WO2001087880A1 - Derives de 1-(benzathiazol-2-yl)pyrazole et inhibiteurs de cox-2 en contenant - Google Patents

Derives de 1-(benzathiazol-2-yl)pyrazole et inhibiteurs de cox-2 en contenant Download PDF

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Publication number
WO2001087880A1
WO2001087880A1 PCT/JP2001/003940 JP0103940W WO0187880A1 WO 2001087880 A1 WO2001087880 A1 WO 2001087880A1 JP 0103940 W JP0103940 W JP 0103940W WO 0187880 A1 WO0187880 A1 WO 0187880A1
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WO
WIPO (PCT)
Prior art keywords
group
lower alkyl
phenyl
compound
difluoromethyl
Prior art date
Application number
PCT/JP2001/003940
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English (en)
Japanese (ja)
Inventor
Tomoji Aotsuka
Nagatoshi Wagatsuma
Kouki Ishitani
Hideaki Kato
Original Assignee
Grelan Pharmaceutical Co., Ltd.
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Grelan Pharmaceutical Co., Ltd. filed Critical Grelan Pharmaceutical Co., Ltd.
Priority to JP2001584274A priority Critical patent/JP4759207B2/ja
Priority to AU2001256705A priority patent/AU2001256705A1/en
Publication of WO2001087880A1 publication Critical patent/WO2001087880A1/fr

