公开(公告)号：US06838484B2

公开(公告)日：2005-01-04

申请号：US10270232

申请日：2002-10-15

申请人： Mitchell S. Steiner ,  Karen A. Veverka ,  James T. Dalton ,  Duane D. Miller ,  Yali He ,  Donghua Yin

发明人： Mitchell S. Steiner ,  Karen A. Veverka ,  James T. Dalton ,  Duane D. Miller ,  Yali He ,  Donghua Yin

IPC分类号： A61K31/167 ,  A61K31/404 ,  A61K31/4706 ,  A61K31/661 ,  C07C235/24 ,  C07D209/08 ,  C07D215/22 ,  C07D215/227 ,  C07D271/12 ,  G01N30/72 ,  G01N30/88 ,  G01N33/543 ,  G01N33/74 ,  A61K31/16

CPC分类号： A61K31/167 ,  A61K31/404 ,  A61K31/4706 ,  A61K31/661 ,  C07C235/24 ,  C07D209/08 ,  C07D215/227 ,  C07D271/12 ,  G01N30/7233 ,  G01N33/5438 ,  G01N33/74 ,  G01N2030/8813

摘要： The present invention relates to pharmaceutical compositions and formulations comprising a novel class of androgen receptor targeting agents (ARTA) which demonstrate androgenic and anabolic activity of a nonsteroidal ligand for the androgen receptor. The agents define a new subclass of compounds which are selective androgen receptor modulators (SARM) which are useful for a) male contraception; b) treatment of a variety of hormone-related conditions, for example conditions associated with Androgen Decline in Aging Male (ADAM), such as fatigue, depression, decreased libido, sexual dysfunction, erectile dysfunction, hypogonadism, osteoporosis, hair loss, anemia, obesity, sarcopenia, osteopenia,osteoporosis, benign prostate hyperplasia, alterations in mood and cognition and prostate cancer; c) treatment of conditions associated with Androgen Decline in Female (ADIF), such as sexual dysfunction, decreased sexual libido, hypogonadism, sarcopenia, osteopenia, osteoporosis, alterations in cognition and mood, depression, anemia, hair loss, obesity, endometriosis, breast cancer, uterine cancer and ovarian cancer; d) treatment and/or prevention of chronic muscular wasting; and/or e) decreasing the incidence of, halting or causing a regression of prostate cancer. The present invention provides pharmaceutical compositions comprising the selective androgen receptor modulator compounds, together with pharmaceutically acceptable excipients.

摘要翻译： 本发明涉及包含新型雄激素受体靶向剂（ARTA）的药物组合物和制剂，其表现出雄激素受体的非甾体配体的雄激素和合成代谢活性。 这些药剂定义了一种新的选择性雄激素受体调节剂（SARM）的化合物亚类，它们可用于a）男性避孕; b）治疗各种激素相关病症，例如与老年雄性雄激素降低有关的病症（ADAM），如疲劳，抑郁，性欲降低，性功能障碍，勃起功能障碍，性腺机能减退，骨质疏松症，脱发，贫血， 肥胖，肌营养不良，骨质减少，骨质疏松症，良性前列腺增生，情绪和认知和前列腺癌的改变; c）治疗与男性雄激素降低相关的病症（ADIF），如性功能障碍，性欲降低，性腺机能减退，肌营养不良，骨质减少，骨质疏松症，认知和情绪改变，抑郁症，贫血，脱发，肥胖，子宫内膜异位症，乳腺癌 癌症，子宫癌和卵巢癌; d）治疗和/或预防慢性肌肉消瘦; 和/或e）降低前列腺癌的发生率，停止或导致消退。 本发明提供了包含选择性雄激素受体调节剂化合物以及药学上可接受的赋形剂的药物组合物。

公开(公告)号：US06569896B2

公开(公告)日：2003-05-27

申请号：US09935045

申请日：2001-08-23

申请人： James T. Dalton ,  Duane D. Miller ,  Donghua Yin ,  Yali He

发明人： James T. Dalton ,  Duane D. Miller ,  Donghua Yin ,  Yali He

IPC分类号： A01N3222

CPC分类号： C07D215/227 ,  A61K31/167 ,  A61K31/404 ,  A61K31/4706 ,  A61K31/661 ,  C07C235/24 ,  C07D209/08 ,  C07D271/12 ,  G01N33/5438 ,  G01N33/74

