TWI739666B - 醫藥組成物 - Google Patents
醫藥組成物 Download PDFInfo
- Publication number
- TWI739666B TWI739666B TW109140115A TW109140115A TWI739666B TW I739666 B TWI739666 B TW I739666B TW 109140115 A TW109140115 A TW 109140115A TW 109140115 A TW109140115 A TW 109140115A TW I739666 B TWI739666 B TW I739666B
- Authority
- TW
- Taiwan
- Prior art keywords
- compound
- cyclopropane
- carbonyl
- amino
- phenyl
- Prior art date
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- 239000008194 pharmaceutical composition Substances 0.000 title claims description 5
- 150000003839 salts Chemical class 0.000 claims abstract description 45
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims description 314
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 184
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 132
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 60
- 239000000203 mixture Substances 0.000 claims description 51
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 11
- 239000003937 drug carrier Substances 0.000 claims description 6
- 150000001875 compounds Chemical class 0.000 abstract description 418
- 239000004480 active ingredient Substances 0.000 abstract description 104
- 229940002612 prodrug Drugs 0.000 abstract description 28
- 239000000651 prodrug Substances 0.000 abstract description 28
- 150000001204 N-oxides Chemical class 0.000 abstract description 27
- 239000003814 drug Substances 0.000 abstract description 25
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 22
- 201000010099 disease Diseases 0.000 abstract description 21
- 230000003042 antagnostic effect Effects 0.000 abstract description 14
- 239000004615 ingredient Substances 0.000 abstract description 14
- 101150109738 Ptger4 gene Proteins 0.000 abstract description 12
- 230000004913 activation Effects 0.000 abstract description 12
- 239000012453 solvate Substances 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 420
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 312
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 307
- 238000005160 1H NMR spectroscopy Methods 0.000 description 177
- 238000004809 thin layer chromatography Methods 0.000 description 167
- -1 1-methyl-1-hydroxyethyl Chemical group 0.000 description 126
- 238000002360 preparation method Methods 0.000 description 106
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 99
- 238000006243 chemical reaction Methods 0.000 description 94
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 74
- 230000000704 physical effect Effects 0.000 description 73
- 239000000243 solution Substances 0.000 description 73
- 239000000654 additive Substances 0.000 description 65
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical group C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 63
- 238000000034 method Methods 0.000 description 59
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 51
- 239000002904 solvent Substances 0.000 description 51
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 48
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 46
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- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 39
- 239000002585 base Substances 0.000 description 37
- 150000002367 halogens Chemical class 0.000 description 36
- 239000003795 chemical substances by application Substances 0.000 description 35
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- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 33
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 33
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- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 31
- 239000007924 injection Substances 0.000 description 28
- 238000002347 injection Methods 0.000 description 28
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 27
- 239000008187 granular material Substances 0.000 description 27
- 229910052736 halogen Inorganic materials 0.000 description 25
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 25
- 239000000126 substance Substances 0.000 description 25
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 24
- 125000000623 heterocyclic group Chemical group 0.000 description 23
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- 229960001701 chloroform Drugs 0.000 description 22
- 239000003921 oil Substances 0.000 description 22
- 239000003960 organic solvent Substances 0.000 description 22
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 21
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- 239000000499 gel Substances 0.000 description 21
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 21
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- 206010028980 Neoplasm Diseases 0.000 description 20
- 239000001257 hydrogen Substances 0.000 description 20
- 229910052739 hydrogen Inorganic materials 0.000 description 20
- 239000012044 organic layer Substances 0.000 description 20
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 20
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- 239000002674 ointment Substances 0.000 description 19
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 18
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 239000000843 powder Substances 0.000 description 18
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 17
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 17
- 238000002156 mixing Methods 0.000 description 17
- 108020003175 receptors Proteins 0.000 description 17
- 102000005962 receptors Human genes 0.000 description 17
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 17
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 16
- DZBUGLKDJFMEHC-UHFFFAOYSA-N acridine Chemical compound C1=CC=CC2=CC3=CC=CC=C3N=C21 DZBUGLKDJFMEHC-UHFFFAOYSA-N 0.000 description 16
- 239000003054 catalyst Substances 0.000 description 16
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 15
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 15
- 239000007921 spray Substances 0.000 description 15
- 238000012360 testing method Methods 0.000 description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 14
- 239000007864 aqueous solution Substances 0.000 description 14
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 14
- 229910052757 nitrogen Inorganic materials 0.000 description 14
- 239000008213 purified water Substances 0.000 description 14
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 description 13
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 13
- 239000002775 capsule Substances 0.000 description 13
- 229940079593 drug Drugs 0.000 description 13
- 238000009472 formulation Methods 0.000 description 13
- 239000012071 phase Substances 0.000 description 13
- 238000000746 purification Methods 0.000 description 13
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 12
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 12
- OBNCKNCVKJNDBV-UHFFFAOYSA-N butanoic acid ethyl ester Natural products CCCC(=O)OCC OBNCKNCVKJNDBV-UHFFFAOYSA-N 0.000 description 12
- 201000011510 cancer Diseases 0.000 description 12
- 238000011049 filling Methods 0.000 description 12
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 12
- 125000002950 monocyclic group Chemical group 0.000 description 12
- 239000000546 pharmaceutical excipient Substances 0.000 description 12
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 description 11
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 11
- 238000000502 dialysis Methods 0.000 description 11
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- 125000000524 functional group Chemical group 0.000 description 11
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- PAQZWJGSJMLPMG-UHFFFAOYSA-N 2,4,6-tripropyl-1,3,5,2$l^{5},4$l^{5},6$l^{5}-trioxatriphosphinane 2,4,6-trioxide Chemical compound CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1 PAQZWJGSJMLPMG-UHFFFAOYSA-N 0.000 description 10
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- 125000002837 carbocyclic group Chemical group 0.000 description 10
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- 239000000523 sample Substances 0.000 description 10
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- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 9
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- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 9
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- 150000001298 alcohols Chemical class 0.000 description 8
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 8
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- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 8
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Classifications
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- C07D311/96—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings spiro-condensed with carbocyclic rings or ring systems
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- A61K31/275—Nitriles; Isonitriles
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- A—HUMAN NECESSITIES
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- A61K31/33—Heterocyclic compounds
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Abstract
Description
本發明是關於EP4受體拮抗劑的三環性螺化合物或其鹽,及含有該等作為有效成分的醫藥。詳細而言,是關於一種通式(I)表示的三環性螺化合物、其鹽、其N-氧化物,其溶媒合物,或該等的前藥(以下,稱為本發明化合物):
前列腺素E2(PGE2)已知為花生四烯酸串列中的代謝產物,已知有細胞保護作用、子宮收縮、疼痛閥值的降低、消化管的蠕動運動促進、覺醒作用、胃酸分泌抑制作用、血壓降低作用、利尿作用等。
近年的研究中,發現PGE2受體有各種分不
同角色的次類型存在。在現時點上已知的次類型是大略分為4種,分別被稱為EP1、EP2、EP3、EP4(非專利文獻1)。
該等的次類型中,EP4受體被認為是關連於抑制由巨噬細胞的MCP-1的產生、抑制由淋巴球的TNF-α、IL-2及IFN-γ的產生,以及抑制由於IL-10產生增強的抗炎症、血管擴張、血管新生、彈性纖維的形成、控制MMP-9的表現。再者,EP4受體也被認為是有關連於介由骨髓(myeloid)由來的免疫抑制細胞(Myeloid Derived Suppressor Cells)、控制性T細胞及自然殺手細胞的癌免疫控制。
由於該等事實,與EP4受體強力結合,有拮抗作用的化合物可認為係對由於EP4受體的活性化的疾病,例如,骨疾病、癌、全身性肉芽腫、免疫疾病、過敏症,異位病,氣喘,齒槽膿漏、牙肉炎、牙周病、阿茲海默症、川崎病、熱傷、多臟器功能不全、慢性頭痛、疼痛、血管炎、靜脈功能不全、靜脈瘤、動脈瘤、大動脈瘤、痔瘡、尿崩症、壓力、子宮內膜症、子宮腺筋症、新生兒開放性動脈導管症(patent ductus arteriosus)、膽石症等的疾病的預防及/或治療有用(非專利文獻2至7)。
另一方面,在專利文獻1中,記載作為對與前列腺素E受體有關連的疾病,例如疼痛、炎症、及癌等的治療用的化合物,係使用下述通式(A)表示的化合物。
通式(A)是
(式中,Ar1a是視情況而經R1a或R3a取代的芳基或雜芳基;R1a是CN、NO2、或CON(R5a)2等;Wa是表示含有由O、N、及S選出的0至2個的雜原子的3至6員鍵結基,前述鍵結基是視情況而含有CO、S(O)na、C=C、或炔基;Ar2a是視情況經R3a取代的芳基或雜芳基;R3a是鹵原子或CN等;Xa是對Wa的鍵結部位而言,在Ar2a的鄰位鍵結的連接基;Qa是COOH等。(摘錄一部分基團的定義))。
又,在專利文獻2中,有說明下述通式(B)的化合物由於對PGE2受體,特別是EP3及/或EP4鍵結,具有拮抗作用,而對疼痛及癌等的疾病的預防及/或治療有用。
通式(B)是
(式中,R1b是表示-COOH等;Ab是表示(i)單鍵、(ii)C1-6伸烷基、(iii)C2-6伸烯基或(iv)C2-6伸炔基等;Bb環是表示C3-12的單環或二環的碳環,或3至12員的單環或二環的雜環;
R2b是表示硝基、或氰基等;Qb是表示C2-6烯基、C2-6炔基、經1至3個鹵原子取代的C1-6烷基、氰基、或硝基等;Db是包含由碳原子、氮原子、氧原子及硫原子選出的原子1或2員的連結鏈,其鏈中亦可含有雙鍵或三鍵,又連結鏈亦可經1至4個R40b取代;R40b是表示側氧基或鹵素等;R3b是表示(1)C1-6烷基,或(2)經1至5個R42b取代或無取代的C3-15的單環、二環或三環的碳環,或3至15員的單環、二環或三環的雜環;R42b是表示C1-6烷基、C1-6烷氧基、鹵素、氰基、-NR46bCOR47b或Cyc10b。(摘錄一部分基團的定義))。
再者,在專利文獻3中,有說明做為用於與前列腺素E受體有關連的疾病,例如用於疼痛、炎症、及癌等的治療的化合物,而使用下述通式(C)的化合物。
通式(C)是
(式中,HETc是表示具有由O、S(O)nc及N(O)mc選出的0至3個雜原子的5至12員的單環式或二環式的芳環系,mc是0或1,nc是0、1或2;Ac是1原子或2原子部分,而由-Wc-或-C(O)-等所成的群中選出,Wc是O、S(O)nc或NR17c;Xc是表示具有由O、S(O)nc及N(O)mc選出的1至3個的雜
