WO2012026765A2 - 신규한 헤테로고리 화합물 및 이를 이용한 염증성 질환 치료용 조성물 - Google Patents
신규한 헤테로고리 화합물 및 이를 이용한 염증성 질환 치료용 조성물 Download PDFInfo
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- WO2012026765A2 WO2012026765A2 PCT/KR2011/006278 KR2011006278W WO2012026765A2 WO 2012026765 A2 WO2012026765 A2 WO 2012026765A2 KR 2011006278 W KR2011006278 W KR 2011006278W WO 2012026765 A2 WO2012026765 A2 WO 2012026765A2
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- 0 *c1cc(C2CC=CCC2)nc2cc(C(N*)O)n[n]12 Chemical compound *c1cc(C2CC=CCC2)nc2cc(C(N*)O)n[n]12 0.000 description 3
- QQHZPWMJVYLXFJ-UHFFFAOYSA-N CC(C1(C)c2ccccc2)N=C(C=C2)N1C=C2C(N(CC1)CCN1S(C)(C1CCCCC1)(O)=O)=O Chemical compound CC(C1(C)c2ccccc2)N=C(C=C2)N1C=C2C(N(CC1)CCN1S(C)(C1CCCCC1)(O)=O)=O QQHZPWMJVYLXFJ-UHFFFAOYSA-N 0.000 description 2
- QMWDUSDCDJGUMH-UHFFFAOYSA-N CC(N(CC1)CCN1C(c1c[n]2c(-c3ccccc3)c(C)nc2cc1)O)=O Chemical compound CC(N(CC1)CCN1C(c1c[n]2c(-c3ccccc3)c(C)nc2cc1)O)=O QMWDUSDCDJGUMH-UHFFFAOYSA-N 0.000 description 2
- VHIXBLVLAJGWLT-UHFFFAOYSA-N CC1(C=CC(C(N(CC2)CCN2C(C2=CC=CCC2)=O)=O)=C2)N2C(c2ccccc2)=C(C)N1 Chemical compound CC1(C=CC(C(N(CC2)CCN2C(C2=CC=CCC2)=O)=O)=C2)N2C(c2ccccc2)=C(C)N1 VHIXBLVLAJGWLT-UHFFFAOYSA-N 0.000 description 2
- XBHWMVLHYYFIAY-UHFFFAOYSA-N CC(C)CC[N+](CC1)(CCN1C(CCCCCN)O)[O-] Chemical compound CC(C)CC[N+](CC1)(CCN1C(CCCCCN)O)[O-] XBHWMVLHYYFIAY-UHFFFAOYSA-N 0.000 description 1
- ONXJPYAEQNHKNZ-UHFFFAOYSA-N CC(C1(C)c2ccccc2)N=C(C=C2)N1C=C2C(N(CC1)CCC1OC)=O Chemical compound CC(C1(C)c2ccccc2)N=C(C=C2)N1C=C2C(N(CC1)CCC1OC)=O ONXJPYAEQNHKNZ-UHFFFAOYSA-N 0.000 description 1
- MWTMOKNQCWXTNG-UHFFFAOYSA-N CC(C1)CN2C(c3ccccc3)=C(C)NC2(C)C1C(N1CCCCC1)=O Chemical compound CC(C1)CN2C(c3ccccc3)=C(C)NC2(C)C1C(N1CCCCC1)=O MWTMOKNQCWXTNG-UHFFFAOYSA-N 0.000 description 1
- NPILWZHEJOIEFR-UHFFFAOYSA-N CC(C1c2ccccc2)N=C(C=C2)N1C=C2C(N(CC1)CCN1C(C1CCCCC1)=O)=O Chemical compound CC(C1c2ccccc2)N=C(C=C2)N1C=C2C(N(CC1)CCN1C(C1CCCCC1)=O)=O NPILWZHEJOIEFR-UHFFFAOYSA-N 0.000 description 1
- WUKQWRQAXZNQOK-UHFFFAOYSA-N CC(CC=C1)C=C1c1c(C)nc2[n]1ccc(C(N1CCCCC1)=O)c2 Chemical compound CC(CC=C1)C=C1c1c(C)nc2[n]1ccc(C(N1CCCCC1)=O)c2 WUKQWRQAXZNQOK-UHFFFAOYSA-N 0.000 description 1
- UXTSFCQLDDRYIY-UHFFFAOYSA-N CC(NCc1c[n]2c(-c3cc(C)ccc3)c(C)nc2cc1)=O Chemical compound CC(NCc1c[n]2c(-c3cc(C)ccc3)c(C)nc2cc1)=O UXTSFCQLDDRYIY-UHFFFAOYSA-N 0.000 description 1
- KOFIYXIXUNAWST-UHFFFAOYSA-N CC1(C=Cc2nc(C)c(-c3ccccc3)[n]2C1)C(N(CC1)CCN1C(CN)=O)=O Chemical compound CC1(C=Cc2nc(C)c(-c3ccccc3)[n]2C1)C(N(CC1)CCN1C(CN)=O)=O KOFIYXIXUNAWST-UHFFFAOYSA-N 0.000 description 1
- YBCQIRHDICUJIR-UHFFFAOYSA-N CC1C(C(NC(CC2)CCN2C(OCc2ccccc2)=O)=O)=C[n]2c(C3(C)C=CC=CC3)c(C)nc2C1 Chemical compound CC1C(C(NC(CC2)CCN2C(OCc2ccccc2)=O)=O)=C[n]2c(C3(C)C=CC=CC3)c(C)nc2C1 YBCQIRHDICUJIR-UHFFFAOYSA-N 0.000 description 1
- OZJKIEQXWPAJEQ-UHFFFAOYSA-N CC1C=CC=CC1c1c(C)nc(cc2)[n]1cc2C(N1CCCCC1)=O Chemical compound CC1C=CC=CC1c1c(C)nc(cc2)[n]1cc2C(N1CCCCC1)=O OZJKIEQXWPAJEQ-UHFFFAOYSA-N 0.000 description 1
- HLBJPGOFIHVZAB-UHFFFAOYSA-N CCCC(CC[NH+](Cc(cc1)c[n]2c1nc(C)c2C1(C)C=CC=CC1)[O-])(C1CCCCC1)O Chemical compound CCCC(CC[NH+](Cc(cc1)c[n]2c1nc(C)c2C1(C)C=CC=CC1)[O-])(C1CCCCC1)O HLBJPGOFIHVZAB-UHFFFAOYSA-N 0.000 description 1
- JKOUBPORTNEVFK-UHFFFAOYSA-N CCN(CC)C(c1c(C)nc(cc2)[n]1cc2Br)=O Chemical compound CCN(CC)C(c1c(C)nc(cc2)[n]1cc2Br)=O JKOUBPORTNEVFK-UHFFFAOYSA-N 0.000 description 1
- LOKOMUHPDSLICW-UHFFFAOYSA-N Cc(cc1)c[n]2c1ncc2C(N1CCCCC1)=O Chemical compound Cc(cc1)c[n]2c1ncc2C(N1CCCCC1)=O LOKOMUHPDSLICW-UHFFFAOYSA-N 0.000 description 1
- RKISYXMPLQOYPU-UHFFFAOYSA-N Cc1c(-c2cccc(C)c2)[n](cc(cc2)C(N3CCCCC3)=O)c2n1 Chemical compound Cc1c(-c2cccc(C)c2)[n](cc(cc2)C(N3CCCCC3)=O)c2n1 RKISYXMPLQOYPU-UHFFFAOYSA-N 0.000 description 1
- JRQRDHSTAUUOHB-UHFFFAOYSA-N Cc1c(C2N(C=C(C=C3)C(N4CCCCC4)=O)C3=NC2)cccc1 Chemical compound Cc1c(C2N(C=C(C=C3)C(N4CCCCC4)=O)C3=NC2)cccc1 JRQRDHSTAUUOHB-UHFFFAOYSA-N 0.000 description 1
- XEYHDDJIJLEKHR-UHFFFAOYSA-N O=C(C(C=C1)=CN2C1=NCC2Cc1ccccc1)N1CCCCC1 Chemical compound O=C(C(C=C1)=CN2C1=NCC2Cc1ccccc1)N1CCCCC1 XEYHDDJIJLEKHR-UHFFFAOYSA-N 0.000 description 1
