts thereof and prodrugs thereof. Moreover, the present invention relates to pharmaceutical compositions comprising the above-mentioned benzimidazole compound, a salt thereof or a prodrug thereof as an active ingredient.
Antidiabetic agents having sulfonylcarbamoyl structure and benzimidazole structure are described in International Publication Nos. WO 97/24334, WO 99/00372 and WO 00/39099.
Antidiabetic agents of the thiazolidinedione (TZD) class, which have been widely used and have proven efficacy in the treatment of patients with type II diabetes via activation of the gamma isoform of the peroxisome proliferator-activated receptor (PPARγ), are known and widely used. However, it has been clarified that the agents of the TZD class have side effects such as edema, weight gain and the like (see Diabetes Metab Res Rev 2002; 18: S23-S29).
There is a demand for development of an antidiabetic agent that has no or decreased side effects.
The present invention aims at providing novel benzimidazole compounds, pharmaceutically acceptable salts thereof, prodrugs thereof and pharmaceutical preparations comprising the above-mentioned benzimidazole compound, or a pharmaceutically acceptable salt thereof, a prodrug thereof as an active ingredient.
The novel benzimidazole compounds induce improvement in plasma lipid metabolism, improvement in plasma lipoprotein composition, hypoglycemic effect, hypoinsulinemic effect, improvement in insulin resistance, enhancement in insulin sensitivity and the like.
In addition, the novel benzimidazole compounds have a superior ligand activity for peroxisome proliferator-activated receptors (PPARα, PPARγ and PPARδ) and are useful as an agonist, a partial agonist, an antagonist or a partial antagonist for these receptors.
Moreover, the novel benzimidazole compounds have a superior ligand activity for peroxisome proliferator-activated receptor in a heterodimer receptor which is formed by retinoid X receptor and peroxisome proliferator-activated receptor (for example, a heterodimer receptor which is formed by RXRα and PPARδ, a heterodimer receptor which is formed by RXRα and PPARγ, and the like).
The novel benzimidazole compounds are used as an agent for the prophylaxis and treatment of impaired glucose tolerance disorder, diabetes (e.g., type II diabetes), gestational diabetes, diabetic complications (e.g., diabetic gangrene, diabetic arthropathy, diabetic osteopenia, diabetic glomerulosclerosis, diabetic nephropathy, diabetic dermatopathy, diabetic neuropathy, diabetic cataract, diabetic retinopathy and the like), insulin resistance syndrome (e.g., insulin receptor abnormality, Rabson-Mendenhall syndrome, leprechaunism, Kobberling-Dunnigan syndrome, Lawrence-Seip syndrome (lipoatrophy), Cushing syndrome, acromegaly and the like), polycystic ovary syndrome, hyperlipidemia, atherosclerosis, cardiovascular diseases (e.g., stenocardia, cardiac failure and the like), hyperglycemia (e.g., those characterized by abnormal saccharometabolism such as eating disorders), pancreatitis, osteoporosis, hyperuricemia, hypertension, inflammatory bowel diseases, skin disorders related to an anomaly of differentiation of epidermic cells, hypertension, Alzheimer's disease, Parkinson's disease, multiple sclerosis, stroke, traumatic brain and spinal cord injury, and the like. In addition, they, in combination with a retinoid, are useful for treating disease states caused by uncontrolled cell proliferation, including cancer, restenosis and atherosclerosis.
The benzimidazole compound [hereinafter to be also referred to as the objective compound (I)], which is the novel compound of the present invention, has the formula (I):
wherein
The preferable embodiments of the benzimidazole compound of the present invention represented by the general formula (I) are follows.
(1) The compound of general formula (I) wherein ring X is benzene ring, pyridine ring, oxazole ring or thiazole ring, Y is lower alkylene, phenylene optionally substituted by substituent(s) selected from the group consisting of lower alkyl, halogen, amino or nitro or bivalent residue derived from pyridinyl, thiophenyl, imidazolyl or oxazolyl, each of which is optionally mono-substituted by lower alkyl, or a salt thereof or a prodrug thereof.
(2) The compound of (1) above wherein L is methylene, and Z is bond, —O—, —CH2O— or —OCH2—, or a salt thereof or a prodrug thereof.
(3) The compound of (2) above wherein Z is —O—, and Y is lower alkylene, or a salt thereof or a prodrug thereof.
(4) The compound of (2) wherein Z is bond, —CH2O— or —OCH2— and Y is phenylene optionally substituted by substituent(s) selected from the group consisting of lower alkyl, halogen, amino or nitro, or bivalent residue derived from pyridinyl, thiophenyl, imidazolyl or oxazolyl, each of which is optionally mono-substituted by lower alkyl, or a salt thereof or a prodrug thereof.
(5) The compound of (2), which is selected from the group consisting of
Preferable salts of the objective compound (I) are conventional salts that are non-toxic and acceptable for use as pharmaceuticals. Examples thereof include salts with alkali metal such as sodium and potassium, salts with alkaline earth metal such as calcium and magnesium, salts with inorganic base such as ammonium salt, salts with organic amine such as triethylamine, pyridine, picoline, ethanolamine and triethanolamine, salts with inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid, salts with organic carboxylic acid such as formic acid, acetic acid, trifluoroacetic acid, maleic acid and tartaric acid, addition salts with sulfonic acid such as methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid, and salts or acid addition salts with base such as basic or acidic amino acid such as arginine, aspartic acid and glutamic acid.
The objective compound (I) or a salt therof may be a prodrug. A prodrug of the objective compound (I) or a salt therof refers to a compound capable of being converted to the objective compound (I) or a salt therof by reactions of an enzyme, gastric juice, and the like, under physiological conditions in vivo, specifically a compound capable of being converted to the objective compound (I) or a salt therof upon enzymatic oxidation, reduction, hydrolysis, and the like, or a compound capable of being converted to the objective compound (I) or a salt therof upon hydrolysis and the like by gastric juice and the like.
The objective compound (I), a salt thereof and a prodrug thereof of the present invention [hereinafter also referred to as the compound of the present invention] can be produced by the method shown by the following reaction formulas.
wherein R6 is hydroxyl, halogen or carboxy, R7is lower alkyl, R8 is carboxy protective group, L1 and L2 are each leaving group such as halogen (e.g., bromine, iodine etc.), alkylsulfonyloxy, group (e.g., methanesulfonyloxy, ethanesulfonyloxy etc.), optionally substituted arylsulfonyloxy group (e.g., benzenesulfonyloxy, p-toluenesulfonyloxy etc.), and the like and other symbols in the formulas are as defined above.
The starting compounds can be prepared by the method of Preparation Example below or a process known in the art for preparing their structurally analogous compounds.
Various definitions included in the present specification are explained in detail in the following.
Specific examples of “halogen” include fluorine, bromine, chlorine and iodine.
Specific examples of “esterified carboxy” in “optionally esterified carboxy” include alkoxycarbonyl having 2 to 5 carbon atoms (e.g., methoxycarbonyl, ethoxycarbonyl etc.) and the like. Preferable examples of “optionally esterified carboxy” include carboxy and ethoxycarbonyl.
“Lower alkyl” is preferably linear or branched alkyl having up to 6 carbon atoms. Specific examples thereof include methyl, ethyl, 1-propyl, isopropyl, 1-butyl, isobutyl, tert-butyl, sec-butyl, 1-pentyl, isopentyl, tert-pentyl, sec-pentyl, methylbutyl, 1,1-dimethylpropyl, 1-hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1-ethylbutyl, 2-ethylbutyl, 3-ethylbutyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1-ethyl-1-methylpropyl and the like. Of these, linear alkyl having 1 to 4 carbon atoms is preferable and methyl and ethyl are especially preferable.
“Lower alkoxy” is linear or branched alkyloxy having up to 6 carbon atoms. Specific examples thereof include methoxy, ethoxy, 1-propyloxy, isopropyloxy, 1-butyloxy, isobutyloxy, sec-butyloxy, tert-butyloxy, 1-pentyloxy, isopentyloxy, sec-pentyloxy, tert-pentyloxy, 2-methylbutoxy, 1-hexyloxy, isohexyloxy, tert-hexyloxy, sec-hexyloxy, 2-methylpentyloxy, 3-methylpentyloxy, 1-ethylbutyloxy, 2-ethylbutyloxy, 1,1-dimethylbutyloxy, 2,2-dimethylbutyloxy, 3,3-dimethylbutyloxy, 1-ethyl-1-methylpropyloxy, and the like. Of these, linear alkoxy having 1 to 5 carbon atoms is preferable and methoxy, ethoxy and 1-pentyloxy are especially preferable.
“Lower alkylthio” is linear or branched alkylthio having up to 6 carbon atoms. Specific examples thereof include methylthio, ethylthio, 1-propylthio, isopropylthio, 1-butylthio, isobutylthio, sec-butylthio, tert-butylthio, 1-pentylthio, isopentylthio, sec-pentylthio, tert-pentylthio, 2-methylbutylthio, 1-hexylthio, isohexylthio, tert-hexylthio, sec-hexylthio, 2-methylpentylthio, 3-methylpentylthio, 1-ethylbutylthio, 2-ethylbutylthio, 1,1-dimethylbutylthio, 2,2-dimethylbutylthio, 3,3-dimethylbutylthio, 1-ethyl-1-methylpropyloxy, and the like. Of these, linear alkylthio having 1 to 4 carbon atoms is preferable and ethylthio is especially preferable.
“Mono- or di-(lower alkyl)amino” is amino which is mono- or di-substituted by linear or branched alkyl having up to 6 carbon atoms. Specific examples thereof include methylamino, ethylamino, 1-propylamino, isopropylamino, 1-butylamino, isobutylamino, sec-butylamino, tert-butylamino, 1-pentylamino, isopentylamino, sec-pentylamino, tert-pentylamino, 2-methylbutylamino, 1-hexylamino, isohexylamino, tert-hexylamino, sec-hexylamino, 2-methylpentylamino, 3-methylpentylamino, 1-ethylbutylamino, 2-ethylbutylamino, 1,1-dimethylbutylamino, 2,2-dimethylbutylamino, 3,3-dimethylbutylamino, 1-ethyl-1-methylpropylamino, and the like. Of these, linear alkylamino having 1 to 4 carbon atoms is preferable and methylamino is especially preferable. “Optionally substituted amino” is preferably amino which is optionally substituted by substituent(s) selected from aforementioned lower alkyl and aforementioned optionally esterified carboxy. Preferable examples thereof include dimethylamino and (ethoxycarbonyl)(methyl)amino.
“Mono-, di- or trihalo(lower)alkyl” is linear or branched alkyl having up to 6 carbon atoms, which is substituted by 1 to 3 halogen atom such as fluorine atom, chlorine atom, bromine atom and iodine atom. Specific Examples thereof include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, bromomethyl, dibromomethyl, tribromomethyl, 1-fluoroethyl, 1-chloroethyl, 1-bromoethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 1,2-difluoroethyl, 1,2-dichloroethyl, 1,2-dibromoethyl, 2,2,2-trifluoroethyl, heptafluoroethyl, 1-fluoropropyl, 1-chloropropyl, 1-bromopropyl, 2-fluoropropyl, 2-chloropropyl, 2-bromopropyl, 3-fluoropropyl, 3-chloropropyl, 3-bromopropyl, 1,2-difluoropropyl, 1,2-dichloropropyl, 1,2-dibromopropyl, 2,3-difluoropropyl, 2,3-dichloropropyl, 2,3-dibromopropyl, 3,3,3-trifluoropropyl, 2,2,3,3,3-pentafluoropropyl, 2-fluorobutyl, 2-chlorobutyl, 2-bromobutyl, 4-fluorobutyl, 4-chlorobutyl, 4-bromobutyl, 4,4,4-trifluorobutyl, 2,2,3,3,4,4,4-heptafluorobutyl, perfluorobutyl, 2-fluoropentyl, 2-chloropentyl, 2-bromopentyl, 5-fluoropentyl, 5-chloropentyl, 5-bromopentyl, perfluoropentyl, 2-fluorohexyl, 2-chlorohexyl, 2-bromohexyl, 6-fluorohexyl, 6-chlorohexyl, 6-bromohexyl, perfluorohexyl and the like. Of these, trifluoromethyl is preferable.
“Optionally substituted aryl” is aryl having 6 to 10 carbon atoms, which is optionally substituted by substituent(s) such as optionally substituted lower alkyl. Suitable examples of aryl include phenyl, tolyl and naphthyl, in which more preferable one is phenyl. Preferable examples thereof include phenyl optionally substituted by aforementioned mono-, di- or trihalo (lower) alkyl, especially trihalo (lower) alkyl. Phenyl and (4-trifluoromethyl)phenyl are especially preferable.
“Lower alkenyl” is linear or branched alkenyl having 2 to 6 carbon atoms. Specific examples thereof include vinyl, 1-propenyl, 2-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 1-ethylvinyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1,2-dimethyl-1-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-1-propenyl, 1-ethyl-2-propenyl, 1-methyl-1-butenyl, 1-methyl-2-butenyl, 2-methyl-1-butenyl, 1-isopropylvinyl, 2,4-pentadienyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2,4-hexadienyl, 1-methyl-1-pentenyl and the like. Of these, linear alkenyl having 2 to 4 carbon atoms is preferable and vinyl is especially preferable.
“Lower alkylene” is preferably linear or branched alkylene having up to 6 carbon atoms. Specific examples thereof include methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, methylmethylene, dimethylmethylene, 1-methylethylene, 1,1-dimethylethylene, 1-methyltrimethylene, 1,1-dimethyltrimethylene, and the like. Of these, linear or branched alkylene having 1 to 5 carbon atoms is preferable and methylene, trimethylene, tetramethylene, pentamethylene, dimethylmethylene and 1,1-dimethyltrimethylene are especially preferable.
“Optionally substituted phenylene” is preferably phenylene which is optionally substituted by substituent(s). Examples of the substituent include aforementioned lower alkyl (e.g., methyl etc.), aforementioned halogen (e.g., fluorine, chlorine etc.), amino, nitro and the like.
“Heteroaryl ring” is 5- or 6-membered aromatic heteromonocyclic ring containing 1 to 4 heteroatom(s) selected from sulfur atom, oxygen atom and nitrogen atom. Specific examples thereof include pyridine ring, pyrimidine ring, pyrazine ring, pyridazine ring, pyrrole ring, imidazole ring, pyrazole ring, triazole ring, tetrazole ring, thiazole ring, isothiazole ring, thiadiazole ring, oxazole ring, isoxazole ring, furan ring, thiophene ring and the like. Of these, pyridine ring, oxazole ring and thiazole ring are preferable.
“Heteroaryl” is 5- or 6-membered aromatic heteromonocyclic group containing 1 to 4 heteroatom(s) selected from sulfur atom, oxygen atom and nitrogen atom. Specific examples thereof include pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, furanyl, thiophenyl, and the like. Of these, pyridinyl, pyrazolyl and oxazolyl are preferable.
“Bivalent residue derived from optionally substituted heteroaryl” is bivalent 5- or 6-membered aromatic heteromonocyclic group containing 1 to 4 heteroatom(s) selected from sulfur atom, oxygen atom and nitrogen atom, wherein the group may be substituted. Preferable examples of “heteroaryl” of “bivalent residue derived from optionally substituted heteroaryl” include pyridinyl, thiophenyl, imidazolyl and oxazolyl. “Heteroaryl” of “bivalent residue derived from optionally substituted heteroaryl” is optionally mono-substituted by aforementioned lower alkyl (e.g., methyl etc.).
Suitable examples of “carboxy protective group” include lower alkyl (e.g., methyl, ethyl, tert-butyl etc.), mono(or di or tri)phenyl(lower alkyl) optionally substituted by nitro (e.g., benzyl, 4-nitrobenzyl, benzhydryl, trityl etc.) and lower alkylcarbonyloxy(lower)alkyl) (e.g., pivaloyloxymethyl).
Preferable specific compounds as the objective compound (I) are exemplified by the following:
The production methods of the objective compound (I) are explained in detail in the following.
Process (1)
The objective compound (I) and a salt thereof can be produced by reacting compound (II) or a salt thereof with compound (III) or a salt thereof.
Preferable salts of compound (II) and compound (III) are exemplified by those shown with regard to compound (I).
Preferable leaving group for L1 is halogen, with more preference to bromine.
The reaction generally proceeds in a conventional solvent such as water, alcohol (e.g., methanol and ethanol), acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine and a mixture thereof, or in any other solvent which does not adversely affect the reaction. These conventional solvents may be used alone or in combination.
The reaction can be carried out in the presence of an inorganic or organic base such as alkali metal bicarbonate, tri(lower)alkylamine, pyridine, 4-dimethylaminopyridine, N-(lower)alkylmorpholine, N,N-di(lower)alkylaniline (e.g., N,N-dimethylaniline), N,N-di(lower)alkylbenzylamine, and the like.
The reaction temperature is not particularly limited, and the reaction is generally carried out under cooling to heating.
Process (2)
The compound (I) or a salt thereof can be prepared by reacting the compound (IV) or a salt thereof with the compound (V) or salt thereof.
Preferable leaving group for L2 is halogen, with more preference to bromine.
The reaction is usually carried out in a conventional solvent such as tetrahydrofuran, dioxane, toluene, methylene chloride, ethylene dichloride, N,N-dimethylformamide, N,N-dimethylacetamide, or any other organic solvents which do not adversely affect the reaction, or a mixture thereof.
The reaction temperature is not particularly limited, and the reaction is generally carried out under cooling to heating.
Process (3)
The compound (I)-1 or a salt thereof can be prepared by dehydrating the compound (VI) or a salt thereof.
This dehydration reaction is carried out by a conventional method in the presence of potassium carbonate or sulfuric acid in a conventional solvent such as ethanol, tetrahydrofuran, dioxane, toluene, methylene chloride, ethylene dichloride, N,N-dimethylformamide, N,N-dimethylacetamide, or any other organic solvents which do not adversely affect the reaction, or a mixture thereof.
The reaction temperature is not particularly limited, and the reaction is generally carried out under heating.
Process (4)
The compound (I)-3 or a salt thereof can be prepared by hydrolyzing the compound (I)-2 or a salt thereof.
This hydrolysis reaction is carried out by a conventional method in the presence of an acid or a base in a hydrated solvent.
Examples of the acid include hydrochloric acid, hydrobromic acid, sulfuric acid and acetic acid.
Examples of the base include alkali metal carbonates such as potassium carbonate and sodium carbonate; alkali metal alkoxides such as sodium methoxide; and alkali metal hydroxides such as potassium hydroxide, sodium hydroxide and lithium hydroxide.
Examples of the hydrated solvent include solvent mixtures of water and one or more solvents selected from alcohols such as methanol and ethanol; ethers such as tetrahydrofuran, dioxane and diethyl ether; dimethyl sulfoxide and acetone.
The reaction temperature is not particularly limited, and the reaction is generally carried out under cooling to heating.
The aforementioned compounds can be converted to preferable salts or prodrugs as necessary by a conventional method. All of them can be purified as necessary according to a conventional method for purifying an organic compound (i.e., recrystallization, column chromatography, thin layer chromatography, high performance liquid chromatography and the like). The compound can be identified by NMR spectrum analysis, mass spectrum analysis, IR spectrum analysis, elemental analysis, melting point measurement and the like.
The compound of the present invention may have one or more chiral centers and, therefore, may be presented in enantiomers or diastereomers. The present invention encompasses these isomers and mixtures thereof.
The compound of the present invention may be in the form of a solvate, which is also encompassed in the present invention. The solvate is preferably exemplified by hydrate and ethanol solvate.
The compound of the present invention can be used for therapeutic purposes in the form of a pharmaceutical preparation. This pharmaceutical preparation contains any one of the compounds (I) as an active ingredient in admixture with a pharmaceutically acceptable organic or inorganic excipient which is a solid, semisolid or liquid and which is suitable for oral, parenteral or external (local) administration. Examples of the pharmaceutical preparation include capsules, tablets, sugar coating tablets, granules, suppositories, liquid, lotion, suspension, emulsion, ointment, gel and the like. When desired, these preparations may contain adjuvant, auxiliary substance, stabilizer, moistening agent, emulsifier, buffering agent, and other conventional additives. While the dose of the compound (I) varies depending on the age and symptom of patients, compound (I) may be administered for the therapy of the above-mentioned diseases in an average single dose amount of about 0.1 mg, 1 mg, 10 mg, 50 mg, 100 mg, 250 mg, 500 mg or 1000 mg. In general, its daily dose may be from about 0.1 mg/patient to about 1000 mg/patient.
The compound of the present invention shows a superior hypoglycemic activity. Therefore, it can be used as a medicament for mammals (e.g., human, calf, horse, pig, dog, cat, monkey, mouse, rat etc., particularly human).
The compound of the present invention may be used in combination with other pharmaceutical agents.
As the pharmaceutical agent used in combination with the compound of the present invention, α-glucosidase inhibitor, sulfonylurea, insulin secretagogue, insulin preparation, biguanide, β-hydroxy-β-methylglutaryl CoA (HMG-CoA) reductase inhibitor, calcium antagonist, fibrate, diuretic, angiotensin converting enzyme (ACE) inhibitor, angiotensin II antagonist, cholesterol absorption inhibitor, antioxidant, nicotinic acid derivative, squalene synthesis inhibitor, aldose reductase inhibitor, β3 agonist, peroxisome proliferator-activated receptor (PPAR) modulator, dipeptidylpeptidase 4 (DPP4) inhibitor, glucagon-like peptide-1 (GLP-1) analog, sodium-dependent glucose cotransporter (SGLT) inhibitor, 11β-hydroxysteroiddehydrogenase 1 (11β-HSD1) inhibitor, microsomal triglyceride transfer protein (MTP) inhibitor, acyl-CoA: cholesterol.acyltransferase (ACAT) inhibitor, ileal bile acid transporter (IBAT) inhibitor, ezetimibe, vascular adhesion protein 1 (VAP1) inhibitor, advanced glycation end products (AGE) inhibitor, lipase inhibitor, anorexiant, leptin, adiponectin and the like can be mentioned. Of these, α-glucosidase inhibitor, insulin secretagogue, sulfonylurea and biguanide are preferable.
The α-glucosidase inhibitor is a pharmaceutical agent having an action of delaying digestion of starch or sucrose by inhibiting digestive enzymes such as amylase, maltase, α-dextrinase, sucrase and the like.
As preferable α-glucosidase inhibitor, miglitol; [2R(2α,3β,4α,5β)]-1-(2-hydroxyethyl)-2-(hydroxymethyl)-3,4,5-piperidinetriol), voglibose; 3,4-dideoxy-4-[[2-hydroxy-1-(hydroxymethyl)ethyl]amino]-2-C-(hydroxymethyl)-D-epi-inositol, miglustat; N-butyl-1-deoxynojirimicin, acarbose; O-4,6-dideoxy-4-[[1S-(1α,4α,5β,6α)-4,5,6-trihydroxy-3-(hydroxymethyl)-2-cyclohexen-1-yl]amino]-α-D-glucopyranosyl-(1→4)-O-α-D-glucopyranosyl-(1→4)-D-glucose, celgosivir hydrochloride; [1S-(1α,6β,7α,8β,8αβ)]-octahydro-1,7,8-trihydroxy-6-indolizinyl butanoate hydrochloride and the like can be mentioned.
Insulin secretagogue is a pharmaceutical agent having an action to promote secretion of insulin from pancreatic β cells. As the insulin secretagogue, for example, sulfonylurea (SU) can be mentioned. Said sulfonylurea (SU) is an agonist of cell membrane SU receptors, thereby promoting secretion of insulin from pancreatic β cells.
As preferable insulin secretagogue, nateglinide; N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine, glimepiride; trans-3-ethyl-2,5-dihydro-4-methyl-N-2-[4-[[[[(4-methylcyclohexyl)amino]carbonyl]amino]sulfonyl]phenyl]ethyl-2-oxo-1H-pyrrole-1-carboxamide, repaglinide; (+)-2-ethoxy-α-[[(S)-α-isobutyl-o-piperidinobenzyl]carbamoyl]-p-toluic acid, glisentide; 1-cyclopentyl-3-p-(2-o-anisamideethyl)benzenesulfonylurea, mitiglinide; (−)-2(S)-benzyl-4-oxo-4-(cis-perhydroisoindol-2-yl)butyric acid calcium salt.dihydrate, glucagon-like peptide-17-36-amide, glucagon-like peptide-1-amylin, CJC1131 and the like can be mentioned.
As other insulin secretagogues, for example, N-[[4-(1-methylethyl)cyclohexyl]carbonyl]-D-phenylalanine (AY-4166), (2S)-2-benzyl-3-(cis-hexahydro-2-isoindolinylcarbonyl)propionic acid calcium.dihydrate (KAD-1229), glimepiride (Hoe490) can be mentioned.
As preferable sulfonylurea, glimepiride; trans-3-ethyl-2,5-dihydro-4-methyl-N-2-[4-[[[[(4-methylcyclohexyl)amino]carbonyl]amino]sulfonyl]phenyl]ethyl-2-oxo-1H-pyrrole-1-carboxamide, glisentide; 1-cyclopentyl-3-p-(2-o-anisamideethyl)benzenesulfonylurea and the like can be mentioned.
As other sulfonylureas, for example, tolbutamide, chlorpropamide, tolazamide, acetohexamide, 4-chloro-N-[(1-pyrrolidinylamino)carbonyl]-benzenesulfonamide (glyclopyramide) and its ammonium salt, glibenclamide (glyburide), gliclazide, 1-butyl-3-metanilylurea, carbutamide, glibornuride, glipizide, gliquidone, glisoxepide, glybuthiazole, glybuzole, glyhexamide, glymidine, glypinamide, phenbutamide, tolycyclamide and the like can be mentioned.
Biguanide is a pharmaceutical agent that acts to enhance anaerobic glycolysis, sensitize insulin in the periphery, inhibit glucose absorption from the intestine, inhibit hepatic gluconeogenesis, increase fatty acid oxidation and the like.
As preferable biguanide, phenformin; 1-phenethyl biguanide, metformin; 1,1-dimethylbiguanide, buformin; 1-butyl biguanide and the like can be mentioned.
Examples of the HMG-CoA reductase inhibitor include rosuvastatine calcium, atorvastatine calcium hydrate, pitavastatine calcium, fluvastatine sodium, simvastatine, lovastatine, pravastatine sodium and the like.
As the calcium antagonist, aranidipine, lacidipine, naftopidil, felodipine, azelnidipine, cilnidipine, lomeridine, diltiazem, gallopamil, efonidipine, nisoldipine, amlodipine, lercanidipine, bevantolol, nicardipine, isradipine, benidipine, verapamil, nitrendipine, barnidipine, propafenone, manidipine, bepridil, nifedipine, nilvadipine, nimodipine, fasudil, pirmenol, carvedilol, trimetazidine, ethosuximide, zonisamide, felodipine, propiverine, manidipine, temiverine, ziconotide and the like can be mentioned.
As the fibrate, gemfibrozil, fenofibrate, bezafibrate, ciprofibrate, clinofibrate, clofibrate and the like can be mentioned.
As the diuretic, cicletanine hydrochloride, torasemide, tripamide, potassium canrenoate, isosorbide, piretanide, azosemide, indapamide, hydrochlorothiazide, trichlormethiazide, benzylhydrochlorothiazide, meticrane, chlortalidone, mefruside, furosemide, spironolactone, triamterene, amiloride and the like can be mentioned.
As the ACE inhibitor, trandolapril, moexipril, perindopril, quinapril hydrochloride, spirapril hydrochloride, temocapril, cilazapril, fosinopril, zofenopril calcium, imidapril hydrochloride, quinaprilate, benazepril hydrochlorde, lisinopril, captopril, ramipril, delapril, alacepril, enalapril malate, omapatrilat and the like can be mentioned.
As the angiotensin II antagonist, candesartan cilexetil, irbesartan, olmesartan medoxomil, telmisartan, valsartan, eprosartan mesilate, losartan potassium and the like can be mentioned.
As the cholesterol absorption inhibitor, colesevelam, ezetimibe, colestilan, colestyramine, ion exchange resin preparation and the like can be mentioned.
As the antioxidant, probucol, vitamin E and the like can be mentioned.
As the nicotinic acid derivative, tocopherol nicotinate, nicomol, niceritrol and the like can be mentioned.
As the squalene synthesis inhibitor, TAK-475, YM-53601 and the like can be mentioned.
As the aldose reductase inhibitor, lindolrestat, epalrestat, zenarestat, IDD-598, NZ-314, AS-3201 and the like can be mentioned.
As the PPAR modulator, thiazolidinedione antidiabetic agents such as rosiglitazone, pioglitazone, troglitazone, EML-16336 and the like, and the like can be mentioned.
As the β3 agonist, GRC-1087, YM-178, SR58611A, L 796568 and the like can be mentioned.
As the ACAT inhibitor, melinamide, eflucimibe, pactimibe and the like can be mentioned.
As the lipase inhibitor, docosanol, orlistat and the like can be mentioned.
As the anorexiant, mazindol and the like can be mentioned.
The present invention is described in more detail by way of the following Preparation Examples and Examples. However, they are not intended to limit the present invention in any way.
Some of the compounds obtained in the following Preparation Examples are encompassed within the scope of the present invention.
Test Animal
Female C57BL/KsJ-db/db (db/db) mice and C57BL/KsJ-+m/+m (lean) mice (5 weeks old) were purchased from Jackson Laboratory, and subjected to the test after 1-2 weeks of acclimating period. Animals were maintained on standard laboratory chow and water ad libitum.
Administration of Test Compound
Test compound was dissolved or suspended in 0.5% methylcellulose solution and administered orally once a day at a volume of 5 mL/kg of body weight.
Test Compound:
At 6 weeks of age, blood was obtained from the retro-orbital sinus by capillary pipette with heparin under feeding condition. Mice were divided into groups matched for body weight, plasma glucose and triglyceride. From 6-7 weeks of age, test compound was administered orally once daily for 7 days. On the next morning of the last administration day, body weight was measured and blood was obtained under feeding condition, and plasma glucose and triglyceride were measured.
Measurement Method
Plasma glucose and triglyceride were determined by a mutarotase.glucose oxidase method and a glycerol-3-phosphate oxidase.3,5-dimethoxy-N-ethyl-N-(2′-hydroxy-3′-sulfopropyl)aniline natrium method, respectively, using assay kits from Wako Pure Chemical Industries, Ltd. (Osaka, Japan).
Result
Values of plasma glucose and triglyceride for the lean group (+m/+m) were set as 100% inhibition, and for the control group (db/db) as 0% inhibition. The inhibition rate of plasma glucose and triglyceride for the test group was determined. Results are shown in Table 1.
A mixture of 4-(acetylamino)-3-aminophenyl acetate (3.0 g), 1-(bromomethyl)-2-chloro-4-(pentyloxy)benzene (5.0 g), potassium carbonate (2.4 g) and N,N-dimethylformamide (30 mL) was stirred at 80° C. for half an hour. After cooling, the mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (gradient elution; chloroform to chloroform-methanol 100:1 to 5:1) to give 4-(acetylamino)-3-{[2-chloro-4-(pentyloxy)benzyl]amino}phenyl acetate (4.25 g) as a solid.
NMR(DMSO-d6,δ): 0.88 (3H, t, J=7 Hz), 1.2-1.8 (6H, m), 2.04 (3H, s), 2.17 (3H, s), 3.95 (2H, t, J=6 Hz), 4.26 (2H, d, J=6 Hz), 5.76 (1H, t, J=6 Hz), 6.10 (1H, d, J=2 Hz), 6.29 (1H, dd, J=2 Hz, 8 Hz), 6.85 (1H, dd, J=2 Hz, 9 Hz), 7.02 (1H, d, J=2 Hz), 7.07 (1H, d, J=8 Hz), 7.28 (1H, d, J=9 Hz), 9.19 (1H, s).
A mixture of 4-(acetylamino)-3-{[2-chloro-4-(pentyloxy)benzyl]amino}phenyl acetate (2.8 g), concentrated sulfuric acid (3 mL) and ethanol (30 mL) was stirred at 80° C. for 8 hours. After cooling, the mixture was concentrated in vacuo and the residue was neutralized with 4 N sodium hydroxide with cooling in an ice-bath. The resulting suspension was diluted-with ethyl acetate-and filterd to give 1-[2-chloro-4-(pentyloxy)benzyl]-2-methyl-1H-benzimidazol-6-ol (0.80 g) as a white solid.
NMR(DMSO-d6,δ): 0.87 (3H, t, J=7 Hz), 1.15 (3H, t, J=7 Hz), 1.2-1.4 (4H, m), 1.6-2.1 (4H, m), 2.39 (3H, s), 2.43 (2H, t, J=7 Hz), 3.92 (2H, t, J=6 Hz), 3.93 (2H, t, J=6 Hz), 4.04 (2H, q, J=7 Hz), 5.39 (2H, s), 6.46 (1H, d, J=8 Hz), 6.7-6.9 (2H, m), 6.94 (1H, d, J=2 Hz), 7.10 (1H, d, J=2 Hz), 7.42 (1H, d, J=9 Hz).
A mixture of 1-[2-chloro-4-(pentyloxy)benzyl]-2-methyl-1H-benzimidazol-6-ol (108 mg), ethyl bromoacetate (60 mg), potassium carbonate (62 mg) and N,N-dimethylformamide (2 mL) was stirred at 90° C. for an hour. Additional ethyl bromoacetate (10 mg) was added to the mixture and stirring was continued for 2 hours. After cooling, the mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with 1 N sodium hydroxide and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (elution with 1:1 dichloromethane-ethyl acetate) to give ethyl ({1-[2-chloro-4-(pentyloxy)benzyl]-2-methyl-1H-benzimidazol-6-yl}oxy)acetate (63 mg).
MS(API-ES, Posi): 445.3.
Ethyl 2-({1-[2-chloro-4-(pentyloxy)benzyl]-2-methyl-1H-benzimidazol-6-yl}oxy)-2-methylpropanoate (124 mg) was synthesized from 1-[2-chloro-4-(pentyloxy)benzyl]-2-methyl-1H-benzimidazol-6-ol (108 mg) in a manner similar to that described in Preparation Example 3 except that ethyl 2-bromo-2-methylpropanoate (294 mg) was used instead of ethyl bromoacetate.
NMR(DMSO-d6,δ): 0.87 (3H, t, J=7.0 Hz), 1.09 (3H, t, J=7.1 Hz), 1.2-1.4 (6H, m), 1.42 (6H, s), 1.5-1.8 (2H, m), 2.46 (3H, s), 3.9-4.1 (4H, m), 5.35 (2H, s), 6.54 (1H, d, J=8.6 Hz), 7.6-7.9 (3H, m), 7.10 (1H, d, J=2.5 Hz), 7.42 (1H, dd, J=8.0 Hz, 1.3 Hz).
MS(API-ES, Posi): 473.4.
To a suspension of 1-[2-chloro-4-(pentyloxy)benzyl]-2-methyl-1H-benzimidazol-6-ol (0.25 g) in a solvent mixture of tetrahydrofuran (2.5 mL) and N,N-dimethylformamide (2.5 mL) was added sodium hydride (60% dispersion in mineral oil; 31 mg). The mixture was stirred at 80° C. for 15 minutes and allowed to cool to ambient temperature. To the mixture was added ethyl 4-bromobutanoate (0.15 g) in an ice-bath. After stirring overnight at ambient temperature, the mixture was partitioned between ethyl acetate and saturated aqueous ammonium chloride. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (elution; 50:1 chloroform-methanol) to give ethyl 4-({1-[2-chloro-4-(pentyloxy)benzyl]-2-methyl-1H-benzimidazol-6-yl}oxy)butanoate (0.29 g) as an oil.
NMR(DMSO-d6,δ): 0.87 (3H, t, J=7 Hz), 1.15 (3H, t, J=7 Hz), 1.2-1.4 (4H, m), 1.6-2.1 (4H, m), 2.39 (3H, s), 2.43 (2H, t, J=7 Hz), 3.92 (2H, t, J=6 Hz), 3.93 (2H, t, J=6 Hz), 4.04 (2H, q, J=7 Hz), 5.39 (2H, s), 6.46 (1H, d, J=8 Hz), 6.7-6.9 (2H, m), 6.94 (1H, d, J=2 Hz), 7.10 (1H, d, J=2 Hz), 7.42 (1H, d, J=9 Hz).
Ethyl 5-({1-[2-chloro-4-(pentyloxy)benzyl]-2-methyl-1H-benzimidazol-6-yl}oxy)pentanoate (0.23 g) was synthesized from 1-[2-chloro-4-(pentyloxy)benzyl]-2-methyl-1H-benzimidazol-6-ol (200 mg) in a manner similar to that described in Preparation Example 5 except that ethyl 5-bromopentanoate (128 mg) was used instead of ethyl 4-bromobutanoate.
NMR(DMSO-d6,δ): 0.87 (3H, t, J=7 Hz), 1.16 (3H, t, J=7 Hz), 1.2-1.7 (10H, m), 2.33 (2H, t, J=7 Hz), 2.39 (3H, s), 3.8-4.0 (4H, m), 4.03 (2H, q, J=7 Hz), 5.39 (2H, s), 6.48 (1H, d, J=8 Hz), 6.7-6.9 (2H, m), 6.94 (1H, d, J=2 Hz), 7.10 (1H, d, J=2 Hz), 7.39 (1H, d, J=9 Hz).
Ethyl 6-({1-[2-chloro-4-(pentyloxy)benzyl]-2-methyl-1H-benzimidazol-6-yl}oxy)hexanoate (0.30 g) was synthesized from 1-[2-chloro-4-(pentyloxy)benzyl]-2-methyl-1H-benzimidazol-6-ol (250 mg) in a manner similar to that described in Preparation Example 5 except that ethyl 6-bromohexanoate (171 mg) was used instead of ethyl 4-bromobutanoate.
NMR(DMSO-d6,δ): 0.87 (3H, t, J=7 Hz), 1.19 (3H, t, J=7 Hz), 1.2-1.7 (12H, m), 2.29 (2H, t, J=7 Hz), 2.39 (3H, s), 3.89 (2H, t, J=6 Hz), 3.93 (2H, t, J=6 Hz), 4.03 (2H, q, J=7 Hz), 5.39 (2H, s), 6.48 (1H, d, J=9 Hz), 6.74 (1H, dd, J=2 Hz, 9 Hz), 6.81 (1H, dd, J=2 Hz, 9 Hz), 6.93 (1H, d, J=2 Hz), 7.10 (1H, d, J=2 Hz), 7.41 (1H, d, J=9 Hz).
A mixture of N-(2-hydroxy-6-nitrophenyl)acetamide (3 g), ethyl 4-bromobutanoate (3.43 g), potassium carbonate (2.54 g), potassium iodide (254 mg) and N,N-dimethylformamide (15 mL) was stirred at ambient temperature for 16 hours. The mixture was poured into water, and the suspension was stirred for 15 minutes and filtered to give ethyl 4-[2-(acetylamino)-3-nitrophenoxy]butanoate (4.48 g) as a solid.
NMR(DMSO-d6,δ): 1.17 (3H, t, J=7.1 Hz), 1.9-2.1 (5H, m), 2.5-2.6 (2H, m), 4.0-4.1 (4H, m), 7.3-7.5 (3H, m), 9.69 (1H, s).
MS(API-ES, Posi): 333.2 (M+Na).
A mixture of ethyl 4-[2-(acetylamino)-3-nitrophenoxy]butanoate (333 mg), 1-(bromomethyl)-2-chloro-4-(pentyloxy)benzene (375 mg), potassium carbonate (193 mg) and N,N-dimethylformamide (3 mL) was stirred at 100° C. for 16 hours. After cooling, the mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed successively with 1 N sodium hydroxide, saturated aqueous ammonium chloride, water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was triturated with diisopropyl ether and filtered to remove the starting material. The filtrate was concentrated in vacuo, and the residue was dissolve in a solvent mixture of acetic acid (3 mL) and ethanol (9 mL). The mixture was heated with iron (300 mg) at 80° C. for 2 hours and at 110° C. for 2 hours. After cooling, the mixture was concentrated in vacuo and the residue was neutralized with sodium bicarbonate. The suspension was diluted with ethyl acetate and stirred for 5 minutes. The insoluble materials were filtered off, and the filtrate was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (elution; 2% methanol in dichloromethane) to give ethyl 4-({1-[2-chloro-4-(pentyloxy)benzyl]-2-methyl-1H-benzimidazol-7-yl}oxy)butanoate (322 mg).
NMR(DMSO-d6,δ): 0.87 (3H, t, J=7.1 Hz), 1.15 (3H, t, J=7.1 Hz), 1.3-1.4 (4H, m), 1.6-1.8 (4H, m), 2.14 (2H, t, J=7.8 Hz), 2.40 (3H, s), 3.9-4.1 (6H, m), 5.58 (2H, s), 6.11 (1H, d, J=8.6 Hz), 6.7-6.9 (2H, m), 7.0-7.1 (1H, m), 7.16 (1H, d, J=8.1 Hz).
MS(API-ES, Posi): 473.3.
A mixture of ethyl 4-[2-(acetylamino)-3-nitrophenoxy]butanoate (1 g), 10% palladium on carbon (50% wet; 200 mg), tetrahydrofuran (5 mL) and ethanol (10 mL) was stirred under 1 atmosphere of hydrogen at ambient temperature for 3 hours. The catalyst was filtered off and the filtrate was concentrated in vacuo. The residue was triturated with diisopropyl ether to give ethyl 4-[2-(acetylamino)-3-aminophenoxy]butanoate (805 mg) as a white solid.
NMR(DMSO-d6,δ): 1.18 (3H, t, J=7.1 Hz), 1.8-1.9 (2H, m), 2.00 (3H, s), 2.45 (2H, t, J=7.5 Hz), 3.88 (2H, t, J=6.2 Hz), 4.06 (2H, q, J=7.1 Hz), 4.74 (2H, s), 6.20 (1H, d, J=8.0 Hz), 6.31 (1H, d, J=8.0 Hz), 6.86 (1H, t, J=8.0 Hz), 8.70 (1H, s).
MS(API-ES, Posi): 303 (M+Na).
A mixture of ethyl 4-[2-(acetylamino)-3-aminophenoxy]butanoate (400 mg), 1-(bromomethyl)-2-chloro-4-(pentyloxy)benzene (541 mg), potassium carbonate (256 mg) and N,N-dimethylformamide (10 mL) was stirred at ambient temperature for 16 hours. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with water (twice) and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give ethyl 4-(2-(acetylamino)-3-{[2-chloro-4-(pentyloxy)benzyl]amino}phenoxy)butanoate (374 mg).
NMR(DMSO-d6,δ): 0.88 (3H, t, J=7.1 Hz), 1.86 (3H, t, J=7.1 Hz), 1.3-1.4 (4H, m), 1.6-1.9 (4H, m), 2.03 (3H, s), 2.46 (2H, t, J=7.4 Hz), 3.9-4.0 (4H, m), 4.06 (2H, q, J=7.1 Hz), 4.28 (2H, d, J=6.3 Hz), 5.58 (1H, t, J=6.3 Hz), 5.96 (1H, d, J=8.1 Hz), 6.81 (1H, dd, J=8.6 Hz, 2.5 Hz), 6.89 (1H, t, J=8.3 Hz), 7.00 (1H, d, J=2.5 Hz), 7.22 (1H, d, J=8.6 Hz), 8.75 (1H, s).
MS(API-ES, Posi): 491.3.
Ethyl 4-({1-[2-chloro-4-(pentyloxy)benzyl]-2-methyl-1H-benzimidazol-4-yl}oxy)butanoate (192 mg) was synthesized from ethyl 4-(2-(acetylamino)-3-{[2-chloro-4-(pentyloxy)benzyl]amino}phenoxy}butanoate (200 mg) in a manner similar to that described in Preparation Example 27.
NMR(DMSO-d6,δ): 0.87 (3H, t, J=7.1 Hz), 1.18 (3H, mt, J=7.1 Hz), 1.3-1.4 (4H, m), 1.6-1.7 (2H, m), 2.0-2.1 (2H, m), 2.44 (3H, s), 3.93 (2H, t, J=6.5 Hz), 4.08 (22H, sq, J=7.1 Hz), 4.21 (3H, t, J=6.3 Hz), 5.40 (2H, s), 6.48 (1H, d, J=8.7 Hz), 6.66 (1H, d, J=7.7 Hz), 6.80 (1H, dd, J=8.6, 2.6 Hz), 6.90 (1H, d, J=8.0 Hz), 7.01 (1H, t, J=8.0 Hz), 7.09 (1H, d, J=2.6 Hz).
MS(API-ES, Posi): 473.3.
tert-Butyl [2-(acetylamino)-3-nitrophenoxy]acetate (1.41 g) was synthesized from N-(2-hydroxy-6-nitrophenyl)acetamide (895 mg) in a manner similar to that described in Preparation Example 8 except that tert-butyl bromoacetate (1.02 g) was used instead of ethyl 4-bromobutanoate.
MS(API-ES, Posi): 333.3(M+Na).
tert-Butyl (2-{acetyl[2-chloro-4-(pentyloxy)benzyl]amino}-3-nitrophenoxy)acetate (239 mg) was synthesized from tert-butyl [2-(acetylamino)-3-nitrophenoxy]acetate (310 mg) in a manner similar to that described in Preparation Example 26.
NMR(DMSO-d6,δ): 0.87 (3H, t, J=7.0 Hz), 1.3-1.4 (4H, m), 1.43 (9H, s), 1.6-1.7 (2H, m), 1.87 (3H, s), 3.92 (2H, t, J=6.5 Hz), 4.46 (1H, d, J=7.1 Hz), 4.72 (1H, d, J=8.2 Hz), 4.82 (1H, d, J=8.2 Hz), 5.01 (1H, d, J=7.1 Hz), 6.74 (1H, dd, J=4.3 Hz, 1.3 Hz), 6.83 (1H, d, J=1.3 Hz), 7.05 (1H, d, J=4.3 Hz), 7.35 (1H, dd, J=4.3 Hz, 0.6 Hz), 7.45 (1H, dd, J=4.1 Hz, 0.6 Hz), 7.55 (1H, t, J=4.2 Hz).
MS(ESI, Posi): 521.29.
tert-Butyl ({1-[2-chloro-4-(pentyloxy)benzyl]-2-methyl-1H-benzimidazol-7-yl}oxy)acetate (215 mg) was synthesized from tert-butyl (2-{acetyl [2-chloro-4-(pentyloxy)benzyl]amino}-3-nitrophenoxy)acetate (222 mg) in a manner similar to that described in Preparation Example 27.
NMR(DMSO-d6,δ): 0.87 (3H, t, J=7.1 Hz), 1.2-1.4 (13H, m), 1.6-1.7 (2H, m), 2.36 (3H, s), 3.92 (2H, t, J=6.5 Hz), 4.65 (2H, s), 5.71 (2H, s), 6.34 (1H, d, J=8.7 Hz), 6.69 (1H, d, J=7.6 Hz), 6.77 (1H, dd, J=8.7 Hz, 2.6 Hz), 7.0-7.1 (2H, m), 7.19 (1H, d, J=7.5 Hz).
MS(API-ES, Posi): 473.2.
Ethyl 6-[2-(acetylamino)-3-nitrophenoxy]hexanoate (9.55 g) was synthesized from N-(2-hydroxy-6-nitrophenyl)acetamide (6.0 g) in a manner similar to that described in Preparation Example 25.
Ethyl 6-[2-(acetylamino)-3-aminophenoxy]hexanoate (1.0 g) was synthesized from 6-[2-(acetylamino)-3-nitrophenoxy]hexanoate (1.5 g) in a manner similar to that described in Preparation Example 10.
NMR(DMSO-d6,δ): 1.17 (3H, t, J=7 Hz), 1.3-1.7 (6H, m), 1.98 (3H, s), 2.29 (2H, t, J=7 Hz), 3.83 (2H, t, J=6 Hz), 4.04 (2H, q, J=7 Hz), 4.72 (2H, br s), 6.20 (1H, d, J=8 Hz), 6.30 (1H, d, J=7 Hz), 6.86 (1H, t-like, J=8 Hz), 8.67 (1H, br s).
A mixture of ethyl 6-[2-(acetylamino)-3-aminophenoxy]hexanoate (0.95 g), 1-(bromomethyl)-2-chloro-4-(pentyloxy)benzene (1.0 g), potassium carbonate (0.51 g) and N,N-dimethylformamide (6 mL) was stirred at 80° C. for 2 hours. After cooling, the mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to give ethyl 6-(2-(acetylamino)-3-{[2-chloro-4-(pentyloxy)benzyl]amino}phenoxy)hexanoate (1.59 g).
Ethyl 6-({1-[2-chloro-4-(pentyloxy)benzyl]-2-methyl-1H-benzimidazol-4-yl}oxy)hexanoate (1.16 g) was synthesized from ethyl 6-(2-(acetylamino)-3-{[2-chloro-4-(pentyloxy)benzyl]amino}phenoxy)hexanoate (1.59 g) in a manner similar to that described in Preparation Example 27.
NMR(DMSO-d6,δ): 0.87 (3H, t, J=7 Hz), 1.17 (3H, t, J=7 Hz), 2.32 (2H, t, J=6 Hz), 1.2-1.8 (12H, m), 2.44 (3H, s), 3.93 (2H, t, J=6 Hz), 4.05 (2H, q, J=7 Hz), 4.17 (2H, t, J=6 Hz), 5.39 (2H, s), 6.47 (1H, d, J=9 Hz), 6.65 (1H, d, J=7 Hz), 6.7-7.1 (3H, m), 7.09 (1H, d, J=2 Hz).
Ethyl 6-(2-{acetyl[2-chloro-4-(pentyloxy)benzyl]amino}-3-nitrophenoxy)hexanoate (1.6 g) was synthesized ethyl 6-[2-(acetylamino)-3-nitrophenoxy]hexanoate (1.0 g) in a manner similar to that described in Example 26.
Ethyl 6-({1-[2-chloro-4-(pentyloxy)benzyl]-2-methyl-1H-benzimidazol-7-yl}oxy)hexanoate (0.73 g) was synthesized from ethyl 6-(2-{acetyl[2-chloro-4-(pentyloxy)benzyl]amino}-3-nitrophenoxy)hexanoate (1.622 g) in a manner similar to that described in Preparation Example 27.
A mixture of 4-(acetylamino)-3-nitrophenyl acetate (1.19 g), 1-(bromomethyl)-2-chloro-4-(pentyloxy)benzene (1.89 g), potassium carbonate (898 mg) and N,N-dimethylformamide (12 mL). was stirred at ambient temperature for 4 days. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed successively with aqueous ammonium chloride (twice), water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (elution with 2:1. n-hexane-ethyl acetate) to give 4-{acetyl[2-chloro-4-(pentyloxy)benzyl]amino}-3-nitrophenyl acetate (1.36 g) as a yellow oil.
MS(API-ES, posi): 471.1(M+Na).
A mixture of 4-{acetyl[2-chloro-4-(pentyloxy)benzyl]amino}-3-nitrophenyl acetate (1.35 g), iron (672 mg), acetic acid (3 mL) and ethanol (9 mL) was stirred at 80° C. for 2 hours. After cooling, the mixture was concentrated in vacuo. The residue was neutralized with sodium hydrogen carbonate and diluted with ethyl acetate. The suspension was stirred at ambient temperature for 5 minutes and filtered through a celite pad. The filtrate was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was dissolved in ethanol (5 mL) and concentrated sulfuric acid (1 mL) was added. The mixture was refluxed for 2 hours and allowed to cool to ambient temperature. The mixture was concentrated in vacuo, and the residue was neutralized with sodium hydroxide and partitioned between ethyl acetate and water. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was triturated with ethanol followed by filtration to give 1-[2-chloro-4-(pentyloxy)benzyl]-2-methyl-1H-benzimidazol-5-ol (100 mg) as a white solid. The filtrate was concentrated in vacuo and the residue was triturated with diisopropyl ether to give the further product (92 mg).
NMR(DMSO-d6,δ); 0.87 (3H, t, J=7.0 Hz), 1.2-1.4 (4H, m), 1.6-1.8 (2H, m), 2.41 (3H, s), 3.93 (2H, t, J=6.4 Hz), 5.34 (2H, s), 6.51 (1H, d, J=8.7 Hz), 6.60 (1H, dd, J=8.6 Hz, 2.3 Hz), 6.81 (1H, dd, J=8.6 Hz, 2.5 Hz), 6.88 (1H, d, J=2.2 Hz), 7.0-7.1 (2H, m), 8.93 (1H, s).
MS(API-ES, Posi): 359.2.
Ethyl 4-({1-[2-chloro-4-(pentyloxy)benzyl]-2-methyl-1H-benzimidazol-5-yl}oxy)butanoate (64 mg) was synthesized from 1-[2-chloro-4-(pentyloxy)benzyl]-2-methyl-1H-benzimidazol-5-ol (90 mg) in a manner similar to that described in Preparation Example 5.
NMR(DMSO-d6,δ); 0.87 (3H, t, J=7.1 Hz), 1.17 (3H, t, J=7.1 Hz), 1.2-1.4 (4H, m), 1.6-1.7 (2H, m), 1.9-2.0 (2H, m), 2.4-2.5 (5H, m), 3.93 (2H, t, J=6.5 Hz), 3.98 (2H, t, J=6.3 Hz), 4.06 (2H, q, J=7.1 Hz), 5.39 (2H, s), 6.51 (1H, d, J=8.6 Hz), 6.74 (1H, dd, J=8.8 Hz, 2.4 Hz), 6.81 (1H, dd, J=8.6 Hz, 2.6 Hz), 7.0-7.1 (2H, m), 7.18 (1H, d, J=8.8 Hz).
MS(API-ES, Posi): 473.3.
A mixture of N-(4-hydroxy-2-nitrophenyl)acetamide (1.6 g), ethyl 6-bromohexanoate (2.0 g), potassium carbonate (1.2 g) and N,N-dimethylformamide (30 mL) was stirred at ambient temperature overnight. The mixture was diluted with EtOAc (30 mL) and the insoluble materials were filtered off. The filtrate was washed successively with aq. sodium bicarbonate, water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The resulting solid was triturate with diisopropyl ether (50 mL) and filtered to give ethyl 6-[4-(acetylamino)-3-nitrophenoxy]hexanoate (1.9 g) as a yellow solid.
NMR(DMSO-d6,δ): 1.17 (3H, t, J=7 Hz), 1.4-1.8 (6H, m), 2.01 (3H, s), 2.30 (2H, t, J=7 Hz), 4.02 (2H, t, J=6 Hz), 4.04 (2H, q, J=7 Hz), 7.26 (1H, dd, J=3 Hz, 9 Hz), 7.4-7.5 (2H, m), 10.02 (1H, br s).
To a solution of ethyl 6-[4-(acetylamino)-3-nitrophenoxy]hexanoate (1.5 g) in a solvent mixture of tetrahydrofuran (15 mL) and N,N-dimethylformamide (15 mL) was added sodium hydride (60% dispersion in mineral oil; 186 mg) in an ice-bath. The ice-bath was removed and the mixture was stirred at ambient temperature for half an hour. To the mixture was added 1-(bromomethyl)-2-chloro-4-(pentyloxy)benzene (1.55 g) and stirring was continued for 3 hours at ambient temperature. The mixture was partitioned between ethyl acetate and saturated aqueous ammonium chloride. The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give ethyl 6-(4-{acetyl[2-chloro-4-(pentyloxy)benzyl]amino}-3-nitrophenoxy)hexanoate (2.4 g) as a yellow oil.
NMR(DMSO-d6,δ): 0.88 (3H, t, J=7 Hz), 1.16 (3H, t, J=7 Hz), 1.2-1.8 (12H, m), 1.78 (3H, s), 2.29 (2H, t, J=7 Hz), 3.92 (2H, t, J=6 Hz), 4.03 (2H, t, J=6 Hz), 4.04 (2H, q, J=7 Hz), 5.02, 4.44 (2H AB q, J=14 Hz), 6.81 (1H, dd, J=2 Hz, 8 Hz), 6.89 (1H, d, J=2 Hz), 7.15 (1H, d, J=8 Hz), 7.1-7.3 (2H, m), 7.52 (1H, d, J=3 Hz).
A mixture of ethyl 6-(4-{acetyl[2-chloro-4-(pentyloxy)benzyl]amino}-3-nitrophenoxy)hexanoate (2.4 g) and iron (977 mg) in a solvent mixture of ethanol (25 mL) and acetic acid (7.5 mL) was reflux for 5 hours. After cooling, the insoluble materials were filtered off and the residue was partitioned between ethyl acetate and 1 N sodium hydroxide. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (gradient elution; n-hexane-ethyl acetate 1:1 to 1:2 to 1:3) to give ethyl 6-({1-[2-chloro-4-(pentyloxy)benzyl]-2-methyl-1H-benzimidazol-5-yl}oxy)hexanoate (1.58 g) as a solid.
NMR(DMSO-d6,δ): 0.87 (3H, t, J=7 Hz), 1.17 (3H, t, J=7 Hz), 1.2-1.8 (12H, m), 2.30 (2H, t, J=7 Hz), 2.43 (3H, s), 3.93 (2H, t, J=6 Hz), 3.94 (2H, t, J=6 Hz), 4.04 (2H, q, J=7 Hz), 5.38 (2H, s), 6.51 (1H, d, J=9 Hz), 6.73 (1H, dd, J=2 Hz, 9 Hz), 6.80 (1H, dd, J=3 Hz, 9 Hz), 7.0-7.1 (2H, m), 7.17 (1H, d, J=9 Hz).
To nitric acid (HNO3) (fuming) (8 ml) was added 4-(acetylamino)-3-methylphenyl acetate (2.0 g) at −40-−50° C. After stirring for 2 hours, the reaction mixture was added ice-water and neutralized with 20%-sodium hydroxide (NaOH). The precipitates were collected by filtration and washed with water (3×5 ml). The crude crystals were triturated with ethyl acetate (EtOAc) to give 4-(acetylamino)-3-methyl-5-nitrophenyl acetate (0.91 g) as pale yellow crystals.
NMR(DMSO-d6,δ): 2.04 (3H, s), 2.28 (3H, s), 2.29 (3H, s), 7.44 (1H, d, J=2.5 Hz), 7.62 (1H, d, J=2.5 Hz), 9.85 (1H, br s).
MS: 275 (M+Na).
To a suspension of 4-(acetylamino)-3-methyl-5-nitrophenyl acetate (500 mg) in a mixture of ethyl alcohol (EtOH) (5 ml) and tetrahydrofuran (THF) (2.5 ml) was added palladium on carbon (10%, 50% wet, 0.2 g) at ambient temperature, and the resultant mixture was hydrogenated under atmospheric pressure of hydrogen for 3 hours. The catalyst was removed by filtration (washed with EtOH). The filtrate was evaporated and triturated with EtOAc to give 4-(acetylamino)-3-amino-5-methylphenyl acetate (377 mg) as crystals.
NMR(DMSO-d6,δ): 2.01 (3H, s), 2.02 (3H, s), 2.21 (3H, s), 4.95 (2H, br s), 6.14 (1H, d, J=2.5 Hz), 6.26 (1H, d, J=2.5 Hz), 8.82 (1H, br s).
MS: 245 (M+Na).
A mixture of 4-(acetylamino)-3-amino-5-methylphenyl acetate (50 mg), 1-(bromomethyl)-2-chloro-4-(pentyloxy)benzene (66 mg), potassium carbonate (K2CO3) (31 mg) and N,N-dimethylformamide (DMF) (1 ml) was heated at 80° C. for 3 hours. After cooling, the reaction mixture was diluted with EtOAc (40 ml) and washed with water (2×30 ml) and brine (20 ml). The organic layer was dried over magnesium sulfate (MgSO4). filtered, and evaporated to give 4-(acetylamino)-3-{[2-chloro-4-(pentyloxy)benzyl]amino}-5-methylphenyl acetate (109 mg) as a crude oil.