摘要： This invention provides a novel class of androgen receptor targeting agents (ARTA). The agents define a new subclass of compounds which are tissue-selective androgen receptor modulators (SARM), which are useful for oral testosterone replacement therapy, male contraception, maintaining sexual desire in women, treating prostate cancer and imaging prostate cancer. These agents have an unexpected in-vivo activity for an androgenic and anabolic activity of a nonsteroidal ligand for the androgen receptor. These agents may be active alone or in combination with progestins or estrogens. The invention further provides a novel class of non-steroidal agonist compounds. The invention further provides compositions containing the selective androgen modulator compounds or the non-steroidal agonist compounds and methods of binding an androgen receptor, modulating spermatogenesis, treating and imaging prostate cancer, and providing hormonal therapy for androgen-dependent conditions.

公开(公告)号：US06998500B2

公开(公告)日：2006-02-14

申请号：US10270732

申请日：2002-10-16

申请人： James T. Dalton ,  Duane D. Miller ,  Yali He ,  Donghua Yin

发明人： James T. Dalton ,  Duane D. Miller ,  Yali He ,  Donghua Yin

IPC分类号： C07C255/50 ,  A61K31/275

CPC分类号： C07C235/24 ,  C07B2200/07 ,  C07C255/60

摘要： This invention provides a class of androgen receptor targeting agents (ARTA). The agents define a new subclass of compounds, which are selective androgen receptor modulators (SARM). Several of the SARM compounds have been found to have an unexpected androgenic and anabolic activity of a nonsteroidal ligand for the androgen receptor. Other SARM compounds have been found to have an unexpected antiandrogenic activity of a nonsteroidal ligand for the androgen receptor. The SARM compounds, either alone or as a composition, are useful for a) male contraception; b) treatment of a variety of hormone-related conditions, for example conditions associated with Androgen Decline in Aging Male (ADAM), such as fatigue, depression, decreased libido, sexual dysfunction, erectile dysfunction, hypogonadism, osteoporosis, hair loss, anemia, obesity, sarcopenia, osteopenia, osteoporosis, benign prostate hyperplasia, alterations in mood and cognition and prostate cancer; c) treatment of conditions associated with Androgen Decline in Female (ADIF), such as sexual dysfunction, decreased sexual libido, hypogonadism, sarcopenia, osteopenia, osteoporosis, alterations in cognition and mood, depression, anemia, hair loss, obesity, endometriosis, breast cancer, uterine cancer and ovarian cancer; d) treatment and/or prevention of acute and/or chronic muscular wasting conditions; e) preventing and/or treating dry eye conditions; f) oral androgen replacement therapy; and/or g) decreasing the incidence of, halting or causing a regression of prostate cancer.

公开(公告)号：US07919647B2

公开(公告)日：2011-04-05

申请号：US11355187

申请日：2006-02-16

申请人： James T. Dalton ,  Duane D. Miller ,  Yali He ,  Donghua Yin

发明人： James T. Dalton ,  Duane D. Miller ,  Yali He ,  Donghua Yin

IPC分类号： C07C255/49 ,  A61K31/275 ,  A61K31/13 ,  A01N37/34 ,  A01N33/02

CPC分类号： A61K31/277

摘要： This invention provides a class of androgen receptor targeting agents. The agents define a new subclass of compounds, which are selective androgen receptor modulators (SARM).

