KR20110022736A - (+)-2-[1-(3-에톡시-4-메톡시페닐)-2-메틸설포닐에틸]-4-아세틸아미노이소인돌린-1,3-디온: 그것의 조성물 및 사용 방법 - Google Patents
(+)-2-[1-(3-에톡시-4-메톡시페닐)-2-메틸설포닐에틸]-4-아세틸아미노이소인돌린-1,3-디온: 그것의 조성물 및 사용 방법 Download PDFInfo
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- KR20110022736A KR20110022736A KR1020117003333A KR20117003333A KR20110022736A KR 20110022736 A KR20110022736 A KR 20110022736A KR 1020117003333 A KR1020117003333 A KR 1020117003333A KR 20117003333 A KR20117003333 A KR 20117003333A KR 20110022736 A KR20110022736 A KR 20110022736A
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Abstract
입체이성질체적으로 순수한 (+)-2-[1-(3-에톡시-4-메톡시페닐)-2-메틸설포닐에틸]-4-아세틸아미노이소인돌린-1,3-디온, 실질적으로 그것의 (-)이성질체가 없는 것 또는 그것의 약학적으로 허용가능한 프로드러그, 대사산물, 결정다형(polymorph), 염, 용매화물(solvate), 수화물 또는 포접물(clathrate)에 관한 것이다. 또 2-[1-(3-에톡시-4-메톡시페닐)-2-메틸설포닐에틸]-4-아세틸아미노이소인돌린(acetylaminoisoindoline)-1,3-디온의 (+) 에난티오머를 포함하는 약학 조성물 및 그것의 사용방법에 관한 것이다. 또 TNF-α 또는 PDE4의 억제에 의하여 질병을 치료 및 예방하는 방법에 관한 것이다.
Description
1. 발명의 분야
본 발명은 2-[1-(3-에톡시-4-메톡시페닐)-2-메틸설포닐에틸]-4-아세틸아미노이소인돌린-1,3-디온의 (+)-이성질체를 사용하는 방법 및 그의 화합물에 관한 것이다.
2. 본 발명의 배경
종양 괴사 인자 알파(TNF-α)는 면역자극제에 반응하는 단핵포식세포에 의해 최초로 방출되는 시토카인이다. TNF-α는 분화, 원기회복, 증식 및 단백질 가수 분해와 같은 대부분의 세포 프로세스를 강화하는 능력이 있다. 낮은 농도에서, TNF-α는 감염요소, 종양 및 조직손상에 대응하여 보호작용에 관계한다. 그러나 TNF-α는 역시 많은 질병에서 역할을 한다. 포유류 또는 인간에게 투여되었을때, TNF-α는 염증, 발열, 심장혈관영향, 출혈, 응고 및 급성 감염 및 쇼크상태에서 보여지는 것과 비슷한 급성반응을 유발하거나 더욱 악화시킨다. 강화되거나 조절되지 않은 TNF-α의 생산은 수많은 질병 및 예를 들어 암, 경성 종양 및 혈액에 근거한 종양; 출혈성 심장쇠약같은 심장병; 그리고 바이러스성, 유전성, 염증성, 알레르기성 및 자기면역성 질병과 같은 병적인 상태를 유발시킨다.
또한 아데노신 3',5'-시클릭 모노포스페이트(cAMP)는 많은 질병과 천식 및 염증에 한하지 않는 병적인 상태에서 역할을 한다(Lowe and Cheng, Drugs of the Future, 17 (9), 799-807, 1992). 염증을 일으키는 백혈구에 있어 cAMP의 상승은 그들의 활성화 및 TNF-α 및 NF-KB를 포함하는 염증매개체의 지속적인 방출을 방해사는 것이 증명되었다. 또한 증가된 cAMP의 농도는 호흡기 평활근의 이완을 유도한다.
cAMP의 비활성화에 대한 주요 세포 메카니즘은 시클릭 뉴클레오티드 포스포디에스터라아제(PDE)라고 인용된 이소엔자임의 일종류에 의한 cAMP의 파손인 것으로 믿어지고 있다(Beavoand Reitsnyder, Erends n Pharm., 11,150-155, 1990). PDE의 집합에는 11가지가 알려져 있다. 예를 들어, PDE 타입 4의 억제는 특히 염증 매개체의 방출 및 호흡기 평활근의 이완을 모두 억제하는 효과가 있는 것으로 알려져 있다(Verghese, et al.,Journal of Plarmacology and Experimental Therapeutics, 272 (3), 1313-1320,1995).이처럼, PDE4를 억제하는 화합물은 특히, 심장혈관 또는 항혈소판 효과와 같은 의도하지 않은 부작용을 최소한으로 하면서 염증을 억제하거나 기도 평활근의 이완을 도울 수 있다. 현재 사용되는 PDE4 억제제는 허용가능한 치료 투여량에서 선택적인 활성이 결핍된다.
암은 특히 질병을 악화시키고 암의 위험 및 확산에 관련되어 혈중 TNF-α 농도를 증가시킨다. 보통, 정상적인 환자에 있어 암세포는 순환계에서 살아남기 어려운데 그 하나의 이유는 종양세포 분출물에 대한 장벽으로서 혈관의 내막 때문이다. 그러나 증가된 시토카인은 실질적으로 생체외에 내피세포층에 암이 집착이 증가되는 것으로 보인다. TNF-α와 같은 시토카인에 대한 어떤 설명은 생합성 및 ELAM-1(내피 백혈구 부착분자)이라 불리우는 세포 표면의 수용체의 발현을 자극한다. ELAM-1은 LECAM-1 및 GMP-140를 포함하는 LEC-CAMs로 알려진 칼슘 의존 세포 부착 수용체들의 일족중 하나이다. 염증반응동안 ELAM-1은 내피세포에서 백혈구에 "귀소 수용체"로서 기능한다. 최근, 내피세포에 있어 ELAM-1은 증가하는 콜론 암세포들의 증진된 접착을 매개하는 것으로 보여졌다 (Rice et al., 1989, Science 246: 1303-1306).
관절염 상태(예를 들어 골관절염 및 류마티스 관절염)와 관련한 염증성 질병, 염증성 장 질환(예를 들어 크론병 및 궤양 대장염), 패혈증, 건선, 아토피성 피부염, 접촉성 피부염, 그리고 만성 폐쇄성 폐질환은 역시 대부분이고 문제가 되는 질병이다. TNF-α는 염증 질병의 동물 모델에 있어 염증 반응과 그들의 길항제 블록 만성 및 급성 반응의 투여에 주역할을 한다.
강화되거나 조절되지 않은 TNF-α의 생산은 바이러스성, 유전성, 염증성, 알레르기성, 자기면역 질병과 관련된다. 이러한 질병의 예는 HIV; 간염; 성인성 호흡곤란 증후군; 뼈흡수병; 만성 폐쇄성 폐질환; 만성 폐 염증 질환; 천식, 피부염;낭포성 섬유증; 패혈성 쇼크; 혈류역학 쇼크; 패혈증 증후군; 국소 빈혈 상처; 뇌막염; 건선; 피브리오병; 카케시아; 이식거부; 자가 면역질환; 류마티스양 척추염; 류마티스 관절염 및 골관절염과 같은 관절염 상태; 골다공증; 크론병; 궤양 대장염; 염증성 잘 질환; 다발성 경화증; 전신홍반루푸스; 나병에 있어서 ENL ;방사선 손상; 천식; 그리고 고농도산소 꽈리 손상을 포함하나 이에 한정되지는 않는다. Tracey et al., 1987, Nature 330: 662-664 및 Hinshaw et al., 1990, Circ. Shock 30: 279-292 (내독소성 쇼크); Dezube et al., 1990, Lancet, 335: 662 (cachexia); Millar et al., 1989, Lancet 2: 712-714 및 Ferrai-Baliviera et al., 1989, Arch. Surg. 124: 1400-1405 (성인성 호흡곤란 증후군); Bertolini et al., 1986, Nature 319: 516-518, Johnsonet et al., 1989, Endocrinology 124: 1424-1427, Holler et al., 1990, Blood 75: 1011-1016, 및 Grau et al., 1989, N. Engt. J. Med. 320:1586-1591 (뼈흡수병); Pignet et al., 1990, Nature, 344: 245-247, Bissonnette et al., 1989, Inflammation 13: 329-339 및 Baughman et al., 1990, J; Lab. Cli71. Med. 115: 36-42 (만성 폐 염증 질환); Elliot et al., 1995, Itit. J. Pharmac. 17: 141-145 (류머티스 관절염); von Dullemen et al., 1995, Gastroenterology, 109: 129-135 (크론병); Duh et al., 1989, Proc. Nat. Acad. Sci. 86 : 5974-5978, Poll et al ., 1990, Proc. Nat. Acad. Sci. 87: 782-785, Monto et al., 1990, Blood 79: 2670, Clouse et al., 1989, J. Immunol. 142, 431-438, Poll et al., 1992, AIDS Res. Hum. Retrovirus, 191-197, Poli et al. 1990, Proc. Natl. Acad. Sci. 87: 782-784, Folks et al., 1989, PNAS 86: 2365-2368 (HIV 및 HIV로 인한 기회감염).
활성을 막을 수 있거나 어떠한 시토카인의 생산을 방해할 수 있는 약학 화합물들(TNF-α를 포함)은 유리한 치료제일 것이다. 많은 미세 분자 억제제들은 TNF-α에 의해 관련된 염증 질병을 치료하거나 예방할 능력이 있다는 것을 증명하였다 (검토를 위해, Lowe, 1998 Exp. Opin. Ther. Patents 8: 1309-1332 참조). 분자들 중 하나는 미국 특허 번호 제6,020,358호에 개시된 펜에틸설폰이다.
따라서 본 발명이 이루고자 하는 기술적 과제는 (+)-2-[1-(3-에톡시-4-메톡시페닐)-2-메틸설포닐에틸]-4-아세틸아미노이소인돌린-1,3-디온의 상기 질병을 위한 용도, 이것을 포함하는 조성물 및 사용 방법을 제공하는 것이다.
3. 발명의 요약
본 발명은 치환된 펜에틸설폰 화합물과 약학적으로 허용가능한, 염, 수화물, 용매화물, 포접물, 프로드러그, 및 결정다형의 이성질체를 활용하는 질병 및 장애를 치료하는 방법 및 포유류에서 시토카인과 그들의 전구물질의 농도를 경감하기 위한 방법에 관한 것이다. 또한 본 발명은 2-[1-(3-에톡시-4-메톡시페닐)-2-페틸설포닐에틸]-4-아세틸아미노이소인돌린-1,3-디온(2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione)을 포함하는 약학 조성물과 그 약학적으로 허용가능한 담체에 관한 것이다. 본 발명은 또한 그 다른 에난티오머(enantiomer)가 실질적으로 없는 2-[1-(3-에톡시-4-메톡시페닐)-2-페틸설포닐에틸]-4-아세틸아미노이소인돌린-1.3-디온의 에난티오머에 관한 것이다.
본 발명은 특히 2-[1-(3-에톡시-4-메톡시페닐)-2-페틸설포닐에틸]-4-아세틸아미노이소인돌린-1.3-디온의 (+) 에난티오머에 관한 것이다. 본 화합물은 2-[1-(3-에톡시-4-메톡시페닐)-2-페틸설포닐에틸]-4-아세틸아미노이소인돌린-1.3-디온의 라세미화합물과 비교하여 증가된 잠재력과 다른 이익을 갖는 것으로 믿어진다.
본 발명은 포유동물의 TNF-α 생성을 억제함으로써 개선되는 질병 및 장애를 치료하거나 예방하기 위한 2-[1-(3-에톡시-4-메톡시페닐)-2-메틸설포닐에틸]-4-아세틸아미노이소인돌린-1,3-디온의 (+) 에난티오머를 사용하는 것을 포함한다. 특정 구현예에서, 이 치료는 머리, 갑상선, 목, 눈, 피부, 입, 목구멍, 식도, 가슴, 뼈, 피, 골수, 폐, 결장, S자 결장, 직장, 위, 전립선, 유방, 난소, 신장, 간, 췌장, 뇌, 소장, 심장, 부신, 피하조직, 림프절, 심장 및 이들의 혼합의 암을 포함하는, 그러나 이에 한정되지는 않는, 암을 포함하고, 그러나 이에 한정되지는 않는다.
본 발명은 또한 울혈성 심부전, 심근증, 폐부종, 독소-중화 패혈증성 쇼크, 급성 바이러스성 심근염, 심장 타가이식 거부 및 심근경색을 포함하는, 그러나 이에 한정되지는 않는, 심장질병의 치료 및 예방에 2-[1-(3-에톡시-4-메톡시페닐)-2-메틸설포닐에틸]-4-아세틸아미노이소인돌린-1,3-디온의 (+) 에난티오머를 사용하는 것을 포함한다.
본 발명은 또한 PDE4를 억제하여 개선되는 질병 및 장애를 처리하기 위해 2-[1-(3-에톡시-4-메톡시페닐)-2-메틸설포닐에틸]-4-아세틸아미노이소인돌린-1,3-디온의 (+) 에난티오머(enantiomer)를 사용하는 것을 포함한다. 예를 들어, 본 발명의 화합물 및 조성물은 바이러스성, 유전성, 염증성, 자가면역 질병을 치료하거나 및 예방하는데 유용할 수 있다. 이러한 질병의 예는 다음을 포함하지만 이에 한정되지는 않는다: HIV; 간염; 성인 호흡 곤란 증후군; 뼈흡수병(bone-resorption disease); 만성 폐색성 폐질환; 만성 폐 염증 질환; 피부염; 염증성 피부병, 아토피성 피부염, 낭포성 섬유증 ; 패혈증성 쇼크; 패혈증; 내독서성 충격; 혈류역학적 쇼크(hemodynamic shock); 패혈증 증후군; 후허혈성 재관류 손상(post ischemic reperfusion injury); 뇌막염; 건선; 피브로틱 질병(fibrotic disease); 카케시아(cachexia); 이식편대숙주질환을 포함하는 이식 거부(graft rejection icluding graft versus host disease); 자기 면역 질병; 류머티즘 척추염; 류머티스 관절염 및 골관절염과 같은 관절염 이상; 골다공증; 크론병; 궤양 대장염; 염증성 내장 병; 다발성 경화증; 전신홍반루푸스(systemic lupus erythrematosus); 나병에서 나병결절홍반(erythema nodosum leprosum, ENL); 방사선 장애; 천식; 및 고농도산소 꽈리 손상(hyperoxic alveolar injury).
다른 구현예에서, 2-[1-(3-에톡시-4-메톡시페닐)-2-메틸설포닐에틸]-4-아세틸아미노이소인돌린-1,3-디온 (2-[1-(3-Ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione)의 입체이성질체적으로(stereomerically) 순수한 (+) 에난티오머(enantiomer)는 박테리아 감염, 균에 의한 전염병, 말라리아, 마이코박테리얼 감염(mycobacterial infection) 및 HIV로 인한 기회감염을 포함하는, 그러나 이에 제한되지는 않는, 세균에 의한 감염 또는 세균 감염 증상을 치료 및 예방하는데 유용하다.
본 발명은 2-[1-(3-에톡시-4-메톡시페닐)-2-메틸설포닐에틸]-4-아세틸아미노이소인돌린-1,3-디온 (2-[1-(3-Ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione)의 에난티오머, 및 이의 결정다형(polymorphs), 프로드러그(prodrugs), 염, 수산화물, 포접물(clathrates) 및 용매화물을 포함하는 약학 조성물 및 단일 단위 투여 형태을 더 포함한다.
독립된 구현예에서, 본 발명은 2-[1-(3-에톡시-4-메톡시페닐)-2-메틸설포닐에틸]-4-아세틸아미노이소인돌린-1,3-디온의 (+) 에난티오머를 포함한다.
다른 실시예에서, 본 발명은 1-(3-에톡시-4-메톡시-페닐)-2-메탄설포닐-에틸아민 (3-Ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethylamine)을 키랄 아미노산(chiral amino acid)과 접촉시키는 단계 및 상기 단계의 생성물을 N-(1,3-디옥소-1,3-디하이드로-이소벤조푸란-4-일)-아세타마이드 (N- (1, 3-Dioxo-1, 3-dihydro-isobenzofuran-4-yl) -acetamide)와 접촉시키는 단계를 포함하는 2-[1-(3-에톡시-4-메톡시페닐)-2-메틸설포닐에틸]-4-아세틸아미노이소인돌린-1,3-디온 (2-[1-(3-Ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione)의 입체이성질체적으로(stereomerically) 순수한 (+) 에난티오머(enantiomer)를 생성하는 단계를 포함한다. 관련된 구현예에서, 본 발명은 1-(3-에톡시-4-메톡시-페닐)-2-메탄설포닐-에틸아민 (3-Ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethylamine)의 키랄 염(chiral salt)를 포함한다.
3.2. 정의
여기서 사용된 용어 "화합물 A"는, 칼럼이 150 mm x 4.6 mm Ultron Chiral ES-OVS 키랄 HPLC 칼럼(Agilent 테크놀러지)이고 , 용리액은 pH 3.5에서 15:85 에탄올:20 mM KH2PO4이고, 관찰 파장은 240 nm인 경우, 대략 25.4분에 HPLC 칼럼에서 떨어진 2-[1-(3-에톡시-4-메톡시페닐)-2-메틸설포닐에틸]-4-아세틸아미노이소인돌린-1,3-디온 (2-[1-(3-Ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione)의 순수한 에난티오머(enantiomer)제형을 말한다. 화합물 A의 1H NMR 스펙트럼은 실질적으로 다음과 같다: δ(CDCl3):1.47(t, 3H), 2.26 (s, 3H), 2.87 (s, 3H), 3.68-3.75 (dd, 1H), 3.85 (s, 3H), 4.07-4.15 (q, 2H), 4.51-4.61 (dd, 1H), 5.84―5.90 (dd, 1H), 6.82-8.77 (m, 6H), 9.46 (s, 1H). 화합물 A의 13C NMR 스펙트럼은 실질적으로 다음과 같다: δ(DMSO-d6): 14.66, 24.92, 41.61, 48.53, 54.46, 55.91, 64.51, 111.44, 112.40, 115.10, 118.20, 120.28, 124.94, 129.22, 131.02, 136.09, 137.60, 148.62, 149.74, 167.46, 169.14, 169.48. 메탄올에 용해된 화합물 A는 또한 (+) 방향으로 평면 편광을 회전시킨다.
이론에 의하여 제한되지 않고, 화합물 A는 다음 구조를 갖는 S-{2-[1-(3-에톡시-4-메톡시페닐)-2-메틸설포닐에틸]-4-아세틸아미노이소인돌린-1,3-디온} [S-{2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione}]라고 여겨진다.
