CA2659055A1 - 2-phenyl-indoles as prostaglandin d2 receptor antagonists - Google Patents

Info

Publication number

CA2659055A1

CA2659055A1 CA002659055A CA2659055A CA2659055A1 CA 2659055 A1 CA2659055 A1 CA 2659055A1 CA 002659055 A CA002659055 A CA 002659055A CA 2659055 A CA2659055 A CA 2659055A CA 2659055 A1 CA2659055 A1 CA 2659055A1

Authority

CA

Canada

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
• CIPO
• Discuss

• KLLLJCACIRKBDT-UHFFFAOYSA-N 2-phenyl-1H-indole Chemical class N1C2=CC=CC=C2C=C1C1=CC=CC=C1 KLLLJCACIRKBDT-UHFFFAOYSA-N 0.000 title abstract description 3
• 102000009389 Prostaglandin D receptors Human genes 0.000 title description 5
• 108050000258 Prostaglandin D receptors Proteins 0.000 title description 5
• 229940044551 receptor antagonist Drugs 0.000 title description 3
• 239000002464 receptor antagonist Substances 0.000 title description 3
• 150000001875 compounds Chemical class 0.000 claims abstract description 117
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 26
• 208000006673 asthma Diseases 0.000 claims abstract description 19
• 201000008937 atopic dermatitis Diseases 0.000 claims abstract description 16
• 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 16
• 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
• 208000035475 disorder Diseases 0.000 claims abstract description 12
• 208000026935 allergic disease Diseases 0.000 claims abstract description 11
• 208000010668 atopic eczema Diseases 0.000 claims abstract description 11
• 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims abstract description 9
• 206010012438 Dermatitis atopic Diseases 0.000 claims abstract description 9
• 210000003630 histaminocyte Anatomy 0.000 claims abstract description 8
• 206010061218 Inflammation Diseases 0.000 claims abstract description 7
• 208000024780 Urticaria Diseases 0.000 claims abstract description 7
• 230000004054 inflammatory process Effects 0.000 claims abstract description 7
• 208000030603 inherited susceptibility to asthma Diseases 0.000 claims abstract description 6
• 206010002198 Anaphylactic reaction Diseases 0.000 claims abstract description 4
• 206010006482 Bronchospasm Diseases 0.000 claims abstract description 4
• 208000002177 Cataract Diseases 0.000 claims abstract description 4
• 206010008190 Cerebrovascular accident 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
• 206010016946 Food allergy 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
• 208000006011 Stroke 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
• 230000036783 anaphylactic response Effects 0.000 claims abstract description 4
• 208000003455 anaphylaxis Diseases 0.000 claims abstract description 4
• 238000010009 beating Methods 0.000 claims abstract description 4
• 206010006451 bronchitis Diseases 0.000 claims abstract description 4
• 230000007885 bronchoconstriction Effects 0.000 claims abstract description 4
• 230000020411 cell activation Effects 0.000 claims abstract description 4
• 208000026106 cerebrovascular disease Diseases 0.000 claims abstract description 4
• 230000001684 chronic effect 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
• 238000006748 scratching Methods 0.000 claims abstract description 4
• 230000002393 scratching effect Effects 0.000 claims abstract description 4
• 230000035939 shock Effects 0.000 claims abstract description 4
• 230000009885 systemic effect Effects 0.000 claims abstract description 4
• 150000003839 salts Chemical class 0.000 claims description 91
• -1 2,6-dichloro-benzyl Chemical group 0.000 claims description 57
• 229940002612 prodrug Drugs 0.000 claims description 52
• 239000000651 prodrug Substances 0.000 claims description 52
• 239000012453 solvate Substances 0.000 claims description 45
• 238000000034 method Methods 0.000 claims description 36
• 239000001257 hydrogen Substances 0.000 claims description 15
• 229910052739 hydrogen Inorganic materials 0.000 claims description 15
• 125000001309 chloro group Chemical group Cl* 0.000 claims description 10
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 10
• 125000005843 halogen group Chemical group 0.000 claims description 9
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
• 239000005557 antagonist Substances 0.000 claims description 7
• 239000003937 drug carrier Substances 0.000 claims description 7
• 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 5
• ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 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
• 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
• 239000000739 antihistaminic agent Substances 0.000 claims description 4
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
• 125000006125 ethylsulfonyl group Chemical group 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
• LDXDSHIEDAPSSA-OAHLLOKOSA-N Ramatroban Chemical group N([C@@H]1CCC=2N(C3=CC=CC=C3C=2C1)CCC(=O)O)S(=O)(=O)C1=CC=C(F)C=C1 LDXDSHIEDAPSSA-OAHLLOKOSA-N 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
• 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
• 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 2
• 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 2
• 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 2
• 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 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
• 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 2
• 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 2
• 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 2
• 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 2
• 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 2
• 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 2
• 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 2
• 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 2
• 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 2
• 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 2
• 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 2
• 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 2
• 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 2
• 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 2
• 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 2
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• 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
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• IHOYMGOWUYJGID-UHFFFAOYSA-N methyl 2-[2-[4-chloro-3-[(3-chlorophenyl)methylsulfonyl]phenyl]-1h-indol-3-yl]acetate Chemical compound N1C2=CC=CC=C2C(CC(=O)OC)=C1C(C=1)=CC=C(Cl)C=1S(=O)(=O)CC1=CC=CC(Cl)=C1 IHOYMGOWUYJGID-UHFFFAOYSA-N 0.000 description 1
• TVBMYWBZASFVQX-UHFFFAOYSA-N methyl 2-[2-[4-chloro-3-[(3-chlorophenyl)methylsulfonylamino]phenyl]-1h-indol-3-yl]-2-oxoacetate Chemical compound N1C2=CC=CC=C2C(C(=O)C(=O)OC)=C1C(C=1)=CC=C(Cl)C=1NS(=O)(=O)CC1=CC=CC(Cl)=C1 TVBMYWBZASFVQX-UHFFFAOYSA-N 0.000 description 1
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