US20070037772A1 - Pyrazolidinol compounds - Google Patents
Pyrazolidinol compounds Download PDFInfo
- Publication number
- US20070037772A1 US20070037772A1 US11/371,226 US37122606A US2007037772A1 US 20070037772 A1 US20070037772 A1 US 20070037772A1 US 37122606 A US37122606 A US 37122606A US 2007037772 A1 US2007037772 A1 US 2007037772A1
- Authority
- US
- United States
- Prior art keywords
- hydroxy
- hiv
- pyrazolidine
- patient
- sulphur
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- HELODTZNVFWOIK-UHFFFAOYSA-N 1-hydroxypyrazolidine Chemical class ON1CCCN1 HELODTZNVFWOIK-UHFFFAOYSA-N 0.000 title claims abstract description 18
- 238000000034 method Methods 0.000 claims abstract description 22
- 210000001744 T-lymphocyte Anatomy 0.000 claims abstract description 13
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 13
- 150000003839 salts Chemical class 0.000 claims abstract description 11
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000005864 Sulphur Substances 0.000 claims abstract description 10
- KQZLFGLJDLVKKC-UHFFFAOYSA-N 1-hydroperoxypyrazolidine-3,5-dione Chemical compound OON1NC(=O)CC1=O KQZLFGLJDLVKKC-UHFFFAOYSA-N 0.000 claims abstract description 9
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000001301 oxygen Substances 0.000 claims abstract description 9
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 8
- 125000003072 pyrazolidinyl group Chemical group 0.000 claims abstract description 8
- 208000031886 HIV Infections Diseases 0.000 claims abstract description 6
- 208000037357 HIV infectious disease Diseases 0.000 claims abstract description 4
- 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 claims abstract description 4
- 238000011282 treatment Methods 0.000 claims description 10
- 201000010099 disease Diseases 0.000 claims description 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 8
- 239000003443 antiviral agent Substances 0.000 claims description 7
- 241000700605 Viruses Species 0.000 claims description 6
- NQDJXKOVJZTUJA-UHFFFAOYSA-N nevirapine Chemical compound C12=NC=CC=C2C(=O)NC=2C(C)=CC=NC=2N1C1CC1 NQDJXKOVJZTUJA-UHFFFAOYSA-N 0.000 claims description 6
- 229960002555 zidovudine Drugs 0.000 claims description 5
- BXZVVICBKDXVGW-NKWVEPMBSA-N Didanosine Chemical compound O1[C@H](CO)CC[C@@H]1N1C(NC=NC2=O)=C2N=C1 BXZVVICBKDXVGW-NKWVEPMBSA-N 0.000 claims description 4
- 229960001936 indinavir Drugs 0.000 claims description 4
- CBVCZFGXHXORBI-PXQQMZJSSA-N indinavir Chemical compound C([C@H](N(CC1)C[C@@H](O)C[C@@H](CC=2C=CC=CC=2)C(=O)N[C@H]2C3=CC=CC=C3C[C@H]2O)C(=O)NC(C)(C)C)N1CC1=CC=CN=C1 CBVCZFGXHXORBI-PXQQMZJSSA-N 0.000 claims description 4
- 241000713772 Human immunodeficiency virus 1 Species 0.000 claims description 3
- 229960000689 nevirapine Drugs 0.000 claims description 3
- 241001529453 unidentified herpesvirus Species 0.000 claims description 3
- 230000003612 virological effect Effects 0.000 claims description 3
- 206010014612 Encephalitis viral Diseases 0.000 claims description 2
- 206010061192 Haemorrhagic fever Diseases 0.000 claims description 2
- 206010019799 Hepatitis viral Diseases 0.000 claims description 2
- 206010020460 Human T-cell lymphotropic virus type I infection Diseases 0.000 claims description 2
- 241000714260 Human T-lymphotropic virus 1 Species 0.000 claims description 2
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- 229940124158 Protease/peptidase inhibitor Drugs 0.000 claims 1
- WZPBZJONDBGPKJ-VEHQQRBSSA-N aztreonam Chemical compound O=C1N(S([O-])(=O)=O)[C@@H](C)[C@@H]1NC(=O)C(=N/OC(C)(C)C(O)=O)\C1=CSC([NH3+])=N1 WZPBZJONDBGPKJ-VEHQQRBSSA-N 0.000 claims 1
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 47
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 36
- 150000001875 compounds Chemical class 0.000 description 30
- HFHZKZSRXITVMK-UHFFFAOYSA-N oxyphenbutazone Chemical compound O=C1C(CCCC)C(=O)N(C=2C=CC=CC=2)N1C1=CC=C(O)C=C1 HFHZKZSRXITVMK-UHFFFAOYSA-N 0.000 description 20
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 19
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- 239000000243 solution Substances 0.000 description 15
- 241000725303 Human immunodeficiency virus Species 0.000 description 14
- 238000002360 preparation method Methods 0.000 description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 10
- 239000000203 mixture Substances 0.000 description 10
- -1 sulphonyl group Chemical group 0.000 description 10
- 238000005160 1H NMR spectroscopy Methods 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- 229910052739 hydrogen Inorganic materials 0.000 description 8
- 239000001257 hydrogen Substances 0.000 description 8
- 239000003826 tablet Substances 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 230000000840 anti-viral effect Effects 0.000 description 7
- DPLOKDYHDJEJST-UHFFFAOYSA-N 4-butyl-4-hydroxy-1-(4-hydroxyphenyl)-2-phenylpyrazolidine-3,5-dione Chemical compound O=C1C(CCCC)(O)C(=O)N(C=2C=CC=CC=2)N1C1=CC=C(O)C=C1 DPLOKDYHDJEJST-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
- VYMDGNCVAMGZFE-UHFFFAOYSA-N phenylbutazonum Chemical compound O=C1C(CCCC)C(=O)N(C=2C=CC=CC=2)N1C1=CC=CC=C1 VYMDGNCVAMGZFE-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 5
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 5
- 210000004027 cell Anatomy 0.000 description 5
- 238000003818 flash chromatography Methods 0.000 description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- 229910052708 sodium Inorganic materials 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- 125000003396 thiol group Chemical group [H]S* 0.000 description 5
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 4
- 241000699670 Mus sp. Species 0.000 description 4
- 230000036436 anti-hiv Effects 0.000 description 4
- 210000004970 cd4 cell Anatomy 0.000 description 4
