CN1639112A - Substituted amides active at the cannabinoid-1 receptor - Google Patents

Substituted amides active at the cannabinoid-1 receptor Download PDF

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Publication number
CN1639112A
CN1639112A CNA03805678XA CN03805678A CN1639112A CN 1639112 A CN1639112 A CN 1639112A CN A03805678X A CNA03805678X A CN A03805678XA CN 03805678 A CN03805678 A CN 03805678A CN 1639112 A CN1639112 A CN 1639112A
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Prior art keywords
methyl
phenyl
chloro
propyl
trifluoromethyl
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W·K·哈曼
L·S·林
S·K·沙
R·N·古蒂康达
H·齐
L·L·常
P·刘
H·M·阿姆斯特朗
J·P·朱厄尔
T·J·小兰扎
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Merck and Co Inc
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Merck and Co Inc
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Abstract

Novel compounds of the structural formula (I) are antagonists and/or inverse agonists of the Cannabinoid-1 (CB1) receptor and are useful in the treatment, prevention and suppression of diseases mediated by the CB1 receptor. The compounds of the present invention are useful as centrally acting drugs in the treatment of psychosis, memory deficits, cognitive disorders, migraine, neuropathy, neuro-inflammatory disorders including multiple sclerosis and Guillain-Barre syndrome and the inflammatory sequelae of viral encephalitis, cerebral vascular accidents, and head trauma, anxiety disorders, stress, epilepsy, Parkinson s disease, movement disorders, and schizophrenia. The compounds are also useful for the treatment of substance abuse disorders, the treatment of obesity or eating disorders, as well as the treatment of asthma, constipation, chronic intestinal pseudo-obstruction, and cirrhosis of the liver.

Description

Acid amides with replacement of cannaboid-1 receptor active
Related application: do not have
Background of invention
Bang (Cannabis sativa L.) and derivative thereof are used for medicine and existing hundreds of years of entertainment purposes.The main active ingredient of hemp and hashish has been defined as Δ 9-tetrahydrocannabinol (Δ 9-THC).The detailed Δ that studies show that 9-THC and other member's of cannaboid family biological action is to be called as acceptor CB1 and CB2 and the G-albumen coupling by two kinds to take place.The CB1 acceptor mainly is present in maincenter and the peripheral nervous system, but also exists a small amount of in some peripheral organs.The CB2 acceptor mainly is present in Lymphoid tissue and the cell.Three kinds of endogenic ligands (anandamide, 2-arachidonic acylglycerol and 2-arachidonic acylglycerol ether) have been identified derived from arachidonic Cannabined receptor.They all are agonist, activity and Δ 9-THC is similar, comprises that calmness, cooling, intestines fix (intestinal immobility), anti-nociception, pain relieving, catalepsy, antiemetic and stimulate appetite.
People have carried out destroying the research of every kind of mouse Cannabined receptor gene.Taken CB1-/-mouse of acceptor shows normal and can give birth to.They resist Δ 9The effect of-THC, and showed the severity of syndromes after effect and the withdrawal of forcing that obviously alleviates morphine.They also demonstrate activity and the hypalgia activity that reduces motion.The excessive contact Δ 9-THC can cause gluttony, psychosis, hypothermia, memory loss and calmness.Has a kind of CB1 conditioning agent that is characterized as being inverse agonist or antagonist at present at least, N-(piperidino)-5-(4-chloro-phenyl-)-1-(2,4 dichloro benzene base)-4-methylpyrazole-3-methane amide (SR141716A) is used for the treatment of the eating disorder disease in clinical experiment.But still need be suitable for use as the CB1 of the lower molecular weight efficiently conditioning agent with pharmacokinetics and pharmacodynamic properties of human medicine.
It is found that the restraining effect that presynaptic cannabinoid CB 1 receptor mediation discharges cavy lung norepinephrine, can treat asthma for CB1 receptor modulators (as the CB1 inverse agonist) thus evidence (Europ.J.of Pharmacology is provided, 2001,431 (2), 237-244).
Have been found that the CB1 receptor modulators can reverse the ypotension of liver cirrhosis rat due to the tetracol phenixin, reduce the mesentery volume of blood flow and the portal venous pressure that increase, provide evidence (Nature Medicine, 2001 thereby treat liver cirrhosis for the CB1 receptor modulators, 7 (7), 827-832).
U.S. Pat 5,624,941 and US6,028,084, PCT application WO98/43636 and WO98/43635 and EPO application EP-658546 disclose the pyrazole compound of the replacement with anti-cannaboid receptor active.
PCT application WO98/31227 and WO98/41519 also disclose the substituted pyrazolecarboxylic compounds with anti-cannaboid receptor active.
PCT applies for WO98/37601, and WO00/10967 and WO00/10968 disclose the diaryl ether sulfonamides with anti-cannaboid receptor active.
PCT application WO97/29079 and WO99/02499 disclose alkoxyl group-isoindolone and the alkoxyl group-carbostyril compound with anti-cannaboid receptor active.
U.S. Pat 5,532,237 disclose the N-benzoyl-indole derivatives with anti-cannaboid receptor active.
U.S. Pat 4,973,587, US5,013,837, US5,081,122 and US5,112,820, US5,292,736 disclose the aminoalkyl indole derivative with anti-cannaboid receptor active.
PCT application WO01/58869 discloses pyrazoles, pyrroles and the imidazoles Cannibinoid receptor modulators of the disease relevant with leukocyte activation that can be used for treating respiratory tract and non-respiratory tract.
The PCT application WO01/64632,01/64633 and 01/64634 that transfers Aventis has described the azetidine derivatives that is used as the cannaboid antagonist.
Schultz, E.M etc. be at J.Med.Chem.1967, and in 10,717 and Pines, S.H. etc. are at J.Med.Chem.1967, and disclosing in 10,725 influences plasma cholesterol and penicillin excretory maleinamide acid compounds.
Compound of the present invention is the conditioning agent of cannaboid-1 (CB1) acceptor, thereby can be used for treatment, prevention and inhibition by the receptor-mediated disease of cannaboid-1 (CB1).Specifically, compound of the present invention is the antagonist or the inverse agonist of CB1 acceptor.The present invention relates to these compounds and regulate the purposes of cannaboid-1 (CB1) acceptor.Therefore, compound of the present invention can be used as the central action medicine for the treatment of following disease: psychosis, lethe, disturbance in cognition, migraine, neuropathy, nerve-inflammatory diseases comprise inflammatory sequela, cerebrovascular accident and a wound, anxiety disorder, emergency reaction, epilepsy, Parkinson's disease, dyskinesia and the schizophrenia of multiple sclerosis and Ge-Ba two syndromes and viral encephalitis.The compounds of this invention also can be used for the treatment of the abuse disease of substance abuse disease, particularly opiate, alcohol, hemp and Nicotine.The compounds of this invention can also be used for the treatment of eating disorder disease and consequent obesity and relative various complication by suppressing excessive ingestion of food.Compound of the present invention also can be used for the treatment of constipation and chronic pseudoileus, and is used for the treatment of asthma and liver cirrhosis.
Summary of the invention
The present invention relates to the amide compound of the replacement of new general formula I:
Figure A0380567800121
And pharmacologically acceptable salt, they are the antagonist and/or the inverse agonist of cannaboid-1 (CB1) acceptor, can be used for treatment, prevention and suppress cannaboid-1 (CB1) disease that acceptor mediated.The present invention relates to the optionally purposes of antagonism cannaboid-1 (CB1) acceptor of these new compounds.Therefore, compound of the present invention can be used as the central action medicine for the treatment of following disease: psychosis, lethe, disturbance in cognition, migraine, neuropathy, nerve-inflammatory diseases comprise inflammatory sequela, cerebrovascular accident and a wound, anxiety disorder, emergency reaction, epilepsy, Parkinson's disease, dyskinesia and the schizophrenia of multiple sclerosis and Ge-Ba two syndromes and viral encephalitis.Compound of the present invention also can be used for the treatment of the abuse disease of substance abuse disease, particularly opiate, alcohol, hemp and Nicotine.The compounds of this invention can also be used for the treatment of obesity or excessively absorb relevant eating disorder disease and relevant therewith various complication with food.Compound of the present invention also can be used for the treatment of constipation and chronic pseudoileus.Compound of the present invention also can be used for the treatment of liver cirrhosis.These compounds can also be used for the treatment of asthma.
The present invention also relates to these treatment of diseases, and The compounds of this invention is used for the treatment of application in the medicine of these diseases in preparation.The invention still further relates to by coming these diseases are treated with formula I compound and other existing medication combined administration.
The invention still further relates to new structural formula I compound.
The invention still further relates to and comprise the pharmaceutical preparation of a kind of The compounds of this invention as activeconstituents.
The invention further relates to the method for preparing The compounds of this invention.
Detailed Description Of The Invention
The compound of Shi Yonging is represented by compound in structural formula I or its pharmacologically acceptable salt in the methods of the invention:
Wherein:
R 1Be selected from:
(1) Heterocyclylalkyl,
(2) aryl,
(3) heteroaryl and
(4)-NR aR c；
Wherein aryl and heteroaryl are optional is independently selected from R by 1-3 bSubstituting group replace;
R 2Be selected from:
(1) C 1-10Alkyl,
(2) C 3-10Cycloalkyl-C 1-4Alkyl,
(3) aryl-C 1-4Alkyl and
(4) heteroaryl-C 1-4Alkyl;
Wherein cycloalkyl, aryl and heteroaryl randomly are independently selected from R by 1-3 separately bSubstituting group replace;
Each R aBe independently selected from:
(1) hydrogen,
(2) methyl and
(3)-CF 3；
Each R bBe independently selected from:
(1) halogen,
(2) cyano group,
(3) trifluoromethyl,
(4) trifluoromethoxy,
(5) C 1-3Alkoxyl group and
(6) C 1-3Alkyl;
R cBe independently selected from:
(1) hydrogen,
(2) C 1-6Alkyl,
(3) aryl,
(4) heteroaryl,
(5) aryl-methyl and
(6) heteroaryl-methyl,
Each R cCan be unsubstituted or be selected from R by 1-3 hSubstituting group replace;
R dBe independently selected from:
(1) cycloalkyl,
(2) aryl and
(3) heteroaryl,
Each R dCan be unsubstituted or be selected from R by 1-3 hSubstituting group replace;
Each R hBe independently selected from:
(1) halogen,
(2) C 1-3Alkyl,
(3)-CN and
(4)-CF 3，
Wherein under the unsubstituted situation of the nitrogen of pyridyl, they may optionally be the N-oxide form.
In one embodiment of the invention, R 1Be selected from:
(1) phenyl,
(2) pyridyl,
(3) indyl,
(4) 7-AZa-indolyl,
(5) thienyl and
(6)
Figure A0380567800141
Wherein each aryl and heteroaryl are optional is independently selected from R by 1 or 2 bSubstituting group replace, and each pyridyl is optional is the N-oxide form.
In a class this embodiment of the present invention, R 1Be selected from:
(1) phenyl,
(2) 3-cyano-phenyl,
(3) 3-aminomethyl phenyl,
(4) 3,5-difluorophenyls,
(5) 3-pyridyl,
(6) 5-chloro-3-pyridyl,
(7) 5-methyl-3-pyridyl,
(8) 5-cyano group-3-pyridyl,
(9) 1-oxidation-5-cyano group-3-pyridyl,
(10) 1-indyl,
(11) 7-azepine-indoles-N-base,
(12) the 2-thienyl and
(13)
Figure A0380567800151
In such group of the present invention, R 1Be 5-cyano group-3-pyridyl.
In another embodiment of the present invention, R 2Be selected from:
(1) C 1-6Alkyl,
(2) C 3-6Methyl cycloalkyl,
(3) phenmethyl,
(4) heteroaryl methyl,
Wherein each cycloalkyl, phenyl and heteroaryl are optional is independently selected from R by 1-3 bSubstituting group replace.
In a class this embodiment of the present invention, R 2Be selected from:
(1) C 1-6Alkyl,
(2) C 4-6Methyl cycloalkyl,
(3) phenmethyl,
(4) pyridyl,
Wherein each cycloalkyl, phenyl and heteroaryl are optional is independently selected from R by 1 or 2 bSubstituting group replace.
In such group of the present invention, R 2Be selected from:
(1) 2-methyl-propyl,
(2) n-pentyl,
(3) cyclobutylmethyl,
(4) cyclopentyl-methyl,
(5) cyclohexyl methyl,
(6) benzyl,
(7) 4-benzyl chloride base,
(8) 4-methyl-benzyl,
(9) 4-luorobenzyl,
(10) the 4-methoxy-benzyl and
(11) (5-chloro-2-pyridyl) methyl.
In one embodiment of the invention, each R aBe independently selected from:
(1) hydrogen,
(2) methyl and
(3)-CF 3。
In a class this embodiment of the present invention, each R aBe independently selected from:
(1) hydrogen and
(2) methyl.
In one embodiment of the invention, each R bBe independently selected from:
(1) halogen,
(2) cyano group,
(3) C 1-3Alkoxyl group and
(4) C 1-3Alkyl.
In a class this embodiment of the present invention, each R bBe independently selected from:
(1) fluorine,
(2) chlorine,
(3) bromine,
(4) iodine,
(5) cyano group,
(6) methoxyl group and
(7) methyl.
In the group of such scheme, each R bBe independently selected from:
(1) fluorine,
(2) chlorine,
(3) cyano group,
(4) methoxyl group and
(5) methyl.
In one embodiment of the invention, each R cBe independently selected from:
(1) hydrogen,
(2) C 1-6Alkyl,
(3) phenyl,
(4) pyridyl,
(5) benzyl and
(6) pyridyl-methyl;
Each R cCan be unsubstituted or be selected from R hSubstituting group replace.
In a class scheme, R cBe phenyl.
In one embodiment of the invention, R dBe selected from:
(1) C 4-6Cycloalkyl,
(2) aryl and
(3) heteroaryl,
R wherein dCan be unsubstituted or be selected from R by 1 or 2 hSubstituting group replace.
In a class the present invention, R dBe selected from:
(1) phenyl,
(2) pyridyl and
(3) pyrimidyl,
R wherein dCan be unsubstituted or be selected from R by 1 or 2 hSubstituting group replace.
In a group of the present invention, R dBe selected from:
(1) phenyl,
(2) 4-chloro-phenyl-,
(3) 3-chloro-phenyl-,
(4) 3,5-difluorophenyls,
(5) 3,5-dichlorophenyls,
(6) 2-pyridyl,
(7) 5-chloro-2-pyridyl,
(8) 6-methyl-2-pyridyl,
(9) 5-trifluoromethyl-2-pyridyl,
(10) 4-trifluoromethyl-2-pyridyl,
(11) 4-trifluoromethyl-2-pyrimidyl and
(12) 6-trifluoromethyl-4-pyrimidyl.
In another group of the present invention, R dBe 5-trifluoromethyl-2-pyridyl.
In one embodiment of the invention, each R hBe independently selected from:
(1) halogen,
(2) C 1-3Alkyl,
(3)-CN and
(4)-CF 3。
In this embodiment of a class, each R hBe independently selected from:
(1) fluorine,
(2) chlorine,
(3) methyl,
(4)-CN and
(5)-CF 3。
The concrete new compound that can be used in method of the present invention, purposes and the composition comprises:
(1) N-[3-(4-chloro-phenyl-)-1-methyl-2-phenyl propyl]-2-(4-chlorophenoxy)-2-methyl propanamide;
(2) N-[3-(4-chloro-phenyl-)-1-methyl-2-phenyl propyl]-2-(2-pyridyloxy)-2-methyl propanamide;
(3) N-[3-(4-chloro-phenyl-)-1-methyl-2-(3-pyridyl) propyl group]-2-(4-chlorophenoxy)-2-methyl propanamide;
(4) N-[3-(4-chloro-phenyl-)-1-methyl-2-phenyl propyl]-2-(3,5-two fluorophenoxies)-2-methyl propanamide;
(5) N-[3-(4-chloro-phenyl-)-2-phenyl-1-methyl-propyl]-2-(3, the 5-dichlorophenoxy)-2-methyl propanamide;
(6) N-[3-(4-chloro-phenyl-)-1-methyl-2-phenyl propyl]-2-(3-chlorophenoxy)-2-methyl propanamide;
(7) N-[3-(4-chloro-phenyl-)-2-(3, the 5-difluorophenyl)-1-methyl-propyl]-2-(2-pyridyloxy)-2-methyl propanamide;
(8) N-[3-(4-chloro-phenyl-)-1-methyl-2-phenyl propyl]-2-(5-chloro-2-pyridyloxy)-2-methyl propanamide;
(9) N-[3-(4-chloro-phenyl-)-1-methyl-2-phenyl propyl]-2-(6-methyl-pyridyloxy)-2-methyl propanamide;
(10) N-[3-(4-chloro-phenyl-)-1-methyl-2-phenyl propyl]-2-(phenoxy group)-2-methyl propanamide;
(11) N-[3-(4-chloro-phenyl-)-1-methyl-2-phenyl propyl]-2-(5-5-flumethiazine oxygen base)-2-methyl propanamide;
(12) N-[3-(4-chloro-phenyl-)-2-(3-pyridyl)-1-methyl-propyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methyl propanamide;
(13) N-[3-(4-chloro-phenyl-)-2-(3-cyano-phenyl)-1-methyl-propyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methyl propanamide;
(14) N-[3-(4-chloro-phenyl-)-2-(5-chloro-3-pyridyl)-1-methyl-propyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methyl propanamide;
(15) N-[3-(4-chloro-phenyl-)-2-(5-methyl-3-pyridyl)-1-methyl-propyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methyl propanamide;
(16) N-[3-(4-chloro-phenyl-)-2-(5-cyano group-3-pyridyl)-1-methyl-propyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methyl propanamide;
(17) N-[3-(4-chloro-phenyl-)-2-(3-aminomethyl phenyl)-1-methyl-propyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methyl propanamide;
(18) N-[3-(4-chloro-phenyl-)-2-phenyl-1-methyl-propyl]-2-(4-trifluoromethyl-2-pyridyloxy)-2-methyl propanamide;
(19) N-[3-(4-chloro-phenyl-)-2-phenyl-1-methyl-propyl]-2-(4-trifluoromethyl-2-2-pyrimidinyl oxy)-2-methyl propanamide;
(20) N-[3-(4-chloro-phenyl-)-1-methyl-2-(thiene-3-yl-) propyl group]-2-(5-chloro-2-pyridyloxy)-2-methyl propanamide;
(2 1) N-[3-(5-chloro-2-pyridyl)-2-phenyl-1-methyl-propyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methyl propanamide;
(22) N-[3-(4-aminomethyl phenyl)-1-methyl-2-phenyl propyl]-2-(4-4-trifluoromethylphenopendant)-2-methyl propanamide;
(23) N-[3-(4-fluorophenyl)-2-(3-cyano-phenyl)-1-methyl-propyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methyl propanamide;
(24) N-[3-(4-chloro-phenyl-)-2-(1-indyl)-1-methyl-propyl]-2-(5-trifluoromethyl-2-oxygen yl pyridines-2-yl)-2-methyl propanamide;
(25) N-[3-(4-chloro-phenyl-)-2-(7-azaindole-N-yl)-1-methyl-propyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methyl propanamide;
(26) N-[3-(4-chloro-phenyl-)-2-(1-indolinyl)-1-methyl-propyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methyl propanamide;
(27) N-[3-(4-chloro-phenyl-)-2-(methylphenylamine base)-1-methyl-propyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methyl propanamide;
(28) N-[3-(4-p-methoxy-phenyl)-2-(3-cyano group-phenyl)-1-methyl-propyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methyl propanamide;
(29) N-[3-(4-chloro-phenyl-)-2-(3-cyano-phenyl)-1-methyl-propyl]-2-(6-trifluoromethyl-4-2-pyrimidinyl oxy)-2-methyl propanamide;
(30) N-[2-(3-cyano-phenyl)-1,4-dimethyl amyl group]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methyl propanamide;
(31) N-[3-(4-chloro-phenyl-)-2-(1-oxidation-5-cyano group-3-pyridyl)-1-methyl-propyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methyl propanamide;
(32) N-[2-(3-cyano-phenyl)-3-cyclobutyl-1-methyl-propyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methyl propanamide;
(33) N-[2-(3-cyano-phenyl)-1-methylheptyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methyl propanamide;
(34) N-[2-(3-cyano-phenyl)-3-cyclopentyl-1-methyl-propyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methyl propanamide;
(35) N-[2-(3-cyano-phenyl)-3-cyclohexyl-1-methyl-propyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methyl propanamide;
And their pharmacologically acceptable salt.
