GB2324242A - Medicaments for treating viral infections - Google Patents

Abstract

The present invention describes methods of treatment of viral infections, including infections carried by retroviruses and HIV. The treatment consists of administering a medicament comprising a piperazine-type H 1 -antagonist and/or a Nalidixic acid-type antimicrobial agent. Chlorcyclizine and ciprofloxacin have proved to be particularly effective, either alone or in combination. Pharmaceutically active salts of these agents may be used.

Description

MEDICAMENTS FOR TREATING VIRAL INFECTIONS The present invention relates to a method of treatment of viral infections. It is particularly applicable, but in no way restricted to, the treatment of infections caused by retroviruses such as HIV.

The invention extends to the use of compounds in the preparation of a medicament for the treatment of such conditions.

It is common practice in pharmaceutical companies to use their own compound libraries or purchase others to screen for leads in different therapeutic areas. The compounds selected are generally those which were inactive or only weakiy active in the screens for which they were originally synthesised. However, we discovered some time ago that many known drugs currently described as antihistamines, tranquillisers, analgesics, psychotrophics, anti-hypertensives, local anaesthetics etc., may have hitherto unrecognised or hidden activities as antibacterial agents. We therefore initiated a systematic study to detect such activities among existing and widely used drugs. This study led to the discovery of powerful antibacterial activity in promazine, promethazine, and methdilazine among the antihistamine phenothiazines; in methyl-DOPA (an antihypertensive), in diclofenac (an anti-inflammatory agent); in ambodryl and benadryi (diphenhydramine antihistamines); in chlorcyclizine (a piperazine-type H1 - antagonist); and weakly in chlorpromazine and cyclizine. (References 1 to 13) We have now investigated the anti-HlV/anti-retroviral activity among some of the known classes of drugs mentioned above and discovered unexpected activity in certain classes.

According to a first aspect, the present invention provides a method of treating viral infections, particularly infections caused by retroviruses such as HIV, in mammals including humans. The method comprises the use of a piperazine or piperazine derivative-type H-antagonist (hereinafter referred to as the piperazine-type H1-antagonist).or pharmaceutically acceptable salt thereof for the manufacture of medicament for the treatment of viral, retroviral or HIV infections. and administering a therapeutic dose to the mammal. including humans.

Preferably, the H1-antagonist has a general formula

wherein R is hydrogen, C: - @ alkyl, CH2CH2OCH2CO2M, CH2CH2OCH2CH2OH or CH: - CH = CH - C6H5 optionally substituted with one or more halogen atoms; and wherein R, and R2 are independently selected from phenyl optionally substituted by one or more halogen atoms or R1 and R2 are otherwise as specified in claim 12.

Preferably, the H1-antagonist has a general formula I: wherein R is methyl; R, is phenyl and P2 is a phenyl group substituted in the para-position with a halogen atom In a particulary preferred embodiment the H,-antagonis. is Chlorcyiizine (CCZ).

According to a second aspect the method comprises the use of a Nalidixic acid-type antimicrobial agent or pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of viral, retroviral or H::V infecticns.

Preferably, the Nalidixic acid-type antimicrobial agent has a general formula II:

wherein R1 is hydrogen, C1~ alkyl, cyclopropyl, CH2CH2F, phenyl, phenyl substituted by halogen; and wherein R2 is hydrogen or C1-4 alkyl, and wherein R3 is a halogen atom or otherwise as specified in claim 12.

In a particularly preferred embcdiment the Nalidixic acid-type antimicrobial agent is Ciprofloxacin (CFC).

According to the third aspect of the present invention the method comprises the use of a combination of a piperazine-tvpe H1-antagonist and t Nalidixic ac:c- type antimicrobial agent or pharmaceutically acceptable salts thereof for the manufacture of a medicament for the treatment of viral, retroviral or HIV infections.

The invention extends to medicaments and treatments comprising piperazlne-type H1-antagonist salts of Nalidixic acid-type antimicrobial agents.

Preferably the combination comprises a combination of piperazine-type H,-antagonist of formula I and a Nalidixic acid-type antimicrobial agent of formula II.

In a particularly preferred embodiment the combination consists of chlorcyclizine and ciprofloxacin, including chlorcyclizine salt of ciprofloxacin.

The present invention extends to the medical treatment of viral, retroviral, HIV and AIDS infections using any combination of the compounds herein described.