- IJKVHSBPTUYDLN-UHFFFAOYSA-N dihydroxy(oxo)silane Chemical compound O[Si](O)=O IJKVHSBPTUYDLN-UHFFFAOYSA-N 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- 210000000987 immune system Anatomy 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 229960000649 oxyphenbutazone Drugs 0.000 description 4
- 229910052717 sulfur Inorganic materials 0.000 description 4
- 210000001519 tissue Anatomy 0.000 description 4
- HBOMLICNUCNMMY-XLPZGREQSA-N zidovudine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](N=[N+]=[N-])C1 HBOMLICNUCNMMY-XLPZGREQSA-N 0.000 description 4
- YBQZXXMEJHZYMB-UHFFFAOYSA-N 1,2-diphenylhydrazine Chemical compound C=1C=CC=CC=1NNC1=CC=CC=C1 YBQZXXMEJHZYMB-UHFFFAOYSA-N 0.000 description 3
- GYEHMALGJMHWFB-UHFFFAOYSA-N 1-(4-methoxyphenyl)-2-phenylhydrazine Chemical compound C1=CC(OC)=CC=C1NNC1=CC=CC=C1 GYEHMALGJMHWFB-UHFFFAOYSA-N 0.000 description 3
- 208000023275 Autoimmune disease Diseases 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- 0 [1*:0]C1([2*])C(=C)N([Ar])N([Ar])C1=C Chemical compound [1*:0]C1([2*])C(=C)N([Ar])N([Ar])C1=C 0.000 description 3
- 125000002252 acyl group Chemical group 0.000 description 3
- 125000003342 alkenyl group Chemical group 0.000 description 3
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- 125000003118 aryl group Chemical group 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
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- DEQYTNZJHKPYEZ-UHFFFAOYSA-N ethyl acetate;heptane Chemical compound CCOC(C)=O.CCCCCCC DEQYTNZJHKPYEZ-UHFFFAOYSA-N 0.000 description 3
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- LGCRPKOHRIXSEG-UHFFFAOYSA-N (4-methoxyphenyl)-phenyldiazene Chemical compound C1=CC(OC)=CC=C1N=NC1=CC=CC=C1 LGCRPKOHRIXSEG-UHFFFAOYSA-N 0.000 description 2
- AFROIFNDTILSCO-UHFFFAOYSA-N 4-(4-methylphenyl)-1,2-diphenylpyrazolidine-3,5-dione Chemical compound C1=CC(C)=CC=C1C1C(=O)N(C=2C=CC=CC=2)N(C=2C=CC=CC=2)C1=O AFROIFNDTILSCO-UHFFFAOYSA-N 0.000 description 2
- GSTJUQAYAGGXPJ-UHFFFAOYSA-N 4-benzyl-1,2-diphenylpyrazolidine-3,5-dione Chemical compound O=C1N(C=2C=CC=CC=2)N(C=2C=CC=CC=2)C(=O)C1CC1=CC=CC=C1 GSTJUQAYAGGXPJ-UHFFFAOYSA-N 0.000 description 2
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- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
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- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D231/28—Two oxygen or sulfur atoms
- C07D231/30—Two oxygen or sulfur atoms attached in positions 3 and 5
Abstract
The invention provides the use of an optionally hydroxyl-protected 4-hydroxy or hydroperoxy-3,5-dioxopyrazolidine or an equivalent wherein a pyrazolidine ring attached oxygen is replaced by a sulphur, or a physiologically acceptable salt thereof, for the manufacture of a medicament for use in drug therapy or prophylaxis. Additionally, the invention provides a method of combating HIV infection which comprises administering to an HIV-infected patient a T-lymphocyte growth suppressing agent, preferably a pyrazolidinol, in an amount sufficient to suppress T-lymphocyte growth in said patient for a period sufficient to reduce the T-lymphocyte concentration in lymph nodes in said patient.
Description
- The present invention relates to certain pyrazolidinols and their sulphur (i.e. thio/thiol) analogs and pharmaceutical compositions thereof for use in antiviral, e.g. anti-HIV therapy and as anti-inflammatories and immunomodulators.
-
- Other 3,5-pyrazolidinediones have likewise been proposed for use as NSAIDs (see for example U.S. Pat. No. 3,968,219 (Rahtz)) and the hydroxy-protected enol forms have been proposed as pro-drug forms of phenbutazone and oxyphenbutazone (see U.S. Pat. No. 4,117,232 (Bodor), U.S. Pat. No. 3,957,803 (Bodor), U.S. Pat. No. 4,169,147 (Bodor), U.S. Pat. No. 4,036,845 (Bodor) and U.S. Pat. No. 4,139,709 (Bodor)).
- In U.S. Pat. No. 4956377 (Miesch) it was proposed that this class of NSAIDs had utility as an antiviral agent, in particular for the treatment of HIV.
- We have now surprisingly found that where the 4-carbon of the N2C3 ring carries an optionally protected hydroxy or thiol group, the compounds have very significantly enhanced antiviral, in particular anti-HIV, efficacy.
- Thus viewed from one aspect the invention provides the use of an optionally hydroxy-protected 4-hydroxy or hydroperoxy-3,5-dioxo-pyrazolidine or an equivalent wherein a pyrazolidine ring attached oxygen is replaced by a sulphur, or a physiologically acceptable salt thereof, for the manufacture of a medicament for use in therapy or prophylaxis.
- Where a particular 4-hydroxy or hydroperoxy-3,5-dioxo-pyrazolidine may exist in more than one stereoisomeric form, it may be used in single isomer form or as an isomer mixture, e.g. a racemic mixture.
- Viewed from a further aspect, the invention provides an optionally hydroxy-protected 4-hydroxy or hydroperoxy-3,5-dioxo-pyrazolidine or an equivalent wherein a pyrazolidine ring attached oxygen is replaced by a sulphur, or a physiologically acceptable salt thereof.
- Viewed from a still further aspect the invention provides a method of treatment of the human or non-human (e.g. mammalian, reptilian or avian) body to combat an inflammatory or viral disease, preferably an immuno-deficiency viral disease, in particular HIV, which method comprises administering to said body an optionally hydroxy-protected 4-hydroxy or hydroperoxy -3,5-dioxo-pyrazolidine or an equivalent wherein a pyrazolidine ring attached oxygen is replaced by a sulphur, or a physiologically acceptable salt thereof.
- Viewed from a still further aspect, the invention provides a pharmaceutical composition comprising an optionally hydroxy-protected 4-hydroxy or hydroperoxy -3,5-dioxo-pyrazolidine or an equivalent wherein a pyrazolidine ring attached oxygen is replaced by a sulphur, or a physiologically acceptable salt thereof, together with at least one pharmaceutically acceptable carrier or excipient.
