CN1404471A - Substituted piperazine compounds - Google Patents

Substituted piperazine compounds Download PDF

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Publication number
CN1404471A
CN1404471A CN01805442A CN01805442A CN1404471A CN 1404471 A CN1404471 A CN 1404471A CN 01805442 A CN01805442 A CN 01805442A CN 01805442 A CN01805442 A CN 01805442A CN 1404471 A CN1404471 A CN 1404471A
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alkyl
hydrogen
compound
halogen
aryl
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杰夫·扎布沃茨基
埃费提·埃尔策英
格雷戈里·努德尔曼
蒂姆·马夸特
瓦布赫沃·瓦尔黑德卡
卜拉布罕·N·易卜拉欣
文卡塔·P·帕列
布伦特·K·布莱克本
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Gilead Palo Alto Inc
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CV Therapeutics Inc
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    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/145—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/15—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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    • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
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Abstract

Novel compounds of the general formula (I) and pharmaceutically acceptable acid addition salts thereof, wherein the compounds are useful in therapy to protect skeletal muscles against damage resulting from trauma or to protect skeletal muscles subsequent to muscle or systemic diseases such as intermittent claudication, to treat shock conditions, to preserve donor tissue and organs used in transplants, in the treatment of cardiovascular diseases including atrial and ventricular arrhythmias, Prinzmetal's (variant) angina, stable angina, and exercise induced angina, congestive heart disease, and myocardial infarction.

Description

The diethylenediamine compound that replaces
The background technology of invention
It is the U.S. Patent application 60/184182 on February 22nd, 2000 that the application requires the applying date, 60/184457, the applying date is the application 60/184457 on February 22nd, 2000, the applying date is the application 60/206396 on May 23rd, 2000, the applying date is the application 60/184306 on February 22nd, 2000, and the applying date be that the U.S. Patent application 60/209262 on June 5th, 2000 is right of priority, its specification sheets inserts that this is incorporated by reference.
1. invention field
The present invention relates to a kind of substituted piperazine like compound; the therapeutical agent that comprises one or more compounds; and the method for treatment mammalian diseases; particularly; in the mankind, carry out following kind treatment of diseases: the damage that the opposing of protection skeletal muscle is caused by wound; skeletal muscle after protection muscle or systemic disease such as the intermittent claudication; treatment shock disease; donor tissue that protection is used for transplanting and organ and treatment comprise atrium and the ARR cardiovascular disorder of ventricle, PrinzmetalShi (variation) angina; stablize angina; with the angina that motion causes, congestive heart disease, and myocardial infarction.
2. prior art
United States Patent (USP) 4,567,264, its specification sheets inserts that this is incorporated by reference, wherein disclose a class and comprised the known compound ranolazine, i.e. (±)-N-(2, the 6-3,5-dimethylphenyl)-4-[2-hydroxyl-3-(2-methoxyl group phenoxy group)-propyl group]-substituted piperazine like compound of 1-piperazine ethanamide, its pharmaceutical salts, and they are in the treatment cardiovascular disorder, comprise arrhythmia, angina that variation and motion cause and the application in the myocardial infarction.
United States Patent (USP) 5,506,229, its specification sheets inserts that this is incorporated by reference, wherein disclose ranolazine and pharmaceutical salts thereof and ester tissue, comprised cardiac anesthesia, hypoxgia at treatment experience physics or chemical damage, or pour into again, and the purposes in the tissue of transplanting to heart or skeletal muscle or brain tissue injury.Particularly, by partly suppressing the oxidation of heart fat acid, ranolazine specifically can be used for treating arrhythmia, angina and myocardial infarction that variation and motion cause.This patent also discloses conventional oral and non-enteron aisle type ranolazine formulation, comprises controlled release preparation.Especially, United States Patent (USP) 5,506, embodiment 7D has described the controlled release preparation of capsule form in 229, and said preparation comprises the ranolazine microballoon and is used for the dressing Microcrystalline Cellulose of the polymkeric substance of sustained release.
Although ranolazine is a great discovery as very useful cardiovascular treatment agent, but still need to find to have than longer transformation period of ranolazine and have at least with ranolazine similar active, as the compound of partial fatty acid oxidation inhibitors.
Summary of the invention
The present invention includes new substituted piperazine like compound, this compound is partial fatty acid oxidation inhibitors and has the good treatment transformation period.
The present invention also comprises new substituted piperazine like compound; this compound can deliver medicine to Mammals, with the damage that protection skeletal muscle opposing wound causes, the skeletal muscle after protection muscle or systemic disease such as the intermittent claudication; treatment shock disease; donor tissue that protection is used for transplanting and organ and treatment cardiovascular disorder comprise atrium and ventricle arrhythmia, PrinzmetalShi (variation) angina; stablize angina; with the angina that motion causes, congestive heart disease, and myocardial infarction.
The present invention includes the substituted piperazine like compound that a class has following structural:
Figure A0180544200291
Wherein X is selected from following groups:
Figure A0180544200292
With
M=1 or 2 or 3 wherein;
R 1, R 2, R 3, R 4And R 5Be selected from independently of one another: hydrogen, halogen, NO 2, CF 3, CN, OR 23, SR 23, N (R 23) 2, S (O) R 22, SO 2R 22, SO 2N (R 23) 2, NR 23CO 2R 22, NR 23CON (R 23) 2, COR 23, CO 2R 23, CON (R 23) 2, NR 23SO 2R 22, C 1-15Alkyl, C 2-15Thiazolinyl, C 2-15Alkynyl, heterocyclic radical, aryl, and heteroaryl, wherein alkyl and aryl substituent can be chosen wantonly by one and be selected from following substituting group replacement: halogen, NO 2, CF 3, CN, OR 23, SR 23, N (R 23) 2, S (O) R 22And SO 2R 22, R wherein 2And R 3Can be joined together to form have 3 to 4 carbon atoms condense ring system and R 4And R 5Can be joined together to form-CH=CH-CH=CH-;
R 6, R 7And R 8Be selected from hydrogen and C independently of one another 1-15Alkyl;
R 9, R 10, R 11, R 12, R 13, R 14, R 15And R 16Be selected from hydrogen independently of one another, CO 2R 23, CON (R 23) 2, C 1-4Alkyl, and aryl, wherein alkyl and aryl substituent can be chosen wantonly by one and be selected from following substituting group replacement: halogen, CF 3, CN, OR 23, N (R 23) 2, CO 2R 23, CON (R 23) 2And aryl, wherein R 9And R 10Can form carbonyl or R together 11And R 12Can form carbonyl or R together 13And R 14Can form carbonyl or R together 15And R 16Can form carbonyl, wherein R together 11And R 13, R 9And R 15, R 9And R 11, R 11And R 15, or R 9And R 13Can be joined together to form bridged ring system with 1-4 carbon atom, and R wherein 9And R 10, R 11And R 12, R 13And R 14Or R 15And R 16Can be joined together to form bridged ring system with 1-5 carbon atom.
R 22Be selected from C 1-15Alkyl, aryl, and heteroaryl, wherein alkyl and aryl substituent can be chosen wantonly by 1 and be selected from halogen, alkyl, alkyl monosubstituted amino, dialkyl amido, alkyl amido, aryl amido, heteroaryl amido, CN, O-C 1-6Alkyl, CF 3, and the substituting group of heteroaryl replaces;
R 23Be selected from H, C 1-15Alkyl, aryl, and heteroaryl, wherein alkyl and aryl substituent can be chosen wantonly by 1 and be selected from halogen, alkyl, alkyl monosubstituted amino, dialkyl amido, alkyl, CN, O-C 1-6Alkyl and CF 3Substituting group replace; And
R 24Be selected from alkyl, cycloalkyl and condensed benzyl ring alkyl, wherein tie point is on cycloalkyl, and alkyl wherein, cycloalkyl and condensed benzyl ring alkyl can be chosen wantonly and be selected from following substituting group by 1 to 3 and replace: halogen, CF 3, CN, OR 20, SR 20, S (O) R 22, SO 2R 22, SO 2N (R 20) 2, NR 20CO 2R 22, C 1-2Alkyl, and aryl, wherein aryl substituent can be chosen wantonly by 1 to 3 and be selected from halogen, phenyl, CF 3, CN, OR 20, and C 1-6The substituting group of alkyl replaces, and
R wherein 17, R 18, R 19, R 20, and R 21Be independently selected from hydrogen, halogen, NO 2, CF 3, CN, OR 23, SR 23, N (R 23) 2, S (O) R 22, SO 2R 22, SO 2N (R 23) 2, NR 23CO 2R 22, NR 23CON (R 23) 2, COR 23, CO 2R 23, CON (R 23) 2, NR 23SO 2R 22, C 1-15Alkyl, C 2-15Thiazolinyl, C 2-15Alkynyl, heterocyclic radical, aryl, and heteroaryl, wherein alkyl and aryl substituent can be chosen wantonly by one and be selected from following substituting group replacement: halogen, NO 2, CF 3, CN, OR 23, SR 23, N (R 23) 2, S (O) R 22And SO 2R 22
In the another one scheme; the invention provides one and take the method that one or more present compositions are used for following treatment: the damage that protection skeletal muscle opposing wound causes to Mammals; skeletal muscle after protection muscle or systemic disease such as the intermittent claudication; treatment shock disease; donor tissue and organ that protection is used for transplanting; comprise atrium and ventricle arrhythmia with treatment; PrinzmetalShi (variation) angina; stablize angina; the angina that causes with motion; the cardiovascular disorder of congestive heart disease and myocardial infarction.Detailed description of the present invention
The present invention includes the substituted piperazine like compound that a class has following structural:
Figure A0180544200311
Wherein X is selected from: With
Figure A0180544200313
M=1 or 2 or 3 wherein;
R 1, R 2, R 3, R 4And R 5Be selected from independently of one another: hydrogen, halogen, NO 2, CF 3, CN, OR 23, SR 23, N (R 23) 2, S (O) R 22, SO 2R 22, SO 2N (R 23) 2, NR 23CO 2R 22, NR 23CON (R 23) 2, COR 23, CO 2R 23, CON (R 23) 2, NR 23SO 2R 22, C 1-15Alkyl, C 2-15Thiazolinyl, C 2-15Alkynyl, heterocyclic radical, aryl, and heteroaryl, wherein alkyl and aryl substituent can be chosen wantonly by one and be selected from following substituting group replacement: halogen, NO 2, CF 3, CN, OR 23, SR 23, N (R 23) 2, S (O) R 22And SO 2R 22, R wherein 2And R 3Can be joined together to form the ring system that condenses with 3 to 4 carbon atoms, and R wherein 4And R 5Can be joined together to form-CH=CH-CH=CH-;
R 6, R 7And R 8Be selected from hydrogen and C independently of one another 1-15Alkyl;
R 9, R 10, R 11, R 12, R 13, R 14, R 15And R 16Be selected from hydrogen independently of one another, CO 2R 23, CON (R 23) 2, C 1-4Alkyl, and aryl, wherein alkyl and aryl substituent can be chosen wantonly by one and be selected from following substituting group replacement: halogen, CF 3, CN, OR 23, N (R 23) 2, CO 2R 23, CON (R 23) 2And aryl, wherein R 9And R 10Can form carbonyl or R together 11And R 12Can form carbonyl or R together 13And R 14Can form carbonyl or R together 15And R 16Can form carbonyl, wherein R together 11And R 13, R 9And R 15, R 9And R 11, R 11And R 15, or R 9And R 13Can be joined together to form bridged ring system with 1-4 carbon atom, and R wherein 9And R 10, R 11And R 12, R 13And R 14, or R 15And R 16Can be joined together to form bridged ring system with 1-5 carbon atom.
R 22Be selected from C 1-15Alkyl, aryl, and heteroaryl, wherein alkyl and aryl substituent can be chosen wantonly by 1 and be selected from halogen, alkyl, alkyl monosubstituted amino, dialkyl amido, alkyl amido, aryl amido, heteroaryl amido, CN, O-C 1-6Alkyl, CF 3, and the substituting group of heteroaryl replaces;
R 23Be selected from H, C 1-15Alkyl, aryl, and heteroaryl, wherein alkyl and aryl substituent can be chosen wantonly by 1 and be selected from halogen, alkyl, alkyl monosubstituted amino, dialkyl amido, alkyl, CN, O-C 1-6Alkyl and CF 3Substituting group replace; And
R 24Be selected from alkyl, cycloalkyl, and condensed benzyl ring alkyl, its tie point is on cycloalkyl; Alkyl wherein, cycloalkyl and condensed benzyl ring alkyl can be chosen wantonly and be selected from following substituting group by 1 to 3 and replace: halogen, CF 3, CN, OR 20, SR 20, S (O) R 22, SO 2R 22, SO 2N (R 20) 2, NR 20CO 2R 22, C 1-2Alkyl, and aryl, this aryl substituent can be chosen wantonly by 1 to 3 and be selected from halogen, phenyl, CF 3, CN, OR 20, and C 1-6The substituting group of alkyl replaces, and following formula
R wherein 17, R 18, R 19, R 20, and R 21Be selected from hydrogen independently of one another, halogen, NO 2, CF 3, CN, OR 23, SR 23, N (R 23) 2, S (O) R 22, SO 2R 22, SO 2N (R 23) 2, NR 23CO 2R 22, NR 23CON (R 23) 2, COR 23, CO 2R 23, CON (R 23) 2, NR 23SO 2R 22, C 1-15Alkyl, C 2-15Thiazolinyl, C 2-15Alkynyl, heterocyclic radical, aryl, and heteroaryl, wherein alkyl and aryl substituent can be chosen wantonly by one and be selected from following substituting group replacement: halogen, NO 2, CF 3, CN, OR 23, SR 23, N (R 23) 2, S (O) R 22And SO 2R 22
The present invention also comprises the subclass of the substituted piperazidine compound that defines among the above-mentioned formula I with following formula (IA) structural formula:
M=1 wherein, 2;
R 1, R 2, R 3, R 4And R 5Be selected from independently of one another: hydrogen, halogen, CF 3, OR 22And C 1-4Alkyl and R wherein 22Be C 1-3Alkyl;
R 6, R 7And R 8Be selected from hydrogen and C independently of one another 1-3Alkyl;
R 9, R 10, R 11, R 12, R 13, R 14, R 15And R 16Be selected from hydrogen independently of one another, C 1-4Alkyl, or R 9And R 10Can form carbonyl or R together 11And R 12Can form carbonyl or R together 13And R 14Can form carbonyl or R together 15And R 16Can form carbonyl, wherein R together 11And R 13, R 9And R 15, R 9And R 11, R 11And R 15, or R 9And R 13Can be joined together to form bridged ring system, wherein two R groups comprise 1 to 4 carbon atom together, and condition is R 9, R 10, R 11, R 12, R 13, R 14, R 15And R 16Be not hydrogen simultaneously.
R 17, R 18, R 19, R 20, and R 21Be selected from hydrogen independently of one another, halogen, CF 3, CN, OR 22, S (O) R 22, SO 2R 22, SON (R 22) 2, CON (R 22) 2, C 1-4Alkyl, wherein R 22Be C 1-3Alkyl, or R 17And R 18Formation-CH=CH-CH=CH-, or R together 18And R 19Can form together-OCH 2O-.
In preferred formula IA compound, R 1, R 2, R 3, R 4And R 5Be selected from hydrogen independently of one another, halogen, CF 3, OR 22And C 1-4Alkyl, wherein R 22Be C 1-3Alkyl; R 6Be selected from hydrogen and methyl; R 7, R 8, R 9, R 10, R 11, R 12, R 13, R 14, R 15And R 16Be selected from hydrogen and methyl independently of one another, or R 9And R 10Form carbonyl together, or R 13And R 14Form carbonyl together, condition is R 9, R 10, R 11, R 12, R 13, R 14, R 15And R 16Be not hydrogen simultaneously; R 17, R 18, R 19, R 20And R 21Be selected from hydrogen independently of one another, halogen, CF 3, OR 22, C 1-3Alkyl, wherein R 22Be C 1-3Alkyl, or R 17And R 18Formation-CH=CH-CH=CH-, or R together 18And R 19Can form together-OCH 2O-.
In preferred formula IA compound also, R 1, R 2, R 3, R 4, R 5, R 6, R 7And R 8Be selected from methyl and hydrogen independently of one another; R 9, R 10, R 11, R 12, R 13, R 14, R 15And R 16Be selected from hydrogen and methyl independently of one another, or R 9And R 10Form carbonyl together, or R 13And R 14Form carbonyl together, condition is R 9, R 10, R 11, R 12, R 13, R 14, R 15And R 16Be not hydrogen simultaneously; R 17, R 18, R 19, R 20And R 21Be selected from hydrogen independently of one another, halogen, CF 3, OR 22, R wherein 22Be methyl, methyl, or R 17And R 18Formation-CH=CH-CH=CH-, or R together 18And R 19Can form together-OCH 2O-.
In further preferred formula IA compound, R 1And R 5All be methyl, R 2, R 3, R 4, R 6, R 7, R 8All be hydrogen; R 9, R 10, R 11, R 12, R 13, R 14, R 15And R 16Be selected from hydrogen and methyl independently of one another, or R 9And R 10Form carbonyl together, or R 13And R 14Form carbonyl together, condition is R 9, R 10, R 11, R 12, R 13, R 14, R 15And R 16Be not hydrogen simultaneously; R 17, R 18, R 19, R 20And R 21Be selected from hydrogen independently of one another, halogen, methyl, OR 22, R wherein 22Be methyl, or R 17And R 18Formation-CH=CH-CH=CH-, or R together 18And R 19Can form together-OCH 2O-.
In going back further preferred formula IA compound, R 1And R 5All be methyl, R 2, R 3, R 4, R 6, R 7, R 8All be hydrogen; R 9, R 10Be selected from hydrogen, methyl or form carbonyl together; R 11And R 12Be selected from hydrogen and methyl; R 13And R 14Be selected from hydrogen and methyl or form carbonyl together; R 15And R 16Be hydrogen, condition is R 9, R 10, R 11, R 12, R 13, R 14, R 15And R 16Be not hydrogen simultaneously; R 17Be selected from hydrogen, chlorine, fluorine or methoxyl group; R 18And R 19Be selected from hydrogen and methoxyl group respectively, or R 18And R 19Can form together-OCH 2O-, or R 17And R 18Formation-CH=CH-CH=CH-together; R 20Be hydrogen; And R 21Be selected from hydrogen or chlorine.
Most preferably; the substituted piperazine like compound of formula IA is selected from: N-(2; the 6-3,5-dimethylphenyl)-2-{4-[2-hydroxyl-3-(2-methoxyl group phenoxy group) propyl group]-3-oxygen piperazinyl } ethanamide; N-(2; the 6-3,5-dimethylphenyl)-and 2-{4-[2-hydroxyl-3-(2-methoxyl group phenoxy group) propyl group]-3; 5-lupetazin base } ethanamide; 2-{ (5S; 2R)-and 4-[2-hydroxyl-3-(2-methoxyl group phenoxy group) propyl group]-2; 5-lupetazin base }-N-(2; the 6-3,5-dimethylphenyl) ethanamide; 2-{2; 5-diaza-5-[2-hydroxyl-3-(2-methoxyl group phenoxy group) propyl group] dicyclo [4.4.0] last of the ten Heavenly stems-2-yl }-N-(2; the 6-3,5-dimethylphenyl) ethanamide; N-(2; the 6-3,5-dimethylphenyl)-2-{4-[2-hydroxyl-3-(2-methoxyl group phenoxy group) propyl group]-3-oxygen piperazinyl } ethanamide; N-(2; the 6-3,5-dimethylphenyl)-and 2-{4-[2-hydroxyl-3-(2-methoxyl group phenoxy group) propyl group]-3; 3-lupetazin base } ethanamide; 2-{5-[(2S)-and 2-hydroxyl-3-(2-methoxyl group phenoxy group) propyl group] (1S; 4S)-2; 5-diazabicyclo [2.2.1] heptan-2-yl }-N-(2; the 6-3,5-dimethylphenyl) ethanamide; N-(2, the 6-3,5-dimethylphenyl)-2-{4-[2-hydroxyl-4-(2-methoxyl group phenoxy group) butyl]-piperazinyl } ethanamide, N-(2; the 6-3,5-dimethylphenyl)-2-{4-[4-(4-fluorophenoxy)-2-hydroxybutyl]-piperazinyl } ethanamide; 2-(4-{4-[4-(tertiary butyl) phenoxy group)-2-hydroxybutyl] piperazinyl }-N-(2, the 6-3,5-dimethylphenyl) ethanamide, N-(2; the 6-3,5-dimethylphenyl)-and 2-{4-[2-hydroxyl-4-(4-phenyl phenoxy group) butyl] piperazinyl } ethanamide; N-(2, the 6-3,5-dimethylphenyl)-2-{4-[2-hydroxyl-4-(4-methoxyl group phenoxy group) butyl]-piperazinyl } ethanamide, 2-{ (3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine base }-N-(2; the 6-3,5-dimethylphenyl) ethanamide; 2-{ (3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine base }-N-(2, the 6-dichlorophenyl) ethanamide, 2-{ (3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine base }-N-(4-sulfamyl phenyl) ethanamide; 2-{ (3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine base }-N-(5-methoxyl group-3-(trifluoromethyl) phenyl] ethanamide; 2-{ (3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine base }-N-indane-5-base-ethanamide, 2-{ (3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine base }-the N-naphthyl acetamide, 2-{ (3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine base }-N-(4-chloronaphthyl, methylnaphthyl) ethanamide; 2-{ (3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine base }-N-(2-pyrryl phenyl) ethanamide; 2-{ (3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine base }-phenyl acetanilide,Phenacetylaniline, 2-(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine base }-N-(2-chloro-phenyl-) ethanamide, 2-{ (3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine base }-N-(2-chloro-4-aminomethyl phenyl) ethanamide; 2-{ (3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine base }-N-[2-(1-methyl ethylene) phenyl] ethanamide; 2-{ (3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine base }-N-(2-aminomethyl phenyl) ethanamide, 2-{ (3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine base }-N-(6-methyl-2-(methylethyl) phenyl] ethanamide, 2-{ (3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine base }-N-(3-methylthio group phenyl) ethanamide; 2-{ (3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine base }-N-(4-chloro-2-methoxyl group-5-aminomethyl phenyl) ethanamide; 2-{ (3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine base }-N-[4-(dimethylamino) phenyl] ethanamide, 2-{ (3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine base }-N-(2, the 4-Dimethoxyphenyl) ethanamide; 2-{ (3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine base }-N-(3; the 4-dichlorophenyl) ethanamide, 2-{ (3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine base }-N-(4-chloro-phenyl-) ethanamide, 2-{ (3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine base }-N-(3-chloro-phenyl-) ethanamide; 2-{ (3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine base }-N-(3; the 5-dichlorophenyl) ethanamide, 2-{ (3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine base }-N-(4-p-methoxy-phenyl) ethanamide, 2-{ (3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine base }-N-(4-aminomethyl phenyl) ethanamide; 2-{ (3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine base }-N-(3-aminomethyl phenyl) ethanamide; 2-{ (3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine base }-N-(4-fluorophenyl) ethanamide, 2-{ (3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine base }-N-(4-cyano-phenyl) ethanamide, 2-{ (3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine base }-N-(4-acetylphenyl) ethanamide; 2-{ (3S)-4-[(2S)-3-(2-fluorophenoxy)-3-hydroxypropyl]-3-methylpiperazine base }-N-(2-p-methoxy-phenyl) ethanamide; 2-{ (3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine base }-N-[4-(trifluoromethyl) phenyl) ethanamide, 2-{ (3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine base }-N-(4-chloro-3-(trifluoromethyl) phenyl] ethanamide, 2-{ (3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine base }-N-(3; the 5-Dimethoxyphenyl) ethanamide; 2-{ (3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine base }-N-(4-morpholine-4-base-phenyl) ethanamide, 2-{ (3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine base }-N-(3-fluoro-4-p-methoxy-phenyl) ethanamide, 2-{ (3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine base }-N-(3; 4; the 5-trimethoxyphenyl) ethanamide, 2-{ (3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine base }-N-(3, the 4-Dimethoxyphenyl) ethanamide; 2-{ (3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine base }-N-(4-chloro-2-fluorophenyl) ethanamide, and 2-{ (3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine base }-N-[2-(hydroxymethyl-6-aminomethyl phenyl] ethanamide.
