公开(公告)号：US06624150B2

公开(公告)日：2003-09-23

申请号：US09747777

申请日：2000-12-22

申请人： Benjamin R. Yerxa ,  Janet L. Rideout ,  William Pendergast ,  Sammy Ray Shaver ,  Zhen Zhang ,  Ward M. Peterson ,  Matthew Cowlen

发明人： Benjamin R. Yerxa ,  Janet L. Rideout ,  William Pendergast ,  Sammy Ray Shaver ,  Zhen Zhang ,  Ward M. Peterson ,  Matthew Cowlen

IPC分类号： A61K3170

CPC分类号： A61K31/7064 ,  A61K31/00 ,  A61K31/7048 ,  A61K31/7068 ,  A61K31/7072 ,  A61K31/7076 ,  A61K31/7084

摘要： The invention provides a method of regulating water and mucin secretions and fluid transport in the gastrointestinal tract. The invention also provides a method for treating a gastrointestinal disease in which the mucosal barrier of the gastrointestinal system is impaired. The invention additionally provides a method for correcting disorders of fluid secretion or absorption in the gastrointestinal system. The method comprises administering to a patient a pharmaceutical composition comprising a purinergic P2Y receptor agonist, in an amount effective to regulate water and mucin secretions or to correct abnormal fluid transport in the gastrointestinal tract. The pharmaceutical composition used in this invention comprises a P2Y purinergic receptor agonist such as uridine 5′-diphosphate (UDP), uridine 5′-triphosphate (UTP), cytidine 5′-diphosphate (CDP), cytidine 5′-triphosphate (CTP), adenosine 5′-diphosphate (ADP), adenosine 5′-triphosphate (ATP), and their analogs; and dinucleotide polyphosphate compounds of general Formula (IV). Said compound is prepared in an oral form, an injectable form, or a suppository form, and administered to a patient.

公开(公告)号：US20080214490A1

公开(公告)日：2008-09-04

申请号：US12043845

申请日：2008-03-06

申请人： William Pendergast ,  Sammy Ray Shaver ,  David J. Drutz ,  Janet L. Rideout ,  Benjamin R. Yerxa

发明人： William Pendergast ,  Sammy Ray Shaver ,  David J. Drutz ,  Janet L. Rideout ,  Benjamin R. Yerxa

IPC分类号： A61K31/7076 ,  A61P15/02

CPC分类号： C07H21/00 ,  A61K31/00

摘要： The present invention provides a method of stimulating cervical and vaginal secretions in a mammal by treatment with P2Y2 and/or P2Y4 purinergic receptor agonists. Treatment of vaginal dryness associated with menopause, chemotherapy, and various disease states as well as the treatment of vulvar pain is discussed. Suitable agonists such as UTP, CTP, ATP, dinucleotides and analogs thereof are disclosed.

摘要翻译： 本发明提供了通过用P2Y2和/或P2Y4N4嘌呤能受体激动剂治疗来刺激哺乳动物的宫颈和阴道分泌物的方法。 讨论了与绝经，化疗和各种疾病状态相关的阴道干燥的治疗以及外阴疼痛的治疗。 公开了合适的激动剂，例如UTP，CTP，ATP，二核苷酸及其类似物。

公开(公告)号：US07432252B1

公开(公告)日：2008-10-07

申请号：US09531851

申请日：2000-03-20

申请人： William Pendergast ,  Sammy Ray Shaver ,  David J. Drutz ,  Janet L. Rideout ,  Benjamin R. Yerxa

发明人： William Pendergast ,  Sammy Ray Shaver ,  David J. Drutz ,  Janet L. Rideout ,  Benjamin R. Yerxa

IPC分类号： A61K31/70

CPC分类号： C07H21/00

摘要： The present invention provides a method of stimulating cervical and vaginal secretions in a mammal by treatment with P2Y2 and/or P2Y4 purinergic receptor agonists. Treatment of vaginal dryness associated with menopause, chemotherapy, and various disease states as well as the treatment of vulvar pain is discussed. Suitable agonists such as UTP, CTP, ATP, dinucleotides and analogs thereof are disclosed.

