公开(公告)号：US09018371B2

公开(公告)日：2015-04-28

申请号：US12530086

申请日：2007-03-07

申请人： Lak Shin Jeong ,  Hea Ok Kim ,  Kenneth A. Jacobson ,  Seung Ah Choe

发明人： Lak Shin Jeong ,  Hea Ok Kim ,  Kenneth A. Jacobson ,  Seung Ah Choe

IPC分类号： C07H19/16 ,  C07H1/00 ,  C07D473/34

CPC分类号： C07D473/34 ,  C07H19/16

摘要： Disclosed are adenosine derivatives, methods for the synthesis thereof, and pharmaceutical compositions for the prevention and treatment of inflammatory diseases, comprising the same as an active ingredient. The adenosine derivatives have high binding affinity and selectivity for adenosine receptors, especially for A3 adenosine receptors and act as A3 adenosine receptor antagonists, and exhibit anti-inflammatory activity. Thus, the adenosine derivatives are useful in the prevention and treatment of inflammatory diseases.

摘要翻译： 公开了腺苷衍生物，其合成方法和用于预防和治疗炎性疾病的药物组合物，其包含与活性成分相同的物质。 腺苷衍生物对腺苷受体具有高结合亲和力和选择性，特别是A3腺苷受体，作为A3腺苷受体拮抗剂，具有抗炎活性。 因此，腺苷衍生物可用于预防和治疗炎性疾病。

公开(公告)号：US08735407B2

公开(公告)日：2014-05-27

申请号：US12935461

申请日：2009-03-24

申请人： Kenneth A. Jacobson ,  Artem Melman

发明人： Kenneth A. Jacobson ,  Artem Melman

IPC分类号： A61K31/522 ,  C07D473/00

CPC分类号： C07D473/34

摘要： Disclosed are (N)-methanocarba adenine nucleosides, e.g., of formula (I) as highly potent A3 adenosine receptor agonists, pharmaceutical compositions comprising such nucleosides, and a method of use of these nucleosides, wherein R1-R6 are as defined in the specification. These nucleosides exhibit similar selectivities as agonists of the A3 versus the A1 receptor for both human and mouse adenosine receptors, and are contemplated for use in the treatment a number of diseases, for example, inflammation, cardiac ischemia, stroke, asthma, diabetes, and cardiac arrhythmias.

摘要翻译： 本发明公开了（N） - 甲烷卡巴腺嘌呤核苷，例如式（I）作为高效A3腺苷受体激动剂，包含这种核苷的药物组合物，以及这些核苷的使用方法，其中R1-R6如说明书中所定义 。 这些核苷显示出与人类和小鼠腺苷受体的A3相对于A1受体的激动剂相似的选择性，并且被考虑用于治疗许多疾病，例如炎症，心脏缺血，中风，哮喘，糖尿病和 心律失常。

公开(公告)号：US20110212924A1

公开(公告)日：2011-09-01

申请号：US13031805

申请日：2011-02-22

申请人： Bruce Liang ,  Kenneth A. Jacobson ,  Bhalchandra V. Joshi ,  Thatikonda Santhosh Kumar

发明人： Bruce Liang ,  Kenneth A. Jacobson ,  Bhalchandra V. Joshi ,  Thatikonda Santhosh Kumar

IPC分类号： A61K31/675 ,  C07F9/6561 ,  A61P9/00

CPC分类号： A61K31/675 ,  A61K31/683 ,  C07F9/65616

摘要： Phosphonate and phosphinate N-methanocarba derivatives of AMP including their prodrug analogs are described. MRS2339, a 2-chloro-AMP derivative containing a (N)-methanocarba (bicyclo[3.1.0]hexane) ring system in place of ribose, activates P2X receptors, ligand-gated ion channels. Phosphonate analogues of MRS2339 were synthesized using Michaelis-Arbuzov and Wittig reactions, based on the expectation of increased half-life in vivo due to the stability of the C—P bond. When administered to calsequestrin-overexpressing mice (a genetic model of heart failure) via a mini-osmotic pump (Alzet), some analogues significantly increased intact heart contractile function in vivo, as assessed by echocardiography-derived fractional shortening (FS) as compared to vehicle-infused mice. The range of carbocyclic nucleotide analogues for treatment of heart failure has been expanded.

