WO1994004139A1 - Traitement d'infections virales chez l'homme - Google Patents

Traitement d'infections virales chez l'homme Download PDF

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Publication number
WO1994004139A1
WO1994004139A1 PCT/US1993/007879 US9307879W WO9404139A1 WO 1994004139 A1 WO1994004139 A1 WO 1994004139A1 US 9307879 W US9307879 W US 9307879W WO 9404139 A1 WO9404139 A1 WO 9404139A1
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substituted
group
unsubstituted
hydrogen
hydroxy
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PCT/US1993/007879
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English (en)
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WO1994004139A9 (fr
Inventor
Arthur B. Pardee
Jia-Qiang Li
Clyde Crumpacker
Lin Zhang
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Dana Farber Cancer Institute
Beth Israel Hospital
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Publication of WO1994004139A1 publication Critical patent/WO1994004139A1/fr
Publication of WO1994004139A9 publication Critical patent/WO1994004139A9/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid

Definitions

  • the human immunodeficiency virus type 1 (HIV-1, also referred to as HTLV-III LAV or HTLV-III/LAV) and, to a lesser extent, human immunodeficiency virus type 2 (HIV-2) is the etiological agent of the acquired immune deficiency syndrome (AIDS) and related disorders.
  • AIDS acquired immune deficiency syndrome
  • Both HIV-1 and 2 share a similar structural and function genomic organization, having regulatory genes such as tat, rev, nef. in addition to structural genes such as env. gag and pol. hile AIDS, itself, does not necessarily cause death, in many individuals the immune system is so severely depressed that various other diseases (secondary infections or unusual tumors) such as herpes, cytomegalovirus, Kaposi's sarcoma and Epstein-Barr virus related lymphomas among others occur, which ultimately results in death. These secondary infections may be treated using other medications. However, such treatment can be adversely affected by the weakened immune system. Some humans infected with the AIDS virus seem to live many years with little or no symptoms, but appear to have persistent infections.
  • PDL persistent generalized lymphadenopathy syndrome
  • ARC AIDS related complex
  • LTR long terminal repeat
  • phorbol 12-myristate-13-acetate (PMA) and Tumor Necrosis Factor- ⁇ (TNF ⁇ ) are believed to be potent activators.
  • NF is present in markedly enhanced levels in HIV infected individuals, suggesting that the cytokine plays an important role in the pathogenesis of AIDS. Lahdevirta, J., Am. J. Med.. 15:289-291 (1988).
  • X is a bond or a hydrogen
  • R is selected from the group consisting of hydroxy and substituted alkylene
  • Ri through R5 are each independently selected from the group consisting of hydrogen, hydroxy, halogen, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstitued alkynyl, a heteroatom such as N, 0, S, and substituted and unsubstituted heteroalkyl.
  • the carbon-carbon double bond of a compound of formula I has a trans configuration.
  • compounds of the following formula IA are used for purposes of the present invention including for use ⁇ ⁇ - treating cells infected by immunodeficiency viruses, preferably human immunodeficiency viruses such as HIV:
  • n is an integer from 1 to 20
  • X and X' are each independently selected from the group of a bond or a hydrogen
  • R-. through Re are the same as defined above in formula I
  • Rg through R- ⁇ Q are each independently selected and defined as said ⁇ through R5.
  • n is from 1 to 4, and more preferably n is one.
  • a specifically preferred compound is curcumin.
  • the present invention includes use of compounds of formula IA where one or both of the carbon-cari: in double bonds are of a trans configuration as well as where one or both of the carbon-carbon double bonds are of a cis configuration. Compounds of formula IA where both the above depicted double bonds are of a trans configuration are generally more preferred.
  • the compounds of the present invention can reduce or inhibit expression of genes operably linked to the LTR of an immunodeficiency virus such as HIV.
  • the compounds of the present invention can treat cells infected acutely and chronically by immunodeficiency viruses, for example, HIV, preferably HIV-1, and thus can be used to treat humans infected by HIV.
  • immunodeficiency viruses for example, HIV, preferably HIV-1
  • These compounds can be used against a different target than the conventional drugs being used to treat humans infected by HIV, e.g., reverse transcriptase inhibitors such as zidovudine (AZT) , 2' ,3' -dideoxyinosine (ddl) and 2' ,3' -dideoxycytidine (ddC) .