- GGCZVAQBWIWMRX-UHFFFAOYSA-N O=C(c1cnc(cc2)[n]1cc2I)N1CCCCC1 Chemical compound O=C(c1cnc(cc2)[n]1cc2I)N1CCCCC1 GGCZVAQBWIWMRX-UHFFFAOYSA-N 0.000 description 1
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- C07—ORGANIC CHEMISTRY
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- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
- C07D235/08—Radicals containing only hydrogen and carbon atoms
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- 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
- C07D401/06—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 linked by a carbon chain containing only aliphatic carbon atoms
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/443—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
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- A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
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- A61K8/00—Cosmetics or similar toiletry preparations
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- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
- A61K8/494—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with more than one nitrogen as the only hetero atom
- A61K8/4946—Imidazoles or their condensed derivatives, e.g. benzimidazoles
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- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Definitions
- the present invention relates to a novel heterocyclic compound, an imidazopyridine derivative and a compound comprising a salt thereof, and a composition for the treatment and prevention of protease activated receptor-2 (PAR-2) inhibitors and inflammatory diseases.
- PAR-2 protease activated receptor-2
- Protease activated receptor-2 belongs to the G-protein-coupled receptor (GPCR), which is associated with the thrombin receptor (PAR-1) receptor discovered in 1991. Receptors.
- GPCR G-protein-coupled receptor
- PAR-2 activation mechanism Studies on the PAR-2 activation mechanism have shown that peptide sequences such as trypsin or mast cell-derived tryptases are present at the end of the extracellular region of the PAR-2 receptor. It is known that the peptide sequence (SLIGRL in the case of human body) appearing at the end of a receptor while decomposing a specific site has a specific activation mechanism that is activated by binding to a specific site of the PAR-2 receptor. (Exp Rev Mol Med. 4 (16): 1-17, 2002)
- PAR-2 has been reported to play an important role in the skin's inflammatory response, skin barrier function and pruritus development, suggesting a strong association between PAR-2's role in atopic dermatitis, which is a major symptom of the disease. It is becoming. PAR-2 is known to be expressed in various cells of the human body, and in particular, it is reported to have an effect such as causing an inflammatory response and an activation response of nerve cells. In addition, the skin has been reported to be closely related to the pigmentation of the skin because it is involved in the signal transduction mechanism between keratinocyte-melanocyte, promoting the movement of melanosome. (Drug Dev Res 59: 408-416, 2003)
- the present inventors synthesized various substances for a long time to synthesize a substance having PAR-2 inhibitory activity and confirmed its activity, and thus, invented a novel compound having excellent PAR-2 inhibitory activity.
- the present invention is to provide an imidazopyridine compound represented by the following formula (1) as a novel heterocyclic compound.
- Another object of the present invention is to provide a pharmaceutical composition for the treatment and prevention of inflammatory diseases comprising a compound of formula 1 or a pharmaceutically acceptable salt thereof, which is a heterocyclic compound according to the present invention, It is to provide a protease activated receptor-2 (PAR-2) inhibitor composition comprising a compound or a pharmaceutically acceptable salt thereof.
- PAR-2 protease activated receptor-2
- the present invention provides an imidazopyridine compound represented by the following Chemical Formula 1 which is a novel heterocyclic compound.