" alkyl ", and other group (as alkoxyl group, alkyloyl) with prefix " alkane " is meant it can is the carbochain of straight or branched or its combination.The example of alkyl comprise methyl, ethyl, propyl group, sec.-propyl, butyl, the second month in a season-and tert-butyl, amyl group, hexyl, heptyl, octyl group, nonyl etc.
" cycloalkyl " is meant saturated monocycle or two ring or bridged ring carbocyclic rings, and they have 3-10 carbon atom separately.For example, cycloalkyl comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl or the like.
" aryl " is meant the monocycle or the two cyclophane rings of a carbon atoms.The example of aryl comprises phenyl, naphthyl etc.
" heteroaryl " is meant and comprises at least one heteroatomic monocycle that is selected from N, O and S or two cyclophane rings, and wherein each ring comprises 5-6 atom.The example of heteroaryl comprise pyrryl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazole base, thiadiazolyl group, thiazolyl, imidazolyl, triazolyl, tetrazyl, furyl, triazinyl, thienyl, pyrimidyl, pyridazinyl, pyrazinyl, benzoxazolyl, benzothiazolyl, benzimidazolyl-, benzofuryl, benzothienyl, furo (2,3-b) pyridyl, quinolyl, indyl, isoquinolyl, Imidazothiazole base etc.Particularly including pyridyl, pyrimidyl and thienyl, heteroaryl ring can be substituted on one or more carbon or nitrogen-atoms " heteroaryl ".
" Heterocyclylalkyl " is meant that comprising at least one is selected from N, S and heteroatomic saturated monocycle of O or two ring or bridged rings, and described ring contains 3-10 atom separately, and wherein link position can be carbon or nitrogen.This term comprises also and aryl or heteroaryl-condensed single heterocycle that wherein link position is positioned at non-aromaticity part.The example of " Heterocyclylalkyl " comprises indyl, azaindolyl etc.Heterocycloalkyl ring can be substituted on ring carbon and/or theheterocyclic nitrogen atom.
" halogen " comprises fluorine, chlorine, bromine and iodine.
As any variable (R for example 1, R dDeng) definition the when definition when it occurs at every turn all is independent of it and occurs under other occasion appears in any part or formula I when once above.And as long as the combination of substituting group and/or variable can produce stable compound, so this combination allows.
In the standard name of using in this specification, the terminal portions of side chain is thereafter the adjacent functional group towards link position shown at first describing.For example, C 1-5Alkyl-carbonyl-amino C 1-6Alkyl substituent is equal to:
Figure A0380567800211
When selecting compound of the present invention, this area those of ordinary skill will recognize that various different substituents (are R 1, R 2Deng) selection should follow chemical structure connection and stability known principles.
Term " replacement " should be believed to comprise by alleged substituting group and replace repeatedly.When open or claimed a plurality of substituting group part, the compound of described replacement can be independently replaced or polysubstituted by one or more disclosed or claimed substituting groups parts are single.The independent meaning that replaces is meant that (two or more) substituting group can be identical or different.
Therefore formula I compound may contain one or more asymmetric centers, can exist with the form of racemic modification and racemic mixture, single enantiomer, non-enantiomer mixture and independent diastereomer.The present invention includes all isomeric forms of formula I compound.
In the compound described herein some contains olefinic double bond, therefore also comprises E and two kinds of geometrical isomers of Z except that specializing the present invention.
Tautomer is meant that proton can move to compound on another atom of compound rapidly from an atom of compound.In the compound described herein some can exist with the tautomeric forms with different hydro atom tie point.The example of this type of tautomer can be ketone and the enol thereof that is called as the keto-enol tautomerism body.Single tautomer and composition thereof is included in the formula I compound.
By for example using appropriate solvent (such as MeOH or EtOAc or its mixture) fractional crystallization, can be that the enantiomorph of non-mapping is right with formula I compound separation.And then for example use optically active amine as resolving agent or the enantiomorph that utilizes chirality HPLC post so to obtain by ordinary method, can be separated into single steric isomer.
Perhaps, use the optically pure raw material of configuration known or reagent to pass through stereospecific synthesis, also can obtain any enantiomorph of compound of Formula I.
Usually preferably use compound of the present invention with the dosage form of enantiomer-pure.Can be single enantiomorph with racemic mixture by multiple ordinary method.These methods comprise chiral chromatography, use chiral auxiliary(reagent) to derive, and utilize chromatography or Crystallization Separation thereafter, and the fractional crystallization diastereoisomeric salt.
In addition, can there be polymorphic forms in some crystal formations of The compounds of this invention, so these polymorphics are also included among the present invention.In addition, some in the The compounds of this invention can form solvate with water or common organic solvent.These solvates are also included within the scope of the present invention.
Term " pharmacologically acceptable salt " is meant the salt by pharmaceutically useful nontoxic alkali or acid (comprising inorganic or organic bases and inorganic or organic acid) preparation.Comprise aluminium salt, ammonium salt, calcium salt, mantoquita, molysite, ferrous salt, lithium salts, magnesium salts, manganic salt, manganous salt, sylvite, sodium salt, zinc salt etc. by the mineral alkali salt that obtains of deriving.Preferred especially ammonium salt, calcium salt, magnesium salts, sylvite and sodium salt.Comprise primary amine by the pharmaceutically useful non-toxic organic alkali salt that obtains of deriving, secondary amine or tertiary amine, replace amine and comprise naturally occurring replacement amine, the salt of cyclammonium and deacidite, the salt of following amine for example: arginine, trimethyl-glycine, trimethyl-xanthine, choline, N, N '-dibenzyl-ethylenediamin, diethylamine, the 2-DEAE diethylaminoethanol, the 2-dimethylaminoethanol, thanomin, quadrol, N-ethylmorpholine, N-ethylpiperidine, glycosamine, glucosamine, Histidine, breathe out amine, Isopropylamine, Methionin, methylglucosamine, morpholine, piperazine, piperidines, the polyamines resin, PROCAINE HCL, PHARMA GRADE, purine, Theobromine, triethylamine, Trimethylamine 99, tripropyl amine, Trometamol etc.Term " pharmacologically acceptable salt " can further comprise all acceptable salt; as acetate; Lactobionate; benzene sulfonate; lauroleate; benzoate; malate; supercarbonate; maleate; hydrosulfate; mandelate; bitartrate; mesylate; borate; MB; bromide; methyl nitrate; Ca-EDTA salt; Methylsulfate; camsilate; mucate; carbonate; naphthalenesulfonate; muriate; nitrate; clavulanate; the N-methylglucosamine; Citrate trianion; ammonium salt; dihydrochloride; oleate; edetate; oxalate; ethanedisulphonate; pounce on the nurse hydrochlorate; dodecyl sulfate; palmitate; esilate; pantothenate; fumarate; phosphoric acid salt/diphosphate; gluceptate; polygalacturonate; gluconate; salicylate; glutaminate; stearate; glycoloyl is to the swollen hydrochlorate of aminophenyl; vitriol; Sucrets salt; subacetate; breathe out amine; succinate; hydrobromate; tannate; hydrochloride; tartrate; Hydroxynaphthoate; 8-Chlorotheophyline; iodide; tosylate; different thion hydrochlorate; triethyl alkoxide (triethiodide); lactic acid salt; panoate; valerate etc.; they can be used as the formulation that is used to improve dissolving or hydrolysis properties, maybe can be used for lasting discharge or prodrug formulation.
Should be appreciated that when mentioning formula I compound in this article, also comprise its pharmacologically acceptable salt.
Compound of the present invention is the conditioning agent of CB1 acceptor.Specifically, compound in structural formula I is the antagonist or the inverse agonist of CB1 acceptor.
" agonist " is meant this compound (hormone, neurotransmitter or synthetic compound), its energy and receptors bind, bringing out receptor conformation changes, produce subsequently and react like the caused response class of agonist ligand relevant on the physiology with acceptor, such as reactions such as contraction, loose, secretion, enzyme activity changes." antagonist " is meant the compound of the effect that can weaken agonist." inverse agonist " refers to act on acceptor but produces the compound opposite with the effect that agonist produced of special receptor.
The compounds of this invention is the conditioning agent of CB1 acceptor, thereby can be used as the central action medicine that the following disease of treatment is used: psychosis, lethe, disturbance in cognition, migraine, neuropathy, neural inflammatory diseases comprise inflammatory sequela, cerebrovascular accident and a wound, anxiety disorder, emergency reaction, epilepsy, Parkinson's disease, dyskinesia and the schizophrenia of multiple sclerosis and Ge-Ba two syndromes and viral encephalitis.The compounds of this invention also can be used for the treatment of the abuse disease of substance abuse disease, particularly opiate, alcohol, hemp and Nicotine.The compounds of this invention can also be used for the treatment of obesity or excessively absorb relevant eating disorder disease and relevant therewith various complication with food.Compound of the present invention also can be used for the treatment of constipation and chronic pseudoileus.The compounds of this invention also can be used for the treatment of liver cirrhosis.These compounds can also be used for the treatment of asthma.
Term " administration " and/or " using " compound should be understood the prodrug that the individuality of showing the needs treatment provides The compounds of this invention or The compounds of this invention.
For implementing methods of treatment of the present invention,, can finish the administration of structural formula I compound by the compound in structural formula I that the patient to this treatment of needs or prevention uses significant quantity.The method according to this invention, the needs of preventive administration determine by adopting known Hazard Factor.In final analysis, the significant quantity of individuation compound determined by the doctor in charge, and depend on multiple factor as subject definite disease, as described in other concomitant drugs and the route of administration of therapeutant and the other factors in doctor's deterministic process of the severity of disease and other disease that the patient suffers from or disease, needs of patients.
The animal disease model that the effectiveness of The compounds of this invention in these diseases or illness has been reported in can be with document confirms.Be the example of this class animal disease model below: a) suppress ingestion of food.And the rat weight saving that produces (Life Sciences 1998,63,113-117); B) the sweet food picked-up of minimizing marmoset (Behavioural Pharm.1998,9,179-181); C) reduce the sucrose of mouse and alcohol panning (Psychopharm.1997,132,104-106); D) locomotor activity of enhancing rat improves position sense (Psychopharm.1998,135,324-332; Psychopharmacol 2000,151:25-30); E) the autonomic movement activity of mouse (J.Pharm.Exp.Ther.1996,277,586-594); F) the personal opiate behavior of minimizing mouse (Sci.1999,283,401-404); G) as same period not asthmatic model sheep and the segmental bronchus hyperergy of cavy (for example, referring to W.M.Abraham etc., " α 4The tardy property of-6 integrin-mediated sheep segmental bronchus reaction and the prolongation of air flue hyperergy " J.Clin.Invest.93; 776 (1993) and A.A.Y.Miline and P.P.Piper; " effect of VLA-4 integrin in cavy leukocyte recruitment and segmental bronchus hyperergy "; Eur.J.Pharmacol.; 282,243 (1995)); H) the mediation of the severe hepatic cirrhosis medium vessels diastole state due to tetracol phenixin (Nature Medicine, 2001,7 (7), 827-832); I) due to the amitriptyline macaque constipation be used to estimate laxative (Biol.Pharm.Bulletin (Japan), 2000,23 (5), 657-9); J) neuropathology of the chronic pseudoileus of paediatrics and the animal model relevant with the neuropathology of the chronic pseudoileus of paediatrics (Journalof Pathology (England), 2001,194 (3), 277-88).
The prevention of formula I compound or the size of therapeutic dose should change with the severity of being treated disease, concrete formula I compound and route of administration thereof certainly.Equally also age, body weight and the reaction with individual patients changes.In general, the per daily dose scope is the about 100mg/ kilogram of an about 0.001mg-weight of mammal, and the preferred about 50mg/kg of 0.01mg-, and 0.1-10mg/kg most preferably give usefulness with single dose or the multidose that separates.On the other hand, in some cases, may need to use the dosage that exceeds these scopes.
For the application of using the intravenously administrable composition, the appropriate dosage scope is the about 25mg of the about 0.001mg-of every kg body weight every day (the preferred about 1mg of a 0.01mg-) formula I compound, and for prophylactic application, it then is the formula I compound of the about 100mg of the about 0.1mg-of every kg body weight every day (the about 100mg of preferably about 1mg-, the more preferably from about about 10mg of 1mg-).
For the situation of oral compositions, the appropriate dosage scope for example is the formula I compound of the about 1000mg of about 0.01mg-every day, the preferred about 10mg of about 0.1mg-every day.For oral administration, composition preferably is tablet form, wherein comprises 0.01-1000mg, and preferred 0.01,0.05,0.1,0.5,1,2.5,5,10,15,20,25,30,40,50,100,250,500,750 or 1000 milligrams of activeconstituentss, adjustment imposes on the dosage of being treated the patient according to symptom.
Another aspect of the present invention provides pharmaceutical composition, and it comprises formula I compound and pharmaceutically acceptable carrier.Term " composition " in pharmaceutical composition, be intended to contain the product that comprises activeconstituents and constitute one or more inert fractions (pharmaceutically acceptable vehicle) of carrier, and by combination, compound or assemble any two or more compositions, or by one or more compositions that dissociate, or other type reaction by one or more compositions or react to each other and any product of directly or indirectly forming.Therefore, pharmaceutical composition of the present invention comprises any composition that obtains by hybrid I compound, one or more other activeconstituentss and pharmaceutically acceptable vehicle.
Can use any suitable route of administration that the The compounds of this invention of effective dose is provided as Mammals (particularly human).For example, can adopt approach such as oral, rectum, part, parenteral, eye, lung, nasal cavity.Formulation comprises tablet, lozenge, dispersion liquid, suspensoid, solution, capsule, ointment, aerosol etc.
Pharmaceutical composition of the present invention comprises the formula I compound or pharmaceutically acceptable salt thereof as activeconstituents, also can contain pharmaceutically useful carrier and other optional treatment component.Term " pharmaceutically useful " be meant carrier, thinner or vehicle must with other component compatibility of preparation, and harmless to the recipient.Specifically, " pharmacologically acceptable salt " is meant the salt by pharmaceutically useful nontoxic alkali or acid (comprising mineral alkali or mineral acid or organic bases or organic acid) preparation.
Described composition comprises the composition that is applicable to following administration: oral, rectum, part, parenteral (comprising subcutaneous, intramuscular and vein), eye (eye with), lung's (aerosol inhalation) or intranasal administration, but the most suitable approach depends on the character of being treated disease and the character of severity and described activeconstituents under any given situation.They can provide easily with unit dosage, and the method for knowing according to pharmacy field is prepared.
For inhalation, The compounds of this invention is with the form administration easily of the aerosol spray that provided by pressurized package container or atomizer.The compounds of this invention can also be with the form administration of processing pulvis, and this dust composition can suck by being blown into the formula powder inhalator.Inhalant preferred drug delivery system is that quantitative suction (MDI) aerosol (it can prepare suspension or the solution form of accepted way of doing sth I compound in suitable propelling agent such as hydrofluoric ether or hydro carbons) and powder suck (DPI) aerosol, and the latter can be formulated into the dry powder form of the formula I compound that contains or do not contain other vehicle.
The preparation that is fit to the formula I compound of local usefulness comprises preparation capable of permeating skin, aerosol, creme, solution, ointment, gelifying agent, lotion, the agent etc. of dusting.The pharmaceutical composition that comprises the part usefulness of The compounds of this invention comprises the active compound of about 0.005%-5% weight and the pharmaceutically acceptable vehicle of blended with it usually.The skin that is applicable to the administration The compounds of this invention with patch comprise known to a person of ordinary skill in the art those.During with the form administration of transdermal drug delivery system, in whole dosage regimen should be continuously but not intermittently administration.
In actual applications, can activeconstituents formula I compound and pharmaceutical carrier densification be mixed according to the hybrid technology of conventional pharmacy.According to the dosage form of administration needs, the form of the required preparation of per os or parenteral (comprising intravenously) administration for example, described carrier can be various form.When the composition of preparation oral dosage form, can use any common medicinal medium, for example when preparing oral liquid such as suspensoid, elixir and solution, can make water, dibasic alcohol, oil, alcohol, perfume compound, sanitas, tinting material etc.; And, can use carrier such as starch, sugar, Microcrystalline Cellulose, thinner, granulating agent, lubricant, tackiness agent, disintegrating agent etc. for for example preparation of pulvis, capsule and tablet of oral solid formulation, and with respect to liquid preparation, more preferably solid orally ingestible.Because tablet and capsule are easy to administration, they become best oral dosage unit form, obviously use the solid medicinal carrier in this case.If desired, can use the water-based of standard or non-aqueous technology that tablet is carried out dressing.
The pharmaceutical composition of the present invention that is fit to oral administration can exist with unit independently, for example capsule (comprising time release formulation and sustained release preparation), pill, cachet, pulvis, granule or tablet, the activeconstituents of their each self-contained predetermined amounts, perhaps be the form of powder or granule or the solution in waterborne liquid, non-aqueous liquid or suspension, oil-in-water emulsion or water-in-oil emulsion, comprise elixir, tincture, solution, suspensoid, syrup and emulsion.This based composition can prepare with any pharmaceutical methods, but all methods all comprise activeconstituents and the carrier blended step that must be become to be grouped into by one or more.Usually, described preparation of compositions comprises mixes densely with activeconstituents and liquid vehicle or finely divided solid carrier or the two are all even, as required product is configured as the form that needs then.For example, suppress or moldedly can prepare tablet with one or more ancillary components by optional.In suitable machine, by compacting randomly with the activeconstituents of the mixed free-flowing form of tackiness agent, lubricant, inert diluent, tensio-active agent or dispersion agent, can prepare the tablet of compacting.Molded tablet can prepare by the mixture of mold pressing in suitable machine with the moistening powder compound of inert liquid diluent.It is desirable to, every tablet of tablet comprises 0.01-1000mg, particularly 0.01,0.05,0.1,0.5,1,2.5,3,5,6,10,15,25,50,75,100,125,150,175,180,200,225,500,750 and 1000 milligrams activeconstituents, and regulate the dosage that gives subject patient according to symptom, every cachet or capsule then comprise about 0.01-1,000mg, particularly 0.01,0.05,0.1,0.5,1.0,2.5,3,5,6,10,15,25,50,75,100,125,150,175,180,200,225,500,750 and 1,000 milligram of activeconstituents is wherein regulated the dosage that gives subject patient according to symptom.
Other suitable mode of using The compounds of this invention comprises injection, intravenous injection or infusion, intraperitoneal, subcutaneous, intramuscular and topical, can be embedding or not embedding mode.
Example of the present invention is the pharmaceutical composition that comprises any above-claimed cpd and pharmaceutically acceptable carrier.Another example of the present invention is by mixing the pharmaceutical composition that any above-claimed cpd and pharmaceutically acceptable carrier are made.A method that example is a pharmaceutical compositions of the present invention, this method comprise mixes any above-claimed cpd and pharmaceutically acceptable carrier.
Described dosage can give with single per daily dose form, and perhaps total per daily dose gives with the dosage that separates of every day twice, three times or four times.In addition, the character according to the particular compound of selecting administration may not need the described dosage of administration continually, for example is administered once weekly, twice or every month one is inferior.For the low frequency administration, unitary dose should correspondingly increase.
When by approach, transdermal route in the nose, during by rectum or vaginal suppository or by continuous intravenous solution administration, the administration in the whole dosage regimen should be continuously but not intermittently carry out.
Below be the example of the typical medicaments formulation of formula I compound:
Injection suspension (I.M.) mg/mL
Formula I compound 10
Methylcellulose gum 5.0
Tween 80 0.5
Benzylalcohol 9.0
Benzalkonium chloride 1.0
Add the cumulative volume of injection water to 1mL.
