FR2483411A1 - MERCAPTOACYL N-SUBSTITUTED PROPIONAMIDES INHIBITING COLLAGENASE IN MAMMALS, AND PROCESS FOR PREPARING SAME - Google Patents

Abstract

COMPOUND OF FORMULA: (CF DRAWING IN BOPI) POSSIBLY IN THE FORM OF A SALT, FORMULA IN WHICH: R IS AN ATOM OF HYDROGEN OR A RADICAL ALKANOYL OF 2 TO 10 ATOMS OF CARBON OR ARYLCARBONYL; R IS A GROUP OF THE FORMULA: (CF DRAWING IN BOPI) OR A RADICAL 1-PYRROLIDINYL, 1-PIPERIDINYL, 4-MORPHOLINYL, 1-PIPERAZINYL OR 4-ALKYL-1-PIPERAZINYL, R BEING A HYDROGEN ATOM OR A RADICAL ALKYL OR ARYL; R IS A RADICAL ALKYL OF 3 TO 8 ATOMS OF CARBON, CYCLOALKYL OF 3 TO 7 ATOMS OF CARBON, ARYL OR ARYLALKYL; AND N IS A WHOLE NUMBER FROM 1 TO 20. THESE COMPOUNDS INHIBIT COLLAGENASE IN MAMMALS.

Description

N-substituted mercaptoacyl propionamides inhibiting collagenase in

  mammals, and process for their preparation Mammalian collagenase is inhibited by the compounds of formula I

R-S-CH 0

  In formula I and throughout the specification, the symbols have the following definitions: R1 is a hydrogen atom or an alkanoyl radical of 2 to 10 carbon atoms (the acetyl radical is preferred) or arylcarbonyl (the benzoyl radical is preferred); R2 is a group of formula

NH 0 14 R4 0 --- CH 2

  i $ o 1 / - -2 -R4, -C- (O-alkyl) e) 2, or | or a 1-pyrrolidinyl, 1-piperidinyl, 4-morpholinyl, 1-piperazinyl or 4-alkylpiperazinyl radical, R4 being a hydrogen atom or an alkyl or aryl radical;

  R3 is an alkyl radical of 3 to 8-atoms of -

  carbon, cycloalkyl of 3 to 7 carbon atoms, aryl or arylalkyl; and

n is an integer from 1 to 20.

  The term "aryl", as used throughout the specification, either alone or as part of a larger group, denotes a phenyl radical optionally substituted with one, two or three alkyl or alkoxy radicals. , halogen atoms, amine or hydroxy groups, or alkanoyloxy radicals. Phenyl radicals and

  Monosubstituted phenyl are the preferred aryl radicals.

  The terms "alkyl" and "alkoxy" as used throughout the specification (unless otherwise defined), either singly or as part of a larger group, refer to

  radicals having 1 to 8 carbon atoms. -

  The term "halogen" as used throughout the specification, either singly or as part of a larger

  atom of fluorine, chlorine, bromine or iodine.

  The compounds according to the invention can be prepared using, as starting material, a carboxylic acid having the formula:

II R.O

13 he

HO-CH2-CH-C-OH.

  Heating a carboxylic acid of formula II with phosphoric acid gives a compound having the formula:

III RO

R3 0I g3 he

CC = CH2-OH,

  that in turn can be reacted with a thio-acid having the formula: IV Ri-SH,! in which R is an alkanoyl or arylcarbonyl radical, to obtain a product having the formula:

V R O

i11 He

R1-S-CH2-CH-C-OH.

  An acid of formula V, or an ester thereof, may be condensed with a compound having the formula: VI NH2- (CH2) n-R2 'or with a salt thereof, to obtain the compounds of formula I in which R1 is other than hydrogen. The condensation reaction can be carried out by first activating the acid of formula V, forming for example a mixed or symmetrical anhydride, an acid chloride, or an active ester,

  or using Woodward's reagent K, EEDQ (N-

  ethoxycarbonyl-2-ethoxy-1,2-dihydroxyquinoline), or similar means. A preferred mode of activation consists in first treating an acid of formula V with an organic base (triethylamine, for example), then adding chlorine.

ethyl formate .. -

  The products of formula I in which R is a hydrogen atom can be prepared from the corresponding compounds of formula I in which R 1 is an alkanoyl or arylcarbonyl radical, by treating the acylthio compound.

by concentrated ammonia. -

  Or, the compounds can be prepared according to

  the invention using as starting material a malonic acid ester derivative having the formula:

VII O R3 O

Vii -Il I It-

  alkyl-O-C-CH-C-O-alkyl. Hydrolysis of a malonic acid ester derivative of formula VII gives the corresponding compound having the formula:

VIII R O

l13 he

HO-C-CH-C-OH.

