CA1157859A - Decaprenylamine derivatives - Google Patents

Abstract

ABSTRACT
New pharmaceutically active decaprenylamines having the general formula:

(I) wherein R is a group capable of forming, together with the adjacent nitrogen atom, a 5- or 6-membered heterocyclic ring which may optionally contain a further hetero atom selected from the group consisting of nitrogen, oxygen and sulfur, the radical R being optionally substituted with a hydrogen atom or a lower alkyl or decaprenyl group when it contains an additional nitrogen atom as the further hetero atom, and the pharmaceutically acceptable acid addition salts thereof, are prepared by converting decaprenol of the formula:

(II) into a corresponding halide or sulfonic acid ester which is thereafter reacted with a heterocyclic compound containing at least one primary or secondary amino group and having the general formula:

Description

I'his inventioll relates to new pharMaceutically active decaprenylamines, their pharmaceutically acceptable acid addition sal~s as well as to a process for thei~ prepa-ration. The new compounds with which the :invention is concerned are useful for con-trolling virus infection of vertebrate animals.
There are known heretofore various substances, which have been decided to have pxeventive or alleviative effects on diseases caused by virus whose host is a vertebrate animal, or which have been recognized to be capable of alleviating symptoms of the diseases by significantly en~anc-ing antibody activity in the animal. Antivirotics reported so far include interferon, substances capable of inducing interferon, i.e. inducers (interferon inducers), amantadine hydrochloride or synthetic substances, such as methysazone, which directly exert inhibitory effect on the virus propaga-tion. Interferon is glycoprotein ha~ing antiviral and anti-tumor activity, said glycoprotein being produced in situ by cells of a vertebrate animal when the cells are infected with virus, and has been suggested for the therapy of infectious viral disease and also for the therapy of cancer. Known inducers, which induce interferon in vertebrate animals by a process other than the virus in~ection, include natural high molecular substances such as double chain ribonucleic acid of bacteriophage of a certain species, or synthetic high molecular substances such as double chain ribonucleic acid, typical of which is polyinosinic acid-polycytidylic acid, or low molecular inducers such as tyrolone.
In the production of interferon, however, there is involved a problem how to carry out the purification there-of, and in fact no economical process for the production thereof has not been established yet. On the other hand, ~ - 2 - ~ , .. . .. ..

conventional lnterf~ron inducer~ have not ~cn put t~ practical use mainly because of to~ic.i-ty thereof. Synthetic antiviral agents which directly exert inhibit.ory effect on the viru~
propagation, which are commercially available at present, have a rather narrow range of viruc,~infected diseases which are curable by administration of said agent, and thus the advent of novel synthetic antiviral agents i.s earnestly desired. Taking such circumstances into consideration, the present inventors extensively couducte~ studies in f.inding compounds capable of producing interferon of hiyh potency and, moreover, having antiviral activity on the biological level, and as the result they have eventually found that compounds represented by the following general formula (I) and pharmaceutically acceptable acid addition salts thereof show excellent interferon inducing ability and, at the same time, demonstrate excellent antiviral activity even in the biological test.
According to one aspect of the present invention, there is thus provided a new class of decaprenylamine derivatives represented by the following general formula:
f~3 ,~ ( I) H ~ CH2-C=CH-CH2 ) N R
wherein R is a group capable of forming, together with the adjacent nitrogen atom, a 5- or 6-membered heterocyclic ring which may optionally contain a further hetero atom selected from the group consisting of nitrogen, oxygen and sulfur, the radical R being optionally substituted with a hydrogen atom or a lower alkyl or decaprenyl group when it contains an additional nitrogen atom as the further hetero atom, and the pharmaceutically acceptable acid addition salts thereof.

