KR20030040225A - 씨오엠티 저해효과를 가지는 쿠마린 유도체 - Google Patents

씨오엠티 저해효과를 가지는 쿠마린 유도체 Download PDF

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KR20030040225A
KR20030040225A KR1020027017767A KR20027017767A KR20030040225A KR 20030040225 A KR20030040225 A KR 20030040225A KR 1020027017767 A KR1020027017767 A KR 1020027017767A KR 20027017767 A KR20027017767 A KR 20027017767A KR 20030040225 A KR20030040225 A KR 20030040225A
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cooh
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자르모 피스티넨
오바스카마르티
비드그렌주카
로타티모
마르조 이리페르투라-이코넨
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오리온 코포레이션
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Abstract

본 발명은 다음 일반구조식　I'의　화합물에 관한 것이다.
　　　　　
　　　여기에서，페닐잔기중의　두　OH-치환체는　상호간에　오르토　위치에　존재하며，　R1도　하이드록시기　하나의　오르토　위치에　존재한다; X , R1내지 R6는 청구항들에서 정의된 바와 같다.
본 발명의 화합물은 COMT 효소의 저해 활성을 보이므로, COMT 저해제로써 유용하다.

Description

씨오엠티　저해효과를　가지는　쿠마린　유도체{Coumarin derivatives with COMT inhibiting activity}
　　　COMT저해효과를　가지는　화합물들은　이미　공지이다．　예를들면，　COMT저해제로서　카테콜류　 및　이소프라본류의　유도체들은　미국특허　제５,４４６,１９４호，　미국특허　제　５,３８９,６５３호 및　미국특허　제　３,９７３,　６０８호에　각각　기술되어　있다．　COMT　저해제들은　예를들면　파킨슨씨병의치료에　사용된다．　COMT　저해제들은　예를들면，　고혈압，　심부전증， 및　우울증（예：전술한　미국특허　제　５,４４６,１９４호）의　치료제 및　당뇨병성　혈관기능장애의　예방을　위한　저해제（예：WO-A-９８　２７９７３호）로서　유용하다．
　　　공지의　쿠마린　유도체에　관하여는，　WO-A-93　１６０６４호는　항암제로사용되는　타이로신　키나제　저해효과를　가지는　쿠마린류를　기술하고　있다．더욱이，　J. Mazur 및　T. Zawadowski(acta Pol. Pharm. vol. 54(5), 1997, p 371-374, 또한　Pol. J. Chem. volv．　５５（５），　１９８，　p　１１５１－５참조）, D. Desai 및　R . H. Mehta(Indian J. Heterochcl. Chem. vol. 6(3), 1997, p. 241-244)　 및　A.C. Jain et al.(Bull. Chem. Soc. Jpn, vol. 52(4), p. 1203-4)에는　예를들면，　항박테리아성，　저혈압，　진경　및／또는　항혈액암　효과를　가지는　여러　쿠마린　유도체들에　관하여　기술하고　있다．
본　발명은　쿠마린　유도체，　그　약학적으로　허용되는　염　 및　에스테르에　관한　것이다．　본　발명은　또한　그　약학적　조성물　및　카테콜－O－메틸트랜스페라제（COMT)　효소의　저해제로서의　용도에　관한　것이다．
본　발명은　일반구조식　I'의　화합물，　또는　그　약학적으로　허용되는염류　또는　그　약학적으로　허용되는　에스테르류를　제공하는　것이다．
　　　　　
　　　여기에서，　페닐잔기중의　두　OH-치환체는　상호간에　오르토　위치에　존재하며，　R1도　하이드록시기　하나의　오르토　위치에　존재한다．
X는　O　또는　NR7;여기에서　R7은　H,(C1-C6)알킬，또는(C1-C6)알킬－COOH;
R1은　NO2,　 CN,　 CHO, 　CF3　또는 (C1-C6)알킬－CO-;
R2및　R3는　각각　독립적으로　H, OH, 할로겐，　NO2, SH, NH2, (C1-C6)알킬，(C2-C6)알케닐, (C1-C6)알콕시, OH-(C1-C6)알킬, 할로－(C1-C6)알킬, 모노－　또는디－(C1-C6)알킬아미노, SO2R10, -CO-(C1-C9)알킬, －（Y)n-(B)m-COOH 및　－（Y)n-(B)m-R8; 여기에서
　 　m은　０　또는　１；
　 　n은　０　또는　１；
　 　Y는　-CO-　또는　-CHOH-;
B는　(C1-C6)알킬렌　또는　(C2-C6)알케닐렌；
R8은　페닐，　나프틸，　(C3-C7)사이클로알킬，　또는　각각　독립적으로 N, O 및　S에서　선택된　헤테로　원자　하나　내지　４개를　가지는　５－　또는６－원　헤테로사이클릴；　전술한　페닐，　나프틸，　(C3-C7)사이클로알킬　또는　５－　또는　６－원　(C3-C7)헤테로사이클은　OH,할로겐，　COOH, 5-테트라졸릴，NO2,SH, NH2, CN, CHO, =O, (C1-C6)알킬， (C1-C6)알콕시， 할로－(C1-C6)알킬，모노－　또는　디－(C1-C6)알킬아미노，CO-(C1-C6)알킬，CO-NH2, 모노－　또는디－(C1-C6)알킬아미노－CO-，NHOH,CONHOH 및　SO2R10에서　선택된　치환체　R9으로　하나　내지　４개로　임의로　치환될　수도　있으며；　또는
R8은　다음의　그룹이거나；　또는
또는　R2와　R3는　함께　－（CH2)r-을　형성하며；　여기에서　r은　３，　４　또는　５이며；
R4　 및　R5는　각각　독립적으로　H, 또는　(C1-C6)알킬이거나；　또는　R4와 R5는　함께　＝O, =S, 또는　=NR11을　형성하며；　여기에서　R11은　H또는(C1-C6)알킬이며；
R6는　H, NO2, CN, OH,　CHO, 할로겐，CF3또는　(C1-C6)알킬이며； 그리고，
R10은　(C1-C6)알킬，　NH2, OH, 또는　모노－　또는　디－(C1-C6)알킬아미노이다．
화합물　I'의　서브그룹으로서　본　발명은　구조식　I의　신규　화합물，　그　약학적으로　허용되는　염류，　또는　그　약학적으로　허용되는　에스테르류를　제공한다．
　　　　　
상기식에서　X, R1내지　R6는　구조식　I'의　화합물에서　정의된　바와　같으며，단，（a)　X가　O, R2가　메틸，　R3가　H, R４　및　R5가　함께　＝O를 형성하고，　R6가　H이고， 두　하이드록시　치환체가　７－　 및　８－위치에　있을　때，　R1은　CHO가　아니며，　（b)　X가　O,　R2가　H　또는　메틸，　R3가　H, R4및　R5가　함께　＝O를　형성하며，　R6가　H이고，　두　하이드록시　치환체가　６－　 및　７－위치에　있을　때，R1은　８－CO-CH3가　아니며，　（c)　X가　O, R2　 및　R3가　H, R4　및　R5가　모두　메틸이고，　R6가　H이고　두　하이드록시　치환체가　７－　 및　８－위치에　있을　때，　R1은　－CO-CH3가　아니다．
구조식　I'　 및　I의　화합물，　그　약학적으로　허용되는　염류，　또는그　약학적으로　허용되는　에스테르류는　COMT　저해　효과를　나타내며，　따라서　예를들면　파킨슨씨병의　치료와　같은　COMT　저해제가　유용한　질병이나　또는　증후군들의　치료에　치료제로　사용될　수　있다．
