- An efficient and cost-effective synthesis of 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid: A key acid synthon of repaglinide
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This report describes an efficient and commercially viable synthesis of 3-ethoxy-4-ethoxy-carbonyl-phenylacetic acid (1), a key intermediate for the preparation of repaglinide, an oral hypoglycemic agent, from 2-hydroxy-4-methylbenzoic acid in two steps. Thus, 2-hydroxy-4-methylbenzoic acid was first alkylated with ethyl bromide in a polar aprotic solvent and in the presence of an inorganic base to afford ethyl 2-ethoxy-4-methylbenzoate; deprotonation with lithium diisopropylamide (LDA) and quenching the resulting carbanion with carbon dioxide provided the desired compound with improved yield and excellent purity. This procedure is significantly better than a previously published synthesis which involves five steps and requires use of expensive and hazardous reagents.
- Salman, Mohammad,Babu, Suresh J.,Ray, Purna C.,Biswas, Sujoy,Kumar, Naresh
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- PRMT5 INHIBITORS
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The present invention provides a compound of Formula (I) and the pharmaceutically acceptable salts, esters, and prodrugs thereof, which are PRMT5 inhibitors. Also provided are methods of making compounds of Formula I, pharmaceutical compositions comprising compounds of Formula I, and methods of using these compounds to treat cancer, sickle cell, and hereditary persistence of foetal hemoglobin (HPFH) mutations.
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Page/Page column 72-73
(2021/06/26)
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- GLUCOSE UPTAKE INHIBITORS
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this invention provides compounds that modulate glucose uptake activity and cellular transport/uptake of glucose, and particularly GLUTS3, but also including but not limited to GLUT1-14 (SLC2A1-SLC2A14). Compounds of the invention are useful for treating diseases, including cancer, autoimmune diseases and inflammation, infectious diseases, and metabolic diseases.
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Paragraph 01103; 01105-01107
(2020/01/24)
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- TETRAHYDROISOQUINOLINES AS PRMT5 INHIBITORS
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A compound of formula (I) wherein: n is 1 or 2; p is 0 or 1; R1a, R1b, R1c and R1d are independently selected from the group consisiting of H, halo, C1-4 alkoxy, C1-4 alkyl, C1-4 fluoroalkyl, C3-4 cycloalkyl, NH-C1-4 alkyl and cyano; R2a and R2b are independently selected from the group consisting of: (i) F; (ii) H; (iii) Me; and (iv) CH2OH; R2c and R2d are independently selected from the group consisting of: (i) F; (ii) H; (iii) Me; and (iv) CH2OH; R2e is H or Me; R3a and R3b are independently selected from H and Me; R4 is either H or Me; R5 is either H or Me; R6a and R6b are independently selected from H and Me; A is either (i) optionally substituted phenyl; (ii) optionally substituted naphthyl; or (iii) optionally substituted C5-12 heteroaryl; wherein when R2e is H, at least one of R1a, R1b, R1c and R1d is selected from C1-4 alkoxy, C2-4 alkyl, C1-4 fluoroalkyl, C3-4 cycloalkyl, NH-C1-4 alkyl and cyano.
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Page/Page column 72
(2017/09/27)
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- 3-OXA-8-AZABICYCLO[3.2.1]OCTANE DERIVATIVES AND THIER USE IN THE TREATMENT OF CANCER AND HEMOGLOBINOPATHIES
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A compound of formula Ia, Ib, Ic or Id: wherein: n is 1 or 2;R N is H or Me; R1 is optionally one or more halo or methyl groups;R2a and R2b are independently selected from the group consisting of: (i) F; (ii) H;(iii) Me; and (iv) CH2 OH; R 2c and R 2d (if present) are independently selected from the group consisting of: (i) F; (ii) H;(iii) Me; and(iv) CH 2 OH;R 3a and R 3b are independently selected from H and Me; R 4a is selected from OH,-NH 2, -C(=O)NH 2, and -CH 2 OH; R 4b is either H or Me; R5 is either H or Me; m is 1 or 2; q is 0 or 1;R 11a, R 11b, R 11c and R 11d are independently selected from H, halo, C1-4 alkyl, C 1-4 fluoroalkyl, C 3-4 cycloalkyl, C 1-4 alkyloxy, NH-C 1-4 alkyl and cyano; R 12a and R 12b are independently selected from the group consisting of: (i) F; (ii) H;(iii) Me; and (iv) CH 2 OH; R 12c and R 12d are independently selected from the group consisting of: (i) F; (ii) H; (iii) Me; and (iv) CH 2 OH;R 12e is H or Me; R 13a and R 13b are independently selected from H and Me; R 14 is either H or Me; R 16a and R 16b are independently selected from H and Me; R 6 is selected from H, OMe, and OEt.