~ ~ - 3 -~ ...., ~, .. ,. . . . ... . . - . I , .. .. . ..

jt7~J~

~ he decaprer-ylamines having the general formula (I) and their pharmaceutically acceptable acid addition salts may be prepared in accordance with known procedures for amine synthesis, starting from decaprenol having khe formula:

CH
1 3 tII) H- ( CH2-C=CH-CH2 ) 10 According to a further aspect of th0 invention, there is thus provided a proce~s for the preparation of the decaprenylamines having the general formula (I),which comprises;
a) converting decaprenol of the formula:

CH
1 3 (II) H ( CH2-C=CH-CH2 )10 OH
into a corresponding halide or sulfonic acid ester which is thereafter reacted with a heterocyclic compound containing at least one primary or secondary amino group and having the general formula: ~
HN ~ (III) wherein R has the aforesaid meaning, in the presence or absence of a base, to obtain the desired decaprenylamine of the formula (I), and b) when a pharmaceutically acceptable acid addition salt is desired, further reacting the decaprenylamine of the formula (I) thus obtained with a pharmaceutically acceptable acid to pîovide the desired salt.
The pharmaceutically acceptable acid addition salt thus obtained can be isolated by crystallizing the salt out of the solution by evaporation or by other means to recover the same. The acid addition salts suitable for use as medicines include, for example, those formed with hydrochloric acid, acetic acid, citric acid, fumaric acid and the like.

.` ~

The compounds of the general forrnula (I~ and their pharmaceutically acceptab.Le acid add.ition salts are illustrated hereinbelow with reference to prepara-tive examples.

- 4a -. . . . . . . . . .. .. . .. .

Preparative Example 1 N-decaprenyl~ methylpiperazine dihydrochloride aH3 ~~
H~ CH2-C=C~~CH2--~1oN~ J~T-cH3 2H~l ~o a solution of N-me-thylpiperazine (10 g.) in isopropylether (20 ml) a solution of decaprenyl bromide (10 g.) in isopropyle-ther (20 ml) was added dropwise at room temperature for 2hours with stirring9 which was continued ~or further 2 hours, ~hereafter9 the reaction mixture was allowed to stand o~ernight~ ~he resulting reaction mixture was added wi-th 2N NaOH t 20 ml) with stirring and then extracted wi-th i~opropyletherO ~he liquid extract was washed with water and saturated saline9 dried over anhydrous sodium sul~ate and then conce~-trated under reduced pressureO ~he residue (8.5 g.) was puri~ied by column chromatography using silica gel (85 gO)~ '~he hexane/acetone fraction (608 g.) obtained was dissolved in acetone 9 added with HCl~ethanol to weakly acidic and then cooled. ~he crystallized masswas separated by ~iltration and recrystallized ~rom ethanol to recover N-decaprenyl-N'-methylpiperazine dihydrochloride (5.3 gO)g mO p ~ 142 - 145Co ~lementary analysis as C55H92~2o2HCl H20 showed the followingo ~ H% N~o CalcdO : 75.73 11~09 3021 25Found o 75048 10095 3019 ~ 7 Prepara-tive Example 2 -to 7 The same procedures as in Example 1 were carrled out for the reaction o~ decaprenyl bromlde wlth a hetero~
cyclic compound having a secondary ami.no group thereby -to produce the below~indica-ted compound~ 9 the Ytructural formula9 molecular formula9 melting point and elementary analysis of which also are listed in ~able 1.

co ~ ~ ~ r-~
t--c~ ~o r- ~f,) CO
Z ~ ~ O U 7 1 _ æ ~ ~ co ~ t~, c~
_ ~:C Cl~ ~ > CO
~l ~- O ~ O
~1 . O
~4 ~ D O J
c~ c- ~t~ co ~o a~
~ o r~ J C-- ~ cO
c~ co C- co r- co ~-~ ~ O ~ ~ ~ CO
c~ t~ co c~
æ ~ r ~ ~ ~ r-~
~ ._ r~ o 0 ~i a~ u~ o ~ c~ ~ rt~
F~ +' ~
~a l ~ ~ ~ o ::~
- r r o c V V
O ~ ~ co ~ cr~
C~ C- CO C- CO C~
~ ~ ~U
O t~l ~ o r-~ o o ~_ ~ ~ ~ ~ ~D ~
~V ~ I I i 1 oo O tO t~ C~
E~-- O ~ ~ tJ~ ~O CO
~-- ~
~ 0~
o ~ .Tr.
E~ ~ V ~ V~
~; ~; o ~; Z
~- o t~ t~ cr~ co co co C~
:r r~ r-~
~o r~ v v V

