IE46169B1

IE46169B1 - Thiazolidine, thiazane and morpholine carboxylic acids and esters

Info

Publication number: IE46169B1
Application number: IE2397/77A
Authority: IE
Original assignee: Squibb & Sons Inc
Priority date: 1976-12-03
Filing date: 1977-11-25
Publication date: 1983-03-09
Also published as: CH634062A5; CA1146940A; FR2372817B1; GR72453B; SE441267B; AU3037977A; HK55881A; FI773640A; DD133798A5; NO148416C; NL7713274A; SE7713722L; NL8201146A; ATA857677A; DE2752719C2; AT363467B; NO774126L; IN146945B; IL53352A0; NL171055C

Abstract

The novel compounds of the general formula I, and their salts, are suitable for alleviating or eliminating angiotensin-induced hypertension. These compounds are prepared by acylating a compound of the formula II with a compound of the formula III. The symbols which are used in the formulae are defined in the claims. The compounds of the formula I in which R4 is a hydrogen atom can be oxidised to the corresponding disulphides.

Description

This invention relates to substituted thiazolidine-, thiazane- and morpholine carboxylic acids; more specifically it provides compounds of the general formula X (I) (CH-R.) R4-S~(CH2>p l'n 0—R •5 and such compounds in the form of a salt with a base, wherein R is hydroxy or lower alkoxy; R^ and R2 each is hydrogen or lower alkyl; R3 is hydrogen, lower alkyl or mercapto-lower alkylene R^ is hydrogen, lower alkanoyl, benzoyl or -S(CH_)—CHz P * -R (in which formula the variables are identical to those in formula I) with the proviso that when R^ is mercapto-lower alkylene, R^ is hydrogen; X is 0, S, SO or S02; m is 1,2 or 3; n Is 0, 1 or 2; such that m + n is 2 or 3, with the proviso that when X is 0,m is 2 and n is 1, p is 0 or 1.

The asterisks denote centers of asymmetry.

The compounds of this invention are characterized by an unsubstituted or lower alkyl substituted 5- or 6-membered heterocyclic carboxylic acid having one nitrogen atom and one sulfur or oxygen atom in the ring, the remaining members of the ring being carbon, preferably thiazolidine-, thiazaneand morpholine carboxylic acids. The ring, as indicated, contains a hetero atom in the addition to the nitrogen, which is oxygen or sulfur and the sulfur can be oxidized to the sulfinyl ' 0 0. 0 ii (—S—) or sulfonyl (—S—) state. The side chain, attached to the nitrogen of the heterocyclic ring, is an unsubstituted or substituted mercaptoalkanoyl group. The compound can also be a dimer wherein the sulfur containing substituted R4 is a similar unit.

The lower alkyl groups represented by any of the variables mean straight and branched chain hydrocarbon radicals from methyl to heptyl, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl and isopentyl. The lower alkylene groups are of the same kind also having 1 to 7 carbons. Similarly the lower alkoxy groups are of the same kind with a link to oxygen, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy and t-butoxy. The members, especially and C2 members, of all types are preferred. The lower alkanoyl groups are the acyl radicals of the lower (up to 7 carbons) saturated fatty acids, e.g., acetyl, propionyl and butyryl, acetyl being preferred.

The symbols have the foregoing meanings throughout this specification.

Preferred are those compounds of formula I wherein R is hydroxy or lower alkoxy especially hydroxy, methoxy or ethoxy; and R2 each is hydrogen or lower alkyl, especially hydrogen, methyl or ethyl, most especially hydrogen; R^ is hydrogen, lower alkyl, especially methyl or ethyl, or mercapto3 lower alkylene, especially mercapto-methyl; is hydrogen, lower alkanoyl, especially acetyl or benzoyl; X is sulfur or oxygen, especially sulfur; m is 1 or 2; n is 1; and p is 0 or 1, especially 1.

The products of formula I and the preferred subgroups can be produced by various methods of synthesis.

According to a preferred method, the acid of the formula (II) HN(CH-Rpn -CH-— -cowherein R is hydroxy and the other symbols have the same meaning as above, is acylated with an acid of the formula (III) I R.—S—(CH-) —CH—COOH z p to give a product wherein R^ is hydrogen, lower alkanoyl or benzoyl, by one of the known procedures in which the acid III may be activated, prior to reaction with the acid II, involving, e.g. formation of a mixed anhydride, symmetrical anhydride, acid chloride, active ester, Woodward reagent K, N,N' carbonylbisimidazole or EEDQ (N - ethoxycarbonyl - 2 - ethoxy - 1,2 - dihydroquinoline). When R is lower alkoxy, this method or other known methods for coupling such moieties can be used. CFor review of these methods, see Methoden der Organischen Chemie (Houben-Weyl) Vol. XV, parts 1 and 2 (1974)] . - 4 46169 The acid of ester of formula II can, of course, be acylated stagewise. For example, a fragment of the acylating agent III can be first attached to the acid of formula II, e.g., by reacting that acid with a haloacyl halide of the formula (Ilia) Rq I3 hal-(CH„) -CH-CO-hal 2 P wherein hal represents a halogen, preferably chlorine or bromine, 3-bromopropanoyl chloride for instance. This yields a product of the formula (Illb) X / \ (R,-CH)m (CH-R,)„ hal- (CH ) -CH-CO-— N-CH-CO-R p The reaction of this intermediate with a thiol R^-SH then yields the desired product of formula I. This stepwise .acylation is illustrated in Example 1.

