KR20010012321A - New cysteine derivatives, processes for their production, and pharmaceuticals containing them - Google Patents

New cysteine derivatives, processes for their production, and pharmaceuticals containing them Download PDF

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KR20010012321A
KR20010012321A KR1019997010273A KR19997010273A KR20010012321A KR 20010012321 A KR20010012321 A KR 20010012321A KR 1019997010273 A KR1019997010273 A KR 1019997010273A KR 19997010273 A KR19997010273 A KR 19997010273A KR 20010012321 A KR20010012321 A KR 20010012321A
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뮐러줄리안느콘스탠쯔데지레
그라프본뢰데른에리히
모로더루이스
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막스-플랑크-게젤샤프트 츄어 푀르더룽 데어 비쎈샤프텐 에.파우.
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Abstract

본 발명은 매트릭스 메탈로프로테이나제 (MMP) 에 결합하고 저해하며, 시스테인 부위가 보호되지 않은 티올기를 함유하고, 시스테인 부위가 L- 또는 D- 배향인 것을 특징으로 하는 하기 화학식 I 로 나타내어지는 화합물, 제조 방법, 약제학적 조성물 및 이들의 약제에의 용도에 관한 것이다 :The present invention binds and inhibits matrix metalloproteinases (MMP), the cysteine moiety contains an unprotected thiol group, and the cysteine moiety is in the L- or D-alignment, wherein the compound is represented by the following formula (I) , Methods of preparation, pharmaceutical compositions, and their use in medicaments:

[화학식 I][Formula I]

[상기 식중,[In the above meal,

A 는 -CO-, -SO2-, -NH-CO- 또는 -O-CO- 를 나타내고,A represents -CO-, -SO 2- , -NH-CO- or -O-CO-,

R1은 수소, 직쇄 또는 분지쇄, 포화 또는 불포화 C1-15알킬기, 또는 할로겐, 메르캅토, 히드록시, 알콕시, 아미노 또는 니트로, 또는 한번 또는 수번 임의 치환된 비방향족 또는 방향족 고리 시스템으로 치환된 C1-15알킬기, 또는 임의 치환된 방향족 또는 비방향족 헤테로사이클, 이들의 약제학상 허용 가능 염 또는 이의 광학 활성 형태이며,R 1 is substituted with hydrogen, a straight or branched chain, saturated or unsaturated C 1-15 alkyl group, or halogen, mercapto, hydroxy, alkoxy, amino or nitro, or a non-aromatic or aromatic ring system optionally substituted one or several times A C 1-15 alkyl group, or optionally substituted aromatic or non-aromatic heterocycle, pharmaceutically acceptable salts thereof, or optically active forms thereof,

R 은 히드록시, 직쇄 또는 분지쇄, 포화 또는 불포화 C1-15알킬기 또는 한번 또는 수번 임의 치환된 카르보시클릭 비방향족 또는 방향족 고리 시스템으로 치환된 C1-15알킬기, 임의 치환된 방향족 또는 비방향족 헤테로사이클, 이들의 약학적 허용 가능 염 또는 이의 광학 활성 형태이다].R is hydroxy, linear or branched, saturated or unsaturated C 1-15 alkyl group or an optionally substituted once or subeon carbocyclic non-aromatic or a C 1-15 alkyl group substituted by an aromatic ring system, optionally substituted aromatic or non-aromatic Heterocycle, pharmaceutically acceptable salts thereof, or optically active forms thereof.

Description

신규의 시스테인 유도체, 이의 제조 방법 및 이를 함유한 약제 {NEW CYSTEINE DERIVATIVES, PROCESSES FOR THEIR PRODUCTION, AND PHARMACEUTICALS CONTAINING THEM}Novel cysteine derivatives, preparation methods thereof, and pharmaceuticals containing the same {NEW CYSTEINE DERIVATIVES, PROCESSES FOR THEIR PRODUCTION, AND PHARMACEUTICALS CONTAINING THEM}

본 발명은 비-펩티드형 기 (화학식 I) 를 갖는 카르복실 및 아미노 관능기로부터 유도된 아미노산 D- 또는 L- 시스테인의 사용에 기초한 신규한 매트릭스 메탈로프로테이나제 저해제를 포함한다. 본 발명은 저해제의 제조 방법 및 치료 분야에서의 이들의 용도를 포함한다.The present invention includes novel matrix metalloproteinase inhibitors based on the use of amino acids D- or L-cysteine derived from carboxyl and amino functional groups having non-peptidic groups (Formula I). The present invention includes methods of making inhibitors and their use in the field of treatment.

매트릭스 메탈로프로테아제의 군 (MMPs) 은, 이들 효소가 섬유 리모델링 및 결합 조직 교체에 관계하고, 따라서 (i) 예를 들어 울혈성 심부전 및 높은 전이성 종양 세포의 일혈 도중 급속한 세포외 매트릭스 퇴화가 일어나거나, (ii) 예를 들어 관절 경화증 장애 형성 및 탈장, 골관절염 중 연골 매트릭스 손실, 골다공증 중 골 매트릭스 퇴화, 치주 질환 중 잇몸 퇴화, 알츠하이머 플라크 형성 및 류마티스성 관절염 중 매트릭스 리모델링 및 침착과 같은 느린 세포의 매트릭스 퇴화가 일어나는 수개의 질병에 관계하기 때문에, 의약 디자인의 주요 목표가 되었다.Groups of matrix metalloproteases (MMPs) indicate that these enzymes are involved in fiber remodeling and connective tissue replacement, and thus (i) rapid extracellular matrix degeneration occurs, for example, during congestive heart failure and acupuncture of highly metastatic tumor cells. matrices of slow cells such as, for example, the formation and hernia of arteriosclerosis disorders, cartilage matrix loss during osteoarthritis, bone matrix degeneration during osteoporosis, gum degeneration during periodontal disease, Alzheimer's plaque formation and matrix remodeling and deposition in rheumatoid arthritis As it is related to several diseases in which degeneration occurs, it has become the main goal of pharmaceutical design.

MMP 의 군은 현재 14 개로 이루어져 있으며, 이중 10 개는 가용성 형태의 세포로부터 분비되고, 4 개는 멤브레인-인접 효소로부터 분비된다. MMP 들은 메탈로프로테이나제 (TIMP) 군의 섬유 저해제의 하나에 의해 저해되는, 아연에 독립적이며 칼슘을 필요로 하는 효소이다. 상기 효소의 계열의 합성 저해제는 히드록사메이트, N-카르복시알킬 유도체, 포스폰아미데이트 및 포스피네이트 뿐만 아니라 활성부 아연 원자에 대해 리간드로서 티올기를 사용하거나 개발되었다.The group of MMPs currently consists of 14, of which 10 are secreted from soluble form cells and 4 are secreted from membrane-adjacent enzymes. MMPs are zinc-independent and calcium-required enzymes that are inhibited by one of the fiber inhibitors of the metalloproteinase (TIMP) family. Synthetic inhibitors of this class of enzymes have been developed or used with thiol groups as ligands for hydroxysmate, N-carboxyalkyl derivatives, phosphonamidates and phosphinates as well as active part zinc atoms.

약 80 개의 잔기의 N-말단 프로펩티드를 갖는 MMP-3 의 효소원의 구조 뿐만 아니라, MMP 의 촉매 도메인 및 다양한 저해제의 착물의 3차원 구조가 발표되었다. 프로펩티드는 활성부를 차지하는 신장 펩티드 (extended peptide) 및 세 개의 α-헬릭스를 함유하는 별개의 작은 도메인을 형성한다. 이러한 모든 구조 내의 촉매 도메인은 두 개의 Zn2+이온, 즉 "구조" 아연 이온 및 "촉매" 아연 이온을 함유한다. "구조" 아연 이온은 교감 시퀀스 HEXXHXXGXXH 의 세 개의 히스티딜 잔기의 곁가지로 배위된다. 저해된 효소 내의 "촉매" 아연의 네 번째 리간드는 히드록사메이트 또는 카르복실레이트와 같은 저해제의 배위기이다; 프로-MMP 프로펩티드에서, 시스테인 잔기의 티올기이다 (1).As well as the structure of the enzyme source of MMP-3 having an N-terminal propeptide of about 80 residues, the three-dimensional structure of the catalytic domain of MMP and complexes of various inhibitors has been published. The propeptide forms a separate small domain containing an extended peptide that occupies the active site and three α-helices. The catalytic domain in all these structures contains two Zn 2+ ions, namely “structural” zinc ions and “catalyst” zinc ions. "Structural" zinc ions are coordinated with the side branches of three histidyl residues of the sympathetic sequence HEXXHXXGXXH. The fourth ligand of the “catalyst” zinc in the inhibited enzyme is the coordination of the inhibitor, such as hydroxyxamate or carboxylate; In pro-MMP propeptide, it is the thiol group of the cysteine residue (1).

따라서, 현재까지 제안된 티올 기재 콜라게나제 저해제는 일반적으로 시스테인 또는 시스테인과 유사한 아미노산을 함유한 펩티드 구조이며, 이들의 디자인은 기질의 바인딩 모드에, 최근에는 시스테인 함유 프로펩티드의 바인딩 모드에 기초한다.Thus, the thiol based collagenase inhibitors proposed to date are generally peptide structures containing cysteine or cysteine-like amino acids, and their design is based on the binding mode of the substrate and more recently on the binding mode of the cysteine containing propeptide. .

본 발명은 하기 화학식 I 에 나타낸 바와 같은 비-펩티드 방식의 시스테인으로부터 유도된 신규한 MMP 저해제의 계열 및 이들 화합물을 함유한 약제학적 조성물 및 이들의 의약에의 치료적 용도에 관한 것이다 :The present invention relates to a class of novel MMP inhibitors derived from cysteine in a non-peptide mode as shown in formula I and to pharmaceutical compositions containing these compounds and their therapeutic use in medicine:

[상기 식중,[In the above meal,

A 는 -CO-, -SO2-, -NH-CO- 또는 -O-CO- 를 나타내고,A represents -CO-, -SO 2- , -NH-CO- or -O-CO-,

R1은 수소, 직쇄 또는 분지쇄, 포화 또는 불포화 C1-15알킬기, 또는 할로겐, 메르캅토, 히드록시, 알콕시, 아미노 또는 니트로 또는 한번 또는 수번 임의 치환된 비방향족 고리 시스템 또는 카르보시클릭 방향족, 또는 임의 치환된 방향족 또는 비방향족 헤테로사이클로 치환된 C1-15알킬기, 이들의 약제학상 허용 가능 염 또는 이의 광학 활성 형태이며,R 1 is hydrogen, a straight or branched chain, a saturated or unsaturated C 1-15 alkyl group, or a halogen, mercapto, hydroxy, alkoxy, amino or nitro or a non-aromatic ring system or carbocyclic aromatic optionally substituted one or several times, Or a C 1-15 alkyl group substituted with an optionally substituted aromatic or non-aromatic heterocycle, a pharmaceutically acceptable salt thereof, or an optically active form thereof,

R 은 히드록시, 직쇄 또는 분지쇄, 포화 또는 불포화 C1-15알킬기 또는 한번 또는 수번 임의 치환된 카르보시클릭 방향족 또는 비방향족 고리 시스템, 또는 방향족 또는 비방향족 헤테로사이클로 치환된 C1-15알킬기, 이들의 약제학상 허용 가능 염 또는 이의 광학 활성 형태이다].R is a hydroxy, straight or branched chain, saturated or unsaturated C 1-15 alkyl group or one or several optionally substituted carbocyclic aromatic or nonaromatic ring systems, or C 1-15 alkyl group substituted with an aromatic or nonaromatic heterocycle, Their pharmaceutically acceptable salts or optically active forms thereof.

