CN101284838A - Ethylene imine derivates with thienopyridine, preparation method and applications thereof - Google Patents
Ethylene imine derivates with thienopyridine, preparation method and applications thereof Download PDFInfo
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- CN101284838A CN101284838A CNA2008100534446A CN200810053444A CN101284838A CN 101284838 A CN101284838 A CN 101284838A CN A2008100534446 A CNA2008100534446 A CN A2008100534446A CN 200810053444 A CN200810053444 A CN 200810053444A CN 101284838 A CN101284838 A CN 101284838A
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- pyridine
- carbonyl
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Abstract
The invention belongs to the anti-platelet aggregation drug technical field and provides Piperazine derivatives containing thieno pyridine with the structure as showed in general formula (I) and pharmaceutically acceptable salt thereof, wherein R1 and R2=hydrogen, methyl, ethide, carboxyl and hydroxyl; R3=hydrogen; C1-C4 is for alkyl; C5-C6 is for naphthenic base; CH2R5, COR6, SO2R7, R8, R9 and R10 replace phenyl; R11 replace heterocyclic radical, wherein the definition of R4-R11 is the same as described in the instructions. The invention also relates to a preparation method of the compound, and meanwhile discloses a drug combination that uses the compound or the pharmaceutically acceptable salt as active ingredients and an application thereof in respect to anti-platelet aggregation drugs.
Description
Technical field
The invention belongs to medical technical field, or rather, relate to a class and have compound of antiplatelet aggregative activity and preparation method thereof.
Background technology
The most normal clinically antiplatelet drug that uses is acetylsalicylic acid or thiophene chloropyridine (Ticlopidine) at present.Adp receptor antagonist thiophene chloropyridine is first thienopyridine medicine, by the exploitation listing of French Sanofi company.Because the effect of thiophene chloropyridine inhibition thrombocyte reaches with acetylsalicylic acid, double density and does not wait traditional antiplatelet drug different, it not only suppresses a certain platelet aggregation incitant, and suppressed accumulation process itself, so once in clinical, used widely.Clopidogrel is second thienopyridine medicine of French Sanofi company development, compares with thiophene chloropyridine, and many carboxymethyls on the side chain only on the structure, but its anti-bolt effect is stronger, and ADR is then little than thiophene chloropyridine.In June, 1998, Britain went on the market in the U.S., and go on the market in China August calendar year 2001.In multinomial broad scale research, clopidogrel is better than other drug aspect the prognosis that improves the ischemia incident, and ADR is few than thiophene chloropyridine, and security is better than acetylsalicylic acid, thereby clopidogrel has replaced the application of thiophene chloropyridine in many cases.But accept the clopidogrel treatment and TTP and hemolytic uremic syndrome (HUS) have also occurred.So need to seek more safe and effective such medicine.
Synthetic method and summary about Thienopyridines are found in following document:
CN1683373；US4681888；US4529596；GB1501797；WO02059128；US4174448；GB1561504；WO2004094374；JP6135970；JP63264588。
Summary of the invention
One object of the present invention is, discloses the piperazine derivative and the pharmaceutical salts thereof of thienopyridine.
Another object of the present invention is that the piperazine derivative and the pharmaceutical salts thereof that disclose with thienopyridine are the pharmaceutical composition of main active ingredient.
A further object of the present invention is, discloses the piperazine derivative of thienopyridine and the preparation method of pharmaceutical salts thereof.
A further object of the invention is, the piperazine derivative and the pharmaceutical salts thereof of thienopyridine are disclosed, application as the antiplatelet drug aspect, particularly be used to prepare the coronary syndrome that prevention or treatment cause because of platelet aggregation, myocardial infarction, myocardial ischemia, the purposes of cardiovascular and cerebrovascular diseases medicament aspect.
The present invention is specifically related to the compound and the pharmacy acceptable salt thereof of general formula I structure:
X is
(q=0,1,2), R
4Be hydrogen, methyl, ethyl;
Y is a nitrogen, carbon, oxygen;
m＝1，2；
n＝0，1；
p＝0，1，2；
R
1, R
2Be hydrogen, methyl, ethyl, carboxyl, hydroxyl;
R
3(when Y is nitrogen, carbon, R
3Exist) be
(a) hydrogen; C
1-C
4Alkyl, C
5-C
6Cycloalkyl, this alkyl or cycloalkyl can be replaced by halogen, hydroxyl, carboxyl, amino, phenyl, and this phenyl can be by halogen, C
1-C
4Alkyl, C
1-C
4Alkoxyl group, hydroxyl, carboxyl, nitro replace;
(b) CH
2R
5, R
5For containing O, S, N five yuan, hexa-member heterocycle, these five yuan, hexa-member heterocycle can be by halogen, C
1-C
4Alkyl, hydroxyl, carboxyl, nitro replace; Phenyl, this phenyl can be by halogen, C
1-C
4Alkyl, C
1-C
4Alkoxyl group, hydroxyl, carboxyl, nitro, styryl replace;
(c) COR
6, R
6Be C
1-C
4Alkyl, this alkyl can be by halogen, hydroxyl, carboxyl substituted; Phenyl, this phenyl can be by halogen, C
1-C
4Alkyl, C
1-C
4Alkoxyl group, hydroxyl, carboxyl, nitro replace; Contain O, S, N five yuan, hexa-member heterocycle, these five yuan, hexa-member heterocycle can be by halogen, C
1-C
4Alkyl, halogenophenyl replace;
(d) SO
2R
7, R
7Be C
1-C
4Alkyl, this alkyl can be by halogen, hydroxyl, carboxyl substituted; Phenyl, this phenyl can be by halogen, C
1-C
4Alkyl, C
1-C
4Alkoxyl group, hydroxyl, carboxyl, nitro replace; Contain O, S, N five yuan, hexa-member heterocycle, these five yuan, hexa-member heterocycle can be by halogen, C
1-C
4Alkyl, halogenophenyl replace;
R wherein
8, R
9, R
10Be hydrogen, C
1-C
4Alkyl, this alkyl can be by halogen, hydroxyl, carboxyl, nitro, the amino replacement, halogen, hydroxyl, carboxyl, nitro, amino, C
1-C
4Alkoxyl group;
Wherein Z is O, S, N, (r=0,1), R
11Be halogen, C
1-C
4Alkyl, C
1-C
4Alkylamino, C
1-C
4Replace alkylamino, C
1-C
4Dialkyl amido, C
1-C
4Replace dialkyl amido, halogenophenyl.
C of the present invention
1-C
4Alkyl and replaced C by halogen, hydroxyl, carboxyl, phenyl
1-C
4Alkyl comprises methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, trifluoromethyl, chloroethyl, fluoro ethyl, hydroxyethyl, propyloic, diphenyl-methyl, dichlorobenzene methyl, tolyl methyl, anisole ylmethyl; C
1-C
4Alkoxyl group or chlorine, fluorine list or disubstituted C
1-C
4Alkoxyl group can be methoxyl group, oxyethyl group, propoxy-, uncle's propoxy-, butoxy, isopropoxy, chloroethoxy, chlorine propoxy-, 1,1-dichloro propoxy-, 1-fluoro-2-chlorine propoxy-or the like.
Described C
1-C
4Alkylamino, C
1-C
4Replace alkylamino, C
1-C
4Dialkyl amido, C
1-C
4Replacing dialkyl amido can be ethylamino, third amino, fourth amino, hydroxyethylamino, hydroxy propyl amido, hydroxyl fourth amino, chloroethene amino, chlorine third amino, neoprene amino, two hydroxyethylaminos, dichloro ethylamino or the like.
Described replacement contain heteroatomic five yuan, hexa-member heterocycle, heteroatoms is selected from O, S, N, can be N-methyl piperidine-4-base, N-ethylpiperidine-4-base, N-sec.-propyl piperidin-4-yl, 2,2,6,6-tetramethyl piperidine-4-base, tetramethylene sulfide-3-base, tetrahydrofuran (THF)-4-base, tetrahydric thiapyran-4-group or the like.
Compound or its pharmacy acceptable salt with formula I structure of the present invention means: The compounds of this invention and mineral acid, organic acid salify; particularly preferred salt is: hydrochloride, hydrobromate, hydriodate, vitriol, hydrosulfate, phosphoric acid salt, acetate, propionic salt, butyrates, lactic acid salt, mesylate; tosilate, maleate, benzoate, succinate, tartrate, Citrate trianion, fumarate, taurate or the like.As described salt, they can also be the salt that forms with conventional alkali, for example basic metal (for example sodium salt or sylvite), alkaline-earth metal (for example calcium salt and magnesium salts) or derived from the ammonium salt of ammonia or organic amine.
