(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(19) World Intellectual Property Organization
`International Bureau
`
`
`
`(43) International Publication Date
`16 January 2003 (16.01.2003)
`
`(10) International Publication Number
`
`PCT
`
`WO 03/004498 A1
`
`(51) International Patent Classification":
`A61K 31/4985, A61P 3/10
`
`C07D 487/04,
`
`(74) Common Representative: MERCK & CO., INC.; 126
`East Lincoln Avenue, Rahway, NJ 07065—0907 (US).
`
`(21) International Application Number:
`
`PCT/USO2/21349
`
`(22) International Filing Date:
`
`5 July 2002 (05.07.2002)
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`(30) Priority Data:
`60/303,474
`
`English
`
`English
`
`6 July 2001 (06.07.2001)
`
`US
`
`(71) Applicant Uror all designated States except US): MERCK
`& CO., INC. [US/US]; 126 East Lincoln Avenue, Rahway,
`NJ 07065-0907 (US).
`
`(72) Inventors; and
`(7S) Inventors/Applicants (for US only): EDMONDSON,
`Scott, D. [US/US]; 126 East Lincoln Avenue, Rahway, NJ
`07065—0907 (US). FISHER, Michael, H. [US/US]; 126
`Eastljncoln Avenue, Rahway, NJ 07065—0907 (US). KIM,
`Dooseop [KR/US]; 126 East Lincoln Avenue, Rahway,
`NJ 07065—0907 (US). MACCOSS, Malcolm [GB/US];
`126 East Lincoln Avenue, Rahway, NJ 07065—0907 (US).
`PARMEE, Emma, R. [GB/US]; 126 East Lincoln Ave
`enue, Rahway, NJ 07065—0907 (US). WEBER, Ann,
`E.
`[US/US]; 126 East Lincoln Avenue, Rahway, NJ
`07065—0907 (US). XU, Jinyou [CN/US]; 126 East Lincoln
`Avenue, Rahway, NJ 07065—0907 (US).
`
`(81) Designated States (national): AE, AG, AL, AM, AT, AU,
`AZ, BA, BB, BG, BR, BY, BZ, CA, CH, CN, CO, CR, CU,
`CZ, DE, DK, DM, DZ, EC, EE, ES, FI, GB, GD, GE, GH,
`GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KR, KZ, LC, LK,
`LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX,
`MZ, NO, NZ, OM, PH, PL, PT, RO, RU, SD, SE, SG, SI,
`SK, SL, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VN,
`YU, ZA, ZM, ZW.
`
`(84) Designated States (regional): ARIPO patent (GH, GM,
`KE, LS, MW, MZ, SD, SL, SZ, TZ, UG, ZM, ZW),
`Eurasian patent (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM),
`European patent (AT, BE, BG, CH, CY, CZ, DE, DK, EE,
`ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE, SK,
`TR), OAPI patent (BF, BJ, CF, CG, CI, CM, GA, GN, GQ,
`GW, ML, MR, NE, SN, TD, TG).
`
`Published:
`
`with international search report
`before the expiration of the time limit for amending the
`claims and to be republished in the event of receipt of
`amendments
`
`For two-letter codes and other abbreviations, refer to the ”Guid-
`ance Notes on Codes andAbbreviations " appearing at the begin-
`ning ofeach regular issue ofthe PCT Gazette.
`
`/004498A1
`
`BETA—AMINO TETRAHYDROIMIDAZO (1, 2—A) PYRAZINES AND TETRAHYDROTRIOAZOLO (4, 3—A)
`(54) Title:
`PYRAZINES AS DIPEPTIDYL PEPTIDASE INHIBITORS FOR THE TREATMENT OR PREVENTION OF DIABETES
`
`g (57) Abstract: The present invention is directed to compounds which are inhibitors of the dipeptidyl peptidase—IV enzyme ("DP—IV
`inhibitors") and which are useful in the treatment or prevention of diseases in which the dipeptidyl peptidase—IV enzyme is involved,
`C such as diabetes and particularly type 2 diabetes. The invention is also directed to pharmaceutical compositions comprising these
`compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which the dipeptidyl
`K peptidase—IV enzyme is involved.