- R 1 is hydrogen, (C 1 -C 7) alkyl, (C 3 -C 6) cycloalkyl, (C 6 -C 12) aryl, (C 6 -C 12) ar (C 1 -C 7) alkyl, Is selected from;
- R 2 and R 3 independently of one another are hydrogen, halogen, (C 1 -C 7) alkyl, (C 1 -C 7) alkoxy, (C 1 -C 7) alkoxycarbonyl, (C 3 -C 6) cycloalkyl, (C 6 -C 10) aryl , (C6-C10) ar (C1-C7) alkyl, (C1-C7) alkylamido (C1-C7) alkyl, -NR 11 R 12 , , Is selected from; R 11 , R 12 , R 13 , R 14 and R 15 are independently of each other hydrogen, (C1-C7) alkyl, (C3-C6) cycloalkyl, (C6-C10) aryl, heterocycloalkyl (C6-C12)
- Aryl, heteroaryl, R 11 and R 12 , R 13 and R 14 may combine with each other alkylene, oxyalkylene or aminoalkylene to form a five or six member
- n is an integer from 1-4;
- Heterocycles formed from (C6-C12) aryl, R 11 and R 12 and R 13 and R 14 of R 2 and R 3 are halogen, hydroxy, (C 1 -C 7) alkyl, (C 3 -C 6) cycloalkyl, 5 Or 6 membered heterocycloalkyl, 5 or 6 membered heteroaryl, 5 or 6 membered heterocycloalkylcarbonyl, (C6-C10) aryl, (C6-C10) arylcarbonyl, (C1-C6) alkoxy, (C1-C7) alkoxycarbonyl, (C1-C7) alkylcarbonyl, (C3-C6) cyclo (C1-C7) alkylcarbonyl, (C6-C10) ar (C1-C7) alkylcarbonyl, (C3 -C6) heteroarylcarbonyl, 5- or 6-membered cycloalkylsulfonyl, (C1-C7) alkylsul
- Substituents comprising the "alkyl", “alkoxy” and other "alkyl” moieties described in the invention described herein include both straight-chain or pulverized forms, wherein (C1-C7) alkyl in the present invention is methyl, ethyl, n -Propyl, i-propyl, n-butyl, i-butyl, t-butyl, n-pentyl, i-pentyl, n-hexyl, n-heptyl, and (C1-C6) alkoxy is methoxy, ethoxy , n-propoxy, i-propoxy, n-butoxy, i-butoxy, t-butoxy, n-pentoxy, i-pentoxy, n-hexyloxy, and (C3-C6) cyclo Alkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclo
- 5- or 6-membered hetero rings include both aliphatic heterocycles and heteroaryls, in particular heterocycloalkyls, ie aliphatic hetero rings are morpholinyl, thiomorpholinyl, pyrrolidinyl, piperidinyl, piperazinyl, Pyrrolidoneyl, piperidonyl, oxazolidinonyl, thiazolidinonyl, and heteroaryls include furyl, thiophenyl, pyrrolyl, pyranyl, imidazolyl, pyrazolyl, thiazolyl, thiadiazolyl Monocyclic heteroaryl such as isothiazolyl, isoxazolyl, oxazolyl, oxdiazolyl, triazinyl, tetrazinyl, triazolyl, tetrazolyl, furazanyl, pyridyl, pyrazinyl, pyrimidinyl,
- the compound of Formula 1, which is a heterocyclic compound, according to the present invention includes an imidazopyridine compound represented by the following Formula 2.
- R 1 is hydrogen, (C 1 -C 7) alkyl, (C 3 -C 6) cycloalkyl, (C 6 -C 12) aryl, Is selected from;
- R 2 independently of one another is hydrogen, halogen, amino , (C 1 -C 7) alkyl, (C 6 -C 10) aryl, —NR 11 R 12 , , Is selected from;
- R 4 is hydrogen, halogen, (C 1 -C 7) alkyl, (C 1 -C 7) alkoxy, (C 1 -C 7) alkoxycarbonyl, (C 6 -C 10) aryl, (C 1 -C 7) alkylamido (C 1 -C 7) Alkyl, -NR 11 R 12 , , Is selected from; R 11 , R 12 , R 13 , R 14 and R 15 are independently of each other hydrogen, (C1-C7) alkyl, (C3-C6) cycloalkyl, (C6-C10) aryl, heterocycloalkyl (C6-C12) Aryl, heteroaryl, R 11 and R 12 , R 13 and R 14 may combine with each other alkylene, oxyalkylene or aminoalkylene to form a five or six membered heterocycle; R 16 is selected from hydrogen, (C1-C7) alkyl, (C3-C6) cycloalkyl or (C6
- Heterocycles formed from (C6-C12) aryl, R 11 and R 12 and R 13 and R 14 of R 2 and R 4 are halogen, hydroxy, (C 1 -C 7) alkyl, (C 3 -C 6) cycloalkyl, 5 Or 6 membered heterocycloalkyl, 5 or 6 membered heteroaryl, 5 or 6 membered heterocycloalkylcarbonyl, (C6-C10) aryl, (C6-C10) arylcarbonyl, (C1-C6) alkoxy, (C1-C7) alkoxycarbonyl, (C1-C7) alkylcarbonyl, (C3-C6) cyclo (C1-C7) alkylcarbonyl, (C6-C10) ar (C1-C7) alkylcarbonyl, (C3 -C6) heteroarylcarbonyl, 5- or 6-membered cycloalkylsulfonyl, (C1-C7) alkylsul
- R 5 are independently of each other selected from halogen, (C 1 -C 7) alkyl
- n is an integer of 1 to 3.
- the compound of Formula 1 as a heterocyclic compound according to the present invention includes an imidazopyridine compound represented by the following Formula 3.