  The successive reaction of a diacid of formula VIII with a secondary amine (such as dimethylamine) and with formaldehyde gives the corresponding compound having the formula: IX

Ix O R O-

iI 13 0i

* HO-C-C-C-OH

I -

CH2

N (CH3) 2 3 -

  Transformation of a compound of formula IX into the corresponding compound having the formula:

CH2 = C-C-OH

  can be done by melting the precursor compound. The compounds according to this invention can be prepared from the compounds of formula III using the procedures

described above.-

  The compounds of formula I can be further prepared

-5 - O

  Wherein R2 is a group of formula -C-R4, from the corresponding product of formula I wherein R2- is a

R R

  14 group of formula -C- (O-alkyl) 2 or, O-.

-O-CH

acid hydrolysis.

  The compounds of formula I have at least one asymmetric carbon atom which is marked with an asterisk (*) in formula I. Therefore, the compounds exist in stereoisomeric forms or as racemic mixtures. All these forms enter the field

  application of the invention. The synthesis mode described above

  above can use the starting compounds in the form

  of a racemic mixture or in the form of a stereoisomer.

  In mammals, collagenase is one of the key enzymes involved in the destruction of cartilage and joints of rheumatoid arthritis; see, for example, Arthritis and Rheumatism, 20 (6): 1231 (1977). It is therefore desirable to inhibit the action of the

collagenase.

  Without wishing to limit the scope of this invention to a specific theory or mechanism of operation, it is nevertheless useful for the proper understanding of the invention to review the possible reasons for the activity of the compounds of the invention. Formula I. The main constituents of cartilage are the molecules of -polypeptides of collagen. These polypeptides are cleaved by mammalian collagenase at a single site. The compounds of this invention resemble the supposed sequence of collagen molecules, and, in theory, bind to mammalian collagenase and inhibit its activity. Mammalian collagenase is an enzyme that contains zinc, which promotes cleavage of a glycine-leucine bond or a glycineisoleucine bond and contains a kind of long crack that interacts with an elongated portion of the collagen molecule. This molecule itself contains arginine as the last homologous amino acid in the substrate sequence adjacent to the cleavage site, which sequence has a high degree of homology among the various types of collagen molecules. The inhibitors according to this invention make use of these features of the enzyme and effect modifications by improving the binding to the mammalian collagenase molecule. The action of mammalian collagenase has also been blamed for several other mammalian diseases. These diseases include periodontitis, corneal ulceration and epidermolysis bullosa; see for example American Journal of Pathology, 92 (2): 509 (1978) and

  The New England Journal of Medicine, 291 (13): 652 (1974).

  For use in the treatment of rheumatoid arthritis, the compounds according to the invention may be administered to a mammal afflicted with the disease, either orally or by intra-articular injection into the joint concerned. The daily dosage for a mammal of 70 kilograms will be between 10 milligrams

and about 1 gram.

  The compounds according to the invention can be formulated into compositions such as tablets, capsules or elixirs for oral administration, or in the form of sterile solutions or suspensions for parenteral administration. About 10 to 500 mg of a compound of formula I may be formulated with a pharmaceutically acceptable carrier, carrier, binder, preservative, stabilizer, flavoring agent, etc., in a form unit dosage as required by the accepted pharmaceutical practice. The amount of active ingredient contained in these compositions or preparations is such that a dosage is obtained

  suitable within the indicated range.

  The salts of the compounds of formula I wherein R 2 NH is a group of formula -NH-C-NH 2 are also useful for the inhibition of mammalian collagenase, and may be used and formulated according to the procedures described above. The compounds of formula NH II I in which R2 is a group of formula -NH-C-NH2 form acid addition salts with organic and inorganic acids. These acid addition salts are not only useful as mammalian collagenase inhibitors, but also often provide useful means for isolating the reaction mixture products to form the salt in a medium in which it is insoluble. isolate the salt and then neutralize the salt. The salts of the compounds of formula I in which R2 is an NH I group of formula -NH-C-NH2 can also be formed using

  a salt of a compound of formula VI as starting material.

