CN1798732A - Substituted tetralins and indanes - Google Patents

Substituted tetralins and indanes Download PDF

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CN1798732A
CN1798732A CN 200380106566 CN200380106566A CN1798732A CN 1798732 A CN1798732 A CN 1798732A CN 200380106566 CN200380106566 CN 200380106566 CN 200380106566 A CN200380106566 A CN 200380106566A CN 1798732 A CN1798732 A CN 1798732A
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base
compound
urea groups
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ethyl
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X·陈
J·M·马特斯
J·李
P·赖比茨恩斯基
K.T.德马雷斯特
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Janssen Pharmaceutica NV
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Abstract

The invention features tetralin and indane compounds, compositions containing them, and methods of using them as PPAR alpha modulators to treat or inhibit the progression of, for example, dyslipidemia.

Description

The tetraline and the indane that replace
The cross reference of related application
The application is that title is U.S. Provisional Patent Application number 60/419,935 (submission on October 21st, 2002) of " tetraline of replacement and indane " and the non-temporary patent application of U.S. Provisional Patent Application number 60/495,270 (submission on August 15th, 2003).
Invention field
The present invention is characterised in that the tetraline and the indan derivative of replacement, the method that contains their composition and use them.
Background of invention
The member of nuclear receptor family (a group ligand activated transcription factor), peroxisome proliferation body-activated acceptor α (PPAR α) is the transcription factor of necessity of adjusting and fatty acid metabolism and insulin action genes involved.
PPAR α acceptor is mainly found in liver.The important component apo A1 that comprises the enzyme, liver fatty acid translocator and a kind of high-density lipoprotein (HDL) (HDL) that relate to the lipid acid β-Yang Hua by the gene of PPAR α adjusting.Selectivity, high-affinity PPAR alfa agonists increase the oxidation of liver fatty acid, and this is the circulation of triglyceride reducing and free fatty acids successively.When handling with the PPAR alfa agonists, the round-robin of triglyceride level reduce can mediate the reduction of being found or improve insulin resistance or the diabetic animal patient in insulin resistance.This treatment in the fat model of animal with lose weight relevant.Known special class (fibrates) medicine of shellfish that can be used for treating hyperlipidemia is weak PPAR alfa agonists.
The various examples that are used for the treatment of hyperlipidemia, diabetes or atherosclerotic known PPAR alfa agonists comprise the special class of shellfish, as fenofibrate (Foumier), gemfibrozil (Parke-Davis/Pfizer, Mylan, Watson), Serotinex (Wyeth-Ayerst, Novopharm), bezafibrate and Win-35833 and the special class of urea groups shellfish, as GW 7647, GW 9578 and GW9820 (GlaxoSmithKline).
Summary of the invention
Feature of the present invention is with following formula (I) compound or its pharmacy acceptable salt, C 1-6Ester or C 1-6Acid amides:
Figure A20038010656600111
Formula (I)
R 1And R 2Independent separately is H, C 1-6Alkyl, (CH 2) mNR aR b, (CH 2) mOR 8, (CH 2) mNH (CO) R 8Or (CH 2) mCO 2R 8, R wherein a, R bAnd R 8Independent separately is H or C 1-6Alkyl, perhaps R 1And R 2Connected carbon atom constitutes C together 3-7Cycloalkyl;
M is the integer of 1-6;
N is 1 or 2;
X is O or S; Wherein when n was 1, X was at 5 or 6; And when wherein n was 2, X was at 6 or 7;
R 3Be H, phenyl, C 1-3Alkoxyl group, C 1-3Alkylthio, halogeno-group, cyano group, C 1-6Alkyl, nitro, NR 9R 10, NHCOR 10, CONHR 10And COOR 10And R 3Adjacent or position at X;
R 4For H or-(C 1-5Alkylidene group) R 15, R wherein 15Be H, C 1-7Alkyl, [two (C 1-2Alkyl) amino] (C 1-6Alkylidene group), (C 1-3The alkoxyl group acyl group) (C 1-6Alkylidene group), C 1-6Alkoxyl group, C 3-7Alkenyl or C 3-8Alkynyl group, wherein R 4Have and be no more than 9 carbon atom; R 4Also can be-(C 1-5Alkylidene group) R 15, R wherein 15Be C 3-6Cycloalkyl, phenyl, phenyl-O-, phenyl-S-or have the heteroatomic 5-6 unit heterocyclic radical that 1-2 is selected from N, O and S;
Y is NH, NH-CH 2Or O;
R 5And R 7Independently be selected from H, C separately 1-6Alkyl, halogeno-group, cyano group, nitro, COR 11, COOR 11, C 1-4Alkoxyl group, C 1-4Alkylthio, hydroxyl, phenyl, NR 11R 12And have 1-2 and be selected from the heteroatomic 5-6 unit heterocyclic radical of N, O and S;
R 6Be selected from C 1-6Alkyl, halogeno-group, cyano group, nitro, COR 13, COOR 13, C 1-4Alkoxyl group, C 1-4Alkylthio, hydroxyl, phenyl, NR 13R 14And have 1-2 and be selected from the heteroatomic 5-6 unit heterocyclic radical of N, O and S;
In addition, R 5And R 6Perhaps R 6And R 7Can form saturated or undersaturated divalent moiety together separately, be selected from-(CH 2) 3-,-(CH 2) 4-and (CH 1-2) pN (CH 1-2) q,
P is 0-2, and q is 1-3, wherein (p+q) and be at least 2;
R 9And R 10Independent separately is C 1-6Alkyl;
R 11, R 12, R 13And R 14Independent separately is H or C 1-6Alkyl;
Wherein above alkyl and assorted hydrocarbyl portion can be replaced by 1-3 substituting group that independently is selected from F, Cl, Br, I, amino, methyl, ethyl, hydroxyl, nitro, cyano group and methoxyl group separately.
Feature of the present invention also is to comprise the composition of one or more formula (I) compound and pharmaceutical carrier or vehicle.
These compositions and following method also can comprise other pharmaceutical active medicine, as lipid lowering agent or hypotensive agent or both.
The present invention is included in the method that adopts disclosed compound or composition prevention, treatment in the whole bag of tricks or suppress the alpha mediated advancing of disease of PPAR on the other hand.The example of the disease that PPAR-is alpha mediated comprises unusual blood fat disease and atherosclerosis.Unusual blood fat disease comprises hypertriglyceridemia, hypercholesterolemia, mixed type hyperlipidemia and low-HDL-hypercholesterolemia.For example, unusual blood fat disease can have following one or more index: low HDL (＜35 or 40mg/dl), high triglyceride (＞200mg/dl) and high LDL (＞150mg/dl).
From following detailed discussion, embodiment and claims, will obviously find out other features and advantages of the present invention.
Detailed Description Of The Invention
A. term
With the following term of giving a definition, its usage through the disclosure in full.
" alkyl " comprises having and removes straight chain and the branched-chain hydrocarbon of at least one hydrogen with the optional replacement that forms group.Alkyl comprises methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, 1-methyl-propyl, amyl group, isopentyl, sec.-amyl sec-pentyl secondary amyl, hexyl, heptyl, octyl group etc.Alkyl comprises cycloalkyl, as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
" alkenyl " comprises having at least one carbon-to-carbon double bond (sp 2) the straight chain and the branched hydrocarbyl of above-mentioned optional replacement.Alkenyl comprise vinyl, third-1-thiazolinyl, third-2-thiazolinyl (or allyl group), pseudoallyl (or 1-methyl ethylene), but-1-ene base, but-2-ene base, butadienyl, pentenyl, oneself-2,4-dialkylene etc.Having two keys and triple bond blended alkyl (as 2-amylene-4-alkynyl) ranges in the alkynyl at this.Alkenyl comprises cycloalkenyl group.Cis and trans or (E) and (Z) form be also included within the scope of the invention.
" alkynyl " comprises the straight chain and the branched hydrocarbyl of the above-mentioned optional replacement with at least one carbon-to-carbon double bond (sp).Alkynyl comprises ethynyl, proyl, butynyl and pentynyl.Having two keys and triple bond blended alkyl (as 2-amylene-4-alkynyl) ranges in the alkynyl at this.Alkynyl does not comprise cycloalkynyl radical.
" alkoxyl group " comprises having the straight or branched alkyl of optional replacement that described alkyl is connected in the terminal oxygen of molecule remainder.Alkoxyl group comprises methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, tert.-butoxy, pentyloxy etc." aminoalkyl group ", " alkylthio " and " alkylsulfonyl alkyl " are similar with alkoxyl group, use NH (or NR), S and SO respectively 2The terminal Sauerstoffatom that replaces alkoxyl group.Assorted alkyl comprises alkoxyl group, aminoalkyl group, alkylthio etc.
" aryl " comprises any phenyl that is optionally substituted, naphthyl, xenyl, tetralyl, indenyl etc.Aryl also comprises arylalkyl, as benzyl, styroyl and hydrocinnamyl.Aryl comprises the ring system that contains the optional 6-unit carbocyclic ring aromatic ring that replaces, and this system can be dicyclo, bridged ring and/or fused rings.This ring system can be included as aromatics or partially or completely saturated ring.The example of ring system comprises indenyl, pentalene base, 1,4-dihydro naphthyl, indanyl, benzimidazolyl-, benzothienyl, indyl, benzofuryl, isoquinolyl etc.
" heterocyclic radical " is included in has carbon atom and at least one heteroatoms (O, S, N) or heteroatom moiety (SO in the ring 2, CO, CONH, COO) the aromatics and the non-aromatic ring of optional replacement.
Unless otherwise indicated, heterocyclic radical can have one by carbon atom with its valency that is connected with described molecule remainder, as 3-furyl or 2-imidazolyl, perhaps by heteroatoms with its valency that is connected with described molecule remainder, as N-piperidyl or 1-pyrazolyl.The monocyclic heterocycles base preferably has 5-7 annular atoms, or 5-6 annular atoms; In ring, can there be 1-5 heteroatoms or heteroatom moiety, preferred 1-3 or 1-2.Heterocyclic radical can be saturated, unsaturated, aromatics (as heteroaryl), non-aromatics or condensed.
Heterocyclic radical also comprises condensed (as dicyclo) ring, as with those rings of the optional carbocyclic ring that replaces or heterocycle 5-or the optional condensation of 6-unit aromatic ring.For example, " heteroaryl " comprises and the 5-of optional replacement or 6 yuan of heteroaromatic rings of 6-unit's carbocyclic ring or the optional replacement condensation of heterocyclic aromatic ring, that contain 1,2 or 3 nitrogen-atoms.The heterocycle 5-of described and this 5-or the aromatic ring condensation of 6-unit or 6-unit aromatic ring when it is 6 yuan of rings, can contain 1,2 or 3 nitrogen-atoms, are 5 yuan when encircling when it perhaps, can contain 1,2 or 3 heteroatoms that is selected from oxygen, nitrogen and sulphur.
The example of heterocyclic radical comprises thiazolyl, furyl, thienyl, pyranyl, isobenzofuran-base, pyrryl, imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, indolizine base, pseudoindoyl, indyl, indazolyl, purine radicals, quinolyl, furazan base, pyrrolidyl, pyrrolinyl, imidazolidyl, imidazolinyl, pyrazolidyl, pyrazolinyl, piperidyl, piperazinyl, indolinyl and morpholinyl.For example, preferred cycloalkyl or heterocyclic radical comprise morpholinyl, piperazinyl, pyrrolidyl, pyridyl, cyclohexyl imino-, thienyl, more preferably piperidyl or morpholinyl.
Exemplary heteroaryl example is thienyl, furyl, pyrryl, imidazolyl, oxazolyl, thiazolyl, benzothienyl, benzofuryl, benzimidazolyl-, benzoxazolyl, benzothiazolyl.
" acyl group " refers to and hydrogen atom (as formyl radical) or the carbonyl moiety that is connected with the optional alkyl that replaces or alkenyl chain or heterocyclic radical.
" halogeno-group " or " halogen " comprises as substituent on the alkyl, as to have one or more halogen atom fluoro base, chloro base, bromo base or iodo base, preferred fluoro base or chloro base, for example trifluoromethyl, trifluoromethoxy, trifluoromethylthio, difluoro-methoxy or fluoro methylthio group.
" alkane two bases " or " alkylidene group " are represented divalent alkyl straight or branched, that choose replacement wantonly, for example methylene radical, ethylidene, propylidene, butylidene, pentylidene or hexylidene.
" alkylene group " represents divalence alkenyl straight or branched, optional replacement, for example propenylidene, crotonylidene, inferior pentenyl or inferior hexenyl with above similar.In these groups, the carbon atom that connects nitrogen preferably should not be undersaturated.
" aroyl " refers to the carbonyl moiety that is connected with optional aryl that replaces or heteroaryl, and wherein the above definition that provides is provided for aryl and heteroaryl.Specifically, the benzyl acyl group is a phenylcarbonyl group.
Press this paper definition, the atom that two groups connect with their can form the optional 4-7 unit that replaces, 5-7 unit or 5-6 unit's carbocyclic ring or heterocycle, and this ring can be saturated, undersaturated or aromatic ring.This ring can be by the definition in the above overview section of the present invention.The specific examples of these rings provides in the lower section.
" pharmacy acceptable salt, ester and acid amides " comprises carboxylate salt, amino acid addition salt, ester and acid amides, they have rational interests/risk ratio, effectively and be suitable for contacting, there are not unsuitable toxicity, pungency or anaphylaxis simultaneously on the pharmacology with patient's tissue.These salt, ester and acid amides can be C for example 1-8Alkyl, C 3-8Cycloalkyl, aryl, C 2-10Heteroaryl or C 2-10The salt of non-aromatic heterocyclic, ester and acid amides.Salt, free acid and ester more are better than the acid amides on terminal carboxylate radical/carboxylic acid group on formula (I) left side.Representational salt comprises hydrobromate, hydrochloride, vitriol, hydrosulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, lauroleate, borate, benzoate, lactic acid salt, phosphoric acid salt, tosylate, Citrate trianion, maleate, fumarate, succinate, tartrate, naphthoate (naphthylate), mesylate, gluceptate, Lactobionate and dodecane sulfonate.These salt can comprise basic metal and alkaline earth metal cation (as sodium, potassium, calcium and magnesium) and atoxic ammonium, quaternary ammonium and amine ion, as tetramethyl-ammonium, methylamine, Trimethylamine 99 and ethamine.Example is referring to being attached among the present invention as a reference S.M.Berge etc. at J.Pham.Sci., and 1977, " the Pharmaceutical Salts " among the 66:1-19.The representational pharmaceutically acceptable acid amides of the present invention comprises derived from ammonia, uncle C 1-6Alkylamine and secondary two (C 1-6Alkyl) those acid amides of amine.Secondary amine comprises and contains at least one nitrogen-atoms and optional 1-2 other heteroatomic 5-or 6-unit's heterocycle or heteroaromatic rings part.Preferred acid amides is derived from ammonia, C 1-3Kiber alkyl amine and two (C 1-2Alkyl) amine.The representational pharmaceutically acceptable ester of the present invention comprises C 1-7Alkyl, C 5-7Cycloalkyl, phenyl and phenyl (C 1-6) alkyl ester.Preferred ester is methyl and ethyl ester.
" patient " or " experimenter " comprises that having relative disease or illness needs the Mammals observing, test, treat or prevent, as humans and animals (dog, cat, horse, rat, rabbit, mouse, non-human primate).Described patient or experimenter be the people preferably.
" composition " is meant a kind of product of the special component that comprises specified quantitative and any product that is obtained by the specific components combination of specified quantitative.
" treatment significant quantity " or " significant quantity " refer to the amount that can bring out physiology or medicinal reactive activity compound or medicine in the tissue system of investigator, animal doctor, doctor or other clinician research, animal or human, it comprise alleviate the amount of symptom of the illness for the treatment of or disease.
The various groups that relate in the disclosure and claims provide three kinds of universal description at this.At first indicated is valency.When relating to all alkyl, no matter be saturated, unsaturated or aromatics and no matter whether be ring-type, straight or branched and also similar that each group comprises the group of the replacement of indicated type in claims content and unit price, divalence and multivalence group to all heterocyclic radicals.This content shows that described substituting group is alkylidene group or the alkyl with at least two hydrogen atoms of removing (divalence) or a plurality of hydrogen atom of removing (multivalence).The example of the divalent group of two parts of link molecule is the Y in the formula (I), and it will be by R 5, R 6And R 7The phenyl that replaces is connected with the rest part of molecule.
Secondly, should know group or the structure fragment that group that this paper defines or structure fragment comprise replacement.Alkyl comprises the monoradical that contains carbon and hydrogen, as alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl group (no matter be aromatics or unsaturated) and corresponding divalence (or multivalence) group, as alkylidene group, alkylene group, phenylene etc.Assorted alkyl comprises and contains carbon, optional hydrogen and at least one heteroatomic unit price and divalence (multivalence) group.The example of the assorted alkyl of unit price comprises acyl group, acyloxy, alkoxyl group acyl group, heterocyclic radical, heteroaryl, aroyl, benzoyl, dialkyl amido, hydroxyalkyl etc.Adopt " alkyl " as an example, should understand the alkyl that " alkyl " comprises replacement, it has 1 or a plurality of substituting group, as 1-5, and 1-3 or 2-4 substituting group.Described substituting group can identical (dihydroxyl, dimethyl), similarly (chloro fluoro) or different (chloro benzyls-or amino methyl-replacement).The example of the alkyl that replaces comprises haloalkyl (as methyl fluoride, chloromethyl, difluoromethyl, perchloro-methyl, 2-bromotrifluoromethane, trifluoromethyl and 3-iodo cyclopentyl), hydroxyalkyl (as methylol, hydroxyethyl, 2-hydroxypropyl), aminoalkyl group (as amino methyl, 2-amino-ethyl, 3-aminopropyl and 2-aminopropyl), 4-nitro alkyl, alkyl-alkyl etc.Two (C 1-6Alkyl) amino comprises the alkyl in order to the independent selection that forms and sec.-propyl methylamino-amino such as methyl-propyl, and the dialkyl amido with two identical alkyl, as dimethylamino or diethylin.
The 3rd, formation only be stable compound.For example, when there being NR 11R 12, and R is can be for alkenyl the time, this pair key have at least one with nitrogen-atoms carbon at interval, to avoid forming enamine.Similarly, as-(CH 2) p-N-(CH 2) q-in the time of can being unsaturated, comprising or omit suitable hydrogen atom, as at-(CH 2)-N=(CH)-(CH 2)-or-(CH 2)-NH-(CH)=(CH)-shown in.
Further specifying The compounds of this invention with the lower section.
B. compound
The compound composition that contains the formula of describing (I) in above overview section and the method for application formula (I) compound of providing is provided.Example comprises those compounds, wherein (a) R 1And R 2One of be methyl or ethyl; (b) R wherein 1And R 2The methyl of respectively doing for oneself; (c) R 1And R 2Be cyclobutyl or cyclopentyl together; (d) R 3Be H; (e) R 4Be H or C 2-7Alkyl; (e) R 4Be H or C 2-5Alkyl; (f) R 4Be ethyl; (g) R 4Be H; (h) n is 1; (i) n is 2; (j) Y is NHCH 2(k) Y is NH; (1) X is S; (m) X is O; (n) R 5And R 7At least one is H; (o) R 6Be C 1-4Alkyl, halogenated methoxy or halo methylthio group; (p) R 6Be the tertiary butyl, sec.-propyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, difluoro-methoxy or dimethylamino; (q) R 3Be H, R 4Be C 2-7Alkyl, and Y is NH; (r) R 4Be C 2-5Alkyl; (s) R 6Be cyclopropyl methyl, sec.-propyl, isobutyl-, methyl ethylamino or diethylin; (t) (S) enantiomorph of C-2 position on described indane or the tetraline; (u) (R) enantiomorph of C-2 position on described indane or the tetraline; (v) R wherein 15Be C 1-7Alkyl, [two (C 1-2Alkyl) amino] (C 1-6Alkylidene group), (C 1-3The alkoxyl group acyl group) (C 1-6Alkylidene group), C 1-6Alkoxyl group, C 3-7Alkenyl or C 3-8Alkynyl; (w) R 6Be trifluoromethylthio or trifluoromethoxy; Perhaps (x) above combination.
