`
`Of) 0‘7 0/
`
`HEW
`
`PROVISIONAL APPLICATION FOR PATENT COVER SHEET
`
`SUBSTITUTE for Provxsmnal Application for Patent Cover Sheet NOISE/16 (
`Approved for use through 10/3112002 OMB 0651-0037
`=
`U S Patent arid ’lTademark OffiCe. U S DEPARTMENT OF COMMERg
`n.
`=—
`1.. E
`:5 EH
`‘fl' ED
`”Em =\
`3:5: =8
`This is a request for filing a PROVISIONAL APPLICATION FOR PATENT under 37 CFR 1.53 (0).
`m\§\
`
`no
`h
`w 0
`H
`
`'7
`
` y Type 3 p155 sign (+) inside this box *3
`: Li
`D=
`E S
`33‘ g;
`a
`35 c
`3; m
`a2 '
`E—
`§ "U
`\_§ -i
`a O
`
`
`
`
`DOCKET NUMBER
`
`20907PV
`
`INVENTOR(S)
`
`Given—Name (first and rmddle [if any])
`Family Name or Surname
`i
`Resulence (City and either State or Foreign Country)
`Scott D.
`Edmondson
`New York. NY
`Michael H.
`Fisher
`Ringoes. NJ
`Dooseop
`Kim
`Westfield, NJ
`Malcolm
`MacCoss
`Freehold, NJ
`Emma R,
`Parmee
`Scotch Plains, NJ
`Ann E.
`Webcr
`Scotch Plains, N]
`Jinyou
`Xu
`Scotch Plains, NJ
`
`
`i: Additional inventors are being named on the
`separately numbered sheets attached hereto
` TITLE OF THE INVENTION (280 characters max)
` BETA-AMINO HETEROCYCLIC DIPEPTIDYL PEPTIDASE INHIBITORS FOR THE TREATMENT OR PREVENTION OF DIABETES
`
`
`
`
`
`
` CORRESPONDENCE ADDRESS
`
`Merck & Co . Inc.
`
`Patent Department — RY60—30
`PO. Box 2000
`Rahway
`
`
`
`XI Customer Number
`
`000210
`
`
`
` New Jersey
`
`U.S A
`i
`COUNTRY
`]
`07065
`ZIP CODE
`ENCLOSED APPLICATION PARTS (check all that apply)
`
`
`
`
`D Other (speCIfy) F
`Nun1ber 0fSheets
`Drawing(s)
`
`Application Data Sheet. See 37 CFR 1.76
` METHOD OF PAYMENT OF FILING FEES FOR THIS PROVISIONAL APPLICATION FOR PATENT (check one)
`
`
`
`Specification
`
`Number of Page:
`
`66
`
`A check or money order is enclosed to cover the filing fees
`
`
`
`
`x The Commissmner is hereby authorized
`1
`.
`,
`to tharee Fling fees or credit any
`‘
`c
`overpayment to Deposit Account Number:
`
`13—2755
`
`FILING FEE
`AMOUNT ($)
`
`$15000
`
`The invention was made by an agency of the United States Government or under a contract with an agency of the United States Government.
`
`:1 No.
`D Yes, the name of the U.S. Government agency and the Government contract number are:
`
`
`
`Respectfully sub
`
`SIGNATURE
`TYPED or PR1
`TELEPHONE
`
`tt (1&40
`
`D NAME
`32-594-3904
`
`J. Eric
`
`165
`
`Date
`
`REGISTRATION NO.
`(ifappropriate)
`
`07/06/2001
`
`35,382
`
`
`
`EXPRESS MAIL CERTIFICATE
`July 6 2001
`DATE OF DEPOSIT
`EXPRESS IVIAIL NO. E1523910547US
`I HEREBY CERTIFY TIIAT THIS CORRESPONDENCE IS BEING DEPOSITED WITH TIIE
`UNITED STATES POSTAL SERVICE AS EXPRESS MAIL "POST OFFICE T0 ADDRESSEE"
`
`DATE July 6, 2001
`
`In Duplicate
`
`Computer generated form "Transmittal Form-PV" (Application Filing Folder) Merck & Col, Inc, 9/28/00
`
`MAILED BY
`
`'
`
`.
`
`,
`
`'
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`,
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`INVENTOR INFORMATION
`
`Inventor One Given Name:: Scott D.
`
`: Edmondson
`Family Name
`Postal Address Line One:: Merck & Co., Inc., P.O. Box 2000
`City:: Rahway
`State or Province:: NJ
`
`Country:: U.S.A.
`Postal or Zip Code:: 07065—0907
`City of Residence:: New York
`
`State or Province of Residence:: NY
`
`Country of Residence:: U.S.A.
