Classifications

• • 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
  • C07D231/06—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/415—1,2-Diazoles
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
  • A61P11/06—Antiasthmatics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/06—Antipsoriatics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/06—Antimigraine agents
• • 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]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• the present invention relates to new pyrazoline derivatives, of general formula (I), and to physiologically acceptable salts thereof, to the procedures for their preparation, to their application as medicaments in human and or veterinary therapy and to the pharmaceutical composition that contain them.
• the new compounds object of the present invention can be used in the pharmaceutical industry as intermediates and for the preparation of medicaments.
• Non-steroid anti-inflammatory drugs are traditionally classified as anti-inflammatory, antipyretic and analgesic agents for the symptomatic alleviation of inflammation, fever and light to moderate pain.
• the main indications for these drugs are osteoarthritis, rheumatoid arthritis and other inflammatory diseases of articulations, as well as for the treatment of inflammations associated with small lesions and as analgesics of broad use.
• the NSAIDS are essentially inhibitors of acute inflammatory response, but in rheumatic disorders they have little effect on the underlying degenerative changes occurring in tissue.
• the COX-1 isoenzyme is essentially expressed in most of tissues with the function of synthesising prostaglandins which regulate the normal cell activity.
• the isoenzyme COX-2 is not normally present in cells but in chronic inflammation the levels of the protein COX-2 increase in parallel with the over-production of prostaglandins [J. R. Vane, R. M. Hotting, Infalmm. Res., 1995, 44, 1]. Therefore, a selective COX-2 inhibitor has the same anti-inflammatory, antipyretic and analgesic properties as a conventional non-steroid anti-inflammatory agent and also inhibits the uterine contractions induced by hormones and presents potential anti-carcinogenic effects and beneficial effects in the prevention of the development of Alzheimer disease.
• a selective COX-2 inhibitor reduces the potential gastrointestinal toxicity, reduces the potential renal side effects and reduces the effects of bleeding time.
• the tri-dimensional structure of COX-1 has been determined by x-ray diffraction [D. Picot, P J. Loll, R. M Garavito, Nature, 1994, 367, 243].
• Three of the helixes of the structure form the entrance to the cyclooxygenase channel and its insertion in the membrane allows the arachidonic acid to access the active site from inside the bilayer.
• the active site of cyclooxygenase is a large hydrophobic channel and the authors argue that the NSAIDS inhibit COX-1 by excluding arachidonic acid from the upper part of the channel. Recently [R. S.
• COX-2 the three-dimensional structure of COX-2 has been described, which allows comparison of the similarities and differences between the two isoforms and therefore study of new drugs that selectively inhibit COX-2.
• the structures of COX-1 and COX-2 show that the sites where the anti-inflammatory agents bind to the enzymes are very similar but there is a difference of at least one important amino acid.
• a voluminous isoleucine present in the active site of COX-1 is replaced by a valine in COX-2.
• the isoleucine blocks the lateral cavity that is separated from the principle bond of both isoenzymes.
• the blocked cavity of COX-1 does not impede the binding of classic NSAIDS, but an inhibitor that needs the extra support point supplied by the lateral cavity will bind more easily to COX-2 than to COX-1.
• a model for a new generation of anit-inflammatory agents is one where the inhibitors of cyclooxygenase have a large preference for the lateral cavity of COX-2.
• novel compounds derived from pyrazolines of general formula (I) show interesting biological properties and these make them particularly useful for their employment in human and/or veterinary therapy.
• the compounds object of this invention are useful as agents with anti-inflammatory activity and for other diseases in which cyclooxygenase-2 plays a part, without having the gastric and renal toxicity of the classic NSAIDS.
• the present invention provides new pyrazolines that inhibit the enzyme cyclooxygenase-2, with application in human and/or veterinary medicine as anti-inflammatories and for other diseases in which cyclooxygenase-2 plays a part, and that have low or no gastric and renal toxicity. These anti-inflammatories therefore have a better safety profile.
• the new compounds object of the present invention are derivatives of ⁇ 2 -pyrazolines, also known as 4,5-dihydro-1H-pyrazoles. They are therefore nitrogenated heterocyclic compounds. As a result the pyrazoline rings are not planar as opposed to the azoles described previously.
• the compounds object of the present invention have the general formula (I) where
• R 1 represents a methyl group
• the new compounds of general formula (I) have an asymmetric carbon atom and so can be prepared enantiomerically pure or as racemates.