EXAMPLE 1

  N- (2,2-dimethoxyethyl) -2 - [(acetylthio) methyl] -4-methyl-

  pentanamide. A) Isocaproic acid 28 g of potassium cyanide are partially dissolved in 125 ml of ethanol and 30 ml of water. 63.6 g of amyl bromide are added and the reaction mixture is digested on the steam cone for 24 hours. The potassium bromide solution is decanted on 35 g of potassium hydroxide. The decanted product is digested on the steam cone for 20 hours, diluted with 50 ml of water and concentrated in vacuo to drive off the ethanol. A 1: 1 mixture of sulfuric acid and water is added to the reaction mixture and the product is extracted with petroleum ether to give 6 g of crude product. Vacuum distillation gives

  43.4 g of product boiling at 90-98 C under 9 mm of mercury.

  B) 4-methyl-2- (hydroxymethyl) pentanoic acid 20.6 g of diisopropylamine are dissolved in 80 ml of dry tetrahydrofuran. This solution is cooled to -30 ° C. n-Butyllithium (77 ml) is added dropwise.

248341 1

  of a 2.6 M solution in hexane), under a nitrogen atmosphere, at a rate which keeps the reaction mixture between -30 and -20 ° C., and this solution is stirred at -20 ° C.

  minutes. 11.6 g of isoacidic acid is added dropwise.

  caproique in 10 ml of tetrahydrofuran between - 20 and - 10 C, then stirred at - 10 C for 30 minutes. In a separate flask, 28 g of paraformaldehyde are heated to about 200 ° C. and the vapors are entrained in a stream of nitrogen above the surface of the solution of the dilithium salt of isocaproic acid in tetrahydrofuran. During this

  process, keep the temperature between - 10 and + 10 C.

  After all of the paraformaldehyde has evaporated, the reaction mixture is cooled to 0 ° C and 10% hydrochloric acid is added dropwise until the reaction mixture becomes acidic. The product is extracted with two ether fractions of 400 ml each. The ether extracts are dried with magnesium sulfate, filtered and concentrated in vacuo to give 13.2 g of crude material. The product is distilled under vacuum to obtain 9.0 g of substance,

  boiling point 135-142 ° C at 9 mm Hg.

  C) 4-methyl-2-methylenepentanoic acid

  8.7 g of 4-methyl-2- (hydroxymethyl) -

  pentanolque with 10 drops of 85% phosphoric acid in a metal bath of Wood, 220 C for 20 minutes. A distillation head is fixed and the pressure is slowly decreased to 60 mm while raising the temperature to 270 C. The product begins to distil, and the pressure is further reduced to 10 mm. The vapor temperature varies between 180 and 190 C. The yield of the title compound under

distillate form is 7.0 g.

  D) 2 - [(acetylthio) methyl] -4-methylpentanoic acid

  6.8 g of 4-methyl-2-methylene-

  pentanoic with 5 ml of thiolacetic acid, under argon, for five days, concentrated in vacuo and distilled a fraction. The product boils at 117-120 C under

9 mm of mercury.

  E) N- (2,2-Dimethoxyethyl) -2 - [(acetylthio) methyl] -4-methyl pentanamide A solution of 2.0 g of 2 - [(acetylthio) methyl] - acid is cooled to -5 ° C. 4-methylpentanol and 1.0 g of triethylamine in 50 ml of tetrahydrofuran (THF). 1.1 g of ethyl chloroformate in 5 ml of THF is added dropwise and the reaction mixture is stirred at -50 ° C. for 30 minutes. It is added dropwise to the solution

  of mixed anhydride, at -5 ° C., 1.1 g of amino dimethyl acetal

  acetaldehyde in 20ml of THF. After this addition, it is stirred at 10-20 C for two hours and stored at 0 C for about 16 hours. The triethylamine hydrochloride is filtered off and the filtrate is concentrated in vacuo. The residue (2.1 g) is dissolved in 3 ml of ether. 5 g of silica gel are added and the ether is evaporated. The residue is placed on 40 g of dry silica gel and washed with pentane, a 1: 1 mixture of pentane and ether and finally with ether. The product is eluted with ether to give 1.3 g of product which solidifies to give a waxy solid at low temperature.

