CN1944424A - Aryl formyl piperazine compound and its preparing method and use in medicine production - Google Patents
Aryl formyl piperazine compound and its preparing method and use in medicine production Download PDFInfo
- Publication number
- CN1944424A CN1944424A CN 200610097267 CN200610097267A CN1944424A CN 1944424 A CN1944424 A CN 1944424A CN 200610097267 CN200610097267 CN 200610097267 CN 200610097267 A CN200610097267 A CN 200610097267A CN 1944424 A CN1944424 A CN 1944424A
- Authority
- CN
- China
- Prior art keywords
- replaces
- compound
- preparation
- aryl formyl
- formyl piperazine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Abstract
The present invention discloses one kind of aryl formyl piperazine compound and its preparation process and application in preparing medicine. The compound and its medicinal salt have the general expressions shown. The compound may be used in preparing medicine for arrhythmia. The compound has rich material source, mild reaction condition and simple preparation process and post-treatment.
Description
Technical field
The present invention relates to a kind of aryl formyl piperazine compound, the invention still further relates to the preparation method and the purposes of this aryl formyl piperazine compound.
Background technology
Present clinical use has four class anti-arrhythmics, but the effective and safe medicine of clinical shortage, and most anti-arrhythmic produces the proarrhythmia side effect when clinical use.But, found potassium-channel the beginning of the nineties from eighties of last century, and carried out drug development on this basis, over past ten years, huge variation has taken place in the pharmacological agent irregular pulse, whole world new drug development personnel more pay attention to the security and the validity of antiarrhythmic drug, and the CAST result of experiment made its research focus forward III class anti-arrhythmic to from I class anti-arrhythmic in 1998, and the research of potassium channel blocking agent has been obtained remarkable progress.Thereafter Bao Dao anti-arrhythmic almost is the potassium channel blocking agent, and they compare safer, wide spectrum, efficient with other antiarrhythmic drug, be expected to become first-selected antiarrhythmic drug.
The main specific retardance quick active potassium channel electric current (I of traditional III anti-arrhythmic
Kr).There are two big shortcomings in it: proarrhythmia and when the rhythm of the heart is accelerated and stimulate beta-receptor effect weaken.This is considered to because I
KrBlocked back QT ripple prolongs, and then causes activating potassium channel electric current (I at a slow speed
Ks) intensive raises due to the reaction.
Owing to have I
KrAnd I
KsThe anti-arrhythmic of dual retardation is than other selectivity I
KrRetarding agent has more antiarrhythmic effect, and can reduce the generation of proarrhythmia side effect.So a lot of drugmakers and research staff are devoted to seek I
Kr, I
KsThe III class antiarrhythmic drug of dual retardation, this also is the new focus of present antiarrhythmic drug research and development.
Summary of the invention
The purpose of this invention is to provide a class and have Delayed Rectifier Potassium Current (I potassium-channel
K) quick active potassium channel electric current (I
Kr) and activating potassium channel electric current (I at a slow speed
Ks) aryl formyl piperazine compound of dual retardation arranged.
Another purpose of the present invention provides the preparation method of above-mentioned aryl formyl piperazine compound.
Still a further object of the present invention provides the application of above-mentioned aryl formyl piperazine compound at the preparation antiarrhythmic drug.
The objective of the invention is to realize by following technical measures:
A kind of aryl formyl piperazine compound is general formula (I) or (II) described compound or pharmaceutically acceptable salt thereof:
In the formula, R1 is single the replacement or polysubstituted C on the phenyl ring
1-4Alkyl, C
1-4Alkoxyl group, trifluoromethyl, trifluoromethoxy or halogen; R2 is five yuan or hexa-member heterocycle, or replaces the benzo furan nucleus, or replaces aromatic ring.
Described aryl formyl piperazine compound, wherein the substituting group of R1 representative is-CH
3,-C
2H
5,-C
3H
7,-C
4H
9,-OCH
3,-OC
2H
5,-OC
3H
7,-OC
4H
9,-CF
3,-OCF
3,-F ,-Cl ,-Br ,-among the I one or more; Substituting group among the R2 is-CH
3,-C
2H
5,-C
3H
7,-C
4H
9,-OCH
3,-OC
2H
5,-OC
3H
7,-OC
4H
9,-CF
3,-OCF
3,-F ,-Cl ,-Br ,-I ,-NO
2In one or more, five-membered ring is furan nucleus, thiphene ring or pyrrole ring.
Described aryl formyl piperazine compound, wherein R1 is polysubstituted is meant 2, and 6-is two to be replaced, 2, and 5-is two to be replaced, 2, and 4-is two to be replaced and 2, and 3-is two to be replaced; Perhaps 2,3,4-three replaces, 2,3, and 5-three replaces, 2,3, and 6-three replaces, 2,4, and 5-three replaces, 2,4, and 6-three replaces and 2,5, and 6-three replaces; Perhaps 2,3,4,5-four replaces, 2,3,4, and 6-four replaces and 2,4,5, and 6-four replaces.
The preparation method of described aryl formyl piperazine compound, this method comprises the following steps:
(1) will add propyl carbinol and Anhydrous potassium carbonate in mustargen, the R1 substituted aniline, stirring and refluxing is fully reacted, and concentrates, and solid is separated out in refrigeration, and recrystallization gets R1 substituted phenylpiperazine or its pharmaceutical salts;
(2) R2 replaced add chloroform in the formic acid, the ice-water bath cooling, dripping thionyl chloride, the fully reaction that refluxes, after concentrating acyl chlorides; R1 substituted phenylpiperazine or its pharmaceutical salts or 2-naphthalene substituted-piperazinyl or its pharmaceutical salts are dissolved with chloroform, and stirring at room adds acyl chlorides, and fully reaction refluxes; Be chilled to room temperature, reaction solution washes with water, anhydrous Na
2SO
4Drying, column chromatography, chromatographic solution concentrate formula (I) or (II) described compound or pharmaceutically acceptable salt thereof;
R1 is single the replacement or polysubstituted C on the phenyl ring in the above-mentioned reactions steps
1-4Alkyl, C
1-4Alkoxyl group, trifluoromethyl, trifluoromethoxy or halogen; R2 is five yuan or hexa-member heterocycle, or replaces the benzo furan nucleus, or replaces aromatic ring.
The application of described aryl formyl piperazine compound in the preparation anti-arrhythmic.
The pharmaceutical salts of described compound is meant the hydrochloride or the fumarate of this compound.