구조식　I'의　화합물들의　（１）　내지　（１５）의　다음의　서브　그룹들은　단독　또는　기타　바람직한　약물들과　병용하여　투여될　수　있다．
（１）R1이　NO2, CN, CF3, 바람직하게는　NO2또는　CN, 가장　바람직하게는　NO2;
（2） X가　O;
（3）X가　NR7;여기에서　R7은　H　또는　(C1-C6)알킬，바람직하게는　H;
（4） R2및　R3가　각각　독립적으로　H, OH, 할로겐，NO2, NH2, (C1-C6)알킬， (C2-C6)알케닐，(C1-C6)알콕시，OH-(C1-C6)알킬，할로－(C1-C6)알킬，모노－또는 디－(C1-C6)알킬아미노，　－CO-(C1-C9)알킬，　바람직하게는　-CO-(C1-C6)알킬，　 －（Y)n-(B)m-COOH, 바람직하게는　－（B)m-COOH 및　Y-B-C　OOH, 및　-(Y)n-(B)m-R8;여기에서　n은　０　또는　１；　m은　０　또는　１；　Y는　－CO- 또는　-CHOH-, 바람직하게는　－CO-；　B는　(C1-C6)알킬렌　또는　(C2-C6)알케닐렌，　바람직하게는　(C1-C6)알킬렌；　R8은　페닐，　나프틸，　(C3-C7)사이클로알킬，　또는５－또는　６－원　헤테로　사이클，　여기에서　헤테로원자는　각각　독립적으로　N, O 및　S에서　선택된다．　바람직하게는　페닐，(C3-C7)사이클로알킬，　또는　N, O，S에서　선택된　하나　내지　４개의　헤테로원자를　가지는　５－　또는６－원　헤티로사이클　환이다．　바람직하게는　페페리딜，　피페라지닐，　모르포리닐，테트라졸릴，　티에닐　또는　피리딜，　더욱　바람직하게는　테트라졸릴　또는　피리딜이며，　이들은　임의로　하나　또는　５개의　치환체，　바람직하게는　하나　내지　３개의　치환체，　더욱　바람직하게는　하나　내지　２개의치환체　R9（들）을　가진다．　이　R9치환체는　OH, 할로겐，　NO2, SH, NH2, CN, CHO,=O, (C1-C6)알킬， (C1-C6)알콕시， 할로－(C1-C6)알킬，　모노－　또는　디－(C1-C6)알킬아미노，-CO-(C1-C6)알킬，-CONH2,모노－　또는　디－(C1-C6)알킬아미노－CO-，－NHOH,CONHOH및　SO2R10,여기에서　R10은　전술한　바와　같은　OH,할로겐，COOH,５－테트라졸릴，NO2,NH2, CN, CHO, (C1-C6)알킬， (C1-C6)알콕시，　할로－(C1-C6)알킬，모노－　또는　디－(C1-C6)알킬아미노，　-CO-(C1-C6)알킬，　－CO-NH2, 모노－또는디－(C1-C6)알킬아미노－CO-, -NHOH, 및　－CONHOH; 바람직하게는　OH, 할로겐，　COOH, ５－테트라졸릴，　NO2, (C1-C6)알킬，　(C1-C6)알콕시　 및　할로－(C1-C6)알킬，가장　바람직하게는　OH, 할로겐，　COOH, 5-테트라졸릴，　NO2　및 (C1-C6)알킬에서　선택된다．
（５）　R2및　R3가　각각　독립적으로　H, -CO－(C1-C9)알킬，　－(Y)n-(B)m-COOH,(바람직하게는　－(B)m-COOH, 또는　-Y-B-COOH) 및　（Y)n-B)m-R8; 여기에서　n은　０　또는　１；　m은　０　또는　１；　Y는　－CO- 또는　-CHOH-(바람직하게는　-CO-); B는　(C1-C6)알킬렌　또는　(C2-C6)알케닐렌（바람직하게는　(C1-C6)알킬렌）；　R8은　페닐，　나프틸，　(C3-C7)사이클로알킬　또는　５－또는　６－원　헤테로사이클　환；　이　헤테로사이클　환은　N, O, S에서　선택된 하나　내지　４개의　헤테로원자를　포함하며（바람직하게는　피페리딜，　피페라지닐，모르포리닐，　테트라졸릴，　티에닐，　퓨릴　또는　피리딜；　　가장　바람직하게는　테트라졸릴　또는　피리딜），이　환은　치환되지　않거나　또는 치환체　R9(들）에　의하여　하나　내지　５개，　바람직하게는　하나　내지　３，가장　바람직하게는　하나　내지　２로　치환될　수　있으며，　R9은　OH, 할로겐，　COOH, ５－테트라졸릴，　NHOH, CONHOH, NO2, SH, NH2, CN, CHO, =O, (C1-C6)알킬，(C1-C6)알콕시，　할로－(C1-C6)알킬（바람직하게는　CF3）에서　선택된 치환체에서　선택된다．　또는　R8은　다음　구조의　그룹이다；
　　　　　　　　　
　　（６）R2및　R3가　각각　독립적으로 -CO－(C1-C９)알킬，－(Y)n-(B)m-COOH,(바람직하게는　－(B)m-COOH, 또는　-Y-B-COOH) 및　（Y)n-B)m-R8; 여기에서　n은　０또는　１；　m은　０　또는　１；　Y는　－CO- 또는　-CHOH-(바람직하게는　-CO-); B는（C1-C6)알킬렌　또는　(C2-C6)알케닐렌（바람직하게는　(C1-C6)알킬렌）；R8은　페닐，　나프틸，　(C3-C7)사이클로알킬　또는　５－　또는　６－원　헤테로사이클환；　이　헤테로사이클　환은　N, O, S에서　선택된　하나　내지　４개의 헤테로원자를　포함하며（바람직하게는　피페리딜，　피페라지닐，　모르포리닐，테트라졸릴，　티에닐，　퓨릴　또는　피리딜；　　가장　바람직하게는　테트라졸릴　또는　피리딜），　이　환은　치환되지　않거나　또는　치환체　R9(들）에　의하여　하나　내지　５개，　바람직하게는　하나　내지　３，가장　바람직하게는 하나　내지　２로　치환될　수　있으며，　R9은　OH, 할로겐，COOH,５－테트라졸릴，　NHOH,CONHOH, NO2, SH, NH2, CN, CHO, =O, (C1-C6)알킬，　(C1-C6)알콕시，　할로－(C1-C6)알킬（바람직하게는　CF3）；　바람직하게는　COOH, 5-테트라졸릴，　NHOH　 및　CONHOH, 더욱　바람직하게는　CPPH　또는　５－테트라졸릴에서 선택된　치환체에서　선택된다．　또는　R8은　다음　구조의　그룹이다；
　　　　　　　　　
（７）　R2　및　R3의　하나는　OH, 할로겐，NO2, NH2, (C1-C6)알킬，(C2-C6)알케닐，(C1-C6)알콕시，OH-(C1-C6)알킬，할로－(C1-C6)알킬，모노- 또는　디-(C1-C6)알킬아미노，-CO-(C1-C9)알킬　및　-(Y)n-（B)m-R8이고；　R2및　R3의　하나는　(Y)n-(B)-R8이다，　여기에서　n은　０　또는　１；　m은　０　또는　１；　Y는　－CO- 또는　-CHOH-(바람직하게는　-CO-); B는　(C1-C6)알킬렌 또는　(C2-C6)알케닐렌（바람직하게는　(C1-C6)알킬렌）；　R8은　페닐，　나프틸，　(C3-C7)사이클로알킬　또는　５－　또는　６－원　헤테로사이클　환；　이헤테로사이클　환은　N, O, S에서선택된　하나　내지　４개의　헤테로원자를　포함하며（바람직하게는　피페리딜，피페라지닐，　모르포리닐，　테트라졸릴，　티에닐，　퓨릴　또는　피리딜；　　가장　바람직하게는　테트라졸릴　또는　피리딜），　이　환은　치환되지　않거나또는　치환체　R9(들）에　의하여　하나　내지　５개，　바람직하게는　하나　내지３，　가장　바람직하게는　하나　내지　２로　치환될　수　있으며，　R9은　OH, 할로겐，　COOH, ５－테트라졸릴， NO2, SH, NH2, CN, CHO, =O, (C1-C6)알킬，(C1-C6)　알콕시，　할로－(C1-C6)알킬（바람직하게는　CF3）에서　선택된　치환체，　바람직하게는　OH, 할로겐，　COOH, 5-테트라졸릴，　NO2, CN, CHO, (C1-C6)알킬，(C1-C6)알콕시　 및　할로－(C1-C6)알킬（바람직하게는　CF3), 가장　바람직하게는　할로겐，　NO2, (C1-C6)알킬　 및　(C1-C6)알콕시에서　선택된다．　；
（８）　R2는　전술한　（７）에서　선택된다．
