FR2470111A1 - DECAPRENYLAMINE DERIVATIVES, THEIR ACID ADDITION SALTS AND PHARMACEUTICAL COMPOSITION USING THE SAME - Google Patents

Abstract

DECAPRENYLAMINE DERIVATIVES, THEIR ACID ADDITIONAL SALTS AND PHARMACEUTICAL COMPOSITION USING THESE PRODUCTS. THE PRESENT INVENTION DESCRIBES COMPOUNDS OF THE FORMULA: (CF DRAWING IN BOPI) IN WHICH N REPRESENTS A WHOLE NUMBER OF 0 TO 2; R IS H, A LOWER ALKYL GROUP OR A DECAPRENYL GROUP, AND R REPRESENTS A CH OR PYRIDYL GROUP, IT ALSO DESCRIBES THE ACID ADDITIONAL SALTS OF THESE COMPOUNDS. USE OF THESE COMPOUNDS AS INDUCTERS OF INTERFERON.

Description

2470 'Derivatives of decaprenylamine, their acid addition salts

  and a pharmaceutical composition using these products.

  The present invention relates to novel decaprenylamines and their acid addition salts which are used for the prevention of viral infections of vertebrate animals. Hitherto, various substances have been known to have the preventive or softening effect on diseases caused by viruses whose host is a vertebrate animal / or which have been recognized as capable of softening the symptoms.

  of these diseases by significantly increasing the

  Antibody activity in animals. Antiviral products heretofore included include interferon, substances capable of inducing interferon, i.e., inductors (interferon inducteu), amantadine hydrochloride, or synthetic substances, such as methysazone, which directly exerts an inhibitory effect on the spread of viruses. The interféi

  is a glycoprotein with antiviral and anti-

  tumor, said glycoprotein being produced in situ by the cells of a vertebrate animal when these cells are infected with a virus and has been proposed for the therapy of diseases

  viral infections and also for cancer therapy.

  Known inducers inducing interferon in vertebrate animals by a process other than virz infection include high molecular weight natural substances.

  such as double chain ribonucleic acid. of bacteria

  of a certain species, or high-molecular synthetic substances such as double chain ribonucleic acid, the type is polyinosinic acid-polycytidylic acid, or low-weight inducers. molecular

such as tyrolone.

  However in the production of interferon, prob.

  the purification of it is raised and in fact no economic process for the production of interferon has been achieved so far. In addition, conventional inducers of interferon have not received practical application mainly because of their toxicity. Synthetic antiviral agents

2470111 -

  which exert a direct inhibitory effect on the spread of the virus, which are commercially available at present, have a rather narrow range of virus-infected diseases which are curable by administration of said agent and hence the development of syn - Taking into account these considerations, the authors of the present invention have conducted extensive studies to find compounds capable of producing high activity interferon and further, having an antiviral activity on the biological level. ,

  and as a result, the inventors have found that

  that the compounds represented by the following general formula (I) and their acid addition salts show an excellent inducing power for interferon and at the same time exhibit excellent antiviral activity even in

the biological test.

  Therefore, the object of the present invention is to provide a new class of a decaprenylamine derivative represented by the general formula below

CH R

- {C2 C - & - 12 RB - (H .-) J 1

  Wherein n represents an integer from 0 to 2, R1 represents a hydrogen atom, a lower alkyl group or a decaprenyl group. , and R2 represents a phenyl group or a pyridyl group, and also provide salts

addition acids of this compound.

  For the preparation of decaprenylamine represented by the above-mentioned general formula (I), and its acid addition salts, there can be taken a process in which the known amine synthesis processes are applied to the starting decaprenol represented by the formula Ti4-C11 C = -CII-CH2-O11 (II)

247011 '

  to obtain a desired amine derivative.

  In addition, the aminated derivative thus obtained can be trans-

  formed into a corresponding salt in a conventional manner. More specific

  Typically, a desired amine may be prepared by a process which comprises converting a suitable decaprenyl alcohol having the above general formula (II) to a corresponding halide or sulfonic acid ester followed by reaction with a suitable primary or secondary amine compound corresponding to the desired end product in the presence or absence of a base. On the other hand, the desired amine can be prepared by oxidation of a decaprenol to a corresponding aldehyde which is then condensed with a suitable primary amine compound, starting with water to form a corresponding imino compound which in turn is reduced with a reducing agent. suitable (eg sodium borohydride). An acid addition salt of the amine derivative thus obtained can be prepared by mixing said amine in a suitable solvent.

  with a desired acid to form a salt and by crystallizing

  salt the solution by evaporation or other means to recover it. Suitable acid addition salts for use as medicaments include, for example, those with hydrochloric acid, acetic acid, citric acid, fumaric acid and the like. The compounds represented by the general formula (I) and their acid addition salts are illustrated below with reference to the following preparative examples.

