CN102432593A - 光学活性的3-(邻苯二甲酰亚氨基)哌啶及其制备方法 - Google Patents

光学活性的3-(邻苯二甲酰亚氨基)哌啶及其制备方法 Download PDF

Info

Publication number
CN102432593A
CN102432593A CN2011103551125A CN201110355112A CN102432593A CN 102432593 A CN102432593 A CN 102432593A CN 2011103551125 A CN2011103551125 A CN 2011103551125A CN 201110355112 A CN201110355112 A CN 201110355112A CN 102432593 A CN102432593 A CN 102432593A
Authority
CN
China
Prior art keywords
methyl
piperidines
phthaloyl imino
tartrate
liters
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN2011103551125A
Other languages
English (en)
Inventor
沃尔德马.弗兰格尔
索尔斯藤.帕彻
托马斯.尼古拉
阿迪尔.杜兰
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Boehringer Ingelheim International GmbH
Original Assignee
Boehringer Ingelheim International GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Boehringer Ingelheim International GmbH filed Critical Boehringer Ingelheim International GmbH
Publication of CN102432593A publication Critical patent/CN102432593A/zh
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
    • C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Abstract

本发明涉及具有光学活性的3-(邻苯二甲酰亚氨基)哌啶、其酒石酸盐及其制备方法。

Description

光学活性的3-(邻苯二甲酰亚氨基)哌啶及其制备方法
本申请是中国发明申请(发明名称：手性8-(3-氨基-哌啶-1-基)-黄嘌呤的制备方法；申请日：2005年11月02日；申请号：200580037243.1)的分案申请。
技术领域
本发明涉及制备手性8-(3-氨基哌啶-1-基)-黄嘌呤、其对映异构体及其生理上可耐受盐的改良方法。
背景技术
下列通常结构的8-(3-氨基哌啶-1-基)-黄嘌呤
Figure BDA0000107094690000011
其中R1为，例如任选取代的芳基甲基或任选取代的杂芳基甲基，R2为，例如烷基，及R3为，例如任选取代的苄基或直链或支链链烯基或炔基，已从国际专利申请案WO 02/068420、WO 04/018468、WO 04/018467、WO2004/041820及WO 2004/046148中得知，其中描述了具有有价值药理性质的化合物，其包括，特别是对酶二肽基肽酶IV(DPP-IV)活性的抑制作用。因此，此类化合物适合用于预防或治疗增加的DPP-IV活性相关的疾病或症状，或其可通过降低DPP-IV活性来预防或减轻疾病或症状，特别是I型或II型糖尿病或葡萄糖耐量的降低。
WO 04/018468公开了一种制备方法，其中8-(3-氨基哌啶-1-基)-黄嘌呤是通过将相应的通式(II)的叔丁氧羰基保护的衍生物去保护来制备。
在该方法中，杂质很难移除，特别是在工业级制备上会发生，这可归因于所用的保护基。因此，此方法不适合用于工业上制备8-(3-氨基哌啶-1-基)-黄嘌呤，特别是对纯度有严格要求的药品制备。再者，此方法在制备对映异构体性的纯的(enantiomerically pure)前体3-(叔丁氧羰基氨基)哌啶上具有复杂且昂贵的缺点。然而，由于副作用的风险及将剂量降至最低的考虑，对映异构体性纯的活性物质对医药的应用是优选的。这些情况对该现知的工业制备对映异构性纯8-(3-氨基哌啶-1-基)-黄嘌呤的适用性为不利的。
考虑了上述该已知制备方法的缺点，本发明的目的是提供一种使用易得的高化学纯及光学纯的起始物质，及无高技术成本及不便性下制备对映异构体性纯的8-(3-氨基哌啶-1-基)-黄嘌呤的方法。该新颖方法亦适用于工业级合成，因此可作为商业应用。
此目的可通过以本发明的方法制备手性8-(3-氨基哌啶-1-基)-黄嘌呤来达到。除了高产率的工业可行性外，绝佳的化学及光学纯度为本发明合成路径的其他的优点。
发明内容
根据本发明的方法，适当的黄嘌呤前体(III)是根据流程1的对映异构体性纯的或外消旋的(3-邻苯二甲酰亚氨基(phthalimido))-哌啶，在适当的溶剂中于20至160℃、优选为80至140℃的温度下反应。所用的溶剂，例如可为四氢呋喃(THF)、二烷、N，N-二甲基甲酰胺(DMF)、二甲基乙酰胺(DMA)、N-甲基-2-吡咯烷酮(NMP)或二甲基亚砜(DMSO)。优选的是使用NMP。随后以本身已知的方法将邻苯二甲酰基保护基除去。可能的除去方法是描述于，例如T.W.Greene的“Protective Groups in Organic Synthesis”，Wiley 1981，第265页(例如溶于乙醇中的肼)。
Figure BDA0000107094690000031
在上述的化学式中，
X为离去基团，其是选自卤素，例如氟、氯或溴原子，或磺酸酯，例如苯基磺酰基氧基、对甲苯磺酰基氧基、甲基磺酰基氧基或三氟甲基磺酰基氧基的基团。
R1为苯基羰基甲基、苄基、萘基甲基、吡啶基甲基、嘧啶基甲基、喹啉基甲基，异喹啉基甲基、喹唑啉基甲基、喹喔啉基甲基、萘啶基甲基或菲啶基甲基，其中芳族或杂芳族基团在各情况下被Ra单或二取代，而该取代基可为相同或不同，及
Ra为氢、氟、氯或溴原子或氰基、甲基、三氟甲基、乙基、苯基、甲氧基、二氟甲氧基、三氟甲氧基或乙氧基，
或二个Ra基，当它们与相邻的碳原子键结时，还可为-O-CH2-O-或-O-CH2-CH2-O-基，
R2为甲基、乙基、丙基、异丙基、环丙基或苯基及
R3为2-丁烯-1-基、3-甲基-2-丁烯-1-基、2-丁炔-1-基、2-氟苄基、2-氯苄基、2-溴苄基、2-碘苄基、2-甲基苄基、2-(三氟甲基)苄基或2-氰基苄基。
该方法优选的是用于这些化合物，其中
X为氯或溴原子，
R1为苯基羰基甲基、苄基、萘基甲基、吡啶基甲基、嘧啶基甲基、喹啉基甲基，异喹啉基甲基、喹唑啉基甲基、喹喔啉基-甲基或萘啶基甲基，其中芳族或杂芳族基团在各情况下被Ra单或二取代，而该取代基可为相同或不同，及
Ra为氢、氟或氯原子或氰基、甲基、乙基、甲氧基或乙氧基，
R2为甲基、乙基、丙基、异丙基、环丙基或苯基及
R3为2-丁烯-1-基、3-甲基-2-丁烯-1-基、2-丁炔-1-基、2-氟苄基、2-氯苄基、2-溴苄基、2-碘苄基、2-甲基苄基、2-(三氟甲基)苄基或2-氰基苄基基团。
该方法优选的是用于那些化合物，其中
X为氯或溴原子
R1为氰基苄基、(氰基吡啶基)甲基、喹啉基甲基，(甲基喹啉基)甲基、异喹唑啉基甲基、(甲基异喹啉基)甲基、喹唑啉基甲基、(甲基喹唑啉基)甲基、喹喔啉甲基、(甲基喹喔啉基)甲基、(二甲基喹喔啉基)甲基或萘啶基甲基，
R2为甲基、环丙基或苯基及
R3为2-丁烯-1-基、3-甲基-2-丁烯-1-基、2-丁炔-1-基、2-氯苄基、2-溴苄基或2-氰基苄基，
但特别是对化合物1-[(4-甲基喹唑啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-(R)-氨基哌啶-1-基)-黄嘌呤、1-[(3-甲基异喹啉-1-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-((R)-3-氨基哌啶-1-基)-黄嘌呤及1-[(3-氰基哌啶-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-(R)-氨基哌啶-1-基)-黄嘌呤，其中X为溴。
在各情况下优选的是使用(R)-3-(邻苯二甲酰亚氨基)哌啶作为试剂。式(III)化合物的制备已描述于上述引用的文献中，且可根据已知的方法来进行。
本发明还提供制备光学活性3-(邻苯二甲酰亚氨基)哌啶的方法。在此方法中，先将3-氨基吡啶根据已知的方法氢化。然后将由此得到的外消旋3-氨基哌啶通过邻苯二甲酸酐转变为相应的邻苯二甲酰亚胺。从外消旋、粗邻苯二甲酰亚胺(IV)溶液中通过D-酒石酸可选择性地沉淀出该(R)对映异构体。毋须先将原来存在母液中的过量的D-酒石酸移除，以简单方法通过添加L-酒石酸还可由盐沉淀的母液中得到(IV)的(S)对映异构体。
此极简单的式(IV)化合物的对映异构体的分离，令本领域技术人员非常惊讶。由氢化反应得来的外消旋碱不必预先纯化来达到此目的。该方法本身甚至在工业级制备仍无任何问题。
此外，3-氨基哌啶与邻苯二甲酸酐的出乎意料完全的反应本身令人惊讶，因为根据文献(例如美国专利4,005,208，特别是实施例27)，除了所需的产物外，混合物中预期会含有环上氮原子被酰化的衍生物。
Figure BDA0000107094690000051
下列实施例将更详细的说明本发明：
实施例1：
3-(邻苯二甲酰亚氨基)哌啶的R对映异构体的D-酒石酸盐
a.氢化作用：
Figure BDA0000107094690000052
将10.00kg(106.25mol)的3-氨基吡啶、500g工业级的活性炭及65升醋酸先装入氢化反应器中。将50g的Nishimura催化剂(市售的铑/铂混合催化剂)加入2.5升的醋酸中形成浆液并冲入(flush in)2.5升的醋酸。于50℃及100bar的氢气压下进行氢化，直到停止吸收氢气，及随后于50℃进行后氢化(post-hydrogenation)反应30分钟。将催化剂及活性炭滤出并以10升的醋酸洗涤。毋须纯化将产物溶液进行进一步的反应。
反应亦可在较不严格的压力下进行。
b.酰化作用
Figure BDA0000107094690000061
先将15.74kg(106.25mol)的邻苯二甲酸酐装入反应器中。并与由氢化反应得来的滤液混合。将其冲入7.5升的醋酸并随后将反应混合物加热回流，在此期间一小时内，蒸馏出约30％所用的醋酸。将反应溶液冷却至90℃。毋须纯化将产物溶液进行进一步的反应。
c.旋光拆开
将加热至50℃的11.16kg D(-)-酒石酸(74.38mol)的50升的无水乙醇溶液于90℃计量加入酰化反应溶液中。将其中冲入10升的无水乙醇并于90℃搅拌30分钟，在此期间产物结晶出。冷却至5℃后，将产物离心及以无水乙醇洗涤。毋须纯化将产物溶液进行进一步的反应。
d.重结晶
将湿的粗产物置于50升丙酮及90升水的混合物中加热回流直到溶液形成。随后，溶液冷却至5℃，在此期间有产物结晶出。将悬浮液于5℃搅拌30分钟，并将产物离心，最后用20升丙酮和10升水的混合物洗涤。将混合物在45℃在惰性条件下在干燥箱中干燥。
产率：11.7-12.5kg(理论值的29-31％)
实施例2
合成1-[(4-甲基喹唑啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-(R)-氨基哌啶-1-基)-黄嘌呤
a.2-氯甲基-4-甲基喹唑啉
Figure BDA0000107094690000071
先装入10.00kg(73.98mol)的2-氨基苯乙酮并加入24.5升的1，4-二
Figure BDA0000107094690000072
烷。将溶液冷却至10℃，与引入的16.72kg(458.68mol)的氯化氢混合。将反应混合物加温至22-25℃。于此温度下再引入氯化氢。约至总引入量的一半时，混合物冷却至-10℃并继续引入。随后，将形成的悬浮液放置于-10℃下过夜。于-10℃，一小时内加入6.70kg(88.78mol)氯乙腈的2.5升1，4-二
Figure BDA0000107094690000073
烷溶液。向原料容器(feed vessel)冲入2升的1，4-二烷。之后，将反应器的内容物加温至6℃并再搅拌约2小时。
先向另一反应器中装入122升水及62.04kg(775.31mol)氢氧化钠溶液(50％)的混合物并冷却至6℃。分次加入第一反应器的反应混合物。内部的温度不超过11℃。随后，首先将第一反应器用6升1，4-二
Figure BDA0000107094690000075
烷冲洗，然后用6升的水冲洗。将生成的悬浮液于5℃再搅拌30分钟。将产物离心，以41升的水洗涤并于35℃在惰性条件下在干燥箱中干燥。
产率：10.5-12.1kg(理论值的74-85％)
b.1-[(4-甲基喹唑啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-溴黄嘌呤
Figure BDA0000107094690000076
将10.00kg(33.66mol)的3-甲基-7-(2-丁炔-1-基)-8-溴黄嘌呤、7.13kg(37.02mol)2-氯甲基-4-甲基喹唑啉、3.92kg(37.02mol)无水碳酸钠及30升N-甲基-2-吡咯烷酮先装入反应器中。将反应器内容物加热至140℃并于140℃搅拌2小时。反应结束后，将反应混合物冷却至80℃并用60升的96％乙醇稀释，随后于70℃用55升的水稀释。于60℃，计量加入4.04kg(67.32mol)醋酸并冲入5升的水。将生成的悬浮液于60℃搅拌30分钟，然后冷却至23℃并再搅拌30分钟。随后将产物离心并先以20升96％乙醇及20升水的混合物洗涤，然后以40升96％乙醇及40升水的混合物洗涤。于45℃在惰性条件下(under inertization)在干燥箱中干燥。
产率：11.6-12.6kg(理论值的76-83％)
c.1-[(4-甲基喹唑啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-(R)-邻苯二甲酰亚氨基哌啶-1-基)-黄嘌呤
将10.00kg(22.06mol)的1-[(4-甲基喹唑啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-溴黄嘌呤、12.59kg(33.09mol)的3-(邻苯二甲酰亚氨基)哌啶D-酒石酸盐及17.5升的N-甲基-2-吡咯烷酮先装入反应器中。将反应器内容物加热至140℃。达到此温度后，于20分钟内计量加入11.41kg(88.24mol)的二异丙基乙胺。向原料容器中冲入2.5升的N-甲基-2-吡咯烷酮及随后将反应混合物于140℃搅拌2小时。反应结束后，将反应混合物冷却至60℃并以80升的甲醇稀释。将生成的悬浮液于50℃搅拌30分钟，然后冷却至23℃并再搅拌30分钟。随后将产物离心并各以20升的甲醇洗涤3次。于45℃在惰性条件下在干燥箱中干燥。
产率：12.0-12.5kg(理论值的90-94％)
d.1-[(4-甲基喹唑啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-(R)-氨基哌啶-1-基)-黄嘌呤
将1800kg(3mol)的1-[(4-甲基喹唑啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-(R)-邻苯二甲酰亚氨基哌啶-1-基)-黄嘌呤于18升的甲苯中加热至80-85℃。随后，于75-80℃将1.815升(30mol)的乙醇胺加到悬浮液中。将混合物于80-85℃搅拌2小时使反应完全，在此期间有固体进入溶液中。随后进行相分离。用温热的甲苯洗涤乙醇胺层二次(每次4升)。将合并的甲苯层每次各以8升的水于75-80℃洗涤二次。将22升的甲苯于减压下由甲苯层中蒸馏出。于40-50℃计量4升的叔丁基甲醚加至生成的悬浮液中并随后冷却至0-5℃。经过滤分离出产物，用叔丁基甲醚洗涤并抽真空干燥(suction dry)。之后将湿的粗物质与5倍量的无水乙醇加热回流并将该热溶液经活性炭过滤净化。将滤液冷却至20℃后，开始结晶，将其用叔丁基甲基醚稀释成二倍体积。将悬浮液冷却至2℃，另再搅拌2小时，抽滤并于45℃在真空干燥箱中干燥。
产率：1174g(理论值的83.2％)
步骤d的另一种方法：
将1400kg(2.32mol)的1-[(4-甲基喹唑啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-(R)-邻苯二甲酰亚氨基哌啶-1-基)-黄嘌呤先置入4.9升的四氢呋喃中，随后加热至55-65℃。之后，将350ml的水及1433g(2.32mol)的乙醇胺加到悬浮液中。将混合物于60-63℃再搅拌3小时使反应完全。之后，加入619ml的45％的氢氧化钠溶液及3.85升的水，并将混合物于55-65℃搅拌30分钟，然后向反应混合物中加入5.6升的甲苯，将混合物搅拌15分钟，之后进行相分离。以2.8升的水于55-65℃洗涤有机层，随后分离。减压下从有机层蒸馏出4.2升。之后，于65-75℃加入1.4升的甲基环己烷，在此期间产物结晶。将悬浮液在15-25℃搅拌8-16小时，然后冷却至0-5℃。将产物过滤分离，用4.2升的甲基环己烷洗涤，抽真空干燥并于35℃减压干燥。随后将干燥的粗物质(991g)与5倍量的甲醇加热回流，加入活性炭并过滤混合物。将甲醇蒸馏出使滤液体积降至1.5升。将滤液冷却至45-55℃后，以叔丁基甲醚稀释成四倍体积。悬浮液冷却至0-5℃，搅拌2小时，抽滤、用叔丁基甲醚洗涤并于35℃在真空干燥箱中干燥。
产率：899g(81.9％的理论值)
实施例3
1-[(3-氰基-吡啶-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-(R)-氨基-哌啶-1-基)-黄嘌呤
a.3-氰基-2-(氯甲基)-吡啶
将165.5g(0.98mol)的2-羟基甲基-3-吡啶甲酰胺(pyridinecarboxamide)与270ml的三氯氧化磷(phosphorus oxychloride)共同于90-100℃加热1小时。将反应混合物冷却至室温及随后于50-60℃逐滴加入约800ml的水。待三氯氧化磷水解后，冷却下以氢氧化钠溶液中和，在此期间沉淀出产物。将其过滤，以300ml的水洗涤及随后于35-40℃下干燥。
产率：122.6g(理论值的82％)
步骤a的另一种方法：3-氰基-2-(氯甲基)吡啶
将20.0g(131.45mmol)的2-羟基甲基-3-吡啶甲酰胺悬浮于110ml的乙腈中并加热至78℃。于15分钟内，计量加入60.65g(395.52mmol)的三氯氧化磷至混合物中并将混合物于81℃加热2小时。于22℃冷却后，将反应混合物置于200ml的水中于40℃下搅拌。加入100ml的甲苯后，以氢氧化钠溶液冷却下中和。进行相分离后，以100ml的水洗涤有机层。移出有机层并减压蒸发溶剂得到起初生成的油状残留物，将其静置使其结晶。
产率：16.66g(理论值的83％)
b.1-[(3-氰基-吡啶-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-溴黄嘌呤
Figure BDA0000107094690000101
将202g(0.68mol)的3-甲基-7-(2-丁炔-1-基)-8-溴黄嘌呤、188.5g(1.36mol)的无水碳酸钾及1.68升的N-甲基-2-吡咯烷酮(pyrrolidone)先装入反应器中并加热至70℃。随后，逐滴加入119g(0.75mol)的2-氯甲基-3-氰基吡啶的240ml的N-甲基-2-吡咯烷酮(pyrrolidine)(NMP)溶液。将反应器内容物于70℃下搅拌19小时。待反应结束后，将2.8升的水加到反应混合物中并冷却至25℃。将产物过滤出，以2升的水洗涤并于70℃在惰性条件下在干燥箱中干燥。
产率：257.5g(理论值的91％)
c.1-[(3-氰基-吡啶-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-(R)-邻苯二甲酰亚氨基哌啶-1-基)-黄嘌呤
Figure BDA0000107094690000111
将230g(0.557mol)的1-[(3-氰基-吡啶-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-溴黄嘌呤、318g(0.835mol)的3-(邻苯二甲酰亚氨基)哌啶D-酒石酸盐及1.15升的N-甲基-2-吡咯烷酮先装入反应器中。将反应器内容物加热至140℃。待达到此温度后，在20分钟内计量加入478ml(2.78mol)的二异丙基乙胺，随后将反应混合物于140℃搅拌2小时。之后，将反应混合物冷却至75℃并以720ml的甲醇稀释，之后，于68-60℃加入2.7升水并将混合物冷却至25℃。将产物过滤出并以2升的水洗涤。于70℃在惰性条件下在干燥箱中进行干燥。
之后将得到的粗产物置于1升的甲醇中煮沸搅拌，热过滤，以200ml的甲醇冲洗，随后于70℃惰性条件下干燥。
产率：275g(理论值的88％)
d.1-[(3-氰基-吡啶-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-(R)-氨基哌啶-1-基)-黄嘌呤
将412.5g(0.733mol)的1-[(3-氰基-吡啶-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-(R)-邻苯二甲酰亚氨基哌啶-1-基)-黄嘌呤于4125ml的甲苯中加热至80℃。随后于75-80℃将445ml的乙醇胺(7.33mol)加到悬浮液中。将混合物于80-85℃再搅拌2小时，使反应完全，在此期间有固体进入溶液中。之后，进行相分离。将乙醇胺相用温甲苯萃取二次(每次1升)。将合并的甲苯相于75-80℃以每次2升的水洗涤二次。用硫酸钠干燥甲苯相，过滤并随后于减压下蒸馏将体积降至约430ml。之后于50-55℃计量加入1升的叔丁基甲醚，然后将混合物冷却至0-5℃。将产物过滤分离，用叔丁基甲醚洗涤并于60℃在干燥箱中干燥。
产率：273g(理论值的86％)
熔点：188±3℃
类似实施例2及3，还制备出1-[(3-甲基异喹啉-1-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-((R)-3-氨基-哌啶-1-基)-黄嘌呤。

