- METHODS FOR TREATING CHRONIC FATIGUE SYNDROME AND MYALGIC ENCEPHALOMYELITIS
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In one aspect the invention relates to a method of treatment selected from the group consisting of: (a) treating a symptom such as pain in a subject identified or diagnosed as having Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS); (b) treating a symptom such as pain in a subject having dysfunctional TRPM3 ion channel activity; (c) restoring NK cell function in a subject having dysfunctional TRPM3 ion channel activity; and (d) restoring calcium homeostasis in a subject having dysfunctional TRPM3 ion channel activity. The method comprises the step of administering to the subject a therapeutically effective amount of at least one therapeutic compound selected from the group consisting of: (i) an opioid receptor antagonist; (ii) an opioid antagonist; and (iii) a therapeutic compound that restores TRPM3 ion channel activity. In some embodiments the therapeutic compound is naltrexone hydrochloride.
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- Ac2O/K2CO3/DMSO: An efficient and practical reagent system for the synthesis of nitriles from aldoximes
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The transformation of aldoximes to nitriles using acetic anhydride as dehydration agent under mild reaction conditions is reported. The reaction, which proceeds under weak alkaline condition, allows for the conversion of a range of aldoximes including aromatic aldoximes, alphatic aldoximes, and heterocyclic aldoximes in good to excellent yields. This method has also been successfully applied to the synthesis of calcium channel blocker nilvadipine in pilot scale.
- Song, Yaoping,Shen, Dongguo,Zhang, Qinghua,Chen, Bo,Xu, Guangyu
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supporting information
p. 639 - 641
(2014/01/23)
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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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- 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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- (+)-5-isopropyl 3-methyl 2-cyano-6 methyl-4-(3-nitrophenyl)-1, 4-dihydropyridine-3, 5-dicarboxylate
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This invention relates to novel (+)-5-isopropyl 3-methyl 2-cyano-6-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate. More particularly, it relates to novel (+)-5-isopropyl 3-methyl 2-cyano-6-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate, which has pharmacological activities such as hypotensive and vasodilating activities, to a pharmaceutical composition comprising the same and to a method for treating hypertension, cardiovascular diseases, and the like. Accordingly, one object of this invention is to provide novel (+)-5-isopropyl 3-methyl 2-cyano-6-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate, which is of use for treating hyperxtension, cardiovascular diseases, and the like.
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- Inclusion complexes of optically active 1,4-dihydropyridines with methyl-β-cyclodextrin
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Novel inclusion complexes of racemic 1,4-dihydropyridines and enantiomers thereof of the formula STR1 wherein R represents a phenyl group, substituted with nitro, trifluoromethyl, difluoromethoxy group or with one or two halo atoms (especially chlorine), R1 and R2, if the same, represent methyl groups and if one of them has the meaning of a 2-aminoethoxymethyl or cyano group, the other represents a methyl group, R3 and R4, if different, stand each time for a hydrogen, linear or branched C1 -C6 -alkyl, 2-methoxyethyl, 1-(phenylmethyl)-3-piperidinylphenyl, styryl, furyl, piperidino, 4-diphenylmethyl-1-piperazinylethyl, 5-phenyl-3-pirazolyloxy, 1-phenyl-methyl-3-pyrrolidinyl group or a group of the formula STR2 or, if the same, stand each time C1 -C4 alkyl group, and of acid addition salts thereof with methyl-β-cyclodextrin, hydroxy-ethyl-β-cyclodextrin or hydroxypropyl-β-cyclodextrin, with the exception of inclusion complexes of racemic dihydropyridines with HP-β-CD, or, in case of amlodipine and enantiomeric nicardipine, also with β-cyclodextrin, are disclosed. Whilst inclusion complexes of racemic dihydropyridines with the cites cyclodextrins are prepared in a well-known manner disclosed in the literature, enantiomerically pure dihydropyridines and inclusion complexes thereof with cyclodextrins are prepared in a novel way by means of preparative column chromatography. The invention also relates to a pharmaceutical formulation containing novel inclusion complexes and to the use thereof as calcium antagonists for the treatment of hypertension, angina pectoris and cerebrovascular disorders.
