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`
`US006395767B2
`
`(12) United States Patent
`Robl et al.
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 6,395,767 B2
`May 28, 2002
`
`(54) CYCLOPROPYL-FUSED
`PYRROLIDINE-BASED INHIBITORS OF
`DIPEPTIDYL PEPTIDASE IV AND METHOD
`
`(75)
`
`Inventors: Jeffrey A. Robl, Newtown, PA (US);
`Richard B. Sulsky, West Trenton, NJ
`(US); David J. Augeri, Princeton, NJ
`(US); David R. Magnin, Hamilton, NJ
`(US); Lawrence G. Hamann, Cherry
`Hill, NJ (US); David A. Betebenner,
`Lawrenceville, NJ (US)
`
`(73) Assignee: Bristol-Myers Squibb Company,
`Princeton, NJ (US)
`
`( * ) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`(21) Appl. No.1 09/788,173
`
`(22)
`
`Filed:
`
`Feb. 16, 2001
`
`(60)
`
`Related U.S. Application Data
`Provisional application No. 60/188,555, filed on Mar. 10,
`2000.
`
`C07D 209/07; A61K 31/403
`Int. Cl.7
`(51)
`...................................... .. 514/412; 548/452
`(52) U.S. Cl.
`(58) Field of Search ......................... .. 548/452; 514/412
`
`(56)
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`3/1981 Day et 211.
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`5,939,560 A
`12/1999 Hulin et al.
`5,998,463 A
`1/2000 Villhauer
`6,011,155 A
`8/2000 Villhauer
`6,110,949 A
`FOREIGN PATENT DOCUMENTS
`
`DE
`DE
`EP
`EP
`EP
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`
`33 24 263 A1
`39 26 606 A1
`0 007 652 A1
`0 219 782 A2
`1050540 A2
`WO 99/26659
`W0 99/38501
`W0 99/47545
`WO 99/67279
`WO 00/10549
`W0 034241 A1
`WO 00/53171
`WO 00/56296
`WO 00/56297
`W0 00/69868
`WO 97/40832
`
`1/1985
`2/1991
`2/1980
`4/1987
`11/2000
`6/1999
`8/1999
`9/1999
`12/1999
`3/2000
`6/2000
`9/2000
`9/2000
`9/2000
`11/2000
`11/2001
`
`OTHER PUBLICATIONS
`
`Lin, J. et al, Proc. Natl. Acad. Sci, USA, vol. 95, pp.
`14020-14024, Nov. 1998.
`Augustyns, KJL et al, Eur. J. Med. Chem. 32, 301-309,
`(1997).
`Hughes, T.E. et al, Biochemistry, 28, 11597-11603, 19993
`
`Yamada, M. et al, Bioorganic & Medicinal Chemistry Let-
`ters 8, 1537-1540 (1998).
`Tanaka, S. et al, Immunopharmacology 40, 21-26 (1998).
`Li, J. et al, Archives of Biochemistry and Biophysics, vol.
`323, No. 1, pp. 148-154, Oct. 20, 1995.
`Ashworth, D.M. et al, Bioorganic & Medicinal Chemistry
`Letter, vol. 6, No. 22, pp. 2745-2748, 1996.
`Yamada, M. et al, Bioorganic & Medicinal Chemistry Letter
`8, 1537-1540 (1998).
`Ashworth, D.M. et al, Bioorganic & Medicinal Chemistry
`Letter, vol. 6, No. 10, pp. 1163-1166, 1996.
`Lambeir, A.-M., et al, Biochimica et Biophysica Acts, 1290,
`pp. 76-82 (1996).
`Yoshimoto, T. et al, Agric. Biol. Chem., 55(4), pp.
`1135-1136, 1991.
`Belyaev, A. et al, J. Med. Chem., 42, 1041-1052, 1999.
`Stockel, A. et al, Peptides: Chemistry, Structure and Biology,
`pp. 709-710, 1996.
`Asai, Y. et al, The Journal ofAntibiotics, vol. 50, No. 8, pp.
`653-657, Aug. 1997.
`Demuth, H.-U. et al, FEBS Letters, vol. 320, No. 1, pp.
`23-27, Mar. 1993.
`Ohnuki, T. et al, Drugs of the Future, 24(6):665-670, 1999.
`Demuth, H.-U. et al, Diabetes, 2000, vol. 49, suppl. 1,A102.