原子的5至10員的單環式或二環式的芳基或雜芳基,Yc是表示O、S(O)nc、NR17c、或鍵等;Bc是-(C(R18c)2)pc-Yc-(C(R18c)2)qc-;pc及qc是各獨立為0至3;Zc是OH等;R1c、R2c及R3c分別獨立表示,鹵素、-CO2R9c、或-CON(R6c)2等。(摘錄一部分基團的定義))。
又,在任何先前技術文獻中,對本發明化合物的三環性螺化合物都沒有任何說明或暗示。
[先前技術文獻]
[專利文獻]
[專利文獻1]國際公開第2000/020371號小冊
[專利文獻2]國際公開第2003/016254號小冊
[專利文獻3]國際公開第1999/047497號小冊
[非專利文獻]
[非專利文獻1]Journal of Lipid Mediators and Cell Signalling,第12卷,379-391頁,1995年
[非專利文獻2]Pharmacological Reviews,第65卷,1010-1052頁,7月,2013年
[非專利文獻3]第105屆 美國癌研究會議(American Association for Cancer Research(AACR)),要旨編號:LB-265,口頭報告標題:ONO-AE3-208 inhibits myeloid derived
suppressor cells and glioma growth,口頭報告日時:2014年4月8日
[非專利文獻4]FEBS Letters,第364卷,339-341頁,1995年
[非專利文獻5]Cancer Science,第105卷,1142-1151頁,2014年
[非專利文獻6]Cancer Research,第70卷,1606-1615頁,2010年
[非專利文獻7]Cancer Research,第62卷,28-32頁,2002年
本發明的課題是要創製一種化合物,該化合物係對EP4受體具有強力的拮抗活性,表現良好的藥物動力學性質的化合物,而發現作為對起因於EP4受體的活性化的疾病的預防及/或治療藥有用的化合物。
本發明者等為了要解決前述課題,要找出對EP4受體具有強力的拮抗活性,表現良好藥物動力學性質的化合物而精心研究之結果,發現後述的通式(I)表示的化合物對EP4受體具有強力的拮抗,而完成本發明。
即,本發明是關於:
[1]通式(I)表示的化合物、其鹽、其N-氧化物、其溶媒合物、或該等的前藥:
[2]如前述[1]所述的化合物,其係由通式(I-1)表示:
[3]如前述[1]或[2]所述的化合物,其中至少一個R5是-CONHR11。
[4]如前述[1]至[3]任一項中所述的化合物,其中L2是-NHCO-或-CONH-。
[5]如前述[1]至[4]任一項中所述的化合物,其係由通式(I-2)表示:
[6]如前述[1]所述的化合物,其係
(21)4-[4-氰基-2-({[(1R,2R)-6’-(甲基胺甲醯基)-2’,3’-二氫螺[環丙烷-1,1’-茚]-2-基]羰基}胺基)苯基]丁酸,
(22)4-{4-氰基-2-[({(1R,2R)-6’-[(2-甲氧基乙基)胺甲醯基]-2’,3’-二氫螺[環丙烷-1,1’-茚]-2-基}羰基)胺基]苯基}丁酸,
(23)4-{4-氰基-2-[({(1R,2R)-6’-[(1-甲基-1H-吡唑-4-基)胺甲醯基]-2’,3’-二氫螺[環丙烷-1,1’-茚]-2-基}羰基)胺基]苯基}丁酸,
(31)4-[4-氰基-2-({[(2’R,3S)-5-(甲基胺甲醯基)螺[1-苯并呋喃-3,1’-環丙烷]-2’-基]羰基}胺基)苯基]丁酸,
(32)4-{4-氰基-2-[({(2’R,3S)-5-[(2-甲氧基乙基)胺甲醯基]螺[1-苯并呋喃-3,1’-環丙烷]-2’-基}羰基)胺基]苯基}丁酸,
(33)4-[4-氰基-2-({[(1S,2R)-6’-[(2-甲氧基乙基)胺甲醯基]-3’,3’-二甲基-2’,3’-二氫螺[環丙烷-1,1’-茚]-2-基]羰基}胺基)苯基]丁酸,或
(34)4-[4-氰基-2-({[(1S,2R)-3’,3’-二甲基-6’-(甲基胺甲醯基)-2’,3’-二氫螺[環丙烷-1,1’-茚]-2-基]羰基}胺基)苯基]
丁酸。
[7]如前述[1]或[2]所述的化合物,其中至少一個R5是可經1至3個R18所取代的C4-10碳環或4至10員雜環,該R18有複數個時,各R18是分別獨立而可相同或不相同。
[8]如前述[7]所述的化合物,其中的L2是-NHCO-或-CONH-。
[9]如前述[1]、[2]、[7]、及[8]任一項中所述的化合物,其係由通式(I-3)表示:
[10]如前述[1]所述的化合物,其係
(19)4-[4-氰基-2-({[(2’R,3S)-5-(3-吡啶基)螺[1-苯并呋喃-3,1’-環丙烷]-2’-基]羰基}胺基)苯基]丁酸,或
[11]一種醫藥組成物,其係含有前述[1]所述的通式(I)表示的化合物、其鹽、其N-氧化物、其溶媒合物、或該等的前藥作為有效成分者。
[12]如前述[11]所述的組成物,其係為EP4受體拮抗劑。
[13]如前述[11]所述的組成物,其係為起因於EP4受體的活性化的疾病的預防及/或治療劑。
[14]如前述[13]所述的組成物,其中,起因於EP4受體的
活性化的疾病是骨疾病、癌、全身性肉芽腫、免疫疾病、齒槽膿漏、牙肉炎、牙周病、川崎病、多臟器功能不全、慢性頭痛、疼痛、血管炎、靜脈功能不全、靜脈瘤、動脈瘤、大動脈瘤、痔瘡、尿崩症、新生兒開放性動脈導管症、或膽石症。
[15]前述[14]所述的組成物,其中的癌是乳癌、卵巢癌、大腸癌、肺癌、前列腺癌、頭頸部癌、淋巴腫、葡萄膜惡性黑色瘤、胸腺瘤、間皮瘤、食道癌、胃癌、十二指腸癌、肝細胞癌、膽管癌、膽囊癌、胰臟癌、腎細胞癌、腎盂/尿管癌、膀胱癌、陰莖癌、睪丸癌、子宮癌、陰道癌、外陰癌、皮膚癌、惡性骨腫瘤、軟組織肉瘤、軟骨肉瘤、白血病、骨髓增生異常症候群、或多發性骨髓瘤。
[16]一種醫藥,其係將前述[1]所述的通式(I)表示的化合物、其鹽、其N-氧化物、其溶媒合物、或該等的前藥,與至少1種以上由烷基化劑、代謝拮抗劑、抗癌性抗生物質、植物性製劑、荷爾蒙劑、鉑化合物、拓樸異構酶抑制劑、激酶抑制劑、抗CD20抗體、抗HER2抗體、抗EGFR抗體、抗VEGF抗體、蛋白酶體抑制劑、HDAC抑制劑、及免疫調整藥選出的藥劑組合而成者。
[17]一種醫藥,其係將前述[1]所述的通式(I)表示的化合物,其鹽、其N-氧化物、其溶媒合物、或該等的前藥,與至少1種以上由HMG-CoA還原酶抑制劑、降壓劑、及四環素系抗生物質中選出的藥劑組合而成者。
[18]一種醫藥,其係將前述[1]所述的通式(I)表示的化合
物、其鹽、其N-氧化物、其溶媒合物、或該等的前藥,與至少1種由N型鈣通道阻斷劑、一氧化氮合成酶(NOS)抑制劑、及大麻素-2受體促效劑(cannabinoid-2-receptor agonist)中選出的藥劑組合而成者。
[19]一種起因於EP4受體的活性化的疾病的預防及/或治療方法,其係將前述[1]所述的通式(I)表示的化合物、其鹽、其N-氧化物、其溶媒合物、或該等的前藥的有效量,投與對起因於EP4受體的活性化的疾病的預防及/或治療有需要的患者。
[20]一種前述[1]所述的通式(I)表示的化合物、其鹽、其N-氧化物、其溶媒合物,或該等的前藥的用途,其係用於預防及/或治療起因於EP4受體的活性化的疾病。
[21]一種前述[1]所述的通式(I)表示的化合物、其鹽、其N-氧化物,或其溶媒合物的用途,其係用於製造起因於EP4受體的活性化的疾病的預防及/或治療劑。
本發明化合物是對EP4具有強力的拮抗活性,並且呈現良好的藥物動力學性質,因而可成為對起因於EP4受體的活性化的疾病的預防及/或治療藥。
第1圖表示本發明化合物對小鼠大腸癌細胞株CT26的同種移植模型的抗腫瘤效果的圖。
以下,詳細說明本發明。
在本發明中,「C1-4烷基」就是例如,甲基、乙基、正丙基、異丙基、正丁基、二級丁基、三級丁基、及異丁基。
在本發明中,「C1-3烷基」就是例如,甲基、乙基、正丙基、及異丙基。
在本發明中,「C1-5伸烷基」就是例如,亞甲基、伸乙基、伸丙基、伸丁基、及伸戊基。
在本發明中,「C2-5伸烯基」就是例如,伸乙烯基、1-伸丙烯基、2-伸丙烯基、1-伸丁烯基、2-伸丁烯基、3-伸丁烯基,1-伸戊烯基、2-伸戊烯基、3-伸戊烯基、及4-伸戊烯基等。
在本發明中,「C2-5伸炔基」就是例如,伸乙炔基、1-伸丙炔基、2-伸丙炔基、1-伸丁炔基、2-伸丁炔基、3-伸丁炔基、1-伸戊炔基、2-伸戊炔基、3-伸戊炔基、及4-伸戊炔基等。
在本發明中,「鹵素」就是氟、氯、溴、及碘。
在本發明中,「C1-4烷氧基」就是例如,甲氧基、乙氧基、丙氧基、異丙氧基、丁氧基、1-甲基丙氧基、三級丁氧基、異丁氧基等。
在本發明中,「C1-4烷硫基」就是例如,甲硫基,乙硫基、丙硫基、異丙硫基、丁硫基、1-甲基丙硫基、三級丁硫基、異丁硫基等。
在本發明中,「C2-4烯基」就是例如,乙烯基(ethenyl)、1-丙烯基、2-丙烯基、1-丁烯基、2-丁烯基、及3-丁烯基等。
在本發明中,「C2-4炔基」就是例如,乙炔基、1-丙炔基、2-丙炔基、1-丁炔基、2-丁炔基、及3-丁炔基等。
在本發明中,「C1-4鹵烷基」就是表示經鹵素取代的C1-4烷基,例如,可舉單氟甲基、二氟甲基、三氟甲基、2-氟乙基、1-氟乙基、2,2-二氟乙基、1,2-二氟乙基、1,1-二氟乙基、2,2,2-三氟乙基、1,2,2-三氟乙基、1,1,2-三氟乙基、1,2,2,2-四氟乙基、1,1,2,2-四氟乙基、五氟乙基、1,2-二溴-1,2,2-三氟乙基、1-氯-1,2,2,2-四氟乙基、3-氟丙基、3-氯丙基、2-氟丙基、2-氯丙基、1-氟丙基、1-氯丙基、3,3-二氟丙基、2,3-二氟丙基、1,3-二氟丙基、1,2-二氟丙基、2,2-二氟丙基、1,1-二氟丙基、3,3,3-三氟丙基、2,3,3-三氟丙基、1,3,3-三氟丙基、1,2,2-三氟丙基、1,1,2-三氟丙基、1,1,3-三氟丙基、1,1,2,2-四氟丙基、2,2,3,3,3-五氟丙基、4-氟丁基、4-氯丁基、3-氟丁基、3-氯丁基、2-氟丁基、2-氯丁基、1-氟丁基、1-氯丁基、3,3-二氟丁基、2,3-二氟丁基、1,3-二氟丁基、1,2-二氟丁基、2,2-二氟丁基、1,1-二氟丁基、3,3,3-三氟丁基、2,3,3-三氟丁基、1,3,3-三氟丁基、1,2,2-三氟丁基、1,1,2-三氟丁基、1,1,3-三氟丁基、1,1,2,2-四氟丁基、及2,2,3,3,3-五氟丁基等。
在本發明中,「可經氧化的硫」就是表示硫
(S)、亞碸(S(O))、及碸(SO2)。
在本發明中,「4至10員雜環」就是指含有由氧原子、氮原子及硫原子選出的1至5個雜原子的4至10員的單環或二環式雜環,例如,氧環丁烷(oxetane)、四氫氮唉(azetidine)、吡咯啶、吡咯、咪唑、三唑、四唑、吡唑、吡啶、哌啶、哌、吡、嘧啶、嗒、吖呯(azepine)、二吖呯、呋喃、哌喃、呯(oxepine)、噻吩、硫哌喃、硫呯(thiepine)、唑、異唑、噻唑、異噻唑、呋呫(furazane)、二唑、(oxazine)、二(oxadiazine)、吖呯(oxazepine)、二吖呯、噻二唑、噻(thiazine)、噻二(thiadiazine)、噻吖呯、噻二吖呯、吲哚、異吲哚、吲哚(indolizine)、苯并呋喃、異苯并呋喃、苯并噻吩、異苯并噻吩、吲唑、喹啉、異喹啉、喹(quinolizine)、嘌呤、酞(phthalazine)、喋啶(pteridine)、萘啶(naphthyridine)、喹喔啉(quinoxaline)、喹唑啉(quinazoline)、噌啉(cinnoline)、苯并唑、苯并噻唑、苯并咪唑、苯并二唑、苯并硫醇、唏、苯并呋呫、苯并噻二唑、苯并三唑、二氫吡咯(pyrroline)、吡咯啶、咪唑啉(imidazoline)、咪唑啶(imidazolidine)、三唑啉(trizoline)、三唑啶(triazolidine)、四唑啉、四唑啶、吡唑啉、吡唑啶、二氫咪唑、四氫咪唑、三唑啉、三唑啶、四唑啉、四唑啶、吡唑啉、吡唑啶、二氫吡啶、四氫吡啶、二氫吡、四氫吡、二氫嘧啶、四氫嘧啶、全氫嘧啶、二氫嗒、四氫嗒、全氫嗒、二氫吖呯、四氫吖呯、全氫吖呯、二氫二吖呯、四氫二吖呯、
全氫二吖呯、二氫呋喃、四氫呋喃、二氫哌喃、四氫哌喃、二氫呯、四氫呯、全氫呯、二氫噻吩、四氫噻吩、二氫硫哌喃、四氫硫哌喃、二氫硫呯、四氫硫呯、全氫硫呯、二氫唑、四氫唑(唑啶)、二氫異唑、四氫異唑(異唑啶)、二氫噻唑、四氫噻唑(噻唑啶)、二氫異噻唑、四氫異噻唑(異噻唑啶)、二氫呋呫、四氫呋呫、二氫二唑、四氫二唑(二唑啶)、二氫、四氫、二氫二、四氫二、二氫吖呯、四氫吖呯、全氫吖呯、二氫二吖呯、四氫二吖呯、全氫二吖呯、二氫噻二唑、四氫噻二唑(噻二唑啶)、二氫噻、四氫噻、二氫噻二、四氫噻二、二氫噻吖呯、四氫噻吖呯、全氫噻吖呯、二氫噻二吖呯、四氫噻二吖呯、全氫噻二吖呯、四氫三唑并吡(tetrahydrotriazolopyrazine)、嗎福林、硫代嗎福林、氧硫(oxathiane)、吲哚啉、異吲哚啉、二氫苯并呋喃、全氫苯并呋喃、二氫異苯并呋喃、全氫異苯并呋喃、二氫苯并噻吩、全氫苯并噻吩、二氫異苯并噻吩、全氫異苯并噻吩、二氫吲唑、全氫吲唑、二氫喹啉、四氫喹啉、全氫喹啉、二氫異喹啉、四氫異喹啉、全氫異喹啉、二氫酞、四氫酞、全氫酞、二氫萘啶、四氫萘啶、全氫萘啶、二氫喹喔啉、四氫喹喔啉、全氫喹喔啉、二氫喹唑啉、四氫喹唑啉、全氫喹唑啉、二氫噌啉、四氫噌啉、全氫噌啉、苯并氧硫、二氫苯并、二氫苯并噻、吡并嗎福林、二氫苯并唑、全氫苯并唑、二氫苯并噻唑、全氫苯并噻唑、二氫苯并咪唑、全氫苯并咪唑、二
氧戊環(dioxolane)、二烷、二氧雜茚烷(dioxaindane)、苯并二烷、硫唍(thiochromane)、二氫苯并二英(dihydrobenzodioxin)、二氫苯并氧硫雜環己二烯(dihydrobenzooxathiin)、唍(chromane)、吡唑并嘧啶、咪唑并嗒、咪唑并吡啶、咪唑并嘧啶、吡咯并吡啶、吡咯并嘧啶、吡咯并嗒、咪唑并吡、吡唑并吡啶(pyrazolopyridine)、吡唑并嘧啶、三唑并吡啶、及二氫吡啶并環等。
在本發明中,「3至10員雜環」就是指含有由氧原子、氮原子及硫原子選出的1至5個雜原子的3至10員的單環或二環式雜環,例如,吖環丙烷(aziridine)、環氧乙烷(oxirane)、噻喃(thiirane)、及在前述「4至10員雜環」所述的雜環等。
在本發明中,「5至10員芳族雜環」就是指含有由氧原子、氮原子及硫原子選出的1至4個雜原子的5至10員的單環或二環式芳族雜環,例如、吡咯、咪唑、三唑、四唑、吡唑、呋喃、噻吩、唑、異唑、噻唑、異噻唑、呋呫、二唑、噻二唑、吡啶、吡、嘧啶、嗒、吲哚、異吲哚、苯并呋喃、異苯并呋喃、苯并噻吩、異苯并噻吩、吲唑、嘌呤、苯并唑、苯并噻唑、苯并咪唑、苯并呋呫、苯并噻二唑、苯并三唑、喹啉、異喹啉、酞、喋啶、萘啶、喹喔啉、喹唑啉、及噌啉環等。
在本發明中,「C4-10碳環」就是指C4-10的單環或二環式碳環,例如,環丁烷、環戊烷、環己烷、環庚烷、環辛烷、環壬烷、環癸烷、環戊烯、環己烯、環庚烯、環辛烯、環戊二烯、環己二烯、環庚二烯、環辛二烯、苯、並環戊二烯(pentalene)、全氫並環戊二烯、薁(azulene)、全氫薁、茚、全氫茚、茚烷、萘、二氫萘、四氫萘、及全氫萘環等。
在本發明中,「C3-10碳環」就是指C3-10的單環或二環式碳環,例如,環丙烷、及前述「C4-10碳環」所述的碳環等。
在本發明中,「C1-6烷基」就是例如,甲基、乙基、正丙基、異丙基、正丁基、二級丁基、三級丁基、異丁基、戊基、1-甲基丁基、2-甲基丁基、3-甲基丁基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、己基、1-甲基戊基、2-甲基戊基、3-甲基戊基、4-甲基戊基、1,1-二甲基丁基、1,2-二甲基丁基、1,3-二甲基丁基、2,2-二甲基丁基、2,3-二甲基丁基、1-甲基-1-乙基丙基、2-甲基-2-乙基丙基、1-乙基丁基、2-乙基丁基、及1,1-二甲基戊基等。
在本發明中,「C3-6環烷基」就是環丙基、環丁基、環戊基、及環己基。
在本發明中,「4至6員雜環」就是指含有由氧原子、氮原子及硫原子選出的1至4個雜原子的4至
6員的單環式雜環,例如,氧環丁烷、四氫氮唉、吡咯啶、哌啶、吡、哌喃、硫哌喃、、二、噻、噻二、吡咯、咪唑、三唑、四唑、吡唑、吡啶、嘧啶、嗒、呋喃、噻吩、唑、異唑、噻唑、異噻唑、呋呫、二唑、及噻二唑環等。
在本發明中,R1理想是COOR8。
在本發明中,R8理想是氫原子或C1-4烷基,較理想是氫原子。
在本發明中,R8-1理想是C1-4烷基、苯或吡啶,該苯及吡啶是可經C1-4烷基、C1-4鹵烷基、C1-4烷氧基、-O(C1-4鹵烷基)、C1-4烷硫基、-S(C1-4鹵烷基)、鹵素、或腈基所取代。
在本發明中,L1理想是C1-5伸烷基或C2-5伸烯基,較理想是C1-5伸烷基,特別理想是伸丙基。
在本發明中,R2理想是氟。
在本發明中,X1理想是CR6。
在本發明中,R6理想是氫原子或氟,較理想是氫原子。
在本發明中,X2理想是CR7。
在本發明中,R7理想是氟、腈基、-CH2R9、或-OR9,較理想是腈基。
在本發明中,R9理想是可經甲基或三氟甲基所取代的4至10員雜環基,該4至10員雜環理想是5至10員芳族雜環基,較理想是5至10員含氮芳族雜環(例
如,吡唑、咪唑、三唑、吡咯并吡啶、吡咯并嘧啶、吡咯并嗒、咪唑并嗒、咪唑并吡啶、咪唑并嘧啶、咪唑并吡、吡唑并吡啶、吡唑并嘧啶等)。
在本發明中,L2理想是-CH=CH-、-NHCO-、-CONH-、-NHSO2-、或-SO2NH-,較理想是-NHCO-或-CONH-,特別理想是-NHCO-。
在本發明中,R3理想是氟。
在本發明中,R4理想是甲基、乙基、或三氟甲基,較理想是甲基。
在本發明中,X3理想是亞甲基或氧原子,較理想是氧原子。
在本發明中,R10理想是甲基,乙基、甲基羰基、乙基羰基、甲磺醯基、乙基磺醯基、或三級丁氧基羰基。
在本發明中,ring理想是苯、噻吩、或吡唑環,較理想是苯環。
在本發明中,R5理想是-CONHR11、氟、甲氧基、苯環、或4至10員雜環,該4至10員雜環理想是四氫氮唉、吡咯啶、哌啶、唑啶、二唑、三唑、噻吩、呋喃、吡唑、噻唑、唑、咪唑、吡啶、吡、嗒、嘧啶、吡唑并嘧啶、吡咯并嘧啶、吡唑并吡啶、吡咯并吡啶、或二氫吡啶并環。
在本發明中,R13理想是鹵素、C1-6烷基、C3-6環烷基、C1-4烷氧基、羥基、-NR20R21、苯、氧環丁烷、吡啶、吡唑、或唑環,較理想是氟、甲基、乙基、正丙基、異丙基、正丁基、二級丁基、三級丁基、異丁基、環戊基、環丁烷、氧環丁烷、羥基、甲氧基、乙氧基、丙氧基、異丙氧基、二甲胺基、苯、吡啶、吡唑、或唑環。
在本發明中,R20理想是氫原子或甲基。
在本發明中,R21理想是氫原子或甲基。
在本發明中,R12理想是C1-3烷基、C3-6環烷基、苯、或4至6員雜環。該4至6員雜環理想是氧環丁烷、四氫氮唉、吡咯啶、哌啶、吡、哌喃、硫哌喃、、二、噻、噻二、吡咯、咪唑、三唑、四唑、吡唑、吡啶、吡、嘧啶、嗒、呋喃、噻吩、唑、異唑、噻唑、異噻唑、呋呫、二唑、或噻二唑環。該4至6員雜環是可經C1-4烷氧基所取代。
在本發明中,R14理想是氫原子,甲基、乙基、苯、或苄基。
在本發明中,R15理想是甲基、環丙基、或苯。
在本發明中,R16理想是羥基。
在本發明中,R17理想是甲基、乙基、環丙
基、或苯,較理想是甲基。
在本發明中,R18理想是氟、甲基、乙基、正丙基、異丙基、正丁基、二級丁基、三級丁基、異丁基、環丙基、甲氧基、乙氧基、正丙氧基、異丙氧基、側氧基、腈基、羥基、羥甲基、1-甲基-1-羥乙基、甲磺醯基、吡啶、二甲胺基。
在本發明中,m理想是1至2的整數,較理想是1。
在本發明中,n理想是0至1的整數,較理想是1。
在本發明中,p理想是0。
在本發明中,q理想是0。
在本發明中,r理想是0至4的整數,較理想是0至2的整數。
在本發明中,s理想是0至2的整數,較理想是1或2。
在本發明中,t理想是0至2的整數。
在本發明中,X3a理想是氧原子。
在本發明中,na理想是0至1的整數。
在本發明中,qa理想是0。
在本發明中,ra理想是0至2的整數。
在本發明中,通式(I)理想是前述的ring、R1、R2、R3、R4、R5、R6、R7、R8、R8-1、R9、R10、R11、R12、R13、R14、R15、R16、R17、R18、R19、R20、R21、L1、
L2、L3、X1、X2、X3、X3a、m、n、na、p、q、qa、r、ra、s、及t的各別理想定義的組合。
在本發明中,通式(I)表示的化合物,理想是通式(I-a)表示的化合物、其鹽、其N-氧化物、其溶媒合物、或該等的前藥:
較理想是通式(I-1)表示的化合物、其鹽、其N-氧化物、其溶媒合物,或該等的前藥:
在本發明中,通式(I)表示的化合物另一種態樣,更理想是通式(I-b)表示的化合物、其鹽、其N-氧化物、其溶媒合物、或該等的前藥:
又更理想是通式(I-c)表示的化合物、其鹽、其N-氧化物、其溶媒合物、或該等的前藥:
尤更理想是通式(I-d)表示的化合物、其鹽、其N-氧化物、其溶媒合物、或該等的前藥:
又再更理想是通式(I-e)表示的化合物、其鹽、其N-氧化物、其溶媒合物、或該等的前藥:
特別理想是通式(I-2)表示的化合物、其鹽、其N-氧化物、其溶媒合物、或該等的前藥:
最理想是通式(I-4)表示的化合物、其鹽、其N-氧化物、其溶媒合物、或該等的前藥:
在本發明中,通式(I)表示的化合物再另外一種態樣,更理想是通式(I-f)表示的化合物、其鹽、其N-氧化物、其溶媒合物、或該等的前藥:
又更理想是通式(I-g)表示的化合物、其鹽、其N-氧化物、其溶媒合物、或該等的前藥:
尤更理想是通式(I-h)表示的化合物、其鹽、其N-氧化物、其溶媒合物、或該等的前藥:
再又更理想是通式(I-i)表示的化合物、其鹽、其N-氧化物、其溶媒合物、或該等的前藥,
特別理想是通式(I-3)表示的化合物、其鹽、其N-氧化物、其溶媒合物、或該等的前藥:
最理想是通式(I-5)表示的化合物、其鹽、其N-氧化物、其溶媒合物、或該等的前藥:
在本發明中,在由上述的通式(I-a)、通式(I-b)、通式(I-c)、通式(I-d)、通式(I-e)、通式(I-f)、通式(I-g)、通式(I-h)、通式(I-i)、及通式(I-1)的群中選出的通式中,分別獨立,理想是,L1是伸丙基,L2是-CH=CH-、-NHCO-、-CONH-、-NHSO2-、或-SO2NH-。較理想是L1是伸丙基,L2是-NHCO-或-CONH-。更理想是L1是伸丙基,L2是-NHCO-。
在本發明中,在由上述的通式(I-2)、通式(I-3)、通式(I-4)、及通式(I-5)的群選出的通式中,分別獨立,理想是,L1是伸丙基。
在本發明中,通式(I)的另外一種態樣最理想是在後述的實施例1的本發明化合物,實施例2-1至實施例2-47的本發明化合物,實施例3的本發明化合物,實施例4-1至實施例4-3的本發明化合物,實施例5至6的本發明化合物,實施例7-1至實施例7-28的本發明化合物,實施例8至9的本發明化合物,實施例10-1至實施例
10-12的本發明化合物,實施例11的本發明化合物,實施例12-1至實施例12-3的本發明化合物,實施例13至17的本發明化合物,實施例18-1至實施例18-3的本發明化合物,實施例19的本發明化合物,實施例20-1至實施例20-5的本發明化合物,實施例21至22的本發明化合物,實施例23-1至實施例23-2的本發明化合物,實施例24至27的本發明化合物,實施例28-1至實施例28-2的本發明化合物,實施例29至30的本發明化合物,實施例31-1至實施例31-2的本發明化合物,實施例32的本發明化合物,實施例33-1至實施例33-5的本發明化合物,實施例34至36的本發明化合物,實施例37-1至實施例37-2的本發明化合物,實施例38-1至實施例38-2的本發明化合物,或實施例39的本發明化合物,其鹽、其N-氧化物、其溶媒合物、或該等的前藥。
在本發明中,如未特別指明係包含其全部異構物。例如,烷基、烷氧基及伸烷基等是包含直鏈及分枝鏈的基團。再者,雙鍵、環、縮合環中的異構物(E、Z、順、反體)、不對稱碳的存在等而產生的異構物(R、S體,α、β體,鏡像異構物,非鏡像異構物)、有旋光性的光學活性體(D、L、d、l體)、由層析法分離的極性體(高極性體、低極性體)、平衡化合物、旋轉異構物、該等的任意比例的混合物、消旋混合物,全部包含在本發明中。又,在本發明中也包含全部互變異構性的異構物。
[鹽]
通式(I)表示的化合物是由公知的方法轉換為鹽。
鹽是以藥學上可容許的鹽為理想。
鹽是水溶性的鹽為理想。
藥學上可容許的鹽是例如,可舉酸附加鹽,鹼金屬鹽、鹼土金屬鹽、銨鹽、或胺鹽等。
酸附加鹽而言,例如,可舉鹽酸鹽、氫溴酸鹽、氫碘酸鹽、硫酸鹽、磷酸鹽、硝酸鹽等的無機酸鹽,或乙酸鹽、乳酸鹽、酒石酸鹽、安息香酸鹽、檸檬酸鹽、甲磺酸鹽、乙磺酸鹽、三氟乙酸鹽、苯磺酸鹽、甲苯磺酸鹽、羥乙基磺酸(isethionic acid)、葡萄糖醛酸鹽、或葡萄糖酸鹽等的有機酸鹽。
鹼金屬鹽而言,例如,可舉鉀及鈉等。
鹼土金屬鹽而言,例如,可舉鈣及鎂等。
銨鹽而言,例如,四甲銨等。
胺鹽而言,例如,可舉三乙胺、甲胺、二甲
胺、環戊胺、苄胺、苯乙胺、哌啶、單乙醇胺、二乙醇胺、三(羥甲基)胺基甲烷、離胺酸、精胺酸、及N-甲基-D-還原葡糖胺等。
又,本發明化合物是可由任意的方法製成N-氧化物。N-氧化物是表示通式(I)表示的化合物的氮原子被氧化者。
通式(I)表示的化合物及其鹽是也可轉換為溶媒合物。
溶媒合物是以非毒性並且水溶性為理想。適當的溶媒合物而言,例如,可舉水、或醇系的溶媒(例如,乙醇等)等的溶媒合物。
[前藥]
