AU666725B2

AU666725B2 - New pharmaceutical compositions and new pharmaceutical products allowing the regeneration of leukocytes and their use in the treatment of acquired immuno-deficient syndrom

Info

Publication number: AU666725B2
Application number: AU39806/93A
Authority: AU
Inventors: Francois Dietlin; Daniele Fredj
Original assignee: S C R NEWPHARM
Current assignee: Scr Newpharm
Priority date: 1988-12-19
Filing date: 1993-05-25
Publication date: 1996-02-22
Anticipated expiration: 2009-12-19
Also published as: EP0375471A3; FR2640508A1; CA2005925C; PT92620B; NZ231854A; JPH02258722A; AU3980693A; PT92620A; IL92759A0; HU896683D0; HU213510B; MA21964A1; EP0375471B1; EP0375471A2; ATE136463T1; DK646489A; DE68926222D1; CA2005925A1; MY106032A; OA09250A

Description

Regulation 3.2(2)

AUSTRALIA

Patents Act 1990 666725

ORIGINAL

COMPLETE SPECIFICATION STANDARD PATENT ii ii. St St ii S ti it-

S

C

t~ S Ci i St~ tt i a ii ii 0* Application ;Number: Lodged: Invention Title: NEW PHARMACEUTICAL COMPOSITIONS AND NEW PHARMACEUTICAL PRODUCTS ALLOWING THE REGENERATION OF LEUKOCYTES AND THEIR USE IN THE TREATMENT OF ACQUIRED IMMUNO-DEFICIENT SYNDROM The following statement is a. full description of this invention, including the best method of performing it known to :-US i-~ F; Y-~ri.r~-ri -x r NEW PHARMACEUTICAL COMPOSITIONS AND NEW PHARMACEUTICAL PRODUCTS ALLOWING THE REGENERATION OF LEUKOCYTES AND THEIR USE IN THE TREATMENT OF ACQUIRED IMMUNO-DEFICIENT SYNDROME This invention relates to the field of medicinal therapy and more particularly to the field of immunological therapy.

It has more precisely as subject matter some products and some pharmaceutical compositions which allow alone or in combination with another active ingredient the treatment of acquired or non-acquired immuno deficitary syndromes.

Specifically it provides pharmaceutical compositions intended for the regeneration of T 4 lymphocytes or the increase of the number of T 4 lymphocytes in patients showing an immuno-deficitary syndrome which contain as active ingredient the 9-(or 5) amino 1,2,3,4-Tetrahydroacridine NH2 6) 4 9 3 7) 1

N

15 as a free base or as an acid addition salt thereof or a closely related chemical *"derivative thereof in admixture or conjunction with an inert non-toxic S-C pharmaceutically-accaptable carrier or vehicle.

t This invention also relates as new compounds to the closely related ^,chemical derivatives of 9-amino 1,2,3,4-Tetrahydroacridine having the formula N B x

N

wherein A and B are labile functional groupings easily split in the body and namely in the digestive tract and X is a substituent selected from the group consisting of hydrogen, a C 1

-C

6 l alkyl, a C1-C6 alkoxy, a Ci-C6 alkanoyl, a (0-C6 dialkyl) amino Ci-C6 alkyl, a (CI-C alkyl), a phenoxy, an amino grouping of the formula N6 r06 wherein R 5 and R 6 the same or different and are hydrogen, a Ci-C 6 alkyl or a Ci- C6 acyl group, a trifluoromethyl, a trifluoromethoxy radical, a carboxamido or a

(C

1 -Cs alkyl) mercapto radical.