Compound or its pharmacy acceptable salt with formula I structure of the present invention, wherein part of compounds is:
I-1-1 N-{[(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) carbonyl] methyl } piperazine
I-1-2 N-{[(4,5,6, the 7-tetramethylene sulfide is [2,3-c] pyridine-5-yl also) carbonyl] ethyl } high piperazine
I-1-3 1-methyl-4-{[(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) carbonyl] methyl } piperazine
I-1-4 1-ethyl-4-{[(4,5,6, the 7-tetramethylene sulfide is [2,3-c] pyridine-5-yl also) carbonyl] ethyl } piperazine
I-1-5 1-methylol-4-{1-[(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) carbonyl] propyl group } piperazine
I-1-6 1-cyclohexyl-4-{[(4,5,6, the 7-tetramethylene sulfide is [2,3-c] pyridine-5-yl also) carbonyl] ethyl } piperazine
I-1-7 N-{[(4,5,6, the 7-tetramethylene sulfide is [2,3-c] pyridine-5-yl also) carbonyl] ethyl } Pyrrolidine
I-1-8 1-{[(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) carbonyl] methyl }-3,5-dimethyl-piperidines
I-1-9 N-{[(4,5,6, the 7-tetramethylene sulfide is [2,3-c] pyridine-5-yl also) carbonyl] ethyl } piperidines
I-1-10 1-{[(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) carbonyl] methyl }-the 3-hydroxy-piperdine
I-1-11 1-{1-[(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) carbonyl] propyl group }-3-carboxyl-piperidines
I-1-12 1-{[(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) carbonyl] methyl }-4-carbamyl phenylpiperidines
I-1-13 N-{[(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) carbonyl] ethyl } morpholine
I-1-14 1-(diphenyl-methyl)-4-{[(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) carbonyl] methyl } piperazine
I-1-15 1-(4-chloro-diphenyl-methyl)-4-{[(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) carbonyl] methyl } piperazine
I-2-1 1-styryl-4-{1-[(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) carbonyl] propyl group } piperazine
I-3-1 1-(2-furancarbonyl)-4-{[(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) carbonyl] methyl } piperazine
I-3-2 1-(2-tetrahydrofuran (THF) formyl radical)-4-{[(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) carbonyl] methyl } piperazine
I-3-3 1-(2-tetrahydrofuran (THF) formyl radical)-2-methyl-4-{[(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) carbonyl] methyl } piperazine
I-4-1 1-(to the Methyl benzenesulfonyl base)-4-{1-[(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) carbonyl] propyl group } piperazine
I-4-2 1-(to the Methyl benzenesulfonyl base)-2-carboxyl-4-{[(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) carbonyl] methyl } piperazine
I-5-1 1-(2, the 4-3,5-dimethylphenyl)-4-{[(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) carbonyl] methyl } piperazine
I-5-2 1-phenyl-4-{[(4,5,6, the 7-tetramethylene sulfide is [2,3-c] pyridine-5-yl also) carbonyl] ethyl } piperazine
I-5-3 1-(3-trifluoromethyl)-4-{[(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) carbonyl] methyl } piperazine
I-5-4 1-(2-trifluoromethyl)-4-{1-[(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) carbonyl] propyl group } piperazine
I-5-5 1-(4-trifluoromethyl)-4-{[(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) carbonyl] methyl } piperazine
I-5-6 1-(2,4-two trifluoromethyls)-4-{[(4,5,6, the 7-tetramethylene sulfide is [2,3-c] pyridine-5-yl also) carbonyl] ethyl } piperazine
I-5-7 1-(2-chloro-phenyl-)-4-{[(4,5,6, the 7-tetramethylene sulfide is [2,3-c] pyridine-5-yl also) carbonyl] ethyl } piperazine
I-5-8 1-(3-chloro-phenyl-)-4-{1-[(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) carbonyl] propyl group } piperazine
I-5-9 1-(4-chloro-phenyl-)-4-{[(4,5,6, the 7-tetramethylene sulfide is [2,3-c] pyridine-5-yl also) carbonyl] ethyl } piperazine
I-5-10 1-(2,4 dichloro benzene base)-4-{1-[(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) carbonyl] propyl group } piperazine
I-5-11 1-(2-fluorophenyl)-4-{[(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) carbonyl] methyl } piperazine
I-5-12 1-(3-fluorophenyl)-4-{[(4,5,6, the 7-tetramethylene sulfide is [2,3-c] pyridine-5-yl also) carbonyl] ethyl } piperazine
I-5-13 1-(4-fluorophenyl)-4-{[(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) carbonyl] methyl } piperazine
I-5-14 1-(2,4 difluorobenzene base)-4-{[(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) carbonyl] methyl } piperazine
I-5-15 1-(4-nitrophenyl)-4-{[(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) carbonyl] methyl } piperazine
I-5-16 1-(2-nitrophenyl)-4-{[(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) carbonyl] methyl } piperazine
I-5-17 1-(4-nitrophenyl)-4-{[(4,5,6, the 7-tetramethylene sulfide is [2,3-c] pyridine-5-yl also) carbonyl] ethyl } piperazine
I-5-18 1-(4-nitrophenyl)-4-{1-[(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) carbonyl] propyl group } piperazine
I-5-19 1-(2-p-methoxy-phenyl)-4-{[(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) carbonyl] methyl } piperazine
I-6-1 1-(2-pyridyl)-4-{[(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) carbonyl] methyl } piperazine
The preparation route of formula I compound:
Wherein compound 2, and (EP0342118, EP0465358 JP62103088) can conveniently make to press document.
Wherein two kinds are expressed as follows with reaction:
(2) and (4) then (
Br-X-Cl) under alkaline condition, make (3) in-30 ℃～35 ℃ reactions; (3) respectively with (5), (6), (10), (11) in 0 ℃～90 ℃ down reactions, generate I-1, I-2, I-5 and I-6, i.e. formula I compound under alkaline condition; And (3) earlier with (7) reaction, more respectively with (8) and (9) under alkaline condition, 0 ℃～90 ℃ reactions generate I-3 and I-4 respectively.
Reaction makes all cpds or oxide compound or oxyhydroxide that products therefrom is dissolved in dropping inorganic acid, organic acid, basic metal, alkaline-earth metal among DMF, acetone, methyl alcohol, ethanol or the DMSO is made pharmacy acceptable salt.
Specifically be that products therefrom is dissolved among DMF, acetone, methyl alcohol, ethanol or the DMSO, dripping hydrochloric acid ethanol is made hydrochloride to pH2.Or products therefrom is dissolved in DMF, acetone, methyl alcohol or ethanol, molar lactic acid such as adding, its lactic acid salt.Also this compound can be dissolved in DMF or the ethanol, drip the aqueous solution of potassium hydroxide, transfer pH9, make its sylvite or the like.
This compounds is effective for the human disease that causes because of platelet aggregation of treatment.Although compound of the present invention can be without the direct administration of any preparation, described all cpds preferably uses with the form of pharmaceutical preparation, and route of administration can be non-enteron aisle approach (as vein, muscle administration) and oral administration.
The preparation of pharmaceutical compositions of The compounds of this invention is as follows: use standard and conventional technology; acceptable solid or liquid vehicle are combined, and make it at random to combine and be prepared into particulate or microballoon with acceptable auxiliary and vehicle on the technology of pharmaceutics.Solid dosage comprises tablet, discrete particles, capsule, slow releasing tablet, sustained release pellet or the like.Solid carrier can be at least a material, and it can serve as thinner, flavouring agent, solubilizing agent, lubricant, suspension agent, tackiness agent, disintegrating agent and coating agent.Inert solid carrier comprises trimagnesium phosphate, Magnesium Stearate, smoothers sugar, lactose, pectin, propylene glycol, Polysorbate 80, dextrin, starch, gelatin, cellulose substances for example methylcellulose gum, Microcrystalline Cellulose, low melt point paraffin, polyoxyethylene glycol, N.F,USP MANNITOL, theobroma oil etc.Liquid dosage form comprises solvent, suspension for example injection, pulvis or the like.
The amount of the active ingredient that contains in pharmaceutical composition and the unit dosage form (The compounds of this invention) can specifically be applied according to patient's the state of an illness, the situation of diagnosis, and the amount of used compound or concentration are regulated in the scope of a broad.Usually, the weight range of active compound is 0.5%～90% (weight) of composition, and another preferred range is 0.5%-70%.
Compound or its pharmacy acceptable salt with formula I structure of the present invention has the obvious suppression effect aspect platelet aggregation.
Further specify The compounds of this invention to the rat platelet aggregation restraining effect below by pharmacodynamic experiment.
Test materials:
Medicine and preparation: The compounds of this invention (TY I-1-1～TY I-6-1) is made into suspension with 0.5%CMC and uses for animals administer; Adenosine diphosphate (ADP) (ADP) (SERVA company).
Animal: male rat, Tianjin Inst. of Materia Medica laboratory animal room provides, animal conformity certification number: No. the 001st, Tianjin animal word.
Instrument: PK121R type whizzer (Italian ALC International SPL product), SPA-3 type PPP platelet aggregation instrument (Shanghai Kodak testing tool factory).
Test method:
Male Wistar rat, about body weight 300g, per os is irritated stomach and is given Clopidogrel Hydrogensulfate and analogue thereof, and dosage is 10mg/kg, the administration volume is 10mL/kg, behind the 2h, etherization, aorta abdominalis blood sampling, 3.8% Sodium Citrate anti-freezing, whole blood is 9: 1 with the ratio of antithrombotics, the centrifugal 7min of 1000rpm, preparation platelet rich plasma (PPP).Transfer PRP with PPP, make its platelet count remain on 2 * 10
6Individual/mL.Get PRP and add in the test cup, 37 ℃ of temperature are incubated 10min.With the PRP zeroing, PPP transfers 100%, is inductor with ADP (final concentration is 5 μ M), measures platelet aggregation percentage ratio by turbidimetry with SPA-3 type PPP platelet aggregation instrument, with t-check carrying out statistics relatively, the results are shown in following table.
