CA1037964A - 2-((3,5-di-tert-buryl-4-hydroxyphenyl)thio)alkanoic acids and derivatives and esters - Google Patents
2-((3,5-di-tert-buryl-4-hydroxyphenyl)thio)alkanoic acids and derivatives and estersInfo
- Publication number
- CA1037964A CA1037964A CA191,746A CA191746A CA1037964A CA 1037964 A CA1037964 A CA 1037964A CA 191746 A CA191746 A CA 191746A CA 1037964 A CA1037964 A CA 1037964A
- Authority
- CA
- Canada
- Prior art keywords
- butyl
- tert
- thio
- acid
- hydroxyphenyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
- C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/10—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C323/18—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
- C07C323/20—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton with singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
- C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
- C07C323/52—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
ABSTRACT
2-(3,5-Di-tert-butylphenyl)- and 2-((3,5-di-tert-butyl-4-hydroxyphenyl)-(thio or sulfonyl) alkanoic acids and ester derivatives and pharmaceutically-acceptable salts thereof and pharmaceutical compositions containing said compounds are disclosed. The compounds and compositions are useful for reducing plasma lipid levels in mammals.
2-(3,5-Di-tert-butylphenyl)- and 2-((3,5-di-tert-butyl-4-hydroxyphenyl)-(thio or sulfonyl) alkanoic acids and ester derivatives and pharmaceutically-acceptable salts thereof and pharmaceutical compositions containing said compounds are disclosed. The compounds and compositions are useful for reducing plasma lipid levels in mammals.
Description
7~i4 This invention relates to novel 2-(3,5-di-t~rt-butylphenyl)- and 2-((3,5-di-tert-butyl-4-hydroxyphenyl)- ;~
(thio or sulfonyl) alkanoic acids and ester derivatives thereof (hereinafter referred to~ for convenience~ as "alkanoic acids"). This invention also relates to compo-sitions for reducing plasma lipid levels, especially choles-terol and triglycericide levels and, in particular, trigly-glyceride levels. `-- As established by various studies, it is recognized that cholesterol and triglycerides pl~y a major role in the formation of atherosclerotic plaques by accelerating the deposition of blood lipids in the arterial wall. The pxesent compounds can be effective in reducing cholesterol levels, and particularly triglyceride levels in the blood of mammals.
These activities make the compounds herein useful as compo-sitions in ameliorating such conditions as atherosclerosis and other clinical entities in which the underlying etiology ;
is associated with lipid imbalance or hyperlipidemia.
The alkanoic acids and derivatives with which the :
present invention is concern~d are represented by the general formula~
R ~ Rl Z ~ X-C-COOR3 R ~2 wherein:
each R represents a tert-butyl group;
X represents S or SO2;
Z represents hydrogen or hydroxy; ~ ;
Rl represents hydrogen or methyl;
R2 represents an aIkyl group of from one to -~ -six carbon atoms;
~ ~ '';
~.
, ~ .... . .
~(137~
R3 represents hydrogen or an alkyl group of from one to threa carbon atoms; or the salts thereof formed with pharmaceutically acceptable base.
In generalJ any base which will form an acid addition salt with a carboxylic acid and whose pharmacologic-al properties will not cause an adverse physiological effect when ingested by the body system is considered as being within the scope of this invention. Suitable bases thus include, for example, the alkali metal and alkaline earth metal hydroxides, carbonates, and bicarbonates, such ;
as sodium hydroxide, potassium hydroxide, calcium hydroxide, ~
. . .. ~.
potassium carbonate, sodium bicarbonate, or magnesium ;- `
-~ carbonate; ammonia, primary, secondary and tertiary amines.
Also, aluminum salts of the compounds may be obtained by treating the corresponding sodium salt with an appropriate ~ -aluminum complex such as aluminum chloride hexahydrate. The acid addition salts thus obtained are the functional equi~
; valent of the corresponding alkanoic acids and are lLmited only by the criterion that the bases employed in forming --the salts be both non-toxic and physiologically acceptable.
The term "aLkyl" as used in the specification and claims means both straight and branched chain alkyl radicals containing from 1 to 6 carbon atoms, e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, amyl, and - hexyl.
Preferred compounds of the above formula include those wherein X is sulfur. In another embodiment, compounds - wherein X is sulfonyl are preferred. In a further embodi-mentJ preferred compounds i~clude those wherein Rl is ~ ' ' " ~ '.
1649o/l7o93-F -2-~ .. .. . . .
~(3379~;~
hydrogen. In still another emhodiment, preferred compounds include those wherein Rl is hydrogen, X is sulfur and R3 is hydrogen. An additional preferred class of compounds include those wherein Rl is hydrogen~ X is sulfonyl and R3 is hydrogen. Still another preferred class of compounds includes those wherein Rl is hydrogen, R2 is methyl, ethyl, butyl~ or n-pentyl, and R3 is hydrogen. A further preferred class of compounds includes those wherein Rl is hydrogen, R3 is alkyl, and X is sulfur. Another preferred class of compounds includes those wherein Rl is hydrogen, R2 is n- -propyl or n-butyl, R3 is ethyl, and X is sulfur. Still ~`
another preferred class of compounds are those wherein R
is hydrogen, R3 is alkyl, and X is sulfonyl. Another class of compounds which are preferred are those wherein Rl is methyl, X is sulfur and R3 is hydrogen. A further pre~erred class includes compounds wherein Rl is methyl, R2 is methyl, ethyl, n-pentyl, or n-hexyl, R3 is hydrogen and X is sulfur.
Another pre~erred class of compounds includes those wherein Rl is methyl, R3 is alkyl and X is sulfur. Pre~erred com-pounds of the present invention include 2-((3,5-di-t.-butyl~
4-hydroxyphenyl)thio~hexanoic acid and its pharmaceutically-acceptable acid addition salts.
The compounds of the present invention wherein X is sulfur can be prepared by reacting 3,5-di-tert-butyl-thiophenol or 2,6-di-tert-butyl-4-mercaptophenol with a ~--haloalkanoic acid or alkanoate reactant of the formula:
. 1 ''-.
.~
R2 .
wherein, in the above formula3~ Y is halogen such as bromo '~
, -- ` 7 : , - . . . . . . . . .
.: . .. ,. : - : `
~(~379~i~
or chloro and each of R, Rl, R2 and R3 are as previously defined and where required reacting the rcsul.ing compound with a pharmaceutically acceptable `
base. The reaction is ordinarily carri~d out in the presence of an inert liquid reaction medium such as, for example, methanol, ethanol, propanol, t-butanol, benzene, dimethylformamide, or toluene, and a base, such as, for example, alkali metal and alkaline earth hydroxides, and carbonates.
Representative of such bases are sodium hydroxide, po~assium hydroxide, calcium hydroxide, and potassium carbonate. For compounds wherein R3 is hydrogen, i.e. the acid derivatives, a ratio of about two moles of base per mole of phenol reactant is usually employed while e~uimolar amounts of base ;
and phenol reactant are usually employed for compounds wherein R3 is alkyl.
Generally, equimolar amounts of the phenol and alkanoic acid or alkanoate reactants are employed. Compounds wherein R3 is hydrogen, can, of course, be obtained by hydrolyzing the compounds wherein R3 is alkyl with excess ;~
base.
In carrying out the reaction, the phenol reactant is usually dis- -persed in a selected reaction medium and a solution of base added slowly thereto with stirring. During the base addition, the reaction mixture is usually cooled. Following the completion of the base addition, the alkanoic acid or alkanoate reactant is added to the reaction mixture and the re~
sulting reaction mixture, which warms slightly due to exothermic reaction, is usually maintained, with stirring, at ambient temperatures for from 4 to 24 or more hours in order to allow for substantial completion of the reaction. Upon completion of the reaction period, the reac~ion mixture is acidified with aqueous hydrochloric acid and stirred. The resulting product precipitate, ~hich is obtained by ~' ~
'`:
, .,-) :
~ - 4 -~ 7~
filtration of the reaction mixture, is washed with water and dried. The dried precipitate can be further purified ; if desired by recrystallizing the same ~rom a suitable solvent such as, for exampleJ ethanol, methylene chloride, hexane, or chloroform.
The compounds of the present invention wherein X is sulfonyl can be prepared by oxidizing the compounds of the present invention wherein X is sulfur. The oxidation preferably is carried out with hydrogen peroxide in the presence of a water-miscible solvent such as glacial acetic ~-acid or an alcohol, e.g. methanol, ethanol. In carrying ;~
out the reaction3 the phenylthioalkanoic acid or ester reactant is dissoived in the selected water-miscible solvent and the resulting mixture is usually cooled to a temperature of from 20 to 30C. Hydrogen peroxide is slowly added portionwise thereto with stirring, with a precipitate form-- ing near the end of the hydrogen peroxide addition. Follow-ing the completion of the hydrogen peroxide addition, the reaction mixture is usually warmed slightly to redissolve the precipitate, and subsequently maintained at ambient temperatures ~or a period of from 10 to 20 hours. Subseguent -mixing of the reaction mixture with ice water yields an oily product residue, which usually congeals upon stirring~
The desired product residue can be recovered from the - 25 aqueous mixture and further purified according to the pro- cedures set forth hereinabove.
The compounds of the present invention exhibit -~
valuable pharmacological properties useful in the chemo-therapeutic treatment of disord~rs and conditions associated with lipid imbalance or hyperlipidemia. In this respect, .
'',, ' '.
.: . . . . , . .:
~037~
it has been found that many compounds of the class herein described exhibit hypocolesterolenic activity as well as unusually high hypotriglyceridemic activity. Such pro-nounced hypotriglyceridemic activity thus renders such compounds particularly useful in the chemotherapeutic treat-ment of pathological states characterized by high glyceride levels, i.e. hypertriglyceridemia.
For oral administration, pharmaceutical prepar~
ations of this invention may be made by following the con-ventional techniques of the pharmaceutical chemist. These techniques involve granulating and compressing when necessary or variously mixing and dissolving or suspending the ingre-dients as appropriate to the desired end product. ~umerous `~
pharmaceutical forms to carry the compounds can be used.
For example, the pure compound can be used or it can be mixed with a solid carrier. Generally~ inorganic pharma-ceutical carriers are preferable and particularly solid inorganic carriers. One reason for this is the large number of inorganic materials which are known to be pharma~
ceutically safe and acceptable, as well as very convenient ~-in preparing formulations. The compositions may take the form o~ tablets, linguets, powders, capsules, slurries, troches, or lozenges, and such compositions may be prepared by standard pharmaceutical techniques. Tablet compositions may be coated or uncoated, and they may be effervescent or non-effervescent. Conventional excipients for tablet formations may be used. For example, inert diluents, such as magnesium carbonate or lactose, disintegrating agents such as maize starch or alginic acidJ and lubxicating agents such as magnesium stearate may be used.
. :
. -. .~ .
- . . .: :
~11379~
If a liquid carrier is u~edJ the preparation may be in the form of a soft gelatin capsule, a syrupJ a liquid solution or suspension.
The hydrocarbon solubility o~ most of the com-pounds of this invention is high enough to allow the use ofpharmaceutically-acceptable oils as carriers. For example vegetable or animal oils such a~ sunflower oil, safflower `
oil, maize oil or codliver oil can be used. Glycerine can also be used. With this latter solvent, from 2 to 30 per ~-- 10 cent water may be added. When water alone is the carrierJ
or when the solubility of the compound in the oil is 1OWJ ~i'.~, the preparations can be administered in the form of a slurry.