여기에서 사용되는 "환자"라는 용어는 포유류, 특히 사람을 말한다.
여기서 사용되는 용어 "약학적으로 허용가능한 염"은 약학적으로 허용가능한 무기산 및 염기와 유기산 및 염기를 포함하는 비독성 산 및 염기로부터 제조된 염을 말한다. 본 발명의 화합물을 위한 적절한 약학적으로 허용가능한 염기 추가 염은 알루미늄, 칼슘, 리튬, 마그네슘, 칼륨, 나트륨과 아연으로 제조된 금속염, 또는 리신, N,N'-디벤질에틸렌아민(N,N'-dibenzylethylenediamine), 클로로프로카인(chloroprocaine), 콜린, 디에탄올아민(diethanolamine), 에틸렌디아민, 메글루민(meglumine (N-methylglucamine)) 및 프로카인으로 제조된 유기염을 포함한다. 적절한 비독성 산은 초산, 알긴산, 안트라닐릭(anthranilic), 벤조술포닉(benzenesulfonic)산, 안식향산, 캄포르술포닉(camphorsulfonic)산, 구연산, 에덴술포닉(ethenesulfonic)산, 개미산, 푸마릭(fumaric)산, 푸로익(furoic)산, 갈락투로닉(galacturonic)산, 글루코닉(gluconic)산, 글로쿠로닉(glucuronic)산, 글루타믹(glutamic)산, 글리콜산, 브롬화 수소산, 염화수소산, 이세티오닉(isethionic)산, 젖산, 말레익산, 사과산, 만델릭(mandelic)산, 메탄술포닉(methanesulfonic)산, 무식(mucic)산, 질산, 파모익(pamoic)산, 판토테닉(pantothenic)산, 페닐아세틱(phenylacetic)산, 인산, 프로피오닉(propionic)산, 살리실산, 스테아르산, 숙신산, 술파닐릭(sulfanilic)산, 타르타르산, 및 p-톨루엔술포닉(p-toluenesulfonic)산을 포함하고, 이에 한정되지는 않는다. 특정 비독성 산은 염화수소, 브롬화 수소, 인, 유황, 메탄술포닉산을 포함한다. 특정 산의 예는 따라서 염화수소산 염 및 메실레이트 염을 포함한다.
다르게 지시되지 않는다면 여기 사용된 용어 "프로드러그(progrug)"는 화합물을 제공하기 위한 생물학적 조건(생체조건 내 또는 생체조건 외)에서 가수분해하거나, 산화되거나, 다른 반응을 할 수 있는 화합물의 유도체를 의미한다. 프로드러그의 예는 생가수분해가능한 아미드, 생가수분해가능한 에스테르, 생가수분해가능한 카바메이트, 생가수분해가능한 카보네이트, 생가수분해가능한 우레이드, 및 생가수분해가능한 포스페이트 아나로그와 같은 생가수분해가능한 성분(moieties)을 포함하지만, 이에 한정되지는 않는다. 프로드러그는 일반적으로 1 Burger's Medicinal Chemistry and Drug Discovery, 172-178, 949-982 (Manfred E.Wolff ed., 5th ed. 1995)에 기재된 것과 같은 공개된 방법을 이용하여 조제될 수 있다.
다르게 사용되지 않는다면 여기서 사용된, 용어 "생가수분해가능한 아미드(biohydrolyzable amide)", "생가수분해가능한 에스테르(biobhdrolyzable ester)", "생가수분해가능한 카바메이트(biohydrolyzable carbamate))", "생가수분해가능한 카보네이트(biohydrolyzable carbonate)", "생가수분해가능한 우레이드(biohydrolyzable ureide)", "생가수분해가능한 포스페이트(biohydrolyzable phosphate)"는 각각: 1) 화합물의 생물학적인 활성에 의해서 방해받지 않지만, 섭취율, 활동기간 또는 활동징후와 같은 생체안에서 장점을 화합물에 수여하거나; 또는 2) 생물학적으로 비활성이지만, 생체안에서 생물학적으로 활성인 화합물로 전환될 수 있는 화합물의 아미드, 에스테르, 카바메이트, 카보네이드, 우레이드, 또는 포스페이트을 의미한다. 생가수분해가능한 에스테르의 예는 저급 알킬 에스테르, 알콕시아실옥시 에스테르, 알킬 아실아미노 알킬 에스테르, 콜린 에스테르를 포함하지만, 이에 한정되지는 않는다. 생가수분해가능한 아미드의 예는 저급 알킬 아미드, α-아미노산 아미드, 알콕시아실 아미드, 알킬아미노알킬카보닐 아미드를 포함하지만, 이에 한정되지는 않는다. 생가수분해가능한 카바메이트의 예는 더 작은 알킬아민, 치환된 에틸렌디아민, 아미노산, 하이드록시알킬아민, 헤테로시클릭 아민, 헤테로아로마틱 아민 및 폴리에테르 아민을 포함하지만, 이에 한정되지는 않는다.
다르게 사용되지 않는다면 여기서 사용된, 용어 "입체이성질체적으로 순수한(stereomerically pure)"은 화합물의 한가지 입체이성질체(stereoisomer) 일종을 포함하며 그 화합물의 다른 입체이성질체를 실질적으로 포함하지 않는 조성물을 의미한다. 예를 들어, 하나의 키랄(chiral) 중심을 갖는 화합물의 입체이성질체적으로 순수한 조성물은 반대되는 에난티오머(enantiomer)의 화합물로 자유롭게 교체될 것이다. 두개의 키랄(chiral) 중심을 갖는 화합물의 입체이성질체적으로 순수한 조성물은 그 화합물의 부분입체이성질체(diastereomer)가 실질적으로 없는 것이다. 전형적인 입체이성질체적으로 순수한 화합물은 하나의 입체이성질체 화합물 80중량% 이상 및 다른 입체이성질체 화합물 20중량% 이하를 포함하며, 바람직하게, 하나의 입체이성질체 화합물 90중량% 이상 및 다른 입체이성질체 화합물 10중량% 이하를 포함하며, 더욱 바람직하게 하나의 입체이성질체 화합물 95중량% 이상 및 다른 입체이성질체 화합물 5중량% 이하를 포함하며, 가장 바람직하게 하나의 입체이성질체 화합물 97중량% 이상 및 다른 입체이성질체 화합물 3중량% 이하를 포함한다.
다르게 사용되지 않는다면 여기서 사용된, 용어 "에난티오머적으로 순수한(enantiomerically pure)"은 하나의 키랄(chiral) 중심을 갖는 화합물의 입체이성질체적으로 순수한 조성물을 의미한다.
여기서 사용된, 용어 "반대(역) 효과(adverse effects)"는 위장, 신장, 간 유독성, 백혈구감소증, 출혈 증가 등등, 저혈소판증, 임신기간 증가, 구역, 구토, 졸림, 무력증, 현기증, 최기형성, 추체외로병 징후, 정좌불능증, 심장혈관 방해를 포함하는 심독성(cardiotoxicity), 염증, 남성 성 기능장애, 그리고, 혈청 간 효소 농도 상승을 포함하지만, 이에 한정되지는 않는다. 용어 "위장 유독성" 은 위와 창자의 궤양화, 진무름을 포함하지만, 이에 한정되지는 않는다. 용어 " 신장 유독성"은 유두 괴사, 만성 간질성 신장염(interstitial nephritis)를 포함하지만 이에 한정되지는 않는다.
다르게 사용되지 않는다면 여기서 사용된, 문장 "반대효과(adverse effects)를 줄이거나 없애는"과 "반대효과(adverse effects)의 줄임과 감소"는 여기서 정의된 하나 또는 그 이상의 반대 효과의 심화를 줄이는 것을 의미한다.
만약 설명된 구조와 그 구조에서 주어진 명칭 사이에 불일치가 존재한다면, 설명된 구조가 보다 중요하게 일치되어야 한다. 게다가, 만약 구조의 일부, 또는 구조의 입체화학이 굵은글씨체 또는 밑줄로 지시되지 않는다면, 구조의 일부 또는 구조는 그것의 모든 입체이성질체를 포함하는 것으로 해석되어야 한다.
4. 발명의 상세한 설명
본 발명은 입체이성질체적으로 순수한 화합물 A와 관련되며, 이는 실질적으로 다른 이성질체가 없는 2-[1-(3-에톡시-4-메톡시페닐)-2-메틸설포닐에틸]-4-아세틸아미노이소인돌린-1,3-디온과 새로운 방법 및 입체이성질체적으로 순수한 화합물 A를 포함하는 조성물에 관한 것이다. 예를 들어, 본 발명은 실험관내 및 생체내에서 사용되는 화합물 A를 포함하며, 다양한 병과 장애의 예방과 치료에 유용하도록 약학 조성물로 되어, 단일 단위 투여 형태물을 포함한다. TNF-α의 농도를 줄임으로써 개선되거나, 또는 PDE4의 억제에 의해 개선된 병과 장애는 여기서 설명되고, 이 분야에서 잘 알려져 있다. 본 발명의 특정한 방법은 여기서 사용된 TNF-α억제제와 연관된 반대효과를 줄이거나 피하게 한다. 본 발명의 다른 특별한 방법은 2-[1-(3-에톡시-4-메톡시페닐)-2-메틸설포닐에틸]-4-아세틸아미노이소인돌린-1,3-디온의 라세미 화합물의 사용과 관련된 반대효과를 줄이거나 피하게 한다.
본 발명의 특별한 방법은 고형 종양 암, 혈액 유래 암(blood born cancer), 그리고 염증을 포함하지만, 이제 한정되지는 않는 병과 장애를 예방하고 치료하는 방법을 포함한다.
화합물 A 또는, 약학적으로 허용가능한 결정다형(polymorph), 프로드러그(prodrug), 염, 포접물(clathrate), 용매화물 또는 수화물로 구성되는 본 발명의 약학 및 투여 형태물은 본 발명의 방법에서 사용될 수 있다.
이론에 의해 한정되지 않으며, 화합물 A는 TNF-α의 생산을 억제하는 것으로 믿어진다. 결과적으로, 본 발명의 첫 구현예는, 입체이성질체적으로 순수한 화합물 A 또는 그의 약학적으로 허용가능한 전구약물, 대사산물, 전구약물, 염, 용매화물, 수화물, 또는 포접물의 유효한 양을 비정상적인 TNF-α를 생산하는 세포와 접촉시키는 단계를 포함하는 TNF-α 생산을 억제하는 방법과 관련된다.
본 발명의 구현예에서, 본 발명은 입체이성질체적으로 순수한 화합물 A 또는 그의 약학적으로 허용가능한 전구약물, 대사산물, 전구약물, 염, 용매화물, 수화물, 또는 포접물의 유효한 양을 비정상적인 TNF-α를 생산하는 포유류 세포와 접촉시키는 단계를 포함하는 TNF-α 생산을 억제하는 방법과 관련된다.
본 발명은 또한, 입체이성질체적으로 순수한 화합물 A 또는 그의 약학적으로 허용가능한 전구약물, 대사물, 전구약물, 염, 용매화물, 수화물, 또는 포접물의 치료적으로 또는 예방적으로 유효한 양을 예방과 치료가 필요한 환자에 투요하는 단계를 포함하는, 환자의 TNF-α의 농도를 줄임으로써 개선되는 장애를 예방하거나 또는 치료하는 방법과 관련된다.
본 발명의 다른 실시예는, 입체이성질체적으로 순수한 화합물 A 또는 그의 약학적으로 허용가능한 전구약물, 대사산물, 전구약물, 염, 용매화물, 수화물, 또는 포접물의 약학적으로 유효한 양을 예방 또는 치료를 필요로 하는 환자에 투여하는 단계를 포함하는 고형 종양, 혈액 유래 암(blood born cancer), 백혈병, 그리고 특히, 다발성 골수종 암을 포함하지만 이제 한정되지 않는 암을 예방하거나 치료하는 방법과 관련된다. 특히, 환자가 포유류인 경우에 특히 관련이 있다.
또 다른 실시예에서, 본 발명은 입체이성질체적으로 순수한 화합물 A 또는 약학적으로 허용가능한 전구약물, 대사물, 전구약물, 염, 용매화물, 수화물, 또는 포접물의 유요한 양을 PDE4와 접촉하는 단계를 포함하는 PDE4를 억제하는 방법과 관련된다.
또 다른 실시예에서, 본 발명은 입체이성질체적으로 순수한 화합물 A 또는 약학적으로 허용가능한 전구약물, 대사물, 전구약물, 염, 용매화물, 수화물, 또는 포접물의 유효한 양을 세포와 접촉시키는 단계를 포함하는 세포내의 cAMP 농도를 조절하는 방법과 관련된다. 여기서 사용된 용어 "cAMP 농도의 조절"이란, 세포내, 바람직하게는 포유류 세포에서, 보다 바람직하게는 사람 세포에서, 아데노신(Adenosine) 3',5'-시클릭 모노포스페이트(cAMP)의 붕괴율을 줄이거나 예방하는 것을 포함한다. 특정한 방법에 의해, cAMP 붕괴율은 본 발명의 화합물과 접촉하지 않은 세포와 비교하여 비율에 있어서, 약 10,25,50,100,200, 또는 500 퍼센트까지 줄일수 있다.
발명의 또 다른 실시예는 PDE4의 억제에 의하여 호전되는 병을 치료하거나 예방하는 방법을 포함한다. 상기 방법은 전술한 병을 치료하거나 예방하기 위해 입체이성질체적으로 순수 화합물 A 또는 그의 약학적으로 허용가능한 염, 용매화물, 수화물, 입체 이성체, 포접물, 또는 프로드러그의 유효량을 환자에게 투여하는 것을 포함한다. PDE4의 억제에 의해 호전되는 질환은 천식, 주종(즉, 에 의한 부종), 만성 또는 급성 폐쇄성 폐질환 , 만성 또는 급성 폐 염증 질환, 염증성 장 질환, 크론병, 베체트병, 또는 홍역 등을 포함하지만 이에 한하지 않는다.
발명의 또 다른 실시예는 우울증, 천식, 염증(즉, 접촉 피부염, 아토피성 피부염, 건선, 류머티스 관절염, 골관절염, 염증성 피부병, 타박에 의한 염증), 만성 또는 급성 폐쇄성 폐질환, 만성 또는 급성 폐 염증 질환, 염증성 장 질환, 크론병, 베체트병, 홍역 등의 병을 치료하거나 예방하는 방법을 포함한다. 상기 방법은 상술한 병을 치료하기 위해 하거나 예방하기 위해 입체이성질체적으로 순수 화합물 A 또는 약학적으로 허용가능한 염, 용매화물, 수화물, 입체 이성체, 포접물, 프로드러그의 유효량을 환자 특히, 포유류인 환자에게 투여하는 것을 포함한다.
발명의 또 다른 실시예는 골수형성이상 증후군(myelodysplastic syndrome, MDS)을 치료하거나 예방의 방법을 포함한다. 상기 방법은 골수형성이상 증후군(MDS)을 치료하거나 예방하기 위해 입체이성질체적으로 순수 화합물 A 또는 그의 약학적으로 허용가능한 염, 용매화물, 수화물, 입체 이성체, 포접물, 또는 프로드러그의 유효량을 환자에게 투여하는 것을 포함한다. MDS는 조혈 줄기 세포 질환의 다양한 그룹을 나타낸다. MDS는 무익한 혈구 생산 때문에 손상된 형태와 성숙(골수조혈이상(dysmyelopoiesis)), 말초혈액 혈구감소증, 그리고 급성 백혈병으로의 진행의 가변적인 위험을 가진 세포 골수에 의하여 특성이 나타내어진다. Merck Manual 953(1999년 제 7판)과 LIST et al, 1990, J.Clin. Oncol. 8 : 1424.MDS 참조.
발명의 또 다른 실시예는 골수증식성 질병(MPD)을 치료하거나 예방의 방법을 포함한다. 상기 방법은 골수증식성 질병(MPD)을 치료하거나 예방하기 위해 입체이성질체적으로 순수한 화합물 A 또는 그의 약학적으로 허용가능한 염, 용매화물, 수화물, 입체 이성체, 포접물, 또는 프로드러그의 유효량을 환자에게 투여하는 것을 포함한다. 골수증식성 질병(MPD)은 조혈 줄기 세포의 클론 변종들에 의해 특성이 나타내어진 일단의 질환을 나타낸다. Current Medical Diagnosis & Treatment, pp. 499(37판. Tierney et al . ed, Appleton & Lange(1998)) 참조.
발명은 또한 복합적이고 부분적인 통증을 치료하거나, 막거나 관리하는 방법을 포함한다. 상기 방법은 상술한 질병을 치료하거나 예방 또는 관리하기 위해 입체이성질체적으로 순수 화합물 A 또는 그의 약학적으로 허용가능한 염, 용매화물, 수화물, 입체 이성체, 포접물, 또는 프로드러그의 유효량을 환자에게 투여하는 것을 포함한다. 구체적인 예에서, 투여는 외과수술전, 외과 수술후, 외과수술 동안, 또는 외과 수술후에 환자에 복합적이고 부분적인 통증 증후군의 증상을 줄이거나 없애도록 지시된다.
특히, 본 발명에 따른 방법에서 입체이성질체적으로 순수 화합물 A, 또는 그의 약학적으로 허용가능한 결정다형, 프로드러그, 염, 용매화물, 수화물, 또는 포접물는 적어도 하나의 추가적인 치료제와 함께 투여된다.
추가적인 치료제의 예는 항암제, 항염증제, 항히스타민제 그리고 울혈 제거제 등을 포함하지만 이에 제한되지 않는다.
4.1. 합성 및 제조
2-[1-(3-에톡시-4-메톡시페닐)-2-메틸설포닐에틸]-4-아세틸아미노이소인돌린-1,3-디온의 라세미화합물은 참조에 의하여 여기에 포함된 미국 특허권 6,020,358번에 개시된 방법을 사용하여 쉽게 제조된다.
화합물 A는 알려져 있는 기술에 의해 라세미 화합물로부터 분리될 수 있다. 실시예는 키랄 염의 형성과 키랄 또는 고성능 액체 크로마토그래피 "HPLC"의 사용 및 키랄 염의 결정화 및 형성을 포함하나 이에 제한되지 않는다. Jacques, J., et al., Enantionaers, Race7nates a7ld Resolutions(Wiley-Interscience, New York,1981) ; Wilen, S. H., et al., Tetrahedron 33: 2725 (1977); Eliel, E. L., Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); 및 Wilen, S. H., Tables of Resolving Agents and Optical Resolutions p.268 (E. L. Eliel, Ed. , Univ. of Notre Dame Press, Notre Dame, IN, 1972) 참조.
