CN106565698B - Substituted thiazole analog derivative and its preparation method and application - Google Patents
Substituted thiazole analog derivative and its preparation method and application Download PDFInfo
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- CN106565698B CN106565698B CN201610927946.1A CN201610927946A CN106565698B CN 106565698 B CN106565698 B CN 106565698B CN 201610927946 A CN201610927946 A CN 201610927946A CN 106565698 B CN106565698 B CN 106565698B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
The present invention relates to the new substituted thiazole analog derivatives and its pharmaceutically acceptable salt with logical formula (I) structure, wherein each group definition is as used in the description.The invention further relates to the preparation method of the compound, containing they pharmaceutical composition and its as bioactive substance be used to prepare prevention and/or treat thrombotic disease drug purposes.
Description
Technical field
The present invention relates to anticoagulant fields, and specifically the present invention relates to new substituted thiazole analog derivatives, preparation method
It is being used to prepare prevention with it and/or is treating the purposes of thrombotic disease drug or pharmaceutical composition.
Background technique
In the angiocarpy of people, blood occurs certain visible components precipitations, agglutination in solidification or blood and forms solid mass
Process, referred to as thrombosis, being formed by solid mass is thrombus.Blood clotting was a kind of protection machine of organism originally
System, however, triggering abnormal coagulation process, blood in the case where blood flow anomalies, blood vessel change in wall or coagulation factor exception
Liquid can form thrombus or embolism, so as to cause thromboembolisms such as myocardial infarction, apoplexy, deep vein thrombosis or pulmonary embolism
Property disease.Thrombotic disease is the disease that most serious is endangered in cardiovascular disease, is the first killer of human health.
The drug of existing antithrombotic embolism class diseases is divided into antiplatelet drug, anticoagulation medicine and fibrinolytic drug
Object.Wherein, anticoagulation medicine mainly has thrombin inhibitor, vitamin K antagon and Xa factor inhibitor.With heparin and low point
Sub- heparin is that the thrombin inhibitor of representative has the disadvantages of taking orally invalid, non-selective inhibition and High risk of bleeding.With magnificent method
Although the vitamin K antagon that Lin Wei is represented can take orally, therapeutic index is narrow, big with food drug interaction, individual
Dose difference is also bigger.
Studies have shown that Xa factor is the best target of development of new anticoagulant, have razaxaban, Eliquis at present
It is listed with edoxaban.The direct inhibition of Xa factor should generate efficient blood coagulation resisting function, and without thrombin inhibitor
Side effect.
Summary of the invention
The technical problem to be solved in the present invention is to provide a kind of completely new substituted thiazole analog derivative, which has anti-
Solidifying effect can be used in preventing and/or treating thrombotic disease.
In order to solve the above technical problems, there is the structure as shown in formula (I) the present invention provides a kind of compound:
Or its pharmaceutically acceptable salt, in which:
R1Selected from fluorine, chlorine, bromine；
R2It is selected from
Preferably, the compound of the present invention is selected from following compounds:
I-1:N- (4- chlorphenyl) -2- ((4- (3- oxomorpholin) phenyl) amido) thiazole -4-carboxamide；
I-2:N- (4- bromophenyl) -2- ((4- (3- oxomorpholin) phenyl) amido) thiazole -4-carboxamide；
I-3:N- (4- chlorphenyl) -2- ((4- (2- oxo-piperidine -1- base) phenyl) amido) thiazole -4-carboxamide；
I-4:N- (4- fluorophenyl) -2- ((4- (2- oxo-piperidine -1- base) phenyl) amido) thiazole -4-carboxamide；
Or its pharmaceutically acceptable salt.
The compound pharmaceutically acceptable salt of logical formula (I) of the present invention, both officinal salt, was logical formula (I) structure
Compound and various inorganic acids (including but not limited to, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid) or organic acid (including
But it is not limited to, such as formic acid, acetic acid, propionic acid, trifluoroacetic acid, malic acid, citric acid, oxalic acid, fumaric acid, maleic acid, amino acid, first
Sulfonic acid, ethanesulfonic acid, benzene sulfonic acid etc.) generate salt.
