CA1146940A

CA1146940A - Derivatives of thiazolidinecarboxylic acids and related acids

Info

Publication number: CA1146940A
Application number: CA000291351A
Authority: CA
Inventors: Miguel A. Ondetti
Original assignee: ER Squibb and Sons LLC
Current assignee: ER Squibb and Sons LLC
Priority date: 1976-12-03
Filing date: 1977-11-21
Publication date: 1983-05-24
Also published as: FR2372817A1; NL171055C; CH634062A5; JPS618834B2; JPS5382778A; ES464555A1; NZ185800A; PT67352B; RO72596B; HK55881A; AU518147B2; GR72453B; IT1092179B; NO148416C; DE2752719C2; IN146945B; NO774126L; NL7713274A; FR2372817B1; NO148416B

Abstract

ABSTRACT

New substituted derivatives of thiazolidine-, thiazane-and related carboxylic acids which have the general formula

Description

llA142a This invention relates to new thiazolidine-, thiazane and related carboxylic acids which have the general formula (I) X
/ \
R3 (R2-fH)m (~1 Rl)n R4 --~5 -(CH2)p CH - CO - N - H ~ CO- R

and salts thereof, wherein R ls hydroxy or lower alkoxy;
Rl and R2 each is hydrogen or lower alkyl;
~: R3 is hydroqen, lower alkyl or mercapto-lower alkylenei!
R4 is hydrogen, lower alkanoyl, benzoyl or ~ ~

: */X\ * ' '' R3 (R2-fH~m(fI~ Rl)n ~ 20 ~ -S (CH2)p ~H CO - N - ~H - CO-R

:: :
X is 0, S, SO or S02; wh.en ~ is o, m is 2 and n is 1;
: ~ ~ m is 1, 2 or 3; n is 0, 1 or 2; and m ~ n is 2 or 3;
p is O or 1.
The asterisks denote centers of asymmetry.
~: : :
The inventlon in its: broad aspects includes derivatives of thiazolidine-, thi~azane- and related carboxylic acids having formula I above.

6~
~A142a 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 , thiazane- and morpholine carhoxylic acids.
- The ring,as indicated, contains a hetero atom in addition - to the nitrogen, which is oxygen oO sulfur and the sulfur ; can be oxidized to the sulfinyl (-S-) or sulfonyl ( -S-' state. The side chain, attached to the nitrogen of the heterocyclic ring, is an unsuhstituted or suhstituted ; mercapto-alkanoyl group. The compound can also he a "dimer"
wherein the sulfur containing substituted R4 is a similar - unit.
The lower alkyl groups represented by any of the variables include straight and branched chain hydrocarbon radicals from methyl to heptyl, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, iso-; pentyl and the like. The lower alkylene groups are of the same kind also having 1 to 7 carbons. Similarly the loweralkoxy groups are of the same kind with a link to oxygen, for example, methoxy, ethoxy, propoxy, isopropoxy, butOxyr isobutoxy, t-hutoxy and the Iike. The Cl-C4 members, especially Cl and C2 members, of all types are preferred~
The lower alkanoyl groups are the acyl radicals of the lower (up to 7 carbons) fatty acids, e.g., acetyl, propionyl, ~' butyryl and the Iike, acetyl being preferred.

The symbols have the foregoing meanings througho~t this specification.
:
~ ~ 30 ''~

HA142a Preferred are those compounds of formula I wherein R is hydroxy or lower alkoxy especially hydroxyt methoxy or ethoxy; Rl and R2 each is hydrogen or lower alkyl, especially hydrogen, methyl or ethyl, most especially hydrogen; R3 is hydrogenr lower alkyl, especially methyl or ethyl, or mercapto-lower alkylene, especially mercapto-methyl; R4 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 n or 1, especially 1.
The products of formula I and the preferred subgroups can be produced by various methods of synthesis.

