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(12) United States Patent (10) Patent No.: US 8,329,697 B2 Garbaccio Et Al

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(12) United States Patent (10) Patent No.: US 8,329,697 B2 Garbaccio Et Al US008329697B2 (12) United States Patent (10) Patent No.: US 8,329,697 B2 Garbaccio et al. (45) Date of Patent: Dec. 11, 2012 (54) IMIDIZO 1.2-APYRAZINES USEFUL AS (56) References Cited AHCY HYDROLASE INHIBITORS U.S. PATENT DOCUMENTS (75) Inventors: Robert M. Garbaccio, Lansdale, PA 4,507,294 A 3, 1985 Bristol et al. (US); Antonella Converso, Elkins Park, 56.6 f 3.3: Ret , al PA (US); Mark E. Fraley, North Wales, 4. W w Wa (a. PA (US); Timothy J. Hartingh, Blue 2004/0204429 A1 10, 2004 Yuan Bell, PA (US) FOREIGN PATENT DOCUMENTS WO WO 2009/108546 * 9/2009 (73) Assignee: Merck Sharp & Dohme Corp., OTHER PUBLICATIONS Rahway, NJ (US) Jordan, V. C. Nature Reviews: Drug Discovery, 2, 2003, 205.* (*) Notice: Subject to any disclaimer, the term of this Hackam, et al. JAMA, 296(14), 2006, 1731-1732.* patent is extended or adjusted under 35 * cited b U.S.C. 154(b) by 163 days. c1ted by examiner Primary Examiner — Douglas MWillis (21) Appl. No.: 12/811,911 (74) Attorney, Agent, or Firm — Kenrick L. Vidale; John C. Todaro (22) PCT Filed: Feb. 18, 2009 (57) ABSTRACT (86). PCT No.: PCT/US2O09/034344 The present invention is directed to AHCY inhibitors of for mula (I) which are useful in the treatment of diseases charac S371 (c)(1), terized by high homocysteine levels, such as Alzheimer's (2), (4) Date: Jul. 7, 2010 disease. The invention is also directed to pharmaceutical compositions comprising the compounds, and to the use of (87) PCT Pub. No.: WO2009/108546 the compounds and compositions in the treatment of diseases PCT Pub. Date: Sep.e 3,a 9 2009 characterized by high homocysteine levels. (65) Prior Publication Data (I) US 2010/0305135 A1 Dec. 2, 2010 NH2 Related U.S. Application Data N21 N2N (60) ProvisionalrOV1S1Onal apol1Cat1Onapplication No.NO. 61/067,210,Z 1U, Tilledfiled onOn FebFeb. N-N / 26, 2008. OH (51) Int. Cl. X A6 IK3I/495 (2006.01) Y (52) U.S. Cl. ........................................ 514/249; 544/350 6H (58) Field of Classification Search .................. 514/249; 544/350 See application file for complete search history. 7 Claims, No Drawings US 8,329,697 B2 1. 2 IMIDIZO 1.2-APYRAZINES USEFUL AS 2003 207):425-8. Further, the known AHCY inhibitor AHCY HYDROLASE INHIBITORS 3-deaza-adenosine (DZA) has been shown to prevent oxida tive damage and cognitive impairment in mice. Shea et al. CROSS-REFERENCE TO RELATED Neuromolecular Medicine 2004, 5:173-182. In clinical stud APPLICATIONS ies, folate deficiency was associated with neurological disor derS Such as Alzheimer's disease. Ho et al., Neurobiology of This application claims the benefit under 35 U.S.C. 119(e) Disease, 2003 14:1, 32-42. of U.S. Provisional Application No. 61/067,210, filed 26 Feb. Seshadri et al, N Engl. J. Med, 2002, 346:476-483, in a 2008. study of data from the Framingham Heart Study, found that 10 increased homocysteine levels in plasma was an independent BACKGROUND OF THE INVENTION risk factor for dementia and Alzheimer's Disease. See also 1. Field of the Invention Morris, Lancet Neurology 2003, 2:425-428. The invention is directed to a class of S-adenosylhomocys Hyperhomocysteinemia is a known risk factor for arterial teine hydrolase (AHCY) inhibitors, their salts, pharmaceuti 15 vascular disease and venous thrombosis. Gellekink et al., Eur cal compositions comprising them and their use in therapy of J Hum Genet. 2004 12(11):942-8; cardiovascular disease, the human body. In particular, the invention is directed to a Levine etal, Prog Neuropsych Biol Psych 2005, 29(7): 1181 class of AHCY inhibitors, which are useful in the treatment of 91; Schizophrenia, Haidemenos et al. Prog Neuropsychop diseases characterized by high homocysteine levels. harmacol Biol Psychiatry. 2007 15:31(6):1289-96; and bipo 2. Description of Related Art lar disorder, Levine et al. Elevated homoscysteine levels have S-adenosylhomocysteine, known as AdoHcy, is an inter also been shown to be risk factors for stroke and Parkinson's mediate in the metabolism of the Sulfur-containing amino Disease. Herrmann et al. Fortschr Neurol Psychiatr. 2007 acids methionine and cysteine. AdoHcy is formed by the 75(9):515-27. Further, animal studies suggest that increased donation of a methyl group from S-adenosylmethionine homocycsteine levels may be a factor in osteoporosis. Her (SAM) to biomolecules undergoing methylation reactions. 