KR20090039735A - 프로스타글란딘 ｄ2 수용체 길항제로서의 2-페닐-인돌 - Google Patents

Info

Publication number

KR20090039735A

KR20090039735A KR1020097001687A KR20097001687A KR20090039735A KR 20090039735 A KR20090039735 A KR 20090039735A KR 1020097001687 A KR1020097001687 A KR 1020097001687A KR 20097001687 A KR20097001687 A KR 20097001687A KR 20090039735 A KR20090039735 A KR 20090039735A

Authority

KR

South Korea

Prior art keywords

chloro

phenyl

indol

pharmaceutically acceptable

acetic acid

Prior art date

2006-07-25

Legal status (The legal status 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 status listed.)

Abandoned

Links

• Espacenet
• Global Dossier
• Discuss

• KLLLJCACIRKBDT-UHFFFAOYSA-N 2-phenyl-1H-indole Chemical compound N1C2=CC=CC=C2C=C1C1=CC=CC=C1 KLLLJCACIRKBDT-UHFFFAOYSA-N 0.000 title abstract description 3
• 229940122913 Prostaglandin D2 receptor antagonist Drugs 0.000 title description 4
• 150000001875 compounds Chemical class 0.000 claims abstract description 114
• 238000000034 method Methods 0.000 claims abstract description 41
• 208000006673 asthma Diseases 0.000 claims abstract description 19
• 201000008937 atopic dermatitis Diseases 0.000 claims abstract description 16
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 15
• 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 14
• 206010039085 Rhinitis allergic Diseases 0.000 claims abstract description 13
• 201000010105 allergic rhinitis Diseases 0.000 claims abstract description 13
• 201000010099 disease Diseases 0.000 claims abstract description 13
• 206010010744 Conjunctivitis allergic Diseases 0.000 claims abstract description 12
• 208000003251 Pruritus Diseases 0.000 claims abstract description 12
• 208000002205 allergic conjunctivitis Diseases 0.000 claims abstract description 12
• 208000024998 atopic conjunctivitis Diseases 0.000 claims abstract description 12
• 208000010668 atopic eczema Diseases 0.000 claims abstract description 11
• 208000026935 allergic disease Diseases 0.000 claims abstract description 10
• 206010012438 Dermatitis atopic Diseases 0.000 claims abstract description 9
• 230000007803 itching Effects 0.000 claims abstract description 9
• 206010061218 Inflammation Diseases 0.000 claims abstract description 8
• 210000003630 histaminocyte Anatomy 0.000 claims abstract description 8
• 230000004054 inflammatory process Effects 0.000 claims abstract description 8
• 210000000232 gallbladder Anatomy 0.000 claims abstract description 7
• 230000001684 chronic effect Effects 0.000 claims abstract description 6
• 208000030603 inherited susceptibility to asthma Diseases 0.000 claims abstract description 6
• 206010002199 Anaphylactic shock Diseases 0.000 claims abstract description 4
• 208000002177 Cataract Diseases 0.000 claims abstract description 4
• 206010009900 Colitis ulcerative Diseases 0.000 claims abstract description 4
• 201000004624 Dermatitis Diseases 0.000 claims abstract description 4
• 208000004262 Food Hypersensitivity Diseases 0.000 claims abstract description 4
• 206010063837 Reperfusion injury Diseases 0.000 claims abstract description 4
• 206010038848 Retinal detachment Diseases 0.000 claims abstract description 4