`Rotherberg, P. et al, Diabetes, 2000, vol. 49, Suppl. 1, A39.
`Hiltmann, Arzneim. —Forsch. 24 (4) 548-600 1974 Abstract
`only.*
`Sagnard, I. et al, Tetrahedron Letters, vol. 36, No. 18, pp.
`3149-3152, 1995.
`Tverezovsky, V. V. et a1., Tetrahedron, vol. 53, No. 43, pp.
`14773-14792, 1997.
`Hanessian, S. et al, Bioorganic & Medicinal Chem. Letters,
`vol. 8, No. 16, pp. 2123-2128, Aug. 18, 1998.
`* cited by examiner
`Primary Examiner-Robert Gerstl
`(74) Attorney, Agent, or Firm—Burton Rodney
`(57)
`ABSTRACT
`
`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 x=0 when y=1);
`nis0or1;XisHorCN;
`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 combi-
`nation of such DP 4 inhibitor and one or more of another
`antidiabetic agent such as metformin, glyburide,
`troglita-
`zone, pioglitazone, rosiglitazone and/or insulin and/or one or
`more of a hypolipidemic agent and/or anti-obesity agent
`and/or other therapeutic agent.
`
`24 Claims, No Drawings
`
`AURQ - EXHIBIT 1002
`
`

`
`B2
`US 6,395,767
`US 6,395,767 B2
`
`1
`1
`CYCLOPROPYL-FUSED PYRROLIDINE-
`CYCLOPROPYL-FUSED PYRROLIDINE
`BASED INHIBITORS OF DIPEPTIDYL
`BASED INHIBITORS OF DIPEPTIDYL
`PEPTIDASE IV AND METHOD
`PEPTIDASE IV AND METHOD
`
`This application takes priority from U.S. provisional
`This application takes priority from US. provisional 5
`application No. 60/188,555, filed Mar. 10, 2000.
`application No. 60/188,555, ?led Mar. 10, 2000.
`
`R3
`R3
`N
`/
`N
`H
`/
`H
`
`FIELD OF THE INVENTION
`FIELD OF THE INVENTION
`
`The present
`invention relates to cyclopropyl-fused
`The present invention relates to cyclopropyl-fused
`pyrrolidine-based inhibitors of dipeptidyl peptidase IV (DP
`pyrrolidine-based inhibitors of dipeptidyl peptidase IV (DP-
`4), and to a method for treating diabetes, especially Type II
`4), and to a method for treating diabetes, especially Type II
`diabetes, as well as hyperglycemia, Syndrome X, diabetic
`diabetes, as Well as hyperglycemia, Syndrome X, diabetic
`complications, hyperinsulinemia, obesity, atherosclerosis
`complications, hyperinsulinemia, obesity, atherosclerosis
`and related diseases, as well as various immunomodulatory
`and related diseases, as Well as various immunomodulatory
`diseases and chronic inflammatory bowel disease, employ-
`diseases and chronic in?ammatory boWel disease, employ
`ing such cyclopropyl-fused pyrrolidines alone or in combi-
`ing such cyclopropyl-fused pyrrolidines alone or in combi
`nation with another type antidiabetic agent and/or other type
`nation With another type antidiabetic agent and/or other type
`therapeutic agent.
`therapeutic agent.
`
`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
`CD-26). It is responsible for the metabolic cleavage of
`certain endogenous peptides (GLP-1(7-36), glucagon) in
`certain endogenous peptides (GLP-1(7-36), glucagon) in
`vivo and has demonstrated proteolytic activity against a
`vivo and has demonstrated proteolytic activity against a
`variety of other peptides (GHRH, NPY, GLP-2, VIP) in
`variety of other peptides (GHRH, NPY, GLP-2, VIP) in
`vitro.