Fusion point.

  Anal. calc. for C13H25NO4S · 15H2O: C, 53.09; H, 8.67;

N, 4.76; S, 10.90.

  Found: C, 53.09; H, 8.73; N, 4.67; S, 10.89.

EXAMPLE 2

  N- (2,2-dimethoxyethyl) -2- (mercaptomethyl) -4-methylpentanamide

  N- (2,2-) is dissolved in 15 ml of absolute ethanol.

  dimethoxyethyl) -2 - [(acetylthio) methyl] -4-methylpentanamide obtained in Example 1, and the atmosphere is purged with argon. 2 ml of concentrated ammonia are added and this solution is stirred at room temperature for three hours, concentrated to dryness in vacuo and dried at 50 ° C. for 8 hours under phosphorus pentoxide. The title compound

  (0.8 g) crystallizes, m.p. 34-37 ° C.

  Anal. calc. for C11H23NO3S · 0.125H2: C, 52.04; H, 9.33;

N, 5.51; S, 12.63.

  Found: C, 52.09; H, 9.05; N, 5.64; S, 12.40.

EXAMPLE 3

  N- [2- (mercaptomethyl) -4-méthylpentanoyll] aminoacetaldehyde

  N- (2,2-dimethoxy) is dissolved in 10 ml of water.

  ethyl) -2- (mercaptomethyl) -4-methylpentanamide obtained in Example 2 and the solution is treated with a few drops of 10% hydrochloric acid. After one hour of rest at C, the water is removed under vacuum and the product is obtained.

  in the form of a powder while triturating with

nitrile.

EXAMPLES 4-7

  Following the procedures of Examples 1 and 2 (in order), but replacing the amino acetaldehyde dimethyl acetal with the compound indicated in column I below, the compound is obtained. indicated in column II below, and by hydrolysis as in Example 3, the

  compound indicated in. column III below.

Column I

4. H2N-CH2-CH (OCH2CH3) 2

CH

- H2N-CH 2- (OCH32

/ IO - CH2

6. H N-CH -CH -COH

2 2 2 N'O'CH2

/ O - CH2

7. H2N-CH -CH -C {

22 O 2

Column II

CH (CH3)

  CH 1 2 1 HS-CH 2 -CH-C-NH-CH 2 -CH (oCH CH) 2

CH (CH3) 2

CH CH

H21 l CfH3

HS-CH2-CH-C- .NH-CH2'C (OCH3) 2

HS-CH-CH-C-NH-CH-CH-CH

2 2 3 2 CH

CH (CH3) 2

3CH2

2 O-CH

HS-CH 2 -CH-C-NH-CH-CH 2 C2

2 'NU O CH

Column III

CH (CH3) 2

CH O O

H2 l He

HS-CH-CH-C-NH-CH2 -CH

2 2

CH (CH3) 2

CH O O

H20I He

HS-CH2-CH - C-NH-CH2-C-CH

CH (CH3) 2

2CH 22 3

HSCH 2-CH - C-NH-CH 2 -CH 2c

CH (CH)

3 2 CH O H 2 0 l

HS-CH 2 -CH-C-NH-CH -2CH 2-C

o co Wa

248341!

EXAMPLE 8

  Acetate (1: 1) of 2 - [(acetylthio) methyl] -4-methyl-N- [4-

  [(Aminoiminomethyl) amino] butyll] pentanamide

  A) para-nitrophenyl ester of 2 - [(acetylthio) acid -

methyl] -4-methylpentanoic acid

  2 - [(acetylthio) methyl] - is cooled to 5 ° C.

  4-methylpentanoic (5.1 g, see Example 1D) in 100 ml

  ethyl acetate, and treated with 3.5 g of para-nitro-

  phenol and then 5.1 g of dicyclohexylcarbodiimide in fractions. After stirring for 4 hours at 5 ° C., the dicyclohexylurea is filtered off and the ethyl acetate is removed under vacuum. The resulting solid is washed with hexane to

  get the compound. of the title, 8.0 g, in the form of an oil.

