WO2015078417A1 - Composé pyrrolopyrimidine et son utilisation dans la préparation d'un médicament hypoglycémiant - Google Patents

Composé pyrrolopyrimidine et son utilisation dans la préparation d'un médicament hypoglycémiant Download PDF

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Publication number
WO2015078417A1
WO2015078417A1 PCT/CN2014/092580 CN2014092580W WO2015078417A1 WO 2015078417 A1 WO2015078417 A1 WO 2015078417A1 CN 2014092580 W CN2014092580 W CN 2014092580W WO 2015078417 A1 WO2015078417 A1 WO 2015078417A1
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WIPO (PCT)
Prior art keywords
compound
mmol
alkyl
added
group
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Application number
PCT/CN2014/092580
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English (en)
Chinese (zh)
Inventor
谢永美
魏于全
耿福能
Original Assignee
四川好医生药业集团有限公司
四川大学
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Application filed by 四川好医生药业集团有限公司, 四川大学 filed Critical 四川好医生药业集团有限公司
Publication of WO2015078417A1 publication Critical patent/WO2015078417A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to pyrrolopyrimidine compounds and their use in the preparation of hypoglycemic agents.
  • the number of patients with diabetes in China has reached 92.4 million, ranking first in the world (Yang W, et al. NEngl J Med, 2010, 362 (12): 1090-1101).
  • the cost of diabetes treatment in China is as high as 173.4 billion yuan per year.
  • the direct medical expenses caused by diabetes account for 13% of China's total medical expenditure (Alcorn T, et al. Lancet, 2012, 379 (9833): 2227-2228). It can be seen that diabetes not only seriously jeopardizes the health of the people, but also brings a heavy economic burden to the country. It is imperative to prevent and treat diabetes.
  • diabetes is mainly divided into four types: insulin-dependent (type 1), non-insulin-dependent (type 2), malnutrition-related and secondary diabetes.
  • type 2 diabetes (T2D) patients accounted for more than 90% of the total number of people with diabetes. Therefore, the research of T2D therapeutic drugs is the focus and hot spot.
  • T2D therapeutic drugs commonly used in clinical practice include insulin, biguanide, sulfonylurea, glycosidase inhibitor, thiazolidinedione, glitazone and glinide, but they often have different degrees of side effects, such as Hypoglycemia, weight gain, cardiovascular side effects, etc.
  • R 1 is selected from the group consisting of H, hydrazine, and -YR 20 ;
  • R 2 is selected from the group consisting of H, hydrazine, halogen, amino, -Y-R20;
  • Y is selected from O, S;
  • R 20 is selected from C1-C5 alkyl, deuterated or aryl C1-C4 alkyl;
  • R 3 and R 4 are each independently selected from H or
  • R 7 , R 8 and R 9 are each independently selected from H, halogen, C1-C4 alkyl or alkoxy, or halogenated C1-C4 alkyl or alkoxy;
  • R 3 and R 4 are formed together with the N connected thereto. among them:
  • Z is selected from C, O or N;
  • n 1 or 2;
  • R 10 is selected from the group consisting of H, a C1-C4 alkyl group, a halogenated C1-C4 alkyl group or
  • R 11 is selected from C 1 -C 4 alkyl or alkoxy, halogen substituted C 1 -C 4 alkyl or alkoxy or R 12 is selected from H or a C1-C4 alkyl group;
  • R 13 is selected from a C1-C4 alkyl group or a halogenated C1-C4 alkyl group
  • W 1 is selected from O or S, and W 2 is selected from C or N;
  • R 14 is selected from H, halogen, C1-C4 alkyl or haloalkyl, 5- or 6-membered cycloalkyl containing O or S, or
  • R 15 and R 16 are each independently selected from H, C1-C4 alkyl or haloalkyl
  • R 17 is selected from H, C1-C4 alkyl or haloalkyl
  • R 18 is selected from H, C1-C4 alkyl or haloalkyl
  • R 19 is selected from H, C1-C6 alkyl or haloalkyl, C5-C10 aryl or heterocyclic aromatic hydrocarbon, or halogenated C5-C10 aryl or heterocyclic aromatic hydrocarbon;
  • R 5 is selected from an alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted hetero atom-containing aryl group, and the substituent is selected from a C 1 -C 4 alkyl group, a halogen or a sulfonyl group;
  • R 6 is selected from C 1 -C 4 alkyl, aryl or deuterated C 1 -C 4 alkyl;
  • X is selected from Or not;
  • the halogen is F, Cl or Br.
  • R 1 is selected from H and hydrazine
  • R 2 is selected from H, hydrazine, halogen or -OR 20 , and R 20 is selected from C1 to C5 alkyl;
  • R 3 and R 4 are each independently selected from H or
  • R 7 to R 9 are each independently selected from H, halogen, C1-C4 alkyl or alkoxy, or halogenated C1-C4 alkyl or alkoxy;
  • Z is selected from C, N, O or S
  • n 1 or 2;
  • R 10 is selected from the group consisting of H, C1-C4 alkyl, or
  • R 11 is selected from a C 1 -C 4 alkyl or alkoxy group
  • R 13 is selected from a C1 to C4 alkyl group or a halogenated alkyl group
  • R 5 is a phenyl group
  • R 6 is a C1-C4 alkyl group.
