US3890331A - 3-Substituted-5-hydroxy (mercapto) alkylidene-rhodanine derivatives - Google Patents

3-Substituted-5-hydroxy (mercapto) alkylidene-rhodanine derivatives Download PDF

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US3890331A
US3890331A US379037A US37903773A US3890331A US 3890331 A US3890331 A US 3890331A US 379037 A US379037 A US 379037A US 37903773 A US37903773 A US 37903773A US 3890331 A US3890331 A US 3890331A
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rhodanine
ethyl
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benzyl
chlorophenyl
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Arthur Magnani
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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
    • C07D277/36—Sulfur atoms
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof

Definitions

  • This invention relates to novel 3-substituted-5- hydroxy(mercapto)alkylidene-rhodanine derivatives having useful pharmacodynamic activity. More specifically the compounds of this invention have antiarthritic activity as measured by their ability to inhibit or suppress adjuvant-induced polyarthritis in rats. Thus the compounds of this invention decrease the inflamed hind leg volumes in experimental rats when compared to controls at oral doses of from 12.5 to 100 mg/kg/day.
  • R represents lower alkyl of from 1 to 4 carbon atoms, straight or branched chain, cycloalkyl of from 3 to 6 carbon atoms for example cyclopropyl or cyclohexyl, alkenyl of from 3 to carbon atoms for example allyl or dimethylallyl, phenyl, phenylalkyl of from 7 to 9 carbon atoms, substituted phenyl, such as monohalophenyl for example monochloro, monobromo or monofluorophenyl, dichlorophenyl for example 2,6-dichlorophenyl or 3,4- dichlorophenyl, alkylphenyl for example tolyl, or methylchlorophenyl for example 2-chloro-4- methylphenyl, or pyridylmethyl for example 2-, 3-or 4-pyridylmethyl;
  • R represents lower alkyl of from 1 to 4 carbon atoms, phenylalkyl of from 7 to 9 carbon atoms, said alkyl moieties may be straight or branched chain, or substituted benzyl, such as monochloro or monomethylbenzyl, and Y represents oxygen or sulfur.
  • Preferred compounds of formula I are those wherein R is methyl, ethyl, propyl butyl, phenyl, monochlorophenyl, especially when the latter is 2'-or 4-- lows:
  • the compounds of formula I werein Y is sulfur are prepared from the intermediate 5-alkoxyalkylidene rhodanines, obtained as outlined above, by reaction with sodium sulfide in aqeuous ethanol at room temperature for from 15 to 60 minutes followed by acidification of the reaction product with hydrochloric acid.
  • the S-unsubstituted rhodanines used as starting materials described hereinabove are either known or are prepared by one of the following synthetic methods.
  • the required isothiocyanates are prepared, for example, by the reaction of an appropriate amine (RNI-I with thiophosgene (CSCI Starting with a di thiocarbamate, a compound of the formula R-NH- C-SH,
  • rhodanine derivative preferably as a triethylamine salt, is condensed with chloroacetic acid (or ester) followed by treatment with mineral acid to give the rhodanine derivative.
  • the required orthoester reactants are prepared by known procedures from the appropriate cyanide shown, for example, as follows:
  • the dosage units will contain a compound of formula I in an amount of from about mg. to about 200 mg. per unit.
  • the pharmaceutical carrier employed may be, for example, either a solid or liquid.
  • solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like.
  • liquid carriers are syrup, peanut oil, olive oil, water and the like.
  • the carrier or diluent includes any time delay material well known to the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax.
  • a wide variety of pharmaceutical forms can be employed.
  • a solid carrier the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form or in the form of a troche or lozenge.
  • the amount of solid carrier will vary widely but preferably will be from about 25 mg. to about 1 g. If a liquid carrier is used, the preparation will be in the.
  • a syrup, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampule or an aqueous or nonaqueous liquid suspension.
  • the method of producing anti-arthritic activity in accordance with this invention comprises administering internally to an animal organism a compound of formula 1 above, usually combined with a pharmaceutical carrier, in an amount sufficient to produce antiarthritic activity without limiting side effects.
  • the active medicament will be administered in a dosage unit, as described above, orally or parenterally, the oral route being preferred.
  • Advantageously equal doses will be administered 1 or 2 times daily with the daily dosage regimen being from about 10 mg. to about 400 mg.
  • the pharmaceutical preparations are made following the conventional techniques of the pharmaceutical chemist involving mixing, granulating and compressing when necessary, or variously mixing and dissolving the ingredients as appropriate to the desired end product.
  • EXAMPLE 1 A mixture of 27 g. (0.16 m.) of p-chlorophenyl isothiocyanate, 33 ml. (42.5 g., 0.475 m.) of mercaptoacetic acid and 5 drops of triethylamine is heated in a pressure bottle at l-130C. for 2%: hours. The reaction mixture is allowed to stand at room temperature overnight and filtered. The crude product is recrystallized from ethanol to give 3-(4-chlorophenyl)- rhodanine, m.p. l24.5-126C.
  • EXAMPLE 2 Following the procedures of Example 1, triethylorthopropionate is reacted with 3-(4'-chlorophenyl)- rhodanine in acetic anhydride for 5V2 hours to give 3- (4'-chlorophenyl)-5-( 1 '-ethoxypropylidene)- rhodanine. To a suspension of the latter (25 g., 0.0765 In.) in 200 ml. of dioxane and 200 ml. of water is added 50 ml. of 10% sodium hydroxide solution. The mixture is stirred at room temperature for 4 hours and then concentrated in vacuo at 40-45C.
