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WO2009130242A1 - Low molecular weight derivatives and use thereof in treatment of prostaglandin e synthase related diseases - Google Patents

Low molecular weight derivatives and use thereof in treatment of prostaglandin e synthase related diseases Download PDF

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Publication number
WO2009130242A1
WO2009130242A1 PCT/EP2009/054811 EP2009054811W WO2009130242A1 WO 2009130242 A1 WO2009130242 A1 WO 2009130242A1 EP 2009054811 W EP2009054811 W EP 2009054811W WO 2009130242 A1 WO2009130242 A1 WO 2009130242A1
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Prior art keywords
alkyl
treatment
compound according
monocyclic
inflammation
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PCT/EP2009/054811
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French (fr)
Inventor
Jacob Westman
Björn KULL
Patric Stenberg
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Novasaid Ab
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D231/10—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
    • 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
    • C07D231/44—Oxygen and nitrogen or sulfur and nitrogen atoms
    • C07D231/46—Oxygen atom in position 3 or 5 and nitrogen atom in position 4
    • C07D231/50—Acylated on said nitrogen atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to disubstituted hydrazono-5-oxo-4,5-dihydro-pyrazole- 1 -carbothioic acid amide derivatives and to the use thereof in disease therapy. More particularly, the present invention relates to derivatives for the treatment of inflammation related diseases. Even more particularly, the present invention relates to compounds acting on microsomal prostaglandin E synthase for the treatment and prevention of fever, pain and inflammation as well as cancer.
  • the present invention relates to compounds which inhibit, regulate and/ or modulate the activity of microsomal prostaglandin E synthase, compositions which contain these compounds, and methods of using them to treat diseases and conditions such as pain, fever, inflammations and cancer, and the like in mammals.
  • Prostaglandin (PG) E 2 is produced in a sequential action including liberation of arachidonic acid, conversion into PGG2/PGH2 by cyclooxygenase (Cox- 1 or Cox-2) and finally prostaglandin E synthase converts PGH2 into PG E2 (Fig. 1 ) .
  • MPGES l microsomal prostaglandin E synthase 1
  • CPGES cytosolic prostaglandin E synthase
  • MPGES2 microsomal prostaglandin E synthase 2
  • the latter two enzymes are constitutively expressed whereas MPGES l is inducible by proinflammatory cytokines.
  • MPGES 1 was regarded as the enzyme predominantly coupled with Cox-2 activity however; later results demonstrate that MPGES 1 can also catalyze the conversion of Cox- 1 derived PGH2 into PGE2.
  • MPGES l possesses the highest catalytic efficiency of the known PGE synthases.
  • PGE2 as one of the most potent mediators of inflammation together with many in vitro reports on the presence of MPGES l in different models of inflammation suggested this enzyme to be an attractive drug target for development of new anti inflammatory drugs with fewer side effects than the currently available NSAIDs and selective Cox-2 inhibitors.
  • the rationale being that MPGES 1 is predominantly expressed during inflammation and that other enzymes exist that mediate house keeping functions.
  • NSAIDs constitute many drugs that inhibit Cox- 1 and Cox-2 with a continuum of different potencies on respective enzymes.
  • Acetyl salicylic acid being a preferred Cox- 1 inhibitor along the way to selective Cox-2 inhibitors e.g. rofecoxib, or celecoxib (Vioxx and Celebrex, respectively).
  • Cox- 1 inhibitors are cardio-protective by their capability to prevent thromboxane formation in platelets while deleterious vascular effects after prolonged usage of selective Cox-2 inhibitors have been reported, likely through the effect of Cox-2 dependent prostacyclin formation in endothelial cells. The ratio of thromboxane:prostacylin is diminished by Cox- 1 inhibitors but increased by Cox-2 inhibitors.
  • Cox-1 inhibitors are also known to result in increased frequency of gastric bleedings and kidney function impairments.
  • Cox-2 inhibitors also result in gastric side effects as well as negative changes in the body water-salt balance with problems of edema formation and hypertension as a consequence. This seems particularly a problem for rofecoxib.
  • MPGES 1 Specific inhibition of MPGES 1 may overcome many of these side effects due to the fact that the balance among the prostaglandins will not primarily be influenced. Thus only the proinflammatory pressure during induced PGE2 formation will be targeted.
  • an MPGES 1 inhibitor will possess enforced anti-inflammatory potential since Cox-2 generated anti-inflammatory prostaglandins such as cyclopentenons may increase due to shunting of PGH2 in macrophages (Fig 2B). Such shunting will not occur in platelets (there is no evidence for PGE synthase activity in these cells).
  • endothelial cells there might occur a shunting upon activation since these cells become activated during inflammation which leads to high formation of PGE2 and prostacyclin. In that case, we expect increased prostacyclin formation with protecting effects against vascular side effects.
  • the present invention relates a compound of formula (I)
  • R 1 is a moiety selected from alkyl or monocyclic carbocyclyl which moiety optionally is substituted with one or more R 4 ;
  • R 2 and R 3 are each independently selected from H and a moiety selected from alkyl and monocyclic or bicyclic carbocyclyl and heterocyclyl, which moiety optionally is substituted with one or more R 5 ;
  • R 4 and R 5 are independently selected from halogen, alkyl, monocyclic or bicyclic carbocyclyl and heterocyclyl, alkoxy, CN, CF 3 , OH, NO 2 , COOH, C(O)Oalkyl, OC(O)alkyl, NC(O)alkyl, N(alkyl) 2 ; as well as pharmaceutically acceptable salts or prodrugs of the compounds of formula (I), for use as a medicament.
  • R 1 is methyl
  • R 2 is hydrogen
  • R 3 is selected from monocyclic or bicyclic carbocyclyl and monocyclic or bicyclic heterocyclyl.
  • R 5 is selected from halogen and alkyl.
  • R 3 is selected from monocyclic carbocyclyl and R 5 is selected from halogen and alkyl.
  • the compound of formula (I) is (E) -4- (2- (3 - bromophenyl)hydrazono)-3-methyl-5-oxo-4,5-dihydro-lH-pyrazole-l-carbothioamide, of formula:
  • the invention provides new pharmaceutical compositions comprising said compounds, or salts or prodrugs thereof.
  • the invention provides a method of medical treatment by use of said pharmaceutical compositions.
  • the invention provides the use of the inventive compounds, or salts or prodrugs thereof in the manufacture of a medicament for the treatment or prevention of a disorder selected from pain, fever, inflammation and cancer.
