CN1683373A - Thiophenopyridine substituted acetyl hyarazine derivative - Google Patents
Thiophenopyridine substituted acetyl hyarazine derivative Download PDFInfo
- Publication number
- CN1683373A CN1683373A CN 200510016205 CN200510016205A CN1683373A CN 1683373 A CN1683373 A CN 1683373A CN 200510016205 CN200510016205 CN 200510016205 CN 200510016205 A CN200510016205 A CN 200510016205A CN 1683373 A CN1683373 A CN 1683373A
- Authority
- CN
- China
- Prior art keywords
- phenyl
- chloro
- pyridine
- acethydrazide
- compound
- 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
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
The present invention discloses thiopheno pyridine substituted acetyl hyarazine derivative compound as shown in expression I and its pharmaceutically acceptable salt, medicine composition with the compound as effective component, and their application as platelet aggregation resisting medicine, especially as medicine for preventing and treating platelet aggregation caused coronary artery syndromes, myocardial infarction, myocardial ischemia and other cardiac and cerebral vascular diseases.
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
Along with problem of an aging population order benefit is serious, cardiovascular and cerebrovascular diseases has become " the No.1 killer " who has a strong impact on health of people and life.For this reason, lot of manpower and material resources is dropped in countries in the world aspect the diagnosis and treatment of such disease, make it to become a lasting research, the exploitation focus.Thrombosis can cause the heart, brain, pulmonary circulation illness such as Acute Myocardial Infarction apoplexy, pulmonary infarction, is threatening human beings'health and life, also is common complication and the inaccessible again factor of intervention property postangioplasty in the surgical operation.Because platelet aggregation plays an important role aspect thrombosis, antiplatelet drug has become the main medicine of these diseases of control.145 relate to the clinical discussion of following up a case by regular visits to of 70000 routine patients and show that the application antiplatelet drug can reduce vascular incident about 25%.Simultaneously, adenosine diphosphate (ADP) (ADP) is the important agonist that platelet activation, buildup effect amplify, and suppressing the thrombocyte effect by the blocking-up adp receptor has become the important means that stops pathologic thrombosis (coronary heart disease, cerebro-vascular diseases, pulmonary infarction, thrombophlebitis etc.) and myocardial infarction, unstable angina pectoris, peripheral vascular disease, congestive heart failure etc.
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 do not wait traditional antiplatelet drug different, it not only suppresses a certain platelet aggregation incitant, and has suppressed accumulation process itself.Relevant clinical trial is observed and is confirmed that thiophene chloropyridine can significantly reduce the heart, cerebrovascular accident, more slightly have superiority with traditional antiplatelet drug acetylsalicylic acid but untoward reaction (ADR) is more, especially can cause neutrophilic granulocytopenia (Chinese Journal of New Drugs, 1995,4 (3): 36), cause lethality thrombotic thrombocytopenic purpura (TTP), therefore, various countries have taked relative measures, and U.S. FDA is only ratified thiophene chloropyridine and is used for the invalid patient that maybe can not tolerate of acetylsalicylic acid.
Clopidogrel is second thienopyridine medicine of French Sanofi company development, compares with thiophene chloropyridine, and many carboxymethyls but its anti-bolt effect is stronger on the side chain only on the structure, ADR is then little than thiophene chloropyridine.In June, 1998, annual sales amount was above 1,000,000,000 dollars now in U.S.'s Initial Public Offering.Go on the market in Britain in October, 1998, and China went on the market in 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.Although (Lancet in the research of the CAPRIE before listing, 1996,348:1329), the TTP relevant with clopidogrel do not take place in the patient that nearly 20,000 examples are accepted monitoring closely, but in 2000, Chicago,U.S city Veterans Administration Hospital's Bennett doctor waits and has reported that TTP appears in the patient that 11 examples are accepted the clopidogrel treatment, and the overwhelming majority betides in the 2wk that takes medicine, and clearly points out both to have cause-effect relationship.In addition, the report (Ann Intern Med, 2000,132 (12): 1006) that have also had the 2 examples hemolytic uremic syndrome (HUS) relevant since 2000 with clopidogrel.
Simultaneously because clopidogrel is oily matter, alkalescence extremely a little less than, need and strong acid could salify, but meet the moisture instability, free alkali is separated out, and purifying has certain difficulty.Because its strongly-acid has been subjected to certain restriction aspect preparation.
Synthetic method and summary about Thienopyridines are found in following document:
US4681888；US4529596；GB1501797；WO02059128；US4174448；GB1561504；WO2004094374；JP6135970；JP63264588。
Summary of the invention
One object of the present invention is, discloses hydrazide derivatives and pharmaceutical salts thereof that thieno-[3.2-c] pyridine replaces.
Another object of the present invention is that disclosing the hydrazide derivatives and the pharmaceutical salts thereof that replace with thieno-[3.2-c] pyridine is the pharmaceutical composition of main active ingredient.
A further object of the present invention is, discloses the hydrazide derivatives of thieno-[3.2-c] pyridine replacement and the preparation method of pharmaceutical salts thereof.
A further object of the invention is, hydrazide derivatives and pharmaceutical salts thereof that thieno-[3.2-c] pyridine replaces 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, the purposes of myocardial ischemia, cardiovascular and cerebrovascular diseases medicament aspect.
The present invention relates to the compound and the pharmacy acceptable salt thereof of general formula (I) structure
Wherein:
X is O, S;
R
1, R
2Be hydrogen at the same time or separately, fluorine, chlorine, nitro, C
1-C
8Straight chain, branched-chain alkyl, this alkyl can at random be replaced by following one or more group: fluorine, chlorine, hydroxyl, methylol, itrile group, C
1-C
6Alkoxyl group;
R
3Can be hydrogen, fluorine, chlorine, nitro, itrile group, C
1-C
3The C that alkyl or chlorine, fluorine replace
1-C
3Alkyl, C
1-C
3Alkoxyl group or chlorine, fluorine list or disubstituted C
1-C
3Alkoxyl group;
R
4Be (a) amino;
(b)-NH-R
5；
R
5Be C
1-C
8Alkyl, this alkyl can at random be replaced by following one or more group: fluorine, chlorine, hydroxyl, itrile group, carboxyl, amino, nitro, C
1-C
8Alkoxyl group, C
1-C
8Acyl group, phenyl, substituted-phenyl, five yuan, hexa-member heterocycle and substituted heterocycle;-CO-R
6Or-SO
2-R
7, R
6, R
7Be C
1-C
8Alkyl or by fluorine, chlorine, hydroxyl, itrile group waits the C of replacement
1-C
8Alkyl; By chlorine, fluorine, C
1-C
6Alkyl, C
1-C
8Alkoxyl group, hydroxyl, itrile group, carboxyl, amino, single, double or polysubstituted aryl such as nitro;
R
8, R
9Be hydrogen at the same time or separately, C
1-C
8Alkyl, this alkyl can be replaced by following one or more groups arbitrarily: fluorine, chlorine, hydroxyl, C
1-C
8Alkoxyl group, amino, C
1-C
8Alkylamino, C
1-C
8Replace alkylamino, C
1-C
8Two replace alkylamino, C
1-C
8Dialkyl amido, R
9Be H, then R
8Be aryl, this aryl can be replaced by following one or more group: C
1-C
6Alkyl, C
1-C
6Alkoxyl group, fluorine, chlorine, itrile group, carboxyl, amino, hydroxyl, aryl, substituted aryl; If heterocyclic aryl can contain sulphur, oxygen, nitrogen heteroatom;
(d)-N＝R
10；
R
10Be C
3-C
6Cycloalkyl or by C
1-C
3Alkyl, hydroxyl, fluorine, the C that chlorine etc. replace
3-C
6Cycloalkyl contains heteroatomic triatomic ring, tetra-atomic ring, five-ring, six-ring, and this ring texture can be replaced hydroxyl, fluorine, chlorine, C by following one or more groups
1-C
4Alkyl, C
1-C
4Alkoxyl group and by fluorine, the C that chlorine replaces
1-C
4Alkyl and C
1-C
4Alkoxyl group, phenyl, fluorine, chlorine, methyl, fluoro methyl, methoxyl group, single or disubstituted phenyl.