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`BETA—AMINO TETRAHYDROIMIDAZO (1,2—A) PYRAZINES AND TETRAHYDROTRIAZOLO (4,3—A)
`PYRAZINES AS DIPEPTIDYL PEPTIDASE INHIBITORS FOR THE TREATMENT OR PREVENTION
`
`OF DIABETES
`
`5
`
`BACKGROUND OF THE INVENTION
`
`10
`
`15
`
`20
`
`Diabetes refers to a disease process derived from multiple causative
`
`factors and characterized by elevated levels of plasma glucose or hyperglycemia in the
`
`fasting state or after administration of glucose during an oral glucose tolerance test.
`
`Persistent or uncontrolled hyperglycemia is associated with increased and premature
`
`morbidity and mortality. Often abnormal glucose homeostasis is associated both
`
`directly and indirectly with alterations of the lipid, lipoprotein and apolipoprotein
`
`metabolism and other metabolic and hemodynamic disease. Therefore patients with
`
`Type 2 diabetes mellitus are at especially increased risk of macrovascular and
`
`microvascular complications, including coronary heart disease, stroke, peripheral
`
`vascular disease, hypertension, nephropathy, neuropathy, and retinopathy. Therefore,
`
`therapeutical control of glucose homeostasis, lipid metabolism and hypertension are
`
`critically important in the clinical management and treatment of diabetes mellitus.
`
`There are two generally recognized forms of diabetes. In type 1
`
`diabetes, or insulin—dependent diabetes mellitus (IDDM), patients produce little or no
`
`insulin, the hormone which regulates glucose utilization. In type 2 diabetes, or
`
`noninsulin dependent diabetes mellitus (NIDDM), patients often have plasma insulin
`
`levels that are the same or even elevated compared to nondiabetic subjects; however,
`
`these patients have developed a resistance to the insulin stimulating effect on glucose
`
`and lipid metabolism in the main insulin-sensitive tissues, which are muscle, liver and
`
`adipose tissues, and the plasma insulin levels, while elevated, are insufficient to
`
`overcome the pronounced insulin resistance.
`
`Insulin resistance is not primarily due to a diminished number of
`
`insulin receptors but to a post—insulin receptor binding defect that is not yet
`
`understood. This resistance to insulin responsiveness results in insufficient insulin
`
`30
`
`activation of glucose uptake, oxidation and storage in muscle and inadequate insulin
`
`repression of lipolysis in adipose tissue and of glucose production and secretion in the
`
`liver.
`
`The available treatments for type 2 diabetes, which have not changed
`
`substantially in many years, have recognized limitations. While physical exercise and
`
`35
`
`reductions in dietary intake of calories will dramatically improve the diabetic
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`condition, compliance with this treatment is very poor because of well—entrenched
`
`sedentary lifestyles and excess food consumption, especially of foods containing high
`
`amounts of saturated fat. Increasing the plasma level of insulin by administration of
`
`sulfonylureas (e.g. tolbutamide and glipizide) or meglitinide, which stimulate the
`
`pancreatic B—cells to secrete more insulin, and/or by injection of insulin when
`
`sulfonylureas or meglitinide become ineffective, can result in insulin concentrations
`
`high enough to stimulate the very insulin—resistant tissues. However, dangerously low
`
`levels of plasma glucose can result from administration of insulin or insulin
`
`secretagogues (sulfonylureas or meglitinide), and an increased level of insulin
`
`10
`
`resistance due to the even higher plasma insulin levels can occur. The biguanides
`
`increase insulin sensitivity resulting in some correction of hyperglycemia. However,
`
`the two biguanides, phenformin and metformin, can induce lactic acidosis and
`
`nausea/diarrhea. Metformin has fewer side effects than phenformin and is often
`
`prescribed for the treatment of Type 2 diabetes.
