WO2001010454A9 - Pharmaceutical composition comprising peg-asparaginase for the treatment of hiv infection - Google Patents
Pharmaceutical composition comprising peg-asparaginase for the treatment of hiv infectionInfo
- Publication number
- WO2001010454A9 WO2001010454A9 PCT/US2000/021462 US0021462W WO0110454A9 WO 2001010454 A9 WO2001010454 A9 WO 2001010454A9 US 0021462 W US0021462 W US 0021462W WO 0110454 A9 WO0110454 A9 WO 0110454A9
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compound
- peg
- htv
- asnase
- compounds
- Prior art date
Links
- 0 *c(cc1C(N2OS(*)(=O)=O)=O)ccc1C2=O Chemical compound *c(cc1C(N2OS(*)(=O)=O)=O)ccc1C2=O 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
- A61K38/46—Hydrolases (3)
- A61K38/50—Hydrolases (3) acting on carbon-nitrogen bonds, other than peptide bonds (3.5), e.g. asparaginase
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
Definitions
- the invention is directed to a pharmaceutical composition
- a pharmaceutical composition comprising a PEG- ASNase compound or a pharmaceutically acceptable salt thereof, and optionally at least one compound selected from the group consisting of protease inhibitor compounds, ribonucleotide reductase inhibitor compounds and HIV reverse transcriptase inhibitor compounds, and a pharmaceutically acceptable carrier.
- the invention is also directed to a method of inhibiting or treating Human Immunodeficiency Virus (HIV) infection, comprising administering to a patient in need thereof a therapeutically effective amount of a PEG- ASNase compound or a pharmaceutically acceptable salt thereof, and optionally at least one compound selected from the group consisting of protease inhibitor compounds, ribonucleotide reductase inhibitor compounds and HIV reverse transcriptase inhibitor compounds, or a pharmaceutically acceptable salt thereof.
- HIV Human Immunodeficiency Virus
- the human immunodeficiency virus is a retrovirus and is the agent of the complex disease that includes progressive destruction of the immune system (acquired immune deficiency syndrome; AIDS) and degeneration of the central and peripheral nervous system.
- This retrovirus is previously known as LAV, HTLV-UI, or ARV.
- AIDS immunodeficiency syndrome
- Protease inhibitor compounds in combination with reverse transcriptase (RT) inhibitor compounds have shown success both in vitro and in vivo in patients infected with the virus.
- RT reverse transcriptase
- Protease inhibitor compounds interfere with the production of new infectious virus.
- a common feature of the HIV retrovirus replication is extensive post-translational processing of precursor poly-proteins by a virally encoded protease to generate mature viral proteins required for virus assembly and function. Inhibition of this processing prevents the production of new infectious virus.
- HTV-reverse transcriptase HTV-reverse transcriptase
- nucleoside analogue drug combinations show that they cannot alone inhibit the RT function completely, but instead can lead to the emergence of drug resistant viral strain. These strains of escape mutants repopulate and render nucleoside analogue therapy ineffective.
- protease inhibitor compounds to known nucleoside analogue combination therapies has helped to reduce the viral burden for a prolonged period of time.
- Ribonucleotide reductase is an allosterically regulated enzyme that converts the nucleoside diphosphates to their corresponding deoxynucleoside diphosphates through a complex regulatory mechanism involving one or several electron transfer pathways.
- HISJJD 2-hydroxy-lH-isoindole-l,3-dione
- PEG-asparaginase the polyethylene glycosylated form of E.coli-ASP
- E.coli-ASP polyethylene glycosylated form of E.coli-ASP
- PEG-asparaginase has been shown to be useful as a chemotherapeutic agent.
- PEG-asparaginase has been found to be an alternative preparation with a longer circulating half-life than E.coli L- asparaginase and has been useful in multiagent chemotherapy for childhood acute lymphoblastic leukemia.
- PEG-ASNase may increase the anti-leukemic effect in isolated CNS relapse.
- Covalent attachment of the polymer to the peptide is affected often by reacting PEG-succinimide derivatives with amino groups on the exterior of protein molecules.
- Other methods are also disclosed in U.S. Patent No. 4,179,337, in Pollack et al., JACS, 98, 289 (1976), U.S. Patent No. 4,847,325 and elsewhere in the art.
- PEG-asparaginase effectively works alone and synergistically works in combination with one or more of the following: protease inhibitor compounds, HIV reverse transcriptase inhibitor compounds, or ribonucleotide reductase inhibitor compounds, to treat infection by HIV.
- this invention is directed to a pharmaceutical composition comprising a PEG-ASNase compound and optionally at least one compound selected from the group consisting of: protease inhibitor compounds, ribonucleotide reductase inhibitor compounds and HIV reverse transcriptase inhibitor compounds, and a pharmaceutically acceptable carrier.
- Figure 5 represents T-Cell cytotoxicity of PEG-ASNase and Saquinavir alone, and in concurrent combination, for different drug concentrations.
- Figure 6 represents T-Cell synergism of PEG-ASNase and Saquinavir in concurrent combination for different drug concentrations.
- Figure 7 represents the combination index (CI) in CEM/0 of sequential combination of Saquinavir followed by PEG-ASNase, and sequential combination of PEG-ASNase followed by Saquinavir, and concurrent combination of PEG-ASNase and Saquinavir.
- Figure 8 represents the depletion of Asparagine, Glutamine and Aspartic acid concentrations in CEM/0 T-cells after exposure to different concentrations of PEG-ASNase for 24 hours.
- Figure 8a represents a calibration curve of the optical density (OD) of different concentrations of HTV-1 RT.
- Figure 9 represents the number of HIV RNA copies per cell pellets after exposure of the cells to PEG-ASNase and Saquinavir alone and in combination.
- Figure 9a represents Log ⁇ 0 of the number of HIV RNA copies per cell pellets after exposure of the cells to PEG-ASNase and Saquinavir alone and in combination.
- Figure 10 represents the calibration curves for the HTV-RT Elisa assay.
- acyl means an H-CO- or alkyl-CO- group wherein the alkyl group is as herein described. Preferred acyls contain a lower alkyl. Exemplary acyl groups include formyl, acetyl, propanoyl, 2-methylpropanoyl, butanoyl and palmitoyl.
- “Acylamino” is an acyl-NH- group wherein acyl is as defined herein.
- Alkenyl means an aliphatic hydrocarbon group containing a carbon-carbon double bond and which may be straight or branched having about 2 to about 15 carbon atoms in the chain. Preferred alkenyl groups have 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 4 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl are attached to a linear alkenyl chain.
- “Lower alkenyl” means about 2 to about 4 carbon atoms in the chain which may be straight or branched.
- the alkenyl group may be substituted by one or more halo or cycloalkyl group.
- exemplary alkenyl groups include ethenyl, propenyl, n-butenyl, z ' -butenyl, 3-methylbut-2- enyl, 7 -pentenyl, heptenyl, octenyl, cyclohexylbutenyl and decenyl.
- Alkoxy means an alkyl-O- group wherein the alkyl group is as herein described.
- Exemplary alkoxy groups include methoxy, ethoxy, n-propoxy, t-propoxy, «-butoxy and heptoxy.
- Alkoxycarbonyl means an alkyl-O-CO- group, wherein the alkyl group is as herein defined.
- exemplary alkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl, or t- butyloxycarbonyl.
- Alkyl means an aliphatic hydrocarbon group which may be straight or branched having about 1 to about 20 carbon atoms in the chain. Preferred alkyl groups have 1 to about 12 carbon atoms in the chain. Most preferred alkyl groups have 1 to about 3 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl are attached to a linear alkyl chain. “Lower alkyl” means about 1 to about 3 carbon atoms in the chain which may be straight or branched.
- alkyl may be substituted with one or more "alkyl group substituents" which may be the same or different, and include halo, cycloalkyl, hydroxy, alkoxy, amino, acylamino, aroylamino, carboxy, alkoxycarbonyl,
- Y and Y are independently hydrogen, optionally substituted allcyl, optionally substituted aryl, optionally
- alkyl groups include methyl, trifluoromethyl, cyclopropylmethyl, cyclopentylmethyl, ethyl, n- propyl, z ' -propyl, re-butyl, t-butyl, re-pentyl, 3-pentyl, methoxyethyl, carboxymethyl, formyl, methoxycarbonylethyl, benzyloxycarbonylmethyl, pyridylmethyloxycarbonylmethyl.