Claims (8)

1.(R)-3-(邻苯二甲酰亚氨基)哌啶。
2.(S)-3-(邻苯二甲酰亚氨基)哌啶。
3.(R)-3-(邻苯二甲酰亚氨基)哌啶D-酒石酸盐。
4.(S)-3-(邻苯二甲酰亚氨基)哌啶L-酒石酸盐。
5.一种制备(R)-3-(邻苯二甲酰亚氨基)哌啶的方法，其包括下列合成步骤：
a)将外消旋-3-氨基哌啶于适当的溶剂中与邻苯二甲酸酐反应，及
b)通过加入D-酒石酸并分离沉淀的酒石酸盐，从得到的外消旋-3-(邻苯二甲酰亚氨基)哌啶的溶液中分离出(R)-3-(邻苯二甲酰亚氨基)哌啶。
6.一种制备(S)-3-(邻苯二甲酰亚氨基)哌啶的方法，其包括下列合成步骤：
a)将外消旋-3-氨基哌啶于适当的溶剂中与邻苯二甲酸酐反应，及
b)通过加入L-酒石酸及分离沉淀的酒石酸盐，从得到的外消旋-3-(邻苯二甲酰亚氨基)哌啶的溶液中分离出(S)-3-(邻苯二甲酰亚氨基)哌啶。
7.一种制备(S)-3-(邻苯二甲酰亚氨基)哌啶的方法，其包括下列合成步骤：
a)将外消旋-3-氨基哌啶于适当的溶剂中与邻苯二甲酸酐反应，及
b)通过加入D-酒石酸并分离沉淀的酒石酸盐，从得到的外消旋-3-(邻苯二甲酰亚氨基)哌啶的溶液中分离出(R)-3-(邻苯二甲酰亚氨基)哌啶，及
c)将L-酒石酸加至由第一次盐沉淀所得到的母液中并分离出沉淀的(S)-3-(邻苯二甲酰亚氨基)哌啶酒石酸盐。
8.根据权利要求5至7中任一项所述的方法，其中用于步骤b)中的溶剂为乙醇。
CN2011103551125A 2004-11-05 2005-11-02 光学活性的3-(邻苯二甲酰亚氨基)哌啶及其制备方法 Pending CN102432593A (zh)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102004054054.3 2004-11-05
DE102004054054A DE102004054054A1 (de) 2004-11-05 2004-11-05 Verfahren zur Herstellung chiraler 8-(3-Amino-piperidin-1-yl)-xanthine

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
CN200580037243.1A Division CN101048409B (zh) 2004-11-05 2005-11-02 手性8-（3-氨基-哌啶-1-基）-黄嘌呤的制备方法

Publications (1)

Publication Number Publication Date
CN102432593A true CN102432593A (zh) 2012-05-02

Family

ID=36010287

Family Applications (6)

Application Number Title Priority Date Filing Date
CN2011103540629A Pending CN102391267A (zh) 2004-11-05 2005-11-02 8-(3-氨基-哌啶-1-基)-黄嘌呤、其制备方法及其用途
CN201710405988.3A Active CN107266449B (zh) 2004-11-05 2005-11-02 手性8-(3-氨基-哌啶-1-基)-黄嘌呤的制备方法
CN201310264236.1A Active CN103351388B (zh) 2004-11-05 2005-11-02 手性8-(3-氨基-哌啶-1-基)-黄嘌呤的制备方法
CN200580037243.1A Active CN101048409B (zh) 2004-11-05 2005-11-02 手性8-（3-氨基-哌啶-1-基）-黄嘌呤的制备方法
CN2011103551125A Pending CN102432593A (zh) 2004-11-05 2005-11-02 光学活性的3-(邻苯二甲酰亚氨基)哌啶及其制备方法
CN201110002001.6A Active CN102127080B (zh) 2004-11-05 2005-11-02 手性8-(3-氨基-哌啶-1-基)-黄嘌呤的制备方法

Family Applications Before (4)

Application Number Title Priority Date Filing Date
CN2011103540629A Pending CN102391267A (zh) 2004-11-05 2005-11-02 8-(3-氨基-哌啶-1-基)-黄嘌呤、其制备方法及其用途
CN201710405988.3A Active CN107266449B (zh) 2004-11-05 2005-11-02 手性8-(3-氨基-哌啶-1-基)-黄嘌呤的制备方法
CN201310264236.1A Active CN103351388B (zh) 2004-11-05 2005-11-02 手性8-(3-氨基-哌啶-1-基)-黄嘌呤的制备方法
CN200580037243.1A Active CN101048409B (zh) 2004-11-05 2005-11-02 手性8-（3-氨基-哌啶-1-基）-黄嘌呤的制备方法

Family Applications After (1)

Application Number Title Priority Date Filing Date
CN201110002001.6A Active CN102127080B (zh) 2004-11-05 2005-11-02 手性8-(3-氨基-哌啶-1-基)-黄嘌呤的制备方法

Country Status (35)

Country Link
US (6) US7820815B2 (zh)
EP (4) EP3539956A1 (zh)
JP (3) JP5063356B2 (zh)
KR (3) KR101583264B1 (zh)
CN (6) CN102391267A (zh)
AR (1) AR051947A1 (zh)
AU (1) AU2005300559B2 (zh)
BR (1) BRPI0517093B8 (zh)
CA (1) CA2586938C (zh)
CY (1) CY1115036T1 (zh)
DE (1) DE102004054054A1 (zh)
DK (2) DK2287164T5 (zh)
EA (3) EA016752B1 (zh)
ES (2) ES2731334T3 (zh)
HK (1) HK1109405A1 (zh)
HR (1) HRP20140373T2 (zh)
HU (1) HUE044308T2 (zh)
IL (2) IL182923A (zh)
ME (1) ME01667B (zh)
MX (2) MX2007005404A (zh)
MY (1) MY145604A (zh)
NO (1) NO20071522L (zh)
NZ (3) NZ555324A (zh)
PE (2) PE20100232A1 (zh)
PL (2) PL2287164T3 (zh)
PT (1) PT2287164E (zh)
RS (1) RS53166B (zh)
SG (3) SG189768A1 (zh)
SI (1) SI2287164T1 (zh)
TR (1) TR201908974T4 (zh)
TW (2) TWI374885B (zh)
UA (1) UA100221C2 (zh)
UY (1) UY29190A1 (zh)
WO (1) WO2006048427A1 (zh)
ZA (1) ZA200701996B (zh)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103319483A (zh) * 2012-10-19 2013-09-25 药源药物化学（上海）有限公司 一种利拉列汀重要中间体的制备方法
CN104496989A (zh) * 2014-12-26 2015-04-08 寿光富康制药有限公司 一种利格列汀工业化制备工艺
CN104892609A (zh) * 2015-04-23 2015-09-09 深圳市海滨制药有限公司 一种利拉利汀中间体及其制备方法和应用