The invention compound is to the influence of ADP inductive platelet aggregation
By table as seen, compound of the present invention can obviously suppress ADP inductive platelet aggregation.Therefore, they can be used for preventing or treating the coronary syndrome that causes because of platelet aggregation, myocardial infarction, cardiovascular and cerebrovascular diseases such as myocardial ischemia.
Embodiment
The present invention is described further below in conjunction with embodiment, and embodiment only is indicative, means that never it limits the scope of the invention by any way.Described compound is through high performance liquid chromatography (HPLC), and thin-layer chromatography (TLC) detects.Can adopt subsequently such as infrared spectra (IR), nuclear magnetic resonance spectrum (
1HNMR,
13C NMR), mass spectrum (MS) etc. is further proved conclusively its structure.
Embodiment 1:
The preparation of intermediate 3 (3.1)
Add 4,5,6 in the reaction flask that stirring, condenser, thermometer are housed, the 7-tetramethylene sulfide is [3,2-c] pyridine 27.8g also, with the 150mL methylene dichloride it is dissolved, and is cooled to-20 ℃ under stirring, and adds salt of wormwood 41.9g.Chloroacetyl chloride 24.8g is dissolved in the 200mL methylene dichloride, slowly is added dropwise to reaction system, dropwise, continue reaction 2h (the flaggy demonstration reacts completely) down in-20 ℃.With 3 * 300mL water washing reaction solution, divide and get dichloromethane layer, use the anhydrous sodium sulphate thorough drying, to filter, methylene dichloride is to the greatest extent steamed in decompression, promptly gets light yellow oily product 42.5g (HPLC:98.5%).The Rf=0.75[single-point, developping agent: v (sherwood oil): v (ethyl acetate)=1: 3].
1H?NMR(CDCl
3，400MHz)δ：2.741～2.769(t，1H，＝C-CH
2-C-)，2.851～2.879(t，1H，＝C-CH
2-C-)，3.660～3.688(t，1H，-C-CH
2-N-)，3.780～3.809(t，1H，-C-CH
2-N-)，4.074～4.085(d，2H，＝C-CH
2-N-)，4.502～4.538(d，2H，O＝C-CH
2-Cl)，6.683～6.715(m，1H，-C-CH-C＝)，7.028～7.057(t，1H，-C＝CH-S-)。
Embodiment 2:
The preparation of intermediate 3 (3.2)
Add 4,5,6 in the reaction flask that stirring, condenser, thermometer are housed, the 7-tetramethylene sulfide is [2,3-c] pyridine 27.8g also, with the 150mL trichloromethane it is dissolved, and is cooled to-15 ℃ under stirring, and adds triethylamine 40.5g.34.6g is dissolved in the 200mL trichloromethane with 1-chlorine propionyl bromide, slowly is added dropwise to reaction system, dropwises, and continues reaction 2h (the flaggy demonstration reacts completely) down in-15 ℃.With 3 * 300mL water washing reaction solution, divide and get the trichloromethane layer, use the anhydrous sodium sulphate thorough drying, to filter, trichloromethane is to the greatest extent steamed in decompression, promptly gets light yellow oily product 41.7g (HPLC:99.1%).The Rf=0.68[single-point, developping agent: v (sherwood oil): v (ethyl acetate)=1: 3].
Embodiment 3:
The preparation of intermediate 3 (3.3)
Add 4,5,6 in the reaction flask that stirring, condenser, thermometer are housed, the 7-tetramethylene sulfide is [3,2-c] pyridine 27.8g also, with the 150mL methylene dichloride it is dissolved, and is cooled to-5 ℃ under stirring, and adds pyridine 38.6g.50.6g is dissolved in the 200mL methylene dichloride with 2-bromo butyryl bromide, slowly is added dropwise to reaction system, dropwises, and continues reaction 2h (the flaggy demonstration reacts completely) down in-5 ℃.With 3 * 300mL water washing reaction solution, divide and get dichloromethane layer, use the anhydrous sodium sulphate thorough drying, to filter, methylene dichloride is to the greatest extent steamed in decompression, promptly gets orange oily product 56.4g (HPLC:97.8%).The Rf=0.82[single-point, developping agent: v (sherwood oil): v (ethyl acetate)=1: 3].
Embodiment 4:
N-{[(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) carbonyl] methyl } piperazine (Compound I-1-1)
In the reaction flask that stirring, condenser, thermometer are housed, add 1.42g intermediate 3.1, it is dissolved, stir adding salt of wormwood 2.8g down with the 10mL methylene dichloride.The 0.6g Piperazine anhydrous is added reaction system in batches.Add, continue reaction 8h (the flaggy demonstration reacts completely) down in 10 ℃.With 3 * 15mL water washing reaction solution, divide and get dichloromethane layer, use the anhydrous sodium sulphate thorough drying, to filter, methylene dichloride is to the greatest extent steamed in decompression, promptly gets light yellow oily product (HPLC:99.3%).The Rf=0.43[single-point, developping agent: v (methylene dichloride): v (methyl alcohol)=1: 1].
1H?NMR(D
2O，400MHz)δ：2.794～2.902(m，4H，＝N-CH
2-C-)，3.192～3.286(m，2H，＝C-CH
2-C-)，3.509～3.556(m，9H，O＝C-CH-N；＝C-CH
2-NH；＝N-CH
2-C-)，3.747～3.800(m，1H，＝C-CH
2-N＝)，4.563～4.590(d，1H，＝C-CH
2-N＝)，6.847～6.869(t，1H，-C＝CH-C＝)，7.235～7.257(t，1H，-C＝CH-S-)。MS，m/Z：265.0(M)，223.0，153.1，110.0，99.0，69.0，35.9。
Embodiment 5:
N-{[(4,5,6, the 7-tetramethylene sulfide is [2,3-c] pyridine-5-yl also) carbonyl] ethyl } high piperazine (Compound I-1-2)
In the reaction flask that stirring, condenser, thermometer are housed, add 1.42g intermediate 3.2, it is dissolved, stir adding triethylamine 1.3g down with the 10mL trichloromethane.The high piperazine of 0.66g is added reaction system in batches.Add, reflux and continue reaction 6h (the flaggy demonstration reacts completely).With 3 * 15mL water washing reaction solution, divide and get the trichloromethane layer, use the anhydrous sodium sulphate thorough drying, to filter, trichloromethane is to the greatest extent steamed in decompression, promptly gets nearly colorless oil product (HPLC:98.2%).
Embodiment 6:
1-methyl-4-{[(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) carbonyl] methyl } piperazine (Compound I-1-3)
In the reaction flask that stirring, condenser, thermometer are housed, add 1.89g intermediate 3.1, it is dissolved, stir adding pyridine 1.4g down with the 10mL methylene dichloride.The 0.9g methylpiperazine slowly is added dropwise to reaction system.Dropwise, continue reaction 7h (the flaggy demonstration reacts completely) down in 30 ℃.With 3 * 15mL water washing reaction solution, divide and get dichloromethane layer, use the anhydrous sodium sulphate thorough drying, to filter, methylene dichloride is to the greatest extent steamed in decompression, promptly gets colorless oil product (HPLC:98.9%).The Rf=0.54[single-point, developping agent: v (methylene dichloride): v (methyl alcohol)=1: 1],
1H NMR (DMSO-d
6, 400MHz) δ: 2.817～2.933 (m, 5H ,-CH
3=C-CH
2-C-), 3.153～3.843 (m, 10H ,-N-CH
2-C-), 4.344～4.592 (m, 4H, O=C-CH-N;=C-CH
2-N), 6.875～6.928 (m, 1H ,-C=CH-C=), 7.349～7.475 (m, 1H ,-C=CH-S-).MS，m/Z：279.1(M)，223.1，179.1，113.1，99.1，70.1，36.0。
Embodiment 7:
1-ethyl-4-{[(4,5,6, the 7-tetramethylene sulfide is [2,3-c] pyridine-5-yl also) carbonyl] ethyl } piperazine (Compound I-1-4)
Method with reference to embodiment 4 replaces piperazine with ethyl piperazidine, with intermediate 3.2 reactions, gets colorless oil (HPLC:98.6%).The Rf=0.57[single-point, developping agent: v (methylene dichloride): v (methyl alcohol)=1: 1].
Embodiment 8:
1-methylol-4-{1-[(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) carbonyl] propyl group } piperazine (Compound I-1-5)
With reference to the method for embodiment 4, replace piperazine with the methylol piperazine, with intermediate 3.3 reactions, get colorless oil (HPLC:97.5%).The Rf=0.48[single-point, developping agent: v (methylene dichloride): v (methyl alcohol)=1: 1].
Embodiment 9:
1-cyclohexyl-4-{[(4,5,6, the 7-tetramethylene sulfide is [2,3-c] pyridine-5-yl also) carbonyl] ethyl } piperazine (Compound I-1-6)
With reference to the method for embodiment 4, replace piperazine with the cyclohexyl piperazine, with intermediate 3.2 reactions, get light yellow oil (HPLC:99.2%).The Rf=0.68[single-point, developping agent: v (methylene dichloride): v (methyl alcohol)=1: 1].
Embodiment 10:
N-{[(4,5,6, the 7-tetramethylene sulfide is [2,3-c] pyridine-5-yl also) carbonyl] ethyl } Pyrrolidine (Compound I-1-7)
Method with reference to embodiment 4 replaces piperazine with Pyrrolidine, with intermediate 3.2 reactions, gets grey oily matter (HPLC:98.6%).The Rf=0.56[single-point, developping agent: v (methylene dichloride): v (methyl alcohol)=1: 1].