According to apreferred method, t.he acid of the formula (II) X
(R2-C ~m (I~I Rl)n HN - CH ~ CO - R
wherein R is hydroxy and the other symbols have the same meaning as i above, is acylated with an acid of the formula R4--S - (CH2) F CH - COOH

by one of the known procedures in which the acid III is activated, prior to reaction with the acid II, involving formation of a mixed anhydride, symmetrical anhydride, acid ; chlori~e, active ester, ~bodward reagent K, N,N'-carbonylbisi~idazole, EEDQ
(N-ethoxycarbonyl -2-ethoxy-1,2-dihydroquinoline) or the like.
: :~
When R is lower alkoxy, this method or other known methods for coupling such moieties can be used. [For review of ~lese methods, see Methoden der Organischen Chemue (Houben-Weyl) Vol. XV, parts 1 and 2 (1974)3.

;~ -3-) :.~

~ ~Y~ HA142a The acid 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 ha].ide of the formula (IIIa) R3 hal-(CH2)p-CH-CO-hal wherein hal represents a halogen, preferably chlorine or bromine, 3-bromopropanoyl chloride for instance. Thi~ yields a ~oduct of the formula (IIIb) X
/ \
R3 (~ -CH) (CH-R ) hal-(CH2) -CH-CO~ - N -- - - C~-CO-R

The reaction of this intermediate with a thiol R4-SH then yields the desired product of formula I. This stepwise .acylation is illustrated in Example.
When the product obtained is an ester, e.g., R is lower alkoxy, the ester can be convertud to the free carhoxy :, ~, :

-4~

., ' ~6~ A142a group by a~kaline hydrolysis, or by treatment with trifluoroacetic ac~d and anisole. Conversaly the free acid can be esterified by conventional procedures.
The disulfides, i.e., when R~ is R3 R2~1~l (fH Rl)m -S-(CH2)p- CH~-CO - N -- CH- CO ~ R
are obtained by oxidation of a compound of the formula (IV) ~X ~
~3 (R2-CH)m tlH Rl)m HS-(CH2)p CH - CO - N ~ CH- CO -R
e.g., with an alcoholic solution of iodine.
Products of ~ormula I have at least one or may have up to 4 as~m~tric carbon atoms. ~'hese carb~n atoms are indicated by an asterisk m formula I. The compounds accordingly exist in diastereo-isomeric 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 chromato-graphic 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 ~asic salts with various inorganic and organic bases which are also within the scope of the invention. Such salts inc]ude ammonium salts, alkall 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-~-, ~ .

~ -5-,. , 14 2 a glucamine, hydrabamine salts, salts with amino acids like arginine, lysine and the like. 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 case of the dicyclohexylamine salt.
The salts are formed in conventional manner by reacting the free acid form of the proauct 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 removinq the water by freeze drying. -By neutralizing the salt with an insoluble acid like a cation exchange resin in the hydrogen form ~e.g., pol~styrene sulfonic acid resin - Dowex 50 ~Mikes, Laboratory Handbook of Chromatographic Methods, Van Nostrand, 1961) page ~56]
or with an aqueous acid and extraction with an organic solvent, e.g., ethyl acetate, dichloromethane or the like, 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 :1 ~
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 are useful 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 substanoe present which has been implicated as the causative agent in various forms of hypertension in 3Q various mammalian species, e.g., rats, dogs, etc. The .!

*Trade Mark ~1~1 4 ~a compounds of this invention intervene in the angiotensinogen -~angiotensin I -~ angiotensin II sequence by inhibiting angiotensin converting enzyme and reducing or eliminating the ormation o~ the pressor substance angiotensin II.
The inhibition of ~he angiotensin converting enzyme by compounds of formula I can be measured in vitro with isolated angiotensin converting enzyme from rabbit lungs f~llowing 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.
i single dose, or preferably two to four divided daily doses, provided on a basis of about 5 to 1000 mg. per kilogram per day, preferably about 10 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. H. Waugh and B. Rubin, Proc. Soc. Exp. Biol. Med. 143, 4~3 (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 th~ls invention can be utilized to achieve the reduction of blood pressure by formulating .

-7- !

