`01014)]
`SUBSTITUTE for Provrsronal Application for Patent Cover Sheet PTO/S /16 ( -00)
`Approved for use through 10/31/2002 OMB 06510037
`U S I’atent arid 'I'Iadcmark Office, U 5 DEPARTMENT OF COMMEREF
`[-
`Ill/Ill!!!”
`OldS'nSSSDI.‘
`n‘Q‘
`1‘
`WIJUILU
`‘w—
`"3,06—
`Dc:—
`lllllllllllllIll/ll
`This is a request for filing aPROVISIONAL APPLICATION FOR PATENT under 37 CFR 1.53 (c).
`1.")m\_
`MC) —ll
` Dw—
`H
`
`
`DOCKET NUMBER
`'1
`
`
`
` ! Type a p133 sign (+) inside this box —>:’
`
`PROVISIONAL APPLICATION FOR PATENT COVER SHEET
`
`20907PV
`
`1NVENTOR(S)
`
`Given Name (first and middle [if any])
`Farmly Name or Surname
`Resrdenee (City and either State or Foreign Country)
`
`Scott D.
`Edmondson
`New York. NY
`Michael H.
`Fisher
`Ringoes, NJ
`Dooseop
`K1111
`Westfield, NJ
`Malcolm
`l MaeCoss
`Freehold, NJ
`Emma R.
`Parmee
`Scotch Plains, NJ
`Ann E.
`Weber
`Scotch Plains, NJ
`Jinyou
`Xu
`Scotch Plains, NJ
`
`
`
`
`[3 Additional inventors are being named on the separately numbered sheets attached hereto
`
`TITLE OF THE INVENTION (280 Characters max)
`t BETA—AMINO HETEROCYCLIC DIFEPTIDYL PEPTIDASE INHIBITORS FOR THE TREATMENT OR PREVENTION OF DIABETES
`
`CORRESPONDENCE ADDRESS
`
`
`- uect all Cnirespondence to:
`Merck & Co , Inc.
`Patent Department - RY60—30
`PO. Box 2000
`
`Customer Number
`
`000210
`
`
`
`Specification
`
`Number of Page:
`
`66
`
`Drawing(s)
`
`Number of Sheets
`
`D Other (specify)
`
`Application Data Sheet. See 37 CFR 1.76
`METHOD OF PAYMENT OF FILING FEES FOR THIS PROVISIONAL APPLICATION FOR PATENT (check one)
`
`
`
`
`
`
`
`Rahway
`‘
`
`TATE
`New Jersey
`ZIP CODE
`l
`07065
`’
`COUNTRY
`US A
`
`
`
`ENCLOSED APPLICATION PARTS (check all that apply)
`
`
`
`
`
`
`A check or money order is enclosed to cover the fiIing fees
`
`
`
`
` X The Commisswner is hereby authorized
`
`FILING FEE
`AMOUNT (5)
`
`$150.00
`
`to charge filing fees or credit any
`13—2755
`overpayment to Deposit Account Number:
`
`The invention was made by an agency of the United States Government or under a contract with an agency of the United States Government.
`
`I: No.
`D Yes, the name of the US. Government agency and the Government contract number are:
`/'
`.
`_,
`
`
`
`
`
`SIGNATURE
`TYPED 0r PRI '
`TELEPHONE
`
`D NAME
`32-594—3904
`
`J. Eric
`
`ies
`
`Date
`
`07/06/2001
`
`REGISTRATION NO.
`(lf'appropriate)
`
`
`
`35,382
`
`
`
`EXPRESS MAIL CERTIFICATE
`
`July 6, 2001
`DATE OF DEPOSIT
`EXPRESS MAIL N0. EL523910547US
`I HEREBY CERTIFY THAT THIS CORRESPONDENCE IS BEH‘IG DEPOSITED WITH TIDE
`UNITED STATES POSTAL SERVICE AS EXPRESS IVIAIL "POST OFFICE T0 ADDRESSEE"
`. N ENVELOPE ADDRESSED T0 ASSISTANT COMMISSIONER
`ON THE ABOVE A
`FOR PATENTS,
`i
`IVIAILED BY
`
`
`
`DATE July 6 2001
`
`In Duplicate
`
`Computer generated form "Transmittal Form-PV" (Application Filing Folder) Merck & Co, Inc, 9/28/00
`
`SUN - |PR2020-01072, Ex. 1012, p. 1 of 70
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`SUN - IPR2020-01072, Ex. 1012, p. 1 of 70
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`
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`INVENTOR INFORMATION
`
`Inventor One Given Name:: Scott D.