通式(I)表示的化合物的前藥就是指在生體內由酶或胃酸等的反應而轉換為通式(I)表示的化合物的化合物。通式(I)表示的化合物的前藥而言,例如,可舉通式(I)表示的化合物具有胺基時,該胺基被醯基化、烷基化、磷酸化的化合物(例如,通式(I)表示的化合物的胺基被二十醯基化、丙胺醯基化、戊胺基羰基化、(5-甲基-2-側氧基-1,3-二雜氧環戊烯(dioxolene)-4-基)甲氧基羰基化、四氫呋喃基化、吡咯啶基甲基化、三甲基乙醯氧基甲基化、乙醯氧基甲基化、三級丁基化的化合物等);通式(I)表示的化合物具有羥基時,該羥基被醯基化、烷基化、磷酸化、硼酸化的化合物(例如,通式(I)表示的化合物的羥基被乙醯基化、軟脂醯基化、丙醯基化、三甲基乙醯基化、琥珀醯基
化、反丁烯二醯基化、丙胺醯基化、二甲胺基甲基羰基化的化合物等);通式(I)表示的化合物具有羧基時,該羧基被酯化、醯胺化的化合物(例如,通式(I)表示的化合物的羧基被乙酯化、苯酯化、漿甲酯化、二甲胺基甲酯化、三甲基乙醯氧基甲酯化、1-{(乙氧基羰基)氧基}乙酯化、酞酯化、(5-甲基-2-側氧基-1,3-二雜氧環戊烯-4-基)甲酯化、1-{[(環己基氧基)羰基]氧基}乙酯化、甲基醯胺化的化合物等)等。該等的化合物是可由自體本身公知的方法製造。又,通式(I)表示的化合物的前藥是水合物及非水合物的任一種都可以。又,通式(I)表示的化合物的前藥亦可為廣川書店1990年刊「醫藥品之開發」第7卷「分子設計」163至198頁所述等的在生理的條件下變化成為通式(I)表示的化合物。
再者,構成通式(I)表示的化合物的各原子亦可經其同位元素(例如,2H,3H,13C,14C,15N,16N,17O,18O,18F,35S,36Cl,77Br,125I等)等所取代。
[本發明化合物的製造方法]
通式(I)表示的本發明化合物是以公知的方法,例如可由以下所示的方法,遵照以該等為基準之方法或依照實施例所示的方法製造。又,在以下的各製造方法中,原料化合物是可使用鹽。該鹽而言,可使用記載於通式(I)表示的本發明化合物的藥學上可容許的鹽。
通式(I)表示的本發明化合物中,L2是-NHCO-的通式(IVa)表示的本發明化合物,或L2是-CONH-
的通式(IVb)表示的本發明化合物是分別依照下述的反應製程式(Ia)或反應製程式(Ib)所示的方法而可製造。
即,通式(IVa)表示的本發明化合物是將通式(IIa)表示的化合物及通式(IIIa)表示的化合物加以醯胺化反應而可製造。又,通式(IVb)表示的本發明化合物是可以將通式(IIb)表示的化合物及通式(IIIb)表示的化合物加以醯胺化反應而製造。
醯胺化反應是公知的方法,例如,可舉:
(1)使用醯基鹵的方法,
(2)使用混合酸酐的方法,
(3)使用縮合劑的方法等。
具體的說明該等的方法如下,
(1)使用醯基鹵的方法是例如,將羧酸在有機溶媒(三氯甲烷、二氯甲烷、二乙醚、四氫呋喃等)中或無溶媒下,與醯基鹵化劑(草醯氯、亞硫醯氯(thionyl chloride)等)在約-20℃至回流溫度下反應,將所得的醯基鹵與鹼(吡啶、三乙胺、二甲基苯胺、二甲胺基吡啶、二異丙基乙胺等)的存在下,與胺在有機溶媒(三氯甲烷、二氯甲烷、二乙醚、四氫呋喃等)中,在約0至40℃的溫度反應而實施。又,也可以將所得的醯基鹵在有機溶媒(二烷、四氫呋喃等)中,使用鹼水溶液(碳酸氫鈉或氫氧化鈉溶液等),與胺在約0至40℃反應而實施。
(2)使用混合酸酐的方法是例如,將羧酸在有機溶媒(三氯甲烷、二氯甲烷、二乙醚、四氫呋喃等)中或無溶媒下,在鹼(吡啶、三乙胺、二甲基苯胺、二甲胺基吡啶、二異丙基乙胺等)的存在下,與醯基鹵(三甲基乙醯氯、甲苯磺醯氯(tosyl chloride)、甲磺醯氯(mesyl chloride)等),或酸衍生物(氯甲酸乙酯、氯甲酸異丁酯等),在約0至40℃反應,將所得的混合酸酐在有機溶媒(三氯甲烷、二氯甲烷、二乙醚、四氫呋喃等)中,與胺在約0至40℃反應而實施。
(3)使用縮合劑的方法是例如,將羧酸及胺,在有機溶
媒(三氯甲烷、二氯甲烷、二甲基甲醯胺、二甲基乙醯胺、二乙醚、四氫呋喃等)中,或無溶媒下,在鹼(吡啶、三乙胺、二甲基苯胺、二甲胺基吡啶等)的存在下或非存在下,使用縮合劑(1,3-二環己碳二亞胺(1,3-dicyclohexyl carbodiimide,DCC)、1-乙基-3-[3-(二甲胺基)丙基]碳二亞胺(EDC)、1,1’-羰基二咪唑(CDI)、2-氯-1-甲基碘化吡啶鎓、1-丙基膦酸環酐(1-propanephosphonic acid cyclic anhydride(T3P)等),使用1-羥苯并三唑(HOBt)或不使用,在約0℃至回流溫度反應而實施。
該等(1)、(2)及(3)的反應任一者均以在惰性氣體(氬、氮等)環境下,無水條件下實施為理想。
在通式(I)表示的本發明化合物中,L2是-NHSO2-的通式(IVc)表示的本發明化合物,或L2是-SO2NH-的通式(IVd)表示的本發明化合物是分別可由下述的反應製程式(Ic)或反應製程式(Id)所示的方法製造。
即,通式(IVc)表示的本發明化合物是可以將通式(IIc)表示的化合物及通式(IIIc)表示的化合物加以磺醯胺化反應而製造。又,通式(IVd)表示的本發明化合物是可以將通式(IId)表示的化合物及通式(IIId)表示的化合物加以磺醯胺化反應而製造。
磺醯胺化反應是公知的反應,例如,將磺酸在有機溶媒(三氯甲烷、二氯甲烷、二氯乙烷、二乙醚、四氫呋喃、甲基三級丁基醚等)中或無溶媒下,與醯基鹵(草醯氯、亞硫醯氯、五氯化磷、三氯化磷等)在-20℃至回流溫度反應,將所得的磺醯基鹵在鹼(二異丙基乙胺、吡啶、三乙胺、二甲基苯胺、二甲胺基吡啶等)的存在下,在有機溶媒(三氯甲烷、二氯甲烷、二氯乙烷、二乙醚、四氫呋喃等)中,與胺在約0至40℃反應而實施。
在通式(I)表示的本發明化合物中,L2是-NHCH2-的通式(IVe)表示的本發明化合物,或L2是-CH2NH-的通式(IVf)表示的本發明化合物是可以分別由下述的反
應製程式(Ie)或反應製程式(If)所示的方法製造。
即,通式(IVe)表示的本發明化合物是可以使通式(IIe)表示的化合物及通式(IIIe)表示的化合物進行還原性胺化反應而製造。又,通式(IVf)表示的本發明化合物是可以使通式(IIf)表示的化合物及通式(IIIf)表示的化合物進行還原性胺化反應而製造。
還原性胺化反應是公知的反應,例如,在有
機溶媒(二氯乙烷、二氯甲烷、二甲基甲醯胺、乙酸及該等的混合物等)中,在還原劑(三乙醯氧基硼氫化鈉、氰基硼氫化鈉、硼氫化鈉等)的存在下,在約0至40℃的溫度實施。
在通式(I)表示的本發明化合物中,L2是-OCH2-的通式(IVg)表示的本發明化合物,或L2是-CH2O-的通式(IVh)表示的本發明化合物是可以分別依照下述的反應製程式(Ig)或反應製程式(Ih)所示的方法製造。
即,通式(IVg)表示的本發明化合物是可以使通式(IIg)表示的化合物及通式(IIIg)表示的化合物進行醚化反應而製造。又,通式(IVh)表示的本發明化合物是可以使通式(IIh)表示的化合物及通式(IIIh)表示的化合物進行醚化反應而製造。
該醚化反應是公知的反應,例如在有機溶媒(二甲基甲醯胺、二甲基亞碸、三氯甲烷、二氯甲烷、二乙醚、四氫呋喃、甲基三級丁基醚等)中,在鹼金屬的氫氧化物(氫氧化鈉、氫氧化鉀、氫氧化鋰等)、鹼土金屬的氫氧化物(氫氧化鋇、氫氧化鈣等)或碳酸鹽(碳酸鈉、碳酸鉀等)或其水溶液或該等的混合物的存在下,在約0至100℃反應而實施。
在通式(I)表示的本發明化合物中,L2是-SCH2-的通式(IVj)表示的本發明化合物,或L2是-CH2S-的通式(IVk)表示的本發明化合物是可以分別依照下述的反應製程式(Ij)或反應製程式(Ik)所示的方法製造。
即,通式(IVj)表示的本發明化合物是使通式(IIj)表示的化合物及通式(IIIj)表示的化合物進行硫醚化反應而可製造。又,通式(IVk)表示的本發明化合物是可以使通式(IIk)表示的化合物及通式(IIIk)表示的化合物進行硫醚化反應而製造。
該硫醚化反應是公知的反應,例如在有機溶媒(二甲基甲醯胺、二甲基亞碸、三氯甲烷、二氯甲烷、二乙醚、四氫呋喃、甲基三級丁基醚等)中,在鹼金屬的氫氧化物(氫氧化鈉、氫氧化鉀、氫氧化鋰等)、鹼土金屬的氫氧化物(氫氧化鋇、氫氧化鈣等)或碳酸鹽(碳酸鈉、碳酸鉀等)或其水溶液或該等的混合物的存在下,在0至100℃反應而實施。
在通式(I)表示的本發明化合物中,L2是-S(O)CH2-或-SO2CH2-的本發明化合物是可以將上述的通式
(IVj)表示的本發明化合物的硫原子適當地進行氧化反應而製造。
在通式(I)表示的本發明化合物中,L2是-CH2S(O)-或-CH2SO2-的本發明化合物是可以將上述的通式(IVk)表示的本發明化合物的硫原子適當地進行氧化反應而製造。
該氧化反應(亞磺化反應:-SCH2-→-S(O)CH2-,或-CH2S-→-CH2S(O)-)是公知的反應,例如,在有機溶媒(二氯甲烷、三氯甲烷、苯、己烷、甲醇、三級丁醇、丙酮、乙腈、四氫呋喃、乙酸、N,N-二甲基甲醯胺等)中,在水中或該等的混合溶媒中,1至1.2當量的氧化劑(過氧化氫、過碘酸鈉、亞硝酸醯基酯、過硼酸鈉、次亞氯酸鈉、過酸(3-氯過安息香酸、過乙酸等)、OXONE(商品名,過一硫酸氫鉀複合鹽(potassium peroxymonosulfate))、過錳酸鉀、鉻酸、二甲基二氧戊環等)的存在下,在約-40至0℃的溫度反應而實施。
該氧化反應(磺化反應:-SCH2-→-SO2CH2-,或-CH2S-→-CH2SO2-)是公知的反應,例如,在適當的有機溶媒(二氯甲烷、三氯甲烷、苯、己烷、甲醇、三級丁醇、丙酮、乙腈、四氫呋喃、乙酸、N,N-二甲基甲醯胺等)中,水中或該等的混合溶媒中,與過剰的氧化劑(過氧化氫、過碘酸鈉、亞硝酸醯基酯、過硼酸鈉、次亞氯酸鈉、過酸(3-氯過安息香酸、過乙酸等)、OXONE(商品名;過一硫酸氫鉀複合鹽)、過錳酸鉀、鉻酸、二甲基二氧戊環
等)的存在下,在約20至60℃的溫度反應而實施。
在通式(I)表示的本發明化合物中,L2是-CH=CH-的通式(IVm)表示的化合物是可以依照下述的反應製程式(Im)所示的方法製造。
即,通式(IVm)表示的本發明化合物是可以使通式(IIIm)表示的化合物加以乙烯化反應所製造的通式(Vm)表示的化合物及通式(IIm)表示的化合物進行Heck化反應而製造。
該乙烯化反應是公知的反應,例如,使用通式(IIIm)表示的化合物及甲基三苯基溴化鏻,在有機溶媒
(例如,乙腈、二氯甲烷、四氫呋喃、甲苯、苯、或將該等的有機溶媒適當地混合的溶媒等)中,鹼(例如,碳酸鉀、氫化鈉、氫化鉀、正丁基鋰、三級丁氧基鉀、1,8-二氮雜雙環[5.4.0]十一-7-烯三乙胺(DBU)等)存在下,在約0℃至120℃的溫度反應而實施。
該Heck化反應是公知的反應,例如,在有機溶媒(例如,甲苯、二乙醚、苯、二氯苯、二甲基甲醯胺,或將該等的有機溶媒適當地混合的溶媒等)中,在鹼(例如,磷酸三鉀、碳酸氫鈉、三乙胺等)及觸媒(例如,鈀觸媒(例如,氯化鈀、乙酸鈀、四(三苯基膦)鈀(0)等)、鎳觸媒(例如,四(三苯基膦)鎳、雙(三苯基膦)鎳(II)等)、鈷觸媒(例如,氯化鈷等)、銅觸媒(例如,氯化銅等)、鋅觸媒(例如,鋅等)、或該等的觸媒適當地混合的觸媒等)存在下,再在磷試藥(例如,1,3-雙(二苯基膦基)丙烷(dppp)、Ph2P-(CH2)6-PPh2等)存在下或非存在下,在約0℃至120℃的溫度反應而實施。
在通式(I)表示的本發明化合物中,L2是-CH2CH2-的本發明化合物是將上述的通式(IVm)表示的本發明化合物的「-CH=CH-」適當地加以還原反應而可製造。
該還原反應是公知的反應,例如,在有機溶媒(例如,四氫呋喃、二烷、二甲氧基乙烷、二乙醚、甲醇、乙醇、苯、甲苯、丙酮、甲基乙基酮、乙腈、二甲基甲醯胺、水、乙酸乙酯、乙酸、或該等的有機溶媒適當地混合的溶媒等)中,在氫化觸媒(鈀-碳、鈀黑、鈀、氫氧化
鈀、二氧化鉑、鉑-碳、鎳、雷尼鎳、氯化釕等)的存在下,在酸(鹽酸、硫酸、次亞氯酸、硼酸、四氟硼酸、乙酸、對甲苯磺酸、草酸、三氟乙酸、甲酸等)的存在下或非存在下,在常壓或加壓下的氫環境下,在甲酸銨存在下或聯胺存在下,在約0至200℃的溫度實施。
在反應製程式(Ia)的通式(IIIa)表示的化合物中,q是0,m是1的通式(IIIaa)表示的化合物是依照下述的反應製程式(Iaa)所示的方法而可製造。
即,通式(IIIaa)表示的化合物是使通式(Vaa)表示的化合物加以乙烯化反應所製造的通式(VIaa)表示的化合物進行環化反應,繼而進行加水分解反應而可製造。
該乙烯化反應是公知的反應,例如,使用通
式(Vaa)表示的化合物及甲基三苯基溴化鏻,在有機溶媒(例如,乙腈、二氯甲烷、四氫呋喃、甲苯、苯,或該等的有機溶媒適當地混合的溶媒等)中,在鹼(例如,碳酸鉀、氫化鈉、氫化鉀、正丁基鋰、三級丁氧基鉀、1,8-二氮雜雙環[5.4.0]十一-7-烯三乙胺(DBU)等)存在下,在約0℃至120℃的溫度反應而實施。
該環化反應是公知的反應,例如,使用通式(VIaa)表示的化合物及二偶氮化合物,在有機溶媒(例如,甲苯、苯、二氯甲烷、二氯乙烷、甲醇、乙醇、己烷、四氫呋喃、水、或該等的有機溶媒適當地混合的溶媒等)中,觸媒(釕觸媒(例如,二氯(異丙基甲苯)釕二聚物([Ru(p-cymene)Cl2]2)、RuCl2(PPh3)3、RuCl(Cp)(PPh3)2等)、銠觸媒(例如,Rh2(O-CO-hepty)4、Rh2(O-CO-tBu)4、Rh2(OAc)4、Rh2(O-Piv)4、Rh2((S)-PTTL)4、Rh2((S)-DOSP)4、Rh2(esp)2、Rh2((S)-NTTL)4等)、銀觸媒(例如,四氟硼酸銀(I)等)、銅觸媒(例如,CuOTf、Cu(OAc)2、[Cu(MeCN)4]PF6等)、錫觸媒(例如,Sn(tpp)(OTf)2等)、鐵觸媒(例如,[Fe(Cp)(CO)2(thf)]BF4等)、鈷觸媒、2,6-雙(4-異丙基-4,5-二氫唑-2-基)吡啶、2,6-雙((S)-4-異丙基-4,5-二氫唑-2-基)吡啶、2,6-雙((R)-4-異丙基-4,5-二氫唑-2-基)吡啶)的存在下,在約-78℃至120℃的溫度反應而實施。又,在該環化反應中,使用公知的具有光學活性的不對稱觸媒,而可製造具有光學活性的三環性螺化合物(通式(VIIaa)表示的化合物的光學活性體)。
該加水分解反應(羧基的脫保護反應)是公知的反應,例如,可舉鹼加水分解等。藉由鹼加水分解的脫保護反應是例如,在有機溶媒(甲醇、四氫呋喃、二烷等)中,使用鹼金屬的氫氧化物(氫氧化鈉、氫氧化鉀、氫氧化鋰等)、鹼土金屬的氫氧化物(氫氧化鋇、氫氧化鈣等)或碳酸鹽(碳酸鈉、碳酸鉀等)或其水溶液或該等的混合物,在0至100℃的溫度實施。
在反應製程式(Ib)的通式(IIIb)表示的化合物,反應製程式(Id)的通式(IIId)表示的化合物,或反應製程式(If)的通式(IIIf)表示的化合物中,m是1的化合物是將上述的反應製程式(Iaa)的通式(IIIaa)表示的化合物使用公知的方法,例如,「Comprehensive Organic Transformations:A Guide to Functional Group Preparations 2nd Edition(Richard C.Larock,John Wiley & Sons Inc,1999)」所述的方法而可製造。
在反應製程式(Ic)的通式(IIIc)表示的化合物中,m是1的整數表示的化合物是將上述的反應製程式(Iaa)的通式(IIIaa)表示的化合物使用公知的方法,例如,「Comprehensive Organic Transformations:A Guide to Functional Group Preparations 2nd Edition(Richard C.Larock,John Wiley & Sons Inc,1999)」所述的方法而製造。
在反應製程式(Ie)的通式(IIIe)表示的化合物或反應製程式(Im)的通式(IIIm)表示的化合物中,m是1的化合物是將上述的反應製程式(Iaa)的通式(IIIaa)表示的
化合物使用公知的方法,例如,「Comprehensive Organic Transformations:A Guide to Functional Group Preparations 2nd Edition(Richard C.Larock,John Wiley & Sons Inc,1999)」所述的方法,加以還原反應而可製造。
在反應製程式(Ig)的通式(IIIg)表示的化合物或反應製程式(Ij)的通式(IIIj)表示的化合物中,m是1的化合物是將上述的反應製程式(Iaa)的通式(IIIaa)表示的化合物使用公知的方法,例如,「Comprehensive Organic Transformations:A Guide to Functional Group Preparations 2nd Edition(Richard C.Larock,John Wiley & Sons Inc,1999)」所述的方法,將羧酸加以還原而成為一級醇衍生物後,將該醇衍生物轉換為鹵衍生物、甲苯磺酸酯衍生物,或甲磺酸酯衍生物而製造。
在反應製程式(Ih)的通式(IIIh)表示的化合物中,m是1的化合物是可以將上述的反應製程式(Iaa)的通式(IIIaa)表示的化合物使用公知的方法,例如,「Comprehensive Organic Transformations:A Guide to Functional Group Preparations 2nd Edition(Richard C.Larock,John Wiley & Sons Inc,1999)」或在「Tetrahedron Letter、第28卷,4489-4492頁,1987年」所述的方法製造。
在反應製程式(Ik)的通式(IIIk)表示的化合物中,m是1的化合物是可以將上述的反應製程式(Iaa)的通式(IIIaa)表示的化合物使用公知的方法,例如,
「Comprehensive Organic Transformations:A Guide to Functional Group Preparations 2nd Edition(Richard C.Larock,John Wiley & Sons Inc,1999)」或「Tetrahedron Letter、第28卷,4489-4492頁,1987年」所述的方法,使成為二級醇衍生物後,將該醇衍生物轉換為硫醇衍生物而製造。
在反應製程式中,做為出發原料而使用的通式(IIIa)、通式(IIIb)、通式(IIIc)、通式(IIId)、通式(IIIe)、通式(IIIf)、通式(IIIg)、通式(IIIh)、通式(IIIj)、通式(IIIk)、或通式(IIIm)表示的化合物中,m是1,q是1至3的整數的化合物,或m是2至4的整數,q是1至6的整數的化合物是公知的,或可以使用公知的方法,例如,「Comprehensive Organic Transformations:A Guide to Functional Group Preparations 2nd Edition(Richard C.Larock,John Wiley & Sons Inc,1999)」所述的方法而容易製造。
在反應製程式中,做為出發原料而使用的通式(IIa)、(IIb)、(IIc)、(IId)、(IIe)、(IIf)、(IIg)、(IIh)、(IIj)、(IIk)、(IIm)、及(Vaa)表示的化合物是公知的,或可以使用公知的方法,例如,「Comprehensive Organic Transformations:A Guide to Functional Group Preparations 2nd Edition(Richard C.Larock,John Wiley & Sons Inc,1999)」所述的方法而容易製造。
又,具有胺基,羧基,或羥基的本發明化合
物視需要,可使用對該等基團以汎用的保護基,例如,「Comprehensive Organic Transformations:A Guide to Functional Group Preparations 2nd Edition(Richard C.Larock,John Wiley & Sons Inc,1999)」所述的保護基加以保護的化合物,實施上述的反應製程式(Ia)或(Ib)所述的醯胺化反應,上述的反應製程式(Ic)或(Id)所述的磺醯胺化反應,上述的反應製程式(Ie)或(If)所述的還原性胺化反應,上述的反應製程式(Ig)或(Ih)所述的醚化反應,上述的反應製程式(Ij)或(Ik)所述的硫醚化反應,或上述的反應製程式(Im)所述的Heck反應為止的反應後或在合適的反應製程之後,實施公知的脫保護反應,或,例如,「Comprehensive Organic Transformations:A Guide to Functional Group Preparations 2nd Edition(Richard C.Larock,John Wiley & Sons Inc,1999)」所述的脫保護反應而製造。
在通式(I)表示的本發明化合物中,上文所示以外的化合物是可將本說明書中所述的實施例,或公知的方法,例如,「Comprehensive Organic Transformations:A Guide to Functional Group Preparations 2nd Edition (Richard C.Larock,John Wiley & Sons Inc,1999)」所述的方法加以組合而製造。
本發明化合物中,具有光學活性的化合物可使用具有光學活性的出發原料或試藥而製造,或將消旋體的製造中間體加以光學分割,繼而導向本發明化合物,或將消旋體的本發明化合物加以光學分割而製造。
該光學分割的方法是公知的,例如,可舉與其他的光學活性化合物形成鹽/錯合物等,實施再結晶後,將作為目的之化合物單離,或直接使用掌性管柱等而分離的方法等。
在本說明書中的各反應中,需要加熱的反應是對本行業者而言是明瞭的,可使用水浴,油浴,砂浴,或微波爐而實施。
在本說明書中的各反應中,適當地,使用載持在高分子聚合物(例如,聚苯乙烯、聚丙烯醯胺、聚丙烯、聚乙二醇等)的固相載持試藥也可以。
在本說明書中的各反應中,反應生成物是可由通常的精製手段,例如,常壓下或減壓下的蒸餾、使用矽膠或矽酸鎂的高速液體層析法、薄層層析法、離子交換樹脂,去污樹脂或管柱層析法或清洗、再結晶等方法而精製。精製可在各反應中實施,或在完成數個反應後實施。
[毒性]
本發明化合物的毒性低,所以可作為醫藥品而安全使用。
[使用於醫藥品]
本發明的課題是創製對EP4呈現強力的拮抗活性,有良好的藥物動力學性質的化合物,找出對起因於EP4受體的活性化的疾病有用的預防及/或治療藥的化合物。
本發明化合物是對EP4受體呈現拮抗活性,
所以對起因於EP4受體的活性化的疾病有用,例如,骨疾病、癌、全身性肉芽腫、免疫疾病、過敏症性疾病、氣喘、齒槽膿漏、牙肉炎、牙周病、阿茲海默症、川崎病、熱傷、多臟器功能不全、慢性頭痛、疼痛、血管炎、靜脈功能不全、靜脈瘤、動脈瘤、大動脈瘤、痔瘡、尿崩症、壓力、子宮內膜症、子宮腺筋症、新生兒開放性動脈導管症、膽石症等的預防及/或治療劑。
更具體而言,骨疾病是例如,可舉骨疏鬆症、類風濕性關節炎、變形性關節症、骨形成異常等。癌是例如,可舉乳癌、卵巢癌、大腸癌(例如,結腸癌等)、肺癌(例如,非小細胞肺癌等)、前列腺癌、頭頸部癌(例如,口腔扁平上皮癌、頭頸部扁平上皮癌、咽頭癌、喉頭癌、舌癌、甲狀腺癌、聴神經鞘腫等)、淋巴腫(例如,B細胞淋巴腫、T細胞淋巴腫等)、葡萄膜惡性黑色瘤、胸腺瘤、間皮瘤、食道癌、胃癌、十二指腸癌、肝細胞癌、膽管癌、膽囊癌、胰臟癌、腎細胞癌、腎盂/尿管癌、膀胱癌、陰莖癌、睪丸癌、子宮癌、陰道癌、外陰癌、皮膚癌(例如,惡性黑色腫等)、惡性骨腫瘤、軟組織肉瘤、軟骨肉瘤、白血病(例如,急性骨髓性白血病、急性淋巴性白血病、慢性骨髓性白血病、慢性淋巴性白血病等)、骨髓異形成症候群、或多發性骨髓腫等。免疫疾病是例如,可舉肌萎縮性側索硬化症(ALS)、多發性硬化症、修格蘭氏症候群(Sjogren’s syndrome)、全身性紅斑性狼瘡(SLE;systemic lupus erythematosus)、AIDS等。過敏症性疾病是例如,可舉過
敏症性結膜炎、過敏症性鼻炎、接觸性皮膚炎、乾癬等。慢性頭痛是例如,可舉偏頭痛、緊張型頭痛或該等的混合型頭痛、或群發性頭痛等。
本發明化合物可為了:
1)該化合物的預防及/或治療效果的補全及/或增強,
2)該化合物的動態/吸收改善,投與量的減低,及/或
3)該化合物的副作用的減輕而與其他的藥劑組合,作為併用劑而投與。
本發明化合物與其他的藥劑的併用劑可為於1種製劑中調配兩種成分的調配劑的形態投與,或為採取個別的製劑而投與的形態。該做為個別的製劑而投與時,包括同時投與及不同時投與。又,不同時投與可為將本發明化合物先投與,將其他的藥劑後投與;亦可為其他的藥劑先投與,而將本發明化合物後投與。分別的投與方法可以是相同或不相同。
藉由上述併用劑,可以奏效的預防及/或治療的疾病並無特別的限定,只要是本發明化合物的預防及/或治療效果能補全及/或增強的疾病即可。
用於本發明化合物的對大動脈瘤的預防及/或治療效果的補全及/或增強的其他的藥劑而言,例如,可舉HMG-CoA還原酶抑制劑、降壓劑、及四環素系抗生物質等。
HMG-CoA還原酶抑制劑而言,例如,可舉帕伐他丁(鈉)(pravastatin sodium)、辛伐他汀(simvastatin)、
