US3746717A - Certain 2,4-thiazolidinedione-2-thiosemicarbazones - Google Patents

Certain 2,4-thiazolidinedione-2-thiosemicarbazones Download PDF

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US3746717A
US3746717A US00186808A US3746717DA US3746717A US 3746717 A US3746717 A US 3746717A US 00186808 A US00186808 A US 00186808A US 3746717D A US3746717D A US 3746717DA US 3746717 A US3746717 A US 3746717A
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thiazolidinedione
methyl
allyl
mol
formula
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A Meisels
E Schott
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Novartis Corp
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Ciba Geigy Corp
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/54—Nitrogen and either oxygen or sulfur atoms

Definitions

  • the present invention relates in a first aspect to 2,2- azines of 2,4-thiazolidinediones and in a second aspect to intermediate 2,4-thiazolidinedione-2- (3 thiosemicarbazones) useful for the production thereof.
  • the present invention' in its first aspect relates to compounds of the formula R is hydrogen, methyl, allyl, 2-methylallyl or 2-propiny1;
  • each of R and R independent of each other is hydrogen or methyl.
  • alkenyl having 3 to 4 carbon atoms is meant a nonterminally unsaturated hydrocarbon such as allyl, l-methylallyl, Z-methylallyl, 2 butenyl (crotyl-), or 3-butenyl.
  • R is methyl, R is allyl and each of R and R is methyl;
  • R is allyl, R is allyl and each of R and R is hydrogen;
  • R is hydrogen, R is 2-methylallyl, and each of R and R is methyl;
  • R is methyl, R is Z-methylallyl, and each of R and R is methyl;
  • R is allyl, R is 2-methylallyl and each of R and R is hydrogen;
  • each of R and R is 2-propinyl, and each of R and R is methyl;
  • R is methyl, R is allyl, R is hydrogen and R is methyl;
  • R is methyl, R is Z-methylallyl, R is hydrogen and R is methyl;
  • R is methyl, R is 2-propinyl, and each of R and R is hydrogen;
  • R is methyl, R is Z-methylallyl, R is methyl and R is hydrogen;
  • R is allyl, R is 2-methylallyl, R is methyl and R is hydrogen;
  • R is methyl, R is allyl, R is methyl and R is hydrogen;
  • R is allyl, R is allyl, R is methyl and R is hydrogen;
  • each of R and R is 2-methylallyl, and each of R and R is hydrogen.
  • the present invention concerns the valuable chemical intermediates of the formula wherein R is methyl, allyl, 2-methylallyl or 2-propinyl,
  • R is hydrogen, methyl, alkenyl having 3 to 4 carbon atoms or cyclohexenyl; at least one of the symbols R and R being an unsaturated group;
  • R is hydrogen or methyl
  • Typical compounds of Formula H are those wherein R is methyl, R is allyl and R is methyl;
  • R is methyl, R is allyl and R is hydrogen
  • R is allyl, R is hydrogen and R is hydrogen;
  • (a) Walker carcino-sarcoma 256 Male rats (Wistar or Sprague Dawley strains) weighing 100-120 g. are used. The tumor is transplanted by intramuscular injection of 1 ml. of a mixture consisting of a tumor cell suspension and Ringer or Hanks solution (1 g. of tumor cell suspension and 1 ml. of Ringer or Hanks solution) into the left thigh. Treatment with the test compounds starts 20 hours thereafter. The test compounds are given either subcutaneously on the right side or orally daily on 4 consecutive days. The animals are sacrificed to 12 days after the tumor transplantation. The weight of the tumors of the treated animals and the untreated controls are determined. The results are expressed in percent inhibition of the growth of the tumors (weight) as compared to the untreated controls.
  • the animals are sacrificed ten days after the last dose is given; the diameters of the tumors are determined and the results expressed in percent inhibition of the tumor growth (diameter) of the untreated controls.
  • the values obtained with the preferred compounds of Formula I are given in the table below.
  • the maximal tolerated dose (dt is determined in mice with one single subcutaneous administration and observation during 10 days.
  • R R R and R have the meanings given in Formula I, or a functional derivative thereof with regard to one or both carboxyl functions, or the tautomeric form thereof, is exposed to ring closing conditions, for example, at a raised temperature.
