公开(公告)号：WO0031081A3

公开(公告)日：2000-11-23

申请号：PCT/US9927739

申请日：1999-11-24

Applicant: BUCKMAN LABOR INC ,  HEINDEL NED D ,  LASKIN JEFFREY D ,  HECK DIANE E ,  RAPP ROBERT D ,  MCNEEL THOMAS E ,  JABIN IVAN ,  WHITTEMORE MARILYN S

Inventor： HEINDEL NED D ,  LASKIN JEFFREY D ,  HECK DIANE E ,  RAPP ROBERT D ,  MCNEEL THOMAS E ,  JABIN IVAN ,  WHITTEMORE MARILYN S

IPC: A61P17/06 ,  A61P35/00 ,  C07D311/44 ,  C07D311/56 ,  C07D493/04 ,  C07F3/14 ,  A61K31/34

CPC classification number: C07D493/04 ,  C07D311/44 ,  C07D311/56 ,  C07F3/14

Abstract: 5'- substituted, 4', 5'- dihydropsoralen compounds (5) bearing tertiary amines (and salts thereof), quaternary ammonium moieties or organomercurial moieties are described. Also described are 2- substituted mercurimethyl -2-3- dihydro -benzofurans of formula (7). Also reported are versatile direct syntheses through a hitherto unknown compounds such as 3-R-4, 8-dimethyl -4',5'-dihydro -5'-bromomethylpsoralen or a 3-R-4, 8-dimethyl-4, 5'-dihydro- 5'-iodomethylpsoralen to prepare a structurally diverse array of partially reduced psoralens and benzofurans. The presence of a permanent ammonium charge in these psoralens precludes membrane passage and the mono-unsaturation precludes the cross linking of nuclear DNA, thereby minimizing the mutagenic/carcinogenic side effects long associated with psoralen-derived therapies. The presence of a mercury functionality provides a reactive cell-binding group on these psoralens with unique cytotoxicity without light activation and an enhancement of cytotoxicity activity upon light activation. The invention also relates to these partially reduced and quaternized psoralens, amino-substituted psoralens, and mercurio psoralens display impressive pharmacology against PAM 212 keratinocytes, a model cell line employed as a test system to indicate epidermal cytotoxicity and cancer. The compounds of the invention also have antimicrobicidal activity useful in pharmacologic agents for mammals (e.g. the treatment of tuberculosis) as well as in controlling the growth of microorganisms on substrates and in aqueous systems.

Abstract translation: 描述了带有叔胺（及其盐），季铵部分或有机金属部分的5'-取代的，4'，5'-二氢补骨脂化合物（5）。 还描述了式（7）的2-取代的汞甲基-2-3-二氢 - 苯并呋喃。 还报道了通过迄今未知的化合物如3-R-4,8-​​二甲基-4'，5'-二氢-5'-溴甲基补骨脂素或3-R-4,8-​​二甲基-4,5 ' - 二氢-5'-碘甲基补骨脂素以制备结构多样化的部分减少的补骨脂素和苯并呋喃。 这些补骨脂素中永久性铵电荷的存在排除了膜通道，单不饱和度排除了核DNA的交联，从而使与补骨脂素衍生疗法长期相关的致突变/致癌性副作用最小化。 汞功能的存在提供了这些补骨脂素上的反应性细胞结合基团，其具有独特的细胞毒性而没有光激活并且在光活化时增强细胞毒性活性。 本发明还涉及这些部分还原的和季铵化的补骨脂素，氨基取代的补骨脂素和补骨脂素显示出对PAM212角质形成细胞的令人印象深刻的药理学，PAM212角质形成细胞是用作表明表皮细胞毒性和癌症的测试系统的模型细胞系。 本发明化合物还具有抗哺乳动物药理活性剂（例如治疗结核病）以及控制微生物在底物和水系统中生长的抗微生物活性。