摘要翻译： 本发明提供一类雄激素受体靶向剂。 这些药剂定义了一种新的化合物亚类，它们是选择性雄激素受体调节剂（SARM）。

公开(公告)号：US07759520B2

公开(公告)日：2010-07-20

申请号：US11062752

申请日：2005-02-23

申请人： James T. Dalton ,  Duane D. Miller ,  Donghua Yin ,  Yali He

发明人： James T. Dalton ,  Duane D. Miller ,  Donghua Yin ,  Yali He

IPC分类号： C07C233/05

CPC分类号： C07C231/12 ,  C07C235/24

摘要： The present invention relates to a synthetic process for the preparation of a novel class of androgen receptor targeting agents (ARTA) which demonstrate androgenic and anabolic activity of a nonsteroidal ligand for the androgen receptor. The agents define a new subclass of compounds which are selective androgen receptor modulators (SARM) which are useful for a) male contraception; b) treatment of a variety of hormone-related conditions, for example conditions associated with Androgen Decline in Aging Male (ADAM), such as fatigue, depression, decreased libido, sexual dysfunction, erectile dysfunction, hypogonadism, osteoporosis, hair loss, anemia, obesity, sarcopenia, osteopenia, osteoporosis, benign prostate hyperplasia, alterations in mood and cognition and prostate cancer; c) treatment of conditions associated with Androgen Decline in Female (ADIF), such as sexual dysfunction, decreased sexual libido, hypogonadism, sarcopenia, osteopenia, osteoporosis, alterations in cognition and mood, depression, anemia, hair loss, obesity, endometriosis, breast cancer, uterine cancer and ovarian cancer; d) treatment and/or prevention of chronic muscular wasting; e) decreasing the incidence of, halting or causing a regression of prostate cancer; f) oral androgen relacement and/or other clinical therpauetic and/or diagnostic areas. The process of the present invention is suitable for large-scale preparation, since all of the steps give rise to highly pure compounds, thus avoiding complicated purification procedures which ultimately lower the yield. Thus the present invention provides methods for the synthesis of non-steroidal agonist compounds, that can be used for industrial large-scale synthesis, and that provide highly pure products in high yield.

摘要翻译： 本发明涉及一种用于制备新型雄激素受体靶向剂（ARTA）的合成方法，其表现出雄激素受体的非甾族化合物的雄激素和合成代谢活性。 这些药剂定义了一种新的选择性雄激素受体调节剂（SARM）的化合物亚类，它们可用于a）男性避孕; b）治疗各种激素相关病症，例如与老年雄性雄激素降低有关的病症（ADAM），如疲劳，抑郁，性欲降低，性功能障碍，勃起功能障碍，性腺机能减退，骨质疏松症，脱发，贫血， 肥胖，肌营养不良，骨质减少，骨质疏松症，良性前列腺增生，情绪和认知和前列腺癌的改变; c）治疗与男性雄激素降低相关的病症（ADIF），如性功能障碍，性欲降低，性腺机能减退，肌营养不良，骨质减少，骨质疏松症，认知和情绪改变，抑郁症，贫血，脱发，肥胖，子宫内膜异位症，乳腺癌 癌症，子宫癌和卵巢癌; d）治疗和/或预防慢性肌肉消瘦; e）降低前列腺癌的发生率，停止或导致消退; f）口服雄激素替代和/或其他临床治疗和/或诊断领域。 本发明的方法适用于大规模制备，因为所有步骤都产生高纯度的化合物，因此避免了复杂的纯化方法，从而降低产率。 因此，本发明提供了可用于工业大规模合成的非甾体激动剂化合物的合成方法，并以高产率提供高纯度产品。

公开(公告)号：US20090264534A1

公开(公告)日：2009-10-22

申请号：US12420731

申请日：2009-04-08

申请人： James T. Dalton ,  Duane D. Miller ,  Yali He ,  Donghua Yin

发明人： James T. Dalton ,  Duane D. Miller ,  Yali He ,  Donghua Yin

IPC分类号： A61K31/165 ,  C07C237/14 ,  A61P5/00

CPC分类号： C07C235/24 ,  A61K31/165

摘要： The present invention relates to androgen receptor targeting agents (ARTA) which demonstrate androgenic and anabolic activity, which are nonsteroidal ligands for the androgen receptor. The selective androgen receptor modulators (SARM) are useful for a) male contraception; b) treatment of a variety of hormone-related conditions, for example conditions associated with Androgen Decline in Aging Male (ADAM), such as fatigue, depression, decreased libido, sexual dysfunction, erectile dysfunction, hypogonadism, osteoporosis, hair loss, anemia, obesity, sarcopenia, osteopenia, osteoporosis, benign prostate hyperplasia, alterations in mood and cognition and prostate cancer; c) treatment of conditions associated with Androgen Decline in Female (ADIF), such as sexual dysfunction, decreased sexual libido, hypogonadism, sarcopenia, osteopenia, osteoporosis, alterations in cognition and mood, depression, anemia, hair loss, obesity, endometriosis, breast cancer, uterine cancer and ovarian cancer; d) treatment and/or prevention of chronic muscular wasting; e) decreasing the incidence of, halting or causing a regression of prostate cancer; f) oral androgen replacement and/or other clinical therapeutic and/or diagnostic areas.

