公开(公告)号：US07939510B2

公开(公告)日：2011-05-10

申请号：US12430684

申请日：2009-04-27

申请人： Benjamin R. Yerxa ,  Edward G. Brown

发明人： Benjamin R. Yerxa ,  Edward G. Brown

IPC分类号： A61K31/70

CPC分类号： A61K31/7048 ,  A61K31/7068 ,  A61K31/7072 ,  A61K31/7076 ,  C07H19/10 ,  C07H19/20 ,  C07H21/00 ,  Y10S514/851

摘要： The present invention are directed to P1,P4-di(uridine 5′-)tetraphosphate, tetra-alkali metal salts such as tetrasodium, tetralithium, tetrapotassium, and mixed tetra-alkali metal cations thereof. The tetra alkali metal salts of P1,P4-di(uridine 5′-)tetraphosphate are water-soluble, nontoxic, and easy to handle during manufacture. These tetra-monovalent alkali metal salts are more resistant to hydrolysis than the mono-, di-, or tri-acid salts, therefore, they provide an improved stability and a longer shelf life for storage. The present invention also provides methods for the synthesis of P1,P4-di(uridine 5′-)tetraphosphate, and its pharmaceutically acceptably acceptable salts thereof, and demonstrates the applicability to the production of large quantities. The methods substantially reduce the time required to synthesize diuridine tetraphosphate, for example, to three days or less.

摘要翻译： 本发明涉及P1，P4-二（尿苷5'-）四磷酸盐，四碱金属盐如四钠，四锂，四钾及其混合四碱金属阳离子。 P1，P4-二（尿苷5' - ）四磷酸的四碱金属盐是水溶性的，无毒的，在制造过程中易于处理。 这些四价一价碱金属盐比单 - ，二 - 或三 - 酸盐更耐水解，因此，它们提供了改进的稳定性和更长的储存期限。 本发明还提供了合成P1，P4-二（尿苷5' - ）四磷酸及其药学上可接受的盐的方法，并且证明了对大量生产的适用性。 所述方法基本上减少了合成二脯氨酸四磷酸酯所需的时间，例如为3天或更短。

公开(公告)号：US20100330164A1

公开(公告)日：2010-12-30

申请号：US12825051

申请日：2010-06-28

申请人： Benjamin R. Yerxa ,  Karla M. Jacobus ,  William Pendergast ,  Janet L. Rideout

发明人： Benjamin R. Yerxa ,  Karla M. Jacobus ,  William Pendergast ,  Janet L. Rideout

IPC分类号： A61K31/7076 ,  A61K31/7072 ,  A61K9/127 ,  A61P27/04

CPC分类号： C07H19/10 ,  A61K9/0048 ,  A61K31/7084 ,  A61K45/06 ,  C07H19/20 ,  C07H21/00 ,  Y10S514/912 ,  Y10S514/915

摘要： A method and preparation for the stimulation of tear secretion in a subject in need of such treatment is disclosed. The method comprises administering to the ocular surfaces of the subject a purinergic receptor agonist such as uridine 5′-triphosphate (UTP), dinucleotides, cytidine 5′-triphosphate (CTP), adenosine 5′-triphosphate (ATP), or their therapeutically useful analogs and derivatives, in an amount effective to stimulate tear fluid secretion and enhance drainage of the lacrimal system. Pharmaceutical formulations and methods of making the same are also disclosed. Methods of administering the same would include: topical administration via a liquid, gel, cream, or as part of a contact lens or selective release membrane; or systemic administration via nasal drops or spray, inhalation by nebulizer or other device, oral form (liquid or pill), injectable, intra-operative instillation or suppository form.

