公开(公告)号：WO1993016064A1

公开(公告)日：1993-08-19

申请号：PCT/HU1993000010

申请日：1993-02-12

Applicant: BIOSIGNAL, Kutató-Fejleszto Kft. ,  KÉRI, György ,  BAJOR, Tamás ,  ORFI, László ,  TIHANYI, Endre ,  BALOGH, Agnes ,  BÖKÖNYI, Gyöngyi ,  HORVATH, Anikó ,  IDEI, Miklós

Inventor： BIOSIGNAL, Kutató-Fejleszto Kft.

IPC: C07D311/08

CPC classification number: C07D335/06 ,  C07D215/54 ,  C07D311/16 ,  C07D311/18 ,  C07D311/64

Abstract: The invention relates to novel compounds of general formula (I), wherein R1 stands for -CN, -COOH, -CSOH, -COSH, -CONH2, -CSNH2, -NHCHO, -COOCH3, -CSOCH3, -COSCH3, -COOCH2CH3, -CSOCH2CH3, -COSCH2CH3, -NHCOCH3, -NHCSCH3, -CS-NH-CONH2, -CO-NH-CONH2, -CO-NH-CSNH2, -CS-NH-CSNH2, -C(NH2)=C(CN)2, -CH(CN)2, -CH(CN)-COOH, -CH(CN)-CONH2, -CH(CN)-CSNH2, -CH(CN)CSNH-C1-4 alkyl, -NO2 or -NO group; X means =O, =S or =NH group; Y means -O-, -S- or -NH- group; R2 and R4, independently from each other, represent hydrogen atom, -OH, -SH, -NH2, -CF3, C1-4 alkoxy or C1-4 alkylthio group; R3 stands for -OH, -SH, -NH2, -CF3, -NO, -O-SO2-V , -O-CO-V , -O-CS-V , -S-CO-V , -NH-CO-V or -CH=CH-V group, wherein V stands for 3,4,5-tri-V -phenyl group; and the V substituents, independently from each other, mean hydrogen or halogen atom or -OH, -SH, -NH2, -CF3, C1-4 alkoxy, C1-4 alkylthio or C1-4 alkylamino group; or V bound in the 3- or 4-position may be -COOH, -CSOH, -COSH, -CONH2, C1-4 dialkylamino, pyridyl, -CH2-2-pyridyl, -O-CH2-O- or -N(CH2-V )-CH2-V group, wherein V and V , independently from each other, stand for -OH, -SH, -NH2, -CF3, C1-4 alkyl, C1-4 alkoxy or C1-4 alkylthio group; or V and V together stand for -NH-CH2-NH- or -N(CH3)-CH2-N(CH3)- group; R5 represents hydrogen, C1-4 alkyl, C1-4 alkoxy group or halogen; and the double bond belonging to the skeletal atom substituted by R1 can also be saturated when R3 is a substituent containing the -3,4,5-tri-V -phenyl moiety, as well as physiologically acceptable salts and complexes of these compounds. The invention furthermore relates to pharmaceutical compositions containing the above compounds as well as processes for the preparation of the above compounds and compositions. The compounds of formula (I) are prepared by condensing a phenol or benzaldehyde derivative with a bifunctional carboxylic acid derivative. The compounds of formula (I) show a tumour-inhibititing action: they inhibit the activity of tyrosine kinase enzymes playing a role in the signal transfer mechanism, but do not practically influence the activity of insulin-receptor tyrosine kinase.

Abstract translation: 本发明涉及通式（I）的新化合物，其中R1代表-CN，-COOH，-CSOH，-COSH，-CONH2，-CSNH2，-NHCHO，-COOCH3，-CSOCH3，-COSCH3，-COOCH2CH3， -CSOCH 2 CH 3，-COSCH 2 CH 3，-NHCOCH 3，-NHCSCH 3，-CS-NH-CONH 2，-CO-NH-CONH 2，-CO-NH-CSNH 2，-CS-NH-CSNH 2，-C（NH 2）= C（CN） 2，-CH（CN）2，-CH（CN）-COOH，-CH（CN）-CONH 2，-CH（CN）-CSNH 2，-CH（CN）CSNH-C 1-4烷基，-NO 2或-NO 组; X表示= O，= S或= NH基; Y表示-O-，-S-或-NH-基团; R 2和R 4彼此独立地表示氢原子，-OH，-SH，-NH 2，-CF 3，C 1-4烷氧基或C 1-4烷硫基; R 3代表-OH，-SH，-NH 2，-CF 3，-NO，-O-SO 2 -V，-O-CO-V 0，-O-CS-V 0，-S -CO-V 0，-NH-CO-V 0或-CH = CH-V 0，其中V 0代表3,4,5-三-V-苯基 组; 和V 1取代基彼此独立地表示氢或卤素原子或-OH，-SH，-NH2，-CF3，C1-4烷氧基，C1-4烷硫基或C1-4烷基氨基; 或V 3连接在3-或4-位可以是-COOH，-CSOH，-COSH，-CONH 2，C 1-4二烷基氨基，吡啶基，-CH 2 -2-吡啶基，-O-CH 2 -O-或 -N（CH 2 -V 2）-CH 2 -V 3基，其中V 2和V 3彼此独立地代表-OH，-SH，-NH 2，-CF 3，C 1 -4-烷基，C 1-4烷氧基或C 1-4烷硫基; 或V 2和V 3一起代表-NH-CH 2 -NH-或-N（CH 3）-CH 2 -N（CH 3） - 基; R5表示氢，C1-4烷基，C1-4烷氧基或卤素; 当R 3是含有-3,4,5-三-V-苯基部分的取代基时，属于由R 1取代的骨架原子的双键也可以饱和，以及这些的生理上可接受的盐和络合物 化合物。 本发明还涉及含有上述化合物的药物组合物以及制备上述化合物和组合物的方法。 式（I）化合物通过将苯酚或苯甲醛衍生物与双官能羧酸衍生物缩合来制备。 式（I）化合物显示肿瘤抑制作用：它们抑制在信号转导机制中起作用的酪氨酸激酶的活性，但实际上不影响胰岛素受体酪氨酸激酶的活性。

