公开(公告)号：WO2008044095A1

公开(公告)日：2008-04-17

申请号：PCT/IB2006/053741

申请日：2006-10-11

Applicant: TECHFIELDS BIOCHEM CO. LTD ,  YU, Chongxi ,  XU, Lina

Inventor： YU, Chongxi ,  XU, Lina

IPC: C07D513/04 ,  C07D417/12 ,  C07D279/16

CPC classification number: C07D417/12 ,  C07D279/02 ,  C07D513/04

Abstract: The novel positively charged pro-drugs of oxicams 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 ~100 times faster than do oxicams and related compounds. It takes 1-2 hours for oxicams 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 change back to the parent drugs in a few minutes. The prodrugs can be used medicinally in treating any oxicams-treatable conditions in humans or animals. Second, 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 oxicams. Controlled transdermal administration systems of the prodrugs enable oxicams and related compounds to reach constantly optimal therapeutic blood levels to increase effectiveness and reduce the side effects of oxicams and related compounds. Another great benefit of the transdermal administration of these pro-drugs is that administering medication, especially to children, will be much easier.

Abstract translation: 设计并合成了通式（1）“结构1”中的oxicams和相关化合物的新型带正电荷的前药。 这些前药的带正电荷的氨基不仅大大增加了药物的溶解度，而且还与磷酸盐头基团上的负电荷键合，并将前药推入细胞溶质中。 结果表明，前药通过人类皮肤扩散比oxicams和相关化合物快100倍。 奥昔康星及相关化合物口服时，需要1-2小时达到峰值血浆水平，但这些前药在经皮摄取后仅花费约50分钟达到峰值血浆水平。 在血浆中，超过90％的这些前药可以在几分钟内改变为母体药物。 前药可以在医学上用于治疗人类或动物中任何oxicam可治疗的病症。 其次，前药不仅可以口服给药，也可以经皮用于任何种类的药物治疗，并避免oxicam的大部分副作用。 前药的受控经皮给药系统使奥昔康星和相关化合物达到不断优化的治疗血液水平以增加有效性并降低oxicam和相关化合物的副作用。 这些前药的透皮给药的另一大好处是，给予药物，尤其是给儿童服用药物将容易得多。

公开(公告)号：WO2008041054A1

公开(公告)日：2008-04-10

申请号：PCT/IB2006/053594

申请日：2006-10-02

Applicant: TECHFIELDS BIOCHEM CO. LTD ,  YU, Chongxi ,  XU, Lina

Inventor： YU, Chongxi ,  XU, Lina

IPC: C07C215/40 ,  C07C215/42

CPC classification number: C07C405/0041

Abstract: 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.

Abstract translation: 设计并合成了通式（2）“结构2”中前列腺素，前列环素及相关化合物的新型带正电荷的前药。 上述通式（2）“结构2”的化合物可以由保护的前列腺素，前列环素和相关化合物通过与合适的醇，硫醇或胺的反应和偶联试剂如N，N'-二环己基碳二亚胺 ，N，N'-二异丙基碳二亚胺，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' 四甲基脲六氟磷酸盐，苯并三唑-1-基 - 氧 - 三（二甲基氨基）鏻六氟磷酸盐等。 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，而且还与磷酸盐头基上的负电荷键合，并将前药推入胞质溶胶中。 结果表明，前药通过人体皮肤分散，比前列腺素，前列环素及相关化合物快1000倍。 在血浆中，超过90％的这些前药可以在几分钟内改变为母体药物。 前药可以在医学上用于治疗人或动物中的任何前列腺素，前列环素和相关化合物 - 可治疗的病症。 前药可以通过皮肤施用于任何种类的医学治疗，并避免前列腺素，前列环素和相关化合物的大部分副作用。 前药的受控透皮给药系统使前列腺素，前列环素和相关化合物达到不断优化的治疗血液水平以增加有效性并减少前列腺素，前列环素和相关化合物的副作用。 经皮给药这些前药的另一大好处是给予药物，尤其是给儿童服用药物将容易得多。

