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Europäisches Patentamt *EP001553091A1* (19) European Patent Office Office européen des brevets (11) EP 1 553 091 A1 (12) EUROPEAN PATENT APPLICATION published in accordance with Art. 158(3) EPC (43) Date of publication: (51) Int Cl.7: C07D 263/32, C07D 417/14, 13.07.2005 Bulletin 2005/28 C07D 333/20, C07D 413/12, C07D 417/06 (21) Application number: 04726765.3 (86) International application number: (22) Date of filing: 09.04.2004 PCT/JP2004/005119 (87) International publication number: WO 2004/089918 (21.10.2004 Gazette 2004/43) (84) Designated Contracting States: • SAKAMOTO, Johei AT BE BG CH CY CZ DE DK EE ES FI FR GB GR Takatsuki-shi, Osaka 569-1125 (JP) HU IE IT LI LU MC NL PL PT RO SE SI SK TR • NAKANISHI, Hiroyuki Designated Extension States: Takatsuki-shi, Osaka 569-1125 (JP) AL HR LT LV MK • NAKAGAWA, Yuichi Takatsuki-shi, Osaka 569-1125 (JP) (30) Priority: 09.04.2003 JP 2003105267 • OHTA, Takeshi 03.06.2003 JP 2003157590 Takatsuki-shi, Osaka 569-1125 (JP) • SAKATA, Shohei (71) Applicant: Japan Tobacco Inc. Takatsuki-shi, Osaka 569-1125 (JP) Tokyo 105-8422 (JP) • MORINAGA, Hisayo Takatsuki-shi, Osaka 569-1125 (JP) (72) Inventors: • IKEMOTO, Tomoyuki (74) Representative: Takatsuki-shi, Osaka 569-1125 (JP) von Kreisler, Alek, Dipl.-Chem. et al • TANAKA, Masahiro Deichmannhaus am Dom, Takatsuki-shi, Osaka 569-1125 (JP) Postfach 10 22 41 • YUNO, Takeo 50462 Köln (DE) Takatsuki-shi, Osaka 569-1125 (JP) (54) HETEROAROMATIC PENTACYCLIC COMPOUND AND MEDICINAL USE THEREOF (57) A 5-membered heteroaromatic ring compound represented by the formula [I] 1 2 4 5 7 wherein V is CH or N; W is S or O; R and R are each H etc.; X is -N(R )-, -O-, -S-, -SO2-N(R )-, -CO-N(R )- etc.; L is EP 1 553 091 A1 Printed by Jouve, 75001 PARIS (FR) (Cont. next page) EP 1 553 091 A1 wherein R20,R21,R22 and R25 are each H etc.; E is aryl or heteroaromatic ring group; R is -COOH etc.; B is aryl etc.; R3 is H etc.; Y is -C(R13)(R14)-N(R12)-, -C(R13)(R14)-O-, -N(R11)-, -O- etc.; A is alkylene; and Z is aryl etc., a prodrug thereof and a pharmaceutically acceptable salt thereof. The compound [I] has a superior protein tyrosine phosphatase 1B inhibitory activity and is useful as a therapeutic agent for diabetes, diabetic complications, hyperlipidemia, obesity and the like. 2 EP 1 553 091 A1 Description TECHNICAL FIELD OF THE INVENTION 5 [0001] The present invention relates to a novel 5-membered heteroaromatic ring compound. More particularly, the present invention relates to a 5-membered heteroaromatic ring compound having a protein tyrosine phosphatase 1B (PTP1B) inhibitory activity, a pharmaceutically acceptable salt thereof, and a pharmaceutical composition containing the same. 10 BACKGROUND OF THE INVENTION [0002] Diabetes causes various dysbolisms mainly characterized by a chronic hyperglycemic state. It shows a broad range of symptoms based on hyperglycemia, such as mouth dryness, polydipsia, diuresis, loss of body weight and the like. When such a state of hyperglycemia lasts for a long time, it is known to cause all kinds of complications such as 15 retinopathy, nephropathy, neuropathy, cardiac infarction and cerebral infarction based on arteriosclerosis, and the like. [0003] Diabetes is generally classified into four types: type I diabetes (IDDM; insulin dependent diabetes mellitus) accompanying absolute insulin deficiency due to damage or destruction of β cell of pancreas; type II diabetes (NIDDM; non-insulin dependent diabetes mellitus) accompanying relative insulin deficiency due to insulin resistance and de- creased insulin secretion; special diabetes secondarily developed