CA1090354A

CA1090354A - Carboxymethyl esters of mercaptopropanoic acids

Info

Publication number: CA1090354A
Application number: CA306,339A
Authority: CA
Inventors: Miguel A. Ondetti
Original assignee: ER Squibb and Sons LLC
Current assignee: ER Squibb and Sons LLC
Priority date: 1977-07-14
Filing date: 1978-06-27
Publication date: 1980-11-25
Also published as: NL7807492A; DK315378A; GB2001963B; FR2397401B1; IE47423B1; NO146024C; AU3758878A; AU522452B2; NO146024B; FR2397401A1; DK149770B; BE869014A; DE2830635A1; JPS5419914A; HU177904B; GB2001963A; JPS6216943B2; CH632490A5; DE2830635C2; IT1105098B

Abstract

ABSTRACT New carboxymethyl esters of mercaptopropanoic acids,and salts thereof,have the formula wherein R is hydrogen or lower alkanoyl; R1 is hydrogen or lower alkyl; and R2 is hydrogen, lower alkyl, phenyl, phenyl-lower alkyl, 4-hydroxyphenyl-lower alkyl or indolyl-lower alkyl. They are useful as hypotensive agents.

Description

This invention relates to new carboxymethyl esters of mercaptopropanoic acids which have the formula (I) IRl lR2 R-S-CH2-(~H-CO-O-CH-COOH
and to salts thereof.
In formula I and throughout this specification the symbols have the meanings described below.
,~ R is hydrogen or lower alkanoyl.
Rl is hydrogen or lower alkyl.
;~ R2 is hydrogen, lower alkyl, phenyl, phenyl-lower ..: .
alkyl, 4-hydroxyphenyl-lower alkyl or indolyl-lower alkyl.
The lower alkyl groups are straight or branched chain hydrocarbon radicals having up to seven carbon atoms, e.g., methyl, ethyl, propyl, isopropyl, butyl, sec.butyl and the like. The Cl-C4 and especially Cl-C2 alkyl groups are preferred. The phenyl-lower alkyl and indolyl-, lower alkyl groups include lower alkyl groups of the same type (with the same preferences expressed above.) : The lower alkanoyl groups are the acyl radicals of the lower (C2-C7~ fatty acids, e.g., acetyl, propionyl, butyryl, isobutyryl and the like. The members mentioned, and especially acetyl, are preferred.
Preferred members of the invention are those compounds of formula I wherein R is hydrogen or lower alkanoyl, especially acetyl; Rl is hydrogen or lower alkyl, especially _ / _ '.~

-~ _ HAl54 methyl; and R2 is hydrogen, phenyl-lower alkyl or indolyl lower alkyl especially phenylmethyl.
The compounds of formula I are produced by acylation of an a-hydroxy acid having the formula (II) 12 HO-CH-COOH
with an acid having the formula : (III) Rl by conventional esterification procedures.
A preferred method comprises activating the acid of formula III with carbodiimidazole to form the acylimidazole intermediate having the formula (IV) R

;. , I ~
, R-S-CH2-CH-CO-N~N
which is used without isolation. It is also preferred to form a product wherein R is lower alkanoyl, then treat the ` acyl derivative with ammonia or concentrated ammonium hydroxide to obtain the product wherein R is hydrogen.
The carbon atoms marked with an asterisk in formula I are asymmetric if Rl and R2 are other than hydrogen. Thus the compoundswith the asymmetric carbon exist as_diastereoisomers or in racemic mixtures thereof. All of these are within the scope of the invention.
The a-hydroxy acids of formula II are well known ~; in the literature and can be produced by the many methods available.
The mercaptopropanoic acids of formula III can be produced as described in U.S. Patent No. 4,053,651 . : .
. .