Preparative Example 1.

  N-benzyldidecaprenylamine hydrochloride Ci-Cl 2 C0l2} -OtXCIT3 HCl

I2CIH = C-CH2- 10H

  To a solution of benzylamine (10 g) in ethanol (100 ml) a solution of decaprenyl bromide (-20 g) in benzene (40 ml) is added dropwise at room temperature for 1 hour with stirring. is continued for another 2 hours. Then, the mixture obtained is refluxed for 2 hours with stirring. The reaction mixture obtained after cooling is added with a 2N aqueous solution of sodium hydroxide (100 ml) and then extracted with isopropyl ether. The liquid extract obtained is washed with water and saturated saline, dried over anhydrous sodium sulphate and then concentrated under reduced pressure. The residue

  (21.4 g) is purified by column chromatography using

  reading the silica gel (200 g). Elution is carried out with a mixture of isopropyl ether and benzene. The fraction eluted initially (7 g) is dissolved in ethyl acetate, ether added containing HCl to make it slightly acidic and then cooled. The crystallized mass is separated by filtration to recover Nbenzyldidecapromenylamine hydrochloride (4.9 g), mp 52-54 C. Elemental analysis of C107H169N.HCl gives the following results:

C% H% N%

  Calculated: 85.34 11.38 0.93 Found: 85.08 11.23 0.94

Preparative Example 2.

  N-benzyldecaprenylamine hydrochloride CHil j) t

51+ CH2. - = CIL..CH0 * 2 \. -1,

Y

  The fraction eluted last (7.3 g) obtained in

  Preparative Example 1 is dissolved in acetone and then added to

  ether containing HCl. The mixture is worked up in the same way as in Example 1, which thus makes it possible to obtain Nbenzyldecaprenylamine hydrochloride (5.8 g), mp 105-107 C. Elemental analysis of C57H89N.HC1 gives the results below:

C% H% N%

  Calculated: 83.00 11.00 1, -0 Found: 82.82 10.87 l, (5

Preparative Examples 3 to 9.

  The same procedure as in Example 1 is repeated for the reaction of decaprenyl bromide with a primary or secondary amino compound to thereby obtain the compounds mentioned below, the structural formula, the molecular formula, the melting point and the elemental analysis of

  these compounds are mentioned in Table 1.

t-o 'rN

Table 1

CH3 R1

1 I

  H --- UtH2-CU = CH-CH2 -) - -O N -CH2-R2 Structure rN rLL R1 R2

3 H O_ 0

4 H 0

H 2

6 CH3

7 C3 C H3 1

CH3

8 + CI-H2CH = C-CH2) -10H 4

CH 9 3

9 + CH CH = C-CH 2 -) - H -Q 2

Molecular formula

C56H87N

C55H86N2

C58H91N'HC1

C57H89N

C58H91N-HCl H20

C106H167N

P.F. (C) or refractive index

41 - 42

- 56

103 - 105

37 - 38

87 - 89

  n25 = 1 5213 D C108H171N.HC1l2H20 40 - 43 Elemental analysis Calculated (%) Found (%)

C H N C H N

86 (87 11.32 1.81 87 12 11.43 1I77

/ 21 l1118 3.61 85? 03 11737 3.51 I /

83/05 11105 167 83:15 11,18 '1; 61

  86t84 11 38 1778 86! 94 11.38 1/75 81} 30 11., 06 1l64 81.67 10T86 1 63

87; 47 11.56 0.96 87.58 11 60. 0) 90

83 36 11.40 0.90 83.0.1 11.18 0.82

Have

83 / 36I

Example of q.

247011 1

Preparative Examples 10 to 13

  To a solution of 3-aminomethylpyridine (25 g) in ethanol (100 ml), a solution of decaprenyl bromide (30 g) in chloroform is added dropwise at room temperature for 1 hour with stirring which is continued. for another 3 hours. The resulting reaction mixture after cooling was added with 2N aqueous sodium hydroxide solution (100 ml) and extracted with isopropyl ether. The liquid extract obtained is washed with water and with saturated saline, dried over anhydrous sodium sulphate, and then concentrated under reduced pressure. The residue (21 g) is purified by column chromatography using silica gel (200 g). Elution is carried out with a mixture

  20% ethyl acetate and 80% hexane. 3-didecabenyl-

  aminomethylpyridine (about 1.38 g) is obtained in the form

an oily substance.

