公开(公告)号：EP2115140B8

公开(公告)日：2017-01-25

申请号：EP07705747.9

申请日：2007-01-31

申请人： Yu, Chongxi

发明人： Yu, Chongxi

IPC分类号： C07D471/04 ,  A61K31/437 ,  A61P31/18 ,  A61P35/00 ,  C12N15/29 ,  C12N15/09 ,  C12N15/10

CPC分类号： C07D471/04 ,  A61K9/0014 ,  A61K31/44 ,  A61K31/4745

公开(公告)号：EP2660247A3

公开(公告)日：2014-09-03

申请号：EP13170316.7

申请日：2010-05-10

申请人： Yu, Chongxi ,  Techfields Biochem Co. Ltd

发明人： Yu, Chongxi ,  Xu, Lina ,  Chen, Yuhua ,  Yan, Binbing ,  Tu, Shiqian

IPC分类号： C07K7/06 ,  C07K7/08 ,  C07K14/00 ,  C07K1/04 ,  A61K38/08 ,  A61K38/10 ,  A61K38/16 ,  A61P17/00 ,  A61P25/00 ,  A61K47/48

CPC分类号： A61K31/145 ,  A61K9/0014 ,  A61K31/222 ,  A61K31/40 ,  A61K31/4184 ,  A61K38/00 ,  A61K47/42 ,  A61K47/54 ,  A61K47/64 ,  A61K47/645 ,  C07D403/12 ,  C07D403/14 ,  C07K1/04 ,  C07K5/06026 ,  C07K5/06078 ,  C07K5/1013 ,  C07K5/1016 ,  C07K5/1019 ,  C07K7/06 ,  C07K7/56

摘要： Provided is a high penetration composition or high penetration prodrugs of peptide or peptide-related compound comprising functional unit, linker, and transportational unit. The functional unit is covalently linked to the transportational unit via the linker, and comprises a moiety of the peptide or the peptide-related compound. The transportational unit comprises protonatable amine group. The linker comprises chemical bond that is capable of being cleaved after the composition penetrates across a biological barrier.

摘要翻译： 提供了包含功能单元，接头和运输单元的肽或肽相关化合物的高渗透组合物或高渗透前药。 功能单元通过接头与运输单元共价连接，并且包含肽或肽相关化合物的部分。 运输单元包括可质子胺基团。 连接体包括能够在组合物渗透生物屏障之后被切割的化学键。

公开(公告)号：EP2746251A3

公开(公告)日：2014-07-02

申请号：EP14153622.7

申请日：2006-09-03

申请人： Techfields Biochem Co. Ltd ,  Yu, Chongxi

发明人： Yu, Chongxi ,  Xu, Lina

IPC分类号： C07C233/25 ,  A61K31/167 ,  A61K31/22 ,  A61P29/00 ,  A61P11/06 ,  A61P35/00 ,  A61P27/06 ,  A61P27/16 ,  A61P17/00

CPC分类号： C07C233/25 ,  A61P11/06 ,  A61P17/00 ,  A61P27/06 ,  A61P27/16 ,  A61P29/00 ,  A61P35/00

摘要： The novel positively charged pro-drugs of acetaminophen, acetaminosalol, and related compounds in the general formula (1) 'Structure 1' were designed and synthesized. The positively charged amino groups of these pro-drugs not only largely increases the solubility of the drugs, but also bonds to the negative charge on the phosphate head group of membranes and pushes the pro-drug into the cytosol. The results suggest that the pro-drugs diffuses through human skin ∼150 times faster than does acetaminophen, acetaminosalol, and related compounds. It takes 1-2 hours for acetaminophen and acetaminosalol, and related compounds to reach the peak plasma level when they are taken orally, but these prodrugs only took about ∼50 minutes to reach the peak plasma level when they are taken transdermally. In plasma, more than 90% of these pro-drugs can be changed back to the parent drugs in a few minutes. The prodrugs can be used medicinally for treating any NSAIAs-treatable conditions in humans or animals. The prodrugs can be administered not only orally, but also transdermally for any kind of medical treatments and avoid most of the side effects of NSAIAs. Controlled transdermal administration systems of the prodrugs enables acetaminophen, acetaminosalol, and related compounds to reach constantly optimal therapeutic blood levels to increase effectiveness and reduce the side effects of acetaminophen, acetaminosalol, and related compounds. Another great benefit of transdermal administration of these pro-drugs is that administering medication, especially to children, will be much easier.

