WO1991016907A1

WO1991016907A1 - Improvements in chemical compounds

Info

Publication number: WO1991016907A1
Application number: PCT/GB1991/000731
Authority: WO
Inventors: Michael Jeffrey Abrams
Original assignee: Johnson Matthey Public Limited Company
Priority date: 1990-05-08
Filing date: 1991-05-08
Publication date: 1991-11-14
Also published as: PT97609A; AU7854091A; IL98083A0; ZA913504B; IE911559A1

Abstract

Niobates containing the Nb6O19 group, eg K7H[Nb6O19], have been found to be active against viruses such as HIV and CMV, in in vitro tests. The invention provides pharmaceutical compositions containing the niobates.

Description

IMPROVEMENTS IN CHEMICAL COMPOUNDS

This invention concerns improvements in chemical compounds, more especially it concerns pharmaceutical compositions. In particular it concerns compositions and compounds having activity in iji vitro tests on Human Immunodeficiency Virus-infected cells.

The disease known as Acquired Immune Deficiency Syndrome (AIDS) caused by infection by HIV has attracted immense research effort because of the effects of the disease on infected individuals and the dangers of the disease spreading to a wider section of the population. In general, although various chemo-therapeutic treatments have been advocated, and some compounds have emerged as a potential basis for treatment, there is still a need for alternatives. In particular, most treatments such as the compound known as AZT have a high toxicity to cells, and it would be desirable to find compounds which are less toxic. We have found a group of compounds which show interesting properties in ill vitro screens of human cells challenged with HIV-1 and/or HIV-2, and are therefore indicated as having potential for the treatment of AIDS and AIDS Related Complex. Accordingly, the present invention provides the use of compounds defined below, in pharmaceutical compositions for treating viral-infected patients. The invention further provides pharmaceutical compositions comprising a said compound in combination or association with a pharmaceutically acceptable carrier, diluent or excipient, for the treatment of viral-infected patients. The invention may also be defined as the use of a said compound for the manufacture of a medicament for the treatment of viral-infected patients. The invention further provides a process for the production of a pharmaceutical composition for the treatment of a viral-infected patient, comprising the combination of a compound as defined below with a pharmaceutically acceptable carrier, diluent or excipient, and formulating said composition into a form suitable for adminstration to said patient. The invention also provides a method of treatment of an viral-infected patient, comprising administering to said patient an effective dose of a said compound. It is to be understood that treatment includes prophylactic treatment of patients at risk, in view of the protective properties observed. Heteropolyanions such as heteropolytungstates are generally known, and reference is made to "Comprehensive Coordination Chemistry" Eds G Wilkinson et al, Pergamon 1987, vol 3 chapter 38. These compounds appear to be of essentially academic interest and not to have achieved any use in commerce. GBP 1,385,489 in the name of ANVAR states that certain of these compounds are useful in the formation of therapeutic preparations for the inhibition of the development of viruses which propagate by budding on the suface of infected cells. Typical of such viruses are stated to be leukemogenic and sarcomagenic viruses, rubella virus, vesicular stomatis virus and Myxoviruses and Paramyxoviruses including Rhinovirus. It is not believed that those compounds have been commercialised for the treatment of virus infections, nor is it believed that there has been any suggestion that any of the compounds could have activity against HIV. Certain of the compounds of the classes disclosed in said GBP do not appear to demonstrate selectivity against HIV-infected cells.

It has been suggested, in JP 64-38,022, that certain salts of heteropolyacid ions of general formula

where X is an ion selected from Groups III to VI or transition metal, M is one to three species selected from Mo, W, Al, V, Nb, Ta, Co and Ti and P is a positive integer, exemplified by the two compounds

^K5^BW12°40 ^{and K}7^PW10^Ti2°40 ^{wh cn have} activity against herpes virus, could be expected to have activity against human retrovirus. We are not aware that any of these compounds have been studied for activity against HIV, nor that any of the compounds are being developed for such use. It has also been reported in Chemical and Engineering News, December 1986, that silicotungstate acid, H,SiW.„0,₀ has activity against HHI; this compound has, however, been abandoned because of its toxicity in higher animals.