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Classifications

    • 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
    • C07D417/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • A61K31/425—Thiazoles
    • A61K31/428—Thiazoles condensed with carbocyclic rings
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a novel 1- (benzothiazol-1-yl) birazol derivative having cyclooxygenase (C0X) -2 inhibitory activity, or a wakefully acceptable salt thereof, and a salt thereof.
  • the present invention relates to a pharmaceutical curable product containing:
  • the compound of the present invention can be effectively used for suppressing and improving inflammation and various symptoms associated with inflammation.
  • NSAIDs non-steroidal anti-inflammatory drugs
  • arachidonic acid the enzyme that synthesizes prostaglandins
  • prostaglandins are involved in various physiological actions, such as suppression of gastric acid secretion and increase in toughness, in addition to inflammation.
  • Conventional NSAIDs are involved in prostaglandins that are involved in physiological actions other than inflammation
  • side effects such as gastric mucosal disorder and renal disorder are highly ruptured, and the limbus is often limited. It has become clear that C0X is present at a high level with isozyme, and C0X, which is constantly present in the stomach and kidney, is called C0X-1, and C0X induced at newly discovered inflammation sites is It was named C0X-2.
  • Wei's NSAID is considered to have suffered from the above side effects because it inhibits both COX-1 and C0X-2. Therefore, selective inhibition of C0X- lj would make it difficult to achieve the desired anti-inflammatory effect and would be difficult to achieve.
  • the present inventors have found that the anti-inflammatory activity is excellent and the side effects are expected to be reduced. Long-awaited selective COX-2 obstruction [The search was repeated with the search for J as an issue.
  • the present inventors have studied various compounds in order to overcome the above-mentioned problems, and as a result, have found that a novel pyrazolyl bond having a nitrogen-containing complex such as a benzothiazole group at the 3- or 5-position is obtained. And found that it exhibited selective C0X-2 inhibition, and filed an application (PCT Publication No. 9846594 (W098 / 46594, A1)). Furthermore, as a result of this study, it was found that the novel pyrazole derivative having a benzothiazol group at the 1-position is superior to the conventional C0X-2 blocking IJ in terms of drug effect and safety. Heading, the present invention has been completed.
  • the compound of the present invention has a thiazolyl group or a substituted benzothiazolyl group at the 1-position of the pyrazole ring, and a lower alkylthio group or a lower alkyl at the 5-position of the pyrazole ring as shown below. It is a compound having a phenyl group substituted with an io-containing substituent selected from the group consisting of a sulfinyl group and a lower alkylsulfonyl group.
  • R 1 is a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group
  • R 2 is a halo lower alkyl group or a lower alkyl group
  • R 3 is a lower alkyl group
  • n is an integer of 0 to 2.
  • a salt thereof; 2 a compound represented by the formula (2)
  • R 1 is a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group
  • R 2 is a halo alkyl group or a lower alkyl group
  • R 3 is a lower alkyl group
  • n is an integer of 0 to 2.
  • an anti-inflammatory agent comprising the compound according to any one of the above 1) to 3) or a pharmaceutically acceptable salt thereof;
  • an anti-inflammatory analgesic comprising the compound according to any one of the above 1) to 3) or a pharmaceutically acceptable salt thereof;
  • an anti-inflammatory agent comprising the compound according to 8) or a pharmaceutically acceptable salt thereof;
  • Rheumatoid arthritis arthritis associated with other collagen diseases, ⁇ rheumatoid arthritis, intractable spondylosis, lumbago, tendon.
  • the salt to be used and the medicinal substance containing it are combined.
  • a pharmaceutical composition containing the same and further contain a C0X-2P harmful agent, an anti-inflammatory agent, an anti-inflammatory drug, and the like.
  • the halogen atom is a fluorine atom, a chlorine atom or a bromine atom
  • the lower alkyl group is a carbon atom alkyl group having 1 to 4 carbon atoms.
  • the lower alkoxy group is an alkoxy group of 1 to 4 carbon atoms, and specifically, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a sec-butoxy group or a tert- group. Butoxy group.
  • the above-mentioned “low-alkyl group” refers to a lower alkyl group substituted with a halogen atom, and specifically, a fluoromethyl group, a difluoromethyl group, a trifluorenolomethyl group.
  • Preferred compounds in the present invention are compounds represented by the above general formula (1). More preferred compounds include compounds represented by the above general formula (2). Specific compounds of the present invention are shown below.
  • the present invention provides a method for preparing a pyrazole represented by the above formula (1).
  • Such salts include the salts of non-toxic and / or crucible inorganic and organic acids that are medically or pharmacologically reproducible, and specifically include hydrochloric acid. Salts, hydrobromic acid, sulfate, acetate, tartaric acid, citric acid, succinic acid, methanesulfonate and the like.
  • the compound of the present invention can be produced by various methods, for example, the compound represented by the general formula (1) can be produced by the following process or by a modification thereof.
  • the base used in this reaction is an alkali metal alkoxide, an alkali metal hydride, an alkali metal amide, and the like.
  • Specific examples of the base include sodium methoxide, sodium ethoxide, potassium tert-butoxide, Lithium hydrogen, sodium hydrogen, potassium hydride, sodium amide, potassium amide, lithium diisopropyl amide and the like.
  • This reaction can be carried out in the presence or absence of a solvent, and the reaction can be carried out in the presence of a solvent.
  • a common solvent that does not adversely affect the reaction can be used.Preferred is tetrahydrofuran (THF ), Dimethylformamide (DMF), getylether, dimethylene chloride, benzene, toluene and the like.
  • the reaction iSg is from 180 to 100 ° C, preferably from 130 ° C to room temperature.
  • the hydrazine drug book represented by the general formula (7) (wherein R 1 is the same as described above) can be prepared by a known method [Example: EP418, 845 (1991)].
  • R 1 is the same as defined above), followed by diazotization and reduction. Then, the compound represented by the general formula (5) is reacted with the compound represented by the general formula (7) or an acid addition salt thereof, whereby one of the compounds represented by the general formula (1) A (Wherein R ′, R 2 and R 3 are the same as described above).
  • the acid addition salt of the compound represented by the general formula (7) include salts such as hydrochloric acid, hydrobromic acid, and sulfuric acid.
  • the reaction with the compound represented by the formula (7) or an acid addition salt thereof is preferably carried out under a solvent ⁇ the ability to convert a common solvent which does not adversely affect the reaction. Acids, ethanol, DMF, etc. are ⁇ ffl.