,~ ~
C~C~ ~J C~ C~

v~ vrt~ vr~ v1~ v v 11 ~11W 11W 11 W 11 ~1~ V ~ V V--V V--V ~--U~ 1~ !C~l C~l C~J ~ Vl w V--V
~) V ~ V V
~ V~
~ 1' w ~, O ~; w P, h X o c~ r \ ~ u~

Physiological effect~ of -the compounds of the prcsent invention are illustrat~ed below in detail.
(1) Interfero~ ;induci~ ac-tivity tes-t ~ ach te~t compound su3pended in water ~ith a surfactart was intraperitoneall;y admini.s-tered to each group conæisting of 5 ICR female rnice weighing about 25 gO
~wenty hours a~ter administration9 blood was collec-ted from the mice and serum was separated therefrom to ob-tain a ~erum inter~eron. ~he ~ollowing steps wexe taken in order to determine potency of the serum interferon thus inducedO I-929 cells derived from mice and incubated previously in a monola~er was brought into contact with -the tes-t serum solution diluted 10 times 9 incubated overnight at 37C. in an incubator placed in carbon ~5 dioxide atmosphere and the dilute test serum solu-tion was removed there~rom. Thereafter 9 the cells were inocula-ted with vesicular stomatitis vixus and placed on a tissue culture meaium containing 1~o agar. After incubation at 37C. for 24 hours J the cells were dyed with neutral red solution diluted to an appropria-te concentration to count the number of plaques foxmed thereon and thereby to calculate the plaque inhibition rate in each of -the test groups against a group to which no test compound had been administered. ~he plaque inhibition ra-te of each test compound :is shown in Table 20

(2) Effect on mice infected wi-th vaccinia virus Groups 9 each consisting of 10 ICP~ female mice 9 were intravenousl~ injected vaccinia virus (DI~ strain) from the vein of tail. On the 8th day after -the inoculationg the number o~ lesions in form of small pocks on the tail ~ '7~

surface was counted af'ter d~eing the tail with an ethanol solu-tion containing 1~o :~luorescein and 0.5~ me-thylene blue.
In this -test 9 each tes-t compound was ad~ninisterea intraperitoneally -to the mice on the day ju~-t before inoculation of the v.irus 9 whereby antivirus ac-ti~ity o~
the te~t ~ompound was evalua-ted in terms of inhibition of -tail lesions as calculated in each test group agains-t a group to which no test compound had been administered.
~he rate of -tail lesion inhibition of each test compound is shown in ~llable 2.

(3) Effect on mice infec-ted with in~luenza viru~
Groups~ each consisting of 10 ICR female mioe weighin~ about 25 g. were challenged by inhalation of neblyzed influenza virus .A/PR-8. A solution of each -test compound in an aqueous solution containing a surfactant wa3 intraperi-toneally administered to the mice 24 hours and 3 hours before the ~irus infec-tion9 and 5 times every other day from the secona day after the infection. ~he mice that ~urvived 21 days after the challenge were regarded as survivors~ and survival rate was obtained according to the following equation.

Number of survivors ~ x 100 = survival rate l\~umber of mice trea-ted o o rl F~
-1~ a) o t~
~ tD C`J

O
h .
~1 0 _~
N O ~ O ~ O
rl I>~1 0-1' ~r~
~Ih P~

~r~0 rl O+~
h C>
tH
o tH
. . I
L~
C~l O ~rl t~ t_ ,1 ~ t~d ,a,~a o ~

H r-l ~ p r~
tQ ~ O O O
-rl 1~`~ ~
(V
r~
r~
~rl O
'd N
h C~
o ~I a) o

4 ~ a d!;~rl ~d O ~ rl~ N ~rl C) h 0P~ ~l O
.~,, ~ ,J
H ~, o~ ~ o r~ o ~ rc~
,~ ,h,~ ~ ", ~ o ~, ;d~i ~ rd - 10_ oxic i ty In order to inve~stigate acute toxlcity of the compounds of -the present inven-tion 7 50~0 le-thal dose o~
each compound was obtained by using daY male mice weighing 20 - 25 g. From the resu].-ts sho~m in T~ble ~9 it is understood that the compounds had high safe-tg margin b~
intraperitoneal administration.