When the product obtained is an ester, e.g., R is lower alkoxy, the ester can be converted to the free carboxy 616 3 group by alkaline hydrolysis, or by treatment with trifluoroacetic acid and anisole. Conversely the free acid can be esterified by conventional procedures.

The disulfides,'i.e., when R4 is R3 R2-Cli\cH-R1)m —S— (CH2)p—CH— CO— N-- CH—CO—R are obtained by oxidation of a compound of the formula (IV) HS- (CH-) CH CO— N--CH—CO—R P e.g., with an alcoholic solution of iodine.

Products of formula I have at least one or may have up to 4 asynnetric carbon atoms. These carbon atoms are indicated by an asterisk in formula I. The compounds accordingly exist in diastereoisomeric forms or in racemic mixtures thereof. All of these are within the scope of the invention. The above described syntheses can utilize the racemate or one of the enantiomers as starting material. When the racemic starting material is used in the synthetic procedure, the stereoisomers obtained in the product can be separated by conventional chromatographic or fractional crystallization methods. In general, the L-isomer with respect to the carbon of the amino acid constitutes the preferred isomeric form.

The compounds of this invention form salts with various inorganic and organic bases which are also within the scope of the invention. Such salts include ammonium salts, alkali metal salts like sodium and potassium salts (which are preferred), alkaline earth metal salts like the calcium and magnesium salts, salts with organic bases e.g., dicyclohexylamine salt, benzathine, N-methyl-D48169 glucamine, hydrabamine salts, and salts with amino acid such as arginine and lysine. The non-toxic, physiologically acceptable salts are preferred, although other salts are also useful, e.g., in isolating or purifying the product as in the cas* of the dicyclohexylamine salt.

The salts are formed in conventional manner by reacting the free acid form of the product with one or more equivalents of the appropriate base providing the desired cation in a solvent or medium in which the salt is insoluble and filtering, or in water and removing the water by freeze drying. By Ιθ neutralizing the salt with an insoluble acid such as a cation exchange resin in the hydrogen form [e.g., polystyrene sulfonic acid resin - Dowex (Trade Mark) 50 (Mikes, Laboratory Handbook of Chromatographic Methods, Van Nostrand, 1961) page 256) or with an aqueous acid and extraction with an organic solvent, e.g., ethyl acetate, and dichioromethane, the free acid form can be obtained, and, if desired, another salt formed.

Additional experimental details are found in the examples which are preferred embodiments and also serve as models for the preparation of other members of the group.

The compounds of this invention inhibit the conversion of the decapeptide angiotensin I to angiotensin II and therefore may be used in reducing or relieving angiotensin related hypertension. The action of the enzyme renin on angiotensinogen, a pseudoglobulin in blood plasma, produces angiotensin I. Angiotensin I is converted by angiotensin converting enzyme (ACE) to angiotensin II. The latter is an active pressor substance present which has been implicated as the causative agent in various forms of hypertension in various mammalian species, e.g., rats and dogs. The -74 616 9 compounds of this invention intervene in the emgiotensinogen * angiotensin I + angiotensin II sequence by inhibiting angiotensin converting enzyme and reducing or eliminating the formation of the pressor substance angiotensin II.

The inhibition of the angiotensin converting enzyme by compounds of formula I can be measured in vitro with isolated angiotensin converting enzyme from rabbit lungs following the procedure described by Cushman and Cheung [Biochem. Pharmacol., 20, 1637 (1971)], and with an excised smooth muscle assay [E, O'Keefe, et al., Federation Proc. 31, 511 (1972)] in which these compounds have been shown to be powerful inhibitors of the contractile activity of angiotensin I and potentiators of the contractile activity of bradykinin.

The administration of a composition containing one or a combination of compounds of formula I or physiologically acceptable salt thereof to the species of hypertensive mammal alleviates or reduces angiotensin dependent hypertension. Λ single dose, or preferably two to four divided daily doses, 20 provided on a basis of 5 to 1000 mg. per kilogram per day, preferably lo to 500 mg. per kilogram per day is appropriate to reduce blood pressure. The animal model experiments described by S. L. Engel, T. R. Schaeffer, M. It. Waugh and B. Rubin, Proc. Soc. Exp. Biol. Med. 143, 483 (1973) serve as a useful guide.

