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`IllllllgllllllllllullIlllllllllll
`I17---
`
`
`
`ate 0 Deposit
`
`{E Z
`
`1
`
`FILING BY “EXPRESS MAIL” UNDER 37 CFR 1.10
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`EL600712719US
`
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`
`Express Mail Label Number
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`Address to: Assistant Commissioner for Patents
`Box Patent Application
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`
`Fa‘
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`UTILITY PATENT APPLICATION TRANSMITTAL AND FEE SHEET
`
`Transmitted herewith for filing under 37 CFR §1.53(b) is the utility patent application of
`
`Applicant (or identifier): ROBL ET AL.
`
`Title:
`
`CYCLOPROPYL-FUSED PYRROLIDINE-BASED INHIBITORS OF
`DIPEPTIDYL PEPTIDASE IV AND METHOD
`
`-
`
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`
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`TEVA - EXHIBIT 1005 - PART 1 OF 3
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`
`Docket No. LA005O NP
`
`X] Please charge Deposit Account No. 19-3880 in the name of Bristol—Myers Squibb Company
`in the amount of $782. An additional copy of this paper is enclosed. The Commissioner is
`hereby authorized to charge any additional fees under 37 CFR §1.16 and §1.17 which may
`be required in connection with this application, or credit any overpayment, to Deposit
`Account No. 19-3880 in the name of Bristol—Myers Squibb Company.
`
`Please address all correspondence to the address associated with Customer No. 23914, which
`is currently:
`Marla J. Mathias
`
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`
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`
`Please direct all telephone calls to the undersigned at the number given below, and all telefaxes
`to (609) 252-4526.
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`Respectfully submitted,
`
` Date: % /
`
`Attorney for Applicants
`Reg. No. 22,076
`Tel. No. (609) 252-4336
`
`
`
`0002
`
`0002
`
`

`
`LAOO50 NP ‘
`
`O
`
`CYCLOPROPYL-FUSED PYRROLIDINE-BASED INHIBITORS OF
`
`DIPEPTIDYL PEPTIDASE IV AND METHOD
`
`This application takes priority from U.S.
`
`provisional application No. 60/188,555, filed March 10,
`2000.
`
`
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`
`Field of the Invention
`
`The present invention relates to cyclopropyl—fused
`
`pyrrolidine—based inhibitors of dipeptidyl peptidase IV
`
`(DP—4), and to a method for treating diabetes, especially
`
`Type II diabetes, as well as hyperglycemia, Syndrome X,
`
`diabetic complications, hyperinsulinemia, obesity,
`
`atherosclerosis and related diseases, as well as various
`
`immunomodulatory diseases and chronic inflammatory bowel
`
`disease, employing such cyclopropyl—fused pyrrolidines
`
`alone or in combination with another type antidiabetic
`
`agent and/or other type therapeutic agent.
`
`Background of the Invention
`
`Depeptidyl peptidase IV (DP—4)
`
`is a membrane bound
`
`non—classical serine aminodipeptidase which is located in
`
`a variety of tissues (intestine,
`
`liver,
`
`lung, kidney) as
`
`well as on circulating T—lymphocytes
`
`(where the enzyme is
`
`known as CD—26).
`
`It is responsible for the metabolic
`
`cleavage of certain endogenous peptides (GLP—l(7—36),
`
`glucagon)
`
`in vivo and has demonstrated proteolytic
`
`activity against a variety of other peptides (GHRH, NPY,
`
`GLP—2, VIP)
`
`in vitro.
`
`GLP—l(7—36)
`
`is a 29 amino—acid peptide derived by
`
`post—translational processing of proglucagon in the small
`
`intestine.
`
`GLP—l(7—36) has multiple actions in vivo
`
`including the stimulation of insulin secretion,
`
`inhibition of glucagon secretion,
`
`the promotion of
`
`satiety, and the slowing of gastric emptying. Based on
`
`its physiological profile,
`
`the actions of GLP—l(7—36) are
`
`expected to be beneficial in the prevention and treatment
`
`0003
`
`0003
`
`

`
`LAOO50 NP .
`
`.
`
`of type II diabetes and potentially obesity.
`
`To support
`
`this claim, exogenous administration of GLP—1(7—36)
`
`(continuous infusion)
`
`in diabetic patients has
`
`demonstrated efficacy in this patient population.
`
`Unfortunately GLP—l(7—36)
`
`is degraded rapidly in vivo and
`
`has been shown to have a short half—life in vivo
`
`(tl/2~1.5 min).
`
`Based on a study of genetically bred DP-
`
`4 KO mice and on in vivo/in vitro studies with selective
`
`DP—4 inhibitors, DP—4 has been shown to be the primary
`
`degrading enzyme of GLP—l(7—36)
`
`in vivo.
`
`GLP—l(7—36)
`
`is
`
`degraded by DP—4 efficiently to GLP—1(9—36), which has
`
`been speculated to act as a physiological antagonist to
`
`GLP—l(7—36).
`
`Thus,
`
`inhibition of DP—4
`
`in vivo should
`
`potentiate endogenous levels of GLP—1(7—36) and attenuate
`
`formation of its antagonist GLP-l(9—36) and thus serve to
`
`ameliorate the diabetic condition.
`
`Description of the Invention
`
`In accordance with the present invention,
`
`cyclopropyl—fused pyrrolidine—based compounds are
`
`provided which inhibit DP—4 and have the structure
`I
`
`wherein x is O or 1 and y is O or 1
`
`(provided that
`
`o
`
`x
`
`x = 1 when y = 0 and
`
`x = 0 when y = 1);
`
`n is 0 or 1;
`
`X is H or CN (that is cyano);
`
`R1, R2, R3 and R5 are the same or different and are
`
`independently selected from H, alkyl, alkenyl, alkynyl,
`
`cycloalkyl, cycloalkylalkyl, bicycloalkyl,
`
`tricycloalkyl,
`
`alkylcycloalkyl, hydroxyalkyl, hydroxyalkylcycloalkyl,
`
`hydroxycycloalkyl, hydroxybicycloalkyl,
`
`hydroxytricycloalkyl, bicycloalkylalkyl, alkylthioalkyl,
`
`-2-
`
`
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`0004
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`0004
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`