Families Citing this family (91)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PT1368349E (pt) * 2001-02-24 2007-04-30 Boehringer Ingelheim Pharma Derivados de xantina, sua preparação e sua utilização como medicamento
US7407955B2 (en) 2002-08-21 2008-08-05 Boehringer Ingelheim Pharma Gmbh & Co., Kg 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions
US7495005B2 (en) * 2002-08-22 2009-02-24 Boehringer Ingelheim Pharma Gmbh & Co. Kg Xanthine derivatives, their preparation and their use in pharmaceutical compositions
US7569574B2 (en) 2002-08-22 2009-08-04 Boehringer Ingelheim Pharma Gmbh & Co. Kg Purine derivatives, the preparation thereof and their use as pharmaceutical compositions
US7482337B2 (en) 2002-11-08 2009-01-27 Boehringer Ingelheim Pharma Gmbh & Co. Kg Xanthine derivatives, the preparation thereof and their use as pharmaceutical compositions
DE10254304A1 (de) * 2002-11-21 2004-06-03 Boehringer Ingelheim Pharma Gmbh & Co. Kg Neue Xanthinderivate, deren Herstellung und deren Verwendung als Arzneimittel
US7566707B2 (en) 2003-06-18 2009-07-28 Boehringer Ingelheim International Gmbh Imidazopyridazinone and imidazopyridone derivatives, the preparation thereof and their use as pharmaceutical compositions
DE10355304A1 (de) 2003-11-27 2005-06-23 Boehringer Ingelheim Pharma Gmbh & Co. Kg Neue 8-(Piperazin-1-yl)-und 8-([1,4]Diazepan-1-yl)-xanthine, deren Herstellung und deren Verwendung als Arzneimittel
US7501426B2 (en) 2004-02-18 2009-03-10 Boehringer Ingelheim International Gmbh 8-[3-amino-piperidin-1-yl]-xanthines, their preparation and their use as pharmaceutical compositions
DE102004009039A1 (de) 2004-02-23 2005-09-08 Boehringer Ingelheim Pharma Gmbh & Co. Kg 8-[3-Amino-piperidin-1-yl]-xanthine, deren Herstellung und Verwendung als Arzneimittel
US7393847B2 (en) * 2004-03-13 2008-07-01 Boehringer Ingleheim International Gmbh Imidazopyridazinediones, their preparation and their use as pharmaceutical compositions
US7179809B2 (en) * 2004-04-10 2007-02-20 Boehringer Ingelheim International Gmbh 2-Amino-imidazo[4,5-d]pyridazin-4-ones, their preparation and their use as pharmaceutical compositions
US7439370B2 (en) * 2004-05-10 2008-10-21 Boehringer Ingelheim International Gmbh Imidazole derivatives, their preparation and their use as intermediates for the preparation of pharmaceutical compositions and pesticides
DE102004030502A1 (de) * 2004-06-24 2006-01-12 Boehringer Ingelheim Pharma Gmbh & Co. Kg Neue Imidazole und Triazole, deren Herstellung und Verwendung als Arzneimittel
DE102004043944A1 (de) * 2004-09-11 2006-03-30 Boehringer Ingelheim Pharma Gmbh & Co. Kg Neue 8-(3-Amino-piperidin-1-yl)-7-(but-2-inyl)-xanthine, deren Herstellung und deren Verwendung als Arzneimittel
DE102004044221A1 (de) * 2004-09-14 2006-03-16 Boehringer Ingelheim Pharma Gmbh & Co. Kg Neue 3-Methyl-7-butinyl-xanthine, deren Herstellung und deren Verwendung als Arzneimittel
DE102004054054A1 (de) 2004-11-05 2006-05-11 Boehringer Ingelheim Pharma Gmbh & Co. Kg Verfahren zur Herstellung chiraler 8-(3-Amino-piperidin-1-yl)-xanthine
DE102005035891A1 (de) * 2005-07-30 2007-02-08 Boehringer Ingelheim Pharma Gmbh & Co. Kg 8-(3-Amino-piperidin-1-yl)-xanthine, deren Herstellung und deren Verwendung als Arzneimittel
MX2008014024A (es) 2006-05-04 2008-11-14 Boehringer Ingelheim Int Formas poliformas.
PE20080251A1 (es) 2006-05-04 2008-04-25 Boehringer Ingelheim Int Usos de inhibidores de dpp iv
EP1852108A1 (en) * 2006-05-04 2007-11-07 Boehringer Ingelheim Pharma GmbH & Co.KG DPP IV inhibitor formulations
WO2008017670A1 (en) 2006-08-08 2008-02-14 Boehringer Ingelheim International Gmbh Pyrrolo [3, 2 -d] pyrimidines as dpp-iv inhibitors for the treatment of diabetes mellitus
CL2008002427A1 (es) 2007-08-16 2009-09-11 Boehringer Ingelheim Int Composicion farmaceutica que comprende 1-cloro-4-(b-d-glucopiranos-1-il)-2-[4-((s)-tetrahidrofurano-3-iloxi)bencil]-benceno combinado con 1-[(4-metilquinazolin-2-il)metil]-3-metil-7-(2-butin-1-il)-8-(3-(r)-aminopiperidin-1-il)xantina; y su uso para tratar diabetes mellitus tipo 2.
PE20091730A1 (es) 2008-04-03 2009-12-10 Boehringer Ingelheim Int Formulaciones que comprenden un inhibidor de dpp4
UY32030A (es) 2008-08-06 2010-03-26 Boehringer Ingelheim Int "tratamiento para diabetes en pacientes inapropiados para terapia con metformina"
BRPI0916997A2 (pt) 2008-08-06 2020-12-15 Boehringer Ingelheim International Gmbh Inibidor de dpp-4 e seu uso
WO2010018217A2 (en) 2008-08-15 2010-02-18 Boehringer Ingelheim International Gmbh Organic compounds for wound healing
US8513264B2 (en) 2008-09-10 2013-08-20 Boehringer Ingelheim International Gmbh Combination therapy for the treatment of diabetes and related conditions
US20200155558A1 (en) 2018-11-20 2020-05-21 Boehringer Ingelheim International Gmbh Treatment for diabetes in patients with insufficient glycemic control despite therapy with an oral antidiabetic drug
CN107011345A (zh) * 2008-12-23 2017-08-04 勃林格殷格翰国际有限公司 有机化合物的盐形式
AR074990A1 (es) 2009-01-07 2011-03-02 Boehringer Ingelheim Int Tratamiento de diabetes en pacientes con un control glucemico inadecuado a pesar de la terapia con metformina
TWI466672B (zh) 2009-01-29 2015-01-01 Boehringer Ingelheim Int 小兒科病人糖尿病之治療
EA029759B1 (ru) 2009-02-13 2018-05-31 Бёрингер Ингельхайм Интернациональ Гмбх Антидиабетические лекарственные средства, содержащие ингибитор dpp-4 (линаглиптин) необязательно в комбинации с другими антидиабетическими средствами
AU2010212867B2 (en) 2009-02-13 2013-05-16 Boehringer Ingelheim International Gmbh Pharmaceutical composition comprising a SGLT2 inhibitor, a DPP-IV inhibitor and optionally a further antidiabetic agent and uses thereof
UY32427A (es) 2009-02-13 2010-09-30 Boheringer Ingelheim Internat Gmbh Composicion farmaceutica, forma farmaceutica, procedimiento para su preparacion, metodos de tratamiento y usos de la misma
JP2011057619A (ja) * 2009-09-10 2011-03-24 Tokai Univ 光学活性アミン化合物の製造方法、並びに、ジアステレオマー塩及びその製造方法
KR101763659B1 (ko) 2009-10-02 2017-08-01 베링거 인겔하임 인터내셔날 게엠베하 Ｂｉ―1356 및 메트포르민을 포함하는 약제학적 조성물
EP3646859A1 (en) 2009-11-27 2020-05-06 Boehringer Ingelheim International GmbH Treatment of genotyped diabetic patients with dpp-iv inhibitors such as linagliptin
US20130109703A1 (en) 2010-03-18 2013-05-02 Boehringer Ingelheim International Gmbh Combination of a GPR119 Agonist and the DPP-IV Inhibitor Linagliptin for Use in the Treatment of Diabetes and Related Conditions
AU2011249722B2 (en) 2010-05-05 2015-09-17 Boehringer Ingelheim International Gmbh Combination therapy
EP2566464A1 (en) 2010-05-05 2013-03-13 Boehringer Ingelheim International GmbH Pharmaceutical formulations comprising pioglitazone and linagliptin
BR112012032579B1 (pt) 2010-06-24 2021-05-11 Boehringer Ingelheim International Gmbh uso de linagliptina e composição farmacêutica compreendendo linagliptina e insulina basal de longa duração
US9034883B2 (en) 2010-11-15 2015-05-19 Boehringer Ingelheim International Gmbh Vasoprotective and cardioprotective antidiabetic therapy
IT1403282B1 (it) * 2010-12-23 2013-10-17 Dipharma Francis Srl Procedimento per la preparazione di linagliptin
AR085689A1 (es) 2011-03-07 2013-10-23 Boehringer Ingelheim Int Composiciones farmaceuticas de metformina, linagliptina y un inhibidor de sglt-2
US8785455B2 (en) * 2011-05-10 2014-07-22 Sandoz Ag Polymorph of linagliptin benzoate
HUE043540T2 (hu) 2011-07-15 2019-08-28 Boehringer Ingelheim Int Szubsztituált dimer kinazolin-származék, elõállítása, valamint alkalmazása 1-es és 2-es típusú cukorbetegség kezelésére szolgáló gyógyászati készítményekben
CN102372691A (zh) * 2011-11-15 2012-03-14 海门慧聚药业有限公司 (r)-3-苯二甲酰亚胺哌啶酒石酸盐的制备工艺
US20130123282A1 (en) 2011-11-16 2013-05-16 Leonid Metsger Solid state forms of linagliptin
CN102516225A (zh) * 2011-11-18 2012-06-27 海门慧聚药业有限公司 新型医药中间体(r)-3-苯二甲酰亚胺哌啶盐酸盐的合成
US9056112B2 (en) 2011-12-28 2015-06-16 Dr. Reddy's Laboratories Limited Process for preparation of pure linagliptin
US20130172244A1 (en) 2011-12-29 2013-07-04 Thomas Klein Subcutaneous therapeutic use of dpp-4 inhibitor
US9555001B2 (en) 2012-03-07 2017-01-31 Boehringer Ingelheim International Gmbh Pharmaceutical composition and uses thereof
EP2825539A1 (en) * 2012-03-12 2015-01-21 Cadila Healthcare Limited Amorphous form of linagliptin and process for preparation thereof
WO2013171166A1 (en) 2012-05-14 2013-11-21 Boehringer Ingelheim International Gmbh A xanthine derivative as dpp-4 inhibitor for use in the treatment of sirs and/or sepsis
EP3685839A1 (en) 2012-05-14 2020-07-29 Boehringer Ingelheim International GmbH Linagliptin for use in the treatment of albuminuria and kidney related diseases
EP2854812A1 (en) 2012-05-24 2015-04-08 Boehringer Ingelheim International GmbH A xanthine derivative as dpp -4 inhibitor for use in the treatment of autoimmune diabetes, particularly lada
WO2013174767A1 (en) 2012-05-24 2013-11-28 Boehringer Ingelheim International Gmbh A xanthine derivative as dpp -4 inhibitor for use in modifying food intake and regulating food preference
EP2854824A1 (en) 2012-05-25 2015-04-08 Boehringer Ingelheim International GmbH Use of keratinocytes as a biologically active substance in the treatment of wounds, such as diabetic wounds, optionally in combination with a dpp-4 inhibitor
CN103450201B (zh) * 2012-05-30 2017-04-12 博瑞生物医药（苏州）股份有限公司 手性8‑（3‑氨基哌啶‑1‑基）‑黄嘌呤的制备方法
ES2663389T3 (es) 2012-08-17 2018-04-12 Glenmark Pharmaceuticals Limited Procedimiento de preparación de los inhibidores de dipeptidilpeptidasa
CN105073749A (zh) * 2012-12-17 2015-11-18 迈兰实验室有限公司 制备利拉利汀的改进方法
US20140303097A1 (en) 2013-04-05 2014-10-09 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
PT2981271T (pt) 2013-04-05 2019-02-19 Boehringer Ingelheim Int Utilizações terapêuticas de empagliflozina
US11813275B2 (en) 2013-04-05 2023-11-14 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
CN113181161A (zh) 2013-04-18 2021-07-30 勃林格殷格翰国际有限公司 药物组合物、治疗方法及其用途
US20160304520A1 (en) * 2013-07-11 2016-10-20 Wockhardt Limited An improved process for preparing Linagliptin and its key Intermediates
WO2015011609A1 (en) 2013-07-23 2015-01-29 Ranbaxy Laboratories Limited Process for the preparation of linagliptin and an intermediate thereof
ITMI20131836A1 (it) * 2013-11-06 2015-05-07 Chemelectiva S R L Processo ed intermedi per la preparazione di linagliptina
WO2015087240A1 (en) 2013-12-11 2015-06-18 Ranbaxy Laboratories Limited Process for the preparation of linagliptin and an intermediate thereof
WO2015107533A1 (en) * 2014-01-15 2015-07-23 Harman Finochem Limited A process for preparation of 1h-purine-2,6-dione, 8-[(3r)-3-amino-1-piperidinyl]-7 (2-butyn-1-yl)-3,7-dihydro-3-methyl-1-[(4-methyl-2quinazolinyl) methyl] and its pharmaceutically acceptable salts
ES2950384T3 (es) 2014-02-28 2023-10-09 Boehringer Ingelheim Int Uso médico de un inhibidor de DPP-4
CN106458897A (zh) 2014-03-14 2017-02-22 武田药品工业株式会社 制备杂环化合物的方法
CN104478880B (zh) * 2014-12-26 2016-03-02 浙江永太科技股份有限公司 作为dpp-iv抑制剂的双胍衍生物
CN105503873B (zh) * 2014-12-26 2017-03-22 浙江永太科技股份有限公司 一种作为二肽基肽酶‑4抑制剂的化合物的制备方法
CN105367572B (zh) * 2014-12-26 2017-03-29 浙江永太科技股份有限公司 一种制备作为二肽基肽酶‑4抑制剂的化合物的中间体
CN104478879B (zh) * 2014-12-26 2016-03-02 浙江永太科技股份有限公司 一种作为二肽基肽酶-4抑制剂的化合物
CN104557935B (zh) * 2015-01-27 2016-08-17 江苏嘉逸医药有限公司 制备(r)-8-(3-氨基哌啶-1-基)-黄嘌呤的提纯方法
CN104844602B (zh) * 2015-04-14 2018-07-20 威海迪素制药有限公司 一种利格列汀的制备方法
TWI682931B (zh) * 2015-05-29 2020-01-21 大陸商江蘇天士力帝益藥業有限公司 黃嘌呤衍生物、其藥物組成物、其製劑以及其用途
JP6901976B2 (ja) * 2015-06-25 2021-07-14 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング キサンチンをベースとする化合物の調製方法
EP3156048A1 (en) 2015-10-13 2017-04-19 Galenicum Health S.L. Stable pharmaceutical composition of linagliptin in the form of immediate release tablets
BR112018072401A2 (pt) 2016-06-10 2019-02-19 Boehringer Ingelheim International Gmbh combinações de linagliptina e metformina
US20180247672A1 (en) * 2017-02-24 2018-08-30 Entry Point Vr, Inc. Bundling Separate Video Files to Support a Controllable End-User Viewing Experience with Frame-Level Synchronization
IT201800005383A1 (it) * 2018-05-15 2019-11-15 Intermedi e processi per la preparazione di linagliptin e suoi sali
HU231374B1 (hu) 2018-08-06 2023-04-28 Richter Gedeon Nyrt. Eljárás BOC-Linagliptin előállítására
CN110590780B (zh) * 2019-10-29 2020-10-09 深圳市第二人民医院 治疗糖尿病的药物利拉利汀的制备方法
CA3170233A1 (en) 2020-02-13 2021-08-19 Zaklady Farmaceutyczne Polpharma S.A. Pharmaceutical composition comprising linagliptin and metformin
CN111187223B (zh) * 2020-03-09 2022-02-22 沧州那瑞化学科技有限公司 利拉利汀中间体2-氯甲基-4-甲基喹唑啉的合成方法
CN112592320A (zh) * 2020-12-22 2021-04-02 江苏慧聚药业有限公司 一种利拉利汀中间体的有关物质及其合成方法
WO2023156675A1 (en) 2022-02-21 2023-08-24 Krka, D.D., Novo Mesto Process for purification of linagliptin

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4005208A (en) * 1975-05-16 1977-01-25 Smithkline Corporation N-Heterocyclic-9-xanthenylamines
US20040097510A1 (en) * 2002-08-21 2004-05-20 Boehringer Ingelheim Pharma Gmbh & Co. Kg 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions

Family Cites Families (418)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2056046A (en) * 1933-05-19 1936-09-29 Rhone Poulenc Sa Manufacture of bases derived from benz-dioxane
US2375138A (en) * 1942-05-01 1945-05-01 American Cyanamid Co Alkamine esters of aryloxymethyl benzoic acid
US2629736A (en) * 1951-02-24 1953-02-24 Searle & Co Basically substituted n-alkyl derivatives of alpha, beta, beta-triarylpropionamides
US2730544A (en) * 1952-07-23 1956-01-10 Sahyun Lab Alkylaminoalkyl esters of hydroxycyclohexylbenzoic acid
US2750387A (en) * 1953-11-25 1956-06-12 Searle & Co Basically substituted derivatives of diarylaminobenzamides
DE1211359B (de) * 1955-11-29 1966-02-24 Oreal Oxydationsmittelfreies Kaltfaerbemittel fuer menschliches Haar
US2928833A (en) * 1959-03-03 1960-03-15 S E Massengill Company Theophylline derivatives
US3174901A (en) * 1963-01-31 1965-03-23 Jan Marcel Didier Aron Samuel Process for the oral treatment of diabetes
US3454635A (en) * 1965-07-27 1969-07-08 Hoechst Ag Benzenesulfonyl-ureas and process for their manufacture
US3673241A (en) * 1968-04-04 1972-06-27 Ciba Geigy Corp Substituted benzaldehyde guanylhydrazones
ES385302A1 (es) 1970-10-22 1973-04-16 Miquel S A Lab Procedimiento para la obtencion de derivados trisubstitui- dos de etilendiamina.
DE2205815A1 (de) 1972-02-08 1973-08-16 Hoechst Ag Piperazinderivate und verfahren zu ihrer herstellung
JPS5512435B2 (zh) * 1972-07-01 1980-04-02
US4061753A (en) 1976-02-06 1977-12-06 Interx Research Corporation Treating psoriasis with transient pro-drug forms of xanthine derivatives
NO154918C (no) 1977-08-27 1987-01-14 Bayer Ag Analogifremgangsmaate til fremstilling av terapeutisk aktive derivater av 3,4,5-trihydroksypiperidin.
DE2758025A1 (de) 1977-12-24 1979-07-12 Bayer Ag Neue derivate von 3,4,5-trihydroxypiperidin, verfahren zu ihrer herstellung und ihre verwendung
DE2929596A1 (de) 1979-07-21 1981-02-05 Hoechst Ag Verfahren zur herstellung von oxoalkyl-xanthinen
CY1306A (en) 1980-10-01 1985-12-06 Glaxo Group Ltd Aminoalkyl furan derivative
US4382091A (en) 1981-04-30 1983-05-03 Syntex (U.S.A.) Inc. Stabilization of 1-substituted imidazole derivatives in talc
EP0109281A1 (en) 1982-11-15 1984-05-23 The Upjohn Company Compositions comprising flurbiprofen or ibuprofen
JPS6092912A (ja) 1983-10-27 1985-05-24 Nippon Denso Co Ltd 車高制御装置
FR2558162B1 (fr) * 1984-01-17 1986-04-25 Adir Nouveaux derives de la xanthine, leurs procedes de preparation et les compositions pharmaceutiques les renfermant
FI79107C (fi) * 1984-06-25 1989-11-10 Orion Yhtymae Oy Foerfarande foer framstaellning av stabil -form av prazosinhydroklorid.
AR240698A1 (es) * 1985-01-19 1990-09-28 Takeda Chemical Industries Ltd Procedimiento para preparar compuestos de 5-(4-(2-(5-etil-2-piridil)-etoxi)benzil)-2,4-tiazolidindiona y sus sales
US5258380A (en) * 1985-06-24 1993-11-02 Janssen Pharmaceutica N.V. (4-piperidinylmethyl and -hetero)purines
GB8515934D0 (en) * 1985-06-24 1985-07-24 Janssen Pharmaceutica Nv (4-piperidinomethyl and-hetero)purines
ES2058061T3 (es) 1985-10-25 1994-11-01 Beecham Group Plc Derivado de piperidina, su preparacion y su uso como medicamento.
US5433959A (en) 1986-02-13 1995-07-18 Takeda Chemical Industries, Ltd. Stabilized pharmaceutical composition
DE3683760D1 (de) 1986-03-21 1992-03-12 Heumann Pharma Gmbh & Co Kristalline, wasserfreie sigma -form von 2-(4-(2-furoyl-(2-piperazin)-1-yl)-4-amino-6,7-dimethoxychinazolinhydrochlorid und verfahren zu ihrer herstellung.
ATE110083T1 (de) 1986-05-05 1994-09-15 Gen Hospital Corp Insulinotropes hormon.
US5120712A (en) 1986-05-05 1992-06-09 The General Hospital Corporation Insulinotropic hormone
AU619444B2 (en) 1986-06-02 1992-01-30 Nippon Chemiphar Co. Ltd. 2-(2-aminobenzylsulfinyl)- benzimidazole derivatives
US4968672A (en) 1987-01-02 1990-11-06 The United States Of America As Represented By The Department Of Health And Human Services Adenosine receptor prodrugs
US4743450A (en) 1987-02-24 1988-05-10 Warner-Lambert Company Stabilized compositions
JPS6440433A (en) 1987-08-05 1989-02-10 Green Cross Corp Aqueous liquid composition of thrombin
EP0342675B1 (en) 1988-05-19 1995-01-25 Chugai Seiyaku Kabushiki Kaisha Novel quinolonecarboxylic acid derivatives
US5329025A (en) * 1988-09-21 1994-07-12 G. D. Searle & Co. 3-azido compound
DE3926119A1 (de) 1989-08-08 1991-02-14 Bayer Ag 3-amino-5-aminocarbonyl-1,2,4-triazol-derivate
US5234897A (en) * 1989-03-15 1993-08-10 Bayer Aktiengesellschaft Herbicidal 3-amino-5-aminocarbonyl-1,2,4-triazoles
GB8906792D0 (en) 1989-03-23 1989-05-10 Beecham Wuelfing Gmbh & Co Kg Treatment and compounds
DE3916430A1 (de) 1989-05-20 1990-11-22 Bayer Ag Verfahren zur herstellung von 3-amino-5-aminocarbonyl-1,2,4-triazol-derivaten
US5332744A (en) * 1989-05-30 1994-07-26 Merck & Co., Inc. Substituted imidazo-fused 6-membered heterocycles as angiotensin II antagonists
US5223499A (en) * 1989-05-30 1993-06-29 Merck & Co., Inc. 6-amino substituted imidazo[4,5-bipyridines as angiotensin II antagonists
IL94390A (en) 1989-05-30 1996-03-31 Merck & Co Inc The 6-membered trans-nitrogen-containing heterocycles are compressed with imidazo and pharmaceutical preparations containing them
FI94339C (fi) 1989-07-21 1995-08-25 Warner Lambert Co Menetelmä farmaseuttisesti käyttökelpoisen /R-(R*,R*)/-2-(4-fluorifenyyli)- , -dihydroksi-5-(1-metyylietyyli)-3-fenyyli-4-/(fenyyliamino)karbonyyli/-1H-pyrroli-1-heptaanihapon ja sen farmaseuttisesti hyväksyttävien suolojen valmistamiseksi
HU208115B (en) 1989-10-03 1993-08-30 Biochemie Gmbh New process for producting pleuromutilin derivatives
FR2654935B1 (fr) * 1989-11-28 1994-07-01 Lvmh Rech Utilisation de xanthines, eventuellement incorporees dans des liposomes, pour favoriser la pigmentation de la peau ou des cheveux.
ES2084801T3 (es) 1990-02-19 1996-05-16 Ciba Geigy Ag Acil compuestos.
KR930000861B1 (ko) 1990-02-27 1993-02-08 한미약품공업 주식회사 오메프라졸 직장투여 조성물
ATE112491T1 (de) 1990-09-13 1994-10-15 Akzo Nobel Nv Stabilisierte feste chemische zusammensetzungen.
GB9020959D0 (en) 1990-09-26 1990-11-07 Beecham Group Plc Novel compounds
US5084460A (en) * 1990-12-24 1992-01-28 A. H. Robins Company, Incorporated Methods of therapeutic treatment with N-(3-ouinuclidinyl)-2-hydroxybenzamides and thiobenzamides
US5594003A (en) 1991-02-06 1997-01-14 Dr. Karl Thomae Gmbh Tetrahydroimidazo[1,2-a]pyridin-2-yl-(benzimidazol-1-yl)-methyl-biphenyls useful as angiotensin-II antagonists
US5602127A (en) 1991-02-06 1997-02-11 Karl Thomae Gmbh (Alkanesultam-1-yl)-benzimidazol-1-yl)-1yl)-methyl-biphenyls useful as angiotensin-II antagonists
US5614519A (en) 1991-02-06 1997-03-25 Karl Thomae Gmbh (1-(2,3 or 4-N-morpholinoalkyl)-imidazol-4-yl)-benizimidazol-1-yl-methyl]-biphenyls useful as angiotensin-II antagonists
GB9109862D0 (en) 1991-05-08 1991-07-03 Beecham Lab Sa Pharmaceutical formulations
DE4124150A1 (de) 1991-07-20 1993-01-21 Bayer Ag Substituierte triazole
US5300298A (en) * 1992-05-06 1994-04-05 The Pennsylvania Research Corporation Methods of treating obesity with purine related compounds
GB9215633D0 (en) 1992-07-23 1992-09-09 Smithkline Beecham Plc Novel treatment
ATE165360T1 (de) * 1992-07-31 1998-05-15 Shionogi & Co Triazolylthiomethylthiocephalosporin- hydrochlorid, sein kristallines hydrat und seine herstellung
TW252044B (zh) * 1992-08-10 1995-07-21 Boehringer Ingelheim Kg
DE4242459A1 (de) * 1992-12-16 1994-06-23 Merck Patent Gmbh Imidazopyridine
CA2118117A1 (en) 1993-02-18 1994-08-19 Shigeki Fujiwara Adenosine uptake inhibitor
JP3726291B2 (ja) 1993-07-05 2005-12-14 三菱ウェルファーマ株式会社 安定な結晶構造を有するベンゾオキサジン化合物およびその製造法
FR2707641B1 (fr) 1993-07-16 1995-08-25 Fournier Ind & Sante Composés de l'imidazol-5-carboxamide, leur procédé de préparation leurs intermédiaires et leur utilisation en thérapeutique.
DE4339868A1 (de) 1993-11-23 1995-05-24 Merck Patent Gmbh Imidazopyridazine
DE4404183A1 (de) 1994-02-10 1995-08-17 Merck Patent Gmbh 4-Amino-1-piperidylbenzoylguanidine
US5545745A (en) * 1994-05-23 1996-08-13 Sepracor, Inc. Enantioselective preparation of optically pure albuterol
CO4410191A1 (es) 1994-09-19 1997-01-09 Lilly Co Eli SINTESIS DE 3-[4-(2-AMINOETOXI)BENZOIL]-2-ARIL-6- HIDROXIBENZO [b] TIOFENOS
WO1996011917A1 (en) 1994-10-12 1996-04-25 Euro-Celtique, S.A. Novel benzoxazoles
GB9501178D0 (en) * 1995-01-20 1995-03-08 Wellcome Found Guanine derivative
CA2218548A1 (en) 1995-05-19 1996-11-21 Chiroscience Limited Xanthines and their therapeutic use
JPH08333339A (ja) * 1995-06-08 1996-12-17 Fujisawa Pharmaceut Co Ltd 光学活性なピペリジン酢酸誘導体の製造法
GB9523752D0 (en) 1995-11-21 1996-01-24 Pfizer Ltd Pharmaceutical formulations
DE19543478A1 (de) 1995-11-22 1997-05-28 Bayer Ag Kristallines Hydrochlorid von {(R)-(-)-2- N-[4-(1,1-Dioxido-3-oxo-2,3-dihydrobenzisothiazol-2-yl)-buytl]-aminomethyl}-chroman
FR2742751B1 (fr) 1995-12-22 1998-01-30 Rhone Poulenc Rorer Sa Nouveaux taxoides, leur preparation et les compositions pharmaceutiques qui les contiennent
WO1997023447A1 (en) 1995-12-26 1997-07-03 Alteon Inc. N-acylaminoalkylhydrazinecarboximidamides
DE122010000020I1 (de) * 1996-04-25 2010-07-08 Prosidion Ltd Verfahren zur Senkung des Blutglukosespiegels in Säugern
WO1997046526A1 (en) 1996-06-07 1997-12-11 Eisai Co., Ltd. Stable polymorphs of donepezil (1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-yl]methylpiperidine) hydrochloride and process for production
US5965555A (en) * 1996-06-07 1999-10-12 Hoechst Aktiengesellschaft Xanthine compounds having terminally animated alkynol side chains
US5958951A (en) * 1996-06-14 1999-09-28 Novo Nordiskials Modified form of the R(-)-N-(4,4-di(3-methylthien-2-yl)but-3-enyl)-nipecotic acid hydrochloride
US5753635A (en) * 1996-08-16 1998-05-19 Berlex Laboratories, Inc. Purine derivatives and their use as anti-coagulants
EA001881B1 (ru) 1996-09-23 2001-10-22 Эли Лилли Энд Компани Форма d дигидрата оланзапина
WO1998018770A1 (en) 1996-10-28 1998-05-07 Novo Nordisk A/S A process for the preparation of (-)-3,4-trans-diarylchromans
UA65549C2 (uk) 1996-11-05 2004-04-15 Елі Ліллі Енд Компані Спосіб регулювання ожиріння шляхом периферійного введення аналогів та похідних glp-1 (варіанти) та фармацевтична композиція
DE69732572T2 (de) 1996-11-12 2005-12-29 Novo Nordisk A/S Verwendung von glp-1 peptiden
GB9623859D0 (en) 1996-11-15 1997-01-08 Chiroscience Ltd Novel compounds
EE04266B1 (et) 1996-12-24 2004-04-15 Biogen, Incorporated Interferooni stabiilne vedelkompositsioon
DE19705233A1 (de) 1997-02-12 1998-08-13 Froelich Juergen C Verfahren zur Herstellung einer Formulierung enthaltend Arginin
US6011049A (en) 1997-02-19 2000-01-04 Warner-Lambert Company Combinations for diabetes
DK0991407T4 (da) 1997-03-13 2005-08-08 Hexal Ag Stabilisering af syresensitive benzimidazoler med amino/cyclodextrin-kombinationer
US5972332A (en) 1997-04-16 1999-10-26 The Regents Of The University Of Michigan Wound treatment with keratinocytes on a solid support enclosed in a porous material
ZA984697B (en) 1997-06-13 1999-12-01 Lilly Co Eli Stable insulin formulations.
TR200001603T2 (tr) * 1997-12-05 2000-10-23 Astrazeneca Uk Limited Yeni bileşikler
ID21411A (id) 1997-12-10 1999-06-10 Takeda Chemical Industries Ltd Agen untuk mengobati daya tahan glukosa yang berisiko tinggi rusak
JPH11193270A (ja) * 1997-12-26 1999-07-21 Koei Chem Co Ltd 光学活性１−メチル−３−ピペリジンメタノールの製造方法
CA2315736A1 (en) * 1998-01-05 1999-07-15 Eisai Co., Ltd. Purine compounds and adenosine a2 receptor antagonist as preventive or therapeutic for diabetes mellitus
AU766219B2 (en) 1998-02-02 2003-10-09 1149336 Ontario Inc. Method of regulating glucose metabolism, and reagents related thereto
JP2002509919A (ja) 1998-03-31 2002-04-02 日産化学工業株式会社 ピリダジノン化合物塩酸塩及びその製造法
CA2268621A1 (en) 1998-04-13 1999-10-13 Takeda Chemical Industries, Ltd. 2-pipirazinone-1-acetic acid derivative, production and use thereof
US6207207B1 (en) 1998-05-01 2001-03-27 Mars, Incorporated Coated confectionery having a crispy starch based center and method of preparation
DE19823831A1 (de) * 1998-05-28 1999-12-02 Probiodrug Ges Fuer Arzneim Neue pharmazeutische Verwendung von Isoleucyl Thiazolidid und seinen Salzen
DE19828114A1 (de) 1998-06-24 2000-01-27 Probiodrug Ges Fuer Arzneim Produgs instabiler Inhibitoren der Dipeptidyl Peptidase IV
WO2000003735A1 (fr) 1998-07-15 2000-01-27 Asahi Kasei Kogyo Kabushiki Kaisha Excipient
CO5150173A1 (es) 1998-12-10 2002-04-29 Novartis Ag Compuestos n-(glicilo sustituido)-2-cianopirrolidinas inhibidores de peptidasa de dipeptidilo-iv (dpp-iv) los cuales son efectivos en el tratamiento de condiciones mediadas por la inhibicion de dpp-iv
IT1312018B1 (it) * 1999-03-19 2002-04-04 Fassi Aldo Procedimento migliorato per la produzione di sali non igroscopicidella l(-)-carnitina.
AU4431000A (en) 1999-05-12 2000-12-05 Fujisawa Pharmaceutical Co., Ltd. Novel use
US20040152659A1 (en) 1999-05-12 2004-08-05 Fujisawa Pharmaceutical Co. Ltd. Method for the treatment of parkinson's disease comprising administering an A1A2a receptor dual antagonist
WO2000072799A2 (en) 1999-05-27 2000-12-07 The University Of Virginia Patent Foundation Method and compositions for treating the inflammatory response
US6545002B1 (en) 1999-06-01 2003-04-08 University Of Virginia Patent Foundation Substituted 8-phenylxanthines useful as antagonists of A2B adenosine receptors
YU90901A (sh) 1999-06-21 2004-07-15 Boehringer Ingelheim Pharma Gmbh. & Co.Kg. Biciklični heterocikli, lekovi koji sadrže ta jedinjenja, njihova primena i postupci za njihovo pripremanje
US6448323B1 (en) 1999-07-09 2002-09-10 Bpsi Holdings, Inc. Film coatings and film coating compositions based on polyvinyl alcohol
ES2166270B1 (es) 1999-07-27 2003-04-01 Almirall Prodesfarma Sa Derivados de 8-fenil-6,9-dihidro-(1,2,4,)triazolo(3,4-i)purin-5-ona.
US6515117B2 (en) 1999-10-12 2003-02-04 Bristol-Myers Squibb Company C-aryl glucoside SGLT2 inhibitors and method
US6586438B2 (en) 1999-11-03 2003-07-01 Bristol-Myers Squibb Co. Antidiabetic formulation and method
