발생일자 2014.12.09 

사건번호 1:14-cv-01469 

법원국가 UNITED STATES OF AMERICA 

관할법원명 D.C.Delaware(지방법원) 

침해권리 특허 

원고명 Astrazeneca AB ( 스웨덴 / 외국기업 )  

피고명 Aurobindo Pharma Ltd./ Aurobindo Pharma USA, Inc. ( 인도 / 외국기업 )  

소송유형 침해금지 

[Astrazeneca AB v. Aurobindo Pharma Ltd. et al] 사건번호 1:14-cv-01469에 따르면 원고 Astrazeneca AB는 피고 Aurobindo Pharma Ltd./ Aurobindo Pharma USA, Inc.을 상대로 특허 USRE44186, US6395767, US7951400을 침해하였다는 이유로 미국 델라웨어 지방법원에 소를 제기하였다. 

분쟁결과 분쟁중 

산업분류 화학∙바이오 > 의약품 

계쟁제품 generic versions of ONGLYZA drug product, generic axagliptin hydrochloride tablets 

지재권번호/명칭

USRE44186   Cyclopropyl-fused pyrrolidine-based inhibitors of dipeptidyl peptidase IV and method 

 US6395767   Cyclopropyl-fused pyrrolidine-based inhibitors of dipeptidyl peptidase IV and method 

 US7951400   Coated tablet formulation and method 

Cyclopropyl-fused pyrrolidine-based inhibitors of dipeptidyl peptidase IV and method 

Dipeptidyl peptidase IV (DP 4) inhibiting compounds are provided having the formula ##STR00001## where x is 0 or 1 and y is 0 or 1 (provided that x=1 when y=0 and x=0 when y=1); n is 0 or 1; X is H or CN; and wherein R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are as described herein. A method is also provided for treating diabetes and related diseases, especially Type II diabetes, and other diseases as set out herein, employing such DP 4 inhibitor *or a combination of such DP 4 inhibitor and one or more of another antidiabetic agent such as metformin, glyburide, troglitazone, pioglitazone, rosiglitazone and/or insulin and/or one or more of a hypolipidemic agent and/or anti-obesity agent and/or other therapeutic agent. 

Claims

What is claimed is: 

 1. A compound having the structure ##STR00214## wherein x is 0 or 1 and y is 0 or 1, provided that x=1 when y=0 and x=0 when y=1; and wherein n is 0 or 1; X is H or CN; R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are the same or different and are independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, bicycloalkyl, tricycloalkyl, alkylcycloalkyl, hydroxyalkyl, hydroxyalkylcycloalkyl, hydroxycycloalkyl, hydroxybicycloalkyl, hydroxytricycloalkyl, bicycloalkylalkyl, alkylthioalkyl, arylalkylthioalkyl, cycloalkenyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, cycloheteroalkyl or cycloheteroalkylalkyl; all optionally substituted through available carbon atoms with 1, 2, 3, 4 or 5 groups selected from hydrogen, halo, alkyl, polyhaloalkyl, alkoxy, haloalkoxy, polyhaloalkoxy, alkoxycarbonyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, heteroarylamino, arylamino, cycloheteroalkyl, cycloheteroalkylalkyl, hydroxy, hydroxyalkyl, nitro, cyano, amino, substituted amino, alkylamino, dialkylamino, thiol, alkylthio, alkylcarbonyl, acyl, alkoxycarbonyl, aminocarbonyl, alkynylaminocarbonyl, alkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, alkylsulfonylamino, alkylaminocarbonylamino, alkoxycarbonylamino, alkylsulfonyl, aminosulfinyl, aminosulfonyl, alkylsulfinyl, sulfonamido or sulfonyl; and R.sup.1 and R.sup.3 may optionally be taken together to form --(CR.sup.5R.sup.6).sub.m-- where m is 2 to 6, and R.sup.5 and R.sup.6 are the same or different and are independently selected from hydroxy, alkoxy, H, alkyl, alkenyl, alkynyl, cycloalkyl, halo, amino, substituted amino, cycloalkylalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl, alkylcarbonylamino, arylcarbonylamino, alkoxycarbonylamino, aryloxycarbonylamino, alkoxycarbonyl, aryloxycarbonyl, or alkylaminocarbonylamino, or R.sup.1 and R4 may optionally be taken together to form --(CR.sup.7R.sup.8).sub.p-- wherein p is 2 to 6, and R.sup.7 and R.sup.8 are the same or different and are independently selected from hydroxy, alkoxy, cyano, H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, halo, amino, substituted amino, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl, alkylcarbonylamino, arylcarbonylamino, alkoxycarbonylamino, aryloxycarbonylamino, alkoxycarbonyl, aryloxycarbonyl, or alkylaminocarbonylamino, or optionally R.sup.1 and R.sup.3 together with ##STR00215## form a 5 to 7 membered ring containing a total of 2 to 4 heteroatoms selected from N, O, S, SO, or SO.sub.2; or optionally R.sup.1 and R.sup.3 together with ##STR00216## form a 4 to 8 membered cycloheteroalkyl ring wherein the cycloheteroalkyl ring has an optional aryl ring fused thereto or an optional 3 to 7 membered cycloalkyl ring fused thereto; with the proviso that where x is 1 and y is 0, X is H, n is o, and one of R.sup.1 and R.sup.2 is H and the other is alkyl, then R.sup.3 is other than pyridyl or substituted pyridyl; including all stereoisomers thereof; .[.and.]. .Iadd.or .Iaddend.a pharmaceutically acceptable salt thereof.[., or a prodrug ester thereof.]., and all stereoisomers thereof. 