Tablet mg/ sheet
Formula I compound 25
Microcrystalline Cellulose 415
Polyvinylpyrrolidone 14.0
The starch 43.5 of pre-gelledization
Magnesium Stearate 2.5
500
Capsule mg/ capsule
Formula I compound 25
Lactose powder 573.5
Magnesium Stearate 1.5
600
Every jar of aerosol
Formula I compound 24mg
Yelkin TTS, NF liquid concentrate 1.2mg
Trichlorofluoromethane, NF 4.025g
Refrigerant 12, NF 12.15g
Formula I compound can be used for the treatment of/prevent/suppress or alleviate that formula I compound is fit to the disease of treatment or the other medicines of illness are united use.These other medicines can be by approach and consumption and the administration simultaneously or sequentially of formula I compound commonly used.When formula I compound and one or more other medicines are used simultaneously, the preferred pharmaceutical composition that comprises formula I compound and these other medicines that uses.Therefore, pharmaceutical composition of the present invention comprises that those also contain the pharmaceutical composition of one or more other activeconstituentss except containing formula I compound.Can include but not limited to the example of other activeconstituents of formula I compound coupling: major tranquilizer, understanding toughener, anti-migraine agent, antiasthmatics, antiphlogistic, separate anxiety agent, Antiparkinsonian agent, Anti-epileptics, appetite-inhibiting agent and serotonin reuptake inhibitor, and other antiobesity agent, they can be used separately or use in same pharmaceutical composition.
Should be appreciated that when being used for the treatment of or prevent to comprise the feed disease of obesity, bulimia nervosa and mandatory feed disease, compound of the present invention can share with other appetite-inhibiting agent.
The present invention also provides the method for a kind of treatment or prevention feed disease, and this method comprises The compounds of this invention and an amount of appetite-inhibiting agent, as a result their the jointly generation effective mitigation an amount of to patient's administration of this treatment of needs.
" obesity " is the too much symptom of body fat.The definition of the obesity of carrying out is a benchmark with weight index (MBI), the latter is calculated as square (kg/m of body weight/height 2)." obesity " be meant others health but weight index (BMI) more than or equal to 30kg/m 2The state of individuality, or refer to have at least a complication and BMI more than or equal to 27kg/m 2Individual state." obese person " be meant others health but weight index (BMI) more than or equal to 30kg/m 2Individuality, or have at least a complication and BMI more than or equal to 27kg/m 2Individuality." obesity dangerous individual " is meant others health, 25kg/m 2≤ BMI＜30kg/m 2Individual or have at least a complication and a 25kg/m 2≤ BMI＜27kg/m 2Individuality.
There is the higher danger relevant with obesity down in asian population at under-weight index (BMI).In the Asian countries that comprises Japan, " obesity " is meant that BMI is more than or equal to 25kg/m 2, have at least aly by due to the obesity or the state of the individuality of the complication relevant with obesity, this complication need reduce body weight or be improved by losing weight.In the Asian countries that comprises Japan, " obese person " is meant that BMI is more than or equal to 25kg/m 2, have at least aly by due to the obesity or the individuality of the complication relevant with obesity, this complication need reduce body weight or be improved by losing weight.In Asian countries, " obesity dangerous individual " is meant that BMI is greater than 23kg/m 2But less than 25kg/m 2Individuality.
Term used herein " obesity " is intended to comprise the obesity of above-mentioned various definition.
By due to the obesity or the complication relevant with obesity include but not limited to diabetes, II type non-insulin-dependent diabetes mellitus (NIDDM), impaired glucose tolerance, fasting plasma glucose deficiency (impaired fastingglucose), insulin resistance syndromes, hyperlipemia, hypertension, hyperuricemia, gout, coronary artery disease, myocardial infarction, chest stenocardia sleep apnea, Pickwick syndromes, fatty liver; Cerebral infarction, cerebral thrombosis, transient ischemic attack, shaping disease, arthritis deformans, pain in the back, menopathy, and infertility.Complication is particularly including hypertension, hyperlipidaemia, hyperlipemia, glucose intolerance, cardiovascular diseases, sleep apnea, diabetes, and other illness relevant with obesity.
" treatment " (obesity and the illness relevant with obesity) is meant that administration compound of the present invention or composition are in order to alleviate or to keep obese person's body weight.A kind of result of treatment is with respect to proper patient's body weight before administration compound of the present invention or composition, can alleviate obese person's body weight.The another kind of result of treatment is the recovery again that can prevent before the body weight that deducts owing to diet, motion or pharmacotherapy.The another kind of the possibility of result of treatment can reduce the disease generation relevant with obesity and/or alleviate its severity.Treatment may suitably make patient's food or calorie intake reduce, and comprises that the total foodstuff intake reduces, or the picked-up of the special component in the diet such as carbohydrate or fat reduces; And/or the absorption of inhibition nutritive ingredient; And/or the reduction of inhibition metabolic rate; And alleviate the patient's who needs treatment body weight.The result of treatment changes metabolic rate, for example increases metabolic rate, rather than suppresses the metabolic rate reduction or can also increase metabolic rate except that the inhibition metabolic rate reduces; And/or the caused metabolism of common loss of weight hindered reduce to minimum degree.
" prevention " (obesity and the illness relevant with obesity) is meant that administration compound of the present invention or composition are in order to alleviate or to keep the body weight of obesity dangerous individual.A kind of result of prevention is with respect to proper individual body weight before administration compound of the present invention or composition, can alleviate the body weight that is in the individuality among the obesity danger.The another kind of result of prevention is the recovery again that can prevent before the body weight that deducts owing to diet, motion or pharmacotherapy.The another kind of result of prevention is if being in individuality among the fat danger just took medicine before the beginning obesity and treat, and then can stop fat the generation.The another kind of result of prevention is if just took medicine before the beginning obesity and treat being in individuality among the fat danger, then can reduce the disease generation relevant with obesity and/or alleviate its severity.In addition, if treatment is that fat individuality is begun, then this treatment can prevent with the generation of fat relevant disease, block its progress or alleviate its severity, and described disease is (but being not limited to) arteriosclerosis, type ii diabetes, many cystic ovaries disease, cardiovascular diseases, osteoarthritis, tetter, hypertension, insulin resistance, hypercholesterolemia, hypertriglyceridemia and chololithiasis for example.
The illness relevant with obesity is with fat relevant or by due to the obesity or cause.The example of the illness relevant with obesity comprises gluttony and Bulimia nerovsa, hypertension, diabetes, high plasma insulin concentration and insulin resistance, hyperlipemia, hypercholesterolemia, carcinoma of endometrium, mammary cancer, prostate cancer and colorectal carcinoma, osteoarthritis, obstructive sleep apnea, chololithiasis, gallbladdergallstonecholetithiasis, heart trouble, the unusual and arrhythmia of cardiac rhythm, myocardial infarction, congestive heart failure, coronary heart disease, sudden death, apoplexy, polycystic disease and ovariopathy, craniopharyngioma, Pu-Wei two syndromes, Fu Lelixi syndrome, GH-lacks the patient, normal variant height is short and small, and other illness that low metabolic activity of Tener that syndrome and demonstration or rest energy expenditure (as the percentage ratio of total degreasing quality) reduce is for example suffered from acute lymphoblastic leukemia.Other example of the illness relevant with obesity is a metabolic syndrome, also claim the X syndromes, insulin resistance syndrome, sexual dysfunction and growing barrier, as Infertility, male gonad hypofunction and female hirsutism, the active obstacle of stomach and intestine is as the obesity-related gastroesophageal reflux, dyspnoea, as the obesity low syndromes (Pickwick syndromes) of ventilating, cardiovascular diseases, inflammation, systemic inflammation as vascular system, arteriosclerosis, hypercholesterolemia lipidemia, hyperuricemia, back pain, cholecystopathy, gout, and kidney.Composition of the present invention also is applicable to the danger of the Secondary cases morbidity that reduces obesity, for example reduces the danger of left ventricular hypertrophy.
Term used herein " diabetes " comprises two kinds of insulin-dependent diabetes (be IDDM, also claim type i diabetes) and non-insulin-dependent diabetes mellitus (NIDDM) (be NIDDM, also claim type ii diabetes).Type i diabetes, or insulin-dependent diabetes are absolute damaged the causing owing to Regular Insulin, and Regular Insulin is the hormone of regulating glucose utilization.Type ii diabetes or Regular Insulin independence diabetes (being non-insulin-dependent diabetes mellitus (NIDDM)), usually be normal or even the situation of the insulin level that raises under take place, and may be that tissue can not be replied the result of Regular Insulin suitably.Most of type ii diabetes also show obesity.Compound of the present invention and composition can be used for treating I type and II type two paradiabetess.Compound of the present invention and composition are effective especially for the treatment of type ii diabetes.Compound of the present invention and composition also can be used for treating and/or preventing gestational diabetes.
Term used herein " substance abuse disease " comprises substance depilatory or has or do not have the substance abuse of physical dependence.The material relevant with these illnesss is: alcohol, amphetamine (or class amphetamine material), caffeine, hemp products, Cocaine, halluoinogen class, inhalation class, cannaboid (marijuana), Nicotine, opioid, phencyclidine (or class phencyclidine compound), the mutual benzodiazepines of tranquilizing soporific class material, and the combination of other (or unknown) material and all above-mentioned substances.
Term " substance abuse disease " particularly including drug withdrawal disease as with or without the disorderly abstinence from alcohol of consciousness reaction; The smart delirium of abstinence from alcohol; Amphetamine de-addiction brain syndromes; Narcotic withdrawal brain syndromes; Opiates de-addiction brain syndromes; With or tranquilizer, soporific or the anxiolytic de-addiction brain syndromes of imperception reaction obstacle; Tranquilizer, soporific or anxiolytic de-addiction delirium; And the withdrawal symptom syndromes that causes of other material.Should be appreciated that the treatment that comprises when mentioning treatment narcotic withdrawal brain syndromes the symptom relevant with smoking cessation.
Other " substance abuse disease " comprises the caused anxiety disorder of showing effect of material during withdrawal symptom; The caused mood disorder that during withdrawal symptom, shows effect of material; And the caused somnopathy of during withdrawal symptom, showing effect of material.
Should be appreciated that the coupling of conventional antipsychotics and CB1 receptor modulators can improve the effect of treatment mania.This class coupling medicine expection can provide the quick acting effect to the treatment of maniac access, thereby can become the prescription drug on " Demand Base ".In addition, this coupling can also reduce the using dosage of major tranquilizer, but can not weaken the effectiveness of major tranquilizer, thereby the danger of untoward reaction is reduced to minimum level.Because the effect of CB1 receptor modulators, another advantage of this coupling be bad side reaction such as acute dystonia, the dyskinesia that can reduce or prevent to be caused by major tranquilizer, cathisophobia and tremble.
The present invention also provides treatment or has prevented manic method, this method comprises the patient of this treatment of needs or is in patient administration proper C B1 receptor modulators and an amount of major tranquilizer of development among the manic danger, makes their produce effective mitigation jointly.
Should be appreciated that CB1 receptor modulators and major tranquilizer can be to be used for the treatment of or to prevent manic combined preparation form simultaneously, respectively or in proper order.
Should be appreciated that CB1 receptor modulators and major tranquilizer can be in same pharmaceutically acceptable carrier, thereby can give simultaneously and use when using coupling medicine of the present invention.They can be in the isolating pharmaceutical carrier, as the conventional oral dosage form of while administration.Term " coupling medicine " refers to that also each compound is wherein provided by isolating formulation and the medicine of order administration.Therefore, as an example, major tranquilizer can be with the tablet form administration, and in the suitable time limit, the CB1 receptor modulators can be with oral dosage form such as tablet or the administration of fast dissolving orally formulation then." fast dissolving orally preparation " be meant when being placed on the patient's tongue can be in about 10 seconds the dissolved oral Preparation.
Should be appreciated that the conventional antipsychotic drug and the coupling of CB1 receptor modulators can improve schizoid therapeutic action.This class coupling medicine expection can provide the quick acting effect to schizoid treatment, thereby can become the prescription drug on " Demand Base ".In addition, this coupling can also reduce the using dosage of major tranquilizer, but can not weaken the effectiveness of major tranquilizer, thereby the danger of untoward reaction is reduced to minimum level.Because the effect of CB1 receptor modulators, another advantage of this coupling be bad side reaction such as acute dystonia, the dyskinesia that can reduce or prevent to be caused by major tranquilizer, cathisophobia and tremble.
Should be appreciated that the conventional anti-asthmatic and the coupling of CB1 receptor modulators can improve the treatment of asthma effect.
Therefore, another aspect of the present invention provide CB1 receptor modulators and antiasthmatics preparation be used for the treatment of or the medicine of prevention of asthma in purposes.
The present invention also provides the method for treatment or prevention of asthma, and this method comprises administration proper C B1 receptor modulators and an amount of major tranquilizer to the patient of this treatment of needs, makes the effective mitigation of they common generations.
Methods of treatment of the present invention comprises by the The compounds of this invention of the nontoxic treatment significant quantity of patient's administration of this treatment of needs being regulated the method for CB1 acceptor and the receptor-mediated disease of treatment CB1, compare with other CB or G-protein linked receptor, The compounds of this invention is antagonism CB1 acceptor optionally preferentially.
Term " treatment significant quantity " is the amount of the structural formula I compound that causes food or medical response (comprising the symptom of alleviating subject disease) in tissue, system, animal or human's body looked for of researchist, animal doctor, doctor or other clinical staff.These new treatments of the present invention can be used for illness well known by persons skilled in the art.Term " Mammals " comprises the people.
Use following abbreviation: aq. among following reaction process and the embodiment: aqueous; API-ES: atmospheric ionization-electron spray(ES) (mass spectrum term); DMF: dimethyl formamide; DMSO: methyl-sulphoxide; EDC:1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride; EPA: ethene polyacrylamide (a kind of plastics); EtOAc: ethyl acetate; H: hour; Hex: hexane; The HOBt:1-hydroxybenzotriazole; HPLC: high pressure liquid chromatography; HPLC/MS: high pressure liquid chromatography/mass spectrum; In vacuo: rotary evaporation; IPAC: isopropyl acetate; KHMDS: hexamethyldisilane yl amino potassium; LC: liquid chromatography; LC/MS, LC-MS: liquid chromatography-mass spectrography; M: mole; Me: methyl; MeOH: methyl alcohol; Mmol: mmole; MS or ms: mass spectrum; N: equivalent; NaHMDS: hexamethyldisilane yl amino sodium; NMR: nucleus magnetic resonance; PyBOP:(benzotriazole-1-base oxygen base) tripyrrole alkane subbase phosphine hexafluorophosphate; R t: retention time; Rt or RT: room temperature; TFA: trifluoroacetic acid; THF: tetrahydrofuran (THF); TLC: thin-layer chromatography.
Compound of the present invention can be according to the method preparation of describing among following reaction process and the embodiment.
Reaction scheme 1.
In reaction scheme 1, allow the amine of suitable replacement AWith carboxylic acid BUnder the condition of the formation amido linkage of standard, react, obtain arylamide CFor illustrating the present invention, the present invention includes the following example.But these embodiment are not construed as limiting the invention.They only are used for disclosing the method for the present invention of implementing.Those skilled in the art can find to implement other method of the present invention apparently.And these methods also are deemed to be within the scope of the present invention.
Universal method.LC/MS analyzes and uses MICROMASS ZMD mass spectrograph-AGILENT1100 series HPLC to carry out, wherein use YMC ODS-A 4.6 * 50mm post, in 4.5 minutes with the solvent gradient elution of 10-95%B, then with 95%B wash-out 0.5 minute, flow velocity is 2.5mL/min, solvent orange 2 A=0.06%TFA/ water; Solvent B=0.05%TFA/ acetonitrile. 1H-NMR spectrum is at pointed CDCl 3Or CD 3Obtain on 500MHz VARIAN spectrograph among the OD, chemical shift uses solvent peak to make reference with δ value report, and coupling constant is the unit report with hertz (Hz).
Reference example 1
Figure A0380567800342
N-[2, two (4-the chloro-phenyl-)-1-methyl-propyls of 3-]-amine hydrochlorate
N-[2, two (4-chloro-phenyl-)-1-methyl-propyls of 3-]-preparation of two kinds of diastereomers (α and β) of amine hydrochlorate is disclosed (Schultz, E.M. etc., J.Med.Chem.1967,10,717).Diastereomer α: LC-MS: calculated value (C 16H 17Cl 2N): 293, measured value m/e294 (M+H) +(retention time 2.5min).Diastereomer β: LC-MS: calculated value (C 16H 17Cl 2N): 293, measured value m/e 294 (M+H) +(retention time 2.2min).
Reference example 2
Figure A0380567800351
2-amino-4-(4-chloro-phenyl-)-3-phenyl butane hydrochloride
Prepare title compound according to reference example 1 described method.
Diastereomer α:
LC-MS: calculated value (C 16H 18ClN): 259, measured value m/e 260 (M+H) +(2.3min).
Diastereomer β
LC-MS: calculated value (C 16H 18ClN): 259, measured value m/e 260 (M+H) +(2.2min).
Reference example 3
Figure A0380567800352
N-[3-(4-chloro-phenyl-)-2-phenyl-1-methyl-propyl]-amine hydrochlorate
(diastereomer α)
Steps A 3-(4-chloro-phenyl-)-2-phenylpropionic acid methyl esters
At-78 ℃, to methyl phenylacetate (12g, 80mmol) with 4-chlorine bromotoluene (16g, 80mmol) add hexamethyldisilane yl amino sodium (1MTHF solution in the solution in the anhydrous THF of 250mL, 80mL, 80mmol) (also can use hexamethyldisilane yl amino potassium, obtain similar results).Warm reactant is to ambient temperature overnight.Utilize rotatory evaporator to remove volatile matter, the gained mixture is assigned between saturated ammonium chloride (200mL) and the EtOAc (200mL).Separate organic layer, (2 * 200mL) extract with EtOAc with water layer.The organic extraction anhydrous sodium sulfate drying that merges, filtration is concentrated into driedly, obtains title compound.
1H?NMR(500MHz，CD 3OD)：δ7.36-7.10(m，9H)，3.81(dd，1H)，3.52(s，3H)，3.36(dd，1H)，3.02(dd，1H).
Step B 3-(4-chloro-phenyl-)-2-phenylpropionic acid
To 3-(4-chloro-phenyl-)-2-phenylpropionic acid methyl esters (steps A, 20g, 74mmol) in the mixture in acetonitrile (100mL) and the water (100mL) the adding lithium hydroxide monohydrate (8.8g, 0.21mol).After at room temperature stirring 3 days, concentrate by rotatory evaporator and to remove volatile matter, with residue be assigned to water (300mL) and hexane/ether (1: 1,200mL) between.Separate water layer, be acidified to pH=2-3, (2 * 200mL) extract with EtOAc.With the organic extraction anhydrous sodium sulfate drying after merging, filtration is concentrated into driedly, obtains title compound. 1H?NMR(500MHz，CD 3OD)：δ7.34-7.10(m，9H)，3.82(dd，1H)，3.36(dd，1H)，2.98(dd，1H).
Step C N-methoxyl group-N-methyl-3-(4-chloro-phenyl-)-2-Phenylpropionamide
At 0 ℃, to 3-(4-chloro-phenyl-)-2-phenylpropionic acid (step B, 14g, CH 55mmol) 2Cl 2(125mL) dropwise add in the solution dimethyl formamide (50 μ L) and oxalyl chloride (14g, 0.11mol).Warm reactant is concentrated into the dried acyl chlorides crude product that obtains to ambient temperature overnight, need not to be further purified and can directly use.Like this in 0 ℃ of CH to this acyl chlorides 2Cl 2(250mL) add in the solution N-methoxyl group-N-methylamine hydrochloride (11g, 0.11mol) and triethylamine (activated molecular sieve drying, 30mL, 0.22mol).After 4 hours, use ether (500ml) diluted reaction mixture in stirring at room, so water, sodium pyrosulfate dilute aqueous soln and salt water washing successively, anhydrous MgSO 4Drying filters and is concentrated into dried, obtains crude product, and it need not to be further purified and can directly use. 1H?NMR(500MHz，CD 3OD)：δ7.4-7.1(m，9H)，4.38(s，3H)，3.35(dd，1H)，3.10(s，3H)，2.92(dd，1H)；LC-MS：m/e?304(3.6min)。
Step D 4-(4-chloro-phenyl-)-3-phenyl-2-butanone
At 0 ℃, to N-methoxyl group-N-methyl-3-(4-chloro-phenyl-)-2-Phenylpropionamide (step C, 16g, 53mmol, through and the methylbenzene azeotropic drying) anhydrous THF (200mL) solution in add methyl-magnesium-bromide (the 3M diethyl ether solution, 35mL, 0.11mol).In 0 ℃ stir 2 hours after, with reactant with MeOH (5mL) and 2M hydrochloric acid (50mL) quencher.Utilize rotatory evaporator to concentrate and remove volatile matter, residue is assigned between saturated ammonium chloride (200mL) and the ether (200mL).Separate organic layer, (2 * 200mL) extract with ether with water layer.With the organic extraction anhydrous magnesium sulfate drying after merging, filtration is concentrated into driedly, obtains title compound, and it need not to be further purified just and can use. 1H?NMR(500MHz，CD 3OD)：δ7.45-7.02(m，9H)，4.08(dd，1H)，3.34(dd，1H)，2.90(dd，1H)，2.03(s，3H).