by abnormality in gene, other diseases and the like; 20 and gestational diabetes. In some cases, patients diagnosed with type II diabetes shortly after the onset may come to show decreased insulin secretion with the progression of the disease and ultimately lead to type I diabetes. [0004] To treat diabetes, it is essential to improve the above-mentioned hyperglycemic conditions and prevent the onset and progression of complications. For this end, there have been tried diet therapy, exercise therapy and the like, as well as treatments using a variety of pharmaceutical agents with the aim of controlling the blood glucose level to 25 be within the normal range. As the representative existing pharmaceutical agents, there are mentioned insulin prepa- rations, insulin secretagogues (sulfonylurea agent, sulfonamide agent, phenylalanine derivative etc.) that promote in- sulin secretion from β cell of pancreas, α-glucosidase inhibitors that delay sugar absorption, biguanide agents consid- ered to have a liver glyconeogensis inhibitory action, wherein the detail of the mechanism is unknown, insulin sensitizers (thiazolidinedione derivative etc.) that promote differentiation from fibroblast to adipose cell via a peroxisome prolifer- 30 ator-activated receptor (PPAR) agonist action to increase the number of insulin sensitive cells and the like. However, all these are problematic in terms of effectiveness and safety (e.g., secondary failure due to fatigue of pancreatic β cell, risk of hypoglycemia and promotion of obesity associated with insulin secretagogue, edema and adverse influence on the heart based thereon, anemia, overeating, promotion of obesity, presence of non-responder associated with insulin sensitizer and the like) and they fail to achieve sufficient control of blood glucose. 35 [0005] Referring to glucose metabolism in living organism, materials to be the energy source and constituent com- ponents of living organism have been intermittently taken into the body and, for example, brain continuously consumes glucose. In this situation, the blood glucose level is maintained at a constant level, and blood glucose control is enabled by hormone involved in the blood glucose control, metabolism in organ and interaction for exchange of saccharide and the like between organs. Of these, the action of insulin, which is a hormone particularly responsible for the blood 40 glucose control, is significant and disorder thereof, or lower insulin resistance and decreased insulin secretion are considered to be deeply involved in diabetes. [0006] Insulin is secreted from β cell of pancreas, binds with insulin receptor, which is a receptor type tyrosine kinase present on the membrane surface of its target cell or skeletal muscle cell and adipose cell, after which the tyrosine residue in the intracellular domain is self-phosphorylated. Thereafter, the tyrosine residue such as IRS (insulin receptor 45 substrate), APS (adapter protein containing PH and SH2 domain) and the like, which is a substrate of an insulin receptor, is phosphorylated and PI3 kinase-Akt path is activated, which in turn transfers a glucose transporter onto the cell membrane, causing glucose uptake and decreased blood glucose concentration. On the other hand, tyrosine phos- phatase is also present, which performs tyrosine dephosphorylation to negatively control intracellular signaling by insulin, thereby suppressing the activation. As mentioned above, tyrosine phosphorylation plays a major role in the 50 action of insulin. In consideration of the fact that tyrosine phosphorylation is determined by the balance of the activity of tyrosine kinase (phosphorylation