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IE911559A1 - Improvements in chemical compounds - Google Patents

Improvements in chemical compounds

Info

Publication number
IE911559A1
IE911559A1 IE155991A IE155991A IE911559A1 IE 911559 A1 IE911559 A1 IE 911559A1 IE 155991 A IE155991 A IE 155991A IE 155991 A IE155991 A IE 155991A IE 911559 A1 IE911559 A1 IE 911559A1
Authority
IE
Ireland
Prior art keywords
value
compounds
trivalent
tetravalent
formula
Prior art date
Application number
IE155991A
Original Assignee
Johnson Matthey Plc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Johnson Matthey Plc filed Critical Johnson Matthey Plc
Publication of IE911559A1 publication Critical patent/IE911559A1/en

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Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00Medicinal preparations containing inorganic active ingredients
    • A61K33/24Heavy metals; Compounds thereof

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Inorganic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

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 compounds, more especially it 5 In particular it concerns activity in in vitro tests on cells. concerns improvements in chemical concerns pharmaceutical compositions. compositions and compounds having Human Immunodeficiency Virus-infected Syndrome research infected a wider various and some The disease known as Acquired Immune Deficiency (AIDS) caused by infection by HIV has attracted immense effort because of the effects of the disease on individuals and the dangers of the disease spreading to section of the population. In general, although chemo-therapeutic treatments have been advocated, - 2 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 in 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. - 3 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 5 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 p_ salts of heteropolyacid ions of general formula (ΧΜ^θ^θ) 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 K5BW12°40 a°d K7PW10Ti2°40 which 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. - 4 It has also been reported in Chemical and Engineering News, December 1986, that silicotungstate acid, H^SiW^2®4Q Has activity against HHI; this compound has, however, been abandoned because of its toxicity in higher animals.
We have now discovered certain heteropolyniobates which exhibit not only activity standard in vitro screening tests, but also a toxicity against cells. isopoly and against HIV in relatively low There activity against are also indications cytomegalovirus. that the compounds have The present invention provides as active compound for the 15 various aspects of the invention, a compound selected from isopoly and heteropolyniobates of formula Ia, lb, Ic and Id M8 ^Nb6°19^ Ia My lMl6O19>2J lb 20 Mz [L1M1(H20)(Nb6019)] Ic Mz [iVdib^)] Id wherein, M is a cation, M1 is a trivalent or tetravalent transition metal ion, 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 is tetravalent, and 1 z has the value 5 when M is trivalent and the value 4 when is tetravalent. - 5 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 Mx may be selected from Fe , RhJ , Pt4+, Ni4+, Mn4+, Co^+ and Pd4+. Ligand may suitably be any 1, 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. - 6 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 10 (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^q 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 C02 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 Εϋ^θ (ug/ml) and (ug/ml), respectively. The potential therapeutic usefulness was assessed by calculating a Selectivity Index (SI) corresponding to the ratio of CD^q to Εϋ^θ. A control test was performed using the compound HPA-23 (NaSb^W^Og^)» 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. - 7 TABLE 1 Compound ®50 HIV-1 K°50 SICD50 HIV-2 ED50 SI Comparisons HPA-23 7.4 2.8 3 2.4 >4 <1 AZT (uM) >1 <0.008 >125 ND ND ND According to the Invention K7H[Nb6019] >1000 3.41 >293 >1000 3.31 >302 Na12[MnNb6O19] 596.3 5.69 105 571.1 9.97 57 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. - 8 TABLE 2 Compound Antiviral Activy(ID^Q ug/ml) Cytotoxicity CD50 ug/ml AD-169 Strain Davis Strain Na12[MnNbgO19] 12.71 12.50 N.A. 12.5 >200 K?H[Nb6019] 11.77 12.50 N.A. 11.67 >200 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 KyH[NbgO|p], Na12[Mn(NbgO^g)], NayH[NbgOjg] and Na^ [(enJCotNbgO^g)] 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 25 solutions or suspensions for injection or for irrigation, or be in capsule, tablet, dragee, or other solid composition or as a - 9 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 such 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 (9)