公开(公告)号：WO2008029200A1

公开(公告)日：2008-03-13

申请号：PCT/IB2006/053091

申请日：2006-09-03

Applicant: TECHFIELDS BIOCHEM CO. LTD ,  YU, Chongxi ,  XU, Lina

Inventor： YU, Chongxi ,  XU, Lina

IPC: C07C211/64 ,  C07C215/42 ,  C07C233/07

CPC classification number: C07C233/25 ,  A61P11/06 ,  A61P17/00 ,  A61P27/06 ,  A61P27/16 ,  A61P29/00 ,  A61P35/00

Abstract: 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.

Abstract translation: 设计并合成了通式（1）“结构1”中对乙酰氨基酚，乙酰氨基酚和相关化合物的新型带正电荷的前药。 这些前药的带正电荷的氨基不仅大大增加了药物的溶解度，而且还与磷酸盐头基团上的负电荷键合，并将前药推入细胞溶质中。 结果表明，前药通过人体皮肤扩散比对乙酰氨基酚，乙酰氨基酚和相关化合物快约150倍。 对乙酰氨基酚和乙酰氨基奥沙罗芬需要1-2小时，口服相关化合物达到峰值血浆水平，但这些前药在经皮摄取后仅花费约50分钟达到峰值血浆水平。 在血浆中，超过90％的这些前药可以在几分钟内更换回母体药物。 前药可用于医学上用于治疗人或动物中任何NSAIAs可治疗的病症。 前药不仅可以口服给药，也可以经皮给予任何类型的药物治疗，并避免NSAIAs的大部分副作用。 前药的受控经皮给药系统使对乙酰氨基酚，乙酰氨基酚和相关化合物达到不断优化的治疗血液水平，以增加对乙酰氨基酚，乙酰氨基酚和相关化合物的效力并降低副作用。 经皮给药这些前药的另一大好处是给予药物，尤其是给儿童服用药物将容易得多。

公开(公告)号：WO2008012603A1

公开(公告)日：2008-01-31

申请号：PCT/IB2006/052563

申请日：2006-07-26

Applicant: TECHFIELDS BIOCHEM CO. LTD ,  YU, Chongxi ,  XU, Lina

Inventor： YU, Chongxi ,  XU, Lina

IPC: C07C215/72 ,  C07C215/40 ,  C07C215/42 ,  C07C225/16

CPC classification number: C07C219/14 ,  C07C53/08 ,  C07C59/265 ,  C07C229/12 ,  C07C235/60 ,  C07C327/30

Abstract: The novel positively charged pro-drugs of diflunisal, salicylsalicylic acid, and salicylic acid in the general formula(1) 'Structure 1' and general formula(2) 'Structure 2' were designed and synthesized. The compounds of the general formula(1) 'Structure 1' or general formula(2) 'Structure 2' indicated above can be prepared from functional derivatives of diflunisal, salicylsalicylic acid, or salicylic acid, (for example acid halides or mixed anhydrides), by reaction with suitable alcohols, thiols, or amines. 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-drug, diethylaminoethyl 5-(2,4-difluorophenyl) salicylate. AcOH diffuses through human skin ~150 times faster than does diflunisal itself. 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 diflunisal, salicylsalicylic acid, or salicylic acid-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 diflunisal, salicylsalicylic acid, or salicylic acid, most notably GI disturbances such as dyspepsia, gastroduodenal bleeding, gastric ulcerations, and gastritis. Controlled transdermal administration systems of the prodrug enables diflunisal, salicylsalicylic acid, or salicylic acid to reach constantly optimal therapeutic blood levels to increase effectiveness and reduce the side effects of diflunisal, salicylsalicylic acid, or salicylic acid.