摘要翻译： 本发明提供了通过用P2Y2和/或P2Y4N4嘌呤能受体激动剂治疗来刺激哺乳动物的宫颈和阴道分泌物的方法。 讨论了与绝经，化疗和各种疾病状态相关的阴道干燥的治疗以及外阴疼痛的治疗。 公开了合适的激动剂，例如UTP，CTP，ATP，二核苷酸及其类似物。

公开(公告)号：US08008274B2

公开(公告)日：2011-08-30

申请号：US12436679

申请日：2009-05-06

申请人： Benjamin R. Yerxa ,  Ward M. Peterson ,  Janet L. Rideout ,  William Pendergast

发明人： Benjamin R. Yerxa ,  Ward M. Peterson ,  Janet L. Rideout ,  William Pendergast

IPC分类号： A61K31/7072 ,  C07H19/10

CPC分类号： C07H19/10 ,  A61K31/7072 ,  A61K31/7084 ,  C07H19/04 ,  C07H19/20 ,  C07H21/00 ,  Y10S514/851

摘要： The present invention provides a method of treating edematous retinal disorders. The method comprises administration of a pharmaceutical formulation comprising a hydrolysis-resistant P2Y receptor agonist to stimulate the removal of pathological extraneous fluid from the subretinal and retinal spaces and thereby reduce the accumulation of said fluid associated with retinal detachment and retinal edema. The P2Y receptor agonist can be administered with therapeutic and adjuvant agents commonly used to treat edematous retinal disorders. The present invention also provides a method of treating cystic fibrosis. The present invention also provides a method of treating sinusitis. The present invention further provides P1-(2′-deoxycytidine 5′-)P4-(uridine 5′-)tetraphosphate, tetra-(alkali metal) salts such as tetrasodium, tetralithium, tetrapotassium, and mixed (tetra-alkali metal) salts. The present further provides a pharmaceutical formulation comprising a P1-(2′-deoxycytidine 5′-)P4-(uridine 5′-)tetraphosphate, tetra-(alkali metal) salt, in a pharmaceutically acceptable carrier.

摘要翻译： 本发明提供治疗水肿性视网膜病变的方法。 该方法包括施用包含水解抗性P2Y受体激动剂的药物制剂，以刺激从视网膜下和视网膜空间中除去病理性外来流体，从而减少与视网膜脱离和视网膜水肿相关的所述流体的积聚。 P2Y受体激动剂可以与通常用于治疗水肿性视网膜疾病的治疗剂和辅助剂一起施用。 本发明还提供治疗囊性纤维化的方法。 本发明还提供治疗鼻窦炎的方法。 本发明还提供了P1-（2'-脱氧胞苷5' - ）P4-（尿苷5'-）四磷酸盐，四钠（碱金属）盐，例如四钠，四锂，四钾和混合（四碱金属）盐 。 本发明还提供了药学上可接受的载体中包含P1-（2'-脱氧胞苷5' - ）P4-（尿苷5' - ）四磷酸盐，四 - （碱金属盐）的药物制剂。

公开(公告)号：US20090306010A1

公开(公告)日：2009-12-10

申请号：US12436679

申请日：2009-05-06

申请人： Benjamin R. Yerxa ,  Ward M. Peterson ,  Janet L. Rideout ,  William Pendergast

发明人： Benjamin R. Yerxa ,  Ward M. Peterson ,  Janet L. Rideout ,  William Pendergast

IPC分类号： A61K31/7072 ,  A61P11/00

CPC分类号： C07H19/10 ,  A61K31/7072 ,  A61K31/7084 ,  C07H19/04 ,  C07H19/20 ,  C07H21/00 ,  Y10S514/851

摘要： The present invention provides a method of treating edematous retinal disorders. The method comprises administration of a pharmaceutical formulation comprising a hydrolysis-resistant P2Y receptor agonist to stimulate the removal of pathological extraneous fluid from the subretinal and retinal spaces and thereby reduce the accumulation of said fluid associated with retinal detachment and retinal edema. The P2Y receptor agonist can be administered with therapeutic and adjuvant agents commonly used to treat edematous retinal disorders. The present invention also provides a method of treating cystic fibrosis. The present invention also provides a method of treating sinusitis. The present invention further provides P1-(2′-deoxycytidine 5′-)P4-(uridine 5′-)tetraphosphate, tetra-(alkali metal) salts such as tetrasodium, tetralithium, tetrapotassium, and mixed (tetra-alkali metal) salts. The present further provides a pharmaceutical formulation comprising a P1-(2′-deoxycytidine 5′-)P4-(uridine 5′-)tetraphosphate, tetra-(alkali metal) salt, in a pharmaceutically acceptable carrier.