issued October 11, 1977 and Belgian Patent No. 851,361 granted August 11, 1977 e.g., by reacting a thioacid of the formula (VI) wherein R4 is lower alkyl, with an acrylic acid having the formula (VII) CH2=C-COOH
The R4-CO group can be removed at this stage or later by treatment with ammonia or concentrated ammonium hydroxide as described above.
The compounds of formula I form the common (basic) ~; salts of carboxylic acids, e.g., by reaction with inorganic - or organic bases. Such salts include ammonium salts, alkali metal salts like sodium and potassium salts, alkaline earth meta~ like calcium and magnesium salts, salts with organic bases, e.g., dicyclohexylamine, benzathine, hydrabamine and N-methyl-D-glucamine salts. Since some of the compounds of formula I are not readily obtainable as crystalline ; substances with well defined melting points, the salts (which are not necessarily physiologically acceptable) provide means to isolate and characterize the product.
Additional experimental details can be found in the illustrative examples below.
The compounds of this invention are angiotensin .
converting enzyme inhibitors and are useful as hypotensive : agents, particularly for the reduction of renin-angiotcnsin dependent hypertension. By administering a composition containing one or a combination of angiotensin converting \
~O 3 j'~ HA154 enzyme inhibitors of this invention to a hypertensive mammal, it intervenes in the renin ~ angiotensinogen ~
angiotensin I ~ angiotensin II sequence and the hypertension is reduced or alleviated.
A singledose, or preferably two to four divided daily doses, provided on a basis of about 1 to 1000 mg.
per ~ilogram per day and especially about 10 to 100 mg.
per kilogram per day is appropriate to bring about a reduction in elevated blood pressure. The animal model experiments described by Engel et al., Proc. Soc. Exp. Biol. Med. 143, 483 (1973) provide a valuable guide.

:
The composition is preferably administered orally, but it can also be administered subcutaneously, intramuscularly, intravenously or intraperitoneally. The compound or ; compounds of formula I can be formulated as tablets, capsules or elixirs for oral administration. Sterile solutions or suspensions can be used for parenteral use.
About 20 to 1000 mg. of a compound or compounds of formula I or physiologically acceptable salt thereof can be compounded with a physiologically acceptable vehicle, carrier, excipient, binder, preservative, stabilizer, flavor, etc., in a conventional unit dosage form as called for by accepted pharmaceutical practice. The amount of active substance is selected so as to provide a dosage in the range indicated.
The following examples are illustrative of the invention -and represent preferred embodiments. All temperatures are in degrees Celsius.

~ HA154 Example 1 o-(3-Acetylthiopropanoyl)glycolic Acid 3-(Acetylthio)propanoic acid (2.96 g.) and l,l'-car-bonyldiimidazole (3.24 g.) are dissolved in 20 ml. of dry tetrahydrofuran with stirring at room temperature. After twenty minutes,a solution of glycolic acid (1.52 g.) and

- 2.80 ml. of triethylamine in 15 ml. of dry tetrahydrofuran are added. The reaction mixture is stored overnight at room temperature. The tetrahydrofuran is removed in vacuo, the crude residue taken up into ethyl acetate, washed with lN
hydrochloric acid and three times with water, dried over magnesium sulfate and the 0-(3-acetylthiopropanoyl)glycolic acid is concentrated to dryness in vacuo, yield 3.9 g.
` This is dissolved in ether and dicyclohexylamine is added.
The dicyclohexylamine salt precipitates, yield 2.85 g.;
m.p. 150-157. The salt is converted to the free acid by adding to ethyl acetate and adding 10% potassium bisulfate solution, yield 1.5 g.
: Example 2 0-(3-Mercaptopropanoyl)~lycolic Acid 0-~3-acetylthiopropanoyl)glycolic acid from Example 1 ' (1.3 g.), under a blanket of argon is treated for fifteen - minutes with a cold solution of 7 ml. of water and 7 ml. of concentrated ammonium hydroxide. This is chilled, acidified with concentrated hydrochloric acid and extracted into ethyl acetate, yield: 1.2 g. This product 0-(3-mercaptopropanoyl)-glycolic acid is chromatographed on DEAE Sephadex A25 ~Polidextrane* anion exchange resin) with a linear gradient of ammonium bicarbonate. The desired fractions (45-70; U.V.

peak at 254 nm.) are pooled, concentrated and lyophilized.