' ' ~IA142a in compositions such as tablets, capsules or elixirs for oral administr~tion or in sterile solution or suspensions for parentaral administration. About 10 to 500 mg. of a compound or mixture of compounds of ormula I or physiologically acceptable salt is compounded wit~ a physiologically accept-able vehicle, carrier, excipient, binder, preservative, stabilizer, flavor, etc., 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 degree~ celsius.
Example 1 3-_(3-Benzoylthiopropanoyl)-4-~-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 20 chloride (8.5 g.) are added in that order, with vigorous stirring. After three hours, a suspension of thioben~oic acid (7.5 g.) and potassium carbonate (4.8 g.) in water (50 ml.) -l 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-t3-' benzoylthiopropanoyl)-4-L-thiazolidinecarboxylic acid, .,~ : .
~ -8-6~

HA1~2a m.p. 105-106 .
The above product is dissolved in water and an equivalent proportion of sodium hydroxide solution is added. The solution i5 then freeze dri2d ko 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.) and concentrated ammonia (7.5 ml.) under a blanket of argon. After one hour storage ak room temperature, the reaction mixture is diluted with water (20 ml.) and iltered.
The filtrate is extracted with e~hyl 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-mercaptopro-panoyl)-L-4-thiazolidinecarboxylic acid is crystallized from ethyl acetate, m.p. 110-112.
Example 3 . ~ .
3-~cetylthio-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 eiyhteen hours. The reaction mixture is distilled in vacuo and the fraction of b.p. 2 6mm 128-5-131 is collected-The 3-acetylthio-2-methy1propanoic acid can also be isolated by allowing the reaction mixture to crystallize , after dilution with hexane, m.p. 40-42.
'~
, _9_ ,, .
. . .

~ HA142a 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-acetyl-2-methyl-propanoic acid (4.9 g.) in dichloromethane (5 ml.). Afterfifteen minutes stirring in the ice bath, and sixteen hours at room temperature, the precipi~ate is ~iltered ofE and the filtrate is washed neutral. The organic layer is dried and concentrated to dryness in vacuo to give 3-~3-acetylthio-2-methylpropanoyl~-2-~hi~olidinecarboxylic acid methyl ester.

.
Example 5

3-(3-Mercapto-2-methylpropanoyl)-2-thiazolidinecarbox~ilc acid ~i 3-(3-Acetylthio-2-methylpropanoyl)-2-thiazolidinecarboxyliC
acid methyl ester (2.9 g.) is dlssolved in methanol (30 ml.) and N sodium hydroxide (30 ml.) is added. The reaction mixture is stirred at room temperature, aliquots are with-drawn every hour and checked by paper electrophoresis for the hydrolysis of the methyl ester. When this hydrolysis is completed (ca. thr~e hours), the reaction mixture is neutralized, concentrated in vacuo to eliminate methanol, acidified with concentrated hydrochloric acid and extracted 1 .
with ethyl acetate. The organic layer is dried and concen-trated to dryness to yield 3-(3-mercapto-2-methylpropanoyl)-2-thiazolidinecarboxylic acid.

.,;:

:' i:

HA142a Example 6 _ (3-Acetylthio-2-methylpropanoyl)-2-ethyl-4-thiazolidine-carboxylic acid _ 3-Acetylthio-2-methylpropanoic acid chloride (S~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 tempera~ure, ~he mixture is extracted with ether, the aqueous phase is acidified and extracted with ethyl acetate. The organic phase is dr~ed over magnesium sulfate and concentrated to dryness in vacuo to yield 3-t3-acetylthio-2-methylpropanoyl)-2-ethyl-4- thia-zolidinecarboxylic acid.
~ Example 7 ; ?-Ethyl-3-~3-mercapto-2-methylpropanoyl)-4-thiazolidine-i carboxylic acid 3-(3-Acetylthio-2-methylpropanoyl)-~-ethyl-4-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-ethyl-3-t3 mercapto-2-methylpropanoyl)~4-thiazolidinecarboxylic ;i acid.
;~ Example 8 ¦ 3-(3-Mercapto-2-methylpropanoyl)-5-methyl-4-thiazolidine ; 30 carboxylic acid By substituting 5-methyl-4-thiazolidinecarboxylic ;; ~

