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1. 发明申请

WO2008062359A2 METHOD OF USE OF EPIREGULIN PROTEIN AND NUCLEIC ACID ENCODING THE SAME IN INFLAMMATORY CONDITIONS 审中-公开
标题翻译：使用EPIREGULIN蛋白质和将其编码在炎症条件下的核酸的方法
公开(公告)号：WO2008062359A2
公开(公告)日：2008-05-29
申请号：PCT/IB2007/054689
申请日：2007-11-19
申请人： NICHOLAS PIRAMAL INDIA LIMITED , PADIGARU, Muralidhara , SHARMA, Somesh , THAKKAR, Arvind , RATHINA SABAPATHY, Anandharajan , PARIKH, Sapna, Hasit , GHOSH, Usha
发明人： PADIGARU, Muralidhara , SHARMA, Somesh , THAKKAR, Arvind , RATHINA SABAPATHY, Anandharajan , PARIKH, Sapna, Hasit , GHOSH, Usha
IPC分类号： C12Q1/68
CPC分类号： C12Q1/6883 , C12Q2600/158
摘要： The present invention relates to nucleotide and protein sequences of epiregulin and epiregulin like proteins and nucleotides and methods employing them as a drug response marker in inflammatory conditions. The invention also provides epiregulin protein for treatment of inflammatory conditions like psoriasis and rheumatoid arthritis alone or in combination with one or more anti-inflammatory compounds.
摘要翻译：本发明涉及上皮蛋白和外调蛋白样蛋白和核苷酸的核苷酸和蛋白质序列以及在炎症状态下使用它们作为药物反应标记的方法。本发明还提供了用于治疗单独的银屑病和类风湿性关节炎或与一种或多种抗炎化合物组合的炎性病症的外用蛋白。

2. 发明申请

WO2009141786A3 ANTI-INFLAMMATORY COMPOUNDS 审中-公开
标题翻译：抗炎化合物
公开(公告)号：WO2009141786A3
公开(公告)日：2010-01-14
申请号：PCT/IB2009052069
申请日：2009-05-19
申请人： PIRAMAL LIFE SCIENCES LTD , MISHRA PRABHU DUTT , MAHAJAN GIRISH , KULKARNI-ALMEIDA ASHA , PARIKH SAPNA HASIT , RANADIVE PRAFULL VASANT , JAIN ROOPESH , VISHWAKARMA RAM
发明人： MISHRA PRABHU DUTT , MAHAJAN GIRISH , KULKARNI-ALMEIDA ASHA , PARIKH SAPNA HASIT , RANADIVE PRAFULL VASANT , JAIN ROOPESH , VISHWAKARMA RAM
IPC分类号： A01N37/12
CPC分类号： A61K31/365
摘要： The present invention provides use of borrelidin, an isomer, or pharmaceutically acceptable salt thereof, for the treatment of an inflammatory disorder. The invention further relates to a pharmaceutical composition comprising borrelidin, an isomer, or pharmaceutically acceptable salt thereof, for use in the treatment of an inflammatory disorder. The invention also relates to a method for the treatment of an inflammatory disorder by administering a therapeutically effective amount of borrelidin, an isomer, or pharmaceutically acceptable salt thereof to a subject in need thereof. The said inflammatory disorder may be mediated by elevated levels of one or more inflammatory cytokines selected from Tumor Necrosis Factor-alpha (TNF-a) and interleukins (IL-1 ß, IL-6, IL-8) or increased expression of one or more cell adhesion molecules such as intercellular adhesion molecule 1 (ICAM-1 ), vascular-cell adhesion molecule 1 (VCAM-1 ) and E-Selectin or a combination thereof.
摘要翻译：本发明提供了用于治疗炎性疾病的硼替雷宁，异构体或其药学上可接受的盐的用途。本发明进一步涉及用于治疗炎症性疾病的药物组合物，其包含硼替瑞啶，异构体或其药学上可接受的盐。本发明还涉及通过向有需要的受试者施用治疗有效量的硼替瑞林，异构体或其药学上可接受的盐来治疗炎症性疾病的方法。所述炎症性疾病可以由升高的一种或多种选自肿瘤坏死因子-α（TNF-α）和白细胞介素（IL-1β，IL-6，IL-8）的炎症细胞因子的水平介导，或增加一种或更多的细胞粘附分子如细胞间粘附分子1（ICAM-1），血管细胞粘附分子1（VCAM-1）和E-选择蛋白或其组合。

