PT97609A - A process for the preparation of a pharmaceutical composition for the treatment of cells infected with human immunodeficiency virus and a device or article treated with such composition. - Google Patents

Description

Description Referred to Johnson Matthey Public Limited Company Patent, British, Industrial and Commercial, Headquarters, Hatton Garden, London EGIU 8JP, England (Inventor: Michael J. Abrams, US Resident), " PROCESS FOR PREPARATION OF AN EARMAC & JIEIC COMPOSITION FOR THE TREATMENT OF CELLS STOCKS WITH HUMAN IMMUNODEFIOIKOIA VIRUS AND DEVICE Οϋ ARTICLE TREATED WITH THAT COMPOSITION '.

The present invention relates to improvements in a process for preparing chemical compounds, more particularly pharmaceutical compositions. In particular it relates to compositions and compounds which have in vitro assay activity on cells infected with the Human Immunodeficiency Virus. The disease known as Acquired Immune Deficiency Syndrome (AIDS) caused by HIV infection has attracted an immense research effort given the effects of the disease in infected individuals and the dangers of a disease spread to a larger section of the population. In general, it has% - 1 -

several chemotherapeutic treatments have been initiated, and some compounds have appeared as a potential base for treatment, but there is a need for alternatives. In particular, most treatments, such as the compound known as AZT, have a high toxicity to the cells and it would be desirable to find compounds that are less toxic. A group of compounds which exhibit interesting properties in in vitro scrutinies of human cells challenged with HI-1 and / or HIV-2 are disclosed and are thus reported to have a potential use for the treatment of AIDS and Related to AIDS. Accordingly, the present invention provides the use of the compounds to be defined in processes for the preparation of pharmaceutical compositions used in the treatment of patients infected with the virus. The invention further provides pharmaceutical compositions comprising one of said compounds in combination or combination with a pharmaceutically acceptable carrier, diluent or excipient, for the treatment of patients infected with the virus. The invention may also be defined as the use of one of said compounds in the preparation of a medicament for the treatment of patients infected with the virus. The invention further provides a process for the preparation of a pharmaceutical composition used in the treatment of a patient infected with the virus comprising the combination of a compound as defined below with a pharmaceutically acceptable carrier, diluent or excipient and the formulation of said compound composition in a form suitable for administration to said patient. The invention also relates to a method of treating a patient infected with the virus comprising administering to said patient an effective dose of one of said compounds. It is to be understood that the treatment includes the prophylactic treatment of patients at risk, in view of the protective properties observed. Heterocyanions such as

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heteropolitungstates and reference is made to " Gomprehensive Ooordination Chemistry " Ed. G-. Wilkinson et al., Pergamon 1987, vol 38, 38. These compounds appear to be of primarily academic interest and have not achieved any commercial use. The patent GBP 1 385 489 in the name of ANVAR states that some of these compounds are useful in the preparation of therapeutic compositions for inhibiting the development of viruses that propagate by building on the surface of the infected cells. Typical of these viruses are leukemogenic and sarcomagenic viruses, rubella virus, vesicular stomatitis virus and Mixovirus and Paramyxovirus including Rhinoviruses. These compounds are not believed to be marketed for the treatment of virus infections, nor is it thought that any suggestion of any of the compounds may have activity against HIV. Some of the compounds of the classes referred to in said GBP patent do not appear to demonstrate selectivity against HIY-infected cells.

It has been suggested in JP-A-64-38222 that certain heteropoly acids ions of formula (XM) in which X1 is selected from Group III and VI or a transition metal, M is one of three species chosen from Mo, W, 11, V, Nb, Ta, Oo and Ti and P is a positive integer, exemplified by the two compounds, which has an efficacy against the herpes virus, could also have activity against human retrovirus. It is not thought that any of these compounds have been studied for activity against HIV, nor that any of these compounds have been developed to be objective.

Also referenced in " Chemical and Engineering News " December 1986, that the silicon acid tartrate H 2 -SiW 12 40 has activity against HHI; this compound was, however, abandoned given its toxicity in higher animals.

It has now been found that certain isopoli and hetero-3-

polyniobates which exhibit not only activity against HIV in conventional in vitro screening assays but also relatively low anti-cell toxicity.