 2. The compound as defined in claim 1 having the structure: ##STR00217## 

 3. The compound as defined in claim 1 having the structure: ##STR00218## 

 4. The compound as defined in claim 1 having the structure: ##STR00219## 

 5. The compound as defined in claim 1 having the structure: ##STR00220## 

 6. The compound as defined in claim 1 wherein: R.sup.3 is H, R.sup.1 is H, alkyl, cycloalkyl, bicycloalkyl, tricycloalkyl, alkylcycloalkyl, hydroxyalkyl, hydroxyalkylcycloalkyl, hydroxycycloalkyl hydroxybicycloalkyl, or hydroxytricycloalkyl, R.sup.2 is H or alkyl, n is 0, X is CN. 

 7. The compound as defined in claim 1 wherein the cyclopropyl fused to the pyrrolidine has the configuration: ##STR00221## 

 8. A compound having the structure: ##STR00222## or a pharmaceutically acceptable salt thereof. 

 9. The compound as defined in claim 8 wherein the pharmaceutically acceptable salt is the hydrochloride salt or the trifluoroacetic acid salt. 

 10. A compound which is ##STR00223## wherein R.sup.1 is alkyl, cycloalkyl, bicycloalkyl, tricycloalkyl, alkylcycloalkyl, hydroxyalkyl, hydroxycycloalkyl, hydroxyalkylcycloalkyl, hydroxybicycloalkyl, or hydroxytricycloalkyl, or ##STR00224## wherein R.sup.1 is alkyl, cycloalkyl, bicycloalkyl, tricycloalkyl, alkylcycloalkyl, hydroxyalkyl, hydroxycycloalkyl, hydroxyalkylcycloalkyl, hydroxybicycloalkyl, or hydroxytricycloalkyl. 

 11. A pharmaceutical composition comprising a compound as defined in claim 1 and a pharmaceutically acceptable carrier therefor. 

 12. A pharmaceutical combination comprising a .[.DP4 inhibitor.]. compound as defined in claim 1 and an antidiabetic agent other than a DP4 inhibitor for treating diabetes and related diseases, an anti-obesity agent and/or a lipid-modulating agent. 

 13. The pharmaceutical combination as defined in claim 12 comprising said .[.DP4 inhibitor.]. compound .Iadd.as defined in claim 1 .Iaddend.and .[.an.]. .Iadd.the .Iaddend.antidiabetic agent .Iadd.other than a DP4 inhibitor.Iaddend.. 

