CN106518859A - Thiazole derivative as well as preparing method and application thereof - Google Patents
Thiazole derivative as well as preparing method and application thereof Download PDFInfo
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- C07—ORGANIC CHEMISTRY
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- 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
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Abstract
The invention relates to a novel thiazole derivative having a general formula (I) structure and a pharmaceutically acceptable salt thereof. The definitions of all groups are described in the specifications. The invention further relates to a preparing method of the compound, drug compositions containing the novel thiazole derivative and the pharmaceutically acceptable salt thereof and an application of the novel thiazole derivative and the pharmaceutically acceptable salt thereof to the preparation of drugs for preventing and/or treating thromboembolism diseases as bioactive substances.
Description
Technical field
The present invention relates to anti-freezing field, specifically the present invention relates to new thiazole derivative, its preparation method and its
In the purposes for preparation prevention and/or treatment thrombotic disease medicine or pharmaceutical composition.
Background technology
In the angiocarpy of people, in blood generation solidification or blood, some visible components are separated out, aggegation forms solid mass
Process, referred to as thrombosis, the solid mass for being formed are thrombus.Blood clotting was a kind of protection machine of organism originally
System, however, in the case of blood flow anomalies, blood vessel change in wall or clotting factor exception, triggering abnormal coagulation process, blood
Liquid just can form thrombus or embolism, so as to cause the thromboembolisms such as myocardial infarction, apoplexy, DVT or pulmonary embolism
Property disease.Thrombotic disease is the disease of harm most serious in angiocardiopathy, is the first killer of human health.
The medicine of existing antithrombotic embolism class diseases is divided into antiplatelet drug, anticoagulation medicine and fibrinolytic drug
Thing.Wherein, anticoagulation medicine mainly has thrombin inhibitor, vitamin K antagon and Xa factor inhibitor.With heparin and low point
Sub- heparin is the shortcomings of thrombin inhibitor of representative has oral invalid, non-selective suppression and High risk of bleeding.With magnificent method
Although the vitamin K antagon that Lin Wei is represented can be oral, therapeutic index is narrow, and food drug interaction it is big, it is individual
Dose difference is also than larger.
Research shows that Xa factor is the best target of development of new anticoagulant, at present razaxaban, Eliquis
List with edoxaban.The direct suppression of Xa factor can produce efficient blood coagulation resisting function, and without thrombin inhibitor
Side effect.
The content of the invention
The technical problem to be solved in the present invention is to provide a kind of brand-new thiazole derivative, and there is the compound anti-freezing to make
With can be used in preventing and/or treat thrombotic disease.
To solve above-mentioned technical problem, the invention provides a kind of compound, with the structure as shown in formula (I):
Or its pharmaceutically acceptable salt, wherein:
R1Selected from fluorine, chlorine, bromine;
R2Selected from hydrogen, fluorine, chlorine, methyl.
Preferably, compound of the invention is selected from following compounds:
I-1:N- (4- chlorphenyls) -2- ((4- (5- oxo -2- thiocarbamoyl imidazole alkane -1- bases) phenyl) amido) thiazole -4- first
Acid amides;
I-2:N- (4- bromophenyls) -2- ((4- (5- oxo -2- thiocarbamoyl imidazole alkane -1- bases) phenyl) amido) thiazole -4- first
Acid amides;
I-3:N- (4- bromophenyls) -2- ((the fluoro- 4- of 2- (5- oxo -2- thiocarbamoyl imidazole alkane -1- bases) phenyl) amido) thiazole -
4- formamides;
I-4:N- (4- fluorophenyls) -2- ((2- methyl -4- (5- oxo -2- thiocarbamoyl imidazole alkane -1- bases) phenyl) amido) thiophene
Azoles -4- formamides;
I-5:N- (4- chlorphenyls) 2- ((the chloro- 4- of 2- (5- oxo -2- thiocarbamoyl imidazole alkane -1- bases) phenyl) amido) thiazole -
4- formamides;
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 (is included with various inorganic acids (including but not limited to, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid etc.) or organic acid
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, ethyl sulfonic acid, benzene sulfonic acid etc.) salt that generates.