C of the present invention
1-C
8The straight or branched alkyl comprises methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, amyl group, isopentyl or the like.
Described C
1-C
3The C that alkyl or chlorine, fluorine replace
1-C
3Alkyl can be methyl, ethyl, propyl group, chloroethyl, fluoro ethyl; C
1-C
3Alkoxyl group or chlorine, fluorine list or disubstituted C
1-C
3Alkoxyl group, C
1-C
8Alkoxyl group can be methoxyl group, oxyethyl group, propoxy-, butoxy, isobutoxy; Chloroethoxy, chlorine propoxy-, 1,1-dichloro propoxy-, 1-fluoro-2-chlorine propoxy-or the like.
Described C
1-C
8Alkylamino, C
1-C
8Replace alkylamino, C
1-C
8Dialkyl amido, C
1-C
8Replacing dialkyl amido can be ethylamino, third amino, hydroxyethylamino, two hydroxyethylaminos or the like.
Described C
2-C
8Alkyloyl such as ethanoyl, propionyl, butyryl radicals, isobutyryl or the like.
Described C
3-C
6Cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or the like.
The heteroatomic triatomic ring of described replacement, tetra-atomic ring, five-ring, six-ring, 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 with conventional alkali form, for example basic metal (for example sodium salt or sylvite), alkaline-earth metal (for example calcium 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, preferable compound is: X=S, R
1=R
2=H, R
3=ortho position chlorine.
Compound or its pharmacy acceptable salt with formula I structure of the present invention, wherein part of compounds is:
(1) (S)-and α, α-[(2-chloro-phenyl-)-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also)] acethydrazide (compound 1)
(2) (S)-and α, α-[(2-chloro-phenyl-)-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also)]-N '-[(E)-(styryl) first subunit] acethydrazide (compound 2)
(3) (S)-and α, α-[(2-chloro-phenyl-)-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also)]-N '-[(E)-(4-methoxyphenyl) first subunit] acethydrazide (compound 3)
(4) (S)-and α, α-[(2-chloro-phenyl-)-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also)]-N '-[(E)-and phenyl first subunit] acethydrazide (compound 4)
(5) (S)-and α, α-[(2-chloro-phenyl-)-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also)]-N '-[(E)-(piperonyl) first subunit] acethydrazide (compound 5)
(6) (S)-and α, α-[(2-chloro-phenyl-)-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also)]-N '-[(E)-(4-aminophenyl) first subunit] acethydrazide hydrochloride or Citrate trianion (compound 6)
(7) (S)-and α, α-[(2-chloro-phenyl-)-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also)]-N '-[(E)-(3,4, the 5-2,4,5-trimethoxyphenyl) first subunit] acethydrazide (compound 7)
(8) (S)-and α, α-[(2-chloro-phenyl-)-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also)]-N '-[(E)-(4-chloro-phenyl-) first subunit] acethydrazide (compound 8)
(9) (S)-and α, α-[(2-chloro-phenyl-)-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also)]-N '-[(E)-(2-hydroxyphenyl) first subunit] acethydrazide sylvite (compound 9)
(10) (S)-and α, α-[(2-chloro-phenyl-)-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also)]-N '-[(E)-(thiophene-2) first subunit] acethydrazide (compound 10)
(11) (S)-and α, α-[(2-chloro-phenyl-)-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also)]-N '-[(E)-(furans-2) first subunit] acethydrazide (compound 11)
(12) (S)-and α, α-[(2-chloro-phenyl-)-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5--yl also)]-N '-{ (E)-[5-(4-chlorobenzene) furans-2-yl] first subunit } acethydrazide (compound 12)
(13) (S)-and α, α-[(2-chloro-phenyl-)-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also)]-N '-[(E)-(2-chloro-phenyl-) first subunit] acethydrazide (compound 13)
(14) (S)-and α, α-[(2-chloro-phenyl-)-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also)]-N '-{ (E)-[(3-methoxyl group-4-hydroxy phenyl) first subunit] } acethydrazide sylvite (compound 14)
(15) (S)-and α, α-[(2-chloro-phenyl-)-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also)]-N '-[(E)-(4-hydroxyphenyl) first subunit] acethydrazide sodium salt (compound 15)
(16) (S)-and α, α-[(2-chloro-phenyl-)-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also)]-N '-[(E)-(4-tolyl) first subunit] acethydrazide (compound 16)
(17) (S)-and α, α-[(2-chloro-phenyl-)-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also)]-N '-[(E)-(2-nitrophenyl) first subunit] acethydrazide (compound 17)
(18) (S)-and α, α-[(2-chloro-phenyl-)-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also)]-N '-[(E)-(3-nitrophenyl) first subunit] acethydrazide (compound 18)
(19) (S)-and α, α-[(2-chloro-phenyl-)-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also)]-N '-[(E)-[(2-normal-butyl-4-chloro-imidazoles-5-yl) first subunit] acethydrazide (compound 19)
(20) (S)-and α, α-[(2-chloro-phenyl-)-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also)]-N '-(dimethyl methyl subunit) acethydrazide (compound 20)
(21) (S)-and α, α-[(2-chloro-phenyl-)-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also)]-N '-methylsulfonyl acethydrazide (compound 21)
(22) (S)-and α, α-[(2-chloro-phenyl-)-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also)]-N '-benzene first sulfo group acethydrazide (compound 22)
(23) (S)-and α, α-[(2-chloro-phenyl-)-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also)]-N '-(S)-the 1-[(2-chloro-phenyl-)-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also)] ethanoyl } acethydrazide (compound 23)
(24) (S)-and α, α-[(2-chloro-phenyl-)-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also)]-N '-[(nitrile ethyl) first subunit] acethydrazide (compound 24)
(25) (S)-and α, α-[(2-chloro-phenyl-)-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also)]-N '-[(dipropyl) first subunit] acethydrazide (compound 25)
(26) (S)-and α, α-[(2-chloro-phenyl-)-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also)]-N '-[1-(3-methoxy-4-acetyl oxygen phenyl) third rare acyl group] acethydrazide (compound 26)
(27) (S)-and α, α-[(2-chloro-phenyl-)-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also)]-N '-[(cyclohexyl) first subunit] acethydrazide (compound 27)
The preparation method of formula I compound of the present invention, mainly be (S)-α, α-[(2-chloro-phenyl-)-(4,5,6,7-tetramethylene sulfide also [3,2-c] pyridine-5-yl)] acethydrazide (being called for short the hydrazides thing) and aldehyde, ketone, acyl chlorides, SULPHURYL CHLORIDE, acid anhydrides, halogenide etc., at ethanol, methyl alcohol, Virahol, methylene dichloride, trichloromethane, acetonitrile, tetrahydrofuran (THF), in the solvents such as water, 10 ℃～90 ℃ reactions make all cpds or products therefrom are dissolved in dropping inorganic acid among DMF or the DMSO, organic acid, basic metal, alkaline-earth metal or make pharmacy acceptable salt derived from the ammonia salt of ammonia and organic amine.