  • Figure l(A) represents the biosynthesis of prostaglandin E 2 and (B) the hypothetic effect of MPGES 1 blockage - shunting into the anti-inflammatory PGD2 pathway and formation of cyclopentenons.
  • Figure 2 is a diagram showing the net paw swelling (ml*0.01) as a function of number of days after administration of a single dose of Complete Freund's Adjuvant (CFA) into the subplantar region of the right hind paw of Lewis-derived male rats, in an Adjuvant-Induced Arthritis rat model.
  • CFA Complete Freund's Adjuvant
  • Prostaglandins detection kits were purchased from Cayman Chemicals and used according to the instruction of the manufacturer. In vitro toxicology assay kit, MTT based from Sigma, cat N - TOXl.
  • prostaglandins can be separated by RP-HPLC and detected by UV spectrophotometry (Terragno et al. Prostaglandins 21(1), 101-12 (1981); Powell Anal. Biochem. 148(1), 59-69 (1985)).
  • the molar extinction coefficient of PGE2 is 16,500 at 192.5 nm (Terragno et al. Prostaglandins 21(1), 101-12 (1981)).
  • the main products of PGH2 are PGF2 ⁇ , PGE 2 and PGD 2 .
  • the retention times were 19.0, 23.8 and 28.6 minutes for PGF2 ⁇ , PGE 2 and PGD 2 , respectively.
  • PGE synthase Care must be taken when assaying PGE synthase with PGH 2 .
  • the substrate is very labile and decomposes non-enzymatically, with a half-life of about 5 min at 37°C, into a mixture of PGE 2 and PGD 2 with an E/ D ratio of about 3.
  • the PGE synthase catalysis is very fast, which is why substrate depletion easily can occur within seconds thus preventing a quantitative analysis. After the reaction has been terminated, any remaining PGH 2 must also rapidly be separated from the products in order not to interfere with the results.
  • the substrate PGH2
  • PGH2 and reduced glutathione GSH
  • a stop-solution was used, containing FeCl2, which converted any remaining PGH2 into HHT.
  • the products are much more stable in organic solvents so we immediately extracted the sample after termination by solid phase extraction and kept the eluate in acetonitrile.
  • Protein samples were diluted in potassium inorganic phosphate buffer (0.1M, pH 7.4) containing 2.5 mM reduced glutathione (GSH). 4 ⁇ l PGH2, dissolved in acetone (0,284 mM) were added to Eppendorf tubes and kept on C ⁇ 2-ice (-78 0 C). Prior to the incubation, both the substrate and samples were transferred onto wet-ice (or 37°C) for 2 min temperature equilibration. The reaction was started by the addition of the lOO ⁇ l sample to the tubes containing PGH2.
  • potassium inorganic phosphate buffer 0.1M, pH 7.4
  • PGH2 reduced glutathione
  • the reaction was terminated by the addition of 400 ⁇ l stop solution (25 mM FeCl 2 , 50 mM citric acid and 2.7 ⁇ M 1 1 - ⁇ PGE 2 ), lowering the pH to 3, giving a total concentration of 20 mM FeCl 2 , 40 mM citric acid and 2. 1 ⁇ M 1 1 - ⁇ PGE 2 .
  • Solid phase extraction was performed immediately using C 18-chromabond columns. The samples were eluted with 500 ⁇ l acetonitrile and thereafter ImI H 2 O was added.
  • an aliquot 150 ⁇ l was analyzed by RP-HPLC, combined with UV detection at 195 nm.
  • the reverse-phase HPLC column was Nova-Pak C 18 (3.9 X 150 mm, 4 ⁇ m particle size) obtained from Waters and the mobile phase was water, acetonitrile and trifluoroacetic acid (72:28:0.007, by volume). The flow rate was 0.7 ml/ min and the products were quantified by integration of the peak areas.
  • TSA-MDA assay Thiobarbituric acid assay (TBA-MDA assay or Malondialdehyde assay)
  • Malondialdehyde is a product of lipid peroxidation and reacts with thiobarbituric acid forming a red product that absorbs at 535 nm (W.G. Niehaus, Jr and B. Samuelsson, Eur. J. Biochem 6, 126 (1968).
  • the extinction coefficient of the TBA-MDA conjugate is 1.56 x IO 5 M- i cm- i (E.D. Wills. Biochem. J. 1 13, 315 ( 1969).
  • the method used for detection of inhibition of mPGES- 1 is based on the detection of the amount of remaining PGH2. This method was described more than 20 years ago by Basevich et al (Bioorg. Khim. 1983, 9(5), 658-665.
  • the assay used was a modified variant and used citric acid instead of the TCA-TBA- HCl reagent described in the original assay.
  • membrane- bound mPGES- 1 was incubated with PGH2.
  • the reaction was stopped by adding citric acid with a final pH of 3 and a large excess of FeC12 (20 mM) to convert any remaining PGH2 into MDA and 12 -HHT.
  • TBA reagent was finally added (0.67%) and the samples were heated at 80 0 C for 30 min.
  • the absorbance of the conjugate was measured at 535 nm.
  • Synovial fibroblasts from human RA patients (passage four) growing in 96 well tissue culture plates were induced with IL-I beta (10ng/ml) and TNFalfa (10ng/ml).
  • Test compound at a concentration of 10, 1, 0.1 or 0 ⁇ M was added and the cells were further cultured for 24h. After 24 hours, supernatants were collected and number of viable cells was evaluated using MTT test according to manufacturer's instructions. PG E2 levels in supernatants were measured by EIA according to manufacturer's instructions. Results were expressed as PGE2 levels in supernatants (and adjusted for MTT) and related to PGE2 levels in supernatants from cells which were induced without adding test compound. Since the test compound did not affect cell viability at any concentration tested, normalization for MTT did not contribute to observed differences in PGE2 content. Results
  • A549 lung carcinoma cells seeded at a density of 10, 000 cells/ well, were grown in 96 well tissue culture plates. TNFalfa (5ng/ml) and IL-lbeta (5ng/ml) were added and the cells were incubated for 16 hours. Cells were washed in PBS and test compounds at the appropriate concentration in HBSS/0.1% BSA were added. After 30 minutes incubation with test compounds, 10 ⁇ M arachidonic acid was added and cells were further incubated for 30 minutes. Supernatant was collected and analyzed for PGE2 content by EIA according to manufacturer's instructions.