氟伐地汀(鈉)(fluvastatin sodium)、西立伐他汀(鈉)(cerivastatin sodium)、伊伐他汀(itavastatin)、阿托伐他汀(鈣水合物)(atorvastantin calcium)、洛伐他汀(lovastantin),匹伐他汀鈣(pitavastantin calcium)等。
降壓劑而言,例如,可舉鈣拮抗藥、血管收縮素II(angiotensin II)拮抗藥、血管收縮素轉換酶抑制藥、磷酸二酯酶4抑制藥、利尿藥、前列腺素類、醛固酮拮抗藥、交感神經抑制藥等。
鈣拮抗藥而言,例如,可舉硝苯地平(nifedipine)、鹽酸貝尼地平(benidipine hydrochloride)、鹽酸迪太贊(diltiazem hydrochloride)、鹽酸唯律脈必利(verapamil hydrochloride)、尼索地平(nisoldipine)、尼群地平(nitrendipine)、鹽酸芐普地爾(bepridil hydrochloride)、苯磺酸氨氯地平(amlodipine besilate)、鹽酸洛美利(lomerizine hydrochloride)、鹽酸依福地平(efonidipine hydrochloride)等。
血管收縮素II拮抗藥而言,例如,可舉氯沙坦鉀(losartan potassium)、甘地沙坦(candesartan(西列迪cilexetil))、纈沙坦(valsartan)、厄貝沙坦(irbesartan)、奧美沙坦酯(olmesartan medoxomil)、替米沙坦(telmisartan)等。
血管收縮素轉換酶抑制藥而言,例如,可舉阿拉普利(alacepril)、鹽酸咪唑普利(imidapril hydrochloride)、鹽酸喹那普利(quinapril hydrochloride)、鹽酸替莫普利(temocapril hydrochloride)、鹽酸地拉普利
(delapril hydrochloride)、鹽酸貝那普利(benazepril hydrochloride)、卡特普(captopril)、泉多普利(trandolapril)、培林哚普利(perindopril)、埃魯補命(Erbumine)、馬來酸依那普利(enalapril maleate)、賴諾普利(Lisinopril)等。
磷酸二酯酶4抑制藥而言,例如,可舉西洛司特(cilomilast)、羅氟司特(roflumilast)、阿羅茶堿(arofylline)、阿替佐姆(atizoram)、西潘茶堿(cipamfylline)、咯利普蘭(rolipram)等。
利尿藥而言,例如,可舉乙酰唑胺(acetazolamide)、阿米諾惠寧(aminophylline)、異山梨酯(isosorbide)、二氯苯磺胺(dichlorphenamide)、螺環固醇內酮(spironolactone)、三氯噻(trichlormethiazide)、服樂泄麥(furosemide)、甘露糖醇、甲醋唑胺(methazolamide)、美夫西特(mefruside)等。
醛固酮拮抗藥而言,例如,可舉屈螺酮(drospirenone)、甲吡酮(metyrapone)、坎利酸鉀(potassium canrenoate)、刊利酮(canrenone)、依普利酮(eplerenone)等。
四環素系抗生物質而言,例如,可舉多西環素(doxycycline)等。
用於作為本發明化合物對癌的預防及/或治療效果的補全及/或增強的其他的藥劑而言,例如,可舉烷基化劑、代謝拮抗劑、抗癌性抗生物質、植物性製劑、荷爾蒙劑、鉑化合物、拓樸異構酶抑制劑、激酶抑制劑、抗CD20抗體、抗HER2抗體、抗EGFR抗體、抗VEGF抗
體、蛋白酶體抑制劑、HDAC抑制劑、及免疫調整藥等。
烷基化劑而言,例如,可舉環磷醯胺(cyclophosphamide)、依弗醯胺(ifosfamide)、達卡巴仁(dacarbazine)、帝盟多(temozolomide)、鹽酸尼莫司汀(nimustine hydrochloride)、雷莫司汀(ranimustine)、苯達莫司汀(bendamustine)、硫替派(thiotepa)、及卡巴醌(carboquone)等。
代謝拮抗劑而言,例如,可舉甲胺喋呤(methotrexate)、培美曲塞(pemetrexed)、氟尿嘧啶(fluorouracil)、替加氟(tegafur)、特復拉西(tegafur‧uracil)、替加氟(tegafur)‧吉美司特(gimestat)‧奧替拉西鉀(Potassium otastat)、去氧氟尿苷(doxifluridine)、卡培他濱(capecitabine)、阿糖胞苷(cytarabine)(=胞嘧啶阿拉伯醣(cytosine arabinoside))、鹽酸吉西他濱(gemcitabine hydrochloride)、氟達拉濱(fludarabine)、奈拉濱(nelarabine)、卡莫氟(carmofur)、及鹽酸丙卡巴肼(procarbazine hydrochloride)等。
抗癌性抗生物質而言,例如,可舉絲裂霉素C(mitomycin C)、鹽酸多柔比星(doxorubicin hydrochloride)、鹽酸阿柔比星(aclarubicin Hydrochloride)、鹽酸吡柔比星(pirarubicin hydrochloride)、表柔比星(epirubicin)、色霉素A3(chromomycin A3)、博萊霉素(bleomycin)、硫酸培來霉素(peplomycin sulfate)、及吡柔比星(pirarubicin)等。
植物性製劑而言,例如,可舉鹽酸伊立替康(irinotecan hydrochloride)、依託泊西(etoposide)、硫酸長春新堿(vincristine)、硫酸長春堿(vinblastine sulfate)、硫酸長春地辛(vindesine sulfate)、重酒石酸長春瑞濱(vinorelbine tartrate)、多烯紫杉醇水合物(docetaxel hydrate)、甲磺酸艾日布林(eribulin mesylate)、及太平洋紫杉醇(paclitaxel)等。
荷爾蒙劑而言,例如,可舉雌莫司汀磷酸鈉(estramustine phosphate sodium)、氟他胺(flutamide)、白卡羅他邁(bicalutamide)、醋酸戈舍瑞林(goserelin acetate)、醋酸亮丙瑞林(leuprorelin acetate)、檸檬酸他莫昔芬(tamoxifen citrate)、檸檬酸托瑞米芬(toremifene citrate)、阿那曲唑(anastrozole)、來曲唑(letrozole)、依西美坦(exemestane)、美雄烷(mepitiostane)、醋酸甲羥孕酮(medroxyprogesterone acetate)、環硫雄醇(epitiostanol)、磷雌酚(fosfestrol)、鹽酸法羅唑啉(fadrozole hydrochloride)水合物、阿比特龍(abiraterone)、氟維司群(fulvestrant)、及氨魯米特(aminoglutethimide)等。
鉑化合物而言,例如,可舉剋鉑停(carboplatin)、順鉑(cisplatin)、奈達鉑(nedaplatin)、及草酸鉑(oxaliplatin)等。
拓樸異構酶抑制劑的例而言,例如,癌康定(topotecan)及索布佐生(sobuzoxane)等。
激酶抑制劑而言,例如,可舉EGFR抑制劑
厄洛替尼(erlotinib)、吉非替尼(gefitinib)、阿法替尼(afatinib)、HER2抑制劑拉帕替尼(lapatinib)、BCR-ABL抑制劑伊馬替尼(imatinib)、ALK抑制劑克唑替尼(crizotinib)、多種激酶抑制劑瑞戈非尼(regorafenib)、及達沙替尼(dasatinib)等。
抗CD20抗體而言,例如,可舉利妥昔單抗(rituximab)、異貝莫(ibritumomab)、替伊莫單抗(ibritumomab tiuxetan)、及ocrelizumab等。
抗HER2抗體而言,例如,可舉曲妥珠單抗(trastuzumab)、賀癌寧(trastuzumab emtansine)、及帕妥珠單抗(pertuzumab)等。
抗EGFR抗體而言,例如,可舉西妥昔單抗(cetuximab)及帕尼單抗(panitumumab)等。
抗VEGF抗體而言,例如,可舉貝伐單抗(bevacizumab)等。
蛋白酶體抑制劑而言,例如,可舉硼替佐米(bortezomib)等。
HDAC抑制劑而言,例如,可舉伏立諾他(vorinostat)等。
免疫調整藥而言,例如,可舉沙利度胺(thalidomide)、來那度胺(lenalidomide)、及泊馬度胺(pomalidomide)等。
用於作為本發明化合物對疼痛的預防及/或治療效果的補全及/或增強的其他的藥劑而言,例如,可舉
N型鈣通道阻斷劑、一氧化氮合成酶(NOS)抑制劑、及大麻素-2受體促效劑等。
N型鈣通道阻斷劑而言,例如,可舉西尼地平(cilnidipine)等。
一氧化氮合成酶(NOS)抑制劑而言,例如,可舉D-精胺酸及NG-單甲基-L-精胺酸等。
本發明化合物與其他的藥劑的質量比是沒有特別的限定。
其他的藥劑亦可組合任意的2種以上而投與也可以。
又,用於作為將本發明化合物的預防及/或治療效果補全及/或增強的其他的藥劑是根據上述的機制,不僅是到現在為止被發現的藥劑,也包含今後將被發現的藥劑。
將本發明化合物作為單劑,或將本發明化合物與其他的藥劑組合作為併用劑,而用於上述的疾病的預防及/或治療的目的時,將有效成分的該物質,通常,與各種的添加劑或溶媒等的藥學上可容許的載劑一起製劑化之後,以全身或局部,經口或非經口的形式投與。此處,藥學上可容許的載劑就是指一般在醫藥品的製劑所用的,有效成分以外的物質。藥學上可容許的載劑是以在製劑的投與量中沒有藥理作用、無害、不抑制有效成分的治療效果為理想。又,藥學上可容許的載劑是提高有效成分及製劑的有用性、容易製劑化、謀圖品質的安定化、或提高使
用性等之目的而使用。具體而言,將在藥事日報社2000年刊「醫藥品添加物事典」(日本醫藥品添加劑協會編集)等所述的物質,適當地視目的而選出即可。
用於投與的劑型而言,例如,可舉經口投與用製劑(例:片劑、膠囊劑、顆粒劑、散劑、經口液劑、糖漿劑、經口膠凍劑等)、口腔用製劑(例:口腔用片劑、口腔用噴霧劑、口腔用半固形劑、漱口劑等)、注射用製劑(例:注射劑等)、透析用製劑(例:透析用劑等)、吸入用製劑(例:吸入劑等)、眼科用製劑(例:點眼劑、眼軟膏劑等)、耳科用製劑(例:點耳劑等)、鼻科用製劑(例:點鼻劑等)、直腸用製劑(例:栓劑、直腸用半固形劑、腸注劑等)、陰道用製劑(例:陰道片、陰道用栓劑等)、及皮膚用製劑(例:外用固形劑、外用液劑、噴霧劑、軟膏劑、霜劑、凝膠劑、貼膏劑等)等。
[經口投與用製劑]
經口投與用製劑是包含例如,片劑、膠囊劑、顆粒劑、散劑、經口液劑、糖漿劑、經口膠凍劑等。又,經口投與用製劑是製劑有效成分的釋放性未特別調節的速崩性製劑,及藉由固有的製劑設計及製法配合目的而調節釋放性者,例如,腸溶性製劑及緩釋性製劑等的釋放調節製劑。腸溶性製劑是指防止有效成分在胃內分解,或減低有效成分對胃的刺激作用等之目的,設計成使有效成分不在胃內釋放,而主要在小腸內釋放的製劑,通常是使用酸不溶性的腸溶性基劑施加皮膜而製造。緩釋性製劑是
指謀圖投與次數的減少或副作用的減低等之目的,而調節有效成分由製劑釋放的速度、釋放時間、釋放部位的製劑,通常是使用合適的緩釋化劑而可製造。經口投與用製劑中,膠囊劑、顆粒劑、片劑等為了使服用容易,或防止有效成分的分解之目的,也可使用糖類或糖醇類,高分子化合物等合適的被覆劑加施劑皮也可以。
(1)片劑
片劑是經口投與,具有一定形狀的固形製劑,包括素片、膜衣片、糖衣片、多層片、有核片等的一般稱為片劑之外,亦包含口腔內速崩片、咀嚼片、發泡片、分散片、溶解片等。在製造素片時,通常是使用下述的(a)、(b)、或(c)的手法:
(a)在有效成分中添加賦形劑、黏合劑、崩壞劑等的添加劑而混合成均質後,使用水或含有黏合劑的溶液而以合適的方法形成粒狀後,添加滑澤劑等而混合,加以壓縮成形;
(b)在有效成分中添加賦形劑、黏合劑、崩壞劑等的添加劑而混合成均質後,直接壓縮成形,或在預先以添加劑製得的顆粒中添加有效成分及滑澤劑等而混合成為均質後,壓縮成形;
(c)在有效成分中添加賦形劑、黏合劑等的添加劑而混合成均質,將以溶媒潤濕的揉合物倒入於一定的模中成形後,以合適的方法乾燥。
膜衣片通常是對素片以高分子化合物等的
合適的被覆劑加施薄的劑皮而可製造。糖衣片通常是對素片以含有糖類或糖醇的被覆劑加施劑皮而可製造。多層片是以合適的方法,將不同組成的粉粒體堆積成層狀,壓縮成形而可製造。有核片是將內核片以不同組成的外層被覆而可製造。又,片劑是也可使用公知的合適的手法而成為腸溶片或緩釋片。口腔內速崩片、咀嚼片、發泡片、分散片、及溶解片是藉由添加劑的合適的選擇而對片劑賦予獨特機能的片劑,可遵照前述片劑的製造手法而可製造。又,口腔內速崩片就是在口腔內迅速溶解或崩壞而可服用的片劑;咀嚼片就是咀嚼而服用的片劑;發泡片就是在水中急速發泡而溶解或分散的片劑;分散片就是在水中分散而服用的片劑;溶解片就是以水溶解而服用的片劑。發泡片是使用合適的酸性物質、碳酸鹽、碳酸氫鹽等作為添加劑而可製造。
(2)膠囊劑
膠囊劑是包含充填於膠囊或以膠囊基劑包裹成形的製劑,包含硬膠囊劑、軟膠囊劑等。硬膠囊劑是在有效成分中添加賦形劑等的添加劑而混合成均質,或以合適的方法成為粒狀或成形物,以原狀或輕微成形後充填於膠囊中而可製造。軟膠囊劑是將在有效成分中添加添加劑者,以添加甘油,D-山梨醇等而增加塑性的明膠等的合適的膠囊基劑,包裹成一定的形狀而可製造。膠囊劑是使用公知的合適的手法而成為腸溶性膠囊劑或緩釋性膠囊劑,或也可在膠囊基劑中添加著色劑或保存劑等。
(3)顆粒劑
顆粒劑是造粒成為粒狀的製劑,除一般稱為顆粒劑的粒劑之外,也包含發泡性顆粒劑等。製造顆粒劑時是通常,使用下述的(a)、(b)、或(c)的手法:
(a)在粉末狀的有效成分中添加賦形劑,黏合劑,崩壞劑,或其他的添加劑而混合成均質後,以合適的方法製成粒狀;
(b)在預先製成粒狀的有效成分中添加賦形劑等的添加劑而混合,成為均質;
(c)在預先製成粒狀的有效成分中添加賦形劑等的添加劑而混合,以合適的方法製成粒狀。
顆粒劑是視必要而可加施劑皮,或,也可使用公知的合適的手法製成腸溶性顆粒劑或緩釋性顆粒劑。
發泡顆粒劑是使用合適的酸性物質、碳酸鹽、碳酸氫鹽等作為添加劑而可製造。又,發泡顆粒劑就是指在水中迅速發泡而溶解或分散的顆粒劑。顆粒劑是藉由調節粒子大小,也可製成細粒劑。
(4)散劑
散劑是粉末狀的製劑,通常是在有效成分中添加賦形劑或其他的添加劑而混合成均質而可製造。
(5)經口液劑
經口液劑是液狀或有流動性的黏稠的凝膠狀的製劑,一般除稱為經口液劑者之外,亦包含酏劑、懸劑、乳劑、檸檬劑等。經口液劑是通常,在有效成分中添
加添加劑及精製水,混合溶解成均質,或乳化或懸浮,視必要過濾而可製造。酏劑就是有甘味及芳香的含有乙醇的清澄的液狀的經口液劑,通常,在固形的有效成分或其浸出液中,添加乙醇、精製水、著香劑、及白糖、其他的糖類、或甘味劑使溶解,並以過濾或其他的方法成為清澄的液而可製造。懸劑就是指將有效成分懸浮成微細均質的經口液劑,通常,在固形的有效成分中添加懸浮化劑或其他的添加劑及精製水或油,以合適的方法懸浮,使全體成均質而可製造。乳劑就是指將有效成分乳化成微細均質的經口液劑,通常,在液狀的有效成分中添加乳化劑及精製水,以合適的方法乳化,使全體成為均質而可製造。又,檸檬劑(lemonade)就是指有甘味及酸味的清澄的液狀的經口液劑。
(6)糖漿劑
糖漿劑是含有糖類或甘味劑的黏稠性的液狀或固形的製劑,包含糖漿用劑等。糖漿劑是通常,在白糖、其他的糖類、或甘味劑的溶液,或單糖漿中添加有效成分而溶解、混合、懸浮、或乳化,視必要將混液煮沸後,趁熱時過濾而可製造。糖漿用劑就是添加水就可成為糖漿劑的顆粒狀或粉末狀的製劑,也有時稱為乾糖漿劑。糖漿用劑是通常,以糖類或甘味劑作為添加劑而使用,遵照前述顆粒劑或散劑的製造手法而可製造。
(7)經口膠凍劑
經口膠凍劑是沒有流動性的成形的凝膠狀
的製劑,通常,在有效成分中添加添加劑及高分子凝膠基劑而混合,以合適的方法凝膠化成形為一定的形狀而可製造。
[口腔用製劑]
(1)口腔用片劑
口腔用片劑是施用於口腔內的一定形狀的固形的製劑,包含喉片劑、舌下含服片、口頰片、附著片、嚼劑等。口腔用片劑是通常,遵照前述片劑的製造手法而可製造。又,喉片劑就是在口腔內緩緩溶解或崩壞,在口腔、咽頭等的局部施用的口腔用片劑;舌下含服片就是將有效成分在舌下迅速溶解,由口腔黏膜吸收的口腔用片劑;口頰片就是將有效成分在臼齒與頬之間緩緩溶解,由口腔黏膜吸收的口腔用片劑;附著片就是在口腔黏膜附著而使用的口腔用片劑;嚼劑就是由咀嚼而釋放有效成分的口腔用片劑。
(2)口腔用噴霧劑
口腔用噴霧劑是使有效成分成霧狀、粉末狀、泡沫狀、或糊狀等而噴霧的製劑,通常,在溶劑等中將有效成分及添加劑溶解或懸浮,視必要過濾後,與液化氣體或壓縮氣體一起充填於容器,或,使用有效成分及添加劑調製溶液或懸浮液,充填於容器後,裝配噴霧用幫浦而可製造。
(3)口腔用半固形劑
口腔用半固形劑是包含施用於口腔黏膜的
製劑、霜劑、凝膠劑、軟膏劑等。口腔用半固形劑是通常,將有效成分與添加劑一起以精製水及凡士林等的油性成分乳化,或以高分子凝膠或油脂作為基劑而與有效成分及添加劑一起混合成均質而可製造。霜劑就是乳化成水中油型或油中水型的半固形的製劑,乳化成油中水型的親油性的製劑有時也稱為油性霜劑。霜劑是通常,將凡士林、高級醇等以原狀,或添加乳化劑等的添加劑成為油相,另外,將精製水以原狀,或添加乳化劑等的添加劑而成為水相,在其任一者中添加有效成分,分別加溫,油相及水相合併攪拌至全體乳化成為均質而可製造。凝膠劑就是凝膠狀的製劑,包含水性凝膠劑、油性凝膠劑等。水性凝膠劑是在有效成分中添加高分子化合物、其他的添加劑及精製水而溶解或懸浮、加溫及冷卻,或添加凝膠化劑使橋聯而可製造。油性凝膠劑是在有效成分中添加二醇類、高級醇等的液狀的油性基劑及其他的添加劑並混合而可製造。軟膏劑就是將有效成分在基劑溶解或分散的半固形的製劑,包含油脂性軟膏劑、水溶性軟膏劑等。油脂性軟膏劑是通常,將油脂類、蠟類、石蠟等的烴類等的油脂性基劑加溫融解,添加有效成分,混合溶解或分散,捏揉至全體成均質而可製造。水溶性軟膏劑是通常,將Macrogol(聚乙二醇)等的水溶性基劑加溫融解,添加有效成分,捏揉至全體成均質而可製造。
(4)漱口劑
漱口劑是施用於口腔,咽頭等的局部的液
狀的製劑,也包含用時溶解而使用的固形的製劑等。漱口劑是通常,在有效成分中添加溶劑及添加劑而混合溶解成均質,視必要過濾而可製造。用時溶解而使用的固形的製劑的情況是通常,遵照前述片劑或顆粒劑等的製造手法而可製造。
[注射用製劑]
(1)注射劑
注射劑是在皮下、肌肉內、或血管等的體內組織或器官直接投與的溶液、懸浮液,或乳液,或使用時溶解或使用時懸浮而使用的固形的無菌製劑,通常除稱為注射劑的製劑之外,亦包含凍結乾燥注射劑、粉末注射劑、預充填式劑、匣式劑、輸液劑、埋入注射劑、及持續性注射劑等。製造注射劑時,通常,使用下述的(a)或(b)的手法:
(a)將有效成分以原狀,或在有效成分中添加添加劑者以注射用水、其他的水性溶劑、或非水性溶劑等溶解、懸浮、或乳化成均質,充填於注射劑用的容器並密封、滅菌;
(b)將有效成分以原狀,或在有效成分中添加添加劑者,以注射用水、其他的水性溶劑、或非水性溶劑等溶解、懸浮、或乳化成為均質並無菌過濾,或在無菌下調製成為均質,充填於注射劑用的容器並密封。
凍結乾燥注射劑是通常,將有效成分以原狀,或將有效成分及賦形劑等的添加劑溶解於注射用水,無菌過濾,充填於注射劑用的容器後冷凍乾燥,或以專用
容器冷凍乾燥後直接充填於容器而可製造。粉末注射劑是通常,在無菌過濾處理後,在經晶析而得的粉末或在該粉末中添加滅菌處理過的添加劑並充填於注射劑用的容器而可製造。預充填式劑是通常,將有效成分以原狀,或使用有效成分及添加劑調製溶液、懸浮液、或乳液再充填於注射筒而可製造。匣式劑就是指將充填藥液的匣裝入於專用的注射器而使用的注射劑,充填藥液的匣是通常,有效成分以原狀,或使用有效成分及添加劑調製溶液、懸浮液、或乳液並充填於匣而可製造。輸液劑就是指在靜脈內投與的通常100mL以上的注射劑。埋入注射劑就是以長期間釋放有效成分為目的,而在皮下、肌肉內等使用埋入用的器具,或以手術施用的固形或凝膠狀的注射劑。埋入注射劑是通常,使用生物分解性高分子化合物,藉由使成為顆粒狀,微小球狀,或凝膠狀而可製造。持續性注射劑就是以長期間釋放有效成分作為目的,在肌肉內等施用的注射劑,通常,將有效成分溶解或懸浮於植物油等,或藉由作成使用生物分解性高分子化合物的微小球狀的懸浮液而可製造。
[透析用製劑]
(1)透析用劑
透析用劑是使用於腹膜透析或血液透析的液狀或在使用時溶解的固形的製劑,包含腹膜透析用劑、血液透析用劑。腹膜透析用劑就是指用於腹膜透析的無菌的透析用劑,通常,在有效成分中添加添加劑,溶解於溶
劑成為一定容量,或在有效成分中添加添加劑並充填於容器,密封,視必要加以滅菌處理而可製造。使用時溶解的固形的製劑的情況是通常,遵照前述片劑或顆粒劑等的製造手法而可製造。血液透析用劑就是指用於血液透析的透析用劑,通常,在有效成分中添加添加劑,溶解於溶劑成為一定容量,或在有效成分中添加添加劑再充填於容器而可製造。使用時溶解的固形的製劑的情況是通常,遵照前述片劑或顆粒劑等的製造手法而可製造。
[吸入用製劑]
(1)吸入劑
吸入劑是使有效成分成為氣霧劑而吸入,而施用於支氣管或肺的製劑,包含粉末吸入劑、吸入液劑、吸入氣霧劑等。粉末吸入劑就是將調製成為吸入量為一定的,固體粒子的氣霧劑而吸入的製劑,通常,將有效成分製成微細粒子,視必要與乳糖等的添加劑混合成為均質而可製造。吸入液劑就是指以霧化器等而施用的液狀的吸入劑,通常,在有效成分中添加溶劑及合適的等張化劑,pH調節劑等,混合而溶解或懸浮成為均質,視必要過濾而可製造。吸入氣霧劑就是與充填於容器的噴射劑一起,將一定量的有效成分噴霧的定量噴霧式吸入劑。吸入氣霧劑是通常,在有效成分中添加溶劑及合適的分散劑、安定化劑等,製成溶液或懸浮液,與液狀的噴射劑一起充填於耐壓性的容器,裝配定量閥而可製造。
[眼科用製劑]
(1)點眼劑
點眼劑是施用於結膜囊等的眼組織的,液狀,或用時溶解或用時懸浮而使用的固形的無菌製劑。點眼劑是通常,在有效成分中添加添加劑,溶解或懸浮於溶劑等而成為一定容量,或在有效成分中添加添加劑再充填於容器而可製造。
(2)眼軟膏劑
眼軟膏劑是施用於結膜囊等的眼組織的半固形的無菌製劑,通常,將凡士林等的基劑與有效成分的溶液或微細粉末混合成為均質,充填於容器而可製造。
[耳科用製劑]
(1)點耳劑
點耳劑是在外耳或中耳投與的,液狀、半固形、或用時溶解或用時懸浮而使用的固形的製劑。點耳劑是通常,在有效成分中添加添加劑,溶解或懸浮溶劑等並使成為一定容量,或在有效成分中添加添加劑再充填容器而可製造。
[鼻科用製劑]
(1)點鼻劑
點鼻劑是在鼻腔或鼻黏膜投與的製劑,包含點鼻粉末劑、點鼻液劑等。點鼻粉末劑就是指在鼻腔投與的微粉狀的點鼻劑,通常,將有效成分製成適度的微細粒子,視必要與添加劑混合成為均質而可製造。點鼻液劑就是指在鼻腔投與的液狀,或用時溶解或用時懸浮而使用
的固形的點鼻劑,通常,在有效成分中添加溶劑及添加劑等,溶解或懸浮,視必要過濾而可製造。點鼻液劑的添加劑而言,可使用等張化劑,pH調節劑等。
[直腸用製劑]
(1)栓劑
栓劑是在直腸內施用的,由體溫融化,或緩緩溶解或分散於水而釋放有效成分的一定形狀的半固形的製劑。栓劑是通常,在有效成分中添加分散劑、乳化劑等的添加劑混合成為均勻,在加熱等而液狀化的基劑中溶解或分散均勻,將一定量充填容器,固化/成形而可製造。栓劑的基劑而言,通常,使用油脂性基劑或親水性基劑。
(2)直腸用半固形劑
直腸用半固形劑是在肛門周圍或肛門內施用的製劑,包含直腸用霜劑,直腸用凝膠劑,直腸用軟膏劑等。直腸用半固形劑是通常,將有效成分與添加劑一起以精製水及凡士林等的油性成分乳化,或將高分子凝膠或油脂作為基劑而與有效成分及添加劑一起混合成為均質而可製造。直腸用霜劑是通常,將凡士林,高級醇等以原狀,或添加乳化劑等的添加劑製成油相,另外,將精製水以原狀,或添加乳化劑等的添加劑而製成水相,在其任一相中添加有效成分,分別加溫,將油相及水相合併攪拌將全體乳化成為均質而可製造。直腸用凝膠劑就是指凝膠狀的製劑,包含水性凝膠劑、油性凝膠劑等。水性凝膠劑是在有效成分中添加高分子化合物,其他的添加劑及精製水而溶
解或懸浮、加溫及冷卻,或添加凝膠化劑橋聯而可製造。油性凝膠劑是有效成分中添加乙二醇類、高級醇等的液狀的油性基劑及其他的添加劑並混合而可製造。直腸用軟膏劑就是指將有效成分溶解或分散於基劑的半固形的製劑,包含油脂性軟膏劑、水溶性軟膏劑等。油脂性軟膏劑是通常,將油脂類、蠟類、石蠟等的烴類等的油脂性基劑加溫融化,添加有效成分,混合而溶解或分散,將全體捏揉成為均質而可製造。水溶性軟膏劑是通常,將Macrogol等的水溶性基劑加溫融化,添加有效成分,將全體捏揉成為均質而可製造。
(3)注腸劑
腸注劑是通過肛門施用的液狀或黏稠的凝膠狀的製劑,通常,使用精製水或合適的水性溶劑,將有效成分在溶劑等中溶解或懸浮成一定容量,充填於容器而可製造。腸注劑的添加劑而言,可使用分散劑、安定化劑、pH調節劑等。
[陰道用製劑]
(1)陰道片
陰道片是施用於陰道的,在水中緩緩溶解或分散而釋放有效成分的一定形狀的固形製劑,通常,遵照前述片劑的製造手法而可製造。