Step e 4-(4-chloro-phenyl-)-3-phenyl-2-butanols
At 0 ℃, to 4-(4-chloro-phenyl-)-3-phenyl-2-butanone (step D, 13g, add in MeOH 50mmol) (100mL) solution sodium borohydride (3.8g, 100mmol).In 0 ℃ stir 30 minutes after, by adding 2M hydrochloric acid (50mL) termination reaction.Utilize rotatory evaporator to concentrate and remove volatile matter, residue is assigned between water (100mL) and the EtOAc (200mL).Separate organic layer, (2 * 200mL) extract with EtOAc with water layer.With the organic layer extract salt water washing after merging, pass through anhydrous sodium sulfate drying, filtration also is concentrated into dried, obtain crude product, and then by silica gel flash column chromatography purifying (is eluent with the 10%EtOAc/ hexane), the mixture of isomers of the isomer that obtains the pure product of isomer of very fast wash-out and comprise very fast wash-out and slow wash-out.
The isomer of very fast wash-out: 1H NMR (500MHz, CD 3OD): δ 7.25-7.00 (m, 9H), 4.00 (m, 1H), 3.15 (m, 1H), 2.97 (m, 1H), 2.85 (m, 1H), 1.10 (d, 3H).
Step F 4-(4-chloro-phenyl-)-2-mesyloxy-3-phenyl butane
At 0 ℃, to 4-(4-chloro-phenyl-)-3-phenyl-2-butanols (step e, very fast wash-out isomer, 9.0g, add triethylamine (activated molecular sieve drying, 5.8mL in EtOAc 34mmol) (100mL) solution, 42mmol) and methylsulfonyl chloride (3.0mL, 38mmol).After 30 minutes, add saturated sodium bicarbonate aqueous solution (100mL) termination reaction 0 ℃ of stirring.Stirring at room 1 hour is separated organic layer then, uses anhydrous sodium sulfate drying, filters, and is concentrated into driedly, obtains title compound, and it need not to be further purified direct use. 1H?NMR(500MHz，CD 3OD)：δ7.3-7.0(m，9H)，5.05(m，1H)，3.2-3.0(m，3H)，2.80(s，3H)，1.40(d，3H).
Step G 2-azido--4-(4-chloro-phenyl-)-3-phenyl butane
To 4-(4-chloro-phenyl-)-2-mesyloxy-3-phenyl butane (step F, 12g, add in DMF 34mmol) (50mL) solution sodiumazide (11g, 0.17mol).After 1 hour, in reaction mixture impouring water (200mL), (2 * 100mL) extract product with ether in 120 ℃ of stirrings.The organic extraction that merges washes with water, by dried over mgso, filters, and is concentrated into driedly, and residue is by silica gel chromatography (eluent: hexane), obtain title compound.
Step H 2-(N-tertbutyloxycarbonyl) amino-4-(4-chloro-phenyl-)-3-phenyl butane
To 2-azido--4-(4-chloro-phenyl-)-3-phenyl butane (step G, 7.0g, add in EtOAc 24mmol) (150mL) solution tert-Butyl dicarbonate (8.0g, 37mmol) and platinum dioxide (0.50g, 2.2mmol).With the mixture processing that outgases, utilize air bag to inject hydrogen then.Stir after 1 day, by the CELITE diatomite filtration, concentrated filtrate obtains crude product with reaction mixture, and it contains some unreacted tert-Butyl dicarbonate impurity. 1H?NMR(500MHz，CD 3OD)：δ7.25-6.88(m，9H)，3.89(m，1H)，3.20(m，1H)，2.86-2.77(m，2H)，1.54(s，9H)，0.92(d，3H).
Step I N-[3-(4-chloro-phenyl-)-2-phenyl-1-methyl-propyl]-amine hydrochlorate (diastereomer α)
At room temperature, with 2-(N-tertbutyloxycarbonyl) amino-4-(4-chloro-phenyl-)-3-phenyl butane (step H, 7.0g, 24mmol) handle 30 minutes (also can use 4M hydrogenchloride De dioxane solution, the result is similar) with the saturated solution (100mL) of hydrogenchloride in EtOAc.Enriched mixture obtains title compound to doing. 1H?NMR(500MHz，CD 3OD)：δ7.35-6.98(m，9H)，3.62(m，1H)，3.20(dd，1H)，3.05(m，1H)，2.98(dd，1H)，1.19(d，3H).LC-MS：m/e?260(M+H) +(2.3min).
Reference example 4
Figure A0380567800381
N-[3-(4-chloro-phenyl-)-2 (S)-phenyl-1 (S)-methyl-propyls]-amine hydrochlorate
Steps A 4-(4-chloro-phenyl-)-3 (S)-phenyl-2 (R)-butanols
(20g, 0.82mol) stirring was activated in 12 hours in nitrogen atmosphere, added anhydrous diethyl ether (100mL) then and covered this solid matter with the magnesium sample.Cooling mixture to 0 ℃, dropwise be added in 4-chlorobenzyl chloride in the 400mL anhydrous diethyl ether (40g, 0.25mmol).In stirring at room after 1 hour, get the above-mentioned liquor sample of 32mL by syringe be added to (1R, 2R)-1-phenyl propylene oxide (1.0g, 7.5mmol)/100mL ether (0 ℃) in.After 2 hours, add saturated aqueous ammonium chloride (100mL) termination reaction 0 ℃ of stirring.Separate organic layer, (2 * 100mL) extract with ether with water layer.With the organic extraction salt water washing that merges, by anhydrous magnesium sulfate drying, filter and be concentrated into dried, residue by silica gel flash column chromatography purifying (is eluent with hexane-15%EtOAc/ hexane), is obtained title compound. 1H?NMR(500MHz，CD 3OD)：δ7.28-7.02(m，9H)，4.01(m，1H)，3.14(dd，1H)，2.97(dd，1H)，2.85(m，1H)，1.12(d，3H).
Step B N-[3-(4-chloro-phenyl-)-2 (S)-phenyl-1 (S)-methyl-propyls]-amine hydrochlorate
According to reference example 3, the described step of step F-I, use hydrogenchloride De dioxane solution (4M) replaces the EtOAc solution of hydrogenchloride, with steps A product (4-(4-chloro-phenyl-)-3 (S)-phenyl-2 (R)-butanols, 1.8g, 7.0mmol) change into title compound. 1H?NMR(500MHz，CD 3OD)：δ7.35-6.98(m，9H)，3.62(m，1H)，3.20(dd，1H)，3.05(m，1H)，2.98(dd，1H)，1.19(d，3H).LC-MS：m/e?260(M+H) +(2.3min).
Reference example 5
N-[3-(4-chloro-phenyl-)-2-(3-pyridyl)-1-methyl-propyl]-amine, hydrochloride (diastereomer 10: 1 mixtures of α/β)
Steps A 4-(4-chloro-phenyl-)-3-pyridyl-2-butanone
At-78 ℃, (10g, 58mmol) (9.1g is 58mmol) at 100mL CH with the 4-chlorobenzyl chloride to 3-pyridyl acetone hydrochloride (Wibaud, van der V.Recl.Trav.Chim.Pays-Bas.1952,71,798) 2Cl 2In solution in add the cesium hydroxide monohydrate (39g, 0.23mol) and tetrabutylammonium iodide (1g).The warm ambient temperature overnight that is reacted to is assigned to the gained mixture between salt solution (100mL) and the EtOAc (100mL).Separate organic layer, (2 * 100mL) extract water layer with EtOAc.Organic extraction after the merging is with anhydrous MgSO 4Drying is filtered, and is concentrated into driedly, obtains title compound. 1H?NMR(500MHz，CD 3OD)：δ8.42(d，1H)，8.34(d，1H)，7.72(d，1H)，7.40(dd，1H)，7.18(d，2H)，7.06(d，1H)，4.23(dd，1H)，3.38(dd，1H)，2.95(dd，1H)，2.10(s，3H).LC-MS：m/e?260(M+H) +(1.9min).
Step B N-[3-(4-chloro-phenyl-)-2-(3-pyridyl)-1-methyl-propyl]-amine, hydrochloride (10: 1 mixtures of diastereomer α/β)
According to reference example 3, the described method of step e-I, (14g 57mmol) changes into title compound with the product (4-(4-chloro-phenyl-)-3-pyridyl-2-butanone) of steps A.LC-MS：m/e?261(M+H) +(1.2min)。
Reference example 6
2-(2-fluorophenoxy)-2 Methylpropionic acid
Steps A 2-(2-fluorophenoxy)-2 Methylpropionic acid
(2.0g, 18mmol) with 1,1, (7.9g, (7.1g 0.18mol), periodically applies ice bath to keep gentle reflux to 1-three chloro-2-methyl-2-propyl alcohol to add sodium hydroxide in acetone 45mmol) (100mL) solution to the 2-fluorophenol.After backflow is calmed down, restir reactant 1 hour.Utilize rotatory evaporator to remove volatile matter, residue is assigned between ether (100mL), hexane (100mL) and the water (200mL).Separate water layer, with concentrated hydrochloric acid acidifying (pH=2), (3 * 100mL) extract to use ether then.Extract anhydrous magnesium sulfate drying after the merging filters, and is evaporated to driedly, obtains title compound, and it need not to be further purified and can directly use. 1H?NMR(500MHz，CD 3OD)：δ7.15-7.05(m，4H)，1.56(s，6H).LC-MS：m/e?199(M+1) +(2.3min).
According to the method for reference example 6, replace the 2-fluorophenol to prepare the acid of reference example 7 and 8 with the phenol that suitably replaces.
Reference example 7
Figure A0380567800411
2-(3-chlorophenoxy)-2 Methylpropionic acid
1H?NMR(500MHz，CD 3OD)：δ7.23(t，1H)，7.00(dd，1H)，6.93(t，1H)，6.84(dd，1H)，1.59(s，6H).
LC-MS：m/e?215(M+1) +，(2.7min).
Reference example 8
Figure A0380567800412
2-(3, the 5-dichlorophenoxy)-2 Methylpropionic acid
1H?NMR(500MHz，CD 3OD)：δ7.05(t，1H)，6.84(d，2H)，1.60(s，6H).
Reference example 9
2-(2-pyridyloxy)-2-Methyl Butyric Acid
Steps A 2-(2-pyridyloxy) benzyl propionate
In 0 ℃, to 2 hydroxy pyrimidine (2.9g, 30mmol), benzyl lactate (5.0g, 21mmol) and triphenylphosphine (12g is 47mmol) at 100mL CH 2Cl 2In mixture in add the diethylazodicarboxylate (7.8mL, 45mmol).Warm reactant arrives room temperature 4 hours.Add hexane (100mL) dilution gained mixture, concentrate with 20g silica gel then.With silicagel column on the gained material,, obtain title compound with 10%EtOAc/ hexane wash-out. 1H?NMR(500MHz，CD 3OD)：δ8.00(dd，1H)，7.68(ddd，1H)，7.36-7.28(m，5H)，6.94(dd，1H)，6.84(dd，1H)，5.30(q，1H)，5.18(s，2H)，1.59(d，3H).LC-MS：m/e?258(M+H) +(3.3min).
Step B 2-(2-pyridyloxy)-2-Methyl Butyric Acid benzyl ester
At-78 ℃, to 2-(2-pyridyloxy) benzyl propionate (1.6g, 6.2mmol) and iodoethane (1.5mL, 25mmol) add hexamethyldisilane yl amino sodium (1M THF solution in the solution in the anhydrous THF of 10mL, 9.3mL, 9.3mmol) (also can use the toluene solution of hexamethyldisilane yl amino potassium, the result is similar).The warm room temperature that is reacted in 2 hours, and then be assigned between saturated ammonium chloride (100mL) and the EtOAc (100mL).Separate organic layer, (2 * 50mL) extract water layer with EtOAc.The organic extraction anhydrous sodium sulfate drying that merges, filtration is concentrated into driedly, and residue obtains title compound by silica gel flash column chromatography purifying (is eluent with the 10%EtOAc/ hexane). 1H?NMR(500MHz，CD 3OD)：δ7.87(dd，1H)，7.63(ddd，1H)，7.27(m，3H)，7.18(m，2H)，6.85(dd，1H)，6.74(dd，1H)，5.08(Abq，2H)，2.13(m，1H)，1.94(m，1H)，1.65(s，3H)，0.95(t，3H).LC-MS：m/e?286(M+H) +(3.8min).
Step C 2-(2-pyridyloxy)-2-Methyl Butyric Acid
(1.6g 5.5mmol) and the processing that outgases of the mixture of 10% palladium/charcoal (50mg) in 50mL MeOH, utilizes the air bag hydrogen supply then with 2-(2-pyridyloxy)-2-Methyl Butyric Acid benzyl ester.After at room temperature stirring was spent the night, by the CELITE diatomite filtration, with MeOH (20mL) washing, concentrated filtrate obtained title compound to dried with reaction mixture. 1H?NMR(500MHz，CD 3OD)：δ8.03(dd，1H)，7.64(ddd，1H)，6.89(dd，1H)，6.76(dd，1H)，2.14(m，1H)，1.94(m，1H)，1.64(s，3H)，0.99(t，3H).LC-MS：m/e?196(M+H) +(1.8min).
Reference example 10
Figure A0380567800421
2-(2-pyridyloxy)-2 Methylpropionic acid
Prepare title compound according to reference example 9 described methods, wherein in step B, use methyl-iodide and hexamethyldisilane yl amino potassium to replace iodoethane and hexamethyldisilane yl amino sodium respectively. 1H?NMR(500MHz，CD 3OD)：δ8.04(dd，1H)，7.6?4(ddd，1H)，6.89(dd，1H)，6.76(dd，1H)，1.66(s，6H).LC-MS：m/e?182(M+H) +(1.5min).
Reference example 11
N-[3-(4-chloro-phenyl-)-2-(3, the 5-difluorophenyl)-1-methyl-propyl] amine hydrochlorate (non-mapping Body α)
Prepare title compound according to reference example 3 described methods, wherein in steps A, use 3,5-difluorophenylacetic acid methyl esters is (by 3,5-difluorophenyl acetic acid and the preparation of trimethyl silyl diazomethane) replace methyl phenylacetate, and in step e, use the sodium borohydride of three (sec-butyl) lithium borohydride replacement in MeOH in THF.LC-MS：m/e?296(M+H) +(2.39min).
Reference example 12
Figure A0380567800432
N-[3-(4-chloro-phenyl-)-2-(3-cyano-phenyl)-1-methyl-propyl] amine hydrochlorate (diastereomer α)
Steps A 2-(N-tert-butoxycarbonyl) amino-4-(4-chloro-phenyl-)-3-(3-cyano-phenyl) fourth Alkane
(method by reference example 3 step H prepares to 2-(N-tertbutyloxycarbonyl) amino-3-bromophenyl-4-(4-chloro-phenyl-) butane, 1.0g, 2.3mmol) 5mL DMF solution in add zinc cyanide (0.16g, 1.4mmol), three (dibenzylidene-acetone) two palladium chloroform mixture (3.0mg, 2.8 μ mol), 1,1 '-two (diphenylphosphino) ferrocene (5.0mg, 9.0 μ mol) and water (0.1mL).In nitrogen atmosphere in 120 ℃ the heating 6 hours after, add another batch zinc cyanide (0.16g, 1.4mmol), three (dibenzylidene-acetone) two palladium chloroform mixture (5.0mg, 4.8 μ mol), 1,1 '-two (diphenylphosphino) ferrocene (5.0mg, 9.0 μ mol) and water (0.05mL), continue heating 18 hours again.Behind the cool to room temperature, the gained mixture is assigned between water (50mL) and the ether (50mL).Separate organic layer, (2 * 50mL) extract with ether with water layer.The united extraction thing is with anhydrous MgSO 4Drying is filtered, and concentrates, and residue obtains title compound by silica gel flash column chromatography purifying (is eluent with the 20%EtOAc/ hexane). 1H?NMR(400MHz，CD 3OD)：δ7.6-7.3(m，4H)，7.10(d，2H)，6.92(d，2H)，3.88(m，1H)，3.20(m，1H)，2.97(m，1H)，1.82(m，1H)，1.45(s，9H)，0.94(d，3H).LC-MS：m/e?385(M+H) +(3.9min).
Step B N-[3-(4-chloro-phenyl-)-2-(3-cyano-phenyl)-1-methyl-propyl] amine hydrochlorate (diastereomer α)
By reference example 3, the described method of step I prepares title compound.LC-MS：m/e?285(M+H) +(2.2min)。
Reference example 13
2-methyl-2-(5-chloro-2-pyridyloxy) propionic acid
Steps A 2-methyl-2-(5-chloro-2-pyridyloxy) ethyl propionate
With 5-chloro-2 hydroxy pyrimidine (5.0g, 39mmol), the 2-isobutyl ethyl bromide (5.7mL, 39mmol) and cesium carbonate (25g, 77mmol) mixture in the 50mL acetonitrile is in 50 ℃ of heated overnight.Utilize rotatory evaporator to concentrate and remove volatile matter, residue is assigned between water (100mL) and the EtOAc (100mL).Separate organic layer, (2 * 100mL) extract water layer with EtOAc.Organic extraction anhydrous sodium sulfate drying after the merging filters, and is concentrated into driedly, and residue obtains title compound by silica gel flash column chromatography purifying (is eluent with the 5%EtOAc/ hexane). 1H?NMR(500MHz，CD 3OD)：δ7.99(d，1H)，7.67(dd，1H)，6.68(d，1H)，4.13(q，2H)，1.64(s，6H)，1.14(t，3H).LC-MS：m/e?244(M+H) +(3.41min).
Step B 2-methyl-2-(5-chloro-2-pyridyloxy) propionic acid
50 ℃ of heating by 2-methyl-2-(5-chloro-2-pyridyloxy) ethyl propionate and sodium hydroxide (0.85g, 21mmol) mixture overnight of in 15mL acetonitrile and 15ml water, forming.Remove volatile matter by rotatory evaporator is concentrated, then residue is assigned between 2M hydrochloric acid (100mL) and the ether (100mL).Separate organic layer, washing (2 * 50mL), anhydrous magnesium sulfate drying filters, be concentrated into dried, title compound. 1H?NMR(500MHz，CD 3OD)：δ8.02(d，1H)，7.65(ddd，1H)，6.77(d，1H)，1.66(s，6H).LC-MS：m/e?216(M+H) +(2.33min).
Reference example 14
2-methyl-2-(5-trifluoromethyl-2-pyridyloxy) propionic acid
Prepare title compound according to reference example 13 described methods, wherein in steps A, use 5-trifluoromethyl-2 hydroxy pyrimidine to replace 5-chloro-2 hydroxy pyrimidine. 1H?NMR(500MHz，CD 3OD)：δ8.38(br?s，1H)，7.93(dd，1H)，7.13(d，1H)，1.70(s，6H).LC-MS：m/e?250(M+H) +(2.6min).
Reference example 15
Figure A0380567800461
2-methyl-2-(6-methyl-2-pyridyloxy) propionic acid
Prepare title compound according to reference example 13 described methods, wherein in steps A, use 6-methyl-2 hydroxy pyrimidine to replace 5-chloro-2 hydroxy pyrimidine. 1H?NMR(500MHz，CD 3OD)：δ6.74(d，1H)，6.53(d，1H)，2.34(s，3H)，1.64(s，6H).LC-MS：m/e?196(M+H) +(1.3min).