특정한 방법에서, 화합물 A는 3-아세트아미도프탈산 무수물과 (S)-2-(3-에톡시-4-메톡시페닐)-1-(메틸설포닐)-에트(eth)-2-일아민의 키랄 아미노산 염으로부터 합성된다. (S)-2-(3-에톡시-4-메톡시페닐)-1-(메틸설포닐)-에트-2-일아민의 키랄 아미노산 염은 알라닌, 아르기닌, 아스파라긴, 아스파르트산, 시스테인, 글루타민, 글루탐산, 글리신, 히스티딘, 이소루신, 루이신, 라이신, 메티오닌, 페닐알라닌, 프롤린, 세린, 트레오닌, 트립토판, 티로신, 발린, 오르니틴, 4-아미노부티르산, 2-아미노 이소부티르산, 3-아미노 프로피온산, 오르니틴, 노르루이신, 노르발린, 하이드록시프롤린, 사르코신, 시트룰린, 시스테인 산, t-부틸글라이신, t-부틸알라닌, 페닐글라이신, 시클로헥실알라닌, 및 N-아세틸-루이신의 L-이성질체로 형성된 염을 포함하나 이에 한정되지 않는다. 특정한 키랄 아미노산 염은 메탄올에 2-(3-에톡시-4-메톡시페닐)-1-(메틸설포닐)-2-에트(eth)-2-일아민 및 N-아세틸-L-루이신이 용해된 (S)-2-(3-에톡시-4-메톡시페닐)-1-(메틸설포닐)-2-에트(eth)-2-일아민 N-아세틸-L-루이신 염이다.
4.2. 치료 방법
본 발명은 TNF-α의 감소에 의하여 호전된 병 또는 장애를 예방 또는 치료하는 방법을 포함한다. 상기 방법은 상술한 질병을 치료하거나 예방 또는 투여하기 위해 입체이성질체적으로 순수한 화합물 A 또는 그의 약학적으로 허용가능한 염, 용매화물, 수화물, 입체 이성체, 포접물, 또는 프로드러그의 유효량을 환자에게 투여하는 것을 포함한다.
예를 들면, TNF-α의 억제에 의하여 개선된 질환들은 심장쇠약, 심근증, 폐부종, 엔도톡신 매개된 패혈증 쇼크, 급성 바이러스성 심근염, 심장 동종 이식 거부 및 심근경색과 같은 심장병; 육종, 암선종, 피브로사코마(fibrosarcoma), 미소사코마(myxosarcoma), 리포사코마(liposarcoma), 콘드로사코마(chondrosarcoma), 골육종, 코르도마(chordoma), 앤지오사코마(angiosarcoma), 엔도쎄리얼사코마(endotheliosarcoma), 림판지오사코마(lymphangiosarcoma), 림판지오엔도쎄리얼사코마(lymphangioendotheliosarcoma), 시노비오마(synovioma), 메소쎄리오마(mesothelioma), 유잉 종암, 레이오미오사코마(leiomyosarcoma), 라브도미오사코마(rhabdomyosarcoma), 콜론 암종, 췌장 암, 유방암, 난소 암, 전립선 암, 편평세포 암종, 기저 세포암종, 선암종, 땀샘 암, 피지 선 암, 유두암종, 유두선암종, 낭샘암종(stadenocarcinoma), 골수 암, 기관지유래 암종, 신장 세포 암종, 간암, 담관 암종, 융모막암종(choriocarcinoma), 고환종(seminoma), 배아 암종, 윌름스 종양(Wilms'tumor), 자궁 경암, 고환 종양, 허파 암종, 작은 세포 허파 암종, 방광 암종, 상피 암종, 신경교종, 별아교세포종(astrocytoma), 속질모세포종(medulloblastoma), 두개인두종(craniopharyngioma), 뇌실막세포종(ependymoma), 카포시 육종, 송과체종(pinealoma), 혈관모세포종(hemangioblastoma), 청신경종, 희소돌기아교세포종(oligodendroglioma), 수막종(menangioma), 흑색종, 신경아종, 및 망막모세포종(retinoblastoma)을 포함하나, 이에 한정하지 않는 고형 종양; 및 급성 림프모세포성 백혈병(acute lymphoblastic leukemia, ALL), 급성 림프모세포성 B-세포 백혈병, 급성 림프모세포성 T-세포 백혈병, 급성 골수모세포성 백혈병(acute myeloblastic leukemia, AML), 급성 전골수구성 백혈병(acute promyelocytic leukemia, APL), 급성 단핵구성 백혈병, 급성 적백혈병성 백혈병, 급성 거핵아구성 백혈병, 급성 골수단핵구성 백혈병, 급성 비림프성 백혈병, 급성 미분화성 백혈병, 만성 골수구성 백혈병(chronic myelocytic leukemia, CML), 만성 림프성 백혈병(chronic lymphocytic leukemia, CLL), 모발상 세포 백혈병, 다발성 골수종 및 림프모세포성, 골수성, 림프성, 및 골수구성 백혈병 등과 같은 만성 또는 급성 백혈병을 포함하나 이에 한정되지 않는 혈액 유래 종양을 포함한다.
본 발명의 특별한 방법은 추가적인 치료제(즉, 화합물 A 이외의 치료제)의 투여를 더 포함한다. 추가적인 치료제의 예는, 그러나 이에 한정되지는 않는데, 알킬화제, 질소 머스타드, 에틸렌이민, 메틸멜라민, 알킬 설포네이트, 니트로소우레아, 트리아젠, 엽산 아나로그, 피리미딘 아나로그, 퓨린 아나로그, 빈카 알카로이드, 에피포도필로톡신, 항생제, 국소이성화효소 억제제 및 항암 백신과 같은, 그러나 이에 한정되지는 않는 항암제를 포함한다.
특별한 추가적인 치료제는 애시비신 acivicin; 애클라루비신 aclarubicin; 아코다졸 하이드로클로라이드 acodazole hydrochloride; 아크로닌 acronine; 아도젤레신 adozelesin; 알데슬루킨 aldesleukin; 알트레타민 altretamine; 암보마이신 ambomycin; 아메탄트론 아세테이트 ametantrone acetate; 아미노글루테트이미드 aminoglutethimide ; 암사크린 AMSACRINE ; 아나스트로졸 anastrozole; 안트라마이신 anthramycin; 아스파라기나제 asparaginase; 아스퍼린 asperlin; 아자시티딘 azacitidine; 아제테파 azetepa; 아조토마이신 azotomycin; 바티마스타트 batimastat; 벤조데파 benzodepa; 비칼루트아미드 bicalutamide; 비산트렌 하이드로클로라이드 bisantrene hydrochloride; 비스나피드 디메실레이트 bisnafide dimesylate; 비젤레신 bizelesin; 블레오마이신 설페이트 bleomycin sulfate; 브레퀴나 소디움 brequinar sodium; 브로피리민 bropirimine; 부술판 busulfan; 칵티노마이신 CACTINOMYCIN ; 칼루스테론 calusterone; 카라세미드 caracemide; 카르베티머 carbetimer; 카르보플라틴 carboplatin; 카무스틴 CARMUSTINE ; 카루비신 하이드로클로라이드 carubicin hydrochloride; 카젤레신 carzelesin ; 세데핀골 cedefingol ; 클로람부실 chlorambucil; 시로레마이신 cirolemycin; 시스플라틴 cisplatin; 클라드리빈 cladribine; 크리스나톨 메실레이트 crisnatol mesylate ; 시클로포스파미드 CYCLOPHOSPHAMIDE; 시타라빈 cytarabine; 다카바진 dacarbazine; 닥티노마이신 dactinomycin; 다우노루비신 하이드로클로라이드 daunorubicin hydrochloride; 데시타빈 decitabine; 덱소마플라틴 dexormaplatin; 데자구아닌 dezaguanine; 데자구아닌 메실레이트 dezaguanine mesylate; 디아지쿠온 diaziquone; 도세탁셀 docetaxel; 독소루비신 doxorubicin; 독소루비신 하이드로클로라이드 doxorubicin hydrochloride ; 드롤옥시펜 droloxifene; 드롤옥시펜 시트레이트 droloxifene citrate; 드로모스타놀론 프로피오네이트 dromostanolone propionate; 두아조마이신 duazomycin; 에다트렉세이트 edatrexate; 에플로니틴 하이드로클로라이드 eflornithine hydrochloride; 엘사미트루신 elsamitrucin; 엔로플라틴 enloplatin; 엔프로메이트 enpromate; 에피프로피딘 epipropidine; 에피루비신 하이드로클로라이드 epirubicin hydrochloride; 에르불로졸 erbulozole; 에소루비신 하이드로클로라이드 esorubicin hydrochloride; 에스트라무스틴 estramustine; 에스트라무스틴 포스페이트 소디움 ESTRAMUSTINE phosphate sodium; 에탄이다졸 ETANIDAZOLE ; 에토포시드 etoposide; 에토포시드 포스페이트 etoposide phosphate; 에토프린 ETOPRINE ; 파드로졸 하이드로클로라이드 fadrozole hydrochloride; 파자라빈 fazarabine; 펜레티니드 fenretinide; 플록수리딘 floxuridine; 플루다라빈 포스페이트 fludarabine phosphate; 플루오로우라실 fluorouracil; 플루로시타빈 flurocitabine; 포스퀴돈 fosquidone ; 포스트리에신 소디움 fostriecin sodium; 젬시타빈 gemcitabine; 젬시타빈 하이드로클로라이드 gemcitabine hydrochloride; 하이드록시우레아 hydroxyurea; 이다루비신 하이드로클로라이드 idarubicin hydrochloride; 이포스파미드 ifosfamide ; 일모포신 ilmofosine ; 인터루킨 II interleukin II (재조합 인터루킨 II 또는 rII2를 포함하여), 인터페론 알파-2a interferon alfa-2a; 인터페론 알파-2b interferon alfa-2b; 인터페론 알파-n1 interferon alfa-nl; 인터페론 알파-n3 interferon alfa-n3; 인터페론 베타-I a interferon BETA-I a; 인터페론 감마-I b interferon gamma-I b; 이프로플라틴 iproplatin; 이리노테칸 하이드로클로라이드 irinotecan hydrochloride; 란레오티드 아세테이트 lanreotide acetate; 레트로졸 letrozole; 루플로리드 아세테이트 leuprolide acetate; 리아로졸 하이드로클로라이드 liarozole hydrochloride; 로메트렉솔 소디움 lometrexol sodium; 로무스틴 lomustine; 로스옥산트론 하이드로클로라이드 losoxantrone hydrochloride; 마소프로콜 masoprocol; 마이타신 maytansine; 메클로레트아민 하이드로클로라이드 mechlorethamine hydrochloride; 메게스트롤 아세테이트 megestrol acetate; 멜렌게스트롤 아세테이트 melengestrol acetate; 멜파란 melphalan; 메노가릴 menogaril; 머캅토퓨린 mercaptopurine; 메토트렉세이트 methotrexate; 메토트렉세이트 소디움 methotrexate sodium; 메토프린 metoprine; 메투레데파 meturedepa; 미틴도미드 mitindomide; 미토카신 mitocarcin; 미토크로민 mitocromin; 미토길린 mitogillin; 미토말신 mitomalcin; 미토마이신 mitomycin; 미토스퍼 mitosper; 미토탄 mitotane; 미트옥산트론 하이드로클로라이드 mitoxantrone hydrochloride; 미코페놀릭 애시드 mycophenolic acid; 노코다졸 nocodazole ; 노갈라마이신 nogalamycin; 오마플라틴 ORMAPLATIN ; 옥시수란 oxisuran; 파클리탁셀 paclitaxel; 페가스파가제 pegaspargase; 펠리오마이신 peliomycin; 펜타무스틴 PENTAMUSTINE ; 펩로마이신 설페이트 peplomycin sulfate; 퍼포스파미드 perfosfamide ; 피포브로만 pipobroman; 피포술판 PIPOSULFAN ; 피록산트론 하이드로클로라이드 piroxantrone hydrochloride; 플리카마이신 PLICAMYCIN ; 플로메스탄 plomestane; 포피머 소디움 porfimer sodium ; 포피로마이신 porfiromycin ; 프레드니무스틴 prednimustine; 프로카바진 하이드로클로라이드 procarbazine hydrochloride; 퓨로마이신 puromycin; 퓨로마이신 하이드로클로라이드 puromycin hydrochloride; 피라조퓨린 PYRAZOFURIN ; 리보프린 RIBOPRINE ; 로글레트이미드 rogletimide; 사핀골 safingol ; 사핀골 하이드로클로라이드 safingol hydrochloride; 세무스틴 semustine; 심트라젠 simtrazene; 스파포세이트 소디움 SPARFOSATE sodium; 스파소마이신 sparsomycin ; 스피로겐나니움 하이드로클로라이드 spirogennanium hydrochloride; 스피로무스틴 spiromustine; 스피로플라틴 spiroplatin; 스트레토니그린 streptonigrin; 스트렙토조신 streptozocin; 술로페누르 sulofenur ; 탈리소마이신 talisomycin; 테코갈란 소디움 tecogalan sodium; 테가푸르 tegafur; 텔옥산트론 하이드로클로라이드 teloxantrone hydrochloride; 템포르핀 temoporfin; 테니포시드 teniposide; 테록시론 teroxirone; 테스토락톤 testolactone; 티아미프린 thiamiprine; 티오구아닌 thioguanine ; 티오테파 thiotepa; 티아조푸린 tiazofurin ; 티라파자민 tirapazamine; 토레미펜 시트레이트 TOREMIFENE citrate; 트레스톨론 아세테이트 trestolone acetate; 트리시리빈 포스페이트 triciribine phosphate; 트리메트렉세이트 trimetrexate; 트리멕세이트 글루쿠로네이트 trimetrexate glucuronate; 트리프토레린 triptorelin; 투불로졸 하이드로클로라이드 tubulozole hydrochloride ; 우라실 머스타드 uracil mustard; 우레데파 uredepa; 바프레오티드 vapreotide; 베테포르핀 verteporfin ; 빈블라스틴 설페이트 vinblastine sulfate ; 빈크리스틴 설페이트 vincristine sulfate; 빈데신 vindesine; 빈데신 설페이트 vindesine sulfate; 비네피딘 설페이트 vinepidine sulfate; 빈글리시네이트 설페이트 vinglycinate sulfate; 빈루로신 설페이트 vinleurosine sulfate; 비노렐빈 타르트레이트 vinorelbine tartrate; 빈로시딘 설페이트 vinrosidine sulfate; 빈콜리딘 설페이트 vinzolidine sulfate; 보로졸 vorozole; 제니플라틴 zeniplatin ; 지노스타틴 zinostatin ; 조루비신 하이드로클로라이드ZORUBICIN hydrochloride를 포함하는데, 이에 한정되는 것은 아니다. 다른 항암제는 20-EPI-1, 25 디하이드록시비타민 D3 ; 5-에티닐우라실 ethynyluracil; 아비라테론 abiraterone; 애클라루빈 ACLARUBICIN ; 아실풀벤 ACYLFULVENE ; 아데시페놀 adecypenol; 아도젤레신 adozelesin; 알데스루킨 aldesleukin ; ALL-TK 길항제; 알트레트아민 altretamine; 암바머스틴 ambamustine; 아미독스 amidox; 아미포스틴 amifostine ; 아미노레불리닉 애시드 aminolevulinic acid; 암루비신 AMRUBICIN ; 암사크린 amsacrine; 애나글레리드 anagrelide; 애나스트로졸 anastrozole; 앤드로그라폴리드 andrographolide; 혈관형성 억제제 angiogenesis inhibitors; 길항제 D antagonist D; 길항제 G antagonist G; 앤타렐릭스 antarelix; 항-도살라이징 모르포제네틱 프로테인-1 ANTI-DORSALIZING MORPHOGENETIC PROTEIN-1 ; 안티안드로겐 antiandrogen, 전립샘 암종 prostatic carcinoma; 항에스트로겐 antiestrogen; 안티네오플라톤 antineoplaston; 안티센스 올리고뉴클레오티드 antisense oligonucleotides; 아피디콜린 글리시네이트 aphidicolin glycinate; 아포토시스 유전자 모듈레이터 apoptosis gene modulators; 아포토시스 레귤레이터 apoptosis regulators; 아푸리닉 애시드 apurinic acid; 아라-CDP-DL-PTBA ara-CDP-DL-PTBA; 아르기닌 디아미나제 arginine deaminase; 아술아크린 asulacrine; 아타메스탄 atamestane; 아트리무스틴 atrimustine; 액시나스타틴 1 AXINASTATIN 1; 액시나스타틴 2 axinastatin 2 ; 액시타스타틴 3 AXINASTATIN 3; 아자세트론 azasetron; 아자톡신 azatoxin; 아자티로신 azatyrosine; 바카틴 NI 유도체 baccatin NI derivatives; 발라놀 balanol; 바티마스타트 batimastat; BCR/ABL 길항제; 벤조클로린 BENZOCHLORINS ; 벤조일스타우로스포린 BENZOYLSTAUROSPORINE ; 베타락탐 유도체 beta lactam derivatives; 베타-알레틴 beta-alethine; 베타클라마이신 B betaclamycin B; 베투리닉 애시드 betulinic acid; BFGF 억제제; 비칼루타미드 bicalutamide; 비산트렌 bisantrene; 비사지리디닐스페민 BISAZIRIDINYLSPERMINE ; 비스나피드 bisnafide; 비스트라텐 A bistratene A; 비젤레신 bizelesin; 브레플레이트 breflate; 브로피리민 BROPIRIMINE ; 부도티탄 budotitane; 부티오닌 설폭시민 BUTHIONINE sulfoximine ; 칼치포트리올 calcipotriol; 칼포스틴 C calphostin C; 캄프토테신 유도체 camptothecin derivatives; 카나리폭스 canarypox IL-2 ; 카페시타빈 capecitabine; 카르복스아미드-아미노-트리아졸 CARBOXAMIDE-AMINO-TRIAZOLE ; 카르목시아미도트리아졸 carboxyamidotriazole; 카레스트 CaRest M3; CARN 700; 카틸라지 유도 억제제 cartilage derived inhibitor; 카젤레신 carzelesin ; 카제인 키나제 억제제 casein kinase inhibitors (ICOS); 카스타노스페민 CASTANOSPERMINE ; 세크로핀 B cecropin B; 세트로렐릭스 cetrorelix; 클로른 chlorlns; 클로로퀴녹살린 설폰아미드 chloroquinoxaline sulfonamide ; 