Below the present invention is further illustrated:
The synthetic route of aryl formyl piperazine compound of the present invention (I) is as follows:
1. prepare compound (III)
Add propyl carbinol and Anhydrous potassium carbonate in mustargen, the substituted aniline (IV), stir, refluxed 30 hours, concentration of reaction solution, solid is separated out in refrigeration, with the dehydrated alcohol recrystallization, gets compound (III).
2. prepare compound (I)
Be dissolved in the chloroform in the compound (II), the ice-water bath cooling, dripping thionyl chloride refluxed 1 hour, got acyl chlorides after concentrating.Compound (III) is with the chloroform dissolving, and stirring at room slowly adds acyl chlorides, refluxes 5 hours.Be chilled to room temperature, successively with clear water and saturated NaHCO
3Solution washing, anhydrous Na
2SO
4Drying, column chromatography, chromatographic solution merge to concentrate compound (I).
Beneficial effect of the present invention:
Aryl formyl piperazine compound provided by the invention has very strong antiarrhythmic activity, and the proarrhythmia side effect of medicine as none; Characteristics such as its preparation method has the reaction conditions gentleness, and abundant raw material is easy to get, and operation and aftertreatment are simple.
One, biological activity determination:
The experiment title: the PC12 cell membrane potential changes experiment
Experimental technique: VSP is a kind of based on FRET (fluorescence resonance energy transfer) principle (Fluorescence Resonance EnergyTransfer, FRET) fluorescence dye, the variation of fluorescence can reflect the variation of cytolemma voltage indirectly, (Pheochromocytoma 12 to rat adrenal medullary pheochromocytoma cell to adopt this fluorescence dye to measure medicine, the PC12 cell) high flux screening of potassium channel inhibitors is carried out in the influence of membrane potential.
Experimental result sees Table 1.
The pharmacological action The selection result of aryl formyl piperazine compound in table 1 embodiment of the invention
| Compound number | Final concentration (M) | Reactivity | Active | IC 50(μM) | SD(n＝2) |
| Triethylamine blank embodiment 1 embodiment 2 embodiment 3 | 1.0×10 -4 1.0×10 -4 1.0×10 -4 1.0×10 -4 1.0×10 -4 | 1.50 2.00 1.45 1.47 1.34 | + + + | - - 91.26 66.49 77.89 | - - 9.69 3.58 8.16 |
| Embodiment 4 embodiment 5 embodiment 6 embodiment 7 embodiment 8 embodiment 10 embodiment 11 embodiment 12 embodiment 13 embodiment 14 embodiment 15 embodiment 16 embodiment 17 embodiment 18 embodiment 19 embodiment 20 embodiment 21 embodiment 22 DDPH Azimilide sotalol hydrochloride Amiodarone Hydrochlorides | 1.0×10 -4 1.0×10 -4 1.0×10 -4 1.0×10 -4 1.0×10 -4 1.0×10 -4 1.0×10 -4 1.0×10 -4 1.0×10 -4 1.0×10 -4 1.0×10 -4 1.0×10 -4 1.0×10 -4 1.0×10 -4 1.0×10 -4 1.0×10 -4 1.0×10 -4 1.0×10 -4 1.0×10 -4 1.0×10 -4 - - | 1.40 1.54 1.60 1.61 1.61 1.57 1.50 1.51 1.59 1.59 1.63 1.63 1.62 1.55 1.53 1.52 1.66 1.65 1.26 0.77 - - | + + + + + + + + + + + + + + + + + + + + | 71.33 371.36 51.71 51.30 27.22 52.88 64.86 98.42 78.34 92.34 53.16 86.61 63.12 69.95 73.42 101.72 104.74 126.29 4.16 - 99.45 33.81 | 33.30 67.98 33.19 26.21 3.00 9.58 1.06 6.93 3.65 23.26 27.68 35.58 22.46 12.43 50.45 16.33 42.57 31.08 0.99 - 39.73 5.22 |
Active regulation reactivity in the table is 1.75, the mean value that is positive control triethylamine and blank reactivity is diacritical point, "+" and " one " represent respectively reactivity less than or greater than 1.75, "+" represents that we think that this compound activity is better, and to its IC
50Calculate with the standard deviation of three mensuration.Because compd A zimilide solution is deep yellow, when strength of solution was big, strafing in the mensuration process at fluorescence had interference to the result, so do not calculate its IC
50Value.
The reactivity of compound has activity less than 2.00 these compounds of explanation.
Expressing aryl formyl piperazine compound from experimental result has very strong antiarrhythmic activity, can be used as antiarrhythmic drug.
Specific implementation method:
The invention will be further elaborated by the following examples, but do not limit the present invention.
General explanation:
Fusing point is measured with the micro-fusing point instrument of XT-4 type binocular (manufacturing of Tyke, Beijing Instr Ltd.); The IR spectrum is measured the KBr compressing tablet with NicoletImpact 410 type Fourier transform infrared spectroscopy determinators; Ultimate analysis is measured with Elementar VarioEL III type elemental analyser;
1H-NMR spectrum Bruker AMX-300, ACF-300, ACF-500 type nmr determination, TMS is interior mark; The MS spectrum is measured with Agilent 6890 GC/MS and Agilent 1100 Series LC/MSD type mass spectrographs.Thin-layer chromatography (TLC) plate adopts silica gel G F
254(Haiyang Chemical Plant, Qingdao) fully grinds shop, back system with 8 ‰ CMC-Na distilled water, and be standby after 1 hour through 100-120 ℃ of activation, ultraviolet lamp (3650 ) or iodine colour developing; Column chromatography adopts 100-200 order silica gel (Haiyang Chemical Plant, Qingdao's production), wet method dress post; Reagent is commercially available chemical pure or analytical pure product, except that specifying, and not treated direct use.
Embodiment 1:2-thienyl-[1-(4-(3-methyl) phenyl) piperazine] ketone hydrochloride
(1) adds meta-aminotoluene 1.07g (0.01mol), anhydrous K among the preparation of 1-(3-aminomethyl phenyl) piperazine hydrochloride: the mustargen 1.785g (0.01mol)
2CO
30.69g (0.005mol) and the 20ml propyl carbinol, stirring and refluxing 48 hours.Concentrate, solid is separated out in refrigeration, leaches, and solid gets white plates crystal 1.05g, m.p.:127-129 ℃ (dec), yield:49.41% with the dehydrated alcohol recrystallization.
(2) add the 10ml chloroform among the preparation of title compound: the thiophene-2-carboxylic acid 0.64g (0.005mol), dropping contains 2.38g (0.02mol) SOCl
2The 10ml chloroformic solution, refluxed 1 hour.Be concentrated into dried, with 15ml chloroform dissolving, the acyl chlorides chloroformic solution, stand-by.