- R 1 is hydrogen, (C 1 -C 7) alkyl, (C 3 -C 6) cycloalkyl, (C 6 -C 12) aryl, Is selected from;
- R 2 independently of one another is hydrogen, halogen, amino, (C 1 -C 7) alkyl, (C 6 -C 10) aryl, —NR 11 R 12 , , Is selected from;
- R 6 is -NR 11 R 12 ;
- R 11 and R 12 independently of one another are hydrogen, (C1-C7) alkyl, (C3-C6) cycloalkyl, (C6-C10) aryl, heterocycloalkyl (C6-C12) aryl, heteroaryl, R 11 and R 12 may combine with each other alkylene, oxyalkylene or aminoalkylene to form a 5- or 6-membered heterocycle;
- R 16 is selected from hydrogen, (C1-C7) alkyl, (C3-C6) cycloalkyl or (C6-C10) aryl;
- the hetero rings formed from (C6-C12) aryl, R 11 and R 12 of R 2 and R 6 are halogen, hydroxy, (C 1 -C 7) alkyl, (C 3 -C 6) cycloalkyl, 5 or 6 membered heterocyclo Alkyl, 5 or 6 membered heteroaryl, 5 or 6 membered heterocycloalkylcarbonyl, (C6-C10) aryl, (C6-C10) arylcarbonyl, (C1-C6) alkoxy, (C1-C7) alkoxy Carbonyl, (C1-C7) alkylcarbonyl, (C3-C6) cyclo (C1-C7) alkylcarbonyl, (C6-C10) ar (C1-C7) alkylcarbonyl, (C3-C6) heteroarylcarbon Bonyl, 5- or 6-membered cycloalkylsulfonyl, (C1-C7) alkylsulfonyl, amino (C
- the compound of Formula 1 which is a heterocyclic compound according to the present invention, includes an imidazopyridine compound represented by the following Formula 4.
- R 2 is amino, (C 6 -C 10) aryl, (C 6 -C 10) ar (C 1 -C 7) alkyl;
- A is -CH 2 or -NR 31 ;
- R 31 is selected from hydrogen, (C1-C7) alkyl, (C1-C7) alkylcarbonyl, (C3-C6) cycloalkylcarbonyl;
- the aryl and aralkyl of R 2 are halogen, hydroxy, amino, (C 1 -C 7) alkyl, (C 3 -C 6) cycloalkyl, (C 1 -C 6) alkoxy, 5 or 6 membered heterocycloalkyl, 5 or 6 May be further substituted with a heteroaryl of the original.
- the hetero compound represented by Formula 1 according to the present invention may be selected from the following structures, but is not limited thereto.
- the present invention provides a pharmaceutical composition for the treatment and prevention of inflammatory skin diseases, including the heterocyclic compound of formula (1), or a pharmaceutically acceptable salt thereof according to the invention.
- the inflammatory skin disease is a skin disease accompanied by inflammation, such as acne, rosacea, seborrheic dermatitis, atopic dermatitis, post-inflammatory hyperpigmentation (PIH), contact dermatitis, pruritus, psoriasis, and psoriasis ( Lichen planus), eczema, skin infections, Netherson Syndrome, and the like.
- inflammation such as acne, rosacea, seborrheic dermatitis, atopic dermatitis, post-inflammatory hyperpigmentation (PIH), contact dermatitis, pruritus, psoriasis, and psoriasis ( Lichen planus), eczema, skin infections, Netherson Syndrome, and the like.
- the present invention also provides a pharmaceutical composition for healing skin wounds comprising a heterocyclic compound of Formula 1 according to the present invention, or a pharmaceutically acceptable salt thereof.
- the skin wound includes but is not limited to wounds, cuts, abrasions, lacerations, bites.
- the present invention also provides a pharmaceutical composition for the treatment and prevention of cancer metastasis, gastrointestinal diseases, asthma, cirrhosis, including the heterocyclic compound of formula (1), or a pharmaceutically acceptable salt thereof according to the present invention.
- the present invention also provides a protease activated receptor-2 (PAR-2) inhibitor composition comprising a heterocyclic compound of Formula 1 according to the present invention, or a pharmaceutically acceptable salt thereof.
- PAR-2 protease activated receptor-2
- the present invention also provides a cosmetic composition comprising a heterocyclic compound of formula (1) according to the present invention.
- PAR-2 protease activated receptor-2
- IBD inflammatory bowel disease
- cirrhosis a protease activated receptor-2 inhibitory activity including the compound of formula 1 or a salt thereof according to the present invention.
- PAR-2 is known to play an important role in diseases such as inflammation, cardiovascular disease, cancer, especially cancer metastasis, gastrointestinal disorders including inflammatory bowel disease (IBD), asthma, cirrhosis.
- IBD inflammatory bowel disease
- asthma cirrhosis
- PAR-2 is known to be involved in important reactions such as pigmentation and pruritis in addition to inflammation.
- PAR-2 plays an important role in maintaining skin barrier function and wound healing. It has been reported that inhibitors to PAR-2 are also likely in the treatment of skin diseases.
- atopic dermatitis which is a skin disease in which various skin diseases appear simultaneously, it is a refractory chronic inflammatory skin disease caused by activation of PAR-2 such as severe pruritus, skin barrier damage, and post-inflammatory hyperpigmentation (PIH). It is considered that the disease is most likely to be the primary application of PAR-2 inhibitors because of the simultaneous appearance of various symptoms.
- the compound of formula 1 or salts thereof according to the present invention can be used for the purpose of healing skin, including the treatment and prevention of inflammatory diseases such as skin barrier damage, skin inflammation or atopic dermatitis, and is useful as a pharmaceutical or cosmetic composition.
- PAR-2 protease activated receptor-2
- Figure 7 is a graph showing the effect on skin thickness reduction in chronic dermatitis animal model using oxazolone.
- the present invention provides an imidazopyridine compound represented by the following Chemical Formula 1 as a novel heterocyclic compound.