`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 of proglucagon in the small intes-
`translational processing of proglucagon in the small intes
`tine. GLP-1(7-36) has multiple actions in vivo including the
`tine. GLP-1(7-36) has multiple actions in vivo including the
`stimulation of insulin secretion,
`inhibition of glucagon
`stimulation of insulin secretion, inhibition of glucagon
`secretion, the promotion of satiety, and the slowing of gastric
`secretion, the promotion of satiety, and the sloWing of gastric
`emptying. Based on its physiological profile, the actions of
`emptying. Based on its physiological pro?le, the actions of
`GLP-1(7-36) are expected to be beneficial in the prevention
`GLP-1(7-36) are expected to be bene?cial in the prevention
`and treatment of type II diabetes and potentially obesity. To
`and treatment of type II diabetes and potentially obesity. To
`support this claim, exogenous administration of GLP-1(7-
`support this claim, eXogenous administration of GLP-1(7
`36) (continuous infusion) in diabetic patients has demon-
`36) (continuous infusion) in diabetic patients has demon
`strated efficacy in this patient population. Unfortunately
`strated ef?cacy in this patient population. Unfortunately
`GLP-1(7-36) is degraded rapidly in vivo and has been
`GLP-1(7-36) is degraded rapidly in vivo and has been
`shown to have a short half-life in vivo (t1/2z1.5 min). Based
`shoWn to have a short half-life in vivo (t1/2z1.5 min). Based
`on a study of genetically bred DP-4 KO mice and on in
`on a study of genetically bred DP-4 KO mice and on in
`vivo/in vitro studies with selective DP-4 inhibitors, DP-4
`vivo/in vitro studies With selective DP-4 inhibitors, DP-4
`has been shown to be the primary degrading enzyme of
`has been shoWn to be the primary degrading enZyme of
`GLP-1(7-36) in vivo. GLP-1(7-36) is degraded by DP-4
`GLP-1(7-36) in vivo. GLP-1(7-36) is degraded by DP-4
`efficiently to GLP-1(9-36), which has been speculated to act
`ef?ciently to GLP-1(9-36), Which has been speculated to act
`as a physiological antagonist to GLP-1(7-36). Thus, inhibi-
`as a physiological antagonist to GLP-1(7-36). Thus, inhibi
`tion of DP-4 in vivo should potentiate endogenous levels of
`tion of DP-4 in vivo should potentiate endogenous levels of
`GLP-1(7-36) and attenuate formation of its antagonist GLP-
`GLP-1(7-36) and attenuate formation of its antagonist GLP
`1(9-36) and thus serve to ameliorate the diabetic condition.
`1(9-36) and thus serve to ameliorate the diabetic condition.
`
`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
`
`1
`I
`
`X
`X
`
`(
`(
`N
`N
`
`)
`Y
`)
`Y
`
`0
`o
`
`X
`X
`
`R2
`R1
`R2 R1
`
`11
`II
`
`R4
`R4
`
`10
`10
`
`15
`15
`
`20
`
`25
`25
`
`30
`
`35
`35
`
`40
`
`45
`45
`
`50
`
`55
`55
`
`60
`
`65
`65
`
`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
`X=1 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
`R1, R2, R3 and R4are the same or different and are
`independently selected from H, alkyl, alkenyl, alkynyl,
`independently selected from H, alkyl, alkenyl, alkynyl,
`cycloalkyl, cycloalkylalkyl, bicycloalkyl, tricycloalkyl,
`cycloalkyl, cycloalkylalkyl, bicycloalkyl, tricycloalkyl,
`alkylcycloalkyl,
`hydroXyalkyl,
`alkylcycloalkyl,
`hydroxyalkyl,
`hydroxyalkylcycloalkyl, hydroXycyclo alkyl,
`hydroxyalkylcycloalkyl, hydroxycyclo alkyl,
`hydroXybicyclo alkyl, hydroXytricycloalkyl,
`hydroxybicyclo alkyl, hydroxytricycloalkyl,
`bicycloalkylalkyl, alkylthioalkyl, arylalkylthioalkyl,
`bicycloalkylalkyl, alkylthioalkyl, arylalkylthioalkyl,
`cycloalkenyl, aryl, aralkyl, heteroaryl, heteroarylalkyl,
`cycloalkenyl, aryl, aralkyl, heteroaryl, heteroarylalkyl,
`cycloheteroalkyl and cycloheteroalkylalkyl, all option
`cycloheteroalkyl and cycloheteroalkylalkyl, all option-
`ally substituted through available carbon atoms with 1,
`ally substituted through available carbon atoms With 1,
`2, 3, 4 or 5 groups selected from hydrogen, halo, alkyl,
`2, 3, 4 or 5 groups selected from hydrogen, halo, alkyl,
`polyhaloalkyl, alkoXy, haloalkoXy, polyhaloalkoXy,
`polyhaloalkyl, alkoxy, haloalkoxy, polyhaloalkoxy,
`alkoXycarbonyl, alkenyl, alkynyl, cyclo alkyl,