`Citizenship Country:: U.S.A.
`Inventor Two Given Name:: Michael H.
`
`Family Name:: Fisher
`Postal Address Line Onez: Merck & Co., Inc., P.O. Box 2000
`City:: Rahway
`State or Province:: NJ
`
`Country:: U.S.A.
`Postal or Zip Code:: 07065—0907
`City of Residence:: Ringoes
`State or Province of Residence:: NJ
`Country of Residence:: U.S.A.
`Citizenship Country:: U.S.A.
`Inventor Three Given Name:: Dooseop
`Family Name:: Kim
`Postal Address Line Onezz Merck & Co., Inc., P.O. Box 2000
`City:: Rahway
`State or Province:: NJ
`Country:: U.S.A.
`Postal or Zip Code : 07065—0907
`City of Residence:: Westfield
`State or Province of Residence:: NJ
`
`Country of Residence:: U.S.A.
`Citizenship Country:: Korea
`Inventor Four Given Name:: Malcolm
`Family Name:: MacCoss
`Postal Address Line Onezz Merck & Co., Inc., P.O. Box 2000
`City:: Rahway
`State or Province:: NJ
`
`Country:: U.S.A.
`Postal or Zip Code:: 07065—0907
`City of Residence:: Freehold
`State or Province of Residence:: NJ
`
`Country of Residence:: U S.A.
`Citizenship Country : United Kingdom
`Inventor Five Given Name:: Emma R.
`Family Name:: Parmee
`Postal Address Line One:: Merck & Co., Inc., P.O. Box 2000
`City:: Rahway
`
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`State or Province : NJ
`Countryzz U.S.A.
`Postal or Zip Code:: 07065—0907
`City of Residence:: Scotch Plains
`State or Province of Residence:: NJ
`
`Country of Residence:: U.S.A.
`Citizenship Country:: United Kingdom
`Inventor Six Given Name:: Ann B.
`
`Family Name:: Weber
`Postal Address Line Onezz Merck & Co., Inc., P.O. BOX 2000
`City:: Rahway
`State or Province:: NJ
`Countryzz U.S.A.
`Postal or Zip Code:: 07065—0907
`City of Residence:: Scotch Plains
`State or Province of Residence:: NJ
`Country of Residence:: U.S.A.
`Citizenship Country:: U.S.A.
`Inventor Seven Given Name:: Jinyou
`Family Name:: Xu
`Postal Address Line Onez: Merck & Co., Inc., P.O. Box 2000
`City:: Rahway
`State or Province:: NJ
`
`Country:: U.S.A.
`Postal or Zip Code:: 07065—0907
`City of Residence:: Scotch Plains
`State or Province of Residence:: NJ
`Country of Residence:: U.S.A.
`Citizenship Country:: China
`
`CORRESPONDENCE INFORMATION
`
`Correspondence Customer Number:: 000210
`
`APPLICATION INFORMATION
`
`Title Line One::
`Title Line Twozz
`Title Line Three::
`
`BETA—AMINO HETEROCYCLIC DIPEPTIDYL PEPTI
`DASE INHIBITORS FOR THE TREATMENT OR PRE
`VENTION OF DIABETES
`
`Formal Drawings?:: No
`Application Type:: Utility
`Docket Number:: 20907PV
`
`Secrecy Order in Parent Appl.?:: No
`
`REPRESENTATIVE INFORMATION
`
`Registration Number One:: 35382
`Registration Number Two:: 26332
`
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`PrintEFS Version 1.0.1
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`T
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`20907PV
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`
`
`TITLE OF THE INVENTION
`
`BETA-AMINO HETEROCYCLIC DIPEPTIDYL PEPTIDASE INHIBITORS FOR
`
`THE TREATIVIENT OR PREVENTION OF DIABETES
`
`5
`
`BACKGROUND OF THE INVENTION
`
`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
`
`IO 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
`
`15
`
`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
`
`20
`
`insulin, the hormone which regulates glucose utilization. In type 2 diabetes, or
`
`noninsulin dependent diabetes mellitus (NlDDM), 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
`
`25
`
`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 (eg. tolbutamide and glipizide) or meglitinide, which stimulate the
`
`5
`
`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 phenforrnin and is often
`
`prescribed for the treatment of Type 2 diabetes.
`
`15
`
`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
`
`20
`
`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 I] 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 (eg. liver toxicity) have occurred with some of the glitazones,
`
`such as troglitazone.
`
`Additional methods of treating the disease are still under investigation.