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 bicarbonate such as alkali metal or alkaline-earth metal, including
But it is not limited to:NaOH, potassium hydroxide, calcium hydroxide, sodium carbonate etc.) salt that generates, such as corresponding sodium salt, sylvite or calcium salt
Deng.Nontoxic organic base such as methylamine, triethylamine or meglumine etc. may also be employed and generates salt.
The compound of the present invention is synthesized by following steps:
Wherein:R1Selected from fluorine, chlorine, bromine;R2Selected from hydrogen, fluorine, chlorine, methyl;
Reaction prepares the compound of formula (VII) in a solvent for the compound of formula (VIII) and chloracetyl chloride;Formula (VII)
Compound prepares the compound of formula (VI) in a solvent with potassium rhodanide or sodium sulfocyanate reaction;The compound of formula (VI) with
The compound of formula (V) reacts the compound for generating formula (IV) in a solvent;The compound Jing hydrolysis of formula (IV) prepares logical
The compound of formula (III);The compound of formula (III) reacts the change for generating formula (I) in a solvent with the compound of formula (II)
Compound.
Wherein, the compound of formula (II), (V) and (VIII) can be obtained by commercial sources, such as the public affairs such as lark prestige, Ah method Sha
Department, also 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 etc.;Halogenated hydrocarbons, such as 1,2- dichloroethanes, dichloromethane, chloroform, four
Chlorination carbon etc.;Alcohol, such as methyl alcohol, ethanol, isopropanol, the tert-butyl alcohol etc.;Hydrocarbon, such as benzene,toluene,xylene, hexane, hexamethylene etc.;Its
It, such as dimethyl sulfoxide, dimethylformamide, acetonitrile, pyridine, water, HPT etc..Solvent can also be above-mentioned molten
The mixture of agent.
Wherein, in preparation method, can also add in the reaction of synthesis formula VII, formula IV, general formula III and formula I
Enter alkali, suitable alkali can be conventional inorganic base or organic base in reaction, including but not limited to, alkali-metal hydroxide,
Such as potassium hydroxide or NaOH etc.;Alkali-metal carbonate, such as potassium carbonate or sodium carbonate etc.;Alkoxide, such as sodium methoxide, methyl alcohol
Potassium, caustic alcohol, potassium ethoxide or potassium tert-butoxide etc.;Amine, such as methylamine, hydrazine hydrate, triethylamine, diisopropylethylamine, pyridine etc..Alkali
Consumption is 1~5 mole, preferably 1~2 mole based on 1 molar reactive substrate.
Reaction can be carried out at various pressures, such as decompression, normal pressure or pressurization, carry out under preferred normal pressure.
Reaction is typically carried out at a temperature of -78 DEG C to reflux temperature, and preferably 0 DEG C to reflux temperature of scope is carried out.
The compound or pharmaceutically acceptable salt thereof of the logical formula (I) structure of the present invention can play anticoagulation by suppressing Xa,
Therefore can be used for preparing prevention and/or treat the medicine or pharmaceutical composition of thrombotic disease.Wherein, thromboembolia type disease
The concept of disease is known to those skilled in the art.
Additionally, the compound or pharmaceutically acceptable salt thereof of the logical formula (I) structure of the present invention can be additionally used in preventing external solidification, for example
For preventing the solidification containing Xa factor biological sample.
The compound or pharmaceutically acceptable salt thereof of the logical formula (I) structure of the present invention, can be pharmaceutically acceptable with one or more
Carrier, excipient or diluent make jointly pharmaceutical composition.The pharmaceutical composition can make solid orally ingestible, liquid
The formulation such as oral formulations or injection.
The solid orally ingestible includes:Tablet, dispersible tablet, enteric coatel tablets, chewable tablets, oral disintegrating tablet, capsule, granule.Adopt
With lactose or starch as the solid orally ingestible diluent;Using gelatin, methylcellulose, Hydroxypropyl methylcellulose, poly-
Vinylpyrrolidone, starch slurry etc. are used as adhesive;Using starch, sodium carboxymethylcellulose, carboxyrnethyl starch sodium, low-substituted hydroxypropyl
Methylcellulose, PVPP, microcrystalline cellulose are used as disintegrant;Using 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 comprised the following steps:By active component and carrier and disintegration additive
Composition mixture, then makes the aqueous solution of the mixture and adhesive, alcohol or aqueous alcohol solution in suitable equipment
Wet method or dry granulation are carried out, dry particle is subsequently added other disintegrants, lubricant and antiplastering aid and makes appropriate system
Agent.