`alkoxycarbonyl, alkenyl, alkynyl, cyclo alkyl,
`cycloalkylalkyl, polycycloalkyl, heteroarylamino,
`cycloalkylalkyl, polycycloalkyl, heteroarylamino,
`arylamino, cycloheteroalkyl, cycloheteroalkylalkyl,
`arylamino, cycloheteroalkyl, cycloheteroalkylalkyl,
`hydroxy, hydroxyalkyl, nitro, cyano, amino, substituted
`hydroXy, hydroXyalkyl, nitro, cyano, amino, substituted
`amino, alkylamino, dialkylamino, thiol, alkylthio,
`amino, alkylamino, dialkylamino,
`thiol, alkylthio,
`alkylcarbonyl, acyl, alkoXycarbonyl, aminocarbonyl,
`alkylcarbonyl, acyl, alkoxycarbonyl, aminocarbonyl,
`alkynylaminocarbonyl, alkylaminocarbonyl,
`alkynylaminocarbonyl, alkylaminocarbonyl,
`alkenylaminocarbonyl, alkylcarbonyloXy,
`alkenylaminocarbonyl, alkylcarbonyloxy,
`alkylcarbonylamino, arylcarbonylamino,
`alkylcarbonylamino, arylcarbonylamino,
`alkylsulfonylamino, alkylaminocarbonylamino,
`alkylsulfonylamino, alkylaminocarbonylamino,
`alkoXycarbonylamino, alkylsulfonyl, aminosulfonyl,
`alkoxycarbonylamino, alkylsulfonyl, aminosulfonyl,
`alkylsulfinyl, sulfonamido or sulfonyl;
`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
`—(CR3R6)m— where m is 2 to 6, and R3 and R6 are the
`—(CR5R6)m— 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,
`cyclo alkyl, cycloalkylalkyl, cyclo alkenyl, aryl,
`cyclo alkyl, cycloalkylalkyl, cyclo alkenyl, aryl,
`arylalkyl, heteroaryl, heteroarylalkyl, cycloheteroalkyl,
`arylalkyl, heteroaryl, heteroarylalkyl, cycloheteroalkyl,
`halo, amino, substituted amino, cycloheteroalkylalkyl,
`halo, amino, substituted amino, cycloheteroalkylalkyl,
`alkylcarbonylamino, arylcarbonylamino,
`alkylcarbonylamino, arylcarbonylamino,
`alkoXycarbonylamino, aryloXycarbonylamino,
`alkoxycarbonylamino, aryloxycarbonylamino,
`alkoxycarbonyl,
`aryloxycarbonyl,
`or
`alkoXycarbonyl, aryloXycarbonyl, or
`alkylaminocarbonylamino, or R1 and R4 may option-
`alkylaminocarbonylamino, or R1 and R4 may option
`ally be taken together to form —(CR7R8)P— Where p
`ally be taken together to form —(CR7R8)p— where p
`is 2 to 6, and R7 and R8 are the same or different and
`is 2 to 6, and R7 and R8 are the same or different and
`are independently selected from hydroxy, alkoxy,
`are independently selected from hydroXy, alkoXy,
`cyano, H, alkyl, alkenyl, alkynyl, cycloalkyl,
`cyano, H, alkyl, alkenyl, alkynyl, cycloalkyl,
`cycloalkylalkyl, cycloalkenyl, aryl, arylalkyl,
`cycloalkylalkyl, cycloalkenyl, aryl, arylalkyl,
`heteroaryl, heteroarylalkyl, cycloheteroalkyl, halo,
`heteroaryl, heteroarylalkyl, cycloheteroalkyl, halo,
`amino, substituted amino, cycloheteroalkylalkyl,
`amino, substituted amino, cycloheteroalkylalkyl,
`alkylcarbonylamino, arylcarbonylamino,
`alkylcarbonylamino, arylcarbonylamino,
`alkoXycarbonylamino, aryloXycarbonylamino,
`alkoxycarbonylamino, aryloxycarbonylamino,
`alkoxycarbonyl,
`aryloxycarbonyl,
`or
`alkoXycarbonyl, aryloXycarbonyl, or
`alkylaminocarbonylamino, or optionally R1 and R3
`alkylaminocarbonylamino, or optionally R1 and R3
`together with
`together With
`
`

`
`US 6,395,767 B2
`US 6,395,767 B2
`
`5
`
`form a 5 to 7 membered ring containing a total of 2 to
`form a 5 to 7 membered ring containing a total of 2 to
`4 heteroatoms selected from N, O, S, S0, or S02;
`4 heteroatoms selected from N, O, S, SO, or S02;
`or optionally R1 and R3 together With
`or optionally R1 and R3 together with
`
`10
`10
`
`HjN
`
`\(‘Pn/
`
`R4
`
`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
`
`20
`20
`
`25
`25
`
`IA
`[A
`
`30
`30
`
`4
`4
`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 of a combination of a compound of struc-
`effective amount of a combination of a compound of struc
`ture I and one,
`two,
`three or more of other types of
`ture I and one, tWo, three or more of other types of
`antidiabetic agent(s)
`(which may be employed to treat
`antidiabetic agent(s) (Which may be employed to treat
`diabetes and related diseases) and/or one, two or three or
`diabetes and related diseases) and/or one, tWo or three or
`more other types of therapeutic agent(s) is administered to a
`more other types of therapeutic agent(s) is administered to a
`human patient in need of treatment.