Reference example 16
2-amino-3-(1-(1,2,3-triazoles base))-4-(4-chloro-phenyl-) butane
Steps A 2-(1-(1,2,3-triazoles base)) jasmal
Stirring at room by 1,2,3-triazoles (2.07g, 30mmol), phenyl bromoacetate (6.9g, 30mmol) and diisopropylethylamine (5.1mL is 30mmol) at 40mL CH 2Cl 2The middle mixture overnight of forming.Add diethyl ether then and dilute this mixture, till no precipitation form becomes.Cross filter solid, wash with ether.Concentrated filtrate (uses 10% hexane/CH by the silica gel purification residue 2Cl 2Be eluent), obtain the isomer of title compound, 2-(2-(1,2,3-triazoles base)) jasmal is amorphous solid.With containing equivalent ether and CH 2Cl 2The further wash-out of solvent mixture, obtain title compound, be amorphous solid. 1H?NMR(400MHz，CDCl 3)：δ2.251(s，2H)，7.26-7.390(m，5H)，7.723(s，1H)，7.785(s，1H).
Step B 2-(1-(1,2,3-triazoles base)) acetate:
To 2-(1-(1,2,3-triazoles base)) jasmal (steps A, 8.68g, 39.9mmol) add in the solution in 150mL MeOH palladium hydroxide (20%/charcoal, 800mg), mixture under room temperature and 45psi, is spent the night with the hydrogenation of normal pressure hydrogen in the Parr wobbler.By CELITE bed of diatomaceous earth filtering catalyst, wash with MeOH.Concentrated filtrate obtains solid, 50 ℃ of vacuum-dryings 36 hours, gets title compound. 1H?NMR(400MHz，CD 3OD)：δ5.3(s，2H)，7.75(s，1H)，8.016(s，1H).
Step C N-methoxyl group-N-methyl-2-(1-(1,2,3-triazoles base)) ethanamide:
(step B, 1.27g 10mmol) are containing the 10mL CH of 0.05mL DMF to 2-(1-(1,2,3-triazoles base)) acetate 2Cl 2In suspension in drip oxalyl chloride (0.95mL, 11mmol).Observe violent effervesce.In this mixture of stirring at room 4 hours, be cooled to-78 ℃ then.In 3 minutes, slowly add N, the O-dimethyl hydroxylamine hydrochloride (1.2g, 13mmol) and diisopropylethylamine (6.0mL is 35mmol) at 10mL CH 2Cl 2In solution.Then mixture is warmed up to room temperature, stirring is spent the night.Use the ether diluted reaction mixture subsequently, till no longer including the precipitation appearance.Filter solids, wash with ether.Concentrated filtrate with residue purifying on silica gel, uses EtOAc as eluent, obtains title compound, is amorphous solid. 1H?NMR(400MHz，CDCl 3)：δ3.252(s，3H)，3.812(s，3H)，5.379(s，2H)，7.753?&?7.761(s’s，2H).
Step D N-methoxyl group-N-methyl-3-(4-chloro-phenyl-)-2-(1-(1,2,3-triazoles base)) third Acid amides
At-78 ℃, to N-methoxyl group-N-methyl-2-(1-(1,2,3-triazoles base)) ethanamide (step C, 1.19g, drip in 15mL THF solution 7mmol) hexamethyldisilane yl amino lithium (1M THF solution, 8.4mL, 8.4mmol).After stirring 30 minutes in addition, dropwise add 4-chlorine bromotoluene (1.65g, 8mmol) solution in 5mL THF.Mixture is warmed up to room temperature, stirs 5.5h.Then this mixture is passed through silica gel purification, use the 40%EtOAc/ hexane to be eluent, obtain title compound. 1H?NMR(400MHz，CDCl 3)：δ3.186(s，3H)，3.234-3.267(m，1H)，3.453-3.506(m，1H)，3.582(s，3H)，6.145-6.188(m，1H)，7.048-7.279(m，4H)，7.726(s，1H)，7.954(s，1H).
Step e 2-azido--3-(1-(1,2,3-triazoles base))-4-(4-chloro-phenyl-) butane:
According to reference example 3, the method for describing among the step D-G, with the product of step D, N-methoxyl group-N-methyl-3-(4-chloro-phenyl-)-2-(1-(1,2,3-triazoles base)) propionic acid amide is converted into title compound. 1H?NMR(400MHz，CDCl 3)：δ1.219-1.246(d’s，3H)，3.253-4.754(m，4H)，6.866-7.299(d’s，4H)，7.313，7.618，7.63&?7.706(s’s，2H).
Step F 2-amino-3-(1-(1,2,3-triazoles base))-4-(4-chloro-phenyl-) butane:
(step e, 138mg add platinum oxide (14mg) in 4mL MeOH solution 0.5mmol) to 2-azido--3-(1-(1,2,3-triazoles base))-4-(4-chloro-phenyl-) butane.Utilize the air bag of filling hydrogen, this mixture of hydrogenation at room temperature is 3 hours under an atmospheric hydrogen-pressure.By CELITE bed of diatomaceous earth filtering catalyst, wash with MeOH.Concentrated filtrate obtains the oily title compound. 1H?NMR(400MHz，CDCl 3)：δ1.085-1.174(d’s，3H)，3.220-3.361(m，2H)，3.517-3.563(m，3H)，4.379-4.431(m，1H)，6.679-7.719(d’s，4H)，7.297，7.40，7.592?&?7.607(s’s，2H).
Reference example 17
Figure A0380567800481
N-[3-(4-chloro-phenyl-)-2-(3-aminomethyl phenyl)-1-methyl-propyl] amine hydrochlorate (diastereomer α)
Steps A 2-(N-tertbutyloxycarbonyl) amino-4-(4-chloro-phenyl-)-3-(3-aminomethyl phenyl) butane
With 2-(N-tertbutyloxycarbonyl) amino-3-(3-bromophenyl)-4-(4-chloro-phenyl-) butane (reference example 3, step H, 0.50g, 1.1mmol), tin tetramethide (0.41g, 2.3mmol), triphenylphosphine (0.12g, 0.46mmol), lithium chloride (0.38g, 9.1mmol) and dichloride two (triphenylphosphine) palladium (0.12g, 0.17mmol) mixture in the 20mL dry DMF in nitrogen atmosphere in 100 ℃ the heating 18 hours.Reaction mixture is assigned between water (100mL) and the ether (100mL) to room temperature.Separate organic layer, anhydrous magnesium sulfate drying filters, be concentrated into dried, and then with residue by silica gel flash column chromatography purifying (is eluent with the 10%EtOAc/ hexane), obtain title compound. 1H?NMR(400MHz，CD 3OD)：δ7.2-6.8(m，8H)，3.84(m，1H)，3.16(m，1H)，2.80-2.68(m，2H)，2.24(s，3H)，1.45(s，9H)，0.86(d，3H).LC-MS：m/e?396(M+Na) +(4.4min).
Step B N-[3-(4-chloro-phenyl-)-2-(3-aminomethyl phenyl)-1-methyl-propyl] amine hydrochlorate (diastereomer α)
Title compound is by the described method preparation of reference example 3 step I.LC-MS：m/e?274(M+H) +(2.5min)。
Reference example 18
Figure A0380567800491
N-[3-(5-chloro-2-pyridyl)-2 (S)-phenyl-1 (S)-methyl-propyls] amine hydrochlorate is (non-right Reflect body α)
Steps A 5-chloro-2-picoline
In nitrogen atmosphere, in 110 ℃ the heating 2, the 5-dichloropyridine (15g, 0.10mol), tin tetramethide (15mL, 0.11mol) and molybdenyl dichloride (triphenylphosphine) palladium (2.0g, 2.8mmol) mixture in the 200mL dry DMF reaches 72 hours.Reaction mixture is poured in the Potassium monofluoride saturated solution (200mL) to room temperature.The gained mixture is assigned between water (500mL) and the ether (500mL).Separate organic layer, water layer extracts with ether (200mL).The united extraction thing is used anhydrous magnesium sulfate drying, filters, and is concentrated into driedly, and residue is through silica gel flash column chromatography purifying (ether/hexane of eluent: 2-10%), title compound. 1H?NMR(500MHz，CD 3OD)：δ8.41(d，1H)，7.75(dd，1H)，7.30(d，1H)，2.53(s，3H).
Step B 4-(5-chloro-2-pyridyl)-3 (S)-phenyl-2 (R)-butanols
In 0 ℃, to 5-chloro-2-picoline (steps A; 1.1g (1.8M hexanaphthene/diethyl ether solution, 7.2mL 13mmol), reacted 30 minutes in stirring at room 8.7mmol) to add phenyl lithium in the solution in the 15mL anhydrous diethyl ether.The gained mixture is cooled to 0 ℃ once more, add (1R, 2R)-(2.3g, 17mmol), warm reactant is to ambient temperature overnight for 1-phenyl propylene oxide.Reaction mixture is assigned between EtOAc (100mL) and the water (100mL).Separate organic layer, (2 * 100mL) extract water layer with EtOAc.Merge organic extraction, use anhydrous magnesium sulfate drying, filter and be concentrated into dried, and then with residue through silica gel flash column chromatography purifying (eluent: the 10-40%EtOAc/ hexane), must title compound. 1H?NMR(500MHz，CD 3OD)：δ8.28(d，1H)，7.59(dd，1H)，7.25-7.12(m，5H)，7.05(d，1H)，4.03(m，1H)，3.29(dd，1H)，3.19(dd，1H)，3.12(m，1H)，1.12(d，3H).
Step C 2 (S)-azido--4-(5-chloro-2-pyridyl)-3 (S)-phenyl butanes
To 4-(5-chloro-2-pyridyl)-3-phenyl-2-butanols (step B, 0.24g, 0.92mmol), triphenylphosphine (1.5g, 1.4mmol) and diphenylphosphine acylazide (0.30mL, 1.4mmol) add in the mixture in the anhydrous THF of 5mL the diethylazodicarboxylate (0.24mL, 1.4mmol).Stirred overnight at room temperature concentrates the gained mixture then with silica gel (10g), and with silicagel column on the residue.With 5-15%EtOAc/ hexane wash-out, get title compound. 1H?NMR(500MHz，CD 3OD)：δ8.35(d，1H)，7.52(dd，1H)，7.25-7.05(m，5H)，6.95(d，1H)，3.81(m，1H)，3.48(m，1H)，3.15-3.05(m，2H)，1.14(d，3H).
Step D N-[3-(5-chloro-2-pyridyl)-2 (S)-phenyl-1 (S)-methyl-propyls] amine salt acid Salt
According to reference example 3, the method for step H-I replaces hydrogenchloride/EtOAc with hydrogenchloride/dioxane solution (4M), and (0.20g 0.70mmol) is converted into title compound with the product of step C. 1H?NMR(500MHz，CD 3OD)：δ8.75(d，1H)，8.19(dd，1H)，7.55(d，1H)，7.4-7.2(m，5H)，3.78(m，1H)，3.62(dd，1H)，3.48(m，1H)，3.43(dd，1H)，1.22(d，3H).LC-MS：m/e?261(M+H) +(2.2min).
Reference example 19
N-[2-(3-bromophenyl)-3-(5-chloro-2-pyridyl)-1-methyl-propyl] amine hydrochlorate is (non-right Reflect body α)
Steps A 3-bromophenyl acetone
In 0 ℃, to N-methoxyl group-N-methylacetamide (10g, add in 100mL anhydrous ether solution 100mmol) 3-bromobenzyl bromination magnesium (the 0.25M diethyl ether solution, 200mL, 50mmol).Warm reactant adds saturated ammonium chloride (100mL) cancellation to ambient temperature overnight.Separate organic layer, extract water layer with hexane (100mL).The united extraction thing is used anhydrous magnesium sulfate drying, filters also, be concentrated into dried, title compound. 1H?NMR(500MHz，CD 3OD)：δ7.45-7.40(m，2H)，7.26(t，1H)，7.19(d，1H)，2.20(s，3H).
Step B 3-(3-bromophenyl)-4-(5-chloro-2-pyridyl)-2-butanone
Heating 5-chloro-2-picoline (reference example 18, steps A, 6.4g, 50mmol) and N-bromosuccinimide (12.5g, 70mmol) suspension in the 100mL tetracol phenixin is to little reflux state (bathing 90 ℃ of temperature), in 30 minutes, divide and add 2,2 '-Diisopropyl azodicarboxylate (0.74g) for several times.After stirring 5 hours under this temperature, concentrated reaction mixture.The gained slurries are diluted water (100mL), saturated aqueous solution of sodium bicarbonate/thiosulfuric acid saturated aqueous solution of sodium and salt water washing then with EtOAc (100mL).With the organic solution anhydrous sodium sulfate drying, filter, be concentrated into driedly, residue is through silica gel flash column chromatography purifying (eluent: the 2-15% ether/CH in hexane 2Cl 2(1: 1)), obtain 2-brooethyl-5-chloropyridine (6.0g, 60%), it is used for subsequent reactions immediately.Like this, under-78 ℃ and vigorous stirring, to 2-brooethyl-5-chloropyridine (6.0g, 29mmol) and 3-bromophenyl acetone (steps A, 6.0g, 28mmol) and tetrabutylammonium iodide (20mg) at 30mL CH 2Cl 2In solution in add the cesium hydroxide monohydrate (10g, 60mmol), slow then warm reactant be to ambient temperature overnight.Reaction mixture is assigned between ethyl acetate (100mL) and the water (100mL).Separate organic layer, (2 * 100mL) extract water layer with EtOAc.Merge organic extraction, anhydrous sodium sulfate drying filters, be concentrated into dried, residue through silica gel flash column chromatography purifying (eluent: the 5-40%EtOAc/ hexane), title compound. 1H?NMR(500MHz，CD 3OD)：δ8.44(d，1H)，7.66(dd，1H)，7.46-7.41(m，2H)，7.24(t，1H)，7.22(d，1H)，7.15(d，1H)，4.42(dd，1H)，3.54(dd，1H)，3.07(dd，1H)，2.12(s，3H).LC-MS：m/e?338(M+H) +(3.0min).
Step C 3-(3-bromophenyl)-4-(5-chloro-2-pyridyl)-2-butanols
At-78 ℃, to 3-(3-bromophenyl)-4-(5-chloro-2-pyridyl)-2-butanone (step B, 6.7g, add three (sec-butyl) lithium borohydride (1.0M THF solution in 50mL anhydrous THF solution 20mmol), 30mL, 30mmol), warm reactant is to ambient temperature overnight.Cooling reactant to 0 ℃ adds 2M hydrochloric acid (50mL) carefully, then the mixture that forms is assigned between hexane (200mL) and the water (200mL).Separate water layer, (2 * 100mL) extract organic layer with 2M hydrochloric acid.The combining water layer extract, with 5N aqueous sodium hydroxide solution neutralization (pH＞12), (2 * 200mL) extract to use EtOAc then.The extract anhydrous sodium sulfate drying that merges filters, be concentrated into dried, must title compound.
Step D: N-[2-(3-bromophenyl)-3-(5-chloro-2-pyridyl)-1-methyl-propyl] amine salt acid Salt
According to reference example 18, (5.9g 17mmol) is converted into title compound to the method for describing among the step C-D with the product of step C.LC-MS：m/e?338(M+H) +(2.3min).
Reference example 20
Figure A0380567800521
N-[2-(5-bromo-2-pyridyl)-3-(4-chloro-phenyl-)-1-methyl-propyl] amine hydrochlorate is (non-right Reflect body α)
Steps A 5-bromo-3-pyridyl acetone
With 3,5 dibromo pyridine (50g, 0.21mol), acetate pseudoallyl ester (26mL, 0.23mmol), three (dibenzalacetone) two palladium (1.0g, 1.1mmol) and 2-(diphenylphosphino)-2 '-(N, the N-dimethylamino) (1.6g, 4.2mmol) mixture in 400mL toluene heated 2 hours in 100 ℃ in nitrogen atmosphere biphenyl.Reaction mixture is concentrated into about 100mL to room temperature.With silicagel column on the gained mixture,, get title compound with 0-60%EtOAc/ hexane wash-out. 1H?NMR(500MHz，CD 3OD)：δ8.54(br?s，1H)，8.33(br?s，1H)，7.88(br?s，1H)，3.90(s，2H)，2.25(s，3H).
Step B 3-(5-bromo-3-pyridyl)-4-(4-chloro-phenyl-)-2-butanols
According to reference example 19, the described method of step B-C prepares title compound, and wherein replace 2-brooethyl-5-pyridine and replace 3-bromophenyl acetone (steps A) with 5-bromo-3-pyridyl acetone with the 4-chlorobenzyl chloride. 1H?NMR(500MHz，CD 3OD)：δ8.43(d，1H)，8.24(d，1H)，7.98(dd，1H)，7.17(d，2H)，7.07(d，2H)，4.04(m，1H)，3.16(dd，1H)，3.0-2.9(m，2H)，1.04(d，3H).
Step C N-[2-(5-bromo-3-pyridyl)-3-(4-chloro-phenyl-)-1-methyl-propyl] amine salt acid Salt (diastereomer α)
According to reference example 4, the described method of step B prepares title compound.LC-MS：m/e339(M+H) +(2.5min).
Reference example 21
Figure A0380567800531
N-[3-(4-chloro-phenyl-)-2-(5-cyano group-3-pyridyl)-1-methyl-propyl] amine hydrochlorate is (non- Enantiomorph α)
Steps A 5-cyano group-3-pyridyl acetone
The method of describing according to reference example 20 prepares title compound, wherein uses 5-bromine cigarette nitrile (5-bromo-3-cyanopyridine) to replace 3, the 5-dibromo pyridine in steps A. 1H?NMR(400MHz，CD 3OD)：δ8.89(d，1H)，8.60(d，1H)，8.02(t，1H)，3.98(s，2H)，2.24(s，3H).
Step B N-[3-(4-chloro-phenyl-)-2-(5-cyano group-3-pyridyl)-1-methyl-propyl] amine salt Hydrochlorate (diastereomer α/β 5: 1)
Prepare title compound according to reference example 5 described methods, wherein in steps A, replace 3-pyridyl acetone with 5-cyano group-3-pyridyl acetone.LC-MS：m/e?286(M+H) +(1.9min).
Reference example 22
Figure A0380567800541
N-[3-(4-chloro-phenyl-)-2-(5-chloro-3-pyridyl)-1-methyl-propyl] amine hydrochlorate is (non-right Reflect body α)
Steps A 5-chloro-3-pyridyl acetone
Prepare title compound according to reference example 20 described methods, wherein in steps A with 3, the 5-dichloropyridine replaces 2,5-dibromo pyridine and with 2-(two-tertiary butyl phosphino-) biphenyl replacement 2-(diphenylphosphino)-2 '-(N, N-dimethylamino) biphenyl. 1H?NMR(500MHz，CD 3OD)：δ8.42(d，1H)，8.27(d，1H)，7.73(dd，1H)，3.90(s，2H)，2.25(s，3H).
Step B N-[3-(4-chloro-phenyl-)-2-(5-chloro-3-pyridyl)-1-methyl-propyl] amine salt acid Salt (diastereomer α)
According to reference example 20, the described method of step B-C prepares title compound, wherein uses 5-chloro-3-pyridyl acetone to replace 5-bromo-3-pyridyl acetone in step B.LC-MS：m/e?295(M+H) +(1.9min).
Reference example 23
N-[3-(4-chloro-phenyl-)-2-(5-methyl-3-pyridyl)-1-methyl-propyl] amine hydrochlorate is (non- Enantiomorph α)
Prepare title compound according to reference example 17 described methods, wherein in steps A, use 2-(N-tertbutyloxycarbonyl) amino-3-(5-bromo-3-pyridyl)-4-(4-chloro-phenyl-) butane (reference example 20, the intermediate of step B) to replace 2-(N-tertbutyloxycarbonyl) amino-3-(3-bromophenyl)-4-(4-chloro-phenyl-) butane.LC-MS：m/e?275(M+H) +(1.3min).
Reference example 24
Figure A0380567800551
2-methyl-2-(2-2-pyrimidinyl oxy) propionic acid
Prepare title compound according to reference example 13 described methods, wherein in steps A, use the 2-hydroxy pyrimidine to replace 5-chloro-2 hydroxy pyrimidine. 1H?NMR(500MHz，CD 3OD)：δ8.53(d，2H)，7.09(t，1H)，1.74(s，6H).