3. 发明申请

WO2009019656A1 PYRIDYL DERIVATIVES, THEIR PREPARATION AND USE 审中-公开
标题翻译：吡啶衍生物，其制备和使用
公开(公告)号：WO2009019656A1
公开(公告)日：2009-02-12
申请号：PCT/IB2008/053151
申请日：2008-08-06
申请人： PIRAMAL LIFE SCIENCES LIMITED , KUMAR, Sanjay , JOSHI, Kalpana, Sanjay , DEORE, Vijaykumar , BHONDE, Mandar, Ramesh , YEWALKAR, Nilambari, Nilkanth , PADGAONKAR, Amol, Arun , RATHOS, Maggie, Joyce , KULKARNI-ALMEIDA, Asha, Adrian , PARIKH, Sapna , DAGIA, Nilesh, Madhukar
发明人： KUMAR, Sanjay , JOSHI, Kalpana, Sanjay , DEORE, Vijaykumar , BHONDE, Mandar, Ramesh , YEWALKAR, Nilambari, Nilkanth , PADGAONKAR, Amol, Arun , RATHOS, Maggie, Joyce , KULKARNI-ALMEIDA, Asha, Adrian , PARIKH, Sapna , DAGIA, Nilesh, Madhukar
IPC分类号： C07D213/73 , C07D213/75 , C07D213/78 , C07D401/04 , C07D407/04 , C07D413/04 , A61K31/44 , A61K31/4439 , A61K31/00
CPC分类号： C07D213/73 , C07D213/75 , C07D213/78 , C07D401/04 , C07D407/04 , C07D413/04
摘要： The present invention relates to pyridyl derivatives capable of inhibiting phosphatidylinositol-3-kinase (PI3k), mammalian target of rapamycin (mTOR) and/or hypoxia inducible factor 1α (HIF-1α) mediated signaling. Also disclosed are processes for preparation of the pyridyl derivatives, and their use in the manufacture of pharmaceutical compositions for the treatment of clinical conditions caused by deregulation of signaling pathways selected from one or more of PI3K, mTOR and HIF-1α pathways. The pyridyl derivatives are also useful for the treatment of conditions or disorders mediated by TNF-α.
摘要翻译：本发明涉及能够抑制磷脂酰肌醇-3-激酶（PI3k），雷帕霉素哺乳动物靶（mTOR）和/或缺氧诱导因子1a（HIF-1a）介导信号传导的吡啶衍生物。还公开了制备吡啶基衍生物的方法及其在制备用于治疗由选自PI3K，mTOR和HIF-1a途径中的一种或多种的信号传导途径失调引起的临床病症的药物组合物中的用途。吡啶基衍生物也可用于治疗由TNF-α介导的病症或病症。

4. 发明申请

WO2009016565A1 TRICYCLIC COMPOUNDS FOR THE TREATMENT OF INFLAMMATORY DISORDERS 审中-公开
标题翻译：用于治疗炎症性疾病的三联化合物
公开(公告)号：WO2009016565A1
公开(公告)日：2009-02-05
申请号：PCT/IB2008/052990
申请日：2008-07-25
申请人： PIRAMAL LIFE SCIENCES LIMITED , BHEDI, Dilip, Narayanrao , VISHWAKARMA, Ram, Asrey , DEKA, Vaishali , MORE, Dattatray, Maruti , RAMALINGAM, Manivannan , SUTHAR, Ashish , DALAL, Roda , PARIKH, Sapna , TANNU, Aditi, Amol
发明人： BHEDI, Dilip, Narayanrao , VISHWAKARMA, Ram, Asrey , DEKA, Vaishali , MORE, Dattatray, Maruti , RAMALINGAM, Manivannan , SUTHAR, Ashish , DALAL, Roda , PARIKH, Sapna , TANNU, Aditi, Amol
IPC分类号： C07D307/92 , C07D405/06 , C07D407/12 , A61K31/343 , A61P19/02 , A61P29/00
CPC分类号： C07D307/92 , C07D405/06 , C07D405/12 , C07D417/06 , C07H17/04
摘要： The present invention provides compounds represented by general formula (1) wherein, R 1 R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 and X are as defined in the specification, in all its stereoisomeric and tautomeric forms and mixtures thereof in all ratios, and its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable polymorphs and prodrugs. These compounds are useful for treatment of inflammatory disorders including those caused by elevated levels of proinflammatory cytokines such as Tumor Necrosis Factor (TNF-α and/or interleukins (IL-1β, IL-6, IL-8). The invention also relates to processes for the manufacture of compounds of formula (1) and pharmaceutical compositions containing them.
摘要翻译：本发明提供由通式（1）表示的化合物，其中R1 R2，R3，R4，R5，R6，R7，R8，R9，R10，R11，R12，R13和X如说明书中所定义，立体异构体和互变异构形式及其混合物，以及其药学上可接受的盐，药学上可接受的溶剂合物，药学上可接受的多晶型物和前药。这些化合物可用于治疗炎性疾病，包括由升高的促炎细胞因子如肿瘤坏死因子（TNF-α和/或白细胞介素（IL-1β，IL-6，IL-8））水平引起的炎症性疾病，本发明还涉及用于制备式（1）化合物和含有它们的药物组合物的方法。