 14. The combination as defined in claim 13 wherein the antidiabetic agent is 1, 2, 3 or more of a biguanide, a sulfonyl urea, a glucosidase inhibitor, a PPAR .gamma. agonist, a PPAR .alpha./.gamma. dual agonist, an SGLT2 inhibitor, an aP2 inhibitor, a glycogen phosphorylase inhibitor, an AGE inhibitor, an insulin sensitizer, a glucagon-like peptide-1 (GLP-1) or mimetic thereof, insulin and/or a meglitinide. 

 15. The combination as defined in claim 14 wherein the antidiabetic agent is 1, 2, 3 or more of metformin, glyburide, glimepiride, glipyride, glipizide, chlorpropamide, gliclazide, acarbose, miglitol, pioglitazone, troglitazone, rosiglitazone, insulin, G1 -262570, isaglitazone, JTT-501, NN-2344, L895645, YM-440, R-119702, AJ9677, repaglinide, nateglinide, KAD1129, AR-HO39242, GW-409544, KRP297, AC2993, Exendin-4, LY307161, NN2211, and/or LY315902. 

 16. The combination as defined in claim 13 wherein the compound .Iadd.as defined in claim 1 .Iaddend.is present in a weight ratio to the antidiabetic agent within the range from about 0.01 to about 100:1. 

 17. The combination as defined in claim 12 wherein the anti-obesity agent is a beta 3 adrenergic agonist, a lipase inhibitor, .[.a serotonin (and dopamine) reuptake inhibitor,.]. a thyroid receptor beta compound, an anorectic agent, and/or a fatty acid oxidation upregulator. 

 18. The combination as defined in claim 17 wherein the anti-obesity agent is orlistat, ATL-962, AJ9677, L750355, CP331648, sibutramine, topiramate, axokine, dexamphetamine, phentermine, phenylpropanolamine, famoxin, and/or mazindol. 

 19. The combination as defined in claim 12 wherein the lipid modulating agent is an MTP inhibitor, an HMG CoA reductase inhibitor, a squalene synthetase inhibitor, a fibric acid derivative, an upregulator of LDL receptor activity, a lipoxygenase inhibitor, an ACAT inhibitor, a cholesteryl ester transfer protein inhibitor, or an ATP citrate lyase inhibitor. 

 20. The combination as defined in claim 19 wherein the lipid modulating agent is pravastatin, lovastatin, simvastatin, atorvastatin, cerivastatin, fluvastatin, nisvastatin, visastatin, fenofibrate, gemfibrozil, clofibrate, implitapide, CP-529, 414, avasimibe, TS-962, MD-700, and/or LY295427. 

 21. The combination as defined in claim 19 wherein the .[.DP4 inhibitor.]. .Iadd.compound as defined in claim 1 .Iaddend.is present in a weight ratio to the lipid-modulating agent within the range from about 0.01 to about 100:1. 

 22. A pharmaceutical combination comprising a .[.DP4 inhibitor.]. compound as defined in claim 1 and an agent for treating infertility, an agent for treating polycystic ovary syndrome, an agent for treating a growth disorder and/or frailty, an anti-arthritis agent, an agent for preventing .Iadd.or .Iaddend.inhibiting allograft rejection in transplantation, an agent for treating autoimmune disease, an anti-AIDS agent, an agent for treating inflammatory bowel disease/syndrome, an agent for treating anorexia nervosa, an anti-osteoporosis agent and/or an anti-obesity agent. 

 .[.23. A method for treating diabetes, insulin resistance, hyperglycemia, hyperisulinemia, or elevated blood levels of free fatty acids or glycerol, obesity, Syndrome X, dysmetabolic syndrome, diabetic complications, hypertriglyceridemia, hyperinsulinemia, atherosclerosis, impaired glucose homeostasis, impaired glucose tolerance, infertility, polycystic ovary syndrome, growth disorders, frailty, arthritis, allograft rejection in transplantation, autoimmune diseases, AIDS, intestinal diseases, inflammatory bowel syndrome, nervosa, osteoporosis, or an immunomodulatory disease or a chronic inflammatory bowel disease, which comprises administering to a mammalian species in need of treatment a therapeutically effective amount of a compound as defined in claim 1..]. 