$~
HA142a acid [Org. Mag. ~esonance, 6 48 (1974)] for the ethyl-4-thiazolidinecarboxylic acid in the procedure of Example 6 and then submitting the product to the procedure of Example 7, 3-(acetylthio-2-methylpropanoyl)-5-methyl--4-thiazolidine-carboxylic acid and 3-(3-mercapto-2-methylpropanoyl)-5-methyl-

4-thiazolidinecarboxylic acid are obtained.
Example 9 3-[(2-Acetylthiomethyl)-3-acetylthiopropanoyl]-4-L-thia-_ zolidinecarboxylic acid To a solution of 4-L-thiazolidinecarboxylic acid (1.66 g.~ and sodium carbonate t2.7 g.) in water (25 ml.) in an ice bath, 2-(acetylthiomethyl)-3-ace-tyl-thiopropanoic acid chloride ~3.9 g. prepared from 2-acethylthiomethyl)-3-acetylthiopropanoic 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 ace-tate.
The organic layer is dried and concentrated to dryness to yield 3-[(2-acetylthiomethyl)-3-acetylthiopropanoyl~-4-L-thiazolidinecarboxylic acid.
Example 10 3-[(2-Mercaptomethyl)-3-mercaptopropanoyl]-4-L-thiazolidine-carboxy.lic acid By substituting 3-[(2-acetylthiomethyl)-3-acetylthio-propanoyl~-4-L-thiazolidinecarboxylic acid for 3-(3-acetyl-thio-2-methylpropanoyl)-2-ethyl-4-thiazolidinecarboxylic :l acid in the procedure of Example 7, 3-[(2-mercaptomethyl)-3-mercaptopropanoyl]-4-L-thiazolidinecarboxylic acid is obtained.

. .
~ -12-,:

HA142a Example 11 3-(3-Mercaptopropanoyl)-1,3-thiazane-4-carboxylic acid By substituting 1,3-thiazane-4-carboxylic acid [J. Biol.
Chem., 607 (1957)] for 4-L-thiazolidinecarboxylic acid in the procedure of Example 1 and then submitting the produc-t ~o the procedure of Example 2, 3-(3-benzoylthiopropanoyl)-1,3-thiazane-4-carboxylic acid and 3-(3-mercaptopropanoyl)-1,3-thiazane-4-carboxylic acid are obtained.
Example 12 _ _ .
3-(3-Mercapto-2-methylpropanoyl)-1,3-thiazane-4-carboxylic acid By substi-tuting 1,3-thiazane-4-carboxylic acid for th~ 2-ethyl-4-thiazolidinecarboxylic acid in the procedure of Example G, and then submitting the product to the procedure of Example 7, 3-(3-acetylthio-2-methylpropanoyl)-1,3-thiazane-4-carboxylic acid and 3-(3-mercapto-2-methyl-propanoyl)-1,3-thiazane-4-carboxylic acid are ob-tained.
Example 13 3-[(2-Mercapt~tl~ s~,~e~propanoyl]-1,3-thiazane-4-carboxylic acid By substi-tuting 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]-1,3-thiazane-4-carboxylic acid and 3-[(2-mercaptomethyl)-3-mercapto-propanoyl]-1,3-thiazane-4-carboxylic acid are obtained.
Example 14 4-(3-~cetylthiopropanoyl)-3-methyl-1,4-thiazane-5-carboxylic acid , I
3-Acetylthiopropanoyl chloride ~8.3 g.) is added to a mixture of 3-methyl-1,4-thiazane-5-carboxylic acid ~ :
~ -13-:~ ' H~142a [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 temperature 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-(3-acetylthiopropanoyl)-3-methyl-1,4-thiazane-5-carboxylic acid.
Example 15 4~(3-Merca~topropanoyl)-3-methyl-1,4-thiazane-5-carboxylic acid By substituting 4-(3-acetylthiopropanoyl)-3-methyl-1,4-thiazane-5-carboxylic acid for the 3-(3-acetylthio-2-methylpropanoyl)-2-ethyl~4-thiazolidinecarboxylic acid in the procedure of Example 7, 4-(3-mercaptopropanoyl)-3-; methyl-1,4-thiazane-5-carboxylic acid is obtained.
Example 16 4-(3-Merca~to-2-methylpropanoyl)~3-met_yl-1,4-thiazane-5-carboxylic aci__ By substituting 3-acetylthio-2-methylpropanoyl chloride ;