- R 1 is hydrogen, (C 1 -C 7) alkyl, (C 3 -C 6) cycloalkyl, (C 6 -C 12) aryl, (C 6 -C 12) ar (C 1 -C 7) alkyl, Is selected from;
- R 2 and R 3 independently of one another are hydrogen, halogen, (C 1 -C 7) alkyl, (C 1 -C 7) alkoxy, (C 1 -C 7) alkoxycarbonyl, (C 3 -C 6) cycloalkyl, (C 6 -C 10) aryl , (C6-C10) ar (C1-C7) alkyl, (C1-C7) alkylamido (C1-C7) alkyl, -NR 11 R 12 , , Is selected from; R 11 , R 12 , R 13 , R 14 and R 15 are independently of each other hydrogen, (C1-C7) alkyl, (C3-C6) cycloalkyl, (C6-C10) aryl, heterocycloalkyl (C6-C12)
- Aryl, heteroaryl, R 11 and R 12 , R 13 and R 14 may combine with each other alkylene, oxyalkylene or aminoalkylene to form a five or six member
- n is an integer from 1-4;
- Heterocycles formed from (C6-C12) aryl, R 11 and R 12 and R 13 and R 14 of R 2 and R 3 are halogen, hydroxy, (C 1 -C 7) alkyl, (C 3 -C 6) cycloalkyl, 5 Or 6 membered heterocycloalkyl, 5 or 6 membered heteroaryl, 5 or 6 membered heterocycloalkylcarbonyl, (C6-C10) aryl, (C6-C10) arylcarbonyl, (C1-C6) alkoxy, (C1-C7) alkoxycarbonyl, (C1-C7) alkylcarbonyl, (C3-C6) cyclo (C1-C7) alkylcarbonyl, (C6-C10) ar (C1-C7) alkylcarbonyl, (C3 -C6) heteroarylcarbonyl, 5- or 6-membered cycloalkylsulfonyl, (C1-C7) alkylsul
- Preferred heterocyclic compounds in the present invention are imidazopyridine compounds represented by the following formulas (1a) and (1b) in the imidazopyridine derivative compound represented by the formula (1).
- the compound of formula 1 according to the present invention to evaluate the inhibitory activity against PAR-2 known as a mechanism involved in the treatment and prevention of inflammatory skin diseases, skin barrier damage, skin inflammation or psoriasis, Netherson Syndrome, atopic dermatitis
- the compounds of the present invention was able to confirm the inhibitory activity against PAR-2 in cells.
- the present invention provides a pharmaceutical composition, cosmetic composition, protease activated receptor-2 (PAR-2) inhibitor composition for the treatment and prevention of inflammatory skin diseases comprising the compound of formula (1) or a pharmaceutically acceptable salt thereof
- the inflammatory skin disease includes skin barrier damage, psoriasis accompanied by skin inflammation, Netherson Syndrome, atopic dermatitis, and the like.
- the use of the inhibition of PAR-2 expression to promote wound healing can provide a composition for skin wound healing.
- the composition or the PAR-2 inhibitor may include 0.001 to 90% by weight, more preferably 0.001 to 50% by weight of the compound of formula 1 according to the present invention as an active ingredient.
- the pharmaceutical composition and PAR-2 (protease activated receptor-2) inhibitor composition for the treatment and prevention of inflammatory skin disease or for the treatment of skin wounds can be administered to a living body including external preparations, injections, inhalants or oral preparations. All compositions are included.
- the formulation is not particularly limited as long as it is applicable to the skin or mucous membrane, but may be prepared in liquid, emulsion, suspension, cream, ointment, gel, jelly, and spray forms.
- 6-aminonicotinic acid methylester 500 mg, 3.29 mmol
- chloroacetone 1.83 g, 19.74 mmol
- the solvent was removed, diluted with 15 mL of water, basified with saturated aqueous sodium hydrogen carbonate solution, and extracted three times with MC (10 mL).
- step 1 The compound (80 mg, 0.30 mmol) obtained in step 1 was dissolved in a mixed solvent of tetrahydrofuran (2 mL) and ethanol (2 mL), and lithium hydroxide (20 mg, 0.48 mmol) was added thereto, and water (1 mL) was added thereto at room temperature. Stir for 12 hours. After neutralization with 1N HCl, the residue was concentrated under reduced pressure to obtain the title compound (78mg, 98%). It was used for the next reaction without purification.
- PAR-2 is a type of G-protein coupled receptor (GPCR).
- GPCR G-protein coupled receptor
- PIP2 phosphatidylinositol 4,5-bisphosphate
- IP3 inositol triphosphate
- DAG diacyl glycerol
- IP3 produced at this time promotes the release of calcium ions from ER (endoplasmic reticulum), which is a calcium ion reservoir in the cell, resulting in an increase in intracellular calcium ions.
- ER endoplasmic reticulum
- IP3 calcium ion reservoir in the cell
- the cell line used in the experiment was HCT-15, a cell line overexpressed with PAR-2, and treated with inhibitor for 5 minutes, treated with AP, and then flexibly changed the fluorescence for 2 minutes using FlexStation II of Molecular Device. Observed by.
- an in vitro assay protocol for detecting the activation of PAR-2 was further introduced to measure the activity of the selected material.
- PAR- was tested on two samples using DiscoveRx's PathHunter TM ⁇ -arrestin GPCR assay kit, which can detect the accumulation of ⁇ -arrestin, the first intracellular reaction caused by PAR-2 activation. Inhibitory activity of 2 was measured. The experiment was carried out by diluting 1/2 to 1000 ⁇ M from 50 ⁇ M, and treated with 10 ⁇ M SKIGKV-NH 2 with a PAR-2 inhibitor. In both experiments, the inhibition of b-arrestin was confirmed at 500 ⁇ M. The results showed that the IC 50 values were slightly different from the Calcium immobilization assay (Table 1).
- a cell line having the following structure was prepared with reference to existing references, and the activation of PAR-2 was observed using a confocal microscope.
- KNRK cells Kirsten Murine Sarcoma Virus transformed rat kidney epithelial cells
- stable transfected cells were constructed by tagging flag epitope on N-terminal and tagging Myc epitope on C-terminal.
- PAR-2 is not activated, Flag and Myc are dyed twice, and a yellow image appears in the merged image. In contrast, when PAR-2 is activated, the flag falls off and a red image appears.
- Efficacy was evaluated using a chronic dermatitis animal model for the selected materials.
- An animal model was used to induce chronic dermatitis by continuously applying oxazolone, a hapten type, to hairless mice.
- the recently developed oxazolone model has been reported to show the symptoms of various atopic dermatitis relatively accurately.