Initially, we screened in vitro a number of compounds which we considered had anti-HIV potential. Two principles guided us in our approach. First, that prior to the present invention there were really no effective drugs against HIV and AIDS.

Secondly, that most or all of the current anti-HIV agents are directed to cause errors of nucleic acid synthesis including nucleosides, which have generally failed to stop viral replication and infections of the patients. This is bome out by the proceedings of both the recent Vancouver and Birmingham congresses on AIDS which offered typical combinations e.g. zidovudine (AZT), lamivudine (3TC) and the protease inhibitors, choosing to replace one or two of these with DDI, saquinavir, nevirapine, vinorelbine etc.

Our approach was, therefore, based on the concept of preventing viral nucleic acid synthesis by multiple irreversible binding of one or more agents with the DNAIRNA strands, and stopping their enzymatic functions. We have unexpectedly discovered that antivirai activity is to be found in two classes of known pharmaceuticals which have not previously been associated with antiviral activity.

The first of these classes consists of the piperazine based antihistamines.

This is a distinct sub-type of H1-antagonists and they have been much-studied in the past, primarily in relation to their efficiency and reduced tendency to produce sedation as a side effect. Several members of this class of chemical entities have been used in man. That piperazine-type H1-antagonists represent a defined and recognised class of therapeutic agents can be seen from their listing in the Merck Index (for example page THER-13 in the eieventh edition).

Piperazine-type H,-antagonists have a general formula I:

wherein R typically represents hydrogen, C1-7 alkyl, substituted alkyl, CH2CH2OCH2CO2H, CH2CH2OCH2CH2OH, CH2CH=CH-C6H5; and wherein R and R2 are independently selected from phenyl optionally substituted by one or more halogen atoms. Alternative alkyl, substituted alkyl, aryl substituted aryl, aralkyl and heteroaryl groups have been investigated. This disciosure is intended to cover known and yet-to-be discovered piperazine-type H1-antagonists, Cyclizine can ce regarded as the parent compound in This class and has been shown .c exhibit some activity as an ant,viral agent in the screens selected (see below). Importantly and unexpectedly the analogue chlorocyclizine (CCZ) has been shown to exhibit very much greater activity than cyctizine itself. This increase in activity is far greater than would have been predicted from their respective H- antagonist activities. me second class of compounds are referred to generically as Nalidixic acidtype antimicrobial agents. Again this is a clearly defined class of antimicrobial agents which has been much studied and investigated by other workers.

Representatives of this class are listed in the Merck index, Eieventh Edition page THER-10 under the heading "Quinolones and Analogues" A very wide variety of Quinolone and 4-oxo-1,8-naphtyyridine analogues have been prepared in the past and their antimicrobial agent activity investigated.

They are generally well-tolerated by man and have an acceptable therapeutic index and have a general formula fI:

wherein P, represents hydrogen C. alkyl, cyclopropyl, CH2 CH2 =, phenyl, substituted phenyl, aminoalkyl, and aikoxy; R2 represents hydrogen. C alkyl; and wherein P3 represent a halogen. Alternative alkyl, substituted alkyl, aryl, substituted aryl, aralkyl and heteroaryl groups, optionally carrying one or more halogen atoms as substituents, have been investigated. This disclosure is intended to cover all known and yet-to-be discovered Nalidixic acid-type antimicrobial agents or compounds similar thereto in composition, structure and properties.

Whilst Nalidixic acid itseif, a substituted 1,8-napthyridine derivative, has some weak activity in cur tests it has unexpectedly been discovered That ciprofloxacin (CFC) shows potent antiviral and virustatic activity in our screens.

It has also been discovered that a co-administration of a piperazine-type H1- antagonist and a Nalidixic acid-type antimicrobial agent and particuiarly coadministration of chlorcyclizine and ciprofioxacin results in activity significantly greater than would be expected from the additive effect of the two separate doses.

That is to say, these compounds have a synergistic effect when used in combination.

Since the piperazine-type H, antagonists are, by definition, basic and Nalidixic acid-type analogues are acidic, it follows that they will form salts! when brought into contact with each other under pre-determined or appropriate conditions.

In order to achieve a suitable combination therapy it is proposed, for the first time, to prepare a substituted piperzine salt of a Nalidixic acid analogue.

This new form of salt enables the active ingredients to be administered in a 1:1 ratio.

