- Five-membered nitrogen-containing heteroaryl substituted pyrimidinedione compound and application thereof
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The invention belongs to the technical field of medicines, and relates to a five-membered nitrogen-containing heteroaryl substituted pyrimidinedione compound and application thereof, and a pharmaceutical composition containing the five-membered nitrogen-containing heteroaryl substituted pyrimidinedione compound, and the five-membered nitrogen-containing heteroaryl substituted pyrimidinedione compound and the pharmaceutical composition can be used as gonadotropin releasing hormone receptor antagonists. The invention also relates to a method for preparing the compound and the pharmaceutical composition, and application of the compound and the pharmaceutical composition in prevention or treatment of sex hormone dependent diseases including but not limited to prostate cancer, endometriosis, hysteromyoma, precocious puberty and the like.
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Paragraph 0131; 0137-0141
(2021/01/15)
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- Substituted pyrimidinedione compound and application thereof
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The invention belongs to the technical field of medicines, and relates to a substituted pyrimidinedione compound and application thereof, and a pharmaceutical composition containing the compound, which can be used as a gonadotropin releasing hormone receptor antagonist. The invention also relates to a method for preparing the compound and the pharmaceutical composition, and application of the compound and the pharmaceutical composition in prevention or treatment of sex hormone dependent diseases including but not limited to prostate cancer, endometriosis, hysteromyoma, precocious puberty and the like.
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- Heterocyclyl-substituted thieno[2,3-d]pyrimidine-2,4-(1H,3H)-diketone compound and application thereof
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The invention belongs to the technical field of medicines, and relates to heterocyclyl-substituted thieno[2,3-d]pyrimidine-2,4-(1H,3H)-diketone compounds and application thereof, and a pharmaceuticalcomposition containing the compounds; wherein the compounds and the pharmaceutical composition can be used as gonadotropin releasing hormone receptor antagonists. The invention also relates to a method for preparing the compound and the pharmaceutical composition, and application of the compounds and the pharmaceutical compositions in prevention or treatment of sex hormone dependent diseases, including but not limited to: prostate cancer, endometriosis, hysteromyoma, precocious puberty and the like.
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Paragraph 0141; 0147-0151
(2020/11/22)
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- Phenyl-substituted thieno[2,3-d]pyrimidine-2,4 (1H,3H)-dione compounds and application thereof
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The invention belongs to the technical field of medicines, and relates to phenyl-substituted thieno[2,3-d]pyrimidine-2,4 (1H,3H)-dione compounds, application thereof, and a pharmaceutical compositioncontaining the compounds. The compounds and the pharmaceutical composition can be used as gonadotropin releasing hormone receptor antagonists. The invention also relates to a method for preparing thecompounds and the pharmaceutical composition, and application of the compounds and the pharmaceutical composition in prevention or treatment of sex hormone dependent diseases including but not limitedto prostate cancer, endometriosis, hysteromyoma, precocious puberty and the like.
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Paragraph 0143; 0149-0153
(2020/09/09)
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- Nitrogen-containing heterocyclic group substituted pyrimidinedione compound and application thereof
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The invention belongs to the technical field of medicines, and relates to a nitrogen-containing heterocyclic group substituted pyrimidinedione compound and application thereof, and a pharmaceutical composition containing the compound, which can be used as a gonadotropin releasing hormone receptor antagonist. The invention also relates to a method for preparing the compound and the pharmaceutical composition, and application of the compound and the pharmaceutical composition in prevention or treatment of sex hormone dependent diseases including but not limited to prostate cancer, endometriosis,hysteromyoma, precocious puberty and the like.
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Paragraph 0139; 0144; 0145; 0146; 0147
(2020/11/23)
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- Nitrogen-containing heteroaryl substituted pyrimidinedione compound and application thereof
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The invention belongs to the technical field of medicines, and relates to a nitrogen-containing heteroaryl substituted pyrimidinedione compound and application thereof, and a pharmaceutical composition containing the compound, and the nitrogen-containing heteroaryl substituted pyrimidinedione compound and the pharmaceutical composition can be used as gonadotropin releasing hormone receptor antagonists. The invention also relates to a method for preparing the compound and the pharmaceutical composition, and application of the compound and the pharmaceutical composition in prevention or treatment of sex hormone dependent diseases including but not limited to prostate cancer, endometriosis, hysteromyoma, precocious puberty and the like.
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Paragraph 0130; 0135; 0140-0145
(2020/11/25)
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- Bicyclic nitrogen-containing heteroaryl substituted pyrimidinedione compounds and application thereof
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The invention belongs to the technical field of medicines, and relates to bicyclic nitrogen-containing heteroaryl substituted pyrimidinedione compounds, application thereof, and a pharmaceutical composition containing the compounds. The compounds can be used as a gonadotropin releasing hormone receptor antagonist. The invention also relates to a method for preparing the compounds and the pharmaceutical composition, and application of the compounds and the pharmaceutical composition in prevention or treatment of sex hormone dependent diseases including but not limited to prostate cancer, endometriosis, hysteromyoma, precocious puberty and the like.