Embodiment 11:
1-{[(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) carbonyl] methyl }-3,5-dimethyl-piperidines (Compound I-1-8)
In the reaction flask that stirring, condenser, thermometer are housed, add 1.2g intermediate 3.1, it is dissolved, stir adding yellow soda ash 1.1g down with 10mL toluene.With 0.62g3,5-dimethyl-piperidines adds reaction system in batches.Add, continue reaction 5h (the flaggy demonstration reacts completely) down in 55 ℃.With 3 * 15mL water washing reaction solution, divide and get toluene layer, use the anhydrous sodium sulphate thorough drying, to filter, toluene is to the greatest extent steamed in decompression, promptly gets faint yellow solid product (HPLC:97.3%).The Rf=0.40[single-point, developping agent: v (sherwood oil): v (ethyl acetate)=3: 2],
1H NMR (DMSO-d
6, 400MHz) δ: 0.417～0.898 (m, 7H, CH
3-C-CH
2-C-), 1.222～1.652 (m, 5H ,-C-CH
2-C-; CH;=C-CH
2-C-), 1.702～2.863 (m, 4H ,=N-CH
2-C-), 3.144～3.299 (m, 2H, O=C-CH-N), 3.727～3.796 (m, 2H ,-C-CH
2-N=), 4.494 (s, 1H ,=C-CH
2-N-), 4.653 (s, 1H ,=C-CH
2-N-), 6.849～6.882 (t, 1H ,-C=CH-C=), 7.306～7.319 (d, 1H ,-C=CH-S-).MS，m/Z：292.1(M)，126.1，110.0，55.1，30.0。
Embodiment 12:
N-{[(4,5,6, the 7-tetramethylene sulfide is [2,3-c] pyridine-5-yl also) carbonyl] ethyl } piperidines (Compound I-1-9)
With reference to the method for embodiment 11, replace 3 with piperidines, 5-dimethyl-piperidines with intermediate 3.2 reactions, gets yellow solid (HPLC:96.9%).The Rf=0.36[single-point, developping agent: v (sherwood oil): v (ethyl acetate)=3: 2].
Embodiment 13:
1-{[(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) carbonyl] methyl }-the 3-hydroxy-piperdine (Compound I-1-10)
In the reaction flask that stirring, condenser, thermometer are housed, add 1.2g intermediate 3.1, it is dissolved, stir adding yellow soda ash 1.1g down with the 10mL methylene dichloride.The 0.62g3-hydroxy piperidine is added reaction system in batches.Add, continue reaction 5h (the flaggy demonstration reacts completely) down in 55 ℃.With 3 * 15mL water washing reaction solution, divide and get dichloromethane layer, use the anhydrous sodium sulphate thorough drying, to filter, methylene dichloride is to the greatest extent steamed in decompression, promptly gets faint yellow solid product (HPLC:97.3%).The Rf=0.40[single-point, developping agent: v (sherwood oil): v (ethyl acetate)=3: 2],
1H NMR (CDCl
3, 400MHz) δ: 1.788 (m, 4H ,-C-CH
2-C-;-C-CH
2-C-), 2.363 (m, 1H ,-OH), 2.840～2.867 (t, 1H ,-N-CH
2-C-), 2.996 (s, 1H ,-N-CH
2-C-), 3.422 (s, 2H ,-N-CH
2-C-), 3.589～3.617 (d, 2H ,=C-CH
2-C-), 3.720～3.769 (t, 1H ,-CH-OH), 3.865～3.891 (t, 1H ,-CO-CH
2-N-), 4.251 (s, 1H ,-CO-CH
2-N-), 4.319 (s, 1H ,-C-CH
2-N-), 4.478 (s, 1H ,-C-CH
2-N-), 4.587～4.629 (d, 2H ,=C-CH
2-N-), 6.772～6.824 (dd, 1H ,-C=CH-C=), 7.125～7.144 (m, 1H ,-C=CH-S-).MS，m/Z：280.0(M)，179.0，137.0，114.1，84.0，44.0，30.0。
Embodiment 14:
1-{1-[(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) carbonyl] propyl group }-3-carboxyl-piperidines (Compound I-1-11)
With reference to the method for embodiment 13, replace the 3-hydroxy-piperdine with 3-carboxyl-piperidines, with intermediate 3.3 reactions, get white solid (HPLC:98.6%).The Rf=0.13[single-point, developping agent: v (sherwood oil): v (ethyl acetate)=3: 2].
Embodiment 15:
1-[[(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) carbonyl] methyl }-4-carbamyl phenylpiperidines (Compound I-1-12)
In the reaction flask that stirring, condenser, thermometer are housed, add 1.5g intermediate 3.1, it is dissolved, stir adding sodium bicarbonate 1.8g down with the 10mL trichloromethane.0.82g4-carbamyl phenylpiperidines is added reaction system in batches.Add, continue reaction 10h (the flaggy demonstration reacts completely) in refluxing down.With 3 * 15mL water washing reaction solution, divide and get the trichloromethane layer, use the anhydrous sodium sulphate thorough drying, to filter, trichloromethane is to the greatest extent steamed in decompression, promptly gets light yellow sticky oily product (HPLC:99.3%).The Rf=0.53[single-point, developping agent: v (methyl alcohol): v (water)=1: 1],
1H NMR (DMSO-d
6, 400MHz) δ: 1.441～1.659 (m, 4H ,-C-CH
2-C-), 1.933～2.055 (m, 3H, O=C-CH-C;=C-CH
2-C-), 2.737～2.880 (m, 4H ,-N-CH
2-C-), 3.165～3.186 (d, 2H, O=C-CH-N), 3.726～3.806 (m, 2H ,-C-CH
2-N-), 4.495 (s, 1H ,=C-CH
2-N-), 4.659 (s, 1H ,=C-CH
2-N-), 6.672～6.705 (d, 1H ,-C=CH-C=), 6.868～6.881 (d, 1H ,-NH
2), 7.173～7.210 (d, 1H ,-C=CH-S-), 7.308～7.321 (d, 1H ,-NH
2).MS，m/Z：307.0(M)，141.0，98.0，69.0，28.0。
Embodiment 16:
N-{[(4,5,6, the 7-tetramethylene sulfide is [2,3-c] pyridine-5-yl also) carbonyl] ethyl } morpholine (Compound I-1-13)
With reference to the method for embodiment 15, for 4-carbamyl phenylpiperidines,, get pink colour oily matter (HPLC:97.4%) with intermediate 3.2 reactions with morpholino.The Rf=0.25[single-point, developping agent: v (sherwood oil): v (ethyl acetate)=3: 2].
Embodiment 17:
1-(diphenyl-methyl)-4-{[(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) carbonyl] methyl } piperazine (Compound I-1-14)
In the reaction flask that stirring, condenser, thermometer are housed, add 2.2g intermediate 3.1, it is dissolved, stir adding potassium hydroxide 1.68g down with the 10mL methylene dichloride.The 2.5g1-benzhydryl piperazidine is added reaction system in batches.Add, continue reaction 7.5h (the flaggy demonstration reacts completely) down in 35 ℃.With 3 * 15mL water washing reaction solution, divide and get dichloromethane layer, use the anhydrous sodium sulphate thorough drying, to filter, methylene dichloride is to the greatest extent steamed in decompression, promptly gets yellow sticky oily product (HPLC:98.6%).The Rf=0.52[single-point, developping agent: v (sherwood oil): v (ethyl acetate)=1: 3],
1H NMR (DMSO-d
6, 400MHz) δ: 2.799～2.957 (d, 2H ,-C-CH
2-N-), 3.299～3.456 (m, 2H ,-C-CH
2-N-), 3.706～3.820 (m, 6H ,-N-CH
2-C-,=C-CH
2-C-), 3.989～4.043 (m, 1H ,-N-CH-ph), 4.452～4.573 (m, 6H ,-N-CH
2-C-,-CO-CH
2-N-), 6.864～6.911 (m, 1H ,-C=CH-C=), 7.332～7.431 (m, 7H ,-C=CH-S-, ph-H), 7.918 (s, 4H, ph-H).
Embodiment 18:
1-(4-chloro-diphenyl-methyl)-4-{[(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) carbonyl] methyl } piperazine (Compound I-1-15)
In the reaction flask that stirring, condenser, thermometer are housed, add 2.16g intermediate 3.1, it is dissolved, stir adding triethylamine 2.02g down with the 10mL methylene dichloride.2.87g1-(4-chlorobenzhydryl) piperazine is added reaction system in batches.Add, continue reaction 10h (the flaggy demonstration reacts completely) in refluxing down.With 3 * 15mL water washing reaction solution, divide and get dichloromethane layer, use the anhydrous sodium sulphate thorough drying, to filter, methylene dichloride is to the greatest extent steamed in decompression, promptly gets lightpink solid (HPLC:96.2%).The Rf=0.50[single-point, developping agent: v (sherwood oil): v (ethyl acetate)=1: 3],
1H NMR (DMSO-d
6, 400MHz) δ: 2.781～2.947 (d, 3H ,-C-CH
2-N-), 3.348～3.818 (m, 10H ,-C-CH
2-N-,-N-CH-ph), 4.453～4.571 (m, 4H ,-N-CH
2-C-,=C-CH
2-C-), 6.870～6.907 (m, 1H ,-C=CH-C=), 7.286～7.733 (m, 11H ,-C=CH-S-, ph-H).