`
`15
`
`20
`
`The glitazones (i.e. 5—benzylthiazolidine-2,4—diones) are a more
`
`recently described class of compounds with potential for ameliorating many
`
`symptoms of type 2 diabetes. These agents substantially increase insulin sensitivity in
`
`muscle, liver and adipose tissue in several animal models of type 2 diabetes resulting
`
`in partial or complete correction of the elevated plasma levels of glucose without
`
`occurrence of hypoglycemia. The glitazones that are currently marketed are agonists
`
`of the peroxisome proliferator activated receptor (PPAR), primarily the PPAR—gamma
`
`subtype. PPAR—gamma agonism is generally believed to be responsible for the
`
`improved insulin sensititization that is observed with the glitazones. Newer PPAR
`
`agonists that are being tested for treatment of Type II diabetes are agonists of the
`
`25
`
`alpha, gamma or delta subtype, or a combination of these, and in many cases are
`
`chemically different from the glitazones (i.e., they are not thiazolidinediones).
`
`Serious side effects (e.g. liver toxicity) have occurred with some of the glitazones,
`
`such as troglitazone.
`
`Additional methods of treating the disease are still under investigation.
`
`3O
`
`New biochemical approaches that have been recently introduced or are still under
`
`development include treatment with alpha—glucosidase inhibitors (e. g. acarbose) and
`
`protein tyrosine phosphatase—1B (FTP-1B) inhibitors.
`
`Compounds that are inhibitors of the dipeptidyl peptidase—IV ("DP-IV"
`
`or "DPP—IV") enzyme are also under investigation as drugs that may be useful in the
`
`35
`
`treatment of diabetes, and particularly type 2 diabetes. See for example WO
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`97/40832, W0 98/ 19998, US. Patent No. 5,939,560, Bioorg. Med. Chem. Lett, 6(10),
`
`1163—1166 (1996); and Bioorg. Med. Chem. Lett, 6(22), 2745—2748 (1996). The
`
`usefulness of DP-IV inhibitors in the treatment of type 2 diabetes is based on the fact
`
`that DP—IV in vivo readily inactivates glucagon like peptide-1 (GLP—1) and gastric
`
`inhibitory peptide (GIP). GLP-1 and GIP are incretins and are produced when food is
`
`consumed. The incretins stimulate production of insulin. Inhibition of DP—IV leads to
`
`decreased inactivation of the incretins, and this in turn results in increased
`
`effectiveness of the incretins in stimulating production of insulin by the pancreas.
`
`DP—IV inhibition therefore results in an increased level of serum insulin.
`
`10
`
`Advantageously, since the incretins are produced by the body only when food is
`
`consumed, DP—IV inhibition is not expected to increase the level of insulin at
`
`inappropriate times, such as between meals, which can lead to excessively low blood
`
`sugar (hypoglycemia). Inhibition of DP—IV is therefore expected to increase insulin
`
`without increasing the risk of hypoglycemia, which is a dangerous side effect
`
`15
`
`associated with the use of insulin secretagogues.
`
`DP—IV inhibitors also have other therapeutic utilities, as discussed
`
`herein. DP-IV inhibitors have not been studied extensively to date, especially for
`
`utilities other than diabetes. New compounds are needed so that improved DP—IV
`
`inhibitors can be found for the treatment of diabetes and potentially other diseases and
`
`20
`
`conditions.
`
`SUMMARY OF THE lNVENTION
`
`The present invention is directed to compounds which are inhibitors of
`
`the dipeptidyl peptidase—IV enzyme ("DP-IV inhibitors") and which are useful in the
`
`treatment or prevention of diseases in which the dipeptidyl peptidase-IV enzyme is
`involved, such as diabetes and particularly type 2 diabetes. The invention is’also
`
`directed to pharmaceutical compositions comprising these compounds and the use of
`
`these compounds and compositions in the prevention or treatment of such diseases in
`
`which the dipeptidyl peptidase—IV enzyme is involved.