  • Lewis-derived male rats weighing 205 ⁇ 15 g were used. Test compound at 50 mg/kg was administered intraperitoneally for 5 consecutive days. A well-ground suspension of killed Mycobacterium tuberculosis (0.3 mg in 0. 1 mL of light mineral oil; Complete Freund's Adjuvant, CFA) was administered in a single dose into the subplantar region of the right hind paw 1 hour following the first dose of test substance (denoted day 1). Right hind paw volume was measured by plethysmometer and water cell (25 mm Diameter) on day 0 (before CFA treatment), and on days 1 , 5, 8, 1 1 , 14 and 18 after CFA treatment of right paw (with CFA).
  • CFA Complete Freund's Adjuvant
  • the compounds according to formula (I) will be useful for treating various diseases such as pain, fever, inflammations and cancer.
  • the treatment may be preventive, palliative or curative.
  • Examples of pharmaceutically acceptable addition salts for use in the pharmaceutical compositions of the present invention include those derived from mineral acids, such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric and sulphuric acids, and organic acids, such as tartaric, acetic, citric, malic, lactic, fumaric, benzoic, glycolic, gluconic, succinic, and arylsulphonic acids.
  • mineral acids such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric and sulphuric acids
  • organic acids such as tartaric, acetic, citric, malic, lactic, fumaric, benzoic, glycolic, gluconic, succinic, and arylsulphonic acids.
  • the pharmaceutically acceptable excipients described herein, for example, vehicles, adjuvants, carriers or diluents are well-known to those who are skilled in the art and are readily available to the public.
  • the pharmaceutically acceptable carrier may be one that is chemically inert to the active compounds and that has no detrimental side effects or toxicity under the conditions of use.
  • Pharmaceutical formulations are found e.g. in Remington: The Science and Practice of Pharmacy, 19th ed., Mack Printing Company, Easton, Pennsylvania ( 1995).
  • Prodrugs of the compounds of formula (I) may be prepared by modifying functional groups present on the compound in such a way that the modifications are cleaved, in vivo when such prodrug is administered to a mammalian subject. The modifications typically are achieved by synthesizing the parent compound with a prodrug substituent.
  • Prodrugs include compounds of formula (I) wherein a hydroxy, amino, sulfhydryl, carboxy or carbonyl group in a compound of formula (I) is bonded to any group that may be cleaved in vivo to regenerate the free hydroxyl, amino, or sulfhydryl group, respectively.
  • prodrugs include, but are not limited to, esters and carbamates of hydroxy functional groups, esters groups of carboxyl functional groups, N-acyl derivatives, N-Mannich bases. General information on prodrugs may be found e.g. in Bundegaard, H. "Design of Prodrugs” pl-92, Elesevier, New York-Oxford (1985).
  • composition according to the invention may be prepared for any route of administration, e.g. oral, intravenous, cutaneous or subcutaneous, nasal, intramuscular, or intraperitoneal.
  • routes of administration e.g. oral, intravenous, cutaneous or subcutaneous, nasal, intramuscular, or intraperitoneal.
  • a parenterally acceptable aqueous solution is employed, which is pyrogen free and has requisite pH, isotonicity and stability.
  • the dose administered to a mammal, particularly a human, in the context of the present invention should be sufficient to affect a therapeutic response in the mammal over a reasonable time frame.
  • dosage will depend upon a variety of factors including the potency of the specific compound, the age, condition and body weight of the patient, as well as the stage /severity of the disease.
  • the dose will also be determined by the route (administration form) timing and frequency of administration. In the case of oral administration the dosage can vary from about 0.01 mg to about 1000 mg per day of a compound of formula (I) or the corresponding amount of a pharmaceutically acceptable salt thereof.
  • the compounds of the present invention may be used or administered in combination with one or more additional drugs useful in the treatment of pain, fever, inflammations and cancer.
  • the components may be in the same formulation or in separate formulations for administration simultaneously or sequentially.
  • the compounds of the present invention may also be used or administered in combination with other treatment such as irradiation for the treatment of cancer.
  • alkyl unless otherwise stated, means an unbranched or branched, cyclic, saturated or unsaturated (alkenyl or alkynyl) hydrocarbyl radical.
  • the alkyl group is preferably C3 to C 12, more preferably C5 to C lO, most preferably C5-C7.
  • the alkyl group is preferably C l to C lO, more preferably C l to C6, more preferably methyl, ethyl, propyl (n-propyl, isopropyl), butyl (branched or unbranched) or pentyl, most preferably methyl.
  • aryl means an aromatic group, such as phenyl or naphthyl.
  • functional groups means in the case of unprotected: hydroxy-, thiolo-, aminofunction, carboxylic acid and in the case of protected: lower alkoxy, N-, O-, S- acetyl, carboxylic acid ester.
  • heteroaryl means a mono-, bi-, or tricyclic heteroaromatic group containing one or ore heteroatom(s) preferably selected from N, O and S, such as pyridyl, pyrrolyl, quinolinyl, furanyl, thienyl, oxadiazolyl, thiadiazolyl, thiazolyl, oxazolyl, pyrazolyl, triazolyl, tetrazolyl, tetrahydroquinolinyl, tetrazolyl, thiadiazolyl, thiazolyl, thiochromanyl, thienyl, triazolyl, isoxazolyl, isothiazolyl, isoquinolinyl, naphthyridinyl, imidazolyl, pyrimidinyl, phenazinyl, phenothiazinyl, phthalazinyl, indolyl,
  • non-aromatic heterocycle means a non-aromatic cyclic group containing one or more heteroatom(s) preferably selected from N, O and S, such as a aziridinyl, azetidinyl, dihydropyranyl, dihydropyridyl, dihydropyrrolyl, dioxolanyl, dioxanyl, dithianyl, dithiolanyl, imidazolidinyl, imidazolinyl, morpholinyl, oxetanyl, oxiranyl, pyrrolidinyl, pyrrolidinonyl, piperidyl, piperazinyl, piperidinyl, pyranyl, pyrazolidinyl, quinuclidinyl, sulfalonyl, 3-sulfolenyl, tetrahydrofuranyl tetrahydropyranyl tetrahydropyrid
  • halogen means a fluorine, chlorine, bromine or iodine.
  • substituted means that the concerned groups are substituted with at least one functional group, such as hydroxyl, amine, sulfide, silyl, carboxylic acid, carboxylic acid ester, halogen, acylgroups, aryl, etc.
  • the compounds according to formula (I) will be useful for treating various diseases such as pain, fever, inflammations and cancer.
  • the treatment may be preventive, palliative or curative.
  • Examples of pharmaceutically acceptable addition salts for use in the pharmaceutical compositions of the present invention include those derived from mineral acids, such as hydrochlorid, hydrobromic, phosphoric, metaphosphoric, nitric and sulphuric acids, and organic acids, such as tartaric, acetic, citric, malic, lactic, fumaric, benzoic, glycolic, gluconic, succinic, and arylsulphonic acids.
