公开(公告)号：KR100508627B1

公开(公告)日：2005-08-17

申请号：KR1020020015016

申请日：2002-03-20

Applicant: (주)케비젠

Inventor： 신홍식 ,  엄수종 ,  노영쇠 ,  박시호 ,  권윤자 ,  박명순 ,  한혜숙 ,  김소미 ,  김동명 ,  오덕근 ,  박종섭 ,  배태성

IPC: C07C235/78

Abstract: 본 발명은 화학식1로 표시되는 신규한 레티노이드 유도체 화합물 또는 이의 약제학적으로 허용되는 염에 관한 것이다:
화학식 1

상기식에서, X, R
1 , R
2 및 R
3 은 본원에 정의한 바와 같다. 또한, 본 발명은 상기 레티노이드 유도체 화합물의 제조 방법 및 그러한 화합물을 함유하는 항암제 조성물에 관한 것이다. 본 발명에 따른 화학식1의 화합물은 고도의 항암 활성을 나타내면서 유해한 부작용을 유발하지 않는다.

公开(公告)号：KR100424251B1

公开(公告)日：2004-03-22

申请号：KR1020010025012

申请日：2001-05-08

Applicant: (주)케비젠 ,  신홍식

Inventor： 신홍식 ,  박명순 ,  노영쇠 ,  권윤자 ,  박시호 ,  엄수종 ,  장판식 ,  조성동

IPC: C07C227/18

Abstract: PURPOSE: A novel method for preparing α-L-aspartyl-L-phenylalanine methyl ester·HCl salt is provided, to reduce the amount of by-products, to allow the by-products to be reused after hydrolysis and to increase the production yield by 20% or more. CONSTITUTION: The method comprises the steps of reacting L-aspartic acid with trimethyl silyl chloride in the presence of an alcohol solvent to esterify the β-COOH selectively to obtain α-L-aspartyl-L-phenylalanine methyl ester·HCl. Preferably the alcohol solvent is selected from the group consisting of methyl alcohol, ethyl alcohol, allyl alcohol and benzyl alcohol. Preferably the method comprises further the steps of protecting an amine group with -CHO, Boc, benzyloxycarbonyl group, or -C(O)OR¬2 (R2 is methyl. ethyl or isobutyl group) by using acetic anhydride and formic acid.

Abstract translation: 目的：提供一种制备α-L-天冬氨酰-L-苯丙氨酸甲酯盐酸盐的新方法，以减少副产物的量，使副产物在水解后重新使用和 将产量提高20％以上。 构成：该方法包括以下步骤：在醇溶剂存在下使L-天冬氨酸与三甲基甲硅烷基氯化物反应以选择性酯化β-COOH以获得α-L-天冬氨酰-L-苯丙氨酸甲酯和amp ; middot; HCl中。 优选醇溶剂选自甲醇，乙醇，烯丙醇和苯甲醇。 优选地，该方法还包括通过使用乙酸酐和甲酸，用-CHO，Boc，苄氧基羰基或-C（O）OR 2（R 2为甲基，乙基或异丁基）保护胺基的步骤。

公开(公告)号：KR100822757B1

公开(公告)日：2008-04-17

申请号：KR1020020052026

申请日：2002-08-30

Applicant: (주)케비젠

Inventor： 신홍식 ,  엄수종 ,  권윤자 ,  한혜숙 ,  박시호 ,  박명순 ,  백대헌

IPC: C07C403/20

Abstract: 본 발명은 화학식(I)로 표시되는 신규한 시스 형태의 레티노이드 유도체 화합물 또는 이의 약제학적으로 허용되는 염에 관한 것이다:

(I)

상기식에서, X, R
1 , R
2 및 R
3 은 본원에 정의한 바와 같다. 또한, 본 발명은 상기 레티노이드 유도체 화합물의 제조 방법 및 그러한 화합물을 함유하는 항암제 조성물에 관한 것이다. 본 발명에 따른 화학식(I)의 화합물은 고도의 항암 활성을 나타내면서 유해한 부작용을 유발하지 않는다.
항암제, 레티노이드 유도체, 아폽토시스

公开(公告)号：KR1020020090850A

公开(公告)日：2002-12-05

申请号：KR1020020015016

申请日：2002-03-20

Applicant: (주)케비젠

Inventor： 신홍식 ,  엄수종 ,  노영쇠 ,  박시호 ,  권윤자 ,  박명순 ,  한혜숙 ,  김소미 ,  김동명 ,  오덕근 ,  박종섭 ,  배태성