Emulsion compositions may be formulated using ~ ;
emulsifying agents such as sorbitan tri-oleate, polyoxy~
ethylene sorbitan monooleateJ lecithinJ gum acacia or gum gragacanth. Aqueous based suspensions may be prepared with the aid o~ wetting agents such as polyethylene oxide conden-sation products of alkylphenols, fatty alcohols or fatty `
acids with the suspending agents, for example a hydrophilic colloid such as polyvinylpyrrolidone. The emulsions andsuspensions may contain conventional excipients such as sweeting agents, flowing agents, coloring materials, or preservatives.
The compounds of this invention can also be in-corporated in a nutritive foodstuff such as, for example,butter, margarine, edible oils, casein, or carbohydrates~
Such nutritive compositions are adapted to be administered as a partial or total diet or as a supplement to the diet.
Such compositions preferably contain from 0.02 or less to ~.0 or more percent of the active ingredient whan administer-' ' ~()379 ed as the total diet. The compo~itions can contain higher --conc~ntrations of the active in~redient when administered as a supplement.
For parenteral use~ the compounds of this invention can be formulated with sterile ingredients, compounded and packaged asceptically. They may be administered intra-venously or intramuscularly. Usleful solvents for formu-lation in such use are the polyhydric aliphatic alcohols and mixtures thereof. Especially satisfactory are the ~-pharmaceutically acceptable glycols, such as propylene glycol, and mixtures thereof. Glycerine is another example of a polyol which is particularly useful. Up to 25-30 percent by volume of water may be incorporated in the vehicle if desired. An 80 percent aqueous propylene glycol solution ~`
is a particularly convenient solvent system. A pH range, about 7.4, and isotonicity compatible with body isotonicity, is desirable. Basicity may be controlled by addition of a base as required, and a particularly convenient base is monoethanolamine. It may often be desirable to incorporate ~ -a local anaesthetic and such are well known to those skilled in the art.
The percentage of the compound to be used in the pharmaceutical carrier may be varied. It is necessary that the compound constitute a proportion such that a suitable dosage will be obtained, and it is preferred to use pharma-oeutical compositions containing at least 10 weight percent of the compound. Activity increases with concentration of the agent in the carrier, but those compositions containing ` a significant amount of carrier, e.g. at least 1 percent and preferably at least 5 percent, are preferred as they allow for the easier administration of the compound.
~ .
~ 16490/17093-F -4- ~
~379~i~
Generally, an effective daily dosage of the active ingredient can be from less than 1 to 4000 milligrams or more per kilogram (mg./kg.) of body weight for most mammals. Dosage unit forms usually contain from 1 to 1000 - ;
mg., usually from 1 to 500 mg. o~ an active compound. One or more unit dosage forms are administered internally to a mammal to provide an active compound daily dosage level of ~`
from 1 to 4000 mg.
However, it is not intended that the dosage `~
regimens of the compounds or compositions be limited to any particular range. The dosage range desired in this invention is that range necessary to accomplish the desired ;-~
end of lowering serum lipid levels. The amount of lipid level reduction desired will not be the same in all instances, but depends upon such factors as initial lipid level, pre- -dominance of one form of lipid over another~ etc. The dosage, whether oral or parenteral must, therefore, o~
n,ecessity be individually determined. Likewise, the concentration range of the compounds in the various formu-lations of this invention is not limited. The concentration should be high enough to avoid any excessive number o~
administrations per day, but low enough to allow ~lexibility in administration.
The active acid compound and/or their corresponding esters or salts may be administered. In addition, other complementary hypolipidemicJ hypocholesteremic or hypo- `
glycemic agents as well as vitamins, analgesics, ox androgens compatible with the present compounds can be included in the present formulations to secure advantageous combination -therapy. Moreover, preservatives, stabilizers, wetting 16490/17093-F -9~
: . ... . - . .
- 1~379~ :
agents, or buffers can be incorpor~ted, if desired, into the above formulations. Additionally, the formulations may also contain other therapeutically valuable substances.
The term "unit dosage form" as used in the specification and claims herein re~ers to physically dis-crete units suitable as unitary dosages, each unit contain- ~ `
ing a predetermined quantity o~ active material calculated to produce the desired therapeutic effect in association ~ -- with the required pharmaceutical diluent, carrier or vehicle.
The specification for the novel unit dosage forms of this ~ ;~
invention is dictated by and directly dependent on ~a) the - ~ ;
unique characteristics of the active material and the particular therapeutic effect to be achieved and (b) the ; limitations inherent in the art of compounding such an active material for therapeutic use, as disclosed in detail in this specification. ~
The invention is illustrated by the examples which ~-follow.
EXAMPLE 1 ;~
~ -- 20 A base solution (22 grams of ~aOH in 41 milliliters :.:
(ml) of water) was added to a solution of 2,6-di-t-butyl-4-mercaptophenol ~64.3 grams; 0.27 male) in 540 ml. of absolute ethanol with stirring while cooling the reaction ;
mixture under nitrogen. Following the base addition, a -~
- 25 solution o~ 2-bromohexanoic acid (52.8 grams; 0.27 mole~in 27 ml. of ethanol was added and the resulting reaction . . .
~r mixture was stirred at room temperature for about 6 hours ~
, and left standing overnight. The reaction mixture was then diluted with about 400 ml. of water and acidified with cold 30 6N HCl. The yellow brown precipitate resulting from the ~
. . :
16490/17093-F -10- ~
~(~37~
acidification was obtained by filtration, washed with water and recrystallized from a methylenechloride-hexane mixture.
The desired 2-((3~5-di-tert-butyl-4-hydroxyphenyl)thio)-hexanoic acid compound was obtained as a white crystalline solid having a melting point of 140-142C. Analysis calcu-lated for C20H3203S: C, 68.15; ~, 9.14; S, 9.10. Found:
C, 68.14; H, 9.34; S, 8.86. `-EXAMPLE 2 -~
(thio or sulfonyl) alkanoic acids and ester derivatives thereof (hereinafter referred to~ for convenience~ as "alkanoic acids"). This invention also relates to compo-sitions for reducing plasma lipid levels, especially choles-terol and triglycericide levels and, in particular, trigly-glyceride levels. `-- As established by various studies, it is recognized that cholesterol and triglycerides pl~y a major role in the formation of atherosclerotic plaques by accelerating the deposition of blood lipids in the arterial wall. The pxesent compounds can be effective in reducing cholesterol levels, and particularly triglyceride levels in the blood of mammals.
These activities make the compounds herein useful as compo-sitions in ameliorating such conditions as atherosclerosis and other clinical entities in which the underlying etiology ;
is associated with lipid imbalance or hyperlipidemia.
The alkanoic acids and derivatives with which the :
present invention is concern~d are represented by the general formula~
R ~ Rl Z ~ X-C-COOR3 R ~2 wherein:
each R represents a tert-butyl group;
X represents S or SO2;
Z represents hydrogen or hydroxy; ~ ;
Rl represents hydrogen or methyl;
R2 represents an aIkyl group of from one to -~ -six carbon atoms;
~ ~ '';
~.
, ~ .... . .
~(137~
R3 represents hydrogen or an alkyl group of from one to threa carbon atoms; or the salts thereof formed with pharmaceutically acceptable base.
In generalJ any base which will form an acid addition salt with a carboxylic acid and whose pharmacologic-al properties will not cause an adverse physiological effect when ingested by the body system is considered as being within the scope of this invention. Suitable bases thus include, for example, the alkali metal and alkaline earth metal hydroxides, carbonates, and bicarbonates, such ;
as sodium hydroxide, potassium hydroxide, calcium hydroxide, ~
. . .. ~.
potassium carbonate, sodium bicarbonate, or magnesium ;- `
-~ carbonate; ammonia, primary, secondary and tertiary amines.
Also, aluminum salts of the compounds may be obtained by treating the corresponding sodium salt with an appropriate ~ -aluminum complex such as aluminum chloride hexahydrate. The acid addition salts thus obtained are the functional equi~
; valent of the corresponding alkanoic acids and are lLmited only by the criterion that the bases employed in forming --the salts be both non-toxic and physiologically acceptable.
The term "aLkyl" as used in the specification and claims means both straight and branched chain alkyl radicals containing from 1 to 6 carbon atoms, e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, amyl, and - hexyl.
Preferred compounds of the above formula include those wherein X is sulfur. In another embodiment, compounds - wherein X is sulfonyl are preferred. In a further embodi-mentJ preferred compounds i~clude those wherein Rl is ~ ' ' " ~ '.
1649o/l7o93-F -2-~ .. .. . . .
~(3379~;~
hydrogen. In still another emhodiment, preferred compounds include those wherein Rl is hydrogen, X is sulfur and R3 is hydrogen. An additional preferred class of compounds include those wherein Rl is hydrogen~ X is sulfonyl and R3 is hydrogen. Still another preferred class of compounds includes those wherein Rl is hydrogen, R2 is methyl, ethyl, butyl~ or n-pentyl, and R3 is hydrogen. A further preferred class of compounds includes those wherein Rl is hydrogen, R3 is alkyl, and X is sulfur. Another preferred class of compounds includes those wherein Rl is hydrogen, R2 is n- -propyl or n-butyl, R3 is ethyl, and X is sulfur. Still ~`
another preferred class of compounds are those wherein R
is hydrogen, R3 is alkyl, and X is sulfonyl. Another class of compounds which are preferred are those wherein Rl is methyl, X is sulfur and R3 is hydrogen. A further pre~erred class includes compounds wherein Rl is methyl, R2 is methyl, ethyl, n-pentyl, or n-hexyl, R3 is hydrogen and X is sulfur.
Another pre~erred class of compounds includes those wherein Rl is methyl, R3 is alkyl and X is sulfur. Pre~erred com-pounds of the present invention include 2-((3,5-di-t.-butyl~
4-hydroxyphenyl)thio~hexanoic acid and its pharmaceutically-acceptable acid addition salts.
The compounds of the present invention wherein X is sulfur can be prepared by reacting 3,5-di-tert-butyl-thiophenol or 2,6-di-tert-butyl-4-mercaptophenol with a ~--haloalkanoic acid or alkanoate reactant of the formula:
. 1 ''-.
.~
R2 .
wherein, in the above formula3~ Y is halogen such as bromo '~
, -- ` 7 : , - . . . . . . . . .
.: . .. ,. : - : `
~(~379~i~
or chloro and each of R, Rl, R2 and R3 are as previously defined and where required reacting the rcsul.ing compound with a pharmaceutically acceptable `
base. The reaction is ordinarily carri~d out in the presence of an inert liquid reaction medium such as, for example, methanol, ethanol, propanol, t-butanol, benzene, dimethylformamide, or toluene, and a base, such as, for example, alkali metal and alkaline earth hydroxides, and carbonates.
Representative of such bases are sodium hydroxide, po~assium hydroxide, calcium hydroxide, and potassium carbonate. For compounds wherein R3 is hydrogen, i.e. the acid derivatives, a ratio of about two moles of base per mole of phenol reactant is usually employed while e~uimolar amounts of base ;
and phenol reactant are usually employed for compounds wherein R3 is alkyl.