（９）R2및　R3중의　하나，바람직하게는　R3가　-CO-(C1-C9)알킬，－（Y)n-(B)m-COOH, 바람직하게는　(B)m-COOH　또는　-Y-B-COOH, 또는　－（Y)n-(B)m-R8; 여기에서　n은　０　또는　１；　Y는　CO; m은　０　또는　１；　B는　(C1-C6)알킬렌，　바람직하게는　－CH2-; R8은　COOH로　치환되거나　비치환된　페닐이거나 또는테트라졸이거나；　또는　R8은　테트라졸，　바람직하게는　５－테트라졸，또는　피리딜이다．
（10）Y는　CO;
(11) B는　(C1-C6)알킬렌；
(12)　R2및　R3의　하나는　전술한　（４）　내지　（７）　및／또는　（９）에서　정의된　바와　같고，　R2및　R3의　하나는　각각　독립적으로　H, OH, 할로겐， NO2, NH2, (C1-C6)알킬，(C2-C6)알케닐，(C1-C6)알콕시， OH-(C1-C6),알킬，　할로－(C1-C6)알킬　 및　모노－　또는　디－(C1-C6)알킬아미노；　바람직하게는　H, OH, (C1-C6)알킬 및 (C1-C6)알콕시；　더욱　바람직하게는　H, OH 및 (C1-C6)알킬；
(13) R2와　R3가　함께　－（CH2)r-, 여기에서　r은　３，　４　또는　５，바람직하게는　３　또는　４；
(14) R6가　H, NO2, CHO, 할로겐，　CF3또는　(C1-C6)알킬（바람직하게는　메틸）；　바람직하게는　H, NO2, CHO 또는　(C1-C6)알킬（바람직하게는　메틸）；더욱바람직하게는　H; 및／또는
(15) R4및　R5가　각각　독립적으로　H 또는　(C1-C6)알킬；　바람직하게는 R4및　R5모두가　메틸；　또는　R4와　R5가　함께　＝O, =S 또는　＝NH; 바람직하게는 =O인　화합물들이다．
구조식　I' 또는 I의　화합물들의　서브그룹은　구조식　Ia의　화합물들이다．
　　　　　　　
여기에서　X, R1내지　R5는　전술한　바와　같다．
구조식　I'　또는　I의　화합물들의　다른　서브그룹은　구조식　Ib의　화합물들이다．
　　　　　　　　　　　　　
여기에서　X, R1내지　R5는　전술한　바와　같다．
구조식　I'　또는　I，Ia 및　Ib의　화합물들의　또　다른　서브그룹에서，R2및　R3，바람직하게는　R3의　하나는　-(Y)n-(B)m-COOH,바람직하게는　－(B)m-COOH 또는　Y-B-COOH이거나　또는　-(Y)n-(B)m-R8인　화합물들이다．　구조식　I'　또는 I，　Ia 및　Ib의　화합물들의　또　다른　서브그룹에서，R2및　R3，바람직하게는 R3의　하나는　-(Y)n-(B)m-COOH,바람직하게는　－(B)m-COOH，Y-B-COOH이거나 또는　-(Y)n-(B)m-R8；　여기에서　n은　０　또는　１，　Y는　CO; m은　０　또는１；　B는　(C1-C6)알킬렌；　R8은　５－테트라졸릴，　또는　R8은　각각　독립적으로 OH, 할로겐， NO2, (C1-C6)알킬，(C1-C6)알콕시，　COOH 및　５－테트라졸릴에서　선택된　치환체　하나　또는　둘로　치환되거나　비치환된　화합물들이다．　구조식
I'　또는　I，Ia 및　Ib의　화합물들의　또　다른　서브그룹에서，R2및　R3，바람직하게는　R3의　하나는　－CO-(C1-C6)알킬，-(Y)n-(B)m-COOH, 바람직하게는　－(B)m-COOH　또는　Y-B-COOH이거나，　또는　-(Y)n-(B)m-R8인　화합물들이다．
구조식　I'　또는　I，　Ia 및　Ib의　화합물들의　또　다른　서브그룹에서，R2및　R3의　하나는　H,(C1-C6)알킬, (C2-C6)알케닐，(C1-C6)알콕시，－CO-(C1-C9)알킬　또는　-(Y)n-(B)m-COOH, 바람직하게는　－(B)m-COOH 또는　Y-B-COOH이거나　또는 -(Y)n-(B)m-R8，　여기에서　n, m, Y 및　R8은　전술한　바와　같고；　R2및　R3의　다른　하나는　－CO-(C1-C6)알킬，　-(Y)n-(B)m-COOH, 바람직하게는　-(B)m-COOH 또는　-Y-B-COOH, 또는　－（Y)n-(B)m-R8, 여기에서　R8은　전술한　바와같다．　예를　들면，　R2및　R3，　바람직하게는 R3의　하나는　H 또는　(C1-C6)알킬；　R2　및　R3，　바람직하게는　R3의　나머지　하나는　－(B)m-COOH，Y-B-COOH이거나，　또는　-(Y)n-(B)m-R8；　여기에서　R8은　전술한　바와　같다，　바람직하게는　－（B)m-COOH　또는　－（Y)n-(B)m-R8, 바람직하게는　(C1-C6)알킬렌－COOH 또는　－（Y)n-R8, 여기에서　Y는　CO;　R8은　각각　독립적으로　OH, 할로겐， NO2, (C1-C6)알킬，　(C1-C6)알콕시，　COOH 및　５－테트라졸릴，　바람직하게는　OH, 할로겐， NO2, (C1-C6)알킬，　또는 (C1-C6)알콕시에서　선택된　치환체　하나　내지　둘，　바람직하게는　하나로　치환되거나　비치환된　페닐　또는　피리딜기이거나，　또는　테트라졸릴，　바람직하게는　５－테트라졸릴이다．
구조식　I'　또는　I，　Ia 및　Ib의　화합물들의　또　다른　서브그룹에서，R2및　R3는　함께　－（CH2)r-　（여기에서　r은　３　또는　４，　바람직하게는４이다．）를　형성한다．　더욱이，　구조식　I'　또는　I，　Ia 및　Ib의　화합물들중에서　바람직한　화합물들은　R4및　R5가　함께　＝O, 또는　=NH，　바람직하게는　＝O를　형성하거나　또는　R4　및　R5가　모두　(C1-C6)알킬，　바람직하게는　메틸인　화합물들이다．
　　　구조식　I'　또는　I의　바람직한　서브그룹에서，　페닐　환의　두　하이드록시　치환체는　６－　 및　７－위치에　있는　화합물이고，　R2및　R3의　하나는 H가　아닌　화합물들이다．
　　　구조식　I'　또는　I，　Ia 및　Ib의　화합물들　 및　그　약학적으로　허용되는　염류　 및　그　약학적으로　허용되는　에스테르류는　다른　지시가　없는　한，　본　발명의　화합물들은　다음에　언급한다．
본　발명의　화합물들은　그　구조내에　카이랄　탄소원자（들）을　가질수있다．　본　발명은　그　기하학적인　이성체４들，　예를들면　Z 및　E이성체들（시스　 및　트랜스　이성체들），　광학이성체들，　예를들면　디아스테레오머들 및　에낱티오머들을　포함하는　화합물　I，　I'의　모든　가능한　이성체들을　포함한다．더욱이，　본　발명은　그　범위내에　각각의　이성체들과　그들의 혼합물，　예를들면　라세치체들을　포함한다．　각각의　이성체들은　출발물질의 상응하는　이성체　형태를　사용하여　얻어지든가，　또는　통상의　분리방법에　의하여최종화합물의　제조후에　분리하여　얻어질　수　있다．　에난티오머들과 같은　광학이성체들을　그　혼합물로부터　분리하기　위하여서는，　예를들면　분별　결정화와　같은　통상의　분할　방법이　사용될　수　있다．
생리적으로　허용되는　염류는　공지의　방법으로　제조될　수　있다．　약학적으로　허용되는　염류는　공지된　통상의　유기　 및　무기　염류이다．　더욱이，　본　발명의　화합물중에　존재하는　예를들면　COOH- 및／또는　OH－관능기등과　같은　COOH-, OH- 및／또는　아미노관능기는　문헌에　공지인　약학적으로　허용되는　산，　약학적으로　허용되는　염기　또는　약학적으로　허용되는　알콜류를　사용하여　공지방법으로　약학적으로　허용되는　염류，　에스테르류　또는아마이드류로　전환시킬　수　있다．　약물류의　분야에서　통상인　약학적으로　허용되고　유리　형태의　약리학적　특성을　가지는　산　 및　알콜류의　예는　지방족（예를들면，　(C1-C9), 바라직하게는 (C1-C6))의　산류　 및　알콜류，　또는　방향족　산류　 및　알콜류이다．