The liquid oral medicine includes syrup and oral solution.
The series compound of the present invention can also be administered by non-bowel form.Optimizing injection is administered, including injection
Liquid drugs injection, injection powder pin and primary infusion.
The series compound of the present invention is effective in comparatively wide measures range, and the dosage for example taken daily is 1
In the range of~1000mg/ people, can divide and be administered once or for several times.The dosage for actually taking the compounds of this invention should be by doctor's root
Determine according to relevant situation, these situations include the condition of patient, it is the method for administration of patient, the age, body weight, right
Order of severity of individual reaction and symptom of medicine etc..
Specific embodiment
With reference to embodiment, the present invention is described further, and embodiment is only explanatory, is in no way intended to it
The scope of the present invention is limited by any way.
Embodiment 1:
Compound I-1:N- (4- chlorphenyls) -2- ((4- (5- oxo -2- thiocarbamoyl imidazole alkane -1- bases) phenyl) amido) thiophene
Azoles -4- formamides;
Addition 5.00g paraiodoanilines (compound VIII -1) in reaction bulb, 25ml tetrahydrofurans, 4.60g triethylamines, 0.1g's
DMAP (DMAP), agitation and dropping 3.86g chloracetyl chloride add 25-35 insulated and stirreds 2 hours, heat up 50 DEG C, protect
Temperature reaction 2h, decompression steam solvent to the greatest extent, add 30ml water, agitation and filtration to be dried, obtain 5.6g gray solids, be compound VII -1.
5.0g compounds VII -1,1.7g sodium sulfocyanates, 0.5g tetrabutylammonium iodides are put in 50ml acetonitriles, is stirred
Backflow is warming up to, insulated and stirred, point plate control reaction are complete, and solvent to the greatest extent is steamed in decompression, add 250ml water agitation and filtrations, filter cake to use
Washing (20ml × 2), is dried, obtains 3.60g gray solids, be compound VI -1.
Addition 3.2g compounds VI -1 in reaction bulb, 2.4g compounds V, 1g cuprous iodides, 0.5g8- oxyquinolines,
1.4g potassium carbonate, 25mlDMF (dimethylformamide), nitrogen protection, stirring are warming up to backflow, and insulated and stirred, point plate control are anti-
Should be complete.Solvent to the greatest extent is steamed in decompression, adds 30ml water, ethyl acetate extraction (100ml × 3) to merge organic phase, saturated sodium-chloride water
Solution is washed (15ml × 1), anhydrous sodium sulfate drying, silica gel column chromatography, obtains 2.6g pale solids, is compounds Ⅳ -1.
2.5g compounds Ⅳ -1 is added in reaction bulb, 20ml absolute ethyl alcohols, 20ml mass concentrations are 15% lithium hydroxide
The aqueous solution, is stirred at room temperature, and point plate control reaction is complete.Ethanol to the greatest extent, 0-10 DEG C of dropwise addition 20% (mass concentration) acetic acid water are steamed in decompression
Solution adjust pH to 6-7, there is solid, filter, wash (25ml × 3), be dried, obtain 1.6g pale solids, be compound III-
1。
Addition 0.5g compound III -1 in reaction bulb, 0.3g compound ii -1,0.5gTBTU (O- BTA-N, N,
N', N'- tetramethylurea tetrafluoro boric acid), 0.5g triethylamines, 10mlDMF, nitrogen protection are stirred at room temperature, and point plate control has been reacted
Entirely.Reactant liquor adds 100ml water, ethyl acetate extraction (100ml × 3) to merge organic phase, and saturated sodium-chloride water solution is washed
(15ml × 1), anhydrous sodium sulfate drying, silica gel column chromatography obtains 0.15g off-white powders, is chemical compounds I -1.