摘要翻译： 本发明提供治疗水肿性视网膜病变的方法。 该方法包括施用包含水解抗性P2Y受体激动剂的药物制剂，以刺激从视网膜下和视网膜空间中除去病理性外来流体，从而减少与视网膜脱离和视网膜水肿相关的所述流体的积聚。 P2Y受体激动剂可以与通常用于治疗水肿性视网膜疾病的治疗剂和辅助剂一起施用。 本发明还提供治疗囊性纤维化的方法。 本发明还提供治疗鼻窦炎的方法。 本发明还提供了P1-（2'-脱氧胞苷5' - ）P4-（尿苷5'-）四磷酸盐，四钠（碱金属）盐，例如四钠，四锂，四钾和混合（四碱金属）盐 。 本发明还提供了药学上可接受的载体中包含P1-（2'-脱氧胞苷5' - ）P4-（尿苷5' - ）四磷酸盐，四 - （碱金属盐）的药物制剂。

公开(公告)号：US07531525B2

公开(公告)日：2009-05-12

申请号：US11690385

申请日：2007-03-23

申请人： Benjamin R. Yerxa ,  Ward M. Peterson ,  Janet L. Rideout ,  William Pendergast

发明人： Benjamin R. Yerxa ,  Ward M. Peterson ,  Janet L. Rideout ,  William Pendergast

IPC分类号： A61K31/7072 ,  C07H19/10

CPC分类号： C07H19/10 ,  A61K31/7072 ,  A61K31/7084 ,  C07H19/04 ,  C07H19/20 ,  C07H21/00 ,  Y10S514/851

摘要： The present invention provides a method of treating edematous retinal disorders. The method comprises administration of a pharmaceutical formulation comprising a hydrolysis-resistant P2Y receptor agonist to stimulate the removal of pathological extraneous fluid from the subretinal and retinal spaces and thereby reduce the accumulation of said fluid associated with retinal detachment and retinal edema. The P2Y receptor agonist can be administered with therapeutic and adjuvant agents commonly used to treat edematous retinal disorders. The present invention also provides a method of treating cystic fibrosis. The present invention further provides P1-(2′-deoxycytidine 5′-)P4-(uridine 5′-) tetraphosphate, tetra-(alkali metal) salts such as tetrasodium, tetralithium, tetrapotassium, and mixed (tetra-alkali metal) salts. The present further provides a pharmaceutical formulation comprising a P1-(2′-deoxycytidine 5′-)P4-(uridine 5′-) tetraphosphate, tetra-(alkali metal) salt, in a pharmaceutically acceptable carrier.

摘要翻译： 本发明提供治疗水肿性视网膜病变的方法。 该方法包括施用包含水解抗性P2Y受体激动剂的药物制剂，以刺激从视网膜下和视网膜空间中除去病理性外来流体，从而减少与视网膜脱离和视网膜水肿相关的所述流体的积聚。 P2Y受体激动剂可以与通常用于治疗水肿性视网膜疾病的治疗剂和辅助剂一起施用。 本发明还提供治疗囊性纤维化的方法。 本发明还提供了P1-（2'-脱氧胞苷5' - ）P4-（尿苷5'-）四磷酸盐，四钠（碱金属）盐，例如四钠，四锂，四钾和混合（四碱金属）盐 。 本发明还提供了药学上可接受的载体中包含P1-（2'-脱氧胞苷5' - ）P4-（尿苷5'-）四磷酸盐，四 - （碱金属盐）的药物制剂。