  • R 20 is selected from a methyl group
  • R 3 and R 4 are each independently selected from H, or
  • R 7 to R 9 are each independently selected from H, halogen, methyl or methoxy;
  • R 3 and R 4 are formed together with the N connected thereto.
  • the compound is as shown in formula II:
  • R 6 is selected from a C 1 -C 4 alkyl group, a partially halogenated alkyl group or a fully halogenated alkyl group;
  • R 13 is selected from a C1-C4 haloalkyl group
  • R 20 is selected from a C1 to C5 alkyl group, a partially halogenated alkyl group or a fully halogenated alkyl group.
  • R 13 is selected from the group consisting of perhalogenated C1-C4 alkyl groups.
  • R 6 and R 20 are each independently selected from methyl, deuterated methyl, ethyl or deuterated ethyl; R 13 is selected from trifluoromethyl, trichloromethyl, pentafluoroethyl or pentachloroethyl. base.
  • R 13 is selected from the group consisting of trifluoromethyl.
  • the structural formula of the compound is as follows:
  • the present invention also provides the use of the above compound or a pharmaceutically acceptable salt, hydrate or solvate thereof for the preparation of a hypoglycemic agent.
  • the drug is a drug for treating type 2 diabetes.
  • the present invention also provides a pharmaceutical composition for treating diabetes, which comprises the above compound or a pharmaceutically acceptable salt, hydrate or solvate thereof as an active ingredient, together with a pharmaceutically-acceptable adjuvant or auxiliary ingredient.
  • a pharmaceutical composition for treating diabetes which comprises the above compound or a pharmaceutically acceptable salt, hydrate or solvate thereof as an active ingredient, together with a pharmaceutically-acceptable adjuvant or auxiliary ingredient.
  • the preparation of the present invention is an injection.
  • the salt of the present invention may be the above compound and hydrochloric acid, phosphoric acid, acetic acid, propionic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, p-toluenesulfonic acid,
  • the pharmaceutically acceptable salt formed by methanesulfonic acid or the like is not limited to the kind of the above acid.
  • the invention prepares a novel pyrrolopyrimidine compound, which can significantly reduce the fasting blood glucose of diabetic mice, and has high safety, and provides a new choice for clinical medication.
  • Et ethyl
  • NaOEt sodium ethoxide
  • EtOH ethanol
  • Formamide formamide
  • DMF N, N-dimethylformamide
  • Malonic acid malonic acid
  • HOBT 1-hydroxybenzotriazole
  • TEA triethanolamine
  • DMSO dimethyl sulfoxide
  • TLC thin layer chromatography
  • EA ethyl acetate
  • 2 (dba) 3 tris(dibenzylideneacetone)dipalladium
  • BINAP ( ⁇ )-2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl
  • Boc tert-butoxy Carbonyl
  • HATU 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate
  • mice Five-week-old C57BL/6J mice, male, were fed with normal and high fat diets for 10 weeks. Male mice with successful modeling were randomly divided into groups of 5, and body weight was recorded. The drug-administered group was given 10 mg/kg of different compounds, and the blank control group and the normal group were given the same volume of physiological saline. The rats were intraperitoneally administered once a day for 5 days, and the fasting basal blood glucose and glucose tolerance of the mice were measured. Data were presented as mean ⁇ standard deviation and significant differences were determined by t test. When P ⁇ 0.05, it was considered to have a significant difference. The test results of some of the compounds of the present invention are shown in Table 2.
  • test results showed that compared with the blank control group, compounds 6, 8, 9, 10, 11, 12, 13, 16, 18, 22, 23, 25, 28, 31, 40 can all have blood glucose levels in diabetic animal models. Different degrees of reduction; in particular, compounds 13, 25 and 40 can significantly reduce blood glucose levels in diabetic animal models.
  • the present invention investigated the acute toxicity of compounds 13, 25 and 40.
  • Compounds 13, 25 and 40 were dispersed in 1% sodium carboxymethylcellulose, ground to a suspension, and formulated into 300 mg/ml.
  • Kunming mice were given 1g/kg by oral gavage alone. During the 14-day observation period, the mice did not die.
  • blood biochemical tests were performed, and no obvious abnormal changes were found in blood biochemical indicators.
  • no abnormal drug-related changes were observed in the main organs of the pathological anatomy of mice.
  • the animals in the drug-administered group showed no abnormalities compared with the vehicle control group and the normal group.
  • the novel pyrrolopyrimidine compound prepared by the invention can significantly reduce the fasting blood glucose of diabetic mice, and has high safety, and provides a new choice for clinical use.