`
`25
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`DETAILED DESCRIPTION OF THE INVENTION
`
`The present invention is directed to compounds of the formula I:
`
`NH2 0
`
`ArMN/YN
`
`wherein:
`
`Ar is phenyl which is unsubstituted or substituted with 1—5 of R3, wherein R3 is
`
`independently selected from the group consisting of:
`
`(1)
`
`(2)
`
`halogen,
`
`C1_6alkyl, which is linear or branched and is unsubstituted or
`
`10
`
`substituted with 1—5 halogens,
`
`(3)
`
`OC1_6alkyl, which is linear or branched and is unsubstituted or
`
`substituted with 1—5 halogens, and
`
`(4)
`
`CN;
`
`15
`
`X is selected from the group consisting of:
`
`(1)
`
`(2)
`
`N, and
`
`CR2;
`
`20
`
`25
`
`30
`
`R1 and R2 are independently selected from the group consisting of:
`
`(1)
`
`(2)
`
`(3)
`
`hydrogen,
`
`CN,
`
`C1-10alkyl, which is linear or branched and which is unsubstituted or
`
`substituted with 1—5 halogens or phenyl, which is unsubstituted or
`
`substituted with 1—5 substituents independently selected from halogen,
`CN, OH, R4, 0R4, NHSOZR4, 302114, COQH, and C02C1_5alkyl,
`
`wherein the C02C1_6all<yl is linear or branched,
`
`(4)
`
`phenyl which is unsubstituted or substituted with 1-5 substituents
`independently selected from halogen, CN, 0H, R4, 0R4, NI-ISOZR4,
`
`SOgR4, COzH, and C02C1_6alkyl, wherein the C02C1_6alkyl is
`
`linear or branched, and
`
`_4_
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`(6)
`
`a 5- or 6—membered heterocycle which may be saturated or unsaturated
`
`comprising 1-4 heteroatoms independently selected from N, S and O,
`
`the heterocycle being unsubstituted or substituted with 1—3 substituents
`
`independently selected from oxo, OH, halogen, C1_6all<yl, and
`
`5
`
`OC1_6alkyl, wherein the C1_6alkyl and OC1_6alkyl are linear or
`
`branched and optionally substituted with 1-5 halogens;
`
`R4 is C1_6alky1, which is linear or branched and which is unsubstituted or substituted
`
`with 1-5 groups independently selected from halogen, COZH, and
`
`10
`
`C02C1_6alkyl, wherein the C0201_6alkyl is linear or branched;
`
`and pharmaceutically acceptable salts thereof and individual diastereomers thereof.
`
`15
`
`formula Ia:
`
`An embodiment of the present invention includes compounds of the
`
`NH2 0
`
`ArMN/YN
`
`wherein X, Ar and R1 are defined herein;
`
`Ia
`
`and pharmaceutically acceptable salts and individual diastereomers thereof.
`
`20
`
`the formula Ib:
`
`Another embodiment of the present invention includes compounds of
`
`NH2 0
`
`AI‘MNVN‘
`
`25
`
`wherein Ar and R1 are defined herein;
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`and pharmaceutically acceptable salts and individual diastereomers thereof.
`
`Another embodiment of the present invention includes compounds of
`
`the formula 10:
`
`NH2 0
`
`”MN /N
`wft
`
`F11
`
`wherein Ar, R1 and R2 are defined herein;
`
`Ic
`
`and pharmaceutically acceptable salts thereof and individual diastereomers thereof.
`
`In the present invention it is preferred that Ar is phenyl which is
`
`unsubstituted or substituted with 1-5 substitutents which are independently selected
`
`from the group consisting of:
`
`(l)
`
`(2)
`
`(3)
`
`fluoro,
`
`bromo, and
`
`CF3.
`
`In the present invention it is more preferred that Ar is selected from the
`
`group consisting of:
`
`( 1)
`
`(2)
`
`(3)
`
`(4)
`
`(5)
`
`(6)
`
`(7)
`
`Phenyl,
`
`2—fluorophenyl,
`
`3,4-difluorophenyl,
`
`2,5-difluoropheny1,
`
`2,4,5—trifluoropheny1,
`
`2—fluoro—4—(triflouromethyl)phenyl, and
`
`4—bromo—2,5—difluorophenyl.
`
`5
`
`10
`
`15
`
`20
`
`25
`
`In the present invention it is preferred that R1 is selected from the
`
`group consisting of:
`
`(1)
`
`hydrogen, and
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`(2)
`
`C1_6a1kyl, which is linear or branched and which is
`
`unsubstituted or substituted with phenyl or 1-5 fluoro.