여기에서　사용된　용어는　다음의　의미를　가진다．　할로겐　또는　할로는　불소，　염소，　브롬　또는　요드를　의미한다．　여기에서　다른　그룹의　일부로서의　(C1-C6)알킬은　직쇄　또는　분자상의　탄소수　６까지，　바람직하게는　１，２，４　또는　４의　탄소원자를　가지는　고리형　그룹을　포함한다．　 C0-(C1-C9)알킬에서　알킬잔기는　탄소수９까지，바람직하게는　탄소수　１，２，３또는　４까지의　직쇄　또는　분지상의　고리형　그룹을　포함한다．다른　그룹의일부로서　(C1-C6)알콕시는　(C1-C6)알킬이　앞에　정의된 바와　같은　－O-(C1-C6)알킬을　의미한다．　(C2-C6)알케닐이란　용어는　탄소수６까지，　바람직하게는　탄소수　２，　３　또는　４의　이중결합을　함유하는（예를들면　하나의２중결합）직쇄　또는　분지상의　고리형　그룹을　의미한다．할로－(C1-C6)알킬은　(C1-C6)알킬　그룹이　전술한　바와　같으며，　하나　이상의　할로　그룹을　가지는，　예를들면　트리풀루오로메틸，디풀루오로메틸，모노플루오로메틸，　모노클로로프로필，트리클로로메틸등과　같이　하나이상의 할로　그룹에　의하여　치환된　(C1-C6)알킬　그룹을　의미한다．　(C1-C6)알킬렌은　예를들면　메틸렌，　에틸렌，　프로필렌　또는　부틸렌과　같은　직쇄　또는　분지상의　포화　탄화수소　２가　그룹을　의미한다．(C1-C6)알케닐렌이란　용어는　예를들면　비닐렌，　프로페닐렌，　부테닐렌　등과　같은　하나　이상의 이중결합（들）이　존재하는　직쇄상　또는　분지상의　불포화　탄화수소　고리의２가　그룹을　의미한다．(C3-C7)사이클로알킬이란　용어는　예를들면，사이클로프로필，　사이클로부틸，　사이클로펜틸，　사이클로헥실　또는　사이클로헵틸환과　같은　모노사이클　３－원　내지　７원의　포화　탄화수소　환을　의미한다．　각각　독립적으로　N, O, S에서　선택된　헤테로　원자　하나　내지　４개를　가지는　５－원　또는　６－원의　헤테로사이클이란　용어는　부분적으로　또는　완전히　포화된　모노사이클을　의미한다．　이러한　헤테로사이클의　예로서는　피페리디닐，　피페라지닐，모르포리닐，　피롤릴，　테트라하이드로피리딜，　디하이드로피리딜，　피리딜，　피라지닐，　피리미디닐，　피리다지닐，　티에닐，퓨릴，　티아졸릴，　옥사디아졸릴，　티아디아졸릴，　테트라졸릴，　등，　바람직하게는　테트라졸릴，　예를들면　５－테트라졸릴，　티에틸　또는　피리딜을　포함한다．
디(C1-C6)알킬아미노의　경우에，　(C1-C6)알킬　고리는　같거나　다를　수　있다．
화합물　I'，I, Ia　또는　Ib에서　임의의　치환체（들）　R9의　성질과　환에서　최대의　가능한　숫자는　환　R8의　성질에　의한다는　것은　이분야에　지식을　가진　자들에게는　명백하다．　예를들면　R9으로서　＝O는　R8으로서　(C3-C7)사이클로알킬이나　포화　또는　부분적　포화된　헤테로　사이클인　경우에만 가능한　것이다．여기에서　이중결합은　R8의　환원자와　전술한　산소원자사이에 형성될수　있다．
본　발명의　화합물들은　적당한　출발물질들을　사용한　문헌에　공지인　방법　또는　이와　유사한　방법에　의하여　여러　합성　경로에　따라서　제조될수　있다.
일반적으로，　R4　와　R5가　함께　＝O를　형성하는　구조식　I', I, Ia 　또는　Ib의　화합물들은　다음의　스킴　１에　의하거나　또는　유사한　방법에　의하여　제조될　수　있다．
스킴　１：
　　　　　　
　　　여기에서　X, R1내지　R3및　R6는　전술한　바와　같으며，각　R'는　독립적으로　H，통상의　하이드록시　보호기（예를들면　(C1-C6)알킬）이며，R은　(C1-C6)알킬（예를들면　메틸　또는　에틸）이다．
따라서，　스킴　１의　반응은　공지의　폰　퍼치만　반응（von Pechman reaction). 화합물　II는　산성조건하（예를들면　HCl/알콜　또는　７５％　H2SO4에서)　０℃　및　실온의　조건하에서　화합물　III와　반응시켜서　화합물　Ic'를 얻고，　다음에　보호기를　제거한　후　통상의　방법으로　치환체　R1（예를들면 NO2)을　도입하여　화합물　Ic를　얻는다．
R4및　R5가　함께　＝O를　형성하는　화합물　I',I,Ia　또는　Ib（화합물Ic)는　또한　다음의　스킴　２에　의하거나　또는　이와　유사한　방법으로　제조될수도　있다．
스킴　２：
　　　　　　　
여기에서　X, R1내지　R3및　R6는　전술한　바와　같으며，　각　R'는　각각　독립적으로　H,　또는　통상의　하이드록시　보호기（예를들면，(C1-C6))알킬）이며，　L은　통상의　리빙　그룹（예를들면，　OH, O-(C1-C6)알킬，또는　할로겐）이다．
스킴　２의　반응은　공지의　크뇌베나겔　축합반응（Knoevenagel condensation)에　유사하게　행한다．　일반적으로　화합물　IV는　예를들면　알콜류，　DMF,　알콜성　DMF, 또는　THF와　같은　적당한　용매중에서　염기，　예를들면　무기　플루오라이드　화합물　또는　유기아민，　예를들면　피페리딘의　존재하에　상승된　온도에서　화합물　V와　반응시켜서　화합물　Ic'를　얻고，　보호기를　제거하여　전술한　화합물　Ic를　얻는다．
더욱　상세하게는，　R4와　R5가　함께　＝O를　형성하고，　R2가　H이고　R3가　－（B)m-COOH인　화합물　I', I, Ia 또는　Ib（화합물　(Id)는　다음의　스킴３　또는　유사한　방법으로　제조한다．
스킴　３：
　　　　　　
여기에서　X 및　R1및　R6는　전술한　바와　같으며，　각각의　R'는　독립적으로　H　또는　하이드록시　보호기（예를들면　(C1-C6)알킬）이며，R은　(C1-C6)알킬（예를들면　메틸　또는　에틸）이다．
스킴　３의　반응은　공지의　스토베　축합（Stobbe condensation)과　유사한　반응이다．　따라서，　화합물　VI는　적당한　용매（예를들면，　알콜류）중에서　강한　염기（예를들면　(C1-C6)알킬－OMe, 여기에서　Me는　Na와　같은　알칼리　금속이온과　같은　금속이온이다．）의　존재하에　상승된　온도에서　화합물 VII과　반응시켜서　화합물　VIII를　얻는다．　화합물　VIII는　환화시키고　문헌에　공지인　방법으로　탈메틸화제，　예를들면　보론트리브로마이드와　같은탈메틸화제로　냉각된　온도（예를들면　－２０℃）에서　탈메틸화시키고，　다음에　R1（예를들면　니트로기）을　결과로　얻어진　화합물　Id'에　통상의　방법으로　도입켜서　전술한　화합물　Id를　얻는다．　
R4및　R5가　함께　＝O를　형성하고，R1이　NO2, X가　NR7,　여기에서　R7은전술한　바와　같은　화합물　I（화합물　Ie)의　또　다른　제조방법은　다음의　스킴　４에　예시되어　있다．
　　　　　　　
　　　여기에서　R2, R3및　R6는　전술한　바와　같으며，　R'는　통상의　하이드록시보호기（예를들면　(C1-C6)알킬）이며，　R은　(C1-C6)알킬이다．
따라서，　화합물　IX는　적당한　용매의　존재하　또는　용매없이　상승된온도，　예를들면　약　１６０℃의　온도에서　화합물　III와　일정시간　반응시켜서　얻는다．　다음에，　바람직하게는　반응생성물을　분리함에　없이　반응혼합물에　５０－１００℃의　농도에서　산을　가하여　화합물　X를　얻고，　이것은　임의로　다음　단계에서　Hal-R7,(여기에서　Hal은　할로겐이고，　R7은　(C1-C6)알킬임)로　알킬화시킨다．　화합물　X　또는　임의로　XI은　보호기를　제거（예를들면　탈메틸화）하고，　통상의　방법으로　니트로화시켜서　전술한　화합물　Ie로　정의된　목적화합물을　얻는다．
R4및　R5가　함께　(C1-C6)알킬，　예를들면　메틸이고，　X가　O인　화합물I은　쿠크　들의　방법（Cook et al, J. Org. Chem., vol. 30, 1965, p. 4114)에　의한　방법이나　그　유사한　방법으로 제조될　수　있으며，　다음의　스킴　５에예시한다．
　　　　　　　
　　　여기에서　R1내지　R3및　R6는　전술한　바와　같으며，　R'는　통상의　하이드록시　보호기，　예를들면　Me3Si이다．
이리하여，　화합물　XIII는　적당한　용매，　예를들면　THF중에서　MeMgCl과　반응시키고，다음에　산으로　보호기를　제거하여　전술한　최종　화합물　If를　얻는다．　