公开(公告)号：EP2091914A1

公开(公告)日：2009-08-26

申请号：EP06821378.4

申请日：2006-11-08

申请人： Yu, Chongxi

发明人： Yu, Chongxi

IPC分类号： C07C323/26 ,  C07C323/22 ,  C07C235/12

CPC分类号： C07C317/28 ,  A61K9/0014 ,  A61K31/145 ,  A61K31/222 ,  A61K31/40 ,  A61K31/4184 ,  A61K47/54 ,  C07C323/58 ,  C07D403/12 ,  C07D403/14 ,  C07K5/1016 ,  C07K7/56

摘要： The novel positively charged pro-drugs of peptides and related compounds in the general formula (1) 'Structure 1' were designed and synthesized. The compounds of the general formula (1) 'Structure 1' indicated above can be prepared by standard peptide synthesis protocols. The positively charged amino group of the pro-drug of peptides not only makes the drugs soluble in water, but also bonds to the negative charge on the phosphate head group of membranes and pushes the pro-drug into the cytosol. The lipophilic portion (by modification of the polar groups with lipophilic alkyl groups) of the prodrugs will facilitate the entering of the drugs into the skin membrane. The results suggest that the pro-drugs diffuses through human skin ~100-1000 times faster than do peptides and related compounds. In plasma, more than 40% of these pro-drugs can change back to the parent drugs in a few minutes. The prodrugs can be used medicinally in treating any peptides and related compounds-treatable conditions in humans or animals. The prodrugs can be administered transdermally for any kind of medical treatments and avoid proteolysis by proteolytic enzymes in the GI tract. Controlled transdermal administration systems of the prodrug enables peptides and related compounds to reach constantly optimal therapeutic blood levels to increase effectiveness and reduce the side effects of peptides and related compounds. Another great benefit of transdermal administration of these pro-drugs is that administering medication, especially to children, will be much easier.

公开(公告)号：EP2121593B1

公开(公告)日：2015-06-17

申请号：EP06832186.8

申请日：2006-12-10

申请人： Yu, Chongxi

发明人： Yu, Chongxi

IPC分类号： A61K31/43 ,  A61P31/04 ,  C07D499/00 ,  A61K9/70

CPC分类号： C07D499/00 ,  A61P31/04

摘要： The novel positively charged pro-drugs of beta-lactam antibiotics in the general 'Structure 4' were designed. The positively charged amino group of the pro-drug not only makes the drugs soluble in water, but also bonds to the negative charge on the phosphate head group of membranes. This bonding will disturb the membrane a little bit and may make some room for the lipophilic portion of the prodrug. When the molecules of membrane move, the membrane may 'crack' a little bit due to the bonding of the prodrug. This will let the prodrug insert into the membrane. At pH 7.4, only about 99% of amino group is protonated. When the amino group is not protonated, the bonding between the amino group of the prodrug and the phosphate head group of membrane will disassociate, and the prodrug will enter the membrane completely. When the amino group of the prodrug flips to the other side of the membrane and thus become protonated, then the prodrug is pulled into the cytosol, a semiliquid concentrated aqueous solution or suspension. The results suggest that the pro-drugs diffuses through human skin, blood-brain, and blood-milk barriers hundreds times faster than do beta-lactam antibiotics. In plasma, more than 90% of these pro-drugs can change back to the parent drugs in a few minutes. The prodrugs can be used medicinally in treating beta-lactam antibiotics-treatable conditions in humans or animals. The prodrugs can be administered transdermally for any kind of medical treatments. Controlled transdermal administration systems of the prodrug enables beta-lactam antibiotics to reach constantly optimal therapeutic blood levels to increase effectiveness and reduce the side effects of beta-lactam antibiotics. Another great benefit of transdermal administration of these pro-drugs is that administering medication, especially to children or animals, will be much easier.