• 201000008736 Systemic mastocytosis Diseases 0.000 claims abstract description 4
• 201000006704 Ulcerative Colitis Diseases 0.000 claims abstract description 4
• 208000003455 anaphylaxis Diseases 0.000 claims abstract description 4
• 206010006451 bronchitis Diseases 0.000 claims abstract description 4
• 230000020411 cell activation Effects 0.000 claims abstract description 4
• 230000008602 contraction Effects 0.000 claims abstract description 4
• 235000020932 food allergy Nutrition 0.000 claims abstract description 4
• 208000015181 infectious disease Diseases 0.000 claims abstract description 4
• 230000000302 ischemic effect Effects 0.000 claims abstract description 4
• 208000008423 pleurisy Diseases 0.000 claims abstract description 4
• 230000004264 retinal detachment Effects 0.000 claims abstract description 4
• 206010039073 rheumatoid arthritis Diseases 0.000 claims abstract description 4
• 238000010079 rubber tapping Methods 0.000 claims abstract description 4
• 238000006748 scratching Methods 0.000 claims abstract description 4
• 230000002393 scratching effect Effects 0.000 claims abstract description 4
• 208000019116 sleep disease Diseases 0.000 claims abstract description 4
• 230000009885 systemic effect Effects 0.000 claims abstract description 4
• 230000006399 behavior Effects 0.000 claims abstract description 3
• -1 2,6-dichloro-benzyl Chemical group 0.000 claims description 116
• 150000003839 salts Chemical class 0.000 claims description 89
• 229940002612 prodrug Drugs 0.000 claims description 52
• 239000000651 prodrug Substances 0.000 claims description 52
• 239000012453 solvate Substances 0.000 claims description 44
• 239000001257 hydrogen Substances 0.000 claims description 15
• 229910052739 hydrogen Inorganic materials 0.000 claims description 15
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 11
• 125000001309 chloro group Chemical group Cl* 0.000 claims description 10
• 125000005843 halogen group Chemical group 0.000 claims description 9
• 239000000126 substance Substances 0.000 claims description 9
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
• 239000005557 antagonist Substances 0.000 claims description 8
• 239000003937 drug carrier Substances 0.000 claims description 8
• 150000004677 hydrates Chemical class 0.000 claims description 8
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
• OAFWQOKONGHPNE-UHFFFAOYSA-N 2-[4-chloro-2-[4-chloro-3-(cyclohexylsulfamoyl)phenyl]-1h-indol-3-yl]acetic acid Chemical compound N1C2=CC=CC(Cl)=C2C(CC(=O)O)=C1C(C=1)=CC=C(Cl)C=1S(=O)(=O)NC1CCCCC1 OAFWQOKONGHPNE-UHFFFAOYSA-N 0.000 claims description 6
• 150000002431 hydrogen Chemical class 0.000 claims description 6
• ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 5
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
• 125000004441 haloalkylsulfonyl group Chemical group 0.000 claims description 5
• 239000011591 potassium Substances 0.000 claims description 5
• 229910052700 potassium Inorganic materials 0.000 claims description 5