The compound pharmaceutically acceptable salt of logical formula (I) of the present invention, both officinal salt, can also be logical formula (I)
The compound of structure and various alkaline matters (hydroxide, carbonate or the bicarbonate of such as alkali or alkaline earth metal, including
But be not limited to: sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate etc.) generate salt, such as corresponding sodium salt, sylvite or calcium salt
Deng.Nontoxic organic base such as methylamine, triethylamine or meglumine etc. can also be used and generate salt.
The compound of the present invention is synthesized by following steps:
Wherein: R1Selected from fluorine, chlorine, bromine；
R2It is selected from
The compound of general formula (VI) reacts the compound for generating general formula (IV) with the compound of general formula (V) in a solvent；It is logical
The compound of formula (IV) prepares the compound of general formula (III) through hydrolysis；The compound of general formula (III) and the compound of general formula (II) exist
Reaction generates the compound of general formula (I) in solvent.
Wherein, the compound of general formula (II) and (V) can be obtained by commercial sources, such as lark prestige, Ah Fa Aishadeng company,
It can be prepared by known method.
Wherein, solvent used in preparation method refers to inert organic solvent at reaction conditions, including but not limited to,
Ether, such as tetrahydrofuran, ether, glycol dimethyl ether；Halogenated hydrocarbons, such as 1,2- dichloroethanes, methylene chloride, chloroform, four
Chlorination carbon etc.；Alcohol, such as methanol, ethyl alcohol, isopropanol, the tert-butyl alcohol；Hydrocarbon, such as benzene,toluene,xylene, hexane, hexamethylene；Its
It, such as dimethyl sulfoxide, dimethylformamide, acetonitrile, pyridine, water, hexamethylphosphoric triamide.Solvent can also be above-mentioned molten
The mixture of agent.
Wherein, in preparation method, alkali can also be added, suitable alkali can be conventional inorganic base or organic in reaction
Alkali, including but not limited to, the hydroxide of alkali metal, such as potassium hydroxide or sodium hydroxide；The carbonate of alkali metal, such as carbonic acid
Potassium or sodium carbonate etc.；Alkoxide, such as sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide or potassium tert-butoxide；Amine, as methylamine, hydrazine hydrate,
Triethylamine, diisopropylethylamine, pyridine etc..It is 1~5 mole, preferably 1~2 mole that the dosage of alkali, which is based on 1 molar reactive substrate,.
Reaction can carry out at various pressures, such as decompression, normal pressure or pressurization, preferably carry out under normal pressure.
Reaction generally -78 DEG C to reflux temperature at a temperature of carry out, preferably 0 DEG C to reflux temperature of range carries out.
The compound or pharmaceutically acceptable salt thereof of logical formula (I) structure of the invention can play anticoagulation by inhibition Xa,
Therefore it can be used for preparing prevention and/or treat the drug or pharmaceutical composition of thrombotic disease.Wherein, thromboembolia type disease
The concept of disease is known to those skilled in the art.
In addition, the compound or pharmaceutically acceptable salt thereof of logical formula (I) structure of the invention can also be used to prevent to solidify in vitro, such as
For preventing the solidification of the biological sample containing Xa factor.
The compound or pharmaceutically acceptable salt thereof of logical formula (I) structure of the invention, can with it is one or more pharmaceutically acceptable
Carrier, excipient or diluent pharmaceutical composition is made jointly.Solid orally ingestible, liquid can be made in the pharmaceutical composition
The dosage forms such as oral preparation or injection.
The solid orally ingestible includes: tablet, dispersible tablet, enteric coatel tablets, chewable tablets, oral disintegrating tablet, capsule, granule.It adopts
Use lactose or starch as the diluent of the solid orally ingestible；Using gelatin, methylcellulose, hydroxypropyl methylcellulose, gather
Vinylpyrrolidone, starch slurry etc. are used as adhesive；Use starch, sodium carboxymethylcellulose, carboxyrnethyl starch sodium, low-substituted hydroxypropyl
Methylcellulose, crospovidone, microcrystalline cellulose are as disintegrating agent；Use talcum powder, micro- part of silica gel, tristerin, hard
Resin acid calcium or magnesium etc. are used as antiadhesives and lubricant.