5. 发明申请

WO2007036900A2 HERBAL COMPOSITION FOR INFLAMMATORY DISORDERS 审中-公开
标题翻译：用于炎症性疾病的草本组合物
公开(公告)号：WO2007036900A2
公开(公告)日：2007-04-05
申请号：PCT/IB2006/053540
申请日：2006-09-28
申请人： NICHOLAS PIRAMAL INDIA LTD , CHAUHAN, Vijay , SUTHAR, Ashish , SAPRE, Dhananjay , BAL-TEMBE, Swati , GANGOPADHYAY, Ashok Kumar , KULKARNI-ALMEIDA, Asha , PARIKH, Sapna Hasit
发明人： CHAUHAN, Vijay , SUTHAR, Ashish , SAPRE, Dhananjay , BAL-TEMBE, Swati , GANGOPADHYAY, Ashok Kumar , KULKARNI-ALMEIDA, Asha , PARIKH, Sapna Hasit
CPC分类号： A61K36/28
摘要： This invention relates to a novel herbal composition comprising an extract of flowering and fruiting heads of the plant, Sphaeranthus indicus. The said extract of Sphaeranthus indicus contains a compound, 3a-hydroxy-5a,9-dimethyl-3- methylene-3a,4,5,5a,6,7,8,9b-octahydro-3H-naphtho[1 ,2-b]furan-2-one (7- Hydroxy-4,1 1 (13)-eudesmadien-12,6-olide) (compound 1 ), as a bioactive marker. The invention also relates to a composition comprising 3a-hydroxy-5a,9-dimethyl- 3-methylene-3a,4,5,5a,6,7,8,9b-octahydro-3H-naphtho[1 ,2-b]furan-2-one (compound 1 ) as an active ingredient. The invention also relates to methods of manufacture of the said compositions. The invention also relates to methods of administration of the said compositions to a subject in need of treatment for an inflammatory disorder. The invention also relates to tumor necrosis factor-α (TNF- α) and interleukin (IL-1 , IL-6, IL-8) inhibitory activity of the said compositions. The invention relates to inhibition of the expression of intercellular adhesion molecule 1 (ICAM-1 ), vascular-cell adhesion molecule 1 (VCAM-1 ), and E-Selectin by the said compositions. The said compositions may optionally contain at least one anti- inflammatory agent or can be used in combination with at least one anti- inflammatory agent.
摘要翻译：本发明涉及一种新颖的草药组合物，其包含植物的开花和果实头的提取物，Sphaeranthus indicus。所述所述Sphaeranthus indicus提取物含有一种化合物，3a-羟基-5a，9-二甲基-3-亚甲基-3a，4,5,5a，6,7,8,9b-八氢-3H-萘并[1,2- b]呋喃-2-酮（7-羟基-4,1 1（13） - 去马来麦地 - 12,6-二醇）（化合物1）作为生物活性标记物。本发明还涉及包含3a-羟基-5a，9-二甲基-3-亚甲基-3a，4,5,5a，6,7,8,9b-八氢-3H-萘并[1,2-b] 呋喃-2-酮（化合物1）作为活性成分。本发明还涉及制备所述组合物的方法。本发明还涉及将所述组合物给予需要治疗炎症性疾病的受试者的方法。本发明还涉及所述组合物的肿瘤坏死因子-α（TNF-α）和白介素（IL-1，IL-6，IL-8）抑制活性。本发明涉及通过所述组合物抑制细胞间粘附分子1（ICAM-1），血管细胞粘附分子1（VCAM-1）和E-选择蛋白的表达。所述组合物可任选地含有至少一种抗炎剂或可与至少一种抗炎剂组合使用。