The present invention includes the substituted piperazine like compound subclass of the formula I with structural formula IB:
Figure A0180544200371
M=0 wherein, 1 or 2 or 3;
R 1, R 2, R 3, R 4And R 5Be selected from independently of one another: hydrogen, halogen, NO 2, CF 3, CN, OR 23, SR 23, N (R 23) 2, S (O) R 22, SO 2R 22, SO 2N (R 23) 2, NR 23CO 2R 22, NR 23CON (R 23) 2, COR 23, CO 2R 23, CON (R 23) 2, NR 23SO 2R 22, C 1-15Alkyl, C 2-15Thiazolinyl, C 2-15Alkynyl, heterocyclic radical, aryl, and heteroaryl, wherein alkyl and aryl substituent can be chosen wantonly by one and be selected from following substituting group replacement: halogen, NO 2, CF 3, CN, OR 23, SR 23, N (R 23) 2, S (O) R 22And SO 2R 22
R 6, R 7And R 8Be selected from hydrogen or C independently of one another 1-15Alkyl;
R 9, R 10, R 11, R 12, R 13, R 14, R 15And R 16Be selected from hydrogen independently of one another, CO 2R 23, CON (R 23) 2, C 1-4Alkyl, or aryl, wherein alkyl and aryl substituent can be chosen wantonly by one and be selected from following substituting group replacement: halogen, CF 3, CN, OR 23, N (R 23) 2, CO 2R 23, CON (R 23) 2Or aryl, wherein R 9And R 10Can form carbonyl or R together 11And R 12Can form carbonyl or R together 13And R 14Can form carbonyl or R together 15And R 16Can form carbonyl, wherein R together 11And R 13, R 9And R 15, R 9And R 11, R 11And R 15, or R 9And R 13Can be joined together to form bridged ring system, wherein two R groups comprise 1-4 carbon atom together, and R wherein 9And R 10, R 11And R 12, R 13And R 14, or R 15And R 16Can be joined together to form spiro system and wherein two R groups comprise 1-5 carbon atom together.
R 17, R 18, R 19, R 20, and R 21Be selected from hydrogen independently of one another, halogen, NO 2, CF 3, CN, OR 23, SR 23, N (R 23) 2, S (O) R 22, SO 2R 22, SO 2N (R 23) 2, NR 23CO 2R 22, NR 23CON (R 23) 2, COR 23, CO 2R 23, CON (R 23) 2, NR 23SO 2R 22, C 1-15Alkyl, C 2-15Thiazolinyl, C 2-15Alkynyl, heterocyclic radical, aryl, and heteroaryl, wherein alkyl and aryl substituent can be chosen wantonly by one and be selected from following substituting group replacement: halogen, NO 2, CF 3, CN, OR 23, SR 23, N (R 23) 2, S (O) R 22And SO 2R 22, or R wherein 17And R 18Be joined together to form-CH=CH-CH=CH-, or R wherein 17And R 18, R 18And R 19, R 19And R 20, or R 20And R 21Comprise 3 to 6 carbon atoms in conjunction with forming, 0 to 2 carbon atom saturated ring system that can be replaced by Sauerstoffatom wherein, and this ring can randomly be selected from hydrogen, halogen, NO by 1 to 3 2, CF 3, CN, OR 23, SR 23, N (R 23) 2, S (O) R 22, SO 2R 22, SO 2N (R 23) 2, NR 23CO 2R 22, NR 23CON (R 23) 2, COR 23, CO 2R 23, CON (R 23) 2, NR 23SO 2R 22, C 1-15Alkyl, C 2-15Thiazolinyl, C 2-15Alkynyl, heterocyclic radical, aryl, and the replacement of the substituting group of heteroaryl, wherein alkyl and aryl substituent can be chosen wantonly by one and be selected from following substituting group replacement: halogen, NO 2, CF 3, CN, OR 23, SR 23, N (R 23) 2, S (O) R 22And SO 2R 22
R 22Be selected from C 1-15Alkyl, aryl, or heteroaryl, wherein alkyl and aryl substituent can be chosen wantonly by 1 and be selected from halogen, alkyl, alkyl monosubstituted amino, dialkyl amido, alkyl amido, aryl amido, heteroaryl amido, CN, O-C 1-6Alkyl, CF 3, or the substituting group of heteroaryl replaces; And
R 23Be selected from H, C 1-15Alkyl, aryl, or heteroaryl, wherein alkyl and aryl substituent can be chosen wantonly by 1 and be selected from halogen, alkyl, list or dialkyl amido, alkyl, CN, O-C 1-6Alkyl or CF 3Substituting group replace;
In preferred composition of the present invention, m=0,1 or 2 or 3; R 1, R 2, R 3, R 4And R 5Be selected from independently of one another: hydrogen, halogen, CF 3, OR 22And C 1-4Alkyl; R 6, R 7And R 8Be selected from hydrogen or C independently of one another 1-3Alkyl; R 9, R 10, R 11, R 12, R 13, R 14, R 15And R 16Be selected from hydrogen and C independently of one another 1-4Alkyl, perhaps R 9And R 10Form carbonyl together, or R 11And R 12Form carbonyl together, or R 13And R 14Form carbonyl together, or R 15And R 16Form carbonyl together, or R wherein 11And R 13, R 9And R 15, R 9And R 11, R 11And R 15, or R 9And R 13Can be joined together to form the ring that comprises 1-4 carbon atom, wherein R 9, R 10, R 11, R 12, R 13, R 14, R 15And R 16Be not hydrogen entirely; And R 17, R 18, R 19, R 20, and R 21Be selected from hydrogen independently of one another, halogen, CF 3, CN, OR 22, S (O) R 22, SO 2R 22, SON (R 22) 2, CON (R 22) 2, C 1-4Alkyl, or R 17And R 18Formation-CH=CH-CH=CH-, and phenyl together.
In other preferred compounds, R 1, R 2, R 3, R 4And R 5Be selected from independently of one another: hydrogen, halogen, CF 3, OR 22And C 1-2Alkyl, wherein R 22Be C 1-3Alkyl; R 6, R 7And R 8Be selected from hydrogen and methyl independently of one another; R 9, R 10, R 11, R 12, R 13, R 14, R 15And R 16Be selected from hydrogen and C independently of one another 1-2Alkyl, or R 9And R 10Form carbonyl together, or R 15And R 16Form carbonyl together, condition is R 9, R 10, R 11, R 12, R 13, R 14, R 15And R 16Be not hydrogen, wherein R simultaneously 11And R 13, R 9And R 15, R 9And R 11, R 11And R 15, or R 9And R 13Be joined together to form the ring that comprises 1-4 carbon atom, and R 17, R 18, R 19, R 20, and R 21Be selected from hydrogen independently of one another, halogen, CF 3, CN, OR 22And C 1-4Alkyl, wherein R 22Be C 1-3Alkyl, and R wherein 17And R 18Can form together and be selected from-substituting group of CH=CH-CH=CH-and phenyl.
In preferred compound, m=1 or 2; R 1, R 2, R 3, R 4And R 5Be selected from independently of one another: hydrogen, halogen, CF 3, OR 22And C 1-4Alkyl, wherein R 22Be C 1-3Alkyl; R 6, R 7, R 8, R 9, R 10, R 11, R 12, R 13, R 14, R 15And R 16Be selected from hydrogen and methyl independently of one another; R 17, R 18, R 19, R 20, and R 21Be selected from hydrogen independently of one another, halogen, CF 3, OR 22, C 1-3Alkyl, wherein R 22It is methyl; Or R 17And R 18Formation-CH=CH-CH=CH-, or R together 18And R 19Formation-OCH together 2O-.
In preferred compound, m=1 or 2; R 1, R 2, R 3, R 4, R 5, R 6, R 7And R 8Be selected from methyl and hydrogen independently of one another; R 9, R 10, R 11, R 12, R 13, R 14, R 15And R 16Be selected from hydrogen independently of one another; And R 17, R 18, R 19, R 20, and R 21Be selected from hydrogen independently of one another, halogen, CF 3, OR 22, R wherein 22Be methyl, or R 17And R 18Formation-CH=CH-CH=CH-, or R together 18And R 19Formation-OCH together 2O-.
In other preferred compound compounds, m=1 or 2; R 1And R 5Be methyl; R 2, R 3, R 4, R 6, R 7, R 8, R 9, R 10, R 11, R 12, R 13, R 14, R 15And R 16Be hydrogen; R 17, R 18, R 19, R 20And R 21Be selected from hydrogen independently of one another, halogen, OR 22, R wherein 22Be methyl, or R 17And R 18Formation-CH=CH-CH=CH-, or R together 18And R 19Formation-OCH together 2O-.
In preferred compound further, R 1And R 5Be methyl; R 2, R 3, R 4, R 6, R 7, R 8, R 9, R 10, R 11, R 12, R 13, R 14, R 15And R 16Be hydrogen; R 17Be selected from hydrogen, chlorine, fluorine and methoxyl group; R 18Be selected from hydrogen and methoxyl group; R 19Be selected from hydrogen and methoxyl group; R 20Be hydrogen; R 21Be selected from hydrogen and chlorine, or R 17And R 18Formation-CH=CH-CH=CH-, or R together 18And R 19Formation-OCH together 2O-.
Most preferably, substituted piperazine like compound of the present invention is selected from N-(2, the 6-3,5-dimethylphenyl)-2-[4-(2-hydroxy-4-phenyl butyl) piperazinyl] ethanamide; N-(2, the 6-3,5-dimethylphenyl)-2-{4-[2-hydroxyl-3-(2-p-methoxy-phenyl) propyl group] piperazinyl } ethanamide; 2-[4-(3-(2H-benzo [d] 1,3-dioxole (dioxolen)-5-yl)-2-hydroxypropyl) piperazinyl]-N-(2,6 3,5-dimethylphenyl) ethanamide; N-(2, the 6-3,5-dimethylphenyl)-2-{4-[2-hydroxyl-3-(4-p-methoxy-phenyl) propyl group] piperazinyl } ethanamide; N-(2, the 6-3,5-dimethylphenyl)-2-{4-[2-hydroxyl-3-phenyl propyl] piperazinyl } ethanamide; N-(2, the 6-3,5-dimethylphenyl)-2-{4-[4-(4-p-methoxy-phenyl)-2-hydroxybutyl] piperazinyl } ethanamide; 2-{4-[4-(2, the 6-difluorophenyl)-2-hydroxybutyl] piperazinyl }-N-(2, the 6-3,5-dimethylphenyl) ethanamide; N-(2, the 6-3,5-dimethylphenyl)-2-{4-[4-(2-chloro-phenyl-)-2-hydroxybutyl] piperazinyl } ethanamide; 2-(4-{4-[4-(tertiary butyl) phenyl-2-hydroxybutyl } piperazinyl)-N-(2, the 6-3,5-dimethylphenyl) ethanamide; N-(2, the 6-3,5-dimethylphenyl)-2-{4-[4-(2-fluorophenyl)-2-hydroxybutyl] piperazinyl } ethanamide; N-(2, the 6-3,5-dimethylphenyl)-2-(4-{2-hydroxyl-4-[4-(trifluoromethyl) phenyl] butyl } piperazinyl) ethanamide; 2-[4-(3-(2H-benzo [d] 1,3-dioxole-5-yl)-and the 2-hydroxypropyl) piperazinyl]-N-(2, the 6-3,5-dimethylphenyl)-the 2-methyl propanamide, N-(2, the 6-3,5-dimethylphenyl)-2-[4-(2-hydroxyl-3-phenyl propyl) piperazinyl]-the 2-methyl propanamide, N-(2, the 6-3,5-dimethylphenyl)-2-{4-[2-hydroxyl-3-(3,4, the 5-trimethoxyphenyl) propyl group] piperazinyl }-the 2-methyl propanamide, N-(2, the 6-3,5-dimethylphenyl)-and 2-[4-(2-hydroxyl-5-phenylpentyl) piperazinyl] ethanamide, N-(2, the 6-3,5-dimethylphenyl)-2-{4-[5-(2-fluorophenyl)-2-hydroxyl-amyl group] piperazinyl } ethanamide, and N-(2, the 6-3,5-dimethylphenyl)-2-{4-[5-(2-chloro-phenyl-)-2-hydroxyl-amyl group] piperazinyl } ethanamide.
The present invention further comprises the above-mentioned formula I compound subclass with structural formula IC:
Figure A0180544200411
M=1 wherein, 2, or 3;
R 1, R 2, R 3, R 4And R 5Be selected from independently of one another: hydrogen, halogen, NO 2, CF 3, CN, OR 20, SR 20, N (R 20) 2, S (O) R 22, SO 2R 22, SO 2N (R 20) 2, NR 20CO 2R 22, NR 20CON (R 20) 2, COR 20, CO 2R 20, CON (R 20) 2, NR 20SO 2R 22, C 1-15Alkyl, C 2-15Thiazolinyl, C 2-15Alkynyl, heterocyclic radical, aryl, and heteroaryl, wherein alkyl and aryl substituent can be chosen wantonly by one and be selected from following substituting group replacement: halogen, NO 2, CF 3, CN, OR 20, SR 20, N (R 20) 2, S (O) R 22And SO 2R 22
R 6, R 7And R 8Be selected from hydrogen or C independently of one another 1-3Alkyl;
R 9, R 10, R 11, R 12, R 13, R 14, R 15And R 16Be selected from hydrogen independently of one another, CO 2R 20, CON (R 20) 2, C 1-4Alkyl, or aryl, wherein alkyl and aryl substituent can be chosen wantonly by one and be selected from following substituting group replacement: halogen, CF 3, CN, OR 20, N (R 20) 2, CO 2R 20, CON (R 20) 2Or aryl, wherein R 9And R 10Can form carbonyl or R together 11And R 12Can form carbonyl or R together 13And R 14Can form carbonyl or R together 15And R 16Can form carbonyl together, condition is R 11And R 13, R 9And R 15, R 9And R 11, R 11And R 15Or R 9And R 13Can be joined together to form the ring that comprises 1-3 carbon atom;
R 24Be selected from alkyl, cycloalkyl and condensed benzyl ring alkyl, wherein tie point is on cycloalkyl, and alkyl wherein, cycloalkyl and condensed benzyl ring alkyl can be chosen wantonly and be selected from following substituting group by 1 to 3 and replace: halogen, CF 3, CN, OR 20, SR 20, S (O) R 22, SO 2R 22, SO 2N (R 20) 2, NR 20CO 2R 22, C 1-2Alkyl, and aryl, wherein aryl substituent can be chosen wantonly by 1 to 3 and be selected from halogen, phenyl, CF 3, CN, OR 20, and C 1-6The substituting group of alkyl replaces;
R 20Be selected from H, C 1-15Alkyl, aryl, or heteroaryl, wherein alkyl and aryl substituent can be chosen wantonly by 1 and be selected from following substituting group replacement: halogen, alkyl, single-or two-alkylamino, alkyl, CN ,-O-C 1-6Alkyl or CF 3And
R 22Be selected from C 1-15Alkyl, aryl, or heteroaryl, wherein alkyl and aryl substituent can be chosen wantonly by 1 and be selected from halogen, alkyl, alkyl monosubstituted amino, dialkyl amido, alkyl amido, aryl amido, heteroaryl amido, CN, O-C 1-6Alkyl, CF 3, or the substituting group of heteroaryl replaces.
In formula IC, preferred m=1 or 2 most preferably is m=1.
In preferred formula IC forms, R 1, R 2, R 3, R 4And R 5Be selected from independently of one another: hydrogen, halogen, CF 3, OR 22And C 1-4Alkyl, and R wherein 22Be C 1-3Alkyl.In another is preferably formed, R 1, R 2, R 3, R 4And R 5Be selected from hydrogen independently of one another, CF 3, OR 20Or C 1-2Alkyl.More preferably, R 1, R 2, R 3, R 4And R 5Be selected from hydrogen or methyl independently of one another, preferably, R 2, R 3, R 4Be hydrogen, R 1And R 5It is methyl.
In another preferred formula IC forms, R 6, R 7And R 8Be selected from hydrogen and C independently of one another 1-3Alkyl, preferred hydrogen or methyl, most preferably hydrogen.
In another preferred formula IC forms, R 9, R 10, R 11, R 12, R 13, R 14, R 15And R 16Be selected from hydrogen independently of one another, CON (R 20) 2, C 1-4Alkyl, or aryl, wherein alkyl and aryl substituent can be chosen wantonly by one and be selected from following substituting group replacement: halogen, CF 3, OR 20, N (R 20) 2, CON (R 20) 2Or aryl, wherein R 9And R 10Can form carbonyl or R together 11And R 12Can form carbonyl or R together 13And R 14Can form carbonyl or R together 15And R 16Can form carbonyl together, condition is R 11And R 13, R 9And R 15, R 9And R 11, R 11And R 15, or R 9And R 13Can be joined together to form ring.In another is preferably formed, R 9, R 10, R 11, R 12, R 13, R 14, R 15And R 16Be selected from hydrogen and C independently of one another 1-4Alkyl, or R 9And R 10Form carbonyl together, or R 11And R 12Form carbonyl together, or R 13And R 14Form carbonyl together, or R 15And R 16Form carbonyl together, R 10And R 11Formation-CH together 2CH 2CH 2CH 2-.In another scheme, R 9, R 10, R 11, R 12, R 13, R 14, R 15And R 16Be selected from hydrogen or C independently of one another 1-2Alkyl, wherein alkyl substituent is optional is selected from N (R by 1 20) 2, or the substituting group of aryl replaces, or R wherein 9And R 10Form carbonyl together.More preferably, R 9, R 10, R 11, R 12, R 13, R 14, R 15And R 16Be selected from hydrogen or C independently of one another 1-2Alkyl, or R wherein 9And R 10Form carbonyl together.In another scheme, R 11And R 15Be selected from hydrogen or methyl independently of one another, R 9, R 10, R 12, R 13, R 14And R 16Be respectively hydrogen, and R 9And R 10Form carbonyl together, perhaps, R 9, R 10, R 11, R 12, R 13, R 14, R 15And R 16Be respectively hydrogen.
In formula IC compound, R 24Be selected from alkyl, cycloalkyl and condensed benzyl ring alkyl, wherein tie point is on cycloalkyl, and alkyl wherein, cycloalkyl and condensed benzyl ring alkyl can be chosen wantonly and be selected from following substituting group by 1 to 3 and replace: halogen, CF 3, CN, OR 20, SR 20, S (O) R 22, SO 2R 22, SO 2N (R 20) 2, NR 20CO 2R 22, C 1-2Alkyl, and aryl, wherein Ren Xuan aryl substituent can be chosen wantonly again by 1 to 3 and be selected from halogen, phenyl, CF 3, CN, OR 20And C 1-6The substituting group of alkyl replaces.In some preferred formula IC compound, R 24Be selected from alkyl, cycloalkyl and condensed benzyl ring alkyl, wherein tie point is on cycloalkyl, and alkyl wherein, cycloalkyl and condensed benzyl ring alkyl can be chosen wantonly and be selected from following substituting group by 1 to 2 and replace: halogen, CF 3, CN, OR 20, SR 20, S (O) R 22, SO 2R 22, C 1-2Alkyl and aryl, wherein Ren Xuan aryl substituent can be chosen wantonly by 1 to 3 and be selected from halogen, phenyl, CF 3, CN, OR 20, and C 1-6The substituting group of alkyl replaces.In another preferred formula IC compound, R 24Be selected from alkyl, cycloalkyl and condensed benzyl ring alkyl, wherein tie point is on cycloalkyl, and alkyl wherein, cycloalkyl and condensed benzyl ring alkyl can be chosen wantonly and be selected from following substituting group by 1 to 2 and replace: halogen, CF 3, OR 20And aryl, wherein Ren Xuan aryl substituent can be chosen wantonly by 1 to 3 and be selected from halogen, phenyl, CF 3, CN, OR 20, and C 1-6The substituting group of alkyl replaces.In another preferred formula IC compound, R 24Be selected from alkyl, have the cycloalkyl of 4 to 6 carbon atoms with 1 to 6 carbon atom, condensed benzyl ring alkyl, phenyl wherein is optional to be selected from halogen, CF by 1 to 2 3, OH, the substituting group of methyl and aryl replaces, and this aryl is optional to be selected from halogen, CF by 1 to 2 3, OH, C 1-2The substituting group of alkyl and aryl replaces.In other preferred formula IC compounds, R 24Be alkyl and cycloalkyl with 1 to 6 carbon atom, or R 24Be condensed benzyl ring alkyl, this benzyl ring alkyl is optional to be selected from halogen, CF by 1 to 2 3, OR 20, C 1-2The substituting group of alkyl and aryl replaces, or R 24Be to choose wantonly to be selected from halogen, CF by 1 to 2 3, OR 20, C 1-4The phenyl methyl that alkyl and aryl replace.
In formula IC compound, R 20Be selected from H, C 1-3Alkyl or aryl, wherein alkyl and aryl substituent can be chosen wantonly by 1 and be selected from following substituting group replacement: halogen ,-OMe, and CF 3More preferably, R 20Be selected from H or C 1-3Alkyl, most preferably, R 20Be methyl or H.
Most preferably, the substituted piperazine like compound of formula IC is selected from: 2-(2-[4-(3-isopropoxy-2-hydroxypropyl) piperazinyl]-N-(2, the 6-3,5-dimethylphenyl) ethanamide; N-(2, the 6-3,5-dimethylphenyl)-2-[4-(2-hydroxyl-3-indane-2-base-oxygen propyl group) piperazinyl] ethanamide; N-(2, the 6-3,5-dimethylphenyl)-and 2-{4-[2-hydroxyl-3-(phenyl methoxyl group) propyl group] piperazinyl } ethanamide, 2-[4-(3{[4-(tertiary butyl) phenyl] methoxyl group } the 2-hydroxypropyl) piperazinyl]-N-(2,6 dimethyl propyls) ethanamide, N-(2, the 6-3,5-dimethylphenyl)-2-(4-{3-[(2-fluorophenyl) methoxyl group]-the 2-hydroxypropyl } piperazinyl) ethanamide, 2-(4-{3-[(2, the 4-difluorophenyl) methoxyl group]-the 2-hydroxypropyl } piperazinyl)-N-(2,6 dimethyl propyls) ethanamide, N-(2, the 6-3,5-dimethylphenyl)-and 2-[4-(2-hydroxyl-3-{[4-(trifluoromethyl) phenyl] methoxyl group } propyl group) piperazinyl] ethanamide, N-(2, the 6-3,5-dimethylphenyl)-and 2-(4-{2-hydroxyl-3-[(2-p-methoxy-phenyl) methoxyl group] propyl group } piperazinyl) ethanamide, 2-(4-{3[(2, the 4-Dimethoxyphenyl) methoxyl group]-the 2-hydroxypropyl } piperazinyl)-N-(2,6 3,5-dimethylphenyls) ethanamide, N-(2, the 6-3,5-dimethylphenyl)-and 2-(4-{2-hydroxyl-3-[(4-p-methoxy-phenyl) methoxyl group] propyl group } piperazinyl) ethanamide, N-(2, the 6-3,5-dimethylphenyl)-2-(4-{3-[(4-fluorophenyl) methoxyl group]-the 2-hydroxypropyl } piperazinyl) ethanamide, N-(2, the 6-3,5-dimethylphenyl)-and 2-(4-{2-hydroxyl-3-[(4-aminomethyl phenyl) methoxyl group] propyl group } piperazinyl) ethanamide, N-(2, the 6-3,5-dimethylphenyl)-and 2-(4-{2-hydroxyl-3-[(4-phenyl) methoxyl group] propyl group } piperazinyl) ethanamide, N-(2, the 6-3,5-dimethylphenyl)-2-(4-{3-[(4-butyl phenyl) methoxyl group]-the 2-hydroxypropyl } piperazinyl) ethanamide, N-(2, the 6-3,5-dimethylphenyl)-and 2-{4-[2-hydroxyl-3-(2-naphthyl methoxyl group) propyl group] piperazinyl } ethanamide, N-(2, the 6-3,5-dimethylphenyl)-and 2-{4-[3-(cyclohexyl methoxyl group)-2-hydroxypropyl] piperazinyl } ethanamide, and N-(2, the 6-3,5-dimethylphenyl)-2-(4-{3-[(4-fluorophenyl) methoxyl group]-the 2-hydroxypropyl }-3,3-lupetazin base) ethanamide.
Term used herein has following definition.
" halogen " or " halogen "---separately or in conjunction with being meant halogen, i.e. chlorine (Cl), fluorine (F), bromine (Br), iodine (I).
" hydroxyl " is meant group-OH.
" mercaptan " or " sulfydryl " is meant group-SH.