摘要翻译： 描述了膦酸盐和次膦酸盐，其包括其前体药物类似物的N-甲基碳酰胺衍生物。 含有（N） - 甲烷卡巴（双环[3.1.0]己烷）环体系的代替核糖的2-氯-AMP衍生物MRS2339激活P2X受体，配体门控离子通道。 基于由于C-P键的稳定性而增加的体内半衰期的期望，使用Michaelis-Arbuzov和Wittig反应合成MRS2339的膦酸酯类似物。 当通过小型渗透泵（Alzet）将氯雷斯特林过度表达的小鼠（心力衰竭的遗传模型）施用时，一些类似物显着增加体内完整的心脏收缩功能，如通过超声心动图来源的分数缩短（FS）评估的，与 车辆输注小鼠。 用于治疗心力衰竭的碳环核苷酸类似物的范围已经扩大。

公开(公告)号：US07790735B2

公开(公告)日：2010-09-07

申请号：US11500860

申请日：2006-08-08

申请人： Kenneth A Jacobson ,  Victor E Marquez

发明人： Kenneth A Jacobson ,  Victor E Marquez

IPC分类号： C07D239/54 ,  A61K31/513

CPC分类号： C07D473/34

摘要： The present invention provides novel nucleoside and nucleotide derivatives that are useful agonist or antagonists of P1 and P2 receptors. For example, the present invention provides a compound of formula A-M, wherein A is modified adenine or uracil and M is a constrained cycloalkyl group. The adenine or uracil is bonded to the constrained cycloalkyl group. The compounds of the present invention are useful in the treatment or prevention of various diseases including airway diseases (through A2B, A3, P2Y2 receptors), cancer (through A3, P2 receptors), cardiac arrhythmias (through A1 receptors), cardiac ischemia (through A1, A3 receptors), epilepsy (through A1, P2X receptors), and Huntington's Disease (through A2A receptors).

摘要翻译： 本发明提供了新的核苷和核苷酸衍生物，其是P1和P2受体的有用的激动剂或拮抗剂。 例如，本发明提供式A-M的化合物，其中A是修饰的腺嘌呤或尿嘧啶，M是受限制的环烷基。 腺嘌呤或尿嘧啶与受限制的环烷基键合。 本发明的化合物可用于治疗或预防各种疾病，包括气道疾病（通过A2B，A3，P2Y2受体），癌症（通过A3，P2受体），心律失常（通过A1受体），心脏缺血（通过 A1，A3受体），癫痫（通过A1，P2X受体）和亨廷顿病（通过A2A受体）。

公开(公告)号：US20090258836A1

公开(公告)日：2009-10-15

申请号：US12419062

申请日：2009-04-06

申请人： Mortimer M. Civan ,  Kenneth A. Jacobson ,  Marcel Y. Avila ,  Richard Stone

发明人： Mortimer M. Civan ,  Kenneth A. Jacobson ,  Marcel Y. Avila ,  Richard Stone

IPC分类号： A61K31/7076 ,  A61P27/06

CPC分类号： A61K31/52

摘要： Provided are methods for reducing intraocular pressure in an individual having an ocular disorder causing elevated intraocular pressure, such as glaucoma. The method comprises administering to the individual an effective intraocular pressure-reducing amount of a pharmaceutical composition comprising an A3 subtype adenosine receptor (A3AR) antagonist, including dihydropyridine, pyridine, pyridinium salt or triazoloquinazoline, and derivatives thereof expressly having A3AR antagonist activity, including, e.g., the nucleoside-based A3AR antagonist, MRS-3820. Further provided is a method for ensuring the delivery of a topically administered therapeutic composition for reducing intraocular pressure, wherein the method expressly requires physically opening a channel through the corneal barrier of the patient's eye by a microneedle or micropipette to permit transport of the topical composition to the anterior chamber of the eye.

摘要翻译： 本发明提供了降低眼内压引起眼内压升高的患者眼内压的方法，例如青光眼。 该方法包括向个体施用有效降低眼内压的包含A3亚型腺苷受体（A3AR）拮抗剂（包括二氢吡啶，吡啶，吡啶鎓盐或三唑并喹唑啉）及其明确具有A3AR拮抗剂活性的衍生物的药物组合物， 例如，基于核苷的A3AR拮抗剂MRS-3820。 还提供了一种用于确保局部施用的用于降低眼内压的治疗组合物的递送的方法，其中所述方法明确地要求通过微针或微量移液管物理性地打开穿过患者眼睛的角膜屏障的通道，以允许将局部组合物运输到 眼睛的前房。

公开(公告)号：US07087589B2

公开(公告)日：2006-08-08

申请号：US10169975

申请日：2001-01-12

申请人： Kenneth A. Jacobson ,  Victor E. Marquez

发明人： Kenneth A. Jacobson ,  Victor E. Marquez

IPC分类号： C07D473/16 ,  C07D473/18 ,  C07D473/34 ,  A61K31/52 ,  A61K31/522

CPC分类号： C07D473/34

摘要： The present invention provides novel nucleoside and nucleotide derivatives that are useful agonists or antagonists of P1 or P2 receptors. For example, the present invention provides a compound of formula A-M, wherein A is modified adenine or uracil and M is a constrained cycloalkyl group. The adenine or uracil is bonded to the constrained cycloakyl group. The compounds of the present invention are useful in the treatment or prevention of various diseases including airway diseases (through A2B, A3, P2Y2 receptors), cancer (through A3, P2 receptors), cardiac arrhythmias (through A1 receptors), cardiac ischemia (through A1, A3 receptors), epilepsy (through A1, P2X receptors), and Huntington's Disease (through A2A receptors).