출발물질인　II, III, IV, V, VI, VII, IX 및　XIII는　시판중이거나　또는문헌에　공지인　공지의　여러　합성　방법이나　또는　전술한　바에　의하여　제조될　수　있다．
상술한　반응들에서，　어떠한　출발물질　또는　반응중간물질들은，　필요하면，　화학분야에서　잘　알려진　방법으로　보호될　수도　있음은　이분야의　통상의　지식을　가진　사람들에게는　자명하다．　어떠한　보호된　관능기는　다음에　통상의　방법으로　보호기를　제거한다．
더욱이，　전술한　반응스킴들에서，　본　발명의　중간물질　및／또는　최종　화합물은，　원하면，　이분야　숙련자들에게　공지인　방법에　따라서　본　발명의　다른　관능기로　다시　전환시킬　수　있다．
앞에　기술된　합성　방법들은　본　발명의　화합물들의　제조를　예시하기위한　것이며，　이　제조방법이　본　발명의　범위를　제한하는　것은　아니다．예를들면　이분야의　숙련자들에게　일반적인　지식의　범위내에　있는　다른　합성방법들도　가능하다．
본　발명의　화합물들은，　원하면，　문헌에　잘　알려진　방법을　사용하여　그　약학적으로　허용되는　염류，　에스테르로　전환시킬　수　있다．
　
앞에서　이미　언급한　바와　같이，　본　발명의　화합물들은　흥미있는　약리학적　특성，　즉，　카테콜－O-메틸트랜스페라제（COMT)　효소　저해　작용을나타낸다．　본　발명의　화합물들의　전술한　작용은　다음에　나타내는　약리학적　실험들로　나타낸다．　
실험예　I：　COMT　작용（IC50)의　측정
IC50의　측정은　０．１M　인산염　완충액중에서　pH 7.4, 37℃에서　S-COMT 효소（약　３０nM),도파민　３mM（COMT의　기질로서），마그네슘　클로라이드　5mM, S-아데노실－L-메치오닌（Adomet) 0.05mM, 및　본　발명의　실험화합물을　여러농도로　함유하는　실험　시료에서　COMT　작용을　측정하였다．
실험시료중의　반응은　시료　혼합물에　도파민　기질을　첨가하여　개시시킨다．　３７℃에서　１５분간　배양한　후에　반응을　４M의　과염소산으로　중지시키고，　빙욕중에서　더　４분간　안정화시킨다．　그　후에　침전된　단백질을원심분리（４０００ x G, 10분간）하여　제거한다．　COMT효소　작용은　HPLC에　의하여　반응생성물，　３－메틸도파민　 및　４－메틸도파민의　농도를　측정하여측정한다．　결과는　３－메틸도파민　표준품으로　조정한다．　T. Lotta et.,Biochemistry, vol.34(13), 1995, p. 4204　참조．　IC50값은　COMT 작용에서　５０％를　감소시키는　실험화합물의　농도이다．　결과는　표　１에　나타내었다．
실시예의 화합물 IC50(nM)
실시예6(b) 30
실시예7 30
실시예8 50
실시예9(c) 20
실시예10(d) 35
실시예11(c) 10
실시예12(b) 10
실시예13(c) 60
　　　 특히，　본　발명의　화합물들은　치료제로서　바람직한　특성을　가진다．그들은　COMT　저해제가　유용한　질병이나　조건들，　예를들면，　레보도파（+ DDC)　요법을　강화시키기　위한　파킨슨씨병의　체료와　같은 질병이나　증후군들의　치료에　사용될　수　있다．
본 발명의 화합물들은 장내, 국소적 또는 비경구로 투여될 수 있다.
본　발명의　화합물들은　투여　경로에　따라서　통상의　기술들을　사용하여　예를들면　정제，　캡슐제，　액제，　유제， 및　산제　등과　같은　여러 다른 약학적　단위　용량형태로　１종　또는　２종이상의　활성　성분과　약학적으로허용되는　부형제와　함께　제형화　할　수　있다．약학적으로　허용되는　부형제는　투여경로에　따라서　선택되는　약학적　분야에서　통상으로　사용되는 부형제들중에서　선택될　수　있다．
활성성분의　양은　예를들면，　용량형태의　종류에　따라서　０．０１　내지　１００중량％를　사용할　수　있다．
본　발명의　화합물들의　특정　용량　레벨은　물론　투여될　화합물，　투여되는　대상물의　종，나이，성별，투여조건 및　투여방법　 및　그　경로와　같은　여러　인자들에　따른다．　예를들면，　본　발명의　화합물들은　성인　남자의　경우　일일　０．５μg 내지　１００mg의　범위로　투여될　수　있다．
본　발명은　또한　인간이나　동물체의　치료방법에서　사용을　위하여　본발명의　화합물，　그　에스테르류　또는　그　염류를　제공한다．
　　
본　발명은　또한　COMT　저해제，　예를들면　파킨슨씨병의　치료에　유용한　COMT 저해제의　용도로서　본　발명의　화합물，　그　에스테르류，　그　염류 및　그　약학적　조성물을　제공한다．　전술한　증상에　사용될　치료제의　제조에　본　발명의　화합물을　사용하는　용도도　또한　제공된다．　본　발명은　또한　이러한　치료에　필요한　본　발명의　화합물，　그　약학적으로　허용되는　에스테르，　또는　그　염류의　유효량을　전술한　질병이나　증후군의　치료에　유효량을　투여하여　질병을　치료하는　방법을　제공하는　것이다．
본　발명은　다음의　실시예들에　의하여　더욱　상세히　설명된다．이들　실시예들은　단지　예시적　목적만을　위한　것이며，청구범위들에　정의된　본　발명의　범위를　제한하는　것은　아니다．
제조실시예　１：
　
　　（１a）　２－하이드록시－３，４－디메톡시－５－니트로－벤즈알데히드
초산（１０ml)중의　３，４－디메톡시－２－하이드록시벤즈알데히드（０．５g）의　용액에　발연　질산（０．１２ml)을　가한다．　반응혼합물을　빙수에　쏟아　붓고，　생성물을　에틸　아세테이트로　추출하고　물로　세척한　다음，건조 및　증발시킨다．　생성물을　물로　처리하고　여과한다．　수율：　０．１５g
실시예　１：
　　（a)7,8－디메톡시－６－니트로－３－（４－니트로－페닐）－크로멘－２－온
　　　１，２－디클로로에탄（３０ml）중의　（제조실시예　（１a)에서　얻어진　２－하이드록시－３，４－디메톡시－５－니트로－벤즈알데히드　（０．４６g），　４－니트로페닐　아세트　산（０．３９g）　 및　트리에틸아민（０．８４ml）의　용액을　０℃에서　페닐　디클로로포스페이트（０．４４ml）로　처리한다．　혼합물을　５시간　환류시키고　냉각시킨다．　냉각된　반응혼합물을　메틸렌　클로라이드로　희석시키고，　２．５M　NaOH, 2M HCl　 및　물로　차례로　세척한　다음건조시키고　증발시킨다．　생성물은　마지막으로　석유　에테르로　처리한후　여과한다．
수율：　０．５２g, 융점　２１９－２２３℃．
　　（b)7,8－디하이드록시－６－니트로－３－（4-니트로-페닐）－크로멘－２－온
앞의　단계（a)에서　얻어진 ７，８－디메톡시－６－니트로－３－（４－니트로－페닐）－크로멘－２－온（０．５g）을　진한　요드화수소（１０ml）중에서　질소　기류하에　５시간동안　환류시킨다．　생성물을　통상의　방법으로　처리하고메탄올중에서　재결정시킨다．
수율：　０．１８g，　융점　２７０－２８０℃．
실시예　2：
　　（a)7,8-디메톡시-６-니트로-２-옥소-２H-크로멘-３-카르복실산　에틸　에스테르
제조실시예　(１a)에서　얻어진　　２－하이드록시－３，４－디메톡시－５－니트로－벤즈알데히드（０．４６g)，　디에틸　말로네이트（０．６１ml）　 및　피페리딘（２적）의　용액을　하룻밤　환류시킨다．　생성물을　냉각시켜서　결정화시킨다．
수율：　０．３０g．
　
　　（b)7,8-디하이드록시-6-니트로-2-옥소-2H-크로멘-3-카르복실산
상기　단계（a)에서의　생성물（０．２５g）을　４７％　HBr（３ml)중에서　질소기류하에　６시간　환류시킨다음，　증발시키고　물로　처리한다．
수율：　０．１１g,　융점　２８７－２９５℃
　　
실시예　３：
　
　　（a) ７，８－디메톡시－６－니트로－３－페닐－크로멘－２－온
제조실시예　（１a)에서　얻어진　２－하이드록시－３，４－디메톡시－５－니트로－벤즈알데히드（０．９１g)，　펜아세틸클로라이드（１．９ml)　 및　탄산칼륨（２．０g)의혼합물을　건조　아세톤（４０ml)중에서　하룻밤　환류시킨다．　아세톤을　증발시키고，　냉수를　가한후　여과한다．
수율：　０．６９g.