시카프로스트 cicaprost; 시스-포피린 cis-porphyrin; 클라드리빈 cladribine; 클로미펜 아나로그 clomifene analogues; 클로트리마졸 clotrimazole; 콜리스마이신 A collismycin A; 콜리스마이신 collismycin B; 콤브레타스틴 combretastatin A4; 콤브레사스타틴 아나로그 combretastatin analogue; 코나게닌 conagenin; 클라베시딘 816 crambescidin 816; 그리스나톨 crisnatol; 크립토피신 8 cryptophycin 8; 크립토피신 A 유도체 cryptophycin A derivatives; 쿠라신 A curacin A; 시클로펜타안트라퀴논 cyclopentanthraquinones ; 시클로플라탐 cycloplatam; 시페마이신 cypemycin; 시타라빈 옥포스페이트 cytarabine OCFOSFATE ; 시토리틱 팩터 cytolytic factor ; 시토스타틴 cytostatin; 다클릭시맙 dacliximab; 덱시타빈 decitabine; 디하이드로디뎀닌 B DEHYDRODIDEMNIN B; 디슬로레린 deslorelin; 덱사메타손 dexamethasone; 덱시포스파미드 dexifosfamide ; 덱스라족산 dexrazoxane; 덱스베라파밀 dexverapamil; 디아지쿠온 diaziquone; 디뎀닌 B DIDEMNIN B; 디독스 didox; 디에틸노스페른진 DIETHYLNORSPERNZINE ; 디하이드로-5-아자시티딘 DIHYDRO-5-AZACYTIDINE ; 디히드로탁솔, 9- dihydrotaxol, 9- ; 디옥사마이신 dioxamycin; 디페닐 스피로무스틴 diphenyl spiromustine ; 도세탁셀 docetaxel; 도코사놀 docosanol; 돌라세트론 dolasetron; 독시플루리딘 doxifluridine; 드록시펜 droloxifene; 드로나비놀 dronabinol; 듀오카마이신 SA DUOCARMYCIN SA; 에브셀렌 ebselen; 에코머스틴 ECOMUSTINE ; 에델포신 edelfosine ; 에드레콜로맵 edrecolomab; 에프로니틴 eflornithine ; 엘레멘 elemene; 에미테퍼 EMITEFUR ; 에피루비신 epirubicin; 에프리스테리드 epristeride; 에스트라무스틴 아나로그 ESTRAMUSTINE analogue; 에스트로겐 작용제 estrogen agonists; 에스트로겐 길항제 estrogen antagonists; 에타니다졸 etanidazole; 에토포시드 포스페이트 etoposide phosphate ; 엑젬메스탄 EXEMESTANE ; 파드로졸 fadrozole; 파자라빈 fazarabine; 펜레티니드 fenretinide; 필그라스팀 filgrastim ; 피나스테리드 finasteride; 플라보피리돌 flavopiridol ; 플레젤라스틴 flezelastine ; 플루스테론 fluasterone; 플루다라빈 fludarabine; 플루오로다우노루니신 하이드로클로라이드 fluorodaunorunicin hydrochloride ; 포페니멕스 forfenimex ; 포르메스탄 FORMESTANE ; 포스트리에신 fostriecin ; 포테무스틴 fotemustine ; 가돌리늄 텟사피린 gadolinium texaphyrin; 갈륨 니트레이트 gallium nitrate; 갈로시타빈 galocitabine; 간니렐릭스 ganirelix; 젤라티나제 억제제 gelatinase inhibitors; 젬시타빈 gemcitabine; 글루타티온 억제제 glutathione inhibitors; 헵술팜 hepsulfam ; 헤레굴린 heregulin; 헥사메틸렌 비스아세트아미드 HEXAMETHYLENE bisacetamide; 하이퍼리신 hypericin; 이반드로닉 애시드 ibandronic acid; 이다루비신 idarubicin; 이독시펜 idoxifene ; 이드라만톤 idramantone; 일모포신 ilmofosine ; 일로마스타트 ilomastat; 이미다조아크리돈 imidazoacridones; 이미퀴모드 imiquimod; 이뮤노스티뮬란트 펩티드 IMMUNOSTIMULANT peptides; 인슐린-유사 성장인자-1 수용체 억제제 insulin-like growth factor-1 receptor inhibitor; 인터페론 작용제 interferon agonists; 인터페론 interferons; 인터루킨 interleukins; 이오벤구안 iobenguane; 아이오도독소루비신 iododoxorubicin; 입포메아놀, 4- IPOMEANOL, 4- ; 이로플락트 iroplact; 이르소글라딘 irsogladine; 이소벤가졸 isobengazole; 이소호모할리콘드린 B isohomohalicondrin B; 이타세트론 itasetron; 자스플라키놀리드 jasplakinolide; 카할라리드 kahalalide F; 라멜라린 lamellarin-N 트리아세테이트 triacetate; 란레오티드 lanreotide; 레이나마이신 leinamycin; 레노글라팀 lenograstim; 렌티난 설페이트 lentinan sulfate ; 렙톨스타틴 leptolstatin; 레트로졸 letrozole ; 루케미아 억제인자 leukemia inhibiting factor ; 루코사이트 알파 인터페론 leukocyte alpha interferon ; 루플롤리드+에스트로겐+프로게스테론 leuprolide+estrogen+progesterone ; 루프로레린 leuprorelin; 레바미솔 LEVAMISOLE ; 리아로졸 liarozole; 선형 폴리아민 아나로그 linear polyamine analogue; 리포필릭 디사카라이드 펩티드 lipophilic disaccharide peptide; 리포필릭 플라티눔 화합물 lipophilic platinum compounds; 리소클린아미드 7 lissoclinamide 7; 로바플라틴 lobaplatin; 롬브리신 LOMBRICINE ; 로메트렉솔 lometrexol; 론이다민 lonidamine; 로스옥산트론 losoxantrone; 로바스타틴 lovastatin; 록소리빈 loxoribine; 루토테칸 lurtotecan; 쿠테티움 텍사플리린 lutetium TEXAPLIYRIN ; 리소필린 lysofylline; 리틱 펩티드 lytic peptides; 마이타신 maitansine; 만노스타틴 A mannostatin A; 마리마스타트 marimastat; 마소그로콜 masoprocol; 마스핀 maspin; 마트릴리신 억제제 MATRILYSIN inhibitors; 매트릭스 메탈로프로테나제 억제제 matrix metalloproteinase inhibitors; 메노갈릴 menogaril; 메르바론 MERBARONE ; 메테렐린 meterelin; 메티온니나제 methioninase; 메토클로프라민 METOCLOPRAMIDE ; MIF 억제제 ; 미페프리스톤 mifepristone; 밀테포신 miltefosine; 미리모스팀 mirimostim; 미스매치 이중 사슬 RNA mismatched double stranded RNA; 미토구아존 mitoguazone; 미토락톨 mitolactol; 미토마이신 아나로그 mitomycin analogues; 미토나피드 mitonafide; 미토톡신 피브로블라스트 성장 인자-사포린 mitotoxin fibroblast growth factor-saporin; 미톡산톤 mitoxantrone; 모파로텐 mofarotene ; 몰그라모스팀 molgramostim; 모노클로날 항체 monoclonal antibody, 인간 클로닉 고나도트로핀 human chorionic gonadotrophin ; 모노포스포릴 리피드 A+ 미오박테리움 세포벽 SK monophosphoryl lipid A+MYOBACTERIUM cell wall sk; 모피다몰 MOPIDAMOL ; 다중 약물 저항 유전자 억제제 multiple drug resistance gene inhibitor ; 다중 종양 억제 1-근거 치료 multiple tumor suppressor 1-based therapy; 머스타드 항암제 mustard anticancer agent; 미카퍼록사이드 B mycaperoxide B; 미코박테리아 세포벽 추출물 mycobacterial cell wall extract ; 미리아포론 MYDAPORONE ; N-아세틸디날린 acetyldinaline; N-치환 벤즈아미드 substituted benzamides; 나파렐린 nafarelin ; 나그레스팁 nagrestip; 날록손 naloxone+펜타조신 pentazocine; 나파빈 napavin; 나파테핀 naphterpin; 나토그라스팀 nartograstim; 네다플라틴 nedaplatin; 네모루비신 nemorubicin ; 네리드로닉 애시드 neridronic acid; 중성 엔도펩티다제 neutral endopeptidase; 닐루트아미드 nilutamide; 니사마이신 nisamycin; 니트릭 옥사이드 모듈레이터 nitric oxide modulators; 니트록사이드 항산화제 nitroxide antioxidant; 니트룰린 NITRULLYN ; 06-벤질구아닌 benzylguanine; 옥트레오티드 octreotide; 옥키세논 okicenone; 올리고뉴클레오티드 oligonucleotides; 오나프리스톤 onapristone; 온단세트론 ONDANSETRON ; 온다세트론 ONDANSETRON ; 오라신 oracin; 오랄 시토킨 인듀서 oral cytokine inducer; 오마플라틴 ormaplatin; 오사테론 osaterone; 옥살플라틴 oxaliplatin; 옥사누노아이신 oxaunomycin; 파클리탁셀 paclitaxel; 파클리탁셀 아나로그 paclitaxel analogues; 파클리탁셀 유도체 paclitaxel derivatives; 팔라우아민 palauamine; 팔미토일리족신 PALMITOYLRHIZOXIN ; 팔미드로닉 애시드 pamidronic acid; 파나자이트리올 panaxytriol; 파노미펜 panomifene ; 파라박틴 parabactin; 파젤립틴 pazelliptine; 페가스라가제 pegaspargase; 펠데신 peldesine; 펜토산 폴리설페이트 소디움 pentosan polysulfate sodium; 펜토스타틴 pentostatin; 펜트로졸 pentrozole; 퍼플루브론 perflubron; 퍼포스파미드 perfosfamide; 페릴릴 알콜 perillyl alcohol; 페나지노마이신 phenazinomycin; 페닐아세테이트 phenylacetate; 포스페이트 억제제 phosphatase inhibitors; 피시바닐 picibanil; 필로카핀 하이드로클로라이드 pilocarpine hydrochloride; 피라루비신 PIRARUBICIN ; 피리트렉심 PIRITREXIM ; 플라세틴 placetin A; 플라세틴 placetin B; 플라미노겐 활성화제 억제제 plasminogen activator inhibitor; 플라티눔 착물 platinum complex; 플라티툼 화합물 platinum compounds; 플라티눔-트리아민 착물 platinum-triamine complex; 포피머 소디움 porfimer sodium ; 포피로마이신 porfiromycin; 프레드니손 prednisone; 프로필 비스-아크리돈 propyl bis-acridone; 프로스타글라딘 prostaglandin J2; 프로테아좀 억제제 proteasome inhibitors; 프로틴-A-기초 면역 모듈레이터 protein A-based immune modulator; 프로테인 키나제 C 억제제 protein kinase C inhibitor; 프로테인 키나제 C 억제제 protein kinase C inhibitors, 마이크로알갈 microalgal; 프로테인 티로신 포스파타제 억제제 protein tyrosine phosphatase inhibitors; 퓨린 뉴클레오시드 포스포릴라제 억제제 purine nucleoside phosphorylase inhibitors; 퍼퓨린 purpurins; 피라졸로아크리딘 pyrazoloacridine; 피리독실레이티드 헤모글로빈 폴리옥시에틸렌 컨쥬게이트 pyridoxylated hemoglobin polyoxyethylene conjugate; 라프 길항제 raf antagonists; 랄티트렉스드 raltitrexed ; 라모세트론 ramosetron ; 라스 파네실 단백질 트랜스퍼레이즈 억제제; ras 억제제; 라스-GAP 억제제 ras-GAP inhibitor; 레텔립틴 데메틸레이트 retelliptine demethylated; 레니움 Re 186 에티드로네이트 enium Re 186 etidronate; 리족신 rhizoxin; 리보자임 ribozymes; RII 레틴아미드 RII retinamide; 로글렛이미드 rogletimide; 로히투킨 rohitukine; 로무르티드 romurtide; 로퀴니멕스 roquinimex; 루비기논 Bl rubiginone Bl; 루복실 ruboxyl ; 사핀골 safingol; 사인토핀 saintopin; SarCNU ; 사르코피톨 A sarcophytol A; 사르그라모스팀 sargramostim; Sdi 1 미메틱스 Sdi 1 mimetics; semustine; 세네신스(senescence) 유래 억제제1; 센스 올리고뉴크레오타이드; 신호 전달 억제제; 신호전달 조절제; 단일 체인 항원 결합 단백질; 시조피란 sizofiran ; 소부족산 sobuzoxane; 소듐 보로캅테이트 sodium borocaptate; 소듐 페닐아세테이트 sodium phenylacetate; solverol; 소마토메딘(somatomedin) 결합 단백질; 소네르민 sonermin; 스파르포식 산 sparfosic acid; 스피카미신드 spicamycind ; 스피로무스틴 spiromustine; 스플레노펜틴 splenopentin; 스폰기스타틴 1 spongistatin 1; 스쿠알라민 squalamine; 줄기세포 억제제; 줄기세포 분열 억제제; 스티피아미드 stipiamide; 스트로멜리신 억제제 STROMELYSIN inhibitors; 설피노신 sulfinosine; 과다활동성 혈관작용성 장 펩티드 길항제 superactive vasoactive intestinal peptide antagonist; 수라디스타 suradista; 수라민 SURAMIN ; 스와인소닌 swainsonine; 합성 글리코스아미노글리칸 synthetic glycosaminoglycans; 탈리무스틴 tallimustine; 타목시펜 메티오디드 tamoxifen methiodide; 타우로무스틴 tauromustine; 타자로텐 tazarotene; 테코갈란 소듐 tecogalan sodium; 테가퍼 tegafur; 텔루라피릴리움 tellurapyrylium ; 텔로머레이즈 억제제; 테모포핀 temoporfin; 테모졸로미드 temozolomide; 테니포시드 teniposide; 테트라클로로데카옥사이드; 테트라조민 ; 탈리블라스틴 thaliblastine; 티오코랄린 thiocoraline; 트롬보단백질 ; 트롬보단백질 유사체; 티말파신 thymalfasin ; 싸이모포이에틴 수용체 작용제; 티모트리난 thymotrinan ; 싸이로이드 촉진 호르몬; 틴 에틸 에티오푸린 tin ethyl etiopurpurin; 티라파자민 tirapazamine; 티타노센 비클로라이드 titanocene bichloride; 톱센틴 topsentin; 토레미펜 toremifene; 토티포텐트 줄기 세포 요소 totipotent stem cell factor; 번역 억제제; 트레티노인 tretinoin; 트리아세틸우리딘 triacetyluridine; 트리시리빈 triciribine; 트리메트렉세이트 trimetrexate; 트리프토렐린 triptorelin; 트로피세트론 tropisetron ; 투로스테리드 turosteride; 타이로신 카이네지즈 억제제; UBC 억제제; 우베니멕스 ubenimex ; 우로제이탈 시누스(urogenital sinus) -유래 성장 억제 인자; 우로카이네이지 수용체 길항제; 바프레오티드 vapreotide; 바리올린 B variolin B; 벡터 시스템, 적혈구 유전자 치료제; 벨라레솔 velaresol; 베라민 veramine; 베르딘스 verdins; 베르테포르핀 verteporfin; 비노렐빈 vinorelbine; 빈크살틴 vinxaltine; 비탁신 vitaxin; 보로졸 vorozole; 자노테론 ZANOTERONE ; 제니플라틴 zeniplatin; 질라스코릅 zilascorb; 및 지노스타틴 스티말라머 zinostatin stimalamer를 포함하는데, 이에 한정되는 것은 아니다.
본 발명은 치료적 또는 예방적으로 유효한 양의 입체이성질체적으로 순수한 상기 화합물 A 또는 그것의 약학적으로 허용가능한 프로드러그, 대사산물, 결정다형(polymorph), 염, 용매화물(solvate), 수화물 또는 포접물(clathrate)을 그러한 치료 또는 예방이 필요한 환자에게 투여하는 것을 포함하는 환자에서 PDE4의 억제에 의하여 개선되는 질병 또는 장애들을 치료 또는 예방하는 방법을 더욱 포함한다.
본 발명의 PDE4의 억제에 의하여 개성된 이상들은 천식, 염증, 급성 또는 만성 폐쇄성 폐질환, 급성 또는 만성 폐 염증 질환, 염증성 장 질환, 크론병, 베체트병, 대장염, 궤양 대장염 및 재관류에 기인한 염증 또는 관절염을 포함한다.
바람직한 실시예에 있어서, 치료되거나 예방되어질 상기 질병이나 이상은 만성 폐쇄성 폐질환이다.
본 발명의 특정 방법은 항흥분제, 항히스타민제 및 소염제와 같은 추가적인 치료제를 포함할 수 있다. 이러한 추가적인 치료제는 에탄올아민, 에틸렌디아민, 피퍼라진 및 페노티아진과 같은 항히스타민제; 아스피린, 살리실레이트, 아세토미노펜, 인도메타신, 술린닥, 에토돌락, 페나메이트, 톨메틴, 케토로락, 디클로페낙, 이부프로펜, 나프로젠, 페노프로젠, 케토프로펜, 플루비프로펜, 옥사프로진, 피락시캠, 멜로시캠, 피라졸론 유도체와 같은 NSAID; 코티컬 스테로이드와 아드레무코티컬 스테로이드와 같은 스테로이드를 포함한다.
본 발명은 특정 방법은 라센산의 대체 페닐에틸설폰을 포함하는 약제간의 상호작용과 상기 장애의 치료 과정에서 사용되는 제제와 연관된 다른 부작용을 없애거나 줄일 수 있다. 어떠한 이론에 제한됨이 없이, 입체이성질체적으로 순수한 화합물 A는 전체적으로 향상된 치료효과, 2-[1-(3-에톡시-4-메톡시페닐)-2-메틸설포닐에틸]-4-아세틸아미노이소인돌린-1,3-디온의 라세미화합물 이상의 치료 인덱스를 제공한다. 예를 들면, 상기 약제의 작은 양은 어떤 환경에서는 같은 수준의 효과를 얻기 위해 투여될 수도 있다.
