CS199693B2 - Process for preparing derivatives of thiazolidin-,thiazan- and morpholincarboxylic acids - Google Patents

Description

The invention relates to a process for the preparation of novel substituted thiazolidine-, thiazane- and morpholinecarboxylic acid derivatives, in particular to a process for the preparation of compounds of the formula I

Ί I

RfS- (CH _{z) p} -CH-CO-N-CH-CO-R '* (() *

in which

R represents a hydroxyl group, a salt residue or a C1-C7 alkyl ester residue,

R2 represents a hydrogen atom or an alkyl group having 1 to 7 carbon atoms,

R3 represents a hydrogen atom or an alkyl group having 1 to 7 carbon atoms,

R 1 represents an alkanoyl group containing up to 7 carbon atoms, a benzoyl group or a hydrogen atom,

X represents oxygen or sulfur. m has a value of 1 or 2, n has a value of 0, 1 or 2, and p has a value of 0 or 1, with -11 X being oxygen, m having a value of 2 and n having a value of 1; or 2 and n are 0, 1 or 2, and the sum of m + n must be 2 or 3.

The asterisks (*) indicate the asymmetric centers in the above general formula.

The compounds produced by the process of the invention contain an unsubstituted or alkyl-substituted five- or six-membered heterocyclic carboxylic acid moiety containing one nitrogen atom and one oxygen or sulfur atom as heteroatoms in the molecule, the remaining ring members being carbon atoms, preferably the thiazolidine, thiazane and morpholinecarboxylic acids. The side chain attached to the nitrogen atom of the heterocyclic ring forms an optionally substituted mercaptoalkanoyl group.

Alkyl groups having from 1 to 7 carbon atoms in the meaning of the above symbols are straight or branched chain hydrocarbon radicals such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl and the like. groups containing 1 to 4 carbon atoms, in particular 1 or 2 carbon atoms. The lower alkanoyl groups R @ 4 are acyl radicals of fatty acids containing up to 7 carbon atoms, such as acetyl, propionyl, butyryl and the like. A preferred acyl radical is the acetyl radical.

The individual general symbols have the above-mentioned meanings throughout.

Preferred are those compounds of formula (I) in which R represents a hydroxyl, methoxy or ethoxy group, R2 represents a hydrogen atom or a methyl or ethyl group, in particular a hydrogen atom, R3 represents a hydrogen atom or a methyl or ethyl group, R4 represents a hydrogen atom, acetyl or benzoyl, X is sulfur, m is 1 or 2, n is lap and 1.

In accordance with the invention, the compounds of formula (I) above are prepared by preparing a compound of formula (II) (R (CWAn (CH _z ) _and HN-CH-COR (ID wherein:

R, R2, X, m and n are as defined above, acylated in a manner known per se with an acid of formula III • I R3

R 4 -S- (CH 2) -CH-COOH (III) in which

R 3, R 4 and p are as defined above, whereupon the product obtained wherein R 4 is C 7 -C 7 alkanoyl or benzoyl is optionally hydrolyzed to give the corresponding compound wherein R 4 is hydrogen.

In accordance with conventional practice, the acid of formula III is conveniently activated prior to reaction with acid of formula II, such as by conversion to mixed anhydride, symmetrical anhydride, acid chloride, ester activated, by Woodward's reagent, Ν, Ν'-carbonylbisimidazole, N-ethoxycarbonyl- 2-ethoxy-1,2-dihydroquinoline and the like. When R is C 1 -C 7 alkoxy, the above procedure or other known methods can be used to combine the above two moieties (see Methoden der Organischen Chemie (Houben-Weyl), Vol. XV. Part 1 and 2 (1974)].

However, the acid of formula II can also be acylated sequentially. For example, a fragment of an acylating agent of formula III may first be coupled to an acid of formula II, for example by reacting the acid with a haloacyl halide of formula IIIa.

R3

Hal - (CH 2) p - CH - CO - Hal (Ulaj in which

Hal represents a halogen atom, preferably a chlorine or bromine atom,

R 3 is as defined above, for example with 3-bromopropanoyl chloride. The product of formula IIIb is obtained

H * 1 - (CH 2 CH-CO-N-CH-COR (IIIb) wherein

Hal, R 3, R 2, R, X, m, n and p are as defined above.