摘要翻译： 本发明涉及雄激素和合成代谢活性的雄激素受体靶向剂（ARTA），其是雄激素受体的非甾体配体。 选择性雄激素受体调节剂（SARM）可用于a）男性避孕; b）治疗各种激素相关病症，例如与老年雄性雄激素降低有关的病症（ADAM），如疲劳，抑郁，性欲降低，性功能障碍，勃起功能障碍，性腺机能减退，骨质疏松症，脱发，贫血， 肥胖，肌营养不良，骨质减少，骨质疏松症，良性前列腺增生，情绪和认知和前列腺癌的改变; c）治疗与男性雄激素降低相关的病症（ADIF），如性功能障碍，性欲降低，性腺机能减退，肌营养不良，骨质减少，骨质疏松症，认知和情绪改变，抑郁症，贫血，脱发，肥胖，子宫内膜异位症，乳腺癌 癌症，子宫癌和卵巢癌; d）治疗和/或预防慢性肌肉消瘦; e）降低前列腺癌的发生率，停止或导致消退; f）口服雄激素替代物和/或其他临床治疗和/或诊断领域。

公开(公告)号：US07518013B2

公开(公告)日：2009-04-14

申请号：US11353225

申请日：2006-02-14

申请人： James T. Dalton ,  Duane D. Miller ,  Yali He ,  Donghua Yin

发明人： James T. Dalton ,  Duane D. Miller ,  Yali He ,  Donghua Yin

IPC分类号： C07C255/49 ,  A61K31/275

CPC分类号： C07C255/60

摘要： The present invention relates to androgen receptor targeting agents (ARTA) which demonstrate androgenic and anabolic activity, which are nonsteroidal ligands for the androgen receptor. The selective androgen receptor modulators (SARM) are useful for a) male contraception; b) treatment of a variety of hormone-related conditions, for example conditions associated with Androgen Decline in Aging Male (ADAM), such as fatigue, depression, decreased libido, sexual dysfunction, erectile dysfunction, hypogonadism, osteoporosis, hair loss, anemia, obesity, sarcopenia, osteopenia, osteoporosis, benign prostate hyperplasia, alterations in mood and cognition and prostate cancer; c) treatment of conditions associated with Androgen Decline in Female (ADIF), such as sexual dysfunction, decreased sexual libido, hypogonadism, sarcopenia, osteopenia, osteoporosis, alterations in cognition and mood, depression, anemia, hair loss, obesity, endometriosis, breast cancer, uterine cancer and ovarian cancer; d) treatment and/or prevention of chronic muscular wasting; e) decreasing the incidence of, halting or causing a regression of prostate cancer; f) oral androgen relacement and/or other clinical therpauetic and/or diagnostic areas.

摘要翻译： 本发明涉及雄激素和合成代谢活性的雄激素受体靶向剂（ARTA），其是雄激素受体的非甾体配体。 选择性雄激素受体调节剂（SARM）可用于a）男性避孕; b）治疗各种激素相关病症，例如与老年雄性雄激素降低有关的病症（ADAM），如疲劳，抑郁，性欲降低，性功能障碍，勃起功能障碍，性腺机能减退，骨质疏松症，脱发，贫血， 肥胖，肌营养不良，骨质减少，骨质疏松症，良性前列腺增生，情绪和认知和前列腺癌的改变; c）治疗与男性雄激素降低相关的病症（ADIF），如性功能障碍，性欲降低，性腺机能减退，肌营养不良，骨质减少，骨质疏松症，认知和情绪改变，抑郁症，贫血，脱发，肥胖，子宫内膜异位症，乳腺癌 癌症，子宫癌和卵巢癌; d）治疗和/或预防慢性肌肉消瘦; e）降低前列腺癌的发生率，停止或导致消退; f）口服雄激素替代和/或其他临床治疗和/或诊断领域。