• CYEFWBZXGDCMEV-UHFFFAOYSA-N 2-[2-[4-chloro-3-(2-phenylethylsulfamoyl)phenyl]-1h-indol-3-yl]acetic acid Chemical compound N1C2=CC=CC=C2C(CC(=O)O)=C1C(C=1)=CC=C(Cl)C=1S(=O)(=O)NCCC1=CC=CC=C1 CYEFWBZXGDCMEV-UHFFFAOYSA-N 0.000 claims description 4
• MFZJSYNRDODMGM-UHFFFAOYSA-N 2-[2-[4-chloro-3-(3-phenylpropylsulfamoyl)phenyl]-1h-indol-3-yl]acetic acid Chemical compound N1C2=CC=CC=C2C(CC(=O)O)=C1C(C=1)=CC=C(Cl)C=1S(=O)(=O)NCCCC1=CC=CC=C1 MFZJSYNRDODMGM-UHFFFAOYSA-N 0.000 claims description 4
• ACORQNNZIIDWOY-UHFFFAOYSA-N 2-[2-[4-chloro-3-(cyclohexylsulfamoyl)phenyl]-1h-indol-3-yl]propanoic acid Chemical compound N1C2=CC=CC=C2C(C(C(O)=O)C)=C1C(C=1)=CC=C(Cl)C=1S(=O)(=O)NC1CCCCC1 ACORQNNZIIDWOY-UHFFFAOYSA-N 0.000 claims description 4
• CBVVTYCQHBTMAE-UHFFFAOYSA-N 2-[2-[4-chloro-3-(cyclohexylsulfamoyl)phenyl]-4-fluoro-1h-indol-3-yl]acetic acid Chemical compound N1C2=CC=CC(F)=C2C(CC(=O)O)=C1C(C=1)=CC=C(Cl)C=1S(=O)(=O)NC1CCCCC1 CBVVTYCQHBTMAE-UHFFFAOYSA-N 0.000 claims description 4
• MYZYKAAKVDKIFT-UHFFFAOYSA-N 2-[2-[4-chloro-3-(cyclohexylsulfamoyl)phenyl]-4-methyl-1h-indol-3-yl]acetic acid Chemical compound OC(=O)CC=1C=2C(C)=CC=CC=2NC=1C(C=1)=CC=C(Cl)C=1S(=O)(=O)NC1CCCCC1 MYZYKAAKVDKIFT-UHFFFAOYSA-N 0.000 claims description 4
• HIVJYGKMPHTWPG-UHFFFAOYSA-N 2-[2-[4-chloro-3-[(3,5-dichlorophenyl)methylsulfamoyl]phenyl]-1h-indol-3-yl]acetic acid Chemical compound N1C2=CC=CC=C2C(CC(=O)O)=C1C(C=1)=CC=C(Cl)C=1S(=O)(=O)NCC1=CC(Cl)=CC(Cl)=C1 HIVJYGKMPHTWPG-UHFFFAOYSA-N 0.000 claims description 4
• SPDHCHUIPQCJIT-UHFFFAOYSA-N 2-[2-[4-chloro-3-[(3-chlorophenyl)methylsulfonyl]phenyl]-1h-indol-3-yl]acetic acid Chemical compound N1C2=CC=CC=C2C(CC(=O)O)=C1C(C=1)=CC=C(Cl)C=1S(=O)(=O)CC1=CC=CC(Cl)=C1 SPDHCHUIPQCJIT-UHFFFAOYSA-N 0.000 claims description 4
• GJWJWZDDQPPQAT-UHFFFAOYSA-N 2-[2-[4-chloro-3-[(3-chlorophenyl)methylsulfonylamino]phenyl]-1h-indol-3-yl]acetic acid Chemical compound N1C2=CC=CC=C2C(CC(=O)O)=C1C(C=1)=CC=C(Cl)C=1NS(=O)(=O)CC1=CC=CC(Cl)=C1 GJWJWZDDQPPQAT-UHFFFAOYSA-N 0.000 claims description 4
• PQGJVVKDJSJIMD-UHFFFAOYSA-N 2-[2-[4-chloro-3-[2-(3-methoxyphenyl)ethylsulfamoyl]phenyl]-1h-indol-3-yl]acetic acid Chemical compound COC1=CC=CC(CCNS(=O)(=O)C=2C(=CC=C(C=2)C2=C(C3=CC=CC=C3N2)CC(O)=O)Cl)=C1 PQGJVVKDJSJIMD-UHFFFAOYSA-N 0.000 claims description 4
• XEPDDBGYBLDMOH-UHFFFAOYSA-N 2-[2-[4-chloro-3-[2-(4-methoxyphenyl)ethylsulfamoyl]phenyl]-1h-indol-3-yl]acetic acid Chemical compound C1=CC(OC)=CC=C1CCNS(=O)(=O)C1=CC(C2=C(C3=CC=CC=C3N2)CC(O)=O)=CC=C1Cl XEPDDBGYBLDMOH-UHFFFAOYSA-N 0.000 claims description 4
• VTPVWOAMVGZZKJ-UHFFFAOYSA-N 2-[7-chloro-2-[4-chloro-3-(cyclohexylsulfamoyl)phenyl]-1h-indol-3-yl]acetic acid Chemical compound N1C2=C(Cl)C=CC=C2C(CC(=O)O)=C1C(C=1)=CC=C(Cl)C=1S(=O)(=O)NC1CCCCC1 VTPVWOAMVGZZKJ-UHFFFAOYSA-N 0.000 claims description 4
• 125000000940 2-methoxyphenyl ethyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 4
• 230000009471 action Effects 0.000 claims description 4
• 239000000739 antihistaminic agent Substances 0.000 claims description 4
• 125000006125 ethylsulfonyl group Chemical group 0.000 claims description 4
• 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 4
• 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 4
• 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 4
