公开(公告)号：KR101109122B1

公开(公告)日：2012-06-12

申请号：KR1020090105096

申请日：2009-11-02

Applicant: 한국화학연구원

Inventor： 정희정 ,  이철해 ,  김재학 ,  정원장 ,  김비치 ,  박선필

IPC: C07C239/14 ,  C07C231/14 ,  A61K31/165 ,  A61P35/00

Abstract: PURPOSE: A 6-amido-n-hydroxyhexanamide compound is provided to selectively induce the terminal differentiation of tumor cell by effectively inhibiting enzyme activity of histone deacetylase, and to inhibit the proliferation of tumor cell. CONSTITUTION: A compound is selected from a 6-amido-n-hydroxyhexanamide compound represented by chemical formula 1 and pharmaceutically acceptable salts thereof. In chemical formula 1, X is selected from a single bond or the group of C1-6 alkylenyl; R is amino, C1-6 alkylamino, di(C1-6 alkyl)amino, 5-9-membered aryl, 5-9-membered aryl C1-6 alkyl, 5-9-membered aryl C1-6 alkyloxy, 5-9-membered heteroaryl including 1-3 hetero atoms selected from N and O, and 5-7-membered heterocycloalkyl including 1-3 hetero atoms selected from N and O.

公开(公告)号：KR100814098B1

公开(公告)日：2008-03-14

申请号：KR1020060108228

申请日：2006-11-03

Applicant: 한국화학연구원 ,  크리스탈지노믹스(주)

Inventor： 이철해 ,  정희정 ,  김재학 ,  정원장 ,  조중명 ,  노성구 ,  현영란 ,  이철순

IPC: C07C237/16 ,  C07C237/14 ,  C07C233/19

Abstract: An alkylcarbamoyl naphthalenyloxy methyloct N-hydroxyenamide derivative, its pharmaceutically acceptable salt, a method for preparing the derivative, and an anticancer pharmaceutical composition containing the derivative are provided to inhibit the enzymatic activity of histone deacetylase effectively and the proliferation of tumor cells. An alkylcarbamoyl naphthalenyloxy methyloct N-hydroxyenamide derivative is represented by the formula 1, wherein R1 is a C1-C3 alkyl group substituted or unsubstituted with at least one substituent selected from the group consisting of a C1-C3 alkyl group, a C1-C3 alkoxy group, a hydroxy C1-C3 alkyl group, a halophenyl group, a piperidinyl group, a morpholinyl group, a cyanomethyl group, a piperazinyl group, a di-C1-C3 alkylamino group, a di-C1-C3 alkylamino C1-C3 alkyl group, a piperidinyl C1-C3 alkyl group, a C1-C3 alkoxy C1-C3 alkyl group, a morpholino C1-C3 alkyl group, a piperazino C1-C3 alkyl group, a pyrrolidinyl group, an oxopyrrolidinyl group, a C1-C3 alkylpyrrolidinyl group, an imidazole group, an imidazolyl C1-C3 alkyl group and a thiophenyl group.

Abstract translation: 提供烷基氨基甲酰基萘氧基甲基N-羟基酰胺衍生物，其药学上可接受的盐，制备该衍生物的方法和含有该衍生物的抗癌药物组合物，以有效抑制组蛋白脱乙酰酶的酶活性和肿瘤细胞的增殖。 烷基氨基甲酰基萘氧基甲基N-羟基酰胺衍生物由式1表示，其中R 1是被至少一个选自C 1 -C 3烷基，C 1 -C 3烷氧基的取代基取代或未取代的C 1 -C 3烷基 基团，羟基C 1 -C 3烷基，卤代苯基，哌啶基，吗啉基，氰基甲基，哌嗪基，二-C 1 -C 3烷基氨基，二-C 1 -C 3烷基氨基C 1 -C 3烷基 基团，哌啶基C1-C3烷基，C1-C3烷氧基C1-C3烷基，吗啉代C1-C3烷基，哌嗪基C1-C3烷基，吡咯烷基，氧代吡咯烷基，C1-C3烷基吡咯烷基 基团，咪唑基，咪唑基C1-C3烷基和噻吩基。

