US3562256A - 1,3-dialkyl-5-(substituted arylsulfonyl)-tetrahydro-1,3,5-triazine-4-thiones - Google Patents

1,3-dialkyl-5-(substituted arylsulfonyl)-tetrahydro-1,3,5-triazine-4-thiones Download PDF

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Publication number
US3562256A
US3562256A US644779A US3562256DA US3562256A US 3562256 A US3562256 A US 3562256A US 644779 A US644779 A US 644779A US 3562256D A US3562256D A US 3562256DA US 3562256 A US3562256 A US 3562256A
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triazine
tetrahydro
compounds
hypoglycemic
thiones
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US644779A
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Fred E Boettner
Michael C Seidel
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Rohm and Haas Co
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Rohm and Haas Co
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
    • C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
    • C07D251/08—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member

Definitions

  • This invention relates to novel 1,3-dialkyl-5-(substituted arylsulfonyl)-tetrahydro-1,3,5-triazine-4-ones and thiones; processes for their preparation; pharmaceutical compositions thereof; and a method of lowering blood sugar in animals.
  • hyperglycemia has been treated by the regular parenteral administration of insulin.
  • insulin due to the necessity of frequent injections, patient discomfort, and related general difiiculties, there has been a continual search to uncover new and improved means for controlling hyperglycemia.
  • hypoglycemic agents As a result thereof, various hypoglycemic agents have been discovered which can be administered orally. Typical examples of such materials are disclosed in the following United States Pats. 3,150,178; 3,242,174; 3,259,544 and 3,282,784. For the most part, hypoglycemic or antidiabetic agents, such as these, are Wanting in suflicient activity over a prolonged period of time. Consequently, substantial or repeated dosing is necessitated.
  • the present invention overcomes these problems by providing hypoglycemic agents of high activity and lower toxicity.
  • this invention provides hypoglycemic agents which are readily utilized in the treatment of hyperglycemia. Because of such valuable properties, the present invention must be considered a substantial advance in the state of the art.
  • triazines The novel compounds of this invention which may be referred to generically at times throughout this disclosure as triazines can be represented by the formula wherein:
  • X is methyl, chlorine, nitro, amino, methoxy or acetyl
  • Y is oxygen or sulfur
  • R is alkyl of 2 to 7 carbon atoms, provided that when X is chlorine or methoxy, R is alkyl of 3 to 6 carbon atoms.
  • R in Formula I is an alkyl of 2 to 7 carbon atoms and as such can be branched, cyclic, or normal.
  • Typical alkyls which fall within this classification include: ethyl, propyl, isopropyl, cyclopropyl, butyl, t-butyl, cyclobutyl, pentyl, isopentyl, hexyl, cyclohexyl, and heptyl.
  • R positions (1 and 3) in 3,562,256 Patented Feb. 9, 1971 any particular compound will be substituted by the same alkyl group.
  • this is not to be construed as a limitation of this invention since disparate alkyl groups in such positions are contemplated and within the scope thereof.
  • Preparation of the novel triazines represented by Formula I may be effected by reacting a substituted arylsulfonyl isocyanate or arylsulfonyl isothiocyanate of the formula IUD-S OzNOY with an alkyl substituted trimethylene triamine of the formula N H LR (III) wherein Y and R represent the same substituents as defined for Formula I and X is methyl, chlorine, nitro, methoxy or acetyl.
  • trimethylene triamine represented by Formula III is commonly referred to as an azomethine trimer.
  • This reaction proceeds on a molar basis of one mole substituted arylsulfonyl isocyanate or arylsulfonyl isothiocyanate to /2. mole of alkyl substituted azomethine trimer to produce one mole of triazine. While the reaction requires one mole of isocyanate or isothiocyanate for each mole of azomethine trimer, it is advantageous to have a slight molar excess of isocyanate or isothiocyanate present. With this slight molar excess, the reaction proceeds much more readily.
  • an inert solvent such as for example, toluene, benzene, xylene, ethyl acetate, ethylene dichloride and the like.
  • Reaction temperature is not critical and under most circumstances the reaction will proceed at any temperature above 0 C. However, a temperature range of 25 to C. is preferred and will insure a rapid completion of the reaction.
  • Recovery of the product, namely, the triazine from the reaction solution is accomplished by any suitable means available to one skilled in the art. Typically, this would include filtration, crystallization, distillation, or any com bination thereof and the like.
  • the isocyanate reactants represented by Formula II when Y is oxygen are known in the art and may be prepared by reacting a substituted arylsulfonamide and phosgene in the presence of a catalyst such as an alkyl isocyanate. Such preparations are reported in the Journal of Organic Chemistry, vol. 31, pages 26582661 (1966).
  • arylsulfonyl isothiocyanate reactants that is, the compounds represented by Formula II when Y is sulfur, are likewise known in the art. They may be obtained by the reaction of phosgene on N-substituted iminodithiocarbonates as reported in Chem. Ber., vol. 99, pages 2885-2899 (1966).
