WO2003064410A1 - Nouveau compose 1,2,4-triazole - Google Patents
Nouveau compose 1,2,4-triazole Download PDFInfo
- Publication number
- WO2003064410A1 WO2003064410A1 PCT/JP2002/012662 JP0212662W WO03064410A1 WO 2003064410 A1 WO2003064410 A1 WO 2003064410A1 JP 0212662 W JP0212662 W JP 0212662W WO 03064410 A1 WO03064410 A1 WO 03064410A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- group
- pyridyl
- substituted
- triazole
- lower alkyl
- Prior art date
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
-
- 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
- A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
- C07D311/08—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring
- C07D311/16—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring substituted in position 7
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
Definitions
- the present invention provides a novel 1,2,4-triazole compound having a substituted alkyl group at the 1, 2, or 4 position and having an aromatic ring at the 3 and 5 position, a hydrate thereof, or a hydrate thereof. And a method for producing the same, and an agent for treating hyperuricemia and gout containing these as an active ingredient.
- treatment with therapeutic agents is the main focus, but only aloprinol can be used for the uric acid production-enhancing type, and its metabolite oxypurinol has a cumulative effect and can cause stones.
- this drug may cause rashes and impaired renal function 2/12662
- Compounds that have a xanthine oxidase inhibitory activity that can be used in the form of enhanced uric acid production and that are effective for hyperuricemia and gout caused by hyperuricemia include J. Medicinal Chem. 1975, Vol. 18, No. 9, pp. 895-900, Japanese Patent Publication No. 49-46622, and Japanese Patent Publication No. 50-24315, some 1, 3, 5, or 3, 5 substitutions 1,2,4-triazole compounds are disclosed.
- Hyperuricemia and gout due to hyperuricemia tend to spread to younger people in Japan due to changes in the living environment, etc., and it has become impossible to overcome this disease only with guidance on improving lifestyle habits .
- therapeutic drugs for these diseases have difficulty in developing compounds with improved efficacy and have not progressed slowly.
- An object of the present invention is to provide a novel 1,2,4-triazole-based compound which has a high xanthine oxidase inhibitory activity and is also useful as a therapeutic agent for gout caused by hyperuricemia and hyperuricemia with enhanced uric acid production. Is to do. Disclosure of the invention
- a second invention of the present invention relates to a method for producing a compound represented by the above general formula (1), wherein R a is hydrogen, comprising a corresponding aromatic nitrile iminoether and an aromatic aromatic nitrile. Characterized by reacting with an aromatic carboxylic acid hydrazide.
- a third invention of the present invention provides a method for producing a compound represented by the above general formula (1), wherein the group R 3 is a bivaloyloxy-substituted lower alkyl group, wherein the compound represented by the general formula (1) is A group in which R a is hydrogen is reacted with a halo-lower alkyl ester of pivalic acid.
- a fourth invention of the present invention relates to a medicament comprising a compound represented by the general formula (1), a hydrate thereof, or a salt thereof as an active ingredient.
- the present inventors have developed a compound having a xanthine oxidase-inhibiting action that is also effective against hyperuricemia of hyperuricemia and gout caused by hyperuricemia, of which only one component is presently enhanced.
- the research was continued with the basic substance being defined as a 1,2,4-triazole-based compound.
- R 2 represents an unsubstituted pyridyl group or a substituted pyridyl group having a cyano group, a lower alkyl group, a halogen, a lower alkoxy group or a lower alkylthio group as a substituent.
- R 1 is an unsubstituted or substituted pyridyl group which may have a halogen, cyano group or phenyl group as a substituent, or a corresponding pyridine N-oxide group of the pyridyl group, or a substituent
- R 1 is not an unsubstituted pyridyl group or lower alkyl-substituted pyridyl group, or the corresponding pyridine N-oxide group of those pyridyl groups .
- R 3 represents hydrogen or a pivaloyloxy-substituted lower alkyl group, each of which is bonded to one nitrogen of the 1,2,4-triazolyl ring represented by the general formula (1).
- both the 3- and 5-position substituents are pyridine, it is preferred that at least one of them is substituted with a cyano group or halogen, and when one of them is a phenyl ring
- the phenyl ring may be substituted with a substituted or unsubstituted lower alkoxy group, a thiol, a substituted piperazino group, a substituted amino group, etc., but is substituted with at least either a cyano group or a nitro group. Is required.
- the present invention was completed based on the fact that the compound of the present invention exhibited a high inhibitory activity that could not be achieved with the known compound in the prior art in an in vivo xanthine oxidase inhibition test.