  B) Acetate (1: 1) of 4 - [(aminoiminomethyl) amino] butylamine A solution of 1.4 g of agmatine sulfate and 1.0 g of sodium acetate in vacuo was concentrated in vacuo. ml of water, and the residue is slurried with hot absolute ethanol and filtered. The filtrate is evaporated and washed with ethyl acetate to give 1.5 g of the title compound,

melting point & 32-136C.

  C) Acetate (1: 1) 2 '- [(Acetylthio) methyl-4-methyl-N- [4-

  [amino-iminomethyl) amino] butyl] pentanamide 3.5 g of dimethylformamide (75 ml) are dissolved in

  para-nitrophenyl ester of 2 - [(acetylthio) - -

  methyl] -4-methylpentanoic acid, cooled to 5 ° C., and treated

  by a solution of 1.6 g of the monoacetate of 4 - [(amino)

  iminomethyl) amino] butylamine in 10 ml of water. The mixture is stirred for about 16 hours at 25 ° C, evaporated in vacuo to leave an aqueous solution, and extracted thoroughly with ethyl acetate. Freeze-dried

  the aqueous layer into a solid which is washed with acetone

  nitrile and dried under vacuum to obtain 2.8 g of

composed of the title. -

EXAMPLE 9

  Acetate (1: 1) of 2- (mercaptomethyl) -4-methyl-N- [4 - [(amino)

  iminomethyl) amino] butyl] pentanamide

  1 g of acetate (1: 1) of 2 - [(acetylthio) -

  methyl] -4-methyl-N- [4 - [(aminoiminomethyl) amino] butyl] -

  pentanamide in 30 ml of water, cooled in ice, and purged with argon. 4 ml of concentrated ammonia are added and the mixture is allowed to warm to 25 ° C. for two hours. The solution was lyophilized and the resulting solid triturated with acetonitrile. Vacuum drying at

   C gives 0.8 g of the title compound.

  EXAMPLES 10 and 11 By following the procedures of Examples 8 and 9 (in order), but replacing the 4 - [(aminoiminomethyl) amino] butylamine monoacetate with the compound indicated in column I below, the following is obtained: acetate of the compound

  indicated in column II below.

Column I Column II.

CH (CH3)

1 32

NH CHO NH

10. H2 N-CH2-CH21-NHCNH2

  2 2 -NH-C-NH HS-CH 2 -CHCNHCH 2 -CH 2 NHH

2 2 2 2 2 2

CH (CH3) 2

3 2

NH CH O NH

N (H il j 21

  11. H2N- (CH-2) NH HS-CH-CH-C-NH- (CH-NHNH2)

2 7 -2 2 27

EXAMPLE 12

  (+) - 2 - [(Acetylthio) methyl-] -4-methyl-N- [2- (4-morpholinyl) -

ethyl] pentanamide

  2 - [(acetylthio) methyll-4- acid can be prepared

  methyl pentanoic as described in Example 1 or in the following manner: i) 2-carboxy-4-methylpentanoic acid is treated for 6 hours at 80 C, with 400 ml of 10% sodium hydroxide, a solution of 91-, 1 g of 2- (ethyloxycarbonyl) -4-methylpentanoic acid ethyl ester in 300 ml of methanol. The solution is concentrated under vacuum to 400 ml and acidified with 10% hydrochloric acid. The product is extracted with ethyl acetate to give 67.6 g of the compound of

  title, which crystallizes at rest. Recrystallization in a -

  mixture of ethyl acetate and hexane gives the compound of

248 3411

title, melting point 102-105 ° C.

  ii) 2-Carboxy-4-methyl-2 - [(dimethylamino) -

  Methyl pentanoic solution 67 g of 2-carboxy-4-methylpentanolacic acid are suspended in 400 ml of water and the suspension C is cooled down. 50 g of 40% aqueous dimethylamine and then 35.7 ml are added to the suspension. g of 37% aqueous formaldehyde. The resulting solution is stirred for about 16 hours and the solid product is filtered and dried in vacuo to give 57.3 g of the title compound, mp 134 ° -137 ° C.

  with release of carbon dioxide and dimethylamine.

  iii) 4-methyl-2-methylenepentanoic acid

  57.3 g of 2-carboxy-4-

  methyl-2 - [(dimethylamino) methyl] pentanoic, melted at 140-

  145 C, in an oil bath, and maintained at this temperature until bubbling ceases. The molten product is cooled, taken up in water and

  it is acidified with 10% hydrochloric acid.