  • the pharmaceutically acceptable excipients described herein, for example, vehicles, adjuvants, carriers or diluents, are well-known to those who are skilled in the art and are readily available to the public.
  • the pharmaceutically acceptable carrier may be one that is chemically inert to the active compounds and that has no detrimental side effects or toxicity under the conditions of use.
  • Pharmaceutical formulations are found e.g. in Remington: The Science and Practice of Pharmacy, 19th ed., Mack Printing Company, Easton, Pennsylvania ( 1995).
  • Prodrugs of the compounds of formulas (I) may be prepared by modifying functional groups present on the compound in such a way that the modifications are cleaved, in vivo when such prodrug is administered to a mammalian subject. The modifications typically are achieved by synthesizing the parent compound with a prodrug substituent.
  • Prodrugs include compounds of formula (I) wherein a hydroxy, amino, sulfhydryl, carboxy or carbonyl group in a compound of formula (I) is bonded to any group that may be cleaved in vivo to regenerate the free hydroxyl, amino, or sulfhydryl group, respectively.
  • prodrugs include, but are not limited to, esters and carbamates of hydroxy functional groups, esters groups of carboxyl functional groups, N-acyl derivatives, N-Mannich bases. General information on prodrugs may be found e.g. in Bundegaard, H. "Design of Prodrugs” pl-92, Elesevier, New York-Oxford (1985).
  • composition according to the invention may be prepared for any route of administration, e.g. oral, intravenous, cutaneous or subcutaneous, nasal, intramuscular, or intraperitoneal.
  • routes of administration e.g. oral, intravenous, cutaneous or subcutaneous, nasal, intramuscular, or intraperitoneal.
  • a parenterally acceptable aqueous solution is employed, which is pyrogen free and has requisite pH, isotonicity and stability.
  • the dose administered to a mammal, particularly a human, in the context of the present invention should be sufficient to affect a therapeutic response in the mammal over a reasonable time frame.
  • dosage will depend upon a variety of factors including the potency of the specific compound, the age, condition and body weight of the patient, as well as the stage /severity of the disease.
  • the dose will also be determined by the route (administration form) timing and frequency of administration.
  • the dosage can vary from about 0.01 mg to about 1000 mg per day of a compound of formulas (I) for the corresponding amount of a pharmaceutically acceptable salt thereof.
  • the compounds of the present invention may be used or administered in combination with one or more additional drugs useful in the treatment of pain, fever, inflammations and cancer.
  • the components may be in the same formulation or in separate formulations for administration simultaneously or sequentially.
  • the compounds of the present invention may also be used or administered in combination with other treatment such as irradiation for the treatment of cancer.

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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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Abstract

A compound of formula (I) for use as a medicament, and a pharmaceutical composition comprising the compound. The compound is useful for the treatment of a disorder selected from pain, fever, inflammation and cancer.

Description

Low molecular weight derivatives and use thereof in treatment of prostaglandin E synthase related diseases
Field of the invention The present invention relates to disubstituted hydrazono-5-oxo-4,5-dihydro-pyrazole- 1 -carbothioic acid amide derivatives and to the use thereof in disease therapy. More particularly, the present invention relates to derivatives for the treatment of inflammation related diseases. Even more particularly, the present invention relates to compounds acting on microsomal prostaglandin E synthase for the treatment and prevention of fever, pain and inflammation as well as cancer.
Background of the invention
The present invention relates to compounds which inhibit, regulate and/ or modulate the activity of microsomal prostaglandin E synthase, compositions which contain these compounds, and methods of using them to treat diseases and conditions such as pain, fever, inflammations and cancer, and the like in mammals.
The following is provided as background information only and should not be taken as an admission that any subject matter discussed or that any reference mentioned is prior art to the instant invention.
Prostaglandin (PG) E2 is produced in a sequential action including liberation of arachidonic acid, conversion into PGG2/PGH2 by cyclooxygenase (Cox- 1 or Cox-2) and finally prostaglandin E synthase converts PGH2 into PG E2 (Fig. 1 ) . There exist three known enzymes that catalyze the latter reaction i.e. microsomal prostaglandin E synthase 1 (MPGES l), cytosolic prostaglandin E synthase (CPGES), and microsomal prostaglandin E synthase 2 (MPGES2). The latter two enzymes are constitutively expressed whereas MPGES l is inducible by proinflammatory cytokines. Initially, MPGES 1 was regarded as the enzyme predominantly coupled with Cox-2 activity however; later results demonstrate that MPGES 1 can also catalyze the conversion of Cox- 1 derived PGH2 into PGE2. MPGES l possesses the highest catalytic efficiency of the known PGE synthases. The role of PGE2 as one of the most potent mediators of inflammation together with many in vitro reports on the presence of MPGES l in different models of inflammation suggested this enzyme to be an attractive drug target for development of new anti inflammatory drugs with fewer side effects than the currently available NSAIDs and selective Cox-2 inhibitors. The rationale being that MPGES 1 is predominantly expressed during inflammation and that other enzymes exist that mediate house keeping functions.
NSAIDs constitute many drugs that inhibit Cox- 1 and Cox-2 with a continuum of different potencies on respective enzymes. Acetyl salicylic acid being a preferred Cox- 1 inhibitor along the way to selective Cox-2 inhibitors e.g. rofecoxib, or celecoxib (Vioxx and Celebrex, respectively). Cox- 1 inhibitors are cardio-protective by their capability to prevent thromboxane formation in platelets while deleterious vascular effects after prolonged usage of selective Cox-2 inhibitors have been reported, likely through the effect of Cox-2 dependent prostacyclin formation in endothelial cells. The ratio of thromboxane:prostacylin is diminished by Cox- 1 inhibitors but increased by Cox-2 inhibitors. Cox-1 inhibitors are also known to result in increased frequency of gastric bleedings and kidney function impairments. Cox-2 inhibitors also result in gastric side effects as well as negative changes in the body water-salt balance with problems of edema formation and hypertension as a consequence. This seems particularly a problem for rofecoxib.
Specific inhibition of MPGES 1 may overcome many of these side effects due to the fact that the balance among the prostaglandins will not primarily be influenced. Thus only the proinflammatory pressure during induced PGE2 formation will be targeted. Although unexpected side effects of course may evolve, the possibility also exists that an MPGES 1 inhibitor will possess enforced anti-inflammatory potential since Cox-2 generated anti-inflammatory prostaglandins such as cyclopentenons may increase due to shunting of PGH2 in macrophages (Fig 2B). Such shunting will not occur in platelets (there is no evidence for PGE synthase activity in these cells). In endothelial cells there might occur a shunting upon activation since these cells become activated during inflammation which leads to high formation of PGE2 and prostacyclin. In that case, we expect increased prostacyclin formation with protecting effects against vascular side effects.
