公开(公告)号：US5314905A

公开(公告)日：1994-05-24

申请号：US973174

申请日：1992-11-09

Applicant: Ravindra K. Pandey ,  Thomas J. Dougherty

Inventor： Ravindra K. Pandey ,  Thomas J. Dougherty

IPC: A61K31/40 ,  A61K41/00 ,  A61K51/04 ,  A61P31/12 ,  A61P35/00 ,  C07D487/22 ,  C07D519/00

CPC classification number: C07D487/22 ,  A61K41/0071 ,  A61K51/0485 ,  C07D519/00 ,  A61K2123/00

Abstract: Conjugate are formed by covalently linking a target-specific compound to pyropheophorbide compound which conjugated are injected into a host and accumulate in tumor tissue to a higher degree than surrounding normal tissues. When the pyropheophorbide compound component of the conjugate is exposed to a particular wavelength of light the compound becomes cytotoxic destroying the tumor or diseased tissue without causing irreversible normal tissue damage. The pyropheophorbide compounds have been shown to have a variety of characteristics when used in photodynamic therapy. These characteristics are further improved when the compounds are bound to a target specific component such as a ligand capable of binding to a specific cellular receptor (e.g. growth hormones and growth factors) or an antibody capable of binding to a particular antigen.

Abstract translation: 共轭体通过将靶特异性化合物与焦磷酸脱氢化合物共价连接而形成，所述化合物与缀合物注入宿主中，并且在肿瘤组织中积聚到比周围正常组织更高的程度。 当缀合物的焦偏心复合物组分暴露于特定波长的光时，该化合物变得细胞毒性破坏肿瘤或患病组织而不引起不可逆的正常组织损伤。 已经显示焦磷酸脱氢化合物在用于光动力疗法中具有多种特征。 当化合物结合到靶特异性组分如能够结合特定细胞受体的配体（例如生长激素和生长因子）或能够结合特定抗原的抗体时，这些特征进一步改善。

公开(公告)号：US5225433A

公开(公告)日：1993-07-06

申请号：US724749

申请日：1991-07-02

Applicant: Thomas J. Dougherty ,  William R. Potter ,  Kenneth R. Weishaupt

Inventor： Thomas J. Dougherty ,  William R. Potter ,  Kenneth R. Weishaupt

IPC: A61B5/00 ,  A61K31/40 ,  A61K41/00 ,  A61K49/00 ,  A61K51/00 ,  A61N5/06 ,  A61P35/00 ,  A61P43/00 ,  C07D487/22 ,  C07D519/00 ,  C09B47/00 ,  G02B6/04 ,  G02B6/26 ,  G02B6/42

CPC classification number: A61K31/40 ,  A61B5/411 ,  A61B5/416 ,  A61K41/0071 ,  A61N5/0601 ,  A61N5/062 ,  C07D519/00 ,  G02B6/262 ,  G02B6/4204 ,  A61B5/0071 ,  A61B5/0084 ,  G02B6/4298 ,  Y10S607/901

Abstract: To obtain tumor-selective, photosensitizing drugs useful in the localization of neoplastic tissue and treatment of abnormal neoplastic tissue such as tumors, one of two methods is used. In the first method, a hydrolyzed mixture of the products of reaction of hematoporphyrin with acetic acid and sulfuric acid is cycled through a microporous membrane system to exclude low molecular weight products. In the second method, drugs are synthesized or derived from other pyrrole compounds. The drugs: (1) include two covalently bound groups, each with four rings, some of which are pyrroles such as phlorins, porphyrins, chlorins, substituted pyrroles, substituted chlorins or substituted phlorins, each group being arranged in a ring structure, connected covalently to another group and have a triplet energy state above 37.5 kilocalories per mole; (2) are soluble in water, forming an aggregate of over 10,000 molecular weight in water and have an affinity for each other compared to serum protein such that 10 to 100 per cent remain self aggregated in serum protein; and (3) are lipophyllic and able to disaggregate and attach to cell plasma, nuclear membrane, mitochondria, lysosomes and tissue. The drug obtained by the first method has an empirical formula of approximately C.sub.68 H.sub.70 N.sub.8 O.sub.11 or C.sub.68 H.sub.66 N.sub.8 O.sub.11 Na.sub.4. Neoplastic tissue retains the drug after it has cleared normal tissues and illumination results in necrosis. Moreover, other photosensitizing materials may be combined with a carrier that enters undesirable tissues and cells of the reticular endothelial system such as macrophages. These photosensitizing materials: (1) must have a triplet energy state above 3.5 kilocalories per mole; (2) cannot be easily oxidized; and (3) not physically quench any required energy state. Preferably, this photosensitizing material should be liRIGHTS IN THE U.S. GOVERNMENTThis invention was made with federal support under research grants CA 30840-01 and CA 16717 and contract No. 1-CM-97311, awarded by the National Career Institute, U.S. Department of Health and Human Services. The Government has certain rights to this invention.

