ABSTRACT
Although there have been increasing reports, which suggest that angiotensin receptor blockers (ARBs) may have anti-atherogenic actions, most of them are performed in vitro and there are a few reports about anti-atherogenic action in vivo. Especially, in humans, there have been no reports about effect of ARBs on atheroslocerosis. On the other hand, there have been several reports, including ours, which indicate that amlodipine, a calcium channel blocker, has a unique property to cause a reduction in the intima-media thickness (IMT) of common carotid artery, which is established to be an indicator of early atherosclerotic lesion, in humans. The present study investigated which of amlodipine and/or ARBs might have more profound effect on IMT progression. The study included 104 hypertensive patients with type 2 diabetes. They were divided into the two groups: the amlodipine group (n=58), who received amlodipine (2.5-5mg/day) and the ARB group (n=46), who received losartan (25-50mg/day), candesartan (4-8 mg/day), valsaratan (40-80 mg/day) or telmisartan (20-40 mg/day). IMT changes were examined during an average of 56.9 weeks. The amlodipine group showed a significant decrease in IMT compared to the ARB group (-0.046 [S.E. 0.161] mm vs. 0.080 [S.E. 0.255] mm, P<0.05). These results suggest that amlodipine has an inhibitory effect on early atherosclerotic process, and that ARBs do not have any effect on it in hypertensive patients with type 2 diabetes.
Subject(s)
Amlodipine/therapeutic use , Angiotensin II Type 1 Receptor Blockers/therapeutic use , Calcium Channel Blockers/therapeutic use , Tunica Intima/drug effects , Tunica Media/drug effects , Aged , Carotid Arteries/drug effects , Diabetes Mellitus, Type 2/complications , Female , Humans , Hypertension/complications , Hypertension/drug therapy , Losartan/therapeutic use , Male , Middle AgedABSTRACT
Pd-catalyzed aminocarbonylation between aryl bromide and NH-benzazepinone was effectively carried out to furnish the key intermediate for tolvaptan (up to 85%) in one step.
Subject(s)
Benzazepines/chemical synthesis , Chemistry, Pharmaceutical/methods , Catalysis , Palladium/chemistry , Tolvaptan , Vasopressins/chemical synthesisABSTRACT
Continuing search for beneficial additive toward the Beckmann rearrangement (BR) of indanone oxime has revealed that common Lewis acid catalyst in methanesulfonyl chloride (MsCl) showed increasing efficiency in this ionic rearrangement. The new protocol with MsCl is superior to the classical phosphorus-based methods such as PPA and Eaton reagent, especially in the reaction of indanone oximes.
Subject(s)
Indans/chemical synthesis , Oximes/chemistry , Amides/chemistry , Catalysis , Mesylates , Oximes/chemical synthesis , SolventsABSTRACT
New and effective method for the Beckmann rearrangement of indanone oxime mesylate is described, in which a selective and controlled production of the isomeric isocarbostyrils is achieved.
Subject(s)
Isoquinolines/chemical synthesis , Mesylates/chemistry , Oximes/chemistry , Indicators and Reagents , Isomerism , Solvents , Titanium/chemistryABSTRACT
We have surveyed the utility of Beckmann rearrangement for the conversion of indanones into carbostyrils. Initial attempts at the conversion of 6-methoxy indanone oxime under classical conditions resulted in the formation of the two unusual products: 2-sulfonyloxyindanone and the dimeric product. This unusual rearrangement was also observed by the treatment of some metal triflates species. Further investigation has led to the development of reliable conditions starting from oxime mesylate (not oxime tosylate), in which some strong Lewis acid catalyst (ZrCl(4)) was employed in either a conventional or non-conventional solvent system. The advantage of the new protocol is highlighted by the simple work up and direct isolation of the product in 65% isolated yield.
