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Pyrazolidinol compoundsRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), O-glycoside, , Nitrogen Containing Hetero Ring, Purines (including Hydrogenated) (e.g., Adenine, Guanine, Etc.)Pyrazolidinol compounds description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20070037772, Pyrazolidinol compounds. Brief Patent Description - Full Patent Description - Patent Application Claims
[0001] 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. [0002] Phenbutazone and oxyphenbutazone are 1,2-bis aromatic-3,5-pyrazolidinediones which have been used as non-steroidal anti-inflammatory drugs (NSAIDs) [0003] 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)). [0004] 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. [0005] We have now surprisingly found that where the 4-carbon of the N.sub.2C.sub.3 ring carries an optionally protected hydroxy or thiol group, the compounds have very significantly enhanced antiviral, in particular anti-HIV, efficacy. [0006] 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. [0007] 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. [0008] 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. [0009] 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. [0010] 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. [0011] 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. [0012] The compounds of the invention, hereinafter referred to as pyrazolidinols for convenience, will preferably be of formula I (where each X.sub.2, which may be the same or different is O or S, preferably O; [0013] X.sub.1 is O, OO or S, preferably O or S, most preferably O; [0014] R.sub.1 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; [0015] R.sub.2 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 [0016] each Ar, which may be the same or different, is a homo or heterocyclic aromatic group, optionally substituted, e.g. by C.sub.1-6 alkyl or alkoxy groups) or a salt thereof. [0017] In the compounds of the invention 0, 1 or 2 of the X.sub.1 and X.sub.2 groups may be S. It is thought that it is especially preferred that one thio X.sub.2 group be present. [0018] In the compounds of the invention, the R.sub.2 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 C.sub.1-6 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. [0019] Where R.sub.1 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 R.sub.1,OH metabolite. Acyl groups are preferred in this regard. [0020] In the compounds of formula I, where each X.sub.2 is oxygen and one Ar is phenyl, the other Ar is preferably other than phenyl e.g. parahydroxyphenyl. [0021] 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 R.sub.1 is a protecting group may be useful as intermediates in the production of compounds of formula I in which R.sub.1 is hydrogen. [0022] 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 C.sub.1-6 alkyl groups but especially by electron withdrawing substituents, e.g. hydroxy, thiol, phenyl, C.sub.1-6 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 --X.sub.1--R.sub.1 or Cl (where --X.sub.1--R.sub.1 is as defined above). Especially preferably one Ar is phenyl and the other is p-hydroxy-phenyl. [0023] 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. [0024] 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. [0025] 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. [0026] The pyrazolidinols of the invention may be prepared by oxidation of a corresponding compound where R.sub.1X.sub.1 is replaced by hydrogen; by reaction of a corresponding compound where R.sub.1X.sub.1 is HX.sub.1 with a hydroxy or thiol protecting agent to introduce a non-hydrogen R.sub.1 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 IIAr-HN--NH-Ar (II) with a compound of formula III where R.sub.1, R.sub.2, X.sub.1, X.sub.2 and Ar are as hereinbefore defined and X.sub.2R.sub.3 is a leaving group, for example where R.sub.3 is an alkyl group, e.g. a C.sub.1-6 alkyl group. [0027] Alternatively, a compound of formula II may be condensed with a compound of formula IV (where X.sub.2 and R.sub.3 are as defined above) and then reacted with an alkylating agent, e.g. (R.sub.2).sub.2Zn to produce a compound of formula I in which XR.sub.1 is OH or SH. [0028] 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. Continue reading about Pyrazolidinol compounds... Full patent description for Pyrazolidinol compounds Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Pyrazolidinol compounds patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. Fill in the keywords to be monitored. 3. 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