Abstract translation: 在通式（1）'结构1'和通式（2）'结构2'中设计并合成了新颖的带正电荷的二氟尼柳，水杨酸水杨酸和水杨酸的前药。 上述通式（1）“结构1”或通式（2）“结构2”的化合物可以由二氟尼柳胺，水杨酸水杨酸或水杨酸的官能衍生物（例如酰卤或混合酸酐）制备， 通过与合适的醇，硫醇或胺反应。 这些前药的带正电荷的氨基不仅大大增加了药物的溶解度，而且还与磷酸盐头基团上的负电荷键合，并将前药推入细胞溶质中。 结果表明，前药，5-（2,4-二氟苯基）水杨酸二乙氨基乙酯。 AcOH通过人体皮肤扩散〜比双螺旋体本身快150倍。 在血浆中，超过90％的这些前药可以在几分钟内恢复到药物。 前药可以在医学上用于治疗人或动物中的任何二氟苯胺酸水杨酸或水杨酸可治疗的病症，并且不仅口服给药，而且经皮用于任何种类的药物治疗，并避免二氟尼柳， 水杨酸水杨酸或水杨酸，最显着的GI紊乱如消化不良，胃十二指肠出血，胃溃疡和胃炎。 前药的受控经皮给药系统使得二月桂酸，水杨酸水杨酸或水杨酸达到不断优化的治疗血液水平以提高效力并降低二氟尼柳酸，水杨酸水杨酸或水杨酸的副作用。

公开(公告)号：WO2008020270A1

公开(公告)日：2008-02-21

申请号：PCT/IB2006/052815

申请日：2006-08-15

Applicant: TECHFIELDS BIOCHEM CO. LTD ,  YU, Chongxi ,  XU, Lina

Inventor： YU, Chongxi ,  XU, Lina

IPC: C07D209/12 ,  C07D491/04 ,  C07D209/82 ,  C07D263/57

CPC classification number: C07D333/22 ,  C07D209/08 ,  C07D209/46 ,  C07D209/88 ,  C07D263/57 ,  C07D333/32 ,  C07D491/04

Abstract: The novel positively charged pro-drugs of aryl- and heteroarylpropionic acids in the general formula (1) 'Structure 1' and general formula (2) 'Structure 2' were designed and synthesized. The compounds of the general formula (1) 'Structure 1' and general formula (2) 'Structure 2' indicated above can be prepared from functional derivatives of naproxen, suprofen, α- methyl-(p-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetic acid, flurbiprofen, carprofen, pranoprofen, benoxaprofen, alminoprofen, tiaprofenic acid, pirprofen, zaltoprofen, bermoprofen, loxoprofen, indoprofen, fenclorac, oxaprozin, fenbufen, orpanoxin, ketorolac, clidanac, and related compounds, (for example acid halides or mixed anhydrides), by reaction with suitable alcohols, thiols, or amines. 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 -100-130 times faster than do their parent drugs. It takes 2-4 hours for naproxen, suprofen, α- methyl-(p-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetic acid, flurbiprofen, carprofen, pranoprofen, benoxaprofen, alminoprofen, tiaprofenic acid, pirprofen, zaltoprofen, bermoprofen, loxoprofen, indoprofen, fenclorac, oxaprozin, fenbufen, orpanoxin, ketorolac, clidanac, and related compounds to reach the peak plasma level when they are taken orally, but these prodrugs only took about 40-50 minutes to reach the peak plasma level when they are taken transdermally. 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 NS AIAs-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, most notably GI disturbances such as dyspepsia, gastroduodenal bleeding, gastric ulcerations, and gastritis. Controlled transdermal administration systems of the prodrugs enable naproxen, suprofen, α- methyl-(p-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetic acid, flurbiprofen, carprofen, pranoprofen, benoxaprofen, alminoprofen, tiaprofenic acid, pirprofen, zaltoprofen, bermoprofen, loxoprofen, indoprofen, fenclorac, oxaprozin, fenbufen, orpanoxin, ketorolac, clidanac, and related compounds to reach constantly optimal therapeutic blood levels to increase effectiveness and reduce the side effects of NSAIAs. Another great benefit of transdermal administration of these pro-drugs is that administering medication, especially to children, will be much easier.