1. A pharmaceutical composition for the antiviral treatment 5 of a patient, comprising an active compound selected from water soluble niobates of formula Ia, Ib, Ic and Id, M 8 [Nb 6 0i 9 ] Ia M y IM 1 (Nb 6 O 19 ) 2 ] Ib 10 M z [LVdtjOXNbgO^)] Ic M z [L 2 M 1 (Nb 6 O 19 )] Id wherein, M is a cation, M is a trivalent or tetravalent transition metal ion, 1 2 15 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, 20 in admixture with a pharmaceutically acceptable carrier, diluent or excipient.
2. A composition according to claim 1, wherein in the compounds of formula Ia, Ib, Ic and Id, M is selected from alkali 25 metals, ammonium, H+ and quaternary ammonium including protonated amino acids. - 11 3. A composition according to claim 1 or 2, wherein in the 1 3+ compounds of formula Ia, lb, Ic and Id, M 1 is selected from Fe J+ , Rh^ + , Pt 4+ , Ni 4+ , Mn 4+ , Co 4+ and Pd 4+ . 54. A composition according to claim 1, 2 or 3, wherein the active compound is of formula Ia or lb.
3. 5. A composition according to claim 4, wherein the active 10 compound is selected from KyHlNb^O^g] and Na^[MnNbgO^gJ.
4. 6. A composition according to any one of the preceding claims, in unit dosage form. 15
5. 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.
6. 8. A device or article treated to reduce the incidence of 20 transmission of viral diseases and incorporating or coated with an active compound selected from niobates of formula Ia, lb, Ic or Id, M 8 [Nb 6 0 i9] Ia M y [M 1 (Nb 6 O 19 ) 2 J lb 25 M z [LVd^OXNbgO^)] Ic M z [L 2 M 1 (Nb 6 0 19 >] Id - 12 wherein, M is a cation, 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 is tetravalent, and z has the value 5 when is trivalent and the value 4 1 when M is tetravalent.
7. 9. A device or article treated to reduce the incidence of transmission of viral diseases substantially as hereinbefore
8. 10 described by way of Example.
9. A pharmaceutical composition for the antiviral treatment of a patient substantially as hereinbefore described by way of Example
IE155991A 1990-05-08 1991-05-08 Improvements in chemical compounds IE911559A1 (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US52055490A 1990-05-08 1990-05-08

Publications (1)

Publication Number Publication Date
IE911559A1 true IE911559A1 (en) 1991-11-20

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Application Number Title Priority Date Filing Date
IE155991A IE911559A1 (en) 1990-05-08 1991-05-08 Improvements in chemical compounds

Country Status (6)

Country Link
AU (1) AU7854091A (en)
IE (1) IE911559A1 (en)
IL (1) IL98083A0 (en)
PT (1) PT97609A (en)
WO (1) WO1991016907A1 (en)
ZA (1) ZA913504B (en)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2686515B1 (en) * 1992-01-28 1994-04-29 Ir2M USE OF NIOBIUM DERIVATIVES AS ACTIVE INGREDIENT OF MEDICINES USEFUL IN THE TREATMENT AND / OR PREVENTION OF CARBOHYDRATE AND / OR LIPID METABOLISM DISORDERS.
WO1993014772A1 (en) * 1992-01-28 1993-08-05 I. R. 2. M. Utilization of niobium derivatives as active principle of medicaments useful in the treatment and/or prevention of glucid and/or lipid metabolium troubles
CN112900097B (en) * 2021-01-21 2021-12-14 南通大学 Durable super-hydrophobic anti-ultraviolet cotton fabric and preparation method thereof

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3643001A1 (en) * 1986-12-17 1988-06-23 Daniel Albert Dubrulle Pharmaceutical composition
JP2993674B2 (en) * 1989-02-01 1999-12-20 利博 山瀬 Anti-acquired immunodeficiency syndrome virus agent

Also Published As

Publication number Publication date
PT97609A (en) 1992-02-28
AU7854091A (en) 1991-11-27
WO1991016907A1 (en) 1991-11-14
ZA913504B (en) 1992-03-25
IL98083A0 (en) 1992-06-21

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