Specifically be that products therefrom is dissolved among DMF or the DMSO, dripping hydrochloric acid ethanol is made hydrochloride to PH2.Or products therefrom is dissolved in DMF, add and wait a mole citric acid, its Citrate trianion.Also this compound can be dissolved in DMF, drip the ethanolic soln 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 be according to patient's the state of an illness, specific being applied of situation of diagnosis, 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.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 rat platelet aggregation restraining effect test materials below by pharmacodynamic experiment
Medicine and preparation: The compounds of this invention (1-27) is made into suspension with 0.5%CMC and uses for animals administer; Adenosine diphosphate (ADP) (ADP) (SERVA company, lot number 01993)
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
| Compound sample | Number of animals | The maximum gathering | Inhibiting rate (%) |
| Contrast | ????9 | ????53.6±6.0 | |
| ????1 | ????7 | ????42.9±11.7 * | ????20.0 |
| ????2 | ????7 | ????36.7±8.0 *** | ????31.5 |
| ????3 | ????7 | ????39.1±14.1 * | ????27.1 |
| ????4 | ????6 | ????38.8±8.5 ** | ????27.6 |
| ????5 | ????6 | ????36.7±13.6 ** | ????31.5 |
| ????6 | ????8 | ????33.5±16.3 ** | ????37.5 |
| ????7 | ????8 | ????32.0±8.8 *** | ????40.3 |
| ????8 | ????6 | ????35.7±11.9 ** | ????33.4 |
| ????9 | ????6 | ????42.0±15.4 | ????21.6 |
| ????10 | ????6 | ????45.9±22.6 | ????14.4 |
| ????11 | ????6 | ????41.2±17.7 | ????23.1 |
| ????12 | ????6 | ????35.2±8.2 *** | ????34.3 |
| ????13 | ????6 | ????40.4±10.4 * | ????24.6 |
| ????14 | ????8 | ????37.2±8.5 *** | ????30.6 |
| ????15 | ????6 | ????36.1±8.6 ** | ????32.6 |
| ????16 | ????8 | ????39.0±16.5 * | ????27.2 |
| ????17 | ????6 | ????35.1±10.2 ** | ????34.5 |
| ????18 | ????6 | ????33.1±12.3 ** | ????38.2 |
| ????19 | ????6 | ????32.7±10.3 *** | ????39.0 |
| ????20 | ????8 | ????31.0±6.9 *** | ????42.2 |
| ????21 | ????6 | ????34.8±13.7 ** | ????35.1 |
| ????22 | ????6 | ????36.7±9.6 ** | ????31.5 |
| ????23 | ????6 | ????41.1±9.9 * | ????23.3 |
| ????24 | ????8 | ????34.6±10.7 *** | ????35.4 |
| ????25 | ????8 | ????31.2±8.8 *** | ????41.8 |
| ????26 | ????6 | ????36.5±9.9 ** | ????31.9 |
| ????27 | ????8 | ????34.6±8.9 *** | ????35.4 |
| Clopidogrel Hydrogensulfate | ????8 | ????9.4±5.5 *** | ????82.5 |
Annotate: compare with control group:
*P＜0.05,
*P＜0.01,
* *P＜0.001.
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.
Description of drawings
Fig. 1 is the acethydrazide derivatives structural formula that thienopyridine replaces, X wherein, R
1, R
2, R
3, R
4Such as claim 1 definition.
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), thin-layer chromatography (TLC), and fusing point (m.p.) detects.Can adopt subsequently such as infrared spectra (IR), nuclear magnetic resonance spectrum (
1HNMR,
13CNMR), mass spectrum (MS) etc. is further proved conclusively its structure.Used starting raw material S-(+)-2-(the 2-chlorophenyl)-2-of the present invention (4,5,6,7-tetrahydrothieno[3,2-c] pyridin-5-y1) acetic acid methyl ester (clopidogrel), reference EP465358; EP342118; EP420706; US4847265; J Org Chem, 1968,33 (6): the 2565-2566 method is synthetic, the IR of product,
1HNMR,
13CNMR, MS, the ultimate analysis value, optically-active is consistent with reference substance.
Example 1:
(S)-and α, α-[(2-chloro-phenyl-)-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also)] acethydrazide (compound 1) (hereinafter to be referred as the hydrazides thing)
In the reaction flask that stirring, condenser, thermometer are housed, add clopidogrel 38g, dehydrated alcohol 30ml, stir down slowly heating, make the reaction raw materials dissolving, add 45.6g hydrazine hydrate (80%), continue to be heated to backflow, insulation reaction 4 hours (the flaggy demonstration reacts completely).Solvent is to the greatest extent steamed in decompression then, steams and finishes, and adds 50ml distilled water and 30ml methylene dichloride in resistates, fully stirs, and tells organic layer, and water layer merges organic layer with 3 * 30ml dichloromethane extraction, uses the anhydrous sodium sulphate thorough drying.Methylene dichloride is to the greatest extent steamed in decompression, gets white solid 23.4g.(HPLC：97.16％)，m.p.139.0℃～139.3℃。
Embodiment 2:
(S)-and α, α-[(2-chloro-phenyl-)-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also)]-N '-[(E)-(styryl) first subunit] acethydrazide (compound 2)
In the reaction flask that stirring, condenser, thermometer are housed, add hydrazides thing 4g, anhydrous methanol 40ml, start stirring, heating makes its dissolving.Continue to be heated to 40 ℃, drip the 1.8g cinnamic aldehyde, finish insulation reaction 3 hours.Stopped reaction, cooling has yellow solid to generate.Filter, anhydrous methanol washing 3 * 2ml, drying gets yellow solid 4.4g.(HPLC:97.92%), m.p.173.3 ℃～174.2 ℃, Rf=0.65 (developping agent: sherwood oil (60 ℃～90 ℃): ethyl acetate=1: 1)
Embodiment 3:
(S)-and α, α-[(2-chloro-phenyl-)-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also)]-N '-[(E)-(4-methoxyphenyl) first subunit] acethydrazide (compound 3)
The preparation process that this compound provides by embodiment 2 is by the reaction of hydrazides thing and aubepine and get.
HPLC:95.92%, m.p.193.3-194.6 ℃, Rf=0.54 (developping agent: sherwood oil (60-90 ℃): ethyl acetate=1: 1).
Embodiment 4:
(S)-and α, α-[(2-chloro-phenyl-)-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also)]-N '-[(E)-and phenyl first subunit] acethydrazide (compound 4)
The preparation process that this compound provides by embodiment 2 is by the reaction of hydrazides thing and phenyl aldehyde and get.
HPLC:98.2%, m.p.186.9-187.7 ℃, Rf=0.67 (developping agent: sherwood oil (60-90 ℃): ethyl acetate=1: 1).