The labile groupings A and B can be selected from the acyl residues from organic aliphatic or aromatic carboxylic acids and lower alkyl radicals or the alkylidene groups or arylidene moiety of a Schiff's Base deriving from a ketone of the formula CC R, -C-R 2 C II

CO

or from an a!dehyde of the formula R, CHO wherein R 2 is a lower alkyl radical, a monocyclic aryl radical which is 15 unsubstituted or substituted by one, two or three substituents, a monocyclic C t Cqt. heterocyclic radical S and R 1 th4 same or different, has the same meanings as R 2 In the foregoing, the acid addition salt of 9-amino tetrahydroacridine or of the derivatives thereof are those obtained by adding a mineral or organic therapeutically-compatible acid such as a hydrochloride, a hydrobromide, a sulphate, a nitrate, a phosphate, a sulphite, a thiosulphate, an acetate, a butyrate, a caproate, a suberate, a succinate, a tartarate, a citrate, an ascorbate, a gluconate, a cetaglutarate, a glutamate, an aspartate, a benzoate, a gentisate, a salicylate, a trimethoxybenzoate, a vanillinate, an eugenate, a nicotinate, a naphtoate, a benzene sulfonate, a methane sulfonate, an isethionate, an ethane sulfonate, a p.toluene sulfonate, a camphosulfonate, a naphtalene sulfonate, a glucose 1-phosphate and a glucose 1,6-diphosphate.

The closely related chemical derivatives of 9-amino 1,2,3,4- Tetrahydroacridine are namely the mono- and di-acyl amines such as for example: the compounds of formula A NH Ac X

(A)

N

in which Ac is the acyl residue of an organic carboxylic acid having from 1 to carbon atoms such as acetyl, propionyl, benzoyl, 2,6-dichlorobenzoyl, 3,4,5trimethoxybenzoyl, cinnamoyl, nicotinoyl, isonicotinoyl, furoyl, thenoyl or naphtoyl and X has the above-mentioned meanings.

10 the compounds of formula B Ac t Ac I t (B) l consisting of alkanoyl radicals with 1 to 6 carbon atoms and mono- cyclic aroyl radicals which are unsubstituted or substituted with from 1 to 3 substituents 15 selected from the group consisting of lower alkyl, lower alkoxy, halogens, trifluoromethyl and trifluoromethoxy and X has the above-mentioned meanings.

the compounds of formula C N =CH Ri three substituents selected from the group consisting of a lower alkyl radical, a lower alkoxy radical, halogens, trifluoromethyl and trifluoromethoxy and X has the above-mentioned meanings the compounds of formula D

R,

N C

R

2 x (D) wherein R 1 and R 2 are the same or different and are selected from the group consisting of a lower alkyl radical, a phenyl radical and a monocyclic heterocyclic radical.

10 9-amino 1,2,3,4-Tetrahydroacridine and its structural analogs are I prepared according to a general process which consists of reacting an authranitronitrile suitably substituted with a cyclohexanone in the presence of p.toluene sulphonic acid then cyclising with lithium isopropyl amidee, the tett resulting imine according to the following schematic diagram: X benzene OHi iC t I

NH

2

NH

2

N

In this respect the 8-fluorinated and 7-chlorinated analogs of 9-amino tetrahydroacridine are presently the most preferred analogs.

Starting from 9-amino 1,2,3,4-Tetrahydroacridine, it is allowable to perform the alkylation or araikylation of the amine function by means of an aldehyde or a ketone in the presence of an hydrogenating reagent or in the presence of a reducing agent such as formic acid. The Schiff's Bases are L 4 K ri~h~ obtained in a suitable manner by reacting 9-amino 1,2,3,4-Tetrahydroacridine with an aldehyde or a ketone such as formaldehyde, benzaldehyde, 2,6diL. lorobenzaldehyde or acetone in the presence of a basic organic reagent such as morpholine or piperidine.

Numerous examples of the preparation of similar compounds have been disclosed in the European Patent Application 0,306,825.

9-amino 1,2,3,4-Tetrahydroacridine and its analogs may also be acylated using a functional derivative of an organic carboxylic acid such as for example an acid halide, an acid anhydride, a mixed anhydride or by means of a carboxylic acid in the presence of a carbodiimide such a dicyclohexyl carbodiimide.

