A new class of antibronchospastic agents: 7-(2,2-dimethyl)propyl substituted xanthines.

A series of 7-(2,2-dimethyl)propyl substituted xanthines were synthesized and tested for their antibronchospastic activity in comparison with theophylline. In vitro, the inhibition of carbachol-induced increase in bronchial tone was determined. In vivo, the inhibition of antigen-induced bronchoconstriction in guinea pigs was determined 1, 3 and 5 h after oral administration. Central side effects were evaluated. In vitro, the majority of compounds were more effective than theophylline. In vivo, three compounds 2, 14 and 15 showed an effect comparable to theophylline but longer lasting. A mild sedative effect was generally observed. Compound 2, 7-(2,2-dimethyl)propyl-1-methyl xanthine, coded MX2/120, was selected for a deeper evaluation.

Lack of hypotensive and brain catecholamine depleting effects by erythro- and threo-alpha-methyl DOPS.

An investigation was carried out to ascertain whether erythro- and threo-alpha-methyl-dihydroxy-phenyl-serine were able of depleting cerebral and peripheral norepinephrine (NE) through their metabolization to alpha-mNE. The results show that the alpha-methyl-aminoacids were decarboxylated only at the periphery and that the threo-form caused depletion in cardiac NE. In any case, both isomers were unable to cross the blood-brain barrier leaving the cerebral NE unaffected. Consequently the use of alpha-mDOPS as alternative tool to alpha-mDOPA in the therapy for hypertension seems unlikely to occur. The results also provide evidence for differences in the pharmacokinetics of the two isomers.

Determination of the antihypertensive drug 1-[2-ethoxy-2-(3'-pyridyl)ethyl]-4-(2'-methoxyphenyl) piperazine (IP/66) in rat and human plasma by high-performance liquid chromatography and isotope dilution mass spectrometry.

In connection with pharmacokinetic studies on the antihypertensive drug 1-[2-ethoxy-2-(3'-pyridyl)ethyl]-4-(2'-methoxyphenyl)piperazine (IP/66) (I), appropriate high-performance liquid chromatographic (HPLC) and gas chromatographic-mass spectrometric isotope dilution (GC-MS-ID) methods for its determination in rat and human plasma, respectively, were developed. In both techniques, deproteinized and basified plasma samples were extracted and purified by adsorption on an Extrelut-1 column, then the drug was eluted with dichloromethane. Quantitative HPLC analysis was performed on a C8 reversed-phase column. The mobile phase was phosphate buffer (0.02 M, pH 2.8)-acetonitrile (65:35), with UV detection at 208 nm. The internal standard was 1-[2-butoxy-2-(3'-pyridyl)ethyl]-4-(2'-methoxyphenyl)piperazine, a homologue of I. The inter-assay coefficient of variation (C.V.) was 9.9% for a drug level of 2 micrograms/ml. Quantitative GC-MS-ID analysis was performed with a DB-17 fused-silica capillary column using the selected-ion monitoring technique. The deuterated form of I, 1-[2-ethoxy-2-(3'-pyridyl)ethyl]-4-2'-trideuteromethoxyphenyl)pipe razine, utilized as internal standard, was synthesized. The inter-assay C.V. was 7.36% for a drug level of 1 ng/ml.

Physico-chemical properties of the new antibronchospastic agent isbufylline.

Physico-chemical properties, i.e. elemental analysis, spectra (NMR, MS, IR, UV), X-ray crystal structure, solubilities, partition coefficient, melting point, HPLC, GC, and data about purity and stability of 1,3-dimethyl-7-isobutyl xanthine (isbufylline, TE/06, CAS 90162-60-0), a new drug with antibronchospastic properties, are reported.

Synthesis and analytical profile of the new potent antibronchospastic agent 7-[(2,2-dimethyl)propyl]-1-methyl xanthine.

7-[(2,2-Dimethyl)propyl]-1-methyl xanthine (CAS 155006-67-0, MX2/120) is a new potent antibronchospastic agent with negligible side effects. The synthesis involves the alkylation of 3-benzyl-1-methyl xanthine with neopentyl bromide followed by removal of the benzyl protecting group. Main physico-chemical properties were determined using NMR, MS, IR, UV spectra and X-ray crystal structure. A quantitative determination of substances related to MX2/120 and of residual solvents by means of HPLC and GC, respectively, is described. MX2/120 is safely stored at room temperature for a long time.

Resolution and pharmacological properties of the enantiomers of the potent alpha-adrenoceptor antagonist 1-[2-ethoxy-2-(3'-pyridyl)ethyl]-4-(2'-methoxy-phenyl)piperazine.

Resolution of the optical isomers of the alpha-adrenoceptor antagonist IP-66 (1-[2-ethoxy-2-(3'-pyridyl)ethyl]-4-(2'-methoxy-phenyl)piperazine) and its intermediate IP-30 (1-[2-hydroxy-2-(3'-pyridyl)ethyl]-4- (2'-methoxy-phenyl)piperazine have been carried out. Optical purity was assayed by high-pressure liquid chromatography. The antagonistic potencies of racemic mixtures and stereoisomers toward phenylephrine- and norepinephrine-induced contraction in isolated rat aortic strips have been compared. (+)-IP-66 and (+)-IP-30 were resp. 363 and 170 times more potent than respective (-) isomers in eliciting competitive alpha 1-adrenoceptor blockade. Similarly IP-66 (+) or (+/-) were extremely more effective than the (-) isomer in antagonizing norepinephrine-induced pressor responses in pithed rat.

Metabolism of isbufylline in humans. Isolation, identification, and synthesis of plasma and urine metabolites.

Isbufylline metabolism after oral administration to humans was studied. The main metabolites detected by the HPLC method, in plasma, were 1-methyl-7-(2-hydroxy-2-methyl-propyl) xanthine (I), 1,3-dimethyl-7-(2-hydroxy-2-methyl-propyl) xanthine (II), and 1-methyl-7-(2-methyl-propyl) xanthine (III). The main metabolites detected in urine were 1-methyl-7-(2-hydroxy-2-methyl-propyl) xanthine (I), 1,3-dimethyl-7-(2-carboxy-propyl) xanthine (IV), and 1,3-dimethyl-7-(2-hydroxymethyl-propyl) xanthine glucuronic acid (V)-Gluc. They were isolated by HPLC, identified by GC/MS, HPLC/MS, or HPLC/MS/MS, and finally synthesized. Recovery of these metabolites, along with the absence of unmetabolized isbufylline in the urine, indicated biotransformation and renal excretion as the main routes of isbufylline elimination in humans. HPLC quantitation of the characterized urine metabolites revealed that 49% of the drug was eliminated as (I), 9% as (V)-Gluc, and 5% as (IV).