  • reverse transcriptase inhibitors such as zidovudine (AZT) , 2' ,3' -dideoxyinosine (ddl) and 2' ,3' -dideoxycytidine (ddC) .
  • the present compounds should be effective in cells that are resistant to such compounds.
  • compounds of the present invention can be used to block HIV-1 LTR directed expression in AZT resistant cell lines.
  • the invention also provides pharmaceutical compositions comprising a compound of formula I or IA and a suitable carrier therefor for use in the conditions referred to above.
  • Figure 1 shows the inhibitory effects of curcumin (varying concentrations) on TNF ⁇ and PMA induced HIV LTR directed gene expression.
  • Figure 2 shows the inhibition of HIV-1 replication by curcumin (varying concentrations) in acutely infected human peripheral blood mononuclear cells.
  • R is selected from the group consisting of hydroxy and a substituted alkylene group, e.g., an alkylene group having from 1 to about 15 carbon atoms, more preferably from about 1 to 8 carbon atoms, still more preferable from 1 to about 4 carbon atoms.
  • the substituents of said alkylene group suitably may be, for example, halogen such as fluoro, chloro or bromo, alkyl such as alkyl having from 1 to about 12 carbon atoms or from 1 to 6 carbon atoms, alkenyl such as alkenyl having from 2 to 10 carbon atoms or 2 to 6 carbon atoms, alkynyl such as alkynyl having from 2 to about 10 carbon atoms or from 2 to 6 carbon atoms, aryl (including both substituted and unsubstituted aryl) having from 6 to 10 carbon atoms, and N, 0, S, including heteroalkyl, e.g., heteroalkyl having one or more of said hetero atoms and from 1 to 10 carbon atoms or from 1 to 6 carbon atoms.
  • halogen such as fluoro, chloro or bromo
  • alkyl such as alkyl having from 1 to about 12 carbon atoms or from 1 to 6 carbon atoms
  • alkenyl
  • R3. -R4 a n R*- are each independently selected from the group consisting of hydrogen, hydroxy, halogen, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, a heteroatom such as N, 0, S, and substituted and unsubstituted heteroalkyl.
  • Alkyl ring substituents suitably have from 1 to about 10 carbon atoms, more preferably 1 to 6 carbon atoms.
  • Alkenyl and alkynyl phenyl ring substituents suitably have from 2 to about 10 carbon atoms, preferably 2 to 6 carbon atoms.
  • Heteroalkyl ring substituents include groups containing one or more hetero atoms linkages and from 1 to about 15 carbon atoms, or from 1 to 8 carbon atoms.
  • Preferred heteroalkyl ring substituents are alkoxy, aminoalkyl and thioalkyl groups where the specified heteroatoms is bonded to the aromatic ring and the substituents contain one or more carbon atoms, for example, 1 to about 10 carbon atoms, more preferably from 1 to about 4 carbon atoms.
  • Said substituted RT through Re groups may be substituted at one or more available positions by one or more available groups such as, for example, alkyl groups such as alkyl groups having from 1 to 10 carbon atoms or from 1 to 6 carbon atoms, alkenyl groups such as alkenyl groups having from 2 to 10 carbon atoms or 2 to 6 carbon atoms, substituted and unsubstituted aryl groups having from 6 to 10 carbon atoms, halogen such as fluoro, chloro and bromo, and N, 0 and S, including heteroalkyl, e.g., heteroalkyl having from one or more of N, 0 and/or S linkages (and thus including alkoxy, aminoalkyl and thioalkyl) and from 1 to 10 carbon atoms or from 1 to 6 carbon atoms.
  • alkyl groups such as alkyl groups having from 1 to 10 carbon atoms or from 1 to 6 carbon atoms
  • alkenyl groups such as alkenyl groups having from
  • ring is at least mono-substituted, i.e., at least one of RT through R5 is other than hydrogen.
  • the phenyl ring suitably may be substituted by more than one group other than hydrogen, for example, di- or tri-substituted by groups other than hydrogen. Hydroxy and lower alkoxy such as methoxy and ethoxy are particularly preferred substituents on the phenyl ring.
