- Synthetic method of pindolol medicine intermediate (I)-4-(2-hydroxyl-3-isopropyl amino propoxy)indole
-
The invention relates to a synthetic method of pindolol medicine intermediate (I)-4-(2-hydroxyl-3-isopropyl amino propoxy)indole. The synthetic method comprises the following steps: adding 0.17 mol of 4-Hydroxyindole, 0.18 mol of sodium sulfite and 230 to 260 ml of sodium chloride solution into a reaction vessel with a stirrer and a thermometer, controlling a stirring speed at 110 to 130 rpm, dropwise adding 0.176 to 0.179 mol of (I) epoxy amine propane, then continuously stirring for 16 to 18 h, extracting by virtue of cyclohexane, merging extraction solutions, dehydrating by virtue of phosphorus pentoxide, steaming out a solvent, adding 230 to 260 ml of acetonitrile and 90 to 130 ml of isopropylamine into the remainder, increasing the temperature of the solution to 90 to 95 DEG C, performing the reaction for 26 to 29 h, concentrating and steaming, extracting for 6 to 8 times by virtue of trichloro ethylene, merging the trichloro ethylene layers, adding a sodium hydrogen sulfite solution, adjusting the pH of the solution to 9 to 10, extracting the solution by virtue of methylbenzene, dehydrating by virtue of a dehydrating agent, decompressing and concentrating, adding the remainder into chlorobenzene, increasing the temperature of the solution to 40 to 45 DEG C, concentrating a filtrate, precipitating crystals, and re-crystallizing for 7 to 9 times in the chlorobenzene to obtain (I)-4(2-hydroxyl-3-isopropyl amino propoxy)indole.
- -
-
Paragraph 0015-0016
(2017/03/08)
-
- COMPOSITIONS AND METHODS FOR DIAGNOSING AND TREATING SALT SENSITIVITY OF BLOOD PRESSURE
-
To characterize the urinary exosome miRNome, microarrays were used to identify the miRNA spectrum present within urinary exosomes from ten individuals that were previously classified for their salt sensitivity status. The present application discloses distinct patterns of selected exosomal miRNA expression that were different between salt-sensitive (SS), salt-resistant (SR), and inverse salt-sensitive (ISS) individuals. These miRNAs can be useful as biomarkers either individually or as panels comprising multiple miRNAs. The present invention provides compositions and methods for identifying, diagnosing, monitoring, and treating subjects with salt sensitivity of blood pressure. The applications discloses panels of miRNAs useful for comparing profiles, and in some cases one or more of the miRNAs in a panel can be used. The miRNAs useful for distinguishing SS and SR or ISS and SR subjects. One or more of the 45 miRNAs can be used. Some of the miRNAs have not been previously reported to be circulating. See those miRNAs with asterisks in FIG. 1 and below. The present invention encompasses the use of one or more of these markers for identifying and diagnosing SR, SS, and ISS subjects.
- -
-
-
- THERAPY FOR COMPLICATIONS OF DIABETES
-
A method for enhancing glycemic control and/or insulin sensitivity in a human subject having diabetic nephropathy and/or metabolic syndrome comprises administering to the subject a selective endothelin A (ETA) receptor antagonist in a glycemic control and/or insulin sensitivity enhancing effective amount. A method for treating a complex of comorbidities in an elderly diabetic human subject comprises administering to the subject a selective ETA receptor antagonist in combination or as adjunctive therapy with at least one additional agent that is (i) other than a selective ETA receptor antagonist and (ii) effective in treatment of diabetes and/or at least one of said comorbidities other than hypertension. A therapeutic combination useful in such a method comprises a selective ETA receptor antagonist and at least one antidiabetic, anti-obesity or antidyslipidemic agent other than a selective ETA receptor antagonist.
- -
-
-
- ANTIHYPERTENSIVE THERAPY
-
A new use of darusentan is provided in preparation of a pharmaceutical composition for lowering blood pressure in a patient exhibiting resistance to a baseline antihypertensive therapy with one or more drugs. The composition comprises darusentan in an amount providing a therapeutically effective daily dose; wherein (a) the composition is orally deliverable and/or (b) the daily dose of darusentan is effective to provide a reduction of at least about 3 mmHg in one or more blood pressure parameters selected from trough sitting systolic, trough sitting diastolic, 24-hour ambulatory systolic, 24-hour ambulatory diastolic, maximum diurnal systolic and maximum diurnal diastolic blood pressures. Further provided is a new use of darusentan in preparation of a pharmaceutical composition for lowering blood pressure in a patient exhibiting resistance to a baseline antihypertensive therapy, wherein the composition is administered adjunctively with at least one diuretic and at least one antihypertensive drug selected from ACE inhibitors, angiotensin II receptor blockers, beta-adrenergic receptor blockers and calcium channel blockers.
