The present invention provides compounds that elevate cellular expression of the ABCA-1 gene, promoting cholesterol efflux from cells and increasing HDL levels in the plasma of a mammal, in particular humans The compounds are useful for treating coronary artery disease

ABCA-1 elevating compounds

Based on the active ingredient of the drug Ximedon (1,2-dihydro-4,6-dimethyl-1-N-(2-hydroxyethyl)pyrimidone-2, referred below to as pyrimidine (I), novel derivatives containing biogenic acids: succinic, L-ascorbic, para-aminobenzoic, nicotinic, and L-2-amino-4-(methylthio)butanoic (L-methionine) acids have been synthesized. The parameters of acute toxicity (LD50) have been studied. The antitoxic effect of the compounds upon the injury by the hepatotropic poison carbon tetrachloride has been examined as the primary evaluation of their hepatoprotective properties. It has been found that, according to toxicological safety, the compounds synthesized belong to classes III and IV (moderately and little toxic compounds). The conjugates of pyrimidine (I) with ascorbic acid and methionine (LD50 more than 5400 mg/kg) are least toxic. Pyrimidine (I) and its derivatives possess the antitoxic activity upon acute poisoning with carbon tetrachloride; the combined injection of carbon tetrachloride with pyrimidine (I) or its derivatives leads to an increase in the survival of animals and the normalization of the integral functional parameters, weight and body temperature, which decrease upon toxic injury. In addition, pyrimidine (I) and some of its derivatives (conjugates with L-ascorbic, succinic, para-aminobenzoic, and nicotinic acids) decrease the weight coefficients of the liver and kidneys (the organ-to-body-weight ratio) and the activity of transaminases, the markers of hepatic cytolysis, which increase upon toxic injury with carbon tetrachloride. The area of the pathological injury of the liver by steatosis and necrosis decreases by the action of pyrimidine (I) and its novel derivatives (conjugates with L-ascorbic, succinic, and nicotinic acids) two to three times. Advantages of pyrimidine (I) and its novel derivatives over the hepatoprotective drug Thiotriazolin have been revealed.

Synthesis and primary evaluation of the hepatoprotective properties of novel pyrimidine derivatives

Antiradical activity and antioxidant properties of a conjugate of Xymedon with l-ascorbic acid were studied. In contrast to Xymedon, a conjugate of Xymedon with l-ascorbic acid was found to react with free radicals. Pro-oxidant activity of the conjugate of Xymedon with l-ascorbic acid in a chemiluminescence system is weaker as compared to individual l-ascorbic acid. This is the evidence of the increase in the stability of ascorbic acid upon conjugation with a molecule of Xymedon. Conjugate of Xymedon with l-ascorbic acid facilitates the decrease in the concentration of a lipid peroxidation product (malondialdehyde) and the activity of superoxide dismutase in liver and serum of laboratory animals exposed to intoxication with a known hepatotropic toxin CCl4. This observation shows the contribution of the antioxidant action to the hepatoprotective effect of the studied Xymedon derivative.

Xymedon conjugate with biogenic acids. Antioxidant properties of a conjugate of Xymedon with l -ascorbic acid

Publisher Summary The monocyclic diazines, triazines, and tetrazines are all theoretically subject to electrophilic attack at one or more of their annular nitrogen atoms by protons; alkylating, acylating, and aminating reagents; and peracids. This chapter amplifies and updates current knowledge of this material, with the exception of metal coordination. It also emphasizes that, any quantitative studies which come within the scope of the review, and to collate data on regiochemical effects of substituents in the azine rings. It is unfortunate that some of the quantitative information about yields of isomeric products was reported before the use of modern physical methods became routine. Accordingly, some of the data must remain suspect, as do some of the structures reported. This chapter highlights the reactivities of particular ring nitrogen atoms with proton acids, as these reactivities are frequently related to trends observed in N-alkylation, N-acylation, and N-oxidation.

