(12) United States Patent
`Robl et al.
`
`(10) Patent N0.:
`(45) Date of Patent:
`
`US 6,395,767 B2
`May 28, 2002
`
`US006395767B2
`
`(54) CYCLOPROPYL-FUSED
`PYRROLIDINE-BASED INHIBITORS OF
`DIPEPTIDYL PEPTIDASE IV AND METHOD
`
`(75)
`
`Inventors: Jeifrey A. Rob], 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.2 09/788,173
`
`(22) Filed:
`
`Feb. 16, 2001
`
`Related U.S. Application Data
`Provisional application No. 60/188,555, filed on Mar. 10,
`2000.
`
`(60)
`
`Int. Cl.7 ................... .. C07D 209/07; A61K 31/403
`(51)
`(52) US. Cl.
`.................. .. 514/412; 548/452
`
`(58) Field of Search ......................... .. 548/452; 514/412
`
`(56)
`
`References Cited
`U.S. PATENT DOCUMENTS
`
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`10/1995 Bachovchin et al.
`8/1999 Jenkins et al.
`12/1999 Hulin et al.
`1/2000 Villhauer
`8/2000 Villhauer
`
`FOREIGN PATENT DOCUMENTS
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`WO
`W0
`W0
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`WO
`W0
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`
`33 24 263 A1
`39 26 606 A1
`0 007 652 A1
`0 219 782 A2
`1050540 A2
`WO 99/26659
`VVO 99/38501
`VVO 99/47545
`WO 99/67279
`VVO 00/10549
`W0 034241 A1
`VVO 00/53171
`VVO 00/56296
`WO 00/56297
`WO 00/69868
`VVO 97/40832
`
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`9/2000
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`11/2001
`
`OTHER PUBLICATIONS
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`14020-14024, Nov. 1998.
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`(1997).
`Hughes,
`
`et al, Biochemistry, 28, 11597-11603, 19993
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`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).
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`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 of Antibiotics, 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 al., 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 FL'rm—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
`
`troglita-
`antidiabetic agent such as metformin, glyburide,
`zone, pioglitazone, rosiglitazone and/or insulin and/or one or
`uiore of a liypolipidemic agent and/or anti-obesity agent
`and/or other therapeutic agent.
`
`24 Claims, N0 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:21)(cid:15)(cid:3)(cid:83)(cid:17)(cid:3)(cid:3)(cid:20)(cid:3)(cid:82)(cid:73)(cid:3)(cid:24)(cid:21)
`Sun-Amneal-|PR2016-01104- Ex. 1002, p.
`1 of 52
`
`EXHIBIT
`
`Ex. 1002
`
`

`
`US 6,395,767 B2
`
`1
`CYCLOPROPYL-FUSED PYRROLIDINE-
`BASED INHIBITORS OF DIPEPTIDYL
`PEPTI])ASE IV AND METHOD
`
`This application takes priority from U.S. provisional
`application No. 60/188,555, filed Mar. 10, 2000.
`
`FIELD OF THE INVENTION
`
`invention relates to cyclopropyl-fused
`The present
`pyrrolidine-based inhibitors of dipeptidyl peptidase IV (DP-
`4), and to a method for treating diabetes, especially Type II
`diabetes, as well as hyperglycemia, Syndrome X, diabetic
`complications, hyperinsulinemia, obesity, atherosclerosis
`and related diseases, as well as various immunomodulatory
`diseases and chronic inflammatory bowel disease, employ-
`ing such cyclopropyl-fused pyrrolidines alone or in combi-
`nation with another type antidiabetic agent and/or other type
`therapeutic agent.
`
`BACKGROUND OF THE INVENTION
`
`Depeptidyl peptidase IV (DP-4) is a membrane bound
`non—classical serine aminodipeptidase which is located in a
`variety of tissues (intestine, liver, lung, kidney) as well as on
`circulating T-lymphocytes (where the enzyme is known as
`CD-26). It
`is responsible for the metabolic cleavage of
`certain endogenous peptides (GLP-1('7-36), glucagon) in
`vivo and has demonstrated proteolytic activity against a
`variety of other peptides (GHRH, NPY, GLP-2, VIP) in
`vitro.