" alkyl "---independent or combination is meant alkane deutero-group, contains 1 to 20 carbon atom, preferred 1 to 15 carbon atom (unless special definition).It is a straight chained alkyl, branched-chain alkyl or cycloalkyl.Preferably, the straight or branched alkyl contains 1-15, and more preferably 1 to 8, further preferred 1-6, also more preferably 1-4 and most preferably 1-2 carbon atom, as methyl, ethyl, propyl group, sec.-propyl, butyl, tertiary butyl or the like.Term used herein " low alkyl group " directly is meant above-mentioned straight chained alkyl.Preferably, cycloalkyl is meant monocycle, dicyclo, or three ring systems and each ring is 3-8 person's ring, preferred 3-6 person encircles, and as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, golden steel alkyl or the like.Alkyl comprises also that straight or branched contains or by cycloalkyl moiety alkyl at interval.The straight or branched alkyl is connected on the available point that can produce stable compound arbitrarily.The example includes, but not limited to 4-(sec.-propyl)-cyclohexyl ethyl or 2-methyl-cyclopropyl amyl group.The alkyl that replaces is meant the straight chained alkyl of aforementioned definitions, branched-chain alkyl, or cycloalkyl; it is replaced by 1 to 3 following groups or substituting group independently: halogen, hydroxyl, alkoxyl group; alkylthio, alkyl sulphinyl, alkyl sulphonyl; acyloxy, aryloxy, heteroaryloxy; optional by alkyl, aryl or heteroaryl list or dibasic amino, amidino groups; the urea optional by alkyl, that aryl or heteroaryl or heterocyclic radical replace, optional by N-single-or N; N-two-alkyl; the amino-sulfonyl that aryl or heteroaryl replace, alkyl sulfonyl-amino, arlysulfonylamino; heteroarylsulfonyl amino; alkyl-carbonyl-amino, aryl-amino-carbonyl, heteroaryl carbonylamino or the like.
" thiazolinyl "---contain 2-20 separately or in conjunction with being meant, preferred 2-17, more preferably 2-10, preferred again 2-8, most preferably 2 to 4 carbon atoms have at least one, and preferred 1-3, more preferably 1-2, the straight chain of 1 carbon-to-carbon double bond most preferably, side chain, or cyclic hydrocarbon radical.Under the situation of cycloalkyl, therefore a plurality of carbon-carbon double bond conjugation do not come aromaticity to endless belt.Carbon-carbon double bond can be included in a cycloalkyl moiety except that cyclopropyl, or is included in the straight or branched part.The example of thiazolinyl comprises vinyl, propenyl, pseudoallyl, butenyl, cyclohexenyl, cyclohexenyl alkyl or the like.The thiazolinyl that replaces is meant the straight-chain alkenyl of aforementioned definitions, and branched-chain alkenyl or cycloalkenyl group are replaced by 1 to 3 following groups or substituting group: halogen independently; hydroxyl, alkoxyl group, alkylthio; alkyl sulphinyl, alkyl sulphonyl, acyloxy; aryloxy, heteroaryloxy, optional by alkyl; aryl or heteroaryl list or dibasic amino, amidino groups, optional by alkyl; the urea that aryl or heteroaryl or heterocyclic radical replace; optional by alkyl, aryl or heteroaryl N-list or N, the dibasic amino-sulfonyl of N-; alkyl sulfonyl-amino; arlysulfonylamino, heteroarylsulfonyl amino, alkyl-carbonyl-amino; aryl-amino-carbonyl; the heteroaryl carbonylamino, carboxyl, alkoxy carbonyl; aryloxycarbonyl, heteroaryloxy carbonyl or the like and being connected on the available point that can produce stable compound arbitrarily.
" alkynyl "---contain 2-20 separately or in conjunction with being meant, preferred 2-17, more preferably 2-10, preferred again 2-8, most preferably 2-4 carbon atom has at least one, the straight or branched hydrocarbon of preferred 1 carbon-to-carbon triple bond.The example of alkynyl comprises ethynyl, proyl, butynyl or the like.The alkynyl that replaces is meant a straight-chain alkynyl or an alkynyl group of aforementioned definitions; it is replaced by 1 to 3 following groups or substituting group independently: halogen, hydroxyl, alkoxyl group; alkylthio; alkyl sulphinyl, alkyl sulphonyl, acyloxy; aryloxy; heteroaryloxy, optional by alkyl, aryl or heteroaryl list or dibasic amino; amidino groups; optional by alkyl, the urea that aryl or heteroaryl or heterocyclic radical replace, optional by alkyl; aryl or heteroaryl N-list or N; the dibasic amino-sulfonyl of N-, alkyl sulfonyl-amino, arlysulfonylamino; heteroarylsulfonyl amino; alkyl-carbonyl-amino, aryl-amino-carbonyl, heteroaryl carbonylamino or the like and being connected on the available point that can produce stable compound arbitrarily.
" alkyl thiazolinyl " is meant group-R-CR '=CR " ' R " ", wherein R is the low alkyl group of low alkyl group or replacement, R '; R " ', R " " be respectively hydrogen, halogen; low alkyl group; the low alkyl group that replaces, acyl group, aryl; the aryl that replaces; heteroaryl, or substituted heteroaryl are as following definition.
" alkyl alkynyl " be meant-RC ≡ CR ' wherein R be the low alkyl group of low alkyl group or replacement, R ' is a hydrogen, low alkyl group, the low alkyl group of replacement, acyl group, aryl, the aryl of replacement, heteroaryl, or the heteroaryl that replaces are as following definition.
" alkoxyl group " is meant group-OR, and wherein R is meant low alkyl group, the low alkyl group of replacement, acyl group, the aryl of replacement; aralkyl, the aralkyl of replacement, assorted alkyl, heteroarylalkyl, cycloalkyl; the cycloalkyl that replaces, the assorted alkyl of ring, or the assorted alkyl of the ring that replaces are as following definition.
" alkylthio " is meant group-SR ,-S (O) N=1-2-R, wherein R is a low alkyl group, the low alkyl group of replacement, aryl, the aryl of replacement, the aralkyl of aralkyl or replacement, so place definition.
" acyl group " is meant group-C (O) R, and wherein R is a hydrogen, low alkyl group, the low alkyl group of replacement, aryl, aryl of replacement or the like, so place definition.
" aryloxy " is meant group-OAr, and wherein Ar is an aryl, the aryl of replacement, heteroaryl, or the heteroaryl that replaces, so place definition.
" amino " is meant group NRR ', and wherein R and R ' are respectively hydrogen, low alkyl group, the low alkyl group of replacement, aryl, the aryl of replacement, heteroaryl, or the substituted heteroaryl as define herein, or acyl group.
" amido " is meant group-C (O) NRR ', and wherein R and R ' are respectively hydrogen, low alkyl group, the low alkyl group of replacement, aryl, the aryl of replacement, heteroaryl, the heteroaryl of replacement, so place definition.
" carboxyl " is meant group-C (O) OR, and wherein R is a hydrogen, low alkyl group, the low alkyl group of replacement, aryl, the aryl of replacement, heteroaryl and the heteroaryl that replaces, so place definition.
" aryl "---separately or in conjunction with being meant phenyl or naphthyl, optional and 5-7, preferred 5-6 person is Cycloalkylfused and/or optionally be selected from following substituting group by 1 to 3 and replace: halogen; hydroxyl; alkoxyl group, alkylthio, alkyl sulphinyl; alkyl sulphonyl; acyloxy, aryloxy, heteroaryloxy; optional by alkyl; aryl or heteroaryl list or dibasic amino, amidino groups, optional by alkyl; the urea that aryl or heteroaryl or heterocyclic radical replace; optional by alkyl, aryl or heteroaryl N-list or N, the dibasic amino-sulfonyl of N-; alkyl sulfonyl-amino; arlysulfonylamino, heteroarylsulfonyl amino, alkyl-carbonyl-amino; aryl-amino-carbonyl, heteroaryl carbonylamino or the like.
" aryl of replacement " is meant optional by 1 aryl to a plurality of functional groups replacements, as halogen, and low alkyl group, lower alkoxy, alkylthio, ethynyl, amino, amido, carboxyl, hydroxyl, aryl, aryloxy, heterocyclic radical, heteroaryl, the heteroaryl of replacement, nitro, cyano group, thiol group, sulfonamido or the like.
" heterocyclic radical "-separately or combination are meant saturated, and unsaturated or aromatic carbon cyclic group has monocycle (as morpholinyl, pyridyl or furyl) or a plurality of fused rings (as naphthyridinyl (naphthpyridyl), quinolyl, indolizine base or benzo [b] thienyl) and the ring in have at least one heteroatoms, as N, O or S, and can choose wantonly and to replace or to be replaced: halogen, low alkyl group, lower alkoxy by following groups, alkylthio, ethynyl, amino, amido, carboxyl, hydroxyl, aryl, aryloxy, heterocyclic radical, heteroaryl, the heteroaryl that replaces, nitro, cyano group, thiol group, sulfonamido or the like.
" heteroaryl "-separately or combination are meant the monocycle aromatic ring structure with 5-6 annular atoms, or have the twin nuclei of 8 to 10 atoms, contain one or more; preferred 1-4 is individual, more preferably 1-3, the most preferably individual O that is independently selected from of 1-2; the heteroatoms of S and N, and optional be selected from following group by 1 to 3 and replace: halogen; hydroxyl, alkoxyl group, alkylthio; alkyl sulphinyl, alkyl sulphonyl, acyloxy; aryloxy, heteroaryloxy, optional by alkyl; aryl or heteroaryl list or dibasic amino, amidino groups, optional by alkyl; aryl, the urea that heteroaryl or heterocyclic radical replace, optional by alkyl; aryl or heteroaryl N-list or N; the dibasic amino-sulfonyl of N-, alkyl sulfonyl-amino, arlysulfonylamino; heteroarylsulfonyl amino; alkyl-carbonyl-amino, aryl-amino-carbonyl, heteroaryl carbonylamino or the like.Heteroaryl also comprises oxidized S or N, as sulfinyl, and the N-oxide compound of alkylsulfonyl and level Four theheterocyclic nitrogen atom.Carbon or nitrogen-atoms are that the tie point of heteroaryl ring structure is to keep stablizing aromatic ring structure.The example of heteroaryl comprises pyridyl, pyridazinyl, pyrazinyl, quinazolyl, purine radicals, quinolyl, isoquinolyl, pyrimidyl, pyrryl ， oxazolyl, thiazolyl, thienyl isoxazolyl, oxa-thiadiazolyl group, isothiazolyl, tetrazyl, imidazolyl, triazinyl, furyl, benzofuryl, indyl, benzothiazolyl, benzoxazolyl or the like.The heteroaryl that replaces comprises and is connected the carbon that can produce stable compound or the substituting group on the nitrogen.
" heterocyclic radical "-separately or combination are meant non--aromatic nucleus alkyl, has 1 to 3 carbon atom that 5-10 atom wherein encircle by O, the displacement of the heteroatoms of S or N, and optional benzo-fused or condense 5-6 person's heteroaryl and/or optional as under the cycloalkyl situation, be substituted.Heterocyclic radical also comprises the S or the N of oxidation, as sulfinyl, and the N-oxide compound of alkylsulfonyl and level Four ring nitrogen.Tie point is on carbon atom or nitrogen-atoms.The example of heterocyclic radical is a tetrahydrofuran base, the dihydropyridine base, and piperidyl, pyrrolidyl, piperazinyl, dihydro benzo furyl, indolinyl, or the like.The heterocyclic radical that replaces contains and is connected the carbon that can produce stable compound or the substituting group nitrogen on the nitrogen-atoms.
" heteroaryl of replacement " is meant optional by one or more functional group lists or polysubstituted heterocyclic radical, and functional group is as halogen, low alkyl group, lower alkoxy, alkylthio, ethynyl, amino, amido, carboxyl, hydroxyl, aryl, aryloxy, heterocyclic radical, the heterocyclic radical of replacement, heteroaryl, the heteroaryl of replacement, nitro, cyano group, thiol group, sulfonamido or the like.
" aralkyl " is meant group-R-Ar, and wherein Ar is an aryl, and R is the low alkyl group of low alkyl group or replacement.Aryl is optional not to be replaced or is replaced by following group: halogen, low alkyl group, alkoxyl group, alkylthio, ethynyl, amino, amido, carboxyl, hydroxyl, aryl, aryloxy, heterocyclic radical, the heterocyclic radical of replacement, heteroaryl, the heteroaryl of replacement, nitro, cyano group, thiol group, sulfonamido or the like.
" heteroarylalkyl " is meant group-R-HetAr, and wherein HetAr is that heteroaryl and R are the low alkyl groups of low alkyl group or replacement.Heteroarylalkyl can be chosen wantonly and not replace or replaced by following group: halogen, low alkyl group, the low alkyl group of replacement, alkoxyl group, alkylthio, ethynyl, aryl, aryloxy, heterocyclic radical, the heterocyclic radical of replacement, heteroaryl, the heteroaryl that replaces, nitro, cyano group, thiol group, sulfonamido or the like.
" cycloalkyl " is meant divalence (divalent) ring or the multi-ring alkyl that contains 3-15 carbon atom.
" cycloalkyl of replacement " is meant and contains one or more following substituent cycloalkyl: halogen, low alkyl group, the low alkyl group of replacement, alkoxyl group, alkylthio, ethynyl, aryl, aryloxy, heterocyclic radical, the heterocyclic radical that replaces, heteroaryl, the heteroaryl of replacement, nitro, cyano group, thiol group, sulfonamido or the like.
" alkyl-cycloalkyl " is meant group-R-cycloalkyl, and wherein cycloalkyl is that cycloalkyl and R are the low alkyl groups of low alkyl group or replacement.Cycloalkyl can be chosen wantonly and not replace or replaced by following groups: halogen, low alkyl group, lower alkoxy, alkylthio, ethynyl, amino, amido, carboxyl, hydroxyl, aryl, aryloxy, heterocyclic radical, the heterocyclic radical of replacement, heteroaryl, the heteroaryl of replacement, nitro, cyano group, thiol group, sulfonamido or the like.
" optional " or " randomly " is meant that incident or the situation described subsequently can occur or not occur.And situation and the wherein absent variable situation comprise that incident wherein or condition occur are described.For example, " optional pharmaceutical excipient " is meant that described preparation can comprise, also can not comprise vehicle, rather than refers in particular to described situation appearance.And described preparation comprises situation and their non-existent situations that wherein optional vehicle exists.
" treatment " and " therapy " is meant the disease of treatment Mammals, particularly people, comprising:
(i) disease appears in the prevention patient, and wherein the patient has the tendency of disease, but is not also diagnosed out disease;
(ii) suppress disease, as stoping disease progression; Or
(iii) palliate a disease, promptly cause disease to disappear.
The present composition is used for treating Mammals in following therapy: the damage that protection skeletal muscle opposing wound causes; skeletal muscle after protection muscle or systemic disease such as the intermittent claudication; treatment shock disease; donor tissue that protection is used for transplanting and organ and treatment cardiovascular disorder comprise atrium and ventricle arrhythmia, PrinzmetalShi (variation) angina; stablize angina; with the angina that motion causes, congestive heart disease, and myocardial infarction.Treatment is to mix with pharmaceutical excipient with at least a The compounds of this invention of treatment significant quantity and/or its medicinal acid salt to realize.
The compound that falls in the scope of the invention comprises the compound (+) of above-mentioned definition and optically active isomer and R-and S-isomer and its mixture of (-).The present invention includes one isomer and its possible mixture.
All such schemes comprise its medicinal acid addition salt, particularly list and dihydrochloride, with and composition thereof.
Compound with general formula I and IA can prepare with the scheme of reaction formula 1A-7A.The routine of The compounds of this invention is synthetic to be the scheme of Chemical formula 1 A.The N-acidylate of the chloro-acetyl chloride III that compound IV can replace by the aniline II and the 2-of replacement prepares.Compound I I can be purchased or by corresponding nitrobenzene derivative (acid/SnCl 2Or catalytic hydrogenation, see Advanced Organic Chemistry, Ed.J.March (1992) A.Wileyinterscience) reduction easily prepares.Some commercially available substituted aniline corresponding to formula II comprises 2,6-xylidine, 23 dimethyl aniline, 2-aminotoluene, the 4-monomethylaniline, 4-monomethylaniline, 2,4 dichloro aniline, 3, the 4-dichlorphenamide bulk powder, 2,5-dichlorphenamide bulk powder, 2,4 dichloro aniline, the 2-chloroaniline, 3-chloroaniline, 2,6-difluoroaniline, 2, the 5-difluoroaniline, 3,4-difluoroaniline, 2-fluoroaniline, the 4-fluoroaniline, 3-fluoroaniline, 2-fluoro-6-chloroaniline, 4-fluoro-3-chloroaniline.
Reaction formula 1
Figure A0180544200501
Compound VI can by with the substituted-piperazinyl V of compound IV and N-protected The suitable solvent (as DMF, EtOH) middle reacting by heating and obtaining.The protection of compound V nitrogen-atoms is only just to need during the regional chemistry when it is used to control compound V and compound IV addition.In some cases, compound V can obtain from commercial channels.Commercially available and general formula V structure corresponding compounds example comprises the 2-methylpiperazine, 2, and 5-lupetazin, 2,6-lupetazin.The deprotection of formula VI compound can carry out (as Boc TFA, CBz and benzyl hydrogenation) under standard conditions.Compound I can by with formula VII compound and epoxide VIII in The suitable solvent (ethanol, DMF) middle reacting by heating and preparing.
Reaction formula 2A
Figure A0180544200511
Epoxide VIII (wherein m=1 or 2) can be by the described preparation of reaction formula 2A.With the phenol IX and the Epicholorohydrin that replace, epoxy bromopropane, or 4-bromo-1,2-butylene oxide ring and salt of wormwood heat in acetone can obtain epoxide VIII.Compound I X can obtain by commercial sources.The formula XI compound that can be purchased comprises the 2-chlorophenol, 2-fluorophenol, 2-methoxyphenol, the 2-methylphenol, sesamol, 2, the 6-chlorophenesic acid, 3, the 5-chlorophenesic acid, 2,6-difluorophenol, 2,4-difluorophenol-5-dihydro-indene alcohol, 3-chloro-4-fluorophenol, 2-chloro-4-fluorophenol and 5,6,7,8-tetrahydrochysene-2-naphthalene alcohol.In some cases, formula VIII compound can obtain by commercial sources.Commercially available corresponding and compound formula VIII comprise benzyl glycidyl ether, Racemic glycidol 2-methyl phenyl ether, Racemic glycidol 4-p-methoxy-phenyl ether, Racemic glycidol 4-chloro-phenyl-ether, Racemic glycidol 2-chloro-phenyl-ether, Racemic glycidol 2-p-methoxy-phenyl ether, Racemic glycidol 4-methyl phenyl ether, Racemic glycidol 3,4-dichlorophenyl ether, Racemic glycidol 4-fluorophenyl ether.
Reaction formula 3A
Figure A0180544200521
Compound can be by the described preparation of reaction formula 3A.With tert-butyl lithium as alkali, the passing through alkylation and can obtain compounds X III of compounds X II and alkyl halide, as Pohlman etc. (J.Org.Chem. (1977), 62,1016-1022) described.XIV can obtain the remodeling of the compound V of N-benzyl protection with diborane reduction, subsequently with N-Boc with trifluoroacetic acid (TFA) deprotection [diborane reduces J.Med.Chem. (1992) such as seeing Jacobson, 42,1123-1144].
Reaction formula 4A
Figure A0180544200522
Compound V also can prepare by D or the amino acid whose standard coupling of L (as EDC or PyBrop) and the deprotection of standard; as as described in the reaction formula 4A [the preparation diketopiperazine sees-P.Cledera etc.; Tetrahedron, (1998) p.12349-12360 with Bioorg.Med.Chem.Lett (1998) p2369-2374 such as R.A.Smith].Diketopiperazine is with the former remodeling that obtains the compound V of N-benzyl protection of diborane ring.
Compound V also comprise piperazine the dicyclo homologue (1S, 4S)-(+)-2,5-diazabicyclo [2.2.1] heptane 83,3,8-diazabicyclo [3.2.1] octane 84 and 2,5-diazabicyclo [2.2.2] octane 85.
Figure A0180544200531
Commercially available dicyclo homologue comprise (1S, 4S)-(+)-2,5-diazabicyclo [2.2.1] heptane 83, compound 84,85 and 83 (1R, 4R) isomer can (be seen Sturm, J such as P.A. for 84 and 85 by the preparation of disclosed method, Med.Chem.1974,17,481-487; See Barish for 83, T.F. and Fox, D.E.J.Org.Chem., 1990,55,1684-1687).
The specific examples of preparation formula IA compound is disclosed in reaction formula 5A, how to prepare The compounds of this invention to further specify among 6A and the 7A.Especially, as alkali and solubility promoter, with 2,6-dichlorphenamide bulk powder and 2-chloro-acetyl chloride 2 carry out acylation reaction, obtain chloro-acetamide derivative 3 respectively with saturated supercarbonate and ether (1: 1).Further with compound 3 and 2, the 6-lupetazin obtains compound 5 by reacting by heating in ethanol.Compound 5 and epoxide 6 heating reflux reaction in ethanol are obtained 2,6-lupetazin derivative 7.Compound 6 can by successively with Epicholorohydrin and 2-methoxyphenol in acetone at K 2CO 3Existence is heated down and is prepared, shown in reaction formula 6A.
Reaction formula 5A
Figure A0180544200532
Reaction formula 6A
Compound 14 concrete synthetic as described in the reaction formula 7A.Compound 11 prepares by epoxide 6 usefulness Boc-ethylene diamines are heated open loop in EtOH.The acidylate of compound 11 is that alkali carry out with diisopropyl ethyl amine with chloro-acetyl chloride in methylene dichloride.Remove the Boc group with TFA and obtain compound 13 by encircling in EtOH, to heat to open subsequently.Compound 13 and 6 is reacted as stated above obtain compound 14.
Figure A0180544200551
Compound with general formula I and IB can prepare in the scheme of reaction formula 1B-7B.General synthetic the listing among the reaction formula 1B of The compounds of this invention.The N-acidylate that compound IV can replace chloro-acetyl chloride III by substituted aniline and the 2-with general formula I I prepares.Compound I I commercially available or by the reduction of corresponding nitrobenzene derivative preparation (acid/SnCl easily 2Or catalytic hydrogenation, see Advanced Organic Chemistry, Ed.J.March, (1992) A.Wiley-Interscience)。Commercially available general formula I I substituted aniline comprises 2,6-xylidine, 23 dimethyl aniline, 2-aminotoluene, the 4-monomethylaniline, 2,4 dichloro aniline, 3,4-dichlorphenamide bulk powder, 2,5-dichlorphenamide bulk powder, 2,4 dichloro aniline, 2-chloroaniline, the 3-chloroaniline, 2,6-difluoroaniline, 2, the 5-difluoroaniline, 3,4-difluoroaniline, 2-fluoroaniline, the 4-fluoroaniline, 3-fluoroaniline, 2-fluoro-6-chloroaniline, 4-fluoro-3-chloroaniline. Compound VI can be by making compound IV and N-protected substituted-piperazinyl V The suitable solvent (as DMF, EtOH) in reacting by heating and preparing.The protection of compound V nitrogen-atoms is only just to need when it is used to control the regional chemistry of compound V and compound IV addition.In some cases, compound V can obtain from commercial channels.Commercially available and general formula V structure corresponding compounds example comprises the 2-methylpiperazine, 2, and 5-lupetazin, 2,6-lupetazin.The deprotection of formula VI compound can carry out (as Boc TFA, CBz and benzyl hydrogenation) under standard conditions.Compound I can by with formula VII compound and epoxide VIII in The suitable solvent (ethanol, DMF) middle reacting by heating and preparing.
Reaction formula 2B
Epoxide VIII can prepare with reaction formula 2B.With the allyl benzene XI that replaces with mCPBA or hydrogen peroxide carry out epoxidation obtain epoxide VIII (G.Majetich, R.Hicks, G.Sun and P.McGill, (1998), 63,2564-2573).Compounds X I can be successively by making aldehyde IX and methylene tri phenyl phosphorane [Advanced Organic Chemistry under Wei Tixi conditioned disjunction Homer Emmons condition, EdS.J.March (1992) Wiley-Intersxience publishes and S.Pine, G.Shen and H.Hoang, Synthesis (1991), 1] reaction and preparing.Compounds X I also can be by making general formula X halogenide and the magnesium coupling of bromination allyl group and preparation easily.In some cases, compounds X I can obtain from commercial channels.Commercially available compound corresponding to formula XI comprises (wherein m=0) 3-fluorobenzene ethene, 4-fluorobenzene ethene, 2-chloro-styrene, 3-chloro-styrene, 4-chloro-styrene, 2,6-dichlorostyrene, 3,4-dichlorostyrene, 3,4-dimethoxy styrene.Other commercially available will have the compound of general formula X I to comprise (wherein m=1) 4-methoxyl group allyl benzene, 2-hydroxyl allyl benzene, 4,5-dimethoxy allyl benzene, 2-methacrylic benzene safrole and 1-allyl group naphthalene.
