CN101475538A - Triazole derivatives as inhibitors of 11-beta-hydroxysteroid dehydrogenase-1 - Google Patents
Triazole derivatives as inhibitors of 11-beta-hydroxysteroid dehydrogenase-1 Download PDFInfo
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Abstract
Triazole derivatives of structural formula (I) are selective inhibitors of the 11beta-hydroxysteroid dehydrogenase-1. The compounds are useful for the treatment of diabetes, such as noninsulin-dependent diabetes (NIDDM), hyperglycemia, obesity, insulin resistance, dyslipidemia, hyperlipidemia, hypertension, Metabolic Syndrome, and other symptoms associated with NIDDM.
Description
The application is that application number is dividing an application of 200380106415.7 applications, and application number is that the applying date of 200380106415.7 applications is on December 16th, 2003, and the applicant is a Merck ﹠ Co., Inc.
Invention field
The present invention relates to be used as the triazole derivative of I type 11-beta-hydroxysteroid dehydrogenase (11 β-HSD-1 or HSD-1) inhibitor and utilize above-claimed cpd to treat the method for some disease.Compound of the present invention is used for the treatment of diabetes B (NIDDM), insulin resistance, obesity, lipid disorders, the hypertension of diabetes such as non-insulin-dependent, and other disease and illness.
Background of invention
Diabetes are caused by multiple factor, and the most general feature is the concentration of glucose rising (hyperglycemia) in the blood plasma when the empty stomach state.That usually generally acknowledges has two kinds of diabetes forms: type 1 diabetes, or insulin-dependent diabetes mellitus (IDDM), this patient secretes minute quantity Regular Insulin or excreting insulin not, described Regular Insulin is the hormone of regulating glucose utilization, and diabetes B, or non insulin dependent diabetes (NIDDM), this patient's excreting insulin, even show hyperinsulinemia (insulin concentration of blood plasma is compared identical or higher with ND individuality), and show hyperglycemia simultaneously.Type 1 diabetes is generally used exogenous insulin by injection and is treated.Yet diabetes B often develops into " insulin resistance ", makes Regular Insulin at main insulin sensitivity tissue, and promptly the effect of muscle, liver and fatty tissue moderate stimulation glucose and lipid metabolism reduces.The insulin concentration that is not the insulin resistance patient of diabetes raises, and is used to compensate their insulin resistance, so that the glucose concn of serum can not raise.In NIDDM patient, even plasma insulin concentration is raised, also be not enough to overcome described insulin resistance, cause hyperglycemia.
Insulin resistance is the bonding defective of understanding fully not yet owing to so far of acceptor at first.The opposing of Regular Insulin has been caused the incomplete absorption of glucose, and the storage of the oxidation of glucose and glycogen reduces in the muscle, and inadequate Regular Insulin suppresses and the deficiency of liver preparation and secretion glucose in the fatty tissue steatolysis.
The increase of the hyperglycemia that continues or do not add control that takes place in diabetes and sickness rate and too early mortality ratio is relevant.Unusual glucose homeostasis is also directly or with relevant with the metabolic change of obesity, hypertension and lipid, lipoprotein and lipophorin indirectly.Diabetes B has increased the danger that develops into cardiovascular complication, as atherosclerosis, coronary heart disease, apoplexy, peripheral vascular disease, hypertension, ephrosis, neuropathy and retinopathy.Therefore, glucose homeostasis, lipid metabolism, obesity and hypertensive treatment control is vital in the Clinical Processing of diabetes and treatment.
Many patients that suffer from insulin resistance but also do not develop into diabetes B also have and develop into the danger that is known as " syndrome X " or " metabolic syndrome ".Syndrome X or metabolic syndrome are characterised in that insulin resistance, with abdominal obesity, hyperinsulinemia, hypertension, low HDL and high VLDL.Above-mentioned patient, no matter whether develop into tangible diabetes, but the danger that develops into above-mentioned cardiovascular complication increases.
2 type treatment of diabetes generally comprise physical activity and go on a diet.By using the plasma concentration that sulfonylurea (as tolbutamide and Glipizide) or meglitinide improve Regular Insulin, said medicine can be secreted more Regular Insulin by the stimulating pancreas beta cell, and/or when sulfonylurea or meglitinide do not have effect insulin injection, can make insulin concentration be high enough to stimulate the tissue of insulin resistance.Yet dangerous is, can cause the lower concentration of plasma glucose, and the intensity that insulin resistance can take place at last increases.
Biguanides has increased the susceptibility of Regular Insulin, makes hyperglycemia obtain some corrections.Yet many biguanides medicines as phenformin and N1,N1-Dimethylbiguanide, have caused the too much disease of lactic acid, gastric disorder causing nausea and diarrhoea.
Glitazone medicine (Glitazone) (being 5-benzyl thiazolidine-2, the 4-diketone) has formed a new class and has had the compound that potential improves other symptoms of hyperglycemia and diabetes B.Said medicine has mainly increased the insulin sensitivity in muscle, liver and the fatty tissue, has partially or completely revised the glucose plasma concentration that is improved, and does not cause hypoglycemia basically.Lattice row ketone in the market is the agonist of peroxisome hyperplasia activated receptors (PPAR) γ hypotype.The PPAR-gamma agonist is considered to use the viewed reason that causes insulin sensitivity to improve of lattice row ketone usually.The PPAR agonist of the renewal that is used for the treatment of diabetes B and/or unusual lipidemia of developing is one or more in PPAR α, γ and the δ hypotype.About the insulin sensitivity medicine of treatment diabetes B and the summary of other mechanism, referring to M.Tadayyon and S.A.Smith, " Insulin sensitisation in the treatment of Type 2 diabetes; " Expert Opin.Investig.Drugs, 12:307-324 (2003).
Still need to treat diabetes and related symptoms, as the novel method of metabolic syndrome.The present invention has satisfied these needs and other needs.
Summary of the invention
The present invention relates to two ring [2.2.2]-Xin-1-bases-1,2 of structural formula I, the 4-triazole compounds
Above-mentioned two ring [2.2.2]-octyl group triazole derivatives can be used as the I type 11-beta-hydroxysteroid dehydrogenase (inhibitor of 11 β-HSD-1) effectively.Therefore, the disease that they can be used for treating, control or prevent the inhibition for 11 β-HSD-1 to respond is as hyperglycemia, insulin resistance, diabetes B, lipid disorders, obesity, atherosclerosis and metabolic syndrome.
The invention still further relates to the pharmaceutical composition that comprises The compounds of this invention and pharmaceutically acceptable carrier.
The invention still further relates to by using compound of the present invention and pharmaceutical composition and treat or control the method for hyperglycemia, insulin resistance, diabetes B, obesity, lipid disorders, atherosclerosis and metabolic syndrome.
Detailed Description Of The Invention
The present invention relates to two ring [2.2.2]-Xin-1-bases-1,2, the 4-triazole derivative as 11 β-HSD-1 inhibitor.Compound of the present invention is shown in structural formula I:
Or its pharmacy acceptable salt; Wherein
Each p is 0,1 or 2 independently;
Each n is 0,1 or 2 independently;
X is selected from singly-bound, O, S (O)
p, NR
6,
R
1Be selected from
Aryl carbonyl,
(CH
2)
n-aryl and
(CH
2)
n-heteroaryl;
Wherein, aryl and heteroaryl are not substituted or are independently selected from R by 1-3
5Substituting group replace;
R
2Be selected from
Hydrogen,
C
1-8Alkyl,
C
2-6Thiazolinyl and
(CH
2)
n-C
3-6Cycloalkyl,
Wherein, alkyl, thiazolinyl and cycloalkyl are not substituted or are independently selected from R by 1-3
8Replace with the substituting group of oxo base;
Each R
4Be independently selected from
Hydrogen,
Halogen,
Hydroxyl,
The oxo base,
C
1-3Alkyl and
C
1-3Alkoxyl group;
R
3Be selected from
Hydrogen,
C
1-10Alkyl,
C
2-10Thiazolinyl,
(CH
2)
n-C
3-6Cycloalkyl,
(CH
2)
n-aryl,
(CH
2)
n-heteroaryl and
(CH
2)
n-heterocyclic radical;
Wherein, aryl, heteroaryl and heterocyclic radical are not substituted or are independently selected from R by 1-3
5Substituting group replace; Alkyl, thiazolinyl and cycloalkyl are not substituted or are independently selected from R by 1-5
8Replace with the substituting group of oxo base;
R
5And R
8Each is independently selected from
Hydrogen,
Formyl radical,
C
1-6Alkyl,
(CH
2)
n-aryl,
(CH
2)
n-heteroaryl,
(CH
2)
n-heterocyclic radical,
(CH
2)
nC
3-7Cycloalkyl,
Halogen,
OR
7，
(CH
2)
nN(R
7)
2，
Cyano group,
(CH
2)
nCO
2R
7，
NO
2，
(CH
2)
nNR
7SO
2R
6，
(CH
2)
nSO
2N(R
7)
2，
(CH
2)
nS(O)
pR
6，
(CH
2)
nSO
2OR
7，
(CH
2)
nNR
7C(O)N(R
7)
2，
(CH
2)
nC(O)N(R
7)
2，
(CH
2)
nNR
6C(O)R
6，
(CH
2)
nNR
6CO
2R
7，
O(CH
2)
nC(O)N(R
7)
2，
CF
3，
CH
2CF
3，
OCF
3，
OCHCF
2And
OCH
2CF
3；
Wherein, aryl, heteroaryl, cycloalkyl and heterocyclic radical are not substituted or are independently selected from halogen, hydroxyl, C by 1-3
1-4Alkyl, trifluoromethyl, trifluoromethoxy and C
1-4The substituting group of alkoxyl group replaces; Wherein, R
5And R
8In arbitrary methylene radical (CH
2) carbon atom is not substituted or is independently selected from halogen, hydroxyl and C by 1-2
1-4The group of alkyl replaces; Perhaps at same methylene radical (CH
2) two substituting groups on the carbon atom form cyclopropyl with the carbon atom that their connect;
Each R
6Be independently selected from
C
1-8Alkyl,
(CH
2)
n-aryl,
(CH
2)
n-heteroaryl and
(CH
2)
nC
3-7Cycloalkyl;
Wherein, alkyl and cycloalkyl are not substituted or are independently selected from halogen, oxo base, C by 1-5
1-4Alkoxyl group, C
1-4Alkylthio, hydroxyl, amino substituting group replace; Aryl and heteroaryl are not substituted or are independently selected from cyano group, halogen, hydroxyl, amino, carboxyl, trifluoromethyl, trifluoromethoxy, C by 1-3
1-4Alkyl and C
1-4The substituting group of alkoxyl group replaces;
Perhaps, two R
6The atom that group is connected with them forms the list or the second cycle line of 5-8 unit, and described ring system randomly contains other O, S and the NC of being selected from
1-4The heteroatoms of alkyl; And
Each R
7Be hydrogen or R
6
In an embodiment of The compounds of this invention, R
2Be cyclopropyl, C
1-3Alkyl or C
2-3Thiazolinyl, and R
1Be phenyl or naphthyl, wherein phenyl and naphthyl are not substituted or are independently selected from R by 1-3
5Substituting group replace.In a class of this embodiment, R
5Be selected from halogen, hydroxyl, trifluoromethyl, trifluoromethoxy, C
1-3Alkyl, C
1-3Alkoxyl group, C
1-3Alkylthio and C
1-3Alkyl sulphonyl.In such subclass, R
2Be methyl and R
4Be hydrogen.
In second embodiment of The compounds of this invention,
X is a singly-bound;
R
1Be phenyl or naphthyl, wherein phenyl and naphthyl are not substituted or are independently selected from R by 1-3
5Substituting group replace;
R
2Be cyclopropyl, C
1-3Alkyl or C
2-3Thiazolinyl; And
R
3Be C
1-6Alkyl, described alkyl are not substituted or are independently selected from R by 1-3
8Replace with the substituting group of oxo base.
In a class of second embodiment, R
5Be selected from halogen, hydroxyl, trifluoromethyl, trifluoromethoxy, C
1-3Alkyl, C
1-3Alkoxyl group, C
1-3Alkylthio and C
1-3Alkyl sulphonyl.In such subclass, R
2Be methyl and R
4Be hydrogen.In this embodiment another kind of, R
8Be selected from halogen, hydroxyl, oxo base, C
1-4Alkoxyl group, C
1-4Alkylthio, C
1-4Alkyl sulphinyl, C
1-4Alkyl sulphonyl and phenyl, described phenyl are not substituted or are replaced by 1-3 group that is independently selected from halogen and trifluoromethyl.In such subclass, R
2Be methyl and R
4Be hydrogen.In the 3rd class of this embodiment, R
5Be selected from halogen, hydroxyl, trifluoromethyl, trifluoromethoxy, C
1-3Alkyl, C
1-3Alkoxyl group, C
1-3Alkylthio and C
1-3Alkyl sulphonyl; And R
8Be selected from halogen, hydroxyl, oxo base, C
1-4Alkoxyl group, C
1-4Alkylthio, C
1-4Alkyl sulphonyl and phenyl, described phenyl are not substituted or are replaced by 1-3 group that is independently selected from halogen and trifluoromethyl.In such subclass, R
2Be methyl and R
4Be hydrogen.