`
`GLP-1(7-36) is a 29 amino-acid peptide derived by post-
`translational processing of proglucagon in the small intes-
`tine. GLP-1(7-36) has multiple actions in vivo including the
`stimulation of insulin secretion,
`inhibition of glucagon
`secretion, the promotion of satiety, and the slowing of gastric
`emptying. Based on its physiological profile, the actions of
`GLP-1(7-36) are expected to bc bcncficial in the prevention
`and treatment of type II diabetes and potentially obesity. To
`support this claim, exogenous administration of GLP-1(7-
`36) (continuous infusion) in diabetic patients has demon-
`strated eflicacy in this patient population. Unfortunately
`GLP-1(7-36) is degraded rapidly in vivo and has been
`shown to have a short half—life in vivo (t1/2==1.5 min). Based
`on a study of genetically bred DP-4 KO mice and on in
`vivo/in vitro studies with selective DP-4 inhibitors, DP-4
`has been shown to be the primary degrading enzyme of
`GLP-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
`as a physiological antagonist to GLP-1(7-36). Thus, inhibi-
`tion of DP-4 in vivo should potentiate endogenous levels of
`GLP-1(_'7-36) and attenuate formation of its antagonist GLP-
`1(9-36) and thus serve to ameliorate the diabetic condition.
`
`DESCRIPTION OF THE INVENTION
`
`In accordance with the present invention, cyclopropyl-
`fused pyrrolidine-based compounds are provided which
`inhibit DP-4 and have the structure
`
`10
`
`15
`
`30
`
`35
`
`40
`
`45
`
`SO
`
`55
`
`60
`
`65
`
`1
`
`R3
`
`I\
`
`H/
`
`R2
`
`R1
`
`(
`
`X
`
`n
`R4
`
`N
`
`)y
`
`o
`
`X
`
`wherein
`
`X is 0 or 1 and y is 0 or 1 (provided that
`x=1 when y=0 and
`x=0 when y=1);
`n is 0 or 1;
`
`X is H or CN (that is cyano);
`R1, R2, R3 and R4are the same or different and are
`independently selected from H, alkyl, alkenyl, alkynyl,
`cycloalkyl, cycloalkylalkyl, bicycloalkyl, tricycloalkyl,
`alkylcycloalkyl,
`hydroxyalkyl,
`hydroxyalkylcycloalkyl, hydroxycycloalkyl,
`hydroxybicycloalkyl, hydroxytricycloalkyl,
`bicycloalkylalkyl, alkylthioalkyl, arylalkylthioalkyl,
`cycloalkenyl, aryl, aralkyl, heteroaryl, heteroarylalkyl,
`cycloheteroalkyl and cycloheteroalkylalkyl, all option-
`ally substituted through available carbon atoms with 1,
`2, 3, 4 or 5 groups selected from hydrogen, halo, alkyl,
`polyhaloalkyl, alkoxy, haloalkoxy, polyhaloalkoxy,
`alkoxycarbonyl, alkenyl, alkynyl, cycloalkyl,
`cycloalkylalkyl, polycycloalkyl, hctcroarylamino,
`arylamino, cycloheteroalkyl, cycloheteroalkylalkyl,
`hydroxy, hydroxyalkyl, nitro, cyano, amino, substituted
`amino, alkylamino, dialkylamino,
`thiol, alkylthio,
`alkylcarbonyl, acyl, alkoxycarbonyl, aminocarbonyl,
`alkynylaminocarbonyl, alkylaminocarbonyl,
`alkenylaminocarbonyl, alkylcarbonyloxy,
`alkylcarbonylamino, arylcarbonylamino,
`alkylsulfonylamino, alkylaminocarbonylamino,
`alkoxycarbonylamino, alkylsulfonyl, aminosulfonyl,
`alkylsulfinyl, sulfonamido or sulfonyl;
`and R1 and R3 may optionally be taken together to form
`—(CR5R5)m— where m is 2 to 6, and R5 and R5 are the
`same or different and are independently selected from
`hydroxy, alkoxy, cyano, H, alkyl, alkenyl, alkynyl,
`cyclo alkyl, cycloalkylalkyl, cyclo alkenyl, aryl,
`arylalkyl, heteroaryl, heteroarylalkyl, cycloheteroalkyl,
`halo, amino, substituted amino, cycloheteroalkylalkyl,
`alkylcarbonylamino, arylcarbonylamino,
`alkoxycarbonylamino, aryloxycarbonylamino,
`alkoxycarbonyl,
`aryloxycarbonyl,
`or
`alkylaminocarbonylamino, or R1 and R4 may option-
