(19) United States
`(12) Reissued Patent
`Robl et al.
`
`USO0RE44186E
`
`US RE44,186 E
`(10) Patent Number:
`(45) Date of Reissued Patent:
`Apr. 30, 2013
`
`(54) CYCLOPROPYL-FUSED
`PYRROLIDINE-BASED INHIBITORS OF
`DIPEPTIDYL PEPTIDASE IVAND METHOD
`.
`.
`(75) Inventors. Jeffrey A. Robl, NeWtoWn, PA (US),
`Richard B- Sulsky, Pennmgton,
`(US); David J. Augeri, Princeton, NJ
`
`EP
`W0
`W0
`W0
`W0
`W0
`
`0026189628‘; A2 1421;
`1050540 A2 11/2000
`WO 97/15576
`5/1997
`WO 99/26659
`6/1999
`WO 99/38501
`8/1999
`WO 99/47545
`9/1999
`WO 99/67279
`12/1999
`
`(US); David R. Magnin, Sumter, SC (Us); Lawrence G‘ Hamalfl"
`
`Cambridge,
`DaVld A.
`Betebenner, LaWrenceville, NJ (US)
`
`(73) Assignee: Bristol-Myers Squibb Company,
`Princeton NJ (Us)
`’
`(21) Appl. No.: 13/308,658
`(22) Filedi
`Dec- 1, 2011
`Related US. Patent Documents
`
`Reissue of;
`
`6’395’767
`May 28a 2002
`09/788,173
`Feb 16, 2001
`
`_
`(64) Patent NO"
`Issued:
`Appl. No.:
`Filed;
`US. Applications:
`(60) Provisional application No. 60/188,555, ?led on Mar.
`10, 2000.
`
`(2006.01)
`(2006.01)
`
`(51) Int. Cl.
`C07D 209/02
`A61K 31/403
`(52) US. Cl.
`USPC ......................................... .. 514/412; 548/452
`(58) Field of Classi?cation Search ................ .. 514/412;
`548/452
`See application ?le for complete search history.
`
`(56)
`
`References Cited
`
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`2006/0287317 A1 12/2006 Smith et al.
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`Al
`
`W0
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`‘Va/806 WO 00/4720?
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`8/2000
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`9/2000
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`11/2001
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`8/2002
`OTHER PUBLICATIONS
`Hermann Stetter and Elli Rauscher, Zur Kenntnis der Adamantan
`b
`-1 Ch I h B 'ht,1960, l.93,N.5, .1161
`?ggnsaure ( )
`emlsc e enc e
`V0
`0
`pp
`Von R. Hiltrnann et al., "2-Acylaminopyridin-Derivate mit
`morphinagonistischer und antagonisterischer
`Wirksamkeit,
`ArZneimittel-Forschung,” 1974, vol. 24, No. 4a, pp. 584-600.
`Peter Beak et al.,“Intramolecular CycliZations of alpha-Lithioamine
`Synthetic Equivalents: Convenient Synthesis of 3-, 5-, and 6-Mem
`bered Ring Heterocyclic Nitrogen Compounds and Elaborations of
`3-Mimbered Ring Systems,” J. Org. Chem. vol. 59, No. 2. 1994, pp.
`276-277.
`David J. Augeri et al., “Discovery and Preclinical Pro?le of
`Saxagliptin (BMS-477118): A Highly Potent, Long-Acting, Orally
`Active Dipeptidyl Peptidase IV Inhibitor for the Treatment of Type 2
`Diabetes,” J. Med. Chem. 2005, 48, 5025-5037.
`David R. Magnin et al. “Synthesis of Novel Potent Dipeptidyl
`Peptidase IV Inhibitors With Enhanced Chemical Stability: Interplay
`Between the N-Terminal Amino Acid Alkyl Side Chain and the
`Cyclopropyl
`Group
`of
`ot-Arninoacyl-L-cis-4,5
`methanoloprolinenitrile-Based Inhibitors,” J. Med. Chem. 2004, 47,
`2587-2598.
`Hiltmann, ArZneim.-Forsch. 24 (4) 548-600 1974 Abstract only.*
`Lin, J. et al, Proc. Natl. Acad. Sci, USA, vol. 95, pp. 14020-14024,
`Nov. 1998.
`
`(Continued)
`
`Primary Examiner * Gregg Polansky
`(74) Attorney, Agent, or Firm * Woodcock Washburn LLP
`
`ABSTRACT
`(57)
`Dipeptidyl peptidase IV (DP 4) inhibiting compounds are
`provided having the formula
`
`Where
`X is 0 or 1 and y is 0 or 1 (provided that
`X:1 When y:0 and XIO When y:1);
`
`and Wherein R1, R2, R3 and R4 are as described herein.