Generally, equimolar amounts of the phenol and alkanoic acid or alkanoate reactants are employed. Compounds wherein R3 is hydrogen, can, of course, be obtained by hydrolyzing the compounds wherein R3 is alkyl with excess ;~
base.
In carrying out the reaction, the phenol reactant is usually dis- -persed in a selected reaction medium and a solution of base added slowly thereto with stirring. During the base addition, the reaction mixture is usually cooled. Following the completion of the base addition, the alkanoic acid or alkanoate reactant is added to the reaction mixture and the re~
sulting reaction mixture, which warms slightly due to exothermic reaction, is usually maintained, with stirring, at ambient temperatures for from 4 to 24 or more hours in order to allow for substantial completion of the reaction. Upon completion of the reaction period, the reac~ion mixture is acidified with aqueous hydrochloric acid and stirred. The resulting product precipitate, ~hich is obtained by ~' ~
'`:
, .,-) :
~ - 4 -~ 7~
filtration of the reaction mixture, is washed with water and dried. The dried precipitate can be further purified ; if desired by recrystallizing the same ~rom a suitable solvent such as, for exampleJ ethanol, methylene chloride, hexane, or chloroform.
The compounds of the present invention wherein X is sulfonyl can be prepared by oxidizing the compounds of the present invention wherein X is sulfur. The oxidation preferably is carried out with hydrogen peroxide in the presence of a water-miscible solvent such as glacial acetic ~-acid or an alcohol, e.g. methanol, ethanol. In carrying ;~
out the reaction3 the phenylthioalkanoic acid or ester reactant is dissoived in the selected water-miscible solvent and the resulting mixture is usually cooled to a temperature of from 20 to 30C. Hydrogen peroxide is slowly added portionwise thereto with stirring, with a precipitate form-- ing near the end of the hydrogen peroxide addition. Follow-ing the completion of the hydrogen peroxide addition, the reaction mixture is usually warmed slightly to redissolve the precipitate, and subsequently maintained at ambient temperatures ~or a period of from 10 to 20 hours. Subseguent -mixing of the reaction mixture with ice water yields an oily product residue, which usually congeals upon stirring~
The desired product residue can be recovered from the - 25 aqueous mixture and further purified according to the pro- cedures set forth hereinabove.
The compounds of the present invention exhibit -~
valuable pharmacological properties useful in the chemo-therapeutic treatment of disord~rs and conditions associated with lipid imbalance or hyperlipidemia. In this respect, .
'',, ' '.
.: . . . . , . .:
~037~
it has been found that many compounds of the class herein described exhibit hypocolesterolenic activity as well as unusually high hypotriglyceridemic activity. Such pro-nounced hypotriglyceridemic activity thus renders such compounds particularly useful in the chemotherapeutic treat-ment of pathological states characterized by high glyceride levels, i.e. hypertriglyceridemia.
For oral administration, pharmaceutical prepar~
ations of this invention may be made by following the con-ventional techniques of the pharmaceutical chemist. These techniques involve granulating and compressing when necessary or variously mixing and dissolving or suspending the ingre-dients as appropriate to the desired end product. ~umerous `~
pharmaceutical forms to carry the compounds can be used.
For example, the pure compound can be used or it can be mixed with a solid carrier. Generally~ inorganic pharma-ceutical carriers are preferable and particularly solid inorganic carriers. One reason for this is the large number of inorganic materials which are known to be pharma~
ceutically safe and acceptable, as well as very convenient ~-in preparing formulations. The compositions may take the form o~ tablets, linguets, powders, capsules, slurries, troches, or lozenges, and such compositions may be prepared by standard pharmaceutical techniques. Tablet compositions may be coated or uncoated, and they may be effervescent or non-effervescent. Conventional excipients for tablet formations may be used. For example, inert diluents, such as magnesium carbonate or lactose, disintegrating agents such as maize starch or alginic acidJ and lubxicating agents such as magnesium stearate may be used.
. :
. -. .~ .
- . . .: :
~11379~
If a liquid carrier is u~edJ the preparation may be in the form of a soft gelatin capsule, a syrupJ a liquid solution or suspension.
The hydrocarbon solubility o~ most of the com-pounds of this invention is high enough to allow the use ofpharmaceutically-acceptable oils as carriers. For example vegetable or animal oils such a~ sunflower oil, safflower `
oil, maize oil or codliver oil can be used. Glycerine can also be used. With this latter solvent, from 2 to 30 per ~-- 10 cent water may be added. When water alone is the carrierJ
or when the solubility of the compound in the oil is 1OWJ ~i'.~, the preparations can be administered in the form of a slurry.
Emulsion compositions may be formulated using ~ ;
emulsifying agents such as sorbitan tri-oleate, polyoxy~
ethylene sorbitan monooleateJ lecithinJ gum acacia or gum gragacanth. Aqueous based suspensions may be prepared with the aid o~ wetting agents such as polyethylene oxide conden-sation products of alkylphenols, fatty alcohols or fatty `
acids with the suspending agents, for example a hydrophilic colloid such as polyvinylpyrrolidone. The emulsions andsuspensions may contain conventional excipients such as sweeting agents, flowing agents, coloring materials, or preservatives.
The compounds of this invention can also be in-corporated in a nutritive foodstuff such as, for example,butter, margarine, edible oils, casein, or carbohydrates~
Such nutritive compositions are adapted to be administered as a partial or total diet or as a supplement to the diet.
Such compositions preferably contain from 0.02 or less to ~.0 or more percent of the active ingredient whan administer-' ' ~()379 ed as the total diet. The compo~itions can contain higher --conc~ntrations of the active in~redient when administered as a supplement.
For parenteral use~ the compounds of this invention can be formulated with sterile ingredients, compounded and packaged asceptically. They may be administered intra-venously or intramuscularly. Usleful solvents for formu-lation in such use are the polyhydric aliphatic alcohols and mixtures thereof. Especially satisfactory are the ~-pharmaceutically acceptable glycols, such as propylene glycol, and mixtures thereof. Glycerine is another example of a polyol which is particularly useful. Up to 25-30 percent by volume of water may be incorporated in the vehicle if desired. An 80 percent aqueous propylene glycol solution ~`
is a particularly convenient solvent system. A pH range, about 7.4, and isotonicity compatible with body isotonicity, is desirable. Basicity may be controlled by addition of a base as required, and a particularly convenient base is monoethanolamine. It may often be desirable to incorporate ~ -a local anaesthetic and such are well known to those skilled in the art.
The percentage of the compound to be used in the pharmaceutical carrier may be varied. It is necessary that the compound constitute a proportion such that a suitable dosage will be obtained, and it is preferred to use pharma-oeutical compositions containing at least 10 weight percent of the compound. Activity increases with concentration of the agent in the carrier, but those compositions containing ` a significant amount of carrier, e.g. at least 1 percent and preferably at least 5 percent, are preferred as they allow for the easier administration of the compound.
~ .
~ 16490/17093-F -4- ~
~379~i~
Generally, an effective daily dosage of the active ingredient can be from less than 1 to 4000 milligrams or more per kilogram (mg./kg.) of body weight for most mammals. Dosage unit forms usually contain from 1 to 1000 - ;
mg., usually from 1 to 500 mg. o~ an active compound. One or more unit dosage forms are administered internally to a mammal to provide an active compound daily dosage level of ~`
from 1 to 4000 mg.
However, it is not intended that the dosage `~
regimens of the compounds or compositions be limited to any particular range. The dosage range desired in this invention is that range necessary to accomplish the desired ;-~
end of lowering serum lipid levels. The amount of lipid level reduction desired will not be the same in all instances, but depends upon such factors as initial lipid level, pre- -dominance of one form of lipid over another~ etc. The dosage, whether oral or parenteral must, therefore, o~
n,ecessity be individually determined. Likewise, the concentration range of the compounds in the various formu-lations of this invention is not limited. The concentration should be high enough to avoid any excessive number o~
administrations per day, but low enough to allow ~lexibility in administration.
The active acid compound and/or their corresponding esters or salts may be administered. In addition, other complementary hypolipidemicJ hypocholesteremic or hypo- `
glycemic agents as well as vitamins, analgesics, ox androgens compatible with the present compounds can be included in the present formulations to secure advantageous combination -therapy. Moreover, preservatives, stabilizers, wetting 16490/17093-F -9~
: . ... . - . .
- 1~379~ :
agents, or buffers can be incorpor~ted, if desired, into the above formulations. Additionally, the formulations may also contain other therapeutically valuable substances.
The term "unit dosage form" as used in the specification and claims herein re~ers to physically dis-crete units suitable as unitary dosages, each unit contain- ~ `
ing a predetermined quantity o~ active material calculated to produce the desired therapeutic effect in association ~ -- with the required pharmaceutical diluent, carrier or vehicle.
The specification for the novel unit dosage forms of this ~ ;~
invention is dictated by and directly dependent on ~a) the - ~ ;
unique characteristics of the active material and the particular therapeutic effect to be achieved and (b) the ; limitations inherent in the art of compounding such an active material for therapeutic use, as disclosed in detail in this specification. ~
The invention is illustrated by the examples which ~-follow.
EXAMPLE 1 ;~
~ -- 20 A base solution (22 grams of ~aOH in 41 milliliters :.:
(ml) of water) was added to a solution of 2,6-di-t-butyl-4-mercaptophenol ~64.3 grams; 0.27 male) in 540 ml. of absolute ethanol with stirring while cooling the reaction ;
mixture under nitrogen. Following the base addition, a -~
- 25 solution o~ 2-bromohexanoic acid (52.8 grams; 0.27 mole~in 27 ml. of ethanol was added and the resulting reaction . . .
~r mixture was stirred at room temperature for about 6 hours ~
, and left standing overnight. The reaction mixture was then diluted with about 400 ml. of water and acidified with cold 30 6N HCl. The yellow brown precipitate resulting from the ~
. . :
16490/17093-F -10- ~
~(~37~
acidification was obtained by filtration, washed with water and recrystallized from a methylenechloride-hexane mixture.
The desired 2-((3~5-di-tert-butyl-4-hydroxyphenyl)thio)-hexanoic acid compound was obtained as a white crystalline solid having a melting point of 140-142C. Analysis calcu-lated for C20H3203S: C, 68.15; ~, 9.14; S, 9.10. Found:
C, 68.14; H, 9.34; S, 8.86. `-EXAMPLE 2 -~
2,6-Di-t-butyl-4-mercaptophenol (80.0 grams; 0.34 -mole) was added to a stirred solution of sodium hydroxide (13.4 grams; 0.34 mole) in 500 ml. of 95% ethanol. To this mixture, ethyl 2-bromohexanoate ~76.2 grams; 0.34 mole) was added, and the resulting reaction mixture was allowed to warm slightly and then was stirred at ambient temperatures for about 16 hours. The reaction mixture was subsequently poured into about 2500 ml. of S% HCl with stirring. The oily layer which ~ormed upon acidification was separated from the reaction mixture and extracted with ethyl acetate. `
The extract was dried and evaporated to obtain a light brown - 20 oil representing the desired ethyl 2-((3,5-di-tert-butyl-4-hydroxyphenyl)thio)hexanoate having a boiling point o 190C.
at 5 mm. of Hg at about 95% purity.