Although, the bulk of evidence already suggested MPGES l to constitute a drug target, the results using gene targeted knock out mice have provided unequivocal important data regarding the physiological role of MPGES l . 1) These mice develop significantly less arthritis symptoms in experimental models of arthritis (CIA and AIA). 2) These mice demonstrate less sensitivity to pain both induced in inflammatory settings and neuropathic settings. 3) These mice do not develop endotoxin, IL- lbeta or cytokine induced fever. 4) Finally, as of today, gross histopathological examinations of various organs including the GI tract, behavioural and reproductive parameters have not demonstrated any differences to the results obtained for wild type animals. However, in an ongoing study, the healing phase after heart damage caused by permanent ligation of one major coronary vessel in MPGES l knock out mice suggest impaired healing or remodeling of the heart. This must be compared with Cox-2 knock out mice where the heart spontaneously develop fibrosis and can not be used in such models. Also, in higher mammals, MPGES2 may take over this function since it is predominantly expressed in the heart.
Kalluarya et al (Arch. Pharm. Pharm. Med. Chem. 2001 , 334, 263-268) disclose compounds of formula
Figure imgf000004_0001
as intermediates for further synthesis.
Summary of the invention
According to one aspect, the present invention relates a compound of formula (I)
Figure imgf000004_0002
(I)
wherein
R1 is a moiety selected from alkyl or monocyclic carbocyclyl which moiety optionally is substituted with one or more R4;
R2 and R3 are each independently selected from H and a moiety selected from alkyl and monocyclic or bicyclic carbocyclyl and heterocyclyl, which moiety optionally is substituted with one or more R5; R4 and R5 are independently selected from halogen, alkyl, monocyclic or bicyclic carbocyclyl and heterocyclyl, alkoxy, CN, CF3, OH, NO2, COOH, C(O)Oalkyl, OC(O)alkyl, NC(O)alkyl, N(alkyl)2; as well as pharmaceutically acceptable salts or prodrugs of the compounds of formula (I), for use as a medicament.
In one embodiment, in a compound of formula (I) R1 is methyl, R2 is hydrogen and R3 is selected from monocyclic or bicyclic carbocyclyl and monocyclic or bicyclic heterocyclyl.
In one embodiment, in a compound of formula (I), R5 is selected from halogen and alkyl.
In one embodiment, in a compound of formula (I), R3 is selected from monocyclic carbocyclyl and R5 is selected from halogen and alkyl.
In one embodiment, the compound of formula (I) is (E) -4- (2- (3 - bromophenyl)hydrazono)-3-methyl-5-oxo-4,5-dihydro-lH-pyrazole-l-carbothioamide, of formula:
Figure imgf000005_0001
According to a still further aspect, the invention provides new pharmaceutical compositions comprising said compounds, or salts or prodrugs thereof.
According to a still further aspect the invention provides a method of medical treatment by use of said pharmaceutical compositions.
According to one aspect, the invention provides the use of the inventive compounds, or salts or prodrugs thereof in the manufacture of a medicament for the treatment or prevention of a disorder selected from pain, fever, inflammation and cancer.
Any further aspects are as defined in the claims. Brief description of the drawings
Figure l(A) represents the biosynthesis of prostaglandin E2 and (B) the hypothetic effect of MPGES 1 blockage - shunting into the anti-inflammatory PGD2 pathway and formation of cyclopentenons.
Figure 2 is a diagram showing the net paw swelling (ml*0.01) as a function of number of days after administration of a single dose of Complete Freund's Adjuvant (CFA) into the subplantar region of the right hind paw of Lewis-derived male rats, in an Adjuvant-Induced Arthritis rat model.
Detailed description of the invention
Biological test
Prostaglandins detection kits were purchased from Cayman Chemicals and used according to the instruction of the manufacturer. In vitro toxicology assay kit, MTT based from Sigma, cat N - TOXl.
HPLC Assay
Earlier studies have demonstrated that prostaglandins can be separated by RP-HPLC and detected by UV spectrophotometry (Terragno et al. Prostaglandins 21(1), 101-12 (1981); Powell Anal. Biochem. 148(1), 59-69 (1985)). The molar extinction coefficient of PGE2 is 16,500 at 192.5 nm (Terragno et al. Prostaglandins 21(1), 101-12 (1981)). The main products of PGH2 are PGF2α, PGE2 and PGD2. Using the described RP-HPLC conditions, the retention times were 19.0, 23.8 and 28.6 minutes for PGF2α, PGE2 and PGD2, respectively. 1 lβ-PGE2 was used as the internal standard and 1 lβ-PGE2 was eluted with a retention time of 25.3 min with almost baseline separation from PGE2. In order to quantify PGE2, a standard curve of PGE2 was made. The curve was linear over the range from 0.9 pmol to 706 pmol (R2 = 0.9997, k = 0.0012). For quantification we routinely use both the external standard as well as the internal standard technique, the latter method accounting also for losses during preparation.
Care must be taken when assaying PGE synthase with PGH2. The substrate is very labile and decomposes non-enzymatically, with a half-life of about 5 min at 37°C, into a mixture of PGE2 and PGD2 with an E/ D ratio of about 3. Also, the PGE synthase catalysis is very fast, which is why substrate depletion easily can occur within seconds thus preventing a quantitative analysis. After the reaction has been terminated, any remaining PGH2 must also rapidly be separated from the products in order not to interfere with the results. In order to minimize non-enzymatic production of PGE2, the substrate (PGH2) was always kept on CO2-ice (-780C) until use and the enzyme reaction was performed at 00C in the presence of PGH2 and reduced glutathione (GSH). A stop-solution was used, containing FeCl2, which converted any remaining PGH2 into HHT. Also, the products are much more stable in organic solvents so we immediately extracted the sample after termination by solid phase extraction and kept the eluate in acetonitrile.