화학식 I 에서, R 및/또는 R1은 분지쇄 포화 또는 불포화 C1-15알킬기로, 메틸, 에틸, 프로필, n-부틸 tert-부틸, 펜틸, 헥실, 헵틸, 옥틸, 노닐, 데실, 운데실, 도데실 등, 비닐 등, 및 상응하는 알키닐기, 예컨대 아세틸렌으로부터 선택된다.In formula (I), R and / or R 1 are branched saturated or unsaturated C 1-15 alkyl groups, methyl, ethyl, propyl, n-butyl tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl , Dodecyl and the like, vinyl and the like, and corresponding alkynyl groups such as acetylene.

상기 알킬기의 카르보시클릭 방향족 또는 비방향족 치환체는 C3-6시클로알킬, 예컨대 시클로프로필, 시클로부틸, 시클로펜틸 또는 시클로헥실, 또는 C6-14카르보시클릭 방향족 치환체, 예컨대 페닐, 나프틸 또는 안트릴, 또는 헤테로시클릭 비방향족 치환체, 예컨대 피롤리디닐, 피페리디닐, 피페라지닐 또는 몰포리닐, 또는 헤테로시클릭 방향족 치환체, 예컨대 피롤릴, 피리디닐, 푸릴, 티에닐, 티아졸릴, 이미다졸릴, 피리미디닐, 푸리닐, 인돌릴, 퀴놀릴, 카르바졸릴로부터 선택된다. 카르보시클릭 방향족 또는 비방향족 고리 시스템은 각각 예를 들어 할로겐, 니트로, 히드록시, C1-6알킬, C1-6알콕시, 아미노, 메르캅토, 카르복실, 시아노 또는 술포닐기로 한번 또는 수번 임의 치환될 수 있다.Carbocyclic aromatic or non-aromatic substituents of the alkyl groups are C 3-6 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, or C 6-14 carbocyclic aromatic substituents such as phenyl, naphthyl or an Trilyl, or heterocyclic non-aromatic substituents such as pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl, or heterocyclic aromatic substituents such as pyrrolyl, pyridinyl, furyl, thienyl, thiazolyl, already Dazolyl, pyrimidinyl, furinyl, indolyl, quinolyl, carbazolyl. Carbocyclic aromatic or non-aromatic ring systems may be used once or several times, for example with halogen, nitro, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, amino, mercapto, carboxyl, cyano or sulfonyl groups May be optionally substituted.

A 가 -CO- 를 나타내는 경우, R1CO- 의 잔기는 바람직하게는 하기의 카르복실산으로부터 선택된다 :When A represents -CO-, the residue of R 1 CO- is preferably selected from the following carboxylic acids:

포름산, 아세트산, 프로피온산, 헥사논산, 라우르산, 미리스트산, 팔미트산, 스테아르산, 아라키돈산, 베헨산, 옥타데세논산, 리놀레산, 리놀렌산, 3-메르캅토프로피온산, 글리옥실산, 말론산, 숙신산, 4-아미노부타논산, 6-아미노카프로산, 3-니트로프로피온산, 나프틸아세트산, 4-아미노페닐아세트산, 아크릴산, 신남산, 4-아미노-신남산, 아미노크로톤산, 푸마르산, 말레인산, 프탈산, 벤조산, 니트로벤조산, 3-아미노벤조산, 4-아미노벤조산, 안트라닐산, 살리실산, 3-아미노-살리실산, 4-아미노-살리실산, 5-아미노-살리실산, 나프토산, p-페닐벤조산, 페난트로산, 니코틴산, 3-아미노피라진-2-카르본산, 피리딘 카르복실산, 피페라진 카르복실산, 피페리딘 카르복실산.Formic acid, acetic acid, propionic acid, hexanoic acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidonic acid, behenic acid, octadecenonic acid, linoleic acid, linolenic acid, 3-mercaptopropionic acid, glyoxylic acid, malonic acid , Succinic acid, 4-aminobutanoic acid, 6-aminocaproic acid, 3-nitropropionic acid, naphthyl acetic acid, 4-aminophenylacetic acid, acrylic acid, cinnamic acid, 4-amino-cinnamic acid, aminocrotonic acid, fumaric acid, maleic acid, Phthalic acid, benzoic acid, nitrobenzoic acid, 3-aminobenzoic acid, 4-aminobenzoic acid, anthranilic acid, salicylic acid, 3-amino-salicylic acid, 4-amino-salicylic acid, 5-amino-salicylic acid, naphthoic acid, p-phenylbenzoic acid, phenanthro Acids, nicotinic acid, 3-aminopyrazine-2-carboxylic acid, pyridine carboxylic acid, piperazine carboxylic acid, piperidine carboxylic acid.

A 가 -SO2를 나타내는 경우, R1SO2- 는 바람직하게는 하기 술폰산의 잔기로부터 선택된다 :When A represents -SO 2 , R 1 SO 2 -is preferably selected from the residues of the following sulfonic acids:

메탄술폰산, 에탄술폰산, 프로판술폰산, 3-히드록시프로판술폰산, 오르타닐산 (아닐린-2-술폰산), 나프탈렌술폰산, 나프틸아민술폰산, 아미노메탄술폰산, 2-메르캅토에탄 술폰산, 2-클로로에탄술폰산, N,N'-디메틸술팜산, 피페리딘술폰산, 5-(2-아미노에틸아미노)-1-나프탈렌-술폰산, 요오도옥시퀴놀린술폰산, 피리딘-3-술폰산, p-톨루엔술폰산, 2-(p-톨루이디노)나프탈렌-6-술폰산, 데실메탄술폰산, 2-[(2-아미노-2-옥소에틸)아미노]에탄술폰산, 2-(N-시클로헥실아미노)에탄술폰산, 2-[비스(2-히드록시에틸)아미노]에탄술폰산, N-2-히드록시에틸피페라진-N'-2-에탄술폰산, N-트리스(히드록시메틸)메틸-2-아미노-에탄술폰산, 2-(N-모르폴리노)에탄술폰산, 피페라진-N,N'-비스(2-에탄술폰산), 3-(2-피리딜)-5,6-비스(4-페닐술폰산)-1,2,4-트리아진.Methanesulfonic acid, ethanesulfonic acid, propanesulfonic acid, 3-hydroxypropanesulfonic acid, ortanylic acid (aniline-2-sulfonic acid), naphthalenesulfonic acid, naphthylaminesulfonic acid, aminomethanesulfonic acid, 2-mercaptoethane sulfonic acid, 2-chloroethanesulfonic acid , N, N'-dimethylsulfamic acid, piperidinesulfonic acid, 5- (2-aminoethylamino) -1-naphthalene-sulfonic acid, iodooxyquinolinesulfonic acid, pyridine-3-sulfonic acid, p-toluenesulfonic acid, 2- (p-toluidino) naphthalene-6-sulfonic acid, decylmethanesulfonic acid, 2-[(2-amino-2-oxoethyl) amino] ethanesulfonic acid, 2- (N-cyclohexylamino) ethanesulfonic acid, 2- [ Bis (2-hydroxyethyl) amino] ethanesulfonic acid, N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid, N-tris (hydroxymethyl) methyl-2-amino-ethanesulfonic acid, 2- (N-morpholino) ethanesulfonic acid, piperazine-N, N'-bis (2-ethanesulfonic acid), 3- (2-pyridyl) -5,6-bis (4-phenylsulfonic acid) -1,2 , 4-triazine.

A 가 -NHCO- 를 나타내는 경우, 잔기 R1-NH-CO- 는 바람직하게는 하기의 우레아 유도체로부터 선택된다 :When A represents -NHCO-, the residue R 1 -NH-CO- is preferably selected from the following urea derivatives:

n-부틸-, R-(+)-알파-페닐에틸-, R-(-)-1-(1-나프틸)-에틸-, 에틸-, 프로필-, 헥실-, 옥틸-, 벤질-, 클로로벤질-, 메틸벤질-, 3-피콜릴-, 2-(아미노메틸)-피리딜 우레아.n-butyl-, R-(+)-alpha-phenylethyl-, R-(-)-1- (1-naphthyl) -ethyl-, ethyl-, propyl-, hexyl-, octyl-, benzyl-, Chlorobenzyl-, methylbenzyl-, 3-picolyl-, 2- (aminomethyl) -pyridyl urea.

A 가 -O-CO- 를 나타내는 경우, 잔기 R1-O-CO- 는 바람직하게는 하기의 카르바메이트의 잔기로부터 선택된다 :When A represents -O-CO-, the residue R 1 -O-CO- is preferably selected from the residues of the following carbamates:

메틸카르바메이트, 에틸카르바메이트, 9-플루오레닐메틸카르바메이트, 9-(2-술포)플루오레닐메틸카르바메이트, 9-(2,7-디브로모)플루오레닐메틸카르바메이트, 4-메톡시페나실카르바메이트, 2,2,2-트리클로로에틸카르바메이트, 2-페닐에틸카르바메이트, 1-(1-아다만틸)-1-메틸에틸카르바메이트, 1,1-디메틸-2-할로에틸카르바메이트, 1-메틸-1-(4-비페닐)-1-메틸에틸카르바메이트, 2-(2'-피리딜)에틸카르바메이트, 1-아다만틸카르바메이트, 비닐카르바메이트, 알릴카르바메이트, 1-이소프로필알릴카르바메이트, 4-니트로신나밀카르바메이트, 8-퀴놀릴카르바메이트, 시클로헥실카르바메이트, 벤질카르바메이트, p-메톡시벤질카르바메이트, p-니트로벤질카르바메이트, p-브로모벤질카르바메이트, 9-안트릴메틸카르바메이트, 디페닐메틸카르바메이트, 2-메틸술포닐에틸카르바메이트, 2-(p-톨루엔술포닐)에틸카르바메이트, 4-메틸티오페닐카르바메이트.Methylcarbamate, ethylcarbamate, 9-fluorenylmethylcarbamate, 9- (2-sulfo) fluorenylmethylcarbamate, 9- (2,7-dibromo) fluorenylmethyl Carbamate, 4-methoxyphenacylcarbamate, 2,2,2-trichloroethylcarbamate, 2-phenylethylcarbamate, 1- (1-adamantyl) -1-methylethylcarba Barmate, 1,1-dimethyl-2-haloethylcarbamate, 1-methyl-1- (4-biphenyl) -1-methylethylcarbamate, 2- (2'-pyridyl) ethylcarba Mate, 1-adamantylcarbamate, vinylcarbamate, allylcarbamate, 1-isopropylallylcarbamate, 4-nitrocinnamilcarbamate, 8-quinolylcarbamate, cyclohexylcar Barmate, benzylcarbamate, p-methoxybenzylcarbamate, p-nitrobenzylcarbamate, p-bromobenzylcarbamate, 9-anthrylmethylcarbamate, diphenylmethylcarbamate, 2-methylsulfonylethyl Yerba mate, 2- (p- toluenesulfonyl) ethyl carbamate, 4-methylthiophenyl carbamate.

R 은 바람직하게는 하기 잔기로부터 선택된다 :R is preferably selected from the following residues:

에틸-, 프로필-, 헥실-, 옥틸-, 벤질-, 4-클로로벤질-, 4-메틸벤질-, 3-피콜릴-, 2-(메틸)-피리딜-, 4-(메틸)피리딜-, 3-페닐프로필-, 4-페닐부틸-, 2-(p-톨릴)에틸-, 3-니트로벤질-, 벤질에틸-, 2-페닐에틸-, 아다만틸-, 피리딜-, 페닐, 콜레스테닐-, 나프틸-, 4-페녹시-페닐 또는 인돌릴에틸.Ethyl-, propyl-, hexyl-, octyl-, benzyl-, 4-chlorobenzyl-, 4-methylbenzyl-, 3-picolyl-, 2- (methyl) -pyridyl-, 4- (methyl) pyridyl -, 3-phenylpropyl-, 4-phenylbutyl-, 2- (p-tolyl) ethyl-, 3-nitrobenzyl-, benzylethyl-, 2-phenylethyl-, adamantyl-, pyridyl-, phenyl , Cholesteryl-, naphthyl-, 4-phenoxy-phenyl or indolylethyl.