enzyme) and that of tyrosine phosphatase (dephosphorylation enzyme), tyrosine phosphatase is considered to directly play a significant role in controlling insulin signaling together with tyrosine kinase. [0007] At present, tyrosine phosphatase forms a large gene family, and more than seven dozen kinds of isozymes have been reported. Of these, protein tyrosine phosphatase 1B (PTP1B) is considered to be a major phosphatase 55 involved in insulin signaling. Particularly, because gene expression of PTP1B increases in high glucose culture and changes in intracellular localization thereof decreases tyrosine phosphorylation of insulin receptor and IRS-1 and in- duces insulin resistance (J. Biol. Chem., 1995, Vol. 270, pp. 7724-7730; J. Biochem. (Tokyo), 1998, Vol. 123, pp. 813-820), introduction of wild type PTP1B inhibits translocation of glucose transporter GLUT4, such effect was not 3 EP 1 553 091 A1 found in phosphatase activity defective mutants, and insulin sensitivity was enhanced in PTP1B knockout mice and the mice became obesity resistant to a high fat diet (Science, 1999, Vol. 283, pp. 1544-1548), there is a possibility that this enzyme may become one target to enhance the action of from activation of insulin receptor to glucose uptake that insulin is responsible for. In fact, vanadic acid conventionally known as a tyrosine phosphatase inhibitor shows an 5 insulin-like action in animal tests and the like. [0008] Accordingly, a drug that suppresses and/or inhibits activation of such tyrosine phosphatase, particularly PTP1B, enhances the action up to glucose uptake by inhibiting an insulin receptor activated signal from being negatively controlled through dephosphorylation, and can be a new type of therapeutic agent for diabetes, which decreases blood glucose based on direct enhancement of insulin action. In addition, application to various therapeutic agents for dis- 10 eases such as obesity, neurodegenerative disease and the like is expected. [0009] There are various reports in recent years on compounds aiming at treatment of diseases, such as diabetes and the like, by inhibiting such protein tyrosine phosphatase. [0010] For example, WO00/17211 discloses a phosphonic acid derivative having a PTP1B inhibitory activity. How- ever, this publication does not disclose
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    US008158152B2 (12) United States Patent (10) Patent No.: US 8,158,152 B2 Palepu (45) Date of Patent: Apr. 17, 2012 (54) LYOPHILIZATION PROCESS AND 6,884,422 B1 4/2005 Liu et al. PRODUCTS OBTANED THEREBY 6,900, 184 B2 5/2005 Cohen et al. 2002fOO 10357 A1 1/2002 Stogniew etal. 2002/009 1270 A1 7, 2002 Wu et al. (75) Inventor: Nageswara R. Palepu. Mill Creek, WA 2002/0143038 A1 10/2002 Bandyopadhyay et al. (US) 2002fO155097 A1 10, 2002 Te 2003, OO68416 A1 4/2003 Burgess et al. 2003/0077321 A1 4/2003 Kiel et al. (73) Assignee: SciDose LLC, Amherst, MA (US) 2003, OO82236 A1 5/2003 Mathiowitz et al. 2003/0096378 A1 5/2003 Qiu et al. (*) Notice: Subject to any disclaimer, the term of this 2003/OO96797 A1 5/2003 Stogniew et al. patent is extended or adjusted under 35 2003.01.1331.6 A1 6/2003 Kaisheva et al. U.S.C. 154(b) by 1560 days. 2003. O191157 A1 10, 2003 Doen 2003/0202978 A1 10, 2003 Maa et al. 2003/0211042 A1 11/2003 Evans (21) Appl. No.: 11/282,507 2003/0229027 A1 12/2003 Eissens et al. 2004.0005351 A1 1/2004 Kwon (22) Filed: Nov. 18, 2005 2004/0042971 A1 3/2004 Truong-Le et al. 2004/0042972 A1 3/2004 Truong-Le et al. (65) Prior Publication Data 2004.0043042 A1 3/2004 Johnson et al. 2004/OO57927 A1 3/2004 Warne et al. US 2007/O116729 A1 May 24, 2007 2004, OO63792 A1 4/2004 Khera et al.