NMR(DMSO-d6,δ): 0.88 (3H, t, J=3.5 Hz), 1.2-1.5 (4H, m), 1.6-1.8 (2H, m), 2.04 (3H, s), 2.06 (3H, s), 2.15 (3H, s), 3.94 (2H, t, J=3.2 Hz), 4.25 (2H, d, J=3.1 Hz), 5.78 (1H, t, J=3.1 Hz), 5.89 (1H, d, J=1.2 Hz), 6.18 (1H, d, J=1.2 Hz), 6.82 (1H, dd, J=1.3 Hz, 4.3 Hz), 7.01 (1H, d, J=1.3 Hz), 7.23 (1H, d, J=4.3 Hz), 8.92 (1H, br s).
MS: 433 (M+1).
A mixture of 4-(acetylamino)-3-{[2-chloro-4-(pentyloxy)benzyl]amino}-5-methylphenyl acetate (600 mg) and 4N-hydrochloric acid (HCl)/dioxane (3.5 ml) was stirred at ambient temperature for 18 hours. The reaction mixture was poured into ice-water, neutralized with saturated aqueous sodium hydrogencarbonate (NaHCO3), and extracted with EtOAc (2×50 ml). The combined organic layers were dried over MgSO4 and filtered. Evaporation gave a residue (370 mg) which was chromatographed (silica gel, dichloromethane (CH2Cl2)—methyl alcohol (MeOH); 1→2%) to give 1-[2-chloro-4-(pentyloxy)benzyl]-2,4-dimethyl-1H-benzimidazol-6-yl acetate (204 mg) as a pale brown oil.
NMR(DMSO-d6,δ): 0.87 (3H, t, J=6.7 Hz), 1.2-1.4 (4H, m), 1.5-1.8 (2H, m), 2.22 (3H, s), 2.45 (3H, s), 2.49 (3H, s), 3.94 (2H, t, J=6.4 Hz), 5.39 (2H, br s), 6.47 (1H, d, J=8.7 Hz), 6.74 (1H, d, J=2.0 Hz), 6.82 (1H, dd, J=2.5 Hz, 8.7 Hz), 6.99 (1H, d, J=2.0 Hz), 7.10 (1H, d, J=2.5 Hz).
MS: 415 (M+1).
To a solution of 1-[2-chloro-4-(pentyloxy)benzyl]-2,4-dimethyl-1H-benzimidazol-6-yl acetate (197 mg) in MeOH (2 ml) was added K2CO3 (146 mg) at ambient temperature. After stirring for 2 hours, the reaction mixture was neutralized with 1 N-HCl. The precipitates were collected by filtration and washed with water (3×2 ml) and MeOH (1 ml) to give 1-[2-chloro-4-(pentyloxy)benzyl]-2,4-dimethyl-1H-benzimidazol-6-ol (142 mg) as pale brown crystals.
NMR(DMSO-d6,δ): 0.87 (3H, t, J=6.8 Hz), 1.2-1.4 (4H, m), 1.5-1.8 (2H, m), 2.41 (3H, s), 2.42 (3H, s), 3.94 (2H, t, J=6.4 Hz), 5.28 (2H, br s), 6.38 (1H, d, J=2.0 Hz), 6.4-6.5 (2H, m), 6.82 (1H, dd, J=2.5 Hz, 8.6 Hz), 7.10 (1H, d, J=2.5 Hz), 8.98 (1H, br s).
MS: 373 (M+1).
To a solution of 1-[2-chloro-4-(pentyloxy)benzyl]-2,4-dimethyl-1H-benzimidazol-6-ol (50 mg) in a mixture of DMF (0.5 ml) and THF (0.5 ml) was added sodium hydride (NaH; 60% dispersion in mineral oil) (6.4 mg) at ambient temperature. After stirring for 30 minutes, the reaction mixture was added ethyl 4-bromobutanoate (29 mg) and the stirring was continued for 12 hours. The reaction mixture was added water (30 ml) and extracted with EtOAc (2×20 ml). The combined organic extracts were washed with brine (20 ml), dried over MgSO4, and filtered. Evaporation gave a residue (63 mg) which was chromatographed (preparative thin-layer chromatography (TLC), EtOAc/n-hexane=2/1) to give ethyl 4-({1-[2-chloro-4-(pentyloxy)benzyl]-2,4-dimethyl-1H-benzimidazol-6-yl}oxy)butanoate (50 mg) as an oil.
NMR(DMSO-d6,δ): 0.87 (3H, t, J=6.8 Hz), 1.16 (3H, t, J=7.1 Hz), 1.2-1.4 (4H, m), 1.5-1.8 (2H, m), 2.39 (3H, s), 2.3-2.5 (5H, m), 3.8-4.0 (4H, m), 4.05 (2H, q, J=7.1 Hz), 5.37 (2H, br s), 6.42 (1H, d, J=8.6 Hz), 6.59 (1H, d, J=2.0 Hz), 6.76 (1H, d, J=2.0 Hz), 6.81 (1H, dd, J=2.5 Hz, 8.6 Hz), 7.10 (1H, d, J=2.5 Hz).
MS: 487 (M+1).
To a suspension of 4-(acetylamino)-3-methyl-5-nitrophenyl acetate (330 mg) in EtOH (6.6 ml) was added sulfuric acid (H2SO4) (1.28 g) at ambient temperature. After stirring for 2 hours, the reaction mixture was diluted with ice-water (20 ml), and the pH of the mixture was adjusted to around 3.5 with 20%-NaOH, and then extracted with EtOAc (2×30 ml). The combined organic extracts were washed with brine (20 ml), dried over MgSO4, and evaporated to give N-(4-hydroxy-2-methyl-6-nitrophenyl)acetamide (274 mg) as dark yellow crystals.
NMR(DMSO-d6,δ): 1.98 (3H, s), 2.17 (3H, s), 6.98 (1H, d, J=2.8 Hz), 7.06 (1H, d, J=2.8 Hz), 9.52 (1H, br s), 10.20 (1H, br s).
MS: 233 (M+Na).
To a suspension of NaH (60% dispersion in mineral oil) (1.37 g) was washed with ether (Et2O) twice) in a mixture of DMF (60 ml) and THF (60 ml) was added N-(4-hydroxy-2-methyl-6-nitrophenyl)acetamide (6.0 g) under ice cooling. After stirring for 30 minutes at ambient temperature, the reaction mixture was added ethyl 4-bromobutanoate (6.12 g) and the stirring was continued for 5 days. The reaction mixture was added water (100 ml) and extracted with EtOAc (3×100 ml). The combined organic extracts were washed with brine (2×200 ml), dried over MgSO4, and filtered. Evaporation gave a residue which was triturated with EtOAc (6 ml)—n-hexane (6 ml) to give ethyl 4-[4-(acetylamino)-3-methyl-5-nitrophenoxy]butanoate (4.57 g) as pale yellow crystals.
NMR(DMSO-d6,δ): 1.18 (3H, t, J=7.1 Hz), 1.8-2.1 (2H, m), 1.99 (3H, s), 2.22 (3H, s), 2.45 (2H, t, J=7.2 Hz), 4.0-4.2 (4H, m), 7.20 (1H, d, J=2.8 Hz), 7.26 (1H, d, J=2.8 Hz), 9.62 (1H, br s).
MS: 347 (M+Na).
To a suspension of ethyl 4-[4-(acetylamino)-3-methyl-5-nitrophenoxy]butanoate (4.5 g) in EtOH (45 ml) was added palladium on carbon (10%, 50% wet, 1.35 g) at ambient temperature, and the resultant mixture was hydrogenated under atmospheric pressure of hydrogen for 6 hours. The catalyst was removed by filtration. The filtrate was evaporated to give ethyl 4-[4-(acetylamino)-3-amino-5-methylphenoxy]butanoate (4.33 g) as an oil.
NMR(DMSO-d6,δ): 1.18 (3H, t, J=7.1 Hz), 1.8-2.1 (2H, m), 1.99 (3H, s), 2.42 (2H, t, J=7.2 Hz), 3.85 (2H, t, J=6.3 Hz), 4.07 (2H, q, J=7.1 Hz), 4.73 (2H, br s), 5.99 (1H, d, J=2.6 Hz), 6.09 (1H, d, J=2.6 Hz), 8.68 (1H, br s).
MS: 317 (M+Na).
To a suspension of ethyl 4-[4-(acetylamino)-3-amino-5-methylphenoxy]butanoate (4.33 g) in EtOH (20 ml) was added H2SO4 (2 ml) at ambient temperature. After stirring for 23 hours, the reaction mixture was heated at 50° C. for 5 hours. After cooling, the reaction mixture was evaporated, ice was added, and the pH of the mixture was adjusted to around 8.5 with 20%-NaOH. The mixture was extracted with EtOAc (2×50 ml). The combined organic extracts were washed with brine (50 ml), dried over MgSO4, and filtered. Evaporation gave a residue which was triturated with EtOAc (4 ml)—n-hexane (4 ml) to give ethyl 4-[(2,4-dimethyl-1H-benzimidazol-6-yl)oxy]butanoate (2.9 g) as white crystals.
NMR(DMSO-d6,δ): 1.18 (3H, t, J=7.1 Hz), 1.8-2.1 (2H, m), 2.3-2.5 (8H, m), 3.94 (2H, t, J=6.3 Hz), 4.07 (2H, q, J=7.1 Hz), 6.53 (1H, br s), 6.74 (1H, br s), 11.93 (1H, br s).
MS: 277 (M+1).
To a mixture of ethyl 4-[(2,4-dimethyl-1H-benzimidazol-6-yl)oxy]butanoate (200 mg), K2CO3 (130 mg) and DMF (2 ml) was added 2,4-dichloro-1-(chloromethyl)benzene (170 mg) at ambient temperature. After stirring for 24 hours, the reaction mixture was heated at 70° C. for 7 hours. After cooling, the reaction mixture was diluted with EtOAc (50 ml) and washed with 5%-NaHCO3 (20 ml) and brine (2×30 ml). The organic layer was dried over MgSO4 and filtered. Evaporation gave a residue (346 mg) which was triturated with n-hexane (4 ml) to give ethyl 4-{[1-(2,4-dichlorobenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]oxy}butanoate (280 mg) as white crystals.
NMR(DMSO-d6,δ): 1.15 (3H, t, J=7.1 Hz), 1.8-2.1 (2H, m), 2.3-2.5 (8H, m), 3.90 (2H, t, J=6.3 Hz), 4.04 (2H, q, J=7.1 Hz), 5.44 (2H, br s), 6.39 (1H, d, J=8.4 Hz), 6.61 (1H, d, J=2.0 Hz), 6.79 (1H, d, J=2.0 Hz), 7.32 (1H, dd, J=2.1 Hz, 8.4 Hz), 7.72 (1H, d, J=2.1 Hz).
MS: 435 (M+1).
To a mixture of ethyl 4-[(2,4-dimethyl-1H-benzimidazol-6-yl)oxy]butanoate (200 mg), K2CO3 (130 mg) and DMF (2 ml) was added 3-chloro-2-(chloromethyl)-5-(trifluoromethyl)pyridine (200 mg) at ambient temperature. After stirring for 24 hours, the reaction mixture was diluted with EtOAc (50 ml) and washed with 5%-NaHCO3 (30 ml) and brine (2×30 ml). The organic layer was dried over MgSO4 and filtered. Evaporation gave a residue which was triturated with n-hexane (4 ml) to give ethyl 4-[(1-{[3-chloro-5-(trifluoromethyl)-2-pyridinyl]methyl}-2,4-dimethyl-1H-benzimidazol-6-yl)oxy]butanoate (290 mg) as white crystals.
NMR(DMSO-d6,δ): 1.15 (3H, t, J=7.1 Hz), 1.8-2.0 (2H, m), 2.3-2.5 (8H, m), 3.89 (2H, t, J=6.3 Hz), 4.04 (2H, q, J=7.1 Hz), 5.70 (2H, br s), 6.56 (!H, d, J=1.8 Hz), 6.77 (1H, d, J=1.8 Hz), 8.55 (1H, d, J=1.2 Hz), 8.77 (1H, d, J=1.2 Hz).
MS: 470 (M+1).
To a mixture of ethyl 4-[(2,4-dimethyl-1H-benzimidazol-6-yl)oxy]butanoate (200 mg), K2CO3 (130 mg) and DMF (2 ml) was added 4-(chloromethyl)-5-methyl-2-phenyl-1,3-oxazole (180 mg) at ambient temperature. After stirring for 13 hours at 70-90° C., the reaction mixture was diluted with EtOAc (30 ml) and washed with 5%-NaHCO3 (20 ml) and brine (2×20 ml). The organic layer was dried over MgSO4 and filtered. Evaporation gave a residue (361 mg) which was triturated with EtOAc (2 ml)—n-hexane (2 ml) to give ethyl 4-({2,4-dimethyl-1-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methyl]-1H-benzimidazol-6-yl}oxy)butanoate (160 mg) as white crystals.
NMR(DMSOd6, δ): 1.16 (3H, t, J=7.1 Hz), 1.9-2.1 (2H, m), 2.3-2.5 (8H, m), 2.65 (3H, s), 3.9-4.2 (4H, m), 5.29 (2H, br s), 6.57 (1H, d, J=1.8 Hz), 6.93 (1H, d, J=1.8 Hz), 7.4-7.6 (3H, m), 7.8-7.9 (2H, m).
MS: 448 (M+1).
Ethyl 4-{[2,4-dimethyl-1-({4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)-1H -benzimidazol-6-yl]oxy}butanoate (144 mg) was synthesized from 5-(chloromethyl)-4-methyl-2-(4-trifluoromethyl)phenyl-1,3-thiazole (120 mg) in a manner similar to that described in Preparation Example 40.
NMR(DMSO-d6,δ): 1.15 (3H, t, J=7.1 Hz), 1.8-2.1 (2H, m), 2.4-2.5 (8H, m), 2.58 (3H, s), 3.9-4.2 (4H, m), 5.66 (2H, br s), 6.62 (1H, d, J=1.8 Hz), 6.95 (1H, d, J=1.8 Hz), 7.77 (2H, d, J=8.3 Hz), 8.02 (2H, d, J=8.3 Hz).
MS: 532 (M+1).
A mixture of ethyl 4-[(2,4-dimethyl-1H-benzimidazol-6-yl)oxy]butanoate (265 mg), 4-ethoxy-2-methylbenzyl methanesulfonate (351 mg), K2CO3 (199 mg), sodium iodide (NaI) (216 mg) and DMF (5 ml) was heated at 80° C. for 2 hours. After cooling, the reaction mixture was diluted with EtOAc (40 ml) and washed with saturated NaHCO3 (30 ml) and brine (2×30 ml). The organic layer was dried over MgSO4 and filtered. Evaporation gave a residue (487 mg) which was chromatographed (silica gel, EtOAc) to give ethyl 4-{[1-(4-ethoxy-2-methylbenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]oxy}butanoate (279 mg) as an oil.
NMR(DMSO-d6,δ): 1.1-1.2 (3H, m), 1.27 (3H, t, J=7.0 Hz), 1.8-2.0 (2H, m), 2.32 (3H, s), 2.35 (3H, s), 2.42 (2H, t, J=7.3 Hz), 2.46 (3H, s), 3.8-4.1 (6H, m), 5.28 (2H, br s), 6.15 (1H, d, J=8.5 Hz), 6.5-6.7 (2H, m), 6.70 (1H, d, J=2.3 Hz), 6.80 (1H, d, J=2.3 Hz).
MS: 425 (M+1).
To a mixture of ethyl 4-[(2,4-dimethyl-1H-benzimidazol-6-yl)oxy]butanoate (200 mg), K2CO3 (120 mg) and DMF (2 ml) was added 1-(bromomethyl)-2-chlorobenzene (164 mg) at ambient temperature. After stirring at 80° C. for 3 hours, the reaction mixture was diluted with EtOAc (40 ml) and washed with water (30 ml) and brine (2×30 ml). The organic layer was dried over MgSO4, filtered, and evaporated to give ethyl 4-{[1-(2-chlorobenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]oxy}butanoate (304 mg) as a crude oil.
To a mixture of ethyl 4-[(2,4-dimethyl-1H-benzimidazol-6-yl)oxy]butanoate (200 mg), (3,5-dichloro-2-pyridinyl)methyl methanesulfonate (204 mg) and DMF (2 ml) was added K2CO3 (150 mg) at ambient temperature. After stirring at 80° C. for 6 hours, the reaction mixture was diluted with EtOAc (40 ml) and washed with water (30 ml) and brine (2×30 ml). The organic layer was dried over MgSO4 and filtered. Evaporation gave a residue (369 mg) which was triturated with n-hexane (6 ml)—EtOAc (1 ml) to give ethyl 4-({1-[(3,5-dichloro-2-pyridinyl)methyl]-2,4-dimethyl-1H-benzimidazol-6-yl}oxy)butanoate (236 mg) as white crystals.
NMR(DMSO-d6,δ): 1.16 (3H, t, J=7.1 Hz), 1.8-2.0 (2H, m), 2.3-2.5 (8H, m), 3.89 (2H, t, J=6.2 Hz), 4.05 (2H, q, J=7.1 Hz), 5.58 (2H, br s), 6.56 (1H, d, J=1.8 Hz), 6.74 (1H, d, J=1.8 Hz), 8.32 (1H, d, J=2.1 Hz), 8.44 (1H, d, J=2.1 Hz).
MS: 436 (M+1).
Ethyl 4-({1-[(2,6-dichloro-3-pyridinyl)methyl]-2,4-dimethyl-1H-benzimidazol-6-yl}oxy)butanoate (254 mg) was synthesized from ethyl 4-[(2,4-dimethyl-1H-benzimidazol-6-yl)oxy]butanoate (200 mg) in a manner similar to that described in Preparation Example 44 except that (2,6-dichloro-3-pyridinyl)methyl methanesulfonate (204 mg) was used instead of (3,5-dichloro-2-pyridinyl)methyl methanesulfonate.
NMR(DMSO-d6,δ): 1.15 (3H, t, J=7.1 Hz), 1.8-2.0 (2H, m), 2.3-2.5 (8H, m), 3.90 (2H, t, J=6.3 Hz), 4.05 (2H, q, J=7.1 Hz), 5.45 (2H, br s), 6.61 (1H, d, J=1.5 Hz), 6.7-6.9 (2H, m), 7.45 (1H, d, J=8.1 Hz).
MS: 436 (M+1).
To a mixture of ethyl 4-[(2,4-dimethyl-1H-benzimidazol-6-yl)oxy]butanoate (200 mg), 2,5-dichlorobenzyl methanesulfonate (203 mg) and DMF (2 ml) were added K2CO3 (150 mg) and NaI (108 mg) at ambient temperature. After stirring at 80° C. for 2 hours, the reaction mixture was diluted with EtOAc (40 ml) and washed with water (30 ml) and brine (2×30 ml). The organic layer was dried over MgSO4, filtered, and evaporated to give ethyl 4-{[1-(2,5-dichlorobenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]oxy}butanoate (350 mg) as a crude oil.
Ethyl 4-[(1-{2-chloro-4-[(ethoxycarbonyl)(methyl)amino]benzyl}-2,4-dimethyl-1H-benzimidazol-6-yl)oxy]butanoate (280 mg) was synthesized from ethyl 4-[(2,4-dimethyl-1H-benzimidazol-6-yl)oxy]butanoate (157 mg) in a manner similar to that described in Preparation Example 43 except that ethyl 4-(bromomethyl)-3-chlorophenyl(methyl)carbamate (192 mg) was used instead of 1-(bromomethyl)-2-chlorobenzene.
Ethyl 4-{[1-(2,3-dichlorobenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]oxy}butanoate (199 mg) was synthesized from ethyl 4-[(2,4-dimethyl-1H-benzimidazol-6-yl)oxy]butanoate (200 mg) in a manner similar to that described in Preparation Example 38 except that 2,3-dichloro-1-(chloromethyl)benzene (170 mg) was used instead of 2,4-dichloro-1-(chloromethyl)benzene.
NMR(DMSO-d6,δ): 1.15 (3H, t, J=7.1 Hz), 1.8-2.1 (2H, m), 2.3-2.5 (8H, m), 3.89 (2H, t, J=6.3 Hz), 4.04 (2H, q, J=7.1 Hz), 5.50 (2H, br s), 6.28 (1H, dd, J=1.2 Hz, 7.9 Hz), 6.61 (1H, d, J=1.8 Hz), 6.81 (1H, d, J=1.8 Hz), 7.24 (1H, t, J=7.9 Hz), 7.59 (1H, dd, J=1.2 Hz, 7.9 Hz).
MS: 435 (M+1).
Ethyl 4-{[1-(3,4-dichlorobenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]oxy}butanoate was synthesized from ethyl 4-[(2,4-dimethyl-1H-benzimidazol-6-yl)oxy]butanoate (200 mg) in a manner similar to that described in Preparation Example 43 except that 3,4-dichloro-1-(chloromethyl)benzene (170 mg) was used instead of 1-(bromomethyl)-2-chlorobenzene.
To a mixture of ethyl 4-[(2,4-dimethyl-1H-benzimidazol-6-yl)oxy]butanoate (200 mg), K2CO3 (150 mg) and DMF (0.6 ml) was added 4-(bromomethyl)-3-chloro-1,1′-biphenyl (306 mg) at ambient temperature. After stirring for 2 hours, the reaction mixture was diluted with EtOAc (40 ml) and washed with water (30 ml) and brine (2×30 ml). The organic layer was dried over MgSO4 and filtered. Evaporation gave a residue (395 mg) which was chromatographed (silica gel, EtOAc) to give ethyl 4-({1-[(3-chloro-1,1′-biphenyl-4-yl)methyl]-2,4-dimethyl-1H-benzimidazol-6-yl}oxy)butanoate (266 mg) as a pale yellow oil.
NMR(DMSO-d6,δ): 1.13 (3H, t, J=7.1 Hz), 1.8-2.0 (2H, m), 2.3-2.5 (8H, m), 3.91 (2H, t, J=6.3 Hz), 4.03 (2H, q, J=7.1 Hz), 5.50 (2H, br s), 6.48 (1H, d, J=8.1 Hz), 6.62 (1H, d, J=1.7 Hz), 6.82 (1H, d, J=1.7 Hz), 7.3-7.7 (6H, m), 7.83 (1H, d, J=1.8 Hz).
MS: 477 (M+1).
To a mixture of ethyl 4-[(2,4-dimethyl-1H-benzimidazol-6-yl)oxy]butanoate (400 mg), K2CO3 (260 mg) and DMF (4 ml) was added 4-(bromomethyl)-3-chlorophenyl acetate (458 mg) at ambient temperature. After stirring for 24 hours, the reaction mixture was diluted with EtOAc (40 ml) and washed with water (30 ml) and brine (2×30 ml). The organic layer was dried over MgSO4, filtered and evaporated to give ethyl 4-({1-[4-(acetyloxy)-2-chlorobenzyl]-2,4-dimethyl-1H-benzimidazol-6-yl}oxy)butanoate (772 mg) as a crude oil.
To a suspension of ethyl 4-({1-[4-(acetyloxy)-2-chlorobenzyl]-2,4-dimethyl-1H-benzimidazol-6-yl}oxy)butanoate (770 mg: crude) in MeOH (7 ml) was added K2CO3 (464 mg) at ambient temperature. After stirring for 5 hours, the pH of the reaction mixture was adjusted to around 4 with 1 N-HCl. The precipitates were collected by filtration and washed with water. The crude crystals were triturated with EtOAc—n-hexane to give methyl 4-{[1-(2-chloro-4-hydroxybenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]oxy}butanoate (330 mg) as white crystals.
NMR(DMSO-d6,δ): 1.8-2.1 (2H, m), 2.3-2.5 (8H, m), 3.59 (3H, s), 3.90 (2H, t, J=6.3 Hz), 5.32 (2H, br s), 6.39 (1H, d, J=8.5 Hz), 6.59 (1H, d, J=1.8 Hz), 6.64 (1H, dd, J=2.4 Hz, 8.5 Hz), 6.74 (1H, d, J=1.8 Hz), 6.88 (1H, d, J=2.4 Hz), 9.97 (1H, br s).
MS: 403 (M+1).
To a solution of methyl 4-{[1-(2-chloro-4-hydroxybenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]oxy}butanoate (150 mg) in DMF (1.5 ml) were added K2CO3 (67 mg) and iodomethane (MeI) (106 mg) at ambient temperature. The mixture was stirred at 40° C. for 3 hours. The reaction mixture was diluted with EtOAc (40 ml) and washed with brine (2×30 ml). The organic layer was dried over MgSO4, filtered, and evaporated to give methyl 4-{[1-(2-chloro-4-methoxybenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]oxy}butanoate (96 mg) as white crystals.
NMR(DMSO-d6,δ): 1.8-2.1 (2H, m), 2.3-2.5 (8H, m), 3.59 (3H, s), 3.74 (3H, s), 3.90 (2H, t, J=6.3 Hz), 5.37 (2H, br s), 6.46 (1H, d, J=8.7 Hz), 6.59 (1H, d, J=1.8 Hz), 6.75 (1H, d, J=1.8 Hz), 6.82 (1H, dd, J=2.4 Hz, 8.7 Hz), 7.12 (1H, d, J=2.4 Hz).
MS: 417 (M+1).
Methyl 4-{[1-(2-chloro-4-ethoxybenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]oxy}butanoate (158 mg) was synthesized from methyl 4-{[1-(2-chloro-4-hydroxybenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]oxy}butanoate (150 mg) in a manner similar to that described in Preparation Example 53 except that iodoethane (MeI). (EtI) (116 mg) was used instead of iodomethane (MeI).
NMR(DMSO-d6,δ): 1.29 (3H, t, J=6.9 Hz), 1.8-2.1 (2H, m), 2.3-2.5 (8H, m), 3.59 (3H, s), 3.90 (2H, t, J=6.4 Hz), 4.00 (2H, q, J=6.9 Hz), 5.37 (2H, br s), 6.43 (1H, d, J=8.6 Hz), 6.59 (1H, d, J=1.8 Hz), 6.75 (1H, d, J=1.8 Hz), 6.81 (1H, dd, J=2.5 Hz, 8.6 Hz), 7.09 (1H, d, J=2.5 Hz).
MS: 431 (M+1).
To a mixture of ethyl 4-[4-(acetylamino)-3-aminophenoxy]butanoate hydrochloride (300 mg), K2CO3 (288 mg) and DMF (3 ml) was added 2,4-dichloro-1-(chloromethyl)benzene (204 mg) at ambient temperature. The mixture was heated at 80° C. for 2 hours and at 90° C. for 2 hours. After cooling, the. reaction mixture was diluted with EtOAc (50 ml) and washed with water (30 ml) and brine (2×30 ml). The organic layer was dried over MgSO4, filtered, and evaporated to give ethyl 4-{4-(acetylamino)-3-[(2,4-dichlorobenzyl)amino]phenoxy}butanoate (448 mg) as a crude oil.
To a solution of ethyl 4-{4-(acetylamino)-3-[(2,4-dichlorobenzyl)amino]phenoxy}butanoate (448 mg: crude) in EtOH (4.5 ml) was added H2SO4 (200 mg) at ambient temperature. The mixture was stirred at room temperature for 3 days and at 80° C. for 1 hour. After cooling, the pH of the reaction mixture was adjusted to around 8 with 1 N-NaOH and extracted with EtOAc (2×20 ml). The combined organic extracts were washed with water (30 ml) and brine (30 ml). The organic layer was dried over MgSO4 and filtered. Evaporation gave a residue (277 mg) which was chromatographed (silica gel, EtOAc) to give ethyl 4-{[1-(2,4-dichlorobenzyl)-2-methyl-1H-benzimidazol-6-yl]oxy}butanoate (102 mg) as white crystals.
NMR(DMSO-d6,δ): 1.15 (3H, t, J=7.1 Hz), 1.8-2.1 (2H, m), 2.38 (3H, s), 2.44 (2H, t, J=7.2 Hz), 3.93 (2H, t, J=6.3 Hz), 4.05 (2H, q, J=7.1 Hz), 5.47 (2H, br s), 6.42 (1H, d, J=8.4 Hz), 6.77 (1H, dd, J=2.2 Hz, 8.7 Hz), 6.99 (1H, d, J=2.2 Hz), 7.33 (1H, dd, J=2.1 Hz, 8.4 Hz), 7.44 (1H, d, J=8.7 Hz), 7.73 (1H, d, J=2.1 Hz).
MS: 423 (M+1).
Ethyl 4-{4-(acetylamino)-3-[(2-chloro-4-ethoxybenzyl)amino]phenoxy}butanoate (454 mg) was synthesized from ethyl 4-[4-(acetylamino)-3-aminophenoxy]butanoate hydrochloride (300 mg) in a manner similar to that described in Preparation Example 55 except that 1-(bromomethyl)-2-chloro-4-ethoxybenzene (284 mg) was used instead of 2,4-dichloro-1-(chloromethyl)benzene.
Ethyl 4-{[1-(2-chloro-4-ethoxybenzyl)-2-methyl-1H-benzimidazol-6-yl]oxy}butanoate (200 mg) was synthesized from ethyl 4-{4-(acetylamino)-3-[(2-chloro-4-ethoxybenzyl)amino]phenoxy}butanoate (454 mg) in a manner similar to that described in Preparation Example 56.
NMR(DMSO-d6,δ): 1.16 (3H, t, J=7.1 Hz), 1.29 (3H, t, J=7.0 Hz), 1.8-2.1 (2H, m), 2.3-2.5 (5H, m), 3.8-4.2 (6H, m), 5.40 (2H, br s), 6.47 (1H, d, J=8.6 Hz), 6.7-6.9 (2H, m), 6.95 (1H, d, J=2.2 Hz), 7.10 (1H, d, J=2.5 Hz), 7.42 (1H, d, J=8.7 Hz).
MS: 431 (M+1).
Ethyl 4-[4-(acetylamino)-3-({2-chloro-4-[(ethoxycarbonyl)(methyl)amino]benzyl}amino)phenoxy]butanoate was synthesized from ethyl 4-[4-(acetylamino)-3-aminophenoxy]butanoate hydrochloride (300 mg) in a manner similar to that described in Preparation Example 55 except that ethyl 4-(bromomethyl)-3-chlorophenyl(methyl)carbamate (348 mg) was used instead of 2,4-dichloro-1-(chloromethyl)benzene.
Ethyl 4-[(1-{2-chloro-4-[(ethoxycarbonyl)(methyl)amino]benzyl}-2-methyl-1H-benzimidazol-6-yl)oxy]butanoate (199 mg) was synthesized from ethyl 4-[4-(acetylamino)-3-({2-chloro-4-[(ethoxycarbonyl)(methyl)amino]benzyl]amino}phenoxy]butanoate (509 mg) in a manner similar to that described in Preparation Example 56.
NMR(DMSO-d6,δ): 1.1-1.2 (6H, m), 1.8-2.0: (2H, m)), 2.40 (3H, s), 2.44 (2H, t, J=7.3 Hz), 3.19 (3H, s), 3.93 (2H, t, J=6.3 Hz), 4.0-4.2 (4H, m), 5.47 (2H, br s), 6.43 (1H, d, J=8.4 Hz), 6.77 (1H, dd, J=2.4 Hz, 8.7 Hz), 7.00 (1H, d, J=2.4 Hz), 7.18 (1H, dd, J=2.2 Hz, 8.4 Hz), 7.44 (1H, d, J=8.7 Hz), 7.56 (1H, d, J=2.2 Hz).
MS: 488 (M+1).
To a mixture of ethyl 4-[4-(acetylamino)-3-aminophenoxy]butanoate hydrochloride (300 mg), K2CO3 (314 mg) and DMF (3 ml) were added 3-chloro-2-(chloromethyl)-5-(trifluoromethyl)pyridine (261 mg) and NaI (170 mg) at ambient temperature. After stirring for 4 hours, the reaction mixture was diluted with EtOAc (40 ml) and washed with water (30 ml) and brine (2×30 ml). The organic layer was dried over MgSO4 and filtered. Evaporation gave a residue which was triturated with EtOAc (3 ml)—n-hexane (2 ml) to give ethyl 4-[4-(acetylamino)-3-({[3-chloro-5-(trifluoromethyl)-2-pyridinyl]methyl}amino)phenoxy]butanoate (240 mg) as white crystals.
NMR(DMSO-d6,δ): 1.17 (3H, t, J=7.1 Hz), 1.8-2.1 (2H, m), 2.03 (3H, s), 2.42 (2H, t, J=7.3 Hz), 3.90 (2H, t, J=6.3 Hz), 4.06 (2H, q, J=7.1 Hz), 4.56 (2H, d, J=5.3 Hz), 5.77 (1H, t, J=5.3 Hz), 6.1-6.3 (2H, m), 6.94 (1H, d, J=8.4 Hz), 8.50 (1H, d, J=1.3 Hz), 8.95 (1H, d, J=1.3 Hz), 9.11 (1H, br s).
MS: 496 (M+Na)
To a solution of ethyl 4-[4-(acetylamino)-3-({[3-chloro-5-(trifluoromethyl)-2-pyridinyl]methyl}amino)phenoxy]butanoate (200 mg) in EtOH (2 ml) was added H2SO4 (41 mg) at ambient temperature. The mixture was heated at 80° C. for 2 hours. After cooling, the pH of the reaction mixture was adjusted to around 8 with 1 N-NaOH and extracted with EtOAc (2×20 ml). The combined organic extracts were washed with water (30 ml) and brine (30 ml). The organic layer was dried over MgSO4, filtered, and evaporated to give ethyl 4-[(1-{[3-chloro-5-(trifluoromethyl)-2-pyridinyl]methyl)-2-methyl-1H-benzimidazol-6-yl)oxy]butanoate (188 mg) as pale brown crystals.
NMR(DMSO-d6,δ): 1.15 (3H, t, J=7.1 Hz), 1.8-2.1 (2H, m), 2.38 (3H, s), 2.43 (2H, t, J=7.4 Hz), 3.92 (2H, t, J=6.3 Hz), 4.04 (2H, q, J=7.1 Hz), 5.73 (2H, br s), 6.73 (1H, dd, J=2.3 Hz, 8.6 Hz), 6.98 (1H, d, J=2.3 Hz), 7.39 (1H, d, J=8.6 Hz), 8.56 (1H, d, J=1.2 Hz), 8.77 (1H, d, J=1.2 Hz).
MS: 456 (M+1).
To a suspension of ethyl 4-[4-(acetylamino)-3-methyl-5-nitrophenoxy]butanoate (18.2 g) in EtOH (182 ml) was added 1 N-NaOH (112 ml) at ambient temperature. The mixture was heated at 80-90° C. for 2 days. After cooling, the pH of the reaction mixture was adjusted to around 3 with 1 N-HCl. The precipitates were collected by filtration and washed with water to give 4-(4-amino-3-methyl-5-nitrophenoxy)butanoic acid (13.7 g) as orange crystals.
NMR(DMSO-d6,δ): 1.8-2.0 (2H, m), 2.20 (3H, s), 2.37 (2H, t, J=7.4 Hz), 3.92 (2H, t, J=6.4 Hz), 6.99 (2H, br s), 7.14 (1H, d, J=2.6 Hz), 7.30 (1H, d, J=2.6 Hz), 12.09 (1H, br s).
MS: 253 (M−1).
To a suspension of 4-(4-amino-3-methyl-5-nitrophenoxy)butanoic acid (13 g) in EtOH (130 ml) was added H2SO4 (10 g) at ambient temperature. The mixture was heated at reflux. for 13 hours. After cooling, the reaction mixture was poured into ice-water (200 ml) and EtOAc (200 ml). The aqueous layer was neutralized with 20%-NaOH and the organic layer was separated. The aqueous layer was extracted with EtOAc (2×200 ml). The combined organic extracts were washed with saturated NaHCO3 (3×200ml) and brine (300 ml). The organic layer was dried over MgSO4, filtered, and evaporated to give ethyl 4-(4-amino-3-methyl-5-nitrophenoxy)butanoate (12.8 g) as a red oil.
NMR(DMSO-d6,δ): 1.18 (3H, t, J=7.1 Hz), 1.8-2.1 (2H, m), 2.20 (3H, s), 2.44 (2H, t, J=7.3 Hz), 3.93 (2H, t, J=6.4 Hz), 4.07 (2H, q, J=7.1 Hz), 7.00 (2H, br s), 7.13 (1H, d, J=2.6 Hz), 7.30 (1H, d, J=2.6 Hz).
MS: 305 (M+Na).
To a solution of ethyl 4-(4-amino-3-methyl-5-nitrophenoxy)butanoate (5.0 g) in EtOH (50 ml) was added palladium on carbon (10%, 50% wet, 2 g) at ambient temperature, and the resultant mixture was hydrogenated under atmospheric pressure of hydrogen for 2 hours. The catalyst was removed by filtration. The filtrate was evaporated to give ethyl 4-(3,4-diamino-5-methylphenoxy)butanoate (4.12 g) as a brown oil.
NMR(DMSO-d6,δ): 1.18 (3H, t, J=7.2 Hz), 1.7-2.0 (2H, m), 2.00 (3H, s), 2.40 (2H, t, J=7.2 Hz), 3.76 (2H, t, J=6.3 Hz), 4.06 (2H, q, J=7.2 Hz), 4.45 (2H, br s), 5.91 (1H, d, J=2.7 Hz), 6.05 (1H, d, J=2.7 Hz).
MS: 275 (M+Na).
A mixture of ethyl 4-(3,4-diamino-5-methylphenoxy)butanoate (4.1 g), tetraethyl orthocarbonate (17 ml) and AcOH (1.27 g) was heated at 80° C. for 1 hour. After cooling, the reaction mixture was evaporated. The residue was dissolved in EtOAc (100 ml) and washed with saturated NaHCO3 (2×50 ml) and brine (50 ml). The organic layer was dried over MgSO4 and filtered. Evaporation gave a residue which was triturated with n-hexane (20 ml) to give ethyl 4-[(2-ethoxy-4-methyl-1H-benzimidazol-6-yl)oxy]butanoate (4.35 g) as pale brown crystals.
NMR(DMSO-d6,δ): 1.18 (3H, t, J=7.1 Hz), 1.36 (3H, t, J=7.0 Hz), 1.8-2.1 (2H, m), 2.33 (3H, s), 2.45 (2H, t, J=7.3 Hz), 3.92 (2H, t, J=6.3 Hz), 4.07 (2H, q, J=7.1 Hz), 4.44 (2H, q, J=7.0 Hz), 6.46 (1H, d, J=1.7 Hz), 6.66 (1H, br s), 11.58 (1H, br s).
MS: 307 (M+1).
Ethyl 4-{[1-(2,4-dichlorobenzyl)-2-ethoxy-4-methyl-1H-benzimidazol-6-yl]oxy}butanoate (151 mg) was synthesized from ethyl 4-[(2-ethoxy-4-methyl-1H-benzimidazol-6-yl)oxy]butanoate (200 mg) in a manner similar to that described in Preparation Example 38.
NMR(DMSO-d6,δ): 1.16 (3H, t, J=7.1 Hz), 1.31 (3H, t, J=7.0 Hz), 1.8-2.0 (2H, m), 2.3-2.5 (5H, m), 3.89 (2H, t, J=6.3 Hz), 4.05 (2H, q, J=7.1 Hz), 4.48 (2H, q, J=7.0 Hz), 5.23 (2H, br s), 6.55 (1H, d, J=1.9 Hz), 6.71 (1H, d, J=1.9 Hz), 6.78 (1H, d, J=8.3 Hz), 7.36 (1H, dd, J=2.1 Hz, 8.3 Hz), 7.68 (1H, d, J=2.1 Hz).
MS: 465 (M+1).
To a mixture of ethyl 4-[(2-ethoxy-4-methyl-1H-benzimidazol-6-yl)oxy]butanoate (200 mg), K2CO3 (117 mg) and DMF (2 ml) was added 1-(bromomethyl)-2-chloro-4-ethoxybenzene (195 mg) at ambient temperature. The mixture was heated at 80° C. for 3 hours. After cooling, the reaction mixture was diluted with EtOAc (50 ml) and washed with water (30 ml) and brine. (2×30 ml). The organic layer was dried over MgSO4 and filtered. Evaporation gave a residue which was chromatographed (silica gel, EtOAc/n-hexane=1/4) to give ethyl 4-{[1-(2-chloro-4-ethoxybenzyl)-2-ethoxy-4-methyl-1H-benzimidazol-6-yl]oxy}butanoate (215 mg) as an oil.
NMR(DMSO-d6,δ): 1.1-1.4 (9H, m), 1.8-2.0 (2H, m), 2.3-2.5 (5H, m), 3.89 (2H, t, J=6.3 Hz), 3.9-4.2 (4H, m), 4.48 (2H, q, J=7.0 Hz), 5.15 (2H, br s), 6.53 (1H, d, J=2.0 Hz), 6.65 (1H, d, J=2.0 Hz), 6.7-6.9 (2H, m), 7.05 (1H, d, J=1.9 Hz).
MS: 475 (M+1).
Ethyl 4-({1-[2-chloro-4-(pentyloxy)benzyl]-2-ethoxy-4-methyl-1H-benzimidazol-6-yl}oxy)butanoate (209 mg) was synthesized from ethyl 4-[(2-ethoxy-4-methyl-1H-benzimidazol-6-yl)oxy]butanoate (200 mg) in a manner similar to that described in Preparation Example 68 except that 1-(bromomethyl)-2-chloro-4-(pentyloxy)benzene (228 mg) was used instead of 1-(bromomethyl)-2-chloro-4-ethoxybenzene.
NMR(CDCl3,δ): 0.8-1.0-(3H, m), 1.1-1.5 (10H, m), 1.6-1.9 (2H, m), 1.9-2.2 (2H, m), 2.49 (2H, t, J=7.3 Hz), 2.54 (3H, s), 3.8-4.0 (4H, m), 4.13 (2H, q, J=7.2 Hz), 4.60 (2H, q, J=7.1 Hz), 5.12 (2H, br s), 6.42 (1H, d, J=2.3 Hz), 6.58 (1H, d, J=2.3 Hz), 6.64 (1H, dd, J=2.4 Hz, 8.6 Hz), 6.73 (1H, d, J=8.6 Hz), 6.94 (1H, d, J=2.4 Hz).
MS: 517 (M+1).
To a mixture of ethyl 4-[(2-ethoxy-4-methyl-1H-benzimidazol-6-yl)oxy]butanoate (200 mg), K2CO3 (108 mg), NaI (98 mg) and DMF (2 ml) was added 5-(chloromethyl)-4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazole (229 mg) at ambient temperature. The mixture was heated at 80° C. for 4 hours. After cooling, the reaction mixture was diluted with EtOAc (50 ml) and washed with water (30 ml) and brine (2×30 ml). The organic layer was dried over MgSO4 and filtered. Evaporation gave a residue (410 mg) which was triturated with n-hexane (2 ml)—EtOAc (2 drops) to give ethyl 4-{[2-ethoxy-4-methyl-1-({4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)-1H-benzimidazol-6-yl]oxy}butanoate (250 mg) as crude crystals.
MS: 562 (M+1).
To a solution of ethyl 4-(4-amino-3-methyl-5-nitrophenoxy)butanoate (350 mg) in DMF (3.5 ml) were added 4-(dimethylamino)pyridine (DMAP) (30 mg) and propanoyl chloride (138 mg) at ambient temperature. After stirring for 14 hours, the reaction mixture was diluted with EtOAc (50 ml), and washed with 1 N-HCl (2×30 ml), saturated NaHCO3 (2×30 ml), and brine (20 ml). The organic layer was dried over MgSO4 and evaporated to give ethyl 4-[3-methyl-5-nitro-4-(propionylamino)phenoxy]butanoate (411 mg) as pale yellow crystals.
NMR(DMSO-d6,δ): 1.06 (3H, t, J=7.5 Hz), 1.18 (3H, t, J=7.2 Hz), 1.8-2.1 (2H, m), 2.22 (3H, s), 2.28 (2H, q, J=7.5 Hz), 2.45 (2H, t, J=7.2 Hz), 4.0-4.2 (4H, m), 7.20 (1H, d, J=2.7 Hz), 7.26 (1H, d, J=2.7 Hz), 9.54 (1H, br s).
MS: 361 (M+Na).
To a solution of ethyl 4-[3-methyl-5-nitro-4-(propionylamino)phenoxy]butanoate (410 mg) in a mixture of EtOH (4.1 ml) and ACOH (4.1 ml) was added iron powder (338 mg) at ambient temperature. The mixture was heated at 110° C. for 1 hour. The reaction mixture was evaporated, added saturated NaHCO3 (40 ml), and extracted with EtOAc (2×30 ml). The combined organic extracts were washed with saturated NaHCO3 (30 ml) and brine (30 ml). The organic layer was dried over MgSO4, decolored (activated carbon), and evaporated to give ethyl 4-[(2-ethyl-4-methyl-1H-benzimidazol-6-yl)oxy]butanoate (341 mg) as an oil.
NMR(DMSO-d6,δ): 1.18 (3H, t, J=7.1 Hz), 1.29 (3H, t, J=7.5 Hz), 1.8-2.1 (2H, m), 2.3-2.5 (5H, m), 2.77 (2H, q, J=7.5 Hz), 3.95 (2H, q, J=6.2 Hz), 4.07 (2H, q, J=7.1 Hz), 6.54 (1H, br s), 6.77 (1H, br s), 11.90 (1H, br s).
MS: 291 (M+1).
Ethyl 4-{[1-(2,4-dichlorobenzyl)-2-ethyl-4-methyl-1H-benzimidazol-6-yl]oxy}butanoate (181 mg) was synthesized from ethyl 4-[(2-ethyl-4-methyl-1H-benzimidazol-6-yl)oxy]butanoate (165 mg) in a manner similar to that described in Preparation Example 38.
NMR(DMSO-d6,δ): 1.0-1.3 (6H, m), 1.8-2.0 (2H, m), 2.3-2.5 (5H, m), 2.70 (2H, q, J=7.4 Hz), 3.90 (2H, t, J=6.3 Hz), 4.04 (2H, q, J=7.1 Hz), 5.45 (2H, br s), 6.36 (1H, d, J=8.4 Hz), 6.61 (1H, d, J=1.7 Hz), 6.79 (1H, d, J=1.7 Hz), 7.31 (1H, dd, J=2.1 Hz, 8.4 Hz), 7.72 (1H, d, J=2.1 Hz).
MS: 449 (M+1).
Ethyl 4-{3-methyl-5-nitro-4-[(trifluoroacetyl)amino]phenoxy}butanoate (548 mg) was synthesized from ethyl 4-(4-amino-3-methyl-5-nitrophenoxy)butanoate (400 mg) in a manner similar to that described in Preparation Example 71 except that trifluoroacetic anhydride (357 mg) was used instead of propanoyl chloride.
NMR(DMSO-d6,δ): 1.18 (3H, t, J=7.1 Hz), 1.8-2.1 (2H, m), 2.24 (3H, s), 2.47 (2H, t, J=7.2 Hz), 4.0-4.2 (4H, m), 7.32 (1H, d, J=2.8 Hz), 7.43 (1H, d, J=2.8 Hz), 11.23 (1H, br s).
MS: 401 (M+Na).
Ethyl 4-{[4-methyl-2-(trifluoromethyl)-1H-benzimidazol-6-yl]oxy}butanoate (461 mg) was synthesized from ethyl 4-{3-methyl-5-nitro-4-[(trifluoroacetyl)amino]phenoxy}butanoate (533 mg) in a manner similar to that described in Preparation Example 72.
NMR(DMSO-d6,δ): 1.18 (3H, t, J=7.1 Hz), 1.9-2.1 (2H, m), 2.3-2.6 (5H, m), 3.9-4.2 (4H, m), 6.80 (1H, br s), 6.90 (1H, br s), 13.63 (1H, br s).
MS: 353 (M+Na).
Ethyl 4-{[1-(2,4-dichlorobenzyl)-4-methyl-2-(trifluoromethyl)-1H-benzimidazol-6-yl]oxy}butanoate (237 mg) was synthesized from ethyl 4-{[4-methyl-2-(trifluoromethyl)-1H-benzimidazol-6-yl]oxy}butanoate (225 mg) in a manner similar to that described in Preparation Example 38.
NMR(DMSO-d6,δ): 1.16 (3H, t, J=7.1 Hz), 1.8-2.1 (2H, m), 2.44 (2H, t, J=7.1 Hz), 2.55 (3H, s), 3.9-4.2 (4H, m), 5.68 (2H, br s), 6.36 (1H, d, J=8.4 Hz), 6.86 (1H, d, J=1.7 Hz), 7.08 (1H, d, J=1.7 Hz), 7.32 (1H, dd, J=2.1 Hz, 8.4 Hz), 7.75 (1H, d, J=2.1 Hz).
MS: 489 (M+1).
To a solution of ethyl 4-(3,4-diamino-5-methylphenoxy)butanoate (442 mg) in DMF (2.2 ml) was added 1-(1H-imidazol-1-ylcarbothioyl)-1H-imidazole (375 mg) at ambient temperature. After stirring for 19 hours, to the reaction mixture was added water (4 ml) dropwise and the mixture was stirred for 1 hour. The precipitates were collected by filtration and washed with water and MeOH (1 ml) to give ethyl 4-[(7-methyl-2-thioxo-2,3-dihydro-1H-benzimidazol-5-yl)oxy]butanoate (447 mg) as pale brown crystals.
NMR(DMSO-d6,δ): 1.18 (3H, t, J=7.1 Hz), 1.8-2.1 (2H, m), 2.32 (3H, s), 2.44 (2H, t, J=7.2 Hz), 3.93 (2H, t, J=6.3 Hz), 4.07 (2H, q, J=7.1 Hz), 6.47 (1H, d, J=1.8 Hz), 6.54 (1H, d, J=1.8 Hz), 12.35 (1H, br s), 12.46 (1H, br s).
MS: 317 (M+Na).
To a mixture of N-(4-hydroxy-2-methyl-6-nitrophenyl)acetamide (215 mg), ethyl 4-bromo-2,2-dimethylbutanoate (251 mg) and DMF (1 ml) was added K2CO3 (170 mg) at ambient temperature. After stirring for 6 hours at 60° C., the reaction mixture was diluted with EtOAc (30 ml) and washed with water (20 ml), 1 N-NaOH (2×20 ml), and brine (20 ml). The organic layer was dried over MgSO4 and filtered. Evaporation gave a residue (260 mg) which was triturated with EtOAc (0.5 ml)—n-hexane (1 ml) to give ethyl 4-[4-(acetylamino)-3-methyl-5-nitrophenoxy]-2,2-dimethylbutanoate (171 mg) as pale yellow crystals.
NMR(DMSO-d6,δ): 1.16 (3H, t, J=7.1 Hz), 1.19 (6H, s), 1.9-2.1 (5H, m), 2.22 (3H, s), 3.9-4.2 (4H, m), 7.15 (1H, d, J=2.8 Hz), 7.23 (1H, d, J=2.8 Hz), 9.62 (1H, br s).
MS: 375 (M+Na).
To a solution of ethyl 4-[4-(acetylamino)-3-methyl-5-nitrophenoxy]-2,2-dimethylbutanoate (2.51 g) in a mixture of EtOH (25 ml) and AcOH (25 ml) was added iron powder (1.19 g) at ambient temperature. The mixture was heated at 110° C. for 1 hour. After cooling, the reaction mixture was evaporated, saturated NaHCO3 (150 ml) added thereto, and the mixture was extracted with EtOAc (3×100 ml). The combined organic extracts were washed with saturated NaHCO3 (100 ml) and brine (100 ml). The organic layer was dried over MgSO4, decolored (activated carbon), and evaporated to give ethyl 4-[(2,4-dimethyl-1H-benzimidazol-6-yl)oxy]-2,2-dimethylbutanoate (1.46 g) as a yellow oil.
NMR(DMSO-d6,δ): 1.17 (3H, t, J=7.0 Hz), 1.19 (6H, s), 1.97 (2H, t, J=6.7 Hz), 2.3-2.5 (6H, m), 3.94 (2H, t, J=6.7 Hz), 4.07 (2H, q, J=7.0 Hz), 6.48 (1H, br s), 6.73 (1H, br s), 11.92 (1H, br s).
MS: 305 (M+1).
To a mixture of ethyl 4-[(2,4-dimethyl-1H-benzimidazol-6-yl)oxy]-2,2-dimethylbutanoate (250 mg), K2CO3 (159 mg) and DMF (1.2 ml) was added 2,4-dichloro-1-(chloromethyl)benzene (209 mg) at ambient temperature. The mixture was heated at 90° C. for 3 hours. After cooling, the reaction mixture was diluted with EtOAc (50 ml) and washed with water (20 ml) and brine (2×50 ml). The organic layer was dried over MgSO4, decolored (activated carbon), and evaporated-to give ethyl 4-{[1-(2,4-dichlorobenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]oxy}-2,2-dimethylbutanoate (430 mg) as a crude oil.
Ethyl 4-({1-[2-chloro-4-(pentyloxy)benzyl]-2,4-dimethyl-1H-benzimidazol-6-yl}oxy)-2,2-dimethylbutanoate was synthesized from ethyl 4-[(2,4-dimethyl-1H-benzimidazol-6-yl)oxy]-2,2-dimethylbutanoate (250 mg) in a manner similar to that described in Preparation Example 80 except that 1-(bromomethyl)-2-chloro-4-(pentyloxy)benzene (335 mg) was used instead of 2,4-dichloro-1-(chloromethyl)benzene.
To a mixture of ethyl 4-[(2,4-dimethyl-1H-benzimidazol-6-yl)oxy]-2,2-dimethylbutanoate (200 mg), 3-chloro-2-(chloromethyl)-5-(trifluoromethyl)pyridine (212 mg), K2CO3 (136 mg) and DMF (1 ml) was added NaI (49 mg) at ambient temperature. The mixture was heated at 90° C. for 2 hours. After cooling, the reaction mixture was diluted with EtOAc (50 ml) and washed with water (20 ml) and brine (2×50 ml). The organic layer was dried over MgSO4, decolored (activated carbon), and filtered. Evaporation gave a residue (348 mg) which was triturated with EtOAc (1 ml)—n-hexane (5 ml) to give ethyl 4-[(1-{[3-chloro-5-(trifluoromethyl)-2-pyridinyl]methyl}-2,4-dimethyl-1H-benzimidazol-6-yl)oxy]-2,2-dimethylbutanoate (140 mg) as white crystals.
NMR(DMSO-d6,δ): 1.10 (3H, t, J=7.1 Hz), 1.15 (6H, s), 1.92 (2H, t, J=6.6 Hz), 2.39 (3H, s), 2.44 (3H, s), 3.88 (2H, t, J=6.6 Hz), 4.02 (2H, q, J=7.1 Hz), 5.70 (2H, br s), 6.51 (1H, d, J=1.8 Hz), 6.71 (1H, d, J=1.8 Hz), 8.56 (1H, br s), 8.77 (1H, br s).
MS: 498 (M+1).
2,5-Dichlorobenzyl methanesulfonate was synthesized from (2,5-dichlorophenyl)methanol (354 mg) in a manner similar to that described in Preparation Example 204.
A mixture of ethyl 4-[(2-ethoxy-4-methyl-1H-benzimidazol-6-yl)oxy]butanoate (200 mg), 3-chloro-2-(chloromethyl)-5-(trifluoromethyl)pyridine (165 mg), NaI (98 mg) and K2CO3 (108 mg) in N,N-dimethylformamide (DMF) (2 mL) was stirred for 4 hours at room temperature. The mixture was then diluted with EtOAc (10 mL) and poured into water (20 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2×10 mL), the combined organic layers were washed with brine (20 mL), dried (Na2SO4), and concentrated. Purification of the residue by column chromatography (silica gel 20g, EtOAc/n-hexane=1/4) afforded 178 mg of ethyl 4-[(1-{[3-chloro-5-(trifluoromethyl)-2-pyridinyl]methyl}-2-ethoxy-4-methyl-1H-benzimidazol-6-yl)oxy]butanoate as a yellow oil.
NMR(200 MHz,DMSO-d6,δ): 1.15 (3H, t, J=7.1 Hz), 1.25 (3H, t, J=7.0 Hz), 1.87-1.99 (2H, m), 2.40 (3H, s), 2.42 (2H, t, J=7.4 Hz), 3.88 (2H, t, J=6.3 Hz), 4.08 (2H, q, J=7.1 Hz), 4.44 (2H, q, J=7.0 Hz), 5.48 (2H, s), 6.51 (1H, d, J=2.0 Hz), 6.73 (1H, d, J=2.0 Hz), 8.53 (1H, s), 8.90 (1H, s).
MS: 522 (M+Na).
To a 0° C. suspension of NaH (5.82 g, 60% oil dispersion), previously washed with n-hexane, in DMF (500 mL) was added a solution of ethyl 4-(4-amino-3-nitrophenoxy)butanoate (15 g) in DMF (50 mL). After 30 minutes at room temperature, the solution was treated with a solution of di-tert-butyl dicarbonate (14.1 ml) in DMF (30 mL). The resultant mixture was stirred for 3 hours at room temperature before the reaction was quenched by addition of water (200 mL). The mixture was extracted with EtOAc (3×100 mL). The combined organic extracts were washed with brine (200 mL), dried (Na2SO4), and filtered, and the filtrates were concentrated under reduced pressure. Purification by chromatography on silica gel (EtOAc/n-hexane 1/1) gave ethyl 4-{4-[(tert-butoxycarbonyl)amino]-3-nitrophenoxy}butanoate (8.4 g) as a gray oil which solidified upon standing.
NMR(200 MHz,DMSO-d6,δ): 1.18 (3H, t, J=7.2 Hz), 1.42 (9H, s), 1.93-2.05 (2H, m), 2.45 (2H, t, J=7.2 Hz), 4.03 (2H, t, J=7.0 Hz), 4.06 (2H, q, J=7.2 Hz), 7.25 (1H, dd, J=2.7 Hz, 8.8 Hz), 7.43 (1H, d, J=2.7 Hz), 7.45 (1H, d, J=8.8 Hz), 9.30 (1H, s).
MS: 391 (M+Na).
To a solution of ethyl 4-{4-[(tert-butoxycarbonyl)amino]-3-nitrophenoxy}butanoate (2.95 g) in EtOH (60 mL) was added palladium on carbon (10%, 50% wet, 1.7 g) at room temperature, and the resultant mixture was hydrogenated under atmospheric pressure of hydrogen for 3 hours. The catalyst was removed by filtration. The filtrate was evaporated to give ethyl 4-{3-amino-4-[(tert-butoxycarbonyl)amino]phenoxy}butanoate (2.66 g).
NMR(200 MHz,DMSO-d6,δ): 1.14 (3H, t, J=7.1 Hz), 1.46 (9H, s), 1.88-1.99 (2H, m), 2.42 (2H, t, J=7.2 Hz), 3.85 (2H, t, J=6.2 Hz), 4.06 (2H, q, J=7.1 Hz), 5.24 (2H, s), 6.08 (1H, dd, J=2.8 Hz, 8.6 Hz), 6.24 (1H, d, J=2.8 Hz), 6.94 (1H, d, J=8.6 Hz), 8.08 (1H, s).
MS: 361 (M+Na).
A mixture of ethyl 4-{3-amino-4-[(tert-butoxycarbonyl)amino]phenoxy}butanoate (658 mg), 2,4-dichlorobenzylchloride (0.3 mL) and K2CO3 (198 mg) in DMF (7 mL) was stirred for 1.5 hours at room temperature. The mixture was heated at 80° C. for 1 hour and 90° C. for 2 hours. NaI (20 mg), K2CO3 (198 mg) and 2,4-dichlorobenzylchloride (0.3 mL) were added at room temperature, and the resulting suspension was heated at 80° C. for 3 hours. After cooling to room temperature, the reaction mixture was poured into a saturated NH4Cl solution (30 mL). The phases were separated and the aqueous layer was extracted with EtOAc (2×15 mL). The combined extracts were washed with brine (20 mL), dried over Na2SO4, and concentrated to provide the crude ester (840 mg) Purification of the product by column chromatography (EtOAc/n-hexane 1/8) provided ethyl 4-{4-[(tert-butoxycarbonyl)amino]-3-[(2,4-dichlorobenzyl)amino]phenoxy}butanoate (502 mg).