IPC: C07C235/78

Abstract: PURPOSE: A novel retinoid derivative, its preparation method, a compound used for preparing the derivative, and an anticancer medicine composition containing the derivative are provided, which retinoid derivative shows the excellent anticancer activity and no toxic side effect. CONSTITUTION: The retinoid derivative is represented by the formula I, wherein R¬1 and R¬2 are independent each other and are OH, SH, NH2, COOH, -R(CH2)mCH3, -RCOCO(CH2)mCH3, -RCO(CH2)mCHCH3CH3, or -RCOCH(NCOCH3)CH2CH2CONH2, and R¬3 is H; R¬1 and R¬3 are independent each other and are OH, SH, NH2, COOH, -R(CH2)mCH3, -RCOCO(CH2)mCH3, or -RCOCH(NCOCH3)CH2CH2CONH2, and R¬2 is H; R¬1 is OH, SH, NH2, COOH, -R(CH2)mCH3, R¬2 is H, and R¬3 is H, OH or Cl; R¬3 is OH, SH, NH2, COOH, -R(CH2)mCH3, or -RCOCH(NCOCH3)CH2CH2CONH2, R¬2 is H, and R¬1 is H, OH or Cl; or R¬1, R¬2 and R¬3 are independent each another and are OH, SH, NH2, COOH, -R(CH2)mCH3, or -RCOCH(NCOCH3)CH2CH2CONH2; and R is CH2, O, NH or S, R¬4 is H or an alkyl group of C1-C6, and m is an integer of 0-5.

Abstract translation: 目的：提供一种新型类视黄醇衍生物及其制备方法，用于制备衍生物的化合物和含有该衍生物的抗癌药物组合物，其视黄酸衍生物显示出优异的抗癌活性，无毒副作用。 构型：类视黄醇衍生物由式I表示，其中R 1和R 2彼此独立，为OH，SH，NH 2，COOH，-R（CH 2）m CH 3，-RCOCO（CH 2）m CH 3，-RCO （CH 2）m CHCH 3 CH 3或-RCOCH（NCOCH 3）CH 2 CH 2 CONH 2，R 3 3是H; R 1和R 3彼此独立地是OH，SH，NH 2，COOH，-R（CH 2）mCH 3，-OCOO（CH 2）mCH 3或-RCOCH（NCOCH 3）CH 2 CH 2 CONH 2，R 12是H; R 1是OH，SH，NH 2，COOH，-R（CH 2）mCH 3，R 2是H，R 3是H，OH或Cl; R 3是OH，SH，NH 2，COOH，-R（CH 2）m CH 3或-RCOCH（NCOCH 3）CH 2 CH 2 CONH 2，R 2是H，R 1是H，OH或Cl; 或R 1，R 2和R 3彼此独立，并且是OH，SH，NH 2，COOH，-R（CH 2）mCH 3或-RCOCH（NCOCH 3）CH 2 CH 2 CONH 2; 且R为CH 2，O，NH或S，R 4为H或C 1 -C 6烷基，m为0-5的整数。

公开(公告)号：KR1020020085491A

公开(公告)日：2002-11-16

申请号：KR1020010025012

申请日：2001-05-08

Applicant: (주)케비젠 ,  신홍식

Inventor： 신홍식 ,  박명순 ,  노영쇠 ,  권윤자 ,  박시호 ,  엄수종 ,  장판식 ,  조성동

IPC: C07C227/18

Abstract: PURPOSE: A novel method for preparing α-L-aspartyl-L-phenylalanine methyl ester·HCl salt is provided, to reduce the amount of by-products, to allow the by-products to be reused after hydrolysis and to increase the production yield by 20% or more. CONSTITUTION: The method comprises the steps of reacting L-aspartic acid with trimethyl silyl chloride in the presence of an alcohol solvent to esterify the β-COOH selectively to obtain α-L-aspartyl-L-phenylalanine methyl ester·HCl. Preferably the alcohol solvent is selected from the group consisting of methyl alcohol, ethyl alcohol, allyl alcohol and benzyl alcohol. Preferably the method comprises further the steps of protecting an amine group with -CHO, Boc, benzyloxycarbonyl group, or -C(O)OR¬2 (R2 is methyl. ethyl or isobutyl group) by using acetic anhydride and formic acid.