Other preferred compound comprises:
2-{6-[1-ethyl-3-(4-Trifluoromethoxyphen-l)-urea groups]-1,4-two fluoro-5,6,7,8-tetraline-2-base sulfane base }-2 Methylpropionic acid
Figure A20038010656600182
2-{4-chloro-6-[1-ethyl-3-(4-Trifluoromethoxyphen-l) urea groups]-1-fluoro-5,6,7,8-tetraline-2-base sulfane base }-2 Methylpropionic acid
Figure A20038010656600183
2-{3-ethyl-6-[1-ethyl-3-(4-Trifluoromethoxyphen-l) urea groups]-5,6,7,8-tetraline-2-base sulfane base }-2 Methylpropionic acid
Figure A20038010656600184
3-(1-carboxyl-1-methyl-ethylmercapto group)-7-[1-ethyl-3-(4-Trifluoromethoxyphen-l) urea groups]-5,6,7,8-tetraline-2-ethyl formate
Figure A20038010656600185
2-{6-[ethyl-(4-Trifluoromethyl phenyl ether oxygen base carbonyl)-amino]-3-fluoro-5,6,7,8-tetraline-2-base sulfane base }-2 Methylpropionic acid
2-{6-[1-ethyl-3-(4-Trifluoromethoxyphen-l) urea groups]-3-methoxyl group-5,6,7,8-tetraline-2-base sulfane base }-2 Methylpropionic acid
2-{6-[1-ethyl-3-(4-Trifluoromethoxyphen-l) urea groups]-3-chloro-5,6,7,8-tetraline-2-base sulfane base }-2 Methylpropionic acid
2-{6-[1-ethyl-3-(4-Trifluoromethoxyphen-l) urea groups]-3-bromo-5,6,7,8-tetraline-2-base sulfane base }-2 Methylpropionic acid
2-{6-[1-ethyl-3-(4-Trifluoromethoxyphen-l) urea groups]-3-methyl-5,6,7,8-tetraline-2-base sulfane base }-2 Methylpropionic acid
2-{6-[1-ethyl-3-(4-Trifluoromethoxyphen-l) urea groups]-3-trifluoromethoxy-5,6,7,8-tetraline-2-base sulfane base }-2 Methylpropionic acid
2-{6-[1-ethyl-3-(4-hydroxy phenyl) urea groups]-5,6,7,8-tetraline-2-base sulfane base }-2 Methylpropionic acid
The 2-{6-[4-aminophenyl)-and 1-ethyl-urea groups]-5,6,7,8-tetraline-2-base sulfane base }-2 Methylpropionic acid
Most preferred is selected from:
2-{6-[1-ethyl-3-(4-Trifluoromethoxyphen-l) urea groups]-5,6,7,8-tetraline-2-base sulfane base }-2 Methylpropionic acid;
2-{6-[3-(4-Trifluoromethoxyphen-l)-urea groups]-5,6,7,8-tetraline-2-base sulfane base }-2 Methylpropionic acid;
2-{2-[1-ethyl-3-(4-Trifluoromethoxyphen-l) urea groups] indane-5-base sulfane base }-2 Methylpropionic acid;
2-{2-[1-ethyl-3-(4-trifluoromethylthio phenyl) urea groups] indane-5-base sulfane base }-2 Methylpropionic acid;
2-{6-[1-ethyl-3-(4-Trifluoromethoxyphen-l) urea groups]-3-fluoro-5,6,7,8-tetraline-2-base sulfane base }-2 Methylpropionic acid; With
2-methyl-2-{2-[1-propyl group-3-(4-Trifluoromethoxyphen-l) urea groups] indane-5-base sulfane base } propionic acid.
Related compound
The invention provides the pharmaceutically acceptable form that is closely related of disclosed compound and disclosed compound, as its salt, ester, acid amides, acid, hydrate or solvate form thereof; Conductively-closed or protected form; And racemic mixture, or enantiomer-pure or optically pure form.Related compound also comprises and has been modified to the The compounds of this invention that can detect, for example as in the Positron Emission Tomography (PET) or single photon emission computed x-ray tomography art (SPECT) middle probe use isotope-labeled 18F.
The present invention also comprises the disclosed compound of the functional group's (as hydroxyl, amino or carboxyl) with one or more protected base shielding.Referring to for example third edition Greene and Wuts, Protective Groups in organic Synthesis, (1999), John Wiley﹠amp; Sons, NY.Some this class conductively-closed or protected compound are pharmaceutically acceptable; Other can be used as intermediate.Synthetic intermediate disclosed herein and method with and minimum modification be also included within the scope of the present invention.
Hydroxyl protecting group
The protection of hydroxyl comprises the methyl ether of methyl ether, replacement, the ethyl ether of replacement, the benzylic ether and the silyl ether of replacement.
The methyl ether that replaces
The example of the methyl ether that replaces comprises methoxymethyl, methylthiomethyl, uncle's butylthio methyl, benzyloxymethyl, to methoxyl group benzyloxy ylmethyl, (4-methoxyl group phenoxy group) methyl, tert.-butoxy methyl.
The ethyl ether that replaces
The example of the ethyl ether that replaces comprises 1-ethoxyethyl group, 1-methyl isophthalic acid-methoxy ethyl, 1-methyl isophthalic acid-benzyloxy ethyl, 2,2,2-three chloroethyls, the tertiary butyl, allyl group, rubigan, p-methoxyphenyl and benzyl.
The benzylic ether that replaces
The example of the benzylic ether that replaces comprises methoxy-benzyl, 3,4-dimethoxy-benzyl, to halogeno-benzyl, 2,6-dichloro benzyl, to the cyano group benzyl, to phenylbenzyl, diphenyl methyl.Ester
Except that ethers, can be ester with hydroxyl protection.The example of ester comprises manthanoate, benzoyl manthanoate, acetic ester, trichloroacetic esters, trifluoro-acetate, methoxyacetic acid ester, phenylium ester, parachlorophen-oxyacetic acid ester, benzoic ether.
Sulphonate
The example of sulphonate comprises sulfuric ester, methanesulfonates (mesylate), benzyl sulphonate and tosylate.
Amino protecting group
Amino protecting group comprises carbamate, acid amides and specific-NH protecting group.
The example of carbamate comprise Urethylane and ethyl ester, replacement urethanum, help cracked carbamate, photodissociation cracked carbamate, urea type derivative and other carbamate.
Carbamate
The example of Urethylane and ethyl ester comprises methyl esters and ethyl ester, 9-fluorenes methyl esters and 4-methoxybenzoyl methyl esters.
The ethyl ester that replaces
The example of the urethanum that replaces comprises 2,2,2-three chloro-ethyl esters, 2-phenethyl ester, the tert-butyl ester, vinyl ester, allyl ester, 1-sec.-propyl allyl ester, benzyl ester, to the methoxy-benzyl ester, to the nitrobenzyl ester, to bromobenzyl ester, p-chlorobenzyl ester, 2,4-dichloro benzyl ester and phenylbenzene methyl esters.
Photodissociation cracked carbamate
The example of photodissociation cracked carbamate comprises m-nitro base ester, 3,5-dimethoxy-benzyl ester, ortho-nitrophenyl base ester, 3,4-dimethoxy-6-nitrobenzyl ester and phenyl (ortho-nitrophenyl base) methyl esters.
Acid amides
The example of acid amides comprises that N-methane amide, N-ethanamide, N-trichloroacetamide, N-TFA amine, N-phenylacetamide, N-3-hydrocinnamamide, N-picolinamide (picolinoyl), N-3-pyridyl carboxamide, N-benzamide, N-are to phenylbenzamaide and phthalic diamide.
The carbonyl-protection base
Cyclic acetal and ketal
The example of cyclic acetal and ketal comprises 1,3-dioxane and 5-methylene radical-1,3-dioxane.
Carboxyl-protecting group
Ester
The methyl esters that replaces
The example of the methyl esters that replaces comprises 9-fluorenyl methyl esters, methoxyl group methyl esters, methylthio group methyl esters, methoxy ethoxy methyl esters, 2-(three silyls) oxyethyl group methyl esters, benzyloxy methyl esters, phenacylate, to bromobenzene carbamoyl methyl, Alpha-Methyl phenacylate with to the methoxybenzoyl methyl esters.The example of ester also comprises the straight or branched alkyl ester, as tertiary butyl ester, ethyl ester, propyl ester, isopropyl ester and butyl ester.
The benzyl ester that replaces
The example of the benzyl ester that replaces comprises triphenyl methyl esters, phenylbenzene methyl esters, 9-anthryl methyl esters, 2,4,6-trimethylammonium benzyl ester, to bromobenzyl ester, adjacent nitrobenzyl ester, to the nitrobenzyl ester, to methoxy-benzyl ester, 2,6-dimethoxy-benzyl ester, piperonyl ester, 4-picolyl ester (picolyl) and right-P-benzyl ester.
The silylation ester
The example of silylation ester comprises three silyl esters, three disilanyl-esters, tertiary butyl dimethylsilyl ester, sec.-propyl dimethylsilyl ester, phenyl dimethylsilyl ester and di-t-butyl methyl-monosilane base ester.
C. synthetic method
The invention provides according to traditional methodology of organic synthesis and matrix or form the method that synthesis method prepares described disclosed compound.Flow process 1-10 describes the synthetic route that is proposed.Adopt these flow processs, following governing principle and described embodiment, those skilled in the art can develop the isostructural or similar method of compound given within the scope of the invention.
It will be appreciated by those skilled in the art that the synthetic influence that may be subjected to buying intermediate described in any flow process disclosed herein or protected intermediates compound of The compounds of this invention.Those of skill in the art also will appreciate that: in any process of preparation The compounds of this invention, may and/or need protect sensitivity or active group on any relevant molecule.This can finish by conventional protecting group (for example at " Protective Groups in Organic Synthesis ", John Wiley and Sons, those disclosed protecting group in 1991).These blocking groups can adopt methods known in the art to remove in stage easily.
The example of described synthetic route comprises synthetic embodiment 1-57.With the target compound similar compounds of these embodiment can according to and under many circumstances according to similar path of preparing.These disclosed compounds can be used for fundamental research and can be used as at the medicine described in the next section.
General guidance
Provide formula 14 among the flow process 1-5 (when X is S (and R 3Be H)) preferred synthetic method.
Abbreviation or initialism that the present invention uses comprise:
AcOH (Glacial acetic acid); DCC (1, the 3-dicyclohexylcarbodiimide); DCE (1, the 2-ethylene dichloride); DIC (hydrochloric acid 2-dimethylamino isopropyl chloride); DIEA (diisopropylethylamine); DMF (dimethyl formamide); EDC (1-(3-dimethylamino-propyl)-3-ethyl carbodiimide); EtOAc (ethyl acetate); MCPBA (3-chloroperoxybenzoic acid); NMI (1-Methylimidazole); TEA (triethylamine); TFA (trifluoroacetic acid); THF (tetrahydrofuran (THF)); TMEDA (N, N, N ', N '-Tetramethyl Ethylene Diamine).
Flow process 1
Figure A20038010656600241
By shown in the flow process 1, can be by compound 1 being converted into the described tetraline of compound 2 preparations.For example, methoxyl group-2-Tetralone an intermediate of Sertraline (as 6-methoxyl group-2-Tetralone an intermediate of Sertraline) can be used such as agent treated such as ammonium acetate or ammonia or azanols.The imines of correspondence can be handled with suitable reductive agent such as sodium borohydride or sodium cyanoborohydride or sodium triacetoxy borohydride, then in polar aprotic solvent (as methyl alcohol, ethanol or ethyl acetate), the oxime that obtains with palladium or platinum catalytic reduction, is obtained racemic compound 2.Those skilled in the art can easily finish the preparation of its hydrochloride.
Flow process 2
Figure A20038010656600251
By shown in the flow process 2, can be by compound 3 being converted into the described indane of compound 5 preparations.For example; in the presence of acid (example hydrochloric acid or Hydrogen bromide) at catalytic amount; in polar solvent (as methyl alcohol or ether), melonia indone (as 5-methoxyl group-1-indone) is used when handling such as the acylating agent of butyl nitrite or nitrous acid isopentyl ester, obtain ketone group-oxime 4.In suitable solvent (as acetate-sulfuric acid, THF or methyl alcohol), under suitable temperature, adopt suitable reductive agent, as lithium aluminium hydride or hydrogen and catalyzer (as palladium or platinum), can be with compound 4 reduction.Those skilled in the art can easily determine the selection of salt formation method.
Flow process 3
By shown in the flow process 3, compound 2 or 5 can be converted into compound 12.For example,, racemic amine hydrochlorate is handled with alkali such as sodium hydride or lithium hydride, then under elevated temperature, during with acid anhydrides such as phthalic anhydride, can be prepared the inferior acid amides 6 of ring when in polar aprotic solvent such as DMF or THF.In nonpolar, aprotic solvent such as toluene, methylene dichloride or ethylene dichloride, have or do not have cooling down,, the methyl aryl ether-splitting of formula 6 can be separated such as boron tribromide, boron trichloride, aluminum chloride or TMS iodine with Lewis acid, obtain formula 7 compounds.In aprotic solvent such as methylene dichloride, DMF or THF; have or do not have cooling down; adopt thiocarbamyl chlorine (as dimethylamino thiocarbamyl chlorine or diethyl sulfide for urea chloride) and non-reacted tertiary amine (as triethylamine, 1; 8-diazabicyclo [5.4.D] 11-7-alkene or 1; 4-diazabicyclo [2.2.2] octane); with the phenol acylations of formula 7, can obtain formula 8 compounds.Under the temperature between 180 ℃ to 350 ℃, formula 8 compounds are as melt itself or adopt high boiling solvent such as the DOWTHERM  A (mixture of a kind of biphenyl and xenyl ether, for example by Fluka Chemical Corp., Milwaukee, WI USA buys), N, accelerine, biphenyl ether or naphthane can be formula 9 compounds with formula 8 compound thermal rearrangements.By in suitable polar solvent such as ethanol or THF, under elevated temperature, formula 9 compounds are handled with suitable electrophilic reagent (as hydrazine, sulfuration disodium or methylamine), but preparation formula 10 compounds.Adopt suitable reagent, as potassium hydroxide in the alcohol solvent (as ethanol or methyl alcohol) or the lithium aluminum hydride in THF or the ether, then, formula 10 compounds can be converted into formula 11 compounds with the alkyl halide (as 2-bromo acid tertiary butyl ester, bromoethyl acetate or 2-bromo ethyl butyrate) and reductive agent (as lithium borohydride or the sodium borohydride) alkylation that suitably replace.Adopt inert solvent such as THF, methylene dichloride or hexane, adopt carboxylic acid or acyl chlorides and suitable reductive agent (as borine-THF or borine-methyl-sulfide), formula 11 compounds can be replaced, obtain formula 12 compounds.In addition, in inert solvent such as THF, methylene dichloride or ethylene dichloride, adopt aldehyde and reductive agent such as sodium cyanoborohydride or sodium triacetoxy borohydride, can finish replacement.
Flow process 4
By shown in the flow process 4, can be by only using thionyl chloride or oxalyl chloride or in toluene or methylene dichloride,, making the secondary amine acylations, by formula 12 compound formulas 13 compounds with Arylacetic acids having or not having in the presence of the catalysis DMF.In addition, in methylene dichloride, adopt the standard peptide condition,, can finish described coupling as EDC, DCC or DIC.When Y=NH or O, can adopt aryl isocyanate or carbonochloridic acid aryl ester preparation formula 13 compounds in nonpolar, the inert solvent (as THF, methylene dichloride or hexane) respectively.Those skilled in the art are easy to determine the selection of deprotection method, with preparation formula 14 compounds.
Flow process 5
Similarly, described by flow process 5, can by formula 11 compounds, obtain formula 15 compounds, preparation formula 16 compounds by with the primary amine acylations.Those skilled in the art can be easy to determine to select the method for deprotection, to obtain formula 16 compounds.
Flow process 6
By shown in the flow process 6, can be by formula 10 compound formulas 18 compounds.For example, do not having or having appropriate solvent (as methylene dichloride or ethylene dichloride) in the presence of, having or do not have heating and descend, formula 10 compounds with ethyl formate or ammonium formiate processing, are being obtained formula 17 compounds.By in appropriate solvent such as THF or ether, adopt suitable reagent such as lithium aluminum hydride, then adopt alkyl halide (as 2-isobutyl bromide tertiary butyl ester, bromoethyl acetate or 2-bromo ethyl butyrate) and reductive agent (as lithium borohydride or the sodium borohydride) alkylation that suitably replaces, formula 17 compounds are converted into formula 18 compounds.
Flow process 7
Figure A20038010656600291
Formula 21 compounds are (when X is O (and R 3Be H)) preferred synthesis method be shown in the flow process 7.For example, when by the above with carboxylic acid or acyl chlorides during with the compound acylations of formula 2 or 5, preparation formula 19 compounds.In nonpolar, aprotic solvent such as toluene, methylene dichloride or ethylene dichloride, have or do not have cooling down, with Lewis acid such as boron tribromide, boron trichloride, aluminum chloride or TMS iodine, the methyl aryl ether-splitting of formula 19 can be separated, obtain formula 20 compounds.By in appropriate solvent such as DMF or methyl alcohol, alkyl halide (as 2-bromo acid tertiary butyl ester, bromoethyl acetate or 2-bromo ethyl butyrate) with suitable alkali (as salt of wormwood, cesium carbonate or potassium hydroxide) and suitably replacement is handled, and formula 20 compounds can be converted into formula 21 compounds.
Flow process 8
By shown in the flow process 8, with formula 22 compound formulas 24 compounds.For example, in appropriate solvent such as ether or THF, have or do not have TMEDA to exist down, under cooling, formula 22 compounds are handled with suitable alkali (as butyllithium or s-butyl lithium) and suitable electrophilic reagent (as alkyl halide, aldehyde or disulphide), obtained formula 23 compounds.By in the flow process 3 compound 8 being converted into the similar mode described in the compound 9, formula 23 compounds are converted into formula 24 compounds.
Flow process 9
Figure A20038010656600301
Provide the another kind of synthetic method of formula 32 compounds in the flow process 9.For example, when in the presence of methyl alcohol, when 4-methylthio phenyl guanidine-acetic acid (formula 26) is handled with oxalyl chloride or thionyl chloride, obtain formula 27 compounds.In chlorinated solvent (as chloroform or ethylene dichloride), in the presence of alkene (as ethene), formula 27 compounds are handled with Lewis acid (as aluminum chloride), obtain the Tetralone an intermediate of Sertraline of formula 28.Adopt the method for general introduction in the flow process 1, tetraline that can preparation formula 29.In appropriate solvent such as methylene dichloride or ethylene dichloride, under coupling condition mentioned above, adopt carboxylic acid, perhaps in the presence of tertiary amine such as diisopropylethylamine or triethylamine, use acyl chlorides, formula 29 compounds can be replaced, obtain formula 30 compounds.Appropriate solvent such as methylene dichloride in, adopt oxygenant (as mCPBA or hydrogen peroxide), then have or solvent-free (as chloroform) under, formula 30 compounds are handled with trifluoroacetic anhydride, subsequently appropriate solvent such as methyl alcohol in, handle with tertiary amine such as triethylamine or diisopropylethylamine, obtain formula 31 compounds, thereby formula 30 compounds can be converted into formula 31 compounds.In addition, in appropriate solvent such as DMF, N-N-methyl-2-2-pyrrolidone N-or ammonia, adopt alkali,, the thioether deprotection in formula 30 compounds can be obtained formula 31 compounds as tertiary butyl sodium sulphite, sodium, methyl mercaptan sodium.Adopt in the flow process 3 compound 10 is converted into the similar chemical process described in the compound 11, be easy to formula 31 compounds are converted into formula 32 compounds.
Flow process 10
Figure A20038010656600311
Shown in flow process 10, be easy to formula 22 compounds are converted into formula 32a compound, wherein R 3=OCH 3For example, in appropriate solvent such as ether or THF, have or do not have TMEDA to exist down, under cooling, formula 22 compounds are handled with suitable alkali (as butyllithium or s-butyl lithium) and suitable disulphide (as methyl-sulfide or dibenzyl disulfide), obtained formula 33 compounds.In appropriate solvent such as water, methyl alcohol or ethanol, under having or not having heating, adopt potassium hydroxide or sodium, from formula 33 compounds, remove the dimethylamino thiocarbamate, obtain formula 34 compounds.In appropriate solvent such as DMF, methyl alcohol or methylene dichloride, have or alkali-free (as cesium carbonate or salt of wormwood) exists down, adopt methyl iodide, methyl-sulfate or diazomethane, formula 34 compounds are methylated, obtain formula 19a compound.By in the flow process 9 formula 30 compounds being converted into the similar chemical process described in formula 32 compounds, be easy to compound by formula 19a compounds accepted way of doing sth 32a.
Route 1
Figure A20038010656600312
2-{6-[1-ethyl-3-(4-Trifluoromethoxyphen-l urea groups]-5,6,7,8-tetraline-2-base sulfane base }-2 Methylpropionic acid
Compound 1.0 (embodiment 1)
A.6-methoxyl group-1,2,3,4-tetralin-2-base amine hydrochlorate
6-methoxyl group-2-Tetralone an intermediate of Sertraline (the 10.0g of flow process 1. in being dissolved in MeOH (400mL); 56.7mmol) add ammonium acetate (65g in the solution; 0.84mol), under the room temperature reactant was stirred 30 minutes.In this reactant, add sodium cyanoborohydride (17.8g then; 0.28mol), reactant was refluxed 1-2 hour.With the reactant cooling, removal of solvent under reduced pressure is diluted residue with EtOAc, adds 1N NaOH quencher reactant.Water phase separated is with organic phase water, salt water washing, through Na 2SO 4Drying is filtered, and removal of solvent under reduced pressure obtains the crude product residue, through flash chromatography (SiO 2) purifying, use CH 2Cl 2/ MeOH:NH 4OH (10%) wash-out obtains 6-methoxyl group-1,2,3,4-tetralin of 5.0g (50%)-2-base amine, is dark oily matter.Bubbling feeds HCl (g) in the ether that is cooled to the title compound under 0 ℃ (100mL) solution, and is saturated until solution.Again this suspension was stirred 30 minutes solvent evaporated under reduced pressure under the room temperature.Remaining solid is ground with ether, filter,, obtain the 6-methoxyl group-1,2,3,4-tetralin-2-base amine hydrochlorate of 4.9g white solid with ether washing, drying under reduced pressure.