- the process for producing the compounds of the present invention is based on the reaction of the corresponding aromatic nitrile imino ether with an aromatic carboxylic acid hydrazide.
- the imino ether of nitrile represented by R 2 CN is reacted with a hydrazide represented by the general formula (5): ⁇ ⁇ ⁇ 0 ⁇ ⁇ 2.
- Imino ether (imino ether) produced by reaction with alcohol under basic conditions that may react sodium methoxide or sodium ethoxide, or by reaction with alcohol such as methanol or ethanol under acidic conditions Acid ester) can be used.
- Salts produced under acidic conditions can be isolated, and iminoethers produced under basic conditions can be isolated either by free-form or by conversion to salts.
- the solvent that can be used in the method for producing the compound of the present invention include aqueous solvents such as methanol and ethanol, and methanol is suitable. Although the reaction proceeds at room temperature, the reaction proceeds even at room temperature, but heating is preferable because of the speed and dehydration reaction. When methanol is used as a solvent, a temperature close to the boiling point (about 65 ° C) is preferable. In the production examples of the compound of the present invention, heating and reflux were employed. The reaction time depends on the balance with the temperature, but it can be adopted as long as side reactions and generation of decomposition products are suppressed.
- the reaction when a bivaloyloxy-substituted lower alkyl group is introduced, the reaction may be carried out by a well-known dehydrohalogenation reaction, and may be carried out by using a well-known organic base or a dehydrohalogenating agent such as an alkali agent. It is preferable to carry out the reaction in the coexistence, and the reaction proceeds sufficiently even at room temperature.
- the reaction may be performed in a solvent.
- the medium include dimethylformamide (hereinafter abbreviated as DMF).
- dimethyl sulfoxide is abbreviated as DMS0.
- a 7-week-old male Wistar rat (four rats per group) was administered with a test substance suspended in a 0.5% methylcellulose (MC) aqueous solution at a dose of 0.3 mg Z5 ml / kg [Example Gavage was administered by gavage using a stomach probe so that the journal and medical chemistry of 17 and the control (197 compounds were ⁇ !!!!).
- 6 hours after administration of the test substance Blood was collected, and the blood was left at room temperature for 1 hour, and centrifuged at 2000 X g for 10 minutes to collect serum.
- the serum uric acid level was determined using a uric acid measurement kit (Wako Pure Chemical Industries, Ltd.
- Example 340.0% (1—average serum in the group given the negative MK ⁇ ⁇ / average serum in the MC group) it x 100 Serum uric acid reduction rate
- Example 166.5% Example 262.3%
- Example 340.0% Example 44 39%
- Example 53 39 9%
- Example 7 42.7% Example 8 32.5%
- Example 9 35.7%
- Example 10 4 1.6% M M 41.6%
- Example 1 3 46.8% Example 1 4 43.0%
- Example of Japanese Patent Publication No. 49-46622 3 Compound 1 1.1%
- Example of Japanese Patent Publication No. 50-24243 2 Compound 26.1%
- Compound 1 of Japanese Patent Publication No. 50-24315 1 Compound -0.4% Journal off ', Medicinal Chemis
- a compound which is useful as a therapeutic agent for gout caused by hyperuricemia and hyperuricemia having a high xanthinoxidase inhibitory activity and a high uric acid production type by selecting a compound represented by the general formula (1), a compound which is useful as a therapeutic agent for gout caused by hyperuricemia and hyperuricemia having a high xanthinoxidase inhibitory activity and a high uric acid production type. , 2,4-Triazole compounds were provided.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Physical Education & Sports Medicine (AREA)
