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Novel compound and pharmaceutically-acceptable salt thereof

A technology of pharmacology and compounds, applied in the fields of active ingredients of heterocyclic compounds, organic chemistry, antitumor drugs, etc.

Active Publication Date: 2019-08-09
MEIJI SEIKA KAISHA LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition, it has also been reported that PDE4 is related to the proliferation and angiogenesis of lung cancer, and its inhibitor may also have an effect on lung cancer (see Non-Patent Document 7: Oncogene, 2013, 32, p.1121-1134). In addition, it is pointed out that It may become a kind of brain tumor (refer to non-patent literature 8: Trends in Pharmacological Sciences, June 2011, Vol.32, No.6, p.337-344) or acute lymphoblastic leukemia (refer to non-patent literature 9: Blood, May 2002, Vol.99, No.9, p.3390-3397) promising therapy, PDE4 inhibitors may be effective for various cancers

Method used

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  • Novel compound and pharmaceutically-acceptable salt thereof
  • Novel compound and pharmaceutically-acceptable salt thereof
  • Novel compound and pharmaceutically-acceptable salt thereof

Examples

Experimental program
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Embodiment

[1032] Hereinafter, although an Example demonstrates this invention in more detail, this invention is not limited to these Examples. In addition, the production methods of the raw material compounds used in the examples are described as reference examples, but these are also illustrations for concretely explaining the implementation of the present invention, and the scope of the present invention is not limited by these examples, and will not be limited by these examples. It is obvious that various applications, modifications, corrections, etc. can be made within the scope of the present invention.

[1033] Hereinafter, the abbreviations in Examples and Reference Examples have the following meanings.

[1034] M: mol / L

[1035] DMSO: dimethyl sulfoxide

[1036] DMPU: N,N'-dimethylpropylene urea

[1037] ESI: Electrospray Ionization

[1038] ee: enantiomeric excess

[1039] HPLC: High Performance Liquid Chromatography

[1040] mCPBA: m-chloroperbenzoic acid

[1041] MS: m...

reference example 1

[1049] 7-Bromo-5-isopropylbenzo[d]oxazole-2-thiol

[1050] (a) 2-Bromo-4-isopropyl-6-nitrophenol

[1051]Dissolve 2.5 g of 2-bromo-4-isopropylphenol in dichloromethane (50 mL), add concentrated sulfuric acid (0.8 mL, 1.3 equivalents) dropwise at 0° C. over 5 minutes, and then add 70% nitric acid (0.7 mL , 1.0 equivalent) was added over 5 minutes, and stirred at room temperature for 2 hours. After confirming the product by TLC, the pH was adjusted to 7 by adding solid sodium bicarbonate. The reaction solution was filtered, the filtrate was extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. This was filtered, and the filtrate was concentrated under reduced pressure to obtain 2.8 g of the resulting title compound as a crude product.

[1052] MS (ESI) m / z: 260 (M-H) -

[1053] (b) 2-Amino-6-bromo-4-isopropylphenol

[1054] Sodium dithionite (9.4 g, 5 equivalents) was dissolved in distilled water (32 mL) at 0° C., and 2.8 g of 2-br...

reference example 2

[1059] 7-Bromo-4-methylbenzo[d]oxazole-2-thiol

[1060] (a) 6-bromo-3-methyl-2-nitrophenol

[1061] The title compound was obtained from 2.5 g of 2-bromo-5-methylphenol in the same manner as in Reference Example 1(a) except that the crude product was purified by silica gel column chromatography (hexane:ethyl acetate=95:5). 1.5g.

[1062] MS (ESI) m / z: 230 (M-H) -

[1063] (b) 2-Amino-6-bromo-3-methylphenol

[1064] Using the same method as in Reference Example 1(b), 610 mg of the title compound was obtained from 1.5 g of 6-bromo-3-methyl-2-nitrophenol obtained in Reference Example 2(a).

[1065] MS (ESI) m / z: 200 (M-H) -

[1066] (c) 7-bromo-4-methylbenzo[d]oxazole-2-thiol

[1067] Using the same method as in Reference Example 1(c), 360 mg of the title compound was obtained from 610 mg of 2-amino-6-bromo-3-methylphenol obtained in Reference Example 2(b).

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Abstract

Provided is a compound represented by general formula (1) or a pharmaceutically-acceptable salt thereof. In formula (1), R1 and R2 may be the same or different from each other, and each represents a hydrogen atom, a halogen atom, a hydroxy group, a carboxy group, a cyano group, or an optionally-substituted C1-6 alkyl group or the like; R3 represents a hydrogen atom; R4 represents an optionally-substituted 4- to 10-membered monocyclic heterocyclic group containing 1-4 heteroatoms selected from an oxygen atom, a nitrogen atom, and a sulfur atom; X represents a group represented by -CH2-, -CH2-CH2-, -CH2-CH2-CH2-, or -CH2-O-CH2-; and Z represents a hydrogen atom or a hydroxy group.

Description

technical field [0001] The present invention relates to a novel compound and a pharmacologically acceptable salt thereof, and more specifically, to a novel compound, a pharmacologically acceptable salt thereof, and a PDE4 inhibitor containing the same. Background technique [0002] Phosphodiesterase (PDE) is well known as an important biological enzyme that inactivates cyclic nucleotides (cAMP or cGMP) present in second messengers by unilaterally hydrolyzing their phosphodiester bonds . The PDE that decomposes cAMP is classified into several isoforms, among which, type 4 PDE (PDE4) is one of the main cAMP decomposing enzymes present in various inflammatory cells, immune cells, blood, brain, lungs and other organs ( Refer to Non-Patent Document 1: International Journal of Chronic Obstructive Pulmonary Disease, 2008, 3(4), p.543-561). [0003] Since PDE4 inhibitors can inhibit the production and release of various inflammatory cytokines such as TNF-α and IL-23, they are know...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/08A61K31/4995A61K31/501A61K31/506A61K31/5377A61K31/5386A61K31/541A61K31/55A61P11/06A61P17/06A61P25/24A61P25/28A61P35/00C07D487/08C07D498/08
CPCA61K31/4995A61K31/501A61K31/506A61K31/5377A61K31/5386A61K31/541A61K31/55A61P11/06A61P17/06A61P25/24A61P25/28A61P35/00C07D471/08C07D487/08C07D498/08C07D451/14
Inventor 田村圭司山川建一色聪志胁山佳也大内祥平松平崇石田那月田端祐二
Owner MEIJI SEIKA KAISHA LTD