NMR(200 MHz,DMSO-d6,δ): 1.13 (3H, t, J=7.1 Hz), 1.44 (9H, s), 1.86-1.99 (2H, m), 2.36 (2H, t, J=7.3 Hz), 3.82 (2H, t, J=6.3 Hz), 4.02 (2H, q, J=7.1 Hz), 4.34 (2H, d, J=5.9 Hz), 5.64 (1H, t, J=5.9 Hz), 5.82 (1H, d, J=2.5 Hz), 6.12 (1H, dd, J=2.5 Hz, 8.6 Hz), 6.96 (1H, d, J=8.6 Hz), 7.38 (1H, s), 7.39 (1H, s), 7.62 (1H, s), 8.15 (1H, s).
MS: 497 (M+1).
To a solution of ethyl 4-{4-[(tert-butoxycarbonyl)amino]-3-[(2,4-dichlorobenzyl)amino]phenoxy}butanoate (502 mg) in EtOH (3.3 mL) was added hydrogen chloride, 4M solution in 1,4-dioxane (4N HCl in dioxane) (2.6 mL) at room temperature. The mixture was stirred at room temperature for 14 hours, and then concentrated in vacuo without external heating. The residue was dissolved in 5 mL of EtOAc, and neutralized with 1N NaOH. The phases were separated and the aqueous layer was extracted with EtOAc (2×10 mL). The combined organic extracts were washed with brine (10 mL), dried (Na2SO4), and concentrated. The residue was purified by column chromatography on silica gel (EtOAc/hexane 1/4) to afford ethyl 4-{4-amino-3-[(2,4-dichlorobenzyl)amino]phenoxy}butanoate (240 mg) as a pale brown solid.
NMR(200 MHz,DMSO-d6,δ): 1.15 (3H, t, J=7.2 Hz), 1.78-1.85 (2H, m), 2.34 (2H, t, J=7.3 Hz), 3.72 (2H, t, J=6.4 Hz), 4.02 (2H, q, J=7.2 Hz), 4.16 (2H, br), 4.31 (2H, d, J=5.8 Hz), 5.35 (1H, t, J=5.8 Hz), 5.76 (1H, d, J=2.6 Hz), 6.00 (1H, dd, J=2.6 Hz, 8.2 Hz), 6.48 (1H, d, J=8.2 Hz), 7.37 (1H, s), 7.38 (1H, d, J=1.9 Hz), 7.61 (1H, d, J=1.9 Hz).
MS: 397 (M+1).
A mixture of ethyl 4-{4-amino-3-[(2,4-dichlorobenzyl)amino]phenoxy}butanoate (236 mg), tetraethyl orthocarbonate (C(OEt)4) (0.62 ml) and acetic acid (AcOH) (0.044 mL) was heated at 80° C. for 1 hour. After cooling to room temperature, the mixture was evaporated. The residue was dissolved in EtOAc (5 mL) and washed with saturated aqueous sodium hydrogencarbonate (NaHCO3) solution (2×20 mL) and brine (20 mL). The organic layer was dried (Na2SO4), filtered and concentrated. The residue was triturated with hexane to give ethyl 4-{[1-(2,4-dichlorobenzyl)-2-ethoxy-1H-benzimidazol-6-yl]oxy}butanoate (170 mg) as pale red crystals.
NMR(200 MHz,DMSO-d6,δ): 1.16 (3H, t, J=7.2 Hz), 1.31 (3H, t, J=7.0 Hz), 1.89-1.99 (2H, m), 2.43 (2H, t, J=7.2 Hz), 3.91 (2H, t, J=6.3 Hz), 4.04 (2H, q, J=7.2 Hz), 4.46 (2H, q, J=7.0 Hz), 5.25 (2H, s), 6.70 (1H, dd, J=2.4 Hz, 8.6 Hz), 6.80 (1H, d, J=8.4 Hz), 6.91 (1H, d, J=2.4 Hz), 7.30 (1H, d, J=8.6 Hz), 7.37 (1H, dd, J=2.2 Hz, 8.4 Hz), 7.69 (1H, d, J=2.2 Hz).
MS: 451 (M+1).
To a 0° C. suspension of NaH (184 mg, 60% oil dispersion) in DMF (10 mL) was added a solution of ethyl 4-(4-amino-3-methyl-5-nitrophenoxy)butanoate (0.5 g) in DMF (10 mL). After 30 minutes at room temperature, the solution was treated with di-tert-butyl dicarbonate (0.9 ml). The resultant mixture was stirred for 3 hours at room temperature before the reaction was quenched by addition of water (20 mL). The mixture was extracted with EtOAc (3×20 mL). The combined extracts were washed with brine (20 mL), dried over Na2SO4 and concentrated under reduced pressure. Purification of the residue by filtration through a pad of silica gel (EtOAc/hexane 1/2) afforded ethyl 4-{4-[bis(tert-butoxycarbonyl)amino]-3-methyl-5-nitrophenoxy}butanoate (1.2 g) as a dark yellow oil.
NMR(200 MHz,DMSO-d6,δ): 1.14 (3H, t, J=7.2 Hz), 1.47 (18H, s), 1.95-2.02 (2H, m), 2.18 (3H, s), 2.46 (2H, t, J=7.2 Hz), 4.03 (2H, t, J=7.1 Hz), 4.09 (2H, q, J=7.2 Hz), 7.29 (1H, d, J=2.6 Hz), 7.43 (1H, d, J=2.6 Hz).
MS: 505 (M+Na)
To a solution of ethyl 4-{4-[bis(tert-butoxycarbonyl)amino]-3-methyl-5-nitrophenoxy}butanoate (834 mg) in EtOH (16 mL) was added palladium on carbon (10%, 50% wet, 300 mg) at room temperature, and the resultant mixture was hydrogenated under atmospheric pressure of hydrogen for 3 hours. The catalyst was removed by filtration. The filtrate was evaporated to give ethyl 4-{3-amino-4-[bis(tert-butoxycarbonyl)amino]-5-methylphenoxy}butanoate (534 mg).
NMR(200 MHz,DMSO-d6,δ): 1.18 (3H, t, J=7.2 Hz), 1.36 (18H, s), 1.85-1.99 (5H, m), 2.43 (2H, t, J=7.2 Hz), 3.86 (2H, t, J=6.3 Hz), 4.03 (2H, q, J=7.2 Hz), 4.73 (2H, s), 6.00 (1H, d, J=2.6 Hz), 6.13 (1H, d, J=2.6 Hz).
MS: 475 (M+1).
A mixture of ethyl 4-{3-amino-4-[bis(tert-butoxycarbonyl)amino]-5-methylphenoxy}butanoate (528 mg), 2,4-dichlorobenzylchloride (251 mg), NaI (17.5 mg) and K2CO3 (194 mg) in DMF (5 mL) was heated at 80° C. for 5 hours. After cooling to room temperature, the reaction mixture was poured into a saturated NH4Cl solution (30 mL). The phases were separated and the aqueous layer was extracted with 2×15 mL of EtOAc. The combined extracts were washed with brine (20 mL), dried over Na2SO4, and concentrated to provide the crude ester. Purification of the product by column chromatography (EtOAc/n-hexane 1/4) provided ethyl 4-{4-[bis(tert-butoxycarbonyl)amino]-3-[(2,4-dichlorobenzyl)amino]-5-methylphenoxy}butanoate (480 mg), which was used in the next step without further purification.
To a solution of ethyl 4-{4-[bis(tert-butoxycarbonyl)amino]-3-[(2,4-dichlorobenzyl)amino]-5-methylphenoxy}butanoate (560 mg) in EtOH (4 mL) was added 4N HCl in dioxane (2.3 mL) at room temperature. The mixture was stirred at room temperature for 14 hours, and then concentrated in vacuo without external heating. The residue was dissolved in 5 mL of EtOAc, and neutralized with 1N NaOH. The phases were separated and the aqueous layer was extracted with EtOAc (2×10 mL). The combined organic extracts were washed with brine (10 mL), dried (Na2SO4), and concentrated. The residue was purified by column chromatography on silica gel (EtOAc/hexane 1/4) to afford ethyl 4-{4-amino-3-[(2,4-dichlorobenzyl)amino]-5-methylphenoxy}butanoate (206 mg) as a pale brown solid.
NMR(200 MHz,DMSO-d6,δ): 4.30(2H, d, J=5.8 Hz), 5.43 (1H, t, J=5.8 Hz), 5.67 (1H, d, J=2.5 Hz), 5.96 (1H, d, J=2.5 Hz), 7.33 (1H, d, J=8.4 Hz), 7.38 (1H, dd, J=1.8 Hz, 8.4 Hz), 7.61 (1H, d, J=1.8 Hz).
MS: 411 (M+1).
To a solution of ethyl 4-{4-amino-3-[(2,4-dichlorobenzyl)amino]-5-methylphenoxy}butanoate (200 mg) in EtOH (2 mL) was added methyl isothiocyanate (46 mg) at room temperature. The resulting solution was heated at 50° C. for 2 hours. After cooling to room temperature, methyl isothiocyanate (80 mg) was added. The resulting solution was heated at 60° C. for 2 hours. After cooling, to the reaction mixture was added dropwise water (10 mL). The mixture was extracted with EtOAc (2×10 mL). The combined extracts were washed with brine (10 mL), dried over Na2SO4. Removal of the solvent proceeded the crude ethyl 4-(3-[(2,4-dichlorobenzyl)amino]-5-methyl-4-{[(methylamino)carbonothioyl]amino}phenoxy)butanoate (252 mg), which was used in the next step without further purification.
To a solution of ethyl 4-(3-[(2,4-dichlorobenzyl)amino]-5-methyl-4-{[(methylamino)carbonothioyl]amino}phenoxy)butanoate (252 mg) in toluene (5 ml) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (WSCD.HCl) (150 mg) at ambient temperature. The mixture was heated at 110° C. for 1 hour. After cooling to room temperature, the reaction mixture was diluted with EtOAc (20 ml), and washed with saturated aq NaHCO3 (2×20 ml), saturated aqueous NH4Cl (2×20 ml), and brine (20 ml). The organic layer was dried (Na2SO4) and filtered. Evaporation gave a residue (606 mg) which was triturated with EtOAc (1 ml)—n-hexane (3 ml) to give ethyl 4-{[1-(2,4-dichlorobenzyl)-4-methyl-2-(methylamino)-1H-benzimidazol-6-yl]oxy}butanoate (156 mg) as white crystals.
NMR(200 MHz,DMSO-d6,δ): 1.14 (3H, t, J=7.1 Hz), 1.85-1.95 (2H, m), 2.38 (3H, s), 2.40 (2H, t, J=7.0 Hz), 2.86 (3H, d, J=4.6 Hz), 3.84 (2H, t, J=6.3 Hz), 6.03 (2H, q, J=7.1 Hz), 5.21 (2H, s), 6.35 (1H, d, J=8.4 Hz), 6.42-6.52 (3H, m), 7.31 (1H, dd, J=2.1 Hz, 8.3 Hz), 7.69 (1H, d, J=2.1 Hz).
MS: 450 (M+1).
A mixture of ethyl 4-[(7-methyl-2-thioxo-2,3-dihydro-1H-benzimidazol-5-yl)oxy]butanoate (350 mg), iodoethane (EtI) (0.191 mL), diisopropylethylamine (0.414 mL) and DMF (3.5 mL) was stirred overnight at room temperature. The mixture was then diluted with EtOAc (15 mL) and poured into water (20 mL). The phases were separated and the aqueous layer was extracted with EtOAc (2×10 mL). The combined extracts were washed with brine (20 mL), dried over Na2SO4, and concentrated to provide the crude ester. Purification by chromatography on silica gel (EtOAc/n-hexane 1/1) gave ethyl 4-{[2-(ethylthio)-4-methyl-1H-benzimidazol-6-yl]oxy}butanoate (434 mg) as a dark brown oil.
NMR(200 MHz,DMSO-d6,δ): 1.18 (3H, t, J=7.1 Hz), 1.36 (3H, t, J=7.3 Hz), 1.94-1.99 (2H, m), 2.46 (2H, t, J=7.3 Hz), 2.51 (3H, S), 3.22 (2H, q, J=7.3 Hz), 3.94 (2H, t, J=6.3 Hz), 4.07 (2H, q, J=7.1 Hz), 6.55 (1H, s), 6.7 (1H, br), 12.2 (1H, br).
MS: 323 (M+1).
A mixture of ethyl 4-{[2-(ethylthio)-4-methyl-1H-benzimidazol-6-yl]oxy}butanoate (384 mg), 2,4-dichlorobenzyl chloride (0.18 mL) and K2CO3 (198 mg) in DMF (4 mL) was stirred overnight at room temperature. The mixture was then diluted with EtOAc (10 mL) and poured into water (25 mL). The phases were separated and the aqueous layer was extracted with EtOAc (2×15 mL). The combined organic extracts were washed with brine (20 mL), dried over Na2SO4, and concentrated to provide the crude ester (840 mg). Purification of the product by column chromatography (EtOAc/n-hexane 1/6) provided ethyl 4-{[1-(2,4-dichlorobenzyl)-2-(ethylthio)-4-methyl-1H-benzimidazol-6-yl]oxy}butanoate (477 mg).
NMR(200 MHz,DMSO-d6,δ): 1.22 (3H, t, J=7.1 Hz), 1.39 (3H, t, J=7.3 Hz), 2.00-2.13 (2H, m), 2.46 (2H, t, J=7.2 Hz), 2.62 (3H, s), 3.29 (2H, q, J=7.3 Hz), 3.94 (2H, t, J=6.1 Hz), 4.12 (2H, q, J=7.1 Hz), 5.32 (2H, s), 6.40 (1H, d, J=2.2 Hz), 6.46 (1H, d, J=8.4 Hz), 6.67 (1H, d, J=2.2 Hz), 7.06 (1H, dd, J=2.0 Hz, 8.4 Hz), 7.45 (1H, d, J=2.0 Hz).
MS: 481 (M+1).
Ethyl 2-[4-(acetylamino)-3-methyl-5-nitrophenoxy]-2-methylpropanoate (1.49 g) was synthesized from N-(4-hydroxy-2-methyl-6-nitrophenyl)acetamide (1.0 g) in a manner similar to that described in Preparation Example 35 except that ethyl 2-bromo-2-methylpropanoate (1.39 g) was used instead of ethyl 4-bromobutanoate.
NMR(CDCl3,δ): 1.28 (3H, t, J=6.0 Hz), 1.62 (6H, s), 2.20 (3H, s), 2.28 (3H, s), 4.26 (2H, q, J=6.0 Hz), 7.02 (1H, d, J=1.0 Hz), 7.29 (1H, d, J=1.0 Hz), 8.02 (1H, br s).
MS: 347 (M+Na).
Ethyl 2-[(2,4-dimethyl-1H-benzimidazol-6-yl)oxy]-2-methylpropanoate (1.43 g) was synthesized from ethyl 2-[4-(acetylamino)-3-methyl-5-nitrophenoxy]-2-methylpropanoate (1.49 g) in a manner similar to that described in Preparation Example 72.
NMR(CDCl3,δ): 1.28 (3H, t, J=6.0 Hz), 1.56 (6H, s), 2.48 (3H, s), 2.57 (3H, s), 4.24 (2H, q, J=6.0 Hz), 6.66 (1H, br s), 6.84 (1H, br s).
MS: 276 (M+).
Ethyl 2-({1-[(3-chloro-1,1′-biphenyl-4-yl)methyl]-2,4-dimethyl-1H-benzimidazol-6-yl)oxy)-2-methylpropanoate (155 mg) was synthesized from ethyl 2-[(2,4-dimethyl-1H-benzimidazol-6-yl)oxy]-2-methylpropanoate (100 mg) in a manner similar to that described in Preparation Example 105 except that (3-chloro-1,1′-biphenyl-4-yl)methyl bromide (122 mg) was used instead of (3-methoxy-1,1′-biphenyl-4-yl)methyl chloride.
NMR(CDCl3,δ): 1.26 (3H, t, J=6.0 Hz), 1.52 (6H, s), 2.57 (3H, s), 2.62 (3H, s), 4.12 (2H, q, J=6.0 Hz), 5.33 (2H, s), 6.45-6.55 (2H, m), 6.68 (1H, br s), 7.22-7.57 (6H, m), 7.68 (1H, br s).
MS: 477 (M+).
Ethyl 2-({1-[2-chloro-4-(pentyloxy)benzyl]-2,4-dimethyl-1H-benzimidazol-6-yl}oxy)-2-methylpropanoate (142 mg) was synthesized from ethyl 2-[(2,4-dimethyl-1H-benzimidazol-6-yl)oxy]-2-methylpropanoate (100 mg) in a manner similar to that described in Preparation Example 105 except that 1-bromomethyl-2-chloro-4-(pentyloxy)benzene (158 mg) was used instead of (3-methoxy-1,1′-biphenyl-4-yl)methyl chloride.
NMR(CDCl3,δ): 0.90 (3H, t, J=6.0 Hz), 1.20 (3H, t, J=6.0 Hz), 1.26-1.48 (4H, m), 1.52 (6H, s), 1.65-1.87 (2H, m), 2.53 (3H, s), 2.61 (3H, s), 3.88 (2H, t, J=6.0 Hz), 4.12 (2H, q, J=6.0 Hz), 5.22 (2H, s), 6.37 (1H, d, J=8.0 Hz), 6.51 (1H, d, J=2.0 Hz), 6.60 (1H, dd, J=8.0 Hz, 2.0 Hz), 6.67 (1H, d, J=2.0 Hz), 6.97 (1H, d, J=2.0 Hz).
MS: 487 (M+).
Ethyl 4-({1-[(3-chloro-5-ethoxy-2-pyridinyl)methyl]-2,4-dimethyl-1H-benzimidazol-6-yl}oxy)butanoate (188 mg) was synthesized from ethyl 2-[(2,4-dimethyl-1H-benzimidazol-6-yl)oxy]butanoate (146 mg) in a manner similar to that described in Preparation Example 105 except that (3-chloro-5-ethoxy-2-pyridinyl)methyl methanesulfonate (140 mg) was used instead of (3-methoxy-1,1′-biphenyl-4-yl)methyl chloride.
NMR(CDCl3,δ): 1.23 (3H, t, J=6.0 Hz), 1.40 (3H, t, J=6.0 Hz), 2.00-2.18 (2H, m), 2.52 (2H, t, J=6.0 Hz), 2.58 (3H, s), 2.65 (3H, s), 3.90-4.20 (6H, m), 5.36 (2H, s), 6.63 (2H, s), 7.20 (1H, d, J=2.0 Hz), 8.08 (1H, d, J=2.0 Hz).
MS: 446 (M+).
Ethyl 4-({1-[2-chloro-4-(1,3-oxazol-2-yl)benzyl]-2,4-dimethyl-1H-benzimidazol-6-yl}oxy)butanoate (153 mg) was synthesized from ethyl 2-[(2,4-dimethyl-1H-benzimidazol-6-yl)oxy]butanoate (100 mg) in a manner similar to that described in Preparation Example 105 except that 1-bromomethyl-2-chloro-4-(1,3-oxazol-2-yl)benzene (108 mg) was used instead of (3-methoxy-1,1′-biphenyl-4-yl)methyl chloride.
NMR(DMSO-d6,δ): 1.13 (3H, t, J=6.0 Hz), 1.84-2.00 (2H, m), 2.40 (2H, t, J=6.0 Hz), 2.41 (3H, s), 2.51 (3H, s), 3.90 (2H, t, J=6.0 Hz), 4.02 (2H, q, J=6.0 Hz), 5.52 (2H, s), 6.50-6.62 (2H, d), 6.80 (1H, d, J=1.0 Hz), 7.40 (1H, s), 7.92 (1H, dd, J=8.0 Hz, 1.0 Hz), 8.05 (1H, d, J=1.0 Hz), 8.24 (1H, s).
MS: 468 (M+).
Ethyl 4-({1-[(2-chloro-6-phenyl-3-pyridinyl)methyl]-2,4-dimethyl-1H-benzimidazol-6-yl}oxy)butanoate (365 mg) was synthesized from ethyl 2-[(2,4-dimethyl-1H-benzimidazol-6-yl)oxy]butanoate (236 mg) in a manner similar to that described in Preparation Example 105 except that (2-chloro-6-phenyl-3-pyridinyl)methyl methanesulfonate (280 mg) was used instead of (3-methoxy-1,1′-biphenyl-4-yl)methyl chloride.
NMR(CDCl3,δ): 1.22 (3H, t, J=6.0 Hz), 2.00-2.18 (2H, m), 2.50 (2H, t, J=6.0 Hz), 2.56 (3H, s), 2.64 (3H, s), 3.97 (2H, t, J=6.0 Hz), 4.11 (2H, q, J=6.0 Hz), 5.34 (2H, s), 6.49 (1H, d, J=1.0 Hz), 6.72 (1H, d, J=1.0 Hz), 6.78 (1H, d, J=8.0 Hz), 7.39-7.52 (4H, m), 7.90-8.00 (2H, m).
MS: 478 (M+)
A mixture of ethyl 4-[(2,4-dimethyl-1H-benzimidazol-6-yl)oxy]butanoate (148 mg), (3-methoxy-1,1′-biphenyl-4-yl)methyl chloride (125 mg), sodium carbonate (222 mg) and N,N-dimethylformamide (DMF, 2 mL) was stirred at 80° C. for 7 hours. The mixture was partitoned between ethyl acetate and brine. The organic layer was washed with brine, dried over magnesium sulfate (MgSO4) and evaporated in vacuo. The residue was purified by preparative thin layer chromatography (p-TLC, ethyl acetate) to give ethyl 4-({1-[(3-methoxy-1,1′-biphenyl-4-yl)methyl]-2,4-dimethyl-1H-benzimidazol-6-yl}oxy)butanoate as a pale yellow oil (181 mg).
NMR(CDCl3,δ): 1.22 (3H, t, J=6.0 Hz), 2.00-2.18 (2H, m), 2.50 (2H, t, J=6.0 Hz), 2.57 (3H, s), 2.63 (3H, s), 3.97 (2H, t, J=6.0 Hz), 3.98 (3H, s), 4.12 (2H, q, J=6.0 Hz), 5.27 (2H, s), 6.52-6.72 (3H, m), 7.02 (1H, dd, J=8.0 Hz, 1.0 Hz), 7.10 (1H, d, J=1.0 Hz), 7.28-7.58 (5H, m).
MS: 473 (M+).
Ethyl 4-[(1-{4-[bis(tert-butoxycarbonyl)amino]-2-chlorobenzyl}-2,4-dimethyl-1H-benzimidazol-6-yl)oxy]butanoate (1.67 g) was synthesized from ethyl 2-[(2,4-dimethyl-1H-benzimidazol-6-yl)oxy]butanoate (10 g) in a manner similar to that described in Preparation Example 134.
NMR(DMSO-d6,δ): 1.15 (3H, t, J=7 Hz), 1.36 (18H, s), 1.8-2.0 (2H, m), 2.40 (3H, s), 2.4-2.6 (total 5H: 3H, s and 2H, t), 3.89 (2H, t, J=6 Hz), 4.04 (2H, q, J=7 Hz), 5.48 (2H, s), 6.45 (1H, d, J=8 Hz), 6.60 (1H, d, J=1 Hz), 6.78 (1H, d, J=2 Hz), 7.08 (1H, dd, J=2 Hz, 8 Hz), 7.47 (1H, d, J=2 Hz).
MS: 616 (M+H).
Ethyl 4-{[1-(4-amino-2-chlorobenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]oxy}butanoate (1.0 g) was synthesized from ethyl 4-[(1-(4-[bis(tert-butoxycarbonyl)amino]-2-chlorobenzyl}-2,4-dimethyl-1H-benzimidazol-6-yl)oxy]butanoate (1.67 g) in a manner similar to that described in Preparation Example 135.
NMR(DMSO-d6,δ): 1.16 (3H, t, J=7 Hz), 1.8-2.0 (2H, m), 2.40 (3H, s), 2.44 (3H, s), 2.4-2.6 (2H, t), 3.90 (2H, t, J=6 Hz), 4.05 (2H, q, J=7 Hz), 5.23 (2H, s), 5.39 (2H, br s), 6.3-6.5 (2H, m), 6.57 (1H, d, J=1 Hz), 6.65 (1H, d, J=2 Hz), 6.72 (1H, d, J=2 Hz).
MS: 415 (M+H).
Ethyl 4-({1-[2-chloro-4-(dimethylamino)benzyl]-2,4-dimethyl-1H-benzimidazol-6-yl}oxy)butanoate (0.18 g) was synthesized from ethyl 4-{[1-(4-amino-2-chlorobenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]oxy}butanoate (600 mg) in a manner similar to that described in Preparation Example 136.
NMR(DMSO-d6,δ): 1.15 (3H, t, J=7 Hz), 1.8-2.0 (2H, m), 2.40 (3H, s), 2.42 (2H, t, J=7 Hz), 2.44 (3H, s), 2.85 (6H, s), 3.90 (2H, t, J=6 Hz), 4.04 (2H, q, J=7 Hz), 5.30 (2H, s), 6.43 (1H, d, J=8 Hz), 6.5-6.6 (2H, m), 6.72 (1H, d, J=2 Hz), 6.75 (1H, d , J=2 Hz).
MS: 444 (M+H).
A mixture of N-(4-hydroxy-2-nitrophenyl)acetamide (5.0 g), ethyl 4-bromobutanoate (5.47 g), potassium carbonate (3.88 g) and N,N-dimethylformamide (50 mL) was stirred at ambient temperature for 2 days. The mixture was poured into water and extracted twice with ethyl acetate. The extracts were combined, washed with 1-N sodium hydroxide and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The resulting solid was suspended in diisopropyl ether (150 mL). The suspension was stirred at ambient temperature for an hour and filtered to give ethyl 4-[4-(acetylamino)-3-nitrophenoxy]butanoate (6.8 g) as a yellow solid.
NMR(DMSO-d6,δ): 1.17 (3H, t, J=7 Hz), 1.9-2.0 (2H, m), 2.01 (3H, s), 2.45 (2H, t, J=6 Hz), 4.06 (2H, t, J=6 Hz), 4.06 (2H, q, J=7 Hz), 7.26 (1H, dd, J=3 Hz, 9 Hz), 7.42 (1H, d J=3 Hz), 7.44 (1H, d , J=9 Hz), 10.04 (1H, br s).
MS: 333 (M+Na)
A mixture of ethyl 4-[4-(acetylamino)-3-nitrophenoxy]butanoate (8.0 g), 10% palladium on carbon (50% wet; 0.80 g), tetrahydrofuran (180 mL) and ethanol (180 mL) was stirred under 1 atmosphere of hydrogen at ambient temperature for 3 hours. The catalyst was filtered off and washed with ethanol. The filtrate and washings were concentrated in vacuo. The residue was dissolved in ethanol (20 mL) and treated with 4 N hydrogen chloride/1,4-dioxane (8 mL). The resulting suspension was stirred at ambient temperature for half an hour and diluted with diisopropyl ether (80 mL). After stirring for additional half an hour, the suspension was filtered to give ethyl 4-[4-(acetylamino)-3-aminophenoxy]butanoate hydrochloride (7.2 g) as a white solid.
To an ice-cooled solution of 3-methoxy-1,1′-biphenyl-4-carbaldehyde (940 mg) in methanol (9.4 mL) and tetrahydrofuran (THF, 9.4 mL) was added sodium borohydride (168 mg). The mixture was stirred at the same temperature for 40 minutes. The reaction mixture was partitioned between ethyl acetate and brine. The organic layer was separated, dried over magnesium sulfate (MgSO4) and evaporated in vacuo to give (3-methoxy-1,1′-biphenyl-4-yl)methanol (985 mg) as a colorless oil.
NMR(CDCl3,δ): 2.30 (1H, t, J=6.4 Hz), 3.93 (3H, s), 4.73 (2H, d, J=6.4 Hz), 7.09 (1H, d, J=1.4 Hz), 7.19 (1H, dd, J=8.0 Hz, 1.4 Hz), 7.22-7.61 (6H, m).
MS: 237 (M+Na).
To a solution of (3-methoxy-1,1′-biphenyl-4-yl)methanol (500 mg) in toluene (5 mL) was added methanesulfonyl chloride (294 mg), then to the mixture was added triethylamine (260 mg) dropwise with cooling in an ice bath. And the mixture was stirred at ambient temperature for 1 hour. The reaction mixture was partitioned between ethyl acetate and water, and the organic layer was separated, washed with saturated NaHCO3 and brine, dried over MgSO4 and concentrated in vacuo to give 4-(chloromethyl)-1,1′-biphenyl-3-yl methyl ether (694 mg) as a pale yellow oil, which was used without further purification.
1H-NMR(CDCl3,δ): 3.95 (3H, s), 4.71 (2H, s), 7.09 (1H, d, J=2 Hz), 7.17 (1H, dd, J=2.8 Hz), 7.34-7.48 (4H, m), 7.55-7.61 (2H, m).
To a solution of oxazole (800 mg) in tetrahydrofuran (60 mL) was added n-butyllithium (1.59 M solution in hexanes, 8.01 mL) at −70° C. After stirring for 30 minutes, the mixture was added zinc chloride (1.0 M solution in diethyl ether, 34.7 mL). The reaction mixture was warmed to 0° C., and added a solution of 2-chloro-4-iodotoluene (2.92 g) in tetrahydrofuran (40 mL) and tetrakis (triphenylphosphine) palladium(0) (1.34 g). The resulting mixture was heated to reflux for 7 hours. After cooling, the final reaction mixture was evaporated in vacuo. The residue was partitioned between ethyl acetate with H2O. The organic layer was separated, washed with brine, dried over MgSO4, filtered, and evaporated in vacuo. The crude product was purified by column chromatography on silica gel (eluted with hexane-ethyl acetate=15-1 to 10-1) to give 2-(3-chloro-4-methylphenyl)-1,3-oxazole (843 mg).
1H-NMR(CDCl3,δ): 2.43 (3H, s), 7.23 (1H, s), 7.32 (1H, d, J=8 Hz), 7.70 (1H, s), 7.83 (1H, dd, J=2 Hz, 8 Hz), 8.03 (1H, d, J=2 Hz).
MS (ESI): m/z 194 (M+1)
To a mixture of 2-(3-chloro-4-methylphenyl)-1,3-oxazole (200 mg) in carbon tetrachloride (3.1 mL) were added N-bromosuccinimide (184 mg) and V-70 (15.9 mg). The mixture was stirred at room temperature for 1 hour, at 60° C. for 2 hours and at 80° C. for 2 hours. To the reaction mixture were added N-bromosuccinimide (92 mg) and V-70 (15.9 mg). The resulting mixture was stirred at 80° C. for 1 hour. After cooling, to the final reaction mixture was added hexane. A resulting precipitate was filtered out, and the filtrate was evaporated in vacuo to give 2-[4-(bromomethyl)-3-chlorophenyl]-1,3-oxazole (346 mg).
1H-NMR(CDCl3,δ): 4.63 (2H, s), 7.27 (1H, s), 7.55 (1H, d, J=8 Hz), 7.75 (1H, s), 7.94 (1H, dd, J=2.8 Hz), 8.10 (1H, d, J=2 Hz).
MS (ESI): m/z 272 (M+1).
Methyl 3-[({1-[2-chloro-4-(pentyloxy)benzyl]-2,4-dimethyl-1H-benzimidazol-6-yl}oxy)methyl]benzoate (50 mg) was synthesized from 1-[2-chloro-4-(pentyloxy)benzyl]-2,4-dimethyl-1H-benzimidazol-6-ol (50 mg) in a manner similar to that described in Preparation Example 33 except that methyl 3-(bromomethyl)benzoate (30.7 mg) was used instead of 4-bromobutanoate.
NMR(DMSO-d6,δ): 0.8-1.0 (3H, m), 1.2-1.5 (4H, m), 1.5-1.8 (2H, m), 2.40 (3H, s), 2.47 (3H, s), 3.85 (3H, s), 3.93 (2H, t, J=6.4 Hz), 5.12 (2H, br s), 5.36 (2H, br s), 6.41 (1H, d, J=8.7 Hz), 6.72 (1H, d, J=2.0 Hz), 6.78 (1H, dd, J=2.5 Hz, 8.6 Hz), 6.87 (1H, d, J=2.0 Hz), 7.08 (1H, d, J=2.5 Hz), 7.51 (1H, t, J=7.7 Hz), 7.68 (1H, d, J=7.7 Hz), 7.89 (1H, d, J=7.7 Hz), 8.01 (1H, br s).
MS: 521 (M+1).
A two-phase mixture of 4-amino-3-nitrophenol (1.0 g), methyl 2-(bromomethyl)benzoate (1.78 g), tetra-n-butylammonium hydrogen sulfate (0.22 g), 1 N sodium hydroxide (13 mL) and dichloromethane (26 mL) was stirred vigorously at ambient temperature for 6 hours. The pH of the mixture was adjusted to 3 with 10N hydrochloric acid. The precipitate formed was collected and washed successively with water and ethyl acetate to give methyl 2-[(4-amino-3-nitrophenoxy)methyl]benzoate (0.76 g) as an orange solid. The filtrate was diluted with tetrahydrofuran, and the organic layer was separated, washed with 1N sodium hydroxide, water and brine, dried over anhydrous magnesium sulfate, concentrated in vacuo. The resulting solid was suspended in ethanol (20 mL) and filtered to afford the further product (0.45 g).
NMR(DMSO-d6,δ): 3.82 (3H, s), 5.35 (2H, s), 7.02 (1H, d, J=9 Hz), 7.24 (1H, dd, J=3 Hz, 9 Hz), 7.29 (2H, br s), 7.43 (1H, d, J=3 Hz), 7.4-8.0 (4H, m).
MS: 325 (M+Na).
To a solution of methyl 2-[(4-amino-3-nitrophenoxy)methyl]benzoate (0.50 g) in a solvent mixture of tetrahydrofuran (5 mL) and N,N-dimethylformamide (5 mL) was added sodium hydride (60% dispersion in mineral oil; 72 mg), and the mixture was stirred at ambient temperature for half an hour. To the mixture was added di-tert-butyl dicarbonate (0.39 g) and stirring was continued overnight at ambient temperature. The mixture was partitioned between ethyl acetate and saturated aqueous ammonium chloride. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (100:1 chloroform-ethyl acetate) to give methyl 2-({4-[(tert-butoxycarbonyl)amino]-3-nitrophenoxy}methyl)benzoate (0.19 g) as a yellow solid.
NMR(DMSO-d6,δ): 1.42 (9H, s), 3.81 (3H, s), 5.47 (2H, s), 7.32 (1H, dd; J=3 Hz, 9 Hz), 7.48 (1H, d, J=9 Hz), 7.51 (1H, d, J=3 Hz), 7.4-8.0 (4H, m), 9.34 (1H, s).
MS: 425 (M+Na).
A mixture of methyl 2-({4-[(tert-butoxycarbonyl)amino]-3-nitrophenoxy}methyl)benzoate (0.15 g), iron (0.28 g) and ammonium chloride (0.40 g) in a solvent mixture of methanol (10 mL) and water (4 mL) was refluxed for an hour. After cooling, the mixture was filtered and the insoluble material was washed with methanol. The filtrate and the washings were combined and concentrated in vacuo. The residue was partitioned between ethyl acetate and 1 N sodium hydroxide. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (elution; 1:10 chloroform-ethyl acetate) followed by trituration with a mixture of n-hexane and ethyl acetate to give methyl 2-({3-amino-4-[(tert-butoxycarbonyl)amino]phenoxy}methyl)benzoate (0.10 g).
NMR(DMSO-d6,δ): 1.43 (9H, s), 3.82 (3H, s), 4.84 (2H, br s), 5.30 (2H, s), 6.15 (1H, dd, J=3 Hz, 9 Hz), 6.32 (1H, d, J=3 Hz), 6.96 (1H, d, J=9 Hz), 7.4-8.0 (4H, m), 8.10 (1H, br s).
MS: 395 (M+Na).
A mixture of methyl 2-({3-amino-4-[(tert-butoxycarbonyl)amino]phenoxy}methyl)benzoate (0.20 g), 4-(bromomethyl)-3-chloro-1,1′-biphenyl (0.18 g), potassium carbonate (89 mg) and N,N-dimethylformamide (4 mL) was stirred at 80° C. for 2 hours. After cooling, the mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, and-concentrated in vacuo. The residue was purified by column chromatography on silica gel (elution; 4:1 n-hexane-acetone) to give methyl 2-[(4-[(tert-butoxycarbonyl)amino]-3-{[(3-chloro-1,1′-biphenyl-4-yl)methyl]amino}phenoxy)methyl]benzoate (0.27 g) as an amorphous form.
NMR(DMSO-d6,δ): 1.45 (9H, s), 3.73 (3H, s), 4.37 (2H, br d, J=6 Hz), 5.26 (2H, s), 5.69 (1H, t, J=6 Hz), 5.93 (1H, d, J=2 Hz), 6.16 (1H, dd, J=2 Hz, 8 Hz), 6.98 (1H, d, J=8 Hz), 7.3-7.9 (12H, m), 8.1-8.3 (1H, br m).
MS: 573 (M+H).
A solution of methyl 2-[(4-[(tert-butoxycarbonyl)amino]-3-{[(3-chloro-1,1′-biphenyl-4-yl)methyl]amino}phenoxy)methyl]benzoate (0.25 g) in methanol (4 mL) was treated with 4 N hydrochloric acid/1,4-dioxane (4 mL), and the mixture was stirred at 50° C. for an hour. After cooling, the mixture was partitioned between ethyl acetate and 1 N sodium hydroxide. The organic layer was separated in vacuo, washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to give the crude product which was used in the next reaction without further purification.
A mixture of the crude product, acetic acid (0.50 mL) and tetraethoxymethane (4.2 mL) was stirred at 80° C. for half an hour. After cooling, the mixture was partitioned between ethyl acetate and 1 N sodium hydroxide. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (gradient elution; chloroform-ethyl acetate 50:1 to 10:1) to afford the product which was triturated with methanol to give methyl 2-[({1-[(3-chloro-1,1′-biphenyl-4-yl)methyl]-2-ethoxy-1H-benzimidazol-6-yl}oxy)methyl]benzoate (0.12 g).
NMR(DMSO-d6,δ): 1.35 (3H, t, J=7 Hz), 3.76 (3H, s), 4.51 (2H, q, J=7 Hz), 5.30 (2H, s), 5.35 (2H, s), 6.8-7.9 (15H, m).
MS: 527 (M+H).
A mixture of N-(4-hydroxy-2-methyl-6-nitrophenyl)acetamide (10 g), methyl 2-(bromomethyl)benzoate (14.2 g), potassium carbonate (7.23 g) and N,N-dimethylformamide (100 mL) was stirred at ambient temperature overnight. To the mixture was added water (400 mL) to afford the precipitate and the suspension was stirred at ambient temperature for an hour. The precipitate was collected by filtration, washed with water, and dried in vacuo to give methyl 2-{[4-(acetylamino)-3-methyl-5-nitrophenoxy]methyl}benzoate (16.5 g) as a solid.
NMR(DMSO-d6,δ): 2.00 (3H, s), 2.24 (3H, s), 3.82 (3H, s), 5.47 (2H, s), 7.27 (1H, d, J=3 Hz), 7.34 (1H, d, J=3 Hz), 7.4-7.9 (4H, m), 9.64 (1H, s).
MS: 381 (M+Na).
A mixture of methyl 2-{[4-(acetylamino)-3-methyl-5-nitrophenoxy]methyl}benzoate (15.5 g) and iron (12.1 g) in a solvent mixture of tetrahydrofuran (80 mL), methanol (40 mL) and acetic acid (40 mL) was reflux for 8 hours. After cooling, the mixture was evaporated in vacuo. The residue was partitioned between ethyl acetate and 1 N sodium hydroxide/brine to afford the white precipitate which was collected to give methyl 2-{[(2,4-dimethyl-1H-benzimidazol-6-yl)oxy]methyl}benzoate (4.1 g). The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was suspended in ethyl acetate (50 mL) and the suspension was stirred at ambient temperature for half an hour, filtered to give the further product (4.1 g) as a white solid.
NMR(DMSO-d6,δ): 2.52 (3H, s), 2.74 (3H, s), 3.81 (3H, s), 5.48 (2H, s), 7.05 (1H, s), 7.07 (1H, d, J=2 Hz), 7.4-7.9 (4H, m), 14.33 (1H, br s).
MS: 311 (M+H).
A mixture of methyl 2-{[(2,4-dimethyl-1H-benzimidazol-6-yl)oxy]methyl}benzoate (0.20 g), 4-(bromomethyl)-3-chloro-1,1′-biphenyl (0.29 g), potassium carbonate (0.10 g) and N,N-dimethylformamide (4 mL) was stirred at 80° C. for 5 hours. After cooling, the mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (gradient elution; chloroform-methanol 100:1 to 50:1) to afford the solid which was recrystallized from a mixture of diisopropyl ether (15 mL) and ethyl acetate (3 mL) to give methyl 2-[({1-[(3-chloro-1,1′-biphenyl-4-yl)methyl]-2,4-dimethyl-1H-benzimidazol-6-yl}oxy)methyl]benzoate (0.17 g).
NMR(DMSO-d6,δ): 2.45 (3H, s), 2.49 (3H, s), 3.75 (3H, s), 5.34 (2H, s), 5.48 (2H, s), 6.54 (1H, d, J=8 Hz), 6.69 (1H, d, J=1 Hz), 6.83 (1H, d, J=2 Hz), 7.3-7.9 (11H, m).
MS: 511 (M+H).
Methyl 2-({[1-(2-chloro-4-ethoxybenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]oxy}methyl)benzoate (0.27 g) was synthesized from methyl 2-{[(2,4-dimethyl-1H-benzimidazol-6-yl)oxy]methyl}benzoate (300 mg) in a manner similar to that described in Preparation Example 123 except that 2-chloro-4-ethoxybenzyl bromide (289 mg) was used instead of 4-(bromomethyl)-3-chloro-1,1′-biphenyl.
NMR(DMSO-d6,δ): 1.29 (3H, t, J=7 Hz), 2.42 (3H, s), 2.47 (3H, s), 3.78 (3H, s), 3.99 (2H, q, J=7 Hz), 5.34 (4H, s), 6.4-6.6 (1H, m), 6.67 (1H, d, J=1 Hz), 6.76 (1H, d, J=1 Hz), 6.7-6.9 (1H, m), 7.05 (1H, d, J=3 Hz), 7.4-7.7 (4H, m).
MS: 479 (M+H).
Methyl 2-{[(1-{[3-chloro-5-(trifluoromethyl)-2-pyridinyl]methyl}-2,4-dimethyl-1H-benzimidazol-6-yl)oxy]methyl}benzoate (0.30 g) was synthesized from methyl 2-{[(2,4-dimethyl-1H-benzimidazol-6-yl)oxy]methyl}benzoate (300 mg) in a manner similar to that described in Preparation Example 123 except that 3-chloro-2-(chloromethyl)-5-(trifluoromethyl)pyridine (311 mg) was used instead of 4-(bromomethyl)-3-chloro-1,1′-biphenyl.
NMR(DMSO-d6,δ): 2.42 (3H, s), 2.46 (3H, s), 3.77 (3H, s), 5.33 (2H, s), 5.67 (2H, s), 6.64 (1H, d, J=1 Hz), 6.76 (1H, d, J=2 Hz), 7.3-8.0 (4H, m), 8.52 (1H, d , J=1 Hz), 8.74 (1H, s).
MS: 504 (M+H).
Methyl 2-{[(1-{2-chloro-4-[(ethoxycarbonyl)(methyl)amino]benzyl}-2,4-dimethyl-1H-benzimidazol-6-yl)oxy]methyl}benzoate (1.10 g) was synthesized from methyl 2-{[(2,4-dimethyl-1H-benzimidazol-6-yl)oxy]methyl}benzoate (200 mg) in a manner similar to that described in Preparation Example 123 except that {1-bromomethyl-2-chloro-4-[(ethoxycarbonyl)(methyl)amino]}benzene (257 mg) was used instead of 4-(bromomethyl)-3-chloro-1,1′-biphenyl.
NMR(DMSO-d6,δ): 1.14 (3H, t, J=7 Hz), 2.43 (3H, s), 2.48 (3H, s), 3.19 (3H, s), 3.76 (3H, s), 4.06 (2H, q, J=Hz), 5.33 (2H, S), 5.42 (2H, s), 6.47 (1H, d, J=8 Hz), 6.69 (1H, d, J=1 Hz), 6.83 (1H, d, J=2 Hz), 7.16 (1H, dd, J=2 Hz, 8 Hz), 7.3-7.7 (4H, m), 7.8-8.0 (1H, m).
MS: 536 (M+H).
Methyl 2-[({1-[(3,5-dichloro-2-pyridinyl)methyl]-2,4-dimethyl-1H-benzimidazol-6-yl}oxy)methyl]benzoate (0.48 g) was synthesized from methyl 2-{[(2,4-dimethyl-1H-benzimidazol-6-yl)oxy]methyl}benzoate (560 mg) in a manner similar to that described in Preparation Example 123 except that (3,5-dichloro-2-pyridinyl)methyl methanesulfonate (508 mg) was used instead of 4-(bromomethyl)-3-chloro-1,1′-biphenyl.
NMR(DMSO-d6,δ): 2.43 (3H, s), 2.45 (3H, s), 3.79 (3H, s), 5.33 (2H, s), 5.55 (2H, s), 6.64 (1H, d, J=1 Hz), 6.71 (1H, d, J=2 Hz), 7.3-8.0 (4H, m), 8.27 (1H, d, J=2 Hz), 8.40 (1H, d, J=2 Hz).
MS: 470 (M+H).
Methyl 2-({[1-(2,4-dichlorobenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]oxy}methyl)benzoate (0.60 g) was synthesized from methyl 2-{[(2,4-dimethyl-1H-benzimidazol-6-yl)oxy]methyl}benzoate (500 mg) in a manner similar to that described in Preparation Example 123 except that 1-chloromethyl-2,4-dichlorobenzene (346 mg) was used instead of 4-(bromomethyl)-3-chloro-1,1′-biphenyl.
NMR(DMSO-d6,δ): 2.41 (3H, s), 2.47 (3H, s), 3.77 (3H, s), 5.33 (2H, s), 5.42 (2H, s), 6.46 (1H, d, J=8 Hz), 6.68 (1H, d, J=1 Hz), 6.76 (1H, d, J=2 Hz), 7.28 (1H, dd, J=2 Hz, 8 Hz), 7.4-7.6 (3H, m), 7.68 (1H, d, J=2 Hz), 7.8-7.9 (1H, m).
MS: 469 (M+H).
Methyl 2-[({1-[(2,6-dichloro-3-pyridinyl)methyl]-2,4-dimethyl-1H-benzimidazol-6-yl}oxy)methyl]benzoate (0.54 g) was synthesized from methyl 2-{[(2,4-dimethyl-1H-benzimidazol-6-yl)oxy]methyl}benzoate (560 mg) in a manner similar to that described in Preparation Example 123 except that (2,6-dichloro-3-pyridinyl)methyl methanesulfonate (508 mg) was used instead of 4-(bromomethyl)-3-chloro-1,1′-biphenyl.
NMR(DMSO-d6,δ): 2.43 (3H, s), 2.48 (3H, s), 3.77 (3H, s), 5.34 (2H, s), 5.43 (2H, s), 6.69 (1H, d, J=1 Hz), 6.8-6.9 (2H, m), 7.41 (1H, d, J=8 Hz), 7.4-8.0 (4H, m).
MS: 472, 470 (M+H).
Methyl 2-[({1-[(2-chloro-6-phenyl-3-pyridinyl)methyl]-2,4-dimethyl-1H-benzimidazol-6-yl}oxy)methyl]benzoate (0.18 g) was synthesized from methyl 2-{[(2,4-dimethyl-1H-benzimidazol-6-yl)oxy]methyl}benzoate (200 mg) in a manner similar to that described in Preparation Example 123 except that (2-chloro-6-phenyl-3-pyridinyl)methyl methanesulfonate (230 mg) was used instead of 4-(bromomethyl)-3-chloro-1,1′-biphenyl.
Methyl 2-[({1-[(3-methoxy-1,1′-biphenyl-4-yl)methyl]-2,4-dimethyl-1H-benzimidazol-6-yl}oxy)methyl]benzoate (0.12 g) was synthesized from methyl 2-{[(2,4-dimethyl-1H-benzimidazol-6-yl)oxy]methyl}benzoate (180 mg) in a manner similar to that described in Preparation Example 123 except that (3-methoxy-1,1′-biphenyl-4-yl)methyl methanesulfonate (162 mg) was used instead of 4-(bromomethyl)-3-chloro-1,1′-biphenyl.
Methyl 2-[({1-[2-chloro-4-(1,3-oxazol-2-yl)benzyl]-2,4-dimethyl-1H-benzimidazol-6-yl}oxy)methyl]benzoate (87 mg) was synthesized from methyl 2-{[(2,4-dimethyl-1H-benzimidazol-6-yl)oxy]methyl}benzoate (200 mg) in a manner similar to that described in Preparation Example 123 except that 1-bromomethyl-2-chloro-4-(1,3-oxazol-2-yl)benzene (132 mg) was used instead of 4-(bromomethyl)-3-chloro-1,1′-biphenyl.
NMR(DMSO-d6,δ): 2.44 (3H, s), 2.49 (3H, s), 3.77 (3H, s), 5.33 (2H, s), 5.55 (2H, s), 6.63 (1H, d, J=8 Hz), 6.69 (1H, d, J=1 Hz), 6.77 (1H, d, J=2 Hz), 7.3-7.9 (6H, m), 8.02 (1H, d, J=1 Hz), 8.26 (1H, s).
MS: 502 (M+H).
Methyl 2-[({1-[(3-chloro-5-ethoxy-2-pyridinyl)methyl]-2,4-dimethyl-1H-benzimidazol-6-yl}oxy)methyl]benzoate (0.21 g) was synthesized from methyl 2-{[(2,4-dimethyl-1H-benzimidazol-6-yl)oxy]methyl}benzoate (170 mg) in a manner similar to that described in Preparation Example 123 except that (3-chloro-5-ethoxy-2-pyridinyl)methyl methanesulfonate (146 mg) was used instead of 4-(bromomethyl)-3-chloro-1,1′-biphenyl.
NMR(DMSO-d6,δ): 1.30 (3H, t, J=7 Hz), 2.44 (3H, s), 2.46 (3H, s), 3.80 (3H, s), 4.09 (2H, q, J=7 Hz), 5.33 (2H, s), 5.44 (2H, s), 6.63 (1H, d, J=1 Hz), 6.71 (1H, d, J=2 Hz), 7.4-7.7 (4H, m), 7.8-8.0 (1H, m), 8.08 (1H, d , J=2 Hz).
MS: 480 (M+H).
A mixture of methyl 2-{[(2,4-dimethyl-1H-benzimidazol-6-yl)oxy]methyl}benzoate (1.0 g), 1-(bromomethyl)-4-bis(tert-butoxycarbonyl)amino-3-chlorobenzene (1.76 g), potassium carbonate (579 mg) and sodium iodide (483 mg) in N,N-dimethylformamide (10 mL) was stirred at ambient temperature for 3 days. The mixture was partitioned between ethyl acetate and water, and the organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (elution; 4:1 chloroform-ethyl acetate) to give methyl 2-{[(1-{4-[bis(tert-butoxycarbonyl) amino]-2-chlorobenzyl}-2,4-dimethyl-1H-benzimidazol-6-yl)oxy]methyl}benzoate (1.02 g) as a white solid.
NMR(DMSO-d6,δ): 1.35 (18H, s), 2.40 (3H, s), 2.48-2.52 (3H, s), 3.77 (3H, s), 5.31 (2H, s), 5.48 (2H, s), 6.52 (1H, d, J=8 Hz), 6.67 (1H, d, J=1 Hz), 6.85 (1H, d, J=2 Hz), 7.09 (1H, dd, J=2 Hz, 8 Hz), 7.4-8.0 (5H, m).
MS: 650 (M+H).
A mixture of methyl 2-{[(1-(4-[bis(tert-butoxycarbonyl)amino]-2-chlorobenzyl}-2,4-dimethyl-1H-benzimidazol-6-yl)oxy]methyl}benzoate (1.0 g), 4 N hydrogen chloride/1,4-dioxane (8 mL) and methanol (40 mL) was stand at ambient temperature overnight. The mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and 0.1N sodium hydroxide. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to give methyl 2-({[1-(4-amino-2-chlorobenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]oxy}methyl)benzoate (0.647 g) as a yellow solid.
NMR (DMSO-d6,δ): 2.43 (3H, s), 2.45 (3H, s), 3.79 (3H, s), 5.22 (2H, s), 5.34 (2H, s), 5.40 (2H, br s), 6.37 (2H, s), 6.5-6.7 (2H, m), 6.77 (1H, d, J=2 Hz), 7.4-8.0 (4H, m).
MS: 450 (M+H).
To a mixture of methyl 2-({[1-(4-amino-2-chlorobenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]oxy}methyl) benzoate (0.53 g) and iodomethane (836 mg) in a solvent mixture of tetrahydrofuran (3 ml) and N,N-dimethylformamide (3 mL) was added sodium hydride (60% dispersion in mineral oil; 118 mg). The mixture was stirred at ambient temperature for 4 days and partitioned between ethyl acetate and water. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel (gradient elution; chloroform-ethyl acetate 10:1 to 8:1 to 4:1) to give methyl 2-[({1-[2-chloro-4-(dimethylamino)benzyl]-2,4-dimethyl-1H-benzimidazol-6-yl}oxy)methyl]benzoate (0.12 g) as an oil.
NMR(DMSO-d6,δ): 2.43 (3H, s), 2.46 (3H, s), 2.86 (6H, s), 3.78 (3H, s), 5.28 (2H, s), 5.34 (2H, s), 6.4-6.8 (5H, m), 7.4-8.0 (4H, m).
MS: 478 (M+H).
To a suspension of methyl 2-{[4-(acetylamino)-3-methyl-5-nitrophenoxy]methyl}benzoate (12 g) in methanol (240 mL) was added dropwise conc. sulfuric acid (5 mL), and the resulting solution was refluxed for 36 hours. After cooling, the mixture was concentrated in vacuo and the residue was suspended in water (100 mL). The pH of the suspension was adjusted to 4 with 50% sodium hydroxide with cooling in an ice-bath. The suspension was diluted with ethyl acetate (300 mL), stirred in an ice-bath for half an hour, and filtered to give (3.48 g) as a orange solid. The second crop (0.79 g) was obtained from the mother liquor by filtration. The filtrate was partitioned between ethyl acetate and brine. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was suspended in ethyl acetate (30 mL) and filtered to give the product (5.0 g). The filtrate was concentrated in vacuo and the residue was purified by column chromatography on silica gel (gradient elution; chloroform to 50:1 chloroform-ethyl acetate) followed by trituration with ethyl acetate to give the further product methyl 2-[(4-amino-3-methyl-5-nitrophenoxy)methyl]benzoate (0.36 g).
NMR(DMSO-d6,δ): 2.21 (3H, s), 3.82 (3H, s), 5.35 (2H, s), 7.03 (2H, br s), 7.2-7.7 (5H, m), 7.91 (1H, d, J=7 Hz).
MS: 316 (M+Na).
To a solution of methyl 2-[(4-amino-3-methyl-5-nitrophenoxy)methyl]benzoate (0.50 g) in tetrahydrofuran (10 mL) was added trifluoroacetic anhydride (1 mL). The mixture was stirred at ambient temperature for 2 hours and concentrated in vacuo. The residue was suspended in n-hexane (15 mL). The suspension was stirred at ambient temperature for half an hour and filtered to give methyl 2-({3-methyl-5-nitro-4-[(trifluoroacetyl)amino]phenoxy}methyl)benzoate (0.62 g) as a white solid.
NMR(DMSO-d6,δ): 2.25 (3H, s), 3.82 (3H, s), 5.51 (2H, s), 7.39 (1H, d, J=2 Hz), 7.4-7.7 (4H, m), 7.94 (1H, d, J=8 Hz).
MS: 411 (M−H).
A mixture of methyl 2-({3-methyl-5-nitro-4-[(trifluoroacetyl)amino]phenoxy}methyl)benzoate (0.60 g), iron (0.40 g), acetic acid (6 mL) and methanol (30 mL) was refluxed overnight. After cooling, the insoluble materials were filtered off and the filtrate was concentrated in vacuo. The residue was partitioned between ethyl acetate and 1 N sodium hydroxide. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (10:1 chloroform-ethyl acetate) to give methyl 2-({[4-methyl-2-(trifluoromethyl)-1H-benzimidazol-6-yl]oxy}methyl)benzoate (0.46 g) as a white amorphous form.
NMR(DMSO-d6,δ): 2.48-2.52 (3H, s), 3.82 (3H, s), 5.45 (2H, s), 6.89 (2H, br s), 7.4-8.0 (4H, m), 13.62 (1H, br s).
MS: 365 (M+H).
Methyl 2-({[1-[(3-chloro-1,1′-biphenyl-4-yl)methyl]-4-methyl-2-(trifluoromethyl)-1H-benzimidazol-6-yl]oxy}methyl)benzoate (0.10 g) was synthesized from methyl 2-({[4-methyl-2-(trifluoromethyl)-1H-benzimidazol-6-yl]oxy}methyl)benzoate (110 mg) in a manner similar to that described in Preparation Example 123.
NMR(DMSO-d6,δ): 2.58 (3H, s), 3.75 (3H, s), 5.39 (2H, s), 5.72 (2H, s), 6.47 (1H, d, J=8 Hz), 6.94 (1H, d, J=1 Hz), 7.09 (1H, d, J=2 Hz), 7.3-7.7 (11H, m).
MS: 565 (M+H).
To a suspension of methyl 2-[(4-amino-3-methyl-5-nitrophenoxy)methyl]benzoate (0.50 g) in 1,4-dioxane (10 mL) was added 4 N hydrogen chloride/1,4-dioxane (5 mL) followed by addition of propionic anhydride (2.2 mL). The mixture was stirred at ambient temperature for 2 hours and concentrated in vacuo. The residue was suspended in methanol (10 mL) and filtered to give methyl 2-{[3-methyl-5-nitro-4-(propionylamino)phenoxy]methyl}benzoate (0.49 g) as a white solid. The filtrate was concentrated in vacuo and the residue was triturated with n-hexane (15 mL) to give the second crop of the further product (95 mg).
NMR(DMSO-d6,δ): 1.06 (3H, t, J=7 Hz), 2.21 (3H, s), 2.28 (2H, q, J=7 Hz), 3.82 (3H, s), 5.47 (2H, s), 7.27 (1H, d, J=1 Hz), 7.34 (1H, d, J=1 Hz), 7.4-7.7 (3H, m), 7.92 (1H, d, J=8 Hz), 9.56 (1H, s).
MS: 373 (M+H).
A mixture of methyl 2-{[3-methyl-5-nitro-4-(propionylamino)phenoxy]methyl}benzoate (0.56 g), iron (0.42 g), acetic acid (6 mL) and methanol (30 mL) was refluxed overnight. After cooling, the insoluble materials were filtered off and the filtrate was concentrated in vacuo. The residue was partitioned between ethyl acetate and 1 N sodium hydroxide. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel (gradient elution; 10:1 chloroform-ethyl acetate) to give methyl 2-{[(2-ethyl-4-methyl-1H-benzimidazol-6-yl)oxy]methyl}benzoate (0.22 g) which was solidified on standing overnight.
NMR(DMSO-d6,δ): 1.28, 1.29 (total 3H, each t, J=7 Hz), 2.43 (3H, d, J=6 Hz), 2.44 (3H, s), 2.76 (2H, q, J=7 Hz), 3.82 (3H, s), 5.39 (2H, s), 6.68, 6.85 (total 2H, δ6.68: dd, J=2 Hz, 16 Hz, δ6.85: d, J=2 Hz), 7.4-7.8 (4H, m), 7.90 (1H, d, J=8 Hz), 11.91 (1H, br d, J=16 Hz).
MS: 325 (M+H).