A preferred salt of this type is the chlorcyclizine salt of ciprofloxacin. Such salts are prepared in conventional fashion by dissolving in a soivent the free acid and adding a stochiometric amount of the free base. The pure salt can he obtained by precipitation or by evaporation of the solvent followed by re-crystallisation if necessary.

Because of the problems involved in carrying out prospective drug sensitivity tests on HIV and AIDS patients directiy, in the next stage of the experiments, we used a mouse model and a mouse virulent retrovirus, as a substitute for HIV. The Swiss A strain of mouse was challenged with killing doses of Ehrlich's ascites carcinoma cells carrying the retrovirus'4 The two most promising drug candidates were tested on such tumour-challenged mice, and showed that singly these could generate considerable protection, but when administered jointly, these offered highiy significant protection. By in vitro experiments, it couid be demonstrated that these drugs become bound to the nucleic acids of the tumour retrovirus of mouse.

Extensive tests on human lymphobiastoid cell lines C8166 using HIV-1 and these two drugs of choice, with all controls showed that these drugs were non-toxic even at high effective doses, both were remarkably virustatic singly/jointly, and also virucidal significantly; CCZ was more virucidal than CEC and their combination was found to have synergistically greater effectiveness.

Various laboratories are using different mouse models, iike the human chimeric mouse which acts as a surrogate for propagating human cells that allow HIV to multiply, or for multiplying murine AIDS virus, or virus of RauscheMs leukaemia, all of which are closely related to, and form variants of the retroviruses, and may produce the same/similar basic information of their potential for evaluating anti-HIV agents for final applicationitreatment in AIDS.

As mentioned already, we had worked on a mouse model infected with transplantable tumour (Ehrlich ascites cell tumour) caused by a mouse retro-virus (RV)'4 Using this model, we found the piperazine type H,-antagonist denvatives possessed remarkable anti-tumour and anti-H IV actions. We found, in addition, that ciprofloxacin, when used in combination with the former, exhibited significant synergistic activity. However, action of these drugs including ciprofloxacin on HIV, singly and jointly remained unknown before our search/research, and so far ,we explain, reports on such action have not been published to date.

There is no information on antiretroviral activity of ciprofloxacin cn the reverse transcriptase of HIVs.

Relevant information from our studies shows that the action of a piperazinetype antihistamines derivative can be potentiated by other compounds like Ciprofloxacin, hence a combination study is indicated.

It appeared worthwhile to evaluate both these drugs in intact animal model(s), as well as in cell culture systems against HIV.

In summary, despite most intensive research to find and induct an effective anti-HIV drug(s) all over the world, until today, there are really no effective/curative drugs against the HlV and AIDS disease. Thus, a new and radical approach was required. Having analysed the piffalls of the existing approaches, we formed the view that existing classes of drugs whose use is tried and tested for other conditions may also possess affinity to bind to the DNA and/or RNA at the molecular level in an irreversible manner, and also critically interfere with major enzymes that are invoived in replication of the DNA/RNA, thereby halting any further formation of infectious HlV-copies, and also act as virostatic agents in synergistic combination.

It is hypothesised that chlorcyclizine is capable of disrupting the envelope layer of HIV, singly/jointly with ciprofloxacin thereby exerting powerful virucidal effects The compounds identified herein on theoretical as well as tactical grounds fulfil the requirements for an effective treatment in a way which no other compound(s) has been known to have when used against HIV in AIDS.

We were caught by the imagination of a striking structural and functional homology between the retroviruses including the HIV, and the widely prevalent predatory molecular species present among microbes and also cells of hug her plants and animals, known as 'Transposons'. The Transposons provided the necessary working model for a resign of our drugs.

Description of the Inventions: DRUG (1) CHLORCYCLIZINE HCl : C18H21ClN2HCl (CCZ)

DRUG (2) CIPROFLOXACIN HCI (CFC)

The CCZ and OFO because of their structures and stereic configurations are likely to bind to DNA/RNA at different sites, possibly irreversibly. In vitro tests show mutagenic (teratogenic/antimetabolic) effects for both the drugs lending support to this theory.