　　
　　（b)　7,8-디하이드록시－６－니트로－３－페닐－크로멘－２－온
앞의　단계（a)에서　얻어진　생성물（０．６g）을　４７％　HBr（６ml)중에서　질소기류하에　１０시간　환류시킨　다음　얼음물에　쏟아　붓고　여가한다．
수율：　０．３８g,　융점　２１７－２２３℃．
　　　
실시예　４：
　　（a)３-（４－클로로－페닐）－７，８－디메톡시－６－니트로－크로멘－２－온
　
１，２－디클로로에탄（１２５ml)중의　２－하이드록시－３，４－디메톡시－５－니트로－벤즈알데히드（２．４４g)，　４－클로로페닐　아세트산（１．８２g)， PhOPOCl2(1.6ml)　 및　트리에틸아민（４．５ml)의　혼합물을　실시예　１（a)에기술된　방법으로　５시간동안　환류시킨다．　
수율：　２．４０g.
　　（b)３-（４-클로로-페닐）-７，８-디하이드록시-６-니트로-크로멘-２-온
앞의　단계（a)에서　얻어진　생성물（２g）과　４７％　브롬화수소산（５０ml)의　혼합물을　질소기류하에서　６시간동안　환류시킨다．통상의　방법으로　처리한후에　생성물을　메탄올로　재결정시킨다．
수율：　０．８５g.
　　　
실시예　５：
　　（a)　７，８－디메톡시－６－니트로－３－o-톨릴－크로멘－２－온
　 　２－메틸페닐　아세트산（０．６g), 2-하이드록시－３，４－디메톡시－５－니트로－벤즈알데히드（0.91g)， PhPOCl2(0.60ml) 및　트리에틸아민（1.7ml)의　혼합물을 실시예　４에　기술된　방법과　마찬가지로　１，２－디클로로에탄중에서　반응시킨다．
수율：　０．６８g.
　　　　　　
　　（b)　７，８－디하이드록시－６－니트로－３－o-톨릴－크로멘－２－온
앞의　단계（a)에서　얻어진　생성물（０．６８g)을　４７％　HBr(10m)중에서　질소기류하에　８시간　환류시키고　통상의　방법으로　처리한다．　끓는　에테르로　처리하여　생성물을　얻는다．
수율：　０．２４g,　융점　２３６－２４１℃．
　　
실시예　６：
　　（a)　７－하이드록시－６－메톡시－８－니트로－３－페닐－크로멘－２－온
아세톤（４０ml)중의　７－하이드록시－６－메톡시－３－페닐－크로멘－２－온（１．３４g)의　용액에　질산（메틸렌클로라이드　５ml중의　０．２２ml)을　가하고　결과로　얻어진　혼합물을　２０분간　교반한다．　용매를　증발시킨후　생성물을　에탄올로　재결정시킨다．
수율：　０．８５g.
　　（b)　６，７－디하이드록시－８－니트로－３－페닐－크로멘－２－온
앞의　단계（a)의　생성물（０．８g)을　디클로로메탄（２５ml)중에서　질소기류하에　실온에서　보론트리브로마이드（１．１ml)와　하룻밤　반응시킨다．　반응혼합물을　물로　처리하고，　에틸　아세테이트로　추출하고，　마지막으로　에탄올로　재결정시킨다．
수율：　１００mg,　융점　１９５－２１０℃
　　
실시예　７：
　　３－벤조일－６，７－디하이드록시－５－니트로－크로멘－２－온
질산　용액（메틸렌클로라이드중의　２M용액　１．６ml）을　에틸　아세테이트（５０ml)중의　３－벤조일－６，７－디하이드록시－크로멘－２－온（０．８９g)의　용액에　－１６～１０℃에서　가한다．　용매를　증발시킨　생성물을　용매로톨루엔－에틸　아세테이트－아세트산（８：１：１）을　사용한　실리카겔　칼럼을통과시킨다．　생성물을　에테르에서　결정화시킨다．
수율：　４０mg,　융점　９４－９６℃
　　
실시예　８：
２，３－디하이드록시－１－니트로－７，８，９，１０－테트라하이드로－벤조［c]크로멘－６－온
진한　황산（20ml)중의　아세타산　３－아세톡시－６－옥소－７，８，９，１０－테트라하이드로－６H－벤조［c]크로멘－２－일　에스테르（１．６g)의　용액에황산（1ml)중의　５M　HNO3　의　용액을　가하고　실온에서　１시간　교반한다．　혼합물을　얼음（150g）으로　처리한다．　생성물을　실리카에서　칼럼크로마토그래피（메틸렌클로라이드중의　１０％　메탄올）하여　정제한다．　
수율：　５０mg,　융점　２３８－２５５℃．
　　
실시예　９：
　　（a)6,7-디하이드록시-２-이미노-２H-크로멘-３-카르복실산　에틸에스테르
DMF(20ml)중의　２，４，５－트리하이드록시벤즈알데히드（2.94g）과　에틸시아노아세테이트（１．６２g)의　용액에　피페리딘　２０적（Pasteur pipette)　 및　아세트산　８적을　가하고　용액을　질소기류하에서　２시간　유지한다．　생성물을　여과하고　DMF　 및　에틸　에테르로　세척한다．
수율：　２．００g.
　　
　　（b)　６，７－디하이드록시－２－옥소－２H－크로멘－３－카르복실산
앞의　단계（a)의　생성물을　１M의　염산중에서　４시간　환류시키고　냉각한　다음　여과한다．
수율：　９７％．
　　
　　（c)6,7－디하이드록시－５－니트로－２－옥소－２H-크로멘－３－카르복실산
진한　황산（6ml)중의　앞의　단계（b)의　생성물（０．２２g）을　－１０℃에서　질산칼륨（０．１０g)으로　처리하고，　얼음물에　쏟아　붓고　여과한다．
수율：　０．２１g,　융점　３００℃이상．
　　　
실시예　１０：
　　（a)7-하이드록시-6-메톡시-2-옥소-2H-크로멘-3-카르복실산 에틸 에스테르
DMF(5ml)중의　２，４－디하이드록시－５－메톡시벤즈알데히드（１．６８g)과　디에틸　말로네이트（１．７６g)의　혼합물을　피페리딘　 및　아세트산　수적으로　처리하고　８０－９５℃에서　하룻밤　유지한다．　반응혼합물을　얼음물에쏟아　붓고　산성화시킨후　여과한다．
수율：　２．２g.
　 　
　　（b)７－하이드록시－６－메톡시－８－니트로－２－옥소－２H－크로멘－３－카르복실산　에틸　에스테르
아세트산（４．１ml)중의　１M　질산용액을　아세트산（20ml)중의　앞의　단계（a)의　생성물의　현탁액에　실온에서　가한다．출발　현탁액이　용해되며　생성물이　결정으로　석출된다．　결정을　여과하고　아세트산　 및　에틸　에테르로세척한다．
수율：　０．５３g．
　　　　　　　　　　　
　　（c)　７－하이드록시－６－메톡시－８－니트로－２－옥소－２H－크로멘－３－카르복실산
앞의　단계（b)의　생성물을　４M HCl(25ml) 및　아세트산（１５ml)의　혼합물중에서　３０분간　환류시켜서　가수분해시킨다．　반응혼합물을　얼음욕에서　진탕하고　여과한다．
수율：　０．３４g.
　　　
（d)6,7-디하이드록시-8-니트로-2-옥소-2H-크로멘-3-카르복실산
메틸렌클로라이드（３０ml)중의　앞의　단계（c)의　생성물（０．３g)의　현탁액을　－２５℃에서　보론트리브로마이드（１．０５ml)로　처리하고，　실온에서２일간　유지한다．　반응혼합물을　얼음수로　처리하고　에틸　아세테이트로　추출한다．　생성물을　물과　２－프로판올의　혼합물로　재결정시킨다．
수율：　０．１８g.