Reactions of annular nitrogens of azines with electrophiles

1
Introduction

2
The Formation of PC(sp3) Bonds. Syntheses of Alkyl, Cycloalkyl and Aralkyl Phosphonic and Phosphinic Acids

3
The Formation of PC(sp2) Bonds. Syntheses of Alkenyl and Alkadienyl Phosphonic and Phosphinic Acids

4
The Formation of PC(sp) Bonds. Syntheses of Alkynyl Phosphonic and Phosphinic Acids

5
The Formation of PC (Aromatic) Bonds. Syntheses of Aryl Phosphonic and Phosphinic Acids

6
Syntheses of Phosphonic and Phosphinic Acids by Modification Procedures



Keywords:

Michaelis–Arbuzov–Kaehne reaction;
alkylating agent nature;
reaction mechanism;
hydrogen phosphonate and hydrogen phosphinate alkylation;
synthesis from alkyl halides and phosphorus (III) halides;
synthesis from hydrocarbons and phosphorus (III) halides;
oxidative phosphonation of alkanes;
saturated hydrocarbon hydrophosphanation;
organometallic reagent synthesis

The Synthesis of Phosphonic and Phosphinic Acids and their Derivatives: Non‐Functionalized Acids

In the reactions of pyrimidinethiols and pyrimidinols with 2-chloroethanol and 2-chloro-1-propanol 2-(pyrimidinylthio)alkanols and N-(hydroxyalkyl)pyrimidinones are formed.

Reactions of pyrimidinols and pyrimidinethiols with 2-chloroethanol and with 2-chloro-1-propanol

1.

The acylation of 4,6-diamino-2-mercaptopyrimidine with carboxylic acid chlorides in the presence of an organic base proceeds at all of the nucleophilic centers: the S atom, the ring N atom, or the amino group. The direction of the acylation depends on the temperature, the nature of the reactants, and the order of their addition.




2.

Members of all three types of monoacylated derivatives were obtained, and specifically the 2-acylthio-4,6-diaminopyridines, the 1-acyl-4,6-diamino-1,2-dihydro-2-pyrimidinethiones, and the 6-amino-4-acylamide-1H(3H)-dihydro-2-pyrimidinethiones.




3.

The acylation of the 4,6-diamino-2-mercaptopyrimidine salts gives a mixture of the S- and N1-acylated derivatives, whose composition is affected by the nature of the cation.

Acylation of 4,6-diamino-2-mercaptopyrimidine and its salts with carboxylic acid chlorides

1.

2-Acylthiopyrimidines and 1-acyl-4,6-diamino-1,2-dihydro-2-pyrimidinethiones react with nucleophilic reagents to give 2-mercaptopyrimidines and the corresponding carboxylic acid derivatives.




2.

The 6-amino-4-acylamido-1H(3H)-dihydro-2-pyrimidinethiones are acylated by acyl halides either at the S atom or at the NH2 group, while their salts are alkylated by alkyl halides at the S atom.




3.

2-Acylthio-4,6-diaminopyrimidines and 1-acyl-4,6-diamino-1,2-dihydro-2-pyrimidinethiones are capable of rearranging to the isomeric acyl derivatives.

Chemical properties of acylated derivatives of 4,6-diamino-2-mercaptopyrimidine

Synthesis and properties of pyrimidinylalkylphosphonic acids: Communication 5. Synthesis of?-(oxopyrimidinyl-n)-ethylphosphonic acids

The reaction of the sodium salts of some 2-hydroxypyrimidines with α,ω-dichloroalkanes gave the N,N′-, N,O′-, and O,O′-bis(pyrimidinyl)alkanes.

N. G. Pashkurov

Papers

Reactions of pyrimidinols and pyrimidinethiols with 2-chloroethanol and with 2-chloro-1-propanol

Acylation of 4,6-diamino-2-mercaptopyrimidine and its salts with carboxylic acid chlorides

Chemical properties of acylated derivatives of 4,6-diamino-2-mercaptopyrimidine

Synthesis and properties of pyrimidinylalkylphosphonic acids: Communication 5. Synthesis of?-(oxopyrimidinyl-n)-ethylphosphonic acids

Reaction of salts of 2-hydroxypyrimidines with α,ω-dihaloalkanes