- Preferred allcyl substituents are halo, hydroxy, alkoxy, amino, acylamino, aroylamino, carboxy, alkoxycarbonyl, aralkoxycarbonyl, heteroaralkoxycarbonyl, sulfonyl, sulfmyl, acyl, alkanoyl, or Y ⁇ NCO-.
- Alkylthio means an alkyl-S- group wherein the alkyl group is as herein described.
- alkylthio groups include methylthio, ethylthio, z ' -propylthio and heptylthio.
- Alkylsulf ⁇ nyl means an alkyl-SO- group wherein the alkyl group is as defined above. Preferred groups are those wherein the allcyl group is lower allcyl.
- Alkylsulfonyl means an alkyl-S0 2 -group wherein the alkyl group is as defined above. Preferred groups are those wherein the alkyl group is lower allcyl.
- Alkynyl means an aliphatic hydrocarbon group containing a carbon-carbon triple bond and which may be straight or branched having about 2 to about 15 carbon atoms in the chain. Preferred allcynyl groups have 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 4 carbon atoms in the chain. Branched means that one or more lower allcyl groups such as methyl, ethyl or propyl are attached to a linear allcynyl chain.
- “Lower alkynyl” means about 2 to about 4 carbon atoms in the chain which may be straight or branched.
- the alkynyl group may be substituted by one or more halo.
- Exemplary allcynyl groups include ethynyl, propynyl, M-butynyl, 2-butynyl, 3-methylbutynyl, zz-pentynyl, heptynyl, octynyl and decynyl.
- “Analogue” means a compound which comprises a chemically modified form of a specific compound or class thereof, and which maintains the pharmaceutical and/or pharmacological activities characteristic of said compound or class.
- Alkoxy means an aralkyl-O- group wherein the aralkyl groups is as herein described.
- exemplary aralkoxy groups include benzyloxy and 1- or 2-naphthalenemethoxy.
- Alkoxycarbonyl means an aralkyl-O-CO- group wherein the aralkyl groups is as herein described.
- An exemplary aralkoxycarbonyl group is benzyloxycarbonyl.
- Aralkyl means an aryl-alkyl- group wherein the aryl and alkyl are as herein described. Preferred aralkyls contain a lower allcyl moiety. Exemplary aralkyl groups include benzyl, 2-phenethyl and naphthlenemethyl.
- Alkylthio means an aralkyl-S- group wherein the aralkyl group is as herein described.
- An exemplary aralkylthio group is benzylthio.
- Aryloxycarbonyl means an aryl-O-CO- group wherein the aryl group is as defined herein.
- exemplary aryloxycarbonyl groups include phenoxycarbonyl and naphthoxycarbonyl.
- Aroylamino is an aroyl-NH- group wherein aroyl is as defined herein.
- Aroyl means an aryl-CO- group wherein the aryl group is as herein described.
- Exemplary groups include benzoyl and 1- and 2-naphthoyl.
- Aryl means an aromatic monocyclic or multicyclic ring system of about 6 to about 14 carbon atoms, preferably of about 6 to about 10 carbon atoms.
- the aryl is optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined herein.
- Exemplary aryl groups include phenyl or naphthyl, or phenyl substituted or naphthyl substituted.
- Aryldiazo means an aryl -diazo- group wherein the aryl and diazo groups are as defined herein.
- Aryloxy means an aryl-O- group wherein the aryl group is as defined herein.
- exemplary groups include phenoxy and 2-naphthyloxy.
- Arylsulfonyl means an aryl-S0 2 - group wherein the aryl group is as defined herein.
- Exemplary arylthio groups include phenylthio and naphthylthio.
- Carboxy means a HO(0)C- (carboxylic acid) group.
- Cycloalkenyl means a non-aromatic mono- or multicyclic ring system of about 3 to about 10 carbon atoms, preferably of about 5 to about 10 carbon atoms, and which contains at least one carbon-carbon double bond. Preferred ring sizes of rings of the ring system include about 5 to about 6 ring atoms.
- the cycloalkenyl is optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined herein.
- Exemplary monocyclic cycloalkenyl include cyclopentenyl, cyclohexenyl, cycloheptenyl, and the like.
- An exemplary multicyclic cycloalkenyl is norbornylenyl.
- Cycloalkyl means a non-aromatic mono- or multicyclic ring system of about 3 to about 10 carbon atoms, preferably of about 5 to about 10 carbon atoms. Preferred ring sizes of rings of the ring system include about 5 to about 6 ring atoms.
- the cycloalkyl is optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined herein.
- Exemplary monocyclic cycloalkyl include cyclopentyl, cyclohexyl, cycloheptyl, and the like.
- Exemplary multicyclic cycloalkyl include 1-decalin, norbornyl, adamant-(l- or 2-)yl, and the like.
- “Derivative” means a chemically modified compound wherein the modification is considered routine by the ordinary skilled chemist, such as an ester or an amide of an acid, protecting groups, such as a benzyl group for an alcohol or thiol, and tert-butoxycarbonyl group for an amine.
- Effective amount means an amount of a compound/composition according to the present invention effective in producing the desired therapeutic effect.
- Forms suitable for rectal administrations means formulations which are in a form suitable to be administered rectally to a patient.
- the formulation is preferably in the form of suppositories which can be prepared by mixing the compounds useful according to this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore, melt in the rectum or vaginal cavity and release the active component.
- suitable for systemic administration means formulations which are in a form suitable to be administered systemically to a patient.
- the formulation is preferably administered by injection, including transmuscular, intravenous, intraperitoneal, and subcutaneous.
- the compounds useful according to the invention are formulated Swift in liquid solutions, preferably in physiologically compatible buffers such as Hank's solution or Ringer's solution.
- the compounds may be formulated in solid form and redissolved or suspended immediately prior to use. Lyophilized forms are also included.
- Systematic administration also can be by transmucosal or transdermal means, or the compounds can be administered orally.
- penetrants appropriate to the barrier to be permeated are used in the formulation.
- penetrants are generally known in the art, and include, for example, bile salts and fusidic acid derivatives for transmucosal administration.
- detergents may be used to facilitate permeation.
- the active ingredients When formulated in an ointment, the active ingredients may be employed with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with an oil-in-water cream base. Formulations suitable for topical administration in the eye include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient.
- Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient 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 active ingredient in a suitable liquid carrier.
- Forms suitable for vaginal administration means formulations which are in a form suitable to be administered vaginally to a patient.
- the formulation 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.
- Heteroaralkoxycarbonyl means an heteroarallcyl-O-CO- group wherein the heteroaralkyl groups is as herein described.
- An exemplary heteroaralkoxycarbonyl group is thienylmethylcarbonyl.
- Heteroaralkyl means a heteroaryl-allcyl- group wherein the heteroaryl and alkyl are as herein described.
- Preferred heteroaralkyls contain a lower alkyl moiety.
- Exemplary heteroaralkyl groups may contain thienylmethyl, pyridylmethyl, imidazolylmethyl and pyr azinylmethyl .
- Heteroaralkylthio means an heteroaralkyl-S- group wherein the heteroaralkyl group is as herein described.
- An exemplary heteroaralkylthio group is pyridylmethylthio.
- Heteroaryl means an aromatic monocyclic or multicyclic ring system of about 5 to about 14 carbon atoms, preferably about 5 to about 10 carbon atoms, in which one or more of the carbon atoms in the ring system is/are hetero element(s) other than carbon, for example nitrogen, oxygen or sulfur. Preferred ring sizes of rings of the ring system include about 5 to about 6 ring atoms.
- the "heteroaryl” may also be substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein.
- the designation of the aza, oxa or thia as a prefix before heteroaryl define that at least a nitrogen, oxygen or sulfur atom is present respectively as a ring atom.
- a nitrogen atom of an heteroaryl may be a basic nitrogen atom and may also be optionally oxidized to the corresponding N-oxide.