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`0005
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`LAoo5o NP “
`
`.
`
`arylalkylthioalkyl, cycloalkenyl, aryl, aralkyl,
`
`heteroaryl, heteroarylalkyl, cycloheteroalkyl and
`
`Cycloheteroalkylalkyl, all optionally substituted through
`
`available carbon atoms with 1, 2, 3, 4 or 5 groups
`
`selected from hydrogen, halo, alkyl, polyhaloalkyl,
`
`alkoxy, haloalkoxy, polyhaloalkoxy, alkoxycarbonyl,
`
`alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,
`
`polycycloalkyl, heteroarylamino, arylamino,
`
`cycloheteroalkyl, cycloheteroalkylalkyl, hydroxy,
`
`hydroxyalkyl, nitro, cyano, amino, substituted amino,
`
`alkylamino, dialkylamino,
`
`thiol, alkylthio,
`
`alkylcarbonyl, acyl, alkoxycarbonyl, aminocarbonyl,
`
`alkynylaminocarbonyl, alkylaminocarbonyl,
`
`alkenylaminocarbonyl, alkylcarbonyloxy,
`
`alkylcarbonylamino, arylcarbonylamino,
`
`alkylsulfonylamino, alkylaminocarbonylamino,
`
`alkoxycarbonylamino, alkylsulfonyl, aminosulfonyl,
`
`alkylsulfinyl, sulfonamido or sulfonyl;
`
`and R1 and R3 may optionally be taken together to
`
`form —(CR%f)m— where m is 2 to 6, and R5 and R6 are the
`
`same or different and are independently selected from
`
`hydroxy, alkoxy, cyano, H, alkyl, alkenyl, alkynyl,
`
`cycloalkyl, cycloalkylalkyl, cycloalkenyl, aryl,
`
`arylalkyl, heteroaryl, heteroarylalkyl, cycloheteroalkyl,
`
`halo, amino, substituted amino, cycloheteroalkylalkyl,
`
`alkylcarbonylamino, arylcarbonylamino,
`
`alkoxycarbonylamino, aryloxycarbonylamino,
`
`alkoxycarbonyl, aryloxycarbonyl, or
`
`alkylaminocarbonylamino, or R1 and R3 may optionally be
`
`taken together to form —(CRWV)P— where p is 2 to 6, and R7
`
`and R? are the same or different and are independently
`
`selected from hydroxy, alkoxy, cyano, H, alkyl, alkenyl,
`
`alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, aryl,
`
`arylalkyl, heteroaryl, heteroarylalkyl, cycloheteroalkyl,
`
`halo, amino, substituted amino, cycloheteroalkylalkyl,
`
`alkylcarbonylamino, arylcarbonylamino,
`
`alkoxycarbonylamino, aryloxycarbonylamino,
`
`10
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`15
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`20
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`30
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`35
`
`
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`0005
`
`

`
`LAO050 NP
`
`.
`
`alkoxycarbonyl, aryloxycarbonyl, or
`
`alkylaminocarbonylamino, or optionally R? and R3 together
`-1,
`( pg)4
`
`with
`
`R
`
`form a 5 to 7 membered ring containing a
`
`total of 2 to 4 heteroatoms selected from N, O, S, S0, or
`
`5
`
`S02;
`
`or optionally R? and R3 together with
`
`(rwpg)
`
`R‘
`
`form
`
`a 4 to 8 membered cycloheteroalkyl ring wherein the
`
`cycloheteroalkyl ring has an optional aryl ring fused
`
`thereto or an optional 3 to 7 membered cycloalkyl ring
`
`10
`
`fused thereto;
`
`and including pharmaceutically acceptable salts
`
`thereof, and prodrug esters thereof, and all
`stereoisomers thereof.
`
`Thus,
`
`the compounds of formula I of the invention
`
`15
`
`include the following structures
`IA
`
`R3
`
`R2 R1
`
`‘/N
`
`H
`
`1'1
`
`N
`
`R4
`
`0
`
`X
`
`R3
`
`R; R1
`
`/ N
`
`H
`
`1').
`
`R4
`
`N
`
`o
`
`X
`
`IB
`
`20
`
`In addition,
`
`in accordance with the present
`
`invention, a method is provided for treating diabetes,
`
`especially Type II diabetes, as well as impaired glucose
`
`homeostasis,
`
`impaired glucose tolerance, infertility,
`
`25
`
`polycystic ovary syndrome, growth disorders,
`
`frailty, arthritis, allograft rejection in transplant-
`
`ation, autoimmune diseases (such as scleroderma and
`
`
`
`0006
`
`0006
`
`

