Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1980-11-14
1982-06-22
Jiles, Henry R.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C07D23354
Patent
active
043363946
DESCRIPTION:
BRIEF SUMMARY
The cyano-urea and cyano-thiourea functional groups fixed at the end of a lateral chain of the radical 2-((4-methyl-5-imidazolyl) thiomethyl)-ethyl characterize the compound of the invention: ##STR2## These functional groups determine, by their properties of acceptor and donor of hydrogen bond in the prototropic nature of their grouping and in the reciprocal interconversion of their tautomers, strong interactions with the peptidic functional groups of the polypeptides and the proteins. These interactions are schematized as per the formulas (a), (b), (c) and (d): ##STR3##
These functional groups determine by their properties of acceptor and donor of hydrogen bond strong interactions with the proteins. The hydrogen bond donated by the functional groups ##STR4## represented in the formulas (b) and (d) is particularly strong, due to the relative acidity of these functional groups that determine the electron-attraction effect of the nitrile radical on the amino-nitrogen.
The cyano-ureas and cyano-thioureas of the formulas (A), (B), (C) and (D) antagonize the histamine in the H.sub.2 receptors of the gastric parietal cells. Due to this fact, these cyano-ureas and cyano-thioureas lessen or prevent the production of the hydrochloric acid by those cells.
In the H.sub.2 receptors the radical imidazole of the invention's compounds is fixed in a suitable manner on a site proper to the said receptor and by which the stimulating action of histamine is being made; in other respects, the cyano-ureas and cyano-thioureas functional groups, at the other end of the molecules of the compounds of the formulas (A), (B), (C) and (D) enter into strong hydrogen bonds with another site of the same H.sub.2 receptor.
These interactions allow a better fixation of the histamine's antagonist in the H.sub.2 receptors, which lengthen the duration of the medicinal action and lessens the therapeutically useful dose.
In other respects, the cyano-urea and cyano-thiourea functional groups favor the biodisposability of the said compounds in the hydric compartment of the organism.
The invention's compounds caracterised by the formulas (A), (B), (C) and (D) can be used therapeutically for the treatment of duodenal and gastric ulcer.
The suitable excipients for the pharmaceutical preparation of the invention's compounds are, for example, lactose, saccharose, talcum, magnesium stearate, gelatine.arabic gum.olive oil.
EXAMPLE 1
N-(2-mercapro-ethyl)-N'-cyano-urea
To a solution of 5.25 g of 2-thiazolone in dry ethanol, is added 3.2 g of mono-sodium cyanamide derivative and taken to reflux 4 hours. The solvent is evaporated and the sodium-N-(2-mercapto-ethyl)N'-cyano urea is crystallized in tetrahydrofuran(IR(nujol): 3450,3350,2150,2120,1670,1610,1535,1410(sh),1305,1260,1200, 1115,1060,1040(sh),970,920,880,840,760,720 cm.sup.-1). The crystallized fraction is dissolved in methanol, then neutralized by the equivalent quantity of HCl. The residue of evaporation is extracted with acetonitrile in order to separate NaCl. The mother liquor evaporated under reduced pressure gives the product; it is made up of a mixture of tautomers(imino-nitrile: IR 2170 and 2150 cm.sup.-1 and amino-nitrile IR 2250 cm.sup.-1). The imino-nitrile tautomeric fraction is not very soluble in ethyl acetate, the amino-nitrile tautomeric fraction is more soluble. IR(film) of the tautomeric mixture: 3280,2250,2170,2150,1700, 1670,1630,1550-1520,1460,1430,1390,1370,1300,1250,1230,1170, 1130,1040,1030,780-769 cm.sup.-1.
EXAMPLE 2
N-(2-mercapto-ethyl)-N-cyano-urea
11.3 g of cysteineamine hydrochloride are dissolved in dry ethanol with 0.54 g of sodium methoxide, then 1.114 g of crystallized N-ethoxyoxy-carbonyl cyanamide is added. After 5 h. of reaction at an ordinary temperature, NaCl is isolated and one obtains a product as oil by evaporation of the solvent; which is homogeneous in c.c.m chromatography (n-butanol-acet.ac.-Water 10/2/5 vol.) revealing by sodium nitroprusside reagent (red coloring). EXAMPLE 3
N-2-((4-methyl-5-imidazolyl)-thiomethyl)-ethyl N'-imino-cyano-urea.
REFERENCES:
patent: 4192879 (1980-03-01), Durant et al.
Jiles Henry R.
Whittenbaugh Robert C.
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