  • the compounds of Formula III or their functional derivatives are produced in their turn by reacting a 2,5-dithiobiurea (N,N'-bis-thiocarbamoylhydrazine) of the Formula 'IV lh-NH-CS-NH-NH-CS-NH-R;
  • acid esters of Formula V which are reactive with regard to the hydroxyl function for example, halogen hydracid and sulfonic acid esters, particularly arene sulfonic acid and methane sulfonic acid esters, i.e. lower 2-halogen-, 2- arenesulfonyloxyand methane sulfonyloxyalkanoic acids, are suitable.
  • Suitable functional derivatives of these esters which are reactive with regard to the carboxyl function are, e.g. the anilides or lower alkyl esters, i.e. lower 2-halogen-, Z-arene-sulfonyloxyand Z-methane sulfonyloxy-alkanoic acid anilides or the corresponding esters.
  • R, and R have the meanings given in Formula I, with half the molar amount of a salt of hydrazine.
  • the reaction is preferably performed at a raised temperature, for example by boiling the reaction components in a suitable lower alkanol such as ethanol or butanol.
  • Thiosemicarbazones of Formulae X and XI are obtained, eg by reacting rhodanine or rhodanines substituted in the 3- and/or 5-position corresponding to the definitions of R or R and/or R or k with 3-thiosemicarbazides substituted in the 4-position by R or R
  • rhodanines unsubstituted in the 3-position
  • reactive derivatives thereof can be used, i.e.
  • reaction time is, dependent on the reaction temperature and the reactivity of the starting material, between about /2 and 24 hours.
  • thiocyanic acid is used, it is preferably liberated in water from one of its saltse.g. from the ammonium, sodium or potassium thiocyanate by either utilising the starting material of Formula XII in the form of an acid addition salt, e.g. the hydrochloride, or by adding to the reaction mixture slowly the calculated amount of an acid, such as hydrochloric, sulfuric, phosphoric, perchloric, trichloroacetic or acetic acid.
  • an acid such as hydrochloric, sulfuric, phosphoric, perchloric, trichloroacetic or acetic acid.
  • the first step in this process can be carried out e.g. in water as reaction medium, at moderately low temperatures preferably between 0 and room temperature utilising alkaline bicarbonates or carbonates, especially sodium carbonate, as acid binding agents, whereby as cyanogen halide preferably cyanogen chloride is used.
  • cyanogen halide preferably cyanogen chloride is used.
  • the latter is passed into the reaction mixture until the corresponding amount of acid binding agent is neutralised by the liberated hydrogen chloride.
  • the desired reaction product of Formula XIV precipitates and is filtered 01f after termination of the reaction.
  • cyanogen halide cyanogen bromide can also be used.
  • the reaction can be carried out in an inert organic solvent.
  • the addition of hydrogen sulfide as the second reaction step is carried out preferably at temperatures of between 0 and 50 in an anhydrous lower alkanol such as methanol, ethanol or propanol.
  • the reaction time is between about 5-48 hours.
  • mono basic salt of hydrogen sulfide e.g. ammonium hydrogen sulfide can be used.
  • the starting material of Formula XV is refluxed for l to 15 hours in a mixture consisting of an anhydrous lower alkanol, particularly ethanol, but also in methanol or propanol and absolute etherical hydrogen chloride, the content of hydrogen chloride being sufficient at least to form a salt with the liberated hydrazone.
  • a mixture consisting of an anhydrous lower alkanol, particularly ethanol, but also in methanol or propanol and absolute etherical hydrogen chloride, the content of hydrogen chloride being sufficient at least to form a salt with the liberated hydrazone.
  • an organic solvent which decreases the solubility of the hydrochloride in the reaction mixture such as petroleum ether or diethylether is added, whereupon the crystallised hydrochloride of the desired hydrazone of Formula XII is filtered off.
  • the alkali metal derivatives of compounds of Formula XVIII are obtained for example by the reaction of a compound of Formula XVIII with sodium hydride, lithium or sodium amide in dimethylformamide at a temperature of between 0 and room temperature. They are in the same medium reacted at room temperature or slightly raised temperature with reactive esters of alkanols of the Formula XD(e.g.