• 125000003831 tetrazolyl group Chemical group 0.000 claims description 4
• YZHLQIDOXFFHIC-UHFFFAOYSA-N 2-[2-[3-(cyclohexylsulfamoyl)-4-ethylphenyl]-1h-indol-3-yl]acetic acid Chemical compound CCC1=CC=C(C2=C(C3=CC=CC=C3N2)CC(O)=O)C=C1S(=O)(=O)NC1CCCCC1 YZHLQIDOXFFHIC-UHFFFAOYSA-N 0.000 claims description 3
• SSWLGNBAUDIWAV-UHFFFAOYSA-N 2-[2-[4-chloro-3-(cyclohexylsulfamoyl)phenyl]-1h-indol-3-yl]-n-(2h-tetrazol-5-yl)acetamide Chemical compound ClC1=CC=C(C2=C(C3=CC=CC=C3N2)CC(=O)NC=2NN=NN=2)C=C1S(=O)(=O)NC1CCCCC1 SSWLGNBAUDIWAV-UHFFFAOYSA-N 0.000 claims description 3
• YSASBPWWXZDHDU-UHFFFAOYSA-N 2-[2-[4-chloro-3-(cyclohexylsulfamoyl)phenyl]-1h-indol-3-yl]-n-ethylsulfonylacetamide Chemical compound N1C2=CC=CC=C2C(CC(=O)NS(=O)(=O)CC)=C1C(C=1)=CC=C(Cl)C=1S(=O)(=O)NC1CCCCC1 YSASBPWWXZDHDU-UHFFFAOYSA-N 0.000 claims description 3
• PTZZCYIVRWCWRR-UHFFFAOYSA-N 2-[2-[4-chloro-3-(cyclohexylsulfamoyl)phenyl]-1h-indol-3-yl]-n-methylacetamide Chemical compound N1C2=CC=CC=C2C(CC(=O)NC)=C1C(C=1)=CC=C(Cl)C=1S(=O)(=O)NC1CCCCC1 PTZZCYIVRWCWRR-UHFFFAOYSA-N 0.000 claims description 3
• YQKSEPAFDYUFEA-UHFFFAOYSA-N 2-[2-[4-chloro-3-(cyclohexylsulfamoyl)phenyl]-1h-indol-3-yl]-n-methylsulfonylacetamide Chemical compound N1C2=CC=CC=C2C(CC(=O)NS(=O)(=O)C)=C1C(C=1)=CC=C(Cl)C=1S(=O)(=O)NC1CCCCC1 YQKSEPAFDYUFEA-UHFFFAOYSA-N 0.000 claims description 3
• OKWAHZPLRUETRX-UHFFFAOYSA-N 2-[2-[4-chloro-3-[(2,6-dichlorophenyl)methylsulfamoyl]phenyl]-1h-indol-3-yl]acetic acid Chemical compound N1C2=CC=CC=C2C(CC(=O)O)=C1C(C=1)=CC=C(Cl)C=1S(=O)(=O)NCC1=C(Cl)C=CC=C1Cl OKWAHZPLRUETRX-UHFFFAOYSA-N 0.000 claims description 3
• LUOMPFDGGGWODV-UHFFFAOYSA-N 2-[2-[4-chloro-3-[2-(2,4-dichlorophenyl)ethylsulfamoyl]phenyl]-1h-indol-3-yl]acetic acid Chemical compound N1C2=CC=CC=C2C(CC(=O)O)=C1C(C=1)=CC=C(Cl)C=1S(=O)(=O)NCCC1=CC=C(Cl)C=C1Cl LUOMPFDGGGWODV-UHFFFAOYSA-N 0.000 claims description 3
• NUCYUFBDBJIVJR-UHFFFAOYSA-N 2-[2-[4-chloro-3-[2-(2-methoxyphenyl)ethylsulfamoyl]phenyl]-1h-indol-3-yl]acetic acid Chemical compound COC1=CC=CC=C1CCNS(=O)(=O)C1=CC(C2=C(C3=CC=CC=C3N2)CC(O)=O)=CC=C1Cl NUCYUFBDBJIVJR-UHFFFAOYSA-N 0.000 claims description 3
• FXGKECGOCFYIRG-UHFFFAOYSA-N 2-[2-[4-chloro-3-[2-[2-(trifluoromethoxy)phenyl]ethylsulfamoyl]phenyl]-1h-indol-3-yl]acetic acid Chemical compound N1C2=CC=CC=C2C(CC(=O)O)=C1C(C=1)=CC=C(Cl)C=1S(=O)(=O)NCCC1=CC=CC=C1OC(F)(F)F FXGKECGOCFYIRG-UHFFFAOYSA-N 0.000 claims description 3
• 229940125715 antihistaminic agent Drugs 0.000 claims description 3
• 229940125388 beta agonist Drugs 0.000 claims description 3
• RWTNPBWLLIMQHL-UHFFFAOYSA-N fexofenadine Chemical group C1=CC(C(C)(C(O)=O)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 RWTNPBWLLIMQHL-UHFFFAOYSA-N 0.000 claims description 3
• 229960003592 fexofenadine Drugs 0.000 claims description 3
• 239000003199 leukotriene receptor blocking agent Substances 0.000 claims description 3
• 229960003088 loratadine Drugs 0.000 claims description 3
• JCCNYMKQOSZNPW-UHFFFAOYSA-N loratadine Chemical compound C1CN(C(=O)OCC)CCC1=C1C2=NC=CC=C2CCC2=CC(Cl)=CC=C21 JCCNYMKQOSZNPW-UHFFFAOYSA-N 0.000 claims description 3
• LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 3
• XWTYSIMOBUGWOL-UHFFFAOYSA-N (+-)-Terbutaline Chemical compound CC(C)(C)NCC(O)C1=CC(O)=CC(O)=C1 XWTYSIMOBUGWOL-UHFFFAOYSA-N 0.000 claims description 2
• ZVYJBOYQGOAXMO-UHFFFAOYSA-N 2-[2-[4-chloro-3-(cyclohexylsulfamoyl)phenyl]-1h-indol-3-yl]-n-(trifluoromethylsulfonyl)acetamide Chemical compound N1C2=CC=CC=C2C(CC(=O)NS(=O)(=O)C(F)(F)F)=C1C(C=1)=CC=C(Cl)C=1S(=O)(=O)NC1CCCCC1 ZVYJBOYQGOAXMO-UHFFFAOYSA-N 0.000 claims description 2
• ZKLPARSLTMPFCP-UHFFFAOYSA-N Cetirizine Chemical compound C1CN(CCOCC(=O)O)CCN1C(C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 ZKLPARSLTMPFCP-UHFFFAOYSA-N 0.000 claims description 2
• UCHDWCPVSPXUMX-TZIWLTJVSA-N Montelukast Chemical group CC(C)(O)C1=CC=CC=C1CC[C@H](C=1C=C(\C=C\C=2N=C3C=C(Cl)C=CC3=CC=2)C=CC=1)SCC1(CC(O)=O)CC1 UCHDWCPVSPXUMX-TZIWLTJVSA-N 0.000 claims description 2
• JAUOIFJMECXRGI-UHFFFAOYSA-N Neoclaritin Chemical compound C=1C(Cl)=CC=C2C=1CCC1=CC=CN=C1C2=C1CCNCC1 JAUOIFJMECXRGI-UHFFFAOYSA-N 0.000 claims description 2
• YEEZWCHGZNKEEK-UHFFFAOYSA-N Zafirlukast Chemical compound COC1=CC(C(=O)NS(=O)(=O)C=2C(=CC=CC=2)C)=CC=C1CC(C1=C2)=CN(C)C1=CC=C2NC(=O)OC1CCCC1 YEEZWCHGZNKEEK-UHFFFAOYSA-N 0.000 claims description 2
• NDAUXUAQIAJITI-UHFFFAOYSA-N albuterol Chemical group CC(C)(C)NCC(O)C1=CC=C(O)C(CO)=C1 NDAUXUAQIAJITI-UHFFFAOYSA-N 0.000 claims description 2
• 229960001803 cetirizine Drugs 0.000 claims description 2
• 229960001271 desloratadine Drugs 0.000 claims description 2
• 229960005127 montelukast Drugs 0.000 claims description 2
• 230000000414 obstructive effect Effects 0.000 claims description 2
• 230000002685 pulmonary effect Effects 0.000 claims description 2
• MNDBXUUTURYVHR-UHFFFAOYSA-N roflumilast Chemical group FC(F)OC1=CC=C(C(=O)NC=2C(=CN=CC=2Cl)Cl)C=C1OCC1CC1 MNDBXUUTURYVHR-UHFFFAOYSA-N 0.000 claims description 2
• 229960002586 roflumilast Drugs 0.000 claims description 2
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• 229940123932 Phosphodiesterase 4 inhibitor Drugs 0.000 claims 2
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• 206010016946 Food allergy Diseases 0.000 claims 1
• GUGOEEXESWIERI-UHFFFAOYSA-N Terfenadine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 GUGOEEXESWIERI-UHFFFAOYSA-N 0.000 claims 1
• 230000001387 anti-histamine Effects 0.000 claims 1
• UUEVFMOUBSLVJW-UHFFFAOYSA-N oxo-[[1-[2-[2-[2-[4-(oxoazaniumylmethylidene)pyridin-1-yl]ethoxy]ethoxy]ethyl]pyridin-4-ylidene]methyl]azanium;dibromide Chemical compound [Br-].[Br-].C1=CC(=C[NH+]=O)C=CN1CCOCCOCCN1C=CC(=C[NH+]=O)C=C1 UUEVFMOUBSLVJW-UHFFFAOYSA-N 0.000 claims 1
• BHMBVRSPMRCCGG-OUTUXVNYSA-N prostaglandin D2 Chemical compound CCCCC[C@H](O)\C=C\[C@@H]1[C@@H](C\C=C/CCCC(O)=O)[C@@H](O)CC1=O BHMBVRSPMRCCGG-OUTUXVNYSA-N 0.000 abstract description 21
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• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 24
• 239000011734 sodium Substances 0.000 description 24
• 238000003756 stirring Methods 0.000 description 24
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• 239000002585 base Substances 0.000 description 21
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