- The applicants have found that oxyphenbutazone, as commercially available, contains minute quantities of certain impurities, presumably as a result of undesired oxidative breakdown. One of these, present at about 0.4% wt, is 4-butyl-4-hydroxy-2(p-hydroxyphenyl)-1-phenyl-3,5-pyrazolidinedione (hereinafter “4-OH-OPB”), i.e.
4-OH-OPB is of course a compound according to the invention and thus it should be understood that references to the 4-hydroxy compounds of the invention, their use and compositions thereof should not be taken to include references to such compounds when in intimate admixture with overwhelmingly larger quantities of a 3,5-pyrazolidinedione which carries no optionally protected 4-hydroxy or 4-thiol group. By overwhelmingly larger is meant a relative weight ratio of at least 98:2. In general, the compounds of the invention should not desirably be used in intimate admixture with larger quantities (i.e. a relative weight ratio of more than 50:50) of such compounds carrying no O or S attached group at the 4-position, and more desirably they should not be used with such compounds present in greater than 10:90 weight ratio. -
- X1 is O, OO or S, preferably O or S, most preferably O;
- R1 is hydrogen or a hydroxyl or thiol protecting group (e.g. an acyl group, preferably containing up to 6 carbons, e.g. an acyl group such as an alkylcarbonyl group, for example acetyl), preferably hydrogen;
- R2 is hydrogen or more preferably a carbon attached organic group containing up to 10 carbons, e.g. an alkyl, alkenyl, alkynyl, alkaryl, aralkyl or aralkenyl group, optionally substituted, e.g. by a sulphonyl group; and
- each Ar, which may be the same or different, is a homo or heterocyclic aromatic group, optionally substituted, e.g. by C1-6 alkyl or alkoxy groups) or a salt thereof.
- In the compounds of the
invention - In the compounds of the invention, the R2 group is preferably other than hydrogen and may for example be straight chain, branched, cyclic or cyclic-attached-to-straight chain. Preferably it is an alkyl or alkenyl group, especially a C1-6 alkyl or alkenyl group, e.g. n-propyl, n-butyl, n-pentyl or 1-methyl-but-2-en.-4-yl or an aralkyl (e.g. benzyl) or alkaryl (e.g. methylphenyl) or arylsulphonylalkyl (eg phenylsulphonylethyl) group.
- Where R1 in the compounds of the invention is other than hydrogen it is preferably a metabolically labile hydroxy- or thiol-protecting group which yields a physiologically tolerable R1,OH metabolite. Acyl groups are preferred in this regard.
- In the compounds of formula I, where each X2 is oxygen and one Ar is phenyl, the other Ar is preferably other than phenyl e.g. parahydroxyphenyl.
- A wide range of hydroxy- and thiol-protecting groups however is known from the literature (see McOmie, “Protective groups in organic chemistry”, Plenum, 1973 and Greene, “Protective groups in organic synthesis”, Wiley Interscience, NY, 1981) and many compounds of formula I in which R1 is a protecting group may be useful as intermediates in the production of compounds of formula I in which R1 is hydrogen.
- The Ar groups in the compounds of formula I are preferably 5 to 7 membered aromatic rings, optionally carrying a fused aromatic ring and optionally substituted on ring atoms, for example by C1-6 alkyl groups but especially by electron withdrawing substituents, e.g. hydroxy, thiol, phenyl, C1-6 alkoxy, cyano, halo (e.g. Cl, F, Br or I), protected hydroxy, or protected thiol. Ring heteroatoms will generally be selected from O, N and S, preferably with a single ring heteroatom in any aromatic Ar heterocycle. Ar is preferably phenyl optionally substituted, especially in the para-position by —X1—R1 or Cl (where —X1—R1 is as defined above). Especially preferably one Ar is phenyl and the other is p-hydroxy-phenyl.
- Where the substitution of the pyrazolidinols of the invention is such that they may form addition salts with acids or bases, the addition salts which have physiologically tolerable counterions are of course preferred, e.g. sodium, organic amine, halides, phosphates, hydrogen carbonates, etc.
- The pyrazolidinols of the invention may particularly advantageously be used in combination therapy with other antiviral, especially anti-HIV, agents, in particular reverse transcriptase inhibitors and/or protease inhibitors, e.g. zidovudine, didanovine, zalcitabine, stavudine, lamivudine, nevirapine, delavirdine, indinavir, ritonavir, nelfinavir, hydroxyurea kolchicine, AZT and 2′,3′-dideoxyinosine (ddI). Such combination therapy forms a further aspect of the present invention.
- A drawback of traditional combination therapy, has often been that even under intensive antiviral treatment with a combination of drugs, a little HIV production continues and is unaffected by treatment. The compounds of the invention may prove to have an effect in reducing this residual HIV production when given in combination with other antiviral agents. This may be due to the increasing antiviral effect which has been seen in long term cell culture experiments and which may counteract any development of resistance to the compounds.
- The pyrazolidinols of the invention may be prepared by oxidation of a corresponding compound where R1X1 is replaced by hydrogen; by reaction of a corresponding compound where R1X1 is HX1 with a hydroxy or thiol protecting agent to introduce a non-hydrogen R1 group; or by condensation of a hydrazine derivative with an optionally protected 2-hydroxy-propane dioic acid ester (or a sulphur analog), e.g. by condensation of a compound of formula II
Ar-HN—NH-Ar (II)
with a compound of formula III
where R1, R2, X1, X2 and Ar are as hereinbefore defined and X2R3 is a leaving group, for example where R3 is an alkyl group, e.g. a C1-6 alkyl group. -
- For administration, the pyrazolidinols of the invention may be formulated in any convenient form, e.g. tablets, coated tablets (e.g. delayed release tablets), capsules, solutions, suspensions, dispersions, syrups, powders, sprays, suppositories, transdermal patches, gels, emulsions and creams. Administration may be via any convenient route, e.g. oral, rectal, transdermal, nasal, subcutaneous, intravenous, intramuscular, etc. Oral administration, e.g. of tablets or capsules is preferred. The pyrazolidinols may be formulated together with conventional pharmaceutical carriers, diluents or excipients, e.g. aqueous carriers (for example water for injections), binders, fillers, stabilizers, osmolality adjusting agents, effervescing agents, pH modifiers, viscosity modifiers, sweeteners, lubricants, emulsifiers, flavours, coating agents (e.g. gastric juice resistant coatings), etc. Where any formulation results in a loss of compound, this loss should be calculated. and the dosage increased proportionally to obtain the desired active concentration.