Abstract translation: 为了获得肿瘤选择性的光敏药物，可用于肿瘤组织的定位和治疗异常肿瘤组织如肿瘤，使用两种方法之一。 在第一种方法中，血卟啉与乙酸和硫酸的反应产物的水解混合物循环通过微孔膜系统以排除低分子量产物。 在第二种方法中，合成或衍生自其他吡咯化合物的药物。 药物：（1）包括两个共价结合的基团，每个具有四个环，其中一些是吡咯，例如卟啉，卟啉，二氢卟酚，取代的吡咯，取代的二氢卟酚或取代的藜芦烯，每个组排列成环结构，共价连接 到另一组，并具有高于每摩尔37.5千卡的三线态能量状态; （2）可溶于水，在水中形成超过10,000分子量的聚集体，并且与血清蛋白质相互之间具有亲和力，使得10％至100％在血清蛋白中保持自我聚集; 和（3）是脂蛋白的并且能够解聚并附着于细胞血浆，核膜，线粒体，溶酶体和组织。 通过第一种方法获得的药物具有约C68H70N8O11或C68H66N8O11Na4的经验式。 肿瘤组织清除正常组织后保留药物，照明会导致坏死。 此外，其它光敏材料可以与进入网状内皮系统的不希望的组织和细胞如巨噬细胞的载体组合。 这些光敏材料：（1）必须具有每千克3.5千卡以上的三线态能量状态; （2）不易氧化; 和（3）不能物理地淬灭任何所需的能量状态。 优选地，该光敏材料应该是脂肪族的。

公开(公告)号：US5198460A

公开(公告)日：1993-03-30

申请号：US822409

申请日：1992-01-17

Applicant: Ravindra K. Pandey ,  Thomas J. Dougherty

Inventor： Ravindra K. Pandey ,  Thomas J. Dougherty

IPC: A61K31/40 ,  A61K31/409 ,  A61K41/00 ,  A61K51/04 ,  A61P9/10 ,  A61P17/06 ,  A61P17/12 ,  A61P31/04 ,  A61P31/10 ,  A61P31/12 ,  A61P35/00 ,  C07D487/22 ,  C07D519/00

CPC classification number: A61K51/0485 ,  A61K41/0071 ,  C07D487/22 ,  C07D519/00 ,  A61K2123/00

Abstract: Pyropheophorbide compounds are injected into a host and accumulate in tumor tissue to a higher degree than surrounding normal tissues. When the pyropheophorbide compounds are exposed to a particular wavelength of light the compounds become cytotoxic and destroy the tumor or diseased tissue without causing irreversible normal tissue damage. The pyropheophorbide compounds have shown improved results as compared to drugs currently used in photodynamic therapy. Further, they absorb light further in the red, optimizing tissue penetration and are retained in the skin for short time periods relative to other drugs used in photodynamic therapy.