Abstract translation: 通式（1）'结构1'和通式（2）'结构2'中的芳基 - 和杂芳基丙酸新型带正电荷的前药被设计并合成。 上述通式（1）'结构1'和通式（2）'结构2'的化合物可以由萘普生，脱丙苯，α-甲基 - （对氯苯甲酰）-5-甲氧基 - 2-甲基吲哚3-乙酸，氟比洛芬，卡洛芬，替潘洛芬，苯普洛芬，替洛芬，噻吗洛芬，吡罗芬，扎洛芬，倍他波芬，洛索洛芬，吲哚洛芬，芬氯洛芬，奥沙普秦，芬布芬，奥司匹林，酮咯酸，氯吡旦和相关化合物 酰卤或混合酸酐），通过与合适的醇，硫醇或胺反应。 这些前药的带正电荷的氨基不仅大大增加了药物的溶解度，而且还与磷酸盐头基团上的负电荷键合，并将前药推入细胞溶质中。 结果表明，前药通过人体皮肤比其母体药物扩散快100〜130倍。 萘普生，依洛芬，α-甲基 - （对氯苯甲酰）-5-甲氧基-2-甲基吲哚3-乙酸，氟比洛芬，卡洛芬，双吡苯丙酸，苯诺洛芬，阿仑洛芬，噻吗啡，吡柔芬，扎洛芬， 倍他波芬，洛索洛芬，吲哚洛芬，芬克洛芬，奥沙普秦，芬布芬，西班牙毒素，酮咯酸，氯吡旦和相关化合物，当口服口服时达到峰值血浆水平，但这些前药仅需40-50分钟即可达到峰值血浆水平 他们是经皮摄取。 在血浆中，超过90％的这些前药可以在几分钟内恢复到药物。 前药可以在医学上用于治疗人类或动物中任何NSAAs可治疗的病症。 前药可以不仅口服给药，而且可以经皮用于任何类型的医学治疗，并且避免NSAIAs的大多数副作用，最明显的是GI紊乱如消化不良，胃十二指肠出血，胃溃疡和胃炎。 前药的对照经皮给药系统使得萘普生，对羟基苯甲酸，α-甲基 - （对氯苯甲酰）-5-甲氧基-2-甲基吲哚3-乙酸，氟比洛芬，卡洛芬，双吡苯丙酸，苯丙酮酸，阿仑洛芬，噻吗啡酸，吡丙芬，扎洛芬 ，倍他波芬，洛索洛芬，吲哚洛芬，芬克洛芬，奥沙普秦，芬布芬，西班牙毒素，酮咯酸，氯吡旦和相关化合物，以达到不断优化的治疗血液水平，以增加有效性并减少NSAIA的副作用。 经皮给药这些前药的另一大好处是给予药物，尤其是给儿童服用药物将容易得多。