`
`LAOOSO NP 0
`
`.
`
`multiple sclerosis), various immunomodulatory diseases
`
`(such as lupus erythematosis or psoriasis), AIDS,
`
`intestinal diseases (such as necrotizing enteritis,
`
`microvillus inclusion disease or celiac disease),
`
`inflammatory bowel syndrome, chemotherapy—induced
`
`intestinal mucosal atrophy or injury, anorexia nervosa,
`
`osteoporosis, Syndrome X, dysmetabolic syndrome, diabetic
`
`complications, hyperinsulinemia, obesity, atherosclerosis
`
`and related diseases, as well as inflammatory bowel
`
`disease(such as Crohn's disease and ulcerative colitis),
`
`wherein a therapeutically effective amount of a compound
`
`of structure I
`
`(which inhibits DP 4)
`
`is administered to a
`
`human patient in need of treatment.
`
`The conditions, diseases, and maladies collectively
`
`referenced to as “Syndrome X” or Metabolic Syndrome are
`
`detailed in Johannsson J. Clin. Endocrinol. Metab., 32,
`
`727-734 (l997).
`
`10
`
`15
`
`In addition,
`
`in accordance with the present
`
`invention, a method is provided for treating diabetes and
`
`20
`
`related diseases as defined above and hereinafter as well
`
`as any of the other disease states mentioned above,
`
`wherein a therapeutically effective amount of a
`
`combination of a compound of structure I and one,
`
`two,
`
`three or more of other types of antidiabetic agent(s)
`
`(which may be employed to treat diabetes and related
`
`diseases) and/or one,
`
`two or three or more other types of
`
`therapeutic agent(s)
`
`is administered to a human patient
`
`in need of treatment.
`
`The term “diabetes and related diseases” refers to
`
`Type II diabetes, Type I diabetes,
`
`impaired glucose
`
`tolerance, obesity, hyperglycemia, Syndrome X,
`
`dysmetabolic syndrome, diabetic complications,
`
`dysmetabolic syndrome, and hyperinsulinemia.
`
`The conditions, diseases and maladies collectively
`
`referred to as “diabetic complications” include
`
`retinopathy, neuropathy and nephropathy, and other known
`
`complications of diabetes.
`
`25
`
`30
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`35
`
`
`
`0007
`
`0007
`
`

`
`0008
`
`LA0050 NP
`
`.
`
`The term “other type(s) of therapeutic agents” as
`
`employed herein refers to one or more antidiabetic agents
`
`(other than DP4 inhibitors of formula I), one or more
`
`anti—obesity agents, and/or one or more lipid—modulating
`
`agents (including anti—atherosclerosis agents), and/or
`
`one or more infertility agents, one or more agents for
`
`treating polycystic ovary syndrome, one or more agents
`
`for treating growth disorders, one or more agents for
`
`treating frailty, one or more agents for treating
`
`arthritis, one or more agents for preventing allograft
`
`rejection in transplantation, one or more agents for
`
`treating autoimmune diseases, one or more anti—AIDS
`
`agents, one or more anti—osteoporosis agents, one or more
`
`agents for treating immunomodulatory diseases, one or
`
`more agents for treating chronic inflammatory bowel
`
`disease or syndrome and/or one or more agents for
`
`treating anorexia nervosa.
`
`The term “lipid—modulating” agent as employed
`
`herein refers to agents which lower LDL and/or raise HDL
`
`and/or lower triglycerides and/or lower total cholesterol
`
`and/or other known mechanisms for therapeutically
`
`treating lipid disorders.
`
`In the above methods of the invention,
`
`the
`
`compound of structure I will be employed in a weight
`
`ratio to the antidiabetic agent or other type therapeutic
`
`agent
`
`(depending upon its mode of operation) within the
`
`range from about 0.01:1 to about 500:1, preferably from
`
`about 0.1:1 to about 100:1, more preferably from about
`
`0.2:1 to about 10:1.
`
`Preferred are compounds of formula I wherein R3 is
`
`H or alkyl, R1 is H, alkyl, cycloalkyl, bicycloalkyl,
`
`tricycloalkyl, alkylcycloalkyl, hydroxyalkyl,
`
`hydroxytricycloalkyl, hydroxycycloalkyl,
`
`hydroxybicycloalkyl, or hydroxyalkylcycloalkyl, R? is H or
`
`alkyl, n is 0, X is CN, x is O or 1 and y is 0 or 1.
`
`10
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`0008
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`

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`LAOOSO NP .
`
`.
`
`Most preferred are preferred compounds of formula
`I
`I as described above where X is CN °r “CN I
`
`and/or wherein the fused cyclopropyl group is
`
`identified as
`
`i
`
`.
`
`5
`
`Thus, preferred compounds of formula I of the
`
`invention will include the moiety:
`
`/N
`
`)3,
`
`CN
`
`([?‘<x1
`
`I
`
`,
`
`X
`
`x
`
`or
`
`(
`/N
`
`)y
`
`CN
`
`Particularly preferred are the following compounds:
`
`
`
`10
`
`15
`
`
`
`[1S,2(2S),3S,5S]
`
`wherein R1 is alkyl, cycloalkyl, bicycloalkyl,
`
`tricycloalkyl, alkylcycloalkyl, hydroxyalkyl,
`
`20
`
`hydroxycycloalkyl, hydroxyalkylcycloalkyl,
`
`hydroxybicycloalkyl or hydroxytricycloalkyl;
`
`0009
`
`0009
`
`