6. 发明申请

WO2006051477A3 FUSED TRICYCLIC COMPOUNDS AS INHIBITORS OF TUMOR NECROSIS FACTOR-ALPHA 审中-公开
标题翻译：作为肿瘤坏死因子ALPHA的抑制剂的融合三聚体化合物
公开(公告)号：WO2006051477A3
公开(公告)日：2006-08-03
申请号：PCT/IB2005053654
申请日：2005-11-08
申请人： NICHOLAS PIRAMAL INDIA LTD , LAL BANSI , SHARMA SOMESH , GHOSH USHA , BAL-TEMBE SWATI , MORE TULSIDAS , GAGARE PRAVIN , JADHAV SUNIL , PATIL SHASHIKANT , KULKARNI-ALMEIDA ASHA , PARIKH SAPNA , PANICKER RADHA , DAMRE ANAGHA , GUPTE RAVINDRA
发明人： LAL BANSI , SHARMA SOMESH , GHOSH USHA , BAL-TEMBE SWATI , MORE TULSIDAS , GAGARE PRAVIN , JADHAV SUNIL , PATIL SHASHIKANT , KULKARNI-ALMEIDA ASHA , PARIKH SAPNA , PANICKER RADHA , DAMRE ANAGHA , GUPTE RAVINDRA
IPC分类号： C07D327/02 , A61K31/39 , C07D411/04
CPC分类号： C07D327/02
摘要： Compounds of formula (1): are disclosed, wherein V is CH 2 ; W is S(O) m ; m is the integer 0, 1 or 2; U is O, C(O), CR 13 R 14 or NR 15 ; where R 13 is H, alkyl; R 14 is H, OH, OR 13 or OCOR 13 ; R 15 is H, alkyl, cycloalkyl, alkenyl, C(O)R 13 , C(O)OR 13 or alkylaminocarbonyl; R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are as defined herein. These compounds are inhibitor of tumor necrosis factor-alpha (TNF- ) and are useful as medicaments for the treatment and prevention of disorders caused by increased TNF- activity, in particular inflammations.
摘要翻译：公开了式（1）的化合物：其中V是CH 2 2; W是S（O）m。 m是整数0,1或2; U是O，C（O），CR 13 R 14或NR 15; 其中R 13是H，烷基; R 14是H，OH，OR 13或OCOR 13; R 15是H，烷基，环烷基，烯基，C（O）R 13，C（O）OR 13或烷基氨基羰基; R 1，R 2，R 3，R 4，R 5， R 6，R 7和R 8是如本文所定义的。这些化合物是肿瘤坏死因子-α（TNF-）的抑制剂，可用作治疗和预防由TNF-活性增加引起的疾病，特别是炎症的药物。