`
`In the present invention it is more preferred that R1 is selected from the
`
`5
`
`group consisting of:
`
`10
`
`15
`
`20
`
`25
`
`30
`
`(1)
`
`(2)
`
`(3)
`
`(4)
`
`(5)
`
`(5)
`
`(6)
`
`(7)
`
`hydrogen,
`
`methyl,
`
`ethyl,
`
`C133,
`
`CH2CF3,
`
`CF2CF3
`
`phenyl, and
`
`benzyl.
`
`In the present invention it is more preferred that R1 is selected from the
`
`group consisting of:
`
`(1)
`
`(2)
`
`(3)
`
`(4)
`
`(5)
`
`hydrogen,
`
`methyl,
`
`ethyl,
`
`CF3, and
`
`CH2CF3.
`
`In the present invention it is even more preferred that R1 is hydrogen
`
`or CF3.
`
`In the present invention it is preferred that R2 is selected from:
`
`(1)
`
`(2)
`
`(3)
`
`hydrogen,
`
`C1_6a1ky1, which is linear or branched and which is
`
`unsubstituted or substituted with 1-5 fluoro,
`
`phenyl, which is unsubstituted or substituted with 1-3
`substituents independently selected from fluoro, OCH3, and
`
`OCF3.
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`In the present invention it is more preferred that R2 is selected from the
`
`group consisting of:
`
`(1)
`
`(2)
`
`(3)
`
`(4)
`
`(5)
`
`(5)
`
`(6)
`
`(7)
`
`(8)
`
`(9)
`
`hydrogen,
`
`methyl,
`
`ethyl,
`
`CF3,
`
`CH2CF3,
`
`CF2CF3
`
`Phenyl,
`
`(4—methoxy)phenyl,
`
`(4-trifluoromethoxy)phenyl,
`
`4-fluorophenyl, and
`
`(10)
`
`3,4—difluorophenyl.
`
`In the present invention it is even more preferred that R2 is CF3 or
`
`CF2F3.
`
`In the present invention it is preferred that R3 is F, Br or CF3.
`
`10
`
`15
`
`The compounds of the present invention may contain one or more
`
`20
`
`asymmetric centers and can thus occur as racemates and racemic mixtures, single
`
`enantiomers, diastereomeric mixtures and individual diastereomers. The compounds
`
`of the instant invention have one asymmetric center at the beta carbon atom.
`
`Additional asymmetric centers may be present depending upon the nature of the
`
`various substituents on the molecule. Each such asymmetric center will
`
`25
`
`independently produce two optical isomers and it is intended that all of the possible
`
`optical isomers and diastereomers in mixtures and as pure or partially purified
`
`compounds are included within the ambit of this invention. The present invention is
`
`meant to comprehend all such isomeric forms of these compounds.
`
`Some of the compounds described herein contain olefinic double
`
`30
`
`bonds, and unless specified otherwise, are meant to include both E and Z geometric
`
`isomers.
`
`.
`
`Some of the compounds described herein may exist as tautomers,
`
`which have different points of attachment of hydrogen accompanied by one or more
`
`double bond shifts. For example, a ketone and its enol form are keto—enol tautomers.
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`The individual tautomers as well as mixtures thereof are encompassed with
`
`compounds of the present invention.
`
`Formula I shows the structure of the class of compounds without
`
`preferred stereochemistry. Formula Ia shows the preferred sterochemistry at the
`
`carbon atom that is attached to the amine group of the beta amino acid from which
`
`these compounds are prepared.
`
`The independent syntheses of these diastereomers or their
`
`chromatographic separations may be achieved as known in the art by appropriate
`
`modification of the methodology disclosed herein. Their absolute stereochemistry
`
`10
`
`may be determined by the x-ray crystallography of crystalline products or crystalline
`
`intermediates which are derivatized, if necessary, with a reagent containing an
`
`asymmetric center of known absolute configuration.
