NZ562772A - Tricyclic spiro derivatives as CRTH2 modulators - Google Patents

Info

Publication number

NZ562772A

NZ562772A NZ562772A NZ56277206A NZ562772A NZ 562772 A NZ562772 A NZ 562772A NZ 562772 A NZ562772 A NZ 562772A NZ 56277206 A NZ56277206 A NZ 56277206A NZ 562772 A NZ562772 A NZ 562772A

Authority

NZ

New Zealand

Prior art keywords

chloro

pyrrolidin

indole

trioxospiro

acetic acid

Prior art date

2005-05-24

Links

• Espacenet
• Global Dossier
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• 125000003003 spiro group Chemical group 0.000 title claims abstract description 95
• 102000009389 Prostaglandin D receptors Human genes 0.000 title claims abstract description 5
• 108050000258 Prostaglandin D receptors Proteins 0.000 title claims abstract description 5
• 230000002757 inflammatory effect Effects 0.000 claims abstract description 20
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 18
• 208000026935 allergic disease Diseases 0.000 claims abstract description 16
• 201000010099 disease Diseases 0.000 claims abstract description 15
• 230000000694 effects Effects 0.000 claims abstract description 14
• 208000017520 skin disease Diseases 0.000 claims abstract description 13
• 230000002265 prevention Effects 0.000 claims abstract description 6
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 725
• 150000001875 compounds Chemical class 0.000 claims description 257
• 239000002253 acid Substances 0.000 claims description 129
• -1 hydroxy, amino, aminocarbonyl Chemical group 0.000 claims description 112
• 238000000034 method Methods 0.000 claims description 106
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 95
• 125000003118 aryl group Chemical group 0.000 claims description 51
• 125000001072 heteroaryl group Chemical group 0.000 claims description 51
• FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims description 46
• RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Substances C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 26
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 25
• 229910052736 halogen Inorganic materials 0.000 claims description 24
• 229910052739 hydrogen Inorganic materials 0.000 claims description 24
• 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 23
• 239000001257 hydrogen Substances 0.000 claims description 23
• 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 20
• 150000002367 halogens Chemical class 0.000 claims description 20
• 150000003839 salts Chemical class 0.000 claims description 19
• 208000024376 chronic urticaria Diseases 0.000 claims description 18
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 17
• 230000029936 alkylation Effects 0.000 claims description 15
• 238000005804 alkylation reaction Methods 0.000 claims description 15
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 14
• 230000008569 process Effects 0.000 claims description 14
• 239000003814 drug Substances 0.000 claims description 13
• HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 11
• 208000022559 Inflammatory bowel disease Diseases 0.000 claims description 11
• 125000003545 alkoxy group Chemical group 0.000 claims description 11
• 208000006673 asthma Diseases 0.000 claims description 11
• 208000010247 contact dermatitis Diseases 0.000 claims description 11
• 239000008194 pharmaceutical composition Substances 0.000 claims description 11
• 208000017983 photosensitivity disease Diseases 0.000 claims description 11
• 206010012442 Dermatitis contact Diseases 0.000 claims description 10
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 10
• 125000000217 alkyl group Chemical group 0.000 claims description 10
• 150000002431 hydrogen Chemical group 0.000 claims description 10
• 101100439663 Arabidopsis thaliana CHR7 gene Proteins 0.000 claims description 9
• 206010012438 Dermatitis atopic Diseases 0.000 claims description 9
• 201000008937 atopic dermatitis Diseases 0.000 claims description 9
• 229910052757 nitrogen Inorganic materials 0.000 claims description 9
• 238000002360 preparation method Methods 0.000 claims description 9
• 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 7
• 206010052568 Urticaria chronic Diseases 0.000 claims description 7
• 125000004442 acylamino group Chemical group 0.000 claims description 7
• 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 7
• 201000009961 allergic asthma Diseases 0.000 claims description 7
• 206010010744 Conjunctivitis allergic Diseases 0.000 claims description 6
• 208000010201 Exanthema Diseases 0.000 claims description 6