Add the 10ml chloroform among 1-(3-methyl) the phenylpiperazine hydrochloride 0.53g (0.0025mol), stirring at room slowly drips above-mentioned acyl chlorides chloroformic solution, refluxes 8 hours.Reaction solution is successively with clear water, saturated NaHCO
3Solution washing, anhydrous Na
2SO
4Dry.Concentrate, (developping agent: ethyl acetate: sherwood oil=1: 4), product merges concentrated column chromatography, is yellow oil, drips HCl, separates out solid, leaches, and solid gets white powder 0.22g with the dehydrated alcohol recrystallization.m.p.：201-203℃，yield：27.23％
IR(KBr)，cm
-1：3057，2338，1610，1462，1432，1272，989，720，693
EI-MS：m/z286：
m/z111：
1H-NMR(CDCl
3)，δ：7.67(s，1H，
)，7.60(d，1H，
)，7.54(dd，1H，Ar-H)，7.39(m，2H，Ar-H)，7.28(d，1H，Ar-H)，7.10(q，1H，
)，4.54(s，4H，
)，3.50(s，4H，
)，2.42(s，3H，-CH
3)ppm。
Embodiment 2:2-benzofuryl-[1-(4-(3-methyl) phenyl) piperazine] ketone
Press the method preparation of embodiment 1, substitute thiophene-2-carboxylic acid with benzofurancarboxylic acid in the step (2), get the yellowish tabular crystal 0.29g of title compound, m.p.:167-168 ℃, yield:45.31%.
IR(KBr)，cm
-1：2823，1612，1443，1432，1248，953，773，748，689
EI-MS：m/z320：
m/z146：
1H-NMR(CDCl
3)，δ：7.67(dd，1H，
)，7.54(dd，1H，Ar-H)，7.42(t，1H，Ar-H)，7.35(s，1H，Ar-H)，7.31(t，1H，Ar-H)，7.18(t，1H，
)，6.75(t，3H，
)，4.01(s，4H，
)，3.27(d，4H，
)，2.33(s，3H，-CH
3)ppm。
Embodiment 3:3-chloro-phenyl--[1-(4-(3-methyl) phenyl) piperazine] ketone hydrochloride
Press the method for embodiment 1, substitute thiophene-2-carboxylic acid with m-chlorobenzoic acid in the step (2), get title compound white loose solid 0.30g.m.p.：199-200℃，yield：34.19％。
IR(KBr)，cm
-1：2998，2328，1655，1427，1256，1110，1035，926，767
EI-MS：m/z314：
m/z146：
1H-NMR(CDCl
3)，δ：7.68(s，1H，Ar-H)，7.60(dd，1H，Ar-H)，7.45-7.49(m，2H，Ar-H)，7.38-7.43(m，2H，Ar-H)，7.33-7.38(m，1H，Ar-H)，7.28-7.31(d，1H，Ar-H)，4.39(s，4H，
3.49(d，4H，
)，2.42(s，3H，-CH
3)ppm。
Embodiment 4:2-thienyl-[1-(4-(4-methyl) phenyl) piperazine] ketone
(1) preparation method of 1-(4-aminomethyl phenyl) piperazine hydrochloride: press the preparation of embodiment 1 method, step (1) raw material substitutes meta-aminotoluene with para-totuidine, gets 1-(4-aminomethyl phenyl) piperazine hydrochloride, is white plates crystal 1.21g, m.p.:232-233 ℃ (dec), yield:32.51%.
(2) press step (2) the method preparation of embodiment 1, substitute 1-(3-methyl) phenylpiperazine hydrochloride with 1-(4-aminomethyl phenyl) piperazine hydrochloride, the yellowish needle-like crystal 0.54g of title compound.m.p.：129-130℃，yield：76.22％；
IR(KBr)，cm
-1：3087，2818，1605，1513，1436，1231，1003，831，750；
EI-MS：m/z286：
m/z146(Base Peak)：
m/z111：
1H-NMR(CDCl
3)，δ：7.46(dd，1H，
)，7.33(dd，1H，
)，7.10(d，2H，Ar-H)，7.06(q，1H，
)，6.85(d，2H，Ar-H)，3.90(s，4H，
)，3.17(t，4H，
)，2.28(s，3H，-CH
3)ppm。
Embodiment 5:2-benzofuryl-[1-(4-(4-methyl) phenyl) piperazine] ketone
Press the method preparation of embodiment 4, substitute thiophene-2-carboxylic acid with benzofurancarboxylic acid in the step (2), get the yellowish tabular crystal 0.51g of title compound.m.p.：175-176℃，yield：79.69％。
IR(KBr)，cm
-1：2814，1612，1444，1431，1243，947，807，744；
EI-MS：m/z320：
m/z146(Base Peak)：
1H-NMR(CDCl
3)，δ：7.67(dd，1H，
)，7.54(dd，1H，Ar-H)，7.43(td，1H，Ar-H)，7.35(d，1H，Ar-H)，7.29(td，1H，Ar-H)，7.12(t，2H，
)，6.87(d，2H，
)，4.02(s，4H，
)，3.23(t，4H，
)，2.28(s，3H，-CH
3)ppm。
Embodiment 6:3-chloro-phenyl--[1-(4-(4-methyl) phenyl) piperazine] ketone
Press the method preparation of embodiment 4, substitute thiophene-2-carboxylic acid with m-chlorobenzoic acid in the step (2), get title compound white needle-like crystals 0.47g.m.p.：83-85℃，yield：74.72％。
IR(KBr)，cm
-1：2915，2811，1626，1515，1237，1020，816，763；
EI-MS：m/z314：
m/z146：
1H-NMR(CDCl
3)，δ：7.43-7.45(d，2H，Ar-H)，7.39(dt，1H，Ar-H)，7.34(d，1H，Ar-H)，7.28(d，1H，Ar-H)，7.12(d，2H，Ar-H)，6.89(s，1H，Ar-H)，3.61-3.95(d，4H，
3.16(d，4H，
)，2.31(s，3H，-CH
3)ppm。
Embodiment 7:3-nitrophenyl-[1-(4-(4-methyl) phenyl) piperazine] ketone
Press the method preparation of embodiment 4, substitute thiophene-2-carboxylic acid with M-NITROBENZOIC ACID in the step (2), get the golden yellow needle-like crystal 0.36g of title compound.m.p.：154-155℃，yield：44.31％。
IR(KBr)，cm
-1：2919，2826，1629，1525，1445，1347，1024，812，723；
EI-MS：m/z325：
m/z146：
1H-NMR(CDCl
3)，δ：8.31(m，2H，Ar-H)，7.78(dt，1H，Ar-H)，7.64(m，1H，Ar-H)，7.01-7.12(d，2H，Ar-H)，6.89(s，2H，Ar-H)，3.58-3.97(d，4H，
)，3.12(d，4H，
)，2.29(s，3H，-CH
3)ppm。
Embodiment 8:2-thienyl-[1-(4-(2, the 4-dimethyl) phenyl) piperazine] ketone
(1) 1-(2, the 4-3,5-dimethylphenyl) piperazine hydrochloride: press the method preparation of step among the embodiment 1 (1), with 2, the 4-xylidine substitutes meta-aminotoluene, gets white powder 1.15g, m.p.:226-228 ℃ (dec), yield:32.51%.