公开(公告)号：EP2781505A1

公开(公告)日：2014-09-24

申请号：EP14156640.6

申请日：2006-10-02

申请人： Techfields Biochem Co. Ltd ,  Yu, Chongxi

发明人： Yu, Chongxi ,  Xu, Lina

IPC分类号： C07C215/40 ,  C07C215/42 ,  C07C405/00 ,  A61K31/5575 ,  A61P9/12 ,  A61P15/00

CPC分类号： C07C405/0041

摘要： The novel positively charged pro-drugs of prostaglandins, prostacyclins and related compounds in the general formula (2) 'Structure 2' were designed and synthesized. The compounds of the general formula (2) 'Structure 2' indicated above can be prepared from protected prostaglandins, prostacyclins, and related compounds, by reaction with suitable alcohols, thiols, or amines and coupling reagents, such as N, N'-Dicyclohexylcarbodiimide, N, N'-Diisopropylcarbodiimide, O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate, O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, Benzotriazol-1-yl-oxy-tris (dimethylamino)phosphonium hexafluorophosphate, et al. The positively charged amino groups of these pro-drugs not only largely increases the solubility of the drugs in water, but also bonds to the negative charge on the phosphate head group of membranes and pushes the pro-drug into the cytosol. The results suggest that the pro-drugs diffuse through human skin ∼1000 times faster than do prostaglandins, prostacyclins, and related compounds. In plasma, more than 90% of these pro-drugs can change back to the parent drugs in a few minutes. The prodrugs can be used medicinally in treating any prostaglandins, prostacyclins, and related compounds-treatable conditions in humans or animals. The prodrugs can be administered transdermally for any kind of medical treatments and avoid most of the side effects of prostaglandins, prostacyclins, and related compounds. Controlled transdermal administration systems of the prodrug enable prostaglandins, prostacyclins, and related compounds to reach constantly optimal therapeutic blood levels to increase effectiveness and reduce the side effects of prostaglandins, prostacyclins, and related compounds. Another great benefit of transdermal administration of these pro-drugs is that administering medication, especially to children, will be much easier.

摘要翻译： 新颖的带正电荷的前列腺素，前列环素和相关化合物的前体药物的通式（2）“结构2”设计并合成英寸 上面所示的通式（2）“结构2”的化合物可以从受保护的前列腺素，前列环素，和相关的化合物与合适的醇，硫醇，或cardamines和偶联试剂，：如N，N'-二环己基来制备，通过反应 ，N，N'-二异丙基，O-（苯并三唑-1-基）-N，N，N 'N'-四甲基脲四氟硼酸盐，O-（苯并三唑-1-基）-N，N，N'，N' 四甲基脲，苯并三唑-1-基 - 氧基 - 三（二甲氨基）鏻六氟磷酸盐等。 毕业论文前药带正电荷的氨基不仅大大增加在水中的药物的溶解度，因此而债券对磷酸头基膜的负电荷和推动有利于药物进入细胞质。 结果表明确实亲药物通过人体皮肤扩散的速度比¼1000次做前列腺素，前列腺素和相关化合物。 在血浆中，90％以上的合成前体药物可以在几分钟内变回母体药物。 所述前药可药用治疗任何前列腺素，前列环素一起使用，以及与人类或动物的化合物可治疗的条件。 前药可经皮对任何种类的药物治疗被施用，避免大部分的前列腺素，前列环素和相关化合物的副作用。 前药的控制透皮给药系统使前列腺素，前列环素，和相关的化合物以达到最佳不断治疗血液水平，以增加效率和减少前列腺素，前列环素，和相关化合物的副作用。 毕业论文的前体药物透皮给药的另一大好处是没有管理的药物，尤其是爱孩子，会容易得多。

