HRP20041231A2 - Acyloxypyrrolidine derivatives and use thereof as ligands of v1b or both v1b and v1a receptors - Google Patents
Acyloxypyrrolidine derivatives and use thereof as ligands of v1b or both v1b and v1a receptors Download PDFInfo
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- HRP20041231A2 HRP20041231A2 HR20041231A HRP20041231A HRP20041231A2 HR P20041231 A2 HRP20041231 A2 HR P20041231A2 HR 20041231 A HR20041231 A HR 20041231A HR P20041231 A HRP20041231 A HR P20041231A HR P20041231 A2 HRP20041231 A2 HR P20041231A2
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- Prior art keywords
- compound
- formula
- dimethoxyphenyl
- methoxyphenyl
- sulfonyl
- Prior art date
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- 239000003446 ligand Substances 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 87
- 150000003839 salts Chemical class 0.000 claims description 19
- 229940126062 Compound A Drugs 0.000 claims description 15
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 claims description 15
- 239000012453 solvate Substances 0.000 claims description 12
- 238000011282 treatment Methods 0.000 claims description 11
- 239000002253 acid Substances 0.000 claims description 7
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 7
- 239000000126 substance Substances 0.000 claims description 7
- 206010041067 Small cell lung cancer Diseases 0.000 claims description 6
- 150000007529 inorganic bases Chemical class 0.000 claims description 6
- 150000007530 organic bases Chemical class 0.000 claims description 6
- 208000000587 small cell lung carcinoma Diseases 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 229940127554 medical product Drugs 0.000 claims description 5
- NJXZWIIMWNEOGJ-SKOIZEAASA-N (2s,4r)-1-[5-chloro-1-(2,4-dimethoxyphenyl)sulfonyl-3-(2-methoxyphenyl)-2-oxoindol-3-yl]-4-hydroxy-n,n-dimethylpyrrolidine-2-carboxamide Chemical compound COC1=CC(OC)=CC=C1S(=O)(=O)N1C2=CC=C(Cl)C=C2C(N2[C@@H](C[C@@H](O)C2)C(=O)N(C)C)(C=2C(=CC=CC=2)OC)C1=O NJXZWIIMWNEOGJ-SKOIZEAASA-N 0.000 claims description 4
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 4
- SSWJUXDXNLHQTN-XMBZSLMXSA-N [(3r,5s)-1-[(3r)-5-chloro-1-(2,4-dimethoxyphenyl)sulfonyl-3-(2-methoxyphenyl)-2-oxoindol-3-yl]-5-(dimethylcarbamoyl)pyrrolidin-3-yl] carbamate Chemical compound COC1=CC(OC)=CC=C1S(=O)(=O)N1C2=CC=C(Cl)C=C2[C@@](N2[C@@H](C[C@H](C2)OC(N)=O)C(=O)N(C)C)(C=2C(=CC=CC=2)OC)C1=O SSWJUXDXNLHQTN-XMBZSLMXSA-N 0.000 claims description 4
- 230000002496 gastric effect Effects 0.000 claims description 4
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 4
- AHWALFGBDFAJAI-UHFFFAOYSA-N phenyl carbonochloridate Chemical compound ClC(=O)OC1=CC=CC=C1 AHWALFGBDFAJAI-UHFFFAOYSA-N 0.000 claims description 4
- 208000019901 Anxiety disease Diseases 0.000 claims description 3
- 208000014311 Cushing syndrome Diseases 0.000 claims description 3
- XFUACMXGZPONPX-UBLOXDIOSA-N [(3r,5s)-1-[(3r)-5-chloro-1-(2,4-dimethoxyphenyl)sulfonyl-3-(2-methoxyphenyl)-2-oxoindol-3-yl]-5-(dimethylcarbamoyl)pyrrolidin-3-yl] acetate Chemical compound COC1=CC(OC)=CC=C1S(=O)(=O)N1C2=CC=C(Cl)C=C2[C@@](N2[C@@H](C[C@H](C2)OC(C)=O)C(=O)N(C)C)(C=2C(=CC=CC=2)OC)C1=O XFUACMXGZPONPX-UBLOXDIOSA-N 0.000 claims description 3
- QQLPFBJGJMTBKC-KXRXZPDRSA-N [(3r,5s)-1-[(3r)-5-chloro-1-(2,4-dimethoxyphenyl)sulfonyl-3-(2-methoxyphenyl)-2-oxoindol-3-yl]-5-(dimethylcarbamoyl)pyrrolidin-3-yl] cyclohexanecarboxylate Chemical compound COC1=CC(OC)=CC=C1S(=O)(=O)N1C2=CC=C(Cl)C=C2[C@@](N2[C@@H](C[C@H](C2)OC(=O)C2CCCCC2)C(=O)N(C)C)(C=2C(=CC=CC=2)OC)C1=O QQLPFBJGJMTBKC-KXRXZPDRSA-N 0.000 claims description 3
- GRTGENZVGSQWRL-DLHNHZGJSA-N [(3r,5s)-1-[(3r)-5-chloro-1-(2,4-dimethoxyphenyl)sulfonyl-3-(2-methoxyphenyl)-2-oxoindol-3-yl]-5-(dimethylcarbamoyl)pyrrolidin-3-yl] formate Chemical compound COC1=CC(OC)=CC=C1S(=O)(=O)N1C2=CC=C(Cl)C=C2[C@@](N2[C@@H](C[C@H](C2)OC=O)C(=O)N(C)C)(C=2C(=CC=CC=2)OC)C1=O GRTGENZVGSQWRL-DLHNHZGJSA-N 0.000 claims description 3
- GCVIBTMZDYDLCV-OSOIBMAMSA-N [(3r,5s)-1-[(3r)-5-chloro-1-(2,4-dimethoxyphenyl)sulfonyl-3-(2-methoxyphenyl)-2-oxoindol-3-yl]-5-(dimethylcarbamoyl)pyrrolidin-3-yl] n,n-dimethylcarbamate Chemical compound COC1=CC(OC)=CC=C1S(=O)(=O)N1C2=CC=C(Cl)C=C2[C@@](N2[C@@H](C[C@H](C2)OC(=O)N(C)C)C(=O)N(C)C)(C=2C(=CC=CC=2)OC)C1=O GCVIBTMZDYDLCV-OSOIBMAMSA-N 0.000 claims description 3
- KXCMDVVFKBSGDK-OSOIBMAMSA-N [(3r,5s)-1-[(3r)-5-chloro-1-(2,4-dimethoxyphenyl)sulfonyl-3-(2-methoxyphenyl)-2-oxoindol-3-yl]-5-(dimethylcarbamoyl)pyrrolidin-3-yl] propanoate Chemical compound C1[C@H](OC(=O)CC)C[C@@H](C(=O)N(C)C)N1[C@@]1(C=2C(=CC=CC=2)OC)C2=CC(Cl)=CC=C2N(S(=O)(=O)C=2C(=CC(OC)=CC=2)OC)C1=O KXCMDVVFKBSGDK-OSOIBMAMSA-N 0.000 claims description 3
- 230000036506 anxiety Effects 0.000 claims description 3
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 3
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 150000004677 hydrates Chemical class 0.000 claims description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 201000009395 primary hyperaldosteronism Diseases 0.000 claims description 3
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 3
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 2
- 201000001320 Atherosclerosis Diseases 0.000 claims description 2
- 208000005171 Dysmenorrhea Diseases 0.000 claims description 2
- 206010013935 Dysmenorrhoea Diseases 0.000 claims description 2
- 206010022489 Insulin Resistance Diseases 0.000 claims description 2
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- 206010033664 Panic attack Diseases 0.000 claims description 2
- 208000005107 Premature Birth Diseases 0.000 claims description 2
- 206010036590 Premature baby Diseases 0.000 claims description 2
- BBDJTPVXOSQBBO-OTZIMPAASA-N [(3r,5s)-1-[(3r)-5-chloro-1-(2,4-dimethoxyphenyl)sulfonyl-3-(2-methoxyphenyl)-2-oxoindol-3-yl]-5-(dimethylcarbamoyl)pyrrolidin-3-yl] 2-methylpropanoate Chemical compound COC1=CC(OC)=CC=C1S(=O)(=O)N1C2=CC=C(Cl)C=C2[C@@](N2[C@@H](C[C@H](C2)OC(=O)C(C)C)C(=O)N(C)C)(C=2C(=CC=CC=2)OC)C1=O BBDJTPVXOSQBBO-OTZIMPAASA-N 0.000 claims description 2
- 125000003277 amino group Chemical group 0.000 claims description 2