`ally be taken together to form —(CR7R8)P— where p
`is 2 to 6, and R7 and R8 are the same or diiferent and
`are independently selected from hydroxy, alkoxy,
`cyano, H, alkyl, alkenyl, alkynyl, cycloalkyl,
`cycloalkylalkyl, cycloalkenyl, aryl, arylalkyl,
`heteroaryl, heteroarylalkyl, cycloheteroalkyl, halo,
`amino, substituted amino, cycloheteroalkylalkyl,
`alkylcarbonylamino, arylcarbonylamino,
`alkoxycarbonylamino, aryloxycarbonylamino,
`alkoxycarbonyl,
`aryloxycarbonyl,
`or
`alkylaminocarbonylamino, or optionally R1 and R3
`together with
`
`(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:21)(cid:15)(cid:3)(cid:83)(cid:17)(cid:3)(cid:3)(cid:21)(cid:3)(cid:82)(cid:73)(cid:3)(cid:24)(cid:21)
`Sun-Amneal-lPR2016-01104- Ex. 1002, p. 2 of 52
`
`

`
`US 6,395,767 B2
`
`4
`as defined above and hereinafter as well as any of the other
`disease states mentioned above, wherein a therapeutically
`effective amount of a combination of a compound of struc-
`ture I and one,
`two,
`three or more of other types of
`antidiabetic agent(s)
`(which may be employed to treat
`diabetes and related diseases) and/or one, two or three or
`more other types of therapeutic agent(s) is administered to a
`human patient in need of treatment.
`The term “diabetes and related diseases” refers to Type II
`diabetes, Type I diabetes,
`impaired glucose tolerance,
`obesity, hyperglycemia, Syndrome X, dysmetabolic
`syndrome, diabetic complications, dysmetabolic syndrome,
`and hyperinsulineniia.
`The conditions, diseases and maladies collectively
`referred to as “diabetic complications” include retinopathy,
`neuropathy and nephropathy, and other known complica-
`tions of diabetes.
`
`type(s) of therapeutic agents” as
`The term “other
`employed herein refers to one or more antidiabetic agents
`(other than DP4 inhibitors of formula I), one or more
`anti-obesity agents, and/or one or more lipid-modulating
`agents (including anti-atherosclerosis agents), and/or one or
`more infertility agents, one or more agents for treating
`polycystic ovary syndrome, one or more agents for treating
`growth disorders, one or more agents for treating frailty, one
`or more agents for treating arthritis, one or more agents for
`preventing allograft rejection in transplantation, one or more
`agents for treating autoimmune diseases, one or more anti-
`AIDS agents, one or more anti-osteoporosis agents, one or
`more agents for treating immunomodulatory diseases, one or
`more agents for treating chronic inflammatory bowel disease
`or syndrome and/or one or more agents for treating anorexia
`nervosa.
`
`The term “lipid-modulating” agent as employed herein
`refers to agents which lower LDL and/or raise HDL and/or
`lower triglycerides and/or lower total cholesterol and/or
`other known mechanisms for therapeutically treating lipid
`disorders.
`
`In the above methods of the invention, the compound of
`structure I will be employed in a weight ratio to the
`antidiabetic agent or other type therapeutic agent (depending
`upon its mode of operation) within the range from about
`0.01:1 to about 500:1, preferably from about 0.1:1 to about
`100:1, more preferably from about 0.2:1 to about 10:1.
`Preferred are compounds of formula I wherein R3 is H or
`alkyl, R1 is H, alkyl, cycloalkyl, bicycloalkyl, tricycloalkyl,
`alkylcycloalkyl, hydroxyalkyl, hydroxytricycloalkyl,
`hydroxycycloalkyl, hydroxybicycloalkyl, or
`hydroxyalkylcycloalkyl, R2 is H or alkyl, n is 0, X is CN, X
`is0or1andyis0or 1.