There are some indications that the compounds have cytomegalovirus activity. The present invention provides as an active compound for the various aspects of the invention a compound selected from isopropionic and heteropolyniobates of formula Ia, Ib, le and Id

Mg

My ZV (Nb60lg) 2_7 Ib

(H 2 O) (Nb 6019)

Mz Id in which M is a cation, Μ 1 and an ion of a trivalent or tetravalent transition metal, ΙΓ * is a bidentate and 1? and a trivalent amine linker is trivalent and the value is trivalent and the value 4 is 13 when M 'is when M is tetravalent, and z is 5 when M is tetravalent.

The compounds having the above formulas are generally known, and can be prepared as described in the literature. It is preferred that the compounds are readily water soluble, and therefore, the preferred cations are those which provide soluble compounds. Suitable cations may be selected from alkali metals, ammonium,

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H + and quaternary ammonium, including protonated amino acids. The desired solubilities in water are greater than 1 mg in 1 ml of water. w, η

Preferred metal ions M may be selected from Ee4 +, Bh4 +, Pt4 +, Ni4 +, Mn4 +, Q2 + and Pd2 +. The ligand may suitably be any amine 1,2-benzene linker which may be a straight or branched chain or cyclic molecule. Examples of binders suitable for use in the present invention are 1,2-diaminocyclohexane, 2,3-diaminobutane and 1,4,7-triazacyclononane.

It should be noted that the above-identified compounds are likely to exist in the form of α-choses solutions at various states of equilibrium according to prevailing conditions, and although the compounds can readily be isolated only in certain salt forms, active in a biological environment may not be readily determined or in fact may be made available from a number of apparently different materials. All such variations are included within the scope of the present invention,

Preferred compounds preferably have a selectivity index as defined herein greater than 10, more preferably greater than 50, for at least one of the HI 7 types. The invention is illustrated by testing the compounds as will be more particularly described below. It should be noted that there is no recognized in vivo assay for the determination of the anti-HIV activity; only humans develop AIDS and ARC diseases from HIV infection. In addition, assays of activity against other in vivo retroviruses can not be readily correlated with anti-HIY activity in humans.

The compounds were assayed in a MTT method (J. Yirol, Methods 120, 309-321, 2, 988). MT-4 cells (2.5 x 10V) were incubated with HIV-1 (HTLY-IIIB) or HIY-2 (LAV-2 ROD) at a concentration of 100 CCIDj and were incubated. in the presence of various concentrations of the test compounds, which were added immediately after infection with the virus. After a 5 day culture at 37 ° C in a CO 2 incubator, the number of viable cells was assessed by the MTT (tetrazolium) method. The antifungal activity and cytotoxicity of the compounds are set forth in Table 1 below as values of EBβ -q (pg / ml) and CBβQ (μg / ml) respectively. Potential therapeutic usefulness was assessed by calculating the index of Selectivity (IS) was determined based on the ratio of CD50 to ED50. A control assay was performed using the compound HPA-23 (NaSb9W21086), known as a reverse transcriptase inhibitor, which was used in clinical trials, and treatment with known anti-HIY AZT, and several comparison compounds were also used in the scrutiny as is detailed below.

Compound HIY-1 HIY-2 CD50 EI) 50 SI H co 0 O 0 Comparisons HPA-23 7.4- 2.8 3 2.4 &gt; 4 <1 ΑΖΤ (μΜ) &gt; 1 <0.008> 125 with the Invention ΚγΗ / &quot; m6olg_7> 1000 3.41> 293> 1000 3.31> 302 Na12rMnNb6019_7 596.3 5.69 105 571.1 9.97 57

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η

It can be seen from the above results that compounds of general formula I exhibit selective activity against HXY in infected cells, and their toxicity is much lower than that of HPA-23. Although AZT has a selectivity index of 125, this is achieved with very high toxicity.