• the racemates of compounds (I) can be resolved into their optical isomers by conventional methods, such as separation by chiral stationary phase chromatography for example, or by fractionated crystallisation of its diastereoisomeric salts, which can be prepared by reacting the compounds (I) with enantiomerically pure acids. Similarly, they can also be obtained by enantioselective synthesis using enantiomerically pure chiral precursors.
• the present invention also relates to the physiologically acceptable salts of the compounds of general formula (I), in particular, to the addition salts formed with mineral acids such as hydrochloric, hydrobromic, phosphoric, sulphuric, nitric acid, etc, and with organic acids such as citric, maleic, fumaric acid, tartaric acids or its derivatives, p-toluenesulphonic, methanosulphonic, camphosulphonic acid etc.
• mineral acids such as hydrochloric, hydrobromic, phosphoric, sulphuric, nitric acid, etc
• organic acids such as citric, maleic, fumaric acid, tartaric acids or its derivatives, p-toluenesulphonic, methanosulphonic, camphosulphonic acid etc.
• novel derivatives of general formula (I) can be used in mammals, including man, as anti-inflammatory agents for the treatment of inflammation and for the treatment of other disorders associated with inflammation, such as analgesics for the treatment of pain and migraine, and as anti-pyretics in the treatment of fever.
• the new derivatives of general formula (I) can be used in the treatment of arthritis, including but limited to the treatment of rheumatoid arthritis, spondyloarthropathies, gouty arthritis, systemic lupus erythematosus, osteoarthritis and juvenile arthritis.
• novel derivatives of general formula (I) can be used in the treatment of asthma, bronchitis, menstrual disorders, tendinitis, bursitis and different states that affect the skin such as psoriasis, eczema, burns and dermatitis.
• the novel derivatives of general formula (I) can also be used in the treatment of gastrointestinal afflictions such as syndrome of inflamed intestine. Crohn's disease, gastritis, irritated colon syndrome and ulcerous colitis.
• the preparation of the compounds of general formula (I) is carried out by reacting a compound of general formula (II) wherein R 1 represents a hydrogen atom, a methyl, fluoromethyl, difluoromethyl, trifluoromethyl and carboxylic acid groups, and R 2 , R 3 , R 4 and R 5 have the same meaning as that indicated for general formula (I), with a phenylhydrazine of general formula (III) in base or salt form wherein R 6 , R 7 and R 8 have the same meaning as that described previously for general formula I.
• the reaction is carried out in the presence of a suitable solvent such as, for example, alcohols such as methanol, ethanol, ethers such as dioxane, tetrahydrofuran, or mixtures thereof or other solvents.
• a suitable solvent such as, for example, alcohols such as methanol, ethanol, ethers such as dioxane, tetrahydrofuran, or mixtures thereof or other solvents.
• the reaction takes place in acid medium, that can be organic, such as acetic acid, for example, or inorganic such as hydrochloric acid for example, or a mixture of the two, or in a base medium such as piperidine, piperazine, sodium hydroxide, potassium hydroxide, sodium methoxide or sodium ethoxide for example, or a mixture thereof.
• the acidic or base medium itself can act as a solvent.
• the most suitable temperatures vary between room temperature and the reflux temperature of the solvent and the reaction times can lie between several hours and several days.
• the reaction is carried out in the reagent as its own solvent or in other appropriate solvents such as halogenated hydrocarbons such as dichloromethane, chloroform or carbon tetrachloride, ethers such as dioxane, tetrahydrofuran, ethyl ether or dimethoxyethane.
• halogenated hydrocarbons such as dichloromethane, chloroform or carbon tetrachloride
• ethers such as dioxane, tetrahydrofuran, ethyl ether or dimethoxyethane.
• the most appropriate temperatures vary between 0° C. and the reflux temperature of the solvent and the reaction times lie between ten minutes and 24 hours.
• the reaction is carried out in a suitable solvent such as, for example, ethers such as dioxane, tetrahydrofuran, ethyl ether or dimethoxyethane.
• a suitable solvent such as, for example, ethers such as dioxane, tetrahydrofuran, ethyl ether or dimethoxyethane.
• ethers such as dioxane, tetrahydrofuran, ethyl ether or dimethoxyethane.