Possible mode of action of CCZ CCZ is a tricyclic piperazine type H1-antagonist. It is hypothesised that CCZ, binds to pro-virus DNA of HIV(RV)/RNA by binding/stacking itself between G + C base pairs at multiple points. It may also interfere with the pro-virus synthesis by preventing reverse transcriptase and subsequent production of DNA polymerase, RNA synthesis and synthesis of proteins by 'large terminal repeats', and inhibit DNA gyrase. CCZ/CPZ may alter host cell permeability, and penetration and multiplication of the virus. In vivo we have discovered that there is an increase in survival of EACTS infected mice when treated with CCZ.

Possible modes of action of Ciprofloxacins: Ciprofloxacin (CFC) is a third-generation derivative of nalidixic acid which is a potent inhibitor of DNA synthesis. It acts by inhibition of bacterial DNA gyrase, and at higher concentrations, inhibits RNA synthesis.

There are no previous reports of this drug being used against viruses/HIV.

However, it is proposed that it may similarly act on HIV by inhibiting viral DNA gyrase as well as on the RNA-reverse transcriptase. Furthermore, it can act in conjunction with CCZ in binding to the retroviral RNA/provirus DNA, and thereby function as a virustatic drug, as well as a virucidal drug working in synergy with CCZ.

Thus, we have identified and discovered new therapeutic properties in each of the above classes of drugs. CCZ acts as virucidal drug as well as a virostatic drug against all the retroviruses including HTLV-I, HTLV-II, HIV-1, HIV-2 and SIV-1 causing human diseases, as well as diseases of monkeys, mice, cats, dogs, fowls and horses. CFC acts similarly in a synergistic manner when combined with CCZ as well as with existing anti-HIV drugs such as Zidovudine, DDI, protease inhibitors and have wide therapeutic applications in all the diseases due to retroviruses. These classes of drugs, and especially CCZ and CFC act as useful adjuvants being verustatic and virucidal drugs alone or in combination to existing therapies as well as being effective treatments in their own right.

The results show that two drugs, namely the CCZ and CFC may be highly suitable partners in exerting crucial anti-HIV effects, by binding at the different sites of DNA and RNA of the retroviruses/HIV and interfering with the enzymes that are essential for copying the virus units; they may chemically bind to each other as well as binding cc the HIV.

EXPERIMENTAL RESULTS Actual data on the efficacy of these drugs are shown below: Table 1 . Life span and survival of retrovirus induced Swiss white mice bearing EACT (Ehriich's Ascites Cell Tumour), following only CCZ treatment in acute experiment.

No. Animals Dose CCZ Mode Survival (days) % increase life mg/Mouse 7 injecs Range Median soan 36 (Control) 0 Saline 8-14 10 36 (Test) 1.2 (a) Alternate day 8-16 12 + 20 36 (Test) 1.2 (a) Every day 10-19 15 + 50 (a) Optimum dosage calculated after determination of LD p < C.C5 according to X test.

Table II: Life span and survival of retrovirus induced tumour (EACT) bearing mice following CCZ, CFC, or CCZ - CFC treatment in Subacute Experiments.

No. Of I Drug(s) Dosage Mode for | SURVVAL (days) Animals | | mg/Mouse | 14 days i Range Survivor Mean Survival 8 Saline Nil Daily 16-59 0 33 (Control) only 8 (Test) CCZ 1 Daily 20-52 > 95x5 > 71.5* 8 (Test) CFC 0.6 Daily 20-66 > 95x3 > 65.5** 8 (Test) CCZ + 1 + 0.6 Daily | 57-64 > 95x6 > 83.6*** CFC p, < 0.01, ** < 0.05, ***0.001, according to X text.

Survivor = [ < T/(C-1 x 100] according to Dasgupta and Lahiri, 1987 Conclusions The two drugs CCZ and CFC have not previously been used jointly/singly for treatment of AIDS, nor against retro-viruses. It has unexpectedly been discovered that they act as virustatic agents. It is proposed that they may act in a unique way by intercalating and binding to different active sites of the pro-virus DNA and the RNA of the HIV/RV, preventing their replication, and separation of the nucleic acid strands, and also interfere with the mechanisms of DNA/RNA synthesis and synthesis of viral enzymes that account for their repiication. Since together these drugs may act at a large number of points in nucleic acids and their enzymes, their success as anti-viral and anti-HIV agents seems to be confirmed. CCZ singly/jointly with CFC may disrupt the HIV envelope and acts as a virucidal drug. These drugs, therefore, need to be subjected to evaluation in human trials on the basis of results in tissue culture systems involving HIV/other retroviruses obtained by the inventors Up to this point despite periodic claims, there is no really effective drug(s) against HIV-1 to treat and cure AIDS disease. (Vide reports of Vancouver and Birmingham Congresses on AIDS). Therefore, any prospective new anti-retroviral and anti-HIV agents based on preliminary in vitro and cell-culture tests, and also in in vivo animal models, if found to be effective and not unduly toxic, ought to be examined for human trials with a view to their eventual application against AIDS.