Embodiment 5:
(S)-and α, α-[(2-chloro-phenyl-)-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also)]-N '-[(E)-(piperonyl) first subunit] acethydrazide (compound 5)
The preparation process that this compound provides by embodiment 2 is by the reaction of hydrazides thing and piperonylaldehyde and get.
HPLC:98.85%, m.p.145.4-146.9 ℃, Rf=0.59 (developping agent: sherwood oil (60-90 ℃): ethyl acetate=1: 1).
Embodiment 6:(S)-and α, α-[(2-chloro-phenyl-)-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also)]-N '-[(E)-(4-aminophenyl) first subunit] acethydrazide hydrochloride or Citrate trianion (compound 6)
The preparation process that this compound provides by embodiment 2 is by the reaction of hydrazides thing and p-Aminobenzaldehyde and get.
HPLC:99.8%, m.p.214 ℃～216 ℃ decomposition, Rf=0.3 (developping agent: sherwood oil (60-90 ℃): ethyl acetate=1: 1).Products therefrom is dissolved in DMF, and dripping hydrochloric acid ethanol gets its hydrochloride to PH2.HPLC：99.5％，m.p.＞230℃。Or products therefrom is dissolved in DMF, add and wait a mole citric acid, its Citrate trianion, HPLC:99.3%, m.p.230 ℃.
Embodiment 7:
(S)-and α, α-[(2-chloro-phenyl-)-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also)]-N '-[(E)-(3,4, the 5-2,4,5-trimethoxyphenyl) first subunit] acethydrazide (compound 7)
The preparation process that this compound provides by embodiment 2, by hydrazides thing and 3,4, the 5-TMB is reacted and is got.
HPLC:99.31%, m.p.＞220 ℃, Rf=0.33 (developping agent: sherwood oil (60-90 ℃): ethyl acetate=1: 1).
Embodiment 8:
(S)-and α, α-[(2-chloro-phenyl-)-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also)]-N '-[(E)-(4-chloro-phenyl-) first subunit] acethydrazide (compound 8)
The preparation process that this compound provides by embodiment 2 is by the reaction of hydrazides thing and 4-chloro-benzaldehyde and get.
HPLC:99.7%, m.p.184.4-185.8 ℃, Rf=0.64 (developping agent: sherwood oil (60-90 ℃): ethyl acetate=1: 1).
Embodiment 9:
(S)-and α, α-[(2-chloro-phenyl-)-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also)]-N '-[(E)-(2-hydroxyphenyl) first subunit] acethydrazide sylvite (compound 9)
The preparation process that this compound provides by embodiment 2 is by the reaction of hydrazides thing and salicylaldhyde and get.
HPLC:98.5%, m.p.176.5-178.2 ℃, Rf=0.779 (developping agent: sherwood oil (60-90 ℃): ethyl acetate=1: 1).This compound is dissolved in DMF, drips the ethanolic soln of potassium hydroxide, transfer PH9, its sylvite, HPLC:99.3%, m.p.＞250 ℃,
Embodiment 10:
(S)-and α, α-[(2-chloro-phenyl-)-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also)]-N '-[(E)-(thiophene-2) first subunit] acethydrazide (compound 10)
The preparation process that this compound provides by embodiment 2 is by the reaction of hydrazides thing and thiophenecarboxaldehyde and get.
HPLC:95.7%, m.p.205.8-207.3 ℃, Rf=0.64 (developping agent: sherwood oil (60-90 ℃): ethyl acetate=1: 1).
Embodiment 11:
(S)-and α, α-[(2-chloro-phenyl-)-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also)]-N '-[(E)-(furans-2) first subunit] acethydrazide (compound 11)
The preparation process that this compound provides by embodiment 2 is by the reaction of hydrazides thing and furtural and get.
HPLC:98.8%, m.p.165.9-167.0 ℃, Rf=0.63 (developping agent: sherwood oil (60-90 ℃): ethyl acetate=1: 1).
Embodiment 12:
(S)-and α, α-[(2-chloro-phenyl-)-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also)]-N '-{ (E)-[5-(4-chlorobenzene) furans-2-yl] first subunit } acethydrazide (compound 12)
The preparation process that this compound provides by embodiment 2 is by the reaction of hydrazides thing and 5-(4-chloro-phenyl-) furtural and get.
HPLC:99.9%, m.p.191.7-192.2 ℃, Rf=0.61 (developping agent: sherwood oil (60-90 ℃): ethyl acetate=1: 1).
Embodiment 13:
(S)-and α, α-[(2-chloro-phenyl-)-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also)]-N '-[(E)-(2-chloro-phenyl-) first subunit] acethydrazide (compound 13)
The preparation process that this compound provides by embodiment 2 is by the reaction of hydrazides thing and o-chlorobenzaldehyde and get.
HPLC:100%, m.p.182.1-182.6 ℃, Rf=0.84 (developping agent: sherwood oil (60-90 ℃): ethyl acetate=1: 1).
Embodiment 14:
(S)-and α, α-[(2-chloro-phenyl-)-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also)]-N '-{ (E)-[(3-methoxyl group-4-hydroxy phenyl) first subunit] } acethydrazide sylvite (compound 14)
The preparation process that this compound provides by embodiment 2 is by hydrazides thing and 3-methoxyl group-4-hydroxy benzaldehyde reaction and get.
HPLC:99.9%, m.p.208.3-208.9 ℃, Rf=0.35 (developping agent: sherwood oil (60-90 ℃): ethyl acetate=1: 1).This compound is dissolved in DMSO, drips the ethanolic soln of potassium hydroxide, transfer PH9, get its sylvite.HPLC：99.9％，m.p.＞250℃。
Embodiment 15:
(S)-and α, α-[(2-chloro-phenyl-)-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also)]-N '-[(E)-(4-hydroxyphenyl) first subunit] acethydrazide sodium salt (compound 15)
The preparation process that this compound provides by embodiment 2 is by the reaction of hydrazides thing and p-Hydroxybenzaldehyde and get.HPLC:99.87%, m.p.169.7-170.8 ℃, Rf=0.44 (developping agent: sherwood oil (60-90 ℃): ethyl acetate=1: 1).This compound is dissolved in the anhydrous methanol, and the dropping sodium aqueous solution is transferred PH9, gets its sodium salt.HPLC：99.7％，m.p.＞250℃
Embodiment 16:
(S)-and α, α-[(2-chloro-phenyl-)-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also)]-N '-[(E)-(4-tolyl) first subunit] acethydrazide (compound 16)
The preparation process that this compound provides by embodiment 2 is by the reaction of hydrazides thing and p-tolyl aldehyde and get.HPLC:99.67%, m.p.212.8-213.5 ℃, Rf=0.66 (developping agent: sherwood oil (60-90 ℃): ethyl acetate=1: 1).
Embodiment 17:
(S)-and α, α-[(2-chloro-phenyl-)-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also)]-N '-[(E)-(2-nitrophenyl) first subunit] acethydrazide (compound 17)
The preparation process that this compound provides by embodiment 2 is by the reaction of hydrazides thing and Ortho Nitro Benzaldehyde and get.HPLC:99.64%, m.p.191.5-192.2 ℃, Rf=0.71 (developping agent: sherwood oil (60-90 ℃): ethyl acetate=1: 1).