 .[.24. The method as defined in claim 23 for treating type II diabetes and/or obesity..]. 

 .Iadd.25. A compound that is ##STR00225## or a pharmaceutically acceptable salt thereof..Iaddend. 

 .Iadd.26. The compound as defined in claim 25, wherein the pharmaceutically acceptable salt is the hydrochloride salt..Iaddend. 

 .Iadd.27. A pharmaceutical composition comprising the compound of claim 25 and a pharmaceutically acceptable carrier therefor..Iaddend. 

 .Iadd.28. A pharmaceutical composition comprising the compound of claim 26 and a pharmaceutically acceptable carrier therefor..Iaddend. 

 .Iadd.29. The composition of claim 27 or 28 further comprising an antidiabetic agent other than a DP4 inhibitor..Iaddend. 

 .Iadd.30. The composition of claim 29 wherein the antidiabetic agent is metformin..Iaddend. 

 .Iadd.31. The composition of claim 29, wherein the antidiabetic agent is a SGLT2 inhibitor..Iaddend. 

 .Iadd.32. A method for treating diabetes, insulin resistance, hyperglycemia, hyperinsulinemia, impaired glucose homeostasis, or impaired glucose tolerance in a mammal comprising administering to the mammal a pharmaceutical composition comprising a compound that is ##STR00226## or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier therefor..Iaddend. 

 .Iadd.33. The method of claim 32, wherein the pharmaceutically acceptable salt is the hydrochloride salt..Iaddend. 

 .Iadd.34. The method of claim 32, for treating diabetes..Iaddend. 

 .Iadd.35. The method of claim 33, for treating diabetes..Iaddend. 

 .Iadd.36. The method of any one of claim 32, 33, 34, or 35 wherein the pharmaceutical composition further comprises an antidiabetic agent other than a DP4 inhibitor..Iaddend. 

 .Iadd.37. The method of claim 36, wherein the antidiabetic agent is metformin..Iaddend. 

 .Iadd.38. The method of claim 36, wherein the antidiabetic agent is a SGLT2 inhibitor..Iaddend. 

 .Iadd.39. A method for treating type II diabetes in a mammal comprising administering to the mammal a pharmaceutical composition comprising a compound that is ##STR00227## or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier therefor..Iaddend. 

 .Iadd.40. The method of claim 39, wherein the pharmaceutically acceptable salt is the hydrochloride salt..Iaddend. 

 .Iadd.41. The method of any one of claims 39 or 40, wherein the pharmaceutical composition further comprises an antidiabetic agent other than a DP4 inhibitor..Iaddend. 

 .Iadd.42. The method of claim 41, wherein the antidiabetic agent is metformin..Iaddend. 

 .Iadd.43. The method of claim 41, wherein the antidiabetic agent is a SGLT2 inhibitor..Iaddend. 

A coated tablet formulation is provided which includes a medicament such as the DPP4-inhibitor, saxaglipitin ##STR00001## or its HCl salt, which is subject to intra-molecular cyclization, which formulation includes a tablet core containing one or more fillers, and other conventional excipients, which tablet core includes a coating thereon which may include two or more layers, at least one layer of which is an inner seal coat layer which is formed of one or more coating polymers, a second layer of which is formed of medicament which is the DPP4-inhibitor and one or more coating polymers, and an optional, but preferable third outer protective layer which is formed of one or more coating polymers. A method for forming the coated tablet is also provided. 

