New designer drug 1-(3-trifluoromethylphenyl) piperazine (TFMPP): gas chromatography/mass spectrometry and liquid chromatography/mass spectrometry studies on its phase I and II metabolism and on its toxicological detection in rat urine

Studies are described on the phase I and II metabolism and the toxicological analysis of the piperazine-derived designer drug 1-(3-trifluoromethylphenyl)piperazine (TFMPP) in rat urine using gas chromatography/mass spectrometry (GC/MS) and liquid chromatography/mass spectrometry (LC/MS). The identified metabolites indicated that TFMPP was extensively metabolized, mainly by hydroxylation of the aromatic ring and by degradation of the piperazine moiety to N-(3-trifluoromethylphenyl)ethylenediamine, N-(hydroxy-3-trifluoromethylphenyl)ethylenediamine, 3-trifluoromethylaniline, and hydroxy-3-trifluoromethylaniline. Phase II reactions included glucuronidation, sulfatation and acetylation of phase I metabolites. The authors' systematic toxicological analysis (STA) procedure using full-scan GC/MS after acid hydrolysis, liquid-liquid extraction and microwave-assisted acetylation allowed the detection of TFMPP and its above-mentioned metabolites in rat urine after single administration of a dose calculated from the doses commonly taken by drug users. Assuming similar metabolism, the described STA procedure should be suitable for proof of an intake of TFMPP in human urine.     

5-(N-Arylnortropan-3-yl)- and 5-(N-Arylpiperidin-4-yl)-2,4-diaminopyrimidines. Novel Inhibitors of Dihydrofolate Reductase

Based on a computer-assisted analysis of the three-dimensional structure of the binary complex of E.coli dihydrofolate reductase (DHFR) with methotrexate, 5-(N-arylnortropan-3-yl)- and 5-(N-arylpiperidin-4-yl)-2,4-diaminopyrimidines 2 and 4 were designed as inhibitors of DHFR. Syntheses of the designed compounds have been carried out. The most potent compound 2a inhibited E. coli DHFR with K_i = 0.49.10^?9M. The activities within the series of compounds synthesized could be rationalized by molecular-modelling experiments which served as the basis of this work. Several compounds within the presented series exhibit antimalarial activities in vitro and in vivo.     

Die Strommer-Zykliden des Flaggenraumes

According to H. BRAUNER a flag space is a three-dimensional affine space with an absolute {,f,F}, wheref is a line in the plane of infinity andF a point onf. A cyclide is a surface of order 4 that intersects only atf. A STROMMER-cyclide is a cyclide generated by translation of a circle in an isotropic plane. In this paper we proof that all STROMMER-cyclides can be generated by translation of an isotropic circle along a divergent Newton-parabola or a conic in a full isotropic plane. We give normal-forms and CAD-pictures of these surfaces. Finaly some geometrical results about STROMMER-cyclides are developed.

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Herrn o.Prof. Dr. Gy. Strommer zum 70. Geburtstag gewidmet.     

Experiments in Solving Mixed Integer Programming Problems on a Small Array of Transputers

The time-consuming process of solving large-scale Mixed Integer Programming problems using the branch-and-bound technique can be speeded up by introducing a degree of parallelism into the basic algorithm. This paper describes the development and implementation of a parallel branch-and-bound algorithm created by adapting a commercial MIP solver. Inherent in the design of this software are certain ad hoc methods, the use of which are necessary in the effective solution of real problems. The extent to which these ad hoc methods can successfully be transferred to a parallel environment, in this case an array of at most nine transputers, is discussed. Computational results on a variety of real integer programming problems are reported.     

Discrepancies in the distribution of prime numbers

Chebyshev has noticed a certain predominance of primes of the form 4n + 3 over those of the form 4n + 1. He asserted that $\text{lim}{}_{\mathrm{x\to \infty }}\text{∑}\text{p > 2}\text{(?1)}{}^{\mathrm{<mtext>(p\; ?\; 1)</mtext><mtext>2</mtext>}}\text{e}{}^{\mathrm{<mtext>?p</mtext><mtext>x</mtext>}}\text{= ?∞}$. This was unproven until today. G. H. Hardy, J. E. Littlewood and E. Landau have shown its equivalence with an analogue to the famous Riemann hypothesis, namely, L(s, χ₁mod 4) ≠ 0, $\text{Re}\text{(s) >}\text{1}\text{2}$. S. Knapowski and P. Turán have given some similar (unproven) relations, e.g., , which are also equivalent to the above. Using Explixit Formulas the author shows that

$\text{lim}{}_{\mathrm{x\to \infty }}\text{∑}\text{p > 2}\text{(?1)}{}^{\mathrm{<mtext>(p\; ?\; 1)</mtext><mtext>2</mtext>}}\text{log}\text{pp}{}^{\mathrm{<mtext>?1</mtext><mtext>2</mtext>}}\text{e}{}^{\mathrm{<mtext>?</mtext><mtext>(</mtext><mtext>log</mtext><mtext>2p)</mtext><mtext>x</mtext>}}\text{= ?∞ (1)}$

holds without any conjecture. (In addition, the order of magnitude of divergence is calculated.) It turns out that (1) is only a special case (in several respects). At first, it may be enlarged into