The compounds prepared according to the present invention were tested against cytomegalovirus (CVM) in human embryonic lung (HEI) cells according to a standard methodology against two strains of CMY, and the results obtained are shown in Table 2 TABLE 2

Compound Antiviral Activity (IB50 pg / ml) Cytotoxicity CD50 Âμg / ml Strain AB-169 Davis Strain η & 12 / &quot;, 12.91 12.50 N.A. 12.5 &gt; 200 Âμg / ml 19.7 11.77 12.50 F.A. 11.67 &gt; 200

Eotas: N.A. - not available; PMJ * Plaque-forming Units Additional activity against CMV, which can be considered as a member of the same group of Herpes viruses, indicates that the compounds of the invention have an eon-

if virus type envelope.

Compounds of particular interest for use in the various aspects of the present invention include Na 12 Mn (Hb 6019) 7, N 4 H 3 -Hbg 19 19 and Na 2 - (en) O (Nb 2 Og) 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 a limited dosage form, in combination with a pharmaceutically acceptable excipient or excipient. Such compositions may be in the form of solutions or suspensions for injection or irrigation, or may be in the form of a capsule, tablet, dragee, or other Bolida composition or as a solution or suspension for oral administration or may be formulated in the form of pessaries or suppositories with sustained release forms of any of the above-mentioned compounds or for implantation. Suitable diluents, carriers, excipients and other components are known. It may also be desirable 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 isolates, and possibly supported on a finely divided carrier, or as coating on devices or articles that are in contact during use with body fluids, to prevent transmission of viral infections . Examples of devices and articles to be considered in this aspect of the invention are surgical and contraceptive gloves and devices such as condoms, and other dressings, applications, dressings and dressings for wounds, implements, etc.

The pharmaceutical compositions according to the invention may contain dosage units determined according to conventional pharmacological processes, suitably

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Claims (1)

to provide the active compound in the human dosage range of 0.1 to 100 mg / kg body weight per day in a single dose or in a few smaller doses. Preferred dosage ranges are 1 to 30 mg / kg of body weight per day. Other active compounds may be used in the compositions or administered separately or as supplementary therapy in the course of treatment of a patient. A process for the preparation of a pharmaceutical composition for the antiviral treatment of a patient in the form of a dosage unit, characterized in that a compound selected from water-soluble niobates of the formulas Ia , Ib, Ic and Id M8 Z &gt; 6019_7 Ia My Ib / (ii) Hg019 (Hbg019) Ic mz Id where M is a cation, M is a trivalent or tetravalent transition metal, L1 is a binder of amino-bidentate and a tridentate, and has the value of 13 when M1 is trivalent and the value 12 when tetravalent Μ I, and z has 5 when ΜΓ is trivalent and 4 when Mx • is tetravalent, in combination with a pharmaceutically acceptable carrier, diluent or excipient, wherein the dosage unit form is provided such that 0.1 to 100 mg of active compound per day is provided in a single dose or in several smaller doses. - 2* - A process according to claim 1 wherein in the compounds of formulas Ia, Tb, Ic and Id, M is selected from alkali metals, ammonium, H + and quaternary ammonium including protonated amino acids. 3. A process according to claim 1 or 2, characterized in that in the compounds of the formulas Ia, Ib, Ie and Id, Μ &quot; be chosen from Pe2 +, Rh2 +, P2 +, Ni4 +, Mn4 +, Co4 + and Pd4 + t4 + A process according to claim 1, 2 or 3 characterized in that the active compound is of the formula Ia or Tb. - 5 &amp; A process according to claim 4, characterized in that the active compound is selected from N, N'-ClO 2, and Na 12 / Mn Ng 2 O 3. A device or article treated to reduce the incidence of transmission of viral diseases characterized by incorporating or being coated with an active compound selected from water soluble niobates of the formulas Ia, Xb, Ic and Id, M8 ^ Nl36019- ^ Ia and ^ cWz-? Wherein M is a cation, M is a trivalent or tetravalent transition metal ion, 1, 2, and a Mdentate amino linker and I is a tridentate, and has the value of 13 when Μ is trivalent and the value 12 when M is tetravalent, and z is 5 when M is trivalent and 4 when tetravalent. The applicant claims the priority of the U.S. patent application filed May 8, 1990, under serial number 07 / 520,554. * Lisbon, May 8, 1991 - 11 -