  • halides such as methyl iodide, ethyl-, propyl-, allyl, 2-methyl-ally1, 2-buteny1-or 2-propinyl iodide or bromide, allyl-, 2-methyl-allyl-, 2-butenyl-, or 2- propinyl-chloride, alkanesulfonic acid or arene sulfonic acid esters such as the corresponding methane sulfonic acid and p-toluenesulfonic acid esters or also with dimethylsulfate or diethylsulfate.
  • Some of the 1-alkanoyl-3-thiosemicarbazides and of the 4 substituted 1 alkanoyl-3-thiosemicarbazides of the Formula XVII are known and others are prepared analogously to the known compounds from 3-thiosemicarbazides and the corresponding 4-substituted 3-thiosemicarbazides by heating with anhydrous formic acid, acetic anhydride or anhydrides of other lower fatty acids, respectively.
  • Azines of the Formula I wherein R is hydrogen are weakly acid substances which can be converted, e.g. into sodium, potassium or lithium salts or into salts with organic bases such as ethylamine, dimethylamine, diethylamine, aminoethanol, diethylaminoethanol, diethanolamine, triethanolamine, ethylenediamine or morpholine.
  • organic bases such as ethylamine, dimethylamine, diethylamine, aminoethanol, diethylaminoethanol, diethanolamine, triethanolamine, ethylenediamine or morpholine.
  • the azines mentioned, therefore, can be dissolved, e.g. in aqueous solutions of inorganic basic substances such as sodium or potassium hydroxide, sodium of potassium carbonate.
  • the compounds of Formula I are administered orally or parenterally, particularly intramuscularly and subcutaneously, in amounts depending on the species, and the age, weight and the particular condition of the individual being treated.
  • the azines of the present invention are administered parenterally or orally to achieve a tumor growth inhibiting effect, in any of the usual pharmaceutical forms.
  • These include solid and liquid unit oral dosage forms such as tablets, capsules, powders, suspensions, solutions, syrups and the like, including sustained release preparations, and fluid injectable forms such as steril solutions and suspensions.
  • dosage unit form as used in this specification refers to physically discrete units to be administered in single or multiple dosage to animals, each unit containing a predetermined quantity of active material in association with the required diluent, carrier or vehicle. The quantity of active material is that calculated to produce the desired therapeutic efiect upon administration of one or more of such units.
  • Powders are prepared by comminuting the compound to a suitably fine size and mixing with a similarly comminuted diluent pharmaceutical carrier such as an edible carbohydrate material as for example, starch. Sweetening, flavoring, preservative, dispersing and coloring agents can also be added.
  • a similarly comminuted diluent pharmaceutical carrier such as an edible carbohydrate material as for example, starch. Sweetening, flavoring, preservative, dispersing and coloring agents can also be added.
  • medicaments can also be combined with free flowing inert carriers and compressed into tablets directly without going through the granulating or slugging steps.
  • a protective coating consisting of a sealing coat of shellac, a coating of sugar or polymeric material and a polish coating of wax can be provided.
  • Dyestuffs can be added to these coatinlzs to distinguish different unit dosages.
  • Oral fluids such as syrups and elixirs can be prepared in unit dosage form so that a given quantity, e.g., a teaspoonful, contains a predetermined amount of the compound.
  • Syrups can be prepared by dissolving the compound in a suitably flavored aqueous sucrose solution While elixirs are prepared through the use of a non-toxic alcoholic vehicle.
  • Suspensions and emulsions can be formulated by dispersing the medicament in a non-toxic vehicle.
  • Dosage unit forms for oral administration preferably contain between 1% and 90% of an azine of Formula I.
  • Ampoules for parenteral, particularly intravenous intramuscular or subcutaneous administration contain preferably 05-10% of a compound of Formula I in form of an aqueous dispersion.
  • the latter are produced by means of suitable solubility promoters and/or emulsifying agents.
  • EXAMPLE 1 20.4 g. (0.1 mol) of 1-(l-methylallyl)-2,5-dithiobiurea (N [(1 methylallyl) thiocarbamoyl] N thiocarbamoyl hydrazine) (M.P. 179-18l) (see below), 20.8 g. (0.22 mol) of chloroacetic acid and 20 g. of anhydrous sodium acetate in 100 ml. of ethanol are refluxed for 6 hours. The reaction mixture is then cooled to 0, the white precipitate is filtered off under suction and washed with a large quantity of water.