摘要翻译： 本发明提供了作为P1或P2受体的有用的激动剂或拮抗剂的新型核苷和核苷酸衍生物。 例如，本发明提供式A-M的化合物，其中A是修饰的腺嘌呤或尿嘧啶，M是受限制的环烷基。 腺嘌呤或尿嘧啶与受限制的环亚基结合。 本发明的化合物可用于治疗或预防各种疾病，包括气道疾病（通过A 2B，A 3，P 2，N 2， 受体），癌症（通过Aβ3 P2受体），心律失常（通过Aβ1受体），心脏缺血（通过Aβ1， Aβ受体），癫痫（通过Aβ1 P2X受体）和亨廷顿舞蹈病（通过2A2受体）。

公开(公告)号：US5620676A

公开(公告)日：1997-04-15

申请号：US414438

申请日：1995-03-31

申请人： Kenneth A. Jacobson ,  Bilha Fischer ,  Michel Maillard

发明人： Kenneth A. Jacobson ,  Bilha Fischer ,  Michel Maillard

IPC分类号： A61K51/04 ,  C07H19/20 ,  A61K51/00 ,  A61M36/14

CPC分类号： A61K51/0491 ,  C07H19/20 ,  A61K2121/00

摘要： The present invention provides certain novel adenosine triphosphate (ATP) analogs, pharmaceutical compositions, and methods of using such analogs in the treatment of septic shock and other disease conditions. Examples of the ATP analogs include the mono-, di- and triphosphates of adenosines with various selected substituents at the 2, 6, 8, and 9-positions, such as alkyl, alkylphenyl, phenylalkyl, S-alkyl, S-alkenyl, S-alkylcyano, S-phenyl, S-alkylphenyl, S-alkylamino, S-alkylthioalkyl, S-alkylthiocyanato, S-alkylaminophenyl, S-alkylnitrophenyl, hydroxy, bromo, fluoro, chloro, and aminoalkylamino. The present invention also provides pharmaceutical compositions of and methods of using certain xanthine and uracil derivatives for the above disease conditions. Examples of the xanthine derivatives include xanthines having alkyl or alkyltriphosphate substituents at the 1, 3, and 7-positions. Examples of the uracil derivatives include 5-fluoro- and 5-bromo uracil triphosphates. Also provided are assays for assessing the binding of the ATP analogs.

摘要翻译： 本发明提供某些新颖的三磷酸腺苷（ATP）类似物，药物组合物，以及在治疗败血性休克和其它疾病状况中使用这些类似物的方法。 ATP类似物的实例包括在2,6,8和9位具有各种选择的取代基的腺苷的单，二和三磷酸，例如烷基，烷基苯基，苯基烷基，S-烷基，S-链烯基，S - 烷基氰基，S-苯基，S-烷基苯基，S-烷基氨基，S-烷硫基烷基，S-烷硫基氰基，S-烷基氨基苯基，S-烷基硝基苯基，羟基，溴，氟，氯和氨基烷基氨基。 本发明还提供了用于上述疾病状况的药物组合物和使用某些黄嘌呤和尿嘧啶衍生物的方法。 黄嘌呤衍生物的实例包括在1,3和7位具有烷基或烷基三磷酸取代基的黄嘌呤。 尿嘧啶衍生物的实例包括5-氟 - 和5-溴尿嘧啶三磷酸。 还提供了用于评估ATP类似物的结合的测定。

公开(公告)号：US20240150290A1

公开(公告)日：2024-05-09

申请号：US18272435

申请日：2022-01-05

申请人： Kenneth A. Jacobson ,  Young-Hwan Jung ,  Zhiwei Wen

发明人： Kenneth A. Jacobson ,  Young-Hwan Jung ,  Zhiwei Wen

IPC分类号： C07D211/34 ,  A61P25/02 ,  C07D205/04 ,  C07D205/12 ,  C07D207/08 ,  C07D209/52 ,  C07D211/62 ,  C07D221/04 ,  C07D221/22 ,  C07D223/04 ,  C07D225/02 ,  C07D249/06 ,  C07D261/08 ,  C07D401/10 ,  C07D401/14 ,  C07D403/10 ,  C07D413/10 ,  C07D451/06 ,  C07F9/6518