• the most suitable temperatures vary between 0° C. and the reflux temperature of the solvent and the reaction times lie between 1 and 24 hours.
• the preparation of the compounds of general formula (I), wherein R 1 represents a cyano group and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 y R 8 have the same meaning as that indicated above, is carried out by reacting a compound of general formula (I) wherein R 1 represents a carboxamide group and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 have the same meaning as that indicated above, with a suitable reagent such as, for example, the thionyl dimethylformamide-chloride or methanosulphonyl chloride.
• a suitable solvent such as, for example, dimethylformamide or pyridine.
• the most suitable temperatures vary between 0° C. and the reflux temperature of the solvent and the reaction times lies between fifteen minutes and 24 hours.
• the reaction is carried out in a suitable solvent such as, for example, dichloromethane, chloroform or benzene, or an ether such as tetrahydrofurane, ethyl ether, dimethoxyethane or dioxane.
• a suitable solvent such as, for example, dichloromethane, chloroform or benzene, or an ether such as tetrahydrofurane, ethyl ether, dimethoxyethane or dioxane.
• a suitable solvent such as, for example, dichloromethane, chloroform or benzene, or an ether such as tetrahydrofurane, ethyl ether, dimethoxyethane or dioxane.
• the most suitable temperatures vary between ⁇ 70° C. and the reflux temperature of the solvent, and the reaction times lie between fifteen minutes and twenty hours.
• the reaction is carried out in a suitable solvent such as, for example, halogenated hydrocarbons such as dichloromethane, chloroform or carbon tetrachloride or ethers such as dioxane, tetrahydrofuran, ethyl ether or dimethoxyethane.
• a suitable solvent such as, for example, halogenated hydrocarbons such as dichloromethane, chloroform or carbon tetrachloride or ethers such as dioxane, tetrahydrofuran, ethyl ether or dimethoxyethane.
• halogenated hydrocarbons such as dichloromethane, chloroform or carbon tetrachloride
• ethers such as dioxane, tetrahydrofuran, ethyl ether or dimethoxyethane.
• the reaction is carried out in a suitable solvent such as, for example, an alcohol such as methanol or ethanol, a halogenated hydrocarbon such as carbon tetrachloride, chloroform or dichloromethane, an ether such as tetrahydrofuran, ethyl ether, dioxane or dimethoxyethane, water or a mixture thereof.
• a suitable solvent such as, for example, an alcohol such as methanol or ethanol, a halogenated hydrocarbon such as carbon tetrachloride, chloroform or dichloromethane, an ether such as tetrahydrofuran, ethyl ether, dioxane or dimethoxyethane, water or a mixture thereof.
• a suitable solvent such as, for example, an alcohol such as methanol or ethanol, a halogenated hydrocarbon such as carbon tetrachloride, chloroform or dichloromethane, an ether such as te
• R 1 , R 2 , R 3 , R 4 , R 7 and R 8 have the same meaning as that indicated above and R 5 represents a hydrogen, chlorine, fluorine atom, a methyl, trifluoromethyl, methoxy or trifluoromethoxy group, provided—in all cases—that R 6 represents an acetylaminosulphonyl group, or R 6 represents a hydrogen, chlorine, fluorine atom, a methyl, trifluoromethyl, methoxy or trifluoromethoxy group, provided—in all cases—that R 5 represents an acetylaminosulphonyl group, is carried out by reacting a compound of general formula (I) wherein R 1 , R 2 , R 3 , R 4 , R 7 and R 8 have the same meaning as that indicated above and R 5 represents a hydrogen, chlorine, fluorine atom, a methyl, trifluoromethyl, methoxy or trifluoromethoxy group, provided—
• the invention provides pharmaceutical compositions that comprise, as well as a pharmaceutically acceptable excipient, at least one compound of general formula (I) or a physiologically acceptable salt thereof.
• the invention also relates to use of a compound of general formula (I) and its physiologically acceptable salts in the preparation of a medicament for the treatment of inflammation and/or for the treatment of other disorders associated with inflammation.
• the crude oil obtained is purified using column chromatography through silica gel under pressure (eluting with AcOEt-petrol ether 1:9) to obtain (E)-1,1,1-trifluoro-4-(4-methylphenyl)-3-butene-2-one (0.8 g, yield: 75%) in the form of a clear oil.