公开(公告)号：US07223744B2

公开(公告)日：2007-05-29

申请号：US10962016

申请日：2004-10-07

申请人： Benjamin R. Yerxa ,  Ward M. Peterson ,  Janet L. Rideout ,  William Pendergast

发明人： Benjamin R. Yerxa ,  Ward M. Peterson ,  Janet L. Rideout ,  William Pendergast

IPC分类号： C07H21/00 ,  A61K37/70

CPC分类号： C07H19/10 ,  A61K31/7072 ,  A61K31/7084 ,  C07H19/04 ,  C07H19/20 ,  C07H21/00 ,  Y10S514/851

摘要： The present invention provides a method of treating edematous retinal disorders. The method comprises administration of a pharmaceutical formulation comprising a hydrolysis-resistant P2Y receptor agonist to stimulate the removal of pathological extraneous fluid from the subretinal and retinal spaces and thereby reduce the accumulation of said fluid associated with retinal detachment and retinal edema. The P2Y receptor agonist can be administered with therapeutic and adjuvant agents commonly used to treat edematous retinal disorders. The pharmaceutical formulation useful in this invention comprises a P2Y receptor agonist with enhanced resistance to extracellular hydrolysis, such as dinucleoside polyphosphate compounds, or hydrolysis-resistant mononucleoside triphosphate salts. The present invention also provides P1-(2′-deoxycytidine 5′-)P4-(uridine 5′-)tetraphosphate, tetra-(alkali metal) salts such as tetrasodium, tetralithium, tetrapotassium, and mixed (tetra-alkali metal) salts. The present further provides a pharmaceutical formulation comprising a P1-(2′-deoxycytidine 5′-)P4-(uridine 5′-)tetraphosphate, tetra-(alkali metal) salt, in a pharmaceutically acceptable carrier.

摘要翻译： 本发明提供治疗水肿性视网膜病变的方法。 该方法包括施用包含水解抗性P2Y受体激动剂的药物制剂，以刺激从视网膜下和视网膜空间中除去病理性外来流体，从而减少与视网膜脱离和视网膜水肿相关的所述流体的积聚。 P2Y受体激动剂可以与通常用于治疗水肿性视网膜疾病的治疗剂和辅助剂一起施用。 可用于本发明的药物制剂包含具有增强的细胞外水解抗性的P2Y受体激动剂，例如二核苷多磷酸酯化合物或耐水解的单核苷三磷酸盐。 本发明还提供了P 1 - （2'-脱氧胞苷5' - ）P 4 - （尿苷5'-）四磷酸盐，四（碱金属盐）盐 作为四钠，四锂，四钾和混合（四碱金属）盐。 本发明还提供一种药物制剂，其包含P 1 - （2'-脱氧胞苷5' - ）P 4 - （尿苷5' - ）四磷酸酯，四 - （碱 金属）盐，在药学上可接受的载体中。

公开(公告)号：US06451288B1

公开(公告)日：2002-09-17

申请号：US09645161

申请日：2000-08-24

申请人： Richard C. Boucher, Jr. ,  Sammy Ray Shaver ,  William Pendergast ,  Benjamin Yerxa ,  Janet L. Rideout ,  Robert Dougherty ,  Dallas Croom

发明人： Richard C. Boucher, Jr. ,  Sammy Ray Shaver ,  William Pendergast ,  Benjamin Yerxa ,  Janet L. Rideout ,  Robert Dougherty ,  Dallas Croom