~'able 3 Intravenous y n raperl oneally ~est com~ound administered administered N-decaprenyl-piperazine 35.7 ~500 dihydrochloride 15 N-decaprenyl~N'-methylpiperazine 42.0 ~500 dihydrochloride As is clear from -the ~oregoing test resul-ts 9 the active ingredients of the present invention have interferon inducing activity in vivo and are low in toxicity with showing excellent antiviral activity. In the light of the fact that the strict correlation o~
interferon activity with the individual antivirus activities is not always observed for the presen-t ingredients 9 there is considered also a possibility tha-t the antivirus activities of said ingredients at biological level are concerned not only in interfexon bu-t also in other defensive mechanism of host. Accordinglyg when the active lngredients of the present invention are used for treatment of virus infected diseases, they are adminis-tered to patien-ts by such techniques involving oral 7 inhalantg or the like 'Btl~

administration as well as subcut~neous 9 intramascular and intravenous injection. Accorcling to the condition of patient such as age9 symptom and route by which the ingredient i9 administered9 -the active ingreaient of the present invention is used in a tlose of 0.5 - 20 mg/kg9 preferably 3 - 5 mg/kg several times (2 - ~ times) per aay ~ he active ingredients of the present in~en-tion can be ~ormulated in-to compositions ~or medication9 for example 9 tablets 9 capsules 9 granules 9 powder liquid preparatlon ~or oral use9 eye lotionsg suppositories9 ointments, injections and the like.
When the present active ingredients are orally administered9 they may be formulated in-to tablets9 capsules, granules ox powder. ~hese solid preparations ~or oral use may contain commonly used excipients9 for example, silicic anhydride9 metasilicic acid, magnesium alginate9 synthetic aluminum silicate, lac-tose9 cane sugar9 corn starch, microcrys~alline cellulose9 hydroxypropylatea starch or glycine9 and the like 9 binders9 for example9 gum arabic, gelatin9 tragacanth9 hydroxypropyl cellulose or polyvinyl-pyrrolidone9 lubricants9 for example9 magnesium stearate 9 talc or silica9 disintegrating agents9 ~or example9 po-tato starch and carboxyme-thyl cellulose 9 or wetting agents9 for example9 polyethylene glycol9 sorbitan monooleate9 hydrogenated cas-tor oil9 sodium laurylsulfateO In preparing so~t capsules, in particular9 the present active ingredients may be formulated by dissolving or suspending them in commonly used oily substrates such as sesame oil9 peanut oil9 germ oil9 fractionated coconut oil such as Miglyol ~ 9 or the like. Tablet or granule preparations may be coated ~ 12 ~

according to the usual method~
Liquid preparation I'or oral use may be in the form of aqueous or oily emulsion or syrup9 or alternatively in the form of dry product whic.h can be re-dissolved before use by means of a suitable vehicle. To these liquid preparations7 there may be added commonly usea adaitives7 for example7 emulsifying aids such as sorbitol syrup7 methyl cellulose 7 gela-tin7 hydroxyeth,yl cellulose and the like9 or emulsifiers7 for example7 lecithin7 sorbitan monooleate7 hydrogenated cas-tor oil7 non-aqueous veh.icles7 for example, fractiona-t~d coconut oil9 almond oil9 peanu-t oil and the like9 or antisep-tics 9 for example 9 methyl p-hydroxybenzoa-te 9 propyl p-hydroxybenæoate or sorbic acid.
Fur-ther, these preparations ~or oral use may contain7 if necesæary preservatives9 stabilizers and the like additives.
In case where the present active in~redients are administered in the ~orm o~ non~oral suppository9 they may be ~ormulated according to the ordinary method using oleophilic subs-trates such as cacao oil or Witepsol ~ , or may be used in the form of rectum capsule obtained by wrapping a mixture o~ polyethylene glycol9 sesame oil, germ oil9 fractionated coconut oil and the like in a gelatin sheet. ~he rectum capsule may be coated9 if necessary9 with waxy materialsO
~,~hen the present active ingredients are used in the form of injection9 they may be formula-ted into preparations o~ oil solution9 emulsified solution or aqueous solution9 and these solutions may contain commonly used emulsifiers, stabilizers or the like additives.
According to the method of administration9 -the ~L ~ ' r;j~