  • 1-(l-methylallyl)-2,5-dithiobiurea N [(1 methylallyl) thiocarbamoyl] N thiocarbamoyl hydrazine
  • the 1(l-methylallyl)-2,5-dithio-biurea necessary starting material is produced, e.g. as follows:
  • EXAMPLE 3 20.4 g. (0.1 mol) of 1-(l-methylallyl)-2,5-dithiobiurea (see Example 1), 33.6 g. (0.22 mol) of 2-bromo-n-propionic acid and 40 g. of anhydrous sodium acetate in 200 ml. of ethanol are refluxed for 25 hours. After cooling to room temperature, the sodium salts are filtered off, the filtrate is greatly concentrated under water jet vacuum and water is carefully added.
  • EXAMPLE (a) 1.73 g. (0.01 mol) of 3-allyl-rhodanine are heated for 2 hours to 120 with 0.54 g. (0.011 mol) of hydrazine hydrate, 2 ml. of glacial acetic acid and ml. of triethylene glycol. After cooling, the precipitated 2,2-azine of 3-allyl-2,4-thiazolidinedione is removed by suction, washed with 10 ml. of cold methanol and recrystallised from chloroform-hexane; M.P. 210-211".
  • EXAMPLE 6 (a) 2.54 g. (0.01 mol) of 2,2-azine of 2,4-thiazolidinedione, decomposition approx. 300 (prepared according to G. Frerichs and P. Forster, Ann. 371, 257 [1909]) are suspended in ml. of absolute dimethyl formamide. 0.46 g. (0.02 mol) of sodium hydride are added while stirring. After development of hydrogen has ceased, 3 g. (0.022 mol) of crotyl bromide are added dropwise and the reaction mixture is stirred for 12 hours at -25 and for 15 minutes at 80. After cooling, the reaction mixture is poured onto 50 g.
  • the precipitated l-acetyl-4-allyl-3-thiosemicarbazide is filtered under suction, washed with ether and dried in a water jet vacuum for 20 hours at 70.
  • the yield amounts to 586.6 g. (93.7% of theory), M.P. 131-132.
  • 3,5-dimethyl-2,4-thiazolidinedione 2 (4-allyl-3-thiosemicarbazone, M.P. -116", 10.7 g. (88.1% of theory), starting from 7.53 g. (0.047 mol) of 3,5-dimethyl-2,4-thiazolidinedione-Z-hydrazone and allyl isothiocyanate.
  • the chloroform solution is washed neutral with water, dried over sodium sulfate and evaporated under reduced pressure.
  • EXAMPLE 11 (a) 18.9 g. (0.11 mol) of 3-allyl-2,4-thiazolidinedione- Z-hydrazone (see Example 10) are dissolved in 280 m1. of water and with ice cooling and stirring 5.8 g. (0.055 mol) of sodium carbonate are added. At a reaction temperature of 3 to 5 cyanogen chloride is introduced until the solution reaches pH 7. The precipitated 3-(3-allyl-4- oxo-2-thiazolidinylidene)-carbazic acid nitrile is filtered under suction and washed with 30 ml. of water. After drying for 15 hours at 40 under reduced pressure, the yield amounts to 14.5 g. (67.1% of theory), M.P. 155 (with decomposition).
  • EXAMPLE 12 47.0 g. (0.1725 mol) of 3-(2-methylallyl)-5-methyl-2,4- thiazolidinedione-2- (4-methyl-3-thiosemicarbazone) 17.9 g. (0.19 mol) of chloroacetic acid and 35.4 g. (0.431 mol) of anhydrous sodium acetate are boiled under reflux and stirring for 3 hours with 400 ml. of n-propanol.
  • the reaction mixture is treated with 700 ml. of water and allowed to ccol to room temperature.
  • the precipitated 2,2'-azine of 3-methyl-2,4-thiazolidinedione and of 3-(2- methylallyl)-5-methyl-2,4-thiazolidinedione is filtered ofl and washed with 300 ml. of water. After one recrystallisation from methylenechloride-hexane, 40.5 g. (78-1% of theory) of the pure azine, M.P. 154", is obtained.
  • EXAMPLE 15 250 g. of active substance, e.g. 2,2-azine of 5-methyl-2,4- thiazolidinedione and of 5-methyl-3-(1-methylally1)-2,4- thiazolidinedione, are mixed with 175.80 g. of lactose and 169.70 g. of potato starch. The mixture is moistened with an alcoholic solution of 10 g. of stearic acid and granulated through a sieve. After drying, 160 g. of potato starch, 200 g. of talcum, 2.50 g. of magnesium stearate and 32 g. of colloidal silicon dioxide are mixed in and the mixture is pressed into 10,000 tablets each weighing mg. and containing 25 mg. of active substance. If desired, the tablets can be grooved for better adaptation of the dosage.
  • active substance e.g. 2,2-azine of 5-methyl-2,4- thiazolidinedione and of 5-methyl-3-(1-methylally1)-2,4-
  • R is hydrogen, alkenyl having 3 to 4 carbon atoms or 2-cyclohexenyl, at least one of the symbols R and R, being an unsaturated group, and

