CA1118419A - Hexahydro-1-mercaptoacyl-1h-azepine-2- carboxylic acids and esters - Google Patents

Abstract

ABSTRACT

HEXAHYDRO-l-MERCAPTOACYL-lH-AZEPINE-2-CARBOXYLIC
ACIDS AND ESTERS
New hexahydro-l-mercaptoacyl-lH-azepine-2-carboxylic acids and esters which have the general formula

Description

- `~
1118419 HAl63 ,.

HEXAHYDRO-l-MERCAPTOACYL-lH-AZEPINE-2-CARBOXYLIC
ACIDS AND ESTERS

This invention relates to new hexahydro-l-mercaptoacyl-lH-azepine-2-carboxylic acids and esters which have the general formula~
(I) o R

C~ ~ :
OOR ~ ~
wherelll R lS; hydrogen, lower qlkyl or a salt forming ion;
~ Rl~is~hydrogen or lower alkyl;
;~ ~ 15 R2~is~hydrogen or~ lower alkanoyl;
n is 0 or l;
and to the~corresponding dlsulfides, i.~e. wherein R2 is . ;i , , ~ : ' R
S CH2 ~(CH)n CO

and R,~Rl, and~n have~the ~same~meanlng as above.
~- The asterisks indicate~asymmetric carbon atoms.
25~ The carbon in the mercaptoacyl~sidechain is asymmetric -~ when Rl is other than hydrogen~
:
;~ The lower alkyl groups represented by the ` symbols are straight or branched~ chain hydrocarbon radicals having up to seven carbons like methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl and the like. The Cl-C4 member~, especially Cl-C2 members, are preferred.

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:

- `~ - . :. : : :
: , ,: ' :', ,~ , ': :
: , -~ 419 HA163 The ~ower alkanoyl groups are those having the acyl radicals of the lower (up to seven carbon) fatty acids like acetyl, propionyl, butyryl, isobutyryl and the like. Similarly, those lower alkanoyl groups having up to four carbons, and especially acetyl, are preferred.
The salt forming ions represented by R are the ions derived from inorganic or organic bases, including such salts as alkali metal salts, especially sodium and potassium, alkaline earth metal salts, especially calcium and maqnesium, aluminum, dicyclohexylamine salt, benzathine salt, N-methylglucamine salt, hydrabamine salt, salts with naturally ocurring amino acids like arginine, lysine and the like, lower alkylamine salts like methyl-amine, ethylamine, dimethylamine, triethylamine salts, etc.
The compounds of formula I are produced by reacting hexahydro-lH-azepine-2-carboxylic acid (J.
Med. Chem. 14, 501 (1971)) or lower alkyl ester or Z0 salt thereof with an acyl halide (preferably chloride) having the formula (II) 1l 1l X-c-(cH)n-cH2-s-R3 wherein X is halogen and R3 is lower alkanoyl, in an inert organic solvent like dimethylaceta~mide, dimethylformamide, or the like, in the presence of an organic base like N-methylmorpholine, triethylamine, pyridine at a temperature in the range of about 20 -100 C.
The acyl group can be removed, making R2=H, by 4i9 ammonolysis, uslng aqueous ammonia.
When hexahydro~ -azepine-2-carboxylic acid is used as the starting material, the product carboxylic acid can be converted to the lower alkyl ester by conventional esterification techniques, e.g. with a diazoalkane like diazomethane, l-n-butyl-3-p-tolyl-triazene or the like.
When R ln the starting material is lower alkyl, the product ester can be converted to the free carboxylic acid by conventional procedures such as hydrolysis or, in the c~se of the t-butyl ester with trifluoro-acetic acid and anisole.
The disulfides, i.e., compounds of formula I
wherein R2 is R
-S-CH2-(CH)n-CO-N ~

are produced by direct oxidation of a compound of formula I in which R2 i5 hydrogen, e.g., with iodine, to obtain the symmetrical bis compound.
The products of this invention have one or more asymmetric carbon atoms as indicated by the asterisks above. The compounds accordingly exist in stereoisomeric forms or in racemic mixtures thereof.
All of these are within the scope of the invention.
In general, the L-isomer with respect to the carbon of the hexahydroazepine carboxylic acid constitutes the preferred isomeric form.