25 rmann etal, Clin. Chem. 2007, 53(8): 1455-61. AdoHcy is then metabolized by the enzyme S-adenosylho One possible method for treating diseases via the AHCY mocysteine hydrolase, known as AHCY, SAHH or SAH pathway is to develop mechanisms for clearing homocysteine hydrolase, which reversibly hydrolyses AdoHcy to adenosine from the body. For example, compounds or Substances that and homocysteine. Homocysteine can be remethylated back increase the rate of vitamin B clearance of homocysteine in to methionine or undergo a series of metabolic steps leading 30 Vivo may find utility as agents for treating disease associated to the biosynthesis of glutathione or cysteine. Following the with high levels of homocysteine. A second method of inter hydrolysis of AdoHcy, homocysteine can also be secreted fering with the AHCY pathway is to decrease production of from the body or converted into the anti-oxidant, glutathione, homocytseine, i.e. to develop compounds that can inhibit by a series of transulfuration pathway reactions. Glutathione production of homocysteine in vivo. For example, com is a major anti-oxidant in the body. The relative ratio between 35 pounds or substances which inhibit AHCY may decrease the oxidized and reduced forms of glutathione is thought to be an extent of hydrolysis of S-adenosyl homocysteine into important indicator of oxidative state. homocysteine and adenosine. Furthermore, the ratio between SAM and AdoHcy is criti The inventors have identified a novel group of compounds cal for many biological processes, as AdoHcy can inhibit which act as inhibitors of S-adenosyl homocysteine hydro many methyltransferases that use SAM as a methyl donor. 40 lase, thereby inhibiting the hydrolysis of S-adenosyl Thus, the rate of conversion of AdoHcy to Hey is a critical homocysteine into homocysteine and adenosine. regulator of many biological reactions involving phospholip ids, proteins, and nucleic acids. Chiang, Pharmacol Ther BRIEF SUMMARY OF THE INVENTION 1998, 77, 2, 115-134. Various nucleosides and nucleoside derivatives act as inhibitors of AHCY. Chiang. 45 The present invention is directed to novel compounds of Homocysteine metabolism is also dependent on the nutri generic formula (I) ents folate, vitamin B12 and vitamin B6. Obeid etal, FEBS Letters 2006, 580:2994-3005. These nutrients are cofactors for the enzymes that remethylate Hey back to methionine NH2 (folate, B12) or convert it to glutathione (B6). 50 AHCY is a 432 amino acid protein, which is a thioether N 21 2N. hydrolase. AHCY is a cytosolic enzyme that has been found in a wide variety of cells. Walker, et al. Can. J. Biochem. 1975 N- N / 53: 312-319. The sequence of AHCY is disclosed in Interna tional Patent Application Publication No. WO 2005/015221. 55 wOH X AHCY catalyzes the conversion of S-adenosyl-homocys V teine to homocysteine and adenosine. Because of the key role Y of AdoHcy in the synthesis of cysteine, and the role of S-ad enosylmethionine as a universal methyl donor, misregulation OH of AHCY can affect methylation of phosphlipids, proteins, 60 DNA and RNA. orpharmaceutically acceptable salts thereof, which are useful Epidemiological evidence demonstrates that increased lev as AHCY inhibitors. els of homocysteine are associated with many diseases, The invention is further directed to methods of treating a including cardiovascular disease, stroke, and neurodegenera patient (preferably a human) for diseases or disorders which tive diseases such as Alzheimer's Disease. Hyperhomocys 65 are characterized by high homocysteine levels, such as Alzhe teinemia, which may be caused by folic acid deficiency, can imer's disease, by administering to the patient a therapeuti contribute to Alzheimer's Disease. Morris, Lancet Neurol. cally effective amount of a compound of general formula (I), US 8,329,697 B2 3 4 or a pharmaceutically acceptable salt thereof. The invention is The invention is also directed to medicaments or pharma also directed to pharmaceutical compositions which include ceutical compositions for treating diseases or disorders char an effective amount of a compound of formula (I), or a phar acterized by high homocysteine levels, such as Alzheimer's maceutically acceptable salt thereof, and a pharmaceutically disease, hypertension, cardiovascular disease, stroke and acceptable carrier, and the use of the compounds and phar 5 Schizophrenia, which comprise a compound of formula (I), or maceutical compositions of the invention in the treatment of a pharmaceutically acceptable salt thereof, and a pharmaceu Such diseases. tically acceptable carrier. The invention is further directed to a method for the manu DETAILED DESCRIPTION OF THE INVENTION facture of a medicament or a composition for treating diseases 10 or disorders characterized by high homocysteine levels, such as Alzheimer's disease, hypertension, cardiovascular disease, In one embodiment, the invention is directed to compounds stroke or Schizophrenia, comprising combining a compound of general formula (I) of formula (I) with one or more pharmaceutically acceptable carriers. NH2 15 Specific embodiments of formula (I) are described herein as Examples 1 ((1S,2R,5S)-5-(8-aminoimidazo[1,2-a pyrazin-3-yl)-3-(hydroxymethyl)cyclopent-3-ene-1,2-diol) N 21 2N and 2 (1R,2S,3S)-3-(8-aminoimidazo[1,2-alpyrazin-3-yl)cy clopentane-1,2-diol, and pharmaceutically acceptable salts N- N / thereof. Where a variable occurs more than once in Formula (I) or X WOH in a substituent thereof, the individual occurrences of that V variable are independent of each other, unless otherwise Y specified.
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