US3158626A

US3158626A - 3-thiosteroids and method of preparation

Info

Publication number: US3158626A
Application number: US143265A
Authority: US
Inventors: Clarence G Stuckwisch; Nathan F Blau
Original assignee: Individual
Current assignee: Individual
Priority date: 1961-08-31
Filing date: 1961-08-31
Publication date: 1964-11-24
Anticipated expiration: 1981-11-24

Description

United States Patent 0 ice 3,158,626 3-THIOSTEROIDS AND METHQD 0F PREPARATION Clarence G. Stuckwisch, Las Vegas, N. Mex and Nathan F. Blau, Wichita, Kane, assignors to the United States of America as represented by the Secretary of the Army N0 Drawing. Filed Aug. 31, 1961, Ser. No. 143,265 (Fiierl under Rule 47(a) and 35 U.S.Q. 116) 16 Ciairns. (Cl. 269-3972) (Granted under Title 35, U.S. Code (1952), see. 266) The invention described herein may be manufactured and used by or for the Government for governmental purposes without the payment of any royalty thereon.

The present invention relates to the preparation of sulphur-containing derivatives of cholesterol and the resulting products as new compositions of matter having Formulas I and H below:

CH CH3 3 I l R! CHa TsO

' Patented Nov. 24, 1964 wherein R is alkyl or aryl, R is hydrogen, alkyl or aryl, X- is arylsulphonate, X- and 8+ indicating the ionic nature or saltlike nature of the compound, in which X- is the anion and S+ means a positive charge-bearing ion or cation.

In accordance with the instant invention, there has been made the important discovery that derivatives of Type I above can be prepared directly and in good yields by reaction of a sulphhydryl compound, RSH, wherein R is alkyl or aryl, and a cholesteryl arylsulphonate. Also, there has been made in accordance with the instant invention,

the discovery that compounds of Type II above can be prepared by the reaction of a sulphide, RSR, wherein R is alkyl, with a cholesteryl arylsulphonate in a polar solvent such as nitromethane or acetonitrile.

It is thought that the mechanism leading to the production of the cholesterol derivatives of the present invention is represented by the following reactions using cholesteryl p-toluenesulphonate as an example:

on 011, CH:

+ TsO- CH3 CH3 cates, as has been noted previously, a positive chargebearing ion or cation.

On this basis, the general reactions for the syntheses of the present invention may be expressed as follows:

CH3 om CH3 nsrr g .AR-S-O our 3 CH3 CH C on, RS Q on, on, on; CH3 2 ms ARS-O CH3 CH3 CH3 2 R AR-SO s+ L R 0 In the above reaction, the arrows in the group 0 T an-s-o indicate coordinate covalent bonds contrasting with simple covalent bonds. These signs are significant with respect to the electronic constitution of the atoms and thus as regards the stability of the radical as a whole. The same explanation for the plus sign associated with sulphur in the first product of the above-indicated general reaction is the same as has been indicated above, that is, it indicates a positive charge-bearing ion or cation, whereas the minus sign attached to the last product of the aboveindicated general reaction again indicates a negative charge-bearing ion, or an anion.

In the instant disclosure and claims, by the terms alkyl and aryl are meant, respectively, so-called lower alkyls as represented by, but not necessarily limited to, methyl, ethyl, propyl, isopropyl, and by the aryl radicals are meant groups represented by, but not limited necessarily to, phenyl, p-tolyl, furyl, thenyl, and the like.

The sulphonium arylsulphonates of the present invention can be converted to sulphoniurn halides by means of ion-exchange. The derivatives of the instant invention are anti-metabolites for cholesterol in physiological processes.

It appears that the reactions involved in the present invention take place in two steps. The first step is the dissociation of cholesteryl p-toluenesulphonate into the p-toluenesulphonate ion and a resonating carbonium ion, as indicated by the double-headed" arrow in the aboveindicated reactions representing the conversion of cholesteryl p-toluenesulphonate into the cholesterol derivatives. The resonating carbonium ion then reacts with a mercaptan to yield the 3-alkylthio-5-cholestene or with a dialkyl sulphide to yield a 3-dialkylsulphonio-5-cholestene p-toluenesulphonate. in that it allows the reaction to proceed with retention of configuration at carbon atom No. 3 in the steroid molecule.