  • the reaction ⁇ is about 0 to 200 ° C, preferably 50 ° C to the boiling point of the solvent.
  • the compound represented by the general formula (1) —B by subjecting the compound represented by the general formula (1) —B (wherein R ′ R 2 and R 3 are as defined above; m is 1 or (Indicating an integer of 2).
  • oxidizing agent used in this reaction examples include m-chloroperbenzoic acid, oxone (trade name: Aldrich Chemical Co., Ltd.), aqueous hydrogen peroxide, periodic acid and the like.
  • This reaction can be carried out in the presence or absence of a solvent, and the reaction in the presence of a solvent can be carried out using a conventional solvent that does not adversely affect the reaction. Examples include methylene, black form, acetone, and water.
  • the reaction is performed at about 110 to 100 ° C., preferably about 0 to 50 ° C.
  • the compounds in which m is 1 and 2 can be produced respectively. .
  • the present invention relates to a pharmaceutical composition containing the compound represented by the above general formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient] ⁇ , and a medicinal 0X-2 inhibitor, Embodiments that are anti-inflammatory agents are also included.
  • C0X exists in the living body in two types, COX-1 and C0X-2.
  • C0X-1 is a constituent enzyme that constantly covers the stomach, kidneys, and the like
  • C0X-2 is a constituent enzyme. It is an enzyme that is induced at the site of inflammation.
  • the compound of the present invention has a strong inhibitory effect on C0X-2, whereas it has a weaker effect on COX-1 resident in the stomach, kidney and the like.
  • -2 P which is effectively used as an anti-inflammatory agent that can reduce side effects such as gastric mucosal damage and renal damage.
  • the compound of the present invention suppresses various symptoms associated with inflammation and inflammation, such as edema, brain length, pain and fever, by selectively blocking C0X-2 as described above. It is the ability to improve.
  • the compound of the present invention exhibits excellent analgesic activity and is useful as an anti-inflammatory analgesic for improving pain associated with inflammation.
  • the compound of the present invention is used for amelioration and treatment of the following inflammations and diseases accompanied by inflammation: rheumatoid arthritis, arthritis associated with other collagen diseases, osteoarthritis, , Lumbago, tendon / tenosynovitis, cervico-brachialgia, shoulder periarthritis, neuralgia, common cold, upper respiratory tract, bronchitis, back labor, pelvic inflammation, uterine attachment, dysmenorrhea, cystitis, 3 ⁇ Izumiitis, anterior eye inflammation, trauma.
  • ⁇ can also be a component selected from known preparation additives (hereinafter sometimes referred to as "pharmaceutical components").
  • the age by oral administration and the above-mentioned additives may be any pharmaceutical ingredients that can constitute an oral agent and that can achieve the object of the present invention.
  • a known formulation component such as an agent, a disintegrant, a lubricant, and a coating agent is selected.
  • Specific examples of oral preparations include tablets, capsules, granules, fine granules, powders, and syrups.
  • the age according to Nada as the above additives, formulation ingredients that can constitute aqueous wet preparations or non-aqueous thighs are usually inverted. Usually, dissolving agents, dissolution aids, suspending agents, buffering agents, stabilizers.
  • a production method known per se for example, (13)
  • the administration pattern of the pharmaceutical composition of the present invention is a mammal, particularly a human, and the dosage is converted into the amount of the compound of the present invention: f ⁇ ⁇ , as an oral preparation: ⁇ is usually 5 to I, 000 mg (/ B), preferably 10-500 mg (/ day).
  • the age for use as a measuring agent is 2 to 200 mg (Z days) 1 kg of cereal, and preferably about 5 to 100 mg (day).
  • the age for use as a topical agent is usually about 0.5 to 200 mg (/ day), preferably 1 to 100 mg (/ day).
  • the fiber and the final product should be considered in consideration of the patient's condition (Ht-like condition, medical condition, presence or absence of co-morbidity, etc.), age, ' ⁇ weight, etc. * Is determined. Test example
  • test compound was suspended orally in a 0.5% CMC-Na aqueous solution at a dose of 30 mg / kg orally at a dose of 30 mg / kg.
  • the anti-nociceptive stimulatory action was taken from the number of screaming reactions when extended. The results are shown in Table 3.
  • mice Male ICR mice (5 mice / group) were orally administered 300 mg / kg of the test compound as a test compound, and observation was continued for 1 week.
  • the test compound was administered by suspending it in a pool of 0.5% CMC-Na water, and a group administered with only 0.5% CMC-Na water intense night (5 animals per group) was used as a control.
  • Example 1 is based on the meanings of the terms commonly used in the art.
  • 2-Aminobenzothiazole (7.5 g, 0.050 mol) is suspended in 45 ml of concentrated hydrochloric acid, and ice-cooled. Dissolve sodium nitrite (4.0 g, 0.058 mol) in 20 ml of water. The solution was dropped in about 30 minutes. 30 minutes after dropping, stannous chloride. Dihydrate (3.1.9 g, 0.141 mol) dissolved in 25 ml of concentrated hydrochloric acid. It took about 2 hours to complete.
  • the precipitate was filtered from the reaction solution by suction filtration, washed with ethyl acetate, and 10.6 g of a mixture of (benzothiazol-2-yl) hydrazine hydrochloride and a small amount of raw materials was obtained as an orange powder. The resulting mixture was used in the next step as it was because separation and purification were difficult.
  • Formulation example per tablet (23 Omg in total): 10 Omg of the compound of the present invention, 100 mg of crystalline cellulose, 28 mg of corn starch, 2 mg of magnesium stearate
  • Capsule Formulation example in 1 capsule 100 mg of lactose compound of the present invention, lactose 10 Omg. Corn starch 28 mg, magnesium stearate 2 mg According to the above prescription, a forcepsel preparation was obtained according to a known method described in the general rules of preparations of JP XI11. Formulation Example 3
  • the compound of the present invention (50 mg) was dissolved in physiological saline (71 ml). After adjusting the pH to 7 at 0.1 N, the pH was adjusted to 7 in the water pool, and then adding menstrual ⁇ to 20 m1 and disinfection dispensed into the sample was performed. Agent was obtained.
  • physiological saline 71 ml
  • An ointment was obtained by sufficiently mixing 10 ⁇ g of the finely powdered compound of the present invention and 1 ⁇ g of white petrolatum. Availability
  • novel 1- (benzothiazol-2-yl) pyrazole derivative of the present invention is induced at an inflammatory site during inflammation by drowning against COX-1 resident in the stomach, kidney and the like. It has strong inhibitory effects on COX-2 and selectively inhibits the biosynthesis of prostaglandins at sites of inflammation.
  • a selective C0X-2 inhibitor according to the present invention a novel compound having excellent anti-inflammatory activity and capable of reducing the side effects such as gastric mucosal disorder and renal disorder can be used as a Si inhibitor. Power to do