LC/MS：C 11H 15NO：m/z 178(M+1)
B.2-(6-methoxyl group-1,2,3,4-tetralin-2-yl) isoindole-1, the 3-diketone
Flow process 3. under 0 ℃ to the 60%NaH (6g that stirs; 0.182mmol) DMF (400mL) suspension in gradation add 6-methoxyl group-1,2,3,4-tetralin-2-base amine (30g; 0.140mol).Reaction mixture is warmed to room temperature, restir 1 hour.Under the room temperature, disposable adding Tetra hydro Phthalic anhydride (20.7g; 0.139mol), again reaction mixture was stirred 1 hour, stirred 18 hours down at 120 ℃ then.Reaction mixture is cooled to room temperature, dilute with water, with ethyl acetate extraction for several times.With organic extraction water, the salt water washing that merges, through Na 2SO 4Drying, removal of solvent under reduced pressure.The crude product solid is ground with methyl alcohol, filter, vacuum-drying obtains 2-(6-methoxyl group-1,2,3,4-tetralin-2-yl) isoindole-1 of 29.1g (67%) pale solid, 3-diketone.
1H NMR(300MHz，CDCl 3)：δ7.83-7.86(m，2H)，7.70-7.73(m，2H)，6.96-6.99(d，1H)，6.67-6.72(m，2H)，4.50-4.59(m，1H)，3.78(s，3H)，3.52-3.61(m，1H)，2.95-2.98(m，2H)，2.81-2.88(m，1H)，2.65-2.76(m，1H)，1.97-2.01(m，1H)
LC/MS：C 19H 17NO 3：m/z 308(M+1)
C.2-(6-hydroxyl-1,2,3,4-tetralin-2-yl) isoindole-1, the 3-diketone
Flow process 3. is to 2-(6-methoxyl group-1,2,3,4-tetralin-2-yl) isoindole-1 in the anhydrous methylene chloride (500mL) of being dissolved in that is cooled under-60 ℃, 3-diketone (29g; 94.3mmol) in be added dropwise to 1.0M boron tribromide-methylene dichloride (471mL) solution, keep temperature of reaction between-50 to-60 ℃.After adding is finished, reaction mixture is warmed to room temperature, restir 4 hours.Reactant is cooled to 0 ℃,, at room temperature stirred again 0.5 hour with saturated sodium bicarbonate (400mL) quencher.Filtering-depositing, the water thorough washing is suspended in the ether, filters, and vacuum-drying obtains 2-(6-hydroxyl-1,2,3,4-tetralin-2-yl) isoindole-1 of 25.4g (92%) pale solid, 3-diketone.
1H NMR(300MHz，DMSO-d 6)：δ9.11(bs，1H)，7.82-7.89(m，4H)，6.84-6.87(d，1H)，6.52-6.56(m，2H)，4.29-4.37(m，1H)，3.45(bs，1H)，3.25-3.34(m，1H)，2.73-2.84(m，3H)，2.37-2.47(m，1H)，1.94-1.98(m，1H)
LC/MS：C 18H 15NO 3：m/z 294(M+1)
D. dimethyl-thiocarbamate-O-[6-(1,3-dioxo-1,3-dihydro-isoindole-2-yl)-5,6,7,8-tetraline-2-yl] ester
2-(6-hydroxyl-1,2,3,4-tetralin-2-yl) isoindole-1 of flow process 3. in being dissolved in dry DMF (200mL), 3-diketone (25.4g; 86.5mmol) in add 1 in turn, 4-diazabicyclo [2.2.2] octane (48.5g; 4.32mol) and dimethylamino thiocarbamyl chlorine (53.4g; 4.32mol), under the room temperature with this solution stirring 4 hours.Reactant is poured in the frozen water (1L), stirred 18 hours.Filtering-depositing washes with water, vacuum-drying.The crude product solid is through flash chromatography purifying (SiO 2), with hexane-ethyl acetate gradient elution, obtain the dimethyl thiocarbamate-O-[6-(1,3-dioxo-1,3-dihydro-isoindole-2-yl)-5,6,7 of 30g (91%) white solid, 8-tetraline-2-yl] ester.
1H NMR(300MHz，CDCl 3)：δ7.83-7.86(m，2H)，7.70-7.73(m，2H)，7.07-7.10(d，1H)，6.83-6.86(m，2H)，4.54-4.85(m，1H)，3.60-3.69(m，1H)，3.46(s，3H)，3.34(s，3H)，2.88-3.09(m，3H)，2.64-2.78(m，1H)，1.97-2.01(m，1H)
LC/MS：C 21H 20N 2O 3S：m/z 381(M+1)
E. dimethyl thiocarbamate S-[6-(1,3-dioxo-1,3-xylylenimine-2-yl)-5,6,7,8-tetraline-2-yl] ester
Flow process 3. disposable adding dimethyl-thiocarbamate O-[6-(1 in the flask at the bottom of in sand-bath, being preheated to 330 ℃ the 50mL garden that is equipped with reflux exchanger and stirring rod, 3-dioxo-1,3-xylylenimine-2-yl)-5,6,7,8-tetraline-2-yl] ester (5.32g; 13.9mmol).Under 330 ℃, this melt was stirred 7-8 minute, be quickly cooled to room temperature with nitrogen gas stream then.Thick residue is through flash chromatography purifying (SiO 2), with hexane-ethyl acetate gradient elution, obtain the dimethyl thiocarbamate S-[6-(1,3-dioxo-1,3-dihydro-isoindole-2-yl)-5,6,7 of 3.1g (58%) white solid, 8-tetraline-2-yl] ester.
1H NMR(300MHz，CDCl 3)：δ7.82-7.86(m，2H)，7.72-7.75(m，2H)，7.23-7.26(m，2H)，7.07-7.10(d，1H)，4.52-4.63(m，1H)，3.61-3.70(m，1H)，2.89-3.09(m，9H)，2.61-2.75(m，1H)，1.97-2.04(m，1H)
LC/MS：C 21H 20N 2O 3S：m/z 381(M+1)
F. dimethyl thiocarbamate S-[6-amino-5,6,7,8-tetraline-2-yl] ester
Flow process 3. adds ethanol (115mL) and dimethyl thiocarbamate S-[6-(1,3-dioxo-1,3-xylylenimine-2-yl)-5,6,7,8-tetraline-2-yl in the 3-neck bottle that is equipped with reflux exchanger and mechanical stirrer] ester (8.7g; 23.5mmol).Room temperature property adding next time hydrazine (6.6mL; 2.11mol), under the mechanical stirring reactant was refluxed 40 minutes.Reactant is cooled to room temperature, gelatinous white solid is filtered, use the ether thorough washing.The ether washings is merged, and reduction vaporization further grinds thick residue with ether, filters, and the reduction vaporization ether obtains the dimethyl thiocarbamate S-[6-amino-5,6,7 of 6.1g (100%) yellow oil, 8-tetraline-2-yl] ester.
LC/MS：C 13H 18N 2OS：m/z 251(M+1)
G.2-(6-amino-5,6,7,8-tetraline-2-base sulfane base)-2 Methylpropionic acid tertiary butyl ester
Under flow process 3. room temperatures, the dimethyl thiocarbamate S-[6-amino-5,6,7 in being dissolved in methyl alcohol (25mL), 8-tetraline-2-yl] ester (6.1g; 24.4mmol) the middle KOH (4.1g that adds; 73.2mmol) methyl alcohol (25mL) solution.Reflux down,, be cooled to room temperature this solution stirring 5 hours.In this solution, add 2-isobutyl bromide tertiary butyl ester (16.3g; 73.2mmol), stirred 16 hours under the room temperature.Add NaBH 4(9.2g; 2.44mol), again reactant was stirred 48 hours under the room temperature.With the quencher of reactant water, solvent evaporated under reduced pressure is distributed thick residue between water and methylene dichloride.With the water dichloromethane extraction, with organic extracting solution of merging through Na 2SO 4Drying is filtered, and reduction vaporization obtains 2-(6-amino-5,6,7,8-tetraline-2-base sulfane base)-2 Methylpropionic acid tertiary butyl ester of 4.7g (60%) brown oil.
LC/MS：C 181H 27NO 2S：m/z 266(M+1)
H.2-(6-acetamido-5,6,7,8-tetraline-2-base sulfane base)-2 Methylpropionic acid tertiary butyl ester
2-(6-amino-5,6,7,8-tetraline-2-base sulfane the base)-2 Methylpropionic acid tertiary butyl ester (4.7g of flow process 3. in being dissolved in methylene dichloride (25mL); 14.6mmol) the middle DIEA (3.3mL that adds; 18.9mmol), reaction mixture is cooled to 0 ℃.To maintain the temperature at the speed between 0-5 ℃, dripping acetyl chloride (1.25mL; 17.5mmol).Reactant is warmed to room temperature, stirred 16 hours.Reactant is diluted with methylene dichloride, wash with water, through Na 2SO 4Drying, reduction vaporization, crude product oily matter is through flash chromatography purifying (SiO 2), with hexane-ethyl acetate gradient elution, obtain 2-(6-acetamido-5,6,7,8-tetraline-2-base sulfane the base)-2 Methylpropionic acid tertiary butyl ester of 1.7g (32%) brown solid.
1H NMR(300MHz，CDCl 3)：δ7.23-7.26(m，2H)，6.99-7.01(d，1H)，5.46-5.48(m，1H)，4.25-4.29(m，1H)，3.08-3.15(dd，1H)，2.82-2.88(m，2H)，2.58-2.66(m，1H)，2.01-2.04(m，1H)，1.98(s，3H)，1.70-1.82(m，1H)，1.43(s，15H)
LC/MS：C 20H 29NO 3S：m/z 308(M+1)
I.2-(6-ethylamino-5,6,7,8-tetraline-2-base sulfane base)-2 Methylpropionic acid tertiary butyl ester
Under flow process 3. room temperatures, to 2-(6-acetamido-5,6,7,8-tetraline-2-base sulfane base)-2 Methylpropionic acid tertiary butyl ester (1.7g; 4.64mmol) THF (42mL) solution in be added dropwise to 1.0M borine-THF (42mL) solution.Under the room temperature, reactant was stirred 18 hours, carefully use the methyl alcohol quencher, solvent evaporated under reduced pressure.With residual oily matter and methanol azeotropic (3x), obtain 2-(6-ethylamino-5,6,7,8-tetraline-2-base sulfane the base)-2 Methylpropionic acid tertiary butyl ester of 1.9g (100%) oily matter and the mixture of its borane complexes again.
LC/MS：C 20H 31NO 2S·BH 3：m/z 308((M+BH 3)+1)
J.2-{6-[1-ethyl-3-(4-fluoroform hydrogen base phenyl) urea groups]-5,6,7,8-tetraline-2-base sulfane base }-the 2 Methylpropionic acid tertiary butyl ester
Mixture (the 1.9g of the 2-of flow process 4. in being dissolved in methylene dichloride (15mL) (6-ethylamino-5,6,7,8-tetraline-2-base sulfane base)-2 Methylpropionic acid tertiary butyl ester and its borane complexes; Add isocyanic acid 4-trifluoromethoxy phenyl ester (1.6g 52mmol); 7.8mmol), under the room temperature reactant was stirred 18 hours.Removal of solvent under reduced pressure, residue is through flash chromatography purifying (SiO 2), with hexane-ethyl acetate gradient elution, obtain 2-{6-[1-ethyl-3-(4-Trifluoromethoxyphen-l) urea groups of 1.66g (58%) white foam shape thing]-5,6,7,8-tetraline-2-base sulfane base }-the 2 Methylpropionic acid tertiary butyl ester.
LC/MS：C 28H 35F 3N 2O 4S：m/z 497((M-C 4H 8)+1)
K.2-{6-[1-ethyl-3-(4-Trifluoromethoxyphen-l) urea groups]-5,6,7,8-tetraline-2-base sulfane base }-2 Methylpropionic acid
2-{6-[1-ethyl-3-(4-Trifluoromethoxyphen-l) urea groups of flow process 4. in being dissolved in methylene dichloride (15mL)]-5,6,7,8-tetraline-2-base sulfane base }-2 Methylpropionic acid tertiary butyl ester (1.66g; 3.0mmol) the middle TFA (15mL) that adds, under the room temperature reactant was stirred 1.5 hours.Removal of solvent under reduced pressure, residue is through flash chromatography purifying (SiO 2), with hexane-ethyl acetate gradient elution, obtain 2-{6-[1-ethyl-3-(4-Trifluoromethoxyphen-l) urea groups of 0.643g (43%) white solid]-5,6,7,8-tetraline-2-base sulfane base }-2 Methylpropionic acid.
1H NMR(300MHz，CD 3OD)：δ7.45-7.48(m，2H)，7.06-7.24(m，5H)，4.44(m，1H)，3.43-3.45(m，2H)，2.96-3.02(m，4H)，2.00-2.05(m，2H)，1.41-1.46(s，6H)，1.21-1.29(m，3H)
LC/MS：C 24H 27F 3N 2O 4S：m/z 497(M+1)
Route 2
Figure A20038010656600371
2-{2-[1-ethyl-3-(4-Trifluoromethoxyphen-l) urea groups] indane-5-base sulfane base }-2 Methylpropionic acid compound 2.0 (embodiment 2)
A.5-methoxyl group-indane-1,2-diketone-2-oxime
Flow process 2. usefulness 45 minutes, the 5-methoxyl group-indan-1-one (75.8g under 45 ℃; 0.467mol) MeOH (1.4L) solution in drip butyl nitrite (81mL; 0.693mol).Then with adding dense HCl (45mL) in 20 fens these hot solution of clockwise, under 45 ℃, with reaction solution restir 1.5-2 hour.With the reaction suspension cooling, filtering-depositing with cold methanol washing several, vacuum-drying, obtains the 5-methoxyl group-indane-1 of 55.8g (62%) beige solid, 2-diketone-2-oxime.
1H NMR(300MHz，CD 3OD)：δ7.80-7.83(m，1H)，6.95(bs，2H)，3.92(s，3H)，3.78(s，2H)，3.47(bs，1H)
LC/MS：C 10H 9NO 3：m/z 192(M+1)
B.5-methoxyl group-indane-2-base amine hydrochlorate
5-methoxyl group-the indane-1 of flow process 2. in being suspended in Glacial acetic acid (0.99L), 2-diketone-2-oxime (55.7g; 0.291mol) the middle vitriol oil (67mL) that adds, then add 10%Pd-C (27g), at H 2, under the 60psi, reactant was mixed 18 hours in the Parr device.With reactant N 2Clean, filter, wash with AcOH by Celite pad.Removal of solvent under reduced pressure to 1/5 volume with remaining water used in solvent (500mL) dilution, is cooled to 0 ℃.Be neutralized to pH10 with the 50%NaOH aqueous solution.Water is fully extracted for several times with chloroform, the united extraction thing, water, salt water washing are through Na 2SO 4Drying is filtered, and reduction vaporization obtains 77.3g (66%) crude product oily matter.This oily matter is through flash chromatography (SiO 2) purifying, with 40: 2.2: 0.2CHCl 3: MeOH: NH 4The OH wash-out obtains the dark oily matter of 43.8g (37%).This oily matter is dissolved in the ether (1L), is cooled to 0 ℃, this solution is saturated with HCl (g).Removal of solvent under reduced pressure is ground solid with ether, filter, and with the ether washing, obtains the 5-methoxyl group-indane-2-base amine hydrochlorate of 43.8g (30%) white solid.
1H NMR(300MHz，CD 3OD)：δ7.08-7.11(d，1H)，6.77(s，1H)，6.69-6.72(d，1H)，3.78-3.85(m，1H)，3.77(s，3H)，3.08-3.19(m，2H)，2.57-2.68(m，2H)，1.51(s，2H)
LC/MS：C 10H 9NO 3：m/z 192(M+1)
M.P.＝240-241℃
C.2-(5-methoxyl group-indane-2-yl) isoindole-1, the 3-diketone
Flow process 3. is at the 60%NaH (8g that is cooled to 0 ℃; 0.240mol) DMF (250mL) suspension in add 5-methoxyl group-indane-2-base amine hydrochlorate (40.0g; 0.2mol), under the room temperature, suspension was stirred 1 hour.Under the room temperature, disposable adding Tetra hydro Phthalic anhydride (30g; 0.2mol), again this suspension was stirred 1-1.5 hour, stirred 96 hours down at 120 ℃ then.With the reactant cooling, dilute with ethyl acetate.Organic phase is washed with water,,, obtain 2-(5-methoxyl group-indane-2-yl) isoindole-1 of 25.2g (43%) white solid, the 3-diketone with ethyl acetate, methanol wash, vacuum-drying with the sedimentation and filtration that obtains.Organic phase is washed with water, and reduction vaporization grinds solid with methyl alcohol, filters, and drying obtains 2-(5-methoxyl group-indane-2-yl) isoindole-1 of other 19.7g (33%) white solid, 3-diketone.
1H NMR(300MHz，CD 3OD)：δ7.83-7.87(m，2H)，7.68-7.74(m，2H)，7.10-7.13(d，1H)，6.73-6.78(m，2H)，5.08-5.21(m，1H)，3.79(s，3H)，3.48-3.65(m，2H)，3.07-3.18(m，2H)
LC/MS：C 18H 15NO 3：m/z 294(M+1)
D.2-(5-hydroxyl-indane-2-yl) isoindole-1, the 3-diketone
Flow process 3. is to 2-(5-methoxyl group-indane-2-yl) isoindole-1 in the anhydrous methylene chloride (350mL) of being dissolved in that is cooled under-60 ℃, 3-diketone (19.7g; Be added dropwise to 1.0M boron tribromide-methylene dichloride (340mL) solution 67mmol), the control rate of addition is with warm between-50 to-60 ℃ in keeping.Reaction mixture is warmed to room temperature, restir 5 hours.Reactant is cooled to 0 ℃,, at room temperature stirred again 0.5 hour with saturated sodium bicarbonate (500mL) quencher.Filtering-depositing, the water thorough washing is suspended in the ether, filters, and vacuum-drying obtains 2-(5-hydroxyl-indane-2-yl) isoindole-1 of 14.8g (79%) beige solid, 3-diketone.
1H NMR(300MHz，DMSO-d 6)：δ9.16(s，1H)，7.82-7.91(m，4H)，6.98-7.01(d，1H)，6.56-6.62(m，2H)，4.91-5.03(m，1H)，3.27-3.43(m，3H)，2.99-3.10(m，2H)
LC/MS：C 17H 13NO 3：m/z 280(M+1)
F. dimethyl thiocarbamate O-[2-(1,3-dioxo-1,3-xylylenimine-2-yl) indane-5-yl] ester
2-(5-hydroxyl-indane-2-yl) isoindole-1 of flow process 3. in being dissolved in dry DMF (400mL), 3-diketone (31g; 0.11mol) in add 1 in turn, 4-diazabicyclo [2.2.2] octane (62g; 0.55mol) and dimethylamino thiocarbamyl chlorine (68g; 0.55mol), under the room temperature with this solution stirring 16 hours.Reactant is poured in the frozen water (1L), stirred 18 hours.Filtering-depositing washes with water, and vacuum-drying obtains dimethyl thiocarbamate O-[2-(1,3-dioxo-1, the 3-xylylenimine-2-yl) indane-5-yl of 41.6g (100%) beige solid] ester.
1H NMR(300MHz，CDCl 3)：δ7.82-7.87(m，2H)，7.69-7.75(m，2H)，7.17-7.24(d，1H)，6.87-6.93(m，2H)，5.13-5.25(m，1H)，3.53-3.68(m，2H)，3.46(s，3H)，3.34(s，3H)，3.09-3.23(m，2H)
G. dimethyl thiocarbamate S-[2-(1,3-dioxo-1,3-xylylenimine-2-yl) indane-5-yl] ester
Flow process 3. disposable adding dimethyl thiocarbamate O-[2-(1,3-dioxo-1,3-xylylenimine-2-yl) indane-5-yl in the flask at the bottom of in sand-bath, being preheated to 330 ℃ the 50mL garden that is equipped with reflux exchanger and stirring rod] ester (6.30g; 18.7mmol).Under 338 ℃, this melt was stirred 12 minutes, be quickly cooled to room temperature with nitrogen gas stream then, thick residue is through flash chromatography purifying (SiO 2), with hexane-ethyl acetate gradient elution, obtain dimethyl thiocarbamate S-[2-(1,3-dioxo-1, the 3-xylylenimine-2-yl) indane-5-yl of 3.88g (61%) pale solid] ester.
1H NMR(300MHz，CDCl 3)：δ7.81-7.87(m，2H)，7.69-7.74(m，2H)，7.22-7.36(m，3H)，5.10-5.22(m，1H)，3.59-3.67(m，2H)，3.06-3.23(m，9H)LC/MS：C 20H 18N 2O 3S：m/z 367(M+1)
H. dimethyl thiocarbamate S-(2-aminoidan-5-yl) ester
Flow process 3. adds ethanol (98mL) and dimethyl thiocarbamate S-[2-(1,3-dioxo-1,3-xylylenimine-2-yl) indane-5-yl in the 3-neck bottle that is equipped with reflux exchanger and mechanical stirrer] ester (6.9g; 20.6mmol).Room temperature property adding next time hydrazine (5.8mL; 186mmol), under the mechanical stirring reactant was refluxed 30 minutes.Reactant is cooled to room temperature, gelatinous white solid is filtered, for several times with the ether washing.The ether washings is merged, and reduction vaporization further grinds thick residue with ether, filters, and the reduction vaporization ether obtains dimethyl thiocarbamate S-(2-aminoidan-5-yl) ester of 4.6g (95%) brown oil.