  • Substituted trimethylene triamines are similarly well known and readily available. They may be prepared by reacting a primary amine with formaldehyde and purified by drying with potassium hydroxide.
  • Preparation of the compounds of Formula I Where X is amino involves the catalytic reduction of a Formula I compound where X is nitro. Typically, the reduction is carried out with platinum oxide under about 30 to 40 pounds of pressure per square inch at a temperature in the range of 25 to 30 C. and in an inert solvent, such as benzene, toluene, alcohol and the like. Saparation of the amino substituted triazine may be accomplished by conventional procedures, such as for example, filtration, crystallization, distillation or any combination thereof.
  • the hypoglycemic score is determined as follows: The blood glucose value for an individual rat at each of the post dose sampling intervals, namely, 1, 2, 3 and 5 hours, is substracted from that rats control blood glucose value. Thus, a decrease in blood glucose would be expressed as a positive number and an increase in blood glucose as a negative number. The sum of these diiferences for the individual rat is designated as that rats hypoglycemic score.
  • Example 1 The compounds of Examples 1 to 11 were evaluated by the above procedure at varying dose levels and the results thereof are given in Table II. Since for statistical purposes more than one rat is tested at each dose level, the hypoglycemic score is reported as the mean thereof.
  • the triazines are especially important and useful because of their minimal toxicity.
  • both 1,3 di n butyl 5 (p tolylsulfonyl)- tetrahydro 1,3,5 triazine 4 one and 1,3 di n propyl 5 (p tolylsulfonyl) tetrahydro 1,3,5 triazine 4 one exhibited and LD greater than 2000 rug/kg.
  • tolbutamide and chlorpropamide both commercially available oral hypoglycemics, had an LD of 1600 mg./kg. and 1000 mg./kg. respectively.
  • the triazines are not only substantially less toxic than other oral hypoglycemic agents, but lower efiective dosages are necessitated to achieve a desired level of hypoglycemic activity. Consequently, the compounds of this invention prove to be a particularly valuable group of hypoglycemic agents.
  • the triazines of this invention may be administered alone, they are generally and preferably taken in the form of pharmaceutical compositions, that is, the triazine is administered as a therapeutically effective active agent in combination with a pharmaceutically acceptable carrier.
  • the triazine usually constitutes by weight about 0.5 to 99.5% of the total composition.
  • the amount of active ingredient therein will vary depending upon the therapeutic form selected, i.e., capsules, tablets, emulsions, etc., along with the dose level of each unit and the like.
  • diluents such as lactose, sucrose and starch
  • binders such as starch paste, gelatin solution, methylcellulose and ethylcellulose
  • disintegrators such as dried corn or potato starch
  • lubricants such as calcium stearate, magnesium stearate, talc and cocoa butter
  • coating materials such as acacia, kaolin, shellac, and calcium carbonate
  • vehicles such as wa- 1161, alcohol, glycerin and citric acid
  • thickening agents such as tragacanth, carrageenin and pectin
  • wetting agents such as sodium lauryl sulfate and benzalkonium chloride
  • preservatives such as benzoic and sorbic acid.
  • compositions are usually and pref erably in suitable therapeutic or dosage form, such as for example, capsules, tablets, solutions, emulsions and the like.
  • Coated or uncoated tablets and capsules are the preferable unit dosage forms.
  • concentration of active agent namely, triazine, selected for any individual unit thereof will be contingent upon numerous variables.
  • Typical tablet, capsule and powder formulations may contain from 50 to 2000 mg. and preferably 250 to 1000 mg. of triazine per unit.
  • composition formulations are set forth below. In each such formulation, the designated materials are given in proportions by weight.
  • CAPSULES Ingredients: Parts by Weight 1,3-di-n-butyl 5 (p-tolylsulfonyl)-tetrahydro 1,3,5 triazine 4 one 500 Corn starch 50 Talc 50 III per unit.
  • 1,3-di-n-butyl 5 (p-tolylsulfonyl)-tetrahydro 1,3,5 triazine 4 one 500 Corn starch 50 Talc 50 III per unit.
  • larger or smaller capsules for differ ent concentrations of active agent may be readily employed where desired or necessitated.
  • Lowering of blood sugar in animals is induced in accordance with this invention by orally administering to such animals at least one of the triazines described herein in an amount which is effective for such purpose.
  • the treatment thereof comprises the oral administration in a therapeutically effective amount of at least one triazine.
  • the actual dosage to be administered at one time or over any extended period will, of course, vary with the particular animal being treated.
  • a daily dose of to 3000 mgs. of triazine will satisfactorily treat hyperglycemia in an adult human.
  • this may be administered as a single daily dose, or more preferably, extended through multiple doses of 2 to 4 times daily.
  • the triazine will be administered as the active agent in an orally ingestible pharmaceutical composition such as previously described.