  • EXAMPLE 3 As described in Example 1, triethylorthophenylacetate is reacted with 3-(4-chlorophenyl)-rhodanine in acetic anhydride for 12 hours to yield 3-(4'- chlorophenyl)-5-( 1 '-ethoxy-2'-phenylethylidene)- rhodanine. To a suspension of the latter 15 g., 0.0385 m.) in ml. of dioxane and 100 ml. of water is added 22 ml. of 10% sodium hydroxide solution. The mixture is stirred at room temperature for 3 hours, concentrated in vacuo at 40-40C. and the remaining solution is washed with ether, then decolorized.
  • aqueous layer is acidified with dilute hydrochloric acid and the precipitate is taken up in methylene chloride.
  • the latter solution (after being washed with water and dried) is evaporated in vacuo.
  • the residue is dissolved in 10% sodium hydroxide and water, washed with ether and acidified with dilute hydrochloric acid to give 3-(4'- chlorophenyl)-5-( l -hydroxy-2'-phenylethylidene)- rhodanine, m.p. 134-137C.
  • EXAMPLE 5 A mixture of 25 g. (0.12 m) of 3-phenylrhodanine, 80 g. (0.34 m.) of triethylorthophenylacetate [prepared as described in J.A.C.S. 68, 1917 (1946)] and 250 ml. of acetic anhydride is heated under reflux for 20 hours and the solution is then concentrated in vacuo. The residue is filtered and the solid is stirred with ml. of dioxane, 160 ml. of water and 40 ml. of 10% sodium hydroxide for four hours. The solution is concentrated in vacuo at 3540C. to evaporate the dioxane.
  • the aqueous solution after washing with ether and decolorizing with charcoal, is made acidic with dilute hydrochloric acid.
  • the solid product is purified by chromatography to give 5-(l-hydroxy-2'- phenylethylidene)-3-phenylrhodanine, m.p. 146-l48C.
  • a mixture of 6 g. (0.029 m.) of 3- phenyl-rhodanine, 15 g. (0.063 m.) of triethylorthophenylacetate and 15 ml. of n-butyl ether is heated to reflux and then distillate is removed until the temperature of the mixture reaches 150C. After heating at this temperature for 1 hour, an additional 5 g. of orthoester is added and heating is continued for 30 minutes. To the reaction mixture is added 5 ml. of acetic anhydride and heating is continued for 5 minutes. The resulting mixture is concentrated in vacuo and the residue is eluted through a column of silica gel with 2:1- cyclohexane-benzene.
  • EXAMPLE 6 A mixture of 7.5 g. (0.05 m.) of 3-ethylrhodanine, 25 g. (0.128 m.) of trimethylorthophenylacetate and 80 ml. of acetic anhydride is heated under reflux for 18 hours. The solution is concentrated in vacuo and the residue chromatographed through silica gel using 50% benzene in cyclohexane as the eluant to give 3-ethyl-5- (1 '-methoxy-2-phenylethylidene)-rhodanine, m.p. 120l22C.
  • the above prepared 5-substituted rhodanine (2 g., 0.0068 m.) is stirred with 25 ml. of dioxane, 20 ml. of water and 8 ml. of 10% sodium hydroxide solution for 2 /2 hours.
  • the resulting solution is concentrated in vacuo at 40C. to remove dioxane.
  • the aqueous solution is washed with ether and acidified with dilute hydrochloric acid to yield 3-ethyl-5-( l -hydroxy-2- phenylethylidene)rhodanine, m.p. 74-76C.
  • EXAMPLE 7 A mixture of5 g. (0.033 m.) of 3-ethylrhodanine, 12 ml. of triethylorthoacetate and 35 ml. of acetic anhydride is heated under reflux for 18 hours and the solution is then concentrated in vacuo. The cooled residue is filtered and the solid is dissolved in ether. The ether solution is washed with water, dried and evaporated in vacuo to give 5(1-ethoxyethylidene)-3- ethylrhodanine. The latter (3.6 g.) is stirred with ml. of dioxane, 15 ml. of water and 15 ml. of 10% sodium hydroxide solution for 4 hours.
  • the resulting solution is concentrated in vacuo at 40C. and the aqueous solu tion is washed with ether, decolorized, then made acidic with dilute hydrochloric acid.
  • the precipitate is dissolved in 10% sodium hydroxide solution, washed with ether and the aqueous solution is made acidic with dilute hydrochloric acid to give the product, 3ethyl-5- (l'-hydroxyethylidene)-rhodanine, m.p. 93C.
  • EXAMPLE 8 A mixture of 8.4 g. (0.04 m.) of 3-phenylrhodanine, 21 g. (0.12 m.) of triethylorthopropionate and 80 ml. of acetic anhydride is heated under reflux for 6 hours, cooled and filtered. The solid is washed with 50% aqueous acetic acid to afford 5-(1-ethoxypropylidene)-3- phenylrhodanine, m.p. 178-181C.
  • EXAMPLE 9 A mixture of 1 24.4 g. (0.1 m.) of 3-(4- chlorophenyl)rhodanine, g. of trimethyl fi-phenylorthopropionate [prepared as described in J.A.C.S. 69, 2665 (1947)] and 150 ml. of acetic anhydride is heated under reflux for 18 hours. Upon standing at room temperature the solid separates from the reaction mixture which is filtered and washed with acetic acid to give 3- (4-chlorophenyl)-5-(1-ethoxy 3'-' phenylpropylidene)-rhodanine. The latter (20 g. 0.052 m.) is stirred at room temperature with 250 ml.