CCZ has currently been withdrawn from the market because of its potential teratogenic effects. However, this should not affect its use as a treatment for AIDS in the male population as well as in pregnant and non-pregnant females. CCZ can easily cross the placental barrier and act on the HlV-infected foetus. The balance of advantages thus obtained being far greater than any remotely possibie teratogenic effects. CCZ can also be secreted into the mother's milk and thus help in the treatment of suckling new-borns. CCZ therefore still has the potential to be a successful anti-RV agent and a potential anti-HIV drug.

The second drug CFC is a derivative of nalidixic acid, but had not been ever known for its actions on virus/RV/HIV, until we demonstrated its activity in vitro in an animal model and later in the cell or tissue culture system as well.

We are quite confident that both classes of drugs, not only singly but also jointly are anti-RV agents and are likely to be highly effective against HIV for final use in AIDS patients. Both these classes of drugs are of generally low toxicity and have all the requisites for solubilisation in water, other solvents, are stable, and will tend to be used in single/multi-dose formulations in capsules, in dragees, or parental or other dispensable forms and dosages in acceptable manner to-humans, on a short/long term basis. Moreover, both these drugs can be manufactured in large bulk with high degree of punty in stable condition, and the cost of the product(s) will be quite reasonable for the consumers. The toxicity of these drugs is of low crder and the first drug will offer in addition, a means of amelioration of the symptom-complex of the AIDS patients, and psychologically stabilise them.

The administration of the compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof may be by way of oral or parenteral administration.

An amount effective to treat the disorders hereinbefore described depends on the relative efficacies of the compounds of the invention, the nature and severity of the disorder being treated and the weight of the mammal. However, a unit dose for a 70kg adult will normally contain 0.5 g to 2.59 of the compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof. Unit doses may be administered once or more than once a day, for example, 2, 3 or 4 times a day, more usually 1 to 3 times a day.

It is preferred that the compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof is administered in the form of a unit dose pharmaceutical composition in which it is combined with a pharmaceutically acceptable carrier.

Such compositions are prepared by admixture and are suitably adapted for oral or parenteral administration, and as such may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable and infusible solutions or suspensions or suppositories. Orally administrable compositions are preferred, since they are more convenient for general use.

Tablets and capsules for oral administration are usually presented in a unit dose, and contain conventional excipients such as binding agents, fillers, diluents, tabletting agents, lubricants, disintegrants, colourants, flavourings, and wetting agents. The tablets may be coated according to well known methods in the art, for example with an enteric coating.

Suitable fillers for use include cellulose, mannitol, lactose and other similar agents. Suitable disintegrants include starch, polyvinylpolypyrrolidone and starch derivatives such as sodium starch glycollate. Suitable lubricants include, for example, magnesium stearate.

Suitable pharmaceutically acceptable wetting agents include sodium lauryl sulphate. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel or hydrogenated adible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; nonaqueous vehicles (which may include edible oils), for example, almond oil, fractionated coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents.

Oral liquid preparations are usually in the form of aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs or are presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), preservatives, and flavouring or colouring agents.

The oral compositions may be prepared by conventional methods of blending, filling or tabletting Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are, of course, conventional in the art.

For parenteral administration, fluid unit dose forms are prepared containing a compound of the present invention and a steriie vehicle. The compound, depending on the vehicle and the concentration, can be either suspended or dissolved.

Parenteral solutions are normally prepared by dissolving the compound in a vehicle and filter sterilising before filling into a suitable vial or ampoule and sealing.

Advantageously, adjuvants such as a local anaesthetic, preservatives and buffering agents are also dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum.

Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilised by exposure of ethylene oxide before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate unifcrm distribution of the compound.