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Paragraph 0139; 0141; 0147-0151
(2020/10/30)
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- Substituted pyrimidinedione compound and application thereof
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The invention belongs to the technical field of medicines, and relates to a substituted pyrimidinedione compound and application thereof, and a pharmaceutical composition containing the compound, which can be used as a gonadotropin releasing hormone receptor antagonist. The invention also relates to a method for preparing the compound and the pharmaceutical composition, and application of the compound and the pharmaceutical composition in prevention or treatment of sex hormone dependent diseases including but not limited to prostate cancer, endometriosis, hysteromyoma, precocious puberty and the like.
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Paragraph 0151; 0171; 0176-0179
(2020/12/29)
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- Preparation method of Rugolix key intermediate
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The invention relates to a preparation method of a Rugolix key intermediate. 4-nitrophenyl acetic acid is used as a raw material, and a target product is obtained through four steps of reaction. The preparation method avoids the use of toxic reagents and has the advantages of mild reaction conditions, low cost, high yield and simple route and is suitable for industrial large-scale production.
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- Relugolix synthesis method
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The present invention provides a method for preparing a relugolix intermediate compound 8. The method comprises: (a) carrying out a reaction on a compound 2 and N,N'-carbonyldiimidazole to obtain a compound 3; (b) carrying out a reaction on the compound 3 and 2,6-difluorobenzyl chloride to obtain a compound 4; (c) carrying out a reaction on the compound 4 and 3-amino-6-methoxypyridazine to obtaina compound 5; (d) carrying out a reaction on the compound 5 and N,N'-carbonyldiimidazole to obtain a compound 6; (e) carrying out a reaction on the compound 6, N-bromosuccinimide and azobisisobutyronitrile to obtain a compound 7; and (f) carrying out a reaction on the compound 7 and dimethylamine hydrochloride to obtain a compound 8. The invention further provides a relugolix preparation method, which comprises: (g) carrying out a reaction on the compound 8 obtained by the method and hydrogen under a catalyst to obtain a compound 9; and (h) carrying out a reaction on the compound 9, N,N'-carbonyldiimidazole and methoxy amine hydrochloride to obtain relugolix. According to the present invention, the method adopts the route sequentially comprising loop closing and coupling, such that the method has characteristics of simple operation, less side-reaction, mild reaction condition, high yield, high product purity and easy product purification, and is suitable for commercial scale production.
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Paragraph 0059; 0061; 0063-0064
(2019/09/14)
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- Synthesis and biological evaluation of novel thieno[2,3-d]pyrimidine-based FLT3 inhibitors as anti-leukemic agents
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The most common mutations in acute myeloid leukemia (AML) are those that cause the activation of FMS-like tyrosine kinase 3 (FLT3). Therefore, FLT3 is regarded as a potential target for the treatment of AML. A novel series of thieno[2,3-d]pyrimidine-based analogs was designed and synthesized as FLT3 inhibitors. All synthesized compounds were assayed for the tyrosine kinase activity of FLT3 and growth inhibitory activity in four human leukemia cell lines (THP1, MV4-11, K562, and HL-60). Among these compounds, compound 17a, which possesses relatively short and simple substituents at the C6 position of thieno[2,3-d]pyrimidine, emerged as the most promising anti-leukemic agent. Compound 17a exhibited potent inhibition of FLT3-positive leukemic cell growth and of the FLT3 D835Y kinase; such inhibition is required for the successful treatment of AML. The data supports the further investigation of this class of compounds as potential anti-leukemic agents.
- Yang, Jee Sun,Park, Chun-Ho,Lee, Chulho,Kim, Hwan,Oh, Changmok,Choi, Yejoo,Kang, Jong Soon,Yun, Jieun,Jeong, Jin-Hyun,Kim, Myung-Hwa,Han, Gyoonhee
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p. 399 - 407
(2014/09/03)
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- Synthesis and biological evaluation of novel thieno[2,3-d[pyrimidine-based FLT3 inhibitors as anti-leukemic agents
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The most common mutations in acute myeloid leukemia (AML) are those that cause the activation of FMS-like tyrosine kinase 3 (FLT3). Therefore, FLT3 is regarded as a potential target for the treatment of AML. A novel series of thieno[2,3-d]pyrimidine-based analogs was designed and synthesized as FLT3 inhibitors. All synthesized compounds were assayed for the tyrosine kinase activity of FLT3 and growth inhibitory activity in four human leukemia cell lines (THP1, MV4-11, K562, and HL-60). Among these compounds, compound 17a, which possesses relatively short and simple substituents at the C6 position of thieno[2,3-d]pyrimidine, emerged as the most promising anti-leukemic agent. Compound 17a exhibited potent inhibition of FLT3-positive leukemic cell growth and of the FLT3 D835Y kinase; such inhibition is required for the successful treatment of AML. The data supports the further investigation of this class of compounds as potential anti-leukemic agents.