The substance is preferably administered orally, but parenteral routes such as subcutaneously, intramuscularly, intravenously or intraperitoneally can also be employed.

The compounds of this invention can be utilized to achieve the reduction of blood pressure by formulating - 8 46169 in compositions such as tablets, capsules or elixirs for oral administration or in sterile solution or suspensions for parenteral administration. 10 to 500 mg. of a compound or mixture of compounds of formula X or physiologically acceptable salt is compounded with, a physiologically acceptable vehicle, carrier, excipient, binder, preservative, stabilizer, and/or flavor, in a unit dosage form as called for by accepted pharmaceutical practice. The amount of active substance in these compositions or preparations is such that a suitable dosage in the range indicated is obtained.

The following examples are illustrative of the invention and constitute preferred embodiments. All temperatures are in degrees Celsius.

Example 1 3-(3-Benzoylthiopropanoyl)-4-L-thiazolidinecarboxylic acid To a solution of L-4-thiazolidinecarboxylic acid (6.6 g.) in normal sodium hydroxide (50 ml.) chilled in an ice bath, 2N sodium hydroxide (25 ml.) and 3-bromopropionyl chloride (8.5 g.) are added in that order, with vigorous stirring. After three hours, a suspension of thiobenzoic acid (7.5 g.) and potassium carbonate (4.8 g.) in water (50 ml.) is added. The reaction mixture is stirred overnight at room temperature and filtered. The filtrate is acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The organic layer is dried and concentrated to dryness. The residue is purified by silica gel chromatography (benzene:acetic acid, 7:1) and the purified material is crystallized from ethyl acetate-ether hexane to obtain 3-(3benzoylthiopropanoyl)-4-L-thiazolidinecarboxylic acid, -946169 m.p. 105-106°.

The above product is dissolved in water and an equivalent proportion of sodium hydroxide solution is added. The solution is then freeze dried to obtain the sodium salt.

Example 2 3-(3-(Mercaptopropanoyl)-L-4-thiazolidinecarboxylic acid 3-(3-Benzoylthiopropanoyl)-L-4—thiazolidinecarboxylic acid (6.7 g.) is dissolved in a mixture of water (15 ml.) 1° and concentrated ammonia (7.5 ml.) under a blanket of argon. After one hour storage at room temperature, the reaction mixture is diluted with water (20 ml.) and filtered. The filtrate is extracted with ethyl acetate, acidified with concentrated hydrochloric acid and reextracted with ethyl acetate. The second ethyl acetate extract is dried and concentrated to dryness. The residue, 3-(3-mercaptopropanoyl)-L-4-thiazolidinecarboxylic acid is crystallized from ethyl acetate, m.p. 110-112°.

Example 3 3-Acetylthio-2-methylpropanoic acid A mixture of thioacetic acid (50 g.) and methacrylic acid (40.7 g.) is heated on the steam bath for one hour and then stored at room temperature for eighteen hours. The reaction mixture is distilled in vacuo and the fraction of b.p. _ , 128.5-131° is collected. 2. 6mm The 3-acetylthio-2-methylpropanoic acid can also be isolated by allowing the reaction mixture to crystallize after dilution with hexane, m.p. 40-42°.

Example 4 3-(3-Acetylthio-2-methylpropanoyl)-2-thiazolidinecarboxylic acid methyl ester 2- Thiazolidinecarboxylic acid methyl ester (C.A. 53, 12,281d) (4.4 g.) and 3-hydroxybenzotriazole (4.0 g.) are dissolved in dichloromethane (40 ml.) and the solution is stirred and chilled in an ice bath. Dicyclohexylcarbodiimide (6,2 g.) dissolved in dichloromethane (15 ml.) is added followed immediately by a solution of 3-acetylthio-2-methylpropanoic acid (4.9 g.) in dichloromethane (5 ml.). After fifteen minutes stirring in the ice bath, and sixteen hours at room temperature, the precipitate is filtered off and the filtrate is washed neutral. The organic layer is dried and concentrated to dryness in vacuo to give 3-(3-acetylthio2- methylpropanoyl)-2-thiazolidinecarboxylic acid methyl ester.

Example 5 3- (3-Mercapto-2-methylpropanoyl)-2-thiazolidinecarboxylic acid 3- (3-Acetylthio-2-methylpropanoyl)-2-thiazolidinecarboxylic acid methyl ester (2.9 g.) is dissolved in methanol (30 ml.) and N sodium hydroxide (30 ml.) is added. The reaction mixture is stirred- at room temperature, aliquots are withdrawn every hour and checked by paper electrophoresis for the hydrolysis of the methyl ester. When this hydrolysis is completed (ca. three hours), the reaction mixture is neutralized, concentrated in vacuo to eliminate methanol, acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The organic layer is dried and concentrated to dryness to yield 3-(3-mercapto-2-methylpropanoyl)2-thiazolidinecarboxylic acid.