Treatment of this intermediate with a thiol of formula R4-SH yields the desired product of formula I.

When the product obtained is an ester (for example R is an alkoxy group as defined above), the ester can be converted to the corresponding free carboxylic acid by alkaline hydrolysis or treatment with trifluoroacetic acid and anisole. Conversely, the free acid can be esterified in a conventional manner.

The products of formula I above contain at least one and may contain up to three centers of asymmetry. The carbon atoms constituting these centers of asymmetry are marked with an asterisk in formula I.

Thus, the compounds of the invention may exist in the form of diastereoisomers or racemic mixtures thereof. All forms are within the scope of the invention. In the synthetic procedures described above, the racemate or one of the enantiomers may be used as the starting material. When a racemate is used as the starting material for the synthesis, the resulting product can be separated into stereoisomers by conventional chromatographic techniques or fractional crystallization. The preferred isomeric form is generally the L-isomer (with respect to the amino acid carbon).

The compounds produced according to the invention form salts with various inorganic and organic bases, which salts are also within the scope of the invention. Such salts include ammonium salts, alkali metal salts such as sodium and potassium salts (preferred salts), alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine, benzathine, N-methyl -D-glucamine and hydrabamine, salts with amino acids such as arginine, lysine and the like. Preferred salts are nontoxic, physiologically acceptable salts, but other salts are also useful, for example, to isolate or purify the product (such as dicyclohexylamine salt). j.

The aforementioned salts are prepared in a conventional manner by reacting the free acid product with one or more equivalents of the appropriate base to provide the desired cation, in a solvent or salt-insoluble medium, followed by filtration, or in water followed by water removal by lyophilization. Neutralization of the salt with an insoluble acid such as an ion exchanger in an H ⁺ -cycle (for example with a polystyrenesulfonic acid resin such as Dowex 50 - see Mikeš, Laboratory Handbook of Chromatography Methods, Van Nostrand, 1961, p. 256), or aqueous acid, and extraction with an organic solvent, for example ethyl acetate, dichloromethane and the like, yields the free acid again, optionally converting it into another salt.

Further experimental details are set forth in the Examples, which are preferred embodiments and also serve as model procedures for preparing other compounds of the invention.

The compounds of the invention inhibit the conversion of the angiotensin I decapeptide to angiotesin II and are therefore useful for suppressing or alleviating angiotensin-induced hypertension. The effect of renin on angiotensinogen, which is pseudoglobulin in blood plasma, produces angiotensin I. Angiotensin converting enzyme (ACE) converts angiotensin I to angiotensin II.

The latter compound is an active presoric agent which causes various forms of hypertension in various mammalian species, such as rats and dogs. The compounds of the invention violate the angiotensionogen --- (renin) --- ► procedure

--- ► Angiotensin I ---> (ACE --- ►)

--- ► angiotensin II by inhibiting the enzyme

ACE and suppress or eliminate the formation of the angiotensin II pressor.

Inhibition of ACE by compounds of Formula I can be measured in vitro on isolated ACE enzyme from rabbit lung as described by Cusham and Cheung [Biochem. Pharmacol., 20, 1637 (1971)], and a smooth muscle excision assay [see E. O'Keefe et al., Federation Proc. 31, 511 (1972)]. In these assays, the compounds of the invention appear to be potent inhibitors of the contractile activity of angiotensin1 and potentiate the contractile activity of bradykinin.

Administration of a composition comprising a compound of Formula I or a physiologically tolerable salt thereof, or a combination of several, to hypertensive mammals reduces or suppresses angiotensin-dependent hypertension.

For lowering blood pressure, a single dose of about 5 to 1000 mg / kg / day, preferably about 10 to 500 mg / kg / day, is preferably divided into 2-4 divided daily doses. The model experiments on the animals they have described serve as a useful guide

S.L. Engel, T.R. Schaeffer, Μ. H Waugh and B. Ruby, Why. Soc. Exp. Biol. Copper. 143, 483 (1973).