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- 235000020824 obesity Nutrition 0.000 claims description 2
- 208000019906 panic disease Diseases 0.000 claims description 2
- JJXNGRKBAGVMJV-OTZIMPAASA-N 4-[(3r,5s)-1-[(3r)-5-chloro-1-(2,4-dimethoxyphenyl)sulfonyl-3-(2-methoxyphenyl)-2h-indol-3-yl]-5-(dimethylcarbamoyl)pyrrolidin-3-yl]oxy-4-oxobutanoic acid Chemical compound COC1=CC(OC)=CC=C1S(=O)(=O)N1C2=CC=C(Cl)C=C2[C@@](N2[C@@H](C[C@H](C2)OC(=O)CCC(O)=O)C(=O)N(C)C)(C=2C(=CC=CC=2)OC)C1 JJXNGRKBAGVMJV-OTZIMPAASA-N 0.000 claims 1
- 206010012601 diabetes mellitus Diseases 0.000 claims 1
- 230000002526 effect on cardiovascular system Effects 0.000 claims 1
- 210000005227 renal system Anatomy 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 39
- 108020003175 receptors Proteins 0.000 description 35
- 102000005962 receptors Human genes 0.000 description 34
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 30
- 239000000203 mixture Substances 0.000 description 26
- KBZOIRJILGZLEJ-LGYYRGKSSA-N argipressin Chemical compound C([C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CSSC[C@@H](C(N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N1)=O)N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCN=C(N)N)C(=O)NCC(N)=O)C1=CC=CC=C1 KBZOIRJILGZLEJ-LGYYRGKSSA-N 0.000 description 25
- 239000002904 solvent Substances 0.000 description 25
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 21
- 102400000059 Arg-vasopressin Human genes 0.000 description 20
- 101800001144 Arg-vasopressin Proteins 0.000 description 20
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 18
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 18
- 239000002585 base Substances 0.000 description 14
- 235000019439 ethyl acetate Nutrition 0.000 description 14
- 238000000034 method Methods 0.000 description 13
- 239000000243 solution Substances 0.000 description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
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- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 9
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 8
- 239000000275 Adrenocorticotropic Hormone Substances 0.000 description 8
- 102400000739 Corticotropin Human genes 0.000 description 8
- 101800000414 Corticotropin Proteins 0.000 description 8
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 8
- IDLFZVILOHSSID-OVLDLUHVSA-N corticotropin Chemical compound C([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)NC(=O)[C@@H](N)CO)C1=CC=C(O)C=C1 IDLFZVILOHSSID-OVLDLUHVSA-N 0.000 description 8
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- OWMZNFCDEHGFEP-NFBCVYDUSA-N secretin human Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(N)=O)[C@@H](C)O)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)C1=CC=CC=C1 OWMZNFCDEHGFEP-NFBCVYDUSA-N 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
- 230000009329 sexual behaviour Effects 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 1
- 208000019116 sleep disease Diseases 0.000 description 1
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- 230000004936 stimulating effect Effects 0.000 description 1
- 239000002438 stress hormone Substances 0.000 description 1
- 208000011117 substance-related disease Diseases 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 229940037128 systemic glucocorticoids Drugs 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 210000001541 thymus gland Anatomy 0.000 description 1
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- FAQYAMRNWDIXMY-UHFFFAOYSA-N trichloroborane Chemical compound ClB(Cl)Cl FAQYAMRNWDIXMY-UHFFFAOYSA-N 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
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- 239000008096 xylene Substances 0.000 description 1
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Description
Ovaj se izum odnosi na derivate aciloksipirolidina, njihovu pripravu i upotrebu u terapijske svrhe.
Spojevi prema ovom izumu odlikuju se afinitetom i selektivnošću prema V1b receptorima ili prema V1b i V1a receptorima arginin-vazopresina (AVP).
AVP je hormon za kojeg je poznato da se odlikuje antidijuretičkim učinkom i da regulira arterijski tlak. Ovaj hormon stimulira nekoliko vrsta receptora: V1 (V1a, V1b) i V2. Ovi se receptori nalaze u jetri, žilama (koronarnim, bubrežnim, cerebralnim), plateletima, bubrezima, uterusu, nadbubrežnoj žlijezdi, pankreasu, centralnom živčanom sustavu i u hipofizi. Prema tome, AVP potiče kardiovaskularni sustav, jetru, pankreas i agregaciju plateleta, utječe na centralni i periferni živčani sustav, te na maternicu, a odlikuje se i antidijuretičkim učinkom.
Mjesta nalaženja različitih vrsta receptora opisana su u S. Jard et al., Vasopressin and oxytocin receptors: an overview, u Progress in Endocrinology, H. Imura i K. Shizurne ed., Experta Medica, Amsterdam, 1988, 1183-1188, a također i u slijedećim člancima: J. Lab. Clin. Med., 1989, 114 (6), 617-632 i Pharmacol. Rev., 1991, 43 (1), 73-108.
Određenije, V1a receptori za AVP smješteni su u mnogim perifernim organima i mozgu. Uspješno su klonirani, naročito u štakora i ljudi, te reguliraju većinu od poznatih učinaka AVP: agregaciju plateleta, kontrakcije maternice, kontrakcije žila, sekreciju aldosterona, kortizola, CRF (kortikotropin-otpuštajući faktor) i adrenokortikotropnog hormona (ACTH), te glikogenolizu u jetri, staničnu proliferaciju i druge osnovne učinke AVP (hipotermija, pamćenje itd.).
V1b receptori su prvo otkriveni u adenohipofizi različitih životinjskih vrsta (štakora, svinja, goveda, ovaca itd.) uključujući i ljude (S. Jard et al., Mol. Pharmacol., 1986, 30, 171-177; Y. Arsenijevic et al., J. Endocrinol., 1994, 141, 383-391; J. Schwartz et al., Endocrinology, 1991, 129 (2), 1107-1109; Y. de Keyser et al., FEBS Letters, 1994, 356, 215-220), te je otkriveno da oni stimuliraju otpuštanje adrenokortikotropnog hormona s AVP i potenciraju učinak CRF na otpuštanje ACTH (G. E. Gillies et al., Nature, 1982, 299, 355). U hipotalamusu, V1b receptori induciraju neposredno otpuštanje CRF (Neuroendocrinology, 1994, 60, 503-508), te su na različite načine uključeni prilikom pojave stresa.