$\text{lim}{}_{\mathrm{x\to \infty }}\text{∑}\text{p > 2}\text{(?1)}{}^{\mathrm{<mtext>(p\; ?\; 1)</mtext><mtext>2</mtext>}}\text{log}\text{pp}{}^{\mathrm{?\alpha }}\text{e}{}^{\mathrm{<mtext>?</mtext><mtext>(</mtext><mtext>log</mtext><mtext>2p)</mtext><mtext>x</mtext><mtext>)</mtext>}}\text{= ?∞, 0?α?}\text{1}\text{2}\text{.}$

Then, it can be generalised to a wider class of progressions. For example, the same is true if one sums over the primes in the classes 3n + 2 and 3n + 1, with a “?” and a “+” sign, respectively. All results of this type depend on the location of the first nontrivial zero of the corresponding L-series. D. Shanks has given some arguments for the predominance of primes in residue classes of nonquadratic type. He conjectured “If m₁ mod k is a quadratic residue and m₂ mod k a non-residue, then there are “more” primes congruent m₂ than congruent m₁ mod k.” This indeed turns out to be true in the sense of (1), not only for k = 3, 4, but for some higher moduli as well. Finally, numerical calculations were made to investigate the behaviour of Δ₃(X) ? π(X, 2 mod 3) ? π(X, 1 mod 3) in the interval 2 ≤ X ≤ 18, 633, 261. No zero was found in this range. In the analogue case of Δ₄(X) ? π(X, 3 mod 4) ? π(X, 1 mod 4) the first sign change occurs at X = 26, 861.     

Zur Kennzeichnung von Lorentztransformationen in Endlichen Ebenen

Given a commutative field K we define d(A,B):= (a₁–b₁)²–(a₂–b₂)² for A=(a₁,a₂), B=(b₁,b₂) K². Given moreover a fixed k K^O, W. Benz has asked for all mappings : K²K² such that d(A,B)=k implies. This paper gives an answer if K=GF(p), p=5,7,11: must be a bijective collineation in case p = 7,11; there are non-injective mappings in case p=5. To obtain some of these results we have mads use of a computer.

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Prof. R. Artzy zum 70. Geburtstag gewidmet.     

Confirmation of the Structures of Lutein and Zeaxanthin

A series of new esters of lutein ( 1a ) have been prepared with the aim of confirming the structure of lutein via an X‐ray crystal‐structure analysis. Although well crystallized, only one of the derivatives, the (?)‐(1R)‐menthyl carbonate ( 1i ) proved to be useful for a complete structure analysis. The same derivative of zeaxanthin ( 2a ) also allowed its crystal structure to be determined. Both analyses represent the first successful X‐ray crystal structure analyses of the most important xanthophylls. At the same time, they confirm both the constitution and absolute configuration of 1a and 2a that had been deduced earlier by classical methods.     

Interaction of nonionic detergents and swelling clays

Summary The 25° sorption isotherms of a polyoxyethylated n-dodecanol with 14 ethylene oxide units (C₁₂EO₁₄) on sodium and calcium montmorillonite were determined. Sorption complexes of the two clays were also prepared with C₁₂EO₃₀, n-dodecanol, polyethylene glycol and polypropylene glycol. X-ray powder diagrams show that the sorbed organic molecules are intercalated with their chains parallel to the montmorillonite lamellae, in layers one or two molecules thick. Sodium montmorillonite sorbs C₁₂ EO₁₄ and C₁₂EO₃₀ in excess of close-packed double layers: the excess detergent is occluded in interstices and absorbs moisture at 85% relative humidity to the same extent as the bulk detergents. The double layer complexes are not swelled by water; the single layer complexes sorb a single layer of water molecules at 85% relative humidity.Apparent densities of the sorbed organic molecules decrease with increasing EO content while bulk densities increase. This is explained in terms of chain flexibility and polarity.

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Zusammenfassung Die 25°-Absorptions-Isothermen von polyoxyäthyliertem n-Dodekanol mit 14Äthylenoxyd-Einheiten(C₁₂EO₁₄) an Na- und Ca-Montmorillonit wurden bestimmt. Sorptions-Komplexe der 2 Tone wurden ebenfalls mit nDodekanol, Polyäthylenglykol und Polypropylenglykol präpariert. Pulverdiagramme zeigen, daß die sorbierten organischen Moleküle mit ihren Ketten parallel zu den Montmorillonitlamellen eingelagert sind, in Schichten 1 oder 2 Moleküle dick. Na-Montmorillonit sorbiert C₁₂EO₁₄ und C₁₂EO₃₀ im Überschuß zur dichtgepackten Doppelschicht. Der Überschuß ist in Hohlräumen eingelagert und absorbiert Wasser bei 85° relativer Feuchtigkeit im selben Ausmaß wie die reinen Detergentien. Die Doppelschichtkomplexe werden nicht durch Wasser gequollen. Die Einschichtkomplexe sorbieren eine Monoschicht von Wasser-Molekülen bei 85° relativer Luftfeuchtigkeit.Scheinbare Dichten der sorbierten organischen Moleküle nehmen mit steigendem Äthylenoxydgehalt ab, während die Dichten der reinen Substanz ansteigen. Dies läßt sich auf Grund der Kettenbeweglichkeit und Polarität erklären.

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Presented at the 145^th Meeting of the American Chemical Society, New York, N. Y., September 1963.