`(12) Reissued Patent
`Rob] et al.
`
`USO0RE44186E
`
`(10) Patent Number:
`
`(45) Date of Reissued Patent:
`
`US RE44,186 E
`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, Pennington, NJ
`(US); David J. Augeri, Princeton, NJ
`(US); David R. Magnin, Sumter, SC
`(US); Lawrence G. Hamann,
`Cambridge, MA (US); David A.
`Betebenner, Lawrenceville, NJ (US)
`
`(73) Assignee: Bristol-Myers Squibb Company,
`Princeton, NJ (US)
`
`EP
`EP
`EP
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`
`0 219 782 A2
`0686642
`1050540 A2
`WO 97/15576
`WO 99/26659
`WO 99/38501
`WO 99/47545
`WO 99/67279
`WO 00/10549
`W0 034241 A1
`WO 00/47207
`WO 00/53171
`WO 00/56296
`WO 00/56297
`WO 00/69868
`WO 97/40832
`W0 02/060894
`
`4/1987
`12/1995
`11/2000
`5/1997
`6/1999
`8/1999
`9/1999
`12/1999
`3/2000
`6/2000
`8/2000
`9/2000
`9/2000
`9/2000
`11/2000
`11/2001
`8/2002
`
`(21)
`(22)
`
`Appl. No .:
`Filed:
`
`13/308,658
`Dec. 1, 2011
`Related U.S. Patent Documents
`
`Reissue of:
`
`(64) Patent No.:
`Issued:
`
`Appl. No.:
`Filed:
`
`6,395,767
`May 28, 2002
`09/788,173
`Feb. 16, 2001
`
`U.S. Applications:
`(60) Provisional application No. 60/188,555, filed on Mar.
`10, 2000.
`
`(51)
`
`Int. Cl.
`C07D 209/02
`A6IK 31/403
`(52) U.S. Cl.
`USPC ......................................... .. 514/412; 548/452
`(58) Field of Classification Search ................ .. 514/412;
`548/452
`
`(2006.01)
`(2006.01)
`
`See application file for complete search history.
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`3,325,478 A
`3,906,044 A
`4,254,057 A
`4,255,334 A
`4,379,785 A
`5,462,928 A
`5,561,146 A
`5,939,560 A
`5,998,463 A
`6,011,155 A
`6,060,432 A
`6,110,949 A
`6,166,063 A
`6,297,233 B1
`6,555,542 B1
`6,803,357 B1
`6,890,898 B2
`7,078,381 B2
`7,205,432 B2
`7,250,529 B2
`2006/0287317 A1
`
`6/1967 Hermann et al.
`9/1975 Aigami et al.
`3/1981 Day et al.
`3/1981 Day et al.
`4/1983 Weyer et al.
`10/1995 Bachovchin etal.
`10/1996 Kim et al.
`8/1999 Jenkins et al.
`12/1999 Hulin et al.
`1/2000 Villhauer
`5/2000 Adams et al.
`8/2000 Villhauer
`12/2000 Villhauer
`10/2001 Stein et al.
`4/2003 O’Connor et al.
`10/2004 Bachovchin et al.
`5/2005 Bachovchin et al.
`7/2006 Bachovchin et al.
`4/2007 Berner et al.
`7/2007 Williams
`12/2006 Smith et al.
`
`DE
`DE
`DE
`DE
`EP
`
`FOREIGN PATENT DOCUMENTS
`2449 840
`4/1975
`2521895
`4/1976
`33 24 263 A1
`1/1985
`39 26 606 A1
`2/1991
`0 007 652 A1
`2/1980
`
`OTHER PUBLICATIONS
`
`Hermann Stetter and Elli Rauscher, Zur Kenntnis der Adamantan-
`carbonsaure-(1) Chemische Berichte, 1960, vol. 93, No. 5, pp. 1161-
`1 166.
`"2-Acylaminopyridin-Derivate mit
`a1.,
`Von R. Hiltmarm et
`antagonisterischer Wirksamkeit,
`und
`morphinagonistischer
`Arzneimittel-Forschung,” 1974, vol. 24, No. 4a, pp. 584-600.
`Peter Beak et a1.,“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 a1., “Discovery and Preclinical Profile 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
`oL-Aminoacyl-L-cis-4,5-
`methanoloprolinenitrile-Based Inhibitors,” J. Med. Chem. 2004, 47,
`2587-2598.
`Hi1tmaIm,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 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 combination
`of such DP 4 inhibitor and one or more of another antidiabetic
`
`agent such as metformin, glyburide, troglitazone, pioglita-
`zone, rosiglitazone and/or msulin and/or one or more of a
`hypolipidemic agent and/or anti-obesity agent and/or other
`therapeutic agent.
`
`41 Claims, No Drawings
`(cid:54)(cid:88)(cid:81)(cid:16)(cid:36)(cid:80)(cid:81)(cid:72)(cid:68)(cid:79)(cid:16)(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:20)(cid:25)(cid:16)(cid:19)(cid:20)(cid:20)(cid:19)(cid:23)(cid:16)(cid:3)(cid:40)(cid:91)(cid:17)(cid:3)(cid:20)(cid:19)(cid:19)(cid:20)(cid:15)(cid:3)(cid:83)(cid:17)(cid:3)(cid:20)(cid:3)(cid:82)(cid:73)(cid:3)(cid:24)(cid:21)
`Sun-Amneal-|PR2016-01104- Ex. 1001, p. 1 of 52
`
`EXHIBIT
`
`Ex. 1001
`
`
`
`US RE44,186 E
`Page 2
`
`OTHER PUBLICATIONS
`Augustyns, KJL et al, Eur. J. Med. Chem. 32, 301-309, (1997).
`Hughes, T.E. et al, Biochemistry, 28, 11597-11603, 19993.
`Yarnada, M. et al, Bioorganic & Medicinal Chemistry Letters 8,
`1537-1540 (1998).
`Tanaka, S. et al, Immunopharmacology 40, 21-26 (1998).
`Li, J. et al, Archives ofBiochemistry and Biophysics, Vol. 323, No. 1,
`pp. 148-154, Oct. 20, 1995.
`Ashworth, D.M. et al, Bioorganic & Medicinal Chemistry Letter, V01.
`6, No. 22, pp. 2745-2748, 1996.
`Yarnada, M. et al, Bioorganic & Medicinal Chemistry Letter 8, 1537-
`1540 (1998).
`Ashworth, D.M. et al, Bioorganic & Medicinal Chemistry Letter, V01.
`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, V01. 50, No. 8, pp. 653-657,
`Aug. 1997.
`Demuth, H.-U. et al, FEBS Letters, Vol. 320, No. 1, pp. 23-27, Mar.
`1993.
`Ol111uki, T. et al, Diugs of the Future, 24(6):665-670, 1999.
`Demuth, H.-U. et al, Diabetes, 2000, V01. 49, suppl. 1,A102.
`Rotherberg, P et al, Diabetes, 2000, V01. 49, Suppl. 1, A39.
`Sagnard, I. et al, Tetrahedron Letters, Vol. 36, No. 18, pp. 3149-3152,
`1995.
`Tverezovsky, V. V. et al., Tetrahedron, V01. 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
`
`(cid:54)(cid:88)(cid:81)(cid:16)(cid:36)(cid:80)(cid:81)(cid:72)(cid:68)(cid:79)(cid:16)(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:20)(cid:25)(cid:16)(cid:19)(cid:20)(cid:20)(cid:19)(cid:23)(cid:16)(cid:3)(cid:40)(cid:91)(cid:17)(cid:3)(cid:20)(cid:19)(cid:19)(cid:20)(cid:15)(cid:3)(cid:83)(cid:17)(cid:3)(cid:21)(cid:3)(cid:82)(cid:73)(cid:3)(cid:24)(cid:21)
`Sun-Amneal-IPR2016-01104- Ex. 1001, p. 2 of 52
`
`
`
`US RE44,l86 E
`
`1
`CYCLOPROPYL-FUSED
`PYRROLIDINE-BASED INHIBITORS OF
`DIPEPTIDYL PEPTIDASE IVAND METHOD
`
`Matter enclosed in heavy brackets [ ] appears in the
`original patent but forms no part of this reissue specifica-
`tion; matter printed in italics indicates the additions
`made by reissue.
`
`This application takes priority from U.S. provisional appli-
`cation No. 60/188,555, filed Mar. 10,2000.
`
`5
`
`10
`
`15
`
`2
`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
`
`
`
`FIELD OF THE INVENTION
`
`20
`
`The present invention relates to cyclopropyl-fused pyrro-
`lidine-based inhibitors ofdipeptidyl peptidase IV (DP-4), and
`to a method for treating diabetes, especially Type II diabetes,
`as well as hyperglycemia, Syndrome X, diabetic complica-
`tions, hyperinsulinemia, obesity, atherosclerosis and related
`diseases, as well as various immunomodulatory diseases and 25
`chrome inflammatory bowel disease, employing such cyclo-
`propyl-fused pyrrolidines alone or in combination with
`another type antidiabetic agent a11d/or other type therapeutic
`agent.
`
`wherein
`x is 0 or 1 and y is 0 or 1 (provided that
`x:l when y:0 and
`x:0 when y:l);
`n is 0 or 1;
`X is H or CN (that is cyano);
`R1, R2, R3 and R4are the same or different and are inde-
`pendently selected from H, alkyl, alkenyl, alkynyl,
`cycloalkyl, cycloalkylalkyl, bicycloalkyl, tricycloalkyl,
`alkylcycloalkyl, hydroxyalkyl, hydroxyalkylcycloalkyl,
`hydroxycycloalkyl, hydroxybicycloalkyl, hydroxytricy-
`cloalkyl, bicycloalkylalkyl, alkylthioalkyl, arylalkylth-
`ioalkyl, cycloalkenyl, aryl, aralkyl, heteroaryl, het-
`eroarylalkyl,
`cycloheteroalkyl
`and
`cycloheteroalkylalkyl, all optionally substituted through
`available carbon atoms with l, 2, 3, 4 or 5 groups
`selected from hydrogen, halo, alkyl, polyhaloalkyl,
`alkoxy, haloalkoxy, polyhaloalkoxy, alkoxycarbonyl,
`alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, polycy-
`cloalkyl, heteroarylarnino, arylarnino, cycloheteroalkyl,
`cycloheteroalkylalkyl, hydroxy, hydroxyalkyl, nitro,
`cyano, amino, substituted amino, alkylarnino, dialky-
`lamino, thiol, alkylthio, alkylcarbonyl, acyl, alkoxycar-
`bonyl, aminocarbonyl, alkynylaminocarbonyl, alky-
`laminocarbonyl,
`alkenylarninocarbonyl,
`alkylcarbonyloxy, alkylcarbonylamino,
`arylcarbony—
`lamino,
`alkylsulfonylarnino,
`alkylaminocarbony-
`lamino, alkoxycarbonylarnino, alkylsulfonyl, aminosul-
`fonyl, alkylsulfinyl, sulfonamido or sulfonyl;
`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
`same or different and are independently selected from
`hydroxy, alkoxy, cyano, H, alkyl, alkenyl, alkynyl,
`cycloalkyl, cycloalkylalkyl, cycloalkenyl, aryl, aryla-
`lkyl, heteroaryl, heteroarylalkyl, cycloheteroalkyl, halo,
`an1ino, substituted amino, cycloheteroalkylalkyl, alkyl-
`carbonylamino,
`arylcarbonylamino,
`alkoxycarbony-
`lamino, aryloxycarbonylamino, alkoxycarbonyl, ary-
`loxycarbonyl, or alkylarninocarbonylamino, or R1 and
`R4 may optionally be
`taken together
`to
`form
`—(CR7R8)P— where p is 2 to 6, and R7 and R8 are the
`same or different and are independently selected from
`hydroxy, alkoxy, cyano, H, alkyl, alkenyl, alkynyl,
`cycloalkyl, cycloalkylalkyl, cycloalkenyl, aryl, aryla-
`lkyl, heteroaryl, heteroarylalkyl, cycloheteroalkyl, halo,
`an1ino, substituted amino, cycloheteroalkylalkyl, alkyl-
`carbonylamino,
`arylcarbonylamino,
`alkoxycarbony-
`lamino, aryloxycarbonylamino, alkoxycarbonyl, ary-
`(cid:54)(cid:88)(cid:81)(cid:16)(cid:36)(cid:80)(cid:81)(cid:72)(cid:68)(cid:79)(cid:16)(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:20)(cid:25)(cid:16)(cid:19)(cid:20)(cid:20)(cid:19)(cid:23)(cid:16)(cid:3)(cid:40)(cid:91)(cid:17)(cid:3)(cid:20)(cid:19)(cid:19)(cid:20)(cid:15)(cid:3)(cid:83)(cid:17)(cid:3)(cid:22)(cid:3)(cid:82)(cid:73)(cid:3)(cid:24)(cid:21)
`Sun-Amneal-IPR2016-01104- Ex. 1001, p. 3 of 52
`
`30
`
`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(7-3 6) is a 29 amino-acid peptide derived by post-
`translational processing ofproglucagon in the small intestine.
`GLP-l (7-36) has multiple actions in vivo including the stimu-
`lation of insulin secretion, inhibition of glucagon secretion,
`the promotion of satiety, and the slowing of gastric emptying.
`Based on its physiological profile, the actions ofGLP-l (7-36)
`are expected to be beneficial in the prevention and treatment
`of type II diabetes and potentially obesity. To support this
`claim, exogenous administration of GLP-l(7-3 6) (continu-
`ous infusion) in diabetic patients has demonstrated efficacy in
`this patient population. Unfortunately GLP-l(7-3 6)
`is
`degraded rapidly in vivo and has been shown to have a short
`half-life in vivo (tl/Zzl .5 min). Based on a study of geneti-
`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
`primary degrading enzyme of GLP-l(7-36) in vivo. GLP-l
`(7-36) is degraded by DP-4 efiiciently 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 poten-
`tiate endogenous levels of GLP-l (7-36) and attenuate forma-
`tion of its antagonist GLP-l(9-36) and thus serve to amelio-
`rate the diabetic condition.
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`
`
`US RE44,186 E
`
`3
`loxycarbonyl, or alkylaminocarbonylamino, or option-
`ally R1 and R5 together with
`
`H*N
`
`‘Raf
`R4
`
`form a 5 to 7 membered ring containing a total of 2 to 4
`heteroatoms selected from N, O, S, S0, or S02;
`or optionally R1 and R3 together with
`
`H—N
`
`‘effR4
`
`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
`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 include
`the following structures
`
`10
`
`15
`
`20
`
`25
`
`30
`
`R3
`N
`
`H/
`
`R2
`
`R1
`
`N
`
`R4
`
`0
`
`X
`
`R2
`
`R1
`
`R3
`N
`
`N
`
`H/ (gr/. V
`
`R4
`
`0
`
`X
`
`IA
`
`35
`
`40
`
`1B
`
`45
`
`_
`
`50
`
`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, polycystic ovary syndrome,
`growth disorders, frailty, arthritis, allograft rejection in trans-
`plantation, autoimmune diseases (such as scleroderma and
`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, obe-
`sity, atherosclerosis and related diseases, as well as inflam-
`matory bowel disease (such as Crohn’ s disease and ulcerative
`colitis), wherein a therapeutically effective amount of a com-
`(cid:54)(cid:88)(cid:81)(cid:16)(cid:36)(cid:80)(cid:81)(cid:72)(cid:68)(cid:79)(cid:16)(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:20)(cid:25)(cid:16)(cid:19)(cid:20)(cid:20)(cid:19)(cid:23)(cid:16)(cid:3)(cid:40)(cid:91)(cid:17)(cid:3)(cid:20)(cid:19)(cid:19)(cid:20)(cid:15)(cid:3)(cid:83)(cid:17)(cid:3)(cid:23)(cid:3)(cid:82)(cid:73)(cid:3)(cid:24)(cid:21)
`Sun-Amneal-IPR2016-01104- Ex. 1001, p. 4 of 52
`
`4
`
`pound of structure I (which inhibits DP 4) is administered to
`a human patient in need of treatment.
`The conditions, diseases, and maladies collectively refer-
`enced to as “Syndrome X” or Metabolic Syndrome are
`detailed in Joharmsson J. Clin. Endocrinol. Metab., 82, 727-
`734 (1997).
`In addition, in accordance with the present invention, a
`method is provided for treating diabetes and related diseases
`as defined above and hereinafter as well as any of the other
`disease states mentioned above, wherein a therapeutically
`effective amount ofa combination ofa 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 glucosetolerance, obesity,
`hyperglycemia, Syndrome X, dysmetabolic syndrome, dia-
`betic complications, dysmetabolic syndrome, and hyperin-
`sulinemia.
`
`The conditions, diseases and maladies collectively referred
`to as “diabetic complications” include retinopathy, neuropa-
`thy and nephropathy, and other known complications of dia-
`betes.
`
`The term “other type(s) oftherapeutic 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 autoim-
`mune 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 disor-
`ders.
`
`In the above methods of the invention, the compound of
`structure I will be employed in a weight ratio to the antidia-
`betic 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 0.221 to about 10:1.
`Preferred are compounds of formula I wherein R3 is H or
`alkyl, R1 is H, alkyl, cycloalkyl, bicycloalkyl, tricycloalkyl,
`alkylcyclo alkyl, hydroxyalkyl, hydroxytricyclo alkyl,
`hydroxycycloalkyl, hydroxybicycloalkyl, or hydroxyalkyl-
`cycloalkyl, R2 is H or alkyl, n is 0, X is CN, x is 0 or 1 and y
`is 0 or 1.
`
`Most preferred are preferred compounds of formula I as
`described above where X is
`
`CN or
`
`-<CN,
`
`55
`
`60
`
`65
`
`
`
`5
`and/or wherein the fused cyclopropyl group is identified as
`
`-continued
`
`US RE44,186 E
`
`V.
`
`5
`
`HO
`
`Thus, preferred compounds of formula I of the invention
`will include the moiety:
`
`(
`
`X
`
`(
`
`X
`
`(
`
`X
`
`10
`
`15
`
`X N
`
`)y, X N
`
`)y,
`
`or X N
`
`)y,
`
`HZN
`
`CN
`
`X
`
`CN
`
`Particularly preferred are the following compounds:
`
`A)
`
`20
`
`HO
`
`25
`
`HZN
`
`0
`
`N
`
`NC
`
`HZN
`
`F
`
`7
`
`H2N
`
`N
`
`7
`
`0
`
`NC
`
`N
`
`,
`
`0
`
`CN
`
`N
`
`,
`
`0
`
`NC
`
`HZN
`
`HO
`
`N
`
`0
`
`NC
`
`and
`
`HZN
`
`N
`
`0
`
`CN.
`
`
`
`[1S, 2(2S), 3S, 5S]
`
`wherein R1 is alkyl, cycloalkyl, bicycloalkyl, tricycloalkyl,
`alkylcycloalkyl, hydroxyalkyl, hydroxycycloalkyl, hydroxy-
`alkylcycloalkyl,
`hydroxybicycloalkyl
`or
`hydroxytricy-
`cloalkyl;
`
`13)
`
`H21\'
`
`R1
`
`5
`
`[1R, 2S, 3(2S), 5S]
`
`wherein R1 is alkyl, cycloalkyl, bicycloalkyl, tricycloalkyl,
`hydroxybicycloalkyl, hydroxytricycloalkyl, alkylcycloalkyl,
`hydroxyalkyl, hydroxycycloalkyl or hydroxyalkylcycloalkyl
`as well as the following:
`
`N:
`
`N:
`
`CN,
`
`HO
`
`CN,
`
`1:
`
`NH2
`
`0
`
`HZN
`
`o
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`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 1, where PG1
`is a common amine protecting group such as Boc, Cbz, or
`FMOC and X1 is H or CO2R9 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, 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 arnine 2 Amine 2 may be coupled to
`various protected amino acids such as 3 (where PG2 can be
`any of the PG1 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 com-
`pound Ia of the invention where X:H.
`In the case where X1:CO2R9 (where R9 is alkyl or aralkyl
`groups such as methyl, ethyl, t-butyl, or benzyl), the ester may
`be hydrolyzed under a variety ofconditions, for example with
`aqueous NaOH in a suitable solvent such as methanol, THF,
`or dioxane, to provide the acid 5. Conversion ofthe acid group
`to the primary carboxamide, affording 6, may be effected by
`activation of the acid group (e.g. employing i-BuOCOCl/
`TEA or EDAC) followed by treatment with NH3 or an ammo-
`nia equivalent in a solvent such as dioxane, ether, or metha-
`nol. The amide functionality may be converted to the nitrile
`group by a variety of standard conditions (e.g. POCl3/pyri-
`dine/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.
`
`(cid:54)(cid:88)(cid:81)(cid:16)(cid:36)(cid:80)(cid:81)(cid:72)(cid:68)(cid:79)(cid:16)(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:20)(cid:25)(cid:16)(cid:19)(cid:20)(cid:20)(cid:19)(cid:23)(cid:16)(cid:3)(cid:40)(cid:91)(cid:17)(cid:3)(cid:20)(cid:19)(cid:19)(cid:20)(cid:15)(cid:3)(cid:83)(cid:17)(cid:3)(cid:24)(cid:3)(cid:82)(cid:73)(cid:3)(cid:24)(cid:21)
`Sun-Amneal-IPR2016-01104- Ex. 1001, p. 5 of 52
`
`
`
`7
`
`US RE44,l86 E
`
`2
`
`R3 R1 R
`\I|\I
`
`PG; 0
`
`-continued
`
`(I{I)X
`\r( >y
`
`x1
`
`4
`
`/ <
`1 ,
`(|)X
`3 R1 R2
`C
`x —H R\§>H‘/N\/( )y
`
`o
`
`la
`
`d
`
`x1:Co;R9
`
`2
`
`R3 Rlj\ll/Ki? <
`
`)
`
`CO;H
`
`l|’G; o
`5
`
`e—>
`
`2
`
`(11?
`
`R3 R1 R
`
`l|’G; o
`6
`
`(
`
`> if’
`
`CONH;
`
`In a different sequence (Scheme 2), compound 1 where X1
`is CO2R9 may be saponified to the acid and subsequently
`an1idated as described above to give amide 8. Removal of the
`PG1 group followed by peptide coupling to 3 affords com-
`pound 6, an intermediate in the synthesis of lb.
`
`Altemately, the carboxarnide group in 8 may be converted
`to the nitrile as described above to give compound 9. Depro-
`tection of PG1 affords 10 which may be subject to standard
`peptide coupling conditions to afford 7, an intermediate in the
`synthesis of lb. 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 conven-
`tional procedures) to afford a mixture of stereoisomers.
`
`Schemel
`
`1 R2
`, R
`OH
`R'\I|\I
`PG; 0
`‘Rx T,
`HNW/(
`)3
`b
`1
`X
`2
`
`a
`
`(I); q
`/N (
`PG1 W’
`X1
`1
`
`>y
`
`x1:H,Co;R9
`
`10
`
`15
`
`20
`
`25
`
`30
`
`(l);
`R1R2
`\I|\IflW‘/ \r y
`
`R3
`
`N
`
`(
`
`)
`
`CN
`
`_c_
`
`R. R2
`xlfi
`
`R3
`
`:l
`(l);
`\r( );
`
`N
`
`.
`
`CN
`
`0
`PG; 0
`1b
`7
`a. PG] : Boc, TFA or HCl;PG1 : Cbz, H2/Pd/C or TMSI; PG1 : FMOC, Et2N'H
`b. EDAC, HOBT,Dl\/J1: or i-BuOCOCl/TEA or PyBop, NMM
`c. PG2 : PG1, (see conditions for a)
`d. LiOH or NaOH MeOH or TH]:/H30 or dioxane
`e. i-BuOCOCl/NMM or i-BuOCOCl/TEA or EDAC, then NH; in dioxane or Et2O
`f. POCI3, pyridine, imidazole or cyanuric chloride, DM1: or Tl-‘AA, THI, pyridine.
`
`Scheme 2
`
`()X
`I
`/N
`PG1 Y
`co;R9
`1
`
`(
`
`)y
`
`6
`
`c
`()x
`3 I R?’ 6
`/
`J’
`1
`N
`(
`)
`OH
`PG1
`R3 R
`\N
`l
`PG;
`
`CONH2
`
`3
`
`0
`
`3
`d. peptide coupling
`conditions
`
`R2
`
`R1
`
`R3
`
`\TPG;
`
`0
`
`OH
`
`L»
`
`(
`
`)y
`
`()x
`IN
`/
`PG] Y
`CN
`9
`
`(
`
`3
`)
`lx e> 7 j> lb
`
`HM” 3
`
`CN
`10
`
`3'"?::::.:::::‘1“g
`
`I
`
`(cid:54)(cid:88)(cid:81)(cid:16)(cid:36)(cid:80)(cid:81)(cid:72)(cid:68)(cid:79)(cid:16)(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:20)(cid:25)(cid:16)(cid:19)(cid:20)(cid:20)(cid:19)(cid:23)(cid:16)(cid:3)(cid:40)(cid:91)(cid:17)(cid:3)(cid:20)(cid:19)(cid:19)(cid:20)(cid:15)(cid:3)(cid:83)(cid:17)(cid:3)(cid:25)(cid:3)(cid:82)(cid:73)(cid:3)(cid:24)(cid:21)
`Sun-Amneal-IPR2016-01104- Ex. 1001, p. 6 of 52
`
`
`
`9
`
`-continued
`
`US RE44,186 E
`
`10
`
`1
`
`()x
`
`I H
`
`N\/< )y
`2
`a. LiOH or NaOH in MeOH or TH1:/H20 or dioxane
`b. i-BuOCOCl/NMM or i-BuOCOCl/TEA or EDAC, then NH; in dioxane or Et3O
`c. PG] : Boc, TFA or HCI; PG] : Cbz, H2/Pd/C or TMSI; PG] : FMOC, Et2NH
`d. EDAC, HOBT, DM1: or i-BuOCOCl/TEA or PyBop, NMM
`e. POCI3, pyridine, irnidazole or cyanuric chloride, DM1-‘.
`
`In a like manner, |3-amino acids such as
`
`R3
`\N
`PG2/
`
`R2
`
`R1
`
`OH
`
`R4
`
`0
`
`-continued
`
`A (D @179]
`
`any of which groups may be optionally subsituted with 1 to 4
`substituents such as halogen, alkyl, alkoxy, hydroxy, aryl,
`aryloxy, arylalkyl, cycloalkyl, hydroxyalkyl, alkylamido,
`alkanoylamino, oxo, acyl, arylcarbonylamino, amino, nitro,
`cyano, thiol and/or alkylthio and/or any ofthe substituents for
`alkyl.
`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 cyclopente-
`nyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclohexadi-
`enyl, and cycloheptadienyl, which may be optionally substi-
`tuted 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
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`may be coupled with 2, the free amine of 8, or 10 to give the
`corresponding amides which may be converted to the
`[3-amino acid derivatives of compound Ia or lb 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 chain hydrocarbons, con-
`taining 1 to 20 carbons, preferably 1 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, 2,2,4-tri-
`methyl-pentyl, nonyl, decyl, undecyl, dodecyl, 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, C1 or I or CF3, alkyl, alkoxy, aryl, aryloxy, aryl(aryl) or
`diaryl,
`arylalkyl,
`arylalkyloxy,
`alkenyl,
`cycloalkyl,
`cycloalkylalkyl,
`cycloalkylalkyloxy,
`amino,
`hydroxy,
`hydroxyalkyl, acyl, heteroaryl, heteroaryloxy, heteroaryla-
`lkyl, heteroarylalkoxy, aryloxyalkyl, alkylthio, arylalkylthio,
`aryloxyaryl,
`alkylamido,
`alkanoylamino,
`arylcarbony-
`lamino, nitro, cyano,
`thiol, haloalkyl,
`trihaloalkyl and/or
`alkylthio.
`
`the term “cycloalkyl” as
`Unless otherwise indicated,
`employed herein alone or as part of another group includes
`saturated or partially unsaturated (containing 1 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 10 carbons, forming
`the ring and which may be fused to 1 or 2 aromatic rings as
`described for aryl, which includes cyclopropyl, cyclobutyl,
`cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl
`and cyclododecyl, cyclohexenyl, adamantyl,
`
`Qlvbvbgo
`
`and the like, and may optionally be 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 of2 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-tetradecatri-
`enyl, a11d the like, and which may be optionally substituted
`with 1 to 4 substituents, namely, halogen, haloalkyl, alkyl,
`alkoxy, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, amino,
`hydroxy, heteroaryl, cycloheteroalkyl, alkanoylamino, alky-
`lamido, arylcarbonyl-an1ino, nitro, cyano,
`thiol, alkylthio
`and/or any of the alkyl 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 radicals of2 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
`(cid:54)(cid:88)(cid:81)(cid:16)(cid:36)(cid:80)(cid:81)(cid:72)(cid:68)(cid:79)(cid:16)(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:20)(cid:25)(cid:16)(cid:19)(cid:20)(cid:20)(cid:19)(cid:23)(cid:16)(cid:3)(cid:40)(cid:91)(cid:17)(cid:3)(cid:20)(cid:19)(cid:19)(cid:20)(cid:15)(cid:3)(cid:83)(cid:17)(cid:3)(cid:26)(cid:3)(cid:82)(cid:73)(cid:3)(cid:24)(cid:21)
`Sun-Amneal-IPR2016-01104- Ex. 1001, p. 7 of 52
`
`
`
`11
`
`12
`
`US RE44,l86 E
`
`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-octenyl, 3-nonenyl, 4-decenyl,3-
`undecenyl, 4-dodecenyl and the like, and which may be
`optionally substituted with l to 4 substituents, namely, halo-
`gen, haloalkyl, alkyl, alkoxy, alkenyl, alkynyl, aryl, arylalkyl,
`cycloalkyl, amino, heteroaryl, cycloheteroalkyl, hydroxy,
`alkanoylarnino,
`alkylamido,
`arylcarbonylamino,
`nitro,
`cyano, thiol, and/or alkylthio, and/or any ofthe alkyl substitu-
`ents 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 substi-
`tuted as defined above for “alkyl”.
`Where alkenyl groups as defined above and alkynyl groups
`as defined above, respectively, have single bonds for attach-
`ment at two different carbon atoms, they are termed “alk-
`enylene 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 alumi-
`num.
`
`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 1 -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
`
`o
`
`o
`
`I_
`\' i
`
`/I_
`\' ’
`
`0
`
`/
`
`\
`—\’
`
`O
`
`/
`
`/
`
`and may be optionally substituted through available carbon
`atoms with l, 2, or 3 groups selected from hydrogen, halo,
`haloalkyl, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, trif-
`luoromethyl,
`trifluoromethoxy,
`alkynyl, cycloalkylalkyl,
`cycloheteroalkyl, cycloheteroalkylalkyl, aryl, heteroaryl,
`arylalkyl, aryloxy, aryloxyalkyl, arylalkoxy, arylthio, ary-
`lazo,
`heteroarylalkyl,
`heteroarylalkenyl,
`heteroarylhet-
`eroaryl, heteroaryloxy, hydroxy, nitro, cyano, amino, substi-
`tuted 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, het-
`eroarylthio, arylthioalkyl, alkoxyarylthio, alkylcarbonyl,
`arylcarbonyl,
`alkylarninocarbonyl,
`arylaminocarbonyl,
`alkoxycarbonyl, arninocarbonyl, alkylcarbonyloxy, arylcar-
`bonyloxy, alkylcarbonylamino, arylcarbonylamino, aryl-
`sulfinyl, arylsulfinylalkyl, arylsulfonylamino or arylsulfon-
`aminocarbonyl and/or any of the alkyl substituents set out
`herein.
`
`the term “lower alkoxy”,
`Unless otherwise indicated,
`“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 a11 oxygen atom.
`Unless otherwise indicated, the term “substituted amino”
`as employed herein alone or as part of another group refers to
`amino substituted with one or two sub stituents, which may be
`the same or different, such as alkyl, aryl, arylalkyl, heteroaryl,
`heteroarylalkyl,
`cycloheteroalkyl,
`cycloheteroalkylalkyl,
`cycloalkyl, cycloalkylalkyl haloalkyl, hydroxyalkyl, alkoxy-
`alkyl or thioalkyl. These substituents may be further substi-
`tuted with any ofthe 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, l-azepinyl, 4-morpholi-
`nyl, 4-