- Preparation method and application of hydrazide indoles drugs
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The invention provides a preparation method and application of hydrazide indoles drugs, and discloses a 2-hydrazide substituted indole compound and a preparation method and application thereof. The novel 2-hydrazide substituted indole compound has quite high activity of inhibiting growth of tumor cells, and particularly has remarkable inhibiting effect on growth of human rectal cancer cells and colon cancer cells which have vascular endothelial growth factor receptor-2 subtype high expression; the IC50 value of the novel 2-hydrazide substituted indole compound can be about 10 mu M; the novel 2-hydrazide substituted indole compound has good antiangiogensis activity on a CAM (chick chorioallantoic membrane) model; and moreover, the compound 21 has good capability of resisting cell proliferation after HUVEC is stimulated by VEGF and specificity of resisting proliferation after HUVEC is simulated by VEGF.
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Paragraph 0037; 0038; 0041
(2017/08/28)
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- NEW PROCESSES FOR THE PREPARATION OF OPTICALLY PURE INDOLINE-2-CARBOXYLIC ACID AND N-ACETYL-INDOLINE-2-CARBOXYLIC ACID
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Processes for: a) separating the enantiomers of indoline-2-carboxylic acid of formula (I): comprising of: (i) combining the (R, S) indoline-2-carboxylic acid with (1S)- or (1R)-10- camphorsulfonic acid as the resolving agent in a resolution solvent and crystallizing from the said mixture the diastereomeric salt of (S)- or (R)-indoline-2-carboxylic acid with optically pure (1S)- or (1R)-10-camphorsulfonic acid; (ii) regenerating the (S)- or (R)-indoline-2-carboxylic acid from the crystallized diastereomeric salt by using a suitable base or basic ion-exchange resin; and b) for the optical resolution of N-acetyl-indoline-2-carboxylic acid of formula, (II): comprising of: (i) combining the (R, S)-N-acetyl-indoline-2-carboxylic acid with (S)- or (R)- phenylglycinol as the resolving agent in a resolution solvent and crystallizing from the said mixture the diastereomeric salt of (S)- or (R)-N-acetyl-indoline-2-carboxylic acid with optically pure phenylglycinol; (ii) regenerating the (S)- or (R)-N-acetyl-indoline-2-carboxylic acid from the crystallized salt by using a suitable acid or acidic ion-exchange resin. The non-selected enantiomer may then be racemized and the process (a) or (b) repeated thus to obtain substantial conversion of the material to one enantiomer.
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Page/Page column 16-17
(2008/06/13)
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- Novel method for the synthesis of s-indoline-2- carboxylic acid and application thereof in the synthesis of perindopril
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Process for the synthesis of (2S)-indoline-2-carboxylic acid of formula (I): Application in the synthesis of perindopril and its pharmaceutically acceptable salts.
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Page/Page column 3
(2008/06/13)
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- The effects of conformational constraints and steric bulk in the amino acid moiety of philanthotoxins on AMPAR antagonism
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Philanthotoxin-343 (PhTX-343), a synthetic analogue of wasp toxin PhTX-433, is a noncompetitive antagonist at ionotropic receptors (e.g., AChR or iGluR). To determine possible effects of variations of the amino acid side chain, a library consisting of seventeen PhTX-343 analogues was prepared. Thus, tyrosine was replaced by either apolar, conformationally constrained, or bulky amino acids, whereas the acyl unit and the polyamine moiety were kept unchanged. Analogues with tertiary amide groups were prepared for the first time. Pentafluorophenyl esters were employed for amide bond formation, establishing general protocols for philanthotoxin solution- and solid-phase synthesis (39-90% and 42-54% overall yields, respectively). The analogues were tested for their ability to antagonize kainate-induced currents of 2-amino-3-(3-hydroxy-5-methyl- 4-isoxazoyl)propanoic acid receptors (AMPAR) expressed in Xenopus oocytes from rat brain mRNA. This showed that steric bulk in the amino acid moiety is well tolerated and suggests that binding to AMPAR does not involve the α-NHCO group as a donor in hydrogen bonding.
- J?rgensen, Malene R.,Olsen, Christian A.,Mellor, Ian R.,Usherwood, Peter N. R.,Witt, Matthias,Franzyk, Henrik,Jaroszewski, Jerzy W.
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- PROCESS AND PRODUCT
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A process of preparing perindopril of formula (I), or a pharmaceutically acceptable salt thereof which process comprises protecting a compound of formula (II) where R denotes a hydrogen atom, in the presence of benzene sulphonic acid as a catalyst, to obtain the benzene sulphonic acid salt of an ester of formula (III) where Rl is a carboxyl protecting group and reacting said ester of formula (III) with N-[(S)-1-carbethoxybutyl]-(S)-alanine to obtain a compound of formula (IV) where Rl is as defined above; and deprotecting a compound of formula (IV) to yield perindopril of formula (I), or a pharmaceutically acceptable salt thereof. There is also provided by the present invention the benzene sulphonic acid salt of an ester of formula (III), and perindopril or a pharmaceutically acceptable salt thereof prepared by the above process.
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Page 7; 22; scheme
(2010/02/09)
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- Anti-heparin peptides
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The invention concerns a compound exhibiting an anti-heparin activity, of formula Z Bm ! (AXA)x Bn ! (AXA)y Bo (AXA)z Bp, the diagnostic reagents comprising it and the use of said compound in an in vitro diagnostic test of a medicine for anti-heparin activity.
