公开(公告)号：US09243003B2

公开(公告)日：2016-01-26

申请号：US13639594

申请日：2011-04-06

Applicant: Jose J. Conde ,  John Anthony Kowalski ,  Matthew Allen Zajac

Inventor： Jose J. Conde ,  John Anthony Kowalski ,  Matthew Allen Zajac

IPC: C07F5/04 ,  C07F5/02

CPC classification number: C07F5/025 ,  C07F5/04 ,  Y02P20/55

Abstract: The present invention is a process comprising contacting a compound of formula 6: or a pharmaceutically acceptable salt thereof; with a deprotecting reagent to form a compound of formula A: or a pharmaceutically acceptable salt thereof; where R is H or OR1; R1 and each R1′ are protecting groups; R1″ is H or OH, and n is 0, 1, 2, 3, 4 , or 5.

Abstract translation: 本发明是一种方法，其包括使式6化合物或其药学上可接受的盐接触; 与脱保护试剂形成式A化合物或其药学上可接受的盐; 其中R为H或OR 1; R1和R1各自为保护基; R1“是H或OH，n是0,1,2,3,4或5。

公开(公告)号：US20110166170A1

公开(公告)日：2011-07-07

申请号：US12913091

申请日：2010-10-27

Applicant: Andrew G. Myers ,  Seth B. Herzon ,  Jeremy Earle Wulff ,  Romain Siegrist ,  Jakub Svenda ,  Matthew Allen Zajac

Inventor： Andrew G. Myers ,  Seth B. Herzon ,  Jeremy Earle Wulff ,  Romain Siegrist ,  Jakub Svenda ,  Matthew Allen Zajac

IPC: A61K31/437 ,  C07D487/04 ,  C07D471/22 ,  C07D209/56 ,  C07D209/82 ,  A61K31/407 ,  A61K31/403 ,  A61P35/00

CPC classification number: C07D209/88 ,  C07D471/22 ,  C07D491/052 ,  C07D491/22 ,  C07D495/22

Abstract: The syntheses of the natural products, avrainvillamide and stephacidin B, are provided. The α,β-unsaturated nitrone functionality of avrainvillamide and its 3-alkylidene-3H-indole 1-oxide core is shown to covalently and reversibly bond to heteroatom-based nucleophiles. This capability may allow these molecules to bind active site nucleophiles and may provide the basis for designing potent and selective enzyme inhibitors. Both avrainvillamide and its dimer stephacidin B have been reported to exhibit antiproliferative activity, and avrainvillamide has been reported to exhibit antimicrobial activity against multi-drug resistant bacteria. Avrainvillamide has been found to target cytoskeleton-linking membrane protein (CLIMP-63) thereby preventing cells from undergoing mitosis. The invention provides syntheses of these natural products as well as analogs of these natural products and their functional cores. The compounds of the invention may be used in the treatment of diseases such as cancer, autoimmune diseases, and bacterial infection.

Abstract translation: 提供了天然产物，维生素A和抗抑郁素B的合成。 显示出avrainvillamide及其3-亚烷基-3H-吲哚-1-氧化物核心的α，bgr-不饱和硝酮官能团共价和可逆地键合到基于杂原子的亲核试剂。 这种能力可以允许这些分子结合活性位点亲核试剂，并且可以为设计有效和选择性酶抑制剂提供依据。 已经报道了丙氨酰维他命和其二聚杀生物素蛋白B都具有抗增殖活性，据报道，抗谷氨酰胺具有抗多药耐药细菌的抗微生物活性。 已经发现Avrainvillamide靶向细胞骨架连接膜蛋白（CLIMP-63），从而防止细胞发生有丝分裂。 本发明提供这些天然产物以及这些天然产物及其功能核心的类似物的合成。 本发明的化合物可用于治疗诸如癌症，自身免疫性疾病和细菌感染等疾病。