Depending on. the concentrations of the acylating agent and the nature of the solvent, the monoacylated derivative or the diacylated derivative may be 1:5, obtained.

15 9-amino 1,2,3,4-Tetrahydroacridine is a known therapeutic agent and has already been used under the Trade Name Tacrine for many years as an antidote of the curarizing agents and the choiinesterasic agents. Its use has also be proposed in the treatment of Alzheimer's disease as anticholinesterasic agent and cerebral stimulant but its efficiency can not yet be judged lacking the 20 necessary background. The mode of action of this active ingredient is still not determined with certainty due to the high number of pharmacological studies *o perfonried thereon.

More recently J. Byrne and T. Acie (British Med. J. 298 (1989) 845) have axplained why 9-amino tetrahydroacridine could not be utilized in this treatment due to its hepato toxicity which attained from 1/5 to 1/3 of the treated patients.

Now it has been found that 9-amino 1,2,3,4-Tetrahydroacridine and the acid addition salts thereof with a mineral or organic acid as well as their closely related chemical derivatives or biological precursors (pro-drugs) are efficient drugs for allowing the regeneration of T 4 lymphocytes and more particularly T 4 lymphocytes the number of which significantly and dangerously, decreases during and in the cases of immuno-deficitary syndrome.

27; s] It thus appears valuable in order to decrease the occurrence of toxic sideeffects to use either 9-amino tetrahydroacridine or better to use one of its closely related chemical derivatives the purification of which may be more easily reached.

It has been evidenced in patients the number of T 4 lymphocytes of which was deeply decreased, that it was possible after a few weeks of treatment to obtain a very marked increase of the levels of lymphocytes in the blood and that in the patient where the count of T 4 lymphocytes has fallen to a level close to disappearance, it was possible to get under the same conditions a recovery to subnormal levels of T 4 lymphocytes. At the same time the clinical cases stated a significant regression of the opportunistic infectious symptoms and/or the disappearance of the seropositivity.

S9-amino 1,2,3,4-Tetrahydroacridine appears to act mainly as an inhibitor 5 of the RNA polymerase of the viruses and more precisely of the HIV Viruses which are involved in the origin of AIDS.

The biological precursors of 9-amino tetrahydroacridine behave in about the same manner and lead to the formation of 9-amino tetrahydroacridine in the stomach. It has been shown that in an artificial gastric juice, at pH 1, methylene 9-amino tetrahydroacridine, isopropylidene 9-amino tetrahydroacridine or benzylidene 9-amino tetrahydroacridine are split into the 9-amino derivative in t l f about quantitative manner in less that 15 mn.

t't; 9-amino tetrahydroacridine and its closely related chemical derivatives are also endowed with ability to strengthen the action of antiviral drugs such as the thymidine, uracil or uridine derivatives (AZT, DDI namely) and thus to allow a very marked decrease of the doses of antiviral drug to be efficient.

It is now known that the treatment of AIDS using Azathymidine (AZT) progressively losses its efficiency and lets an only very limited chance of life to the patients affected with AIDS. The mixed treatment of AIDS with an antiviral drug and with 9-amino tetrahydroacridine or a salt thereof or one of its closely related chemical derivatives have shown a significant presumption of life. It appears as very significative the clinical case of a patient treated for 15 months with AZT for which the number of T 4 lymphocytes was about zero and after accordingly two possible therapeutic schemes: administration, of 9-amino tetrahydroacridine alone or administration of 9-amino tetrahydroacridine in admixture or in support of a treatment with an antiviral drug.

More specifically in the case of antiviral drugs such as AZT or HPAZI, a synergistic action has been shown which allows a decrease in the dosology of the antiviral drug of a factor of 10 while preserving the efficacy of the antiviral drug.

The pharmaceutical compositions.according to this invention contain from to 300 mg of 9-amino 1,2,3,4-Tetrahydroacridine or an addition salt thereof or one of its closely related chemical derivatives in admixture or conjunction with an inert non-toxic pharmaceutically-acceptable diluerit or carrier and preferably t V;C from 50 to 200 mg of active ingredient.