`
`30
`
`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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`20907PV
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`
`
`97/40832, WO 98/19998, U.S. 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-l (GLP-1) and gastric
`
`5
`
`inhibitory peptide (GIP). GLP-1 and GI? 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
`conditions.
`
`20
`
`SUMMARY OF THE INVENTION
`
`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
`
`25
`
`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.
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`)
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`20907PV
`
`
`
`DETAILED DESCRIPTION OF THE LNVENTION
`
`The present invention is directed to compounds of the formula I:
`
`NH2 0
`AFM N
`N
`/ \
`
`R1
`
`5
`
`wherein:
`
`Ar is phenyl which is unsubstituted or substituted with 1—5 of R3, wherein R3 is
`
`independently selected from the group consisting of:
`
`(l)
`
`(2)
`
`halogen,
`
`C 1-6alkyl, which is linear or branched and is unsubstituted or
`
`10
`
`substituted with 1‘5 halogens,
`
`(3)
`
`OC1_6all<yl, 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:
`
`(l)
`
`(2)
`
`N, and
`
`CR2;
`
`R1 and R2 are independently selected from the group consisting of:
`
`( 1)
`
`(2)
`
`(3)
`
`20
`
`25
`
`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, 502124, com, and C02C1_6alkyl,
`
`wherein the C02C1_6alkyl is linear or branched,
`
`(4)
`
`phenyl which is unsubstituted or substituted with 1-5 substituents
`independently selected from halogen, CN, OH, R4, 0R4, NHSOZR4,
`
`SOZR4, COQH, and C02C1-6all<yl, wherein the C02C1_5all<yl is
`
`30
`
`linear or branched, and
`
`-4-
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`209D7PV
`
`
`
`
`(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 0x0, OH, halogen, C1_6alkyl, and
`
`5
`
`OC1_6alkyl, wherein the C 1-6alkyl and OC1-6alkyl are linear or
`
`branched and optionally substituted with 1—5 halogens;
`
`R4 is C1_6alkyl, 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 C02C1_6alkyl is linear or branched;
`
`and pharmaceutically acceptable salts thereof and individual diastereorners thereof.
`
`15
`
`formula Ia:
`
`An embodiment of the present invention includes compounds of the
`
`NH2 0
`
`“MN/YB]
`big/X
`
`\
`
`R1
`
`Ia
`
`wherein X, Ar and R1 are defined herein;
`
`and pharmaceutically acceptable salts and individual diastereorners thereof.
`
`20
`
`the formula Ib:
`
`Another embodiment of the present invention includes compounds of
`
`NH2 0
`
`AFNNVN
`
`25
`
`wherein Ar and R1 are defined herein;
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`!
`
`20907PV
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`
`
`
`5
`
`10
`
`15
`
`20
`
`25
`
`and pharmaceutically acceptable salts and individual diastereorners thereof.
`
`the formula Ic:
`
`Another embodiment of the present invention includes compounds of
`
`NH2 0
`
`Ar\/'\/U\N /N
`i
`N /
`\/
`
`2
`
`R
`
`R1
`
`10
`
`wherein Ar, R1 and R2 are defined herein;
`
`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)
`
`phenyi,
`
`Z—fluorophenyl,
`
`3,4—difluorophenyl,
`
`2,5—difluorophenyl,
`
`2,4,5—t1ifluorophenyl,
`
`2-fluoro-4—(triflourornethyl)phenyl, and
`
`4—bromo-2,5—difluorophenyl.
`
`In the present invention it is preferred that R1 is selected from the
`
`group consisting of:
`
`(1)
`
`hydrogen, and
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`20907PV
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`(2)
`
`C1_6alkyl, 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:
`
`(1)
`
`(2)
`
`(3)
`(4)
`
`(5)
`
`(5)
`
`(6)
`
`(7)
`
`hydrogen,
`
`methyl,
`
`ethyl,
`CF3,
`
`CHZCF3,
`
`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.
`
`10
`
`15
`
`or CF3.
`
`25
`
`3O
`
`In the present invention it is even more preferred that R1 is hydrogen
`
`In the present invention it is preferred that R2 is selected from:
`
`(1)
`
`(2)
`
`(3)
`
`hydrogen,
`
`C 1-6alkyl, 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,
`C133,
`
`CH2CF3,
`
`CF2CF3
`
`phenyi,
`
`(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.
`
`5
`
`10
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`15
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`20
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`asymmetric centers and can thus occur as racemates and racemic mixtures, single
`
`The compounds of the present invention may contain one or more
`
`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
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`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
`
`5
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`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
`
` by chromatographic methods utilizing chiral stationary phases, which methods are
`
`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
`
`20
`
`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
`
`well known in the art.