화학식 I 에 따른 바람직한 화합물은 실시예 5 내지 22 의 화합물 및 하기 표의 화합물이다 :Preferred compounds according to formula (I) are the compounds of Examples 5 to 22 and the compounds of the following table:

R1-COR 1 -CO RR 포르밀-Formyl 벤질-benzyl- 페닐-Phenyl- 나프틸-Naphthyl 나프틸아세틸-Naphthylacetyl 3-피콜릴-3-picolyl- 4-비페닐-4-biphenyl- 2-페닐에틸-2-phenylethyl- R1-SO2 R 1 -SO 2 RR 피리딘-3-술포닐-Pyridine-3-sulfonyl- 페닐프로필-Phenylpropyl- p-톨루엔술포닐-p-toluenesulfonyl- p-클로로벤질-p-chlorobenzyl- R1-NH-COR 1 -NH-CO RR 벤질-benzyl- 피리딜-Pyridyl- R1-O-COR 1 -O-CO RR 2-페닐에틸-2-phenylethyl- 4-페닐옥시페닐-4-phenyloxyphenyl- 벤질-benzyl- 2-페닐에틸-2-phenylethyl- 2-(p-톨루엔술포닐)에틸-2- (p-toluenesulfonyl) ethyl- 벤질-benzyl-

화학식 I 에 따른 화합물은 상이한 구조 및 상이한 특성을 갖는 세 개의 부위로 이루어진다. 활성부 Zn2+이온의 킬레이트기 SH, 소수성기 R1또는 R 은 소수성 S'1프로테인 포켓과 상호 작용할 뿐만 아니라, P' 기질 바인딩 틈을 따라 추가의 소수성 상호 작용에 기여한다.Compounds according to formula (I) consist of three sites with different structures and different properties. The chelating group SH, hydrophobic group R 1 or R of the active moiety Zn 2+ ion not only interacts with the hydrophobic S ′ 1 protein pocket, but also contributes to further hydrophobic interactions along the P ′ substrate binding gap.

화학식 I 의 저해제는 예를 들어 골다공증 류마티스성 관절염, 치주 질환, 관절경화증, 울혈성 심부전, 종양 침입 및 전이, 및 혈관 형성과 같은 변이된 병리 관계에 요구되는 상이한 MMP 들의 선택적인 저해제의 개발을 가능하게 한다.Inhibitors of Formula I allow the development of selective inhibitors of the different MMPs required for mutated pathological relationships such as, for example, osteoporosis rheumatoid arthritis, periodontal disease, arteriosclerosis, congestive heart failure, tumor invasion and metastasis, and angiogenesis. Let's do it.

문헌에 기술된 유사한 화합물이 공지되어 있다. 하지만, 이들은 펩티드 화합물이며, 인간의 원형질에서 불량한 반감기를 나타낸다.Similar compounds described in the literature are known. However, they are peptide compounds and exhibit poor half-life in human plasma.

시스테인 유도체의 화학적 구조는 대사 안정성을 증가시킬 목적으로 선택되었다. 따라서, 아미노기는 카르복실산으로 아실화되어 아미드를 생성하지만, 우선적으로 효소 대사에 더욱 안정한 것으로 알려진 우레타닐 유도체를 생성한다. 유사하게, C-말단 카르복실 관능기는 에스테르화 대신 아미드로 유도되어 리파제에 의한 에스테르의 가수분해에 기인한 급속한 제거 속도를 방지한다. 또한, 펩티다제에 더욱 안정한 것으로 알려진 N-알킬 및 N-아릴아미드가 선택되었다.The chemical structure of the cysteine derivative was chosen for the purpose of increasing metabolic stability. Thus, amino groups are acylated with carboxylic acids to produce amides, but preferentially to produce uretanyl derivatives which are known to be more stable to enzymatic metabolism. Similarly, C-terminal carboxyl functional groups are directed to amides instead of esterification to prevent rapid removal rates due to hydrolysis of esters by lipases. In addition, N-alkyl and N-arylamides, which are known to be more stable to peptidase, were selected.

저해제의 합성을 위해 유기 합성의 전통적인 방법이 사용되었다 (2). 화학식 II 의 관련된 L- 및 D-시스틴 유도체를 펩티드 화학의 표준 방법으로 제조하였으며, 이어서 반응식 1 에 따라 EDCI/HOBt 로 아미드화 하였다. 이어지는 화학식 III 의 시스틴 화합물의 화학식 I 의 시스테인 유도체로의 환원은, 메르캅탄과 같은 환원제로, 또는 우선적으로 트리부틸포스핀과 같은 포스핀으로 반응식 1 에 나타낸 바와 같이 수행하였다.Traditional methods of organic synthesis have been used for the synthesis of inhibitors (2). Relevant L- and D-cystine derivatives of Formula II were prepared by standard methods of peptide chemistry and then amidated with EDCI / HOBt according to Scheme 1. Subsequent reduction of the cystine compound of formula III to a cysteine derivative of formula I was carried out as shown in Scheme 1 with a reducing agent such as mercaptan or preferentially with a phosphine such as tributylphosphine.

반응식 1. 본 발명의 MMP 저해제의 일반적인 합성 경로Scheme 1. General synthetic route of MMP inhibitors of the invention

MMP 들을 특정적으로 저해하는 본 발명의 화합물은, 류마티스성 관절염 및 교원 분해 (collagenolytic) 활성이 기여 인자인 관련된 질병, 예를 들어, 각막 궤양, 골다공증, 치주염, 파제트병, 치은염, 종양 침투, 이영양 표피 박리, 수포증, 전신 궤양, 상피 궤양, 위궤양 등과 같은 질병의 치료에 약학적으로 유용하다. 상기 화합물은 류마티스성 관절염 (제 1 기 만성 다발관절염, PCP), 전신 낭창 홍반증 (SLE), 유년기 류마티스성 관절염, 쇼그렌 증후군 (RA + 시카 증후군), 다발성 동맥염 결절 및 관련 맥관염, 예를 들어 베그너 육아종증, 거대 세포 동맥염, 굿파스튜어 증후군, 과민성 맥관염, 다발성근염 및 피부근염, 진행성 전신 경화증, M. 베세트, 라이터 증후군 (관절염 + 요도염 + 결막염), 혼합 결합 조직 질환 (샤프 증후군), 척추염 강직형성 (M. Bechterew) 의 치료에 특히 유용하다.Compounds of the present invention that specifically inhibit MMPs are related diseases in which rheumatoid arthritis and collagenolytic activity are contributing factors such as corneal ulcer, osteoporosis, periodontitis, Paget's disease, gingivitis, tumor infiltration, It is pharmaceutically useful for the treatment of diseases such as dystrophic epidermal detachment, bullous, systemic ulcer, epithelial ulcer, gastric ulcer. The compound may include rheumatoid arthritis (first stage chronic polyarthritis, PCP), systemic lupus erythematosus (SLE), childhood rheumatoid arthritis, Sjogren's syndrome (RA + Cica syndrome), multiple arteritis nodules and related vasculitis, for example Wegner's granulomatosis, giant cell arteritis, Goodpasture syndrome, irritable vasculitis, polymyositis and dermatitis, progressive systemic sclerosis, M. beset, Reiter syndrome (arthritis + urethritis + conjunctivitis), mixed connective tissue disease (Sharp syndrome) , Especially useful for the treatment of spondylitis stiffness (M. Bechterew).

본 발명의 화합물은 임의의 적절한 경로로 투여될 수 있으며, 바람직하게는 그러한 경로에 적합한 약제학적 조성물 형태로 의도한 치료에 효과적인 양으로 투여될 수 있다. 의학적 상태의 진전을 방지하거나 저지하기 위해 요구되는 본 발명의 화합물의 치료상 유효한 투여량은 당업자가 용이하게 확정할 수 있다.The compounds of the present invention may be administered by any suitable route, and may preferably be administered in an amount effective for the intended treatment in the form of a pharmaceutical composition suitable for such route. Therapeutically effective dosages of the compounds of the present invention required to prevent or arrest the progress of a medical condition can be readily ascertained by those skilled in the art.

따라서, 본 발명은 본 발명의 하나 이상의 화합물 및 하나 이상의 무독성 약제학적 허용 가능 담체 및/또는 보조제 (총괄하여 "담체 물질" 로 지칭한다), 및 희망에 따라 다른 활성 성분을 함유하는 신규한 약제학적 조성물의 계열을 제공하며, 상기 화합물 및 조성물은 예를 들어 혈관내, 복막조직내, 피하, 근육내 또는 국소적으로 투여될 수 있다.Thus, the present invention is a novel pharmaceutical containing one or more compounds of the invention and one or more non-toxic pharmaceutically acceptable carriers and / or adjuvants (collectively referred to as “carrier materials”), and optionally other active ingredients. Provided are a family of compositions, wherein the compounds and compositions can be administered, for example, intravascularly, intraperitoneally, subcutaneously, intramuscularly or topically.

모든 투여에 있어서, 약제학적 조성물은 예를 들어 정제, 캡슐, 현탁액 또는 액체의 형태일 수 있다. 약제학적 조성물은 바람직하게는 활성 성분의 특정량을 함유한 투여 단위 형태로 제조된다. 이러한 투여 단위의 예로는 정제 또는 캡슐이 있다. 포유 동물에 매일 투여하기 위한 적절한 복용량은 환자의 상태 또는 다른 인자에 따라 폭 넓게 변할 수 있다. 하지만, 체중 1 kg 당 약 0.1 내지 300 mg, 특히 약 1 내지 30 mg 의 복용량이 적절할 수 있다. 또한, 활성 성분은 주사에 의해 투여될 수 있다.For all administrations, the pharmaceutical composition may be in the form of a tablet, capsule, suspension or liquid, for example. Pharmaceutical compositions are preferably prepared in dosage unit form containing a specific amount of the active ingredient. Examples of such dosage units are tablets or capsules. Suitable dosages for daily administration to a mammal can vary widely depending on the condition of the patient or other factors. However, a dosage of about 0.1 to 300 mg, in particular about 1 to 30 mg per kg of body weight may be appropriate. In addition, the active ingredient may be administered by injection.

본 발명의 조성물 및/또는 화합물로 질환 상태를 치료하기 위한 투여 양생법은 환자의 병형, 연령, 체중, 성별 및 의학적 상태를 포함하는 다양한 인자에 따라 선택된다. 감염의 정도 및 투여의 역할, 및 사용된 특정 화합물도 따라서 폭 넓게 변할 수 있다.Dosage regimens for treating disease states with the compositions and / or compounds of the present invention are selected according to a variety of factors including the patient's disease type, age, weight, sex and medical condition. The extent of infection and the role of administration, and the particular compound used may thus vary widely.