1H NMR(300MHz，CDCl 3)：δ7.15-7.33(m，3H)，3.80-3.88(m，1H)，3.05-3.22(m，8H)，2.64-2.72(m，1H)，2.17(bs，2H)
LC/MS：C 12H 16N 2OS：m/z 237(M+1)
I.2-(2-aminoidan-5-base sulfane base)-2 Methylpropionic acid tertiary butyl ester
Under flow process 3. room temperatures, the dimethyl thiocarbamate S-in being dissolved in methyl alcohol (60mL) (2-aminoidan-5-yl) ester (4.9g; 20.9mmol) the middle KOH (11.8g that adds; 0.210mol) methyl alcohol (110mL) solution.Reflux down,, be cooled to room temperature this solution stirring 5 hours.In this solution, add 2-isobutyl bromide tertiary butyl ester (7.0g; 31.3mmol), stirred 18 hours under the room temperature.With solvent removed under reduced pressure, thick residue is distributed between water and ethyl acetate.With the water ethyl acetate extraction, with organic extracting solution water, the salt water washing that merges, through Na 2SO 4Drying is filtered, and reduction vaporization obtains 2-(2-aminoidan-5-base sulfane base)-2 Methylpropionic acid tertiary butyl ester of 4.9g (76%) brown oil.
LC/MS：C 17H 25NO 2S：m/z 308(M+1)
J.2-(2-acetamido-indane-5-base sulfane base)-2 Methylpropionic acid tertiary butyl ester
2-(2-aminoidan-5-base sulfane the base)-2 Methylpropionic acid tertiary butyl ester (14.6g of flow process 3. in being dissolved in methylene dichloride (100mL); 47.4mmol) the middle TEA (8.6mL that adds; 61.7mmol), reaction mixture is cooled to 0 ℃.To maintain the temperature at the speed between 0-5 ℃, dripping acetyl chloride (4.1mL; 57.6mmol).Reactant is warmed to room temperature, stirred 16 hours,, wash with water, through Na with the methylene dichloride dilution 2SO 4Drying, reduction vaporization.Crude product oily matter is through flash chromatography purifying (SiO 2), with hexane-ethyl acetate gradient elution, obtain 2-(2-acetamido-indane-5-base sulfane the base)-2 Methylpropionic acid tertiary butyl ester of 11.7g (71%) beige solid.
1H NMR(300MHz，CDCl 3)：δ7.31-7.35(m，2H)，7.15-7.18(d，1H)，5.73(m，1H)，4.68-4.78(m，1H)，3.25-3.39(dd，2H)，2.74-2.80(d，2H)，1.94(s，3H)，1.43(s，15H)
LC/MS：C 19H 27NO 3S：m/z 294(M+1)
K.2-(2-ethylamino indane-5-base sulfane base)-2 Methylpropionic acid tertiary butyl ester
Under flow process 3. room temperatures, to 2-(2-acetamido-indane-5-base sulfane base)-2 Methylpropionic acid tertiary butyl ester (11.7g; 33.5mmol) THF (280mL) solution in be added dropwise to 1.0M borine-THF (226mL).Under the room temperature, reactant was stirred 5 hours, be cooled to 0 ℃, with methyl alcohol (100mL) quencher, reduction vaporization.With residual oily matter and methanol azeotropic (3x), obtain 2-(2-ethylamino indane-5-base sulfane the base)-2 Methylpropionic acid tertiary butyl ester of 11g (100%) oily matter and the mixture of its borane complexes again.
LC/MS：C 19H 29NO 2S·BH 3：m/z 336((M+BH 3)+1)
L.2-{2-[1-ethyl-3-(4-Trifluoromethoxyphen-l) urea groups] indane-5-base sulfane base }-the 2 Methylpropionic acid tertiary butyl ester
Mixture (the 11.0g of the 2-of flow process 4. in being dissolved in methylene dichloride (100mL) (2-ethylamino indane-5-base sulfane base)-2 Methylpropionic acid tertiary butyl ester and its borane complexes; Add isocyanic acid 4-trifluoromethoxy phenyl ester (10.2g 33mmol); 50.2mmol), under the room temperature reactant was stirred 18 hours.Removal of solvent under reduced pressure, the crude product residue is through flash chromatography purifying (SiO 2), with hexane-ethyl acetate gradient elution, obtain 2-{2-[1-ethyl-3-(4-Trifluoromethoxyphen-l) urea groups of 11.2g (62%) white foam shape thing] indane-5-base sulfane base }-the 2 Methylpropionic acid tertiary butyl ester.
1H NMR(300MHz，CDCl 3)：δ7.30-7.36(m，4H)，7.10-7.19(m，3H)，6.31(s，1H)，4.97-5.08(m，1H)，3.22-3.39(m，4H)，3.01-3.09(dd，2H)，1.42-1.44(m，15H)，1.23-1.28(t，3H)
LC/MS：C 27H 33F 3N 2O 4S：m/z 483((M-C 4H 8)+1)
M.2-{2-[1-ethyl-3-(4-Trifluoromethoxyphen-l) urea groups] indane-5-base sulfane base }-2 Methylpropionic acid
2-{2-[1-ethyl-3-(4-Trifluoromethoxyphen-l) urea groups of flow process 4. in being dissolved in methylene dichloride (15mL)] indane-5-base sulfane base }-2 Methylpropionic acid tertiary butyl ester (4.8g; 8.91mmol) the middle TFA (15mL) that adds, under the room temperature reactant was stirred 2 hours.Removal of solvent under reduced pressure, residue is through flash chromatography purifying (SiO 2), with hexane-ethyl acetate gradient elution, obtain 2-{2-[1-ethyl-3-(4-Trifluoromethoxyphen-l) urea groups of 3.13g (73%) white solid] indane-5-base sulfane base }-2 Methylpropionic acid.
1H NMR(300MHz，CDCl 3)：δ7.29-7.35(m，4H)，7.15-7.17(d，1H)，7.08-7.11(d，2H)，6.45(s，1H)，4.94-5.04(m，1H)，3.18-3.36(m，4H)，2.98-3.07(m，2H)，1.48(s，6H)，1.19-1.28(t，3H)
LC/MS：C 23H 26F 3N 2O 4S：m/z483(M+1)
M.P.＝73-77℃
According to flow process 3 and 4 and the method for step J, K, L and the M of route 2, displacer reagent is also adjusted reaction conditions on demand, prepares following 14 compounds:
(S)-and 2-{2-[1-ethyl-3-(4-Trifluoromethoxyphen-l) urea groups] indane-5-base sulfane base }-2 Methylpropionic acid
Compound 2.1 (embodiment 3)
By chiral chromatography (Chiralpak AD post; With hexane/methanol/ethanol: 92/4/4 constant gradient wash-out) split the intermediate L (11g) of route 2, obtain (S)-intermediate L (4.8g).Adopt the step M of route 2, preparation compound 2.1 (3.1g).
LC/MS：C 23H 25F 3N 2O 4S：m/z 483(M+1)
2-{2-[1-ethyl-3-(4-trifluoromethylthio phenyl) urea groups] indane-5-base sulfane base }-2 Methylpropionic acid compound 2.2 (embodiment 4)
Figure A20038010656600431
According to the method for route 2, by replace isocyanic acid 4-Trifluoromethoxyphen-l ester, preparation compound 2.2 (0.33g with 4-trifluoromethyl thio-methoxy isocyanic ester; Two steps 57%; White solid).
1H NMR(CD 3OD)；δ1.16-1.20(t，3H)，1.38(s，6H)，3.09-3.23(m，4H)，3.37-3.44(q，2H)，4.95-5.06(m，1H)，7.14-7.17(m，1H)，7.32-7.35(m，1H)，7.40(s，1H)，7.55(s，4H)
LC/MS：C 23H 25F 3N 2O 3S 2：m/z 499(M+1)
2-methyl-2-{2-[1-amyl group-3-(4-trifluoromethylthio phenyl) urea groups] indane-5-base sulfane base } phenylpropionic acid compound 2.3 (embodiment 5)
According to the method for route 2 and compound 2.2, by using the valeryl chloride replacing acetyl chloride, preparation compound 2.3 (0.22g; Two steps 32%; White solid).
1H NMR(CD 3OD)；δ0.844-0.890(t，3H)，1.20-1.31(m，4H)，1.39(s，6H)，1.45-1.58(m，2H)，3.07-3.22(m，6H)，4.89-4.99(m，1H)，7.15-7.18(m，1H)，7.33-7.35(m，2H)，7.33-7.35(m，1H)，7.40(s，1H)，7.50-7.57(m，4H)
LC/MS：C 26H 31F 3N 2O 3S2：m/z 541(M+1)
2-{2-[1-ethyl-3-(4-isopropyl phenyl) urea groups] indane-5-base sulfane base }-2 Methylpropionic acid compound 2.4 (embodiment 6)
Figure A20038010656600441
According to the method for route 2, by replacing isocyanic acid 4-Trifluoromethoxyphen-l ester with isocyanic acid 4-isopropyl phenyl ester, preparation compound 2.4 (0.18g; Two steps 34%; White solid).
1H NMR(CD 3OD)；δ1.16-1.23(m，9H)，1.38(s，6H)，2.82-2.87(m，1H)，3.10-3.21(m，4H)，3.37-3.39(m，2H)，4.99-5.04(m，1H)，7.14-7.17(m，3H)，7.23-7.26(m，2H)，7.32-7.50(m，2H)，7.40(s，1H)
LC/MS：C 25H 32N 2O 3S；m/z 441(M+1)
2-{2-[3-(4-dimethylamino phenyl)-1-ethyl urea groups] indane-5-base sulfane base }-2 Methylpropionic acid compound 2.5 (embodiment 7)
Figure A20038010656600442
According to the method for route 2, by replacing isocyanic acid 4-Trifluoromethoxyphen-l ester with isocyanic acid 4-dimethylamino phenyl ester, preparation compound 2.5 (0.34g; Two steps 66%; White solid).
1H NMR(CD 3OD)；δ1.15-1.20(t，3H)，1.42(s，6H)，2.88(s，1H)，3.05-3.69(m，4H)，3.31-3.69(m，2H)，4.94-5.06(m，1H)，6.78-6.81(m，2H)，7.16-7.21(m，3H)，7.29-7.41(m，2H)
LC/MS：C 24H 31N 3O 3S：m/z 442(M+1)
2-methyl-2-{2-[1-amyl group-3-(4-Trifluoromethoxyphen-l) urea groups] indane-5-base sulfane base }-2 Methylpropionic acid
Compound 2.6 (embodiment 8)
According to the method for route 2, by using the valeryl chloride replacing acetyl chloride, preparation compound 2.6 (0.29g; Two steps 77%; White solid).
1H NMR(CD 3OD)；δ0.847-0.893(t，3H)，1.20-1.29(m，4H)，1.39(s，6H)，1.58-1.60(m，2H)，3.04-3.29(m，6H)，4.89-4.99(m，1H)，7.14-7.17(m，3H)，7.32-7.34(m，1H)，7.40-7.45(m，3H)
LC/MS：C 26H 31F 3NaO 4S：m/z 525(M+1)
2-{2-[3-(4-dimethylamino phenyl)-1-amyl group urea groups] indane-5-base sulfane base }-2 Methylpropionic acid compound 2.7 (embodiment 9)
According to the method for route 2 and compound 2.5, by using the valeryl chloride replacing acetyl chloride, preparation compound 2.7 (0.25g; Two steps 36%; White solid).
1H NMR(CD 3OD)；δ0.869-0.915(t，3H)，1.17-1.31(m，4H)，1.44(s，6H)，1.57-1.65(m，2H)，2.91(s，6H)，3.12-3.29(m，6H)，4.94-5.02(m，1H)，6.80-6.83(d，2H)，7.17-7.23(m，3H)，7.32-7.38(m，2H)
LC/MS：C 27H 37N 3O 3S：m/z 484(M+1)
2-{2-[3-(4-isopropyl phenyl)-1-(3-amyl group) urea groups] indane-5-base sulfane base }-2 Methylpropionic acid compound 2.8 (embodiment 10)
Figure A20038010656600461
According to the method for route 2 and compound 2.4, by using the valeryl chloride replacing acetyl chloride, preparation compound 2.8 (5mg; Two steps 14%; White solid).
LC/MS：C 28H 38N 2O 3S：m/z 483(M+1)
2-{2-[3-(4-tert-butyl-phenyl)-1-(3-amyl group) urea groups] indane-5-base sulfane base }-2 Methylpropionic acid compound 2.9 (embodiment 11)
Figure A20038010656600462
According to the method for route 2 and compound 2.3, by replacing isocyanic acid 4-trifluorothio phenylester with isocyanic acid 4-tert-butyl-phenyl ester, preparation compound 2.9 (4mg; Two steps 9%; White solid).
LC/MS：C 29H 40N 2O 3S：m/z 497(M+1)
2-[2-(3-(biphenyl-4-yl)-1-amyl group urea groups) indane-5-base sulfane base]-2 Methylpropionic acid compound 2.10 (embodiment 12)
According to the method for route 2 and compound 2.3, by replace isocyanic acid 4-trifluorothio phenylester, preparation compound 2.10 (3mg with isocyanic acid 4-biphenyl ester; Two steps 7%; White solid).
LC/MS：C 31H 36N 2O 3S：m/z 517(M+1)
2-{2-[3-(4-isopropyl phenyl)-1-(3-hexyl) urea groups] indane-5-base sulfane base }-2 Methylpropionic acid compound 2.11 (embodiment 13)
Figure A20038010656600472
According to the method for route 2 and compound 2.4, by replacing valeryl chloride with caproyl chloride, preparation compound 2.11 (13mg; Two steps 44%; Oily matter).
LC/MS：C 29H 40N 2O 3S：m/z 497(M+1)
2-methyl-2-{2-[1-hexyl-3-(4-Trifluoromethoxyphen-l) urea groups] indane-5-base sulfane base } phenylpropionic acid compound 2.12 (embodiment 14)
Figure A20038010656600481
According to the method for route 2, by replacing valeryl chloride with caproyl chloride, preparation compound 2.12 (18mg; Two steps 54%; White solid).
LC/MS：C 27H 33F 3N 2O 4S：m/z 539(M+1)
2-methyl-2-{2-[1-hexyl-3-(4-trifluoromethylthio phenyl) urea groups] indane-5-base sulfane base } phenylpropionic acid compound 2.13 (embodiment 15)
Figure A20038010656600482
According to the method for route 2 and compound 2.2, by replacing valeryl chloride with caproyl chloride, preparation compound 2.13 (14mg; Two steps 36%; White solid).
LC/MS：C 27H 33F 3N 2O 3S 2：m/z 555(M+1)
2-methyl-2-{2-[1-propyl group-3-(4-Trifluoromethoxyphen-l) urea groups] indane-5-base sulfane base } phenylpropionic acid compound 2.14 (embodiment 16)
Figure A20038010656600483
According to the method for route 2, by using the propionyl chloride replacing acetyl chloride, preparation compound 2.14 (1.2mg; Two steps 3%; Oily matter).
LC/MS：C 24H 27F 3N 2O 4S：m/z 497(M+1)
2-methyl-2-{2-[1-butyl-3-(4-trifluoromethylthio phenyl) urea groups] indane-5-base sulfane base } phenylpropionic acid compound 2.15 (embodiment 17)
According to the method for route 2 and compound 2.2, by using the butyryl chloride replacing acetyl chloride, preparation compound 2.15 (11mg; Two steps 32%; Oily matter).
LC/MS：C 25H 29F 3N 2O 3S 2：m/z 527(M+1)
2-methyl-2-{2-[3-(4-Trifluoromethoxyphen-l) urea groups] indane-5-base sulfane base } phenylpropionic acid compound 2.16 (embodiment 18)
According to the method for route 2,, prepare compound 2.16 (11mg by with isocyanic acid 4-Trifluoromethoxyphen-l ester acylations; Two steps 49%; Oily matter).
LC/MS：C 21H 21F 3N 2O 4S：m/z 455(M+1)
Route 3
2-methyl-2-{2-[1-penta-4-thiazolinyl-3-(4-Trifluoromethoxyphen-l) urea groups] indane-5-base sulfane base } propionic acid
Compound 3.0 (embodiment 19)
2-in being dissolved in DCE (4mL) (2-aminoidan-5-base sulfane base)-2 Methylpropionic acid tertiary butyl ester (0.220g; 0.72mmol) middle penta-4-olefine aldehydr (0.060mg that adds; 0.72mmol), then add triacetoxy borohydride sodium cyanide (0.21g; 1.0mmol), under the room temperature, reaction mixture was stirred 18 hours.Reaction mixture is diluted with methylene dichloride, and water, salt water washing are through Na 2SO 4Drying is filtered, and solvent evaporated under reduced pressure obtains 2-methyl-2-(2-penta-4-alkenyl amino indane-5-base sulfane base) propionic acid tertiary butyl ester of crude product oily matter.
According to the method for route 2 and step L and M,, prepare compound 3.0 (0.149mg by with isocyanic acid 4-Trifluoromethoxyphen-l ester acylations; 3 steps 40%; White solid).
LC/MS：C 26H 29F 3N 2O 4S：m/z 522(M+1)
According to the step L of flow process 3 and 4, route 3, route 2 and the method for M, displacer reagent is also adjusted reaction conditions on demand, prepares following 2 compounds:
2-methyl-2-{2-[1-(3-methyl butyl)-3-(4-Trifluoromethoxyphen-l) urea groups] indane-5-base sulfane base }-2 Methylpropionic acid
Compound 3.1 (embodiment 20)
According to the method for route 3, replace penta-4-olefine aldehydr with isobutyric aldehyde, and, prepare compound 3.1 (13mg with isocyanic acid 4-Trifluoromethoxyphen-l ester acylations; 3 steps 29%; White solid).
LC/MS：C 26H 31F 3N 2O 4S：m/z 525(M+1)
2-{2-[3-(4-isopropyl phenyl)-1-(3-methyl butyl) urea groups] indane-5-base sulfane base }-2 Methylpropionic acid
Compound 3.2 (embodiment 21)
Figure A20038010656600511
According to the method for route 3 and compound 3.1, replace isocyanic acid 4-Trifluoromethoxyphen-l ester with isocyanic acid 4-isopropyl phenyl ester, preparation compound 3.2 (11mg; 3 steps 27%; White solid).
1H NMR(CD 3OD)：δ0.877-0.895(dd，6H)，1.19-1.22(dd，6H)，1.42-1.53(m，9H)，2.80-2.89(m，1H)，2.99-3.08(m，2H)，3.17-3.48(m，4H)，4.98-5.03(m，1H)，6.26(s，1H)，7.10-7.22(m，5H)，7.32-7.35(m，2H)
LC/MS：C 28H 38N 2O 3S；m/z 483(M+1)
According to flow process 1 and 3 and the step J of route 1 and the method for K, displacer reagent is also adjusted reaction conditions on demand, prepares following 3 compounds:
2-{6-[1-butyl-3-(4-Trifluoromethoxyphen-l) urea groups]-5,6,7,8-tetraline-2-base sulfane base }-2 Methylpropionic acid
Compound 1.1 (embodiment 22)
Figure A20038010656600512
According to the method for route 1, use the butyryl chloride replacing acetyl chloride, preparation compound 1.1 (41mg; Two steps 68%; White solid).
LC/MS：C 26H 31F 3N 2O 4S：m/z 525(M+1)
2-{6-[1-butyl-3-(4-trifluoromethylthio phenyl) urea groups]-5,6,7,8-tetraline-2-base sulfane base }-2 Methylpropionic acid
Compound 1.2 (embodiment 23)
According to the method for route 1 and compound 1.1, use the butyryl chloride replacing acetyl chloride, and replace isocyanic acid 4-Trifluoromethoxyphen-l ester, preparation compound 1.2 (23mg with isocyanic acid 4-trifluorothio phenylester; Two steps 34%; White solid).
LC/MS：C 26H 31F 3N 2O 3S 2：m/z 541(M+1)
2-{6-[1-hexyl-3-(4-Trifluoromethoxyphen-l) urea groups]-5,6,7,8-tetraline-2-base sulfane base }-2 Methylpropionic acid
Compound 1.3 (embodiment 24)
Figure A20038010656600522
According to the method for route 1, use the caproyl chloride replacing acetyl chloride, preparation compound 1.3 (36mg; Two steps 57%; White solid).
LC/MS：C 28H 35F 3N 2O 4S：m/z 553(M+1)
According to flow process 3 and 4 and the step L of route 2 and the method for M, displacer reagent is also adjusted reaction conditions on demand, prepares following 2 compounds:
2-{2-[3-(3-bromo-4-Trifluoromethoxyphen-l)-1-ethyl urea groups] indane-5-base sulfane base }-2 Methylpropionic acid
Compound 2.17 (embodiment 25)
Figure A20038010656600531
According to the method for route 2, replace isocyanic acid 4-Trifluoromethoxyphen-l ester, preparation compound 2.17 (0.018g with isocyanic acid 3-bromo-4-Trifluoromethoxyphen-l ester; 3 steps 19%; White solid).3-bromo-4-trifluoro-methoxyaniline (0.214g in THF (1mL); 0.836mmol) in add two dimethyl dicarbonate butyl ester (0.255g in turn; 1.17mmol) and 4-Dimethylamino pyridine (0.102g; 0.835mmol).Effervesce stops back (30 minutes), adds 2-(2-ethylamino indane-5-base sulfane base)-2 Methylpropionic acid tertiary butyl ester (0.058g; 0.167mmol) THF (1mL) solution, under the room temperature reaction mixture was stirred 18 hours.Adopt the step K and the L of route 2, the preparation title compound.