상술한 바와 같이, 본 발명의 활성인 화합물(예를 들면, 화합물 A)는 넓은 범위의 질병과 상태의 치료와 예방에 있어서 사용될 수 있다. 본 발명의 특정 성분의 예방적 또는 치료적 투여량은 다양하다. 상기 투여, 아마 투여 빈도는 나이, 몸무게와 환자 개개인의 반응에 따라 또한 다양하다. 적당한 투여 처방계획은 당업자에 의해 적절히 선택되어질 수 있다. 일반적으로 이하에서 묘사되는 상태에 대한 권고 매일의 투여량 범위는 하루에 약 1mg 내지 1000mg의 범위이다. 보다 상세하게는, 상기 1일 투여량은 동일하게 배분된 투여량으로 1일 2번 투여된다. 보다 상세히는, 1일 투여량은 하루 5mg 내지 500mg의 범위이어야 한다. 1일 투여량은 5mg, 10mg, 15mg, 20mg, 25mg, 50mg, 또는 100mg 식으로 투여될 수 있다. 환자를 투여하는 데에 있어서, 치료법은 가장 낮은 투여량, 대략 1mg 내지 약 25mg 정도로 초기화되어야 하며, 단일 투여량이나 분배된 투여량으로서 필요한 경우에 한하여 200mg 내지 1000mg으로 올릴 수는 있다. 대안적으로 1일 투여량은 0.01mg/kg 내지 100mg/kg이다.
어떤 경우에는 당업자에게 널리 알려진 바와 같이, 여기서 공개된 범위이상의 투여량을 사용하는 것이 필요할 수도 있다. 게다가, 임상치료자나 치료적응자는 환자의 개개인의 반응과 연계하여 어떻게, 언제 치료를 개입시키고, 적응하고, 마칠지를 알아야 한다.
여기서 사용된 '치료적으로 유효한 양', '예방적으로 유효한 양', '치료적으로 또는 예방적으로 유효한 양'이라는 표현은 상술된 투여량과 투여 빈도 스케쥴을 포함한다. 다른 치료적으로 유효한 양은 당업자에게 알려진 바와 같이 다른 질병과 조건에 대해 적용될 수 있다. 유사하게, 그러한 장애를 치료하거나 예방하기에 충분한 양은 2-[1-(3-에톡시-4-메톡시페닐)-2-메틸설포닐에틸]-4-아세틸아미노이소인돌린-1,3-디온의 라세미화합물과 연관된 부작용을 일으키기에는 불충분하고 감소시키기에는 충분한 양이며 상술된 투여량과 투여빈도 스케쥴에 의해 역시 포함된다.
4.3. 약학 조성물(
PHARMACEUTICAL
COMPOSITIONS
)
약학 조성물과 화합물 A를 포함하는 단일 단위 투여 형태, 또는 약학적으로 허용가능한 결정다형, 프로드러그, 염, 용매화물, 수화물, 또는 그것의 포접물도 본 발명에 의해 포함된다. 본 발명의 개별적인 투여 형태는 경구, 점막(직장, 코, 또는 질을 포함하는), 비경구(피하, 근육내, 일시주사, 동맥 내, 또는 정맥 내), 혀밑, 피부에 투여 등의 방법으로 이루어질 수 있다.
약학 조성물과 발명의 투여 형태는 정제된 화합물 A, 또는 그의 약학적으로 허용가능한 프로드러그, 대사산물, 결정다형, 염, 용매화물, 수화물, 또는 그것들의 포접물을 포함한다. 제약 조성물과 발명의 투여 형태는 일반적으로 1 또는 더 많은 약학적으로 허용가능한 부형제(excipients)를 포함한다.
본 실시예에 의해 포함되는 특정 제약 화합물은 순수한 화합물 A, 또는 그의 약학적으로 허용가능한 결정다형, 프로드러그, 염, 용매화물, 수화물 또는 포접물 및 적어도 하나의 추가적인 치료제를 포함한다. 추가적인 치료제들은 4.2절에 나열된 항암제와 항염증제를 포함한다.
본 발명의 단일 유닛 복용 형태는 환자에게 경구, 점막(mucosal)(예를 들면, 비강, 혀 밑, 질, 구강, 또는 직장), 비경구(예를 들면, 피하, 정맥 내, 일시주사, 근육내, 또는 동맥내) 또는 경피로 투여될 수 있다.
투여 형태의 예로서는 정제; 카플렛; 부드럽고 탄력있는 캡슐; 캐칫(cachets); 트로키제 ; 로젠즈(lozenges); 살포; 좌약; 연고; 찜질약; 페이스트; 가루; 드레싱; 크림; 고약; 용액; 패치; 에어로졸(예를 들면, 비음 분무기 또는 흡입기); 겔; 경구나 점막 투여에 적당한 용액 투여 형태(예를 들면, 수성 또는 비수성 액체 서스펜션, oil-in-water 에멀젼, 또는 water-in-oil 액체 에멀젼이다), 용액, 그리고 엘릭시르를 포함하여 환자에게 경구 또는 점막 투여를 위하여 적당한 액체 투여 형태 ; 환자에게 비경구적인 투여를 위하여 적당한 액체 투여 형태 ; 그리고 무균 고형분을 포함한다.
본 발명의 조성물, 형태, 투여 형태의 유형은 그것들의 사용 형태에 따라 다양하다. 예를 들면, 연관된 장애의 단기간 치료에 사용된 투여 형태는 같은 병의 장기간에 걸친 치료에 사용하였던 투여 형태보다 포함되는 하나 이상의 활성 성분들이 더 많이 포함될 수도 있다.
마찬가지로, 비경구적인 투여 형태는 같은 병 또는 장애를 치료했던 경구 투여 형태보다 하나 이상의 활성 성분들이 더 작게 포함할 수도 있다. 본 발명에 의해 포함된 특정 투여 형태는 당업자의 실시 형태에 따라 다양하게 이루어질 수 있다. 예를 들면, Remington's Pharmaceutical Sciences,18thed., Mack Publishing, Easton PA (1990) 참조.
전형적인 약학 조성물과 투여 형태는 하나 이상의 부형제(excipients)를 포함한다. 적당한 부형제(excipients)는 조제업 분야의 당업자에게 잘 알려져 있고, 적절한 부형제의 비제한적인 예시는 여기에서 기술되어진다. 특정 부형제(excipient)가 약학 조성물이나 투여 형태로 결합되어지는 데 적합한지의 여부는 환자에게 투여되는 투여 형태 등의 다양한 요소에 의해 결정되어진다.
상기 발명의 락토오스가 없는 조성물은 당해 분야에서 잘 알려지고, 예를 들면, 미국 파마코피아(pharmocopia)에 나열된 부형제(excipients)를 포함할 수 있다. 대체로, 락토오스가 없는 조성물은 활성 성분, 바인더(binder)/필러(filler) 그리고 윤활제(lubricant)를 호환성과 약학적으로 허용가능한 양만큼 포함한다.
바람직한 락토오스가 없는 투여 형태는 활성 성분, 미정질 셀룰로오스, 선젤라틴화된 녹말(pre-gelatinized starch), 그리고 마그네슘 스테아르산염을 포함한다. 물이 어떤 화합물들의 디그리데이션(degradation)을 촉진할 수 있기 때문에 상기 발명은 무수 약학 조성물(anhydrous pharmaceutical compositions) 및 활성 성분들을 포함하는 투여 형태를 더 포함한다.
예를 들면, 물(예를 들면, 5 %)의 추가는 제약 기술 분야에서 시간에 대한 제형들의 셀프-라이프(shelf-life) 또는 안정과 같은 특성을 결정하기 위하여 장기 저장을 조장하기위한 수단으로 널리 인정받는다. 젠스 티(Jens T) 원칙과 조작(2d).ed., 뉴욕(1995)의 뉴욕의 마르셀식 웨이브 Dekker, pp. 379- 80 참조. 사실상, 물과 열은 몇몇 화합물들(compounds)의 분해를 가속한다. 이처럼, 습기 및/또는 습도(humidity)는 제조, 다루는 것, 포장, 저장, 선적, 및 사용동안에 일반적으로 만나지기 때문에 제형(formulation)에 대하여 물은 중요한 영향을 끼친다.
낮은 습기 또는 낮은 습도 조건에서 무수 또는 낮은 습기의 성분들을 사용하며 무수 약학 조성물과 발명의 투여 형태(dosage forms)는 준비될 수 있다. 1차(primary) 또는 2차 아민을 포함한 약학 조성물 그리고 유당을 포함한 투여 형태 그리고 적어도 1개의 활성 성분은 제조 과정, 포장, 및/또는 저장 동안에 습기 및/또는 습도와 실질적인 접촉되면 무수물인 것이 바람직하다.
무수 약학 조성물은 그것의 무수물 특성이 유지되도록 준비되고 저장되어야 한다. 그러므로, 무수 조성물은 그들이 적당한 포뮬러 키트에 포함되도록 물에 대한 노출을 방지하는 것으로 알려진 물질을 사용하여 포장되는 것이 바람직하다.
적당한 포장은, 그러나 여기에 한정되지는 않고, 헤르메티컬리 실드 포일(hermetically sealed foils), 플라스틱, 유니트도즈 컨테이너(unit dose containers (e. g., vials), 블리스터 팩(blister packs) 및 스트립 팩(strip packs)을 포함한다.
상기 발명은 약학 조성물과 활성 성분이 분해되는 속도를 줄일 수 있는 하나 내지 그 이상의 화합물(compounds)들을 포함한 투여 형태와 (약학 조성물(pharmaceutical compositions)을 포함한다.
여기에서 안정화제("stabilizers")라고 언급된 화합물(compounds)들은 아스코르빅 산, pH 버퍼, 또는 솔트 버퍼와 같은 안티옥시던트(antioxidants)를 포함하지만, 여기에 제한되는 것은 아니다.
부형제(excipients)의 양과 유형과 마찬가지로, 투여시 활성 성분의 양과 특정 타입은 이에 한정되는 것은 아니지만, 환자들에게 투여되는 경로와 같은 요소에 따라 달라진다. 그러나, 상기 발명의 전형적인 투여 형태는 대략 1 mg 내지 대략 1000 mg까지의 양을 아침에 하루에 한번 주어지지만 바람직하게는 음식과 함께 나누어 복용되어지는 화합물 A 또는 그의 약학적으로 허용가능한 염, 용매화물, 포접물, 수화물, 결정다형 또는 프로드러그를 포함한다. 더욱 구체적으로, 매일 투여 방법은 동등하게 분할된 약을 하루에 두 번 투여한다. 특정하게, 매일 1회 투여량 범위는 대략 5 mg로부터 하루에 대하여 대략 500 mg에, 더 많이 특정하게, 하루에 대하여 대략 10 mg와 대략 200 mg 사이에 있다. 환자를 치료하는데 있어서, 상기 치료는 아마도 대략 1 mg에서 대략 25 mg인, 보다 낮은 1회 투여량에서 시작되어야 한다, 그리고, 만약 필요하다면 단일로서 또는 나누어진 투여방법으로서 하루에 대하여 대략 1000 mg에 대략 200 mg까지 약을 먹거나 환자의 전체적인 반응에 따라 약을 점차적으로 증가한다.
4.3.1. 경구 투여 형태
경구 투여(oral administration)를 위하여 적당한 발명의 약학 조성물은 독립된 투여 형태, 정제(예를 들면, 씹을 수 있는 정제), 카플렛, 캡슐 및, 액체(예를 들면, 향기나는 시럽)형태로서 제공될 수 있지만 여기에 제한되지는 않는다. 전술한 투여 형태는 당업자에게 널리 알려진 제약의 방법에 의하여 준비될 수 있는 소정량의 활성 성분들을 포함한다. Remington's Pharmaceutical Sciences,15th ed., Mack Publishing, Easton PA (1990) 참조.
상기 발명의 전형적인 경구 투여 형태는 통상적인 제약 혼합 기술에 따른 적어도 어떤 부형제(excipient)와 절친한 혼합물에서 활성 성분(들)을 결합시키는 것에 의하여 준비된다. 부형제(Excipients)는 투여를 위한 준비 형태에 따라 다양한 형태를 취할 수 있다. 예를 들면, 경구 액체 또는 에어로졸 투여에 사용을 위하여 적당한 부형제는 물, 글리콜, 오일, 알코올, 향미료, 보존제, 그리고 착색제를 포함하나, 이에 제한되지 않는다. 고형의 경구 투여 형태(예를 들면, 가루, 정제, 캡슐, 그리고 카플렛)에 사용을 위하여 적당한 부형제의 예시는 녹말, 설탕, 미정질 셀룰로오스, 희석액들, 과립화제, 윤활제, 바인더, 그리고 붕괴제를 포함하나, 이에 제한되지 않는다.
투여의 편리함 때문에, 정제(tablets)와 캡슐들은 가장 유리한 경구 투여 형태를 나타낸다. 이런 경우에 고체 부형제가 적용된다. 원한다면 정제(tablets)는 표준 수성 또는 비수성 기술에 의하여 코팅될 수 있다. 전술한 투여 형태는 조제술의 방법의 어떠한 방법에 의하여도 준비될 수 있다. 대체로, 약학 조성물과 투여 형태는 액체 담체들, 미세하게 나누어진 고체 운반체들, 또는 둘 모두를 활성 성분들과 균일하고 친밀하게 혼합함으로써 준비된다. 그리고 필요하다면 상기 제품을 상기 바람직한 형태로 성형된다.
예를 들면, 정제(tablet)은 압축 또는 몰딩에 의하여 준비될 수 있다. 압축된 정제(tablet)은 부형제와 선택적으로 섞인 가루 또는 작은 알갱이들 또는 파우더와 같은 자유롭게 흐르는 형태에서 적당한 기계내에서 활성 성분들을 압축하는 것에 의하여 준비될 수 있다. 성형된 정제(tablet)은 적당한 기계를 불활성 액체 희석액을 가지고 축축해진 가루인 화합물의 혼합물을 성형하는 것에 의하여 만들어질 수 있다. 상기 발명의 구술 투여 형태에서 사용될 수 있는 부형제는 바인더들, 필러, 붕괴제, 그리고 윤활제를 포함한다, 그러나, 여기에 제한되지 않는다.
약학 조성물과 투여에 사용을 위하여 적당한 결합제들은 옥수수 녹말, 감자 녹말, 또는 다른 녹말들, 젤라틴, 아카시아와 같은 자연적이고 인조 껌들, 나트륨 이트, 알긴산, 다른 알기네이트, 가루로 만들어진 트래거캔스 고무, 구아 껌, 셀룰로오스와 그것의 유도체(e.g., 에틸 셀룰로오스, 초산 셀룰로스, 카르복시메틸 셀룰로오스 칼슘, 나트륨 카르복시메틸 셀룰로오스), 폴리비닐 피롤리딘, 메틸 셀룰로오스, 선젤라틴화된 녹말, 하이드록시프로필 메틸기 셀룰로오스, 미정질 셀루로오스, 및 그들의 혼합물(microcrystalline cellulose, and mixtures thereof)들을 포함한다. 그러나 , 여기에 제한되지 않는다. (e.g., Nos.2208, 2906,2910)
약학 조성물과 투여에 사용을 위하여 적당한 필러의 보기는 활석, 탄산 칼슘(e.g., 작은 알갱이들 또는 가루), 미정질 셀룰로오스, 가루로 만들어진 셀룰로오스, 덱스트레이트, 고령토, 만니톨, 규산, 소르비톨, 녹말, 선젤라틴화된 녹말과 그들의 혼합들을 포함한다. 그러나, 여기에 제한되지 않는다. 상기 발명의 약학 조성물에서 바인더 또는 필러는 전형적으로 약학 조성물 또는 복용 형태의 약 50로부터 99 무게 퍼센트까지 존재한다.
미정질 셀룰로오스의 적당한 형태는 AVICELEL-PH-101, AVICEL-PH-103 AVICEL RC-581, AVICEL-PH-105(이용할 수 있다 FMC 법인, 미국 끈적인 분할, Avicel 판매, Marcus 갈고리, 펜실베니아로부터 판매), 그리고 혼합들을 포함한다, 그러나 여기에 제한되지 않는다. 특정 바인더는 AVICELRC-581와 같이 시판되는 미정질 셀룰로오스 및 카르복시메틸 셀룰로오스 나트륨의 혼합물이다.
적당한 무수 또는 저 수분 부형제 또는 첨가제 AVICEL-PH-103TM 및 녹말 1500 LM을 포함한다. 본 발명의 조성물에서 사용된 붕괴제(disintegrant)는 수분 환경에 노출된 경우에 붕괴되는 정제를 제공한다. 과량의 붕괴제를 갖는 정제는 저장시에 붕괴되고, 너무 소량의 붕괴제를 갖는 경우에는 원하는 조건 또는 속도에서 붕괴되지 않을 수 있다. 따라서 활성 성분의 분해를 나쁘게 하는 너무 많은 또는 너무 적은 양이 아닌 충분한 양의 붕괴제가 본 발명의 경구 투여 형태를 형성하기 위하여 사용되어야 한다. 상기 붕괴제의 양은 제형 형태에 근거하여 다양하게 사용되며, 종래의 일반적인 제형으로 쉽게 식별 가능하다. 일반적인 약학 조성물은 약 0.5 ~ 15 중량%, 바람직하게는 1 ~ 5중량%의 정제 분해 물질을 포함한다.
본 발명의 약학 조성물에 사용될 수 있는 붕괴제와 조제 형태는, 한정되는 것은 아니지만, 우뭇가사리(agar-agar), 알긴산, 칼슘 카보네이트, 소디움 스타치 글리코레이트, 감자 또는 타피오카 녹말, 프리-젤라틴나이즈드 녹말, 그 외 녹말, 점토, 그외 알긴들, 셀룰로스, 껌(gums), 및 이들의 혼합물을 포함한다.
본 발명의 약학 조성물에 사용될 수 있는 윤활제와 투여 형태는 특히 한정되는 것은 아니지만, 칼슘 스테아레이트(calcium stearate), 마그네슘 스테아레이트, 광유, 경 광유(light mineral oil), 글리세린, 소비톨(sorbitol), 마니톨(mannitol), 폴리에틸렌 글리콜, 다른 글리콜들, 스테아린산, 나트륨 라우릴 황산염, 활석, 수소와 화합시킨 식물성 기름(예를 들면, 땅콩 기름, 면실유, 해바라기 기름, 참깨 기름, 올리브 유, 옥수수 기름, 그리고 콩기름), 아연 스테아르산염, 에틸 올레인산 염, 에틸 라우레이트(ethyl laureate), 우뭇가사리류, 그리고 이들의 혼합들을 포함한다. 또한, 추가적으로 윤활제는 예를 들어, 실로이드 실리카 겔(AEROSIL 200, Baltimore의 W. R. Crace Co.제조, MD), 합성 실리카의 응고된 에어로졸(Plano의 Degussa Co. 판매, TX), CAB-O-SIL(보스턴 MA의 Cabot Co에 의해 시판된 발열성 이산화 규소 생성물), 그리고 혼합물들을 포함한다. 만약 모두 사용한다면, 윤활제는 일반적으로 약제 조성의 약 1중량% 미만, 또는 이들과 통합되는 투여 형태로 사용된다.