Abstract translation: 将焦磷偏磷酸酯化合物注射到宿主中并在肿瘤组织中积聚到比周围正常组织更高的程度。 当焦偏磷酸酯化合物暴露于特定波长的光时，化合物变成细胞毒性并破坏肿瘤或患病组织而不引起不可逆的正常组织损伤。 与目前在光动力疗法中使用的药物相比，焦偏镁离子化合物显示出改善的结果。 此外，它们进一步吸收红色的光，优化组织穿透，并相对于光动力疗法中使用的其他药物，在短时间内保留在皮肤中。

公开(公告)号：US5190966A

公开(公告)日：1993-03-02

申请号：US584204

申请日：1990-09-18

Applicant: Thomas J. Dougherty ,  Ravindra K. Pandey

Inventor： Thomas J. Dougherty ,  Ravindra K. Pandey

IPC: A61K31/40 ,  A61K41/00 ,  C07D519/00

CPC classification number: C07D519/00 ,  A61K31/40 ,  A61K41/0071

Abstract: Pure dimer and trimer compounds of hematoporphyrin are prepared and shown to be effective agents in photodynamic therapy. The compounds of the invention are of the formula ##STR1## wherein each X is independently 1-hydroxyethyl or vinyl and wherein R is H or lower alkyl. The compounds of the invention can be conjugated to targeting substances such as immunoglobulins or to labels.

Abstract translation: 制备血卟啉的纯二聚体和三聚体化合物，并显示为光动力学治疗中的有效试剂。 本发明的化合物具有下式：其中每个X独立地是1-羟基乙基或乙烯基，并且其中R是H或更低的（R 1，R 2，R 3， 烷基。 本发明的化合物可以与靶向物质例如免疫球蛋白缀合，或与标记缀合。

公开(公告)号：US5171741A

公开(公告)日：1992-12-15

申请号：US341591

申请日：1989-04-21

Applicant: Thomas J. Dougherty

Inventor： Thomas J. Dougherty

IPC: A61K31/555 ,  A61K41/00 ,  A61K49/00 ,  A61P31/04 ,  A61P31/10 ,  A61P31/14 ,  A61P31/20 ,  A61P33/00 ,  A61P35/00 ,  C07D487/22 ,  C07F20060101 ,  G01N33/50 ,  G01N33/58

CPC classification number: C07D487/22 ,  A61K41/0071

Abstract: Compounds of fomula (1) or formula (2): ##STR1## wherein M is a non-paramagnetic metal selected from Mg.sup.+2, and Zn.sup.+2, or represents 2 H.sup.+ each H.sup.+ bonded to one of the N atoms connected by the solid lines;R.sup.1 is a saturated or unsaturated hydrocarbyl residue of 8-25C;each R.sup.2 is independently selected from the group consisting of vinyl, ethyl, acetyl and 1-hydroxyethyl, andX is COOR.sup.3, wherein R.sup.3 is alkyl (1-4C);are useful in photodynamic therapy and diagnosis.These compounds photosensitize target biological substrates to irradiation, and treating said substrates with these sensitizers followed by irradiation leads to the impairment or destruction of the biological substrate. When administered systemically, these compounds accumulate in the undesired target biological substrate. The compounds can also be utilized in vitro, for example to destroy infectious cells or viruses in blood intended for transfusion.

Abstract translation: （1）或式（2）的化合物：其中M是选自Mg +2和Zn + 2的非顺磁性金属，或表示2 H +，每个H +键合 通过实线连接的N个原子之一; R1是8-25℃的饱和或不饱和烃基残基; 每个R 2独立地选自乙烯基，乙基，乙酰基和1-羟乙基，X是COOR 3，其中R 3是烷基（1-4C）; 可用于光动力疗法和诊断。 这些化合物对目标生物底物进行光敏照射，用这些敏化剂处理所述底物，然后照射导致生物底物的损伤或破坏。 当全身施用时，这些化合物积聚在不需要的靶生物底物中。 也可以在体外使用这些化合物，例如以破坏用于输血的血液中的感染性细胞或病毒。

公开(公告)号：US5156932A

公开(公告)日：1992-10-20

申请号：US694907

申请日：1991-05-02

Applicant: Thomas J. Dougherty ,  James S. Symanski

Inventor： Thomas J. Dougherty ,  James S. Symanski

IPC: H01M2/12 ,  H01M2/24 ,  H01M10/18

CPC classification number: H01M2/1288 ,  H01M10/18 ,  H01M2/1229 ,  H01M2/24 ,  Y10T29/4911

Abstract: A simple, optimized lead-acid battery includes a stack of a plurality of film pouches, each containing positive and negative electrode elements and separators. The pouches are prepared by folding an elongate film strip, and collector tabs are provided for the electrodes at either end of the stack. Electrode pairs intermediate the ends of the stack are electrically connected through adjoining openings in the pouch walls, e.g. be welding. In the most preferred embodiment, an integral vent is formed from flaps cut in the film strip and the pouch edges and top are heat sealed for electrolyte containment.