LC/MS：C 23H 24BrF 3N 2O 4S：m/z 563(M+1)
2-{2-[1-ethyl-3-(3-Trifluoromethoxyphen-l) urea groups] indane-5-base sulfane base }-2 Methylpropionic acid compound 2.18 (embodiment 26)
Figure A20038010656600532
According to the method for embodiment 2.0, replace isocyanic acid 4-Trifluoromethoxyphen-l ester with isocyanic acid 3-Trifluoromethoxyphen-l ester, preparation compound 2.18 (13mg; 3 steps 12%; White solid).Carbonyl dimidazoles (0.454g in being heated to 50 ℃ THF (2mL); 2.8mmol) be added dropwise to 3-trifluoro-methoxyaniline (0.522g in the solution; 2.94mmol).After 15 minutes, with reaction solution cooling and join 2-(2-ethylamino indane-5-base sulfane base)-2 Methylpropionic acid tertiary butyl ester (0.077g; 0.22mmol) THF (1mL) solution in.
LC/MS：C 23H 25F 3N 2O 4S：m/z 483(M+1)
2-{2-[3-(4-dimethylamino phenyl)-1-methyl urea groups] indane-5-base sulfane base }-2 Methylpropionic acid compound 2.19 (embodiment 27)
Figure A20038010656600541
A. dimethyl thiocarbamate S-(2-formyl radical aminoidan-5-yl) ester
The dimethyl thiocarbamate S-[2-aminoidan-5-yl of flow process 6. in chloroform (10mL)] ester (2.0g; 8.46mmol) the middle ethyl formate (50mL) that adds.With reactant be heated to 55 ℃ following 24 hours.With the reactant cooling, removal of solvent under reduced pressure, crude product oily matter is through flash chromatography purifying (SiO 2), with ethyl acetate-methyl alcohol gradient elution, obtain dimethyl thiocarbamate S-(the 2-formyl radical aminoidan-5-yl) ester of 0.77g (35%) white solid.
LC/MS：C 13H 16N 2O 2：m/z 264(M+1)
B.2-methyl-2-(2-methylamino-indane-5-base sulfane base)-propionic acid tertiary butyl ester
Flow process 6. under 0 ℃, nitrogen, the dimethyl thiocarbamate S-in THF (9mL) (2-formyl radical aminoidan-5-yl) ester (0.772g; 2.9mmol) the middle 1.0M lithium aluminum hydride (9mL) that adds.Reactant is warmed to room temperature, under refluxing, stirred 24 hours then.Reactant is cooled to 0 ℃, water quencher, removal of solvent under reduced pressure.Residue is dissolved in the methyl alcohol (4mL), to wherein adding Cs 2CO 3(0.304g; 0.93mmol), 2-isobutyl bromide tertiary butyl ester (0.311mL; 1.39mmol) and NaBH 4(2.0g; 52.8mmol).Reactant was stirred 18 hours, and removal of solvent under reduced pressure is distributed residue between ethyl acetate and water.Separate each layer,, merge organic extracting solution, use the salt water washing, through Na with the water ethyl acetate extraction 2SO 4Drying is filtered reduction vaporization.The crude product residue is through flash chromatography purifying (SiO 2), use the methylene chloride-methanol gradient elution, obtain 2-methyl-2-(2-methylamino-indane-5-base sulfane base) propionic acid tertiary butyl ester of 0.186g (20%) oily matter.
LC/MS：C 18H 27NO 2S：m/z 321(M+1)
According to the method for route 2 and step L and M, replace isocyanic acid 4-Trifluoromethoxyphen-l ester with isocyanic acid 4-dimethylamino phenyl ester, preparation compound 2.19 (44mg; Two steps 65%; White solid).
LC/MS：C 23H 29N 3O 3S：m/z 428(M+1)
2-{2-[1-(3-cyclopentyl propyl group)-3-(4-Trifluoromethoxyphen-l) urea groups] indane-5-base sulfane base }-2 Methylpropionic acid
Compound 2.20 (embodiment 28)
Figure A20038010656600551
According to the method for route 2, with 3-cyclopentyl propionyl chloride replacing acetyl chloride, preparation compound 2.20 (39mg; Two steps 49%; White solid).
LC/MS:C 29H 35F 3N 2O 4S:m/z 565 (M 10)
2-[2-(3-indane-5-base-1-amyl group urea groups) indane-5-base sulfane base }-2 Methylpropionic acid compound 2.21 (embodiment 29)
According to the method for route 2 and compound 2.3, use the valeryl chloride replacing acetyl chloride, and replace isocyanic acid 4-Trifluoromethoxyphen-l ester, preparation compound 2.21 (9.3mg with isocyanic acid indanyl ester; Two steps 24%; White solid).
LC/MS：C 28H 36N 2O 3S：m/z 481(M+1)
2-methyl-2-{2-[3-(4-methyl-3-nitro phenyl)-1-amyl group urea groups] indane-5-base sulfane base } propionic acid
Compound 2.22 (embodiment 30)
Figure A20038010656600561
According to the method for route 2 and compound 2.3, replace isocyanic acid 4-Trifluoromethoxyphen-l ester with isocyanic acid 4-methyl-3-nitro phenylester, preparation compound 2.22 (5.0mg; Two steps 12%; White solid).
LC/MS：C 26H 33N 3O 5S：m/z 500(M+1)
2-methyl-2-{2-[1-naphthalene-1-ylmethyl-3-(4-Trifluoromethoxyphen-l) urea groups] indane-5-base sulfane base } propionic acid
Compound 3.4 (embodiment 31)
According to the method for route 3, replace penta-4-olefine aldehydr with the 1-naphthaldehyde, preparation compound 3.4 (2.9mg; Two steps 4%; White solid).
LC/MS：C 32H 29F 3N 2O 4S：m/z 595(M+1)
2-{2-[3-(4-p-methoxy-phenyl)-1-propyl group urea groups] indane-5-base sulfane base }-2 Methylpropionic acid compound 2.23 (embodiment 32)
Figure A20038010656600571
According to the method for route 2 and compound 2.14, replace isocyanic acid 4-Trifluoromethoxyphen-l ester with isocyanic acid 4-p-methoxy-phenyl ester, preparation compound 2.23 (21mg; Two steps 64%; White solid).
LC/MS：C 24H 27F 3N 2O 4S：m/z 443(M+1)
2-{2-[3-(3, the 5-3,5-dimethylphenyl)-1-propyl group urea groups] indane-5-base sulfane base }-2 Methylpropionic acid compound 2.24 (embodiment 33)
According to the method for route 2 and compound 2.14, with isocyanic acid 3,5-3,5-dimethylphenyl ester replaces isocyanic acid 4-Trifluoromethoxyphen-l ester, preparation compound 2.24 (19mg; Two steps 57%; White solid).
LC/MS：C 25H 32N 2O 3S：m/z 441(M+1)
2-{2-[1-(2-methoxy ethyl)-3-(4-trifluoromethylthio phenyl) urea groups] indane-5-base sulfane base }-2 Methylpropionic acid
Compound 2.25 (embodiment 34)
According to the method for route 2 and compound 2.2, use the methoxyacetyl chloride replacing acetyl chloride, preparation compound 2.25 (7.0mg; Two steps 16%; Oily matter).
LC/MS：C 24H 27F 3N 2O 4S 2：m/z 529(M+1)
2-methyl-2-{2-[1-propyl group-3-(4-trifluoromethyl) urea groups] indane-5-base sulfane base } phenylpropionic acid compound 2.26 (embodiment 35)
According to the method for route 2 and compound 2.14, replace isocyanic acid 4-Trifluoromethoxyphen-l ester with isocyanic acid 4-trifluoromethyl ester, preparation compound 2.26 (20mg; Two steps 56%; White solid).
LC/MS：C 24H 27F 3N 2O 3S 2：m/z 481(M+1)
2-methyl-2-{2-[1-(4,4,4-trifluoro butyl)-3-(4-Trifluoromethoxyphen-l) urea groups] indane-5-base sulfane base } propionic acid
Compound 2.27 (embodiment 36)
Figure A20038010656600582
According to the method for route 2 and compound 2.0, with trifluoromethyl butyryl chloride replacing acetyl chloride, preparation compound 2.27 (10mg; Two steps 26%; Oily matter).
LC/MS：C 25H 26F 6N 2O 4S：m/z 564(M+1)
2-{2-[1-(3-cyclopentyl propyl group)-3-phenyl urea groups] indane-5-base sulfane base }-2 Methylpropionic acid
Compound 2.28 (embodiment 37)
Figure A20038010656600591
According to the method for route 2 and compound 2.0,, and, prepare compound 2.28 (38mg with isocyanic acid phenylester replacement isocyanic acid 4-Trifluoromethoxyphen-l ester by usefulness cyclopentyl propionyl chloride replacing acetyl chloride; Two steps 56%; Oily matter).
LC/MS：C 28H 36N 2O 3S：m/z 481(M+1)
6-[1-[5-(1-carboxyl-1-methylethyl sulfane base) indane-2-yl]-3-(4-isopropyl phenyl) urea groups] methyl caproate
Compound 2.29 (embodiment 38)
Figure A20038010656600592
According to the method for route 2 and compound 2.4, with the chloroformyl methyl propionate replacing acetyl chloride of 5-, preparation compound 2.29 (12mg; Two steps 38%; White solid).
LC/MS：C 30H 40N 2O 5S：m/z 541(M+1)
2-methyl-2-[2-(3-naphthalene-2-base-1-amyl group urea groups) indane-5-base sulfane base] phenylpropionic acid compound 2.30 (embodiment 39)
Figure A20038010656600601
According to the method for route 2 and compound 2.3, by replacing isocyanic acid 4-Trifluoromethoxyphen-l ester with isocyanic acid 2-naphthyl ester, preparation compound 2.30 (15mg; Two steps 39%; White solid).
LC/MS：C 29H 34N 2O 3S：m/z 491(M+1)
2-{2-[1-cyclohexyl methyl-3-(4-Trifluoromethoxyphen-l) urea groups] indane-5-base sulfane base }-2 Methylpropionic acid
Compound 2.31 (embodiment 40)
Figure A20038010656600602
According to the method for route 2 and compound 2.0, with cyclohexyl Acetyl Chloride 98Min. replacing acetyl chloride, preparation compound 2.31 (15mg; Two steps 25%; White solid).
LC/MS：C 28H 33F 3N 2O 4S：m/z 551(M+1)
2-{2-[1-isobutyl--3-(4-Trifluoromethoxyphen-l) urea groups] indane-5-base sulfane base }-2 Methylpropionic acid
Compound 3.5 (embodiment 41)
Figure A20038010656600611
According to the method for route 3 and compound 3.0, by replacing penta-5-olefine aldehydr with 2 methyl propanal, preparation compound 3.5 (10mg; Two steps 12%; Oily matter).
LC/MS：C 25H 29F 3N 2O 4S：m/z 511(M+1)
2-{2-[3-(3, the 4-dichlorophenyl)-1-heptyl urea groups] indane-5-base sulfane base }-2 Methylpropionic acid compound 2.32 (embodiment 42)
According to the method for route 2 and compound 2.0, by using the oenanthyl chloro replacing acetyl chloride, and with isocyanic acid 3,4-dichlorophenyl ester replaces isocyanic acid 4-Trifluoromethoxyphen-l ester, preparation compound 2.32 (6.7mg; Two steps 12%; Oily matter).
LC/MS：C 27H 34C l2N 2O 3S：m/z 538(M+1)
2-{2-[1-(2-dimethylaminoethyl)-3-(4-trifluoromethylthio phenyl) urea groups] indane-5-base sulfane base }-2 Methylpropionic acid
Compound 2.33 (embodiment 43)
According to the method for route 2 and compound 2.2,, and, prepare compound 2.33 (1.9mg with isocyanic acid 4-trifluoromethylthio phenylester replacement isocyanic acid 4-Trifluoromethoxyphen-l ester by usefulness dimethylamino Acetyl Chloride 98Min. replacing acetyl chloride; Two steps 4%; Oily matter).
LC/MS：C 25H 30F 3N 3O 3S 2：m/z 542(M+1)
2-{2-[3-(3-chloro-phenyl-)-1-heptyl urea groups] indane-5-base sulfane base }-2 Methylpropionic acid
Compound 2.34 (embodiment 44)
Figure A20038010656600622
According to the method for route 2 and compound 2.32, by replacing isocyanic acid 4-Trifluoromethoxyphen-l ester with isocyanic acid 3-chloro-phenyl-ester, preparation compound 2.34 (7.4mg; Two steps 14%; White solid).
LC/MS：C 27H 35ClN 2O 3S：m/z 542(M+1)
1-{2-[1-heptyl-3-(4-Trifluoromethoxyphen-l) urea groups] indane-5-base sulfane base } cyclobutylmethyl acid compound 2.35 (embodiment 45)
Figure A20038010656600631
According to the method for route 2 and compound 2.32, by replacing 2-isobutyl bromide tertiary butyl ester with 1-bromine cyclobutyl ethyl formate, preparation compound 2.35 (1.0mg; Two steps 1.3%; White solid).
LC/MS：C 29H 35F 3N 2O 4S：m/z 565(M+1)
2-methyl-2-{7-[1-propyl group-3-(4-Trifluoromethoxyphen-l) urea groups]-5,6,7,8-tetraline-2-base sulfane base } propionic acid
Compound 1.4 (embodiment 46)
According to the method for route 1 and compound 1.0, by using the propionyl chloride replacing acetyl chloride, preparation compound 1.4 (53mg; Two steps 25%; Oily matter).
LC/MS：C 25H 29F 3N 2O 4S：m/z 511(M+1)
According to flow process 10 and 4 and step I, the J of route 1 and the method for K, displacer reagent is also adjusted reaction conditions on demand, can prepare following 2 compounds:
2-{6-[1-ethyl-3-(4-Trifluoromethoxyphen-l) urea groups]-3-methoxyl group-5,6,7,8-tetraline-2-base sulfane base }-2 Methylpropionic acid
Compound 1.5 (embodiment 47)
According to the method for route 1 step I, J and K and flow process 4 and 10, preparation compound 1.5 (9.8mg; Oily matter).
1H NMR(300MHz，CD 3OD)：δ7.45-7.48(d，2H)，7.15-7.18(m，3H)，6.71(s，1H)，4.43-4.79(m，1H)，3.75(s，3H)，3.43-3.45(m，2H)，2.88-3.08(m，4H)，1.99-2.03(m，2H)，1.38(s，6H)，1.25-1.52(t，3H)
LC/MS：C 25H 29F 3N 2O 5S：m/z 527(M+1)
Route 4
2-{6-[1-ethyl-3-(4-Trifluoromethoxyphen-l) urea groups]-5,6,7,8-tetraline-2-base oxygen base }-2 Methylpropionic acid compound 4.0 (embodiment 48)
A.N-(6-methoxyl group-1,2,3,4-tetralin-2-yl) ethanamide
Flow process 7. is to the 6-methoxyl group-1,2,3,4-tetralin that stirs-2-base amine (2.54g; 14.3mmol) methylene dichloride (20mL) suspension in add DIEA (3.4mL), reaction mixture is cooled to 0 ℃.Under 0 ℃, be added dropwise to Acetyl Chloride 98Min. (1.22mL; 17.1mmol), reactant is warmed to room temperature, stirred 18 hours.Reaction mixture is diluted with methylene dichloride, wash with water, through Na 2SO 4Drying is filtered, and removal of solvent under reduced pressure obtains the crude product solid.Through flash chromatography purifying (SiO 2), with hexane-eluent ethyl acetate, obtain N-(6-methoxyl group-1,2,3,4-tetralin-2-yl) ethanamide of 1.57g (50%) white solid.
LC/MS：C 13H 17NO 2：m/z 220(M+1)
B.N-(6-hydroxyl-1,2,3,4-four oxidations naphthalene-2-yl) ethanamide
Flow process 7. is to N-(6-methoxyl group-1,2,3,4-tetralin-2-yl) ethanamide (1.57g that is cooled to-60 ℃; 7.2mmol) methylene dichloride (70mL) suspension in be added dropwise to boron tribromide-methylene dichloride (36mL) solution, keep temperature of reaction therebetween between-50 to-60 ℃.This gel suspension is warmed to room temperature, stirred 30 minutes.Reactant is cooled to 0 ℃, uses the saturated sodium bicarbonate quencher, stirred 30 minutes under the room temperature.With mixture dichloromethane extraction (2x), united extraction liquid is through Na 2SO 4Drying is filtered, and reduction vaporization obtains the crude product solid, through flash chromatography purifying (SiO 2), use the methylene chloride-methanol gradient elution, obtain N-(6-hydroxyl-1,2,3,4-tetralin-2-yl) ethanamide of 1.13g (76%) beige solid.
LC/MS：C 12H 15NO 2：m/z 206(M+1)
C.2-(6-acetylaminohydroxyphenylarsonic acid 5,6,7,8-tetraline-2-base oxygen base)-2 Methylpropionic acid tertiary butyl ester
Flow process 7. is to N-(6-hydroxyl-1,2,3,4-tetralin-2-yl) ethanamide (0.439g; 2.1mmol) DMF (6mL) suspension in add Cs 2CO 3(1.7g; 5.2mmol) and 2-isobutyl bromide tertiary butyl ester (2.1mL; 9.4mmol), under 100 ℃, reaction mixture was stirred 18 hours.Reactant is cooled to room temperature, and with the ethyl acetate dilution, water and salt water washing are through Na 2SO 4Drying is filtered, and removal of solvent under reduced pressure obtains crude product oily matter, through flash chromatography purifying (SiO 2), with hexane-ethyl acetate gradient elution, obtain 2-(6-acetylaminohydroxyphenylarsonic acid 5,6,7,8-tetraline-2-base oxygen the base)-2 Methylpropionic acid tertiary butyl ester of 0.51g (69%) oily matter.
1H NMR(300MHz，CDCl 3)：δ6.89-6.92(d，1H)，6.58-6.65(m，2H)，5.85-5.88(m，1H)，4.24-4.30(m，1H)，2.99-3.06(dd，1H)，2.76-2.86(m，2H)，2.51-2.59(dd，1H)，2.04(s，2H)，1.98-2.02(m，1H)，1.74-1.79(m，1H)，1.54(s，6H)，1.46(s，9H)
LC/MS：C 20H 29NO 4：m/z 292(M+1)
According to flow process 3 and 4 and step I, the J of route 1 and the method for K, displacer reagent is also adjusted reaction conditions on demand, the preparation following compounds:
According to the method for route 1 and compound 1.0, preparation compound 4.0 (0.0168g; Two steps 23%; Oily matter).
LC/MS：C 24H 27F 3N 2O 5：m/z 481(M+1)
2-{6-[3-(4-tert-butyl-phenyl)-1-ethyl urea groups]-3-methoxyl group-5,6,7,8-tetraline-2-base sulfane base }-2 Methylpropionic acid
Compound 1.6 (embodiment 49)
Figure A20038010656600661
Adopt step I, the J of route 1 and the method for K and flow process 4 and 10, by replacing isocyanic acid 4-Trifluoromethoxyphen-l ester with isocyanic acid 4-tert-butyl-phenyl ester, preparation compound 1.6 (10mg; Oily matter).
LC/MS：C 28H 38N 2O 4S：m/z 499(M+1)
2-{6-[1-ethyl-3-(4-Trifluoromethoxyphen-l) urea groups]-3-fluoro-5,6,7,8-tetraline-2-base sulfane base }-2 Methylpropionic acid
Compound 1.7 (embodiment 50)
Adopt step I, the J of route 1 and the method for K and flow process 4 and 10, preparation compound 1.7 (16mg; Two steps 30%; White solid).
1H NMR(300MHz，CDCl 3)：δ7.46-7.51(m，2H)，7.25-7.28(d，1H)，7.17-7.20(d，2H)，6.92-6.95(d，1H)，4.43(m，1H)，3.42-3.49(m，2H)，2.90-3.11(m，4H)，2.02-2.07(m，2H)，1.45(s，6H)，125-1.31(t，3H)
LC/MS：C 25H 29F 3N 2O 5S：m/z 515(M+1)
2-{6-[1-ethyl-3-(4-Trifluoromethoxyphen-l) urea groups]-3-chloro-5,6,7,8-tetraline-2-base sulfane base }-2 Methylpropionic acid
Compound 1.8 (embodiment 51)
Adopt step I, the J of route 1 and the method for K and flow process 4 and 10, preparation compound 1.8 (15mg; Two steps 22%; White solid).
LC/MS：C 25H 29F 3N 2O 5S：m/z 532(M+1)
2-{6-[1-ethyl-3-(4-Trifluoromethoxyphen-l) urea groups]-3-bromo-5,6,7,8-tetraline-2-base sulfane base }-2 Methylpropionic acid
Compound 1.9 (embodiment 52)
Adopt step I, the J of route 1 and the method for K and flow process 4 and 10, can prepare compound 1.9 (55mg; Two steps 43%; White solid).
1H NMR(300MHz，CDCl 3)：δ7.45-7.48(m，3H)，7.36(s，1H)，7.15-7.18(d，2H)，4.41-4.79(m，1H)，3.40-3.47(m，2H)，2.90-3.07(m，4H)，2.01-2.03(m，2H)，1.45(s，6H)，1.24-1.29(t，3H)
LC/MS：C 25H 29F 3N 2O 5S：m/z 576(M+1)
2-{6-[1-ethyl-3-(4-Trifluoromethoxyphen-l) urea groups]-3-methyl-5,6,7,8-tetraline-2-base sulfane base }-2 Methylpropionic acid
Compound 1.10 (embodiment 53)
Figure A20038010656600672
Adopt step I, the J of route 1 and the method for K and flow process 4 and 10, can prepare compound 1.10 (73mg; Two steps 26%; White solid).