* -5-Trade Mark .' '.' This ammonium salt of 0-(3-mercaptopropanoyl)glycolic acid is converted to the free acid by treatment with Dowex 50WX2 cation exchange resin, yield 320 mg. The 0-(3-mercapto-- propanoyl)glycolic acid is converted to the dicyclo-hexylamine salt by dissolving in ether and precipitating by the addition of dicyclohexylamine, m.p. 143-144 .
Example 3 0-[3-(Acetylthio)-2-Methylpropanoyl]Glycolic 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 18 hours. After confirming by nmr spectroscopy that complete reaction of the methacrylic acid has been achieved, the reaction mixture is distilled in vacuo and the desired 3-acetylthio-2-methylpropanoic --acid is separated in the fraction with boiling point 128.5-131 (2.6 mmHg.), yield 64 g.

3-Acetylthio-2-methylpropanoic acid (6.48 g.) is taken into 40 ml. of dry tetrahydrofuran. To this l,l'-carbonyl-diimidazole (0.48 g.) is added and stirred for 30 minutes at room temperature. Glycolic acid (6.08 g.) and 11.2 ml.
of triethylamine in 60 ml of dry tetrahydrofuran are added. !~
After several minutes, the imidazole salt of glycolic acid begins to come out of solution. The reaction is permitted to run overnight at room temperature. The crystalline salt is filtered and the filtrate concentrated to dryness in vacuo.
The residue is taken up into ethyl acetate, washed with lN
hydrochloric acid and three times with water, dried over magnesium sulfate and concentrated to dryness in vacuo.
This product is converted to its dicycloehxylamine salt by dissolving in ether/hexane and precipitating by the addition *
Trade Mark :' .

~ o~

of dicyclohexylamine. The salt is recrystallized from ether, m.p. 120-122 . This salt is then converted to the free acid, 0-[3-(acetylthio)-2-methylpropanoyl]glycolic acid, by adding to ethyl acetate, addin~ 10~ potassium bisulfate solution, then crystallizing from ethyl/hexane, yield 2.96 g., m.p. 50-51.
Example 4 O-(DL-3-Mercapto-2 Methylpropanoyl)Glycolic Acid 0-[3-(Acetylthio)-2-methylpropanoyl]glycolic acid (1.5 g.) is placed under a blanket of argon. To this a cold solution of 7.5 ml. of concentrated ammonium hydroxide and .~,.
~,l 7.5 ml. of water is added and the mixture is stored for ; 15 minutes at room temperature. This is then acidified with concentrated hydrochloric acid and extracted with ethyl acetate, yield 1.3 g. This product is dissolved in ether/hexane and dicyclohexylamine is added to precipitate the dicyclohexylamine salt, yield 2.24 g., m.p. 96-98.
A 1.9 g. aliquot of the salt is converted to the free O-(DL-3-mercapto-2-methylpropanoyl)glycolic acid by adding to ethyl acetate and adding 10~ potassium bisulfate ~solution, yield 0.9 g. The product is a heavy oil which is chromatographed on silica gel (benzene 7:2 acetic acid), Rf=0.49, traces Rf=0.32 and 0.57.
Example 5 O-L-[3-(Acetylthio)propanoyl]-3-Phenyllactic Acid 3-(Acetylthio)propanoic acid (1.48 g.) is added to 10 ml. of dry tetrahydrofuran with stirring. To this l,l'-carbonyldiimidazole (1.62 g.) is added ~nd the mixture stirred for twenty minutes at room temperature. L-(-)-3-phenyllactic acid (1.66 g.) is added in a solution of '''' 7.5 ml. of dry tetrahydrofuran and 1.4 ml. of triethyl-amine. The reaction mixture is stored overnight at room temperature. The tetrahydrofuran is removed in vacuo, the residue is taken up into ethyl acetate, washed with lN
hydrochloric acid, three times with water, dried over magnesium sulfate and concentrated to dryness in vacuo, yield 2.8 g. The O-L-[3-(Acetylthio)propanoyl]-3-pheny~actic acid is purified on a silica gel column,eluting with benzene 7:1 acetic acid, yield 1.7 g. -Example 6 O-L-(3-Merca~topropanoyl)-3-Phenyllactic Acid To 1.5 g. of O-L-[3-(acetylthio)propanoyl]-3-phenyllactic acid a solution of 7.5 ml. of water and 7.5 ml. of concentrated ammonium hydroxide is added under an argon blanket. After fifteen minutes, the reaction mixture is chilled, acidified - with concentrated hydrochloric acid and extracted into ethyl acetate, yield 1.1 g. The product, O-L-(3-mercapto-propanoyl)-3-phenyllactic acid is purified on a silica gel column, eluting with benzene 14:1 acetic acid, yield 357 mg.
A small portion of the semi-solid product is converted to its dicyclohexylamine salt by dissolving in ether/hexane and precipitating with dicyclohexylamine, m.p. 100.
Example 7 O-DL-(3-Acetylthiopropanoyl)-3-Indolelactic Acid By substituting DL-3-indolelactic acid for the L-~-- phenyllactic acid in the procedure of Example 5, O-DL-(3-acetylthiopropanoyl)-3-indolelactic acid is obtained.
Example 8 O-DL-(3-Mercaptopro~ano~1)-3-Indolelactic Acid - 30 By substituting O-DL-(3-acetylthiopropanoyl)-3-.' :

