CN102643249A - 2-arylthiazole derivative and medicinal salt and application thereof - Google Patents

2-arylthiazole derivative and medicinal salt and application thereof Download PDF

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CN102643249A
CN102643249A CN2011100400725A CN201110040072A CN102643249A CN 102643249 A CN102643249 A CN 102643249A CN 2011100400725 A CN2011100400725 A CN 2011100400725A CN 201110040072 A CN201110040072 A CN 201110040072A CN 102643249 A CN102643249 A CN 102643249A
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acceptable salt
pharmacologically acceptable
arylthiazole derivative
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arylthiazole
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殷建明
朱惠霖
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SUZHOU BORUI PARMACEUTICALS Inc
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SUZHOU BORUI PARMACEUTICALS Inc
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Abstract

The invention relates to a novel 2-arylthiazole derivative and medicinal salts thereof, and an application in the preparation of medicaments for preventing and/or treating gout. The compound of the invention is an ideal selective xanthine oxidoreductase inhibitor, is applicable to the treatment and prevention of various indications associated with uric acid synthesis in the body, and is especially applicable to the treatment of gout. The compound has reduced oxidative metabolism and acyl glucuronidation metabolism, reduced first-pass effect, higher effective bioavailability, and less side effect due to its low using amount.

Description

The 2-arylthiazole derivative, its pharmacologically acceptable salt and purposes
Technical field
The present invention relates to the 2-arylthiazole derivative, its pharmacologically acceptable salt and they prevent and/or treat the purposes in the medicine of gout in preparation.
Background technology
Gout (Gout) claims that again metabolic sacroiliitis (metabolic arthritis) is a kind of because of the purine metabolism obstacle, and uric acid is accumulated in vivo, and causes urate crystal in the joint and the perienchyma deposition and the inflammation of bursting that causes, and belongs to a kind of acute arthritis.Uric acid concentration in the blood can finally induce the uric acid crystal body of accumulating in soft tissue such as membrana articulata or tendon to disengage when reaching capacity, and causes health immunity system appearance allergy and causes inflammation.
Gout is a kind of global metabolic disease, and the height of its morbidity receives influence of various factors such as economic development level, environment, food habits, race, heredity, medical level and Case definition.European and American areas hyperuricemia morbidity is about 2%～18%, and the morbidity of gout is 0.2%～1.7%.The morbidity of China's hyperuricemia and gout is ascendant trend linearly also.There is statistics to show that the morbidity total in all age bracket gouts is about 0.84% in recent years.Control and treatment if the too high patient of blood uric acid is not careful in one's diet, about 5%～12% finally can develop into gout.
The means that the treatment of gout is taked usually are: promote uric acid excretion and suppress uricogenesis, and adopt adequate measure to improve relevant symptoms.The generation of uric acid is relevant with purine metabolism in the body; In the final step of purine metabolism; Xanthoglobulin is at xanthine oxidoreductase enzyme (xanthine oxidoreductase; XOR) effect generates xanthine down, further generates uric acid again, thereby the activity of inhibition XOR can effectively reduce the generation of uric acid.
Over 30 years, allopurinol (allopurinol) is a unique clinically medicine that is used to suppress uricogenesis, and is widely used in clinical as the medicine of gout.But because allopurinol only has restraining effect to the XOR of reduced form, in the interaction of allopurinol (and active metabolite oxypurinol) and XOR, XOR can recover active owing to the spontaneous reduction in the molybdenum active site in the enzyme; Because allopurinol is a purine analogue, inevitably cause the influence that relates to purine and other enzymic activitys of pyridine metabolism in addition.Therefore in the allopurinol treatment, need the heavy dose of administration of repetition to keep higher levels of drugs.Also bring thus because the serious even fatal untoward reaction due to the drug accumulation.
Febuxostat (Febuxostat) is up-to-date in the world and obtained the medicine that drugs approved by FDA is used to treat gout in 2009 at present.Febuxostat is a kind of non-purine class XOR suppressor factor of high selectivity, and to reduce in the body uric acid synthetic through acting on this oxydase, uric acid reducing concentration, thus effectively treat gout.Febuxostat all has significant inhibitory effect to the XOR of oxidized form and reduced form, and its Ki value that suppresses XOR is respectively 0.6 and 3.1nM; And under concentration,, therefore has better security to relating to purine and the not influence of the metabolic following enzymic activity of pyridine in the body up to 100 μ M.But serious oxidative metabolism (main metabolites is 67M-1,67M-2,67M-4) and acyl group glucuronidation metabolism (22%～44%) can take place in Febuxostat in human body, thereby have influenced the bioavailability of Febuxostat.
Summary of the invention
Technical problem to be solved by this invention is the deficiency that overcomes prior art, and a kind of improved 2-arylthiazole derivative and pharmacologically acceptable salt thereof are provided.
For solving above technical problem, the present invention takes following technical scheme:
The 2-arylthiazole derivative and the pharmacologically acceptable salt thereof of general formula (I) expression:
Figure BSA00000435859900021
In the formula (I):
R 01, R 02And R 03Be hydrogen or deuterium independently;
R 04, R 05And R 06Be hydrogen, deuterium or fluorine independently;
R 07Represent C 1～C 12Saturated alkyl or C 2～C 12Unsaturated thiazolinyl or alkynyl or Ene alkynyl base; They can optionally be interrupted with the form of ether or ketone by an oxygen; Perhaps optionally be interrupted with the form of ester or acid by two oxygen; And optionally be interrupted with the form of alcohol by one or more oxygen, and the part or all of Wasserstoffatoms in them is that its isotropic substance deuterium substitutes;
R 08Be any prodrug group.
According to a preferred aspect of the present invention, R 07Represent the C of straight or branched 1～C 6Saturated alkyl, its part or all of Wasserstoffatoms is replaced by deuterium, more preferably, R 07Representative-CH (CD 3) CD 3,-CH 2CH (CD 3) CD 3Or-CH 2CH 2CH (CD 3) CD 3
Among the present invention, described prodrug group refers to outside organism or human body, not have activity or activity very little, and under the effect of organism or the intravital enzyme of people, regains active group.In the present invention, the prodrug group includes but not limited to following group :-C nH 2n+1-CH 2CF 3-CH 2CF 2C nH 2n+1-CH 2CHFC nH 2n+1-CH 2C 6H 5-CH 2C 6H 4X;-CH 2C 6H 3X 2-CH 2C 5H 4N;-CH 2C 3H 3N 2-CH 2C 3H 2N 3-CH 2C 5H 3NX;-CH 2C 4H 2NX 2-C nH 2n-5O 3-C nH 2nN;-C nH 2nNO;-C nH 2n+1N 2-C nH 2n+1N 2O;-C nH 2n+2N 3-C nH 2n+2N 3O;-C nH 2nOCOOC nH 2n+1-C nH 2nOCOOC nH 2n-1-C nH 2nOCOC nH 2nNH (C nH 2n+1);-C nH 2nOCOC nH 2nN (C nH 2n+1) 2-C nH 2nOCOC nH 2nNH (C nH 2n-1);-C nH 2nOCOC nH 2nN (C nH 2n-1) 2-C nH 2nCOC nH 2nNH (COC nH 2n+1);-C nH 2nCOC nH 2nNH (COC nH 2n-1);-C nH 2nN (C nH 2n+1) C nH 2n+1COOH;-C nH 2nOPO (OH) 2, wherein X is F, Cl, Br, OC mH 2m+1, SC mH 2m+1Or NHC mH 2m+1, n, m are the integer between 1～8 independently.
According to the present invention, the compound that representational 2-arylthiazole derivative has for example formula (II), formula (III), formula (IV) and formula V to represent.
Figure BSA00000435859900031
Among the present invention, mentioned alkyl, thiazolinyl, alkynyl can not be straight chain, side chain or ring-type when having special definition.
According to the present invention, described pharmacologically acceptable salt includes but not limited to hydrochloride, phosphoric acid salt, vitriol, acetate, PHENRAMINE MALEATE, benzene sulfonate, toluenesulfonate, fumarate, tartrate etc.
The invention still further relates to 2-arylthiazole derivative and pharmacologically acceptable salt thereof with any that can form and can be used as medicament forms and the prodrug used, and their meta-bolitess of forming in any form.These prodrugs, meta-bolites, 2-arylthiazole derivative and pharmacologically acceptable salt thereof will be referred to as " The compounds of this invention " hereinafter.
The compounds of this invention can by separately or with other medicines combine be used to prepare prevention and/or or treatment and body in the relevant indication of the uric acid complex functionality medicine of gout for example.
The preparation of The compounds of this invention can be through the route of synthesis of well-known those the similar methods of chemical field, the synthetic compound of the present invention of description that particularly comprises according to this paper.Reagent generally obtains or is easy to use the well-known method preparation of those skilled in the art from commercial source.
Because the enforcement of above technical scheme, the present invention compared with prior art has following advantage:
2-arylthiazole derivative with structure of the present invention can suppress the xanthine oxidoreductase enzyme through high selectivity ground, and to reduce in the body uric acid synthetic, uric acid reducing concentration, thus effectively treat gout.Compare with existing xanthine oxidoreductase inhibitors, this compounds has the oxidative metabolism and the metabolism of acyl group glucuronidation of reduction, and first pass effect reduces and higher effective bioavailability, thereby its using dosage is less, few side effects.As xanthine oxidoreductase inhibitors highly effectively and optionally, The compounds of this invention can be used for treating or prevents the relevant indication of uric acid complex functionality in various and the body, and particularly it can be used for treating gout.
Embodiment
Below in conjunction with specific embodiment the present invention is done further detailed explanation, but the present invention is not limited to following examples.
Embodiment 1
Present embodiment provides the compound of a kind of formula (II) expression:
Figure BSA00000435859900041
Embodiment 2
Present embodiment provides the compound of a kind of formula (III) expression:
Figure BSA00000435859900051
Embodiment 3
Present embodiment provides the compound of a kind of formula (IV) expression:
Figure BSA00000435859900052
Embodiment 4
The compound that present embodiment provides a kind of formula V to represent:
Figure BSA00000435859900053
The foregoing description only is explanation technical conceive of the present invention and characteristics, and its purpose is to let the personage who is familiar with this technology can understand content of the present invention and enforcement according to this, can not limit protection scope of the present invention with this.All equivalences of doing based on spirit of the present invention change or modify, and all should be encompassed within protection scope of the present invention.