GB9928330D0 (en) 1999-11-30 2000-01-26 Ferring Bv Novel antidiabetic agents
SG149676A1 (en) 1999-12-23 2009-02-27 Novartis Ag Use of hypoglycemic agent for treating impaired glucose metabolism
WO2001051919A2 (en) 2000-01-07 2001-07-19 Transform Pharmaceuticals, Inc. High-throughput formation, identification, and analysis of diverse solid-forms
US6362172B2 (en) 2000-01-20 2002-03-26 Bristol-Myers Squibb Company Water soluble prodrugs of azole compounds
ES2436610T3 (es) 2000-01-21 2014-01-03 Novartis Ag Combinaciones que contienen inhibidores de la dipeptidilpeptidasa-IV y agentes antidiabéticos
JP4621326B2 (ja) 2000-02-01 2011-01-26 エーザイ・アール・アンド・ディー・マネジメント株式会社 テプレノンの安定化組成物
CA2369076A1 (en) * 2000-02-05 2001-08-09 Vertex Pharmaceuticals Incorporated Pyrazole compositions useful as inhibitors of erk
AU2001234114A1 (en) 2000-02-24 2001-09-03 Takeda Chemical Industries Ltd. Drugs containing combined active ingredients
EP1132389A1 (en) 2000-03-06 2001-09-12 Vernalis Research Limited New aza-indolyl derivatives for the treatment of obesity
US6395767B2 (en) 2000-03-10 2002-05-28 Bristol-Myers Squibb Company Cyclopropyl-fused pyrrolidine-based inhibitors of dipeptidyl peptidase IV and method
GB0006133D0 (en) 2000-03-14 2000-05-03 Smithkline Beecham Plc Novel pharmaceutical
JP2001278812A (ja) 2000-03-27 2001-10-10 Kyoto Pharmaceutical Industries Ltd 錠剤用崩壊剤及びこれを用いた錠剤
DK2055302T3 (da) 2000-03-31 2014-10-27 Royalty Pharma Collection Trust Fremgangsmåde til forbedring af signalering af øceller ved diabetes mellitus og til forebyggelse deraf
JP2001292388A (ja) 2000-04-05 2001-10-19 Sharp Corp 再生装置
GB0008694D0 (en) 2000-04-07 2000-05-31 Novartis Ag Organic compounds
WO2001096301A1 (fr) 2000-06-14 2001-12-20 Toray Industries, Inc. Procedes de production de derive de piperidine racemique et de production de derive de piperidine a activite optique
JP2002193933A (ja) * 2000-06-14 2002-07-10 Toray Ind Inc 光学活性ピペリジン誘導体またはその酸塩の製造方法
US7078397B2 (en) 2000-06-19 2006-07-18 Smithkline Beecham Corporation Combinations of dipeptidyl peptidase IV inhibitors and other antidiabetic agents for the treatment of diabetes mellitus
GB0014969D0 (en) 2000-06-19 2000-08-09 Smithkline Beecham Plc Novel method of treatment
MXPA02012272A (es) 2000-07-04 2003-04-25 Novo Nordisk As Compuestos heterociclicos que son inhibidores de la enzima dipeptidilpeptidasa-iv.
US6448281B1 (en) * 2000-07-06 2002-09-10 Boehringer Ingelheim (Canada) Ltd. Viral polymerase inhibitors
EP1950199B1 (en) * 2000-08-10 2009-12-02 Mitsubishi Tanabe Pharma Corporation Proline derivatives and use thereof as drugs
US6821978B2 (en) 2000-09-19 2004-11-23 Schering Corporation Xanthine phosphodiesterase V inhibitors
US20060034922A1 (en) 2000-11-03 2006-02-16 Andrx Labs, Llc Controlled release metformin compositions
JPWO2002051836A1 (ja) 2000-12-27 2004-04-22 協和醗酵工業株式会社 ジペプチジルペプチダーゼ−ｉｖ阻害剤
FR2819254B1 (fr) 2001-01-08 2003-04-18 Fournier Lab Sa Nouveaux composes de la n-(phenylsulfonyl) glycine, leur procede de preparation et leur utilisation pour obtenir des compostions pharmaceutiques
DE10109021A1 (de) 2001-02-24 2002-09-05 Boehringer Ingelheim Pharma Xanthinderivate, deren Herstellung und deren Verwendung als Arzneimittel
DE10117803A1 (de) 2001-04-10 2002-10-24 Boehringer Ingelheim Pharma Xanthinderivate, deren Herstellung und deren Verwendung als Arzneimittel
PL364221A1 (en) 2001-02-02 2004-12-13 Takeda Chemical Industries, Ltd. Fused heterocyclic compounds
WO2002066015A1 (en) 2001-02-16 2002-08-29 Bristol-Myers Squibb Pharma Company Use of polyalkylamine polymers in controlled release devices
PT1368349E (pt) * 2001-02-24 2007-04-30 Boehringer Ingelheim Pharma Derivados de xantina, sua preparação e sua utilização como medicamento
US6936590B2 (en) 2001-03-13 2005-08-30 Bristol Myers Squibb Company C-aryl glucoside SGLT2 inhibitors and method
US6693094B2 (en) 2001-03-22 2004-02-17 Chrono Rx Llc Biguanide and sulfonylurea formulations for the prevention and treatment of insulin resistance and type 2 diabetes mellitus
JP2002348279A (ja) 2001-05-25 2002-12-04 Nippon Kayaku Co Ltd 光学活性ピリジルケトン誘導体の製造方法並びに光学活性ピリジルケトン誘導体
DE10130371A1 (de) 2001-06-23 2003-01-02 Boehringer Ingelheim Pharma Neue Arzneimittelkompositionen auf der Basis von Anticholinergika, Corticosteroiden und Betamimetika
GB0115517D0 (en) 2001-06-25 2001-08-15 Ferring Bv Novel antidiabetic agents
ATE370943T1 (de) 2001-06-27 2007-09-15 Smithkline Beecham Corp Fluoropyrrolidine als dipeptidyl-peptidase inhibitoren
IL158923A0 (en) 2001-06-27 2004-05-12 Smithkline Beecham Corp Fluoropyrrolidines as dipeptidyl peptidase inhibitors
EP1404675B1 (en) 2001-07-03 2008-03-12 Novo Nordisk A/S Dpp-iv-inhibiting purine derivatives for the treatment of diabetes
US6869947B2 (en) * 2001-07-03 2005-03-22 Novo Nordisk A/S Heterocyclic compounds that are inhibitors of the enzyme DPP-IV
UA74912C2 (en) 2001-07-06 2006-02-15 Merck & Co Inc Beta-aminotetrahydroimidazo-(1,2-a)-pyrazines and tetratriazolo-(4,3-a)-pyrazines as inhibitors of dipeptylpeptidase for the treatment or prevention of diabetes
US7638522B2 (en) 2001-08-13 2009-12-29 Janssen Pharmaceutica N.V. Salt of 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino] benzonitrile
WO2003024965A2 (en) * 2001-09-19 2003-03-27 Novo Nordisk A/S Heterocyclic compounds that are inhibitors of the enzyme dpp-iv
DK1435877T3 (da) 2001-10-15 2009-08-03 Hemoteq Ag Overtrækning af stents for at forhindre restenose
DE10151296A1 (de) 2001-10-17 2003-04-30 Boehringer Ingelheim Pharma Keratinozyten verwendbar als biologisch aktive Substanz bei der Behandlung von Wunden
US6723340B2 (en) 2001-10-25 2004-04-20 Depomed, Inc. Optimal polymer mixtures for gastric retentive tablets
US6861440B2 (en) 2001-10-26 2005-03-01 Hoffmann-La Roche Inc. DPP IV inhibitors
US20030083354A1 (en) 2001-10-26 2003-05-01 Pediamed Pharmaceuticals, Inc. Phenylephrine tannate and pyrilamine tannate salts in pharmaceutical compositions
CA2363053C (en) 2001-11-09 2011-01-25 Bernard Charles Sherman Clopidogrel bisulfate tablet formulation
JP2003342259A (ja) * 2001-12-21 2003-12-03 Toray Ind Inc 光学活性シスピペリジン誘導体の製造法
KR20040064687A (ko) 2001-12-21 2004-07-19 도오레 화인케미칼 가부시키가이샤 광학 활성 시스 피페리딘 유도체의 제조법
US6727261B2 (en) 2001-12-27 2004-04-27 Hoffman-La Roche Inc. Pyrido[2,1-A]Isoquinoline derivatives
WO2003057200A2 (en) 2002-01-11 2003-07-17 Novo Nordisk A/S Compositions comprising inhibitors of dpp-iv and nep enzymes for the treatment of diabetes
EP1854454B1 (en) 2002-01-16 2013-11-06 Boehringer Ingelheim Pharma GmbH & Co. KG Method for the preparation of amorphous telmisartan
EP1333033A1 (en) 2002-01-30 2003-08-06 Boehringer Ingelheim Pharma GmbH & Co.KG FAP-activated anti-tumor compounds
JP2005517690A (ja) 2002-02-01 2005-06-16 ファイザー・プロダクツ・インク 固体薬物分散物を含有する即時放出剤形
US7610153B2 (en) 2002-02-13 2009-10-27 Virginia Commonwealth University Multi-drug titration and evaluation
SI1476138T1 (sl) 2002-02-21 2012-07-31 Valeant Internat Barbados Srl Formulacije s prirejenim sproščanjem vsaj ene oblike tramadola
US7074798B2 (en) * 2002-02-25 2006-07-11 Eisai Co., Ltd Xanthine derivative and DPPIV inhibitor
HUP0200849A2 (hu) 2002-03-06 2004-08-30 Sanofi-Synthelabo N-aminoacetil-2-ciano-pirrolidin-származékok, e vegyületeket tartalmazó gyógyszerkészítmények és eljárás előállításukra
JP4298212B2 (ja) 2002-03-29 2009-07-15 大日本印刷株式会社 塩酸エピナスチン高融点型結晶の製造法
JP2003300977A (ja) 2002-04-10 2003-10-21 Sumitomo Pharmaceut Co Ltd キサンチン誘導体
EP1496982A4 (en) 2002-04-16 2006-07-19 Merck & Co Inc SOLID FORMS OF SALTS WITH TYROSINE KINASE EFFECT
CA2484306A1 (en) 2002-04-26 2003-11-06 Katsumi Maezono Prophylactic and therapeutic agent of diabetes mellitus
AU2003231252A1 (en) 2002-05-09 2003-11-11 Enos Pharmaceuticals, Inc. Methods and compositions for the treatment and prevention of intermittent claudication or alzheimer's disease
GB0212412D0 (en) 2002-05-29 2002-07-10 Novartis Ag Combination of organic compounds
DK1509525T5 (da) 2002-05-31 2007-07-30 Schering Corp Fremgangsmåde til fremstilling af xanthin-phosphodiesterase V-inhibitorer og præcursorer derfor
BR0311697A (pt) 2002-06-06 2005-03-22 Eisai Co Ltd Novos derivados condensados de imidazol
FR2840897B1 (fr) 2002-06-14 2004-09-10 Fournier Lab Sa Nouveaux derives d'arylsulfonamides et leur utilisation en therapeutique
US20040002615A1 (en) * 2002-06-28 2004-01-01 Allen David Robert Preparation of chiral amino-nitriles
US20040023981A1 (en) 2002-07-24 2004-02-05 Yu Ren Salt forms with tyrosine kinase activity
AR040661A1 (es) 2002-07-26 2005-04-13 Theravance Inc Diclorhidrato cristalino de n-{2-[-((r)-2-hidroxi-2-feniletilamino)fenil]etil}-(r)-2hidroxi-2-(3-formamido-4-hidroxifenil)etilamina, agonista del receptor adrenergico beta 2
TW200404796A (en) 2002-08-19 2004-04-01 Ono Pharmaceutical Co Nitrogen-containing compound
DE10238243A1 (de) 2002-08-21 2004-03-04 Boehringer Ingelheim Pharma Gmbh & Co. Kg 8-[3-Amino-piperidin-1-yl]-xanthine, deren Herstellung und deren Verwendung als Arzneimittel
EP2070539A1 (de) 2002-08-21 2009-06-17 Boehringer Ingelheim Pharma GmbH & Co. KG 8-[3-Amino-Piperidin-1-YL]-Xanthine, deren Herstellung und deren Verwendung als Arzneimittel
US7569574B2 (en) * 2002-08-22 2009-08-04 Boehringer Ingelheim Pharma Gmbh & Co. Kg Purine derivatives, the preparation thereof and their use as pharmaceutical compositions
DE10238477A1 (de) 2002-08-22 2004-03-04 Boehringer Ingelheim Pharma Gmbh & Co. Kg Neue Purinderivate, deren Herstellung und deren Verwendung als Arzneimittel
US7495005B2 (en) * 2002-08-22 2009-02-24 Boehringer Ingelheim Pharma Gmbh & Co. Kg Xanthine derivatives, their preparation and their use in pharmaceutical compositions
DE10238470A1 (de) * 2002-08-22 2004-03-04 Boehringer Ingelheim Pharma Gmbh & Co. Kg Neue Xanthinderivate, deren Herstellung und deren Verwendung als Arzneimittel
DE10238723A1 (de) 2002-08-23 2004-03-11 Bayer Ag Phenyl-substituierte Pyrazolyprimidine
DE10238724A1 (de) 2002-08-23 2004-03-04 Bayer Ag Alkyl-substituierte Pyrazolpyrimidine
US20060039974A1 (en) 2002-09-11 2006-02-23 Takeda Pharmaceutical Company Limited Sustained release preparation
CN1688293A (zh) 2002-09-16 2005-10-26 韦思公司 多肽治疗剂口服给药的缓释配方及其使用方法
AU2003266559B2 (en) * 2002-09-26 2008-01-24 Eisai R&D Management Co., Ltd. Combination drug
US20060039968A1 (en) 2002-10-08 2006-02-23 Ramalingam Manikandan Gabapentin tablets and method for their preparation
AU2003269850A1 (en) 2002-10-08 2004-05-04 Novo Nordisk A/S Hemisuccinate salts of heterocyclic dpp-iv inhibitors
US20040122048A1 (en) 2002-10-11 2004-06-24 Wyeth Holdings Corporation Stabilized pharmaceutical composition containing basic excipients
US6861526B2 (en) * 2002-10-16 2005-03-01 Pfizer Inc. Process for the preparation of (S,S)-cis-2-benzhydryl-3-benzylaminoquinuclidine
JP4352001B2 (ja) 2002-10-18 2009-10-28 メルク エンド カムパニー インコーポレーテッド 糖尿病の治療または予防のためのベータ−アミノ複素環式ジペプチジルペプチダーゼ阻害剤
JP2004161749A (ja) * 2002-10-24 2004-06-10 Toray Fine Chemicals Co Ltd 光学活性含窒素化合物の製造方法
WO2004048379A1 (ja) 2002-11-01 2004-06-10 Sumitomo Pharmaceuticals Co., Ltd. キサンチン化合物
RU2005117383A (ru) 2002-11-07 2006-01-20 Мерк энд Ко., Инк. (US) Производные фенилаланина в качестве ингибиторов дипептидилпептидазы для лечения или профилактики диабета
DE10251927A1 (de) 2002-11-08 2004-05-19 Boehringer Ingelheim Pharma Gmbh & Co. Kg Neue Xanthinderivate, deren Herstellung und deren Verwendung als Arzneimittel
US7482337B2 (en) 2002-11-08 2009-01-27 Boehringer Ingelheim Pharma Gmbh & Co. Kg Xanthine derivatives, the preparation thereof and their use as pharmaceutical compositions
DE10254304A1 (de) * 2002-11-21 2004-06-03 Boehringer Ingelheim Pharma Gmbh & Co. Kg Neue Xanthinderivate, deren Herstellung und deren Verwendung als Arzneimittel
US7109192B2 (en) * 2002-12-03 2006-09-19 Boehringer Ingelheim Pharma Gmbh & Co Kg Substituted imidazo-pyridinones and imidazo-pyridazinones, the preparation thereof and their use as pharmaceutical compositions
UY28103A1 (es) 2002-12-03 2004-06-30 Boehringer Ingelheim Pharma Nuevas imidazo-piridinonas sustituidas, su preparación y su empleo como medicacmentos
ATE404191T1 (de) 2002-12-10 2008-08-15 Novartis Pharma Ag Kombinationen von einem dpp-iv inhibitor und einem ppar- alpha agonist
US20040152720A1 (en) 2002-12-20 2004-08-05 Boehringer Ingelheim Pharma Gmbh & Co. Kg Powdered medicaments containing a tiotropium salt and salmeterol xinafoate
DE10351663A1 (de) 2002-12-20 2004-07-01 Boehringer Ingelheim Pharma Gmbh & Co. Kg Pulverförmige Arzneimittel enthaltend ein Tiotropiumsalz und Salmeterolxinafoat
DK1599222T3 (da) 2003-01-08 2009-04-27 Novartis Vaccines & Diagnostic Stabiliserede vandige pr parater omfattende v vsfaktorvej-inhibitor (TFPI) eller v vsfaktorvej-inhibitorvariant
EP1599468B1 (en) 2003-01-14 2007-10-03 Arena Pharmaceuticals, Inc. 1,2,3-trisubstituted aryl and heteroaryl derivatives as modulators of metabolism and the prophylaxis and treatment of disorders related thereto such as diabetes and hyperglycemia
DE10335027A1 (de) 2003-07-31 2005-02-17 Boehringer Ingelheim Pharma Gmbh & Co. Kg Verwendung von Angiotensin II Rezeptor Antagonisten
PE20040950A1 (es) 2003-02-14 2005-01-01 Theravance Inc DERIVADOS DE BIFENILO COMO AGONISTAS DE LOS RECEPTORES ADRENERGICOS ß2 Y COMO ANTAGONISTAS DE LOS RECEPTORES MUSCARINICOS
JP2004250336A (ja) 2003-02-18 2004-09-09 Kao Corp コーティング錠及び糖衣錠の製造法
US7135575B2 (en) 2003-03-03 2006-11-14 Array Biopharma, Inc. P38 inhibitors and methods of use thereof
US7442387B2 (en) 2003-03-06 2008-10-28 Astellas Pharma Inc. Pharmaceutical composition for controlled release of active substances and manufacturing method thereof
CA2515289A1 (en) 2003-03-12 2004-09-23 Arizona Board Of Regents On Behalf Of The University Of Arizona Weak base salts
CN100415224C (zh) 2003-03-18 2008-09-03 诺瓦提斯公司 包含脂肪酸和氨基酸的组合物
WO2004096806A1 (ja) 2003-04-30 2004-11-11 Sumitomo Pharmaceuticals Co. Ltd. 縮合イミダゾール誘導体