We have now discovered certain isopoly and heteropolyniobates which exhibit not only activity against HIV in standard in vitro screening tests, but also a relatively low toxicity against cells.

There are also indications that the compounds have activity against cytomegalovirus.

The present invention provides as active compound for the various aspects of the invention, a compound selected from isopoly and heteropolyniobates of formula la, lb, Ic and Id

M₈ [Nb₆0₁₉] la

M [M^NbgO^] lb

wherein, M is a cation,

M is a trivalent or tetravalent transition metal ion,

1 2 L is a bidentate and L is a tridendate amine ligand,

1 y has the value 13 when M is trivalent and the value 12 when M is tetravalent, and z has the value 5 when M is trivalent and the value 4 when M is tetravalent. The compounds of the above formulae are generally known, and may be prepared as described in the literature. It is preferred that the compounds are readily soluble in water, and therefore, preferred cations are those that provide soluble compounds. Suitable cations may be selected from alkli metals, ammonium, H and quaternary ammonium, including protonated amino acids. Desired solubilities in water are greater than lmg in 1ml water.

Preferred metal ions M may be selected from Fe , Rh ,

Pt ⁺, Ni ⁺, Mn ⁺, Co and Pd ⁺. Ligand L may suitably be any 1, 2 bidentate amine ligand which may be a straight or branched chain or cyclic molecule. Examples of suitable ligands for use in the present invention are 1,2-diaminocyclohexane, 2,3-diaminobutane and 1,4,7-triazacyclononane.

It will be appreciated that the above-identified compounds are capable of existing in aqueous solution in a number of equilibrium states according to the prevailing conditions, and although the compounds may be readily isolated only in certain salt forms, the active species in a biological environment may not easily be determined or indeed may be made available from a number of apparently different materials. All such variations are included within the scope of the present invention.

Preferably, the compounds selected has a selectivity index as hereinafter defined in excess of 10, more preferably in excess of 50, for at least one of the HIV types. The invention is illustrated by the testing of the compounds as will be more particularly described hereinafter. It will be appreciated that there is no recognised in vivo test for anti-HIV activity; only humans develop AIDS and ARC from HIV infection. Also, tests for activity against other retroviruses in vivo cannot reliably be correlated with anti-HIV activity in humans.

The compounds were tested in a screen by the MTT method (J. Virol. Methods 120: 309-321 [1988]). MT-4 cells (2.5 x 10⁴ /well) were infected with HIV-1 (HTLV-IIIB) or HIV-2 (LAV-2 ROD) at a concentration of 100 CCID-.,*, and incubated in the presence of various concentrations of the test compounds, which were added immediately after infection with the virus. After 5 days culture at 37°C in a C0-, incubator, the number of viable cells was assessed by the MTT (tetrazolium) method. Antiviral activity and cytotoxicity of the compounds are expressed in Table 1 below as ^ED50 (ug/m¹-) and CDc_n (ug/ml), respectively. The potential therapeutic usefulness was assessed by calculating a Selectivity Index (SI) corresponding to the ratio of CD-.-, to ED-..,. A control test was performed using the compound HPA-23 (NaSbgW-,..0g,), known to be a reverse transcriptase inhibitor, and which has been used in clinical trials, and the known anti-HIV treatment AZT, and a number of comparison compounds were also run through the screen as detailed below. TABLE 1

It will be seen from the above results that the compounds of general formula I exhibit selective activity against HIV in infected cells, and their toxicity is much less than HPA-23. Although AZT has a selectivity index of 125, this is at a rather high toxicity.

The compounds according to the invention were tested against cytomegalovirus (CMV) in human embryonic lung (HEL) cells, according to standard methodology against two strains of CMV, and the results are shown in Table 2.

TABLE 2

Notes: N.A. - Not available; PFU = Plaque Forming Units

The additional activity against CMV, which may be considered as a member of the same group of viruses as Herpes, indicates that the compounds of the invention have an activity against enveloped-type viruses.