`
`
`
`LA0050 NP .
`
`.
`
`B)
`
`[lR,2S,3(2S),5S]
`
`wherein R1 is alkyl, cycloalkyl, bicycloalkyl,
`
`tricycloalkyl, hydroxybicycloalkyl, hydroxytricycloalkyl,
`
`5
`
`alkylcycloalkyl, hydroxyalkyl, hydroxycycloalkyl or
`
`hydroxyalkylcycloalkyl as well as the following:
`
`F
`
`I
`
`HZN
`
`C
`
`I
`
`NC
`
`I
`
`fig fig
`
`HN
`2
`
`N
`
`o
`
`6;
`
`N
`
`“°
`
`HN
`2
`
`N
`
`o
`
`MN
`
`HN
`2
`
`N
`
`0
`
`10
`
`NC
`
`,
`
`NC
`
`I
`
`0
`
`CN ,
`
`NC
`
`and
`
`H0
`
`H2N
`
`N
`
`0
`
`CN
`
`Detailed Description of the Invention
`
`15
`
`Compounds of the structure I may be generated by
`
`the methods as shown in the following reaction schemes
`
`and the description thereof.
`
`Referring to Reaction Scheme 1, compound l, where
`
`PG1 is a common amine protecting group such as Boc, Cbz,
`
`20
`
`or FMOC and X1 is H or COZR9 as set out below, may be
`
`generated by methods as described herein or in the
`
`literature (for example see Sagnard et al, Tet—Lett.,
`
`1995, 36, pp. 3148-3152, Tverezovsky et al, Tetrahedron,
`
`-8-
`
`0010
`
`0010
`
`

`
`LAo05o NP 0
`
`.
`
`1997, 53, pp. 14773-14792, Hanessian et al, Bioorg. Med.
`
`Chem. Lett., 1998, 8, p. 2123—2128).
`
`Removal of the PG1
`
`group by conventional methods
`
`(e.g.
`
`(1) TFA or HCl when
`
`PG1 is Boc, or
`
`(2) H2/Pd/C, TMSI when PG1 is Cbz, or
`
`(3)
`
`Et2NH when PG1 is (FMOC) affords the free amine 2. Amine
`
`2 may be coupled to various protected amino acids such as
`
`3
`
`(where PG2 can be any of the PG; protecting groups)
`
`using standard peptide coupling conditions (e.g.
`
`EDAC/HOAT,
`
`i—BuCOCOCl/TEA, PyBop/NMM)
`
`to afford the
`
`corresponding dipeptide 4. Removal of the amine
`
`protecting group PG2 provides compound Ia of the invention
`where X=H.
`
`In the case where Xl=CO2R9
`
`(where R9 is alkyl or
`
`aralkyl groups such as methyl, ethyl,
`
`t-butyl, or
`
`benzyl),
`
`the ester may be hydrolyzed under a variety of
`
`conditions, for example with aqueous NaOH in a suitable
`
`solvent such as methanol, THF, or dioxane,
`
`to provide the
`
`acid 5. Conversion of the acid group to the primary
`
`carboxamide, affording 6, may be effected by activation
`
`of the acid group (e.g. employing i—BuOCOC1/TEA or EDAC)
`
`followed by treatment with NH3 or an ammonia equivalent in
`
`a solvent such as dioxane, ether, or methanol.
`
`The amide
`
`functionality may be converted to the nitrile group by a
`
`variety of standard conditions (e.g.
`
`POCl3/pyridine/imidazole or cyanuric chloride/DMF or
`
`trifluoroacetic anhydride, THF, pyridine) to give 7.
`
`Finally,
`
`removal of the PG2 protecting group similar to
`
`above provides compound of the invention Ib.
`
`In a different sequence (Scheme 2), compound 1
`
`where X1 is con? may be saponified to the acid and
`
`subsequently amidated as described above to give amide 8.
`
`Removal of the PG; group followed by peptide coupling to 3
`
`affords compound 6, an intermediate in the synthesis of
`Ib.
`
`Alternately,
`
`the carboxamide group in 8 may be
`
`converted to the nitrile as described above to give
`
`compound 9. Deprotection of PG1 affords 10 which may be
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`
`
`0011
`
`0011
`
`

`
`
`
`LAoo5o NP .
`
`.
`
`subject to standard peptide coupling conditions to afford
`
`7, an intermediate in the synthesis of Ib.
`
`Compound 10
`
`may also be generated by oxidation of the amine 2
`
`(e.g.
`
`NCS)
`
`followed by hydrolysis and subsequent cyanide
`
`treatment.' Compound 10 may be obtained as a mixture of
`
`stereoisomers or a single isomer/diastereomer which may
`
`be epimerized (employing conventional procedures)
`
`to
`
`afford a mixture of stereoisomers.
`
`10
`
`Scheme 1
`
`a
`
`
`
`( I),/<1
`HN
`()y
`Y
`1
`2 x
`
`R2
`
`3 R1R\Jfl\WDH
`3
`I
`
`P62 °
`b
`
`__JL_,.
`X‘: H
`
`mR1
`‘N
`H
`
`R2
`
`( )/<1
`hx(»
`V
`
`0
`
`la
`
`( 1)x/<1
`Pef/N\T})v
`fl
`1
`
`x‘ = H, CO2R9
`
`my
`\N
`no
`
`R2
`
`2
`
`0
`
`< A
`&
`(»
`Y
`x‘
`
`4
`
`d
`
`x‘ = co,R
`
`R2 Hf}
`:5
`< i,
`
`R35;
`
`i
`PG2 O
`
`Y m>'
`COZH
`
`e
`
`1
`
`(>x’<]
`R2
`f
`n3\RNfl\r(:'«
`()y
`Y
`CONH2
`
`I
`PG; 0
`
`5
`
`6
`
`:l
`(|)x
`R1 R2
`c
`(|)x/<1
`R1R2
`R3\ Nu ()y j» Ra fl\H,~ Hy
`N
`N
`I
`Y
`H
`E‘
`Pg 0
`CN
`7
`
`0
`lb
`
`a. PG1 =Boc, TFA or HCI; PG1 = Cbz, H2/Pd/C or TMSI; PG, = FMOC, Et2NH b. EDAC, HOBT. DMF or
`i-BuOCOC|/ TEA or PyBop, NMM c. PG2 = PG1, (see conditions for a) d. LiOH or NaOH MeOH or THF/H20
`or dioxane e. i-BuOCOC|/ NMM or i-BUOCOCI/TEA or EDAC, then NH3 in dioxane or Et2O f. POCI3,
`pyridine, imidazoie or cyanuric chloride, DMF or TFAA, THF, pyridine.
`
`0012
`
`0012
`
`