(2)陰道用栓劑
陰道用栓劑是施用於陰道的,由體溫融化,或在水中緩緩溶解或分散而釋放有效成分的一定的形狀的
半固形製劑,通常,遵照前述直腸用栓劑等的製造手法而可製造。
[皮膚用製劑]
(1)外用固形劑
外用固形劑是對包括頭皮的皮膚或爪,塗布或散布的固形的製劑,包含外用散劑等。外用散劑就是指粉末狀的外用固形劑,通常,在有效成分中添加賦形劑等的添加劑混合成均質後,製成粉末狀而可製造。
(2)外用液劑
外用液劑是塗布在包括頭皮的皮膚或爪的液狀的製劑,包含塗敷劑(liniment)、外用藥水(lotion)等。外用液劑是通常,在有效成分中添加溶劑、添加劑等,溶解、乳化、或懸浮,視必要過濾而可製造。塗敷劑就是擦入於皮膚用的液狀或泥狀的外用液劑。外用藥水就是將有效成分溶解於水性液或乳化或微細分散的外用液劑,通常,使用有效成分、添加劑、及精製水,製成溶液、懸浮液、或乳液,並使全體成為均質而可製造。
(3)噴霧劑
噴霧劑是使有效成分成為霧狀、粉末狀、泡沫狀、或糊狀等而在皮膚上噴霧的製劑,包含外用氣霧劑、幫浦噴霧劑等。噴霧劑是通常,調製有效成分的溶液或懸浮液,並視必要過濾後,充填於容器而可製造。外用氣霧劑就是指將容器充填的液化氣體或壓縮氣體與有效成分一起噴霧的噴霧劑。外用氣霧劑是通常,調製有效成分的溶
液或懸浮液,並將液狀的噴射劑一起充填於耐壓性的容器,裝配連續噴射閥而可製造。外用氣霧劑是視必要,也可添加分散劑、安定化劑等的添加劑。幫浦噴霧劑就是指以幫浦將容器內的有效成分噴霧的噴霧劑。幫浦噴霧劑是通常,將有效成分及添加劑溶解或懸浮,並在充填後的容器裝配幫浦而可製造。
(4)軟膏劑
軟膏劑是在皮膚塗布的,將有效成分在基劑中溶解或分散的半固形的製劑,包含油脂性軟膏劑、水溶性軟膏劑等。油脂性軟膏劑是通常,將油脂類、蠟類、石蠟等的烴類等的油脂性基劑加溫融化,添加有效成分,混合溶解或分散,捏揉全體成均質而可製造。水溶性軟膏劑是通常,將Macrogol等的水溶性基劑加溫融化,添加有效成分,捏揉全體成均質而可製造。
(5)霜劑
霜劑是在皮膚塗布的,乳化成水中油型或油中水型的半固形的製劑,乳化成油中水型的親油性的製劑則有時稱為油性霜劑。霜劑是通常,將凡士林、高級醇等以原狀,或添加乳化劑等的添加劑製成油相,另外,將精製水以原狀,或添加乳化劑等的添加劑製成水相,在其任一相中添加有效成分,分別加溫,合併油相及水相攪拌全體乳化成均質而可製造。
(6)凝膠劑
凝膠劑是在皮膚塗布的凝膠狀的製劑,包
含水性凝膠劑,油性凝膠劑等。水性凝膠劑是在有效成分中添加高分子化合物、其他的添加劑及精製水使溶解或懸浮、加溫及冷卻,或添加凝膠化劑使橋聯而可製造。油性凝膠劑是在有效成分中添加二醇類、高級醇等的液狀的油性基劑及其他的添加劑混合而可製造。
(7)貼膏劑
貼膏劑是在皮膚貼附的製劑,包含橡膠膏劑(tape)、巴布貼劑(poultis)等。貼膏劑是通常,將高分子化合物或該等的混合物作為基劑,將有效成分與基劑混合成均質,在支持體或襯墊(剝離體)上展延成形而可製造。又,也可使用釋放調節膜製成經皮吸收型製劑。貼膏劑是視必要,也可使用黏著劑或吸收促進劑等的添加劑。橡膠膏劑就是使用幾乎不含水的基劑的貼膏劑,包含石膏劑,硬膏劑等。橡膠膏劑是通常,將樹脂、塑膠、橡膠等的非水溶性的天然或合成高分子化合物作為基劑,將有效成分以原狀,或在有效成分中添加添加劑,全體製成均質,在布上展延或塑膠製膜等展延或封入成形而可製造。又,也可以將有效成分及基劑或其他的添加劑所成的混合物封入於釋放調節膜、支持體及襯墊(剝離體)所成的釋放體成形而製造。巴布貼劑就是指使用含水的基劑的貼膏劑,通常是將有效成分與精製水、甘油等的液狀的物質混合,全體製成均質,或將水溶性高分子、吸水性高分子等的天然或合成高分子化合物與精製水混合捏揉,添加有效成分,全體製成均質,在布等展延成形而可製造。
如沒有其他的定義,本說明書中使用的全部的技術的,科學的用語,及簡稱是具有本發明的領域所屬的本行業者一般所理解的同樣的意思。
又,在本說明書中,明白表示的所引用的全部的專利文獻及非專利文獻或參考文獻的內容是全部作為本說明書的一部分而可引用。
[實施例]
以下,以實施例詳述本發明,但本發明不受該等的限定。
藉由層析法分離之處及在TLC所示的括弧內的溶媒是表示所使用的溶出溶媒或展開溶媒,比率是表示體積比。
NMR之處所示的括弧內的溶媒是表示在測定所使用的溶媒。
本說明書中所用的化合物名是使用一般依照IUPAC的規則命名的電腦軟體程式,ACD/Name(登錄商標),或使用Chemdraw Ultra(version 12.0,Cambridge Soft社製),或依照IUPAC命名法而命名。
在氮氣流下,在溴化甲基三苯基鏻(435g)的四氫呋喃(以下,簡稱為THF)(1500mL)溶液中在冰冷下滴下雙(三甲基矽基)胺基鋰(lithium bis(trimethylsilyl)amide)的THF
(1.3mol/L,931mL)溶液後,在室溫下攪拌1小時。將4-酮(chromanone)(150g)的THF(180mL)溶液在-5℃滴下後,在室溫下攪拌1小時。在反應混合物中,冰冷下,添加飽和氯化銨水溶液後,以乙酸乙酯萃取。將所得的有機層以飽和食鹽水清洗,以無水硫酸鈉乾燥後,減壓濃縮。將所得的殘渣以矽膠管柱層析法精製,得以下物性值的標題化合物(75.9g)。
TLC:Rf 0.62(己烷:乙酸乙酯=9:1);1H-NMR(CDCl3):δ 2.59-2.75,4.18-4.31,4.89,5.51,6.79-6.94,7.12-7.20,7.56。
在氮氣流下,在參考例1製造的化合物(75.9g)的二氯甲烷(2500mL)溶液中添加二氯(對異丙基甲苯)釕(II)二聚物(dichloro p-cymene ruthenium(II)dimer,15.8g)、(S,S)-2,6-雙(4-異丙基-2-唑啉-2-基)吡啶(15.6g)。將二偶氮乙酸乙酯(含有13%二氯甲烷,134g)的二氯甲烷(150mL)溶液在室溫緩緩滴下後,攪拌1小時。在反應混合物中添加飽和氯化銨水溶液後,以二氯甲烷萃取,將所得的有機層以無水硫酸鈉乾燥後,減壓濃縮。將所得的殘渣以矽膠管柱層析法精製,得以下物性值的標題化合物(91.2g)。
1H-NMR(CDCl3):δ1.26,1.54-1.67,2.07-2.22,4.05-4.21,
4.27,6.68,6.78-6.89,7.04-7.12。
在參考例2製造的化合物(91.2g)的甲醇(400mL)及1,2-二甲氧基乙烷(400mL)溶液,添加氫氧化鋰一水合物(29.6g)的水(160mL)溶液,在室溫下攪拌一夜。在反應混合物中添加10%檸檬酸水溶液後,以乙酸乙酯萃取。將所得的有機層以飽和食鹽水清洗,以無水硫酸鈉乾燥後,減壓濃縮。將所得的殘渣以二氯甲烷再結晶,得以下物性值的標題化合物(55.2g)。
1H-NMR(CDCl3):δ1.59-1.67,1.68-1.76,2.15,2.21-2.29,4.12-4.23,4.25-4.36,6.70,6.80-6.92,7.06-7.16;HPLC保持時間:6.9分(CHIRALPAK IC 4.6mm×250mm己烷:乙酸乙酯:甲酸=97:3:1)。
在氮氣流下,在參考例3製造的化合物(40.0g)的N,N-二甲基甲醯胺(以下,簡寫為DMF)(200mL)溶液中添加碳酸鉀(28.5g)後,滴下碘甲烷(31.9g),在室溫下攪拌一夜。將反應混合物注入於冰水,以己烷-乙酸乙酯混合溶液萃
取。將所得的有機層以水、飽和食鹽水清洗,以無水硫酸鈉乾燥後,減壓濃縮,得以下物性值的標題化合物(40.1g)。
TLC:Rf 0.30(己烷:乙酸乙酯=9:1);1H-NMR(CDCl3):δ1.57-1.69,2.09-2.22,3.71,4.07-4.17,4.27,6.68,6.78-6.90,7.04-7.14。
在氮氣流下,在參考例4製造的化合物(40.1g)的甲醇(320mL)溶液在冰冷下,添加1,3-二碘-5,5-二甲基尿囊素(35.6g)、濃硫酸3滴後,在此狀態下攪拌1.5小時,在室溫下攪拌2.5小時。將反應混合物以己烷-乙酸乙酯混合溶液稀釋後,以飽和碳酸氫鈉水溶液清洗,將水層以己烷-乙酸乙酯混合溶液萃取。將所得的有機層以水、飽和食鹽水清洗,以無水硫酸鈉乾燥後,減壓濃縮,得以下物性值的標題化合物(63.8g)。
TLC:Rf 0.33(己烷:乙酸乙酯=9:1);1H-NMR(CDCl3):δ1.60,2.06-2.19,3.71,4.09,4.20-4.31,6.59,6.93,7.36。
在參考例5製造的化合物(15.0g)的甲醇(60mL)及1,2-二甲氧基乙烷(60mL)溶液,添加氫氧化鈉水溶液(2mol/L,44mL),在室溫下攪拌1.5小時。在反應混合物中添加鹽酸後,以乙酸乙酯萃取。將所得的有機層以水、飽和食鹽水清洗,以無水硫酸鈉乾燥後,減壓濃縮,得以下物性值的標題化合物(14.4g)。
TLC:Rf 0.42(二氯甲烷:甲醇=9:1);1H-NMR(CDCl3):δ1.57-1.74,2.11,2.16-2.25,4.10-4.20,4.23-4.33,6.59,6.94,7.37。
參考例7:4-(4-甲醯基-2-硝基苯基)丁酸乙酯
在氮氣流下,在鋅粉末(99.2g)的N,N-二甲基乙醯胺(以下,簡寫為DMA)(700mL)溶液中添加碘(26.0g),攪拌10分鐘。將4-溴丁酸乙酯(200g)滴下後,在80℃下攪拌2小時而調製鋅試藥。在氮氣流下,在3-硝基-4-溴苯甲醛(100g)的THF(500mL)溶液中添加2-二環己基膦基-2’,6’-二甲氧基聯苯(7.14g)、乙酸鈀(1.96g)後,在冰冷下滴下調製的鋅試藥(500mL),在室溫下攪拌30分鐘。在反應混合物中添加飽和氯化銨水溶液、添加水後,以乙酸乙酯萃取。將所得的有機層以水、飽和食鹽水清洗,以無水硫酸鈉乾燥後,減壓濃縮。將所得的殘渣以矽膠管柱層析法精製,得以下物性值的標題化合物(91.2g)。
TLC:Rf 0.61(己烷:乙酸乙酯=2:1);1H-NMR(CDCl3):δ1.27,1.97-2.09,2.42,3.01,4.15,7.57,8.04,8.38,10.03。
參考例8:4-(4-氰基-2-硝基苯基)丁酸乙酯
在參考例7製造的化合物(92.0g)的DMF(350mL)溶液中添加羥胺鹽酸鹽(26.0g),在50℃下攪拌1小時。添加乙醯氯(30mL),在90℃下攪拌2小時。在反應混合物中添加水後,以乙酸乙酯萃取。將所得的有機層以水、飽和碳酸氫鈉水溶液、飽和食鹽水清洗,以無水硫酸鈉乾燥後,減壓濃縮。將所得的殘渣以矽膠管柱層析法精製,得以下物性值的標題化合物(81.0g)。
TLC:Rf 0.65(己烷:乙酸乙酯=2:1);1H-NMR(CDCl3):δ1.27,1.92-2.10,2.37-2.45,2.91-3.06,4.15,7.55,7.81,8.21。
參考例9:4-(2-胺基-4-氰基苯基)丁酸乙酯
在參考例8製造的化合物(17.0g)的乙醇(80mL)溶液,添加鈀碳(50%濕物,8.0g),在氫環境下,在室溫下攪拌9小時。將反應混合物以矽藻土(商品名:Celite)過濾後,將濾液濃縮,得以下物性值的標題化合物(12.0g)。
TLC:Rf 0.56(己烷:乙酸乙酯=2:1);
1H-NMR(CDCl3):δ1.28,1.79-1.95,2.38-2.45,2.50-2.60,4.09-4.30,6.89,6.93-6.98,7.04-7.10。
在參考例6製造的化合物(14.4g)、及參考例9製造的化合物(10.0g)的DMA(90mL)溶液中添加4-甲基嗎福林(24.0mL)、4-二甲胺基吡啶(5.33g)、丙基膦酸酐環狀三聚物(以下,簡寫為T3P)(1.7mol/L,46.5mL),在室溫下攪拌一夜。在反應混合物中添加乙酸乙酯、水、鹽酸水溶液,以乙酸乙酯萃取。將所得的有機層以水、飽和碳酸氫鈉水溶液、飽和食鹽水清洗,以無水硫酸鈉乾燥後,減壓濃縮。將所得的殘渣以己烷-乙酸乙酯混合溶液清洗,得以下物性值的標題化合物(19.3g)。
TLC:Rf 0.42(己烷:乙酸乙酯=2:1);1H-NMR(CDCl3):δ1.20,1.61,1.66-1.79,1.83,2.18-2.28,2.39-2.49,2.60,3.66,3.90,4.00-4.12,4.26,6.58,7.05,7.15-7.22,7.26-7.31,7.33,8.72,9.39。
在參考例10製造的化合物(7.40g)的DMF(60mL)溶液中添加乙酸鈉(3.35g)、[1,1’-雙(二苯基膦基)鐵莘]二氯化鈀(II)二氯甲烷錯合物(555mg),在一氧化碳環境、80℃下攪拌6小時。在反應混合物中添加碳酸鉀水溶液,短暫攪拌後,添加三級丁基甲基醚、水,以Celite(商品名)過濾。在濾液中添加鹽酸水溶液後,以乙酸乙酯萃取。將所得的有機層以水、飽和食鹽水清洗,以無水硫酸鈉乾燥後,減壓濃縮。將所得的殘渣以矽膠管柱層析法(山善自動精製裝置)精製,得以下物性值的標題化合物(6.14g)。
TLC:Rf 0.48(二氯甲烷:乙酸乙酯:甲醇=8:4:1);1H-NMR(CDCl3):δ1.08,1.65-1.80,1.83-1.92,2.25-2.36,2.37-2.49,2.55-2.66,2.71,3.55,3.79,4.12-4.23,4.37,6.88,7.15-7.22,7.27-7.32,7.61,7.83,8.73,9.40。
代替參考例6製造的化合物而使用在參考例11製造
的化合物(60.0mg),代替參考例9製造的化合物而使用甲胺鹽酸鹽(87.5mg),實施與參考例10同樣的操作,而得以下物性值的標題化合物(53.0mg)。
1H-NMR(CDCl3):δ1.07,1.64-1.79,1.81-1.89,2.20-2.35,2.40,2.60,2.69,2.98,3.44-3.59,3.68-3.83,4.07-4.19,4.27-4.38,6.05,6.82,7.15-7.22,7.27-7.32,7.35-7.44,8.72,9.37。
使用參考例12製造的化合物(53mg),且代替甲醇而使用乙醇,實施與參考例6同樣的操作,而得有下述物性值的本發明化合物(45mg)。
TLC:Rf 0.45(二氯甲烷:甲醇=9:1);1H-NMR(CDCl3):δ1.21-1.30,1.55,1.65-1.82,2.06-2.26,2.38-2.67,2.67-2.76,3.02,3.57,4.33,4.49-4.58,6.25,6.81,7.19,7.23-7.30,7.94,8.87,9.93。
實施例2
代替甲胺鹽酸鹽,而使用相對應的胺化合物,實施與參考例12→實施例1同樣的操作,而得有以下物性值的本發明化合物。
TLC:Rf 0.45(二氯甲烷:甲醇=9:1);1H-NMR(CDCl3):δ 0.23-0.31,0.52-0.63,0.96-1.14,1.22-1.30,1.55,1.66-1.81,2.06-2.24,2.38-2.66,2.66-2.76,3.31,3.57,4.34,4.49-4.59,6.31,6.83,7.19,7.24-7.29,7.32,7.95,8.87,9.93。
TLC:Rf 0.51(二氯甲烷:甲醇=9:1);1H-NMR(CDCl3):δ 1.26,1.55,1.67-1.84,2.06-2.27,2.39-2.67,2.67-2.78,3.39,3.51-3.78,4.33,4.49-4.59,6.62,6.82,7.19,7.24-7.29,7.32,7.92,8.86,9.88。
TLC:Rf 0.63(三氯甲烷:甲醇=19:1);1H-NMR(DMSO-d6):δ1.37,1.57,1.64-1.85,2.04-2.25,2.42-2.48,2.60-2.71,4.01-4.15,4.24-4.38,6.80,7.34-7.45,7.52-7.66,7.88,9.89,12.11。
TLC:Rf 0.62(乙酸乙酯:甲醇=19:1);1H-NMR(CD3OD):δ 1.22,1.65-1.89,2.12-2.26,2.33,2.62-2.77,3.30-3.32,3.37,3.41,3.47,4.21-4.39,6.82,7.37-7.51,7.58,8.05。
TLC:Rf 0.51(三氯甲烷:甲醇=9:1);1H-NMR(DMSO-d6):δ 1.61,1.66-1.87,2.08-2.25,2.50,2.59-2.73,3.81,4.06-4.19,4.28-4.42,6.90,7.41,7.49-7.61,7.73,7.88,7.99,9.91,10.19,12.10。
實施例2-6:4-{4-氰基-2-[({(2’R,4S)-6-[(3-甲氧基-1-二氫氮唉基(azetidinyl))胺甲醯基]-2,3-二氫螺[唏-4,1’-環丙烷]-2’-基}羰基)胺基]苯基}丁酸
TLC:Rf 0.54(乙酸乙酯:甲醇=19:1);1H-NMR(DMSO-d6):δ 1.56,1.67-1.80,2.04-2.26,2.45,2.58-2.72,3.21,3.74-3.91,4.06-4.27,4.30,4.37-4.51,6.83,7.15,7.34-7.44,7.57,7.88,9.89,12.11。
TLC:Rf 0.64(三氯甲烷:甲醇=9:1);1H-NMR(DMSO-d6):δ 1.53-1.63,1.65-1.83,2.07-2.25,2.48,2.58-2.70,4.03-4.16,4.27-4.40,4.47-4.64,6.87,7.15,7.40,7.48,7.56,7.67,7.87,8.04,9.02,9.90,12.10。
TLC:Rf 0.40(三氯甲烷:甲醇=9:1);1H-NMR(DMSO-d6):δ 1.61,1.66-1.80,1.86,2.11-2.25,2.52,2.61-2.72,4.14,4.38,6.93,7.19,7.42,7.54-7.65,
7.76,7.88,7.96,9.92,11.38,12.10。
TLC:Rf 0.62(三氯甲烷:甲醇=9:1);1H-NMR(DMSO-d6):δ 1.59,1.67-1.81,1.92,2.10-2.25,2.54,2.60-2.72,3.77,4.12,4.35,6.59,6.89,7.42,7.55-7.62,7.68,7.77,7.88,9.92,10.75,12.10。
TLC:Rf 0.65(乙酸乙酯:甲醇=19:1);1H-NMR(DMSO-d6):δ 0.49-0.59,0.65-0.75,1.58,1.66-1.82,2.06-2.26,2.47,2.61-2.71.2.81,4.09,4.34,6.83,7.36-7.45,7.54-7.65,7.88,8.30,9.89,12.09。
TLC:Rf 0.79(乙酸乙酯:甲醇=19:1);1H-NMR(CDCl3):δ 0.93-1.00,1.21-1.83,2.06-2.25,2.37-2.77,3.41-3.50,3.51-3.63,4.33,4.54,6.18,6.81,7.15-7.31,7.94,8.87,9.93。
TLC:Rf 0.86(乙酸乙酯:甲醇=19:1);1H-NMR(CDCl3):δ 1.10-1.87,1.94-2.26,2.38-2.79,3.50-3.64,3.85-4.04,4.33,4.54,6.04,6.81,7.14-7.31,7.93,8.87,9.93。
TLC:Rf 0.74(乙酸乙酯:甲醇=19:1):1H-NMR(CDCl3):δ 1.27,1.34-1.92,2.01-2.30,2.38-2.80,3.50-3.61,4.18-4.43,4.54,6.00,6.81,7.15-7.31,7.94,8.87,9.93。
TLC:Rf 0.83(乙酸乙酯:甲醇=19:1);1H-NMR(CDCl3):δ 1.20-1.86,2.00-2.26,2.38-2.79,3.50-3.64,4.25-4.45,4.46-4.61,6.13,6.81,7.13-7.31,7.94,8.87,9.93。
TLC:Rf 0.83(乙酸乙酯:甲醇=19:1);1H-NMR(CDCl3):δ 0.84-1.03,1.21-2.01,2.06-2.26,2.37-2.79,3.20-3.38,3.51-3.62,4.34,4.49-4.59,6.18-6.32,6.82,7.14-7.32,7.94,8.87,9.93。
TLC:Rf 0.84(乙酸乙酯:甲醇=20:1);1H-NMR(CDCl3):δ 0.95,1.18-1.91,2.05-2.25,2.39-2.78,3.50-3.64,4.03-4.20,4.33,4.48-4.60,5.97,6.81,7.13-7.32,7.94,8.87,9.93。
TLC:Rf 0.84(乙酸乙酯:甲醇=20:1);1H-NMR(CDCl3):δ 0.98,1.18-1.32,1.49-1.86,2.05-2.25,2.39-2.81,3.57,4.11,4.33,4.54,5.95,6.81,7.13-7.33,7.93,8.81,8.86,9.93。
TLC:Rf 0.84(乙酸乙酯:甲醇=20:1);1H-NMR(CDCl3):δ 1.20-1.86,2.06-2.26,2.40-2.79,3.58,4.34,4.48-4.72,6.47,6.80,7.15-7.42,7.99,8.87,9.92。
TLC:Rf 0.56(乙酸乙酯:甲醇=19:1);1H-NMR(DMSO-d6):δ 1.59,1.67-1.83,1.90,2.07-2.26,2.46,2.61-2.71,3.58,3.72,3.82-3.92,4.10,4.33,4.48,6.85,7.38-7.48,7.58,7.67,7.88,8.39,9.91,12.11。
TLC:Rf 0.57(乙酸乙酯:甲醇=9:1);1H-NMR(CDCl3):δ 0.77-1.85,1.95-2.26,2.38-2.77,3.48-3.77,3.83-4.04,4.33,4.54,5.97,6.81,7.15-7.35,7.92,8.87,9.92。
TLC:Rf 0.64(乙酸乙酯:甲醇=9:1);1H-NMR(CDCl3):δ 1.20-1.31,1.51-1.86,2.05-2.24,2.38-
2.79,3.51-3.62,3.94-4.09,4.33,4.54,6.16,6.82,7.13-7.31,7.92,8.87,9.92。
TLC:Rf 0.17(乙酸乙酯:甲醇=9:1,Chromatorex Diol TLC板(富士Silysia));1H-NMR(CDCl3):δ 1.19-1.34,1.59,1.66-1.84,2.09-3.16,3.38,3.62-3.81,4.33,4.52,6.85,7.15-7.31,7.52-7.64,7.87,8.80,9.55。
TLC:Rf 0.83(乙酸乙酯:甲醇=19:1);1H-NMR(DMSO-d6):δ 1.58,1.73,1.88-1.99,2.10-2.24,2.60-2.70,4.06-4.18,4.30-4.40,6.90,7.14,7.41,7.57,7.72,7.77-7.90,8.18,8.38,9.91,10.78,12.09。
TLC:Rf 0.62(乙酸乙酯:甲醇=9:1);1H-NMR(DMSO-d6):δ 1.58,1.63-1.84,2.01-2.24,2.59-2.69,4.04-4.16,4.27-4.39,4.55,6.87,7.22-7.33,7.40,7.55,7.66-7.80,7.87,8.45-8.55,9.01,9.90,12.09。
TLC:Rf 0.76(乙酸乙酯:甲醇=19:1);1H-NMR(DMSO-d6):δ 1.12,1.59,1.67-1.83,2.08-2.25,2.47,2.61-2.70,3.23-3.31,3.40,4.09,4.20,4.33,6.85,7.39-7.46,7.58,7.65,7.89,8.09,9.90,12.11。
TLC:Rf 0.56(三氯甲烷:甲醇=9:1);1H-NMR(DMSO-d6):δ 1.59,1.66-1.80,2.09-2.25,2.46,2.61-2.71,3.15,3.52,4.10,4.28-4.39,4.63,6.85,7.37-7.47,7.57-7.64,7.89,8.50,9.92,12.10。
TLC:Rf 0.50(乙酸乙酯:甲醇=19:1);1H-NMR(DMSO-d6):δ 1.51-1.63,1.64-1.97,2.04-2.28,2.41-2.47,2.60-2.70,3.58,3.64-3.77,3.80-3.92,4.02-4.16,
4.26-4.38,4.38-4.53,6.84,7.36-7.48,7.58,7.67,7.87,8.37,9.91,12.10。
TLC:Rf 0.63(二氯甲烷:甲醇=9:1);1H-NMR(DMSO-d6):δ 1.52-1.62,1.62-1.88,1.88-2.06,2.06-2.24,2.60-2.70,3.23-3.30,4.01-4.14,4.26-4.37,6.83,7.36-7.45,7.59,7.88,8.31,9.91,12.10。
TLC:Rf 0.65(二氯甲烷:甲醇=9:1);1H-NMR(DMSO-d6):δ1.59,1.72,1.87-1.99,2.05-2.24,2.54-2.70,4.05-4.23,4.30-4.44,6.93,7.41,7.57,7.72,7.76-7.93,8.38,9.00,9.99,11.45,12.11。
