US3714191A - Dioxathiocin carboxylic acids, esters, salts and amides - Google Patents

Dioxathiocin carboxylic acids, esters, salts and amides Download PDF

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Publication number
US3714191A
US3714191A US00180117A US3714191DA US3714191A US 3714191 A US3714191 A US 3714191A US 00180117 A US00180117 A US 00180117A US 3714191D A US3714191D A US 3714191DA US 3714191 A US3714191 A US 3714191A
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dioxathiocin
compound
carbon atoms
carboxylic acid
lower alkyl
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US00180117A
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R Parker
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Richardson Vicks Inc
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Richardson Merrell Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D327/00—Heterocyclic compounds containing rings having oxygen and sulfur atoms as the only ring hetero atoms
    • C07D327/10—Heterocyclic compounds containing rings having oxygen and sulfur atoms as the only ring hetero atoms two oxygen atoms and one sulfur atom, e.g. cyclic sulfates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Definitions

  • ABSTRACT Novel dioxathiocin carboxylic acids, esters, salts and amides which reduce blood lipids in warm blooded animals, are useful in the treatment of hyperlipidemic states and possess anti-infective properties, are represented by compounds of the following formula:
  • each Y, Y, Z and Z represent hydrogen, halogen such as chlorine, fluorine, bromine or iodine,
  • each set of Y and Y' or each set of Z and Z forms a napthalene ring which may be, unsubstituted or substituted with a substituent selected from a halogen atom such as chlorine, fluorine, bromine or iodine or lower alkyl of from one to four carbon atoms; W represents hydroxy, lower alkoxy of from one to four carbon atoms; or NRR R and R represent hydrogen or lower alkyl of from 1 to 4 carbon atoms and may be the same or different; or R and R taken together with the nitrogen atom to which each is attached form a saturated monocyclic heterocyclic group such as pyrrolidino, piperidino, morpholino, piperazino or N-(lower)-alkyl-piperazino.
  • a halogen atom such as chlorine, fluorine, bromine or iodine or lower alkyl of from one to four carbon atoms
  • W represents hydroxy, lower alkoxy of from one to four
  • This invention relates to novel dibenzo[d,g][ 1,3,61dioxathiocin, dinaphtho[2,l-d:l, 2-g][l,3,6]di oxathiocin, and dinaphtho[ l ,2-d:-2',1 -g][ I,3,6]dioxathiocin carboxylic acids, esters, salts, and amides which reduce blood lipids in warm blooded animals, are useful in the treatment of hyperlipidemic states and possess anti-infective properties.
  • novel compounds of this invention are l5 represented by the following formula,
  • each Y, Y, Z and Z represents hydrogen, halogen such as chlorine, fluorine, bromine or iodine, or lower alkyl of from one to four carbon atoms; or each set of Y and Y or each set of Z and 2' taken together with the aromatic ring to which each is attached forms a naphthalene ring which may be unsubstituted or substituted with a substituent selected from a halogen atom such as chlorine, fluorine, bromine or iodine or lower alkyl of from one to four carbon atoms; W represents hydroxy or lower alkoxy of from one to four carbon atoms or -NRR R and R represent hydrogen or lower alkyl of from one to four carbon atoms and may be the same or different; or R and R taken together with the nitrogen atom to which each is attached form a saturated monocyclic heterocyclic group such as 'pyrrolidino, pipe
  • Formula I compounds of this invention can be dibenzo[d,g][l,3,6]dioxathio cin derivatives as represented by the following Formula Formula II 12 11 Formula 111 I 168 8 H-(l-W 59 mi 14 v 12 R Formula IV
  • each of Z, Z, Y, Y and R represent hydrogen, halogen such as chlorine, fluorine, bromine or iodine, or lower alkyl of from one to four carbon atoms and W has the meaning defined hereinbefore.
  • novel compounds of this invention reduce blood lipids, particularly lipoproteins containing cholesterol and triglycerides in warm-blooded animals and are useful in thetreatment of hyperlipidemic states such as are encountered in patients with cardiovascular diseases, especially atherosclerotic diseases that can result in heart failure and stroke. Also, the compounds of this invention possess anti-infective properties.
  • the compounds of this invention can be used in th form'of pharmaceutical preparations which contain the novel compound suitable for oral or parenteral administration.
  • the quantity of compound in unit dosage form can vary a wide range to provide from about 0.5 mg/kg'to about 4 g/kg of body weight and preferably 1 mg/kg to 1 g/kg of body weight of the subject per day to achieve the desired effect.
  • compounds of this invention when administered subcutaneously havebeen found to be effective in mice against certain types of viruses,'for-example, encephalomyocarditis; bacteria, for example Staphylococcus aureus and Salmonella schottmuelleri; and fungi, for example, Candida albicans.
  • viruses for-example, encephalomyocarditis
  • bacteria for example Staphylococcus aureus and Salmonella schottmuelleri
  • fungi for example, Candida albicans.
  • the compounds of this invention are prepared be reacting one equivalent of a compound of the formula Formula VII or a salt thereof and at least two equivalents of dihaloacetate salt, for example, dichloroacetate salt, in a suitable solvent and in the presence of excess base to give dioxathiocin carboxylate salts of Formula VII];