The compounds of the invention are preferably administered orally, but can also be administered parenterally, such as subcutaneously, intramuscularly, intravenously or intraperitoneally.

The compounds of the invention may be used to lower blood pressure in the form of compositions, such as tablets, capsules or elixirs for oral administration, or sterile solutions or suspensions for parenteral administration. The so-called "unit dose", commonly known in pharmaceutical practice, contains about 10 to 500 mg of a compound or mixture of compounds of formula I or their physiologically acceptable salts, in combination with a physiologically acceptable carrier, binder, preservative, stabilizer, flavoring, optionally with another excipient. Said compositions contain an amount of active ingredient such that a suitable dosage will be obtained within the above range when administered.

The invention is illustrated by the following non-limiting examples. All temperatures in the examples are given in ° C.

He did

3- (3-Benzoylthiopropanoyl) -4-L-thiazolidinecarboxylic acid

To a solution of 6.6 g of L-4-thiazolidinecarboxylic acid in 50 ml of 1 N sodium hydroxide is added first with 25 ml of 2N sodium hydroxide and then 8.5 g of 3-bromopropionyl chloride under cooling with ice and vigorous stirring. After 3 hours, a suspension of 7.5 g of thiobenzoic acid and 4.8 g of potassium carbonate in 50 ml of water was added. The reaction mixture was stirred at room temperature overnight, then filtered, acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The organic layer was dried, concentrated to dryness and the residue purified by silica gel chromatography eluting with benzene / acetic acid (7: 1). The purified material was crystallized from ethyl acetate / ether / hexane to give 3- (3-benzoylthiopropanoyl) -4-L-thiazolidinecarboxylic acid, m.p. 105 DEG-106 DEG.

The above product was dissolved in water and an equivalent amount of sodium hydroxide solution was added to the solution. Lyophilization of the above solution yielded the corresponding sodium salt.

Example 2

3- (3-Mercaptopropanoyl) -L-4-thiazolidinecarboxylic acid

6.7 g of 3- (3-benzoylthiopropanoyl) -L-4-thiazolidinecarboxylic acid are dissolved under argon in a mixture of 15 ml of water and

7.5 ml of concentrated ammonia. After standing at room temperature for 1 hour, the reaction mixture was diluted with 20 mL of water and filtered. The filtrate was extracted with ethyl acetate, then acidified with concentrated hydrochloric acid and extracted again with ethyl acetate. This second ethyl acetate extract was dried and concentrated to dryness. The residue consisting of 3- (3-mercaptopropanoyl) -L-4-thiazolidinecarboxylic acid melts after crystallization from ethyl acetate at 110-112 °.

Example 1 a d 3

3-Acetylthio-2-methylpropanoic acid

A mixture of 50 g of thioacetic acid and 40.7 g of methacrylic acid was heated on a steam bath for 1 hour and then allowed to stand at room temperature for 18 hours. The reaction mixture is then subjected to vacuum distillation to collect the fractions boiling at 128.5-131 ° / 347Pa.

3-Acetylthio-2-methylpropanoic acid can also be isolated by diluting the reaction mixture with hexane and allowing it to crystallize. The product melts at 40-42 °.

Example 1 a d 4

3- (3-Acetylthio-2-methylpropanoyl) -L-4-thiazolidinecarboxylic acid

To a solution of 4.2 g of L-4-thlazolidinecarboxylic acid in 30 ml of 1 N sodium hydroxide is added 5.4 g of 3-acetylthio-2-methylpropanoic acid chloride (prepared from 3-acetylthio-2-methylpropanoic acid) while cooling in ice-water. acid and thionyl chloride, b.p. 80 °) and 15 ml of 2 N sodium hydroxide, the reaction mixture is stirred at room temperature for 3 hours, then extracted with ether, the aqueous phase is acidified and extracted with ethyl acetate. The organic phase is dried over magnesium sulphate and concentrated in vacuo to give 3- (3-acetylthio-2-methylpropanoyl) -4-thiazolidinecarboxylic acid, the dicyclohexylammonium salt of which melts after crystallization from acetonitrile at 172-186 ° (sintered at 130 °).