• 201000002481 Myositis Diseases 0.000 claims description 6
• 206010051246 Photodermatosis Diseases 0.000 claims description 6
• 206010036087 Polymorphic light eruption Diseases 0.000 claims description 6
• 206010039085 Rhinitis allergic Diseases 0.000 claims description 6
• 208000002205 allergic conjunctivitis Diseases 0.000 claims description 6
• 201000010105 allergic rhinitis Diseases 0.000 claims description 6
• 229910052782 aluminium Inorganic materials 0.000 claims description 6
• 150000001412 amines Chemical class 0.000 claims description 6
• 208000024998 atopic conjunctivitis Diseases 0.000 claims description 6
• 208000029407 autoimmune urticaria Diseases 0.000 claims description 6
• 229940079593 drug Drugs 0.000 claims description 6
• 201000005884 exanthem Diseases 0.000 claims description 6
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• 206010037844 rash Diseases 0.000 claims description 6
• 206010039073 rheumatoid arthritis Diseases 0.000 claims description 6
• QECVIPBZOPUTRD-UHFFFAOYSA-N N=S(=O)=O Chemical compound N=S(=O)=O QECVIPBZOPUTRD-UHFFFAOYSA-N 0.000 claims description 5
• 125000000304 alkynyl group Chemical group 0.000 claims description 5
• 230000007062 hydrolysis Effects 0.000 claims description 5
• 238000006460 hydrolysis reaction Methods 0.000 claims description 5
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
• 125000006528 (C2-C6) alkyl group Chemical group 0.000 claims description 3
• 230000001684 chronic effect Effects 0.000 claims description 3
• 239000003085 diluting agent Substances 0.000 claims description 3
• 239000003937 drug carrier Substances 0.000 claims description 3
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
• 229940124530 sulfonamide Drugs 0.000 claims description 3
• 150000003456 sulfonamides Chemical class 0.000 claims description 3
• 125000006516 2-(benzyloxy)ethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 2
• GQTOGHHFCWMRPS-UHFFFAOYSA-N 2-[6-chloro-1'-[(4-fluorophenyl)methyl]-2,2',5'-trioxospiro[indole-3,3'-pyrrolidine]-1-yl]acetic acid Chemical compound C12=CC=C(Cl)C=C2N(CC(=O)O)C(=O)C1(C1=O)CC(=O)N1CC1=CC=C(F)C=C1 GQTOGHHFCWMRPS-UHFFFAOYSA-N 0.000 claims description 2
• 208000027866 inflammatory disease Diseases 0.000 claims description 2
• SKLDVYDFQCXARY-UHFFFAOYSA-N 2-[5-chloro-1'-[(2-fluorophenyl)methyl]-2,2',5'-trioxospiro[indole-3,3'-pyrrolidine]-1-yl]acetic acid Chemical compound C12=CC(Cl)=CC=C2N(CC(=O)O)C(=O)C1(C1=O)CC(=O)N1CC1=CC=CC=C1F SKLDVYDFQCXARY-UHFFFAOYSA-N 0.000 claims 2
• AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims 2
• BDWQUHFLKUXBHZ-UHFFFAOYSA-N 2-(1'-benzyl-5-chloro-2,2'-dioxospiro[indole-3,4'-pyrrolidine]-1-yl)acetic acid Chemical compound C12=CC(Cl)=CC=C2N(CC(=O)O)C(=O)C1(CC1=O)CN1CC1=CC=CC=C1 BDWQUHFLKUXBHZ-UHFFFAOYSA-N 0.000 claims 1
• PPJOWJPPYWTPOD-UHFFFAOYSA-N 2-[6-chloro-1'-[(3-fluorophenyl)methyl]-2,2',5'-trioxospiro[indole-3,3'-pyrrolidine]-1-yl]acetic acid Chemical compound C12=CC=C(Cl)C=C2N(CC(=O)O)C(=O)C1(C1=O)CC(=O)N1CC1=CC=CC(F)=C1 PPJOWJPPYWTPOD-UHFFFAOYSA-N 0.000 claims 1
• NRPFMALMXVEMQL-UHFFFAOYSA-N 4-[5-chloro-1'-[(4-fluorophenyl)methyl]-2,2',5'-trioxospiro[indole-3,3'-pyrrolidine]-1-yl]butanoic acid Chemical compound C12=CC(Cl)=CC=C2N(CCCC(=O)O)C(=O)C1(C1=O)CC(=O)N1CC1=CC=C(F)C=C1 NRPFMALMXVEMQL-UHFFFAOYSA-N 0.000 claims 1
• 206010002198 Anaphylactic reaction Diseases 0.000 claims 1
• 206010048768 Dermatosis Diseases 0.000 claims 1
• 230000000172 allergic effect Effects 0.000 claims 1
• 208000003455 anaphylaxis Diseases 0.000 claims 1
• 208000010668 atopic eczema Diseases 0.000 claims 1
• 230000009610 hypersensitivity Effects 0.000 claims 1
• 206010021247 idiopathic urticaria Diseases 0.000 claims 1
• 238000004519 manufacturing process Methods 0.000 claims 1
• 239000000543 intermediate Substances 0.000 description 195
• 238000004949 mass spectrometry Methods 0.000 description 175
• 229960000583 acetic acid Drugs 0.000 description 167
• 235000011054 acetic acid Nutrition 0.000 description 164
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 156
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 119
• 238000004128 high performance liquid chromatography Methods 0.000 description 112
• 239000007787 solid Substances 0.000 description 99
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 78
• 238000007429 general method Methods 0.000 description 66
• 239000002904 solvent Substances 0.000 description 58
• 235000019439 ethyl acetate Nutrition 0.000 description 52
• 239000000203 mixture Substances 0.000 description 52