above-mentioned composi-tions can contain the presen-t active ingredien-t~ in an amount of a-t least 1~, preferably

5 to 50~0.
The procedure of ~or~llating -the pre~en-t aetive ingredien-ts lnto various preparations is illustra-ted below with reference to PharmaceuticaL Examples~
Pharmaceutica]. Example 1 Hard capsule preparation~
for oral use ~ mixture of 25 gO of N~decaprenyl-pipera~ine dihydroehloride and 7.5 g. of polyoxyethylene castor oil in aeetone was mixed with 25 gO of silicic anhydride.
After e~aporation of the acetone 9 -the mi~-ture was mixed further with 5 g. of calcium carboxymethylcellulose 9 5 g. of corn starch9 7.5 g. of hydroxypropylcellulose and 20 g. of microcrystalline cellulose9 and 30 ml o~ water was added thereto and kneaded to give a granular mass.
~he mass was pelletized by means of a pelleti~er (~CK
pelletter of Fuji Paudal CoO9 Japan) equipped with No. 24 mesh (B.S.) screen to obtain granulesO ~he granules were dried to less than 5% moisture content and screened with NoO 16 mesh (B~S.) screen. The screened granules were eapsuled by means of a capsule filling machine so as to be eontained in an amount o~ 190 mg per capsule.
5 Pharmaeeutieal Example 2 Soft capsule preparations for oral use A homogeneous solution was prepared by mixing 50 g. of N-decaprenyl-piperazine dihydrochloride with 130 g. of polyethylene glycol (Macrogol 400). Separately9 a gelatin solution was prepared which contained 93 gO of gelatin9 19 g. of glycerine9 10 g, of D sorbitol9 004 g.
of ethyl p-hydroxybenzoate9 002 g. of propyl ~ '7~,9~

p--hydroxybenzoate and 0.4 g. of tit~nium oxiae and which was used as a capsule film ~orming agent. The previou~ly obtained solution~ together with the cap~ule ~ilm forming agent 9 was treated with a manual type ~la~ punching machine to obtain capsules each ha~ing the contents of 180 mg.
Pharmaceutical Example 3 lnaections A mixture o~ 5 g. o~ N~decaprenyl-N'-methyl-piperazine dihydrochloride, an appropriate amount o~
peanut oil and 1 g. o~ benzyl alcohol was made a total volume o~ 100 cc by addition of peanut oilO ~he solu-tion waæ portionwise poured in an amount of 1 cc under asepsis operation in-to an c~mpule which was then sealed.
Pharmaceutical ~xample 4 Injections A mixture of 1.0 g. of N-decaprenyl-N'-methyl-piperazine dihydrochloride9 5.0 g. Nikkol HaO 60 (a tradename) (hydro~enated castor oil polyoxyethylene-60 mols-ether)9 20 g. of propylene glycol9 10 g. of gl~cerol and 5.0 g~ of ethyl alcohol was mixea with 100 ml of distilled water and s-tirred. Under asepsis operation9 the solution was portionwise poured in an amoun-t o~ 1.4 ml into an ampule which was then sealed.