公开(公告)号：KR100718493B1

公开(公告)日：2007-05-16

申请号：KR1020050103689

申请日：2005-11-01

Applicant: 한국화학연구원 ,  크리스탈지노믹스(주)

Inventor： 이철해 ,  정희정 ,  김재학 ,  정원장 ,  조중명 ,  노성구 ,  이태규 ,  현영란

IPC: C07D295/155 ,  C07D295/112 ,  A61P35/00

Abstract: 본 발명은 하기
화학식 1 의 알킬아미노 나프탈렌일옥시메틸 프로페닐 하이드록시벤즈아마이드 유도체(alkylamino naphthalenyloxymethyl propenyl hydroxybenzamide derivatives), 이의 제조방법 및 이를 유효성분으로 하는 항암제용 약학 조성물에 관한 것으로, 본 발명의 알킬아미노 나프탈렌일옥시메틸 프로페닐 하이드록시벤즈아마이드 유도체는 히스톤 디아세틸라제(histone deacetylase)의 효소활성을 효과적으로 저해하여 종양세포의 증식을 억제하는데 유용하게 사용될 수 있다.


상기 식에서,
R
1 은 수소 또는 메틸이고;
R
2 는 각각 독립적으로 C
1-2 알킬, 하이드록시C
1-2 알킬, 할로C
1-2 알킬, 피페리디닐, 몰포리닐, 사이아노메틸, 피페라지닐, 다이C
1-2 알킬아미노C
1-3 알킬, 피페리디닐C
1-2 알킬, 몰포리노C
1-2 알킬 및 피페라지노C
1-2 알킬로 구성된 군으로부터 선택된 하나 이상의 치환체로 치환되거나 치환되지 않은 C
1
-
2 알킬이거나;
R
1 및 R
2 는 서로 연결되어 그들이 부착된 질소 원자와 함께 몰포리닐, 피페리디닐 또는 피페라지닐 고리를 형성한다.

公开(公告)号：KR100696139B1

公开(公告)日：2007-03-20

申请号：KR1020050103693

申请日：2005-11-01

Applicant: 한국화학연구원 ,  크리스탈지노믹스(주)

Inventor： 이철해 ,  정희정 ,  김재학 ,  정원장 ,  조중명 ,  노성구 ,  이태규 ,  신동규

IPC: C07C237/32

CPC classification number: C07C259/06 ,  C07C2601/14 ,  C07C2601/16 ,  C07D207/12 ,  C07D207/14 ,  C07D211/58 ,  C07D213/75 ,  C07D233/54 ,  C07D233/61 ,  C07D295/185 ,  C07D307/66 ,  C07D333/20

Abstract: Provided are an alkylcarbamoyl naphthalenyloxyoctenoylhydroxyamide derivative which inhibits the enzymatic activity of histone diacetylase effectively, its preparation method, and an antitumor pharmaceutical composition containing the derivative. The alkylcarbamoyl naphthalenyloxyoctenoylhydroxyamide derivative is represented by the formula 1, wherein R1 is independently a C1-C2 alkyl group substituted or unsubstituted with at least one substituent selected from the group consisting of a C1-C3 alkyl group, a hydroxyalkyl group of C1-C2, a haloalkyl group of C1-C2, a piperidinyl group, a morpholinyl group, a cyanomethyl group, a piperazinyl group, a di(C1-C2)alkylamino(C1-C2)alkyl group, a piperidinyl(C1-C2)alkyl group, a morpholinyl(C1-C2)alkyl group, a piperazino(C1-C2)alkyl group, a pyrrolidinyl group and a (C1-C2)alkylpyrrolidinyl group; and R2 is H or a methyl group.