V1b receptori klonirani su u štakora, ljudi i miševa (Y. de Keyser, FEBS Letters, 1994, 356, 215-220; T. Sugimoto et al., J. Biol. Chem., 1994, 269 (43), 27088-27092; M. Saito et al., Biochem. Biophys. Res. Commun., 1995, 212 (3), 751-757; S. J. Lolait et al., Neurobiology, 1996, 92, 6783-6787; M. A. Ventura et al., Journal of Molecular Endocrinology, 1999, 22, 251-260), te su različitim istraživanjima (hibridizacija in situ, PCR (polimerazna lančana reakcija) itd.) otkrivene pozicije tih receptora u različitim centralnim tkivima (mozak, hipotalamus i adenohipofiza) i perifernim tkivima (bubrezi, pankreas, žlijezde, srce, pluća, crijeva, trbuh, jetra, mezenterij, mokraćni mjehur, timus, žuč, uterus, retina, štitnjača itd.), a također i u nekim tumorima (hipofiza, plućni tumor itd.) što upućuje na raznolikost u biološkoj i/ili patološkoj ulozi ovih receptora, te njihovo moguće sudjelovanje u različitim bolestima.
Na primjer, može se navesti da su istraživanja djelovanja AVP, putem V1b receptora na štakorima, pokazala da AVP regulira pankreas stimulirajući sekreciju inzulina i glukagona (B. Lee et al., Am. J. Physiol. 269 (Endocrinal. Metab. 32): E1095-E1100, 1995), a također i stvaranje katekolamina u moždini nadbubrežne žlijezde, dakle u središtu lokalne sinteze AVP (E. Grazzini et al., Endocrinology, 1996, 137 (a), 3906-3914). Prema tome, AVP se odlikuje esencijalnom ulogom u određenih vrsta feokromocitoma nadbubrežne žlijezde koji ga luče, te posljedično uzrokuju povećanu proizvodnju katekolamina, što dovodi do hipertenzije otporne na antagoniste angiotenzin II receptora i inhibitore angiotenzin-pretvorbenog enzima. Korteks nadbubrežne žlijezde također sadrži obilje V1a receptora koji su uključeni u proizvodnju glukokortikoida i mineralokortikoida (aldosteron i kortizol). Prema tome, AVP (koji dolazi u rečeno tkivo putem cirkulacije ili je pak lokalno sintetiziran) može, putem rečenih receptora, inducirati stvaranje aldosterona učinkovitošću usporedivom s onom od angiotenzina II (G. Guillon et al., Endocrinology, 1995, 136 (3), 1285-1295). Kortizol je snažan regulator stvaranja ACTH (hormona stresa).
Nedavna istraživanja su pokazala da je nadbubrežna žlijezda sposobna neposredno otpuštati CRF i/ili ACTH postupkom u kojem je uključena aktivacija V1b i/ili V1a receptora koji se nalaze na stanicama medule (G. Mazzocchi et al., Peptides, 1997, 18 (2), 191-195; E. Grazzini et al., J. Clin. Endocrinal. Metab., 1999, 84 (6), 2195-2203).
Također se smatra da su V1b receptori markeri za tumor. Na primjer, prekomjerna ekspresija V1b receptora opažena je u tumora koji luče ACTH, kao što su to na primjer određeni tumori hipofize i određeni karcinomi bronhija (kanceri malih stanica pluća, SCLC), karcinomi pankreasa, karcinomi nadbubrežne žlijezde i karcinomi štitnjače uključujući u nekim slučajevima i Cushingov sindrom (J. Bertherat et al., Eur. J. Endocrinol., 1996, 135, 173; G. A. Wittert et al., Lancet, 1990, 335, 991-994; G. Dickstein et al., J. Clin. Endocrinol. Metab., 1996, 81 (8), 2934-2941). S druge pak strane V1a receptori su specifičniji kao markeri kancera malih stanica pluća (SCLC) (P. J. Woll et al., Biochem. Biophys. Res. Commun., 1989, 164 (1), 66-73). Prema tome, spojevi prema ovom izumu korisni su za postavljanje dijagnoze, te omogućuju novi terapijski pristup prilikom proliferacije i detekcije navedenih tumora čak i u njihovoj ranoj fazi razvoja (radio označavanje, SPECT (kompjuterizirana tomografija emisijom jednog fotona), PET skeniranje (pozitronska emisijska tomografija).
Velika količina glasnika V1b receptora prisutnih u trbuhu i crijevima sugerira da je AVP, putem ovog receptora, uključen u otpuštanje gastrointestinalnih hormona, kao što su to kolecistokinin, gastrin ili sekretin (T. Sugimoto et al., Molecular cloning and functional expression of V1b receptor gene, Neurohypophysis: Recent Progress of Vasopressin and Oxytocin Research, T. Saito, K. Kurokawa, S. Yoshida ed., Elsevier Science, 1995, 409-413).
U međunarodnoj patentnoj prijavi WO 01/55130 opisana je skupina spojeva koji se odlikuju afinitetom i selektivnošću prema V1b receptorima ili prema V1b i V1a receptorima arginin-vazopresina.
Određenije, selektivni antagonist V1b receptora (2S, 4R)-1-[5-klor-1-[(2,4-dimetoksifenil)sulfonil]-3-(2-metoksifenil)-2-okso-2,3-dihidro-1H-indol-3-il]-4-hidroksi-N,N-dimetil-2-pirolidinkarboksamid, lijevi izomer (ovdje u nastavku označen kao spoj A), opisan je u WO 01/55130, J. Pharmacol. Exp. Ther., 2002, 300 (3), 1122-1130.
Sada su otkriveni novi spojevi, derivati aciloksipirolidina, koji se odlikuju afinitetom i selektivnošću prema V1b receptorima ili prema V1b i V1a receptorima arginin-vazopresina.
Predmet ovog izuma su spojevi formule (I):
[image]
gdje:
R1 predstavlja atom vodika, (C1- C6)alkil, (C3- C6)cikloalkil,–CH2CH2COOH skupinu ili –NR2R3 skupinu;
R2 i R3 svaki neovisno jedan o drugome predstavlja atom vodika ili (C1- C6)alkil.
Spojevi formule (I) sadrže tri asimetrična atoma ugljika: atom ugljika na kojeg je vezana –CON(CH3)2 skupina odlikuje se (S) konfiguracijom, atom ugljika na kojeg je vezana –OCOR1 skupina odlikuje se (R) konfiguracijom i atom ugljika na trećoj poziciji indol-2-ona odlikuje se (R) konfiguracijom.
Spojevi formule (I) mogu biti oblika baze ili soli organskih ili anorganskih baza, kao što su to soli alkalijskih metala ili zemnoalkalijskih metala, ili pak soli organskih ili anorganskih amina. Sve takve soli obuhvaćene su ovim izumom.
Poželjno je da se soli prirede iz farmaceutski prihvatljivih baza, ali se mogu koristiti i soli drugih baza za na primjer, pročišćavanje ili izolaciju spojeva formule (I), te su sve takve soli obuhvaćene izumom.
Spojevi formule (I) mogu biti oblika hidrata ili solvata, određenije u obliku asocijata ili kombinacije s jednom ili više molekula vode ili otapala. Takvi hidrati i solvati također su obuhvaćeni ovim izumom.
Pojam ʺalkilʺ označuje linearni ili razgranati alkilni dio koji sadrži jedan do šest atoma ugljika, kao što je to metil, etil, propil, izopropil, butil, izobutil, tert-butil, pentil, izopentil, heksil ili izoheksil.
Pojam ʺcikloalkilʺ označuje ciklički alkilni dio koji sadrži tri do šest atoma ugljika, kao što je to ciklopropil, ciklobutil, ciklopentil ili cikloheksil.
Između spojeva formule I, a koji su predmet ovog izuma, mogu se izdvojiti poželjni spojevi za koje vrijedi da:
R1 predstavlja atom vodika, metil, etil, izopropil, cikloheksil, –CH2CH2COOH skupinu, amino skupinu ili pak dimetilamino skupinu,
u obliku baze ili soli nastale dodatkom organske ili anorganske baze, a također i oblika hidrata ili solvata.