1H NMR(300MHz，CDCl 3)：δ7.45-7.48(m，2H)，7.22(s，1H)，7.15-7.18(d，2H)，7.02(s，1H)，4.41-4.79(m，1H)，3.40-3.47(m，2H)，2.85-3.03(m，4H)，2.39(s，3H)，2.01-2.03(m，2H)，1.41(s，6H)，1.24-1，29(t，3H)
LC/MS：C 25H 29F 3N 2O 5S：m/z 511(M+1)
2-{6-[1-ethyl-3-(4-Trifluoromethoxyphen-l) urea groups]-3-trifluoromethoxy-5,6,7,8-tetraline-2-base sulfane base }-2 Methylpropionic acid
Compound 1.11 (embodiment 54)
Figure A20038010656600681
Adopt step I, the J of route 1 and the method for K and flow process 4 and 10, can prepare compound 1.11 (118mg; Two steps 58%; White solid).
1H NMR(300MHz，CDCl 3)：δ7.45-7.48(d，2H)，7.37(s，1H)，7.12-7.18(m，3H)，4.44(m，1H)，3.43-3.48(m，2H)，2.97-3.21(m，4H)，2.03-2.05(m，2H)，1.42(s，6H)，1.25-1.30(t，3H)
LC/MS：C 25H 29F 3N 2O 5S：m/z 580(M+1)
2-{6-[1-ethyl-3-(4-Trifluoromethoxyphen-l) urea groups]-3-phenyl-5,6,7,8-tetraline-2-base sulfane base }-2 Methylpropionic acid
Compound 1.12 (embodiment 55)
Figure A20038010656600682
Adopt step I, the J of route 1 and the method for K and flow process 4 and 10, can prepare compound 1.12 (118mg; Two steps 58%; White solid).
1H NMR(300MHz，CDCl 3)：δ7.45-7.48(d，2H)，7.29-7.38(m，6H)，7.15-7.18(d，2H)，7.10(s，1H)，4.46(m，1H)，3.44-3.49(m，2H)，2.98-3.06(m，4H)，2.04-2.06(m，2H)，1.26-1.30(t，3H)，1.14(s，6H)
LC/MS：C 25H 29F 3N 2O 5S：m/z 573(M+1)
2-{6-[1-ethyl-3-(4-hydroxy phenyl) urea groups]-5,6,7,8-tetraline-2-base sulfane base }-2 Methylpropionic acid (embodiment 56)
2-{6-[4-(aminophenyl)-1-ethyl urea groups]-5,6,7,8-tetraline-2-base sulfane base }-2 Methylpropionic acid (embodiment 57)
Figure A20038010656600691
Route 5
2-[3-chloro-6-(ethyl-to tolyloxy carbonyl-amino)-5,6,7,8-tetraline-2-base sulfane base]-the 2 Methylpropionic acid tertiary butyl ester
Compound 5.0 (embodiment 58)
Under 0 ℃, be dissolved in 2-in the methylene dichloride (2mL) (3-chloro-6-ethylamino-5,6,7,8-tetraline-2-base sulfane base)-2 Methylpropionic acid tertiary butyl ester and borane complexes (80mg; 201 μ mol) add carbonochloridic acid in the mixed solution to toluene ester (35 μ L; 241 μ mol).Reactant slowly is warmed to room temperature, stirred 6 under the room temperature.Removal of solvent under reduced pressure, thick residue is through flash chromatography purifying (SiO 2), with hexane-ethyl acetate gradient elution, obtain the 2-[3-chloro-6-(ethyl-to tolyloxy carbonyl-amino)-5,6,7 of 30mg (29%) clarification oily matter, 8-tetraline-2-base sulfane base]-the 2 Methylpropionic acid tertiary butyl ester.
1H NMR(300MHz，CDCl 3)：δ6.67-7.29(m，6H)，4.28(m，1H)，3.40(m，2H)，2.87-2.97(m，4H)，2.33(s，3H)，1.89-2.06(m，2H)，1.39-1.46(m，15H)，1.21-1.31(m，3H)
According to the method for route 2 step M, preparation compound 5.0 (23mg; 59%).
1H NMR(300MHz，CD 3OD)：δ6.96-7.34(m，6H)，4.27(m，1H)，3.49(m，2H)，2.91-3.14(m，4H)，2.32(s，3H)，2.10(m，2H)，1.45(m，6H)，1.28(m，3H)
LC/MS：C 24H 28ClNO 4S：m/z 462(M+1)
2-{3-chloro-6-[(4-chloro-phenyloxycarbonyl)-and ethyl-amino]-5,6,7,8-tetraline-2-base sulfane base }-2 Methylpropionic acid.Compound 5.1 (embodiment 59)
Figure A20038010656600701
Method according to the step M of route 5 (replacing carbonochloridic acid p-methylphenyl ester with carbonochloridic acid 4-chloro-phenyl-ester) and route 2 prepares compound 5.1 (34mg; Two steps 35%; White solid).
1H NMR(300MHz，CD 3OD)：δ7.11-7.39(m，6H)，4.30(m，1H)，3.47(m，2H)，2.91-3.15(m，4H)，2.06(m，2H)，1.45(m，6H)，1.28(m，3H)
LC/MS：C 23H 25Cl 2NO 4S：m/z 482(M+1)
2-{6-[ethyl-(4-trifluoromethoxy-phenyloxycarbonyl)-amino]-5,6,7,8-tetraline-2-base sulfane base }-2 Methylpropionic acid
Compound 5.2 (embodiment 60)
Figure A20038010656600702
Method according to the step M of route 5 (replacing carbonochloridic acid p-methylphenyl ester with carbonic acid 1-chloro-ethyl ester 4-Trifluoromethoxyphen-l ester) and route 2 prepares compound 5.2.
In addition, can adopt following method to prepare compound 5.2:
A. carbonic acid 1-chloro-ethyl ester 4-Trifluoromethoxyphen-l ester
Flow process 1. is with chloroformic acid 1-chloro ethyl ester (1.03g; 7.20mmol) methylene dichloride (10mL) solution be cooled to 0 ℃, add trifluoro-methoxy-phenol (1.09g; 6.0mmol) and triethylamine, the solution that obtains is warmed to room temperature.Stir after 3 hours, with reactant saturated sodium bicarbonate quencher, with ethyl acetate extraction (3 times).With extracting solution water and the salt water washing that merges, through Na 2SO 4Drying, removal of solvent under reduced pressure.The crude product residue with hexane-ethyl acetate (10: 1) wash-out, obtains the carbonic acid 1-chloro-ethyl ester 4-Trifluoromethoxyphen-l ester of 1.54g (90%) colorless oil through the flash chromatography purifying.
1H NMR(400MHz，CDCl 3)：δ7.26(m，4H)，6.49(q，1H)，1.91(d，3H)
B. ethyl-(6-methoxyl group-1,2,3,4-tetralin-2-yl)-carboxylamine 4-trifluoromethoxy-phenylester
Flow process 1. is to 6-methoxyl group-2-Tetralone an intermediate of Sertraline (950mg; 5.39mmol), the THF (5.4mL of 2M ethamine; 10.78mmol) and acetate (648mg; 10.78mmol) methylene dichloride (5mL) mixed solution in add sodium triacetoxy borohydride (2.29g; 10.78mmol).Under the room temperature, reaction mixture was stirred 3 hours, add 1N NaOH solution then, with ether extraction (3 times).The organic extracting solution that merges is through Na 2SO 4Drying, removal of solvent under reduced pressure obtains light yellow oil.This oily matter is joined carbonic acid 1-chloro-ethyl ester 4-Trifluoromethoxyphen-l ester (1.23g; 4.31mmol) toluene (8mL) solution in, under the room temperature reaction mixture was stirred 1 hour, stirred 1 hour down at 90 ℃ then.Reactant is cooled to room temperature, with the ether dilution, with 1N hydrochloric acid and saturated sodium bicarbonate washing.Organic extracting solution is through Na 2SO 4Drying, removal of solvent under reduced pressure.Residue with hexane-dichloromethane gradient wash-out, obtains ethyl-(6-methoxyl group-1,2,3,4-tetralin-2-the yl)-carboxylamine 4-trifluoromethoxy-phenylester of 1.05g (48%) white solid through flash chromatography.
1H NMR(400MHz，CDCl 3)：δ7.10-7.30(m，4H)，6.99(d，1H)，6.71(d，1H)，6.64(s，1H)，4.33(m，1H)，3.77(s，3H)，3.41(m，2H)，2.93(m，4H)，2.04(m，2H)，1.31(m，3H)
LC/MS：C 21H 23F 3NO 4：m/z 410(M+1)
C. ethyl-(6-hydroxyl-1,2,3,4-tetrahedronaphthalene-2-yl)-carboxylamine 4-trifluoromethoxy-phenylester
Flow process 1. is with ethyl-(6-methoxyl group-1,2,3,4-tetralin-2-yl)-carboxylamine 4-trifluoromethoxy-phenylester (898.6mg; 2.19mmol) anhydrous methylene chloride (8mL) solution be cooled to-78 ℃, slowly add 1.0M boron tribromide-dichloromethane solution (6.57mL; 6.57mmol).After adding is finished, reaction mixture is warmed to room temperature, with methyl alcohol (10mL) quencher, restir 2 hours.Evaporating solvent, residue with hexane-ethyl acetate (2.5: 1) wash-out, obtain ethyl-(6-hydroxyl-1,2,3,4-tetralin-2-the yl)-carboxylamine 4-trifluoromethoxy-phenylester of 649.4mg (75%) white solid through the flash chromatography purifying.
1H NMR(300MHz，CDCl 3)：δ7.05-7.30(m，4H)，6.90(m，1H)，7.41-7.60(m，2H)，5.05(s，1H)，4.30(m，1H)，3.41(m，2H)，2.90(m，4H)，1.99(m，2H)，1.31(m，3H)
LC/MS：C 20H 21F 3NO 4：m/z 396(M+1)
D. ethyl-(6-tri isopropyl silane base alkylthio-1,2,3,4-tetralin-2-yl)-carboxylamine 4-fluoroform hydrogen base-phenylester
Flow process 1. is with ethyl-(6-hydroxyl-1,2,3,4-tetralin-2-yl)-carboxylamine 4-trifluoromethoxy-phenylester (245.1mg; 0.62mmol) solution in anhydrous methylene chloride (3mL) and tetrahydrofuran (THF) (3mL) is cooled to-30 ℃, adds triethylamine (216uL in turn; 1.55mmol) and trifluoroacetic anhydride (125uL; 0.74mmol).Under the room temperature, with the solution stirring that obtains 2 hours, water quencher then was with ether extraction (3 times).With organic extracting solution water, the salt water washing that merges, through Na 2SO 4Drying, removal of solvent under reduced pressure.Residue with hexane-ethyl acetate (5: 1) wash-out, obtains the triflate of 301.6mg (92%) through flash chromatography.Under the room temperature, with this triflate (279.8mg; 0.53mmol) and four (triphenyl phosphine) palladium (61.2mg; 0053mmol) join by tri isopropyl silane base mercaptan (126uL; 0.58mmol) and NaH (13.9mg; 0.58mmol) in the toluene solution that produces.With the mixture vacuum pumping that obtains 2 times, refluxed concentrating under reduced pressure 4 hours.Residue with hexane-ethyl acetate (10: 1) wash-out, obtains ethyl-(6-tri isopropyl silane base sulfane base-1,2,3,4-tetralin-2-the yl)-carboxylamine 4-trifluoromethoxy-phenylester of the light oily matter of 261.8mg (87%) through flash chromatography.
1H NMR(300MHz，CDCl 3)：δ6.82-7.29(m，7H)，4.32(m，1H)，3.40(m，2H)，2.81-3.05(m，4H)，2.05(m，2H)，1.12-1.34(m，6H)，1.03-1.10(m，18H)
LC/MS：C 29H 41F 3NO 3SSI：m/z 568(M+1)
E.2-{6-[ethyl-(4-trifluoromethoxy-phenyloxycarbonyl)-amino]-5,6,7,8-tetraline-2-base sulfane base }-the 2 Methylpropionic acid tertiary butyl ester
Flow process 1. is with ethyl-(6-tri isopropyl silane base sulfane base-1,2,3,4-tetralin-2-yl)-carboxylamine 4-trifluoromethoxy-phenylester (260.0mg; 0.46mmol) and-bromo acid tertiary butyl ester (130uL; 0.69mmol) solution in anhydrous tetrahydro furan (2mL) is cooled to 0 ℃, adds the TBAF solution (690uL of 1.0M; 0.69mmol), then reactant is warmed to room temperature, stirred 1 hour, dilute with water is used ether extraction (3 times) then.With organic extracting solution of merging through Na 2SO 4Drying, removal of solvent under reduced pressure.The crude product residue is through the flash chromatography purifying, with hexane-ethyl acetate (7: 1) wash-out, obtain 2-{6-[ethyl-(4-trifluoromethoxy-phenyloxycarbonyl)-amino of the light oily matter of 229.2mg (90%)]-5,6,7,8-tetraline-2-base sulfane base }-the 2 Methylpropionic acid tertiary butyl ester.
1H NMR(300MHz，CDCl 3)：δ6.95-7.28(m，7H)，4.34(m，1H)，3.41(m，2H)，2.96(m，2H)，2.91(m，2H)，3.41(m，2H)，2.06(m，2H)，1.44(s，6H)，1.42(s，9H)，1.28(m，3H)
LC/MS：C 28H 34F 3NO 5SNa：m/z 576(M+Na)
F.2-{6-[ethyl-(4-trifluoromethoxy-phenyloxycarbonyl)-amino]-5,6,7,8-tetrahydro-steaming-2-base sulfane base }-2 Methylpropionic acid
Flow process 1. is with 2-{6-[ethyl-(4-trifluoromethoxy-phenyloxycarbonyl)-amino]-5,6,7,8-tetraline-2-base sulfane base }-2 Methylpropionic acid (120.8mg; 0.22mmol) methylene dichloride (4mL) solution be cooled to-78 ℃, slowly add trifluoroacetic acid (4mL).Reaction mixture is warmed to room temperature, stirred 1.5 hours.Evaporating solvent, residue with methylene chloride-methanol (94: 6) wash-out, obtain 2-{6-[ethyl-(4-trifluoromethoxy-phenyloxycarbonyl)-amino of white solid through the flash chromatography purifying]-5,6,7,8-tetraline-2-base sulfane base }-2 Methylpropionic acid.
1H NMR(400MHz，CDCl 3)：δ6.96-7.28(m，7H)，4.30(m，1H)，3.39(m，2H)，2.85-3.10(m，4H)，2.06(m，2H)，1.49(s，6H)，1.28(m，3H)
LC/MS：C 24H 27F 3NO 5S：m/z 498(M+1)
D. preparation and administration
The compounds of this invention can be mixed with medicinal forms for various administration purposes.For preparing these medicinal compositionss, with closely mixing with pharmaceutically acceptable carrier of significant quantity as the alkali of active ingredient or the particular compound of acid salt form.
The form of the preparation of the foundation administration that requires, carrier can adopt multiple different form.These medicinal compositionss adopt the unit dosage that is suitable for (preferably) oral administration or parenterai administration ideally.For example, in the composition of preparation oral dosage form, can adopt any medicinal medium commonly used.In oral liquid such as suspensoid, syrup, elixir and solution, these media comprise water, glycols, oils, alcohols etc.; The perhaps solid carrier in powder agent, pill, capsule and tablet is such as starch, sugar, kaolin, lubricant, tackiness agent, disintegrating agent etc.On the administration difficulty or ease, tablet and capsule are best oral unit dosage form, wherein use the solid medicinal carrier usually.For non-enteron aisle composition, though can comprise and for example help other component of dissolved, carrier generally includes most at least sterilized water.For example, can prepare injection solution, wherein carrier comprises the mixed solution of salt brine solution, glucose solution or salt solution and glucose solution.Also the injection suspensoid can be prepared, wherein suitable liquid vehicle, suspension agent etc. can be used.In being suitable for the composition of percutaneous dosing, optional penetration enhancers and/or the suitable wetting agent of comprising of described carrier, the additive combination of any character that is fit to of optional and minimum ratio, described additive does not cause tangible undesirable action to skin.These additives can impel the administration of skin and/or can help to prepare desired composition.These compositions can be with various approach, such as through skin patch, topical patch (spot-on), ointment form administration.The acid salt of formula I compound is water-soluble owing to the form than its corresponding alkali can increase, so be more suitable for preparing water-soluble composition.
Be particularly suitable for medicinal compositions mentioned above is mixed with the dosage unit form that is easy to administration and uniform dose.Used dosage unit form refers to the unit form of dispersive physically that is fit to of single dose in this specification sheets, and constituent parts comprises the activeconstituents of the predetermined amount that can produce desired treatment effect as calculated and mixed with it needed pharmaceutical carrier.The example of these dosage unit forms is tablet (comprising rag tablet or coated tablet), capsule, pill, powder sachet, the agent of bag medicine wafer paper, injection solution agent or suspensoid, spoon amount powder, spoon amount tablet etc. and independent multiple doses form thereof.
Pharmaceutically-acceptable acid addition comprises active nontoxic acid salt form in the treatment that disclosed compound can form.The latter generally can be by obtaining described alkali with suitable acid treatment.Suitable acid comprises for example mineral acid, such as haloid acid, and example hydrochloric acid or Hydrogen bromide; Sulfuric acid; Nitric acid; Acid such as phosphoric acid; Or organic acid, such as acid such as acetate, propionic acid, oxyacetic acid, lactic acid, pyruvic acid, oxalic acid, propanedioic acid, succsinic acid, toxilic acid, fumaric acid, oxysuccinic acid, tartrate, citric acid, methylsulfonic acid, ethyl sulfonic acid, Phenylsulfonic acid, tosic acid, cyclohexane sulfamic acid, Whitfield's ointment, para-aminosalicylic acid, palmitinic acids.The term additive salt also comprises the solvate that disclosed component and salt thereof can form.These solvates are for example hydrate, alcohol adduct etc.Can the form of described salt reversibly be converted into the form of free alkali by using alkaline purification.
The definition of stereoisomer form comprises all possible isomeric forms that formula (I) compound can have.Removing other has and proposes or indicate, and the chemical name of each compound refers to the mixture of all possible stereochemical isomeric forms, and described mixture comprises all diastereomers and the enantiomeric form of this alkalescence molecular structure.More specifically, three-dimensional center can have (R)-or (S)-configuration; Substituting group on the saturated group of two valency ring-types can have cis-or trans-configuration.The present invention includes stereochemical isomeric forms, comprise the mixture of any ratio of diastereomer and disclosed compound thereof.Disclosed compound can also exist with its tautomeric forms.Though these forms above or in the following formula are not clearly indicating, and all comprise within the scope of the present invention.For example, in compound 2.1 or embodiment 3, on the C-2 of indane ring, there is a chirality center.For this compound, (S) ratios of the isomers (R) isomer more has activity.
Treatment from experimental result provided below and out of Memory, can be determined effective per daily dose by the alpha mediated disease of PPAR or the those skilled in the art in the illness at an easy rate.Usually, significant quantity be will treat and every kg body weight 0.001mg-5mg, more preferably 0.01mg/kg-0.5mg/kg body weight will be designed to.Can will treat effective dose and be divided into 2 times, 3 times, 4 times or divided dose administration more frequently in whole day when the middle timed interval to suit.This sub-doses can be mixed with unit dosage, for example the per unit formulation contains 0.05mg to 250mg or 750mg, especially the active ingredient of 0.5-50mg.Embodiment comprises 2mg, 4mg, 7mg, 10mg, 15mg, 25mg and 35mg formulation.Also compound of the present invention can be made the preparation of regularly release or subcutaneous or transdermal patch.Also disclosed compound can be mixed with the preparation that sprays or other part maybe can suck.
Definite dosage and frequency determine that according to seriousness, concrete patient's age, body weight and the general health of employed concrete formula (I) compound, the concrete illness of being treated, the illness of being treated and other medicines that patient may just take this knows for those skilled in the art.In addition, clearly, react difference and/or doctor in charge to leaving the assessment difference of The compounds of this invention prescription, can reduce or increase this effective per daily dose according to the patient that treated.Therefore, the scope of the effective per daily dose that arrives mentioned herein is just as a guidance.Next section comprises the details of the use that relates to disclosed compound and composition.
E. purposes
Compound of the present invention has pharmaceutical activity, for example can be used as the PPAR alfa agonists.In one aspect of the present invention, preferred described compound is the selective PPAR alfa agonists, has more than 10 or 10, preferred 15,25,30,50,100 or higher activity index (for example height of tiring of the potency ratio PPAR γ of PPAR α).
The PPAR alfa agonists can be used for treatment, prevents or suppresses following one or more advancings of disease: I phase hyperlipidemia, clinical preceding hyperlipidemia, II phase hyperlipidemia, hypertension, CAD (coronary artery disease), coronary heart disease and hypertriglyceridemia.Therefore the blood plasma level that the preferred compound of the present invention can be used to reduce low-density lipoprotein (LDL), IDL and/or little density LDL and other atherogenic molecule or cause the molecule of atherosclerosis complication can reduce cardiovascular complication.Preferred compound also can be used to improve the serum level of high-density lipoprotein (HDL) (HDL), the serum level of triglyceride reducing, LDL and/or free fatty acids.It also is gratifying for reducing FPG/HbAlc.