  • hile compounds having the precise structure of formula I where the double bond is conjugated with the phenyl ring are preferred, as the terms are defined herein compounds coming within formula I include structurally related compounds, including those compounds where the depicted carbon-carbon double bond is migrated to an adjacent carbon, e.g. , the compounds of the below structure where the group R and the ring substituents R-. through R ⁇ are the same as defined above for formula I:
  • Such a structure may exist, e.g., where the substituent R stabilizes the depicted double bond such as by conjugation and/or intramolecular hydrogen bonding.
  • n is an integer suitably from 1 to about 20
  • X and X' are each independently selected from the group of a chemical bond (i.e., forms a carbonyl group) and a hydrogen
  • R- ⁇ through R5 are the same as defined above in formula I
  • Rg through R-JQ are each independently selected from the group consisting of those groups set forth above to define R-. through 5 above, namely, hydrogen, hydroxy, halogen, heteroatom of N, 0, or S, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, and substituted and unsubstituted heteroalkyl.
  • n of formula IA is a value of from 1 to 4, and more preferably n is one.
  • those compounds of formula IA where one or both of the phenyl rings are at least mono-substituted, i.e. at least one of the substituents Ri through RI Q is other than hydrogen. Further preferred is where both of said depicted rings are at least mono-substituted by a group other than hydrogen.
  • One or both of the phenyl rings may be substituted by more than one group other than hydrogen, for example, di- and tri-substituted by groups other than hydrogen. Hydroxy and lower alkoxy such as methoxy and ethoxy are particularly preferred ring substituents.
  • each of the above depicted phenyl rings has at least one hydroxy group and at least one alkoxy group such as methoxy or ethoxy.
  • Meta and para ring positions are generally preferred positions for substitution of a group other than hydrogen, and more preferred is substitution of a hydroxy group at a para position and an alkoxy group such as methoxy or ethoxy at a meta position.
  • compounds coming within formula IA include structurally related compounds, including those compounds where one or more of the depicted carbon-carbon double bonds or carbonyl groups is migrated to an adjacent carbon, e.g. , compounds of the following formula IB where the ring substituents R- ⁇ through R- ⁇ Q are the same as described above for formula IA and n is an integer of a value of zero or greater:
  • the aryl groups of such diaryl compounds are suitably ring substituted with groups such as specified for substituents R ] _-R ] _o ⁇ n re f erence to formula IA above.
  • Curcumin has been used as a food additive for years. Curcumin was isolated in nineteenth century and has been identified as an active component of tumeric, the ground dried thizome of the plant Curcuma Longa Linn. See, Ammon. H.P.T., et al., Pharmacology of Curcuma Longa, Planta Med.. 57. 1-7 (1991). Satoskar, R.R. , International Journal of Clinical Pharmacology, 24, 651-654 (1986); Flynn, D.L. , Prostaglandins Leukotrienes and Medicine. 22:357-360 (1986); Mukhopadhyay, A., et al., Agents and Actions.
  • the compounds of the present invention provide effective therapy of chronically infected cells (i.e. cells infected by a virus which is an immunodeficiency virus such as FIV, SIV, HIV, etc.) as evidenced by a reduction in, preferably a complete repression of, e.g. HIV LTR directed gene expression.
  • a gene operably linked to the HIV LTR preferably the gene is operably linked to an HIV-1 LTR.
  • the term operably linked means that the gene is under the control of the HIV LTR and positioned in a nucleotide sequence to accomplish this.
  • the gene is downstream of the LTR, which acts as a promoter.
  • the gene corresponds to a viral gene such as the HIV env gene, HIV tat gene, HIV rev gene, etc.
  • the present invention can be used in treating those diagnosed as having AIDS as well as those having ARC, PGL and those seropositive but asymptomatic patients.
  • a preventative it can also be used prophylactically as a preventative for high risk individuals.
  • Compounds of the present invention can be used to treat cells, especially mammalian cells and in particular human cells, infected by an immunodeficiency virus such as HIV infected cells.
  • an immunodeficiency virus such as HIV infected cells.
  • viral expression is significantly reduced.
  • HIV viral expression can be studied by a number of methods such as looking at the expression of a marker gene, e.g. CAT, LacZ, etc., operably linked to the HIV LTR, which acts as the promoter.