Između spojeva formule I, a koji su predmet ovog izuma, naročito se mogu izdvojiti slijedeći spojevi:
(3R,5S)-1-[(3R)-5-klor-1-[(2,4-dimetoksifenil)sulfonil]-3-(2-metoksifenil)-2-okso-2,3-dihidro-1H-indol-3-il]-5-[(dimetilamino)karbonil]-3-pirolidinil acetat,
(3R,5S)-1-[(3R)-5-klor-1-[(2,4-dimetoksifenil)sulfonil]-3-(2-metoksifenil)-2-okso-2,3-dihidro-1H-indol-3-il]-5-[(dimetilamino)karbonil]-3-pirolidinil propionat,
(3R,5S)-1-[(3R)-5-klor-1-[(2,4-dimetoksifenil)sulfonil]-3-(2-metoksifenil)-2-okso-2,3-dihidro-1H-indol-3-il]-5-[(dimetilamino)karbonil]-3-pirolidinil format,
(3R,5S)-1-[(3R)-5-klor-1-[(2,4-dimetoksifenil)sulfonil]-3-(2-metoksifenil)-2-okso-2,3-dihidro-1H-indol-3-il]-5-[(dimetilamino)karbonil]-3-pirolidinil cikloheksankarboksilat,
(3R,5S)-1-[(3R)-5-klor-1-[(2,4-dimetoksifenil)sulfonil]-3-(2-metoksifenil)-2-okso-2,3-dihidro-1H-indol-3-il]-5-[(dimetilamino)karbonil]-3-pirolidinil 2-metilpropanoat,
4-[[(3R,5S)-1-[(3R)-5-klor-1-[(2,4-dimetoksifenil)sulfonil]-3-(2-metoksifenil)-2-okso-2,3-dihidro-1H-indol-3-il]-5-[(dimetilamino)karbonil]-3-pirolidinil]oksi]-4-oksobutanska kiselina,
(2S,4R)-4-[(aminokarbonil)oksi]-1-[(3R)-5-klor-1-[(2,4-dimetoksifenil)sulfonil]-3-(2-metoksifenil)-2-okso-2,3-dihidro-1H-indol-3-il]-N,N-dimetil-2-pirolidinkarboksamid,
(2S,4R)-4-[[(dimetilamino)karbonil]oksi]-1-[(3R)-5-klor-1-[(2,4-dimetoksifenil)sulfonil]-3-(2-metoksifenil)-2-okso-2,3-dihidro-1H-indol-3-il]-N,N-dimetil-2-pirolidinkarboksamid,
u obliku baze ili soli nastale dodatkom organske ili anorganske baze, a također i oblika hidrata ili solvata.
Prema narednom svojem vidu predmet ovog izuma jest postupak pripreme spojeva formule (I) naznačen time da:
(2S,4R)-1-[5-klor-1-[(2,4-dimetoksifenil)sulfonil]-3-(2-metoksifenil)-2-okso-2,3-dihidro-1H-indol-3-il]-4-hidroksi-N,N-dimetil-2-pirolidinkarboksamid, lijevi izomer formule:
[image]
reagira s funkcionalnim derivatom kiseline formule
[image]
gdje R1 jest kako je to definirano za spoj formule (I).
Opcijski, spoj formule (I) može se prevesti u sol dodatkom baze.
Kao funkcionalni derivat kiseline formule (II) može se koristiti kiselinski klorid, anhidrid ili slobodna kiselina kao takva.
Ukoliko se koristi kiselinski klorid, reakcija se provodi u otapalu kao što je to klorirano otapalo, npr. diklormetan, dikloretan ili kloroform; eter, npr. tetrahidrofuran i dioksan; ili amid, npr. N,N-dimetilformamid, uz prisustvo baze, kao što je to trietilamin, N-metilmorfolin, piridin, 4-dimetilaminopiridin ili N,N-diizopropiletilamin pri temperaturi od –60 °C do sobne temperature.
Ukoliko se koristi anhidrid, reakcija se provodi uz prisustvo ili odsustvo baze, kao što je to piridin ili 4-(dimetilamino)piridin, u otapalu ili bez otapala pri temperaturi od sobne do temperature refluksa reakcijskog medija. Ukoliko se koristi otapalo, ono se odabire između kloriranog otapala kao što je to diklormetan i aromatičnog otapala kao što je to toluen.
Spoj formule (I) u kojem R1 predstavlja –CH2CH2COOH skupinu može se također prirediti reakcijom spoja A sa sukcinatnim anhidridom uz prisutnost baze, kao što je to piridin, u otapalu ili bez njega pri temperaturi od sobne do temperature refluksa reakcijskog medija.
Ukoliko se koristi kiselina takva kakva jest, reakcija se provodi s pomoću sredstva za kondenziranje, kao što je to karbodiimid, npr. 1,3-dicikloheksilkarbodiimid ili 1,3-diizopropilkarbodiimid; ili imidazol npr. 1,1ʹ-oksalildiimidazol ili N,Nʹ-karbonil-diimidazol. Reakcija se provodi uz prisustvo ili odsustvo baze, kao što je to trietilamin, N,N-diizopropiletilamin, piridin, 4-dimetilaminopiridin ili N-metilmorfolin, u otapalu kao što je to klorirano otapalo, npr. diklormetan, dikloretan ili kloroform; ester, npr. etil acetat; eter, npr. dietil eter, diizopropileter, tetrahidrofuran ili dioksan; nitril, npr. acetonitril; amid, npr. N,N-dimetilformamid; aromatično otapalo, npr. toluen ili ksilen pri temperaturi od –20 °C do 80 °C.
Ukoliko se koristi kiselina takva kakva jest, reakcija se također provodi uz prisustvo kiselinskog katalizatora kao što je to anorganska kiselina, npr. klorovodična, bromovodična ili sumporna kiselina; organska kiselina, npr. octena, mravlja, oksalna ili p-toluensulfonska kiselina; ili pak Lewisova kiselina, npr. borov triklorid, borov trifluorid ili borov tribromid. Reakcija se provodi u otapalu, kao što je to klorirano otapalo, npr. diklormetan, dikloretan ili kloroform; eter, npr. dietil eter, diizopropil eter, tetrahidrofuran ili dioksan; keton npr. aceton, metiletil aceton ili metilizobutil keton; nitril npr. acetonitril; ili amid, npr. N,N-dimetilformamid, pri temperaturi od 0 °C do temperature refluksa otapala.
Spoj formule (I) u kojem R1 predstavlja atom vodika može se također prirediti reakcijom spoja A s mravljom kiselinom uz prisustvo acetatnog anhidrida i baze kao što je to piridin pri temperaturi od 0 °C do sobne temperature.
Ukoliko R1 predstavlja –NR2R3 skupinu moguć je i slijedeći način pripreme:
spoj A se podvrgne reakciji s fenilkloroformatom uz prisustvo baze, čime se dobiva spoj B formule:
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spoj B reagira sa spojem formule
HNR2R3 (III)
gdje R2 i R3 jesu kako je to definirano za spoj formule (I), čime se dobiva spoj formule (I) u kojem R1 jest NR2R3.
U koraku a) spoj A reagira s fenil kloroformatom uz prisustvo baze kao što je to piridin ili trietilamin, bez otapala ili pak u otapalu kao što je to diklormetan pri temperaturi od 0 °C do 100 °C.
U koraku b) reakcija spoja B sa spojem formule (III) provodi se u otapalu kao što je to diklormetan ili tetrahidrofuran ili pak u smjesi tih otapala pri temperaturi od –60 °C do temperature refluksa otapala.
Ovako priređeni spojevi formule (I) mogu se potom odvojiti od reakcijskog medija i pročistiti na uobičajen način, na primjer kristalizacijom ili kromatografijom.
Spoj A je priređen na način opisan u WO 01/55130.