　　　　
실시예　１１：
　
　　 （a)2-（２，４，５－트리메톡시－벤질리덴）－석신산　１－에틸　에스테르
에탄올（70ml)중의　２，４，５－트리메톡시－벤즈알데히드（１９．６g), 디에틸　석시네이트（１７．４g)　 및　포타슘　tert-부톡사이드（１１．２g)의　용액을　４시간　환류시킨다음，　에타올을　증발시키고，　여기에　물（400ml）를　가한다음　수용액을　디에틸　에테르로　세척한다．　물층을　산성화시키고，　생성물을　에테르로　추출한다．　에테르로　재결정하여　시스－트랜스　이성체　혼합물（약　４：　１）을　얻는다．
수율：　２２g．
　　　
　　（b) (6,7-디하이드록시－２－옥소－２H－크로멘－３－일）－아세트산
메틸렌클로라이드（４０ml)중의　앞의　단계（a)에서　얻어진　　２－（２，４，５－트리메톡시－벤질리덴）－석신산　１－에틸　에스테르（４g）의　용액에　보론트리브로마이드（３ml)를　질소기류하에서　－２０℃에서　가한다．반응은　얼음위에서　１시간　유지한다음，　실온에서　３일간　유지한다．물로　처리하고，여과하고　더운　２－프로판올로　처리한다음，　생성물을　여과한다．
수율：　１．１g．
　　
　　（c)（６，７－디하이드록시－５－니트로－２－옥소－２H－크로멘－３－일）－아세트산
황산중의　앞의　단계（b)의　생성물（0.46g)의　용액에　질산칼륨(0.2１g)을　조금씩　－１８～－１２℃에서　가하고，　용액을　０℃에서　１시간　유지하고　얼음에　쏟아　붓고　여과한다．　생성물을　더운물로　처리하고　주위온도에서　여과한다．　
수율：　０．１５g,　융점　３５０℃이상．
　　　
실시예　１２：
　　（a)　６，７－디하이드록시－３－（２H－테트라졸－５－일）－크로멘－２－온
DMF(10ml)중의　2,4,5－트리하이드록시벤즈알데히드（1.23g),　（２H-테트라졸－５－일）－아세트산　에틸　에스테르（1.25g)，　피페리딘（1.36g)　 및　아세트산（0.06g)의　혼합물을　질소기류하에서　９０℃에서　２시간　교반한다．　얼음물로　처리하고，　pH２로　산성화시킨다음，　생성물을　여과하고　더운　에탄올로　처리한다．　
수율：　０．５５g.
　　（b)　６，７－디하이드록시－５－니트로－３－（１H－테트라졸－５－일）－크로멘－２－온
황산（１０ml)중의　앞의　단계（a)의　생성물（０．４g)의　용액에　질산칼륨（０．１４g)을　－１８～　－１２℃에서　가한다．　반응혼합물을　얼음물에　쏟아　붓고　여과한다．　생성물을　더운　아세톤으로　추출하고　농축　 및　여과한다．
수율：　５０mg,　융점　３１５℃이상．
　　
실시예　１３：
　　（a)　（６，７－디하이드록시－４－메틸－２－옥소－２H-크로멘－３－일）－아세트산　에틸　에스테르
７５％　황산（３０ml)중의　１，２，４－트리하이드록시벤젠（２．５g)의　용액에　디에틸　２－아세틸　글루타레이트（４．３g)을　５－１０℃에서　가한다．혼합물을　주위온도에서　하룻밤　교반하고　얼음에　쏟아　붓고　여과한다．　생성물（４．２g)은　그대로　다음의　단계（b)에서　사용된다．
　　（b)　아세트산（２０ml) 및　６N　염산（５０ml)중의　（６，７－디하이드록시－４－메틸－２－옥소－２H－크로멘－３일）－아세트산의　용액을　２시간　환류시키고　냉각시킨후　여과한다．
수율：　２．３g．
　　
　　（c)　（６，７－디하이드록시－４－메틸－５－니트로－２－옥소－２H-크로멘－３－일）－아세트산
진한　황산（１０ml)중의　앞의　단계（b)의　생성물（２g）의　용액에　－１５℃에서　질산　칼륨（１．０２g）을　가한다．　혼합물을　０℃에서　１시간　유지하고　얼음물로　처리한　다음　여과한다．
수율：　０．４１g，　융점　３５０℃이상．
　　　
　　　본　발명은　카테콜－O-메틸트랜스페라제　효소　저해　효과를　가지는　화합물들을　제공하는　것이다．
　　　본　발명은　또한，　COMT의　저해가　유용한　질병이나　증후군들의　치료용　화합물，　COMT　저해제로서　사용될　수　있는　의약품의　제조용의　용도를제공하는　것이다．　더욱이，　본　발명의　화합물들을　함유하는　약학적　조성물을　제공하는　것이다．

Claims (20)

  1. 다음　구조식　I의　화합물，　그　약학적으로　허용되는　염류　또는　그　약학적으로　허용되는　에스테르류．
    　　　　
    　
    　　　여기에서，　페닐잔기중의　두　OH-치환체는　상호간에　오르토　위치에　존재하며，　R1도　하이드록시기　하나의　오르토　위치에　존재한다．
    X는　O　또는　NR7;여기에서　R7은　H,(C1-C6)알킬，또는　(C1-C6)알킬－COOH;
    R1은　NO2,　 CN,　 CHO, 　CF3　또는　(C1-C6)알킬－CO-;
    R2및　R3는　각각　독립적으로　H, OH, 할로겐，　NO2, SH, NH2, (C1-C6)알킬，(C2-C6)알케닐, (C1-C6)알콕시, OH-(C1-C6)알킬, 할로－(C1-C6)알킬, 모노－　또는디－(C1-C6)알킬아미노, SO2R10, -CO-(C1-C9)알킬, －（Y)n-(B)m-COOH 및　－（Y)n-(B)m-R8; 여기에서
    　 　m은　０　또는　１；
    　 　n은　０　또는　１；
    　 　Y는　-CO-　또는　-CHOH-;
    B는　(C1-C6)알킬렌　또는　(C2-C6)알케닐렌；
    R8은　페닐，나프틸，(C3-C7)사이클로알킬　또는　각각　독립적으로 N, O 및 S에서　선택된　헤테로　원자　하나　내지　４개를　가지는　５－　또는　６－원　헤테로사이클릴；　전술한　페닐，나프틸，(C3-C7)사이클로알킬　또는　５－또는　６－원 (C3-C7)헤테로사이클은　OH, 할로겐，　COOH, 5-테트라졸릴，NO2, SH, NH2, CN, CHO, =O, (C1-C6)알킬， (C1-C6)알콕시， 할로－(C1-C6))알킬，　모노－또는　디－(C1-C6)알킬아미노，CO-(C1-C6)알킬，CO-NH2, 모노－　또는　디－(C1-C6)알킬아미노－CO-，NHOH, CONHOH 및　SO2R10에서　선택된　치환체　R9으로　하나내지　４개로　임의로　치환될　수도　있으며；　또는
    　　R8은　다음의　그룹이거나；
    　　　
    또는　R2와　R3는　함께　－（CH2)r-을　형성하며；　여기에서　r은　３，　４　또는　５이며；
    R4및　R5는　각각　독립적으로　H, 또는　(C1-C6)알킬이거나；　또는　R4와R5는　함께　＝O, =S, 또는　=NR11을　형성하며；　여기에서　R11은　H　또는 (C1-C6)알킬이며；
    R6는　H, NO2, CN, OH,　CHO, 할로겐，CF3또는　(C1-C6)알킬이며； 그리고，
    　　 R10은　(C1-C6)알킬，　NH2, OH, 또는　모노－　또는　디－(C1-C6)알킬아미노이다．
    단，（a)　X가　O, R2가　메틸，　R3가　H, R４　 및　R5가　함께　＝O를　형성하고，　R6가　H이고，두　하이드록시　치환체가　７－ 및　８－위치에　있을때，R1은　CHO가　아니며，　（b)　X가　O,　R2가　H　또는　메틸，　R3가　H, R4및　R5가함께　＝O를　형성하며，　R6가　H이고，　두　하이드록시　치환체가 ６－ 및　７－위치에　있을　때，R1은　８－CO-CH3가　아니며，　（c)　X가　O, R2및　R3가　H,R4및　R5가　모두　메틸이고，　R6가　H이고　두　하이드록시　치환체가　７－　 및８－위치에　있을　때，　R1은　－CO-CH3가　아니다．
  2. 제　１항에　있어서，　다음　구조식　Ia의　화합물，　그　약학적으로　허용되는　염류　또는　그　약학적으로　허용되는　에스테르류．
    　　　
    　　　여기에서，　X, R1내지　R5는　청구항　１에서　정의된　바와　같다．
  3. 제　１항에　있어서，　다음　구조식　Ib의　화합물，　그　약학적으로　허용되는　염류　또는　그　약학적으로　허용되는　에스테르류．
    　　　　　
    　　　여기에서，　X, R1내지　R5는　청구항　１에서　정의된　바와　같다．
  4. 제　１항　내지　제　３항에　있어서，　X가　O인　화합물，　그　약학적으로　허용되는　염류　또는　그　약학적으로　허용되는　에스테르류．
  5. 제　１항　내지　제　４항에　있어서，　R1이　NO2, CN 또는 CF3인　화합물，그　약학적으로　허용되는　염류　또는　그　약학적으로　허용되는　에스테르류．