(2) preparation method of title compound: the method preparation of pressing step among the embodiment 1 (2), substitute 1-(3-methyl) phenylpiperazine hydrochloride with 1-(2, the 4-dimethyl) phenylpiperazine hydrochloride, get the colourless prism-shaped crystal of title compound 0.30g, m.p.:150-152 ℃, yield:50.0%
IR(KBr)，cm
-1：3078，2813，1601，1429，1261，1003，814，746；
EI-MS：m/z300：
m/z146：
m/z111：
1H-NMR(CDCl
3)，δ：7.45(dd，1H，
)，7.32(dd，1H，
)，7.06(q，1H，Ar-H)，6.97-7.02(t，2H，
Ar-H)，6.89-6.92(d，1H，Ar-H)，3.89(t，4H，
)，2.92(t，4H，
)，2.30(s，3H，-CH
3)，2.27(s，3H，-CH
3)ppm。
Embodiment 9:2-benzofuryl-[1-(4-(2, the 4-methyl) phenyl) piperazine] ketone
(1) add the 25ml chloroform among the preparation method of benzofurancarboxylic acid: the tonka bean camphor 14.6g (0.10mol), stirring and dissolving, ice-water bath cools off, and successively drips the 15ml chloroformic solution and 20ml S-WAT 20% aqueous solution of brominated 16.0g (0.10mol).Drip and finish, tell organic layer, clear water washing, anhydrous Na
2SO
4Drying concentrates, refrigeration, leach little citrine body (3,4-dibromo tonka bean camphor) 14.67g.
Add dehydrated alcohol 80ml among the KOH solid 30.68g (0.55mol), stir, ice-water bath is cooled to below 15 ℃, adds above-mentioned little citrine body, backflow 30min in batches.Add 150ml distilled water, wet distillation to effluent liquid is 250ml.The ice-water bath cooling adds a small amount of trash ice, and dripping concentrated hydrochloric acid adjusting pH is 1.Leach,, get yellowish needle-like crystal 6.58g with ethanol/water (v/v=1/1) recrystallization, m.p.:191-193 ℃, yield:84.62%.
(2) preparation method of title compound: press the method preparation of step among the embodiment 1 (2), substitute thiophene-2-carboxylic acid, get little yellow rounded grain 0.29g with benzofurancarboxylic acid.m.p.：129-130℃，yield：43.41％。
IR(KBr)，cm
-1：2852，1639，1561，1430，1220，1019，953，820，763，750：
EI-MS：m/z334：
m/z160(Base Peak)：
1H-NMR(CDCl
3)，δ：7.64-7.66(d，1H，
)，7.52(dd，1H，Ar-H)，7.39(td，1H，Ar-H)，7.32(d，1H，
)，7.27(t，1H，Ar-H)，7.02(t，1H，
)，6.97(d，1H，
)，6.91(d，1H，
)，3.98(s，4H，
)，2.96(s，4H，
)，2.28-2.32(m，6H，2-CH
3)ppm。
Embodiment 10:2-chloro-phenyl--[1-(4-(2, the 4-dimethyl) phenyl) piperazine] ketone
Press the method for step among the embodiment 8 (2), substitute thiophene-2-carboxylic acid, get title compound white needle-like crystals 0.38g with 0-chloro-benzoic acid.m.p.：132-133℃，yield：57.84％。
IR(KBr)，cm
-1：2997，2809，1642，1430，1222，1012，820，767，740；
EI-MS：m/z328：
m/z160(Base Peak)：
1H-NMR(CDCl
3)，δ：7.40-7.42(m，1H，Ar-H)，7.31-7.35(m，3H，Ar-H)，7.01(s，1H，Ar-H)，6.97(d，1H，Ar-H)，6.90(d，1H，Ar-H)，3.35-3.96(m，4H，
)，2.77-2.98(m，4H，
)，2.27(d，6H，2-CH
3)ppm。
Embodiment 11:3-chloro-phenyl--[1-(4-(2, the 4-dimethyl) phenyl) piperazine] ketone
Press the method for step among the embodiment 8 (2), substitute thiophene-2-carboxylic acid, get title compound white needle-like crystals 0.60g with m-chlorobenzoic acid.m.p.：107-109℃，yield：91.32％。
IR(KBr)，cm
-1：3047，2917，2826，1626，1426，1221，1021，768；
EI-MS：m/z328：
m/z160(Base Peak)：
1H-NMR(CDCl
3)，δ：7.46(t，1H，Ar-H)，7.434(d，1H，Ar-H)，7.39(t，1H，Ar-H)，7.345(d，1H，Ar-H)，7.04(s，1H，Ar-H)，7.01(d，1H，Ar-H)，6.93(d，1H，Ar-H)，3.58-3.95(m，4H，
)，2.92(d，4H，
)，2.31(d，6H，2-CH
3)ppm。
Embodiment 12:2-thienyl-[1-(4-(4-trifluoromethoxy) phenyl) piperazine] ketone hydrochloride
(1) preparation of 1-(4-Trifluoromethoxyphen-l) piperazine hydrochloride: press the method preparation of embodiment 1, raw material gets white crystal 1.27g, m.p.:236-238 ℃ (dec), yield:37.31% so that trifluoro-methoxyaniline is substituted meta-aminotoluene.