Funkcionalni derivati kiseline formule (II) komercijalno su dostupni, poznati ili se pak mogu prirediti dobro poznatim postupcima.
Prema narednom svojem vidu, predmet ovog izuma jest spoj B. Ovaj spoj je koristan kao međuprodukt prilikom sinteze spoja formule (I) u kojem R1 jest NR2R3.
U nastavku dani primjeri opisuju pripremu nekih spojeva prema ovom izumu. Ovi primjeri ne ograničavaju izum već su samo pokazne naravi. Brojevi kojima su spojevi označeni u primjerima odgovaraju brojevima u dolje danoj tablici koja prikazuje kemijske strukture i fizikalna svojstva nekih od spojeva prema ovom izumu.
U primjerima su korištene slijedeće kratice:
EtOAc: etil acetat
Eter: dietil eter
Izoeter: diizopropil eter
DCM: diklormetan
m.p.: temperatura tališta
AT: sobna temperatura
B. p.: temperatura vrelišta
HPLC: tekućinska kromatografija visokog razlučivanja
Spektri protonske magnetske rezonancije (1H NMR) snimljeni su pri 200 MHz u d6-DMSO, gdje je d6-DMSO pik korišten kao standard. Kemijski pomaci (δ) izraženi su u dijelovima na milijun (ppm). Dobiveni signali opisani su kao: s: singlet, bs: široki singlet, d: dublet, dd: dvostruki dublet, t: triplet, q: kvartet, up: nerazlučivi pik, mt: multiplet.
NMR spektri potvrdili su strukture spojeva.
PRIMJER 1
Spoj br. 1 (3R,5S)-1-[(3R)-5-klor-1-[(2,4-dimetoksifenil)sulfonil]-3-(2-metoksifenil)-2-okso-2,3-dihidro-1H-indol-3-il]-5-[(dimetilamino)karbonil]-3-pirolidinil acetat
(I): R1 = -CH3
Smjesa 30 g (2S,4R)-1-[5-klor-1-[(2,4-dimetoksifenil)sulfonil]-3-(2-metoksifenil)-2-okso-2,3-dihidro-1H-indol-3-il]-4-hidroksi-N,N-dimetil-2-pirolidinkarboksamid, lijevi izomer (spoj A), 1,45 g 4-(dimetilamino)piridina i 300 ml acetatnog anhidrida grijana je uz refluks tijekom 2,5 sati. Nakon hlađenja reakcijske smjese na sobnu temperaturu, dodano je 170 ml apsolutnog etanola. Smjesa je koncentrirana pod vakuumom, zaostatak je ekstrahiran s 1000 ml EtOAc, organska faza je isprana sa 670 ml zasićene vodene otopine NH4Cl i dva puta s vodenom otopinom NaHCO3, te je otapalo uklonjeno pod vakuumom. Zaostatak je prenesen u 190 ml 2-propanola, a smjesa je zagrijana do refluksa i potom ohlađena na sobnu temperaturu. Reakcijska smjesa je potom koncentrirana pod vakuumom, a zaostatak je prenesen u izoeter i ostavljen da kristalizira. Iskristalizirani produkt je odfiltriran, ispran s izoeterom i sušen. Dobiveno je 30.28 g očekivanog spoja, M. p. = 194-195 °C.
α25D = -133,9° (c = 0,5, acetonitril).
1H NMR: d6-DMSO: δ (ppm): 1,7 do 2,8: up: 13H, 3,3: bs: 3H, 3,7: s: 3H; 3,9: s: 3H, 4,6 mt: 1H, 5,2: mt: 1H, 6,6 do 8,2: up: 10H.
PRIMJER 2
Spoj br. 2 (3R,5S)-1-[(3R)-5-klor-1-[(2,4-dimetoksifenil)sulfonil]-3-(2-metoksifenil)-2-okso-2,3-dihidro-1H-indol-3-il]-5-[(dimetilamino)karbonil]-3-pirolidinil propionat
(I): R1 = -CH2CH3
Smjesa 5 g spoja A, 0,24 ml 4-(dimetilamino)piridina i 50 ml propanskog anhidrida grijana je uz refluks tijekom 2,5 sati. Nakon hlađenja reakcijske smjese na sobnu temperaturu, dodano je 28 ml apsolutnog etanola. Smjesa je koncentrirana pod vakuumom, zaostatak je ekstrahiran sa 60 ml EtOAc, organska faza je isprana sa 100 ml zasićene vodene otopine NaCl i tri puta sa 110 ml 10 %-tne vodene otopine NaHCO3, te je otapalo uklonjeno pod vakuumom. Zaostatak je prenesen u izoeter, a dobiveni precipitat je odcentrifugiran. Dobiveno je 4,31 g očekivanog spoja.
α25D = -107° (c = 0,5, acetonitril).
1H NMR: d6-DMSO: δ (ppm): 0,95: t: 2H, 1,6 do 2,7: up: 12H, 3,3: bs: 3H, 3,6: s: 3H, 3,8: s: 3H, 4,5 mt: 1H, 5,15: mt: 1H, 6,6 do 8,2: up: 11H.
PRIMJER 3
Spoj br. 3 (3R,5S)-1-[(3R)-5-klor-1-[(2,4-dimetoksifenil)sulfonil]-3-(2-metoksifenil)-2-okso-2,3-dihidro-1H-indol-3-il]-5-[(dimetilamino)karbonil]-3-pirolidinil format
(I): R1 = H
4 ml mravlje kiseline ohlađeno je na 0 °C, te je u nju kap po kap dodano 1,6 ml acetatnog anhidrida. Smjesa je ostavljena 4 sata uz miješanje pri temperaturi nižoj od 20 °C. Reakcijska smjesa je ohlađena na ledenoj kupelji i sušena, te je tijekom 5 minuta u nju dodana otopina 0,63 g spoja A u 7 ml piridina. Smjesa je ohlađena na ledu i ostavljena 48 sati uz miješanje pri sobnoj temperaturi. Dodana je voda koja je potom ekstrahirana s EtOAc, organska faza je isprana s vodom i zasićenom otopinom NaCl, sušena na Na2SO4, a otapalo je upareno pod vakuumom. Dobiveni zaostatak je podvrgnut kromatografiji na silikagelu uz eluaciju sa smjesom DCM/EtOAc (70/30, v/v). Dobiveno je 0,27 g očekivanog produkta. Potom je produkt prenesen u smjesu DCM/izoeter (80/20, v/v), te je očekivani produkt dobiven u obliku praha koji je sadržavao 0,5 ml izoetera.
M.p. = 127 °C.
α25D = -173° (c = 0,11, kloroform).
PRIMJER 4
Spoj br. 4 (3R,5S)-1-[(3R)-5-klor-1-[(2,4-dimetoksifenil)sulfonil]-3-(2-metoksifenil)-2-okso-2,3-dihidro-1H-indol-3-il]-5-[(dimetilamino)karbonil]-3-pirolidinil cikloheksankarboksilat
[image]
Smjesa 1,5 g spoja A, 0,630 ml cikloheksankarbonil klorida, 0,62 g N,N-diizopropiletilamina i nekoliko kristalića 4-(dimetilamino)piridina u 20 ml DCM ostavljena je uz miješanje pri sobnoj temperaturi tijekom 8 dana. Smjesa je koncentrirana pod vakuumom, zaostatak je prenesen u smjesu EtOAc/voda, dobivena smjesa je zalužena dodatkom krutog NaHCO3, te ostavljena da se odvoje slojevi. Organska faza je dva puta isprana sa zasićenom otopinom K2CO3 i sa zasićenom otopinom NaCl, sušena na Na2SO4, a otapalo je upareno pod vakuumom. Zaostatak je podvrgnut kromatografiji na silikagelu uz eluaciju sa smjesom EtOAc/DCM (80/20, v/v). Dobiveni produkt je prenesen u 5 ml izoetera, a smjesa je ostavljena da se miješa pri sobnoj temperaturi tijekom 48 sati. Dobiveni precipitat je odfiltriran uz rotaciju, te je dobiveno 1,0 g očekivanog spoja. M.p. =197-198 °C. Otopina dobivena rotor filtracijom koncentrirana je pod vakuumom, a dobivena krutina je kristalizirana iz smjese DCM/izoeter. Dobiveno je dodatnih 0,9 g očekivanog spoja u obliku kristala M.p. = 197-200 °C.