Abstract translation: 一种简单优化的铅酸电池包括多个膜袋的叠层，每个胶囊包含正极和负极元件和隔板。 通过折叠细长的薄膜条制备袋，并且为堆叠的任一端处的电极提供收集器突片。 在堆叠的端部之间中间的电极对通过袋壁中的相邻开口电连接，例如， 焊接。 在最优选的实施例中，整体通风口由在薄膜条中切割的薄片形成，并且袋边缘和顶部被热密封用于电解液容纳。

公开(公告)号：US5145863A

公开(公告)日：1992-09-08

申请号：US624410

申请日：1990-12-04

Applicant: Thomas J. Dougherty ,  William R. Potter ,  Kenneth R. Weishaupt

Inventor： Thomas J. Dougherty ,  William R. Potter ,  Kenneth R. Weishaupt

IPC: A61B5/00 ,  A61K31/40 ,  A61K41/00 ,  A61K49/00 ,  A61K51/00 ,  A61N5/06 ,  A61P35/00 ,  A61P43/00 ,  C07D487/22 ,  C07D519/00 ,  C09B47/00 ,  G02B6/04 ,  G02B6/26 ,  G02B6/42

CPC classification number: A61K31/40 ,  A61B5/411 ,  A61B5/416 ,  A61K41/0071 ,  A61N5/0601 ,  A61N5/062 ,  C07D519/00 ,  G02B6/262 ,  G02B6/4204 ,  A61B5/0071 ,  A61B5/0084 ,  G02B6/4298 ,  Y10S607/901

Abstract: To obtain tumor-selective, photosensitizing drugs useful in the localization of neoplastic tissue and treatment of abnormal neoplastic tissue such as tumors, one of two methods is used. In the first method, a hydrolyzed mixture of the products of reaction of hematoporphyrin with acetic acid and sulfuric acid is cycled through a microporous membrane system to exclude low molecular weight products. In the second method, drugs are synthesized or derived from other pyrrole compounds. The drugs: (1) include two covalently bound groups, each with four rings, some of which are pyrroles such as phlorins, porphyrins, chlorins, substituted pyrroles, substituted chlorins or substituted phlorins, each group being arranged in a ring structure, connected covalently to another group and have a triplet energy state above 37.5 kilocalories per mole; (2) are soluble in water, forming an aggregate of over 10,000 molecular weight in water and have an affinity for each other compared to serum protein such that 10 to 100 percent remain self aggregated in serum protein; and (3) are lipophyllic and able to disaggregate and attach to cell plasma, nuclear membrane, mitochondria, lysosomes and tissue. The drug obtained by the first method has an empirical formula of approximately C.sub.68 H.sub.70 N.sub.8 O.sub.11 or C.sub.68 H.sub.66 N.sub.8 O.sub.11 Na.sub.4. Neoplastic tissue retains the drug after it has cleared normal tissues and illumination results in necrosis. Moreover, other photosensitizing materials may be combined with a carrier that enters undesirable tissues and cells of the reticular endothelial system such as macrophages. These photosensitizing materials: (1) must have a triplet energy state above 3.5 kilocalories per mole; (2) cannot be easily oxidized; and (3) not physically quench any required energy state. Preferably, this photosensitizing material should be lipophlic.