`A method is also provided for treating diabetes and related
`diseases, especially Type II diabetes, and other diseases as set
`out herein, employing such DP 4 inhibitor *or a combination
`of such DP 4 inhibitor and one or more of another antidiabetic
`agent such as metformin, glyburide, troglitaZone, pioglita
`Zone, rosiglitaZone and/or insulin and/or one or more of a
`hypolipidemic agent and/or anti-obesity agent and/or other
`therapeutic agent.
`
`41 Claims, No Drawings
`
`TEVA - EXHIBIT 1001
`
`

`
`US RE44,186 E
`US RE44,186 E
`Page 2
`Page 2
`
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`Hughes, T.E. et al, Biochemistry, 28, 11597-11603, 19993.
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`Rotherberg, P et al, Diabetes, 2000, V01. 49, Suppl. 1, A39.
`Rotherberg, P et al, Diabetes, 2000, vol. 49, Suppl. 1, A39.
`Sagnard, I. et al, Tetrahedron Letters, Vol. 36, No. 18, pp. 3149-3152,
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`No. 16, pp. 2123-2128, Aug. 18, 1998.
`
`* cited by examiner
`* cited by examiner
`
`

`
`US RE44,186 E
`US RE44,186 E
`
`1
`1
`CYCLOPROPYL-FUSED
`CYCLOPROPYL-FUSED
`PYRROLIDINE-BASED INHIBITORS OF
`PYRROLIDINE-BASED INHIBITORS OF
`DIPEPTIDYL PEPTIDASE IVAND METHOD
`DIPEPTIDYL PEPTIDASE IVAND METHOD
`
`Matter enclosed in heavy brackets [ ] appears in the
`Matter enclosed in heavy brackets [ ] appears in the
`original patent but forms no part of this reissue specifica-
`original patent but forms no part of this reissue speci?ca
`tion; matter printed in italics indicates the additions
`tion; matter printed in italics indicates the additions
`made by reissue.
`made by reissue.
`
`This application takes priority from U.S. provisional appli-
`This application takes priority from Us. provisional appli
`cation No. 60/188,555, filed Mar. 10, 2000.
`cation No. 60/188,555, ?led Mar. 10, 2000.
`
`FIELD OF THE INVENTION
`FIELD OF THE INVENTION
`
`5
`5
`
`10
`
`15
`
`20
`20
`
`The present invention relates to cyclopropyl-fused pyrro-
`The present invention relates to cyclopropyl-fused pyrro
`lidine-based inhibitors ofdipeptidyl peptidase IV (DP-4), and
`lidine-based inhibitors of dipeptidyl peptidase IV (DP-4), and
`to a method for treating diabetes, especially Type II diabetes,
`to a method for treating diabetes, especially Type II diabetes,
`as well as hyperglycemia, Syndrome X, diabetic complica-
`as Well as hyperglycemia, Syndrome X, diabetic complica
`tions, hyperinsulinemia, obesity, atherosclerosis and related
`tions, hyperinsulinemia, obesity, atherosclerosis and related
`diseases, as well as various immunomodulatory diseases and 25
`diseases, as Well as various immunomodulatory diseases and
`25
`chrome inflammatory bowel disease, employing such cyclo-
`chronic in?ammatory boWel disease, employing such cyclo
`propyl-fused pyrrolidines alone or in combination with
`propyl-fused pyrrolidines alone or in combination With
`another type antidiabetic agent and/or other type therapeutic
`another type antidiabetic agent and/ or other type therapeutic
`agent.
`agent.
`
`30
`30
`
`BACKGROUND OF THE INVENTION
`BACKGROUND OF THE INVENTION
`
`Depeptidyl peptidase IV (DP-4) is a membrane bound
`Depeptidyl peptidase IV (DP-4) is a membrane bound
`non-classical serine aminodipeptidase which is located in a
`non-classical serine aminodipeptidase Which is located in a
`variety of tissues (intestine, liver, lung, kidney) as well as on
`variety of tissues (intestine, liver, lung, kidney) as Well as on
`circulating T-lymphocytes (where the enzyme is known as
`circulating T-lymphocytes (Where the enzyme is known as
`CD-26). It is responsible for the metabolic cleavage of certain
`CD-26). It is responsible for the metabolic cleavage of certain
`endogenous peptides (GLP-1(7-36), glucagon) in vivo and
`endogenous peptides (GLP-1(7-36), glucagon) in vivo and
`has demonstrated proteolytic activity against a variety of
`has demonstrated proteolytic activity against a variety of
`other peptides (GHRH, NPY, GLP-2, VIP) in vitro.