公开(公告)号：US08076475B2

公开(公告)日：2011-12-13

申请号：US12921199

申请日：2009-03-06

Applicant: Matthew Allen Zajac

Inventor： Matthew Allen Zajac

IPC: C07D401/00

CPC classification number: C07D401/12

Abstract: The present invention generally relates to a novel process for preparing vitronectin receptor antagonist compounds having a benzodiazepinyl core structure. This invention relates to the preparation of pharmaceutically active compounds which inhibit the vitronectin receptor and are useful for treatment of inflammation, cancer and cardiovascular disorders, such as atherosclerosis and restenosis, and diseases wherein bone resorption is a factor, such as osteoporosis. In particular, the present invention relates to a novel process for preparing (±)-3-oxo-8-{[3-(pyridin-2-ylamino)propyl]oxy}-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid, (R)-3-oxo-8-{[3-(pyridin-2-ylamino)propyl]oxy}-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid and (S)-3-oxo-8-{[3-(pyridin-2-ylamino)propyl]oxy}-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid or a pharmaceutically acceptable salt thereof.

Abstract translation: 本发明一般涉及制备具有苯并二氮杂环核心结构的玻连蛋白受体拮抗剂化合物的新方法。 本发明涉及抑制玻连蛋白受体并且可用于治疗炎症，癌症和心血管疾病如动脉粥样硬化和再狭窄的药学活性化合物的制备，以及其中骨吸收是骨质疏松症的因素。 特别地，本发明涉及制备（±）-3-氧代-8 - {[3-（吡啶-2-基氨基）丙基]氧基} -2-（2,2,2-三氟乙基） -2,3,4,5-四氢-1H-2-苯并氮杂-4-乙酸，（R）-3-氧代-8 - {[3-（吡啶-2-基氨基）丙基]氧基} -2- （2,2,2-三氟乙基）-2,3,4,5-四氢-1H-2-苯并氮杂-4-乙酸和（S）-3-氧代-8 - {[3-（吡啶-2-基） 吡啶-2-基氨基）丙基]氧基} -2-（2,2,2-三氟乙基）-2,3,4,5-四氢-1H-2-苯并氮杂-4-乙酸或其药学上可接受的盐。

公开(公告)号：US20110015390A1

公开(公告)日：2011-01-20

申请号：US12921199

申请日：2009-03-06

Applicant: Matthew Allen Zajac

Inventor： Matthew Allen Zajac

IPC: C07D401/12

CPC classification number: C07D401/12

Abstract: The present invention generally relates to a novel process for preparing vitronectin receptor antagonist compounds having a benzodiazepinyl core structure. This invention relates to the preparation of pharmaceutically active compounds which inhibit the vitronectin receptor and are useful for treatment of inflammation, cancer and cardiovascular disorders, such as atherosclerosis and restenosis, and diseases wherein bone resorption is a factor, such as osteoporosis. In particular, the present invention relates to a novel process for preparing (±)-3-oxo-8-{[3-(pyridin-2-ylamino)propyl]oxy}-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid, (R)-3-oxo-8-{[3-(pyridin-2-ylamino)propyl]oxy}-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid and (S)-3-oxo-8-{[3-(pyridin-2-ylamino)propyl]oxy}-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid or a pharmaceutically acceptable salt thereof.

Abstract translation: 本发明一般涉及制备具有苯并二氮杂环核心结构的玻连蛋白受体拮抗剂化合物的新方法。 本发明涉及抑制玻连蛋白受体并且可用于治疗炎症，癌症和心血管疾病如动脉粥样硬化和再狭窄的药学活性化合物的制备，以及其中骨吸收是骨质疏松症的因素。 特别地，本发明涉及制备（±）-3-氧代-8 - {[3-（吡啶-2-基氨基）丙基]氧基} -2-（2,2,2-三氟乙基） -2,3,4,5-四氢-1H-2-苯并氮杂-4-乙酸，（R）-3-氧代-8 - {[3-（吡啶-2-基氨基）丙基]氧基} -2- （2,2,2-三氟乙基）-2,3,4,5-四氢-1H-2-苯并氮杂-4-乙酸和（S）-3-氧代-8 - {[3-（吡啶-2-基） 吡啶-2-基氨基）丙基]氧基} -2-（2,2,2-三氟乙基）-2,3,4,5-四氢-1H-2-苯并氮杂-4-乙酸或其药学上可接受的盐。