Abstract translation: 目的：提供一种制备α-L-天冬氨酰-L-苯丙氨酸甲酯·HCl盐的新方法，以减少副产物的含量，使副产物在水解后再次使用，并提高产量 减少20％以上。 方法：该方法包括在醇溶剂存在下使L-天冬氨酸与三甲基甲硅烷基氯反应，选择性地酯化β-COOH，得到α-L-天冬氨酰-L-苯丙氨酸甲酯·HCl。 醇溶剂优选选自甲醇，乙醇，烯丙醇和苄醇。 优选地，所述方法还包括通过使用乙酸酐和甲酸保护具有-CHO，Boc，苄氧基羰基或-C（O）OR 2（R2为甲基，乙基或异丁基）的胺基的步骤。

公开(公告)号：KR100437102B1

公开(公告)日：2004-06-23

申请号：KR1020020001178

申请日：2002-01-09

Applicant: (주)케비젠

Inventor： 신홍식 ,  박시호 ,  노영쇠 ,  엄수종 ,  권윤자 ,  박명순 ,  한혜숙 ,  정민숙 ,  김소미 ,  김동명 ,  오덕근 ,  박종섭

IPC: C07K5/00

Abstract: PURPOSE: Provided are a novel retinol derivative, its preparation method in higher yield, and its use. The novel retinol has excellent light-stability, and shows high reactivity to retinoic acid receptor α, while showing low reactivity to retinoic receptor β and γ. It can applied to medical products, cosmetics, soap, shampoo, functional foods, etc., for the prevention and improvement of skin aging. CONSTITUTION: The novel retinol derivative is characterized by carboester bond of a peptide material having COOH group, wherein the peptide material having COOH group is selected from -di, -tri, -poly peptide including N-L- α-aspartyl-L-phenylalanine 1-methylester(AMP;aspartame), N-protection group-aspartame, neotame and the like. Its manufacturing method comprises the steps of: reacting retinylacetate with methanolic solvent and inorganic slat at 25-40 deg.C in a dark room then extracting the reaction product with ether solvent; removing the solvent then followed by mixing a compound having OH group, natural or separated and purified retinol, diethylazodicarboxylate and triphenylphosphate with methylenechloride solvent, and reacting them at room temperature to obtain the ester derivative of retinol; and performing chromatography with reverse-phase, Merck Silicagel 60 RP 18(40-63) micro meter to separate pure ester derivative of retinol.

Abstract translation: 目的：提供一种新颖的视黄醇衍生物及其制备方法，其收率较高，并且其用途。 该新型视黄醇具有优异的光稳定性，并且对视黄酸受体α具有高反应性，而对视黄酸受体β具有低反应性; 和＆amp; gamma ;. 它可以应用于医疗产品，化妆品，肥皂，洗发水，功能性食品等，以预防和改善皮肤老化。 构成：新颖的视黄醇衍生物的特征在于具有COOH基团的肽材料的羧基酯键，其中具有COOH基团的肽材料选自包括NL-和α-天冬氨酰-L- 苯丙氨酸1-甲酯（AMP;天冬甜素），N-保护基 - 阿斯巴甜，纽甜等。 其制造方法包括以下步骤：在25-40℃，在黑暗的房间内将乙酸视黄醇酯与甲醇溶剂和无机薄片反应，然后用乙醚溶剂萃取反应产物; 然后除去溶剂，然后将具有OH基团的化合物，天然或分离纯化的视黄醇，偶氮二羧酸二乙酯和磷酸三苯酯与二氯甲烷溶剂混合，并在室温下反应，得到视黄醇的酯衍生物; 并用反相色谱（Merck Silicagel 60 RP 18（40-63）微米）进行色谱分离以分离视黄醇的纯酯衍生物。

公开(公告)号：KR1020040020426A

公开(公告)日：2004-03-09

申请号：KR1020020052026

申请日：2002-08-30

Applicant: (주)케비젠

Inventor： 신홍식 ,  엄수종 ,  권윤자 ,  한혜숙 ,  박시호 ,  박명순 ,  백대헌

IPC: C07C403/20

Abstract: PURPOSE: Retinoid derivatives in cis form having substantially different chemical structure while having increased antitumor effects but reduced negative side effects compared with the conventional retinoid compounds, are provided. CONSTITUTION: The retinoid derivatives are represented by formula (I) and can be in cis form especially at the position of 9 and/or 13, wherein X is O, NH or S; R1 and R2 are the same or different, and independently -OH, -SH, -NH2, -COOH, -R(CH2)mCH3, -RCOCO(CH2)mCH3, -RCO(CH2)mCHCH3CH3, -RCO(CH2)mNR4CH3, -RCOCHOH(CH2)mCH3, -RCOCH2(CH2)m(CH)3, -RCOCH2CHOH(CH2)mCH3, -RCOCH2(CH2)mCOOH, -RSO2CH2(CH2)mCH4, -RPO2(OH)CH2(CH2)mCH3 or -RCOCH(NHCOCH3)CH2CH2CONH2; and R3 is H, wherein R is CH2, O, NH or S, R4 is H or C1-C6 alkyl, and m is an integer of 0 to 5.