CPC分类号： C07D211/34 ,  A61P25/02 ,  C07D205/04 ,  C07D205/12 ,  C07D207/08 ,  C07D209/52 ,  C07D211/62 ,  C07D221/04 ,  C07D221/22 ,  C07D223/04 ,  C07D225/02 ,  C07D249/06 ,  C07D261/08 ,  C07D401/10 ,  C07D401/14 ,  C07D403/10 ,  C07D413/10 ,  C07D451/06 ,  C07F9/6518

摘要： Disclosed are compounds for treating or preventing a disease or disorder responsive to antagonism of a P2Y14R receptor agonist in a mammal in need thereof, for example, compounds of formulas (I) and (II), wherein R1-R8, X, Y, Z, X′, Y′, Z′, and A are as defined herein, that are useful in treating an inflammatory such as asthma, cystic fibrosis, and sterile inflammation of the kidney.

公开(公告)号：US08822434B2

公开(公告)日：2014-09-02

申请号：US13031805

申请日：2011-02-22

申请人： Bruce Liang ,  Kenneth A. Jacobson ,  Bhalchandra V. Joshi ,  Thatikonda Santhosh Kumar

发明人： Bruce Liang ,  Kenneth A. Jacobson ,  Bhalchandra V. Joshi ,  Thatikonda Santhosh Kumar

IPC分类号： A61K31/675 ,  C07F9/6561

CPC分类号： A61K31/675 ,  A61K31/683 ,  C07F9/65616

摘要： Phosphonate and phosphinate N-methanocarba derivatives of AMP including their prodrug analogs are described. MRS2339, a 2-chloro-AMP derivative containing a (N)-methanocarba (bicyclo[3.1.0]hexane) ring system in place of ribose, activates P2X receptors, ligand-gated ion channels. Phosphonate analogs of MRS2339 were synthesized using Michaelis-Arbuzov and Wittig reactions, based on the expectation of increased half-life in vivo due to the stability of the C—P bond. When administered to calsequestrin-overexpressing mice (a genetic model of heart failure) via a mini-osmotic pump (Alzet), some analogs significantly increased intact heart contractile function in vivo, as assessed by echocardiography-derived fractional shortening (FS) as compared to vehicle-infused mice. The range of carbocyclic nucleotide analogs for treatment of heart failure has been expanded.

摘要翻译： 描述了膦酸盐和次膦酸盐，其包括其前体药物类似物的N-甲基碳酰胺衍生物。 含有（N） - 甲烷卡巴（双环[3.1.0]己烷）环体系的代替核糖的2-氯-AMP衍生物MRS2339激活P2X受体，配体门控离子通道。 基于由于C-P键的稳定性增加的体内半衰期的期望，使用Michaelis-Arbuzov和Wittig反应合成MRS2339的膦酸酯类似物。 当通过小型渗透泵（Alzet）将其加入到氯海洛酮过表达的小鼠（心力衰竭的遗传模型）时，一些类似物在体内显着增加了完整的心脏收缩功能，如通过超声心动图衍生的分数缩短（FS）评估的，与 车辆输注小鼠。 用于治疗心力衰竭的碳环核苷酸类似物的范围已经扩大。

公开(公告)号：US08153781B2

公开(公告)日：2012-04-10

申请号：US12143451

申请日：2008-06-20

申请人： Kenneth A. Jacobson ,  Yoonkyung Kim ,  Athena Klutz ,  Beatrice Hechler ,  Christian Gachet

发明人： Kenneth A. Jacobson ,  Yoonkyung Kim ,  Athena Klutz ,  Beatrice Hechler ,  Christian Gachet

IPC分类号： C07H19/22

CPC分类号： A61K49/0054 ,  A61K47/59 ,  A61K47/595 ,  A61K47/60 ,  A61K49/0041

摘要： Disclosed are conjugates comprising a dendrimer and a ligand, which is a functionalized congener of an agonist or antagonist of a receptor of the G-protein coupled receptor (GPCR) superfamily, for example, wherein the functionalized congener is an A1 adenosine receptor agonist having a purine nucleoside moiety and a functional group at the N6 position of the purine nucleoside moiety, wherein the functional group has the formula (I):N6H—Ar1—CH2—C(═O)NH—R1 (I), wherein Ar1 and R1 as defined herein. Also disclosed are pharmaceutical compositions, methods of treating various diseases, and a diagnostic method employing such conjugates.

摘要翻译： 公开了包含树枝状大分子和配体的缀合物，其是G-蛋白质偶联受体（GPCR）超家族的受体的激动剂或拮抗剂的官能化同族物，其中所述官能化同系物是具有 嘌呤核苷部分和嘌呤核苷部分的N6位置的官能团，其中官能团具有式（I）：N6H-Ar1-CH2-C（= O）NH-R1（I），其中Ar1和R1 如本文所定义。 还公开了药物组合物，治疗各种疾病的方法和使用这种缀合物的诊断方法。