  The above column is further eluted with a mixture of 20% ethanol / 80% ethyl acetate. The fraction eluted (8.6g)

  is recrystallized from acetone to recover 3-decat

  crystalline prenylaminomethylpyridine (7.8 g).

  Using substantially the same methods as those

  mentioned above, 2- (2-decaprenylamino) -

  ethylpyridine, 2- (2-didecaprenylamino) ethylpyridine and 3- (Ndecaprenyl-N-methylamino) methylpyridine. The physicochemical properties of these compounds are

shown in Table 2.

ra,% - r-%, o ('J

Table 2

  ## STR1 ## Preparation example N Structure R1 R2 n Molecular formula P.F. (C) or Analysis Index Calculated δ% ## STR1 ## ## STR2 ##

At C, H N

elementary TrouvE (

C.- W

  CH 3 -1 - (CH 2 -CH = C-CH 2 -11 -H and C 10 H 16 8 N 2

-2 H

N 1 56H88N2

28 / 1-29 2

85721 '11'24 3t55

86/46 11.60 1.86

8% .O4 11734 3/33

>. 04 1l1> 34 3,. 33 "

11 am

_ 2 C57H90N2 "E20 22-28 6

  CH 2 -CH 2 -CH-CH H 2 C 10 H 17 O N 12 - (CH-CH = C-CH 2 -1 -H 2 C 0 H 7 N 2

1 CH 1 C57H90N2

  84t28 11i29 3.45 84j.52 11/33 3 29 n251'5-1 5162 86 57 11 54 1189 86.52 11) 66 1783 n55 = 1.5161 8521 11129 3/49 8511 il 37 330 IDfr11 n25; 5 = I / 5173 861.58 11.51 lr91

13 CH 3

2470 '

Preparative Example 14.

  To a solution of N, N-dimethylbenzylamine (10 g) in ethanol (100 ml) decaprenyl bromide (20 g) is added dropwise at room temperature for 30 minutes. Stirring is continued for 1 1/2 hours at room temperature. The resulting reaction mixture is extracted with isopropyl ether and the extracted phase is washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue (22 g) obtained is

  purified by column chromatography on silica gel.

  Then, the ethyl acetate / chloroform mixtures are passed through the column with a concentration gradient of from 1 to 10% ethyl acetate. The eluted fraction (18, E is dissolved in acetone and the resulting solution is allowed to stand overnight in a refrigerator to recover crystalline N-benzyldecaprenylammonium bromide.

  (15.8 g), mp 51.2-53.10 ° C.

  The physiological effects of the compounds of this

  The invention is illustrated below in detail.

  (1) Interferon inducing activity assay.

  Each test compound suspended in water has a surfactant administered intraperitoneally to each group consisting of 5 female ICR mice weighing approximately 25 g. 20 hours after administration, the blood is collected from the mice and the serum is separated therefrom to obtain serum interferon. The following steps are carried out to determine the activity of the interferon serum thus induced. L-929 cells from mice and previously incubated in a monolayer are brought into contact with the 10-fold diluted serum test solution, incubated overnight at 370 ° C. in an incubator placed in a carbon dioxide atmosphere. and the diluted test serum solution is removed. Then the cells are inoculated with the vesicular stomatitis virus and placed on a tissue culture medium containing 1% agar. After incubation at 370C for 24 hours, the cells are stained with diluted neutral red solution at a suitable concentration to count the number of plaques formed therein and thus to calculate the plaque inhibition rate in each of the cells. test groups versus a group to which no test compound was administered. The inhibition rate of the plates of each test compound is shown in Table 3.

  (2) Effect on mice infected with the vaccine virus.

  Groups each consisting of 10 female ICR mice receive an intravenous injection of vaccinia virus (DIE strain) into the tail vein. On the eighth day after inoculation, the number of pustule-like lesions on the tail surface is counted after staining the tail with an ethanol solution containing 1% fluorescein and 0.5% methylene blue. In this assay, each L5 test compound is administered intraperitoneally to the mice just the day before the virus was inoculated, so that the antiviral activity of the test compound is evaluated in terms of inhibition of the lesions. the tail as calculated in each test group relative to a group to which a compound

test was administered.

  The rate of inhibition of the lesions of the tail of each

  Test compound is shown in Table 3.

  (3) Effect on mice infected with the influenza virus.

  Groups each consisting of 10 female ICR mice weighing approximately 25 g, are infected by inhalation of nebulized influenza A / PR-8 virus. A solution of each surfactant-containing aqueous solution test compound is administered intraperitoneally to the mice 24 hours and 3 hours before infection of the virus, and 5 times daily from the second day after infection. . Mice that survive 21 days after infection are considered survivors and the survival rate is obtained according to the following equation:

  Number of survivors x 100 = survival rate.