Reaction formula 3B
Figure A0180544200581
Compound V can be by the described preparation of reaction formula 3B.Compounds X II and alkyl halide carry out alkylation with tert-butyl lithium as alkali can obtain compounds X III, as Pohlmam etc. (J.Org.Chem., (1997), 62,1016-1022).With trifluoroacetic acid to the N-Boc deprotection after, with XIII with diborane reduction can obtain the N-benzyl protection compound V remodeling (TFA, J.Med.Chem such as Jacobson are seen in reduction for diborane, (1999), 42,1123-1144).
Reaction formula 4B
Compound V also can prepare by the coupling (as EDC or PyBrop) of D or L amino acid standard and the deprotection (handling with TFA as Boc) of standard; as as described in the reaction formula 4B [the preparation diketopiperazine sees-P.Cledera etc.; Tetrahedron, (1998) p.12349-12360 with Bioorg.Med.Chem.Lett (1998) p2369-2374 such as R.A.Smith].Diketopiperazine obtains the remodeling of the compound V of N-benzyl protection with the diborane reduction.
Compound V also comprise piperazine the dicyclo homologue (1S, 4S)-(+)-2,5-diazabicyclo [2.2.1] heptane 83,3,8-diazabicyclo [3.2.1] octane 84 and 2,5-diazabicyclo [2.2.2] octane 85.
Figure A0180544200591
Commercially available dicyclo homologue comprise (1S, 4S)-(+)-2,5-diazabicyclo [2.2.1] heptane 83, compound 84,85 and 83 (1R, 4R) isomer can (be seen Sturm, J such as P.A. for 84 and 85 by the preparation of disclosed method, Med.Chem.1974,17,481-487; See Barish for 86, T.F. and Fox, D.E.J.Org.Chem., 1990,55,1684-1687).
The specific examples of the preparation of The compounds of this invention is disclosed in reaction formula 5B and how prepares The compounds of this invention further to illustrate.Particularly with 2, supercarbonate that 6-dichlorphenamide bulk powder and 2-chloro-acetyl chloride 2 usefulness are saturated and ether (1: 1) obtain chloro-acetamide derivative 3 respectively as alkali and solubility promoter acidylate.Further compound 3 and piperazine are obtained compound 5 by reacting by heating in ethanol.With compound 5 and epoxide 6 all in ethanol heating reflux reaction obtain bridged piperazine derivatives 7.
Reaction formula 5B
Compound 8 can be purchased and with 3-chloro-peroxy benzoic acid epoxidation in methylene dichloride, as described in reaction formula 6B.
Reaction formula 6B
Figure A0180544200602
Four carbocyclic ring oxide compounds 15 can prepare with the mCPBA oxidation then by commercially available 4-methoxy-benzyl chlorine and the coupling of allyl group bromination magnesium, as described in reaction formula 7B.
Reaction formula 7B
Compound with general formula I and IC can be as preparation as described in the reaction formula 1C-6C.General synthetic the listing among the reaction formula 1C of The compounds of this invention.
Figure A0180544200612
Compound IV can be carried out the N-acidylate by substituted aniline II and 2-replacement chloro-acetyl chloride III and be prepared.Compound I I can be purchased or easily prepare by corresponding nitrobenzene derivative reduction (acid/SnCl2 or catalytic hydrogenation are seen Advanced Organic Chemistry, Ed.J.March, (1992) A.Wiley-Interscience).Some example of commercially available substituted aniline II comprises 2,6 xylidines, 23 dimethyl aniline, 2-aminotoluene, the 4-monomethylaniline, 4-monomethylaniline, 2,4 dichloro aniline, 3, the 4-dichlorphenamide bulk powder, 2,5-dichlorphenamide bulk powder, 2,4 dichloro aniline, the 2-chloroaniline, 3-chloroaniline, 2,6-two Fluoroanilines, 2,5-two Fluoroanilines, 3,4-two Fluoroanilines, 2-Fluoroaniline, the 4-Fluoroaniline, 3-Fluoroaniline, 2-fluoro-6-chloroaniline, 4-fluoro-3-chloroaniline.
Compound VI can be by making compound IV and N-protected substituted-piperazinyl V by The suitable solvent (as DMF, EtOH) in reacting by heating and preparing.The protection of compound V nitrogen-atoms is only just to need when it is used to control the regional chemistry of compound V and compound IV addition.In some cases, compound V can obtain from commercial channels.Commercially available and general formula V structure corresponding compounds example comprises the 2-methylpiperazine, 2, and 5-lupetazin, 2,6-lupetazin and 4-benzyloxycarbonyl piperazine-2-ketone.The deprotection of formula VI compound can carry out (as Boc TFA, CBz and benzyl hydrogenation) under standard conditions.Compound I can by with formula VII compound and epoxide VIII in The suitable solvent (ethanol, DMF) middle reacting by heating and preparing.
Reaction formula 2C
Figure A0180544200622
Epoxide VIII can pass through the described preparation of reaction formula 2C.Alkyl alcohol IX and Epicholorohydrin or epoxy bromopropane and sodium hydride heated in DMF can obtain epoxide VIII.Some compound VIII can obtain from commercial channels.Commercially available formula VIII compound comprises the Racemic glycidol isopropyl ether, N butylglycidyl ether and T butylglycidyl ether.
Compound V can prepare as reaction formula 3C.Compounds X II and alkyl halide tert-butyl lithium are that alkali carries out alkylation and can obtain compounds X III, as Pohlman etc. (J.Org.Chem, (1997), 62,1016-1022) described.With trifluoroacetic acid with the N-Boc deprotection after, XIV with diborane reduce the compound V modification that can obtain the N-benzyl protection (TFA, Jacobson etc. is seen in the reduction of diborane, J.Med.Chem., (1999), 42,1123-1144).
Reaction formula 3C
Compound V also can prepare by the coupling (as EDC or PyBrop) of D or L amino acid standard, as as described in the reaction formula 4C [the preparation diketopiperazine sees-P.Cledera etc., Tetrahedron, (1998) p.12349-12360 with Bioorg.Med.Chem.Lett (1998) p2369-2374 such as R.A.Smith].Diketopiperazine obtains the remodeling of the compound V of N-benzyl protection with the diborane reduction.
Reaction formula 4C
Figure A0180544200641
The specific examples of The compounds of this invention preparation is disclosed among reaction formula 5C and the 6C how to prepare The compounds of this invention to further specify.
Figure A0180544200642
Especially, with 2, supercarbonate that 6-dichlorphenamide bulk powder and 2-chloro-acetyl chloride 2 usefulness are saturated and ether (1: 1) obtain chloro-acetamide derivative 3 respectively as alkali and solubility promoter acidylate.Further compound 3 and piperazine are obtained compound 5 by reacting by heating in ethanol.With compound 5 and epoxide 6 all in ethanol heating reflux reaction obtain bridged piperazine derivatives 7.Compound 6 can by successively with Epicholorohydrin and 2-indanol in DMF, reacting by heating in the presence of NaH and preparing is shown in reaction formula 6C.
Reaction formula 6C
Can be with the acid salt of The compounds of this invention with suitable alkali, as salt of wormwood or sodium hydroxide, typically in the presence of water solvent, processing under about 0 to 100 ℃ temperature and change into corresponding free alkali.Free alkali can separate by ordinary method, as uses organic solvent extraction.
Salt of the present invention can utilize different solvabilities and volatility, or exchanges with the ion exchange resin of suitable carrying.This conversion is carried out to the temperature between the solvent boiling point at about 0 ℃, wherein solvent be used to produce medium.The administration of active compound and salt described herein can be undertaken by the acceptable administering mode of any therapeutical agent.This method comprises oral, outside the enteron aisle, and through skin, subcutaneous and other system model.Except patient oneself can not absorb the situation of any medicine, preferred administering mode is oral.In the case, need carry out the enteron aisle external administration.
According to required mode, composition can be a solid form, semi-solid form or liquid preparation form, and as tablet, suppository, pill, capsule, powder, liquid, suspension or the like is preferably with the suitable unit dosage form of taking exact dosage desired separately.Composition can comprise drug excipient and at least a active compound of the present invention or its pharmaceutical salts that one or more are conventional, and can comprise other medical agent, medicament, carrier, auxiliary material, thinner or the like in addition.
The dosage of active compound is certainly according to the patient who is treated, patient's body weight, and the severity of disease, administering mode and prescription doctor's judgement decides.But effectively dosage range is at 0.1-30mg/kg/ days, preferred 0.5-2-mg/kg/ days.For the people of average 70kg, dose is 7-2100mg every day, preferred 35-1400mg/ days.Because many effects of The compounds of this invention (damage that the opposing of protection skeletal muscle is caused by wound; skeletal muscle after protection muscle or systemic disease such as the intermittent claudication; treatment shock disease; donor tissue and organ that protection is used for transplanting; comprise atrium and ventricle arrhythmia with the treatment cardiovascular disorder; Prinzmetal (variation) family name angina; stablize angina; the angina that causes with motion; congestive heart disease; and myocardial infarction) be to obtain by similar mechanism (partial fatty acid oxidation inhibition), dosage (with administering mode) normally identical and preferably in all these purposes scopes.
For solids composition, conventional non-toxic solid comprises, can use for example mannitol of pharmaceutical grade, lactose, and starch, Magnesium Stearate, soluble saccharin, talcum powder, Mierocrystalline cellulose, glucose, sucrose, magnesiumcarbonate, or the like.The active compound of above-mentioned definition can be mixed with suppository as propylene glycol as carrier with for example polyalkylene glycol.The pharmaceutical composition of liquid form of medication can be dispersed in vehicle by for example with the active compound of above-mentioned definition and optional excipient substance dissolving, water for example, and salt solution, D/W, glycerine is in the ethanol etc., to form solution or suspension.If desired, the pharmaceutical composition of administration can contain a small amount of nontoxic auxiliary substance, as wetting agent or emulsifying agent, and pH buffer reagent etc., as sodium acetate, sorbitan monolaurate, trolamine sodium acetate, Emulphor FM etc.The practical methods for preparing this class dosage form is known, or apparent to those skilled in the art; For example, see the pharmaceutical science of Remington, Mack PublishingCompany, Easton, Pennsylvania, the 15th edition, 1975.In any case the composition of administration or preparation, the amount of the active compound that contains are treatment significant quantity, the i.e. patient's that treated the symptoms to alleviate effectively.For oral administration, medicinal non-toxic composite is made by adding any vehicle commonly used, as, the mannitol of pharmaceutical grade, lactose, starch, Magnesium Stearate, soluble saccharin, talcum powder, Mierocrystalline cellulose, glucose, sucrose, magnesiumcarbonate, or the like.This composition can be a solution, suspension, tablet, pill, capsule, powder, sustained release preparation or the like.This composition can contain 10%-95%, the activeconstituents of preferred 1-70%.
The enteron aisle external administration generally with the injection is feature, and is perhaps subcutaneous, muscle or vein.Injection can prepare with conventionally form, is liquor or suspension perhaps, suits to make before injection the solid form of liquor or suspension, or emulsion.Suitable vehicle is, water for example, salt solution, glucose, glycerine, ethanol or the like.In addition, if desired, the pharmaceutical composition of administration also can contain a small amount of nontoxic auxiliary substance, as wetting agent or emulsifying agent, and pH buffer reagent etc., as sodium acetate, sorbitan monolaurate, Emulphor FM etc.
The parenterai administration approach of invention is the implantation with slowly-releasing or controlled release system recently, to keep the constant level of dosage.See United States Patent (USP) 3,710,795, insert that this is incorporated by reference.In the nearest mode of another kind, the present composition can be used U.S. Patent application 09/321,522, May 27 1999 applying date disclosed composition and/or method with the dosage form administration of controlled release, the specification sheets of this patent inserts that this is incorporated by reference.
Give Mammals, it is within the scope of the present invention that preferred people takes one or more The compounds of this invention by other known drug dosage form, include but not limited to pass through bolus, intravenous injection, percutaneous dosing, by sucking subcutaneous administration, or other therapeutical agent medication well known by persons skilled in the art or approach.
The following example is representative of the present invention, but can not be understood that it is qualification to the claim scope.
Embodiment 1
N-(2, the 6-3,5-dimethylphenyl)-2-{4-[2-hydroxyl-3-(2-methoxyl group) propyl group]-3,5-lupetazin base } ethanamide (7)
Figure A0180544200671
The A part
Synthesizing of N-(2, the 6-3,5-dimethylphenyl)-2-chlor(o)acetamide (3)
With 2, (9.8g 81.2mmol) is dissolved in ether (100mL) and saturated NaHCO to the 6-xylidine 3(100mL) in ice/water-bath, cool off in the aqueous solution and with mixture.With in this cooling solution, dripped in 2 hours chloro-acetyl chloride 2 (9.17g, 81.2mmol).Mixture heating up to room temperature, was kept 14 hours.Extract this mixture with ethyl acetate (3 * 50).With bonded organic layer dried over mgso, filter and concentrate.Resistates is ground in ether and filters, obtain compound 3, be white solid.
The B part
Synthesizing of N-(2, the 6-3,5-dimethylphenyl)-2-(3,5-lupetazin base) ethanamide (5)
Compound 3 (5g adds 2 in ethanol 25.2mmol) (100mL) solution, 6-lupetazin 4 (2.1g, 25.0mmol) and N, the N-diisopropylamine (3.2g, 25.2mmol).With reaction mixture reflux 24 hours.Behind the mixture vacuum concentration, (10: 1, DCM: MeOH) purifying resistates obtained compound 5 by column chromatography.
Figure A0180544200681
The C part
Synthesizing of Racemic glycidol 4-p-methoxy-phenyl ether (6)
With the 2-methoxyphenol (1.0g, 8.0mmol) and Epicholorohydrin (3.7g 40.0mmol) is dissolved in the acetone (20mL).Add K 2CO 3(2.2g 16.0mmol) and with mixture heating up to 70 ℃, kept 24 hours.With the reaction mixture vacuum concentration.Resistates is dissolved in the 100mL ethyl acetate, uses the 100mL water washing, dried over mgso.With mixture be evaporated to dry doubling with column chromatography (2: 1, hexane:, obtain compound 6 ethyl acetate) with residue purified.
The D part
N-(2, the 6-3,5-dimethylphenyl)-2-{4-[2-hydroxyl-3-(2-methoxyl group) propyl group]-3,5 lupetazin bases } ethanamide (7) synthetic
The 10mL of compound 5 ethanol (0.4g, 1.4mmol) add in the solution compound 6 (0.27g, 1.5mmol).With reaction mixture reflux 24 hours.(10: 1, DCM: MeOH) purifying resistates obtained compound 7 with the mixture vacuum concentration and with Prep.TLC.
Figure A0180544200691
2-{ (5S, 2R)-4-[2-hydroxyl-3-(2-methoxyl group phenoxy group) propyl group]-2,5-lupetazin base }-N-(2, the 6-3,5-dimethylphenyl) ethanamide (15)
The method preparation of compound 15 usefulness compounds 7, but partly use at B (2R, 5S)-lupetazin replacement 2,6-lupetazin 4 obtains compound 15; Mass spectrum (M+1)=456.4.
Figure A0180544200692
N-(2, the 6-3,5-dimethylphenyl)-2-{4-[2-hydroxyl-3-(2-methoxyl group phenoxy group) propyl group]-2-oxo piperazinyl } ethanamide (16)
The method preparation of compound 16 usefulness compounds 7, but partly replace 2 with 4-benzyloxycarbonyl-2-oxygen-piperazine at the B of compound 7,6-lupetazin 4 proceeds to ultimate aim after removing CBZ protecting group (hydrogenation-20psi, 10% palladium charcoal), obtain compound 16; Mass spectrum (M+1)=442.41.
Figure A0180544200701
2,5-diaza-5-[2-hydroxyl-3-(2-methoxyl group phenoxy group) propyl group] dicyclo [4.4.0] last of the ten Heavenly stems-2-yl }-N-(2, the 6-3,5-dimethylphenyl) ethanamide (17)
The method preparation of compound 17 usefulness compounds 7, but partly replace 2 with the perhydro quinoline at B, 6-lupetazin 4 obtains compound 15; Mass spectrum (M+1)=482.4.
Figure A0180544200702
N-(2, the 6-3,5-dimethylphenyl)-2-{4-[2-hydroxyl-3-(2-methoxyl group phenoxy group) propyl group]-3,3-lupetazin base } ethanamide (18)
The method preparation of compound 18 usefulness compounds 7, but partly use 2 at B, the 2-lupetazin replaces 2, and 6-lupetazin 4 obtains compound 18; Mass spectrum (M+1)=456.51.
2-{5-[(2S)-2-hydroxyl-3-(2-methoxyl group phenoxy group) propyl group] (1S, 4S)-2,5-diazabicyclo [2.2.1] heptan-2-yl }-N-(2,6 3,5-dimethylphenyl) ethanamide (19)
The method preparation of compound 19 usefulness compounds 7, but partly use at B (1S, 4S)-(+)-2,5-diazabicyclo [2.2.1] heptane replaces 2, and 6-lupetazin 4 obtains compound 19; Mass spectrum (M+1)=481.5.
Figure A0180544200711
N-(2, the 6-3,5-dimethylphenyl)-2-{4-[2-hydroxyl-4-(2-methoxyl group phenoxy group) butyl] piperazinyl } ethanamide (20)
The method preparation of compound 20 usefulness compounds 7, but partly use 4-bromo-1 at B, 2-butylene oxide ring 6b substitution list chloropharin 6a obtains compound 20; Mass spectrum (M+1)=442.37.
N-(2, the 6-3,5-dimethylphenyl)-2-{4-[4-(4-fluorophenoxy)-2-hydroxybutyl] piperazinyl } ethanamide (21)
The method preparation of compound 21 usefulness compounds 7, but partly use 4-bromo-1 at B, 2-butylene oxide ring 6b substitution list chloropharin 6a obtains compound 21; Mass spectrum (M+1)=430.35.
Figure A0180544200721
2-(4-{4-[4-(tertiary butyl) phenoxy group]-the 2-hydroxybutyl } piperazinyl)-N-(2, the 6-3,5-dimethylphenyl) ethanamide (22)
The method preparation of compound 22 usefulness compounds 7, but partly use 4-bromo-1 at B, 2-butylene oxide ring 6b substitution list chloropharin 6a obtains compound 22; Mass spectrum (M+1)=468.32.
Figure A0180544200722
N-(2, the 6-3,5-dimethylphenyl)-2-{4-[2-hydroxyl-4-(4-phenyl phenoxy group) butyl] piperazinyl } ethanamide (23)
The method preparation of compound 23 usefulness compounds 7, but partly use 4-bromo-1 at B, 2-butylene oxide ring 6b substitution list chloropharin 6a obtains compound 23; Mass spectrum (M+1)=488.41.
N-(2, the 6-3,5-dimethylphenyl)-2-{4-[2-hydroxyl-4-(4-methoxyl group phenoxy group) butyl] piperazinyl } ethanamide (24)
The method preparation of compound 24 usefulness compounds 7, but partly use 4-bromo-1 at B, 2-butylene oxide ring 6b substitution list chloropharin 6a obtains compound 24; Mass spectrum (M+1)=442.37.
Embodiment 2
N-(2, the 6-3,5-dimethylphenyl)-2-{4-[2-hydroxyl-3-(2-methoxyl group phenoxy group) propyl group]-3-oxo piperazinyl } ethanamide (14)
The E part
(tert.-butoxy)-N-(2-{[2-hydroxyl-3-(2-methoxyl group phenoxy group) propyl group] amino } ethyl) carboxamide (11) synthetic
With epoxide 6 (1.0g, 5.5mmol) and the Boc-quadrol (0.88g 5.5mmol) is dissolved in the 20mL ethanol and mixture heating up was refluxed 24 hours.(1: 1 hexane: ethyl acetate) purifying resistates obtains compound 11 with solvent evaporation and with column chromatography.
The N-{2-[(tert.-butoxy) carbonylamino] ethyl }-2-chloro-N-[2-hydroxyl-3-(2-methoxyl group phenoxy group) propyl group] ethanamide (12) synthetic
(1.0g 3.0mmol) is dissolved among the 20mL DCM also with diisopropylethylamine (0.76g, 4.5mmol) processing with compound 11.Mixture is cooled to ℃.In the refrigerative mixture, drip the 5mL DCM solution of chloro-acetyl chloride.With reaction mixture stirring at room 24 hours.Mixture is washed with 50mL DCM dilution and with 50mL water and 10% citric acid.Organic layer is also filtered with dried over mgso.Solvent evaporated under reduced pressure is also used the ether crystalline residue, obtains compound 12.
1-[2-hydroxyl-3-(2-methoxyl group phenoxy group) propyl group] piperazine-2-ketone (13) synthetic.
(0.5g 1.5mmol) is dissolved among the 10mL TFA with compound 12.With mixture stirring at room 2 hours.TFA is removed in decompression.Resistates is dissolved in the 20mL ethanol also with diisopropylethylamine (0.76g, 4.5mmol) processing.Mixture heating up was refluxed 24 hours.Removal of solvent under reduced pressure obtains compound 13, does not need purifying directly to use.
The F part
N-(2, the 6-3,5-dimethylphenyl)-2-{4-[2-hydroxyl-3-(2-methoxyl group phenoxy group) propyl group]-3-oxo piperazinyl } ethanamide (14) synthetic
The 10mL of compound 13 ethanol (0.1g, 0.30mmol) add in the solution compound 3 (0.7g, 0.36mmol) and diisopropylethylamine (0.76g, 0.36mmol).With reaction mixture reflux 24 hours.(10: 1, DCM: MeOH) purifying resistates obtained compound 14: mass spectrum (M+1)=442.34 with the mixture vacuum concentration and with Prep.TLC.
Embodiment 3
Figure A0180544200741
The compound of listing in the following table 1 uses the method for compound 14 among the embodiment 2 to prepare.
Table 1
?R MH +
?25 2, the 6-3,5-dimethylphenyl 430.3
?26 2, the 6-dichlorophenyl 471
?27 4-amino-sulfonyl phenyl 481.2
?28 3-trifluoromethyl-5-p-methoxy-phenyl 500.2
?29 The 5-indanyl 442.2
?30 The 1-naphthyl 452.3
?31 1-(4-chloronaphthyl, methylnaphthyl) 486.3
?32 2-N-pyrryl-phenyl 467.3
?33 Phenyl 402.2
?34 The 2-chloro-phenyl- 436.2
?35 2-chloro-4-aminomethyl phenyl 450.2
?36 2-(1-methyl ethylene) phenyl 442.3
?37 The 2-aminomethyl phenyl 416.2
?38 2-sec.-propyl-6-aminomethyl phenyl 458.4
?39 3-methylthio group phenyl 448.2
?40 2-methoxyl group-4-chloro-5-aminomethyl phenyl 480.2
?41 The 4-dimethylaminophenyl 445.3
?42 2, the 4-Dimethoxyphenyl 462.3
?43 3, the 4-dichlorophenyl 471.1
?44 The 4-chloro-phenyl- 436.3
?45 The 3-chloro-phenyl- 436.2
?46 3, the 5-dichlorophenyl 471.1
?47 The 4-p-methoxy-phenyl 432.3
?48 The 4-aminomethyl phenyl 416.2
?49 The 3-aminomethyl phenyl 416.2
?50 The 4-fluorophenyl 420.2
?51 The 4-cyano-phenyl 427.3
?52 The 4-acetylphenyl 444
?53 The 2-p-methoxy-phenyl 432.4
?54 The 4-trifluoromethyl 470.2
?55 3-trifluoromethyl-4-chloro-phenyl- 504.1
?56 3, the 5-Dimethoxyphenyl 462.3
?57 4-N-morpholinyl phenyl 487.4
?58 3-fluoro-4-p-methoxy-phenyl 450.2
?59 3,4, the 5-trimethoxyphenyl 492.3
?60 3, the 4-Dimethoxyphenyl 490
?61 2-fluoro-4-chloro-phenyl- 454.2
?62 2-hydroxymethyl-6-aminomethyl phenyl 446
Embodiment 4
2-[4-(3-(2H-benzo [d] 1,3-dioxole-5-yl)-2-hydroxypropyl) piperazinyl]-N-(2,6 3,5-dimethylphenyl) ethanamide (7B)
The A part
Synthesizing of N-(2,6 3,5-dimethylphenyl)-2-chlor(o)acetamide (3B)
(9.8g 81.2mmol) is dissolved in ether (100mL) and the saturated sodium bicarbonate (100mL) and with reaction mixture and cools off in ice/water-bath with 2,6 xylidines.With in refrigerative solution, dripped in 2 hours chloro-acetyl chloride 2B (9.17g, 81.2mmol).More than 14 hours with mixture heating up to room temperature.With ethyl acetate (3 * 50) extraction mixture.With dried over mgso bonded organic layer, filter and concentrate.Grind resistates and filtration with ether, obtain compound 3B, be white solid.