IPC分类号： A61K912

CPC分类号： A61K31/7068 ,  A61K9/0073 ,  A61K31/7072 ,  A61K45/06 ,  C07H19/10 ,  Y10S514/826 ,  Y10S514/851 ,  A61K2300/00

摘要： Compounds of Formula I: wherein: X1, and X2 are each independently either O− or S−; X3 and X4 are each independently either —H or —OH, with the proviso that X3 and X4 are not simultaneously —H; R1 is selected from the group consisting of O, imido, methylene and dihalomethylene; R2 is selected from the group consisting of H, halo, alkyl, substituted alkyl, alkoxyl, nitro and azido; R3 is selected from the group consisting of H, alkyl, acyl, aryl, and arylalkyl; and R4 is selected from the group consisting of —OR′, —SR′, —NR′, and —NR′R″, wherein R′ and R″ are independently selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, alkoxyl, and aryloxyl, with the proviso that R′ is absent when R4 is double bonded from an oxygen or sulfur atom to the carbon at the 4-position of the pyrimidine ring, are used in methods of hydrating lung mucus secretions and treating lung disorders such as cystic fibrosis, ventilator-associated pneumonia, chronic bronchitis, chronic obstructive pulmonary disorder and primary ciliary dyskinesia. Pharmaceutical compositions containing compounds of Formula I, and novel compounds of Formula I are also described.

摘要翻译： 式I化合物：其中：X 1和X 2各自独立地为O-或S-; X 3和X 4各自独立地为-H或-OH，条件是X 3和X 4不同时为-H; R 1为选自 由O，亚氨基，亚甲基和二卤代亚甲基组成的组; R 2选自H，卤素，烷基，取代的烷基，烷氧基，硝基和叠氮基; R 3选自H，烷基，酰基， 芳基和芳基烷基; 和R 4选自-OR'，-SR'，-NR'和-NR'R“，其中R'和R”独立地选自H，烷基，取代的烷基， 芳基，取代的芳基，芳基烷基，烷氧基和芳氧基，条件是当R4与氧或硫原子双键连接到嘧啶环的4位上的碳时，R'不存在，用于水合 肺粘液分泌物和治疗肺部疾病如囊性纤维化，呼吸机相关肺炎，慢性支气管炎，慢性阻塞性肺病和原发性纤毛运动障碍。 还描述了含有式I化合物和式I的新化合物的药物组合物。

公开(公告)号：US6143279A

公开(公告)日：2000-11-07

申请号：US143297

申请日：1998-08-28

申请人： Richard C. Boucher, Jr. ,  Sammy Ray Shaver ,  William Pendergast ,  Benjamin Yerxa ,  Janet L. Rideout ,  Robert Dougherty ,  Dallas Croom

发明人： Richard C. Boucher, Jr. ,  Sammy Ray Shaver ,  William Pendergast ,  Benjamin Yerxa ,  Janet L. Rideout ,  Robert Dougherty ,  Dallas Croom

IPC分类号： A61K9/00 ,  A61K31/7042 ,  A61K31/7052 ,  A61K31/7064 ,  A61K31/7068 ,  A61K31/7072 ,  A61K45/06 ,  A61P11/00 ,  C07H19/10 ,  A61K9/12

CPC分类号： A61K31/7068 ,  A61K31/7072 ,  A61K45/06 ,  A61K9/0073 ,  C07H19/10 ,  Y10S514/826 ,  Y10S514/851

摘要： Compounds of Formula I: ##STR1## wherein: X.sub.1, and X.sub.2 are each independently either O.sup.- or S.sup.- ;X.sub.3 and X.sub.4 are each independently either --H or --OH, with the proviso that X.sub.3 and X.sub.4 are not simultaneously --H;R.sub.1 is selected from the group consisting of O, imido, methylene and dihalomethylene;R.sub.2 is selected from the group consisting of H, halo, alkyl, substituted alkyl, alkoxyl, nitro and azido;R.sub.3 is selected from the group consisting of H, alkyl, acyl, aryl, and arylalkyl; andR.sub.4 is selected from the group consisting of --OR', --SR', --NR', and --NR'R", wherein R' and R" are independently selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, alkoxyl, and aryloxyl, with the proviso that R' is absent when R.sub.4 is double bonded from an oxygen or sulfur atom to the carbon at the 4-position of the pyrimidine ring, are used in methods of hydrating lung mucus secretions and treating lung disorders such as cystic fibrosis, ventilator-associated pneumonia, chronic bronchitis, chronic obstructive pulmonary disorder and primary ciliary dyskinesia. Pharmaceutical compositions containing compounds of Formula I, and novel compounds of Formula I are also described.