公开(公告)号：ES2183636T3

公开(公告)日：2003-03-16

申请号：ES99962909

申请日：1999-11-30

Applicant: BUCKMAN LABOR INC

Inventor： HEINDEL NED D ,  WHITTEMORE MARILYN S ,  GUILLON CHRISTOPHE ,  RAPP ROBERT D ,  LASKIN JEFFREY D ,  MCNEEL THOMAS E

IPC: C07D493/04 ,  A61K31/35

Abstract: The invention relates to 4'-substituted-4',5'-dihydropsoralen compounds of formula(V):In the formula R is hydrogen, a halogen, CN or an acyl group; T is a halogen, CN, a carboalkoxy group NR1R2, or (N+R1R2R3)X-, R1 and R2 are independently a C1-C6 alkyl, or R1 and R2 together with the nitrogen form a 5-8 member heterocyclic ring, or when T is (N+R1R2R3)X-, R1 and R2 together with the nitrogen form a 5-8 member heterocyclic ring or heterocyclic aromatic ring; R3 is hydrogen, a C1-C12 alkyl, or, when R1 and R2 together with the nitrogen form a heterocyclic aromatic ring, R3 is a double bond within the heterocyclic aromatic ring; X- is a halide. In another embodiment, the invention relates to processes for preparing 4'-substituted-4',5'-dihydropsoralen compounds described above. The compounds of the invention have beneficial pharmaceutical properties and can be used alone or in pharmaceutical compositions used to treat a proliferative skin disorder and to treat microbial infections in a mammal by administering to the mammal an effective amount of a compound of the invention and then irradiating the mammal with ultraviolet light.

公开(公告)号：MXPA01005241A

公开(公告)日：2002-06-04

申请号：MXPA01005241

申请日：1999-11-24

Applicant: BUCKMAN LABOR INC

Inventor： LASKIN JEFFREY D

IPC: A61P17/06 ,  A61P35/00 ,  C07D311/44 ,  C07D311/56 ,  C07D493/04 ,  C07F3/14 ,  A61K31/34 ,  C07D307/00 ,  C07D311/00

Abstract: Se describen compuestos 4',5'-dihidropsoralen 5'-substituido que portan aminas terciarias (y sales de las mismas), porciones de amonio cuaternarias o porciones organomercuriales. Tambien se describen mercurimetil-2-3-dihidro-benzofuranos 2-substituidos de la formula (7). Tambien se reportan sintesis directas versatiles a traves de compuestos desconocidos hasta la fecha tales como 3-R-4,8-dimetil-4',5'-dihidro-5'-bromometilpsoralen o un 3-R-4,8- dimetil-4,5'-dihidro-5'-yodometilpsoralen para preparar una disposicion estructuralmente diversa de psoralens parcialmente reducidos y benzofuranos. La presencia de una carga de amonio permanente en estos psoralens descarta el paso de membrana y la mono instauracion descarta la reticulacion de ADN nuclear, minimizando por lo mismo los efectos laterales mutagenicos/carcinogenicos grandes asociados con terapias derivadas de psoralens. La presencia de una funcionalidad de mercurio proporciona un grupo de enlace celula reactivo en estos psoralens con citotoxicidad unica sin activacion de luz y un incremento de actividad de citotoxicidad ante activacion de luz. La invencion tambien se relaciona a estos. psoralens cuaternizados y parcialmente reducidos, psoralens amino substituidos, y psoralens de mercurio exhiben farmacologia impresiva contra queratinocitos PAM 212, una linea celular modelo empleada como un sistema de prueba para indicar citotoxicidad epidermica y cancer. Los compuestos de la invencion tambien tienen actividad antimicrobicida util en agentes farmacologicos para mamiferos (por ejemplo el tratamiento de tuberculosis) asi como tambien para controlar el crecimiento de microorganismos en substratos y en sistemas acuosos.