The B part
Synthesizing of N-(2,6 3,5-dimethylphenyl)-2-piperazinyl ethanamide (5B)
Compound 3 (5g, add in ethanol 25.2mmol) (100mL) solution compound 4B (2.1g, 25.0mmol) and N, the N-diisopropylamine (3.2g, 25.2mmol).With reaction mixture reflux 24 hours.(10: 1, methylene dichloride: purifying resistates methyl alcohol) obtained compound 5B with the mixture vacuum concentration and with column chromatography.
The C part
5-(oxyethane-2-ylmethyl)-2H-benzo [d] 1,3-21 oxanes (6B) synthetic
(1.0g drips 3-chloroperoxybenzoic acid (1.8g, 20mL dichloromethane solutions 10.43mmol) in dichloromethane solution 6.17mmol) ice-cooled 8 in 1 hour.With reaction mixture stirring at room 12 hours.With reaction mixture solids removed by filtration and vacuum concentration.In resistates, add diethyl ether (200ml), and (3 * 100ml) wash with saturated sodium bicarbonate.The organic layer dried over mgso, vacuum concentration.(2: 1 hexanes: ethyl acetate) purifying resistates obtains 6B with Prep.TLC.
The D part
2-[4-(3-2H-benzo [d] 1,3-dioxole-5-yl)-2-hydroxypropyl] piperazinyl]-N-(2, the 6-3,5-dimethylphenyl) ethanamide (7B)
(0.4g adds compound 6B (0.38g, 10mL ethanolic soln 2.14mmol) in ethanol 1.64mmol) (100mL) solution at compound 5B.With reaction mixture refluxed 24 hours.With the mixture vacuum concentration, (10: 1 methylene dichloride: purifying resistates methyl alcohol) obtains 7B: mass spectrum (MH+1)=426.34 with Prep.TLC.
Figure A0180544200771
N-(2, the 6-3,5-dimethylphenyl)-2-[4-(2-hydroxy-4-phenyl butyl) piperazinyl] ethanamide (9B)
Compound 9B prepares with the method for compound 7B, but partly replaces 3-(3,4-methylenedioxyphenyl base)-1-propylene with 4-phenyl-butylene at C, obtains compound 9B: mass spectrum (MH+1)=396.32.
Figure A0180544200772
N-(2, the 6-3,5-dimethylphenyl)-2-{4-[2-hydroxyl-3-(2-p-methoxy-phenyl) propyl group] piperazinyl } ethanamide (10B)
Compound 10B obtains compound 10B but partly use 3-(2-p-methoxy-phenyl)-1-propylene to replace 3-(3, the 4-methylenedioxyphenyl)-1-propylene at C: mass spectrum (MH+1)=412.35 with the method preparation of compound 7B.
N-(2, the 6-3,5-dimethylphenyl)-2-{4-[2-hydroxyl-3-(4-p-methoxy-phenyl) propyl group] piperazinyl } ethanamide (11B)
Compound 11B obtains compound 11B but partly use 3-(4-p-methoxy-phenyl)-1-propylene to replace 3-(3, the 4-methylenedioxyphenyl)-1-propylene at C: mass spectrum (MH+1)=412.35 with the method preparation of compound 7B.
Figure A0180544200781
N-(2, the 6-3,5-dimethylphenyl)-2-{4-[2-hydroxyl-3-phenyl propyl] piperazinyl } ethanamide (12B)
Compound 12B obtains compound 12B but partly replace 3-(3, the 4-methylenedioxyphenyl)-1-propylene with 3-phenyl-1-propylene at C: mass spectrum (MH+1)=382 with the method preparation of compound 7B.
Figure A0180544200782
N-(2, the 6-3,5-dimethylphenyl)-2-[4-(2-hydroxyl-3-naphthyl propyl group] piperazinyl } ethanamide (13B)
Compound 13B obtains compound 13 but partly use 3-(1-naphthyl)-1-propylene to replace 3-(3, the 4-methylenedioxyphenyl)-1-propylene at C: mass spectrum (MH+1)=432.55 with the method preparation of compound 7B.
Embodiment 5
The A part
Intermediate (14B): in anhydrous diethyl ether (10mL) solution of 4-methoxy-benzyl chlorine (2mmol), add allyl group bromination magnesium (4M1,1M THF solution) and with reaction mixture stirring at room 16 hours.Add saturated ammonium chloride solution (91mL) and separate ether layer, wash with water and drying.Alkali presses the evaporation ether to obtain oily matter alkene 14B.Do not need purifying to be used for next step reaction.
The B part
Intermediate (15B): in 1 hour, in the dichloromethane solution (2mmol) of ice-cooled 15B, drip the 20mL dichloromethane solution of 3-chloroperoxybenzoic acid (4mmol).With reaction mixture stirring at room 12 hours.Reaction mixture is removed by filter any solid and vacuum concentration.In resistates, add ether (200mL), with saturated sodium bicarbonate (3 * 100mL) washings.The organic layer dried over mgso, vacuum concentration.(2: 1 hexanes: ethyl acetate) purifying resistates obtains 15B with Prep.TLC.
The C part
N-(2, the 6-3,5-dimethylphenyl)-2-{4-[4-(4-p-methoxy-phenyl)-2-hydroxybutyl] piperazinyl } ethanamide (16B)
At compound 5B (0.4g, the 10mL ethanolic soln of adding compound 15B (2.14mmol) in ethanol 1.64mmol) (100mL) solution.With reaction mixture refluxed 24 hours.With the mixture vacuum concentration, (10: 1 methylene dichloride: purifying resistates methyl alcohol) obtains compound 16B with Prep.TLC.(M+1)＝426.3。
Figure A0180544200791
2-{4-[4-(2, the 6-3,5-dimethylphenyl)-2-hydroxybutyl] piperazinyl }-N-(2, the 6-3,5-dimethylphenyl) ethanamide (17B)
Compound 17B according to compound 16B similar methods preparation, but with 2,6-difluorobenzyl chloro replaces 4-methoxy-benzyl chlorine.(M+1)＝432.2。
N-(2, the 6-3,5-dimethylphenyl)-2-{4-[4-(2-chloro-phenyl-)-2-hydroxybutyl] piperazinyl } ethanamide (18B)
Compound 18B according to compound 16B similar methods preparation, but with 2-chlorobenzyl chloride replacement 4-methoxy-benzyl chlorine.(M+1)＝430.2。
2-(4-{4-[4-(tertiary butyl) phenyl]-the 2-hydroxybutyl } piperazinyl)-N-(2, the 6-3,5-dimethylphenyl) ethanamide (19B)
Compound 19B according to compound 16B similar methods preparation, but with 4-tertiary butyl benzyl chloride replacement 4-methoxy-benzyl chlorine.(M+1)＝452.3。
Figure A0180544200811
N-(2, the 6-3,5-dimethylphenyl)-2-{4-[4-(2-fluorophenyl)-2-hydroxybutyl] piperazinyl } ethanamide (20B)
Compound 20B according to compound 16B similar methods preparation, but with 2-fluorobenzyl chloride replacement 4-methoxy-benzyl chlorine.(M+1)＝414.2。
N-(2, the 6-3,5-dimethylphenyl)-2-(4-{2-hydroxyl-4-[4-(trifluoromethyl) phenyl] butyl } piperazinyl) ethanamide (21B)
Compound 21B according to compound 16B similar methods preparation, but with 4-trifluoromethyl benzyl chloride replacement 4-methoxy-benzyl chlorine.(M+1)＝464.2。
2-[4-(3-(2H-benzo [d] 1,3-dioxole-5-yl)-2-hydroxypropyl) piperazinyl]-N-(2, the 6-3,5-dimethylphenyl)-2-methyl propanamide (22B)
The similar method preparation of this compound with compound 7B, but partly replace chloro-acetyl chloride with 2-chloro-2-methyl-prop acyl chlorides at A.(M+1)＝454.54。
Figure A0180544200821
N-(2, the 6-3,5-dimethylphenyl)-2-[4-(2-hydroxyl-3-phenyl propyl) piperazinyl]-2-methyl propanamide (23B)
The similar method preparation of this compound with compound 7B, but partly replace chloro-acetyl chloride with 2-chloro-2-methyl-prop acyl chlorides at A, replace 8B with allyl benzene.(M+1)＝410.34。
Figure A0180544200822
N-(2, the 6-3,5-dimethylphenyl)-2-{4-[2-hydroxyl-3-(3,4, the 5-trimethylphenyl) propyl group] piperazinyl }-2-methyl propanamide (24B)
The similar method preparation of this compound with compound 7B, but partly replace chloro-acetyl chloride and 3,4 with 2-chloro-2-methyl-prop acyl chlorides at A, 5-trimethoxy alkylbenzene replaces 8B.(M+1)＝472.54。
N-(2, the 6-3,5-dimethylphenyl)-2-[4-(2-hydroxyl-5-phenylpentyl) piperazinyl] ethanamide (25B)
The similar method preparation of this compound with compound 16B, but partly replace-methoxy-benzyl chlorine with the styroyl chloro at A.(M+1)＝410.4。
N-(2, the 6-3,5-dimethylphenyl)-2-{4-[5-(2-fluorophenyl)-amyl group] piperazinyl } ethanamide (26B)
The similar method preparation of this compound with compound 16B, but partly replace 4-methoxy-benzyl chlorine with 2-fluorobenzene ethyl chloro at A.(M+1)＝428.1。
Figure A0180544200832
N-(2, the 6-3,5-dimethylphenyl)-2-{4-[5-(2-chloro-phenyl-)-amyl group] piperazinyl } ethanamide (27B)
The similar method preparation of this compound with compound 16B, but partly replace 4-methoxy-benzyl chlorine with 2-chlorobenzene ethyl chloro at A.(M+1)＝444.3。
Embodiment 6
N-(2, the 6-3,5-dimethylphenyl)-2-[4-(2-hydroxyl-3-indane-2-base oxygen propyl group) piperazinyl ethanamide (7C)
The A part
Synthesizing of N-(2, the 6-3,5-dimethylphenyl)-2-chlor(o)acetamide (3C)
2, (9.8g 81.2mmol) is dissolved in ether (100mL) and the saturated sodium bicarbonate (100mL) the 6-xylidine, and reaction mixture is cooled off in ice/water-bath.With in this cooling solution, dripped in 2 hours chloro-acetyl chloride 2C (9.17g, 81.2mmol).Reaction mixture is heated to room temperature, kept 14 hours.Mixture with the dilution of 100mL ether and with the organic layer dried over mgso, is filtered and concentratedly obtains compound 3C, be white solid.
The B part
Synthesizing of N-(2, the 6-3,5-dimethylphenyl)-2-piperazinyl ethanamide (5C)
The 100mL of compound 3C ethanolic soln (5g, add in 25.2mmol) compound 4C (2.1g, 25.0mmol) and N, the N-diisopropylethylamine (3.2g, 25.2mmol).With reaction mixture refluxed 24 hours.(10: 1, DCM: MeOH) purifying resistates obtained compound 5C with the reaction mixture vacuum concentration and with column chromatography.
The C part
Synthesizing of 2-(oxyethane-2-ylmethoxy) propane (6C)
(0.18g drips 2-propyl alcohol (0.5g, DMF 3.73mmol) (2mL) solution in DMF 4.5mmol) (10mL) solution at the 60%NaH that is cooled to 0 degree.Stir and drip epoxy bromopropane (1.11g, DMF 8.18mmol) (1ml) solution after 30 minutes.Reactant was heated to stirring at room 48 hours.Also (30: 1, DCM: MeOH) purifying resistates obtained compound 6C to solvent removed in vacuo with Prep.TLC.
The D part
N-(2, the 6-3,5-dimethylphenyl)-2-[4-(2-hydroxyl-3-indane-2-base oxygen propyl group) piperazinyl] ethanamide (7C) synthetic
6C (0.43g, add in ethanol 2.3mmol) (4ml) solution 5C (0.405g, 1.64mmol).This vlil was stirred 24 hours.(10: 1, DCM: MeOH) purifying obtained 7C with solution for vacuum concentration and with Prep.TLC after finishing.Mass spectrum (M+1)=438.36.
Figure A0180544200841
2-(2-[4-(3-isopropoxy-2-hydroxypropyl) piperazinyl]-N-(2, the 6-3,5-dimethylphenyl) ethanamide (10C)
Compound 10C similar method preparation with compound 7 C, but partly replace 2-(oxyethane-2-ylmethoxy) indane to obtain 10C with the Racemic glycidol isopropyl ether that is purchased at D: mass spectrum (M+1)=364.37.
Figure A0180544200851
N-(2, the 6-3,5-dimethylphenyl)-2-{4-[2-hydroxyl-3-(phenyl methoxyl group) propyl group] piperazinyl } ethanamide (11C)
Compound 11C similar method preparation with compound 7C, but partly replace 2-(oxyethane-2-ylmethoxy) indane to obtain 11C with the benzyl glycidyl ether that is purchased at D: mass spectrum (M+1)=412.36.
2-(2-[4-(3-cyclopentyloxy-2-hydroxypropyl) piperazinyl]-N-(2, the 6-3,5-dimethylphenyl) ethanamide (12C)
Compound 12C similar method preparation with compound 7C, but partly replace the 2-dihydro-indene alcohol to obtain 12C:MS (MH+1)=390 with the cyclopentanol that is purchased at C.
2-(2-[4-(3-cyclohexyloxy-2-hydroxypropyl) piperazinyl]-N-(2, the 6-3,5-dimethylphenyl) ethanamide (13C)
Compound 13C similar method preparation with compound 7C, but partly replace the 2-dihydro-indene alcohol to obtain 13C:MS (MH+1)=404 with the hexalin that is purchased at C.
2-[4-(3-{[4-(tertiary butyl) phenyl] methoxyl group }-the 2-hydroxypropyl) piperazinyl]-N-(2, the 6-3,5-dimethylphenyl) ethanamide (14C):
Compound 14C similar method preparation with compound 7C, but partly replace the 2-propyl alcohol to obtain 13C:MS (M+1)=468.44 with the 4-tertiary butyl benzyl alcohol that is purchased at C.
N-(2, the 6-3,5-dimethylphenyl)-2-(4-{3-[(2-fluorophenyl) methoxyl group]-the 2-hydroxypropyl } piperazinyl) ethanamide (15C):
Compound 15C similar method preparation with compound 7C, but partly replace 2-propyl alcohol: MS (M+1)=430.39 with the 2-luorobenzyl alcohol that is purchased at C.
2-(4-{3-[(2,4-difluorophenyl) methoxyl group]-the 2-hydroxypropyl } piperazinyl)-N-(2, the 6-3,5-dimethylphenyl) ethanamide (16C):
Compound 16C uses and the similar methods preparation of compound 7, but C partly be purchased 2,4-difluorobenzyl alcohol replaces 2-propyl alcohol: MS (M+1)=448.38.
N-(2, the 6-3,5-dimethylphenyl)-2-[4-(2-hydroxyl-3-{[4-(trifluoromethyl) phenyl] methoxyl group } propyl group) piperazinyl] ethanamide (17C):
Compound 17C similar method preparation with compound 7C, but partly replace 2-propyl alcohol: MS (M+1)=480.37 with the 4-trifluoromethyl that is purchased-benzyl alcohol at C.
Figure A0180544200872
N-(2, the 6-3,5-dimethylphenyl)-2-(4-{2-hydroxyl-3-[(2-p-methoxy-phenyl) methoxyl group] propyl group } piperazinyl) ethanamide (18C):
Compound 18C similar method preparation with compound 7C, but partly replace 2-propyl alcohol: MS (M+1)=442.41 with the 2-methoxyl group that is purchased-benzyl alcohol at C.
Figure A0180544200873
2-(4-{3-[(2,4-p-methoxy-phenyl) methoxyl group]-the 2-hydroxypropyl } piperazinyl)-N-(2, the 6-3,5-dimethylphenyl) ethanamide (19C):
Compound 19C uses and the preparation of the similar method of compound 7C, but C partly be purchased 2,4-dimethoxy-benzyl alcohol replaces 2-propyl alcohol: MS (M+1)=472.42.
Figure A0180544200881
N-(2, the 6-3,5-dimethylphenyl)-2-(4-{2-hydroxyl-3-[(4-p-methoxy-phenyl) methoxyl group] propyl group } piperazinyl) ethanamide (20C):
Compound 20C similar method preparation with compound 7C, but partly replace 2-propyl alcohol: MS (M+1)=442.42 with the 4-methoxyl group that is purchased-benzyl alcohol at C.
N-(2, the 6-3,5-dimethylphenyl)-2-(4-{3-[(4-fluorophenyl) methoxyl group]-the 2-hydroxypropyl } piperazinyl) ethanamide (21C):
Compound 21C similar method preparation with compound 7C, but partly replace 2-propyl alcohol: MS (M+1)=430.40 with the 4-fluoro-benzyl alcohol that is purchased at C.
N-(2, the 6-3,5-dimethylphenyl)-2-(4-{2-hydroxyl-3-[(4-aminomethyl phenyl) methoxyl group] propyl group } piperazinyl) ethanamide (22C):
Compound 22C similar method preparation with compound 7C, but partly replace 2-propyl alcohol: MS (M+1)=426.41 with the 4-methyl that is purchased-benzyl alcohol at C.
Figure A0180544200891
N-(2, the 6-3,5-dimethylphenyl)-2-(4-{2-hydroxyl-3-[(4-phenyl) methoxyl group] propyl group } piperazinyl) ethanamide (23C):
Compound 23C similar method preparation with compound 7C, but partly replace 2-propyl alcohol: MS (M+1)=488.42 with the 4-phenyl that is purchased-benzyl alcohol at C.
Figure A0180544200892
N-(2, the 6-3,5-dimethylphenyl)-2-(4-{3-[(4-butyl phenyl) methoxyl group]-the 2-hydroxypropyl } piperazinyl) ethanamide (24C):
Compound 24C similar method preparation with compound 7C, but partly replace 2-propyl alcohol: MS (M+1)=468.45 with the 4-normal-butyl that is purchased-benzyl alcohol at C.
N-(2, the 6-3,5-dimethylphenyl)-2-{4-[2-hydroxyl-3-(2-naphthyl methoxyl group) propyl group] piperazinyl } ethanamide (25C):
Compound 25C similar method preparation with compound 7C, but partly replace 2-propyl alcohol: MS (M+1)=462.41 with the 2-naphthyl carbinol that is purchased at C.
Figure A0180544200901
N-(2, the 6-3,5-dimethylphenyl)-2-{4-[3-(cyclohexyl methoxyl group)-2-hydroxypropyl] piperazinyl } ethanamide (26C):
Compound 26C similar method preparation with compound 7C, but partly replace 2-propyl alcohol: MS (M+1)=418.55 with the hexahydrobenzyl alcohol that is purchased at C.
Figure A0180544200902
N-(2, the 6-3,5-dimethylphenyl)-2-(4-{3-[(4-fluorophenyl) methoxyl group]-the 2-hydroxypropyl }-3,3-lupetazin base) ethanamide (27C):
Compound 27C similar method preparation with compound 7C, but partly replace the 2-propyl alcohol and partly use 2 at B with the 4-luorobenzyl alcohol that is purchased at C, the 2-lupetazin replaces compound 4.MS(M+1)＝458.5。
Embodiment 7
The plastosome test
Separate the rat heart plastosome with Nedergard and Cannon (Methods in Enzymol, 55,3,1979) etc.
Palmitoyl coenzyme A oxidation---palmitoyl coenzyme A oxidation is to contain in the following reagent for 100 milliliters at cumulative volume to carry out: 110mM KCl, the 33mM Tris damping fluid of pH8,2mM Kpi, 2mM MgCl 2, 0.1mM EDTA, 14.7mM degreasing BSA, 0.5mM oxysuccinic acid, 13mM carnitine, 1mM ADP, 52mg mitochondrial protein and 16mM 1-C14 palmitoyl coenzyme A (the active 60mCi/mmol of Sp.; 20mCi/ml, each is tested with 5 milliliters).The compounds of this invention is added among the DMSO with following concentration: 100mM, 30mM, and 3mM.In each test, use DMSO to compare.At 30 ℃ after 15 minutes,, and 70 milliliters of supernatant liquors are added on the anti-phase silicic acid posts of activatory (about 0.5ml silicic acid) enzyme reaction thing centrifugal (20,000g, 1 minute).With this post of 2ml water elution, and with the 0.5ml elutriant as the C of scintillation counting to catch 14Bicarbonate ion is measured C 14Amount.
Table 1 palmitoyl carnitine is as the inhibition of substrate to the plastosome Fatty Acid Oxidation
---the contrast % under 3 kinds of concentration
Compound # ?100μM 30μM 3μM
Ranolazine ?75％ 90％ --
14 ?-- -- --
7 ?85％ 98％ 107％
15 ?78％ 97％ 103％
17 ?89％ 98％ 100％
16 ?100％ 96％ --
18 ?17％
19 ?-
22 ?25％
23 ?-
9B ?84％ 84％ --
10B ?-- -- --
7B ?-- -- --
11B ?83％ 92％ --
12B ?42％ 95％
13B ?-- -- ?--
16B ?37％
17B ?78％
18B ?78％
19B ?35％
20B ?56％
21B ?56％
23B ?70％
24B ?72％
10C ?100％ 97％ --
7C ?68％ -- --
11C ?79％ -- --
12C ?41％ -- --
13C ?30％ -- --
14C ?21％ - -
15C ?100％ - -
16C ?97％ - -
17C ?35％ - -
18C ?96％ - -
19C ?97％ - -
20C ?100％ - -
21C ?87％ - -
22C ?45％ - -
23C ?12％ - -
24C ?15％ - -
25C ?38％ - -
26C ?70％ - -
27C ?73％ - -
Embodiment 8
The oxidation of palmitoyl carnitine
The oxidation of palmitoyl carnitine contains in the following reagent for 100 milliliters at cumulative volume to be carried out: 110mM KCl, the 33Mm Tris damping fluid of Ph8,2mM Kpi, 2mM MgCl 2, 0.1mMEDTA, 0.1mg/ml degreasing BSA, 0.5mM oxysuccinic acid, 3mM ADP, 52 milligrams of mitochondrial proteins and 43mM 1-C14 palmitoyl carnitine (the active 60mCi/mmol of Sp.; 20mCi/ml, each is tested with 5 milliliters).The compounds of this invention is added in the DMSO solution with following concentration: 100mM, 30mM, and 3mM.In each test, use DMSO to compare.At 30 ℃, after 15 minutes, with the centrifugation of enzyme reaction thing (20,000g, 1 minute), and with on 70 milliliters of anti-phase silicic acid posts of supernatant liquors adding activatory (about 0.5ml silicic acid).With this post of 2ml water elution, and make the C of scintillation counting to catch with the 0.5ml elutriant 14Bicarbonate ion is measured C 14Amount.Data are expressed as the % activity of contrast.
Table 2 palmitoyl carnitine is as the inhibition of substrate to the plastosome Fatty Acid Oxidation
---the contrast % under 3 kinds of concentration
Compound # 100μM ?30μM ?3μM
Ranolazine 63％ ?98％ ?--
14 -- ?-- ?--
7 95％ ?102％ ?109％
15 82％ ?98％ ?106％
17 80％ ?88％ ?103％
16 64％ ?-- ?--
9B -- ?-- ?--
10B -- ?-- ?--
7B -- ?-- ?--
11B -- ?-- ?--
12B 56％ ?-- ?--
13B -- ?-- ?--
10C 80％ ?-- ?--
7C -- ?-- ?--
11C -- ?-- ?--
12C -- ?-- ?--
13C -- ?-- ?--
Embodiment 9
Metabolic stability: in order to measure the metabolic stability of The compounds of this invention, personnel selection liver S-9 microsomal fraction heat insulating culture.At 37 ℃, after 30 minutes, use the amount of the parent drug of LC mass spectroscopy reservation.The response factor of each compound is by setting up typical curve and marking in the use during sample analysis and measure.The mean value of the ranolazine percentage ratio that keeps at 30 minutes time point in 5 tests is 57%.The compounds of this invention is measured in following scheme and is obtained the metabolic stability factor with the parent percentage ratio that keeps divided by the mean value (57%) of the ranolazine that keeps.The stability number of compound is greater than 1.2, and is more stable than ranolazine in liver S-9 measures.The stability number of compound has identical stability with ranolazine in liver S-9 measures between 1.2h and 0.8.The stability number of compound is less than 0.8, in liver S-9 measures than the poor stability of ranolazine.
The purpose of this test is in order, after 30 minutes the reservation percentage ratio of The compounds of this invention and the reservation percentage ratio of ranolazine to be compared in people liver S9 part heat insulating culture.
Reagent:
Use following reagent: potassiumphosphate, 0.5M pH7.4 (insulation damping fluid) remains on room temperature; Remain on 4 ℃ 0.05M MgCl 2β-Triphosphopyridine nucleotide, reduced ester, tetra-na salt, reduction form (NADPH), use the same day from solution water of the 0.02M of Sigma Lot#79H7044 preparation (～16.6mg/mL).1mM ranolazine or compound 43,45,47,52,70,74,76,78 and 80 further dilute in ACN and obtain the solution of 100 μ M in 10% ACN; The people S9 raw material that obtains from Gentest: 20mg/mL.