• the crude product is purified using column chromatography through silica gel under pressure, eluting with AcOEt-petrol ether (4:6) obtaining 1-(4-aminosulphonylphenyl)-4,5-dihydro-5-phenyl-5-methyl-3-trifluoromethyl-1H-pyrazole in the form of a white solid (1.46 g, yield: 47%) with a
• racemic mixture ( ⁇ )-1-(4-aminosulphonylphenyl)-5-(2,4-difluorophenyl)-4,5-dihydro-3-trifluoromethyl-1H-pyrazole is resolved into its enantiomers by high performance liquid chromatography using a CHIRALPAK AS column with 10 ⁇ particles and dimensions of 25 ⁇ 2 cm (Daicel), mobile phase 0.1% diethylamine in methanol and a flow rate of 8 ml/min.
• Table 1 shows some examples that are encompassed by the general formula (I) and in Table 2 the data are indicated for identification of these compounds.
• the examples 1-36, 44-63 and 65-74 have been prepared according to method A, examples 37-39 according to method B, examples 40-42 according to method C, example 64 according to method F and the enantiomerically pure compounds 75-78 by resolution of the racemic mixture.
• the products object of the invention are potent, orally active, anti-inflammatory agents, and selective inhibitors of COX-2, with a notable analgesic activity, lack ulcerogenic effects and are very active in the experimental arthritis test. With a view to demonstrating these activities, by way of example, some pharmacological assays are now indicated.
• the anti-inflammatory activity is also demonstrated, along with the absence of effects on gastric prostaglandins, after oral administration.
• the assay was carried out by modification of a method described by O. Tofanetti et al. (Med. Sci. Res. 1989, 17, 745-746).
• the products under study are administered orally at an initial screening dose of 40 mg/kg
• One hour after treatment the rats were anaesthetised and a sponge soaked in carrageenan was implanted subcutaneously in the interscapular zone.
• Six hours after implantation the rats were sacrificed and the interscapular sponges extracted as well as gastric mucuous.
• PGE 2 content was determined by immunoassay for each one of the samples, in the sponge exudate on the one hand and in the gastric mucus on the other.
• the inhibition of PGE 2 in the inflammatory exudate demonstrates anti-inflammatory activity, both of COX-2 and COX-1 inhibitors, whereas inhibition of PGE 2 in the gastric mucus is considered a COX-1 inhibitory effect.
• Table 3 summaries the results obtained with the compound of examples 3 and in table 4 the ED-50 (effective dose-50) is shown, as well as its selectivity. It is a more potent anti-inflammatory that the reference product.
• the analgesic activity in rat was monitored following the method described by K. Hargreaves et al. (Pain, 1988, 32, 77-78). Firstly, a suspension of carrageenan was injected into the back right paw of each rat. After two hours the products under study were administered orally at a screening dose of 40 mg/kg. Two hours after treatment a heat source was applied to the sole of each back paw of the rats and the time measured that they took to remove the paw measured. Hyperalgesia was determined by comparing the percentage of algesia of the paw injected with carrageenan to the other back paw. The analgesic activity was calculated comparing these hyperalgesia values of the groups treated with product with those of the group treated with the vehicle only.
• the results obtained show that the compound of example 3 has a high anti-arthritic activity, as treatment with 10 mg/kg/day, po, led to an inhibition of secondary inflammation, i.e. of an anti-arthritic activity, or 71%.
• the derivatives of pyrazolines in accordance with the invention can be used in satisfactory manner in human and animal therapy, in particular as anti-inflammatory agents for the treatment of inflammation and for the treatment of other disorders associated with inflammation, such as anti-arthritics, analgesics for the treatment of pain and migraine, or as antipyretics in the treatment of fever.
• the administration dose of the compounds of the present invention varies as a function of the seriousness of the affliction to treat. Normally the dose will lie between 100 and 400 mg/day.
• the compounds of the invention will be administered, for example, in the form of capsules, tablets, or injectable solutions or suspensions.
• Example 3 50 mg Corn flour 16 mg Colloidal silicon dioxide 1 mg Magnesium stearate 1 mg Povidone K-90 3 mg Pre-gelatinased starch 4 mg Micro-crystalline cellulose 25 mg Lactose 200 mg
• Example 3 100 mg Corn flour 20 mg Colloidal silicon dioxide 2 mg Magnesium stearate 4 mg Lactose 200 mg

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