- various symptoms of general atopic dermatitis appear similar to the clinical symptoms.
- 6-week-old hairless mice (SKH-1) were sensitized by applying 5% oxazolone, and 0.1% oxazolone was applied every other day for 2 weeks after 1 week to induce dermatitis symptoms. .
- Samples were applied to the induced animals for 3 days at intervals of once / day, and various skin functions and skin thickness changes were observed. Finally, skin tissue was biopsied and histological observations were performed.
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Abstract
Description
Compound | IC50(μM) | CC50(μM) | |
Calcium-4 | PathHunter™ | ||
Compound 45 | 73.79 | 338.56 | > 100 |
Compound 73 | 76.68 | 400.78 | > 100 |
Claims (11)
- 하기의 화학식 1로 표시되는 헤테로고리 화합물.[화학식 1][상기 화학식1에서,R2 및 R3는 서로 독립적으로 수소, 할로겐, (C1-C7)알킬, 아미노, (C1-C7)알콕시, (C1-C7)알콕시카보닐, (C3-C6)시클로알킬, (C6-C10)아릴, (C6-C10)아르(C1-C7)알킬, (C1-C7)알킬아미도(C1-C7)알킬, -NR11R12, , 로부터 선택되고; R11, R12, R13, R14 및 R15는 서로 독립적으로 수소, (C1-C7)알킬, (C3-C6)시클로알킬, (C6-C10)아릴, 헤테로시클로알킬(C6-C12)아릴, 헤테로아릴, R11 및 R12, R13 및 R14는 서로 알킬렌, 옥시알킬렌 또는 아미노알킬렌으로 결합하여 5원 또는 6원의 헤테로고리를 형성할 수 있으며; R16은 수소, (C1-C7)알킬, (C3-C6)시클로알킬 또는 (C6-C10)아릴로부터 선택되며;m은 1-4의 정수이고;R2 및 R3의 (C6-C12)아릴, R11과 R12 및 R13과 R14로부터 형성된 헤테로 고리는 할로겐, 히드록시, (C1-C7)알킬, (C3-C6)시클로알킬, 5 또는 6원의 헤테로시클로알킬, 5 또는 6원의 헤테로아릴, 5 또는 6원의 헤테로시클로알킬카보닐, (C6-C10)아릴, (C6-C10)아릴카보닐, (C1-C6)알콕시, (C1-C7)알콕시카르보닐, (C1-C7)알킬카르보닐, (C3-C6)시클로(C1-C7)알킬카르보닐, (C6-C10)아르(C1-C7)알킬카르보닐, (C3-C6)헤테로아릴카르보닐, 5 또는 6원의 시클로알킬설포닐, (C1-C7)알킬설포닐, 아미노(C1-C7)알킬카보닐, (C1-C7)알킬옥시카보닐, (C6-C10)아르(C1-C7)알킬옥시카보닐, 아미노, (C1-C7)알킬아미노,(C1-C7)알킬아미도, (C1-C7)알킬카바모일, (C1-C7)알킬설폰아미도, 또는 로 더 치환될 수 있으며; R21 및 R22는 서로 독립적으로 (C1-C7)알킬, (C3-C6)시클로알킬, (C6-C12)아릴 또는 R21과 R22가 서로 알킬렌으로 결합하여 5원 또는 6원의 헤테로고리를 형성할 수 있다.]
- 제 1항에 있어서,하기 화학식 2로 표시되는 헤테로고리 화합물.[화학식 2][상기 화학식 2에서,R4는 수소, 할로겐, (C1-C7)알킬, (C1-C7)알콕시, (C1-C7)알콕시카보닐, (C6-C10)아릴, (C1-C7)알킬아미도(C1-C7)알킬, -NR11R12, , 로부터 선택되고; R11, R12, R13, R14 및 R15는 서로 독립적으로 수소, (C1-C7)알킬, (C3-C6)시클로알킬, (C6-C10)아릴, 헤테로시클로알킬(C6-C12)아릴, 헤테로아릴, R11 및 R12, R13 및 R14는 서로 알킬렌, 옥시알킬렌 또는 아미노알킬렌으로 결합하여 5원 또는 6원의 헤테로고리를 형성할 수 있으며; R16은 수소, (C1-C7)알킬, (C3-C6)시클로알킬 또는 (C6-C10)아릴로부터 선택되며;R2 및 R4의 (C6-C12)아릴, R11과 R12 및 R13과 R14로부터 형성된 헤테로 고리는 할로겐, 히드록시, (C1-C7)알킬, (C3-C6)시클로알킬, 5 또는 6원의 헤테로시클로알킬, 5 또는 6원의 헤테로아릴, 5 또는 6원의 헤테로시클로알킬카보닐, (C6-C10)아릴, (C6-C10)아릴카보닐, (C1-C6)알콕시, (C1-C7)알콕시카르보닐, (C1-C7)알킬카르보닐, (C3-C6)시클로(C1-C7)알킬카르보닐, (C6-C10)아르(C1-C7)알킬카르보닐, (C3-C6)헤테로아릴카르보닐, 5 또는 6원의 시클로알킬설포닐, (C1-C7)알킬설포닐, 아미노(C1-C7)알킬카보닐, (C1-C7)알킬옥시카보닐, (C6-C10)아르(C1-C7)알킬옥시카보닐, 아미노, (C1-C7)알킬아미노,(C1-C7)알킬아미도, (C1-C7)알킬카바모일, (C1-C7)알킬설폰아미도, 또는 로 더 치환될 수 있으며; R21 및 R22는 서로 독립적으로 (C1-C7)알킬, (C3-C6)시클로알킬, (C6-C12)아릴 또는 R21과 R22가 서로 알킬렌으로 결합하여 5원 또는 6원의 헤테로고리를 형성할 수 있으며;R5는 서로 독립적으로 할로겐, (C1-C7)알킬에서 선택되며;n는 1 내지 3의 정수이다.]