`
`If desired, racemic mixtures of the compounds may be separated so
`
`that the individual enantiomers are isolated. The separation can be carried out by
`
`15
`
`methods well known in the art, such as the coupling of a racemic mixture of
`
`compounds to an enantiomerically pure compound to form a diastereomeric mixture,
`
`followed by separation of the individual diastereomers by standard methods, such as
`
`fractional crystallization or chromatography. The coupling reaction is often the
`
`formation of salts using an enantiomerically pure acid or base. The diasteromeric
`
`derivatives may then be converted to the pure enantiomers by cleavage of the added
`
`chiral residue. The racemic mixture of the compounds can also be separated directly
`
`by chromatographic methods utilizing chiral stationary phases, which methods are
`
`well known in the art.
`
`Alternatively, any enantiomer of a compound may be obtained by
`
`stereoselective synthesis using optically pure starting materials or reagents of known
`
`configuration by methods well known in the art.
`
`20
`
`25
`
`The term "pharmaceutically acceptable salts" refers to salts prepared
`
`from pharrnaceutically acceptable non—toxic bases or acids including inorganic or
`
`organic bases and inorganic or organic acids. Salts derived from inorganic bases
`
`30
`
`include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium,
`
`manganic salts, manganous, potassium, sodium, zinc, and the like. Particularly
`
`preferred are the ammonium, calcium, magnesium, potassium, and sodium salts. Salts
`
`in the solid form may exist in more than one crystal structure, and may also be in the
`
`form of hydrates. Salts derived from pharmaceutically acceptable organic non—toxic
`
`35
`
`bases include salts of primary, secondary, and tertiary amines, substituted amines
`
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`including naturally occurring substituted amines, cyclic amines, and basic ion
`exchange resins, such as arginine, betaine, caffeine, choline, N,N1dibenzylethylene—
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`diamine, diethylamine, 2-diethylaminoethanol, 2—dimethylaminoethanol,
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`ethanolamine, ethylenediamine, N—ethyl-morpholine, N—ethylpiperidine, glucamine,
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`glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine,
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`morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine,
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`triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
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`When the compound of the present invention is basic, salts may be
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`prepared from pharmaceutically acceptable non—toxic acids, including inorganic and
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`organic acids. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic,
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`citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric,
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`isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic,
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`pantothenic, phosphoric, succinic, sulfuric, tartaric, p—toluenesulfonic acid, and the
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`like. Particularly preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric,
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`sulfuric, fumaric, and tartaric acids.
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`It will be understood that, as used herein, references to the compounds
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`of Formula I are meant to also include the pharmaceutically acceptable salts.
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`As appreciated by those of skill in the art, halo or halogen as used
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`herein are intended to include fluoro, chloro, bromo and iodo. Similarly, C1_8, as in
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`C1_3alky1 is defined to identify the group as having 1, 2, 3, 4, 5, 6, 7 or 8 carbons in a
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`linear or branched arrangement, such that C1_8alkyl specifically includes methyl,
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`ethyl, n—propyl, iso—propyl, n-butyl, iso-butyl, tert—butyl, pentyl, hexyl, heptyl and
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`octyl. Likewise, Co, as in Coalkyl is defined to identify the presence of a direct
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`covalent bond. A group which is designated as being independently substituted with
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`substituents may be independently substituted with multiple numbers of such
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`substituents. The term "heterocycle" as used herein is intended to include 5- or
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`6-membered ring systems which are within the following listing: benzimidazolyl,
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`benzodioxanyl, benzofuranyl, benzopyrazolyl, benzothiadiazolyl, benzotriazolyl,
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`benzothiophenyl, benzoxadiazolyl, benzoxazolyl, carbazolyl, carbolinyl, chromanyl,
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`cinnolinyl, furanyl, imidazolyl,
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`indolinyl, indolyl, indolazinyl, indazolyl,
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`isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthyridinyl,
`oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridopyridinyl, pyridazinyl, pyIidyl,
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`pyrimidyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrazolyl, thiadiazolyl,
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`thiazolidinyl, thiazolyl, thienyl, tn'azolyl, azetidinyl, 1,4-dioxanyl, hexahydroazepinyl,
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`piperazinyl, pipen'dinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl,
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`dihydrobenzimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl,
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`dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl,
`dihydroisooxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl,
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`dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl,
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`dihydropyrrolyl, dihydroquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl,
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`dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl,
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`methylenedioxybenzoyl, tetrahydrofuranyl, tetrahydroimidazolyl,
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`tetrahydroisoquinolinyl, and tetrahydrothienyl.