Method:
The mixture of heat insulating culture is prepared as follows:
Table 3
Composition The volume of every 0.25mL incubation mixture Ultimate density
10 μ M CMT compounds 25μL ?10μM
?MgCl2 25μL ?0.005M
?NADPH 25μL ?0.002M
?S9 25μL ?2mg/mL
The insulation damping fluid 25μL ?0.05M
Water 125μL ?----
*Use 1% organic solvent (acetonitrile) in the incubation mixture.Usually, by being pre-mixed 0.75mLMgCl 2, 0.75mL is incubated damping fluid, and 0.75mLNADPH, 3.75mL water once prepare 30 cultures.Inhale then and move 200 μ L/ insulation liquid, add 25 μ L test compounds, mix, and begin reaction by adding S-9.
All the components is mixed with the insulation damping fluid, and inhale again and move 200 μ L/ pipe+25 μ L test compounds and 25 μ LS-9.
,, remove the aliquots containig of 50 μ l incubation mixtures and add 100 μ L and contain interior 9: 1 acetonitriles of target: methyl alcohol after 5 minutes 37 ℃ of pre-incubations at 0 and 30 minute stirring reaction liquid.
Mixture is centrifugal and with (0.1% aqueous formic acid) dilution in the 1mL solvent C of the aliquots containig of 100 μ L supernatant liquors.Change compound and interior target ratio and time 0 and 30 minutes by LC/MS (injecting 10 μ L) analytic sample.
Analyze and data computation:
With interior mark and ODS-C18 post flow velocity with 0.25ml/ minute, by LC/MS to be used to begin compound and effectively the sample of metabolite analyze.Below the ranolazine of aforesaid method gained and the relatively stable sex factor of The compounds of this invention comparison are listed in the table 4.If compound is more stable than ranolazine in liver S9 measures, then stability factor is greater than 1.0.If compound does not have ranolazine stable, then stability factor is less than 1.0.
Table 4
Compound # Liver S9 stability factor
Ranolazine ?1.0
?5 ?0.45
?7 ?1.51
?15 ?1.20
?16 ?0.15
?17 ?0.45
?9B ?1.18
?10B ?1.03
?7B ?1.46
?11B ?1.33
?12B ?1.38
?13B ?0.10
?16B ?0.99
?17B ?0.71
?18B ?0.68
?19B ?-
?20B ?-
?21B ?-
?22B ?1.49
?23B ?0.5
?24B ?1.05
?25B ?-
?26B ?-
?27B ?-
?21C ?--
?22C ?0.61
?23C ?0.05
?24C ?0.02
?25C ?0.01
?26C ?--
?27C ?--

Claims (95)

1. the substituted piperazine like compound that has following structural: Wherein X is selected from following groups:
Figure A0180544200022
With
Figure A0180544200023
M=1 or 2 or 3 wherein;
R 1, R 2, R 3, R 4And R 5Be selected from independently of one another: hydrogen, halogen, NO 2, CF 3, CN, OR 23, SR 23, N (R 23) 2, S (O) R 22, SO 2R 22, SO 2N (R 23) 2, NR 23CO 2R 22, NR 23CON (R 23) 2, COR 23, CO 2R 23, CON (R 23) 2, NR 23SO 2R 22, C 1-15Alkyl, C 2-15Thiazolinyl, C 2-15Alkynyl, heterocyclic radical, aryl, and heteroaryl, wherein alkyl and aryl substituent can be chosen wantonly by one and be selected from following substituting group replacement: halogen, NO 2, CF 3, CN, OR 23, SR 23, N (R 23) 2, S (O) R 22And SO 2R 22, R wherein 2And R 3Can be joined together to form have 3 to 4 carbon atoms condense ring system and R 4And R 5Can be joined together to form-CH=CH-CH=CH-;
R 6, R 7And R 8Be selected from hydrogen and C independently of one another 1-15Alkyl;
R 9, R 10, R 11, R 12, R 13, R 14, R 15And R 16Be selected from hydrogen independently of one another, CO 2R 23, CON (R 23) 2, C 1-4Alkyl, and aryl, wherein alkyl and aryl substituent can be chosen wantonly by one and be selected from following substituting group replacement: halogen, CF 3, CN, OR 23, N (R 23) 2, CO 2R 23, CON (R 23) 2And aryl, wherein R 9And R 10Can form carbonyl or R together 11And R 12Can form carbonyl or R together 13And R 14Can form carbonyl or R together 15And R 16Can form carbonyl, wherein R together 11And R 13, R 9And R 15, R 9And R 11, R 11And R 15Or R 9And R 13Can be joined together to form bridged ring system with 1-4 carbon atom, and R wherein 9And R 10, R 11And R 12, R 13And R 14Or R 15And R 16Can be joined together to form the bridged ring system with 1-5 carbon atom, condition is to work as R 24Be phenyl and as X be The time, R 9, R 10, R 11, R 12, R 13, R 15And R 16Be not hydrogen entirely;
R 22Be selected from C 1-15Alkyl, aryl, and heteroaryl, wherein alkyl and aryl substituent can be chosen wantonly by 1 and be selected from halogen, alkyl, alkyl monosubstituted amino, dialkyl amido, alkyl amido, aryl amido, heteroaryl amido, CN, O-C 1-6Alkyl, CF 3And the substituting group of heteroaryl replaces;
R 23Be selected from H, C 1-15Alkyl, aryl, and heteroaryl, wherein alkyl and aryl substituent can be chosen wantonly by 1 and be selected from halogen, alkyl, alkyl monosubstituted amino, dialkyl amido, alkyl, CN, O-C 1-6Alkyl and CF 3Substituting group replace; And
R 24Be selected from alkyl, cycloalkyl and condensed benzyl ring alkyl, wherein tie point is on cycloalkyl, and alkyl wherein, cycloalkyl and condensed benzyl ring alkyl can be chosen wantonly and be selected from following substituting group by 1 to 3 and replace: halogen, CF 3, CN, OR 20, SR 20, S (O) R 22, SO 2R 22, SO 2N (R 20) 2, NR 20CO 2R 22, C 1-2Alkyl, and aryl, this aryl substituent can be chosen wantonly by 1 to 3 and be selected from halogen, phenyl, CF 3, CN, OR 20, and C 1-6The substituting group of alkyl replaces, and
R wherein 17, R 18, R 19, R 20, and R 21Be selected from hydrogen independently of one another, halogen, NO 2, CF 3, CN, OR 23, SR 23, N (R 23) 2, S (O) R 22, SO 2R 22, SO 2N (R 23) 2, NR 23CO 2R 22, NR 23CON (R 23) 2, COR 23, CO 2R 23, CON (R 23) 2, NR 23SO 2R 22, C 1-15Alkyl, C 2-15Thiazolinyl, C 2-15Alkynyl, heterocyclic radical, aryl, and heteroaryl, wherein alkyl and aryl substituent can be chosen wantonly by one and be selected from following substituting group replacement: halogen, NO 2, CF 3, CN, OR 23, SR 23, N (R 23) 2, S (O) R 22And SO 2R 22
2. the substituted piperazine like compound that has the claim of following structural:
Figure A0180544200041
M=1 or 2 or 3 wherein;
R 1, R 2, R 3, R 4And R 5Be selected from independently of one another: hydrogen, halogen, NO 2, CF 3, CN, OR 23, SR 23, N (R 23) 2, S (O) R 22, SO 2R 22, SO 2N (R 23) 2, NR 23CO 2R 22, NR 23CON (R 23) 2, COR 23, CO 2R 23, CON (R 23) 2, NR 23SO 2R 22, C 1-15Alkyl, C 2-15Thiazolinyl, C 2-15Alkynyl, heterocyclic radical, aryl, and heteroaryl, wherein alkyl and aryl substituent can be chosen wantonly by one and be selected from following substituting group replacement: halogen, NO 2, CF 3, CN, OR 23, SR 23, N (R 23) 2, S (O) R 22And SO 2R 22, R wherein 2And R 3Can be joined together to form the ring system that condenses with 3 to 4 carbon atoms, and R wherein 4And R 5Can be joined together to form-CH=CH-CH=CH-;
R 6, R 7And R 8Be selected from hydrogen and C independently of one another 1-15Alkyl;
R 9, R 10, R 11, R 12, R 13, R 14, R 15And R 16Be selected from hydrogen independently of one another, CO 2R 23, CON (R 23) 2, C 1-4Alkyl, and aryl, wherein alkyl and aryl substituent can be chosen wantonly by one and be selected from following substituting group replacement: halogen, CF 3, CN, OR 23, N (R 23) 2, CO 2R 23, CON (R 23) 2And aryl, wherein R 9And R 10Can form carbonyl or R together 11And R 12Can form carbonyl or R together 13And R 14Can form carbonyl or R together 15And R 16Can form carbonyl, wherein R together 11And R 13, R 9And R 15, R 9And R 11, R 11And R 15Or R 9And R 13Can be joined together to form bridged ring system with 1-4 carbon atom, and R wherein 9And R 10, R 11And R 12, R 13And R 14Or R 15And R 16Can be joined together to form the bridged ring system with 1-5 carbon atom, condition is R 9, R 10, R 11, R 12, R 13, R 14, R 15And R 16Be not hydrogen entirely;
R 17, R 18, R 19, R 20, and R 21Be selected from hydrogen independently of one another, halogen, NO 2, CF 3, CN, OR 23, SR 23, N (R 23) 2, S (O) R 22, SO 2R 22, SO 2N (R 23) 2, NR 23CO 2R 22, NR 23CON (R 23) 2, COR 23, CO 2R 23, CON (R 23) 2, NR 23SO 2R 22, C 1-15Alkyl, C 2-15Thiazolinyl, C 2-15Alkynyl, heterocyclic radical, aryl, and heteroaryl, wherein alkyl and aryl substituent can be chosen wantonly by one and be selected from following substituting group replacement: halogen, NO 2, CF 3, CN, OR 23, SR 23, N (R 23) 2, S (O) R 22And SO 2R 22
R 22Be selected from C 1-15Alkyl, aryl, and heteroaryl, wherein alkyl and aryl substituent can be chosen wantonly by 1 and be selected from halogen, alkyl, alkyl monosubstituted amino, dialkyl amido, alkyl amido, aryl amido, heteroaryl amido, CN, O-C 1-6Alkyl, CF 3And the substituting group of heteroaryl replaces; And
R 23Be selected from H, C 1-15Alkyl, aryl, and heteroaryl, wherein alkyl and aryl substituent can be chosen wantonly by 1 and be selected from halogen, alkyl, alkyl monosubstituted amino, dialkyl amido, alkyl, CN ,-O-C 1-6Alkyl and CF 3Substituting group replace.
3. the compound of claim 2, wherein R 1, R 2, R 3, R 4And R 5Be selected from independently of one another: hydrogen, halogen, CF 3, CN, OR 23, SR 23, N (R 23) 2, S (O) R 22, SO 2R 22, SO 2N (R 23) 2, NR 23CO 2R 22, NR 23CON (R 23) 2, COR 23, CO 2R 23, CON (R 23) 2, NR 23SO 2R 22, C 1-8Alkyl, C 2-8Thiazolinyl, C 2-8Alkynyl, heterocyclic radical, aryl, and heteroaryl, wherein alkyl and aryl substituent can be chosen wantonly by one and be selected from following substituting group replacement: halogen, CF 3, CN, OR 23, SR 23And N (R 23) 2, R wherein 2And R 3Can be joined together to form the ring system that condenses with 3 to 4 carbon atoms, and R wherein 4And R 5Can be joined together to form-CH=CH-CH=CH-;
R 6, R 7And R 8Be selected from hydrogen and C independently of one another 1-8Alkyl;
R 9, R 10, R 11, R 12, R 13, R 14, R 15And R 16Be selected from hydrogen independently of one another, C 1-4Alkyl, and aryl, wherein alkyl and aryl substituent can be chosen wantonly by one and be selected from following substituting group replacement: halogen, CF 3, CN, OR 23, N (R 23) 2, CO 2R 23, CON (R 23) 2And aryl, wherein R 9And R 10Can form carbonyl or R together 11And R 12Can form carbonyl or R together 13And R 14Can form carbonyl or R together 15And R 16Can form carbonyl, wherein R together 11And R 13, R 9And R 15, R 9And R 11, R 11And R 15Or R 9And R 13Can be joined together to form the bridged ring system that comprises 1 to 4 carbon atom;
R 17, R 18, R 19, R 20, and R 21Be selected from hydrogen independently of one another, halogen, NO 2, CF 3, CN, OR 23, SR 23, N (R 23) 2, S (O) R 22, SO 2R 22, SO 2N (R 23) 2, NR 23CO 2R 22, NR 23CON (R 23) 2, COR 23, CO 2R 23, CON (R 23) 2, NR 23SO 2R 22, C 1-15Alkyl, C 2-15Thiazolinyl, C 2-15Alkynyl, heterocyclic radical, aryl, and heteroaryl, wherein alkyl and aryl substituent can be chosen wantonly by one and be selected from following substituting group replacement: halogen, NO 2, CF 3, CN, OR 23, SR 23, N (R 23) 2, S (O) R 22And SO 2R 22
4. the compound of claim 2, wherein R 1, R 2, R 3, R 4And R 5Be selected from independently of one another: hydrogen, halogen, CF 3, CN, OR 23, SR 23, N (R 23) 2, SO 2N (R 23) 2, COR 23, CO 2R 23, CON (R 23) 2, C 1-6Alkyl, C 2-6Thiazolinyl, heterocyclic radical, and heteroaryl, wherein alkyl substituent can be chosen wantonly by one and be selected from CF 3And OR 23Substituting group replace R wherein 2And R 3Can be joined together to form the ring system that condenses with 3 to 4 carbon atoms, and R wherein 4And R 5Can be joined together to form-CH=CH-CH=CH-;
R 6, R 7And R 8Be selected from hydrogen and C independently of one another 1-3Alkyl;
R 9, R 10, R 11, R 12, R 13, R 14, R 15And R 16Be selected from hydrogen independently of one another, C 1-4Alkyl, or aryl, wherein alkyl and aryl substituent can be chosen wantonly by one and be selected from following substituting group replacement: halogen, CF 3, CN, OR 23, N (R 23) 2, CO 2R 23, CON (R 23) 2And aryl, wherein R 9And R 10Can form carbonyl or R together 11And R 12Can form carbonyl or R together 13And R 14Can form carbonyl or R together 15And R 16Can form carbonyl, wherein R together 11And R 13, R 9And R 15, R 9And R 11, R 11And R 15Or R 9And R 13Can be joined together to form the ring that comprises 1 to 4 carbon atom;
R 17, R 18, R 19, R 20, and R 21Be selected from hydrogen independently of one another, halogen, CF 3, CN, OR 23, COR 23, CO 2R 23, CON (R 23) 2, C 1-15Alkyl, C 2-15Thiazolinyl, C 2-15Alkynyl, heterocyclic radical, aryl, and heteroaryl, wherein alkyl and aryl substituent can be chosen wantonly by one and be selected from following substituting group replacement: halogen, NO 2, CF 3, CN, OR 23, SR 23, N (R 23) 2, S (O) R 22And SO 2R 22
R 22Be selected from C 1-15Alkyl, aryl, and heteroaryl, wherein alkyl and aryl substituent can be chosen wantonly by 1 and be selected from halogen, alkyl, alkyl monosubstituted amino, dialkyl amido, alkyl amido, aryl amido, heteroaryl amido, CN, O-C 1-6Alkyl, CF 3And the substituting group of heteroaryl replaces; And
R 23Be selected from H, C 1-8Alkyl, aryl, and heteroaryl, wherein alkyl and aryl substituent can be chosen wantonly by 1 and be selected from halogen ,-O-C 1-3Alkyl and CF 3Substituting group replace.
5. the compound of claim 2, wherein R 1, R 2, R 3, R 4And R 5Be selected from independently of one another: hydrogen, halogen, CF 3, CN, OR 23, SR 23, N (R 23) 2, SO 2N (R 23) 2, COR 23, CO 2R 23, CON (R 23) 2, C 1-6Alkyl, C 2-6Thiazolinyl, heterocyclic radical, and heteroaryl, wherein alkyl substituent can be chosen wantonly by OR 23Replace, wherein R 2And R 3Can be joined together to form the ring system that condenses with 3 to 4 carbon atoms, and R wherein 4And R 5Can be joined together to form-CH=CH-CH=CH-;
R 6, R 7And R 8Be selected from hydrogen and methyl independently of one another;
R 9, R 10, R 11, R 12, R 13, R 14, R 15And R 16Be selected from hydrogen and C independently of one another 1-2Alkyl, wherein R 9And R 10Can form carbonyl or R together 11And R 12Can form carbonyl or R together 13And R 14Can form carbonyl or R together 15And R 16Can form carbonyl together;
R 17, R 18, R 19, R 20, and R 21Be selected from hydrogen independently of one another, halogen, CF 3, CN, OR 23, COR 23, CO 2R 23, CON (R 23) 2, C 1-8Alkyl, C 2-8Thiazolinyl, C 2-8Alkynyl, heterocyclic radical, aryl, and heteroaryl, wherein alkyl and aryl substituent can be chosen wantonly by one and be selected from following substituting group replacement: halogen, CF 3And OR 23
R 22Be selected from C 1-4Alkyl, aryl, and heteroaryl, wherein alkyl and aryl substituent can be chosen wantonly by 1 and be selected from halogen, alkyl, O-C 1-3Alkyl and CF 3Substituting group replaces; And
R 23Be selected from H, C 1-5Alkyl, aryl, and heteroaryl, wherein alkyl and aryl substituent can be chosen wantonly by 1 and be selected from halogen ,-OMe and CF 3Substituting group replace.
6. the compound of claim 5, wherein m=1 or 2.
7. the compound of claim 5, wherein R 1, R 2, R 3, R 4And R 5Be selected from independently of one another: hydrogen, halogen, CF 3, CN, OR 23, SR 23, N (R 23) 2, SO 2N (R 23) 2, COR 23, CO 2R 23, CON (R 23) 2, C 1-3Alkyl, C 2-6Thiazolinyl, heterocyclic radical, and heteroaryl, wherein alkyl substituent can be chosen wantonly by OR 23Replace, wherein R 2And R 3Can be joined together to form the ring system that condenses with 3 to 4 carbon atoms, and R wherein 4And R 5Can be joined together to form-CH=CH-CH=CH-;
R 6, R 7And R 8Be selected from hydrogen and methyl independently of one another;
R 9, R 10, R 11, R 12, R 13, R 14, R 15And R 16Be selected from hydrogen and C independently of one another 1-2Alkyl, wherein R 9And R 10Can form carbonyl or R together 11And R 12Can form carbonyl or R together 13And R 14Can form carbonyl or R together 15And R 16Can form carbonyl together;
R 17, R 18, R 19, R 20, and R 21Be selected from hydrogen independently of one another, halogen, CF 3, CN, OR 23, COR 23, CO 2R 23, CON (R 23) 2, C 1-8Alkyl;
R 22Be C 1-4Alkyl; With
R 23Be selected from H and C 1-5Alkyl.
8. the compound of claim 5, wherein R 1, R 2, R 3, R 4And R 5Be selected from independently of one another: hydrogen, halogen, CF 3, CN, OR 23, SR 23, N (R 23) 2, SO 2N (R 23) 2, COR 23, CO 2R 23, CON (R 23) 2, C 1-3Alkyl, C 2-6Thiazolinyl, heterocyclic radical, and heteroaryl, wherein alkyl substituent can be chosen wantonly by OR 23Replace, wherein R 2And R 3Can be joined together to form the ring system that condenses with 3 to 4 carbon atoms, and R wherein 4And R 5Can be joined together to form-CH=CH-CH=CH-;
R 6, R 7And R 8Be respectively hydrogen;
R 9, R 10, R 11, R 12, R 13, R 14, R 15And R 16Be selected from hydrogen and C independently of one another 1-2Alkyl, wherein R 9And R 10Can form carbonyl or R together 11And R 12Can form carbonyl or R together 13And R 14Can form carbonyl or R together 15And R 16Can form carbonyl together;
R 17, R 18, R 19, R 20, and R 21Be selected from hydrogen independently of one another, halogen, CF 3, CN, OR 23, COR 23, CO 2R 23, CON (R 23) 2And C 1-8Alkyl;
R 22Be C 1-2Alkyl; With
R 23Be selected from H and C 1-2Alkyl.
9. the compound of claim 5, wherein R 1, R 2, R 3, R 4And R 5Be selected from independently of one another: hydrogen, halogen, CF 3, CN, OR 23, SR 23, N (R 23) 2, SO 2N (R 23) 2, COR 23, CO 2R 23, CON (R 23) 2, C 1-3Alkyl, C 2-3Thiazolinyl, heterocyclic radical, and heteroaryl, wherein alkyl substituent can be chosen wantonly by OR 23Replace, wherein R 2And R 3Can be joined together to form the ring system that condenses with 3 to 4 carbon atoms, and R wherein 4And R 5Can be joined together to form-CH=CH-CH=CH-;
R 6, R 7And R 8Be respectively hydrogen;
R 9, R 10, R 11, R 12, R 13, R 14, R 15And R 16Be selected from hydrogen and methyl independently of one another, wherein R 9And R 10Can form carbonyl or R together 13And R 14Can form carbonyl together;
R 17, R 18, R 19, R 20, and R 21Be selected from hydrogen independently of one another, halogen, CF 3, CN, OR 23And C 1-2Alkyl;
R 22It is methyl; With
R 23Be selected from H and methyl.
10. the compound of claim 5, wherein R 18, R 19, R 20, and R 21Be respectively hydrogen, and R 17Be selected from halogen and OR 2
11. the compound of claim 10, wherein R 12Be (S)-methyl and R 9, R 10, R 11, R 13, R 14, R 15And R 16Dividing is hydrogen.
12. the compound of claim 10, wherein R 9And R 10Form carbonyl together, R 11, R 12, R 13, R 14, R 15And R 16Dividing is hydrogen.
13. the compound of claim 10, wherein R 9, R 10, R 11, R 12, R 15And R 16Dividing is hydrogen and R 13And R 14Form carbonyl together.
14. the compound that claim 3 to 13 is any, wherein m=1.
15. the compound of claim 10, wherein R 1, R 2, R 3, R 4And R 5Be selected from independently of one another: hydrogen, halogen, CF 3, CN, OR 23, SR 23, N (R 23) 2, SO 2N (R 23) 2, COR 23, CO 2R 23, CON (R 23) 2, C 1-3Alkyl, C 2-3Thiazolinyl, N-morpholinyl, and pyrryl, wherein alkyl substituent can be chosen wantonly by OH and replace, wherein R 2And R 3Can be joined together to form the ring system that condenses with 3 carbon atoms, and R wherein 4And R 5Can be joined together to form-CH=CH-CH=CH-.
16. the compound of claim 2, wherein m=1 or 2;
R 1, R 2, R 3, R 4And R 5Be selected from independently of one another: hydrogen, halogen, CF 3, OR 22, and C 1-2Alkyl, wherein R 22Be C 1-2Alkyl;
R 6, R 7And R 8Be selected from hydrogen and methyl independently of one another;
R 9, R 10, R 11, R 12, R 13, R 14, R 15And R 16Be selected from hydrogen and C independently of one another 1-4Alkyl, or R 9And R 10Can form carbonyl or R together 11And R 12Can form carbonyl or R together 13And R 14Can form carbonyl or R together 15And R 16Can form carbonyl together, condition is R 9, R 10, R 11, R 12, R 13, R 14, R 15And R 16Be not hydrogen simultaneously, and R wherein 11And R 13, R 9And R 15, R 9And R 11, R 11And R 15Or R 9And R 13Can be joined together to form the ring that comprises 1 to 4 carbon atom;
R 17, R 18, R 19, R 20, and R 21Be selected from hydrogen independently of one another, halogen, OR 23, C 1-4Alkyl, C 2-4Thiazolinyl, C 2-4Alkynyl, heterocyclic radical, aryl, and heteroaryl, wherein alkyl and aryl substituent can be chosen wantonly by one and be selected from following substituting group replacement: halogen, CF 3And OR 23R wherein 23Be C 1-2Alkyl.
17. the compound of claim 16, wherein R 1, R 2, R 3, R 4And R 5Be selected from hydrogen independently of one another, and methyl.
18. the compound of claim 16, wherein R 6, R 7And R 8Be respectively hydrogen.