公开(公告)号：US07205437B2

公开(公告)日：2007-04-17

申请号：US11125159

申请日：2005-05-10

申请人： James T. Dalton ,  Duane D. Miller ,  Yali He ,  Donghua Yin

发明人： James T. Dalton ,  Duane D. Miller ,  Yali He ,  Donghua Yin

IPC分类号： C07C233/05 ,  C07C255/00

CPC分类号： C07C235/24

摘要： The present invention relates to androgen receptor targeting agents (ARTA) which demonstrate androgenic and anabolic activity, which are nonsteroidal ligands for the androgen receptor. The selective androgen receptor modulators (SARM) are useful for a) male contraception; b) treatment of a variety of hormone-related conditions, for example conditions associated with Androgen Decline in Aging Male (ADAM), such as fatigue, depression, decreased libido, sexual dysfunction, erectile dysfunction, hypogonadism, osteoporosis, hair loss, anemia, obesity, sarcopenia, osteopenia, osteoporosis, benign prostate hyperplasia, alterations in mood and cognition and prostate cancer; c) treatment of conditions associated with Androgen Decline in Female (ADIF), such as sexual dysfunction, decreased sexual libido, hypogonadism, sarcopenia, osteopenia, osteoporosis, alterations in cognition and mood, depression, anemia, hair loss, obesity, endometriosis, breast cancer, uterine cancer and ovarian cancer; d) treatment and/or prevention of chronic muscular wasting; e) decreasing the incidence of, halting or causing a regression of prostate cancer; f) oral androgen relacement and/or other clinical therpauetic and/or diagnostic areas.

摘要翻译： 本发明涉及雄激素和合成代谢活性的雄激素受体靶向剂（ARTA），其是雄激素受体的非甾体配体。 选择性雄激素受体调节剂（SARM）可用于a）男性避孕; b）治疗各种激素相关病症，例如与老年雄性雄激素降低有关的病症（ADAM），如疲劳，抑郁，性欲降低，性功能障碍，勃起功能障碍，性腺机能减退，骨质疏松症，脱发，贫血， 肥胖，肌营养不良，骨质减少，骨质疏松症，良性前列腺增生，情绪和认知和前列腺癌的改变; c）治疗与男性雄激素降低相关的病症（ADIF），如性功能障碍，性欲降低，性腺机能减退，肌营养不良，骨质减少，骨质疏松症，认知和情绪改变，抑郁症，贫血，脱发，肥胖，子宫内膜异位症，乳腺癌 癌症，子宫癌和卵巢癌; d）治疗和/或预防慢性肌肉消瘦; e）降低前列腺癌的发生率，停止或导致消退; f）口服雄激素替代和/或其他临床治疗和/或诊断领域。

公开(公告)号：US08445534B2

公开(公告)日：2013-05-21

申请号：US12632619

申请日：2009-12-07

申请人： James T. Dalton ,  Duane D. Miller ,  Donghua Yin ,  Yali He

发明人： James T. Dalton ,  Duane D. Miller ,  Donghua Yin ,  Yali He

IPC分类号： A61K31/275

CPC分类号： C07C235/24 ,  A61K31/16 ,  A61K31/167 ,  A61K31/277 ,  C07C255/60

摘要： This invention provides methods for treatment and inhibition of a male subject having an Androgen Decline in Aging Male (ADAM)-associated condition, for example sexual dysfunction, decreased sexual libido, erectile dysfunction, hypogonadism, sarcopenia, osteopenia, osteoporosis, an alteration in cognition and mood, depression, anemia, hair loss, obesity, muscle loss, dry eye, memory loss, benign prostate hyperplasia and/or prostate cancer, by administering to the subject a selective androgen receptor modulator (SARM) compound and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, pro-drug, polymorph, crystal, or any combination thereof.