公开(公告)号：AT223418T

公开(公告)日：2002-09-15

申请号：AT99962909

申请日：1999-11-30

Applicant: BUCKMAN LABOR INC

Inventor： HEINDEL NED D ,  WHITTEMORE MARILYN S ,  GUILLON CHRISTOPHE ,  RAPP ROBERT D ,  LASKIN JEFFREY D ,  MCNEEL THOMAS E ,  HECK DIANE E

IPC: C07D493/04 ,  A61K31/35

Abstract: The invention relates to 4'-substituted-4',5'-dihydropsoralen compounds of formula(V):In the formula R is hydrogen, a halogen, CN or an acyl group; T is a halogen, CN, a carboalkoxy group NR1R2, or (N+R1R2R3)X-, R1 and R2 are independently a C1-C6 alkyl, or R1 and R2 together with the nitrogen form a 5-8 member heterocyclic ring, or when T is (N+R1R2R3)X-, R1 and R2 together with the nitrogen form a 5-8 member heterocyclic ring or heterocyclic aromatic ring; R3 is hydrogen, a C1-C12 alkyl, or, when R1 and R2 together with the nitrogen form a heterocyclic aromatic ring, R3 is a double bond within the heterocyclic aromatic ring; X- is a halide. In another embodiment, the invention relates to processes for preparing 4'-substituted-4',5'-dihydropsoralen compounds described above. The compounds of the invention have beneficial pharmaceutical properties and can be used alone or in pharmaceutical compositions used to treat a proliferative skin disorder and to treat microbial infections in a mammal by administering to the mammal an effective amount of a compound of the invention and then irradiating the mammal with ultraviolet light.

公开(公告)号：AU1925500A

公开(公告)日：2000-06-19

申请号：AU1925500

申请日：1999-11-30

Applicant: BUCKMAN LABOR INC

Inventor： HEINDEL NEIL D ,  WHITTEMORE MARILYN S ,  GUILLON CHRISTOPHE ,  PAPP ROBERT D ,  LASKIN JEFFREY D ,  MCNEEL THOMAS E ,  HECK DIANE E

IPC: C07D493/04 ,  A61K31/35

Abstract: The invention relates to 4'-substituted-4',5'-dihydropsoralen compounds of formula(V):In the formula R is hydrogen, a halogen, CN or an acyl group; T is a halogen, CN, a carboalkoxy group NR1R2, or (N+R1R2R3)X-, R1 and R2 are independently a C1-C6 alkyl, or R1 and R2 together with the nitrogen form a 5-8 member heterocyclic ring, or when T is (N+R1R2R3)X-, R1 and R2 together with the nitrogen form a 5-8 member heterocyclic ring or heterocyclic aromatic ring; R3 is hydrogen, a C1-C12 alkyl, or, when R1 and R2 together with the nitrogen form a heterocyclic aromatic ring, R3 is a double bond within the heterocyclic aromatic ring; X- is a halide. In another embodiment, the invention relates to processes for preparing 4'-substituted-4',5'-dihydropsoralen compounds described above. The compounds of the invention have beneficial pharmaceutical properties and can be used alone or in pharmaceutical compositions used to treat a proliferative skin disorder and to treat microbial infections in a mammal by administering to the mammal an effective amount of a compound of the invention and then irradiating the mammal with ultraviolet light.

公开(公告)号：AU1743300A

公开(公告)日：2000-06-13

申请号：AU1743300

申请日：1999-11-24

Applicant: BUCKMAN LABOR INC

Inventor： HEINDEL NED D ,  LASKIN JEFFREY D ,  HECK DIANE E ,  RAPP ROBERT D ,  MCNEEL THOMAS E ,  JABIN IVAN ,  WHITTEMORE MARILYN S