Abstract translation: 为了获得肿瘤选择性的光敏药物，可用于肿瘤组织的定位和治疗异常肿瘤组织如肿瘤，使用两种方法之一。 在第一种方法中，血卟啉与乙酸和硫酸的反应产物的水解混合物循环通过微孔膜系统以排除低分子量产物。 在第二种方法中，合成或衍生自其他吡咯化合物的药物。 药物：（1）包括两个共价结合的基团，每个具有四个环，其中一些是吡咯，例如卟啉，卟啉，二氢卟酚，取代的吡咯，取代的二氢卟酚或取代的藜芦烯，每个组排列成环结构，共价连接 到另一组，并具有高于每摩尔37.5千卡的三线态能量状态; （2）可溶于水，与血清蛋白质相比，在水中形成了超过10,000分子量的聚集体，并且与血清蛋白质具有亲和力，使得10％至100％在血清蛋白中保持自我聚集; 和（3）是脂蛋白的并且能够解聚并附着于细胞血浆，核膜，线粒体，溶酶体和组织。 通过第一种方法获得的药物具有约C68H70N8O11或C68H66N8O11Na4的经验式。 肿瘤组织清除正常组织后保留药物，照明会导致坏死。 此外，其它光敏材料可以与进入网状内皮系统的不希望的组织和细胞如巨噬细胞的载体组合。 这些光敏材料：（1）必须具有每千克3.5千卡以上的三线态能量状态; （2）不易氧化; 和（3）不能物理地淬灭任何所需的能量状态。 优选地，该光敏材料应该是脂肪族的。

公开(公告)号：US5093349A

公开(公告)日：1992-03-03

申请号：US597786

申请日：1990-10-15

Applicant: Ravindra K. Pandey ,  Thomas J. Dougherty

Inventor： Ravindra K. Pandey ,  Thomas J. Dougherty

IPC: A61K41/00 ,  C07D487/22 ,  C07D519/00

CPC classification number: C07D487/22 ,  A61K41/0071 ,  C07D519/00

Abstract: New classes of photosensitizing compounds useful in photodynamic therapy are disclosed. These compounds are simplified dimers and polymers of monohydroxy deuteroporphyrins, hydrophobic ethers of these monomers, and red light-absorbing derivatives of methyl pheophorbide-a.

Abstract translation: 公开了可用于光动力学治疗的新类型的光敏化合物。 这些化合物是简单的二聚体和单羟基氘卟啉的聚合物，这些单体的疏水性醚，以及脱镁叶绿酸甲酯的红光吸收衍生物。

公开(公告)号：US5015463A

公开(公告)日：1991-05-14

申请号：US515179

申请日：1990-04-26

Applicant: Thomas J. Dougherty ,  William R. Potter ,  Kenneth R. Weishaupt

Inventor： Thomas J. Dougherty ,  William R. Potter ,  Kenneth R. Weishaupt

IPC: A61B5/00 ,  A61K31/40 ,  A61K41/00 ,  A61K49/00 ,  A61K51/00 ,  A61N5/06 ,  A61P35/00 ,  A61P43/00 ,  C07D487/22 ,  C07D519/00 ,  C09B47/00 ,  G02B6/04 ,  G02B6/26 ,  G02B6/42

CPC classification number: A61K31/40 ,  A61B5/411 ,  A61B5/416 ,  A61K41/0071 ,  A61N5/0601 ,  A61N5/062 ,  C07D519/00 ,  G02B6/262 ,  G02B6/4204 ,  A61B5/0071 ,  A61B5/0084 ,  G02B6/4298 ,  Y10S607/901

Abstract: A photosensitizing composition prepared by recovering a portion of hematoporphyrin derivative which has aggregate weight of more than 10 kd is useful in locating tumor tissue to which this improved photosensitizing drug homes. In the invention method, the subject is administered the improved drug and sufficient time is allowed to pass to permit accumulation of the drug in tumor tissue. The subject is then illuminated at suspected sites with radiation capable of absorption by the improved drug and which radiation produces fluorescence by the drug. Detection of the intensity of fluorescence indicates the quantity of drug at the measured location and permits assessment as to whether a tumor is present at that location.

Abstract translation: 通过回收聚集体重超过10kd的血卟啉衍生物的一部分制备的光敏组合物可用于定位这种改善的光敏药物所在的肿瘤组织。 在本发明方法中，给予受试者改进的药物，并允许足够的时间通过以允许药物在肿瘤组织中的积累。 然后将受试者照射到具有能够被改良药物吸收的辐射的可疑位置，并且该辐射由药物产生荧光。 荧光强度的检测表示在测量位置的药物数量，并且允许评估肿瘤是否存在于该位置。