`
`LAOOSO NP .
`
`Scheme 2
`
`a,b
`
`
`
`<){<l
`I
`/N ()y
`PG1 Y
`1
`°°2R9
`
`.
`
`c
`(){<1
`,1‘ My ———————> e—+-lb
`PG1/ \|/
`R1 R2
`8
`CONH2
`R1\‘>i\H,0H
`
`3
`
`‘
`PQ 0
`cl. peptide coupling
`conditions
`
`"X 1
`PG,’ Y
`9
`CN
`
`e
`
`°
`
`,
`
`()/4
`\r
`10 CN
`
`(Fiq
`
`HN\/( )y
`2
`
`w w
`R3\N>‘\[(0H
`5'36
`o 3
`d. peptide coupling
`conditions
`
`a. LiOH or NaOH in MeOH or THF/H20 or dioxane b. i-BuOCOCI/ NMM or i-BuOCOC|/TEA or EDAC, then
`NH3 in dioxane or Et2O c.PG1 =Boc, TFA or HCI; PG1 = Cbz, H2/Pd/C or TMSI; PG1 = FMOC, Et2NH d. EDAC,
`HOBT, DMF or i-BuOCOCI/ TEA or PyBop, NMM e. POCI3, pyridine, imidazole or cyanuric chloride, DMF.
`
`5
`
`In a like manner, B—amino acids such as
`
`R?
`R2
`R1
`PG2/ NWon
`
`R4
`
`0
`
`may be coupled with 2,
`
`the free amine of 8, or 10 to give
`
`the corresponding amides which may be converted to the B-
`
`10
`
`amino acid derivatives of compound Ia or Ib following the
`
`same chemistry.
`
`Unless otherwise indicated,
`
`the term "lower
`
`alkyl", "alkyl" or "alk" as employed herein alone or as
`
`part of another group includes both straight and branched
`
`15
`
`chain hydrocarbons, containing 1 to 20 carbons,
`
`preferably l to 10 carbons, more preferably 1 to 8
`
`carbons,
`
`in the normal chain, such as methyl, ethyl,
`
`propyl,
`
`isopropyl, butyl,
`
`t—butyl,
`
`isobutyl, pentyl,
`
`hexyl,
`
`isohexyl, heptyl, 4,4—dimethylpentyl, octyl,
`
`20
`
`2,2,4~trimethyl—pentyl, nonyl, decyl, undecyl, dodecyl,
`
`-11-
`
`0013
`
`
`
`0013
`
`

`
`LAOOSO NP 0
`
`.
`
`the various branched chain isomers thereof, and the like
`
`as well as such groups including 1 to 4 substituents such
`
`as halo, for example F, Br, Cl or I or CF3, alkyl,
`
`alkoxy, aryl, aryloxy, aryl(aryl) or diaryl, arylalkyl,
`
`5
`
`arylalkyloxy, alkenyl, cycloalkyl, cycloalkylalkyl,
`
`cycloalkylalkyloxy, amino, hydroxy, hydroxyalkyl, acyl,
`
`heteroaryl, heteroaryloxy, heteroarylalkyl,
`
`heteroarylalkoxy, aryloxyalkyl, alkylthio, arylalkylthio,
`
`aryloxyaryl, alkylamido, alkanoylamino,
`
`10
`
`arylcarbonylamino, nitro, cyano,
`
`thiol, haloalkyl,
`
`trihaloalkyl and/or alkylthio.
`
`Unless otherwise indicated,
`
`the term "cycloalkyl"
`
`as employed herein alone or as part of another group
`
`includes saturated or partially unsaturated (containing 1
`
`15
`
`or 2 double bonds) cyclic hydrocarbon groups containing 1
`
`to 3 rings,
`
`including monocyclic alkyl, bicyclic alkyl
`
`(or bicycloalkyl) and tricyclic alkyl (tricycloalkyl),
`
`containing a total of 3 to 20 carbons forming the ring,
`
`preferably 3 to lO carbons,
`
`forming the ring and which
`
` 20 may be fused to l or 2 aromatic rings as described for
`
`
`aryl, which includes cyclopropyl, cyclobutyl,
`
`cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,
`
`cyclodecyl and cyclododecyl, cyclohexenyl, adamantyl,
`
`,5
`
`-\
`
`.
`
`CO .A
`
`any of which groups may be optionally substituted with l
`
`to 4 substituents such as halogen, alkyl, alkoxy,
`
`30
`
`hydroxy, aryl, aryloxy, arylalkyl, cycloalkyl,
`
`hydroxyalkyl, alkylamido, alkanoylamino, oxo, acyl,
`
`arylcarbonylamino, amino, nitro, cyano,
`
`thiol and/or
`
`alkylthio and/or any of the substituents for alkyl.
`
`-12-
`
`0014
`
`0014
`
`