In the 3rd embodiment of The compounds of this invention,
X is a singly-bound;
R
1Be phenyl or naphthyl, wherein phenyl and naphthyl are not substituted or are independently selected from R by 1-3
5Substituting group replace;
R
2Be cyclopropyl, C
1-3Alkyl or C
2-3Thiazolinyl; And
R
3Be phenyl or heteroaryl, wherein phenyl and heteroaryl are not substituted or are independently selected from R by 1-3
5Substituting group replace.
In a class of this embodiment, R
2Be methyl and R
4Be hydrogen.
In this embodiment another kind of, R
3Be phenyl, described phenyl is not substituted or is independently selected from R by 1-3
5Substituting group replace.In such subclass, R
5Be selected from halogen, hydroxyl, trifluoromethyl, trifluoromethoxy, C
1-3Alkyl, C
1-3Alkoxyl group, C
1-3Alkylthio and C
1-3Alkyl sulphonyl.In the subclass of this subclass, R
2Be methyl and R
4Be hydrogen.
In the 3rd class of this embodiment, R
3Shi oxadiazole base, Suo Shu oxadiazole base are not substituted or are independently selected from R by 1-2
5Substituting group replace.In such subclass, R
5Be phenyl, described phenyl is not substituted or is independently selected from halogen, hydroxyl, C by 1-3
1-4Alkyl, trifluoromethyl, trifluoromethoxy and C
1-4The substituting group of alkoxyl group replaces.In the subclass of this subclass, R
2Be methyl and R
4Be hydrogen.
The following definitions of Shi Yonging is suitable for herein.
" alkyl ", and other groups with prefix " alkane ", as alkoxyl group and alkyloyl, the meaning is straight chain carbochain or side chain carbochain and their combination, unless carbochain has other definition.The example of alkyl comprises methyl, ethyl, propyl group, sec.-propyl, butyl, sec-butyl and the tertiary butyl, amyl group, hexyl, heptyl, octyl group, nonyl etc.The number of wherein concrete carbon atom can be, C for example
3-10, the term alkyl also comprises cycloalkyl, and the combination of straight or branched alkyl chain and cycloalkyl structure, when not having concrete carbon atom number, refers to C
1-6
" thiazolinyl " meaning is the carbochain that contains at least one carbon-to-carbon double bond, can be straight chain or side chain or their combination, unless carbochain has other definition.The example of thiazolinyl comprises vinyl, allyl group, pseudoallyl, pentenyl, hexenyl, heptenyl, 1-propenyl, crotyl, 2-methyl-2-butene base etc.Wherein concrete carbon atom number can be, C for example
5-10, the term thiazolinyl also comprises cycloalkenyl group, and the combination of straight chain, side chain and ring texture.When not having concrete carbonatoms, refer to C
2-6
" alkynyl " meaning is the carbochain that contains at least one carbon-to-carbon triple bond, can be straight chain or side chain or their combination.The example of alkynyl comprises ethynyl, propargyl, 3-methyl-1-pentene alkynyl, 2-heptyne base etc.
" cycloalkyl " is the subclass of alkyl, and the meaning is the saturated carbon ring that contains concrete carbonatoms.The example of cycloalkyl comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group etc.Cycloalkyl generally is monocyclic, except as otherwise noted.Cycloalkyl is saturated, unless otherwise defined.
Term " alkoxyl group " refers to the alkoxide (C for example of the appointment carbonatoms of straight or branched
1-6Alkoxyl group) or the alkoxide of the arbitrary numerical value in this scope [being methoxyl group (MeO-), oxyethyl group, isopropoxy etc.].
Term " alkylthio " refers to the alkyl sulfur compounds (C for example of the appointment carbonatoms of straight or branched
1-6Alkylthio) or the alkyl sulfur compounds of the arbitrary numerical value in this scope [being methylthio group (MeS-), ethylmercapto group, iprotiazem base etc.].
Term " alkylamino " refers to the alkylamine (C for example of the appointment carbonatoms of straight or branched
1-6Alkylamino) or the alkylamine of the arbitrary numerical value in this scope [being methylamino-, ethylamino, isopropylamino, uncle's fourth amino etc.].
Term " alkyl sulphonyl " refers to the alkyl sulfone (C for example of the appointment carbonatoms of straight or branched
1-6Alkyl sulphonyl) or the alkyl sulfone of the arbitrary numerical value in this scope [be methyl sulphonyl (MeSO
2-), ethylsulfonyl, sec.-propyl alkylsulfonyl etc.].
Term " alkyl sulphinyl " refers to the alkyl sulfoxide (C for example of the appointment carbonatoms of straight or branched
1-6Alkyl sulphinyl) or the alkyl sulfoxide of the arbitrary numerical value in this scope [being methylsulfinyl (MeSO-), ethyl sulfinyl, sec.-propyl sulfinyl etc.].
Term " alkyl oxy carbonyl " refers to the ester (C for example of carboxylic acid derivative of the present invention of the appointment carbonatoms of straight or branched
1-6The alkyl oxy carbonyl) or the ester of the arbitrary numerical value in this scope [being methyl oxygen base carbonyl (MeOCO-), ethyl oxygen base carbonyl or butyl oxygen base carbonyl].
" aryl " meaning is monocycle or the polycyclic aromatic ring system that contains carboatomic ring atom.Preferred aryl groups is the aromatic ring of monocycle or bicyclic 6-10 unit.Phenyl and naphthyl are preferred aryl groups.Most preferred aryl is a phenyl.
" heterocycle " and " heterocyclic radical " refers to and contains the heteroatoms that at least one is selected from O, S and N, and the oxidised form that also comprises sulphur is SO and SO
2Saturated or undersaturated non-aromatic ring or ring system.The heterocyclic example comprises tetrahydrofuran (THF) (THF), dihydrofuran, 1,4-diox, morpholine, 1,4-dithiane, piperazine, piperidines, 1,3-dioxolane, imidazolidine, tetrahydroglyoxaline, pyrroline, tetramethyleneimine, tetrahydropyrans, dihydropyrane, oxathiolane, dithiolane, 1,3-diox, 1,3-dithiane, oxathiane, thiomorpholine etc.
" heteroaryl " meaning is aromatics or the partially aromatic heterocycle that contains at least one ring hetero atom that is selected from O, S and N.Thereby heteroaryl comprises ring such as aryl, cycloalkyl and the heterocyclic fused heteroaryl of non-aromaticity with other kinds.The example of heteroaryl comprises pyrryl oxazolyl isoxazolyl, isothiazolyl, pyrazolyl, pyridyl oxadiazole base, thiadiazolyl group, thiazolyl, imidazolyl, triazolyl, tetrazyl, furyl, triazinyl, thienyl, pyrimidyl, benzoisoxazole base benzoxazolyl, benzothiazolyl, the diazosulfide base, dihydro benzo furyl, indolinyl, pyridazinyl, indazolyl, pseudoindoyl, the dihydrobenzo thienyl, the indolizine base, the cinnolines base, the 2 base, quinazolyl, naphthyridinyl, carbazyl, the benzo dioxolyl, quinoxalinyl, purine radicals, the furazan base, different benzyl furyl, benzimidazolyl-, benzofuryl, benzothienyl, quinolyl, indyl, isoquinolyl, dibenzofuran group etc.For heterocyclic radical and heteroaryl, comprise the ring and the ring system that contain 3-15 atom, form 1-3 ring.
" halogen " refers to fluorine, chlorine, bromine and iodine.Chlorine and fluorine generally are preferred.When halogen replaced on alkyl or alkoxyl group, fluorine was most preferred (CF for example
3O and CF
3CH
2O).
Term " composition ", as the composition in the pharmaceutical composition, the meaning is the product that comprises the inert fraction that contains activeconstituents and carrier composition, and by the combination of any two or multiple composition, compound or polymerization, perhaps by the disassociation of one or more compositions or by the reaction or the interaction of the other types of one or more compositions, the arbitrary product that directly or indirectly obtains.Therefore, pharmaceutical composition of the present invention comprises compound of the present invention and pharmaceutically acceptable carrier is mixed resulting arbitrary composition.
" administration " of term compound and " giving " compound are construed as to there being the individuality that needs that the prodrug of compound of the present invention or The compounds of this invention is provided.
Compound in structural formula I can contain one or more asymmetric centers, thus can racemoid and the form of racemic mixture, single enantiomorph, non-enantiomer mixture and one diastereomer exist.The present invention's meaning is all above-mentioned isomeric form that comprise structural formula I compound.
Some compounds described herein contain olefinic double bond, unless other descriptions are arranged, the meaning is to comprise E and Z type geometrical isomer.
Some compounds described herein can tautomer such as the form of keto-enol tautomerism body exist.One tautomer and their mixture all are included in the scope of structural formula I compound.
Compound in structural formula I can be separated into one diastereomer in the following way, for example, by the solvent that is fit to fractional crystallization in methyl alcohol or ethyl acetate or its mixture for example, or utilizes the stationary phase of optically-active to separate by chiral chromatography.Absolute stereochemistry can or be derived and determine for the X-radiocrystallography of the crystallization of intermediate of product by crystallized product, if desired, uses the reagent of the asymmetric center that contains known absolute configuration.
Perhaps, the steric isomer of compound of Formula I can utilize the reagent of optically pure initiator or known absolute configuration to obtain by stereospecific synthesis.
At different aspect of the present invention, pharmaceutical composition comprises compound in structural formula I, or its pharmacy acceptable salt or solvate and pharmaceutically acceptable carrier.Term " solvate " meaning is other solvates of hydrate, alcoholate or crystalline.
In another aspect of this invention, provide, comprised the structural formula I compound or its pharmacy acceptable salt or the solvate that give described patient's significant quantity to the method for the mammalian subject treatment hyperglycemia, diabetes or the insulin resistance that need is arranged.
In another aspect of this invention, disclose, comprised the structural formula I compound that gives patient's anti-diabetic significant quantity to the method for mammalian subject treatment non-insulin-depending type (2 type) diabetes that need is arranged.
In another aspect of this invention, disclose, comprised giving described patient compound in structural formula I with the amount of effective treatment of obesity to the method for the mammalian subject treatment of obesity that needs is arranged.
In another aspect of this invention, disclose, comprised giving described patient compound in structural formula I with the amount of effective treatment metabolic syndrome to the method for the mammalian subject treatment metabolic syndrome that needs is arranged.
In another aspect of this invention, disclose to the method for the mammalian subject treatment lipid disorders that needs is arranged, lipid disorders is selected from unusual lipidemia, hyperlipidaemia, hypertriglyceridemia, hypercholesterolemia, low HDL and high LDL, comprises giving described patient compound in structural formula I with the amount of the described lipid disorders of effective treatment.
In another aspect of this invention, disclose, comprised giving the patient compound in structural formula I with the amount of effective treatment atherosclerosis to the method for the mammalian subject treatment atherosclerosis that needs is arranged.
The present invention relates to the purposes of compound in structural formula I in treatment hyperglycemia, insulin resistance, diabetes B, lipid disorders, obesity, atherosclerosis and metabolic syndrome on the other hand.
The compound that another aspect of the present invention provides structural formula I is used for the treatment of purposes in the medicine of the disease that is selected from hyperglycemia, insulin resistance, diabetes B, lipid disorders, obesity, atherosclerosis and metabolic syndrome in preparation.