Example 5

3- (3-Mercapto-2-methylpropanoyl) -4-L-thiazolidinecarboxylic acid

1.3 g of 3- (3-acetylthio-2-methylpropanoyl) -L-4-thiazolidinecarboxylic acid were dissolved in a mixture of 3 ml of water and 3 ml of concentrated ammonia under an argon atmosphere. The reaction mixture was stirred at room temperature for 30 minutes, then acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The organic layer was dried and concentrated to dryness in vacuo to give 3- (3-mercapto-2-methylpropanoyl) -L-4-thiazolidinecarboxylic acid whose melting point of the cyclohexylammonium salt melts at 180-188 ° after crystallization from ethyl acetate / hexane ( sintered at 170 °).

Example 6

3- (D-3-Acetylthio-2-methylpropanoyl) -L-thiazolidine-4-carboxylic acid

5.1 g of dicyclohexylammonium salt of 3- (3-acetylthio-2-methylpropanoyl) -L-thiazolidinecarboxylic acid was refluxed with 250 ml of acetonitrile, cooled, filtered and the crystalline product was recrystallized from isopropanol to give 2 g. g of 3- (D-3-acetylthio-2-methylpropanoyl) -L-thiazolidine-4-carboxylic acid dicyclohexylammonium salt, m.p. 202-204 °; [α] _D ²⁴ = -124.5 ° C = 2, methanol) . The salt was converted to the free acid by shaking between a 10% aqueous solution of potassium potassium sulfate and ethyl acetate. The organic phase is concentrated to dryness and the residue is crystallized from a mixture of ethyl acetate and hexane. The product obtained melts at 104-105 ° and has an optical rotation of [α] _D ²⁴ = -203.6 ° (c = 1.0, methanol). Example 7

3- (D-3-Mercapto-2-methylpropanoyl) -L-thlazolidine-4-carboxylic acid

The procedure is analogous to that in Example 5 except that 3- (D-3-acetylthio-2-methylpropanoyl) is used in place of 3- (3-acetylthio-2-methylpropanoyl) -L-4-thiazolldinecarbaxylic acid. L-thiazolidine-4-carboxylic acid. 3- (D-3-mercapto-2-methylpropanoyl) -L-thiazolidine-4-carboxylic acid is obtained, m.p. 111-113 °; [J _{and D} 24 = -173.7 DEG (c = 6, methanol). Example ¹

4- (3-Acetylthiopropanoyl) -L-1,4-thiazane-5-carboixylic acid

L-4-Thiomorpholine-3-carboxylic acid hydrochloride (6.6 g, 0.036 mol) was dissolved in dimethylacetamide (150 ml) and 3-acetylthiopropanoyl chloride (5.97 g, 0.036 mol) was added to the solution at 28 °. To the resulting solution was added 10.9 g (0.108 mol) of N-methylmorpholine, raising the temperature to 42 ° and immediately forming a white precipitate. The mixture was heated on a steam bath for 1 hour and allowed to stand at room temperature overnight. Filter the solid

Of a 199893 portion, 9.7 g of 4- (3-acetylthiopropanoyl) -L-1,4-thiazane-5-carboxylic acid melting at 202-204 ° were obtained.

The solvent was evaporated to give a viscous residue which was triturated with water and 20% hydrochloric acid. The oily material obtained is extracted three times with 150 ml of ethyl acetate each time, the extracts are dried over magnesium sulphate and the solvent is evaporated off. A 7.5 g viscous residue crystallizes on standing. After recrystallization from acetone / hexane, the product melts at 122-125 °.