Claims (10)

1. the 2-arylthiazole derivative and the pharmacologically acceptable salt thereof of general formula (I) expression:
It is characterized in that: in the formula (I):
R 01, R 02And R 03Be hydrogen or deuterium independently;
R 04, R 05And R 06Be hydrogen, deuterium or fluorine independently;
R 07Represent C 1～C 12Saturated alkyl or C 2～C 12Unsaturated thiazolinyl or alkynyl or Ene alkynyl base; They can optionally be interrupted with the form of ether or ketone by an oxygen; Perhaps optionally be interrupted with the form of ester or acid by two oxygen; And optionally be interrupted with the form of alcohol by one or more oxygen, and the part or all of Wasserstoffatoms in them is that its isotropic substance deuterium substitutes;
R 08Be any prodrug group.
2. 2-arylthiazole derivative according to claim 1 and pharmacologically acceptable salt thereof is characterized in that: R 07Represent the C of straight or branched 1～C 6Saturated alkyl, its part or all of Wasserstoffatoms is replaced by deuterium.
3. 2-arylthiazole derivative according to claim 2 and pharmacologically acceptable salt thereof is characterized in that: R 07Representative-CH (CD 3) CD 3,-CH 2CH (CD 3) CD 3Or-CH 2CH 2CH (CD 3) CD 3
4. 2-arylthiazole derivative according to claim 1 and pharmacologically acceptable salt thereof is characterized in that: R 08For being selected from a kind of in the following groups :-C nH 2n+1-CH 2CF 3-CH 2CF 2C nH 2n+1-CH 2CHFC nH 2n+1-CH 2C 6H 5-CH 2C 6H 4X;-CH 2C 6H 3X 2-CH 2C 5H 4N;-CH 2C 3H 3N 2-CH 2C 3H 2N 3-CH 2C 5H 3NX;-CH 2C 4H 2NX 2-C nH 2n-5O 3-C nH 2nN;-C nH 2nNO;-C nH 2n+1N 2-C nH 2n+1N 2O;-C nH 2n+2N 3-C nH 2n+2N 3O;-C nH 2nOCOOC nH 2n+1-C nH 2nOCOOC nH 2n-1-C nH 2nOCOC nH 2nNH (C nH 2n+1);-C nH 2nOCOC nH 2nN (C nH 2n+1) 2-C nH 2nOCOC nH 2nNH (C nH 2n-1);-C nH 2nOCOC nH 2nN (C nH 2n-1) 2-C nH 2nCOC nH 2nNH (COC nH 2n+1);-C nH 2nCOC nH 2nNH (COC nH 2n-1);-C nH 2nN (C nH 2n+1) C nH 2n+1COOH;-C nH 2nOPO (OH) 2, wherein X is F, Cl, Br, OC mH 2m+1, SC mH 2m+1Or NHC mH 2m+1, n, m are the integer between 1～8 independently.
5. 2-arylthiazole derivative according to claim 1 and pharmacologically acceptable salt thereof is characterized in that: said 2-arylthiazole derivative is a kind of in the compound represented of formula (II), formula (III), formula (IV) and formula V.
Figure FSA00000435859800021
6. the purposes in the medicine of described 2-arylthiazole derivative of each claim and pharmacologically acceptable salt thereof the relevant indication of uric acid complex functionality in preparation and body in the claim 1 to 5.
7. purposes according to claim 6 is characterized in that: said is gout with the interior relevant indication of uric acid complex functionality of body.
In the claim 1 to 5 described 2-arylthiazole derivative of each claim and pharmacologically acceptable salt thereof in the purposes of regulating aspect the selectivity xanthine oxidoreductase enzymic activity.
9. what described 2-arylthiazole derivative of each claim and pharmacologically acceptable salt thereof formed in the claim 1 to 5 can be used as medicament forms and prodrug of using and the meta-bolites that forms in any form.
10. 2-arylthiazole derivative according to claim 9 and pharmacologically acceptable salt thereof form can be used as medicament forms and purposes in the medicine of the relevant indication of the prodrug used and the meta-bolites that forms in any form uric acid complex functionality in preparation and body and in the purposes aspect the adjusting selectivity xanthine oxidoreductase enzymic activity.
CN2011100400725A 2011-02-18 2011-02-18 2-arylthiazole derivative and medicinal salt and application thereof Pending CN102643249A (en)