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Thiazole And Isothizaole Compounds (AREA)
  • Management, Administration, Business Operations System, And Electronic Commerce (AREA)
US00186808A 1965-10-29 1971-10-05 Certain 2,4-thiazolidinedione-2-thiosemicarbazones Expired - Lifetime US3746717A (en)

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CH1498565A CH459216A (de) 1965-10-29 1965-10-29 Verfahren zur Herstellung von neuen Azinen

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US (1) US3746717A (en, 2012)
AT (2) AT263769B (en, 2012)
BE (1) BE689020A (en, 2012)
BR (1) BR6684131D0 (en, 2012)
CH (1) CH459216A (en, 2012)
DE (1) DE1695095C3 (en, 2012)
DK (1) DK121170B (en, 2012)
ES (4) ES332858A1 (en, 2012)
FI (1) FI48739C (en, 2012)
FR (1) FR6874M (en, 2012)
GB (1) GB1122604A (en, 2012)
IL (1) IL26768A (en, 2012)
NL (1) NL149798B (en, 2012)
NO (1) NO128612B (en, 2012)
SE (1) SE346540B (en, 2012)
YU (3) YU36726B (en, 2012)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5958683A (en) * 1994-03-30 1999-09-28 Novartis Corporation Screening method using the RZR receptor family

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5958683A (en) * 1994-03-30 1999-09-28 Novartis Corporation Screening method using the RZR receptor family
US6218359B1 (en) 1994-03-30 2001-04-17 Novartis Corporation Screening method using the RZR receptor family

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ES332858A1 (es) 1967-12-01
GB1122604A (en) 1968-08-07
FI48739B (en, 2012) 1974-09-02
ES332860A1 (es) 1967-12-01
ES332861A1 (es) 1967-12-01
YU256379A (en) 1983-02-28
IL26768A (en) 1970-09-17
YU36726B (en) 1984-08-31
DE1695095A1 (de) 1970-08-20
SE346540B (en, 2012) 1972-07-10
ES332859A1 (es) 1967-12-01
NO128612B (en, 2012) 1973-12-17
YU203566A (en) 1982-02-25
FR6874M (en, 2012) 1969-04-14
BE689020A (en, 2012) 1967-04-28
DK121170B (da) 1971-09-20
DE1695095C3 (de) 1974-05-02
BR6684131D0 (pt) 1973-12-26
NL6615305A (en, 2012) 1967-05-02
DE1695095B2 (de) 1973-09-06
YU256479A (en) 1983-01-21
AT263769B (de) 1968-08-12
CH459216A (de) 1968-07-15
AT267523B (de) 1969-01-10
FI48739C (fi) 1974-12-10
NL149798B (nl) 1976-06-15

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