- Urology & Nephrology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
Claims
Priority Applications (14)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CA2462132A CA2462132C (en) | 2002-01-28 | 2002-12-03 | 1,2,4-triazole compounds |
JP2003564033A JP3600832B2 (ja) | 2002-01-28 | 2002-12-03 | 新規1,2,4−トリアゾール系化合物 |
NZ531673A NZ531673A (en) | 2002-01-28 | 2002-12-03 | Novel 1,2,4-triazole compounds |
DE60225341T DE60225341T2 (de) | 2002-01-28 | 2002-12-03 | Neue 1,2,4-triazolverbindung |
US10/495,322 US7074816B2 (en) | 2002-01-28 | 2002-12-03 | 1 2 4-triazole compound |
AU2002349754A AU2002349754B2 (en) | 2002-01-28 | 2002-12-03 | Novel 1,2,4-triazole compound |
EP02781876A EP1471065B1 (en) | 2002-01-28 | 2002-12-03 | Novel 1,2,4-triazole compound |
MXPA04004037A MXPA04004037A (es) | 2002-01-28 | 2002-12-03 | Compuestos novedosos de 1, 2, 4-de triazol. |
DK02781876T DK1471065T3 (da) | 2002-01-28 | 2002-12-03 | Hidtil ukendt 1,2,4-triazolforbindelse |
CN028192761A CN1561340B (zh) | 2002-01-28 | 2002-12-03 | 1,2,4-三唑类化合物 |
BRPI0212775A BRPI0212775B8 (pt) | 2002-01-28 | 2002-12-03 | composto de 1,2,4-triazol e medicamento |
ZA2004/01777A ZA200401777B (en) | 2002-01-28 | 2004-03-04 | Novel 1,24-triazole compound |
NO20041075A NO326941B1 (no) | 2002-01-28 | 2004-03-15 | 1,2,4-triazolforbindelse, medikament som omfatter forbindelsen, og anvendelse av forbindelsen for fremstilling av farmasoytisk sammensetning mot sykdom |
HK05100651.5A HK1067132A1 (ja) | 2002-01-28 | 2005-01-25 |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2002017825 | 2002-01-28 | ||
JP2002-017825 | 2002-01-28 |
Publications (1)
Publication Number | Publication Date |
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WO2003064410A1 true WO2003064410A1 (fr) | 2003-08-07 |
Family
ID=27653386
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP2002/012662 WO2003064410A1 (fr) | 2002-01-28 | 2002-12-03 | Nouveau compose 1,2,4-triazole |
Country Status (22)
Country | Link |
---|---|
US (1) | US7074816B2 (ja) |
EP (1) | EP1471065B1 (ja) |
JP (1) | JP3600832B2 (ja) |
CN (1) | CN1561340B (ja) |
AR (1) | AR042602A1 (ja) |
AT (1) | ATE387438T1 (ja) |
AU (1) | AU2002349754B2 (ja) |
BR (1) | BRPI0212775B8 (ja) |
CA (1) | CA2462132C (ja) |
DE (1) | DE60225341T2 (ja) |
DK (1) | DK1471065T3 (ja) |
ES (1) | ES2300486T3 (ja) |
HK (1) | HK1067132A1 (ja) |
MX (1) | MXPA04004037A (ja) |
NO (1) | NO326941B1 (ja) |
NZ (1) | NZ531673A (ja) |
PL (1) | PL208260B1 (ja) |
PT (1) | PT1471065E (ja) |
RU (1) | RU2293733C2 (ja) |
TW (1) | TWI257926B (ja) |
WO (1) | WO2003064410A1 (ja) |
ZA (1) | ZA200401777B (ja) |
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PT1471065E (pt) | 2008-03-13 |
CA2462132A1 (en) | 2003-08-07 |
US7074816B2 (en) | 2006-07-11 |
TW200302222A (en) | 2003-08-01 |
EP1471065A1 (en) | 2004-10-27 |
EP1471065B1 (en) | 2008-02-27 |
NZ531673A (en) | 2006-06-30 |
NO326941B1 (no) | 2009-03-16 |
MXPA04004037A (es) | 2004-07-23 |
DE60225341D1 (de) | 2008-04-10 |
BRPI0212775B1 (pt) | 2017-06-06 |
DE60225341T2 (de) | 2009-04-09 |
HK1067132A1 (ja) | 2005-04-01 |
CN1561340A (zh) | 2005-01-05 |
CN1561340B (zh) | 2012-05-23 |
PL368672A1 (en) | 2005-04-04 |
TWI257926B (en) | 2006-07-11 |
ZA200401777B (en) | 2005-08-31 |
JP3600832B2 (ja) | 2004-12-15 |
RU2004106554A (ru) | 2005-07-27 |
CA2462132C (en) | 2010-08-10 |
JPWO2003064410A1 (ja) | 2005-05-26 |
BRPI0212775B8 (pt) | 2021-05-25 |
NO20041075L (no) | 2004-03-15 |
US20050004175A1 (en) | 2005-01-06 |
ES2300486T3 (es) | 2008-06-16 |
RU2293733C2 (ru) | 2007-02-20 |
ATE387438T1 (de) | 2008-03-15 |
PL208260B1 (pl) | 2011-04-29 |
AR042602A1 (es) | 2005-06-29 |
AU2002349754B2 (en) | 2008-01-31 |
EP1471065A4 (en) | 2005-06-15 |
BR0212775A (pt) | 2004-10-13 |
DK1471065T3 (da) | 2008-03-25 |
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