Embodiment 19:
1-styryl-4-{1-[(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) carbonyl] propyl group } piperazine (Compound I-2-1)
With reference to the method for embodiment 18, replace 1-(4-chlorobenzhydryl) piperazine with 1-styryl piperazine, with intermediate 3.3 reactions, get pale solid (HPLC:96.3%).The Rf=0.64[single-point, developping agent: v (sherwood oil): v (ethyl acetate)=3: 2].
Embodiment 20:
1-(2-furancarbonyl)-4-{[(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) carbonyl] methyl } piperazine (Compound I-3-1)
In the reaction flask that stirring, condenser, thermometer are housed, add 2.0g intermediate 3.1, it is dissolved, stir adding triethylamine 2.2g down with the 10mL trichloromethane.1.29g1-(2-furancarbonyl) piperazine is added reaction system in batches.Add, continue reaction 6h (the flaggy demonstration reacts completely) in refluxing down.With 3 * 15mL water washing reaction solution, divide and get the trichloromethane layer, use the anhydrous sodium sulphate thorough drying, to filter, trichloromethane is to the greatest extent steamed in decompression, promptly gets light yellow solid (HPLC:95.8%).The Rf=0.25[single-point, developping agent: ethyl acetate],
1H NMR (CDCl
3, 400MHz) δ: 2.134 (s, 2H ,-C-CH
2-N-), 2.876 (s, 1H ,-C-CH
2-N-), 3.001 (s, 1H ,-C-CH
2-N-), 3.069～3.135 (m, 1H ,-C-CH
2-N-), 3.220 (s, 1H ,-C-CH
2-N-), 3.631～3.723 (m, 4H ,-C-CH
2-N-,=C-CH
2-C-), 3.825～3.908 (m, 2H ,-CO-CH
2-N-), 4.258 (s, 1H ,-C-CH
2-N-), 4.408 (s, 1H ,-C-CH
2-N-), 4.544 (s, 1H ,=C-CH
2-N-), 4.637 (s, 1H ,=C-CH
2-N-), 6.508 (s, 1H ,-C=CH-C=), 6.766～6.809 (m, 1H ,-C=CH-S-), 7.082～7.170 (m, 2H ,-C=CH-C-), 7.491 (s, 1H ,-O-CH=C-).MS，m/Z：359.0(M)，318.0，193.1，152.0，86.1，42.0，36.0。
Embodiment 21:
1-(2-tetrahydrofuran (THF) formyl radical)-4-{[(4,5,6, the 7-tetramethylene sulfide is [2,3-c] pyridine-5-yl also) carbonyl] ethyl } piperazine (Compound I-3-2)
With reference to the method for embodiment 20, replace 1-(2-furancarbonyl) piperazine with 1-(2-tetrahydrofuran (THF) formyl radical) piperazine, with intermediate 3.2 reactions, get light yellow solid (HPLC:96.8%).The Rf=0.23[single-point, developping agent: ethyl acetate].
Embodiment 22:
1-(2-tetrahydrofuran (THF) formyl radical)-2-methyl-4-{[(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) carbonyl] methyl } piperazine (Compound I-3-3)
In the reaction flask that stirring, condenser, thermometer are housed, add 2.16g intermediate 3.1, it is dissolved, stir adding triethylamine 3.0g down with the 10mL methylene dichloride.The 1.01g2-methylpiperazine is added reaction system in batches.Add, continue reaction 8h (the flaggy demonstration reacts completely) in refluxing down.With 3 * 15mL water washing reaction solution, divide and get dichloromethane layer, use the anhydrous sodium sulphate thorough drying, to filter, methylene dichloride is to the greatest extent steamed in decompression, promptly gets yellow oil product.The Rf=0.40[single-point, developping agent: v (methylene dichloride): v (methyl alcohol)=1: 1].
The oily product is added in the reaction flask, it is diluted slightly, stir adding triethylamine 2.5g down with the 10mL trichloromethane.1.34g tetrahydrofuran (THF) formyl chloride is added reaction system in batches.Add, continue reaction 12h (the flaggy demonstration reacts completely) in refluxing down.With 3 * 15mL water washing reaction solution, divide and get the trichloromethane layer, use the anhydrous sodium sulphate thorough drying, to filter, trichloromethane is to the greatest extent steamed in decompression, promptly gets yellow solid (HPLC:97.1%).The Rf=0.27[single-point, developping agent: ethyl acetate].
Embodiment 23:
1-(to the Methyl benzenesulfonyl base)-4-{1-[(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) carbonyl] propyl group } piperazine (Compound I-4-1)
With reference to the method for embodiment 20, with 1-Methyl benzenesulfonyl base-piperazine is replaced 1-(2-furancarbonyl) piperazine, with intermediate 3.3 reactions, get yellow solid (HPLC:98.6%).The Rf=0.34[single-point, developping agent: ethyl acetate].
Embodiment 24:
1-(to the Methyl benzenesulfonyl base)-2-carboxyl-4-{[(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) carbonyl] methyl } piperazine (Compound I-4-2)
With reference to the method for embodiment 22 and 23, replace the 2-methylpiperazine with 2-carboxyl piperazine, with intermediate 3.1 reactions, get colorless oil, Rf=0.30[single-point, developping agent: v (methylene dichloride): v (methyl alcohol)=1: 1].With this oily matter and Tosyl chloride reaction, get yellow solid (HPLC:98.2%).The Rf=0.23[single-point, developping agent: v (methylene dichloride): v (methyl alcohol)=1: 1].
Embodiment 25:
1-(2, the 4-3,5-dimethylphenyl)-4-{[(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) carbonyl] methyl } piperazine (Compound I-5-1)
In the reaction flask that stirring, condenser, thermometer are housed, add 2.16g intermediate 3.1, it is dissolved, stir adding triethylamine 2.02g down with the 10mL methylene dichloride.With 1.62g2, the 4-dimethylphenylpiperazinium slowly is added dropwise to reaction system.Add, continue reaction 12h (the flaggy demonstration reacts completely) in refluxing down.With 3 * 15mL water washing reaction solution, divide and get dichloromethane layer, use the anhydrous sodium sulphate thorough drying, to filter, methylene dichloride is to the greatest extent steamed in decompression, promptly gets yellow oil (HPLC:99.1%).The Rf=0.61[single-point, developping agent: v (sherwood oil): v (ethyl acetate)=1: 3].
1H?NMR(DMSO-d
6，400MHz)δ：2.208(s，6H，-CH
3)，2.828(s，1H，-C-CH
2-N-)，2.966～2.978(t，1H，-C-CH
2-N-)，3.119(s，4H，-C-CH
2-N-)，3.388(s，2H，-C-CH
2-N-)，3.565(s，2H，-CO-CH
2-N-)，3.680～3.708(t，1H，-C-CH
2-N-)，3.837～3.865(t，1H，-C-CH
2-N-)，4.536～4.548(d，2H，＝C-CH
2-N-)，4.614(s，2H，＝C-CH
2-C-)，6.901～6.993(m，4H，-C＝CH-C＝，-C＝CH-S-，ph-H)，7.361～7.411(m，1H，ph-H)。
Embodiment 26:
1-phenyl-4-{[(4,5,6, the 7-tetramethylene sulfide is [2,3-c] pyridine-5-yl also) carbonyl] ethyl } piperazine (Compound I-5-2)
With reference to the method for embodiment 25, replace 2 with phenylpiperazine, the 4-dimethylphenylpiperazinium with intermediate 3.2 reactions, gets white solid (HPLC:99.4%).The Rf=0.59[single-point, developping agent: v (sherwood oil): v (ethyl acetate)=1: 3].
Embodiment 27:
1-(3-trifluoromethyl)-4-{[(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) carbonyl] methyl } piperazine (Compound I-5-3)
In the reaction flask that stirring, condenser, thermometer are housed, add 2.16g intermediate 3.1, it is dissolved, stir adding triethylamine 30.3g down with the 10mL methylene dichloride.2.30g1-(3-trifluoromethyl) piperazine slowly is added dropwise to reaction system.Add, continue reaction 10h (the flaggy demonstration reacts completely) in refluxing down.With 3 * 15mL water washing reaction solution, divide and get dichloromethane layer, use the anhydrous sodium sulphate thorough drying, to filter, methylene dichloride is to the greatest extent steamed in decompression, promptly gets yellow oil (HPLC:98.2%).The Rf=0.51[single-point, developping agent: v (sherwood oil): v (ethyl acetate)=1: 3].
1H?NMR(DMSO-d
6，400MHz)δ：2.811～2.837(t，1H，-C-CH
2-N-)，2.953～2.966(t，1H，-C-CH
2-N-)，2.989～3.055(m，2H，-C-CH
2-N-)，3.316(s，3H，-C-CH
2-N-)，3.599～3.690(m，3H，-C-CH
2-N-，-CO-CH
2-N-)，3.830～3.937(m，2H，＝C-CH
2-C-)，4.531～4.559(d，2H，＝C-CH
2-N-)，4.609～4.650(d，2H，-C-CH
2-N-)，6.880～6.933(dd，1H，ph-H)，7.133～7.151(d，1H，-C＝CH-C＝)，7.253～7.293(m，2H，ph-H，-C＝CH-S-)，7.357～7.401(m，1H，ph-H)，7.446～7.486(m，1H，ph-H)。
Embodiment 28:
1-(2-trifluoromethyl)-4-{1-[(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) carbonyl] propyl group } piperazine (Compound I-5-4)
With reference to the method for embodiment 27, replace 1-(3-trifluoromethyl) piperazine with 1-(2-trifluoromethyl) piperazine, with intermediate 3.3 reactions, get off-white color solid (HPLC:99.0%).The Rf=0.52[single-point, developping agent: v (sherwood oil): v (ethyl acetate)=1: 3].