1H-NMR(DMSO-d6),δ(ppm):4.012(s,2H),6.507(d,2H),6.679(s,1H),7.023(d,
2H),7.456(d,2H),7.738(d,2H),8.389(s,1H),10.643(s,1H),11.452(s,1H)。
Embodiment 2:
Compound I-2:N- (4- bromophenyls) -2- ((4- (5- oxo -2- thiocarbamoyl imidazole alkane -1- bases) phenyl) amido) thiophene
Azoles -4- formamides;
The present embodiment adopts synthetic method same as Example 1, and difference is compound II-2 different, specifically such as
Under,
1H-NMR(DMSO-d6),δ(ppm):4.015(s,2H),6.510(d,2H),6.682(s,1H),7.126(d,
2H),7.558(d,2H),7.748(d,2H),8.688(s,1H),10.743(s,1H),11.482(s,1H)。
Embodiment 3:
Compound I-3:N- (4- bromophenyls) -2- ((the fluoro- 4- of 2- (5- oxo -2- thiocarbamoyl imidazole alkane -1- bases) phenyl) amine
Base) thiazole -4-carboxamide;
The present embodiment adopt synthetic method same as Example 1, difference be compound VIII-3 and II-3 not
It is together, specific as follows,
1H-NMR(DMSO-d6),δ(ppm):4.108(s,2H),6.686(s,1H),7.005(d,1H),7.146(d,
1H),7.346-7.568(m,5H),8.480(s,1H),10.446(s,1H),11.382(s,1H)。
Embodiment 4:
Compound I-4:N- (4- bromophenyls) -2- ((2- methyl -4- (5- oxo -2- thiocarbamoyl imidazole alkane -1- bases) phenyl) amine
Base) thiazole -4-carboxamide;
The present embodiment adopt synthetic method same as Example 1, difference be compound VIII-4 and II-4 not
It is together, specific as follows,
1H-NMR(DMSO-d6),δ(ppm):2.140 (s, 3H), 4.106 (s, 2H), 6.510 (d, 1H), 6.686 (s,
1H),6.935(d,1H),7.226(d,2H),7.468-7.612(m,3H),8.228(s,1H),10.246(s,1H),11.382
(s,1H)。
Embodiment 5:
Compound I-5:N- (4- chlorphenyls) 2- ((the chloro- 4- of 2- (5- oxo -2- thiocarbamoyl imidazole alkane -1- bases) phenyl) amido)
Thiazole -4-carboxamide;
The present embodiment adopts synthetic method same as Example 1, and difference is compound VIII-5 different, specifically
It is as follows,
1H-NMR(DMSO-d6),δ(ppm):4.108(s,2H),6.686(s,1H),7.005(d,1H),7.146(d,
1H),7.426(d,2H),7.568-7.768(m,3H),8.690(s,1H),10.543(s,1H),11.682(s,1H)。
Embodiment 6
The compound or pharmaceutically acceptable salt thereof of the logical formula (I) structure of the present invention to the inhibitory action of factor Xa in the following manner
Determine:
Testing compound is dissolved in DMSO by variable concentrations, and it is (public purchased from HYPHEN BioMed with the Xa factor of the mankind
Department) and Tris buffer solutions 37 DEG C temperature bath 2 minutes.Chromogenic substrate (purchased from HYPHEN BioMed companies) is subsequently adding, 37 DEG C warm
Bath excited measure in 405nm with ELIASA after 50 minutes.Compared with pure DMSO (dimethyl sulfoxide (DMSO)).Test substances will be contained
Test mixing thing excite and the control mixture without test substances comparison, and be calculated IC by these data50Value,
The results are shown in Table 1.
1 compound of table suppresses the IC of FXa activity50
Embodiment | 1 | 2 | 3 | 4 |
Compound | I-1 | I-2 | I-3 | I-4 |
IC50/nM | 30 | 25 | 42 | 48 |
In order to more fully explain the enforcement of the present invention, there is provided following example of formulations.These embodiments only explain,
Rather than limit the scope of the present invention.Preparation can be using any one compound in the present invention as active component.
Embodiment 7
The preparation of tablet:
Prescription | 1000 consumptions |
Compound I-1 obtained in 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 component auxiliary material is crossed 100 mesh sieves respectively, main ingredient and auxiliary material (the half carboxymethyl shallow lake of recipe quantity is weighed
Powder sodium) it is sufficiently mixed, Hydroxypropyl methylcellulose aqueous solution softwood processed in right amount is added, 24 mesh sieves are crossed, wet granular is obtained and is dried in 50-60 DEG C
About 2-3 hours are dried in case, remaining sodium carboxymethyl starch, magnesium stearate and silica are well mixed with particle, whole grain, surveyed
Determine intermediates content, use special-shaped stamping.