US20040220186A1 (en) 2003-04-30 2004-11-04 Pfizer Inc. PDE9 inhibitors for treating type 2 diabetes,metabolic syndrome, and cardiovascular disease
TW200510277A (en) 2003-05-27 2005-03-16 Theravance Inc Crystalline form of β2-adrenergic receptor agonist
AU2003902828A0 (en) 2003-06-05 2003-06-26 Fujisawa Pharmaceutical Co., Ltd. Dpp-iv inhibitor
US7566707B2 (en) * 2003-06-18 2009-07-28 Boehringer Ingelheim International Gmbh Imidazopyridazinone and imidazopyridone derivatives, the preparation thereof and their use as pharmaceutical compositions
DE10327439A1 (de) 2003-06-18 2005-01-05 Boehringer Ingelheim Pharma Gmbh & Co. Kg Neue Imidazopyridazinon- und Imidazopyridonderivate, deren Herstellung und deren Verwendung als Arzneimittel
MXPA05013734A (es) 2003-06-20 2006-03-08 Hoffmann La Roche Hexahidropiroisoquinolinas como inhibidores de dpp-iv.
DE602004030244D1 (de) 2003-06-20 2011-01-05 Hoffmann La Roche Itoren
JO2625B1 (en) 2003-06-24 2011-11-01 ميرك شارب اند دوم كوربوريشن Phosphoric acid salts of dipeptidyl betidase inhibitor 4
AR045047A1 (es) 2003-07-11 2005-10-12 Arena Pharm Inc Derivados arilo y heteroarilo trisustituidos como moduladores del metabolismo y de la profilaxis y tratamiento de desordenes relacionados con los mismos
EP2287165A3 (en) 2003-07-14 2011-06-22 Arena Pharmaceuticals, Inc. Fused-aryl and heteroaryl derivatives as modulators of metabolism and the prophylaxis and treatment of disorders related thereto
US20050027012A1 (en) 2003-07-16 2005-02-03 Boehringer Ingelheim International Gmbh Tablets containing ambroxol
US20060134206A1 (en) 2003-07-24 2006-06-22 Iyer Eswaran K Oral compositions for treatment of diseases
US6995183B2 (en) 2003-08-01 2006-02-07 Bristol Myers Squibb Company Adamantylglycine-based inhibitors of dipeptidyl peptidase IV and methods
CN1829709A (zh) 2003-08-01 2006-09-06 健亚生物科技公司 对抗黄病毒的双环咪唑衍生物
CN102349927A (zh) 2003-08-29 2012-02-15 Hdac默克研究有限责任公司 联合治疗癌症的方法
WO2005026148A1 (en) 2003-09-08 2005-03-24 Takeda San Diego, Inc. Dipeptidyl peptidase inhibitors
US20070072810A1 (en) 2003-10-03 2007-03-29 Takeda Pharmaceutical Company, Limited Agent for treating diabetes
BR0304443B1 (pt) 2003-10-28 2012-08-21 processo para obtenção de concentrados de titánio com elevado teor de tio2 e baixo teor de radionuclìdeos a partir de concentrados mecánicos de anatásio.
US7107714B2 (en) 2003-11-10 2006-09-19 Marketing Displays, Inc. Portable snap-fit sign stand
KR20140089408A (ko) 2003-11-17 2014-07-14 노파르티스 아게 디펩티딜 펩티다제 ⅳ 억제제의 용도
DE10355304A1 (de) * 2003-11-27 2005-06-23 Boehringer Ingelheim Pharma Gmbh & Co. Kg Neue 8-(Piperazin-1-yl)-und 8-([1,4]Diazepan-1-yl)-xanthine, deren Herstellung und deren Verwendung als Arzneimittel
JPWO2005053695A1 (ja) * 2003-12-04 2007-12-06 エーザイ・アール・アンド・ディー・マネジメント株式会社 多発性硬化症予防剤または治療剤
US7217711B2 (en) * 2003-12-17 2007-05-15 Boehringer Ingelheim International Gmbh Piperazin-1-yl and 2-([1,4]diazepan-1-yl)-imidazo[4,5-d]-pyridazin-4-ones, the preparation thereof and their use as pharmaceutical compositions
DE10359098A1 (de) 2003-12-17 2005-07-28 Boehringer Ingelheim Pharma Gmbh & Co. Kg Neue 2-(Piperazin-1-yl)- und 2-([1,4]Diazepan-1-yl)-imidazo[4,5-d]pyridazin-4-one, deren Herstellung und deren Verwendung als Arzneimittel
ATE501135T1 (de) * 2003-12-18 2011-03-15 Tibotec Pharm Ltd Piperidinamino-benzimidazol-derivate al respiratorisches syncytialvirus replikation inhibitoren
DE10360835A1 (de) 2003-12-23 2005-07-21 Boehringer Ingelheim Pharma Gmbh & Co. Kg Bicyclische Imidazolverbindungen, deren Herstellung und deren Verwendung als Arzneimittel
CA2549955A1 (en) 2003-12-24 2005-07-07 Prosidion Limited Heterocyclic derivatives as gpcr receptor agonists
EP1708680A2 (en) 2004-01-21 2006-10-11 Janssen Pharmaceutica N.V. Mitratapide oral solution
PT1758905E (pt) 2004-02-18 2009-07-16 Boehringer Ingelheim Int 8-[3-amino-piperidin-1-il]-xantinas, sua preparação e sua utilização como inibidores de dpp-iv
US7501426B2 (en) 2004-02-18 2009-03-10 Boehringer Ingelheim International Gmbh 8-[3-amino-piperidin-1-yl]-xanthines, their preparation and their use as pharmaceutical compositions
DE102004019540A1 (de) 2004-04-22 2005-11-10 Boehringer Ingelheim Pharma Gmbh & Co. Kg Neue Arzneimittelkombinationen zur Behandlung von Atemwegserkrankungen
DE102004009039A1 (de) 2004-02-23 2005-09-08 Boehringer Ingelheim Pharma Gmbh & Co. Kg 8-[3-Amino-piperidin-1-yl]-xanthine, deren Herstellung und Verwendung als Arzneimittel
EP1593671A1 (en) 2004-03-05 2005-11-09 Graffinity Pharmaceuticals AG DPP-IV inhibitors
US7393847B2 (en) * 2004-03-13 2008-07-01 Boehringer Ingleheim International Gmbh Imidazopyridazinediones, their preparation and their use as pharmaceutical compositions
CN102079743B (zh) 2004-03-15 2020-08-25 武田药品工业株式会社 二肽基肽酶抑制剂
EA011158B1 (ru) 2004-03-16 2009-02-27 Бёрингер Ингельхайм Интернациональ Гмбх Замещённые глюкопиранозилом бензольные производные, содержащие эти соединения лекарственные средства, их применение и способ их получения
EP1577306A1 (de) 2004-03-17 2005-09-21 Boehringer Ingelheim Pharma GmbH & Co.KG Neue Benzoxazinonderivate als langwirksame Betamimetika zur Behandlung von Atemwegserkrankungen
WO2005097798A1 (de) 2004-04-10 2005-10-20 Boehringer Ingelheim International Gmbh Neue 2-amino-imidazo[4,5-d]pyridazin-4-one und 2-amino-imidazo[4,5-c]pyridin-4-one, deren herstellung und deren verwendung als arzneimittel
US7179809B2 (en) * 2004-04-10 2007-02-20 Boehringer Ingelheim International Gmbh 2-Amino-imidazo[4,5-d]pyridazin-4-ones, their preparation and their use as pharmaceutical compositions
US20050239778A1 (en) 2004-04-22 2005-10-27 Boehringer Ingelheim International Gmbh Novel medicament combinations for the treatment of respiratory diseases
US20050244502A1 (en) 2004-04-28 2005-11-03 Mathias Neil R Composition for enhancing absorption of a drug and method
US7439370B2 (en) * 2004-05-10 2008-10-21 Boehringer Ingelheim International Gmbh Imidazole derivatives, their preparation and their use as intermediates for the preparation of pharmaceutical compositions and pesticides
GEP20084421B (en) 2004-05-12 2008-07-10 Pfizer Prod Inc Proline derivatives and their use as dipeptidyl peptidase iv inhibitors
DE102004024454A1 (de) 2004-05-14 2005-12-08 Boehringer Ingelheim Pharma Gmbh & Co. Kg Neue Enantiomerenreine Betaagonisten, Verfahren zu deren Herstellung und deren Verwendung als Arzneimittel
PE20060315A1 (es) 2004-05-24 2006-05-15 Irm Llc Compuestos de tiazol como moduladores de ppar
TWI354569B (en) 2004-05-28 2011-12-21 Bristol Myers Squibb Co Coated tablet formulation and method
WO2005117948A1 (en) 2004-06-01 2005-12-15 Ares Trading S.A. Method of stabilizing proteins
US7935723B2 (en) 2004-06-04 2011-05-03 Novartis Pharma Ag Use of organic compounds
US20050276794A1 (en) 2004-06-09 2005-12-15 Papas Klearchos K Composition and method for improving pancreatic islet cell survival
DE102004030502A1 (de) * 2004-06-24 2006-01-12 Boehringer Ingelheim Pharma Gmbh & Co. Kg Neue Imidazole und Triazole, deren Herstellung und Verwendung als Arzneimittel
CA2573209A1 (en) 2004-07-14 2006-01-19 Novartis Ag Combination of dpp-iv inhibitors and compounds modulating 5-ht3 and/or 5-ht4 receptors
JP2006045156A (ja) * 2004-08-06 2006-02-16 Sumitomo Pharmaceut Co Ltd 縮合ピラゾール誘導体
TW200613275A (en) 2004-08-24 2006-05-01 Recordati Ireland Ltd Lercanidipine salts
EP1782832A4 (en) 2004-08-26 2009-08-26 Takeda Pharmaceutical MEANS FOR THE TREATMENT OF DIABETES
DE102004043944A1 (de) * 2004-09-11 2006-03-30 Boehringer Ingelheim Pharma Gmbh & Co. Kg Neue 8-(3-Amino-piperidin-1-yl)-7-(but-2-inyl)-xanthine, deren Herstellung und deren Verwendung als Arzneimittel
DE102004044221A1 (de) * 2004-09-14 2006-03-16 Boehringer Ingelheim Pharma Gmbh & Co. Kg Neue 3-Methyl-7-butinyl-xanthine, deren Herstellung und deren Verwendung als Arzneimittel
CN1759834B (zh) 2004-09-17 2010-06-23 中国医学科学院医药生物技术研究所 黄连素或其与辛伐他汀联合在制备用于预防或治疗与血脂有关疾病或症状的产品中用途
CA2580461A1 (en) 2004-09-23 2006-04-06 Amgen Inc. Substituted sulfonamidopropionamides and methods of use
BRPI0516446A (pt) 2004-10-08 2008-09-02 Novartis Ag combinação de compostos orgánicos
EA013463B1 (ru) 2004-10-12 2010-04-30 ГЛЕНМАРК ФАРМАСЬЮТИКАЛС Эс.Эй. Новые ингибиторы дипептидилпептидазы iv, содержащие их фармацевтические композиции, способ их получения и способ лечения с их применением
MX2007004934A (es) 2004-10-25 2007-06-12 Novartis Ag Combinacion de inhibidor de dpp-iv, anti-diabetico de ppar, y metformina.
DE102005013967A1 (de) 2004-11-05 2006-10-05 Boehringer Ingelheim Pharma Gmbh & Co. Kg Neue Bradykinin-B1-Antagonisten, Verfahren zu deren Herstellung sowie deren Verwendung als Arzneimittel
DE102004054054A1 (de) 2004-11-05 2006-05-11 Boehringer Ingelheim Pharma Gmbh & Co. Kg Verfahren zur Herstellung chiraler 8-(3-Amino-piperidin-1-yl)-xanthine
BRPI0518651A2 (pt) 2004-12-24 2008-12-02 Dainippon Sumitomo Pharma composto, uma prà-droga do mesmo, ou um sal do composto ou prà-droga farmaceuticamente aceitÁvel, composiÇço farmacÊutica, inibidor de dipeptidil peptidase iv, uso de um composto, uma prà-droga do mesmo ou um sal do composto ou prà-droga farmaceuticamente aceitÁvel, e, mÉtodo para tratar diabetes
KR100760430B1 (ko) 2004-12-31 2007-10-04 한미약품 주식회사 당뇨병 치료제의 경구 투여용 서방성 복합 제제 및 이의제조 방법
MY148521A (en) 2005-01-10 2013-04-30 Arena Pharm Inc Substituted pyridinyl and pyrimidinyl derivatives as modulators of metabolism and the treatment of disorders related thereto
DOP2006000008A (es) 2005-01-10 2006-08-31 Arena Pharm Inc Terapia combinada para el tratamiento de la diabetes y afecciones relacionadas y para el tratamiento de afecciones que mejoran mediante un incremento de la concentración sanguínea de glp-1
GT200600008A (es) 2005-01-18 2006-08-09 Formulacion de compresion directa y proceso
EP1874339A1 (en) 2005-04-21 2008-01-09 Gastrotech Pharma A/S Pharmaceutical preparations of a glp-1 molecule and an anti-emetic drug
AU2006239929B2 (en) 2005-04-22 2011-11-03 Alantos Pharmaceuticals Holding, Inc. Dipeptidyl peptidase-IV inhibitors
WO2006114923A1 (ja) 2005-04-25 2006-11-02 Hitachi, Ltd. 磁気共鳴を用いた検査装置および核磁気共鳴信号受信用コイル
UA91546C2 (uk) 2005-05-03 2010-08-10 Бьорінгер Інгельхайм Інтернаціональ Гмбх КРИСТАЛІЧНА ФОРМА 1-ХЛОР-4-(β-D-ГЛЮКОПІРАНОЗ-1-ИЛ)-2-[4-((S)-ТЕТРАГІДРОФУРАН-3-ІЛОКСИ)-БЕНЗИЛ]-БЕНЗОЛУ, СПОСІБ ЇЇ ОДЕРЖАННЯ ТА ЇЇ ЗАСТОСУВАННЯ ПРИ ПРИГОТУВАННІ ЛІКАРСЬКИХ ЗАСОБІВ
CN101203494A (zh) 2005-05-25 2008-06-18 惠氏公司 合成经取代3-氰基喹啉和其中间物的方法
GT200600218A (es) 2005-06-10 2007-03-28 Formulación y proceso de compresión directa
NZ564285A (en) 2005-06-20 2010-03-26 Decode Genetics Ehf Genetic variants in the TCF7L2 gene as diagnostic markers for risk of type 2 diabetes mellitus
ATE483732T1 (de) 2005-07-08 2010-10-15 Pfizer Ltd Madcam-antikörper
UY29694A1 (es) 2005-07-28 2007-02-28 Boehringer Ingelheim Int Metodos para prevenir y tratar trastornos metabolicos y nuevos derivados de pirazol-o-glucosido
DE102005035891A1 (de) 2005-07-30 2007-02-08 Boehringer Ingelheim Pharma Gmbh & Co. Kg 8-(3-Amino-piperidin-1-yl)-xanthine, deren Herstellung und deren Verwendung als Arzneimittel
MX2008001799A (es) 2005-08-11 2008-04-16 Hoffmann La Roche Composicion farmaceutica que comprende un inhibidor de dipeptidil peptidasa iv.
EP1760076A1 (en) 2005-09-02 2007-03-07 Ferring B.V. FAP Inhibitors
WO2007033350A1 (en) 2005-09-14 2007-03-22 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors for treating diabetes
RS20080112A (en) 2005-09-16 2009-05-06 Arena Pharmaceuticals Inc., Modulators of metabolism and the treatment of disorders related thereto
RU2440143C2 (ru) 2005-09-20 2012-01-20 Новартис Аг Применение ингибитора dpp-iv для снижения приступов гликемии
JOP20180109A1 (ar) 2005-09-29 2019-01-30 Novartis Ag تركيبة جديدة
CA2625646A1 (en) 2005-10-25 2007-05-03 Merck & Co., Inc. Combination of a dipeptidyl peptidase-4 inhibitor and an anti-hypertensive agent for the treatment of diabetes and hypertension
CN101300298A (zh) 2005-11-04 2008-11-05 Ls电线有限公司 Mdh-聚合物混合粒子的合成
EP1962827A4 (en) 2005-12-16 2011-02-16 Merck Sharp & Dohme PHARMACEUTICAL COMPOSITIONS OF COMBINATIONS OF DIPEPTIDYL-PEPTIDASE-4-INHIBITORS WITH METFORMIN
JP2009520763A (ja) 2005-12-23 2009-05-28 ノバルティス アクチエンゲゼルシャフト Ｄｐｐ−ｉｖ阻害剤として有用な縮合ヘテロ環式化合物
GB0526291D0 (en) 2005-12-23 2006-02-01 Prosidion Ltd Therapeutic method
US20090054512A1 (en) 2006-01-06 2009-02-26 Foley James E Use of organic compounds
KR20080102395A (ko) 2006-02-15 2008-11-25 베링거 인겔하임 인터내셔날 게엠베하 글루코피라노실-치환된 벤조니트릴 유도체, 당해 화합물을 함유하는 약제학적 조성물, 이들의 용도 및 이들의 제조방법
WO2007099345A1 (en) 2006-03-02 2007-09-07 Betagenon Ab Medical use of bmp-2 and/ or bmp-4
PE20071221A1 (es) 2006-04-11 2007-12-14 Arena Pharm Inc Agonistas del receptor gpr119 en metodos para aumentar la masa osea y para tratar la osteoporosis y otras afecciones caracterizadas por masa osea baja, y la terapia combinada relacionada a estos agonistas
US8455435B2 (en) 2006-04-19 2013-06-04 Ludwig-Maximilians-Universitat Munchen Remedies for ischemia
MX2008014024A (es) * 2006-05-04 2008-11-14 Boehringer Ingelheim Int Formas poliformas.
EP1852108A1 (en) * 2006-05-04 2007-11-07 Boehringer Ingelheim Pharma GmbH & Co.KG DPP IV inhibitor formulations
PE20080251A1 (es) 2006-05-04 2008-04-25 Boehringer Ingelheim Int Usos de inhibidores de dpp iv
KR20070111099A (ko) 2006-05-16 2007-11-21 영진약품공업주식회사 시타글립틴 염산염의 신규 결정형, 이의 제조 방법과 이를포함하는 약학적 조성물
NZ572368A (en) 2006-05-16 2011-04-29 Gilead Sciences Inc Method and compositions for treating hematological malignancies
WO2007137107A2 (en) 2006-05-19 2007-11-29 Abbott Laboratories Inhibitors of diacylglycerol o-acyltransferase type 1 enzyme
KR100858848B1 (ko) 2006-05-23 2008-09-17 한올제약주식회사 메트포르민 서방정
WO2007149797A2 (en) 2006-06-19 2007-12-27 Novartis Ag Use of organic compounds
WO2007148185A2 (en) 2006-06-21 2007-12-27 Pfizer Products Inc. Substituted 3 -amino- pyrrolidino-4 -lactams as dpp inhibitors
AT503443B1 (de) 2006-06-23 2007-10-15 Leopold Franzens Uni Innsbruck Verfahren zur herstellung einer eisfläche für eissportbahnen
