`
`0s~s~r:::Jfor Prov!Slonal Apphcation for Patent Cover Sheet PTO/Sfj i,J([ /{.J:; J
`PROVISIONAL APPLICATION FOR PATENT COVER SHEET
`
`Th1s 1s a request for filmg a PROVISIONAL APPLICATION FOR PATENT under 37 CFR 1.53 (c).
`
`I DOCKET NUMBER
`
`120907PV
`
`ID---.......
`~-
`
`Approved for use through I 0/3l/2002 OMB 0651-0037
`US I':ttent arrct 1'rademark Office, US DEPARTMENT OF COMMERtf
`-
`E-o
`llo~-
`r-- - . - i
`CJ
`,:..~
`v~~-.......
`:::>~
`~
`Mc=.J =r-
`r-------------------.---------------~~-CJ
`
`Given Name (first and rmddte [if any])
`Scott D.
`l Michael H.
`'Dooseop
`Malcolm
`EmmaR.
`Ann E.
`Jinyou
`
`INVENTOR(S)
`Farmty Name or Surname
`Edmondson
`Fisher
`Kim
`MacCoss
`Parmee
`'.Veber
`Xu
`
`Restdence (City and either State or Foreign Country)
`New York. NY
`Ringoes, NJ
`Westfield, NJ
`Freehold, NJ
`Scotch Plains, NJ
`Scotch Plams, NJ
`Scotch Plams, NJ
`
`j 0 Additional inventors are bemg 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
`
`'~rect all Correspondence to:
`
`CORRESPONDENCE ADDRESS
`
`~'-·
`~'-"]STATE
`'""'
`
`I
`
`Kew Jersey
`
`~ Customer Number
`
`1==0=00=2=10==1
`
`07065
`
`COUNTRY
`
`I
`
`U.S A
`
`I
`1
`ENCLOSED APPLICATION PARTS (check all that apply)
`
`Merck & Co , Inc.
`Patent Department- RY60-30
`P.O. Box 2000
`Rahway
`I
`
`ZIP CODE
`
`I
`
`1 ~ Specification
`
`Number of Pages
`
`Number of Sheets
`
`I
`METHOD OF PAYMENT OF FILING FEES FOR THIS PROVISIONAL APPLICATION FOR PATENT (check one)
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`D Other (specify)
`
`i diJ Drawing(s)
`fu Application Data Sheet. See 37 CFR 1.76
`' D A check or money order is enclosed to cover the filmg fees
`I
`The CommissiOner is hereby authorized
`13-2755
`to charge filing fees or credit any
`overpayment to Deposit Account Number: L------------------'
`The invention was made by an agency of the United States Government or under a contract with an agency of the United States Government.
`0No.
`D Yes, the name of the U.S. Government agency and the Government contract number are:
`
`::..-~:;..
`
`I
`
`FILING FEE
`AMOUNT($)
`
`$150.00
`
`SIGNATURE
`TYPEDorPRI
`TELEPHONE,1~~~~~-----------------------------
`
`Date I 07/06/2001
`REGISTRATION NO. 135,382
`(if appropriate) ' - - - - - - - - - - - - - '
`
`DATE OF DEPOSIT
`
`EXPRESS MAIL CERTIFICATE
`,_,Ju"'-IL6""-=2~00~1,__ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
`
`EXPRESS MAIL NO. =E=L5=2=3"'-9""10""5-'-47'-'U""S"-----------------
`I HEREBY CERTIFY THAT THIS CORRESPONDENCE IS BEING DEPOSITED WITH THE
`UNITED STATES POSTAL SERVICE AS EXPRESS MAIL "POST OFFICE TO ADDRESSEE"
`
`FOR PATENTS,
`MAILED BY
`
`In Duplicate
`
`Computer generated form "Transmittal Form-PV" (Application Filing Folder) Merck & Co., Inc., 9/28/00
`
`DRL Ex. 1012, p. 001
`
`
`
`INVENTOR INFORMATION
`
`Inventor One Given Name:: Scott D.
`Family Name:: Edmondson
`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 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:: 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 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:: 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 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:: 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
`
`DRL Ex. 1012, p. 002
`
`
`
`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.
`Citi
`Country:: United Kingdom
`Inventor Six Given Name:: Ann E.
`Family Name:: Weber
`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:: 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 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:: Scotch Plains
`State or Province of
`: : NJ
`Country of Residence:: U.S.A.
`Citizenship Country:: China
`
`CORRESPONDENCE INFORMATION
`
`Correspondence Customer Number:: 000210
`
`APPLICATION INFORMATION
`
`Title Line One::
`BETA-AMINO HETEROCYCLIC DIPEPTIDYL PEPTI
`Title Line Two::
`DASE INHIBITORS FOR THE TREATMENT OR PRE
`tle Line Three::
`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
`
`DRL Ex. 1012, p. 003
`
`
`
`Source:: PrintEFS Version 1.0.1
`
`DRL Ex. 1012, p. 004
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`
`
`20907PV
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`TITLE OF THE INVENTION
`BET A-AMINO HETEROCYCLIC DIPEPTIDYL PEPTIDASE INHJBITORS FOR
`THE TREATMENT OR PREVENTION OF DIABETES
`
`5
`
`15
`
`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
`10 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
`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.