Compound of the present invention can pharmacy acceptable salt form administration.Term " pharmacy acceptable salt " refers to by pharmaceutically acceptable nontoxic alkali or acid comprises inorganic or organic bases and salt inorganic or the organic acid preparation.The salt that is included in the basic cpd in the term " pharmacy acceptable salt " refers to the non-toxic salt of The compounds of this invention, generally prepares by free alkali and the organic or inorganic acid-respons that is fit to.The representational salt of basic cpd of the present invention includes, but are not limited to following salt: acetate, benzene sulfonate, benzoate, supercarbonate, hydrosulfate, the Tartaric acid hydrogen salt, borate, bromide, d-camphorsulfonic acid salt, carbonate, muriate, Clavulanate, Citrate trianion, dihydrochloride, edetate, ethanedisulphonate, Estolate, esilate, fumarate, gluceptate, gluconate, glutaminate, the glycolyl arsanilate, Sucrets salt (hexylresorcinate), breathe out amine (hydrabamine), hydrobromate, hydrochloride, Hydroxynaphthoate, iodide, different thiosulphate, lactic acid salt, Lactobionate, lauroleate, malate, maleate, mandelate, mesylate, methyl bromide, methyl nitrate, Methylsulfate, mucate, naphthalenesulfonate, nitrate, N-methylglucosamine ammonium salt, oleate, oxalate, embonate (embonate), palmitate, pantothenate, phosphoric acid salt/diphosphate, Polygalacturonate, salicylate, stearate, vitriol, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide and valerate.In addition, compound wherein of the present invention is loaded with acidic moiety, its pharmacy acceptable salt that is fit to includes, but are not limited to, and is comprised deutero-salt such as aluminium, ammonium, calcium, copper, iron, ferrous, lithium, magnesium, manganic, bivalent manganese, potassium, sodium, zinc by mineral alkali.Particularly preferably be ammonium, calcium, magnesium, potassium and sodium salt.Comprise primary by pharmaceutically acceptable organic nontoxic alkali deutero-salt, secondary, and tertiary ammonium salt, cyclammonium salt, and deacidite, as arginine, trimethyl-glycine, trimethyl-xanthine, choline, N, the N-dibenzyl-ethylenediamin, diethylamine, the 2-DEAE diethylaminoethanol, the 2-dimethylaminoethanol, thanomin, quadrol, N-ethylmorpholine, N-ethylpiperidine, glycosamine, glucosamine, Histidine, breathe out amine, Isopropylamine, Methionin, methylglucosamine, morpholine, piperazine, piperidines, versamid 900, PROCAINE HCL, PHARMA GRADE, purine, Theobromine, triethylamine, Trimethylamine 99, tripropyl amine, the salt of trometamol etc.
In addition; carboxylic acid (COOH) or under the alcohol groups situation about existing, can use the pharmaceutically acceptable ester of carboxylic acid derivative, as methyl esters, ethyl ester or new pentane acyloxy methyl esters in The compounds of this invention; or the ester of the acyl derivative of alcohol, as acetic ester or maleic acid ester.Included is that those changes known in the art discharge or the solvability of prodrug preparation or the ester and the acyl group of hydrolysis properties as continuing.
The meaning that should be appreciated that herein the compound in structural formula I of using is also to comprise pharmacy acceptable salt, when they during as the precursor in free cpds, their pharmacy acceptable salts or other synthetic operations, also comprise non-pharmacy acceptable salt.
The solvate, particularly hydrate of structural formula I compound are also included within the scope of the present invention.
Compound described herein is the selection inhibitor of 11 β-HSD1 enzyme.Therefore, the present invention relates to the purposes that 11 beta-HSD 1 inhibitors suppress the reductase activity of 11-beta-hydroxysteroid dehydrogenase, this desaturase is responsible for the conversion of cortisone to hydrocortisone.Too much hydrocortisone is relevant with multiple disease, comprises NIDDM, obesity, unusual lipidemia, insulin resistance and hypertension.Use the concentration that compound of the present invention has reduced the hydrocortisone in the destination organization and other 11-beta-hydroxysteroids, thereby reduced the effect of excessive hydrocortisone and other 11-beta-hydroxysteroids.The inhibition of 11 β-HSD1 can be used for treating and control the disease that the high density by the abnormality of hydrocortisone and other 11-beta-hydroxysteroids causes, for example NIDDM, obesity, hypertension and unusual lipidemia.The active inhibition of 11 β in brain-HSD1 also can be used for treatment or anxiety reduction disease, dysthymia disorders and cognitive disorder as lower hydrocortisone concentration.
The present invention includes structural formula I compound by giving significant quantity or 11 beta-HSD 1 inhibitors of its pharmacy acceptable salt or solvate and be used for the treatment of, control, improve, prevent, postpone the outbreak of disease described herein and symptom or the purposes that minimizing develops into the danger of disease described herein and symptom, above-mentioned disease and symptom are by mammalian subject, and particularly the hydrocortisone of people's excessive or not control amount and/or other reflunomides cause.The inhibition of 11 β-HSD1 enzyme has limited the conversion of cortisone to hydrocortisone, and cortisone is inert normally, can cause or help above-mentioned disease and symptom if hydrocortisone is excessive when existing.
NIDDM and hypertension:
The compounds of this invention is the selective depressant of 11 β-HSD1, and its selectivity is higher than 11 β-HSD2.Though the inhibition of 11 β-HSD 1 is concentration and the associated symptom of treatment that is used to reduce hydrocortisone, the inhibition of 11 β-HSD 2 is accompanied by severe side effect, as hypertension.
Hydrocortisone is important and known anti-inflammatory hormone, also as the antagonist of insulin action in the liver, makes insulin sensitivity reduce, and causes gluconeogenesis in the liver to increase and the concentration rising of glucose.The patient that glucose patience has slackened has the bigger possibility that develops into diabetes B under the situation of the hydrocortisone of the high density of abnormality.
In the tissue that the mineralo-corticoid acceptor exists, the cortisone of high density often causes hypertension.The inhibition of 11 β-HSD 1 changed help cortisone some the tissue in hydrocortisone and the ratio of cortisone.
11 β of administering therapeutic significant quantity-HSD 1 inhibitor is that effectively 11 β of administering therapeutic significant quantity-HSD 1 inhibitor can postpone or prevent the NIDDM of the outbreak, particularly people of NIDDM regularly in the symptom for the treatment of, control and improve NIDDM.
Obesity, metabolic syndrome, unusual lipidemia:
Excessive hydrocortisone concentration is relevant with obesity, perhaps is because the gluconeogenesis of liver increases.Abdominal obesity and glucose allergy, hyperinsulinemia, hypertriglyceridemia, and the factor of other metabolic syndrome such as hypertension, VLDL raises and HDL reduces closely related.People such as Montague, Diabetes, 2000,49:883-888.Yet 11 β-HSD 1 inhibitor of using significant quantity is useful in treatment or controlling obesity disease.For a long time with 11 β-HSD 1 inhibitor treat also can be used for delaying or the outbreak, particularly patient of obesity prevention with going on a diet and exercise when being used in combination 11 β-HSD 1 inhibitor of control arranged.
By reducing insulin resistance and serum glucose being maintained normal concentration, compound of the present invention also can be used for treating and preventing to follow the symptom of type ii diabetes and insulin resistance, comprises the unusual lipidemia of metabolic syndrome or syndrome X, obesity, reactive hypoglycemia and diabetic.
Atherosclerosis:
As indicated above, the reduction of 11 β-HSD 1 active inhibition and hydrocortisone amount helps treatment or control hypertension.Because hypertension and unusual lipidemia help to develop into atherosclerosis, so 11 β of the present invention of administering therapeutic significant quantity-HSD 1 inhibitor can be particularly advantageous in treatment, control, delays the outbreak or the atherosis disease of prevention of arterial of atherosclerosis.
Other application:
Following disease, illness and symptom can be by compounds for treating of the present invention, control, the prevention or delay: (1) hyperglycemia, (2) low dextrose tolerance, (3) insulin resistance, (4) obesity, (5) lipid disorders, (6) unusual lipidemia, (7) hyperlipidaemia, (8) hypertriglyceridemia, (9) hypercholesterolemia, (10) low HDL concentration, (11) high LDL concentration, (12) atherosclerosis and sequela thereof, (13) vascular restenosis, (14) pancreatitis, (15) abdominal obesity, (16) neurodegenerative disease, (17) retinopathy, (18) ephrosis, (19) neuropathy, (20) metabolic syndrome, (21) hypertension and insulin resistance are the other diseases of a part.
The compounds for treating of above-mentioned disease and symptom possible constructions formula I, or this compound can be used for preventing disease described herein and symptom or reduction to develop into the danger of above-mentioned disease and symptom.Because 11 β-suppress to have deleterious side reaction HSD 2 time, or in fact increased the amount of the hydrocortisone in the destination organization, but required is to reduce hydrocortisone, so need the selective depressant of 11 β-HSD 1, and 11 β-HSD 2 almost do not had or do not have restraining effect.
11 β of structural formula I-HSD 1 inhibitor generally has less than about 500nM, preferably less than the inhibition constant IC of about 100nM
50Usually, compound is to the IC of 11 β-HSD 2 and 11 β-HSD1
50Ratio is at least about 2 or bigger, and preferred about 10 or bigger.The IC of 11 β-HSD 2 and 11 β-HSD 1 more preferably
50Ratio about 100 or bigger compound.For example, compound of the present invention has greater than about 1000nM 11 β-HSD 2 in theory, is preferably greater than the inhibition constant IC of 5000nM
50
Arbitrary suitable route of administration can be used for the The compounds of this invention of effective dose is offered Mammals, especially the people.For example, can utilize per os, per rectum, part, parenteral, through eye, through lung, intranasal etc.Formulation comprises tablet, lozenge, dispersion, suspension agent, liquor, capsule, emulsifiable paste, ointment, aerosol etc.Preferably, compound in structural formula I oral administration.
The effective dose of activeconstituents is according to the particular compound of being used, administering mode, the symptom that treat and the severity of this symptom and change.Above-mentioned dosage can be determined easily by those skilled in the art.
When treating or preventing disease described herein and symptom, for structural formula I compound, when can obtain satisfied effect when body weight is used The compounds of this invention with per daily dose about 0.1 to about 100 milligrams of per kilograms (mpk), preferably with the administration of single per daily dose, or one day about dosed administration that separates for 2-6 time.Yet the about 0.1mg of total per daily dose is to about 1000mg, and preferably about 1mg is to about 50mg.General under 70 kilograms adult situation, the about 7mg of total per daily dose is to about 350mg.This dosage can be adjusted to obtain best result of treatment.
Another aspect of the present invention relates to a kind of pharmaceutical composition, comprises compound in structural formula I, or its pharmacy acceptable salt or solvate and pharmaceutically acceptable carrier.
Described composition comprise be suitable for per os, per rectum, part, parenteral (comprising subcutaneous, muscle and intravenously), through eye (medicament for the eyes), through skin, through the composition of lung (nose or oral cavity suck) or nose administration, but optimal approach will depend on kind and the severity and the activeconstituents of the disease of being treated under arbitrary given situation.They can be easily provide with the form of unitary dose, prepare by arbitrary pharmaceutical field known method.
Structural formula I compound can be according to the hybrid technology pharmaceutically of routine and carrier combinations pharmaceutically.Carrier adopts various ways.For example, the carrier that is used for liquid oral compositions comprises, for example water, ethylene glycol, oil, ethanol, seasonings, sanitas, tinting material and other are used for the component that liquid oral suspension agent, elixir and liquor preparation are used.Carrier such as starch, sugar and Microcrystalline Cellulose, thinner, granulating agent, lubricant, tackiness agent, disintegrating agent etc. are used to prepare oral dosage form, for example pulvis, hard and soft capsule and tablet.Solid orally ingestible is preferred with respect to liquid oral.
Oral dosage form also can contain tackiness agent such as Tragacanth, Sudan Gum-arabic, W-Gum or gelatin; Vehicle such as Lin Suanergai; Disintegrating agent such as W-Gum, yam starch, alginic acid; Lubricant such as Magnesium Stearate; With sweeting agent such as sucrose, lactose or asccharin.Capsule also can contain liquid vehicle such as fatty oil.
Multiple other material can be used as the dressing of dose unit or is used to improve its physical aspect.For example, tablet can come dressing with lac, sugar or both.
The water of tablet available standards becomes or non-water becomes technology to come dressing.Certainly, active compound in above-mentioned composition general per-cent based on W/W about 2% to about 60%.Thereby the about 0.1mg of amount of the compound in structural formula I that tablet contains or its salt or hydrate is to about 1.5g, and preferably about 1.0mg is to about 500mg, and more preferably from about 10mg is to about 100mg.
Oral solutions such as syrup or elixir can contain sweeting agent sucrose, sanitas methyl p-hydroxybenzoate and propyl ester, dyestuff and seasonings such as cherry or orange flavor except activeconstituents.
The parenteral medicine generally adopts the form of liquor or suspension agent, and general water prepares, and randomly comprises tensio-active agent such as hydroxypropylcellulose.Dispersion can prepare at glycerine, liquid macrogol and the mixture in oil thereof.Generally the preparation that exists with the form of diluting can contain sanitas.
Injection type pharmaceutically, the pulvis that comprises moisture liquor and dispersion and be used for interim preparation injection liquor or dispersion is also sterilized, and must flow to the degree that can inject easily; They are stable under the condition of preparation and storage, normally are saved.Therefore carrier comprises and contains for example water, ethanol, polyvalent alcohol (for example glycerine, propylene glycol and liquid macrogol), its mixture that is fit to and the solvent or the dispersion medium of vegetables oil.