,, ~ 9 HAl63 The compounds of this invention form basic salts with various inorganic and organic bases as described above. They are also included in the scope of the invention. The non-toxic, physiologically acceptable salts are preferred, although other salts are also useful, e.g., in isolation or purifying the product. The salts are formed in conventian manner by reacting the free acid form of the product with one or more equivalents of the appropriate base providing the desired salt ion in a solvent or medium in wh-cn the salt is insolubie, or in water and removing the water by freeze drying. By neutralizing the salt by conventional methods 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 by angiotensin converting enzyme and therefore are useful in reducing or relieving angio-tensin related hypertension. By the administration of a composition containing one or a combination of compounds of formula I or physiologically acceptable salt thereof, angiotensin dependent hypertension in the species of mammal e.g., rats, cats, dogs, etc., suffering therefrom is alleviated. A single dose, or preferably two to four divided daily doses, provided on a basis of about 0.1 to lO0 mg. per kilogram per day, preferably about 1 to 50 mg. per kilogram per day is appropriate to reduce blood pressure as indicated in the animal model experiments described by S. L.
Engel, T. R. Schaeffer, M. H. Waugh and B . Rubin, Proc.
Soc. Exp. Biol. Med. 143, 483 (1973). The substance ~184~9 HAl63 is preferably administered orally, but parenteral routes such as subcutaneously, intramuscularly, intravenously or intraperitonealy can also be employed.
The compounds of this invention can be utilized to achieve the reduction of blood pressure by form-ulatin~g in conventional compositions such as tablets, capsules or eIixirs for oral administration or in ~sterile solutions or suspensions for parenteral admin-~ istration. About I0 to 500 mg. of a compound or mixture of compounds of formula I or physiologically acceptable sa;~ is compounded with a physiologically acceptable 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 aompositions or preparations is such that a suitable dosage in the range indlcated is obtained.
Sterile compositions for injection can be formulated acaording to conventional pharmaceutical praatice by dissolving or~suspending the active substance in a vehicle such as water for ~injection, a naturally oaaurringvegetable oll Iike sesame oil, oxxnut ;~-oil, peanut oilj aottonseed oil, etc., or a synthetic fatty vehicle like ethyl oleate or the like. Buffers, preservatives, antioxidants and the like can be incor-porated as required.
The following examples are illustrative of the invention and constitute especially preferred embodi-ments. All temperatures are in degrees aelsius.

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1~18419 Example 1 a) l-t3-Acetylthio-l-oxopropyl)hexahydro-lH-azepine-2-carboxylic acid To a suspension of 3.22g of hexahydro-lH-azepine-

2-carboxylic acid and 4.04g of N-methylmorpholine in 100 ml. of dimethylacetamide there is added dropwise, with vigorous stirring at 25 , 3.32g of 3-acetylthio-propionyl chloride. There is a slight temperature rise during this addition. The reaction mixture is heated on a steam bath (internal temperature 85 - 90 ) for 4 hrs., ~uring which time a clear solution forms.
The reaction mixture is cooled and the precipitated solid of N-methylmorpholine hydrochloride is removed by filtration.
The filtrate is concentrated under reduced pressure to remove the solvent and the residue is triturated with dilute hydrochloric acid. The mixture is extracted with ethyl acetate which is then dried with anhydrous magnesium sulfate and concentrated under reduced pressure to yield 1-(3-acetylthio-1-oxopropyl)hexahydro-lH-azepine-2-carboxylic acid as a viscous oil.
b) Hexahydro-1-(3-mercapto-1-oxopropyl)-lH-azepine-2-carboxylic acid A solution of 4.9g of 1-~3-acetylthio-1-oxopropyl)hexahydro-lH-azepine-2-carboxylic acid in dilute aqueous ammonia (30 ml of H2O and 12 ml. of concentrated aqueous ammonia) is stirred under nitrogen, at 10 for 30 mins. and at room temperature for 3 hrs.
The reaction mixture is then extracted with ethyl acetate and made strongly acidic with 20% hydrochloric acid. The precipitated oil is extracted into fresh ethyl acetate and this solution dried over anhydrous magnesium sulfate. The solvent is removed under -~ 419 HA163 reduced pressure, leaving a viscous oily residue. This is dissolved in benzene and lyophilized to yield the desired hexahydro~ 3-mercapto-1-oxopropyl)-lH-azepine-2-carboxylic acid as a hydrated viscous oil. Analysis S calcd. for CloH17NO3S-H2O: C, 48.17~, H, 7.68~;
N, 5.60~; S, 12.85%.
Found: C, 48.39%; H, 7.~7~
N, 5.40~; S, 13.02%.
Example 2 1-(2-Acetylthio-l-oxoethyl)hexahydro-lH-azepine-2-carboxylic acid .