`other peptides (GHRH, NPY, GLP-2, VIP) in vitro.
`GLP-1(7-36) is a 29 amino-acid peptide derived by post-
`GLP-1(7-36) is a 29 amino-acid peptide derived by post
`translational processing ofproglucagon in the small intestine.
`translational processing of pro glucagon in the small intestine.
`GLP-1 (7-36) has multiple actions in vivo including the stimu-
`GLP-l (7-36) has multiple actions in vivo including the stimu
`lation of insulin secretion, inhibition of glucagon secretion,
`lation of insulin secretion, inhibition of glucagon secretion,
`the promotion of satiety, and the slowing of gastric emptying.
`the promotion of satiety, and the sloWing of gastric emptying.
`Based on its physiological profile, the actions ofGLP-1 (7-36)
`Based on its physiological pro?le, the actions of GLP-1 (7-36)
`are expected to be beneficial in the prevention and treatment
`are expected to be bene?cial in the prevention and treatment
`of type II diabetes and potentially obesity. To support this
`of type II diabetes and potentially obesity. To support this
`claim, exogenous administration of GLP-1(7-3 6) (continu-
`claim, exogenous administration of GLP-1(7-3 6) (continu
`ous infusion) in diabetic patients has demonstrated efiicacy in
`ous infusion) in diabetic patients has demonstrated e?icacy in
`this patient population. Unfortunately GLP-1(7-3 6)
`is
`this patient population. Unfortunately GLP-1(7-3 6) is
`degraded rapidly in vivo and has been shown to have a short
`degraded rapidly in vivo and has been shoWn to have a short
`half-life in vivo (t1/2z1.5 min). Based on a study of geneti-
`half-life in vivo (t1/2z1.5 min). Based on a study of geneti
`cally bred DP-4 KO mice and on in vivo/in vitro studies with
`cally 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
`selective DP-4 inhibitors, DP-4 has been shoWn to be the
`primary degrading enzyme of GLP-1(7-36) in vivo. GLP-1
`primary degrading enzyme of GLP-1(7-36) in vivo. GLP-l
`(7-36) is degraded by DP-4 efiiciently to GLP-1 (9-36), which
`(7-36) is degraded by DP-4 e?iciently to GLP- 1 (9-36), Which
`has been speculated to act as a physiological antagonist to
`has been speculated to act as a physiological antagonist to
`GLP-1 (7-36). Thus, inhibition of DP-4 in vivo should poten-
`GLP-l (7-36). Thus, inhibition of DP-4 in vivo should poten
`tiate endogenous levels of GLP-1 (7-36) and attenuate forma-
`tiate endogenous levels of GLP-1 (7-36) and attenuate forrna
`tion of its antagonist GLP-1(9-36) and thus serve to amelio-
`tion of its antagonist GLP-1(9-36) and thus serve to amelio
`rate the diabetic condition.
`rate the diabetic condition.
`
`35
`35
`
`40
`40
`
`45
`45
`
`50
`
`55
`55
`
`60
`60
`
`65
`65
`
`2
`2
`DESCRIPTION OF THE INVENTION
`DESCRIPTION OF THE INVENTION
`
`In accordance with the present invention, cyclopropyl-
`In accordance With the present invention, cyclopropyl
`fused pyrrolidine-based compounds are provided which
`fused pyrrolidine-based compounds are provided Which
`inhibit DP-4 and have the structure
`inhibit DP-4 and have the structure
`
`R3
`
`N
`
`R2 R1
`
`(
`
`X
`
`N
`
`)
`
`R4
`
`o
`
`X
`
`wherein
`wherein
`x is 0 or 1 and y is 0 or 1 (provided that
`X is 0 or 1 and y is 0 or 1 (provided that
`x:1 when y:0 and
`XII When y:0 and
`x:0 when y:1);
`X:0 When y:1);
`n is 0 or 1;
`n is 0 or 1;
`X is H or CN (that is cyano);
`X is H or CN (that is cyano);
`R1, R2, R3 and R4are the same or different and are inde-
`R1, R2, R3 and R4are the same or different and are inde
`pendently selected from H, alkyl, alkenyl, alkynyl,
`pendently selected from H, alkyl, alkenyl, alkynyl,
`cycloalkyl, cycloalkylalkyl, bicycloalkyl, tricycloalkyl,