19. the compound of claim 16, wherein R 9, R 10, R 11, R 12, R 13, R 14, R 15And R 16Be selected from hydrogen and C independently of one another 1-2Alkyl, or R 9And R 10Form carbonyl together, or R 15And R 16Can form carbonyl together, condition is R 9, R 10, R 11, R 12, R 13, R 14, R 15And R 16Be not hydrogen and R wherein simultaneously 11And R 13, R 9And R 15, R 9And R 11, R 11And R 15Or R 9And R 13Can be connected to form the ring that comprises 1 to 2 carbon atom.
20. the compound of claim 16, wherein R 9, R 10, R 11, R 12, R 13, R 14, R 15And R 16Be selected from hydrogen and C independently of one another 1-2Alkyl, or R 9And R 10Form carbonyl together, or R 11And R 12Can form carbonyl, R together 13Or R 14Can form carbonyl or R together 15And R 16Can form carbonyl together.
21. the compound of claim 16, wherein R 9And R 10Form carbonyl together, R 15And R 16Form carbonyl together, perhaps R 9And R 10Form carbonyl R simultaneously together 15And R 16Form carbonyl together.
22. the compound of claim 16, wherein R 17, R 18, R 19, R 20, and R 21Be selected from hydrogen independently of one another, halogen, C 1-4Alkyl and OR 22R wherein 22Be C 1-2Alkyl.
23. the compound of claim 2 wherein
m＝1；
R 1, R 2, R 3, R 4And R 5Be selected from hydrogen independently of one another, and methyl;
R 6, R 7And R 8Be respectively hydrogen;
R 9, R 10, R 11, R 12, R 13, R 14, R 15And R 16Be selected from hydrogen and C independently of one another 1-4Alkyl, or R 9And R 10Form carbonyl together, or R 11And R 12Form carbonyl together, or R 13And R 14Form carbonyl together, or R 15And R 16Can form carbonyl together, condition is R 9, R 10, R 11, R 12, R 13, R 14, R 15And R 16Be not hydrogen simultaneously, and R wherein 11And R 13, R 9And R 15, R 9And R 11, R 11And R 15Or R 9And R 11Can be connected to form the ring that comprises 1 to 4 carbon atom.
R 17, R 18, R 19, R 20, and R 21Be selected from hydrogen independently of one another, halogen, C 1-4Alkyl and OR 22With
R 22Be C 1-2Alkyl;
24. the compound of claim 23, wherein R 1And R 5Be respectively methyl and R 2, R 3, and R 4Be respectively hydrogen.
25. the compound of claim 23, wherein R 11, R 12, R 13, R 14, R 15And R 16Be respectively hydrogen and R 9And R 10Form carbonyl together.
26. the compound of claim 23, wherein R 9, R 10, R 11, R 12, R 15And R 16Be respectively hydrogen and R 13And R 14Form carbonyl together.
27. the compound of claim 23, wherein R 9, R 10, R 11, R 12, R 13, R 14, R 15And R 16Be respectively hydrogen and methyl.
28. the compound of claim 23, wherein R 9, R 12, R 13, R 14, R 15And R 16Be respectively hydrogen and R 10And R 11Form ring together with 1 to 4 carbon atom.
29. the compound of claim 23, wherein R 9, R 10, R 12, R 13, R 14And R 16Be respectively hydrogen and R 11And R 15Form ring together with 1 to 3 carbon atom.
30. the compound of claim 23, wherein R 18, R 19, and R 21Be respectively hydrogen and R 17And R 18Be respectively methyl.
31. the compound of claim 23, wherein R 17Be-OCH 3, and R 18, R 19, R 20And R 21Be respectively hydrogen.
32. the compound of claim 23, wherein R 17, R 18, R 20And R 21Be respectively hydrogen and R 19Be selected from-OCH 3,-F, C 1-4Alkyl and unsubstituted aryl.
33. the compound of claim 2; be selected from N-(2; the 6-3,5-dimethylphenyl)-2-{4-[2-hydroxyl-3-(2-methoxyl group phenoxy group) propyl group]-3-oxygen piperazinyl } ethanamide; N-(2; the 6-3,5-dimethylphenyl)-and 2-{4-[2-hydroxyl-3-(2-methoxyl group phenoxy group) propyl group]-3; 5-lupetazin base } ethanamide; 2-{ (5S; 2R)-and 4-[2-hydroxyl-3-(2-methoxyl group phenoxy group) propyl group]-2; 5-lupetazin base }-N-(2; the 6-3,5-dimethylphenyl) ethanamide; 2-{2; 5-diaza-5-[2-hydroxyl-3-(2-methoxyl group phenoxy group) propyl group] dicyclo [4.4.0] last of the ten Heavenly stems-2-yl }-N-(2; the 6-3,5-dimethylphenyl) ethanamide; N-(2; the 6-3,5-dimethylphenyl)-2-{4-[2-hydroxyl-3-(2-methoxyl group phenoxy group) propyl group]-3-oxygen piperazinyl } ethanamide; N-(2; the 6-3,5-dimethylphenyl)-and 2-{4-[2-hydroxyl-3-(2-methoxyl group phenoxy group) propyl group]-3; 3-lupetazin base } ethanamide; 2-{5-[(2 S)-and 2-hydroxyl-3-(2-methoxyl group phenoxy group) propyl group] (1S; 4S)-2; 5-diazabicyclo [2.2.1] heptan-2-yl }-N-(2; the 6-3,5-dimethylphenyl) ethanamide; N-(2, the 6-3,5-dimethylphenyl)-2-{4-[2-hydroxyl-4-(2-methoxyl group phenoxy group) butyl] piperazinyl } ethanamide, N-(2; the 6-3,5-dimethylphenyl)-and 2-{4-[4-(4-fluorophenoxy)-2-hydroxybutyl] piperazinyl } ethanamide; 2-(4-{4-[4-(tertiary butyl) phenoxy group]-the 2-hydroxybutyl } piperazinyl)-N-(2, the 6-3,5-dimethylphenyl) ethanamide, N-(2; the 6-3,5-dimethylphenyl)-and 2-{4-[2-hydroxyl-4-(4-phenyl phenoxy group) butyl] piperazinyl } ethanamide; N-(2, the 6-3,5-dimethylphenyl)-2-{4-[2-hydroxyl-4-(4-methoxyl group phenoxy group) butyl] piperazinyl } ethanamide, 2-{ (3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine base }-N-(2; the 6-3,5-dimethylphenyl) ethanamide; 2-{ (3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine base }-N-(2, the 6-dichlorophenyl) ethanamide, 2-{ (3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine base }-N-(4-sulfamyl phenyl) ethanamide; 2-{ (3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine base }-N-(5-methoxyl group-3-(trifluoromethyl) phenyl] ethanamide; 2-{ (3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine base }-N-indane-5-yl acetamide, 2-{ (3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine base }-the N-naphthyl acetamide, 2-{ (3S)-4-[(2 S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine base }-N-(4-chloronaphthyl, methylnaphthyl) ethanamide; 2-{ (3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine base }-N-(2-pyrryl phenyl) ethanamide; 2-{ (3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine base }-phenyl acetanilide,Phenacetylaniline, 2-{ (3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine base }-N-(2-chloro-phenyl-) ethanamide, 2-{ (3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine base }-N-(2-chloro-4-aminomethyl phenyl) ethanamide; 2-{ (3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine base }-N-[2-(1-methyl ethylene) phenyl] ethanamide; 2-{ (3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine base }-N-(2-aminomethyl phenyl) ethanamide, 2-{ (3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine base }-N-(6-methyl-2-(methylethyl) phenyl] ethanamide, 2-{ (3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine base }-N-(3-methylthio group phenyl) ethanamide; 2-{ (3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine base }-N-(4-chloro-2-methoxyl group-5-aminomethyl phenyl) ethanamide; 2-{ (3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine base }-N-[4-(dimethylamino) phenyl] ethanamide, 2-{ (3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine base }-N-(2, the 4-Dimethoxyphenyl) ethanamide; 2-{ (3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine base }-N-(3; the 4-dichlorophenyl) ethanamide, 2-{ (3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine base }-N-(4-chloro-phenyl-) ethanamide, 2-{ (3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine base }-N-(3-chloro-phenyl-) ethanamide; 2-{ (3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine base }-N-(3; the 5-dichlorophenyl) ethanamide, 2-{ (3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine base }-N-(4-p-methoxy-phenyl) ethanamide, 2-{ (3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine base }-N-(4-aminomethyl phenyl) ethanamide; 2-{ (3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine base }-N-(3-aminomethyl phenyl) ethanamide; 2-{ (3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine base }-N-(4-fluorophenyl) ethanamide, 2-{ (3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine base }-N-(4-cyano-phenyl) ethanamide, 2-{ (3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine base }-N-(4-acetylphenyl) ethanamide; 2-{ (3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine base }-N-(2-p-methoxy-phenyl) ethanamide; 2-{ (3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine base }-N-[4-(trifluoromethyl) phenyl) ethanamide, 2-{ (3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine base }-N-(4-chloro-3-(trifluoromethyl) phenyl] ethanamide, 2-{ (3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine base }-N-(3; the 5-Dimethoxyphenyl) ethanamide; 2-{ (3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine base }-N-(4-morpholine-4-base phenyl) ethanamide, 2-{ (3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine base }-N-(3-fluoro-4-p-methoxy-phenyl) ethanamide, 2-{ (3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine base }-N-(3; 4; the 5-trimethoxyphenyl) ethanamide, 2-{ (3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine base }-N-(3, the 4-Dimethoxyphenyl) ethanamide; 2-{ (3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine base }-N-(4-chloro-2-fluorophenyl) ethanamide, and 2-{ (3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine base }-N-[2-(hydroxymethyl-6-aminomethyl phenyl] ethanamide.
34. have the substituted piperazine like compound of following structural:
M=or 1 or 2 or 3 wherein;
R 1, R 2, R 3, R 4And R 5Be selected from independently of one another: hydrogen, halogen, NO 2, CF 3, CN, OR 23, SR 23, N (R 23) 2, S (O) R 22, SO 2R 22, SO 2N (R 23) 2, NR 23CO 2R 22, NR 23CON (R 23) 2, COR 23, CO 2R 23, CON (R 23) 2, NR 23SO 2R 22, C 1-15Alkyl, C 2-15Thiazolinyl, C 2-15Alkynyl, heterocyclic radical, aryl, and heteroaryl, wherein alkyl and aryl substituent can be chosen wantonly by one and be selected from following substituting group replacement: halogen, NO 2, CF 3, CN, OR 23, SR 23, N (R 23) 2, S (O) R 22And SO 2R 22
R 6, R 7And R 8Be selected from hydrogen or C independently of one another 1-15Alkyl;
R 9, R 10, R 11, R 12, R 13, R 14, R 15And R 16Be selected from hydrogen independently of one another, CO 2R 23, CON (R 23) 2, C 1-4Alkyl, or aryl, wherein alkyl and aryl substituent can be chosen wantonly by one and be selected from following substituting group replacement: halogen, CF 3, CN, OR 23, N (R 23) 2, CO 2R 23, CON (R 23) 2Or aryl, wherein R 9And R 10Can form carbonyl or R together 11And R 12Can form carbonyl or R together 13And R 14Can form carbonyl or R together 15And R 16Can form carbonyl, wherein R together 11And R 13, R 9And R 15, R 9And R 11, R 11And R 15Or R 9And R 13Can be joined together to form bridged ring system, and wherein two R groups comprise 1-4 carbon atom together, and R wherein 9And R 10, R 11And R 12, R 13And R 14Or R 15And R 16Can be joined together to form spiro system, and wherein two R groups comprise 1-5 carbon atom together.
R 17, R 18, R 19, R 20, and R 21Be selected from hydrogen independently of one another, halogen, NO 2, CF 3, CN, OR 23, SR 23, N (R 23) 2, S (O) R 22, SO 2R 22, SO 2N (R 23) 2, NR 23CO 2R 22, NR 23CON (R 23) 2, COR 23, CO 2R 23, CON (R 23) 2, NR 23SO 2R 22, C 1-15Alkyl, C 2-15Thiazolinyl, C 2-15Alkynyl, heterocyclic radical, aryl, and heteroaryl, wherein alkyl and aryl substituent can be chosen wantonly by one and be selected from following substituting group replacement: halogen, NO 2, CF 3, CN, OR 23, SR 23, N (R 23) 2, S (O) R 22And SO 2R 22And R 17And R 18, R 18And R 19, R 19And R 20Or R 20And R 21Comprise 5 to 6 carbon atoms in conjunction with forming, wherein 0 to 2 carbon atom saturated rings that can be replaced by Sauerstoffatom and wherein R 17And R 18Can form together-CH=CH-CH=CH-;
R 22Be selected from C 1-15Alkyl, aryl, and heteroaryl, wherein alkyl and aryl substituent can be chosen wantonly by 1 and be selected from halogen, alkyl, alkyl monosubstituted amino, dialkyl amido, alkyl amido, aryl amido, heteroaryl amido, CN, O-C 1-6Alkyl, CF 3And the substituting group of heteroaryl replaces; And
R 23Be selected from H, C 1-15Alkyl, aryl, and heteroaryl, wherein alkyl and aryl substituent can be chosen wantonly by 1 and be selected from halogen, alkyl, list or dialkyl amido, alkyl, CN, O-C 1-6Alkyl and CF 3Substituting group replace.
35. the compound of claim 34, wherein R 1, R 2, R 3, R 4And R 5Be selected from independently of one another: hydrogen, halogen, NO 2, CF 3, CN, OR 23, SR 23, N (R 23) 2, S (O) R 22, SO 2R 22, SO 2N (R 23) 2, NR 23CO 2R 22, NR 23CON (R 23) 2, COR 23, CO 2R 23, CON (R 23) 2, NR 23SO 2R 22, C 1-15Alkyl, heterocyclic radical, aryl, and heteroaryl;
R 6, R 7And R 8Be selected from hydrogen or C independently of one another 1-8Alkyl;
R 9, R 10, R 11, R 12, R 13, R 14, R 15And R 16Be selected from hydrogen independently of one another, CO 2R 23, CON (R 23) 2, C 1-4Alkyl, or aryl, wherein R 9And R 10Can form carbonyl or R together 11And R 12Can form carbonyl or R together 13And R 14Can form carbonyl or R together 15And R 16Can form carbonyl, wherein R together 11And R 13, R 9And R 15, R 9And R 11, R 11And R 15Or R 9And R 13Can be joined together to form bridged ring system, wherein two R groups comprise 1-4 carbon atom together;
R 17, R 18, R 19, R 20, and R 21Be selected from hydrogen independently of one another, halogen, CF 3, CN, OR 23, SR 23, N (R 23) 2, COR 23, CO 2R 23, CON (R 23) 2, C 1-15Alkyl, C 2-6Thiazolinyl, C 2-6Alkynyl, heterocyclic radical, aryl, and heteroaryl, wherein alkyl and aryl substituent can be chosen wantonly by one and be selected from following substituting group replacement: halogen, CF 3, CN, OR 23And R wherein 17And R 18, R 18And R 19, R 19And R 20Or R 20And R 21Comprise 5 to 6 carbon atoms in conjunction with forming, 0 to 2 carbon atom saturated rings that can be replaced by Sauerstoffatom wherein, and R wherein 17And R 18Can form together-CH=CH-CH=CH-;
R 22Be selected from C 1-8Alkyl, aryl, and heteroaryl, wherein alkyl and aryl substituent can be chosen wantonly by 1 and be selected from halogen, alkyl, CN, CF 3Substituting group replace; And
R 23Be selected from H, C 1-8Alkyl, aryl, and heteroaryl, wherein alkyl and aryl substituent can be chosen wantonly by 1 and be selected from halogen, alkyl, alkyl, CN, or CF 3Substituting group replace.
36. the compound of claim 34, wherein R 1, R 2, R 3, R 4And R 5Be selected from independently of one another: hydrogen, halogen, CF 3, CN, OR 23, SR 23, N (R 23) 2, C 1-8Alkyl, aryl, and heteroaryl;
R 6, R 7And R 8Be selected from hydrogen or C independently of one another 1-5Alkyl;
R 9, R 10, R 11, R 12, R 13, R 14, R 15And R 16Be selected from hydrogen independently of one another, C 1-4Alkyl, or aryl, wherein R 9And R 10Can form carbonyl or R together 11And R 12Can form carbonyl or R together 13And R 14Can form carbonyl or R together 15And R 16Can form carbonyl, wherein R together 11And R 13, R 9And R 15, R 9And R 11, R 11And R 15Or R 9And R 13Can be joined together to form bridged ring system, wherein two R groups comprise 1-2 carbon atom together;
R 17, R 18, R 19, R 20, and R 21Be selected from hydrogen independently of one another, halogen, CF 3, CN, OR 23, C 1-8Alkyl, aryl, and heteroaryl, and R 19And R 20Can comprise 5 carbon atoms in conjunction with formation, 2 carbon atoms saturated rings that can be replaced by Sauerstoffatom wherein, and R wherein 17And R 18Can form together-CH=CH-CH=CH-;
R 22Be selected from C 1-6Alkyl, aryl; And
R 23Be selected from H, C 1-6Alkyl, aryl.
37. the compound of claim 34, wherein R 1, R 2, R 3, R 4And R 5Be selected from independently of one another: hydrogen, halogen, CF 3, CN, OR 23, C 1-6Alkyl;
R 6, R 7And R 8Be selected from hydrogen or C independently of one another 1-3Alkyl;
R 9, R 10, R 11, R 12, R 13, R 14, R 15And R 16Be selected from hydrogen independently of one another, C 1-3Alkyl, wherein R 9And R 10Can form carbonyl or R together 11And R 12Can form carbonyl or R together 13And R 14Can form carbonyl or R together 15And R 16Can form carbonyl, wherein R together 11And R 13, R 9And R 15, R 9And R 11, R 11And R 15Or R 9And R 13Can be joined together to form bridged ring system, wherein two R groups comprise 1-2 carbon atom together;
R 17, R 18, R 19, R 20, and R 21Be selected from hydrogen independently of one another, halogen, CF 3, CN, OR 23, C 1-6Alkyl, and R 19And R 20Comprise 5 carbon atoms in conjunction with forming, 2 carbon atoms saturated rings that can be replaced by Sauerstoffatom wherein, and R wherein 17And R 18Can form together-CH=CH-CH=CH-;
R 22Be selected from C 1-3Alkyl; And
R 23Be selected from H, C 1-3Alkyl.
38. the compound of claim 37, wherein m=1 or 2 or 3.
39. the compound of claim 37, wherein R 9, R 10, R 11, R 12, R 13, R 14, R 15And R 16Be selected from hydrogen independently of one another, methyl, wherein R 9And R 10Can form carbonyl, R together 13And R 14Can form carbonyl, wherein R together 11And R 13, R 9And R 15, R 11And R 15Or R 9And R 13Can be joined together to form bridged ring system, wherein two R groups comprise 1-2 carbon atom together.
40. the compound of claim 37, wherein R 9, R 10, R 11, R 12, R 13, R 14, R 15And R 16Be selected from hydrogen and methyl independently of one another.
41. the compound of claim 39 or 40, wherein R 6, R 7And R 8Be selected from hydrogen and methyl independently of one another.
42. the compound of claim 37, wherein R 9, R 10, R 11, R 12, R 13, R 14, R 15And R 16Be hydrogen.
43. the compound of claim 37, wherein R 1, R 2, R 3, R 4And R 5Be selected from independently of one another: hydrogen, halogen, C 1-2Alkyl;
R 6It is hydrogen atom; And
R 7And R 8Be selected from hydrogen or methyl independently of one another; And
R 9, R 10, R 11, R 12, R 13, R 14, R 15And R 16Be selected from hydrogen independently of one another, C 1-3Alkyl, wherein R 9And R 10Can form carbonyl or R together 13And R 14Can form carbonyl together;
R 17, R 18, R 19, R 20, and R 21Be selected from hydrogen independently of one another, halogen, CF 3, CN, OR 23, C 1-6Alkyl, and R 19And R 20Can comprise 5 carbon atoms in conjunction with formation, 2 carbon atoms saturated rings that can be replaced by Sauerstoffatom wherein, and R wherein 17And R 18Can form together-CH=CH-CH=CH-;
R 22Be selected from methyl; With
R 23Be selected from H, methyl.
44. the compound of claim 43, wherein R 9, R 10, R 11, R 12, R 13, R 14, R 15And R 16Be selected from hydrogen independently of one another, and methyl.
45. the compound of claim 43, wherein R 9, R 10, R 11, R 12, R 13, R 14, R 15And R 16Be selected from hydrogen independently of one another.
46. the compound of claim 43, wherein R 17, R 18, R 19, R 20, and R 21Be selected from hydrogen independently of one another, halogen, CF 3, OR 23, C 1-4Alkyl, and R 19And R 20Can comprise 5 carbon atoms in conjunction with formation, 2 carbon atoms saturated rings that can be replaced by Sauerstoffatom wherein, and R wherein 17And R 18Can form together-CH=CH-CH=CH-.
47. the compound of claim 43, wherein R 17, R 18, R 19, R 20, and R 21Be selected from hydrogen independently of one another, halogen, CF 3, OR 23, C 1-4Alkyl, and R 19And R 20In conjunction with formation-O-CH 2-O-or-OCH 2CH 2O-and R wherein 17And R 18Can form together-CH=CH-CH=CH-.
48. the compound of claim 34, wherein m=1 or 2;
R 1, R 2, R 3, R 4And R 5Be selected from independently of one another: hydrogen, halogen, CF 3, OR 22, C 1-2Alkyl, wherein R 22Be C 1-2Alkyl;
R 6, R 7And R 8Be selected from hydrogen and methyl independently of one another;
R 9, R 10, R 11, R 12, R 13, R 14, R 15And R 16Be selected from hydrogen and C independently of one another 1-2Alkyl, or R 9And R 10Can form carbonyl or R together 15And R 16Can form carbonyl, wherein R together 11And R 13, R 9And R 15, R 9And R 11, R 11And R 15Or R 9And R 13Can be joined together to form the ring that comprises 1-4 carbon atom; And
R 17, R 18, R 19, R 20, and R 21Be selected from hydrogen independently of one another, halogen, OR 23, C 1-3Alkyl, C 2-4Thiazolinyl, C 2-4Alkynyl, heterocyclic radical, aryl, and heteroaryl, wherein R 23Be C 1-2Alkyl, and R wherein 17And R 18Or R 18And R 19Can form together to be selected from and comprise-CH=CH-CH=CH--O-CH 2-O and-O-CH 2-CH 2The ring of-O-.
49. the compound of claim 48, wherein R 1, R 2, R 3, R 4And R 5Be selected from hydrogen and methyl independently of one another.
50. the compound of claim 48, wherein R 6, R 7And R 8Be respectively hydrogen.
51. the compound of claim 48, wherein R 9, R 10, R 11, R 12, R 13, R 14, R 15And R 16Be selected from hydrogen and C independently of one another 1-3Alkyl.
52. the compound of claim 48, wherein R 9, R 10, R 11, R 12, R 13, R 14, R 15And R 16Be selected from hydrogen and methyl independently of one another.
53. the compound of claim 15, wherein R 9And R 10Form carbonyl together, R 15And R 16Form carbonyl or R together 9And R 10Form carbonyl and R together 15And R 16Also form carbonyl together.
54. the compound of claim 48, wherein R 17, R 18, R 19, R 20, and R 21Be selected from hydrogen independently of one another, halogen, C 1-4Alkyl, OR 22, R wherein 22Be C 1-2Alkyl.
55. the compound of claim 48, wherein R 17And R 18Or R 18And R 19Form to be selected from together and comprise-CH=CH-CH=CH--O-CH 2The ring of-O-.
56. the compound of claim 34, wherein
M=1 or 2;
R 1, R 2, R 3, R 4And R 5Be selected from independently of one another: hydrogen and methyl;
R 6, R 7And R 8Be respectively hydrogen;
R 9, R 10, R 11, R 12, R 13, R 14, R 15And R 16Be selected from hydrogen and C independently of one another 1-4Alkyl, or R 9And R 10Can form carbonyl, R together 11And R 12Can form carbonyl, R together 13And R 14Can form carbonyl or R together 15And R 16Can form carbonyl, wherein R together 11And R 13, R 9And R 15, R 9And R 11, R 11And R 15Or R 9And R 13Can be joined together to form the ring that comprises 1-4 carbon atom;
R 17, R 18, R 19, R 20, and R 21Be selected from hydrogen independently of one another, halogen, C 1-4Alkyl, CF 3And OR 22And
R 22Be C 1-2Alkyl.
57. the compound of claim 56, wherein R 1And R 5Be respectively methyl and R 2, R 3And R 4Be respectively hydrogen.
58. the compound of claim 56, wherein R 9, R 10, R 11, R 12, R 13, R 14, R 15And R 16Be selected from hydrogen and methyl independently of one another.