Reference example 25
2-methyl-2-(4-trifluoromethyl-2-pyridyloxy) propionic acid
Prepare title compound according to reference example 13 described methods, wherein in steps A, use 4-trifluoromethyl-2 hydroxy pyrimidine to replace 5-chloro-2 hydroxy pyrimidine. 1H?NMR(500MHz，CD 3OD)：δ8.30(d，1H)，7.18(d，1H)，7.05(s，1H)，1.71(s，6H).
Reference example 26
Figure A0380567800561
2-methyl-2-(6-trifluoromethyl-4-2-pyrimidinyl oxy) propionic acid
Prepare title compound according to reference example 13 described methods, wherein in steps A, use 6-trifluoromethyl-4-hydroxy pyrimidine to replace 5-chloro-2 hydroxy pyrimidine. 1H?NMR(500MHz，CD 3OD)：δ8.81(s，1H)，7.28(s，1H)，1.75(s，6H).LC-MS：m/e251(M+H) +(2.1min).
Reference example 27
2-methyl-2-(5-trifluoromethyl-2-pyridyloxy) propionic acid
In the 12L three neck round-bottomed flasks that two nitrogen washes are crossed (each all disposes thermometer and reflux exchanger), and the THF solution of adding KHMDS (0.91M, every bottle of each 3.52L, 3.205mol, 1.5eq).Extremely-70 ℃ of cooling solutions, mechanical stirring.(463mL, 447g 3.38mol), keep temperature of reaction to be lower than-62 ℃ to add 2-ethyl butyrate of hydroxyl iso (98%) in 30 minutes in every bottle.After 10 minutes, disposable adding 338g (2.14mol) 2-chloro-5-5-flumethiazine in each bottle.Remove cooling bath, warm reactant to 20 ℃ spend the night (about 16 hours).Utilize TLC (silica gel, 90/10 Hex/EtOAc) and HPLC monitoring reaction:
In each reaction flask, add sodium hydroxide (1.36L, 5N), back flow reaction thing spend the night (about 22 hours).Compile reactant, on rotatory evaporator, concentrate to remove THF.Add entry (4L) in enriched material, (2 * 4L) extract with normal heptane with gained solution.Under agitation, in 10 minutes, water layer is added to 2N HCl (9L, 18mol) in.Aging gained suspension 30 minutes (30 ℃ of temperature) filters then.(3 * 2L) washing leaching cakes, dry air get moist brown solid to water.
At 65 ℃, the gained material is dissolved in normal heptane (4L).Add IPAc (1L) and DARCO KB (40g, 100 orders).Stirred the mixture 15 minutes, by the CELITE diatomite filtration, with heptane/IPAc of 4: 1 (3 * 500mL) washing leaching cakes.Concentrated filtrate gets white suspension to about 2L.(2 * 3L) flushings are concentrated into about 3L with heptane with these slurries.Cooling gained white slurries to 0 ℃, aging 1 hour.Filtration product with cold heptane (1L) washing leaching cake, gets the white crystals title compound.HPLC post: YMC Combiscreen Pro C18,50 * 4.6mm; Moving phase: A 0.1%THF/H 2O; B CH 3CN. gradient: 90/10 A/B-10/90 A/B, 4 minutes.Flow velocity: 4mL/min.Detect: 254nm. room temperature 2-chloro-5-5-flumethiazine 2.1min. room temperature 2-oxyethyl group-5-5-flumethiazine 2.9min. room temperature product ester 3.1min. room temperature end product acid 2.05min.
Reference example 28
Figure A0380567800571
2-amino-3-indoline-N-base-4 (4-chlorine) phenyl butane
Steps A 3-(4-chloro-phenyl-)-2-indoline-N-base ethyl propionateUnder nitrogen atmosphere, in the flask of oven dry, in the stirred suspension of 4 dust molecular sieves, be added in the 1.1g LiOHH among the DMF (20mL) 2O (26.25mmol).After 30 minutes, dropwise add 2.8mL (25mmol) indoline in stirring at room.After at room temperature reacting 1 hour, dropwise add 2.9mL (26.25mmol) ethyl bromoacetate.1.5 elimination solids after hour is with a large amount of EtOAc wash residual things.Wash organic phase with water 3 times, then with the organism dried over mgso.Solvent evaporated under reduced pressure.Subsequently rough material is dissolved among the anhydrous THF of 75ml, in nitrogen atmosphere, is added in the dry round-bottomed flask, be cooled to-78 ℃, use 26.25mL 1M NaHMDS solution-treated afterwards.Stirred formed solution 30 minutes in-78 ℃, then with enolate with 5.4g (26.25mmol) p-chlorobenzyl bromine (solution in the anhydrous THF of 25mL) alkylation.Warm reactant is to ambient temperature overnight.Added the water termination reaction in second day.Extract water layer with 3 one large EtOAc.Merge organic phase, use dried over mgso.Removal of solvent under reduced pressure through purification by flash chromatography, obtains title compound with residue, is the yellow oily body.LC/MS m/e=331 (M+1) .TLCR f=0.22 (20: 1 hexanes: EtOAc). 1H NMR (500MHz, CDCl 3): δ 1.11 (t, J=3.55Hz, 3H), 2.96 (m, 2H), 3.06 (m, 1H), 3.25 (m, 1H), 3.60 (t, 2H), 4.07 (m, 2H), 4.36 (t, J=3.75Hz, 1H).
Step B. N, O-dimethyl-3-(4-chloro-phenyl-)-2-indoline-N-base propionic acid amideUnder nitrogen atmosphere, in the flask of oven dry, utilize feed hopper to 1.15g (11.75mmol) N in 0 ℃, add 11.75mL 1M (CH in the stirred suspension of O-dimethyl hydroxylamine hydrochloride 3) 2The CH of AlCl 2Cl 2Solution.After being warming to room temperature, add the 10mL solution of 970mg (2.94mmol) 3-(4-chloro-phenyl-)-2-indolinyl ethyl propionate (obtaining) through feed hopper by steps A.In stirring at room after 5 hours, add the phosphate buffered saline buffer of 35mL pH8, and vigorous stirring gained mixture 30 minutes.Separate each phase, with twice of chloroform extraction of water layer.Organism after merging is washed with water, then with MgSO 4Dry.Collect brown oil.Should be used for next step by rough material.TLC R f=0.12 (10: 1 hexanes: EtOAc). 1H NMR (500MHz, CDCl 3): δ 2.83 (m, 1H), 2.97 (m, 2H), 3.13 (s, 3H), 3.34 (m, 1H), 3.45 (s, 3H), 3.61 (m, 2H), 4.87 (b, 1H), 6.54 (d, 1H), 6.66 (t, J=7.1Hz, 1H), 7.07 (t, J=7.1Hz, 2H), 7.18 (d, J=8.5Hz, 2H), 7.24 (d, J=8.5Hz, 2H).
Step C. 4-(4-chloro-phenyl-)-3-indoline-N-base butane-2-ketone
Under nitrogen atmosphere, in the flask of oven dry, to N, O-dimethyl-3-(4-chloro-phenyl-)-2-indolinyl propionic acid amide (derives from step B, 965mg) dropwise adds 2.8mL 1M CH in the stirred solution in the anhydrous THF of 25mL 3The THF of MgBr.Stir gained solution 4 hours, and meanwhile solution was warmed up to room temperature.Add about 20mL water then.With 50mL ether extraction mixture three times.With the extract dried over mgso after merging.Removal of solvent under reduced pressure, brown oil, it need not to be further purified and is directly used in next step.LC/MS m/e=301 (M+1) .TLC R f=0.5 (4: 1 hexanes: EtOAc). 1H NMR (500MHz, CDCl 3): δ 2.14 (s, 3H), 2.81 (dd, J=14.6,6.6Hz, 1H), 2.97 (t, J=8.5Hz, 2H), 3.26 (m, 2H), 3.5 (m, 1H), 4.21 (dd, J=6.6,6.6Hz), 6.39 (d, J=8Hz, 1H), 6.66 (dd, J=7.7Hz, 1H), 7.07 (m, 2H), 7.13 (d, J=8.5Hz), 7.22 (d, J=8.3Hz).
Step D. 4-(4-chloro-phenyl-)-3-indoline-N-base butane-2-ketone methyloxime
Solution in dehydrated alcohol is handled with 255 μ L (3.147mmol) pyridines with 472mg (1.573mmol) step C product and 263mg (3.147mmol) methoxy amine hydrochlorate.Stirring at room solution 2 hours.Removal of solvent under reduced pressure is assigned to residue between water and the ether.Water is used ether extraction again.United extraction thing then, dried over mgso is filtered, concentrate, rough material.E and Z isomer both are used for next step.LC/MS m/e=330 (M+1) .TLC R f=0.77 and 0.65 (4: 1 hexanes: EtOAc). 1H NMR (500MHz, CDCl 3): δ 1.78 (2s, 1H), 2.88 (dd, J=6.2,13.8Hz, 1H), 2.95 (m, 2H), 3.30 (m, 2H), 3.45 (m, 1H), 3.75 and 3.89 (2s, 3H), 4.21 (dd, J=6.9,7.8Hz, 1H), 6.28 and 6.47 (2d, J=8.1,1H), 6.61 (m, 1H), 7.02 (m, 2H), 7.22 (m, 4H).
Step e. 2-amino-3-indoline-N-base-4 (4-chlorine) phenyl butane
Under room temperature, nitrogen atmosphere, in the flask of the oven dry of disposing water condenser, with the 1.5mL anhydrous THF solution of 301mg (0.914mmol) 4-(4-chloro-phenyl-)-3-indolinyl butane-2-ketone methyloxime (step D gained) 3.7mL (3.7mmol) 1M BH 3THF handles.Solution is heated to 75 ℃ then and kept 2 days.Cooling solution to 0 ℃ is handled until stopping bubbling with trash ice afterwards.Add 500 μ L 20%KOH then, in 45 ℃ of heated solutions 2 hours.Solution is cool to room temperature then, extracts with ether 3x.The united extraction thing with dried over mgso, filters and concentrates, and obtains the amine crude product, and it need not to be further purified to be directly used in down and goes on foot experiment.LC/MSm/e=302 (M+1). 1H NMR (500MHz, CDCl 3): δ 1.13,1.14 (2d, J=6.5Hz, 1H), 1.55-1.60 (m, 2H), 2.80-3.10 (m, 4H), 3.30-3.60 (m, 2H), 6.348 and 6.38 (2d, J=7.9Hz, 1H), 6.50-6.78 (m, 2H), 6.95-7.24 (m, 5H).
Reference example 29
2-amino-3-indoles-N-base-4 (4-chlorine) phenyl butane
According to preparing this compound, wherein in steps A, use sodium hydride to replace lithium hydroxide monohydrate/molecular sieve combination as alkali with reference example 28 similar methods.LC-MS: calculated value (C 18H 19CLN 2): 299, measured value m/e 300 (M+H) +(2.4min).
Reference example 30
Figure A0380567800601
Amino-4 (4-chlorine) phenyl butane of 2-amino-3-(N-methyl, N-phenyl)
According to preparing this compound, LC-MS: calculated value (C with reference example 28 similar methods 17H 21ClN 2): 289, measured value m/e 290 (M+H) +(2.4min).
Reference example 31
2-amino-3-(7-azaindole-N-yl)-4 (4-chlorine) phenyl butane
According to preparing this compound with reference example 28 similar methods.LC-MS: calculated value (C 17H 18ClN 3): 300, measured value m/e 301 (M+H) +(2.7min).
Reference example 32
4-(4-aminomethyl phenyl)-3-phenyl butane-2-amine (4 kinds of mixture of isomers)
Steps A The 1-phenyl-acetone
In 0 ℃, (9.9mL adds benzylmagnesium chloride (97mL, 1M diethyl ether solution) in ether 97mmol) (300mL) solution to N-methyl-N-methoxyl group ethanamide.The reaction mixture of warm formed white casse was kept 2 hours to room temperature, carefully added 1N hydrochloric acid (100mL) cancellation then.Separate organic phase, by dried over mgso, concentrate with the salt water washing.Crude product is through silica gel chromatography (eluent: the 0-10%EtOAc/ hexane), get title compound. 1H?NMR(500MHz，CDCl 3)：δ7.36(t，J＝7.1Hz，2H)，7.30(t，J＝7.3Hz，1H)，7.24(d，J＝7.3Hz，2H)，3.72(s，2H)，2.18(s，3H).LC-MS?m/e135(M+H) +(1.95min).
Step B 4-(4-aminomethyl phenyl)-3-phenyl fourth-2-ketone
In not solvent-laden flask, mix the 1-phenyl-acetone (200mg, 1.49mmol) with the potassium hydroxide powder (167mg, 2.98mmol) and Tetrabutyl amonium bromide (1mol%, 5mg).In this mixture of stirring at room 90 minutes, add then 1-(chloromethyl)-4-methylbenzene (198 μ l, 1.49mmol).Then reaction mixture is stirred and spend the night, add the dilution of entry and methylene dichloride afterwards.Separate water layer, be neutralized to pH7, use dichloromethane extraction afterwards again with 2N hydrochloric acid.The organic washes dried over mgso that merges concentrates then.Crude product is through silica gel chromatography (eluent: the 0-10%EtOAc/ hexane), get title compound. 1H?NMR(500MHz，CDCl 3)：δ7.35(t，J＝7.0Hz，2H)，7.29(t，J＝7.4Hz，1H)，7.23(d，J＝7.1Hz，2H)，7.05(d，7.8Hz，2H)，6.98(d，J＝7.8Hz，2H)，3.94(t，J＝7.3Hz，1H)，3.43(dd，J＝13.9，7.5Hz，1H)，2.91(dd，J＝14，7.1Hz，1H)，2.32(s，3H)，2.08(s，3H).LC-MS?m/e?239(M+H) +(3.61min).
Step C 4-(4-aminomethyl phenyl)-3-phenyl fourth-2-amine
(308mg, (130mg 2.06mmol), spends the night in the stirring at room reaction 1.29mmol) to add sodium cyanoborohydride in the solution in 7M ammonia/MeOH (5mL) and acetate (3mL) to 4-(4-aminomethyl phenyl)-3-phenyl fourth-2-ketone.Pour cancellation reaction in the 2M yellow soda ash into, extract with EtOAc then.The salinization water layer also extracts once more.Merging organic extraction, with dried over mgso, concentrate and obtain title compound, is 4 kinds of mixture of isomers, and it need not to be further purified direct use.LC-MS：m/e?240(M+H) +(2.22min).
Reference example 33
3-[2-amino-1-(4-luorobenzyl) propyl group] benzonitrile
Adopt embodiment 5, the method for describing among step B and the C is prepared, and wherein uses 3-(2-oxopropyl) benzonitrile and 1-(chloromethyl)-4-fluorobenzene as reactant in step B.LC-MS：m/e?269(M+H) +(2.87min).
Reference example 34
Figure A0380567800622
2-(1H-1,2,3-benzotriazole-1-yl)-3-(4-chloro-phenyl-)-1-methyl-propyl amine
Steps A 2-(1H-1,2,3-benzotriazole-1-yl)-N-methoxyl group-N-methylacetamide
With 1.77g (10mmol) 2-(1H-1,2,3-benzotriazole-1-yl) acetate, 1.07g (11mmol) N, O-dimethyl hydroxylamine hydrochloride, 5.8g (11mmol) PyBOP and the mixture of 3.4mL (24.2mmol) diisopropylethylamine in the 50mL methylene dichloride are in stirred overnight at room temperature.This mixture is assigned between EtOAc and the water.Anhydrous magnesium sulfate drying is used in organic layer salt water washing then.Removing desolvates obtains crude product, and then by silica gel purification, uses the 60%EtOAc/ hexane as solvent, obtains the required acid amides of 2.01g, is solid state. 1H?NMR(CDCl 3)：δ3.26(s，3H)，3.84(s，3H)，5.63(s，2H)，7.35-8.2(m，4H).
Step B 2-(1H-1,2,3-benzotriazole-1-yl)-3-(4-chloro-phenyl-)-N-methoxyl group-N- Methyl-propionic acid amide
At-78 ℃, in the 15mL anhydrous THF solution of 2.0g (9mmol) 2-(1H-1,2,3-benzotriazole-1-yl)-N-methoxyl group-N-methylacetamide, dropwise add two (trimethyl silyl) lithium amides of 10mL (10mmol) 1M.Stir after 25 minutes, add the solution of 2.06g (10mmol) 4-chlorine bromotoluene in the anhydrous THF of 2mL.Warm gained reaction mixture stirred 6 hours to room temperature.Quencher should reaction, with 75mL EtOAc dilution, uses the salt water washing three times of each 10mL then.After the drying, remove the organic phase solvent, obtain crude product, and then, use the 40%EtOAc/ hexane to be solvent, obtain required product, be solid state by silica gel purification. 1H?NMR(CDCl 3)：δ3.2(s，3H)，3.834(s，3H)，3.52(m，1H)，3.7(m，1H)，6.32(t，1H)，6.9-8.2(m，8H).
Step C 2-(1H-1,2,3-benzotriazole-1-yl)-3-(4-chloro-phenyl-)-Ding-2-ketone
In 0 ℃, in the 10mL anhydrous THF solution of 1.73g (5mmol) 2-(1H-1,2,3-benzotriazole-1-yl)-3-(4-chloro-phenyl-)-N-methoxyl group-N-methyl-propionic acid amide, add 4mL (10mmol) 2.5M methyl-magnesium-bromide diethyl ether solution.Stirred reaction mixture is 4 hours when being warming to room temperature.Add 10mL 1N HCl quencher reaction, and the gained mixture is assigned between EtOAc and the water.Anhydrous magnesium sulfate drying is used in organic phase salt water washing then.Remove and desolvate, obtain the ketone crude product, and then use the 40%EtOAc/ hexane to carry out silica gel purification, obtain required ketone.
Step D 2-(1H-1,2,3-benzotriazole-1-yl)-3-(4-chloro-phenyl-)-1-methyl propylamine
In 0 ℃, to 1.18g (4mmol) 2-(1H-1,2,3-benzotriazole-1-yl)-and add 4mL (964mmol) Glacial acetic acid in the solution of 3-(4-chloro-phenyl-)-Ding-2-ketone in 8.5mL (60mmol) 7N ammonia/methyl alcohol, then add 410mg (6.5mmol) sodium cyanoborohydride.Warm reaction mixture is to room temperature, and stirring is spent the night.Reactant distribution is arrived between EtOAc and the saturated sodium bicarbonate solution.The organic phase anhydrous magnesium sulfate drying.Solvent removed in vacuo uses 5%2N methyl alcohol to close ammonia solution and 95%CH 2Cl 2Mixture by the silica gel purification residue, obtain required amine, be non-enantiomer mixture.LC-MS, room temperature=2.0min, m/e=301.
Embodiment 35
3-(4-chloro-phenyl-)-2-(thiene-3-yl-)-1-methyl propylamine
Prepare title amine according to reference example 34 described methods, wherein in steps A, use thiophene-3-acetate to replace 2-(1H-1,2,3-benzotriazole-1-yl) acetate.LC-MS, room temperature=2.19min, m/e=266.
Reference example 36
2-(3-cyano-phenyl)-3-cyclobutyl-1-methyl propylamine
Steps A 1-(3-cyano-phenyl) acetone
With 3-bromobenzyl nitrile and methylvinyl acetate be raw material according to reference example 20, the method for steps A prepares title compound.
Step B 3-(3-cyano-phenyl)-4-cyclobutyl-Ding-2-ketone
In the solution of 1.45g (9.07mmol) 1-(3-cyano-phenyl) acetone in the 18mL acetonitrile, add 1.1mL (9.5mmol) cyclobutyl bromine and 5.91g (18.1mmol) cesium carbonate.After heated solution spent the night in 60 ℃ of bath temperature, cooling was also filtered.To between water and the EtOAc, water layer extracts with EtOAc with filtrate distribution.Merge organic layer, use the salt water washing, dry, concentrated.Residue uses 5-10%EtOAc/ hexane gradient liquid wash-out through quick column purification, separates title compound. 1H?NMR(500MHz，CDCl 3)：δ1.5-2.2(m，9H)，2.13(s，3H)，3.64(m，1H)，7.4-7.7(m，4H).