公开(公告)号：WO2008012605A1

公开(公告)日：2008-01-31

申请号：PCT/IB2006/052575

申请日：2006-07-27

Applicant: TECHFIELDS BIOCHEM CO. LTD ,  YU, Chongxi ,  XU, Lina

Inventor： YU, Chongxi ,  XU, Lina

IPC: C07C215/72 ,  C07C215/40 ,  C07C215/42 ,  C07C225/16

CPC classification number: C07C219/14 ,  C07C235/34

Abstract: The novel positively charged pro-drugs of ketoprofen and fenoprofen 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 from functional derivatives of ketoprofen and fenoprofen, (for example acid halides or mixed anhydrides), by reaction with suitable alcohols, thiols, or amines. 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, diethylaminoethyl 2-(3-benzoylphenyl) propionate.AcOH and diethylaminoethyl 2-(3-phenoxyphenyl) propionate.AcOH diffuses through human skin ~125 times faster than does ketoprofen and fenoprofen. It takes 1-2 hours for ketoprofen or fenoprofen to reach the peak ketoprofen or fenoprofen plasma level when they are taken orally, but diethylaminoethyl 2-(3-benzoylphenyl) propionate.AcOH or diethylaminoethyl 2-(3-phenoxyphenyl) propionate.AcOH only took about 40 minutes to reach the ketoprofen or fenoprofen peak plasma level. 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 ketoprofen and fenoprofen-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 ketoprofen and fenoprofen, most notably GI disturbances such as dyspepsia, gastroduodenal bleeding, gastric ulcerations, and gastritis. Controlled transdermal administration systems of the prodrug enables ketoprofen and fenoprofen to reach constantly optimal therapeutic blood levels to increase effectiveness and reduce the side effects of ketoprofen and fenoprofen. Another great benefit of transdermal administration of these pro-drugs is that administering medication, especially to children, will be much easier.

Abstract translation: 设计并合成了通式（1）“结构1”中酮洛芬和非诺洛芬的新型带正电荷的前药。 上述通式（1）'结构1'的化合物可以通过与合适的醇，硫醇或胺的反应由酮洛芬和非诺洛芬的功能衍生物（例如酰卤或混合酸酐）制备。 这些前药的带正电荷的氨基不仅大大增加了药物的溶解度，而且还与磷酸盐头基团上的负电荷键合，并将前药推入细胞溶质中。 结果表明，前药，2-（3-苯甲酰基苯基）丙酸二乙基氨基乙酯，AcOH和2-（3-苯氧基苯基）丙酸二乙基氨基乙酯。通过人皮肤扩散至酮洛芬和非诺洛芬的125倍。 口服口服酮洛芬或非诺洛芬时，需要1-2小时才能达到酮洛芬或非诺洛芬血药浓度，但2-（3-苯甲酰基苯基）丙酸二乙氨基乙酯。乙酸或二乙基氨基乙基2-（3-苯氧基苯基）丙酸酯。仅AcOH 花了约40分钟达到酮洛芬或非诺洛芬峰值血浆水平。 在血浆中，超过90％的这些前药可以在几分钟内恢复到药物。 前药可以在医学上用于治疗人或动物中的任何酮洛芬和非诺洛芬治疗性病症。 前药可以不仅口服给药，而且可以经皮用于任何种类的药物治疗，并避免酮洛芬和非诺洛芬的大部分副作用，最明显的是GI紊乱如消化不良，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酮洛芬和非诺洛芬达到不断优化的治疗血液水平以增加效力并降低酮洛芬和非诺洛芬的副作用。 经皮给药这些前药的另一大好处是给予药物，尤其是给儿童服用药物将容易得多。

公开(公告)号：WO2008012602A1

公开(公告)日：2008-01-31

申请号：PCT/IB2006/052549

申请日：2006-07-25

Applicant: TECHFIELDS BIOCHEM CO. LTD ,  YU, Chongxi ,  XU, Lina

Inventor： YU, Chongxi ,  XU, Lina

IPC: C07C215/40 ,  C07C215/42

CPC classification number: C07C229/42 ,  C07C237/20

Abstract: The novel positively charged pro-drugs of diclofenac 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 from functional derivatives of diclofenac (for example acid halides or mixed anhydrides), by reaction with suitable alcohols, thiols, or amines. 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 push the pro-drug into the cytosol. The experiment results suggest that the pro-drug, diethylaminoethyl 2[(2,6-dichlorophenyl)amino]benzene acetate.AcOH diffuses through human skin ~250 times faster than do 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 the diclofenac to reach constantly optimal therapeutic blood levels to increase effectiveness and reduce the side effects of diclofenac.