치료 목적으로, 본 발명의 화합물은 지시된 투여 경로에 적합한 하나 이상의 보조제와 일반적으로 배합된다. 구강 투여의 경우, 상기 화합물은 락토스, 수크로스, 전분, 알카논산의 셀룰로스 에스테르, 셀룰로스 알킬에스테르, 탈크, 스테아르산, 마그네슘스테아레이트, 산화마그네슘, 인산 및 황산의 나트륨 및 칼슘염, 젤라틴, 아카시아, 나트륨 알기네이트, 폴리비닐-피롤리돈 및/또는 폴리비닐 알콜과 혼합될 수 있으며, 통상적인 투여를 위해 캡슐화되거나 정제화된다. 대안으로, 상기 화합물은 물, 폴리에틸렌글리콜, 프로필렌글리콜, 에탄올, 옥수수유, 목화씨유, 땅콩유, 참깨유, 벤질알콜, 염화나트륨 및/또는 다양한 완충액에 용해될 수 있다. 다른 보조제 및 투여 방법이 약제학 기술에 널리 공지되어 있다. 임의의 주어진 경우에서의 적절한 투여량은, 물론 처리할 상태의 정도, 투여 경로 및 임의의 개개의 특이 체질 및 크기를 포함한 포유동물의 종에 따라 다르다.For therapeutic purposes, the compounds of the present invention are generally combined with one or more adjuvants suitable for the indicated route of administration. For oral administration, the compounds are lactose, sucrose, starch, cellulose esters of cellulose, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric acid and sulfuric acid, gelatin, acacia, It can be mixed with sodium alginate, polyvinyl-pyrrolidone and / or polyvinyl alcohol and encapsulated or tableted for conventional administration. Alternatively, the compound may be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride and / or various buffers. Other adjuvants and methods of administration are well known in the pharmaceutical art. Appropriate dosages in any given case will of course depend on the species of mammal, including the degree of condition to be treated, the route of administration and any individual specific constitution and size.

대표적인 담체, 희석제 및 보조제로는 예를 들어, 물, 락토스, 젤라틴 전분, 마그네슘 스테아레이트, 탈크, 야채유, 검, 폴리알킬렌글리콜, 바셀린 등이 있다. 약제학적 조성물은 고형, 예컨대 미립, 분말 또는 좌약으로, 또는 액형, 예컨대 용액, 현탁액 또는 유제로 제조될 수 있다. 약제학적 조성물은 통상적인 약제학적 보조제, 예컨대 방부제, 안정화제, 습윤제, 유화제, 완충제 등을 가할 수 있다.Representative carriers, diluents and auxiliaries include, for example, water, lactose, gelatin starch, magnesium stearate, talc, vegetable oils, gums, polyalkylene glycols, petrolatum and the like. Pharmaceutical compositions can be prepared in solids such as particulates, powders or suppositories, or in liquids such as solutions, suspensions or emulsions. The pharmaceutical composition may add conventional pharmaceutical auxiliaries such as preservatives, stabilizers, wetting agents, emulsifiers, buffers and the like.

류마티스성 관절염의 치료에 사용하기 위해, 본 발명의 화합물은 임의의 통상적인 경로, 바람직하게는 이러한 경로에 적당한 약제학적 조성물의 형태로 의도하는 치료에 유효한 투여량으로 투여될 수 있다. 관절염의 치료에 있어서, 투여는 구강 경로로 또는 환부 조인트로 관절 내부로 주사에 의해 용이하게 투여될 수 있다.For use in the treatment of rheumatoid arthritis, the compounds of the present invention may be administered in any conventional route, preferably in dosages effective for the intended treatment in the form of pharmaceutical compositions suitable for this route. In the treatment of arthritis, administration can be easily administered by injection into the joint either by the oral route or by the affected joint.

지시된 바에 따라, 투여된 투여량 및 치료 양생법은, 예를 들어, 질환, 질환의 정도, 치료할 환자 및 치료에 대한 환자의 반응에 의존적이며, 따라서 폭넓게 변할 수 있다.As indicated, the dose administered and treatment regimen depends, for example, on the disease, the extent of the disease, the patient to be treated and the patient's response to the treatment and can therefore vary widely.

효소 평가Enzyme evaluation

MMP8 (Phe79-MMP8) 및 MMP3 의 촉매적 도메인을 저해 실험에 사용하였다. 10 mM CaCl2, 100 mM NaCl, 50 mM 트리스/HCl (pH 7.6) 중 25 ℃ 에서 8 nM 효소 농도 및 MMP8 에 대해 불소 함유 기질 Dnp-Pro-Leu-Gly-Leu-Trp-Ala-D-Arg-NH2(Bachem M-1855, 1.10-5M) 및 MMP3 에 대해 Mca-Arg-Pro-Lys-Pro-Val-Glu-Nva-Trp-Arg-Lys(Dnp)-NH2(Bachem M-2110, 4.10-6M) 를 사용하여 효소 평가를 수행하였다 : 측정은 본질적으로 MMP8 에 대해 Stack 등 (3) 이 기술한 방법에 따라, MMP3 에 대해 Nagase 등 (4) 이 기술한 방법에 따라 수행하였다. 350 nm (MMP8) 또는 390 nm (MMP3) 에서의 형광의 증가를 100 초의 기간 동안 관찰하여 가수분해의 초기 속도를 측정하였다. 동력학적 데이터의 평가를 Copeland 등 (5) 이 보고한 방법에 따라 수행하였다.The catalytic domains of MMP8 (Phe 79 -MMP8) and MMP3 were used for inhibition experiments. Fluorine-containing substrate Dnp-Pro-Leu-Gly-Leu-Trp-Ala-D-Arg for 8 nM enzyme concentration and MMP8 at 25 ° C. in 10 mM CaCl 2 , 100 mM NaCl, 50 mM Tris / HCl, pH 7.6 Mca-Arg-Pro-Lys-Pro-Val-Glu-Nva-Trp-Arg-Lys (Dnp) -NH 2 (Bachem M-2110) for -NH 2 (Bachem M-1855, 1.10 -5 M) and MMP3 , 4.10 -6 M) was used to perform the enzyme evaluation: the measurements were carried out essentially according to the method described by Stack et al. (3) for MMP8 and according to the method described by Nagase et al. (4) for MMP3. . An increase in fluorescence at 350 nm (MMP8) or 390 nm (MMP3) was observed for a period of 100 seconds to determine the initial rate of hydrolysis. Evaluation of the kinetic data was performed according to the method reported by Copeland et al. (5).

합성synthesis

전반적인 방법:Overall way:

A) 아미드화: 1 mmole 의 N,N'-우레탄일-시스틴, 2 mmole 의 HOBT (히드록시벤조트리아졸) 및 2.08 mmole 의 EDCI (N-에틸-N'-(3-디메틸아미노프로필)-카르보디이미드 염산염)를 10 ml의 THF 중에 용해 또는 현탁화시킨다. 아민을 과량으로 (2.5 내지 5 mmol) 첨가하고 염산염의 경우에는 등량의 N-메틸모르폴린을 첨가한다. 반응혼합물을 실온에서 하룻밤동안 교반하고, 농축하여 적은 부피로 하고, 에틸아세테이트와 물 사이에 분배한다. 유기층을 5 % NaHCO3, 5 % KHSO4및 물로 2회 세척하고, MgSO4상에서 건조한다. 용매를 증발시키고, 석유 에테르, 디이소프로필에테르, tert-부틸 메틸 에테르 또는 펜탄 등의 적합한 용매에 의해 에틸아세테이트로부터 잔류물을 침전시킨다.A) Amidation: 1 mmole N, N'-urethaneyl-cystine, 2 mmole HOBT (hydroxybenzotriazole) and 2.08 mmole EDCI (N-ethyl-N '-(3-dimethylaminopropyl)- Carbodiimide hydrochloride) is dissolved or suspended in 10 ml of THF. An excess of amine (2.5-5 mmol) is added and, in the case of hydrochloride, an equivalent amount of N-methylmorpholine. The reaction mixture is stirred overnight at room temperature, concentrated to a small volume and partitioned between ethyl acetate and water. The organic layer is washed twice with 5% NaHCO 3 , 5% KHSO 4 and water and dried over MgSO 4 . The solvent is evaporated and the residue is precipitated from ethyl acetate with a suitable solvent such as petroleum ether, diisopropyl ether, tert-butyl methyl ether or pentane.

B) 환원: 시스틴 화합물 (1 mmol)을 95 % 트리플루오르에탄올 10 ml 중에서 1.5 mmol 트리부틸포스핀과 반응시킨다. 반응혼합물을 실온에서 하룻밤동안 교반하고, 증발시켜 적은 부피로 하고, 에틸아세테이트에 의한 희석 시에 생성물을 석유 에테르, 디이소프로필에테르, tert-부틸 메틸 에테르 또는 펜탄 등의 적합한 용매로 침전시킨다.B) Reduction: The cystine compound (1 mmol) is reacted with 1.5 mmol tributylphosphine in 10 ml of 95% trifluoroethanol. The reaction mixture is stirred overnight at room temperature, evaporated to small volume, and upon dilution with ethyl acetate the product is precipitated with a suitable solvent such as petroleum ether, diisopropyl ether, tert-butyl methyl ether or pentane.

N,N'-비스-벤질옥시카르보닐-L-시스틴-비스-히드록사메이트 (5a)N, N'-bis-benzyloxycarbonyl-L-cystine-bis-hydroxyxamate (5a)

공정 (A) 에 따라서 N,N'-비스-벤질옥시카르보닐-L-시스틴 및 히드록실아민으로부터 제조함. 수율: 22 %; TLC (용매계: 클로로포름/메탄올; 4: 1,Rf=0.5) 상에서 균질함.Prepared from N, N'-bis-benzyloxycarbonyl-L-cystine and hydroxylamine according to step (A). Yield: 22%; Homogeneous on TLC (solvent system: chloroform / methanol; 4: 1, R f = 0.5).

FAB-MS: m/z = 539.2 [M+H+]; Mr= 538.2 C22H26N408S2에 대한 계산치FAB-MS: m / z = 539.2 [M + H + ]; M r = 538.2 Calculated for C 22 H 26 N 4 0 8 S 2

벤질옥시카르보닐-L-시스테인-히드록사메이트 (5)Benzyloxycarbonyl-L-cysteine-hydroxyxamate (5)

공정 (B) 에 따라서 5a로부터 제조함. 플래시 크로마토그래피 (용리액: CH2Cl2/MeOH, 95:5 이후에 45:5)에 의해 정제함. 수율: 18 %.Prepared from 5a according to process (B). Purification by flash chromatography (eluent: CH 2 Cl 2 / MeOH, 45: 5 after 95: 5). Yield: 18%.

1H-NMR (d6-DMSO): 10.7 (bs, 1H, NHOH); 8.89 (bs, 1H, OH); 7.50 (d, IH, NH ureth.); 7.38 (m, 5H, 방향족 H 들); 5.03 (s, 2H, CH2v. Z); 3.99 (m, 1H, H-C(α)); 2.75/2.66 (2xm, 2H, β- CH2); 2.29 (bs, 1H, SH). 1 H-NMR (d 6 -DMSO): 10.7 (bs, 1H, NHOH); 8.89 (bs, 1 H, OH); 7.50 (d, IH, NH ureth.); 7.38 (m, 5H, aromatic Hs); 5.03 (s, 2H, CH 2 v. Z); 3.99 (m, 1 H, HC (α)); 2.75 / 2.66 (2xm, 2H, β-CH 2 ); 2.29 (bs, 1 H, SH).

비스-tert-부틸옥시카르보닐-L-시스틴-비스-벤질아미드 (6a)Bis-tert-butyloxycarbonyl-L-cystine-bis-benzylamide (6a)

(A) 에 따라서 N,N'-비스-tert-부틸옥시카르보닐-L-시스틴 (12) 및 벤질아민으로부터 제조함. 수율: 77 %. TLC (용매계: 시클로헥산/클로로포름/아세트산, 45:45:10, Rf=0.7) 상에서 균질함.Prepared from N, N'-bis-tert-butyloxycarbonyl-L-cystine (12) and benzylamine according to (A). Yield 77%. Homogeneous on TLC (solvent system: cyclohexane / chloroform / acetic acid, 45:45:10, R f = 0.7).