- -
-
-
- FLUORESCENCE BASED DETECTION OF SUBSTANCES
-
A method for the fluorescent detection of a substance, the method comprising providing particles comprising a metal or a metal oxide core, wherein one or more optionally fluorescently tagged antibodies or human specific peptide nucleic acid (PNA) oligomers for binding to a substance is/are bound, directly or indirectly, to the surface of the metal or metal oxide; contacting a substrate, which may or may not have the substance on its surface, with the particles for a time sufficient to allow the antibody/PNA oligomer to bind with the substance; removing those particles which have not bound to the substrate; if the antibodies or PNA oligomers are not fluorescently tagged, contacting the substrate with one or more fluorophores that selectively bind with the antibody and/or substance, then optionally washing the substrate to remove unbound fluorophores; and illuminating the substrate with appropriate radiation to show the fluorophores on the substrate.
- -
-
-
- Method for treating resistant hypertension
-
A method is provided for lowering blood pressure in a patient having clinically diagnosed resistant hypertension. The method comprises administering darusentan to the patient adjunctively with a baseline antihypertensive regimen that comprises administration of at least one diuretic and at least two antihypertensive drugs selected from at least two of (a) ACE inhibitors and angiotensin II receptor blockers, (b) beta-adrenergic receptor blockers and (c) calcium channel blockers. The darusentan is orally administered at a dose and frequency effective, in combination with the baseline regimen, to provide a reduction of at least about 3 mmHg in one or more blood pressure parameters selected from trough sitting systolic, trough sitting diastolic, 24-hour ambulatory systolic, 24-hour ambulatory diastolic, maximum diurnal systolic and maximum diurnal diastolic blood pressures.
- -
-
-
- New, concise route to indoles bearing oxygen or sulfur substituent at the 4-position. Synthesis of (±)- and (S)-(-)-pindolol and (±)-chuangxinmycin
-
A new method for the synthesis of 4-alkoxy- and 4-[alkyl (or aryl)thio]indoles has been developed by using the indolone 3 as a common intermediate. The indolone 3 was prepared from N-(phenylsulfonyl)pyrrole (7) and the α-chlorosulfide 8 in four steps. Heating of a mixture of 3 and an appropriate alcohol in the presence of p-toluenesulfonic acid and cupric chloride afforded the 4-alkoxyindoles 11a-d. The method was applied to the synthesis of (±)-pindolol (19) and (S)-(-)-pindolol (20). Thiols also reacted with 3 in the presence of boron trifluoride to give 4-[aryl (or alkyl)thio]indoles 12, 21a, b, and 22a-d. The (indol-4-ylthio)acetate 22c was employed as a key intermediate for a concise total synthesis of (±)- chuangxinmycin (27).
- Ishibashi,Akamatsu,Iriyama,Hanaoka,Tabata,Ikeda
-
p. 271 - 276
(2007/10/02)
-
- Preparation of alkyl-substituted indoles in the benzene portion. Part 7. Synthesis of (±)- and (S)-(-)-pindolol
-
A new, short-step synthesis of a β-adrenergic blocking agent, pindolol, 1-(4-indolyloxy)-3-(2-propylamino)-2-propanol, is described. The acid-catalyzed indole cyclization reaction of 4-[1-(4-methylphenyl)sulfonyl-3-pyrrolyl]-4-oxobutanal (14) in the presence of (±)-3-chloro-1,2-propanediol (12) and (R)-1-O-[(4-methylphenyl)sulfonyl]glycerol (24) afforded (±)-1-chloro-3-[1-(4-methylphenyl)sulfonyl-4-indolyloxy]-2-propanol (15) and (R)-(-)-3-[1-(4-methylphenyl)sulfonyl-4-indolyloxy]-1-[(4-methylphenyl sulfonyloxy]-2-propanol (25). Reaction of these with isopropylamine and removal of the protecting group at the indole nitrogen gave (±)- and (S)-(-)-pindolol (3 and 4), thus constituting an efficient three-step synthesis of 3 and 4 from the readily available aldehyde (14).