(2) preparation of title compound: the method preparation of pressing step among the embodiment 1 (2), substitute 1-(3-methyl) phenylpiperazine hydrochloride with 1-(4-Trifluoromethoxyphen-l) piperazine hydrochloride, drip concentrated hydrochloric acid at last and make title compound, be white plates crystal 0.40g.m.p.：169-170℃，yield：46.46％。
IR(KBr)，cm
-1：2349，1620，1516，1316，1278，1260，1159，984，726；
EI-MS：m/z356：
m/z216：
m/z111(Base Peak)：
1H-NMR(CDCl
3)，δ：7.90(d，2H，
)，7.54(dd，1H，Ar-H)，7.39(m，3H，Ar-H)，7.11(q，1H，
)，4.50(s，4H，
)，3.50(s，4H，
)ppm。
Embodiment 13:2-chloro-phenyl--[1-(4-(4-trifluoromethoxy) phenyl) piperazine] ketone
Press the method preparation of embodiment 12, substitute thiophene-2-carboxylic acid with 0-chloro-benzoic acid in the step (2), get title compound white powder 0.14g.m.p.：99-100℃，yield：14.58％。
IR(KBr)，cm
-1：2963，1630，1514，1261，1096，1016，799；
EI-MS：m/z384：
m/z216(Base Peak)：
1H-NMR(CDCl
3)，δ：7.41-7.43(m，1H，Ar-H)，7.30-7.37(m，3H，Ar-H)，7.15(d，2H，Ar-H)，6.98(d，2H，Ar-H)，3.46-4.08(m，4H，
)，3.10-3.30(m，4H，
)ppm。
Embodiment 14:3-chloro-phenyl--[1-(4-(4-trifluoromethoxy) phenyl) piperazine] ketone
Press the method preparation of embodiment 12, substitute thiophene-2-carboxylic acid with m-chlorobenzoic acid in the step (2), get the elongated needle-like crystal 0.27g of title compound white.m.p.：91-92℃，yield：35.76％。
IR(KBr)，cm
-1：3052，2314，1628，1512，1438，1278，1236，1161，1019，764；
EI-MS：m/z384：
m/z216：
1H-NMR(CDCl
3)，δ：7.41-7.43(m，2H，Ar-H)，7.35-7.38(m，1H，Ar-H)，7.28(d，1H，Ar-H)，7.13(d，2H，Ar-H)，6.90(d，2H，Ar-H)，3.70(d，4H，
)，3.16-3.20(m，4H，
)ppm。
Embodiment 15:4-chloro-phenyl--[1-(4-(4-trifluoromethoxy) phenyl) piperazine] ketone
Press the method preparation of embodiment 12, substitute thiophene-2-carboxylic acid with Chlorodracylic acid in the step (2), get title compound white needle-like crystals 0.29g.m.p.：100-101℃，yield：36.76％。
IR(KBr)，cm
-1：3059，2904，2812，1635，1505，1266，1220，1160，1005，854；
EI-MS：m/z384：
m/z216：
1H-NMR(CDCl
3)，δ：7.39-7.42(m，4H，Ar-H)，7.14(d，2H，Ar-H)，6.94(d，2H，Ar-H)，3.71(d，4H，
)，3.12(m，4H，
)ppm。
Embodiment 16:2-thienyl-[1-(4-(4-methoxyl group) phenyl) piperazine] ketone
(1) preparation method of 1-(4-p-methoxy-phenyl) piperazine hydrochloride: press the method for step among the embodiment 1 (1), substitute meta-aminotoluene, get faint yellow solid 1.07g, m.p.:230-232 ℃ (dec), yield:36.41% with m-anisidine.
(2) preparation method of title compound: the method preparation of pressing embodiment 1, substitute the meta-aminotoluene piperazine hydrochloride with intermediate 1-(4-p-methoxy-phenyl) piperazine hydrochloride, get the bright orange needle-like crystal 0.36g of title compound, m.p.:99-100 ℃, yield:59.60%;
IR(KBr)，cm
-1：2953，2818，1612，1514，1438，1245，1003，819，728；
EI-MS：m/z302：
m/z111(Base Peak)：
1H-NMR(CDCl
3)，δ：7.46(dd，1H，
)，7.33(dd，1H，
)，7.06(q，1H，
)，6.90(d，2H，Ar-H)，6.85(d，2H，Ar-H)，3.90(t，4H，
)，3.77(s，3H，-OCH
3)，3.10(t，4H，
)ppm。
Embodiment 17:2-benzofuryl-[1-(4-(4-methoxyl group) phenyl) piperazine] ketone
Press the method preparation of embodiment 9, substitute 2 with P-nethoxyaniline in the step (1), the 4-dimethoxyaniline gets title compound white plates crystal 0.40g.m.p.：177-178℃，yield：47.62％。
IR(KBr)，cm
-1：2810，1614，1513，1254，947，816，748；
EI-MS：m/z336：
m/z146：
1H-NMR(CDCl
3)，δ：7.66(d，1H，
)，7.54(dd，1H，Ar-H)，7.40(td，1H，Ar-H)，7.35(d，1H，Ar-H)，7.30(td，1H，Ar-H)，6.93(d，2H，
)，6.87(d，2H，
)，4.02(s，4H，
)，3.77(s，3H，-OCH
3)，3.16(s，4H，
)ppm。
Embodiment 18:2-chloro-phenyl--[1-(4-(4-methoxyl group) phenyl) piperazine] ketone
Press the method preparation of embodiment 16, substitute thiophene-2-carboxylic acid with 0-chloro-benzoic acid in the step (2), get title compound white crystal 0.42g.m.p.：142-144℃，yield：50.85％。
IR(KBr)，cm
-1：2814，1644，1511，1439，1242，1012，827，766；
EI-MS：m/z330：
m/z162：
1H-NMR(CDCl
3)，δ：7.41(m，1H，Ar-H)，7.31-7.34(m，3H，Ar-H)，6.89(d，2H，Ar-H)，6.84(d，2H，Ar-H)，3.94-4.00(m，2H，
)，3.76(s，3H，-OCH
3)，3.35-3.43(m，2H，
)，2.93-3.14(m，4H，
)ppm。
Embodiment 19:3-chloro-phenyl--[1-(4-(4-methoxyl group) phenyl) piperazine] ketone
Press the method preparation of embodiment 16, substitute thiophene-2-carboxylic acid with m-chlorobenzoic acid in the step (2), get title compound white crystal 0.43g.m.p.：92-94℃，yield：65.15％。
IR(KBr)，cm
-1：2833，1627，1511，1432，1251，1017，832，766；
EI-MS：m/z330：
m/z162(Base Peak)：
1H-NMR(CDCl
3)，δ：7.42-7.45(m，2H，Ar-H)，7.38(t，1H，Ar-H)，7.32(d，1H，Ar-H)，6.92(d，2H，Ar-H)，6.88(d，2H，Ar-H)，3.94(s，2H，
)，3.80(s，3H，-OCH
3)，3.65(s，2H，
)，3.09(d，4H，
)ppm。
Embodiment 20:2-thienyl-[1-(4-(2, the 4-difluoro) phenyl) piperazine] ketone
(1) preparation of 1-(2,4 difluorobenzene base) piperazine hydrochloride: press the method preparation of embodiment 1, substitute meta-aminotoluene, get white solid 1.35g with 2,4 difluorobenzene amine, m.p.:180-182 ℃, yield:53.61%.