  • a marker gene e.g. CAT, LacZ, etc.
  • Use of the present compounds such as curcumin can significantly reduce expression of such a marker.
  • HIV viral expression is turned on and enhanced by HIV LTR stimulators such as tumor necrosis factors -a (TNF ⁇ ) or phorbol 12-myristate-13-acetate (PMA) .
  • TNF ⁇ tumor necrosis factors -a
  • PMA phorbol 12-myristate-13-acetate
  • One product of this expression, i.e. tat can further augment such viral expression.
  • a marker gene such as LacZ operably-linked to the HIV LTR in HIV infected cells
  • the addition of an effective amount of compounds of formula I significantly inhibits expression of lacZ gene product, thereby indicating that HIV expression under the control of the HIV LTR such as HIV envelope glycoprotein expression has been inhibited if not completely stopped.
  • P 24 a major structural protein (product of gag), has been widely used for monitoring HIV-1 replication in cells and vireamia in individuals.
  • the effective amount of a compound of the present invention used to obtain such a result can be at micromolar concentratio n s. Furthermore, the administration of the compounds of the present invention at effective concentrations, which inhibit HIV expression, has not been found to adversely affect treated cells.
  • the compounds of the present invention can be administered to HIV infected individuals or to individuals at high risk for HIV infection. For example, those having sexual relations with an HIV infected partner, intravenous drug users, etc. Because °f i- ts inhibitory effect, the compounds of the present invention and a pharmaceutical compositions comprising one or more compounds of formula I can be used prophylactically as a method of prevention for such individuals to minimize their risk. One would administer the compound at an effective amount as set forth below by methodology such as described herein.
  • compounds of the present invention block activation or suppress activity of HIV-1 LTR and HIV-1 expression in infected cells.
  • compounds of the present invention in a dose dependent fashion inhibit HIV LTR directed TNF ⁇ and PMA stimulated gene expression. Moreover, such inhibition is provided with essentially no adverse effects on cell survival or cellular mRNA or total cellular RNA synthesis.
  • compounds of the present invention will have utility in inhibiting the progression of an HIV infection and other retroviral infections in cells and in a human, including utility in extending the latency of an HIV infection in humans.
  • the absence of cytotoxicity of the compounds of the present invention indicates that these compounds affect positive or negative regulators of LTR such as the HIV LTR, preferably HIV-1 LTR, that are more critical to the retrovirus than the host cell.
  • one or more compounds of the invention is administered in an amount sufficient to reduce the amount of protein expressed by the gene by at least about 25 percent relative to an untreated cell, more preferably an amount sufficient to reduce the amount of protein by at least about 50 percent and still more preferably a reduction of the amount of protein expressed by at least about 75 percent relative to an untreated cell.
  • a preferred effective dose of one or more compounds of the present invention in particular compounds of formula IA, will be in the range 0.1 mg to 5g per kilogram body weight of recipient per day, more preferably in the range of 0.1 mg to 1,000 mg per kilogram body weight per day, and still more preferably in the range of 1 to 600 mg per kilogram of body weight per day.
  • the desired dose is suitably administered once or several more sub-doses administered at appropriate intervals throughout the day, or other appropriate schedule. These sub-doses may be administered as unit dosage forms, for example, containing 100 to 4,000 ⁇ g , preferably 100 to 2,000 ⁇ g .
  • a compound of formula I or formula IA is used in accordance with the present invention in an isolated form distinct as it may be naturally found and in a comparatively pure form, e.g., at least 85% by weight pure, more preferably at least 95% pure.
  • a comparatively pure form e.g., at least 85% by weight pure, more preferably at least 95% pure.
  • administered compound of formula I or IA at least 98% or even greater than 99% pure.
  • Such a material would be considered sterile for pharmaceutical purposes.
  • Potential contaminants include side products that may result upon synthesis of a compound of the invention or materials that may be otherwise associated with the compound prior to its isolation and purification.
  • the present compounds should preferably be sterile and pyrogen free. Purification techniques known in the art may be employed, for example chromatography.