  • the two or more equivalents of the dihaloacetate salt reactant can all be added at the start of the reaction, it is preferred that one equivalent of the dihaloacetate salt reactant is placed in the reaction mixture initially, and then at a period of from about to 48 hours from the start of the reaction one or more equivalents of the dihaloacetate salt is added to the reaction mixture.
  • the salts of the thio-bisphenol or thio-bis-naphthol reactant and dihaloacetic acid are prepared in situ by addition of base.
  • bases can be used such as, for example, potassium carbonate, sodium methoxide, potassium tert-butoxide, sodium hydroxide or potassium hydroxide.
  • the preferred base is potassium carbonate, however, when substituted thio-bisphenols which have weaker acid values are used, it may be necessary to use a stronger base such as sodium methoxide or potassium tert-butoxide.
  • solvents suitable for use in the reaction there may be mentioned, for example, ethanol, npropanol, isopropanol, n-butanol, tert-butanol, dimethylformamide, dimethylsulfoxide, water and the like.
  • the preferred solvents are n-propanol and isopropanol.
  • reaction mixture is heated to reflux with vigorous stirring for 10 to 120 hours, preferably 98 hours, after which the solvent is distilled off and replaced with water.
  • the mixture is cooled and the product, a compound of Formula VIII, is collected, which may be converted to the acid by suspending it in water and acidifying the mixture with, for example, hydrochloric acid.
  • the precipitate is collected and recrystallized from, for example, toluene or acetic acid to give the dibenzo [d,g][l,3,6]dioxathiocin-6-carboxylic acids, that is, compounds of Formula I] wherein W represents hydroxy, and the dinaphtho[2,l-d:l,2'-g] [1,3,61dioxathiocin-8-carboxylic acids, that is, compounds of Formulas 111 wherein W represents hydroxy, or dinaphtho[ 1 ,2-d:2',l '-g][ l ,3,6]dioxathiocin-8-carboxylic acids, that is, compounds of Formula 1V wherein W is hydroxy.
  • the corresponding lower alkyl esters may be prepared by esterification of the above mentioned acids with lower aliphatic alcohols by generally known esterification procedures.
  • the corresponding dioxathiocin carboxamides may be obtained by the action of ammonia, or an appropriate primary amine such as ethylamine or propylamine, or an appropriate secondary amine such as dimethylamine, diethylamine, piperidine, morpholine, N-methylpiperazine and the like, on the acid halide or the ester of the above mentioned dioxathiocin carboxylic acids.
  • the ester derivative may be obtained by the procedure described hereinbefore, and the acid halide may be obtained by reacting the dioxathiocin carboxylic acid with thionyl halide, for example, thionyl chloride by generally known procedures.
  • the reactant thiobisphenols and thiobisnaphthols that is, compounds of Formula VII are prepared by reacting, 2 moles of an appropriately substituted phenol or naphthol with 1 mole of sulfur dichloride in the presence of a Lewis acid and under conditions generally employed for a Friedel-Crafts reaction.
  • EXAMPLE 3 Dinaphtho[2,1-d:l ',2'-g] 1 ,3,6]dioxathiocin-8- carboxylic acid
  • each of Y,Y, Z, and Z is selected from the group consisting of hydrogen, halogen, or a lower alkyl radical of from one to four carbon atoms; or each set of Y and Y or each set of Z and Z taken together with the aromatic ring to which each set is attached forms a naphthalene ring which may be unsubstituted or substituted with a substituent selected from a halogen atom, or a lower alkyl radical of from one to four carbon atoms; W is selected from the group consisting of hydroxy, a lower alkoxy radical of from one to four carbon atoms or NR'R wherein each of R and R is selected from the group consisting of hydrogen or a lower alkyl radical of from one to four carbon atoms, or R and R taken together with the nitrogen atom to which each is attached form a saturated monocyclic heterocyclic group selected from pyrrolidino, piperidino, morpholino, piperazino, or
  • W is selected from hydroxy or a lower alkoxy radical of from one to four carbon atoms.
  • each of Y, Y, Z, and Z is selected from hydrogen, halogen or a lower alkyl radical of from one to four carbon atoms.
  • a compound of claim 3 which is 2,10-dimethyldibenzo[d,g][ l ,3,6]dioxathiocin-o-carboxylic acid.
  • a compound of claim 3 which is methyl 2, l 0dimethyldibenzo-[d,g][ l ,3,6]dioxathiocin-6-carboxylate.
  • each of Y, Y, Z, and Z is selected from hydrogen or chlorine.
  • a compound of claim 6 which is methyl 2,4,8,l0- tetrachlorodibenzo[d,g][ l,3,6]dioxathiocin-6-carboxylate.
  • a compound of claim 6 which is methyl 2,10- dichlorodibenzo[d,g]ey[ l,3,6]dioxathiocin-6-carboxylate.
  • each set of Z and Z taken together with the aromatic ring to which each set is attached form a naphthalene ring which may be unsubstituted or substituted with a halogen atom, or a lower alkyl radical of from one to four carbon atoms.
  • a compound of claim 12 which is dinaphtho[2,ld: l ',2-g][ l ,3,61dioxathiocin-8-carboxylic acid.
  • each set of Y and Y taken together with the aromatic ring to which each set is attached forms a naphthalene ring which may be unsubstituted or substituted with a halogen atom, or a lower alkyl radical of from one to four carbon atoms.