TW200811140A (en) 2006-07-06 2008-03-01 Arena Pharm Inc Modulators of metabolism and the treatment of disorders related thereto
TW200811147A (en) 2006-07-06 2008-03-01 Arena Pharm Inc Modulators of metabolism and the treatment of disorders related thereto
WO2008017670A1 (en) 2006-08-08 2008-02-14 Boehringer Ingelheim International Gmbh Pyrrolo [3, 2 -d] pyrimidines as dpp-iv inhibitors for the treatment of diabetes mellitus
JP5384343B2 (ja) 2006-08-15 2014-01-08 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング グルコピラノシル−置換シクロプロピルベンゼン誘導体、そのような化合物を含む医薬組成物、ｓｇｌｔ阻害剤としてのそれらの使用及びそれらの製造方法
JP2010501010A (ja) 2006-08-17 2010-01-14 ウェルスタット セラピューティクス コーポレイション 代謝障害のための併用処置
DE102006042586B4 (de) 2006-09-11 2014-01-16 Betanie B.V. International Trading Verfahren zum mikropartikulären Beladen von hochpolymeren Kohlenhydraten mit hydrophoben Wirkflüssigkeiten
US7956201B2 (en) 2006-11-06 2011-06-07 Hoffman-La Roche Inc. Process for the preparation of (S)-4-fluoromethyl-dihydro-furan-2-one
EP2079753A1 (en) 2006-11-06 2009-07-22 Boehringer Ingelheim International GmbH Glucopyranosyl-substituted benzyl-benzonitrile derivatives, medicaments containing such compounds, their use and process for their manufacture
JP5337040B2 (ja) 2006-11-09 2013-11-06 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Ｓｇｌｔ−２インヒビターとの組み合わせ治療及びそれらの医薬組成物
EA015835B1 (ru) 2006-12-06 2011-12-30 Смитклайн Бичем Корпорейшн Производные 4-окса(тиа)метилпиперидина и их применение в качестве противодиабетических средств
US7638541B2 (en) 2006-12-28 2009-12-29 Metabolex Inc. 5-ethyl-2-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-pyrimidine
AR064736A1 (es) 2007-01-04 2009-04-22 Prosidion Ltd Agonistas de gpcr
CL2008000133A1 (es) 2007-01-19 2008-05-23 Boehringer Ingelheim Int Composicion farmaceutica que comprende un compuesto derivado de pirazol-o-glucosido combinado con al menos un segundo agente terapeutico; y uso de la composicion para el tratamiento de diabetes mellitus, cataratas, neuropatia, infarto de miocardio, e
EP2124901B1 (en) 2007-02-01 2017-07-19 Takeda Pharmaceutical Company Limited Tablet preparation without causing a tableting trouble
ME01239B (me) 2007-02-01 2013-06-20 Takeda Pharmaceuticals Co Čvrsti preparat koji sadrži alogliptin i pioglitazon
WO2008113000A1 (en) 2007-03-15 2008-09-18 Nectid, Inc. Anti-diabetic combinations comprising a slow release biguanide composition and an immediate release dipeptidyl peptidase iv inhibitor composition
EP2143443B1 (en) 2007-04-03 2014-11-19 Mitsubishi Tanabe Pharma Corporation A combination of dipeptidyl peptidase iv inhibitor and sweetener for use in the treatment of obesity
WO2008130998A2 (en) 2007-04-16 2008-10-30 Smith & Nephew, Inc. Powered surgical system
PE20090696A1 (es) 2007-04-20 2009-06-20 Bristol Myers Squibb Co Formas cristalinas de saxagliptina y procesos para preparar las mismas
EP2144902B1 (en) 2007-05-04 2012-05-16 Bristol-Myers Squibb Company [6,6]and [6,7]-bicyclic gpr119 g protein-coupled receptor agonists
WO2007135196A2 (en) 2007-07-09 2007-11-29 Symrise Gmbh & Co. Kg Stable soluble salts of phenylbenzimidazole sulfonic acid at phs at or below 7.0
WO2009011451A1 (en) 2007-07-19 2009-01-22 Takeda Pharmaceutical Company Limited Solid preparation comprising alogliptin and metformin hydrochloride
CL2008002427A1 (es) 2007-08-16 2009-09-11 Boehringer Ingelheim Int Composicion farmaceutica que comprende 1-cloro-4-(b-d-glucopiranos-1-il)-2-[4-((s)-tetrahidrofurano-3-iloxi)bencil]-benceno combinado con 1-[(4-metilquinazolin-2-il)metil]-3-metil-7-(2-butin-1-il)-8-(3-(r)-aminopiperidin-1-il)xantina; y su uso para tratar diabetes mellitus tipo 2.
UY31291A1 (es) 2007-08-16 2009-03-31 Composicion farmacéutica que comprende un derivado de pirazol-0-glucosido
CL2008002424A1 (es) 2007-08-16 2009-09-11 Boehringer Ingelheim Int Composicion farmaceutica que comprende un compuesto derivado de pirazol-o-glucosido; y uso de la composicion farmaceutica para el tratamiento de la diabetes mellitus, tolerancia anormal a la glucosa e hiperglucemia, trastornos metabolicos, entre otras.
CL2008002425A1 (es) 2007-08-16 2009-09-11 Boehringer Ingelheim Int Composición farmacéutica que comprende un inhibidor de sglt2 y 1-(4-metil-quinazolin-2-il)metil-3metil-7-(-2-butin-1-il)-8-(3-(r)-amino-piperidin-1il)-xantina, un inhibidor de dpp iv y su uso para el tratamiento de la obesidad y de la diabetes tipo 1 y 2 y complicaciones de esta.
US20110112069A1 (en) 2007-08-17 2011-05-12 Boehringer Ingelheim International Gmbh Purin derivatives for use in the treatment of fab-related diseases
WO2009037719A1 (en) 2007-09-21 2009-03-26 Lupin Limited Novel compounds as dipeptidyl peptidase iv (dpp iv) inhibitors
JP5241849B2 (ja) 2007-11-16 2013-07-17 ノボ・ノルデイスク・エー／エス インスリン及びインスリン分泌性ペプチドを含む薬学的組成物
CN101234105A (zh) 2008-01-09 2008-08-06 北京润德康医药技术有限公司 一种含有二甲双胍和维格列汀的药用组合物及其制备方法
US20090186086A1 (en) 2008-01-17 2009-07-23 Par Pharmaceutical, Inc. Solid multilayer oral dosage forms
TW200936136A (en) 2008-01-28 2009-09-01 Sanofi Aventis Tetrahydroquinoxaline urea derivatives, their preparation and their therapeutic application
US20100330177A1 (en) 2008-02-05 2010-12-30 Merck Sharp & Dohme Corp. Pharmaceutical compositions of a combination of metformin and a dipeptidyl peptidase-iv inhibitor
CA2716130A1 (en) 2008-03-04 2009-09-11 Nazaneen Pourkavoos Pharmaceutical compositions of a combination of metformin and a dipeptidyl peptidase-iv inhibitor
CA2717138A1 (en) 2008-03-05 2009-09-11 Takeda Pharmaceutical Company Limited 5-membered heterocyclic compounds and bicyclic heteroaryl having glucagon antagonistic action useful for treating diabetes
US8551524B2 (en) 2008-03-14 2013-10-08 Iycus, Llc Anti-diabetic combinations
PL2280704T3 (pl) 2008-03-31 2015-10-30 Cymabay Therapeutics Inc Związki oksymetylenoarylowe i ich zastosowania
PE20091730A1 (es) 2008-04-03 2009-12-10 Boehringer Ingelheim Int Formulaciones que comprenden un inhibidor de dpp4
PE20100156A1 (es) 2008-06-03 2010-02-23 Boehringer Ingelheim Int Tratamiento de nafld
UY32030A (es) 2008-08-06 2010-03-26 Boehringer Ingelheim Int "tratamiento para diabetes en pacientes inapropiados para terapia con metformina"
WO2010018217A2 (en) 2008-08-15 2010-02-18 Boehringer Ingelheim International Gmbh Organic compounds for wound healing
JP2010053576A (ja) 2008-08-27 2010-03-11 Sumitomo Forestry Co Ltd 舗装用マット
US8513264B2 (en) 2008-09-10 2013-08-20 Boehringer Ingelheim International Gmbh Combination therapy for the treatment of diabetes and related conditions
UY32177A (es) 2008-10-16 2010-05-31 Boehringer Ingelheim Int Tratamiento de diabetes en pacientes con control glucémico insuficiente a pesar de la terapia con fármaco, oral o no, antidiabético
WO2010045656A2 (en) 2008-10-17 2010-04-22 Nectid, Inc. Novel sglt2 inhibitor dosage forms
CN107011345A (zh) 2008-12-23 2017-08-04 勃林格殷格翰国际有限公司 有机化合物的盐形式
AR074990A1 (es) 2009-01-07 2011-03-02 Boehringer Ingelheim Int Tratamiento de diabetes en pacientes con un control glucemico inadecuado a pesar de la terapia con metformina
TWI466672B (zh) 2009-01-29 2015-01-01 Boehringer Ingelheim Int 小兒科病人糖尿病之治療
EA029759B1 (ru) 2009-02-13 2018-05-31 Бёрингер Ингельхайм Интернациональ Гмбх Антидиабетические лекарственные средства, содержащие ингибитор dpp-4 (линаглиптин) необязательно в комбинации с другими антидиабетическими средствами
AU2010212867B2 (en) 2009-02-13 2013-05-16 Boehringer Ingelheim International Gmbh Pharmaceutical composition comprising a SGLT2 inhibitor, a DPP-IV inhibitor and optionally a further antidiabetic agent and uses thereof
UY32427A (es) 2009-02-13 2010-09-30 Boheringer Ingelheim Internat Gmbh Composicion farmaceutica, forma farmaceutica, procedimiento para su preparacion, metodos de tratamiento y usos de la misma
TW201031661A (en) 2009-02-17 2010-09-01 Targacept Inc Fused benzazepines as neuronal nicotinic acetylcholine receptor ligands
EP2408780A2 (en) 2009-03-20 2012-01-25 Pfizer Inc. 3-oxa-7-azabicycloý3.3.1¨nonanes
US8815292B2 (en) 2009-04-27 2014-08-26 Revalesio Corporation Compositions and methods for treating insulin resistance and diabetes mellitus
US20120100221A1 (en) 2009-06-02 2012-04-26 Ranbaxy Laboratories Limited Pharmaceutical compositions containing a combination of an antihistamine and a decongestant
AU2010260373A1 (en) 2009-06-15 2012-01-12 Merck Sharp & Dohme Corp. Pharmaceutical compositions of combinations of dipeptidyl peptidase-4 inhibitors with pioglitazone
EP2456426A1 (en) 2009-07-21 2012-05-30 Keryx Biopharmaceuticals, Inc. Ferric citrate dosage forms
US10610489B2 (en) 2009-10-02 2020-04-07 Boehringer Ingelheim International Gmbh Pharmaceutical composition, pharmaceutical dosage form, process for their preparation, methods for treating and uses thereof
KR101763659B1 (ko) 2009-10-02 2017-08-01 베링거 인겔하임 인터내셔날 게엠베하 Ｂｉ―1356 및 메트포르민을 포함하는 약제학적 조성물
EP3646859A1 (en) 2009-11-27 2020-05-06 Boehringer Ingelheim International GmbH Treatment of genotyped diabetic patients with dpp-iv inhibitors such as linagliptin
JP2010070576A (ja) 2009-12-28 2010-04-02 Sato Pharmaceutical Co Ltd 速溶解性錠剤
US20130109703A1 (en) 2010-03-18 2013-05-02 Boehringer Ingelheim International Gmbh Combination of a GPR119 Agonist and the DPP-IV Inhibitor Linagliptin for Use in the Treatment of Diabetes and Related Conditions
EP2566464A1 (en) 2010-05-05 2013-03-13 Boehringer Ingelheim International GmbH Pharmaceutical formulations comprising pioglitazone and linagliptin
AU2011249722B2 (en) 2010-05-05 2015-09-17 Boehringer Ingelheim International Gmbh Combination therapy
AR084698A1 (es) 2010-06-22 2013-06-05 Twi Pharmaceuticals Inc Composiciones de liberacion controlada con reducido efecto de alimentos, reducida interaccion entre farmaco y los alimentos
BR112012032579B1 (pt) 2010-06-24 2021-05-11 Boehringer Ingelheim International Gmbh uso de linagliptina e composição farmacêutica compreendendo linagliptina e insulina basal de longa duração
EP2611442B1 (en) 2010-09-03 2018-07-04 Bristol-Myers Squibb Company Drug formulations using water soluble antioxidants
US9034883B2 (en) 2010-11-15 2015-05-19 Boehringer Ingelheim International Gmbh Vasoprotective and cardioprotective antidiabetic therapy
WO2012088682A1 (en) 2010-12-29 2012-07-05 Shanghai Fochon Pharmaceutical Co Ltd. 2-(3-aminopiperidin-1-yl)-[1,2,4]triazolo[1,5-c]pyrimidine-5,7(3h,6h)-dione derivates as dipeptidyl peptidase iv(dpp-iv) inhibitors
WO2012106303A1 (en) 2011-02-01 2012-08-09 Bristol-Myers Squibb Company Pharmaceutical formulations including an amine compound
AR085689A1 (es) 2011-03-07 2013-10-23 Boehringer Ingelheim Int Composiciones farmaceuticas de metformina, linagliptina y un inhibidor de sglt-2
US8785455B2 (en) 2011-05-10 2014-07-22 Sandoz Ag Polymorph of linagliptin benzoate
HUE043540T2 (hu) 2011-07-15 2019-08-28 Boehringer Ingelheim Int Szubsztituált dimer kinazolin-származék, elõállítása, valamint alkalmazása 1-es és 2-es típusú cukorbetegség kezelésére szolgáló gyógyászati készítményekben
US20130172244A1 (en) 2011-12-29 2013-07-04 Thomas Klein Subcutaneous therapeutic use of dpp-4 inhibitor
MX353496B (es) 2012-01-04 2018-01-16 Procter & Gamble Estructuras fibrosas que contienen activos con múltiples regiones.
US9555001B2 (en) 2012-03-07 2017-01-31 Boehringer Ingelheim International Gmbh Pharmaceutical composition and uses thereof
WO2013171166A1 (en) 2012-05-14 2013-11-21 Boehringer Ingelheim International Gmbh A xanthine derivative as dpp-4 inhibitor for use in the treatment of sirs and/or sepsis
EP3685839A1 (en) 2012-05-14 2020-07-29 Boehringer Ingelheim International GmbH Linagliptin for use in the treatment of albuminuria and kidney related diseases
EP2854812A1 (en) 2012-05-24 2015-04-08 Boehringer Ingelheim International GmbH A xanthine derivative as dpp -4 inhibitor for use in the treatment of autoimmune diabetes, particularly lada
WO2013174767A1 (en) 2012-05-24 2013-11-28 Boehringer Ingelheim International Gmbh A xanthine derivative as dpp -4 inhibitor for use in modifying food intake and regulating food preference
EP2854824A1 (en) 2012-05-25 2015-04-08 Boehringer Ingelheim International GmbH Use of keratinocytes as a biologically active substance in the treatment of wounds, such as diabetic wounds, optionally in combination with a dpp-4 inhibitor
WO2013179307A2 (en) 2012-05-29 2013-12-05 Mylan Laboratories Limited Stabilized pharmaceutical compositions of saxagliptin
JP2015533134A (ja) 2012-10-09 2015-11-19 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング 錠剤の機械的安定性に適切な少なくとも１種の水和物形成活性物質及び／又はアジュバントを含有する機械的に安定な錠剤、特にアルギニン含有錠剤の製造における選択的に水分調整された打錠材料の使用
WO2014056941A1 (en) 2012-10-09 2014-04-17 Boehringer Ingelheim International Gmbh Use of moisture-conditioned disintegrants in tablet manufacture
JP2016510795A (ja) 2013-03-15 2016-04-11 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング 心臓保護及び腎臓保護の抗糖尿病治療におけるリナグリプチンの使用
JP2016518438A (ja) 2013-05-17 2016-06-23 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング ＤＰＰ−４阻害薬とα−グルコシダーゼ阻害薬との組合せ
JP6507154B2 (ja) 2013-06-14 2019-04-24 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング 糖尿病及びその合併症を治療するためのｄｄｐ−４阻害薬
ES2950384T3 (es) 2014-02-28 2023-10-09 Boehringer Ingelheim Int Uso médico de un inhibidor de DPP-4
WO2016059219A1 (en) 2014-10-17 2016-04-21 Boehringer Ingelheim International Gmbh Pharmaceutical composition and uses thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4005208A (en) * 1975-05-16 1977-01-25 Smithkline Corporation N-Heterocyclic-9-xanthenylamines
US20040097510A1 (en) * 2002-08-21 2004-05-20 Boehringer Ingelheim Pharma Gmbh & Co. Kg 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103319483A (zh) * 2012-10-19 2013-09-25 药源药物化学（上海）有限公司 一种利拉列汀重要中间体的制备方法
CN104496989A (zh) * 2014-12-26 2015-04-08 寿光富康制药有限公司 一种利格列汀工业化制备工艺
CN104892609A (zh) * 2015-04-23 2015-09-09 深圳市海滨制药有限公司 一种利拉利汀中间体及其制备方法和应用
CN104892609B (zh) * 2015-04-23 2017-06-20 深圳市海滨制药有限公司 一种利拉利汀中间体及其制备方法和应用