  • Administration of the compounds of the invention may be by any suitable route including oral, rectal, nasal, topical (including buccal and s blingual) , vaginal and parenteral (including subcutaneous, intramuscular, intravenous and intradermal) with oral or parenteral being preferred. It will be appreciated that the preferred route may vary with, for example, the condition and age of the recipient.
  • the administered ingredients may be used in therapy in conjunction with other medicaments such as reverse transcriptase inhibitors such as dideoxynucleosides, e.g. zidovudine (AZT), 2' ,3' -dideoxyinosine (ddl) and 2' ,3' -dideoxycytidine (ddC) , TAT antagonists such as Ro 3-3335 and Ro 24-7429 protease inhibitors and other agents such as 9- (2-hydroxyethoxymethyl)guanine
  • reverse transcriptase inhibitors such as dideoxynucleosides, e.g. zidovudine (AZT), 2' ,3' -dideoxyinosine (ddl) and 2' ,3' -dideoxycytidine (ddC)
  • TAT antagonists such as Ro 3-3335 and Ro 24-7429 protease inhibitors and other agents such as 9- (2-hydroxyethoxymethyl)guanine
  • interferon e.g., alpha-interferon, interleukin II, and phosphonoformate (Foscarnet) or in conjunction with other immune modulation agents including bone marrow or lymphocyte transplants or other medications such as levamisol or thymosin which would increase lymphocyte numbers and/or function as is appropriate.
  • interferon e.g., alpha-interferon, interleukin II, and phosphonoformate (Foscarnet)
  • other immune modulation agents including bone marrow or lymphocyte transplants or other medications such as levamisol or thymosin which would increase lymphocyte numbers and/or function as is appropriate.
  • the present compounds may be effective when the above-described drugs are not or are no longer effective.
  • compounds of the present invention can be used in cells that are resistant to reverse transcriptase inhibitors such as AZT, ddl, and ddC.
  • the compounds of formula (I) can be used to block HIV-1 LTR directed LTR expression in such resistant cell lines and for treatment of such resistant strains.
  • the present compounds can block HIV-1 LTR directed expression in an AZT resistant strain of HIV-1.
  • the present invention can be used therapeutically in an individual as that individual develops resistance to drugs that act on different targets such as AZT, ddl, ddC, R03-3335, etc. It is expected that the present invention can be used for treatment of HIV-1 infected individuals who develop resistance to any drug that targets a different state in the viral life cycle than the present comounds.
  • R and Ri are each independently selected from the group consisting of hydrogen, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted aryl, and substituted and unsubstituted alkoxy, with particularly preferred compounds of formula II including 3-lapachone (i.e., R and R- ⁇ both being hydrogen), and 3-allyl-?-lapachone (i.e., R being allyl and R ⁇ being hydrogen) .
  • the alkyl groups preferably have from 1 to about 15 carbon atoms, more preferably from 1 to about 10 carbon atoms, still more preferably from 1 to about 6 carbon atoms.
  • alkyl as used in reference to formula II unless otherwise modified refers to both cyclic and noncyclic groups, although of course cyclic groups will comprise at least three carbon ring members.
  • Straight or branched chain noncyclic alkyl groups are generally more preferred than cyclic groups.
  • Straight chain alkyl groups are generally more preferred than branched.
  • the alkenyl groups preferably have from 2 to about 15 carbon atoms, more preferably from 2 to about 10 carbon atoms, still more preferably from 2 to about 6 carbon atoms.
  • Especially preferred alkenyl groups have 3 carbon atoms (i.e., 1-propenyl or 2-propenyl) , with the allyl moiety being particularly preferred.
  • Phenyl and napthyl are generally preferred aryl groups.
  • Alkoxy groups include those alkoxy groups having one or more oxygen linkage and preferably have from 1 to 15 carbon atoms, more preferably from 1 to about 6 carbon atoms.
  • Said substituted R and R- * groups may be substituted at one or more available positions by one or more suitable groups such as, for example, alkyl groups such as alkyl groups having from 1 to 10 carbon atoms or from 1 to 6 carbon atoms, alkenyl groups such as alkenyl groups having from 2 to 10 carbon atoms or 2 to 6 carbon atoms, aryl groups having from six to ten carbon atoms, halogen such as fluoro, chloro and bromo, and N, 0 and S, including heteroalkyl, e.g., heteroalkyl having one or more of said hetero atom linkages (and thus including alkoxy, aminolakyl and thioalkyl) and from 1 to 10 carbon atoms or from 1 to 6 carbon atoms.