公开(公告)号：US08759542B2

公开(公告)日：2014-06-24

申请号：US13393174

申请日：2010-09-01

Applicant: Matthew Allen Zajac

Inventor： Matthew Allen Zajac

IPC: C07D207/09

CPC classification number: C07D207/09 ,  C07D207/16

Abstract: The present application provides a process for the preparation of α-carboxamide pyrrolidine derivatives of formula (I), wherein R1 and R2 are independently hydrogen, C1-6alkyl or C3-6cycloalkylC1-6alkyl; or such R1 and R2, together with the nitrogen to which they are attached, may form an unsubstituted 3-, 4-, 5- or 6-membered saturated ring; X is carbon or nitrogen; n is 0, 1 or 2, wherein when present each R5 is independently selected from the list consisting of C1-3alkyl, halogen, cyano, haloC1-3alkyl, hydroxy, C1-3alkoxy and C1-3haloalkoxy; either R6 or R7 is —O—R8, —OCHR9R8, —NCH2R8 or —(CH2)2R8 wherein the other R6 or R7 is hydrogen or R5; and wherein R8 is a phenyl ring or wherein the phenyl ring is optionally substituted by one or more groups independently selected from the list consisting of C1-3alkyl, halogen, cyano, haloC1-3alkyl, hydroxy, C1-3alkoxy and C1-3haloalkoxy; and R9 is hydrogen or C1-3alkyl.

Abstract translation: 本申请提供了制备式（I）的α-甲酰胺吡咯烷衍生物的方法，其中R 1和R 2独立地是氢，C 1-6烷基或C 3-6环烷基C 1-6烷基; 或这样的R 1和R 2与它们所连接的氮一起可以形成未取代的3-，4-，5-或6-元饱和环; X是碳或氮; n为0,1或2，其中当存在时，每个R 5独立地选自C 1-3烷基，卤素，氰基，卤代C 1-3烷基，羟基，C 1-3烷氧基和C 1-3卤代烷氧基; R6或R7为-O-R8，-OCHR9R8，-NCH2R8或 - （CH2）2R8，其中R6或R7为氢或R5; 并且其中R8是苯环或其中苯环任选地被一个或多个独立地选自C 1-3烷基，卤素，氰基，卤代C 1-3烷基，羟基，C 1-3烷氧基和C 1-3卤代烷氧基的基团取代; 并且R 9为氢或C 1-3烷基。

公开(公告)号：US20120226053A1

公开(公告)日：2012-09-06

申请号：US13393174

申请日：2010-09-01

Applicant: Matthew Allen Zajac

Inventor： Matthew Allen Zajac

IPC: C07D207/09

CPC classification number: C07D207/09 ,  C07D207/16

Abstract: The present application provides a process for the preparation of α-carboxamide pyrrolidine derivatives of formula (I), wherein R1 and R2 are independently hydrogen, C1-6alkyl or C3-6cycloalkylC1-6alkyl; or such R1 and R2, together with the nitrogen to which they are attached, may form an unsubstituted 3-, 4-, 5- or 6-membered saturated ring; X is carbon or nitrogen; n is 0, 1 or 2, wherein when present each R5 is independently selected from the list consisting of C1-3alkyl, halogen, cyano, haloC1-3alkyl, hydroxy, C1-3alkoxy and C1-3haloalkoxy; either R6 or R7 is —O—R8, —OCHR9R8,—NCH2R8 or —(CH2)2R8 wherein the other R6 or R7 is hydrogen or R5; and wherein R8 is a phenyl ring or wherein the phenyl ring is optionally substituted by one or more groups independently selected from the list consisting of C1-3alkyl, halogen, cyano, haloC1-3alkyl, hydroxy, C1-3alkoxy and C1-3haloalkoxy; and R9 is hydrogen or C1-3alkyl.