`cycloalkyl, cycloalkylalkyl, bicycloalkyl, tricycloalkyl,
`alkylcycloalkyl, hydroXyalkyl, hydroXyalkylcycloalkyl,
`alkylcycloalkyl, hydroxyalkyl, hydroxyalkylcycloalkyl,
`hydroXycycloalkyl, hydroXybicycloalkyl, hydroXytricy
`hydroxycycloalkyl, hydroxybicycloalkyl, hydroxytricy-
`cloalkyl, bicycloalkylalkyl, alkylthioalkyl, arylalkylth
`cloalkyl, bicycloalkylalkyl, alkylthioalkyl, arylalkylth-
`ioalkyl, cycloalkenyl, aryl, aralkyl, heteroaryl, het
`ioalkyl, cycloalkenyl, aryl, aralkyl, heteroaryl, het-
`eroarylalkyl,
`cycloheteroalkyl
`and
`eroarylalkyl,
`cycloheteroalkyl
`and
`cycloheteroalkylalkyl, all optionally substituted through
`cycloheteroalkylalkyl, all optionally substituted through
`available carbon atoms with 1, 2, 3, 4 or 5 groups
`available carbon atoms With 1, 2, 3, 4 or 5 groups
`selected from hydrogen, halo, alkyl, polyhaloalkyl,
`selected from hydrogen, halo, alkyl, polyhaloalkyl,
`alkoXy, haloalkoXy, polyhaloalkoXy, alkoXycarbonyl,
`alkoxy, haloalkoxy, polyhaloalkoxy, alkoxycarbonyl,
`alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, polycy
`alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, polycy-
`cloalkyl, heteroarylamino, arylamino, cycloheteroalkyl,
`cloalkyl, heteroarylarnino, arylarnino, cycloheteroalkyl,
`cycloheteroalkylalkyl, hydroXy, hydroXyalkyl, nitro,
`cycloheteroalkylalkyl, hydroxy, hydroxyalkyl, nitro,
`cyano, amino, substituted amino, alkylarnino, dialky-
`cyano, amino, substituted amino, alkylamino, dialky
`lamino, thiol, alkylthio, alkylcarbonyl, acyl, alkoXycar
`lamino, thiol, alkylthio, alkylcarbonyl, acyl, alkoxycar-
`bonyl, aminocarbonyl, alkynylaminocarbonyl, alky
`bonyl, aminocarbonyl, alkynylaminocarbonyl, alky-
`laminocarbonyl,
`alkenylaminocarbonyl,
`laminocarbonyl,
`alkenylarninocarbonyl,
`alkylcarbonyloXy, alkylcarbonylamino, arylcarbony
`alkylcarbonyloxy, alkylcarbonylamino,
`arylcarbony-
`lamino,
`alkylsulfonylamino,
`alkylaminocarbony
`lamino,
`alkylsulfonylarnino,
`alkylaminocarbony-
`lamino, alkoXycarbonylamino, alkylsulfonyl, aminosul
`lamino, alkoxycarbonylarnino, alkylsulfonyl, aminosul-
`fonyl, alkylsulfinyl, sulfonamido or sulfonyl;
`fonyl, alkylsul?nyl, sulfonamido or sulfonyl;
`and R1 and R3 may optionally be taken together to form
`and R1 and R3 may optionally be taken together to form
`—(CR5R6)m— where m is 2 to 6, and R5 and R6 are the
`i(CR5R6)mi Where m is 2 to 6, and R5 and R6 are the
`same or different and are independently selected from
`same or different and are independently selected from
`hydroXy, alkoXy, cyano, H, alkyl, alkenyl, alkynyl,
`hydroxy, alkoxy, cyano, H, alkyl, alkenyl, alkynyl,
`cycloalkyl, cycloalkylalkyl, cycloalkenyl, aryl, aryla
`cycloalkyl, cycloalkylalkyl, cycloalkenyl, aryl, aryla-
`lkyl, heteroaryl, heteroarylalkyl, cycloheteroalkyl, halo,
`lkyl, heteroaryl, heteroarylalkyl, cycloheteroalkyl, halo,
`amino, substituted amino, cycloheteroalkylalkyl, alkyl-
`amino, substituted amino, cycloheteroalkylalkyl, alkyl
`carbonylamino, arylcarbonylamino, alkoXycarbony
`carbonylamino,
`arylcarbonylamino,
`alkoxycarbony-
`lamino, aryloxycarbonylamino, alkoxycarbonyl, ary-
`lamino, aryloXycarbonylamino, alkoXycarbonyl, ary
`loxycarbonyl, or alkylarninocarbonylamino, or R1 and
`loXycarbonyl, or alkylaminocarbonylamino, or R1 and
`R4 may optionally be
`taken together
`to
`form
`R4 may optionally be taken together to form
`i(CR7R8)Pi Where p is 2 to 6, and R7 and R8 are the
`—(CR7R8)P— where p is 2 to 6, and R7 and R8 are the
`same or different and are independently selected from
`same or different and are independently selected from
`hydroXy, alkoXy, cyano, H, alkyl, alkenyl, alkynyl,