- exemplary heteroaryl and substituted heteroaryl groups include pyrazinyl, thienyl, isothiazolyl, oxazolyl, pyrazolyl, furazanyl, pyrrolyl, 1,2,4-thiadiazolyl, pyridazinyl, quinoxalinyl, phthalazinyl, imidazo[l,2-a]pyridine, imidazo[2,l-b]thiazolyl, benzofurazanyl, azaindolyl, benzimidazolyl, benzothienyl, thienopyridyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, benzoazaindole, 1 ,2,4-triazinyl, benzthiazolyl, furanyl
- Heteroaryl thio means an aryl-S- group wherein the heteroaryl group is as herein described.
- exemplary heteroarylthio groups include pyridylthio and pyrimidinylthio.
- Exemplary monocyclic azaheterocyclenyl groups include 1,2,3,4- tetrahydrohydropyridine, 1,2-dihydropyridyl, 1 ,4-dihydropyridyl, 1,2,3,6-tetrahydropyridine, 1,4,5,6-tetrahydropyrimidine, 2-pyrrolinyl, 3-pyrrolinyl, 2- imidazolinyl, 2-pyrazolinyl, and the like.
- Exemplary oxaheterocyclenyl groups include 3,4- dihydro-2/J-pyran, dihydrofuranyl, and fluorodihydrofuranyl. Preferred is dihydrofuranyl.
- An exemplary multicyclic oxaheterocyclenyl group is 7-oxabicyclo[2.2.1]heptenyl.
- Preferred monocyclic thiaheterocycleny rings include dihydrothiophenyl and dihydrothiopyranyl; more preferred is dihydrothiophenyl.
- Preferred ring system substituents include amidino, halogen, hydroxy, alkoxycarbonylalkyl, carboxyalkyl or Y*Y 2 N- as defined herein.
- Heterocyclyl means a non-aromatic saturated monocyclic or multicyclic ring system of about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms, in which one or more of the carbon atoms in the ring system is/are hetero element(s) other than carbon, for example nitrogen, oxygen or sulfur.
- Preferred ring sizes of rings of the ring system include about 5 to about 6 ring atoms.
- the designation of the aza, oxa or thia as a prefix before heterocyclyl define that at least a nitrogen, oxygen or sulfur atom is present respectively as a ring atom.
- Exemplary monocyclic heterocyclyl rings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,3-dioxolanyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like.
- Preferred heterocyclyl group substituents include amidino, halogen, hydroxy, alkoxycarbonylalkyl, carboxyalkyl or Y ] Y 2 N- as defined herein.
- “Hydrate” means a solvate wherein the solvent molecule(s) is/are H 2 0.
- Hydroalkyl means a HO-allcyl- group wherein alkyl is as herein defined. Preferred hydroxyallcyls contain lower allcyl. Exemplary hydroxyalkyl groups include hydroxymethyl and 2-hydroxy ethyl.
- “Hygroscopicity” means sorption, implying an acquired amount or state of water sufficient to affect the physical or chemical properties of the substance (Eds. J. Swarbrick and J. C. Boylan, Encyclopedia of Pharmaceutical Technology, Vol. 10, p. 33).
- MISID PL-7
- Rl is a methyl group
- R2 is an isopropyl group
- Modulate means the ability of a compound to either directly (by binding to the receptor as a ligand) or indirectly (as a precursor for a ligand or an inducer which promotes production of a ligand from a precursor) induce expression of gene(s) maintained under hormone control, or to repress expression of gene (s) maintained under such control.
- "Patient” includes both human and other mammals.
- the alkyl group is a -C alkyl group, and most preferably a methyl group.
- the polymer is a monomethyl-substituted PEG homopolymer and has a molecular weight of about 4000 to 40,000 daltons.
- PEG-ASNase is the compound sold under the name ONCASPAR by Rh ⁇ ne-Poulenc Rorer.
- “Pharmaceutical composition” means a composition comprising a compound of the invention and at least one component selected from the group comprising pharmaceutically acceptable carriers, diluents, adjuvants, excipients, or vehicles, such as preserving agents, fillers, disintegrating agents, wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents, perfuming agents, antibacterial agents, antifungal agents, lubricating agents and dispensing agents, depending on the nature of the mode of administration and dosage forms.
- pharmaceutically acceptable carriers such as preserving agents, fillers, disintegrating agents, wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents, perfuming agents, antibacterial agents, antifungal agents, lubricating agents and dispensing agents, depending on the nature of the mode of administration and dosage forms.
- suspending agents examples include ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentomte, agar-agar and tragacanth, or mixtures of these substances.
- Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example sugars, sodium chloride and the like.
- Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monosterate and gelatin.
- “Pharmaceutically acceptable dosage forms” means dosage forms of the compound of the invention, and includes, for example, tablets, dragees, powders, elixirs, syrups, liquid preparations, including suspensions, sprays, inhalants tablets, lozenges, emulsions, solutions, granules, capsules and suppositories, as well as liquid preparations for injections, including liposome preparations. Techniques and formulations generally may be found in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, latest edition.
- the compounds bearing the metabolically cleavable groups have the advantage that they may exhibit improved bioavailability as a result of enhanced solubility and/or rate of absorption conferred upon the parent compound by virtue of the presence of the metabolically cleavable group.
- prodrugs A thorough discussion of prodrugs is provided in the following: Design of Prodrugs, H. Bundgaard, ed., Elsevier, 1985; Methods in Enzymology, K. Widder et al, Ed., Academic Press, 42, p.309-396, 1985; A Textbook of Drug Design and Development, Krogsgaard-Larsen and H.
- Bundgaard ed., Chapter 5; "Design and Applications of Prodrugs” p.113-191, 1991; Advanced Drug Delivery Reviews, H. Bundgard, 8, p.1-38, 1992; Journal of Pharmaceutical Sciences, 77, p. 285, 1988; Chem. Pharm. Bull., N. Nakeya et al, 32, p. 692, 1984; Pro-drugs as Novel Delivery Systems, T. Higuchi and V. Stella, Vol. 14 of the A.C.S. Symposium Series, and Bioreversible Carriers in Drug Design, Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press, 1987, which are incorporated herein by reference.
- “Pharmaceutically acceptable salts” means the relatively non-toxic, inorganic and organic acid addition salts, and base addition salts, of compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds. In particular, acid addition salts can be prepared by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed.
- Exemplary acid addition salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactiobionate, sulphamates, malonates, salicylates, propionates, methylene-bis-b-hydroxynaphthoates, gentisates, isethionates, di-p-toluoyltartrates, methane-sulphonates, ethanesulphonates, benzenesulphonates, p-toluenesulphonates, cyclohexylsulphamates and quinateslaurylsulphon
- Suitable inorganic base addition salts are prepared from metal bases which include sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminium hydroxide, lithium hydroxide, magnesium hydroxide, zinc hydroxide.
- Suitable amine base addition salts are prepared from amines which have sufficient basicity to form a stable salt, and preferably include those amines which are frequently used in medicinal chemistry because of their low toxicity and acceptability for medical use.
- Ring system substituents mean substituents attached to aromatic or non-aromatic ring systems inclusive of hydrogen, alkylaryl, heteroaryl, aralkyl, heteroaralkyl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylsulfinyl, arylsulfinyl, heteroarylsulfinyl, alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, aryldiazo, heteroaryldiazo,
- Y 1 and Y 2 are independently hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl or optionally substituted heteroaralkyl, or for where the substituent is Y*Y 2 N-, then one of Y 1 and Y 2 may be acyl or aroyl as defined herein and the other of Y 1 and Y 2 is as defined previously, or for where the substituent is Y ! Y 2 NCO- or Y 1 Y 2 NS ⁇ 2, Y 1 and Y 2 may also be taken together with the N atom through which Y 1 and Y 2 are linked to form a 4 to 7 membered heterocyclyl or heterocyclenyl.