Abstract translation: 本申请提供了制备式（I）的α-甲酰胺吡咯烷衍生物的方法，其中R 1和R 2独立地是氢，C 1-6烷基或C 3-6环烷基C 1-6烷基; 或这样的R 1和R 2与它们所连接的氮一起可以形成未取代的3-，4-，5-或6-元饱和环; X是碳或氮; n为0,1或2，其中当存在时，每个R 5独立地选自C 1-3烷基，卤素，氰基，卤代C 1-3烷基，羟基，C 1-3烷氧基和C 1-3卤代烷氧基; R6或R7是-O-R8，-OCHR9R8，-NCH2R8或 - （CH2）2R8，其中R6或R7是氢或R5; 并且其中R8是苯环或其中苯环任选地被一个或多个独立地选自C 1-3烷基，卤素，氰基，卤代C 1-3烷基，羟基，C 1-3烷氧基和C 1-3卤代烷氧基的基团取代; 并且R 9为氢或C 1-3烷基。

公开(公告)号：US20130035501A1

公开(公告)日：2013-02-07

申请号：US13639594

申请日：2011-04-06

Applicant: Jose J. Conde ,  John Anthony Kowalski ,  Matthew Allen Zajac

Inventor： Jose J. Conde ,  John Anthony Kowalski ,  Matthew Allen Zajac

IPC: C07F5/04

CPC classification number: C07F5/025 ,  C07F5/04 ,  Y02P20/55

Abstract: The present invention is a process comprising contacting a compound of formula 6: or a pharmaceutically acceptable salt thereof; with a deprotecting reagent to form a compound of formula A: or a pharmaceutically acceptable salt thereof; where R is H or OR1; R1 and each R1′ are protecting groups; R1″ is H or OH, and n is 0, 1, 2, 3, 4, or 5.

Abstract translation: 本发明是一种方法，其包括使式6化合物或其药学上可接受的盐接触; 与脱保护试剂形成式A化合物或其药学上可接受的盐; 其中R为H或OR 1; R1和R1各自为保护基; R1“是H或OH，n是0,1,2,3,4或5。

公开(公告)号：US07902196B2

公开(公告)日：2011-03-08

申请号：US11908901

申请日：2006-03-17

Applicant: Andrew G. Myers ,  Seth B. Herzon ,  Jeremy Earle Wulff ,  Romain Siegrist ,  Jakub Svenda ,  Matthew Allen Zajac

Inventor： Andrew G. Myers ,  Seth B. Herzon ,  Jeremy Earle Wulff ,  Romain Siegrist ,  Jakub Svenda ,  Matthew Allen Zajac

IPC: A61K31/4355 ,  A61K31/4985 ,  A61K31/424 ,  A61K31/403 ,  A61K31/407 ,  C07D221/18 ,  C07D241/00 ,  C07D498/22 ,  C07D209/58 ,  C07D487/04

CPC classification number: C07D209/88 ,  C07D471/22 ,  C07D491/052 ,  C07D491/22 ,  C07D495/22

Abstract: The syntheses of the natural products, avrainvillamide and stephacidin B, are provided. The α,β-unsaturated nitrone functionality of avrainvillamide and its 3-alkylidene-3H-indole 1-oxide core is shown to covalently and reversibly bond to heteroatom-based nucleophiles. This capability may allow these molecules to bind active site nucleophiles and may provide the basis for designing potent and selective enzyme inhibitors. Both avrainvillamide and its dimer stephacidin B have been reported to exhibit antiproliferative activity, and avrainvillamide has been reported to exhibit antimicrobial activity against multi-drug resistant bacteria. Avrainvillamide has been found to target cytoskeleton-linking membrane protein (CLIMP-63) thereby preventing cells from undergoing mitosis. The invention provides syntheses of these natural products as well as analogs of these natural products and their functional cores. The compounds of the invention may be used in the treatment of diseases such as cancer, autoimmune diseases, and bacterial infection.

Abstract translation: 提供了天然产物，维生素A和抗抑郁素B的合成。 显示出avrainvillamide及其3-亚烷基-3H-吲哚-1-氧化物核心的α和bgr-不饱和硝酮官能团共价和可逆地键合到基于杂原子的亲核试剂。 这种能力可以允许这些分子结合活性位点亲核试剂，并且可以为设计有效和选择性酶抑制剂提供依据。 已经报道了丙氨酰维他命和其二聚杀生物素蛋白B都具有抗增殖活性，据报道，抗谷氨酰胺具有抗多药耐药细菌的抗微生物活性。 已经发现Avrainvillamide靶向细胞骨架连接膜蛋白（CLIMP-63），从而防止细胞发生有丝分裂。 本发明提供这些天然产物以及这些天然产物及其功能核心的类似物的合成。 本发明的化合物可用于治疗诸如癌症，自身免疫性疾病和细菌感染等疾病。