TLC:Rf 0.21(二氯甲烷:甲醇:28%氨水=4:1:0.1);
1H-NMR(DMSO-d6):δ 1.49-1.83,1.90-2.06,2.06-2.24,2.65,2.81,3.73,4.02-4.15,4.26-4.37,6.83,7.37-7.46,7.56,7.63,7.90,8.14,10.01。
TLC:Rf 0.45(二氯甲烷:甲醇=9:1);1H-NMR(CD3OD):δ1.65-1.90,2.24,2.35,2.60-2.80,4.20-4.42,6.89,7.39-7.50,7.59,7.70,7.89,8.03。
TLC:Rf 0.76(乙酸乙酯:甲醇=19:1);1H-NMR(DMSO-d6):δ 1.53-1.81,2.06-2.25,2.41-2.47,2.58-2.71,3.55-3.78,4.04-4.17,4.25-4.40,5.84-6.36,6.87,7.41,7.48,7.55,7.67,7.87,8.73,9.91,12.10。
TLC:Rf 0.33(二氯甲烷:甲醇=9:1);1H-NMR(DMSO-d6):δ1.50-1.59,1.62-1.84,2.06-2.23,2.37,2.64,2.74-2.84,4.14,4.24-4.36,4.45,6.83,7.35-7.48,7.55,7.63,7.98,8.45,10.09。
TLC:Rf 0.68(二氯甲烷:甲醇=9:1);1H-NMR(DMSO-d6):δ 1.56-1.64,1.65-1.81,1.86-1.96,2.10-2.24,2.60-2.70,4.07-4.19,4.32-4.43,6.94,7.26,7.41,7.53-7.60,7.79,7.82-7.90,9.92,12.11,12.53。
TLC:Rf 0.53(二氯甲烷:甲醇=9:1);1H-NMR(DMSO-d6):δ 1.58-1.65,1.72,1.83,2.08-2.24,2.61-2.70,4.30-4.43,6.94,7.35-7.45,7.57,7.79,7.88,8.11-8.18,8.30,8.90,9.93,10.24,12.09。
TLC:Rf 0.56(二氯甲烷:甲醇=9:1);1H-NMR(DMSO-d6):δ1.53-1.63,1.63-1.80,1.84-1.95,2.07-2.24,2.60-2.70,4.06-4.19,4.29-4.43,6.90,7.24,7.41,7.57,7.64,7.75,7.86,8.72,9.91,10.94,12.08。
TLC:Rf 0.65(二氯甲烷:甲醇=9:1);
1H-NMR(DMSO-d6):δ1.36-1.50,1.62,1.86-2.15,2.53-2.68,2.68-2.89,4.19-4.37,6.85,6.91,7.31-7.41,7.41-7.49,7.62,7.79,8.36,8.75,11.61,12.62。
TLC:Rf 0.72(乙酸乙酯);1H-NMR(CD3OD):δ 1.62-1.90,2.02-2.44,2.59-2.80,4.19-4.30,4.33,4.49,6.82,7.37-7.51,7.58,8.04。
實施例2-39:4-[4-氰基-2-({[(2’R,4S)-6-{[1-(2-甲基-2-丙基)-1H-吡唑-4-基]胺甲醯基}-2,3-二氫螺[唏-4,1’-環丙烷]-2’-基]羰基}胺基)苯基]丁酸
TLC:Rf 0.64(乙酸乙酯);1H-NMR(CD3OD):δ1.59,1.67-1.92,2.16-2.29,2.30-2.41,2.62-2.78,4.21-4.32,4.33-4.46,6.88,7.37-7.51,7.58,7.65-7.74,8.03,8.11。
TLC:Rf 0.62(乙酸乙酯:甲醇=9:1);1H-NMR(DMSO-d6):δ1.44-1.86,2.02-2.24,2.59-2.70,3.35-3.44,3.80-4.15,4.25-4.37,6.84,7.37-7.46,7.57,7.64,7.87,8.13,9.90,12.09。
TLC:Rf 0.71(乙酸乙酯:甲醇=9:1);1H-NMR(DMSO-d6):δ 1.56-1.66,1.73,1.87,2.06-2.25,2.60-2.70,4.06-4.19,4.31-4.44,6.39,6.94,7.41,7.57,7.67,7.81,7.87,8.50,9.92,11.90,12.09。
TLC:Rf 0.53(二氯甲烷:甲醇=4:1);1H-NMR(DMSO-d6):δ 1.57-1.66,1.73,1.83,2.09-2.24,2.60-2.70,4.08-4.21,4.31-4.42,6.95,7.41,7.52-7.61,7.74-
7.91,8.42-8.52,9.91,10.38,12.09。
TLC:Rf 0.58(三氯甲烷:甲醇=9:1);1H-NMR(DMSO-d6):δ 1.55-1.65,1.66-1.90,2.06-2.29,2.50,2.60-2.74,3.66,4.06-4.22,4.30-4.46,6.17,6.93,7.35-7.45,7.52-7.61,7.77,7.88,9.91,10.15,12.10。
TLC:Rf 0.75(乙酸乙酯);1H-NMR(DMSO-d6):δ 0.88,1.45-1.63,1.68-1.82,2.07-2.25,2.45,2.61-2.72,3.15-3.26,4.10,4.32,6.85,7.39-7.46,7.57-7.63,7.88,8.32,9.90,12.11。
TLC:Rf 0.51(乙酸乙酯);1H-NMR(DMSO-d6):δ1.11,1.59,1.67-1.83,2.07-2.26,2.47,2.61-2.71,3.35-3.52,4.10,4.33,6.85,7.38-7.48,7.57-7.64,7.88,8.42,9.90,12.09。
TLC:Rf 0.59(乙酸乙酯);1H-NMR(DMSO-d6):δ 1.10,1.58,1.65-1.80,2.07-2.24,2.45,2.58-2.69,3.19-3.33,4.09,4.32,6.84,7.37-7.45,7.57,7.62,7.88,8.33,9.89,12.09。
TLC:Rf 0.72(己烷:乙酸乙酯=1:3);1H-NMR(DMSO-d6):δ1.33,1.57,1.67-1.86,2.08-2.25,
2.47,2.62-2.71,3.27,3.53,4.09,4.32,6.82,7.35-7.45,7.48,7.57-7.62,7.88,9.89,12.10。
在參考例11製造的化合物(50mg)及乙醯基聯胺(16mg)的二氯甲烷(0.5mL)溶液,在室溫下添加三乙胺(60μL)及T3P(1.7mol/L乙酸乙酯溶液,95μL)。將反應混合物在室溫下攪拌1.5小時後,減壓濃縮。在所得的殘渣以矽膠管柱層析法(山善自動精製裝置)精製所得的化合物的THF(5mL)溶液中,在室溫下添加伯吉斯試藥(Burgess Reagent:N-(三乙基銨磺醯基)胺甲酸甲酯(methyl N-(triethylammonium sulfonyl)carbamate))(117mg)。使用微波反應裝置(Biotage社製)在100℃下攪拌1小時。在反應混合物中注入飽和碳酸氫鈉水溶液,以乙酸乙酯萃取。將所得的有機層以飽和食鹽水清洗,以無水硫酸鎂乾燥後,減壓濃縮。將所得的殘渣以矽膠管柱層析法(山善自動精製裝置)精製,得以下物性值的標題化合物(22mg)。
TLC:Rf 0.53(己烷:乙酸乙酯=1:3);1H-NMR(CDCl3):δ 0.94,1.65-1.83,1.89,2.26-2.34,2.35-
2.44,2.56-2.63,2.66-2.76,3.12-3.28,3.36-3.55,3.58-3.74,4.07-4.23,4.30-4.41,6.92,7.18,7.28,7.54,7.70,8.72,9.39。
代替參考例12製造的化合物,而使用參考例13製造的化合物,實施與實施例1同樣的操作,而得有以下物性值的本發明化合物。
TLC:Rf 0.93(二氯甲烷:甲醇=9:1);1H-NMR(CDCl3):δ 1.27,1.54,1.70-1.91,2.17,2.32,2.45-2.90,3.64,4.35-4.48,4.56-4.66,6.92,7.20,7.28,7.58,8.15,8.92,9.91,12.68。
實施例4
代替乙醯基聯胺,而使用相對應的聯胺化合物,實施與參考例13→實施例1同樣的操作,而得有以下物性值的本發明化合物。
TLC:Rf 0.64(乙酸乙酯:甲醇=19:1);1H-NMR(CDCl3):δ 1.14-1.32,1.78,2.07-2.41,2.43-2.91,3.63,4.33-4.49,4.61,6.86-6.96,7.16-7.32,7.54,8.13,8.92,9.91。
-TLC:Rf 0.83(乙酸乙酯:甲醇=19:1);1H-NMR(CDCl3):δ 1.19-1.32,1.44-1.52,1.64-1.87,2.10-2.40,2.44-2.90,3.64,4.35-4.49,4.56-4.67,6.93,7.16-7.35,7.60,8.15,8.92,9.92。
TLC:Rf 0.53(二氯甲烷:甲醇=9:1);1H-NMR(DMSO-d6):δ1.32,1.60,1.66-1.82,2.10-2.24,2.60-2.70,2.92,4.09-4.21,4.31-4.42,6.99,7.41,7.46,7.57,7.71,7.88,9.91,12.08。
在參考例11製造的化合物(80mg)及乙醯胺肟(acetamidoxime,32mg)的乙酸乙酯(0.5mL)溶液,在室溫下添加三乙胺(0.144mL)及T3P(1.7mol/L乙酸乙酯溶液,0.380mL)。將反應混合物加熱回流4日後,減壓濃縮。將所得的殘渣以矽膠管柱層析法(山善自動精製裝置)精製,得以下物性值的標題化合物(49mg)。
TLC:Rf 0.55(己烷:乙酸乙酯=1:1);1H-NMR(CDCl3):δ 0.92,1.64-1.83,1.86-1.95,2.22-2.35,2.36-2.44,2.45,2.54-2.65,2.72,3.39-3.54,3.59-3.73,4.10-4.23,4.32-4.44,6.94,7.20,7.28,7.59,7.84,8.74,9.39。
代替參考例12製造的化合物,而使用參考例14製造的化合物,實施與實施例1同樣的操作,而得有以下物性值的本發明化合物。
TLC:Rf 0.74(乙酸乙酯:甲醇=20:1);1H-NMR(DMSO-d6):δ 1.55-1.64,1.67-1.83,2.11-2.29,2.39,2.51-2.60,2.61-2.73,4.11-4.25,4.31-4.44,7.02,7.41,7.52-7.62,7.83,7.88,9.90,12.10。
在參考例10製造的化合物(70mg)的1,2-二甲氧基乙烷(0.4mL)溶液,在室溫下添加碳酸銫(84mg)、4-氟苯基硼酸(36mg)、及精製水(0.4mL)並以氬取代。添加[1,1’-雙(二苯基膦基)鐵莘]二氯化鈀(II)二氯甲烷錯合物(5mg),在85℃下攪拌一夜。將反應混合物以乙酸乙酯稀釋後,添加水以乙酸乙酯萃取。將所得的有機層以水、飽和食鹽水清洗,以無水硫酸鈉乾燥後,減壓濃縮。將所得的殘渣以矽膠管柱層析法(山善自動精製裝置)精製,得以下物性值的標題化合物(54mg)。
TLC:Rf 0.48(己烷:乙酸乙酯=2:1);1H-NMR(CDCl3):δ 0.83,1.64-1.79,1.82-1.93,2.29,2.33-2.43,2.48-2.74,3.30,3.49,4.06-4.19,4.26-4.38,6.84-6.91,6.97,7.04-7.15,7.15-7.22,7.22-7.32,7.39-7.51,8.73,9.30。
代替參考例12製造的化合物,而使用參考例15製造的化合物,而實施與實施例1同樣的操作,得有以下物性值的本發明化合物。
TLC:Rf 0.58(二氯甲烷:甲醇=9:1);1H-NMR(DMSO-d6):δ 1.50-1.60,1.72,1.87,2.06-2.24,2.60-2.69,4.03-4.15,4.24-4.35,6.87,7.11,7.19-7.29,7.32-7.44,7.56,7.61-7.70,7.87,9.88,12.09。
實施例7
代替4-氟苯基硼酸,而使用相對應的硼酸化合物或雜環,實施與參考例15→實施例1同樣的操作,而得有以下物性值的本發明化合物。
TLC:Rf 0.53(二氯甲烷:甲醇=9:1)1H-NMR(CDCl3):δ 1.58-1.81,2.14-2.27,2.36-2.46,2.49-2.71,2.78,4.22-4.37,6.92,7.15,7.16-7.22,7.26-7.51,7.52-7.61,8.69,8.95。
TLC:Rf 0.36(二氯甲烷:甲醇=9:1);1H-NMR(DMSO-d6):δ 1.52-1.63,1.64-1.79,1.87-1.99,2.08-2.30,2.43-2.73,3.99-4.20,4.25-4.41,6.93,7.31,7.40,7.56,7.66-7.71,7.87,8.51-8.62,9.88,11.90-12.18。
TLC:Rf 0.36(二氯甲烷:甲醇=9:1);1H-NMR(DMSO-d6):δ 1.56,1.65-1.77,1.88-2.00,2.06-2.30,2.34-2.75,4.03-4.19,4.25-4.39,6.92,7.22,7.37-7.51,
7.57,7.87,7.99-8.09,8.48-8.53,8.87,9.87。
TLC:Rf 0.45(二氯甲烷:甲醇=9:1);1H-NMR(CDCl3):δ 1.23-1.34,1.62,1.66-1.83,2.05-2.23,2.40-2.59,2.61-2.82,3.37-3.47,4.22-4.35,4.44-4.52,6.49,6.88,7.11,7.20,7.28,7.41,7.71,8.86,9.95。
TLC:Rf 0.35(二氯甲烷:甲醇=9:1);1H-NMR(DMSO-d6):δ 1.51-1.62,1.63-1.86,2.04-2.33,2.34-2.75,3.98-4.14,4.23-4.35,6.65,6.82,7.29,7.40,7.48-7.60,7.63,7.87,9.91,12.47。
TLC:Rf 0.40(二氯甲烷:甲醇=9:1);1H-NMR(DMSO-d6):δ 1.53-1.62,1.63-1.80,1.95-2.06,2.09-2.33,2.34-2.78,4.01-4.22,4.28-4.42,6.97,7.42,7.47,7.57,7.71,7.87,7.94-8.04,9.20,9.60,9.87,12.1。
TLC:Rf 0.25(乙酸乙酯:甲醇=19:1);1H-NMR(CDCl3):δ1.44-1.88,2.22-2.33,2.48,2.58-2.76,3.70,4.16-4.36,6.81-6.95,7.11-7.34,7.39,7.56,8.73,9.16。
TLC:Rf 0.44(二氯甲烷:甲醇=9:1);1H-NMR(DMSO-d6):δ 1.57,1.65-1.79,1.92-2.03,2.06-2.35,2.36-2.77,4.01-4.17,4.27-4.40,6.94,7.33,7.40,7.50-7.61,7.87,9.12,9.86,12.08。
TLC:Rf 0.44(二氯甲烷:甲醇=9:1);1H-NMR(DMSO-d6):δ 1.51-1.61,1.65-1.78,1.79-1.88,2.05-2.31,2.40-2.76,3.98-4.14,4.23-4.36,6.83,7.04-7.16,7.30-7.49,7.57,7.86,9.90,12.08。
TLC:Rf 0.47(二氯甲烷:甲醇=9:1);1H-NMR(DMSO-d6):δ 1.50-1.59,1.60-1.80,1.93-2.12,2.19,2.31-2.51,2.54-2.78,3.78,3.93-4.09,4.19-4.31,6.78,7.09,7.29,7.40,7.56,7.85,9.91,12.08。
TLC:Rf 0.53(乙酸乙酯:甲醇=20:1);1H-NMR(CDCl3):δ1.20-1.30,1.58,1.73-1.90,2.26-2.37,2.52,2.64-2.82,4.19-4.41,6.81-6.97,7.13-7.35,7.77,8.60,
8.69,9.25。
TLC:Rf 0.40(二氯甲烷:甲醇=9:1);1H-NMR(CDCl3):δ 1.59-1.70,1.76-1.84,2.31,2.43-2.53,2.60-2.80,4.15-4.44,6.72,6.89,6.97,7.09-7.36,7.68,7.89,8.43,8.70,9.15。
TLC:Rf 0.56(乙酸乙酯);1H-NMR(CD3OD):δ 1.65-1.93,2.14-2.29,2.33,2.58,2.67-2.78,3.92,4.21,4.32,6.80-6.91,7.06,7.30,7.42,7.48,7.84-7.95,8.31。
TLC:Rf 0.60(三氯甲烷:甲醇=9:1);1H-NMR(DMSO-d6):δ 1.57,1.63-1.79,1.89-2.01,2.08-2.25,2.50-2.56,2.60-2.72,4.03-4.18,4.27-4.40,6.59,6.93,7.27,7.40,7.47-7.60,7.80-7.91,7.96,8.27,8.63,8.76,9.88,12.10。
TLC:Rf 0.58(三氯甲烷:甲醇=9:1);1H-NMR(DMSO-d6):δ 1.51-1.62,1.63-1.80,1.84-1.95,2.06-2.25,2.51-2.57,2.60-2.75,3.18,4.02-4.17,4.23-4.39,6.88,7.01-7.21,7.35-7.47,7.55,7.87,8.10-8.29,9.92,12.10。
TLC:Rf 0.63(二氯甲烷:甲醇=9:1);1H-NMR(DMSO-d6):δ 1.46-1.56,1.56-1.79,2.03,2.16,2.66,4.15,4.22-4.33,6.86,7.20,7.27,7.33-7.44,7.44-7.52,8.08-8.21,8.70,11.11。
TLC:Rf 0.59(二氯甲烷:甲醇=9:1);1H-NMR(DMSO-d6):δ 1.52-1.60,1.65-1.79,1.93,2.07-2.23,2.60-2.70,4.03-4.15,4.27-4.37,6.90,7.19-7.27,7.40,7.45,7.56,7.87,8.25,8.51,9.87,12.09。
TLC:Rf 0.57(二氯甲烷:甲醇=9:1);1H-NMR(DMSO-d6):δ 1.58,1.72,1.92-2.01,2.09-2.24,2.60-2.70,4.06-4.17,4.30-4.40,6.96,7.33-7.45,7.58,7.88,8.06,8.41,9.09,9.90,12.10。
TLC:Rf 0.55(二氯甲烷:甲醇=9:1);1H-NMR(DMSO-d6):δ 1.51-1.61,1.65-1.80,1.91,2.09-2.24,2.60-2.70,4.09,4.25-4.36,6.47,6.89,7.18,7.38-7.45,7.45-7.50,7.56,7.88,8.17,8.47,9.94,11.65,12.06。
實施例7-20:4-[4-氰基-2-({[(2’R,4S}-6-(4-甲基-3,4-二氫-2H-吡啶并[3,2-b][1,4]-7-基)-2,3-二氫螺[唏-4,1’-環丙烷]-2’-基]羰基}胺基)苯基]丁酸
TLC:Rf 0.65(二氯甲烷:甲醇=9:1);1H-NMR(DMSO-d6):δ 1.48-1.58,1.65-1.79,1.88,2.06-2.14,2.19,2.59-2.70,3.03,3.40-3.47,3.99-4.11,4.19-4.33,6.81,7.03,7.23,7.29,7.40,7.56,7.86,7.95,9.87,12.08。
TLC:Rf 0.53(二氯甲烷:甲醇=9:1);1H-NMR(DMSO-d6):δ 1.52-1.61,1.72,1.84-1.94,2.06-
2.23,2.60-2.70,2.94,4.02-4.13,4.25-4.36,6.88,6.99,7.14,7.34-7.43,7.56,7.86,8.09-8.21,9.91,12.13,13.60。
TLC:Rf 0.56(二氯甲烷:甲醇=9:1);1H-NMR(DMSO-d6):δ 1.46,1.54-1.62,1.72,1.79-1.88,2.07-2.24,2.60-2.70,4.02-4.15,4.25-4.36,5.05,6.88,7.09,7.29-7.46,7.57,7.66,7.87,9.90,12.09。
TLC:Rf 0.47(二氯甲烷:甲醇=20:1);1H-NMR(DMSO-d6):δ 1.54-1.79,2.02-2.11,2.19,2.39-2.68,3.01-3.05,3.55-3.61,3.95-4.03,4.20-4.29,6.77-6.81,7.16,7.41,7.56,7.85,9.90,12.10。
TLC:Rf 0.47(二氯甲烷:甲醇=20:1);1H-NMR(DMSO-d6):δ 1.54-1.79,2.05-2.24,2.39-2.68,3.96-4.06,4.23-4.31,4.36-4.45,6.81,7.01,7.27,7.41,7.56,7.86,9.92,12.10。
TLC:Rf 0.40(二氯甲烷:甲醇=20:1);1H-NMR(DMSO-d6):δ1.53-1.80,2.06-2.13,2.19,2.37-2.81,3.47-3.55,4.00-4.08,4.20-4.39,5.29-5.37,6.78,7.14,7.25,7.40,7.55,7.87,9.91,12.10。
TLC:Rf 0.49(二氯甲烷:甲醇=9:1);1H-NMR(DMSO-d6):δ1.58,1.72,1.92,2.08-2.24,2.60-2.70,3.23,4.05-4.17,4.27-4.39,6.93,7.25,7.41,7.50,7.57,7.84-7.99,9.88,12.09。
TLC:Rf 0.58(二氯甲烷:甲醇=9:1);1H-NMR(DMSO-d6):δ1.56,1.72,1.93,2.08-2.24,2.59-2.69,4.04-4.16,4.27-4.38,6.92,7.25,7.40,7.51,7.56,7.87,9.86,12.08。
TLC:Rf 0.59(三氯甲烷:甲醇=9:1);
1H-NMR(DMSO-d6):δ 1.51-1.61,1.64-1.88,2.08-2.28,2.39-2.46,2.58-2.71,3.82,4.05-4.17,4.27-4.39,6.32,6.90,7.00,7.25,7.37-7.45,7.55,7.86,9.89,12.10。
代替4-氟苯基硼酸,而使用1-(2-四氫哌喃基)-1H-吡唑-4-硼酸 頻那醇(pinacol)酯,實施與參考例15同樣的操作,得以下物性值的標題化合物。
TLC:Rf 0.62(己烷:乙酸乙酯=1:2);1H-NMR(CDCl3):δ 0.86,1.64-1.79,1.82-1.90,2.02-2.16,2.21-2.29,2.34-2.43,2.52-2.72,3.28-3.42,3.45-3.60,3.65-3.80,4.03-4.16,4.25-4.40,5.35-5.45,6.81,6.90,7.13-7.23,7.28,7.71,7.76,8.74,9.36。
在參考例16製造的化合物(30mg)的1,4-二烷(1mL)溶液,在室溫下添加鹽酸-1,4-二烷(4mol/L,0.1mL)溶液。將反應混合物在60℃下攪拌3小時。將反應混合物減壓濃縮後,實施與實施例1同樣的操作,而得有以下物性值的本發明化合物。
TLC:Rf 0.40(乙酸乙酯:甲醇=20:1);1H-NMR(DMSO-d6):δ 1.55,1.64-1.79,1.81-1.92,2.04-2.27,2.35-2.47,2.52-2.74,4.02,4.27,6.76,7.09,7.32,7.40,7.56,7.85,7.99,9.89。
參考例17:4-[4-氰基-2-({[(2’R,4S)-6-(4,4,5,5-四甲基-1,3,2-二氧硼戊環(dioxaborolane)-2-基)-2,3-二氫螺[唏-4,1’-環丙烷]-2’-基]羰基}胺基)苯基]丁酸乙酯
在氬取代下,在參考例10製造的化合物(4.00g)的二甲基亞碸(40mL)溶液,添加乙酸鉀(1.44g)、聯硼酸頻那醇
酯(bis(pinacolato)diboron)(2.43g)、及[1,1’-雙(二苯基膦基)鐵莘]二氯化鈀(II)二氯甲烷錯合物(300mg),在90℃下攪拌4小時。將反應混合物以乙酸乙酯稀釋後,添加水以乙酸乙酯萃取。將所得的有機層以水、飽和食鹽水清洗,以無水硫酸鈉乾燥後,減壓濃縮。將所得的殘渣以矽膠管柱層析法(山善自動精製裝置)精製,得以下物性值的標題化合物(3.54g)。