The ethyl 2-((3,5-di-tert-butyl-4-hydroxyphenyl~
thio)hexanoate (75 grams; 0.195 mole) obtained in Example 2 was dispersed in 300 ml. of 95% ethanol and 500 ml. of 5N ;`~
potassium hydroxide added thereto. The resulting reaction ;-mixture was heated on a steam bath at the boiling point under gentle reflux for about 90 minutes with occassional -~
stirring. Following the heating period, the reaction ~ .
, :''' ' ~ ' ' . , , ~3796~ ~
mixture was poured in-to 2000 ml. o~ 5O/o HCl with vigorous stirring. The white precipitate which formed upon acidi-fication was obtained by filtration and washed with water.
Recrystallization (twice) of the precipitate from a methylene chloride-hexane mixture gave 2~-((3,5-di-tert-butyl-4-hydroxy-phenyl)thio)hexanoic acid having a melting point o~
140-142C.
In accordance with the procedure of Example 1~
the following compounds can be prepared by employing the corresponding haloalkanoic acid reactants and, in the instances of saltsJ the corresponding bases:
2-((3,5-di-tert-butyl-4-hydroxyphenyl)thio)-propionic acid (melting at 111-112C.);
2-((3,5-di-tert-butyl-4-hydro~yphenyl)thio)-butyric acid (melting at 109-111C.);
2-((3,5-di-tert-butyl-4-hydroxyphenyl)thio)-heptanoic acid (melting at 85-87C.);
2-((3,5-di-tert-butyl-4-hydroxyphenyl)thio)-2-methyl-butyric acid (melting at 152-153C.);
2-((3,5-di-tert-butyl 4-hydroxypher.yl)thio)-2-methyl-octanoic acid (melting at 103-105C.);
sodium 2-((3,5-di-tert-butyl-4-hydroxyphenyl)-thio)hexanoate (melting at 274-282C.);
2-~(3,5-di-tert-butyl-4-hydroxyphenyl)thio)-2-methyl-pentanoic acid;
2-~(3,5-di-tert-butyl-4-hydroxyphenyl)thio)-2- --` methyl-octanoic acid;
potassium 2-((3,5-di-tert-butyl-4-hydroxyphenyl)-thio)propionate; and calcium 2-((3,5-di-tert-butyl-4-hydroxyphenyl)-thio)heptanoate~
;
- . . . . .
-' ': . ' -. . '' ~
~ ~337g64 ~`
.
The above compounds can also be prepared accord~
ing to Example 3 above if desired.
The following compounds are obtained in accordance with the procedure o~ Example 2 by employing the correspond-ing haloalkanoate:
ethyl 2-((3,5-di-tert-butyl-4-hydroxyphenyl)thio)-valerate (melting at 65-66C.);
ethyl 2-((3,5-di-tert-butyl-4-hydroxyphenyl)thio)-2-methyl-propionate;
propyl 2-((3,5-di-tert-butyl-4-hydroxyphenyl)thio)-2-methyl-octanoate; ,.,~ .' methyl 2-((3,5-di-tert-butyl-4-hydroxyphenyl)thio)-2-methyl-propionate; ~ ;
propyl 2-((3,5-di-tert-butyl-4-hydroxyphenyl)thio)- ~ ~
2-methyl-valerate; `` ?
methyl 2-((3,5-di-tert-butyl-4-hydroxyphenyl)thio)-: . ~
propionate; and propyl 2-((3,5-di-tert-butyl-4-hydroxyphenyl)thio)-octanoate. `
2-((3,5-Di-tert-butyl-4-hydroxyphenyl)thio)~
hexanoic acid (10.0 grams), prepared as in Example l, was dissolved in 150 ml. of glacial acetic acid by warming the solution to about 40 C o and then cooled to about 25C.
Sixteen ml. of 30% hydrogen peroxide was slowly addedJ with stirring, thereto. Following the completion of the hydrogen - peroxide addition, the reaction mixture was warmed to about 41C. to dissolve a white precipitate which had formed near the level of the hydrogen~peroxide addition. The reaction mixture remained clear upon subsequent cooling to about 25C.
.~ '. . ''" ' ~
, '.' ''' 16490/17093-F -13- ~-,. ~ ;~ , .
. ~ .
~LU379~4 The reaction mixture was then stirred at ambient temper-atures for about 16 hours and ~hereafter poured into about 2500 ml. of ice water and the resulting aqueous mixture stirred. A white oily precipitate, which formed in the aqueous mixture and which congealed upon stirring, was recovered by filtration~ washed with water and air-dried.
The product thus obtained was mixed with 100 ml. of methylene chloride and about 350 ml. of hexane, and the resulting cloudy solution was concentrated to a volume of about 400 ml. The concentrated solution was stirred until the temperature of the solution reached room temperature and ; allowed to stand for a few hours at ambient temperatures.
The crystalline precipitate which formed upon standing was recovered by filtration, washed with hexane and dried. The foregoing recrystallization procedure was repeated, and 7.95 grams of 2-((3,5-di-tert-butyl-4-hydroxyphenyl)sul~onyl)-hexanoic acid was recovered as a crystalline solid having a melting point of 153-154C. Analysis - calculated for C20H32S05 (molecular weight 384.5) (percent): C, 62.47;
H, 8.39; Sl 8.34. Found (percent): C, 62.5; ~, 8.14;
S, 8.5.
~n accordance with the procedure of Example 4 and the teachings of the specification, the following sulfonyl -derivatives can be prepared by employing the corresponding '~
2-((3,5-di-tert-butyl-4-hydroxyphenyl)thio)alkanoic acid or esters described hereinabove with respect to Examples 1-3:
2-((3,5-di-tert-but~1-4-hydroxyphenyl)sulonyl)- ~-propionic acid;
2-((3,5-di-tert-butyl-4-hydroxyphenyl)sulfonyl)-butyric acid;
. .
. . .
: ~ ' ' ' ' ~I V37~t;4 2-((3~5-di-tert-butyl-4-hydroxyphenyl)sulfonyl)-heptanoic acid;
2-((3,5-di-tert-buty].-4-hydroxyphenyl)sulfonyl)- .
2-methylbutyric acid; . .
2-((3,5-di-tert-butyl-4-hydroxyphenyl)sulfonyl)--2-methyloctanoic acid;
. sodium 2-((3,5-di-tert-butyl-4-hydroxyphenyl)-: sulfonyl)hexanoate;
2-((3,5-di-tert-butyl-4-hydroxyphenyl)sulfonyl)- :
2-methylpentanoic acid;
2-((3,5-di-tert-butyl-4-hydroxyphenyl)sulfonyl)- ~' -2-methyloctanoic acid;
potassium 2-((3,5-di-tert-butyl-4-hydroxyphenyl)-sulfonyl)propionate;
calcium 2-((3,5-di-tert-butyl-4-hydroxyphenyl)-sulfonyl)heptanoate;
ethyl 2-((3,5-di-tert-butyl-4-hydroxyphenyl)-sulfonyl)valerate;
ethyl 2-((3,5-di-tert-butyl-4-hydroxyphenyl)-sulfonyl)-2~methylpropionate~
propyl 2-((3/5-di-tert-butyl-4-hydroxyphenyl)- ~:
sulfonyl)-3-methyloctanoate:
.~ methyl 2-((3J5-di-tert~butyl-4-hydroxyphenyl)-sulfonyl)-2-methylpropionate;
propyl 2-((3,5-di-tert-butyl-4-hydroxyphenyl)~
sulfonyl)-2-methylvalerate;
methyl 2-((3,5-di-tert-butyl-4-hydroxyphenyl)-. sulfonyl)propionate; and propyl 2-((3,5-di-tert-butyl-4-hydroxyphenyl)- -sulfonyl)octanoate. ' '2 .' 79~
The extract was dried and evaporated to obtain a light brown - 20 oil representing the desired ethyl 2-((3,5-di-tert-butyl-4-hydroxyphenyl)thio)hexanoate having a boiling point o 190C.
at 5 mm. of Hg at about 95% purity.
The ethyl 2-((3,5-di-tert-butyl-4-hydroxyphenyl~
thio)hexanoate (75 grams; 0.195 mole) obtained in Example 2 was dispersed in 300 ml. of 95% ethanol and 500 ml. of 5N ;`~
potassium hydroxide added thereto. The resulting reaction ;-mixture was heated on a steam bath at the boiling point under gentle reflux for about 90 minutes with occassional -~
stirring. Following the heating period, the reaction ~ .
, :''' ' ~ ' ' . , , ~3796~ ~
mixture was poured in-to 2000 ml. o~ 5O/o HCl with vigorous stirring. The white precipitate which formed upon acidi-fication was obtained by filtration and washed with water.
Recrystallization (twice) of the precipitate from a methylene chloride-hexane mixture gave 2~-((3,5-di-tert-butyl-4-hydroxy-phenyl)thio)hexanoic acid having a melting point o~
140-142C.
In accordance with the procedure of Example 1~
the following compounds can be prepared by employing the corresponding haloalkanoic acid reactants and, in the instances of saltsJ the corresponding bases:
2-((3,5-di-tert-butyl-4-hydroxyphenyl)thio)-propionic acid (melting at 111-112C.);
2-((3,5-di-tert-butyl-4-hydro~yphenyl)thio)-butyric acid (melting at 109-111C.);
2-((3,5-di-tert-butyl-4-hydroxyphenyl)thio)-heptanoic acid (melting at 85-87C.);
2-((3,5-di-tert-butyl-4-hydroxyphenyl)thio)-2-methyl-butyric acid (melting at 152-153C.);
2-((3,5-di-tert-butyl 4-hydroxypher.yl)thio)-2-methyl-octanoic acid (melting at 103-105C.);
sodium 2-((3,5-di-tert-butyl-4-hydroxyphenyl)-thio)hexanoate (melting at 274-282C.);
2-~(3,5-di-tert-butyl-4-hydroxyphenyl)thio)-2-methyl-pentanoic acid;
2-~(3,5-di-tert-butyl-4-hydroxyphenyl)thio)-2- --` methyl-octanoic acid;
potassium 2-((3,5-di-tert-butyl-4-hydroxyphenyl)-thio)propionate; and calcium 2-((3,5-di-tert-butyl-4-hydroxyphenyl)-thio)heptanoate~
;
- . . . . .
-' ': . ' -. . '' ~
~ ~337g64 ~`
.
The above compounds can also be prepared accord~
ing to Example 3 above if desired.
The following compounds are obtained in accordance with the procedure o~ Example 2 by employing the correspond-ing haloalkanoate:
ethyl 2-((3,5-di-tert-butyl-4-hydroxyphenyl)thio)-valerate (melting at 65-66C.);
ethyl 2-((3,5-di-tert-butyl-4-hydroxyphenyl)thio)-2-methyl-propionate;
propyl 2-((3,5-di-tert-butyl-4-hydroxyphenyl)thio)-2-methyl-octanoate; ,.,~ .' methyl 2-((3,5-di-tert-butyl-4-hydroxyphenyl)thio)-2-methyl-propionate; ~ ;
propyl 2-((3,5-di-tert-butyl-4-hydroxyphenyl)thio)- ~ ~
2-methyl-valerate; `` ?
methyl 2-((3,5-di-tert-butyl-4-hydroxyphenyl)thio)-: . ~
propionate; and propyl 2-((3,5-di-tert-butyl-4-hydroxyphenyl)thio)-octanoate. `
2-((3,5-Di-tert-butyl-4-hydroxyphenyl)thio)~
hexanoic acid (10.0 grams), prepared as in Example l, was dissolved in 150 ml. of glacial acetic acid by warming the solution to about 40 C o and then cooled to about 25C.