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- Process for the industrial synthesis of perindopril
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Process for the industrial synthesis of perindopril, in which (2S,3aS,7aS)-2-carboxyperhydroindole is condensed with N-[(S)-1-carbethoxybutyl]-(S)-alanine after protection of the carboxyl group, the product resulting from the condensation being then subjected to deprotection of the carboxyl carried by the heterocyclic ring. The (2S,3aS,7aS)-2-carboxyperhydroindole and N-[(S)-1-carbethoxybutyl]-(S)-alanine are themselves obtained in excellent conditions from 2-carboxyindole and from L-alanine respectively, both available on an industrial scale.
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- Method for preparing optically active N-acetylindoline-2-carboxylic acid
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A resolving agent for N-acetylindoline-2-carboxylic acid, comprising an optically active α-amino-ε-caprolactam gives an optically active N-acetylindoline-2-carboxylic acid in both high yield and high optical purity.
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- Process for preparing indoline-2-carboxylic acids via alpha-hydroxy-2-nitrobenzenepropanoic acid
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Disclosed herein is a process for obtaining indoline-2-carboxylic acid (or derivatives thereof) comprising the following steps: (a) reducing α-oxo-2-nitrobenzenepropanoic acid to α-hydroxy-2-nitrobenzenepropanoic acid, (b) replacing the hydroxyl group of the latter with a chlorine atom utilizing a selected Vilsmeier chlorinating reagent at temperatures of at least 20° C., (c) reducing the nitro group of the resulting α-chloro-2-nitrobenzenepropanoic acid to obtain α-chloro-2-aminobenzenepropanoic acid, and (d) cyclizing the latter in aqueous base to form the desired indoline-2-carboxylic acid. Alternately, steps (c) and (d) may be combined in a one pot step by using, for example, a Raney nickel-hydrazine reducing medium.
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- Chemical resolution of (+)-2,3-dihydroindole-2-carboxylic acid
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Described herein is a process for separating the enantiomers of (+)-2,3-dihydroindole-2-carboxylic acid, which process utilizes (+) or (-)-ephedrine as the resolving agent. The resolved acids are useful as intermediates in the preparation of angiotensin converting enzyme inhibitors.
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- Substituted iminodiacids, their preparation and pharmaceutical compositions containing them
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Compounds of the general formula: STR1 wherein: the ring A is saturated and n=0 or 1, or the ring A is a benzene ring and n=1, R1 represents a lower alkyl group which can carry an amino group, R2 represents a hydrogen atom or a lower alkyl group, R3 represents a straight or branched alkyl group, a mono- or di-cycloalkylalkyl or phenylalkyl group having no more than a total of 9 carbon atoms, or a substituted alkyl group, and also the salts thereof. These compounds are useful as therapeutic drugs.
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- Preparation of indoline-2-carboxylic acid via the intermediate indoline-2-carboxylic acid ester tin complex
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Disclosed herein is a process for preparing indoline-2-carboxylic acids from the corresponding indole-2-carboxylic acid or ester in which the indole-2-carboxylic acid or ester is first reduced to the indoline-2-carboxylic acid ester tin complex using stannous chloride and dry hydrogen chloride gas in a lower alkanol solvent at atmospheric pressures; and the resulting tin complex, dissolved in a lower alkanol, is converted directly to the free indoline-2-carboxylic acid by treatment with aqueous potassium or sodium hydroxide. The aqueous hydroxide treatment may take place in situ or after first isolating the intermediate indoline-2-carboxylic acid ester tin complex.
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- Reduction of indole-2-carboxylic acids to indoline-2-carboxylic acids with lithium, sodium, or potassium in ammonia
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Disclosed herein is an efficient and selective reduction of indole-2-carboxylic acids or esters to indoline-2-carboxylic acids using lithium, sodium, or potassium in liquid ammonia. The preferred process uses lithium in liquid ammonia with small amounts of a weak proton donor such as aniline added to the reaction mixture.
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- (Mercaptopropanoyl)indoline-2-carboxylic Acids and Related Compounds as Potent Angiotensin Converting Enzyme Inhibitors and Antihypertensive Agents
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1-(3-Mercapto-2-methyl-1-oxopropyl)indoline-2-carboxylic acids (7b) and related compounds were synthesized in order to examine their ability to inhibit angiotensin converting enzyme (ACE) and to reduce the systolic blood pressure of spontaneously hypertensive rats (SHR).All four possible stereoisomers of the precursor 1-indoline-2-carboxylic acid (6b) were characterized with absolute stereochemical assigment.The removal of the benzoyl group of the precursor to give 7b was conveniently carried out by treatment with 2-methoxyethylamine.Three of the four stereoisomers of the benzoyl derivative 6 showed in vitro ACE inhibitory activity in the following order: 6b(S,S) > 6b(S,R) > 6b(R,S).The stereoisomer having the R,R configuration was essentialy inactive.The substitution at the C5 of the indoline nucleus with the Et or OMe group caused only marginal changes in the inhibitory activity.The mercaptan 7b(S,S) was the most active ACE inhibitor synthesized in this study, showing in vitro potency 3 times that of captopril.The augmentation of the potency may be due to the increased hydrophobicity of 7b (S,S) compared with captopril and suggests the presence of a hydrophobic pocket at the active site of ACE.When tested in spontaneously hypertensive rats, 7b(S,S) exhibited oral antihypertensive activity 27 times that of captopril.The corresponding benzoyl derivative 6b(S,S) was 24 times as potent as captopril.The thio lactone 10 obtained by cyclization of 7b(S,S) as a potential prodrug was less potent than the parent compound, 7b(S,S), in the ACE inhibitory and antihypertensive tests.
- Kim, Dong H.,Guinosso, Charles J.,Buzby, George C.,Herbst, David R.,McCaully, Ronald J.,et al.
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p. 394 - 403
(2007/10/02)
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