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103848796A (en) * 2012-11-30 2014-06-11 镇江新元素医药科技有限公司(中外合资) Deuterium-substituted 2-phenylthiazole compound, and pharmaceutical composition thereof
WO2015196323A1 (en) * 2014-06-23 2015-12-30 北京新天宇科技开发有限公司 New derivatives of 2-(3-cyano-4-isobutyloxyphenyl)-4-methylthiazole-5-formate, preparation method therefor and application thereof
CN105218479A (en) * 2014-06-23 2016-01-06 北京新天宇科技开发有限公司 The new derivatives of 2-[3-cyano-4-isobutoxy phenyl]-4-methylthiazol-5-formic acid, its preparation method and application
WO2019144842A1 (en) * 2018-01-23 2019-08-01 湘北威尔曼制药股份有限公司 Thiazole-5-formic acid derivative, preparation method therefor and use thereof
CN110407876A (en) * 2019-07-10 2019-11-05 郴州市第一人民医院 A kind of Febustat and phosphocreatine derivative and preparation method thereof and preparing the purposes in anti-myocardial damage medicine
CN116836154A (en) * 2022-04-27 2023-10-03 江苏新元素医药科技有限公司 Compounds useful for gout

Citations (1)

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Publication number Priority date Publication date Assignee Title
US5614520A (en) * 1990-11-30 1997-03-25 Teijin Limited 2-arylthiazole derivatives and pharmaceutical composition thereof

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Title
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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103848796A (en) * 2012-11-30 2014-06-11 镇江新元素医药科技有限公司(中外合资) Deuterium-substituted 2-phenylthiazole compound, and pharmaceutical composition thereof
WO2015196323A1 (en) * 2014-06-23 2015-12-30 北京新天宇科技开发有限公司 New derivatives of 2-(3-cyano-4-isobutyloxyphenyl)-4-methylthiazole-5-formate, preparation method therefor and application thereof
CN105218479A (en) * 2014-06-23 2016-01-06 北京新天宇科技开发有限公司 The new derivatives of 2-[3-cyano-4-isobutoxy phenyl]-4-methylthiazol-5-formic acid, its preparation method and application
CN105218479B (en) * 2014-06-23 2019-10-25 湘北威尔曼制药股份有限公司 The new derivatives, preparation method and application of 2- [3- cyano-4-isobutoxy phenyl] -4- methylthiazol-5-formic acid
WO2019144842A1 (en) * 2018-01-23 2019-08-01 湘北威尔曼制药股份有限公司 Thiazole-5-formic acid derivative, preparation method therefor and use thereof
US11401247B2 (en) 2018-01-23 2022-08-02 Xiangbei Welman Pharmaceutical Co., Ltd Thiazole-5-carboxylic acid derivative and preparation method and use thereof
CN110407876A (en) * 2019-07-10 2019-11-05 郴州市第一人民医院 A kind of Febustat and phosphocreatine derivative and preparation method thereof and preparing the purposes in anti-myocardial damage medicine
CN110407876B (en) * 2019-07-10 2021-07-23 郴州市第一人民医院 Febuxostat and phosphocreatine derivative, preparation method thereof and application thereof in preparation of anti-myocardial cell injury drugs
CN116836154A (en) * 2022-04-27 2023-10-03 江苏新元素医药科技有限公司 Compounds useful for gout
WO2023208103A1 (en) * 2022-04-27 2023-11-02 江苏新元素医药科技有限公司 Compound capable of being used for gout

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Application publication date: 20120822