`
`20
`
`25
`
`30
`
`The available treatments for type 2 diabetes, which have not changed
`substantially in many years, have recognized limitations. While physical exercise and
`reductions in dietary intake of calories will dramatically improve the diabetic
`- 1 -
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`35
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`DRL Ex. 1012, p. 005
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`
`
`20907PV
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`5
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`10
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`15
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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 ~-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
`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. Metforrnin has fewer side effects than phenformin and is often
`prescribed for the treatment of Type 2 diabetes.
`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
`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.
`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-lB (PTP-lB) 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
`treatment of diabetes, and particularly type 2 diabetes. See for example WO
`- 2 -
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`35
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`20
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`25
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`DRL Ex. 1012, p. 006
`
`
`
`20907PV
`
`5
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`97/40832, WO 98119998, U.S. Patent No. 5,939,560, Bioorg. 1Vled. Chern. Lett., 6(10),
`1163-1166 (1996); and Bioorg. Med. Chern. 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
`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.
`
`15
`
`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
`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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`30
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`- 3-
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`DRL Ex. 1012, p. 007
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`20907PV
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`DETAILED DESCRIPTION OF THE INVENTION
`The present invention is directed to compounds of the formula I:
`
`I
`
`10
`
`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:
`( 1)
`halogen,
`(2)
`C 1-6alkyl, which is linear or branched and is unsubstituted or
`substituted with 1-5 halogens,
`OC l-6alkyl, which is linear or branched and is unsubstituted or
`substituted with 1-5 halogens, and
`CN;
`
`(3)
`
`(4)
`
`15 X is selected from the group consisting of:
`N, and
`(1)
`CR2;
`(2)
`
`R1 and R2 are independently selected from the group consisting of:
`(1)
`hydrogen,
`CN,
`(2)
`C1-1oalkyl, which is linear or branched and which is unsubstituted or
`(3)
`substituted with 1-5 halogens or phenyl, which is unsubstituted or
`substituted with 1-5 substituents independently selected from halogen,
`CN, OH, R4, OR4, NHS02R4, S02R4, C02H, and C02C1-6alkyl,
`wherein the C02C1-6alkyl is linear or branched,
`phenyl which is unsubstituted or substituted with 1-5 substituents
`independently selected from halogen, CN, OH, R4, OR4, NHS02R4,
`S02R4, C02H, and C02C1-6alkyl, wherein the C02C1-6alkyl is
`linear or branched, and
`
`(4)
`
`20
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`25
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`-4-
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`DRL Ex. 1012, p. 008
`
`
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`20907PV
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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, Sand 0,
`the heterocycle being unsubstituted or substituted with 1-3 substituents
`independently selected from oxo, OH, halogen, C 1-6alkyl, and
`OC 1-6alkyl, wherein the C 1-6alkyl and OC 1-6alkyl are linear or
`branched and optionally substituted with 1-5 halogens;
`
`R 4 is C 1-6alky1, which is linear or branched and which is unsubstituted or substituted
`with 1-5 groups independently selected from halogen, C02H, and
`C02C 1-6alkyl, wherein the C02C I-6alkyl is linear or branched;
`
`5
`
`10
`
`and pharmaceutically acceptable salts thereof and individual diastereomers thereof.
`
`An embodiment of the present invention includes compounds of the
`
`15
`
`formula Ia:
`
`wherein X, Ar and R 1 are defined herein;
`and pharmaceutically acceptable salts and individual diastereomers thereof.
`
`I a
`
`20
`
`Another embodiment of the present invention includes compounds of
`the formula Ib:
`
`25 wherein Ar and R 1 are defined herein;
`
`Ib
`
`- 5-
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`DRL Ex. 1012, p. 009
`
`
`
`20907PV
`
`and pharmaceutically acceptable salts and individual diastereomers thereof.
`
`Another embodiment of the present invention includes compounds of
`the formulaIc:
`
`5
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`10
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`15
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`20
`
`25
`
`Ic
`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:
`fluoro,
`(1)
`bromo, and
`(2)
`CF3.
`(3)
`
`In the present invention it is more preferred that Ar is selected from the
`group consisting of:
`phenyl,
`(1)
`2-fluorophenyl,
`(2)
`3,4-difluorophenyl,
`(3)
`(4)
`2,5-difluorophenyl,
`(5)
`2,4,5-trifluorophenyl,
`2-fluoro-4-(triflouromethyl)phenyl, and
`(6)
`4-bromo-2,5-difluorophenyl.
`(7)
`
`In the present invention it is preferred that R 1 is selected from the
`group consisting of:
`(1)
`
`hydrogen,and
`
`-6-
`
`DRL Ex. 1012, p. 010
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`20907PV
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`;:;:
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`(2)
`
`Ct-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 R 1 is selected from the
`group consisting of:
`(1)
`(2)
`(3)
`(4)
`(5)
`(5)
`(6)
`(7)
`
`hydrogen,
`methyl,
`ethyl,
`CF3,
`CH2CF3,
`CF2CF3
`phenyl, and
`benzyl.