Embodiment 18:
(S)-and α, α-[(2-chloro-phenyl-)-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also)]-N '-[(E)-(3-nitrophenyl) first subunit] acethydrazide (compound 18)
The preparation process that this compound provides by embodiment 2 is by the reaction of hydrazides thing and m-nitrobenzaldehyde and get.HPLC:98.64%, m.p.195.7-196.9 ℃, Rf=0.46 (developping agent: sherwood oil (60-90 ℃): ethyl acetate=1: 1).
Embodiment 19:
(S)-and α, α-[(2-chloro-phenyl-)-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also)]-N '-[(E)-[(2-normal-butyl-4-chloro-imidazoles-5-yl) first subunit] acethydrazide (compound 19)
The preparation process that this compound provides by embodiment 2 is by hydrazides thing and 2-normal-butyl-4-chloro-imidazole formaldehyde reaction and get.
HPLC:94.69%, m.p.109.6-111.8 ℃, Rf=0.57 (developping agent: sherwood oil (60-90 ℃): ethyl acetate=1: 1).
Embodiment 20:
(S)-and α, α-[(2-chloro-phenyl-)-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also)]-N '-(dimethyl methyl subunit) acethydrazide (compound 20)
The preparation process that this compound provides by embodiment 2 is by the reaction of hydrazides thing and acetone and get.
HPLC:99.8%, m.p.169.1-170.8 ℃, Rf=0.3 (developping agent: sherwood oil (60-90 ℃): ethyl acetate=1: 1).
Embodiment 21:
(S)-and α, α-[(2-chloro-phenyl-)-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also)]-N '-methylsulfonyl acethydrazide (compound 21)
In the reaction flask that stirring, condenser, thermometer are housed, add hydrazides thing 5g, dehydrated alcohol 75ml, heating is stirred, and makes its dissolving, rises to 40 ℃, begins to drip the 1.3ml methane sulfonyl chloride, finishes, and continues reaction 2 hours.Most action solvent is steamed in decompression, adds 20ml acetone, feeds the exsiccant hydrogen chloride gas to it, and the adularescent solid generates, and filters absolute ethanol washing, the dry 3.9g that gets.(HPLC:96.4%), m.p.220.7-221.8 ℃, Rf=0.73 (developping agent: sherwood oil (60-90 ℃): ethyl acetate=1: 1).
Embodiment 22:
(S)-and α, α-[(2-chloro-phenyl-)-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also)]-N '-benzene first sulfo group acethydrazide (compound 22)
In the reaction flask that stirring, condenser, thermometer are housed, add hydrazides thing 5g, methylene dichloride 50ml, stir and make its dissolving, heat temperature raising to 30 ℃ drips the 2.3g Benzoyl chloride, insulation reaction 3.5 hours.Cooling to the reaction solution dropping ammonia, is transferred PH8～9 down, adds 50ml water and 20ml methylene dichloride again, tells organic layer, and water layer washs with methylene dichloride 3 * 20ml, combined dichloromethane layer, anhydrous sodium sulfate drying.Methylene dichloride is to the greatest extent steamed in decompression, adds ethanol, makes reflux temperature under molten just clearly, adds proper amount of active carbon, after 10 minutes, and filtered while hot, filtrate placement.The adularescent solid is separated out.Filter, drying gets white solid 4.1g.(HPLC:99.7%), m.p.154.6-155.4 ℃, Rf=0.74 (developping agent: sherwood oil (60-90 ℃): ethyl acetate=1: 1).
Embodiment 23:
(S)-and α, α-[(2-chloro-phenyl-)-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also)]-N '-(S)-the 1-[(2-chloro-phenyl-)-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also)] ethanoyl } acethydrazide (compound 23)
In the reaction flask that stirring, condenser, thermometer are housed, add clopidogrel 13.9g, methyl alcohol 50ml starts and stirs and be heated to backflow.Reflux down, (30%, W/W), 2.5 hours (flaggy show react completely) continues to reflux slowly to drip the 8.1ml aqueous sodium hydroxide solution.Solvent is to the greatest extent steamed in decompression, gets faint yellow waxy solid.Add the 50ml Glacial acetic acid, fully stir and make its dissolving, add 55ml methylene dichloride and 60ml distilled water then respectively, fully stir, leave standstill, tell dichloromethane layer, 3 * 20ml washed with dichloromethane water layer, combined dichloromethane layer, anhydrous sodium sulfate drying.An amount of solvent is divided exactly in decompression, places.The adularescent solid is separated out, and filters, and drying gets 9.2g (S)-α, α-[(2-chloro-phenyl-)-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also)] acetate, m.p.142.7 ℃ (decomposition).
Above-claimed cpd is dropped in the reaction flask, add the 50ml sulfur oxychloride, start stirring, heat temperature raising is to refluxing insulation reaction 5 hours.Reaction is complete, and first normal pressure steams most of sulfur oxychloride, and the back decompression is steamed to the greatest extent, gets the Vandyke brown dope.Add the 215ml acetonitrile, stir and make its dissolving, add hydrazides thing 7.5g, need 20 minutes approximately in 45 ℃～50 ℃ gradation.Finish, insulation reaction 4.5 hours, reaction is finished, acetonitrile is to the greatest extent steamed in decompression, adds entry 50ml, ammoniacal liquor 9.5ml, stirred 30 minutes, there is light yellow solid to generate, filters, an amount of washing, dry, get 14.4g light yellow solid (HPLC:98.8%), m.p.171.7 ℃-173.7 ℃, Rf=0.8 (developping agent: sherwood oil (60-90 ℃): ethyl acetate=1: 1).
Embodiment 24:
(S)-and α, α-[(2-chloro-phenyl-)-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also)]-N '-[(nitrile ethyl) first subunit] acethydrazide (compound 24)
In the reaction flask that stirring, condenser, thermometer are housed, add hydrazides thing 3g, trichloromethane 90ml, heating makes its whole dissolvings, drips methyl sulfo-acetonitrile 0.8ml, 54～60 ℃ of stirring reactions 3.5 hours.React and finish, solvent is to the greatest extent steamed in decompression, gets faint yellow oily thing.Refining by sherwood oil, get white solid 3.1g (HPLC:97.2%), m.p.133.9-135.6 ℃, Rf=0.39 (developping agent: sherwood oil (60-90 ℃): ethyl acetate=1: 1).
Embodiment 25:
(S)-and α, α-[(2-chloro-phenyl-)-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also)]-N '-[(dipropyl) first subunit] acethydrazide (compound 2 5)
In the reaction flask that stirring, condenser, thermometer are housed, add hydrazides thing 5g, water 75ml starts stirring, is heated to 90 ℃, drips 1.7ml pentanone-3 then, finishes insulation reaction 2 hours 40 minutes (the flaggy demonstration reacts completely), stopped reaction.Solvent is to the greatest extent steamed in decompression, stirs down, adds 23ml water, has precipitation to occur.Filter, 3 * 10ml washing, drying gets 6.1g pale solid (HPLC:99.3%).M.p.99 ℃-101.8 ℃, Rf=0.33 (developping agent: sherwood oil (60-90 ℃): ethyl acetate=1: 1).