J~ HA154 indolelactic acid for the O-L-(3-acetylthiopropanoyl)-3-phenyl-lactic acid in the procedure of Example 6, O-DL-(3-mercapto-propanoyl)-3-indolelactic acid is obtained, as the dicyclohexyl-- amine salt, m.p. 151-153C.
Example 9 O-DL-(3-Mercapto-2-Methylpropanoyl)-3-Indolelactic Acid ;~' .
, By substituting 3-indolelactic acid for the glycolic acid in ,~i the procedure of Example 3 and then submitting the product to the procedure of Example 4, O-DL-[3-(acetylthio)-2-methylpropanoyl]-3-indolelactic acid and O-DL-(3-mercapto-2-methylpropanoyl)-3-indolelactic acid are obtained.
Example 10 ' O-L-(3-Mercaptopropanoyl)lactic Acid ~ By substituting L-lactic acid for the glycolic acid in the - procedure of Example 1 and then submitting the product to the ~- procedure of Example 2, O-L-(3-acetylthiopropanoyl)lactic acid ;~ and O-L-(3-mercaptopropanoyl)lactic acid are obtained.
,',:
Example 11 O-L-(3-Mercaptopropanoyl)--Hydroxyisocaproic Acid By substituting L-~-hydroxyisocaproic acid [Winitz, et al., J. Am. Chem. Soc. 78, 2423 (1956)] for the glycolic acid in the procedure of Example 1 and then submitting the product to the procedure of Example 2, O-L-(3-acetylthiopropanoyl)-a-hydroxy-isocaproic acid and O-L-(3-mercaptopropanoyl)-~-hydroxyisocaproic acid are obtained.
~- Example 12 ;~ O-L-(3-Acetylthiopropanoyl)-3-(p-tert-butoxyphenyl)lactic Acid By substituting 3-(p-tert-butoxyphenyl)lactic acid , [obtained from O-tert-butyl-L-tyrosine by the procedure described by H.D. Dakin and H.W. Dudley in J. Biol. Chem., 18, 29 (1914) for the preparation of 3-L-phenyllacetic acid]
, .
.:

. ., _ g _ . ', .
' .

-- ~0'~3~`jf~

. for, the 3-L-phenyllactic acid in the procedure of Example 5, O-L-(3-acetylthiopropanoyl)-3-(p-tert-butoxyphenyl)lactic acid is obtained.
Exampl 13 O-L-(3-Mercaptopropanoyl)-3-p-Hydroxyphenyllactic Acid ;~ O-L-(3-acetylthiopropanoyl)-3-(p-tert-butoxyphenyl)lactic .~ acid (1.8 g.) is dissolved in trifluoroacetic acid (15 ml.) ~ and the solution is stored at room temperature for ; one hour. After removing the trifluoroacetic acid in vacuo, the residue is dissolved in a mixture of water (7.5 ml.) and ~`
concentrated ammonium hydroxide (7.5 ml.) under an argon blanket. After fifteen minutes, the reaction mixture is - chilled, acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The organic layer is con-centrated in vacuo to yield O-L-(3-mercaptopropanoyl)!-3-p-hydroxyphenyllactic acid.
Example 14 0-(3-Mercaptopropanoyl)mandelic Acid By substituting mandelic acid for the L-3-ptienyllactic acid in the procedure of Example 5, and then submitting the product to the procedure of Example 6, 0-(3-acetylthiopro-panoyl)mandelic acid and 0-(3-mercaptopropanoyl)mandelic acid are obtained.