Measure: suppress the measurement of constant:
By flicker approximate test method (Scintillation Proximity Assay) (SPA) in the enzymic activity of external test test compound.In brief, the structural formula I compound of the cortisone matrix of tritiate, NADPH cofactor and titration 37 ℃ with 11 β-HSD 1 enzyme incubation, make it to transform to hydrocortisone.Behind the incubation, preparation is coated with the a-protein of SPA pearl (bead), with the monoclonal antibody of anti-hydrocortisone and non-specific 11 β-HSD inhibitor as 18 β-Potenlini pre-mixing, join in each hole.This mixture is 15 ℃ of concussions, then by being applicable to the liquid scintillation counter reading of 96 porose discs.Control wells with respect to non-inhibition calculates inhibition percentage ratio, obtains IC
50Curve.This mensuration is used for 11 β-HSD 2 similarly, and wherein the hydrocortisone of tritiate and NAD are used separately as matrix and cofactor.Begin to measure, and the matrix of 40 μ L (in the 50mMHEPES of pH7.4 damping fluid, 25nM
3H-cortisone+1.25mMNADPH) join in the specified hole of 96 porose discs.Compound is dissolved among the DMSO with 10mM, subsequently with 50 times of DMSO dilutions.Four times of the titration then of diluted material, seven times.Each titrating compound of 1 μ L joins in the matrix then doublely.Begin reaction, 10 μ L join in each hole with the concentration that is fit to from 11 β-HSD 1 microsome of CHO transfectant, obtain about 10% transformation efficiency of raw material.For suppressing percentile last calculating, add in a series of hole, minimum value and maximum value are measured in representative: one contains matrix, but does not have compound or enzyme (background), and another contains matrix and enzyme, but without any compound (peak signal).Plate rotates precipitation reagent tout court with low speed in whizzer, use rubber belt sealing, stirs lightly, 37 ℃ of incubations 2 hours.Behind the incubation, the SPA pearl of 45 μ L suspends in advance with anti-hydrocortisone monoclonal antibody and formula I compound, joins in each hole.Plate reseals, and shakes above 1.5 hours lightly at 15 ℃.Based on the data on liquid scintillation counter such as the Topcount collection plate.To suppress anti-hydrocortisone antibody/hydrocortisone bonding in order to control, and is mixed with 1.25nM[3] matrix of H hydrocortisone joins in the specified single hole.In each above-mentioned hole, add the 200 μ M compounds of 1 μ L and the damping fluid of 10 μ L, rather than enzyme.The inhibition of arbitrary calculating is because compound has interfered hydrocortisone to be adhered on the antibody of SPA pearl.
Measure; The measurement of inhibiting rate in the body:
Substantially, test compound is oral to the Mammals administration, common 1-24 of the timed interval hour of disappearing of drug effect.The cortisone intravenous injection of tritiate is collected blood behind the several minutes subsequently.Steroid extracts from isolating serum, analyzes by HPLC.
3H-cortisone and reduzate thereof
3The relative concentration of H-hydrocortisone is confirmed as compound and takes the control group of vehicle.Absolute transformation efficiency, and the percentage that suppresses is calculated by above-mentioned value.
More specifically, compound becomes oral type, and they are dissolved in vehicle (5% hydroxy propyl-Beta-cyclodextrin v/v H with required concentration
2O, or Equivalent) in, generally the dosage with 10mg/kg uses.After one night of fasting, by oral gavage takes liquor for ICR mouse (available from Charles River), every animal per dosage 0.5mL, and each is for 3 of examination groups.
Through after the required time, general 4 hours or 16 hours, inject the 3 μ M's of 0.2mL by tail vein
3The dPBS solution of H-cortisone.It is interior after 2 minutes that mouse is put cage into, CO
2The indoor euthanasia of carrying out.After ceasing breathing, take out mouse, cardiac puncture is collected blood.Blood room temperature in serum separator tube is placed and was not less than 30 minutes, makes it abundant coagulation.Behind the incubation, blood is by being separated into serum in centrifugal 10 minutes at 4 ℃ of 3000Xg.
For the steroid in the serum analysis, they at first use organic solvent extraction.0.2mL the serum transfers of volume is in clean micro-centrifuge tube.To the ethyl acetate that wherein adds the 1.0mL volume, violent afterwards eddy current 1 minute.Aqueous serum protein is become granule and removed organic supernatant liquor by little centrifugal fast rotational.0.85mL the top organic phase transfer in the fresh micro-centrifuge tube and dry.Dry sample is suspended among the DMSO of the 0.250mL that contains high density cortisone and hydrocortisone again, is used for HPLC and analyzes.
0.200mL sample is added on the Metachem Inertsil C-18 chromatographic column, the methyl alcohol balance with 30%.The slow linear gradient separate targets steroid of methyl alcohol up to 50%; The cold 254nm of being designated as of target place monitoring in being used as in resuspension solution by UV simultaneously.Be used for analyzing to software by radio-chromatogram law detector collection tritium data and data upload.Ratio with the AUC of the merging of the AUC of hydrocortisone and cortisone and hydrocortisone calculates
3The H-cortisone arrives
3The percentage transformation efficiency of H-hydrocortisone.
The preparation of The compounds of this invention:
Structural formula I compound of the present invention can prepare according to the raw material that the program utilization among following scheme and the embodiment is fit to, and is used as example in addition by the following specific embodiments.But the compound of setting forth among the embodiment is not limited to form and is considered to of the present invention unique a kind of.Embodiment has at length set forth the preparation of The compounds of this invention in addition.Those skilled in the art can understand the known change of described condition easily, and the method for following preparation procedure can be used for preparing above-claimed cpd.The compound for preparing generally separates with neutral form, but the triazole part can add the acid that is fit to afterwards by being dissolved in the organic solvent, evaporates subsequently, precipitation or crystallization further are converted into pharmacy acceptable salt.All temperature are degree centigrade, unless indicate in addition.Mass spectrum (MS) is measured by electrospray ion massspectrum method (ESMS).
Term " the peptide linked reaction condition of the standard " meaning is to utilize acid activators such as EDC, DCC and BOP in inert solvent such as methylene dichloride and carboxylic acid and amine coupling in the presence of catalyzer such as HOBT.Use the protecting group of amine and carboxylic acid functional to be beneficial to required reaction and to reduce the existing a lot of documents of the reaction of not expecting open.Remove the required condition of protecting group and be disclosed in standard textbook such as Greene, T, and Wuts, P G.M., Protective Groups in Organic Synthesis, John Wiley ﹠amp; Sons, Inc., New York, NY, 1991.Cbz and BOC are general protecting group in organic synthesis, and their removal condition is known for a person skilled in the art.
The abbreviation of in the description of preparation The compounds of this invention, using:
| AIBN | 2,2 '-azobis isobutyronitrile |
| BOC | Tert-butoxycarbonyl |
| BBr 3 | Boron tribromide |
| 9-BBN | Assorted two ring [3.3.1] nonanes of 9-boron |
| Bn | Benzyl |
| nBuLi | N-Butyl Lithium |
| Cbz | Benzyloxycarbonyl |
| CDI | 1,1 '-carbonyl dimidazoles |
| MeOTf | The trifluoromethane sulfonic acid methyl esters |
| CH 2Cl 2 | Methylene dichloride |
| CH 2I 2 | Methylene iodide |
| (COCl) 2 | Oxalyl chloride |
| Cs 2CO 3 | Cesium carbonate |
| DAST | (diethylin) sulfur trifluoride |
| DMAP | 4-(dimethylamino) pyridine |
| DMF | N, dinethylformamide |
| Et | Ethyl |
| Et 3N | Triethylamine |
| EtOAc | Ethyl acetate |
| Et 2Zn | Zinc ethyl |
| H 2O 2 | Hydrogen peroxide |
| Me | Methyl |
| MeCN | Acetonitrile |
| MeOH | Methyl alcohol |
| mCPBA | Metachloroperbenzoic acid |
| MS | Mass spectrum |
| NaBH 4 | Sodium borohydride |
| NaHCO 3 | Sodium bicarbonate |
| NaOAc | Sodium-acetate |
| NBS | N-bromine succinimide |
| Ph | Phenyl |
| PyBROP | Bromine tripyrrole Wan Phosphonium hexafluorophosphate |
| PPh 3 | Triphenyl phosphine |
| Pyr | Pyridine |
| SOCl 2 | Thionyl chloride |
| TFA | Trifluoroacetic acid |
| TFFH | N, N, N ', N '-tetramethyl-carbonamidine hexafluorophosphate |
| THF | Tetrahydrofuran (THF) |
| TLC | Tlc |
| TsOH | Tosic acid |
Reaction scheme 1-5 has set forth the synthetic employed method of structural formula I compound of the present invention.All substituting groups as hereinbefore defined, except as otherwise noted.
Reaction scheme 1 has been set forth the committed step of the new compound of synthetic structural formula I of the present invention.Shown in reaction scheme I, secondary amide (
1-1) (N-Me or N-Et are preferred) can by the heating with pure trifluoromethanesulfonic acid methyl ester methylization obtain imino-ether (
1-2).Perhaps, other methylating reagents such as methyl-iodide or methyl-sulfate can use separately or use in non-nucleophilic organic solvent.Shown in scheme 1, two ring [2.2.2] octane-1-formic acid (
1-3) utilize coupling reagent TFFH and hydrazine in the presence of tertiary amine base such as triethylamine, be converted into hydrazides (
1-4).Perhaps, other coupling reagents that are generally used for preparing acid amides can be used for this conversion with hydrazine.Perhaps, two the ring [2.2.2] octane-1-manthanoate can with hydrazine be heated prepare hydrazides (
1-4).Like this Zhi Bei hydrazides (
1-4) and imino-ether (
1-2) can be in inertia high boiling organic solvent such as toluene and in the presence of tertiary amine base such as triethylamine together heating obtain structural formula I two ring [2.2.2] octyl group triazoles (
1-5).
Reaction scheme 1
Perhaps, reaction can reaction scheme 2 described reversing methods be carried out.In the method, secondary amide (
2-1) utilize the peptide linked reaction of standard to prepare by two ring [2.2.2] octane-1-formic acid.This compound methylated form imino-ether (
2-2), with the described hydrazides reaction of reaction scheme 1 obtain structural formula I two ring [2.2.2] octyl group triazoles (
2-3)
Reaction scheme 2
Reaction scheme 3 has been described the other method of the The compounds of this invention that obtains structural formula I, committed step wherein be catalytic two ring [2.2.2] n-octyl bromide triazoles of palladium (
3-1) and aryl boric acid between carry out the Suzuki linked reaction, obtain structural formula I triazole (
3-2).Preferred condition uses tetrakis triphenylphosphine palladium (0) to make catalyzer in containing the DMF solvent of cesium carbonate, but other catalyzer and condition also can use, be well known by persons skilled in the art.
Reaction scheme 3
Reaction scheme 4 has been described the synthetic method of another kind of formation structural formula I compound.Utilize this method, 4-(two ring [2.2.2] octyl group) oxadiazoles (
4-1) dewater with the methylamine condensation, this reaction is not adopted solvent and is carried out with melted state with trifluoroacetic acid first ammonium, perhaps carries out in buffered MeOH solution.Above-mentioned reaction is preferably in the high-temperature high-voltage reaction device to be carried out, to prevent the loss of methylamine.
Reaction scheme 4
Reaction scheme 5 has been described the synthetic method of another kind of formation structural formula I compound.Utilize this method, two ring [2.2.2] octyl group methane amides (
5-1) utilize reagent such as oxalyl chloride, thionyl chloride, phosphoryl chloride or phosphorus pentachloride, randomly in the presence of DMF, be converted into imino-choride (
5-2).Imino-choride (
5-2) in high boiling point inert organic solvents such as toluene with the condensation of aryl tetrazolium obtain triazole (
5-3).
Reaction scheme 5
The preparation of [2.2.2] two ring octyl group intermediates:
The method that is used for preparation [2.2.2] two ring octyl group intermediates provides hereinafter, and this intermediate is used to prepare compound of the present invention.
Gai oxadiazole of preparation ， that intermediate scheme 1-4 describes oxadiazole is the important intermediate of composite structure formula I compound.They for example can utilize, and the reaction described in the reaction scheme 4 is converted into compound in structural formula I.
Intermediate scheme 1 is to utilize dewatering agent such as thionyl chloride to pass through the preferred method of the dehydration Zhi Bei oxadiazole of diacyl-hydrazides.Selectively, also can use other dewatering agent such as phosphoryl chloride, phosphorus pentachloride or oxalyl chloride.Diacyl-hydrazides can prepare in the presence of tertiary amine base preferably by hydrazides and activated acids such as chloride of acid.Selectively, the standard peptide linked reaction can be used for preparing diacyl-hydrazides by hydrazides and carboxylic acid.
Intermediate scheme 2 is useful reagent that are used for diacyl-hydrazides Xiang the oxadiazole dehydration, and promptly the 2-chloro-1,3-dimethyl-4,5-dihydro-1H-imidazoles-3-muriate.This reagent obtains Suo Xu De oxadiazole intermediate effectively in non-polar solvent (methylene dichloride is preferred) and tertiary amine base (triethylamine is preferred).