`
`Alternatively, any enantiomer of a compound may be obtained by
`
`25
`
`stereoselective synthesis using optically pure starting materials or reagents of known
`
`configuration by methods well known in the art.
`
`The term "pharmaceutically acceptable salts" refers to salts prepared
`
`from pharmaceutically acceptable non—toxic bases or acids including inorganic or
`
`organic bases and inorganic or organic acids. Salts derivedfrom 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
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`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,N’—dibenzylethylene-
`diamine, diethylamine, 2-diethylaminoethanol, 2—dimethylarrnnoethanol,
`
`ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine,
`
`5
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`10 ,
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`glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucarnine,
`morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine,
`triethylarnine, trimethylamine, tripropylamine, tromethamine, and the like.
`When the compound of the present invention is basic, salts may be
`prepared from pharmaceutically acceptable non—toxic acids, including inorganic and
`organic acids. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic,
`
`citric, ethanesulfonic, fumaric, gluconic, glutarnic, hydrobromic, hydrochloric,
`
`isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic,
`
`pantothenic, phosphoric, succinic, sulfuric, tartaric, p—toluenesulfonic acid, and the
`like. Particularly preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric,
`
`15
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`sulfuric, furnaric, and tartaric acids.
`
`It will be understood that, as used herein, references to the compounds
`
`of Formula I are meant to also include the pharmaceutically acceptable salts.
`
`As appreciated by those of skill in the art, halo or halogen as used
`herein are intended to include fluoro, chloro, bromo and iodo. Similarly, C1_8, as in
`
`20
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`C1_8alkyl is defined to identify the group as having 1, 2, 3, 4, 5, 6, 7 or 8 carbons in a
`
`linear or branched arrangement, such that C1_8alkyl specifically includes methyl,
`
`ethyl, n-propyl, iso—propyl, n-butyl, iso-butyl, tert-butyl, pentyl, hexyl, heptyl and
`octyl. Likewise, Co, as in Coalkyl is defined to identify the presence of a direct
`
`covalent bond. A group which is designated as being independently substituted with
`
`25
`
`substituents may be independently substituted with multiple numbers of such
`
`substituents. The term "heterocycle" as used herein is intended to include 5- or
`
`6—membered ring systems which are within the following listing: benzimidazolyl,
`
`benzodioxanyl, benzofuranyl, benzopyrazolyl, benzothiadiazolyl, benzotriazolyl,
`
`benzothiophenyl, benzoxadiazolyl, benzoxazolyl, carbazolyl, carbolinyl, chromanyl,
`
`30
`
`cinnolinyl, furanyl, imidazolyl,
`
`indolinyl, indolyl, indolazinyl, indazolyl,
`
`isobenzofuranyl, isoindolyl, isoquinolyl, isothiazoly], isoxazolyl, naphthyridinyl,
`
`oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridopyridinyl, pyridazinyl, pyridyl,
`
`pyrimidyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrazolyl, thiadiazolyl,
`thiazolidinyl, thiazolyl, thienyl, triazolyl, azetidinyl, 1,4-dioxanyl, hexahydroazepinyl,
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`piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl,
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`dihydrobenzimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl,
`
`dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl,
`
`dihydroisooxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl,
`
`dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl,
`
`5
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`dihydropyrrolyl, dihydroquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl,
`
`dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl,
`
`methylenedioxybenzoyl, tetrahydrofuranyl, tetrahydroimidazolyl,
`
`tetrahydroisoquinolinyl, and tetrahydrothienyl.
`
`Exemplifying the invention is the use of the compounds disclosed in
`
`10
`
`the Examples and herein.
`
`Specific compounds within the present invention include a compound
`
`which selected from the group consisting of the compounds disclosed in the following
`
`Examples and pharmaceutically acceptable salts thereof and individual diastereomers
`thereof.
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`15
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`The subject compounds are useful in a method of inhibiting the
`
`dipeptidyl peptidase—IV enzyme in a patient such as a mammal in need of such
`
`,
`
`inhibition comprising the administration of an effective amount of the compound.
`
`The present invention is directed to the use of the compounds disclosed herein as
`
`inhibitors of dipeptidyl peptidase-IV enzyme activity.
`
`In addition to primates, such as humans, a variety of other mammals
`
`can be treated according to the method of the present invention. For instance,
`
`mammals including, but not limited to, cows, sheep, goats, horses, dogs, cats, guinea
`
`pigs, rats or other bovine, ovine, equine, canine, feline, rodent or murine species can
`
`A be treated. However, the method can also be practiced in other species, such as avian
`
`25
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`species (e.g., chickens).