15 As preferred diluent it may be cited a lecithin such as soja lecithin, or a U""l phospholipid such as a ganglioside or a cerebroside, or a chemically-modified cellulose such as hydroxypropyl methylcellulose.

Among the pharmaceutical compositions according to this invention which contain as active ingredient either 9-amino tetrahydroacridine or a salt thereof or a closely related chemical derivative, it may be cited those which are suitable for the administration through the digestive route such as tablets, coated tablets, microgranules with protracted release, dragees, the soft gelatine capsules, the capsules, the hard shell capsules, the lozenges, the solutions or suspensions to be drunk, the jellies and the emulsions For the parenteral adi;linistration it will be preferably used a solution or suspension of active ingredient divided in ampoules, in multidose flasks, or autoinjectible syringes; they are preferably utilized in the form of an acid addition salt.

For the rectal way they will be.preferably given in the form of rectal suppositories or capsules.

The daily dosage varies, dependent on the age of the patients. It ranges from 5 to 100 mg in the children, from 50 to 600 mg in the adult man.

I 8 These pharmaceutical compositions are manufactured in accordance with the usual methods of pharmacotechnology. The following examples are intended to illustrate the invention without limiting it in any manner.

EXAMELE1 N-(phenylmethylene)-1.2.3.4-tetrahvdro-9-acridinamine 1,2,3,4-tetrahydro-9-acridinamine (8.40 g) was refluxed in 300 ml of toluene which contained 7.0 g of mrpholine and 6.4 g of benzaldehyde which had been freshly washed with aqueous K 2

CO

3 The reaction mixture was refluxed overnight and then concentrated and purified by flash chromatography (20% ethyl acetate/CH2CI 2 to give 9.51 g of chromatographically pure product.

Analytically pure material was obtained by recrystallisation from benzenepentane, mp 128-130°C.

ANALYSIS:

Calculated: S 15 84.53%C 6.08%H 9.39%N Found: 84.49%C 6.02%H 9.31%N I EXAMPLE 2 S6-methyl -1.2.3.4-tetrahvdro-9-acridinamine A solution of 2-amino-4-methylbenzonitrile (16.0 g) and zinc chloride (24.7 g) in 70 ml of nitrobenzene was heated at 50°C for 1 hour. To this was added cyclohexanone (20.0 g) and the mixture was stirred at 100°C for 3 houre The reaction mixture was cooled and diluted with ether and the zinc complexi was filtered. This complex was partitioned between aqueous NH 4 0H and 2butanone (MEK) and the aqueous phase was extracted with MEK. The organics were washed with water, dried (saturated NaCI; MgSO 4 and concentrated to an oil which was triturated with ether to give 12.8 g of white popw*r, m.p. 159- 1620C. A 4.0 g ption was recrystallised from isopropyl ether to give 2.5 g of analytically pure white solid, m.p. 162-1640C.

ANALYSIS:

Calculated: 80.32%C 7.19%H 12.49%N J 0 9 Found: 80.29%C 7.05%H 12.52%N EXAMPLE 3 6-methyl-N-(phenylmethylene)-1.2.3.4-tetrahydro-9-acridinamine A solution prepared from 6-methyl-1,2,3,4-tctrahydro-9-acridinamine (8.6 benzaldehyde (6.3 g, freshly washed with K 2

CO

3 solution), morpholine (6.9 ml) and toluene (300 ml) was refluxed, with removal of water, for eighteen (18) hours. At this time, 6.3 g of benzaldehyde was added and reflux was continued for twenty-four (24) hours. The solvent was then removed in vacuo and the imine was purified via flash chromatography (DCM) to give 7.3 g of an orangish solid, m.p. 144-1470C. A 3.5 g portion was recrystallised from isopropyl ether to give 2.54 g of light yellow crystals, m.p. 149-1520C.