Sixteen ml. of 30% hydrogen peroxide was slowly addedJ with stirring, thereto. Following the completion of the hydrogen - peroxide addition, the reaction mixture was warmed to about 41C. to dissolve a white precipitate which had formed near the level of the hydrogen~peroxide addition. The reaction mixture remained clear upon subsequent cooling to about 25C.
.~ '. . ''" ' ~
, '.' ''' 16490/17093-F -13- ~-,. ~ ;~ , .
. ~ .
~LU379~4 The reaction mixture was then stirred at ambient temper-atures for about 16 hours and ~hereafter poured into about 2500 ml. of ice water and the resulting aqueous mixture stirred. A white oily precipitate, which formed in the aqueous mixture and which congealed upon stirring, was recovered by filtration~ washed with water and air-dried.
The product thus obtained was mixed with 100 ml. of methylene chloride and about 350 ml. of hexane, and the resulting cloudy solution was concentrated to a volume of about 400 ml. The concentrated solution was stirred until the temperature of the solution reached room temperature and ; allowed to stand for a few hours at ambient temperatures.
The crystalline precipitate which formed upon standing was recovered by filtration, washed with hexane and dried. The foregoing recrystallization procedure was repeated, and 7.95 grams of 2-((3,5-di-tert-butyl-4-hydroxyphenyl)sul~onyl)-hexanoic acid was recovered as a crystalline solid having a melting point of 153-154C. Analysis - calculated for C20H32S05 (molecular weight 384.5) (percent): C, 62.47;
H, 8.39; Sl 8.34. Found (percent): C, 62.5; ~, 8.14;
S, 8.5.
~n accordance with the procedure of Example 4 and the teachings of the specification, the following sulfonyl -derivatives can be prepared by employing the corresponding '~
2-((3,5-di-tert-butyl-4-hydroxyphenyl)thio)alkanoic acid or esters described hereinabove with respect to Examples 1-3:
2-((3,5-di-tert-but~1-4-hydroxyphenyl)sulonyl)- ~-propionic acid;
2-((3,5-di-tert-butyl-4-hydroxyphenyl)sulfonyl)-butyric acid;
. .
. . .
: ~ ' ' ' ' ~I V37~t;4 2-((3~5-di-tert-butyl-4-hydroxyphenyl)sulfonyl)-heptanoic acid;
2-((3,5-di-tert-buty].-4-hydroxyphenyl)sulfonyl)- .
2-methylbutyric acid; . .
2-((3,5-di-tert-butyl-4-hydroxyphenyl)sulfonyl)--2-methyloctanoic acid;
. sodium 2-((3,5-di-tert-butyl-4-hydroxyphenyl)-: sulfonyl)hexanoate;
2-((3,5-di-tert-butyl-4-hydroxyphenyl)sulfonyl)- :
2-methylpentanoic acid;
2-((3,5-di-tert-butyl-4-hydroxyphenyl)sulfonyl)- ~' -2-methyloctanoic acid;
potassium 2-((3,5-di-tert-butyl-4-hydroxyphenyl)-sulfonyl)propionate;
calcium 2-((3,5-di-tert-butyl-4-hydroxyphenyl)-sulfonyl)heptanoate;
ethyl 2-((3,5-di-tert-butyl-4-hydroxyphenyl)-sulfonyl)valerate;
ethyl 2-((3,5-di-tert-butyl-4-hydroxyphenyl)-sulfonyl)-2~methylpropionate~
propyl 2-((3/5-di-tert-butyl-4-hydroxyphenyl)- ~:
sulfonyl)-3-methyloctanoate:
.~ methyl 2-((3J5-di-tert~butyl-4-hydroxyphenyl)-sulfonyl)-2-methylpropionate;
propyl 2-((3,5-di-tert-butyl-4-hydroxyphenyl)~
sulfonyl)-2-methylvalerate;
methyl 2-((3,5-di-tert-butyl-4-hydroxyphenyl)-. sulfonyl)propionate; and propyl 2-((3,5-di-tert-butyl-4-hydroxyphenyl)- -sulfonyl)octanoate. ' '2 .' 79~
3,5-Di-t-butylthiophenol (22.2 grams; 0.1 mole) was added to a stirred solution o~ sodium hydroxide (4.0 grams; 0.1 mole) in 125 ml. of 95% ethanol. To this mixture, ethyl 2-bromoisobutyrate (19.5 grams; 0.1 mole) was added and the resulting reaction mixt:ure was stirred at ambient temperatures for a period of about 24 hours. The reaction mixture was subsequently pourecL into an aqueous 5% HCl solution with stirring. The oily layer which formed upon acidification was separated from the reaction mixture and extracted with ethyl acetate, washed with water and dried -~
over sodium sulfate. The extract was evaporated to obtain a light yellow oil representing the desired ethyl 2-((3,5- `~
bis(l,l-dimethylethyl)phenyl)thio)-2-methyl-propionate.
- 15 Analysis calculated for C20H3202S: C, 71.38; H, 9.58;
S, 9.53. Found: C, 70.55; H, 9.63; S, 9.01.
20 Grams of the product thus obtained was mixed with 100 ml. of a 5N potassium hydroxide solution and 100 ml. -~
of ethanol and the resulting reaction mixture was allowed to boil on a steam bath for a period of about 2 hours. The reaction mixtuxe was then poured into a 10% HCl - ice water mixture and the resulting precipitate collected by fil- -`~
tration. The precipitate thus obtained was extracted with methylene chloride and the extract washed with a brine solution. The aqueous phase was also extracted with methylene -chloride. The extracts were combined and washed twice with portions of water and dried over anhydrous sodium sulfate.
The solvent was reduced by evaporation and the resulting crystalline precipitate recovered and recrystallized from a benzane-petroleum ether mixture. The desired 2-((3~5-bis-~.
:~ .
,: :
. .... . . . . .
-. . ~ , ~ . , , . . .
~379~"~
(l,l-dimethylethyl)phenyl)thio)-2-methyl propanoic acid w s recovered as a crystalline solid having a melting point of 115-116C. Analysis calculated for C1~H28O2S: C, 70.08;
H, 9.15; S, 10.39. Found: C, 70.47; H~ 9.17; SJ 10.29.
In accordance with the procedure of Example 5 above, the following alkanoic acid compounds can be prepared by employing the corresponding haloalkanoate reactants and, in the instances of salts, further reaction with the corresponding bases:
ethyl 2-((3,5-bis(l,l-dimethylethyl)phenyl)-thio)butyrate;
ethyl 2-((3,5-bis(l,l-dimethylethyl)phenyl)thio)-hexanoate; ~-. , .
ethyl 2-(~3,5-bis(l,l-dimethylethyl)phenyl)-thio)heptanoate; -~
propyl 2-((3,5-bis(l,l-dimethylethyl)phenyl)thio)- ` ~;
octanoate; ;~
methyl 2-((3,5-bis(l,l-d-imethylethyl)phenyl)thio)~
propionate~
ethy~ 2-((3,5-bis(l,l-dLmethylethyl)phenyl)thio)-2-methyl-pentanoate; ~:
methyl 2-((3,5-bis(l,l-dimethylethyl)phenyl)thio)- ;
-2 methyl-propionate;
propyl 2-((3,5-bis(l,l-dimethylethyl)phenyl)thio)--2-methyl-butyrate; ~ ;
ethyl 2-((3,5-bis(l,l-dimethylethyl)phenyl~thio)~
-2-methyl-octanoate;
~,.... ~
propyl 2-(~3,5-bls(l,l-dimethylethyl)phe~yl)thio)- --2-methyl-hexanoate; ,`
., .
2-((3,5-bis(191-dimethylethyl)phenyl)thio)hexanoic acid (melting at 90-91C~);
' .. . : : .. :. :......... . . : - : . . : ..
.. : -: : - .. . . , . . . .: :
~37 ~ ~ ~
2-((3,5-bis(l,l-dLmethylethyl)phenyl)thio) 2-methyl-pentanoic acid (melting at 116-118C.);
2-((3,5-bis(l,l-dimethylethyl)phenyl)thio)-2-methyl-heptanoic acid (melting at 97-99Co ); ;~
2-((3,5-bis(1~1-dimethylethyl)phenyl)thio)-2-methyl-hexanoic acid (melting at 101-103C.):
2-((3,5-bis(l,1-dimethylethyl)phenyl)thio)-propanoic acid;
2-((3,5-bis(l,l-dimethylethyl)phenyl)thio)-octanoic acid;
ethyl 2-((3,5-bis(l,l-dimethylethyl)phenyl)thio)--2-methyl-octanoate;
2-((3,5-bis(l,l-dimethyle~hyl)phenyl)thio)-2-- methyl-octanoic acid (melting at 79-81C.);
2-((3,5-bis(l,l-dimethylethyl)phenyl)thio)-butyric acid;
2-((3,5-bis(l,l-dimethylethyl)phenyl)thio)-heptanoic acid;
sodium 2-((3,5-bis(l,l-dimethylethyl)phenyl)thio)--2-methyl-propionate; ~;
potassium 2-((3,5-bis(l,l-dimethylethyl)phenyl)- -thio)-2-methyl-octanoate; and calsium 2-((3,5-bistl,l-dimethylethyl)phenyl~thio)- ;;~`
2-methyl-heptanoate.
The hypolipidemic effect of the compounds of the invention is illustratively demonstrated in rats. In such procedures, the active test co~pound is dissolved in acetone, ta~en up on silica gel~ and triturated with various aliquots o~ powdered feed until the desired concentration is reached.
The feed mixture is ther thoroughly mixed and fed to test ~, ~
~ . . . . .~
~37~4 groups of rats for a period of 14 days. Control groups of rats are similarly fed with untreated feed. Following the 14 day feeding period, the rats are sacrificea and the relative levels of serum chole3terol in blood samples determined by the Henly method (A. A. Henly, Analyst 82, 286 (1957)). The relative levels of triglyceride levels in blood samples are determined by the Van Handel and Zilversmit method (J. Lab. Clin. Med.; 50: 152 ~1957)) and Clin. Chem., 7, 249 (1961)). Taking the average levels of the control mammals as standard, the mean results obtained ` l`
in the treat~d groups is thereby ascertained.
The data presented in the following Table I
indicate the mean decrease in serum cholesterol and serum triglyceride levels, as compared with the average levels of control mammals, obtained by separately feeding groups of rats medicated feeds containing 0.25% by weight of each o~
the indicated compounds for a period of about 14 days~
, `, .:- .
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~ rl h ~ O Q) ~1 U
.- O ~ rl O ~ ~ ~
tq u ~ rl 0 h ~ Ql ~ ~ ~) C) tJ) Q ~ rl U 111 Ql R a~ U
U ~ I I ~ O G) ~ E~ O
~rl o U 1~ U ~1 ~ U U U :`' ~d O 1 0 s~ J U U U
_I ~ a) a) a) a) o o o .c ,~01 OQ~ g ~ O
~:1 0 O O O ô ô ô O O ~ ~ 'U ~~
H E4 ~ ~ U
~-1 ~ ~ _ ~ ~ ~ ~ ~ Ql ~ Q~
'. ~ ~ ~ 0~ 0~ 0~
u~ Id QI ~QI ~QI ~
a) o~ 0~ ~
O O O O O O O ~;P d~ ~ O ~
S~ ~ 1~ 5 J S~ l h I I I h ~ ~) ~ ~J
~ ~ 7 ~
, . . . .