Step C 2-(3-cyano-phenyl)-3-cyclobutyl-1-methyl propylamine
According to reference example 3, the method for step e-I prepares this amine.LC-MS, room temperature=2.48min, m/e=229.
Obtain the compound of reference example 37 and 38 according to reference example 36 described methods.
Reference example 37
Figure A0380567800651
2-(3-cyano-phenyl)-3-cyclopentyl-1-methyl propylamine
LC-MS，RT＝2.7min，m/e＝243.
Reference example 38
Figure A0380567800652
2-(3-cyano-phenyl)-3-cyclohexyl-1-methyl propylamineLC-MS, RT=2.8min, m/e=257.
Embodiment 1
The automatization in one dimension acid amides storehouse is synthetic
Synthesizing in MYRIAD CORE system of the single pure compound of following unidimensional storehouse carried out.All reactors face with preceding in nitrogen gas stream in 120 ℃ of dryings 12 hours.Before use with solvent all with molecular sieve drying at least 12 hours.Before using, in pyridine, prepare N-[2, two (4-the chloro-phenyl-)-1-methyl-propyls of 3-]-the suitable stock solution of amine hydrochlorate (αYi Gouti), wherein be added with the Dimethylamino pyridine of 0.05 equivalent (with respect to N-[2, two (4-the chloro-phenyl-)-1-methyl-propyls of 3-]-amine hydrochlorate (αYi Gouti)); The various different carboxylic acids of buying are from the market being faced with before being dissolved among the DMSO.Reactant sees Table 1 with the relative consumption of coupling reagent.
Table 1.
Material Consumption/reactor ????MW Concentration ???Mmols Equivalent
Acid is dissolved among the DMSO ??1mL ????N/A ???0.2M ????0.2 ????1.67
The EDC/HOBt mixture is dissolved in the deuterochloroform ??0.8mL ????EDC： ????191.71 ????HOBt： ????135.13 Each 0.25M Each is 0.2 years old Each is 1.67 years old
Amine, be dissolved in the pyridine, wherein contain catalytic amount Dimethylamino pyridine (～0.05eq.) ??0.6mL ????294.227 ???0.2M ????0.12 ????1.0
Method: in nitrogen atmosphere, in one of 10mL MYRIAD mat glass reactors of total 192, add suitable different sour subunit (1.0mL, 0.2mmol, the DMSO solution of 0.2M); Remaining 191 reactors are repeated this operation, till all 192 reactors are drawn up different acid.In nitrogen atmosphere, add EDC/HOBt mixture (each 0.25M is in deuterochloroform for 0.8mL, 0.2mmol) in each in 192 reactors then.At last, add N-[2 in each in 192 reactors, two (4-the chloro-phenyl-)-1-methyl-propyls of 3-]-amine hydrochlorate (αYi Gouti) (0.6mL, 0.12mmol, 0.2M pyridine solution).Under nitrogen jet stirs (per 30 minutes use pulse of nitrogen 1s), then room temperature (20-25 ℃) aging reaction thing 4 hours, then in 65 ℃ aging 16 hours.With HPLC-MS method 1 analytical reaction thing.
Analytical LC method 1:
Post: MetaChem Polaris C-18A, 30mm * 4.6mm, 5.0 μ m
Eluent A:0.1%TFA/ water
Eluent B:0.1%TFA/ acetonitrile
Gradient: in 3.3 minutes from 5%B to 95%B, at 0.3 minute inside gradient
Turn back to 5%B
Flow velocity 2.5mL/min.
Column temperature: 50 ℃
Injection volume: the undiluted crude reaction mixture of 5 μ L
Detect: UV, 220 and 254nm.
MS:API-ES ionization mode, mass scanning scope (100-700)
ELSD: light scattering detector
By preparation HPLC purifying, use the UV method to detect (preparation method 2) rough reactant.Adopt LC-MS to analyze the purity (analytical procedure 3) of each cut of collecting then; Purity is pooled in the 40mL EPA bottle of having determined tare weight lyophilize greater than each cut of 90%.The LC method 2 of preparation property:
Post: MetaChem Polaris C-18A, 100mm * 21.2mm, 10 μ m
Eluent A:0.1%TFA/ water
Eluent B:0.1%TFA/ acetonitrile
Injection forward horizontal stand: 1.0min
The injection back keeps: 0.0min
Gradient: in 6.0 minutes, from 10%B to 100%B, under 100%B, protect again
Held 2.0 minutes, and in 1.5 minutes, returned then from the 100%B gradient
To 5%B
Flow velocity 25mL/min.
Column temperature: room temperature
The undiluted crude reaction mixture of injection volume: 1.5mL
Detect: UV, 220 and 254nm.
Analytical procedure 3:
Post: MetaChem Polaris C-18A, 30mm * 2.0mm, 3.0 μ m
Eluent A:0.1%TFA/ water
Eluent B:0.1%TFA/ acetonitrile
Gradient: from 5%B to 95%B, gradient turned back in 0.1 minute in 2.0 minutes
5％B
Flow velocity 1.75mL/min.
Column temperature: 60 ℃
Injection volume: the undiluted cut of 5 μ L
Detect: UV, 220 and 254nm.
MS:API-ES ionization mode, mass scanning scope (100-700)
ELSD: light scattering detector
The lyophilize parameter:
Initial freezing set(ting)value :-70 ℃, 1h
The set(ting)value of drying stage condenser :-50 ℃
The drying stage table:
Storage temperature (℃) Time length (minute) Vacuum set(ting)value (m torr)
????-60℃ ????240 ?????25
????-40℃ ????240 ?????25
????5℃ ????480 ?????25
????20℃ ????1000 ?????25
Embodiment 2 and 3
N-[2, two (4-the chloro-phenyl-)-1-methyl-propyls of 3-]-2-(4-chlorophenoxy)-2-methyl propanamide (diastereomer α and β)
In 0 ℃, to 2-(4-chlorophenoxy)-2 Methylpropionic acid (Aldrich, 0.22g, CH 1.0mmol) 2Cl 2(2mL) add in the solution DMF and oxalyl chloride (0.27mL, 3.0mmol).After 1 hour, utilize the rotatory evaporator concentrated reaction mixture in stirring at room, dry under vacuum, gained acyl chlorides crude product need not to be further purified direct use.Therefore, gained acyl chlorides crude product is dissolved in 1mL CH 2Cl 2In, and join 2-amino-3, two (4-chloro-phenyl-) the butane hydrochlorides (reference example 1) of 4-(αYi Gouti that contains some diastereomer β impurity, 0.20g, 0.60mmol) and N-methylmorpholine (0.27mL is 2.4mmol) at 4mL CH 2Cl 2Suspension in.After 6 hours,, use the 10%EtOAc wash-out in stirring at room, obtain the pure product of isomer (diastereomer α) of very fast wash-out and the isomer (diastereomer β) of slow wash-out silicagel column on the reaction mixture.
Diastereomer α: 1H NMR (500MHz, CD 3OD): δ 7.24 (d, 2H), 7.20 (d, 2H), 7.05 (d, 2H), 7.01 (d, 2H), 6.94 (d, 2H), 6.76 (d, 2H), 4.25 (m, 1H), 3.03 (dd, 1H), 2.88 (ddd, 1H), 2.67 (dd, 1H), 1.59 (s, 3H), 1.53 (s, 3H), 0.88 (d, 3H) .LC-MS:m/e 490 (M+H) +(4.7min).
Diastereomer β: 1H NMR (500MHz, CD 3OD): δ 7.16 (d, 2H), 7.14 (d, 2H), 7.09 (d, 2H), 6.99 (d, 2H), 6.88 (d, 2H), 6.64 (d, 2H), 4.33 (m, 1H), 3.12 (dd, 1H), 3.03 (ddd, 1H), 2.74 (dd, 1H), 1.36 (s, 3H), 1.30 (d, 3H), 1.30 (s, 3H) .LC-MS:m/e 490 (M+H) +(4.7min).
Embodiment 4-7 (table 2) is according to the method preparation of describing in embodiment 2 and 3, wherein use the suitable amine that makes in the reference example to replace 2-amino-3, two (4-chloro-phenyl-) butane hydrochlorides of 4-and with suitable acid substitution 2-(4-the chlorophenoxy)-2 Methylpropionic acid for preparing in the reference example.In some cases, use commercially available acid or acyl chlorides, and use the N-diisopropylethylamine to replace N-methylmorpholine, obtain similar results.(α or β) is consistent with the name of raw material amine in the name of diastereomer.
Table 2. is according to the compound of the described method preparation of embodiment 2-3.
Figure A0380567800701
Embodiment 8 and 9
Figure A0380567800711
N-[2, two (4-the chloro-phenyl-)-1-methyl-propyls of 3-]-2-(4-chlorophenoxy)-2-methyl propanamide (diastereomer α, enantiomorph A and B)
For enantiomer separation, the HPLC of being prepared property in Gilson HPLC system.Therefore, with N-[2, two (4-the chloro-phenyl-)-1-methyl-propyls of 3-]-2-(4-chlorophenoxy)-(embodiment 60 for 2-methyl propanamide (diastereomer α), 1.0g) Chiralpak AD post on the solution in hexane (3ml)/ethanol (7mL) (2cm * 25cm), with 5% ethanol/hexane wash-out (flow velocity 9mL/min, per injection 500 μ L), obtain two purified enantiomorphs.
The enantiomorph (enantiomorph A) of very fast wash-out: analyze HPLC: retention time=7.8min (Chiralpal AD post, flow velocity=0.75mL/min, 5% ethanol/hexane) .LC-MS:m/e490 (M+H) +(4.7min).
The enantiomorph (enantiomorph B) of slow wash-out: analyze HPLC: retention time=9.6min (Chiralpak AD post, flow velocity=0.75mL/min, 5% ethanol/hexane) .LC-MS:m/e490 (M+H) +(4.7min).
According to the described method of embodiment 8-9, by composition (4-15% ethanol/hexane), (2) flow velocity (6-9mL/min) and (3) volume injected (200-2000 μ L) of appropriate change (1) eluent, the corresponding racemoid (table 2) of emanating obtains the embodiment 10-17 compound (table 3) of single enantiomer form.
The enantiomeric compounds that table 3. obtains according to the described method segregation of embodiment 8-9.
According to N-[3-(4-chloro-phenyl-)-2 (S)-phenyl-1 (the S)-methyl-propyls of the described method of embodiment 2-3 by reference example 4]-amine hydrochlorate makes embodiment 18 (table 4) with suitable carboxylic acid link coupled.
Table 4. is by N-[3-(4-chloro-phenyl-)-2 (S)-phenyl-1 (the S)-methyl-propyls of reference example 4]-the single enantiomeric compounds of amine preparation.
Figure A0380567800741
Embodiment 19
Figure A0380567800742
N-[2, two (4-the chloro-phenyl-)-1-methyl-propyls of 3-]-2-(4-chloro-phenyl-amino)-2-methyl propionyl Amine
To 2-amino-3, two (4-chloro-phenyl-) the butane hydrochlorides of 4-(diastereomer α, first part, reference example 1,0.31g, 0.94mmol) and 2-(4-chloro-phenyl-amino)-2 Methylpropionic acid (0.20g is 0.94mmol) at 5mL CH 2Cl 2In mixture in add N-methylmorpholine (0.41mL, 3.5mmol) and three (pyrrolidyl) phosphorus hexafluorophosphate (0.73g, 1.4mmol).After stirred overnight at room temperature,,, obtain title compound with 30%EtOAc/ hexane wash-out with silicagel column on the reaction mixture. 1H?NMR(400MHz，CD 3OD)：δ7.17(d，2H)，7.04(d，2H)，7.02(d，2H)，6.97(d，2H)，6.70(d，2H)，6.56(d，2H)，4.20(m，1H)，3.02(dd，1H)，2.78(ddd，1H)，2.64(dd，1H)，1.52(s，3H)，1.45(s，3H)，0.82(d，3H).LC-MS：m/e?489(M+H) +(4.3min)
Embodiment 20
Figure A0380567800751
(2,3-phenylbenzene-1-methyl-propyl)-2-(4-chlorophenoxy)-the 2-methyl propanamide is (non-right for N- Reflect body β)
(20mg is 0.095mmol) at CH to handle 2-(4-chlorophenoxy)-2 Methylpropionic acid with oxalyl chloride (11 μ L) 2Cl 2(1mL) and the solution among the DMF (10 μ L).After 30 minutes, the concentration response thing is dissolved in 1mL CH with residue 2Cl 2In.Then this solution is added to 16mgN-(2,3-phenylbenzene-1-methyl propylamine (deriving from the beta isomer of reference example 2) and saturated NaHCO of 1mL 3Mixture in.Reaction stirred is spent the night, and inhales with suction pipe and removes organic layer.This solution of TLC purifying with preparation property with 30%EtOAc/ hexane wash-out, obtains title compound. 1H?NMR(500MHz，CDCl 3)：δ1.17(d，3H)，1.36(s，3H)，1.46(s，3H)，2.85-3.05(m，3H)，4.44(m，1H)，6.37(d，1H)，6.75-7.4(m，14H).LC-MS：R t＝4.4min.m/e?422.2(M+1).
According to the method for embodiment 20, (2,3-phenylbenzene-1-methyl-propyl amine and with suitable carboxylic acid replacement 2-(4-chlorophenoxy)-2-methyl-propionic acid has prepared the compound in the following table 5 to use suitable amine to replace N-.
Table 5
Figure A0380567800761
According to the method for embodiment 2-3, (2,3-phenylbenzene-1-methyl-propyl amine is also replaced 2-(4-chlorophenoxy)-2 Methylpropionic acid with suitable carboxylic acid, has prepared the compound in the following table 6 to use suitable amine to replace N-.
Table 6. is according to the compound of the described method preparation of embodiment 2-3
Figure A0380567800762
Method according to the described enantiomer separation of embodiment 8-9 is separated the compound that obtains in the following table 7.
The enantiomeric compounds that table 7. obtains according to the described method segregation of embodiment 8-9.
Figure A0380567800771
N-[3-(4-chloro-phenyl-)-2 (S)-phenyl-1 (the S)-methyl-propyls that obtain with reference example 4]-amine hydrochlorate and suitable acid prepared the compound in the following table 8, obtained single enantiomorph.
Table 8. is with N-[3-(4-chloro-phenyl-)-2 (S)-phenyl-1 (S)-methyl-propyls]-the single enantiomeric compounds of amine hydrochlorate preparation.
Figure A0380567800781
According to embodiment 2-3 (through the acyl chlorides intermediate) or the described method of embodiment 19 (use coupling agent), with N-[3-(4-chloro-phenyl-)-2 (S)-phenyl-1 (S)-methyl-propyls]-amine hydrochlorate (reference example 4) or N-[3-(5-chloro-2-pyridyl)-2 (S)-phenyl-1 (S)-methyl-propyls]-amine hydrochlorate (reference example 18) and suitable carboxylic acid the have been feedstock production compound (table 9) of embodiment 30-33.
Table 9.
Prepared embodiment 34-39 (table 10) according to embodiment 2-3 (through the acyl chlorides intermediate) or the described method of embodiment 19 (use coupling agent) by the amine and the acid of suitable reference example.
Table 10.
Figure A0380567800801
Figure A0380567800811
According to the described method of embodiment 8-9, form (4-15% ethanol/hexane), (2) flow velocity (6-9mL/min) and (3) volume injected (200-2000 μ L) by appropriate change (1) eluent, the corresponding racemoid (table 10) of emanating has obtained the compound (table 11) of the embodiment 41-52 of single enantiomeric form.
The enantiomeric compounds that table 11. obtains according to the described method segregation of embodiment 8-9.
Figure A0380567800821
Figure A0380567800841
The embodiment 53-56 (table 12) that separates the diastereomer form (isomer A or B) shown in having obtained with silica gel chromatographic column.On above-mentioned chirality AD post, separate the single enantiomorph shown in having obtained.
Table 12.
Embodiment 57
Figure A0380567800871
2-methyl-N-[1-methyl-3-(4-aminomethyl phenyl)-2-phenyl propyl]-2-[[5-(trifluoromethyl) Pyridine-2-yl] the oxygen base } propionic acid amide
At room temperature, to 2-methyl-2-{[5-(trifluoromethyl) pyridine-2-yl] the oxygen base } propionic acid (reference example 14,250mg, 1.04mmol) and 4-(4-aminomethyl phenyl)-3-phenyl fourth-2-amine (reference example 102,260mg, 1.04mmol, 4 kinds of mixture of isomers) at CH 2Cl 2In the solution (5.5mL) order add diisopropylethylamine (272 μ l, 1.56mmol), (649mg, 1.25mmol), stirred reaction mixture spends the night PyBOP.Reaction mixture directly being gone up silicagel column, carry out purifying with 0-30%EtOAc/ hexane wash-out, obtain title compound, is 4 kinds of mixture of isomers.Separate (use 97% hexane: 3% ethanol is with the 20mL/min wash-out) diastereomer by HPLC on ZORBAX RxSi post, its retention time is:
-low polar diastereomer: 4.73 minutes; The diastereomer of high polarity: 5.87 minutes.In addition, with the diastereomer of high polarity on ChiralPak AD post by using 95 hexanes: 5% ethanol separates with the 8mL/min wash-out, obtains enantiomorph, and its retention time is:
-low polar enantiomorph: 6.84 minutes; The enantiomorph of high polarity: 8.36 minutes.
Low polarity diastereomer: 1H NMR (500MHz, CDCl 3): δ 8.44 (s, 1H), 7.86 (dd, J=8.6,2.5Hz, 1H), 7.19 (t, J=3.2Hz, 3H), 7.00 (dd, J=21.3,8.0Hz, 4H), 6.91 (m, 2H), 6.83 (d, J=8.7Hz, 1H), 5.70 (d, J=9.4Hz, 1H), 4.43 (m, 1H), 3.02 (dd, J=13.3,6.7Hz, 1H), 2.84 (dt, J=7.3,4.3Hz, 1H), 2.84 (dd, J=13.2,7.7Hz, 1H), 2.29 (s, 3H), 1.69 (s, 3H), 1.66 (s, 3H), 1.03 (d, J=6.8Hz, 3H) .LC-MS:m/e 471 (M+H) +(4.22min).
The high polarity diastereomer: 1H NMR (500MHz, CDCl 3): δ 8.40 (s, 1H), 7.83 (dd, J=8.7,2.6Hz, 1H), 7.21 (m, 3H), 7.00 (dd, J=30.4,6.2Hz, 4H), 6.82 (t, J=9.2Hz, 3H), 5.84 (d, J=9.2Hz, 1H), 4.36 (ddt, J=9.1,6.7,6.6Hz, 1H), 3.06 (dd, J=12.8,4.1Hz, 1H), 2.88 (m, 1H), 2.26 (s, 3H), 1.78 (s, 3H), 1.73 (s, 3H), 0.92 (d, J=6.6Hz, 3H) .LC-MS:m/e 471 (M+H) +(4.17min).
Embodiment 58
Figure A0380567800881
N-[2-(3-cyano-phenyl)-3-(4-fluorophenyl)-1-methyl-propyl]-2-methyl-2-{[5-(three Methyl fluoride) pyridine-2-yl] the oxygen base } propionic acid amide
Preparation is carried out as described in embodiment 57, only is to use 3-[2-amino-1-(4-luorobenzyl) propyl group] benzonitrile (reference example 33) is as amine component, thus obtain title compound, be 4 kinds of mixture of isomers.Diastereomer is separated (use 96% hexane: 4% ethanol is with the 20mL/min wash-out) by HPLC on Zorbax RxSi post, its retention time is: low polar diastereomer: 11.75 minutes; The diastereomer of high polarity: 15.17 minutes.In addition, with the diastereomer of high polarity on ChiralPak AD post by using 92% hexane: 8% ethanol separates with the 8mL/min wash-out, obtains enantiomorph, and its retention time is: low polar enantiomorph: 9.65 minutes; The enantiomorph of high polarity: 11.78 minutes.