- 제 1항에 있어서,하기 화학식 3으로 표시되는 헤테로고리 화합물.[화학식 3][상기 화학식 3에서,R6는 -NR11R12이며; R11 및 R12는 서로 독립적으로 수소, (C1-C7)알킬, (C3-C6)시클로알킬, (C6-C10)아릴, 헤테로시클로알킬(C6-C12)아릴, 헤테로아릴, R11 및 R12는 서로 알킬렌, 옥시알킬렌 또는 아미노알킬렌으로 결합하여 5원 또는 6원의 헤테로고리를 형성할 수 있으며; R16은 수소, (C1-C7)알킬, (C3-C6)시클로알킬 또는 (C6-C10)아릴로부터 선택되며;R2 및 R6의 (C6-C12)아릴, R11과 R12로부터 형성된 헤테로 고리는 할로겐, 히드록시, (C1-C7)알킬, (C3-C6)시클로알킬, 5 또는 6원의 헤테로시클로알킬, 5 또는 6원의 헤테로아릴, 5 또는 6원의 헤테로시클로알킬카보닐, (C6-C10)아릴, (C6-C10)아릴카보닐, (C1-C6)알콕시, (C1-C7)알콕시카르보닐, (C1-C7)알킬카르보닐, (C3-C6)시클로(C1-C7)알킬카르보닐, (C6-C10)아르(C1-C7)알킬카르보닐, (C3-C6)헤테로아릴카르보닐, 5 또는 6원의 시클로알킬설포닐, (C1-C7)알킬설포닐, 아미노(C1-C7)알킬카보닐, (C1-C7)알킬옥시카보닐, (C6-C10)아르(C1-C7)알킬옥시카보닐, 아미노, (C1-C7)알킬아미노,(C1-C7)알킬아미도, (C1-C7)알킬카바모일, (C1-C7)알킬설폰아미도, 또는 로 더 치환될 수 있으며; R21 및 R22는 서로 독립적으로 (C1-C7)알킬, (C3-C6)시클로알킬, (C6-C12)아릴 또는 R21과 R22가 서로 알킬렌으로 결합하여 5원 또는 6원의 헤테로고리를 형성할 수 있다.]
- 제 1항 내지 제 5항에 따른 화학식 1의 헤테로고리 화합물, 또는 이들의 약학적으로 허용되는 염을 포함하는 염증성 피부질환의 치료 및 예방을 위한 의약조성물.
- 제 6항에 있어서,염증성 피부질환은 염증이 동반되는 피부 질환으로서, 여드름, 주사 (rosacea), 지루성 피부염, 아토피 피부염, 염증 후 색소 침착 (post-inflammatory hyperpigmentation: PIH), 접촉성 피부염, 소양증, 건선, 편평태선 (Lichen planus), 습진, 피부 감염증, Netherson Syndrome 등을 포함하는 염증성 피부질환의 치료 및 예방을 위한 의약조성물.
- 제 1항 내지 제 5항에 따른 화학식 1의 헤테로고리 화합물, 또는 이들의 약학적으로 허용되는 염을 포함하는 피부 상처치유를 위한 의약조성물.
- 제 1항 내지 제 5항에 따른 화학식 1의 헤테로고리 화합물, 또는 이들의 약학적으로 허용되는 염을 포함하는 암의 전이, 위장관계 질환, 천식, 간경변의 치료 및 예방을 위한 의약조성물.
- 제 1항 내지 제 5항에 따른 화학식 1의 헤테로고리 화합물, 또는 이들의 약학적으로 허용되는 염을 포함하는 PAR-2(protease activated receptor-2) 저해제 조성물.
- 제 1항 내지 제 5항에 따른 화학식 1의 헤테로고리 화합물을 포함하는 화장품 조성물.
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US13/818,420 US20130165652A1 (en) | 2010-08-25 | 2011-08-25 | Novel heterocyclic compound, and composition for treating inflammatory diseases using same |
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PCT/KR2011/006281 WO2012026766A2 (ko) | 2010-08-25 | 2011-08-25 | 신규한 헤테로고리 화합물 및 이를 이용한 염증성 질환 치료용 조성물 |
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US (2) | US8809541B2 (ko) |
EP (2) | EP2617721A4 (ko) |
JP (1) | JP5894161B2 (ko) |
KR (2) | KR20130059400A (ko) |
CN (1) | CN103119042B (ko) |
DK (1) | DK2610255T3 (ko) |
ES (1) | ES2573148T3 (ko) |
PL (1) | PL2610255T3 (ko) |
WO (2) | WO2012026765A2 (ko) |
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US8883819B2 (en) | 2011-09-01 | 2014-11-11 | Irm Llc | Bicyclic heterocycle derivatives for the treatment of pulmonary arterial hypertension |
US9073921B2 (en) | 2013-03-01 | 2015-07-07 | Novartis Ag | Salt forms of bicyclic heterocyclic derivatives |
US9309243B2 (en) | 2012-07-13 | 2016-04-12 | Ucb Biopharma Sprl | Imidazopyridine derivatives as modulators of TNF activity |
US10030024B2 (en) | 2013-09-25 | 2018-07-24 | Vertex Pharmaceuticals Incorporated | Imidazopyridazines useful as inhibitors of the PAR-2 signaling pathway |
US10266531B2 (en) | 2016-10-21 | 2019-04-23 | Novartis Ag | Naphthyridinone derivatives and their use in the treatment of arrhythmia |
US10786513B2 (en) * | 2016-01-27 | 2020-09-29 | Universitat Zurich | Use of GABAA receptor modulators for treatment of itch |
WO2020201572A1 (en) | 2019-04-05 | 2020-10-08 | Université De Bretagne Occidentale | Protease-activated receptor-2 inhibitors for the treatment of sensory neuropathy induced by a marine neurotoxic poisoning |
WO2022117882A2 (en) | 2020-12-03 | 2022-06-09 | Domain Therapeutics | Novel par-2 inhibitors |
WO2023233033A1 (en) | 2022-06-03 | 2023-12-07 | Domain Therapeutics | Novel par-2 inhibitors |
US11970493B2 (en) | 2020-10-06 | 2024-04-30 | Ildong Pharmaceutical Co., Ltd. | Autotaxin inhibitor compounds |
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BR112014030940B1 (pt) | 2012-06-11 | 2022-09-06 | UCB Biopharma SRL | Benzimidazóis que modulam tnf-alfa e composição farmacêutica compreendendo os mesmos |
KR101421032B1 (ko) * | 2012-12-28 | 2014-07-22 | 주식회사 레고켐 바이오사이언스 | (2-메틸-1-(3-메틸벤질)-1H-벤조[d]이미다졸-5일)(피페리딘-5-일)메탄온의 제조방법 |
CN103113306A (zh) * | 2013-03-07 | 2013-05-22 | 同济大学 | 一种合成氮茚化合物nps-1577的方法 |
