Syntheses of Potentially Antineoplastic Amides and Esters of N-[N'-(2-Chloroethyl)-N'-nitrosocarbamoyl]amino Acids,II

Syntheses of N-[N'-(2-chloroethyl)-N'-nitrosocarbamoyl]amino acid amides and esters as potential antineoplastic substances are reported. N-[N'-(2-chloroethyl)-N'-nitrosocarbamoyl]amino acids (with the exception of the glycine derivative) were prepared by reaction of 2-chloroethyl isocyanate with the sodium salt of an amino acid in a heterogenous medium followed by nitrosation with sodium nitrite under acidic conditions. Condensation with amines or alcohols using 1,1-carbonyldiimidazole led to the amides or esters.     

Decomposition of N-(2-chloroethyl)-N-nitrosocarbamoyl amino acid amides

The chemical decomposition of N-(2-chloroethyl)-N-nitrosocarbamoyl (Q(NO] prolinamide and valinamide were studied under physiological conditions. The volatile products were identified with GC. Q(NO)-Pro-NH2 gave twice the amount of ethylene glycol and only one-fifth of the 2-chloroethanol produced by Q(NO)-Val-NH2 or BCNU, pointing to different pathways of their decomposition. The carbamoylating activity was also investigated in the presence of cyclohexylamine, and it was found to lead mainly to intramolecular carbamoylation with the formation of hydantoin derivatives.     

Synthesis of N-(2-chloroethyl)-N-nitrosocarbamoyl derivatives of biologically active polypeptide hormone fragments

N-(2-chloroethyl)-N-nitrosocarbamoyl derivatives of α-melanotropin and gastrin fragments were synthesized by the acylation of the peptides with active esters of N-(2-chloroethyl)-N-nitrosocarbamic acid. These compounds are supposed to be antitumor agents of low toxicity and increased selectivity.     

Biochemical and cytotoxic properties of the isomeric forms of N,N'-bis[N-2-chloroethyl)-N-nitrosocarbamoyl] cystamine

Three isomeric forms of a cystamine-containing chloroethylnitrosourea, N,N'-bis[N-(2-chloroethyl)-N-nitrosocarbamoyl]cystamine (CNCC), have been identified and separated by high pressure liquid chromatography. Isomer S, 3,3'-bis[N-(2-chloroethyl)-N-nitrosocarbamoyl] ethyl disulfide, was significantly less cytotoxic than isomer C, 1,1'-bis [N-(2-chloroethyl)-N-nitrosocarbamoyl] ethyl disulfide, or isomer M, 1,3'-bis[N-(2-chloroethyl)-N-nitrosocarbamoyl] ethyl disulfide, in either a human Namalva lymphoblastoid or a rat Walker 256 carcinoma cell line. Both isomers S and C inhibited DNA synthesis at a 50 microM concentration. A structural analysis of the isomeric forms suggested that bioreduction of the disulfide bond would permit both isomers to produce isocyanate moieties which would carbamoylate intracellular proteins and depress nucleic acid synthesis. The reduced cytotoxic potential of isomer S is consistent with a prolongation in the half-life of production of alkylating carbonium species that lack the capacity to cross-link macromolecules. Overall, the relative position of the NH group within each of the nitrosourea isomers appears critical to the biological properties of the drug.     

In vivo acute hematotoxicity of N,N'-bis[N-(2-chloroethyl)-N-nitrosocarbamoyl]cystamine (CNCC), a new nitrosourea analog

The in vivo hematotoxic effects on different hemopoietic cell compartments of a new nitrosourea analog CNCC were compared to another glycosidyl derivative, RFCNU. Bone marrow microenvironment in liquid culture, bone marrow and splenic colony-forming units in agar culture (GM-CFUc), relative spleen index, and spleen and bone marrow cellularity were evaluated in young adult (DBA/2 X C57B1/6)F1 mice. The drugs, dissolved in olive oil, were injected ip at either the minimal or the median or the maximal dose of the "maximally efficient dose range." A single administration of CNCC induced a dramatic depopulation of bone marrow and spleen within 12 and 24 hr and significantly reduced the GM-CFUc in both organs. A rapid recovery of both the total cell number and GM-CFUc was observed between Days 2 and 5 (kinetic experiment). The comparison of toxicity of 20 to 50 mg/kg CNCC and 15 to 30 mg/kg (2-chloroethyl)ribopyranosyl-3-nitrosourea RFCNU at Day 1 and Day 5 showed that the bone marrow microenvironment was modified by the effect of oil and was further impaired by CNCC in a concentration-dependent fashion. In contrast RFCNU had less effect on the microenvironment. Similarly, the bone marrow GM-CFUc population was reversibly impaired by CNCC in a dose-dependent fashion, and again RFCNU had less effect. In the spleen both drugs provoked a higher toxic effect than in the bone marrow; on Day 1 they decreased the GM-CFUc population by 1 to 2 log. On Day 5 a compensatory regeneration was obtained in all cases except the highest tolerable CNCC dose, whose effect was more delayed.     