The process of the present invention may be illustrated by the following illustrative, although not necessarily limiting, specific examples:

EXAMPLE A Five parts of cholesteryl p-toluenesulphonate, 10 parts of methyl mercaptan, and 25 parts of glacialacetic acid (all parts by weight) were placed in a pressure bottle at 30 C. for 24 hours. The crystals which separated were collected on a filter and crystallized from acetone. The thioether thus obtained was four parts by weight and melted at 126 C. This product was identified as 3 3- methylthio-S-cholestene.

Arzalysis.-Calculated for C H S: C, 80.71; H, 11.6. Found: C, 80.44; H, 11.48.

EXAMPLE B Five parts of cholesteryl p-toluenesulphonate, 10 parts of dimethyl sulphide, and parts of nitromethane were placed in a pressure bottle and heated to 70 C. for 24 hours, or at 30 for 20 days. On cooling, crystals separated. These were collected on a filter and crystallized from methanol-ether. The recovered sulphonium compound weighted 4.5 parts by weight and melted at 200" C. This product was identified as Bfi-dimethylsulphonio-S-cholestene p-toluenesulphonate.

Analysis.-Calculated for C i-1 0 C, 71.5; H, 9.9. Found: C, 71.34; H, 9.6.

When an alcoholic solution of the product of Example B was passed over the chloride form of Amberlite IRA 410" (Rohm and Haas Co.), the chloride salt of the sulphonium derivative of the steroid was obtained, M.P. 182-183 C.

EXAMPLE C In Vitro Test for the Inhibition of the Biosynthesis 0 Cholesterol Flasks containing rat liver homogenates in a buffered solution, with sodium acetate and 3,3-dimethylsulfoniocholestene chloride (1 mg. per flask) added, was shaken at 37 C. for approximately five hours. Control mixtures were similarly compounded, except for the omission of the steroid under examination, and treated as indicated above.

Such a mechanism is significant EXAMPLE D In Vivo Test for the Inhibition of the Biosynfhesis 09 Cholesterol I A number of rats, divided into experimental and control groups, were fed a standard diet and observed as to food consumption and gain of weight. One of the groups had the test compound (0.05%) by weight of diet) added to the diet. After the two weeks on this regimen the animals were exsanguinated and the serum, liver, and adrenals were analyzed for cholesterol.

It was found that, as compared to the control groups, 3fi-dimethylsulfonio-S-cholestene chloride lowered the cholesterol concentration in the adrenal glands by 32%, while a lowering of 49% of cholesterol was observed in the adrenal glands of another group of animals that was fed 3,B-methylthio-S-cholestene. Other examples of 3-thiosteroids which can be prepared by the process of this invention and which are useful as anti-metabolites for cholesterol are:

3,3 dimethylsulphonio 6,8 methyl 5 cholestene p-toluenesulphonate 3B dimethylsulphonio 6,8 phenyl 5 cholestene p-toluenesulphonate 3,8 methylthio 6B methyl 5 cholestene p toluenesulphonate 35 dibutylsulphonio 6B methyl 5 cholestene p toluenesulphonate 3 5 butylthio 6,8 methyl 5 cholestene p toluenesulphonate 3,8 methylthio 6e methyl 5 cholestene The fore oing description discloses the preferred compositions of the newly discovered compounds of the present invention and the preferred procedures for their preparation; however, it will be understood that compositional and procedural details may be varied by one skilled in the art without departing from the actual invention hereby presented. Accordingly, it will be understood that it is intended and desired to embody within the scope of this invention such modifications and changes as may be necessary or desirable to adapt the invention to varying conditions and uses as defined by the appended claims.

We claim:

1. A process for preparing 3-thio derivatives of choles terol having the formula wherein R is a radical selected from the group consisting of a lower alkyl and aryl, and R is a radical selected from the group consisting of hydrogen, lower alkyl and aryl which comprises directly reacting a mercaptan selected from the group consisting of a lower alkyl mercaptan and an aryl mercaptan with a cholesteryl arylsulphonate.

2. A process as claimed in claim 1, wherein the cholesteryl arylsulphonate is cholesteryl p-toluenesulphonate, and the mercaptan is methyl mercaptan.