Embodiment 26:
(S)-and α, α-[(2-chloro-phenyl-)-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also)]-N '-[1-(3-methoxy-4-acetyl oxygen phenyl) third rare acyl group] acethydrazide (compound 26)
In the reaction flask that stirring, condenser, thermometer are housed, add hydrazides thing 2g, the 30ml isopropyl acetone, start and stir and extremely backflow of heat temperature raising, molten clear back adds 1.6g4-acetoxy-3-rare acyl chlorides of methoxyl group phenylpropyl alcohol, and back flow reaction 4 hours (the flaggy demonstration reacts completely) stops to stir.Solvent is to the greatest extent steamed in decompression, adds the 20ml ether, and placement is spent the night.The adularescent solid is separated out, and filters, a small amount of ether washing solid, and drying gets light yellow solid 2.5g (HPLC:97%).M.p.187.9 ℃-190.7 ℃, Rf=0.37 (developping agent: methylene dichloride: dehydrated alcohol=1: 1).
Embodiment 27:
(S)-and α, α-[(2-chloro-phenyl-)-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also)]-N '-[(cyclohexyl) first subunit] acethydrazide (compound 27)
In the reaction flask that stirring, condenser, thermometer are housed, add hydrazides thing 3.2g, the 50ml dehydrated alcohol, the 1g pimelinketone starts stirring, heat temperature raising to 50 ℃, insulation reaction 8 hours.Reaction is finished, and decompression steams dehydrated alcohol, adds 30ml acetone in the resistates, is heated to backflow, and after 10 minutes, filtered while hot, filtrate room temperature are placed and spent the night.Separate out solid, filter, drying gets white solid 2.8g (HPLC:99.6%).M.p.181 ℃-181.9 ℃, Rf=0.62 (developping agent: sherwood oil (60-90 ℃): ethyl acetate=1: 1).
For the pharmaceutical composition that contains the acethydrazide 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 in the The compounds of this invention, preferably uses the compound described in the embodiment of 2-27.
Preparation 1
Prepare hard gelatin capsule with following compositions
Consumption/capsule weight concentration (%)
Compound 3 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.
Preparation 2
Consumption/sheet weight concentration (%)
Compound 10 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.
Preparation 3
The preparation of injection liquid
Compound 15 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 pH value and make its dissolving to 4-8.Add gac, whip attachment 30 minutes, carbon removal, smart filter, embedding, sterilization.
Preparation 4
The preparation of injection lyophilized powder
Compound 27 100mg
Medicinal basic 0.1-7%
N.F,USP MANNITOL 55-85%
Get activeconstituents and add water for injection, regulate 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 (9)
1. the compound or its pharmacy acceptable salt that have formula I structure:
Wherein X is O, S;
R
1, R
2Be hydrogen at the same time or separately, fluorine, chlorine, nitro, C
1-C
8The straight or branched alkyl, this alkyl can at random be replaced by following one or more group: fluorine, chlorine, hydroxyl, methylol, itrile group, C
1-C
6Alkoxyl group;
R
3Can be hydrogen, fluorine, chlorine, nitro, itrile group, C
1-C
3The C that alkyl or chlorine, fluorine replace
1-C
3Alkyl, C
1-C
3Alkoxyl group or chlorine, fluorine list or disubstituted C
1-C
3Alkoxyl group;
R
4Be (a) amino;
(b)-NH-R
5；
R wherein
5Be C
1-C
8Alkyl, this alkyl can at random be replaced by following one or more group: fluorine, chlorine, hydroxyl, itrile group, carboxyl, amino, nitro, C
1-C
8Alkoxyl group, C
1-C
8Acyl group, phenyl, substituted-phenyl, five yuan, hexa-member heterocycle being replaced by sulphur, oxygen, nitrogen heteroatom;-CO-R
6Or-SO
2-R
7, R wherein
6, R
7Be C
1-C
8Alkyl or by fluorine, chlorine, hydroxyl, the C that itrile group replaces
1-C
8Alkyl; By chlorine, fluorine, C
1-C
6Alkyl, C
1-C
8Alkoxyl group, hydroxyl, itrile group, carboxyl, amino, the single, double or polysubstituted aryl of nitro;
R wherein
8, R
9Be hydrogen at the same time or separately, C
1-C
8Alkyl, this alkyl can be replaced by following one or more groups arbitrarily: fluorine, chlorine, hydroxyl, C
1-C
8Alkoxyl group, amino, C
1-C
8Alkylamino, C
1-C
8Dialkyl amido; Work as R
9Be H, then R
8During for aryl, this aryl can be replaced by following one or more group: C
1-C
6Alkyl, C
1-C
6Alkoxyl group, fluorine, chlorine, itrile group, carboxyl, amino, hydroxyl, aryl, substituted aryl; If heterocyclic aryl can contain sulphur, oxygen, nitrogen heteroatom;
(d)-N＝R
10；
R wherein
10Be C
3-C
6Cycloalkyl or by C
1-C
3Alkyl, hydroxyl, fluorine, the C that chlorine replaces
3-C
6Cycloalkyl contains the triatomic ring, tetra-atomic ring, five-ring, the six-ring that are replaced by sulphur, oxygen, nitrogen heteroatom, and this ring texture can be replaced hydroxyl, fluorine, chlorine, C by following one or more groups
1-C
4Alkyl, C
1-C
4Alkoxyl group and by fluorine, the C that chlorine replaces
1-C
4Alkyl and C
1-C
4Alkoxyl group, phenyl, fluorine, chlorine, methyl, fluoro methyl, methoxyl group, single or disubstituted phenyl.
2. compound as claimed in claim 1, its pharmacy acceptable salt mean compound and sour salify, comprise mineral acid and organic acid, basic metal, and alkaline-earth metal is derived from the ammonia salt of ammonia and organic amine.
3. the compound described in claim 1, wherein X is a sulphur.
4. the compound described in claim 1, R
3For ortho position chlorine replaces.
5. the compound described in claim 1, the compound of its Chinese style (I) representative is:
(1) (S)-and α, α-[(2-chloro-phenyl-)-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also)]-N '-[(E)-(styryl) first subunit] acethydrazide;
(2) (S)-and α, α-[(2-chloro-phenyl-)-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also)]-N '-[(E)-(piperonyl) first subunit] acethydrazide;
(3) (S)-and α, α-[(2-chloro-phenyl-)-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also)]-N '-[(E)-(4-aminophenyl) first subunit] acethydrazide;
(4) (S)-and α, α-[(2-chloro-phenyl-)-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also)]-N '-[(E)-(3,4, the 5-2,4,5-trimethoxyphenyl) first subunit] acethydrazide;
(5) (S)-and α, α-[(2-chloro-phenyl-)-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also)]-N '-[(E)-(4-chloro-phenyl-) first subunit] acethydrazide;
(6) (S)-and α, α-[(2-chloro-phenyl-)-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also)]-N '-{ (E)-[5-(4-chlorobenzene) furans-2-yl] first subunit } acethydrazide hydrochloride;
(7) (S)-and α, α-[(2-chloro-phenyl-)-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also)]-N '-{ (E)-[(3-methoxyl group-4-hydroxy phenyl) first subunit] } acethydrazide;
(8) (S)-and α, α-[(2-chloro-phenyl-)-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also)]-N '-[(E)-(4-hydroxyphenyl) first subunit] acethydrazide;
(9) (S)-and α, α-[(2-chloro-phenyl-)-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also)]-N '-[(E)-(2-nitrophenyl) first subunit] acethydrazide sylvite;
(10) (S)-and α, α-[(2-chloro-phenyl-)-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also)]-N '-[(E)-(3-nitrophenyl) first subunit] acethydrazide;
(11) (S)-and α, α-[(2-chloro-phenyl-)-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also)]-N '-[(E)-[(2-normal-butyl-4-chloro-imidazoles-5-yl) first subunit] acethydrazide;
(12) (S)-and α, α-[(2-chloro-phenyl-)-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also)]-N '-(dimethyl methyl subunit) acethydrazide;
(13) (S)-and α, α-[(2-chloro-phenyl-)-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also)]-N '-benzene first sulfo group acethydrazide;
(14) (S)-and α, α-[(2-chloro-phenyl-)-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also)]-N '-[(nitrile ethyl) first subunit] acethydrazide sylvite;
(15) (S)-and α, α-[(2-chloro-phenyl-)-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also)]-N '-[(dipropyl) first subunit] acethydrazide sodium salt;
(16) (S)-and α, α-[(2-chloro-phenyl-)-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also)]-N '-[1-(3-methoxy-4-acetyl oxygen phenyl) third rare acyl group] acethydrazide;
(17) (S)-and α, α-[(2-chloro-phenyl-)-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also)]-N '-[(cyclohexyl) first subunit] acethydrazide.