摘要翻译： 式I化合物：其中：X 1和X 2各自独立地为O-或S-; X 3和X 4各自独立地是-H或-OH，条件是X 3和X 4不同时为-H; R1选自O，亚氨基，亚甲基和二卤代亚甲基; R2选自H，卤素，烷基，取代的烷基，烷氧基，硝基和叠氮基; R3选自H，烷基，酰基，芳基和芳基烷基; 并且R 4选自-OR'，-SR'，-NR'和-NR'R“，其中R'和R”独立地选自H，烷基，取代的烷基 ，芳基，取代的芳基，芳基烷基，烷氧基和芳氧基，条件是当R4与氧或硫原子双键连接到嘧啶环的4-位上的碳时，R'不存在，用于 水分肺粘液分泌物和治疗肺部疾病如囊性纤维化，呼吸机相关肺炎，慢性支气管炎，慢性阻塞性肺病和原发性纤毛运动障碍。 还描述了含有式I化合物和式I的新化合物的药物组合物。

公开(公告)号：US6022527A

公开(公告)日：2000-02-08

申请号：US352390

申请日：1999-07-13

申请人： Richard C. Boucher, Jr. ,  Sammy Ray Shaver ,  William Pendergast ,  Benjamin Yerxa ,  Janet L. Rideout ,  Robert Dougherty ,  Dallas Croom

发明人： Richard C. Boucher, Jr. ,  Sammy Ray Shaver ,  William Pendergast ,  Benjamin Yerxa ,  Janet L. Rideout ,  Robert Dougherty ,  Dallas Croom

IPC分类号： A61K9/00 ,  A61K31/7042 ,  A61K31/7052 ,  A61K31/7064 ,  A61K31/7068 ,  A61K31/7072 ,  A61K45/06 ,  A61P11/00 ,  C07H19/10 ,  A61K9/12

CPC分类号： A61K31/7068 ,  A61K31/7072 ,  A61K45/06 ,  A61K9/0073 ,  C07H19/10 ,  Y10S514/826 ,  Y10S514/851

摘要： Compounds of Formula I: ##STR1## wherein: X.sub.1, and X.sub.2 are each independently either O.sup.- or S.sup.- ;X.sub.3 and X.sub.4 are each independently either --H or --OH, with the proviso that X.sub.3 and X.sub.4 are not simultaneously --H;R.sub.1 is selected from the group consisting of O, imido, methylene and dihalomethylene;R.sub.2 is selected from the group consisting of H, halo, alkyl, substituted alkyl, alkoxyl, nitro and azido;R.sub.3 is selected from the group consisting of H, alkyl, acyl, aryl, and arylalkyl; andR.sub.4 is selected from the group consisting of --OR', --SR', --NR', and --NR'R", wherein R' and R" are independently selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, alkoxyl, and aryloxyl, with the proviso that R' is absent when R.sub.4 is double bonded from an oxygen or sulfur atom to the carbon at the 4-position of the pyrimidine ring, are used in methods of hydrating lung mucus secretions and treating lung disorders such as cystic fibrosis, ventilator-associated pneumonia, chronic bronchitis, chronic obstructive pulmonary disorder and primary ciliary dyskinesia. Pharmaceutical compositions containing compounds of Formula I, and novel compounds of Formula I are also described.

摘要翻译： 式I化合物：其中：X 1和X 2各自独立地为O-或S-; X 3和X 4各自独立地是-H或-OH，条件是X 3和X 4不同时为-H; R1选自O，亚氨基，亚甲基和二卤代亚甲基; R2选自H，卤素，烷基，取代的烷基，烷氧基，硝基和叠氮基; R3选自H，烷基，酰基，芳基和芳基烷基; 并且R 4选自-OR'，-SR'，-NR'和-NR'R“，其中R'和R”独立地选自H，烷基，取代的烷基 ，芳基，取代的芳基，芳基烷基，烷氧基和芳氧基，条件是当R4与氧或硫原子双键连接到嘧啶环的4-位上的碳时，R'不存在，用于 水分肺粘液分泌物和治疗肺部疾病如囊性纤维化，呼吸机相关肺炎，慢性支气管炎，慢性阻塞性肺病和原发性纤毛运动障碍。 还描述了含有式I化合物和式I的新化合物的药物组合物。