公开(公告)号：US4866168A

公开(公告)日：1989-09-12

申请号：US889829

申请日：1986-07-24

Applicant: Thomas J. Dougherty ,  William R. Potter ,  Kenneth R. Weishaupt

Inventor： Thomas J. Dougherty ,  William R. Potter ,  Kenneth R. Weishaupt

IPC: A61B5/00 ,  A61K31/40 ,  A61K41/00 ,  A61K49/00 ,  A61K51/00 ,  A61N5/06 ,  A61P35/00 ,  A61P43/00 ,  C07D487/22 ,  C07D519/00 ,  C09B47/00 ,  G02B6/04 ,  G02B6/26 ,  G02B6/42

CPC classification number: A61K31/40 ,  A61B5/411 ,  A61B5/416 ,  A61K41/0071 ,  A61N5/0601 ,  A61N5/062 ,  C07D519/00 ,  G02B6/262 ,  G02B6/4204 ,  A61B5/0071 ,  A61B5/0084 ,  G02B6/4298 ,  Y10S607/901

Abstract: To obtain tumor-selective, photosensitizing drugs useful in the localization of neoplastic tissue and treatment of abnormal neoplastic tissue such as tumors, one of two methods is used. In the first method, a hydrolyzed mixture of the products of reaction of hematoporphyrin with acetic acid and sulfuric acid is cycled through a microporous membrane system to exclude low molecular weight products. In the second method, drugs are synthesized or derived from other pyrrole compounds. The drugs: (1) include two covalently bound groups, each with four rings, some of which are pyrroles such as phlorins, porphyrins, chlorins, substituted pyrroles, substituted chlorins or substituted phlorins, each group being arranged in a ring structure, connected covalently to another group and have a triplet energy state above 37.5 kilocalories per mole; (2) are soluble in water, forming an aggregate of over 10,000 molecular weight in water and have an affinity for each other compared to serum protein such that 10 to 100 percent remain self aggregated in serum protein; and (3) are lipophyllic and able to disaggregate and attach to cell plasma, nuclear membrane, mitochondria, lysosomes and tissue. The drug obtained by the first method has an empirical formula of approximately C.sub.68 H.sub.70 N.sub.8 O.sub.11 or C.sub.68 H.sub.66 N.sub.8 O.sub.11 Na.sub.4. Neoplastic tissue retains the drug after it has cleared normal tissues and illumination results in necrosis. Moreover, other photosensitizing materials may be combined with a carrier that enters undesirable tissues and cells of the reticular endothelial system such as macrophages. These photosensitizing materials: (1) must have a triplet energy state above 3.5 kilocalories per mole; (2) cannot be easily oxidized; and (3) not physically quench any required energy state. Preferably, this photosensitizing material should be lipophlic.

Abstract translation: 为了获得肿瘤选择性的光敏药物，可用于肿瘤组织的定位和治疗异常肿瘤组织如肿瘤，使用两种方法之一。 在第一种方法中，血卟啉与乙酸和硫酸的反应产物的水解混合物循环通过微孔膜系统以排除低分子量产物。 在第二种方法中，合成或衍生自其他吡咯化合物的药物。 药物：（1）包括两个共价结合的基团，每个具有四个环，其中一些是吡咯，例如卟啉，卟啉，二氢卟酚，取代的吡咯，取代的二氢卟酚或取代的藜芦烯，每个组排列成环结构，共价连接 到另一组，并具有高于每摩尔37.5千卡的三线态能量状态; （2）可溶于水，与血清蛋白质相比，在水中形成了超过10,000分子量的聚集体，并且与血清蛋白质具有亲和力，使得10％至100％在血清蛋白中保持自我聚集; 和（3）是脂蛋白的并且能够解聚并附着于细胞血浆，核膜，线粒体，溶酶体和组织。 通过第一种方法获得的药物具有约C68H70N8O11或C68H66N8O11Na4的经验式。 肿瘤组织清除正常组织后保留药物，照明会导致坏死。 此外，其它光敏材料可以与进入网状内皮系统的不希望的组织和细胞如巨噬细胞的载体组合。 这些光敏材料：（1）必须具有每千克3.5千卡以上的三线态能量状态; （2）不易氧化; 和（3）不能物理地淬灭任何所需的能量状态。 优选地，该光敏材料应该是脂肪族的。