  Extraction with hexane, drying and evaporation give

30.5 g of the title compound.

  B) 2 - [(acetylthio) methyl] -4-methylpentanoic acid

  6.8 g of 4-methyl-2-methylene-

  pentanoic with 5 ml of thiolacetic acid for about 16 hours. The reaction mixture is concentrated in vacuo until crystallization occurs, yielding 3.6 g.

  of the title compound, mp 42-47 ° C.

  C) (+) - 2 - [(Acetylthio) methyl] -4-methyl-N- [2- (4-morpholinyl) -

ethyl] pentanamide

  2.0 g of 2 - [(acetylthio) methyl] acid are dissolved

  methylpentanoic in 40 ml of tetrahydrofuran (THF) and 1.0 g of triethylamine. This solution is cooled to -5 ° C. and ethyl chloroformate in ml of THF is added dropwise. The reaction mixture is stirred at -5 ° C. for

  minutes and then 1.3 g of N- (2-

  aminoethyl) morpholine in 20 ml of THF. Stirred at 20 ° C. for four hours and stored at 0 ° C. for about 16 hours. The triethylamine hydrochloride is filtered off and the filtrate is concentrated in vacuo. This residue is dissolved in ether and washed once with

  aqueous sodium bicarbonate and twice with water.

  The ether is dried with magnesium sulfate, filtered and concentrated in vacuo to give 1.6 g of substance. This material is purified by dissolving 0.6 g in 2 ml of ether and placing the solution on a pad of alumina (Activity II, 10 g). The column is washed with 250 ml of ether and concentrated in vacuo. The product crystallizes, and it is

  washed with a 1: 5 mixture of ether and pentane. We sow.

  the remainder of the crude product with a small crystal and then washed with a 1: 5 mixture of ether and pentane. Total yield

  is 1.0 g of the title compound, mp 54-59 ° C.

  Anal. calc. for C 15 H 2 -8 N 2 O 3 S: C, 56.93; H, 8.92, N, 8.85;

S, 10.13.

  Found: C, 56.76 -; H, 8.91; N, 9.10; S, 10.01.

EXAMPLE 3

  (+) - 2 - [(Acetylthio) methyl] -4-methyl-N- [2- (1-piperidinyl) -

ethyl] pentanamide

  A solution of (+) - 2- acid is cooled to 5 ° C.

* [(acetylthio) methyl] -4-methylpentanoic in 40 ml of THF, then 1.0 g of triethylamine in ml of THF is added dropwise. This solution is cooled to -5 ° C. and ethyl chloroformate is added dropwise between -5 ° C. and 0 ° C. in 4 ml of THF. The mixture is stirred for 30 minutes and N- (2-aminoethyl) piperidine is added dropwise in 30 ml of THF. The reaction mixture is stirred at 20 ° C. for four hours.

  hours and stored at 0 C for about 16 hours.

  The triethylamine hydrochloride is filtered off and the filtrate is concentrated in vacuo. The residue is dissolved in ether and washed with aqueous sodium bicarbonate. The ether is dried with magnesium sulfate, filtered and concentrated in vacuo to give 2.1 g of crude product. This crude product is absorbed on a buffer of 20 g of alumina of activity II, and is washed with ether to obtain 1.4 g of product which crystallizes in pentane, point of

fusion 47-50 C.

  Anal. calc. for C 16 H 30 N 2 O 2 S: C, 61.11; H, 9.62;

N, 8.91; S, 10.19.

  Found: C, 61.04; H, 9.82; N, 8.93; S, 9.91.

248341 1

EXAMPLE 14

  2- (mercaptomethyl) -4-methyl-N- [2- (4-morpholinyl) ethyl] -

  pentanamide 20 ml of a 1: 1 mixture of ethanol and water are dissolved in 0.6 g of (+) - 2 - [(acetylthio) methyl] -4-methyl-N- [2- (4- morpholinyl) ethyl] pentanamide. The argon solution is saturated and 2 ml of 47% ammonia is added. It is stirred under argon for two hours at room temperature. The reaction mixture is concentrated in vacuo and lyophilized for about 16 hours. The residue is dissolved in ether and stirred with charcoal to decolorize the product, which is then filtered through diatomaceous earth and dried.

concentrated under vacuum.