Example 9

4- (3-Mercaptopropanoyl) -L-1,4-thiazane-5-carboxylic acid

6.8 g (0.024 mol) of 4- (3-acetylthlopropanoyl) -1,4-thiazane-5-carboxylic acid are added to aqueous ammonia (13 ml of concentrated ammonium hydroxide in 30 ml of water) with stirring under nitrogen for 15 minutes. The resulting solution was extracted with 100 ml of ethyl acetate and the aqueous layer was strongly acidified with 20% hydrochloric acid, and the resulting oil was extracted three times with 150 ml of ethyl acetate each. After evaporation of the solvent, 5.6 g of a partially crystalline material are obtained, which is likely to contain a considerable amount of starting material, so that 5.6 g of this material are hydrolyzed for a further 2 hours using the same procedure as above using A solution of 12 ml of concentrated ammonium hydroxide in 25 ml of water is added. The extracts were combined, dried over magnesium sulfate and the solvent was evaporated, yielding 2.7 g (48%) of 4- (3-mercaptopropanoyl) -1,4,4-thiazane-5-carboxylic acid in m.p. in the form of a viscous substance (after drying overnight at room temperature under 1 mmHg).

Calcd for C8H13NO3S2:

% N, 5.95;% H, -5.82;

27,25% S,

SH: 100%;

found:

6.13:% N, 40.85% C, 5.46% H,

27,38% S,

SH: 96%. ‘

Example 10

DL-3- (3-Acetylthiopropanoyl) -2-thiazolidinecarboxylic acid

7 g of thiazolidine-2-carboxylic acid and 9.1 g of sodium hydrogencarbonate are added to a mixture of 56 ml of water and 63 ml of tetrahydro-10-furan, cooled in an ice / salt cooling bath. 5 ml of β-acetylthiopropanoyl chloride are then added under ice-cooling and vigorous stirring, maintaining the pH at about 7 by the addition of solid sodium bicarbonate. After 1 hour, the mixture is acidified with 1 N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate and concentrated to dryness in vacuo. The residue is chromatographed on a silica gel column, eluting with chloroform / methanol / acetic acid (20: 2: 1).

9.3 g of the material thus purified were converted to 13 g of dicyclohexylammonium salt melting at 197-198 °. The salt can be converted to the free acid again by shaking between 0.2 N sulfuric acid and ethyl acetate. TLC on silica gel in chloroform-methanol-acetic acid (12:

: 2: 1) the product R _{f is} 0.47.

Example 11

DL-3- (3-Mercaptopropanoyl) -2-thiazolinecarboxylic acid

7 g of DL-3- (3-acetylthiopropanoyl) -2-thiazolinecarboxylic acid are added to a mixture of 40 ml of water and 35 ml of 5% aqueous ammonia under an argon atmosphere. After stirring at room temperature for 20 minutes, the mixture was extracted with dichloromethane, the aqueous layer was acidified and extracted with ethyl acetate. The ethyl acetate extracts were washed with water and, after drying, concentrated to dryness in vacuo.

The oily residue in methanol / ether is converted to the dicyclohexylammonium salt melting at 206-210 ° (sintering at 200 °). Yield 5.7 g. The salt can be converted to the free acid again by shaking between ethyl acetate and 0.3 N sulfuric acid. The product had an R _{f of} 0.37 when it was thin-layer chromatographed on silica gel with ethyl acetate-pyridine-methanol-water (60: 20: 6: 11).

Example 12

DL-4- (3-Acetylthiopropanoyl) -3-morpholinic acid

To a solution of 3.9 g of 3-morpholinecarboxylic acid in a mixture of 50 ml of water and 2.2 g of sodium carbonate was added 3.9 g of 3-acetylthiopropanoyl chloride, and the pH was maintained at 8 to 8.2 by addition of aqueous sodium carbonate. After 1.5 hours, the mixture was acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and, after drying, concentrated to dryness. The residue was converted into the dicyclohexylammonium salt in acetonitrile. 5.7 g of salt melting at 187-189 DEG are obtained. This salt was converted back to the free acid by shaking between 99893 between 10% potassium sulfate and ethyl acetate. 3.5 g of acid are obtained, melting at 110 DEG-112 DEG.

Example 13

DL-4- (3-Mercaptopropanoyl) -3-morpholinecarboxylic acid

3.4 g of the thioester of Example 12 are dissolved in a mixture of 8 ml of concentrated ammonia and 19 ml of water. The mixture was allowed to react at room temperature for 2 hours, then acidified and extracted with ethyl acetate.