Abstract translation: 提供了有效抑制组蛋白二乙酰化酶的酶活性的烷基氨基甲酰基萘氧基辛酰基羟基酰胺衍生物，其制备方法和含有该衍生物的抗肿瘤药物组合物。 烷基氨基甲酰基萘氧基辛烯酰羟基酰胺衍生物由式1表示，其中R1独立地为被至少一个选自C1-C3烷基，C1-C2羟烷基，C1-C2烷基， C1-C2的卤代烷基，哌啶基，吗啉基，氰基甲基，哌嗪基，二（C1-C2）烷基氨基（C1-C2）烷基，哌啶基（C1-C2）烷基， 吗啉基（C1-C2）烷基，哌嗪基（C1-C2）烷基，吡咯烷基和（C1-C2）烷基吡咯烷基; R2为H或甲基。

公开(公告)号：KR100523986B1

公开(公告)日：2005-10-26

申请号：KR1020030009843

申请日：2003-02-17

Applicant: 한국화학연구원

Inventor： 김봉진 ,  이철해 ,  정희정 ,  김재학

IPC: C07D417/14

CPC classification number: Y02P20/55

Abstract: 본 발명은 메티실린 내성 포도상 구균(Methicillin Resistant
Staphylococcus Aureus , MRSA)을 비롯한 내성균에 대해 항생작용을 갖는 하기 화학식 1의 카바페넴 유도체, 이의 제조방법 및 이를 함유하는 항생제 조성물에 관한 것으로, 본 발명의 카바페넴 유도체는 항균효과가 매우 우수하여 MRSA 및 오플록사신 내성균주(QRSA)를 비롯한 난치성 내성균의 감염에 대한 항생제로서 유용하게 사용될 수 있다.

상기 식에서,
X는 황 또는 질소 원자를 나타내고;
Y는 페닐기의 특정한 위치에 존재하는, 수소, 니트로기 또는 아민기를 나타내며;
M은 수소 원자 또는 약리학적으로 허용가능한 염을 형성하는 짝이온을 나타낸다.

公开(公告)号：KR100519010B1

公开(公告)日：2005-10-06

申请号：KR1020030070835

申请日：2003-10-11

Applicant: 한국화학연구원 ,  크리스탈지노믹스(주)

Inventor： 이철해 ,  김봉진 ,  정희정 ,  김재학 ,  전미애 ,  황선균 ,  성태현 ,  조중명 ,  노성구 ,  이태규 ,  현영란 ,  신동규

IPC: C07C239/14

Abstract: 본 발명은 하기 화학식 1의 벤즈히드록시아미드 유도체, 이의 제조방법 및 이를 함유하는 항암 조성물에 관한 것으로, 본 발명의 벤즈히드록시아미드 유도체는 히스톤 디아세틸라제의 효소활성을 효과적으로 억제하여 종양세포의 증식을 억제할 수 있다.

상기 식에서,
R
1 및 R
2 는 각각 독립적으로 히드록시, 할로겐, 알킬옥시, 알킬, 아미노, 알킬아미노, 카르복실 및 니트로로 이루어진 군으로부터 선택된 하나 이상의 치환체로 치환되거나 치환되지 않은, 아릴 또는 헤테로아릴이고, 이때 상기 헤테로아릴은 고리 중에 질소 또는 산소를 하나 이상 포함한다.