α25D = -144° (c = 0,18, kloroform).
PRIMJER 5
Spoj br. 5 (3R,5S)-1-[(3R)-5-klor-1-[(2,4-dimetoksifenil)sulfonil]-3-(2-metoksifenil)-2-okso-2,3-dihidro-1H-indol-3-il]-5-[(dimetilamino)karbonil]-3-pirolidinil 2-metil propanoat
(I): R1 = -CH(CH3)2
Smjesa 1,5 g spoja A, 0,75 ml izobutiril klorida i 1,22 g N,N-diizopropiletilamina u 20 ml DCM ostavljena je uz miješanje pri sobnoj temperaturi tijekom 36 sati. Smjesa je koncentrirana pod vakuumom, zaostatak je prenesen u vodu, a dobivena smjesa je zalužena dodatkom krutog NaHCO3 i ekstrahirana s EtOAc. Organska faza je isprana s vodom i sušena na Na2SO4, a otapalo je upareno pod vakuumom. Zaostatak je podvrgnut kromatografiji na silikagelu uz eluaciju sa smjesom DCM/EtOAc (70/30, v/v). Dobiveni produkt je prenesen u smjesu EtOAc/izoeter, te je kristalizacijom dobiveno 1,17 g očekivanog spoja.
M.p. = 183-185 °C.
α25D = -172° (c = 0,15, kloroform).
PRIMJER 6
Spoj br. 6 4-[[(3R,5S)-1-[(3R)-5-klor-1-[(2,4-dimetoksifenil)sulfonil]-3-(2-metoksifenil)-2-okso-2,3-dihidro-1H-indol-3-il]-5-[(dimetilamino)karbonil]-3-pirolidinil]oksi]-4-oksobutanska kiselina
(I): R1 = -CH2CH2COOH
Smjesa 0,2 g spoja A, 0,2 g sukcin anhidrida i 3 ml piridina grijana je pri 50 °C tijekom 5 minuta do otapanja, te je otopina ostavljena uz miješanje tijekom 20 sati pri 25 °C. Reakcijska smjesa je potom koncentrirana pod vakuumom, zaostatak je prenesen u 2N otopinu HCl, te je provedena ekstrakcija s eterom. Smjesa je ostavljena da se odvoje slojevi, a precipitat dobiven u organskoj fazi je odfiltriran uz rotaciju, te je ispran s eterom. Dobiveno je 0,2 g očekivanog spoja u obliku kristala.
M.p. = 225-228 °C.
α25D = -252° (c = 0,25, kloroform).
1H NMR: d6-DMSO: δ (ppm): 1,6 do 1,9: up: 2H, 2,2 do 2,6: up: 12H, 3,0 do 3,4: bs: 3H, 3,5 do 3,7: bs: 3H, 3,7 do 3,9: bs: 3H, 4,4 do 4,6: up: 1H, 5,1 do 5,3: up: 1H, 6,6 do 7,0: up: 5H, 7,26: t: 1H, 7,39: dd: 1H, 7,6 do 7,8: up: 2H, 7,94: d: 1H, 12,0 bs: 1H.
PRIMJER 7
Spoj br. 7 (2S,4R)-4-[(aminokarbonil)oksi]-1-[(3R)-5-klor-1-[(2,4-dimetoksifenil)sulfonil]-3-(2-metoksifenil)-2-okso-2,3-dihidro-1H-indol-3-il]-N,N-dimetil-2-pirolidinkarboksamid
(I): R1 = -NH2
(A) (2S,4R)-4-[(fenoksikarbonil)oksi]-1-[(3R)-5-klor-1-[(2,4-dimetoksifenil)sulfonil]-3-(2-metoksifenil)-2-okso-2,3-dihidro-1H-indol-3-il]-N,N-dimetil-2-pirolidinkarboksamid
U otopinu 1,6 g spoja A u 20 ml piridina dodano je 4 ml fenil kloroformata, te je smjesa ostavljena uz miješanje tijekom 20 sati pri temperaturi od 25 °C. Reakcijska smjesa je potom koncentrirana pod vakuumom, zaostatak je prenesen u 1N otopinu HCl, te je provedena ekstrakcija s EtOAc. Organska faza je sušena na Na2SO4, a otapalo je uklonjeno pod vakuumom. Po kristalizaciji u izoeteru dobiveno je 1,23 g očekivanog spoja.
M.p. = 115-125 °C.
(B) (2S,4R)-4-[(aminokarbonil)oksi]-1-[(3R)-5-klor-1-[(2,4-dimetoksifenil)sulfonil]-3-(2-metoksifenil)-2-okso-2,3-dihidro-1H-indol-3-il]-N,N-dimetil-2-pirolidinkarboksamid.
Otopina 0,7 g spoja dobivenog u prethodnom sintetskom koraku u 15 ml THF, ohlađena je na –60 °C, te je kroz otopinu propušteno 4 g plinovitog NH3, a potom je smjesa ostavljena uz miješanje tijekom 5 sati uz održavanje temperature na 0 °C. Reakcijska smjesa je koncentrirana pod vakuumom, a zaostatak je podvrgnut kromatografiji na silikagelu uz eluaciju s DCM i potom s EtOAc. Po usitnjavanju u izoeteru dobiveno je 0,37 g očekivanog spoja.
M.p. = 155-165 °C.
α25D = -184° (c = 0,25, kloroform).
PRIMJER 8
Spoj br. 8 (2S,4R)-4-[[(dimetilamino)karbonil]oksi]-1-[(3R)-5-klor-1-[(2,4-dimetoksifenil)sulfonil]-3-(2-metoksifenil)-2-okso-2,3-dihidro-1H-indol-3-il]-N,N-dimetil-2-pirolidinkarboksamid
(I): R1 = -N(CH3)2
Smjesa 0,35 g spoja dobivenog u koraku (A) primjera 7 i 10 ml 2 M otopine dimetilamina u THF ostavljena je uz miješanje tijekom 20 sati pri temperaturi od 25 °C. Reakcijska smjesa je koncentrirana pod vakuumom i prenesena u vruć izoeter, a dobiveni precipitat je odfiltriran uz rotaciju. Dobiveno je 0,18 g očekivanog produkta.
M.p. = 138-140 °C.
α25D = -152° (c = 0,25, kloroform).
U nastavku dana tablica prikazuje kemijske strukture i fizikalna svojstva nekih primjera spojeva prema ovom izumu.
TABLICA 1
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Spojevi prema ovom izumu podvrgnuti su biokemijskim istraživanjima.
Afinitet spojeva formule (I) prema ovom izumu spram V1b receptora arginin-vazopresina, određen je in vitro postupkom opisanim u Y. de Keyser et al., Febs Letters, 1994, 356, 215-220. Ovaj se postupak osniva na in vitro istraživanju vezanja arginin-vazopresina obilježenog s tricijem ([3H]-AVP) na V1b receptore štakora ili ljudi prisutne na pripravku stanica ili membrane adenohipofize. Koncentracija 50 %-tne inhibicije (IC50) vezanja arginin-vazopresina obilježenog s tricijem za spojeve prema ovom izumu je u općenitom slučaju manja od 5,0 x 10-9 M. Na primjer, spoj primjera 1 odlikuje se s vrijednošću IC50 od 3,4 x 10-9 M prema humanim V1b receptorima.