`
`In the present invention it is more preferred that R 1 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 R I is hydrogen
`
`or CF3.
`
`In the present invention it is preferred that R2 is selected from:
`hydrogen,
`(1)
`(2)
`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.
`
`(3)
`
`-7-
`
`DRL Ex. 1012, p. 011
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`
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`20907PV
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`5
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`20
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`25
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`30
`
`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)
`(1 0)
`
`hydrogen,
`methyl,
`ethyl,
`CF3,
`CH2CF3,
`CF2CF3
`phenyl,
`(4-methoxy)phenyl,
`(4-trifluoromethoxy)phenyl,
`4-fluorophenyl, and
`3 ,4-difluorophenyl.
`
`In the present invention it is even more preferred that R 2 is CF3 or
`
`In the present invention it is preferred that R3 is F, Br or CF3.
`
`The compounds of the present invention may contain one or more
`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
`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
`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.
`
`- 8-
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`DRL Ex. 1012, p. 012
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`20907PV
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`20
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`25
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`
`The indtvidual 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 deri vatized, if necessary, with a reagent containing an
`asymmetric center of known absolute configuration.
`If desired, r~cemic 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.
`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 derived,from inorganic bases
`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
`bases include salts of primary, secondary, and tertiary amines, substituted amines
`-9-
`
`30
`
`35
`
`DRL Ex. 1012, p. 013
`
`
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`20907PV
`
`5
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`35
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`10
`
`15
`
`25
`
`including naturally occurring substituted arnines, cyclic amines, and basic ion
`exchange resins, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylene-
`diamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol,
`ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine,
`glucosarnine, histidine, hydrabarnine, isopropylamine, lysine, methylglucamine,
`morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine,
`triethylamine, 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, carnphorsulfonic,
`citric, ethanesulfonic, fumaric, gluconic, glutamic, 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,
`sulfuric, fumaric, 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 CI-salkyl 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 C 1-salkyl 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
`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: benzirnidazolyl,
`benzodioxanyl, benzofuranyl, benzopyrazolyl, benzothiadiazolyl, benzotriazolyl,
`benzothiophenyl, benzoxadiazolyl, benzoxazolyl, carbazolyl, carbolinyl, chromanyl,
`cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, indolazinyl, indazolyl,
`isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, 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,
`piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl,
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`dihydrobenzimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl,
`dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl,
`dihydroisooxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl,
`dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl,
`dihydropyrrolyl, dihydroquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl,
`dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl,
`meth ylenedi ox ybenzoyl, tetrah ydrofuranyl, tetrahydroimi dazol yl,
`tetrahydroisoquinolinyl, and tetrahydrothienyl.
`Exemplifying the invention is the use of the compounds disclosed in
`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.
`
`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
`be treated. However, the method can also be practiced in other species, such as avian
`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.
`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,
`35 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
`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.
`The terms "adrp.inistration 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 A1\1C leaving group. The kinetic
`parameters that describe this reaction are as follows: Km =50 ~-tM; kcat = 75 s- 1
`;
`kcat1Km = 1.5 x 106 M-ls-1. A typical reaction contains approximately 50 pM enzyme,
`50 ~-tM Gly-Pro-AMC, and buffer (100 IlllVi HEPES, pH 7.5, 0.1 mg/ml BSA) in a
`total reaction volume of 100 ~-tl. 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 ~-tM AMC is
`produced in 30 minutes at 25 degrees C. The enzyme used in these studies was
`soluble (transmembrane domain and cytoplasmic extension excluded) human protein
`produced in a baculovirus expression system (Bac-To-Bac, Gibco BRL). The kinetic
`constants for hydrolysis of Gly-Pro-Al\IIC 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
`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 (Ki), 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.
`In particular, the compounds of the following examples had activity in
`inhibiting the dipeptidyl peptidase-IV enzyme in the aforementioned assays, generally
`with an ICso of less than about 1 Jl.rvL Such a result is indicative of the intrinsic
`activity of the compounds in use as inhibitors the dipeptidyl peptidase-IV enzyme
`activity.
`
`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
`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.
`
`Tvpe ll 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(-I-)_deficient
`mice and preliminary clinical trials indicate that DP-IV inhibition increases the steady
`state concentrations of GLP-1 and GIP, resulting in improved glucose tolerance. By
`analogy to GLP-1 and GIP, it is likely that other glucagon family peptides involved in
`glucose regulation are also inactivated by DP-IV (eg. PACAP, glucagon).
`Inactivation of these peptides by DP-IV may also play a role in glucose homeostasis.
`The DP-IV inhibitors of the present invention therefore have utility in
`the treatment of type ll diabetes and in the treatment and prevention of the numerous
`conditions that often accompany Type II diabetes, including metabolic syndrome X,
`reac