. h ~) ~
: , - ' ' ,:
. . ..
- . -.: ., , - . .: ` . ::,., . - ,:, : ` .
~L0379~ ;
The data presented in Table I clearly establish the effectiveness and usefulne~s of such compounds in treating hyperlipidemia in the blood of a mammal. Such data ~;
also show the pronounced hypotriglyceridemic effect of such compounds and the usefulness thereof in instances where predominantly high triglyceride levels exist. ;
In other comparative operations, various oxygen analogs of the 2-((3~5-di-tert--butyl-4-hydroxyphenyl)thio)~
aIkanoic acids and esters were prepared and similarly tested for hypolipidemic activity In such operations, feedstuffs ~ -containing the selected analogs at a concentration of 0.125% ~;
were fed to groups (6 rats per group) of rats for a period -of about 14 days and the cholesterol and triglyceride levels then determined as set forth hereinabove. The data obtained - 15 from such tests revealed that 2-(3,5-di-tert-butyl-4-hydroxy-phenoxy)propionic acid was toxic at such concentration to all 6 rats in such test group while the 2-((3~5-di-tert-butyl-4-hydroxyphenoxy)butyric acid test compound was toxic `~
to 2 of the 6 rats and produced a positive increase in the mean cholestexol and triglyceride levels (+7 and +36 percent, ~ ;~
respectively) of the surviving members of the test group.
2-(3,5-Di-tert-butyl-4-hydroxyphenoxy)hexanoic acid was `~
found to reduce the mean cholesterol and triglyceride levels by 7 and 36 percent, respectively. In comparative trials ~-with the claLmed 2-((3,5-di-tert-butyl-4-hydroxyphenyl)- `-thio)hexanoic acid at feed concentrations of 0.125% and 0.03%, respectively, reductions in the mean serum cholesterol and triglyceride levels of 33 and 67 percent, respectively, were obtained at the 0.125% concentration while reductions - 30 of 21 and 35 percent, respectively, were obtained with the '.' 16490/17093 F -21~
~7~
0.03% concentration. The sodium salt derivative of such - compound similarly gave reductions of 27 and 72 percent, respectively, at the 0.125% feed concentration.
Such data clearly indicate the superior safeness and hypolipidemic activity of ~he claimed compounds.
In additional operat:ions, test groups of male rats were administered a feed mixture containing 2-((3,5-di-tert-butyl-4-hydroxyphenyl)thio)hexanoic acid test com-pound at a concentration of 0.25% by weight. Certain of the rats were sacrificed 1, 2J 4, 7 and 14 days after initiation of the treatment and the serum triglyceride levels of the treated animals as compared with the control animals deter-mined as previously set forth. Reductions in serum tri-glyceride levels of about 38%, 54%, 65%, 70% and 77%, respectivelyJ were obtained at the respective 1, 2, 4, 7 -~
and 14 day intervals. Additional operations with the test compound indicate significant lowering of serum triglyceride levels were obtained at concentrations as low as 0.015 percent by weight of the compound in animal feeds.
Daily administration per os to male rats of the 2-((3,5-di-tert-butyl-4-hydroxyphenyl)thio)hexanoic acid test compound formulated in polyglycol 200 at dosage levels -of 25J 50 and 100 mg/kg, respectively, over a 14 day period ; `
gave reductions in mean serum triglyceride levels of about : 25 42%J 57% and 70%, respectively. ` -~
. .
In other representative operations, separate groups of male rats were given daily oral doses of 200 and 'J'' 400 mg/kg, respectively, of the 2-((3,5-di-tert-butyl-4-hydroxyphenyl)thio)hexanoic acid in a methyl cellulose or polyglycol carrier for a period of 14 days. Reductions in , , '`' ~, . . ~
16490~17093-F -22- ~
;:. - . : ^::
~)379~i~
mean serum cholesterol and triglyceride levels of 30 and 62 percent, respectively, were obtained at the dosage rate of 200 mg/kg~ while reductions of 38 and 69 percent, respectively, were obtained at the 400 mg/kg dosage rate.
In further operations, feedstuffs containing 0.25% ~`
2-((3~5-di-tert-butyl-4-hydroxyphenyl)thio)hexanoic acid 5% `
cholesterol and 1% cholic acid were administered to groups of -male rats for a period of 14 days to induce hyperlipidemic. `~
A comparison with control groups of rats indicate reductions - 10 in the mean serum cholesterol and triglyceride levels of 38 and 78 percent, respectively. Other test groups of male rats were maintained on a synthetic atherogenic diet containing ~ ;
the following~
High Protein Casein 20%
Sucrose 41.993%
Peanut Oil 20.0%
Cellulose (Fiber) 7.0%
.
Salt Mix, Wesson 4.0% ~
~ Cholesterol 5.0/O - -Vitamin Mix 1.0%
Cholic Acid 1.0%
Zinc Carbonate 0.06% `~
and 0.25% of the test compound for a period of 14 days. In ¢~
these operations, reductions of the mean serum cholesterol ; ~-~
and triglyceride levels of 68 and 30 percent, respectively, ~ ~ -, were obtained.
~ - :
In other studies involving induced hyperlLpemia conditions by diet control, groups of rabbits were maintained .. .~ ~ .
on a diet containing 0.5% 2-~(3~5-di-tert-butyl-4-hydroxy~
. ~ ,,:
pheny~)thio)hexanoic acid, 2% cholesterol and 6% corn oil for a period of eight weeks. During the eight week period, .: ':: ' ~ .
.-:-. : - - . . ;
: ::: :: - - - .
~37~
separate control groups of rabbits were maintained on a normal diet and on the cholesterol-corn oil diet only. '~
- During such 8 week period, a 2-5 fold elevation of serum ;~
triglyceride levels and a dramatic elevation of serum cholesterol levels from less than 100 mg/100 ml serum ~or ;-- the rabbits on a normal diet to a range of from 3000 to more than 7000 mg/100 ml serum for the control rabbits fed the cholesterol and corn oil diet were ob~erved. Measurement of the serum cholesterol and triglyceride levels of the test ~
groups maintained on the special diet including the test -compound indicated mean reductions in such levels of 80 and 34 percent respectively, after two weeks; 81 and 61 percent respectivelyJ after four weeks; 94 and 48 percent respect- ` ;
ively, after six weeks; and 95 and 68 percent respectivelyJ ~
after eight weeks. ~ ;
The following examples illustrate the preparation ~`
of pharmaceutical compositions o the present invention. ~ `
EXAMP~E 6 `~`
one thousand capsules for oral administration, ;~each containing 100 mg. of 2-((3,5-di-tert-butyl-4-hydroxy~
phenyl)thio)hexanoic acid, can be prepared from the following ingredients:
Grams 2-((3,5-di-tert-butyl-4-hydroxyphenyl)- 100 -~
thio)hexanoic acid Lactose, U.S.P. 100 Starch, U.S.P. 30 ~ `
Talc, U.S.P. ~.5 Calcium Stearate 2.5 :.
16490/170~3-F -24-7~
The active ingredient is powdered and mixed with the starch-lactose mixture followed by the talc and calcium stearate. The final mixture is then encapsulated in the usual manner employing hard gelatin capsules of appropriate size.
EXAMæLE 7 Two thousand tablets for oral use, each containing ;
1~000 mg. of active ingredient are prepared from the follow- ~ ~
ing ingredients: ~ ;
Grams `;~
2-((3,5-di-tert-butyl-4-hydroxyphenyl)-thio)propionic acid 2000 Starch, U.S.P. 140 - Talc, U.S.P. 100 Calcium Stearate 14 ;
The active ingredient is powdered and granulated with a 4% w/v aqueous solution of methylcellulose U.S.P.
(1500 cps.). To the dried granules is added a mixture of ;
the remainder of the ingredients and the final m~xture slugged. The slugs are broken down by forcing through a ~ -. ~
screen and the resulting granules then compressed into tablets of proper weight. ~ ~-An injectable preparation is made from the following ingredients to contain 100 mg. of the 2-((3J5-di~
tert-butyl-4-hydroxyphenyl)thio)hexanoic acid active in-gredient per ml~
~ .,.
1~7atj~
Perc~nt ~
w~v_ Sodium carboxymethylcellulose ~low vi~cosity) 0.5 Tween 80 (polyoxyethylene sorbitan monooleate) 0.4 Sodium chloride 0.9 Benzyl alcohol o.g Active ingredient 10.0 Sterile distilled water, q.s.~ 1000.0 ml.
.:
The previously sterilized active ingredient is homogenized with the already mixed and sterilized vehicle.
.
- The phenol reactants, the haloalkanoic acid and haloaIkanoate reactants are known and are readily available - or can be prepared according to known or analogous procedures.
~- For details, see Organic ReactionsJ vol. III~ chapter 6, by Roger Adams et al; also the article by Muller et al., entitled "Untersuchungen an schwefelhaltigen Aroylen mittels ~-der Electronenresonanz" in Lie~ig's Annalen (1961, Bd. 645, `~
p. 79), and U.S. Patent No. 3,129,262; also Newman, et al., ~. Org. Chem.~ 31, 3980 (1966).
' ' ~:................................ ' ' " ~;
- ~
~`., , '':
.:
.~ ,
over sodium sulfate. The extract was evaporated to obtain a light yellow oil representing the desired ethyl 2-((3,5- `~
bis(l,l-dimethylethyl)phenyl)thio)-2-methyl-propionate.
- 15 Analysis calculated for C20H3202S: C, 71.38; H, 9.58;
S, 9.53. Found: C, 70.55; H, 9.63; S, 9.01.
20 Grams of the product thus obtained was mixed with 100 ml. of a 5N potassium hydroxide solution and 100 ml. -~
of ethanol and the resulting reaction mixture was allowed to boil on a steam bath for a period of about 2 hours. The reaction mixtuxe was then poured into a 10% HCl - ice water mixture and the resulting precipitate collected by fil- -`~
tration. The precipitate thus obtained was extracted with methylene chloride and the extract washed with a brine solution. The aqueous phase was also extracted with methylene -chloride. The extracts were combined and washed twice with portions of water and dried over anhydrous sodium sulfate.
The solvent was reduced by evaporation and the resulting crystalline precipitate recovered and recrystallized from a benzane-petroleum ether mixture. The desired 2-((3~5-bis-~.
:~ .
,: :
. .... . . . . .
-. . ~ , ~ . , , . . .
~379~"~
(l,l-dimethylethyl)phenyl)thio)-2-methyl propanoic acid w s recovered as a crystalline solid having a melting point of 115-116C. Analysis calculated for C1~H28O2S: C, 70.08;
H, 9.15; S, 10.39. Found: C, 70.47; H~ 9.17; SJ 10.29.