`
`The present invention is further directed to a method for the
`
`manufacture of a medicament for inhibiting dipeptidyl peptidase—IV enzyme activity
`
`in humans and animals comprising combining a compound of the present invention
`
`with a pharmaceutical carrier or diluent.
`
`30
`
`The subject treated in the present methods is generally a mammal,
`
`preferably a human being, male or female, in whom inhibition of dipeptidyl peptidase—
`
`IV enzyme activity is desired. The term "therapeutically effective amount" means the
`
`amount of the subject compound that will elicit the biological or medical response of
`
`a tissue, system, animal or human that is being sought by the researcher, veterinarian,
`medical doctor or other clinician.
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`The term "composition" as used herein is intended to encompass a
`
`product comprising the specified ingredients in the specified amounts, as well as any
`
`product which results, directly or indirectly, from combination of the specified
`
`ingredients in the specified amounts. Such term in relation to pharmaceutical
`
`5
`
`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
`
`results, directly or indirectly, from combination, complexation or aggregation of any
`
`two or more of the ingredients, or from dissociation of one or more of the ingredients,
`
`or from other types of reactions or interactions of one or more of the ingredients.
`
`10
`
`Accordingly, the pharmaceutical compositions of the present invention encompass
`
`any composition made by admixing a compound of the present invention and a
`
`pharmaceutically acceptable carrier. By "pharmaceutically acceptable" it is meant the
`
`carrier, diluent or excipient must be compatible with the other ingredients of the
`
`formulation and not deleterious to the recipient thereof.
`
`.15
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`The terms "administration of" and or "administering a" compound
`should be understood to mean providing a compound of the invention or a prodrug of
`
`a compound of the invention to the individual in need of treatment.
`
`The utility of the compounds in accordance with the present invention
`
`as inhibitors of dipeptidyl peptidase—IV enzyme activity may be demonstrated by
`
`20
`
`methodology known in the art. Inhibition constants are determined as follows. A
`
`continuous fluorometric assay is employed with the substrate Gly—Pro—AMC, which is
`
`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];
`km/Km = 1.5 x 106 M‘ls'l. A typical reaction contains approximately 50 pM enzyme,
`
`25
`
`50 MM Gly—Pro-AMC, and buffer (100 mM HEPES, pH 7.5, 0.1 mg/ml BSA) in a
`
`total reaction volume of 100 pl. Liberation of AMC is monitored continuously in a
`
`96—well plate fluorometer using an excitation wavelength of 360 nm and an emission
`
`wavelength of 460 nm. Under these conditions, approximately 0.8 uM AMC is
`
`produced in 30 minutes at 25 degrees C. The enzyme used in these studies was
`
`30
`
`soluble (transmembrane domain and cytoplasmic extension excluded) human protein
`
`produced in a baculovirus expression system (Bac—T0~Bac, Gibco BRL). The kinetic
`
`constants for hydrolysis of Gly-Pro-AMC and GLP-1 were found to be in accord with
`
`literature values for the native enzyme. To measure the dissociation constants for
`
`compounds, solutions of inhibitor in DMSO were added to reactions containing
`
`35
`
`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
`
`above. To determine the dissociation constants (K;), reaction rates were fit by non-
`
`linear regression to the Michaelis—Menton equation for competitive inhibition. The
`
`errors in reproducing the dissociation constants are typically less than two-fold.
`
`5
`
`'
`
`In particular, the compounds of the following examples had activity in
`inhibiting the dipeptidyl peptidase-IV enzyme in the aforementioned assays, generally
`with an IC50 of less than about 1 uM. Such a result is indicative of the intrinsic
`
`activity of the compounds in use as inhibitors the dipeptidyl peptidase—IV enzyme
`
`activity.
`
`10
`
`Dipeptidyl peptidase-IV enzyme (DP—IV) is a cell surface protein that
`
`has been implicated in a wide range of biological functions. It has a broad tissue
`
`distribution (intestine, kidney, liver, pancreas, placenta, thymus, spleen, epithelial
`
`cells, vascular endothelium, lymphoid and myeloid cells, serum), and distinct tissue
`
`and cell—type expression levels. DP—IV is identical to the T cell activation marker
`
`15
`
`CD26, and it can cleave a number of immunoregulatory, endocrine, and neurological
`
`peptides in vitro. This has suggested a potential role for this peptidase in a variety of
`
`disease processes in humans or other species.
`
`Accordingly, the subject compounds are useful in a method for the
`
`prevention or treatment of the following diseases, disorders and conditions.
`
`20
`
`'
`
`Type 11 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“/')-deficicnt
`
`mice and preliminary clinical trials indi