  • suitable groups such as, for example, alkyl
  • R, R- j _ and R 2 are each independently selected from the group consisting of hydrogen, substituted and unsubstituted alkyl, noncyclic heteroalkyl, and substituted and unsubstituted alkenyl, provided at least two of the substituents of R, R-i and R 2 are other than hydrogen; with particularly preferred compounds of formula III including Topotecan (i.e., the compound of formula III where R is hydrogen, R ⁇ is 9-hydroxyl, and Ro is 10-N-N-dimethyl(methylene)amino (i.e., (CHo) NCH 2 -) , and the compound of formula III where R is ethyl, R- * is hydrogen and R 2 is 9-hydroxyl, wherein said 9- and 10- prefixes refer to positions of ring members as indicated in formula III above.
  • Topotecan i.e., the compound of formula III where R is hydrogen, R ⁇ is 9-hydroxyl, and Ro is 10-N-N-dimethyl(methylene)a
  • the alkyl groups preferably have from 1 to about 12 carbon atoms, more preferably from about 1 to 6 carbon atoms.
  • the term alkyl as used in reference to formula III unless otherwise modified refers to both cyclic and noncyclic groups, although of course cyclic groups will comprise at least three carbon ring members.
  • Straight or branched chain noncyclic groups are generally more preferred than cyclic groups.
  • Straight chain alkyl groups are generally more preferred than branched.
  • the alkenyl substituents preferably have from 2 to about 12 carbon atoms, more preferably from 2 to about 6 carbon atoms.
  • Heteroalkyl groups include those noncyclic groups that comprise one or more hetero atoms and each hetero atom has one or more alkyl linkages such as alkyl linkages having from 1 to 8 carbon ato s or 1 to 4 carbon atoms .
  • suitable heteroalkyl groups include those where a hetero atom is directly bonded to the general ring system of formula I as well as those groups where a hetero atoms is spaced from the ring system by an alkylene linkage of, e.g., one to four carbon atoms.
  • heteroalkyl groups include aminoalkyl groups including primary, secondary and tertiary alkylamines, and especially preferred are N-N-dialkyl(alkylene)amino groups, e.g., groups of the formula (alkyl) 2 N(CH 2 ) n - where n is an integer of 1 to 4.
  • N-N-dialkyl(alkylene)amino groups e.g., groups of the formula (alkyl) 2 N(CH 2 ) n - where n is an integer of 1 to 4.
  • N-N-dimethylmethyleneamino N-N-dimethylmethyleneamino.
  • nonylic heteroalkyl
  • Said substituted R, R- ⁇ and R 2 groups may be substituted at one or more available position by one or more suitable groups such as, for example, halogen such as fluoro, chloro or bromo, alkyl such as alkyl having from 1 to 12 carbon atoms or from 1 to 6 carbon atoms, alkenyl such as alkenyl having from 2 to 10 carbon atoms or 2 to 6 carbon atoms, aryl having from 6 to 10 carbon atoms, and N, 0, S, including heteroalkyl, e.g., heteroalkyl alkyl having one or more of said hetero atoms and from 1 to 10 carbon atoms or from 1 to 6 carbon atoms.
  • suitable groups such as, for example, halogen such as fluoro, chloro or bromo, alkyl such as alkyl having from 1 to 12 carbon atoms or from 1 to 6 carbon atoms, alkenyl such as alkenyl having from 2 to 10 carbon atoms or 2 to 6 carbon atoms,
  • the present invention includes use of both racemic mixtures and optically active stereoisomers of compounds of formula III.
  • optically active compounds where the chiral carbon of the lactone moiety (i.e., the ring carbon of position 4 as depicted in formula III above) is of the (R) configuration according to the Cahn-Ingold-Prelog nomenclature system. See Carey, F.A. , Advanced Organic Chemistry. Part A, p. 65-66 (2d ed. , Plenum Press 1984).
  • Such compositions of compounds of formula I or IA used in combination with one or more compounds of formula II and/or III may be employed alone or in combination with acceptable carriers such as those described below.