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des médicaments anti-inflammatoires, ayant d'excellents effets pharmacologiques et présentant une activité inhibitrice sélective vis-à-vis du COX-2 permettant de soulager les effets secondaires y compris des troubles de la muqueuse gastrique. Plus particulièrement, l'invention concerne des composés de la formule générale (1) dans laquelle: R1 est hydrogène, halogène, alkyle inférieur ou alcoxy inférieur; R2 est alkyle inférieur halogéné ou alkyle inférieur; R3 est alkyle inférieur; et n est un entier de 0 à 2; ou de leurs sels médicalement acceptables; et des inhibiteurs de COX-2 contenant ces composés ou leurs sels.
PCT/JP2001/003940 2000-05-15 2001-05-11 Derives de 1-(benzathiazol-2-yl)pyrazole et inhibiteurs de cox-2 en contenant WO2001087880A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
JP2001584274A JP4759207B2 (ja) 2000-05-15 2001-05-11 １−（ベンゾチアゾール−２−イル）ピラゾール誘導体およびそれを含有するｃｏｘ−２阻害剤
AU2001256705A AU2001256705A1 (en) 2000-05-15 2001-05-11 1-(benzothiazol-2-yl)pyrazole derivatives and cox-2 inhibitors containing the same

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JP2000141316 2000-05-15
JP2000-141316 2000-05-15

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7622471B2 (en) 2003-02-07 2009-11-24 Daiichi Pharmaceutical Co., Ltd. Pyrazole derivatives having a pyridazine and pyridine functionality

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0155523A1 (fr) * 1984-03-01 1985-09-25 A. Nattermann & Cie. GmbH 3-Amino-1-(4,5,6,7-tétrahydro-benzothiazolyl)-2-pyrazolines, un procédé pour leur préparation et produits pharmaceutiques contenant ces composés
EP0178035A1 (fr) * 1984-05-12 1986-04-16 FISONS plc 1,N-Diarylpyrazol-3-amines anti-inflammatoires, compositions les contenant et leur préparation
US5242940A (en) * 1987-05-29 1993-09-07 Ortho Pharmaceutical Corporation Pharmacologically active N-1 and C-5 heterocyclic pyrazoles and method for synthesizing the same
WO1996003392A1 (fr) * 1994-07-27 1996-02-08 G.D. Searle & Co. Thiazoles substitues destines au traitement de l'inflammation
WO1996006840A1 (fr) * 1994-08-29 1996-03-07 Merck Frosst Canada Inc. Heterocycles bicycliques diaryles utilises comme inhibiteurs de cyclooxygenase-2
WO1997027181A1 (fr) * 1996-01-26 1997-07-31 G.D. Searle & Co. Imidazoles a substitution heterocyclo utilises pour traiter l'inflammation

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0155523A1 (fr) * 1984-03-01 1985-09-25 A. Nattermann & Cie. GmbH 3-Amino-1-(4,5,6,7-tétrahydro-benzothiazolyl)-2-pyrazolines, un procédé pour leur préparation et produits pharmaceutiques contenant ces composés
EP0178035A1 (fr) * 1984-05-12 1986-04-16 FISONS plc 1,N-Diarylpyrazol-3-amines anti-inflammatoires, compositions les contenant et leur préparation
US5242940A (en) * 1987-05-29 1993-09-07 Ortho Pharmaceutical Corporation Pharmacologically active N-1 and C-5 heterocyclic pyrazoles and method for synthesizing the same
WO1996003392A1 (fr) * 1994-07-27 1996-02-08 G.D. Searle & Co. Thiazoles substitues destines au traitement de l'inflammation
WO1996006840A1 (fr) * 1994-08-29 1996-03-07 Merck Frosst Canada Inc. Heterocycles bicycliques diaryles utilises comme inhibiteurs de cyclooxygenase-2
WO1997027181A1 (fr) * 1996-01-26 1997-07-31 G.D. Searle & Co. Imidazoles a substitution heterocyclo utilises pour traiter l'inflammation

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7622471B2 (en) 2003-02-07 2009-11-24 Daiichi Pharmaceutical Co., Ltd. Pyrazole derivatives having a pyridazine and pyridine functionality

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JP4759207B2 (ja) 2011-08-31
AU2001256705A1 (en) 2001-11-26

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