公开(公告)号：EP2756843A2

公开(公告)日：2014-07-23

申请号：EP14158789.9

申请日：2006-07-25

申请人： Techfields Biochem Co. Ltd ,  Yu, Chongxi

发明人： Yu, Chongxi ,  Xu, Lina

IPC分类号： A61K31/216 ,  A61P29/00 ,  A61P43/00 ,  C07C229/42 ,  C07C237/20

CPC分类号： C07C229/42 ,  C07C237/20

摘要： The novel positively charged pro-drugs of diclofenac in the general formula (1), with X = O or S, were designed and synthesized. The compounds of the general formula (1) can be prepared from functional derivatives of diclofenac by reaction with suitable alcohols, thiols, or amines. The positively charged amino groups of these pro-drugs not only largely increase the solubility of the drugs in water, but also bond to the negative charge on the phosphate head group of membranes and push the pro-drug into the cytosol. Experimental results suggest that the pro-drug diethylaminoethyl 2[(2,6-dichlorophenyl)amino]benzene acetate.AcOH diffuses through human skin 250 times faster than 2[(2,6-dichlorophenyl)amino]benzene acetic acid (diclofenac) and ethyl 2[(2,6-dichlorophenyl)amino]benzene acetate. In plasma, more than 90% of these pro-drugs can change back to the drug in a few minutes. The prodrugs can be used medicinally in treating any diclofenac-treatable conditions in humans or animals and be administered not only orally, but also transdermally for any kind of medical treatments and avoid most of the side effects of diclofenac, most notably GI disturbances such as dyspepsia, gastroduodenal bleeding, gastric ulcerations, and gastritis. Controlled transdermal administration systems of the prodrug enables diclofenac to reach constantly optimal therapeutic blood levels to increase effectiveness and reduce the side effects of diclofenac.

摘要翻译： 设计并合成了具有X = O或S的通式（1）中双氯芬酸的前药带正电的前药。 通式（1）的化合物可以由双氯芬酸的官能衍生物通过与合适的醇，硫醇或胺反应而制备。 这些前药的带正电荷的氨基不仅大大增加了药物在水中的溶解度，而且还与膜的磷酸盐头部组上的负电荷结合，并将前药推入胞质溶胶。 实验结果表明，前药二乙氨基乙基2 [（2,6-二氯苯基）氨基]苯乙酸酯.AcOH通过人皮肤比2 [（2,6-二氯苯基）氨基]苯乙酸（双氯芬酸）快250倍并且 乙基2 [（2,6-二氯苯基）氨基]苯乙酸乙酯。 在血浆中，超过90％的这些前药可以在几分钟内变回药物。 前药可用于药物治疗人或动物中任何双氯芬酸可治疗的病症，并且不仅可以口服给药，而且还可以经皮给药用于任何类型的药物治疗，并且避免双氯芬酸的大部分副作用，最显着的GI障碍例如消化不良 ，胃十二指肠出血，胃溃疡和胃炎。 前药的受控透皮给药系统使得双氯芬酸能够不断达到最佳治疗血液水平以增加效力并减少双氯芬酸的副作用。

公开(公告)号：EP2746251A2

公开(公告)日：2014-06-25

申请号：EP14153622.7

申请日：2006-09-03

申请人： Techfields Biochem Co. Ltd ,  Yu, Chongxi

发明人： Yu, Chongxi ,  Xu, Lina

IPC分类号： C07C233/25 ,  A61K31/167 ,  A61K31/22 ,  A61P29/00 ,  A61P11/06 ,  A61P35/00 ,  A61P27/06 ,  A61P27/16 ,  A61P17/00

CPC分类号： C07C233/25 ,  A61P11/06 ,  A61P17/00 ,  A61P27/06 ,  A61P27/16 ,  A61P29/00 ,  A61P35/00

摘要： The novel positively charged pro-drugs of acetaminophen, acetaminosalol, and related compounds in the general formula (1) 'Structure 1' were designed and synthesized. The positively charged amino groups of these pro-drugs not only largely increases the solubility of the drugs, but also bonds to the negative charge on the phosphate head group of membranes and pushes the pro-drug into the cytosol. The results suggest that the pro-drugs diffuses through human skin ∼150 times faster than does acetaminophen, acetaminosalol, and related compounds. It takes 1-2 hours for acetaminophen and acetaminosalol, and related compounds to reach the peak plasma level when they are taken orally, but these prodrugs only took about ∼50 minutes to reach the peak plasma level when they are taken transdermally. In plasma, more than 90% of these pro-drugs can be changed back to the parent drugs in a few minutes. The prodrugs can be used medicinally for treating any NSAIAs-treatable conditions in humans or animals. The prodrugs can be administered not only orally, but also transdermally for any kind of medical treatments and avoid most of the side effects of NSAIAs. Controlled transdermal administration systems of the prodrugs enables acetaminophen, acetaminosalol, and related compounds to reach constantly optimal therapeutic blood levels to increase effectiveness and reduce the side effects of acetaminophen, acetaminosalol, and related compounds. Another great benefit of transdermal administration of these pro-drugs is that administering medication, especially to children, will be much easier.