for t~e 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-methyl-1,4-thiazane-5-carboxylic acid and 4-(3-mercapto-2~methyl-propanoyl)-3-methyl-1,4-thiazane-5-carboxylic acid are obtained.
Example 17 4-[(2-Mercaptomethyl)-3-mercaptopropanoyl]-3-methyl-1,4-thiazane-5-ca_boxylic acid By substituting 2-(acetylthiomethyl)-3-acethylthio-i ; -14-~ 42a propanoiC acid chloride for the 3-acetylthiopropanoyl chloride in the procedure of Example 14, and then subrnitting the product to the procedure of Example 7, 4-[(2-acetylthiomethyl)-3-(acetylthio)propanoyl~-3-methyl-1,4-thiazane-5-carboxylic acid, and 4-[(2-mercaptomethyl)-3-mercaptopropanoyl}-3-methyl-1,4-thiazane-5-carboxylic acid are ob~ained.
Example 18 4-(3-Mercapto-2-methylpropanoyl)-1-oxo-1,4-L-thia%ane-5-carboxylic acid .... . ~
By substituting 3-acetylthio-2-methylpropanoyl chloride for the 3-acetylthiopropanoyl chloride and 1-oxo-1,4-thiazane-

5-carboxylic acid [C.A., 55, 95801] for the 3-methyl-1,4-thiazane-5-carboxylic acid in the procedure of Ex~mple 14, and then submitting the product to the procedure of Example 7, 4-(3~acetylthio-2-methylpropanoyl)-1-oxo-1,4-L-thiazane-5-carboxylic acid and 4-(3-mercapto-2-methylpropanoyl)-1-oxo-:i 1,4-L-thiazane-5~carboxylic acid are obtaincd.
Example 19 i I Ethyl-4-[(3-acetylthio)-2-methylpropanoyll-1,4-thiazane-3-- 1: ~ , :
carboxylate By substituting ethyl 1,4-thiazane-3-carboxylate [J. Chem. Soc., 203 (1976)] for 2-thiazolidinecarboxylic acid methyl ester in the procedure of Example 4, ethyl-4-[(3-acetylthio)-2-methylpropanoyl]-1,4-thiazane-3-carboxylate is ; ~ obtained.
1:
~ Example 20 ¦~ 4-(3-~erc~p _-2-methylpropanoyl)-1,4-tlliazanc-3- car~oxy L.ic acid 1 ~ .
u By substituting ethyl 4-[(3-acetylthio)-2-methyl-propanoyl]-1,4-~hlaaane-3-carboxylate for the 3-(3-acetyl-. ~ ~ , . .
~ 3~o~ ~ thio-2-methylpropanoy1)-2-thiazolidine carboxylic acid methyl )1~14 ester in the procedure of Example 5, 4-(3-mercapto-2-methylpropanoyl)-1,4-thiazane-3-carboxylic acid is obtained.
~xample 21 N-~(2-Acetylthlomethyl)-3-lacetyl-tllio)propanoyl]-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 ',~-[(2-Mercaptomethyl)-3-mercaptopropanoyl]-3-morpholinc-carbo~lic acicl By substituting N-[t2-acetylthiomethyl)-3-(acetylthio)-propanoyl]-3-morpholinecarboxylic acid for the 3-[(2-acetylthiomethyl)-3-(acetylthio)propanoyl]-4-L-thiazolidine-carboxylic acid in the procedure of ~xample 10,~-[~2-mercaptomethyl)-3-mercaptopropanoyl]-3-morpholinccarboxylic acid is obtained.