Protein samples were diluted in potassium inorganic phosphate buffer (0.1M, pH 7.4) containing 2.5 mM reduced glutathione (GSH). 4 μl PGH2, dissolved in acetone (0,284 mM) were added to Eppendorf tubes and kept on Cθ2-ice (-780C). Prior to the incubation, both the substrate and samples were transferred onto wet-ice (or 37°C) for 2 min temperature equilibration. The reaction was started by the addition of the lOOμl sample to the tubes containing PGH2. The reaction was terminated by the addition of 400μl stop solution (25 mM FeCl2, 50 mM citric acid and 2.7 μM 1 1 -β PGE2), lowering the pH to 3, giving a total concentration of 20 mM FeCl2, 40 mM citric acid and 2. 1 μM 1 1 -β PGE2. Solid phase extraction was performed immediately using C 18-chromabond columns. The samples were eluted with 500 μl acetonitrile and thereafter ImI H2O was added. In order to determine the formation of PGE2 and 1 1 -β PGE2, an aliquot ( 150μl) was analyzed by RP-HPLC, combined with UV detection at 195 nm. The reverse-phase HPLC column was Nova-Pak C 18 (3.9 X 150 mm, 4 μm particle size) obtained from Waters and the mobile phase was water, acetonitrile and trifluoroacetic acid (72:28:0.007, by volume). The flow rate was 0.7 ml/ min and the products were quantified by integration of the peak areas.
Thiobarbituric acid assay (TBA-MDA assay or Malondialdehyde assay)
Malondialdehyde is a product of lipid peroxidation and reacts with thiobarbituric acid forming a red product that absorbs at 535 nm (W.G. Niehaus, Jr and B. Samuelsson, Eur. J. Biochem 6, 126 (1968). The extinction coefficient of the TBA-MDA conjugate is 1.56 x IO5 M-i cm-i (E.D. Wills. Biochem. J. 1 13, 315 ( 1969).
The method used for detection of inhibition of mPGES- 1 is based on the detection of the amount of remaining PGH2. This method was described more than 20 years ago by Basevich et al (Bioorg. Khim. 1983, 9(5), 658-665.
The assay used was a modified variant and used citric acid instead of the TCA-TBA- HCl reagent described in the original assay. In this assay recombinant, membrane- bound mPGES- 1 was incubated with PGH2. The reaction was stopped by adding citric acid with a final pH of 3 and a large excess of FeC12 (20 mM) to convert any remaining PGH2 into MDA and 12 -HHT. TBA reagent was finally added (0.67%) and the samples were heated at 80 0C for 30 min. The absorbance of the conjugate was measured at 535 nm.
The product of mPGES- 1 (PGE2) was not measured directly in this assay, but rather the remaining substrate (PGH2) indirectly by adding FeCl2 that converts PGH2 into MDA and 12 -HHT. As a positive control a known mPGES-1 inhibitor, MK-886, was used and the new inhibitors were compared with the inhibition of MK-886 (% of MK- 886 inhibition).
Red product ~530nM (1.56XlO5M"1 cm"1)
Total Activity = A530-A560 / 1 min 0.265 (U/ml) χ 1.56x105
0.05 Selected results from the TBA-MDA assay (IC50 in μM)
Figure imgf000008_0001
Fibroblast assay
Synovial fibroblasts from human RA patients (passage four) growing in 96 well tissue culture plates were induced with IL-I beta (10ng/ml) and TNFalfa (10ng/ml). Test compound at a concentration of 10, 1, 0.1 or 0 μM was added and the cells were further cultured for 24h. After 24 hours, supernatants were collected and number of viable cells was evaluated using MTT test according to manufacturer's instructions. PG E2 levels in supernatants were measured by EIA according to manufacturer's instructions. Results were expressed as PGE2 levels in supernatants (and adjusted for MTT) and related to PGE2 levels in supernatants from cells which were induced without adding test compound. Since the test compound did not affect cell viability at any concentration tested, normalization for MTT did not contribute to observed differences in PGE2 content. Results
Figure imgf000009_0001
A549 assay
A549 lung carcinoma cells, seeded at a density of 10, 000 cells/ well, were grown in 96 well tissue culture plates. TNFalfa (5ng/ml) and IL-lbeta (5ng/ml) were added and the cells were incubated for 16 hours. Cells were washed in PBS and test compounds at the appropriate concentration in HBSS/0.1% BSA were added. After 30 minutes incubation with test compounds, 10 μM arachidonic acid was added and cells were further incubated for 30 minutes. Supernatant was collected and analyzed for PGE2 content by EIA according to manufacturer's instructions.
Figure imgf000009_0002
In-vivo results
LPS Air Pouch Model of Acute Inflammation in the Rat
(Adapted from "Models of Inflammation: Carrageenan Air Pouch in the Rat" current protocols in pharmacology (1998) 5.6.1-5.6.6)
8-12 weeks old Dark Agouti rats were anesthetized with isofluorane and 20 ml of sterile filtered air was injected to each rat subcutaneously into the intracapsular area of the back (20μm sterile syringe filter, 20ml syringe, 23-G/ l-in needle). The air pouches were allowed to mature for 24h. On the day of the experiment, rats were anesthetized and injected intraperitoneally with 1 mL test compound dissolved in 90% PEG400 / 10% DMSO resulting in a 75mg/kg dose of test compound or PEG/DMSO vehicle alone. 30 minutes post administration of test compound or vehicle, an intra-pouch injection with 2ml of a solution of LPS 5μg/ml in sterile PBS (2ml syringe, 20G/ l -in needle) was made.
6h post-LPS injection the rat was killed by CO2 inhalation. A second 2ml intra-pouch injection of lavage solution (5.4mM EDTA in sterile PBS, freshly prepared from a 54mM EDTA sterile filtered stock solution) ( 10ml syringe, 18G/ 1.5in needle) given. The pouch was immediately drained of lavage fluid and the effect of test compound relative vehicle control on the inflammatory reaction was assessed by analyzing PGE2 content in the pouch exudate. PGE2 was measured by EIA according to the manufacturers instructions.
Figure imgf000010_0001
Test compound.
Performing this test on the test compound resulted in a 65% reduction in inducible PGE2 formation relative to vehicle control.
Adjuvant-Induced Arthritis
Lewis-derived male rats weighing 205 ± 15 g were used. Test compound at 50 mg/kg was administered intraperitoneally for 5 consecutive days. A well-ground suspension of killed Mycobacterium tuberculosis (0.3 mg in 0. 1 mL of light mineral oil; Complete Freund's Adjuvant, CFA) was administered in a single dose into the subplantar region of the right hind paw 1 hour following the first dose of test substance (denoted day 1). Right hind paw volume was measured by plethysmometer and water cell (25 mm Diameter) on day 0 (before CFA treatment), and on days 1 , 5, 8, 1 1 , 14 and 18 after CFA treatment of right paw (with CFA). For CFA-injected right paw volume, the paw volume on days 1 , 5, 8, 1 1 , 14 and 18 was compared to that on day 0. (Fig. 2) The compounds according to formula (I) will be useful for treating various diseases such as pain, fever, inflammations and cancer. The treatment may be preventive, palliative or curative.