Low polar diastereomer: 1H NMR (500MHz, CD 3OD): δ 8.29 (s, 1H), 7.93 (dd, J=8.7,2.5Hz, 1H), 7.50 (m, 1H), 7.42 (m, 1H), 7.27 (m, 2H), 6.96-6.78 (m, 5H), 5.70 (d, J=9.6Hz, 1H), 4.33 (m, 1H), 3.18-3.04 (m, 2H), 2.7 (dd, J=13.5,6.6Hz, 1H), 1.52 (s, 3H), 1.35 (s, 3H), 1.17 (d, J=6.6Hz, 3H) .LC-MS:m/e 500 (M+H) +(4.33min).
The diastereomer of high polarity: 1H NMR (500MHz, CD 3OD): δ 8.28 (s, 1H), 7.95 (dd, J=8.7,2.5Hz, 1H), 7.50 (d, J=7.5Hz, 1H), 7.36 (m, 3H), 7.05 (d, J=8.9Hz, 3H), 6.78 (m, 2H), 6.72 (m, 2H), 4.26 (dq, J=10,6.6Hz, 1H), 3.04 (dd, J=13.7,3.4Hz, 1H), 2.85 (ddt, J=11.2,3.7Hz, 1H), 2.63 (dd, J=13.7,11.4Hz, 1H), 1.77 (s, 3H), 1.74 (s, 3H), 0.81 (d, J=6.8Hz, 3H) .LC-MS:m/e 500 (M+H) +(4.25min).
Table 13 compound is by the amine of suitable reference example and acid preparation according to embodiment 2-3 (through the acyl chlorides intermediate) or the described method of embodiment 19 (use coupling agent).
Table 13.
According to the method for the described enantiomer separation of embodiment 8-9, separate the compound that obtains table 14.
The enantiomeric compounds that table 14. obtains according to the described method segregation of embodiment 8-9.
Figure A0380567800892
Embodiment 64
N-[3-(4-chloro-phenyl-)-2-(5-cyano group-3-pyridyl)-1-methyl-propyl-2-(5-fluoroform Base-2-pyridyloxy)-pyridine N-oxides (enantiomorph B) of 2-methyl propanamide
With N-[3-(4-chloro-phenyl-)-2-(5-cyano group-3-pyridyl)-1-methyl-propyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methyl propanamide (enantiomorph B, embodiment 50,0.10g, 0.19mmol) and-chloroperoxybenzoic acid (77%, 0.15g 0.67mmol) mixture in the 2mL methylene dichloride stirred 14 hours under room temperature.Concentrated reaction mixture then, residue use 30-100% acetonitrile/water (containing 0.1% trifluoroacetic acid) wash-out through anti-phase C18 post HPLC purifying, obtain title compound 1H NMR (500MHz, CD 3OD): δ 8.58 (s, 1H), 8.32 (br s, 1H), 8.1y (s, 1H), 7.99 (br d, 1H), 7.97 (dd, 1H), 7.81 (s, 1H), 7.16 (d, 2H), 7.06 (d, 1H), 6.87 (d, 2H), 4.28 (m, 1H), 3.11 (dd, 1H), 3.01 (m, 1H), 2.71 (dd, 1H), 1.75 (s, 3H), 1.74 (s, 3H), 0.94 (d, 3H) .LC-MS:m/e 533 (M+H) +(4.1min).
Embodiment 65
The combination of Cannabined receptor-1 (CB1) is measured
The mensuration of binding affinity is based on the recombinant human CB1 acceptor (Felder etc., Mol.Pharmacol.48:443-450,1995) of expressing in the grey mouse ovary of China (CHO) cell.Total mensuration volume is 250 μ l (240 μ l CB1 receptor membrane solution+5 μ l test compound solutions+5 μ l[ 3H] CP-55940 solution).[ 3H] final concentration of CP-55940 is 0.6nM.Binding buffer liquid comprises 50mM Tris-HCl, pH7.4,2.5mM EDTA, 5mM MgCl 2, 0.5mg/mL not the bovine serum albumin of fatty acids and proteinase inhibitor (catalog number (Cat.No.) P8340, Sigma).For causing association reaction, add 5 μ l radioligand solution, under slight vibration on electromagnetic shaker, 30 ℃ of following mixtures incubated 1.5 hours.Use 96 holes results instrument, by the GF/C filter filtration termination combination of pre-soaking in 0.05% polymine.Use scintillometer to measure the amount of bonded radioactively labelled substance.Calculate the apparent binding affinity (DeBlasi etc., Trends Pharmacol Sci 10:227-229,1989) of different compounds according to the IC50 value.
The recombinant human CB2 acceptor of expressing in Chinese hamster ovary celI in conjunction with the mensuration use of CB2 acceptor carries out in a similar fashion.
Embodiment 66
The functionally active of Cannabined receptor-1 (CB1) is measured
The function activation of CB1 acceptor is based on the recombinant human CB1 acceptor of expressing in Chinese hamster ovary celI (Felder etc., Mol.Pharmacol.48:443-450,1995).For the agonist activity or the inverse agonist activity of determination test compound, 50 μ l CB1-CHO cell suspensions are mixed in 96 orifice plates with test compound and 70ul test damping fluid (containing 0.34mM 3-isobutyl-1-methylxanthine and 5.1uM forskolin).The test damping fluid is made up of the Earle balanced salt solution, has wherein added 5mM MgCl 2, 1mM glutamine, 10mM HEPES and 1mg/mL bovine serum albumin.At room temperature mixtures incubated is 30 minutes, comes termination reaction by the 0.5M HCl that adds 30 μ L/ holes.Utilize the aggregate level of cAMP in New England's nuclear flicker plate and the cAMP radioimmunoassay kit quantitative assay born of the same parents.
For the antagonistic activity of determination test compound, reaction mixture also contains 0.5M agonist CP55940, and the answer situation of quantitative assay CP55940 effect.Other method is, draws the dose response curve of a series of CP55940, and the test compound concentrations increases progressively in every dose response curve.
The functional examination of CB2 acceptor uses the recombinant human CB2 acceptor of expressing in Chinese hamster ovary celI to carry out in a similar fashion.
Although invention has been described and detailed description with reference to the part embodiment preferred, it will be appreciated by those skilled in the art that under situation without departing from the spirit and scope of the present invention, can carry out various changes, modification and replacement to it.Therefore, the present invention is only by the scope that is subject to appended claim, and should be on rational basis and these claims are made generalized explain.

Claims (17)

1. compound in structural formula I or its pharmacologically acceptable salt:
Wherein:
R 1Be selected from:
(1) Heterocyclylalkyl,
(2) aryl,
(3) heteroaryl and
(4)-NR aR c；
Wherein aryl and heteroaryl randomly are independently selected from R by 1-3 bSubstituting group replace;
R 2Be selected from:
(1) C 1-10Alkyl,
(2) C 3-10Cycloalkyl-C 1-4Alkyl,
(3) aryl-C 1-4Alkyl and
(4) heteroaryl-C 1-4Alkyl;
Wherein cycloalkyl, aryl and heteroaryl randomly are independently selected from R by 1-3 separately bSubstituting group replace;
Each R aBe independently selected from:
(1) hydrogen,
(2) methyl and
(3)-CF 3；
Each R bBe independently selected from:
(1) halogen,
(2) cyano group,
(3) trifluoromethyl,
(4) trifluoromethoxy,
(5) C 1-3Alkoxyl group and
(6) C 1-3Alkyl;
R cBe independently selected from:
(1) hydrogen,
(2) C 1-6Alkyl,
(3) aryl,
(4) heteroaryl,
(5) aryl-methyl and
(6) heteroaryl-methyl,
Each R cCan be unsubstituted or be selected from R by 1-3 hSubstituting group replace;
R dBe independently selected from:
(1) cycloalkyl,
(2) aryl and
(3) heteroaryl,
Each R dCan be unsubstituted or be selected from R by 1-3 hSubstituting group replace;
Each R hBe independently selected from:
(1) halogen,
(2) C 1-3Alkyl,
(3)-CN and
(4)-CF 3，
Wherein under the unsubstituted situation of the nitrogen of pyridyl, they may optionally be the N-oxide form.
2. according to the compound and the pharmacologically acceptable salt thereof of claim 1, R wherein 1Be selected from:
(1) phenyl,
(2) pyridyl,
(3) indyl,
(4) 7-AZa-indolyl,
(5) thienyl and
(6)
Figure A038056780004C1
Wherein each aryl and heteroaryl randomly are independently selected from R by 1 or 2 bSubstituting group replace, and each pyridyl is optional is the N-oxide form.
3. according to the compound and the pharmacologically acceptable salt thereof of claim 2, R wherein 1Be selected from:
(1) phenyl,
(2) 3-cyano-phenyl,
(3) 3-aminomethyl phenyl,
(4) 3,5-difluorophenyls,
(5) 3-pyridyl,
(6) 5-chloro-3-pyridyl,
(7) 5-methyl-3-pyridyl,
(8) 5-cyano group-3-pyridyl,
(9) 1-oxidation-5-cyano group-3-pyridyl,
(10) 1-indyl,
(11) 7-azepine-indoles-N-base,
(12) the 2-thienyl and
(13)
Figure A038056780004C2
4. according to the compound and the pharmacologically acceptable salt thereof of claim 3, R wherein 1Be 5-cyano group-3-pyridyl.
5. according to the compound and the pharmacologically acceptable salt thereof of claim 2, R wherein 2Be selected from:
(1) C 1-6Alkyl,
(2) C 3-6Methyl cycloalkyl,
(3) phenmethyl,
(4) heteroaryl methyl,
Wherein each cycloalkyl, aryl and heteroaryl randomly are independently selected from R by 1-3 bSubstituting group replace.
6. according to the compound and the pharmacologically acceptable salt thereof of claim 5, R wherein 2Be selected from:
(1) 2-methyl-propyl,
(2) n-pentyl,
(3) cyclobutylmethyl,
(4) cyclopentyl-methyl,
(5) cyclohexyl methyl,
(6) benzyl,
(7) 4-benzyl chloride base,
(8) 4-methyl-benzyl,
(9) 4-luorobenzyl,
(10) the 4-methoxy-benzyl and
(11) (5-chloro-2-pyridyl) methyl.
7. according to the compound and the pharmacologically acceptable salt thereof of claim 2, R wherein dBe selected from:
(1) C 4-6Cycloalkyl,
(2) aryl and
(3) heteroaryl,
R wherein dCan be unsubstituted or be selected from R by 1 or 2 hSubstituting group replace.
8. according to the compound and the pharmacologically acceptable salt thereof of claim 7, R wherein dBe selected from:
(1) phenyl,
(2) pyridyl and
(3) pyrimidyl,
R wherein dCan be unsubstituted or be selected from R by 1 or 2 hSubstituting group replace.
9. compound according to Claim 8 and pharmacologically acceptable salt thereof, wherein R dBe selected from:
(1) phenyl,
(2) 4-chloro-phenyl-,
(3) 3-chloro-phenyl-,
(4) 3,5-difluorophenyls,
(5) 3,5-dichlorophenyls,
(6) 2-pyridyl,
(7) 5-chloro-2-pyridyl,
(8) 6-methyl-2-pyridyl,
(9) 5-trifluoromethyl-2-pyridyl,
(10) 4-trifluoromethyl-2-pyridyl,
(11) 4-trifluoromethyl-2-pyrimidyl and
(12) 6-trifluoromethyl-4-pyrimidyl.
10. according to the compound and the pharmacologically acceptable salt thereof of claim 1, described compound is selected from:
(1) N-[3-(4-chloro-phenyl-)-1-methyl-2-phenyl propyl]-2-(4-chlorophenoxy)-2-methyl propanamide;
(2) N-[3-(4-chloro-phenyl-)-1-methyl-2-phenyl propyl]-2-(2-pyridyloxy)-2-methyl propanamide;
(3) N-[3-(4-chloro-phenyl-)-1-methyl-2-(3-pyridyl) propyl group]-2-(4-chlorophenoxy)-2-methyl propanamide;
(4) N-[3-(4-chloro-phenyl-)-1-methyl-2-phenyl propyl]-2-(3,5-two fluorophenoxies)-2-methyl propanamide;
(5) N-[3-(4-chloro-phenyl-)-2-phenyl-1-methyl-propyl]-2-(3, the 5-dichlorophenoxy)-2-methyl propanamide;
(6) N-[3-(4-chloro-phenyl-)-1-methyl-2-phenyl propyl]-2-(3-chlorophenoxy)-2-methyl propanamide;
(7) N-[3-(4-chloro-phenyl-)-2-(3, the 5-difluorophenyl)-1-methyl-propyl]-2-(2-pyridyloxy)-2-methyl propanamide;
(8) N-[3-(4-chloro-phenyl-)-1-methyl-2-phenyl propyl]-2-(5-chloro-2-pyridyloxy)-2-methyl propanamide;
(9) N-[3-(4-chloro-phenyl-)-1-methyl-2-phenyl propyl]-2-(6-methyl-pyridyloxy)-2-methyl propanamide;
(10) N-[3-(4-chloro-phenyl-)-1-methyl-2-phenyl propyl]-2-(phenoxy group)-2-methyl propanamide;
(11) N-[3-(4-chloro-phenyl-)-1-methyl-2-phenyl propyl]-2-(5-5-flumethiazine oxygen base)-2-methyl propanamide;
(12) N-[3-(4-chloro-phenyl-)-2-(3-pyridyl)-1-methyl-propyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methyl propanamide;
(13) N-[3-(4-chloro-phenyl-)-2-(3-cyano-phenyl)-1-methyl-propyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methyl propanamide;
(14) N-[3-(4-chloro-phenyl-)-2-(5-chloro-3-pyridyl)-1-methyl-propyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methyl propanamide;
(15) N-[3-(4-chloro-phenyl-)-2-(5-methyl-3-pyridyl)-1-methyl-propyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methyl propanamide;
(16) N-[3-(4-chloro-phenyl-)-2-(5-cyano group-3-pyridyl)-1-methyl-propyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methyl propanamide;
(17) N-[3-(4-chloro-phenyl-)-2-(3-aminomethyl phenyl)-1-methyl-propyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methyl propanamide;
(18) N-[3-(4-chloro-phenyl-)-2-phenyl-1-methyl-propyl]-2-(4-trifluoromethyl-2-pyridyloxy)-2-methyl propanamide;
(19) N-[3-(4-chloro-phenyl-)-2-phenyl-1-methyl-propyl]-2-(4-trifluoromethyl-2-2-pyrimidinyl oxy)-2-methyl propanamide;
(20) N-[3-(4-chloro-phenyl-)-1-methyl-2-(thiene-3-yl-) propyl group]-2-(5-chloro-2-pyridyloxy)-2-methyl propanamide;
(21) N-[3-(5-chloro-2-pyridyl)-2-phenyl-1-methyl-propyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methyl propanamide;
(22) N-[3-(4-aminomethyl phenyl)-1-methyl-2-phenyl propyl]-2-(4-4-trifluoromethylphenopendant)-2-methyl propanamide;
(23) N-[3-(4-fluorophenyl)-2-(3-cyano-phenyl)-1-methyl-propyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methyl propanamide;
(24) N-[3-(4-chloro-phenyl-)-2-(1-indyl)-1-methyl-propyl]-2-(5-trifluoromethyl-2-oxy picolinate-2-yl)-2-methyl propanamide;
(25) N-[3-(4-chloro-phenyl-)-2-(7-azaindole-N-yl)-1-methyl-propyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methyl propanamide;
(26) N-[3-(4-chloro-phenyl-)-2-(1-indolinyl)-1-methyl-propyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methyl propanamide;
(27) N-[3-(4-chloro-phenyl-)-2-(N-methylbenzene amino)-1-methyl-propyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methyl propanamide;
(28) N-[3-(4-p-methoxy-phenyl)-2-(3-cyano group-phenyl)-1-methyl-propyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methyl propanamide;
(29) N-[3-(4-chloro-phenyl-)-2-(3-cyano-phenyl)-1-methyl-propyl]-2-(6-trifluoromethyl-4-2-pyrimidinyl oxy)-2-methyl propanamide;
(30) N-[2-(3-cyano-phenyl)-1,4-dimethyl amyl group]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methyl propanamide;
(31) N-[3-(4-chloro-phenyl-)-2-(1-oxidation-5-cyano group-3-pyridyl)-1-methyl-propyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methyl propanamide;
(32) N-[2-(3-cyano-phenyl)-3-cyclobutyl-1-methyl-propyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methyl propanamide;
(33) N-[2-(3-cyano-phenyl)-1-methylheptyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methyl propanamide;
(34) N-[2-(3-cyano-phenyl)-3-cyclopentyl-1-methyl-propyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methyl propanamide;
(35) N-[2-(3-cyano-phenyl)-3-cyclohexyl-1-methyl-propyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methyl propanamide.
11. according to the compound and the pharmacologically acceptable salt thereof of claim 9, wherein R dBe 5-trifluoromethyl-2-pyridyl.
12. according to the compound and the pharmacologically acceptable salt thereof of claim 11, described compound is selected from:
(1) N-[3-(4-chloro-phenyl-)-1-methyl-2-phenyl propyl]-2-(5-5-flumethiazine oxygen base)-2-methyl propanamide;
(2) N-[3-(4-chloro-phenyl-)-2-(3-pyridyl)-1-methyl-propyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methyl propanamide;
(3) N-[3-(4-chloro-phenyl-)-2-(3-cyano-phenyl)-1-methyl-propyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methyl propanamide;
(4) N-[3-(4-chloro-phenyl-)-2-(5-chloro-3-pyridyl)-1-methyl-propyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methyl propanamide;
(5) N-[3-(4-chloro-phenyl-)-2-(5-methyl-3-pyridyl)-1-methyl-propyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methyl propanamide;
(6) N-[3-(4-chloro-phenyl-)-2-(5-cyano group-3-pyridyl)-1-methyl-propyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methyl propanamide;
(7) N-[3-(4-chloro-phenyl-)-2-(3-aminomethyl phenyl)-1-methyl-propyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methyl propanamide;
(8) N-[3-(5-chloro-2-pyridyl)-2-phenyl-1-methyl-propyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methyl propanamide;
(9) N-[3-(4-fluorophenyl)-2-(3-cyano-phenyl)-1-methyl-propyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methyl propanamide;
(10) N-[3-(4-chloro-phenyl-)-2-(1-indyl)-1-methyl-propyl]-2-(5-trifluoromethyl-2-oxy picolinate-2-yl)-2-methyl propanamide;
(11) N-[3-(4-chloro-phenyl-)-2-(7-azaindole-N-yl)-1-methyl-propyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methyl propanamide;
(12) N-[3-(4-chloro-phenyl-)-2-(1-indolinyl)-1-methyl-propyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methyl propanamide;
(13) N-[3-(4-chloro-phenyl-)-2-(N-methylbenzene amino)-1-methyl-propyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methyl propanamide;
(14) N-[3-(4-p-methoxy-phenyl)-2-(3-cyano group-phenyl)-1-methyl-propyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methyl propanamide;
(15) N-[2-(3-cyano-phenyl)-1,4-dimethyl amyl group]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methyl propanamide;
(16) N-[3-(4-chloro-phenyl-)-2-(1-oxidation-5-cyano group-3-pyridyl)-1-methyl-propyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methyl propanamide;
(17) N-[2-(3-cyano-phenyl)-3-cyclobutyl-1-methyl-propyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methyl propanamide;
(18) N-[2-(3-cyano-phenyl)-1-methylheptyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methyl propanamide;
(19) N-[2-(3-cyano-phenyl)-3-cyclopentyl-1-methyl-propyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methyl propanamide;
(20) N-[2-(3-cyano-phenyl)-3-cyclohexyl-1-methyl-propyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methyl propanamide.
13. a composition, it comprises compound and pharmaceutically acceptable carrier of claim 1.
14. the compound of claim 1 is used for the treatment of application in the patient's of this treatment of needs the medicine of the receptor-mediated disease of cannaboid-1 in preparation.
15. according to the purposes of claim 14, wherein the receptor-mediated disease of cannaboid-1 is excessively to absorb relevant feed disease with food.
16. according to the purposes of claim 15, wherein excessively absorbing relevant feed disease with food is obesity.
17. the application of the medicine of the individuality generation obesity of the compound of claim 1 among preparation is used for preventing being in fat danger.
CNA03805678XA 2002-11-22 2003-03-07 Substituted amides active at the cannabinoid-1 receptor Pending CN1639112A (en)

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