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Page/Page column 63; 64
(2017/10/05)
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- TETRAHYDROISOQUINOLINE DERIVED PRMT5-INHIBITORS
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A compound of formula I wherein: n is 1 or 2: p is 0 or 1; R1 is optionally one or more halo or methyl groups; R2a and R2b are independently selected from the group consisting of: (i) F; (ii) H; (iii) Me; and (iv) CH2OH; R2c and R2d are independently selected from the group consisting of: (i) F; (ii) H; (iii) Me; and (iv) CH2OH; R3a and R3b are independently selected from H and Me; R4 is either H or Me; R5 is either H or Me; R6a and R6b are independently selected from H and Me; A is either (i) optionally substituted phenyl; (ii) optionally substituted naphthyl; or (iii) optionally substituted C5-12 heteroaryl.
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Page/Page column 103
(2016/03/19)
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- NOVEL DIHYDROPYRIMIDIN-2(1H)-ONE COMPOUNDS AS S-NITROSOGLUTATHIONE REDUCTASE INHIBITORS
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The present invention is directed to novel dihydropyrimidin-2(1H)-one compounds useful as S-nitrosoglutathione reductase (GSNOR) inhibitors, pharmaceutical compositions comprising such compounds, and methods of making and using the same.
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Page/Page column 150
(2011/04/24)
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- Process for the preparation of 3-ethoxy-4-(alkoxy carbonyl)-phenyl acetic acid. (an intermediate of repaglinide)
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The present invention relates to an improved and convenient process for the preparation of 3-Ethoxy-4-(alkoxy carbonyl)-phenyl acetic acid, which can be represented by formula (Ia) where R1 represents ethyl or methyl. Specifically the present invention relates to an improved process for the preparation of compound of formula (Ia), which is the key intermediate for Repaglinide of formula (I), by the process, which involves non-hazardous raw materials with an easy handling, and cost effective process
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Page 2; 3; 5
(2008/06/13)
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- PROCESS FOR THE PREPARATION OF ETHYL 3-ETHOXY-4-ETHOXYCARBONYL-PHENYLACETATE
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The present invention relates to a process for the preparation of ethyl 3-ethoxy-4-ethoxycarbonyl-phenylacetate having formula 1. Ethyl 3-ethoxy-4-ethoxycarbonyl-phenylacetate (1) is an important key intermediate for the synthesis of repaglinide (2) an or
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- Synthesis of 3-ethoxy-4-ethoxycarbonyl phenyl acetic acid, a key acid synthon of repaglinide
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The present invention relates to a new and industrially advantageous process for the preparation of 3-ethoxy-4-ethoxy-carbonyl-phenyl acetic acid. This compound is a key intermediate for the synthesis of Repaglinide, an oral hypoglycemic agent.
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Page column 3-4
(2010/02/05)
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- Repaglinide and related hypoglycemic benzoic acid derivatives
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The structure-activity relationships in two series of hypoglycemic benzoic acid derivatives (5, 6) were investigated. Series 5 resulted from meglitinide (3) when the 2-methoxy was replaced by an alkyleneimino residue. Maximum activity was observed with the cis-3,5-dimethylpiperidino (5h) and the octamethyleneimino (5l) residues. Series 6 resulted from the meglitinide analogon 4 bearing an inversed amido function when the 2-methoxy, the 5- fluoro, and the α-methyl residue were replaced by a 2-piperidino, a 5- hydrogen, and a larger α-alkyl residue, respectively. An alkoxy residue ortho to the carboxy group further increased activity and duration of action in the rat. The most active racemic compound, 6al (R4 = isobutyl; R = ethoxy), turned out to be 12 times more active than the sulfonylurea (SU) glibenclamide (1). Activity was found to reside predominantly in the (S)- enantiomers. Compared with the SUs 1 and 2 (glimepiride), the most active enantiomer, (S)-6al (AG-EE 623 ZW; repaglinide; ED50 = 10 μg/kg po), is 25 and 18 times more active. Repaglinide turned out to be a useful therapeutic for type 2 diabetic patients; approval was granted recently by the FDA and the EMEA. From investigations on the pharmacophoric groups in compounds of type 5 and 6, it was concluded that in addition to the two already known - the acidic group (COOH; S02NH) and the amidic spacer (CONH; NHCO) - the ortho residue R1 (alkyleneimino; alkoxy; oxo) must be regarded as a third one. A general pharmacophore model suitable for hypoglycemic benzoic acid derivatives, SUs, and sulfonamides is proposed (Figure 6). Furthermore, from superpositions of low-energy conformations (LECs) of 1, 2, and (S)-6al, it was concluded that a common binding conformation (LEC II; Figure 10B) may exist and that differences in binding to the SU receptor and in the mechanism of insulin release between repaglinide and the two SUs may be due to specific hydrophobic differences.
- Grell, Wolfgang,Hurnaus, Rudolf
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p. 5219 - 5246
(2007/10/03)
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