Methyl 2-[({1-[(3-chloro-1,1′-biphenyl-4-yl)methyl]-2-ethyl-4-methyl-1H-benzimidazol-6-yl}oxy)methyl]benzoate (0.13 g) was synthesized from methyl 2-{[(2-ethyl-4-methyl-1H-benzimidazol-6-yl)oxy]methyl}benzoate (210 mg) in a manner similar to that described in Preparation Example 123.
NMR(DMSO-d6,δ): 1.26 (3H, t, J=7 Hz), 2.48-2.51 (3H, s), 2.78 (2H, q, J=7 Hz), 3.75 (3H, s), 5.34 (2H, s), 5.49 (2H, s), 6.50 (1H, d, J=8 Hz), 6.70 (1H, d, J=1 Hz), 6.83 (1H, d, J=2 Hz), 7.3-7.9 (11H, m).
MS: 325 (M+H).
A mixture of methyl 2-[(4-amino-3-methyl-5-nitrophenoxy)methyl]benzoate (1.0 g), iron (1.77 g) and ammonium chloride (3.38 g) in a solvent mixture of methanol (40 mL) and water (16 mL) was refluxed for an hour. After cooling, the mixture was filtered and the insoluble material was washed with methanol. The filtrate and the washings were combined and concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was dissolved in methanol (20 mL) and treated with 4 N hydrogen chloride/1,4-dioxane (5 mL). The mixture was concentrated in vacuo and the residue was suspended in ethyl acetate (30 mL) and filtered to give methyl 2-[(3,4-diamino-5-methylphenoxy)methyl]benzoate dihydrochloride (1.1 g) as a grayish red solid.
NMR(DMSO-d6,δ): 2.22 (3H, s), 3.82 (3H, s), 5.32 (2H, s), 6.27 (1H, d, J=2 Hz), 6.35 (1H, d, J=2 Hz), 6.5-8.0 (6H, br m), 7.3-7.7 (3H, m), 7.91 (1H, d, J=7 Hz).
MS: 309 (M+Na)
A mixture of methyl 2-[(3,4-diamino-5-methylphenoxy)methyl]benzoate dihydrochloride (0.50 g), acetic acid (0.10 mL) and tetraethoxymethane (2.9 mL) was stirred at 80° C. for 2 hours. After cooling, the mixture was partitioned between ethyl acetate and 1 N sodium hydroxide. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (gradient elution; chloroform-ethyl acetate 6:1 to 3:1) to afford the product which was solidified on standing overnight. The white solid was triturated with diisopropyl ether (5 mL) and filtered to give methyl 2-{[(2-ethoxy-4-methyl-1H-benzimidazol-6-yl)oxy]methyl}benzoate (0.42 g).
NMR(DMSO-d6,δ): 1.36 (3H, t, J=7 Hz), 2.32, 2.37 (total 3H, each s), 3.82 (3H, s), 4.43 (2H, q, J=7 Hz), 5.36 (2H, s), 6.5-6.6, 6.75 (total 2H, δ6.5-6.6: m, δ6.75: d, J=2 Hz), 7.4-8.0 (3H, m), 7.89 (1H, d, J=8 Hz), 11.58 (1H, br d, J=17 Hz).
MS: 341 (M+H).
Methyl 2-[({1-[(3-chloro-1,1′-biphenyl-4-yl)methyl]-2-ethoxy-4-methyl-1H-benzimidazol-6-yl}oxy)methyl]benzoate (0.17 g) was synthesized from methyl 2-{[(2-ethoxy-4-methyl-1H-benzimidazol-6-yl)oxy]methyl}benzoate (210 mg) in a manner similar to that described in Preparation Example 123.
NMR(DMSO-d6,δ): 1.35 (3H, t, 7 Hz), 2.42 (3H, s), 3.76 (3H, s), 4.52 (2H, q, J=7 Hz), 5.27 (2H, s), 5.33 (2H, s), 6.63 (1H, d, J=2 Hz), 6.76 (1H, d, J=2 Hz), 6.89 (1H, d, J=8 Hz), 7.3-7.9 (11H, m).
MS: 541 (M+H).
Methyl 2-{[(1-{[3-chloro-5-(trifluoromethyl)-2-pyridinyl]methyl}-2-ethoxy-4-methyl-1H-benzimidazol-6-yl)oxy]methyl}benzoate (0.20 g) was synthesized from methyl 2-{[(2-ethoxy-4-methyl-1H-benzimidazol-6-yl)oxy]methyl}benzoate (190 mg) in a manner similar to that described in Preparation Example 123 except that 3-chloro-2-(chloromethyl)-5-(trifluoromethyl)pyridine (167 mg) was used instead of 4-(bromomethyl)-3-chloro-1,1′-biphenyl.
NMR(DMSO-d6,δ): 1.26 (3H, t, 7 Hz), 2.48 (3H, s), 3.77 (3H, s), 4.45 (2H, q, J=7 Hz), 5.31 (2H, s), 5.47 (2H, s), 6.59 (1H, d, J=2 Hz), 6.74 (1H, d, J=2 Hz), 7.3-7.9 (4H, m), 8.51 (1H, d, J=1 Hz), 8.76 (1H, d, J=1 Hz).
MS: 534 (M+H).
To a solution-of methyl 2-[(3,4-diamino-5-methylphenoxy)methyl]benzoate dihydrochloride (0.50 g) in N,N-dimethylformamide (5 mL) was added 1,1′-thiocarbonyldiimidazole (0.32 g). The mixture was stirred at ambient temperature for 10 minutes, and partitioned between ethyl acetate/tetrahydrofuran and water. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting solid was suspended in ethanol (5 mL). The suspension was stirred at ambient temperature for half an hour and filtered to give methyl 2-{[(7-methyl-2-thioxo-2,3-dihydro-1H-benzimidazol-5-yl)oxy]methyl}benzoate (0.39 g) as a yellow ocher solid.
NMR(DMSO-d6,δ): 2.34 (3H, s), 3.81 (3H, s), 5.37 (2H, s), 6.54 (1H, d, J=2 Hz), 6.63 (1H, d, J=2 Hz), 7.4-7.9 (3H, m), 7.91 (1H, d, J=8 Hz).
MS: 351 (M+Na).
To a mixture of methyl 2-{[(7-methyl-2-thioxo-2,3-dihydro-1H-benzimidazol-5-yl)oxy]methyl}benzoate (0.35 g), N,N-diisopropylethylamine (0.22 mL) and N,N-dimethylformamide (7 mL) was added iodoethane (0.10 mL). The mixture was stirred at ambient temperature overnight and partitioned between ethyl acetate and water. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (elution; 10:1 chloroform-ethyl acetate) to give methyl 2-({[2-(ethylthio)-4-methyl-1H-benzimidazol-6-yl]oxy}methyl)benzoate (0.34 g) as an oil.
NMR(DMSO-d6,δ): 1.36 (3H, t, J=7 Hz), 2.42 (3H, s), 3.22 (2H, q, J=7 Hz), 3.82 (3H, s), 5.39 (2H, s), 6.65 (1H, d, J=2 Hz), 6.78 (1H, br s), 7.4-8.0 (4H, m), 12.29 (1H, br s).
MS: 355 (M−H).
Methyl 2-({[1-[(3-chloro-1,1′-biphenyl-4-yl)methyl]-2-(ethylthio)-4-methyl-1H-benzimidazol-6-yl]oxy}methyl)benzoate (0.37 g) was synthesized from methyl 2-({[2-(ethylthio)-4-methyl-1H-benzimidazol-6-yl]oxy}methyl)benzoate (240 mg) in a manner similar to that described in Preparation Example 123.
NMR(DMSO-d6,δ): 1.33 (3H, t, J=7 Hz), 2.48-2.51 (3H, s), 3.26 (2H, q, J=7 Hz), 3.76 (3H, s), 5.35 (2H, s), 5.45 (2H, s), 6.58 (1H, d, J=8 Hz), 6.72 (1H, d, J=1 Hz), 6.91 (1H, d, J=2 Hz), 7.3-7.9 (11H, m).
MS: 557 (M+H).
Methyl 2-{[4-(acetylamino)-3-nitrophenoxy]methyl}benzoate (2.9 g) was synthesized from N-(4-hydroxy-2-nitrophenyl)acetamide (1.6 g) in a manner similar to that described in Preparation Example 121.
NMR(DMSO-d6,δ): 2.02 (3H, s), 3.81 (3H, s), 5.48 (2H, s), 7.33 (1H, dd, J=3 Hz, 9 Hz), 7.4-8.0 (6H, m), 9.6-10.5 (1H, br m).
MS: 424 (M+Na).
A mixture of methyl 2-{[4-(acetylamino)-3-nitrophenoxy]methyl}benzoate (2.3 g), 10% palladium on carbon (50% wet; 0.23 g), methanol (5 mL) and tetrahydrofuran (50 mL) was stirred for 8 hours under 1 atmosphere of hydrogen at ambient temperature. The catalyst was filtered off and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel (10:1 chloroform-methanol) to afford the product which was suspended in ethyl acetate (5 mL). The suspension was diluted with diisopropyl ether (5 mL), stirred at ambient temperature for half an hour, and filtered to give methyl 2-{[4-(acetylamino)-3-aminophenoxy]methyl}benzoate (0.43 g) as a solid.
NMR(DMSO-d6,δ): 1.99 (3H, s), 3.82 (3H, s), 4.90 (2H, br s), 5.31 (2H, s), 6.16 (1H, dd, J=3 Hz, 9 Hz), 6.33 (1H, d, J=3 Hz), 6.96 (1H, d, J=8 Hz), 7.4-8.0 (4H, m), 8.97 (1H, s).
MS: 337 (M+Na).
Methyl 2-({4-(acetylamino)-3-[(2,4-dichlorobenzyl)amino]phenoxy}methyl)benzoate was synthesized from methyl 2-{[4-(acetylamino)-3-aminophenoxy]methyl}benzoate (100 mg) in a manner similar to that described in Preparation Example 155 except that 1-chloromethyl-2,4-dichlorobenzene (68.4 mg) was used instead of 4-(bromomethyl)-3-chloro-1,1′-biphenyl.
Methyl 2-({[1-(2,4-dichlorobenzyl)-2-methyl-1H-benzimidazol-6-yl]oxy}methyl)benzoate (0.14 g) was synthesized from methyl 2-({4-(acetylamino)-3-[(2,4-dichlorobenzyl)amino]phenoxy}methyl)benzoate (150 mg) in a manner similar to that described in Preparation Example 156.
NMR(DMSO-d6,δ): 2.42 (3H, s), 3.77 (3H, s), 5.36 (2H, s), 5.46 (2H, s), 6.49 (1H, d, J=8 Hz), 6.84 (1H, dd, J=2 Hz, 9 Hz), 6.99 (1H, d, J=2 Hz), 7.2-7.7 (5H, m), 7.69 (1H, d, J=2 Hz), 7.8-8.0 (1H, m).
A mixture of 4-(acetylamino)-3-aminophenyl acetate (5.1 g), 4-(bromomethyl)-3-chloro-1,1′-biphenyl (6.9 g), potassium carbonate (3.5 g) and N,N-dimethylformamide (49 mL) was stirred at 80° C. for 1.5 hours. After cooling, the mixture was partitioned between ethyl acetate/tetrahydrofuran and water. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting solid was suspended in toluene (100 mL). The suspension was stirred at ambient temperature for half an hour and filtered to give 4-(acetylamino)-3-{[(3-chloro-1,1′-biphenyl-4-yl)methyl]amino}phenyl acetate (7.0 g) as a white solid. The filtrate was concentrated in vacuo and the residue was purified by column chromatography on silica gel (1:1 chloroform-ethyl acetate) followed by trituration with ethyl acetate (20 mL) to give the further product (1.0 g).
NMR(DMSO-d6,δ): 2.02 (3H, s), 2.16 (3H, s), 4.39 (2H, d, J=6 Hz), 5.95 (1H, t, J=6 Hz), 6.13 (1H, d, J=2 Hz), 6.30 (1H, dd, J=2 Hz, 8 Hz), 7.10 (1H, d, J=8 Hz), 7.3-7.7 (8H, m), 9.28 (1H, s).
MS: 409 (M+H).
To a suspension of 4-(acetylamino)-3-{[(3-chloro-1,1′-biphenyl-4-yl)methyl]amino}phenyl acetate (7.0 g) in ethanol (30 mL) was added dropwise concentrated sulfuric acid (7 mL) and the mixture was stirred at 80° C. overnight. After cooling, the mixture was concentrated in vacuo and the residue was neutralized with sodium hydroxide with cooling in an ice-bath. The resulting suspension was diluted with ethanol (10 mL), stirred at ambient temperature for half an hour, and filtered to give 1-[(3-chloro-1,1′-biphenyl-4-yl)methyl]-2-methyl-1H-benzimidazol-6-ol (5.4 g) as a pale purple solid.
NMR(DMSO-d6,δ): 2.45 (3H, s), 5.45 (2H, s), 6.5-6.7 (3H, m), 7.3-7.7 (7H, m), 8.84 (1H, d, J=2 Hz), 9.14 (1H, s).
MS: 349 (M+H).
To a suspension of 1-[(3-chloro-1,1′-biphenyl-4-yl)methyl]-2-methyl-1H-benzimidazol-6-ol (0.93 g) in a solvent mixture of tetrahydrofuran (5 mL) and N,N-dimethylformamide (2.5 mL) was added sodium hydride (60% dispersion in mineral oil; 117 mg). The mixture was stirred at 80° C. for 15 minutes and allowed to cool to ambient temperature. To the mixture was added methyl 2-(bromomethyl)benzoate. After stirring for 3 days, the mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (elution; 50:1 chloroform-methanol) followed by trituration with ethyl acetate (5 mL) to give methyl 2-[({1-[(3-chloro-1,1′-biphenyl-4-yl)methyl]-2-methyl-1H-benzimidazol-6-yl}oxy)methyl]benzoate (0.97 g) as a white solid. The filtrate was concentrated in vacuo and the residue was triturated with n-hexane (5 mL) to afford the further product (0.35 g).
NMR(DMSO-d6,δ): 2.45 (3H, s), 3.75 (3H, s), 5.36 (2H, s), 5.52 (2H, s), 6.57 (1H, d, J=8 Hz), 6.85 (1H, dd, J=2 Hz, 8 Hz), 7.04 (1H, d, J=2 Hz), 7.3-7.9 (12H, m).
MS: 497 (M+H).
4-(Acetylamino)-3-({[3-chloro-5-(trifluoromethyl)-2-pyridinyl]methyl}amino)phenyl acetate (0.34 g) was synthesized from 4-(acetylamino)-3-aminophenyl acetate (200 mg) in a manner similar to that described in Preparation Example 155 except that 3-chloro-2-(chloromethyl)-5-(trifluoromethyl)pyridine (265 mg) was used instead of 4-(bromomethyl)-3-chloro-1,1′-biphenyl.
NMR(DMSO-d6,δ): 2.06 (3H, s), 2.21 (3H, s), 4.54 (2H, br d, J=6 Hz), 5.90 (1H, t, J=6 Hz), 6.34 (1H, dd, J=2 Hz, 8 Hz), 6.44 (1H, d, J=2 Hz), 7.10 (1H, d, J=8 Hz), 8.50 (1H, d, J=2 Hz), 8.95 (1H, d, J=1 Hz), 9.27 (1H, br s).
MS: 424 (M+Na).
1-{[3-Chloro-5-(trifluoromethyl)-2-pyridinyl]methyl}-2-methyl-1H-benzimidazol-6-ol (0.18 g) was synthesized from 4-(acetylamino)-3-({[3-chloro-5-(trifluoromethyl)-2-pyridinyl]methyl}amino)phenyl acetate (320 mg) in a manner similar to that described in Preparation Example 156.
NMR(DMSO-d6,δ): 2.41 (3H, s), 5.64 (2H, s), 6.5-6.7 (2H, m), 7.2-7.4 (1H, m), 8.55 (1H, d, J=2 Hz), 8.79 (1H, d, J=1 Hz), 9.08 (1H, br s).
MS: 342 (M+H).
Methyl 2-{[(1-{[3-chloro-5-(trifluoromethyl)-2-pyridinyl]methyl}-2-methyl-1H-benzimidazol-6-yl)oxy]methyl}benzoate (0.11 g) was synthesized from 1-{[3-chloro-5-(trifluoromethyl)-2-pyridinyl]methyl}-2-methyl-1H-benzimidazol-6-ol (270 mg) in a manner similar to that described in Preparation Example 157.
[1-(2,4-Dichlorobenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]methanol (1.96 g) was synthesized from ethyl 1-(2,4-dichlorobenzyl)-2,4-dimethyl-1H-benzimidazole-6-carboxylate (2.50 g) in a manner similar to that described in Preparation Example 180.
MS (ES+): 335 (M++1).
Manganese dioxide (1.56 g) was added to a solution of [1-(2,4-dichlorobenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]methanol (200 mg) in acetone (6 mL), and the mixture was stirred at room temperature for 2 hours. Manganese salts were removed by celite pad filtration, and the solution was concentrated in vacuo to give 1-(2,4-dichlorobenzyl)-2,4-dimethyl-1H-benzimidazole-6-carbaldehyde. The crude product was used for the next step without purification.
Ethyl 3-({[1-(2,4-dichlorobenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]methyl}amino)benzoate (224 mg) was synthesized from 1-(2,4-dichlorobenzyl)-2,4-dimethyl-1H-benzimidazole-6-carbaldehyde (200 mg) and ethyl 3-aminobenzoate (149 mg) in a manner similar to that described in Preparation Example 165.
MS (ES+): 482 (M++1).
Sodium triacetoxyborohydride (132 mg) and aqueous solution of formaldehyde (37%, 51 μL) were added to a solution of ethyl 3-({[1-(2,4-dichlorobenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]methyl}amino)benzoate (150 mg) in 1,2-dichloroethane (3 mL). The mixture was stirred at room temperature for 4 days. The reaction was quenched by addition of water, and the organic materials were extracted with chloroform. The organic layer was washed with water, dried over sodium sulfate, and concentrated in vacuo. The crude product was purified over preparative thin layer chromatography (chloroform:methanol=20:1) to give ethyl 3-[{[1-(2,4-dichlorobenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]methyl}(methyl)amino]benzoate (153 mg) as a powder.
MS (ES+): 496 (M++1).
Sodium triacetoxyborohydride (191 mg) and acetic acid (52 μL) were added to a solution of 1-(2,4-dichlorobenzyl)-2,4-dimethyl-1H-benzimidazole-6-carbaldehyde (crude, 150 mg) and 2-aminobenzoic acid (92.6 mg) in tetrahydrofuran (3 mL). Triethylamine (94 μL) was added to the mixture, and it was stirred at room temperature for 15 hours. The reaction was quenched by addition of water, and the organic materials were extracted with chloroform. The organic layer was washed with water, dried over sodium sulfate, and concentrated in vacuo. The crude product was purified over preparative thin layer chromatography (chloroform:methanol=10:1) to give 2-({[1-(2,4-dichlorobenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]methyl)amino)benzoic acid (155 mg) as a powder.
1H NMR (200 MHz, DMSO-d6, δ/ppm): 2.46 (3H, s), 2.50 (3H, s), 4.41 (2H, s), 5.45 (2H, s), 6.48 (1H, d, J=8.3 Hz), 6.53 (1H, t, J=7.5 Hz), 6.63 (1H, d, J=8.3 Hz), 6.99 (1H, s), 7.15 (1H, s), 7.2-7.4 (2H, m), 7.66 (1H, d, J=2.1 Hz), 7.78 (1H, dd, J=7.9 Hz, 1.5 Hz), 12.1-13.0 (1H, br).
A solution of diethyl azodicarboxylate in toluene (40%, 0.14 mL) was added dropwise to a suspension of [1-(2,4-dichlorobenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]methanol (150 mg), methyl salicylate (68 mg) and triphenylphosphine (159 mg) in tetrahydrofuran at room temperature. The mixture was stirred at room temperature for 3 hours. The solution was treated with aqueous solution of sodium bicarbonate and brine and dried over sodium sulfate. The crude product was purified over silica gel chromatography (chloroform:methanol=50:1) to give methyl 2-([1-(2,4-dichlorobenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]methoxy}benzoate (99 mg) as a powder.
MS (ES+): 469 (M++1).
Methyl 3-{[1-(2,4-dichlorobenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]methoxy}benzoate (131 mg) was synthesized from [1-(2,4-dichlorobenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]methanol (150 mg) and methyl 3-hydroxybenzoate (68 mg) in a manner similar to that described in Preparation Example 166.
MS (ES+): 469 (M++1).
Ethyl 2-{[1-(2,4-dichlorobenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]methoxy}isonicotinate (53 mg) was synthesized from [1-(2,4-dichlorobenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]methanol (100 mg) and ethyl 2-hydroxyisonicotinate (60 mg) in a manner similar to that described in Preparation Example 171.
1H NMR (200 MHz, DMSO-d6, δ/ppm): 1.32 (3H, t, J=7.1 Hz), 2.47 (3H, s), 2.52 (3H, s), 4.33 (2H, q, J=7.2 Hz), 5.39 (2H, s), 5.49 (2H, s), 6.47 (1H, d, J=8.4 Hz), 7.09 (1H, s), 7.2-7.4 (3H, m), 7.39 (1H, dd, J=5.1 Hz, 1.3 Hz), 7.69 (1H, d, J=2.1 Hz), 8.32 (1H, d, J=5.3 Hz).
Methyl 6-{[1-(2,4-dichlorobenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]methoxy}-2-pyridinecarboxylate (37 mg) was synthesized from [1-(2,4-dichlorobenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]methanol (100 mg) and methyl 6-hydroxy-2-pyridinecarboxylate (55 mg) in a manner similar to that described in Preparation Example 171.
1H NMR (200 MHz, DMSO-d6, δ/ppm): 2.46 (3H, s), 2.53 (3H, s), 3.86 (3H, s), 5.39 (2H, s), 5.48 (2H, s), 6.40 (1H, d, J=8.4 Hz), 7.06 (1H, d, J=8.6 Hz), 7.16 (1H, s), 7.27 (1H, dd, J=8.3 Hz, 2.2 Hz), 7.39 (1H, s), 7.66 (1H, d, J=7.5 Hz), 7.71 (1H, d, J=2.2 Hz), 7.85 (1H, d, J=8.3 Hz).
{1-[(3-Chloro-1,1′-biphenyl-4-yl)methyl]-2,4-dimethyl-1H-benzimidazol-6-yl}methanol (340 mg) was synthesized from ethyl 1-[(3-chloro-1,1′-biphenyl-4-yl)methyl]-2,4-dimethyl-1H-benzimidazole-6-carboxylate (392 mg) in a manner similar to that described in Preparation Example 180.
MS (ES+): 377 (M++1).
A solution of diethyl azodicarboxylate in toluene (40%, 0.14 mL) was added dropwise to a suspension of {1-[(3-chloro-1,1′-biphenyl-4-yl)methyl]-2,4-dimethyl-1H-benzimidazol-6-yl}methanol (100 mg), methyl salicylate (48 mg) and polystyrene-supported triphenylphosphine (1.12 mmol/g, 284 mg) in tetrahydrofuran at room temperature. The mixture was stirred at room temperature for 3 days, and resin was removed by filtration. The solution was treated with aqueous solution of sodium bicarbonate and brine and dried over sodium sulfate. The crude product was purified over preparative thin layer chromatography (ethyl acetate) to give methyl 2-({1-[(3-chloro-1,1′-biphenyl-4-yl)methyl]-2,4-dimethyl-1H-benzimidazol-6-yl}methoxy)benzoate (102 mg) as a powder.
MS (ES+) 511 (M++1).
Methyl 3-({1-[(3-chloro-1,1′-biphenyl-4-yl)methyl]-2,4-dimethyl-1H-benzimidazol-6-yl}methoxy)benzoate (83 mg) was synthesized from {1-[(3-chloro-1,1′-biphenyl-4-yl)methyl]-2,4-dimethyl-1H-benzimidazol-6-yl}methanol (100 mg) and methyl 3-hydroxybenzoate (49 mg) in a manner similar to that described in Preparation Example 171.
MS (ES+): 511 (M++1).
Manganese dioxide (2.31 g) was added to a solution of {1-[(3-chloro-1,1′-biphenyl-4-yl)methyl]-2,4-dimethyl-1H-benzimidazol-6-yl)methanol (200 mg) in acetone (5 mL), and the mixture was stirred at room temperature for 2 hours. Manganese salts were removed by celite pad filtration, and the solution was concentrated in vacuo. The residue was dissolved in tetrahydrofuran (2 mL), methyl 2-aminoisonicotinate (161 mg) and titanium tetraisopropoxide (0.31 mL) were added to the solution, and the mixture was stirred at room temperature for 15 hours. Sodium borohydride (80 mg in two portions) and methanol (1 mL) were added to it, and the mixture was stirred for further 30 minutes. The reaction was quenched by addition of water, and the product was extracted with ethyl acetate. The organic layer was washed with water and brine and dried over sodium sulfate. The crude product was purified over silica gel chromatography (hexane:ethyl acetate 1:1 to ethyl acetate only) to give isopropyl 2-[({1-[(3-chloro-1,1′-biphenyl-4-yl)methyl]-2,4-dimethyl-1H-benzimidazol-6-yl}methyl)amino]isonicotinate (189 mg).
MS (ES+): 539 (M++1).
Isopropyl 6-[({1-[(3-chloro-1,1′-biphenyl-4-yl)methyl]-2,4-dimethyl-1H-benzimidazol-6-yl}methyl)amino]-2-pyridinecarboxylate (136 mg) was synthesized from {1-[(3-chloro-1,1′-biphenyl-4-yl)methyl]-2,4-dimethyl-1H-benzimidazol-6-yl}methanol (200 mg) and methyl 6-amino-2-pyridinecarboxylate (161 mg) in a manner similar to that described in Preparation Example 173.
MS (ES+): 539 (M++1).
Ethyl 1-(2-chloro-4-ethoxybenzyl)-2,4-dimethyl-1H-benzimidazole-6-carboxylate (2.20 g) was synthesized from ethyl 2,4-dimethyl-1H-benzimidazole-6-carboxylate (1.50 g) and 1-(bromomethyl)-2-chloro-4-ethoxybenzene (2.06 g) in a manner similar to that described in Preparation Example 179.
MS (ES+): 387 (M++1).
[1-(2-Chloro-4-ethoxybenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]methanol (1.86 g) was synthesized from ethyl 1-(2-chloro-4-ethoxybenzyl)-2,4-dimethyl-1H-benzimidazole-6-carboxylate (2.20 g) in a manner similar to that described in preparation example 180.
MS (ES+): 345 (M++1).
Methyl 2-{[1-(2-chloro-4-ethoxybenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]methoxy}benzoate (102 mg) was synthesized from [1-(2-chloro-4-ethoxybenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]methanol (100 mg) and methyl salicylate (53 mg) in a manner similar to that described in Preparation Example 171.
MS (ES+): 479 (M++1).
Methyl 3-{[1-(2-chloro-4-ethoxybenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]methoxy}benzoate (82 mg) was synthesized from [1-(2-chloro-4-ethoxybenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]methanol (100 mg) and methyl 3-hydroxybenzoate (53 mg) in a manner similar to that described in Preparation Example 171.
MS (ES+): 479 (M++1).
Potassium carbonate (633 mg) and 3-chloro-2-(chloromethyl)-5-(trifluoromethyl)pyridine (1.05 g) were added to a solution of ethyl 2,4-dimethyl-1H-benzimidazole-6-carboxylate (800 mg) in N,N-dimethylformamide (16 mL) at room temperature, and the mixture was stirred at 80° C. for 2 hours. The reaction was quenched by addition of water, and the organic materials were extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. The crude product was purified over preparative thin layer chromatography (chloroform methanol=20:1) to give ethyl 1-{[3-chloro-5-(trifluoromethyl)-2-pyridinyl]methyl}-2,4-dimethyl-1H-benzimidazole-6-carboxylate (940 mg) as a powder.
1H NMR (200 MHz, DMSO-d6, δ/ppm): 1.30 (3H, t, J=7.1 Hz), 2.49 (3H, s), 2.56 (3H, s), 4.27 (2H, q, J=7.1 Hz), 5.87 (2H, s), 7.61 (1H, s), 7.87 (1H, s), 8.57 (1H, d, J=1.5 Hz), 8.75 (1H, d, J=0.9 Hz).
A solution of diisobutylalminum hydride in toluene (1.0 M, 3.76 mL) was added dropwise to a cooled solution of ethyl 1-{[3-chloro-5-(trifluoromethyl)-2-pyridinyl]methyl}-2,4-dimethyl-1H-benzimidazole-6-carboxylate (516 mg) in tetrahydrofuran (12 mL) at −78° C. The mixture was stirred for 3 hours with warming slowly to 0° C. The reaction was quenched by careful addition of methanol, followed by addition of water. It was diluted with ethyl acetate, and inorganic salts were removed by celite pad filtration. Organic solvents were removed in vacuo, and the product was extracted with chloroform. The organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo to give (1-{[3-chloro-5-(trifluoromethyl)-2-pyridinyl]methyl}-2,4-dimethyl-1H-benzimidazol-6-yl)methanol (456 mg) as a powder.
MS (ES+): 370 (M++1).
Ethyl 2-[(1-{[3-chloro-5-(trifluoromethyl)-2-pyridinyl]methyl}-2,4-dimethyl-1H-benzimidazol-6-yl)methoxy]isonicotinate (75 mg) was synthesized from (1-{[3-chloro-5-(trifluoromethyl)-2-pyridinyl]methyl}-2,4-dimethyl-1H-benzimidazol-6-yl)methanol (150 mg) and ethyl 2-hydroxyisonicotinate (102 mg) in a manner similar to that described in Preparation Example 171.
MS (ES+): 519 (M++1).
Methyl 6-[(1-{[3-chloro-5-(trifluoromethyl)-2-pyridinyl]methyl}-2,4-dimethyl-1H-benzimidazol-6-yl)methoxy]-2-pyridinecarboxylate (63 mg) was synthesized from (1-{[3-chloro-5-(trifluoromethyl)-2-pyridinyl]methyl}-2,4-dimethyl-1H-benzimidazol-6-yl)methanol (150 mg) and methyl 6-hydroxy-2-pyridinecarboxylate (93 mg) in a manner similar to that described in Preparation Example 171.
MS (ES+): 505 (M++1).
To a mixture of 6-bromo-2,4-dimethyl-1H-benzimidazole (711 mg), K2CO3 (480 mg) and DMF (7 ml) was added 1-(bromomethyl)-2-chloro-4-(pentyloxy)benzene (1.01 g) and the mixture was heated at 50° C. for 6 hours. After cooling, the reaction mixture was diluted with EtOAc (40 ml) and washed with water (30 ml) and brine (2×30 ml). The organic layer was dried over MgSO4 and filtered. Evaporation gave a residue (1.52 g) which was chromatographed (silica gel, EtOAc/n-hexane=2/1→EtOAc) to give 6-bromo-1-[2-chloro-4-(pentyloxy)benzyl]-2,4-dimethyl-1H-benzimidazole (0.70 g) as a pale yellow oil.
NMR(DMSO-d6,δ): 0.87 (3H, t, J=6.8 Hz), 1.2-1.5 (4H, m), 1.5-1.8 (2H, m), 2.45 (3H, s), 2.50 (3H, s), 3.94 (2H, t, J=6.4 Hz), 5.43 (2H, br s), 6.49 (1H, d, J=8.6 Hz.), 6.83 (1H, dd, J=2.5 Hz, 8.6 Hz), 7.11 (1H, d, J=2.5 Hz), 7.14 (1H, br s), 7.46 (1H, br s).
MS: 435, 437 (1:1 ratio, Br isotopes, M+1).
To a suspension of 1-[2-chloro-4-(pentyloxy)benzyl]-2-methyl-1H-benzimidazole-6-carboxylic acid (100 mg) in DMF (2 ml) was added NaH (NaH; 60% dispersion in mineral oil) (12 mg) at 5° C. After stirring for 30 minutes at ambient temperature, ethyl 2-chloro-3-oxobutanoate (51 mg) was added and stirred for 4 hours. The reaction mixture was poured into water (30 ml) and extracted with EtOAc (2×30 ml). The combined organic extracts were washed with brine (2×30 ml), dried over MgSO4, and evaporated to give 1-(ethoxycarbonyl)-2-oxopropyl 1-[2-chloro-4-(pentyloxy)benzyl]-2-methyl-1H-benzimidazole-6-carboxylate (148 mg) as a crude oil.
NMR(DMSO-d6,δ): 0.8-1.0 (3H, m), 1.1-1.5 (7H, m), 1.5-1.8 (2H, m), 2.39 (3H, s), 2.57 (3H, s), 3.94 (2H, t, J=6.4 Hz), 4.22 (2H, q, J=7.1 Hz), 5.57 (2H, br s), 5.84 (1H, s), 6.72 (1H, d, J=8.7 Hz), 6.84 (1H, dd, J=2.4 Hz, 8.7 Hz), 7.10 (1H, d, J=2.4 Hz), 7.71 (1H, d, J=8.4 Hz), 7.88 (1H, dd, J=1.5 Hz, 8.4 Hz), 8.05 (1H, d, J=1.5 Hz).
MS: 515 (M+1).
To a solution of 1-(ethoxycarbonyl)-2-oxopropyl 1-[2-chloro-4-(pentyloxy)benzyl]-2-methyl-1H-benzimidazole-6-carboxylate (610 mg) in AcOH (3 ml) was added ammonium acetate (548 mg) at ambient temperature. The mixture was heated at 120° C. for 1 hour. After cooling, the reaction mixture was added saturated NaHCO3 (40 ml) and extracted with EtOAc (2×30 ml). The combined organic extracts were washed with saturated NaHCO3 (10 ml) and brine (30 ml). The organic layer was dried MgSO4 and filtered. Evaporation gave a residue (549 mg) which was chromatographed (silica gel, CH2Cl2/MeOH=100/1→100/2) to give ethyl 2-{1-[2-chloro-4-(pentyloxy)benzyl]-2-methyl-1H-benzimidazol-6-yl)-4-methyl-1,3-oxazole-5-carboxylate (132 mg) and ethyl 2-{1-[2-chloro-4-(pentyloxy)benzyl]-2-methyl-1H-benzimidazol-6-yl}-4-methyl-1H-imidazole-5-carboxylate (183 mg). Ethyl 2-{1-[2-chloro-4-(pentyloxy)benzyl]-2-methyl-1H-benzimidazol-6-yl}-4-methyl-1,3-oxazole-5-carboxylate
NMR(DMSO-d6,δ): 0.8-1.0 (3H, m), 1.2-1.5 (7H, m), 1.5-1.8 (2H, m), 2.44 (3H, s), 2.53 (3H, s), 3.94 (2H, t, J=6.4 Hz), 4.33 (2H, q, J=7.0 Hz), 5.58 (2H, br s), 6.56 (1H, d, J=8.6 Hz), 6.83 (1H, dd, J=2.3 Hz, 8.6 Hz), 7.13 (1H, d, J=2.3 Hz), 7.73 (1H, d, J=8.4 Hz), 7.87 (1H, dd, J=1.4 Hz, 8.4 Hz), 8.03 (1H, br s).
MS: 496 (M+1).
Ethyl 2-{1-[2-chloro-4-(pentyloxy)benzyl]-2-methyl-1H-benzimidazol-6-yl}-4-methyl-1H-imidazole-5-carboxylate
NMR(DMSO-d6,δ): 0.8-1.0 (3H, m), 1.2-1.4 (7H, m), 1.5-1.8 (2H, m), 2.46 (3H, s), 3.93 (2H, t, J=6.4 Hz), 4.24 (2H, q, J=7.0 Hz), 5.48 (2H, br s), 6.35 (1H, d, J=8.6 Hz), 6.80 (1H, dd, J=2.5 Hz, 8.6 Hz), 7.14 (1H, d, J=2.5 Hz), 7.64 (1H, d, J=8.4 Hz), 7.7-8.2 (2H, m), 12.74 (1H, br s).
MS: 493 (M−1).
To a solution of ethyl 4-amino-3-methylbenzoate (7.43 g) in DMF (35 ml) were added DMAP (506 mg) and acetic anhydride (4.66 g) at ambient temperature. After stirring for 4 hours, the reaction mixture was diluted with water (40 ml) and extracted with EtOAc (4×60 ml). The combined organic extracts were washed with saturated NaHCO3 (2×30 ml) and brine (3×100 ml). The organic layer was dried over MgSO4 and filtered. Evaporation gave a residue which was triturated with EtOAc—n-hexane to give ethyl 4-(acetylamino)-3-methylbenzoate (4.324 g) as white crystals. The filtrate was evaporated and triturated with EtOAc—n-hexane to give second crop (1.64 g).
NMR(DMSO-d6,δ): 1.31 (3H, t, J=7.1 Hz), 2.11 (3H, s), 2.28 (3H, s), 4.29 (2H, q, J=7.1 Hz), 7.7-7.8 (3H, m), 9.37 (1H, br s).
MS: 244 (M+Na).
To a mixture of H2SO4 (3 ml) and HNO3 (70%, d=1.42, 2.5 ml) was added ethyl 4-(acetylamino)-3-methylbenzoate (1.0 g) at 5° C. After stirring for 30 minutes, the reaction mixture was poured into ice and the precipitates were collected by filtration. The precipitates were dissolved in EtOAc (50 ml) and washed with brine (2×30 ml) and small portion of saturated NaHCO3. The organic layer was dried over MgSO4 and filtered. Evaporation gave a residue which was triturated with EtOAc (10 ml)—n-hexane (10 ml) to give ethyl 4-(acetylamino)-3-methyl-5-nitrobenzoate (963 mg) as white crystals.
NMR(DMSO-d6,δ): 1.34 (3H, t, J=7.1 Hz), 2.08 (3H, s), 2.38 (3H, s), 4.35 (2H, q, J=7.1 Hz), 8.1-8.2 (2H, m), 10.10 (1H, br s).
MS: 289 (M+Na).
To a solution of ethyl 4-(acetylamino)-3-methyl-5-nitrobenzoate (900 mg) in EtOH (20 ml) was added palladium on carbon (10%, 50% wet, 270 mg) at ambient temperature, and the resultant mixture was hydrogenated under atmospheric pressure of hydrogen for 9 hours. The catalyst was removed by filtration. Evaporation gave a residue (868 mg) which was triturated with EtOAc (5 ml)—n-hexane (5 ml) to give ethyl 4-(acetylamino)-3-amino-5-methylbenzoate (717 mg) as white crystals.
NMR(DMSO-d6,δ): 1.29 (3H, t, J=7.1 Hz), 2.05 (3H, s), 2.09 (3H, s), 4.26 (2H, q, J=7.1 Hz), 5.06 (2H, br s), 7.02 (1H, d, J=1.6 Hz), 7.20 (1H, d, J=1.6 Hz), 9.04 (1H, br s).
MS: 259 (M+Na).
To a suspension of ethyl 4-(acetylamino)-3-amino-5-methylbenzoate (23.9 g) in EtOH (239 ml) was added H2SO4 (10.8 ml) at ambient temperature. The mixture was heated at reflux for 12 hours. After cooling, the reaction mixture was evaporated, and added ice (300 g) and EtOAc (250 ml). The aqueous layer was neutralized with 20%-NaOH and the organic layer was separated. The aqueous layer was extracted with EtOAc (2×100 ml) again. The combined organic layers were washed with brine (150 ml), dried over MgSO4, and filtered. Evaporation gave a residue which was triturated with EtOAc—n-hexane to give ethyl 2,4-dimethyl-1H-benzimidazole-6-carboxylate (20.47 g) as white crystals. The filtrate was evaporated and triturated with EtOAc—n-hexane to give second crop (685 mg).
NMR(DMSO-d6,δ): 1.33 (3H, t, J=7.1 Hz), 2.4-2.6 (6H), 4.30 (2H, q, J=7.1 Hz), 7.58 (1H, br s), 7.89 (1H, br s), 12.50 (1H, br s).
MS: 219 (M+1).
Ethyl 1-(2,4-dichlorobenzyl)-2,4-dimethyl-1H-benzimidazole-6-carboxylate (714 mg) was synthesized from ethyl 2,4-dimethyl-1H-benzimidazole-6-carboxylate (500 mg) in a manner similar to that described in Preparation Example 38.
NMR(DMSO-d6,δ): 1.30 (3H, t, J=7.1 Hz), 2.52 (3H, s), 2.57 (3H, s), 4.28 (2H, q, J=7.1 Hz), 5.60 (2H, br s), 6.53 (1H, d, J=8.4 Hz), 7.33 (1H, dd, J=2.1 Hz, 8.4 Hz), 7.64 (1H, br s), 7.74 (1H, d, J=2.1 Hz), 7.83 (1H, br s).
MS: 377 (M+1).
1-(2,4-Dichlorobenzyl)-2,4-dimethyl-1H-benzimidazole-6-carboxylic acid (588 mg) was synthesized from ethyl 1-(2,4-dichlorobenzyl)-2,4-dimethyl-1H-benzimidazole-6-carboxylate (690 mg) in a manner similar to that described in Example 14.
NMR(DMSO-d6,δ): 2.52 (3H, s), 2.56 (3H, s), 5.59 (2H, br s), 6.50 (1H, d, J=8.4 Hz), 7.33 (1H, dd, J=2.2 Hz, 8.4 Hz), 7.63 (1H, br s), 7.74 (1H, d, J=2.2 Hz), 7.79 (1H, br s), 12.62 (1H, br s).
MS: 347 (M−1).
1-(Ethoxycarbonyl)-2-oxopropyl 1-(2,4-dichlorobenzyl)-2,4-dimethyl-1H-benzimidazole-6-carboxylate (1.0 g) was synthesized from 1-(2,4-dichlorobenzyl)-2,4-dimethyl-1H-benzimidazole-6-carboxylic acid (550 mg) in a manner similar to that described in Preparation Example 184.
Ethyl 2-[1-(2,4-dichlorobenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]-4-methyl-1,3-oxazole-5-carboxylate (251 mg) as white crystals, and ethyl 2-[1-(2,4-dichlorobenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]-4-methyl-1H-imidazole-5-carboxylate (174 mg) were synthesized from 1-(ethoxycarbonyl)-2-oxopropyl 1-(2,4-dichlorobenzyl)-2,4-dimethyl-1H-benzimidazole-6-carboxylate (750 mg) in a manner similar to that described in Preparation Example 185.
Ethyl 2-[1-(2,4-dichlorobenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]-4-methyl-1,3-oxazole-5-carboxylate
NMR(DMSO-d6,δ): 1.33 (3H, m), 2.44 (3H, s), 2.49 (3H, s), 2.61 (3H, s), 4.33 (2H, q, J=7.0 Hz), 5.64 (2H, br s), 6.49 (1H, d, J=8.3 Hz), 7.32 (1H, dd, J=2.1 Hz, 8.3 Hz), 7.71 (1H, br s), 7.75 (1H, d, J=2.1 Hz), 7.89 (1H, br s).
MS: 458 (M+1).
Ethyl 2-[1-(2,4-dichlorobenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]-4-methyl-1H-imidazole-5-carboxylate
NMR(DMSO-d6,δ): 1.29 (3H, t, J=7.0 Hz), 2.47 (3H, s), 2.4-2.5 (3H, s), 2.58 (3H, s), 4.23 (2H, q, J=7.0 Hz), 5.52 (2H, br s), 6.35 (1H, d, J=8.4 Hz), 7.32 (1H, dd, J=2.2 Hz, 8.4 Hz), 7.5-8.1 (2H, m), 7.76 (1H, d, J=2.2 Hz), 12.66 (1H, br s).
MS: 457 (M+1).
To a mixture of ethyl 2,4-dimethyl-1H-benzimidazole-6-carboxylate (500 mg), K2CO3 (412 mg) and DMF (5 ml) was added 4-(bromomethyl)-3-chloro-1,1′-biphenyl (774 mg) at ambient temperature. The mixture was heated at 80° C. for 4 hours. After cooling, the reaction mixture was diluted with EtOAc (150 ml) and washed with water (50 ml) and brine (2×50 ml). The organic layer was dried over MgSO4 and evaporated to give ethyl 1-[(3-chloro-1,1′-biphenyl-4-yl)methyl]-2,4-dimethyl-1H-benzimidazole-6-carboxylate (1.181 g) as a crude oil.
1-[(3-Chloro-1,1′-biphenyl-4-yl)methyl]-2,4-dimethyl-1H-benzimidazole-6-carboxylic acid (830 mg) was synthesized from ethyl 1-[(3-chloro-1,1′-biphenyl-4-yl)methyl]-2,4-dimethyl-1H-benzimidazole-6-carboxylate (959 mg) in a manner similar to that described in Example 14.
NMR(DMSO-d6,δ): 2.56 (3H, s), 2.57 (3H, s), 5.64 (2H, br s), 6.55 (1H, d, J=8.1 Hz), 7.3-7.6 (4H, m), 7.6-7.7 (3H, m), 7.8-7.9 (2H, m), 12.66 (1H, br s).
1-(Ethoxycarbonyl)-2-oxopropyl 1-[(3-chloro-1,1′-biphenyl-4-yl)methyl]-2,4-dimethyl-1H-benzimidazole-6-carboxylate (1.38 g) was synthesized from 1-[(3-chloro-1,1′-biphenyl-4-yl)methyl]-2,4-dimethyl-1H-benzimidazole-6-carboxylic acid (800 mg) in a manner similar to that described in Preparation Example 184.
Ethyl 2-{1-[(3-chloro-1,1′-biphenyl-4-yl)methyl]-2,4-dimethyl-1H-benzimidazol-6-yl}-4-methyl-1,3-oxazole-5-carboxylate (377 mg) as white crystals, and ethyl 2-{1-[(3-chloro-1,1′-biphenyl-4-yl)methyl]-2,4-dimethyl-1H-benzimidazol-6-yl}-4-methyl-1H-imidazole-5-carboxylate (236 mg) were synthesized from 1-(ethoxycarbonyl)-2-oxopropyl 1-[(3-chloro-1,1′-biphenyl-4-yl)methyl]-2,4-dimethyl-1H-benzimidazole-6-carboxylate (1.06 g) in a manner similar to that described in Preparation Example 185.
Ethyl 2-{1-[(3-chloro-1,1′-biphenyl-4-yl)methyl]-2,4-dimethyl-1H-benzimidazol-6-yl}-4-methyl-1,3-oxazole-5-carboxylate
NMR(DMSO-d6,δ): 1.32 (3H, t, J=7.0 Hz), 2.43 (3H, s), 2.56 (3H, s), 2.62 (3H, s), 4.32 (2H, q, J=7.0 Hz), 5.70 (2H, br s), 6.56 (1H, d, J=8.1 Hz), 7.3-7.8 (7H, m), 7.86 (1H, br s), 7.92 (1H, br s).
MS: 500 (M+1).
Ethyl 2-{1-[(3-chloro-1,1′-biphenyl-4-yl)methyl]-2,4-dimethyl-1H-benzimidazol-6-yl}-4-methyl-1H-imidazole-5-carboxylate
NMR(DMSO-d6,δ): 1.2-1.4 (3H, m), 2.3-2.5 (6H), 2.60 (3H, s), 4.1-4.4 (2H, m), 5.58 (2H, br s), 6.40 (1H, d, J=8.1 Hz), 7.3-8.1 (9H, m), 12.67 (1H, br s).
MS: 499 (M+1).
Ethyl 1-[2-chloro-4-(pentyloxy)benzyl]-2,4-dimethyl-1H-benzimidazole-6-carboxylate (1.28 g) was synthesized from ethyl 2,4-dimethyl-1H-benzimidazole-6-carboxylate (500 mg) in a manner similar to that described in Preparation Example 194 except that 1-(bromomethyl)-2-chloro-4-(pentyloxy)benzene (935 mg) was used instead-of 4-(bromomethyl)-3-chloro-1,1′-biphenyl.
1-[2-Chloro-4-(pentyloxy)benzyl]-2,4-dimethyl-1H-benzimidazole-6-carboxylic acid (716 mg) was synthesized from ethyl 1-[2-chloro-4-(pentyloxy)benzyl]-2,4-dimethyl-1H-benzimidazole-6-carboxylate (984 mg) in a manner similar to that described in Example 14.
NMR(DMSO-d6,δ): 0.87 (3H, t, J=7.0 Hz), 1.2-1.3 (4H, m), 1.6-1.8 (2H,m), 2.53 (3H,s), 2.55 (3H,s), 3.94 (2H, t, J=6.5 Hz), 5.50 (2H, br s), 6.52 (1H, d, J=8.7 Hz), 6.82 (1H, dd, J=2.6 Hz, 8.7 Hz), 7.11 (1H, d, J=2.6 Hz), 7.61 (1H, br s), 7.77 (1H, br s), 12.63 (1H, br s).
1-(Ethoxycarbonyl)-2-oxopropyl 1-[2-chloro-4-(pentyloxy)benzyl]-2,4-dimethyl-1H-benzimidazole-6-carboxylate (1.15 g) was synthesized from 1-[2-chloro-4-(pentyloxy)benzyl]-2,4-dimethyl-1H-benzimidazole-6-carboxylic acid (680 mg) in a manner similar to that described in Preparation Example 184.
Ethyl 2-{1-[2-chloro-4-(pentyloxy)benzyl]-2,4-dimethyl-1H-benzimidazol-6-yl}-4-methyl-1,3-oxazole-5-carboxylate (318 mg) as white crystals, and ethyl 2-{1-[2-chloro-4-(pentyloxy)benzyl]-2,4-dimethyl-1H-benzimidazol-6-yl}-4-methyl-1H-imidazole-5-carboxylate (201 mg) were synthesized from 1-(ethoxycarbonyl)-2-oxopropyl 1-[2-chloro-4-(pentyloxy)benzyl]-2,4-dimethyl-1H-benzimidazole-6-carboxylate (900 mg) in a manner similar to that described in Preparation Example 185. Ethyl 2-{1-[2-chloro-4-(pentyloxy)benzyl]-2,4-dimethyl-1H-benzimidazol-6-yl)-4-methyl-1,3-oxazole-5-carboxylate
NMR(DMSO-d6,δ): 0.7-1.0 (3H, m), 1.1-1.5 (7H, m), 1.5-1.8 (2H, m), 2.43 (3H, s), 2.53 (3H, s), 2.60 (3H, s), 3.94 (2H, t, J=6.4 Hz), 4.33 (2H, q, J=7.1 Hz), 5.54 (2H, br s), 6.52 (1H, d, J=8.6 Hz), 6.82 (1H, dd, J=2.5 Hz, 8.6 Hz), 7.12 (1H, d, J=2.5 Hz), 7.69 (1H, br s), 7.84 (1H, br s).
MS: 510 (M+1).
Ethyl 2-{1-[2-chloro-4-(pentyloxy)benzyl]-2,4-dimethyl-1H-benzimidazol-6-yl}-4-methyl-1H-imidazole-5-carboxylate
NMR(DMSO-d6,δ): 0.8-1.0 (3H, m), 1.2-1.4 (7H, m), 1.5-1.8 (2H, m), 2.46 (3H, s), 2.4-2.6 (3H, s), 2.58 (3H, s), 3.93 (2H, t, J=6.4 Hz), 4.1-4.4 (2H, m), 5.45 (2H, br s), 6.31 (1H, d, J=8.6 Hz), 6.79 (1H, dd, J=2.5 Hz, 8.6 Hz), 7.14 (1H, d, J=2.5 Hz), 7.5-8.1 (2H, m), 12.70 (1H, br s).
MS: 509 (M+1).
A mixture of 5-bromo-3-methyl-1,2-benzenediamine (1.79 g), tetraethyl orthocarbonate (9.3 ml) and acetic acid (AcOH) (695 mg) was heated at 80° C. for 1 hour. After cooling, the reaction mixture was evaporated. The residue was dissolved in EtOAc (50 ml) and washed with saturated NaHCO3 (2×30 ml) and brine (30 ml). The organic layer was dried over MgSO4 and filtered. Evaporation gave a residue which was chromatographed (silica gel, EtOAc/n-hexane=1/2→1/1) to give 6-bromo-2-ethoxy-4-methyl-1H-benzimidazole (1.91 g) as white crystals.
NMR(DMSO-d6,δ): 1.37 (3H, t, J=7.0 Hz), 2.37 (3H, s), 4.48 (2H, q, J=7.0 Hz), 7.02 (1H, br s), 7.28 (1H, br s), 12.01 (1H, br s).
MS: 255, 257 (1:1 ratio, Br isotopes, M+1).
To a mixture of 6-bromo-2-ethoxy-4-methyl-1H-benzimidazole (1.0 g), K2CO3 (704 mg) and DMF (10 ml) was added 1-(bromomethyl)-2-chloro-4-(pentyloxy)benzene (1.49 g) at ambient temperature. After stirring for 2 hours, the reaction mixture was diluted with EtOAc (150 ml) and washed with 5%-NaHCO3 (50 ml) and brine (2×50 ml). The organic layer was dried over MgSO4 and filtered. Evaporation gave a residue (2.25 g) which was triturated with EtOAc (2 ml)—n-hexane (2 ml) to give 6-bromo-1-[2-chloro-4-(pentyloxy)benzyl]-2-ethoxy-4-methyl-1H-benzimidazole (548 mg) as white crystals. The filtrate was evaporated and triturated with n-hexane to give second crop (589 mg).
NMR(DMSO-d6,δ): 0.8-1.0 (3H, m), 1.2-1.5 (7H, m), 1.5-1.8 (2H, m), 2.43 (3H, s), 3.95 (2H, t, J=6.5 Hz), 4.53 (2H, q, J=7.0 Hz), 5.20 (2H, br s), 6.8-6.9 (2H, m), 7.0-7.2 (2H, m), 7.29 (1H, d, J=1.6 Hz).
MS: 465, 467 (1:1 ratio, Br isotopes, M+1).
To a solution of (4-ethoxy-2-methoxyphenyl)methanol (200 mg) in CH2Cl2 (2 ml) were added triethyl amine (Et3N) (167 mg) and then methanesulfonyl chloride (MsCl) (189 mg) dropwise at 5° C. The reaction mixture was stirred for 2 hours at room temperature. The reaction mixture was diluted with EtOAc (30 ml) and washed with saturated NaHCO3 (2×20 ml) and brine (20 ml). The organic layer was dried over MgSO4, filtered, and evaporated to give 4-ethoxy-2-methoxybenzyl methanesulfonate (146 mg) as a crude oil.
Celite powder (38.0 g) and iron powder (27.6 g) were added to a mixture of 4-bromo-2-methyl-6-nitroaniline (38.0 g) and ammonium chloride (4.4 g) in a mixed solvent of ethanol (800 mL), tetrahydrofuran (400 mL) and water (400 mL). The mixture was heated at reflux for 2 hours and then cooled to room temperature. Inorganic salts were removed by celite pad filtration and washed with water and ethyl acetate. The organic layer was separated, washed with brine and dried over sodium sulfate. The crude product of 5-bromo-3-methyl-1,2-benzenediamine was used for the next step without purification.
MS (ES+): 201 (M++1), 242 (M++42).
Acetic anhydride (15.5 mL) was added to a solution of 5-bromo-3-methyl-1,2-benzenediamine (33.1 g) in acetic acid (330 mL) at room temperature, and the mixture was heated at reflux (bath temperature: 150° C.) for 3 hours. Cooled to room temperature, and acetic acid was removed (about a half) in vacuo. Neutralized with aqueous solution of sodium carbonate, and the organic materials were extracted with ethyl acetate. The organic layer was washed with aqueous solution of sodium bicarbonate and brine and dried over sodium sulfate. It was concentrated in vacuo, and the residue was treated with activated carbon in ethyl acetate. The resulted crude product was dissolved in ethanol (360 mL), sulfuric acid was added to this solution, and the mixture was heated at reflux (bath temperature: 120° C.) for 2 hours. After cooled to room temperature, the mixture was poured into ice-cooled aqueous solution of sodium carbonate. Ethanol was removed in vacuo, and the organic materials were extracted with ethyl acetate. The organic layer was washed with aqueous solution of sodium bicarbonate and brine and dried over sodium sulfate. It was concentrated in vacuo to give 6-bromo-2,4-dimethyl-1H-benzimidazole (33.3 g) as a powder.
1H NMR (200 MHz, DMSO-d6, δ/ppm): 2.45 (3H, s), 2.48 (3H, s), 7.07 (1H, br s), 7.44 (1H, br s), 12.3 (1H, br).
6-Bromo-1-(2,4-dichlorobenzyl)-2,4-dimethyl-1H-benzimidazole (3.27 g) was synthesized from 6-bromo-2,4-dimethyl-1H-benzimidazole (2.00 g) and 2,4-dichloro-1-(chloromethyl)benzene (1.91 g) in a manner similar to that described in Preparation Example 221.
1H NMR (200 MHz, DMSO-d6, δ/ppm): 2.44 (3H, s), 2.51 (3H, s), 5.51 (2H, s), 6.44 (1H, d, J=8.4 Hz), 7.16 (1H, s), 7.33 (1H, dd, J=8.4 Hz, 2.1 Hz), 7.52 (1H, d, J=1.6 Hz), 7.73 (1H, d, J=2.1 Hz).
6-Bromo-1-{[3-chloro-5-(trifluoromethyl)-2-pyridinyl]methyl}-2,4-dimethyl-1H-benzimidazole (203 mg) was synthesized from 6-bromo-2,4-dimethyl-1H-benzimidazole (180 mg) and 3-chloro-2-(chloromethyl)-5-(trifluoromethyl)pyridine (230 mg) in a manner similar to that described in Preparation Example 221.
1H NMR (200 MHz, DMSO-d6, δ/ppm): 2.41 (3H, s), 2.52 (3H, s), 5.77 (2H, s), 7.11 (1H, s), 7.53 (1H, d, J=1.5 Hz), 8.56 (1H, d, J=1.5 Hz), 8.75 (1H, s).
6-Bromo-1-(4-ethoxy-2-methylbenzyl)-2,4-dimethyl-1H-benzimidazole (269 mg) was synthesized from 6-bromo-2,4-dimethyl-1H-benzimidazole (200 mg) and 4-ethoxy-2-methylbenzyl methanesulfonate (267 mg) in a manner similar to that described in Preparation Example 221.
1H NMR (200 MHz, DMSO-d6, δ/ppm): 1.28 (3H, t, J=6.9 Hz), 2.32 (3H, s), 2.41 (3H, s), 2.51 (3H, s), 3.94 (2H, q, J=6.9 Hz), 5.35 (2H, s), 6.10 (1H, d, J=8.4 Hz), 6.60 (1H, dd, J=8.4 Hz, 2.6 Hz), 6.82 (1H, d, J=2.4 Hz), 7.13 (1H, s), 7.44 (1H, d, J=1.4 Hz).
6-Bromo-1-(4-ethoxy-2-methoxybenzyl)-2,4-dimethyl-1H-benzimidazole (129 mg) was synthesized from 6-bromo-2,4-dimethyl-1H-benzimidazole (200 mg) and 4-ethoxy-2-methoxybenzyl methanesulfonate (285 mg) in a manner similar to that described in Preparation Example 221.
1H NMR (200 MHz, DMSO-d6, δ/ppm): 1.29 (3H, t, J=6.9 Hz), 2.47 (3H, s), 2.50 (3H, s), 3.77 (3H, s), 3.99 (2H, q, J=6.9 Hz), 5.24 (2H, s), 6.44 (1H, dd, J=8.0 Hz, 2.5 Hz), 6.57 (1H, d, J=2.6 Hz), 6.77 (1H, d, J=8.0 Hz), 7.09 (1H, s), 7.45 (1H, d, J=1.5 Hz).
6-Bromo-1-(2-chloro-4-ethoxybenzyl)-2,4-dimethyl-1H-benzimidazole (292 mg) was synthesized from 6-bromo-2,4-dimethyl-1H-benzimidazole (200 mg) and 1-(bromomethyl)-2-chloro-4-ethoxybenzene (333 mg) in a manner similar to that described in Preparation Example 221.