JANALSIS:

S Calculated: 84.58%C 6.45%H 8.97%N Found: 84.46%C 6.42%H 9.00%N EXAMPLE 4 ct e 1.2.3.4-tetrahydro-6-forometjhyl-9-acridinamine C I 20 To a solution f 1amino-4-trifluoromethylbenzonitrile (12.8 g) in 50 ml of CC nitrobenzene was added freshly fused and pulverised ZnCI 2 (14.1 This was heated at 500C for 1 hour and to this mixture was added cyclohexanone (11.4 g).

The reaction mixture was heated at 1300C for 3 hours, after which it was cooled, diluted with ethyl ether and filtered. The resulting solid was partitioned between 2-butanone (MEK) and aqueous NH 4 0H and the aqueous portion was extracted with MEK. The combined organics were washed with water, dried (saturated NaCI, MgSO 4 and concentrated to a solid which was triturated with ether/hexane to give 10.3 g of a white powder, m.p. 174-1790C. A 4.0 g portion was recrystallised from methanol/water to give 3.5 g of an analytically pure white powder, m.p. 175-1780C.

ANALYSIS.

Calculated: 64.74%C 4.71%H 10.07%N Found: 64.70%C 4.88%H 10.09%N EXAMPLE N-(hen Imethvlene)-6-trifluoromethvl-1.2.3.4-tetrahydro-9-acridinamine A mixture prepared from 1,2,3,4-tetrahydro-6-trifluoromethyl-9acridinamine (7.65 benzaldehyde (4.4 g, freshly washed with K 2

CO

3 morpholine (4.8 ml) and toluene (300 ml) was refluxed with removal of water for eighteen (18) hours. At this point, an additional 4.4 g of benzaldehyde was added and reflux was continued for twenty-four (24) hours.

SThe reaction was then concentrated to a solid and the residue was chromatographed (DCM) to give 8.3 g of an orangish solid, m.p. 120-1260C. A 4.07 g portion was recrystallised from cyclohexane to give 2.56 g of an off-white solid, m.p. 127-130 0

C.

ANALYSIS:

Calculated: S72.12%C 4.68%H 7.65%N Found: 72.15%C 4.83%H 7.61%N EXAMPLE 6 De Preparation of 6-methyl N(dimethylmethylene) imino 1.2.3.4 tetrahydroacridine A solution is made with 8.6 g 6-methyl 1,2,3,4-tetrahydro 9-acridinamine in 200 ml toluene to which 6.9 g morpholine has been added. -A solution of 14 ml acetone in 100 ml toluene is added under strong stirring and the whole mixture is heated to reflux for 12 hours. The precipitate which appeared is let to stay overnight in a cool place. Then, it is filtered by suction, washed several times with cold toluene and dried under vacuum. An aliquot sample is taken for recrystallisation from isopropyl ether. Pure crystals of 6-methyl N(dimethylmethylene)imino 1,2,3,4-tetrahydroacridine are obtained as a yellow powder.

i 72.6 S2 0 F o u n d N 747 in20Q oun owih69gmrhliehsbe de.Aslto f1 01 1 2 oN 2 =240,04 Calculated: 80.8%C 7.3%H 1 2.2%N Found: 80.97%C 7.2%H 12.02%N Determination of the inhibitory action of 6-methyl 9-amino 1,2,3,4tetrahydroacridine, 6-methyl (N phenylmethylene) tetrahydroacridine, 6-trifluoromethyl 1 ,2,3,4-tetrahydroacridine and 6-trifluoromethyl N-phenylmethylene 1 ,2,3,4-tetrahydroacridine against RNA polymerase of HIV viruses.