L-시스틴-비스-벤질아미드 염산염 (6b)L-cystine-bis-benzylamide hydrochloride (6b)

4.6M HCl 100 ml 중의 6a 13.87g (22.4 mmol)을 디옥산 중에서 실온에서 하룻밤동안 교반하였다: 침전물을 수집하고 에테르로 광범위하게 세척하였다. 수율: 11g (정량).13.87 g (22.4 mmol) of 6a in 100 ml of 4.6 M HCl were stirred overnight in dioxane at room temperature: The precipitate was collected and washed extensively with ether. Yield: 11 g (quantity).

N,N'-비스-아세틸-L-시스틴-비스-벤질아미드 (6c)N, N'-bis-acetyl-L-cystine-bis-benzylamide (6c)

6b 300 mg (0.61 mmol)을 에틸아세테이트와 NaHCO3(5 %) 40 ml 사이에 분배하고나서, 아세트산 무수물 (0.27g, 2.6 mmol)과 반응시켰다. 유기층을 물로 세척하고, MgSO4상에서 건조하고, 증발시켜 건조하였다. 수율: 94 %; TLC (용매계: 시클로헥산/클로로포름/아세트산, 45:45:10, Rf=0.4) 상에서 균질함.300 mg (0.61 mmol) of 6b were partitioned between ethyl acetate and 40 ml of NaHCO 3 (5%) and then reacted with acetic anhydride (0.27 g, 2.6 mmol). The organic layer was washed with water, dried over MgSO 4 and evaporated to dryness. Yield: 94%; Homogeneous on TLC (solvent system: cyclohexane / chloroform / acetic acid, 45:45:10, R f = 0.4).

N-아세틸-L-시스테인-벤질아미드 (6)N-acetyl-L-cysteine-benzylamide (6)

6c 를 공정 (B) 에 따라서 환원시켰다. 수율: 65 %; TLC (용매계: CHCl3/MeOH, 4:1, Rf=0.7) 상에서 균질함; 융점 186-189℃;6c was reduced according to process (B). Yield: 65%; Homogeneous on TLC (solvent system: CHCl 3 / MeOH, 4: 1, R f = 0.7); Melting point 186-189 ° C .;

1H-NMR (d6-DMSO): 8.56 (t, 1H, NH, 아미드); 8.23 (d, 1H, NH ureth.); 7.32-7.09 (m, 5H, 방향족 H 들); 4.56, 또는 4.38 (m, 1H, H-Cα); 4.28 (m, 2H, CH2-Bn); 3.12/2.89, 또는 2.79/2.69 (2xm, 2H, β- CH2); 2.30 (bs, 1H, SH); 1.87 (d, 3H, CH3). 1 H-NMR (d 6 -DMSO): 8.56 (t, 1H, NH, amide); 8.23 (d, 1 H, NH ureth.); 7.32-7.09 (m, 5H, aromatic Hs); 4.56, or 4.38 (m, 1H, HC α ); 4.28 (m, 2H, CH 2 -Bn); 3.12 / 2.89, or 2.79 / 2.69 (2xm, 2H, β-CH 2 ); 2.30 (bs, 1 H, SH); 1.87 (d, 3H, CH 3 ).

FAB-MS: m/z = 539.2 [M+H+]; Mr= 538.2 C12H16N202S에 대한 계산치FAB-MS: m / z = 539.2 [M + H + ]; M r = 538.2 Calculation for C 12 H 16 N 2 0 2 S

N,N'-비스-포르밀-L-시스틴-비스-벤질아미드 (7a)N, N'-bis-formyl-L-cystine-bis-benzylamide (7a)

공정 (A) 에 따라서 6b 및 포름산으로부터 제조함. 수율: 59 %; TLC (용매계: 시클로헥산/CHCl3/아세트산, 45:45:10, Rf=0.1) 상에서 균질함.Prepared from 6b and formic acid according to process (A). Yield: 59%; Homogeneous on TLC (solvent system: cyclohexane / CHCl 3 / acetic acid, 45:45:10, R f = 0.1).

N-포르밀-L-시스테인-벤질아미드 (7)N-formyl-L-cysteine-benzylamide (7)

공정 (B) 에 따라서 7a 를 환원함. 수율: 62 %; TLC (용매계: 시클로헥산/CHCl3/아세트산, 45:45:10, Rf=0.45) 상에서 균질함; 융점 180-183℃;7a is reduced according to the step (B). Yield: 62%; Homogenous on TLC (solvent system: cyclohexane / CHCl 3 / acetic acid, 45:45:10, R f = 0.45); Melting point 180-183 ° C .;

1H-NMR (d6-DMSO): 8.58 (t, 1H, NH, 아미드); 8.35 (d, 1H, NH ureth.); 8.10 (s, 1H, 포르밀-H); 7.33-7.21 (m, 5H, 방향족 H 들); 4.49 (m, 1H, H-Cα); 4.30 (d, 2H, CH2-Bn); 2.82/2.72 (2xm, 2H, β- CH2); 2.26 (bs, 1H, SH). 1 H-NMR (d 6 -DMSO): 8.58 (t, 1H, NH, amide); 8.35 (d, 1 H, NH ureth.); 8.10 (s, 1 H, formyl-H); 7.33-7.21 (m, 5H, aromatic Hs); 4.49 (m, 1 H, HC α ); 4.30 (d, 2H, CH 2 -Bn); 2.82 / 2.72 (2xm, 2H, β-CH 2 ); 2.26 (bs, 1 H, SH).

FAB-MS: m/z = 239.0 [M+H+]; Mr= 238.3 C11H14N202S에 대한 계산치FAB-MS: m / z = 239.0 [M + H + ]; M r = 238.3 Calcd for C 11 H 14 N 2 0 2 S

tert-부틸옥시카르보닐-L-시스테인-벤질아미드 (8)tert-Butyloxycarbonyl-L-cysteine-benzylamide (8)

공정 (B) 에 따라서 6a 를 환원함. 수율: 38 %; TLC (용매계: 헵탄/t-부탄올/아세트산, 5:1:1, Rf=0.7) 상에서 균질함; 융점 97-100℃;6a is reduced according to the step (B). Yield: 38%; Homogeneous on TLC (solvent system: heptane / t-butanol / acetic acid, 5: 1: 1, R f = 0.7); Melting point 97-100 ° C .;

1H-NMR (d6-DMSO): 8.38 (m, 1H, NH, 아미드); 7.32-7.21 (m, 5H, 방향족 H 들); 6.95 (d, 1H, NH ureth.); 4.29 (d, 2H, CH2-Bn); 4.08 (m, 1H, H-Cα); 2.81/2.68 (2xm, 2H, β- CH2); 2.29 (bs, 1H, SH); 1.40 (s, 9H, t-Bu). 1 H-NMR (d 6 -DMSO): 8.38 (m, 1H, NH, amide); 7.32-7.21 (m, 5H, aromatic Hs); 6.95 (d, 1 H, NH ureth.); 4.29 (d, 2H, CH 2 -Bn); 4.08 (m, 1 H, HC α ); 2.81 / 2.68 (2xm, 2H, β-CH 2 ); 2.29 (bs, 1 H, SH); 1.40 (s, 9 H, t-Bu).

FAB-MS: m/z = 311.1 [M+H+]; Mr= 310.1 C15H22N203S에 대한 계산치FAB-MS: m / z = 311.1 [M + H + ]; M r = 310.1 Calculated for C 15 H 22 N 2 0 3 S

N,N'-비스-벤질옥시카르보닐-L-시스틴-비스-벤질아미드 (9a)N, N'-bis-benzyloxycarbonyl-L-cystine-bis-benzylamide (9a)

(A) 에 따라서 N,N'-비스-벤질옥시카르보닐-시스틴 및 벤질아민으로부터 제조함. 수율: 90 %Prepared from N, N'-bis-benzyloxycarbonyl-cystine and benzylamine according to (A). Yield: 90%

N-벤질옥시카르보닐-L-시스테인-벤질아미드 (9)N-benzyloxycarbonyl-L-cysteine-benzylamide (9)

(B) 에 따라서 9a 를 환원함. 수율: 41 %; TLC (용매계: 시클로헥산/CHCl3/아세트산, 45:45:10, Rf=0.4) 상에서 균질함; 융점 148-152℃;9a is reduced according to (B). Yield: 41%; Homogeneous on TLC (solvent system: cyclohexane / CHCl 3 / acetic acid, 45:45:10, R f = 0.4); Melting point 148-152 ° C .;

1H-NMR (d6-DMSO): 8.50 (m, 1H, NH, 아미드); 7.49 (d, 1H, NH ureth.); 7.37-7.23 (m, 10H, 방향족 H 들); 5.06 (dd, 2H, CH2v. Z); 4.30 (d, 2H, CH2-Bn); 4.16 (m, 1H, H-Cα); 2.84/2.70 (2xm, 2H, β- CH2); 2.33 (bs, 1H, SH). 1 H-NMR (d 6 -DMSO): 8.50 (m, 1H, NH, amide); 7.49 (d, 1 H, NH ureth.); 7.37-7.23 (m, 10H, aromatic Hs); 5.06 (dd, 2H, CH 2 v. Z); 4.30 (d, 2H, CH 2 -Bn); 4.16 (m, 1 H, HC α ); 2.84 / 2.70 (2xm, 2H, β-CH 2 ); 2.33 (bs, 1 H, SH).

FAB-MS: m/z = 345.0 [M+H+]; Mr= 344.4 C18H20N203S에 대한 계산치FAB-MS: m / z = 345.0 [M + H + ]; M r = 344.4 C 18 H 20 N 2 0 3 S

N,N'-비스-벤질옥시카르보닐-L-시스틴-비스-4-피리딜메틸아미드 (10a)N, N'-bis-benzyloxycarbonyl-L-cystine-bis-4-pyridylmethylamide (10a)

공정 (A) 에 따라서 N,N'-비스-벤질옥시카르보닐-L-시스틴 및 4-(아미노메틸)피리딘으로부터 제조함. 수율: 59 %; TLC (용매계: CHCl3/MeOH, 4:1, Rf=0.65) 상에서 균질함.Prepared from N, N'-bis-benzyloxycarbonyl-L-cystine and 4- (aminomethyl) pyridine according to step (A). Yield: 59%; Homogeneous on TLC (solvent system: CHCl 3 / MeOH, 4: 1, R f = 0.65).

N-벤질옥시카르보닐-L-시스테인-4-피리딜메틸아미드 (10)N-benzyloxycarbonyl-L-cysteine-4-pyridylmethylamide (10)

공정 (B) 에 따라서 10a로부터 제조함. 수율: 65 %; TLC (용매계: CHCl3/MeOH, 4:1, Rf=0.8) 상에서 균질함; 융점 122-125℃;Prepared from 10a according to step (B). Yield: 65%; Homogeneous on TLC (solvent system: CHCl 3 / MeOH, 4: 1, R f = 0.8); Melting point 122-125 ° C .;

1H-NMR (d6-DMSO): 8.61 (t, 1H, NH, 아미드); 8.48/7.37/7.25 (각각 m, 9H, 방향족 H 들); 7.56 (d, 1H, NH-ureth.); 5.08 (dd, 2H, CH2, Z); 4.32 (d, 2H, CH2-Bn); 4.18 (m, 1H, H-Cα); 2.87/2.72 (2xm, 2H, β- CH2); 2.40 (bs, 1H, SH). 1 H-NMR (d 6 -DMSO): 8.61 (t, 1H, NH, amide); 8.48 / 7.37 / 7.25 (m, 9H, aromatic Hs, respectively); 7.56 (d, 1 H, NH-ureth.); 5.08 (dd, 2H, CH 2 , Z); 4.32 (d, 2H, CH 2 -Bn); 4.18 (m, 1 H, HC α ); 2.87 / 2.72 (2xm, 2H, β-CH 2 ); 2.40 (bs, 1 H, SH).