Embodiment 29:
1-(4-trifluoromethyl)-4-{[(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) carbonyl] methyl } piperazine (Compound I-5-5)
With reference to the method for embodiment 27, replace 1-(3-trifluoromethyl) piperazine with 1-(4-trifluoromethyl) piperazine, with intermediate 3.1 reactions, get Off-white solid (HPLC:98.7%).The Rf=0.49[single-point, developping agent: v (sherwood oil): v (ethyl acetate)=1: 3].
Embodiment 30:
1-(2,4-two trifluoromethyls)-4-{[(4,5,6, the 7-tetramethylene sulfide is [2,3-c] pyridine-5-yl also) carbonyl] ethyl } piperazine (Compound I-5-6)
With reference to the method for embodiment 27, replace 1-(3-trifluoromethyl) piperazine with 1-(2,4-two trifluoromethyls) piperazine, with intermediate 3.2 reactions, get light yellow solid (HPLC:97.8%).The Rf=0.50[single-point, developping agent: v (sherwood oil): v (ethyl acetate)=1: 3].
Embodiment 31:
1-(2-chloro-phenyl-)-4-{[(4,5,6, the 7-tetramethylene sulfide is [2,3-c] pyridine-5-yl also) carbonyl] ethyl } piperazine (Compound I-5-7)
With reference to the method for embodiment 27, replace 1-(3-trifluoromethyl) piperazine with 1-(2-chloro-phenyl-) piperazine, with intermediate 3.2 reactions, get white solid (HPLC:98.3%).The Rf=0.47[single-point, developping agent: v (sherwood oil): v (ethyl acetate)=1: 3].
Embodiment 32:
1-(3-chloro-phenyl-)-4-{1-[(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) carbonyl] propyl group } piperazine (Compound I-5-8)
With reference to the method for embodiment 27, replace 1-(3-trifluoromethyl) piperazine with 1-(3-chloro-phenyl-) piperazine, with intermediate 3.3 reactions, get white solid (HPLC:97.8%).The Rf=0.49[single-point, developping agent: v (sherwood oil): v (ethyl acetate)=1: 3].
Embodiment 33:
1-(4-chloro-phenyl-)-4-{[(4,5,6, the 7-tetramethylene sulfide is [2,3-c] pyridine-5-yl also) carbonyl] ethyl } piperazine (Compound I-5-9)
With reference to the method for embodiment 27, replace 1-(3-trifluoromethyl) piperazine with 1-(4-chloro-phenyl-) piperazine, with intermediate 3.2 reactions, get white solid (HPLC:98.0%).The Rf=0.47[single-point, developping agent: v (sherwood oil): v (ethyl acetate)=1: 3].
Embodiment 34:
1-(2,4 dichloro benzene base)-4-{1-[(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) carbonyl] propyl group } piperazine (Compound I-5-10)
With reference to the method for embodiment 27, replace 1-(3-trifluoromethyl) piperazine with 1-(2,4 dichloro benzene base) piperazine, with intermediate 3.3 reactions, get white solid (HPLC:98.2%).The Rf=0.50[single-point, developping agent: v (sherwood oil): v (ethyl acetate)=1: 3].
Embodiment 35:
1-(2-fluorophenyl)-4-{[(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) carbonyl] methyl } piperazine (Compound I-5-11)
With reference to the method for embodiment 27, replace 1-(3-trifluoromethyl) piperazine with 1-(2-fluorophenyl) piperazine, with intermediate 3.1 reactions, obtain sticky oily product (HPLC:97.4%).The Rf=0.50[single-point, developping agent: v (sherwood oil): v (ethyl acetate)=1: 3].
1H?NMR(DMSO-d
6，400MHz)δ：2.585(s，4H，-C-CH
2-N-)，2.756(s，1H，-C-CH
2-N-)，2.907～3.003(m，5H，-C-CH
2-N-，-CO-CH
2-N-)，3.159(s，1H，＝C-CH
2-C-)，3.287～3.308(m，1H，＝C-CH
2-C-)，3.752～3.830(m，2H，-C-CH
2-N-)，4.521(s，1H，＝C-CH
2-N-)，4.670(s，1H，＝C-CH
2-N-)，6.879～7.121(m，5H，ph-H；-C＝CH-C＝)，7.311～7.323(d，1H，-C＝CH-S-)。
Embodiment 36:
1-(3-fluorophenyl)-4-{[(4,5,6, the 7-tetramethylene sulfide is [2,3-c] pyridine-5-yl also) carbonyl] ethyl } piperazine (Compound I-5-12)
With reference to the method for embodiment 27, replace 1-(3-trifluoromethyl) piperazine with 1-(3-fluorophenyl) piperazine, with intermediate 3.2 reactions, get near-white solid (HPLC:97.9%).The Rf=0.50[single-point, developping agent: v (sherwood oil): v (ethyl acetate)=1: 3].
Embodiment 37:
1-(4-fluorophenyl)-4-{[(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) carbonyl] methyl } piperazine (Compound I-5-13)
With reference to the method for embodiment 27, replace 1-(3-trifluoromethyl) piperazine with 1-(4-fluorophenyl) piperazine, with intermediate 3.1 reactions, obtain yellow solid product (HPLC:97.7%).The Rf=0.35[single-point, developping agent: v (sherwood oil): v (ethyl acetate)=1: 3].
1H?NMR(DMSO-d
6，400MHz)δ：2.601(s，4H，-C-CH
2-N-)，2.759(s，1H，-C-CH
2-N-)，2.895(s，1H，-C-CH
2-N-)，3.017(s，2H，-C-CH
2-N-)，3.079(s，2H，-CO-CH
2-N-)，3.354(s，2H，＝C-CH
2-C-)，3.757～3.819(m，2H，＝C-CH
2-N-)，4.525(s，1H，-C-CH
2-N-)，4.658(s，1H，-C-CH
2-N-)，6.861～6.945(m，3H，-C＝CH-C＝，ph-H)，6.994～7.047(m，2H，ph-H)，7.312～7.325(d，1H，-C＝CH-S-)。
Embodiment 38:
1-(2,4 difluorobenzene base)-4-{[(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) carbonyl] methyl } piperazine (Compound I-5-14)
Method with reference to embodiment 27, with 1-(2, the 4-difluorophenyl) piperazine replaces 1-(3-trifluoromethyl) piperazine, with intermediate 3.1 reactions, obtain yellow sticky oily product, post separates [moving phase: v (sherwood oil): v (ethyl acetate)=1: 3], obtains the product component, and low temperature is separated out yellow transparent crystallization (HPLC:99.5%).The Rf=0.43[single-point, developping agent: v (sherwood oil): v (ethyl acetate)=1: 3].
1H?NMR(DMSO-d
6，400MHz)δ：2.576(s，4H，-C-CH
2-N-)，2.753～2.765(t，1H，-C-CH
2-N-)，2.890～2.952(m，6H，-C-CH
2-N-；-CO-CH
2-N-)，3.285～3.305(d，1H，-C-CH
2-N-)，3.750～3.826(m，2H，＝C-CH
2-C-)，4.520(s，1H，＝C-CH
2-N-)，4.665(s，1H，＝C-CH
2-N-)，6.876～6.889(d，1H，-C＝CH-C＝)，6.931～6.974(m，1H，ph-H)，7.024～7.071(m，1H，ph-H)，7.115～7.175(m，1H，ph-H)，7.306～7.328(d，1H，-C＝CH-S-)。
Embodiment 39:
1-(4-nitrophenyl)-4-{[(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) carbonyl] methyl } piperazine (Compound I-5-15)
In the reaction flask that stirring, condenser, thermometer are housed, add 1.8g intermediate 3.1, it is dissolved, stir adding triethylamine 2.52g down with the 15mL methylene dichloride.1.74g1-(4-nitrophenyl) piperazine is added reaction system in batches.Add, continue reaction 12h (the flaggy demonstration reacts completely) in refluxing down.With 3 * 15mL water washing reaction solution, divide and get dichloromethane layer, use the anhydrous sodium sulphate thorough drying, to filter, methylene dichloride is to the greatest extent steamed in decompression, promptly gets yellow solid (HPLC:96.7%).The Rf=0.31[single-point, developping agent: v (sherwood oil): v (ethyl acetate)=1: 3].
1H?NMR(CDCl
3，400MHz)δ：2.669～2.706(q，4H，-C-CH
2-N-)，2.863～2.891(t，1H，＝C-CH
2-C-)，2.940～2.967(t，1H，＝C-CH
2-C-)，3.331～3.482(m，6H，-C-CH
2-N-；-CO-CH
2-N-)，3.851～3.942(m，2H，-C-CH
2-N-)，4.675(s，2H，＝C-CH
2-N-)，6.777～6.840(m，3H，-C＝CH-C＝，ph-H)，7.139～7.152(d，1H，-C＝CH-S-)，8.094～8.131(m，2H，ph-H)。MS，m/Z：386.0(M)，356.1，275.1，220.1，165.0，152.0，119.1，70.1，28.0。
Embodiment 40:
1-(2-nitrophenyl)-4-{[(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) carbonyl] methyl } piperazine (Compound I-5-16)
Method with reference to embodiment 39, replace 1-(4-nitrophenyl) piperazine with 1-(2-nitrophenyl) piperazine, with intermediate 3.1 reactions, obtain the sticky oily product of red-brown, post separates [moving phase: v (sherwood oil): v (ethyl acetate)=1: 3], obtains red oil product component (HPLC:99.7%).The Rf=0.33[single-point, developping agent: v (sherwood oil): v (ethyl acetate)=1: 3].