The preparation method of the solid orally ingestible is the following steps are included: by active constituent and carrier and disintegration additive
Then composition mixture makes the aqueous solution of the mixture and adhesive, alcohol or aqueous alcohol solution are in suitable equipment
Wet process or dry granulation are carried out, dry particle is then added other disintegrating agents, lubricant and antiplastering aid and system appropriate is made
Agent.
The liquid oral medicine includes syrup and oral solution.
Series compound of the invention can also be administered by non-bowel form.Optimizing injection administration, including injection
Water needle, injection powder needle and primary infusion.
Series compound of the invention is effective in comparatively wide measures range, such as the dosage taken daily is 1
Within the scope of~1000mg/ people, it can divide primary or be administered for several times.The dosage for actually taking the compounds of this invention should be by doctor's root
It is determined according to related situation, these situations include the physical condition of patient, the administration route of patient, the age, weight, right
Individual reaction and the severity of symptom of drug etc..
Specific embodiment
The present invention will be further explained with reference to the examples below, and the examples are merely illustrative, is in no way intended to it
It limits the scope of the invention in any way.
Embodiment 1:
Compound I-1:N- (4- chlorphenyl) -2- ((4- (3- oxomorpholin) phenyl) amido) thiazole -4-carboxamide；
8g compound VI -1,6g compound V, 1g cuprous iodide, 0.5g8- oxyquinoline, 1.4g carbon are added in reaction flask
Sour potassium, 25mlDMF (dimethylformamide), nitrogen protection, stirring are warming up to reflux, insulated and stirred, and contact plate controls fully reacting.
Solvent to the greatest extent is steamed in decompression, and 30ml water is added, and ethyl acetate extracts (100ml × 3), merges organic phase, and saturated sodium-chloride water solution is washed
(15ml × 1), anhydrous sodium sulfate is dry, and silica gel column chromatography obtains 6.0g pale solid, is compounds Ⅳ -1.
5g compounds Ⅳ -1,20ml dehydrated alcohol is added in reaction flask, the lithium hydroxide that 20m mass concentration is 15% is water-soluble
Liquid is stirred at room temperature, and contact plate controls fully reacting.Ethyl alcohol to the greatest extent, 0-10 DEG C of 20% (mass concentration) acetic acid aqueous solution of dropwise addition are steamed in decompression
PH to 6-7 is adjusted, solid occurs, is filtered, is washed (25ml × 3), it is dry, 3.2g pale solid is obtained, is compound III -1.
In reaction flask be added 1g compound III -1,0.6g compound ii -1,0.5gTBTU (O- benzotriazole-N, N, N',
N'- tetramethylurea tetrafluoro boric acid), 0.5g triethylamine, 10mlDMF, nitrogen protection is stirred at room temperature, and contact plate controls fully reacting.Instead
Answer liquid be added 100ml water, ethyl acetate extract (100ml × 3), merge organic phase, saturated sodium-chloride water solution wash (15ml ×
1), anhydrous sodium sulfate is dry, and silica gel column chromatography obtains 0.2g off-white powder, is chemical compounds I -1.