, ~
3-(2-Benzoylthiopropanoyl)-4-L-thiazolidinecarboxylic acid By substituting 2-bromopropionyl chloride Eor the 3-bromopropionyl chloride in the procedure of Exampl~ 1, 3-(2-benzoylthiopropanoyl)-4-L-thiazolidinecarboxylic acid is obtained.
~xample 24 3-(2-Mercaptopropanoyl)-4-L-thiazolidinecarboxylic acid By substituting 3-(2-benzoylthiopropanoyl)-4-L-thia-zolidinecarboxyllc acid for the 3-(3-benzvylthiopropanoyl)-4-L-thiazolidinecarboxylic acid in the procedure of Example 2, 30~ 3-(2-mercaptopropanoyl)-4-L-thiazolidinecarboxylic acid is obtalned.

IIAl42a Example 25 3,3'-[Dithiobis-(3-propanoyl?]bis-~-thiazolidine-4-carbox~lic acid An alcoholic solution of iodine is added to an equimolar a~ueous mixture of 3-(3-mercaptopropanoyl)-L-thiazolidine-4-carboxylic acid until persistent yellow color, while main-taining 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)]bls~
thiazolidine-4-carboxylic acid.
Example 26 ltl-Dioxo-3-methyl-1,4-thiazane-5-carboxylic acid A solution of 3-methyl-1j4-thiazane-5-carboxylic acid (6 g.) in acetic acid (300 mlO) ls stirred at 45 for

6 hours whiIe 30% hydrogen peroxide (25 ml.) is added at a rate of S ml~Iiter. The solution is set aside overnight and the solvent is removed in vacuo to yield 1,1-dioxo-3-methyl~1,4-thiazane-5-carboxylic acid.
Example 27 -Dioxo-4-(3-mercapto-2-methylpropanoyl)-3-methyl-1,4-thiazane-5-carboxylic acid ~, ~
By substituting 1,1-dioxo-3-methyl-1,4-thiazane-:
5-carboxylic acid for the 3-methyl-1,4-thiazane-5-carboxylic acid in the procedure of Example 16 and then submitting the product to the procedure of Example 7, dioxo-4-(3-acetylthio-2-methylpropanoyl)-3-methyl-1,4-~
thiazane-5-carboxylic acid and 1,1-dioxo-4-(3-mercapto-2-~ methylpropanoyl)-3-methyl-1,4-thiazane-5-carboxylic acid 6~
HA142a are obtained.
Example 28 3-(3-Mercapto-2-methyl~ropano~l)-L-4-thiazolidinecarboxylic acid By substituting L-4-thiazolidinecarboxylic acid for the 2-ethyl-4-thiazolidinecarboxylic acid in the procedure of Example 6, and then submitting the product to the procedure of Example 7, 3-t3-acetylthio-2-methylpropanoyl)-L-.~I 4-thiazolidinecarboxylic acid [dicyclohexylammonium salt cry~tallized from acetonitrile m.p. (sint. 130) 172-186]
and 3-(3-mercapto-2-methyl-propanoyl)-L-4-thiazalidinecarboxylic acid ~dicyclohexylammonium salt crystallized from ethyl acetate hexane m.p. (sint~ 170) 180-1383 are obtained.

3,3'-[Dithiobis-(2-meth~1-3-propanoyl]bis-thiazolidine-2-carboy~lic acid By substituting 3-(3~mercapto-2-methylpropanoyl)-thiazolidine-2-carboxylic acid for tha 3-(3-mercaptopropanoyl)-L-thiazolidine-4-~arboxylic acid in the procedure of Example 25, ~' 3,3'-~Dithiobis-(2-methyl-3-propanoyl3bis-thiazolidine-2-carboxylic acid is obtained.