公开(公告)号：WO2008050161A2

公开(公告)日：2008-05-02

申请号：PCT/HU2007/000095

申请日：2007-10-19

Applicant: Biostatin Gyógyszerkutató-Fejlesztö Kft. ,  HORVÁTH, Anikó ,  KÉRI, György ,  TÓVÁRI, József ,  SEPRÖDI, János ,  VÁNTUS, Tibor ,  KENESSEY, István ,  IDEI, Miklós ,  TANAI, Gyula Sándorné

Inventor： HORVÁTH, Anikó ,  KÉRI, György ,  TÓVÁRI, József ,  SEPRÖDI, János ,  VÁNTUS, Tibor ,  KENESSEY, István ,  IDEI, Miklós ,  TANAI, Gyula Sándorné

IPC: C07K5/062 ,  C07K5/068 ,  C07K5/087 ,  C07K5/093 ,  C07K5/11 ,  C07K5/117 ,  C07K14/52 ,  A61K38/05 ,  A61K38/06 ,  A61K38/07 ,  A61K38/19

CPC classification number: C07K14/52 ,  A61K38/00 ,  C07K5/0606 ,  C07K5/06086 ,  C07K5/0812 ,  C07K5/0815 ,  C07K5/0819 ,  C07K5/0827 ,  C07K5/1019 ,  C07K5/1027 ,  Y02P20/55

Abstract: The invention provides novel peptides of formula (I) and their salts or metal complexes R0- R1- Q(X) - R2- R3 (I) - wherein the main substituent meanings are as follows: Q represents Lys, Cys or Ser; X is H, Bzl, R0, R0-Tyr-Pro-Asp-Glu-Ile-Glu-Tyr-Ile-Phe, R0- Ile-Lys-Pro-His- Gln-Gly-Gln, or R0- Gly-Val-Ser-Ser-Ser-Ser, R 0 stands for H or NH2-protecting groups commonly used in peptide chemistry, R 1 is Trp, D-Trp, Phe, D-Phe, ß-Asp(a-Dopa), ß-Asp(a-Ind), Tyr-Pro-Asp- Glu-Ile-Glu-Tyr-Ile-Phe, Ile-Lys-Pro-His-Gln-Gly-Gln, Pro-Glu-Ser-Thr- Asn-Leu, Gly-Val-Ser-Ser-Ser-Ser, or a valency bond, R 2 represents Gly, Asn-Asp-Glu-Gly-Leu-Glu-(Gly) n, Asp-Asp-Gly-Gln-Ile-(Gly) n, His, Ser, Cpa, Dopa, Tyr, Thr, Pro, Trp-Ser, Phe-Ser, 2-aminophenyl-, or Cys(X2), wherein X2 is Acm, Bzl or an SH-protecting group commonly used in peptide chemistry, and R 3 is OH, OMe, NH2, or amide substituted by one or two identical or different C1-C6 alkyl group(s), Thr-NH2, or Tyr-OMe. The invention further provides pharmaceutical compositions containing these peptides with the ability of stimulating angiogenesis and vascularization. The invention further relates to the use of these compounds for preparing pharmaceutical compositions for treatment of injured tissues such as chronic wounds, heart tissues injured by ischemia or heart attack, and neural tissues injured by stroke. The invention also relates to a method for preparing tissue samples for testing angiogenesis-inhibiting agents.

Abstract translation: 本发明提供式（I）的新型肽及其盐或金属络合物R0-R1-Q（X）-RR2-R3（Ⅰ） - 其中主要取代基含义如下：Q代表Lys，Cys或Ser; X是H，Bz1，R0，R0-Tyr-Pro-Asp-Glu-Ile-Glu-Tyr-Ile-Phe，R0-Ile-Lys-Pro-His-Gln-Gly-Gln或R0-Gly-Val -Ser-Ser-Ser-Ser，R 0代表肽化学中通常使用的H或NH 2保护基团，R 1是Trp，D-Trp，Phe， D-Phe，ß-Asp（a-Dopa），ß-Asp（a-Ind），Tyr-Pro-Asp-Glu-Ile-Glu-Tyr-Ile-Phe，Ile-Lys-Pro-His-Gln- Gly-Gln，Pro-Glu-Ser-Thr-Asn-Leu，Gly-Val-Ser-Ser-Ser-Ser或价键，R 2代表Gly，Asn-Asp-Glu -Gly-Leu-Glu-（Gly）n，Asp-Asp-Gly-Gln-Ile-（Gly）n，His，Ser，Cpa，Dopa，Tyr，Thr，Pro，Trp-Ser，Phe-Ser， - 氨基苯基 - 或Cys（X2），其中X2是肽化学中通常使用的Acm，Bzl或SH保护基，R 3是OH，OMe，NH 2或被一个 或两个相同或不同的C 1 -C 6烷基，Thr-NH 2或Tyr-OMe。 本发明进一步提供含有能刺激血管生成和血管形成的这些肽的药物组合物。 本发明还涉及这些化合物用于制备用于治疗受伤组织如慢性伤口，由缺血或心脏病发作损伤的心脏组织以及由中风损伤的神经组织的药物组合物的用途。 本发明还涉及一种用于制备用于测试血管发生抑制剂的组织样品的方法。