FAB-MS: m/z = 346.2 [M+H+]; Mr= 345.1 C17H19N303S에 대한 계산치FAB-MS: m / z = 346.2 [M + H + ]; M r = 345.1 Calcd for C 17 H 19 N 3 0 3 S

N,N'-비스-벤질옥시카르보닐-L-시스틴-비스-3-피리딜메틸아미드 (11a)N, N'-bis-benzyloxycarbonyl-L-cystine-bis-3-pyridylmethylamide (11a)

공정 (A) 에 따라서 N,N'-비스-벤질옥시카르보닐-시스틴 및 3-(아미노메틸)피리딘으로부터 제조함. 수율: 69 %; TLC (용매계: CHCl3/MeOH, 4:1, Rf=0.2) 상에서 균질함.Prepared from N, N'-bis-benzyloxycarbonyl-cystine and 3- (aminomethyl) pyridine according to step (A). Yield: 69%; Homogeneous on TLC (solvent system: CHCl 3 / MeOH, 4: 1, R f = 0.2).

N-벤질옥시카르보닐-L-시스테인-3-피리딜메틸아미드 (11)N-benzyloxycarbonyl-L-cysteine-3-pyridylmethylamide (11)

공정 (B) 에 따라서 11a 를 환원함. 수율: 14 %; TLC (용매계: CHCl3/MeOH, 4:1, Rf=0.8) 상에서 균질함; 융점 125-127℃;11a is reduced according to the step (B). Yield: 14%; Homogeneous on TLC (solvent system: CHCl 3 / MeOH, 4: 1, R f = 0.8); Melting point 125-127 ° C .;

1H-NMR (d6-DMSO): 8.58 (t, 1H, NH, 아미드); 8.50/8.45/7.65/7.36 (각각 m, 9H, 방향족 H 들); 7.52 (d, 1H, NH-ureth.); 5.07 (dd, 2H, CH2, v. Z); 4.42 (d, 2H, CH2-Bn); 4.15 (m, 1H, H-Cα); 2.82/2.71 (2xm, 2H, β- CH2); 2.36 (bs, 1H, SH). 1 H-NMR (d 6 -DMSO): 8.58 (t, 1H, NH, amide); 8.50 / 8.45 / 7.65 / 7.36 (m, 9H, aromatic Hs, respectively); 7.52 (d, 1 H, NH-ureth.); 5.07 (dd, 2H, CH 2 , v. Z); 4.42 (d, 2H, CH 2 -Bn); 4.15 (m, 1 H, HC α ); 2.82 / 2.71 (2xm, 2H, β-CH 2 ); 2.36 (bs, 1 H, SH).

FAB-MS: m/z = 346.1 [M+H+]; Mr= 345.1 C17H19N303S에 대한 계산치FAB-MS: m / z = 346.1 [M + H + ]; M r = 345.1 Calcd for C 17 H 19 N 3 0 3 S

N,N'-비스-벤질옥시카르보닐-L-시스틴-비스-2-피리딜메틸아미드 (12a)N, N'-bis-benzyloxycarbonyl-L-cystine-bis-2-pyridylmethylamide (12a)

공정 (A) 에 따라서 N,N'-비스-벤질옥시카르보닐-시스틴 및 2-(아미노메틸)피리딘으로부터 제조함. 수율: 96 %; TLC (용매계: CHCl3/MeOH, 4:1, Rf=0.7) 상에서 균질함.Prepared from N, N'-bis-benzyloxycarbonyl-cystine and 2- (aminomethyl) pyridine according to step (A). Yield: 96%; Homogeneous on TLC (solvent system: CHCl 3 / MeOH, 4: 1, R f = 0.7).

N-벤질옥시카르보닐-L-시스테인-2-피리딜메틸아미드 (12)N-benzyloxycarbonyl-L-cysteine-2-pyridylmethylamide (12)

공정 (B) 에 따라서 12a 를 환원함. 수율: 33 %; TLC (용매계: CHCl3/MeOH, 4:1, Rf=0.8) 상에서 균질함; 융점 129-131℃;12a is reduced in accordance with step (B). Yield: 33%; Homogeneous on TLC (solvent system: CHCl 3 / MeOH, 4: 1, R f = 0.8); Melting point 129-131 ° C .;

1H-NMR (d6-DMSO): 8.59 (t, 1H, NH, 아미드); 8.48/7.72/7.36-7.22 (각각 m, 9H, 방향족 H 들); 7.52 (d, 1H, NH-ureth.); 5.07 (dd, 2H, CH2, v. Z); 4.49 (d, 2H, CH2-Bn); 4.20 (m, 1H, H-Cα); 2.82/2.72 (2xm, 2H, β- CH2); 2.42 (bs, 1H, SH). 1 H-NMR (d 6 -DMSO): 8.59 (t, 1H, NH, amide); 8.48 / 7.72 / 7.36-7.22 (m, 9H, aromatic Hs, respectively); 7.52 (d, 1 H, NH-ureth.); 5.07 (dd, 2H, CH 2 , v. Z); 4.49 (d, 2H, CH 2 -Bn); 4.20 (m, 1 H, HC α ); 2.82 / 2.72 (2xm, 2H, β-CH 2 ); 2.42 (bs, 1 H, SH).

FAB-MS: m/z = 346.1 [M+H+]; Mr= 345.1 C17H19N303S에 대한 계산치FAB-MS: m / z = 346.1 [M + H + ]; M r = 345.1 Calcd for C 17 H 19 N 3 0 3 S

N,N'-비스-벤조일-L-시스틴-비스-벤질아미드 (13a)N, N'-bis-benzoyl-L-cystine-bis-benzylamide (13a)

(A) 에 따라서 6b 및 벤조산으로부터 제조함. 수율: 78 %; TLC (용매계: 시클로헥산/CHCl3/아세트산, 45:45:10, Rf=0.65) 상에서 균질함.Prepared from 6b and benzoic acid according to (A). Yield: 78%; Homogeneous on TLC (solvent system: cyclohexane / CHCl 3 / acetic acid, 45:45:10, R f = 0.65).

N-벤조일-L-시스테인-벤질아미드 (13)N-benzoyl-L-cysteine-benzylamide (13)

(B) 에 따라서 13a 를 환원함. 수율: 57 %; TLC (용매계: 시클로헥산/CHCl3/아세트산, 45:45:10, Rf=0.55) 상에서 균질함; 융점 174-176℃;13a is reduced according to (B). Yield: 57%; Homogeneous on TLC (solvent system: cyclohexane / CHCl 3 / acetic acid, 45:45:10, R f = 0.55); Melting point 174-176 ° C .;

1H-NMR (d6-DMSO): 8.56 (t, 1H, NH, 아미드); 7.92 (d, 1H, NH ureth.); 7.57-7.22 (m, 10H, 방향족 H 들); 4.59 (m, 1H, H-Cα); 4.31 (d, 2H, CH2-Bn); 2.98/2.89 (2xm, 2H, β- CH2); 2.41 (t, 1H, SH). 1 H-NMR (d 6 -DMSO): 8.56 (t, 1H, NH, amide); 7.92 (d, 1 H, NH ureth.); 7.57-7.22 (m, 10H, aromatic Hs); 4.59 (m, 1 H, HC α ); 4.31 (d, 2H, CH 2 -Bn); 2.98 / 2.89 (2xm, 2H, β-CH 2 ); 2.41 (t, 1 H, SH).

FAB-MS: m/z = 315.1 [M+H+]; Mr= 314.1 C17H18N202S에 대한 계산치FAB-MS: m / z = 315.1 [M + H + ]; M r = 314.1 Calculation for C 17 H 18 N 2 0 2 S

N,N'-비스-토실-L-시스틴-비스-벤질아미드 (14a)N, N'-bis-tosyl-L-cystine-bis-benzylamide (14a)

6b 390 mg (0.794 mmol)을 피리딘 6 ml 중에서 토실 180 mg (0.952 mmol)과 반응시켰다. 실온에서 12시간 교반한 후에, 고체를 여과하여 제거하고 여과액을 증발시켜 건조하고 톨루엔을 첨가하여 최종적으로 tert-부틸 메틸 에테르를 얻었다. 수율: 81 %; TLC (용매계: CHCl3/MeOH, 4:1, Rf=0.7) 상에서 균질함.390 mg (0.794 mmol) of 6b was reacted with 180 mg (0.952 mmol) of tosyl in 6 ml of pyridine. After stirring for 12 hours at room temperature, the solid was filtered off, the filtrate was evaporated to dryness and toluene was added to finally give tert-butyl methyl ether. Yield: 81%; Homogeneous on TLC (solvent system: CHCl 3 / MeOH, 4: 1, R f = 0.7).

N-토실-L-시스테인-벤질아미드 (14)N-Tosyl-L-cysteine-benzylamide (14)

(B) 에 따라서 14a 를 환원함. 수율: 54 %; TLC (용매계: CHCl3/MeOH, 4:1, Rf=0.6) 상에서 균질함; 융점 180-182℃;Reducing 14a according to (B). Yield: 54%; Homogeneous on TLC (solvent system: CHCl 3 / MeOH, 4: 1, R f = 0.6); Melting point 180-182 ° C .;

1H-NMR (d6-DMSO): 8.41 (t, 1H, NH, 아미드); 7.98/7.68/7.35-7.14 (각각 m 및 d 들, 10H, 방향족 H 들, NH-ureth.); 4.13 (d, 2H, CH2-Bn); 3.86 (m, 1H, H-Cα); 2.59 (m, 2H, β- CH2); 2.38 (s, 3H, CH3); 2.17 (t, 1H, SH). 1 H-NMR (d 6 -DMSO): 8.41 (t, 1H, NH, amide); 7.98 / 7.68 / 7.35-7.14 (m and ds, 10H, aromatic Hs, NH-ureth, respectively); 4.13 (d, 2H, CH 2 -Bn); 3.86 (m, 1 H, HC α ); 2.59 (m, 2H, β-CH 2 ); 2.38 (s, 3 H, CH 3 ); 2.17 (t, 1 H, SH).

FAB-MS: m/z = 365.1 [M+H+]; Mr= 364.1 C17H20N203S에 대한 계산치FAB-MS: m / z = 365.1 [M + H + ]; M r = 364.1 Calculation for C 17 H 20 N 2 0 3 S

N,N'-비스-벤질옥시카르보닐-L-시스틴-비스-2-페닐에틸아미드 (15a)N, N'-bis-benzyloxycarbonyl-L-cystine-bis-2-phenylethylamide (15a)

(A) 에 따라서 N,N'-비스-벤질옥시카르보닐-L-시스틴 및 2-페닐에틸아민으로부터 제조함. 수율: 34 %; TLC (용매계: CHCl3/MeOH, 19:1, Rf=0.8) 상에서 균질함.Prepared from N, N'-bis-benzyloxycarbonyl-L-cystine and 2-phenylethylamine according to (A). Yield: 34%; Homogeneous on TLC (solvent system: CHCl 3 / MeOH, 19: 1, R f = 0.8).