Example 6 3-(3-Acetylthio-2-methylpropanoyl) -2-ethyl-4-thiazolidinecarboxylic acid 3-Acetylthio-2-methylpropanoic acid chloride (5.4 g. prepared from 3-acetylthio-2-methylpropanoic acid and thionyl chloride, b.p. 80°) and 2N sodium hydroxide (15 ml.) are added to a solution of 2-ethyl-4-thiazolidinecarboxylic acid [Z.Naturforschg, 17b, 765 (1962)] (5.2 g.) in normal sodium hydroxide (30 ml.) chilled in an ice-water bath. After three hours stirring at room temperature, the mixture is extracted with ether, the aqueous phase is acidified and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and concentrated to dryness in vacuo to yield 3-(3-acetylthio-2-methylpropanoyl)-2-ethyl-4- thia15 zolidinecarboxylip acid.

Example 7 2- Ethyl-3-(3-mercapto-2-methylpropanoyl)-4-thiazolidinecarboxylic acid 3-(3-Acetylthio-2-methylpropanoyl)-2-ethyl-420 thiazolidinecarboxylic acid (1 g.) is dissolved in a mixture of water (3 ml.) and concentrated ammonia (3 ml.) under a blanket of argon. The mixture is stirred at room temperature for thirty minutes and acidified with concentrated hydrochloric acid. The organic layer is dried and concentrated to dryness in vacuo to yield 2-ethyl3- (3-mercapto-2-methylpropanoyl)-4-thiazolidinecarboxylic acid.· Example 8 3-(3-Mercapto-2-methylpropanoyl)-5-methyl-4-thiazolidine30 carboxylic acid By substituting 5-methyl-4-thiazolidinecarboxylic 616 9 acid [Org. Mag. Resonance, 6 48 (1974)] for the ethyl-4thiazolidinecarboxylic acid in the procedure of Example 6 and then submitting the product to the procedure of Example 7, 3- (acetylthio-2-methylpropanoyl)-5-methy1-4-thiazolidinecarboxylic acid and 3-(3-mercapto-2-methylpropanoyl)-5-methyl4- thiazolidinecarboxylic acid are obtained.

Example 9 3-[(2-Acetylthiomethyl)-3-acetylthiopropanoyl]-4-L-thiazolidinecarboxylic acid To a solution of 4-L-thiazolidinecarboxylic acid (1.66 g.) and sodium carbonate (2.7 g.) in water (25 ml.) in an ice bath, 2-(acetylthiomethyl)-3-acetylthiopropanoic acid chloride [3.9 g. prepared from 2-. acetylthiomethyl)-3acetylthiopropanoic acid and thionyl chloride] is added and the mixture is vigorously stirred at room temperature for two hours. After extraction with ethyl acetate, the aqueous layer is acidified and extracted with ethyl acetate. The organic layer is dried and concentrated to dryness to yield 3-[(2-acetylthiomethyl)-3-acetylthiopropanoyl]-4L-thiazolidinecarboxylic acid.

Example 10 3-[(2-Mercaptomethyl)-3-mercaptopropanoyl]-4-L-thiazolidinecarboxylic acid By substituting 3-[ (2-acetylthiomethyl)-3-acetylthiopropanoyl]-4-L-thiazolidinecarboxylic acid for 3-(3-acetylthio-2-methylpropanoyl)-2-ethyl-4-thiazolidinecarboxylic acid in the procedure of Example 7, 3-[(2-mercaptomethyl)3-mercaptopropanoyl]-4-L-thiazolidinecarboxylic acid is obtained.

Example 11 3-(3-Mercaptopropanoyl)-1,3-thiazane-4-carboxylie acid By substituting l,3-thiazane-4-carboxylic acid [J. Biol.

Chem., 607 (1957)] for 4-L-thiazolidinecarboxylic acid in 5 the procedure of Example 1 and then submitting the product to the procedure of Example 2, 3-(3-benzoylthiopropanoyl)-l,3thiazane-4-carboxylic acid and 3-(3-mercaptopropanoyl)-l,3thiazane-4-carboxylic acid are obtained.

Example 12 3-(3-Mercapto-2-methylpropanoyll-l,3-thiazane-4-carboxylic acid By substituting l,3-thiazane-4-carboxylic acid for thh 2-ethyl-4-thiazolidinecarboxylic acid in the procedure of Example 6, and then submitting the product to the procedure of Example 7, 3-(3-acetylthio-2-methylpropanoyl)15 1,3-thiazane-4-carboxylic acid and 3-(3-mercapto-2-methylpropanoyl)-l,3-thiazane-4-carboxylic acid are obtained.