Abstract

La présente invention concerne un composé de formule I, ou un sel, hydrate ou solvate pharmaceutiquement acceptable de celui-ci. L'invention concerne également de nouvelles utilisations de ce composé ou de son sel, hydrate ou solvate pharmaceutiquement acceptable. Le composé pyrrolopyrimidine préparé selon la présente invention peut réduire de façon significative la glycémie à jeun chez la souris diabétique et il offre une grande sécurité, ce qui offre une nouvelle possibilité à la médication clinique.
PCT/CN2014/092580 2013-11-29 2014-11-28 Composé pyrrolopyrimidine et son utilisation dans la préparation d'un médicament hypoglycémiant WO2015078417A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201310633681.0 2013-11-29
CN201310633681 2013-11-29

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WO2015078417A1 true WO2015078417A1 (fr) 2015-06-04

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20180112044A (ko) 2016-02-23 2018-10-11 다이호야쿠힌고교 가부시키가이샤 신규 축합 피리미딘 화합물 또는 그의 염
US10233189B2 (en) 2015-09-08 2019-03-19 Taiho Pharmaceutical Co., Ltd. Fused pyrimidine compound or salt thereof
WO2020029980A1 (fr) * 2018-08-06 2020-02-13 Moexa Pharmaceuticals Limited Inhibiteurs de smad3
CN111303160A (zh) * 2020-04-14 2020-06-19 天津法莫西医药科技有限公司 一种取代吡咯并嘧啶中间体的制备方法
WO2022240966A1 (fr) * 2021-05-11 2022-11-17 Opna Immuno-Oncology Sa Composés et procédés de modulation yap-tead et leurs indications

Citations (4)

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CN1409712A (zh) * 1999-12-10 2003-04-09 辉瑞产品公司 吡咯并[2,3－d]嘧啶化合物
WO2009153261A1 (fr) * 2008-06-18 2009-12-23 Solvay Pharmaceuticals Gmbh Dérivés de pyrrolo[2,3d]pyrimidine à substitution hydroxyphényle, procédés et produits intermédiares pour leur préparation et médicaments contenant ces composés
CN102329325A (zh) * 2010-07-07 2012-01-25 中国科学院广州生物医药与健康研究院 吡咯并嘧啶酮类dpp-iv抑制剂
WO2013120104A2 (fr) * 2012-02-10 2013-08-15 Constellation Pharmaceuticals Modulateurs d'enzymes de modification par méthylation, leurs compositions et utilisations

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1409712A (zh) * 1999-12-10 2003-04-09 辉瑞产品公司 吡咯并[2,3－d]嘧啶化合物
WO2009153261A1 (fr) * 2008-06-18 2009-12-23 Solvay Pharmaceuticals Gmbh Dérivés de pyrrolo[2,3d]pyrimidine à substitution hydroxyphényle, procédés et produits intermédiares pour leur préparation et médicaments contenant ces composés
CN102329325A (zh) * 2010-07-07 2012-01-25 中国科学院广州生物医药与健康研究院 吡咯并嘧啶酮类dpp-iv抑制剂
WO2013120104A2 (fr) * 2012-02-10 2013-08-15 Constellation Pharmaceuticals Modulateurs d'enzymes de modification par méthylation, leurs compositions et utilisations

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10233189B2 (en) 2015-09-08 2019-03-19 Taiho Pharmaceutical Co., Ltd. Fused pyrimidine compound or salt thereof
US10787457B2 (en) 2015-09-08 2020-09-29 Taiho Pharmaceutical Co., Ltd. Fused pyrimidine compound or salt thereof
US11014930B2 (en) 2015-09-08 2021-05-25 Taiho Pharmaceutical Co., Ltd. Fused pyrimidine compound or salt thereof
US11236096B2 (en) 2015-09-08 2022-02-01 Taiho Pharmaceutical Co., Ltd. Fused pyrimidine compound or salt thereof
KR20180112044A (ko) 2016-02-23 2018-10-11 다이호야쿠힌고교 가부시키가이샤 신규 축합 피리미딘 화합물 또는 그의 염
US10155768B2 (en) 2016-02-23 2018-12-18 Taiho Pharmaceutical Co., Ltd. Fused pyrimidine compound or salt thereof
US10807986B2 (en) 2016-02-23 2020-10-20 Taiho Pharmaceutical Co., Ltd. Fused pyrimidine compound or salt thereof
US11046696B2 (en) 2016-02-23 2021-06-29 Taiho Pharmaceutical Co., Ltd. Fused pyrimidine compound or salt thereof
WO2020029980A1 (fr) * 2018-08-06 2020-02-13 Moexa Pharmaceuticals Limited Inhibiteurs de smad3
EP3833664A4 (fr) * 2018-08-06 2022-06-08 Moexa Pharmaceuticals Limited Inhibiteurs de smad3
CN111303160A (zh) * 2020-04-14 2020-06-19 天津法莫西医药科技有限公司 一种取代吡咯并嘧啶中间体的制备方法
WO2022240966A1 (fr) * 2021-05-11 2022-11-17 Opna Immuno-Oncology Sa Composés et procédés de modulation yap-tead et leurs indications

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