7. 发明申请

WO2006051476A1 TRICYCLIC GUANIDINE DERIVATIVES AS SODIUM-PROTON EXCHANGE INHIBITORS 审中-公开
标题翻译：三聚氰胺衍生物作为钠基交换剂抑制剂
公开(公告)号：WO2006051476A1
公开(公告)日：2006-05-18
申请号：PCT/IB2005/053653
申请日：2005-11-08
申请人： NICHOLAS PIRAMAL INDIA LIMITED , LAL, Bansi , BAL-TEMBE, Swati , GHOSH, Usha , JAIN, Arun Kumar , MORE, Tulsidas , GHATE, Anil , TRIVEDI, Jacqueline , PARIKH, Sapna
发明人： LAL, Bansi , BAL-TEMBE, Swati , GHOSH, Usha , JAIN, Arun Kumar , MORE, Tulsidas , GHATE, Anil , TRIVEDI, Jacqueline , PARIKH, Sapna
IPC分类号： C07D327/08 , A61K31/382 , A61P25/28
CPC分类号： C07D327/08
摘要： Guanidine derivatives having a condensed tricyclic ring of formula 1: are disclosed, wherein U is C(O), CR a R b , O, NR a or S(O) m V is CR a R b or NR a ; W is S(O) m ; wherein R a is H, alkyl, cycloalkyl, alkenyl or aralkyl; R b is H, alkyl, OH, OR a or OCOR a , and m is the integer 0, 1 or 2; R1, R2, R3, R4, R5, R6, R7 and R8 are as defined herein with the proviso that at least one of R1, R2, R3, R4, R5, R6, R7 or R8 is guanidino or guanidino carbonyl. These derivatives are sodium-proton exchange inhibitors and are useful as medicaments for the treatment of, for example, organ disorders associated with ischemia and reperfusion, cardiac arrhythmia, cardiac hypertrophy, hypertension, cell proliferative disorders and diabetes.
摘要翻译：公开了具有式1的稠合三环的胍衍生物：其中U是C（O），CR 1，O，NR a， SUP>或S（O） V是C B W是S（O）m。其中R a是H，烷基，环烷基，烯基或芳烷基; R b是H，烷基，OH，OR a或OCOR a a，m是整数0,1或2; R1，R2，R3，R4，R5，R6，R7和R8如本文所定义，条件是R 1，R 2，R 3，R 4，R 5，R 6，R 7或R 8中的至少一个是胍基或胍基羰基。这些衍生物是钠 - 质子交换抑制剂，并且可用作治疗例如与缺血和再灌注相关的器官疾病，心律失常，心脏肥大，高血压，细胞增殖性疾病和糖尿病的药物。

8. 发明申请

WO2009141786A2 ANTI-INFLAMMATORY COMPOUNDS 审中-公开
标题翻译：抗炎化合物
公开(公告)号：WO2009141786A2
公开(公告)日：2009-11-26
申请号：PCT/IB2009/052069
申请日：2009-05-19
申请人： PIRAMAL LIFE SCIENCES LIMITED , MISHRA, Prabhu, Dutt , MAHAJAN, Girish , KULKARNI-ALMEIDA, Asha , PARIKH, Sapna, Hasit , RANADIVE, Prafull, Vasant , JAIN, Roopesh , VISHWAKARMA, Ram
发明人： MISHRA, Prabhu, Dutt , MAHAJAN, Girish , KULKARNI-ALMEIDA, Asha , PARIKH, Sapna, Hasit , RANADIVE, Prafull, Vasant , JAIN, Roopesh , VISHWAKARMA, Ram
IPC分类号： A61K31/365
CPC分类号： A61K31/365
摘要： The present invention provides use of borrelidin, an isomer, or pharmaceutically acceptable salt thereof, for the treatment of an inflammatory disorder. The invention further relates to a pharmaceutical composition comprising borrelidin, an isomer, or pharmaceutically acceptable salt thereof, for use in the treatment of an inflammatory disorder. The invention also relates to a method for the treatment of an inflammatory disorder by administering a therapeutically effective amount of borrelidin, an isomer, or pharmaceutically acceptable salt thereof to a subject in need thereof. The said inflammatory disorder may be mediated by elevated levels of one or more inflammatory cytokines selected from Tumor Necrosis Factor-alpha (TNF-α) and interleukins (IL-1 β, IL-6, IL-8) or increased expression of one or more cell adhesion molecules such as intercellular adhesion molecule 1 (ICAM-1 ), vascular-cell adhesion molecule 1 (VCAM-1 ) and E-Selectin or a combination thereof.
摘要翻译：本发明提供了用于治疗炎性疾病的硼替雷宁，异构体或其药学上可接受的盐的用途。本发明进一步涉及用于治疗炎症性疾病的药物组合物，其包含硼替瑞啶，异构体或其药学上可接受的盐。本发明还涉及通过向有需要的受试者施用治疗有效量的硼替瑞林，异构体或其药学上可接受的盐来治疗炎症性疾病的方法。所述炎症性疾病可以由升高的一种或多种选自肿瘤坏死因子-α（TNF-α）和白细胞介素（IL-1β，IL-6，IL-8）的炎症细胞因子的水平介导，或增加一种或更多的细胞粘附分子如细胞间粘附分子1（ICAM-1），血管细胞粘附分子1（VCAM-1）和E-选择蛋白或其组合。