Intermediate scheme 3 is to be used for the dehydration of single jar of formation (by hydrazides and carboxylic acid) and diacyl-hydrazides to Wei the preferred reagent of oxadiazole: 2-chloro-1,3-dimethyl-4,5-dihydro-1H-imidazoles-3-muriate.This reagent obtains Suo Xu De oxadiazole intermediate effectively in non-polar solvent (methylene dichloride is preferred) and tertiary amine base (triethylamine is preferred).
Intermediate scheme 4 is to Cheng the effective means of oxadiazole with hydrazides Xing by secondary amide.Secondary amide (N-Me or N-Et are preferred) can obtain imino-ether with pure trifluoromethanesulfonic acid methyl ester methylization by heating.Selectively, other methylating reagents such as methyl-iodide or methyl-sulfate can use separately or use in non-nucleophilic organic solvent.The imino-ether that heating so forms in the presence of hydrazides in the high boiling point inert organic solvents obtains De oxadiazole as shown in scheme.
Intermediate scheme 1:
Intermediate scheme 2:
Intermediate scheme 3:
Intermediate scheme 4:
Intermediate scheme 5 is preferred method of synthetic two ring [2.2.2] octane-1-formic acid.
Intermediate scheme 5:
Intermediate scheme 6 and 7 be as structural formula I given at R
3The preferred manufacturing procedure that has two ring [2.2.2] octane-1-formic acid of heteroaryl on the position.At R
3The De oxadiazole prepares by two ring [2.2.2] octyl group-1-formic acid and amidoxim condensation shown in intermediate scheme 6 Shang the position.For this linked reaction useful reagent is CDI.Selectively, can use and be used to dewater or other reagent of peptide linked reaction.Intermediate scheme 7 has been set forth and has been synthesized at R
3The preferred synthetic method that has the structural formula I compound intermediate of triazolyl on the position.
Intermediate scheme 6:
Intermediate scheme 7:
Intermediate scheme 8-14 is that preparation is at R
3The preferred method that has the structural formula I compound of different alkyl or alkenyls or substituted alkyl two ring [2.2.2] octane-1-formic acid intermediates in synthetic on the position.Committed step is by the two ring Wittig reactions that [2.2.2] octane-1-formaldehyde carries out, shown in intermediate scheme 8.Two keys in this reaction product can produce the alkyl with different lengths and feature according to Witting reagent hydrogenation (will become the R of structural formula I
3Substituting group), shown in intermediate scheme 9.Selectively, two keys can be used for introducing other functional groups, as hydroxyl or fluorine, shown in intermediate scheme 10.Itself is used in R aldehyde
3Obtain difluoromethyl on the position, shown in intermediate scheme 11.The olefin product of Wittig reaction can carry out multiple other conversion, and is for example Cyclopropanated, shown in intermediate scheme 12.Selectively, Witting reagent can contain the functional group of distance, and ketone acetal for example is shown in intermediate scheme 13.This functional group can carry out characteristic functional group and transform after Wittig/reduction, for example ketone acetal is hydrolyzed to ketone, and as described in intermediate scheme 13, or ketone acetal is reduced to alcohol, as described in intermediate scheme 14.In this way, can obtain to have multiple different R
3Substituent structural formula I compound.Given specific embodiment is to want to express general principle, rather than wants to limit R
3Substituent scope.
Intermediate scheme 8:
Intermediate scheme 9:
Intermediate scheme 10:
Intermediate scheme 11:
Intermediate scheme 12:
Intermediate scheme 13:
Intermediate scheme 14:
The general functional group's chemistry that is used for preparing The compounds of this invention transforms the preparation of particular compound of the present invention hereinafter and sets forth.
It is to well known to a person skilled in the art general variation that above-mentioned functional group transforms.
P=1 or 2
The following examples are to be used for setting forth the present invention, and can not be interpreted as limiting the present invention in arbitrary mode.
Embodiment 1
3-methoxyl group-4-[4-methyl-5-(4-amyl group two ring [2.2.2] suffering-1-yls)-4H-1,2,4-triazole-3-yl] phenol
(1-F)
Steps A:
-5 ° the 4-benzyloxy-2-hydroxy benzonitrile (1-A of being cooled to magnetic agitation, WO00/69841) (7.95g, 35.3mmol) and methyl iodide (5.43mL, disposable adding sodium hydride (60% dispersion in DMF 87.2mmol) (90mL) solution, 2.17g, 54.2mmol).This mixture stirred 30 minutes, rose to room temperature, restir 2 hours.Remove most of DMF under the vacuum condition, resistates distributes between water and ethyl acetate.Water ethyl acetate extraction three times.Organic phase water after the merging and saturated brine washing and dry (MgSO
4).The resistates that vacuum condition removes after desolvating is down developed with hexane, and utilizes hexane-CH by silica gel chromatography
2Cl
2(2:3) obtain 4-benzyloxy-2-HOMOVERATRONITRILE (1-B).MS：m/z?240(M+1)；
1H?NMR(500MHz，CDCl
3)：δ?7.47(d，1H，J＝84Hz)，7.36-7.45(m，5H)，6.58(dd，1H，J＝2.3，84Hz)，6.57(d，1H，J＝23Hz)，5.10(s，2H)，3.88(s，3H)ppm。
Step B:
The 4-benzyloxy of vigorous stirring-2-HOMOVERATRONITRILE (1-B) (1.20g, 5.0mmol), sodiumazide (732mg, 11.3mmol) and triethylamine hydrochloride (1.54g, toluene 11.3mmol) (6mL) suspension 110 ° the heating 48 hours.Suspension cooling with brown adds entry (15mL), stirs this mixture 30 minutes.Remove organic layer and water (5mL) extraction.Aqueous extract after the merging is acidified to about pH1 with dense HCl.Initial sedimentary jelly stirs and solidified in 30 minutes.Cross filter solid, wash with water, drying obtains 5-[4-(benzyloxy)-2-p-methoxy-phenyl]-2H-tetrazolium (1-C).
1H?NMR(500MHz，CDCl
3)：δ?12.9(vbs，1H)，737(d，1H，J＝8.7Hz)，7.34-748(m，5H)，6.78(dd，1H，J＝2.3，8.7Hz)，6.70(d，1H，J＝2.3Hz)，5.15(s，2H)，4.05(s，3H)ppm。
Step C:
(3.49ml 40mmol) dropwise joins N-methyl-4-amyl group two ring [2.2.2] octane-1-methane amide (1-D) (952mg, anhydrous CH 4.0mmol) in room temperature with oxalyl chloride
2Cl
2In the solution.After violent gas produced and calms down, this solution was stirring at room 2 hours.With CH
2Cl
2Remove by vacuum carefully at 50 ° then in room temperature.5-[4-(benzyloxy)-2-p-methoxy-phenyl that limpid pulpous state resistates is dissolved in toluene (8mL) and adds]-2H-tetrazolium (1-C) (1.13g, 4.0mmol) in.This mixture was 120 ° of heating 9 hours.With the mixture cooling, filter out precipitated solid, with toluene wash and dry, obtain the triazolium salt hydrochlorate.This salt is at CH
2Cl
2With 10% K
2CO
3Distribute between the aqueous solution.Water CH
2Cl
2Extract 2 times.With the CH after merging
2Cl
2Extraction liquid drying (MgSO
4), and vacuum-evaporation.Resistates utilizes 5%MeOH/CH by silica gel chromatography
2Cl
2Obtain 3-[4-(benzyloxy)-2-p-methoxy-phenyl]-4-methyl-5-(4-amyl group two ring [2.2.2] suffering-1-yls)-4H-1,2,4-triazole (1-E).MS：m/z?474(M+1)；
1H?NMR(500MHz，CDCl
3)：δ7.33-7.47(m，6H)，6.65(dd，1H，J＝2.3，8.5Hz)，6.60(d，1H，J＝23Hz)，5.10(s，2H)，3.75(s，3H)，348(s，3H)，2.08(m，6H)，1.51(m，6H)，1.00-1.35(m，8H)，0.89(t，3H，J＝7.2)ppm。
Step D:
3-[4-(benzyloxy)-2-p-methoxy-phenyl]-4-methyl-5-(4-amyl group two ring [2.2.2] suffering-1-yls)-4H-1,2, (272mg, MeOH 0.572mmol) (8mL) solution use 10%Pd/C catalyzer (27mg) hydrogenation 19 hours to 4-triazole (1-E) under room temperature and normal atmosphere.Catalyzer is filtered and wash with MeOH.Vacuum is removed MeOH and is obtained 3-methoxyl group-4-[4-methyl-5-(4-amyl group two ring [2.2.2] suffering-1-yls)-4H-1,2,4-triazole-3-yl] phenol (1-F).MS：m/z?384(M+1)；
1H?NMR(500MHz，DMSO-d
6)：δ9.94(s，1H)，7.09(d，1H，J＝8.3)，6.53(d，1H，J＝1.6Hz)，6.46(dd，1H，J＝2.2，8.2Hz)，3.72(s，3H)，3.40(s，3H)，1.95(m，6H)，1.44(m，6H)，1.07-1.33(m，8H)，0.86(t，3H，J＝7.2)。
Embodiment 2
3-chloro-4-[4-methyl-5-(4-amyl group two ring [2.2.2] suffering-1-yls)-4H-1,2,4-triazole-3-yl] phenol (2-G)
Steps A:
(505 μ L 5.79mmol) dropwise join in methylene dichloride (10mL) mixture of 4-amyl group two ring [2.2.2] octane-1-formic acid (2-A) with oxalyl chloride.This solution was stirring at room 3 hours, and vacuum concentration obtains 4-amyl group two ring [2.2.2] octane-1-carbonyl chlorine (2-B) then.
1H?NMR(500MHz，CDCl
3)：δ?0.90(t，3H)；1.21(m，8H)；1.45(m，6H)；1.88(m，6H)ppm。
Step B:
With N, N-diisopropylethylamine (1.44mL, 11.1mmol) join 4-amyl group two ring [2.2.2] octane-1-formic acid (2-A) (1.09g, 4.45mmol) mixture in, add methylamine hydrochloride (1.5g, 22.3mmol) methylene dichloride (10mL) solution, this mixture was stirring at room 18 hours.After the methylene dichloride dilution, this mixture water, salt water washing, dry (MgSO
4) and vacuum concentration obtain N-methyl-4-amyl group two ring [2.2.2] octane 1-methane amides (2-C).
1H?NMR(500MHz，CDCl
3)：δ?0.91(t，3H)；1.22(m，8H)；1.43(m，6H)；1.77(m，6H)；2.82(d，3H)ppm。
Step C:
(846 μ L, (230mg, in methylene dichloride 0.97mmol) (2.0mL) solution, this mixture was stirring at room 4 hours 9.7mmol) dropwise to join N-methyl 4-amyl group two ring [2.2.2] octane-1-methane amides (2-C) with oxalyl chloride.Obtain N-methyl-4-amyl group two except that desolvating with excessive reagent under the vacuum and encircle [2.2.2] octane-1-azomethine acyl chlorides (2-D).Add toluene (1.5mL), (204mg, 0.97mmol), this mixture refluxed 18 hours to add 5-(2-chloro-4-p-methoxy-phenyl)-1H-tetrazolium (2-E) again.Reaction is cooled to room temperature, and filtering-depositing with cold toluene, hexane wash, is dissolved in the methylene dichloride, dry (MgSO
4) and vacuum concentration obtain 3-(2-chloro-4-p-methoxy-phenyl)-4-methyl-5-(4-amyl group two ring [2.2.2] suffering-1-yls)-4H-1,2,4-triazole (2-F).Mass spectrum: 402 (M+1);
1H NMR (500MHz, CDCl
3): δ 0.94 (t, 3H); 1.27 (m, 8H); 1.56 (m, 6H); 2.13 (m, 6H); 3.56 (s, 3H); 3.89 (s, 3H); 6.95 (dd, 1H); 7.07 (d, 1H); 7.43 (d, 1H).
Step D:
With boron tribromide (135 μ L, 1.43mmol) dropwise join 3-(2-chloro-4-p-methoxy-phenyl)-4-methyl-5-(4-amyl group two ring [2.2.2] suffering-1-yls)-4H-1 at 0 ℃, 2, (287mg is in methylene dichloride 0.714mmol) (5mL) solution for 4-triazole (2-F).This mixture was stirring at room 2.5 hours.With this solution with water, 10%NaHCO
3Washing, dry (MgSO
4) and vacuum concentration, resistates obtains 3-chloro-4-[4-methyl-5-(4-amyl group two ring [2.2.2] suffering-1-yls)-4H-1,2,4-triazole-3-yl by column chromatography (silica gel, 5%MeOH/ methylene dichloride) purifying] phenol (2-G).Mass spectrum: 388 (M+1);
1H NMR (500MHz, CDCl
3): δ 0.93 (t, 3H); 1.26 (m, 8H); 1.56 (m, 6H); 2.13 (m, 6H); 3.58 (s, 3H); 6.69 (dd, 1H); 6.92 (d, 1H); 7.09 (d, 1H) ppm.