Abstract translation: 设计并合成了通式（1）“结构1”中双氯芬酸新型带正电荷的前药。 上述通式（1）'结构1'的化合物可以通过与合适的醇，硫醇或胺的反应由双氯芬酸（例如酰卤或混合酸酐）的官能衍生物制备。 这些前药的带正电荷的氨基不仅大大提高了药物在水中的溶解度，而且还与磷酸盐头基上的负电荷键合，并将前药推入细胞溶质中。 实验结果表明，原药二乙氨基乙基2 [（2,6-二氯苯基）氨基]苯乙酸乙酯通过人皮肤扩散比2 [（2,6-二氯苯基）氨基]苯乙酸快250倍 （双氯芬酸）和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恢复到药物。 前药可用于医学上用于治疗人或动物中的任何双氯芬酸可治疗病症，并且不仅口服给药，而且经皮用于任何种类的医疗治疗，并避免双氯芬酸的大多数副作用，最引人注目的是GI紊乱如消化不良 胃十二指肠出血，胃溃疡和胃炎。 前药的对照经皮给药系统使得双氯芬酸能够达到不断优化的治疗血液水平，从而提高效力并降低双氯芬酸的副作用。

公开(公告)号：WO2008041059A1

公开(公告)日：2008-04-10

申请号：PCT/IB2006/053619

申请日：2006-10-03

Applicant: TECHFIELDS BIOCHEM CO. LTD ,  YU, Chongxi ,  XU, Lina

Inventor： YU, Chongxi ,  XU, Lina

IPC: C07C215/40 ,  C07C215/42

CPC classification number: C07C233/47 ,  C07C229/42 ,  C07F9/242 ,  C07F9/2429 ,  C07F9/2458

Abstract: The novel positively charged pro-drugs of mustards 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 from mustards 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 ~100 times faster than do mustards 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 mustards 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 mustards and related compounds. Controlled transdermal administration systems of the prodrug enables mustards and related compounds to reach constantly optimal therapeutic blood levels to increase effectiveness and reduce the side effects of mustards and related compounds. Another great benefit of transdermal administration of these pro-drugs is that administering medication, especially to children, will be much easier.

Abstract translation: 设计并合成了通式（1）“结构1”中芥末和相关化合物的新型带正电荷的前药物。 上述通式（1）'结构1'的化合物可以通过与合适的醇，硫醇或胺和偶联试剂如N，N'-二环己基碳二亚胺，N，N N'-二异丙基碳二亚胺，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'-四甲基脲六氟磷酸盐， 苯并三唑-1-基 - 氧 - 三（二甲氨基）鏻六氟磷酸盐等。 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，而且还与磷酸盐头基上的负电荷键合，并将前药推入胞质溶胶中。 结果表明，前药通过人体皮肤扩散比芥末和相关化合物快100倍。 在血浆中，超过90％的这些前药可以在几分钟内改变为母体药物。 前药可以在医学上用于治疗人或动物中的任何芥末和相关化合物 - 可治疗的病症。 前药可以经皮施用于任何种类的医学治疗，并避免芥末和相关化合物的大部分副作用。 前药的受控透皮给药系统使芥末和相关化合物能够达到不断优化的治疗血液水平，以提高芥末和相关化合物的有效性并降低副作用。 经皮给药这些前药的另一大好处是给予药物，尤其是给儿童服用药物将容易得多。

公开(公告)号：WO2008010025A1

公开(公告)日：2008-01-24

申请号：PCT/IB2006/052461

申请日：2006-07-18

Applicant: TECHFIELDS BIOCHEM CO. LTD ,  YU, Chongxi ,  XU, Lina

Inventor： YU, Chongxi ,  XU, Lina

IPC: C07C211/63

CPC classification number: C07C233/40 ,  C07C211/63 ,  C07C327/30

Abstract: The novel positively charged pro-drugs of ibuprofen in the general formula (I) "Structure 1" were designed and synthesized. The compounds of the general formula (I) "Structure 1" indicated above can be prepared from functional derivatives of ibuprofen, (for example acid halides or mixed anhydrides), by reaction with suitable alcohols, thiols, or amines. 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 experiment results suggest that the pro-drug, diethylaminoethyl 2-(p-isobutylphenyl) propionate.AcOH, diffuses through human skin -250 times faster than ibuprofen itself and -125 times faster than ethyl 2-(p-isobutylphenyl) propionate. 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 ibuprofen-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 ibuprofen, most notably GI disturbances such as dyspepsia, gastroduodenal bleeding, gastric ulcerations, and gastritis. Controlled transdermal administration systems of the prodrug enables the ibuprofen to reach constantly optimal therapeutic blood levels to increase effectiveness and reduce the side effects of ibuprofen.