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`Exemplifying the invention is the use of the compounds disclosed in
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`the Examples and herein.
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`Specific compounds within the present invention include a compound
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`which selected from the group consisting of the compounds disclosed in the following
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`Examples and pharmaceutically acceptable salts thereof and individual diastereomers
`thereof.
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`The subject compounds are useful in a method of inhibiting the
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`dipeptidyl peptidase—IV enzyme in a patient such as a mammal in need of such
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`inhibition comprising the administration of an effective amount of the compound.
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`The present invention is directed to the use of the compounds disclosed herein as
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`inhibitors of dipeptidyl peptidase—IV enzyme activity.
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`In addition to primates, such as humans, a variety of other mammals
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`can be treated according to the method of the present invention. For instance,
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`mammals including, but not limited to, cows, sheep, goats, horses, dogs, cats, guinea
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`pigs, rats or other bovine, ovine, equine, canine, feline, rodent or murine species can
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`be treated. However, the method can also be practiced in other species, such as avian
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`species (e.g., chickens).
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`The present invention is further directed to a method for the
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`manufacture of a medicament for inhibiting dipeptidyl peptidase-IV enzyme activity
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`in humans and animals comprising combining a compound of the present invention
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`with a pharmaceutical carrier or diluent.
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`The subject treated in the present methods is generally a mammal,
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`preferably a human being, male or female, in whom inhibition of dipeptidyl peptidase—
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`IV enzyme activity is desired. The term "therapeutically effective amount" means the
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`amount of the subject compound that will elicit the biological or medical response of
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`a tissue, system, animal or human that is being sought by the researcher, veterinarian,
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`medical doctor or other clinician.
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`The term "composition" as used herein is intended to encompass a
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`product comprising the specified ingredients in the specified amounts, as well as any
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`product which results, directly or indirectly, from combination of the specified
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`ingredients in the specified amounts. Such term in relation to pharmaceutical
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`composition, is intended to encompass a product comprising the active ingredient(s),
`and the inert ingredient(s) that make up the carrier, as well as any product which
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`results, directly or indirectly, from combination, complexation or aggregation of any
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`two or more of the ingredients, or from dissociation of one or more of the ingredients,
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`or from other types of reactions or interactions of one or more of the ingredients.
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`Accordingly, the pharmaceutical compositions of the present invention encompass
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`any composition made by admixing a compound of the present invention and a
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`pharmaceutically acceptable carrier. By "pharmaceutically acceptable” it is meant the
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`carrier, diluent or excipient must be compatible with the other ingredients of the
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`formulation and not deleterious to the recipient thereof.
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`The terms "administration of" and or "administering a" compound
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`should be understood to mean providing a compound of the invention or a prodrug of
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`a compound of the invention to the individual in need of treatment.
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`The utility of the compounds in accordance with the present invention
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`as inhibitors of dipeptidyl peptidase-IV enzyme activity may be demonstrated by
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`methodology known in the art. Inhibition constants are determined as follows. A
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`continuous fluorometric assay is employed with the substrate Gly—Pro-AMC, which is
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`cleaved by DP-IV to release the fluorescent AMC leaving group. The kinetic
`parameters that describe this reaction are as follows: Km = 50 MM; km = 75 s'1;
`kcat/Km = 1.5 x 106 M'ls'l. A typical reaction contains approximately 50 pM enzyme,
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`50 HM Gly-Pro-AMC, and buffer (100 mM HEPES, pH 7.5, 0.1 mg/ml BSA) in a
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`total reaction volume of 100 Ml. Liberation of AMC is monitored continuously in a
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`96-well plate fluorometer using an excitation wavelength of 360 nm and an emission
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`wavelength of 460 nm. Under these conditions, approximately 0.8 ttM AMC is
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`produced in 30 minutes at 25 degrees C. The enzyme used in these studies was
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`soluble (transmembrane domain and cytoplasmic extension excluded) human protein
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`produced in a baculovirus expression system (Bac—To—Bac, Gibco BRL). The kinetic
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`constants for hydrolysis of Gly-Pro-AMC and GLP-1 were found to be in accord with
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`literature values for the native enzyme. To measure the dissociation constants for
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`compounds, solutions of inhibitor in DMSO were added to reactions containing
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`enzyme and substrate (final DMSO concentration is 1%). All experiments were
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`conducted at room temperature using the standard reaction conditions described
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`above. To determine the dissociation constants (K), reaction rates were fit by non-
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`linear regression to the Michaelis—Menton equation for competitive inhibition. The
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`errors in reproducing the dissociation constants are typically less than two-fold.