`hydroxy, alkoxy, cyano, H, alkyl, alkenyl, alkynyl,
`cycloalkyl, cycloalkylalkyl, cycloalkenyl, aryl, aryla
`cycloalkyl, cycloalkylalkyl, cycloalkenyl, aryl, aryla-
`lkyl, heteroaryl, heteroarylalkyl, cycloheteroalkyl, halo,
`lkyl, heteroaryl, heteroarylalkyl, cycloheteroalkyl, halo,
`amino, substituted amino, cycloheteroalkylalkyl, alkyl-
`amino, substituted amino, cycloheteroalkylalkyl, alkyl
`carbonylamino, arylcarbonylamino, alkoXycarbony
`carbonylamino,
`arylcarbonylamino,
`alkoxycarbony-
`lamino, aryloxycarbonylamino, alkoxycarbonyl, ary-
`lamino, aryloXycarbonylamino, alkoXycarbonyl, ary
`
`

`
`US RE44,186 E
`US RE44,186 E
`
`3
`3
`loxycarbonyl, or alkylaminocarbonylamino, or option-
`loxycarbonyl, or alkylaminocarbonylamino, or option
`ally R1 and R3 together With
`ally R1 and R3 together with
`
`H*N
`
`‘Raf
`R4
`
`form a 5 to 7 membered ring containing a total of 2 to 4
`form a 5 to 7 membered ring containing a total of 2 to 4
`heteroatoms selected from N, O, S, S0, or S02;
`heteroatoms selected from N, O, S, S0, or S02;
`or optionally R1 and R3 together With
`or optionally R1 and R3 together with
`
`H—N
`
`‘(PfR4
`
`form a 4 to 8 membered cycloheteroalkyl ring wherein
`form a 4 to 8 membered cycloheteroalkyl ring Wherein
`the cycloheteroalkyl ring has an optional aryl ring fused
`the cycloheteroalkyl ring has an optional aryl ring fused
`thereto or an optional 3 to 7 membered cycloalkyl ring
`thereto or an optional 3 to 7 membered cycloalkyl ring
`fused thereto;
`fused thereto;
`and including pharmaceutically acceptable salts thereof,
`and including pharmaceutically acceptable salts thereof,
`and prodrug esters thereof, and all
`stereoisomers
`and prodrug esters thereof, and all stereoisomers
`thereof.
`thereof.
`Thus, the compounds of formula I of the invention include
`Thus, the compounds of formula I of the invention include
`the following structures
`the folloWing structures
`
`10
`
`15
`
`20
`20
`
`25
`25
`
`30
`30
`
`4
`4
`pound of structure I (which inhibits DP 4) is administered to
`pound of structure I (Which inhibits DP 4) is administered to
`a human patient in need of treatment.
`a human patient in need of treatment.
`The conditions, diseases, and maladies collectively refer-
`The conditions, diseases, and maladies collectively refer
`enced to as “Syndrome X” or Metabolic Syndrome are
`enced to as “Syndrome X” or Metabolic Syndrome are
`detailed in Joharmsson J. Clin. Endocrinol. Metab., 82, 727-
`detailed in Johannsson J. Clin. Endocrinol. Metab., 82, 727
`734 (1997).
`734 (1997).
`In addition, in accordance with the present invention, a
`In addition, in accordance With the present invention, a
`method is provided for treating diabetes and related diseases
`method is provided for treating diabetes and related diseases
`as defined above and hereinafter as well as any of the other
`as de?ned above and hereinafter as Well as any of the other
`disease states mentioned above, wherein a therapeutically
`disease states mentioned above, Wherein a therapeutically
`effective amount ofa combination ofa compound of structure
`effective amount of a combination of a compound of structure
`I and one, two, three or more of other types of antidiabetic
`I and one, tWo, three or more of other types of antidiabetic
`agent(s) (which may be employed to treat diabetes and related
`agent(s) (Which may be employed to treat diabetes and related
`diseases) and/or one, two or three or more other types of
`diseases) and/or one, tWo or three or more other types of
`therapeutic agent(s) is administered to a human patient in
`therapeutic agent(s) is administered to a human patient in
`need of treatment.
`need of treatment.