1H NMR (200 MHz, DMSO-d6, δ/ppm): 1.29 (3H, t, J=6.9 Hz), 2.45 (3H, s), 2.50 (3H, s), 4.01 (2H, q, J=6.9 Hz), 5.43 (2H, s), 6.50 (1H, d, J=8.6 Hz), 6.83 (1H, dd, J=8.6 Hz, 2.5 Hz), 7.10 (1H, d, J=2.5 Hz), 7.13 (1H, m), 7.46 (1H, d, J=1.5 Hz).
6-Bromo-1-[(3,5-dichloro-2-pyridinyl)methyl]-2,4-dimethyl-1H-benzimidazole (260 mg) was synthesized from 6-bromo-2,4-dimethyl-1H-benzimidazole (200 mg) and (3,5-dichloro-2-pyridinyl)methyl methanesulfonate (284 mg) in a manner similar to that described in Preparation Example 221.
1H NMR (200 MHz, DMSO-d6, δ/ppm): 2.41 (3H, s), 2.49 (3H, s), 5.65 (2H, s), 7.11 (1H, t, J=0.9 Hz), 7.50 (1H, d, J=0.9 Hz), 8.33 (1H, d, J=2.3 Hz), 8.42 (1H, d, J=2.2 Hz).
6-Bromo-1-(2-chlorobenzyl)-2,4-dimethyl-1H-benzimidazole (270 mg) was synthesized from 6-bromo-2,4-dimethyl-1H-benzimidazole (200 mg) and 1-chloro-2-(chloromethyl)benzene (179 mg) in a manner similar to that described in Preparation Example 221.
MS (ES+): 349 (M++1).
Ethyl 4-[(6-bromo-2,4-dimethyl-1H-benzimidazol-1-yl)methyl]-3-chlorophenyl(methyl)carbamate (352 mg) was synthesized from 6-bromo-2,4-dimethyl-1H-benzimidazole (225 mg) and ethyl 4-(bromomethyl)-3-chlorophenyl(methyl)carbamate (460 mg) in a manner similar to that described in Preparation Example 221.
MS (ES+): 450 (M++1).
Acetic anhydride (8.58 mL) and sulfuric acid (46 μL) were, added to a solution of 4-bromo-2-methyl-6-nitroaniline (20.0 g) in acetic acid (200 mL) at room temperature, and the mixture was stirred at that temperature for 15 hours. Acetic acid was removed (about a half) in vacuo. Neutralized with aqueous solution of sodium carbonate, and the organic materials were extracted with ethyl acetate. The organic layer was washed with aqueous solution of sodium bicarbonate and brine and dried over sodium sulfate. It was concentrated in vacuo, and the residue was treated with activated carbon in ethyl acetate. The solution was concentrated in vacuo to give N-(4-bromo-2-methyl-6-nitrophenyl)acetamide (9.46 g) as a powder.
1H NMR (200 MHz, DMSO-d6, δ/ppm): 2.03 (3H, s), 2.28 (3H, s), 7.87 (1H, d, J=2.0 Hz), 7.95 (1H, d, J=2.1 Hz).
MS (ES+): 314 (M++42).
Ethyl 4′-(acetylamino)-3′-methyl-5′-nitro-1,1′-biphenyl-3-carboxylate (975 mg) was synthesized from N-(4-bromo-2-methyl-6-nitrophenyl)acetamide (1.0 g) and 3-(ethoxycarbonyl)phenylboronic acid (923 mg) in a manner similar to that described in Preparation Example 242.
1H NMR (200 MHz, DMSO-d6, δ/ppm): 1.35 (3H, t, J=7.1 Hz), 2.07 (3H, s), 2.38 (3H, s), 4.37 (2H, q, J=7.1 Hz), 7.66 (1H, t, J=7.8 Hz), 7.9-8.1 (3H, m), 8.24 (1H, s), 9.94 (1H, s).
Iron (powder) was added to a suspension of ethyl 4′-(acetylamino)-3′-methyl-5′-nitro-1,1′-biphenyl-3-carboxylate (1.56 g) in a mixed solvent of ethanol (10 mL) and acetic acid (3.2 mL), and the mixture was heated at 110° C. for 3 hours. It was diluted with ethyl acetate and neutralized by addition of aoueous solution of sodium bicarbonate. Inorganic salts were removed by celite pad filtration. The organic layer was separated, washed with brine and dried over sodium sulfate. The crude product of ethyl 3-(2,4-dimethyl-1H-benzimidazol-6-yl)benzoate (1.01 g) was purified over silica gel chromatography (chloroform:methanol=10:1).
MS (ES+): 295 (M++1).
Ethyl 3-{1-[(2,6-dichloro-3-pyridinyl)methyl]-2,4-dimethyl-1H-benzimidazol-6-yl}benzoate (210 mg) was synthesized from ethyl 3-(2,4-dimethyl-1H-benzimidazol-6-yl)benzoate (182 mg) and (2,6-dichloro-3-pyridinyl)methyl methanesulfonate (198 mg) in a manner similar to that described in Preparation Example 221.
MS (ES+): 454 (M++1).
Ethyl 3-{2,4-dimethyl-1-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methyl]-1H-benzimidazol-6-yl}benzoate (226 mg) was synthesized from ethyl 3-(2,4-dimethyl-1H-benzimidazol-6-yl)benzoate (150 mg) and 4-(chloromethyl)-5-methyl-2-phenyl-1,3-oxazole (116 mg) in a manner similar to that described in Preparation Example 221.
1H NMR (200 MHz, DMSO-d6, δ/ppm): 2.54 (3H, s), 2.56 (3H, s), 2.75 (3H, s), 4.37 (2H, q, J=7.1 Hz), 5.45 (2H, s), 7.32 (1H, s), 7.4-7.6 (4H, m), 7.64 (1H, d, J=7.9 Hz), 7.76 (1H, s), 5 7.8-8.1 (4H, m), 8.27 (1H, s).
Ethyl 3-{1-[(3-chloro-1,1′-biphenyl-4-yl)methyl]-2,4-dimethyl-1H-benzimidazol-6-yl}benzoate (128 mg) was synthesized from ethyl 3-(2,4-dimethyl-1H-benzimidazol-6-yl)benzoate (150 mg) and 4-(bromomethyl)-3-chloro-1,1′-biphenyl (215 mg) in a manner similar to that described in Preparation Example 221.
1H NMR (400 MHz, DMSO-d6, δ/ppm): 1.32 (3H, t, J=7.1 Hz), 2.52 (3H, s), 2.62 (3H, s), 4.33 (2H, q, J=7.1 Hz), 5.67 (2H, s), 6.57 (1H, d, J=8.1 Hz), 7.3-7.5 (4H, m), 7.5-7.6 (2H, m), 7.6-7.7 (2H, m), 7.84 (1H, d, J=1.8 Hz), 7.89 (1H, d, J=7.9 Hz), 7.94 (1H, d, J=7.9 Hz), 8.18 (1H, t, J=1.6 Hz).
Potassium carbonate (59 mg) and 5-(chloromethyl)-4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazole (109 mg) were added to a solution of ethyl 3-(2,4-dimethyl-1H-benzimidazol-6-yl)benzoate (100 mg) in N,N-dimethylformamide (2 mL) at room temperature, and the mixture was stirred at 80° C. for 3 hours. The reaction was quenched by addition of water, and the organic materials were extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. The crude product was purified over preparative thin layer chromatography (chloroform:methanol=20:1) to give ethyl 3-[2,4-dimethyl-1-({4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)-1H-benzimidazol-6-yl]benzoate (149 mg) as a powder.
MS (ES+): 550 (M++1).
Ethyl 4′-(acetylamino)-3′-nitro-1,1′-biphenyl-3-carboxylate (5.57 g) was synthesized from N-(4-bromo-2-nitrophenyl)acetamide (5.0 g) and 3-(ethoxycarbonyl)phenylboronic acid (4.31 g) in a manner similar to that described in Preparation Example 242.
1H NMR (200 MHz, DMSO-d6, δ/ppm): 1.35 (3H, t, J=7.1 Hz), 2.10 (3H, s), 4.37 (2H, q, J=7.1 Hz), 7.66 (1H, t, J=7.8 Hz), 7.74 (1H, d, J=8.5 Hz), 7.9-8.1 (3H, m), 8.2-8.3 (2H, m), 10.37 (1H, s).
MS (ES+): 370 (M++42).
Palladium on activated carbon (10%, dry, 155 mg) was added to a solution of ethyl 4′-(acetylamino)-3′-nitro-1,1′-biphenyl-3-carboxylate (956 mg) in a mixed solvent of tetrahydrofuran (15 mL) and ethanol (15 mL). The reaction bottle was purged by hydrogen gas, and the mixture was stirred at room temperature under hydrogen atmosphere (3 atm) for 8 hours. The bottle was purged by nitrogen gas, and the catalyst was filtered off. The solution was concentrated in vacuo to give ethyl 4′-(acetylamino)-3′-amino-1,1′-biphenyl-3-carboxylate (515 mg) as a powder.
MS (ES+): 299 (M++1), 340 (M++42).
Ethyl 3-[1-(2-chloro-4-ethoxybenzyl)-2-methyl-1H-benzimidazol-6-yl}benzoate (169 mg) was synthesized from ethyl 4′-(acetylamino)-3′-amino-1,1′-biphenyl-3-carboxylate (180 mg) and 1-(bromomethyl)-2-chloro-4-ethoxybenzene (196 mg) in a manner similar to that described in Preparation Example 230.
MS (ES+): 449 (M++1).
Ethyl 3-[1-(2,4-dichlorobenzyl)-2-methyl-1H-benzimidazol-6-yl]benzoate (73 mg) was synthesized from ethyl 4′-(acetylamino)-3′-amino-1,1′-biphenyl-3-carboxylate (180 mg) and 2,4-dichloro-1-(chloromethyl)benzene (130 mg) in a manner similar to that described in Preparation Example 230.
1H NMR (200 MHz, DMSO-d6, δ/ppm): 1.34 (3H, t, J=7.2 Hz), 2.47 (3H, s), 4.35 (2H, q, J=7.1 Hz), 5.64 (2H, s), 6.51 (1H, d, J=8.4 Hz), 7.33 (1H, dd, J=8.3 Hz, 2.3 Hz), 7.48 (1H, s), 7.5-8.0 (7H, m), 8.19 (1H, s).
Ethyl 3-(1-{[3-chloro-5-(trifluoromethyl)-2-pyridinyl]methyl}-2-methyl-1H-benzimidazol-6-yl)benzoate (160 mg) was synthesized from ethyl 4′-(acetylamino)-3′-amino-1,1′-biphenyl-3-carboxylate (185 mg) and 3-chloro-2-(chloromethyl)-5-(trifluoromethyl)pyridine (157 mg) in a manner similar to that described in Preparation Example 230.
1H NMR (200 MHz, DMSO-d6, δ/ppm): 1.33 (3H, t, J=7.1 Hz), 2.46 (3H, s), 4.34 (2H, q, J=7.2 Hz), 5.90 (2H, s), 7.48 (1H, dd, J=8.4 Hz, 1.5 Hz), 7.58 (1H, t, J=7.8 Hz), 7.65 (1H, d, J=8.4 Hz), 7.82 (1H, d, J=1.1 Hz), 7.92 (2H, m), 8.18 (1H, s), 8.56 (1H, d, J=1.7 Hz), 8.76 (1H, s).
Ethyl 3-[1-(4-ethoxy-2-methylbenzyl)-2-methyl-1H-benzimidazol-6-yl]benzoate (106 mg) was synthesized from ethyl 4′-(acetylamino)-3′-amino-1,1′-biphenyl-3-carboxylate (180 mg) and 4-ethoxy-2-methylbenzyl methanesulfonate (160 mg) in a manner similar to that described in Preparation Example 230.
1H NMR (200 MHz, DMSO-d6, δ/ppm): 1.23 (3H, t, J=7.0 Hz), 1.34 (3H, t, J=7.1 Hz), 2.35 (3H, s), 2.45 (3H, s), 3.94 (2H, q, J=6.9 Hz), 4.34 (2H, q, J=7.1 Hz), 5.47 (2H, s), 6.23 (1H, d, J=8.5 Hz), 6.61 (1H, dd, J=8.4 Hz, 2.6 Hz), 6.82 (1H, d, J=2.4 Hz), 7.49 (1H, dd, J=8.3 Hz, 1.5 Hz), 7.58 (1H, t, J=7.7 Hz), 7.67 (1H, d, J=8.4 Hz), 7.71 (1H, d, J=0.9 Hz), 7.8-8.0 (2H, m), 8.16 (1H, s).
Ethyl 3-{1-[(2,6-dichloro-3-pyridinyl)methyl]-2-methyl-1H-benzimidazol-6-yl}benzoate (234 mg) was synthesized from ethyl 4′-(acetylamino)-3′-amino-1,1′-biphenyl-3-carboxylate (180 mg) and (2,6-dichloro-3-pyridinyl)methyl methanesulfonate (170 mg) in a manner similar to that described in Preparation Example 230.
1H NMR (200 MHz, DMSO-d6, δ/ppm): 1.34 (3H, t, J=7.1 Hz), 2.49 (3H, s), 4.35 (2H, q, J=7.1 Hz), 5.64 (2H, s), 6.92 (1H, d, J=8.1 Hz), 7.45 (1H, d, J=8.1 Hz), 7.53 (1H, dd, J=8.2 Hz, 1.6 Hz), 7.61 (1H, d, J=7.7 Hz), 7.70 (1H, d, J=8.4 Hz), 7.8-8.0 (3H, m), 8.19 (1H, s).
Ethyl 3-(1-{2-chloro-4-[(ethoxycarbonyl)(methyl)amino]benzyl}-2-methyl-1H-benzimidazol-6-yl)benzoate (177 mg) was synthesized from ethyl 4′-(acetylamino)-3′-amino-1,1′-biphenyl-3-carboxylate (180 mg) and ethyl 4-(bromomethyl)-3-chlorophenyl(methyl)carbamate (222 mg) in a manner similar to that described in Preparation Example 230.
1H NMR (200 MHz, DMSO-d6, δ/ppm): 1.13 (3H, t, J=7.1 Hz), 1.34 (3H, t, J=7.1 Hz), 2.50 (3H, s), 3.18 (3H, s), 4.05 (2H, q, J=7.1 Hz), 4.35 (2H, q, J=7.1 Hz), 5.63 (2H, s); 1H, d, J=8.4 Hz), 7.19 (1H, dd, J=8.4 Hz, 2.2 Hz), 7.5-7.7 (3H, m), 7.82 (1H, d, J=0.9 Hz), 7.9-8.0 (2H, m), 8.19 (1H, s).
Potassium carbonate (92 mg) and 4-(bromomethyl)-3-chloro-1,1′-biphenyl (255 mg) were added to a solution of ethyl 4′-(acetylamino)-3′-amino-1,1′-biphenyl-3-carboxylate (180 mg) in N,N-dimethylformamide (4 mL) at room temperature, and the mixture was stirred at 80° C. for 2 hours. The reaction was quenched by addition of water, and the organic materials were extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate.
The crude product was dissolved in ethanol (4 mL), and sulfuric acid (0.80 mL) was added to it at room temperature. The mixture was heated at reflux for 2 hours and cooled to room temperature. The mixture was neutralized by addition of an aqueous solution of sodium carbonate, and the organic materials were extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. The crude product was purified over preparative thin layer chromatography (chloroform:methanol 20:1) to give ethyl 3-{1-[(3-chloro-1,1′-biphenyl-4-yl)methyl]-2-methyl-1H-benzimidazol-6-yl}benzoate (204 mg) as a powder.
MS (ES+): 481 (M++1).
1-(2,4-Dichlorobenzyl)-2,4-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzimidazole was synthesized from 6-bromo-1-(2,4-dichlorobenzyl)-2,4-dimethyl-1H-benzimidazole (100 mg) and 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (65 mg) in a manner similar to that described in Preparation Example 238. The crude solution was used for the next step without further treatment.
Methyl 2-[1-(2,4-dichlorobenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]isonicotinate was synthesized from 1-(2,4-dichlorobenzyl)-2,4-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzimidazole (crude solution, Preparation Example 231) and methyl 2-chloroisonicotinate (98 mg) in a manner similar to that described in Preparation Example 242. The crude solution was used for the next step without further treatment.
1-(2-Chloro-4-ethoxybenzyl)-2,4-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzimidazole was synthesized from 6-bromo-1-(2-chloro-4-ethoxybenzyl)-2,4-dimethyl-1H-benzimidazole (100 mg) and 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (65 mg) in a manner similar to that described in Preparation Example 238. The crude solution was used for the next step without further treatment.
Ethyl 2-[1-(2-chloro-4-ethoxybenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]isonicotinate (86 mg) was synthesized from 1-(2-chloro-4-ethoxybenzyl)-2,4-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzimidazole (crude solution, Preparation Example 233) and ethyl 2-chloroisonicotinate (107 mg) in a manner similar to that described in Preparation Example 242.
1H NMR (200 MHz, DMSO-d6, δ/ppm): 1.27 (3H, t, J=6.9 Hz), 1.37 (3H, t, J=7.1 Hz), 2.5 (3H, s), 2.61 (3H, s), 4.00 (2H, q, J=7.0 Hz), 4.40 (2H, q, J=7.1 Hz), 5.55 (2H, s), 6.50 (1H, d, J=8.7 Hz), 6.82 (1H, dd, J=8.7 Hz, 2.6 Hz), 7.12 (1H, d, J=2.5 Hz), 7.71 (1H, dd, J=5.0 Hz, 1.2 Hz), 7.83 (1H, s), 8.00 (1H, s), 8.30 (1H, s), 8.81 (1H, d, J=5.0 Hz).
Ethyl 6-[1-(2-chloro-4-ethoxybenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]-2-pyridinecarboxylate (94 mg) was synthesized from 1-(2-chloro-4-ethoxybenzyl)-2,4-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzimidazole (crude solution, Preparation Example 233) and ethyl 6-chloro-2-pyridinecarboxylate (54 mg) in a manner similar to that described in Preparation Example 242.
MS (ES+): 464 (M++1).
Methyl 6-[1-(2-chloro-4-ethoxybenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]nicotinate was synthesized from 1-(2-chloro-4-ethoxybenzyl)-2,4-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzimidazole (crude solution, Preparation Example 233) and methyl 6-chloroisonicotinate (50 mg) in a manner similar to that described in Preparation Example 242. The crude solution was used for the next step without purification.
Ethyl 5-[1-(2-chloro-4-ethoxybenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]-2-thiophenecarboxylate was synthesized from 1-(2-chloro-4-ethoxybenzyl)-2,4-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzimidazole (crude solution, Preparation Example 233) and ethyl 5-bromo-2-thiophenecarboxylate (67 mg) in a manner similar to that described-in Preparation Example 242. The crude product was used for the next step without purification.
MS (ES+): 495 (M++1).
Dichlorobis(triphenylphosphine)palladium (17 mg) and potassium acetate (94 mg) were added to a solution of 6-bromo-1-{[3-chloro-5-(trifluoromethyl)-2-pyridinyl]methyl}-2,4-dimethyl-1H-benzimidazole (100 mg) and 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (61 mg) in 1,4-dioxane (1 mL), and the mixture was heated at 80° C. with stirring for 15 hours. The crude solution of 1-{[3-chloro-5-(trifluoromethyl)-2-pyridinyl]methyl}-2,4-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzimidazole was used for the next step without further treatment.
Methyl 2-(1-{[3-chloro-5-(trifluoromethyl)-2-pyridinyl]methyl}-2,4-dimethyl-1H-benzimidazol-6-yl)isonicotinate (82 mg) was synthesized from 1-{[3-chloro-5-(trifluoromethyl)-2-pyridinyl]methyl}-2,4-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzimidazole (crude solution, Preparation Example 238) and ethyl 2-chloroisonicotinate (106 mg) in a manner similar to that described in Preparation Example 242.
1H NMR (200 MHz, DMSO-d6, δ/ppm): 1.36 (3H, t, J=7.1 Hz), 2.47 (3H, s), 2.61 (3H, s), 4.39 (2H, q, J=7.1 Hz), 5.90 (2H, s), 7.70 (1H, dd, J=4.9 Hz, 1.3 Hz), 7.80 (1H, s), 8.02 (1H, s) 8.29 (1H, s), 8.57 (1H, d, J=1.8 Hz), 8.76 (1H, s), 8.80 (1H, d, J=5.0 Hz).
Ethyl 6-(1-{[3-chloro-5-(trifluoromethyl)-2-pyridinyl]methyl}-2,4-dimethyl-1H-benzimidazol-6-yl)-2-pyridinecarboxylate (67 mg) was synthesized from 1-{[3-chloro-5-(trifluoromethyl)-2-pyridinyl]methyl}-2,4-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzimidazole (crude solution, Preparation Example 238) and ethyl 6-chloro-2-pyridinecarboxylate (53 mg) in a manner similar to that described in Preparation Example 242.
MS (ES+): 489 (M++1).
Ethyl 4-[1-(2-chloro-4-ethoxybenzyl)-2,4-dimethyl-1-H-benzimidazol-6-yl]benzoate (95 mg) was synthesized from 6-bromo-1-(2-chloro-4-ethoxybenzyl)-2,4-dimethyl-1H-benzimidazole (100 mg) and 4-(ethoxycarbonyl)phenylboronic acid (64 mg) in a manner similar to that described in Preparation Example 242.
MS (ES+): 463 (M++1).
4-(Ethoxycarbonyl)phenylboronic acid (60 mg), tetrakis(triphenylphosphine)palladium (14 mg), and lithium chloride (30 mg) were added to a solution of 6-bromo-1-{[3-chloro-5-(trifluoromethyl)-2-pyridinyl]methyl}-2,4-dimethyl-1H-benzimidazole (100 mg) in 1,2-dimethoxyethane (2 mL). An aqueous solution of sodium carbonate (2 N, 0.36 mL) was added to it, and the mixture was heated at reflux for 5 hours. It was cooled to room temperature, diluted with chloroform, and neutralized by addition of 1 N hydrochloric acid. The organic layer was separated, washed with water, and dried over sodium sulfate. The crude product was purified over preparative thin-layer chromatography (ethyl acetate) to give ethyl 4-(1-{[3-chloro-5-(trifluoromethyl)-2-pyridinyl]methyl}-2,4-dimethyl-1H-benzimidazol-6-yl)benzoate (92 mg) as a powder.
MS (ES+): 488 (M++1).
1-(2,4-Dichlorobenzyl)-6-(3-methoxyphenyl)-2,4-dimethyl-1H-benzimidazole (1.75 g) was synthesized from 6-bromo-1-(2,4-dichlorobenzyl)-2,4-dimethyl-1H-benzimidazole (2.0 g) and 3-methoxyphenylboronic acid (989 mg) in a manner similar to that described in Preparation Example 242.
MS (ES+): 411 (M++1).
Boron tribromide (0.75 mL) was added dropwise to an ice-cooled solution of 1-(2,4-dichlorobenzyl)-6-(3-methoxyphenyl)-2,4-dimethyl-1H-benzimidazole (1.55 g) in dichloromethane (30 mL), and the mixture was stirred at that temperature for 1 hour. The reaction was quenched by addition of water, and pH was adjusted to 6. The organic layer was separated, washed with water and brine, and dried over sodium sulfate. It was concentrated in vacuo to give 3-[1-(2,4-dichlorobenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]phenol (1.35 g) as a powder.
MS (ES+): 397 (M++1).
Potassium carbonate (115 mg) and ethyl bromoacetate (46 μL) were added to a solution of 3-[1-(2,4-dichlorobenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]phenol (150 mg) in N,N-dimethylformamide (3 mL) at room temperature, and the mixture was stirred at 60° C. for 2 hours. The reaction was quenched by addition of water, and the organic materials were extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. The crude product was purified over preparative thin layer chromatography (chloroform:methanol=20:1) to give ethyl {3-[1-(2,4-dichlorobenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]phenoxy}acetate (142 mg) as a powder.
MS (ES+): 483 (M++1).
Ethyl 3-{1-[2-chloro-4-(pentyloxy)benzyl]-2-ethoxy-4-methyl-1H-benzimidazol-6-yl}benzoate (169 mg) was synthesized from 6-bromo-1-[2-chloro-4-(pentyloxy)benzyl]-2-ethoxy-4-methyl-1H-benzimidazole (200 mg) and 3-(ethoxycarbonyl)phenylboronic acid (108 mg) in a manner similar to that described in Preparation Example 242.
MS (ES+): 535 (M++1).
({1-[2-Chloro-4-(pentyloxy)benzyl]-2-methyl-1H-benzimidazol-6-yl}oxy)acetic acid (15 mg) was synthesized from ethyl 4-({1-[2-chloro-4-(pentyloxy)benzyl]-2-methyl-1H-benzimidazol-6-yl}oxy)acetate (61 mg) in a manner similar to that described in Example 4.
NMR(DMSO-d6,δ): 0.87 (3H, t, J=7.1 Hz), 1.3-1.4 (4H, m), 1.6-1.7 (2H, m), 2.39 (3H, s), 3.94 (2H, t, J=6.5 Hz), 4.60 (2H, s),5.39 (2H, s), 6.50 (1H, d, J=8.6 Hz), 6.7-6.9 (2H, m), 6.98 (1H, d, J=2.3 Hz), 7.10 (1H, d, J=2.5 Hz), 7.43 (1H, d, J=8.7 Hz).
MS(API-ES, Posi): 417.2.
2-({1-[2-Chloro-4-(pentyloxy)benzyl]-2-methyl-1H-benzimidazol-6-yl}oxy)-2-methylpropanoic acid (87 mg) was synthesized from ethyl 2-({1-[2-chloro-4-(pentyloxy)benzyl]-2-methyl-1H-benzimidazol-6-yl}oxy)-2-methylpropanoate (120 mg) in a manner similar to that described in Example 4.
NMR(DMSO-d6,δ): 0.87 (3H, t, J=7.0 Hz), 1.2-1.4 (4H, m), 1.40 (6H, s), 2.45 (3H, s), 3.94 (2H, t, J=6.4 Hz), 5.34 (2H, s), 6.61 (1H, d, J=8.6 Hz), 6.73 (1H, dd, J=8.6 Hz, 2.3 Hz), 7.8-7.9 (2H, m), 7.09 (1H, d, J=2.5 Hz), 7.41 (1H, d, J=8.6 Hz), 13.0 (1H, broad s).
MS(API-ES; Posi): 445.2.
To a suspension of 1-[2-chloro-4-(pentyloxy)benzyl]-2-methyl-1H-benzimidazol-6-ol (1.0 g) in a solvent mixture of tetrahydrofuran (5 mL) and N,N-dimethylformamide (5 mL) was added sodium hydride (60% dispersion in mineral oil; 123 mg). The mixture was stirred at 80° C. for 15 minutes and allowed to cool to ambient temperature. To the mixture was added β-propiolactone (1.0 g) in an ice-bath. After stirring overnight at ambient temperature, the mixture was partitioned between ethyl acetate and saturated aqueous ammonium chloride. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (elution; 10:1 chloroform-methanol) to give 3-({1-[2-chloro-4-(pentyloxy)benzyl]-2-methyl-1H-benzimidazol-6-yl}oxy)propanoic acid (17 mg) as a white solid.
NMR(DMSO-d6,δ): 0.87 (3H, t, J=7 Hz), 1.2-2.0 (6H, m), 2.39 (3H, s), 2.66 (2H, t, J=6 Hz), 3.93 (2H, t, J=6 Hz), 4.11 (2H, t, J=6 Hz), 5.40 (2H, s), 6.47 (1H, d, J=8 Hz), 6.7-6.9 (2H, m), 6.99 (1H, d, J=2 Hz), 7.10 (1H, d, J=2 Hz), 7.42 (1H, d, J=9 Hz).
MS: 431 (M+1).
A solution of ethyl 4-({1-[2-chloro-4-(pentyloxy)benzyl]-2-methyl-1H-benzimidazol-6-yl}oxy)butanoate (0.26 g) in ethanol (4 mL) was treated with 4 N sodium hydroxide (2 mL). After stirring for an hour at ambient temperature, the mixture was acidified with 3 N hydrochloric acid and concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was recrystallized from ethyl acetate to give 4-({1-[2-chloro-4-(pentyloxy)benzyl]-2-methyl-1H-benzimidazol-6-yl}oxy)butanoic acid (0.17 g) as a white solid.
NMR(DMSO-d6,δ): 0.87 (3H, t, J=7 Hz), 1.2-2.0 (8H, m), 2.37 (2H, t, J=7 Hz), 2.40 (3H, s), 3.92 (2H, t, J=6 Hz), 3.93 (2H, t, J=6 Hz), 5.40 (2H, s), 6.48 (1H, d, J=8 Hz), 6.7-6.9 (2H, m), 6.98 (1H, d, J=2 Hz), 7.10 (1H, d, J=2 Hz), 7.44 (1H, d, J=9 Hz), 12.13 (1H, br s).
MS: 443 (M−H).
5-({1-[2-Chloro-4-(pentyloxy)benzyl]-2-methyl-1H-benzimidazol-6-yl}oxy)pentanoic acid (0.15 g) was synthesized from ethyl 5-({1-[2-chloro-4-(pentyloxy)benzyl]-2-methyl-1H-benzimidazol-6-yl}oxy)pentanoate (200 mg) in a manner similar to that described in Example 4.
NMR(DMSO-d6,δ): 0.87 (3H, t, J=7 Hz), 1.2-1.8 (10H, m), 2.27 (2H, t, J=7 Hz), 2.75 (3H, s), 3.97 (4H, t, J=6 Hz), 5.66 (2H, s), 6.89 (1H, dd, J=3 Hz, 9 Hz), 7.04 (1H, d, J=9 Hz), 7.1-7.2 (2H, m), 7.29 (1H, d, J=2 Hz), 7.70 (1H, d, J=9 Hz), 11.5-12.7 (1H, br m).
MS: 457 (M−H).
6-({1-[2-Chloro-4-(pentyloxy)benzyl]-2-methyl-1H-benzimidazol-6-yl}oxy)hexanoic acid (0.14 g) was synthesized from ethyl 6-({1-[2-chloro-4-(pentyloxy)benzyl]-2-methyl-1H-benzimidazol-6-yl}oxy)hexanoate (270 mg) in a manner similar to that described in Example 4.
NMR(DMSO-d6,δ): 0.87 (3H, t, J=7 Hz), 1.2-1.7 (12H, m), 2.22 (2H, t, J=7 Hz), 2.74 (3H, s), 3.97 (4H, t, J=6 Hz), 5.65 (2H, s), 6.89 (1H, dd, J=2 Hz, 9 Hz), 7.03 (1H, d, J=9 Hz), 7.0-7.2 (2H, m), 7.26 (1H, d, J=9 Hz), 7.68 (1H, d, J=9 Hz), 11.5-12.7 (1H, br m).
MS: 473 (M+1).
4-({1-[2-Chloro-4-(pentyloxy)benzyl]-2-methyl-1H-benzimidazol-7-yl}oxy)butanoic acid (80 mg) was synthesized from ethyl 4-({1-[2-chloro-4-(pentyloxy)benzyl]-2-methyl-1H-benzimidazol-7-yl}oxy)butanoate (180 mg) in a manner similar to that described in Example 4.
NMR(DMSO-d6,δ): 0.86 (3H, t, J=7.0 Hz), 1.2-1.4 (4H, m), 1.6-1.8 (4H, m), 2.11 (2H, t, J=7.4 Hz), 2.41 (3H, s), 3.9-4.0 (4H, m), 5.59 (2H, s), 6.13 (1H, d, J=8.7 Hz), 6.67 (1H, d, J=8.0 Hz), 6.75 (1H, d, J=2.5 Hz), 6.77 (1H, d, J=2.6 Hz), 7.0-7.1 (2H, m), 7.16 (1H, d, J=7.9 Hz).
MS(API-ES Nega): 443.2.
4-({1-[2-Chloro-4-(pentyloxy)benzyl]-2-methyl-1H-benzimidazol-4-yl}oxy)butanoic acid (151 mg) was synthesized from ethyl 4-({1-[2-chloro-4-(pentyloxy)benzyl]-2-methyl-1H-benzimidazol-4-yl}oxy)butanoate (209 mg) in a manner similar to that described in Example 4.
NMR(DMSO-d6,δ): 0.87 (3H, t, J=7.1 Hz), 1.3-1.4 (4H, m), 1.6-1.7 (2H, m), 1.9-2.0 (2H, m), 2.4-2.5 (5H, m), 3.93 (2H, t, J=6.5 Hz), 4.20 (2H, t, J=6.4 Hz), 5.39 (2H, s), 6.48 (1H, d, J=8.6 Hz), 6.67 (1H, d, J=6.6 Hz), 6.80 (1H, dd, J=9.0 Hz, 2.5 Hz), 6.89 (1H, d, J=7.6 Hz), 7.01 (1H, t, J=8.0 Hz), 7.09 (1H, d, J=2.5 Hz), 12.2 (1H, broad s).
MS(API-ES, Posi): 445.2.
A mixture of tert-butyl ({1-[2-chloro-4-(pentyloxy)benzyl]-2-methyl-1H-benzimidazol-7-yl}oxy)acetate (210 mg), trifluoroacetic acid (2 mL) and methanol (2 mL) was stirred at ambient temperature for 16 hours to form the corresponding methyl ester. The mixture was concentrated in vacuo and the residue was dissolved in ethanol (2 mL) and treated with 1 N sodium hydroxide (1 mL). After stirring at 60° C. for an hour, the mixture was cooled in an ice-bath and treated with 1 N hydrochloric acid (1 mL). The resulting suspension was filtered to give ({1-[2-chloro-4-(pentyloxy)benzyl]-2-methyl-1H-benzimidazol-7-yl}oxy)acetic acid (180 mg).
NMR(DMSO-d6,δ): 0.87 (3H, t, J=7.1 Hz), 1.2-1.4 (4H, m), 1.6-1.8 (2H, m), 2.36 (3H, s), 3.91 (2H, t, J=6.5 Hz), 4.66 (2H, s), 5.73 (2H, s), 6.31 (1H, d,J=8.7 Hz), 6.69 (1H, d, J=7.8 Hz), 6.76 (1H, dd, J=8.7 Hz, 2.6 Hz), 7.0-7.1 (2H, m), 7.20 (1H, d, J=7.8 Hz).
MS(API-ES, Nega): 415.2.
6-({1-[2-Chloro-4-(pentyloxy)benzyl]-2-methyl-1H -benzimidazol-4-yl}oxy)hexanoic acid (0.35 g) was synthesized from ethyl 6-({1-[2-chloro-4-(pentyloxy)benzyl]-2-methyl-1H -benzimidazol-4-yl}oxy)hexanoate (1.16 g) in a manner similar to that described in Example 4.
NMR(DMSO-d6,δ): 0.87 (3H, t, J=7 Hz), 0.9-1.8 (12H, m), 2.25 (2H, t, J=7 Hz), 2.44 (3H, s), 3.93 (2H, t, J=6 Hz), 4.17 (2H, t, J=6 Hz), 5.39 (2H, s), 6.47 (1H, d, J=9 Hz), 6.65 (1H, d, J=7 Hz), 6.7-7.1 (3H, m), 7.09 (1H, d, J=2 Hz), 12.03 (1H, br s).
MS: 471 (M−1).
6-({1-[2-Chloro-4-(pentyloxy)benzyl]-2-methyl-1H -benzimidazol-7-yl}oxy)hexanoic acid (0.45 g) was synthesized from ethyl 6-({1-[2-chloro-4-(pentyloxy)benzyl]-2-methyl-1H -benzimidazol-7-yl}oxy)hexanoate (730 mg) in a manner similar to that described in Example 4.
NMR(DMSO-d6,δ): 0.87 (3H, t, J=7 Hz), 1.0-1.8 (12H, m), 2.08 (2H, t, J=7 Hz), 2.76 (3H, s), 3.95 (2H, t, J=6 Hz), 3.99 (2H, t, J=6 Hz), 5.72 (2H, s), 6.57 (1H, d, J=9 Hz), 6.78 (1H, dd, J=2 Hz, 9 Hz), 7.05 (1H, d, J=7 Hz), 7.16 (1H, d, J=2 Hz), 7.3-7.5 (2H, m).
MS: 471 (M−1).
4-({1-[2-Chloro-4-(pentyloxy)benzyl]-2-methyl-1H -benzimidazol-5-yl}oxy)butanoic acid (44 mg) was synthesized from ethyl 4-({1-[2-chloro-4-(pentyloxy)benzyl]-2-methyl-1H -benzimidazol-5-yl}oxy)butanoate (62 mg) in a manner similar to that described in Example 4.
NMR(DMSO-d6,δ): 0.87 (3H, t, J=7.1 Hz), 1.3-1.4 (4H, m), 1.6-1.7 (2H, m), 1.9-2.0 (2H, m), 2.38 (2H, t, J=7.7 Hz), 2.43 (3H, s), 3.9-4.0 (4H, m), 5.38 (2H, s), 6.51 (2H, d, J=4.3 Hz), 6.7-6.9 (2H, m), 7.0-7.1 (2H, m), 7.18 (1H, d, J=4.3 Hz), 12.1 (1H, broad s).
MS(API-ES Posi): 445.3.
6-({1-[2-Chloro-4-(pentyloxy)benzyl]-2-methyl-1H -benzimidazol-5-yl}oxy)hexanoic acid (0.76 g) was synthesized from ethyl 6-({1-[2-chloro-4-(pentyloxy)benzyl]-2-methyl-1H -benzimidazol-5-yl)oxy}hexanoate (1.5 g) in a manner similar to that described in Example 4.
NMR(DMSO-d6,δ): 0.87 (3H, t, J=7 Hz), 1.3-1.8 (12H, m), 2.23 (2H, t, J=7 Hz), 2.81 (3H, s), 3.97 (2H, t, J=6 Hz), 4.03 (2H, t, J=6 Hz), 5.65 (2H, s), 6.89 (1H, dd, J=2 Hz, 9 Hz), 7.0-7.2 (3H, m), 7.24 (1H, d, J=2 Hz), 7.50 (1H, d, J=9 Hz), 11.5-12.7 (1H, br m).
To a solution of ethyl 4-({1-[2-chloro-4-(pentyloxy)benzyl]-2,4-dimethyl-1H-benzimidazol-6-yl}oxy)butanoate (46 mg) in dioxane (0.4 ml) was added 1N-NaOH (0.19 ml) at ambient temperature. The mixture was heated at 90° C. for 3 hours. After cooling, the pH of the reaction mixture was adjusted to around 3.5 with 1N-HCl. The precipitates were collected by filtration and washed with water and MeOH to give 4-({1-[2-chloro-4-(pentyloxy)benzyl]-2,4-dimethyl-1H-benzimidazol-6-yl}oxy)butanoic acid (36 mg) as white crystals.
NMR(DMSO-d6,δ): 0.8-1.0 (3H, m), 1.2-1.5 (4H, m), 1.5-1.8 (2H, m), 1.8-2.0 (2H, m), 2.35 (2H, t, J=7.1 Hz), 2.39 (3H, s), 2.46 (3H, s), 3.8-4.0 (4H, m), 5.37 (2H, br s), 6.42 (1H, d, J=8.6 Hz), 6.60 (1H, d, J=1.5 Hz), 6.7-6.9 (2H, m), 7.10 (1H, d, J=2.5 Hz), 12.15 (1H, br s).
MS: 459 (M+1).
4-{[1-(2,4-Dichlorobenzyl)-2,4-dimethyl-1H-benzimidazol -6-yl]oxy}butanoic acid (95 mg) was synthesized from ethyl 4-{[1-(2,4-dichlorobenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]oxy}butanoate (200 mg) in a manner similar to that described in Example 14.
NMR(DMSO-d6,δ): 1.8-2.0 (2H, m), 2.36 (2H, t, J=7.2 Hz), 2.38 (3H, s), 2.47 (3H, s), 3.90 (2H, t, J=6.4 Hz), 5.45 (2H, br s), 6.40 (1H, d, J=8.4 Hz), 6.62 (1H, d, J=1.8 Hz), 6.81 (1H, d, J=1.8 Hz), 7.32 (1H, dd, J=2.2 Hz, 8.4 Hz), 7.72 (1H, d, J=2.2 Hz), 12.12 (1H, br s).
MS: 405 (M−1).
To a solution of ethyl 4-[(1-{[3-chloro-5-(trifluoromethyl)-2-pyridinyl]methyl}-2,4-dimethyl-1H -benzimidazol-6-yl)oxy]butanoate (200 mg) in dioxane (2 ml) was added 1N-NaOH (0.85 ml) at ambient temperature. The mixture was heated at 80° C. for 3 hours. After cooling, the reaction mixture was neutralized with 1N-HCl. The precipitates were collected by filtration and washed with water to give 4-[(1-{[3-chloro-5-(trifluoromethyl)-2-pyridinyl]methyl}-2,4-dimethyl-1H-benzimidazol-6-yl)oxy]butanoic acid (85 mg) as white crystals.
NMR(DMSO-d6,δ): 1.8-2.0 (2H, m), 2.35 (2H, t, J=7.2 Hz), 2.38 (3H, s), 2.45 (3H, s), 3.89 (2H, t, J=6.3 Hz), 5.70 (2H, br s), 6.58 (1H, d, J=1.8 Hz), 6.79 (1H, d, J=1.8 Hz), 8.55 (1H, br s), 8.77 (1H, br s), 12.11 (1H, br s).
MS: 440 (M−1).
4-({2,4-Dimethyl-1-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methyl]-1H-benzimidazol-6-yl}oxy)butanoic acid (100 mg) was synthesized from ethyl 4-({2,4-dimethyl-1-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methyl]-1H-benzimidazol-6-yl}oxy)butanoate (130 mg) in a manner similar to that described in Example 14.
NMR(DMSO-d6,δ): 1.8-2.1 (2H, m), 2.3-2.5 (8H, m), 2.66 (3H, s), 4.00 (2H, t, J=6.3 Hz), 5.30 (2H, br s), 6.59 (1H, d, J=1.8 Hz), 6.95 (1H, d, J=1.8 Hz), 7.4-7.6 (3H, m), 7.8-7.9 (2H, m), 12.15 (1H, br s).
MS: 418 (M−1).
4-{[2,4-Dimethyl-1-({4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)-1H-benzimidazol-6-yl]oxy}butanoic acid (126 mg) was synthesized from ethyl 4-}[2,4-dimethyl-1-({4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)-1H-benzimidazol-6-yl]oxy}butanoate (140 mg) in a manner similar to that described in Example 14.
NMR(DMSO-d6,δ): 1.8-2.1 (2H, m), 2.3-2.6 (8H, m), 2.58 (3H, s), 3.99 (2H, t, J=6.4 Hz), 5.66 (2H, br s), 6.63 (1H, d, J=1.8 Hz), 6.98 (1H, d, J=1.8 Hz), 7.77 (2H, d, J=8.3 Hz), 8.02 (2H, d, J=8.3 Hz), 12.15 (1H, br s).
MS: 502 (M−1).
4-{[1-(4-Ethoxy-2-methylbenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]oxy}butanoic acid (192 mg) was synthesized from ethyl 4-{[1-(4-ethoxy-2-methylbenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]oxy}butanoate (275 mg) in a manner similar to that described in Example 14.
NMR(DMSO-d6,δ): 1.27 (3H, t, J=7.0 Hz), 1.8-2.0 (2H, m), 2.2-2.4 (8H, m), 2.46 (3H, s), 3.8-4.0 (4H, m), 5.28 (2H, br s), 6.14 (1H, d, J=8.5 Hz), 6.5-6.7 (2H, m), 6.73 (1H, d, J=2.2 Hz), 6.80 (1H, d, J=2.2 Hz), 12.15 (1H, br s).
MS: 395 (M+1).
4-{[1-(2-Chlorobenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]oxy}butanoic acid (128 mg) was synthesized from ethyl 4-{[1-(2-chlorobenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]oxy}butanoate (290 mg) in a manner similar to that described in Example 14.
NMR(DMSO-d6,δ): 1.7-2.0 (2H, m), 2.35 (2H, t, J=7.2 Hz), 2.38 (3H, s), 2.47 (3H, s), 3.89 (2H, t, J=6.4 Hz), 5.46 (2H, br s), 6.43 (1H, dd, J=1.5 Hz, 7.6 Hz), 6.61 (1H, d, J=1.8 Hz), 6.79 (1H, d, J=1.8 Hz), 7.1-7.4 (2H, m), 7.54 (1H, dd, J=1.3 Hz, 7.7 Hz), 12.11 (1H, br s).
MS: 371 (M−1).
4-({1-[(3,5-Dichloro-2-pyridinyl)methyl]-2,4-dimethyl-1H-benzimidazol-6-yl}oxy)butanoic acid (173 mg) was synthesized from ethyl 4-({1-[(3,5-dichloro-2-pyridinyl)methyl]-2,4-dimethyl-1H-benzimidazol-6-yl}oxy)butanoate (200 mg) in a manner similar to that described in Example 14.
NMR(DMSO-d6,δ): 1.8-2.0 (2H, m), 2.2-2.5 (8H, m), 3.89 (2H, t, J=6.3 Hz), 5.58 (2H, br s), 6.57 (1H, d, J=1.7 Hz), 6.76 (1H, d, J=1.7 Hz), 8.31 (1H, d, J=2.1 Hz), 8.44 (1H, d, J=2.1 Hz), 12.14 (1H, br s).
MS: 408 (M+1).
4-({1-[(2,6-Dichloro-3-pyridinyl)methyl]-2,4-dimethyl-1H-benzimidazol-6-yl}oxy)butanoic acid (197 mg) was synthesized from ethyl 4-({1-[(2,6-dichloro-3-pyridinyl)methyl]-2,4-dimethyl-1H-benzimidazol-6-yl}oxy)butanoate (200 mg) in a manner similar to that described in Example 14.
NMR(DMSO-d6,δ): 1.8-2.0 (2H, m), 2.3-2.5 (8H, m), 3.90 (2H, t, J=6.3 Hz), 5.45 (2H, br s), 6.62 (1H, d, J=1.8 Hz), 6.80 (1H, d, J=8.1 Hz), 6.85 (1H, d, J=1.8 Hz), 7.45 (1H, d, J=8.1 Hz), 12.13 (1H, br s).
MS: 408 (M+1).
4-{[1-(2,5-Dichlorobenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]oxy}butanoic acid (257 mg) was synthesized from ethyl 4-{[1-(2,5-dichlorobenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]oxy}butanoate (350 mg) in a manner similar to that described in Example 14.
NMR(DMSO-d6,δ): 1.8-2.0 (2H, m), 2.36 (2H, t, J=7.2 Hz), 2.40 (3H, s), 2.47 (3H, s), 3.91 (2H, t, J=6.4 Hz), 5.47 (2H, br s), 6.41 (1H, d, J=2.4 Hz), 6.63 (1H, d, J=1.7 Hz), 6.83 (1H, d, J=1.7 Hz), 7.42 (1H, dd, J=2.4 Hz, 8.6 Hz), 7.60 (1H, d, J=8.6 Hz), 12.16 (1H, br s).
MS: 405 (M−1).
4-[(1-{2-Chloro-4-[(ethoxycarbonyl)(methyl)amino]benzyl}-2,4-dimethyl-1H-benzimidazol-6-yl)oxy]butanoic acid (114 mg) was synthesized from ethyl 4-[(1-{2-chloro-4-[(ethoxycarbonyl)(methyl)amino]benzyl}-2,4-dimethyl-1H-benzimidazol-6-yl)oxy]butanoate (280 mg) in a manner similar to that described in Example 14.
NMR(DMSO-d6,δ): 1.15 (3H, t, J=7.1 Hz), 1.8-2.0 (2H, m), 2.36 (2H, t, J=7.2 Hz), 2.40 (3H, s), 2.47 (3H, s), 3.19 (3H, s), 3.90 (2H, t, J=6.4 Hz), 4.07 (2H, q, J=7.1 Hz), 5.44 (2H, br s), 6.41 (1H, d, J=8.4 Hz), 6.62 (1H, br s), 6.81 (1H, br s), 7.18 (1H, dd, J=2.1 Hz, 8.4 Hz), 7.56 (1H, d, J=2.1 Hz), 12.11 (1H, br s).
MS: 472 (M−1).
4-{[1-(2,3-Dichlorobenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]oxy}butanoic acid (104 mg) was synthesized from ethyl 4-{[1-(2,3-dichlorobenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]oxy}butanoate (140 mg) in a manner similar to that described in Example 14.
NMR(DMSO-d6,δ): 1.7-2.0 (2H, m), 2.35 (2H, t, J=7.2 Hz), 2.38 (3H, s), 2.47 (3H, s), 3.89 (2H, t, J=6.4 Hz), 5.50 (2H, br s), 6.28 (1H, dd, J=1.1 Hz, 7.9 Hz), 6.62 (1H, d, J=1.8 Hz), 6.82 (1H, d, J=1.8 Hz), 7.25 (1H, t, J=7.9 Hz), 7.59 (1H, dd, J=1.1 Hz, 7.9 Hz), 12.12 (1H, br s).
MS: 405 (M−1).
4-{[1-(3,4-Dichlorobenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]oxy}butanoic acid (211 mg) was synthesized from ethyl 4-{λ1-(3,4-dichlorobenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]oxy}butanoate (348 mg) in a manner similar to that described in Example 14.
NMR(DMSO-d6,δ): 1.8-2.0 (2H, m), 2.37 (2H, t, J=7.2 Hz), 2.43 (3H, s), 2.45 (3H, s), 3.93 (2H, t, J=6.4 Hz), 5.43 (2H, br s), 6.61 (1H, d, J=1.8 Hz), 6.88 (1H, d, J=1.8 Hz), 6.97 (1H, dd, J=2.0 Hz, 8.3 Hz), 7.41 (1H, d, J=2.0 Hz), 7.58 (1H, d, J=8.3 Hz), 12.14 (1H, br s).
MS: 405 (M−1).
4-({1-[(3-Chloro-1,1′-biphenyl-4-yl)methyl]-2,4-dimethyl-1H-benzimidazol-6-yl}oxy)butanoic acid (216 mg) was synthesized from ethyl 4-({1-[(3-chloro-1,1′-biphenyl-4-yl)methyl]-2,4-dimethyl-1H-benzimidazol-6-yl}oxy)butanoate (261 mg) in a manner similar to that described in Example 14.
NMR(DMSO-d6,δ): 1.8-2.0 (2H, m), 2.2-2.5 (8H, m), 3.91 (2H, t, J=6.3 Hz), 5.51 (2H, br s), 6.48 (1H, d, J=8.1 Hz), 6.63 (1H, d, J=1.8 Hz), 6.84 (1H, d, J=1.8 Hz), 7.3-7.7 (6H, m), 7.83 (1H, d, J=1.7 Hz), 12.13 (1H, br s).
MS: 449 (M+1).
4-{[1-(2-Chloro-4-methoxybenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]oxy}butanoic acid (49 mg) was synthesized from ethyl 4-{[1-(2-chloro-4-methoxybenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]oxy}butanoate (90 mg) in a manner similar to that described in Example 14.
NMR(DMSO-d6,δ): 1.8-2.1 (2H, m), 2.2-2.5 (8H, m), 3.74 (3H, s), 3.90 (2H, t, J=6.3 Hz), 5.38 (2H, br s), 6.47 (1H, d, J=8.6 Hz), 6.61 (1H, br s), 6.78 (1H, br s), 6.83 (1H, dd, J=2.4 Hz, 8.6 Hz), 7.12 (1H, d, J=2.4 Hz), 12.12 (1H, br s).
MS: 401 (M−1).
4-{[1-(2-Chloro-4-ethoxybenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]oxy}butanoic acid (132 mg) was synthesized from ethyl 4-{[1-(2-chloro-4-ethoxybenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]oxy}butanoate (152 mg) in a manner similar to that described in Example 14.
NMR(DMSO-d6,δ): 1.29 (3H, t, J=6.9 Hz), 1.8-2.0 (2H, m), 2.36 (2H, t, J=7.3 Hz), 3.92 (2H, t, J=6.6 Hz), 4.01 (2H, q, J=6.9 Hz), 5.44 (2H, br s), 6.58 (1H, d, J=8.6 Hz), 6.71 (1H, br s), 6.8-6.9 (2H, m), 7.10 (1H, d, J=2.5 Hz), 12.14 (1H, br s).
MS: 415 (M−1).
4-{[1-(2,4-Dichlorobenzyl)-2-methyl-1H-benzimidazol-6-yl]oxy}butanoic acid (83 mg) was synthesized from ethyl 4-{[1-(2,4-dichlorobenzyl)-2-methyl-1H-benzimidazol-6-yl]oxy}butanoate (98 mg) in a manner similar to that described in Example 14.
NMR(DMSO-d6,δ): 1.8-2.0 (2H, m), 2.3-2.5 (5H, m), 3.93 (2H, t, J=6.3 Hz), 5.49 (2H, br s), 6.45 (1H, d, J=8.4 Hz), 6.80 (1H, dd, J=2.3 Hz, 8.7 Hz), 7.04 (1H, d, J=2.2 Hz), 7.33 (1H, dd, J=2.2 Hz, 8.3 Hz), 7.46 (1H, d, J=8.7 Hz), 7.73 (1H, d, J=2.2 Hz), 12.13 (1H, br s).
MS: 391 (M−1).
4-{[1-(2-Chloro-4-ethoxybenzyl)-2-methyl-1H-benzimidazol-6-yl]oxy}butanoic acid (138 mg) was synthesized from ethyl 4-{[1-(2-chloro-4-ethoxybenzyl)-2-methyl-1H-benzimidazol-6-yl]oxy}butanoate (197 mg) in a manner similar to that described in Example 14.
NMR(DMSO-d6,δ): 1.29 (3H, t, J=6.9 Hz), 1.8-2.0 (2H, m), 2.3-2.5 (5H, m), 3.8-4.1 (4H, m), 5.40 (2H, br s), 6.47 (1H, d, J=8.7 Hz), 6.7-6.9 (2H, m), 6.98 (1H, d, J=2.2 Hz), 7.10 (1H, d, J=2.5 Hz), 7.42 (1H, d, J=8.7 Hz), 12.11 (1H, br s).
MS: 401 (M−1).
To a solution of ethyl 4-[(1-{2-chloro-4-[(ethoxycarbonyl)(methyl)amino]benzyl}-2-methyl-1H-benzimidazol-6-yl)oxy]butanoate (195 mg) in dioxane (2 ml) was added 1N-NaOH (0.8 ml) at ambient temperature. The mixture was heated at 80° C. for 1 hour. After cooling, the pH of the reaction mixture was adjusted to around 4 with 1N-HCl. The precipitates were collected by filtration and washed with water to give crude 4-[(1-{2-chloro-4-[(ethoxycarbonyl)(methyl)amino]benzyl}-2-methyl-1H-benzimidazol-6-yl)oxy]butanoic acid (144 mg). The crude crystals were chromatographed (preparative TLC, CH2Cl2/MeOH=10/1) and triturated with EtOAc (1 ml)—n-hexane (1 ml) to give pure product (83 mg) as white crystals.
NMR(DMSO-d6,δ): 1.15 (3H, t, J=7.0 Hz), 1.8-2.0 (2H, m), 2.3-2.5 (5H, m), 3.19 (3H, s), 3.93 (2H, t, J=6.2 Hz), 4.07 (2H, q, J=7.0 Hz), 5.47 (2H, br s), 6.43 (1H, d, J=8.3 Hz), 6.78 (1H, dd, J=2.1 Hz, 8.7 Hz), 7.01 (1H, br s), 7.16 (1H, br s), 7.20 (1H, br s), 7.44 (1H, d, J=8.7 Hz), 7.56 (1H, d, J=2.1 Hz), 12.15 (1H, br s).
MS: 460 (M+1).
4-[(1-{[3-Chloro-5-(trifluoromethyl)-2-pyridinyl]methyl}-2-methyl-1H-benzimidazol-6-yl)oxy]butanoic acid (121 mg) was synthesized from ethyl 4-[(1-{[3-chloro-5-(trifluoromethyl)-2-pyridinyl]methyl}-2-methyl-1H-benzimidazol-6-yl)oxy]butanoate (183 mg) in a manner similar to that described in Example 14.
NMR(DMSO-d6,δ): 1.8-2.0 (2H, m), 2.2-2.5 (5H, m), 3.91 (2H, t, J=6.3 Hz), 5.73 (2H, br s), 6.74 (1H, dd, J=2.2 Hz, 8.7 Hz), 7.00 (1H, d, J=2.2 Hz), 7.39 (1H, d, J=8.7 Hz), 8.56 (1H, d, J=1.1 Hz), 8.77 (1H, d, J=1.1 Hz), 12.15 (1H, br s).
MS: 426 (M−1).
To a suspension of ethyl 4-{[2-ethoxy-4-methyl-1-({4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)-1H-benzimidazol-6-yl]oxy}butanoate (220 mg) in EtOH (2.2 ml) was added 1N-NaOH (0.78 ml) at ambient temperature. The mixture was heated at 80° C. for 1 hour. After cooling, the pH of the reaction mixture was adjusted to around 4 with 1N-HCl. The precipitates were collected by filtration and the crude crystals were purified by chromatography (preparative TLC, EtOAc) to give pure 4-{[2-ethoxy-4-methyl-1-({4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)-1H-benzimidazol-6-yl]oxy}butanoic acid (96 mg) as white crystals.
NMR(DMSO-d6,δ): 1.41 (3H, t, J=7.0 Hz), 1.8-2.1 (2H, m), 2.37 (3H, s), 2.41 (2H, t, J=7.4 Hz), 2.57 (3H, s), 3.99 (2H, t, J=6.3 Hz), 4.52 (2H, q, J=7.0 Hz), 5.42 (2H, br s), 6.56 (1H, d, J=2.0 Hz), 6.96 (1H, d, J=2.0 Hz), 7.79 (2H, d, J=8.2 Hz), 8.05 (2H, d, J=8.2 Hz), 12.11 (1H, br s).
MS: 532 (M−1).
4-{[1-(2,4-Dichlorobenzyl)-2-ethyl-4-methyl-1H-benzimidazol-6-yl]oxy}butanoic acid (108 mg) was synthesized from ethyl 4-{[1-(2,4-dichlorobenzyl)-2-ethyl-4-methyl-1H-benzimidazol-6-yl]oxy}butanoate (150 mg) in a manner similar to that described in Example 14.
NMR(DMSO-d6,δ): 1.21 (3H, t, J=7.4 Hz), 1.8-2.0 (2H, m), 2.36 (2H, t, J=7.4 Hz), 2.48 (3H, s), 2.70 (2H, q, J=7.4 Hz), 3.90 (2H, t, J=6.4 Hz), 5.45 (2H, br s), 6.37 (1H, d, J=8.4 Hz), 6.63 (1H, d, J=1.8 Hz), 6.81 (1H, d, J=1.8 Hz), 7.31 (1H, dd, J=2.1 Hz, 8.4 Hz), 7.72 (1H, d, J=2.1 Hz), 12.11 (1H, br s).
MS: 419 (M−1).
4-{[1-(2,4-Dichlorobenzyl)-4-methyl-2-(trifluoromethyl)-1H-benzimidazol-6-yl]oxy}butanoic acid (134 mg) was synthesized from ethyl 4-{[1-(2,4-dichlorobenzyl)-4-methyl-2-(trifluoromethyl)-1H-benzimidazol-6-yl]oxy}butanoate (150 mg) in a manner similar to that described in Example 14.
NMR(DMSO-d6,δ): 1.8-2.1 (2H, m), 2.37 (2H, t, J=7.4 Hz), 2.55 (3H, s), 3.96 (2H, t, J=6.3 Hz), 5.68 (2H, br s), 6.37 (1H, d, J=8.4 Hz), 6.87 (1H, d, J=1.6 Hz), 7.10 (1H, d, J=1.6 Hz), 7.32 (1H, dd, J=2.1 Hz, 8.4 Hz), 7.75 (1H, d, J=2.1 Hz), 12.15 (1H, br s).
MS: 459 (M−1).