隣甲氧基-对[双-(2-氯乙基)-氨基]-苯丙氨酸的新法合成

隣甲氧基-对[双-(2-氯乙基)-氨基]-苯丙氨酸(Ⅰ)对多种动物肿瘤有明显的抑制作用,临床试用结果表明:它对某些肿瘤有较好的疗效,为了简化合成方法,提高产率,我们进一步研究了(Ⅰ)的合成方法,本文报导了以间氨基-苯甲醚(Ⅳ)为原料,通过六步反应合成了(Ⅰ),总产率为29%左右,产品的理化性质及抗肿瘤作用均与已知物相同,此外还研究了自(隣甲氧基-对[双-(2-羟乙基)-氨基])-苄基-甲酰氨基-丙二酸乙酯(Ⅱ)制备(Ⅰ)的条件,发现(Ⅱ)在二氯甲烷中以五氯化磷氯化的结果较好,可分得结晶状的氯化产物(Ⅲ),后者水解卽得(Ⅰ),产品的纯度及产率均比用亚硫酰氯或氧氯化磷法为佳。     

N-[2-(4-特戊酰氧基苯磺酰胺基)苯甲酰基]甘氨酸苄酯的合成

目的合成西维来司钠（sivelestat sodium）的关键中间体N—[2-（4-特戊酰氧基苯磺酰胺基）苯甲酰基]甘氨酸苄酯（1）。方法先以特戊酸、氯化亚砜、对羟基苯磺酸为原料，经酯化、苯磺酸成酰氯得到对位特戊酰氧基苯磺酰氯（4）；再以甘氨酸、苄醇、邻硝基苯甲酰氯为原料经酯化、酰氨化、还原得到N-（2-氨基苯甲酰基）甘氨酸苄酯（7）；将4和7两中间体缩合得1。结果及结论本方法原料廉价易得，条件温和易控，收率较高，适合工业化生产。     

2-Chloroethyl (methylsulfonyl)methanesulfonate and related (methylsulfonyl)methanesulfonates. Antineoplastic activity in vivo

2-Haloethyl and ethyl (methylsulfonyl)methanesulfonates were prepared via sulfene intermediates. 2-Chloroethyl (methylsulfonyl)methanesulfonate is highly active against P388 leukemia in vivo; the majority of leukemic mice treated with this compound at 50 mg/kg per day, qd 1-5, survived more than 30 days and about 37% survived for more than 60 days. 2- Fluoroethyl (methylsulfonyl)methanesulfonate is also highly effective against P388 cells in vivo, but it is more toxic. Other (methylsulfonyl)methanesulfonate esters are more active than the analogous methanesulfonates and chloromethanesulfonates .     

Synthesis and antiviral activity of N-[2-hydroxyiminoalkyl[, N-[2-oxoalkyl]-, and N-[2-hydroxyalkyl]-β-hydroxyaminoacid esters

Translated from Khimiko-farmatsevticheskii Zhurnal, Vol. 26, No. 5, pp. 45–47, May, 1992.     

Synthesis of some [N-(2-haloalkyl)amino]tetralin derivatives as potential irreversible labels for bovine anterior pituitary D2 dopamine receptors

A series of hydroxylated 2-aminotetralins were prepared in the search for irreversible labels for D2 dopamine receptors. N-2-Haloacetyl and N-2-haloalkyl substituents were chosen as potential receptor alkylating groups. Titrimetric studies were carried out on [N-(chloroethyl)-N-methylamino]tetralins 10, 10a, 24, and 26 to demonstrate that aziridinium ions were formed as reactive intermediates from these compounds. This observation was confirmed by 1H NMR studies on compound 10. The majority of the aminotetralins prepared showed reasonably high affinity binding to anterior pituitary D2 dopamine receptors and exhibited agonist properties. Structure-activity results are presented together with preliminary studies designed to identify irreversible receptor binding agents. [N-(2-Chloroethyl)-N-propylamino]-6,7-dihydroxytetralin hydrobromide (18) proved most promising in these studies.     

Synthesis and antitumor activity of 4-[p-[bis(2-chloroethyl)amino]phenyl]butyrates

Ten 4-[p-[bis(2-chloroethyl)amino]phenyl]butyrates were synthesized and evaluated for antitumor activity. The 2-phenoxyethyl ester exhibited activity against P-388 lymphocytic leukemia, and the n-butyl and n-pentyl esters exhibited activity against L-1210 lymphoid leukemia in initial screening tests.     

Synthesis and antimicrobial activity of N-[4-(1,3-benzodithiol-2-yl)phenyl]-and N-[4-(4-aryl-1,3-dithiol-2-yl)phenyl]-substituted N-arylmethylamines

Methods for the synthesis of secondary aromatic amines containing 1,3-benzodithiol or 4-aryl-1,3-dithiol cycles have been developed. The antimicrobial activity of the synthesized compounds has been determined. __________ Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 40, No. 10, pp. 28–29, October, 2006.     

Synthesis of 2-Hydroxyethyl and 2-Chloroethyl Esters of 1-Alkyl(1,2-Dialkyl)-4-Aminoimidazolyl-5-Carboxylic Acids

Pharmaceutical Chemistry Journal -