Embodiment 3
5-(4-{1-methyl-5-[2-(trifluoromethyl) phenyl]-1-H-1,2,4-triazole-3-yl } two ring [2.2.2] suffering-1-yls)
Penta-2-alcohol (3-J)
Steps A:
((5.99g 12.7mmol) stirs in anhydrous THF (200mL) triphenyl) phosphonium bromide (3-A, Synthesis:532 (1986)) with [2-(2-methyl isophthalic acid, 3-dioxolane-2-yl) ethyl].Two (trimethyl silyl) potassium amides of adding (20.4mL, the toluene solution of 2M, 10.2mmol).Reactant was stirred 30 minutes.Then reaction mixture is cooled to-78 ℃.Add 4-formyl radical two ring [2.2.2] octane-1-methyl-formiates at-78 ℃ by sleeve pipe.Reactant rises to ambient temperature overnight.THF reduces volume by vacuum-evaporation.The water that adds 100mL.This mixture is used the ether layering of 100mL then.Extract ether layer and dry (MgSO
4).Product (4-[(1E)-3-(2-methyl isophthalic acid, 3-dioxolane-2-yl) third-1-thiazolinyl] two ring [2.2.2] octane-1-methyl-formiates (3-B)) utilize 10/90 ethyl acetate-hexanes mixtures to come purifying by the flash chromatography on silica gel method.
Step B:
With 4-[(1E)-3-(2-methyl isophthalic acid, 3-dioxolane-2-yl) third-1-thiazolinyl] two (1.1g) stirrings in ethanol (75mL) of ring [2.2.2] octane-1-methyl-formiates (3-B).10% carbon that adds a spatula point carries palladium (150mg).Add hydrogen, this mixture stirred 3 hours under nitrogen atmosphere.Filter carbon and carry palladium, vacuum is removed ethanol, obtains 4-[3-(2-methyl isophthalic acid, 3-dioxolane-2-yl) propyl group] two ring [2.2.2] octane 1-methyl-formiates (3-C).
Step C:
With 4-[3-(2-methyl isophthalic acid, 3-dioxolane-2-yl) propyl group] (1.0g 3.38mmol) stirs in the solution of 90% methyl alcohol and 10% water (50mL) two ring [2.2.2] octane-1-methyl-formiates (3-C).Add excessive potassium hydroxide (2.0g).This mixture refluxes and spends the night.The refrigerative mixture is used ethyl acetate (100mL) washed twice then with 1N hydrochloric acid (100mL) acidifying.With the organic layer drying (MgSO after merging
4).Vacuum is removed ethyl acetate and is obtained pure 4-[3-(2-methyl isophthalic acid, 3-dioxolane-2-yl) propyl group] two ring [2.2.2] octane-1-formic acid (3-D).
Step D:
With 4-[3-(2-methyl isophthalic acid, 3-dioxolane-2-yl) propyl group] (0.200g, 0.708mmol) (0.173g 0.847mmol) mixes two ring [2.2.2] octane-1-formic acid (3-D), and azeotropic is twice from toluene with 2-(trifluoromethyl) benzoyl hydrazine (3-E).Then this mixture is stirred in anhydrous methylene chloride (10mL).Add 2-chloro-1, (0.718g 4.25mmol), adds the 1.184mL triethylamine to 3-methylimidazole muriate (3-F) then.Reaction was stirred 2 hours.Reactant dilutes with methylene dichloride and washes with water.Gained De oxadiazole, 2-{4-[3-(2-methyl isophthalic acid, 3-dioxolane-2-yl) propyl group] two ring [2.2.2] suffering-1-yls }-5-[2-(trifluoromethyl) phenyl]-1,3,4 oxadiazoles (3-G) utilize 50/50 ethyl acetate-hexanes mixtures to come purifying by the flash chromatography on silica gel method.
Step e:
2-{4-[3-(2-methyl isophthalic acid, 3-dioxolane-2-yl) propyl group] two ring [2.2.2] suffering-1-yls }-5-[2-(trifluoromethyl) phenyl]-1,3,4-oxadiazole (3-G) (0.158g) stirs in the mixture of 90% acetone/10% water (20mL).In this solution, add tosic acid (10mg).Reaction is heated to and refluxed 1 hour.Fall acetone by vacuum-evaporation and reduce volume.Mixture uses ethyl acetate (25mL) and saturated sodium bicarbonate solution (25mL) to come layering then.Take out ethyl acetate layer and dry (MgSO
4).Solvent removed in vacuo obtain pure 5-(4-{5-[2-(trifluoromethyl) phenyl]-1,3,4-oxadiazole-2-yl } two the ring [2.2.2] suffering-1-yls) penta-2-ketone (3-H).
Step F:
With 5-(4-{5-[2-(trifluoromethyl) phenyl]-1,3,4-oxadiazole-2-yl } two the ring [2.2.2] suffering-1-yls) penta-2-ketone (3-H) (0.072g) 0 ℃ in methyl alcohol (2mL) in the stirring.Add sodium borohydride (20mg).Reaction is at room temperature stirred.This mixture is used ethyl acetate (15mL) and water (15mL) layering then.Take out ethyl acetate layer and dry (MgSO
4).Solvent removed in vacuo obtain pure 5-(4-{5-[2-(trifluoromethyl) phenyl]-1,3,4-oxadiazole-2-yl } two the ring [2.2.2] suffering-1-yls) penta-2-alcohol (3-I).
Step G:
With 5-(4-{5-[2-(trifluoromethyl) phenyl]-1,3,4-oxadiazole-2-yl } two ring [2.2.2] suffering-1-yls) penta-2-alcohol (3-I) (50mg) joins in methyl alcohol (2.5mL) solution of the 2M methylamine in the sealed vial.The methylamine tfa salt that adds a little spatula point, sealed vial.The bottle of sealing is heated to 150 ℃ and kept 3 days.Reactant dilutes with ethyl acetate (15mL), and water (15mL) washing, dry (MgSO
4).Vacuum is removed ethyl acetate.Product 5-(4-{1-methyl-5-[2-(trifluoromethyl) phenyl]-1-H-1,2,4-triazole-3-yl } two ring [2.2.2] suffering-1-yls) penta-2-alcohol (3-J), utilize 0.1% trifluoroacetic acid buffered acetonitrile-water gradient to come purifying by preparation property reversed-phase HPLC by the C-18 silicagel column.The elutriant 10%NaHCO that contains pure triazole
3Become alkalescence, most of acetonitrile is removed in vacuum-evaporation, uses dichloromethane extraction.Organic extract liquid drying (MgSO
4) and evaporation, resistates vacuum-drying obtains required compound.MS(ESI
+)＝422.5(M+1)；
1HNMR(500MHz，CDCl
3)：δ?1.21(2H，m)，1.23(3H，d，J＝6.5Hz)，1.29(2H，m)，1.57(6H，m)，2.13(6H，m)，347(3H，s)，385(1H，m)，7.51(1H，m)，7.70(2H，m)，7.85(1H，m)ppm。
Embodiment 4
Steps A:
To 4-(methoxycarbonyl) two ring [2.2.2] octane-1-formic acid (4-A) (0.906g adds 1 in methylene dichloride 4.27mmol) (20mL) suspension, 1 '-carbonyl dimidazoles (1.04g, 6.41mmol).Reactant becomes limpid solution, produces gas immediately.This mixture is in stirring at room after 1 hour, add 4-flunamine oxime (1.98g, 12.8mmol).Continue to stir and spend the night.This mixture concentrates then, and resistates was reflux in toluene 16 hours.This mixture concentrates, and resistates utilizes hexane/ethyl acetate to make elutriant (7/1) purifying by chromatographic column and obtains 4-[3-(4-fluorophenyl)-1,2,4-oxadiazole-5-yl] two ring [2.2.2] octane-1-methyl-formiates (4-B), white solid.
1H?NMR(500MHz，CDCl
3)：δ?1.96-1.99(m，6H)，2.08-2.14(m，6H)，3.71(s，3H)，7.16-720(m，2H)，8.08-8.10(m，2H)ppm。ESI-MS?m/z(M+H)3492。
Step B:
With ester (4-B) (1.01g, 3.06mmol) with KOH (0.52g, 9.18mmol) methanol (95/5,20mL) handle.After 12 hours, reaction mixture concentrates, dilute with water, twice of ethyl acetate extraction 60 ℃ of heating.Water layer is settled out white solid with the acidified aqueous solution of 1N HCl.Collect solid 4-[3-(4-fluorophenyl)-1,2,4-oxadiazole-5-yl] two ring [2.2.2] octane-1-formic acid (4-C), further use toluene coevaporation drying.ESI-MS?m/z?(M+H)317.2。
Step C:
With acid (4-C) (138.9mg, 0.439mmol) and 2-(trifluoromethyl) benzoyl hydrazine (4-D) (89.7mg, mixture 0.439mmol) at first use the toluene coevaporation three times.In mixture, add methylene dichloride (7mL) as solvent.In the suspension of gained, add 2-chloro-1,3-methylimidazole muriate (743mg, 4.39mmol), add afterwards triethylamine (1.2mL, 8.78mmol).This mixture stirs under room temperature nitrogen and reacted completely guaranteeing in 48 hours.Reaction mixture is then with the methylene dichloride dilution, and the salt water washing is used in water, 1N HCl, saturated sodium bicarbonate aqueous solution washing at last.Organic phase is filtered and is concentrated by anhydrous sodium sulfate drying.Resistates by column chromatography utilize hexane/ethyl acetate (3/1) do the elutriant purifying obtain 3-(4-fluorophenyl)-5-(4-{5-[2-(trifluoromethyl) phenyl]-1,3,4-oxadiazole-2-yl } two ring [2.2.2] suffering-1-yls)-1,2-, 4-oxadiazole (4-E), white solid.
1H?NMR(500MHz，CDCl
3)：δ?2.25(s，12H)，721(t，J＝8.7Hz，2H)，7.74-7.76(m，2H)，7.91(m，1H)，8.11-8.15(m，3H)ppm。ESI-MS?m/z(M+H)485.2。
Step D:
With above-mentioned 1,2, (115.2mg, (1.73g, mixture 11.9mmol) is 150 ℃ of heating 48 hours in the test tube of sealing for the trifluoroacetate of methylamine 0.238mmol) and in methyl alcohol (4mL) solution of 2M methylamine for 4-oxadiazole (4-E).This mixture concentrates then, and resistates is dissolved in the methylene dichloride, with saturated sodium bicarbonate aqueous solution washing.Organic phase concentrates, and resistates utilizes reversed-phase HPLC to come purifying with TFA-buffered acetonitrile/water (40-80%) as elutriant.Merge the cut contain product, with the saturated sodium bicarbonate aqueous solution neutralization, by lyophilize in the acetonitrile/water obtain 3-(4-fluorophenyl)-5-(4-{4-methyl-5-[2-(trifluoromethyl) phenyl]-4H-1,2,4-triazole-3-yl } two ring [2.2.2] suffering-1-yls)-1,2-, 4-oxadiazole (4-F).