IPC: A61P17/06 ,  A61P35/00 ,  C07D311/44 ,  C07D311/56 ,  C07D493/04 ,  C07F3/14 ,  A61K31/34

Abstract: 5'-substituted, 4',5'-dihydropsoralen compounds (5) bearing tertiary amines (and salts thereof), quaternary ammonium moieties or organomercurial moieties are described.Also described are 2-substituted mercurimethyl-2-3-dihydro-benzofurans of forumla (7):Also reported are versatile direct syntheses through a hitherto unknown compounds such as 3-R-4,8-dimethyl-4',5'-dihydro-5'-bromomethylpsoralen or a 3-R-4,8-dimethyl-4', 5'-dihydro-5'-iodomethylpsoralen to prepare a structurally diverse array of partially reduced psoralens and benzofurans. The presence of a permanent ammonium charge in these psoralens precludes membrane passage and the mono-unsaturation precludes the cross-linking of nuclear DNA, thereby minimizing the mutagenic/carcinogenic side effects long associated with psoralen-derived therapies. The presence of a mercury functionality provides a reactive cell-binding group on these psoralens with unique cytotoxicity without light activation and an enhancement of cytotoxicity activity upon light activation. The invention also relates to These partially reduced and quaternized psoralens, amino-substituted psoralens, and mercurio psoralens display impressive pharmacology against PAM 212 keratinocytes, a model cell line employed as a test system to indicate epidermal cytotoxicity and cancer. The compounds of the invention also have antimicrobicidal activity useful in pharmacologic agents for mammals (e.g. the treatment of tuberculosis) as well as in controlling the growth of microorganisms on substrates and in aqueous systems.

公开(公告)号：PT1144417E

公开(公告)日：2002-12-31

申请号：PT99962909

申请日：1999-11-30

Applicant: BUCKMAN LABOR INC

Inventor： MCNEEL THOMAS E ,  WHITTEMORE MARILYN S ,  HEINDEL NED D ,  LASKIN JEFFREY D ,  RAPP ROBERT D ,  GUILLON CHRISTOPHE ,  HECK DIANE E

IPC: C07D493/04 ,  A61K31/35

Abstract: The invention relates to 4'-substituted-4',5'-dihydropsoralen compounds of formula(V):In the formula R is hydrogen, a halogen, CN or an acyl group; T is a halogen, CN, a carboalkoxy group NR1R2, or (N+R1R2R3)X-, R1 and R2 are independently a C1-C6 alkyl, or R1 and R2 together with the nitrogen form a 5-8 member heterocyclic ring, or when T is (N+R1R2R3)X-, R1 and R2 together with the nitrogen form a 5-8 member heterocyclic ring or heterocyclic aromatic ring; R3 is hydrogen, a C1-C12 alkyl, or, when R1 and R2 together with the nitrogen form a heterocyclic aromatic ring, R3 is a double bond within the heterocyclic aromatic ring; X- is a halide. In another embodiment, the invention relates to processes for preparing 4'-substituted-4',5'-dihydropsoralen compounds described above. The compounds of the invention have beneficial pharmaceutical properties and can be used alone or in pharmaceutical compositions used to treat a proliferative skin disorder and to treat microbial infections in a mammal by administering to the mammal an effective amount of a compound of the invention and then irradiating the mammal with ultraviolet light.

公开(公告)号：CA2352258A1

公开(公告)日：2000-06-08

申请号：CA2352258

申请日：1999-11-30

Applicant: BUCKMAN LABOR INC

Inventor： HEINDEL NED D ,  LASKIN JEFFREY D ,  MCNEEL THOMAS E ,  HECK DIANE E ,  WHITTEMORE MARILYN S ,  RAPP ROBERT D ,  GUILLON CHRISTOPHE

IPC: C07D493/04 ,  A61K31/35

Abstract: The invention relates to 4'-substituted-4',5'-dihydropsoralen compounds of formula (V). In the formula R is hydrogen, a halogen, CN or an acyl group; T is a halogen, CN, a carboalkoxy group NR1R2, or (N+R1R2R3)X-, R1 and R2 are independently a C1-C6 alkyl, or R1 and R2 together with the nitrogen form a 5- 8 member heterocyclic ring, or when T is (N+R1R2R3)X-, R1 and R2 together wi th the nitrogen form a 5-8 member heterocyclic ring or heterocyclic aromatic ring; R3 is hydroge, a C1-C12 alkyl, or, when R1 and R2 together with the nitrogen form a heterocyclic aromatic ring, R3 is a double bond within the heterocyclic aromatic ring; X is a halide. In another embodiment, the invention relates to processes for preparing 4'-substituted-4',5'- dihydropsoralen compounds described above. The compounds of the invention ha ve beneficial pharmaceutical properties and can be used alone or in pharmaceutical compositions used to treat a proliferative skin disorder and to treat microbial infections in a mammal by administering to the mammal an effective amount of a compound of the invention and then irradiating the mammal with ultraviolet light.