The present invention also provides the use of a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof in the preparation of a medicament for use in the treatment of viral infections in mammals, including hum

References 1. In vitro and in vivo antimicrobial activities of ambodryl and benadryl: Dastidar S.G, Sanyamat B and Chakrabarty A.N. Jour. Appl. Bacterial (UK) 41, 209 -215, 1976 2. Antibacterial property of promazine hydrochloride: Dash, S.K., Dastidar S.G. and Chakraoarty A.N. (India) 15 324 - 326, 1977 3. Antibiotic cross-resistance patterns or ambocryl and promazine resistant mutants: Roy. S., Dastidar, S.G. and Chakrabarty A.N. Brit. Jour. Exptl. Fathom (UK) 61, 461 - 466, 1980.

4. In vitro study of antimycobacterial activities of methyl-DOPA. Bhattacharya, C.P., Chakrabarty, A.N. and Dastidar, S.G. Indian J.~Med. Microbiol. (india) 6, 97 - 100, 1988 5. Antimicrobial property of metndilazine and its synergism with antibiotics and some chemotherapeutic agents: Chattopadhyay D., Dastidar, S.G. and Chakrabarty, A.N. Arzneimittel-Forschung/Drug Research (FGR) 38 869 - 872, 1988.

6. Antibacterial activity of local anaesthetics procaine and lignocaine: Dastidar, S.G., Das, S., Mukheriee, M., Chattopadhyay, D., Ray, S. and Chakrabarty, A.N.

Indian J. Med. Microbiol. (India) 87 506 - 508, 1988.

7. Drug interaction of some non-conventional antimicrobial chemotherapeutic agents with special reference to promethazine. Chakrabarty, A.N., Acharya, D.P., Niyogi, D.K. and Dastidar, S.G. Indian J. Med. Res. (India) 89, 233 - 237, 1989.

8. Effects of structural modifications on the antimicrobial actions of promethazine, methdilazine and related phenothiazines: Chakrabarty, A.N., Sen, Banerji, Chattopadhyay, D., and Dastidar, S.G., Proc 6th Intl. Conference on Thiazines and structurally related compounds: Editor-in-Chief Keyzer, H., Krieger Publ. Co., Florida, USA, 1993, pp 219 - 227.

9. Antibacterial activity spectrum of promethazine and interaction with several non-antibiotics. Chakrabarty, A.N., Bhettacharye, S., Chakrabarty, T. and Dastidar, S.G. Proc. 6th Int. Conference on Thiazines and structurally related compounds.

Editor-in-Chief, Keyzer, H., Krieger Publ. Co., Florida, USA, 1993, pp 133 - 139.

10. Studies on antimetabolic activity of chlorcyclizine, a structurally related phenothiazine: Dastidar, S.G., Mookerjee, M., Ganguly, M., and Chakrabarty, A.N.: Proc. 6th Int. Conference on Thiazines and structurally related compounds. Editorin-Chief, Keyzer, H., Krieger Pub. Co., Florida, USA, 1993, pp 171 - 178.

11. In vitro and in vivo antibacterial activity of the anti-inflammatory agent Diclofenac sodium: Dastidar, S.G., Basu, S., Annadurai, S., and Chakrabarty, A.N.: Antimicrob. Chemother. (USA) 1994, pp 339 - 340.

12. Antimicrobial activity of methdilazine (Md), an antimicrobic phenothiazine: Chakrabarty, A.N., Bhaltacharya, C.P., and Castidar, S.G. Acta. Path. Microbiol.

Immunol. Scandinav. (Denmark) 101, 449 - 454, 1993.

13. In vitro and in vivo antimicrobial action of fluphenazine. Dastidar, S.G., Chaudhury, A, Annadurai, S., Roy, S., Mookerjee, M., Chakrabarty, A.N. Jour.

Chemoth. (Italy) 1 June 1995.

14. Exploring carcinogenesis with retro-viruses. Bishop, J.M., In Proc. Sympo. of Soc. Gen. Microbiol., 36 (Part I) The Microbe 1984, eds. B.W.J. Mahy and J.R.

Pattison: I 9(ruses Camb. Univ. Press, UK.