US10369121B2 (en) | 2013-08-23 | 2019-08-06 | The Catholic University Of Korea Industry-Academic Cooperation Foundation | Pharmaceutical composition for preventing or treating immune diseases or inflammatory diseases, containing biguanide derivative compound as active ingredient |
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KR101705446B1 (ko) | 2014-04-29 | 2017-02-09 | 가톨릭대학교 산학협력단 | 면역질환 치료효과를 갖는 신규한 화합물 및 이의 용도 |
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KR102394110B1 (ko) | 2020-01-22 | 2022-05-04 | 가톨릭대학교 산학협력단 | 신규 화합물 및 이의 용도 |
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- 2011-08-25 US US13/818,355 patent/US8809541B2/en not_active Expired - Fee Related
- 2011-08-25 CN CN201180041194.4A patent/CN103119042B/zh not_active Expired - Fee Related
- 2011-08-25 EP EP11820192.0A patent/EP2617721A4/en not_active Withdrawn
- 2011-08-25 KR KR1020137004500A patent/KR101477156B1/ko active IP Right Grant
- 2011-08-25 EP EP11820193.8A patent/EP2610255B1/en active Active
- 2011-08-25 JP JP2013525831A patent/JP5894161B2/ja not_active Expired - Fee Related
- 2011-08-25 WO PCT/KR2011/006281 patent/WO2012026766A2/ko active Application Filing
- 2011-08-25 DK DK11820193.8T patent/DK2610255T3/en active
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- 2011-08-25 US US13/818,420 patent/US20130165652A1/en not_active Abandoned
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Cited By (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8883819B2 (en) | 2011-09-01 | 2014-11-11 | Irm Llc | Bicyclic heterocycle derivatives for the treatment of pulmonary arterial hypertension |
US9751876B2 (en) | 2011-09-01 | 2017-09-05 | Novartis Ag | Bicyclic heterocycle derivatives for the treatment of pulmonary arterial hypertension |
US9309243B2 (en) | 2012-07-13 | 2016-04-12 | Ucb Biopharma Sprl | Imidazopyridine derivatives as modulators of TNF activity |
US9073921B2 (en) | 2013-03-01 | 2015-07-07 | Novartis Ag | Salt forms of bicyclic heterocyclic derivatives |
US10030024B2 (en) | 2013-09-25 | 2018-07-24 | Vertex Pharmaceuticals Incorporated | Imidazopyridazines useful as inhibitors of the PAR-2 signaling pathway |
US10786513B2 (en) * | 2016-01-27 | 2020-09-29 | Universitat Zurich | Use of GABAA receptor modulators for treatment of itch |
US11529359B2 (en) | 2016-01-27 | 2022-12-20 | Universitat Zurich | Use of GABAA receptor modulators for treatment of itch |
US10266531B2 (en) | 2016-10-21 | 2019-04-23 | Novartis Ag | Naphthyridinone derivatives and their use in the treatment of arrhythmia |
US10844055B2 (en) | 2016-10-21 | 2020-11-24 | Novartis Ag | Naphthyridinone derivatives and their use in the treatment of arrhythmia |
US11530213B2 (en) | 2016-10-21 | 2022-12-20 | Novartis Ag | Naphthyridinone derivatives and their use in the treatment of arrhythmia |
WO2020201572A1 (en) | 2019-04-05 | 2020-10-08 | Université De Bretagne Occidentale | Protease-activated receptor-2 inhibitors for the treatment of sensory neuropathy induced by a marine neurotoxic poisoning |
US11970493B2 (en) | 2020-10-06 | 2024-04-30 | Ildong Pharmaceutical Co., Ltd. | Autotaxin inhibitor compounds |
WO2022117882A2 (en) | 2020-12-03 | 2022-06-09 | Domain Therapeutics | Novel par-2 inhibitors |
WO2023233033A1 (en) | 2022-06-03 | 2023-12-07 | Domain Therapeutics | Novel par-2 inhibitors |
Also Published As
Publication number | Publication date |
---|---|
EP2617721A2 (en) | 2013-07-24 |
US8809541B2 (en) | 2014-08-19 |
PL2610255T3 (pl) | 2016-08-31 |
EP2617721A4 (en) | 2014-01-08 |
JP5894161B2 (ja) | 2016-03-23 |
US20130158047A1 (en) | 2013-06-20 |
US20130165652A1 (en) | 2013-06-27 |
KR101477156B1 (ko) | 2014-12-29 |
EP2610255A2 (en) | 2013-07-03 |
CN103119042A (zh) | 2013-05-22 |
ES2573148T3 (es) | 2016-06-06 |
JP2013538209A (ja) | 2013-10-10 |
WO2012026765A3 (ko) | 2012-06-07 |
WO2012026766A3 (ko) | 2012-06-07 |
CN103119042B (zh) | 2016-06-01 |
KR20130069737A (ko) | 2013-06-26 |
KR20130059400A (ko) | 2013-06-05 |
DK2610255T3 (en) | 2016-05-30 |
EP2610255A4 (en) | 2014-02-12 |
WO2012026766A2 (ko) | 2012-03-01 |
EP2610255B1 (en) | 2016-02-24 |
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