- The dosage of the pyrazolidinols given according to the invention will depend on the size and species of the subject being treated but will generally be in the range of 0.05 to 2000 mg/day, more particularly 0.5 to 1000 mg/day, especially 1 to 100 mg/day, preferably with administration being effected once, twice, three times or four times daily. For mice, doses of up to 2000 mg/kg (corresponding to 20 mM maximal concentration in extracellular fluid) could be given before lethal dosage was reached, ie effective treatment doses were up to 200000 times smaller than the lethal dose.
- For regular, e.g. continuous daily treatment according to the invention, the daily dosage of the pyrazolidinol will preferably be in the range 5 nmol to 2 μmol/kg bodyweight, more preferably 100 nmol to 1.5 μmol/kg, especially 500 nmol to 1 μmol/kg.
- Inhibition of virus production may be achieved by small intermittent doses of pyrazolidinol, and are expected to induce inhibition of the virus after a latency of about 11 weeks. Subsequently, inhibition may be expected to level out, should resistance to the compound develop. Such doses may be administered at a frequency of 1-14 days, preferably 7 days. The doses should be equivalent to a concentration in plasma/tissue fluid of from 100-1000 nM and may be obtained by ingestion or injection of from 0.7-7 mg in a 70 Kg human.
- However, in a particularly preferred embodiment of the invention, a pyrazolidinol according to the invention is administered at a dose sufficient to suppress T-lymphocyte (CD4 and CD8 cell) growth (e.g. a daily dose of 0.1 to 10 μmol/kg) for a period of 1 to 14 days, preferably 2 to 7 days at intervals of at least 3 months, preferably at least 9 months, e.g. 10 to 18 months. In this way the patient's immune system may be “refreshed” by removal of the preponderance of T-lymphocytes directed to HIV antigens. Such a treatment indeed is novel and forms a further aspect of the invention. Viewed from this aspect the invention provides a method of combatting HIV infection which comprises administering to an HIV-infected. patient a T-lymphocyte growth suppressing agent, e.g. a pyrazolidinol, in an amount sufficient to suppress T-lymphocyte growth in said patient for a period sufficient to reduce the T-lymphocyte concentration in the lymphatic system, e.g. the lymph nodes, in said patient by at least 25%, more preferably at least 50%, said administration being repeated at intervals of at least 3 months, preferably at least 9 months.
- High tissue concentrations intended to give an immunomodulating effect should preferably be given for limited periods at doses of 1 μM or above in plasma/tissue fluid. Such doses and lengths of administration will vary according to the condition of each patient and may be decided with the guidance of tests such as the count of HIV memory subsets of T8 and T4. As stated above, the goal of treatment according to this aspect of the invention should be to reduce subsets which are found to be too prevalent without overly affecting naive T-cells.
- In order to obtain the desired reduction of HIV specific lymphocytes (e.g. HIV memory CD8 and CD4 lymphocytes) without overly affecting naive T-lymphocytes or other essential blood cells, monoclonal antibodies against the unwanted subtypes may also be administered. Further, drugs such as kolchicine and/or hydroxy-urea may be included in the intermittent intensive treatment. Such additional drugs are anticipated to have a somewhat different immunomodulating effect to the compounds of the invention and so may be used advantageously in combination with pyrazolidinols for refreshing the immune system.
- Besides HIV, the pyrazolidinols of the invention may be used to combat other viral infections, especially retroviral infections but also infections by togaviridea, reoviridea, picornaviridea, hantaviridea, orthomyxoviridea, paramyxoviridea, mononegaviralis, viral hepatitis, haemorrhagic fevers, flaviviridea, viral encephalitis, coronaviridea, calciviridea, adenoviridea, papovaviridea, arboviridea, pox virus, rhabdoviridea, herpes virus and arenaviridea. The pyrazolidinols of the invention may in particular be used to combat viral infections of CD4 cells, e.g. HIV-1, HIV-2, HTLV-I, HTLV-II and herpes viruses, for example to combat AIDS, T-cell tumours (e.g. Sezary Syndrome, mycosis fungoides and T-cell lymphoma, and particularly CD4 cell tumours), tropic spastic paraparesis, and Karposi's sarcoma. Moreover despite not being of the accepted formula for NSAIDs (which would require an acid proton in place of R1X1 at the 4-position), they may be used as anti-inflammatory drugs. All these uses form aspects of the invention.
- Due to the immunomodulating effect of the compounds of the invention, they are expected to have uses in control of other immune-system related diseases, such as auto immune diseases and as immunosuppressants. In particular, the compounds of the invention are expected to have a positive effect on the generation of autoimmune diseases, on developed autoimmune diseases and on diseases related to such diseases, such as Addison's disease, Behcet's syndrome, diabetes mellitus and other endocrine diseases, haemolytic anaemia, lupus erythematosus, multiple sclerosis, myasthenia gravis, pernicious anaemia, polyglandular deficiency, polymyositis, dermatomyositis, testicular failure, thrombocytopenic purpura, Crohns disease, ulcerative colitis, rheumatic disorders (e.g. rheumatoid arthritis) etc.
- The effect of the compounds of the invention on the immune system may also be that of immunosuppression. Such an effect may be used, for example, to control rejection of a medical transplant or implant. In particular, the compounds may be used to reduce rejection following tissue or organ transplant.
