IE46011B1 - Derivatives of 2-imino-4-thiazolines and thiazolidines - Google Patents

Abstract

The novel N,N'-bis-(3-methylthiazolidin-2-ylidene)succinamide of the formula is prepared. This compound is obtained by reacting 2-imino-3-methylthiazolidine either with 3-methyl-2-succinyliminothiazolidine in the presence of ethyl chloroformate or with a derivative of succinic acid. The novel compound can be used for treating mental disturbances.

Description

This- Invention is concerned with derivatives of 2-iminothiazolidine and of 2-iminothiazoline, and with pharmaceutical compositions containing them.

J Ν,Ν-dimethylindoleamines such as dimethylserotonin and 5 dimethyltryptamine are psychotomimetic agents and are believed to be produced in excessive amounts by individuals with certain mental aberrations, most commonly classified as schizophrenia. The enzyme indoleamine-N-methyl transferase catalyses the methylation steps in the biosynthesis of these compounds.

Accordingly, it is believed that inhibitors of this enzyme will be of therapeutic value in management of the body chemistry of patients having mental aberrations such as schizophrenia and thus result in alleviating some of the symptoms of the disease.

The compounds of this invention have structural formula I: R or are pharmaceutically acceptable salts thereof, formula the dotted line indicates that the linkage or unsaturated; In the is saturated R represents represents (1) θι_3 alkyl, either straight or branched chain, such as methyl, ethyl or propyl; (2) C3_5 alkenyl, such as allyl, (3) C3_g alkynyl, such as propargyl; (1) 0 II 3 -C-R where R is a C alkyl group having 1-5 amino, alkanoylamino, ^2-4 alkanoylamino and phenyl, carboxy, C2-4 alkanoyl or R substituent(s), R, R and the dotted line in the last formula being identical with those in the ring shown in Formula I, -246011 or R is a pyridyl radical, (2) represents hydrogen, alkyl, phenyl, either unsubstituted or substituted with one or more 0^_3 alkoxy groups, or pyridyl; and R, R^ and the dotted line in the last formula are identical with those in the ring shown in Formula I, or where R^ represents hydrogen or C. J alkyl, and 5 7 -‘-“Λχ 7 R represents C, , alkyl or-COR , where R *-·- a represents C^_3 alkyl or phenyl, or R and r5, together with the nitrogen to which they are attached, represent R represents hydrogen, 0^-3 alkyl or trifluoromethyl.

One preferred group of compounds in accordance with the 1 3 present invention comprises those in which R is -COR , particularly when R is pyridyl, (C2_4 alkanoylamino)methyl, (C2_4 alkanoylamino) (benzyl)methyl, or 2-(3-methylthiazolidin2-ylidenaminocarbonyl) ethyl.

Another preferred group comprises those of formula: -34 6 013. r-s H-CH-N 6 where R, R and R are as defined above, and their pharmaceutically acceptable salts o A preferred compound of the present invention has the formula: s r >= t 0 II It NCCK-NHCCH, or is a pharmaceutically acceptable salt thereof.

She pharmaceutically acceptable salts contemplated by this invention are usually acid-addition salts formed from a compound I and an organic or < inorganic acid recognized as providing a pharmaceutically acceptable acid10 addition salt, such as hydrochloride, hydrobromide, dihydrogen phosphate, sulfate, citrate, pamoate, pyruvate, naphthalenesulfonate, isethionate, maleate or fumarate.

Where the novel compound has a free carboxylic acid group, the pharmaceutically acceptable salt can be in the form of an ammonium, alkaline15 earth metal or alkali taetal salt of the carboxylate group such as the sodium, potassium or calcium salt.

It has been found that compounds of Formula I, by virtue of their ability to inhibit indoleomine-N-methyl transferase, are useful in the treatment of certain mental aberrations in man, such as schizophrenia.

A group of amide compounds in accordance with the present invention is prepared in accordance with the following equation: Β Β II where Υ is C1-, (ci_;, nlhyl)0C0- or and ϊΡ is C._~ aminoalkyl, (Cg alkanoylamino)-(^ g alkyl), (Cg 4 alkanoylaaiao) (phenyl)·» (Cj_5 alkyl), pyridyl, (Cg_4 alkanoyl)-(Cj__ alkyl),, or carboxamido~(c^5 alkyl). Where is aminoalkyl, the reaction is conducted with the amino group protected, e.g. with t-butoxycarbonyl. Where Y is (c.. . alkyl)0C0- the acylating agent can be formed in situ by treating the corresponding free carboxylic acid group with a C^_4 alkyl chloroformate.

The reaction is conducted in an inert organic solvent such as a chlorinated hydrocarbon, for example, methylene chloride, chloroform, or dimethyl fonaaaide, at -5°C to 10°C for 1-72 hours. a Where B^ is carboxy-(C^ alkyl), tbs compounds are prepared by treating the 2-imino compound with a carboxylic anhydride such as succinic anhydride in a chlorinated hydrocarbon such as methylene chloride nt 25°C to reflux for 1-6 hours. η Where Ic io acetylmethyl, it can also be prepared by treating the 2imino compound with diketene at 0-10°C in a C^_^. alkanol such as ethanol and allowing the mixture to warm to room temperature.

A second group of the compounds of this invention is prepared in 23 accordance with the following equation: B B wl.ei'e X is Cl or -N(CH_)(> and 'Κ ,» ΪΓ io -Οξ,-Ν where Ha Is hydrogen or 3 alkyl and ia Cj_3 alkyl®-COR^ where R? ia alkyl or phenyl, or R^ and R^» together with the nitrogen to which they are attached, form a 5 radical -N 0' Shore X ia Cl the process is conducted by mixing the two starting materials at 0-10°C in an inert organic solvent, such a3 a chlorinated hydrocarbon, especially methylene chloride, and wanning to room temperature to 50°C for up to about 6 hours. Where X is (CHj)gN-, the process is conducted by heating a mixture of the starting materials in an inert organic solvent, such os benzene, at 50°C to reflux temperature for 10-24 hours.

Another group of compounds I, that is those in which R^ is i is prepared in accordance with the following equation: In the above equation, the reagent is indicated as an aldehyde for the sake of simplicity, hut it is meant to include functional equivalents thereof, such as aldehyde precursory for example paraformaldehyde or aminals (aminealdehyde reaction products). The process is conducted by mixing the starting material with the aldehyde or aldehyde precursor in an inert organic solvent such as benzene or toluene and heating between 50°C and reflux temperature with provision for removing water produced by the condensation reaction such as adding molecular sieves to the reaction mixture or refluxing in a DeasStark apparatus. ip Under similar reaction conditions pyridoxal provides a compound of structure When using compounds of Formula I for therapeutic treatment, the route of administration can he oral, rectal, intravenous, intramuscular or intra1? peritoneal. Doses of 0.10 to 100 mg/kg/day and preferahly 1 to 10 mg/kg/day of active ingredient are generally adequate, and it is preferred that it he administered in divided doses given two to four times daily.

It is to be noted that the precise unit dosage form and dosage level depend upon the case history of the individual being treated and, consequently, are left to the discretion of a skilieu therapist.

The invention provides pharmaceutical compositions in unit dosage form comprising a compound I (and especially the preferred groups of compounds mentioned above) together with a pharmaceutical carrier. Such compositions may be in any art-recognized form suitable for oral use, such as tablets, troches 2'5 lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard, or soft capsules, syrups or elixirs. For intravenous and intramuscular and intraperitoneal use the pharmaceutical compositions may be in any art-recognized form of a sterile injectable preparation such as a sterile aqueous or oleaginous solution or suspension. The amount of active · ingredient incorporated in a unit dosage of the ahove described pharmaceutical Compositions may he from 1 mg to 500 mg.

Example 1 3,5-jDimethyl-2-iminothiazolidine Fumarate Step Ai Preparation of methyl N-(2-hydroxypropyl)clithiocarbamate I® 60 g (0.262 mmole) of l-amiao-2-propanol oxalate was suspended in 180 ml of pyridine and 101 g of triethylamine was added. The mixture was stirred mechanically for 1 hour, then cooled to 0° and 38 g of carbon dir sulfide (0.5 mole) was added dropwise. After 2 hours at 0®C, 36 g of methyl iodide (0.254 mole) was added dropwise and almost all solids dissolved.

The mixture-was stored in a refrigerator overnight (0-5°C). The mixture was poured into 2.4 1. of 3N H2S®4 an®· extracted with ether 3 times. The ether extracts were washed with water, 3N water, aqueous NaHCOj solution and water, dried over NajSO^ and stripped down to 18.79 g. (47%) of oily methyl N-(2-hydroxypropyl) dithiocarbamate.

Step Bi Preparation of 5-methyl-2-methylthio-2-thiazoline 17.37g.. of the dithiocarbamate from Step A in 30 ml. dry ether was added to 73 ml. thionyl chloride at 0-5’C. The mixture was stirred at 0° for 2 hours, then stored in a refrigerator overnight. The thionyl chloride was evaporated at 30°C. and the residual oil (containing elemental sulfur) was poured into saturated NaHCO^ solution and extracted with ether. The ethereal fraction was extracted with dilute HCl. The aqueous fraction was basified with NaOH solution and extracted with ether. Evaporation of the ether afforded 6.65 g. liquid residue. This was chromatographed on a column of silica gel using benzene as eluant to give 2.5 g. (16.2%) of oily 5-methyl-2-methylthio-2-thiazoline.

Step Ci Preparation of 3,5-Dimethyl-2-methylthio-2thiazoline fluoborate 588 Mg. of the 5-methyl-2-meth.y].thio thiazoline from step B and 592 mg. trimethyl oxonium fluoborate were stirred together in 40 ml. CH2CI2 overnight at room temperature.

The fluoborate dissolved slowly as it reacted. The reaction mixture was stripped to dryness to give a colorless oil which was used directly in the next step.

Step D: Preparation of 3,5-dimethyl-2-ircinothiazolidine fumarate The crude fluooorate salt from Step C was dissolved in 40 ml. of alcohol and the solution was saturated with gaseous NH^. The solution was stirred at room tem-946011 perature for 3 hours. The solution was evaporated to dryness. The resulting oily residue was taken up in 10 ml. of water, then 40 ml. CHClg was added with stirring and 40% NaOH solution was added to make the aqueous fraction strongly basic. The two layers were separated, and the aqueous fraction was extracted once more with CHClg. The combined CHCl^ fraction was dried and concentrated to dryness to give 630 mg. of oil. The compound was converted to the fumarate, and crystallized from isopropanol-ether to give 720 mg. cream-colored crystals, m.p. 130-138°C. (73%) overall. Recrystallization of the fumarate from isopropanol-ether gave 470 mg. 3,5-dimethyl-2-iminothiazolidine fumarate, m.p. 133-6°C.

Example 2 2-Imino-3-methyl-4-trifluoromethyl-4-thiazoline fluorosulfonate 336 mg. of 2-amino-4-trifluoromethylthiazole was dissolved in 15 mg. CII2C12. The flask was placed in an ice bath and 240 mg. of CKgSO^E in 5 ml. CK2C12 was added.

The mixture was then placed in a refrigerator over the weekend. The colorless crystals were collected on a filter to give 450 mg. (80%) of 2-imino-3-methyl-4-trifluoromethyl-4-thiazoline fluorosulfonate, m.p. 177-78°C.

Example 3 2-Imino-3-methyl-4-thiazoline A mixture of 1.0 g. of 2-aminothiazole and 2 ml. of methyliodide in 10 ml. of isopropanol was heated at reflux for 2 hours. The hot solution was treated with decolorizing carbon and filtered, and the filtrate was cooled in the refrigerator. The precipitate was collected on a filter, -10-46011 washed with isopropanol, and dried to give 1.377 g. (57%) of 2-imino-3-methyl-4-thiazoline.

Example 4 2-Imino-3-methylthiazolidine.HCl.1/2 H20 5 A solution of 44.5 g. of the corresponding hydroiodide in 300 ml. of water was added to a suspension of 52.5 g. of silver chloride (0.365 mole) in 300 ml. of water. The mixture was stirred at 80°C. for 3¾ hours, cooled and filtered. The filtrate was evaporated to dryness and the solid was crystallized from isopropanol and a little ether to give 23.73 g. (85%) of 2-imino-3-methylthiazolidine.HCl.1/2 HjO, m.p. 73-76’C.

Concentration of the mother liquors afforded a second crop of 4.17 g. of the product.

By the procedure substantially as described in Example 3, but substituting for the methyl iodide and the 2-aminothiazole used therein, an equiraolecular amount of an organic halide of formula R-Hal and compound of formula: there are produced according to Equation I the 3-R-2 20 iminothiazolidines amd thiazolines identified in Table I.

Equation I R 4®0ii . R_R^ Thiazolidines ch3ch2ch2- H CH-CH.- H 32 CH2=CHCH2 h ch=c-ch2- h Thiazolines CH3CH2CH2- .£ ch3ch2- H CH2=CHCH2 η CH=C-CH2- η Table I R2__Hal H Br Η I H Br H Br H Br Η 'X H Br H Br Example 5 m.p. (°C.) 121-123 80-83 (as maleate salt) 112-116 143-145 2-Dimethylaminomethylimino-3-methylthia2olidine A mixture of 600 mg. of 2-imino-3-methylthiazolidine, 10 mg. of its hydrogen iodide salt, and 550 mg. of bis(dimethylamino)methane in 10 ml. of benzene were refluxed overnight. The mixture was concentrated to dryness, and the residue was twice taken up in chloroform and evaporated to dryness to give 200 mg. of 2-dimethylaminomethylimino3-methylthiazolidine, b.p. 98-102’C. at 2.5 mm of Hg. pressure.

Following the procedure of Example 5, but sub25 stituting for the 2-imano-3-methylthiazolidine used therein, an equivalent amount of the 2-imino-3-R-thiazolidines and thiazolines depicted in Table II, there are produced the 2-dirnethylaminomethylimino-3-R-thiazolidines and thiazolines also depicted in Table II, in accordance with Equation Ils -124 6 011 Equation II ’2-fl R + CH2[n(ch3)2i2E-f5 K'NZ?4SNCK2N(CH3)2 Table II Thiazolines 4-CF3 H Thiazolidines ch3C2H5“ --°3Η7 CH2=CH-CH2 Example 6 3-Methyl-2-Succinimidomethyliminothiazolidine Bromomethylsuccinimide (53.9 g.) was added ‘ portion-wise to a mixture of 32.7 g. of 2~imino-3-methylthiazolidine and 42 ml. of triethylamine and 150 ml. of methylene chloride. A reaction occurred spontaneously.

The mixture was evaporated to dryness, and the residue was taken up in chloroform and sodium hydroxide solution. The aqueous phase was separated and extracted three times with chloroform. The combined chloroform extracts were dried and concentrated to dryness. The residue was crystallized twice from benzene to give 13.5 g. of 3-methyl-2-succinimidomethyliminothiazolidine, m.p. 142-144’C. -1346011 Following the procedure of Example 6, but substituting for the 2-imino-3-methylthiazolidine used therein an equimolar amount of the 2-imino-3-R-thiazolidines and thiazolines depicted in Table III, there are produced the 2-succinimidomethylimino-3-R-thiazolidines and thiazolines also depicted in Table III, in accordance with Equation III Table III Thiazolines ch3ch3Thiazolidines 4-CF3 H ch3C2H5“ CH2=CH-CH2· ch=c-ch2H H H H Example 7 2-Benzamidomethylimino-3methylthiazolidine, maleate A solution of 676 mg. of N-chloromethyl benzamide in 15 ml. of methylene chloride was slowly added to an ice -144 6 ο ι ΐ cold mixture of 2.0 ml. of triethylamine, 488 mg. of 2imino-3-methyithiazolidine, and 25 ml. of methylene chloride. After 2 hours stirring at room temperature, the mixture was evaporated to dryness. The residue was dissolved in methylene chloride and washed with water and dilute hydrochloric acid. The combined aqueous phases were basified with sodium bicarbonate and extracted with methylene chloride. The methylene chloride was washed with water, dried, and evaporated to dryness. The residue 1¾ was triturated with ether and the product, in free base from' (250 mg.)) was collected on a filter.

The maleate salt was prepared from 11.0 g. of free base and 5.12 g. of maleic acid in 100 m. methanol and isolated by adding ether to incipient cloudiness, seeding and cooling to give 10.42 g. of 2-benzamidomethylimino-3-methylthiazolidine, maleate, m.p. 120-121°C.

A second crop of 4.28 g. was isolated from the mother liquors, m.p. 119-120°C.

Employing the procedure substantially as described 20 in Example 7, but substituting for the N-chloromethylbenzamide used therein an equimolar amount of U-chloromethylpropionamide there is produced 2~propionamidomethylimino3-methylthiazolidine and maleate salt thereof.

Following the procedure of Example 7, but sub25 stituting for the 2-imino~3-methylthiazolidine used therein, an equivalent amount of the 2-imino--3-R-thiazolidines and thiazolines depicted in Table IV, there are produced the 2-benzamidomethylimino-3-R”thiazolidines and thiazolines also depicted in Table IV, in accordance with Equation IV: --154 6011 Equation IV + C1CH2NHC-^J^ H2JT v Τκ:η2νη-οTable IV • R Thiazolines 5 ch3ch3Thiazolidines Λ-CF H CH3C2H5 n~C3H7CH2=CH-CH2' Example 8 Bis[3-methylthiazolidin-2-ylideneamino]methane A mixture of 25 g. of 2-imino-3-methylthiazoli15 dine, 6.5 g. of paraformaldehyde, 75 g. of molecular sieves, and 250 ml. of benzene was refluxed for 5 hours. Molecular seives (30 g.) and 6.5 g. of paraformaldehyde were added and refluxing was continued overnight. The molecular sieves were collected on a filter and washed well with benzene.

The combined filtrate and washings were evaporated to dryness to give 21 g. of crystalline bis f3-methylthiazolidin-2-ylideneamino]methane, m.p. 57-59°C.

A hydrochloride salt was prepared by dissolving 350 mg. in 2 ml. of water and 2 ml. of 6N hydrochloric acid -164601 ϊ and evaporating to an oily residue. Evaporation of acetone, iaopropanol and benzene from the residue followed by trituration gave crystalline hydrochloride salt.

Employing the procedure substantially as described 5 in Example 8 but substituting for the paraformaldehyde used therein an equimolar amount of acetaldenyde, benzaldehyde (or aminal}, 3,4-dimethoxybenzaldehyde, 4-pyridinecarboxaldehyde and pyridoxal, there are produced respectively: l, 1-bis(3-methylthiazolidin-2-ylidenamino)ethane dihydro10 chloride, m.p. 292°C. a,α-bis(3-methylthiazolidin-2-ylideneamino)toluene, m. p. 167-169°C.; α,α-bis(3-methylthiazolidin-2-ylideneamino)-3,4-dimethoxytoluene, m.p. 144-145°C. a,α-bis(3-methylthiazolidin-2-ylideneamino)-γ-picolinej m.p. 110-113°C. , m.p. 172-175°C.

Following the procedure of Example 8, but substituting for the 2-imino-3-methylthiazolidine and para20 formaldehyde used therein, an equivalent amount of the 2-imino-3-R-thiazolidines and thiazolines and aldehydes depicted in Table V, there are produced the bis [3-R3 thiazolidin-2-ylideneamino]-R -methanes and bis [3-Rthiazolin-2-ylidineamino]-R^-methanes also depicted in Table V, in accordance with Equation V: -1746011 Equation V . . . »2-Λ8\ 0 + CHO -> R >6 H Thiazolines CH. ch3Thiazolidines CH3C2H5 n- c3h7 CH2=CH-CH2CH=C-CH_ Table V 4-CP.

-CH.

-CH. _ - A -o 0OC OCH. reagent is the aminal, · a,a -Ν,Ν,Ν' ,Ν'-tetramethyltoluenediamine.

Example 9 N,N'-bis-(3-methylthiazolidin-2-ylideno)succinamide Step A; Preparation of bis-(4-nitrophenyl) succinate A mixture of 2.36 g. (20 mmoles) of succinic acid, 6.516 g. (44 mmoles) of 4-nitrophenol and 3.24 g. (40 mmoles) of Ν,Ν'-dicyclohexylcarbodiimide was stirred at room temperature in 225 ml. of ethylacetate for 2 days. -1846011 The mixture was filtered and the filtrate was concentrated to dryness. The residue was triturated with 40 ml. of chloroform and the solids were collected on a filter and air dried to give 1.38 g. of bis-(4-nitrophenyl) succinate, m.p. 176-178’C.

Step B: Preparation of N,Ν'-bis-(3-methylthiazolidin-2ylidene) succinamide A mixture of 80 mg. of 2-iminc-3-methylu;iiazolidine, 118 mg. of bis-(4-nitrophenyl) succinate and 5 ml. of chloroform was refluxed for 5.5 hours. The mixture was diluted with chloroform, washed twice with sodium carbonate solution, dried over sodium sulfate and concentrated to dryness. The residue was recrystallized from 2 ml. of methanol to give 68 mg. of Ν,Ν'-bis-(3-methyl15 thiazolidin-2-ylidene)succinamide, m.p. 181-183°C.

Example 10 N-(3-methylthiazolidin-2-ylidene) aminoacetamide dihydrochloride Step A: Preparation of N-(3-methylthiazolidin-2-ylidene)2 0 t-butoxycarbonylaminoacetamide____ Ethyl chloroformate (0.25 ml.) at -5°C. was added to a solution of 350 mg. of t-butoxycarbonylaminoacetic acid and 0.4 ml. of triethylamine in 10 ml. of methylene chloride at -5°C. After stirring 5 minutes at -5°C. there was added a solution of 610 mg. of 2-imino-3-methylthiazolidine hydrogen iodide and 1.0 ml. of triethylamine in 10 ml. of methylene chl--ide also at -5OC. Stirring was continued at -5°C. for 15 minutes and one hour at room temperature. The reaction mixture was washed with 40 ml. of 20% (w/v) citric acid solution, sodium bicarbonate solution, and water, dried and concentrated to dryness. -1946011 The residue was triturated with ether, petroleum ether and ether and finally collected to give pure N-(3-methylthiazolidin-2-ylidene)-t-butoxycarbonylaminoacetamide.

Step B; Preparation of N-(3-methylthiazolidin-2-ylidene) aminoacetamide dihydrochloride_ The product from Step A, (2.0 g.) was dissolved in 100 ml. of chloroform and the solution was saturated with hydrogen chloride gas by bubbling it through the solution for 20 minutes. After 2 hours at room temperature the excess of hydrogen chlori.de was expelled.by bubbling in nitrogen. The precipitated product was collected and air dried under nitrogen to give 1.66 g. of N-(3-methylthiazolidin-2-ylidene) aminoacetamide dihydrochloride, m. p. 190-194°C.

I& Employing the procedure substantially as described in Example 10, Step A, but substituting for the t-butoxycarbonylaminoacetio acid used therein an equimolar amount of 2-acetylamino-2-benzylacetic acid, nicotinic acid, acetoacetic acid and 3-methyl-2-succinyliminothiazoli20 dine (See Example 11), there are produced respectively: N-(3-methylthiazolidin-2-ylidene) 2-acetylamino-2-benzylacetamide, m.p. 142-149°C.

N-(3-methylthiazolidin-2-ylidene) nicotinamide, m.p. 108-109°C.

N-(3-methylthiazolidin-2-ylidene) acetoacetamide, m.p. 43-45’C.; and N,N'-bis-(3-methylthiazolidin-2-ylidene)succinamide, m.p. 183-184’C.

Following the procedure of Example 10, but sub30 stituting for the 2-imino-3-methylthiazolidine used therein, an equivalent amount of the 2-imino-3-R-thiazolidines and thiazolines depicted in Table VI , there are produced the -204 6 0 11 N-(3-R-thiazolidin-2-ylidene)aminoacetamides and N-(3-Rthiazolin-2-ylidene)aminoacetamides also depicted in Table VI in accordance with Equation VI: Equation VI R' ,2 S IT NH t R + HOOCCH,HHCOOC(CH-), j 3 P. 0 Table VI R· Thiazolines 4-CF.

II Thiazolidines -CH., CH CH2=CH-CH2ch=c-ch2Example 11 H-(3-methylthiazolidin-2-ylidene) acetylaminoacetamide 4-Nitrophenyl acetylaminoacetate (1.19 g.) was added portionwise to a solution of 580 mg. of 2-imino-3methylthiazolidine in 50 ml. of chloroform. After stirring 2 hours at room temperature, the solution was concentrated to dryness. The residue was triturated with ether and collected on a filter. The crude product was dissolved in chloroform, washed with sodium bicarbonate solution, dried and concentrated to dryness. Trituration with ether gave 3 011 600 mg. of N-(3-methylthiazolidin-2-ylidene) acetylaminoacetamide, m.p. 138-139°C.

Following the procedure of Example 11, but substituting for the 2-imino-3-methylthiazolidine used therein, an equivalent amount of the 2-imino-3-R-thiazolidines and thiazolines depicted in Table VII, there are produced the N-(3-R-thiazolidin-2-ylidene) acetylaminoacetamides and N-(3-R-thiazolin-2-ylidene) acetylaminoacetamides also depicted in Table ViI,in accordance with Equation VII: Equation VII I R NH + NO2-©-OOCCH2NHCOCH3—A I R N-CCHoNHC0CH ii 2 0 Table VII Thiazolines 15 CH3ch3Thiazolidines CH3C2H5 n_C3H7 ch2=ch-ch2· CHsC-CH24-CF3 H H H H H Example 12 3-Methyl-2-succinyliminothiazolidine 25 Succinic anhydride (2.0 g.) was added to a solution of 2-imino-3-methylthiazolidine in 70 ml. of methylene -2246011 chloride. After refluxing 3 hours, the mixture was filtered and the filtrate was evaporated to dryness. The residue was triturated with ether and collected on a filter to give 3.63 g. of 3-methyl-2-succinyliminothiazolidine, m.p. 90-105“C.

The product from Example 12 was converted to the sodium salt fay dissolving 864 mg. of it in 25 mi. of water and adding 336 mg. of sodium bicarbonate. The mixture was concentrated to dryness and the residue was triturated with isopropanol. The solids were collected on a filter to give 730 mg. of 3-methyl-2-succinyliminothiazolidine sodium salt, m.p. 205-210eC.

Following the procedure of Example 12, but substituting for the 2-imino-3-methylthia3olidine used therein, an equivalent amount of the 2-imino-3-R-thiazolidines and thiazolines depicted in Table VIII, there are produced the 3-R-2-succinyliminothiazolidines and 3-R-2-succinyliminothiazolines also depicted in Table VIII, in accordance with Equation VIII: Table VIII 7 R R Thiazolines ch3- 4-CF3 ch3- H -234 6 011 Table VIII (con't) Thiazolidines ^2^5n- CgH? ch2=ch-ch2ch=c-ch2 H H H H Example 13 2-Acetoacetylimino-3-methylthiazolidine A solution of 13 g. of diketene in 100 ml. of ethanol was added dropwise to an ice-cold solution of 18 g. of 2-imino-3-methylthiazolidine in 100 ml. of ethanol The mixture was allowed to warm spontaneously to room tem15 perature and then evaporated to dryness. The residue was triturated with ether, collected on a filter and dried in a desiccator to give 2-acetoacetylimino-3-methylthiazolidine, m.p. 43-45°C. ' Following the procedure of Example 13, but sub20 stituting for the 2-imino-3-methylthiazolidine used therein an equivalent amount of the 2-imino-3-R-thiazolidines and thiazolines depicted in Table IX, there are produced the 2-acetoacetylimino-3-p-thiazolidines and 2-acetoacetylimino-3-R-thiazolines also depicted in Table IX, in accord25 ance vzith Equation IX: Equation IX -244 6 G 1 i Table IX Thiazolines CH3 Thiazolidines 4-CF, j H CH, -CH3C2H5c3h7CH2=CH“CH2 CH^C-CH,Example 14 Pharmaceutical compositions A typical tablet containing 5 mg. of N-(3-methyl15 thiazolidin-2-ylidene) acetylaminoacetamide per tablet was prepared by mixing together with the active ingredient calcium phosphate, lactose and starch in the amounts shown in the tables below. After these ingredients had been thoroughly mixed, the dry mixture was blended for an additional three minutes. This mixture was then compressed into tablets weighing approximately 129 mg. each. Similarly prepared were tablets containing N-(3-methylthiazolidin~2-ylidene) 2-acetylamino-2-benzylacetamide; N- (3-methylthia::olidin-2ylidene)nicotinamide; ana N,H'-bis-(3-methylthiazolidin25 2-ylidene)succinamide. -25Tablet Formula Ingredient Mg. per tablet N-(3-methylthiazolidin-2ylidene) acetylaminoacetamide 5 mg. 5 Calcium phosphate 52 mg. Lactose 60 mg. Starch 10 mg. Magnesium stearate Tablet Formula 1 mg. 10 Ingredient N-(3-methylthiazolidin-2ylidene) 2-acetylamino-2- Mg. Per Tablet benzylacetamide 5 mg. Calcium phosphate 52 mg. 15 Lactose 60 mg. Starch 10 mg. Magnesium stearate Tablet Formula 1 mg. Ingredient N-(3-methylthiazolidin-2- Mg. per Tablet ylidene)nicotinamide 5 mg. Calcium phosphate 52 mg. Lactose 60 mg. Starch 10 mg. 25 Magnesium stearate 1 mg. -2646011 Tablet Formula Ingredient Mg. Per Tablet N,Ν’-bis-(3-methylthiazolidin- 2-ylidene)succinamide 5 mg Calcium phosphate 52 mg. Lactose 60 mg. Starch 10 r«g a Magnesium stearate 1 mg. In the process description of the foregoing specification, there is disclosed the following condensation to provide N,N'-bis-(3-methyl-thiazolidin2-ylidene)succinamide: 0=Ih, NH + Y-C-R ~N I CH L ...,1 -tl-C-R wherein R, is carboxamido-lower alkyl, such as o ft 2UQ and Y is Cl, NO,—< CH, -ch2ch {Cx_e alkyl)2 Vo Ph ^ch2 ’ -o~c ''O(C1_4alkyI) , Similarly, the product, N,N'-bis-(3-methylthiazolidin-2-ylidene)succinamide can be prepared as follows: wherein Y is as defined above. These condensation 5 reactions are conducted in an anhydrous inert organic solvent such as chloroform,tetrahydrofuran or toluene from -10°C. to reflux temperature for 1 to T2, hours.

Another procedure for the synthesis of.

N,N'-bis-(3-methyl-thiazolidin-2-ylidene)succinamide is depicted as follows: wherein Z is -OH, -Br, -Cl, or other leaving groups such as tosyloxy or mesyloxy. The cyclisation proceeds under aqueous acidic conditions, the strength of the acid, and time of reaction being dependent on the nature of Z. Where Z is -OH, concentrated hydrochloric acid, or mineral acids of similar strength are required for periods of 10-48 hours, where Z is halo or tosyloxy for example, a trace of the acid produced by the cyclization is sufficient to catalyze the ring closure, so that much shorter times such as a few minutes, and less vigorous acid conditions are required.

Examples 15-18 show the synthesis of ΙΤ,ϊ-Τ' — bis-(3-methyl-thiaeolidin-2-ylidene)succinamide by the above described procedures.

Example 15 To a mixture of 21.6 g. of 5-methyl~2~ succinyliminothiazolidine from Example 12 and 10.2 g. of triethylamine in 80 ml. of anhydrous chloroform is added dropwise 13.7 g. of isobutylchloroformate at -5 to 0cC. After 30 minutes stirring 10.2 g. of 2imino-3-methylthiazolidine in 50 ml. chloroform is added, maintaining the temperature at 06C. by external cooling. After one hour at ambient temperature the precipitated triethylamine hydrochloride is filtered off.

The chloroform filtrate is washed with sodium bicarbonate solution, dried (wa2SO^) and the solvent is removed in vacuo. The residue is recrystallized from methanol to give W,N1-bis-(3-methyl-thiazolidin-2-ylidene)-succinamide Example 16 A mixture of 3.1 g. of succinic acid, 7,4 g. of triethylamine and 10.1 g. of chloroacetonitrile in ml. ethyl acetate is refluxed for three hours. The precipitated triethylamine hydrochloride is filtered and the filtrate is washed with saturated NaCl solution, dried (Na2SO^) and concentrated in vacuo.

The crude di-cyanomethylsuccinate (3.9 g.) is dissolved in 80 ml. of tetrahydrofuran. 2-Imino-3methylthiazolidine (3.88 g.) and 0.8 ml, of acetic acid are added and the reaction mixture is allowed to stand at ambient temperature for 48 hours.

The mixture is quenched onto 300-350 g. icewater and extracted with ethyl acetate. The combined extracts are washed with sodium bicarbonate solution, then with water. The ethylacetate phase is·dried over Na2SO^, filtered and concentrated in vacuo. The residue is recrystallized from methanol to give N,N'-bis-(3methyl-thiazolidine-2-ylidene)-succinamide.

Example 17 A mixture of 15.5 g. of succinylchloride and 20.5 g. of 2-imino-3-methylthiazolidine in 150 ml. dry toluene is refluxed until two equivalents of hydrogen chloride ate formed. The solution is cooled to room temperature and washed with saturated sodium bicarbonate solution. After removing the solvent in vacuo, the residue is recrystallized from methanol to give N,N'bis-(3-methyl-thiazolidine-2-ylidene)-succinamide.

The above described reaction can also be conducted in the presence of equivalent amounts of tert, base such as triethylamine or dimethyl aniline at ambient temperature. 6S ϋ χ Example 18 To a solution of 20 g. of succinyl-di-isothiocyanate (J. Chem. Soc. 67 565.) in 50 ml. acetone is added 7.51 g. of β-methylaminoethanol in 20 ml. acetone.

The reaction mixture is heated under reflux for 30 minutes then quenched, after cooling to room temperature, onto 350-400 ml. of ice-cold water. The precipitated, succinyl-bis(N-methyl-N-2-hydroxyethyl-thioureide) is filtered and purified by crystallization from ethanol.

The substituted urea is dissolved in 100 ml. of 75¾ sulfuric acid and allowed to stand at ambient temperature for 24 hours. Upon pouring the mixture into 5-6 times its volume of ice-water, U,N'-bis-(3methylthiazolidine-2-ylidene)-succinamide is precipitated.

Recrystallization from methanol gives pure N,N'-bis-(3methyl-thiazolidin-2-ylidene)succinamide.

Claims (14)

1. A compound of structural formula I: R or a pharmaceutically acceptable salt thereof, in which the dotted line indicates that the linkage is saturated or unsaturated; R represents (1) C^_ 3 alkyl, either straight .or branched chain;

2. 6 cr pharmaceutically acceptable salt thereof, whert 3, S and F, are as defined in claim 1. (2) C 3 _ 3 alkenyl;

3. The compound of structural formula: 0 0 II I! NCCH,NHCCH, or pharmaceutically acceptable salt thereof. 3.. The compound of structural formulas 0 0 B II NCCH-NHCCH, or pharmaceutically acceptable salt thereof. 3 3 (1) -C-R where R is a C^_ 5 alkyl group having amino, alkanoylamino, C 2 _^ alkanoylamino and phenyl, carboxy, C 2 _ 4 alkanoyl or II -C-N R substituent(s) R, and the dotted line in tne last formula are identical with those in the ring shown in Formula 1, or R is a pyridyl radical, R represents hydrogen, alkyl, phenyl, either unsubstituted or substituted with one or more C^_ 3 alkoxy groups, or ? pyridyl; and R, R and the dotted line in the last formula are identical with those in the ring shown in Formula 1; or ‘1 0 0 i £ A where B represents hydrogen or C. „ I**.? n·' « 7 7 alkyl, and B represents alkyl or -COB , where B' represents (3) C 3 _g alkynyl; r1 represents θ 4. 6 Ο ί 1

4. The compound of structural formula: r=N-CCH 2 CH 2 C (is, or pharmaceutically acceptable salt thereof. 4 5 alkyl or phenyl, or R and R , together with the nitrogen to which they are attached, represent -N ;or (4) represents hydrogen, C·^ alkyl or trifluoroaethyl. '40011

5. A compound of structural formula! n/ / A—a 2 a v

6. A pharmaceutical composition in unit dosage form comprising a pharmaceutical carrier and an effective amount of a compound as claimed, in claim 1.

7. A composition as claimed in claim 6, in which, the said coa^ouad is a compound as claimed in claim 2.

8. A composition as claimed in claim 6, in which the said compound is a compound as claimed in claim J.

9. A composition as claimed in claim 6, in which the said compound is a compound as claimed, m claim 4.

10. A composition as claimed in claim 6, in which.the said compound is a compound as claimed in claim 5.

11. A composition as claimed in any one of claims 6 to 10, in orally administrable form.

12. A corpositicn as claimed in any one of claims 6 to 10, in the form of a sterile injectable preparation.

13. A composition as claimed in any ons of claims 6 to 10, in rectally •administrable form.

14. A canposition as claimed in claim 11, in the form of a tablet, troche, lozenge, aqueous or oily suspension, dispersible powder, granule, eaulsioui hard or soft capsule, syrup or elixir.