Example 13 3-((2-Mercaptomethyl)-3-mercaptopropanoyl]-1,3-thiazane-4carboxylic acid By substituting 1,3-thiazane-4-carboxylic acid for the 4-thiazolidinecarboxylic acid in the procedure of Example 9, and then submitting the product to the procedure of Example 7, 3- [(2-acetylthiomethyl)-3-acetylthiopropanoyl]-l,3-thiazane4- carboxylic acid and 3-[(2-mercaptomethyl)-3-mercapto25 propanoyl]-l,3-thiazane-4-carboxylic acid are obtained.

Example 14 4- Q-AcetylthiopropanoyD-S-methyl-l^-thiazane-S-carboxylic acid 3-Acetylthiopropanoyl chloride (8.3 g.) is added to a mixture of 3-methyl-l,4-thiazane-5-carboxylic acid 1446169 [Acta. Chem. Scand. 13, 623 (1959)] (8 g.) in dimethylacetamide while keeping the temperature below 25°. N-Methylmorpholine (10.1 g.) is added and the mixture is heated on the steam bath for one hour.. After cooling to room temoerature the precipitate formed is filtered and the filtrate is concentrated to dryness in vacuo. The residue is dissolved in ethyl acetate and washed with 10% potassium bisulfate. The organic layer is dried and concentrated to dryness to yield 4-(3acetylthiopropanoyl)-3-methyl-l,4-thiazane-5-carboxylic ac±d.

Example 15 4-(3-Mercaptopropanoyl)-3-methyl-1,4-thiazane-5-carboxylie acid By substituting -4-(3-acetylthiopropanoyl)-3-methyl1,4-thiazane-5-carboxylic acid for the 3-(3-acetylthio-2methylpropanoyl)-2-ethyl-4-thiazolidinecarboxylic acid in the procedure of Example 7, 4-(3-mercaptopropanoyl)-3methyl-1,4-thiazane-5-carboxylic acid is obtained.

Example 16 4-(3-Mercapto-2-methylpropanoyl)-3-methyl-l,4-thiazane-5carboxylic acid By substituting 3-acetylthio-2-methylpropanoyl chloride for the 3-acetylthiopropanoyl chloride in the procedure of Example 14, and then submitting the product to the procedure of Example 7, 4-(3-acetylthio-2-methylpropanoyl)-3-methyl1,4-thiazane-5-carboxylic acid and 4-(3-mercapto-2-methylpropanoyl)-3-methyl-l,4-thiazane-5-carboxylic acid are obtained.

Example 17 4-[(2-Mercaptomethyl)-3-mercaptopropanoyl1-3-methyl-l,4thiazane-5-carboxylic acid By substituting 2-(acetylthiomethyl)-3- acetylthio-1546169 propanoic acid chloride for the 3-acetylthiopropanoyl chloride in the procedure of Example 14, and then submitting the product to the procedure of Example 7, 4-[(2-acetylthiomethyl)3- (acetylthio)propanoyl]-3-methyl-l,4-thiazane-5-carboxylie 5 acid, and 4-[(2-mercaptomethyl)-3-mercaptopropanoyl]-3methyl-1,4-thiazane-5-carboxylic acid are obtained.

Example 18 4- (3-Mercapto-2-methylpropanoyl)-1-oxo-l,4-L-thiazane-5carboxylic acid By substituting 3-acetylthio-2-methylpropanoyl chloride for the 3-acetylthiopropanoyl chloride and 1-oxo-l,4-thiazane5- carboxylic acid [C.A., 5_5, 95801] for the 3-methyl-l,4thiazane-5-carboxylic acid in the procedure of Example 14, and then submitting the product to the procedure of Example 7, 4-(3-acetylthio-2-methylpropanoyl)-1-oxo-l,4-L-thiazane-5carboxylic acid and 4-(3-mercapto-2-methylpropanoyl)-1-oxo1,4-L-thiazane-5-carboxylic acid are obtained.

Example 19 t.lr··'.

- Ethyl-4-[(3-acetylthio?-2-methylpropanoyl]-l,4-thiazane-320 carboxylate By substituting ethyl l,4-thiazane-3-carboxylate [J. Chem. Soc., 203 (1976)] for 2-thiazolidinecarboxylic acid methyl ester in the procedure of Example 4, ethyl-4-[(3acetylthio)-2-methylpropanoyl]-1,4-thiazane-3-carboxylate is obtained.

Example 20 4-(3-Mercapto-2-methylpropanoyl)-l,4-tliiazanc-3- carboxylic acid By substituting ethyl 4-[ (3-acetylthio)-2-mcthylpropanoyl]-l,4-thiazane-3-carboxylate for the 3-(3-acetyl30 thio-2-methylpropanoyl)-2-thiazolidine carboxylic acid methyl ester in the procedure of Example 5, 4-(3-mercapto-2methylpropanoyl)-l,4-thiazane-3-carboxylic acid is obtained.