-
- where Ra to Rd are as set out in Table 1 below:
TABLE 1 Ra Rb Rc Rd H H H C6H5 H H C6H5 C6H5 CH3 H H C6H5 CH3 H H —CH2—C6H5 CH3 H H p-CH3O—C6H4 CH3 H H p-Cl—C6H4 C2H5 H H C6H5 C2H5 H C6H5 C6H5 C2H5 H H N-methyl-piperidin-4-yl iC3H7 H H C6H5 nC3H7 H H C6H5 nC3H7 H C6H5 C6H5 nC3H7 H H 5-phenyl-triazol-1-yl C4H9 H H C6H5 C4H9 H C6H5 C6H5 C4H9 H C6H5 p-OH—C6H4 C4H9 OH C6H5 C6H5 C4H9 OH C6H5 p-OH—C6H4 C4H9 H H N-methyl-piperidin-4-yl C5H11 H H C6H5 C5H11 H C6H5 C6H5 C5H11 H H 5-phenyl-triazol-1-yl Cyclohexyl H H C6H5 Phenyl H H C6H5 Phenyl H C6H5 C6H5 Benzyl H H C6H5 Benzyl H C6H5 C6H5 CH3CO(CH2)2 H C6H5 C6H5 (CH3)2C═CH— H C6H5 C6H5 (CH2)2C═CHCH2 H C6H5 C6H5 C6H5SCH2CH2 H C6H5 C6H5 Pyrrolidin-1-yl H C6H5 C6H5 Piperidin-1-yl H C6H5 C6H5 Morpholin-4-yl H C6H5 C6H5
Such compounds are thus not claimed per se herein; however their use and pharmaceutical compositions containing them do form part of the scope of the invention. - The invention will now be illustrated further by the following non-limiting Examples and by reference to the Figures, in which:
-
FIG. 1 shows the HIV antigen concentration in human CD4 cells infected with HIV and treated with 4-butyl-4-hydroxy-2 (p-hydroxyphenyl)-1-phenyl-3, 5-pyrazolidinedione (4OH-OPB) or phenbutazone (PB) at various concentrations; -
FIG. 2 shows the effect of 4-butyl-4-hydroxy-2(p-hydroxyphenyl)-1-phenyl-3,5-pyrazolidinedione (4OH-OPB) when used in combination with AZT; -
FIG. 3 shows the effect of 4-butyl-4-hydroxy-2(p-hydroxyphenyl)-l-phenyl-3,5-pyrazolidinedione (4OH-OPB) when used in combination with indinavir; and; -
FIG. 4 shows the effect of 4-butyl-4-hydroxy-2(p-hydroxyphenyl)-l-phenyl-3,5-pyrazolidinedione (4OH-OPB) when used in combination with nevirapine; - A similar effect to those shown in
FIGS. 2-4 is seen when OPB is used in combination with 2′,3′-dideoxyinosine (daI). - A mixture of 4-phenylazophenol (9.9g; 50 mmol), iodomethane (7.1 g; 50 mmol), potassium carbonate (6.9 g; 50 mmol), and acetone (100 ml) was refluxed 48 h. After evaporating off the solvent, the residue was dissolved in water (25 ml), diethyl ether (50 ml) and THF (30 ml). The aqueous layer was extracted with ether (3×20 ml) and the combined organic solutions were washed with saturated NaCl solution (1×20 ml) and dried (MgSO4). After filtration and evaporation, the residue was recrystallized from 96% ethanol to give 8.7 g (82%).
- Zinc powder (10.0 g; 0.15 mol) was added to a stirred mixture of 4-methoxyazobenzene (4.24 g; 20.0 mmol) in 96% ethanol (75 ml) and saturated NH4Cl solution (2.0 ml) at 0° C. (bath temperature). Two more portions of saturated NH4Cl solution (2.0 ml) were added at 1.5 h intervals. The yellowish solution was poured into cold water (100 ml) and filtered. The residue was extracted with methylene chloride (5×50 ml). The combined aqueous phases were extracted with methylene chloride (3×25 ml). The combined organic solutions were dried (Na2SO4), filtered, and evaporated to give 4.3 g crude 1-(4-methoxyphenyl)-2-phenylhydrazine as a reddish oil.
- Diethyl butylmalonate (4.33 g; 20.0 mmol) was added to a stirred solution of sodium (0.46 g; 20.0 mmol) in absolute ethanol (20 ml), followed by crude 1-(4-methoxyphenyl)-2-phenylhydrazine (4.3 g; 20 mmol max.) in absolute ethanol (5 ml). About ⅔ of the ethanol was distilled off and xylene (20 ml) was added to the residue. The reaction mixture was heated to 140-145° C. (bath temperature) for 15 h to distill off the rest of the ethanol. The reaction mixture was cooled to 0° C. (bath temperature) and poured into ice water (ca. 100 ml). The aqueous layer was extracted with CH2Cl2 (2×15 ml); the extracts were discarded. The cold aqueous layer was acidified with 6 M HCl (5 ml) and extracted with CH2Cl2 (3×10 ml). The combined extracts were washed with water (2×10 ml) and dried (MgSO4). Filtration and evaporation gave 3.84 g amber oil. Purified by flash chromatography on a 130×65 mm silica gel 60 column eluted with ethyl acetate-heptane (1:3) to give 1.45 g (21%) colourless oil.
- 1H NMR (200 MHz; CDCl3): δ 0.90 (3H, t, J=7.5 Hz), 1.25-1.6 (4H, m), 2.0-2.15 (2H, m), 3.37 (3H, t, J=6.0 Hz), 3.69 (3H, s), 6.81 (2H, d, J=8.4 Hz), 7.22 (2H, d, J=8.6 Hz), 7.1-7.35 (5H, m).
- 13C NMR (50 MHz; CDCl3): δ 13.6, 22.2, 27.5, 27.6, 45.6, 54.7, 112.9, 121.6, 123.3, 125.4, 127.1, 127.4, 133.9, 156.5, 168.2, 168.7.
- Prepared from 1,2-diphenylhydrazine (3.70 g; 20.0 mmol), diethyl 2-(p-tolyl)malonate (5.0 g; 20.0 mmol), and sodium (0.46 g; 20.0 mmol) using the procedure of Example 3. The crude product crystallized on standing and was recrystallized twice from absolute ethanol to give 1.22 g (18%), mp 184-185° C.
- 1H NMR (200 MHz; CDCl3): δ 2.31 (3H, s), 4.51 (1H, s), 7.1-7.4 (14H, m).
- 13C NMR (50 MHz; CDCl3): δ 21.1, 51.9, 122.7, 126.9, 128.3, 129.0, 129.9, 135.8, 138.3, 168.6.
- Prepared from 1,2-diphenylhydrazine (4.60 g; 25.0 mmol), diethyl benzylmalonate (5.0 g; 20 mmol), and sodium (0.46 g; 20.0 mmol) using the procedure of Example 3. The crude product was recrystallized from absolute ethanol to gave 3.51 g (50%), mp 136-137° C. [lit. 137-138° C. (Beil. III/IV, 24, 1463)].
- 1H NMR (200 MHz; CDCl3): δ 3.41 (2H, d, J=4.6 Hz), 3.63 (1H, t, J=5.0 Hz), 6.85-7.3 (10H, m).
- 13C NMR (50 MHz; CDCl3): δ 33.9, 48.5, 123.2, 126.9, 127.3, 128.6, 128.7, 129.9, 135.2, 135.4, 169.3.