Compounds of particular interest for use in the various aspects of the present invention include K-,H[Nb,0.,o] , Na₁₂[Mn(Nb₆0₁₉)], a_?H[Nb₆0₁₉] and a₅ [(en)Co( b₆0₁₉)] where en represents ethylenediamine.

The active compounds as defined may be administered in the form of pharmaceutical compositions formulated according to well known principles and incorporating the compound, preferably in unit dose form, in combination with a pharmaceutically acceptable diluent or excipient. Such compositions may be in the form of solutions or suspensions for injection or for irrigation, or be in capsule, tablet, dragee, or other solid composition or as a solution or suspension for oral administration or formulated into pessaries or suppositories or sustained release forms of any of the above or for implantation. Suitable diluents, carriers, excipients and other components are known. It may be desirable also to formulate a composition for topical administration such as an ointment or cream. The compounds of the invention may be used, in the form of a composition or alone, and possibly supported on a finely divided carrier, as a coating on devices or articles which in use contact body fluids, to discourage transmission of viral infections. Examples of devices and articles to be considered in this aspect of the invention are surgical devices and gloves and contraceptives su..h as condoms, and other items, appliances, wound dressings and coverings, implements etc.

The pharmaceutical compositions according to the invention may contain unit dosages determined in accordance with conventional pharmacological methods, suitably to provide active compound in the dosage range in humans of from 0.1 to 100 mg/kg body weight per day, in a single dose or in a number of smaller doses. Preferred dosage ranges are 1 to 30 mg/kg body weight per day. Other active compounds may be used in the compositions or administered separately or supplemental therapy may be included in a course of treatment for a patient.

Claims

1. A pharmaceutical composition for the antiviral treatment of a patient, comprising an active compound selected from water soluble niobates of formula la, lb, Ic and Id,

Mg [ b₆0₁₉] la

M•i [M (Nb₆0₁₉)₂] lb

M_z [L¹M¹(H₂0)(Nb₆0₁₉)] Ic

wherein, M is a cation,

M is a trivalent or tetravalent transition metal ion,

1 2 L is a bidentate and L is a tridendate amine ligand, y has the value 13 when M is trivalent and the value 12 when M is tetravalent, and

I z has the value 5 when M is trivalent and the value 4 when M is tetravalent, in admixture with a pharmaceutically acceptable carrier, diluent or excipient.

2. A composition according to claim 1, wherein in the compounds of formula la, lb, Ic and Id, M is selected from alkali metals, ammonium, H+ and quaternary ammonium including protonated amino acids.

3. A composition according to claim 1 or 2, wherein in the compounds of formula la, lb, Ic and Id, M is selected from Fe , mRh* +, nPt.4+, N_τi-4+, Mn4+, „Co4+ and, _TP-.dJ4+.

4. A composition according to claim 1, 2 or 3, wherein the active compound is of formula la or lb.

5. A composition according to claim 4, wherein the active compound is selected from K₇H[Nb,0₁₉] and Na-₂[MnNb,0₁₉].

6. A composition according to any one of the preceding claims, in unit dosage form.

7. A composition as claimed in claim 6, wherein the unit dosage is such as to provide 0.1 to lOOmg of active compound per day, in a single dose or in a number of smaller doses.

8. A device or article treated to reduce the incidence of transmission of viral diseases and incorporating or coated with an active compound selected from niobates of formula la, lb, Ic or Id,

M₈ [Nb₆0₁₉] la

M [M¹(Nb₆0₁₉)₂] lb M_z [L¹M¹(H₂0)(Nb₆0₁₉)] Ic

M_z [L^^ bgO^)] Id wherein, M is a cation,

M is a trivalent or tetravalent transition metal ion,

1 2

L is a bidentate and L is a tridendate amine ligand, y has the value 13 when M is trivalent and the value 12 when M is tetravalent, and z has the value 5 when M is trivalent and the value 4 when M is tetravalent.