In accordance with the procedure of Example 5 above, the following alkanoic acid compounds can be prepared by employing the corresponding haloalkanoate reactants and, in the instances of salts, further reaction with the corresponding bases:
ethyl 2-((3,5-bis(l,l-dimethylethyl)phenyl)-thio)butyrate;
ethyl 2-((3,5-bis(l,l-dimethylethyl)phenyl)thio)-hexanoate; ~-. , .
ethyl 2-(~3,5-bis(l,l-dimethylethyl)phenyl)-thio)heptanoate; -~
propyl 2-((3,5-bis(l,l-dimethylethyl)phenyl)thio)- ` ~;
octanoate; ;~
methyl 2-((3,5-bis(l,l-d-imethylethyl)phenyl)thio)~
propionate~
ethy~ 2-((3,5-bis(l,l-dLmethylethyl)phenyl)thio)-2-methyl-pentanoate; ~:
methyl 2-((3,5-bis(l,l-dimethylethyl)phenyl)thio)- ;
-2 methyl-propionate;
propyl 2-((3,5-bis(l,l-dimethylethyl)phenyl)thio)--2-methyl-butyrate; ~ ;
ethyl 2-((3,5-bis(l,l-dimethylethyl)phenyl~thio)~
-2-methyl-octanoate;
~,.... ~
propyl 2-(~3,5-bls(l,l-dimethylethyl)phe~yl)thio)- --2-methyl-hexanoate; ,`
., .
2-((3,5-bis(191-dimethylethyl)phenyl)thio)hexanoic acid (melting at 90-91C~);
' .. . : : .. :. :......... . . : - : . . : ..
.. : -: : - .. . . , . . . .: :
~37 ~ ~ ~
2-((3,5-bis(l,l-dLmethylethyl)phenyl)thio) 2-methyl-pentanoic acid (melting at 116-118C.);
2-((3,5-bis(l,l-dimethylethyl)phenyl)thio)-2-methyl-heptanoic acid (melting at 97-99Co ); ;~
2-((3,5-bis(1~1-dimethylethyl)phenyl)thio)-2-methyl-hexanoic acid (melting at 101-103C.):
2-((3,5-bis(l,1-dimethylethyl)phenyl)thio)-propanoic acid;
2-((3,5-bis(l,l-dimethylethyl)phenyl)thio)-octanoic acid;
ethyl 2-((3,5-bis(l,l-dimethylethyl)phenyl)thio)--2-methyl-octanoate;
2-((3,5-bis(l,l-dimethyle~hyl)phenyl)thio)-2-- methyl-octanoic acid (melting at 79-81C.);
2-((3,5-bis(l,l-dimethylethyl)phenyl)thio)-butyric acid;
2-((3,5-bis(l,l-dimethylethyl)phenyl)thio)-heptanoic acid;
sodium 2-((3,5-bis(l,l-dimethylethyl)phenyl)thio)--2-methyl-propionate; ~;
potassium 2-((3,5-bis(l,l-dimethylethyl)phenyl)- -thio)-2-methyl-octanoate; and calsium 2-((3,5-bistl,l-dimethylethyl)phenyl~thio)- ;;~`
2-methyl-heptanoate.
The hypolipidemic effect of the compounds of the invention is illustratively demonstrated in rats. In such procedures, the active test co~pound is dissolved in acetone, ta~en up on silica gel~ and triturated with various aliquots o~ powdered feed until the desired concentration is reached.
The feed mixture is ther thoroughly mixed and fed to test ~, ~
~ . . . . .~
~37~4 groups of rats for a period of 14 days. Control groups of rats are similarly fed with untreated feed. Following the 14 day feeding period, the rats are sacrificea and the relative levels of serum chole3terol in blood samples determined by the Henly method (A. A. Henly, Analyst 82, 286 (1957)). The relative levels of triglyceride levels in blood samples are determined by the Van Handel and Zilversmit method (J. Lab. Clin. Med.; 50: 152 ~1957)) and Clin. Chem., 7, 249 (1961)). Taking the average levels of the control mammals as standard, the mean results obtained ` l`
in the treat~d groups is thereby ascertained.
The data presented in the following Table I
indicate the mean decrease in serum cholesterol and serum triglyceride levels, as compared with the average levels of control mammals, obtained by separately feeding groups of rats medicated feeds containing 0.25% by weight of each o~
the indicated compounds for a period of about 14 days~
, `, .:- .
'`',.. ;~', ~:
"
": ~ ~ -~ 16490~17093-F -19--- . . ~ - , ~ .
~ u~ 1~)37~
Q 'a d~
U O ~D O ~`1 U~ O ~I d' d' cn O u~ O u~
' ~ :1 .~ ' ~ ~ ~ .
.` ~ U ~
~ ~ ~q ~ ~ ~ ~ ~ ~ ~ I` C~ ~ ~ OD -I ~`3 OD C~
H ~ ~1 ~ ~) t`l ~ ~`1 ~ --I ~ t'`l ~`1 --I ~`1 f~
U O
. ~ U ~ O
~U U l~ U ~rJ ,-:
rl U O "
,,UI ~o ,C~
~ rl h ~ O Q) ~1 U
.- O ~ rl O ~ ~ ~
tq u ~ rl 0 h ~ Ql ~ ~ ~) C) tJ) Q ~ rl U 111 Ql R a~ U
U ~ I I ~ O G) ~ E~ O
~rl o U 1~ U ~1 ~ U U U :`' ~d O 1 0 s~ J U U U
_I ~ a) a) a) a) o o o .c ,~01 OQ~ g ~ O
~:1 0 O O O ô ô ô O O ~ ~ 'U ~~
H E4 ~ ~ U
~-1 ~ ~ _ ~ ~ ~ ~ ~ Ql ~ Q~
'. ~ ~ ~ 0~ 0~ 0~
u~ Id QI ~QI ~QI ~
a) o~ 0~ ~
O O O O O O O ~;P d~ ~ O ~
S~ ~ 1~ 5 J S~ l h I I I h ~ ~) ~ ~J
~ ~ 7 ~
, . . . .
. h ~) ~
: , - ' ' ,:
. . ..
- . -.: ., , - . .: ` . ::,., . - ,:, : ` .
~L0379~ ;
The data presented in Table I clearly establish the effectiveness and usefulne~s of such compounds in treating hyperlipidemia in the blood of a mammal. Such data ~;
also show the pronounced hypotriglyceridemic effect of such compounds and the usefulness thereof in instances where predominantly high triglyceride levels exist. ;
In other comparative operations, various oxygen analogs of the 2-((3~5-di-tert--butyl-4-hydroxyphenyl)thio)~
aIkanoic acids and esters were prepared and similarly tested for hypolipidemic activity In such operations, feedstuffs ~ -containing the selected analogs at a concentration of 0.125% ~;
were fed to groups (6 rats per group) of rats for a period -of about 14 days and the cholesterol and triglyceride levels then determined as set forth hereinabove. The data obtained - 15 from such tests revealed that 2-(3,5-di-tert-butyl-4-hydroxy-phenoxy)propionic acid was toxic at such concentration to all 6 rats in such test group while the 2-((3~5-di-tert-butyl-4-hydroxyphenoxy)butyric acid test compound was toxic `~
to 2 of the 6 rats and produced a positive increase in the mean cholestexol and triglyceride levels (+7 and +36 percent, ~ ;~
respectively) of the surviving members of the test group.
2-(3,5-Di-tert-butyl-4-hydroxyphenoxy)hexanoic acid was `~
found to reduce the mean cholesterol and triglyceride levels by 7 and 36 percent, respectively. In comparative trials ~-with the claLmed 2-((3,5-di-tert-butyl-4-hydroxyphenyl)- `-thio)hexanoic acid at feed concentrations of 0.125% and 0.03%, respectively, reductions in the mean serum cholesterol and triglyceride levels of 33 and 67 percent, respectively, were obtained at the 0.125% concentration while reductions - 30 of 21 and 35 percent, respectively, were obtained with the '.' 16490/17093 F -21~
~7~
0.03% concentration. The sodium salt derivative of such - compound similarly gave reductions of 27 and 72 percent, respectively, at the 0.125% feed concentration.
Such data clearly indicate the superior safeness and hypolipidemic activity of ~he claimed compounds.
In additional operat:ions, test groups of male rats were administered a feed mixture containing 2-((3,5-di-tert-butyl-4-hydroxyphenyl)thio)hexanoic acid test com-pound at a concentration of 0.25% by weight. Certain of the rats were sacrificed 1, 2J 4, 7 and 14 days after initiation of the treatment and the serum triglyceride levels of the treated animals as compared with the control animals deter-mined as previously set forth. Reductions in serum tri-glyceride levels of about 38%, 54%, 65%, 70% and 77%, respectivelyJ were obtained at the respective 1, 2, 4, 7 -~
and 14 day intervals. Additional operations with the test compound indicate significant lowering of serum triglyceride levels were obtained at concentrations as low as 0.015 percent by weight of the compound in animal feeds.
Daily administration per os to male rats of the 2-((3,5-di-tert-butyl-4-hydroxyphenyl)thio)hexanoic acid test compound formulated in polyglycol 200 at dosage levels -of 25J 50 and 100 mg/kg, respectively, over a 14 day period ; `
gave reductions in mean serum triglyceride levels of about : 25 42%J 57% and 70%, respectively. ` -~
. .
In other representative operations, separate groups of male rats were given daily oral doses of 200 and 'J'' 400 mg/kg, respectively, of the 2-((3,5-di-tert-butyl-4-hydroxyphenyl)thio)hexanoic acid in a methyl cellulose or polyglycol carrier for a period of 14 days. Reductions in , , '`' ~, . . ~
16490~17093-F -22- ~
;:. - . : ^::
~)379~i~
mean serum cholesterol and triglyceride levels of 30 and 62 percent, respectively, were obtained at the dosage rate of 200 mg/kg~ while reductions of 38 and 69 percent, respectively, were obtained at the 400 mg/kg dosage rate.
In further operations, feedstuffs containing 0.25% ~`
2-((3~5-di-tert-butyl-4-hydroxyphenyl)thio)hexanoic acid 5% `
cholesterol and 1% cholic acid were administered to groups of -male rats for a period of 14 days to induce hyperlipidemic. `~
A comparison with control groups of rats indicate reductions - 10 in the mean serum cholesterol and triglyceride levels of 38 and 78 percent, respectively. Other test groups of male rats were maintained on a synthetic atherogenic diet containing ~ ;
the following~
High Protein Casein 20%
Sucrose 41.993%
Peanut Oil 20.0%
Cellulose (Fiber) 7.0%
.
Salt Mix, Wesson 4.0% ~
~ Cholesterol 5.0/O - -Vitamin Mix 1.0%
Cholic Acid 1.0%
Zinc Carbonate 0.06% `~
and 0.25% of the test compound for a period of 14 days. In ¢~
these operations, reductions of the mean serum cholesterol ; ~-~
and triglyceride levels of 68 and 30 percent, respectively, ~ ~ -, were obtained.
~ - :
In other studies involving induced hyperlLpemia conditions by diet control, groups of rabbits were maintained .. .~ ~ .
on a diet containing 0.5% 2-~(3~5-di-tert-butyl-4-hydroxy~
. ~ ,,:
pheny~)thio)hexanoic acid, 2% cholesterol and 6% corn oil for a period of eight weeks. During the eight week period, .: ':: ' ~ .
.-:-. : - - . . ;
: ::: :: - - - .