To a solution of ethyl 4-{[1-(2,4-dichlorobenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]oxy}-2,2-dimethylbutanoate (430 mg: crude) in EtOH (4.3 ml) was added 2N-NaOH (1.86 ml) at ambient temperature. The mixture was heated at 90° C. for 4 hours. After cooling, the pH of the reaction mixture was adjusted to around 3.5 with 1N-HCl. The precipitates were collected by filtration and washed with water and MeOH (small portion) to give 4-{[1-(2,4-dichlorobenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]oxy}-2,2-dimethylbutanoic acid (233 mg) as pale yellow crystals.
NMR(DMSO-d6,δ): 1.14 (6H, s), 1.90 (2H, t, J=6.9 Hz), 2.37 (3H, s), 2.46 (3H, s), 3.90 (2H, t, J=6.9 Hz), 5.45 (2H, br s), 6.43 (1H, d, J=8.4 Hz), 6.59 (1H, d, J=1.7 Hz), 6.79 (1H, d, J=1.7 Hz), 7.33 (1H, dd, J=2.2 Hz, 8.4 Hz), 7.72 (1H, d, J=2.2 Hz), 12.28 (1H, br s).
MS: 433 (M−1).
4-({1-[2-Chloro-4-(pentyloxy)benzyl]-2,4-dimethyl-1H-benzimidazol-6-yl}oxy)-2,2-dimethylbutanoic acid (326 mg) was synthesized from ethyl 4-({1-[2-chloro-4-(pentyloxy)benzyl]-2,4-dimethyl-1H-benzimidazol-6-yl}oxy)-2,2-dimethylbutanoate (457 mg) in a manner similar to that described in Example 37.
NMR(DMSO-d6,δ): 0.8-1.0 (3H, m), 1.14 (6H, s), 1.2-1.5 (4H, m), 1.5-1.8 (2H, m), 1.91 (2H, t, J=6.6 Hz), 2.39 (3H, s), 2.45 (3H, s), 3.8-4.0 (4H, m), 5.37 (2H, br s), 6.47 (1H, d, J=8.6 Hz), 6.58 (1H, br s), 6.75 (1H, br s), 6.81 (1H, dd, J=2.5 Hz, 8.6 Hz), 7.09 (1H, d, J=2.5 Hz), 12.19 (1H, br s).
MS: 485 (M−1).
To a suspension of ethyl 4-{[1-(2,4-dichlorobenzyl)-2-ethoxy-4-methyl-1H-benzimidazol-6-yl]oxy}butanoate (125 mg) in ethyl alcohol (EtOH) (1.2 ml) was added sodium hydroxide, 1N solution in water (1N NaOH) (0.54 mL) at room temperature. The mixture was heated at 70° C. for 0.5 hour. After cooling, the reaction mixture was neutralized with hydrochloric acid, 1N solution in water (1N-HCl) (pH 7). The resulting precipitates were collected by filtration and washed with water to give 4-{[1-(2,4-dichlorobenzyl)-2-ethoxy-4-methyl-1H-benzimidazol-6-yl]oxy}butanoic acid (87 mg) as white crystals.
NMR(200 MHz,DMSO-d6,δ): 1.30 (3H, t, J=7.0 Hz), 1.88 (2H, tt, J=6.5 Hz, 7.0 Hz), 2.21 (2H, t, J=7.0 Hz), 2.48 (3H, s), 3.85 (1H, br), 3.86 (2H, t, J=6.5 Hz), 4.49 (2H, q, J=7.0 Hz), 5.22 (2H, s), 6.54 (1H, d, J=2.1 Hz), 6.72 (1H, d, J=2.1 Hz), 6.74 (1H, d, J=8.4 Hz), 7.36 (1H, dd, J=2.1 Hz, 8.4 Hz), 7.67 (1H, d, J=2.1 Hz).
MS: 435 (M−1).
To a solution of ethyl 4-{[1-(2-chloro-4-ethoxybenzyl)-2-ethoxy-4-methyl-1H-benzimidazol-6-yl]oxy}butanoate (150 mg) in EtOH (1.5 ml) was added 1N NaOH (0.63 mL) at room temperature. The mixture was heated at 70° C. for 1 hour. After cooling, the reaction mixture was neutralized with 1N-HCl (pH 7). The resulting precipitates were collected by filtration and washed with water to give 4-{[1-(2-chloro-4-ethoxybenzyl)-2-ethoxy-4-methyl-1H-benzimidazol-6-yl]oxy}butanoic acid (81 mg) as white crystals.
NMR(200 MHz,DMSO-d6,δ): 1.29 (3H, t, J=7.0 Hz), 1.33 (3H, t, J=7.0 Hz), 1.81-1.95 (2H, m), 2.34 (2H, t, J=7.2 Hz), 2.39 (3H, s), 3.30 (1H, br), 3.88 (2H, t, J=6.4 Hz), 4.02 (2H, t, J=7.0 Hz), 4.48 (2H, q, J=7.0 Hz), 5.15 (2H, s), 6.53 (1H, d, J=1.9 Hz), 6.66 (1H, d, J=2.1 Hz), 6.82-6.88 (2H, m), 7.05 (1H, d, J=1.9 Hz).
MS: 445 (M−1).
To a suspension of ethyl 4-[(1-{[3-chloro-5-(trifluoromethyl)-2-pyridinyl]methyl}-2-ethoxy-4-methyl-1H-benzimidazol-6-yl)oxy]butanoate (168 mg) in EtOH (1.7 ml) was added 1N NaOH (0.69 mL) at room temperature. The mixture was heated at 70° C. for 20 minutes. After cooling to room temperature, the reaction mixture was neutralized with 1N-HCl (pH 7). The resulting precipitates were collected by filtration and washed with water to give 4-[(1-{[3-chloro-5-(trifluoromethyl)-2-pyridinyl]methyl}-2-ethoxy-4-methyl-1H-benzimidazol-6-yl)oxy]butanoic acid (129 mg) as white crystals.
NMR(200 MHz,DMSO-d6,δ): 1.25 (3H, t, J=7.0 Hz), 1.85-1.90 (2H, m), 2.31 (2H, t, J=7.3 Hz), 2.39 (3H, s), 3.4 (1H, br), 3.86 (2H, t, J=6.4 Hz), 4.43 (2H, q, J=7.0 Hz), 5.48 (2H, s), 6.52 (1H, d, J=2.2 Hz), 6.74 (1H, d, J=2.2 Hz), 8.52 (1H, d, J=1.0 Hz), 8.80 (1H, d, J=1.0 Hz).
MS: 470 (M−1).
To a suspension of ethyl 4-{[1-(2,4-dichlorobenzyl)-2-ethoxy-1H-benzimidazol-6-yl]oxy}butanoate (116 mg) in EtOH (1 ml) was added 1N NaOH (0.51 mL) at room temperature. The mixture was heated at 70° C. for 20 minutes. After cooling to room temperature, the reaction mixture was neutralized with 1N-HCl (pH 7). The resulting precipitates were collected by filtration and washed with water to give 4-{[1-(2,4-dichlorobenzyl)-2-ethoxy-1H-benzimidazol-6-yl]oxy}butanoic acid (106 mg) as white crystals.
NMR(200 MHz,DMSO-d6,δ): 1.30 (3H, t, J=7.0 Hz), 1.86-1.94 (2H, m), 2.36 (2H, t, J=7.3 Hz), 3.91 (2H, t, J=6.4 Hz), 4.46 (2H, q, J=7.0 Hz), 5.26 (2H, s), 6.71 (1H, dd, J=2.4 Hz, 8.4 Hz), 6.80 (1H, d, J=8.4 Hz), 6.94 (1H, d, J=2.4 Hz), 7.30 (1H, d, J=8.4 Hz), 7.37 (1H, dd, J=2.1 Hz, 8.4 Hz), 7.69 (1H, d, J=2.1 Hz), 12.1 (1H, br).
To a suspension of ethyl 4-{[1-(2,4-dichlorobenzyl)-4-methyl-2-(methylamino)-1H-benzimidazol-6-yl]oxy}butanoate (130 mg) in EtOH (1.3 ml) was added 1N NaOH (0.58 mL) at room temperature. The mixture was heated at 70° C. for 30 minutes. After cooling to room temperature, the reaction mixture was neutralized with 1N-HCl (pH 7). The resulting precipitates were collected by filtration and washed with water to give 4-{[1-(2,4-dichlorobenzyl)-4-methyl-2-(methylamino)-1H-benzimidazol-6-yl]oxy}butanoic acid (119 mg) as pale brown crystals.
NMR(200 MHz,DMSO-d6,δ): 1.78-1.92 (2H, m), 2.33 (2H, t, J=7.2 Hz), 2.39 (3H, s), 2.88 (3H, d, J=4.0 Hz), 3.83 (2H, t, J=6.3 Hz), 5.32 (2H, s), 6.39 (1H, d, J=8.4 Hz), 6.47 (1H, s), 6.52 (1H, s), 6.76 (1H, br), 7.32 (1H, dd, J=2.1 Hz, 8.4 Hz), 7.70 (1H, d, J=2.1 Hz), 12.1 (1H, br).
MS: 422 (M+1).
To a suspension of ethyl 4-{[1-(2,4-dichlorobenzyl)-2-(ethylthio)-4-methyl-1H-benzimidazol-6-yl]oxy}butanoate (261 mg) in EtOH (2.6 ml) was added 1N NaOH (1.0 mL) at room temperature. The mixture was heated at 70° C. for 30 minutes. After cooling to room temperature, the reaction mixture was neutralized with 1N-HCl (pH 7). The resulting precipitates were collected by filtration and washed with water to give 4-{[1-(2,4-dichlorobenzyl)-2-(ethylthio)-4-methyl-1H-benzimidazol-6-yl]oxy}butanoic acid (229 mg) as white crystals.
NMR(200 MHz,DMSO-d6,δ): 1.30(3H, t, J=7.3 Hz), 1.87-1.94 (2H, m), 2.36 (2H, t, J=7.3 Hz), 2.49 (3H, s), 3.22 (2H, q, J=7.3 Hz), 3.91 (2H, t, J=6.4 Hz), 5.41 (2H, s), 6.44 (1H, d, J=8.4 Hz), 6.65 (1H, d, J=2.2 Hz), 6.89 (1H, d, J=2.1 Hz), 7.33 (1H, dd, J=2.1 Hz, 8.4 Hz), 7.72 (1H, d, J=2.2 Hz), 12.1 (1H, s).
MS: 453 (M+1).
2-({1-[(3-Chloro-1,1′-biphenyl-4-yl)methyl]-2,4-dimethyl-1H-benzimidazol-6-yl}oxy)-2-methylpropanoic acid (106 mg) was synthesized from ethyl 2-({1-[(3-chloro-1,1′-biphenyl-4-yl)methyl]-2,4-dimethyl-1H-benzimidazol-6-yl}oxy)-2-methylpropanoate (145 mg) in a manner similar to that described in Example 51.
NMR(DMSO-d6,δ): 1.39 (6H, s), 2.46 (3H, s), 2.48 (3H, s), 5.45 (2H, s), 6.55-6.70 (3H, m), 7.32-7.73 (6H, m), 7.82 (1H, d, J=1.0 Hz).
MS: 449 (M+).
2-({1-[2-Chloro-4-(pentyloxy)benzyl]-2,4-dimethyl-1H-benzimidazol-6-yl}oxy)-2-methylpropanoic acid (106 mg) was synthesized from ethyl 2-({1-[2-chloro-4-(pentyloxy)benzyl]-2,4-dimethyl-1H-benzimidazol-6-yl}oxy)-2-methylpropanoate (136 mg) in a manner similar to that described in Example 51.
NMR(DMSO-d6,δ): 0.87 (3H, t, J=6.0 Hz), 1.20-1.40 (4H, m), 1.41 (6H, s), 1.60-1.75 (2H, m), 2.44 (3H, s), 2.45 (3H, s), 3.95 (2H, t, J=6.0 Hz), 5.31 (2H, s), 6.50-6.63 (3H, m), 6.83 (1H, dd, J=8.0 Hz, 2.0 Hz), 7.10 (1H, d, J=2.0 Hz).
MS: 459 (M+).
4-({1-[(3-Chloro-5-ethoxy-2-pyridinyl)methyl]-2,4-dimethyl-1H-benzimidazol-6-yl}oxy)butanoic acid (121 mg) was synthesized from ethyl 4-({1-[(3-chloro-5-ethoxy-2-pyridinyl)methyl]-2,4-dimethyl-1H-benzimidazol-6-yl}oxy)butanoate (183 mg) in a manner similar to that described in Example 51.
NMR(DMSO-d6,δ): 1.30 (3H, t, J=6.0 Hz), 1.78-1.97 (2H, m), 2.30 (2H, d, J=6.0 Hz), 2.43 (6H, s), 3.88 (2H, t, J=6.0 Hz), 4.10 (2H, q, J=6.0 Hz), 5.47 (2H, s), 6.55 (1H, d, J=1.5 Hz), 6.72 (1H, d, J=1.5 Hz), 7.61 (1H, d, J=1.0 Hz), 8.11 (1H, d, J=1.0 Hz).
MS: 418 (M+).
4-({1-[2-Chloro-4-(1,3-oxazol-2-yl)benzyl]-2,4-dimethyl-1H-benzimidazol-6-yl}oxy)butanoic acid (123 mg) was synthesized from ethyl 4-({1-[2-chloro-4-(1,3-oxazol-2-yl)benzyl]-2,4-dimethyl-1H-benzimidazol-6-yl}oxy)butanoate (149 mg) in a manner similar to that described in Example 51.
NMR(CDCl3-CD3OD,δ): 1.98-2.12 (2H, m), 2.48 (2H, t, J=6.0 Hz), 2.52 (3H, s), 2.60 (3H, s), 3.98 (2H, t, J=6.0 Hz), 5.40 (2H, s), 6.51 (1H, d, J=2.0 Hz), 6.57 (1H, d, J=8.0 Hz), 6.70 (1H, d, J=2.0 Hz), 7.40 (1H, s), 7.75-7.82 (2H, s), 8.15 (1H, d, J=1.0 Hz).
MS: 440 (M+).
4-({1-[(2-Chloro-6-phenyl-3-pyridinyl)methyl]-2,4-dimethyl-1H-benzimidazol-6-yl}oxy)butanoic acid (295 mg) was synthesized from ethyl 4-({1-[(2-chloro-6-phenyl-3-pyridinyl)methyl]-2,4-dimethyl-1H-benzimidazol-6-yl}oxy)butanoate (356 mg) in a manner similar to that described in Example 51.
NMR(DMSO-d6,δ): 1.80-1.99 (2H, m), 2.38 (2H, t, J=6.0 Hz), 2.42 (3H, s), 2.50 (3H, s), 3.90 (2H, t, J=6.0 Hz), 5.51 (2H, s), 6.63 (1H, d, J=1.5 Hz), 6.79-6.92 (2H, m), 7.40-7.58 (3H, m), 7.89 (1H, d, J=8.0 Hz), 7.96-8.08 (2H, m), 12.11 (1H, br s).
MS: 450 (M+).
4-({1-[(3-Methoxy-1,1′-biphenyl-4-yl)methyl]-2,4-dimethyl-1H-benzimidazol-6-yl}oxy)butanoic acid (144 mg) was synthesized from ethyl 4-({1-[(3-methoxy-1,1′-biphenyl-4-yl)methyl]-2,4-dimethyl-1H-benzimidazol-6-yl}oxy)butanoate (175 mg) in a manner similar to that described in Example 51.
NMR(DMSO-d6,δ): 1.80-2.00 (2H, m), 2.38 (2H, t, J=6.0 Hz), 2.46 (3H, s), 2.47 (3H, s), 3.93 (2H, t, J=6.0 Hz), 3.96 (3H, s), 5.33 (2H, s), 6.60 (1H, d, J=1.5 Hz), 6.65 (1H, d, J=8.0 Hz), 6.80 (1H, d, J=1.5 Hz), 7.12 (1H, dd, J=8.0 Hz, 1.5 Hz), 7.26-7.50 (4H, m), 7.66 (2H, d, J=8.0 Hz), 12.13 (1H, br s).
MS: 445 (M+).
A mixture of ethyl 4-({1-[2-chloro-4-(pentyloxy)benzyl]-2-ethoxy-4-methyl-1H-benzimidazol-6-yl}oxy)butanoate (202 mg), 1N sodium hydroxide (NaOH, 0.8 mL) and ethanol (0.8 mL) was stirred at 80° C. for 2 hours. The reaction mixture was neutralized with 1N hydrochloric acid (HCl) to pH 4 under ice-water cooling. The precipitate was collected by vacuum filtration and washed with water to give 4-({1-[2-chloro-4-(pentyloxy)benzyl]-2-ethoxy-4-methyl-1H-benzimidazol-6-yl}oxy)butanoic acid (165 mg) as a white powder.
NMR(DMSO-d6,δ): 0.87 (3H, t, J=6.0 Hz), 1.15-1.46 (4H, m), 1.56-1.97 (4H, m), 2.30 (2H, t, J=6.0 Hz), 2.40 (3H, s), 3.87 (2H, t, J=6.0 Hz), 3.93 (2H, t, J=6.0 Hz), 4.48 (2H, q, J=6.0 Hz), 5.15 (2H, s), 6.53 (1H, d, J=1.5 Hz), 6.66 (1H, d, J=1.5 Hz), 6.76-6.90 (2H, m), 7.05 (1H, d, J=1.5 Hz).
MS: 489 (M+).
4-({1-[2-Chloro-4-(dimethylamino)benzyl]-2,4-dimethyl-1H-benzimidazol-6-yl}oxy)butanoic acid (80 mg) was synthesized from ethyl 4-({1-[2-chloro-4-(dimethylamino)benzyl]-2,4-dimethyl-1H-benzimidazol-6-yl}oxy)butanoate (165 mg) in a manner similar to that described in Example 67.
NMR(DMSO-d6,δ): 1.8-2.0 (2H, m), 2.35 (2H, t, J=7 Hz), 2.40 (3H, s), 2.44 (3H, s), 2.85 (6H, s), 3.89 (2H, t, J=6 Hz), 5.30 (2H, s), 6.44 (1H, d, J=8 Hz), 6.54 (1H, d, J=2 Hz), 6.58 (1H, br s), 6.7-6.8 (2H, m), 11.8-12.5 (1H, br m).
MS: 414 (M−H).
3-[({1-[2-Chloro-4-(pentyloxy)benzyl]-2,4-dimethyl-1H-benzimidazol-6-yl}oxy)methyl]benzoic acid (43 mg) was synthesized from methyl 3-[({1-[2-chloro-4-(pentyloxy)benzyl]-2,4-dimethyl-1H-benzimidazol-6-yl}oxy)methyl]benzoate (47 mg) in a manner similar to that described in Example 14.
NMR(DMSO-d6,δ): 0.8-1.0 (3H, m), 1.2-1.5 (4H, m), 1.5-1.8 (2H, m), 2.40 (3H, s), 2.47 (3H, s), 3.94 (2H, t, J=6.4 Hz), 5.11 (2H, br s), 5.36 (2H, br s), 6.43 (1H, d, J=8.6 Hz), 6.72 (1H, d, J=2.0 Hz), 6.79 (1H, dd, J=2.5 Hz, 8.6 Hz), 6.88 (1H, d, J=2.0 Hz), 7.08 (1H, d, J=2.5 Hz), 7.48 (1H, t, J=7.7 Hz), 7.64 (1H, d, J=7.7 Hz), 7.87 (1H, d, J=7.7 Hz), 8.00 (1H, br s), 13.02 (1H, br s).
MS: 507 (M+1).
To a mixture of 1-[2-chloro-4-(pentyloxy)benzyl]-2-methyl-1H-benzimidazol-6-ol (0.93 g) and N,N-dimethylformamide (2.5 mL) was added sodium hydride (60% dispersion in mineral oil; 11 mg). The mixture was stirred at ambient temperature for 5 minutes. To the mixture was added 2-benzofuran-1(3H)-one (107 mg) and stirring was continued overnight at 140° C. After cooling, the pH of the mixture was adjusted to 4 with 1 N hydrochloric acid. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with water (3 times) and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (gradient elution; dichloromethane to 5% methanol in dichloromethane) to give 2-[({1-[2-chloro-4-(pentyloxy)benzyl]-2-methyl-1H-benzimidazol-6-yl}oxy)methyl]benzoic acid (24 mg).
NMR(DMSO-d6,δ): 0.87 (3H, t, J=7.0 Hz), 1.2-1.4 (6H, m), 1.6-1.8 (2H, m), 2.42 (3H, s), 3.93 (2H, t, J=6.4 Hz), 5.37 (2H, s), 5.40 (2H, s), 6.55 (1H, d, J=8.6 Hz), 6.7-6.9 (1H, m), 6.98 (1H, d, J=2.1 Hz), 7.06 (1H, d, J=2.1 Hz), 7.3-7.7 (4H, m), 7.89 (1H, d, J=6.7 Hz).
MASS (API-ES, Nega): 491.2.
2-[({1-[(3-Chloro-1,1′-biphenyl-4-yl)methyl]-2-ethoxy-1H-benzimidazol-6-yl}oxy)methyl]benzoic acid (84 mg) was synthesized from methyl 2-[({1-[(3-chloro-1,1′-biphenyl-4-yl)methyl]-2-ethoxy-1H-benzimidazol-6-yl}oxy)methyl]benzoate (120 mg) in a manner similar to that described in Example 56.
NMR(DMSO-d6,δ): 1.35 (3H, t, J=7 Hz), 4.50 (2H, q, J=7 Hz), 5.30 (2H, s), 5.39 (2H, s), 6.77 (1H, dd, J=2 Hz, 8 Hz), 6.94 (1H, d, J=8 Hz), 6.98 (1H, d, J=2 Hz), 7.3-8.0 (12H, m), 12.7-13.4 (1H, br m).
MS: 511 (M−H).
A mixture of methyl 2-[({1-[(3-chloro-1,1′-biphenyl-4-yl)methyl]-2,4-dimethyl-1H-benzimidazol-6-yl}oxy)methyl]benzoate (0.14 g), 1 N sodium hydroxide (1 mL) and ethanol (12 mL) was stirred at 80° C. for an hour. After cooling, the mixture was evaporated in vacuo and the residue was partitioned between ethyl acetate/tetrahydrofuran and brine. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting solid was suspended in ethyl acetate (10 mL), and the suspension was stirred at ambient temperature for half an hour. The precipitate was collected by filtration and dried in vacuo to give 2-[({1-[(3-chloro-1,1′-biphenyl-4-yl)methyl]-2,4-dimethyl-1H-benzimidazol-6-yl}oxy)methyl]benzoic acid (101 mg).
NMR(DMSO-d6,δ): 2.43 (3H, s), 2.48 (3H, s), 5.42 (2H, s), 5.46 (2H, s), 6.55 (1H, d, J=8 Hz), 6.70 (1H, d, J=1 Hz), 6.87 (1H, d, J=2 Hz), 7.3-7.9 (11H, m).
MS: 495 (M−H).
2-({[1-(2-Chloro-4-ethoxybenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]oxy)methyl)benzoic acid (0.38 g) was synthesized from methyl 2-({[1-(2-chloro-4-ethoxybenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]oxy}methyl)benzoate (510 mg) in a manner similar to that described in Example 56.
NMR(DMSO-d6,δ): 1.29 (3H, t, J=7 Hz), 2.42 (3H, s), 2.47 (3H, s),4.03 (2H, q, J=7 Hz), 5.34 (2H, s), 5.37 (2H, s), 6.51 (1H, d, J=9 Hz), 6.69 (1H, d, J=1 Hz), 6.7-6.9 (2H, m), 7.04 (1H, d, J=2 Hz), 7.3-8.0 (4H, m), 12.7-13.4 (1H, br m).
MS: 463 (M−H).
2-{[(1-{[3-Chloro-5-(trifluoromethyl)-2-pyridinyl]methyl}-2,4-dimethyl-1H-benzimidazol-6-yl)oxy]methyl}benzoic acid (98 mg) was synthesized from methyl 2-{[(1-{[3-chloro-5-(trifluoromethyl)-2-pyridinyl]methyl}-2,4-dimethyl-1H-benzimidazol-6-yl)oxy]methyl}benzoate (260 mg) in a manner similar to that described in Example 56.
NMR(DMSO-d6,δ): 2.41 (3H, s), 2.45 (3H, s), 5.37 (2H, s), 5.67 (2H, s), 6.65 (1H, d, J=2 Hz), 6.78 (1H, d, J=2 Hz), 7.3-7.6 (3H, m), 7.87 (1H, dd, J=1 Hz, 8 Hz), 8.49 (1H, d, J=1 Hz), 8.74 (1H, s), 12.5-13.5 (1H, br m).
MS: 488 (M−H).
2-{[(1-{2-Chloro-4-[(ethoxycarbonyl)(methyl)amino]benzyl}-2,4-dimethyl-1H-benzimidazol-6-yl)oxy]methyl}benzoic acid (98 mg) was synthesized from methyl 2-{[(1-{2-chloro-4-[(ethoxycarbonyl)(methyl)amino]benzyl}-2,4-dimethyl-1H-benzimidazol-6-yl)oxy]methyl}benzoate (200 mg) in a manner similar to that described in Example 56.
NMR(DMSO-d6,δ): 1.14 (3H, t, J=7 Hz), 2.43 (3H, s), 2.47 (3H, s), 3.18 (3H, s), 4.06 (2H, q, J=Hz), 5.37 (2H, s), 5.42 (2H, s), 6.48 (1H, d, J=8 Hz), 6.69 (1H, d, J=1 Hz), 6.83 (1H, d, J=2 Hz), 7.16 (1H, dd, J=2 Hz, 8 Hz), 7.3-7.7 (4H, m), 7.8-8.0 (1H, m) 12.7-13.4 (1H, br m).
MS: 520 (M−H).
2-[({1-[(3,5-Dichloro-2-pyridinyl)methyl]-2,4-dimethyl-1H-benzimidazol-6-yl}oxy)methyl]benzoic acid (0.37 g) was synthesized from methyl 2-[({1-[(3,5-dichloro-2-pyridinyl)methyl]-2,4-dimethyl-1H-benzimidazol-6-yl}oxy)methyl]benzoate (450 mg) in a manner similar to that described in Example 56.
NMR(DMSO-d6,δ): 2.42 (3H, s), 2.44 (3H, s), 5.39 (2H, s), 5.53 (2H, s), 6.64 (1H, s), 6.74 (1H, s), 7.3-8.0 (4H, m), 8.23 (1H, d, J=2 Hz), 8.40 (1H, d, J=2 Hz).
MS: 455 (M−H).
2-({[1-(2,4-Dichlorobenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]oxy}methyl)benzoic acid (0.49 g) was synthesized from methyl 2-({[1-(2,4-dichlorobenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]oxy}methyl)benzoate (570 mg) in a manner similar to that described in Example 56.
NMR(DMSO-d6,δ): 2.41 (3H, s), 2.47 (3H, s), 5.37 (2H, s), 5.42 (2H, s), 6.47 (1H, d, J=8 Hz), 6.69 (1H, d, J=1 Hz), 6.79 (1H, d, J=2 Hz), 7.29 (1H, dd, J=2 Hz, 8 Hz), 7.4-7.6 (3H, m), 7.67 (1H, d, J=2 Hz), 7.8-8.0 (1H, m), 12.7-13.4 (1H, br m).
MS: 453 (M−H).
2-[({1-[(2,6-Dichloro-3-pyridinyl)methyl]-2,4-dimethyl-1H-benzimidazol-6-yl}oxy)methyl]benzoic acid (0.41 g) was synthesized from methyl 2-[({1-[(2,6-dichloro-3-pyridinyl)methyl]-2,4-dimethyl-1H-benzimidazol-6-yl}oxy)methyl]benzoate (510 mg) in a manner similar to that described in Example 56.
NMR(DMSO-d6,δ): 2.43 (3H, s), 2.48 (3H, s), 5.38 (2H, s), 5.43 (2H, s), 6.70 (1H, d, J=1 Hz), 6.7-7.0 (2H, m), 7.41 (1H, d, J=8 Hz), 7.4-8.0 (4H, m), 12.5-13.4 (1H, br m).
MS: 458, 456 (M+H).
2-[({1-[(2-Chloro-6-phenyl-3-pyridinyl)methyl]-2,4-dimethyl-1H-benzimidazol-6-yl}oxy)methyl]benzoic acid (146 mg) was synthesized from methyl 2-[({1-[(2-chloro-6-phenyl-3-pyridinyl)methyl]-2,4-dimethyl-1H-benzimidazol-6-yl}oxy)methyl]benzoate (180 mg) in a manner similar to that described in Example 56.
NMR(DMSO-d6,δ): 2.50 (6H, s), 5.39 (2H, s), 5.52 (2H, s), 6.75 (1H, s), 6.93 (1H, s), 6.98 (1H, d, J=8 Hz), 7.3-8.1 (9H, m), 12.7-13.4 (1H, br m).
MS: 498, 496 (M−H).
2-[({1-[(3-Methoxy-1,1′-biphenyl-4-yl)methyl]-2,4-dimethyl-1H-benzimidazol-6-yl}oxy)methyl]benzoic acid (78 mg) was synthesized from methyl 2-[({1-[(3-methoxy-1,1′-biphenyl-4-yl)methyl]-2,4-dimethyl-1H-benzimidazol-6-yl}oxy)methyl]benzoate (120 mg) in a manner similar to that described in Example 56.
NMR(DMSO-d6,δ): 2.4-2.6 (3H, s), 2.76 (3H, s), 3.89 (3H, s), 5.46 (2H, s), 5.48 (2H, s), 6.93 (1H, s), 7.11 (1H, s), 7.1-8.0 (12H, m), 12.7-13.4 (1H, br m).
MS: 491 (M−H).
2-[({1-[2-Chloro-4-(1,3-oxazol-2-yl)benzyl]-2,4-dimethyl-1H-benzimidazol-6-yl}oxy)methyl]benzoic acid (76 mg) was synthesized from methyl 2-[({1-[2-chloro-4-(1,3-oxazol-2-yl)benzyl]-2,4-dimethyl-1H-benzimidazol-6-yl}oxy)methyl]benzoate (77 mg) in a manner similar to that described in Example 56.
NMR(DMSO-d6,δ): 2.4-2.6 (6H, s), 5.40 (2H, s), 5.85 (2H, s), 6.77 (1H, d, J=8 Hz), 6.82 (1H, s), 6.88 (1H, s), 7.2-8.1 (6H, m), 8.02 (1H, d, J=8 Hz), 8.27 (1H, s), 12.5-13.5 (1H br m).
MS: 486 (M−H).
2-[({1-[(3-Chloro-5-ethoxy-2-pyridinyl)methyl]-2,4-dimethyl-1H-benzimidazol-6-yl}oxy)methyl]benzoic acid (0.185 g) was synthesized from methyl 2-[({1-[(3-chloro-5-ethoxy-2-pyridinyl)methyl]-2,4-dimethyl-1H-benzimidazol-6-yl}oxy)methyl]benzoate (210 mg) in a manner similar to that described in Example 56.
NMR(DMSO-d6,δ): 1.30 (3H, t, J=7 Hz), 2.44 (3H, s), 2.47 (3H, s), 4.09 (2H, q, J=7 Hz), 5.37 (2H, s), 5.44 (2H, s), 6.64 (1H, d, J=1 Hz), 6.73 (1H, d, J=2 Hz), 7.4-7.7 (4H, m), 7.91 (1H, d, J=1 Hz, 8 Hz), 8.08 (1H, d, J=2 Hz), 12.5-13.5 (1H, br m).
MS: 464 (M−H)
A solution of methyl 2-[({1-[2-chloro-4-(dimethylamino)benzyl]-2,4-dimethyl-1H-benzimidazol-6-yl)oxy)methyl]benzoate (105 mg) in a solvent mixture of tetrahydrofuran (4 mL) and methanol (4 mL) was added 4 N sodium hydroxide (2 mL). The mixture was refluxed for half an hour, cooled to ambient temperature, and acidified with 1 N hydrochloric acid to afford the white precipitate. The suspension was stirred at ambient temperature for half an hour and filtered to give 2-[({1-[2-chloro-4-(dimethylamino)benzyl]-2,4-dimethyl-1H-benzimidazol-6-yl}oxy)methyl]benzoic acid (85 mg) as a white solid.
NMR(DMSO-d6,δ): 2.49-2.51 (3H, s), 2.56 (3H, s), 2.87 (6H, s), 5.37 (2H, s), 5.40 (2H, s), 6.5-6.9 (5H, m), 7.3-8.0 (4H, m), 12.7-13.4 (1H, br m).
MS: 462 (M−H).
2-({[1-[(3-Chloro-1,1′-biphenyl-4-yl)methyl]-4-methyl-2-(trifluoromethyl)-1H-benzimidazol-6-yl]oxy}methyl)benzoic acid (66 mg) was synthesized from methyl 2-({[1-[(3-chloro-1,1′-biphenyl-4-yl)methyl]-4-methyl-2-(trifluoromethyl)-1H -benzimidazol-6-yl]oxy}methyl)benzoate (90 mg) in a manner similar to that described in Example 56.
NMR(DMSO-d6,δ): 2.58 (3H, s), 5.43 (2H, s), 5.72 (2H, s), 6.47 (1H, d, J=8 Hz), 6.95 (1H, d, J=1 Hz), 7.11 (1H, d, J=2 Hz), 7.4-7.9 (11H, m), 13.05 (1H, br s).
MS: 549 (M−H).
2-[({1-[(3-Chloro-1,1′-biphenyl-4-yl)methyl]-2-ethyl-4-methyl-1H-benzimidazol-6-yl}oxy)methyl]benzoic acid (82 mg) was synthesized from methyl 2-[({1-[(3-chloro-1,1′-biphenyl-4-yl)methyl]-2-ethyl-4-methyl-1H-benzimidazol-6-yl)oxy)methyl]benzoate (110 mg) in a manner similar to that described in Example 56.
NMR(DMSO-d6,δ): 1.26 (3H, t, J=7 Hz), 2.51 (3H, s), 2.78 (2H, q, J=7 Hz), 5.38 (2H, s), 5.49 (2H, s), 6.51 (1H, d, J=8 Hz), 6.71 (1H, d, J=1 Hz), 6.83 (1H, d, J=2 Hz), 7.3-7.9 (11H, m), 13.0 (1H, br s).
MS: 509 (M−H).
2-[({1-[(3-Chloro-1,1′-biphenyl-4-yl)methyl]-2-ethoxy-4-methyl-1H-benzimidazol-6-yl)oxy)methyl]benzoic acid (135 mg) was synthesized from methyl 2-[({1-[(3-chloro-1,1′-biphenyl-4-yl)methyl]-2-ethoxy-4-methyl-1H-benzimidazol-6-yl)oxy)methyl]benzoate (150 mg) in a manner similar to that described in Example 56.
NMR(DMSO-d6,δ): 1.35 (3H, t, J=7 Hz), 2.42 (3H, s), 4.52 (2H, q, J=7 Hz), 5.27 (2H, s), 5.37 (2H, s), 6.64 (1H, d, J=2 Hz), 6.78 (1H, d, J=2 Hz), 6.91 (1H, d, J=8 Hz), 7.4-7.9 (11H, m), 12.7-13.4 (1H, br m).
MS: 525 (M−H)
2-{[(1-{[3-Chloro-5-(trifluoromethyl)-2-pyridinyl]methyl}-2-ethoxy-4-methyl-1H-benzimidazol-6-yl)oxy]methyl}benzoic acid (0.12 g) was synthesized from methyl 2-{[(1-{[3-chloro-5-(trifluoromethyl)-2-pyridinyl]methyl}-2-ethoxy-4-methyl-1H-benzimidazol-6-yl)oxy]methyl}benzoate (180 g) in a manner similar to that described in Example 56.
NMR(DMSO-d6,δ): 1.26 (3H, t, J=7 Hz), 2.40 (3H, s), 3.77 (3H, s), 4.45 (2H, q, J=7 Hz), 5.35 (2H, s), 5.46 (2H, s), 6.60 (1H, d, J=2 Hz), 6.75 (1H, d, J=2 Hz), 7.3-8.0 (4H, m), 8.49 (1H, d, J=1 Hz), 8.76 (1H, d, J=1 Hz), 12.7-13.4 (1H, br m).
MS: 518 (M−H).
2-({[1-[(3-Chloro-1,1′-biphenyl-4-yl)methyl]-2-(ethylthio)-4-methyl-1H-benzimidazol-6-yl]oxy}methyl)benzoic acid (117 mg) was synthesized from methyl 2-({[1-[(3-chloro-1,1′-biphenyl-4-yl)methyl]-2-(ethylthio)-4-methyl-1H-benzimidazol-6-yl]oxy}methyl)benzoate (125 mg) in a manner similar to that described in Example 56.
NMR(DMSO-d6,δ): 1.33 (3H, t, J=7 Hz), 2.48-2.51 (3H, s), 3.26 (2H, q, J=7 Hz), 5.39 (2H, s), 5.45 (2H, s), 6.60 (1H, d, J=8 Hz), 6.73 (1H, d, J=1 Hz), 6.93 (1H, d, J=2 Hz), 7.4-7.9 (11H, m), 12.7-13.4 (1H, br m).
MS: 541 (M−H).
2-({[1-(2,4-Dichlorobenzyl)-2-methyl-1H-benzimidazol-6-yl]oxy}methyl)benzoic acid (67 mg) was synthesized from methyl 2-({[1-(2,4-dichlorobenzyl)-2-methyl-1H-benzimidazol-6-yl]oxy}methyl)benzoate (144 mg) in a manner similar to that described in Example 56.
NMR(DMSO-d6,δ): 2.41 (3H, s), 5.40 (2H, s), 5.45 (2H, s), 6.50 (1H, d, J=8 Hz), 6.84 (1H, dd, J=2 Hz, 9 Hz), 6.99 (1H, d, J=2 Hz), 7.3-7.6 (5H, m), 7.68 (1H, d, J=2 Hz), 7.8-8.0 (1H, m).
MS: 443, 441 (M+H).
2-[({1-[(3-Chloro-1,1′-biphenyl-4-yl)methyl]-2-methyl-1H-benzimidazol-6-yl}oxy)methyl]benzoic acid (0.77 g) was synthesized from methyl 2-[({1-[(3-chloro-1,1′-biphenyl-4-yl)methyl]-2-methyl-1H-benzimidazol-6-yl}oxy)methyl]benzoate (950 mg) in a manner similar to that described in Example 56.
NMR(DMSO-d6,δ): 2.45 (3H, s), 5.41 (2H, s), 5.52 (2H, s), 6.58 (1H, d, J=8 Hz), 6.86 (1H, dd, J=2 Hz, 8 Hz), 7.06 (1H, d, J=2 Hz), 7.3-7.9 (12H, m), 12.5-13.5 (1H, br m).
MS: 481 (M−H).
2-{[(1-}[3-Chloro-5-(trifluoromethyl)-2-pyridinyl]methyl}-2-methyl-1H-benzimidazol-6-yl)oxy]methyl}benzoic acid (61 mg) was synthesized from methyl 2-{[(1-{[3-chloro-5-(trifluoromethyl)-2-pyridinyl]methyl}-2-methyl-1H-benzimidazol-6-yl)oxy]methyl}benzoate (110 mg) in a manner similar to that described in Example 56.
NMR(DMSO-d6,δ): 2.41 (3H, s), 5.39 (2H, s), 5.70 (2H, s), 6.81 (1H, dd, J=2 Hz, 8 Hz), 7.00 (1H, d, J=2 Hz), 7.90 (1H, d, J=8 Hz), 7.3-7.9 (4H, m), 8.51 (1H, d, J=2 Hz), 8.75 (1H, d, J=1 Hz), 12.7-13.4 (1H, br m).
MS: 474 (M−H).
Sodium hydride (60% in oil, 36 mg) was added in one portion to an ice-cooled suspension of [1-(2,4-dichlorobenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]methanol (100 mg) and 2-chloronicotinic acid (70.5 mg) in N,N-dimethylformamide (2 mL). The mixture was heated at 80° C. with stirring for 5 hours, and cooled to room temperature. The reaction was carefully quenched by addition of water, and the mixture was neutralized with 1N hydrochloric acid. The resulting precipitate was collected by filtration and purified over preparative thin layer chromatography (chloroform:methanol=10:1) to give 2-{[1-(2,4-dichlorobenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]methoxy}nicotinic acid (52 mg) as a powder.
1H NMR (200 MHz, DMSO-d6, δ/ppm): 2.47 (3H, s), 2.52 (3H, s), 5.45 (1H, d, J=3.1 Hz), 6.48 (1H, d, J=8.4 Hz), 7.06 (1H, dd, J=7.5 Hz, 4.5 Hz), 7.12 (1H, s), 7.2-7.4 (2H, m), 7.70 (1H, d, J=2.1 Hz), 8.09 (1H, dd, J=7.3 Hz, 2.0 Hz), 8.28 (1H, dd, J=4.9 Hz, 2.0 Hz), 12.6-13.3 (1H, br).
An aqueous solution of sodium hydroxide (1N, 0.62 mL) was added to a suspension of ethyl 3-({[1-(2,4-dichlorobenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]methyl}amino)benzoate (60 mg) in 1,4-dioxane at room temperature, and the mixture was heated at 80° C. for 2 hours. It was cooled to room temperature and neutralized with 1N hydrochloric acid. The product was extracted with chloroform, and the organic layer was washed with water and brine and dried over sodium sulfate. The crude product was purified over preparative thin layer chromatography (chloroform:methanol=5:1) to give 3-({[1-(2,4-dichlorobenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]methyl}amino)benzoic acid (50 mg) as a powder.
1H NMR (200 MHz, DMSO-d6, δ/ppm): 2.45 (3H, s), 2.50 (3H, s), 4.27 (2H, d, J=5.7 Hz), 5.43 (2H, s), 6.3-6.5 (2H, m), 6.7-6.8 (1H, m), 7.01 (1H, s), 7.0-7.2 (2H, m), 7.15 (2H, br s), 7.27 (1H, dd, J=8.4 Hz, 2.1 Hz), 7.68 (1H, d, J=2.1 Hz), 12.5-12.7 (1H, br).
3-[{[1-(2,4-Dichlorobenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]methyl}(methyl)amino]benzoic acid (119 mg) was synthesized from ethyl 3-[{[1-(2,4-dichlorobenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]methyl}(methyl)amino]benzoate (123 mg) in a manner similar to that described in Example 77.
1H NMR (200 MHz, DMSO-d6, δ/ppm): 2.46 (3H, s), 2.47 (3H, s), 4.58 (2H, s), 5.41 (2H, s), 6.52 (1H, d, J=8.4 Hz), 6.8-7.0 (3H, m), 7.1-7.3 (4H, m), 7.62 (1H, d, J=2.1 Hz), 12.5-12.9 (1H, br).
Sodium triacetoxyborohydride (50 mg) and aqueous solution of formaldehyde (37%, 19.3 μL) were added to a solution of 2-({[1-(2,4-dichlorobenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]methyl}amino)benzoic acid (54 mg) in 1,2-dichloroethane (1.5 mL). The mixture was stirred at room temperature for 5 hours. It was diluted with methanol, and sodium borohydride (45 mg) was added. After stirring for 1 hour, the reaction was quenched by addition of water, and the organic materials were extracted with chloroform. The organic layer was washed with water, dried over sodium sulfate, and concentrated in vacuo. The crude product was purified over preparative thin layer chromatography (chloroform:methanol=10:1) to give 2-[{[1-(2,4-dichlorobenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]methyl}(methyl)amino]benzoic acid (21 mg) as a powder.
1H NMR (200 MHz, DMSO-d6, δ/ppm): 2.45 (3H, s), 2.46 (3H, s), 2.69 (3H, s), 4.27 (2H, s), 5.40 (2H, s), 6.38 (1H, d, J=8.4 Hz), 6.94 (1H, s), 7.01 (1H, s), 7.2-7.4 (2H, m), 7.57 (1H, t, J=7.4 Hz), 7.6-7.8 (2H, m), 7.86 (1H, dd, J=7.6 Hz, 0.9 Hz), 17.5-17.7 (1H, br).
2-{[1-(2,4-Dichlorobenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]methoxy}benzoic acid (37 mg) was synthesized from methyl 2-{[1-(2,4-dichlorobenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]methoxy}benzoate (84 mg) in a manner similar to that described in Example 77.
1H NMR (200 MHz, DMSO-d6, δ/ppm): 2.47 (3H, s), 2.52 (3H, s), 5.17 (2H, s), 5.47 (2H, s), 6.47 (1H, d, J=8.3 Hz), 6.97 (1H, t, J=7.2 Hz), 7.1-7.2 (2H, m), 7.2-7.5 (3H, m), 7.60 (1H, dd, J=7.6 Hz, 1.6 Hz), 7.71 (1H, d, J=2.2 Hz), 12.2-13.0 (1H, br).
3-{[1-(2,4-Dichlorobenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]methoxy}benzoic acid (82 mg) was synthesized from methyl 3-{[1-(2,4-dichlorobenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]methoxy}benzoate (117 mg) in a manner similar to that described in Example 77.
1H NMR (200 MHz, DMSO-d6, δ/ppm): 2.47 (3H, s), 2.53 (3H, s), 5.13 (2H, s), 5.49 (2H, s), 6.46 (1H, d, J=8.4 Hz), 7.09 (1H, s), 7.1-7.6 (6H, m), 7.71 (1H, d, J=2.1 Hz), 12.7-13.3 (1H, br).
2-{[1-(2,4-Dichlorobenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]methoxy}isonicotinic acid (29 mg) was synthesized from ethyl 2-{[1-(2,4-dichlorobenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]methoxy}isonicotinate (52 mg) in a manner similar to that described in Example 77.
1H NMR (400 MHz, DMSO-d6, δ/ppm): 2.47 (3H, s), 2.52 (3H, s), 5.38 (2H, s), 5.49 (2H, s), 6.47 (1H, d, J=8.4 Hz), 7.09 (1H, s), 7.19 (1H, s), 7.2-7.3 (2H, m), 7.38 (1H, dd, J=5.2 Hz, 1.3 Hz), 7.70 (1H, d, J=2.1 Hz), 8.30 (1H, d, J=5.2 Hz), 13.4-13.9 (1H, br).
6-{[1-(2,4-Dichlorobenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]methoxy}-2-pyridinecarboxylic acid (14 mg) was synthesized from methyl 6-{[1-(2,4-dichlorobenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]methoxy}-2-pyridinecarboxylate (36 mg) in a manner similar to that described in Example 77.
1H NMR (400 MHz, DMSO-d6, δ/ppm): 2.46 (3H, s), 2.52 (3H, s), 5.40 (2H, s), 5.48 (2H, s), 6.46 (1H, d, J=8.4 Hz), 7.03 (1H, d, J=8.3 Hz), 7.15 (1H, s), 7.29 (1H, dd, J=8.4 Hz, 2.0 Hz), 7.38 (1H, s), 7.65 (1H, d, J=7.2 Hz), 7.70 (1H, d, J=2.0 Hz), 7.85 (1H, t, J=7.8 Hz), 12.7-13.4 (1H, br).
2-({1-[(3-Chloro-1,1′-biphenyl-4-yl)methyl]-2,4-dimethyl-1H-benzimidazol-6-yl}methoxy)benzoic acid (26 mg) was synthesized from methyl 2-({1-[(3-chloro-1,1′-biphenyl-4-yl)methyl]-2,4-dimethyl-1H-benzimidazol-6-yl}methoxy)benzoate (100 mg) in a manner similar to that described in Example 77.
1H NMR (200 MHz, DMSO-d6, δ/ppm): 2.5 (3H, s), 2.54 (3H, s), 5.18 (2H, s), 5.53 (2H, s), 6.53 (1H, d, J=8.1 Hz), 6.95 (1H, t, J=7.0 Hz), 7.1-7.2 (2H, m), 7.3-7.7 (9H, m), 7.82 (1H, d, J=1.8 Hz), 12.3-12.9 (1H, br).
3-({1-[(3-Chloro-1,1′-biphenyl-4-yl)methyl]-2,4-dimethyl-1H-benzimidazol-6-yl}methoxy)benzoic acid (44 mg) was synthesized from methyl 3-({1-[(3-chloro-1,1′-biphenyl-4-yl)methyl]-2,4-dimethyl-1H-benzimidazol-6-yl}methoxy)benzoate (80 mg) in a manner similar to that described in Example 77.
1H NMR (400 MHz, DMSO-d6, δ/ppm): 2.51 (3H, s), 2.55 (3H, s), 5.14 (2H, s), 5.55 (2H, s), 6.53 (1H, d, J=8.1 Hz), 7.10 (1H, s), 7.2-7.3 (1H, m), 7.3-7.4 (3H, m), 7.4-7.6 (5H, m), 7.66 (2H, d, J=7.2 Hz), 7.83 (1H, d, J=1.8 Hz), 12.8-13.2 (1H, br).
2-({1-[(3-Chloro-1,1′-biphenyl-4-yl)methyl]-2,4-dimethyl-1H-benzimidazol-6-yl}methoxy)nicotinic acid (71 mg) was synthesized from {1-[(3-chloro-1,1′-biphenyl-4-yl)methyl]-2,4-dimethyl-1H-benzimidazol-6-yl}methanol (200 mg) and 2-chloronicotinic acid (125 mg) in a manner similar to that described in Example 76.
1H NMR (200 MHz, DMSO-d6, δ/ppm): 2.5 (3H, s), 2.53 (3H, s), 5.45 (2H, s), 5.52 (2H, s), 6.55 (1H, d, J=8.1 Hz), 7.02 (1H, dd, J=7.5 Hz, 4.9 Hz), 7.13 (1H, s), 7.3-7.7 (7H, m), 7.82 (1H, d, J=1.8 Hz), 8.06 (1H, dd, J=7.4 Hz, 2.0 Hz), 8.27 (1H, dd, J=4.9 Hz, 2.0 Hz), 12.6-13.4 (1H, br).
6-({1-[(3-Chloro-1,1′-biphenyl-4-yl)methyl]-2,4-dimethyl-1H-benzimidazol-6-yl}methoxy)-2-pyridinecarboxylic acid (72 mg) was synthesized from {1-[(3-chloro-1,1′-biphenyl-4-yl)methyl]-2,4-dimethyl-1H-benzimidazol-6-yl}methanol (100 mg) and 6-chloro-2-pyridinecarboxylic acid (62.7 mg) in a manner similar to that described in Example 76.
MS (ES+): 498 (M++1).
2-({1-[(3-Chloro-1,1′-biphenyl-4-yl)methyl]-2,4-dimethyl-1H-benzimidazol-6-yl}methoxy)isonicotinic acid (35 mg) was synthesized from {1-[(3-chloro-1,1′-biphenyl-4-yl)methyl]-2,4-dimethyl-1H-benzimidazol-6-yl}methanol (100 mg) and 2-chloroisonicotinic acid (62.7 mg) in a manner similar to that described in Example 76.
MS (ES+): 498 (M++1).
2-[({1-[(3-Chloro-1,1′-biphenyl-4-yl)methyl]-2,4-dimethyl-1H-benzimidazol-6-yl}methyl)amino]isonicotinic acid (65 mg) was synthesized from isopropyl 2-[({1-[(3-chloro-1,1′-biphenyl-4-yl)methyl]-2,4-dimethyl-1H-benzimidazol-6-yl}methyl)amino]isonicotinate (80 mg) in a manner similar to that described in Example 77.
1H NMR (200 MHz, DMSO-d6, δ/ppm): 2.5 (3H, s), 2.5 (3H, s), 4.51 (2H, d, J=5.7 Hz), 5.50 (2H, s), 6.51 (1H, d, J=8.1 Hz), 6.81 (1H, d, J=5.2 Hz), 6.99 (2H, s), 7.17 (1H, s), 7.28 (1H, t, J=5.5 Hz), 7.3-7.5 (4H, m), 7.63 (1H, s), 7.65 (1H, d, J=6.7 Hz), 7.80 (1H, d, J=1.5 Hz), 8.02 (1H, d, J=5.2 Hz), 10.0-10.9 (1H, br).
6-[({1-[(3-Chloro-1,1′-biphenyl-4-yl)methyl]-2,4-dimethyl-1H-benzimidazol-6-yl}methyl)amino]-2-pyridinecarboxylic acid (45 mg) was synthesized from isopropyl 6-[({1-[(3-chloro-1,1′-biphenyl-4-yl)methyl]-2,4-dimethyl-1H-benzimidazol-6-yl}methyl)amino]-2-pyridinecarboxylate (60 mg) in a manner similar to that described in Example 77.
1H NMR (200 MHz, DMSO-d6, δ/ppm): 2.5 (3H, s), 2.5 (3H, s), 4.54 (2H, d, J=5.7 Hz), 5.50 (2H, s), 6.50 (1H, d, J=7.9 Hz), 6.66 (1H, d, J=8.3 Hz), 7.04 (1H, s), 7.14 (1H, d, J=7.1 Hz), 7.25 (1H, s), 7.3-7.6 (6H, m), 7.64 (1H, s), 7.65 (1H, d, J=6.7 Hz), 7.81 (1H, d, J=1.6 Hz), 11.8-12.6 (1H, br).
2-{[1-(2-Chloro-4-ethoxybenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]methoxy}benzoic acid (70 mg) was synthesized from methyl 2-{[1-(2-chloro-4-ethoxybenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]methoxy}benzoate (139 mg) in a manner similar to that described in Example 77.
H NMR (200 MHz, DMSO-d6, δ/ppm): 1.28 (3H, t, J=7.0 Hz), 2.46 (3H, s), 2.5 (3H, s), 3.99 (2H, q, J=7.0 Hz), 5.17 (2H, s), 5.40 (2H, s), 6.48 (1H, d, J=8.6 Hz), 6.79 (1H, dd, J=8.6 Hz, 2.5 Hz), 6.97 (1H, t, J=7.5 Hz), 7.0-7.2 (3H, m), 7.33 (1H, s), 7.4-7.5 (1H, m), 7.61 (1H, dd, J=7.6 Hz, 1.7 Hz), 12.3-12.9 (1H, br).
3-{[1-(2-Chloro-4-ethoxybenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]methoxy}benzoic acid (46 mg) was synthesized from methyl 3-{[1-(2-chloro-4-ethoxybenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]methoxy}benzoate (80 mg) in a manner similar to that described in Example 77.
1H NMR (400 MHz, DMSO-d6, δ/ppm): 1.28 (3H, t, J=7.0 Hz), 2.48 (3H, s), 2.53 (3H, s), 4.00 (2H, q, J=7.0 Hz), 5.13 (2H, s), 5.41 (2H, s), 6.48 (1H, d, J=8.6 Hz), 6.79 (1H, dd, J=8.6 Hz, 2.5 Hz), 7.0-7.1 (2H, m), 7.2-7.3 (1H, m), 7.28 (1H, s), 7.38 (1H, t, J=7.9 Hz), 7.4-7.6 (2H, m), 12.8-13.1 (1H, br).
2-[(1-{[3-Chloro-5-(trifluoromethyl)-2-pyridinyl]methyl}-2,4-dimethyl-1H-benzimidazol-6-yl)methoxy]isonicotinic acid (43 mg) was synthesized from ethyl 2-[(1-{[3-chloro-5-(trifluoromethyl)-2-pyridinyl]methyl}-2,4-dimethyl-1H-benzimidazol-6-yl)methoxy]isonicotinate (72 mg) in a manner similar to that described in Example 77.
1H NMR (200 MHz, DMSO-d6, δ/ppm): 2.47 (3H, s), 2.51 (3H, s), 5.37 (2H, s), 5.75 (2H, s), 7.05 (1H, s), 7.18 (1H, s), 7.28 (1H, s), 7.37 (1H, dd, J=7.1 Hz, 1.2 Hz), 8.29 (1H, d, J=5.3 Hz), 8.53 (1H, d, J=1.6 Hz), 8.74 (1H, s), 13.0-14.2 (1H, br).
6-[(1-{[3-Chloro-5-(trifluoromethyl)-2-pyridinyl]methyl}-2,4-dimethyl-1H-benzimidazol-6-yl)methoxy]-2-pyridinecarboxylic acid (41 mg) was synthesized from methyl 6-[(1-{[3-chloro-5-(trifluoromethyl)-2-pyridinyl]methyl}-2,4-dimethyl-1H-benzimidazol-6-yl)methoxy]-2-pyridinecarboxylate (60 mg) in a manner similar to that described in Example 77.
1H NMR (200 MHz, DMSO-d6, δ/ppm): 2.46 (3H, s), 2.51 (3H, s), 5.39 (2H, s), 5.74 (2H, s), 7.02 (1H, d, J=8.6 Hz), 7.12 (1H, s), 7.35 (1H, d, J=6.1 Hz), 7.63 (1H, d, J=6.9 Hz), 7.84 (1H, t, J=7.8 Hz), 8.53 (1H, d, J=1.5 Hz), 8.72 (1H, d, J=1.5 Hz), 12.8-13.6 (1H, br).
To a mixture of 6-bromo-1-[2-chloro-4-(pentyloxy)benzyl]-2,4-dimethyl-1H-benzimidazole (100 mg) and 3-(dihydroxyboryl)benzoic acid (50 mg) in 1,2-dimethoxyethane (DME) (2 ml) were added 2M-sodium carbonate (Na2CO3) (0.38 ml) and tetrakis(triphenylphosphine)palladium(0) {Pd(PPh3)4} (13 mg) at ambient temperature. The mixture was heated at 90° C. for 20 hours. After cooling, the reaction mixture was diluted with EtOAc (40 ml) and washed with brine (2×30 ml). The organic layer was dried over MgSO4 and filtered. Evaporation gave a residue (150 mg) which was triturated with EtOAc—n-hexane to give 3-{1-[2-chloro-4-(pentyloxy)benzyl]-2,4-dimethyl-1H-benzimidazol-6-yl}benzoic acid (40 mg) as pale brown crystals.
NMR(DMSO-d6,δ): 0.8-1.0 (3H, m), 1.2-1.4 (4H, m), 1.5-1.8 (2H, m), 2.48 (3H, s), 2.60 (3H, s), 3.93 (2H, t, J=6.4 Hz), 5.53 (2H, br s), 6.50 (1H, d, J=8.6 Hz), 6.81 (1H, dd, J=2.5 Hz, 8.6 Hz), 7.10 (1H, d, J=2.5 Hz), 7.34 (1H, br s), 7.4-7.7 (2H, m), 7.8-8.1 (2H, m), 8.1-8.3 (1H, m), 13.07 (1H, br s).
MS: 475 (M−1).
To a mixture of 6-bromo-1-[2-chloro-4-(pentyloxy)benzyl]-2,4-dimethyl-1H-benzimidazole (150 mg) and 4-(dihydroxyboryl)benzoic acid (74 mg) in DME (3 ml) were added 2M-Na2CO3 (0.57 ml) and Pd(PPh3)4 (20 mg) at ambient temperature. The mixture was heated at 90° C. for 18 hours. After cooling, the reaction mixture was added water and the pH of the mixture was adjusted to around 3 with 1N-HCl. The aqueous phase was extracted with EtOAc (30 ml). The organic layer was washed with brine (2×30 ml), dried over MgSO4, and filtered. Evaporation gave a residue (133 mg) which was triturated with EtOAc (1.5 ml)—n-hexane (0.5 ml) to give 4-{1-[2-chloro-4-(pentyloxy)benzyl]-2,4-dimethyl-1H-benzimidazol-6-yl}benzoic acid (56 mg) as white crystals.
NMR(DMSO-d6,δ): 0.8-1.0 (3H, m), 1.2-1.5 (4H, m), 1.5-1.8 (2H, m), 2.48 (3H, s), 2.59 (3H, s), 3.93 (2H, t, J=6.4 Hz), 5.52 (2H, br s), 6.50 (1H, d, J=8.6 Hz), 6.82 (1H, dd, J=2.5 Hz, 8.6 Hz), 7.11 (1H, d, J=2.5 Hz), 7.39 (1H, br s), 7.62 (1H, br s), 7.78 (2H, d, J=8.4 Hz) 7.98 (2H, d, J=8.4 Hz), 12.91 (1H, br s).
MS: 477 (M+1).