- Solvate means a physical association of a compound of this invention with one or more solvent molecules. This physical association includes hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. "Solvate” encompasses both solution-phase and isolable solvates. Exemplary solvates include hydrates, ethanolates, methanolates, and the like. In a specific embodiment, the term “about” or “approximately” means withm 20%, preferably withm 10%, and more preferably withm 5% of a given value or range
- a preferred embodiment according to the invention is a method of inhibiting or treating Human Immunodeficiency Virus (HIV) infection, comprising administering to a patient m need thereof an effective amount of a pharmaceutically acceptable composition comprising a PEG-ASNase compound
- Another preferred embodiment according to the invention is a method of inhibiting or treating Human Immunodeficiency Virus (HJV) infection, comprising administering to a patient in need thereof an effective amount of a pharmaceutically acceptable composition comprising a PEG-ASNase compound and at least one protease inhibitor compound
- Another preferred embodiment according to the invention is a method of inhibiting or treating Human Immunodeficiency Virus (HJV) infection, comprising administering to a patient in need thereof an effective amount of a pharmaceutically acceptable composition comprising a PEG-ASNase compound and at least one HJV reverse transcriptase inhibitor compound
- Another preferred embodiment according to the invention is a method of inhibiting or treating Human Immunodeficiency Virus (HIV) infection, comprising administering to a patient m need thereof an effective amount of a pharmaceutically acceptable composition comprising a PEG-ASNase compound and at least one ribonucleotide reductase inhibitor compound
- Another preferred embodiment according to the invention is a method of inhibiting or treating Human Immunodeficiency Virus (HIV) infection, comprising administering to a patient in need thereof an effective amount of a pharmaceutically acceptable composition comprising a PEG-ASNase compound, at least one a protease inhibitor compound and at least one ribonucleotide reductase inhibitor compound
- Another preferred embodiment according to the invention is a method of inhibiting or treating Human Immunodeficiency Virus (HTV) infection, comprising administering to a patient m need thereof an effective amount of a pharmaceutically acceptable composition comprising a PEG-ASNase compound, at least one protease inhibitor compound and at least one HTV reverse transcriptase inhibitor compound
- Another preferred embodiment according to the invention is a method of inhibiting or treating Human Immunodeficiency Virus (HIV) infection, comprising administering to a patient m need thereof an effective amount of a pharmaceutically acceptable composition comprising a PEG-ASNase compound, at least one ribonucleotide reductase inhibitor compound and at least one HIV reverse transcriptase inhibitor compound.
- HIV Human Immunodeficiency Virus
- Another preferred embodiment according to the invention is a method of inhibiting or treating Human Immunodeficiency Virus (HTV) infection, comprising administering to a patient in need thereof an effective amount of a pharmaceutically acceptable composition comprising a PEG-ASNase compound, at least one protease inhibitor compound, at least one ribonucleotide reductase inhibitor compound and at least one HTV reverse transcriptase inhibitor compound.
- HTV Human Immunodeficiency Virus
- Another preferred embodiment according to the invention is a method of inhibiting or treating Human Immunodeficiency Virus (HTV) infection, comprising administering to a patient in need thereof a therapeutically effective amount of a PEG-ASNase compound and at least one compound selected from the group consisting of protease inhibitor compounds, ribonucleotide reductase inhibitor compounds and HIV reverse transcriptase inhibitor • compounds.
- a preferred embodiment according to the invention is a method of inhibiting or treating Human Immunodeficiency Virus (HTV) infection, comprising administering to a patient in need thereof an effective amount of a pharmaceutically acceptable composition comprising asparaginase.
- Another preferred embodiment according to the invention is a method of inhibiting or treating Human Immunodeficiency Virus (HTV) infection, comprising administering to a patient in need thereof an effective amount of a pharmaceutically acceptable composition comprising asparaginase and at least one compound selected from the group consisting of protease inhibitor compounds, ribonucleotide reductase inhibitor compounds and HIV reverse transcriptase inhibitor compounds.
- HTV Human Immunodeficiency Virus
- Another preferred embodiment according to the invention is a method of inhibiting or treating Human Immunodeficiency Virus (HTV) infection, comprising administering to a patient in need thereof an effective amount of a pharmaceutically acceptable composition comprising at least one ribonucleotide reductase inhibitor compound of formula I
- Rl is alkyl, alkenyl, alkynyl or an electron withdrawing group
- R2 is alkyl, alkenyl, alkynyl; or a pharmaceutically acceptable salt thereof, an N-oxide thereof, a solvate thereof, an acid bioisostere thereof, or prodrug thereof.
- Another preferred embodiment according to the invention is a method of inhibiting the production, or limiting the spread, of HTV comprising exposing a cell population infected with HIV to an effective amount of a PEG-ASNase compound or asparaginase, and optionally at least one compound selected from the group consisting of protease inhibitor compounds, ribonucleotide reductase inhibitor compounds and HIV reverse transcriptase inhibitor compounds.
- Another preferred embodiment according to the invention is a method of inhibiting HTV reverse transcriptase activity, comprising contacting HIV reverse transcriptase with a composition comprising a PEG-ASNase compound or asparaginase, and optionally at least one compound selected from the group consisting of protease inhibitor compounds, ribonucleotide reductase inhibitor compounds and HTV reverse transcriptase inhibitor compounds.
- Another preferred embodiment according to the invention is a method of inhibiting HTV reverse transcriptase activity, comprising contacting HIV reverse transcriptase with a composition comprising a compound of formula I. Another preferred embodiment according to the invention is a method of inhibiting
- HIV reverse transcriptase activity comprising contacting HJV reverse transcriptase with a composition comprising MISID having the formula
- H V reverse transcriptase activity comprising contacting HTV reverse transcriptase with a composition comprising a PEG-ASNase compound.
- Another preferred embodiment according to the invention is method of selectively inhibiting HTV-RNA production comprising exposing a cell population infected with HTV to a pharmaceutically acceptable composition comprising a PEG-ASNase compound and at least one protease inhibitor compound.
- Another preferred embodiment according to the invention is method of selectively inhibiting HIV-RNA production comprising exposing a cell population infected with HTV to a pharmaceutically acceptable composition comprising a PEG-ASNase compound and Saquinavir.
- Another preferred embodiment according to the invention is a method of inhibiting
- H ⁇ V-RNA production comprising contacting a cell population infected with HIV with a composition comprising a PEG-ASNase compound or asparaginase, and optionally at least one compound selected from the group consisting of protease inhibitor compounds, ribonucleotide reductase inhibitor compounds and HTV reverse transcriptase inhibitor compounds.
- Another preferred embodiment according to the invention is a method of inhibiting HIV-RNA production, comprising contacting a cell population infected with HIV with a composition comprising a compound of formula I.
- Another preferred embodiment according to the invention is a method of inhibiting HIV-RNA production, comprising contacting a cell population infected with HIV with a composition comprising MISJT
- Another preferred embodiment according to the invention is a method of inhibiting HTV-RNA production, comprising contacting a cell population infected with HTV with a composition comprising a PEG-ASNase compound.
- the protease inhibitor compounds are selected from Saquinovir, Nelfinavir, Endinovere, Indinavir, Ritonavir, Crixivan, Viracept, Norvir, and VX-478.
- the protease inhibitor compound is Saquinovir.
- the HJV reverse transcriptase inhibitor compounds are selected from AZT (Retrovir, zidovudine) ddl (Videx, didanosine) ddC (Hivid, zalcitabine), d4T (Zerit, stavudine) and 3TC (Epivir, lamivudine).
- the HTV reverse transcriptase inhibitor compound is AZT.
- the ribonucleotide reductase inhibitor compounds are selected from Hydroxyurea (HU), BW- 348U87, 3- aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP) Amidox (VF 236; NSC-343341; N,3,4-trihydroxybenzenecarboximidamide), BJXD 1257 (2-benzyl-3-phenylpropionyl-L-(N- methyl)valyl-L-3-(methyl)valyl-L-(N4,N4-tetramethylene)asparaginyl-L-(3,3- tetramethylene)aspartyl-L-(4-methyl)leucine), BILD 1357 (2-benzyl-3-phenylpropionyl-L- (N-methyl)valyl-L-3-(methyl)va
- the ribonucleotide reductase inhibitor compound is the compound of formula I.
- this invention is directed to a method of inhibiting or treating Human Immunodeficiency Virus (HIV) infection, comprising administering to a patient in need of such treatment a pharmaceutically effective amount of compound of formula I wherein Rl is lower alkyl, lower alkenyl, lower alkynyl, or an electron withdrawing group; and
- R2 is lower alkyl, lower alkenyl, lower alkynyl; or a pharmaceutically acceptable salt thereof, an N-oxide thereof, a solvate thereof, an acid bioisostere thereof, or prodrug thereof.