- 15 ~

Claims (20)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:-

1.- A process for the preparation of the decaprenylamines having the general formula:

(I) wherein R is a group capable of forming, together with the adjacent nitrogen atom, a 5- or 6-membered heterocyclic ring which may optionally contain a further hetero atom selected from the group consisting of nitrogen, oxygen and sulfur, the radical R being optionally substituted with a hydrogen atom or a lower alkyl or decaprenyl group when it contains an additional nitrogen atom as the further hetero atom, and the pharmaceutically acceptable acid addition salts thereof, which comprises:
a) converting decaprenol of the formula:

(II) into a corresponding halide or sulfonic acid ester which is thereafter reacted with a heterocyclic compound containing at least one primary or secondary amino group and having the general formula:

(III) wherein R has the aforesaid meaning, in the presence or absence of a base, to obtain the desired decaprenylamine of the formule (I); and b) when a pharmaceutically acceptable acid addition salt is desired, further reacting the decaprenylamine of the formula (I) thus obtained with a pharmaceutically acceptable acid to provide the desired salt.

2.- A process according to claim 1, for the preparation of N-decaprenyl-N'-methylpiperazine, wherein use is made of N-methylpiperazine as said heterocyclic compound of formula (III).

3.- A process according to claim 2, wherein the N-decaprenyl-N'-methylpiperazine thus obtained is reacted with hydrochloric acid to obtain the corresponding dihydro-chloride salt.

4. A process according to claim 1, for the preparation of N-decaprenyl-piperidine, wherein use is made of piperidine as said heterocyclic compound of formula (III).

5.- A process according to claim 4, wherein the N-decaprenyl-piperidine thus obtained is reacted with hydrochloric acid to obtain the corresponding dihydrochloride salt.

6.- A process according to claim 1, for the preparation of N-decaprenyl-imidazole, wherein use is made of imidazole as said heterocyclic compound of formula (III).

7.- A process according to claim 1, for the preparation of N-decaprenyl-piperazine, wherein use is made of piperazine as said heterocyclic compound of formula (III).

8.- A process according to claim 1, for the preparation of N-decaprenyl-morpholine, wherein use is made of morpholine as said heterocyclic compound of formula (III).

9.- A process according to claim 1, for the preparation of N-decaprenyl-thiazolidine, wherein use is made of thiazolidine as said heterocyclic compound of formula (III).

10.- A process according to claim 1, for the preparation of N,N'-didecaprenyl-piperazine, wherein use is made of N-decaprenyl-piperazine as said heterocyclic compound of formula (III).

11.- The decaprenylamines having the general formula:
(I) wherein R is a group capable of forming, together with the adjacent nitrogen atom, a 5- or 6-membered heterocyclic ring which may optionally contain a further hetero atom selected from the group consisting of nitrogen, oxygen and sulfur, the radical R being optionally substituted with a hydrogen atom or a lower alkyl or decaprenyl group when it contains an additional nitrogen atom as the further hetero atom, and the pharmaceutically acceptable acid addition salts thereof, whenever prepared by a process according to claim 1 or its obvious chemical equivalents.

12.- N-Decaprenyl-N'-methylpiperazine whenever prepared by a process according to claim 2 or its obvious chemical equivalents.

13.- N-Decaprenyl-N'-methylpiperazine dihydro-chloride whenever prepared by a process according to claim 3 or its obvious chemical equivalents.

14.- N-Decaprenyl-piperidine whenever prepared by a process according to claim 4 or its obvious chemical equivalents.

15.- N-Decaprenyl-piperidine dihydrochloride when-ever prepared by a process according to claim 5 or its obvious chemical equivalents.

16.- N-Decaprenyl-imidazole whenever prepared by a process according to claim 6 or its obvious chemical equivalents.

17.- N-Decaprenyl-piperazine whenever prepared by a process according to claim 7 or its obvious chemical equivalents.

18.- N-Decaprenyl-morpholine whenever prepared by a process according to claim 8 or its obvious chemical equivalents.

19.- N-Decaprenyl-thiazolidine whenever prepared by a process according to claim 9 or its obvious chemical equivalents.

20.- N,N'-Didecaprenyl-piperazine whenever prepared by a process according to claim 10 or its obvious chemical equivalents.