9. 发明申请

WO2008062359A3 METHOD OF USE OF EPIREGULIN PROTEIN AND NUCLEIC ACID ENCODING THE SAME IN INFLAMMATORY CONDITIONS 审中-公开
标题翻译：使用EPIREGULIN蛋白质和将其编码在炎症条件下的核酸的方法
公开(公告)号：WO2008062359A3
公开(公告)日：2009-04-30
申请号：PCT/IB2007054689
申请日：2007-11-19
申请人： PIRAMAL LIFE SCIENCES LTD , PADIGARU MURALIDHARA , SHARMA SOMESH , THAKKAR ARVIND , RATHINA SABAPATHY ANANDHARAJAN , PARIKH SAPNA HASIT , GHOSH USHA
发明人： PADIGARU MURALIDHARA , SHARMA SOMESH , THAKKAR ARVIND , RATHINA SABAPATHY ANANDHARAJAN , PARIKH SAPNA HASIT , GHOSH USHA
IPC分类号： C12P19/34 , C12Q1/68
CPC分类号： C12Q1/6883 , C12Q2600/158
摘要： The present invention relates to nucleotide and protein sequences of epiregulin and epiregulin like proteins and nucleotides and methods employing them as a drug response marker in inflammatory conditions. The invention also provides epiregulin protein for treatment of inflammatory conditions like psoriasis and rheumatoid arthritis alone or in combination with one or more anti-inflammatory compounds.
摘要翻译：本发明涉及上皮蛋白和外调蛋白样蛋白和核苷酸的核苷酸和蛋白质序列以及在炎症状态下使用它们作为药物反应标记的方法。本发明还提供了用于治疗单独的银屑病和类风湿性关节炎或与一种或多种抗炎化合物组合的炎性病症的外用蛋白。

10. 发明申请

WO2008142623A2 TUMOR NECROSIS FACTOR - ALPHA INHIBITORS 审中-公开
标题翻译：肿瘤坏死因子 - 阿尔法抑制剂
公开(公告)号：WO2008142623A2
公开(公告)日：2008-11-27
申请号：PCT/IB2008/051932
申请日：2008-05-16
申请人： PIRAMAL LIFE SCIENCES LIMITED , BALACHANDRAN, Sarala , VISHWAKARMA, Ram , KAKI, Venkatrao , YADAV, Vitthal , CHAUTHE, Siddheshwar , SHARMA, Somesh , PARIKH, Sapna , KHARAS, Firuza
发明人： BALACHANDRAN, Sarala , VISHWAKARMA, Ram , KAKI, Venkatrao , YADAV, Vitthal , CHAUTHE, Siddheshwar , SHARMA, Somesh , PARIKH, Sapna , KHARAS, Firuza
IPC分类号： A61K31/4741
CPC分类号： C07D213/66 , C07D311/22 , C07D491/056
摘要： The present invention relates to small molecules that inhibit Tumor Necrosis Factor- alpha (TNF-α), for example, by interaction with TNF-α protein or its receptor, thereby lowering the overall TNF-α activity, and that are represented by formula (1) or a stereoisomer thereof, tautomer thereof, or mixture thereof in any ratio; a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable polymorph thereof; wherein: A 1 , A 2 , X 1 , X 2 , n, R 1 , R 2 , R 3 and R 4 are as defined in the specification. The present invention also relates to processes for the preparation of these small molecules and to pharmaceutical compositions containing them. The present invention further relates to a method of treatment of disorders characterized by increased TNF- α activity, such as inflammation.
摘要翻译：本发明涉及例如通过与TNF-α蛋白或其受体的相互作用来抑制肿瘤坏死因子-α（TNF-α）的小分子，从而降低总体TNF-α活性，并且由式 1）或其立体异构体，其互变异构体或其混合物; 其药学上可接受的盐，药学上可接受的溶剂合物或其药学上可接受的多晶型物; 其中：A1，A2，X1，X2，n，R1，R2，R3和R4如说明书中所定义。本发明还涉及制备这些小分子的方法和含有它们的药物组合物。本发明还涉及以TNF-α活性增加为特征的疾病如炎症的治疗方法。

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