2-{1-[2-Chloro-4-(pentyloxy)benzyl]-2-methyl-1H-benzimidazol-6-yl}-4-methyl-1,3-oxazole-5-carboxylic acid (105 mg) was synthesized from ethyl 2-{1-[2-chloro-4-(pentyloxy)benzyl]-2-methyl-1H-benzimidazol-6-yl}-4-methyl-1,3-oxazole-5-carboxylate (112 mg) in a manner similar to that described in Example 14.
NMR(DMSO-d6+NaOD,δ): 0.8-1.0 (3H, m), 1.2-1.5 (4H, m), 1.5-1.8 (2H, m), 2.35 (3H, s), 3.94 (2H, t, J=6.4 Hz), 6.53 (1H, d, J=8.6 Hz), 6.82 (1H, dd, J=2.5 Hz, 8.6 Hz), 7.12 (1H, d, J=2.5 Hz), 7.67 (1H, d, J=8.5 Hz), 7.85 (1H, dd, J=1.3 Hz, 8.5 Hz), 7.96 (1H, d, J=1.3 Hz).
MS: 466 (M−1).
2-{1-[2-Chloro-4-(pentyloxy)benzyl]-2-methyl-1H-benzimidazol-6-yl}-4-methyl-1H-imidazole-5-carboxylic acid (101 mg) was synthesized from ethyl 2-{1-[2-chloro-4-(pentyloxy)benzyl]-2-methyl-1H-benzimidazol-6-yl}-4-methyl-1H-imidazole-5-carboxylate (140 mg) in a manner similar to that described in Example 14.
NMR(DMSO-d6,δ): 0.87 (3H, t, J=6.9 Hz), 1.1-1.5 (4H, m), 1.5-1.8 (2H, m), 2.47 (3H, s), 3.94 (2H, t, J=6.4 Hz), 5.52 (2H, br s), 6.46 (1H, d, J=8.7 Hz), 6.82 (1H, dd, J=2.5 Hz, 8.7 Hz), 7.15 (1H, d, J=2.5 Hz), 7.72 (1H, d, J=8.5 Hz), 7.96 (1H, dd, J=1.1 Hz, 8.5 Hz), 8.16 (1H, br s).
MS: 465 (M−1).
2-[1-(2,4-Dichlorobenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]-4-methyl-1,3-oxazole-5-carboxylic acid (194 mg) was synthesized from ethyl 2-[1-(2,4-dichlorobenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]-4-methyl-1,3-oxazole-5-carboxylate (240 mg) in a manner similar to that described in Example 14.
NMR(CD3OD+NaOD,δ): 2.47 (3H, s), 2.58 (3H, s), 2.67 (3H, s), 5.59 (2H, br s), 6.49 (1H, d, J=8.4 Hz), 7.22 (1H, dd, J=2.0 Hz, 8.4 Hz), 7.59 (1H, d, J=2.0 Hz), 7.86 (1H, br s), 7.94 (1H, br s).
MS: 428 (M−1).
2-[1-(2,4-Dichlorobenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]-4-methyl-1H-imidazole-5-carboxylic acid (114 mg) was synthesized from ethyl 2-[1-(2,4-dichlorobenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]-4-methyl-1H-imidazole-5-carboxylate (140 mg) in a manner similar to that described in Example 14.
NMR(DMSO-d6,δ): 2.23 (3H, s), 2.43 (3H, s), 2.58 (3H, s), 5.52 (2H, br s), 6.36 (1H, d, J=8.4 Hz), 7.32 (1H, dd, J=2.1 Hz, 8.4 Hz), 7.6-8.1 (2H, m), 7.76 (1H, d, J=2.1 Hz), 12.60 (1H, br s).
MS: 427 (M−1).
2-{1-[(3-Chloro-1,1′-biphenyl-4-yl)methyl]-2,4-dimethyl-1H-benzimidazol-6-yl}-4-methyl-1,3-oxazole-5-carboxylic acid (211 mg) was synthesized from ethyl 2-{1-[(3-chloro-1,1′-biphenyl-4-yl)methyl]-2,4-dimethyl-1H-benzimidazol-6-yl}-4-methyl-1,3-oxazole-5-carboxylate (270 mg) in a manner similar to that described in Example 14.
NMR(CD3OD+NaOD,δ): 2.47 (3H, s), 2.60 (3H, s), 2.69 (3H, s), 5.65 (2H, br s), 6.57 (1H, d, J=8.1 Hz), 7.2-7.6 (6H, m), 7.76 (1H, d, J=1.6 Hz), 7.88 (1H, br s), 8.00 (1H, br s).
MS: 470 (M−1).
2-{1-[(3-Chloro-1,1′-biphenyl-4-yl)methyl]-2,4-dimethyl-1H-benzimidazol-6-yl}-4-methyl-1H-imidazole-5-carboxylic acid (182 mg) was synthesized from ethyl 2-{1-[(3-chloro-1,1′-biphenyl-4-yl)methyl]-2,4-dimethyl-1H-benzimidazol-6-yl}-4-methyl-1H-imidazole-5-carboxylate (200 mg) in a manner similar to that described in Example 14.
NMR(DMSO-d6,δ): 2.3-2.7 (9H), 5.58 (2H, br s), 6.41 (1H, d, J=8.1 Hz), 7.3-8.2 (10H, m), 12.61 (1H, br s).
MS: 469 (M−1).
2-{1-[2-Chloro-4-(pentyloxy)benzyl]-2,4-dimethyl-1H-benzimidazol-6-yl}-4-methyl-1,3-oxazole-5-carboxylic acid (196 mg) was synthesized from ethyl 2-{1-[2-chloro-4-(pentyloxy)benzyl]-2,4-dimethyl-1H-benzimidazol-6-yl}-4-methyl-1,3-oxazole-5-carboxylate (250 mg) in a manner similar to that described in Example 14.
NMR(CD3OD+NaOD,δ): 0.8-1.0 (3H, m), 1.2-1.5 (4H, m), 1.6-1.9 (2H, m), 2.47 (3H, s), 2.56 (3H, s), 2.67 (3H, s), 3.93 (2H, t, J=6.3 Hz), 5.52 (2H, br s), 6.49 (1H, d, J=8.6 Hz), 6.75 (1H, dd, J=2.5 Hz, 8.6 Hz), 7.05 (1H, d, J=2.5 Hz), 7.85 (1H, br s), 7.98 (1H, br s).
MS: 480 (M−1).
2-{1-[2-Chloro-4-(pentyloxy)benzyl]-2,4-dimethyl-1H-benzimidazol-6-yl}-4-methyl-1H-imidazole-5-carboxylic acid (157 mg) was synthesized from ethyl 2-{1-[2-chloro-4-(pentyloxy)benzyl]-2,4-dimethyl-1H-benzimidazol-6-yl}-4-methyl-1H-imidazole-5-carboxylate (170 mg) in a manner similar to that described in Example 14.
NMR(DMSO-d6,δ): 0.8-1.0 (3H, m), 1.2-1.5 (4H, m), 1.5-1.8 (2H, m), 2.44 (3H, s), 2.4-2.6 (3H, s), 2.58 (3H, s), 3.94 (2H, t, J=6.4 Hz), 5.47 (2H, br s), 6.38 (1H, d, J=8.6 Hz), 6.80 (1H, dd, J=2.2 Hz, 8.6 Hz), 7.14 (1H, d, J=2.2 Hz), 7.78 (1H, br s), 7.90 (1H, br s).
MS: 479 (M−1).
3-[1-(2,4-Dichlorobenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]benzoic acid (74 mg) was synthesized from 6-bromo-1-(2,4-dichlorobenzyl)-2,4-dimethyl-1H-benzimidazole (143 mg) and 3-(dihydroxyboryl)benzoic acid (80 mg) in a manner similar to that described in Preparation Example 242.
1H NMR (200 MHz, DMSO-d6, δ/ppm): 2.46 (3H, s), 2.61 (3H, s), 5.61 (2H, s), 6.45 (1H, d, J=8.4 Hz), 7.32 (1H, dd, J=8 Hz, 2.1 Hz), 7.54 (1H, t, J=7.7 Hz), 7.63 (1H, s), 7.73 (1H, d, J=2.0 Hz), 7.89 (2H, m), 8.19 (1H, s), 12.9-13.2 (1H, br).
3-(1-{[3-Chloro-5-(trifluoromethyl)-2-pyridinyl]methyl}-2,4-dimethyl-1H-benzimidazol-6-yl)benzoic acid (33 mg) was synthesized from 6-bromo-1-{[3-chloro-5-(trifluoromethyl)-2-pyridinyl]methyl}-2,4-dimethyl-1H-benzimidazole (183 mg) and 3-(dihydroxyboryl)benzoic acid (94 mg) in a manner similar to that described in Preparation Example 242.
1H NMR (200 MHz, DMSO-d6, δ/ppm): 2.45 (3H, s), 2.59 (3H, s), 5.87 (2H, s), 7.31 (1H, s), 7.53 (1H, t, J=7.8 Hz), 7.62 (1H, s), 7.84-7.91 (2H, m), 8.18 (1H, s), 8.55 (1H, s), 8.75 (1H, s), 12.6-13.5 (1H, br).
3-[1-(4-Ethoxy-2-methylbenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]benzoic acid (84 mg) was synthesized from 6-bromo-1-(4-ethoxy-2-methylbenzyl)-2,4-dimethyl-1H-benzimidazole (180 mg) and 3-(dihydroxyboryl)benzoic acid (104 mg) in a manner similar to that described in Preparation Example 242.
1H NMR (200 MHz, DMSO-d6, δ/ppm): 1.26 (3H, t, J=6.9 Hz), 2.36 (3H, s), 2.44 (3H, s), 2.60 (3H, s), 3.93 (2H, q, J=6.9 Hz), 6.18 (1H, d, J=8.5 Hz), 6.59 (1H, dd, J=8.4 Hz, 2.6 Hz), 6.81 (1H, d, J=2.4 Hz), 7.32 (1H, s), 7.52 (1H, s), 7.53 (1H, t, J=7.8 Hz), 7.87 (1H, d, J=7.1 Hz), 8.16 (1H, s), 12.8-13.2 (1H, br).
3-[1-(4-Ethoxy-2-methoxybenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]benzoic acid (33 mg) was synthesized from 6-bromo-1-(4-ethoxy-2-methoxybenzyl)-2,4-dimethyl-1H-benzimidazole (118 mg) and 3-(dihydroxyboryl)benzoic acid (65 mg) in a manner similar to that described in Preparation Example 242.
1H NMR (200 MHz, DMSO-d6, δ/ppm): 1.27 (3H, t, J=6.9 Hz), 2.54 (3H, s), 2.56 (3H, s), 3.81 (3H, s), 3.97 (2H, q, J=7.0 Hz), 5.34 (2H, s), 6.42 (1H, dd, J=8.1 Hz, 2.1 Hz), 6.76 (1H, d, J=8.5 Hz), 7.29 (1H, s), 7.55 (1H, t, J=7.6 Hz), 7.56 (1H, s), 7.88 (1H, d, J=7.3 Hz), 8.18 (1H, s), 12.9-13.3 (1H, br).
3-[1-(2-Chloro-4-ethoxybenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]benzoic acid (58 mg) was synthesized from 6-bromo-1-(2-chloro-4-ethoxybenzyl)-2,4-dimethyl-1H-benzimidazole (180 mg) and 3-(dihydroxyboryl)benzoic acid (99 mg) in a manner similar to that described in Preparation Example 242.
1H NMR (200 MHz, DMSO-d6, δ/ppm): 1.27 (3H, t, J=6.9 Hz), 2.48 (3H, s), 2.59 (3H, s), 3.99 (2H, q, J=6.9 Hz), 5.53 (2H, s), 6.51 (1H, d, J=8.5 Hz), 6.82 (1H, dd, J=8.6 Hz, 2.4 Hz), 7.10 (1H, d, J=2.5 Hz), 7.34 (1H, s), 7.54 (1H, t, J=7.8 Hz), 7.58 (1H, s), 7.8-8.0 (2H, m), 8.17 (1H, s), 12.8-13.4 (1H, br).
3-{1-[(3,5-Dichloro-2-pyridinyl)methyl]-2,4-dimethyl-1H-benzimidazol-6-yl}benzoic acid (47 mg) was synthesized from 6-bromo-1-[(3,5-dichloro-2-pyridinyl)methyl]-2,4-dimethyl-1H-benzimidazole (100 mg) and 3-(dihydroxyboryl)benzoic acid (56 mg) in a manner similar to that described in Preparation Example 242.
1H NMR (200 MHz, DMSO-d6, δ/ppm): 2.45 (3H, s), 2.58 (3H, s), 5.75 (2H, s), 7.30 (1H, s), 7.53 (1H, t, J=7.3 Hz), 7.59 (1H, s), 7.8-8.0 (2H, m), 8.18 (1H, s), 8.32 (1H, d, J=0.8 Hz), 8.43 (1H, d, J=2.0 Hz), 12.8-13.4 (1H, br).
3-[1-(2-Chlorobenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]benzoic acid (54 mg) was synthesized from 6-bromo-1-(2-chlorobenzyl)-2,4-dimethyl-1H-benzimidazole (140 mg) and 3-(dihydroxyboryl)benzoic acid (86 mg) in a manner similar to that described in Preparation Example 242.
1H NMR (200 MHz, DMSO-d6, δ/ppm): 2.47 (3H, s), 2.61 (3H, s), 5.63 (2H, s), 6.49 (1H, dd, J=7.5 Hz, 1.5 Hz), 7.21 (1H, t, J=7.5 Hz), 7.32 (1H, t, J=7.6 Hz), 7.35 (1H, s), 7.5-7.7 (3H, m), 7.8-8.0 (2H, m), 8.18 (1H, s), 12.8-13.3 (1H, br).
3-(1-{2-Chloro-4-[(ethoxycarbonyl)(methyl)amino]benzyl}-2,4-dimethyl-1H-benzimidazol-6-yl)benzoic acid (103 mg) was synthesized from ethyl 4-[(6-bromo-2,4-dimethyl-1H-benzimidazol-1-yl)methyl]-3-chlorophenyl(methyl)carbamate (180 mg) and 3-(dihydroxyboryl)benzoic acid (86 mg) in a manner similar to that described in Preparation Example 242.
1H NMR (200 MHz, DMSO-d6, δ/ppm): 2.5 (3H, s), 2.61 (3H, s), 3.18 (3H, s), 4.05 (2H, q, J=7.0 Hz), 5.61 (2H, s), 6.48 (1H, d, J=8.4 Hz), 7.18 (1H, dd, J=8.4 Hz, 2.2 Hz), 7.35 (1H, s), 7.5-7.6 (3H, m), 7.8-8.0 (2H, m), 8.18 (1H, s), 13.0-13.1 (1H, br).
3-{1-[(2,6-Dichloro-3-pyridinyl)methyl]-2,4-dimethyl-1H-benzimidazol-6-yl}benzoic acid (148 mg) was synthesized from ethyl 3-{1-[(2,6-dichloro-3-pyridinyl)methyl]-2,4-dimethyl-1H-benzimidazol-6-yl}benzoate (190 mg) in a manner similar to that described in Example 134.
1H NMR (200 MHz, DMSO-d6, δ/ppm): 2.48 (3H, s), 2.61 (3H, s), 5.61 (2H, s), 6.87 (1H, d, J=8.1 Hz), 7.37 (1H, s), 7.44 (1H, d, J=8.1 Hz), 7.53 (1H, t, J=6.9 Hz), 7.67 (1H, s), 7.8-8.0 (2H, m), 8.20 (1H, s), 12.9-13.5 (1H, br).
3-{2,4-Dimethyl-1-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methyl]-1H-benzimidazol-6-yl}benzoic acid (94 mg) was synthesized from ethyl 3-{2,4-dimethyl-1-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methyl]-1H-benzimidazol-6-yl}benzoate (160 mg) in a manner similar to that described in Example 134.
1H NMR (200 MHz, DMSO-d6, δ/ppm): 2.52 (3H, s), 2.55 (3H, s), 2.73 (3H, s), 5.44 (2H, s), 7.31 (1H, s), 7.4-7.5 (3H, m), 7.58 (1H, t, J=8.0 Hz), 7.77 (1H, s), 7.8-8.0 (4H, m), 8.28 (1H, s), 12.9-13.3 (1H, br).
MS (ES+): 438 (M++1).
3-{1-[(3-Chloro-1,1′-biphenyl-4-yl)methyl]-2,4-dimethyl-1H-benzimidazol-6-yl}benzoic acid (86 mg) was synthesized from ethyl 3-{1-[(3-chloro-1,1′-biphenyl-4-yl)methyl]-2,4-dimethyl-1H-benzimidazol-6-yl}benzoate (114 mg) in a manner similar to that described in Example 134.
1H NMR (400 MHz, DMSO-d6, δ/ppm): 2.51 (3H, s), 2.62 (3H, s), 5.67 (2H, s), 6.54 (1H, d, J=8.1 Hz), 7.3-7.4 (2H, m), 7.45 (2H, t, J=7.8 Hz), 7.53 (1H, d, J=7.3 Hz), 7.54 (1H, t, J=6.4 Hz), 7.6-7.7 (3H, m), 7.84 (1H, d, J=1.6 Hz), 7.87 (1H, d, J=8.0 Hz), 7.91 (1H, d, J=7.3 Hz), 8.20 (1H, t, J=1.6 Hz), 12.9-13.2 (1H, br).
3-[2,4-Dimethyl-1-({4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)-1H-benzimidazol-6-yl]benzoic acid (113 mg) was synthesized from ethyl 3-[2,4-dimethyl-1-({4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)-1H-benzimidazol-6-yl]benzoate (129 mg) in a manner similar to that described in Example 134.
1H NMR (400 MHz, DMSO-d6, δ/ppm): 2.58 (3H, s), 2.60 (3H, s), 2.62 (3H, s), 5.83 (2H, s), 7.37 (1H, s), 7.60 (1H, t, J=7.7 Hz), 7.75 (2H, d, J=8.4 Hz), 7.80 (1H, s), 7.91 (1H, d, J=7.7 Hz), 7.97 (1H, d, J=7.7 Hz), 8.02 (2H, d, J=8.3 Hz), 8.27 (1H, s), 12.9-13.3 (1H, br).
3-[1-(2-Chloro-4-ethoxybenzyl)-2-methyl-1H-benzimidazol-6-yl]benzoic acid (112 mg) was synthesized from ethyl 3-[1-(2-chloro-4-ethoxybenzyl)-2-methyl-1H-benzimidazol-6-yl]benzoate (158 mg) in a manner similar to that described in Example 134.
1H NMR (200 MHz, DMSO-d6, δ/ppm): 1.28 (3H, t, J=7.0 Hz), 2.48 (3H, s), 4.00 (2H, q, J=7.0 Hz), 5.56 (2H, s), 6.55 (1H, d, J=8.7 Hz), 6.82 (1H, dd, J=8.6 Hz, 2.4 Hz), 7.10 (1H, d, J=2.5 Hz), 7.51 (1H, d, J=7.2 Hz), 7.56 (1H, t, J=7.8 Hz), 7.66 (1H, d, J=8.4 Hz), 7.79 (1H, s), 7.8-8.0 (2H, m), 8.19 (1H, s), 12.8-13.2 (1H, br).
3-[1-(2,4-Dichlorobenzyl)-2-methyl-1H-benzimidazol-6-yl]benzoic acid (78 mg) was synthesized from ethyl 3-[1-(2,4-dichlorobenzyl)-2-methyl-1H-benzimidazol-6-yl]benzoate (212 mg) in a manner similar to that described in Example 134.
1H NMR (400 MHz, DMSO-d6, δ/ppm): 2.46 (3H, s), 5.64 (2H, s), 6.49 (1H, d, J=8.4 Hz), 7.33 (1H, dd, J=8.4 Hz, 2.2 Hz), 7.53 (1H, dd, J=8.4 Hz, 0.9 Hz), 7.56 (1H, d, J=7.8 Hz), 7.68 (1H, d, J=8.4 Hz), 7.74 (1H, d, J=2.1 Hz), 7.83 (1H, d, J=1.3 Hz), 7.9-8.0 (2H, m), 8.20 (1H, t, J=1.6 Hz), 12.8-13.4 (br).
3-(1-{[3-Chloro-5-(trifluoromethyl)-2-pyridinyl]methyl}-2-methyl-1H-benzimidazol-6-yl)benzoic acid (44 mg) was synthesized from ethyl 3-(1-{[3-chloro-5-(trifluoromethyl)-2-pyridinyl]methyl}-2-methyl-1H-benzimidazol-6-yl)benzoate (148 mg) in a manner similar to that described in Example 134.
1H NMR (200 MHz, DMSO-d6, δ/ppm: 2.45 (3H, s), 5.90 (2H, s), 7.48 (1H, dd, J=8.3 Hz, 1.5 Hz), 7.57 (1H, d, J=7.7 Hz), 7.64 (1H, d, J=8.3 Hz), 7.8-8.0 (3H, m), 8.19 (1H, s), 8.56 (1H, s), 8.76 (1H, s), 12.8-13.3 (1H, br).
3-[1-(4-Ethoxy-2-methylbenzyl)-2-methyl-1H-benzimidazol-6-yl]benzoic acid (78 mg) was synthesized from ethyl 3-[1-(4-ethoxy-2-methylbenzyl)-2-methyl-1H-benzimidazol-6-yl]benzoate (92 mg) in a manner similar to that described in Example 134.
MS (ES+): 401 (M++1).
3-{1-[(2,6-Dichloro-3-pyridinyl)methyl]-2-methyl-1H-benzimidazol-6-yl}benzoic acid (156 mg) was synthesized from ethyl 3-{1-[(2,6-dichloro-3-pyridinyl)methyl]-2-methyl-1H-benzimidazol-6-yl}benzoate (208 mg) in a manner similar to that described in Example 134.
MS (ES+): 412 (M++1).
3-(1-{2-Chloro-4-[(ethoxycarbonyl)(methyl)amino]benzyl}-2-methyl-1H-benzimidazol-6-yl)benzoic acid (96 mg) was synthesized from ethyl 3-(1-{2-chloro-4-[(ethoxycarbonyl)(methyl)amino]benzyl}-2-methyl-1H-benzimidazol-6-yl)benzoate (177 mg) in a manner similar to that described in Example 134.
MS (ES+): 478 (M++1).
3-{1-[(3-Chloro-1,1′-biphenyl-4-yl)methyl]-2-methyl-1H-benzimidazol-6-yl}benzoic acid (128 mg) was synthesized from ethyl 3-{1-[(3-chloro-1,1′-biphenyl-4-yl)methyl]-2-methyl-1H-benzimidazol-6-yl}benzoate (150 mg) in a manner similar to that described in Example 134.
1H NMR (200 MHz, DMSO-d6, δ/ppm): 2.5 (3H, s), 5.70 (2H, s), 6.57 (1H, d, J=8.1 Hz), 7.3-7.8 (9H, m), 7.8-8.0 (4H, m), 8.21 (1H, s), 12.8-13.3 (1H, br).
2-[1-(2,4-Dichlorobenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]isonicotinic acid (32 mg) was synthesized from methyl 2-[1-(2,4-dichlorobenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]isonicotinate (98 mg) in a manner similar to that described in Example 134.
1H NMR (400 MHz, DMSO-d6, δ/ppm): 2.47 (3H, s), 2.67 (3H, s), 5.63 (2H, s), 6.45 (1H, d, J=8.4 Hz), 7.32 (1H, dd, J=8.4 Hz, 2.1 Hz), 7.64 (1H, d, J=5.4 Hz), 7.74 (1H, d, J=2.1 Hz), 7.83 (1H, s), 8.01 (1H, s), 8.28 (1H, s), 8.68 (1H, d, J=4.8 Hz).
6-[1-(2,4-Dichlorobenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]-2-pyridinecarboxylic acid (127 mg) was synthesized from 1-(2,4-dichlorobenzyl)-2,4-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzimidazole (crude solution, Preparation Example 231) and 6-chloro-2-pyridinecarboxylic acid (90 mg) in a manner similar to that described in Preparation Example 242.
MS (ES+): 426 (M++1).
6-[1-(2,4-Dichlorobenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]nicotinic acid (41 mg) was synthesized from 1-(2,4-dichlorobenzyl)-2,4-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzimidazole (crude solution, Preparation Example 231) and 6-chloronicotinic acid (90 mg) in a manner similar to that described in Preparation Example 242.
1H NMR (400 MHz, DMSO-d6, δ/ppm): 2.48 (3H, s), 2.62 (3H, s), 5.61 (2H, s), 6.42 (1H, d, J=8.4 Hz), 7.32 (1H, dd, J=8.4 Hz, 2.2 Hz), 7.76 (1H, d, J=2.1 Hz), 7.91 (1H, s), 8.0-8.1 (2H, m), 8.25 (1H, dd, J=8.4 Hz, 2.2 Hz), 9.07 (1H, dd, J=2.1 Hz, 0.5 Hz), 12-14 (1H, br).
2-[1-(2-Chloro-4-ethoxybenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]isonicotinic acid (47 mg) was synthesized from ethyl 2-[1-(2-chloro-4-ethoxybenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]isonicotinate (82 mg) in a manner similar to that described in Example 134.
1H NMR (200 MHz, DMSO-d6, δ/ppm): 1.27 (3H, t, J=7.0 Hz), 2.49 (3H, s), 2.61 (3H, s), 4.00 (2H, q, J=7.0 Hz), 5.55 (2H, s), 6.47 (1H, d, J=8.6 Hz), 6.80 (1H, dd, J=8.6 Hz, 2.4 Hz), 7.11 (1H, d, J=2.4 Hz), 7.69 (1H, d, J=5.0 Hz), 7.83 (1H, s), 8.02 (1H, s), 8.32 (2H, s), 8.78 (1H, d, J=5.0 Hz), 13.2-14.3 (1H, br).
6-[1-(2-Chloro-4-ethoxybenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]-2-pyridinecarboxylic acid (53 mg) was synthesized from ethyl 6-[1-(2-chloro-4-ethoxybenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]-2-pyridinecarboxylate (94 mg) in a manner similar to that described in Example 134.
MS (ES+): 436 (M++1).
6-[1-(2-Chloro-4-ethoxybenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]nicotinic acid (48 mg) was synthesized from methyl 6-[1-(2-chloro-4-ethoxybenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]nicotinate (55 mg) in a manner similar to that described in Example 134.
1H NMR (200 MHz, DMSO-d6, δ/ppm): 1.28 (3H, t, J=6.9 Hz), 2.52 (3H, s), 2.61 (3H, s), 4.00 (2H, q, J=7.0 Hz), 6.45 (1H, d, J=8.6 Hz), 6.81 (1H, dd, J=8.7 Hz, 2.5 Hz), 7.12 (1H, d, J=2.5 Hz), 7.89 (1H, s), 8.07 (1H, s), 8.09 (1H, d, J=8.5 Hz), 8.27 (1H, dd, J=8.3 Hz, 2.3 Hz), 9.08 (1H, d, J=1.8 Hz), 13.26 (1H, br s).
5-[1-(2-Chloro-4-ethoxybenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]-2-thiophenecarboxylic acid (42 mg) was synthesized from ethyl 5-[1-(2-chloro-4-ethoxybenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]-2-thiophenecarboxylate (112 mg) in a manner similar to that described in Example 134.
1H NMR (200 MHz, DMSO-d6, δ/ppm): 1.28 (3H, t, J=6.9 Hz), 2.48 (3H, s), 2.55 (3H, s), 4.01 (2H, q, J=7.0 Hz), 5.50 (2H, s), 6.56 (1H, d, J=8.6 Hz), 6.83 (1H, dd, J=8.6 Hz, 2.5 Hz), 7.11 (1H, d, J=2.5 Hz), 7.36 (1H, s), 7.45 (1H, d, J=3.9 Hz), 7.61 (1H, s), 7.64 (1H, d, J=3.9 Hz), 12.5-13.8 (1H, br).
2-(1-{[3-Chloro-5-(trifluoromethyl)-2-pyridinyl]methyl}-2,4-dimethyl-1H-benzimidazol-6-yl)isonicotinic acid (30 mg) was synthesized from ethyl 2-(1-{[3-chloro-5-(trifluoromethyl)-2-pyridinyl]methyl}-2,4-dimethyl-1H-benzimidazol-6-yl)isonicotinate (86 mg) in a manner similar to that described in Example 134.
1H NMR (200 MHz, DMSO-d6, δ/ppm): 2.46 (3H, S), 2.60 (3H, s), 5.90 (2H, s), 7.65 (1H, d, J=4.4 Hz), 7.80 (1H, s), 8.01 (1H, s), 8.38 (1H, s), 8.90 (1H, s), 8.71 (1H, d, J=4.5 Hz), 8.75 (1H, s), 12.8-14.0 (1H, br).
6-(1-{[3-Chloro-5-(trifluoromethyl)-2-pyridinyl]methyl}-2,4-dimethyl-1H-benzimidazol-6-yl)-2-pyridinecarboxylic acid (20 mg) was synthesized from ethyl 6-(1-{[3-chloro-5-(trifluoromethyl)-2-pyridinyl]methyl}-2,4-dimethyl-1H-benzimidazol-6-yl)-2-pyridinecarboxylate (20 mg) in a manner similar to that described in Example 134.
MS (ES+): 461 (M++1).
4-[1-(2-Chloro-4-ethoxybenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]benzoic acid (85 mg) was synthesized from ethyl 4-[1-(2-chloro-4-ethoxybenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]benzoate (95 mg) in a manner similar to that described in Example 134.
1H NMR (200 MHz, DMSO-d6, δ/ppm): 1.28 (3H, t, J=6.9 Hz), 2.48 (3H, s), 2.59 (3H, s), 3.99 (2H, q, J=7.0 Hz), 5.52 (2H, s), 6.49 (1H, d, J=8.6 Hz), 6.82 (1H, dd, J=8.6 Hz, 2.5 Hz), 7.10 (1H, d, J=2.5 Hz), 7.39 (1H, s), 7.63 (1H, s), 7.78 (2H, d, J=8.5 Hz), 7.97 (2H, d, J=8.4 Hz), 12.4-13.2 (1H, br).
An aqueous solution of sodium hydroxide (1N, 0.94 mL) was added to a suspension of ethyl 4-(1-{[3-chloro-5-(trifluoromethyl)-2-pyridinyl]methyl}-2,4-dimethyl-1H-benzimidazol-6-yl)benzoate (92 mg) in 1,4-dioxane at room temperature, and the mixture was heated at 80° C. for 30 minutes. It was cooled to room temperature and neutralized with 1N hydrochloric acid. The product was extracted with chloroform, and the organic layer was washed with water and brine and dried over sodium sulfate. The crude product was purified over preparative thin layer chromatography (chloroform:methanol=10:1) to give 4-(1-{[3-chloro-5-(trifluoromethyl)-2-pyridinyl]methyl}-2,4-dimethyl-1H-benzimidazol-6-yl)benzoic acid (52 mg) as a powder.
1H NMR (200 MHz, DMSO-d6, δ/ppm): 2.45 (3H, s), 2.59 (3H, s), 5.86 (2H, s), 7.37 (1H, s), 7.67 (1H, s), 7.77 (2H, d, J=8.5 Hz), 7.96 (2H, d,J=8.4 Hz), 8.56 (1H, s), 8.75 (1H, s).
{3-[1-(2,4-Dichlorobenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]phenoxy}acetic acid (93 mg) was synthesized from ethyl {3-[1-(2,4-dichlorobenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]phenoxy}acetate (130 mg) in a manner similar to that described in Example 134.
1H NMR (200 MHz, DMSO-d6, δ/ppm): 2.46 (3H, s), 2.58 (3H, s), 4.72 (2H, s), 5.58 (2H, s), 6.48 (1H, d, J=8.3 Hz), 6.84 (1H, br d, J=7.6 Hz), 7.1-7.4 (5H, m), 7.56 (1H, s), 7.73 (1H, d, J=2.0 Hz).
3-{1-[2-Chloro-4-(pentyloxy)benzyl]-2-ethoxy-4-methyl-1H-benzimidazol-6-yl}benzoic acid (117 mg) was synthesized from ethyl 3-{1-[2-chloro-4-(pentyloxy)benzyl]-2-ethoxy-4-methyl-1H-benzimidazol-6-yl}benzoate (150 mg) in a manner similar to that described in Example 134.
1H NMR (200 MHz, DMSO-d6, δ/ppm): 0.86 (3H, t, J=7.0 Hz), 1.2-1.5 (7H, m), 1.66 (2H, quint, J=6.6 Hz), 2.52 (3H, s), 3.93 (2H, t, J=6.4 Hz), 4.56 (2H, q, J=7.0 Hz), 5.30 (2H, s), 6.8-6.9 (2H, m), 7.06 (1H, d, J=1.6 Hz), 7.28 (1H, s), 7.45 (1H, s), 7.54 (1H, t, J=7.7 Hz), 7.86 (2H, d, J=7.9 Hz), 8.15 (1H, s), 12.7-13.5 (1H, br).
A mixture of 6-bromo-1-[2-chloro-4-(pentyloxy)benzyl]-2-ethoxy-4-methyl-1H-benzimidazol (400 mg), 4-carboxyphenylboronic acid (214 mg), palladium(II) acetate (Pd(OAc)2) (19.3 mg), triphenylphosphine (PPh3) (90.1 mg), K2CO3 (356 mg), 1,2-dimethoxyethane (DME) (8 mL) and water (H2O) (1.6 mL) was evacuated and backfield with nitrogen (N2) three times, then degassed with nitrogen (N2) for 10 minutes. The mixture was heated at reflux for 3 hours. After cooling to room temperature, the mixture was poured into water (20 mL). The phases were separated and the aqueous layer was extracted with 2×10 mL of ethyl acetate. The combined extracts were dried over Na2SO4 and concentrated under reduced pressure. Purification by chromatography on silica gel (CHCl3/hexane 1/20) gave 4-{1-[2-chloro-4-(pentyloxy)benzyl]-2-ethoxy-4-methyl-1H-benzimidazol-6-yl}benzoic acid. Recrystallization from EtOAc-hexane afforded a colorless solid (48 mg).
1H NMR (200 MHz, DMSO-d6, δ): 0.86 (3H, t, J=7.0 Hz), 1.24-1.40 (7H, m), 1.62-1.69 (2H, m), 2.49 (3H, s), 3.93 (2H, t, J=6.4 Hz), 4.57 (2H, q, J=7.0 Hz), 5.30 (2H, s), 6.87 (2H, s), 7.07 (1H, s), 7.34 (1H, s), 7.49 (1H, s), 7.74 (2H, d, J=8.4 Hz), 7.97 (2H, d, J=8.4 Hz), 12.9(1H, br).
MS: 507 (M+1).
To a mixture of N-(4-hydroxy-2-nitrophenyl)acetamide (4.0 g), ethyl 4-bromo-2,2-dimethylbutanoate (11.4 g) and DMF (20 ml) was added K2CO3 (7.1 g) at ambient temperature. After stirring for 5 hours at 80° C., the reaction mixture was diluted with EtOAc (100 ml) and washed with water (100 ml) and brine (2×100 ml). The organic layer was dried over MgSO4 and filtered. Evaporation gave a residue which was chromatographed (silica gel (120 g) EtOAc/n-hexane=1/5-2/1), and triturated with n-hexane (10 ml) to give ethyl 4-[4-(acetylamino)-3-nitrophenoxy]-2,2-dimethylbutanoate (6.93 g) as pale brown crystals.
NMR(DMSO-d6,δ): 1.16 (3H, t, J=7.2 Hz), 1.19 (6H, s), 1.99 (2H, t, J=6.7 Hz), 2.01 (3H, s), 3.9-4.2 (4H, m), 7.22 (1H, dd, J=2.9 Hz, 8.7 Hz), 7.3-7.5 (2H, m), 10.05 (1H, br s).
MS: 361 (M+Na).
To a solution of ethyl 4-[4-(acetylamino)-3-nitrophenoxy]-2,2-dimethylbutanoate (6.8 g) in a mixture of EtOH (20 ml) and THF (14 ml) was added palladium on carbon (10%, 50% wet, 1.4 g) at ambient temperature, and the resultant mixture was hydrogenated under atmospheric pressure of hydrogen for 6 hours. The catalyst was removed by filtration. Evaporation gave a residue which was triturated with EtOAc (2.5 ml)—n-hexane (7 ml) to give ethyl 4-[4-(acetylamino)-3-aminophenoxy]-2,2-dimethylbutanoate (4.9 g) as crystals.
NMR(DMSO-d6,δ): 1.1-1.3 (9H, m), 1.94 (2H, t, J=6.7 Hz), 1.98 (3H, s), 3.86 (2H, t, J=6.7 Hz), 4.06 (2H, q, J=7.1 Hz), 4.84 (2H, br s), 6.06 (1H, dd, J=2.7 Hz, 8.6 Hz), 6.23 (1H, d, J=2.7 Hz), 6.93 (1H, d, J=8.6 Hz), 8.96 (1H, br s).
MS: 331 (M+Na).
A mixture of ethyl 4-[4-(acetylamino)-3-aminophenoxy]-2,2-dimethylbutanoate (200 mg), 2,4-dichloro-1-(chloromethyl)benzene (190 mg), K2CO3 (152 mg) and DMF (1 ml) was heated at 80° C. for 5 hours. After cooling, the reaction mixture was poured into water (30 ml) and extracted with EtOAc (3×30 ml). The combined organic layers were washed with brine (2×30 ml). The organic layer was dried over MgSO4, filtered, and evaporated to give ethyl 4-{4-(acetylamino)-3-[(2,4-dichlorobenzyl)amino]phenoxy}-2,2-dimethylbutanoate (368 mg) as a crude oil.
A mixture of ethyl 4-[4-(acetylamino)-3-aminophenoxy]-2,2-dimethylbutanoate (1.0 g), 1-(bromomethyl)-2-chloro-4-(pentyloxy)benzene (1.32 g), K2CO3 (672 mg) and DMF (5 ml) was heated at 80° C. for 2 hours. After cooling, the reaction mixture was poured into water (40 ml) and extracted with EtOAc (3×30ml). The combined organic layers were washed with brine (2×30ml). The organic layer was dried over MgSO4, filtered, and evaporated to give ethyl 4-(4-(acetylamino)-3-{[2-chloro-4-(pentyloxy)benzyl]amino}phenoxy)-2,2-dimethylbutanoate (2.17 g) as a crude oil.
The following compound was obtained in a similar manner to that of Preparation Example 250.
4-(acetylamino)-3-{[(3-chloro-1,1′-biphenyl-4-yl)methyl]amino}-5-methylphenyl acetate
NMR(DMSO-d6,δ): 2.05 (3H, s), 2.08 (3H, s), 2.14 (3H, s), 4.38 (2H, d, J=6 Hz), 5.9-6.0 (2H, m), 6.1-6.2 (1H, m), 7.3-7.8 (8H, m), 8.97 (1H, s)
MS: 421 (M−H).
A mixture of 5,6-dichloro-3-pyridinol (600 mg, 3.7 mmol), K2CO3 (1.52 g, 11 mmol), 1-iodopentane (1.24 g, 7.3 mmol) and DMF (6 mL) was stirred at room temperature for 3 hours. The mixture was diluted with EtOAc (20 mL) and washed with water (30 mL) and brine (2×30 mL). The organic layer was dried (Na2SO4) and filtered. The residue was purified by column chromatography (EtOAc/hexane 1/25) to give 2,3-dichloro-5-(pentyloxy)pyridine (580 mg) as a colorless oil.
NMR (CDCl3, 200 MHz): 0.94 (3H, t, J=6.9 Hz), 1.29-1.50 (4H, m), 1.73-1.87 (2H, m), 3.99 (2H, t, J=6.4 Hz), 7.32 (1H, d, J=2.8 Hz), 7.99(1H, d, J=2.8 Hz).
MS: 234 (M+1).
To a mixture (degassed under reduced pressure) of 2,3-dichloro-5-(pentyloxy)pyridine (860 mg), 1,3-bis(diphenylphosphino)propane (485 mg), triethylamine (1.54 mL) and EtOH (8.6 ml) was added palladium(II) acetate (264 mg) at ambient temperature. The mixture was stirred under atmospheric pressure of carbon monoxide at 70° C. for 28 hours. After cooling, the reaction mixture was evaporated and to the residue was added isopropyl ether (50 ml). The resulting precipitates were removed off by filtration and the filtrate was evaporated. The residue was purified by column chromatography (silica gel EtOAc/n-hexane=1/10) to give ethyl 3-chloro-5-(pentyloxy)-2-pyridinecarboxylate (675 mg) as a pale yellow oil.
NMR (CDCl3, 200 MHz, δ): 0.94 (3H, t, J=7.0 Hz), 1.30-1.53 (7H, m), 1.76-1.89 (2H, m), 4.04 (2H, t, J=6.5 Hz), 4.46 (2H, q, J=7.0 Hz), 7.25 (1H, d, J=2.5 Hz), 8.27 (1H, d, J=2.5 Hz).
MS: 294(M+Na).
To a solution of ethyl 3-chloro-5-(pentyloxy)-2-pyridinecarboxylate (850 mg) in EtOH (8.5 mL) was added sodium borohydride (473 mg) at 0° C. After stirring for 2 hours, the mixture was allowed to warm to room temperature, and stirred for 2 hours. The mixture was diluted with EtOAc (50 mL) and poured into water (50 mL). The phases were separated and the aqueous layer was extracted with 2×20 mL of EtOAc. The combined extracts were washed with NaHCO3 (20 mL) and brine (20 mL), dried over Na2SO4, and concentrated. The residue was purified by column chromatography (silica gel, EtOAc/hexane=1/2) to give [3-chloro-5-(pentyloxy)-2-pyridinyl]methanol (700 mg) as a colorless oil.
NMR (CDCl3, 200 MHz, δ): 0.94 (3H, t, J=6.9 Hz), 1.37-1.48 (4H, m), 1.74-1.88 (2H, m), 3.37-4.07 (3H, m), 4.73 (2H, d, J=4.7 Hz), 7.25 (1H, d, J=2.4 Hz), 8.17(1H, d, J=2.4 Hz).
MS: 252 (M+Na).
To a solution of [3-chloro-5-(pentyloxy)-2-pyridinyl]methanol (0.6 g) in dichloromethane (7 mL) were added triethylamine (0.583 mL) and then methanesulfonyl chloride (283 uL) dropwise at 0° C. After stirring for 30 minutes, the reaction mixture was diluted with EtOAc (30 mL) and washed with NaHCO3 (2×20 mL) and brine (30 mL). The organic layer was dried (Na2SO4), filtered and evaporated to give [3-chloro-5-(pentyloxy)-2-pyridinyl]methyl methanesulfonate (767 mg) as a dark red oil.
NMR (CDCl3, 200 MHz, δ): 0.94 (3H, t, J=6.8 Hz), 1.37-1.48 (4H, m), 1.49-2.05 (2H, m), 3.08 (3H, s), 4.02 (2H, t, J=6.4 Hz), 5.41 (2H, s), 7.25 (1H, d, J=2.5 Hz), 8.22 (1H, d, J=2.5 Hz).
MS: 330 (M+Na).
A mixture of ethyl 4-[4-(acetylamino)-3-aminophenoxy]-2,2-dimethylbutanoate (500 mg), [3-chloro-5-(trifluoromethyl)-2-pyridinyl]methyl methanesulfonate (564 mg), K2CO3 (269 mg), NaI (292 mg) and DMF (5 ml) was stirred at ambient temperature for 3 hours. To the reaction mixture was added water (30 ml) and the precipitates were collected by filtration and washed with water to give ethyl 4-[4-(acetylamino)-3-({[3-chloro-5-(trifluoromethyl)-2-pyridinyl]methyl}amino)phenoxy]-2,2-dimethylbutanoate as crude crystals. The crude crystals were triturated with EtOAc (3 ml)—n-hexane (3 ml) to give pure ethyl 4-[4-(acetylamino)-3-({[3-chloro-5-(trifluoromethyl)-2-pyridinyl]methyl}amino)phenoxy]-2,2-dimethylbutanoate (591 mg) as white crystals.
NMR(DMSO-d6,δ): 1.13 (3H, t, J=7.1 Hz), 1.15 (6H, s), 1.92 (2H, t, J=6.6 Hz), 1.99 (3H, s), 3.88 (2H, t, J=6.6 Hz), 4.02 (2H, q, J=7.1 Hz), 4.55 (2H, d, J=5.4 Hz), 5.79 (1H, t, J=5.4 Hz), 6.0-6.2 (2H, m), 6.94 (1H, d, J=9.2 Hz), 8.50 (1H, d, J=1.5 Hz), 8.94 (1H, br s), 9.09 (1H, br s).
MS: 524 (M+Na).
The following compound was obtained in a similar manner to that of Example 139.
1-[(3-chloro-1,1′-biphenyl-4-yl)methyl]-2,4-dimethyl-1H-benzimidazol-6-ol
NMR(DMSO-d6,δ): 2.43 (3H, s), 2.45 (3H, s), 5.41 (2H, s), 6.4-6.5 (2H, m), 6.54 (1H, d, J=8 Hz), 7.3-7.7 (6H, m), 7.81 (1H, d, J=2 Hz), 9.04 (1H, s).
MS: 363 (M+H).
To a solution of ethyl 4-{4-(acetylamino)-3-[(2,4-dichlorobenzyl)amino]phenoxy}-2,2-dimethylbutanoate (368 mg: crude) in EtOH (2 ml) was added H2SO4 (154 mg) at ambient temperature. After stirring for 12 hours at room temperature, the reaction mixture was heated at 80° C. for 3 hours. After cooling, the reaction mixture was alkalized with saturated NaHCO3 (20 ml), and extracted with EtOAc (2×20 ml). The combined organic layers were washed with brine (20 ml), dried over MgSO4, and filtered. Evaporation gave a residue (276 mg) which was chromatographed (silica gel (3 g) EtOAc/n-hexane=2/1) to give ethyl 4-{[1-(2,4-dichlorobenzyl)-2-methyl-1H-benzimidazol-6-yl]oxy}-2,2-dimethylbutanoate (141 mg) as an oil.
NMR(DMSO-d6,δ): 1.10 (3H, t, J=7.1 Hz), 1.16 (6H, s), 1.94 (2H, t, J=6.7 Hz), 2.39 (3H, s), 3.92 (2H, t, J=6.7 Hz), 4.02 (2H, q, J=7.1 Hz), 5.48 (2H, br s), 6.47 (1H, d, J=8.3 Hz), 6.72 (1H, dd, J=2.2 Hz, 8.6 Hz), 6.94 (1H, d, J=2.2 Hz), 7.33 (1H, dd, J=2.1 Hz, 8.3 Hz), 7.43 (1H, d, J=8.6 Hz), 7.73 (1H, d, J=2.1 Hz).
MS: 449 (M+1).
To a solution of ethyl 4-(4-(acetylamino)-3-{[2-chloro-4-(pentyloxy)benzyl]amino}phenoxy)-2,2-dimethylbutanoate (2.17 g: crude) in EtOH (10 ml) was added H2SO4 (820 mg) at ambient temperature. After stirring for 12 hours at room temperature, the reaction mixture was heated at 80° C. for 3 hours. After cooling, the reaction mixture was alkalized with saturated NaHCO3 (30 ml), and extracted with EtOAc (2×30 ml). The combined organic layers were washed with brine (30 ml), dried over MgSO4, and filtered. Evaporation gave a residue (1.94 g) which was chromatographed (silica gel (20 g) EtOAc/n-hexane=2/1) to give ethyl 4-({1-[2-chloro-4-(pentyloxy)benzyl]-2-methyl-1H-benzimidazol-6-yl}oxy)-2,2-dimethylbutanoate (876 mg) as an oil.
NMR(DMSO-d6,δ): 0.8-1.0 (3H, m), 1.11 (3H, t, J=7.1 Hz), 1.16 (6H, s), 1.2-1.5 (4H, m), 1.6-1.8 (2H, m), 1.94 (2H, t, J=6.7 Hz), 2.40 (3H, s), 3.8-4.1 (6H, m), 5.40 (2H, br s), 6.52 (1H, d, J=8.6 Hz), 6.70 (1H, dd, J=2.3 Hz, 8.7 Hz), 6.82 (1H, dd, J=2.5 Hz, 8.6 Hz), 6.90 (1H, d, J=2.3 Hz), 7.10 (1H, d, J=2.5 Hz), 7.41 (1H, d, J=8.7 Hz).
MS: 501 (M+1).
To a suspension of ethyl 4-[4-(acetylamino)-3-({[3-chloro-5-(trifluoromethyl)-2-pyridinyl]methyl}amino)phenoxy]-2,2-dimethylbutanoate (550 mg) in EtOH (2.75 ml) was added H2SO4 (215 mg) at ambient temperature. The reaction mixture was heated at 80° C. for 1 hour. After cooling, to the reaction mixture was added ice and the mixture was alkalized with 20%-NaOH (pH˜8), and the mixture was extracted with EtOAc (30 ml). The organic extract was washed with brine (30 ml), dried over MgSO4, and filtered. Evaporation gave a residue which was triturated with n-hexane (5 ml) to give ethyl 4-[(1-{[3-chloro-5-(trifluoromethyl)-2-pyridinyl]methyl}-2-methyl-1H-benzimidazol-6-yl)oxy]-2,2-dimethylbutanoate (478 mg) as white crystals.
NMR(DMSO-d6,δ): 1.10 (3H, t, J=7.1 Hz), 1.16 (6H, s), 1.94 (2H, t, J=6.6 Hz), 2.39 (3H, s), 3.91 (2H, t, J=6.6 Hz), 4.02 (2H, q, J=7.1 Hz), 5.73 (2H, br s), 6.68 (1H, dd, J=2.3 Hz, 8.6 Hz), 6.92 (1H, d, J=2.3 Hz), 7.38 (1H, d, J=8.6 Hz), 8.57 (1H, d, J=1.4 Hz), 8.78 (1H, d, J=0.9 Hz).
MS: 484 (M+1).
To a 0° C. solution of 1-[(3-chloro-1,1′-biphenyl-4-yl)methyl]-2,4-dimethyl-1H-benzimidazol-6-ol (200 mg) in DMF (1.5 mL)-tetrahydrofuran (THF) (0.75 mL) was added sodium hydride (60% dispersion in mineral oil, 26.5 mg). After 1 hour at room temperature, the mixture was treated with a solution of methyl 2-(bromomethyl)nicotinate (165 mg) in DMF (0.5 mL). The resultant mixture was stirred for 4 hours at that temperature before the reaction was quenched by addition of water (20 mL). The mixture was extracted with EtOAc (2×20 mL). The combined organic layers ware washed with brine (1×25 mL), dried over Na2SO4, and concentrated. Purification by chromatography on silica gel (EtOAc/Hexane 2/1) gave methyl 2-[({1-[(3-chloro-1,1′-biphenyl-4-yl)methyl]-2,4-dimethyl-1H-benzimidazol-6-yl}oxy)methyl]nicotinate (223 mg) as a white solid.
NMR (DMSO-d6, 200 MHz, δ): 8.66(1H, d, J=4.9 Hz), 8.13 (1H, d, 7.7 Hz), 7.84 (1H, S), 7.70-7.65 (2H, m), 7.54-7.41 (5H, m), 6.84 (1H, s), 6.63 (1H, s), 6.50 (1H, d, 8.1 Hz), 5.49 (2H, s) 5.33 (2H, s), 3.71 (3H, s), 2.48 (3H, s), 2.45 (3H, s).
MS: 512 (M+1).
The following compounds were obtained in a similar manner to that of Example 141.
methyl 4-[({1-[(3-chloro-1,1′-biphenyl-4-yl)methyl]-2,4-dimethyl-1H-benzimidazol-6-yl}oxy)methyl]benzoate
NMR(DMSO-d6,δ): 2.43 (3H, s), 2.49 (3H, s), 3.80 (3H, s), 5.14 (2H, s), 5.49 (2H, s), 6.47 (1H, d, J=8 Hz), 6.74 (1H, d, J=1 Hz), 6.94 (1H, d, J=2 Hz), 7.4-7.9 (1OH, m), 7.92 (1H, d, J=8 Hz).
MS: 511 (M+H).
methyl 2-[({1-[(3-chloro-1,1′-biphenyl-4-yl)methyl]-2,4-dimethyl-1H-benzimidazol-6-yl}oxy)methyl]-6-methylbenzoate
NMR(DMSO-d6,δ): 2.24 (3H, s), 2.44 (3H, s), 2.48 (3H, s), 3.66 (3H, s), 5.01 (2H, s), 5.50 (2H, s), 6.48 (1H, d, J=8 Hz), 6.61 (1H, d, J=1 Hz), 6.86 (1H, d, J=2 Hz), 7.2-7.7 (9H, m), 7.84 (1H, d, J=2 Hz).
MS: 525 (M+H).
methyl 2-[({1-[(3-chloro-1,1′-biphenyl-4-yl)methyl]-2,4-dimethyl-1H-benzimidazol-6-yl}oxy)methyl]-6-nitrobenzoate
NMR(DMSO-d6,δ): 2.44 (3H, s), 2.49 (3H, s), 3.72 (3H, s), 5.14 (2H, s), 5.50 (2H, s), 6.46 (1H, d, J=8 Hz), 6.65 (1H, d, J=1 Hz), 6.87 (1H, d, J=2 Hz), 7.4-8.1 (10H, m).
MS: 556 (M+H).
methyl 3-chloro-2-[({1-[(3-chloro-1,1′-biphenyl-4-yl)methyl]-2,4-dimethyl-1H-benzimidazol-6-yl}oxy)methyl]benzoate
NMR(DMSO-d6,δ): 2.44 (3H, s), 2.4-2.6 (3H, s), 3.67 (3H, s), 5.29 (2H, s), 5.52 (2H, s), 6.48 (1H, d, J=8 Hz), 6.62 (1H, d, J=1 Hz), 6.91 (1H, d, J=2-Hz), 7.3-7.7 (9H, m), 7.85 (1H, d, J=2 Hz).
MS: 545, 547 (M+H).
methyl 4-chloro-2-[({1-[(3-chloro-1,1′-biphenyl-4-yl)methyl]-2,4-dimethyl-1H-benzimidazol-6-yl}oxy)methyl]benzoate
NMR(DMSO-d6,δ): 2.45 (3H, s), 2.4-2.6 (3H, s), 3.77 (3H, s), 5.36 (2H, s), 5.49 (2H, s), 6.54 (1H, d, J=8 Hz), 6.73 (1H, br s), 6.85 (1H, d, J=2 Hz), 7.4-7.7 (8H, m), 7.80 (1H, d, J=2 Hz), 7.88 (1H, d, J=8 Hz).
MS: 545, 547 (M+H).
ethyl 5-chloro-2-[({(1-[(3-chloro-1,1′-biphenyl-4-yl)methyl]-2,4-dimethyl-1H-benzimidazol-6-yl}oxy)methyl]benzoate
NMR(DMSO-d6,δ): 2.45 (3H, s), 2.4-2.6 (3H, s), 3.76 (3H, s), 5.33 (2H, s), 5.49 (2H, s), 6.52 (1H, d, J=8 Hz), 6.69 (1H, d, J=2 Hz), 6.8-6.9 (1H, m), 7.4-8.0 (10H, m).
MS: 545, 547 (M+H).
methyl 2-[({1-[(3-chloro-1,1′-biphenyl-4-yl)methyl]-2,4-dimethyl-1H-benzimidazol-6-yl}oxy)methyl]-6-fluorobenzoate
NMR(DMSO-d6,δ): 2.44 (3H, s), 2.4-2.6 (3H, s), 3.70 (3H, s), 5.12 (2H, s), 5.50 (2H, s), 6.49 (1H, d, J=8 Hz), 6.63 (1H, d, J=1 Hz), 6.87 (1H, d, J=2 Hz), 7.3-7.6 (7H, m), 7.66 (1H, dd, J=1 Hz, J=8 Hz), 7.83 (1H, d, J=2 Hz).
MS: 529 (M+H)
methyl 2-chloro-6-[({1-[(3-chloro-1,1′-biphenyl-4-yl)methyl]-2,4-dimethyl-1H-benzimidazol-6-yl}oxy)methyl]benzoate
NMR(DMSO-d6,δ): 2.44 (3H, s), 2.4-2.6 (3H, s), 3.71 (3H, s), 5.04 (2H, s), 5.50 (2H, s), 6.48 (1H, d, J=8 Hz), 6.63 (1H, d, J=1 Hz), 6.87 (1H, d, J=2 Hz), 7.3-7.7 (9H, m), 7.84 (1H, d, J=2 Hz).
MS: 545, 547 (M+H).
A mixture of ethyl 4-[(2,4-dimethyl-1H-benzimidazol-6-yl)oxy]butanoate (200 mg), K2CO3 (160 mg), [3-chloro-5-(pentyloxy)-2-pyridinyl]methyl methanesulfonate (334 mg) and DMF (4 mL) was heated at 80° C. for 3 hours. After cooling to room temperature, the reaction mixture was poured into aqueous NH4Cl (20 mL), then extracted with EtOAc (20 mL×3). The combined organic layer was dried and concentrated. The residue was purified by column chromatography (EtOAc/hexane 1/4) to give ethyl 4-[(1-{[3-chloro-5-(pentyloxy)-2-pyridinyl]methyl}-2,4-dimethyl-1H-benzimidazol-6-yl)oxy]butanoate as a colorless oil.
NMR (CDCl3, 200 MHz, δ): 0.91 (3H, t, J=6.9 Hz), 1.24 (3H, t, J=7.1 Hz), 1.26-1.50 (4H, m), 1.61-1.71 (2H, m), 1.65-1.85 (2H, m), 2.05-2.15 (2H, m), 2.50 (2H, t, J=7.3 Hz), 2.59 (3H, s), 2.65 (3H, s), 3.82-4.00 (4H, m), 4.13 (2H, q, J=7.1 Hz), 5.36 (2H, s), 6.63 (2H, s), 7.20 (1H, d, J=2.5 Hz), 8.08 (1H, d, J=2.5 Hz).
MS: 488 (M+1).