6. the preparation method of claim 1 Chinese style I compound, it is characterized in that: (S)-α, α-[(2-chloro-phenyl-)-(4,5,6,7-tetramethylene sulfide also [3,2-c] pyridine-5-yl)] acethydrazide (being called for short the hydrazides thing) and aldehyde, ketone, acyl chlorides, SULPHURYL CHLORIDE, acid anhydrides or halogenide, in alcohol, acetonitrile, tetrahydrofuran (THF) or water-soluble matchmaker, 10 ℃～90 ℃ reactions make compound or products therefrom are dissolved in dropping inorganic acid, organic acid, basic metal among DMF or the DMSO, alkaline-earth metal or make pharmacy acceptable salt derived from the ammonia salt of ammonia and organic amine.
7. pharmaceutical composition, it comprises claim 1-6 claimed compound in any one for the treatment of significant quantity, and one or more pharmaceutically useful vehicle of blended with it.
8. claim 1 Chinese style I compound is in the application that is used to prepare aspect the medicament for resisting platelet aggregation.
9. application as claimed in claim 8 is being used to prepare the coronary syndrome that treatment causes because of platelet aggregation, myocardial infarction, the purposes of myocardial ischemia, cardiovascular and cerebrovascular diseases medicament aspect.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB200510016205XA CN1318428C (en) | 2005-02-23 | 2005-02-23 | Thiophenopyridine substituted acetyl hyarazine derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB200510016205XA CN1318428C (en) | 2005-02-23 | 2005-02-23 | Thiophenopyridine substituted acetyl hyarazine derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1683373A true CN1683373A (en) | 2005-10-19 |
| CN1318428C CN1318428C (en) | 2007-05-30 |
Family
ID=35262895
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB200510016205XA Expired - Fee Related CN1318428C (en) | 2005-02-23 | 2005-02-23 | Thiophenopyridine substituted acetyl hyarazine derivative |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1318428C (en) |
Cited By (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101781311A (en) * | 2010-03-12 | 2010-07-21 | 天津药物研究院 | Novel preparation method of platelet aggregation inhibition compound |
| CN101812073A (en) * | 2010-05-27 | 2010-08-25 | 天津药物研究院 | Method for preparing acethydrazide derivatives |
| CN101812072A (en) * | 2010-05-27 | 2010-08-25 | 天津药物研究院 | Method for preparing anti-platelet aggregation compounds |
| CN101863901A (en) * | 2010-06-29 | 2010-10-20 | 天津药物研究院 | 2-(substituted phenyl)-2-(4,5,6,7-thiophane[3,2-c] pyridine-5(4H)-group)-N-substitute-acetamide as well as preparation method and application thereof |
| CN101974015A (en) * | 2010-10-11 | 2011-02-16 | 天津药物研究院 | Ester compound and preparation method and application thereof |
| CN102010423A (en) * | 2010-11-16 | 2011-04-13 | 天津药物研究院 | Crystal form II of (S)-alpha, alpha-[(2-chlorphenyl)-(4,5,6,7-tetrahydrothieno [3,2-c] pyridine-5-yl)]-N'-(dimethyl) methylene) acethydrazide and preparation method |
| CN102010424A (en) * | 2010-11-16 | 2011-04-13 | 天津药物研究院 | Crystal form III of (S)-alpha, alpha-[(2-chlorphenyl)-(4,5,6,7-thiophane[3,2-c]pyridine-5-yl)-N'-(dimethyl)methylene] acethydrazide and preparation method thereof |
| CN102093385A (en) * | 2010-12-30 | 2011-06-15 | 天津药物研究院 | Schiff base compounds as well as preparation method and application of Schiff base compounds |
| WO2011140816A1 (en) | 2010-05-13 | 2011-11-17 | 天津药物研究院 | Thienopyridine ester derivative containing nitrile, preparation method, use and composition thereof |
| CN101781310B (en) * | 2010-02-23 | 2012-07-04 | 天津药物研究院 | Thiofuran-pyridine [3, 2-c] contained acethydrazide derivative and preparation method and application thereof |
| CN101591344B (en) * | 2008-05-27 | 2012-12-05 | 连云港恒邦医药科技有限公司 | Antithrombotic compound as well as preparation method and application thereof |
| CN105566345A (en) * | 2016-03-02 | 2016-05-11 | 天津药物研究院有限公司 | (5-(2-cyanobenzyl)-4,5,6,7-tetrahydrothiophene[3,2-c]pyridine-2-yl)acetate crystal form III and preparation method and application thereof |
| CN105566346A (en) * | 2016-03-02 | 2016-05-11 | 天津药物研究院有限公司 | (5-(2-cyanobenzyl)-4,5,6,7-tetrahydrothiophene[3,2-c]pyridine-2-yl)acetate crystal form I and preparation method and application thereof |
| CN105777775A (en) * | 2016-03-02 | 2016-07-20 | 天津药物研究院有限公司 | Crystal form IX of Tipidogrel free alkali and preparation method and application thereof |
| CN105777774A (en) * | 2016-03-02 | 2016-07-20 | 天津药物研究院有限公司 | Crystal form X of Tipidogrel free alkali and preparation method and application thereof |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101402641B (en) * | 2008-11-20 | 2011-05-04 | 天津药物研究院 | Oxime derivatives containing thienopyridine, preparation method and application thereof |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE60134508D1 (en) * | 2000-07-06 | 2008-07-31 | Daiichi Sankyo Co Ltd | Acid addition salts of hydropyridine derivatives |
| GB0125708D0 (en) * | 2001-10-26 | 2001-12-19 | Generics Uk Ltd | Novel compounds and processes |
-
2005
- 2005-02-23 CN CNB200510016205XA patent/CN1318428C/en not_active Expired - Fee Related
Cited By (22)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101591344B (en) * | 2008-05-27 | 2012-12-05 | 连云港恒邦医药科技有限公司 | Antithrombotic compound as well as preparation method and application thereof |
| CN101781310B (en) * | 2010-02-23 | 2012-07-04 | 天津药物研究院 | Thiofuran-pyridine [3, 2-c] contained acethydrazide derivative and preparation method and application thereof |
| CN101781311A (en) * | 2010-03-12 | 2010-07-21 | 天津药物研究院 | Novel preparation method of platelet aggregation inhibition compound |
| CN101781311B (en) * | 2010-03-12 | 2012-07-25 | 天津药物研究院 | Novel preparation method of platelet aggregation inhibition compound |
