(19) TZZ Z _T (11) EP 2 059 522 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: C07F 9/32 (2006.01) C07F 9/40 (2006.01) 08.01.2014 Bulletin 2014/02 A61K 31/675 (2006.01) A61P 3/00 (2006.01) (21) Application number: 07812578.8 (86) International application number: PCT/US2007/072708 (22) Date of filing: 03.07.2007 (87) International publication number: WO 2008/005964 (10.01.2008 Gazette 2008/02) (54) PHOSPHONATE AND PHOSPHINATE COMPOUNDS AS GLUCOKINASE ACTIVATORS PHOSPHONAT- UND PHOSPHINATVERBINDUNGEN ALS GLUCOKINASE-AKTIVATOREN DERIVES DE PHOSPHONATE ET DE PHOSPHINATE EN TANT QU’ACTIVATEURS DE LA GLUCOKINASE (84) Designated Contracting States: (74) Representative: Beacham, Annabel Rose AT BE BG CH CY CZ DE DK EE ES FI FR GB GR Dehns HU IE IS IT LI LT LU LV MC MT NL PL PT RO SE St Bride’s House SI SK TR 10 Salisbury Square Designated Extension States: London HR EC4Y 8JD (GB) (30) Priority: 06.07.2006 US 818912 P (56) References cited: 28.06.2007 US 769964 EP-A- 1 074 556 WO-A-2004/013139 WO-A2-2006/063194 (43) Date of publication of application: 20.05.2009 Bulletin 2009/21 • HOLY A ET AL: "SYNTHESIS OF N-(2- PHOSPHONYLMETHOXYETHYL) DERIVATIVES (73) Proprietor: Bristol-Myers Squibb Company OF HETEROCYCLIC BASES" COLLECTION OF Princeton, NJ 08543-4000 (US) CZECHOSLOVAK CHEMICAL COMMUNICATIONS, INSTITUTE OF ORGANIC (72) Inventors: CHEMISTRY & BIOCHEMISTRY, PRAGUE, CZ, • RYONO, Dennis E. vol. 54, no. 8, 1989, pages 2190-2210, Princeton, NJ 08540 (US) XP008046015 ISSN: 0010-0765 • CHENG, Peter T.W. • ENDOVA M ET AL: "TRANSPROTECTION OF N- Pennington, NJ 08534 (US) BENZOYLATED NUCLEOBASE DERIVATIVES •BOLTON,Scott A. BY DIALKYLAMINOMETHYLENE GROUP" Pennington, NJ 08534 (US) NUCLEOSIDES & NUCLEOTIDES, MARCEL • CHEN, Sean S. DEKKER, INC, US, vol. 16, no. 12, 1997, pages Pennington, NJ 08534 (US) 2151-2164, XP000876719 ISSN: 0732-8311 • SHI, Yan • BABOULENE M ET AL: "Reactivity of diethyl 3- Pennington, NJ 08534 (US) bromo-2-oxopropylphosphonate in the Hantzsch •MENG,Wei reaction.(Reactivite du bromo-3 oxo-2 propyl Pennington, NJ 08534 (US) phosphonate de diethyle dans la reaction de • TINO, Joseph A. hantzsch)" PHOSPHORUS AND SULFUR AND Pennington, NJ 08534 (US) THE RELATED ELEMENTS, GORDON AND • ZHANG, Hao BREACH - HARWOOD ACADEMIC, CH, vol. 5, no. Pennington, NJ 08534 (US) 1, 1978, pages 87-94, XP009093025 ISSN: • SULSKY, Richard B. 0308-664X Pennington, NJ 08534 (US) Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 2 059 522 B1 Printed by Jouve, 75001 PARIS (FR) (Cont. next page) EP 2 059 522 B1 • ROSENBERG I ET AL: "Acyclic nucleotide • DANG Q: "Organophosphonic acids as drug analogs. IV. Phosphonylmethoxyalkyl and candidates", EXPERT OPINION ON phosphonylalkyl derivatives of adenine" THERAPEUTIC PATENTS 200603 GB LNKD- DOI: COLLECTION OF CZECHOSLOVAK CHEMICAL 10.1517/13543776.16.3.343, vol. 16, no. 3, March COMMUNICATIONS, INSTITUTE OF ORGANIC 2006 (2006-03), pages 343-348, ISSN: 1354-3776 CHEMISTRY & BIOCHEMISTRY, PRAGUE, CZ, vol. 53, 1988, pages 2753-2777, XP002116171 ISSN: 0010-0765 • RUMTHAO S ET AL: "Design, synthesis, and evaluation of oxyanion-hole selective inhibitor substituents for the S1 subsite of factor Xa" BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, OXFORD, GB, vol. 14, no. 20, 18 October 2004 (2004-10-18), pages 5165-5170, XP004565453 ISSN: 0960-894X 2 EP 2 059 522 B1 Description FIELD OF THE INVENTION 5 [0001] The present invention relates to novel phosphonate and phosphinate compounds which are activators of the enzyme glucokinase and thus are useful in treating diabetes, and to such compounds for use in treating diabetes, especially Type II diabetes. BACKGROUND OF THE INVENTION 10 [0002] The enzyme glucokinase (GK), which is mainly found in pancreatic β-cells and liver parenchymal cells, catalyzes the conversion of glucose to glucose-6-phosphate, which is the first step in the metabolism of glucose. Glucokinase is also a rate-controlling enzyme for glucose metabolism in pancreatic β-cells and liver parenchymal cells, which play an important role in whole-body glucose homeostasis. 15 [0003] Liag, Y. et al., (Biochem. J., 1995, 309:167-173) report the finding that Type II (maturity-onset) diabetes of the young (MODY-2) is caused by loss of function mutations in the glucokinase gene, which suggests that glucokinase also functions as a glucose sensor in humans. Thus, compounds that activate glucokinase and thus increase the sensitivity of the glucokinase sensor system and thereby cause increase in insulin secretion will be useful in the treatment of hyperglycemia and Type II diabetes. 