Compounds Dosage Inhibition 6-methyl [01 pamol/l lamol/I L, prn gol/I 100% tcVt; 15 6-methyl p0.1 lamol/l N-phenylmethylene 10.5 jlimol/l 2 lumol/I 100% 6-trifluoromethyl 9-amino [0.1 gmol/l 0-rfurmty 0.4 jgmol/l 100% ilormty N-phenyl- 0.1 lamol/I0 CC0a0methylene 0.2 go/ 0 0.1 g~mol/l N-dimethylmethylene ~0.4 gmol/l 1 ,2,3,4-tetrahydro 1 pmol/l acridine amine,[ 2 gmol/l 100% 1U7I 1 i 1 I 1 /2 j ,a 12 EXAMPLE 7 Tablets with 100 g of 9-amino 1,2,3,4-tetrahydroacridine 9-amino 1,2,3,4-tetrahydroacridine as the hydrated hydrochloride 117 g Lactose 220 g microcrystalline cellulose 15 g Calcium Carbonate 20 g Calcium Phosphate (P0 4 2 Ca 3 35 g Copolymer of ethylene oxide and propylene oxiae sold under the Trade Name PLURONIC F18 13 g Magnesium stearate 15 g for 1000 tables finished at the mean weight of .43 g S. EXAMPLE 8 Clinical Trial with 9-amino 1,2,3,4-tetrahydroacridine in patients suffering 15 from immuno-deficitary syndrome "CONCENTRATION CONCENTRATION SYMPTOMS OF I

T

4 LYMPHOCYTES T 4 LYMPHOCYTES CLINICAL SPATIENTS DOSES before per mm3 after per mm3 IMPROVEMENT 1 100 mg/day 0 600 Becomes sero- 5 months negative r 2 100 mg/day 80 250 Decrease of the tcE' 3 months infectious symptoms 3 100 mg/day 80 210 No marked symptom 2 months of infection 4 100 mg/day 100 270 2 months 200 mg/day 80 200 Regression of the 2 months opportunist infections Normal level in T 4 is 600-800 per mm3

O'

13 EXAMPLE9 Determination of the inhibitory action of 9-amino 1,2,3,4- Tetrahydroacridine (THA) against RNA polymerase of HIV Viruses.

In vitro THA inhibits RNA polymerase of HIV Viruses with a close window of efficiency at 0.1 imol/I 0% inhibition 1 pimol/I 100% inhibition EXAMPLE Methodology of the clinical trials a) in the adult S 1st week 50 mg/day +1200 mg soja lecithin 2nd week 100 mg/day +1200 mg soja lecithin 3rd week 150 mg/day if necessary soja lecithin e 4th week: 200 mg/day if necessary soja lecithin 15 b) in the children SThe treatment is started at 10 up to 25 mg/day.

An adult patient formerly treated with AZT after which, his blood level of T 4 p lymphocytes was about zero, has been given 9-amino 1,2,3,4-Tetrahydroacridine up to 100 mg/day. After 5 months of this treatment, the T 4 lymphocytes S 20 have been increased and the patient was still alive, whilst under treatment with I c C C r SIAZT alone, the presumption of his survival was minimal.

EXAMPLE 11 N-(methyl pyvridl methylene)-9-amino-1.23.4-tetrahvdro acridine A solution prepared from 9-amino-1,2,3,4-tetrahydro acridine (7,8 methyl pyridyl ketone (7,87 g, freshly washed with K 2

CO

3 solution), morpholine (6,9 ml) and toluene (300 ml) was refluxed, with removal of water, for eighteen (18) hours. At this time, 7,87 g of methyl pyridyl ketone was added and reflux was continued for twenty-four (24) hours. The solvent was then removed in vacuo and the imine was purified via flash chromatography (DCM) to give 7,3 g of an organic solid, m.p. 144-147 0 C. A 3,5 g portion was recrystallized from isopropyl ether to give 3 g of light yellow crystals, m.p. 149-152 0

C.