Subject(s)
Hydroxyquinolines/chemical synthesis , Indans/chemistry , Oximes/chemistry , Quinolones , Alkanesulfonates/chemistry , Catalysis , Chlorides , Hydroxyquinolines/pharmacology , Indans/pharmacology , Isomerism , Mesylates/chemistry , Metals/chemistry , Organometallic Compounds/chemistry , Solvents , ZirconiumABSTRACT
The dimeric derivative of aripiprazole was synthesized via the two notable synthetic technologies as a key step: (1) efficient aldehyde bis-arylation by Bi(OTf)(3) and (2) facile Wynberg amination at room temperature. The synthesis has established the structural identity with the minor contaminant sometimes present in Aripiprazole.
Subject(s)
Antipsychotic Agents/chemical synthesis , Piperazines/chemical synthesis , Quinolones/chemical synthesis , Amination , Antipsychotic Agents/chemistry , Aripiprazole , Dimerization , Drug Contamination , Piperazines/chemistry , Quinolones/chemistryABSTRACT
Careful base and solvent optimization for catalytic amination is described. A Pd-catalyzed amination between some arylbromide and unprotected piperazine (1equiv) was efficiently carried out with Pd/BINAP catalyst in a toluene-DBU solvent system, which is useful for the one-pot preparation of unsymmetrical piperazine through amination and in-situ N-protection. Reaction with N-BOC-piperazine was also successful in toluene-DBU or more polar NMP with Cs(2)CO(3) as a key base. No reports have previously reported such solvent and base optimization in arylpiperazine synthesis.
Subject(s)
Piperazines/chemical synthesis , Amination , Benzene Derivatives/chemical synthesis , Catalysis , Indicators and Reagents , Naphthalenes/chemistry , Palladium/chemistry , Solvents/chemistryABSTRACT
An improved synthetic route of OPC-29030, the platelet adhesion inhibitor, was established via the diastereoselective oxidation of a chiral non-racemic sulfide (R)-5 to (S(S))-6 by the catalytic oxidation using VO(acac)(2) and cumene hydroperoxide (CHP) in the presence of MS4A. Under the current condition, the diastereoselectivity was not influenced by the presence of moisture, and moderate to high selectivity (72% de) was obtained at -30 degrees C. The obtained sulfoxide, which diastereomeric excess was easily raised by the recrystallization, could successfully lead to OPC-29030.
Subject(s)
Platelet Adhesiveness/drug effects , Platelet Aggregation Inhibitors/chemical synthesis , Sulfides/chemical synthesis , Imidazoles , Oxidation-Reduction , Platelet Aggregation Inhibitors/chemistry , Quinolones , Stereoisomerism , Sulfides/chemistry , Sulfur CompoundsABSTRACT
The synthesis of 3,4-diethoxybenzthioamide, the key intermediate for OPC-6535, is achieved by employing Friedel-Crafts reaction of 1,2-diethoxybenzene with potassium thiocyanate in methanesulfonic acid at ambient temperature.
Subject(s)
Thioamides/chemical synthesis , Indicators and Reagents , Mesylates , Superoxides/antagonists & inhibitors , Thiazoles/chemical synthesis , ThiocyanatesABSTRACT
In our solvent optimization study of NaBH(4) reduction, NMP was found to enhance the reactivity. A chemoselective debromination of the bromide and sulfonates can be attained in the new borohydride reagent system: NaBH(4)-LiOTf-NMP. This mixed system worked as an alternative to NaBH(3)CN and Bu(3)SnH for the S(N)2 type displacement of alkylbromide and sulfonate. Also mentioned is an expedient reduction of an azide group into amine by NaBH(4) in NMP without any additive, which offers a convenient protocol for the direct transformation of halides into amines via azide in one flask. Some examples of other reductions were also presented.
Subject(s)
Borohydrides/chemistry , Pyrrolidines/chemistry , Azides/chemistry , Chemistry, Pharmaceutical/methods , Hydrocarbons, Brominated/chemistry , Oxidation-Reduction , Solvents/chemistryABSTRACT
Attempted Beckmann rearrangement of the 6-methoxyindanone oximes in conventional conditions resulted in the formation of the two kinds of unexpected products: 2-sulfonyloxyindanone and the dimeric product. Related rearrangement was also observed in the reaction with RhCl-trifluoromethansulfonic acid system.