' ::

H~142a Example 30 4-~3-Acetylthiopropan_yl)-L=l~4-thiazane-5-c~b~ c~d L-4-thiomorpholine~3-carboxylic acid hydrochloride t6.6 g., 0.036 m) is dissolv~d in 150 m:L. 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 ~or one hour and allowed to stand overnight at room temperature. The solid is filtered off to yield 9.7 g. of 4-t3-acetylthiopropanoyl)-L-1,4-thiazane-5-carboxylic acid, m.p. 202-204. The solvent is removed to yiPlcl 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 i5 removed and the viscous residue t7.5 g.) crystallizes on standin~.
After recrystalliz1ng from acetone-hexane, the product is constant melting at 122-125.
Example 31 4-(3-Mercaptopropanoyl)-L-1,4-thiazane-5-carboxylic acid .~
l Aqueous ammonia (13 ml. conc. ammonium hydroxide in .
; 30 ml. of water) is stirred under nitrogen for lS minutes and solid 4-t3-acetylthiopropanoyl)-L-1,4-thiazane-5-carboxylic acid (6.8 g., 0.024 m) is added. A clear solution forms ~.1 o ;, ~ promptly at 5-10 . The solution is stirred at room ., .
~ temperature under nitrogen for one hour. The solution is ,, extracted with lOO ml. of ethyl acetate and the aqueous layer is made strongly acid with 20% hydrochlorio acid. The ~precipitated oil is extracted with 3 x 150 ml. of ethyl . :

:

~6~
~IAl42a acetate. The extracts are combined and dried over magnesium sulfate, then the solvent is removed to yield 5.6 g. of semi-crystalline 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 a~onium 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 t:he solvent is removed to yield 2.7 g. (48%) of 4-(3-mercap-topropanoyl)-L-1,4-thiazane-5- carboxylic acid as a viscous mass after drying overnight at room temperature and l mm.
Anal. calcd. for C8H13NO3S2: N, 5.95; C, 40.82; H, 5.56;
S, 27.25; SH, 100%
Found: N, 6.13; C, 40.85; H, 5.46; S, 27.38; SH, 96~.

' :, ' :

:
, :

~ ~ -20-

Claims

HA142a THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for preparing a compound of the formula wherein R is hydroxy or lower alkoxy; R1 and R2 each is hydrogen or lower alkyl; R3 is hydrogen or lower alkyl, R4 is hydrogen, lower alkanoyl or benzoyl; m is 1 or 2; n is 0 or 1 and m+n is 2 or 3; p is O or l; characterized by acylating a compound of the formula with an acid of the formula or a reactive equivalent thereof to form a product and treating said product wherein R4 is lower alkanoyl or benzoyl with ammonium hydroxide or sodium hydroxide to form a product wherein R4 is hydrogen.

2. A process as in claim 1 wherein R4 is hydrogen.

3. A process as in claim 1 wherein R4 is acetyl.

4. A process as in claim 1 wherein R4 is benzoyl.

5. A process as in claim 1 wherein R is hydroxy.

6. A process as in claim 1 wherein R3 is methyl.

7. A process as in claim 1 wherein R4 is acetyl, R3 is methyl, R1 and R2 are hydrogen, R is hydroxy and m, n and p are each one.

HA142a

8. A process as in claim 1 wherein R4 is hydrogen, R3 is methyl, R1 and R2 are hydrogen, R is hydroxy and m, n and p are each one.

9. A process as in claim 1 wherein R4 is acetyl R1 and R2 are hydrogen, R is hydroxy and m is two.

10. A process as in claim 1 wherein R4 is hydrogen, R1 and R2 are hydrogen, R is hydroxy and m is two.

11. A process according to claim 1 wherein L-4-thio-morpholine-3-carboxylic acid is reacted with 3-acetylthio-propanoyl chloride to form 4-(3-acetylthiopropanoyl)-L-1,4-thiazane-5-carboxylic acid.

12. A process according to claim 1 wherein L-4-thio-morpholine-3-carboxylic acid is reacted with 3-acetylthio-propanoyl chloride and the product is treated with ammonium hydroxide to form 4(3-mercaptopropanoyl)-L-1,4-thiazane-5-carboxylic acid.