Abstract translation: 目的：提供具有与常规类视黄醇化合物相比具有显着不同化学结构同时具有增加的抗肿瘤作用但降低的副作用的顺式形式的类视黄醇衍生物。 构成：类视黄醇衍生物由式（I）表示，并且可以是顺式，特别是在9和/或13位，其中X是O，NH或S; R1和R2相同或不同，独立地是-OH，-SH，-NH2，-COOH，-R（CH2）mCH3，-RCOCO（CH2）mCH3，-RCO（CH2）mCHCH3CH3，-RCO（CH2）mNR4CH3 ，-RCOCHOH（CH2）mCH3，-RCOCH2（CH2）m（CH）3，-RCOCH2CHOH（CH2）mCH3，-RCOCH2（CH2）mCOOH，-RSO2CH2（CH2）mCH4，-RPO2（OH）CH2（CH2） 或-RCOCH（NHCOCH 3）CH 2 CH 2 CONH 2; 并且R 3是H，其中R是CH 2，O，NH或S，R 4是H或C 1 -C 6烷基，m是0-5的整数。

公开(公告)号：KR1020020060598A

公开(公告)日：2002-07-18

申请号：KR1020020001178

申请日：2002-01-09

Applicant: (주)케비젠

Inventor： 신홍식 ,  박시호 ,  노영쇠 ,  엄수종 ,  권윤자 ,  박명순 ,  한혜숙 ,  정민숙 ,  김소미 ,  김동명 ,  오덕근 ,  박종섭

IPC: C07K5/00

CPC classification number: C07C403/08 ,  A23L33/155 ,  A61K8/671 ,  A61K31/07 ,  A61Q5/02 ,  A61Q19/005 ,  A61Q19/008 ,  A61Q19/10 ,  C07K5/04 ,  C07K19/00

Abstract: PURPOSE: Provided are a novel retinol derivative, its preparation method in higher yield, and its use. The novel retinol has excellent light-stability, and shows high reactivity to retinoic acid receptor α, while showing low reactivity to retinoic receptor β and γ. It can applied to medical products, cosmetics, soap, shampoo, functional foods, etc., for the prevention and improvement of skin aging. CONSTITUTION: The novel retinol derivative is characterized by carboester bond of a peptide material having COOH group, wherein the peptide material having COOH group is selected from -di, -tri, -poly peptide including N-L- α-aspartyl-L-phenylalanine 1-methylester(AMP;aspartame), N-protection group-aspartame, neotame and the like. Its manufacturing method comprises the steps of: reacting retinylacetate with methanolic solvent and inorganic slat at 25-40 deg.C in a dark room then extracting the reaction product with ether solvent; removing the solvent then followed by mixing a compound having OH group, natural or separated and purified retinol, diethylazodicarboxylate and triphenylphosphate with methylenechloride solvent, and reacting them at room temperature to obtain the ester derivative of retinol; and performing chromatography with reverse-phase, Merck Silicagel 60 RP 18(40-63) micro meter to separate pure ester derivative of retinol.

Abstract translation: 目的：提供一种新型视黄醇衍生物，其制备方法较高产率及其用途。 该新型视黄醇具有优异的光稳定性，对视黄酸受体α具有高反应性，而对视黄酸受体β和γ的反应性低。 适用于医疗用品，化妆品，肥皂，洗发水，功能性食品等，用于预防和改善皮肤老化。 构成：新型视黄醇衍生物的特征在于具有COOH基团的肽材料的碳键，其中具有COOH基团的肽材料选自-di，-tri， - 多肽，包括NL-α-天冬氨酰-L-苯丙氨酸1- 甲基酯（AMP;阿斯巴甜），N-保护基 - 阿斯巴甜，neotame等。 其制造方法包括以下步骤：将黑醋酸乙烯酯与甲醇溶剂和无机条板在25-40℃下在暗室中反应，然后用乙醚溶剂萃取反应产物; 除去溶剂，然后将具有OH基团的化合物，天然或分离的纯化的视黄醇，偶氮二甲酸二乙酯和磷酸三苯酯与二氯甲烷溶剂混合，并在室温下使其反应，得到视黄醇的酯衍生物; 并用反相色谱法，Merck Silicagel 60 RP 18（40-63）微米分离纯化的视黄醇酯衍生物。