TLC:Rf 0.37(己烷:乙酸乙酯=2:1);1H-NMR(CDCl3):δ 1.01,1.20-1.29,1.31,1.63-1.77,1.84,2.18-2.27,2.33-2.42,2.53-2.60,3.20-3.34,3.45-3.60,4.00-4.10,4.25-4.37,6.78,7.18,7.28,7.52,8.68,9.37。
在氬取代下,在參考例17製造的化合物(100mg)的1,2-二甲氧基乙烷(0.3mL)溶液、水(0.3mL)溶液,添加2-溴吡啶(36μL)、碳酸銫(120mg)、及[1,1’-雙(二苯基膦基)鐵莘]二氯化鈀(II)二氯甲烷錯合物(7.5mg),在95℃下攪拌17小時。將反應混合物以乙酸乙酯萃取,將所得的有機層以水、飽和食鹽水清洗,以無水硫酸鈉乾燥後,減壓濃縮。使用
將所得的殘渣以矽膠管柱層析法(山善自動精製裝置)精製所得的4-[4-氰基-2-({[(2’R,4S)-6-(2-吡啶基)-2,3-二氫螺[唏-4,1’-環丙烷]-2’-基]羰基}胺基)苯基]丁酸乙酯,實施與實施例1同樣的操作,而得有以下物性值的本發明化合物。
TLC:Rf 0.44(二氯甲烷:甲醇=9:1);1H-NMR(DMSO-d6):δ 1.54-1.66,1.68-1.88,2.07-2.29,2.54-2.76,4.04-4.17,4.26-4.38,6.89,7.23-7.33,7.40,7.52-7.64,7.77-7.99,8.61,9.90,12.10。
實施例10
代替2-溴吡啶,而使用相對應的含鹵雜環,實施與實施例9同樣的操作,而得有以下物性值的本發明化合物。
TLC:Rf 0.45(二氯甲烷:甲醇=9:1);1H-NMR(DMSO-d6):δ 1.54-1.83,2.07-2.28,2.35-2.77,4.05-4.22,4.26-4.42,6.93,7.29-7.45,7.56,7.88,7.94,8.15,8.84,9.93,12.10。
TLC:Rf 0.81(乙酸乙酯:甲醇=20:1);1H-NMR(CDCl3):δ 1.19-1.32,1.34-1.85,2.10-2.25,2.40-2.79,3.61,4.35,4.48-4.62,6.88,7.15-7.30,7.35,7.38-7.47,7.68-7.77,7.85,8.88,10.00。
TLC:Rf 0.81(乙酸乙酯:甲醇=20:1);1H-NMR(CDCl3):δ 1.18-1.29,1.53,1.68-1.86,2.09-2.33,2.43-2.87,3.60,4.39,4.52-4.64,6.90,7.15,7.17,7.28,7.67,7.72,8.05,8.92,9.95。
TLC:Rf 0.58(乙酸乙酯:甲醇=20:1);1H-NMR(CDCl3):δ 1.21-1.32,1.56,1.69-1.86,2.14-2.31,2.44-2.88,3.64,4.15-4.20,4.34,4.53,6.86,7.13-7.31,7.63,7.68,7.79,8.92,10.01。
TLC:Rf 0.40(二氯甲烷:甲醇=9:1);1H-NMR(CDCl3):δ 1.17-1.31,1.61,1.66-1.90,2.11-2.32,2.36-2.82,3.48-3.71,4.35,4.54,6.98,7.21,7.28,7.36,7.66,7.83,7.80-7.83,8.87,9.15,10.07。
TLC:Rf 0.40(二氯甲烷:甲醇=9:1);1H-NMR(CDCl3):δ 1.25,1.61,1.68-1.88,2.08-2.29,2.40-
2.87,3.49,4.25-4.41,4.52,6.97,7.21,7.29,7.46,7.61,8.45,8.62,8.85,8.97,9.93。
TLC:Rf 0.48(二氯甲烷:甲醇=9:1);1H-NMR(DMSO-d6):δ 1.61,1.73,1.80-1.92,2.07-2.28,2.38-2.75,3.34,4.06-4.20,4.26-4.44,6.96,7.41,7.57,7.71,7.88,7.97,8.18-8.36,9.06,9.91,12.08。
TLC:Rf 0.42(二氯甲烷:甲醇=9:1);1H-NMR(DMSO-d6):δ 1.51-1.62,1.63-1.87,2.07-2.30,2.53-2.75,4.03-4.19,4.25-4.39,4.54,5.29,6.88,7.40,7.52-7.64,7.70-7.94,8.53,9.92,12.07。
TLC:Rf 0.64(二氯甲烷:甲醇=9:1);1H-NMR(DMSO-d6):δ 1.53-1.64,1.65-1.88,2.06-2.32,2.40-2.80,4.00-4.19,4.24-4.40,6.89,7.40,7.51-7.65,7.71-7.84,7.88,8.00-8.05,8.60,9.92,12.08。
TLC:Rf 0.50(二氯甲烷:甲醇=9:1);1H-NMR(DMSO-d6):δ 1.53-1.64,1.66-1.79,1.79-1.91,2.03-2.30,2.40-2.79,3.94,4.02-4.16,4.26-4.40,6.70,6.89,7.40,7.48-7.62,7.73,7.80-7.89,9.89,12.07。
TLC:Rf 0.70(二氯甲烷:甲醇=9:1);1H-NMR(CDCl3):δ1.16-1.30,1.57,1.70-1.83,2.04-2.27,2.52,2.59-2.73,2.74-2.92,3.54,3.92,4.30,4.48,6.89,7.19,7.24-7.31,7.38,7.49,7.52,8.18,8.83,10.06。
TLC:Rf 0.69(乙酸乙酯:甲醇=9:1);1H-NMR(CDCl3):δ 1.19-1.31,1.56,1.70-1.88,2.12-2.32,2.42-2.84,3.54,4.37,4.56,6.92,7.16-7.31,7.71-7.82,8.91,9.84。
實施例11:4-(4-氰基-2-{[(2’R,4S)-2,3-二氫螺[1-苯并哌喃-4,1’-環丙烷]-2’-羰基]胺基}苯基)丁酸
使用參考例9製造的化合物及參考例3製造的化合物,實施與參考例10→實施例1同樣的操作,而得有以下
物性值的本發明化合物。
TLC:Rf 0.62(三氯甲烷:甲醇=9:1);1H-NMR(CD3OD):δ 1.66,1.77-1.91,2.08-2.28,2.34,2.48,2.71,4.16,4.28,6.74,6.82-6.91,7.06,7.42,7.48,7.91。
參考例18:(2’R,4S)-2’-{[2-(4-乙氧基-4-側氧基丁基)-5-氟苯基]胺甲醯基}-2,3-二氫螺[1-苯并哌喃-4,1’-環丙烷]-6-羧酸
代替3-硝基-4-溴苯甲醛而使用5-氟-2-碘硝苯,實施與參考例7→參考例9→參考例10→實施例1同樣的操作,得以下物性值的標題化合物。
1H-NMR(DMSO-d6):δ 1.12,1.52-1.77,2.12,2.26,2.51-2.62,3.87-4.02,4.12,4.34,6.86,6.92,7.20,7.41,7.47,7.68,9.68,12.68。
實施例12
代替參考例11製造的化合物而使用參考例18製造的化合物,並使用甲胺鹽酸鹽或相對應的胺化合物,實施與參考例12→實施例1同樣的操作,而得有以下物性值的本發明化合物。
TLC:Rf 0.69(乙酸乙酯:甲醇=19:1);1H-NMR(CD3OD):δ1.62-1.87,2.12-2.28,2.32,2.56-2.78,2.90,4.23,4.34,6.76-6.89,7.20,7.38-7.51,7.54。
TLC:Rf 0.67(乙酸乙酯:甲醇=19:1);1H-NMR(DMSO-d6):δ1.51-1.79,2.06-2.22,2.41-2.61,3.25,3.36-3.46,4.07,4.31,6.83,6.95,7.19,7.33,7.43,7.63,8.42,9.74,12.06。
TLC:Rf 0.64(乙酸乙酯:甲醇=9:1);1H-NMR(CD3OD):δ1.66-1.86,2.12-2.37,2.57-2.70,3.88,4.25,4.37,6.81-6.92,7.21,7.45,7.58,7.63,7.68,8.00。
參考例19:4-(2-{[(1R,2R)-6’-(苄氧基)-2’,3’-二氫螺[環丙烷-1,1’-茚]-2-羰基]胺基}-4-氰基苯基)丁酸乙酯
1H-NMR(CDCl3):δ1.25,1.38-1.45,1.68-1.81,1.82-1.87,2.32-2.46,2.57-2.67,2.86-3.08,3.82-3.92,3.97-4.07,5.00,
6.46,6.77,7.12,7.17,7.25-7.31,7.32-7.43,8.78,9.15。
實施例13:4-[2-({[(1R,2R)-6’-(苄氧基)-2’,3’-二氫螺[環丙烷-1,1’-茚]-2-基]羰基}胺基)-4-氰基苯基]丁酸
代替參考例12製造的化合物而使用參考例19製造的化合物,實施與實施例1同樣的操作,而得有以下物性值的本發明化合物。
TLC:Rf 0.53(二氯甲烷:甲醇=10:1);1H-NMR(CDCl3):δ 1.36-1.43,1.66-1.77,1.79-1.85,2.31,2.42-2.73,2.84-3.09,5.05,6.49,6.81,7.13-7.21,7.24-7.30,7.32-7.47,8.72,8.92。
實施例14:4-[4-氰基-2-({[(1R,2R)-6’-羥基-2’,3’-二氫螺[環丙烷-1,1’-茚]-2-基]羰基}胺基)苯基]丁酸
在實施例13製造的化合物(40mg)的乙酸乙酯(3mL)及1,4-二烷(1mL)溶液中添加10%鈀/碳(12mg),以氫氣取代,在室溫下攪拌9小時。將反應混合物以Celite過濾,將濾液減壓濃縮。將所得的殘渣以矽膠管柱層析法精製,而得有以下物性值的本發明化合物(32mg)。
TLC:Rf 0.40(二氯甲烷:甲醇=10:1);1H-NMR(CDCl3):δ 1.36-1.43,1.65-1.85,2.32,2.47-2.55,2.58-2.76,2.83-3.08,6.37,6.62,7.06,7.22,7.25-7.37,8.74,8.92。
參考例20:4-(4-氰基-2-{[(1R,2R)-6’-羥基-2’,3’-二氫螺[環丙烷-1,1’-茚]-2-羰基]胺基}苯基)丁酸乙
酯
代替實施例13製造的化合物而使用參考例19製造的化合物,實施與實施例14同樣的操作,而得有以下物性值的本發明化合物。
1H-NMR(CDCl3):δ1.24,1.38-1.43,1.70-1.87,2.31-2.49,2.58-2.67,2.85-3.07,3.89-4.01,4.04-4.16,4.49,6.31,6.58,7.04,7.17,7.26-7.31,8.78,9.18。
參考例21:4-[4-氰基-2-({(1R,2R)-6’-[(1-甲基-1H-吡唑-4-基)甲氧基]-2’,3’-二氫螺[環丙烷-1,1’-茚]-2-羰基}胺基)苯基]丁酸乙酯
在氮氣流下,在參考例20製造的化合物(30mg)及(1-甲基吡唑-4-基)甲醇(9.6mg)的甲苯(0.2mL)溶液中滴下氰基亞甲基三丁基磷烷(0.06mL),在100℃下攪拌一夜。將反應混合物減壓濃縮。將所得的殘渣以矽膠管柱層析法精製,得以下物性值的標題化合物(7mg)。
1H-NMR(CDCl3):δ1.26,1.39-1.42,1.68-1.85,2.28-2.51,2.55-2.65,2.83-3.05,3.87-4.01,4.04-4.18,4.89,6.40,6.72-6.79,7.06-7.38,7.41,7.51,8.77,9.13。
實施例15:4-{4-氰基-2-[({(1R,2R)-6’-[(1-甲基-1H-吡唑-4-基)甲氧基]-2’,3’-二氫螺[環丙烷-1,1’-茚]-2-基}羰基)胺基]苯基}丁酸
代替參考例12製造的化合物而使用參考例21製造的化合物,實施與實施例1同樣的操作,而得有以下物性值的本發明化合物。
TLC:Rf 0.26(二氯甲烷:甲醇=20:1);1H-NMR(DMSO-d6):δ 1.45-1.57,1.66-1.79,2.13-2.25,2.26-2.75,2.84-2.92,3.81,4.90,6.51,6.77,7.09,7.39,7.47,7.55,7.77,7.96。
參考例22:4-[4-氰基-2-({(1R,2R)-6’-[2-(甲胺基)-2-側氧基乙氧基]-2’,3’-二氫螺[環丙烷-1,1’-茚]-2-羰基}胺基)苯基]丁酸乙酯
在參考例20製造的化合物(50mg)的DMF(0.5mL)溶液,在室溫下添加碳酸鉀(33mg)及碘化四丁基銨(4.4mg),繼而添加2-氯-N-甲基乙醯胺(25.7mg)。將反應混合物在50℃下攪拌一夜。將反應混合物以乙酸乙酯稀釋,添加飽和氯化銨水溶液及水,以乙酸乙酯萃取。將所得的有機層以水、20%食鹽水清洗,以無水硫酸鈉乾燥後,減壓濃縮。將所得的殘渣以矽膠管柱層析法(山善自動精製裝置)精製,得以下物性值的標題化合物(51mg)。
TLC:Rf 0.26(己烷:乙酸乙酯=4:1);1H-NMR(CDCl3):δ 1.19,1.39-1.44,1.68-1.84,1.86-1.89,2.27-2.70,2.84-3.08,3.79-3.93,3.95-4.06,4.07,4.44,6.38,6.55,6.70,7.13-7.20,7.26-7.30,8.75,9.07。
實施例16:4-{4-氰基-2-[({(1R,2R)-6’-[2-(甲胺基)-2-側氧基乙氧基]-2’,3’-二氫螺[環丙烷-1,1’-茚]-2-基}羰基)胺基]苯基}丁酸
代替參考例12製造的化合物而使用參考例22製造的化合物,實施與實施例1同樣的操作,而得有以下物性值
的本發明化合物。
TLC:Rf 0.59(乙酸乙酯:甲醇=9:1);1H-NMR(DMSO-d6):δ 1.44-1.51,1.56,2.07-2.34,2.66,2.87,6.54,6.76,7.12,7.41,7.56,7.92,8.01,9.75,12.12。
實施例17:4-{4-氰基-2-[({(1R,2R)-6’-[2-(二甲胺基)-2-側氧基乙氧基]-2’,3’-二氫螺[環丙烷-1,1’-茚]-2-基}羰基)胺基]苯基}丁酸
代替2-氯-N-甲基乙醯胺而使用2-氯-N,N-二甲基乙醯胺,實施與參考例22→實施例1同樣的操作,而得有以下物性值的本發明化合物。
TLC:Rf 0.54(乙酸乙酯:甲醇=9:1);1H-NMR(DMSO-d6):δ 1.47-1.58,1.71,2.08-2.32,2.33-2.70,2.82-2.91,3.00,4.74,6.49,6.70,7.10,7.41,7.57,7.91,9.79,12.16。
參考例23:4-[4-氰基-2-({(1R,2R)-6’-[(三氟甲磺醯基)氧基]-2’,3’-二氫螺[環丙烷-1,1’-茚]-2-羰基}胺基)苯基]丁酸乙酯
在氮環境下,在參考例20製造的化合物(100mg)的二氯甲烷(2mL)溶液,添加三乙胺(0.1mL)及1,1,1-三氟-N-苯基-N-(三氟甲磺醯基)甲磺醯胺(128mg),在室溫下攪拌3小
時。再在反應液中添加1,1,1-三氟-N-苯基-N-(三氟甲磺醯基)甲磺醯胺(128mg),在室溫下攪拌2小時。將反應液以矽膠管柱層析法精製,得以下物性值的標題化合物(130mg)。
1H-NMR(CDCl3):δ 1.22-1.29,1.39-1.44,1.70-1.83,1.86-1.91,2.34-2.51,2.60-2.67,2.95-3.14,3.90-4.02,4.05-4.16,6.67,7.03,7.19,7.21-7.31,8.78,9.19。
參考例24:(1R,2R)-2-{[5-氰基-2-(4-乙氧基-4-側氧基丁基)苯基]胺甲醯基}-2’,3’-二氫螺[環丙烷-1,1’-茚]-6’-羧酸
將參考例23製造的化合物(120mg)溶解於DMSO(3mL),減壓下以超音波脫氣。在反應液中添加1,3-雙(二苯基膦基)丙烷(dppp)(18mg)、乙酸鈀(II)(10mg)、氯化鋰(92mg)、甲酸鈉(148mg)、二異丙基乙胺(0.34mL)及乙酸酐(0.19mL),以一氧化碳取代,在90℃下攪拌4小時。在反應混合物中添加0.1N的鹽酸水溶液後,以乙酸乙酯萃取,將所得的有機層以無水硫酸鈉乾燥後,減壓濃縮。將所得的殘渣以矽膠管柱層析法精製,得以下物性值的標題化合物(40mg)。
1H-NMR(CDCl3):δ1.18,1.44-1.51,1.64-1.79,1.85-1.90,2.35-2.48,2.57-2.78,2.99-3.17,3.84-3.91,4.03-4.11,7.18,
7.24-7.36,7.52,7.89,8.81,9.29。
實施例18
代替參考例11製造的化合物而使用參考例24製造的化合物,而使用甲胺鹽酸鹽或使用相對應的胺化合物,實施與參考例12→實施例1同樣的操作,而得有以下物性值的本發明化合物。
實施例18-1:4-[4-氰基-2-({[(1R,2R)-6’-(甲基胺甲醯基)-2’,3’-二氫螺[環丙烷-1,1’-茚]-2-基]羰基}胺基)苯基]丁酸
TLC:Rf 0.29(二氯甲烷:甲醇=20:1);1H-NMR(CDCl3):δ 1.26-1.31,1.66-1.78,1.82-1.87,2.23-2.30,2.34-2.48,2.52-2.71,2.91-3.03,3.04,3.13-3.27,6.21-6.29,7.17,7.19-7.35,7.70,8.82,9.56。
實施例18-2:4-{4-氰基-2-[({(1R,2R)-6’-[(2-甲氧基乙基)胺甲醯基]-2’,3’-二氫螺[環丙烷-1,1’-茚]-2-基}羰基)胺基]苯基}丁酸
TLC:Rf 0.50(二氯甲烷:甲醇=20:1);1H-NMR(CDCl3):δ 1.25-1.31,1.65-1.77,1.81-1.86,2.23-2.30,2.35-2.47,2.51-2.71,2.91-3.03,3.13-3.27,3.41,3.54-3.78,6.62-6.67,7.17,7.19-7.30,7.34,7.66,8.82,9.51。
實施例18-3:4-{4-氰基-2-[({(1R,2R)-6’-[(1-甲基-1H-吡唑-4-基)胺甲醯基]-2’,3’-二氫螺[環丙烷-1,1’-茚]-2-基}羰基)胺基]苯基}丁酸
TLC:Rf 0.28(二氯甲烷:甲醇=20:1);1H-NMR(CDCl3):δ 1.26-1.34,1.68-1.78,1.81-1.88,2.25-2.31,2.43-2.72.2.95-3.06,3.17-3.23,3.92,7.16-7.33,7.42,7.52,7.75,7.86,7.99,8.83,9.54。
實施例19:4-[4-氰基-2-({[(1R,2R}-6’-(3-吡啶基)-2’,3’-二氫螺[環丙烷-1,1-茚]-2-基]羰基}胺基)苯基]丁酸
使用參考例23製造的化合物,代替4-氟苯基硼酸而使用吡啶-3-硼酸,實施與參考例15→實施例1同樣的操作,而得有以下物性值的本發明化合物。
TLC:Rf 0.30(二氯甲烷:甲醇=20:1);1H-NMR(CD3OD):δ 1.58-1.66,1.75-1.90,2.25-2.45,2.47-2.55,2.68-2.79,3.07-3.16,7.15,7.34-7.56.7.98,8.10,
8.52,8.78。
參考例25:(2’R,4S)-2’-{[5-氰基-2-(4-乙氧基-4-側氧基丁基)苯基]胺甲醯基}-7-氟-2,3-二氫螺[1-苯并哌喃-4,1’-環丙烷]-6-羧酸
1H-NMR(CDCl3):δ1.13,1.66-1.78,1.84-1.90,2.25-2.35,2.42-2.47,2.58-2.67,3.60-3.73,3.78-3.90,4.10-4.22,4.35-4.44,6.60,7.19,7.26-7.33,7.50,8.71,9.37。
實施例20
代替參考例11製造的化合物而使用參考例25製造的化合物,而使用甲胺鹽酸鹽或相對應的胺化合物使用,實施與參考例12→實施例1同樣的操作,而得有以下物性值的本發明化合物。
TLC:Rf 0.74(二氯甲烷:甲醇=10:1);1H-NMR(CDCl3):δ 1.18-1.29,1.50-1.62,1.70-1.80,2.05-2.15,2.20-2.27,2.44-2.76,3.03,3.54-3.60,4.31-4.40,4.54-4.59,6.57,6.82-6.95,7.20,7.24-7.33,8.06,8.88,9.94。
TLC:Rf 0.49(二氯甲烷:甲醇=10:1);1H-NMR(CDCl3):δ 1.19-1.26,1.58-1.64,1.68-1.84,2.05-2.29,2.45-2.77,3.39,3.53-3.64,3.65-3.72,4.31-4.43,4.54-4.62,6.57,7.17-7.34,8.05,8.88,9.93。
TLC:Rf 0.62(己烷:乙酸乙酯=1:3);1H-NMR(DMSO-d6):δ1.09,1.55,1.65-1.78,2.02-2.28,
2.47,2.60-2.71,3.17-3.33,4.12,4.33,6.73,7.19,7.41,7.56,7.88,8.07,9.89,12.11。
TLC:Rf 0.56(己烷:乙酸乙酯=1:2);1H-NMR(DMSO-d6):δ0.87,1.42-1.58,1.62-1.78,2.04-2.23,2.42,2.60-2.69,3.11-3.23,4.12,4.31,6.73,7.18,7.41,7.56,7.88,8.06,9.90,12.11。
TLC:Rf 0.68(己烷:乙酸乙酯=1:3);1H-NMR(DMSO-d6):δ1.13,1.53,1.63-1.79,2.02-2.24,2.46,2.61-2.69,3.96-4.18,4.33,6.72,7.14,7.41,7.56,7.80-7.92,9.89,12.11。
TLC:Rf 0.38(二氯甲烷:甲醇=10:1);1H-NMR(CDCl3):δ 1.46-1.80,2.18-2.24,2.48-2.75,4.09-4.32,6.55,6.75-6.87,7.21,7.25-7.34,8.66,9.00。
參考例26:4-(2-{[(2’R,4S)-6-苄醯基-2,3-二氫螺[1-苯并哌喃-4,1’-環丙烷]-2’-羰基]胺基}-4-氰基苯基)丁酸乙酯
在參考例10製造的化合物(30mg)的苯甲醚(1mL)溶液中添加苯基硼酸(10mg)、碳酸鉀(22mg)、[1,1’-雙(二苯基膦基)鐵莘]二氯化鈀(II)二氯甲烷錯合物(9mg),在一氧化碳環境、80℃下攪拌3小時。在反應混合物中注入飽和碳酸氫鈉水溶液,以乙酸乙酯萃取。將所得的有機層以飽和食鹽水清洗,以無水硫酸鎂乾燥後,減壓濃縮。將所得的殘渣以矽膠管柱層析法(山善自動精製裝置)精製,得以下物性值的標題化合物(18mg)。
TLC:Rf 0.38(己烷:乙酸乙酯=1:1);1H-NMR(CDCl3):δ0.99,1.61-1.80,1.87,2.27-2.36,2.37-2.44,2.61,2.71,3.43-3.56,3.66,3.81,4.11-4.23,4.32-4.42,6.86,7.19,7.27,7.42-7.62,7.73,8.73,9.38。
代替參考例12製造的化合物而使用參考例26製造的
化合物,實施與實施例1同樣的操作,而得有以下物性值的本發明化合物。
TLC:Rf 0.42(二氯甲烷:甲醇=9:1);1H-NMR(DMSO-d6):δ 1.53-1.64,1.64-1.78,2.10-2.30,2.41-2.75,3.20-3.49,4.10-4.23,4.33-4.45,6.94,7.36-7.45,7.46-7.59,7.60-7.73,7.87,9.89,12.09。
實施例23
代替苯基硼酸,而使用相對應的硼酸,實施與參考例26→實施例1同樣的操作,而得有以下物性值的本發明化合物。
TLC:Rf 0.41(二氯甲烷:甲醇=9:1);1H-NMR(CDCl3):δ 1.02-1.38,1.67-1.83,2.06-2.38,2.45-2.78,4.33-4.45,4.53-4.67,6.89,7.19,7.25-7.30,7.87,7.98,8.88,9.85。
TLC:Rf 0.40(二氯甲烷:甲醇=9:1);1H-NMR(CDCl3):δ 1.20-1.31,1.70-1.85,2.05-2.20,2.23-2.33,2.44-2.83,4.33-4.45,4.53-4.65,6.85,7.20,7.28,7.70,8.06,8.89,9.83。
參考例27:4-(4-氰基-2-{[(2’R,4S)-6-(甲磺醯基)-2,3-二氫螺[1-苯并哌喃-4,1’-環丙烷]-2’-羰基]胺基}苯基)丁酸乙酯