The following compounds were obtained in a similar manner to that of Example 150.
ethyl 4-{[1-(2-bromo-4-ethoxybenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]oxy}butanoate
NMR(CDCl3,δ): 1.24 (3H, t, J=7.1 Hz), 1.38 (3H, t, J=7.0 Hz), 2.05-2.11 (2H, m), 2.48-2.52 (5H, m), 2.63 (3H, s), 3.95-3.99 (4H, m), 4.13 (2H, q, J=7.1 Hz), 5.21 (2H, s), 6.31 (1H, d, J=8.6 Hz), 6.47 (1H, d, J=2.2 Hz), 6.64 (1H, dd, J=2.5 Hz and 8.6 Hz), 6.69 (1H, m), 7.17 (1H, d, J=2.5 Hz).
ethyl 4-{[6-(4-ethoxy-4-oxobutoxy)-2,4-dimethyl-1H-benzimidazol-1-yl]methyl}-3-methoxybenzoate
NMR(CDCl3,δ): 1.23 (3H, t, J=7.1 Hz), 1.37 (3H, t, J=7.1 Hz), 2.04-2.10 (2H, m), 2.49 (2H, t, J=7.3 Hz), 2.52 (3H, s), 2.63 (3H, s), 3.94 (2H, t, J=6.1 Hz), 3.98 (3H, s), 4.12 (2H, q, J=7.1 Hz), 4.36 (2H, q, J=7.1 Hz), 5.25 (2H, s), 6.46 (1H, d, J=2.1 Hz), 6.52 (1H, d, J=7.9 Hz), 6.68 (1H, J=1.6 Hz), 7.48 (1H, dd, J=1.2 Hz and 7.9 Hz), 7.58 (1H, d, J=1.2 Hz).
ethyl 4-({1-[2-fluoro-4-(trifluoromethyl)benzyl]-2,4-dimethyl-1H-benzimidazol-6-yl}oxy)butanoate
NMR(CDCl3,δ): 1.24 (3H, t, J=7.1 Hz), 2.07-2.10 (2H, m), 2.50 (2H, t, J=7.3 Hz), 2.55 (3H, s), 2.63 (3H, s), 3.97 (2H, t, J=6.1 Hz), 4.12 (2H, q, J=7.1 Hz), 5.34 (2H, s), 6.49 (1H, m), 6.70-6.71 (1H, m), 6.73-6.76 (1H, m), 7.27-7.28 (1H, m), 7.39-7.42 (1H, m).
ethyl 4-({1-[2-chloro-4-(1H-pyrazol-1-yl)benzyl]-2,4-dimethyl-1H-benzimidazol-6-yl}oxy)butanoate
NMR(CDCl3,δ): 1.23 (3H, t, J=7.1 Hz), 2.06-2.10 (2H, m), 2.49 (2H, t, J=7.2 Hz), 2.54 (3H, s), 2.65 (3H, s), 3.96 (2H, t, J=6.1 Hz), 4.12 (2H, q, J=7.1 Hz), 5.33 (2H, s), 6.46-6.48 (2H, m), 6.51 (1H, d, J=8.5 Hz), 6.71 (1H, m), 7.37 (1H, dd, J=2.2 Hz and 8.5 Hz), 7.71 (1H, m), 7.86 (1H, d, J=2.5 Hz), 7.91 (1H, d, J=2.2 Hz).
ethyl 4-({1-[4-ethoxy-2-(trifluoromethyl)benzyl]-2,4-dimethyl-1H-benzimidazol-6-yl}oxy)butanoate
NMR(CDCl3,δ): 1.24 (3H, t, J=7.1 Hz), 1.40 (3H, t, J=7.0 Hz), 2.06-2.10 (2H, m), 2.49 (3H, s), 2.49 (2H, t, J=7.1 Hz), 2.64 (3H, s), 3.95 (2H, t, J=6.1 Hz), 4.01 (2H, q, J=7.0 Hz), 4.12 (2H, q, J=7.1 Hz), 5.36 (2H, s), 6.40 (1H, d, J=8.6 Hz), 6.45 (1H, d, J=2.2 Hz), 6.69-6.70 (1H, m), 6.80 (1H, dd, J=2.6 Hz and 8.7 Hz), 7.25 (1H, d, J=2.6 Hz).
ethyl 4-({1-[2-chloro-4-(2-pyridinyl)benzyl]-2,4-dimethyl-1H-benzimidazol-6-yl}oxy)butanoate
NMR(CDCl3,δ): 1.22 (3H, t, J=7.2 Hz), 2.06-2.10 (2H, m), 2.49 (2H, t, J=7.3 Hz), 2.55 (3H, s), 2.65 (3H, s), 3.96 (2H, q, J=7.1 Hz), 4.11 (2H, q, J=7.1 Hz), 5.37 (2H, s), 6.49 (1H, d, J=2.1 Hz), 6.54 (1H, d, J=8.1 Hz), 6.71 (1H, d, J=1.4 Hz), 7.25-7.27 (1H, m), 7.65-7.67 (2H, m), 7.75 (1H, td, J=6.0 Hz and 1.8 Hz), 8.16 (1H, d, J=1.8 Hz), 8.67-8.69 (1H, m).
ethyl 4-{[1-(2-chloro-4-ethylbenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]oxy}butanoate
NMR(CDCl3,δ): 1.20 (3H, t, J=7.6 Hz), 1.24 (3H, t, J=7.1 Hz), 2.05-2.10 (2H, m), 2.50 (2H, t, J=7.2 Hz), 2.52 (3H, s), 2.59 (2H, q, J=7.6 Hz), 2.64 (3H, s), 3.95 (2H, t, J=6.1 Hz), 4.12 (2H, q, J=7.1 Hz), 5.28 (2H, s), 6.35 (1H, d, J=7.9 Hz), 6.47 (1H, d, J=2.1 Hz), 6.69 (1H, d, J=1.4 Hz), 6.90 (1H, d, J=7.9 Hz), 7.28 (1H, d, J=1.3 Hz).
A mixture of methyl 2-{[(2,4-dimethyl-1H-benzimidazol-6-yl)oxy]methyl}benzoate (0.57 g), K2CO3 (0.508 g), 4-(bromomethyl)-3-chlorobenzonitrile (0.508 g), n-Bu4NI (67.8 mg) and DMF (3.7mL) was stirred at ambient temperature for 2 days. The mixture was partitioned between EtOAc and H2O, and the organic layer was separated, washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by recrystallization from EtOH (5 mL) to give methyl 2-({[1-(2-chloro-4-cyanobenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]oxy}methyl)benzoate (0.32 g).
NMR(DMSO-d6,δ): 2.40 (3H, s), 2.4-2.6 (3H, s), 3.77 (3H, s), 5.32 (2H, s), 5.52 (2H, s), 6.52-(1H, d, J=8 Hz), 6.69 (1H, br s), 6.77 (1H, d, J=2 Hz), 7.4-7.7 (4H, m), 7.86 (1H, d, J=7 Hz), 8.13 (1H, d, J=1 Hz).
MS: 460 (M+H).
The following compound was obtained in a similar manner to that of Example 158.
methyl 2-({[1-(4-cyano-2-fluorobenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]oxy}methyl)benzoate
The following compounds were obtained in a similar manner to that of Preparation Example 153 and Preparation Example 154.
ethyl 2-[({1-[2-chloro-4-(pentyloxy)benzyl]-2,4-dimethyl-1H-benzimidazol-6-yl}oxy)methyl]benzoate
NMR(CDCl3,δ): 0.92 (3H, t, J=7.2 Hz), 1.34 (3H, t, J=7.1 Hz), 1.38 (4H, m), 1.75 (2H, m), 2.52 (3H, s), 2.64 (3H, s), 3.89 (2H, t, J=6.5 Hz), 4.33 (2H, q, J=7.1 Hz), 5.24 (2H, s), 5.44 (2H, s), 6.38 (1H, d, J=8.6 Hz), 6.58 (2H, m), 6.81 (1H, d, J=1.5 Hz), 6.96 (1H, d, J=2.5 Hz), 7.35 (1H, t, J=8.0 Hz), 7.51 (1H, dt, J=1.3 Hz, 7.5 Hz), 7.74 (1H, d, J=7.9 Hz), 8.00 (1H, dd, J=7.9 Hz, 1.1 Hz).
ethyl 2-[({1-[(3-chloro-5-ethoxy-2-pyridinyl)methyl]-2,4-dimethyl-1H-benzimidazol-6-yl}oxy)methyl]-6-methylbenzoate
NMR(CDCl3,δ): 1.25 (3H, t, J=7.1 Hz), 1.43 (3H, t, J=7.1 Hz), 2.39 (3H, s), 2.73 (3H, s), 2.97 (3H, br s), 4.06 (2H, q, J=7.1 Hz), 4.28 (2H, q, J=7.1 Hz), 5.09 (2H, s), 5.44 (2H, s), 6.75 (1H, s), 6.87 (1H, br s), 7.20 (1H, m), 7.25 (1H, m), 7.28 (2H, m), 8.02 (1H, d, J=2.5 Hz).
ethyl 2-[({1-[2-chloro-4-(1,3-oxazol-2-yl)benzyl]-2,4-dimethyl-1H-benzimidazol-6-yl}oxy)methyl]-6-methylbenzoate
NMR(CDCl3,δ): 1.22 (3H, t, J=7.1 Hz), 2.32 (3H, s), 2.58 (3H, s), 2.66 (3H, s), 4.25 (2H, q, J=7.2 Hz), 5.06 (2H, s), 5.35 (2H, s), 6.50 (2H, m), 6.79 (1H, s), 7.10 (1H, m), 7.25 (3H, m), 7.72 (2H, m), 8.15 (1H, d, J=1.6 Hz).
ethyl 2-[({1-[2-fluoro-4-(trifluoromethyl)benzyl]-2,4-dimethyl-1H-benzimidazol-6-yl)oxy}methyl]benzoate
NMR(CDCl3,δ): 1.35 (3H, t, J=7.1 Hz), 2.56 (3H, s), 2.64 (3H, s), 4.34 (2H, q, J=7.1 Hz), 5.32 (2H, s), 5.46 (2H, s), 6.57 (1H, d, J=2.1 Hz), 6.74 (1H, t, J=7.6 Hz), 6.83 (1H, d, J=1.5 Hz), 7.24 (1H, d, J=8.5 Hz), 7.36 (2H, m), 7.50 (1H, dt, J=1.1 Hz, 7.5 Hz), 7.72 (1H, d, J=7.8 Hz), 8.00 (1H, dd, J=7.8 Hz, 1.2 Hz).
ethyl 2-[({1-[2-chloro-4-(2-pyridinyl)benzyl]-2,4-dimethyl-1H-benzimidazol-6-yl}oxy)methyl]benzoate
NMR(CDCl3,δ): 1.32 (3H, t, J=7.2 Hz), 2.55 (3H, s), 2.66 (3H, s), 4.31 (2H, q, J=7.2 Hz), 5.37 (2H, s), 5.44 (2H, s), 6.55 (1H, d, J=8.1 Hz), 6.60 (1H, d, J=1.2 Hz), 6.83 (1H, d, J=1.5 Hz), 7.26 (1H, m), 7.30 (1H, m), 7.50 (1H, m), 7.65 (2H, m), 7.74 (2H, m), 7.97 (1H, dd, J=7.8 Hz, 1.2 Hz), 8.14 (1H, d, J=1.7 Hz), 8.68 (1H, d, J=4.2 Hz).
ethyl 2-[({1-[2-chloro-4-(pentyloxy)benzyl]-2,4-dimethyl-1H-benzimidazol-6-yl}oxy)methyl]-6-methylbenzoate
NMR(CDCl3,δ): 0.92 (3H, t, J=7.1 Hz), 1.22 (3H, t, J=7.1 Hz), 1.40 (4H, m), 1.76 (2H, m), 2.36 (3H, s), 2.57 (3H, s), 2.64 (3H, s), 3.90 (2H, t, J=6.5 Hz), 4.25 (2H, q, J=7.1 Hz), 5.06 (2H, s), 5.25 (2H, s), 6.37 (1H, d, J=8.7 Hz), 6.54 (1H, d, J=7.0 Hz), 6.59 (1H, dd, J=8.7 Hz, 2.5 Hz), 6.76 (1H, d, J=1.3 Hz), 6.97 (1H, d, J=2.5 Hz), 7.16 (1H, dd, J=6.2 Hz, 2.5 Hz), 7.27 (2H, m).
ethyl 2-[({1-[(3,5-dichloro-2-pyridinyl)methyl]-2,4-dimethyl-1H-benzimidazol-6-yl}oxy)methyl]-6-methylbenzoate
NMR(CDCl3,δ): 1.27 (3H, t, J=7.1 Hz), 2.37 (3H, s), 2.76 (3H, s), 3.01 (3H, s), 4.28 (2H, q, J=7.1 Hz), 5.10 (2H, s), 5.51 (2H, s), 6.66 (1H, d, J=1.9 Hz), 6.90 (1H, s), 7.19 (1H, d, J=7.3 Hz), 7.25 (1H, t, J=6.7 Hz), 7.29 (1H, d, J=7.5 Hz), 7.79 (1H, d, J=2.0 Hz), 8.24 (1H, d, J=2.1 Hz).
The following compounds were obtained in a similar manner to that of Preparation Example 249 and Example 138.
ethyl 2-[({1-[2-chloro-4-(1,3-oxazol-2-yl)benzyl]-2-methyl-1H-benzimidazol-6-yl}oxy)methyl]benzoate
ethyl 2-[({1-[(2-chloro-6-phenyl-3-pyridinyl)methyl]-2-methyl-1H-benzimidazol-6-yl}oxy)methyl]benzoate
ethyl 2-[({1-[2-chloro-4-(1,3-oxazol-2-yl)benzyl]-2-methyl-1H-benzimidazol-6-yl}oxy)methyl]-6-methylbenzoate
ethyl 2-[({1-[(3-chloro-1,1′-biphenyl-4-yl)methyl]-2-methyl-1H-benzimidazol-6-yl}oxy)methyl]-6-methylbenzoate
NMR(CDCl3,δ): 1.20 (3H, t, J=7.2 Hz), 2.35 (3H, s), 2.55 (3H, s), 4.24 (2H, q, J=7.2 Hz), 5.09 (2H, s), 5.39 (2H, s), 6.49 (1H, d, J=8.1 Hz), 6.72 (1H, d, J=2.3 Hz), 6.93 (1H, dd, J=8.8 Hz, 2.3 Hz), 7.13 (1H, d, J=7.1 Hz), 7.24 (1H, m), 7.29 (2H, m), 7.37 (1H, m), 7.44 (2H, m), 7.53 (2H, m), 7.62 (1H, d, J=8.8 Hz), 7.67 (1H, d, J=1.8 Hz).
ethyl 2-[({1-[(3,5-dichloro-2-pyridinyl)methyl]-2-methyl-1H-benzimidazol-6-yl}oxy)methyl]-6-methylbenzoate
NMR(CDCl3,δ): 1.24 (3H, t, J=7.2 Hz), 2.38 (3H, s), 2.64 (3H, s), 4.26 (2H, q, J=7.2 Hz), 5.10 (2H, s), 5.42 (2H, s), 6.76 (1H, s), 6.90 (1H, d, J=9.0 Hz), 7.18 (1H, d, J=5.7 Hz), 7.29 (2H, m), 7.58 (1H, d, J=8.4 Hz), 7.74 (1H, s), 8.29 (1H, s).
ethyl 2-[({1-[2-chloro-4-(pentyloxy)benzyl]-2-methyl-1H-benzimidazol-6-yl}oxy)methyl]-6-methylbenzoate
NMR(CDCl3,δ): 0.93 (3H, t, J=7.1 Hz), 1.24 (3H, t, J=7.2 Hz), 1.40 (4H, m), 1.77 (2H, m), 2.37 (3H, s), 2.67 (3H, s), 3.92 (2H, t, J=6.5 Hz), 4.26 (2H, q, J=7.2 Hz), 5.10 (2H, s), 5.32 (2H, s), 6.45 (1H, d, J=8.7 Hz), 6.64 (1H, dd, J=8.6 Hz, 2.4 Hz), 6.77 (1H, d, J=1.9 Hz), 7.00 (2H, m), 7.19 (1H, m), 7.28 (2H, m), 7.70 (1H, d, J=8.8 Hz).
A mixture of methyl 2-[({1-[(3-chloro-1,1′-biphenyl-4-yl)methyl]-2,4-dimethyl-1H-benzimidazol-6-yl}oxy)methyl]-6-nitrobenzoate (1.0 g), Fe (1.0 g), NH4Cl (1.92 g), THF (20 mL), MeOH (20 mL) and H2O (16 mL) was refluxed for 4 hours. After cooling, the mixture was diluted with MeOH and the insoluble materials were filtered off. The filtrate was evaporated in vacuo and the residue was partitioned between EtOAc/THF and H2O. The organic layer was separated, washed with brine, dried over Na2SO4, and concentrated in vacuo to give methyl 2-amino-6-[({1-[(3-chloro-1,1′-biphenyl-4-yl)methyl]-2,4-dimethyl-1H-benzimidazol-6-yl}oxy)methyl]benzoate (0.34 g), which was used in the next step without further purification.
To a solution of ethyl 4-{[1-(2-bromo-4-ethoxybenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]oxy}butanoate (0.19 g) in 1,4-dioxane (10 ml) was added tributyl(vinyl)tin (0.14 g), lithium chloride (0.047 g), and tetrakis (triphenylphsphine)palladium (0) (0.039 g). The solution was heated at 100° C. for 24 hours, and the solvent was removed in vacuo. The residue was partitioned between water and EtOAc. The organic layer was washed with-brine and 5% aqueous potassium fluoride solution, evaporated to dryness, diluted with acetonitrile, filtered, and concentrated in vacuo. The residue was purified using chromatography (silica gel, n-hexane/EtOAc=1/2) to yield ethyl 4-{[1-(4-ethoxy-2-vinylbenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]oxy}butanoate (0.14 g) as a yellow oil.
NMR(CDCl3,δ): 1.23 (3H, t, J=7.1 Hz), 1.39 (3H, t, J=7.0 Hz), 2.04-2.08 (2H, m), 2.48 (3H, s), 2.49 (2H, t, J=7.3 Hz), 2.63 (3H, s), 3.94 (2H, t, J=6.1 Hz), 4.00 (2H, q, J=7.0 Hz), 4.12 (2H, q, J=7.1 Hz), 5.23 (2H, s), 5.45 (1H, dd, J=1.2 Hz and 11 Hz), 5.72 (1H, dd, J=1.2 Hz and 17 Hz), 6.36 (1H, d, J=0.6 Hz), 6.45 (1H, d, J=2.2 Hz), 6.62 (1H, dd, J=2.6 Hz and 8.6 Hz), 6.64-6.68 (1H, m), 6.95-6.99 (1H, m), 7.05 (1H, d, J=2.6 Hz).
Ethyl 4-{[1-(4-ethoxy-2-vinylbenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]oxy}butanoate (0.14 g) was stirred in EtOH (5 ml) in the presence of 10% Pd/C. (14 mg) under H2 ballon for 21 hours at room temperature. The mixture was filtered and evaporated to dryness to give ethyl 4-{[1-(4-ethoxy-2-ethylbenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]oxy}butanoate (0.14 g, 100%) as a colorless oil.
NMR(CDCl3,δ): 1.23 (3H, t, J=7.1 Hz), 1.24 (3H, t, J=7.1 Hz), 1.40 (3H, t, J=7.0 Hz), 2.05-2.10 (2H, m), 2.49 (2H, t, J=7.2 Hz), 2.68-2.72 (8H, m), 3.95 (2H, t, J=6.1 Hz), 4.00 (2H, q, J=7.2 Hz), 4.13 (2H, q, J=7.2 Hz), 5.26 (2H, s), 6.36 (1H, d, J=8.5 Hz), 6.50 (1H, s), 6.58 (1H, dd, J=2.3 Hz and 8.5 Hz), 6.79 (1H, br s), 6.83 (1H, d, J=2.5 Hz).
To a solution of ethyl 4-{[1-(2,4-dichlorobenzyl)-2-methyl-1H-benzimidazol-6-yl]oxy}-2,2-dimethylbutanoate (135 mg) in EtOH (1.4 ml) was added 2N-NaOH (0.6 ml) at ambient temperature. The mixture was heated at 80°.C for 4 hours. After cooling, the reaction mixture was acidified with 1N-HCl (pH 3-4). The precipitates were collected by filtration and washed with water and MeOH (small portion) to give-4-{[1-(2,4-dichlorobenzyl)-2-methyl-1H-benzimidazol-6-yl]oxy}-2,2-dimethylbutanoic acid (112 mg) as pale brown crystals.
NMR(DMSO-d6,δ): 1.15 (6H, s), 1.92 (2H, t, J=7.0 Hz), 2.37 (3H, s), 3.93 (2H, t, J=7.0 Hz), 5.48 (2H, br s), 6.45 (1H, d, J=8.4 Hz), 6.75 (1H, dd, J=2.2 Hz, 8.6 Hz), 7.00 (1H, d, J=2.2 Hz), 7.34 (1H, dd, J=2.1 Hz, 8.4 Hz), 7.43 (1H, d, J=8.6 Hz), 7.73 (1H, d, J=2.1 Hz), 12.22 (1H, br s).
MS: 419 (M−1).
To a solution of 4-({1-[2-chloro-4-(pentyloxy)benzyl]-2-methyl-1H-benzimidazol-6-yl}oxy)-2,2-dimethylbutanoate (800 mg) in EtOH (8 ml) was added 2N-NaOH (3.2 ml) at ambient temperature. The mixture was heated at 80° C. for 2 hours. After cooling, the reaction mixture was acidified with 1N-HCl (pH 3-4). The precipitates were collected by filtration and washed with water and MeOH (small portion) to give 4-({1-[2-chloro-4-(pentyloxy)benzyl]-2-methyl-1H-benzimidazol-6-yl}oxy)-2,2-dimethylbutanoic acid (616 mg) as pale brown crystals.
NMR(DMSO-d6,δ): 0.8-1.0 (3H, m), 1.15 (6H, s), 1.2-1.5 (4H, m), 1.5-1.8 (2H, m), 1.92 (2H, t, J=6.9 Hz), 2.39 (3H, s), 3.8-4.0 (4H, m), 5.40 (2H, br s), 6.50 (1H, d, J=8.7 Hz), 6.73 (1H, dd, J=2.2 Hz, 8.7 Hz), 6.82 (1H, dd, J=2.5 Hz, 8.7 Hz), 6.96 (1H, d, J=2.2 Hz), 7.10 (1H, d, J=2.5 Hz), 7.41 (1H, d, J=8.7 Hz), 12.19 (1H, br s).
MS: 471 (M−1).
To a solution of methyl 2-[({1-[(3-chloro-1,1′-biphenyl-4-yl)methyl]-2,4-dimethyl-1H-benzimidazol-6-yl}oxy)methyl]nicotinate(140 mg) in ethanol (1.4 ml) was added 1N NaOH (0.547 mL) at room temperature. The mixture was heated at 80° C. for 2 hours. After cooling, the reaction mixture was acidified with 1N-HCl (pH 5). The resulting precipitates were collected by filtration and washed with water to give 2-[({1-[(3-chloro-1,1′-biphenyl-4-yl)methyl]-2,4-dimethyl-1H-benzimidazol-6-yl}oxy)methyl]nicotinic acid (132 mg) as white crystals.
NMR(DMSO-d6, 200 MHz, 8): 2.46 (3H, s), 2.48 (3H, s), 5.37 (2H, s), 5.50(2H, s), 6.52 (1H, d, J=8.1 Hz), 6.66 (1H, s), 6.89 (1H, s), 7.35-7.54 (5H, m), 7.66-7.69 (2H, m), 7.83 (1H, S), 8.16 (1H, d, J=7.7 Hz), 8.62 (1H, d, J=4.8 Hz), 13.5 (1H, br s).
MS: 496 (M−1).
The following compounds were obtained in a similar manner to that of Example 178.
2-[({1-[2-chloro-4-(pentyloxy)benzyl]-2,4-dimethyl-1H-benzimidazol-6-yl}oxy)methyl]benzoic acid
NMR(DMSO-d6,δ): 0.86 (3H, t, J=6.9 Hz), 1.33 (4H, m), 1.66 (2H, m), 2.45 (6H, s), 3.92 (2H, t, J=6.4 Hz), 5.36 (4H, s), 6.56 (1H, d, J=8.0 Hz), 6.71 (1H, s), 6.78 (2H, m), 7.05 (1H, d, J=2.2 Hz), 7.40 (1H, t, J=7.5 Hz), 7.52 (1H, t, J=7.6 Hz), 7.58 (1H, d, J=7.7 Hz), 7.89 (1H, d, J=7.7 Hz), 13.20 (1H, br s).
2-[({1-[(2-chloro-6-phenyl-3-pyridinyl)methyl]-2-methyl-1H-benzimidazol-6-yl}oxy)methyl]benzoic acid
NMR(DMSO-d6,δ): 2.54 (3H, s), 5.41 (2H, s), 5.58 (2H, s), 6.95 (1H, d, J=8.6 Hz), 7.07 (1H, d, J=7.7 Hz), 7.18 (1H, s), 7.35 (1H, t, J=7.5 Hz), 7.49 (4H, m), 7.55 (1H, d, J=8.7 Hz), 7.58 (1H, d, J=7.8 Hz), 7.86 (2H, m), 8.01 (2H, d, J=7.1 Hz), 13.01 (1H, br s).
2-[({1-[2-chloro-4-(1,3-oxazol-2-yl)benzyl]-2-methyl-1H-benzimidazol-6-yl}oxy)methyl]benzoic acid
NMR(DMSO-d6,δ): 2.43 (3H, s), 5.39 (2H, s), 5.53 (2H, s), 6.65 (1H, d, J=8.2 Hz), 6.84 (1H, dd, J=8.7 Hz, 2.3 Hz), 7.00 (1H, d, J=2.3 Hz), 7.32 (1H, t, J=7.5 Hz), 7.41 (1H, d, J=0.5 Hz), 7.47 (1H, d, J=8.7 Hz), 7.48 (1H, dt, J=1.2 Hz, 7.5 Hz), 7.56 (1H, d, J=7.6 Hz), 7.79 (1H, dd, J=8.2 Hz, 1.6 Hz), 7.85 (1H, dd, J=7.8 Hz, 1.1 Hz), 8.01 (1H, d, J=1.6 Hz), 8.25 (1H, s), 13.01 (1H, br s).
2-[({1-[2-fluoro-4-(trifluoromethyl)benzyl]-2,4-dimethyl-1H-benzimidazol-6-yl}oxy)methyl]benzoic acid
NMR(DMSO-d6,δ): 2.45 (6H, s), 5.38 (2H, s), 5.52 (2H, s), 6.68 (1H, s), 6.86 (1H, s), 6.94 (1H, t, J=7.9 Hz), 7.38 (1H, t, J=7.7 Hz), 7.46 (1H, d, J=8.1 Hz), 7.51 (1H, t, J=8.5 Hz), 7.58 (1H, d, J=7.8 Hz), 7.70 (1H, d, J=10.0 Hz), 7.88 (1H, d, J=7.8 Hz), 13.02 (1H, br s).
2-[({1-[2-chloro-4-(2-pyridinyl)benzyl]-2,4-dimethyl-1H-benzimidazol-6-yl}oxy)methyl]benzoic acid
NMR(DMSO-d6,δ): 2.48 (3H, s), 2.50 (3H, s), 5.38 (2H, s), 5.53 (2H, s), 6.67 (1H, d, J=7.6 Hz), 6.75 (1H, s), 6.89 (1H, s), 7.32 (1H, t, J=7.5 Hz), 7.38 (1H, dd, J=7.4 Hz, 4.8 Hz), 7.49 (1H, dt, J=1.1 Hz, 7.7 Hz), 7.57 (1H, d, J=7.6 Hz), 7.85 (1H, dd, J=7.7 Hz, 1.1 Hz), 7.89 (2H, m), 7.96 (1H, d, J=8.0 Hz), 8.20 (1H, d, J=1.7 Hz), 8.66 (1H, d, J=4.2 Hz), 13.00 (1H, br s).
To a solution of ethyl 4-[(1-{[3-chloro-5-(pentyloxy)-2-pyridinyl]methyl}-2,4-dimethyl-1H-benzimidazol-6-yl)oxy]butanoate (220 mg) in EtOH (2.2 ml) was added 1N NaOH (0.9 mL) at room temperature. The mixture was heated at 80° C. for 1 hour. After cooling to room temperature, the reaction mixture was acidified with 1N-HCl (pH 4). The precipitates were collected by filtration and washed with water. Recrystallization from MeOH afforded 4-[(1-{[3-chloro-5-(pentyloxy)-2-pyridinyl]methyl)-2,4-dimethyl-1H-benzimidazol-6-yl)oxy]butanoic acid (101 mg) as white crystals.
NMR(DMSO-d6, 200 MHz,δ): 0.87 (3H, t, J=6.7 Hz), 1.26-1.37 (4H, m), 1.61-1.71 (2H, m), 1.85-1.96 (2H, m), 2.35 (2H, t, J=7.1 Hz), 2.39 (3H, s), 2.51 (3H, s), 3.89 (2H, t, J=6.3 Hz), 4.03 (2H, t, J=6.5 Hz), 5.48 (2H, s), 6.55 (1H, d, J=2.1 Hz), 6.72 (1H, d, J=2.1 Hz), 7.63 (1H, d, J=2.5 Hz), 8.11 (1H, d, J=2.5 Hz), 12.3 (1H, br s).
MS: 460 (M+1).
The following compounds were obtained in a similar manner to that of Example 184.
4-{[6-(3-carboxypropoxy)-2,4-dimethyl-1H-benzimidazol-1-yl]methyl}-3-methoxybenzoic acid
NMR(DMSO-d6,δ): 1.85-1.93 (2H, m), 2.35 (2H, t, J=7.3 Hz), 2.48 (3H, s), 2.55 (3H, s), 3.90 (3H, s), 3.92 (2H, t, J=6.5 Hz), 5.45 (2H, s), 6.73 (1H, s), 6.83 (1H, br s), 6.92 (1H, s), 7.46 (1H, dd, J=1.1 Hz, 7.9 Hz), 7.53 (1H, d, J=1.3 Hz), 12.6 (2H, br s).
4-({1-[2-fluoro-4-(trifluoromethyl)benzyl]-2,4-dimethyl-1H-benzimidazol-6-yl}oxy)butanoic acid
NMR(DMSO-d6,δ): 1.86-1.92 (2H, m), 2.35 (2H, t, J=7.3 Hz), 2.42 (3H, s), 2.44 (3H, s), 3.90 (2H, t, J=6.4 Hz), 5.55 (2H, s), 6.60-6.61 (1H, m), 6.86 (1H, d, J=2.2 Hz), 6.90 (1H, t, J=7.7 Hz), 7.51 (1H, d, J=8.0 Hz), 7.74 (1H, d, J=9.2 Hz), 12.1 (1H, br s).
4-({1-[2-chloro-4-(1H-pyrazol-1-yl)benzyl]-2,4-dimethyl-1H-benzimidazol-6-yl}oxy)butanoic acid
NMR(DMSO-d6,δ): 1.86-1.91 (2H, m), 2.34 (2H, t, J=7.3 Hz), 2.40 (3H, s), 2.46 (3H, s), 3.89 (2H, t, J=6.4 Hz), 5.47 (2H, s), 6.54-6.61 (3H, m), 6.82 (1H, d, J=2.1 Hz), 7.71 (1H, dd, J=2.2 Hz, 8.5 Hz), 7.74 (1H, d, J=1.6 Hz), 8.03 (1H, d, J=2.3 Hz), 8.51 (1H, d, J=2.5 Hz), 12.1 (1H, br s).
4-}[1-(2-bromo-4-ethoxybenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]oxy}butanoic acid
NMR(DMSO-d6,δ): 1.27 (3H, t, J=7.0 Hz), 1.85-1.91 (2H, m), 2.34 (2H, t, J=7.3 Hz), 2.37 (3H, s), 2.45 (3H, s), 3.88 (2H, t, J=6.4 Hz), 3.99 (2H, q, J=7.0 Hz), 5.32 (2H, s), 6.33 (1H, d, J=8.7 Hz), 6.59 (1H, d, J=1.4 Hz), 6.74 (1H, d, J=2.2 Hz), 6.83 (1H, dd, J=2.6 Hz and 8.7 Hz), 7.24 (1H, d, J=2.6 Hz), 12.1 (1H, br s).
4-({1-[4-ethoxy-2-(trifluoromethyl)benzyl]-2,4-dimethyl-1H-benzimidazol-6-yl}oxy)butanoic acid
NMR(DMSO-d6,δ): 1.29 (3H, t, J=7.0 Hz), 1.85-1.91 (2H, m), 2.32-2.37 (5H, m), 2.46 (3H, s), 3.88 (2H, t, J=6.4 Hz), 4.04 (2H, q, J=7.0 Hz), 5.44 (2H, s), 6.34 (1H, d, J=8.7 Hz), 6.61-6.62 (1H, m), 6.74 (1H, d, J=2.2 Hz), 7.07 (1H, dd, J=2.6 Hz, 8.6 Hz), 7.27 (1H, d, J=2.6 Hz).
4-({1-[2-chloro-4-(2-pyridinyl)benzyl]-2,4-dimethyl-1H-benzimidazol-6-yl}oxy)butanoic acid
NMR(DMSO-d6,δ): 1.85-1.91 (2H, m), 2.33 (2H, t, J=7.3 Hz), 2.40 (3H, s), 2.47 (3H, s), 3.89 (2H, t, J=6.4 Hz), 5.51 (2H, s), 6.52 (1H, d, J=8.2 Hz), 6.61-6.62 (1H, m), 6.83 (1H, d, J=2.2 Hz), 7.36-7.39 (1H, m), 7.86-7.89 (1H, m), 7.91 (1H, dd, J=1.8 Hz, 8.2 Hz), 7.95-7.97 (1H, m), 8.23 (1H, d, J=1.8 Hz), 8.64-8.66 (1H, m), 12.0 (1H, br s).
4-{[1-(4-ethoxy-2-ethylbenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]oxy}butanoic acid
NMR(DMSO-d6,δ): 1.18 (3H, t, J=7.5 Hz), 1.27 (3H, t, J=7.0 Hz), 1.87-1.91 (2H, m), 2.33-2.36 (5H, m), 2.45 (3H, s), 2.69 (2H, q, J=7.5 Hz), 3.88 (2H, t, J=6.4 Hz), 3.94 (2H, q, J=7.0 Hz), 5.31 (2H, s), 6.16 (1H, d, J=8.5 Hz), 6.58-6.60 (2H, m), 6.72 (1H, d, J=2.1 Hz), 6.79 (1H, d, J=2.1 Hz).
4-{[1-(2-chloro-4-ethylbenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]oxy}butanoic acid
NMR(DMSO-d6,δ): 1.12 (3H, t, J=7.6 Hz), 1.85-1.90 (2H, m), 2.33 (2H, t, J=7.3 Hz), 2.37 (3H, s), 2.45 (3H, s), 2.55 (2H, q, J=7.6 Hz), 3.88 (2H, t, J=6.4 Hz), 5.40 (2H, s), 6.36 (1H, d, J=8.0 Hz), 6.59-6.60 (1H, m), 6.75 (1H, d, J=2.2 Hz), 7.05(1H, dd, J=1.5 Hz, 7.9 Hz), 7.37 (1H, d, J=1.6 Hz).
To a mixture of methyl 4-[({1-[(3-chloro-1,1′-biphenyl-4-yl)methyl]-2,4-dimethyl-1H-benzimidazol-6-yl}oxy)methyl]benzoate (0.32 g), MeOH (6 mL) and THF (6 mL) was added 4 N NaOH (4 mL). After refluxing for an hour, the mixture was acidified with 1 N HCl in an ice-bath. The precipitate formed was collected and dried in vacuo to give 4-[({1-[(3-chloro-1,1′-biphenyl-4-yl)methyl]-2,4-dimethyl-1H-benzimidazol-6-yl}oxy)methyl]benzoic acid (0.29 g).
NMR(DMSO-d6,δ): 2.43 (3H, s), 2.4-2.6 (3H, s), 5.13 (2H, s), 5.51 (2H, s), 6.51 (1H, d, J=8 Hz), 6.76 (1H, d, J=1 Hz), 6.98 (1H, d, J=2 Hz), 7.3-8.0 (10H, m), 12.8-13.2 (1H, br m).
MS: 495 (M−H).
The following compounds were obtained in a similar manner to that of Example 193.
2-chloro-6-[({1-[(3-chloro-1,1′-biphenyl-4-yl)methyl]-2,4-dimethyl-1H-benzimidazol-6-yl}oxy)methyl]benzoic acid
NMR(DMSO-d6,δ): 2.4-2.6 (6H, s), 5.06 (2H, s), 5.57 (2H, s), 6.58 (1H, d, J=8 Hz), 6.76 (1H, br s), 7.03 (1H, br s), 7.3-7.7 (9H, m), 7.85 (1H, d, J=2 Hz), 13.0-14.5 (1H, br m).
MS: 529, 531 (M−H).
4-chloro-2-[({1-[(3-chloro-1,1′-biphenyl-4-yl)methyl]-2,4-dimethyl-1H-benzimidazol-6-yl}oxy)methyl]benzoic acid
NMR(DMSO-d6,δ): 2.54 (3H, s), 2.61 (3H, s), 5.42 (2H, s), 5.61 (2H, s), 6.7-6.8 (1H, m), 6.91 (1H, br s), 7.00 (1H, br s), 7.4-7.8 (9H, m), 7.91 (1H, d, J=8 Hz), 13.1-13.5 (1H, br m).
MS: 531, 533 (M+H).
5-chloro-2-[({1-[(3-chloro-1,1′-biphenyl-4-yl)methyl]-2,4-dimethyl-1H-benzimidazol-6-yl}oxy)methyl]benzoic acid
NMR(DMSO-d6,δ): 2.45 (3H, s), 2.4-2.6 (3H, s), 5.36 (2H, s), 5.48 (2H, s), 6.54 (1H, d, J=8 Hz), 6.70 (1H, br s), 6.85 (1H, d, J=2 Hz), 7.3-7.9 (10H, m), 13.4-13.7 (1H, br m).
MS: 531, 533 (M+H).
3-chloro-2-[({1-[(3-chloro-1,1′-biphenyl-4-yl)methyl]-2,4-dimethyl-1H-benzimidazol-6-yl}oxy)methyl]benzoic acid
NMR(DMSO-d6,δ): 2.56 (3H, s), 2.70 (3H, s), 5.39 (2H, s), 5.73 (2H, s), 6.84 (1H, d, J=8 Hz), 6.94 (1H, br s), 7.28 (1H, br s), 7.4-7.8 (9H, m), 7.89 (1H, d, J=2 Hz), 13.0-13.7 (1H, br m).
MS: 531, 533 (M+H).
2-[({1-[(3-chloro-1,1′-biphenyl-4-yl)methyl]-2,4-dimethyl-1H-benzimidazol-6-yl}oxy)methyl]-6-fluorobenzoic acid
NMR(DMSO-d6,δ): 2.43 (3H, s), 2.4-2.6 (3H, s), 5.12 (2H, s), 5.51 (2H, s), 6.48 (1H, d, J=8 Hz), 6.66 (1H, d, J=1 Hz), 6.94 (1H, d, J=2 Hz), 7.2-7.6 (8H, m), 7.66 (1H, dd, J=1 Hz, J=8 Hz), 7.83 (1H, d, J=2 Hz), 13.3-14.0 (1H, br m).
MS: 513 (M−H).
A mixture of methyl 2-[({1-[(3-chloro-1,1′-biphenyl-4-yl)methyl]-2,4-dimethyl-1H-benzimidazol-6-yl}oxy)methyl]-6-methylbenzoate (0.13 g), 50% NaOH (1 mL) and 2-ethoxyethanol (2 mL) was refluxed for an hour. After cooling, the reaction mixture was acidified with 1 N HCl in an ice-bath. The precipitate formed was collected and dried in vacuo to give 2-[({1-[(3-chloro-1,1′-biphenyl-4-yl)methyl]-2,4-dimethyl-1H-benzimidazol-6-yl}oxy)methyl]-6-methylbenzoic acid (0.13 g).
NMR(DMSO-d6,δ): 2.29 (3H, s), 2.48 (3H, s), 2.58 (3H, s), 5.06 (2H, s), 5.61 (2H, s), 6.66 (1H, d, J=8 Hz), 6.80 (1H, br s), 7.07 (1H, br s), 7.2-7.7 (9H, m), 7.86 (1H, d, J=2 Hz), 13.0-13.5 (1H, br m).
MS: 511 (M+H).
The following compounds were obtained in a similar manner to that of Example 199.
2-[({1-[(3-chloro-1,1′-biphenyl-4-yl)methyl]-2,4-dimethyl-1H-benzimidazol-6-yl}oxy)methyl]-6-nitrobenzoic acid
NMR(DMSO-d6,δ): 2.53 (3H, s), 2.61 (3H, s), 5.19 (2H, s), 5.64 (2H, s), 6.69 (1H, d, J=8 Hz), 6.86 (1H, br s), 7.13 (1H, br s), 7.4-8.2 (10H, m), 14.0-15.0 (1H, br m).
MS: 540 (M−H).
2-amino-6-[({1-[(3-chloro-1,1′-biphenyl-4-yl)methyl]-2,4-dimethyl-1H-benzimidazol-6-yl}oxy)methyl]benzoic acid
NMR(DMSO-d6,δ): 2.4-2.5 (3H, s), 2.60 (3H, s), 5.17 (2H, s), 5.61 (2H, s), 6.6-7.1 (5H, m), 7.3-7.9 (8H, m), 8.3-8.6 (2H, br m).
MS: 512 (M−H).
2-[({1-[2-chloro-4-(1,3-oxazol-2-yl)benzyl]-2-methyl-1H-benzimidazol-6-yl}oxy)methyl]-6-methylbenzoic acid
NMR(DMSO-d6,δ): 2.27 (3H, s), 2.40 (3H, s), 5.04 (2H, s), 5.54 (2H, s), 6.55 (1H, d, J=8.1 Hz), 6.79 (1H, dd, J=8.7 Hz, 2.4 Hz), 7.09 (1H, d, J=2.3 Hz), 7.16 (1H, d, J=7.1 Hz), 7.24 (1H, t, J=7.4 Hz), 7.27 (1H, d, J=6.9 Hz), 7.40 (1H, d, J=1.6 Hz), 7.45 (1H, d, J=8.7 Hz), 7.79 (1H, dd, J=8.1 Hz, 1.6 Hz), 8.04 (1H, d, J=1.7 Hz), 8.24 (1H, d, J=0.4 Hz), 13.02 (1H, br s).
2-[({1-[(3-chloro-1,1′-biphenyl-4-yl)methyl]-2-methyl-1H-benzimidazol-6-yl}oxy)methyl]-6-methylbenzoic acid
NMR(DMSO-d6,δ): 2.28 (3H, s), 2.42 (3H, s), 5.05 (2H, s), 5.53 (2H, s), 6.49 (1H, d, J=8.2 Hz), 6.80 (1H, dd, J=8.7 Hz, 2.3 Hz), 7.12 (1H, dd, J=2.3 Hz), 7.19 (1H, d, J=7.4 Hz), 7.26 (1H, t, J=7.5 Hz), 7.30 (1H, d, J=7.4 Hz), 7.38 (1H, t, J=7.3 Hz), 7.46 (3H, m), 7.52 (1H, dd, J=8.1 Hz, 1.7 Hz), 7.66 (2H, m), 7.83 (1H, d, J=1.8 Hz), 13.14 (1H, br s).
2-[({1-[(3,5-dichloro-2-pyridinyl)methyl]-2-methyl-1H-benzimidazol-6-yl}oxy)methyl]-6-methylbenzoic acid
NMR(DMSO-d6,δ): 2.29 (3H, s), 2.38 (3H, s), 5.03 (2H, s), 5.59 (2H, s), 6.7.4 (1H, dd, J=8.7 Hz, 2.4 Hz), 7.00 (1H, d, J=2.3 Hz), 7.19 (1H, d, J=6.8 Hz), 7.27 (2H, m), 7.38 (1H, d, J=8.7 Hz), 8.30 (1H, d, J=2.1 Hz), 8.40 (1H, d, J=2.1 Hz), 13.20 (1H, br s).
2-[({1-[2-chloro-4-(pentyloxy)benzyl]-2-methyl-1H-benzimidazol-6-yl}oxy)methyl]-6-methylbenzoic acid
NMR(DMSO-d6,δ): 0.86 (3H, t, J=7.1 Hz), 1.32 (4H, m), 1.67 (2H, m), 2.30 (3H, s), 2.39 (3H, s), 3.93 (2H, t, J=6.5 Hz), 5.04 (2H, s), 5.38 (2H, s), 6.46 (1H, d, J=8.7 Hz), 6.78 (1H, dt, J=2.5 Hz, 9.0 Hz), 7.04 (1H, d, J=2.2 Hz), 7.09 (1H, d, J=2.5 Hz), 7.21 (1H, d, J=7.2 Hz), 7.29 (2H, m), 7.42 (1H, d, J=8.7 Hz), 13.14 (1H, br s).
2-[({1-[2-chloro-4-(pentyloxy)benzyl]-2,4-dimethyl-1H-benzimidazol-6-yl)oxy}methyl]-6-methylbenzoic acid
NMR(DMSO-d6, δ): 0.86 (3H, t, J=7.1 Hz), 1.33 (4H, m), 1.67 (2H, m), 2.30 (3H, s), 2.39 (3H, s), 2.45 (3H, s), 3.93 (2H, t, J=6.5 Hz), 5.01 (2H, s), 5.36 (2H, s), 6.43 (1H, d, J=8.6 Hz), 6.62 (1H, s), 6.79 (1H, dd, J=8.7 Hz, 2.5 Hz), 6.84 (1H, d, J=1.6 Hz), 7.09 (1H, d, J=3.5 Hz), 7.21 (1H, m), 7.29 (2H, m), 13.13 (1H, br s).
2-[({1-[(3,5-dichloro-2-pyridinyl)methyl]-2,4-dimethyl-1H-benzimidazol-6-yl}oxy)methyl]-6-methylbenzoic acid
NMR(DMSO-d6,δ): 2.30 (3H, s), 2.39 (3H, s) 2.43 (3H, s), 5.00 (2H, s), 5.56 (2H, s), 6.59 (1H, s), 6.79 (1H, s), 7.21 (1H, m), 7.28 (2H, m), 8.29 (1H, d, J=2.0 Hz), 8.39 (1H, d, J=2.0 Hz), 13.18 (1H, br s).
2-[({1-[(3-chloro-5-ethoxy-2-pyridinyl)methyl]-2,4-dimethyl-1H-benzimidazol-6-yl}oxy)methyl]-6-methylbenzoic acid
NMR(DMSO-d6,δ): 1.30 (3H, t, J=7.0 Hz), 2.30 (3H, s), 2.47 (3H, s), 2.53 (3H, s), 4.09 (2H, q, J=7.0 Hz), 5.04 (2H, s), 5.59 (2H, br s), 6.73 (1H, br s), 6.96 (1H, br s), 7.23 (1H, m), 7.30 (2H, m), 7.65 (1H, d, J=2.2 Hz), 8.07 (1H, d, J=2.4 Hz), 13.19 (1H, br s).
2-[({1-[2-chloro-4-(1,3-oxazol-2-yl)benzyl]-2,4-dimethyl-1H-benzimidazol-6-yl}oxy)methyl]-6-methylbenzoic acid
NMR(DMSO-d6,δ): 2.27 (3H, s), 2.40 (3H, s), 2.47 (3H, s), 5.01 (2H, s), 5.51 (2H, s), 6.53 (1H, d, J=8.2 Hz), 6.64 (1H, s), 6.89 (1H, d, J=2.0 Hz), 7.16 (1H, d, J=7.0 Hz), 7.26 (2H, m), 7.40 (1H, s), 7.79 (1H, dd, J=8.1 Hz, 1.4 Hz), 8.04 (1H, d, J=1.5 Hz), 8.25 (1H, s), 13.16 (1H, br s).
A minture of methyl 2-({[1-(2-chloro-4-cyanobenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]oxy}methyl)benzoate (0.27 g), 4 N NaOH (293 μL) and 2-methoxyethanol (5.9 mL) was stirred at ambient temperature overnight. The mixture was diluted with H2O (3 mL) and acidified with 1 N HCl. The precipitate formed was collected and suspended in a mixture of EtOH (3 mL) and H2O (1 mL). The mixture was stirred at ambient temperature overnight and the precipitate was collected and dried in vacuo to give 2-({[1-(2-chloro-4-cyanobenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]oxy}methyl)benzoic acid (93 mg).
NMR(DMSO-d6,δ): 2.40 (3H, s), 2.4-2.6 (3H, s), 5.36 (2H, s), 5.52 (2H, s), 6.52 (1H, d, J=8 Hz), 6.70 (1H, br s), 6.79 (1H, d, J=2 Hz), 7.3-8.0 (5H, m), 8.12 (1H, d, J=1 Hz), 12.6-13.4 (1H, br m),
MS: 446 (M+H).
The following compound was obtained in a similar manner to that of Example 210.
2-({[1-(4-cyano-2-fluorobenzyl)-2,4-dimethyl-1H-benzimidazol-6-yl]oxy}methyl)benzoic acid
NMR(DMSO-d6,δ): 2.45 (3H, s), 2.46 (3H, s), 5.38 (2H, s), 5.53 (2H, s), 6.69 (1H, br s), 6.84 (1H, d, J=2 Hz), 6.8-7.0 (1H, m), 7.3-8.0 (6H, m), 12.8-13.4 (1H, br m).
MS: 428 (M−H).
The following compounds were obtained in a similar manner to that of Example 151 and Example 184.
4-({1-[2-(2,4-dichlorophenyl)ethyl]-2,4-dimethyl-1H-benzimidazol-6-yl}oxy)butanoic acid
NMR(DMSO-d6,δ): 1.94 (2H, quint, J=6.7 Hz), 2.28 (3H, s), 2.40 (3H, s), 2.37-2.41 (2H, m), 3.10 (2H, t, J=7.0 Hz), 3.92 (2H, t, J=6.4 Hz), 4.31 (2H, t, J=6.9 Hz), 6.55 (1H, br s), 6.69 (1H, d, J=2.0 Hz), 7.20 (1H, d, J=8.2 Hz), 7.30 (1H, dd, J=8.3 Hz, 2.1 Hz), 7.57 (1H, d, J=2.1 Hz), 12.13 (1H, br s).
4-({1-[2-(2,4-difluorophenyl)ethyl]-2,4-dimethyl-1H-benzimidazol-6-yl}oxy)butanoic acid
NMR(DMSO-d6,δ): 1.93 (2H, quint, J=6.9 Hz), 2.24 (3H, s), 2.37-2.41 (5H, m), 3.00 (2H, t, J=6.9 Hz), 3.94 (2H, t, J=6.4 Hz), 4.29 (2H, t, J=6.9 Hz), 6.54 (1H, d, J=1.3 Hz), 6.71 (1H, d, J=2.0 Hz), 6.96 (1H, dt, J=2.4 Hz, 8.5 Hz), 7.15 (1H, dt, J=2.5 Hz, 9.8 Hz), 7.19-7.24 (1H, m), 12.13 (1H, br s).
4-({1-[3-(2,4-dichlorophenyl)propyl]-2,4-dimethyl-1H-benzimidazol-6-yl}oxy)butanoic acid
NMR(DMSO-d6,δ): 1.90-1.99 (4H, m), 2.35-2.41 (5H, m), 2.46 (3H, s), 2.69-2.74 (2H, m), 3.95 (2H, t, J=6.3 Hz), 4.15 (2H, t, J=7.3 Hz), 6.56 (1H, br s), 6.77 (1H, d, J=1.9 Hz), 7.31-7.39 (2H, m), 7.55 (1H, d, J=1.9 Hz), 12.12 (1H, br s).
The following compounds were obtained in a similar manner to that of Preparation Example 250.
4-(acetylamino)-3-({[3-chloro-5-(methoxymethyl)-2-pyridinyl]methyl}amino)-5-methylphenyl acetate
NMR(DMSO-d6,δ): 2.04 (3H, s), 2.08 (3H, s), 2.22 (3H, s), 3.31 (3H, s), 4.37 (2H, d, J=5 Hz), 4.47 (2H, s), 5.86 (1H, t, J=5 Hz), 6.24 (1H, d, J=2 Hz), 6.30 (1H, d, J=2 Hz), 7.91 (1H, d, J=1 Hz), 8.50 (1H, d, J=1 Hz), 9.04 (1H, s).
MS: 414 (M+Na).
4-(acetylamino)-3-({[3-chloro-5-(ethoxymethyl)-2-pyridinyl]methyl}amino)-5-methylphenyl acetate
NMR(DMSO-d6,δ): 1.15 (3H, t, J=7 Hz), 2.04 (3H, s), 2.08 (3H, s), 2.22 (3H, s), 3.50 (2H, q, J=7 Hz), 4.37 (2H, d, J=5 Hz), 4.51 (2H, s), 5.86 (1H, t, J=5 Hz), 6.25 (1H, d, J=2 Hz), 6.30 (1H, d, J=2 Hz), 7.89 (1H, d, J=1 Hz), 8.49 (1H, d, J=1 Hz), 9.04 (1H, s).
MS: 406 (M+H).
The following compounds were obtained in a similar manner to that of Example 139.
1-{[3-chloro-5-(methoxymethyl)-2-pyridinyl]methyl}-2,4-dimethyl-1H-benzimidazol-6-ol
NMR(DMSO-d6,δ): 2.38 (3H, s), 2.44 (3H, s), 3.28 (3H, s), 4.42 (2H, s), 5.49 (2H, s), 6.3-6.5 (2H, m), 7.91 (1H, d, J=2 Hz), 8.32 (1H, d, J=2 Hz), 8.90 (1H, s).
MS: 332 (M+H).
1-{[3-chloro-5-(ethoxymethyl)-2-pyridinyl]methyl}-2,4-dimethyl-1H-benzimidazol-6-ol
NMR(DMSO-d6,δ): 1.13 (3H, t, J=7 Hz), 2.39 (3H, s), 2.44 (3H, s), 3.47 (2H, q, J=7 Hz), 4.45 (2H, s), 5.48 (2H, s), 6.3-6.5 (2H, m), 7.91 (1H, d, J=2 Hz), 8.32 (1H, d, J=2 Hz), 8.90 (1H, s).
MS: 346 (M+H).
The following compounds were obtained in a similar manner to that of Example 141.
methyl 2-{[(1-{[3-chloro-5-(ethoxymethyl)-2-pyridinyl]methyl}-2,4-dimethyl-1H-benzimidazol-6-yl)oxy]methyl}-6-methylbenzoate
NMR(DMSO-d6,δ): 1.12 (3H, t, J=7 Hz), 2.26 (3H, s), 2.42 (3H, s), 2.44 (3H, s), 3.47 (2H, t, J=7 Hz), 3.68 (3H, s), 4.46 (2H, s), 4.99 (2H, s), 5.56 (2H, s), 6.56 (1H, d, J=2 Hz), 6.75 (1H, d, J=2 Hz), 7.3-7.5 (3H, m), 7.91 (1H, d, J=2 Hz), 8.28 (1H, d, J=2 Hz).
MS: 507 (M+H).
methyl 2-{[(1-{[3-chloro-5-(methoxymethyl)-2-pyridinyl]methyl}-2,4-dimethyl-1H-benzimidazol-6-yl)oxy]methyl}benzoate
NMR(DMSO-d6,δ): 2.44 (6H, s), 3.28 (3H, s), 3.79 (3H, s), 4.41 (2H, s), 5.32 (2H, s), 5.55 (2H, s), 6.63 (1H, d, J=2 Hz), 6.73 (1H, d, J=2 Hz), 7.4-7.6 (3H, m), 7.8-8.0 (2H, m), 8.28 (1H, d, J=2 Hz).
MS: 480 (M+H).
methyl 2-{[(1-{[3-chloro-5-(methoxymethyl)-2-pyridinyl]methyl}-2,4-dimethyl-1H-benzimidazol-6-yl)oxy]methyl}-6-methylbenzoate
NMR(DMSO-d6,δ): 2.26 (3H, s), 2.42 (3H, s), 2.44 (3H, s), 3.28 (3H, s), 3.68 (3H, s), 4.42 (2H, s), 4.99 (2H, s), 5.57 (2H, s), 6.56 (1H, d, J=2 Hz), 6.75 (1H, d, J=2 Hz), 7.2-7.4 (3H, m), 7.92 (1H, d, J=1 Hz), 8.28 (1H, d, J=1 Hz).
MS: 494 (M+H).
methyl 2-{[(1-{[3-chloro-5-(ethoxymethyl)-2-pyridinyl]methyl}-2,4-dimethyl-1H-benzimidazol-6-yl)oxy]methyl}benzoate
NMR(DMSO-d6,δ): 1.12 (3H, t, J=7 Hz), 2.45 (6H, s), 3.47 (2H, t, J=7 Hz), 3.79 (3H, s), 4.45 (2H, s), 5.32 (2H, s), 5.54 (2H, s), 6.64 (1H, d, J=2 Hz), 6.73 (1H, d, J=2 Hz), 7.5-7.7 (3H, m), 7.8-8.0 (2H, m), 8.28 (1H, d, J=2 Hz).
MS: 493 (M+H).
The following compounds were obtained in a similar manner to that of Example 193.
2-{[(1-{[3-chloro-5-(ethoxymethyl)-2-pyridinyl]methyl}-2,4-dimethyl-1H-benzimidazol-6-yl)oxy]methyl}benzoic acid
NMR(DMSO-d6,δ): 1.12 (3H, t, J=7 Hz), 2.45 (6H, s), 3.47 (2H, q, J=7 Hz), 4.45 (2H, s), 5.36 (2H, s), 5.54 (2H, s), 6.64 (1H, br s), 6.73 (1H, br s), 7.3-7.7 (3H, m), 7.8-8.0 (2H, m), 8.28 (1H, d, J=2 Hz), 12.5-13.5 (1H, br m).
MS: 480 (M+H).
2-{[(1-{[3-chloro-5-(methoxymethyl)-2-pyridinyl]methyl}-2,4-dimethyl-1H-benzimidazol-6-yl)oxy]methyl}benzoic acid
NMR(DMSO-d6,δ): 2.45 (6H, s), 3.28 (3H, s), 4.41 (2H, s), 5.36 (2H, s), 5.54 (2H, s), 6.65 (1H, d, J=2 Hz), 6.74 (1H, d, J=2 Hz), 7.3-7.7 (3H, m), 7.8-8.0 (2H, m), 8.28 (1H, d, J=2 Hz), 12.5-13.5 (1H, br m).
MS: 466 (M+H).
The following compounds were obtained in a similar manner to that of Example 199.
2-{[(1-{[3-chloro-5-(ethoxymethyl)-2-pyridinyl]methyl}-2,4-dimethyl-1H-benzimidazol-6-yl)oxy]methyl}-6-methylbenzoic acid
NMR(DMSO-d6,δ): 1.12 (3H, t, J=7 Hz), 2.30 (3H, s), 2.41 (3H, s), 2.44 (3H, s), 3.47 (2H, q, J=7 Hz), 4.45 (2H, s), 5.00 (2H, s), 5.57 (2H, s), 6.59 (1H, d, J=2 Hz), 6.80 (1H, d, J=2 Hz), 7.1-7.4 (3H, m), 7.90 (1H, d, J=2 Hz), 8.28 (1H, d, J=2 Hz), 12.8-13.6 (1H, br m).
MS: 494 (M+H).
2-{[(1-{[3-chloro-5-(methoxymethyl)-2-pyridinyl]methyl}-2,4-dimethyl-1H-benzimidazol-6-yl)oxy]methyl}-6-methylbenzoic acid
NMR(DMSO-d6, δ): 2.31 (3H, s), 2.41 (3H, s), 2.44 (3H, s), 3.28 (3H, s), 4.42 (2H, s), 5.00 (2H, s), 5.57 (2H, s), 6.59 (1H, d, J=2 Hz), 6.81 (1H, d, J=2 Hz), 7.2-7.4 (3H, m), 7.91 (1H, d, J=2 Hz), 8.28 (1H, d, J=2 Hz), 13.0-13.4 (1H, br m).
MS: 480 (M+H).
The benzimidazole compounds, pharmaceutically acceptable salts thereof and prodrugs thereof of the present invention are useful for the prophylaxis and treatment of, for example, impaired glucose tolerance disorder, diabetes (e.g., type II diabetes), gestational diabetes, diabetic complications (e.g., diabetic gangrene, diabetic arthropathy, diabetic osteopenia, diabetic glomerulosclerosis, diabetic nephropathy, diabetic dermatopathy, diabetic neuropathy, diabetic cataract, diabetic retinopathy and the like), insulin resistance syndrome (e.g., insulin receptor abnormality, Rabson-Mendenhall syndrome, leprechaunism, Kobberling-Dunnigan syndrome, Lawrence-Seip syndrome (lipoatrophy), Cushing syndrome, acromegaly and the like), polycystic ovary syndrome, hyperlipidemia, atherosclerosis, cardiovascular diseases (e.g., stenocardia, cardiac failure and the like), hyperglycemia (e.g., those characterized by abnormal saccharometabolism such as eating disorders), pancreatitis, osteoporosis, hyperuricemia, hypertension, inflammatory bowel diseases, skin disorders related to an anomaly of differentiation of epidermic cells, hypertension, Alzheimer's disease, Parkinson's disease, multiple sclerosis, stroke, traumatic brain and spinal cord injury, and the like. In addition, they, in combination with a retinoid, are useful for treating disease states caused by uncontrolled cell proliferation, including cancer, restenosis and atherosclerosis.
This application is based on patent application No. 2003902860 filed in Australia, the content of which is hereby incorporated by reference. The references cited herein, including patents and patent applications, are hereby incorporated in their entireties by reference, to the extent that they have been disclosed herein.
| Number | Date | Country | Kind |
|---|---|---|---|
| 2003902860 | Jun 2003 | AU | national |