3. A process for preparing a 3-thiosteroid having the formula wherein R is a radical selected from the group consisting of a lower alkyl and aryl, and R is a radical selected from the group consisting of hydrogen, lower alkyl and aryl which comprises introducing into a pressure bottle a reaction mixture composed of cholesteryl p-toluenesulphonate, methyl mercaptan and glacial acetic acid in substantially relative proportions in parts by weight, of the respective components of the mixture of five parts, ten parts, and 75 parts, allowing the resulting mixture to react at substantially 30 C. for approximately 24 hours, collecting the resulting crystalline reaction product on a filter, and crystallizing the reaction product from acetone.

4. A composition of matter, 3-thio derivatives of cholesterol having the formula H3 CH3 CH R X-s wherein X- is an arylsulphonate, X" and S+ indicating an ionic nature of the compound in which X is an anion and S+ is a positive charge-bearing ion, R is a radical selected from the group consisting of lower alkyl and aryl, and R is a radical selected from the group consisting of hydrogen, lower alkyl, and aryl.

5. A process for preparing 3-thio derivatives of cholesterol having the formula wherein X is an arylsulphonate, X- and 8* indicating the ionic nature of the compound in which X is an anion and S+ is a positive charge-bearing ion, R is a radical selected from the group consisting of lower alkyl and aryl, and R is a radical selected from the group .consisting of hydrogen, lower alkyl and aryl which comprises directly reacting a lower alkyl sulphide with a cholesteryl arylsulphonate in a polar solvent.

6. A process as claimed in claim 5, wherein the lower alkyl sulphide is dimethyl sulphide, the cholesteryl arylsulphonate is cholesteryl p-toluenesulphonate, and the polar solvent is nitromethane.

7. The process as claimed in claim 6 wherein there is employed a reaction mixture composed of cholesteryl p-toluenesulphonate, dimethyl sulphide, and nitromethane, in ratios of substantially five parts by weight of cholesteryl p-toluenesulphonate, ten parts by weight of dimethyl sulphide, and 75 parts by weight of nitromethane.

8. The process as claimed in claim 6 wherein the reaction mixture defined by claim 8 is placed in a pressure bottle, heated to substantially 70 C. for approximately 24 hours, cooling the resulting material, collecting the resulting reaction product, and crystallizing the reaction product from methanol-ether solvent.

9. The process as claimed in claim 6 wherein the reaction mixture set forth in claim 8 is placed in a pressure bottle and maintained at a temperature of substantially 30 C. for a period of 20 days, collecting the resulting reaction product, and crystallizing the reaction product from methanol-ether solvent.

10. The process of producing 3-steroid ethers of cholesterol, which comprises dissociating cholesteryl p-toluenesulphonate into the p-toluenesulphonate ion and a resonating carbonium ion by subjecting the cholesteryl p-toluenesulphonate to heat and pressure in the presence of an alkyl sulphide until a crystalline reaction product forms, and collecting the reaction product.

11. The process of producing 3steroid ethers of cholesterol as claimed in claim 10 wherein the dissociation is effected in the presence of a polar solvent.

12. The process of producing 3-ster0id ethers of cholesterol as claimed in claim 10 wherein the resonating carbonium ion is reacted with an organic sulphide compound selected from the group consisting of a lower alkyl mercaptan and a dialkyl sulphide to yield a reaction product selected from the group consisting of S-alkylthio-S- cholestene and 3-dialkyl-sulphonio-5-cholestene p-tolu enesulphonate.

13. A process for preparing the compounds of claim 4, which comprises directly reacting a lower alkyl sulphide with cholesteryl ptoluenesulphonate in a polar solvent by heating together the .alkyl sulphide and cholesteryl p-toluenesulphonate with the polar solvent until separation of a crystalline reaction product is effected.

14. A process as claimed in claim 13 wherein the polar solvent is selected from the group consisting of nitromethane and acetonitrile.

15. The compound 3,S-dimethylsulphonio-5-cholestene p-toluenesulphonate.

16. The compound BQ-dirnethylsulphonio-S-cholestene chloride.

References Cited in the file of this patent UNITED STATES PATENTS 2,549,991 Strating Apr. 24, 1951

Claims

4. A COMPOSITION OF MATTER, 3-THIO DERIVATIVES OF CHOLESTEROL HAVING THE FORMULA