- this invention is directed to a method of inhibiting or treating Human Immunodeficiency Virus (HIV) infection, comprising administering to a patient in need of such treatment a pharmaceutically effective amount of compound of formula I wherein Rl is lower alkyl, lower alkenyl, lower alkynyl, or a halogen group; and R2 is lower alkyl, lower alkenyl, lower alkynyl; or a pharmaceutically acceptable salt thereof, an N-oxide thereof, a solvate thereof, an acid bioisostere thereof, or prodrug thereof.
- HAV Human Immunodeficiency Virus
- this invention is directed to a method of inhibiting or treating Human Immunodeficiency Virus (HIV) infection, comprising administering to a patient in need of such treatment a pharmaceutically effective amount of compound of formula I wherein Rl is lower alkyl or a halogen group; and
- HIV Human Immunodeficiency Virus
- R2 is lower alkyl; or a pharmaceutically acceptable salt thereof, an N-oxide thereof, a solvate thereof, an acid bioisostere thereof, or prodrug thereof.
- this invention is directed to a method of inhibiting or treating Human Imiriunodeficiency Virus (HIV) infection, comprising administering to a patient in need of such treatment a pharmaceutically effective amount of compound of formula I wherein Rl is a halogen group; and
- HIV Human Imiriunodeficiency Virus
- R2 is lower allcyl; or a pharmaceutically acceptable salt thereof, an N-oxide thereof, a solvate thereof, an acid bioisostere thereof, or prodrug thereof.
- this invention is directed to a method of inhibiting or treating Human Immunodeficiency Virus (HJV) infection, comprising administering to a patient in need of such treatment a pharmaceutically effective amount of compound of formula I wherem Rl is lower alkyl; and
- HJV Human Immunodeficiency Virus
- R2 is lower alkyl; or a pharmaceutically acceptable salt thereof, an N-oxide thereof, a solvate thereof, an acid bioisostere thereof, or prodrug thereof.
- this invention is directed to a method of inhibiting or treating Human Immunodeficiency Virus (HJV) infection, comprising administering to a patient in need of such treatment a pharmaceutically effective amount of compound of formula I wherein Rl is a bromine or chlorine atom; and
- R2 is a methyl group or an isopropyl group; or a pharmaceutically acceptable salt thereof, an N-oxide thereof, a solvate thereof, an acid bioisostere thereof, or prodrug thereof.
- this invention is directed to a method of inhibiting or treating Human Immunodeficiency Virus (HIV) infection, comprising administering to a patient in need of such treatment a pharmaceutically effective amount of compound of formula I wherein Rl is a methyl group; and R2 is lower alkyl; or a pharmaceutically acceptable salt thereof, an N-oxide thereof, a solvate thereof, an acid bioisostere thereof, or prodrug thereof.
- HIV Human Immunodeficiency Virus
- this invention is directed to a method of inhibiting or treating Human Immunodeficiency Virus (HIV) infection, comprising administering to a patient in need of such treatment a pharmaceutically effective amount of compound of formula I wherein Rl is a methyl group; and R2 is an isopropyl group; or a pharmaceutically acceptable salt thereof, an N-oxide thereof, a solvate thereof, an acid bioisostere thereof, or prodrug thereof.
- the protein synthesis inhibitor compound is PEG-ASNase.
- the protein synthesis inhibitor compound is asparaginase.
- the protease inhibitor compound is Saquinovir or Endinovere.
- the protease inhibitor compound is Saquinovir.
- the HIV reverse transcriptase inhibitor compounds are selected from AZT and 3-TC
- the ribonucleotide reductase inhibitor compound is MISJT) (PL-7).
- the compounds of use according to the invention are administered in concurrent combination.
- the compounds of use according to the invention are administered sequentially.
- the compounds of use according to the invention are administered sequentially, preferably by administering a protease inhibitor followed by the PEG-ASNase compound or asparaginase.
- the compounds of use according to the invention are administered sequentially, preferably by administering Saquinavir followed by the PEG-ASNase compound or asparaginase.
- the compounds of use according to the invention are administered sequentially, preferably administering in the order Saquinavir, followed by the PEG-ASNase compound or asparaginase, followed by one or more compounds selected from the group consisting of HJV reverse transcriptase inhibitor compounds and ribonucleotide reductase inhibitor compounds.
- HJV Human Immunodeficiency Virus
- HJV Human Immunodeficiency Virus
- HTV Human Immunodeficiency Virus
- HJV Human Immunodeficiency Virus
- HJV Human Immunodeficiency Virus
- HJV Human Immunodeficiency Virus
- HJV Human Immunodeficiency Virus
- kits having a plurality of active ingredients (with or without carrier) which, together, may be effectively utilized for carrying out the novel combination therapies of the invention.
- T-cells are the main cells in the mammalian body that are infected with HTV virus. T-cells are considered to be the viral factories for HTV infection. In order to re-infect new T-cells, the HTV virus must enter the T-cell and be able to replicate. The viral replication and encapsulation process requires the participation of intracellular enzymes.
- PEG-ASNase a specific protein synthesis inhibitor compound to thymic-lineage cells
- PEG-ASNase or asparaginase and one or more compounds selected from the group consisting of a protease inhibitor compound, a HTV-RT inhibitor compound, and a ribonucleotide reductase inhibitor compound, has a synergistic effect to reduce the viral burden for prolonged periods of time.
- the intracellular mechanism by which PEG-ASNase is believed to operate is to prevent a T-cell infected with HIV virus from synthesizing intracellular and viral proteins by adversely affecting the supply of the amino acid asparagine (Asn).
- an asparaginase such as PEG-ASNase
- synthesis of cellular and viral proteins is inhibited.
- These proteins are necessary for the transcription and translation of the virally coded genes from the provirus, integrated viral origin DNA into mammalian DNA. Once viral-origin RNA is transcribed by RNA polymerases from the provirus, there are two pathways that may be followed.
- This RNA may be used by ribonucleotide s to produce viral-origin proteins, such as HIV-RT. Later, the same RNA may be processed by rev-protein into genomic HTV-1 RNA. This RNA will be attached to an already synthesized HTV-RT and when two such molecules are present together they constitute the genomic material of a new HTV virus is constituted. HIV proteases are involved in processing the viral origin proteins into the final viral packaging. The new HTV-1 virus may then bud off the T-cell as a new, complete virus.
- a protease inhibitor compound in combination with an asparaginase such as PEG-ASNase, can inhibit the processes required for HTV-1 viral replication in a synergistic manner.
- compositions and methods of therapy of the present invention are useful in the inhibition of HTV protease, the prevention or treatment of infection by HTV and the treatment of consequent pathological conditions such as AIDS.
- Treating ADDS or preventing or treating infection by HIV is defined by including but not limited to treating a wide range of states of HTV infection; AIDS, ARC (AIDS) related complex, both symptomatic and asymptomatic and actual or potential exposure to HTV.
- the compounds of this invention are useful in treating infection by HTV after suspected past exposure to HIV by, for example, blood transfusion, exchange of body fluids, bites, accidental needle sticks, and exposure to patient blood during surgery.
- the PEG-ASNase compound or asparaginase and optionally a compound selected from the group consisting of a protease inhibitor compound, a HJV reverse transcriptase inhibitor compound and a ribonucleotide reductase inhibitor compound, may be administered in different ways, such as in combination therapies optionally employing medical procedures.
- a PEG- ASNase compound and optionally one or more compounds selected from the group consisting of protease inhibitor compounds, HJV reverse transcriptase inhibitor compounds and ribonucleotide reductase inhibitor compounds may be administered to a patient concomitantly or at different times provided that they are administered such that at some period of time there are pharmaceutically effective amounts of both compounds present in the patient such that a therapeutic effect according to the invention results.
- kits for treating or preventing a physiological condition associated with HTV comprising a plurality of separate containers, wherein at least one of said containers contains a PEG-ASNase compound or asparaginase, and at least another of said containers contains one or more compounds selected from the group consisting of protease inhibitor compounds, HTV reverse transcriptase inhibitor compounds and ribonucleotide reductase inhibitor compounds, and said containers optionally contain a pharmaceutical carrier, which kit may be effectively utilized for carrying out combination therapies according to the invention.
- kits for treating or preventing a physiological condition associated with HTV comprising a plurality of separate containers, wherein at least one of said containers contains a compound of formula I and at least another of said containers contains one or more compounds selected from the group consisting of PEG-ASNase compounds, protease inhibitor compounds, HPV reverse transcriptase inhibitor compounds and ribonucleotide reductase inhibitor compounds, and said containers optionally contain a pharmaceutical carrier, which kit may be effectively utilized for carrying out combination therapies according to the invention.