公开(公告)号：MXPA01005363A

公开(公告)日：2004-04-21

申请号：MXPA01005363

申请日：1999-11-30

Applicant: BUCKMAN LABOR INC

Inventor： LASKIN JEFFREY D

IPC: C07D493/04

Abstract: La invencion se relaciona a compuestos 4-substituidos-4°, 5°-dihidropsoralen de la formula V. En la formula R es hidrogeno, un halogeno, CN o un grupo acilo; T es halogeno, CN, un grupo carboalcoxi NR1R2 o (N+R1R2R3)X-, R1 y R2 son independientemente un alquilo de C1-C6, o R1 y R2 junto con el nitrogeno forman un anillo heterociclico de 5-8 miembros o cuando T es (N+R1R2R3)X-, R1 y R2 junto con el nitrogeno forman un anillo heterociclico de 5-8 miembros o un anillo aromatico heterociclico; R3 es hidrogeno, un alquilo de C1-C12, o cuando R1 y R2 junto con el nitrogeno forman un anillo aromatico heterociclico, R3 es un doble enlace dentro del anillo aromatico heterociclico; X es haluro. En otra modalidad, la invencion se relaciona a procesos para preparar compuestos 4°-substituido-4°,5°-dihidropsoralen descritos anteriormente. Los compuestos de la invencion tienen propiedades farmaceuticas beneficas y pueden ser usados solos o en composiciones farmaceuticas usadas para tratar un trastorno proliferativo de la piel y para tratar infecciones microbianas en un mamifero al administrar al mamifero una cantidad efectiva de un compuesto de la invencion y despues se irradia el mamifero con luz ultravioleta.

公开(公告)号：CA2352665A1

公开(公告)日：2000-06-02

申请号：CA2352665

申请日：1999-11-24

Applicant: BUCKMAN LABOR INC

Inventor： HEINDEL NED D ,  LASKIN JEFFREY D ,  HECK DIANE E ,  RAPP ROBERT D ,  MCNEEL THOMAS E ,  JABIN IVAN ,  WHITTEMORE MARILYN S

IPC: A61P17/06 ,  A61P35/00 ,  C07D311/44 ,  C07D311/56 ,  C07D493/04 ,  C07F3/14 ,  C07D307/00 ,  C07D311/00 ,  A61K31/34

Abstract: 5'- substituted, 4', 5'- dihydropsoralen compounds (5) bearing tertiary amin es (and salts thereof), quaternary ammonium moieties or organomercurial moietie s are described. Also described are 2- substituted mercurimethyl -2-3- dihydro - benzofurans of formula (7). Also reported are versatile direct syntheses through a hitherto unknown compounds such as 3-R-4, 8-dimethyl -4',5'-dihydr o - 5'-bromomethylpsoralen or a 3-R-4, 8-dimethyl-4, 5'-dihydro- 5'- iodomethylpsoralen to prepare a structurally diverse array of partially reduced psoralens and benzofurans. The presence of a permanent ammonium char ge in these psoralens precludes membrane passage and the mono-unsaturation precludes the cross linking of nuclear DNA, thereby minimizing the mutagenic/carcinogenic side effects long associated with psoralen-derived therapies. The presence of a mercury functionality provides a reactive cell- binding group on these psoralens with unique cytotoxicity without light activation and an enhancement of cytotoxicity activity upon light activation . The invention also relates to these partially reduced and quaternized psoralens, amino-substituted psoralens, and mercurio psoralens display impressive pharmacology against PAM 212 keratinocytes, a model cell line employed as a test system to indicate epidermal cytotoxicity and cancer. The compounds of the invention also have antimicrobicidal activity useful in pharmacologic agents for mammals (e.g. the treatment of tuberculosis) as wel l as in controlling the growth of microorganisms on substrates and in aqueous systems.