`The term “diabetes and related diseases” refers to Type II
`The term “diabetes and related diseases” refers to Type II
`diabetes, Type I diabetes, impaired glucose tolerance, obesity,
`diabetes, Type I diabetes, impaired glucose tolerance, obesity,
`hyperglycemia, Syndrome X, dysmetabolic syndrome, dia
`hyperglycemia, Syndrome X, dysmetabolic syndrome, dia-
`betic complications, dysmetabolic syndrome, and hyperin
`betic complications, dysmetabolic syndrome, and hyperin-
`sulinemia.
`sulinemia.
`The conditions, diseases and maladies collectively referred
`The conditions, diseases and maladies collectively referred
`to as “diabetic complications” include retinopathy, neuropa-
`to as “diabetic complications” include retinopathy, neuropa
`thy and nephropathy, and other known complications of dia-
`thy and nephropathy, and other knoWn complications of dia
`betes.
`betes.
`The term “other type(s) oftherapeutic agents” as employed
`The term “other type(s) of therapeutic agents” as employed
`herein refers to one or more antidiabetic agents (other than
`herein refers to one or more antidiabetic agents (other than
`DP4 inhibitors of formula I), one or more anti-obesity agents,
`DP4 inhibitors of formula I), one or more anti-obesity agents,
`and/or one or more lipid-modulating agents (including anti-
`and/or one or more lipid-modulating agents (including anti
`atherosclerosis agents), and/or one or more infertility agents,
`atherosclerosis agents), and/ or one or more infertility agents,
`one or more agents for treating polycystic ovary syndrome,
`one or more agents for treating polycystic ovary syndrome,
`one or more agents for treating growth disorders, one or more
`one or more agents for treating groWth disorders, one or more
`agents for treating frailty, one or more agents for treating
`agents for treating frailty, one or more agents for treating
`arthritis, one or more agents for preventing allograft rejection
`arthritis, one or more agents for preventing allo graft rejection
`in transplantation, one or more agents for treating autoim-
`in transplantation, one or more agents for treating autoim
`mune diseases, one or more anti-AIDS agents, one or more
`mune diseases, one or more anti-AIDS agents, one or more
`anti-osteoporosis agents, one or more agents for treating
`anti-osteoporosis agents, one or more agents for treating
`immunomodulatory diseases, one or more agents for treating
`immunomodulatory diseases, one or more agents for treating
`chronic inflammatory bowel disease or syndrome and/or one
`chronic in?ammatory boWel disease or syndrome and/ or one
`or more agents for treating anorexia nervosa.
`or more agents for treating anorexia nervosa.
`The term “lipid-modulating” agent as employed herein
`The term “lipid-modulating” agent as employed herein
`refers to agents which lower LDL and/or raise HDL and/or
`refers to agents Which loWer LDL and/or raise HDL and/or
`lower triglycerides and/or lower total cholesterol and/or other
`loWer triglycerides and/ or loWer total cholesterol and/ or other
`known mechanisms for therapeutically treating lipid disor-
`knoWn mechanisms for therapeutically treating lipid disor
`ders.
`ders.
`In the above methods of the invention, the compound of
`In the above methods of the invention, the compound of
`structure I will be employed in a weight ratio to the antidia-
`structure I Will be employed in a Weight ratio to the antidia
`betic agent or other type therapeutic agent (depending upon
`betic agent or other type therapeutic agent (depending upon
`its mode of operation) within the range from about 0.01 :1 to
`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
`about 500:1, preferably from about 0. 1 :1 to about 100: 1, more
`preferably from about 0.2:1 to about 10:1.
`preferably from about 0.2:1 to about 10:1.
`Preferred are compounds of formula I wherein R3 is H or
`Preferred are compounds of formula I Wherein R3 is H or
`alkyl, R1 is H, alkyl, cycloalkyl, bicycloalkyl, tricycloalkyl,
`alkyl, R1 is H, alkyl, cycloalkyl, bicycloalkyl, tricycloalkyl,
`alkylcyclo alkyl, hydroxyalkyl, hydroxytricyclo alkyl,
`alkylcyclo alkyl, hydroxyalkyl, hydroxytricyclo alkyl,
`hydroxycycloalkyl, hydroxybicycloalkyl, or hydroxyalkyl-
`hydroxycycloalkyl, hydroxybicycloalkyl, or hydroxyalkyl
`cycloalkyl, R2 is H or alkyl, n is 0, X is CN, x is 0 or 1 and y
`cycloalkyl, R2 is H or alkyl, n is 0, X is CN, X is 0 or 1 and y
`is 0 or 1.
`is 0 or 1.