Conjoint therapy
Compound of the present invention can be united use with other active medicine pharmaceutically.These medicines comprise lipid lowerers and hypotensor.
No matter whether disclosed medicinal compositions or disclosed combination medicine are the preparations that is formulated among the same composition, determine that it is used for the treatment of and prevents the method for the effective dose of purpose is known in this area.When being used for the treatment of purpose, term used herein " associating significant quantity " is meant when using separately or unite use, in the tissue system of investigator, animal doctor, doctor or other clinician research, animal or human, bring out each active compound of biology or medicinal reaction or the amount of medicine, it comprise alleviate the amount of symptom of the illness for the treatment of or disease.Be used for preventative purpose (as suppressing the outbreak and the development of disease), term " associating significant quantity " is meant when using separately or unite use, can treat or suppress just not to be studied generation and each active compound of development or the amount of medicine of the disease of person, animal doctor, doctor or other clinician concern in the patient.Therefore, the invention provides the use of uniting of two or more medicines, wherein for example, (a) by independently therapeutic or preventative significant quantity give each medicine; (b) if when individually dosed, the amount of at least a medicine in the drug combination by Asia treatment or inferior prevention given, but when the time with second kind or other medicines drug combination of the present invention, give by the treatment or the amount of preventing; Perhaps (c) if when individually dosed, gives two kinds of (or more kinds of) medicines by the amount of Asia treatment or inferior prevention, when giving together, gives by the amount of treatment or prevention.
As the PPAR alfa agonists, compound of the present invention is than known fibrate triglyceride reducing more effectively.The compounds of this invention also can increase the metabolism of fat and/or lipid, thereby provides method for losing weight, alleviate fat weight, reduction weight index, reduction lipid (as triglyceride reducing) or treatment obesity or overweight illness.The example of fat-reducing medicament comprises cholic acid chelating agent, fiber acid derivative, nicotinic acid and HMGCoA reductase inhibitor.Concrete example comprises that Statins (statins) is as LIPITOR TM, ZOCOR TM, PRAVACH[OL TM, LESCOL TMAnd MEVACOR TM, and pitavastatin (Buddhist nun cut down him spit of fland) (Nissan, KowaKogyo, Sankyo, Novartis) and sustained release preparation, as ADX-159 (sustained release preparation of lovastatin), and Colestid, Locholest, Questran, Atromid, Lopid and Tricor.
The example of Altace Ramipril comprises antihypertensive drug, as angiotensin transferase (ACE) inhibitor (quinapril, Ramipril, captopril, lotensin, Mavik, cover promise, the lisinopril sheet, the SPM-925 sheet, enalapril maleate and Zestril), adrenergic blocking drug is (as cardura, phenoxybenzamine, guanadrel sulfate, Vasocaro, PRAZOSINI HYDROCHLORIDE and Minizide), α/Beta-3 adrenergic blocker is (as carvedilol, labetalol hydrochloride and Trate), calcium channel blocker is (as NIFEDIPINE, card is blue, cardene, diltiazem hydrochloride , the verapamil hydrochloride delayed-release tablet, diltiazem hydrochloride slow releasing capsule, Isrodipine, isoptin, Nimoldipine, Norvace, Splendil, nifedipine, nifedipine XL, Sula, diltiazem hydrochloride slow releasing capsule, vascor and Verelan), diuretic(s), angiotensin II receptor antagonists is (as Candesartan, Avapro, losartan and Dai Wen), Beta-3 adrenergic blocker (example hydrochloric acid sotalol preparation, Blocadren, esmolol, the carteolol preparation, Proprasylyte, Ka Erlun, Lavatol, Lopressor, Sectral, Tenormin, Toprol XL and bisoprolol fumarate), vasodilator is (as Deponit TTS, Dilatrate-SR, strontium (SR), Imdur, Ismo, Isordil, sorbide nitrate cut sheet, Monoket, Nitro-Bid, Nitro-Dur, Nitrolingual Spray, the peace of anti-strand sorbide nitrate) and combined preparation (she draws Puli's preparation as toxilic acid, Lotrel, Tarka, she draws Puli and oxysuccinic acid diltiazem slow releasing tablet toxilic acid, lotensin HCT, Prinzide, Uniretic, she draws Puli and Aquazide H toxilic acid, Zestoretic).
F. embodiment
Following chemistry and biology embodiment is used for explanation and also unrestricted the present invention.
Embodiment 1
Figure A20038010656600781
2-{6-[1-ethyl-3-(4-Trifluoromethoxyphen-l) urea groups]-5,6,7,8-tetraline-2-base sulfane base }-2 Methylpropionic acid
EC 50＝0.023μM
Embodiment 2
Figure A20038010656600791
2-{2-[1-ethyl-3-(4-Trifluoromethoxyphen-l) urea groups] indane-5-base sulfane base }-2 Methylpropionic acid
EC 50＝0.027μM
Embodiment 3
(S)-and 2-{2-[1-ethyl-3-(4-Trifluoromethoxyphen-l) urea groups] indane-5-base sulfane base }-2 Methylpropionic acid
EC 50＝0.0002μM
Embodiment 4
Figure A20038010656600793
2-{2-[1-ethyl-3-(4-trifluoromethylthio phenyl) urea groups] indane-5-base sulfane base }-2 Methylpropionic acid
EC 50＝0.037μM
Embodiment 5
Figure A20038010656600794
2-methyl-2-{2-[1-amyl group-3-(4-trifluoromethylthio phenyl) urea groups] indane-5-base sulfane base } propionic acid
EC 50＝0.053μM
Embodiment 6
2-{2-[1-ethyl-3-(4-isopropyl phenyl) urea groups] indane-5-base sulfane base }-2 Methylpropionic acid
EC 50＝0.056μM
Embodiment 7
Figure A20038010656600811
2-{2-[3-(4-dimethylamino phenyl)-1-ethyl urea groups] indane-5-base sulfane base }-2 Methylpropionic acid
EC 50＝0.075μM
Embodiment 8
Figure A20038010656600812
2-methyl-2-{2-[1-amyl group-3-(4-Trifluoromethoxyphen-l) urea groups] indane-5-base sulfane base }-2 Methylpropionic acid
EC 50＝0.073μM
Embodiment 9
2-{2-[3-(4-dimethylamino phenyl)-1-amyl group urea groups] indane-5-base sulfane base }-2 Methylpropionic acid
EC 50＝0.131μM
Embodiment 10
Figure A20038010656600821
2-{2-[3-(4-isopropyl phenyl)-1-(3-amyl group) urea groups] indane-5-base sulfane base }-2 Methylpropionic acid
EC 50＝0.165μM
Embodiment 11
Figure A20038010656600822
2-{2-[3-(4-tert-butyl-phenyl)-1-(3-amyl group) urea groups] indane-5-base sulfane base }-2 Methylpropionic acid
EC 50＝0.173μM
Embodiment 12
Figure A20038010656600823
2-[2-(3-(biphenyl-4-base-1-amyl group urea groups) indane-5-base sulfane base]-2 Methylpropionic acid
EC 50＝0.183μM
Embodiment 13
Figure A20038010656600831
2-{2-[3-(4-isopropyl phenyl)-1-(3-hexyl) urea groups] indane-5-base sulfane base }-2 Methylpropionic acid
EC 50＝0.184μM
Embodiment 14
Figure A20038010656600832
2-methyl-2-{2-[1-hexyl-3-(4-Trifluoromethoxyphen-l) urea groups] indane-5-base sulfane base } propionic acid
EC 50＝0.213μM
Embodiment 15
2-methyl-2-{2-[1-hexyl-3-(4-trifluoromethylthio phenyl) urea groups] indane-5-base sulfane base } propionic acid
EC 50＝0.123μM
Embodiment 16
Figure A20038010656600841
2-methyl-2-{2-[1-propyl group-3-(4-Trifluoromethoxyphen-l) urea groups] indane-5-base sulfane base } propionic acid
EC 50＝0.158μM
Embodiment 17
2-methyl-2-{2-[1-butyl-3-(4-trifluoromethylthio phenyl) urea groups] indane-5-base sulfane base } propionic acid
EC 50＝0.160μM
Embodiment 18
Figure A20038010656600843
2-methyl-2-{2-[3-(4-Trifluoromethoxyphen-l) urea groups] indane-5-base sulfane base } propionic acid
EC 50＝0.135μM
Embodiment 19
2-methyl-2-{2-[1-penta-4-thiazolinyl-3-(4-Trifluoromethoxyphen-l) urea groups] indane-5-base sulfane base } propionic acid
EC 50＝0.125μM
Embodiment 20
Figure A20038010656600851
2-methyl-2-{2-[1-(3-methyl butyl)-3-(4-Trifluoromethoxyphen-l) urea groups] indane-5-base sulfane base }-2 Methylpropionic acid
EC 50＝0.106μM
Embodiment 21
2-{2-[3-(4-isopropyl phenyl)-1-(3-methyl butyl) urea groups] indane-5-base sulfane base }-2 Methylpropionic acid
EC 50＝0.106μM
Embodiment 22
Figure A20038010656600853
2-{6-[1-butyl-3-(4-Trifluoromethoxyphen-l) urea groups]-5,6,7,8-tetraline-2-base sulfane base }-2 Methylpropionic acid
EC 50＝0.219μM
Embodiment 23
Figure A20038010656600861
2-{6-[1-butyl-3-(4-trifluoromethylthio phenyl) urea groups]-5,6,7,8-tetraline-2-base sulfane base }-2 Methylpropionic acid
EC 50＝0.244μM
Embodiment 24
Figure A20038010656600862
2-{6-[1-hexyl-3-(4-Trifluoromethoxyphen-l) urea groups]-5,6,7,8-tetraline-2-base sulfane base }-2 Methylpropionic acid
EC 50＝0.235μM
Embodiment 47
2-{6-[1-ethyl-3-(4-Trifluoromethoxyphen-l) urea groups]-3-methoxyl group-5,6,7,8-tetraline-2-base sulfane base }-2 Methylpropionic acid
EC 50＝0.045μM
Embodiment 49
Figure A20038010656600864
2-{6-[1-ethyl-3-(4-Trifluoromethoxyphen-l) urea groups]-5,6,7,8-tetraline-2-base oxygen base }-2 Methylpropionic acid
EC 50＝0.309μM
Embodiment 50
Figure A20038010656600871
2-{6-[1-ethyl-3-(4-Trifluoromethoxyphen-l) urea groups]-3-fluoro-5,6,7,8-tetraline-2-base sulfane base }-2 Methylpropionic acid
EC 50＝0.010μM
Embodiment 51
Figure A20038010656600872
2-{6-[1-ethyl-3-(4-Trifluoromethoxyphen-l) urea groups]-3-chloro-5,6,7,8-tetraline-2-base sulfane base }-2 Methylpropionic acid
EC 50＝0.027μM
Embodiment 52
2-{6-[1-ethyl-3-(4-Trifluoromethoxyphen-l) urea groups]-3-bromo-5,6,7,8-tetraline-2-base sulfane base }-2 Methylpropionic acid
EC 50＝0.017μM
Embodiment 53
Figure A20038010656600874
2-{6-[1-ethyl-3-(4-Trifluoromethoxyphen-l) urea groups]-3-methyl-5,6,7,8-tetraline-2-base sulfane base }-2 Methylpropionic acid
EC 50＝0.042μM
Embodiment 54
2-{6-[1-ethyl-3-(4-Trifluoromethoxyphen-l) urea groups]-3-trifluoromethoxy-5,6,7,8-tetraline-2-base sulfane base }-2 Methylpropionic acid
EC 50＝0.131μM
Embodiment 55
Figure A20038010656600882
2-{6-[1-ethyl-3-(4-Trifluoromethoxyphen-l) urea groups]-3-phenyl-5,6,7,8-tetraline-2-base sulfane base }-2 Methylpropionic acid
EC 50＝0.545μM
Embodiment 56
Figure A20038010656600883
2-{6-[1-ethyl-3-(4-hydroxy phenyl) urea groups]-5,6,7,8-tetraline-2-base sulfane base }-2 Methylpropionic acid
Embodiment 57
Figure A20038010656600884
The 2-{6-[(4-aminophenyl)-and 1-ethyl urea groups]-5,6,7,8-tetraline-2-base sulfane base }-2 Methylpropionic acid
Embodiment 58
Figure A20038010656600891
2-{3-chloro-6-[(4-methyl-phenyloxycarbonyl)-and ethyl-amino]-5,6,7,8-tetraline-2-base sulfane base }-2 Methylpropionic acid
EC 50＝0.340μM
Embodiment 59
2-{3-chloro-6-[(4-chloro-phenyloxycarbonyl)-and ethyl-amino]-5,6,7,8-tetraline-2-base sulfane base }-2 Methylpropionic acid
EC 50＝0.390μM
Embodiment 60
Figure A20038010656600893
2-{6-[ethyl-(4-trifluoromethoxy-phenyloxycarbonyl)-amino]-5,6,7,8-tetraline-2-base sulfane base }-2 Methylpropionic acid
EC 50＝0.002μM
Biology embodiment 1
HD bDNA test
H4ITE mouse hepatoma cell line derives from ATCC.With cell at 175cm 2Tissue culture flasks in cultivate or be inoculated in 96 well culture plates that have substratum (high serum content, 10% foetal calf serum and 10% calf serum), in whole research process, remain on 37 ℃ and 5%CO 2Under the environment.Manual initial inoculation (about 100,000/ holes) after 24 hours, starts the gene induced test of HD in 96 well culture plates.Remove substratum, contain the low blood serum medium (calf serum of handling with 5% gac/dextran) of medium (DMSO) or testing compound or reference material with 100 μ l.Cell is put back to incubator to be cultivated 24 hours.When this induces (challenge) to finish, with 50 μ l have CE, the LE of HD gene specific, the lysis buffer that BL surveys thing directly joins in each hole, thereby start bDNA HD mRNA test.Draft (Bayer Diagnostics drafts in described chain DNA experimental evidence manufacturer; Emeryville.CA.) implement.Last what test, carry out quantitatively luminous with Dynex MLX microtiter plate plate photometer.Utilize Graphpad Prism data processing software, the non-linear regression by the S fitting of a curve calculates EC 50Value.
Biology embodiment 2
The transfection test of PPAR δ acceptor
The HEK293 cell is grown in the DMEM/F-12 substratum that has added 10%FBS and glutamine (GIBCOBRL).Use DMRIE-C reagent, with the DNA cotransfection of these cells with PPAR-Gal4 acceptor and Gal4-luciferase acceptor.Next day, the FBS growth medium that these substratum that contain DNA are crossed with 5% activated carbon treatment is replaced.After 6 hours, with cell inoculation in 96 well culture plates, at CO 237 ℃ of following overnight incubation in the incubator.Cell is brought out by testing compound, at 5%CO 2Cultivated 24 hours down for 37 ℃ in the incubator.The Steady-Glo luciferase assay test kit of employing Promega is measured the activity of luciferase.DMRIE-C reagent is available from GIBCO Cat.No.10459-014.The OPTI-MEMI serum free medium is purchased the Cat.No.31985 in GIBCO.Steady-Glo luciferase assay test kit is purchased the Part#E254B in Promega.
Vitro data
Embodiment PPARα EC 50(μM) PPARδFI *1 [EC 50(μM)] PPARγFI *2 [EC 50(μM)]
1 0.023
2 0.027 4.2 0.24
3 0.002 [＞10] [＞10]
4 0.037 3.7
5 0.053 2.5 4.0
6 0.056 3.6 1.9
7 0.075 0.8 0
8 0.073 5.9 1.9
9 0.131 1.0 2.9
10 0.165 5.1
11 0.173 6.1
12 0.183 11
13 0.184 1.2
14 0.213 1.3 0.3
15 0.123 1.2
16 0.158 0.37
17 0.160 0.43
18 0.135 0.31
19 0.125 1.4
20 0.106 0.44
21 0.106 0.05
22 0.219
23 0.244
24 0.235
25 0.208 4.5
26 0.130 2.1
27 0.294
28 0.323 8.2
29 0.382
30 0.385
31 0.497
32 0.497 1.5
33 0.537 0.8
34 0.657
35 0.772 5.6
36 0.796
37 0.838 1.9
38 0.950
39 1.00 9.3
40 1.30
41 2.21
42 2.34
43 2.99
44 2.09
45 0.780
46 1.39 6.0
47 0.045 [＞3]
48 0.014 [＞3]
49 0.309 [＞3]
50 0.010 [＞3] [＞3]
51 0.027 [＞10]
52 0.017 [＞3]
53 0.042 [0.873]
54 0.131 [＞3]
55 0.545 [1.72]
58 0.340 [0.613] [＞3]
59 0.390 [0.655] [1.11]
60 0.002 [＞3] [＞3]
* 1Folding the inducing of PPAR δ reference material: FI=36.1
* 2Folding the inducing of PPAR γ reference material: FI=70.3
Biology embodiment 3
The aP2 test of PPAR gamma agonist
This test method is at the Molecular Endocrinology of Burris etc., 1999, have a detailed description among the 13:410, its full content is attached among the present invention as a reference by reference, and the aP2 measurement result of agonist intrinsic activity can be represented with the increase multiple of the relative medium of inducibility that aP2mRNA is generated.
In 96 well culture plates, after 24 hours, can start the differentiation test by manual initial inoculation (about 20,000/ holes).Remove substratum, the division culture medium that contains medium (DMSO) or testing compound with 150 μ l is replaced.Cell is put back to incubator to be cultivated 24 hours.When provocative test finishes, remove substratum, add 100 μ l lysis buffers and start bDNA aP2mRNA test.Described chain DNA test can be drafted draft (Bayer Diagnostics according to manufacturer; Emeryville.CA.) implement.The result can use with respect to the increase multiple of the activation that aP2mRNA is generated of medium contrast and represent.EC 50Value and Emax can determine with the non-linear regression of S fitting of a curve.
After the provocative test of this preceding adipocyte (preadipocytes), can be with cell lysis buffer (Bayer Diagnostics) cracking that contains the aP2 oligonucleotide.Cultivated 15 minutes or after 30 minutes, from every hole, got 70 μ l lysis buffers and join corresponding catching in the hole (cultivating) at 53 ℃ with 70 μ l sealing damping fluids (Bayer Diagnostics) are pre-37 ℃ of cultivations.With capture board 53 ℃ of overnight incubation in dull and stereotyped incubator (Bayer Diagnostics).After the cultivation, can bDNA and marker detection thing be annealed by the guidance of manufacturer.After cultivating 30 minutes, carry out quantitatively luminous with Dynex MLX microtiter plate photometer with luminous alkaline phosphate ester enzyme substrates (dioxitane).Design being designed for the function that aP2mRNA annealed oligonucleotide is surveyed in thing and the bDNA mRNA detection system with ProbeDesigner software (Bayer Diagnostics).This software package comes the target sequence of analysis of key with series of algorithms, purpose be determine which zone in the sequence can bear pounce on obtain, mark or isolate and survey the thing Effect of annealing.The sequence of described oligonucleotide is as follows:
SEQ ID NO.1 CATTTTGTGAGTTTTCTAGGATTATTCTTTTCTCTTGGAAAGAAAGT
SEQ ID NO.2 ATGTTAGGTTTGGCCATGCCTTTCTCTTGGAAAGAAAGT
SEQ ID NO.3 CCTCTCGTTTTCTCTTTATGGTTTTCTCTTGGAAAGAAAGT
SEQ ID NO.4 GCTTATGCTCTCTCATAAACTCTCGTGGTTTCTCTTGGAAAGAAAGT
SEQ ID NO.5 CCAGGTACCTACAAAAGCATCACATTTAGGCATAGGACCCGTGTCT
SEQ ID NO.6 GCCCACTCCTACTTCTTTCATATAATCATTTAGGCATAGGACCCGTGTCT
SEQ ID NO.7 AGCCACTTTCCTGGTGGCAAATTTAGGCATAGGACCCGTGTCT
SEQ ID NO.8 CATCCCCATTCACACTGATGATCTTTAGGCATAGGACCCGTGTCT
SEQ ID NO.9 GTACCAGGACACCCCCATCTAAGGTTTTTAGGCATAGGACCCGTGTCT
SEQ ID NO.10 GGTTGATTTTCCATCCCATTTCTGCACATTTTAGGCATAGGACCCGTGTCT
SEQ ID NO.11 GCATTCCACCACCAGTTTATCATTTTAGGCATAGGACCCGTGTCT
SEQ ID NO.12 GCGAACTTCAGTCCAGGTCAACGTCCCTTGTTTAGGCATAGGACCCGTGTCT
SEQ ID NO.13 TCCCACAGAATGTTGTAGAGTTCAATTTTAGGCATAGGACCCGTGTCT
SEQ ID NO.14 AAAACAACAATATCTTTTTGAACAATATATTTAGGCATAGGACCCGTGTCT
SEQ ID NO.15 TCAAAGTTTTCACTGGAGACAAGTTT
SEQ ID NO.16 AAAGGTACTTTCAGATTTAATGGTGATCA
SEQ ID NO.17 CTGGCCCAGTATGAAGGAAATCTCAGTATTTTT
SEQ ID NO.18 TCTGCAGTGACTTCGTCAAATTC
SEQ ID NO.19 ATGGTGCTCTTGACTTTCCTGTCA
SEQ ID NO.20 AAGTGACGCCTTTCATGAC
Biology embodiment 4
Quantitatively give embodiment 3 compounds 11 days of the female db/db mouse in age in 6-7 week
In footwear carton and crate of the hard end, raising, with 6-7 age in week (female db/db mouse (C57BLK S/J-m+ /+Lepr Db, Jackson Labs, Bar Harbor, ME) 4 in every cage is raised.Room temperature is remained on 68-72 °F, and humidity is at 50-65%.Room illumination is undertaken by hour dark circulation of 12 little time/12.With mouse use through the NIH rat of calibrating and the fat-free food #5K52 of mouse/Auto 6F (PMI Nutrition int ' I, St.Louis, MO, via W.F.Fisher and Son, Inc., Bound Brook NJ) feeds.Food and water are unrestrictedly supplied.