- a further embodiment for a kit would be wherein at least one of said containers should contain a PEG-ASNase compound without the presence of a protease inhibitor compound, a HTV reverse transcriptase inhibitor compound or a ribonucleotide reductase inhibitor compound, and at least another of said containers should contain one or more compounds selected from the group consisting of protease inhibitor compounds, HTV reverse transcriptase inhibitor compounds and ribonucleotide reductase inhibitor compounds, without the presence of a PEG-ASNase compound.
- a further embodiment for a kit would be wherein at least one of said containers should contain a compound of formula I without the presence of a PEG-ASNase compound, a protease inhibitor compound, a HTV reverse transcriptase inhibitor compound or another ribonucleotide reductase inhibitor compound, and at least another of said containers should contain one or more compounds selected from the group consisting of protease inhibitor compounds, HTV reverse transcriptase inhibitor compounds and another ribonucleotide reductase inhibitor compound, without the presence the same compound of formula I.
- a further embodiment for a kit would be wherein of said containers at least one of said containers should contain MISID (PL-7) without the presence of a PEG-ASNase compound, a protease inhibitor compound, a HJV reverse transcriptase inhibitor compound or another ribonucleotide reductase inhibitor compound, and at least another of said containers should contain one or more compounds selected from the group consisting of protease inhibitor compounds, HJV reverse transcriptase inhibitor compounds and ribonucleotide reductase inhibitor compounds, without the presence of MISID (PL-7).
- MISID PL-7
- Compounds of Formula I may be prepared by the application or adaptation of known methods, by which is meant methods used heretofore or described in the literature.
- the compounds useful according to the invention optionally are supplied as salts.
- Those salts which are pharmaceutically acceptable are of particular interest since they are useful in administering the foregoing compounds for medical purposes.
- Salts which are not pharmaceutically acceptable are useful in manufacturing processes, for isolation and purification purposes, and in some instances, for use in separating stereoisomeric forms of the compounds of this invention. The latter is particularly true of amine salts prepared from optically active amines.
- base addition salts may be formed and are simply a more convenient form for use; and in practice, use of the salt form inherently amounts to use of the free acid form.
- acid addition salts may be formed and are simply a more convenient form for use; and in practice, use of the salt form inherently amounts to use of the free base form.
- compositions may also be mixed another therapeutic compound to form pharmaceutical compositions (with or without diluent or carrier) which, when administered, provide simultaneous administration of a combination of active ingredients resulting in the combination therapy of the invention. While it is possible for the compounds useful according to the invention to be administered alone it is preferably to present them as pharmaceutical compositions.
- the pharmaceutical compositions, both for veterinary and for human use, useful according to the present invention comprise at lease one compound of the invention, as above defined, together with one or more acceptable carriers therefor and optionally other therapeutic ingredients.
- active ingredients necessary in combination therapy may be combined in a single pharmaceutical composition for simultaneous administration.
- the choice of vehicle and the content of active substance in the vehicle are generally determined in accordance with the solubility and chemical properties of the active compound, the particular mode of administration and the provisions to be observed in pharmaceutical practice.
- excipients such as lactose, sodium citrate, calcium carbonate, dicalcium phosphate and disintegrating agents such as starch, alginic acids and certain complex silicates combined with lubricants such as magnesium stearate, sodium lauryl sulphate and talc may be used for preparing tablets.
- lactose and high molecular weight polyethylene glycols it is advantageous to use lactose and high molecular weight polyethylene glycols.
- aqueous suspensions When aqueous suspensions are used they can contain emulsifying agents or agents which facilitate suspension.
- the oily phase of the emulsions of this invention may be constituted from known ingredients in a known manner. While the oily phase may comprise merely an emulsifier (otherwise known as an emulgent), it desirably comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both an oil and a fat.
- the emulsifier(s) with or without stabilizer(s) make up the emulsifying wax, and the way together with the oil and fat make up the emulsifying ointment base which forms the oily dispersed phase of a cream formulation.
- Emulgents and emulsion stabilizers suitable for use in the formulation of the present invention include Tween® 60, Span® 80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl mono- stearate and sodium lauryl sulfate.
- the aqueous phase of the cream base may include, for example, a least
- a polyhydric alcohol i.e. an alcohol having two or more hydroxyl groups such as propylene glycol, butane 1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol (including PEG 400) and mixtures thereof.
- the topical formulations may desirably include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethyl sulphoxide and related analogue.
- the choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties.
- the cream should preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers.
- Straight or branched chain, mono- or dibasic allcyl esters such as di-isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters known as Crodamol CAP may be used, the last three being preferred esters. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils can be used.
- Solid compositions of may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols, and the like.
- compositions can be administered in a suitable formulation to humans and animals by topical or systemic administration, including oral, inhalational, rectal, nasal, buccal, sublingual, vaginal, parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural), intracisternal and intraperitoneal. It will be appreciated that the preferred route may vary with for example the condition of the recipient.
- the formulations can be prepared in unit dosage form by any of the methods well known in the art of pharmacy. Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients.
- the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.
- a tablet may be made by compression or moulding, optionally with one or more accessory ingredients.
- Compressed tables 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.
- Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compounds 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.
- Solid compositions for rectal administration include suppositories formulated in accordance with known methods and containing at least one compound of the invention.
- the compounds can be microencapsulated in, or attached to, a slow release or targeted delivery systems such as a biocompatible, biodegradable polymer matrices (e.g. poly(d,l-lactide co-glycolide)), liposomes, and microspheres and subcutaneously or intramuscularly injected by a technique called subcutaneous or intramuscular depot to provide continuous slow release of the compound(s) for a period of 2 weeks or longer.
- the compounds may be sterilized, for example, by filtration through a bacteria retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use.
- compositions of the invention may be varied so as to obtain an amount of active ingredient that is effective to obtain a desired therapeutic response for a particular composition and method of administration.
- the selected dosage level therefore depends upon the desired therapeutic effect, on the route of administration, on the desired duration of treatment and other factors.
- Total daily dose of the compounds useful according to this invention administered to a host in single or divided doses may be in amounts, for example, of from about 0.001 to about 100 mg/kg body weight daily and preferably 0.01 to 10 mg/kg/day.
- Dosage unit compositions may contain such amounts of such submultiples thereof as may be used to make up the daily dose. It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the body weight, general health, sex, diet, time and route of administration, rates of absorption and excretion, combination with other drugs and the severity of the particular disease being treated.
- the amount of each component administered is determined by the attending clinicians taking into consideration the etiology and severity of the disease, the patient's condition and age, the potency of each component and other factors.
- the formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials with elastomeric stoppers, 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.
- sterile liquid carrier for example water for injections
- Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
- the compounds of the invention, their methods or preparation and their biological activity will appear more clearly from the examination of the following examples which are presented as an illustration only and are not to be considered as limiting the invention in its scope.
- Samples are supematants and pellets obtained from the viral ⁇ drug flasks (incubation for seven days). They are not heat inactivated. — Centrifuge the samples at 2000 g for 30 minutes at 4° C.
- Peg solution 30% w/v, 30 g in 100 ml.
- Strips have 8 wells each, therefore need strips
- washing solution is a lOx solution, therefore it must be diluted using autoclaved water.
- the samples produced from this experiment are itemized and then assayed for HTV- RT using the Reverse Transcriptase Assay, non-radioactive (Boehringer Mannheim).
- the standard curve is determined and the HTV-RT levels for the experimental samples are calculated.
- T-cell pellets themselves are then examined for intracellular HTV-RT.
- HTV-RT infracellularly
- these drugs and their combination suppress/inhibit HTV-RT infracellularly, it suggests that they inhibit HTV-1 at the provirus level.
- the integrated HTV provirus is producing mRNA, which is not translated into viral proteins and hence, the inhibition of the production of RT or complete virus particles to be shed in the media.
- no further HTV-1 infection could be achieved of uninfected T-cells.
- CEM/0 A human leukemic T-cell line, hereafter referred to as CEM/0 is used for this experiment.
- PEG-ASNase is obtained from Rhone-Poulenc Rorer Pharmaceuticals Inc under the tradename Oncaspar®.
