- NAFTOPIDIL MONOHYDROCHLORIDE DIHYDRATE AND USE THEREOF FOR PREPARATION OF NAFTOPIDIL
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PROBLEM TO BE SOLVED: To provide an intermediate that is useful for the preparation of naftopidil (Naftopidil, (2RS)-1-[4-(2-methoxyphenyl)piperazin-1-yl]-3-(naphthalene-1-yloxy)propan-2-ol), and a method for preparing naftopidil using the same. SOLUTION: By freeing naftopidil monohydrochloride dihydrate, naftopidil can be obtained in high yield and high purity. In particular, a purity of 99.99% can be achieved without repeating purification operation such as recrystallization multiple times. SELECTED DRAWING: Figure 1 COPYRIGHT: (C)2021,JPOandINPIT
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Paragraph 0030-0034
(2021/07/27)
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- Continuous flow upgrading of glycerol toward oxiranes and active pharmaceutical ingredients thereof
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A robust continuous flow procedure for the transformation of bio-based glycerol into high value-added oxiranes (epichlorohydrin and glycidol) is presented. The flow procedure features a central hydrochlorination/dechlorination sequence and provides economically and environmentally favorable conditions involving an organocatalyst and aqueous solutions of hydrochloric acid and sodium hydroxide. Pimelic acid (10 mol%) shows an exceptional catalytic activity (>99% conversion of glycerol, a high selectivity toward 1,3-dichloro-2-propanol and 81% cumulated yield toward intermediate chlorohydrins) for the hydrochlorination of glycerol (140 °C) with 36 wt% aqueous HCl. These conditions are validated on a sample of crude bio-based glycerol. The dechlorination step is effective (quantitative conversion based on glycerol) with concentrated aqueous sodium hydroxide (20 °C) and can be directly concatenated to the hydrochlorination step, hence providing a ca. 2:3 separable mixture of glycidol and epichlorohydrin (74% cumulated yield). An in-line membrane separation unit is included downstream, providing usable streams of epichlorohydrin (in MTBE, with an optional concentrator) and glycidol (in water). The scalability of the dechlorination step is then assessed in a commercial pilot-scale continuous flow reactor. Next, bio-based epichlorohydrin is further utilized for the continuous flow preparation of β-amino alcohol active pharmaceutical ingredients including propranolol (hypertension, WHO essential), naftopidil (prostatic hyperplasia) and alprenolol (angina pectoris) within a concatenable two-step procedure using a FDA class 3 solvent (DMSO). This work provides the first example of direct upgrading of bio-based glycerol into high value-added pharmaceuticals under continuous flow conditions.
- Morodo, Romain,Gérardy, Romaric,Petit, Guillaume,Monbaliu, Jean-Christophe M.
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p. 4422 - 4433
(2019/08/21)
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- New anticancer agent
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PROBLEM TO BE SOLVED: To provide a compound having excellent anticancer activity equal to or greater than that of naftopidil.SOLUTION: This invention relates to a compound represented by formula (I), where the definition of each symbol is as described in
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Paragraph 0064-0066
(2017/04/03)
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- NOVEL ANTICANCER AGENT
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The present invention aims to provide a compound having an anticancer action comparable or superior to that of naftopidil. A compound represented by the formula (I) wherein each symbol is as defined in the SPECIFICATION, or a pharmaceutically acceptable s
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Paragraph 0179-0181
(2015/12/30)
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- THERAPY FOR COMPLICATIONS OF DIABETES
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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.
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- ANTIHYPERTENSIVE THERAPY
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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.
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- Zinc(II) perchlorate hexahydrate catalyzed opening of epoxide ring by amines: Applications to synthesis of (RS)/(R)-propranolols and (RS)/(R)/(S)-naftopidils
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(Figure Presented) Commercially available zinc(II) Perchlorate hexahydrate [Zn(ClO4)2·6H2O] was found to be a new and highly efficient catalyst for opening of epoxide rings by amines affording 2-amino alcohols in high yields under solvent-free conditions and with excellent chemo-, regio-, and stereoselectivities. For unsymmetrical epoxides, the regioselectivity was influenced by the electronic and steric factors associated with the epoxides and the amines. A complementarity in the regioselectivity was observed during the reaction of styrene oxide with aromatic and aliphatic amines: aromatic amines provided amino alcohols from nucleophilic attack at the benzylic carbon as major products whereas aliphatic amines resulted in formation of the amino alcohols through reaction at the terminal carbon atom of the epoxide ring as the major/sole products. Reaction of aniline with various glycidic ethers gave the amino alcohols by regioselective nucleophilic attack at the terminal carbon atom of the epoxide ring as the only/major product. Zinc(II) Perchlorate hexahydrate was found to be the best catalyst compared to other metal Perchlorates. The counteranion modulated the catalytic property of the various Zn(II) compounds that followed the order Zn(ClO4) 2·6H2O Zn(BF4)2 ～ Zn(OTf)2 ZnI2 > ZnBr2 > ZnCl2 > Zn(OAc)2 > Zn(CO3)2 in parallelism with the acidic strength of the corresponding protic acids (except for TfOH). The applicability of the methodology was demonstrated by the synthesis of cardiovascular drugs propranolol and naftopidil as racemates and optically active enantiomers.
- Shivani,Pujala, Brahmam,Chakraborti, Asit K.
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p. 3713 - 3722
(2008/02/05)
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- Method for treating resistant hypertension
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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.
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- 1-[3-(Naphth-1-yloxy)-2-hydroxypropvl]-piperazine compounds and therapeutic compositions
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New 1-[3-(naphth-1-yloxy)-2-hydroxypropyl]-piperazine compounds of the formula: STR1 and the pharmacologically compatible salts thereof are outstandingly effective in lowering blood pressure and are thus useful as anti-hypertensive agents.
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