Afinitet spojeva formule (I) prema ovom izumu spram V1a receptora arginin-vazopresina, određen je in vitro postupkom opisanim u M. Thibonnier et al., J. Biol. Chem., 1994, 269, 3304-3310. Ovaj se postupak osniva na in vitro istraživanju vezanja arginin-vazopresina obilježenog s tricijem ([3H]-AVP) na V1a receptore štakora ili ljudi prisutne u staničnom pripravku ili pripravku membrane adenohipofize. Neki od spojeva formule (I) pokazuju afinitet spram V1a receptora arginin-vazopresina, te se odlikuju s vrijednošću IC50 reda veličine od 10-8 M. Na primjer, spoj primjera 1 odlikuje se s vrijednošću IC50 od 8,4 x 10-8 M spram humanog V1a receptora.
Literaturno poznati spoj A odlikuje se s vrijednošću IC50 od 1,0 x 10-8 M spram humanog V1b receptora i s vrijednošću IC50 od 3,1 x 10-7 M spram humanog V1a receptora.
Istražen je i afinitet spojeva formule (I) prema ovom izumu spram V2 receptora vazopresina (postupak prema M. Birnbaumer et al., Nature (Lond.), 1992, 357, 333-335). Istraživani spojevi ne iskazuju ili iskazuju malen afinitet spram V2 receptora.
Prema tome, spojevi prema ovom izumu mogu se koristiti za pripremu medicinskih produkata, a naročito medicinskih produkata namijenjenih prevenciji ili tretmanu onih patoloških stanja u koje su uključeni arginin-vazopresin i/ili njegov V1b receptor ili pak oba njegova receptora, V1b i V1a.
Prema tome, u narednom svome vidu predmet ovog izuma su medicinski produkti koji sadrže spoj formule (I) ili njegovu sol s farmaceutski prihvatljivom bazom i otapalo ili pak hidrat spoja formule (I).
Shodno rečenom, spojevi prema ovom izumu mogu se davati ljudima ili životinjama prilikom tretmana ili prevencije različitih stanja povezanih s vazopresinom, kao što su to kardiovaskularne bolesti npr. hipertenzija, plućna hipertenzija, kardijalna insuficijencija, infarkt miokarda ili spazam koronarnih žila, naročito u pušača, Raynaudova bolest, nestabilna angina i PTCA (perkutana transluminalna koronarna angioplastika), kardijalna ishemija ili hemostaza, bolesti centralnog živčanog sustava, kao što su to migrene, spazam žila mozga, cerebralna hemoragija, celebralni edem, depresija, anksioznost, stres, emocionalni poremećaji, opsesivno-kompulzivni poremećaj, napadi panike, psihoze ili poremećaji pamćenja, stanja povezana s bubrezima, kao što je to spazam renalnih žila, nekroza renalnog korteksa ili nefrogeni dijabetes insipidus, bolesti gastričkog sustava npr. spazam gastričkih žila, ciroza jetre, ulcer ili patološko povraćanje, na primjer mučnina, uključujući mučninu izazvanu kemoterapijom ili putovanjem, te dijabetička nefropatija. Spojevi prema ovom izumu mogu se također koristiti za tretman poremećaja seksualnog ponašanja u žena, a također se spojevi prema ovom izumu mogu koristiti i za tretman dismenoreje ili prijevremenog poroda. Spojevi prema ovom izumu mogu se također koristiti i prilikom tretmana kancera malih stanica pluća, hiponatrijemijske encefalopatije, plućnog sindroma, Meniereove bolesti, glaukoma, katarakta, pretilosti, dijabetesa tipa II, ateroskleroze, Cushingovog sindroma, rezistencije na inzulin ili hipertrigliceridemije ili pak prilikom post-operativnog tretmana, naročito poslije operacija abdomena.
Spojevi prema ovom izumu mogu se također koristiti i prilikom tretmana ili prevencije bilo kojih patoloških stanja povezanih sa stresom, kao što je to kroničan umor i njegov sindrom, ACTH-ovisnim poremećajem, poremećajem rada srca, bolom, promjenama u pražnjenju gastričkog sustava, izbacivanju izmeta (kolitis, sindrom nadraženog crijeva ili Crohnova bolest) ili sekrecijom kiseline, hiperglikemijom, imunosupresijom, upalnim procesima (reumatski artritis i osteoartritis), višestrukim infekcijama, kancerima, astmom, sorijazom, alergijama i različitim neuropsihijatrijskim poremećajima, kao što su to anoreksija neuroza, bulimija, poremećaji ponašanja, depresija, anksioznost, poremećaji spavanja, stanja panike, fobije, opsesije, poremećaji percepcije bola (fibromialgija), neurodegenerativnim bolestima (Alzheimerova bolest, Parkinsonova bolest ili Huntingdonova bolest), ovisnošću o drogama, hemoragijskim stresom, spazmom muskulature ili hipoglikemijom. Spojevi prema ovom izumu mogu se također koristiti i prilikom tretmana ili prevencije stanja kroničnog stresa, kao što je to imunodepresija, problema plodnosti ili poremećaja funkcioniranja hipotalamo-pituitarno-adrenalne linije.
Spojevi prema ovom izumu mogu se također koristiti i kao psihostimulansi, čime se povećava svjesnost ili emocionalna aktivnost spram okoline, te olakšava postupak prilagodbe.
Prema narednom svojem vidu, ovaj se izum odnosi na farmaceutske pripravke koji kao aktivnu tvar sadrže spoj prema ovom izumu. Takvi farmaceutski pripravci sadrže učinkovitu dozu barem jednog spoja prema ovom izumu ili njegove farmaceutski prihvatljive soli, solvata ili hidrata rečenog spoja, te barem jednu farmaceutski prihvatljivu dodatnu tvar.
Rečene dodatne tvari odabiru se između uobičajenih dodatnih tvari poznatih stručnjaku na području, a njihov odabir ovisi o farmaceutskom obliku i željenom postupku uzimanja.
U farmaceutskim pripravcima prema ovom izumu namijenjenima oralnom, sublingvalnom, subkutanom, intramuskularnom, intravenoznom, topikalnom, lokalnom, intratrahealnom, intranazalnom, transdermalnom ili rektalnom davanju životinjama ili ljudima, a u svrhu tretmana ili profilakse gore navedenih poremećaja ili bolesti, aktivna tvar gore dane formule (I) ili njegova moguća sol, solvat ili hidrat može se uzeti u obliku pojedinačne doze u smjesi s uobičajenim farmaceutskim dodatnim tvarima.
U pojedinačne dozne oblike uključuju se oblici pogodni za oralno davanje, kao što su to tablete, meke ili tvrde želatinske kapsule, prašci, granule i oralne otopine ili suspenzije, zatim oblici pogodni za sublingvalno, bukalno, intratrahealno, intraokularno ili intranazalno davanje, oblici pogodni za davanje putem inhalacije, oblici namijenjeni topikalnom, transdermalnom, subkutanom, intramuskularnom ili intravenoznom davanju, oblici za rektalno davanje i implatanti. Za topikalno davanje, spojevi prema ovom izumu mogu se koristiti kao kreme, gelovi, ulja ili losioni.
Na primjer, pojedinačni dozni oblik namijenjen davanju spoja prema ovom izumu u obliku tablete može sadržavati slijedeće sastojke:
[image]
Prilikom oralnog uzimanja dnevna doza aktivnog spoja, uzeta odjednom ili višekratno, može iznositi od 0,01 do 100 mg/kg, dok je poželjno da iznosi od 0,02 do 50 mg/kg.