N-벤질옥시카르보닐-L-시스테인-2-페닐에틸아미드 (15)N-benzyloxycarbonyl-L-cysteine-2-phenylethylamide (15)

(B) 에 따라서 15a 를 환원함. 수율: 61 %; TLC (용매계: 시클로헥산/CHCl3/아세트산, 45:45:10, Rf=0.6) 상에서 균질함; 융점 119-121℃;15a is reduced according to (B). Yield: 61%; Homogeneous on TLC (solvent system: cyclohexane / CHCl 3 / acetic acid, 45:45:10, R f = 0.6); Melting point 119-121 ° C .;

1H-NMR (d6-DMSO): 8.02 (t, 1H, NH, 아미드); 7.39-7.18 (m, 11H, 방향족 H 들, NH ureth.); 5.03 (dd, 2H, CH2v. Z); 4.06 (m, 1H, H-Cα); 2.72/2.61 (2xm, 4H, CH2-CH2); 2.22 (bs, 1H, SH). 1 H-NMR (d 6 -DMSO): 8.02 (t, 1H, NH, amide); 7.39-7.18 (m, 11H, aromatic Hs, NH ureth.); 5.03 (dd, 2H, CH 2 v. Z); 4.06 (m, 1 H, HC α ); 2.72 / 2.61 (2xm, 4H, CH 2 -CH 2 ); 2.22 (bs, 1 H, SH).

FAB-MS: m/z = 359.1 [M+H+]; Mr= 358.1 C19H22N203S에 대한 계산치FAB-MS: m / z = 359.1 [M + H + ]; M r = 358.1 C 19 H 22 N 2 0 3 S

N,N'-비스-벤질옥시카르보닐-L-시스틴-비스-2-(4-히드록시페닐)에틸아미드 (16a)N, N'-bis-benzyloxycarbonyl-L-cystine-bis-2- (4-hydroxyphenyl) ethylamide (16a)

(A) 에 따라서 N,N'-비스-벤질옥시카르보닐-시스틴 및 2-(4-히드록시페닐)에틸아민으로부터 제조함. 수율: 71 %; TLC (용매계: 시클로헥산/CHCl3/아세트산, 45:45:10, Rf=0.5) 상에서 균질함.Prepared from N, N'-bis-benzyloxycarbonyl-cystine and 2- (4-hydroxyphenyl) ethylamine according to (A). Yield: 71%; Homogeneous on TLC (solvent system: cyclohexane / CHCl 3 / acetic acid, 45:45:10, R f = 0.5).

N-벤질옥시카르보닐-L-시스테인-2-(4-히드록시페닐)에틸아미드 (16)N-benzyloxycarbonyl-L-cysteine-2- (4-hydroxyphenyl) ethylamide (16)

(B) 에 따라서 16a 를 환원함. 수율: 24 %; TLC (용매계: 시클로헥산/CHCl3/아세트산, 45:45:10, Rf=0.6) 상에서 균질함; 융점 133-135℃;16a is reduced according to (B). Yield: 24%; Homogeneous on TLC (solvent system: cyclohexane / CHCl 3 / acetic acid, 45:45:10, R f = 0.6); Melting point 133-135 ° C .;

1H-NMR (d6-DMSO): 9.11 (s, 1H, 페놀. OH); 7.98 (t, 1H, NH, 아미드); 7.38 (m, 6H, 방향족 v. Z, NH ureth.); 6.99/6.68 (2xd, 4H, 방향족, 페놀. H 들); 5.04 (dd, 2H, CH2v. Z); 4.05 (m, 1H, H-Cα); 2.73/2.60 (2xm, 4H, CH2-CH2); 2.26 (bs, 1H, SH). 1 H-NMR (d 6 -DMSO): 9.11 (s, 1H, phenol. OH); 7.98 (t, 1H, NH, amide); 7.38 (m, 6H, aromatic v. Z, NH ureth.); 6.99 / 6.68 (2xd, 4H, aromatic, phenol. Hs); 5.04 (dd, 2H, CH 2 v. Z); 4.05 (m, 1 H, HC α ); 2.73 / 2.60 (2xm, 4H, CH 2 -CH 2 ); 2.26 (bs, 1 H, SH).

FAB-MS: m/z = 375.2 [M+H+]; Mr= 374.1 C19H22N204S에 대한 계산치FAB-MS: m / z = 375.2 [M + H + ]; M r = 374.1 Calculation for C 19 H 22 N 2 0 4 S

N,N'-비스-벤질옥시카르보닐-L-시스틴-비스-4-클로로벤질아미드 (17a)N, N'-bis-benzyloxycarbonyl-L-cystine-bis-4-chlorobenzylamide (17a)

(A) 에 따라서 N,N'-비스-벤질옥시카르보닐-L-시스틴 및 4-클로로벤질아민으로부터 제조함. 수율: 99 %; TLC (용매계: CHCl3/MeOH, 19:1, Rf=0.8) 상에서 균질함.Prepared from N, N'-bis-benzyloxycarbonyl-L-cystine and 4-chlorobenzylamine according to (A). Yield: 99%; Homogeneous on TLC (solvent system: CHCl 3 / MeOH, 19: 1, R f = 0.8).

N-벤질옥시카르보닐-L-시스테인-4-클로로벤질아미드 (17)N-benzyloxycarbonyl-L-cysteine-4-chlorobenzylamide (17)

(B) 에 따라서 17a 를 환원함. 수율: 71 %; TLC (용매계: 시클로헥산/CHCl3/아세트산, 45:45:10, Rf=0.85) 상에서 균질함; 융점 137-139℃;17a is reduced according to (B). Yield: 71%; Homogeneous on TLC (solvent system: cyclohexane / CHCl 3 / acetic acid, 45:45:10, R f = 0.85); Melting point 137-139 ° C .;

1H-NMR (d6-DMSO): 8.53 (t, 1H, NH, 아미드); 7.51 (d, 1H, NH ureth.); 7.38-7.26 (m, 9H, 방향족 H 들); 5.06 (dd, 2H, CH2v. Z); 4.29 (d, 2H, CH2-Bn); 4.13 (m, 1H, H-Cα); 2.82/2.70 (2xm, 2H, β- CH2); 2.53 (bs, 1H, SH). 1 H-NMR (d 6 -DMSO): 8.53 (t, 1H, NH, amide); 7.51 (d, 1 H, NH ureth.); 7.38-7.26 (m, 9H, aromatic Hs); 5.06 (dd, 2H, CH 2 v. Z); 4.29 (d, 2H, CH 2 -Bn); 4.13 (m, 1 H, HC α ); 2.82 / 2.70 (2xm, 2H, β-CH 2 ); 2.53 (bs, 1 H, SH).

FAB-MS: m/z = 379.1 [M+H+]; Mr= 378.1 C18H19ClN203S에 대한 계산치FAB-MS: m / z = 379.1 [M + H + ]; M r = 378.1 calcd for C 18 H 19 ClN 2 0 3 S

N,N'-비스-벤질옥시카르보닐-L-시스틴-비스-3-페닐프로필아미드 (18a)N, N'-bis-benzyloxycarbonyl-L-cystine-bis-3-phenylpropylamide (18a)

(A) 에 따라서 N,N'-비스-벤질옥시카르보닐-시스틴 및 3-페닐프로필아민으로부터 제조함. 수율: 94 %; TLC (용매계: 시클로헥산/CHCl3/아세트산, 45:45:10, Rf=0.7) 상에서 균질함.Prepared from N, N'-bis-benzyloxycarbonyl-cystine and 3-phenylpropylamine according to (A). Yield: 94%; Homogeneous on TLC (solvent system: cyclohexane / CHCl 3 / acetic acid, 45:45:10, R f = 0.7).

N-벤질옥시카르보닐-L-시스테인-3-페닐프로필아미드 (18)N-benzyloxycarbonyl-L-cysteine-3-phenylpropylamide (18)

(B) 에 따라서 18a 를 환원함. 수율: 76 %; TLC (용매계: 시클로헥산/CHCl3/아세트산, 45:45:10, Rf=0.7) 상에서 균질함; 융점 104-106℃;18a is reduced according to (B). Yield: 76%; Homogeneous on TLC (solvent system: cyclohexane / CHCl 3 / acetic acid, 45:45:10, R f = 0.7); Melting point 104-106 ° C .;

1H-NMR (d6-DMSO): 8.02 (t, 1H, NH, 아미드); 7.43 (d, 1H, NH ureth.); 7.38-7.15 (m, 10H, 방향족 H 들); 5.05 (dd, 2H, CH2v. Z); 4.09 (m, 1H, H-Cα); 3.12 (m, 2H, N-CH2); 2.70/2.69 (2xm, 2H, β- CH2); 2.58 (t, 2H, CH2-Ph); 2.32 (bs, 1H, SH); 1.70 (m, 2H, CH2-CH2-CH2). 1 H-NMR (d 6 -DMSO): 8.02 (t, 1H, NH, amide); 7.43 (d, 1 H, NH ureth.); 7.38-7.15 (m, 10H, aromatic Hs); 5.05 (dd, 2H, CH 2 v. Z); 4.09 (m, 1 H, HC α ); 3.12 (m, 2H, N-CH 2 ); 2.70 / 2.69 (2xm, 2H, β-CH 2 ); 2.58 (t, 2H, CH 2 -Ph); 2.32 (bs, 1 H, SH); 1.70 (m, 2H, CH 2 -CH 2 -CH 2 ).

FAB-MS: m/z = 373.2 [M+H+]; Mr= 372.2 C20H24N203S에 대한 계산치FAB-MS: m / z = 373.2 [M + H + ]; M r = 372.2 Calculation for C 20 H 24 N 2 0 3 S

N,N'-비스-벤질옥시카르보닐-L-시스틴-비스-트립트아미드 (19a)N, N'-bis-benzyloxycarbonyl-L-cystine-bis-tryptamide (19a)

(A) 에 따라서 N,N'-비스-벤질옥시카르보닐-시스틴 및 트립트아민으로부터 제조함. 수율: 75 %; TLC (용매계: 시클로헥산/CHCl3/아세트산, 45:45:10, Rf=0.6) 상에서 균질함.Prepared from N, N'-bis-benzyloxycarbonyl-cystine and tryptamine according to (A). Yield: 75%; Homogeneous on TLC (solvent system: cyclohexane / CHCl 3 / acetic acid, 45:45:10, R f = 0.6).

벤질옥시카르보닐-L-시스테인-트립트아미드 (19)Benzyloxycarbonyl-L-cysteine-tryptamide (19)

(B) 에 따라서 19a 를 환원함. 수율: 62 %; TLC (용매계: 시클로헥산/CHCl3/아세트산, 45:45:10, Rf=0.7) 상에서 균질함; 융점 150-152℃;19a is reduced according to (B). Yield: 62%; Homogeneous on TLC (solvent system: cyclohexane / CHCl 3 / acetic acid, 45:45:10, R f = 0.7); Melting point 150-152 ° C .;

1H-NMR (d6-DMSO): 10.80 (s, 1H, NH-트립트아민); 8.09 (t, 1H, NH, 아미드); 7.54-6.96 (m, 11H, 방향족 H 들, ureth. NH); 5.05 (dd, 2H, CH2v. Z); 4.08 (m, 1H, H-C( α)); 3.32 (m, 2H, NHCH2CH2); 2.82 (t, 2H, NHCH2C H2); 2.77/2.65 (2xm, 2H, β- CH2); 2.26 (m, 1H, SH). 1 H-NMR (d 6 -DMSO): 10.80 (s, 1H, NH-tryptamine); 8.09 (t, 1H, NH, amide); 7.54-6.96 (m, 11H, aromatic Hs, ureth. NH); 5.05 (dd, 2H, CH 2 v. Z); 4.08 (m, 1 H, HC (α)); 3.32 (m, 2H, NHCH 2 CH 2 ); 2.82 (t, 2H, NHCH 2 C H 2 ); 2.77 / 2.65 (2xm, 2H, β-CH 2 ); 2.26 (m, 1 H, SH).