摘要翻译： 本发明提供了用于治疗和抑制雄性雄性雄激素降低（ADAM）相关病症的男性受试者的方法，例如性功能障碍，性欲性降低，勃起功能障碍，性腺机能减退，肌肉减少症，骨质减少症，骨质疏松症，认知改变 通过向受试者施用选择性雄激素受体调节剂（SARM）化合物和/或其类似物，通过向受试者施用选择性雄激素受体调节剂（SARM）化合物和/或其类似物， 衍生物，异构体，代谢物，药学上可接受的盐，药物产品，水合物，N-氧化物，前药，多晶型物，晶体或其任何组合。

公开(公告)号：US06995284B2

公开(公告)日：2006-02-07

申请号：US10277108

申请日：2002-10-22

申请人： James T. Dalton ,  Duane D. Miller ,  Yali He ,  Donghua Yin

发明人： James T. Dalton ,  Duane D. Miller ,  Yali He ,  Donghua Yin

IPC分类号： C07C233/05 ,  C07C231/12

CPC分类号： C07D215/227 ,  A61K31/167 ,  A61K31/404 ,  A61K31/4706 ,  A61K31/661 ,  C07C235/24 ,  C07D209/08 ,  C07D271/12 ,  G01N30/7233 ,  G01N33/5438 ,  G01N33/74 ,  G01N2030/8813

摘要： The present invention relates to a synthetic process for the preparation of a novel class of androgen receptor targeting agents (ARTA) which demonstrate androgenic and anabolic activity of a nonsteroidal ligand for the androgen receptor. The agents define a new subclass of compounds which are selective androgen receptor modulators (SARM) which are useful for a) male contraception; b) treatment of a variety of hormone-related conditions, for example conditions associated with Androgen Decline in Aging Male (ADAM), such as fatigue, depression, decreased libido, sexual dysfunction, erectile dysfunction, hypogonadism, osteoporosis, hair loss, anemia, obesity, sarcopenia, osteopenia, osteoporosis, benign prostate hyperplasia, alterations in mood and cognition and prostate cancer; c) treatment of conditions associated with Androgen Decline in Female (ADIF), such as sexual dysfunction, decreased sexual libido, hypogonadism, sarcopenia, osteopenia, osteoporosis, alterations in cognition and mood, depression, anemia, hair loss, obesity, endometriosis, breast cancer, uterine cancer and ovarian cancer; d) treatment and/or prevention of chronic muscular wasting; e) decreasing the incidence of, halting or causing a regression of prostate cancer; f) oral androgen relacement and/or other clinical therpauetic and/or diagnostic areas. The process of the present invention is suitable for large-scale preparation, since all of the steps give rise to highly pure compounds, thus avoiding complicated purification procedures which ultimately lower the yield. Thus the present invention provides methods for the synthesis of non-steroidal agonist compounds, that can be used for industrial large-scale synthesis, and that provide highly pure products in high yield.

摘要翻译： 本发明涉及一种用于制备新型雄激素受体靶向剂（ARTA）的合成方法，其表现出雄激素受体的非甾族化合物的雄激素和合成代谢活性。 这些药剂定义了一种新的选择性雄激素受体调节剂（SARM）的化合物亚类，它们可用于a）男性避孕; b）治疗各种激素相关病症，例如与老年雄性雄激素降低有关的病症（ADAM），如疲劳，抑郁，性欲降低，性功能障碍，勃起功能障碍，性腺机能减退，骨质疏松症，脱发，贫血， 肥胖，肌营养不良，骨质减少，骨质疏松症，良性前列腺增生，情绪和认知和前列腺癌的改变; c）治疗与男性雄激素降低相关的病症（ADIF），如性功能障碍，性欲降低，性腺机能减退，肌营养不良，骨质减少，骨质疏松症，认知和情绪改变，抑郁症，贫血，脱发，肥胖，子宫内膜异位症，乳腺癌 癌症，子宫癌和卵巢癌; d）治疗和/或预防慢性肌肉消瘦; e）降低前列腺癌的发生率，停止或导致消退; f）口服雄激素替代和/或其他临床治疗和/或诊断领域。 本发明的方法适用于大规模制备，因为所有步骤都产生高纯度的化合物，因此避免了复杂的纯化方法，从而降低产率。 因此，本发明提供了可用于工业大规模合成的非甾体激动剂化合物的合成方法，并以高产率提供高纯度产品。