Claims (19)

1. CLAIMS 1. The use of a piperazine-type H,-antagonist or pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of viral, retroviral or HIV infections.
2. 2. A use according to Claim 1 wherein the piperazine-type H1-antagonist has a general formula I:

   wherein R is hydrogen, Cn 7 alkyl, CH2CHi20CH2CO2H, CH2CH20CH2CH20H or OH2 - CH = CH - C6H5; and wherein R, and R2 are independently selected from phenyl optionally substituted by one or more halogen atoms.
3. 3. A use according to Claim 1 or Claim 2 in which the H1-antagonist has a general formula I: wherein R is methyl; R1 is phenyi and R2 is a phenyl group substituted in the para-position with a halogen atom.
4. 4. A use according to any of Claims 1 - 3 wherein the H-antagonist is Chlorcylizine
5. 5. The use of a Nalidixic acid-type antimicrobial agent or pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of viral, retroviral or HIV infections.
6. 6. A use according to Claim 5 wherein the Nalidixic acid-type antimicrobial agent has a general formula II:

   wherein R1 is hydrogen, C1-4 alkyl, cyclopropyl; and wherein R2 is hydrogen or Ci alkyl; and wherein R3 is a halogen atom
7. 7. A use according to Claim 5 or Claim 6 in which the Nalidixic acid-type antimicrobial agent is Ciprofloxacin.
8. 8. The use of a combination of a piperazine-type H1-antagonist and a Nalidixic acd-type antimicrobiai agent or pharmaceutically acceptable salts thereof for the manufacture of a medicament for the treatment of viral, retroviral or HIV infections.
9. 9. A use according to Claim 8 comprising a combination cf piperazine-type H1- antagonist as claimed in Claim 2 and a Nalidixic acid-type antimicrobial agent as claimed in Claim 6.
10. 10. A use according to Claim 8 or Claim 9 wherein the compounds consist of chlorcyclizine and ciprofloxacin.
11. 11. A use according to Claim 10 wherein the combination comprises the chlorcyciine salt of ciprofloxacin.
12. 12. The use of a combination of a piperazine derivative of general formula

    wherein R is hydrogen, C1 , alkyl, substituted alkyl, CH2CH2OCH2CO2H,CH2CH2OH, or CH2 - CH = CH - C6H5 optionally carrying one or more halogen atoms as substituents, and wherein R1 and R2 are independently selected from alkyl, aryl, substituted aryl, aralkyl and hetero aryl groups optionally carrying one or more halogen substituents., and a Nalidixic acid-type antimicrobial agent having general formula II

    wherein R1 may be hydrogen, C14 alkyl, cycloalkyl5, CH2CH2F, phenyl, substituted phenyl, aminoalkyl and alkoxy; R2 represents hydrogen, C1.4 alkyl, and R3 is selected from halogen, alkyl, substituted alkyl, aryl, substituted aryl, aralkyl and hetero aryl groups optionally carrying one or more halogen atoms as substituents or haloalkenyl radical of formula CH, - CH = CH.CH X, in which Xis hydrogen or halogen and Y is hydrogen, halogen or C1 4 alkyl, with the proviso that both X and Y are not hydrogen or pharmaceutically acceptable salts of compounds of general formulae I and II, optionally in the presence of at least one anti-HIV drug, for the manufacture of a medicament for the treatment of viral, retroviral or HIV infections, and diseases arising therefrom.
13. 13. A use as claimed in Claim 12, wherein the piperazine derivative is a piperazine-type H-antagonist of formula I in which R is hydrogen or C14 alkyl and Rl and R2 each stands for phenyl group optionally substituted by one or more halogen atoms.
14. 14. A use as claimed in Claim 12 or 13, wherein the piperazine-type Hl- antagonist is of general formula I in which R is methyl, R, is phenyl and R, is a phenyl group substituted in the para position by a halogen atom.
15. 15. A use as claimed in any of Claims 12 to 14, wherein the Hl-antagonist is chlorcyclizine or pharmaceutically acceptable salt thereof (ClsHr,Cl N2.HCI).
16. 16. A use as claimed in Claim 12, in which the Nalidixic acid-type antimicrobial agent is ciprofloxacin (CFC) or pharmaceutically acceptable salt thereof.
17. 17. A use as claimed in any of Claims 12 to 16, wherein the compounds consists of chlocyclizine and ciprofloxacin.
18. 18. A use as claimed in Claim 17, wherein the combination comprises both the chlorcyclizine and ciprofloxacin, bound together as a salt.
19. 19. The use of compounds as herein described for the manufacture of a medicament for the treatment of viral, retroviral or HIV infections, and diseases arising therefrom.