  The resulting oil is dried at 45 ° C. under vacuum

  for about 16 hours to obtain the analytical product.

  Anal. calc.-for C13H26N2O2S.1 / 4 H2O C, 55.98; H, 9.58

N, 10O4; S, 11.49. -

  Found: C, 55.78; H, 9.48; N, 10.33; S, 11.41.

EXAMPLE 15

  2- (mercaptomethyl) -4-methyl-N- [2- (1-piperidinyl) ethyl] -

  pentanamide Dissolved in 3 ml of water and 5 ml of absolute ethanol

  0.8 g of (+) - 2 - [(acetylthio) methyl] -4-methyl-N- [2- (1-

  piperidinyl) ethyl] lpentanamide. After purging this solution with argon, 2 ml of 56% aqueous ammonia is added and the reaction mixture is stirred at room temperature for 2.5 hours. It is concentrated first under vacuum to get rid of excess ammonia and ethanol, and then lyophilized for about 16 hours. The resulting dark brown oil was dissolved in ether and stirred with a small shovel of charcoal for 20 minutes. We filter on

  "Celite" and concentrated in vacuo to obtain an oil.

  Drying under vacuum for 4 hours at 40 ° C. gives the analytical product. Anal. calc. for C14H28N2OS · 0.25 H2O: C, 60.72; H, 10.37

N, 10.12; S, 11.58. -

  Found: C, 60.52; Hi 10.38; N, 10.51; S, 11.20.

EXAMPLES 16 to 18

  Following the procedure of Example 13, but replacing N- (2-aminoethyl) piperidine with the compound indicated in column I below, the compound is obtained.

  indicated in column II below.

  Column I Column II N- (3-aminopropyl) - (+) - 2 - [(acetylthio) methyl] -4-

  piperazine methyl-N- [3- (1-piperazinyl) -

propyl] pentanamide -

  1- (4-Aminobutyl) -4- (+) - 2 - [(acetylthio) methyl] -4-

  methyl-piperazine methyl-N- [4- (4-methyl-1-

piperazinyl) butyl] pentanamide

  7 N- (2-aminoethyl) - (+) - 2 - [(acetylthio) methyl] -4-

  pyrrolidine methyl-N- [2- (1-pyrrolidinyl) -

éthylIpentanamide

EXAMPLE 19

  3- (Acetylthio) -N- [2- (1-piperidinyl) ethyl] -2- (phenylmethyl) -

propionamide

  A) 2-Carboxy-3- (dimethylamino) - 2- (phenylmethyl) -

  propionique 13 g of benzylmalonique acid are mixed with -7.6 g of 40% aqueous dimethylamine and 5.4 g of 37% formalin in 150 ml of water. After two hours, the resulting solid is filtered, washed with water and partially dried.

  in the air to obtain 20.8 g of substance.

  B) Benzylacrylic acid The above substance is melted in an oil bath at 170 ° C. and heated for 10 minutes, until

  that the release of amine stops and that the bubbling.

  virtually stops. The cooled product, a mobile liquid, is acidified with 10% potassium bisulfate, extracted with hexane, dried over sodium sulfate and evaporated to give 6.3 g of solid. The aqueous filtrates from the Mannich reaction of Part A were allowed to stand for about 16 hours and then heated to 100 ° C on a steam column until bubbling ceased. Cooling, acidification and extraction as above gives an additional 1.2 g of solid for one hour.

  total yield of 7.5% of benzylacrylic acid.

  C) 3- (acetylthio) -2- (phenylmethyl) propionic acid Following the procedure of Example 1B, but replacing 4-methyl-2-methylenepentanoic acid with

  benzylacrylic acid, the title compound is obtained.

  D) 3- (acetylthio) -N- [2- (1-piperidinyl) ethyl] -2- acid

  (phenylmethyl) propionic By following the procedure of Example 1C, but

  by replacing 2 - [(acetylthio) methyl] -4-methyl-

  pentanoic acid with 3- (acetylthio) -2- (phenylmethyl) -

  propionic acid and N- (2-aminoethyl) morpholine by N- (2-

  aminoethyl) piperidine, the title compound is obtained.