`human patient in 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,
`diabetes, Type I diabetes, impaired glucose tolerance,
`obesity, hyperglycemia, Syndrome X, dysmetabolic
`obesity, hyperglycemia, Syndrome X, dysmetabolic
`syndrome, diabetic complications, dysmetabolic syndrome,
`syndrome, diabetic complications, dysmetabolic syndrome,
`and hyperinsulinemia.
`and hyperinsulinemia.
`The conditions, diseases and maladies collectively
`The conditions, diseases and maladies collectively
`referred to as “diabetic complications” include retinopathy,
`referred to as “diabetic complications” include retinopathy,
`neuropathy and nephropathy, and other known complica-
`neuropathy and nephropathy, and other knoWn complica
`tions of diabetes.
`tions of diabetes.
`The term “other
`type(s) of therapeutic agents” as
`The term “other type(s) of therapeutic agents” as
`employed herein refers to one or more antidiabetic agents
`employed herein refers to one or more antidiabetic agents
`(other than DP4 inhibitors of formula I), one or more
`(other than DP4 inhibitors of formula I), one or more
`anti-obesity agents, and/or one or more lipid-modulating
`anti-obesity agents, and/or one or more lipid-modulating
`agents (including anti-atherosclerosis agents), and/or one or
`agents (including anti-atherosclerosis agents), and/or one or
`more infertility agents, one or more agents for treating
`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 agents for treating frailty, one
`groWth disorders, one or more agents for treating frailty, one
`or more agents for treating arthritis, one or more agents for
`or more agents for treating arthritis, one or more agents for
`preventing allograft rejection in transplantation, one or more
`preventing allograft rejection in transplantation, one or more
`agents for treating autoimmune diseases, one or more anti-
`agents for treating autoimmune diseases, one or more anti
`AIDS agents, one or more anti-osteoporosis agents, one or
`AIDS agents, one or more 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
`more agents for treating chronic in?ammatory boWel disease
`or syndrome and/or one or more agents for treating anorexia
`or syndrome and/or one or more agents for treating anorexia
`nervosa.
`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
`loWer triglycerides and/or loWer total cholesterol and/or
`other known mechanisms for therapeutically treating lipid
`other knoWn mechanisms for therapeutically treating lipid
`disorders.
`disorders.
`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
`structure I Will be employed in a Weight ratio to the
`antidiabetic agent or other type therapeutic agent (depending
`antidiabetic agent or other type therapeutic agent (depending
`upon its mode of operation) within the range from about
`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
`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.
`100:1, more 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,
`alkylcycloalkyl, hydroXyalkyl, hydroXytricycloalkyl,
`alkylcycloalkyl, hydroxyalkyl, hydroxytricycloalkyl,
`hydroxycycloalkyl, hydroxybicycloalkyl, or
`hydroXycycloalkyl, hydroXybicycloalkyl, or
`hydroxyalkylcycloalkyl, R2 is H or alkyl, n is 0, X is CN, X
`hydroxyalkylcycloalkyl, R2 is H or alkyl, n is 0, X is CN, X
`is0or1andyis0or1.
`is0or1andyis0or1.