`
`Family Name:: Edmondson
`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:: New York
`State or Province of Residence:: NY
`
`Country of Residence:: U.S.A.
`Citizenship Countryz: 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
`Countryzz 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 Countryzz U.S.A.
`Inventor Three Given Name:: Dooseop
`Family Name:: Kim
`
`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:: 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
`
`Countryzz 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
`
`
`
`SUN - |PR2020-01072, Ex. 1012, p. 2 of 70
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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 E.
`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 TWO::
`Title Line Threez:
`
`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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`SUN - IPR2020-01072, Ex. 1012, p. 3 of 70
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`PrintEFS Version 1.0.1
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`20907PV
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`TITLE OF THE INVENTION
`
`BETA-AMINO I-IETEROCYCLIC DIPEPTIDYL PEPTIDASE INHIBITORS FOR
`
`THE TREATMENT OR PREVENTION OF DIABETES
`
`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
`
`15
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`25
`
`30
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`35
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`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;strol<e, 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 (lDDM), 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.
`
`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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`condition, compliance with this treatment is very poor because of well-entrenched
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`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,
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`15
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`20
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`25
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`30
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`35
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`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.
`
`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—gamrna 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.
`
`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
`
`treatment of diabetes, and particularly type 2 diabetes. See for example W0
`_ 2 _
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`V
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`20907PV
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`U1
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`10
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`15
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`25
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`3'0
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`97/40832, WO 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 viva readily inactivates glucagon like peptide-l (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.
`
`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.
`
`SUNIMARY 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.
`
`SUN - |PR2020-01072, Ex. 1012, p. 7 of 70
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`DETAILED DESCRIPTION OF THE LNVENTION
`
`The present invention is directed to compounds of the formula I:
`
`uHZ o
`NMNVN\
`LIN/X1
`
`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 1-6a1kyl, which is linear or branched and is unsubstituted or
`
`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;
`
`X is selected from the group consisting of:
`
`(1)
`
`(2)
`
`N, and
`
`CR2;
`
` 10
`
`15
`
`20
`
`25
`
`3O
`
`R1 and R2 are independently selected from the group consisting of:
`
`(1)
`
`(2)
`
`(3)
`
`hydrogen,
`
`CN,
`
`C 1-10alkyl, 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, SOZR4, COzH, 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,
`
`$02114, COQH, and C02C1_6alkyl, wherein the C02C1_6alkyl is
`
`linear or branched, and
`
`-4-
`
`SUN - |PR2020-01072, Ex. 1012, p. 8 of 70
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`SUN - IPR2020-01072, Ex. 1012, p. 8 of 70
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`
`)
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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, S and O,
`
`the heterocycle being unsubstituted or substituted with 1-3 substituents
`
`independently selected from 0x0, OH, halogen, C1_6alkyl, and
`
`5
`
`OC 1-6alkyl, wherein the C 1-6alkyl and OC1-6alkyl are linear or
`
`branched and optionally substituted with 1—5 halogens;
`
`R4 is C 1-6alkyl, 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 diastereomers thereof.
`
`15
`
`formula Ia:
`
`An embodiment of the present invention includes compounds of the
`
`NH2 0
`
`”MN/Y”\
`9N4):
`
`Ia
`
`wherein X, Ar and R1 are defined herein;
`
`and pharmaceutically acceptable salts and individual diastereomers thereof.
`
`20
`
`the formula Ib:
`
`Another embodiment of the present invention includes compounds of
`
`NH2 0
`
`“MN/Ed“
`
`25
`
`wherein Ar and R1 are defined herein;
`
`SUN - |PR2020-01072, Ex. 1012, p. 9 of 70
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`v
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`20907PV
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` 10
`
`15
`
`20
`
`25
`
`and pharmaceutically acceptable salts and individual diastereomers thereof.