What is claimed is: 

 1. A coated tablet comprising (a) a tablet core; (b) an inner seal coating layer coated on the tablet core wherein the inner seal coating layer comprises about 1 mg to about 100 mgs of a polyvinyl alcohol based formulation wherein the polyvinyl alcohol based formulation comprises polyvinyl alcohol; (c) a second coating layer coated on the inner seal coating of the tablet core, wherein the second coating layer comprises about 0.2 mgs to about 140 mgs of saxagliptin, or a pharmaceutically acceptable salt thereof, and about 2 mgs to about 140 mgs of a polyvinyl alcohol based formulation wherein the polyvinyl alcohol based formulation comprises polyvinyl alcohol; and (d) an outer protective coating layer coated on the second coating layer of the tablet core wherein the outer protective coating layer comprises about 1 mg to about 100 mgs of a polyvinyl alcohol based formulation wherein the polyvinyl alcohol based formulation comprises polyvinyl alcohol. 

 2. The coated tablet as defined in claim 1 wherein the tablet core is comprised of one or more fillers, optionally one or more binders, optionally one or more disintegrants and optionally one or more tableting lubricants. 

 3. The coated tablet as defined in claim 2 wherein the tablet core is comprised of microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, and magnesium stearate. 

 4. The coated tablet as defined in claim 1 having the following composition: TABLE-US-00009 Range % by weight for Tablet Core 200 mg tablet core Lactose 20 to 75%/40 to 150 mg Microcrystalline cellulose 20 to 75%/40 to 150 mg Croscarmellose sodium 2 to 10%/4 to 20 mg Magnesium Stearate 0.2 to 2%/0.4 to 4 mg 

 TABLE-US-00010 % by weight of 200 Inner Seal Coating Layer mg tablet core Polyvinyl Alcohol Based Formulation 1 to 3%/2 to 6 mg and optional plazticizer and glidants 

 TABLE-US-00011 % by weight of 200 mg Second Coating Layer tablet core Polyvinyl Alcohol Based Formulation 0.25 to 70%/0.5 to 140 mg and optional plazticizer and glidants 1 to 50%/2 to 100 mg 

 TABLE-US-00012 % by weight of 200 mg Outer Protective Coating Layer tablet core Polyvinyl Alcohol Based Formulation 1 to 5%/2 to 10 mg and optional plazticizer, glidants and color. 

 5. The coated tablet as defined in claim 1 where for a 5 mg potency the second coating layer is comprised of 5 mg saxagliptin, and at least 5 mg polyvinyl alcohol based formulation and for a 2.5 mg potency the second coating layer is comprised of 2.5 mg saxagliptin, and 20 mg polyvinyl alcohol based formulation. 

 6. A coated tablet comprising: a) a tablet core comprising about 49.5% lactose monohydrate, about 45% microcrystalline cellulose, about 5% croscarmellose sodium, and about 0.5% magnesium stearate; b) an inner seal coating layer coated on the tablet core, wherein the inner seal coating layer comprises about 40% polyvinyl alcohol, about 20% polyethylene glycol, about 15% talc, and about 25% titanium dioxide; c) a second coating layer coated on the inner seal coating of the tablet core, wherein the second coating layer comprises saxagliptin or a pharmaceutically acceptable salt thereof, polyvinyl alcohol, polyethylene glycol, talc, and titanium dioxide; and d) optionally an outer protective coating layer coated on the second coating layer of the tablet core, wherein the outer protective coating comprises polyvinyl alcohol, polyethylene glycol, talc, and titanium dioxide. 

 7. The coated tablet as defined in claim 6 wherein the second coating layer comprises saxagliptin or a pharmaceutically acceptable salt thereof, and a coating material comprising about 40% polyvinyl alcohol, about 20% polyethylene glycol, about 15% talc, and about 25% titanium dioxide. 

 8. The coated tablet as defined in claim 7 wherein the outer protective coating layer comprises about 40% polyvinyl alcohol, about 20% polyethylene glycol, about 15% talc, and about 25% titanium dioxide. 

 9. The coated tablet as defined in claim 8 wherein saxagliptin is the hydrochloride salt. 

 10. The coated tablet as defined in claim 1 wherein saxagliptin is the hydrochloride salt.