Embodiment 8
The preparation of capsule:
Prescription | 1000 capsule consumptions |
Compound I-3 obtained in embodiment 3 | 100g |
Microcrystalline cellulose | 20g |
Lactose | 120g |
Low-substituted hydroxypropyl cellulose | 6g |
10% starch slurry | qs |
Magnesium stearate | qs |
Technique:Active component auxiliary material is crossed 100 mesh sieves respectively, the main ingredient and auxiliary material for weighing recipe quantity is sufficiently mixed, adds
PVP aqueous solution softwood processed in right amount, crosses 20 mesh sieves, wet granular is obtained about 2-3 hours are dried in 50-60 DEG C of baking oven, by tristearin
Sour magnesium is well mixed with particle, whole grain, determines intermediates content, filling with No. 2 capsules.
Claims (10)
1. a kind of compound, with the structure as shown in formula (I):
Or its pharmaceutically acceptable salt, wherein:
R1Selected from fluorine, chlorine, bromine;
R2Selected from hydrogen, fluorine, chlorine, methyl.
2. compound as claimed in claim 1, selected from following compounds:
N- (4- chlorphenyls) -2- ((4- (5- oxo -2- thiocarbamoyl imidazole alkane -1- bases) phenyl) amido) thiazole -4-carboxamide;
N- (4- bromophenyls) -2- ((4- (5- oxo -2- thiocarbamoyl imidazole alkane -1- bases) phenyl) amido) thiazole -4-carboxamide;
N- (4- bromophenyls) -2- ((the fluoro- 4- of 2- (5- oxo -2- thiocarbamoyl imidazole alkane -1- bases) phenyl) amido) thiazole -4- formyls
Amine;
N- (4- fluorophenyls) -2- ((2- methyl -4- (5- oxo -2- thiocarbamoyl imidazole alkane -1- bases) phenyl) amido) thiazole -4- formyls
Amine;
N- (4- chlorphenyls) 2- ((the chloro- 4- of 2- (5- oxo -2- thiocarbamoyl imidazole alkane -1- bases) phenyl) amido) thiazole -4-carboxamide;
Or its pharmaceutically acceptable salt.
3. the compound as any one of claim 1 or 2, wherein, the pharmaceutically acceptable salt includes logical formula (I)
The salt that the compound of structure is generated with inorganic acid or organic acid.
4. the preparation method of the compound any one of claim 1 or 2, comprises the following steps:
Wherein:R1Selected from fluorine, chlorine, bromine;R2Selected from hydrogen, fluorine, chlorine, methyl;
Reaction prepares the compound of formula (VII) in a solvent for the compound of formula (VIII) and chloracetyl chloride;The chemical combination of formula (VII)
Thing prepares the compound of formula (VI) in a solvent with potassium rhodanide or sodium sulfocyanate reaction;The compound and formula of formula (VI)
(V) compound reacts the compound for generating formula (IV) in a solvent;The compound Jing hydrolysis of formula (IV) prepares formula
(III) compound;The compound of formula (III) reacts the chemical combination for generating formula (I) in a solvent with the compound of formula (II)
Thing.
5. the compound any one of claim 1 or 2 is preventing and/or treatment thrombotic disease medicine for preparing
The purposes of thing or pharmaceutical composition.
6. a kind of pharmaceutical composition, wherein containing the compound described at least one claim 1 or 2 any one as effectively into
Point, and contain one or more pharmaceutical acceptable carrier, diluent or excipient.
7. pharmaceutical composition as claimed in claim 6, wherein, described pharmaceutical composition is solid orally ingestible, liquid port
Formulation or injection.
8. pharmaceutical composition as claimed in claim 7, wherein, the solid orally ingestible be tablet, dispersible tablet, enteric coatel tablets,
Chewable tablets, 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 liquid drugs injection, injection powder pin or little
Transfusion.
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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 CN201610928140.4A patent/CN106518859B/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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