4.3.2 방출 지연 투여 형태
본 발명의 반응성 내용물들은 종래의 통상적인 기술로 잘 알려져 있는 배달 장치들 또는 제어된 방출 수단에 의해 관리될 수 있다. 예컨대, 제한되는 것은 아니지만, 미국 특허 제3,845,770호; 제3,916,899호; 제3,536,809호; 제3,598,123호; 및 제4,008,719호, 제5,674,533호, 제5,059,595호, 제5,591,767호, 제5,120,548호, 제5,073,543호, 제5,639,476호, 제5,354,556호 및 제5,733,566호 각각은 참조에 의해 여기에 포함된다. 이러한 조제 형태는 천천히 제공하거나, 예를 들어 하이드로프로필메틸 셀룰로오스, 다른 폴리머 주형들, 겔들, 투과막들, 삼투계, 다중층 코팅, 마이크로 입자들, 리포솜들, 중심체들을 하나 또는 그 이상의 반응성 내용물의 제어-방출, 또는 다양한 비율로 소망하는 방출 프로파일을 제공하기 위해 이들을 혼합하여 사용될 수 있다.
여기서 기술하는 것을 포함하는 종래의 통상적인 기술로 알려져 있는 적합한 제어-방출 제형은 본 발명의 반응성 내용물을 사용하여 쉽게 선택될 수 있다. 그래서, 본 발명은 특히 제한되는 것은 아니지만, 제어-방출에 적합한 정제, 캡슐, 젤캡, 및 카플렛(caplet)과 같은 경구 투약에 적합한 단일 단위 투여 형태를 포함한다.
모든 제어-방출된 제약 생산물은 이들 비통제된 대응물에 의해 얻어지는 약 치료를 개선하는 것이 통상의 목적이다. 이상적으로는, 의료 처치에 최적하게 고안된 통제-방출 준비의 사용은 치료 또는 최소 시간량으로 조건을 제어하는데 약 물질을 최소화함으로써 특징지어진다. 통제-방출 제형의 장점은 약의 확장된 반응성, 조제 빈도의 감소, 및 환자 순응의 증가를 포함한다. 또한, 통제-방출 제형은 활동 징후의 시간, 또는 다른 특징들 예컨대, 약물의 혈압에 영향을 미치는데 사용될 수 있으며, 그래서 부가적(예컨대, 반대) 효과의 발생에 영향을 미칠 수 있다.
가장 통제-방출 제형은 즉시 원하는 치료상 결과를 나타내는 약(활성 성분)의 량을 처음에 처방하도록 의도되었다. 그리고, 연장된 기간 동안 치료상 또는 질병 예방 효과를 일정 레벨로 유지하기 위하여 단계적으로 그리고 연속적으로 또 다른 약의 양들을 처방한다. 신체에 약의 이 불변한 농도를 유지하기 위하여, 약은 물질 대사되고 그리고 신체로부터 배설되는 약의 양을 대체할 비율로 투여 형태로 처방될 것이다. 활성 성분의 통제-방출는 특히 제한되는 것은 아니지만, pH, 온도, 효소, 물, 또는 다른 생리적인 조건 또는 혼합물들을 포함하는 다양한 상태에 의해 자극받을 수 있다.
4.3.3
비경구적
투여 형태
비경구적인 투여 형태는 특히 제한되는 것은 아니지만, 피하, 정맥내 (일시 주사를 포함), 근육내, 그리고 동맥안 을 포함하는 다양한 경로를 통해 환자들에게 투여될 수 있다. 왜냐하면, 이들 투여는 오염물질에 대한 환자들의 자연적인 방어를 일반적으로 무시하기 때문에, 비경구적인 투여 형태는 환자 처방에 앞서 살균될 수 있거나 바람직하게는 살균한다. 비경구적인 복용 형태는 특히 제한되는 것은 아니지만 , 주사용으로 준비된 액제, 주사를 위해 약학적으로 허용가능한 비이클에서 용해되거나 부유되도록 준비된 건식 산물, 주사를 위해 준비된 서스펜션, 및 에멀젼을 포함한다.
본 발명의 비경구적인 복용 형태를 제공하는데 사용될 수 있는 적합한 비이클들은 종래 기술에 잘 알려져 있다. 예컨대, 특히 제한되는 것은 아니지만 USP 주사용 물; 특히 제한되는 것은 아니지만 , 나트륨 콜로라이드 주사, 링거 주사, 포도당 주사, 포도당과 나트륨 콜로라이드 주사, 및 유산염 링거 주사와 같은 수성 비이클(aqueous vehicles); 특히 제한되는 것은 아니지만 에틸알콜, 폴리에틸렌 글리콜, 및 폴리프로필렌 글리콜과 같은 물 혼합(water-miscible) 비이클; 특히 한정되는 것은 아니지만 옥수수 기름, 면실유, 땅콩 기름, 참깨 기름, 에틸 올레인산 염, 이소프로필 미리스테이트(isopropyl myristate), 및 벤질 안식향산염과 같은 비수성 비이클을 포함한다. .
하나 또는 여기에 나타내진 활성 성분들의 더 많은 양의 용해도를 증가시킨 혼합물들은 또한 비경구적인 투여로 발명의 모양을 포함될 수 있다.
4.3.4 경피성 ( transdermal ), 국소성( topical ), 및 점막성 ( mucosal ) 복용 형태
본 발명의 경피성, 국소성, 및 점막성 복용 형태는 특히 제한되는 것은 아니지만, 안약 용액, 스프레이, 에어로졸, 크림, 로션, 연고, 겔, 용액, 에멀젼, 서스펜션, 또는 다른 공지된 형태의 것을 포함한다. 예를 들면, Remington's Pharmaceutical Sciences, 16th and 18th eds., Mack Publishing, Easton PA (1980 & 1990) 및 Pharmaceutical Dosage Forms 소개, 4판 Lea & Febiger, 필라델피아(1985)을 참조. 구강내에 점막 조직을 치료하는데 적합한 투여형태는 구강세척액 또는 구강겔로 조제될 수 있다. 경피 투여 형태는 활성성분의 원하는 양의 투과를 허용하는 특정 기간의 시간에 피부에 적용될 수 있는 저장형 타입 또는 매트릭스 타입의 패취를 포함한다.
본 발명에 의하여 포함되는 경피, 국소, 점액 투여 형태를 제공하는데 사용될 수 있는 적당한 부형제(예를 들어, 담체 및 희석제) 및 다른 물질은 약학 분야의 당업자에게 공지되어 있고, 주어진 약학 조성물 또는 투여 형태에 적용될 수 있는 특정한 조직에 의존한다. 비독성 및 약학적으로 허용가능한 로션, 색조, 크림, 유상액, 겔 또는 연고들을 제조하기 위한 전형적인 부형제는 물, 아세톤, 에탄올, 에틸렌글리콜, 프로필렌 글리콜, 부탄-1,3-디올, 이소프로필 미리스테이트, 이소프로필 팔미탄산염, 광유, 및 그것의 혼합물을 포함하나 이에 제한되지 않는다.
필요한 경우 습윤제 또는 보습제가 약학 조성물 및 투여 형태물에 첨가될 수 있다. 그러한 추가적인 성분들의 예는 당업자에 잘 알려져 있다. Remington's Pharmaceutical Sciences, 16th and 18th eds., Mack Publishing, Easton PA (1980 & 1990) 참조.
치료되는 특정 조직에 따라 추가적인 성분이 본 발명의 활성 성분의 치료 전, 치료와 함께 또는 치료 후에 사용될 수 있다.
예를 들어, 조직에 활성 성분을 전달하는 것을 돕기 위해 침투강화제가 사용될 수 있다. 적절한 침투강화제는 다음과 같은 것들을 포함할 수 있는데, 반드시 이에 한하지는 않는다. 즉, 침투강화제는, 아세톤; 에탄올, 올레일, 테트라하이드로퓨릴 등과 같은 다양한 알코올류; 디메틸 설포옥사이드와 같은 알킬 설포옥사이드; 디메틸 아세타미드; 디메틸 포름아미드; 폴리에틸렌 글리콜; 폴리비닐피롤리돈과 같은 피롤리돈; 콜리돈 그레이드(Kollidon grades)(포비돈, 폴리비돈); 요소; 및 Tween 80(폴리소르베이트 80)과 Span 60(소르비탄 모노스테아레이트)와 같은 수용성 또는 수불용성 당 에스테르를 포함한다.
약학적 조성물 또는 투여형태, 또는 이 약학적 조성물 또는 투여형태가 투여되는 조직의 pH는, 하나 또는 그 이상의 활성 성분들의 전달을 증진하기 위해 적절하게 조절될 수 있다. 유사하게, 용제 캐리어의 극성, 그 이온강도, 또는 탄력성(tonicity)은 전달을 증진하기 위해 조절될 수 있다. 또한 하나 또는 그 이상의 활성 성분의 친수성 또는 소수성을 바꾸어 전달을 증진시키기 위해 스테아레이트와 같은 화합물도 약학적 조성물 또는 투여 형태에 첨가될 수 있다. 이러한 측면에서 스테아레이트는 성형을 위한 지질 비이클(lipid vehicle)로서, 에멀젼화제 또는 계면활성제로서, 또한 전달 강화제 또는 침투강화제로서 작용할 수 있다. 활성 성분의 다른 염, 수화물 또는 용매가 결과 조성물의 성질을 좀더 조정하기 위해 사용될 수 있다.
* 4.3.5. 키트
전형적으로, 본 발명의 활성 성분은 환자에게 동시에 투여되거나 동일한 투여경로로 투여되지 않는 것이 바람직하다. 본 발명은 따라서, 의학적 훈련자들에 의해 사용될 때, 환자에게 활성 성분을 적합한 양으로 투여하는 것을 단순화할 수 있는 키트를 포괄한다.
본 발명의 전형적인 키트는 화합물 A의 단위 투여 형태 또는 그의 약학적으로 허용되는 염, 용매화물, 수화물, 포접물, 결정다형 또는 그 프로드러그, 및 2차 활성 성분의 단위 투여 형태를 포함한다. 2차 활성 성분의 예들은 전술한 4.2 절에서 열거된 것들을 포함하는데, 이것들에 한정되지는 않는다.
본 발명의 키트는 활성 성분(들)을 투여하는 데 사용되는 기기를 더 포함할 수 있다. 이러한 기기들의 예는, 한정되지는 않지만, 피하 주사기, 적하 백(drip bag), 패치, 및 흡입기를 포함한다.
본 발명의 키트는 하나 또는 그 이상의 활성 성분을 투여하는 데에 사용될 수 있는 약학적으로 허용되는 비이클을 더 포함할 수 있다. 예컨대, 활성 성분이 고형체로 제공된다면 비경구 투여를 위해 재구성되어야 하는데, 이 키트는 이 안에서 활성 성분이 분해되어 비경구 투여에 적합한 미립자 없는 무균 용액을 형성하는데에 적절한 비이클의 밀봉된 용기를 포함할 수 있다. 약학적으로 허용되는 비이클의 예는, 한정되지는 않지만, USP 주사액을 위한 물; 한정되지는 않지만, 소디움 클로라이드 주사액, 링거 주사액, 덱스트로스(Dextrose) 주사액, 덱스트로제 및 소디움 클로라이드 주사액, 및 젖산처리된(Lactated) 링거 주사액과 같은 수성 비이클; 한정되지는 않지만, 에틸 알코올, 폴리에틸렌 글리콜, 및 폴리프로필렌 글리콜과 같은 물과 혼합가능한 비이클; 및 한정되지는 않지만, 옥수수유, 면화씨유, 땅콩유, 참기름, 에틸 올레이트, 이소프로필 미리스테이트(isopropyl myristate), 및 벤질 벤조에이트와 같은 비수성 비이클을 포함한다.
본 발명은 2-[1-(3-에톡시-4-메톡시페닐)-2-메틸설포닐에틸]-4-아세틸아미노이소인돌린-1,3-디온의 (+)-이성질체를 유효성분으로 포함하는, 배경기술에서 언급된 질환의 치료 또는 예방용 조성물, 상기 이성질체를 포함하는 조성물 자체 및 단위 투여 제형, 및 상기 이성질체의 제조방법과 관련된 화합물 및 제조방법을 제공한다.
3.1. 도면의 설명
도 1은 (+)-2-[1-(3-에톡시-4-메톡시페닐)-2-메틸설포닐에틸]-4-아세틸아미노이소인돌린-1,3-디온(2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione)의 (+) 에난티오머(enantiomer)의 제법을 설명하기 위한 것이다.
도 2는 지각 능력이 있는 흰족제비의 폐의 LPS-유도 호중성백혈구증가증(neutrophilia) 상에서 본 발명의 에난티오머의 효과를 설명하기 위한 것이다.
도 1은 (+)-2-[1-(3-에톡시-4-메톡시페닐)-2-메틸설포닐에틸]-4-아세틸아미노이소인돌린-1,3-디온(2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione)의 (+) 에난티오머(enantiomer)의 제법을 설명하기 위한 것이다.
도 2는 지각 능력이 있는 흰족제비의 폐의 LPS-유도 호중성백혈구증가증(neutrophilia) 상에서 본 발명의 에난티오머의 효과를 설명하기 위한 것이다.
5.
실시예
5.1. 실시예 1 : 2-[1-(3- 에톡시 -4- 메톡시페닐 )-2- 메틸설포닐에틸 ]-4- 아 세틸아미노이소인돌린-1,3-디온의 합성
아세트산(20 mL) 안에 3-아세트아미도프탈릭 무수물(751 mg, 3.66 mmol) 및 1-(3-에톡시-4-메톡시페닐)-2-메틸설포닐에틸아민(1.0g, 3.7mmol)이 섞어진 용액을 15 시간동안 가열 환류했다. 진공에서 용제를 제거하여 오일을 얻었다. 결과 오일의 크로마토그래피로 황색 고체(1.0g, 59% 수율): mp,144 ℃;1H NMR (CDC13) δ1.47 (t, J=7.0 Hz, 3H, CH3), 2.26 (s, 3H, CH3), 2.88 (s, 3H, CH3), 3.75 (dd, J=4.4, 14.3 Hz,1H, CHH), 3.85(s, 3H, CH3), 4.11(q, J= 7 Hz, 2H, CH2), 5.87(dd, J=4.3, 10.5 Hz, 1H, NCH), 6.82-6.86(m, 1H, Ar), 7.09-7.11(m, 2H, Ar), 7.47 (d,J= 7 Hz, 1H., Ar), 7.64 (t, J= 8 Hz, 1H, Ar), 8.74 (d,J=8 Hz, 1H, Ar), 9.49 (br s,1H, NH); 13C NMR (CDC13) δ14.61, 24.85, 41.54, 48.44, 54.34, 55.85, 64.43, 111.37, 112.34, 115.04, 118.11, 120.21, 124.85, 129.17, 130.96, 136.01, 137.52, 148.54, 149.65, 167.38, 169.09, 169.40; Anal Calc'd. for C22H24NO7S:C, 57.38; H, 5.25; N, 6.08. Found: C, 57.31; H, 5.34; N, 5.83을 수득했다.
5.2. 실시예 2 : (+)2-[1-(3- 에톡시 -4- 메톡시페닐 )-2- 메틸설포닐에틸 ]- 4-아세틸아미노이소인돌린-1,3-디온의 합성
3-아미노프탈릭산의 준비
10% Pd/C (2.5g), 3-니트로프탈릭산 (75.0g, 355mmol) 및 에탄올 (1.5L)를 질소 분위기에서, 2.5 L Parr 하이드로제너레이터(hydrogenator)에 충전시켰다. 수소를 55 psi 까지 반응용기에 충전시켰다. 화합물을 50 내지 55 psi의 수소압을 유지하면서 13시간 동안 교반하였다. 화합물에서 수소를 빼내고 질소로 세 번 퍼지하였다. 현탁액을 셀라이트 베드(celite bed)로 여과하고 메탄올로 세정하였다. 여과물을 진공에서 응축하였다. 결과물인 고체를 에테르 안에서 다시 슬러리로 만들고 진공여과에 의해 분리했다. 고체는 진공에서 건조하고 정량하여 54g(84% 수율)의 3-아미노프탈릭산을 황색 산물로서 얻었다. 1H-NMR (DMSO-d6) δ:3.17(s,2H), 6.67(d,1H), 6.67(d,1H), 6.82(d,1H), 7.17(t,1H), 8-10(brs,2H). 13C-NMR(DMSO-d6) δ:112.00, 115.32, 118.20, 131.28, 135.86, 148.82, 169.15, 170.09.
3-아세트아미도프탈릭 무수물의 준비
기계적 혼합기, 온도계, 및 응축기가 구비된 1L 3구 둥근바닥 플라스크를 준비하여 3-아미노프탈릭산 (108g, 596mmol) 및 아세틱 무수물(550mL)를 충전했다. 반응 화합물을 3 시간 동안 가열하고 실온에서 냉각하였으며, 다시 1 시간 동안 0-5℃로 냉각했다. 결정 고체는 진공여과에 의해 수집했고 다시 세정했다. 고체 산물은 실온에서 진공 건조, 정량해서 75g(61% 수율)의 3-아미노프탈릭 무수물을 백색 산물로서 얻었다. 1H-NMR (CDCL3) δ:2.21(s,3H), 7.76(d,1H), 7.94(t,1H), 8.42(d,1H), 9.84(s,1H).
2-(3-에톡시-4-메톡시페닐)-1-(메틸설포닐)-에트-2-일라민 분해
기계적 혼합기, 온도계, 및 응축기가 구비된 1L 3구 둥근바닥 플라스크를 준비하여 2-(3-에톡시-4-메톡시페닐)-1-(메틸설포닐)-에트-2-일라민(137.0g, 500mmol), N-아세틸-L-류신(52g, 300mmol), 및 메탄올(1.0L)을 충전했다. 교반된 슬러리를 1 시간 동안 가열했다. 섞여진 화합물을 실온까지 차게 하고 실온에서 계속하여 3 시간 동안 교반했다. 슬러리를 여과하고 메탄올(250 mL)로 세정하였다. 고체는 실온에서 공기 건조하고 진공건조하여 정량하여, 조산물(crude product) (85.8%ee)의 109.5g을 얻었다.상기 크루드 고체(55.0그램)과 메탄올(440ml)을 1시간 동안 환류하고 상온에서 냉각하고 상온에서 추가적으로 3시간 교반하였다. 상기 슬러리를 여과하고 필터 케이크를 메탄올(200ml)로 세척하였다. 상기 고형물을 공기에서 건조하고 진공조건하에서 30도에서 건조하여 일정한 질량의 49.6그램의 (S)-2-(3-에톡시-4-메톡시페닐)-1-(메틸설포닐)-2-에트(eth)-2-일아민 N-아세틸-L-루이신 염(98.4%ee)을 산출하였다. 키랄 HPLC(아질런트 테크놀로지사, 1/99 EtOH/20mM KH2PO4 @pH7.0, 울트론 키랄 ES-OVS, 150mm x 4.6mm, 0.5ml/min, @240nm: 18.4분 (S-아이소머, 99.2%), 22.5분(R-아이소머, 0.8%).