- Saquinavir is obtained from Roche Laboratories under the tradename InviraseTM.
- RPMI-1640 media obtained from Irvme Scientific, Irvme CA is enriched with 10% Fetal Calf Serum obtained from Gemini Biosource, Calabasas, CA, 5% 1M Hepes buffer solution and 5% non-essential ammo acids obtained from Irvme Scientific, Irvme CA
- the PEG-ASNase concentration that produces a cytostatic condition in CEM/0 cells in vitro is approximately 0.5 IU/ml.
- PEG-ASNase concentrations of 1 and 0.75 IU/ml produced significant cell kill and are cytotoxic to CEM/0 cells by 72 hours.
- the concentrations of 0.03, 0.1, 0.2, 0.3 and 0.4 IU/ml are marginally effective m preventing cell growth as compared to the control (untreated cells) growth rate.
- the cells treated with 0.5 IU/ml PEG-ASNase however, showed a relatively flat cell growth line Thus, a cytostatic effect is produced with this concentration over 72 hours. Therefore, a range of PEG-ASNase concentrations including 0.5 IU/ml are used in the combination regimen investigations. A drug, concentration and time dependent cytotoxic effect of PEG-ASNase in this T-cell line is shown.
- PEG-ASNase 1.020, 0.765, 0.510, 0.255 and 0.0255 IU/ml
- the negative control cells are incubated in a drug-free media for the same duration and under the same conditions as the experimental samples.
- Cell density is measured via cell counting using a Coulter Counter coupled with a Coulter Channelyzer for each of the experimental flasks at 24, 48 and 72 hours after incubation. Additionally, Trypan Blue Exclusion tests are performed for each of these experimental conditions. Cell numbers are corrected for the viability determined by theTrypan Blue test and presented as a percentage of the untreated control.
- Samples of 50 ⁇ l media and 10 ⁇ l of lmM aminoadopic acid are added to 450 ⁇ l of cold methanol in 1.5 ml microfuge tubes.
- the mixtures are vortexed and centrifuged at 8700 g for two minutes.
- the supematants are transferred to borosilicate glass test tubes (13 x 100 mm) and lyophilized.
- the specimens are stored at -20° C until they are analyzed by HPLC. Prior to HPLC analysis, the samples are dissolved in a buffer containing 95% 7 nM disodium hydrogen phosphate and 5% acetonifrile.
- RPMI-1640 media (Irvine Scientific, Irvine, CA), is enriched with 10% Fetal Calf Serum (Gemini Biosource, Calabasas, CA), 5% 1M Hepes Buffer solution and 5% Non-essential amino acids (Irvine Scientific, Irvine, CA).
- the drug concentrations used are as follows:
- the same number of cells are incubated in PHA free media for 48 hours to serve as the negative control. At this point the cells are inoculated with the HJV-1 virus as per standard protocol.
- the HJV containing supernatant from the PHA-stimulated healthy human peripheral mononuclear cells (PBMC) is not removed from the PHA-stimulated CEM/0 cell culture.
- the HTV-1 vims is always present in the supernatant, an experimental condition that simulates the in vivo clinical condition of newly produced and uninfected T-cells, which are always under constant exposure to HIV-1 particles. These virus particles are released by already infected T-cells and/or lymph nodes of patients.
- the experimental drugs are added to the cells in the appropriate concentrations at the same time as viral inoculation or 90 minutes after the viral incubation, a time sufficient for the T-cells to be infected and start producing new HTV-1 virus particles.
- the control cells are resuspended in drug-free media for the duration of the exposure which lasted seven days. Aliquots of media from the control flasks only are obtained on day 5 post Rx. At day seven, three 1 ml each, aliquots of media are removed from the flasks and stored under liquid nitrogen. In addition, the remaining cells are split into three and then pelleted and stored at - 80°C.
- MISID PL-7
- RR ribonucleotide reductase
- MISID a new ribonucleotide reductase (RR) inhibitor, used alone at the IC 50 concentration (0.685 ⁇ M), also demonstrated a significant inhibition of HTV RT as a single agent and in combination with the three other dmgs. This is the result in the cell pellets as well (see Experiment 7) and is the first evidence that a member of this class of RR inhibitors has demonstrated anti-HJV activity in addition to its anti-leukemic activity both infracellularly and in the supernatant specimens of these T-cell cultures.
- Combinations of PEG + SAQ resulted in complete inhibition of HTV-RT in this and in the previously reported experiment in the cell pellets. In the previous experiments there is a 96% inhibition of HIV-RT (see Experiment 7). Combinations of three dmgs, AZT + PEG + SAQ, resulted in complete inhibition of HTV-RT in two of the three wells, and the third well's value is inhibited by 95.3% of control, whereas in the supematants an identical pattern is seen Specimens #20-22.
- the cell line used for these studies is CEM/0, human T-cell leukemic cell line.
- PEG-ASNase OCASPAR
- Saquinavin is commercially available.
- AZT is purchased from Sigma.
- MISID a ribonucleotide reductase inhibitor, is synthesized as indicated in Nandy P, Lien EJ, Avramis VI, Med. Chem. Res. 1995, 5:664-679.
- RPMI-1640 media (Irvine Scientific, Irvine, CA), is enriched with 10% Fetal Calf Serum (Gemini Biosource, Calabasas, CA), 5% 1M Hepes Buffer solution and 5% Non-essential amino acids (Irvine Scientific, Irvine, CA).
- the drug concentrations used are as follows:
- the same number of cells are incubated in PHA free media for 48 hours to serve as the negative control. At this point the cells are inoculated with the HTV-1 vims as per standard protocol.
- the HTV containing supernatant from the PHA-stimulated healthy human peripheral mononuclear cells (PBMC) is not removed from the PHA-stimulated CEM/0 cell culture.
- PBMC peripheral mononuclear cells
- the HTV-1 virus is always present in the supernatant, an experimental condition that simulates the in vivo clinical condition of newly produced and uninfected T-cells, which are always under constant exposure to HTV- Iparticles. These virus particles are released by already infected T-cells and/or lymph nodes of patients.
- the experimental drugs are added to the cells in the appropriate concentrations at the same time as viral inoculation or 90 minutes after the viral incubation, a time sufficient for the T-cells to be infected and start producing new HTV-1 virus particles.
- the control cells are resuspended in drug-free media for the duration of the exposure which lasted seven days. Aliquots of media from the confrol flasks only are obtained on day 5 post Rx. At day seven, three 1 ml each, aliquots of media are removed from the flasks and stored under liquid nitrogen. In addition, the remaining cells are split into three and then pelleted and stored at - 80°C.
- the samples produced from this experiment are itemized.
- the cell pellets of the cellular cultures (see Experiment 7) from the 90 minute viral incubation flasks are assayed for HTV-RNA quantitative assay using a kit for the assay, non-radioactive.
- the standard curve is determined and the HTV-RNA levels for the experimental samples are calculated and reported previously.
- the specimens are from the cultures of the T-cell pellets and are from the same experiment as those we reported for the HTV-RT results. These results are discussed in Experiment 7 (cell pellets) & Experiment 8 (supernatant).
- HTV RNA Inhibition of HTV RNA is quantitative terms cause by AZT alone (Specimens #11- 13) are greater (sensitive HTV-1 vims to AZT), with SAQ and MISTD as single agents following. Greater inhibition of HJV RNA is seen by the combination of SAQ + PEG- ASNase, 38%o of confrol, and from the three dmg combination of PEG-ASNase +SAQ + AZT, 30% of control.
- MISID a new ribonucleotide reductase (RR) inhibitor, used alone at the IC 50 concentration (0.685 ⁇ M), also demonsfrated a significant inhibition of HTV RNA as a single agent and most importantly, in combination with the three other drags. This is the result in the cell pellets as well (Experiment 6) and is the repeat evidence that a member of this class of RR inhibitors has demonsfrated anti-HTV activity in addition to its anti-leukemic activity both infracellularly and in the supernatant specimens of these T-cell cultures.
- MISID the RR inhibitor
- AZTTP AZT-triphosphate
- This augmented inhibitory effect will be either additive or synergistic to the already selectively synergistic effect of a protein plus protease inhibitors against this virus.
- MISTD alone appears to have considerable anti-HTV RNA inhibitory activity, we believe that this syllogism will be shown to be correct in experiments with HTV particles resistant to one or more of these classes of dmgs or in patients who are infected with multi-resistant HTV variants.