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- Novel 2-amino-1,4-dihydropyridine calcium antagonists. I. Synthesis and antihypertensive effects of 2-amino-1,4-dihydropyridine derivatives having nitroxyalkoxycarbonyl groups at 3- and/or 5-position
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Novel 2-amino-1,4-dihydropyridine derivatives, which contain nitroxy-alkoxycarbonyl groups at the 3- and/or 5-position, were synthesized and their pharmaceutical effect was evaluated in spontaneously hypertensive rats. The structure-activity relationships are discussed in terms of potency, onset-rapidity, and duration of antihypertensive activity. Remarkably prolonged duration of antihypertensive action was observed when a tertiary amino group was introduced on either side of an ester chain.
- Kobayashi,Inoue,Kita,Yoshiya,Nishino,Oizumi,Kimura
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p. 788 - 796
(2007/10/02)
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- Use of a dihydropyridine compound for improving inner ear microcirculation
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The invention relates to a method for improving inner ear microcirculation, which comprises administering an effective amount of a dihydropyridine compound of the general formula: STR1 wherein R1 is a nitrophenyl group; and R2, R3 and R4 each is a lower alkyl group, or a pharmaceutically acceptable salt thereof to a human or animal.
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- Studies on nilvadipine. III. Synthesis of metabolites of nilvadipine and their related compounds
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Nilvadipine (I), isopropyl 2-cyano-3-methoxycarbonyl-6-methyl-4-(3-nitrophenyl)-1,4-dihydropyridi ne-5-carboxylate, has a unique 1,4-dihydropyridine structure in that the substituents at all five positions of the nucleus differ from one another. It is an exellent calcium antagonist drug in terms of its potency, its duration of action and its selectivity in the blood vascular system. During the development of I, some metabolites were isolated from the urine and bile of both rats and dogs after oral administration. With data obtained from the metabolism of known 1,4-dihydropyridines at hand, we proposed the synthesis of a series of compounds (1-11) for comparison with the metabolites isolated from I as a method for structure determination. Indeed, of the compounds synthesized five of them (3-7) were found to coincide with the metabolites from both rat and dog urine and bile isolates.
- Satoh,Okumura,Shiokawa
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p. 1799 - 1807
(2007/10/02)
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- Studies on nilvadipine. I. Synthesis and structure-activity relationships of 1,4-dihydropyridines containing novel substituents at the 2-position
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The synthesis of new 1,4-dihydropyridine derivatives containing novel substituent at the 2-position of the nucleus via the key intermediate 2-formyl-1,4-dihydropyridines (X), is described. The aldehydes (X) were prepared by hydrolysis of the acetals (IX) which were obtained from aryl aldehyde (V) and alkyl 4,4-dialkoxyacetoacetate (VI) by the Knoevenagel reaction and treatment with alkyl 3-aminocrotonate (VIII) according to the modified Hantzsch method. The formyl group of the aldehydes (X) was reactive enough to be converted to a variety of functional groups such as hydroxymethyl, cyano, substituted iminomethyl, carbamoyl, semicarbazone, substituted vinyl, ethynyl, and so on. In all of the novel compounds we prepared, 2-hydroxymethyl- and 2-cyano-1,4-dihydropyridines (IV and XXII) were found to possess potent activities in preliminary biological evaluations on hypotension in normotensive rats and on an increase in coronary blood flow in pentobarbital-anesthetized dogs. Optimization research in order to obtain a more potent compound was accomplished in the 2-hydroxymethyl- and 2-cyano-1,4-dihydropyridine series. We selected isopropyl 2-cyano-3-methoxycarbonyl-4-(3-nitrophenyl)-6-methyl-1,4-dihydropyridin e-5-carboxylate (XXIIj) as a candidate compound for further biological evaluation studies. Fortunately, XXIIj (nilvadipine) has been accepted in clinical use for the treatment of hypertension.
- Satoh,Ichihashi,Okumura
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p. 3189 - 3201
(2007/10/02)
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