公开(公告)号：KR1020040085384A

公开(公告)日：2004-10-08

申请号：KR1020030020049

申请日：2003-03-31

Applicant: 한국화학연구원

Inventor： 김봉진 ,  이철해 ,  김재학 ,  정희정 ,  전미애 ,  공재양

IPC: C07D477/20

CPC classification number: Y02P20/55

Abstract: PURPOSE: Arylcarbonylazetidine-substituted carbapenem derivatives with anti-bacterial activity against resistant strains and a preparation method thereof are provided, which carbapenem derivatives have improved anti-bacterial activity against resistant strains such as methicillin resistant Staphylococcus aureus(MRSA) and ofloxacin resistant Staphylococcus aureus(QRSA). CONSTITUTION: The arylcarbonylazetidine-substituted carbapenem derivatives represented by formula (1) or pharmaceutically acceptable salts thereof are provided, wherein n is 0 or 1; Ar is aromatics or aromatics of which ring contains nitrogen which are optionally substituted with halogen, hydroxy or lower alkyloxy; and M is hydrogen or pair ion forming pharmaceutically acceptable salts. The method for preparing the arylcarbonylazetidine-substituted carbapenem derivatives of formula (1) comprises the steps of: (i) heating 3-(tert-butyldimethylsilyloxy) azetidin of formula (5) and arylcarbonylchloride of formula (6) in the presence of organic base in organic solvent to prepare acylated compound of formula (7); (ii) adding 4N hydrochloric acid into the acylated compound of formula (7) in methyl alcohol solvent and stirring the mixture at 0 to 5 deg. C for 1 to 3 hours to prepare tert-butylsilyl removed compound of formula (8); (iii) reacting the compound of formula (8) with triphenylphosphine and diethylazodicarboxylic acid or diisopropylazocarboxylic acid at -5 to 5 deg. C for 30 minutes to 2 hours, and adding thio acetic acid into the reacting compound and reacting them at room temperature for 1 to 3 hours to prepare a compound of formula (9); (vi) reacting the compound of formula (9) with base to prepare a compound of formula (3); reacting the compound of formula (3) with a compound of formula (2) to prepare carbapenem ester derivatives of formula (4); and removing carboxy protecting group and optional carboxyl protecting group from the compound of formula (4), wherein R1 is hydrogen, or hydroxy protecting group such as tert-butylmethylsilyl or triethylsilyl; and R2 is carboxyl protecting group such as p-nitrobenzyl, allyl or p-methoxybenzyl.

Abstract translation: 目的：提供对抗性菌株具有抗菌活性的芳基羰基氮杂环丁烷取代的碳青霉烯衍生物及其制备方法，其中碳青霉烯衍生物具有改善抗耐药菌株如耐甲氧西林金黄色葡萄球菌（MRSA）和耐氧沙星金黄色葡萄球菌（Staphylococcus aureus） QRSA）。 构成：提供由式（1）表示的芳基羰基氮杂环丁烷取代的碳青霉烯衍生物或其药学上可接受的盐，其中n为0或1; Ar是芳族化合物或芳族化合物，其中环含有任选被卤素，羟基或低级烷氧基取代的氮; 并且M是氢或成对离子形成药学上可接受的盐。 制备式（1）的芳基羰基氮杂环丁烷取代的碳青霉烯衍生物的方法包括以下步骤：（i）在有机碱的存在下加热式（5）的3-（叔丁基二甲基甲硅烷氧基）氮杂环丁烷和式（6）的芳基羰基氯 在有机溶剂中制备式（7）的酰化化合物; （ii）在甲醇溶剂中将4N盐酸加入式（7）的酰化化合物中，并在0至5℃搅拌该混合物。 C制备1至3小时以制备叔丁基甲硅烷基除去的式（8）化合物; （iii）使式（8）的化合物与三苯基膦和二乙基偶氮二羧酸或二异丙基偶氮羧酸在-5至5℃反应。 30分钟至2小时，并向反应化合物中加入硫代乙酸，并在室温下反应1至3小时以制备式（9）化合物; （vi）使式（9）的化合物与碱反应以制备式（3）的化合物; 使式（3）的化合物与式（2）的化合物反应制备式（4）的碳青霉烯衍生物; 并从式（4）化合物中除去羧基保护基和任选的羧基保护基，其中R 1是氢，或羟基保护基如叔丁基甲基甲硅烷基或三乙基甲硅烷基; R2为羧基保护基，如对硝基苄基，烯丙基或对甲氧基苄基。

公开(公告)号：KR100441901B1

公开(公告)日：2004-07-27

申请号：KR1020010039222

申请日：2001-07-02

Applicant: 한국화학연구원 ,  일동홀딩스(주)

Inventor： 이철해 ,  김봉진 ,  강재훈 ,  편도규 ,  김재학 ,  정희정 ,  전미애 ,  정원장 ,  권지웅 ,  박용엽 ,  김기원

IPC: C07D501/57

Abstract: PURPOSE: Provided is an improved process for the preparation of cephalosporin derivatives from (cis)-3-acetoxypropen-cephalosporinic acid in higher yield. CONSTITUTION: The improved process for the preparation of cephalosporin derivative of the formula(1) comprises the steps of: radical reaction of a compound of the formula(5) with benzenthiol and azobisisobutyronitrile as a radical initiator in an organic solvent to convert it into a trans form; continuous reaction of the reaction product with a compound of the formula(10) to obtain a compound of the formula(3); and reaction of the compound of the formula(3) with an acylated compound of the formula(8) and a silylated compound of the formula(9).