Number of treated mice

Table 3

Test compound

Intra-dose

  peritoneal mg / kg Inhibition of tail injury (prevention of infection with vaccine virus)% Survival rate (prevention of infection with influenza virus)% Inhibition of plaques (serum interferon)

N-methyl-N-phenyl-

  decaprenylamine N-benzyl-decaprenylamine hydrochloride Hydrochloride

N-N-benzyl-néthyl

Decaprenylamnine Hydrochloride

N-phenethyl

décaprénylamine

3-didécaprényl-

aminomethyl

pyridine 29.3 73.2, 3 51.6

6.4

  % -% - cm 3.8 98.6 24.2, 4 rr- VN T 3rd Cj Table 3 (continued) Test compound

Intra-dose

  peritoneal m / kg Inhibition of tail injury (prevention against infection with vaccine virus)% Survival rate (prevention against infection with influenza virus) Inhibition of plaques (serum interferon)

3-décaprénylamino-

  methylpyridine 2- (2-decaprenylamino) ethylpyridine

2- (2-didecaprenylamino) -

ethylpyridine

3- (N-Decaprenyl N)

methylamino) nméthyl-

pyridine

Benzyl bromide

decaprenyl-dimethyl

  ammonium. Amantadine hydrochloride (control) 47.4 81.1 34.5 47.9 22.8 o '

(4) Toxicity.

  In order to ascertain the acute toxicity of the compounds of the present invention, the lethal dose of 50% of each compound is

  obtained using male ddY mice weighing 20 to 25 g.

  From the results shown in Table 3, it can be seen that the compounds have a high safety margin by intraperitoneal administration.

Table 4

  Lethal dose 50% (mg: kg) Test compound Administered by Intraperitoneal intraperitoneal

N-n-methyl N-phenyl

  decaprenylanmine 180> 500 N-benzyl-decaprenylamine hydrochloride 220 315 Hydrochloride

N-m & thyl-N-benzyl

  decaprenylamine 377 "500 Hydrochloride

N-phenethyl

decaprenylamine 110> 500

3-décaprénylamino-

methylpyridine -> 500

2- (2-décaprénylamino) -

  As can be seen from the results of previous tests, the active ingredients of the present invention have interferon-inducing activity in vivo and have low toxicity by exhibiting excellent antiviral activity. In the light of the fact that a strict correlation of interferon activity with individual antiviral activities is not always observed. for the ingredients

  of the present invention, a possibility is also considered

  However, the antiviral activities of said ingredients at the biological level are not only concerned with interferon, but also with other host defense mechanisms. Therefore, when the active ingredients of the present invention are used for the treatment of virus-infected diseases, they are administered to patients by such methods involving oral, inhalation, or analogous administration as well as by subcutaneous injection. , intramuscular and intravenous. Depending on the condition of the patient, such as age, symptoms and the route by which the ingredient is administered, the active ingredient of the present invention is used in a dose of 0.5 to 20 mg / kg, preferably from 3 to 5 mg / kg several

times a day (2 to 4 times).

  The active ingredients of the present invention may be formulated into drug compositions, for example tablets, cachets, granules, powders, liquid preparation for oral use, lotionsocculates, suppositories,

ointments, injections and the like.

  When the active ingredients of the present invention are administered orally, they may be formulated into tablets, cachets, granules, or powders. These solid preparations for oral use may contain conventionally used excipients, for example silicic anhydride, metasilicic acid, magnesium alginate, synthetic aluminum silicate, lactose, cane sugar, starch but, microcrystallized cellulose, hydroxypropylated starch or glycine, and the like; binders, for example gum

  arabic, gelatin, gum tragacanth, hydroxypropyl-

  cellulose, or polyvinylpyrrolidone; lubricants, for example magnesium stearate, talc or silica; disintegrants, for example potato starch, and carboxymethylcellulose; or wetting agents, for example polyethylene glycol, sorbitan mono-oleate, hydrogenated castor oil, sodium lauryl sulphate. In the preparation of soft cachets, particularly the active ingredients of the present invention, can be formulated by dissolving or suspending them in substrates

24701 11

  oily oils commonly used such as sesame oil, peanut oil, seed oil, coconut oil such as Miglyol, or the like. according to conventional methods, the liquid preparation for oral use can be in the form of an aqueous or oily emulsion or syrup, or else in the form of a dry product which can be redissolved before use with the aid of a suitable vehicle. To these liquid preparations, it is possible to add commonly used additive products, for example emulsifying auxiliaries such as

  sorbitol syrup, methylcellulose, gelatin, hydroxyethyl

  cellulose, and the like; or emulsifiers, for example lecithin, sorbitan monooleate, hydrogenated castor oil, non-aqueous excipient, for example fractionated coconut oil,

  almond oil; peanut oil and the like; or antisep-

  ticks, for example methyl parahydroxybenzoate, parahydroxy-

  propyl benzoate or sorbic acid.In addition, these preparations for oral use may contain, if necessary

  preservatives, stabilizers and similar additives.