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 50
• 239000000243 solution Substances 0.000 description 48
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 47
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 46
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 45
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 44
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 43
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 40
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 37
• LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 34
• 239000002585 base Substances 0.000 description 29
• 238000003756 stirring Methods 0.000 description 29
• 238000006243 chemical reaction Methods 0.000 description 28
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 27
• 229910000104 sodium hydride Inorganic materials 0.000 description 26
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 25
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 24
• 229910000027 potassium carbonate Inorganic materials 0.000 description 24
• 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 description 24
• 239000000377 silicon dioxide Substances 0.000 description 24
• ACCRRLVDDBQSKQ-UHFFFAOYSA-N 5-chlorospiro[1h-indole-3,3'-pyrrolidine]-2,2',5'-trione Chemical compound C12=CC(Cl)=CC=C2NC(=O)C21CC(=O)NC2=O ACCRRLVDDBQSKQ-UHFFFAOYSA-N 0.000 description 23
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 23
• 238000005481 NMR spectroscopy Methods 0.000 description 22
• KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 22
• BHMBVRSPMRCCGG-UHFFFAOYSA-N prostaglandine D2 Natural products CCCCCC(O)C=CC1C(CC=CCCCC(O)=O)C(O)CC1=O BHMBVRSPMRCCGG-UHFFFAOYSA-N 0.000 description 22
• 239000002168 alkylating agent Substances 0.000 description 21
• 229940100198 alkylating agent Drugs 0.000 description 21
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 20
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 20
• 229940093956 potassium carbonate Drugs 0.000 description 20
• 239000000725 suspension Substances 0.000 description 20
• 239000000284 extract Substances 0.000 description 19
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• 238000000746 purification Methods 0.000 description 19
• 229910052740 iodine Inorganic materials 0.000 description 18
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• AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical class CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 16
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• 150000001649 bromium compounds Chemical class 0.000 description 16
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• 238000010992 reflux Methods 0.000 description 16
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• 230000015572 biosynthetic process Effects 0.000 description 15
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• 230000008020 evaporation Effects 0.000 description 15
• QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 14
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• 150000001348 alkyl chlorides Chemical class 0.000 description 14
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• NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 14
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• 239000012267 brine Substances 0.000 description 13
• 125000000592 heterocycloalkyl group Chemical group 0.000 description 13
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• 125000001424 substituent group Chemical group 0.000 description 10
• 238000003786 synthesis reaction Methods 0.000 description 10
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• IPZYDLBTEJEBTM-UHFFFAOYSA-N 1'-chlorospiro[1h-indole-3,3'-pyrrolidine]-2,2',5'-trione Chemical compound O=C1N(Cl)C(=O)CC11C2=CC=CC=C2NC1=O IPZYDLBTEJEBTM-UHFFFAOYSA-N 0.000 description 6
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• CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 6
• CSRZQMIRAZTJOY-UHFFFAOYSA-N trimethylsilyl iodide Substances C[Si](C)(C)I CSRZQMIRAZTJOY-UHFFFAOYSA-N 0.000 description 6
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• ANGDWNBGPBMQHW-UHFFFAOYSA-N methyl cyanoacetate Chemical compound COC(=O)CC#N ANGDWNBGPBMQHW-UHFFFAOYSA-N 0.000 description 5
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• 210000001744 T-lymphocyte Anatomy 0.000 description 4
• HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
• 125000003342 alkenyl group Chemical group 0.000 description 4
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