화합물 A의 제조
교반장치, 온도계 및 콘덴서를 구비한 500mL 용량의 3목 둥근 플라스크를 준비하였다. 반응용기에 (S)-2-(3-에톡시-4-메톡시페닐)-1-(메틸술포닐)-에트(eth)-2-일(yl) 아민 N-아세틸-L-류신 염(25g, 56mmol, 98% ee), 3-아세트아미도프탈릭 안하이드라이드(12.1g 58.8mmol) 및 빙초산(25mL)로 가득 채웠다. 혼합물을 하루동안 리플럭스한 다음 50℃ 미만으로 냉각시켰다. 용매를 진공하에서 제거한 다음, 그 잔유물을 에틸 아세테이트에 용해시켰다. 얻어진 용액을 물(250mL ×2)로 세척하고, NaHCO3 수용액(250mL ×2)으로 포화시키고, 소금물(250mL ×2)을 가한 다음, 소듐 설페이트 하에서 건조시켰다. 용매는 진공건조하였고, 잔유물은 에탄올(150mL)과 아세톤(75mL)을 포함하는 2성분계 혼합용매로 재결정하였다. 진공필터링하여 고체를 분리하였고, 에탄올((100mL ×2)로 세척하였다. 얻어진 산물을 60℃에서 진공건조하여 19.4g(75% 수율), 98% ee의 S-{2-[1-(3-에톡시-4-메톡시페닐)-2-메틸술포닐에틸]-4-아미노이소인돌린-1,3-디온을 얻었다. 키랄 HPLC(15/85 EtOH/20 mM KH2PO4 @pH 3.5, Ultron Chiral ES-OVS-Agilent Technology사-, 150mm × 4.6mm, 0.4mL/min, @240nm): 25.4 min(S-isomer, 98.7%), 29.5 min(R-isomer, 1.2%). 1H-NMR(CDCl3)δ:1.47(t. 3H), 2.26(s, 3H), 2.87(s, 3H), 3.68-3.75(dd, 1H), 3.85(s, 3H), 4.07-4.15(q, 2H), 4.51-4.61(dd, 1H), 5.84-5.90(dd, 1H), 6.82-8.77(m, 6H), 9.46(s, 1H). 13C-NMR(DMSO-d6)δ:14.66, 24.92, 41.61, 48.53, 54.46, 55.91, 64.51, 111.44, 112.40, 115.10, 118.20, 120.28, 124.94, 129.22, 131.02, 136.09, 137.60, 148.62, 149.74, 167.46, 169.14, 169.48.
5.3.
실시예
3 :
TNF
-α 억제
인간 전혈 LPS - 유도된 TNF-α 분석
화합물의 인간 전혈에 의한 LPS - 유도된 TNF-α 생산 억제력은 PBMC 대신에 신선한 전혈을 사용한 것을 제외하고는, 하기에 기재된 인간 PBMC 내에서의 LPS - 유도된 TNF-α 분석을 통해 측정된다(George Muller, et al. 1999, Bioorganic & Medicinal Chemistry Letters 9;1625-1630). 인간의 전혈 LPS - 유도된 TNF-α IC50=294nM
쥐 LPS - 유도된 혈청 TNF-α 억제
화합물은 전술한 방법에 따라 동물 모델로 테스트하였다(Corral et al. 1996, Mol. Med 2:506-515). 쥐 LPS - 유도된 혈청 TNF-α 억제(ED50, mg/kg, p.o.) = 0.05이다.
LPS - 유도된 혈청 TNF-α 생산
리포폴리사카라이드(LPS)는 TNF-α를 포함하여, 많은 프로-인플라머토리 시토카인들의 생산을 유도하는 E. coli와 같은 그람-네가티브 박테리아에 의해 생산된 내독소이다. PBMC 내에서, LPS에 응답하여 생산된 TNF-α는 단핵세포로부터 얻어지는데, 총 PBMC의 약 5-20%를 포함한다. 화합물은 전술한 바와 같이(Muller et al. 1996, J. Med Chem. 39:3238), 인간 PBMC로부터 LPS - 유도 TNF-α 생산 억제력으로 테스트되었다. 통상적인 제공자의 PBMC는 Ficoll Hypaque(Pharmacia, Piscataway, NJ, USA) desity centrifugation으로부터 얻었다. 세포는 10% AB± 인간 혈청(Gemini Bio-products, Woodland, CA, USA), 2mM L-글루타민, 100 U/ml 페니실린 및 100㎍/ml 스트렙토마이신(Life Technologies)으로 보충된 RPMI(Life Technologies, Grand Island, NY, USA)에서 배양하였다.
PBMC(2×105 cells)는 트리플리케이트로 96-well flat-bottom Costar tissue culture plates(Corning, NY, USA)에서 평판배양하였다. 세포는 화합물의 존재 또는 부존재 하에서 100ng/ml에서 LPS(Sigma, St. Louis, MO, USA)로 자극하였다. 화합물들(Celgene Corp., Warren, NY, USA)은 DMSO(Sigma)로 용해시켰고, 사용전 배양배지 내에서 희석시켰다. 최종 DMSO 농도는 모든 샘플에서 0.25%였다. 화합물은 LPS 자극 1시간 전에 세포에 가해졌다. 세포는 5% CO2, 37℃ 하에서 18-20시간 동안 인큐베이트하였으며, 상청액을 채집하여 배양 배지내에서 희석하고 ELISA(Endogen, Boston, MA, USA)로 TNF-α 농도를 분석하였다. LPS - 유도 혈청 TNF-α IC50=77nM.
IL-1β-유도 TNF-α 생산
염증병변의 과정에서, TNF-α의 생산은 박테리아적으로 유도된 LPS보다는 사이토카인 IL-1β에 의해 자주 자극된다. 인간 PBMC로부터 화합물의 IL-1β-유도 TNF-α 생산 억제력은 PBMC를 Ficoll-Paque Plus(Amersham Pharmacia, Piscataway, NJ, USA)에 근거한 원심분리에 의해서 소오스 류코사이트 유니트(Sera-Tec Biologicals, North Brunswick, NJ, USA)로부터 분리하고, 10% 비활성화 처리된 태아 소 혈청(Hyclone), 2mM L-글루타민, 100U/ml 페니실린 및 100mg/ml 스트렙토마이신(complete medium)을 함유하는 RPMI-1640 medium(Bio Whittaker, Walkersville, Maryland, USA) 내에서 3×105 cells/well에서의 96-well 조직 배양 평판에서 평판배양하고, 37℃, 5% 이산화탄소하의 인큐베이터 내에서 0.1%의 최종 DMSO 농도에서 10, 2, 0.4, 0.08, 0.016, 0.0032, 0.00064 및 0μM의 화합물로 전처리하여 복제하고, 18시간동안 50ng/ml 재조합체 인간 IL-1β(Endigen)로 자극한 것을 제외하고는, 전술한 LPS - 유도 TNF-α 생산에 따라 테스트하였다.
5.4.
실시예
4 :
PDE
선택성
PDE1, 2, 3, 5, 및 6 효소 분석
PDE4에 대한 화합물의 특이성은 인간 혈소판과(Hidaka and Asano 1976, Biochem. Biophys. Acta 429:485, and Nicholsen et al. 1991, Trends Pharmaco. Sci. 12:19) 소의 레티날 로드 아우터 세그먼트(Baehr et al. 1979, J. Biol. Chem. 254:11669, 및 Gillespie et al. 1989, Mol. Pharm. 36:773)로부터 소의 PDE1, 인간 PDE2, PDE3 및 PDE5 및 PDE6에 대비하여 단일 농도(10μM)에서 분석하여 평가하였다. 그 결과를 표 1에 나타냈다.
PDE7 효소 분석
PDE7은 주로 T 세포와 골격 근육에 cAMP-선택적 PDE로 발현된다. IL-2 및 IFN_γ와 같은 T 세포-유도 시토카인(cytokine)은 잠재적으로 PDE7 금지를 통해 정규화할 수 있다. PDE7은 Hut78 인간 T 세포로부터 전술한 바와 같은 음이온 교환 크로마토그래피에 의해 정제되었다(Bloom and Beavo 1996, Proc. Natl, Acad Sci. USA 93:14188-14192). 화합물은 아래 표 1에 기재된 바와 같은 10nM cAMP의 존재하에 PDE7 준비에 대하여 테스트되었다.
[표 1]
- 화합물 B는 화합물 A의 역 에난티오머(opposite enantiomer)임.
5.5.
실시예
5:
PDE4
억제
PDE4(U937 cell-derived) 효소 분석 시험
PDE4 효소는 앞서 설명한 바와 같이 겔 여과법 크로마토그래피에 의해 U937 인간 골수 세포로부터 정제되었다(Muller et al. 1998, Bioorg. & Med Chem Lett 8: 2669 - 2674). 포스포디에스터라제(phosphodiesterase) 반응은 전술한 바와 같이 30℃ 30분 동안 50mM Tris HCl pH 7.5, 5mM MgCl2, 1μM cAMP, 10nM [3H]-cAMP에서 수행되었고, 보일링에 의해 터미네이팅되었고, 1mg/ml 뱀 독액에 의해 처리되었고, AG-IXS 이온 교환 레진(BioRad)을 이용하여 분리되었다. Muller et al. 1998, Bioorg. & Med Chem Lett 8:2669-2674). 반응은 가용한 기질(substrate)의 15%를 소비하였다.
5.6.
실시예
6: 인간 세포 분석 시험
SEB - 유도된 IL-2 및 IFN-γ생성물
포도상 구균 장독소 B(SEB)는 그램-포지티브 박테리아 '스타필로코커스 아우레우스'로부터 유래된 초항원(superantigen)이다. SEB는 특별한 T세포 수용체 Vβ 체인을 표현하는 T 세포에 특이한 편리한 생리적 자극을 제공한다. 인간 PBMC(약 50%의 T 세포들로 이루어짐)는 상기에서 설명된 바와 같이 소스 백혈구 유니트로부터 분리되었고, 96-well 세포 컬쳐 플레이트에서 완전한 메디엄으로 3x105 cells/well로 플레이팅되었고, 1시간 동안 5% CO2에서 휴미디파이드된 인큐베이터 안에서 37℃에서 0.1%의 최종 DMSO 농도에서 2중으로 10, 2, 0.4, 0.08, 0.016, 0,0032, 0.00064 및 0 μM의 화합물로 전처리되었고, 18시간동안 100ng/ml SEB(sigma Chemical Co., St.Louis, MO, USA)를 가지고 스티뮬레이팅되었다. IL-2 및 IFN-γ 농도은 ELISA(R&D 시스템, Mineneapolis, MN, USA)에 의해 측정되었다. IL-2 IC50 = 291nM. IFN - γ IC50 = 46nM.
5.7.
실시예
6:
cAMP
상승 분석 시험
PGE2- 유도된 cAMP 상승
프로스타글라딘 E2(PGE2)는 모노사이트 상에서 프로스테노이드 수용체에 결합되고, T 세포와 다른 백혈구는 결과적으로 세포 사이의 cAMP 농도를 상승시키고, 결국 세포적 반응을 억제한다. PGE2 와 PDE4 억제제의 결합은 시너지적으로 이들 셀들에서 cAMP 농도를 상승시키고, PGE2의 존재하에서 PDE4 억제제에 의해 야기되는 PBMC 내의 cAMP의 상승은 PDE4 억제제의 억제적 활성도에 비례한다. 세포 사이의 cAMP는 인간 PBMC 내에서 다음과 같이 측정되었다. PBMC는 전술한 바와 같이 분리되었고, RPMI-1640 내에서 웰 당 1x106 셀로 플레이팅되었다. 셀들은 1시간 동안 5% CO2에서 휴미디파이드된 인큐베이터 안에서 37℃에서 2%의 최종 DMSO 농도에서 100, 10, 1, 0.1, 0.01 및 0 μM의 화합물로 전처리되었다. 셀들은 1시간 동안 PGE2(10μM)(Sigma)에 의해 스티뮬레이팅되었다. 셀들은 포스포디에스터라제 활성을 억제하기 위해 0.1N 최종 농도 HCL에 의해 라이스(LYSED)되었고, 플레이트는 -20도로 냉각되었다. 생성된 cAMP는 cAMP(low pH) 이뮤노에세이(Immunosaasy) 키트(R&D 시스템)를 이용하여 측정되었다. 레세메이트(recemate)에 대한 PBMC cAMP EC50는 3.09μM이다. 화합물 A에 대한 PBMC cAMP EC50는 1.58μM이다.
인간 호중성백혈구에서 cAMP의 상승은 다음과 같이 측정된다. PBMC는 Ficoll--Paque Plus(Amersham Pharmacis) 상에서 원심분리에 의해 소스 백혈구(LeuKocytes)(Sera-Tec Biologicals)에서 제거된다. 결과물로 얻어지는 적혈구/다형핵세포(PMN) 펠레트는 HANK's Balanced Salt Solution(Bio Whittaker)에서 리서스펜디드된다. 그리고, 0.9% 식염수에서 3% 덱스트린 T-500(Amersham Pharmacia)의 동일 볼륨으로 혼합된다. 적혈구는 20분동안 침전된다. 그리고, PMN은 제거되고, 4도에서 8분동안 120알피엠으로 원심분리된다. 남아있는 적혈구는 30초 동안 0.2% 차가운 식염수에서 라스(Lysed)된다. 셀들은 1.6% 식염수의 동일 볼륨의 부가에 의해 등장력으로 보존된다. PMN은 4℃에서 8분동안 1200알피엠으로 원심분리되고, RPMI-1640에서 다시 서스펜디드되고 상술한 바와 같이 cAMP 상승에 대해 분석된다. PMN은 FACSCalibur 상에서 플로우 크리토메트지에 의한 약 74% CD18/CD11b+, 71%CD16+CD9+ 호중성백혈구임이 확인되었다. 결과는 표2에 표시되었다.
fMLF - 유도된 LTB4 생성물
N-포르밀-메티오닌-루신-페닐알라닌(fMLF)는 호중성백혈구를 신속하게 디그레뉼레이트시켜 이동시키고 내피세포에 부착시키고 아라키돈산 대사의 생성물이자 호중성백혈구 화학유인물질인 레우코트린(leukotriene) LTB4를 방출하는, 박테리아적으로 유래된 펩타이드이다. 상술한 바와 같이 화합물은 다음과 같은 마디피케이션에 의해 fMLF- 유도된 호중성백혈구 LTB4 생성을 억제하는 능력이 테스트되었다(Hatzelmann and Schudt 2001, J. Pharm. Exp. Ther. 297:267 - 279). 호중성백혈구는 상술한 바와 같이 분리되었고 칼슘이나 마그네슘이 없고(Bio Whittaker) 10nM HEPES pH 7.2를 포함하는 포스페이트 버퍼드 식염수에서 다시 서스펜디드되었고, 1.7 x 106 cells/well의 농도에서 96-웹 티슈 컬쳐 플레이드에서 플레이티드되었다. 셀들은 50μM 티모로살(sigma)/1mM CaCl2/1mM MgCl2 15분 동안 37도 5% CO2에서 처리되었고, 10분동안 이중으로 0.01% 최종 DMSO 농도에서 1000, 200, 40, 8, 1.6, 0.32, 0.064 및 0nM 화합물과 함께 처리되었다. 호중성백혈구는 1μM fMLF와 함께 30분동안 자극되었고, 메탄올(20% 최종 농도)의 부가에 의해 라스되었고, 10분동안 건조 아이스/이소프로판올 배스에서 냉각되었다. 라세이트는 LTB4의 내용이 컴페터티브 LTB4 ELISA(R&D 시스템)에 의해 측정될때까지 보관되었다. 결과는 표2에 나타내었다.
지모산(zymosan)- 유도된 IL-8 생성물
지모산 A 또는 열에 의해 죽는 이스트 삭카로미세스 세레비시에는 호중성백혈구 표면 상에서 Mac-1 접착 분자에 결합되고, 포식작용, 셀 활성화, IL-8 생성을 유발한다. 지모산 -유도된 IL-8 생성물은 다음과 같은 마디피케이션에 의해 전술한 바와 같이 특정된다(Au et al. 1998. Brit.J.Pharm. 123:1260-1266). 인간 호중성백혈구는 상술한 바와 같이 정제되었고, 완전한 메디엄 내에서 3x105 Cells/well로 96-웰 티슈 컬쳐 플레이트에서 플레이티드되었고, 1시간 동안 37도 5% CO2에서 0.1%의 최종 DMSO 농도에서 2중으로 10, 2, 0.4, 0.08, 0.016, 0.0032, 0.00064 및 1μM 화합물로 처리되었다. 호중성백혈구는 비옵소닌화되고, 가열된 지모산 A(Sigma)로 18시간 동안 2.5x105 particles/well로 스티뮬레이티드되었다. 상청액은 ELISA(R&D 시스템)에 의해 IL-8에 대해 채집되고 테스트되었다. 결과는 표2에 나타내었다.
fMLF - 유도된 CDI8/CD11b 발현
호중성백혈구 상의 CD18/CD11b(Mac-1) 발현은 전술한 바와 같이 다음과 같은 마디피케이션에 의해 측정되었다(Derian et al. 1996, J.Immunol:154:308-3 17). 호중성백혈구는 상술한 바와 같이 분리되었고, 완전한 메디엄에서 1x106 cell/ml로 다시 서스펜디드되었고, 37도 5% CO2에서 10분 동안 0.1%의 최종 DMSO 농도에서 2중으로 10, 1, 0.1, 0.01 및 0μM 화합물로 전처리되었다.
세포가 30nM fMLF로 30분동안 자극된 다음 4℃로 냉각시킨다. 세포들은 Fc 수용기들을 블로킹하기 위하여 토끼 IgG(잭슨 이뮤노 리서치 랩, 서부 그로브, PA, 미국)(10g/1×106셀개의 셀)을 처리하였으며, CD18-FITC와 CD11b-PE(벡톤 딕킨슨)으로 염색하였으며, 팩스 칼리버(FACS Calibur)를 이용한 유동 세포분석법(Flow Cytometry)에 의해 분석되었다. 자극이 없는 상태에서, CD18/CD11b의 발현(형광을 의미함)으로 인하여 모든 샘플로부터 억제 곡선을 획득할 수 있으며, IC50이 계상될 수 있도록 하였다. 그 결과는 하기 표 2에 나타냈다.