摘要翻译： 新颖的带正电荷的对乙酰氨基酚，acetaminosalol，和相关化合物的前体药物的通式（1）“结构1”，设计并合成英寸 毕业论文前药带正电荷的氨基不仅大大增加了药物的溶解度，因此而债券对磷酸头基膜的负电荷和推动有利于药物进入细胞质。 结果表明确实亲药物通过人体皮肤弥漫性比确实对乙酰氨基酚，acetaminosalol和相关化合物更快¼150倍。 这需要1-2个小时对乙酰氨基酚和acetaminosalol，和相关的化合物达到峰值血浆水平的时候都采取口头，但只有论文的前药大约过了¼50分钟达到峰值血浆水平时，他们采取了皮。 在血浆中，90％以上的合成前体药物可以在几分钟内被改回母体药物。 前体药物可入药用于治疗人或动物的任何NSAIAs可治疗的条件。 前体药物不仅可以口服，但如此透皮任何形式的药物治疗和避免大多数的NSAIAs的副作用。 前药的控制透皮给药系统允许对乙酰氨基酚，acetaminosalol，对乙酰氨基酚和相关化合物以达到最佳不断治疗血液水平，以增加效率和减少的，acetaminosalol副作用，和相关化合物。 毕业论文的前体药物透皮给药的另一大好处是没有管理的药物，尤其是爱孩子，会容易得多。

公开(公告)号：EP2121593A1

公开(公告)日：2009-11-25

申请号：EP06832186.8

申请日：2006-12-10

申请人： Yu, Chongxi

发明人： Yu, Chongxi

IPC分类号： C07D205/12 ,  C07D277/00 ,  C07D257/00 ,  A61P31/02

CPC分类号： C07D499/00 ,  A61P31/04

摘要： The novel positively charged pro-drugs of beta-lactam antibiotics in the general 'Structure 4' were designed. The positively charged amino group of the pro-drug not only makes the drugs soluble in water, but also bonds to the negative charge on the phosphate head group of membranes. This bonding will disturb the membrane a little bit and may make some room for the lipophilic portion of the prodrug. When the molecules of membrane move, the membrane may 'crack' a little bit due to the bonding of the prodrug. This will let the prodrug insert into the membrane. At pH 7.4, only about 99% of amino group is protonated. When the amino group is not protonated, the bonding between the amino group of the prodrug and the phosphate head group of membrane will disassociate, and the prodrug will enter the membrane completely. When the amino group of the prodrug flips to the other side of the membrane and thus become protonated, then the prodrug is pulled into the cytosol, a semiliquid concentrated aqueous solution or suspension. The results suggest that the pro-drugs diffuses through human skin, blood-brain, and blood-milk barriers hundreds times faster than do beta-lactam antibiotics. In plasma, more than 90% of these pro-drugs can change back to the parent drugs in a few minutes. The prodrugs can be used medicinally in treating beta-lactam antibiotics-treatable conditions in humans or animals. The prodrugs can be administered transdermally for any kind of medical treatments. Controlled transdermal administration systems of the prodrug enables beta-lactam antibiotics to reach constantly optimal therapeutic blood levels to increase effectiveness and reduce the side effects of beta-lactam antibiotics. Another great benefit of transdermal administration of these pro-drugs is that administering medication, especially to children or animals, will be much easier.