20 [0004] Glucokinase activators have been demonstrated to be effective in enhancing: 1) the effect of glucose on insulin release from isolated rat and human pancreatic islets, and 2) the glucose induction of pancreatic islet glucokinase in isolated cultured rat islets (e.g. Matschinsky, F.M. et al., Diabetes, 2006, 55: 1, and ("Glucokinase and Glycemic Disease, from Basics to Novel Therapeutics", published by Karger, 2004; F.M. Matschinsky and M.A. Magnuson, eds., Ch. 6, pp. 360-378). In diabetic animal model studies, glucokinase activators have been demonstrated to stimulate insulin release, 25 enhance glycogen synthesis and reduce hepatic glucose production in pancreatic clamp studies. Importantly, glucokinase activators have been demonstrated to dose- dependently lower blood glucose levels in different standard animal models of type 2 diabetes, such as the ob/ob mouse, db/db mouse and Zucker in acute single- dose studies and also effectively improved the glucose excursion in both normal C57/BL6J and ob/ob mice in oral glucose tolerance tests (e.g. in "Glu- cokinase and Glycemic Disease, from Basics to Novel Therapeutics", published by Karger, 2004; F.M. Matschinsky and 30 M.A. Magnuson, eds., Ch. 6, pp. 360-378 as well as Fyfe, M.C. et al., Diabetologia, 2007, 50: 1277). [0005] Glucokinase activators have also demonstrated antidiabetic efficacv in chronic animal models of type II diabetes. For instance, in a 9-day study in ob/ob mice, a glucokinase activator improved the overall glucose profile while showing comparable antihyperglycemic effects in oral glucose tolerance tests at the beginning and end of the study (Fyfe, M.C. et al., Diabetologia, 2007, 50: 1277). In another instance, in a chronic 40-week study, a glucokinase activator prevented 35 the development of hyperglycemia in diet-induced obese mice which were glucose intolerant. The diet-induced obese mice treated with a glucokinase activator showed marked improvement in the glucose excursion in an oral glucose tolerance test at the end of the study relative to the control group ("Glucokinase and Glycemic Disease, from Basics to Novel Therapeutics", published by Karger, 2004; F.M. Matschinskv and M.A. Magnuson, eds., Ch. 6, pp. 360-378). [0006] Glucokinase activators are reported in WO2004/063194. 40 SUMMARY OF THE INVENTION [0007] In accordance with one aspect of the invention, compounds are provided having the structure I 45 50 wherein the moiety 55 3 EP 2 059 522 B1 5 is 10 15 20 substituted by R4 and optionally substituted with one or two substituents R 5 and R6; R4 is selected from the group consisting of 25 30 35 40 R5 and R6 are the same or different and are independently selected from hydrogen, C 1-8 alkyl, halogen or carboxyl, or is absent; 45 Y-X-CO- is 50 55 4 EP 2 059 522 B1 5 10 or Y-X-CO- is 15 20 25 or Y-X-CO- is 30 35 40 ; or Y-X-CO- is 45 50 55 or 5 EP 2 059 522 B1 5 10 15 20 25 30 35 40 45 50 55 6 EP 2 059 522 B1 5 10 or 15 Y-X-CO- is 20 25 a compound selected from 30 35 40 45 50 55 7 EP 2 059 522 B1 5 10 15 20 25 30 35 40 45 50 55 8 EP 2 059 522 B1 5 10 15 20 25 30 35 40 45 50 or 55 9 EP 2 059 522 B1 5 10 all stereoisomers thereof, or a pharmaceutically acceptable salt thereof. [0008] Examples of preferred compounds in accordance with the present invention include, but are not limited to, the 15 following: 20 25 30 35 40 45 50 55 10 EP 2 059 522 B1 5 10 15 20 25 30 35 40 45 50 55 11 EP 2 059 522 B1 5 10 15 20 25 30 35 40 45 50 55 12 EP 2 059 522 B1 5 10 15 20 25 30 35 40 45 50 55 13 EP 2 059 522 B1 5 10 15 20 25 30 35 40 45 50 55 14 EP 2 059 522 B1 5 10 [0009] The compounds of the present invention activate or enhance the activity of the enzyme glucokinase. Conse- quently, the compounds of the present invention may be used in the treatment of multiple diseases or disorders associated 15 with a deficit of glucokinase, such as diabetes and related conditions, microvascular complications associated with diabetes, the macrovascular complications associated with diabetes, cardiovascular diseases, Metabolic Syndrome and its component conditions, and other maladies. Examples of diseases or disorders associated with deficit in activity of the enzyme glucokinase that can be prevented, inhibited, or treated according to the present invention include, but are not limited to, diabetes, hyperglycemia, impaired glucose tolerance, insulin resistance, hyperinsulinemia, retinopathy, 20 neuropathy, nephropathy, delayed wound healing, atherosclerosis and its sequelae, abnormal heart function, myocardial ischemia, stroke, Metabolic Syndrome, hypertension, obesity, dyslipidemia, hyperlipidemia, hypertriglyceridemia, hy- percholesterolemia, low HDL, high LDL, non- cardiac ischemia, infection, cancer, vascular restenosis, pancreatitis, neu- rodegenerative disease, lipid disorders, cognitive impairment and dementia, bone disease, HIV protease associated lipodystrophy, and glaucoma.