- Fuji,Muratake,Akiyama,Natsume
-
p. 2353 - 2357
(2007/10/02)
-
- Preparation of alkyl-substituted indoles in the benzene portion. Part 8. Improved practical synthesis of 4,4-dialkoxy-1-(1-arylsulfonyl-3-pyrrolyl)-1-butanone and 4-(1-arylsulfonyl-3-pyrrolyl)-4-oxobutanal, and a novel synthetic procedure for 4-alkoxyindole derivatives
-
Important precursors (1 and 2) for the synthesis of 4-substituted indole derivatives were readily obtained by acid treatment of a tosylamide (13), which was prepared in a single operation by treatment of 10 with N-tosyl-N',N'-dimethylformamidine (TsN=CHNMe2). Compound (10) was effectively synthesized from nitromethane and acrolein by way of a nitro compound (15). A novel indole formation reaction from the tosyl-amide (13) to gain short access to 4-alkoxyindoles, such as 16, 17, 19, and 21 is presented.
- Utsunomiya,Muratake,Natsume
-
p. 2358 - 2361
(2007/10/02)
-
- 4-hydroxyindole derivatives, the process for preparation thereof and their use
-
The invention relates to new 4-hydroxyindole derivatives of general formula: STR1 in which R represents a labile protective group and R1 can represent hydrogen, a C1 -C6 alkyl radical, a C3 -C6 cycloalkyl radical, a lower alkoxy radical, a lower hydroxyalkyl radical, a lower (lower alkoxy) alkyl radical, a phenyl radical optionally substituted with a halogen atom or a lower alkyl or lower alkoxy radical, a cyano radical, a radical of formula STR2 in which R2 and R3, which may be identical or different, each represent hydrogen or a lower alkyl radical, R4 represents a hydroxy group, a lower alkyl or lower alkoxy radical or a radical STR3 in which R2 and R3 have the same meaning as above, R5 represents a lower alkyl radical and Alk represents a single bond or a straight- or branched-chain alkylene radical having from 1 to 4 carbon atoms. The invention also relates to a process for preparing 4-(3-amino-2-hydroxypropoxy)indole derivatives from the said 4-hydroxyindole derivatives.
- -
-
-
- Process for preparing indoles
-
Convenient intermediates for preparing 3-substituted-2-hydroxypropyl aryl ether β-blockers, a reaction to the intermediates of the following formula and a conversion to obtain the said β-blockers are disclosed. STR1 (wherein X is hydrogen or halogen; Y is halogen, hydroxy, lower acyloxy, amino, lower alkylamino, lower aralkylamino, lower acylamino, di-lower alkylamino, lower alkyleneamino, N-lower alkyl-N-lower aralkylamino, di-lower acylamino, N-lower alkyl-N-lower acylamino or N-tri-lower alkylsilylamino; one of P and R combined together with Q represents lower alkylene or alkenylene optionally interrupted by O, N or S and optionally substituted by lower alkyl, lower aralkyl, lower carboxylic acyl, carboxy, protected carboxy; hydroxy, lower alkoxy, lower acyloxy, oxo; amino, lower alkylamino, lower acylamino, nitro, nitroso, lower alkylthio, lower sulfonic acyl or halogen; and the remaining R or P is hydrogen or halogen; and dotted line represents the presence of one or two double bonds).
- -
-
-
- Practical Syntheses of - and -1-Alkylamino-3-aryloxy-2-porpanols from a Single Carbohydrate Precursor
-
A practical synthetic route to optically active - and -1-alkylamino-3-aryloxy-2-propanols (β-blockers) from -2,3-O-isopropylideneglyceraldehyde (-1) was developed.Synthesis of the -isomers was carried out as follows.Borohydride reduction of -1 in the presence of excess alkylamine followed by alkoxycarbonylation, acid hydrolysis, and cyclization under K2CO3 catalysis gave -3-alkyl-5-hydroxymethyl-1,3-oxazolidin-2-ones, the tosylates of which were coupled with various phenols then hydrolyzed by alkali treatment to give -(-)-β-blockers (e.g., propranolol, carteolol) in satisfactory yields. -,-, and rac-pindolol were synthesized from the corresponding 3-isopropyl-5-(2-methyl-3-nitrophenoxymethyl)-1,3-oxazolidin-2-one by application of the Leimgruber-Batcho method.Keywords--- and -1-alkylamino-3-aryloxy-2-propanols; optically active β-blockers; propranolol; carteolol; pindolol; carbohydrate precursor; -2,3-O-isopropylideneglyceraldehyde; -3-alkyl-5-hydroxymethyl-1,3-oxazolidin-2-ones; Leimgruber-Batcho indole synthesis
- Tsuda, Yoshisuke,Yoshimoto, Kimihiro,Nishikawa, Terumi
-
p. 3593 - 3600
(2007/10/02)
-