- Prepared from 1,2-diphenylhydrazine (5.2. g; 28.0 mmol), diethyl allylmalonate (5.0 g; 25.0 mmol), and sodium (0.58 g; 25.0 mmol) using the procedure of Example 3. The crude product was recrystallized from absolute ethanol to give 2.21 g (30%) tan crystals, mp 135-137° C.
- 1H NMR (200 MHz; CDCl3): δ 2.82 (2H, t, J=6.0 Hz), 3.46 (2H, t, J=5.4 Hz), 5.1-5.3 (2H, dd), 5.7-5.95 (1H, m), 7.1-7.3 (10H, m).
- 13C NMR (50 MHz; CDCl3): δ 31.7, 46.4, 119.9, 122.7, 126.8, 128.9, 131.7, 135.6, 169.5.
- Method A
- Oxyphenbutazone.H2O (1 mmol), 30% H2O2 (0.7 mL), 1N NaOH (0.1 mL) and methanol (3.5 mL) are allowed to stand for 13 hours at ambient temperature. The mixture is then poured into 5% HCl (20 mL) and extracted with ethyl acetate (2×20 mL). The ethyl acetate phase is separated, dried over sodium carbonate and the solvent is removed under reduced pressure without heating. The residue is subjected to flash chromatography (silica/ethyl acetate). The title product is recrystallized from ethyl acetate.
- Method B
- A solution of oxyphenbutazone hydrate (2.0 g; 5.8 mmol), 35% hydrogen peroxide solution (3.4 ml; 40 mmol), and 1 M sodium hydroxide solution (0.6 ml; 0.6 mmol) in methanol (20 ml) was allowed to stand for 24 h at ambient temperature. The mixture was acidified with 1 M HCl solution (50 ml) and extracted with ethyl acetate (4×15 ml). The combined extracts were washed with saturated NaCl solution (1×10 ml) and dried (MgSO4) After filtration and evaporation, the residue was purified by flash chromatography on a 100×65 mm silica gel 60 column eluted with ethyl acetate-heptane (1:1), taking 50-ml fractions, giving 1.3 g (66%).
- 1H NMR (200 MHz; CDCl3): δ 0.88 (3H, t, J=6.6 Hz), 1.25-1.5 (4H, m), 1.95-2.05 (2H, m), 6.49 (1H, br s), 6.75 (2H, d, J=8.9 Hz), 7.12 (2H, d, J=8.9 Hz), 7.1-7.35 (5H, m).
- 13C NMR (50 MHz; CDCl3): δ 13.6, 22.3, 24.3, 36.2, 72.8, 114.3, 121.9, 123.8, 125.3, 125.7, 127.2, 133.5, 154.6, 169.0, 169.5.
- Prepared from 4-(1-butyl)-1-(4-methoxyphenyl)-2-phenyl -3,5-pyrazolidinedione (1.35 g; 3.8 mmol), 35% H2O2 (4.3 ml; 50 mmol), 2 M NaOH (0.35 ml; 0.7 mmol), and methanol (50 ml) using the procedure of Example 7. Purified by flash chromatography on a 110×65 mm silica gel 60 column eluted with ethyl acetate-heptane (1:1) to give 0.7 g (52%).
- 1H NMR (200 MHz; CDCl3): δ 0.85 (3H, t, J=6.2 Hz), 1.2-1.5 (4H, m), 2.0-2.1 (2H, m), 3.69 (3H, s), 4.8 (1H, br s), 6.77 (2H, d, J=9.0 Hz), 7.19 (2H, d, J =9.0 Hz), 7.1-7.35 (5H, m).
- 13C NMR (50 MHz; CDCl3): δ 13.5, 22.3, 24.3, 36.7, 54.7, 73.3, 113.0, 122.1, 123.8, 125.8, 126.1, 127.5, 133.0, 156.7, 168.5, 169.0.
- Prepared from (±)-sulfinpyrazone (2.02 g; 5.0 mmol), 35% H2O2 (4.3 ml; 50 mmol), 2 M NaOH (0.35 ml; 0.7 mmol), and methanol (50 ml) using the procedure of Example 7. Purified by flash chromatography on a 130×65 mm silica gel 60 column eluted with ethyl acetate-acetic acid (20:1) to give 80 mg (4%).
- 1H NMR (200 MHz; CDCl3): δ 2.1-2.5 (2H, m), 3.0-3.7 (2H, m), 5.5 (1H, br s), 6.4-7.9 (15H, m).
- 13C NMR (50 MHz; CDCl3): δ 28.7, 47.5, 70.2, 121.5, 122.9, 125.8, 126.5, 127.4, 127.7, 127.9, 129.9, 133.3, 133.4, 136.9, 139.2, 167.5, 168.0.
- A mixture of 1,2-diphenyl-4-(4-methylphenyl)-3,5-pyrazolidinedione (1.10 g; 3.2 mmol), 35% H2O2 (0.47 ml; 5.5 mmol), and acetic acid (40 ml) was stirred 16 days at room temperature. Sodium metabisulfite (1.0 g) was added and excess acetic acid evaporated off. The residue was dissolved in hot ethyl acetate (25 ml) and benzene (25 ml) and filtered. After cooling to room temperature, the mixture was filtered and the residue recrystallized from 50% aqueous ethanol (20 ml) to give 0.58 g (53%).
- 1H NMR (200 MHz; CDCl3: δ 2.32 (3H, s), 7.0-7.45 (14H, m).
- 13C NMR (50 MHz; CDCl3): δ 21.1, 57.9, 123.9, 124.5, 127.0, 128.3, 128.4, 128.7, 130.4, 135.6, 139.0, 168.5.
- Prepared from 4-benzyl-1,2-diphenyl-3,5-pyrazolidinedione (3.3 g; 9.6 mmol), 35% H2O2 (1.4 ml; 16.3 mmol), and acetic acid (50 ml) using the procedure of Example 10 to give 1.0 g (30%).
- 1H NMR (200 MHz; CDCl3): δ 3.30 (2H, s), 6.75-7.3 (15H, m).
- 3C NMR (50 MHz; CDCl3): δ 43.1, 75.4, 123.0, 126.7, 127.5, 128.4, 130.2, 132.1, 134.7, 170.1.