Example 21 N-f (2-Acetylthiomethyl)-3-(acetylthio)propa: ~/-.] -3-morpholine carboxylic acid By substituting 3-morpholinecarboxylic acid for the 4-thiazolidinecarboxylic acid in the procedure of Example 9, N- [ (2-acetylthiomethyl)-3-(acetylthio)propanoyl]-3-morpholine carboxylic acid is obtained.

Example 22 Π-((2-Mercaptomethyl)-3-mercaptopropanoyl]-3-morpholinccarboxylic acid By substituting N-[(2-acetylthiomethyl)-3-(acetylthio)propanoyl]-3-morpholinecarboxylic acid for the 3-((215 acetylthiomethyl)-3-(acetylthio)propanoyl)-4-L-thiazolidinecarboxylic acid in the procedure of Example 10, N- ((2mercaptomethy1)-3-mercaptopropanoyl]-3-morpholinccarboxylie acid is obtained.

Example 23 2rt 3- (2-Benzoylthiopropanoyl)-4-L-thiazolidinecarboxylic acid By substituting 2-bromopropionyl chloride for the 3-bromopropionyl chloride in the procedure of Example 1, 3-(2-benzoylthiopropanoyl)-4-L-thiazolidinecarboxylic acid is obtained.

Example 24 3- (2-Mercaptopropanoyl)-4-L-thiazolidinecarboxylic acid By substituting 3-(2-benzoylthiopropanoyl)~4-L-thiazolidinecarboxylic acid for the 3-(3-benzoylthiopropanoyl)4- L-thiazolidinecarboxylic acid in the procedure of Example 2, 3-(2-mercaptopropanoyl)-4-L-thiazolidinecarboxylic acid is obtained. -174 616 9 Example 25 3,3'-[Dithiobis-(3-propanoyl)]bis-L-thiazolidine-4-carboffilic acid An alcoholic solution of iodine is added to an equimolar aqueous mixture of 3-(3-mercaptopropanoyl)-L-thiazolidine-45 carboxylic acid until persistent yellow color, while maintaining the pH between 5 and 7 by careful addition of N sodium hydroxide. The yellow color is discharged with a few drops of sodium thiosulfate and the mixture is acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The organic layer is. dried and concentrated to dryness in vacuo to yield 3,3'-[dithiobis-(3-propanoyl)]bis-Lthiazolidine-4-carboxylic acid.

Example 26 1.1- Dioxo-3-methyl-l,4-thiazane-5-carboxylic acid A solution of 3-methyl-l,4-thiazane-5-carboxylic acid (6 g.) in acetic acid (300 ml.) is stirred at 45° for 6 hours while 30% hydrogen peroxide (25 ml.) is added at a rate of 5 ml/liter. The solution is set aside overnight and the solvent is removed in vacuo to yield l,l-diox0-3-methyl-l,4-thiazane-5-oarboxylic acid.

Example 27 1.1- Dioxo-4-(3-merCapto-2-methylpropanoyl)-3-methyl-l,4thiazane-5-carboxylic acid By substituting l,l-dioxo-3-methyl-l,4-thiazane25 5-carboxylic acid for the 3-methyl-l,4-thiazane-5carboxylic acid in the procedure of Example 16 and then - submitting the product to the procedure of Example 7, ; l,l-dioxo-4-(3-acetylthio-2-methylpropanoyl)-3-methyl-l,4‘ thiazane-5-carboxylic acid and l,l-dioxo-4-(3-mercapto-230 methylpropanoyl)-3-methyl-lj4-thiazane-5-carboxylic acid -1846169 are obtained.

Example 28 3- (3-Mercapto-2-methylpropanoyl)-L-4-thiazolidinecarboxylic acid By substituting L-4-thiazolidinecarboxylic acid for 5 the 2-ethyl-4-thiazolidinecarboxylic acid in the procedure of Example 6, and then submitting the product to the procedure of Example 7, 3-(3-acetylthio-2-methylpropanoyl)-L4- thiazolidinecarboxylic acid [dicyclohexylammonium salt crystallized from acetonitrile m.p. (sint. 130°) 172-186°] and 3-(3-mercapto-2-methyl-propanoyl)-L-4-thiazolidinecarboxylic acid {dicyclohexylammonium salt crystallized from ethyl acetate hexane m.p. (sint. 170°) 180-188°] are obtained.