59. the compound of claim 56, wherein R 9, R 10, R 11, R 12, R 13, R 14, R 15And R 16Be respectively hydrogen.
60. the compound of claim 56, wherein R 17, R 18, R 19, R 20, and R 21Be selected from hydrogen respectively, Cl, F ,-OCH 3,-CF 3And C 1-4Alkyl.
61. the compound of claim 60, wherein R 18, and R 20Be respectively hydrogen.
62. the compound of claim 60, wherein R 19Be-OCH 3
63. the compound of claim 56, wherein R 17Be-OCH 3, and R 18, R 19, R 20, and R 21Be respectively hydrogen.
64. the compound of claim 56, wherein R 17, R 18, R 20And R 21Be respectively hydrogen and R 19Be selected from-OCH 3,-F ,-CF 3, C 1-4
65. the compound of claim 34 is selected from N-(2, the 6-3,5-dimethylphenyl)-2-[4-(2-hydroxy-4-phenyl butyl) piperazinyl] ethanamide; N-(2, the 6-3,5-dimethylphenyl)-2-{4-[2-hydroxyl-3-(2-p-methoxy-phenyl) propyl group] piperazinyl } ethanamide; 2-[4-(3-(2H-benzo [d] 1,3-dioxole (dioxolen)-5-yl)-2-hydroxypropyl) piperazinyl]-N-(2,6 3,5-dimethylphenyl) ethanamide; N-(2, the 6-3,5-dimethylphenyl)-2-{4-[2-hydroxyl-3-(4-p-methoxy-phenyl) propyl group] piperazinyl } ethanamide; N-(2, the 6-3,5-dimethylphenyl)-2-{4-[2-hydroxyl-3-phenyl propyl] piperazinyl } ethanamide; N-(2, the 6-3,5-dimethylphenyl)-2-{4-[4-(4-p-methoxy-phenyl)-2-hydroxybutyl] piperazinyl } ethanamide; 2-{4-[4-(2, the 6-difluorophenyl)-2-hydroxybutyl] piperazinyl }-N-(2, the 6-3,5-dimethylphenyl) ethanamide; N-(2, the 6-3,5-dimethylphenyl)-2-{4-[4-(2-chloro-phenyl-)-2-hydroxybutyl] piperazinyl } ethanamide; 2-(4-{4-[4-(tertiary butyl) phenyl-2-hydroxybutyl } piperazinyl)-N-(2, the 6-3,5-dimethylphenyl) ethanamide; N-(2, the 6-3,5-dimethylphenyl)-2-{4-[4-(2-fluorophenyl)-2-hydroxybutyl] piperazinyl } ethanamide; N-(2, the 6-3,5-dimethylphenyl)-2-(4-{2-hydroxyl-4-[4-(trifluoromethyl) phenyl] butyl } piperazinyl) ethanamide; 2-[4-(3-(2H-benzo [d] 1,3-dioxole-5-yl)-and the 2-hydroxypropyl) piperazinyl]-N-(2, the 6-3,5-dimethylphenyl)-the 2-methyl propanamide, N-(2, the 6-3,5-dimethylphenyl)-2-[4-(2-hydroxyl-3-phenyl propyl) piperazinyl]-the 2-methyl propanamide, N-(2, the 6-3,5-dimethylphenyl)-2-{4-[2-hydroxyl-3-(3,4, the 5-trimethoxyphenyl) propyl group] piperazinyl }-the 2-methyl propanamide, N-(2, the 6-3,5-dimethylphenyl)-and 2-[4-(2-hydroxyl-5-phenylpentyl) piperazinyl] ethanamide, N-(2, the 6-3,5-dimethylphenyl)-2-{4-[5-(2-fluorophenyl)-2-hydroxyl-amyl group] piperazinyl } ethanamide, and N-(2, the 6-3,5-dimethylphenyl)-2-{4-[5-(2-chloro-phenyl-)-2-hydroxyl-amyl group] piperazinyl } ethanamide.
66. have the substituted piperazine like compound of following structural:
M=1 wherein, 2, or 3;
R 1, R 2, R 3, R 4And R 5Be selected from independently of one another: hydrogen, halogen, NO 2, CF 3, CN, OR 20, SR 20, N (R 20) 2, S (O) R 22, SO 2R 22, SO 2N (R 20) 2, NR 20CO 2R 22, NR 20CON (R 20) 2, COR 20, CO 2R 20, CON (R 20) 2, NR 20SO 2R 22, C 1-15Alkyl, C 2-15Thiazolinyl, C 2-15Alkynyl, heterocyclic radical, aryl, and heteroaryl, wherein alkyl and aryl substituent can be chosen wantonly by one and be selected from following substituting group replacement: halogen, NO 2, CF 3, CN, OR 20, SR 20, N (R 20) 2, S (O) R 22And SO 2R 22
R 6, R 7And R 8Be selected from hydrogen or C independently of one another 1-3Alkyl;
R 9, R 10, R 11, R 12, R 13, R 14, R 15And R 16Be selected from hydrogen independently of one another, CO 2R 20, CON (R 20) 2, C 1-4Alkyl, or aryl, wherein alkyl and aryl substituent can be chosen wantonly by one and be selected from following substituting group replacement: halogen, CF 3, CN, OR 20, N (R 20) 2, CO 2R 20, CON (R 20) 2Or aryl, wherein R 9And R 10Can form carbonyl or R together 11And R 12Can form carbonyl or R together 13And R 14Can form carbonyl or R together 15And R 16Can form carbonyl together, condition is R 11And R 13, R 9And R 15, R 9And R 11, R 11And R 15Or R 9And R 13Can be joined together to form the ring that comprises 1-3 carbon atom;
R 24Be selected from alkyl, cycloalkyl and condensed benzyl ring alkyl, wherein tie point is on cycloalkyl, and alkyl wherein, cycloalkyl and condensed benzyl ring alkyl can be chosen wantonly and be selected from following substituting group by 1 to 3 and replace: halogen, CF 3, CN, OR 20, SR 20, S (O) R 22, SO 2R 22, SO 2N (R 20) 2, NR 20CO 2R 22, C 1-2Alkyl, and aryl, wherein Ren Xuan aryl substituent can be chosen wantonly by 1 to 3 and be selected from halogen, phenyl, CF 3, CN, OR 20, C 1-6The substituting group of alkyl replaces,
R 20Be selected from H, C 1-15Alkyl, aryl, or heteroaryl, wherein alkyl and aryl substituent can be chosen wantonly by 1 and be selected from following substituting group replacement: halogen, alkyl, single-or two-alkylamino, alkyl, CN ,-O-C 1-6Alkyl or CF 3And
R 22Be selected from C 1-15Alkyl, aryl, or heteroaryl, wherein alkyl and aryl substituent can be chosen wantonly by 1 and be selected from halogen, alkyl, alkyl monosubstituted amino, dialkyl amido, alkyl amido, aryl amido, heteroaryl amido, CN, O-C 1-6Alkyl, CF 3And the substituting group of heteroaryl replaces;
67. the compound of claim 66, wherein R 1, R 2, R 3, R 4And R 5Be selected from independently of one another: hydrogen, halogen, CF 3, CN, OR 20, SR 20, N (R 20) 2, SO 2N (R 20) 2, CO 2R 20, CON (R 20) 2, C 1-8Alkyl, C 2-4Thiazolinyl, C 2-4Alkynyl, heterocyclic radical, aryl, and heteroaryl, wherein alkyl and aryl substituent can be chosen wantonly by one and be selected from following substituting group replacement: halogen, NO 2, CF 3, CN, OR 20, SR 20, N (R 20) 2, S (O) R 22And SO 2R 22
R 6, R 7And R 8Be selected from hydrogen or C independently of one another 1-3Alkyl;
R 9, R 10, R 11, R 12, R 13, R 14, R 15And R 16Be selected from hydrogen independently of one another, CON (R 20) 2, C 1-4Alkyl, or R wherein 9And R 10Can form carbonyl or R together 11And R 12Can form carbonyl or R together 13And R 14Can form carbonyl or R together 15And R 16Can form carbonyl together; And
R 20Be selected from H, C 1-15Alkyl, aryl, or heteroaryl, wherein alkyl and aryl substituent can be chosen wantonly by 1 and be selected from following substituting group replacement: halogen, alkyl, single-or two-alkylamino, alkyl cyano group ,-O-C 1-6Alkyl or CF 3
68. the compound of claim 66, wherein R 1, R 2, R 3, R 4And R 5Be selected from independently of one another: hydrogen, halogen, CF 3, OR 20, C 1-5Alkyl, C 2-3Thiazolinyl, or C 2-3Alkynyl, wherein alkyl can be chosen wantonly by CF 3Replace;
R 6, R 7And R 8Be selected from hydrogen or C independently of one another 1-3Alkyl;
R 9, R 10, R 11, R 12, R 13, R 14, R 15And R 16Be selected from hydrogen independently of one another, CON (R 20) 2, or C 1-4Alkyl, wherein R 9And R 10Can form carbonyl or R together 11And R 12Can form carbonyl or R together 13And R 14Can form carbonyl or R together 15And R 16Can form carbonyl together;
R 24Be selected from alkyl, cycloalkyl and condensed benzyl ring alkyl, wherein tie point is on cycloalkyl, and alkyl wherein, cycloalkyl and condensed benzyl ring alkyl can be chosen wantonly and be selected from following substituting group by 1 to 2 and replace: halogen, CF 3, CN, OR 20, SR 20, S (O) R 22, SO 2R 22, C 1-2Alkyl, and aryl, wherein Ren Xuan aryl substituent can be chosen wantonly by 1 to 3 and be selected from halogen, phenyl, CF 3, CN, OR 20, C 1-6The substituting group of alkyl replaces; And
R 20Be selected from H, C 1-8Alkyl, aryl, or heteroaryl, wherein alkyl and aryl substituent can be chosen wantonly by 1 and be selected from following substituting group replacement: halogen ,-O-C 1-3Alkyl or CF 3
69. the compound of claim 66, wherein R 1, R 2, R 3, R 4And R 5Be selected from independently of one another: hydrogen, halogen, CF 3, OR 20, C 1-3Alkyl, C 2-3Thiazolinyl, or C 2-3Alkynyl, wherein alkyl can be chosen wantonly by CF 3Replace;
R 6, R 7And R 8Be selected from hydrogen or methyl independently of one another;
R 9, R 10, R 11, R 12, R 13, R 14, R 15And R 16Be selected from hydrogen or C independently of one another 1-2Alkyl, wherein R 9And R 10Can form carbonyl or R together 11And R 12Can form carbonyl or R together 13And R 14Can form carbonyl or R together 15And R 16Can form carbonyl together;
R 24Be selected from alkyl, cycloalkyl and condensed benzyl ring alkyl, wherein tie point is on cycloalkyl, and alkyl wherein, cycloalkyl and condensed benzyl ring alkyl can be chosen wantonly and be selected from following substituting group by 1 to 2 and replace: halogen, CF 3, OR 20, S (O) R 22, C 1-2Alkyl, and aryl, wherein Ren Xuan aryl substituent can be chosen wantonly by 1 to 3 and be selected from halogen, phenyl, CF 3, CN, OR 20, C 1-6The substituting group of alkyl replaces; And
R 20Be selected from H, C 1-5Alkyl, aryl, or heteroaryl, wherein alkyl and aryl substituent can be chosen wantonly by 1 and be selected from following substituting group replacement: halogen ,-O-Me or CF 3
70. the compound of claim 66, wherein m=1 or 2;
R wherein 1, R 2, R 3, R 4And R 5Be selected from independently of one another: hydrogen, halogen, CF 3, OR 22And C 1-4Alkyl, and R wherein 22Be C 1-3Alkyl;
R 6, R 7And R 8Be selected from hydrogen or C independently of one another 1-3Alkyl;
R 9, R 10, R 11, R 12, R 13, R 14, R 15And R 16Be selected from hydrogen independently of one another, CON (R 20) 2, C 1-4Alkyl, or aryl, wherein alkyl and aryl substituent can be chosen wantonly by 1 and be selected from following substituting group replacement: halogen, CF 3, OR 20, N (R 20) 2, CON (R 20) 2Or aryl, wherein R 9And R 10Can form carbonyl or R together 11And R 12Can form carbonyl or R together 13And R 14Can form carbonyl or R together 15And R 16Can form carbonyl together; Condition is R 11And R 13, R 9And R 15, R 9And R 11, R 11And R 15Or R 9And R 13Can be joined together to form ring;
R 24Be selected from alkyl, cycloalkyl and condensed benzyl ring alkyl, wherein tie point is on cycloalkyl, and alkyl wherein, cycloalkyl and condensed benzyl ring alkyl can be chosen wantonly and be selected from following substituting group by 1 to 2 and replace: halogen, CF 3, OR 20, and aryl, wherein Ren Xuan aryl substituent can be chosen wantonly by 1 to 3 and be selected from halogen, phenyl, CF 3, CN, OR 20, and C 1-6The substituting group of alkyl replaces; And
R 20Be selected from H, C 1-3Alkyl, or aryl, wherein alkyl and aryl substituent can be chosen wantonly by 1 and be selected from following substituting group replacement: halogen ,-O-Me and CF 3
71. the compound of claim 70, wherein R 9, R 10, R 11, R 12, R 13, R 14, R 15And R 16Be selected from hydrogen and C independently of one another 1-4Alkyl, or R 9And R 10Form carbonyl together, or R 11And R 12Form carbonyl together, or R 13And R 14Form carbonyl together, or R 15And R 16Form carbonyl together, R 10And R 11Formation-CH together 2CH 2CH 2CH 2-.
72. the compound of claim 70, wherein R 9, R 10, R 11, R 12, R 13, R 14, R 15And R 16Be selected from hydrogen independently of one another, CON (R 20) 2, C 1-3Alkyl, or aryl, wherein alkyl and aryl substituent can be chosen wantonly by 1 and be selected from following substituting group replacement: halogen, N (R 20) 2, and aryl, or R wherein 9And R 10Can form carbonyl or R together 11And R 12Can form carbonyl together, condition is R 11And R 13, R 9And R 15, R 9And R 11, R 11And R 15Or R 9And R 13Can be joined together to form ring.
73. the compound of claim 70, wherein R 9, R 10, R 11, R 12, R 13, R 14, R 15And R 16Be selected from hydrogen independently of one another, or C 1-2Alkyl, wherein alkyl substituent can be chosen wantonly by 1 and be selected from N (R 20) 2, or the substituting group of aryl replaces, or R wherein 9And R 10Form carbonyl together.
74. the compound of claim 66, wherein R 1, R 2, R 3, R 4And R 5Be selected from independently of one another: hydrogen, halogen, CF 3, OR 20Or C 1-3Alkyl, wherein alkyl substituent can be chosen wantonly by CF 3Replace.
75. the compound of claim 66, wherein R 6, R 7And R 8Be selected from hydrogen or methyl independently of one another.
76. the compound of claim 66, wherein m=1;
R 1, R 2, R 3, R 4And R 5Be selected from independently of one another: hydrogen, CF 3, OR 20Or C 1-2Alkyl;
R 6, R 7And R 8Be respectively hydrogen;
R 9, R 10, R 11, R 12, R 13, R 14, R 15And R 16Be selected from hydrogen or C independently of one another 1-2Alkyl, or R wherein 9And R 10Can form carbonyl together;
R 24Be selected from alkyl, cycloalkyl and condensed benzyl ring alkyl, wherein tie point is on cycloalkyl, and alkyl wherein, cycloalkyl and condensed benzyl ring alkyl can be chosen wantonly and be selected from following substituting group by 1 to 2 and replace: halogen, CF 3, OR 20, and aryl, wherein Ren Xuan aryl substituent can be chosen wantonly by 1 to 2 and be selected from halogen, phenyl, CF 3, OR 20, and C 1-4The substituting group of alkyl replaces; And
R 20Be selected from H or C 1-3Alkyl.
77. the compound of claim 76, wherein R 24Be selected from alkyl, cycloalkyl and condensed benzyl ring alkyl, wherein tie point is on cycloalkyl, and alkyl wherein, cycloalkyl and condensed benzyl ring alkyl can be chosen wantonly and be selected from following substituting group by 1 and replace: halogen, CF 3, OR 20, and aryl, wherein Ren Xuan aryl substituent can be chosen wantonly by 1 to 2 and be selected from halogen, phenyl, CF 3, OR 20, and C 1-4The substituting group of alkyl replaces.
78. the compound of claim 66, wherein R 24Be selected from alkyl, cycloalkyl and condensed benzyl ring alkyl, wherein tie point is on cycloalkyl, and alkyl wherein, cycloalkyl and condensed benzyl ring alkyl can be chosen wantonly and be selected from following substituting group by 1 and replace: halogen, CF 3, OR 20, and aryl, wherein Ren Xuan aryl substituent can be chosen wantonly by 1 to 2 and be selected from halogen, phenyl, CF 3, OR 20, and C 1-4The substituting group of alkyl replaces.
79. the compound of claim 76, wherein R 1, R 2, R 3, R 4And R 5Be selected from independently of one another: hydrogen, halogen, CF 3, OCH 3Or methyl.
80. the compound of claim 76, wherein R 1, R 2, R 3, R 4And R 5Be selected from independently of one another: hydrogen or methyl.
81. the compound of claim 76, wherein R 11And R 15Be selected from hydrogen or methyl respectively, R 9, R 10, R 12, R 13, R 14And R 16Be respectively hydrogen, and R 9And R 10Can form carbonyl together.
82. the compound of claim 66, wherein m=1;
R 1, R 2, R 3, R 4And R 5Be selected from independently of one another: hydrogen, or methyl;
R 6, R 7And R 8Be respectively hydrogen;
R 11And R 15Be respectively hydrogen or methyl, R 9, R 10, R 12, R 13, R 14And R 16Be respectively hydrogen, and R 9And R 10Can form carbonyl together;
R 24Be selected from alkyl, cycloalkyl and condensed benzyl ring alkyl, wherein tie point is on cycloalkyl, and alkyl wherein, cycloalkyl and condensed benzyl ring alkyl can be chosen wantonly and be selected from following substituting group by 1 and replace: halogen, CF 3, OR 20, and aryl, wherein Ren Xuan aryl substituent can be chosen wantonly by 1 to 2 and be selected from halogen, phenyl, CF 3, OR 20, and C 1-4The substituting group of alkyl replaces; And
R 20Be methyl or hydrogen.
83. the compound of claim 82, wherein R 24Be alkyl and cycloalkyl with 1 to 6 carbon atom.
84. the compound of claim 82, wherein R 24Be to choose wantonly to be selected from halogen, CF by 1 to 2 3, OR 20, C 1-2The condensed benzyl ring alkyl that alkyl and aryl replace.
85. the compound of claim 82, wherein R 24Be to choose wantonly to be selected from halogen, CF by 1 to 2 3, OR 20, C 1-4The condensed phenyl methyl that alkyl and aryl replace.
86. the compound of claim 82, wherein R 2, R 3, and R 4Be respectively hydrogen and R 1And R 5Be respectively methyl.
87. the compound of claim 66, wherein m=1;
R 1, R 2, R 3, R 4And R 5Be selected from independently of one another: hydrogen or methyl;
R 6, R 7And R 8Be respectively hydrogen;
R 9, R 10, R 11, R 12, R 13, R 14, R 15And R 16Be respectively hydrogen; And
R 24Be selected from alkyl, have the cycloalkyl of 4 to 6 carbon atoms, and wherein phenyl is optional is selected from halogen, CF by 1 to 2 with 1 to 6 carbon atom 3, OH, the condensed benzyl ring alkyl that the substituting group of methyl and aryl replaces, and aryl is optional is selected from halogen, CF by 1 to 2 3, OH, C 1-2The substituting group of alkyl and aryl replaces.
88. the compound of claim 66 is selected from: 2-{2-[4-(3-isopropoxy-2-hydroxypropyl) piperazinyl]-N-(2, the 6-3,5-dimethylphenyl) ethanamide; N-(2, the 6-3,5-dimethylphenyl)-2-[4-(2-hydroxyl-3-indane-2-base oxygen propyl group) piperazinyl] ethanamide; N-(2, the 6-3,5-dimethylphenyl)-2-{4-[2-hydroxyl-3-(phenyl methoxyl group) propyl group] piperazinyl } ethanamide, 2-(2-[4-(3-cyclopentyloxy-2-hydroxypropyl) piperazinyl]-N-(2, the 6-3,5-dimethylphenyl) ethanamide; 2-(2-[4-(3-cyclohexyl oxygen base-2-hydroxypropyl) piperazinyl]-N-(2, the 6-3,5-dimethylphenyl) ethanamide; 2-[4-(3-{[4-(tertiary butyl) phenyl] methoxyl group } the 2-hydroxypropyl) piperazinyl]-N-(2,6 dimethyl propyls) ethanamide, N-(2, the 6-3,5-dimethylphenyl)-2-(4-{3-[(2-fluorophenyl) methoxyl group]-the 2-hydroxypropyl } piperazinyl) ethanamide, 2-(4-{3[(2, the 4-difluorophenyl) methoxyl group]-the 2-hydroxypropyl } piperazinyl)-N-(2,6 dimethyl propyls) ethanamide, N-(2, the 6-3,5-dimethylphenyl)-and 2-[4-(2-hydroxyl-3-{[4-(trifluoromethyl) phenyl] methoxyl group } propyl group) piperazinyl] ethanamide, N-(2, the 6-3,5-dimethylphenyl)-and 2-(4-{2-hydroxyl-3-[(2-p-methoxy-phenyl) methoxyl group] propyl group } piperazinyl) ethanamide, 2-(4-{3[(2, the 4-p-methoxy-phenyl) methoxyl group]-the 2-hydroxypropyl } piperazinyl)-N-(2,6 dimethyl propyls) ethanamide, N-(2, the 6-3,5-dimethylphenyl)-and 2-(4-{2-hydroxyl-3-[(4-p-methoxy-phenyl) methoxyl group] propyl group } piperazinyl) ethanamide, N-(2, the 6-3,5-dimethylphenyl)-2-(4-{3-[(4-fluorophenyl) methoxyl group]-the 2-hydroxypropyl } piperazinyl) ethanamide, N-(2, the 6-3,5-dimethylphenyl)-and 2-(4-{2-hydroxyl-3-[(4-aminomethyl phenyl) methoxyl group] propyl group } piperazinyl) ethanamide, N-(2, the 6-3,5-dimethylphenyl)-and 2-(4-{2-hydroxyl-3-[(4-phenyl) methoxyl group] propyl group } piperazinyl) ethanamide, N-(2, the 6-3,5-dimethylphenyl)-2-(4-{3-[(4-butyl phenyl) methoxyl group]-the 2-hydroxypropyl } piperazinyl) ethanamide, N-(2, the 6-3,5-dimethylphenyl)-and 2-{4-[2-hydroxyl-3-(2-naphthyl methoxyl group) propyl group] piperazinyl } ethanamide, N-(2, the 6-3,5-dimethylphenyl)-and 2-{4-[3-(cyclohexyl methoxyl group)-2-hydroxypropyl] piperazinyl } ethanamide, and N-(2, the 6-3,5-dimethylphenyl)-2-(4-{3-[(4-fluorophenyl) methoxyl group]-the 2-hydroxypropyl }-3,3-lupetazin base) ethanamide.
89. methods of treatment; comprise claim 1 compound of taking the treatment significant quantity to the Mammals of the following treatment of needs: the damage that the opposing of protection skeletal muscle is caused by wound; skeletal muscle after protection muscle or systemic disease such as the intermittent claudication; treatment shock disease; donor tissue that protection is used for transplanting and organ and treatment cardiovascular disorder.
90. the method for claim 89, wherein cardiovascular disorder is selected from atrium and ventricle arrhythmia, and PrinzmetalShi (variation) angina is stablized the angina that angina and motion cause, congestive heart disease, or myocardial infarction.
91. the method for claim 89, the scope of wherein treating significant quantity about 0.01 to about 100mg/kg weight of mammal.
92. the compound of claim 89, wherein Mammals is the people.
93. comprise the pharmaceutical composition of claim 1 compound and one or more drug excipients.
94. the pharmaceutical composition of claim 93, wherein pharmaceutical composition is the solution form.
95. the pharmaceutical composition of claim 93, wherein pharmaceutical composition is tablet or capsule form.
CN01805442A 2000-02-22 2001-02-22 Substituted piperazine compounds Pending CN1404471A (en)

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CN107043361A (en) * 2017-05-25 2017-08-15 合肥医工医药有限公司 Treat anginal compound, Preparation method and use

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CN107043361A (en) * 2017-05-25 2017-08-15 合肥医工医药有限公司 Treat anginal compound, Preparation method and use
CN107043361B (en) * 2017-05-25 2019-07-02 合肥医工医药股份有限公司 Treat anginal compound, Preparation method and use

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