1H-NMR(DMSO-d6), δ (ppm): 3.540 (m, 4H), 4.280 (s, 2H), 6.512 (d, 2H), 6.578 (d,
2H),6.682(s,1H),7.423(d,2H),7.556(d,2H),8.389(s,1H),10.448(s,1H)。
Embodiment 2:
Compound I-2:N- (4- bromophenyl) -2- ((4- (3- oxomorpholin) phenyl) amido) thiazole -4-carboxamide；
The present embodiment uses synthetic method same as Example 1, the difference is that compound II-2 is different, specifically such as
Under,
1H-NMR(DMSO-d6),δ(ppm):3.542(m,4H),4.300(s,2H),6.514(d,2H),6.580(d,
2H),6.684(s,1H),7.442(d,2H),7.556(d,2H),8.366(s,1H),10.452(s,1H)。
Embodiment 3:
Compound I-3:N- (4- chlorphenyl) -2- ((4- (2- oxo-piperidine -1- base) phenyl) amido) thiazole -4- formyl
Amine；
The present embodiment uses synthetic method same as Example 1, the difference is that compound VI-3 is different, specifically such as
Under,
1H-NMR(DMSO-d6), δ (ppm): 1.780 (m, 2H), 2.180-2.240 (m, 4H), 4.340 (m, 2H), 6.338
(d,2H),6.580(d,2H),6.682(s,1H),7.448(d,2H),7.568(d,2H),8.480(s,1H),10.446(s,
1H)。
Embodiment 4:
Compound I-4:N- (4- fluorophenyl) -2- ((4- (2- oxo-piperidine -1- base) phenyl) amido) thiazole -4- formyl
Amine；
The present embodiment uses synthetic method same as Example 1, the difference is that compound VI-4 and II-4 is different,
It is specific as follows,
1H-NMR(DMSO-d6), δ (ppm): 1.780 (m, 2H), 2.180-2.240 (m, 4H), 4.340 (m, 2H), 6.328
(d,2H),6.480(d,2H),6.682(s,1H),7.248(d,2H),7.468(d,2H),8.480(s,1H),10.446(s,
1H)。
Embodiment 5
The compound or pharmaceutically acceptable salt thereof of logical formula (I) structure of the invention to the inhibiting effect of factor Xa in the following manner
Measurement:
Untested compound is dissolved in DMSO by various concentration, and (public purchased from HYPHEN BioMed with the Xa factor of the mankind
Department) and Tris buffer 37 DEG C warm bath 2 minutes.Then chromogenic substrate (being purchased from HYPHEN BioMed company), 37 DEG C of temperature are added
It is excited and is measured in 405nm with microplate reader after bath 50 minutes.It is compared with pure DMSO (dimethyl sulfoxide).Test substances will be contained
Test mixture excitation and the control mixture without test substances comparison, and IC is calculated by these data50Value,
It the results are shown in Table 1.
1 compound of table inhibits the active IC of FXa50
| Embodiment | 1 | 2 | 3 | 4 |
| Compound | I-1 | I-2 | I-3 | I-4 |
| IC50/nM | 27 | 22 | 31 | 40 |
In order to more fully explain implementation of the invention, following example of formulations are provided.These embodiments be only explain,
It is not intended to limit the scope of the invention.Preparation can be using any one compound in the present invention as active constituent.
Embodiment 6
The preparation of tablet:
| Prescription | 1000 dosages |
| Compound I-1 made from embodiment 1 | 80g |
| Microcrystalline cellulose | 30g |
| Pregelatinized starch | 40g |
| Lactose | 120g |
| Hydroxypropyl methylcellulose | 8g |
| Sodium carboxymethyl starch | 12g |
| Magnesium stearate | qs |
| Silica | qs |
Technique: active constituent auxiliary material is sieved with 100 mesh sieve respectively, and (half carboxymethyl forms sediment the main ingredient and auxiliary material for weighing recipe quantity
Powder sodium) it is sufficiently mixed, hydroxypropyl methylcellulose aqueous solution softwood processed in right amount is added, crosses 24 meshes, wet granular is made and is dried in 50-60 DEG C
About 2-3 hours dry in case, by remaining sodium carboxymethyl starch, magnesium stearate and silica are uniformly mixed with particle, whole grain, are surveyed
Intermediates content is determined, with special-shaped stamping.
Embodiment 7
The preparation of capsule:
| Prescription | 1000 capsule dosages |
| Compound I-3 made from embodiment 3 | 100g |
| Microcrystalline cellulose | 20g |
| Lactose | 120g |
| Low-substituted hydroxypropyl cellulose | 6g |
| 10% starch slurry | qs |
| Magnesium stearate | qs |
Technique: active constituent auxiliary material is sieved with 100 mesh sieve respectively, and the main ingredient and auxiliary material for weighing recipe quantity are sufficiently mixed, and is added
Povidone aqueous solution in right amount dry about 2-3 hours in 50-60 DEG C of baking oven by softwood processed, excessively 20 meshes, obtained wet granular, will be stearic
Sour magnesium is uniformly mixed with particle, whole grain, measures intermediates content, filling with No. 2 capsules.