Also Published As

Publication number Publication date
CN103351388B (zh) 2016-08-24
SG157371A1 (en) 2009-12-29
EA200900536A1 (ru) 2010-04-30
TR201908974T4 (tr) 2019-07-22
JP5947492B2 (ja) 2016-07-06
AU2005300559A1 (en) 2006-05-11
WO2006048427A8 (de) 2007-08-02
HRP20140373T2 (hr) 2014-10-10
UA100221C2 (en) 2012-12-10
US8883805B2 (en) 2014-11-11
US9499546B2 (en) 2016-11-22
SG189768A1 (en) 2013-05-31
ES2458106T3 (es) 2014-04-29
DK3029040T3 (da) 2019-06-24
US8541450B2 (en) 2013-09-24
JP2012211174A (ja) 2012-11-01
MX2007005404A (es) 2007-05-16
BRPI0517093B1 (pt) 2020-12-22
KR20070085744A (ko) 2007-08-27
BRPI0517093A (pt) 2008-09-30
EA201200491A1 (ru) 2012-08-30
UY29190A1 (es) 2006-06-30
IL182923A (en) 2013-09-30
EP3029040B1 (de) 2019-04-03
CN102391267A (zh) 2012-03-28
CN107266449B (zh) 2022-06-07
HK1109405A1 (zh) 2008-06-06
CN103351388A (zh) 2013-10-16
CN101048409A (zh) 2007-10-03
SG185967A1 (en) 2012-12-28
PE20060921A1 (es) 2006-10-30
EA029039B1 (ru) 2018-02-28
EP2287164A1 (de) 2011-02-23
ES2458106T9 (es) 2014-09-09
NZ555324A (en) 2010-12-24
IL182923A0 (en) 2007-09-20
EP1812438A1 (de) 2007-08-01
CN102127080A (zh) 2011-07-20
CA2586938C (en) 2017-01-03
PE20100232A1 (es) 2010-03-29
TW201305166A (zh) 2013-02-01
EP2287164B9 (de) 2014-06-11
NZ589450A (en) 2012-06-29
US7820815B2 (en) 2010-10-26
NO20071522L (no) 2007-05-22
KR101440796B1 (ko) 2014-09-22
EA200700974A1 (ru) 2007-10-26
PL2287164T3 (pl) 2014-07-31
US20150025089A1 (en) 2015-01-22
MY145604A (en) 2012-03-15
AU2005300559B2 (en) 2012-08-02
BRPI0517093B8 (pt) 2021-05-25
CN101048409B (zh) 2014-01-22
NZ617916A (en) 2015-06-26
TWI374885B (en) 2012-10-21
MX344285B (es) 2016-12-13
DE102004054054A1 (de) 2006-05-11
US20170129872A1 (en) 2017-05-11
PL3029040T3 (pl) 2019-10-31
EA012163B1 (ru) 2009-08-28
CN107266449A (zh) 2017-10-20
JP5063356B2 (ja) 2012-10-31
KR20140068267A (ko) 2014-06-05
WO2006048427A1 (de) 2006-05-11
KR20130016414A (ko) 2013-02-14
ME01667B (me) 2014-09-20
CA2586938A1 (en) 2006-05-11
SI2287164T1 (sl) 2014-04-30
HUE044308T2 (hu) 2019-10-28
EP3539956A1 (de) 2019-09-18
US9751855B2 (en) 2017-09-05
ZA200701996B (en) 2008-08-27
EP3029040A1 (de) 2016-06-08
JP2011201908A (ja) 2011-10-13
ES2731334T3 (es) 2019-11-15
DK2287164T5 (da) 2014-07-14
US20060142310A1 (en) 2006-06-29
EA016752B1 (ru) 2012-07-30
TW200621776A (en) 2006-07-01
DK2287164T3 (da) 2014-03-10
RS53166B (en) 2014-06-30
IL211015A0 (en) 2011-04-28
JP2008519005A (ja) 2008-06-05
PT2287164E (pt) 2014-03-17
KR101583264B1 (ko) 2016-01-11
US20090192314A1 (en) 2009-07-30
CY1115036T1 (el) 2016-12-14
US20170029402A1 (en) 2017-02-02
KR101383610B1 (ko) 2014-04-10
EP2287164B1 (de) 2014-01-22
CN102127080B (zh) 2016-01-20
US20130178485A1 (en) 2013-07-11
JP5766661B2 (ja) 2015-08-19
AR051947A1 (es) 2007-02-21
HRP20140373T1 (en) 2014-05-23

Similar Documents

Publication Publication Date Title
CN102432593A (zh) 光学活性的3-(邻苯二甲酰亚氨基)哌啶及其制备方法
CN102812019B (zh) 制备拉帕替尼的方法和中间体
CN101426783B (zh) 作为11-β-羟基甾族化合物脱氢酶1的抑制剂的环己基吡唑-内酰胺衍生物
CN101432263B (zh) 作为11-β-羟类固醇脱氢酶1抑制剂的取代的吡咯烷酮类
CN100376557C (zh) 作为神经肽y受体的配体的喹啉衍生物
CN101454310B (zh) 11-β-羟类固醇脱氢酶1的抑制剂
CN102985416B (zh) 制备凝血酶特异性抑制剂的方法
CN101993406B (zh) 光学活性的吲哚啉化合物及其制备方法
CN109096171B (zh) 制备氘代二苯基脲的方法
CN102863359B (zh) 一种抗流感药物的合成方法
CN104262264B (zh) 一种盐酸乌拉地尔的制备工艺
WO2007146202A2 (en) Succinate salts of 6-methoxy-8-[4-(1-(5-fluoro)-quinolin-8-yl-piperidin-4-yl)-piperazin-1-yl]-quinoline and crystalline forms thereof
CN102516236B (zh) 抗精神分裂症药物伊潘立酮的制备方法
TW201936603A (zh) 唑啶酮化合物之製造方法
CN105523999A (zh) 一种达比加群酯中间体的合成方法
CN103242291A (zh) 一种多晶型高含量苯甲酸阿格列汀的批量生产工艺
CN100545148C (zh) 一种抗良性前列腺肥大药物坦索罗辛之合成方法
KR101001646B1 (ko) (ｒ)-(+)-란소프라졸의 제조방법 및 이에 사용되는 중간체
CN110590780A (zh) 治疗糖尿病的药物利拉利汀的制备方法
JP4796622B2 (ja) （３，４−ジヒドロ−キナゾリン−２−イル）−インダン−１−イル−アミン
CN104418845B (zh) 制备拉帕替尼的方法和中间体
WO2000050416A1 (fr) Derives d'acide heteroquinolinecarboxylique 6-substitues et sels d'addition associes, et procedes de preparation de ces derives et de leurs sels
CN107652269A (zh) 甲磺酸氟马替尼中间体纯化方法
JP3985121B2 (ja) ジヒドロキノリン誘導体
WO2016000230A1 (zh) 一种达比加群酯中间体的制备方法及中间体化合物

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
REG Reference to a national code

Ref country code: HK

Ref legal event code: DE

Ref document number: 1169983

Country of ref document: HK

C53 Correction of patent of invention or patent application
CB02 Change of applicant information

Address after: In Germany

Applicant after: Boehringer Ingelheim Int

Address before: In Germany

Applicant before: Boehringer Ingelheim International GmbH

RJ01 Rejection of invention patent application after publication
RJ01 Rejection of invention patent application after publication

Application publication date: 20120502