  6. 제　１항　내지　제　４항에　있어서，　R4및　R5가　함께　＝O를　형성하는화합물，　그　약학적으로　허용되는　염류　또는　그　약학적으로　허용되는 에스테르류．
  7. 제　１항　내지　제　５항에　있어서，　R３가　－(Y)n-(B)m-COOH 또는　(Y)n-(B)m-R8인　화합물，　그　약학적으로　허용되는　염류　또는　그　약학적으로　허용되는　에스테르류．　
  8. 제　１항　내지　제　７항에　있어서，　R8이　비치환의　페닐　또는　（C3-C7)사이클로알킬이거나　또는　OH, 할로겐，　COOH, 5-테트라졸릴，　NO2,　 및　(C1-C6)알킬에서　각각　독립적으로　선택된　치환체　R9으로　하나　또는　두치환체로　치환된　페닐　또는　（C3-C7)사이클로알킬이거나，　또는　R8이　５－테트라졸릴인　화합물，　그　약학적으로　허용되는　염류　또는　그　약학적으로허용되는　에스테르류．
  9. 제　１항　내지　제　８항에　있어서，　약제로서　사용되는　화합물，　그약학적으로　허용되는　염류　또는　그　약학적으로　허용되는　에스테르류．
  10. 청구항　１　내지　８의　화합물을　적어도　하나의　화합물，　그　약학적으로　허용되는　염류　또는　그　약학적으로　허용되는　에스테르류와　약학적으로　허용되는　부형제를　포함하는　카테콜－O-메틸트랜스페라제　효소　저해　효과를　가지는　약학적　조성물．
  11. 제　１０항에　있어서，　페닐　잔기의　두　하이드록시　치환체가　６－　 및　７－위치에　있는　카테콜－O-메틸트랜스페라제　효소　저해　효과를　가지는약학적　조성물．
  12. 제　１０항에　있어서，　페닐　잔기의　두　하이드록시　치환체가　７－　 및　８－위치에　있는　카테콜－O-메틸트랜스페라제　효소　저해　효과를　가지는약학적　조성물．
  13. 구조식　I'의　화합물，　그　약학적으로　허용되는　염류　또는　그　약학적으로　허용되는　에스테르류를　COMT　저해제로서　의약품의　제조에　사용되는용도．
    　　　
    　 여기에서，　페닐잔기중의　두　OH-치환체는　상호간에　오르토　위치에　존재하며，　R1도　하이드록시기　하나의　오르토　위치에　존재한다．
    X는　O　또는　NR7;여기에서　R7은　H,(C1-C6)알킬，또는　(C1-C6)알킬－COOH;
    　 R1은　NO2,　 CN,　 CHO, 　CF3　또는　(C1-C6)알킬－CO-;
    R2및　R3는　각각　독립적으로　H, OH, 할로겐，　NO2, SH, NH2, (C1-C6)알킬，　(C2-C6)알케닐, (C1-C6)알콕시, OH-(C1-C6)알킬, 할로－(C1-C6)알킬, 모노－또는디－(C1-C6)알킬아미노, SO2R10, -CO-(C1-C9)알킬, －（Y)n-(B)m-COOH 및　－（Y)n-(B)m-R8; 여기에서
    　 　m은　０　또는　１；
    　　 n은　０　또는　１；
    　 　Y는　-CO-　또는　-CHOH-;
    B는　(C1-C6)알킬렌　또는　(C2-C6)알케닐렌；
    R8은　페닐，　나프틸，　（C3-C7)사이클로알킬，　또는　각각　독립적으로 N, O 및　S에서　선택된　헤테로　원자　하나　내지　４개를　가지는　５－　또는６－원　헤테로사이클릴；　전술한　페닐，　나프틸，（C3-C7)사이클로알킬　또는　５－　또는　６－원（C3-C7)헤테로사이클은　OH,할로겐，COOH, 5-테트라졸릴，NO2, SH, NH2, CN, CHO, =O, （C1-C6)알킬，（C1-C6)알콕시， 할로－（C1-C6)알킬，　모노-또는　디－（C1-C6)알킬아미노，CO-（C1-C6)알킬，CO-NH2, 모노－　또는　디-（C1-C6)알킬아미노－CO-，NHOH,CONHOH 및　SO2R10에서　선택된　치환체　R9으로　하나　내지４개로　임의로　치환될　수도　있으며；　또는
    R8은　다음의　그룹이거나；　
    또는　R2와　R3는　함께　－（CH2)r-을　형성하며；　여기에서　r은　３，　４　또는　５이며；
    R4　 및　R5는　각각　독립적으로　H, 또는　（C1-C6)알킬이거나；　또는　R4와　R5는　함께　＝O,=S,또는　=NR11을　형성하며；　여기에서　R11은　H　또는（C1-C6)알킬이며；
    R6는　H, NO2, CN, OH,　CHO, 할로겐，　CF3또는（C1-C6)알킬이며；그리고，
    R10은　（C1-C6)알킬，　NH2, OH, 또는　모노－　또는　디-（C1-C6)알킬아미노이다．
  14. 제　１３항에　있어서，　페닐　잔기에　있는　두　하이드록시　치환체가　６－　 및　７－위치에　있는　화합물，　그　약학적으로　허용되는　염류　또는　그　약학적으로　허용되는　에스테르류를　COMT　저해제로서　의약품의　제조에　사용되는　용도．
  15. 제　１３항에　있어서，　페닐　잔기에　있는　두　하이드록시　치환체가　７－　 및　８－위치에　있는　화합물，　그　약학적으로　허용되는　염류　또는　그　약학적으로　허용되는　에스테르류를　COMT　저해제로서　의약품의　제조에　사용되는　용도．
  16. 제　１３항에　있어서，　구조식　I'의　화합물이　청구항　1,2,3,4,5,6,7 및／또는　８항에　정의된　구조식　I의　화합물인　COMT　저해제로서　의약품의　제조에　사용되는　용도．
  17. COMT　효소　저해제가　필요한　포유동물에　구조식　I'의　화합물，그　약학적으로　허용되는　염류　또는　그　약학적으로　허용되는　에스테르류를　치료에　유효한　양을　투여함을　특징으로　하는，　COMT　효소　저해제가　유효한　질병이나　증후군의　치료방법．
    　　　　　
    　　　여기에서　페닐　잔기에　있는　두　하이드록시　치환체가　서로　오르토　위치에　있고，　R1이　하이드록시　치환체의　하나의　오르토　위치에　있으며；
    X, R1내지　R6는　청구항　13에서　정의된　바와　같다．
  18. 제　１７항에　있어서，　페닐　잔기의　두　하이드록시　치환체가　６－　및　７－위치에　있는　방법．
  19. 제　１７항에　있어서，　페닐　잔기의　두　하이드록시　치환체가　７－　 및　８－위치에　있는　방법．
  20. 제　１７항에　있어서，　구조식　I'의　화합물이　청구항　1,2,3,4,5,6,7 및／또는　８의　어느　하나의　항에　정의된　구조식I의　화합물인　방법．
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CA2414787C (en) 2010-12-14
AU2001272597B2 (en) 2005-07-21
WO2002002548A1 (en) 2002-01-10
US20030186975A1 (en) 2003-10-02
EP1301503B1 (en) 2004-02-25
CN1440399A (zh) 2003-09-03
BG107513A (bg) 2003-06-30
ATE260268T1 (de) 2004-03-15
SK18452002A3 (sk) 2004-04-06
CN1199963C (zh) 2005-05-04
NO20026095D0 (no) 2002-12-18
NO20026095L (no) 2003-03-03
DK1301503T3 (da) 2004-06-28
AU7259701A (en) 2002-01-14
DE60102161D1 (de) 2004-04-01
FI20001593A (fi) 2002-01-04
IL153352A (en) 2009-05-04
NZ523121A (en) 2004-08-27
BR0111969A (pt) 2003-07-01
US20040110750A9 (en) 2004-06-10
IL153352A0 (en) 2003-07-06
PT1301503E (pt) 2004-06-30
CA2414787A1 (en) 2002-01-10
US6951870B2 (en) 2005-10-04
AU2001272597B9 (en) 2005-08-11
PL359068A1 (en) 2004-08-23
MXPA02012657A (es) 2003-05-14
JP4851051B2 (ja) 2012-01-11

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