- Yang, Jee Sun,Park, Chun-Ho,Lee, Chulho,Kim, Hwan,Oh, Changmok,Choi, Yejoo,Kang, Jong Soon,Yun, Jieun,Jeong, Jin-Hyun,Kim, Myung-Hwa,Han, Gyoonhee
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p. 399 - 407
(2015/02/19)
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- PREMATURE OVULATION PREVENTIVE AGENT
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The present invention provides a premature ovulation inhibitor for use in in vitro fertilization or embryo transfer process, which contains a nonpeptidic compound having a gonadotropin releasing hormone antagonistic action. The premature ovulation inhibitor for use in in vitro fertilization or embryo transfer process of the present invention is low toxic, permits oral administration, and has a superior inhibitory effect on premature ovulation in in vitro fertilization or embryo transfer process.
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Page/Page column 30
(2008/12/04)
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- NOVEL THIENOPYRIMIDINE DERIVATIVES OR PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF, PROCESS FOR THE PREPARATION THEREOF AND PHARMACEUTICAL COMPOSITION COMPRISING THE SAME
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The present invention relates to a novel thienopyrimidine derivative having an excellent anti? inflammatory and anti-cancer activity, or a pharmaceutically acceptable salt thereof, a process for the preparation thereof and a pharmaceutical composition comprising the same. The compound according to the present invention strongly inhibits IKB kinase-β (IKK-β) involved in the activation of a transcriptional factor, NF-κB, which is associated with inducing various immune and inflammatory diseases, whereby a composition comprising the compound is a useful therapeutic agent against inflammatory diseases, in particular, arthritis and cancer.
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- PREVENTIVES/REMEDIES FOR HOTFLASH
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It is intended to provide a preventing or treating agent for hot flash which comprises a nonpeptidic compound having gonadotropin releasing hormone antagonistic activity, in particular, a preventing or treating agent for hot flash which comprises a nonpeptidic compound having gonadotropin releasing hormone antagonistic activity, wherein said compound is capable of entering the brain.
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- MEDICINAL SOLUTIONS
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The present invention relates to a pharmaceutical solution containing a physiologically active non-peptide substance, an organic acid and a biocompatible organic solvent, and provides a pharmaceutical solution wherein a physiologically active non-peptide
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- Processes for the production of thienopyrimidine derivatives
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The present invention provides a process for producing an intermediate for thienopyrimidine derivatives having the GnRH antagonistic activity at an industrial large scale. The process for production of the present invention relates to a process for produc
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- Preventives/remedies for alzheimer's disease
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The present invention provides an agent for the prophylaxis or treatment of Alzheimer's disease. The agent for the prophylaxis or treatment of Alzheimer's disease of the present invention containing a compound having a GnRH antagonistic action shows low toxicity and has a superior preventive and therapeutic effect on Alzheimer's disease.
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- SUSTAINED RELEASE COMPOSITIONS
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A composition prepared by containing or blending a physiologically active non-peptide substance and a biodegradable polymer having two or more carboxylic groups at its end or a salt thereof features: (1) larger content of the physiologically active non-peptide substance can be contained, as well as release of the same can be controlled or accelerated, whereby secure pharmaceutical effect is achieved; (2) when the physiologically active non-peptide substance causes subcutaneous stimulation, an activity of canceling the stimulation by strongly acidic group at its end is expected; and (3) high glass transition point and high stability.
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- SOLID PREPARATIONS
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The present invention aims at providing a granule comprising a slightly soluble in water and highly water-repellent physiologically active substance in a large content, and a solid preparation comprising the granule, which is superior in disintegration property and dissolution of the physiologically active substance from the preparation. The present invention relates to (1) a granule comprising a physiologically active substance and a cellulose-type disintegrant, (2) a granule comprising a physiologically active substance, a cellulose-type disintegrant and a binder, (3) a solid preparation comprising the granule described in (1) or (2), a cellulose-type disintegrant and a stearic acid-type lubricant and (4) the solid preparation described in (3), which is an oval tablet.