14 EXAMPLE 12 N-(phenyl pyridyl methylene) 9-amino-1.2.3.4-tetrahydro acridine A solution prepared from 9-amino-1,2,3,4-tetrahydro acridine (7,8 phenyl pyridyl ketone (11 g, freshly washed with K 2 C0 3 morpholine (6,9 ml) and toluene (300 ml) was refluxed, with removal of water for eighteen (18) hours. At this time 11 g of phenyl pyridyl ketone was added and reflux was continued for twenty-four (24) hours. The solvent was then removed in vacuo and the imine was purified via flash chromatography (DCM) to give 7,3 g of an organic solid, m.p. 194-197°C. A 3,5 g portion was recrystallized from isopropyl ether to give 3 g of light yellow crystals, m.p. 199-202°C.

t CI C LC C C S I CC ti SI tC C CC 1 t C .0

Claims

1. A method of allowing the regeneration of T4 lymphocytes or the increase of their number in patients suffering from an immuno-deficitary syndrome which comprises administering to a patient requiring same a pharmaceutical composition which contains as active ingredient a compound selected from the group consisting of 9(or 5) amino 1,2,3,4-tetrahydroacridine of the formula NH 2 4 1 2 7) N as the free base or as an acid addition salt thereof in admixture or conjunction with an inert, non toxic pharmaceutically-acceptable carrier or vehicle.

2. A method of allowing the regeneration of lymphocytes or the increase of their number in patients suffering from an immune deficiency syndrome which comprises administering to a patient requiring same a pharmaceutical composition which contains as active ingredient 9-amino tetrahydroacridine having the formula D R, I N=C R2 C C ix (D) Swherein R 1 and R 2 are the same or different and are selected from the group consisting of hydrogen, a lower alkyl radical, a phenyl radical and a monocyclic heterocyclic ring and where R 1 and R 2 are not both hydrogen and X is a substituent selected from the group consisting of a C 1 -C 6 alkyl, (Cl-C 6 dialkyl) amino (Ci-C 6 alkyl, a (Ci-C 6 alkoxy)(Ci-C 6 alkyl), a trifluoro- 1 16 methyl, a phenyl, a phenylalkyl in which the alkyl chain has from 1 to 6 carbon atoms, a phenoxy, an amino group of the formula N R6 wherein R 5 and R 6 are the same or different and are selected from the group consisting of hydrogen, Ci-C 6 alkyl radical or a C1-C6 acyl group, a trifluoromethyl, a trifluoromethoxy, a carboxamido radical and a (C1-C6 alkly) mercapto radical.

3. A method according to claim 1 or claim 2 wherein the content of active ingredient ranges from 10 to 300 mg per unit dosage.

4. A method according to any one o' claims 1 to 3 in which the pharmaceutical composition further contains antiviral drug selected from the 0: group consisting of derivatives of thymi:" ucl and uridine. C t

5. A method according to any one of claims 1 to 4 in which the inert carrier is suitable for administration through the parenteral, oral, rectal, percutaneous or permucous routes of administration.

6. A method according to any one of claims 1 to 5 in which the S' pharmaceutical composition is in the form of tablets, soft gelatine capsules or dragees. DATED THIS 18TH DAY OF DECEMBER, 1995 S.C.R. NEWPHARM WATERMARK PATENT TRADEMARK ATTORNEYS 290 BURWOOD ROAD HAWTHORN VICTORIA 3122 AUSTRALIA CJH:ML ii (DOC.34) AU3980693.WPC I ABq TRACT This invention relates to novel pharmaceutical compositions, to new products and to method for regenerating or improving the level of lymphocytes T 4 in patients suffering form immuno-deficitary syndrom. The new pharmaceutical compositions according to this invention contain as active ingredient at least one compound selected from the group consisting of 9-amino 1,2,3,4-Tetrahydroacridine, in the free base form or as an acid addition salt, and its biological c precursors, in admixture or conjunction with an inert non toxic rC C 0 pharmaceutically-acceptable carrier or vehicle. This invention also extends to a method for regenerating or e improving the count of lymphocytes T 4 in patients suffering from said symptoms alone or in addition with a therapy with an St antiviral drug selected from the group consisting of derivatives \O of Thymidine, Uracile and Uridine. These new drugs may be given as well to children as to adult men for an extended period of time with significant evidence of recovery. C CC c c S I c c8i' t