`
`LAOOSO NP .
`
`.
`
`The term “cycloalkenyl” as employed herein alone
`
`or as part of another group refers to cyclic hydrocarbons
`
`containing 3 to 12 carbons, preferably 5 to 10 carbons
`and 1 or 2 double bonds.
`
`Exemplary cycloalkenyl groups
`
`include cyclopentenyl, cyclohexenyl, cycloheptenyl,
`
`cyclooctenyl, cyclohexadienyl, and cycloheptadienyl,
`
`which may be optionally substituted as defined for
`
`cycloalkyl.
`
`The term “cycloalkylene” as employed herein refers
`
`to a “cycloalkyl” group which includes free bonds and
`
`thus is a linking group such as
`
`V, I1
`and the like, and may optionally be
`K\//]
`substituted as defined above for “cycloalkyl”.
`
`The term "alkanoyl" as used herein alone or as
`
`part of another group refers to alkyl linked to a
`
`carbonyl group.
`
`Unless otherwise indicated,
`
`the term "lower
`
`alkenyl" or "alkenyl" as used herein by itself or as part
`
`of another group refers to straight or branched chain
`
`radicals of 2 to 20 carbons, preferably 2 to 12 carbons,
`
`and more preferably 1
`
`to 8 carbons in the normal chain,
`
`which include one to six double bonds in the normal
`
`chain, such as vinyl, 2—propenyl, 3—butenyl, 2—butenyl,
`
`4—pentenyl, 3—pentenyl, 2—hexenyl, 3—hexenyl, 2—heptenyl,
`
`3—heptenyl, 4—heptenyl, 3—octenyl, 3-nonenyl, 4—decenyl,
`
`3-undecenyl, 4—dodecenyl, 4,8,12—tetradecatrienyl, and
`
`the like, and which may be optionally substituted with l
`
`to 4 substituents, namely, halogen, haloalkyl, alkyl,
`
`alkoxy, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl,
`
`amino, hydroxy, heteroaryl, cycloheteroalkyl,
`
`alkanoylamino, alkylamido, arylcarbonyl—amino, nitro,
`
`thiol, alkylthio and/or any of the alkyl
`cyano,
`substituents set out herein.
`
`Unless otherwise indicated,
`
`the term "lower
`
`alkynyl" or "alkynyl" as used herein by itself or as part
`
`of another group refers to straight or branched chain
`
`_
`
`_
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`
`
`0015
`
`0015
`
`

`
`LAOOSO NP .
`
`.
`
`radicals of 2 to 20 carbons, preferably 2 to 12 carbons
`
`and more preferably 2 to 8 carbons in the normal chain,
`
`which include one triple bond in the normal chain, such
`
`as 2—propynyl, 3—butynyl, 2—butynyl, 4—pentynyl, 3-
`
`pentynyl, 2—hexynyl, 3-hexynyl, 2—heptynyl, 3—heptynyl,
`
`4—heptynyl, 3-octynyl, 3—nonynyl, 4—decynyl,3—undecynyl,
`
`4—dodecynyl and the like, and which may be optionally
`
`substituted with l to 4 substituents, namely, halogen,
`
`haloalkyl, alkyl, alkoxy, alkenyl, alkynyl, aryl,
`
`arylalkyl, cycloalkyl, amino, heteroaryl,
`
`cycloheteroalkyl, hydroxy, alkanoylamino, alkylamido,
`
`arylcarbonylamino, nitro, cyano, thiol, and/or alkylthio,
`
`and/or any of the alkyl substituents set out herein.
`
`The terms "arylalkenyl" and "arylalkynyl" as used
`
`alone or as part of another group refer to alkenyl and
`
`alkynyl groups as described above having an aryl
`substituent.
`
`Where alkyl groups as defined above have single
`
`bonds for attachment to other groups at two different
`
`carbon atoms,
`
`they are termed "alkylene" groups and may
`
`optionally be substituted as defined above for "alkyl".
`
`Where alkenyl groups as defined above and alkynyl
`
`groups as defined above, respectively, have single bonds
`
`for attachment at two different carbon atoms,
`
`they are
`
`termed "alkenylene groups" and "alkynylene groups",
`
`respectively, and may optionally be substituted as
`
`defined above for "alkenyl" and "alkynyl".
`
`The term "halogen" or "halo" as used herein alone
`
`or as part of another group refers to chlorine, bromine,
`
`fluorine, and iodine as well as CF3, with chlorine or
`
`fluorine being preferred.
`
`The term "metal
`
`ion" refers to alkali metal
`
`ions
`
`such as sodium, potassium or lithium and alkaline earth
`
`metal ions such as magnesium and calcium, as well as zinc
`
`and aluminum.
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`
`
`
`in‘E:
`
`0016
`
`0016
`
`