- Antiviral Activity of 4OH-OPB (Example 7)
- 4OH-OPB was added to cultures of growing MT4 cells (a human CD4 cell line). HIV-1, stored in the culture medium at −75° C. was thawed and added in an amount which infected about 1 in 7 cells in each culture. The virus was absorbed to the cells for 2.3 hours at ambient temperature whereafter the cultures were centrifuged at 1200 rpm, the medium was removed, the cells were suspended in fresh growth medium and 4OH-OPB was added to concentrations of 1, 10 and 100 μM (diluted in medium from a stock solution of 20 mM in DMSO). After 72 hours the HIV antigen concentration was determined using Abbott's test. By way of comparison phenbutazone (PB) was tested analogously. The results are shown in
FIG. 1 and demonstrate inhibition of virus production by 4OH-OPB at concentrations above the lowest tested. - Combination Antiviral Effect with 40H-OPB
- Cell culture experiments were carried out as in Example 12, but in place of 4OH-OPB (0-100 μM) was added:
-
- i) 4OH-OPB (0-10 μM) with AZT (0-1 μM)
- ii) 4OH-OPB (0-100 μM) with Indinavir (0-100 μM)
- iii) 4OH-OPB (0-100 μM) with Nevirapin (0-10 μM)
- iv) 4OH-OPB (0-10 μM) with ddI (0-100 μM)
The results are shown inFIGS. 2-5 respectively and demonstrate the enhanced anti-HIV effect of 4OH-OPB in combination with other anti-viral agents. -
Preparation of capsules for oral use 4-OH OPB (Example 7) 50 mg Amylum maydis q.s.
The powder is mixed and filled into hard gelatin capsules (Capsugel size 00). -
Preparation of tablets Gram 4-OH OPB (Example 7) 200 Lactose 85 Polyvinylpyrrolidone 5 Starch 42 Talcum powder 15 Magnesium stearate 3
4-OH OPB and lactose are screened through a 0.15 mm sieve and mixed together with an aqueous solution of polyvinyl-pyrrolidone. The mass is granulated, and the dried (40° C.) granulate is mixed with starch, talcum powder and magnesium stearate. The granulate is compressed into tablets. The tablet diameter is 11 mm, the tablet weight is 350 mg and each tablet contains 200 mg 4-OH OPB. - Preparation of a Suspension for Rectal Administration
- Methyl p-hydroxybeznzoate (70 mg) and propyl-p-hydroxybenzoate (15 mg) are dissolved in water (100 ml) at 90° C. After cooling to 30° C., methyl cellulose (2g) is added and the mixture is agitated for 3 hours. 1 gram 4-OH OPB (Example 7) is screened through a 0.15 mm sieve, and dispersed in the solution under vigorous stirring. The suspension is filled in a 100 ml tube. The suspension contains 10 mg 4-OH OPB/ml.
-
Preparation of oral suspension Gram 4OH OPB (Example 7) 10 Carboxymethyl cellulose 1.5 Sorbitol 200 Sodium benzoate 1.0 Orange essence 0.3 Apricot essence 0.7 Ethanol 50 Water 236.5
Carboxymethyl cellulose, sorbitol and sodium benzoate are dissolved in water with stirring for 2 hours. A solution of the essences in ethanol is added. 4-OH OPB is screened through a 0.15 mm sieve and dispersed in the solution under vigorous stirring. The suspension (10 gram) is filled in a 20 ml tube. Each tube contains 200 mg 4-OH OPB. - Mouse Toxicity
- 20g mice were given single doses of 4OH-OPB (20 mM in DMSO) intraperitoneally. Doses of 1 to 100 μM (in ECF), corresponding to 0.29 to 29 μM/kg bodyweight, produced no toxic effect. Furthermore, injection of 4OH-OPB could be increased to 2000 mg/kg (corresponding to 20 mM in the extracellular fluid) before the mice started to die (6 out of 10 died at 2000 mg/kg). Thus the concentrations that effectively inhibit HIV replication in cell cultures are up to 200000 times lower than the lethal dose in mice.
Claims (11)
1. (canceled)
2. A method of treatment of the human or non-human body to combat an inflammatory or viral disease, which method comprises administering to said body an optionally hydroxy-protected 4-hydroxy or hydroperoxy-3,5-dioxo-pyrazolidine or an equivalent wherein a pyrazolidine ring attached oxygen is replaced by a sulphur, or a physiologically acceptable salt thereof.
3. A method as claimed in claim 2 comprising administering said optionally hydroxy-protected 4-hydroxy or hydroperoxy-3,5-dioxo-pyrazolidine or an equivalent wherein a pyrazolidine ring attached oxygen is replaced by a sulphur, or a physiologically acceptable salt thereof in combination with another antiviral agent.
4. A method as claimed in claim 3 wherein said additional antiviral agent is at least one antiviral agent selected from a reverse transcriptase inhibitor and a protease inhibitor.
5. A method as claimed in claim 3 wherein said additional antiviral agent is an agent selected from the group of AZT, indinavir, nevirapine and 2′,3′-dideoxyinosine (dal).
6. A method as claimed in claim 2 wherein said disease is a disease caused by a pathogen from the group of togaviridea, reoviridea, picornaviridea, hantaviridea, orthomyxoviridea, paramyxoviridea, mononegaviralis, viral hepatitis, haemorrhagic fevers, flaviviridea, viral encephalitis, coronaviridea, calciviridea, adenoviridea, papovaviridea, arboviridea, pox virus, rhabdoviridea, arenaviridea HIV-1, HIV-2, HTLV-I, HTLV-II and herpes viruses.
7. A method of combatting HIV infection which comprises administering to an HIV-infected patient a T-lymphocyte growth suppressing agent in an amount sufficient to suppress T-lymphocyte growth in said patient for a period sufficient to reduce the T-lymphocyte concentration in the lymphatic system in said patient by at least 25% said administration being repeated at intervals of at least 3 months.
8. A method combatting HIV infection as claimed in claim 6 wherein said T-lymphocyte growth suppressing agent is a pyrazolidinol.
9. A method as claimed in claim 7 wherein said interval is at least 9 months.
10. A method as claimed in claim 7 wherein a 4-hydroxy or hydroperoxy-3,5-dioxo-pyrazolidine or an equivalent wherein a pyrazolidine ring attached oxygen is replaced by a sulphur, or a physiologically acceptable salt thereof is administered in a daily dose of 0.1 to 10 μmol/kg dobyweight.