Examples of pharmaceutically acceptable addition salts for use in the pharmaceutical compositions of the present invention include those derived from mineral acids, such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric and sulphuric acids, and organic acids, such as tartaric, acetic, citric, malic, lactic, fumaric, benzoic, glycolic, gluconic, succinic, and arylsulphonic acids. The pharmaceutically acceptable excipients described herein, for example, vehicles, adjuvants, carriers or diluents, are well-known to those who are skilled in the art and are readily available to the public. The pharmaceutically acceptable carrier may be one that is chemically inert to the active compounds and that has no detrimental side effects or toxicity under the conditions of use. Pharmaceutical formulations are found e.g. in Remington: The Science and Practice of Pharmacy, 19th ed., Mack Printing Company, Easton, Pennsylvania ( 1995).
Prodrugs of the compounds of formula (I) may be prepared by modifying functional groups present on the compound in such a way that the modifications are cleaved, in vivo when such prodrug is administered to a mammalian subject. The modifications typically are achieved by synthesizing the parent compound with a prodrug substituent. Prodrugs include compounds of formula (I) wherein a hydroxy, amino, sulfhydryl, carboxy or carbonyl group in a compound of formula (I) is bonded to any group that may be cleaved in vivo to regenerate the free hydroxyl, amino, or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, esters and carbamates of hydroxy functional groups, esters groups of carboxyl functional groups, N-acyl derivatives, N-Mannich bases. General information on prodrugs may be found e.g. in Bundegaard, H. "Design of Prodrugs" pl-92, Elesevier, New York-Oxford (1985).
The composition according to the invention may be prepared for any route of administration, e.g. oral, intravenous, cutaneous or subcutaneous, nasal, intramuscular, or intraperitoneal. The precise nature of the carrier or other material will depend on the route of administration. For a parenteral administration, a parenterally acceptable aqueous solution is employed, which is pyrogen free and has requisite pH, isotonicity and stability. Those skilled in the art are well able to prepare suitable solutions and numerous methods are described in the literature. A brief review of methods of drug delivery is also found in e.g. Langer, Science 249: 1527-1533 ( 1990).
The dose administered to a mammal, particularly a human, in the context of the present invention should be sufficient to affect a therapeutic response in the mammal over a reasonable time frame. One skilled in the art will recognize that dosage will depend upon a variety of factors including the potency of the specific compound, the age, condition and body weight of the patient, as well as the stage /severity of the disease. The dose will also be determined by the route (administration form) timing and frequency of administration. In the case of oral administration the dosage can vary from about 0.01 mg to about 1000 mg per day of a compound of formula (I) or the corresponding amount of a pharmaceutically acceptable salt thereof.
The compounds of the present invention may be used or administered in combination with one or more additional drugs useful in the treatment of pain, fever, inflammations and cancer. The components may be in the same formulation or in separate formulations for administration simultaneously or sequentially. The compounds of the present invention may also be used or administered in combination with other treatment such as irradiation for the treatment of cancer.
Examples of active compounds of formula I
No Compound structure No Compound structure
Figure imgf000012_0001
Figure imgf000013_0001
Figure imgf000013_0002
Figure imgf000013_0004
51
Figure imgf000013_0005
Figure imgf000013_0003
Figure imgf000014_0001
Figure imgf000015_0001
Figure imgf000016_0001
Figure imgf000016_0002
Figure imgf000016_0004
Figure imgf000016_0005
Figure imgf000016_0003
21
Figure imgf000016_0006
Figure imgf000017_0001
Figure imgf000017_0002
Figure imgf000017_0004
Figure imgf000017_0003
Figure imgf000017_0005
Figure imgf000018_0001
Figure imgf000018_0002
Figure imgf000018_0003
Figure imgf000018_0004
Figure imgf000018_0005
Figure imgf000019_0001
80
Figure imgf000020_0001
Figure imgf000020_0002
Figure imgf000020_0003
Figure imgf000020_0004
Figure imgf000020_0005
Figure imgf000020_0006
Figure imgf000021_0001
Figure imgf000021_0002
Figure imgf000021_0004
Figure imgf000021_0003
Figure imgf000022_0001
As used herein the term "alkyl" unless otherwise stated, means an unbranched or branched, cyclic, saturated or unsaturated (alkenyl or alkynyl) hydrocarbyl radical. Where cyclic, the alkyl group is preferably C3 to C 12, more preferably C5 to C lO, most preferably C5-C7. Where acyclic, the alkyl group is preferably C l to C lO, more preferably C l to C6, more preferably methyl, ethyl, propyl (n-propyl, isopropyl), butyl (branched or unbranched) or pentyl, most preferably methyl.
As used herein, the term "aryl" means an aromatic group, such as phenyl or naphthyl. As used herein, the term "functional groups" means in the case of unprotected: hydroxy-, thiolo-, aminofunction, carboxylic acid and in the case of protected: lower alkoxy, N-, O-, S- acetyl, carboxylic acid ester.
As used herein, the term "heteroaryl" means a mono-, bi-, or tricyclic heteroaromatic group containing one or ore heteroatom(s) preferably selected from N, O and S, such as pyridyl, pyrrolyl, quinolinyl, furanyl, thienyl, oxadiazolyl, thiadiazolyl, thiazolyl, oxazolyl, pyrazolyl, triazolyl, tetrazolyl, tetrahydroquinolinyl, tetrazolyl, thiadiazolyl, thiazolyl, thiochromanyl, thienyl, triazolyl, isoxazolyl, isothiazolyl, isoquinolinyl, naphthyridinyl, imidazolyl, pyrimidinyl, phenazinyl, phenothiazinyl, phthalazinyl, indolyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinolizinyl, quinoxalinyl, tetrahydroisoquinolinyl, pyrazinyl, indazolyl, indolinyl, indolyl, pyrimidinyl, thiophenetyl, pyranyl, carbazolyl, chromanyl, cinnolinyl, acridinyl, quinolinyl, benzimidazolyl, benzodioxanyl, benzodioxepinyl, benzodioxolyl, benzofuranyl, benzothiazolyl, benzobenzoxadiazolyl, benzothiazolyl, benzoxazinyl, benzoxazolyl, benzimidazolyl, benzomorpholinyl, benzoselenadiazolyl, benzothienyl, purinyl, cinnolinyl pteridinyl and the like.