1H?NMR(CDCl
3)：δ?2.25-2.35(m，12H)，3.53(s，3H)，7.21(t，J＝8.7Hz，2H)，7.54(m，1H)，7.73(m，2H)，7.88(m，1H)，8.13(m，2H)。ESI-MS?m/z(M+H)498.2。
Embodiment 5
4-[4-methyl-5-(4-phenyl two ring [2.2.2] suffering-1-yls)-4H-1,2,4-triazole-3-yl]-3-(trifluoromethyl) benzene
Phenol (5-F)
The preparation of 4-phenyl two ring [2.2.2] octane-1-formic acid (5-A)
Reference:
Chapman，N.B，Sotheeswaran，S.，and?Toyne，K.J，J.Org.Chem，35：917-923(1970)
Steps A:
In room temperature, to the 4-of magnetic agitation phenyl two ring [2.2.2] octane-1-formic acid (5-A) (70mg, methylene dichloride (0.61mL, 1.22mmol) solution of adding 2M oxalyl chloride in methylene dichloride 0.30mmol) (1mL) solution.The DMF that adds two catalytics comes this reaction of catalysis.Solvent removed in vacuo and reagent were stirred in this reaction 30 minutes.In resistates, add methylene dichloride (1mL), add afterwards 4-(benzyloxy)-2-(trifluoromethyl) benzoyl hydrazine (5-B) (141mg, 0.46mmol) and triethylamine (0.07mL, 0.46mmol).This is reflected at stirred overnight at room temperature and obtains intermediate 5-C, and N '-[4-(benzyloxy)-2-(trifluoromethyl) benzoyl]-4--phenyl two ring [2.2.2] octane-1-formyl hydrazines need not separate.In crude product (5-C), add 2-chloro-1 then, 3-methylimidazole muriate (257mg, 1.52mmol), add again triethylamine (0.42mL, 3.04mmol) and methylene dichloride (2mL).Reactant was stirring at room 4 hours.Reaction mixture is used methylene dichloride (30mL) dilution then, water (30mL) washed twice, and salt solution (30mL) washs once.Water layer after the merging with methylene dichloride (25mL) extraction once.Organic layer drying (MgSO4) after the merging, solvent removed in vacuo.Resistates utilizes the hexane solution of 10% ethyl acetate to obtain 2-[4-(benzyloxy)-2-(trifluoromethyl) phenyl as elutriant by silica gel chromatography]-5-(4-phenyl two ring [2.2.2] suffering-1-yls)-1,3,4-oxadiazole (5-D).MS：m/z?505(M+1)。
Step B:
Trifluoroacetate (the 380mg of methylamine, 2.61mmol) and 2-[4-(benzyloxy)-2-(trifluoromethyl) phenyl]-5-(4-phenyl two ring [2.2.2] suffering-1-yls)-1,3,4-oxadiazole (5-D) is suspended in the methyl alcohol of 2M methylamine, and (1.3mL is 2.61mmol) in the solution and 150 ℃ of heated overnight.After being cooled to room temperature, reaction mixture distributes between ethyl acetate (25mL) and saturated sodium bicarbonate aqueous solution (30mL).Layer separates, water layer ethyl acetate (25mL) extracting twice.The salt water washing of organic layer after the merging, dry (MgSO
4), solvent removed in vacuo.Resistates is dissolved in the methyl alcohol (8mL) then, utilizes 10% acetonitrile (0.1%TFA)/water (0.1%TFA) (20mL/min) gradient elution to 100% acetonitrile (0.1%TFA) 10 minutes to come purifying by reverse-phase chromatography.The cut that contains product distributes between saturated sodium bicarbonate (25mL) aqueous solution and methylene dichloride (15mL).Separating layer, water layer extracts three times with methylene dichloride (15mL), dry (MgSO
4), solvent removed in vacuo obtains 3-[4-(benzyloxy)-2-(trifluoromethyl) phenyl]-4-methyl-5-(4-phenyl two ring [2.2.2] suffering-1-yls)-4H-1,2,4-triazole (5-E).MS：m/z?518(M+1)。
Step C:
3-[4-(benzyloxy)-2-(trifluoromethyl) phenyl]-4-methyl-5-(4-phenyl two ring [2.2.2] suffering-1-yls)-4H-1,2, (27mg 0.05mmol) is dissolved in ethyl acetate/methanol (1:1 to 4-triazole (5-E), 4mL), carry palladium (4mg) to the carbon that wherein adds 10%.Reactant places under the nitrogen atmosphere then, and stirs 3 hours under room temperature and normal atmosphere.Behind the suitable hydrogen of finding time, filter out palladium with methyl alcohol (40mL) by flocculating aids.Collect filtrate, solvent removed in vacuo obtains 4-[4-methyl-5-(4-phenyl two ring [2.2.2] suffering-1-yls)-4H-1,2,4-triazole-3-yl]-3-(trifluoromethyl) phenol (5-F).MS：m/z?428(M+1)；
1H?NMR(500MHz，CDCl
3)：δ?1.92(6H，m)，2.11(6H，m)，341(3H，s)，7.17(2H，m)，724(1H，m)，731(2H，m)，738(3H，m)ppm。
Embodiment 6
3-{4-[2-(ethylsulfonyl) ethyl] two ring [2.2.2] suffering-1-yls }-4-methyl-5-[2-(trifluoromethyl) benzene
Base]-4H-1,2,4-triazole (6-6)
Steps A:
With (ethyl sulphonyl methane) diethyl phosphoric acid (1.12g, 4.6mmol) (Popoff, people such as I.C., J.OrgChem.34:1128-30 (1969)) and 4-methoxycarbonyl two ring [2.2.2] octane-1-formaldehyde (
6-1) (0.82g, 4.2mmol) (Adcock, W., Kok, G.B.J.Org.Chem.50:1079-1087 (1985)) is dissolved in the anhydrous methanol of 8mL.This mixture places under the nitrogen atmosphere, in ice bath, cools off, and with methyl alcohol (8.8mL, 4.4mmol) solution-treated of the sodium methylate of 0.5M.Kept 4 hours under the reaction mixture refluxed, be cooled to room temperature then, decompression concentrates down, uses the water treatment of 2mL then, standing over night in refrigerator.Mixture filters, a small amount of cold 1:1MeOH/ water washing of solid.Collect the white solid of gained, vacuum-drying obtains undersaturated sulfone
6-2MS(ESI
+)＝287(M+1)。
Step B:
Sulfone
6-2(880mg 3.08mmol) is dissolved in the mixture of ethyl acetate/methanol (30mL) of 1:2, places under the nitrogen atmosphere, uses 10%Pd/C (800mg) to handle then.Reaction places under the nitrogen atmosphere and vigorous stirring 90 minutes.The solution of gained is by diatomite filtration, and with methyl alcohol and ethyl acetate washing, and evaporation obtains 4-[2-(ethylsulfonyl) ethyl] two ring [2.2.2] octane-1-methyl-formiates (
6-3), white solid.
Step C:
Ester
6-3(880mg 3mmol) is dissolved in 10% water/methanol solution (100mL) and uses the 1g potassium hydroxide treatment.Be reflected at 60 ℃ of heating 1 hour, spend the night at 45 ℃ then.This mixture vacuum concentration is acidified to pH2 with 1M HCl then, uses dichloromethane extraction three times.Organic layer merges, and by anhydrous sodium sulfate drying, evaporation obtains 4-[2-(ethylsulfonyl) ethyl] two ring [2.2.2] octane-1-formic acid (
6-4)
Step D:
Carboxylic acid
6-4(810mg 2.96mmol) is dissolved under nitrogen atmosphere in the anhydrous methylene chloride of 12mL, and (dichloromethane solution of 2M, 4.4mL 8.8mmol) handle, and handle with 5 DMF subsequently with oxalyl chloride.Be reflected under the room temperature nitrogen atmosphere and stirred 90 minutes, evaporate then and placed vacuum 20 minutes.Acyl chlorides is dissolved in the anhydrous methylene chloride (12mL), in ice bath, cools off, dropwise use methylene dichloride (the THF solution of 2M, 8.9mL, 17.8mmol) solution-treated then.After adding amine, remove cooling bath, be reflected at stirring at room 30 minutes.This mixture is with the methylene dichloride dilution of 200mL, and with the HCl aqueous solution, saturated sodium bicarbonate aqueous solution and the salt water washing of 1N.Organic layer is by anhydrous sodium sulfate drying and evaporation.Resistates carries out silica gel chromatography and uses the dichloromethane solution gradient elution of 0-3.5% methyl alcohol, obtains 4-[2-(ethylsulfonyl) ethyl]-N-methyl bicyclic [2.2.2] octane-1-methane amide (
6-5), white powder.MS(ESI
+)＝288(M+1)。
Step e:
Methane amide 6-5 (220mg, 0.77mmol) be dissolved in the anhydrous methylene chloride (2mL) and with oxalyl chloride (dichloromethane solution of 2M, 0.77mL, 1.54mmol) and DMF (2) processing.This solution is in stirring at room 1 hour, solvent removed by evaporation at reduced pressure then.Resistates is dissolved in the dry toluene (2mL) and uses 5-[2-(trifluoromethyl) phenyl] (214mg 1mmol) handles the 1H-tetrazolium.This mixture refluxed 18 hours.Reaction is cooled to room temperature, and creamy sedimentation and filtration and washing obtain the HCl salt of 300mg crude product.This salt is dissolved among methylene dichloride/1N HCl, and water layer is with other two parts of washed with dichloromethane.Organic layer merges and evaporation, and resistates comes purifying by the fast silica gel chromatogram method.Utilize the gradient of 0-5% ethanol/methylene to carry out wash-out.Merge the cut that is fit to, evaporation obtains 3-{4-[2-(ethylsulfonyl) ethyl] two ring [2.2.2] suffering-1-yls }-4-methyl-5-[2-(trifluoromethyl) phenyl]-4H-1,2, the 4-triazole (
6-6), white powder.MS(ESI
+)＝456.2(M+1)；
1H?NMR(500MHz，CDCl
3)：δ?1.46(3H，t，J＝7.3Hz)，1.63(6H，m)，1.78(2H，m)，2.19(6H，m)，2.96(2H，m)，3.05(2H，q，J＝7.2Hz)，3.50(3H，m)，7.56(1H，m)，7.72(2H，m)，7.87(1H，m)ppm。
Embodiment 7
3-{4-[3-(ethylsulfonyl) propyl group] two ring [2.2.2] suffering-1-yls }-4-methyl-5-[2-(trifluoromethyl) benzene
Base]-4H-1,2,4-triazole (7-J)
Steps A:
(4.6g, 9.4mmol) azeotropic twice from toluene is suspended among the anhydrous THF of 30mL (benzyloxycarbonyl methyl) three phenyl phosphonium bromides then.(8.4mmol), xanchromatic solution stirring 1 hour becomes oyster white afterwards for the toluene solution of 0.5M, 16.8mL dropwise to add hexamethyl two silicon potassium azide in room temperature.Preparation 4-methoxycarbonyl base two ring [2.2.2] octane-1-formaldehyde (
7-A) (0.50g, 2.55mmol) (0.015g, the anhydrous THF solution of 2mL 0.13mmol) dropwise adds by syringe in room temperature for (Adcock W., Kok, G.B.J.Org.Chem.50:1079-1087 (1985)) and phenylformic acid.This mixture heating up to 90 ℃ also stirs at reflux temperature, and mixture is used 1NHCl (twice), saturated sodium bicarbonate aqueous solution and the salt water washing of 50mL continuously with the ethyl acetate dilution of 200mL afterwards.The organic layer dried over mgso, removal of solvent under reduced pressure.Resistates carries out silica gel chromatography, and the hexane solution gradient elution with 5% to 10% ethyl acetate obtains 4-[(1E)-3-(benzyloxy)-3-oxo third-1-alkene-1-yl] two ring [2.2.2] octane-1-methyl-formiates (
7-B), colourless oil.
1H?NMR(500MHz，CDCl
3)：δ?7.4(5H，m)，6.94(1H，d，J＝17Hz)，5.77(1H，d，J＝17Hz)，5.21(2H，s)，3.69(3H，s)，1.86(6H，m)，1.63(6H，m)ppm。
Step B:
Diester
7-B(0.625g 1.90mmol) is dissolved in the mixture of ethyl acetate/methanol (30mL) of 1:1, places under the nitrogen atmosphere, uses 10%Pd/C (500mg) and 0.1mL acetic acid treatment then.Reaction places under the nitrogen atmosphere and vigorous stirring 2 hours.The solution of gained is by diatomite filtration, removal of solvent under reduced pressure.Resistates distributes between the 1N NaOH solution of the ethyl acetate of 200mL and 200mL.Separate water layer and neutralization, use the dichloromethane extraction three times of 50mL then.Organic layer after the merging is by dried over mgso, and removal of solvent under reduced pressure obtains 3-[4-(methoxycarbonyl) two ring [2.2.2] suffering-1-yls] propionic acid (
7-C).
1H NMR (500MHz, CDCl
3): δ 3.62 (3H, s), 2.20 (2H, broad peak t, J=9Hz), 1.75 (6H, m), 1.47 (2H, broad peak t, J=9Hz), 1.38 (6H, m) ppm.
Step C:
Carboxylic acid
7-C(400mg 1.67mmol) is dissolved in the tetrahydrofuran (THF) (5mL), dropwise adds borine (the THF solution of 1M, 2.17mL, 1.3 equivalents) in room temperature.After 2 hours, in reactant, add the 1N HCl of 50mL, use the dichloromethane extraction three times of 50mL then.Organic layer after the merging is by dried over mgso, removal of solvent under reduced pressure obtain thick 4-(3-hydroxypropyl) two ring [2.2.2] octane-1-methyl-formiates (
7-D), use in next step without purifying.