摘要翻译： 公开了用于刺激需要这种治疗的受试者的泪液分泌的方法和制剂。 该方法包括向受试者的眼表面施用嘌呤能受体激动剂如尿苷5'-三磷酸（UTP），二核苷酸，胞苷5'-三磷酸（CTP），腺苷5'-三磷酸（ATP）或其治疗上有用的 类似物和衍生物，其量有效地刺激泪液分泌并增强泪液系统的引流。 还公开了药物制剂及其制备方法。 施用该方法的方法将包括：通过液体，凝胶，霜剂或作为隐形眼镜或选择性释放膜的一部分局部给药; 或通过鼻滴或喷雾进行全身给药，通过喷雾器或其它装置吸入，口服形式（液体或丸剂），可注射的，术中滴注或栓剂形式。

公开(公告)号：US07759322B2

公开(公告)日：2010-07-20

申请号：US11821091

申请日：2007-06-20

申请人： Benjamin R. Yerxa ,  Karla M. Jacobus ,  William Pendergast ,  Janet L. Rideout

发明人： Benjamin R. Yerxa ,  Karla M. Jacobus ,  William Pendergast ,  Janet L. Rideout

IPC分类号： A01N43/04 ,  A61K31/70

CPC分类号： C07H19/10 ,  A61K9/0048 ,  A61K31/7084 ,  A61K45/06 ,  C07H19/20 ,  C07H21/00 ,  Y10S514/912 ,  Y10S514/915

摘要： A method and preparation for the stimulation of tear secretion in a subject in need of such treatment is disclosed. The method comprises administering to the ocular surfaces of the subject a purinergic receptor agonist such as uridine 5′-triphosphate (UTP), dinucleotides, cytidine 5′-triphosphate (CTP), adenosine 5′-triphosphate (ATP), or their therapeutically useful analogs and derivatives, in an amount effective to stimulate tear fluid secretion and enhance drainage of the lacrimal system. Pharmaceutical formulations and methods of making the same are also disclosed. Methods of administering the same would include: topical administration via a liquid, gel, cream, or as part of a contact lens or selective release membrane; or systemic administration via nasal drops or spray, inhalation by nebulizer or other device, oral form (liquid or pill), injectable, intra-operative instillation or suppository form.

摘要翻译： 公开了用于刺激需要这种治疗的受试者的泪液分泌的方法和制剂。 该方法包括向受试者的眼表面施用嘌呤能受体激动剂如尿苷5'-三磷酸（UTP），二核苷酸，胞苷5'-三磷酸（CTP），腺苷5'-三磷酸（ATP）或其治疗上有用的 类似物和衍生物，其量有效地刺激泪液分泌并增强泪液系统的引流。 还公开了药物制剂及其制备方法。 施用该方法的方法将包括：通过液体，凝胶，霜剂或作为隐形眼镜或选择性释放膜的一部分局部给药; 或通过鼻滴或喷雾进行全身给药，通过喷雾器或其它装置吸入，口服形式（液体或丸剂），可注射的，术中滴注或栓剂形式。

公开(公告)号：US07528119B2

公开(公告)日：2009-05-05

申请号：US11486497

申请日：2006-07-14

申请人： Benjamin R. Yerxa ,  Edward G. Brown

发明人： Benjamin R. Yerxa ,  Edward G. Brown

IPC分类号： A61K31/70

CPC分类号： A61K31/7048 ,  A61K31/7068 ,  A61K31/7072 ,  A61K31/7076 ,  C07H19/10 ,  C07H19/20 ,  C07H21/00 ,  Y10S514/851

摘要： The present invention are directed to P1,P4-di(uridine 5′-)tetraphosphate, tetra-alkali metal salts such as tetrasodium, tetralithium, tetrapotassium, and mixed tetra-alkali metal cations thereof. The tetra alkali metal salts of P1,P4-di(uridine 5′-)tetraphosphate are water-soluble, nontoxic, and easy to handle during manufacture. These tetra-monovalent alkali metal salts are more resistant to hydrolysis than the mono-, di-, or tri-acid salts, therefore, they provide an improved stability and a longer shelf life for storage. The present invention also provides methods for the synthesis of P1,P4-di(uridine 5′-)tetraphosphate, and its pharmaceutically acceptably acceptable salts thereof, and demonstrates the applicability to the production of large quantities. The methods substantially reduce the time required to synthesize diuridine tetraphosphate, for example, to three days or less.