13. A process according to claim 1 wherein L-4-thia-zolidinecarboxylic acid is reacted with 3-acetylthio-2-methylpropanoic acid to form 3-(3-acetylthio-2-methyl-propanoyl)-L-4-thiazolidinecarboxylic acid.

14. A process according to claim 1 wherein L-4-thia-zolidinecarboxylic acid is reacted with 3-acetylthio-2-methylpropanoic acid and the product is treated with ammonium or sodium hydroxide to form 3-(3-mercapto-2-methylpropanoyl)-L-4-thiazolidinecarboxylic acid.

15. A compound of the formula HA142a wherein R is hydroxy or lower alkoxy; R1 and R2 each is hydrogen or lower alkyl; R3 is hydrogen or lower alkyl; R4 is hydrogen, lower alkanoyl or benzoyl; m is 1 or 2; n is 0 or 1 and m + n is 2 or 3; p is 0 or 1, whenever prepared by the process of claim 1.

16. A compound as in claim 15 wherein R4 is hydrogen, whenever prepared by the process of claim 2.

17. A compound as in claim 15 wherein R4 is acetyl, whenever prepared by the process of claim 3.

18. A compound as in claim 15 wherein R4 is benzoyl, whenever prepared by the process of claim 4.

19. A compound as in claim 15 wherein R is hydroxy, whenever prepared by the process of claim 5.

20. A compound as in claim 15 wherein R3 is methyl, whenever prepared by the process of claim 6.

21. A compound as in claim 15 wherein R4 is acetyl, R3 is methyl, R1 and R2 are hydrogen, R is hydroxy and m, n and p are each one, whenever prepared by the process of claim 7.

22. A compound as in claim 15 wherein R4 is hydrogen, R3 is methyl, R1 and R2 are hydrogen, R is hydroxy and m, n and p are each one, whenever prepared by the process of claim 8.

23. A compound as in claim 15 wherein R4 is acetyl, R1 and R2 are hydrogen, R is hydroxy and m is two, whenever prepared by the process of claim 9.

24. A compound as in claim 15 wherein R4 is hydrogen, R1 and R2 are hydrogen, R is hydroxy and m is two, whenever prepared by the process of claim 10.

25. A compound according to claim 15 having the name 4-(3-acetylthiopropanoyl)-L-1,4-thiazane-5-carboxylic acid, whenever prepared by the process of claim 11.

26. A compound according to claim 15 having the name 4-(3-mercaptopropanoyl)-L-1,4-thiazane-5-carboxylic acid, whenever prepared by the process of claim 12.

27. A compound according to claim 15 having the name 3-(3-acetylthio-2-methylpropanoyl)-L-4-thiazolidinecarboxylic acid, whenever prepared by the process of claim 13.

28. A compound according to claim 15 having the name 3-(3-mercapto-2-methylpropanovl)-L-4-thiazolidinecarboxylic acid, wnenever prepared by the process of claim 14.

29. A process for preparing a compound of the for-mula I
wherein X is hydroxy or lower alkoxy R1 and R2 each is hydro-gen or lower alkyl; R3 is hydrogen or lower alkyl; m is 1.or 2; n is 1 and m + n is 2 or 3 characterized by reacting a compound of the formula with an acid of the formula wherein R1 is the remains of an organic carboxylic acid and then treating the product thus obtained with an alkaline hydroxide to form a product where R1 is hydrogen.

30. A process according to claim 29 wherein L-4-thiazolidine carboxylic acid or a corresponding ester deri-vative is reacted with 3-acetylthio-2-methylpropanoic acid and the product is treated with an alkaline hydroxide to form 3-(3-mercapto-2-methylpropanoyl)-L-4-thiazolidine car-boxylic acid.

31. A compound of the formula I

wherein X is hydroxy or lower alkoxy; R1 and R2 each is hy-drogen or lower alkyl; R3 is hydrogen or lower alkyl; m is 1 or 2; n is 1 and m + n is 2 or 3 whenever prepared by the process of claim 29.

32. The compound 3-(3-mercapto-2-methylpropanoyl)-L-4-thiazolidine carboxylic acid whenever prepared by the process of claim 30.