유도된
fMLF
를
HUVEC
에의 고착
인간 배꼽정맥 내피세포(Human umbilical vein endothelial cells, HUVEC이라 약하기도 함)은 다음의 변형에 따라 전술한 호중성백혈구(neutrophil)의 고착을 위한 기질로서 사용되는 (데리안 등. 1995, J.Immunol.:154:308-317). HUVEC 셀은 안트로제네시스(Cendar Knolls, NJ, USA)로부터 얻어질 수 있으며, 호중성백혈구(neutrophil)은 사이토칼라신 B로 처리되지 않았다. 셀은 0.1%의 최종적인 DMSO 농도 내에서 10분동안 이중으로 10, 1, 0.1, 0.01, 0.001 및 0μM 상태의 화합물로 처리되었으며, 500nM fMLF로 30분 동안 자극되었으며, FLX800 플레이트 리더(바이텍 연구소, 위눅스키, 버몬트주, 미국)로 형광을 측정하고 전에 PBS로 2회 세척되었다. 그 결과는 하기 표 2에 나타냈다.
[표 2]
5.8
실험예
8: 수용성 용해도
평형 용해도는 pH 7.4의 수용성 완충액에서 측정되었다. pH 7.4의 완충액은 0.07M NaH2P04 용액에 10N NaOH로 부가하여 pH를 7.4가 되도록 하면서 준비하였다. 상기 용액의 이온화도는 0.15이다. 적어도 분말의 1mg이 완충액 1ml를 섞어줌으로써 1mg/ml 이상의 혼합물이 되도록 조합하였다. 이러한 샘플은 2시간 이상 흔들어 주고, 상온에서 밤새도록 방치시켰다. 이러한 샘플은 샘플로서 포화되어져 있는 0.45μm 나일론 주사기 필터를 통과하도록 여과하였다. 여과물은 두번 연속적으로 샘플로 만들어졌다. 여과물은 미리 준비된 50%의 메탄올 표준에 대비하여 고성능 액체 크로마토그래피(HPLC)에 의해 분석된다. 화합물 A는 라세미체로서보다는 3.5배 정도 더 큰 농도를 갖는 수용액이다. 측정된 화합물 A의 농도는 0.012mg/ml;라세미체 농도는 0.0034mg/ml를 갖고 있다.
5.9 실험예 8 : 허파의 호중성백혈구증가증 ( neutrophilia ) 페렛 ( ferret ) 모델을 찾기 위해 유도된 LPS
인식능력을 갖는 페렛 모델은 경구(p.o.) 경로에 의해 투여된 PDH4 억제제의 항염증(anti-inflammatory), 구역질 및 행동효과를 관찰하기 위해 사용되어 왔다. 이 실험들로부터, 각각의 PDE4 억제제를 위한 치료지수(TI)가 측정될 수도 있다. TI는 항염증제(호중성백혈구증가증(neutrophilia)으로부터 유도된 LPS에 대한 50%의 억제 효과를 목적으로 투여됨)에 의해 구토에 관한 다양한 상황과 행동의 변화를 일으키는 것을 위한 한계 조사량을 구분하기 위해 계산되어진다.
축산학
수컷 페렛은[머스텔라 풀로리어스 유로(1-2킬로그램)]
수컷 페렛은 베리 그린 팜 또는 미사이 컨설턴시에 의해 공급되었다. 운송후에, 동물들은 7일 이상의 기간 동안 한정된 방 내부에서 새로운 환경에 적응할 수 있도록 조치하였다. 식이요법은 SDS 식이요법 탄소를 포함하고 있으며, 주당 3번 휘스커스캣(Whiskers cat)용 음식과 펠렛화된 음식이 주당 3회 정도 주어지도록 하였다. 물은 저온 살균된 동물 등급의 식수이며, 매일 변화를 주면서 공급하였다.
PDE4
억제제의 투약
PDE4 억제제들은 경구로(p.o.) 초기에는 복용량이 1-10 mg/kg으로 관리되었으나, 점차적으로 TI가 10 또는 그 이상이 주어지도록 하기 위해 순차적으로 30mg/kg까지 점진적으로 증가시키면서 공급하였으며, 이와 더불어 호중성백혈구증가증의 50%의 억제를 일으키기 위해 최소 투약량을 유지되도록 하였다. 페렛 위성은 물에 단식시킨 하룻밤 사이에는 물에의 접근은 자유로이 허용되었다. 동물들은 비이클 또는 PDE4 억제제를 식도로 목의 뒤쪽 아래로 늘어뜨린 15cm의 투약 바늘을 이용하여 경구 투여하였다. 약을 먹은 후에 동물들은 물에 대한 자유로운 접근을 허락하기 위하여 방풍유리 문과 망이 설치된 홀딩 케이지 내에 되돌려졌다. 약을 먹은 후에 동물들은 변함없이 관찰되었으며, 어떠한 구토(emesis)나 행동상의 변화는 기록되었다. 동물들은 경구투여 이후에 60-90분 동안의 음식에 대한 접근을 허용하였다.
LPS
에의 노출
화합물 또는 비이클에 의해 경구 투여하고 30분이 경과된 후, 페렛은 밀봉된 방풍유리 용기내에 놓여져 있으며, LPS(100 μg/ml)의 에어로졸에 배분동안 노출시켰다. 분무기(미국 데빌비스사 제품)에 의해 생성되는 LPS의 에어로졸은 방풍유리 노출 쳄버에 주입시킨다. 10분 동안의 노출기간이 경과된 이후, 동물은 물에 대한 접근이 자유로이 허용되며, 마지막 단계에서는 음식에 대해서까지도 접근이 허용되는 홀딩 케이지로 되돌려진다. 이러한 관찰은 적어도 2.5시간의 주기 동안 경구 투여, 구토증상 및 행동변화를 기록하였다.
기관지폐포세척
동물에 대한 LPS 노출 후 6시간이 경과한 후 동물들은 소디움 펜토바리비톤의 과복용으로 인해 죽게되었다. 기관은 폴리프로필렌 튜빙과 20ml의 헤파린(10 units/ml)을 포함하는 인산염완충식염수(phosphate buffered saline, PBS라 약하기도 함)를 이용한 두 번의 허파 세척을 통해 응혈이 방지되었다.
혈액 샘플링 / 조직 제거
최종적인 혈액 샘플(10 ml)은 가슴경유 심장 천자에 의해 제거되었다. 혈액은 15분동안 2500rpm에서 늘여지고, 원형질은 -20℃에서 제거되고 저장되었다. 또한, 뇌수는 화합물의 성분을 분석하기 위해서 -20℃에서 제거되고 응고되었다.
세포 측정
기관지폐포세척(bronchoalveolar lavage, BAL이라 약하기도 함) 샘플은 5분동안 1500rpm으로 원심분리된다. 상청액이 제거되고, 결과된 세포 펠릿은 1ml의 PBS로 다시 부양시켰다(re-suspended). 재부유된(re-suspended) 유동체의 세포 염색은 미세한 세포수를 계산하기 위해 라이쉬만(Leishmans)의 염색제로 처리되고 염색하였다. 전체 세포의 수는 재부유된(re-suspended) 샘플의 잔여물을 이용하여 이루어진다. 이로부터 BAL 내의 호중성백혈구(neutrophil)의 전체 갯수는 다음과 같은 방법에 의해 측정되었다.
변수 측정 :
1. 폐에 관한 호중성백혈구증가증(neutrophilia)으로부터 유도된 LPS의 억제%
2. 구토현상- 구토와 구역질의 수를 계산함
3. 행동변화- 수반되는 행동효과를 기록한다. 침분비, 헐떡임, 입할큄, 단조로운 자세, 조화운동불능, 활 모양이 된 등 및 뒤로 걷기. 임의의 행동 변화는 엄격한 판정의 적용을 위해 준정량적(가벼운, 보통 또는 심각)으로 측정하였다.
4 . 치료지수(TI)는 구토 에피소드(episodes)를 초래하지 않는 최대 투여량을 폐 호중성백혈구증가증(neutrophilia)을 50% 또는 그 이상 억제하는 최소 투여량으로 나누는 것에 의해 계산된다.
의식-페렛(ferrets)에서 LPS-유도된 호중성백혈구증가증에 관한 화합물 A의 효능이 도 1에 설명된다.
구토와 행동 변화
PDE4의 p.o 투여 후, 페렛(ferrets)은 적어도 2시간 동안 관찰되고, 구토 에피소드(구토와 구역질)와 행동 변화가 기록되었다. 어떤 구토 에피소드들(구역질 나거나 토하며)도 관련된 매개체(아세톤/크레모포르(cremophor)/증류수)와 함께 페렛 치료전 p.o에서 관찰되지 않았다. 통제 처리된 동물들(7/22)중 낮은 비율에서, 가벼운 행동 변화[립 리킹(lip licking)과 뒤로 걷기(backward walking]가 보였다.
화합물 A(0.1~3 mg/kg, p.o.)는 구토 에피소드(구토와 구역질)를 초래하지 않는다. 소정의 행동 변화[단조로운 자세(flattened posture), 립 리킹, 뒤로 걷기]가 관찰되었고 가벼운 것으로 분류되었다. 2/6 페렛(ferrets)내에 10mg/kg에서, 약간의 구역질이 나지만, 침분비와 행동 변화(가벼운 또는 보통으로 기록)와 함께 명백한 구토는 관찰되지 않았다. 최대 투여량 테스트(30mg/kg)에서, "보통"으로 표시되는 구토가 뚜렷한 행동 변화와 함께 3/4의 동물들에서 관찰되었다. 이 데이터는 테이블 Ⅲ에 요약되어 있다.
[표 3]
의식-페렛 : 화합물 A의 경구 투여에 따른 구토 에피소드와 행동변화
투여후 3시간 이상 동안 동물들을 관찰하였다. 괄호내의 숫자는 4 - 22의 각 그룹 범위에 속하는 동물들에 대한 응답한 동물들의 숫자를 나타낸다.
치료 지수 계산
이 실험들로부터, 치료 지수(TI)는 구토 에피소드(emetic episodes)를 유발하는 한계 투여량을 폐 호중성백혈구증가증(neutrophilia)을 억제하기 위한 ED50값으로 나누는 것에 의해 각 화합물들에 대해 결정되어 진다.
상기 TI값이 테이블 IV에 요약되어 있다.
화합물 A는 1 mg/kg의 항염증 투여량에서 구토 에피소드를 유발하지 않는 TI값 12를 갖는다.
[표 4]
구토의 유발과 LPS-유도된 폐 호중성백혈병증가증(neutrophilia)의 억제를 위한 효과적인 투여량(ED50) 및 이들 값으로부터 파생되는 치료지수의 요약
5.10. :
실시예
9 : 200
MG
투여 캡슐
테이블 V는 200mg의 화합물 A 단일 투여 유닛, 즉 #0 캡슐 사이즈, 40중량%에 대한 단일 투여 제형 표시와 뱃치(batch) 제형 표시를 설명한다.
[표 5]
200 mg 캡슐의 제형 표시
선젤라틴화된 옥수수 녹말(SPRESS B-820)와 화합물 A를 710㎛ 스크린을 통과시키고, 배플 인서트(baffle insert)를 가진 확산 혼합기(Diffusion Mixer)내에 넣고, 15분 동안 교반한다. 마그네슘 스테아르산염을 210㎛ 스크린을 통과시킨 후, 확산 혼합기에 첨가한다. 그리고 나서, 이 혼합물을 Dosator 타입 캡슐 충전 기계(Dosator type capsule filling machine)를 이용하여 500 mg/캡슐(8400 캡슐 뱃치 사이즈), 사이즈 #0 캡슐로 캡슐화시켰다.
5.11.
실시예
10: 100
MG
경구 투여 형태
테이블 Ⅵ는 100 mg의 화합물 A를 함유하는 단일 복용 단위 제형 표시와 뱃치 제형 표시를 나타낸다.
[표 6]
100mg 정제에 대한 제형 표시
미정질 셀룰로오스, 크로스카멜로스(Croscarmellose) 나트륨, 그리고 화합물 A를 #30 메쉬 스크린(대략 430㎛ ~ 655㎛)을 통과시킨다. 플루로닉(Pluronic) F-68 (Lenexa의 JRH 바이오사이언스에 의해 제조, KS) 계면활성제를 #20 메쉬 스크린(대략 457㎛ ~ 1041㎛)에 통과시킨다. 플루로닉 F-48 계면활성제와 0.5kg의 크로스카멜로스 나트륨을 16qt. 트윈 셀 텀블 브렌더(twin shell tumble blender)에 넣고, 5분동안 교반한다. 그리고나서, 이 혼합물을 미정질 셀룰로오스가 첨가된 3 큐빅(cubic) 피트의 트윈 셀 텀블 브렌더로 옮기고, 5분동안 교반한다. 탈리도미드(thalidomide)를 첨가하고, 추가적으로 25 분동안 혼합한다. 이 사전 혼합물은 롤러 컴팩터(roller compactor)의 디스차지(discharge)에 부착된 해머밀을 가진 롤러 콤팩터를 통과하고, 텀블 브렌더 뒤로 운반된다. 크로스카멜로스(croscarmellose) 나트륨과 마그네슘 스테아르산염을 이 텀블 브렌더에 첨가하고, 대략 3분동안 교반한다. 최종 혼합물은 250mg/정제(200,000 정제 배치 사이즈)을 가지는 로터리 태블릿 프레스(rotary tablet press)에서 압축된다.
5.12.
실시예
11: 에어로졸 투여 형태
고응축 믹서에 설치된 밀봉된 스테인레스 스틸 용기(vessel)내에 화합물 A와 12.6kg의 트리클로로모노플루오르메탄을 혼합시키는 것에 의해 농축물을 준비한다. 혼합은 대략 20분 동안 이루어진다. 그리고 나서, 온도가 21℃ ~ 27℃로 조절되고, 압력이 2.8 ~ 4.0bar로 조절된 벌크 생성 탱크내에 프로펠란트(propellants)의 균형을 가진 농축물을 혼합하는 것에 의해 밀봉된 용기내에 벌크 서스펜션을 준비한다. 본 발명 조성물의 100 흡입을 제공하도록 디자인된 메테르 밸브(metered valve)를 가진 17ml 에어로졸 용기를 준비한다.
각 용기에는 다음 성분들이 공급된다.
화합물 A : 0.0120g
트리클로로모노플루오로메탄 : 1.6939g
디클로로디플루오로메탄 : 3.7175g
디클로로테트라플루오로메탄 : 1.5766g
전체 : 7.000g
Claims (8)
- (-)-2-[1-(3-에톡시-4-메톡시페닐)-2-메틸설포닐에틸]-4-아세틸아미노이소인돌린-1,3-디온을 20중량% 이하로 포함하는 것을 의미하는, 입체이성질체적으로 순수한 (+)-2-[1-(3-에톡시-4-메톡시페닐)-2-메틸설포닐에틸]-4-아세틸아미노이소인돌린-1,3-디온, 또는 그것의 약학적으로 허용가능한 염, 용매화물 또는 수화물.
- (S)-2-(3-에톡시-4-메톡시페닐)-1-(메틸설포닐)-에트-2-일아민의 입체이성질체적으로 순수한 염.
- 제 2항에 있어서, 상기 염은 키랄 아미노산 염인 것을 특징으로 하는 입체이성질체적으로 순수한 염.
- 제 3항에 있어서, 상기 염은 알라닌, 아르기닌, 아스파라긴, 아스파르트산, 시스테인, 글루타민, 글루탐산, 글리신, 히스티딘, 이소루신, 루이신, 라이신, 메티오닌, 페닐알라닌, 프롤린, 세린, 트레오닌, 트립토판, 티로신, 발린, 오르니틴, 4-아미노부티르산, 2-아미노 이소부티르산, 3-아미노 프로피온산, 오르니틴, 노르루이신, 노르발린, 하이드록시프롤린, 사르코신, 시트룰린, 시스테인산, t-부틸글라이신, t-부틸알라닌, 페닐글라이신, 시클로헥실알라닌, 또는 N-아세틸-루이신의 L-이성질체의 염인 것을 특징으로 하는 입체이성질체적으로 순수한 염.
- 제 4항에 있어서, 상기 염은 (S)-2-(3-에톡시-4-메톡시페닐)-1-(메틸설포닐)-에트-2-일아민 N-아세틸-L-루이신 염인 것을 특징으로 하는 입체이성질체적으로 순수한 염.
- (a) 1-(3-에톡시-4-메톡시페닐)-2-메탄설포닐에틸아민의 키랄 아미노산 염을 형성하기에 충분한 조건하에서 키랄 아미노산과 1-(3-에톡시-4-메톡시페닐)-2-메탄설포닐에틸아민을 접촉하는 단계; 및
(b) 최종산물을 형성하기에 충분한 조건에서 상기 1-(3-에톡시-4-메톡시페닐)-2-메탄설포닐-에틸아민의 키랄 아미노산 염을 N-(1,3-디옥소-1,3-디하이드로-이소벤조푸란-4-일)-아세트아미드와 접촉시키는 단계를 포함하는 것을 특징으로 하는,
(-)-2-[1-(3-에톡시-4-메톡시페닐)-2-메틸설포닐에틸]-4-아세틸아미노이소인돌린-1,3-디온을 20중량% 이하로 포함하는 것을 의미하는 입체이성질체적으로 순수한 2-[1-(3-에톡시-4-메톡시페닐)-2-메틸설포닐에틸]-4-아세틸아미노이소인돌린-1,3-디온 에난티오머의 제조방법. - 제 6항에 있어서, 상기 키랄 아미노산은 알라닌, 아르기닌, 아스파라긴, 아스파르트산, 시스테인, 글루타민, 글루탐산, 글리신, 히스티딘, 이소루신, 루이신, 라이신, 메티오닌, 페닐알라닌, 프롤린, 세린, 트레오닌, 트립토판, 티로신, 발린, 오르니틴, 4-아미노부티르산, 2-아미노 이소부티르산, 3 아미노 프로피온산, 오르니틴, 노르루이신, 노르발린, 하이드록시프롤린, 사르코신, 시트룰린, 시스테인산, t-부틸글라이신, t-부틸알라닌, 페닐글라이신, 시클로헥실알라닌, 또는 N-아세틸-루이신의 L-이성질체인 것을 특징으로 하는 제조방법.
- 제 7항에 있어서, 상기 키랄 아미노 염은 N-아세틸-L-루이신인 것을 특징으로 하는 제조방법.
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