`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
`
`IC
`
`N or :(:N,
`CN or _CN,
`
`and/or wherein the fused cyclopropyl group is identified as
`and/or Wherein the fused cyclopropyl group is identi?ed as
`
`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:
`
`35
`35
`
`40
`40
`
`45
`45
`
`50
`50
`
`55
`55
`
`60
`60
`
`65
`65
`
`R3
`R3
`N
`N
`/
`
`H/
`
`R2
`R1
`R2 R1
`
`N
`N
`
`R4
`R4
`
`0
`o
`
`X
`X
`
`1
`2
`R
`R
`1
`2
`R R
`
`R3
`R3
`N
`N
`
`N
`N
`
`1B
`[B
`
`.
`.
`
`H/
`?
`/ H W 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
`groWth disorders, frailty, arthritis, allograft rejection in
`transplantation, autoimmune diseases (such as scleroderma
`transplantation, autoimmune diseases (such as scleroderma
`and multiple sclerosis), various immunomodulatory diseases
`and 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,
`syndrome, diabetic complications, hyperinsulinemia,
`obesity, atherosclerosis and related diseases, as well as
`obesity, atherosclerosis and related diseases, as Well as
`inflammatory bowel disease (such as Crohn’s disease and
`in?ammatory boWel disease (such as Crohn’s disease and
`ulcerative colitis), wherein a therapeutically effective
`ulcerative colitis), Wherein a therapeutically effective
`amount of a compound of structure I (which inhibits DP 4)
`amount of a compound of structure I (Which inhibits DP 4)
`is administered to a human patient in need of treatment.
`is administered to 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 Johannsson J. Clin. Endocrinol. Metab., 82,
`detailed in Johannsson J. Clin. Endocrinol. Metab, 82,
`727-734 (1997).
`727—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
`
`

`
`5
`
`US 6,395,767 B2
`US 6,395,767 B2
`
`6
`6
`-continued
`-continued
`
`(
`
`X
`
`(
`
`X
`
`(
`
`X
`
`F
`F
`
`/ N
`
`)y> / N
`
`)y>
`
`or / N
`
`y:
`
`5
`
`CN
`CN
`
`X
`
`CN
`CN
`
`H2N
`
`Particularly preferred are the following compounds:
`Particularly preferred are the following compounds:
`
`A)
`A)
`
`R1
`
`HZN
`
`s
`
`
`
`0
`
`[15, 2(2S), 35,55]
`[15, 2(25), 3s, 55]
`
`HO
`HO
`
`H2N
`HZN
`
`10
`10
`
`15
`
`20
`
`N
`N
`
`:
`>
`
`HZN
`
`N
`N
`
`:
`,
`
`0
`NC
`0 NC
`
`0
`0
`
`CN
`CN
`
`N
`N
`
`and
`and
`
`HO
`HO
`
`HZN
`HzN
`
`N
`N
`
`0
`NC
`0 NC
`
`0
`0
`
`CN.
`CN
`
`DETAILED DESCRIPTION OF THE
`DETAILED DESCRIPTION OF THE
`INVENTION
`INVENTION
`
`wherein R1 is alkyl, cycloalkyl, bicycloalkyl, tricycloalkyl,
`wherein R1 is alkyl, cycloalkyl, bicycloalkyl, tricycloalkyl,
`alkylcycloalkyl, hydroXyalkyl, hydroXycycloalkyl,
`alkylcycloalkyl, hydroxyalkyl, hydroxycycloalkyl,
`hydroxyalkylcycloalkyl, hydroxybicycloalkyl or hydroX-
`hydroXyalkylcycloalkyl, hydroXybicycloalkyl or hydrox
`.
`ytricycloalkyl;
`ytricycloalkyl;
`
`25
`25
`
`B)
`B)
`
`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.
`d€SCripti0I1 th€r€0f.
`Referring to Reaction Scheme 1, compound 1, where PG1
`Referring to Reaction Scheme 1, compound 1, where PG1
`30 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 COZRQ 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.
`(for eXample see Sagnard et al, Tet-Lett., 1995, 36, pp.
`3148—3152, TvereZovsky et al, Tetrahedron, 1997, 53, pp.
`35 3148-3152, Tverezovsky et al, Tetrahedron, 1997, 53, pp.