`Most preferred are preferred compounds of formula I as
`described above where X is
`
`ICN or ——(;N,
`
`and/or wherein the fused cyclopropyl group is identified as
`
`Thus, preferred compounds of formula I of the invention
`will include the moiety:
`
`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
`
`10
`
`H*N
`
`\(\Pn/
`
`R4
`
`form a 4 to 8 membered cycloheteroalkyl ring wherein
`the eycloheteroalkyl 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
`
`IA
`
`30
`
`R3
`N
`
`“/
`
`R3
`
`N
`
`“/
`
`R2
`
`R1
`
`N
`
`0
`
`X
`
`R4
`
`R
`
`2
`
`R
`
`1
`
`.
`
`N
`
`R4
`
`0
`
`X
`
`113
`
`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
`transplantation, 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,
`ehemotherapy-induced intestinal mucosal atrophy or injury,
`anorexia nervosa, osteoporosis, Syndrome X, dysmetabolic
`syndrome, diabetic complications, hyperinsulinemia,
`obesity, atherosclerosis and related diseases, as well as
`inflammatory bowel disease (such as Crohn’s disease and
`ulcerative colitis), wherein a therapeutically effective
`amount of a compound of structure I (which inhibits DP 4)
`is administered to a human patient in need of treatment.
`The conditions, diseases, and maladies collectively refer-
`enced to as “Syndrome X” or Metabolic Syndrome are
`detailed in Johannsson 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
`
`35
`
`40
`
`45
`
`SO
`
`55
`
`60
`
`65
`
`(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:21)(cid:15)(cid:3)(cid:83)(cid:17)(cid:3)(cid:3)(cid:22)(cid:3)(cid:82)(cid:73)(cid:3)(cid:24)(cid:21)
`Sun-Amneal-lPR2016-01104- Ex. 1002, p. 3 of 52
`
`

`
`US 6,395,767 B2
`
`6
`-continued
`
`F
`
`HZN
`
`HO
`
`H2N
`
`N
`
`.-
`
`N
`
`»
`
`HZN
`
`0
`
`NC
`
`0
`
`CN
`
`N
`
`and
`
`0
`
`NC
`
`HO
`
`HZN
`
`N
`
`0
`
`CN.
`
`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 amino 2. Amino 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-BuCOCOC1/TEA, PyBop/NMM)
`to afford the corre-
`sponding dipeptide 4. Removal of the amine protecting
`group PG2 provides compound 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 of conditions, for
`example with aqueous NaOH in a suitable solvent such as
`methanol, THF, or dioxane, to provide the acid 5. Conver-
`sion of the acid group to the primary carboxamide, affording
`6, may be effected by activation of the acid group (e.g.
`cmploying i-BuOCOC1/TEA or EDAC) followed by treat-
`ment with NH3 or an ammonia equivalent in a solvent such
`as dioxane, ether, or methanol. The amide functionality may
`be converted to the nitrile group by a variety of standard
`conditions (e.g. POC13/pyridine/imidazole or cyanuric
`chloride/DMF or trifluoroacetic anhydride, THF, pyridine)
`to give 7. Finally, removal of the PG2 protecting group
`similar to above provides compound of the invention Ib.
`
`In a different sequence (Scheme 2), compound 1 where X1
`is CO2R9 may be saponifled to the acid and subsequently
`
`10
`
`15
`
`30
`
`35
`
`40
`
`SO
`
`55
`
`60
`
`65
`
`CN
`
`X
`
`CN
`
`Particularly preferred are the following compounds:
`
`A)
`
`
`
`[1S, 2(2S), 3S, SS]
`
`wherein R1 is alkyl, cycloalkyl, bicycloalkyl, tricycloalkyl,
`alkylcycloalkyl, hydroxyalkyl, hydroxycycloalkyl,
`hydroxyalkylcycloalkyl, hydroxybicycloalkyl or hydrox-
`ytricycloalkyl;
`
`B)
`
`
`
`[1R, 2S, 3(2S), 5S]
`
`wherein R1 is alkyl, cycloalkyl, bicycloalkyl, tricycloalkyl,
`hydroxybicycloalkyl, hydroxytricycloalkyl, alkylcycloalkyl,
`hydroxyalkyl, hydroxycycloalkyl or hydroxyalkylcy-
`cloalkyl as well as the following:
`
`,;;§2-
`
`F
`
`NH,
`
`0
`
`HZN
`
`o
`
`0
`
`HO
`
`N
`
`a
`
`:
`
`HZN
`
`NC
`
`HZN
`
`N
`
`0
`
`NC
`
`(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:21)(cid:15)(cid:3)(cid:83)(cid:17)(cid:3)(cid:3)(cid:23)(cid:3)(cid:82)(cid:73)(cid:3)(cid:24)(cid:21)
`Sun-Amneal-lPR2016-01104- Ex. 1002, p. 4 of 52
`
`

`
`US 6,395,767 B2
`
`7
`amidated as described above to give amide 8. Removal of
`the PG1 group followed by peptide coupling to 3 affords
`compound 6, an intermediate in the synthesis of Ib.
`Alternately, the carboxamide group in 8 may be converted
`to the nitrile as described above to give compound 9.
`Deprotection of PGI affords 10 which may be subject to
`standard peptide coupling conditions to afford 7, an inter-
`
`5
`
`8
`mediate in the synthesis of Ib. Compound 10 may also be
`generated by oxidation of the amine 2 (e.g. NCS) followed
`by hydrolysis and subsequent cyanide treatment. Compound
`10 may be obtained as a mixture of stereoisomers or a single
`isomer/diastereomer which may be epimerized (employing
`conventional procedures) to afford a mixture of stereoiso-
`mers.
`
`Scheme 1
`
`<
`HN
`
`2
`
`<
`
`)y
`
`x1
`
`—‘“1»
`
`R2
`
`R3
`0“
`R\N
`[[6
`O
`3
`
`2 b
`
`(
`/N <
`PG1
`
`)3.
`
`x1
`
`1
`
`X1=H,C0zR9
`
`‘
`)5
`
`C
`. —>
`X1=H
`
`(
`
`R1
`R3
`\N
`H
`
`R2
`
`(
`
`)x
`|
`N
`
`‘
`\/( )y
`
`la
`
`R2
`
`1:
`
`)x
`|
`N
`
`R1
`R3
`\N
`
`x1
`
`0
`4
`
`PG;
`
`d
`
`X1: COZR9
`
`R1
`
`RKN
`
`PG2
`
`R2
`
`( L;
`
`N
`
`O
`5
`
`C
`
`(
`
`)3’ T’
`
`COZH
`
`A R1
`
`RKN
`
`PGQ
`
`R2
`
`(
`
`)x
`|
`
`O
`6
`
`.\)y
`
`(TONH2
`
`f
`
`?’
`
`R1 R1
`
`<
`
`R3
`SN
`PG2
`
`)x
`N
`
`(
`W/
`CN
`
`)
`
`Y
`
`4»
`
`R3
`
`R1
`
`R1
`
`<
`
`)x
`iv
`
`0
`
`lb
`
`(
`
`)
`
`CN
`
`Y
`
`0
`7
`a. PG1 = Boo, TFA or HCI; PG1 = Cbz, H1/Pd/C or TMSI; PG1 = FMOC, EtZNH b. EDAC, HOBT, DMF or
`i-R11OCOCl/TVRA or PyRnp, NMNI C. PC; = PG1, (see conditions for 2) d. l.iOl-l or Naol-l MeOl-l or Tl-ll:/H30
`or dioxane e. i—BuOCOCl/NMM or i—BuOCOCl/TEA or EDAC, then NH3 in dioxane or EtZ0 f. POCI5,
`pyridine, irnidazole or cyanmic chloride, DMF or TFAA, THF, pyridine.
`
`(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:21)(cid:15)(cid:3)(cid:83)(cid:17)(cid:3)(cid:3)(cid:24)(cid:3)(cid:82)(cid:73)(cid:3)(cid:24)(cid:21)
`Sun-Amneal-lPR2016-01104- Ex. 1002, p. 5 of 52
`
`

`
`US 6,395,767 B2
`
`10
`
`Scheme 2
`
`C R
`
`
`2
`
`R1
`R3
`\ N
`|
`0
`PG2
`d. peptide coupling
`conditions
`
`OH
`
`3
`
`R2
`
`R1
`
`3
`
`R
`
`on
`
`\N
`I
`3
`
`PG;
`0
`d. peptide coupling
`conditions
`
`a. LiOH or NaOH in MeOH or THF/H20 or diuxane b. i-BUOCOCI/NMM or i-BuOCOCl/TEA or EDAC, then
`NH3 in dioxane or Et1O e. PG1 = Boe, TFA or HCl; PG1 = Cbz, H3/Pd/C or TMSI: PG1 = FMOC, Et2NH d. EDAC,
`HOBT, DMF or i-Bu0COCl/TEA or PyBop, NMM e. POCI3, pyridine, imidazole or eyanurie chloride, DMF.
`
`In a like manner, [3-amino acids such as
`
`R2
`
`R1
`
`OH
`
`R3\
`N
`PG2/
`
`R4
`
`0
`
`may be coupled with 2, the free amine of 8, or 10 to give the
`corresponding amides which may be converted to the
`[5-amino acid derivatives of compound Ia or Ib following the
`same chemistry.
`the term “lower alkyl”,
`Unless otherwise indicated,
`“alkyl” or “alk” as employed herein alone or as part of
`another group includes both straight and branched chain
`hydrocarbons, containing 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-trimethyl-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, Cl or I or CF3, alkyl, alkoxy, aryl,
`aryloxy, aryl(aryl) or diary], arylalkyl, arylalkyloxy, alkenyl,
`cycloalkyl, cycloalkylalkyl, cycloalkylalkyloxy, amino,
`hydroxy, hydroxyalkyl, acyl, heteroaryl, heteroaryloxy,
`heteroarylalkyl, heteroarylalkoxy, aryloxyalkyl, alkylthio,
`arylalkylthio, aryloxyaryl, alkylamido, alkanoylamino,
`arylcarbonylamino, nitro, cyano,
`thiol, haloalkyl,
`triha-
`loalkyl and/or alkylthio.
`
`40
`
`45
`
`SO
`
`55
`
`60
`
`65
`
`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,
`
`A,
`
`,
`
`,
`
`,
`
`any of which groups may be optionally substituted with 1 to
`4 substituents such as halogen, alkyl, alkoxy, hydroxy, aryl,
`
`(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:21)(cid:15)(cid:3)(cid:83)(cid:17)(cid:3)(cid:3)(cid:25)(cid:3)(cid:82)(cid:73)(cid:3)(cid:24)(cid:21)
`Sun-Amneal-lPR2016-01104- Ex. 1002, p. 6 of 52
`
`

`
`US 6,395,767 B2
`
`11
`aryloxy, arylalkyl, cycloalkyl, hydroxyalkyl, alkylamido,
`alkanoylamino, oxo, acyl, arylcarbonylamino, amino, nitro,
`cyano, thiol and/or alkylthio and/or any of the substituents
`for alkyl.
`The term “cycloalkenyl” as employed herein alone or as
`part of another group refers to cyclic hydrocarbons contain-
`ing 3 to 12 carbons, preferably 5 to 10 carbons and 1 or 2
`double bonds. Exemplary cycloalkenyl groups include
`cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl,
`cyclohexadienyl, and cycloheptadienyl, which may be
`optionally substituted as defined for cycloalkyl.
`The term “cycloalkylene” as employed herein refers to a
`“cycloalkyl” group which includes free bonds and thus is a
`linking group such as
`
`12
`The term “halogen” or “halo” as used herein alone or as
`part of another group refers to chlorine, bromine, fluorine,
`and iodine as well as CF3, with chlorine or fluorine being
`preferred.
`The term “metal ion” refers to alkali metal ions such as
`
`sodium, potassium or lithium and alkaline earth metal ions
`such as magnesium and calcium, as well as zinc and
`aluminum.
`
`10
`
`15
`
`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
`
`I?’
`\ '
`
`0 /
`
`|_’
`\ '
`
`(0
`o /
`
`\ ’
`_\
`
`/
`
`/
`
`O
`
`/
`
`o
`
`/
`
`o
`
`/
`
`N \
`\
`_ /
`_ /
`
`N \
`_
`
`/ » ></1 » >
`O:<N l L <N ’
`<\g /><,I2’N£’
`
`O
`
`N
`
`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 of 2 to 20
`carbons, preferably 2 to 12 carbons, and more preferably 1
`to 8 carbons in the normal chain, which include one to six
`double bonds in the normal chain, such as vinyl, 2-propenyl,
`3-butcnyl, 2-butcnyl, 4-pcntcnyl, 3-pcntcnyl, 2-hexcnyl,
`3-hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 3-octenyl,
`3-nonenyl, 4-decenyl, 3-undecenyl, 4-dodecenyl, 4,8,12-
`tetradecatrienyl, and the like, and which may be optionally
`substituted with 1
`to 4 substituents, namely, halogen,
`haloalkyl, alkyl, alkoxy, alkenyl, alkynyl, aryl, arylalkyl,
`cycloalkyl, amino, hydroxy, heteroaryl, cycloheteroalkyl,
`alkanoylamino, alkylamido, arylcarbonyl-amino, 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 of 2 to 20
`carbons, preferably 2 to 12 carbons and more preferably 2 to
`8 carbons in the normal chain, which include one triple bond
`in the normal chain, such as 2-propynyl, 3-butynyl,
`2-butynyl, 4-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl,
`2—heptynyl, 3—heptynyl, 4—heptynyl, 3—octenyl, 3—nonenyl,
`4-decenyl,3-undecenyl, 4-dodecenyl and the like, and which
`may be optionally substituted with 1 to 4 substituents,
`namely, halogen, haloalkyl, alkyl, alkoxy, alkenyl, alkynyl,
`aryl, arylalkyl, cycloalkyl, amino, heteroaryl,
`cycloheteroalkyl, hydroxy, alkanoylamino, alkylamido,
`arylcarbonylamino, nitro, cyano,
`thiol, and/or alkylthio,
`and/or any of the alkyl substituents set out herein.
`The terms “arylalkenyl” and “arylalkynyl” as used alone
`or as part of another group refer to alkenyl and alkynyl
`groups as described above having an aryl substituent.
`Where alkyl groups as defined above have single bonds
`for attachment to other groups at two different carbon atoms,
`they are termed “alkylene” groups and may optionally be
`substituted as defined above for “alkyl”.
`Where alkenyl groups as defined above and alkynyl
`groups as defined above, respectively, have single bonds for
`attachment at two different carbon atoms, they are termed
`“alkenylene groups” and “alkynylene groups”, respectively,
`and may optionally be substituted as defined above for
`“alkenyl” and “alkynyl”.
`
`30
`
`35
`
`40
`
`45
`
`SO
`
`55
`
`60
`
`65
`
`T In
`N/ / i
`0
`0 \ I
`
`i
`
`and may be optionally substituted through available carbon
`atoms with 1, 2, or 3 groups selected from hydrogen, halo,
`haloalkyl, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl,
`trifluoromethyl, trifluoromethoxy, alkynyl, cycloalkylalkyl,
`cycloheteroalkyl, cycloheteroalkylalkyl, aryl, heteroaryl,
`arylalkyl, aryloxy, aryloxyalkyl, arylalkoxy, arylthio,
`arylazo, heteroarylalkyl, heteroarylalkenyl,
`heteroarylheteroaryl, heteroaryloxy, hydroxy, nitro, cyano,
`amino, substituted amino wherein the amino includes 1 or 2
`substituents (which are alkyl, aryl or any of the other aryl
`compounds mentioned in the definitions), thiol, alkylthio,
`arylthio, heteroarylthio, arylthioalkyl, alkoxyarylthio,
`alkylcarbonyl, arylcarbonyl, alkylaminocarbonyl,
`arylaminocarbonyl, alkoxycarbonyl, aminocarbonyl,
`alkylcarbonyloxy, arylcarbonyloxy, alkylcarbonylamino,
`arylcarbonylamino, arylsulfinyl, arylsulfinylalkyl, arylsulfo-
`nylamino 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 an 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 substituents, which
`may be the same or different, such as alkyl, aryl, arylalkyl,
`
`(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:21)(cid:15)(cid:3)(cid:83)(cid:17)(cid:3)(cid:3)(cid:26)(cid:3)(cid:82)(cid:73)(cid:3)(cid:24)(cid:21)
`Sun-Amneal-lPR2016-01104- Ex. 1002, p. 7 of 52
`
`

`
`US 6,395,767 B2
`
`14
`-continued
`
`o/\/o
`K)
`
`and the like. The above groups may include 1 to 4 substitu-
`ents such as alkyl, halo, oxo and/or any of the alkyl
`substituents set out herein. In addition, any of the cyclohet-
`eroalkyl rings can be fused to a cycloalkyl, aryl, heteroaryl
`or cycloheteroalkyl ring.
`Unless otherwise indicated, the term “heteroaryl” as used
`herein alone or as part of another group refers to a 5- or 6-
`membered aromatic ring which includes 1, 2, 3 or 4 hetero
`atoms such as nitrogen, oxygen or sulfur, and such rings
`fused to an aryl, cycloalkyl, heteroaryl or cycloheteroalkyl
`ring (e.g. benzothiophenyl, indolyl), and includes possible
`N-oxides. The heteroaryl group may optionally include 1 to
`4 substituents such as any of the substituents set out above
`for alkyl. Examples of heteroaryl groups include the fol-
`lowing:
`
`O
`
`666:,
`
`V“ ffi
`S), N/
`’
`0 \ '
`fN
`l N:/W
`
`’
`
`/‘/o
`
`—
`N*N
`
`/N,
`
`.\I:N
`
`II\TéN
`
`_
`
`/N ,
`N
`\N/;» \/
`\z
`N/\/S O/N3
`\=/’
`\N/ /’
`
`13
`heteroaryl, heteroarylalkyl, cycloheteroalkyl,
`cycloheteroalkylalkyl, cycloalkyl, cycloalkylalkyl
`haloalkyl, hydroxyalkyl, alkoxyalkyl or thioalkyl. These
`substituents may be further substituted with any of the R1
`groups or substituents for R1 as set out above. In addition,
`the amino substituents may be taken together with the
`nitrogen atom to which they are attached to form
`1-pyrrolidinyl, 1-piperidinyl, 1-azepinyl, 4-morpholinyl,
`4-thiamorpholinyl, 1-pipcrazinyl, 4-alkyl-l-pipcrazinyl,
`4-arylalkyl-1-piperazinyl, 4-diarylalkyl-l-piperazinyl,
`1-pyrrolidinyl, 1-piperidinyl, or 1-azepinyl, optionally sub-
`stituted with alkyl, alkoxy, alkylthio, halo, trifiuoromethyl or
`hydroxy.
`Unless otherwise indicated, the term “lower alkyltliio”,
`“alkylthio”, “arylthio” or “aralkylthio” as employed herein
`alone or as part of another group includes any of the above
`alkyl, aralkyl or aryl groups linked to a sulfur atom.
`Unless otherwise indicated, the term “lower alkylamino”,
`“alkylamino”, “arylamino”, or “arylalkylamino” as
`employed herein alone or as part of another group includes
`any of the above alkyl, aryl or arylalkyl groups linked to a
`nitrogen atom.
`Unless otherwise indicated, the term “acyl” as employed
`herein by itself or part of another group, as defined herein,
`refers to an organic radical linked to a carbonyl
`
`Ci)
`
`group; examples of acyl groups include any of the R1 groups
`attached to a carbonyl, such as alkanoyl, alkenoyl, aroyl,
`aralkanoyl, heteroaroyl, cycloalkanoyl, cycloheteroalkanoyl
`and the like.
`
`Unless otherwise indicated, the term “cycloheteroalkyl”
`as used herein alone or as part of another group refers to a
`5-, 6- or 7-membered saturated or partially unsaturated ring
`which includes 1 to 2 hetero atoms such as nitrogen, oxygen
`a