  In the case where the active ingredients of the present invention are administered in the form of suppositories, they can be formulated according to conventional methods using oleophilic substrates such as cocoa oil or Witepsol, where they can be used in the form of rectal capsules obtained in the form of suppositories. coating a mixture of polyethylene glycol, sesame oil, seed oil, fractionated coconut oil and the like in a sheet of gelatin. The rectal capsule

  can be coated if necessary waxy materials.

  When the active ingredients of the present invention are used in the form of injection, they can be formulated in preparation of oily solution, emulsified solution or aqueous solution, and these solutions may contain stabilizing emulsifiers or similar additives commonly

used.

  Depending on the method of administration, the above-mentioned compositions may contain the active ingredients of the present invention in an amount of at least 1% and preferably

from 5 to 50%.

2470111 '

  The process for formulating the active ingredients of the

  The present invention in various preparations is illustrated below.

  below with reference to pharmaceutical examples.

  Pharmaceutical example 1 - Preparation of hard tablets for oral use.

  A mixture of 25 g of N-benzyldecaprenyl hydrochloride

  amine and 7.5 g of polyoxyethylated castor oil in acetone is mixed with 25 g of silicic anhydride. After evaporation of the acetone, the mixture is further kneaded with g of calcium carboxymethylcellulose, 5 g of corn starch,

  7.5 g of hydroxypropylcellulose and 20 g of micro-cellulose

  crystallized and 30 ml of water are added and mixed to obtain a granular mass. The mass is granulated by means of a granulator (ECK granulator Fuji Paudal CO., Japan) equipped with a sieve (B.S) mesh n 24 to obtain granules. The granules are dried until the moisture content is less than 5% and sieved with the sieve (B.S.) mesh n 16. The granulestamisés are puten cachets by means of a

  filling machine at 190 mg / stamp.

  Pharmaceutical example 2 - Preparation of soft cachets

for oral use.

  A homogeneous solution is prepared by mixing 50 g of N-methyl-N-benzyl-decaprenylamine hydrochloride with 130 g of polyethylene glycol (Macrogol 400). Separately, a gelatin solution is prepared which contains 93 g of gelatin,

  19 g of glycerin, 10 g of D-sorbitol, 0.4 g of parahydroxy-

  ethyl benzoate, 0.2 g of propyl parahydroxybenzoate and 0.4 g of titanium oxide and which is used as a film-forming agent for seals. The solution obtained above at the same time as the film-forming agent for cachets are treated with a flat punch of the manual type to obtain seals.

each containing 180 mg.

  Pharmaceutical Example 3 - Injections.

  A mixture of 5 g of N-methyl-N-phenylhydrochloride

  decaprenylamine, a suitable amount of peanut oil and 1 g of benzyl alcohol are completed to a total of 100 cm by addition of peanut oil. The solution is poured in portions of 1 cm under aseptic conditions in

  a bulb that is then sealed.

  Pharmaceutical example 4 - Injections.

  A mixture of 1 g of N-phenyldecafenylamine hydrochloride, 5 g of "Nikkol HICO 60" (trade name)

  (Hydrogenated castor oil etherified with 60 moles of polyoxy

  ethylene), 20 g of propylene glycol, 10 g of glycerol and 5 g of ethyl alcohol are mixed with 100 ml of distilled water and stirred. Under aseptic conditions, the solution is poured portionwise at a rate of 1.4 ml into a bulb which is

then sealed.

24701] t

Claims (7)

1. Compound of formula: I -> R1 cl-   Wherein n represents an integer of 0 to 2; R1 represents a hydrogen atom, a lower alkyl group or a decaprenyl group, and R2 represents a phenyl group or   a pyridyl group, and the acid addition salts of this compound.   2. N-benzyldecaprenylamine hydrochloride.   3. N-benzyldidecaprenylamine hydrochloride.   4. 3-Decaprenylaminomethylpyridine.   5. 2-Decaprenylaminomethylpyridine.   6. Drug characterized by the fact that it is a   compound as defined in claim 1.   7. Pharmaceutical composition characterized in that it comprises at least one compound as defined in claim 1, together with excipients and / or   auxiliary materials acceptable in pharmacy.