`35
`14773-14792, Hanessian et al, Bioorg. Med. Chem. Lett.,
`14773—14792, Hanessian et al, Bioorg. Med. Chem. Lett.,
`1998, 8, p. 2123—2128). Removal of the PG1 group by
`1998, 8, p. 2123-2128). Removal of the PG1 group by
`conventional methods (e.g. (1) TFA or HCl when PG1 is
`conventional methods (eg (1) TFA or HCl when PG1 is
`Boc, or (2) H2/Pd/C, TMSI when PG1 is Cbz, or (3) Et2NH
`Boc, or (2) HZ/Pd/C, TMSI when PG1 is CbZ, or (3) EtZNH
`40 when PG1 is (FMOC) affords the free amine 2. Amine 2 may
`when PG1 is (FMOC) affords the free amine 2. Amine 2 may
`be coupled to various protected amino acids such as 3
`be coupled to various protected amino acids such as 3
`(where PG2 can be any of the PG1 protecting groups) using
`(where PG2 can be any of the PG1 protecting groups) using
`standard peptide coupling conditions (eg EDAC/HOAT,
`standard peptide coupling conditions (e.g. EDAC/HOAT,
`wherein R1 is alkyl, cycloalkyl, bicycloalkyl, tricycloalkyl,
`wherein R1 is alkyl, cycloalkyl, bicycloalkyl, tricycloalkyl, 45 i-BuCOCOC1/TEA, PyB0p/NMM)
`to afford the Cone-
`i-BuCOCOCl/T EA, PyBop/NMM) to afford the corre
`45
`hydroXybicycloalkyl, hydroXytricycloalkyl, alkylcycloalkyl,
`sponding dipeptide 4. Removal of the amine protecting
`hydroxybicycloalkyl,hydroxytricycloalkyl,alkylcycloalkyl,
`sponding dipeptide 4. Removal of the amine protecting
`hydroXyalkyl, hydroXycycloalkyl or hydroXyalkylcy
`hydroxyalkyl, hydroxycycloalkyl Or hydr0Xya1ky1cy—
`group PG2 provides compound Ia of the invention where
`group PG2 provides compound Ia of the invention where
`cloalkyl as well as the following:
`X=H.
`cloalkyl as well as the following:
`X=H.
`
`R1
`
`HZN
`
`S
`
`
`
`[1R, 2s, 3(2s), 5S]
`[1R, 2s, 3(25), 55]
`
`@ m
`
`N
`
`CN,
`CN’
`
`HO
`HO
`
`N
`
`CN,
`CN’
`
`F
`
`NH2
`0
`NH 2 O
`
`HZN
`HZN
`
`O
`O
`
`0
`
`H0
`
`N
`
`,
`
`HZN
`
`NC
`
`HZN
`HZN
`
`,
`
`N
`N
`
`NC
`NC
`
`In the case where X1=CO2R9 (where R9 is alkyl or
`In the case where X1=CO2R9 (where R9 is alkyl or
`50 aralkyl groups such as methyl, ethyl, t-butyl, or benzyl), the
`aralkyl groups such as methyl, ethyl, t-butyl, or benZyl), the
`ester may be hydrolyzed under a variety of conditions, for
`ester may be hydrolyZed under a variety of conditions, for
`eXample with aqueous NaOH in a suitable solvent such as
`example with aqueous NaOH in a suitable solvent such as
`methanol, THF, or dioXane, to provide the acid 5. Conver-
`methanol, THF, or dioXane, to provide the acid 5. Conver
`55 sion of the acid group to the primary carboXamide, affording
`sion of the acid group to the primary carboXamide, affording
`55
`6, may be effected by activation of the acid group (eg
`6, maybe ‘effected by activation of the acid group (e.g.
`employing 1-BuOCOC1/TEA or EDAC) followed by treat-
`employing i-BuOCOCl/TEA or EDAC) followed by treat
`ment with NH3 or an ammonia equivalent in a solvent such
`ment with NH3 or an ammonia equivalent in a solvent such
`as dioXane, ether, or methanol. The amide functionality may
`as dioXane, ether, or methanol. The amide functionality may
`50 be converted to the nitrile group by a variety of standard
`be converted to the nitrile group by a variety of standard
`conditions (eg POCl3/pyridine/imidaZole or cyanuric
`conditions (e.g. POCl3/pyridine/imidazole or cyanuric
`chloride/DMF or trifluoroacetic anhydride, THF, pyridine)
`chloride/DMF or tri?uoroacetic anhydride, THF, pyridine)
`to give 7. Finally, removal of the PG2 protecting group
`to give 7. Finally, removal of the PG2 protecting group
`similar to above provides compound of the invention Ib.