| WO2011140816A1 (en) | 2010-05-13 | 2011-11-17 | 天津药物研究院 | Thienopyridine ester derivative containing nitrile, preparation method, use and composition thereof |
| CN101812073A (en) * | 2010-05-27 | 2010-08-25 | 天津药物研究院 | Method for preparing acethydrazide derivatives |
| CN101812072A (en) * | 2010-05-27 | 2010-08-25 | 天津药物研究院 | Method for preparing anti-platelet aggregation compounds |
| CN101812072B (en) * | 2010-05-27 | 2012-07-04 | 天津药物研究院 | Method for preparing anti-platelet aggregation compounds |
| CN101863901A (en) * | 2010-06-29 | 2010-10-20 | 天津药物研究院 | 2-(substituted phenyl)-2-(4,5,6,7-thiophane[3,2-c] pyridine-5(4H)-group)-N-substitute-acetamide as well as preparation method and application thereof |
| CN101863901B (en) * | 2010-06-29 | 2012-12-05 | 天津药物研究院 | 2-(substituted phenyl)-2-(4,5,6,7-thiophane[3,2-c] pyridine-5(4H)-group)-N-substitute-acetamide as well as preparation method and application thereof |
| CN101974015A (en) * | 2010-10-11 | 2011-02-16 | 天津药物研究院 | Ester compound and preparation method and application thereof |
| CN101974015B (en) * | 2010-10-11 | 2012-05-09 | 天津药物研究院 | Ester compound and preparation method and application thereof |
| CN102010423A (en) * | 2010-11-16 | 2011-04-13 | 天津药物研究院 | Crystal form II of (S)-alpha, alpha-[(2-chlorphenyl)-(4,5,6,7-tetrahydrothieno [3,2-c] pyridine-5-yl)]-N'-(dimethyl) methylene) acethydrazide and preparation method |
| CN102010423B (en) * | 2010-11-16 | 2012-06-27 | 天津药物研究院 | Crystal form II of (S)-alpha, alpha-[(2-chlorphenyl)-(4,5,6,7-tetrahydrothieno [3,2-c] pyridine-5-yl)]-N'-(dimethyl) methylene) acethydrazide and preparation method |
| CN102010424B (en) * | 2010-11-16 | 2012-05-30 | 天津药物研究院 | Crystal form III of (S)-alpha, alpha-[(2-chlorphenyl)-(4,5,6,7-thiophane[3,2-c]pyridine-5-yl)-N'-(dimethyl)methylene] acethydrazide and preparation method thereof |
| CN102010424A (en) * | 2010-11-16 | 2011-04-13 | 天津药物研究院 | Crystal form III of (S)-alpha, alpha-[(2-chlorphenyl)-(4,5,6,7-thiophane[3,2-c]pyridine-5-yl)-N'-(dimethyl)methylene] acethydrazide and preparation method thereof |
| CN102093385A (en) * | 2010-12-30 | 2011-06-15 | 天津药物研究院 | Schiff base compounds as well as preparation method and application of Schiff base compounds |
| CN102093385B (en) * | 2010-12-30 | 2013-03-27 | 天津药物研究院 | Schiff base compounds as well as preparation method and application of Schiff base compounds |
| CN105566345A (en) * | 2016-03-02 | 2016-05-11 | 天津药物研究院有限公司 | (5-(2-cyanobenzyl)-4,5,6,7-tetrahydrothiophene[3,2-c]pyridine-2-yl)acetate crystal form III and preparation method and application thereof |
| CN105566346A (en) * | 2016-03-02 | 2016-05-11 | 天津药物研究院有限公司 | (5-(2-cyanobenzyl)-4,5,6,7-tetrahydrothiophene[3,2-c]pyridine-2-yl)acetate crystal form I and preparation method and application thereof |
| CN105777775A (en) * | 2016-03-02 | 2016-07-20 | 天津药物研究院有限公司 | Crystal form IX of Tipidogrel free alkali and preparation method and application thereof |
| CN105777774A (en) * | 2016-03-02 | 2016-07-20 | 天津药物研究院有限公司 | Crystal form X of Tipidogrel free alkali and preparation method and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1318428C (en) | 2007-05-30 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN1683373A (en) | Thiophenopyridine substituted acetyl hyarazine derivative | |
| CN101260112B (en) | Acethydrazide derivatives containing thieno[3.2-c]pyridine, preparation method and use thereof | |
| CN1028104C (en) | Carbostyril derivatives | |
| CN1089584C (en) | Treatment for arteriosclerosis and vitiligoidea | |
| CN1048245C (en) | Novel 5-pyrrolyl-2-pyridylmethylsulfinyl benzimidazole derivatives | |
| TWI617554B (en) | Benzoimidazol-2-yl pyrimidine modulators of the histamine h4 receptor | |
| CN1946398A (en) | Thiadiazolidinones as gsk-3 inhibitors | |
| EP1812409A1 (en) | Aminoquinazolines compounds | |
| CN1478076A (en) | MCH antagonists and their use in treatment of obesity | |
| CN101061123A (en) | Thienopyridinone compounds and methods of treatment | |
| CN1423640A (en) | 8,8a-dihydro-indeno [1,2-d] thiazole derivatives, substituted in position 8a, a method for their production and their use as medicaments, e.g. anorectic agents | |
| CN1028232C (en) | Therapeutically active substituted benzimidazole and process for its preparation | |
| CN1046718C (en) | 6-(2-imidzolinylamino) quinoline compounds useful as alpha-2 adrenoceptor agonists | |
| CN1161120C (en) | Utilization of polycyclic 2-amino-thiazole systems in the production of medicaments for prophylaxis treatment of obesity | |
| CN1014245B (en) | Prepn. of pyrazoline derivatives | |
| US11434200B2 (en) | Solid forms comprising an oxime ether compound and a coformer, compositions and methods of use thereof | |
| CN1948297A (en) | Alkylol piperazine derivative optical isomer or its salt and its application | |
| CN1070911A (en) | The treatment compound | |
| CN1564686A (en) | 8-amino- [1,2,4]triazolo [1,5-a]pyridine-6-carboxylic acid amide | |
| CN1251571A (en) | 2-phenoxyaniline derivatives | |
| CN1596112A (en) | Benzothiazole derivatives | |
| CN1708303A (en) | Derivatives of pyridinalkyl-amonoalkyl-1h-indole inhibiting receptors 5-HT and recapture of serotonin which can be used as antidepressant and anxiolitic | |
| US11013723B1 (en) | Solid forms of a thiazolidinone compound, compositions and methods of use thereof | |
| KR20230058609A (en) | Deuterium-enriched crystalline form of pioglitazone | |
| CN1041589A (en) | The preparation method who contains cardioprotective agent and the ischemic disease therapeutical agent and the compound of N-heterogeneous ring compound |
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 | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20070530 Termination date: 20160223 |