公开(公告)号：EP3176169A1

公开(公告)日：2017-06-07

申请号：EP16200797.5

申请日：2007-01-31

申请人： Yu, Chongxi

发明人： Yu, Chongxi

IPC分类号： C07D471/04 ,  A61K31/437 ,  A61P31/18 ,  A61P35/00 ,  C12N15/29 ,  C12N15/09 ,  C12N15/10

CPC分类号： C07D471/04 ,  A61K9/0014 ,  A61K31/44 ,  A61K31/4745

摘要： The novel positively charged pro-drugs of 1H-imidazo[4, 5-c]quinolin-4-amines and related compounds in the general formula (1) 'Structure 1' or formula (2) 'Structure 2' were designed and synthesized. The compounds of the general formula (1) 'Structure 1' or formula (2) 'Structure 2' indicated above can be prepared from 1H-imidazo[4, 5-c]quinolin-4-amines and related compounds, by reaction with suitable acetic anhydride or acetic chloride. The positively charged amino groups of these pro-drugs not only largely increases the solubility of the drugs in water, but also bonds to the negative charge on the phosphate head group of membranes. This bonding will disturb the membrane a little bit and may make some room for the lipophilic portion of the prodrug. When the molecules of membrane move, the membrane may 'crack' a little bit due to the bonding of the prodrug. This will let the prodrug insert into the membrane. At pH 7.4, only about 99% of the amino group is protonated. When the amino group is not protonated, the bonding between the amino group of the prodrug and the phosphate head group of the membrane will disassociate, and the prodrug will enter the membrane completely. When the amino group of the prodrug flips to the other side of the membrane and thus becomes protonated, then the prodrug is pulled into the cytosol, a semi-liquid concentrated aqueous solution or suspension. The results suggest that the pro-drugs diffuse through human skin -25 times faster than do 1H-imidazo[4, 5-c]quinolin-4-amines and related compounds. In plasma, more than 90% of these pro-drugs can change back to the parent drugs in a few minutes. The prodrugs can be used medicinally in treating any 1H-imidazo[4,5-c]quinolin-4-amines and related compounds-treatable conditions in humans or animals. The prodrugs can be administered transdermally for any kind of medical treatments and avoid most of the side effects of 1H-imidazo[4,5-c] quinolin-4-amines and related compounds. Controlled transdermal administration systems of the prodrug enables 1H-imidazo[4, 5-c]quinolin-4-amines and related compounds to reach constantly optimal therapeutic blood levels to increase effectiveness and reduce the side effects of 1H-imidazo[4, 5-c]quinolin-4-amines and related compounds.

摘要翻译： 新颖的带正电荷的[5-C 4，]通式（1）“结构1”或式（2）“结构2”喹啉-4-胺和相关化合物，设计并合成-1H-咪唑的前体药物 ， 上面所示的通式（1）“结构1”或式（2）“结构2”的化合物可以从-1H-咪唑来制备[4,5-c]喹啉-4- cardamines和相关化合物，通过与反应 合适的乙酸酐或乙酰氯。 毕业论文前药带正电荷的氨基不仅大大增加在水中的药物的溶解度，因此而债券对磷酸头基膜的负电荷。 该接合将干扰膜一点点，可能使一些空间用于前药的亲脂性部分。 当膜移动的分子，所述膜可以“破解”有点由于前药的结合。 这将让前体药物插入膜。 在pH 7.4，只有约99％的氨基的被质子化。 当未质子化的氨基基团，氨基基团的前药和磷酸头基膜的之间的结合解离会，以及所述前药将完全进入该膜。 当该前药的氨基翻转到该膜的另一侧，并因此变成质子化的，则该前药被拉动到胞质溶胶中，半液体浓缩的水溶液或悬浮液。 结果表明做了前体药物通过人皮肤扩散的速度比-25倍做-1H-咪唑并[4,5-c]喹啉-4- cardamines和相关化合物。 在血浆中，90％以上的合成前体药物可以在几分钟内变回母体药物。 所述前药可药用治疗任何-1H-咪唑并使用[4,5-c]喹啉-4- cardamines和人类或动物的相关化合物可治疗的条件。 前体药物可以经皮给药对于任何种类的医学治疗和避免大部分-1H-咪唑的副作用并[4,5-c]喹啉-4- cardamines和相关化合物。 前药的控制透皮给药系统启用-1H-咪唑并[4,5-c]喹啉-4- cardamines和相关化合物以达到最佳不断治疗血液水平，以增加效率和减少-1H-咪唑并[4，5-的副作用 c]喹啉-4- cardamines和相关化合物。