摘要翻译： 本发明涉及P1，P4-二（尿苷5'-）四磷酸盐，四碱金属盐如四钠，四锂，四钾及其混合四碱金属阳离子。 P1，P4-二（尿苷5' - ）四磷酸的四碱金属盐是水溶性的，无毒的，在制造过程中易于处理。 这些四价一价碱金属盐比单 - ，二 - 或三 - 酸盐更耐水解，因此，它们提供了改进的稳定性和更长的储存期限。 本发明还提供了合成P1，P4-二（尿苷5' - ）四磷酸及其药学上可接受的盐的方法，并且证明了对大量生产的适用性。 所述方法基本上减少了合成二脯氨酸四磷酸酯所需的时间，例如为3天或更短。

公开(公告)号：US06881725B2

公开(公告)日：2005-04-19

申请号：US10355699

申请日：2003-01-31

申请人： Benjamin R. Yerxa ,  Ward M. Peterson ,  Christopher S. Crean

发明人： Benjamin R. Yerxa ,  Ward M. Peterson ,  Christopher S. Crean

IPC分类号： C07H19/20 ,  A61K31/675 ,  A61K31/7072 ,  A61K31/7076 ,  A61K31/7084 ,  A61P23/00 ,  A61P25/04 ,  A61P25/06 ,  A61P29/00 ,  C07H19/207 ,  C07H21/00 ,  A61K31/70

CPC分类号： A61K31/7076 ,  A61K31/675 ,  A61K31/7072 ,  A61K31/7084 ,  Y10S514/851

摘要： The present invention is directed to a method of treating pain. The method comprises administering to a subject a pharmaceutical composition comprising an effective amount of a P2X receptor antagonist. The methods of the present invention are useful in reducing pain, such as traumatic pain, neuropathic pain, organ pain and pain associated with diseases. The P2X receptor antagonists particularly useful for this invention are mononucleoside polyphosphate derivatives or dinucleoside polyphosphate derivatives of general Formula I. The compounds of the present method can be used alone to treat pain. The compounds of the present method can also be used in conjunction with other therapeutic agents or adjunctive therapies commonly used to treat pain, thus enhancing the overall pain-reducing effect in a subject in need of such treatment.

摘要翻译： 本发明涉及治疗疼痛的方法。 该方法包括向受试者施用包含有效量的P2X受体拮抗剂的药物组合物。 本发明的方法可用于减轻疼痛，例如创伤性疼痛，神经性疼痛，器官疼痛和与疾病相关的疼痛。 特别可用于本发明的P2X受体拮抗剂是通式I的单核苷多磷酸衍生物或二核苷多磷酸衍生物。本发明方法的化合物可单独用于治疗疼痛。 本发明方法的化合物还可以与通常用于治疗疼痛的其它治疗剂或辅助疗法结合使用，从而增强需要这种治疗的受试者的整体疼痛减轻作用。

公开(公告)号：US06765090B2

公开(公告)日：2004-07-20

申请号：US09805332

申请日：2001-03-12

申请人： Benjamin R. Yerxa ,  William Pendergast

发明人： Benjamin R. Yerxa ,  William Pendergast

IPC分类号： C07H1904

CPC分类号： C07H21/00 ,  Y10S514/912

摘要： The present invention provides new methods for the synthesis of the therapeutic dinucleotide, P1,P4-di(uridine 5′-tetraphosphate), and demonstrates applicability to the production of large quantities. The methods of the present invention substantially reduce the time period required to synthesize diuridine tetraphosphate, preferably to three days or less. The novel tetrammonium and tetrasodium salts of P1,P4-di(uridine 5′-tetraphosphate) (Formula I) prepared by these methods are stable, soluble, nontoxic, and easy to handle during manufacture. wherein: X is Na, NH4 or H, provided that all X groups are not H.

摘要翻译： 本发明提供了合成治疗性二核苷酸P 1，P 4 - 二（尿苷5'） - 四磷酸的新方法，并证明其适用于大量生产。 本发明的方法基本上减少了合成二尿苷四磷酸酯所需的时间，优选为3天以下。 通过这些方法制备的P 1，P 4 - 二（尿苷5'） - 四磷酸（式I）的新型四铵盐和四钠盐在制备过程中是稳定的，可溶的，无毒的，易于处理。其中：X 是Na，NH4或H，条件是所有X基团不是H.