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- Discovery of a thieno[2,3-d]pyrimidine-2,4-dione bearing a p-methoxyureidophenyl moiety at the 6-position: A highly potent and orally bioavailable non-peptide antagonist for the human luteinizing hormone-releasing hormone receptor
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We have previously disclosed the first potent and orally effective non-peptide antagonist for the human luteinizing hormone-releasing hormone (LHRH) receptor, a thieno[2,3-b]pyridin-4-one derivative, T-98475 (1). Extensive research on developing non-peptide LHRH antagonists has been carried out by employing a strategy of replacing the thienopyridin-4-one nucleus with other heterocyclic surrogates. We describe herein the design and synthesis of a series of thieno-[2,3-d]pyrimidine-2,4-dione derivatives containing a biaryl moiety, which led to the discovery of a highly potent and orally active non-peptide LHRH antagonist, 5-(N-benzyl-N-methylaminomethyl)-1-(2,6-difluorobenzyl)-6-[4- (3-methoxyureido)phenyl]-3-phenylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (9k: TAK-013). Compound 9k showed high binding affinity and potent in vitro antagonistic activity for the human receptor with half-maximal inhibition concentration (IC50) values of 0.1 and 0.06 nM, respectively. Oral administration of 9k caused almost complete suppression of the plasma LH levels in castrated male cynomolgus monkeys at a 30 mg/kg dose with sufficient duration of action (more than 24 h). The results demonstrated that the thienopyrimidine-2,4-dione core is an excellent surrogate for the thienopyridin-4-one and that thienopyrimidine-2,4-diones and thienopyridin-4-ones constitute a new class of potent and orally bioavailable LHRH receptor antagonists. Furthermore, molecular modeling studies indicate that the unique methoxyurea side chain of 9k preferentially forms an intramolecular hydrogen bond between the aniline NH and the methoxy oxygen atom. The hydrogen bond will shield the hydrogen bonding moieties from the solvent and reduce the desolvation energy cost. It is therefore speculated that the intramolecular hydrogen bond resulting from judicious incorporation of an oxygen atom into the terminal alkyl group of the urea may increase the apparent lipophilicity to allow increased membrane permeability and consequently to improve the oral absorption of 9k in monkeys. On the basis of its profile, compound 9k has been selected as a candidate for clinical trials and it is expected that it will provide a new class of potential therapeutic agents for the clinical treatment of a variety of sex-hormone-dependent diseases.
- Sasaki, Satoshi,Cho, Nobuo,Nara, Yoshi,Harada, Masataka,Endo, Satoshi,Suzuki, Nobuhiro,Furuya, Shuichi,Fujino, Masahiko
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p. 113 - 124
(2007/10/03)
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- Synthesis and structure-activity relationships of thieno[2,3-d]pyrimidine-2,4-dione derivatives as potent GnRH receptor antagonists
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The synthesis and SAR studies of thieno[2,3-d]pyrimidine-2,4-diones as human GnRH receptor antagonists to treat reproductive diseases are discussed. It was found that the 2-(2-pyridyl)ethyl group on the 5-aminomethyl functionality of the core structure wa
- Guo, Zhiqiang,Chen, Yongsheng,Wu, Dongpei,Zhu, Yun-Fei,Struthers, R. Scott,Saunders, John,Xie, Qiu,Chen, Chen
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p. 3617 - 3622
(2007/10/03)
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- Thienopyrimidine compounds, their production and use
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A compound of the formula: wherein R1and R2each is hydrogen, hydroxy, C1-4alkoxy, C1-4alkoxy-carbonyl or C1-4alkyl which may be substituted; R3is hydrogen, halogen, hydroxy or C1-4alkoxy which may be substituted; or adjacent two R3may form C1-4alkylenedioxy; R4is hydrogen or C1-4alkyl; R6is C1-4alkyl which may be substituted or a group of the formula: wherein R5is hydrogen or R4and R5may form heterocycle; and n is 0-5, or a salt thereof, has an excellent GnRH-antagonizing activity, and is useful for preventing or treating sex hormone-dependent diseases.
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Page column 16-17
(2010/01/30)
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- Thienopyridine derivatives, their intermediates and production thereof
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The present invention provides an intermediate for producing a thienopyridine derivative useful as a GnRH antagonist as well as an efficient and safe method for producing the same in an industrial scale at a high yield.
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- Thienopyrimidine compounds, their production and use
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A compound of formula (I) wherein R1and R2each is hydrogen, hydroxy, C1-4alkoxy, C1-4alkoxy-carbonyl or C1-4alkyl which may be substituted; R3is hydrogen, halogen, hydroxy or C1-4alkoxy which may be substituted; or adjacent two R3may form C1-4alkylenedioxy; R4is hydrogen or C1-4alkyl; R6is C1-4alkyl which may be substituted or a group of the formula (A) wherein R5is hydrogen of R4and R5may form heterocycle; and n is 0-5, or a salt thereof, has an excellent GnRH-antagonizing activity, and is useful for preventing or treating sex hormone-dependent diseases.
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