Following the procedure of Example la but substituting an equivalent amount of acetylthioacetyl chloride for the 3-acetylthiopropionyl chloride, there is obtained the desired 1-(2-acetylthio-1-oxoethyl) hexahydro-lH-azepine-2-carboxylic acid.
Example 3 Hexahydro-1-(2-mercepto-1-oxoethyl)-lH-azepine-2-carboxylic acid.
Following the procedure of Example lb but substituting an equivalent amount of l-(2-acetylthio-l-oxoethyl)hexahydro-lH-azepine-2-carboxylic acid for the l-(3-acetylthio-1-oxopropyl)hexahydro-1_-azepine-2-carboxylic acid, there is obtained the desired hexahydro-l-(2-mercapto-1-oxoethyl)-lH-azepine-2-carboxylic acid.
Example 4 1-(3-(Acetylthio)-2-methyl-1-oxopropyl)hexahydro-lH-azepine-2-carboxylic acid.
Following the procedure of Example la but substituting an equivalent amount of 3-(acetylthio)-~ 4i9 HA163 2-methylpropionyl chloride for the 3-acetylthiopropionyl chloride there is obtained the desired l-(3-acetylthio)-2-methyl-1-oxopropyl)hexahydro-lH-azepine-2-carboxylic acid.
Example S
Hexah dro-1-(3-merca to-2-methyl-1-oxoproPyl)-lH-Y P
azepine-2-carboxylic acid.
Following the procedure of Example lb but substituting an equivalent amount of l-(3-(acetylthio)-2-methyl-1-oxopropyl)-hexahydro-lH-azepine-2-carboxylic acid for the l-(3-acetylthio-1-oxopropyl~-hexahydro-lH-azepine-2-carboxylic acid there is obtained the desired hexahydro-l-(3-mercapto-2-methyl-1-oxo-5 propyl)-lH-azepine-2-carboxylic acid.
Example 6 1,1'-(Dithiobis(l-oxopropane-3,1-diyl))bis(hexahydro-lH-aze~ine-2-carboxYlic acid).
-Three grams of hexahydro-1-(3-mercapto-1-oxopropyl)-lH-azepine-2-carboxylic acid is dissolved in 75 ml. of water by adding sufficient lN-sodium hydroxide to adjust the pH to 6.5. To this solution there i8 added dropwise, with vigorous stirring, 26 ml.
of a 0.5M iodine solution (95~ ethanol), while maintain-ing the pH between 5.5 and 6.5. After 15 mins., the reaction mixture is treated with an aqueous sodium thiosulfate solution to remove unreacted iodine. The reaction mixture lS concentrated under reduced pressure and is then acidified with 20% hydrochloric acid. The precipitated product is extracted into ethyl acetate, the solvent dried over anhydrous magnesium sulphate and concentrated under reduced pressure to yield the desired 1,1'-(dithiobis(l-oxopropane-3,1-diyl)bis(hexahydro-lH-azepine-2-carboxylic acid).

Claims (14)

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 and R1 each is hydrogen or lower alkyl R2 is hydrogen or lower alkanoyl; and n is 0 or 1, and basic salts thereof, characterized by reacting a hexahydro-lH-azepine-2-carboxylic acid or lower alkyl ester thereof or basic salt thereof having the formula with an acyl halide of the formula wherein R3 is lower alkanoyl and X is halogen and R1 and n are as previously defined, to form a product wherein R2 is lower alkanoyl and further subjecting said product to ammonolysis to form a product wherein R2 is hydrogen.

2. A process according to claim 1 wherein R is hydrogen.

3. A process according to claim 1 wherein R1 is hydrogen or methyl.

4. A process according to claim 1 wherein R2 is acetyl.

5. A process as in claim 1 wherein n is 1.

6. A process as in claim 1 wherein n is 1, R1 is hydrogen or methyl and R2 is acetyl.

7. A process as in claim 1 wherein n is 1, R1 is hydrogen or methyl and R2 is hydrogen.

8. A compound of the formula wherein R and R1 each is hydrogen or lower alkyl;
R2 is hydrogen or lower alkanoyl; and n is 0 or l, and basic salts thereof, whenever prepared by the process of claim 1.

9. A compound according to claim 8 wherein R is hydrogen, whenever prepared by the process of claim 2.

10. A compound according to claim 8 wherein R1 is hydrogen or methyl, whenever prepared by the process of claim 3.

11. A compound according to claim 8 wherein R2 is acetyl, whenever prepared by the process of claim 4.

12. A compound as in claim 8 wherein n is 1, whenever prepared by the process of claim 5.

13. A compound as in claim 8 wherein n is 1, R1 is hydrogen or methyl and R2 is acetyl, whenever prepared by the process of claim 6.

14. A compound as in claim 8 wherein n is 1, R1 is hydrogen or methyl and R2 is hydrogen, whenever prepared by the process of claim 7.