公开(公告)号：US06448276B1

公开(公告)日：2002-09-10

申请号：US09574831

申请日：2000-05-17

申请人： Benjamin R. Yerxa

发明人： Benjamin R. Yerxa

IPC分类号： A61K3144

CPC分类号： A61K31/4025 ,  A61K31/00 ,  A61K31/423 ,  A61K31/435 ,  A61K31/44 ,  A61K31/4412 ,  A61K31/4427 ,  A61K31/444 ,  A61K31/445 ,  A61K31/465

摘要： The invention provides a method for treating vaginal dryness by increasing hydration and lubrication of vaginal and cervical tissues in a subject in need of such treatment. The method comprises administering to the subject a nicotinic acetylcholine receptor agonist such as nicotine and its analogs, transmetanicotine and its analogs, epibatidine and it analogs, lobeline and its analogs, pyridol derivatives, para-alkylthiophenol derivatives, and imidacloprid and its analogs, in an amount effective to stimulate cervical and vaginal secretions. Pharmaceutical formulations and methods of making the same are also disclosed. Methods of administering the formulation include: topical administration via a liquid, gel, cream, ointment, foam, pessary, or tablet; systemic administration via nasal drops or spray, inhalation by nebulizer or other device, oral form (liquid or pill), injectable, suppository form, or transdermal form. The invention is useful for treating vaginal dryness and vulvar pain.

摘要翻译： 本发明提供了通过增加需要这种治疗的受试者中阴道和宫颈组织的水合和润滑来治疗阴道干燥的方法。 所述方法包括向所述受试者施用烟碱乙酰胆碱受体激动剂如尼古丁及其类似物，西咪替丁及其类似物，表巴巴胺及其类似物，叶片及其类似物，吡啶衍生物，对烷基苯硫酚衍生物和吡虫啉及其类似物， 有效刺激宫颈和阴道分泌物的量。 还公开了药物制剂及其制备方法。 施用该制剂的方法包括：通过液体，凝胶，霜剂，软膏，泡沫，子宫托或片剂局部施用; 通过鼻滴或喷雾进行全身给药，通过喷雾器或其他装置吸入，口服形式（液体或丸剂），可注射，栓剂形式或透皮形式。 本发明可用于治疗阴道干燥和外阴疼痛。

公开(公告)号：US06331529B1

公开(公告)日：2001-12-18

申请号：US09512867

申请日：2000-02-25

申请人： Benjamin R. Yerxa ,  Janet L. Rideout ,  Arthur C. Jones

发明人： Benjamin R. Yerxa ,  Janet L. Rideout ,  Arthur C. Jones

IPC分类号： A61K3170

CPC分类号： A61K31/7064 ,  A61K31/7048 ,  A61K31/7068 ,  A61K31/7072 ,  A61K31/7076 ,  Y10S514/912

摘要： A method and preparation for the stimulation of mucosal hydration in a subject in need of such treatment is disclosed. The method comprises administering to the mucosal surfaces of the subject a purinergic receptor agonist such as uridine 5′-diphosphate (UDP), dinucleotides, cytidine 5′-diphosphate (CDP), adenosine 5′-diphosphate (ADP), or their therapeutically useful analogs and derivatives, in an amount effective to stimulate mucin secretion. Pharmaceutical formulations and methods of making the same are also disclosed. Methods of administering the same would include: topical administration via a liquid, gel, cream, or as part of a contact lens or selective release membrane; or systemic administration via nasal drops or spray, inhalation by nebulizer or other device, oral form (liquid or pill), injectable, intra-operative instillation or suppository form. A method for facilitating the expectoration of sputum for the purpose of detecting cellular abnormalities indicative of lung disease is also disclosed.

摘要翻译： 公开了在需要这种治疗的受试者中刺激粘膜水合的方法和制备方法。 该方法包括向受试者的粘膜表面施用嘌呤能受体激动剂如尿苷5'-二磷酸（UDP），二核苷酸，胞苷5'-二磷酸（CDP），腺苷5'-二磷酸（ADP）或其治疗上有用的 类似物和衍生物，有效刺激粘蛋白分泌的量。 还公开了药物制剂及其制备方法。 施用该方法的方法将包括：通过液体，凝胶，霜剂或作为隐形眼镜或选择性释放膜的一部分局部给药; 或通过鼻滴或喷雾进行全身给药，通过喷雾器或其它装置吸入，口服形式（液体或丸剂），可注射的，术中滴注或栓剂形式。 还公开了为了检测指示肺部疾病的细胞异常的目的而促进痰吐出的方法。