`Most preferred are preferred compounds of formula I as
`Most preferred are preferred compounds of formula I as
`described above where X is
`described above Where X is
`
`CN or
`-<CN,
`CN or -_CN,
`
`R2
`R1
`R2 R1
`
`R3
`R3
`N
`N
`
`N
`N
`
`H/ R4
`R4
`
`o
`0
`
`X
`X
`
`H/
`
`R2
`R1
`R R1
`2
`
`R3
`R3
`N
`N
`
`N
`N
`
`,5 (9%/. V
`H/ (94% V
`
`R4
`R4
`
`0
`o
`
`X
`X
`
`_
`.
`
`In addition, in accordance with the present invention, a
`In addition, in accordance With the present invention, a
`method is provided for treating diabetes, especially Type II
`method is provided for treating diabetes, especially Type II
`diabetes, as well as impaired glucose homeostasis, impaired
`diabetes, as Well as impaired glucose homeostasis, impaired
`glucose tolerance, infertility, polycystic ovary syndrome,
`glucose tolerance,
`infertility, polycystic ovary syndrome,
`growth disorders, frailty, arthritis, allograft rejection in trans-
`groWth disorders, frailty, arthritis, allograft rejection in trans
`plantation, autoimmune diseases (such as scleroderma and
`plantation, autoimmune diseases (such as scleroderrna and
`multiple sclerosis), various immunomodulatory diseases
`multiple sclerosis), various immunomodulatory diseases
`(such as lupus erythematosis or psoriasis), AIDS, intestinal
`(such as lupus erythematosis or psoriasis), AIDS, intestinal
`diseases (such as necrotizing enteritis, microvillus inclusion
`diseases (such as necrotiZing enteritis, microvillus inclusion
`disease or celiac disease), inflammatory bowel syndrome,
`disease or celiac disease), in?ammatory boWel syndrome,
`chemotherapy-induced intestinal mucosal atrophy or injury,
`chemotherapy-induced intestinal mucosal atrophy or injury,
`anorexia nervosa, osteoporosis, Syndrome X, dysmetabolic
`anorexia nervosa, osteoporosis, Syndrome X, dysmetabolic
`syndrome, diabetic complications, hyperinsulinemia, obe-
`syndrome, diabetic complications, hyperinsulinemia, obe
`sity, atherosclerosis and related diseases, as well as inflam-
`sity, atherosclerosis and related diseases, as Well as in?am
`matory bowel disease (such as Crohn’ s disease and ulcerative
`matory boWel disease (such as Crohn’ s disease and ulcerative
`colitis), wherein a therapeutically effective amount of a com-
`colitis), Wherein a therapeutically effective amount of a com
`
`IA
`
`35
`35
`
`40
`40
`
`1B
`1B
`
`45
`45
`
`50
`50
`
`55
`55
`
`60
`60
`
`65
`65
`
`

`
`5
`5
`and/or wherein the fused cyclopropyl group is identified as
`and/ or wherein the fused cyclopropyl group is identi?ed as
`
`-continued
`-continued
`
`US RE44,186 E
`US RE44,l86 E
`
`V.
`V.
`
`5
`
`HO
`HO
`
`Thus, preferred compounds of formula I of the invention
`Thus, preferred compounds of formula I of the invention
`will include the moiety:
`will include the moiety:
`
`10
`
`0
`O
`
`N
`N
`
`NC
`NC
`
`HZN
`HZN
`
`F
`F
`
`7
`
`7
`
`H2N
`HZN
`
`N
`
`N
`
`7
`
`7
`
`0
`NC
`0 NC
`
`(
`(
`
`X
`x
`
`(
`(
`
`X
`X
`
`(
`(
`
`X
`X
`
`15
`
`/ N
`X N
`
`)y, / N
`)y, X N
`
`)y,
`)y,
`
`or / N
`or X N
`
`)y,
`)y,
`
`HZN
`HZN
`
`CN
`CN
`
`X
`X
`
`CN
`CN
`
`N
`N
`
`,
`.
`
`HZN
`HZN
`
`0
`NC
`0 NC
`
`N
`N
`
`,
`.