11-26. (canceled)
Priority Applications (2)
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US11/371,226 US20070037772A1 (en) | 1999-06-29 | 2006-03-09 | Pyrazolidinol compounds |
US12/007,694 US20080287390A1 (en) | 1999-06-29 | 2008-01-14 | Pyrazolidinol compounds |
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GBGB9915184.7A GB9915184D0 (en) | 1999-06-29 | 1999-06-29 | Compounds |
GB9915184.7 | 1999-06-29 | ||
PCT/GB2000/002513 WO2001000585A1 (en) | 1999-06-29 | 2000-06-29 | Pyrazolidinol compounds |
US10/019,229 US6852749B1 (en) | 1999-06-29 | 2000-06-29 | Pyrazolidinol compounds |
US10/701,498 US20040152751A1 (en) | 1999-06-29 | 2003-11-06 | Pyrazolidinol compounds |
US11/371,226 US20070037772A1 (en) | 1999-06-29 | 2006-03-09 | Pyrazolidinol compounds |
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US10/701,498 Abandoned US20040152751A1 (en) | 1999-06-29 | 2003-11-06 | Pyrazolidinol compounds |
US11/371,226 Abandoned US20070037772A1 (en) | 1999-06-29 | 2006-03-09 | Pyrazolidinol compounds |
US12/007,694 Abandoned US20080287390A1 (en) | 1999-06-29 | 2008-01-14 | Pyrazolidinol compounds |
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EP (1) | EP1194409B1 (en) |
JP (1) | JP2003503389A (en) |
AT (1) | ATE316960T1 (en) |
AU (1) | AU775355B2 (en) |
CA (1) | CA2377200A1 (en) |
DE (1) | DE60025826T2 (en) |
GB (1) | GB9915184D0 (en) |
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PT1399156E (en) * | 2001-06-18 | 2007-02-28 | Applied Research Systems | Alkylidene pirazolidinedione derivatives and their use for treating diabetes and obesity |
US7091232B2 (en) * | 2002-05-21 | 2006-08-15 | Allergan, Inc. | 4-(substituted cycloalkylmethyl) imidazole-2-thiones, 4-(substituted cycloalkenylmethyl) imidazole-2-thiones, 4-(substituted cycloalkylmethyl) imidazol-2-ones and 4-(substituted cycloalkenylmethyl) imidazol-2-ones and related compounds |
NO326130B1 (en) * | 2002-10-08 | 2008-10-06 | Enok Tjotta | Method for selecting and testing compounds that inhibit or stimulate clonal cell growth |
GB0317269D0 (en) * | 2003-07-23 | 2003-08-27 | Viral Asa A | Compounds |
JP2007537221A (en) * | 2004-05-12 | 2007-12-20 | エー−ヴァイラル エーエスエー | Tonic treatment with oxyphenbutazone derivatives |
US9034968B2 (en) | 2011-03-31 | 2015-05-19 | W. R. Grace & Co.-Conn. | Cationic polymers for treating construction aggregates |
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US4117232A (en) * | 1976-03-08 | 1978-09-26 | Interx Research Corporation | Transient pro-drug forms of phenylbutazone |
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US6551360B2 (en) * | 1996-03-22 | 2003-04-22 | Laurent Vidal | Pyrazoline-3,5-dione-containing compositions for dyeing keratin fibres; their use in dyeing as couplers; dyeing process |
Family Cites Families (1)
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DE2022712C3 (en) * | 1970-05-09 | 1975-01-02 | Chem.-Pharmaz. Fabrik Dr. Hermann Thiemann Gmbh, 4628 Luenen | Anti-phlogistic agent |
-
1999
- 1999-06-29 GB GBGB9915184.7A patent/GB9915184D0/en not_active Ceased
-
2000
- 2000-06-29 EP EP00940667A patent/EP1194409B1/en not_active Expired - Lifetime
- 2000-06-29 DE DE60025826T patent/DE60025826T2/en not_active Expired - Lifetime
- 2000-06-29 AT AT00940667T patent/ATE316960T1/en not_active IP Right Cessation
- 2000-06-29 CA CA002377200A patent/CA2377200A1/en not_active Abandoned
- 2000-06-29 AU AU55575/00A patent/AU775355B2/en not_active Ceased
- 2000-06-29 JP JP2001506995A patent/JP2003503389A/en active Pending
- 2000-06-29 WO PCT/GB2000/002513 patent/WO2001000585A1/en active IP Right Grant
- 2000-06-29 US US10/019,229 patent/US6852749B1/en not_active Expired - Lifetime
-
2002
- 2002-01-17 ZA ZA200200432A patent/ZA200200432B/en unknown
-
2003
- 2003-11-06 US US10/701,498 patent/US20040152751A1/en not_active Abandoned
-
2006
- 2006-03-09 US US11/371,226 patent/US20070037772A1/en not_active Abandoned
-
2008
- 2008-01-14 US US12/007,694 patent/US20080287390A1/en not_active Abandoned
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US3629282A (en) * | 1961-04-24 | 1971-12-21 | Georges Negrevergne | 3 5-dioxo - 1 2 - diphenyl-4-n-butyl-4-polyoxyethylene pyrazolidines |
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US3845213A (en) * | 1972-11-20 | 1974-10-29 | Thiemann Chem Pharm Fab | 1,2-diphenyl-3,5-dioxopyrazolidine compounds used to treat inflammation |
US3968219A (en) * | 1974-07-29 | 1976-07-06 | Schering Aktiengesellschaft | Hydroxy phenylbutazone derivatives and their preparation |
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US4169147A (en) * | 1975-01-06 | 1979-09-25 | Interx Research Corporation | Novel transient pro-drug forms of phenylbutazone and oxyphenbutazone in compositions and methods of use |
US4117232A (en) * | 1976-03-08 | 1978-09-26 | Interx Research Corporation | Transient pro-drug forms of phenylbutazone |
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US6551360B2 (en) * | 1996-03-22 | 2003-04-22 | Laurent Vidal | Pyrazoline-3,5-dione-containing compositions for dyeing keratin fibres; their use in dyeing as couplers; dyeing process |
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Publication number | Publication date |
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ATE316960T1 (en) | 2006-02-15 |
US20080287390A1 (en) | 2008-11-20 |
AU5557500A (en) | 2001-01-31 |
DE60025826D1 (en) | 2006-04-13 |
GB9915184D0 (en) | 1999-09-01 |
EP1194409A1 (en) | 2002-04-10 |
DE60025826T2 (en) | 2006-11-02 |
US20040152751A1 (en) | 2004-08-05 |
EP1194409B1 (en) | 2006-02-01 |
WO2001000585A1 (en) | 2001-01-04 |
ZA200200432B (en) | 2003-03-26 |
US6852749B1 (en) | 2005-02-08 |
AU775355B2 (en) | 2004-07-29 |
CA2377200A1 (en) | 2001-01-04 |
JP2003503389A (en) | 2003-01-28 |
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