在氬環境下,在L-脯胺酸(7mg)的DMSO(2mL)溶液中添加氫氧化鈉(2.3mg),在室溫下攪拌30分。在所得的反應混合物中添加參考例10製造的化合物(40mg)、碘化銅(11mg)、甲基亞磺酸鈉(37mg),使用微波反應裝置(Biotage社製)在100℃下攪拌1小時。將反應混合物以矽膠管柱層析法(山善自動精製裝置)精製,得以下物性值的標題化合物(33mg)。
TLC:Rf 0.58(己烷:乙酸乙酯=1:3);1H-NMR(CDCl3):δ1.13,1.66-1.80,1.91,2.20-2.45,2.53-2.64,2.67,3.01,3.45-3.60,3.73-3.86,4.11-4.20,4.40,6.96,7.20,7.30,7.40,7.63,8.71,9.44。
代替參考例12製造的化合物而使用參考例27製造的化合物,實施與實施例1同樣的操作,而得有以下物性值的本發明化合物。
TLC:Rf 0.42(二氯甲烷:甲醇=9:1);1H-NMR(DMSO-d6):δ1.53-1.64,1.72,1.80-1.87,2.08-2.29,2.35-2.74,3.18,4.05-4.20,4.32-4.44,7.02,7.40,7.42,7.57,7.64,7.87,9.95,12.10。
代替甲基亞磺酸鈉而使用環丙基亞磺酸鈉,實施與參考例27→實施例1同樣的操作,而得有以下物性值的本發明化合物。
TLC:Rf 0.40(二氯甲烷:甲醇=9:1);1H-NMR(CDCl3):δ 1.00-1.15,1.20-1.43,1.60-1.82,2.09-2.35,2.38-2.60,2.63-2.75,3.39,4.35,4.57,6.95,7.20,7.29,7.59,7.71,8.90,9.64。
參考例28:(2’R,4S)-7-(苄氧基)-2,3-二氫螺[1-苯并哌喃-4,1’-環丙烷]-2’-羧酸
TLC:Rf 0.21(己烷:乙酸乙酯=1:1);1H-NMR(CDCl3):δ 1.53-1.70,2.07,2.20,4.20-4.09,4.23-4.33,5.01,6.46,6.52,6.60,7.27-7.44。
HPLC保持時間:12.2分(CHIRALPAK IC 4.6mm×250mm己烷:乙酸乙酯:甲酸=97:3:1)。
參考例29:4-(2-{[(2’R,4S)-7-(苄氧基)-2,3-
二氫螺[1-苯并哌喃-4,1’-環丙烷]-2’-羰基]胺基}-4-氰基苯基)丁酸乙酯
代替參考例6製造的化合物而使用參考例28製造的化合物,實施與參考例10同樣的操作,得以下物性值的標題化合物。
1H-NMR(CDCl3):δ 1.13,1.54-1.61,1.64-1.81,2.22,2.37-2.45,2.51-2.66,3.55-3.68.3.72-3.86,4.03,4.16,4.22-4.32,4.99,6.42-6.51,6.73,7.18,7.28,7.29-7.44,8.72,9.28。
代替參考例12製造的化合物而使用參考例29製造的化合物,實施與實施例1同樣的操作,而得有以下物性值的本發明化合物。
TLC:Rf 0.42(二氯甲烷:甲醇=9:1);1H-NMR(CDCl3):δ1.58,1.68-1.84,2.10-2.20,2.36,2.46,
2.50-2.75,4.03-4.16,4.20-4.32,5.02,6.48,6.54,6.71,7.20,7.27-7.45,8.54,8.82。
參考例30:4-(4-氰基-2-{[(2’R,4S)-7-羥基-2,3-二氫螺[1-苯并哌喃-4,1’-環丙烷]-2’-羰基]胺基}苯基)丁酸乙酯
在參考例29製造的化合物(650mg)的乙醇(50mL)及乙酸乙酯(10mL)的混合溶液,添加ASCA-2(商品名,50%濕物,300mg),在氫環境下,在室溫下攪拌8小時。將反應混合物以Celite(商品名)過濾後,將濾液減壓濃縮。將所得的殘渣以矽膠管柱層析法(山善自動精製裝置)精製後,以三級丁基甲基醚及己烷清洗,得以下物性值的標題化合物(368mg)。
TLC:Rf 0.28(己烷:乙酸乙酯=1:1);1H-NMR(CDCl3):δ1.16,1.55-1.62,1.66-1.80,2.16-2.25,2.38-2.47,2.52-2.66,3.60-3.73,3.76-3.87,4.04-4.15,4.22-4.32,4.63,6.28-6.37,6.69,7.18,7.28,8.71,9.28。
代替參考例20製造的化合物而使用參考例30製造的化合物,代替4-氟苯基硼酸而使用吡啶-3-硼酸,實施與參
考例23→參考例15→實施例1同樣的操作,而得有以下物性值的本發明化合物。
TLC:Rf 0.39(二氯甲烷:甲醇=9:1);1H-NMR(DMSO-d6):δ1.55-1.63,1.65-1.80,2.09-2.18,2.21,2.40-2.47,2.53-2.77,4.04-4.16,4.28-4.38,7.05,7.15,7.25,7.41,7.43-7.50,7.57,7.88,8.02-8.08,8.55,8.85,9.90,12.10。
實施例28
代替參考例20製造的化合物而使用參考例30製造的化合物,並使用甲胺鹽酸鹽或2-甲氧基乙胺,實施與參考例23→參考例24→參考例12→實施例1同樣的操作,而得有以下物性值的本發明化合物。
TLC:Rf 0.40(二氯甲烷:甲醇=9:1):1H-NMR(DMSO-d6):δ1.56,1.63-1.80,2.02-2.15,2.20,2.42,2.57-2.69,2.74,4.01-4.13.4.23-4.37,6.99,7.24,7.36,7.40,7.56,7.86,8.34,9.89,12.11。
TLC:Rf 0.40(二氯甲烷:甲醇=9:1);1H-NMR(CDCl3):δ 1.63-1.89,2.00-2.13,2.25-2.47,2.48-2.73,2.78-2.93,3.24-3.39,3.51,3.55-3.65,3.85-4.06,6.68,6.79,7.06,7.20,7.29,7.98,8.78,9.84。
代替4-酮而使用6-(苄氧基)-3,4-二氫-2H-1-苯并哌喃-4-酮,代替碘甲烷而使用碘乙烷,實施與參考例1→參考例2→參考例3→參考例4→參考例6→參考例10→實施例1同樣的操作,而得有以下物性值的本發明化合物。
TLC:Rf 0.47(二氯甲烷:甲醇=9:1);1H-NMR(CDCl3):δ 1.46-1.55,1.62-1.80,2.12-2.18,2.43-2.48,2.51-2.76,4.18-4.26,4.95-5.07,6.62,6.75-6.80,7.18,7.28,7.31-7.45,8.68,9.14。
參考例31:4-(4-氰基-2-{[(2’R,4S)-6-羥基-2,3-二氫螺[1-苯并哌喃-4,1’-環丙烷]-2’-羰基]胺基}苯基)丁酸乙酯
TLC:Rf 0.66(己烷:乙酸乙酯=1:2);1H-NMR(CDCl3):δ1.16,1.52-1.58,1.66-1.83,2.21,2.41,2.55-2.73,3.65-3.78,3.84-3.98,4.02-4.13,4.17-4.27,4.54,6.33,6.55,6.68,7.19,7.28,8.74,9.38。
代替參考例12製造的化合物而使用參考例31製造的化合物,實施與實施例1同樣的操作,而得有以下物性值的本發明化合物。
TLC:Rf 0.38(二氯甲烷:甲醇=9:1);1H-NMR(CD3OD):δ1.55-1.70,1.77-1.90,2.11-2.20,2.33,2.40-2.48,2.67-2.78,4.04-4.15,4.17-4.26,6.28,6.53,6.64,7.41,7.48,7.90。
實施例31
TLC:Rf 0.45(二氯甲烷:甲醇=9:1);1H-NMR(CD3OD):δ 1.58-1.76,1.77-1.90,2.09-2.21,2.33,2.47,2.72,4.08-4.17,4.18-4.29,5.11,6.53,6.70,6.77,7.21,7.42,7.48,7.92,7.96。
實施例31-2:4-(4-氰基-2-{[(2’R,4S)-6-甲氧基-2,3-二氫螺[1-苯并哌喃-4,1’-環丙烷]-2’-羰基]胺基}苯基)丁酸
TLC:Rf 0.35(乙酸乙酯);1H-NMR(DMSO-d6):δ1.50-1.56,1.65-1.80,2.00-2.09,2.20,2.35-2.47,2.55-2.60,2.61-2.69,2.70-2.75,3.69,3.92-4.04,4.15-4.26,6.43,6.71,7.40,7.56,7.85,9.86,12.11。
TLC:Rf 0.47(二氯甲烷:甲醇=9:1);1H-NMR(CDCl3):δ 1.58-1.68,1.68-1.80,2.03-2.15,2.18-2.46,2.41-2.50,2.50-2.63,2.64-2.83,4.00-4.13,4.20-4.31,5.05,5.17,6.33,6.48,6.63,7.10,7.20,7.28,7.73,8.62,8.91。
參考例32:(2’R,4S)-7-甲氧基-2,3-二氫螺[1-苯并哌喃-4,1’-環丙烷]-2’-羧酸乙酯
代替參考例3製造的化合物而使用參考例28製造的化合物,代替碘甲烷而使用碘乙烷,實施與參考例4同樣的操作。在所得的化合物(2.1g)的乙酸乙酯(5mL)溶液,添加氫氧化鈀/碳(10%濕物,0.2g),在氫環境、室溫下攪拌30分鐘。將反應混合物以Celite(商品名)過濾後,將濾液減壓濃縮。在所得的殘渣(1.31g)的DMF(5mL)溶液中添加碳酸鉀(1.46g)後,滴下碘甲烷(1.5g),在室溫下攪拌一夜。將反應混合物注入於冰水,以己烷-乙酸乙酯混合溶液萃取。將所得的有機層以水、飽和食鹽水清洗,以無水硫酸鈉乾燥後,減壓濃縮,得以下物性值的標題化合物(1.38g)。
TLC:Rf 0.69(己烷:乙酸乙酯=1:1);1H-NMR(CDCl3):δ1.25,1.55-1.60,2.05,2.13-2.20,3.75,4.05-4.20,4.23-4.31,6.38,6.45,6.59。
實施例33
代替參考例4製造的化合物而使用參考例32製造的化合物,使用甲胺鹽酸鹽或相對應的胺化合物,實施與參考例5→參考例6→參考例10→參考例11→參考例12→實施例1同樣的操作,而得有以下物性值的本發明化合物。
TLC:Rf 0.39(二氯甲烷:甲醇=9:1);1H-NMR(DMSO-d6):δ1.42-1.60,1.65-1.79,2.00-2.29,2.32-2.74,2.77,3.83,4.05-4.17,4.24-4.38,6.54,7.35-7.45,7.55,7.89,7.98,9.88,12.12。
TLC:Rf 0.39(二氯甲烷:甲醇=9:1);1H-NMR(DMSO-d6):δ1.46-1.60,1.64-1.81,2.00-2.29,2.36-2.76,3.27,3.38-3.48,3.85,4.06-4.18,4.25-4.36,6.56,7.40,7.41,7.55,7.89,8.09,9.87,12.10。
TLC:Rf 0.54(己烷:乙酸乙酯=1:3);1H-NMR(DMSO-d6):δ1.09,1.47-1.58,1.65-1.78,2.04-2.23,2.47,2.60-2.69,3.21-3.30,3.84,4.11,4.30,6.54,7.35-7.44,7.56,7.89,8.04,9.88,12.11。
TLC:Rf 0.70(己烷:乙酸乙酯=1:3);1H-NMR(DMSO-d6):δ0.87,1.41-1.58,1.63-1.76,2.00-2.23,2.43,2.59-2.70,3.13-3.28,3.84,4.11,4.29,6.55,7.32-7.42,7.56,7.90,8.02,9.88,12.11。
TLC:Rf 0.68(己烷:乙酸乙酯=1:3);1H-NMR(DMSO-d6):δ1.14,1.46-1.58,1.63-1.78,2.01-2.22,2.46,2.58-2.69,3.84,3.97-4.16,4.31,6.55,7.34-7.43,7.56,7.74,7.89,9.87,12.09。
代替參考例4製造的化合物而使用參考例32製造的化合物,實施與參考例5→參考例6→參考例10→參考例11→參考例13→實施例1同樣的操作,而得有以下物性值
的本發明化合物。
TLC:Rf 0.38(二氯甲烷:甲醇=9:1);1H-NMR(CDCl3):δ 1.16-1.27,1.50-1.58,1.66-1.85,2.09-2.30,2.42-2.83,3.46,3.85,4.35,4.55,6.48,7.19,7.27,7.68,8.88,9.90。
在參考例10製造的化合物(72mg)的DMF(1mL)溶液中添加碳酸銫(129mg)、[(2-二環己基膦基-2’,4’,6’-三異丙基-1,1’-聯苯)[2-(2-胺基乙基)苯基]氯化鈀(II)(9mg)、嗎福林(34mg),使用微波反應裝置(Biotage社製)在110℃下攪拌1小時。在反應混合物中注入碳酸鉀水溶液,以乙酸乙酯萃取。將所得的有機層以飽和食鹽水清洗,以無水硫酸鎂乾燥後,減壓濃縮。將所得的殘渣以矽膠管柱層析法(山善自動精製裝置)精製,而得乙酯體(46mg)。使用所得的乙酯體代替參考例12製造的化合物實施與實施例1同樣的反應而得本發明化合物。
TLC:Rf 0.36(二氯甲烷:甲醇=9:1);1H-NMR(DMSO-d6):δ 1.45-1.55,1.62-1.80,2.00-2.10,2.16-2.26,2.32-2.77,2.89-3.06,3.65-3.78,3.90-4.05,4.13-4.26,6.39,6.67,6.74,7.40,7.56,7.84,9.87,12.08。
參考例33:4-(4-氰基-2-{[(2’R,3S)-5-碘-2H-螺[1-苯并呋喃-3,1’-環丙烷]-2’-羰基]胺基}苯基)丁酸
乙酯
代替4-酮而使用二氫苯并呋喃-3-酮(3-coumaranone),代替碘甲烷而使用碘乙烷,實施與參考例1→參考例2→參考例3→參考例4→參考例5→參考例6→參考例10同樣的操作,得以下物性值的標題化合物。
1H-NMR(CDCl3):δ1.32,1.57,1.66-1.82,2.36-2.70,2.79,3.95-4.22,4.70,6.60,7.02,7.20,7.24-7.32,7.38,8.74,9.40。
實施例36:4-[4-氰基-2-({[(2’R,3S)-5-(3-吡啶基)螺[1-苯并呋喃-3,1’-環丙烷]-2’-基]羰基}胺基)苯基]丁酸
代替參考例10製造的化合物而使用參考例33製造的化合物,代替4-氟苯基硼酸而使用吡啶-3-硼酸,實施與參考例15→實施例1同樣的操作,而得有以下物性值的本發明化合物。
TLC:Rf 0.42(二氯甲烷:甲醇=9:1);1H-NMR(CDCl3):δ1.06,1.62-1.92,2.58,2.78,2.94,4.85,6.47,6.87,7.01-7.40,8.41,8.61,8.79,9.75。
實施例37
代替參考例10製造的化合物而使用參考例33製造的化合物,並使用甲胺鹽酸鹽或2-甲氧基乙胺,實施與參考例11→參考例12→實施例1同樣的操作,而得有以下物性值的本發明化合物。
實施例37-1:4-[4-氰基-2-({[(2’R,3S)-5-(甲基胺甲醯基)螺[1-苯并呋喃-3,1’-環丙烷]-2’-基]羰基}胺基)苯基]丁酸
TLC:Rf 0.47(二氯甲烷:甲醇=9:1);1H-NMR(CDCl3):δ1.57,1.61-1.86,2.30-2.73,3.02,3.22,4.59,4.73,6.18,6.76,7.18,7.20-7.32,7.59,8.70,9.51。
實施例37-2:4-{4-氰基-2-[({(2’R,3S)-5-[(2-甲氧基乙基)胺甲醯基]螺[1-苯并呋喃-3,1’-環丙烷]-2’-基}羰基)胺基]苯基}丁酸
TLC:Rf 0.57(二氯甲烷:甲醇=9:1);1H-NMR(CDCl3):δ1.58,1.60-1.85,2.30-2.75,3.19,3.41,3.50-3.73,4.61,4.74,6.47-6.62,6.77,7.19,7.21-7.40,7.56,8.72,9.47。
參考例34:6-碘-3,3-二甲基-2,3-二氫-1H-茚-1-酮
在6-胺基-3,3-二甲基-茚烷-1-酮(2.1g)的鹽酸(5mol/L,15mL)水溶液,在冰冷下,滴下亞硝酸鈉的水溶液(4.5mol/L,4mL)後,攪拌30分鐘。確認原料消失以後,在冰冷下,滴下碘化鉀的水溶液(4mol/L,6mL)後,添加乙腈(20mL),在室溫下攪拌1小時。在反應混合物中,在冰冷下添加飽和碳酸氫鈉水溶液後,以乙酸乙酯萃取。將所得的有機層以飽和硫代硫酸鈉水溶液清洗,以無水硫酸鈉乾燥後,減壓濃縮。將所得的殘渣以矽膠管柱層析法精製,得以下物性值的標題化合物(2.66g)。
TLC:Rf 0.86(己烷:乙酸乙酯=1:1);1H-NMR(CDCl3):δ1.38-1.44,2.59,7.25-7.30,7.90,8.03。
參考例35:4-(4-氰基-2-{[(1S,2R)-6’-碘-3’,3’-二甲基-2’,3’-二氫螺[環丙烷-1,1’-茚]-2-羰基]胺基}苯基)丁酸乙酯
代替4-酮而使用參考例34製造的化合物,實施與參考例1→參考例2→參考例3→參考例10同樣的操作,得以下物性值的標題化合物。
1H-NMR(CDCl3):δ 1.14-1.35,1.44,1.64-1.79,1.79-1.88,2.17,2.28-2.50,2.50-2.71,3.83,4.05,6.91,7.11,7.19,7.22-7.31,7.45-7.53,8.79,9.28。
實施例38
代替參考例10製造的化合物而使用參考例35製造的化合物,並使用甲胺鹽酸鹽或2-甲氧基乙胺,實施與參考例11→參考例12→實施例1同樣的操作,而得有以下物性值的本發明化合物。
實施例38-1:4-[4-氰基-2-({[(1S,2R)-6’-[(2-甲氧基乙基)胺甲醯基]-3’,3’-二甲基-2’,3’-二氫螺[環丙烷-1,1’-茚]-2-基]羰基}胺基)苯基]丁酸
TLC:Rf 0.64(乙酸乙酯:甲醇=9:1);1H-NMR(CDCl3):δ 1.28-1.40,1.72,1.86,2.01-2.10,2.14-2.23,2.63,3.16,3.40,3.53-3.81,6.64,7.17,7.22-7.31,7.33-7.44,7.70,8.82,9.51。
實施例38-2:4-[4-氰基-2-({[(1S,2R)-3’,3’-二甲基-6’-(甲基胺甲醯基)-2’,3’-二氫螺[環丙烷-1,1’-茚]-2-基]羰基}胺基)苯基]丁酸
TLC:Rf 0.55(乙酸乙酯:甲醇=9:1);1H-NMR(CDCl3):δ1.29-1.42,1.63-1.801.83-1.90,1.98-2.11,2.11-2.24,2.32-2.56,2.57-2.69,3.04,3.19,6.24,7.11-7.19,7.21-7.34,7.72,8.82,9.57。
實施例39:4-[4-氰基-2-({[(1S,2R)-3’,3’-二甲基-6’-(3-吡啶基)-2’,3’-二氫螺[環丙烷-1,1’-茚]-2-基]羰基}胺基)苯基]丁酸
代替參考例10製造的化合物而使用參考例35製造的化合物,代替4-氟苯基硼酸而使用吡啶-3-硼酸,實施與參考例15→實施例1同樣的操作,而得有以下物性值的本發明化合物。
TLC:Rf 0.62(乙酸乙酯:甲醇=9:1);1H-NMR(CDCl3):δ 0.59,1.27-1.43,1.55-1.69,1.79,2.18-2.38,2.52-2.64,2.64-2.91,6.53,7.16-7.35,7.54,8.39-8.50,8.75-8.84,9.35。
藥理實驗例:
藥理實驗例1:使用前列腺素類受體亞型(prostanoid receptor subtype)表現細胞的EP4拮抗活性測定實驗
遵照西垣(Nishigaki)等的方法(非專利文獻4),調製分別表現大鼠EP4受體亞型的CHO細胞以供實驗。將培養到次匯合的細胞剝離,以分析培養基(assay medium)(MEM含1mmol/L IBMX,1% HSA)懸浮成為1×106cells/mL。在細胞懸浮液(25μL)中添加獨立含有PGE2,或含有其與試驗化合物的溶液(25μL)使終濃度成為10nmol PGE2/L而開始反應,在室溫下反應30分鐘後,遵照cAMP分析套組(assay kit)(CISBIO社製)所述的方法,定量細胞內的cAMP量。
又,試驗化合物的拮抗作用(IC50值)是以作為對PGE2獨立的次極大量(submaximal)的cAMP產生作用的濃度10nM的反應的抑制率計算,求得IC50值。
其結果,得知本發明化合物具有強力的EP4受體拮抗活性。例如,數種本發明化合物的IC50值是如下述的第1表所示。另一方面,專利文獻2所述的實施例8-128的EP4受體拮抗活性是非常弱的2800nM。
藥理實驗例2:藥物動力學性質試驗(肝微粒體安定性試驗)
(1)被驗物質溶液的調製
將被驗物質(本發明化合物及比較化合物)的DMSO溶液(10mmol/L;5μL)以50%乙腈水溶液(195μL)稀釋,調製250μmol/L的被驗物質溶液。
(2)調製標準試樣(反應開始後即刻的試樣)
在以水浴預先加溫37℃的反應用容器中,添加含有NADPH-輔助因子(BD-Bioscience社)及1mg/mL人肝微粒體的0.1mol/L磷酸緩衝液(pH7.4)245μL,預培養5分鐘。在其中添加先前的被驗物質溶液5μL,開始反應(最終濃度1μmol/L)。反應開始後即刻採取反應溶液20μL,將該溶液添加於乙腈(含有內部標準物質坎地沙坦西(Candesartan))180μL而停止反應。將該停止反應的溶液(20μL;反應開始後即刻的試樣溶液)在除蛋白用過濾板上與50%乙腈(180μL)攪拌後,吸引過濾,將該濾液作為標準試樣。
(3)調製反應試樣(反應60分鐘後的試樣)
將先前的反應溶液於37℃下培養60分鐘後,採取該反應溶液20μL,添加乙腈(含有內部標準物質坎地沙坦西)180μL,而停止反應。將該反應已停止的溶液(20μL;反應60分鐘的試樣溶液)在除蛋白用過濾板上與50%乙腈(180μL)攪拌後,吸引過濾,將該濾液作為反應試樣。
(4)評估方法
使用由LC-MS/MS所得的尖峰面積,將標準試樣的被
驗物質量(X)及反應試樣的被驗物質量(Y),依照下式,算出被驗物質的殘存率(%)。
殘存率(%)=(Y/X)×100
X:標準試樣的被驗物質量(Ratio=被驗物質的尖峰面積/內部標準物質的尖峰面積)
Y:反應試樣的被驗物質量(Ratio=被驗物質的尖峰面積/內部標準物質的尖峰面積)
(5)結果
得知本發明化合物是對人肝微粒體安定性高(殘存率(%)的值大)。例如,數種本發明化合物的殘存率的值是如下述的第2表所示。另一方面,專利文獻2所述的實施例6-117的殘存率是35%。
藥理實驗例3:小鼠大腸癌細胞株CT26的同種移植模型的抗腫瘤效果
以小鼠大腸癌細胞株CT26的同種移植模型,評估本發明化合物的抗腫瘤效果。CT26是以含有10vol%的去活化牛胎兒血清(Fetal Bovine Serum;FBS)、100units/mL的盤尼西林及100μg/mL的鏈黴素的RPMI-1640培養基在
CO2保溫箱內培養。移植當日,除去培養上清液,以磷酸緩衝液(以下,簡寫為PBS。)清洗CT26後,回收。將回收的CT26懸浮於漢克氏緩衝液(Hank’s buffer),作為移植用細胞。在麻醉下在雌性Balb/C小鼠(日本Charles River公司)的右側背部,皮下移植30萬個的移植用細胞。將10mg/kg的本發明化合物,在移植當日實施1次經口投與,移植日以後實施每日2次的經口投與。又,對照群是與本發明化合物投與群在同期間投與蒸餾水。腫瘤體積(mm3)是使用電子測微器,測定腫瘤的短徑及長徑,依照以下的數式1及數式2算出相對腫瘤體積。
[數1]腫瘤體積=[(短徑)2×長徑]/2
[數2]相對腫瘤體積=移植第21日的各群的腫瘤體積中央值/移植第21日的對照群的腫瘤體積中央值
其結果,本發明化合物具有腫瘤增殖的抑制作用。例如,實施例2-2及實施例2-13的相對腫瘤體積是如第1圖所示。
[製劑例]
製劑例1
將以下的各成分以常法混合後打片,得一片中含有10mg的活性成分的片劑1萬片。
製劑例2
將以下的各成分以常法混合後,以除塵過濾器過濾,每安瓿充填5ml,以高壓釜加熱滅菌,得1安瓿中含有20mg的活性成分的安瓿1萬支。
[產業上的可利用性]
本發明化合物是對EP4受體具有拮抗活性,對起因於EP4受體的活性化的疾病的預防及/或治療有效。
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EA201992677A1 (ru) | 2017-05-18 | 2020-04-23 | Идорсия Фармасьютиклз Лтд | Пиримидиновые производные в качестве модуляторов pge2 рецепторов |
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JP7211358B2 (ja) * | 2017-05-22 | 2023-01-24 | 小野薬品工業株式会社 | Ep4アンタゴニスト |
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