公开(公告)号：US06323187B1

公开(公告)日：2001-11-27

申请号：US09316571

申请日：1999-05-21

申请人： Benjamin R. Yerxa ,  William Pendergast ,  Janet L. Rideout ,  Maryse Picher ,  Richard C. Boucher, Jr. ,  M. Jackson Stutts

发明人： Benjamin R. Yerxa ,  William Pendergast ,  Janet L. Rideout ,  Maryse Picher ,  Richard C. Boucher, Jr. ,  M. Jackson Stutts

IPC分类号： A01N4304

CPC分类号： A61K31/7048 ,  A61K31/70 ,  C07H19/207 ,  C07H21/00

摘要： The present invention relates to P1-(cytidine 5′-)-P-(uridine 5′-)tetraphosphates and its salts, esters and amides, and formulations thereof which are highly stable and selective agonists of the P2Y2 and/or P2Y4 purinergic receptor. The compounds of the invention are useful in the treatment of chronic obstructive pulmonary diseases such as chronic bronchitis, primary ciliary dyskinesia, cystic fibrosis, as well as prevention of pneumonia due to immobility, and the induction of sputum and its expectoration. Furthermore, because of their general ability to clear retained mucus secretions and stimulate ciliary beat frequency, the compounds of the present invention are also useful in the treatment of sinusitis and otitis media.

摘要翻译： 本发明涉及P2Y2和/或P2Y4嘌呤能受体的高度稳定和选择性激动剂的P1-（胞苷5' - ） - （ - 尿苷5' - ）四磷酸及其盐，酯和酰胺及其制剂 。 本发明的化合物可用于治疗慢性阻塞性肺疾病如慢性支气管炎，原发性纤毛运动障碍，囊性纤维化，以及预防由于不动的肺炎，以及诱导痰及其咳痰。 此外，由于它们具有清除保留的粘液分泌物和刺激睫状肌搏动频率的一般能力，本发明的化合物也可用于治疗鼻窦炎和中耳炎。

公开(公告)号：US20130344139A1

公开(公告)日：2013-12-26

申请号：US14013794

申请日：2013-08-29

申请人： Benjamin R. Yerxa ,  Jason L. Vittitow ,  John C. Ice ,  Ramesh Krisnamoorthy

发明人： Benjamin R. Yerxa ,  Jason L. Vittitow ,  John C. Ice ,  Ramesh Krisnamoorthy

IPC分类号： A61K31/55

CPC分类号： A61K31/55 ,  Y10S514/912

摘要： A method and preparation for reducing dry eye symptoms and promoting tear secretion in a subject in need of such treatment is disclosed. The method is useful in treating dry eye diseases. The method is also useful in reducing contact lens intolerance in the eyes. The method comprises administering to the eyes of a subject in need thereof a non-drying antihistamine compound, such as epinastine hydrochloride, in an amount effective to reduce dry eye symptoms and stimulate tear fluid secretion. Pharmaceutical formulations and methods of making the same are also disclosed. Methods of administering the compound include topical administration via a liquid, gel, cream, or as part of a contact lens or a continuous or selective release device; or systemic administration via nasal drops or spray, inhalation by nebulizer or other device, oral form, injectable, intra-operative instillation or suppository form.

摘要翻译： 公开了减少需要这种治疗的受试者的干眼症状和促进泪液分泌的方法和制剂。 该方法可用于治疗干眼病。 该方法也可用于减少眼睛中的隐形眼镜不耐受。 该方法包括以有效减少干眼症状并刺激泪液分泌的量向有需要的受试者的眼睛施用非干燥的抗组胺药化合物，例如盐酸依诺斯汀。 还公开了药物制剂及其制备方法。 施用化合物的方法包括通过液体，凝胶，霜剂或作为隐形眼镜或连续或选择性释放装置的一部分的局部给药; 或通过鼻滴或喷雾进行全身给药，通过喷雾器或其他装置吸入，口服形式，可注射的，术中滴注或栓剂形式。