FAB-MS: m/z = 398.2 [M+H+]; Mr= 397.2 C21H23N303S에 대한 계산치FAB-MS: m / z = 398.2 [M + H + ]; M r = 397.2 Calculated for C 21 H 23 N 3 0 3 S

N,N'-비스-헥사노일-L-시스틴-비스-벤질아미드 (20a)N, N'-bis-hexanoyl-L-cystine-bis-benzylamide (20a)

공정 (A) 에 따라서 6b 및 헥산산으로부터 제조함. 수율: 86 %; TLC (용매계: 시클로헥산/클로로포름/아세트산, 45:45:10, Rf=0.6) 상에서 균질함.Prepared from 6b and hexanoic acid according to process (A). Yield: 86%; Homogeneous on TLC (solvent system: cyclohexane / chloroform / acetic acid, 45:45:10, R f = 0.6).

1H-NMR (d6-DMSO): 8.48 (t, 1H, NH, 아미드); 8.02 (d, 1H, NH ureth.); 7.3-7.2 (m, 5H, 방향족 H 들); 4.41 (m, 1H, H-Cα); 4.28 (d, 2H, CH2-Bn); 2.80/2.70 (2xm, 2H, β- CH2); 2.25 (t, 1H, SH); 2.17 (m, 2H, -CH2-CO-); 1.49-1.21 (m, 10H, 알킬), 0.87 (t, 3H, -CH3). 1 H-NMR (d 6 -DMSO): 8.48 (t, 1H, NH, amide); 8.02 (d, 1 H, NH ureth.); 7.3-7.2 (m, 5H, aromatic Hs); 4.41 (m, 1 H, HC α ); 4.28 (d, 2H, CH 2 -Bn); 2.80 / 2.70 (2xm, 2H, β- CH 2); 2.25 (t, 1 H, SH); 2.17 (m, 2H, -CH 2 -CO-); 1.49-1.21 (m, 10H, alkyl), 0.87 (t, 3H, -CH 3 ).

N-헥사노일-L-시스테인-벤질아미드 (20)N-hexanoyl-L-cysteine-benzylamide (20)

공정 (B) 에 따라서 20a 를 환원함. 수율: 69 %; 융점 141-143℃;20a is reduced in accordance with step (B). Yield: 69%; Melting point 141-143 ° C;

1H-NMR (d6-DMSO): 8.48 (t, 1H, NH, 아미드); 8.02 (d, 1H, NH ureth.); 7.31-7.2 (m, 5H, 방향족 H 들); 4.40 (m, 1H, H-Cα); 4.22 (d, 2H, CH2-Bn); 2.80/2.70 (2xm, 2H, β- CH2); 2.3 (bs, 1H, SH); 2.12 (m, 2H, -CH2-CO-); 1.50-1.19 (m, 6H, 알킬), 0.85 (t, 3H, -CH3). 1 H-NMR (d 6 -DMSO): 8.48 (t, 1H, NH, amide); 8.02 (d, 1 H, NH ureth.); 7.31-7.2 (m, 5H, aromatic Hs); 4.40 (m, 1 H, HC α ); 4.22 (d, 2H, CH 2 -Bn); 2.80 / 2.70 (2xm, 2H, β-CH 2 ); 2.3 (bs, 1 H, SH); 2.12 (m, 2H, -CH 2 -CO-); 1.50-1.19 (m, 6H, alkyl), 0.85 (t, 3H, -CH 3 ).

FAB-MS: m/z = 309.2 [M+H+]; Mr= 308.2 C16H24N202S에 대한 계산치FAB-MS: m / z = 309.2 [M + H + ]; M r = 308.2 Calcd for C 16 H 24 N 2 0 2 S

N,N'-비스-옥타노일-L-시스틴-비스-벤질아미드 (21a)N, N'-bis-octanoyl-L-cystine-bis-benzylamide (21a)

공정 (A) 에 따라서 6b 및 옥탄산으로부터 제조함. 수율: 86 %; TLC (용매계: 시클로헥산/클로로포름/아세트산, 45:45:10, Rf=0.6) 상에서 균질함.Prepared from 6b and octanoic acid according to process (A). Yield: 86%; Homogeneous on TLC (solvent system: cyclohexane / chloroform / acetic acid, 45:45:10, R f = 0.6).

N-옥타노일-시스테인-벤질아미드 (21)N-octanoyl-cysteine-benzylamide (21)

공정 (B) 에 따라서 21a 를 환원함. 수율: 73 %; 융점 137-139℃;21a is reduced according to step (B). Yield: 73%; Melting point 137-139 ° C .;

1H-NMR (d6-DMSO): 8.48 (t, 1H, NH, 아미드); 8.02 (d, 1H, NH ureth.); 7.3-7.2 (m, 5H, 방향족 H 들); 4.41 (m, 1H, H-Cα); 4.28 (d, 2H, CH2-Bn); 2.80/2.70 (2xm, 2H, β- CH2); 2.25 (bs, 1H, SH); 2.17 (m, 2H, -CH2-CO-); 1.49-1.21 (m, 10H, 알킬), 0.87 (t, 3H, -CH3). 1 H-NMR (d 6 -DMSO): 8.48 (t, 1H, NH, amide); 8.02 (d, 1 H, NH ureth.); 7.3-7.2 (m, 5H, aromatic Hs); 4.41 (m, 1 H, HC α ); 4.28 (d, 2H, CH 2 -Bn); 2.80 / 2.70 (2xm, 2H, β-CH 2 ); 2.25 (bs, 1 H, SH); 2.17 (m, 2H, -CH 2 -CO-); 1.49-1.21 (m, 10H, alkyl), 0.87 (t, 3H, -CH 3 ).

FAB-MS: m/z = 337.2 [M+H+]; Mr= 336.2 C18H28N202S에 대한 계산치FAB-MS: m / z = 337.2 [M + H + ]; M r = 336.2 Calculated for C 18 H 28 N 2 0 2 S

N,N'-비스-데카노일-L-시스틴-비스-벤질아미드 (22a)N, N'-bis-decanoyl-L-cystine-bis-benzylamide (22a)

공정 (A) 에 따라서 6b 및 데칸산으로부터 제조함. 수율: 정량; TLC (용매계: 시클로헥산/클로로포름/아세트산, 45:45:10, Rf=0.9) 상에서 균질함.Prepared from 6b and decanoic acid according to process (A). Yield: quantitation; Homogeneous on TLC (solvent system: cyclohexane / chloroform / acetic acid, 45:45:10, R f = 0.9).

N-데카노일-시스테인-벤질아미드 (22)N-Decanoyl-Cysteine-Benzylamide (22)

공정 (B) 에 따라서 22a 를 환원함. 수율: 33 %; 융점 138-140℃;22a is reduced in accordance with step (B). Yield: 33%; Melting point 138-140 ° C .;

1H-NMR (d6-DMSO): 8.46 (t, 1H, NH, 아미드); 8.02 (d, 1H, NH ureth.); 7.3-7.2 (m, 5H, 방향족 H 들); 4.4 (m, 1H, H-Cα); 4.29 (d, 2H, CH2-Bn); 2.80/2.70 (2xm, 2H, β- CH2); 2.25 (t, 1H, SH); 2.18 (m, 2H, -CH2-CO-); 1.49-1.19 (m, 14H, 알킬), 0.85 (t, 3H, -CH3). 1 H-NMR (d 6 -DMSO): 8.46 (t, 1H, NH, amide); 8.02 (d, 1 H, NH ureth.); 7.3-7.2 (m, 5H, aromatic Hs); 4.4 (m, 1 H, HC α ); 4.29 (d, 2H, CH 2 -Bn); 2.80 / 2.70 (2xm, 2H, β-CH 2 ); 2.25 (t, 1 H, SH); 2.18 (m, 2H, -CH 2 -CO-); 1.49-1.19 (m, 14H, alkyl), 0.85 (t, 3H, -CH 3 ).

FAB-MS: m/z = 365.2 [M+H+]; Mr= 364.2 C20H32N202S에 대한 계산치FAB-MS: m / z = 365.2 [M + H + ]; M r = 364.2 Calculated for C 20 H 32 N 2 0 2 S

1. Beckett. R.P.; Davidson. A.H.; Drummond. A.H.; Huxiey. P.; Whittaker. M. Drug Disc. Today 1996Beckett. R.P .; Davidson. A.H .; Drummond. A.H .; Huxiey. P .; Whittaker. M. Drug Disc. Today 1996

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Claims (5)

매트릭스 메탈로프로테이나제 (MMP) 에 결합하고 저해하며, 시스테인 부위가 보호되지 않은 티올기를 함유하고, 시스테인 부위가 L- 또는 D- 배향인 것을 특징으로 하는 하기 화학식 I 로 나타내어지는 화합물 :A compound represented by the following formula (I), which binds to and inhibits matrix metalloproteinases (MMP), the cysteine moiety contains an unprotected thiol group, and the cysteine moiety is in the L- or D- orientation: [화학식 I][Formula I] [상기 식중,[In the above meal, A 는 -CO-, -SO2-, -NH-CO- 또는 -O-CO- 를 나타내고,A represents -CO-, -SO 2- , -NH-CO- or -O-CO-, R1은 수소, 직쇄 또는 분지쇄, 포화 또는 불포화 C1-15알킬기, 또는 할로겐, 메르캅토, 히드록시, 알콕시, 아미노 또는 니트로, 또는 한번 또는 수번 임의 치환된 카르보시클릭 비방향족 또는 방향족 고리 시스템으로 치환된 C1-15알킬기, 또는 임의 치환된 방향족 또는 비방향족 헤테로사이클, 이들의 약학적 허용 가능 염 또는 이의 광학 활성 형태이며,R 1 is hydrogen, a straight or branched chain, saturated or unsaturated C 1-15 alkyl group, or halogen, mercapto, hydroxy, alkoxy, amino or nitro, or a carbocyclic non-aromatic or aromatic ring system optionally substituted once or several times A C 1-15 alkyl group substituted with an optionally substituted aromatic or non-aromatic heterocycle, a pharmaceutically acceptable salt thereof, or an optically active form thereof, R 은 히드록시, 직쇄 또는 분지쇄, 포화 또는 불포화 C1-15알킬기 또는 한번 또는 수번 임의 치환된 카르보시클릭 비방향족 또는 방향족 고리 시스템, 또는 임의로 치환된 방향족 또는 비방향족 헤테로사이클, 이들의 약학적 허용 가능 염 또는 이의 광학 활성 형태이다].R is a hydroxy, straight or branched chain, saturated or unsaturated C 1-15 alkyl group or one or several optionally substituted carbocyclic non-aromatic or aromatic ring systems, or optionally substituted aromatic or non-aromatic heterocycle, pharmaceuticals thereof Acceptable salts or optically active forms thereof. 제 1 항 기재의 화합물, 또는 약학적 허용 가능 염, 또는 이의 광학 활성 형태 및 약학적 허용 가능 담체를 함유한 약학적 조성물.A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt, or an optically active form thereof, and a pharmaceutically acceptable carrier. 제 2 항에 있어서, 류마티스성 관절염 및 교원 분해 (collagenolytic) 활성이 기여 인자인 관련 질병의 치료를 위한 치료용 조성물.The therapeutic composition according to claim 2, wherein the rheumatoid arthritis and collagenolytic activity are contributing factors. 치료제의 투여량이 체중 1 kg 에 대해 0.1 내지 300 mg 인 것을 특징으로 하는 제 3 항의 화합물의 용도.Use of the compound of claim 3, wherein the dosage of the therapeutic agent is 0.1 to 300 mg per 1 kg of body weight. 제 3 항 또는 제 4 항에 있어서, 치료제가 구강, 혈관내, 복막조직내, 피하, 근육내 또는 국소 투여되는 것을 특징으로 하는 용도.Use according to claim 3 or 4, characterized in that the therapeutic agent is administered orally, intravascularly, intraperitoneally, subcutaneously, intramuscularly or topically.
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