(2) preparation of title compound: pressing the preparation of embodiment 1 method, is raw material with intermediate 1-(2,4 difluorobenzene base) piperazine hydrochloride, gets title compound white plates crystal 0.41g, m.p.:89-90 ℃, and yield:66.56%;
IR(KBr)，cm
-1：3075，2841，1601，1508，1444，1272，1139，1002，846，718；
EI-MS：m/z308：
m/z197：
m/z111(Base Peak)：
1H-NMR(CDCl
3)，δ：7.46(d，1H，
)，7.32(d，1H，
)，7.06(t，1H，Ar-H)，6.83(m，1H，
)，6.80(d，2H，Ar-H)，3.92(t，4H，
)，3.06(t，4H，
)ppm。
Embodiment 21:4-chloro-phenyl--[1-(4-(2, the 4-difluoro) phenyl) piperazine] ketone
Press the method preparation of embodiment 20, substitute thiophene-2-carboxylic acid with Chlorodracylic acid in the step (2), get the tiny needle-like crystal 0.21g of title compound white.m.p.：124-125℃，yield：31.20％。
IR(KBr)，cm
-1：2823，1636，1504，1442，1283，1010，838；
EI-MS：m/z336：
m/z197：
1H-NMR(CDCl
3)，δ：7.39(t，4H，Ar-H)，6.84(m，1H，Ar-H)，6.80(m，2H，Ar-H)，3.70(d，4H，
)，3.02(m，4H，
)ppm。
Embodiment 22:2-thienyl-[1-(4-(5-naphthyl)) piperazine] ketone
(1) preparation of 1-naphthylpiperazine hydrochloride: press the method preparation of embodiment 1, substitute meta-aminotoluene, get yellowish tabular crystal 1.00g with naphthalidine.m.p.：218-220℃(dec)，yield：53.80％。
(2) preparation of title compound: pressing the preparation of embodiment 1 method, is raw material with intermediate 1-naphthylpiperazine hydrochloride, gets the little yellow needle-like crystal 0.37g of title compound.m.p.：108-110℃，yield：57.45％；
IR(KBr)，cm
-1：2935，2831，1602，1433，1262，998，777；
EI-MS：m/z322：
m/z127：
m/z111(Base Peak)：
1H-NMR(CDCl
3)，δ：8.20(d，1H，
)，7.90(d，1H，
)，7.59(d，1H，
)，7.46-7.50(m，3H，
)，7.36(dd，1H，
)，7.35(m，1H，
)，7.06(m，2H，
)，4.09(s，4H，
)，3.17(s，4H，
)ppm。
Embodiment 23:2-furyl-[1-(4-(2-ethyl-5-methoxyl group) phenyl)-piperazine] ketone
Press the preparation of embodiment 1 method, substitute meta-aminotoluene with 2-ethyl-4 anisidine in the step (1), substitute thiophene-2-carboxylic acid with furancarboxylic acid in the step (2), get white solid 0.87g.m.p.：78-80℃，yield：67.65％。
IR(KBr)，cm
-1：2935，2851，1612，1420，1262，998，797；
EI-MS：m/z314：
m/z95(Base Peak)：
1H-NMR(CDCl
3)，δ：7.7(d，1H，
)，7.23(d，1H，
)，6.83(m，1H，Ar-H)，6.61(m，1H，
)，6.00-6.12(m，2H，Ar-H)，3.73(s，3H，OCH
3)，3.61(s，4H，
)，3.20(s，4H，
)，2.59(q，2H，CH
2CH
3)，1.60(t，3H，CH
2CH
3)ppm。
Embodiment 24:(2, the 5-dichlorophenyl) [1-(4-p-methylphenyl) piperazine] ketone
Press the preparation of embodiment 1 method, with 2, the 5-dichlorobenzoic acid substitutes meta-aminotoluene in the step (2), gets white solid 0.91g.m.p.：98-100℃，yield：77.65％。
IR(KBr)，cm
-1：2933，2853，1603，1415，1263，994，794；
EI-MS：m/z349：
m/z174(Base Peak)：
1H-NMR(CDCl
3)，δ：7.90(d，1H，Ar-H)，7.39-7.46(m，2H，Ar-H)，6.88-6.92(m，2H，Ar-H)，645-6.48(m，2H，Ar-H)，3.65(s，4H，
)，3.27(s，4H，
)，2.35(s，3H，phCH
3)ppm。
Embodiment 25:[(3,4-two trifluoromethoxies) phenyl] [1-(4-(3,4, the 5-trichlorine) phenyl) piperazine] ketone
Press the preparation of embodiment 1 method, with 3,4, the 5-trichloroaniline substitutes meta-aminotoluene in the step (1), and with 3,4-two trifluoro-methoxy-benzoic acids substitute thiophene-2-carboxylic acid in the step (2), gets white solid 1.10g.m.p.：128-130℃，yield：57.52％。
IR(KBr)，cm
-1：2934，2853，1613，1417，1265，997，798；
EI-MS：m/z537：
m/z273(Base Peak)：
1H-NMR(CDCl
3)，δ：7.35-7.40(m，2H，Ar-H)，6.84-6.86(m，1H，Ar-H)，6.40-6.44(m，2H，Ar-H)，3.67(s，4H，
)，3.45(s，4H，
)ppm。
Embodiment 26:[4-(3-bromo-4-propyl group) phenylpiperazine-1-yl] (3-chloro-4-p-methoxy-phenyl) ketone
Press the preparation of embodiment 1 method, substitute meta-aminotoluene with 2-bromo-4-n-propyl aniline in the step (1), substitute thiophene-2-carboxylic acid with 3-chloro-4-methoxybenzoic acid in the step (2), get white solid 0.67g.m.p.：113-115℃，yield：69.62％。
IR(KBr)，cm
-1：2932，2853，1613，1412，1263，997，792；
EI-MS：m/z452：
m/z169(Base Peak)：
1H-NMR(CDCl
3)，δ：7.72-7.85(m，2H，Ar-H)，6.86-6.89(m，1H，Ar-H)，6.68-6.73(m，2H，Ar-H)，6.41-6.46(m，1H，Ar-H)，3.73(s，3H，-OCH
3)，3.67(s，4H，
)，3.45(s，4H，
)，2.55(t，2H，phCH
2CH
2CH
3)，1.66(m，2H，phCH
2CH
2CH
3)，0.96(q，3H，phCH
2CH
2CH
3)ppm。
Get this white solid and be dissolved in an amount of ethanol, drip the saturated ethanolic soln of fumaric acid, reaction promptly gets the fumarate of target compound.