  • suitable effective dose of a compound of formula II in such a composition will be in the range of 1 to 5,000 ⁇ g per kilogram body weight of recipient per day, preferably in the range of 10 to 4,000 ⁇ g per kilogram body weight of recipient per day; and a suitable effective dose of a compound of formula III in such a composition will be in the range of 0.4 to 10,000 ⁇ g per kilogram body weight of recipient per day, preferably in the range of 5 to 500 ⁇ g per kilogram body weight of recipient per day.
  • the compounds are administered together it is expected one can use the lower portion of these ranges with excellent results.
  • One or more compounds of formula I or formula IA may be administered alone, or as part of a pharmaceutical composition, comprising at least one compound of formula I or IA together with one or more acceptable carriers thereof and optionally other therapeutic ingredients, including those therapeutic agents discussed, supra such as one or more compounds of formula II or III.
  • the carrier(s) must be "acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • compositions include those suitable for oral, rectal, nasal, topical (including buccal and sublingual) , vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration.
  • the formulations may conveniently be presented in unit dosage form, e.g., tablets and sustained release capsules, and in liposomes, and may be prepared by any methods well known in the art of pharmacy. Such methods include the step of bringing into association the to be administered ingredients with the carrier which constitutes one or more accessory ingredients.
  • the compositions are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers, liposomes or finely divided solid carriers or both, and then if necessary shaping the product.
  • compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion, or packed in liposomes and as a bolus, etc.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface-active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein.
  • compositions suitable for topical administration include lozenges comprising the ingredients in a flavored basis, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the ingredient to be administered in a suitable liquid carrier.
  • Compositions suitable for topical administration to the skin may be presented as ointments, creams, gels and pastes comprising one or more compounds of the present invention and a pharmaceutically acceptable carrier.
  • a suitable topical delivery system is a transdermal patch containing the ingredient to be administered.
  • compositions suitable for rectal administration may be presented as a suppository with a suitable base comprising, for example, cocoa butter or a salicylate.
  • compositions suitable for nasal administration wherein the carrier is a solid include a coarse powder having a particle size, for example, in the range 20 to 500 microns which is administered in the manner in which snuff is taken, i.e., by rapid inhalation through the nasal passage from a container of the powder held close up to the nose.
  • Suitable formulations wherein the carrier is a liquid, for administration, as for example, a nasal spray or as nasal drops, include aqueous or oily solutions of the active ingredient.
  • compositions suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
  • compositions suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the formulations may be presented in unit-dose or multi-dose containers, for example, sealed ampules and vials, and may be stored in a freeze dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
  • formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example, those suitable for oral administration may include flavoring agents.
  • HIV-1 was obtained from the culture supernatant of HTLV-III B -producing H9 (H9/HTLV-IIIg) cells. During the exponential phase of growth, cell free supernatant was harvested, standardized for reverse transcriptase (RT) activity, and frozen in aliquots at -70°C. Clinical isolates of HIV-1 were prepared from patients testing positive for the human immunodeficiency virus, and standardized for RT activity.
  • PNAZ is an expression construct of lacZ gene driven by HIV-1 LTR.
  • PBMC peripheral blood mononuclear cells
  • FCS Sigma
  • penicillin streptomycin
  • L-glutamine in the presence of PHA (3 ⁇ g/ml)
  • RPMI 8402 cell line a present from Toshiwo Ando (Aichi Cancer Research Institute, Nagoya, Japan) is a human T lymphatic cell line. It was grown in RPMI 1640 medium supplemented with 15% FCS and L-glutamine.
  • PBMC peripheral blood mononuclear cells
  • RTU reverse transcriptase unit
  • RNA of HIV-1 reverse transcriptase was assayed with HIV-1 RNA Detection Kit (GeneTrak, Framingham, MA) according to manufacturer's instructions. Briefly, total cellular RNA was prepared, dot blotted onto a nitrocellulose membrane, and hybridized with 32 P labeled probe for RT RNA.
  • 293.27.2 cells were plated in 6 well plates at 2 X 10 s cells/well in 2 ml of growth medium (DMEM) .