- the cell line used for these studies is CEM/0, a human T- cell leukemic cell line.
- PEG-ASNase OCASPAR
- Saquinavin is commercially available.
- AZT is purchased from Sigma.
- MISTD a ribonucleotide reductase inhibitor, is as described in Nandy P, Lien EJ, Avramis VI, Med. Chem. Res. 1995, 5:664-679.
- RPMI-1640 media (Irvine Scientific, Irvine, CA), is enriched with 10%) Fetal Calf Semm (Gemini Biosource, Calabasas, CA), 5% 1M Hepes Buffer solution and 5% Non-essential amino acids (Irvine Scientific, Irvine, CA).
- the drug concenfrations used are as follows:
- 3 x 10 6 cells/ml are stimulated with PHA+ media for 48 hours at 37°C with 5% C0 2 . Also, the same number of cells are incubated in PHA free media for 48 hours to serve as the negative confrol. At this point the cells are inoculated with the HTV-1 virus as per standard protocol. Note that in this experiment, the HTV containing supernatant from the PHA-stimulated healthy human peripheral mononuclear cells (PBMC) is not removed from the PHA-stimulated CEM/0 cell culture.
- PBMC peripheral mononuclear cells
- HTV-1 vims is always present in the supernatant, an experimental condition that simulates the in vivo clinical condition of newly produced and uninfected T-cells, which are always under constant exposure to HTV- 1 particles.
- HTV-1 titers as per our control HTV- RNA in the T-cells (see Experiment 9). These virus particles are continuously released by already infected T-cells and/or lymph nodes of patients.
- the experimental drugs are added to the cells in the appropriate concentrations at the same time as viral inoculation or 90 minutes after the viral incubation, a time sufficient for the T-cells to be infected and start producing new HTV-1 virus particles.
- the control cells are resuspended in drug-free media for the duration of the exposure which lasted seven days. Aliquots of media from the control flasks only are obtained on day 5 post Rx. At day seven, three 1 ml each, aliquots of media are removed from the flasks and stored under liquid nitrogen. In addition, the remaining cells are split into three and then pelleted and stored at - 80°C. Supernatant specimens are obtained form these T-cell cultures and are frozen at -80°C.
- the samples produced from this experiment are itemized.
- the cell pellets of the cellular cultures (see Experiment 9) from the 90 minute viral incubation flasks are assayed for HTV- RNA quantitative assay using a kit for the assay, non-radioactive.
- the standard curve is determined and the HTV-RNA levels for the experimental samples are calculated and reported previously.
- HTV-RNA in quantitative terms caused by SAQ, AZT or MISID alone are non-statistically significant among themselves (sensitive HTV-1 virus to AZT). Similar inhibition percentages of HTV-RNA in the supematants is seen by either the combination of SAQ + PEG-ASNase, or the three dmg combination of PEG-ASNase + SAQ + AZT, in comparison to unfreated control.
- the data suggest that: a) these combination regimens must be given continuously under these conditions, i.e., in patients with high HTV-RNA copy number and/or viremia and b) the potentiation of the AZT + SAQ is required by either a third RT inhibitor, such as 3TC or and an RR inhibitor, such as, MISTD or hydroxyurea, to potentiate the activity of AZT triphosphate (AZTTP) against HTV-RT.
- a third RT inhibitor such as 3TC or and an RR inhibitor, such as, MISTD or hydroxyurea
- MISTD a new ribonucleotide reductase (RR) inhibitor, used alone at the IC 50 concentration (0.685 ⁇ M), also demonstrated a significant inhibition of HTV-RNA as a single agent which is approximately equal to the inhibition of either SAQ or AZT. Most importantly, MISTD showed it significant usefulness in combination with the three other dmgs both against HTV-RT in T-cell pellets and supematants (see Experiments 7 and 8), respectively, and in suppressing HTV-RNA left in the supernatant (Table 8).
- N is the number of virus genomic copieVmL of supernatant or copiescell pellet Dynamic range of the HIV-1 Monitor Assay is 400 to 750.000 copies/ml. Inquire with laboratory if quanti tio ⁇ below 400 copies/mL is needed. Table 2
- N is the number of virus gc ⁇ omic copics mL of supernatant or copies cell pellet Dynamic range of the HIV- 1 Monitor Assay is 400 to 750,000 copies/mL Inquire with laboratory if quantitation below 400 copies mL is needed. Table 5
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Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
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AU68944/00A AU6894400A (en) | 1999-08-06 | 2000-08-07 | Composition and methods for treatment of HIV infection |
CA002346063A CA2346063A1 (en) | 1999-08-06 | 2000-08-07 | Composition and methods for treatment of hiv infection |
JP2001514970A JP2003506409A (en) | 1999-08-06 | 2000-08-07 | Compositions and methods for treating HIV infection |
EP00957306A EP1143990A3 (en) | 1999-08-06 | 2000-08-07 | Pharmaceutical compostions comprising peg-asparaginase for the treatment of hiv infections |
HK02102802.2A HK1041444A1 (en) | 1999-08-06 | 2002-04-13 | Pharmaceutical compositions comprising peg-asparaginase for the treatment of hiv infections |
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US09/370,390 US6689762B1 (en) | 1998-02-09 | 1999-08-06 | Composition and methods for treatment of HIV infection |
US09/370,390 | 1999-08-06 |
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WO2001010454A3 WO2001010454A3 (en) | 2002-01-24 |
WO2001010454B1 WO2001010454B1 (en) | 2002-07-11 |
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JP (1) | JP2003506409A (en) |
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CA (1) | CA2346063A1 (en) |
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WO2002085358A2 (en) * | 2001-04-20 | 2002-10-31 | Vion Pharmaceuticals, Inc. | Antiviral agents and methods of treating viral infections |
US8029815B2 (en) | 2004-04-28 | 2011-10-04 | Elford Howard L | Methods for treating or preventing restenosis and other vascular proliferative disorders |
EP2030615A3 (en) | 2007-08-13 | 2009-12-02 | ELFORD, Howard L. | Ribonucleotide reductase inhibitors for use in the treatment or prevention of neuroinflammatory or autoimmune diseases |
US9556216B2 (en) | 2012-08-31 | 2017-01-31 | Novartis Ag | 2′-Ethynyl nucleoside derivatives for treatment of viral infections |
BR112018074646A2 (en) * | 2016-05-31 | 2019-03-06 | Taiho Pharmaceutical Co., Ltd. | sulfonamide compound or salt thereof |
US10889555B2 (en) | 2016-05-31 | 2021-01-12 | Taiho Pharmaceutical Co., Ltd. | Sulfonamide compound or salt thereof |
CA3084030C (en) * | 2017-11-29 | 2023-03-21 | Taiho Pharmaceutical Co., Ltd. | Sulfonamide compounds and use thereof |
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WO1998056410A1 (en) * | 1997-06-09 | 1998-12-17 | Childrens Hospital Los Angeles | Utilization of wolinella succinogenes asparaginase to treat diseases associated with asparagine dependence |
ES2203072T3 (en) * | 1998-02-09 | 2004-04-01 | Enzon Pharmaceuticals, Inc. | PHARMACEUTICAL COMPOSITIONS THAT INCLUDE PEG-ASPARAGINASE FOR THE TREATMENT OF HIV INFECTIONS. |
-
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- 2000-08-07 AU AU68944/00A patent/AU6894400A/en not_active Abandoned
- 2000-08-07 EP EP00957306A patent/EP1143990A3/en not_active Withdrawn
- 2000-08-07 JP JP2001514970A patent/JP2003506409A/en active Pending
- 2000-08-07 WO PCT/US2000/021462 patent/WO2001010454A2/en not_active Application Discontinuation
- 2000-08-07 CA CA002346063A patent/CA2346063A1/en not_active Abandoned
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ZA200102506B (en) | 2002-03-27 |
AU6894400A (en) | 2001-03-05 |
CA2346063A1 (en) | 2001-02-15 |
EP1143990A2 (en) | 2001-10-17 |
EP1143990A3 (en) | 2002-03-27 |
WO2001010454B1 (en) | 2002-07-11 |
HK1041444A1 (en) | 2002-07-12 |
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WO2001010454A3 (en) | 2002-01-24 |
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