1H?NMR(500MHz，CD
3OD)：δ?3.66(3H，s)，3.62(2H，t，J＝6.5Hz)，1.78(6H，m)，1.50(2H，m)，1.41(2H，m)，1.17(2H，m)ppm。
Step D:
Hydroxy ester
7-D(430mg 1.9mmol) is dissolved under the nitrogen atmosphere in the anhydrous methylene chloride of 2.5mL, with pyridine (0.5mL) and Methanesulfonyl chloride (0.368mL, 4.8mmol) processing and stirring at room 4 hours.This mixture is with the ethyl acetate dilution of 100mL, with the HCl aqueous solution, saturated sodium bicarbonate aqueous solution and the salt water washing of 1N.Organic layer is by anhydrous sodium sulfate drying and evaporation.The thick 4-{3-[(methyl sulphonyl that obtains like this) oxygen base] propyl group } two ring [2.2.2] octane-1-methyl-formiates (
7-E) use in next reaction without purifying.
1H?NMR(500MHz，CDCl
3)：δ?4.22(2H，t，J＝7.5Hz)，3.68(3H，s)，3.04(3H，s)，1.82(6H，m)，1.70(2H，m)，1.44(6H，m)，1.24(2H，m)ppm。
Step e:
Methanesulfonates
7-E(3.30g 10.9mmol) is dissolved among the DMF (20mL) also with ethanethio sodium (1.82g, 21.7mmol) processing.This solution stirred 3 hours at 45 ℃, and this mixture is with the ethyl acetate dilution of 100mL then, and with the HCl solution washing twice of 1N, used saturated sodium bicarbonate aqueous solution and salt water washing then.Organic layer is by anhydrous sodium sulfate drying, and evaporation obtains 4-[3-(ethylmercapto group) propyl group] two ring [2.2.2] octane-1-methyl-formiates (
7-F) thick oil, use in next step without purifying.
1H?NMR(500MHz，CDCl
3)：δ?3.68ppm(3H，s)，2.56(2H，q，J＝7Hz)，2.51(2H，t，J＝7.5Hz)，1.80(6H，m)，1.52(2H，m)，1.42(6H，m)，1.28(2H，t，J＝7Hz)，1.02(2H，m)。
Step F:
Sulfide
7-F(3.0g, 11mmol) be dissolved in the methylene dichloride (50mL) and with metachloroperbenzoic acid (75%, 6.2g) handle.This solution was stirring at room 2 hours, this mixture with the saturated sodium bicarbonate aqueous solution washing, is used saturated aqueous solution of sodium bisulfite washed twice with the methylene dichloride dilution of 100mL then then, use the saturated sodium bicarbonate aqueous solution washed twice then, use the salt water washing again.Organic layer is by anhydrous sodium sulfate drying, and evaporation obtains 4-[3-(ethylsulfonyl) propyl group] two ring [2.2.2] octane-1-methyl-formiates (
7-G), use in next step without purifying.
1H?NMR(500MHz，CDCl
3)：δ?3.68ppm(3H，s)，2.56(2H，q，J＝7Hz)，2.51(2H，t，J＝7.5Hz)，1.80(6H，m)，1.52(2H，m)，1.42(6H，m)，1.28(2H，t，J＝7Hz)，1.02(2H，m)ppm。
Step G:
Sulfone
7-G(3.1g 10mmol) is dissolved in the MeOH/ water (50mL) of 9:1 also with potassium hydroxide (3g) processing.This solution is in stirred overnight at room temperature, and this mixture is with 1N HCl acidifying then, and with 50mL dichloromethane extraction four times.Organic layer is by anhydrous sodium sulfate drying, and evaporation obtains 4-[3-(ethylsulfonyl) propyl group] two ring [2.2.2] octane-1-formic acid (
7-H) thick oil, use in next step without purifying.
1H?NMR(500MHz，CDCl
3)：δ?3.03(2H，q，J＝7Hz)，2.94(2H，dd，J＝7.5Hz)，1.84(8H，m)，1.45(8H，m)，1.30(2H，m)ppm。
Step H:
Formic acid
7-H(3.0g 11mmol) is dissolved under nitrogen in the anhydrous methylene chloride of 50mL, and (dichloromethane solution of 2M, 16.2mL 32.4mmol) handle, and handle with 5 DMF subsequently with oxalyl chloride.Reactant stirred 90 minutes under room temperature nitrogen, and evaporation was also placed 20 minutes in a vacuum then.Chloride of acid is dissolved in the anhydrous methylene chloride (12mL), cools off in ice bath, and (the THF solution of 2M, 27mL 54mmol) handle dropwise to use methylamine solution then.After adding methylamine, remove cooling bath, reactant was stirring at room 30 minutes.This mixture is with the methylene dichloride dilution of 200mL, with the HCl aqueous solution, saturated sodium bicarbonate aqueous solution and the salt water washing of 1N.Organic layer is by anhydrous sodium sulfate drying and evaporation.Resistates carries out silica gel chromatography, obtains 4-[3-(ethylsulfonyl) propyl group with the ethyl acetate solution gradient elution of 0-3% methyl alcohol]-N-methyl bicyclic [2.2.2] octane-1-methane amide (
7-I), white powder.MS(ESI
+)＝302(M+1)。
1H?NMR(500MHz，CDCl
3)：δ?5.56(1H，br，s)，3.02(2H，q，J＝7Hz)，2.94(2H，dd，J＝7.5Hz)，2.82(3H，d，J＝4Hz)，1.80(8H，m)，1.45(9H，m)，1.28(2H，m)ppm。
Step I:
Methane amide
7-I(0.470g, 1.56mmol) be dissolved in the anhydrous methylene chloride (5mL) and with oxalyl chloride (dichloromethane solution of 2M, 1.56mL, 3.12mmol) and DMF (2) processing.This solution is in stirring at room 1 hour, solvent removed by evaporation at reduced pressure then.This resistates is dissolved in the dry toluene (7mL) and uses 5-[2-(trifluoromethyl) phenyl] (368mg 1.72mmol) handles the 1H-tetrazolium.This mixture refluxed 18 hours.This reaction is cooled to room temperature, and filtering-depositing and washing obtain the HCl salt of 300mg crude product.This salt is dissolved among methylene dichloride/1N HCl, and water layer is with other two portions washed with dichloromethane.Organic layer merges and evaporation, and resistates is by fast silica gel chromatogram method purifying.Gradient with the 0-5% ethanol/methylene is carried out wash-out.Merge the cut and the evaporation that are fit to and obtain 3-{4-[3-(ethylsulfonyl) propyl group] two ring [2.2.2] suffering-1-yls }-4-methyl-5-[2-(trifluoromethyl) phenyl]-4H-1,2, the 4-triazole (
7-J), white powder.MS(ESI
+)＝470.4(M+1)。
1H?NMR(500MHz，CDCl
3)：δ?7.87(1H，m)，7.72(2H，m)，7.56(1H，m)，3.49(3H，s)，3.05(2H，q，J＝7.2Hz)，2.96(2H，m)，2.18(6H，m)，1.86(2H，m)，1.62(6H，m)，1.46(3H，t，J＝73Hz)，1.36(2H，m)ppm。
Embodiment 8
4-methyl-3-[2-(trifluoromethyl) phenyl]-5-(4-{2-[(trifluoromethyl) alkylsulfonyl] ethyl } two ring [2.2.2] sufferings
-1-yl)-and 4H-1,2,4-triazole (8-G)
Steps A:
0 ℃ to the first base three phenyl phosphonium bromides that stir (9.1g, dropwise add in 5 minutes in THF 12.8mmol) (50ml) solution hexamethyl two silicon potassium azide (toluene solution of 0.5M, 48.6ml).The mixture of gained rose to room temperature in 1 hour, and then was cooled to 0 ℃, and (2.5g 12.8mmol) handles with 4-formyl radical two ring [2.2.2] octane-1-methyl-formiate 8-A (Chapman, people such as N.B., J.Org.Chem., 1970,35,917).This reaction mixture is used EtOAc (350ml) dilution then stirring at room 18 hours.Organic phase HCl (1N) aqueous solution, saturated sodium bicarbonate aqueous solution and salt water washing, dry then (Na2SO4) and vacuum concentration.The solid of gained is by fast silica gel chromatogram method purifying, with 0-4%EtOAc/ hexane gradient wash-out.Separating obtained 4-vinyl two ring [2.2.2] octane-1-methyl-formiates (8-B), limpid colourless oil.
Step B:
To the alkene 8-B that stirs (1.6g, dropwise add in THF 8.3mmol) (20ml) solution 9-BBN (the THF solution of 0.5M, 49ml).This solution was stirring at room 18 hours, and then in turn with ethanol (14.5ml), NaOH (5N, 5ml) (9.7ml) handle for the aqueous solution and hydrogen peroxide by 30% the aqueous solution.This reaction mixture is acidified to pH=2 and uses CH with the HCl aqueous solution (1N)
2Cl
2Extract three times.Organic layer merges, and uses the salt water washing, dry (Na
2SO
4) and stripping.The pure 8-C of gained with 30-50%EtOAc/ hexane gradient wash-out, is separated to limpid colourless oil by the silica gel chromatography purifying.
Step C:
Alcohol 8-C (1.5g, CH 7.1mmol)
2Cl
2(7.5ml), pyridine (1.5ml) solution is cooled to 0 ℃, and (1.65ml 21.3mmol) dropwise handles in 5 minutes with methylsulfonyl chloride.Reaction mixture rises to room temperature, stirs then 3 hours.Add EtOAc (300ml), organic phase HCl (1N) solution washing three times, the saturated sodium bicarbonate aqueous solution washed twice is used the salt water washing again.Organic layer drying (Na
2SO
4), stripping obtains the 4-{2-[(methyl sulphonyl) the oxygen base] ethyl } two ring [2.2.2] octane-1-methyl-formiate 8-D, white solid.
1H?NMR(500MHz，CDCl
3)：δ?1.52(6H，m)，1.66(2H，t，J＝7.1Hz)，1.84(6H，m)，3.04(3H，s)，3.69(3H，s)4.29(2H，t，J＝7.2Hz)ppm。
Step D:
8-D (0.25g, 0.86mmol), trifluoromethanesulpacidc acidc potassium (0.3g, 1.72mmol) and tetrabutylammonium iodide (0.15g, DMF 0.4mmol) (5ml) solution heated 5 hours under 140 ℃ of nitrogen atmosphere.This solution is cooled to room temperature then, with EtOAc (100ml) dilution, with HCl (1N) solution washing twice, uses the salt water washing again.Organic layer drying (Na
2SO
4), stripping carries out the fast silica gel chromatogram method, with the gradient elution of 5-20%EtOAc/ hexane.Separating obtained trifluoromethyl sulfone 8-E, white solid.
1H?NMR(500MHz，CDCl
3)：δ?1.50(6H，m)，1.78(2H，m)，1.82(6H，m)，3.17(2H，m)，3.67(3H，s)ppm。
Step e:
(0.035g 0.11mmol) utilizes embodiment 6 step C and the described method of D to be converted into methane amide 8-F to methyl esters 8-E.Separate N-methyl-4-{2-[(trifluoromethyl) alkylsulfonyl] ethyl } two ring [2.2.2] octane-1-methane amides, white solid; MS (ESI
+)=328.2 (M+1).
Step F:
(0.030g 0.092mmol) utilizes the described method of embodiment 6 step e to be converted into triazole 8-G to methane amide 8-F.Separate 4-methyl-3-[2-(trifluoromethyl) phenyl]-5-(4-{2-[(trifluoromethyl) alkylsulfonyl] ethyl } two ring [2.2.2] suffering-1-yls)-4H-1,2,4-triazole (8-G), white powder; MS (ESI
+)=4964 (M+1).
Embodiment 9-102
According to similar methods mentioned above, also can prepare following formula II compound:
The embodiment of pharmaceutical preparation
As the specific embodiments of the oral compositions of The compounds of this invention, to make total amount with lactose processing enough in small, broken bits be 580-590mg to arbitrary compound among the 50mg embodiment 1-8, with the hard gelatin capsule of filling O model.
Though the present invention is described and sets forth according to its specific embodiments, those skilled in the art will appreciate that under the condition that does not break away from essence of the present invention and scope and can carry out multiple change, correction and replacement.For example,, can carry out reasoning and change the use effective dose according to the people's that will treat reaction for special symptom, rather than preferred dose mentioned above.Similarly, viewed pharmacological effect can according to or depend on selected sp act compound or whether have pharmaceutical carrier, and the type of preparation and administering mode and change, the change of above-mentioned expectation or the result of difference are predictable according to purpose of the present invention and practice.Therefore, the meaning is the restriction that the present invention only is subjected to following claim, and aforesaid right requires to be interpreted as a reasonable wide scope.
Claims (3)
1. the compound of following formula I:
Or its pharmacy acceptable salt.
2. pharmaceutical composition, described composition comprises the compound and the pharmaceutically acceptable carrier of claim 1.
3. the compound of claim 1 is used for the treatment of purposes in the medicine of the disease that is selected from hyperglycemia, insulin resistance, diabetes B, lipid disorders, obesity, atherosclerosis and metabolic syndrome in preparation.
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| US60/503410 | 2003-09-16 |
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