  • TNF ⁇ (40 u/ml) and PMA (2 ng/ml) together with various concentrations of curcumin as indicated in Figure 1 were added to culture media 48 hours after the cells were plated.
  • Enzymatic activity is expressed as percentage of maximum expression which is referred to that in drug untreated sample (taken as 100) .
  • OMlO.l contains one copy of HIV-1 per cell integrated into its genome and continually produces a low of HIV-1 proteins. This cell line was kindly supplied by NIH-AIDS Research and Reference Reagent Program.

Abstract

Traitement de cellules infectées ou d'êtres humains porteurs d'un virus provoquant une maladie immunodéficitaire, à l'aide de composés spécifiques comprenant ceux correspondant à la formule (IA), dans laquelle n est un nombre entier entre 1 et 20, X et X' sont sélectionnés chacun indépendamment dans le groupe composé d'hydrogène et d'une liaison chimique, et R1 à R10 sont sélectionnés chacun indépendamment dans le groupe composé d'hydrogène, hydroxy, halogène, alkyle substitué ou non substitué, alcényle substitué ou non substitué, alkynyle substitué ou non substitué, un hétéroatome, et hétéroalkyle substitué ou non substitué.
PCT/US1993/007879 1992-08-21 1993-08-23 Traitement d'infections virales chez l'homme WO1994004139A1 (fr)

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WO1997032587A1 (fr) * 1996-03-04 1997-09-12 Dana-Farber Cancer Institute Methodes de traitement d'infections virales
US6642275B2 (en) 1995-11-14 2003-11-04 Euro- Celtique, S.A. Formulation for respiratory tract administration
WO2003049717A3 (fr) * 2001-10-12 2004-04-15 Univ Yale Transport de proteines mal pliees par la voie secretoire et methodes de traitement de maladies associees
US20110003841A1 (en) * 2008-09-09 2011-01-06 Mukesh Harilal Shukla Bioactive composition for the treatment of the hiv/aids, method for manufacturing and using the same

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Title
CHEMICAL ABSTRACTS, Volume 110, No. 17, issued 24 April 1989, TAKE et al., "Comparitive Studies of the Inhibitory Properties of Antibiotics on Human Immunodeficiency Virus and Avian Myeloblastosis Virus Reverse Transcriptases and Cellular DNA Polymerases", (Sch. Med., Hiroshima, Univ., Hiroschima, Japan 734); & J. ANTIBIOT., 1989, Vol. 42, No. 1, pp. 107-115, Abstract No. 147191m. *
CHEMICAL ABSTRACTS, Volume 110, No. 23, issued 05 June 1989, BANKOVA et al., "On the Chemical Composition of Some Propolis Fractions with Antiviral Action", (Inst. Microbiol., Bulg.); & ACTA MICROBIOL BULG., 1988, Vol. 23, pp. 52-57, Abstract No. 209208h. *
CHEMICAL ABSTRACTS, Volume 114, No. 5, issued 04 February 1991, SAKAGAMI et al., "Anti-Influenza Virus Activity of Synthetically, Polymerized Phenylpropenoids", (Sch. Med., Showa Univ., Tokyo, Japan 142); & BIOCHEM. BIOPHYS. RES. COMMUN., 1990, Vol. 172, No. 3, pp. 1267-72, Abstract No. 35491k. *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6642275B2 (en) 1995-11-14 2003-11-04 Euro- Celtique, S.A. Formulation for respiratory tract administration
WO1997032587A1 (fr) * 1996-03-04 1997-09-12 Dana-Farber Cancer Institute Methodes de traitement d'infections virales
US8058314B2 (en) 1999-10-27 2011-11-15 Yale University Conductance of improperly folded proteins through the secretory pathway and related methods for treating disease
WO2003049717A3 (fr) * 2001-10-12 2004-04-15 Univ Yale Transport de proteines mal pliees par la voie secretoire et methodes de traitement de maladies associees
US20110003841A1 (en) * 2008-09-09 2011-01-06 Mukesh Harilal Shukla Bioactive composition for the treatment of the hiv/aids, method for manufacturing and using the same
US8431153B2 (en) * 2008-09-09 2013-04-30 Celebrity Biogens, Llc Bioactive composition for the treatment of the HIV/AIDS, method for manufacturing and using the same

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