Abstract translation: 设计并合成了通式（I）“结构1”中布洛芬的新型带正电荷的前药。 上述通式（I）“结构1”的化合物可以通过与合适的醇，硫醇或胺的反应由布洛芬（例如酰卤或混合酸酐）的官能衍生物制备。 这些前药的带正电荷的氨基不仅大大增加了药物的溶解度，而且还与磷酸盐头基团上的负电荷键合，并将前药推入细胞溶质中。 实验结果表明，原药二乙基氨基乙基2-（对异丁基苯基）丙酸酯，AcOH通过人体皮肤扩散比布洛芬本身快250倍，比2-（对异丁基苯基）丙酸乙酯快125倍。 在血浆中，超过90％的这些前药可以在几分钟内恢复到药物。 前药可用于医学上用于治疗人或动物中的任何布洛芬治疗性病症，并且不仅口服给药，而且经皮用于任何种类的医疗治疗，并避免布洛芬的大部分副作用，尤其是GI紊乱如消化不良 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布洛芬能够达到不断优化的治疗血液水平以增加有效性并降低布洛芬的副作用。

公开(公告)号：WO2008007171A1

公开(公告)日：2008-01-17

申请号：PCT/IB2006/052318

申请日：2006-07-09

Applicant: TECHFIELDS BIOCHEM CO. LTD ,  YU, Chongxi ,  XU, Lina

Inventor： YU, Chongxi ,  XU, Lina

IPC: C07C235/42 ,  C07C235/16 ,  C07C211/64

CPC classification number: C07C219/14 ,  C07C235/60 ,  C07C327/30

Abstract: The novel positively charged prodrugs of acetylsalicylic acid and its analogues 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 from functional derivatives of ASA or its analogues,(for example acid halides or mixed anhydrides), by reaction with suitable alcohols, thiols, or amines. 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 push the pro-drug into the cytosol. The experiment results suggest that the pro-drug, diethylaminoethyl acetylsalicylate.AcOH, diffuses through human skin ~400 times faster than acetylsalicylic acid itself and ~100 times faster than ethyl acetylsalicylate. In plasma, 80% of these pro-drugs can change back to the drug in a few minutes. The pro-drugs can be used medicinally in treating any aspirin-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 aspirin, most notably GI disturbances such as dyspepsia, gastroduodenal bleeding, gastric ulcerations, and gastritis. Controlled transdermal administration systems of the prodrug enables the aspirin to reach constantly optimal therapeutic blood levels to increase effectiveness and reduce the side effects of aspirin.

Abstract translation: 设计并合成了通式（1）“结构1”中乙酰水杨酸及其类似物的新型带正电荷前体药物。 上述通式（1）“结构1”的化合物可以由ASA或其类似物的官能衍生物（例如酰卤或混合酸酐）通过与合适的醇，硫醇或胺的反应制备。 这些前药的带正电荷的氨基不仅大大增加药物的溶解度，而且还与磷酸盐头基上的负电荷键合，并将前药推入细胞溶质中。 实验结果表明，前药二乙氨基乙酰水杨酸AcAc通过人皮肤扩散至乙酰水杨酸本身的400倍，乙酰水杨酸乙酯比乙酰水杨酸乙酯快100倍。 在等离子体中，这些前药中有80％可以在几分钟内恢复药物。 前药可以在医学上用于治疗人或动物中的任何阿斯匹林可治疗的病症，并且不仅口服给药，而且经皮用于任何种类的治疗，并且避免阿司匹林的大部分副作用，特别是GI紊乱 如消化不良，胃十二指肠出血，胃溃疡和胃炎。 前药的控制透皮给药系统使得阿司匹林能够达到不断优化的治疗血液水平以增加有效性并降低阿司匹林的副作用。