`
`LAOOSO NP .
`
`.
`
`Unless otherwise indicated,
`
`the term "aryl" as
`
`employed herein alone or as part of another group refers
`
`to monocyclic and bicyclic aromatic groups containing 6
`
`to 10 carbons in the ring portion (such as phenyl or
`
`naphthyl including l—naphthyl and 2—naphthyl) and may
`
`optionally include one to three additional rings fused to
`
`a carbocyclic ring or a heterocyclic ring (such as aryl,
`cycloalkyl, heteroaryl or cycloheteroalkyl rings
`for example
`
`%;. r%. Pb
`
`.
`
`<‘;©- J o=<ol >~ <’:©— . {F3 v
`
`</Z1©—. (fie, KI}
`
`and may be optionally substituted through available
`
`carbon atoms with 1, 2, or 3 groups selected from
`
`hydrogen, halo, haloalkyl, alkyl, haloalkyl, alkoxy,
`
`haloalkoxy, alkenyl,
`
`trifluoromethyl,
`
`trifluoromethoxy,
`
`alkynyl, cycloalkylalkyl, cycloheteroalkyl,
`
`cycloheteroalkylalkyl, aryl, heteroaryl, arylalkyl,
`
`aryloxy, aryloxyalkyl, arylalkoxy, arylthio, arylazo,
`
`heteroarylalkyl, heteroarylalkenyl, heteroarylheteroaryl,
`
`heteroaryloxy, hydroxy, nitro, cyano, amino, substituted
`
`amino wherein the amino includes 1 or 2 substituents
`
`(which are alkyl, aryl or any of the other aryl compounds
`
`mentioned in the definitions),
`
`thiol, alkylthio,
`
`arylthio, heteroarylthio, arylthioalkyl, alkoxyarylthio,
`
`alkylcarbonyl, arylcarbonyl, alkylaminocarbonyl,
`
`arylaminocarbonyl, alkoxycarbonyl, aminocarbonyl,
`
`alkylcarbonyloxy, arylcarbonyloxy, alkylcarbonylamino,
`
`arylcarbonylamino, arylsulfinyl, arylsulfinylalkyl,
`
`
`
`10
`
`15
`
`20
`
`25
`
`0017
`
`0017
`
`

`
`LAOOSO NP 0
`
`.
`
`arylsulfonylamino or arylsulfon—aminocarbonyl and/or any
`
`of the alkyl substituents set out herein.
`
`Unless otherwise indicated,
`
`the term "lower
`
`alkoxy", "alkoxy", "aryloxy" or "aralkoxy" as employed
`
`herein alone or as part of another group includes any of
`
`the above alkyl, aralkyl or aryl groups linked to an
`
`oxygen atom.
`
`Unless otherwise indicated,
`
`the term "substituted
`
`amino" as employed herein alone or as part of another
`
`10
`
`group refers to amino substituted with one or two
`
`substituents, which may be the same or different, such as
`
`alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,
`
`cycloheteroalkyl, cycloheteroalkylalkyl, cycloalkyl,
`
`cycloalkylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl or
`
`thioalkyl.
`
`These substituents may be further substituted
`
`with any of the R1 groups or substituents for R1 as set
`
`out above.
`
`In addition,
`
`the amino substituents may be
`
`taken together with the nitrogen atom to which they are
`
`attached to form l—pyrrolidinyl,
`
`l—piperidinyl, 1-
`
`20
`
`azepinyl, 4—morpholinyl, 4—thiamorpholinyl,
`
`l-
`
`piperazinyl, 4—alkyl—1—piperazinyl, 4—arylalkyl—1—
`
`piperazinyl, 4—diarylalkyl—l—piperazinyl,
`
`l—pyrrolidinyl,
`
`l-piperidinyl, or 1—azepinyl, optionally substituted with
`
`alkyl, alkoxy, alkylthio, halo,
`
`trifluoromethyl or
`
`25
`
`hydroxy.
`
`Unless otherwise indicated,
`
`the term "lower
`
`alkylthio", alkylthio", "arylthio" or "aralkylthio" as
`
`employed herein alone or as part of another group
`
`includes any of the above alkyl, aralkyl or aryl groups
`linked to a sulfur atom.
`
`30
`
`Unless otherwise indicated,
`
`the term "lower
`
`alkylamino", "alkylamino", "arylamino", or
`
`"arylalkylamino" as employed herein alone or as part of
`
`another group includes any of the above alkyl, aryl or
`
`35
`
`arylalkyl groups linked to a nitrogen atom.
`
`Unless otherwise indicated,
`
`the term "acyl" as
`
`employed herein by itself or part of another group, as
`
`_.
`
`_
`
`
`
`0018
`
`0018
`
`

`
`LAOOSO NP .
`
`.
`
`defined herein, refers to an organic radical linked to a
`carbonyl
`( 3 ) group; examples of acyl groups include any
`of the R1 groups attached to a carbonyl, such as
`
`alkanoyl, alkenoyl, aroyl, aralkanoyl, heteroaroyl,
`
`5
`
`cycloalkanoyl, cycloheteroalkanoyl and the like.
`
`Unless otherwise indicated,
`
`the term
`
`“cycloheteroalkyl” as used herein alone or as part of
`
`another group refers to a 5-, 6- or 7—membered saturated
`
`or partially unsaturated ring which includes 1 to 2
`
`10
`
`hetero atoms such as nitrogen, oxygen and/or sulfur,
`
`linked through a carbon atom or a heteroatom, where
`
`possible, optionally Via the linker (CHfir
`
`(where r is l,
`
`2 or 3), such as:
`
`15
`
`
`
`N
`
`\_, or
`
`"L
`O’)
`
`’
`
`N.
`/
`
`,
`
`[:Sfi1—
`Nfi1_
`N2, N2=
`O\
`
`N
`
`/N
`
`°,
`
`~\/@>,EN},
`
`and the like.
`
`The above groups may include l to 4
`
`20
`
`substituents such as alkyl, halo, oxo and/or any of the
`
`alkyl substituents set out herein.
`
`In addition, any of
`
`the cycloheteroalkyl rings can be fused to a cycloalkyl,
`
`aryl, heteroaryl or cycloheteroalkyl ring.
`
`Unless otherwise indicated,
`
`the term "heteroaryl"
`
`25
`
`as used herein alone or as part of another group refers
`
`to a 5- or 6- membered aromatic ring which includes 1, 2,
`
`_
`
`_
`
`0019
`
`0019
`
`