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`In particular, the compounds of the following examples had activity in
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`inhibiting the dipeptidyl peptidase—IV enzyme in the aforementioned assays, generally
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`with an IC50 of less than about 1 MM. Such a result is indicative of the intrinsic
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`activity of the compounds in use as inhibitors the dipeptidyl peptidase-IV enzyme
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`activity.
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`Dipeptidyl peptidase—IV enzyme (DP—IV) is a cell surface protein that
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`has been implicated in a wide range of biological functions. It has a broad tissue
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`distribution (intestine, kidney, liver, pancreas, placenta, thymus, spleen, epithelial
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`cells, vascular endothelium, lymphoid and myeloid cells, serum), and distinct tissue
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`and cell—type expression levels. DP—IV is identical to the T cell activation marker
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`CD26, and it can cleave a number of immunoregulatory, endocrine, and neurological
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`peptides in vitro. This has suggested a potential role for this peptidase in a variety of
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`disease processes in humans or other species.
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`Accordingly, the subject compounds are useful in a method for the
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`prevention or treatment of the following diseases, disorders and conditions.
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`Type II Diabetes and Related Disorders: It is well established that the incretins GLP-1
`and GIP are rapidly inactivated in vivo by DP—IV. Studies with DP—IV('/')-deficient
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`mice and preliminary clinical trials indicate that DP—IV inhibition increases the steady
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`state concentrations of GLP-1 and GIP, resulting in improved glucose tolerance. By
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`analogy to GLP-1 and GIP, it is likely that other glucagon family peptides involved in
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`glucose regulation are also inactivated by DP—IV (eg. PACAP, glucagon).
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`Inactivation of these peptides by DP—IV may also play a role in glucose homeostasis.
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`The DP—IV inhibitors of the present invention therefore have utility in
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`the treatment of type II diabetes and in the treatment and prevention of the numerous
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`conditions that often accompany Type ]I diabetes, including metabolic syndrome X,
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`reactive hypoglycemia, and diabetic dyslipidemia. Obesity, discussed below,
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`is
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`another condition that is often found with Type II diabetes that may respond to
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`treatment with the compounds of this invention.
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`The following diseases, disorders and conditions are related to Type 2
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`diabetes, and therefore may be treated, controlled or in some cases prevented, by
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`treatment with the compounds of this invention: (1) hyperglycemia, (2) low glucose
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`tolerance, (3) insulin resistance, (4) obesity, (5) lipid disorders, (6) dyslipidemia,
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`(7) hyperlipidemia, (8) hypertriglyceridemia, (9) hypercholesterolemia,
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`(10) low
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`HDL levels, (11) high LDL levels, (12) atherosclerosis and its sequelae, (13)
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`vascular restenosis, (14) irritable bowel syndrome, (15) inflammatory bowel disease,
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`including Crohn’s disease and ulcerative colitis, (16) other inflammatory conditions,
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`(17) pancreatitis, (18) abdominal obesity, (19) neurodegenerative disease, (20)
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`retinopathy, (21) nephropathy, (22) neuropathy, (23) Syndrome X, (24) ovarian
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`hyperandrogenism (polycystic ovarian syndrome), and other disorders where insulin
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`resistance is a component.
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`Obesity: DP-IV inhibitors may be useful for the treatment of obesity. This is based
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`on the observed inhibitory effects on food intake and gastric emptying of GLP—1 and
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`GLP—2. Exogenous administration of GLP—1 in humans significantly decreases food
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`intake and slows gastric emptyi