~37~
separate control groups of rabbits were maintained on a normal diet and on the cholesterol-corn oil diet only. '~
- During such 8 week period, a 2-5 fold elevation of serum ;~
triglyceride levels and a dramatic elevation of serum cholesterol levels from less than 100 mg/100 ml serum ~or ;-- the rabbits on a normal diet to a range of from 3000 to more than 7000 mg/100 ml serum for the control rabbits fed the cholesterol and corn oil diet were ob~erved. Measurement of the serum cholesterol and triglyceride levels of the test ~
groups maintained on the special diet including the test -compound indicated mean reductions in such levels of 80 and 34 percent respectively, after two weeks; 81 and 61 percent respectivelyJ after four weeks; 94 and 48 percent respect- ` ;
ively, after six weeks; and 95 and 68 percent respectivelyJ ~
after eight weeks. ~ ;
The following examples illustrate the preparation ~`
of pharmaceutical compositions o the present invention. ~ `
EXAMP~E 6 `~`
one thousand capsules for oral administration, ;~each containing 100 mg. of 2-((3,5-di-tert-butyl-4-hydroxy~
phenyl)thio)hexanoic acid, can be prepared from the following ingredients:
Grams 2-((3,5-di-tert-butyl-4-hydroxyphenyl)- 100 -~
thio)hexanoic acid Lactose, U.S.P. 100 Starch, U.S.P. 30 ~ `
Talc, U.S.P. ~.5 Calcium Stearate 2.5 :.
16490/170~3-F -24-7~
The active ingredient is powdered and mixed with the starch-lactose mixture followed by the talc and calcium stearate. The final mixture is then encapsulated in the usual manner employing hard gelatin capsules of appropriate size.
EXAMæLE 7 Two thousand tablets for oral use, each containing ;
1~000 mg. of active ingredient are prepared from the follow- ~ ~
ing ingredients: ~ ;
Grams `;~
2-((3,5-di-tert-butyl-4-hydroxyphenyl)-thio)propionic acid 2000 Starch, U.S.P. 140 - Talc, U.S.P. 100 Calcium Stearate 14 ;
The active ingredient is powdered and granulated with a 4% w/v aqueous solution of methylcellulose U.S.P.
(1500 cps.). To the dried granules is added a mixture of ;
the remainder of the ingredients and the final m~xture slugged. The slugs are broken down by forcing through a ~ -. ~
screen and the resulting granules then compressed into tablets of proper weight. ~ ~-An injectable preparation is made from the following ingredients to contain 100 mg. of the 2-((3J5-di~
tert-butyl-4-hydroxyphenyl)thio)hexanoic acid active in-gredient per ml~
~ .,.
1~7atj~
Perc~nt ~
w~v_ Sodium carboxymethylcellulose ~low vi~cosity) 0.5 Tween 80 (polyoxyethylene sorbitan monooleate) 0.4 Sodium chloride 0.9 Benzyl alcohol o.g Active ingredient 10.0 Sterile distilled water, q.s.~ 1000.0 ml.
.:
The previously sterilized active ingredient is homogenized with the already mixed and sterilized vehicle.
.
- The phenol reactants, the haloalkanoic acid and haloaIkanoate reactants are known and are readily available - or can be prepared according to known or analogous procedures.
~- For details, see Organic ReactionsJ vol. III~ chapter 6, by Roger Adams et al; also the article by Muller et al., entitled "Untersuchungen an schwefelhaltigen Aroylen mittels ~-der Electronenresonanz" in Lie~ig's Annalen (1961, Bd. 645, `~
p. 79), and U.S. Patent No. 3,129,262; also Newman, et al., ~. Org. Chem.~ 31, 3980 (1966).
' ' ~:................................ ' ' " ~;
- ~
~`., , '':
.:
.~ ,
Claims (21)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for producing compounds corresponding to the formula (I) and salts thereof formed with a pharmaceutically acceptable base wherein each R represents a tert-butyl group;
X represents sulfur or SO2;
Z represents hydrogen or hydroxy;
R1 is hydrogen or methyl;
R2 represents an alkyl group containing from 1 to about 6 carbon atoms;
R3 represents hydrogen or an alkyl group containing from 1 to about 3 carbon atoms, which comprises reacting 3,5-di-tert-butylthiophenol or 2,6-di-tert-butyl-4-mercaptophenol with a haloalkanoic acid or haloalkanoate corresponding to the formula wherein R1, R2 and R3 are as defined hereinbefore and Y is halogen to prepare the compounds wherein X is sulfur, and for the preparation of the compounds wherein X is SO2, oxidizing the compounds wherein X is sulfur, and where required reacting the resulting compound with a pharmaceutically acceptable base.
X represents sulfur or SO2;
Z represents hydrogen or hydroxy;
R1 is hydrogen or methyl;
R2 represents an alkyl group containing from 1 to about 6 carbon atoms;
R3 represents hydrogen or an alkyl group containing from 1 to about 3 carbon atoms, which comprises reacting 3,5-di-tert-butylthiophenol or 2,6-di-tert-butyl-4-mercaptophenol with a haloalkanoic acid or haloalkanoate corresponding to the formula wherein R1, R2 and R3 are as defined hereinbefore and Y is halogen to prepare the compounds wherein X is sulfur, and for the preparation of the compounds wherein X is SO2, oxidizing the compounds wherein X is sulfur, and where required reacting the resulting compound with a pharmaceutically acceptable base.
2. A process as defined in claim 1 wherein the reaction of 3,5-di-tert-butylthiophenol or 2,6-di-tert-butyl-4-mercaptophenol with a halo-alkanoic acid or haloalkanoate is carried out in presence of an inert liquid and a base.
3. A process as defined in claim 2 wherein the inert liquid is methanol, ethanol, propanol, or tert-butanol.
4. A process as defined in claim 2 wherein the base is an alkali metal or alkaline earth metal hydroxide or carbonate.
5. A process as defined in claim 2 wherein the base is sodium hydroxide or potassium hydroxide.
6. A process as defined in claim 1 wherein the oxidizing of the compounds wherein X is sulfur is carried out with hydrogen peroxide in presence of a water-miscible solvent.
7. A process as defined in claim 6 wherein the water-miscible solvent is glacial acetic acid, methanol, or ethanol.
8. A process for producing 2-(3,5-di-tert-butyl-4-hydroxyphenylthio) hexanoic acid which comprises reacting 2,6-di-tert-butyl-4-mercaptophenol with 2-bromohexanoic acid in presence of an alkali metal hydroxide and an inert liquid reaction medium.
9. A process according to claim 1 wherein ethyl 2-((3,5-di-tert butyl-4-hydroxyphenyl)thio)hexanoate is prepared by reacting 2,6-Di-t-butyl-4-mercaptophenol with ethyl 2-bromohexanoate.
10. Ethyl 2-((3,5-di-tert-butyl-4-hydroxyphenyl)thio)hexanoate and salts thereof formed with a pharmaceutically acceptable base whenever pre-pared by a process according to claim 9, or by an obvious chemical equivalent thereof.
11. A process according to claim 1 wherein 2-((3,5-di-tert-butyl-4-hydroxyphenyl)thio)-propionic acid is prepared by reacting 2,6-di-t-butyl-4-mercaptophenol with 2-bromopropionic acid.
12. 2-((3,5-di-tert-butyl-4-hydroxyphenyl)thio)-propionic acid and salts thereof formed with a pharmaceutically acceptable base whenever prepared by a process according to claim 11 or by an obvious chemical equivalent thereof.
13. A process according to claim 1, wherein 2-((3,5-di-tert-butyl-4-hydroxyphenyl)thio)-butyric acid is prepared by reacting 2,6-di-t-butyl-4-mercaptophenol with 2-bromobutyric acid.
14. 2-((3,5-di-tert-butyl-4-hydroxyphenyl)thio)-butyric acid and salts thereof formed with a pharmaceutically acceptable base whenever prepared by a process according to claim 13, or by an obvious chemical equivalent thereof.
15. A process according to claim 1 wherein 2-((3,5-di-tert-butyl-4-hydroxyphenyl)thio)-heptanoic acid is prepared by reacting 2,6-di-t-butyl-4-mercaptophenol with 2-bromoheptanoic acid.
16. 2-((3,5-di-tert-butyl-4-hydroxyphenyl)thio)-heptanoic acid and salts thereof formed with a pharmaceutically acceptable base whenever pre-pared by a process according to claim 15, or by an obvious chemical equivalent thereof.
17. A process according to claim 1, wherein 2-((3,5-di-tert-butyl-4-hydroxyphenyl)thio)-2-methyl-butyric acid is prepared by reacting 2,6-di-t-butyl-4-mercaptophenol with 2-bromo-2-methyl-butyric acid.
18. 2-((3,5-di-tert-butyl-4-Hydroxyphenyl)thio)-2-methyl-butyric acid and salts thereof formed with a pharmaceutically acceptable base, whenever prepared by a process according to claim 17, or by an obvious chemical equivalent thereof.
19. A process according to claim 1 wherein 2-((3,5-di-tert-butyl-4-hydroxyphenyl)thio)-2-methyl-octanoic acid is prepared by reacting 2,6 di-t-butyl-4-mercaptophenol with 2 bromo-2-methyloctanoic acid.
20. 2-((3,5-di-tert-butyl-4-hydroxyphenyl)thio)-2-methyl-octanoic acid and salts thereof formed with a pharmaceutically acceptable base whenever prepared by a process according to claim 20 or by an obvious chemical equivalent thereof.
21. A compound of formula I, as defined in claim 1, whenever prepared by a process according to claim 1, or by an obvious chemical equivalent thereof.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US33232273A | 1973-02-14 | 1973-02-14 | |
| US33232373A | 1973-02-14 | 1973-02-14 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1037964A true CA1037964A (en) | 1978-09-05 |
Family
ID=26988168
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA191,746A Expired CA1037964A (en) | 1973-02-14 | 1974-02-05 | 2-((3,5-di-tert-buryl-4-hydroxyphenyl)thio)alkanoic acids and derivatives and esters |
Country Status (4)
| Country | Link |
|---|---|
| CA (1) | CA1037964A (en) |
| DE (1) | DE2406812A1 (en) |
| FR (1) | FR2217018A1 (en) |
| HU (1) | HU167915B (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4755524A (en) * | 1986-01-31 | 1988-07-05 | G. D. Searle & Co. | Novel phenolic thioethers as inhibitors of 5-lipoxygenase |
| JP2754039B2 (en) * | 1988-06-24 | 1998-05-20 | 塩野義製薬株式会社 | Di-tert-butylhydroxyphenylthio derivative |
| JP2627003B2 (en) * | 1989-01-25 | 1997-07-02 | 塩野義製薬株式会社 | G-tert-butylhydroxyphenylthio derivative |
| JP2834501B2 (en) * | 1989-11-25 | 1998-12-09 | 鐘淵化学工業株式会社 | Production method and intermediate of 3,4-epoxybutyrate |
-
1974
- 1974-02-05 CA CA191,746A patent/CA1037964A/en not_active Expired
- 1974-02-13 FR FR7404831A patent/FR2217018A1/en active Granted
- 1974-02-13 DE DE19742406812 patent/DE2406812A1/en active Pending
- 1974-02-14 HU HUDO000378 patent/HU167915B/hu unknown
Also Published As
| Publication number | Publication date |
|---|---|
| FR2217018B1 (en) | 1977-01-28 |
| FR2217018A1 (en) | 1974-09-06 |
| HU167915B (en) | 1976-01-28 |
| DE2406812A1 (en) | 1974-08-22 |
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