`
`LAoo5o NP 0
`
`O
`
`3 or 4 hetero atoms such as nitrogen, oxygen or sulfur,
`
`and such rings fused to an aryl, cycloalkyl, heteroaryl
`
`or cycloheteroalkyl ring (e.g. benzothiophenyl,
`
`indolyl),
`
`and includes possible N—oxides.
`
`The heteroaryl group may
`
`optionally include l to 4 substituents such as any of the
`
`substituents set out above for alkyl.
`
`Examples of
`
`heteroaryl groups include the following:
`
`0
`
`
`
`10
`
`, QC‘? , [Zia <33:
`CL?
`rs’
`/NV N//0
`/\/S /K X
`K\=m©N»’Q1’\=/9b~C\N3f),
`
`Q «Q,» «Q ,4/3. KN),
`
`15
`
`and the like.
`
`The term "cycloheteroalkylalkyl" as used herein
`
`alone or as part of another group refers to
`
`cycloheteroalkyl groups as defined above linked through a
`
`C atom or heteroatom to a
`
`(CH2)r chain.
`
`The term "heteroarylalkyl" or "heteroarylalkenyl"
`
`as used herein alone or as part of another group refers
`
`to a heteroaryl group as defined above linked through a C
`
`atom or heteroatom to a —(CH2)r- chain, alkylene or
`
`alkenylene as defined above.
`
`The term "polyhaloalkyl" as used herein refers to
`
`an "alkyl" group as defined above which includes from 2
`
`to 9, preferably from 2 to 5, halo substituents, such as
`
`F or Cl, preferably F, such as CF3CH2, CF3 or CF3CF2CH2.
`
`20
`
`25
`
`-18-
`
`0020
`
`0020
`
`

`
`LAOOSO NP .
`
`.
`
`The term "polyhaloalkoxy" as used herein refers to
`
`an "alkoxy" or "alkyloxy" group as defined above which
`
`includes from 2 to 9, preferably from 2 to 5, halo
`
`substituents, such as F or Cl, preferably F, such as
`CF3CH2O, CF30 or CF3CF2CH2O.
`
`5
`
`All stereoisomers of the compounds of the instant
`
`invention are contemplated, either in admixture or in
`
`pure or substantially pure form.
`
`The compounds of the
`
`present invention can have asymmetric centers at any of
`
`10
`
`the carbon atoms including any one or the R substituents.
`
`Consequently, compounds of formula I can exist in
`
`enantiomeric or diastereomeric forms or in mixtures
`
`thereof.
`
`The processes for preparation can utilize
`
`racemates, enantiomers or diastereomers as starting
`
`
`
`
`15 materials. When diastereomeric or enantiomeric products
`
`are prepared,
`
`they can be separated by conventional
`
`methods for example, chromatographic or fractional
`
`crystallization.
`
`Where desired,
`
`the compounds of structure I may be
`
`20
`
`used in combination with one or more other types of
`
`antidiabetic agents (employed to treat diabetes and
`
`related diseases) and/or one or more other types of
`
`therapeutic agents which may be administered orally in
`
`the same dosage form,
`
`in a separate oral dosage form or
`
`7"
`
`25
`
`by injection.
`
`The other type of antidiabetic agent which may be
`
`optionally employed in combination with the DP4 inhibitor
`
`of formula I may be 1,2,3 or more antidiabetic agents or
`
`antihyperglycemic agents including insulin secretagogues
`
`30
`
`or insulin sensitizers, or other antidiabetic agents
`
`preferably having a mechanism of action different from
`
`DP4 inhibition and may include biguanides, sulfonyl
`
`ureas, glucosidase inhibitors, PPAR y agonists, such as
`
`thiazolidinediones, SGLT2 inhibitors, PPAR a/y dual
`
`35
`
`agonists, aP2 inhibitors, glycogen phosphorylase
`
`inhibitors, advanced glycosylation end (AGE) products
`
`inhibitors, and/or meglitinides, as well as insulin,
`
`-19-
`
`0021
`
`0021
`
`

`
`0022
`
`LAoo50 NP .
`
`.
`
`and/or glucagon—like peptide—l
`thereof.
`
`(GLP—1) or mimetics
`
`It is believed that the use of the compounds of
`
`structure I in combination with 1, 2,
`
`3 or more other
`
`antidiabetic agents produces antihyperglycemic results
`
`greater than that possible from each of these medicaments
`
`alone and greater than the combined additive anti-
`
`hyperglycemic effects produced by these medicaments.
`
`The other antidiabetic agent may be an oral
`
`10
`
`antihyperglycemic agent preferably a biguanide such as
`
`metformin or phenformin or salts thereof, preferably
`metformin HCl.
`
`Where the other antidiabetic agent is a biguanide,
`
`the compounds of structure I will be employed in a weight
`
`ratio to biguanide within the range from about 0.01:1 to
`
`about
`
`lOO:l, preferab

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