The organic layer was washed with water and, after drying, concentrated to dryness in vacuo. 2.7 g of the expected product are obtained with an _{Rf of} 0.54 (silica gel, methanol).

Example 14

3- (3-Acetylthiopropanoyl) -2-methyl-4-L-thiazolidinecarboxylic acid

To a solution of 2-methyl-4-L-thiazolidinecarboxylic acid (1.72 g) and sodium carbonate (2.7 g) in water (25 ml) under ice-cooling was added 3-acetylthiopropanoic acid chloride and the mixture was stirred vigorously at room temperature for 2 hours. After extraction with ethyl acetate, the aqueous layer was acidified and extracted again with ethyl acetate. The organic layer was dried and concentrated to dryness to give 3- (3-acetylthiopropanoyl) -2-methyl-4-L-thiazolidinecarboxylic acid melting at 119-122 °.

3- (3-Mercaptopropanoyl) -2-methyl-4-L-thiazolidinecarboxylic acid

The procedure is analogous to that in Example 5 except that 3- (3-acetylthiopropanol) -2-methyl-1-4-L is substituted for 3- (3-acetylthio-2-methylpropanoyl) -4-L-thiazolidinecarboxylic acid. -thiazolidinkarboxylová acid. to give 3- (3-mercaptopropanoyl] ^and 2-methyl-4-L-thiazolidine carboxylic acid, melting at 89-95 °.

Example 16

3- (2-Mercaptoacetyl) -4-L-thiazolidinecarboxylic acid

Substituting 3-bromopropionyl chloride with chloroacetyl chloride for the procedure of Example 1 and following the procedure of Example 2, 3- (2-mercaptoacetyl) -4-L-thiazolidinecarboxylic acid melting at 115-122 ° is obtained.

Example 17

3- (3-Mercaptopropanoyl) -1,3-thlazane-4-carboxylic acid

The procedure is analogous to Example 1 except that 1,3-thiazane-4-carboxylic acid is used instead of 4-L-thiazolidinecarboxylic acid [Ji Biol. Chem., 607 (1957)].

The product obtained, which is 3- (3-benzoylthiopropanoyl) -1,3-thiazane-4-carboxylic acid, is then subjected to the reaction described in Example 2. An oily 3-mercaptopropanoyl) -1,3-thiazane-4-carboxylic acid is obtained. acid o R _f 0.32 (silica gel, 7: 1 benzene-acetic acid).

Calcd for C8H13NO3S2:

N 5.95, C 40.83, H 5.57,

27.25% S;

found ’

N 6.02, C 40.96, H 5.54,

26,94% S.

Claims (1)

A process for the preparation of thiazolidine-, thiazane- and morpholinecarboxylic acid derivatives of the general formula I X RS- (CH ₂ \ CH-CO-N-- CH-COR (f) in which R represents a hydroxyl group, a salt residue or a C 1 -C 7 alkyl ester residue, yn Alzez R 2 represents a hydrogen atom or an alkyl group having 1 to 7 carbon atoms, R3 represents a hydrogen atom or an alkyl group having 1 to 7 carbon atoms, R4 represents an alkanoyl group containing up to 7 carbon atoms, a benzoyl group or a hydrogen atom, X is oxygen or sulfur, m is 1 or 2, n is 0, 1 or 2, and p is 0 or 1, provided that when X is oxygen, m is 2 and n is 1 when X is sulfur, m has a value of an or 2 and n has a value of 0, 1 or 2, and provided that the sum of m-j- must be 2 or 3, characterized in that the compound of formula II 199893 R 3 (CH 2 CH 2 CH 3) n -c'h-cor (II) in which R, R, X, m and n are as defined above, acylated with an acid of formula III R 4 -S- (CH 2) _p —CH-COOH (III) wherein R 3, R 3 and p are as defined above, whereupon the product obtained wherein R 4 is C 7 -C 7 alkanoyl or benzoyl is optionally hydrolyzed to give the corresponding compound wherein R 4 is hydrogen and the resulting product is optionally converted to salt.