As used herein, the term "non-aromatic heterocycle" means a non-aromatic cyclic group containing one or more heteroatom(s) preferably selected from N, O and S, such as a aziridinyl, azetidinyl, dihydropyranyl, dihydropyridyl, dihydropyrrolyl, dioxolanyl, dioxanyl, dithianyl, dithiolanyl, imidazolidinyl, imidazolinyl, morpholinyl, oxetanyl, oxiranyl, pyrrolidinyl, pyrrolidinonyl, piperidyl, piperazinyl, piperidinyl, pyranyl, pyrazolidinyl, quinuclidinyl, sulfalonyl, 3-sulfolenyl, tetrahydrofuranyl tetrahydropyranyl tetrahydropyridyl, thietanyl, thiiranyl, thiolanyl, thiomorpholinyl, trithianyl, tropanyl, monosaccharide and the like, .
As used herein the term "halogen" means a fluorine, chlorine, bromine or iodine.
As used herein, and unless specified otherwise, the term "substituted" means that the concerned groups are substituted with at least one functional group, such as hydroxyl, amine, sulfide, silyl, carboxylic acid, carboxylic acid ester, halogen, acylgroups, aryl, etc.
The compounds according to formula (I) will be useful for treating various diseases such as pain, fever, inflammations and cancer. The treatment may be preventive, palliative or curative.
Examples of pharmaceutically acceptable addition salts for use in the pharmaceutical compositions of the present invention include those derived from mineral acids, such as hydrochlorid, hydrobromic, phosphoric, metaphosphoric, nitric and sulphuric acids, and organic acids, such as tartaric, acetic, citric, malic, lactic, fumaric, benzoic, glycolic, gluconic, succinic, and arylsulphonic acids. The pharmaceutically acceptable excipients described herein, for example, vehicles, adjuvants, carriers or diluents, are well-known to those who are skilled in the art and are readily available to the public. The pharmaceutically acceptable carrier may be one that is chemically inert to the active compounds and that has no detrimental side effects or toxicity under the conditions of use. Pharmaceutical formulations are found e.g. in Remington: The Science and Practice of Pharmacy, 19th ed., Mack Printing Company, Easton, Pennsylvania ( 1995).
Prodrugs of the compounds of formulas (I) may be prepared by modifying functional groups present on the compound in such a way that the modifications are cleaved, in vivo when such prodrug is administered to a mammalian subject. The modifications typically are achieved by synthesizing the parent compound with a prodrug substituent. Prodrugs include compounds of formula (I) wherein a hydroxy, amino, sulfhydryl, carboxy or carbonyl group in a compound of formula (I) is bonded to any group that may be cleaved in vivo to regenerate the free hydroxyl, amino, or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, esters and carbamates of hydroxy functional groups, esters groups of carboxyl functional groups, N-acyl derivatives, N-Mannich bases. General information on prodrugs may be found e.g. in Bundegaard, H. "Design of Prodrugs" pl-92, Elesevier, New York-Oxford (1985).
The composition according to the invention may be prepared for any route of administration, e.g. oral, intravenous, cutaneous or subcutaneous, nasal, intramuscular, or intraperitoneal. The precise nature of the carrier or other material will depend on the route of administration. For a parenteral administration, a parenterally acceptable aqueous solution is employed, which is pyrogen free and has requisite pH, isotonicity and stability. Those skilled in the art are well able to prepare suitable solutions and numerous methods are described in the literature. A brief review of methods of drug delivery is also found in e.g. Langer, Science 249: 1527-1533 ( 1990).
The dose administered to a mammal, particularly a human, in the context of the present invention should be sufficient to affect a therapeutic response in the mammal over a reasonable time frame. One skilled in the art will recognize that dosage will depend upon a variety of factors including the potency of the specific compound, the age, condition and body weight of the patient, as well as the stage /severity of the disease. The dose will also be determined by the route (administration form) timing and frequency of administration. In the case of oral administration the dosage can vary from about 0.01 mg to about 1000 mg per day of a compound of formulas (I) for the corresponding amount of a pharmaceutically acceptable salt thereof.
The compounds of the present invention may be used or administered in combination with one or more additional drugs useful in the treatment of pain, fever, inflammations and cancer. The components may be in the same formulation or in separate formulations for administration simultaneously or sequentially. The compounds of the present invention may also be used or administered in combination with other treatment such as irradiation for the treatment of cancer.

Claims

Claims
1. A compound of formula (I)
Figure imgf000025_0001
(I)
wherein
R1 is a moiety selected from alkyl or monocyclic carbocyclyl which moiety optionally is substituted with one or more R4;
R2 and R3 are each independently selected from H and a moiety selected from alkyl and monocyclic or bicyclic carbocyclyl and heterocyclyl, which moiety optionally is substituted with one or more R5;
R4 and R5 are independently selected from halogen, alkyl, monocyclic or bicyclic carbocyclyl and heterocyclyl, alkoxy, CN, CF3, OH, NO2, COOH, C(O)Oalkyl, OC(O)alkyl, NC(O)alkyl, N(alkyl)2 wherein any cyclyl moiety may be substituted with one or more R4
as well as pharmaceutically acceptable salts or prodrugs of the compounds of formula (I), for use as a medicament.
2. A compound according to claim 1 , wherein R1 is methyl, R2 is hydrogen and R3 is selected from monocyclic or bicyclic carbocyclyl and monocyclic or bicyclic heterocyclyl.
3. A compound according to claim 1 or 2, wherein R5 is selected from halogen and alkyl.
4. A compound according to any one of claims 1-3, wherein R3 is selected from monocyclic carbocyclyl and R5 is selected from halogen and alkyl.
5. A compound according to any one of claims 1 -4, which is (E) -4- (2- (3 - bromophenyl)hydrazono)-3-methyl-5-oxo-4,5-dihydro-lH-pyrazole-l -carbothioamide
Figure imgf000026_0001
6. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 -5, or a pharmaceutically acceptable salt or prodrug thereof, and at least one pharmaceutically acceptable excipient.
7. Use of a compound according to any one of claims 1 -5, for preparing a medicament for the treatment of a disorder selected from pain, fever, inflammation and cancer.
8. The use according to claim 7, wherein the disorder is inflammation.
9. A compound according to any one of claims 1 -5, for use in the treatment of a disorder selected from pain, fever, inflammation and cancer.
10. A method of treatment of a disease selected from pain, fever, inflammation anc cancer by administration of a therapeutically effective amount of a compound according to any one of claims 1 -5, or a pharmaceutically acceptable salt or prodrug thereof to a patient in the need of such treatment.
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