1H?NMR(DMSO-d
6，400MHz)δ：2.820(s，1H，＝C-CH
2-C-)，2.956(s，1H，＝C-CH
2-C-)，3.348(s，8H，-C-CH
2-N-)，3.673～3.701(t，1H，-C-CH
2-N-)，3.825～3.853(t，1H，-C-CH
2-N-)，4.504～4.602(m，4H，＝C-CH
2-N-，-CO-CH
2-N-)，6.892～6.931(m，1H，-C＝CH-C＝)，7.219～7.258(m，1H，ph-H)，7.354～7.433(m，2H，ph-H)，7.634～7.676(m，1H，ph-H)，7.875～7.899(d，1H，-C＝CH-S-)。
Embodiment 41:
1-(4-nitrophenyl)-4-{[(4,5,6, the 7-tetramethylene sulfide is [2,3-c] pyridine-5-yl also) carbonyl] ethyl } piperazine (Compound I-5-17)
Method with reference to embodiment 39, replace intermediate 3.1 with intermediate 3.2,, obtain pale brown look sticky oily product with the reaction of 1-(4-nitrophenyl) piperazine, post separates [moving phase: v (sherwood oil): v (ethyl acetate)=1: 3], obtains yellow oil product component (HPLC:99.0%).The Rf=0.35[single-point, developping agent: v (sherwood oil): v (ethyl acetate)=1: 3].
Embodiment 42:
1-(4-nitrophenyl)-4-{1-[(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) carbonyl] propyl group } piperazine (Compound I-5-18)
With reference to the method for embodiment 39, replace intermediate 3.1 with intermediate 3.3, with the reaction of 1-(4-nitrophenyl) piperazine, obtain colorless oil product (HPLC:98.2%).The Rf=0.26[single-point, developping agent: v (sherwood oil): v (ethyl acetate)=1: 3].
Embodiment 43:
1-(2-p-methoxy-phenyl)-4-{[(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) carbonyl] methyl } piperazine (Compound I-5-19)
Method with reference to embodiment 39, replace 1-(4-nitrophenyl) piperazine with 1-(2-p-methoxy-phenyl) piperazine, with intermediate 3.1 reactions, obtain light yellow sticky oily product, post separates [moving phase: v (sherwood oil): v (ethyl acetate)=1: 3], obtains colorless oil product component (HPLC:99.8%).The Rf=0.41[single-point, developping agent: v (sherwood oil): v (ethyl acetate)=1: 3].
1H?NMR(DMSO-d
6，400MHz)δ：2.825(m，1H，-N-CH
2-C-)，2.949～2.985(m，1H，-N-CH
2-C-)，3.108～3.165(m，2H，＝C-CH
2-C-)，3.449～3.480(d，2H，-N-CH
2-C-)，3.581～3.610(d，2H，-C-CH
2-N-)，3.671～3.699(t，1H，-C-CH
2-N-)，3.780(s，3H，-OCH
3)，3.832～3.861(t，1H，-C-CH
2-N-)，4.002(s，1H，-CO-CH
2-N-)，4.541～4.612(d，4H，-C-CH
2-N-；＝C-CH
2-N-)，5.745(s，1H，-CO-CH
2-N-)，6.895～7.013(m，5H，-C＝CH-C＝；ph-H)，7.358～7.406(m，1H，-C＝CH-S-)。
Embodiment 44:
1-(2-pyridyl)-4-{[(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) carbonyl] methyl } piperazine (Compound I-6-1)
With reference to the method for embodiment 39, replace 1-(4-nitrophenyl) piperazine with 1-(2-pyridyl) piperazine, with intermediate 3.1 reactions, solvent evaporated obtains the near-white solid product, and is refining with dehydrated alcohol, obtains white solid product (HPLC:99.0%).The Rf=0.30[single-point, developping agent: v (sherwood oil): v (ethyl acetate)=1: 3].
1H?NMR(DMSO-d
6，400MHz)δ：2.480(s，4H，-N-CH
2-C-)，2.732(s，1H，＝C-CH
2-C-)，2.875(s，1H，＝C-CH
2-C-)，3.266(s，2H，-CO-CH
2-N-)，3.360～3.435(m，4H，-C-CH
2-N-)，3.727～3.811(m，2H，-C-CH
2-N-)，4.497～4.651(d，2H，＝C-CH
2-N-)，6.576～6.606(m，1H，ph-H)，6.728～6.773(m，1H，ph-H)，6.841～6.867(d，1H，-C＝CH-C＝)，7.285～7.298(d，1H，-C＝CH-S-)，7.461～7.499(m，1H，ph-H)，8.058～8.066(d，1H，ph-H)。
Embodiment 45:
Compound I-1-1 becomes hydrochloride: get I-1-1 oily product 0.88g, be dissolved in the 7mL dehydrated alcohol.Ice-water bath is cooled to 5 ℃, drip 11.1% ethanol solution hydrochloride to pH be 2, continue at stir about 1h under the ice-water bath.Filter, white solid, vacuum-drying, m.p.＞230 ℃.
Embodiment 46:
Compound I-1-3 becomes vitriol: get I-1-3 oily product 1.20g, be dissolved in 10mL acetone.Ice-water bath is cooled to 5 ℃, drip 9.8% sulfuric acid acetone soln to pH be 3, continue at stir about 1h under the ice-water bath.Filter, brown solid, vacuum-drying, m.p.＞230 ℃.
Embodiment 47:
Compound I-1-8 becomes lactic acid salt: get I-1-8 oily product 1.0g, be dissolved in the 20mL anhydrous methanol.Be heated to molar lactic acid such as the back adding that refluxes, continue at the about 1h of stirring reaction down that refluxes.Reaction finishes, and leaves standstill 24h under room temperature.Separate out white crystals, filter, vacuum-drying, m.p.＞230 ℃.
Embodiment 48:
Compound I-1-11 becomes sylvite: get I-1-11 white solid product 1.0g, be dissolved in the 40mL dehydrated alcohol.Ice-water bath is cooled to 5 ℃, stir drip down 20% potassium hydroxide aqueous solution to pH be 9, continue at stir about 1h under the ice-water bath.Under room temperature, leave standstill 24h.Separate out white crystals, filter, vacuum-drying, m.p.＞230 ℃.
For the pharmaceutical composition that contains the bridged piperazine derivatives of thienopyridine replacement of the present invention is described more fully, following example of formulations is provided below, described embodiment only is used for explanation, rather than is used to limit the scope of the invention.Described preparation can use any active compound and the salt thereof in the The compounds of this invention, preferably uses the compound described in the embodiment of 4-48.
Embodiment 49:
Prepare hard gelatin capsule with following compositions:
Consumption/capsule weight concentration (%)
Compound I-1-1 20mg 10.0
Dry starch 200mg 43.0
Magnesium Stearate 10mg 2.0
After the mentioned component mixing, be packed in the hard gelatin capsule with 460mg.
Embodiment 50:
Prepare tablet with following compositions:
Consumption/sheet weight concentration (%)
Compound I-3-1 10mg 10.0
Starch 45mg 45.0
Carboxymethyl starch sodium salt 4.5mg 4.5
Magnesium Stearate 0.5mg 0.5
Talcum powder 1mg 1.0
Supplementary material is dry in advance, and it is standby to cross 100 mesh sieves.Earlier with the abundant mixing of the auxiliary material of recipe quantity.Bulk drug is added in the auxiliary material to increase progressively dilution method, and each abundant mixing of added-time 2-3 time guarantees medicine and the abundant mixing of auxiliary material, cross 20 mesh sieves, dry 2h in 55 ℃ of ventilated drying ovens, dried particle cross the arrangement of 16 mesh sieves, measure intermediate content, mix compressing tablet on tabletting machine.
Embodiment 51:
The preparation of injection liquid:
Compound I-5-13 200mg
Propylene glycol 100mg
Polysorbate 80 is an amount of
Distilled water 300ml
Get activeconstituents and join in the water for injection that dissolves sorbyl alcohol and propylene glycol, add medicinal basic and regulate the pH value and make its dissolving to 4-8.Add gac, whip attachment 30min, carbon removal, smart filter, embedding, sterilization.
Embodiment 52:
The preparation of injection lyophilized powder:
Compound I-5-15 100mg
Medicinal basic 0.1-7%
N.F,USP MANNITOL 55-85%
Get activeconstituents and add water for injection, regulate the pH value with medicinal basic and make its dissolving to 4-8.Add N.F,USP MANNITOL again, carry out autoclaving by the requirement of injection, add gac, adopt filtering with microporous membrane, filtrate is carried out packing, adopts freeze-drying, makes loose block, seals, promptly.