(Dow Chemical, Midland MI) becomes suspension with compound with 0.5% hydroxypropyl-methylcellulose gum.The administration volume is the 10ml/kg body weight.In 11 days, give the dH of female db/db diabetic mice (8/group) 1 time 0.5% methylcellulose gum of oral tube feed every day 2The PPAR agonist of one of O liquid (medium) or 0.03,0.1,0.3,1,3,10mg/kg day dosage.Before administration in morning on the firstth, before morning on the 12nd blood sampling, measure body weight.Each organizes after the administration the last time 18-24 hour, and mouse is used CO 2/ O 2(70: 30) anesthesia by eye socket hole puncture blood collecting, joins and contains in the microminiature tube that solidifies activator, and is freezing then.By centrifugal preparation serum sample.(Roche Diagnostics NJ) measures blood sugar and triglyceride level with COBAS Mira Plus bichromatic analyser.Blood insulin ALPCO Regular Insulin ELISA kit measurement.
(Graphpad, Monrovia CA) carry out statistical study, with Dunnett ' s multiple comparisons check carrying out one-way analysis of variance (ANOVA) with the Prism program.
Data in the body
Embodiment 1 The Δ plasma TG
1 2 -52％
2 3 -56％
3 4 -66％
4 4 -47％
5 4 -19％
6 4 -50％
7 4 -63％
8 4 -27％
9 4 -6％
1Give db/db mouse with the 1.0mpk amount.Data change expression with the % with respect to the media processes animal groups; The NC=no change
2Oral administration on the 10th
3Oral administration on the 11st
4Oral administration on the 5th
Biology embodiment 5
Quantitatively give the embodiment compound 11 days of the female ob/ob mouse in 7 ages in week
In footwear carton and crate of the hard end, raising, with 7 age in week (female ob/ob mouse (C57BL/6J-Lep Ob, Jackson Labs, Bar Harbor, ME) 2 in every cage is raised.Room temperature is remained on 68-72 °F, and humidity is at 50-65%.Room illumination is undertaken by hour dark circulation of 12 little time/12.With mouse use through the NIH rat of calibrating and mouse food #5K50 (PMI NutritionInt ' I, St.Louis, MO, via W.F.Fisher and Son, Inc., Bound Brook NJ) feeds.Food and water are unrestrictedly supplied.
(Dow Chemical, Midland MI) becomes suspension with compound with 0.5% hydroxypropyl-methylcellulose gum.The administration volume is the 10mL/kg body weight.In 11 days, give the dH of female ob/ob diabetic mice (8/group) 1 time 0.5% methylcellulose gum of oral tube feed every day 2The PPAR agonist of one of O liquid (medium) or 0.003,0.01,0.03,0.1,0.3,1mg/kg/ day dosage.Before administration in morning on the firstth, before morning on the 12nd blood sampling, measure body weight.Each organizes after the administration the last time 18 hours, and mouse is used CO 2/ O 2(70%: 30%) anesthesia by eye socket hole puncture blood collecting, joins and contains in the microminiature tube that solidifies activator, and is freezing then.By centrifugal preparation serum sample.(RocheDiagnostics NJ) measures blood sugar and triglyceride level with COBAS Mira Plus bichromatic analyser.Blood insulin and free fatty acids adopt ALPCO Regular Insulin ELISA test kit and Wako NEFA kit measurement respectively.
(Graphpad, Monrovia CA) carry out statistical study, with Dunnett ' s multiple comparisons check carrying out one-way analysis of variance (ANOVA) with the Prism program.
Data in the body
Embodiment 1 The Δ plasma TG The Δ plasma glucose The Δ plasma insulin
50 -86％ -74％ -93％
1Give ob/ob mouse with the 1.0mpk amount.Data change expression with the % with respect to the media processes animal groups.
F. other embodiment
Feature of the present invention and principle have obtained elaboration in this discussion, embodiment and claims.Various changes and improvements of the present invention all are very conspicuous for those of ordinary skills, and other embodiment is also included within this scope of invention.The thing of publishing cited herein all is attached among the present invention as a reference.

Claims (39)

1. a formula I compound or its pharmacy acceptable salt, C 1-6Ester or C 1-6Acid amides:
Figure A2003801065660002C1
Formula I
R 1And R 2Independent separately is H, C 1-6Alkyl, (CH 2) mNR aR b, (CH 2) mOR 8, (CH 2) mNH (CO) R 8Or (CH 2) mCO 2R 8, R wherein a, R bAnd R 8Independent separately is H or C 1-6Alkyl, perhaps R 1And R 2The carbon atom that connects with them constitutes C 3-7Cycloalkyl;
M is the integer of 1-6;
N is 1 or 2;
X is O or S; Wherein when n was 1, X was at 5 or 6; And when wherein n was 2, X was at 6 or 7;
R 3Be H, phenyl, C 1-3Alkoxyl group, C 1-3Alkylthio, halogeno-group, cyano group, C 1-6Alkyl, nitro, NR 9R 10, NHCOR 10, CONHR 10And COOR 10And R 3Adjacent or position at X;
R 4For H or-(C 1-5Alkylidene group) R 15, R wherein 15Be H, C 1-7Alkyl, [two (C 1-2Alkyl) amino] (C 1-6Alkylidene group), (C 1-3The alkoxyl group acyl group) (C 1-6Alkylidene group), C 1-6Alkoxyl group, C 3-7Alkenyl or C 3-8Alkynyl group, wherein R 4Have and be no more than 9 carbon atom; R 4Also can be-(C 1-5Alkylidene group) R 15, R wherein 15Be C 3-6Cycloalkyl, phenyl, phenyl-O-, phenyl-S-or have the heteroatomic 5-6 unit heterocyclic radical that 1-2 is selected from N, O and S;
Y is NH, NH-CH 2And O;
R 5And R 7Independently be selected from H, C separately 1-6Alkyl, halogeno-group, cyano group, nitro, COR 11, COOR 11, C 1-4Alkoxyl group, C 1-4Alkylthio, hydroxyl, phenyl, NR 11R 12And have 1-2 and be selected from the heteroatomic 5-6 unit heterocyclic radical of N, O and S;
R 6Be selected from C 1-6Alkyl, halogeno-group, cyano group, nitro, COR 13, COOR 13, C 1-4Alkoxyl group, C 1-4Alkylthio, hydroxyl, phenyl, NR 13R 14And have 1-2 and be selected from the heteroatomic 5-6 unit heterocyclic radical of N, O and S;
In addition, perhaps R 5And R 6Perhaps R 6And R 7Can form saturated or undersaturated divalent moiety together, it is selected from-(CH 2) 3-,-(CH 2) 4-and (CH 1-2) pN (CH 1-2) q,
P is 0-2, and q is 1-3, wherein (p+q) and be at least 2;
R 9And R 10Independent separately is C 1-6Alkyl;
R 11, R 12, R 13And R 14Independent separately is H or C 1-6Alkyl;
Wherein above alkyl and assorted hydrocarbyl portion can be replaced by 1-3 substituting group that independently is selected from F, Cl, Br, I, amino, methyl, ethyl, hydroxyl, nitro, cyano group and methoxyl group separately.
2. the compound of a claim 1, wherein R 1And R 2One of be methyl or ethyl.
3. the compound of a claim 2, wherein R 1And R 2The methyl of respectively doing for oneself.
4. the compound of a claim 1, wherein R 1And R 2Be cyclobutyl or cyclopentyl together.
5. the compound of a claim 1, wherein R 3Be H.
6. the compound of a claim 1, wherein R 3Be C 1-3Alkoxyl group, C 1-3Alkylthio, halogeno-group, cyano group, C 1-6Alkyl, nitro, NR 9R 10, NHCOR 10, CONHR 10Or COOR 10
7. the compound of a claim 1, wherein R 4Be H or C 2-7Alkyl.
8. the compound of a claim 7, wherein R 4Be H or C 2-5Alkyl.
9. the compound of a claim 8, wherein R 4Be ethyl.
10. the compound of a claim 8, wherein R 4Be H.
11. the compound of a claim 1, wherein n is 1.
12. the compound of a claim 1, wherein n is 2.
13. the compound of a claim 1, wherein Y is NH-CH 2
14. the compound of a claim 1, wherein Y is NH.
15. the compound of a claim 1, wherein X is S.
16. the compound of a claim 1, wherein X is O.
17. the compound of a claim 1, wherein R 5And R 7At least one is H.
18. the compound of a claim 17, wherein R 6Be C 1-4Alkyl, halogenated methoxy, halo methylthio group or two (C 1-3Alkyl) amino.
19. the compound of a claim 18, wherein R 6Be trifluoromethoxy, difluoro-methoxy, trifluoromethyl, trifluoromethylthio, the tertiary butyl, sec.-propyl or dimethylamino.
20. the compound of a claim 3, wherein R 3Be H, R 4Be C 2-7Alkyl and Y are NH.
21. the compound of a claim 20, wherein X is S.
22. the compound of a claim 20, wherein n is 1.
23. the compound of a claim 20, wherein n is 2.
24. the compound of a claim 20, wherein R 4Be C 2-5Alkyl.
25. the compound of a claim 24, wherein R 4Be ethyl.
26. the compound of a claim 20, wherein R 6Be trifluoromethoxy, difluoro-methoxy, trifluoromethyl, trifluoromethylthio, the tertiary butyl, sec.-propyl or dimethylamino.
27. the compound of a claim 1, wherein R 1And R 2Independent separately is H, C 1-6Alkyl, (CH 2) mNR aR bOr (CH 2) mOR 8, R wherein a, R bAnd R 8Independent separately is H or C 1-6Alkyl;
M is the integer of 1-6;
N is 1 or 2;
X is O or S; Wherein when n was 1, X was at 5 or 6; And when wherein n was 2, X was at 6 or 7;
R 3Be H, phenyl, C 1-3Alkoxyl group, C 1-3Alkylthio, halogeno-group, C 1-6Alkyl or NR 9R 10, and R 3Adjacent or position at X;
R 4For H or-(C 1-5Alkylidene group) R 15, R wherein 15Be H, C 1-7Alkyl, [two (C 1-2Alkyl) amino] (C 1-6Alkylidene group), (C 1-3The alkoxyl group acyl group) (C 1-6Alkylidene group), C 1-6Alkoxyl group or C 3-7Alkenyl, wherein R 4Have and be no more than 9 carbon atom;
R 4Also can be-(C 1-5Alkylidene group) R 15, R wherein 15Be C 3-6Cycloalkyl, phenyl, phenyl-O-, phenyl-S-or have the heteroatomic 5-6 unit heterocyclic radical that 1-2 is selected from N, O and S;
Y is NH or NHCH 2
R 5And R 7Independently be selected from H, C separately 1-6Alkyl, halogeno-group, COR 11, COOR 11, C 1-4Alkoxyl group, C 1-4Alkylthio, hydroxyl and NR 11R 12
R 6Be selected from C 1-6Alkyl, halogeno-group, COR 13, COOR 13, C 1-4Alkoxyl group, C 1-4Alkylthio, phenyl, NR 13R 14And have 1-2 and be selected from the heteroatomic 5-6 unit heterocyclic radical of N, O and S;
R 9And R 10Independent separately is C 1-6Alkyl;
R 11, R 12, R 13And R 14Independent separately is H or C 1-6Alkyl;
Wherein above alkyl and assorted hydrocarbyl portion can be replaced by 1-3 substituting group that independently is selected from F, Cl, amino, methyl, ethyl, hydroxyl and methoxyl group separately.
28. the compound of a claim 1, it is selected from;
(1) 2-{6-[1-ethyl-3-(4-Trifluoromethoxyphen-l) urea groups]-5,6,7,8-tetraline-2-base sulfane base }-2 Methylpropionic acid;
(2) 2-{2-[1-ethyl-3-(4-Trifluoromethoxyphen-l) urea groups] indane-5-base sulfane base }-2 Methylpropionic acid;
(3) 2-{2-[1-ethyl-3-(4-trifluoromethylthio phenyl) urea groups] indane-5-base sulfane base }-2 Methylpropionic acid;
(4) 2-methyl-2-{2-[1-amyl group-3-(4-trifluoromethylthio phenyl) urea groups] indane-5-base sulfane base } propionic acid;
(5) 2-{2-[1-ethyl-3-(4-isopropyl phenyl) urea groups] indane-5-base sulfane base }-2 Methylpropionic acid;
(6) 2-methyl-2-{2-[1-amyl group-3-(4-Trifluoromethoxyphen-l) urea groups] indane-5-base sulfane base }-2 Methylpropionic acid;
(7) 2-{2-[3-(4-dimethylamino phenyl)-1-ethyl urea groups] indane-5-base sulfane base }-2 Methylpropionic acid;
(8) 2-methyl-2-{2-[1-(3-methyl butyl)-3-(4-Trifluoromethoxyphen-l) urea groups] indane-5-base sulfane base }-2 Methylpropionic acid;
(9) 2-{2-[3-(4-isopropyl phenyl)-1-(3-methyl butyl) urea groups] indane-5-base sulfane base }-2 Methylpropionic acid;
(10) 2-methyl-2-{2-[1-penta-4-thiazolinyl-3-(4-Trifluoromethoxyphen-l) urea groups] indane-5-base sulfane base } propionic acid;
(11) 2-{6-[1-ethyl-3-(4-Trifluoromethoxyphen-l) urea groups]-3-methoxyl group-5,6,7,8-tetraline-2-base sulfane base }-2 Methylpropionic acid;
(12) 2-{6-[1-ethyl-3-(4-Trifluoromethoxyphen-l) urea groups]-3-fluoro-5,6,7,8-tetraline-2-base sulfane base }-2 Methylpropionic acid;
(13) 2-{6-[1-ethyl-3-(4-Trifluoromethoxyphen-l) urea groups]-3-chloro-5,6,7,8-tetraline-2-base sulfane base }-2 Methylpropionic acid;
(14) 2-{6-[1-ethyl-3-(4-Trifluoromethoxyphen-l) urea groups]-3-bromo-5,6,7,8-tetraline-2-base sulfane base }-2 Methylpropionic acid;
(15) 2-{6-[1-ethyl-3-(4-Trifluoromethoxyphen-l) urea groups]-3-methyl-5,6,7,8-tetraline-2-base sulfane base }-2 Methylpropionic acid; With
(16) 2-{6-[1-ethyl-3-(4-Trifluoromethoxyphen-l) urea groups]-3-trifluoromethoxy-5,6,7,8-tetraline-2-base sulfane base }-2 Methylpropionic acid.
29. the compound of a claim 1, it is selected from:
(1) 2-methyl-2-{2-[1-hexyl-3-(4-trifluoromethylthio phenyl) urea groups] indane-5-base sulfane base } propionic acid;
(2) 2-{2-[3-(4-dimethylamino phenyl)-1-amyl group urea groups] indane-5-base sulfane base }-2 Methylpropionic acid;
(3) 2-methyl-2-{2-[3-(4-Trifluoromethoxyphen-l) urea groups] indane-5-base sulfane base } propionic acid;
(4) 2-methyl-2-{2-[1-propyl group-3-(4-Trifluoromethoxyphen-l) urea groups] indane-5-base sulfane base } propionic acid;
(5) 2-methyl-2-{2-[1-butyl-3-(4-trifluoromethylthio phenyl) urea groups] indane-5-base sulfane base } propionic acid;
(6) 2-{2-[3-(4-isopropyl phenyl)-1-(3-amyl group) urea groups] indane-5-base sulfane base }-2 Methylpropionic acid;
(7) 2-{2-[3-(4-tert-butyl-phenyl)-1-(3-amyl group) urea groups] indane-5-base sulfane base }-2 Methylpropionic acid;
(8) 2-[2-(3-(biphenyl-4-base-1-amyl group urea groups) indane-5-base sulfane base]-2 Methylpropionic acid;
(9) 2-{2-[3-(4-isopropyl phenyl)-1-(3-hexyl) urea groups] indane-5-base sulfane base }-2 Methylpropionic acid;
(10) 2-methyl-2-{2-[1-butyl-3-(4-Trifluoromethoxyphen-l) urea groups] indane-5-base sulfane base } propionic acid;
(11) 2-{6-[1-ethyl-3-(4-Trifluoromethoxyphen-l) urea groups]-3-methoxyl group-5,6,7,8-tetraline-2-base sulfane base }-2 Methylpropionic acid;
(12) 2-{6-[1-ethyl-3-(4-Trifluoromethoxyphen-l) urea groups]-3-fluoro-5,6,7,8-tetraline-2-base sulfane base }-2 Methylpropionic acid;
(13) 2-{6-[1-ethyl-3-(4-Trifluoromethoxyphen-l) urea groups]-3-chloro-5,6,7,8-tetraline-2-base sulfane base }-2 Methylpropionic acid;
(14) 2-{6-[1-ethyl-3-(4-Trifluoromethoxyphen-l) urea groups]-3-bromo-5,6,7,8-tetraline-2-base sulfane base }-2 Methylpropionic acid;
(15) 2-{6-[1-ethyl-3-(4-Trifluoromethoxyphen-l) urea groups]-3-methyl-5,6,7,8-tetraline-2-base sulfane base }-2 Methylpropionic acid; With
(16) 2-methyl-2-{2-[1-hexyl-3-(4-Trifluoromethoxyphen-l) urea groups] indane-5-base sulfane base } propionic acid.
30. the compound of a claim 1, it is selected from:
(1) 2-{6-[1-ethyl-3-(4-Trifluoromethoxyphen-l) urea groups]-5,6,7,8-tetraline-2-base sulfane base }-2 Methylpropionic acid;
(2) 2-{6-[3-(4-Trifluoromethoxyphen-l) urea groups]-5,6,7,8-tetraline-2-base sulfane base }-2 Methylpropionic acid;
(3) 2-{2-[1-ethyl-3-(4-Trifluoromethoxyphen-l) urea groups] indane-5-base sulfane base }-2 Methylpropionic acid;
(4) 2-{6-[1-ethyl-3-(4-Trifluoromethoxyphen-l) urea groups]-3-fluoro-5,6,7,8-tetraline-2-base sulfane base }-2 Methylpropionic acid;
(5) 2-{6-[1-ethyl-3-(4-Trifluoromethoxyphen-l) urea groups]-3-methyl-5,6,7,8-tetraline-2-base sulfane base }-2 Methylpropionic acid;
(6) 2-{2-[1-ethyl-3-(4-trifluoromethylthio phenyl) urea groups] indane-5-base sulfane base }-2 Methylpropionic acid; With
(7) 2-methyl-2-{2-[1-propyl group-3-(4-Trifluoromethoxyphen-l) urea groups] indane-5-base sulfane base } propionic acid.
31. the compound of a claim 1, it is selected from:
(1) 2-{2-[1-ethyl-3-(4-Trifluoromethoxyphen-l) urea groups] indane-5-base sulfane base }-2 Methylpropionic acid;
(2) 2-{2-[1-ethyl-3-(4-trifluoromethylthio phenyl) urea groups] indane-5-base sulfane base }-2 Methylpropionic acid;
(3) 2-methyl-2-{2-[1-propyl group-3-(4-Trifluoromethoxyphen-l) urea groups] indane-5-base sulfane base } propionic acid; With
(4) 2-{6-[1-ethyl-3-(4-Trifluoromethoxyphen-l) urea groups]-3-fluoro-5,6,7,8-tetraline-2-base sulfane base }-2 Methylpropionic acid.
32. a medicinal compositions, it comprises claim 1,20,27,28,30 or 31 compound.
33. a treatment or suppress the method for the alpha mediated advancing of disease of PPAR-, this method comprise to the patient treatment significant quantity of this kind of needs treatment comprise claim 1,20,27,28 or 31 compound compositions.
34. the method for a claim 33, the alpha mediated disease of wherein said PPAR-is selected from unusual blood fat disease and cardiovascular disorder.
35. the method for a claim 34, wherein said disease are unusual blood fat disease.
36. the method for a claim 34, wherein said unusual blood fat disease are selected from I phase hyperlipidemia, clinical preceding hyperlipidemia, II phase hyperlipidemia, hypercholesterolemia, low-HDL-hypercholesterolemia and hypertriglyceridemia.
37. the method for a claim 34, wherein said cardiovascular disorder is selected from atherosclerosis, coronary artery disease, coronary heart disease and hypertension.
38. a claim 33,35 or 36 method, it also comprises and gives the step that described patient unites the lipid lowerers of significant quantity.
39. a claim 33,35,36 or 38 method, it also comprises and gives the step that described patient unites the hypotensor of significant quantity.
CN 200380106566 2002-10-21 2003-10-17 Substituted tetralins and indanes Pending CN1798732A (en)

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US60/419,935 2002-10-21
US60/495,270 2003-08-15

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