  • EXAMPLE 10 As described in Example 1, a mixture of 6. l 2 g. (0.04 m.) of p-fluorophenyl isothiocyanate, 4.15 ml. (5.5 g., 0.06 m.) of mercaptoacetic acid and 5 drops of triethylamine is heated in a pressure bottle at 1 10-130C. for 3 hours to yield after cooling and filtration the product, 3-(4-fluorophenyl)-rhodanine, m.p. l55158C.
  • EXAMPLE 1 To a solution of 4.73 g. (0.05 m.) of chloroacetic acid in 40 ml. of water is added a solution of 2.7 g. (0.025 m.) of sodium carbonate in 20 ml. of water. The solution is cooled in an ice bath and 14.2 g. (0.05 m.) of the triethylamine salt of p-tolyl dithiocarbamic acid is added portionwise over five minutes. The resulting mixture is stirred at room temperature for 1 /2 hours. Water is added to bring total volume to 150 ml. and the resulting mixture is warmed on the steam bath for 5 minutes, then filtered. The filtrate is acidified with 40 ml. of 6N hydrochloric acid, heated to C., cooled, filtered and the solid washed with water to leave 3-(4'- tolyl)-rhodanine, m.p. l64l65C.
  • EXAMPLE 12 A mixture of6. 12 g. (0.03 m.) of 3,4-dichlorophenyl isothiocyanate, 2.8 ml. (3.68 g., 0.04 m.) of mercaptoacetic acid and a few drops of triethylamine is heated in a pressure bottle at 130C. for'2 hours. The cooled reaction mixture is filtered to give 3-(3',4- dichlorophenyl)-rhodanine, m.p. 176-178C.
  • rhodanine is reacted as described in Examples 1 and 3 with tr iethylorthophenylacetate in acetic anhydride to yield 3-(3',4-dichlorophenyl)-5-(1'-ethoxy- 2'-phenylethylidene)-rhodanine which is similarly hydrolyzed to 3-(3,4'-dichlorophenyl)-5-(1-hydroxy-2'- phenylethylidene )-rhodanine.
  • the residue mediate 5-alkoxy derivative is hydrolyzed to give 3-(2- 5 hl o-4- th 1 h 1) 5 (1-h d 2 is chromatographed on a silica gel column, eluting phenylethylidene)-rh danine with mixtures of cyclohexane-benzene.
  • EXAMPL l B The 3-substituted rhodanine is heated with the apred, ms E 3 M /T bl t basementte orthoester (2-3 moles) at a temperature I e g a c of l 50l 55C. for a perlod of from 2-3 hours, with 3-(4-chlorophenyl)-5-(l'- 25 workup as in (A).
  • the residual 9 8 mlxed and granulated 11th hot 10% gelatin solution is extracted with ether and the product is pre- Solutlon-
  • the Wetted mass Passed through a 6 cipitated by acidification with dilute hydrochloric acid. mesh screen directly onto drying trays.
  • the granules are dried at 120F. and passed through a No. 20 mesh screen, mixed with the starch, talc and stearic acid, and TABLE I compressed into tablets.
  • R is lower alkyl of from 1 to 4 carbon atoms, straight or branched chain, cycloalkyl of from 3 to 6 carbon atoms, alkenyl of from 3 to carbon atoms, phenyl, phenylalkyl of from 7 to 9 carbon atoms, monohalophenyl, dichlorophenyl, alkylphenyl, methylchlorophenyl or pyridylmethyl;
  • R is lower alkyl of from 1 to 4 carbon atoms, phenylalkyl of from 7 to 9 carbon atoms, said alkyl moieties being straight or branched chain, monochlorobenzyl or monomethylbenzyl;
  • Y is oxygen or sulfur, or a 2-aminopyridine or 2- aminothiazole salt thereof.
  • R is lower alkyl, phenyl, monochlorophenyl, cyclohexyl or benzyl.
  • R is methyl, ethyl, benzyl or phenethyl.

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Abstract

3-Substituted-5-hydroxy(mercapto)alkylidenerhodanine derivatives in which the 3-substituent is lower alkyl, cycloalkyl, alkenyl, phenyl, phenylalkyl, substituted phenyl or pyridylmethyl and having anti-arthritic activity are generally prepared from the appropriate 5-unsubstituted rhodanine by reaction with an orthoester followed by alkaline hydrolysis of the intermediate 5alkoxyalkylidene rhodanine to give the 5-hydroxyalkylidene products or treatment of the intermediate rhodanine derivative with sodium sulfide to give the 5-mercaptoalkylidene products.

Description

United States Patent Magnani [45] June 17, 1975 3-SUBSTITUTED-5-HYDROXY OTHER PUBLICATIONS (MERCAPTO) ALKYLIDENE-RHODANINE v DERIVATIVES Behringer et al., Berichte, 91, 2773-2783 (1958). [75] Inventor: Arthur Magnani, Wynnewood, Pa.
Primary ExaminerR. J. Gallagher Asslgnee: SnllthKlm Corporatlon, Attorney, Agent, or Firm--Richard D. Foggio Philadelphia, Pa.
[22] Filed: July 13, 1973 ABSTRACT [21] Appl 379037 3-Substituted-5-hydroxy(mercapto)alkylidenerhoda- Related U.S. Application Data nine derivatives in which the 3-substituent is lower al- [63] Continuation-in-part of Ser. No. 254,363, May 18, y cycloalkyl, alkeny], p y P y y Substi' 197 2, abandoned. tuted phenyl or pyridylmethyl and having anti-arthritic activity are generally prepared from the appropriate [52] U.S. CL... 260/2943 D; 260/306.7 R; 424/263; 5-unsubstituted rhodanine by reaction with an ortho- 424/270 ester followed by alkaline hydrolysis of the intermedi- [51] Int. Cl C07d 91/16 ate 5-alk0xyalkylidene rhodanine to give the 5- [58] Field of Search 260/306.7 R, 294.8 D hydroxyalkylidene products or treatment of the intermediate rhodanine derivative with sodium sulfide to [56] References Cited give the S-mercaptoalkylidene products.
UNITED STATES PATENTS 20 Claims No Drawings 2,739,970 3/1956 Knott 260/306] 1 3'SUBSTITUTED-5-HYDROXY (MERCAPTO) ALKYLIDENE-RHODANINE DERIVATIVES This application is a continuation-in-part application of Ser. No. 254,363 filed May 18, 1972 now abandoned.
This invention relates to novel 3-substituted-5- hydroxy(mercapto)alkylidene-rhodanine derivatives having useful pharmacodynamic activity. More specifically the compounds of this invention have antiarthritic activity as measured by their ability to inhibit or suppress adjuvant-induced polyarthritis in rats. Thus the compounds of this invention decrease the inflamed hind leg volumes in experimental rats when compared to controls at oral doses of from 12.5 to 100 mg/kg/day.
The compounds of this invention are represented by the following structural formula:
wherein:
R represents lower alkyl of from 1 to 4 carbon atoms, straight or branched chain, cycloalkyl of from 3 to 6 carbon atoms for example cyclopropyl or cyclohexyl, alkenyl of from 3 to carbon atoms for example allyl or dimethylallyl, phenyl, phenylalkyl of from 7 to 9 carbon atoms, substituted phenyl, such as monohalophenyl for example monochloro, monobromo or monofluorophenyl, dichlorophenyl for example 2,6-dichlorophenyl or 3,4- dichlorophenyl, alkylphenyl for example tolyl, or methylchlorophenyl for example 2-chloro-4- methylphenyl, or pyridylmethyl for example 2-, 3-or 4-pyridylmethyl;
R represents lower alkyl of from 1 to 4 carbon atoms, phenylalkyl of from 7 to 9 carbon atoms, said alkyl moieties may be straight or branched chain, or substituted benzyl, such as monochloro or monomethylbenzyl, and Y represents oxygen or sulfur. Preferred compounds of formula I are those wherein R is methyl, ethyl, propyl butyl, phenyl, monochlorophenyl, especially when the latter is 2'-or 4-- lows:
w-jg -OR S S 2 o R N I R c(oR in which R and R are as defined above and R is methyl or ethyl. The initial reaction is advantageously carried out at reflux temperature for from 4 to 20 hours. The separated intermediate in a solvent such as aqueous dioxane or aqueous methanol is hydrolyzed with dilute aqueous sodium hydroxide solution preferably at room temperature for several hours. Acidification of the reaction mixture with dilute hydrochloric acid gives the 5-hydroxyalkylidene rhodanine derivative.
Alternatively, good yields of the intermediate 5- alkoxyalkylidene rhodanine intermediates are obtained by heating the S-unsubstituted rhodanine with the orthoester at a temperature of about C. for from onehalf to 3 hours.
The compounds of formula I werein Y is sulfur are prepared from the intermediate 5-alkoxyalkylidene rhodanines, obtained as outlined above, by reaction with sodium sulfide in aqeuous ethanol at room temperature for from 15 to 60 minutes followed by acidification of the reaction product with hydrochloric acid.
The S-unsubstituted rhodanines used as starting materials described hereinabove are either known or are prepared by one of the following synthetic methods. Starting with an isothiocyanate, a compound of the formula RN=C=S is condensed with an excess of mercaptoacetic acid in the presence of triethylamine, by heating in a pressure bottle at l0O140C. for from 1 to 4 hours to give the desired 3-R-substituted rhodanine. The required isothiocyanates are prepared, for example, by the reaction of an appropriate amine (RNI-I with thiophosgene (CSCI Starting with a di thiocarbamate, a compound of the formula R-NH- C-SH,
preferably as a triethylamine salt, is condensed with chloroacetic acid (or ester) followed by treatment with mineral acid to give the rhodanine derivative.
The required orthoester reactants are prepared by known procedures from the appropriate cyanide shown, for example, as follows:
OCH
c a on R c NH l-lCl 2 5 5 o R-N l u S)\S i 0 cepted procedures. Preferably the dosage units will contain a compound of formula I in an amount of from about mg. to about 200 mg. per unit.
The pharmaceutical carrier employed may be, for example, either a solid or liquid. Exemplary of solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like. Exemplary of liquid carriers are syrup, peanut oil, olive oil, water and the like. Similarly the carrier or diluent includes any time delay material well known to the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax.
A wide variety of pharmaceutical forms can be employed. Thus, if a solid carrier is used the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form or in the form of a troche or lozenge. The amount of solid carrier will vary widely but preferably will be from about 25 mg. to about 1 g. If a liquid carrier is used, the preparation will be in the.
form of a syrup, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampule or an aqueous or nonaqueous liquid suspension.
The method of producing anti-arthritic activity in accordance with this invention comprises administering internally to an animal organism a compound of formula 1 above, usually combined with a pharmaceutical carrier, in an amount sufficient to produce antiarthritic activity without limiting side effects. The active medicament will be administered in a dosage unit, as described above, orally or parenterally, the oral route being preferred. Advantageously equal doses will be administered 1 or 2 times daily with the daily dosage regimen being from about 10 mg. to about 400 mg. When the method described above is carried out, antiarthritic activity is produced with a minimum of side effects.
The pharmaceutical preparations are made following the conventional techniques of the pharmaceutical chemist involving mixing, granulating and compressing when necessary, or variously mixing and dissolving the ingredients as appropriate to the desired end product.
The following examples illustrate the preparation of compounds of this invention and their incorporation into pharmaceutical compositions, and as such are not to be considered as limiting the invention set forth in the claims appended hereto.
EXAMPLE 1 A mixture of 27 g. (0.16 m.) of p-chlorophenyl isothiocyanate, 33 ml. (42.5 g., 0.475 m.) of mercaptoacetic acid and 5 drops of triethylamine is heated in a pressure bottle at l-130C. for 2%: hours. The reaction mixture is allowed to stand at room temperature overnight and filtered. The crude product is recrystallized from ethanol to give 3-(4-chlorophenyl)- rhodanine, m.p. l24.5-126C.
A mixture of 50 g. (0.2 m.) of the above-prepared rhodanine and 140 g. (0.86 m.) of triethylorthoacetate in 350 ml. of acetic anhydride is refluxed for 4 hours. The cooled reaction solution is filtered and the product is washed with 100 ml. of 70% aqueous acetic acid to yield 3-(4-chlorophenyl)-5-( l '-ethoxyethylidene)- rhodanine, m.p. 16817lC.
To a mixture of 32 g. (0.1 m.) of 3-(4- chlorophenyl)-5-( l '-ethoxyethylidene)-rhodanine in 400 ml. of water and 250 ml. of methanol is added 85 ml. of 5% sodium hydroxide solution and the resulting suspension is stirred at room temperature for five hours. The reaction mixture is filtered and thefiltrate is decolorized, then acidified with dilute hydrochloric acid to give 3'-(4-chlorophenyl)-5-(l'-hydroxyethylidene)-rhodanine, m.p. 200205C.
EXAMPLE 2 Following the procedures of Example 1, triethylorthopropionate is reacted with 3-(4'-chlorophenyl)- rhodanine in acetic anhydride for 5V2 hours to give 3- (4'-chlorophenyl)-5-( 1 '-ethoxypropylidene)- rhodanine. To a suspension of the latter (25 g., 0.0765 In.) in 200 ml. of dioxane and 200 ml. of water is added 50 ml. of 10% sodium hydroxide solution. The mixture is stirred at room temperature for 4 hours and then concentrated in vacuo at 40-45C. The residual solution is washed with ether, decolorized and acidified with dilute hydrochloric acid to yield 3-(4- chlorophenyl)-5-( l -hydroxypropylidene )-rhodanine, m.p. l45-l49C.
EXAMPLE 3 As described in Example 1, triethylorthophenylacetate is reacted with 3-(4-chlorophenyl)-rhodanine in acetic anhydride for 12 hours to yield 3-(4'- chlorophenyl)-5-( 1 '-ethoxy-2'-phenylethylidene)- rhodanine. To a suspension of the latter 15 g., 0.0385 m.) in ml. of dioxane and 100 ml. of water is added 22 ml. of 10% sodium hydroxide solution. The mixture is stirred at room temperature for 3 hours, concentrated in vacuo at 40-40C. and the remaining solution is washed with ether, then decolorized. The aqueous layer is acidified with dilute hydrochloric acid and the precipitate is taken up in methylene chloride. The latter solution (after being washed with water and dried) is evaporated in vacuo. The residue is dissolved in 10% sodium hydroxide and water, washed with ether and acidified with dilute hydrochloric acid to give 3-(4'- chlorophenyl)-5-( l -hydroxy-2'-phenylethylidene)- rhodanine, m.p. 134-137C.
EXAMPLE 4 To a suspension of 3 g. (0.091 m.) of 3-(4- chlorophenyl)-5( 1 -ethoxypropylidene )-rhodanine in 15 ml. of ethanol is added a solution of sodium sulfide in 10 ml. of water and the mixture is stirred at room temperature until solution is complete (15-20 minutes). This solution is added to 100 ml. of water, allowed to stand for 15 minutes, filtered and the filtrate is acidified with 2N hydrochloric acid to give 3-(4'- chlorophenyl)-5-( l -mercaptopropylidene)-rhodanine, m.p. l63-165C.
EXAMPLE 5 A mixture of 25 g. (0.12 m) of 3-phenylrhodanine, 80 g. (0.34 m.) of triethylorthophenylacetate [prepared as described in J.A.C.S. 68, 1917 (1946)] and 250 ml. of acetic anhydride is heated under reflux for 20 hours and the solution is then concentrated in vacuo. The residue is filtered and the solid is stirred with ml. of dioxane, 160 ml. of water and 40 ml. of 10% sodium hydroxide for four hours. The solution is concentrated in vacuo at 3540C. to evaporate the dioxane. The aqueous solution, after washing with ether and decolorizing with charcoal, is made acidic with dilute hydrochloric acid. The solid product is purified by chromatography to give 5-(l-hydroxy-2'- phenylethylidene)-3-phenylrhodanine, m.p. 146-l48C.
Alternatively, a mixture of 6 g. (0.029 m.) of 3- phenyl-rhodanine, 15 g. (0.063 m.) of triethylorthophenylacetate and 15 ml. of n-butyl ether is heated to reflux and then distillate is removed until the temperature of the mixture reaches 150C. After heating at this temperature for 1 hour, an additional 5 g. of orthoester is added and heating is continued for 30 minutes. To the reaction mixture is added 5 ml. of acetic anhydride and heating is continued for 5 minutes. The resulting mixture is concentrated in vacuo and the residue is eluted through a column of silica gel with 2:1- cyclohexane-benzene. The product from the first eluates give 5-(1 -ethoxy-2'-phenylethylidene)-3- phenylrhodanine, m.p. 119121C. Alkaline hydrolysis as described above of this intermediate furnishes the identical hydroxy derivative.
EXAMPLE 6 A mixture of 7.5 g. (0.05 m.) of 3-ethylrhodanine, 25 g. (0.128 m.) of trimethylorthophenylacetate and 80 ml. of acetic anhydride is heated under reflux for 18 hours. The solution is concentrated in vacuo and the residue chromatographed through silica gel using 50% benzene in cyclohexane as the eluant to give 3-ethyl-5- (1 '-methoxy-2-phenylethylidene)-rhodanine, m.p. 120l22C.
The above prepared 5-substituted rhodanine (2 g., 0.0068 m.) is stirred with 25 ml. of dioxane, 20 ml. of water and 8 ml. of 10% sodium hydroxide solution for 2 /2 hours. The resulting solution is concentrated in vacuo at 40C. to remove dioxane. The aqueous solution is washed with ether and acidified with dilute hydrochloric acid to yield 3-ethyl-5-( l -hydroxy-2- phenylethylidene)rhodanine, m.p. 74-76C.
EXAMPLE 7 A mixture of5 g. (0.033 m.) of 3-ethylrhodanine, 12 ml. of triethylorthoacetate and 35 ml. of acetic anhydride is heated under reflux for 18 hours and the solution is then concentrated in vacuo. The cooled residue is filtered and the solid is dissolved in ether. The ether solution is washed with water, dried and evaporated in vacuo to give 5(1-ethoxyethylidene)-3- ethylrhodanine. The latter (3.6 g.) is stirred with ml. of dioxane, 15 ml. of water and 15 ml. of 10% sodium hydroxide solution for 4 hours. The resulting solution is concentrated in vacuo at 40C. and the aqueous solu tion is washed with ether, decolorized, then made acidic with dilute hydrochloric acid. The precipitate is dissolved in 10% sodium hydroxide solution, washed with ether and the aqueous solution is made acidic with dilute hydrochloric acid to give the product, 3ethyl-5- (l'-hydroxyethylidene)-rhodanine, m.p. 93C.
EXAMPLE 8 A mixture of 8.4 g. (0.04 m.) of 3-phenylrhodanine, 21 g. (0.12 m.) of triethylorthopropionate and 80 ml. of acetic anhydride is heated under reflux for 6 hours, cooled and filtered. The solid is washed with 50% aqueous acetic acid to afford 5-(1-ethoxypropylidene)-3- phenylrhodanine, m.p. 178-181C.
The above prepared ethoxy derivative (10 g. 0.034 m.) in 80 ml. of dioxane, 80 ml. of water and ml. of 10% sodium hydroxide solution is stirred for four hours. The resulting solution is concentrated in vacuo at 3540C. and the aqueous solution is washed with ether, followed by acidification with dilute hydrochloric acid to yield 5-(1-hydroxypropylidene)-3- phenylrhodanine, m.p. l05-111C.
EXAMPLE 9 A mixture of 1 24.4 g. (0.1 m.) of 3-(4- chlorophenyl)rhodanine, g. of trimethyl fi-phenylorthopropionate [prepared as described in J.A.C.S. 69, 2665 (1947)] and 150 ml. of acetic anhydride is heated under reflux for 18 hours. Upon standing at room temperature the solid separates from the reaction mixture which is filtered and washed with acetic acid to give 3- (4-chlorophenyl)-5-(1-ethoxy 3'-' phenylpropylidene)-rhodanine. The latter (20 g. 0.052 m.) is stirred at room temperature with 250 ml. of dioxane, 250 ml. of water and 35 ml. of 10% sodium hydroxide solution for 2 hours. The solution is concentrated in vacuo at 40C. and then washed with ether. The aqueous solution is made acidic with dilute hydrochloric acid to give 3-(4'-chlorophenyl)-5'(1-hydroxy- 3'-phenylpropylidene)-rhodanine, m.p. 170l73C.
EXAMPLE 10 As described in Example 1, a mixture of 6. l 2 g. (0.04 m.) of p-fluorophenyl isothiocyanate, 4.15 ml. (5.5 g., 0.06 m.) of mercaptoacetic acid and 5 drops of triethylamine is heated in a pressure bottle at 1 10-130C. for 3 hours to yield after cooling and filtration the product, 3-(4-fluorophenyl)-rhodanine, m.p. l55158C.
Similar reaction of this rhodanine (0.2 m.) with 140 g. (0.86 m.) of triethylorthoacetate in 350 ml. of acetic anhydride followed by alkaline hydrolysis of the intermediate 5-( l '-ethoxyethylidene)-3-(4-fluorophenyl)- rhodanine gives the corresponding 3-( 4'- fluorophenyl)-5-( 1 '-hydroxyethylidene)-rhodanine.
EXAMPLE 1 1 To a solution of 4.73 g. (0.05 m.) of chloroacetic acid in 40 ml. of water is added a solution of 2.7 g. (0.025 m.) of sodium carbonate in 20 ml. of water. The solution is cooled in an ice bath and 14.2 g. (0.05 m.) of the triethylamine salt of p-tolyl dithiocarbamic acid is added portionwise over five minutes. The resulting mixture is stirred at room temperature for 1 /2 hours. Water is added to bring total volume to 150 ml. and the resulting mixture is warmed on the steam bath for 5 minutes, then filtered. The filtrate is acidified with 40 ml. of 6N hydrochloric acid, heated to C., cooled, filtered and the solid washed with water to leave 3-(4'- tolyl)-rhodanine, m.p. l64l65C.
Following the procedures of Examples 1 and 2, triethylorthopropionate is reacted with 3-(4-toly1)- rhodanine in acetic anhydride to give 5-(1'- ethoxypropylidene)-3-(4'-tolyl)-rhodanine. The latter is hydrolyzed with 10% sodium hydroxide solution to yield upon workup, 5-(1-hydroxypropylidene)-3-(4'- tolyl)-rhodanine.
EXAMPLE 12 A mixture of6. 12 g. (0.03 m.) of 3,4-dichlorophenyl isothiocyanate, 2.8 ml. (3.68 g., 0.04 m.) of mercaptoacetic acid and a few drops of triethylamine is heated in a pressure bottle at 130C. for'2 hours. The cooled reaction mixture is filtered to give 3-(3',4- dichlorophenyl)-rhodanine, m.p. 176-178C.
The rhodanine is reacted as described in Examples 1 and 3 with tr iethylorthophenylacetate in acetic anhydride to yield 3-(3',4-dichlorophenyl)-5-(1'-ethoxy- 2'-phenylethylidene)-rhodanine which is similarly hydrolyzed to 3-(3,4'-dichlorophenyl)-5-(1-hydroxy-2'- phenylethylidene )-rhodanine.
7 Similarly, employing 2-chloro-4-methylphenyl isothiocyanate as described above yields the corresponding 3-(2'-chloro-4'-methylphenyl)-rhodanine-which is reacted with triethylorthophenylacetate and the, interdanine, 3 moles of orthoester and approximately moles of acetic anhydride. The reaction mixture is worked up by concentration in vacuo to remove the acetic anhydride, then crystallization by the addition of petroleum ether. Alternatively the residue mediate 5-alkoxy derivative is hydrolyzed to give 3-(2- 5 hl o-4- th 1 h 1) 5 (1-h d 2 is chromatographed on a silica gel column, eluting phenylethylidene)-rh danine with mixtures of cyclohexane-benzene.
EXAMPL l B. The 3-substituted rhodanine is heated with the apred, ms E 3 M /T bl t propriate orthoester (2-3 moles) at a temperature I e g a c of l 50l 55C. for a perlod of from 2-3 hours, with 3-(4-chlorophenyl)-5-(l'- 25 workup as in (A). hydroxy-3 '-phenylpropylidene rhodanine Cal i m lfat (hydrate 150 The final products are obtamed by hydrolyzmg the 233: intermediates in 3 to 5 parts by volume of dioxane to Talc 5 which is added 3 parts by volume of 10% sodium hystearic acid 3 droxide solution followed by 3 parts by volume of water. The mixture is stirred at room temperature for l-2 I The Sucrose, Calclum Sulfate and P y hours to affect complete hydrolysls, then concentrated I n I 1 y y -P P PY 9 f in vacuo to remove most of the dloxane. The residual 9 8 mlxed and granulated 11th hot 10% gelatin solution is extracted with ether and the product is pre- Solutlon- The Wetted mass Passed through a 6 cipitated by acidification with dilute hydrochloric acid. mesh screen directly onto drying trays. The granules are dried at 120F. and passed through a No. 20 mesh screen, mixed with the starch, talc and stearic acid, and TABLE I compressed into tablets.
EXAMPLE 14 In redients M .ICapsule g g R-N o 3-(4'-chlgrophenyil)-5-(1'5 150 hydroxy- '-pheny propyi ene)- 0 rhodanine 3 S S l OH(CH2CH3) Magnesium stearate 5 Lactose 300 R Ethoxy Intermediate Hydroxy Product Example R R Method M.P. C. M.P. C.
15 4-ch1orophenyl 4-chlorobenzyl B l 18-120 133-135 16 4-chlorophenyl 4-methylbenzyl B 165-166 139-140 17 isopropyl benzyl B 105-106 91-93 18 4-chlorophenyl isobutyl B 106-107 168-170 19 n-propyl benzyl B 66-68 68-69 20 isobutyl benzyl B syrup 91-93 21 benzyl benzyl B 11 l-l 16 108-110 22 ethyl ethyl B 62-64 -46 23 isopropyl ethyl A -57 55-56 24 benzyl ethyl A 98-99 93 2s allyl ethyl A -61 72-74 26 isobutyl ethyl A 59-61 78-79 27 cyclopropyl ethyl B -78 103 28 n-butyl ethyl A 39-41 50-52 29 cyclohexyl ethyl A 91-93 100-101 30 phenethyl ethyl B 97-98 1 18-1 19 3 l sec-butyl ethyl B syrup syrup 32 n-propyl ethyl B 52-54 68-69 33 methyl ethyl B 96-98 -98 34 3-pyridylmethyl ethyl A 86-88 186 35 2-pyridylmethyl ethyl A 82-83 215-216 36 crotyl ethyl A 48-50 68-71 37 2-methylallyl ethyl A 46-48 53-55 Also useful are amine salts of the compounds of formula l, for example, salts formed with Z-aminopyridine and 2-aminothiazole. Such salts similarly have antiarthritic activity and are prepared as follows:
a. A solution containing 3.6 g. of 3-ethyl-5-( 1 hydroxy-2 '-p henylethylidene )-rhodanine (prepared as in Example 6) and 1.2 g. of 2- aminopyridine in 25 m1. of 30% aqueous methanol is warmed on a steam bath for 5 minutes. The resultant reddish solution is then concentrated to remove most of the methanol and allowed to crystallize. The crude product is isolated by filtration and R- NI i Y' wherein:
R is lower alkyl of from 1 to 4 carbon atoms, straight or branched chain, cycloalkyl of from 3 to 6 carbon atoms, alkenyl of from 3 to carbon atoms, phenyl, phenylalkyl of from 7 to 9 carbon atoms, monohalophenyl, dichlorophenyl, alkylphenyl, methylchlorophenyl or pyridylmethyl;
R is lower alkyl of from 1 to 4 carbon atoms, phenylalkyl of from 7 to 9 carbon atoms, said alkyl moieties being straight or branched chain, monochlorobenzyl or monomethylbenzyl; and
Y is oxygen or sulfur, or a 2-aminopyridine or 2- aminothiazole salt thereof.
2. A compound according to claim 1 in which Y is oxygen.
3. A compound according to claim 2 in which R is lower alkyl, phenyl, monochlorophenyl, cyclohexyl or benzyl.
4. A compound according to claim 3 in which R is methyl, ethyl, benzyl or phenethyl.
5. A compound according to claim 4 in which R is 4'- chlorophenyl and R is methyl.
6. A compound according to claim 4 in which R is 4- chlorophenyl and R is ethyl.
7. A compound according to claim 4 in which R is 4- chlorophenyl and R is benzyl.
8. A compound according to claim 4 in which R is 4- chlorophenyl and R is phenethyl.
9. A compound according to claim 4 in which R is phenyl and R, is ethyl.
10. A compound according to claim 4 in which R is phenyl and R is benzyl.
11. A compound according to claim 4 in which R is ethyl and R is benzyl.
12. A compound according to claim 4 in which R is benzyl and R is benzyl.
13. A compound according to claim 4 in which R is benzyl and R is ethyl.
14. A compound according to claim 4 in which R is methyl and R is ethyl.
15. A compound according to claim 4 in which R is n-propyl and R is ethyl.
16. A compound according to claim 4 in which R is n-butyl and R is ethyl.
17. A compound according to claim 4 in which R is cyclohexyl and R is ethyl.
18. A compound according to claim 4 in which R is benzyl and R is ethyl.
19. A compound according to claim 2 in which R is allyl and R is ethyl.
20. A 2-aminopyridine or 2-aminothiazole salt of a compound defined in claim 1.

Claims (20)

1. A CHEMICAL COMPOUND OF THE FORMULA:
2. A compound according to claim 1 in which Y is oxygen.
3. A compound according to claim 2 in which R is lower alkyl, phenyl, monochlorophenyl, cyclohexyl or benzyl.
4. A compound according to claim 3 in which R1 is methyl, ethyl, benzyl or phenethyl.
5. A compound according to claim 4 in which R is 4''-chlorophenyl and R1 is methyl.
6. A compound according to claim 4 in which R is 4''-chlorophenyl and R1 is ethyl.
7. A compound according to claim 4 in which R is 4''-chlorophenyl and R1 is benzyl.
8. A compound according to claim 4 in which R is 4''-chlorophenyl and R1 is phenethyl.
9. A compound according to claim 4 in which R is phenyl and R1 is ethyl.
10. A compound according to claim 4 in which R is phenyl and R1 is benzyl.
11. A compound according to claim 4 in which R is ethyl and R1 is benzyl.
12. A compound according to claim 4 in which R is benzyl and R1 is benzyl.
13. A compound according to claim 4 in which R is benzyl and R1 is ethyl.
14. A compound according to claim 4 in which R is methyl and R1 is ethyl.
15. A compound according to claim 4 in which R is n-propyl and R1 is ethyl.
16. A compound according to claim 4 in which R is n-butyl and R1 is ethyl.
17. A compound according to claim 4 in which R is cyclohexyl and R1 is ethyl.
18. A compound according to claim 4 in which R is benzyl and R1 is ethyl.
19. A compound according to claim 2 in which R is allyl and R1 is ethyl.
20. A 2-aminopyridine or 2-aminothiazole salt of a compound defined in claim 1.
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4104467A (en) * 1976-07-16 1978-08-01 E. R. Squibb & Sons, Inc. 1,3-Benzodithiolanes

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US2739970A (en) * 1956-03-27 Tfflazolone berivative

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2739970A (en) * 1956-03-27 Tfflazolone berivative

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4104467A (en) * 1976-07-16 1978-08-01 E. R. Squibb & Sons, Inc. 1,3-Benzodithiolanes

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