Claims (7)
1. the compound or its pharmacy acceptable salt that have formula I structure:
X is
(q=0,1,2), R
4Be hydrogen, methyl, ethyl;
Y is a nitrogen, carbon, oxygen;
m＝1，2；
n＝0，1；
p＝0，1，2；
R
1, R
2Be hydrogen, methyl, ethyl, carboxyl, hydroxyl;
R
3(when Y is nitrogen, carbon, R
3Exist) be
(a) hydrogen; C
1-C
4Alkyl, C
5-C
6Cycloalkyl, this alkyl or cycloalkyl can be replaced by halogen, hydroxyl, carboxyl, amino, phenyl, and this phenyl can be by halogen, C
1-C
4Alkyl, C
1-C
4Alkoxyl group, hydroxyl, carboxyl, nitro replace;
(b) CH
2R
5, R
5For containing O, S, N five yuan, hexa-member heterocycle, these five yuan, hexa-member heterocycle can be by halogen, C
1-C
4Alkyl, hydroxyl, carboxyl, nitro replace; Phenyl, this phenyl can be by halogen, C
1-C
4Alkyl, C
1-C
4Alkoxyl group, hydroxyl, carboxyl, nitro, styryl replace;
(c) COR
6, R
6Be C
1-C
4Alkyl, this alkyl can be by halogen, hydroxyl, carboxyl substituted; Phenyl, this phenyl can be by halogen, C
1-C
4Alkyl, C
1-C
4Alkoxyl group, hydroxyl, carboxyl, nitro replace; Contain O, S, N five yuan, hexa-member heterocycle, these five yuan, hexa-member heterocycle can be by halogen, C
1-C
4Alkyl, halogenophenyl replace;
(d) SO
2R
7, R
7Be C
1-C
4Alkyl, this alkyl can be by halogen, hydroxyl, carboxyl substituted; Phenyl, this phenyl can be by halogen, C
1-C
4Alkyl, C
1-C
4Alkoxyl group, hydroxyl, carboxyl, nitro replace; Contain O, S, N five yuan, hexa-member heterocycle, these five yuan, hexa-member heterocycle can be by halogen, C
1-C
4Alkyl, halogenophenyl replace;
R wherein
8, R
9, R
10Be hydrogen, C
1-C
4Alkyl, this alkyl can be by halogen, hydroxyl, carboxyl, nitro, amino replacement, halogen, hydroxyl, carboxyl, nitro, amino, C
1-C
4Alkoxyl group;
Wherein Z is O, S, N, (r=0,1), R
11Be halogen, C
1-C
4Alkyl, C
1-C
4Alkylamino, C
1-C
4Replace alkylamino, C
1-C
4Dialkyl amido, C
1-C
4Replace dialkyl amido, halogenophenyl.
2. compound as claimed in claim 1, pharmacy acceptable salt refers to: compound and mineral acid, organic acid salify; Oxide compound, oxyhydroxide salify with basic metal, alkaline-earth metal.
3. (I) compound of the general formula described in claim 1 and pharmacy acceptable salt thereof, preferred following compound:
I-1-1 N-{[(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) carbonyl] methyl } piperazine
I-1-2 N-{[(4,5,6, the 7-tetramethylene sulfide is [2,3-c] pyridine-5-yl also) carbonyl] ethyl } high piperazine
I-1-3 1-methyl-4-{[(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) carbonyl] methyl } piperazine
I-1-4 1-ethyl-4-{[(4,5,6, the 7-tetramethylene sulfide is [2,3-c] pyridine-5-yl also) carbonyl] ethyl } piperazine
I-1-5 1-methylol-4-{1-[(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) carbonyl] propyl group } piperazine
I-1-6 1-cyclohexyl-4-{[(4,5,6, the 7-tetramethylene sulfide is [2,3-c] pyridine-5-yl also) carbonyl] ethyl } piperazine
I-1-7 N-{[(4,5,6, the 7-tetramethylene sulfide is [2,3-c] pyridine-5-yl also) carbonyl] ethyl } Pyrrolidine
I-1-8 1-{[(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) carbonyl] methyl }-3,5-dimethyl-piperidines
I-1-9 N-{[(4,5,6, the 7-tetramethylene sulfide is [2,3-c] pyridine-5-yl also) carbonyl] ethyl } piperidines
I-1-10 1-{[(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) carbonyl] methyl }-the 3-hydroxy-piperdine
I-1-11 1-{1-[(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) carbonyl] propyl group }-3-carboxyl-piperidines
I-1-12 1-{[(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) carbonyl] methyl }-4-carbamyl phenylpiperidines
I-1-13 N-{[(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) carbonyl] ethyl } morpholine
I-1-14 1-(diphenyl-methyl)-4-{[(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) carbonyl] methyl } piperazine
I-1-15 1-(4-chloro-diphenyl-methyl)-4-{[(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) carbonyl] methyl } piperazine
I-2-1 1-styryl-4-{1-[(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) carbonyl] propyl group } piperazine
I-3-1 1-(2-furancarbonyl)-4-{[(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) carbonyl] methyl } piperazine
I-3-2 1-(2-tetrahydrofuran (THF) formyl radical)-4-{[(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) carbonyl] methyl } piperazine
I-3-3 1-(2-tetrahydrofuran (THF) formyl radical)-2-methyl-4-{[(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) carbonyl] methyl } piperazine
I-4-1 1-(to the Methyl benzenesulfonyl base)-4-{1-[(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) carbonyl] propyl group } piperazine
I-4-2 1-(to the Methyl benzenesulfonyl base)-2-carboxyl-4-{[(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) carbonyl] methyl } piperazine
I-5-1 1-(2, the 4-3,5-dimethylphenyl)-4-{[(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) carbonyl] methyl } piperazine
I-5-2 1-phenyl-4-{[(4,5,6, the 7-tetramethylene sulfide is [2,3-c] pyridine-5-yl also) carbonyl] ethyl } piperazine
I-5-3 1-(3-trifluoromethyl)-4-{[(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) carbonyl] methyl } piperazine
I-5-4 1-(2-trifluoromethyl)-4-{1-[(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) carbonyl] propyl group } piperazine
I-5-5 1-(4-trifluoromethyl)-4-{[(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) carbonyl] methyl } piperazine
I-5-6 1-(2,4-two trifluoromethyls)-4-{[(4,5,6, the 7-tetramethylene sulfide is [2,3-c] pyridine-5-yl also) carbonyl] ethyl } piperazine
I-5-7 1-(2-chloro-phenyl-)-4-{[(4,5,6, the 7-tetramethylene sulfide is [2,3-c] pyridine-5-yl also) carbonyl] ethyl } piperazine
I-5-8 1-(3-chloro-phenyl-)-4-{1-[(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) carbonyl] propyl group } piperazine
I-5-9 1-(4-chloro-phenyl-)-4-{[(4,5,6, the 7-tetramethylene sulfide is [2,3-c] pyridine-5-yl also) carbonyl] ethyl } piperazine
I-5-10 1-(2,4 dichloro benzene base)-4-{1-[(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) carbonyl] propyl group } piperazine
I-5-11 1-(2-fluorophenyl)-4-{[(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) carbonyl] methyl } piperazine
I-5-12 1-(3-fluorophenyl)-4-{[(4,5,6, the 7-tetramethylene sulfide is [2,3-c] pyridine-5-yl also) carbonyl] ethyl } piperazine
I-5-13 1-(4-fluorophenyl)-4-{[(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) carbonyl] methyl } piperazine
I-5-14 1-(2,4 difluorobenzene base)-4-{[(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) carbonyl] methyl } piperazine
I-5-15 1-(4-nitrophenyl)-4-{[(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) carbonyl] methyl } piperazine
I-5-16 1-(2-nitrophenyl)-4-{[(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) carbonyl] methyl } piperazine
I-5-17 1-(4-nitrophenyl)-4-{[(4,5,6, the 7-tetramethylene sulfide is [2,3-c] pyridine-5-yl also) carbonyl] ethyl } piperazine
I-5-18 1-(4-nitrophenyl)-4-{1-[(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) carbonyl] propyl group } piperazine
I-5-19 1-(2-p-methoxy-phenyl)-4-{[(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) carbonyl] methyl } piperazine
I-6-1 1-(2-pyridyl)-4-{[(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) carbonyl] methyl } piperazine
4. the preparation method of claim 1 Chinese style (I) compound, it is characterized in that: 4,5,6,7-tetramethylene sulfide and pyridine and halogen acyl halide, in methylene dichloride, trichloromethane or toluene, in the presence of acid binding agents such as triethylamine, pyridine, salt of wormwood, yellow soda ash, sodium bicarbonate, potassium hydroxide ,-30 ℃～35 ℃ reactions make key intermediate.Intermediate again with aminated compounds in methylene dichloride, trichloromethane or toluene, in the presence of acid binding agents such as triethylamine, pyridine, salt of wormwood, yellow soda ash, sodium bicarbonate, potassium hydroxide, 0 ℃～90 ℃ reactions make Compound I.
5. the pharmaceutical composition of a platelet aggregation-against, it comprises formula I compound or its salt and one or more pharmaceutical excipients for the treatment of significant quantity.
6. claim 1～3 Chinese style I compound is in the application that is used to prepare aspect the medicament for resisting platelet aggregation.
7. application as claimed in claim 6 is being used to prepare the coronary syndrome that treatment causes because of platelet aggregation, myocardial infarction, myocardial ischemia, the purposes of cardiovascular and cerebrovascular diseases medicament aspect.
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