Mogući su slučajevi u kojima će preporučena dnevna doza biti veća ili manja od navedenih i sve takve doze obuhvaćene su ovim izumom. U skladu s uobičajenom praksom dozu pogodnu za svakog pacijenta određuje liječnik u skladu s načinom uzimanja, masom pacijenta i reakcijom pacijenta na tretman.
Prema narednom svojem vidu, ovaj se izum odnosi na postupak tretmana gore naznačenih patoloških stanja, a koji uključuje davanje, pacijentu, učinkovite doze spoja prema ovom izumu ili njegove farmaceutski prihvatljive soli, hidrata ili solvata.
Claims (9)
1. Spoj, naznačen time, da je isti formule (I):
[image]
gdje:
R1 predstavlja atom vodika, (C1-C6)alkil, (C3-C6)cikloalkil,–CH2CH2COOH skupinu ili –NR2R3 skupinu;
R2 i R3 svaki neovisno jedan o drugome predstavljaju atom vodika ili (C1-C6)alkil
u obliku baze ili soli organske ili anorganske baze, a također i u obliku hidrata ili solvata.
2. Spoj prema zahtjevu 1, naznačen time, da je isti formule (I), gdje R1 predstavlja atom vodika, metil, etil, izopropil, cikloheksil, –CH2CH2COOH skupinu, amino skupinu ili pak dimetilamino skupinu, u obliku baze ili soli organske ili anorganske baze, a također i u obliku hidrata ili solvata.
3. Spoj, naznačen time, da je isti odabran iz grupe koju tvore:
(3R,5S)-1-[(3R)-5-klor-1-[(2,4-dimetoksifenil)sulfonil]-3-(2-metoksifenil)-2-okso-2,3-dihidro-1H-indol-3-il]-5-[(dimetilamino)karbonil]-3-pirolidinil acetat,
(3R,5S)-1-[(3R)-5-klor-1-[(2,4-dimetoksifenil)sulfonil]-3-(2-metoksifenil)-2-okso-2,3-dihidro-1H-indol-3-il]-5-[(dimetilamino)karbonil]-3-pirolidinil propionat,
(3R,5S)-1-[(3R)-5-klor-1-[(2,4-dimetoksifenil)sulfonil]-3-(2-metoksifenil)-2-okso-2,3-dihidro-1H-indol-3-il]-5-[(dimetilamino)karbonil]-3-pirolidinil format,
(3R,5S)-1-[(3R)-5-klor-1-[(2,4-dimetoksifenil)sulfonil]-3-(2-metoksifenil)-2-okso-2,3-dihidro-1H-indol-3-il]-5-[(dimetilamino)karbonil]-3-pirolidinil cikloheksankarboksilat,
(3R,5S)-1-[(3R)-5-klor-1-[(2,4-dimetoksifenil)sulfonil]-3-(2-metoksifenil)-2-okso-2,3-dihidro-1H-indol-3-il]-5-[(dimetilamino)karbonil]-3-pirolidinil 2-metilpropanoat,
4-[[(3R,5S)-1-[(3R)-5-klor-1-[(2,4-dimetoksifenil)sulfonil]-3-(2-metoksifenil)-2,3-dihidro-1H-indol-3-il]-5-[(dimetilamino)karbonil]-3-pirolidinil]oksi]-4-oksobutanska kiselina,
(2S,4R)-4-[(aminokarbonil)oksi]-1-[(3R)-5-klor-1-[(2,4-dimetoksifenil)sulfonil]-3-(2-metoksifenil)-2-okso-2,3-dihidro-1H-indol-3-il]-N,N-dimetil-2-pirolidinkarboksamid,
(2S,4R)-4-[[(dimetilamino)karbonil]oksi]-1-[(3R)-5-klor-1-[(2,4-dimetoksifenil)sulfonil]-3-(2-metoksifenil)-2-okso-2,3-dihidro-1H-indol-3-il]-N,N-dimetil-2-pirolidinkarboksamid,
u obliku baze ili soli organske ili anorganske baze, a također i u obliku hidrata ili solvata.
4. Postupak pripreme spojeva formule (I) prema zahtjevu 1, naznačen time, da:
(2S,4R)-1-[5-klor-1-[(2,4-dimetoksifenil)sulfonil]-3-(2-metoksifenil)-2-okso-2,3-dihidro-1H-indol-3-il]-4-hidroksi-N,N-dimetil-2-pirolidinkarboksamid, lijevi izomer formule:
[image]
reagira s funkcionalnim derivatom kiseline formule
[image]
gdje R1 jest kako je to definirano za spoj formule (I) u zahtjevu 1.
5. Postupak pripreme spojeva formule (I) prema zahtjevu 1, gdje R1 predstavlja –NR2R3 skupinu, naznačen time, da:
a) spoj A, definiran zahtjevom 4, reagira s fenil kloroformatom uz prisustvo baze, čime se dobiva spoj B formule:
[image]
b) spoj B reagira sa spojem formule:
HNR2R3 (III)
gdje R2 i R3 jesu kako je to definirano za spoj formule (I) u zahtjevu 1, čime se dobiva spoj formule (I) u kojem R1 = NR2R3.
6. Spoj, naznačen time, da je isti formule:
[image]
7. Medicinski proizvod, naznačen time, da isti sadrži spoj formule (I) prema bilo kojem zahtjevu 1 do 3, ili njegovu sol s farmaceutski prihvatljivom bazom ili pak hidrat ili solvat spoja formule (I).
8. Farmaceutski pripravak, naznačen time, da isti sadrži spoj formule (I) prema bilo kojem zahtjevu 1 do 3, ili njegovu farmaceutski prihvatljivu sol, hidrat ili solvat rečenog spoja i barem jednu farmaceutski prihvatljivu dodatnu tvar.
9. Upotreba spoja formule (I) prema bilo kojem zahtjevu 1 do 3, naznačena time, da se ista odnosi na pripremu medicinskih proizvoda namijenjenih tretmanu kardiovaskularnih stanja, stresa, anksioznosti, depresije, opsesivno-kompulzivnog poremećaja, napada panike, bubrežnog sustava, gastričkog sustava, kancera malih stanica pluća, pretilosti, dijabetesa tipa I i II, rezistencije na inzulin, hipertrigliceridemije, ateroskleroze, Cushingova sindroma, dismenoreje i preranog poroda.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR0209242A FR2842527B1 (fr) | 2002-07-19 | 2002-07-19 | Derives d'acyloxypyrolidine, leur preparation et leur application en therapeutique |
| PCT/FR2003/002262 WO2004009585A2 (fr) | 2002-07-19 | 2003-07-17 | Derives d'acyloxypyrrolidine et leur utilisation en tant que ligands des recepteurs v1b et v1a de avp |
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| TW200643015A (en) | 2005-03-11 | 2006-12-16 | Akzo Nobel Nv | 2-(4-oxo-4H-quinazolin-3-yl)acetamide derivatives |
| DE102005015957A1 (de) * | 2005-03-31 | 2006-10-05 | Abbott Gmbh & Co. Kg | Substituierte Oxindol-Derivate, diese enthaltende Arzneimittel und deren Verwendung |
| US8350043B2 (en) | 2005-06-07 | 2013-01-08 | Pharmacopeia, Inc. | Azinone and diazinone V3 inhibitors for depression and stress disorders |
| CA2663161C (en) | 2006-09-11 | 2014-10-28 | N.V. Organon | Quinazolinone and isoquinolinone acetamide derivatives |
| CN103864658B (zh) * | 2014-03-06 | 2016-06-15 | 南京工业大学 | 氮杂环丁酮衍生物及其制备方法与应用 |
| CN104447489B (zh) * | 2014-12-29 | 2017-01-11 | 南京工业大学 | 3,4-二芳基马来酰亚胺衍生物及其制备方法与应用 |
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