`5 similar to above provides compound of the invention lb.
`In a different sequence (Scheme 2), compound 1 where X1
`In a different sequence (Scheme 2), compound 1 where X1
`is COZRQ may be saponified to the acid and subsequently
`is COZR9 may be saponi?ed to the acid and subsequently
`
`6
`
`

`
`US 6,395,767 B2
`US 6,395,767 B2
`
`8
`7
`8
`7
`mediate in the synthesis of Ib. Compound 10 may also be
`amidated as described above to give amide 8. Removal of
`mediate in the synthesis of Ib. Compound 10 may also be
`amidated as described above to give amide 8. Removal of
`the PG1 group followed by peptide coupling to 3 affords
`the PG1 group followed by peptide coupling to 3 affords
`generated by oxidation of the amine 2 (eg NCS) folloWed
`generated by oxidation of the amine 2 (e.g. NCS) followed
`compound 6, an intermediate in the synthesis of Ib.
`by hydrolysis and subsequent cyanide treatment. Compound
`compound 6, an intermediate in the synthesis of Ib.
`by hydrolysis and subsequent cyanide treatment. Compound
`10 may be obtained as a mixture of stereoisomers or a single
`Alternately, the carboxamide group in 8 may be converted
`Alternately, the carboXamide group in 8 may be converted
`10 may be obtained as a miXture of stereoisomers or a single
`isomer/diastereomer which may be epimerized (employing
`to the nitrile as described above to give compound 9.
`5
`to the nitrile as described above to give compound 9. 5 isomer/diastereomer Which may be epimeriZed (employing
`Deprotection of PGI affords 10 which may be subject to
`conventional procedures) to afford a mixture of stereoiso-
`Deprotection of PGI affords 10 Which may be subject to
`conventional procedures) to afford a miXture of stereoiso
`standard peptide coupling conditions to afford 7, an inter-
`mers.
`standard peptide coupling conditions to afford 7, an inter-
`mers.
`
`Scheme 1
`Scheme 1
`
`< >
`(
`)y
`Y
`
`<
`)x
`( )X
`HI|\I
`H111
`\r
`x1
`X1
`
`2
`2
`
`‘*1
`*1
`j’
`—>
`
`R2
`R2
`
`R1
`3
`R1
`OH
`R3
`OH
`R\N
`\N
`3
`I
`3
`|
`
`PG2
`O
`PG;
`0
`b
`
`b
`
`<
`)x
`( )X
`I|\I
`< >
`IL
`R (
`)y
`PG1 \r
`/ y
`PGl
`
`x1
`X1
`
`1
`1
`
`X1=H,COzR9
`X1=H,C0ZR9
`
`R2
`R2
`
`R1
`R1
`R3
`R3\N
`\N
`I
`I
`PG;
`PG2
`
`(
`)x
`( )X
`|
`|
`N
`N
`
`0
`o
`4
`4
`
`d
`d
`x1= COZRQ
`X1: COZRQ
`
`(
`)y
`( )y
`
`x1
`X1
`
`R1
`C
`R1
`C
`R3
`R3\N
`?'X1=H
`m’ \N
`H
`H
`
`R2
`R2
`
`(
`)x
`( )X
`|
`|
`N
`N\/( )y
`\/( )y
`
`0
`la
`la
`
`(
`)x
`( )X
`
`R2
`R2
`
`R1
`R1
`R3\
`RKN
`N
`PG;
`PG;
`
`0
`0
`5
`5
`
`R1
`e
`R1
`C
`NW/( )y —> R3\
`NH/( )y ?’
`RKN
`N
`COZH
`PG;
`COZH
`PG;
`
`R2
`R2
`
`(
`)x
`( )X
`|
`|
`N
`( )y
`N\r( )y
`CONH2
`CONHZ
`
`0
`0
`6
`6
`
`f
`f
`—>
`7’
`
`R1 R2
`R1 R2
`
`R3
`R3
`\N
`EN
`PG2
`PG;
`
`<
`)x
`( )x
`>
`<
`IL
`)
`(
`N
`W/ y
`W/
`Y
`CN
`CN
`
`—°»
`C
`
`—>
`
`0
`0
`7
`7
`a. PG1 = Boc, TFA or HCI; PG1 = Cbz, Hz/Pd/C or TMSI; PG1 = FMOC, EtZNH b. EDAC, HOBT, DMF or
`a. PGl = Boc, TFA