Abstract translation: 目的：提供一种由（顺式）-3-乙酰氧基丙烯酸头孢菌素酸以较高产率制备头孢菌素衍生物的改进方法。 构成：制备式（1）头孢菌素衍生物的改进方法包括以下步骤：将式（5）化合物与苯硫醇和偶氮二异丁腈作为自由基引发剂在有机溶剂中进行自由基反应，将其转化为 转变; 使反应产物与式（10）化合物连续反应，得到式（3）化合物; 和式（3）化合物与式（8）酰化化合物和式（9）甲硅烷基化化合物的反应。

公开(公告)号：KR1020030002925A

公开(公告)日：2003-01-09

申请号：KR1020010039222

申请日：2001-07-02

Applicant: 한국화학연구원 ,  일동홀딩스(주)

Inventor： 이철해 ,  김봉진 ,  강재훈 ,  편도규 ,  김재학 ,  정희정 ,  전미애 ,  정원장 ,  권지웅 ,  박용엽 ,  김기원

IPC: C07D501/57

Abstract: PURPOSE: Provided is an improved process for the preparation of cephalosporin derivatives from (cis)-3-acetoxypropen-cephalosporinic acid in higher yield. CONSTITUTION: The improved process for the preparation of cephalosporin derivative of the formula(1) comprises the steps of: radical reaction of a compound of the formula(5) with benzenthiol and azobisisobutyronitrile as a radical initiator in an organic solvent to convert it into a trans form; continuous reaction of the reaction product with a compound of the formula(10) to obtain a compound of the formula(3); and reaction of the compound of the formula(3) with an acylated compound of the formula(8) and a silylated compound of the formula(9).

Abstract translation: 目的：提供从（顺式）-3-乙酰氧基丙基 - 头孢菌酸制备头孢菌素衍生物的较高产率的改进方法。 构成：制备式（1）的头孢菌素衍生物的改进方法包括以下步骤：将式（5）化合物与苯并二酚和偶氮二异丁腈作为自由基引发剂在有机溶剂中进行自由基反应，将其转化为 转变; 反应产物与式（10）化合物的连续反应，得到式（3）化合物; 和式（3）的化合物与式（8）的酰化化合物和式（9）的甲硅烷基化合物的反应。

公开(公告)号：KR1020020079654A

公开(公告)日：2002-10-19

申请号：KR1020020052421

申请日：2002-09-02

Applicant: 동화약품주식회사 ,  한국화학연구원

Inventor： 이철해 ,  김봉진 ,  정원장 ,  김재학 ,  정희정 ,  김은정 ,  송신섭 ,  정용호 ,  곽현정 ,  이진수 ,  편도규

IPC: C07D265/22

Abstract: PURPOSE: Provided are azetidinone compound of the formula(I) as an intermediate useful for the manufacture of carbapenem antibiotics and a process for the preparation thereof. CONSTITUTION: The azetidine compound is represented by the formula(I). It is useful as an intermediate for the manufacture of beta-methylcarbapenem antibiotics and manufactured by reacting 4-acetoxy-azetidine compound of the formula(II) and alpha-halo propionic acid amide compound of the formula(III).

Abstract translation: 目的：提供式（I）的氮杂环丁酮化合物作为制备碳青霉烯类抗生素的中间体及其制备方法。 构成：氮杂环丁烷化合物由式（I）表示。 通过使式（II）的4-乙酰氧基 - 氮杂环丁烷化合物与式（III）的α-卤代丙酸酰胺化合物反应制备β-甲基碳青霉烯类抗生素的中间体是有用的。