EXAMPLES 20 TO 22

  Following the procedure of Example 19, but replacing the benzylmalonic acid with the indicated compound

  in column I below and N- (2-aminoethyl) -

  morpholine by the compound indicated in Column II below.

  below, the compound indicated in column III below is obtained. Column I Phenylmalonic acid

21 cyclopropyl acid

malonic

22 cyclohexyl acid

Malonic Column II

N- (20-amino-eicosyl) -

  piperidine N- (aminomethyl) pyrrolidine

N- (10-aminodécyl) -

morpholine Column III

3- (acetylthio) -N- [20- (1-

piperidinyl) eicosyl] -2-

phenylpropionamide

3- (acetylthio) -N - [(1-

pyrrolidinyl) methyl] -2-

(Cyclopropyl) propionamide

3- (acetylthio) -N- [10- (4-

morpholinyl) decyl] -2

(cyclohexyl) propionamide Co oo wq

Claims (21)

  A compound of the formula: R 3 O R 1 -S-CH 2 -CH-C-NH- (CH 2) n -R 2, optionally in the form of a salt, wherein R is a hydrogen atom or an alkanoyl radical of 2 to 10 carbon atoms or arylcarbonyl; R2 is a group of formula IWH O R4 R4 - CH2   --NH-C-NH2, -C-R4, -C- (O-alkyl) 2 or-CN | or a 1-pyrrolidinyl, piperidinyl, 4-morpholinyl, 1-piperazinyl or 4-alkyl-1-piperazinyl radical, R4 being a hydrogen atom or an alkyl or aryl radical; R3 is an alkyl radical of 3 to 8 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, aryl or arylalkyl; and n is an integer from 1 to 20.   2. The compound of claim 1, wherein   R1 is a hydrogen atom or an acetyl or benzoyl radical.   The compound of claim 1, wherein   R 1 is an alkanoyl radical of 2 to 10 carbon atoms.   The compound of claim 1 wherein R1 is an arylcarbonyl radical.   5. The compound of claim 1. in which NH   R2 is a group of formula -NH-C-NH2.   The compound of claim 1, wherein O Il.   R2 is a group of formula -C-R4.   7. A compound according to claim 1 wherein R2 is a group of the formula -C- (O-alyl) 2 '   R2 is the grouping of the formula -C- (O-alkyl) 2. 248341 1   The compound of claim 6 wherein R4 is a hydrogen atom.   The compound of claim 7 wherein - R4 is a hydrogen atom.   The compound of claim 1 wherein n is 2, 3 or 4.   The compound of claim 1 wherein R3 is a 2-methylpropyl radical.   12. A compound according to claim 1, which is the   N- (2,2-dimethoxyethyl) -2 - [(acetylthio) methyl] -4-methyl-   pentanamide. The compound of claim 1 which is N- (2,2-dimethoxyethyl) -2- (mercaptomethyl) -4-methylpentanamide. The compound of claim 1, which is   acetate (1: 1) of 2 - [(acetylthio) methyl] -4-methyl-N- [4-   [(Aminoiminomethyl) amino] butyl] pentanamide. 15. The compound of claim 1, which is   acetate (1: 1) of 2- (mercaptomethyl) -4-methyl-N- [4 - [(amino)   iminomethyl) amino] butyl] pentanamide. 16. A compound according to claim 1, which is the   (+) - 2 - [(acetylthio) methyl] -4-methyl-N- [2- (4-morpholinyl) -   ethyl] pentanamide. 17. A compound according to claim 1, which is the   (+) - 2 - [(acetylthio) methyl] -4-methyl-N- [2- (1-piperidinyl) - ethyl] pentanamide.   18. A compound according to claim 1, which is the   2- (mercaptomethyl) -4-methyl-N- [2- (4-morpholinyl) ethyl] -   pentanamide. 19. A compound according to claim 1, which is the   2- (mercaptomethyl) -4-methyl-N- [2- (1-piperidinyl) ethyl] -   pentanamide. 20. Process for the preparation of the compounds of formula I, characterized in that it consists, when R1 is other than a hydrogen atom, in reacting a compound of formula V, or an ester thereof, with a compound of formula VI, and when R 1 is a hydrogen atom, reacting a compound of formula I wherein R 1 is alkanoyl or arylcarbonyl with ammonia to form a compound of formula I wherein R 1 is a hydrogen atom. 21. Therapeutically active composition, characterized in that its active ingredient is a compound according to claim 1. it