. . .

. ~

` ` --10--

Claims

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 hydrogen or lower alkanoyl; R1 is hydrogen or lower alkyl; R2 is hydrogen, lower alkyl, phenyl, phenyl-lower alkyl, 4-hydroxyphenyl-lower alkyl or indolyl-lower alkyl; and salts thereof, characterized by reacting an alpha-hydroxy acid of the formula with an acid having the formula by conventional esterification procedures.

2. A process as in claim 1 wherein R is hydrogen or lower alkanoyl; R1 is hydrogen or lower alkyl; and R2 is hydrogen or phenyl-lower alkyl.

3. A process as in claim 1 wherein R is hydrogen.

4. A process as in claim 1 wherein R is lower alkanoyl.

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

6. A process as in claim 1 wherein R, R1 and R2 each is hydrogen.

7. A process as in claim 1 wherein R is lower alkanoyl;
R1 is lower alkyl; and R2 is hydrogen.

8. A process as in claim 1 wherein R is acetyl; R1 is methyl and R2 is hydrogen.

9. A process as in claim 1 wherein R and R2 each is hydrogen and R1 is methyl.

10. A process as in claim 1 wherein R and R1 each is hydrogen and R2 is phenyl-lower alkyl.

11. A process as in claim 1 wherein R and R1 each is hydrogen and R2 is phenylmethyl.

12. A process as in claim 1 wherein R and R1 each is hydrogen, R2 is phenylmethyl and the product is in the L-form.

13. A process as in claim 1 wherein R2 is indolylmethyl.

14. A process as in claim 1 wherein R and R1 each is hydrogen and R2 is 3-indolylmethyl.

15. A process as in claim 1 wherein R is hydrogen, R1 is methyl and R2 is 3-indolylmethyl.

16. A compound of the formula wherein R is hydrogen or lower alkanoyl; R1 is hydrogen or lower alkyl; R2 is hydrogen, lower alkyl, phenyl, phenyl-lower alkyl, 4-hydroxyphenyl-lower alkyl or indolyl-lower alkyl; and salts thereof, whenever prepared by the process of claim 1.

17. A compound as in claim 16 wherein R is hydrogen or lower alkanoyl; R1 is hydrogen or lower alkyl and R2 is hydrogen or phenyl-lower alkyl, whenever prepared by the process of claim 2.

18. A compound as in claim 16 wherein R is hydrogen, whenever prepared by the process of claim 3.

19. A compound as in claim 16 wherein R is lower alkanoyl, whenever prepared by the process of claim 4.

20. A compound as in claim 16 wherein R is acetyl, whenever prepared by the process of claim 5.

21. A compound as in claim 16 wherein R, R1 and R2 each is hydrogen, whenever prepared by the process of claim 6.

22. A compound as in claim 16 wherein R is lower alkanoyl; R1 is lower alkyl; and R2 is hydrogen, whenever prepared by the process of claim 7.

23. A compound as in claim 16 wherein R is acetyl, R1 is methyl and R2 is hdyrogen, whenever prepared by the process of claim 8.

24. A compound as in claim 16 wherein R and R2 each is hydrogen and R1 is methyl, whenever prepared by the process of claim 9.

25. A compound as in claim 16 wherein R and R1 each is hydrogen and R2 is phenyl-lower alkyl, whenever prepared by the process of claim 10.

26. A compound as in claim 16 wherein R and R1 each is hydrogen, and R2 is phenylmethyl; whenever prepared by the process of claim 11.

27. A compound as in claim 16 wherein R and R1 each is hydrogen, R2 is phenylmethyl and the product is in the L-form, whenever prepared by the process of claim 12.

28. A compound as in claim 16 wherein R2 is indolyl-methyl, whenever prepared by the process of claim 13.

29. A compound as in claim 16 wherein R and R1 each is hydrogen and R2 is 3-indolylmethyl, whenever prepared by the process of claim 14.

30. A compound as in claim 16 wherein R is hydrogen, R1 is methyl and R2 is 3-indolylmethyl, whenever prepared by the process of claim 15.