`
`0
`0
`
`CN
`CN
`
`Particularly preferred are the following compounds:
`Particularly preferred are the following compounds:
`A)
`A)
`
`
`
`[1S, 2(2S), 3S, 5S]
`
`wherein R1 is alkyl, cycloalkyl, bicycloalkyl, tricycloalkyl,
`wherein R1 is alkyl, cycloalkyl, bicycloalkyl, tricycloalkyl,
`alkylcycloalkyl, hydroxyalkyl, hydroxycycloalkyl, hydroxy
`alkylcycloalkyl, hydroxyalkyl, hydroxycycloalkyl, hydroxy-
`alkylcycloalkyl,
`hydroxybicycloalkyl
`or
`hydroxytricy-
`alkylcycloalkyl, hydroxybicycloalkyl or hydroxytricy
`cloalkyl;
`cloalkyl;
`13)
`B)
`
`R1
`R1
`
`HZN
`5
`HZN S
`
`O
`
`O
`[1R, 2S, 3(2S), 5S]
`
`wherein R1 is alkyl, cycloalkyl, bicycloalkyl, tricycloalkyl,
`wherein R1 is alkyl, cycloalkyl, bicycloalkyl, tricycloalkyl,
`hydroxybicycloalkyl, hydroxytricycloalkyl, alkylcycloalkyl,
`hydroxybicycloalkyl, hydroxytricycloalkyl, alkylcycloalkyl,
`hydroxyalkyl, hydroxycycloalkyl or hydroxyalkylcycloalkyl
`hydroxyalkyl, hydroxycycloalkyl or hydroxyalkylcycloalkyl
`as well as the following:
`as well as the following:
`
`N:
`N:
`
`CN,
`HO
`CN, HO
`
`N:
`N:
`
`CN,
`CN,
`
`1:
`F
`
`NH2
`0
`NH2 0
`
`HZN
`HZN
`
`o
`0
`
`20
`20
`
`HO
`HO
`
`HZN
`HZN
`
`25
`25
`
`N
`N
`
`0
`NC
`0 NC
`
`HO
`HO
`
`and
`and
`
`HZN
`HZN
`
`N
`N
`
`0
`0
`
`CN.
`CN.
`
`30
`30
`
`35
`35
`
`40
`40
`
`45
`45
`
`50
`50
`
`55
`55
`
`60
`
`65
`65
`
`DETAILED DESCRIPTION OF THE INVENTION
`DETAILED DESCRIPTION OF THE INVENTION
`
`Compounds of the structure I may be generated by the
`Compounds of the structure I may be generated by the
`methods as shown in the following reaction schemes and the
`methods as shown in the following reaction schemes and the
`description thereof.
`description thereof.
`Referring to Reaction Scheme 1, compound 1, where PG1
`Referring to Reaction Scheme 1, compound 1, where PGl
`is a common amine protecting group such as Boc, Cbz, or
`is a common amine protecting group such as Boc, CbZ, or
`FMOC and X1 is H or CO2R9 as set out below, may be
`FMOC and X1 is H or COZR9 as set out below, may be
`generated by methods as described herein or in the literature
`generated by methods as described herein or in the literature
`(for example see Sagnard et al, Tet-Lett., 1995, 36, pp. 3148-
`(for example see Sagnard et al, Tet-Lett., 1995, 36, pp. 3148
`3152, Tverezovsky et al, Tetrahedron, 1997, 53, pp. 14773-
`3152, TvereZovsky et al, Tetrahedron, 1997, 53, pp. 14773
`14792, Hanessian et al, Bioorg. Med. Chem. Lett., 1998, 8, p.
`14792, Hanessian et al, Bioorg. Med. Chem. Lett., 1998, 8, p.
`2123-2128). Removal of the PG1 group by conventional
`2123-2128). Removal of the PGl group by conventional
`methods (e.g. (1) TFA or HCl when PG1 is Boc, or (2) H2/Pd/
`methods (eg (1) TFA or HCl when PGl is Boc, or (2) Hz/Pd/
`C, TMSI when PG1 is Cbz, or (3) Et2NH when PG1 is
`C, TMSI when PGl is CbZ, or (3) Et2NH when PGl is
`(FMOC) affords the free amine 2 Amine 2 may be coupled to
`(FMOC) affords the free amine 2 Amine 2 may be coupled to
`various protected amino acids such as 3 (where PG2 can be
`various protected amino acids such as 3 (where PG2 can be
`any of the PGl protecting groups) using standard peptide
`any of the PG1 protecting groups) using standard peptide
`coupling conditions (e.g. EDAC/HOAT, i-BuCOCOCl/TEA,
`coupling conditions (eg EDAC/HOAT, i-BuCOCOCl/TEA,
`PyBop/NMM) to afford the corresponding dipeptide 4.
`PyBop/N MM) to afford the corresponding dipeptide 4.
`Removal of the amine protecting group PG2 provides com-
`Removal of the amine protecting group PG2 provides com
`pound Ia of the invention where X:H.
`pound Ia of the invention where XIH.
`In the case where X1:CO2R9 (where R9 is alkyl or aralkyl
`In the case where Xl:CO2R9 (where R9 is alkyl or aralkyl
`groups such as methyl, ethyl, t-butyl, or benzyl), the ester may
`groups such as methyl, ethyl, t-butyl, or benZyl), the ester may
`be hydrolyzed under a