Claims (7)
1. aryl formyl piperazine compound is general formula (I) or (II) described compound or pharmaceutically acceptable salt thereof:
In the formula, R1 is single the replacement or polysubstituted C on the phenyl ring
1-4Alkyl, C
1-4Alkoxyl group, trifluoromethyl, trifluoromethoxy or halogen; R2 is five yuan or hexa-member heterocycle, or replaces the benzo furan nucleus, or replaces aromatic ring.
2. according to claims 1 described aryl formyl piperazine compound, it is characterized in that the substituting group of R1 representative is-CH
3,-C
2H
5,-C
3H
7,-C
4H
9,-OCH
3,-OC
2H
5,-OC
3H
7,-OC
4H
9,-CF
3,-OCF
3,-F ,-Cl ,-Br ,-among the I one or more; Substituting group among the R2 is-CH
3,-C
2H
5,-C
3H
7,-C
4H
9,-OCH
3,-OC
2H
5,-OC
3H
7,-OC
4H
9,-CF
3,-OCF
3,-F ,-Cl ,-Br ,-I ,-NO
2In one or more, five-membered ring is furan nucleus, thiphene ring or pyrrole ring.
3. according to claims 1 described aryl formyl piperazine compound, it is characterized by that described R1 is polysubstituted to be meant 2,6-is two to be replaced, 2, and 5-is two to be replaced, 2, and 4-is two to be replaced and 2, and 3-is two to be replaced; Perhaps 2,3,4-three replaces, 2,3, and 5-three replaces, 2,3, and 6-three replaces, 2,4, and 5-three replaces, 2,4, and 6-three replaces and 2,5, and 6-three replaces; Perhaps 2,3,4,5-four replaces, 2,3,4, and 6-four replaces and 2,4,5, and 6-four replaces.
4, aryl formyl piperazine compound according to claim 1, the pharmaceutical salts that it is characterized in that described compound is meant the hydrochloride or the fumarate of this compound.
5. as the preparation method of aryl formyl piperazine compound as described in claims 1, it is characterized in that this method comprises the following steps:
(1) will add propyl carbinol and Anhydrous potassium carbonate in mustargen, the R1 substituted aniline, stirring and refluxing is fully reacted, and concentrates, and solid is separated out in refrigeration, and recrystallization gets R1 substituted phenylpiperazine or its pharmaceutical salts;
(2) R2 replaced add chloroform in the formic acid, the ice-water bath cooling, dripping thionyl chloride, the fully reaction that refluxes, after concentrating acyl chlorides; R1 substituted phenylpiperazine or its pharmaceutical salts or 2-naphthalene substituted-piperazinyl or its pharmaceutical salts are dissolved with chloroform, and stirring at room adds acyl chlorides, and fully reaction refluxes; Be chilled to room temperature, reaction solution washes with water, anhydrous Na
2SO
4Drying, column chromatography, chromatographic solution concentrate formula (I) or (II) described compound or pharmaceutically acceptable salt thereof;
R1 is single the replacement or polysubstituted C on the phenyl ring in the above-mentioned reactions steps
1-4Alkyl, C
1-4Alkoxyl group, trifluoromethyl, trifluoromethoxy or halogen; R2 is five yuan or hexa-member heterocycle, or replaces the benzo furan nucleus, or replaces aromatic ring.
6, preparation method according to claim 5 is characterized in that described pharmaceutical salts is hydrochloride or fumarate.
7. the application of the described aryl formyl piperazine compound of claim 1 in the preparation anti-arrhythmic.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200610097267A CN1944424B (en) | 2006-10-27 | 2006-10-27 | Aryl formyl piperazine compound and its preparing method and use in medicine production |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200610097267A CN1944424B (en) | 2006-10-27 | 2006-10-27 | Aryl formyl piperazine compound and its preparing method and use in medicine production |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1944424A true CN1944424A (en) | 2007-04-11 |
| CN1944424B CN1944424B (en) | 2010-05-12 |
Family
ID=38044096
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN200610097267A Expired - Fee Related CN1944424B (en) | 2006-10-27 | 2006-10-27 | Aryl formyl piperazine compound and its preparing method and use in medicine production |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1944424B (en) |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102285962A (en) * | 2011-06-23 | 2011-12-21 | 中国药科大学 | Phenoxy alkyl piperazine compounds, preparation method thereof and medicinal use thereof |
| CN102363615A (en) * | 2011-11-14 | 2012-02-29 | 连云港宏业化工有限公司 | Method for synthesizing 2-thiophenecarbonyl chloride |
| JP2013536873A (en) * | 2010-09-06 | 2013-09-26 | グアンジョウ インスティテュート オブ バイオメディスン アンド ヘルス，チャイニーズ アカデミー オブ サイエンスィズ | Amide compounds |
| CN103833711A (en) * | 2013-12-13 | 2014-06-04 | 成都丽璟科技有限公司 | Preparation method for benzofuran-2-carboxylic acid |
| WO2017046794A1 (en) | 2015-09-14 | 2017-03-23 | The National Institute for Biotechnology in the Negev Ltd. | Novel piperazine and piperidine derivatives, their synthesis and use thereof in inhibiting vdac oligomerization, apoptosis and mitochondria dysfunction |
| US10434099B2 (en) | 2016-09-22 | 2019-10-08 | The National Institute for Biotechnology in the Negev Ltd. | Methods for treating central nervous system disorders using VDAC inhibitors |
| US10787423B2 (en) | 2015-09-14 | 2020-09-29 | The National Institute For Biotechnolgy In The Negev Ltd. | Piperazine and piperidine derivatives, their synthesis and use thereof in inhibiting VDAC oligomerization, apoptosis and mitochondria dysfunction |
| CN112430223A (en) * | 2020-11-24 | 2021-03-02 | 中国人民解放军海军军医大学 | Substituted benzoyl piperazine compounds and application thereof |
-
2006
- 2006-10-27 CN CN200610097267A patent/CN1944424B/en not_active Expired - Fee Related
Cited By (17)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2013536873A (en) * | 2010-09-06 | 2013-09-26 | グアンジョウ インスティテュート オブ バイオメディスン アンド ヘルス，チャイニーズ アカデミー オブ サイエンスィズ | Amide compounds |