`
`the formula 10:
`
`Another embodiment of the present invention includes compounds of
`
`NH2 0
`
`Ar\/'\)J\N/\FN
`ow
`
`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:
`(l)
`fluoro,
`
`(2)
`(3)
`
`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—difluorophenyl,
`
`2,4,5-t1ifluorophenyl,
`
`2-fluoro—4—(triflouromethyl)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
`
`SUN - |PR2020-01072, Ex. 1012, p. 10 of 70
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`SUN - IPR2020-01072, Ex. 1012, p. 10 of 70
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`20907PV
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`
`
`(2)
`
`C1_6all<yl, 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,
`CF3,
`
`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,
`CF“ , 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)
`hydrogen,
`
`(2)
`
`C 1-6alkyl, which is linear or branched and which is
`
`unsubstituted or substituted with 1-5 fluoro,
`
`(3)
`
`phenyl, which is unsubstituted or substituted with 1-3
`substituents independently selected from fluoro, OCH3, and
`
`OCF3.
`
`_ 7 _
`
`SUN - |PR2020-01072, Ex. 1012, p. 11 of 70
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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-trifluoromethox y)phen yl,
`
`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
`
`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
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`meant to comprehend all such isomeric forms of these compounds.
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`Some of the compounds described herein contain olefinic double
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`bonds, and unless specified otherwise, are meant to include both E and Z geometric
`isomers.
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`Some of the compounds described herein may exist as tautomers,
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`which have different points of attachment of hydrogen accompanied by one or more
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`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
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`compounds of the present invention.
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`Formula I shows the structure of the class of compounds without
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`preferred stereochemistry. Formula Ia. shows the preferred sterochemistry at the
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`carbon atom that is attached to the amine group of the beta amino acid from which
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`these compounds are prepared.
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`The independent syntheses of these diastereomers or their
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`chromatographic separations may be achieved as known in the art by appropriate
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`modification of the methodology disclosed herein. Their absolute stereochemistry
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`may be determined by the x-ray crystallography of crystalline products or crystalline
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`intermediates which are derivatized, if necessary, with a reagent containing an
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`asymmetric center of known absolute configuration.
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`If desired, racemic mixtures of the compounds may be separated so
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`that the individual enantiomers are isolated. The separation can be carried out by
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`methods well known in the art, such as the coupling of a racernic mixture of
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`compounds to an enantiomerically pure compound to form a diastereomeric mixture,
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`followed by separation of the individual diastereomers by standard methods, such as
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`fractional crystallization or chromatography. The coupling reaction is often the
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`formation of salts using an enantiomerically pure acid or base. The diasteromeric
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`derivatives may then be converted to the pure enantiomers by cleavage of the added
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`chiral residue. The racemic mixture of the compounds can also be separated directly
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`by chromatographic methods utilizing chiral stationary phases, which methods are
`well known in the art.
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`Alternatively, any enantiomer of a compound may be obtained by
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`stereoselective synthesis using optically pure starting materials or reagents of known
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`configuration by methods well known in the art.
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`The term "pharmaceutically acceptable salts" refers to salts prepared
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`from pharmaceutically acceptable non—toxic bases or acids including inorganic or
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`organic bases and inorganic or organic acids. Salts derivedfrom inorganic bases
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`include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium,
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`manganic salts, manganous, potassium, sodium, zinc, and the like. Particularly
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`preferred are the ammonium, calcium, magnesium, potassium, and sodium salts. Salts
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`in the solid form may exist in more than one crystal structure, and may also be in the
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`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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`a
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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—
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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, isopropylamjne, lysine, methylglucamine,
`morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine,
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`triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
`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
`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
`like. Particularly preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric,
`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
`herein are intended to include fluoro, chloro, bromo and iodo. Similarly, C1_8, as in
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`C1_3alkyl 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
`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,
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`oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridopyridinyl, pyridazinyl, pyridyl,
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`pyrimidyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrazolyl, thiadiazolyl,
`thiazolidinyl, thiazolyl, thienyl, triazolyl, 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,
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`dihydroisooxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl,
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`dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrirnidinyl,
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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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`the Examples and herein.
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`Exemplifying the invention is the use of the compounds disclosed in
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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 pharrnaceutically 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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`.
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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 mun'ne 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 (eg, 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,
`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),
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`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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`pharrnaceutically 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
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`parameters that describe this reaction are as follows: Km = 50 MM; kcat = 75 s};
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`km/Km = 1.5 x 106 M‘ls‘l. A typical reaction contains approximately 50 pM enzyme,
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`50 MM 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 ul. 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 uM 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—T0~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
`
`inhibiting the dipeptidyl peptidase—IV enzyme in the aforementioned assays, generally
`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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`hpe II Diabetes and Related Disorders: It is well establish