Example 29 3,31-[Dithiobis-(2-methyl-3-propanoyl]bis-thiazolidine-215 carboyxlic acid By substituting 3-(3-mercapto-2-methylpropanoyl)thiazolidine-2-carboxylic acid for the 3-(3-mercaptopropanoyl)L-thiazolidine-4-earboxylic acid in the procedure of Example 25, 3,3'-{Dithiobis-(2-methyl-3-propanoyl]bis-thiazolidine20 2-carboxylic acid is obtained. -1946169 Example 30 4-(3-Acetylthiopropanoyl)-L-l,4-thiazane-5-carboxylic acid L-4-thiomorpholine-3-carboxylie acid hydrochloride (6.6 g., 0.036 m) is dissolved in 150 ml, dimethylacetamide and 3-acetylthiopropanoyl chloride (5.97 g., 0.036 m) is added. The temperature rises to 28°. To this solution is added N-methylmorpholine (10.9 g., 0.108 m). The temperature rises to 42° and a white precipitate forms immediately. The mixture is heated on a steam bath for one hour and allowed to stand overnight at room temperature. The solid is filtered off to yield 9.7 g. of 4-(3-acetylthiopropanoyl)-L-l,4thiazane-5-carboxylic acid, m.p. 202-204°. The solvent is removed to yield a viscous residue which is triturated with water and 20% hydrochloric acid. The precipitated oil is extracted with 3 x 150 ml. of ethyl acetate and the extracts are dried over magnesium sulfate. The solvent is removed and the viscous residue (7.5 g.) crystallizes on standing.

After recrystallizing from acetone-hexane, the product is constant melting at 122-125°.

Example 31 4-(3-Mercaptopropanoyl)-L-l,4-thiazane-5-carboxylie acid Aqueous ammonia (13 ml. cone, ammonium hydroxide in 30 ml. of water) is stirred under nitrogen for 15 minutes and solid 4-(3-acetylthiopropanoyl)-L-l,4-thiazane-5-carboxylic acid (6.8 g., 0.024 m) is added. A clear solution forms promptly at 5-10°. The solution is stirred at room temperature under nitrogen for one hour. The solution is extracted with 100 ml. of ethyl acetate and the aqueous layer is made strongly acid with 20% hydrochloric acid. The precipitated oil is extracted with 3 x 150 ml. of ethyl -2046169 acetate. The extracts are combined and dried over magnesium sulfate, then the solvent is removed to yield 5.6 g. of semicrystalline mass which appears to contain an appreciable amount of starting material. The recovered.material (5.6 g.) is hydrolyzed again as above with 12 ml. of concentrated ammonium hydroxide in 25 ml. of water for an additional two hours. This solution is acidified and the precipitated oil is extracted with 3 x 150 ml. of ethyl acetate. The extracts are combined and dried over magnesium sulfate, then the solvent is removed to yield 2.7 g. (48%) of 4-(3-mercaptopropanoyl)-Ll,4-thiazane-5- carboxylic acid as a viscous mass after drying overnight at room temperature and 1 mm.

Anal, calcd. for CgH^NG^S^: N' 5.95; C, 40.32; H, 5.56; S, 27.25; SH, 100% Found: N, 6.13; C, 40.85; H, 5.46; S, 27.38; SH, 96%.

(SH = percentage conversion acetylthio to mercapto) “21-

Claims

1. CLAIMS:46169

1. A compound of the formula (I) -WpR-, 1' 3H/ \ (R 2 -CH) m (CH- Rl ) n -CO-N-CH-C0wherein R is hydroxy or lower alkoxy; R^ and R 2 each is hydrogen or lower alkyl; R 3 is hydrogen, lower alkyl or mercaptolower aklylene; R 4 is hydrogen, lower alkanoyl, benzoyl or Λ /\ •(CH,) 2. 'p I 3 -CH-CO-rφπ^ΐ’η -CH-CO-R (in which formula, the variables are identical to those in formula I) with the proviso that when R 3 is mercapto-lower alkylene, R^ is hydrogen; X is 0, S, SO or S0 2 ; m is 1, 2 or 3; n is 0, 1 or 2 such that m + n is 2 or 3 with the proviso that when X is 0, m is 2 and n is 1; p is 0 or 1; or such a compound in the form of a salt with a base.

2. A compound as claimed in Claim 1 wherein R, R^, R 2 , R 3 and p are as defined in Claim 1; R^ is hydrogen, lower alkanoyl or benzoyl; X is sulfur or oxygen; m is 1 or 2; and n is 1 subject ’to the proviso given in Claim 1).

3. A compound as in Claim 1 wherein R is hydroxy, methoxy or ethoxy; R^, R 2 and R 3 each is hydrogen, methyl or ethyl; R^ is hydrogen, acetyl or benzoyl; X is sulfur; m is 1 or 2; n is 1; and p is 0 or 1.

4. A compound as in Claim 1 wherein R 4 is hydrogen

5. A compound as in Claim 1 wherein R 4 is acetyl.

6. A compound as in Claim 1 wherein R 4 is benzoyl.

7. A compound as in ι claim 1 wherein R 4 is X /\ R 3 1 (r 2 - •CH) (CH- 1 m 1 r i : 'n • 2 ) p CO- N -CH-CO-R

8. A compound as in any one of Claims 1 to 7 wherein R is hydroxy.

9. A compound as in any one of Claims 1 to 8 wherein p is 1.

10. A compound as in Claim 1 or 2 wherein X is oxygen.

11. A compound as in Claim 1 wherein X is sulfur or sulfoxide.

12. A compound as in Claim 11 wherein X is sulfur, R is hydroxy, Rg, Rg, and Rg each is hydrogen; R^ is benzoyl; m and n each is 1; and p is 1.,

13. A compound as in Claim 11 wher. in X is sulfur, R is hydroxy, Rg, R 2 , Rg and R^ each is hydrogen; m and n each is 1; and p is 1.

14. A compound as in Claim 11 wherein X is sulfur, R is hydroxy; Rg, R 2 and each is hydrogen; Rg is methyl; m and n each is 1; and p is 1.

15. A compound as in Claim 11 wherein X is sulfur, R is hydroxy; R^Rj and Rg each is hydrogen; R^ is acetyl; m is 2; n is 1; and p is 1.

16. A compound as in Claim 11 wherein X is sulfur, R is hydroxy; Rg, Rg, Rg and R 4 each is hydrogen; m is 2; n is 1; and p is 1.

17. A process for preparing a compound according to Claim 1 which comprises reacting a compound of the formula X HN-CH— with a compound of the formula ca R '4 R. '3 4. 616^ or a reactive derivative thereof, to form a product wherein R 4 is other than X *3 2 -CH) m CH- Rl ) n -S- (CH 2 ) p—-CH-CO-N-CH-CO-R and if desired, oxidizing said product where R 4 is hydrogen to form a product wherein R 4 is as defined immediately above.

18. A process as in claim 17 wherein R, R^, R 2 , Rj and p are as defined in Claim 1; R 4 is hydrogen, lower alkanoyl or benzoyl, X is sulfur or oxygen; m is 1 or 2; and n is 1 (subject to the proviso given in Claim 1)

19. A process as in Claim 17 wherein R is hydroxy, methoxy, or ethoxy; R^, R 2 and R 3 each is hydrogen, methyl or ethyl; R 4 is hydrogen, acetyl or benzoyl; X is sulfur; m is 1 or 2; n is 1; and p is 0 or 1.

20. A process as in Claim 17 wherein R 4 is hydrogen

21. A process as in Claim 17 wherein R 4 is acetyl.

22. A process as in Claim 17 wherein R 4 is benzoyl.

23. A process as in Claim 17 wherein R 4 is -S—(CH O ) -CH-CO-N-CH-CO-R 2 p

24. A process as in any one of Claims 17 to 23 wherein R is hydroxy.

25. A process as in ( any one of Claims 17 to 24 wherein p is 1.

26. A process as in Claim 17 or 18 wherein X is oxygen.

27. A process as in Claim 17 wherein X is sulfur or sulfoxide.

28. A process as in Claim 17 wherein X is sulfur, R is hydroxy, Rp R 2 and R 3 each is hydrogen.; R 4 is benzoyl; m and n each is 1; and p is 1.

29. A process as in Claim 17 wherein X is sulfur, R is hydroxy; Rp R 2 ( R and R each 3 4 is hydrogen; m and n each is 1; and p is I.

30. A process as in Claim 17 wherein X is sulfur; R is hydroxy; R^, R 2 and R 4 each is hydrogen; R 3 is methyl; m and n each is 1; and p is 1.

31. A process as in Claim 17 wherein X is sulfur; ι R^, R 2 and Rj each is hydrogen; R^ is acetyl; ra is 2; n is 1; and p is 1.

32. A process as in Claim 17 wherein X is sulfur; R is hydroxy; , R 2 , R 3 and R^ each is hydrogen; ra is 2; n is 1; and p is 1.

33. A compound as in Claim 1 when prepared by a process as in any one of Claims 17 to 32..

34. A compound as in Claim 1 as named in any of the Examples.

35. A stereoisomer of a compound according to any one of Claims 1 to 16, 33 and 34.

36. A diastereoisomer of the compound of Claim 14.

37. 3-(3-Mercapto-2-methyl-propanoyl)-L-4thiazolidinecarboxylic acid

38. A pharmaceutical composition conprising a compound according to any of Claims 1 to 16 and 33 to 37 and a pharmaceutical carrier. I

39. A composition according to Claim 28 in the form of a tablet, capsule, elixir, or sterile injectable preparation.

40. A composition according to Claim 38 or 39 including an excipient, binder, preservative, stabilizer or flavor. MACLACHLAN & DONALDSON