| US9238643B2 (en) | 2010-09-06 | 2016-01-19 | Guangzhou Institutes Of Biomedicine And Health, Chinese Academy Of Sciences | Amide compounds |
| CN102285962A (en) * | 2011-06-23 | 2011-12-21 | 中国药科大学 | Phenoxy alkyl piperazine compounds, preparation method thereof and medicinal use thereof |
| CN102285962B (en) * | 2011-06-23 | 2013-04-10 | 中国药科大学 | Phenoxy alkyl piperazine compounds, preparation method thereof and medicinal use thereof |
| CN102363615A (en) * | 2011-11-14 | 2012-02-29 | 连云港宏业化工有限公司 | Method for synthesizing 2-thiophenecarbonyl chloride |
| CN103833711A (en) * | 2013-12-13 | 2014-06-04 | 成都丽璟科技有限公司 | Preparation method for benzofuran-2-carboxylic acid |
| EP3350182A4 (en) * | 2015-09-14 | 2019-03-13 | The National Institute for Biotechnology in the Negev Ltd. | Novel piperazine and piperidine derivatives, their synthesis and use thereof in inhibiting vdac oligomerization, apoptosis and mitochondria dysfunction |
| CN108290889A (en) * | 2015-09-14 | 2018-07-17 | 内盖夫国家生物技术研究所 | New piperazine and piperidine derivative, their synthesis and its purposes in inhibiting VDAC oligomerizations, Apoptosis and mitochondria dysfunction |
| WO2017046794A1 (en) | 2015-09-14 | 2017-03-23 | The National Institute for Biotechnology in the Negev Ltd. | Novel piperazine and piperidine derivatives, their synthesis and use thereof in inhibiting vdac oligomerization, apoptosis and mitochondria dysfunction |
| US10508091B2 (en) | 2015-09-14 | 2019-12-17 | The National Institute for Biotechnology in the Negev Ltd. | Piperazine and piperidine derivatives, their synthesis and use thereof in inhibiting VDAC oligomerization, apoptosis and mitochondria dysfunction |
| US10787423B2 (en) | 2015-09-14 | 2020-09-29 | The National Institute For Biotechnolgy In The Negev Ltd. | Piperazine and piperidine derivatives, their synthesis and use thereof in inhibiting VDAC oligomerization, apoptosis and mitochondria dysfunction |
| EP3736272A1 (en) * | 2015-09-14 | 2020-11-11 | The National Institute for Biotechnology in the Negev Ltd. | Novel piperazine and piperidine derivatives, their synthesis and use thereof in inhibiting vdac oligomerization, apoptosis and mitochondria dysfunction |
| US10946013B2 (en) | 2015-09-14 | 2021-03-16 | The National Institute for Biotechnology in the Negev Ltd. | Methods for treating central nervous system disorders using vdac inhibitors |
| CN108290889B (en) * | 2015-09-14 | 2021-08-10 | 内盖夫国家生物技术研究所 | Novel piperazine and piperidine derivatives, their synthesis and their use in inhibiting VDAC oligomerization, apoptosis and mitochondrial dysfunction |
| US11472777B2 (en) | 2015-09-14 | 2022-10-18 | The National Institute for Biotechnology in the Negev Ltd. | Piperazine and piperidine derivatives, their synthesis and use thereof in inhibiting VDAC oligomerization, apoptosis and mitochondria dysfunction |
| US10434099B2 (en) | 2016-09-22 | 2019-10-08 | The National Institute for Biotechnology in the Negev Ltd. | Methods for treating central nervous system disorders using VDAC inhibitors |
| CN112430223A (en) * | 2020-11-24 | 2021-03-02 | 中国人民解放军海军军医大学 | Substituted benzoyl piperazine compounds and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1944424B (en) | 2010-05-12 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN1944424A (en) | Aryl formyl piperazine compound and its preparing method and use in medicine production | |
| CN1319958C (en) | Phenyl-piperazine derivatives as serotonin reuptake inhibitors | |
| CN1157366C (en) | Dimethyl-(3-aryl-but-3-enyl)-amine compounds as pharmaceutical active ingredients | |
| CN1922162A (en) | Derivatives of alkylpiperazine- and alkylhomopiperazine-carboxylates, preparation method thereof and use of same as FAAH enzyme inhibitors | |
| CN1186492A (en) | Imidazo [1, 2-alpha] pyridine derivatives | |
| CN1891220A (en) | 2-amino-3-(alkyl)-pyrimidone derivatives as gsk3.beta. inhibitors | |
| KR20100017885A (en) | Heteroaryl-substituted urea modulators of fatty acid amide hydrolase | |
| CN1069309C (en) | N-(3-aminopropyl)-N-phenyl-5,6,7,8-tetrahydronaphtalene-2-carboxamide derivative, preparation and application of same | |
| CN1028521C (en) | Therapeutic agents | |
| CN1105360A (en) | 1-[2H-1-benzopyran-2-one-8yl]-piperazin derivative | |
| CN1071755C (en) | Heterocyclylcarboxamide derivatives and their use as therapeutic agents | |
| CN1203235A (en) | New chromene compounds, process for their preparation and pharmaceutical compositions containing them | |
| CN1944404A (en) | Indolyl alkyl-amine compounds and their preparing method and use in medicine production | |
| US20060094719A1 (en) | Tetralin histamine-3 receptor antagonists | |
| CN1768053A (en) | Pyrazole compounds. | |
| CN1743316A (en) | 2-substituted phenyl-4,4,5,5-tetramethyl-1,3,-dioxy imidazolines, their preparation and pharmaceutical use | |
| CN1041088C (en) | Optically active imidazolidinone derivative and process for prodn. of same | |
| CN1069491A (en) | 2-(piperidines-1-yl) alcohol derivative, its method for making and treatment thereof are used | |
| CN1738808A (en) | Cyclization process for substituted benzothiazole derivatives | |
| CN88101782A (en) | antiarrhythmic agents | |
| CN1944416A (en) | Benzimidazole compound and its preparing method and use in medicine production | |
| CN1564686A (en) | 8-amino- [1,2,4]triazolo [1,5-a]pyridine-6-carboxylic acid amide | |
| CN1469862A (en) | 2,2-diphenyl butanamide derivatives and medicines containing the same | |
| CN1107469A (en) | Cyclic amine derivatives | |
| CN1721416A (en) | Substituted methylene pyrones derivatives and their preparing process and use |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20100512 Termination date: 20171027 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |