2933-94-0

Usage

InChI:InChI=1/C13H21NO2/c1-10(2)14-8-12(15)9-16-13-6-4-5-11(3)7-13/h4-7,10,12,14-15H,8-9H2,1-3H3

Upstream product

• 2186-25-6 m-tolyl glycidyl ether 
• 75-31-0 isopropylamine 
• 108-39-4 3-methyl-phenol 
• 42865-04-3 1-chloro-3-(3-methylphenoxy)-2-propanol 

Downstream Products

• 4198-88-3 (R)-toliprolol 
• 4198-87-2 (2S)-1-(isopropylamino)-3-(3-methylphenoxy)propan-2-ol 

Relevant academic research and scientific papers

Asymmetric hydrolytic kinetic resolution with recyclable polymeric Co(iii)-salen complexes: A practical strategy in the preparation of (S)-metoprolol, (S)-toliprolol and (S)-alprenolol: Computational rationale for enantioselectivity

A series of chiral polymeric Co(iii)-salen complexes based on a number of achiral and chiral linkers were synthesized and their catalytic performances were assessed in the asymmetric hydrolytic kinetic resolution of terminal epoxides. The effects of the linker were judiciously studied and it was found that in the case of the chiral BINOL-based polymeric salen complex 1, there was an enrichment in catalyst reactivity and enantioselectivity of the unreacted epoxide, particularly in the case of short as well as long chain aliphatic epoxides. Good isolated yields of the unreacted epoxide (up to 46% compared to 50% theoretical yield) along with high enantioselectivity (up to 99%) were obtained in most cases using catalyst 1. Further studies showed that catalyst 1 could retain its catalytic activity for six cycles under the present reaction conditions without any significant loss in activity or enantioselectivity. To show the practical applicability of the above synthesized catalyst we have synthesised some potent chiral β-blockers in moderate yield and high enantioselectivity using complex 1. The DFT (M06-L/6-31+G??//ONIOM(B3LYP/6-31G?:STO-3G)) calculations revealed that the chiral BINOL linker influences the enantioselectivity achieved with Co(iii)-salen complexes. Further, the transition state calculations show that the R-BINOL linker with the (S,S)-Co(iii)-salen complex is energetically preferred over the corresponding S-BINOL linker with the (S,S)-Co(iii)-salen complex for the HKR of 1,2-epoxyhexane. The role of non-covalent C-H?π interactions and steric effects has been discussed to control the HKR reaction of 1,2-epoxyhexane.

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.

Facile radiosynthesis of fluorine-18 labeled β-blockers. Synthesis, radiolabeling, and ex vivo biodistribution of [18F]-(2S and 2R)-1-(1-fluoropropan-2-ylamino)-3-(m-tolyloxy)propan-2-ol

An efficient and general method has been developed for fluorine-18 labeling of β-blockers that possess the propanolamine moiety. A new synthetically versatile intermediate, 3-(1-(benzyloxy)propan-2-yl)-2-oxooxazolidin-5-yl)methyl 4-methylbenzenesulfonate (13), was prepared and can be conjugated to any phenoxy core. To demonstrate the synthetic methodology, fluorinated derivatives of toliprolol were prepared, namely, [18F]-(2S and 2R)-1-(1-fluoropropan-2-ylamino)-3-(m-tolyloxy)propan-2-ol ((2S and 2R)-[ 18F]1). The radiosyntheses were accomplished in 96% radiochemical and >99% enantiomeric purities, with specific activities of 0.9-1.1 Ci/μmol (EOS). Ex vivo biodistribution studies with the radiotracers demonstrated excessively rapid washout that may limit their use for cerebral PET imaging.

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.

Enteric coated mixture of 4-(2-hydroxy-3-isopropylamino-propoxy) indole and sodium lauryl sulphate

The present invention provides a pharmaceutical composition for controlled release of 4-(2-hydroxy-3-isopropylamino-propoxy) indole in the intestinal tract, admixed with sodium lauryl sulphate, and enteric coated.

β-Adrenoceptor studies. 5. 1H NMR and IR spectroscopic analysis of the conformation of the hydrohalide salts of β-adrenoceptor-blocking aryloxypropanolamines. Evidence for a seven-membered ring structure with participation of two hydrogen bonds

A conformational analysis of hydrohalide salts of the β-adrenoceptor antagonist toliprolol [3-(isopropylamino)-1-(3-methylphenoxy)-2-propanol)] and of its isomer 2-(isopropylamino)-3-(3-methylphenoxy)-1-propanol, in which the hydroxy and isopropylamino groups in the side chain had changed place, was performed using 1H NMR and IR spectroscopic methods. Derivatives of both compounds in which the hydroxy group had been replaced by a methoxy group or a chloro atom were synthetized and included in the investigation as well. In addition, the β-adrenoceptor-blocking activities of the hydrochloride salts of the compounds were determined on the isolated guinea pig right atrium and tracheal strip preparation, using isoprenaline as the agonist. In an aprotic apolar medium (deuteriochloroform), the 1H NMR spectra of all compounds studied showed an upfield shift of the ammonium protons on variation of the anion from chloride via bromide to iodide. The same phenomenon was seen with the hydroxyl proton both of toliprolol and its isomer. In the IR spectra of these two compounds, measured in chloroform, very intense bonded ν(OH stretch) bands were noted and no free ν(OH stretch) bands. The shifts in the ν(OH stretch, υ(NH2+stretch), and υ(NH2+def) bands confirmed the indication from the 1H NMR data that in the hydrohalide salts of toliprolol and its isomer the halide ion is bonded intramolecularly to both the hydroxyl and ammonium protons. Such an interaction gives rise to a seven-membered ring structure. The assignment of the various bands in the IR spectra was confirmed by measuring the spectra of the compounds with deuterio-exchanged hydroxyl and ammonium groups. The temperature dependence of the resonance frequency of the hydroxyl proton indicated the intramolecular interaction in toliprolol to be somewhat stronger than in its isomer. Although multiplicity changes of the carbon-bound protons of the side to be somewhat stronger than in its isomer. Although multiplicity changes of the carbon-bound protons of the side chains and the absence of any effects of anion variation indicated that, as anticipated, these intramolecular interactins ceased to be present in aqueous medium, the possibility of such an interaction with anionic sites in the hydrophobic microenvironment of the plasma membrane carrying β-adrenoceptors can be imagined. The pharmacological data on toliprolol and its methoxy and chloro derivatives might be interpreted in line with this hypothesis, since replacement of the β-hydroxy group had pronounced negative effects on β-adrenoceptor-blocking activities. However, the low affinity of the isomer and the effects of methoxy and chloro substitution on it indicate additional factors in β-adrenoceptor interaction to be involved as well.