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  • Chemical & Material Sciences (AREA)
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US00180117A 1971-09-13 1971-09-13 Dioxathiocin carboxylic acids, esters, salts and amides Expired - Lifetime US3714191A (en)

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US18011771A 1971-09-13 1971-09-13

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US (1) US3714191A (fr)
JP (1) JPS5543473B2 (fr)
AU (1) AU458572B2 (fr)
BE (1) BE788770A (fr)
CA (1) CA1016182A (fr)
CH (1) CH569728A5 (fr)
DE (1) DE2242841A1 (fr)
FR (1) FR2154491B1 (fr)
GB (1) GB1374370A (fr)
NL (1) NL7212396A (fr)
ZA (1) ZA725744B (fr)

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US3553234A (en) * 1969-06-18 1971-01-05 Richardson Merrell Inc Dibenzo(d,g)(1,3)dioxocin-6-carboxylic acids, esters and salts

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Adams, Chemical Abstracts, 53:1213 (1 1959) *

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JPS4836184A (fr) 1973-05-28
FR2154491A1 (fr) 1973-05-11
DE2242841A1 (de) 1973-03-22
FR2154491B1 (fr) 1975-08-08
CA1016182A (en) 1977-08-23
AU4592472A (en) 1974-02-28
BE788770A (fr) 1973-01-02
NL7212396A (fr) 1973-03-15
CH569728A5 (fr) 1975-11-28
GB1374370A (en) 1974-11-20
AU458572B2 (en) 1975-02-27
JPS5543473B2 (fr) 1980-11-06
ZA725744B (en) 1973-05-30

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