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Inorganic Compounds Of Heavy Metals (AREA)
US644779A 1967-06-09 1967-06-09 1,3-dialkyl-5-(substituted arylsulfonyl)-tetrahydro-1,3,5-triazine-4-thiones Expired - Lifetime US3562256A (en)

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US64477967A 1967-06-09 1967-06-09

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US (1) US3562256A (en:Method)
AT (1) AT283376B (en:Method)
BE (1) BE716233A (en:Method)
CA (1) CA920128A (en:Method)
CH (1) CH493540A (en:Method)
DE (1) DE1770508A1 (en:Method)
DK (1) DK123412B (en:Method)
ES (1) ES354639A1 (en:Method)
FI (1) FI48192C (en:Method)
FR (2) FR7454M (en:Method)
GB (1) GB1217749A (en:Method)
IL (1) IL30143A (en:Method)
NL (1) NL6807670A (en:Method)
NO (1) NO122429B (en:Method)
SE (1) SE343063B (en:Method)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3694551A (en) * 1970-01-30 1972-09-26 Ciba Geigy Corp Hypoglycemic compositions and methods for 1-phenylsulfonyl-2-imino-imidazolidines and hexahydropyridines

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3694551A (en) * 1970-01-30 1972-09-26 Ciba Geigy Corp Hypoglycemic compositions and methods for 1-phenylsulfonyl-2-imino-imidazolidines and hexahydropyridines

Also Published As

Publication number Publication date
NO122429B (en:Method) 1971-06-28
CA920128A (en) 1973-01-30
DK123412B (da) 1972-06-19
FR1584300A (en:Method) 1969-12-19
CH493540A (fr) 1970-07-15
FI48192B (en:Method) 1974-04-01
IL30143A (en) 1972-09-28
GB1217749A (en) 1970-12-31
AT283376B (de) 1970-08-10
DE1770508A1 (de) 1971-10-28
ES354639A1 (es) 1970-02-16
FI48192C (fi) 1974-07-10
SE343063B (en:Method) 1972-02-28
NL6807670A (en:Method) 1968-12-10
BE716233A (en:Method) 1968-12-09
FR7454M (en:Method) 1969-11-24

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