Claims (10)
1. a kind of compound has the structure as shown in formula (I):
Or its pharmaceutically acceptable salt, in which:
R1Selected from fluorine, chlorine, bromine；
R2It is selected from
2. compound as described in claim 1 is selected from following compounds:
I-1:N- (4- chlorphenyl) -2- ((4- (3- oxomorpholin) phenyl) amido) thiazole -4-carboxamide；
I-2:N- (4- bromophenyl) -2- ((4- (3- oxomorpholin) phenyl) amido) thiazole -4-carboxamide；
I-3:N- (4- chlorphenyl) -2- ((4- (2- oxo-piperidine -1- base) phenyl) amido) thiazole -4-carboxamide；
I-4:N- (4- fluorophenyl) -2- ((4- (2- oxo-piperidine -1- base) phenyl) amido) thiazole -4-carboxamide；
Or its pharmaceutically acceptable salt.
3. the compound as described in any one of claims 1 or 2, wherein the pharmaceutically acceptable salt includes logical formula (I)
The salt that the compound and inorganic acid or organic acid of structure generate.
4. the preparation method of compound described in any one of claims 1 or 2, comprising the following steps:
Wherein: R1Selected from fluorine, chlorine, bromine；
R2It is selected from
The compound of general formula (VI) reacts the compound for generating general formula (IV) with the compound of general formula (V) in a solvent；General formula
(IV) compound prepares the compound of general formula (III) through hydrolysis；The compound of the compound of general formula (III) and general formula (II) is molten
Reaction generates the compound of general formula (I) in agent.
5. compound described in any one of claims 1 or 2 is being used to prepare prevention and/or treatment thrombotic disease medicine
The purposes of object or pharmaceutical composition.
6. a kind of pharmaceutical composition, wherein contain at least one described in any item compounds of claims 1 or 2 as effectively at
Point, and contain one or more pharmaceutical acceptable carrier, diluent or excipient.
7. pharmaceutical composition as claimed in claim 6, wherein the pharmaceutical composition is solid orally ingestible, liquid port
Formulation or injection.
8. pharmaceutical composition as claimed in claim 7, wherein the solid orally ingestible is dispersible tablet, enteric coatel tablets, chewing
Piece, oral disintegrating tablet, capsule or granule.
9. pharmaceutical composition as claimed in claim 7, wherein the liquid oral medicine is syrup or oral solution.
10. pharmaceutical composition as claimed in claim 7, wherein the injection is injection water needle, injection powder needle or small
Infusion.
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| CN201610672180 | 2016-08-15 | ||
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101967145A (en) * | 2010-09-09 | 2011-02-09 | 华东理工大学 | Method for preparing antithrombotic medicament apixaban |
| CN102702186A (en) * | 2012-06-20 | 2012-10-03 | 安润医药科技（苏州）有限公司 | Synthesis method of rivaroxaban |
| CN103342704A (en) * | 2013-07-25 | 2013-10-09 | 甘肃皓天化学科技有限公司 | Preparation method of Apixaban as anti-thrombotic drug |
| CN103562183A (en) * | 2011-03-29 | 2014-02-05 | 赛诺菲 | Benzoic acid salt of otamixaban |
-
2016
- 2016-10-31 CN CN201610927946.1A patent/CN106565698B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101967145A (en) * | 2010-09-09 | 2011-02-09 | 华东理工大学 | Method for preparing antithrombotic medicament apixaban |
| CN103562183A (en) * | 2011-03-29 | 2014-02-05 | 赛诺菲 | Benzoic acid salt of otamixaban |
| CN102702186A (en) * | 2012-06-20 | 2012-10-03 | 安润医药科技（苏州）有限公司 | Synthesis method of rivaroxaban |
| CN103342704A (en) * | 2013-07-25 | 2013-10-09 | 甘肃皓天化学科技有限公司 | Preparation method of Apixaban as anti-thrombotic drug |
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