(12; United States Patent
`Hamann et al.
`
`(10) Patent N0.:
`
`(45) Date of Patent:
`
`US 6,846,836 B2
`Jan. 25, 2005
`
`USU06846836B2
`
`(54) N-SUHS'l”I'l'U'l”EI] PHENYLUREA
`INHIBITORS OF MITOCHONDRIAI. FIF0
`ATP HYDROLASE
`
`(75)
`
`Inventors: Lawrence C. Hamann, (fheny Ilill, NJ
`(US); Andrew '1‘. Pudziannwski,
`Yardley, PA (US)
`
`(73) Assignee: Bristol-Myers Squibb Company,
`Princeton, NJ (US)
`
`( * ) Notice:
`
`Subject to any disclaimer, the term ofthis
`patent is extended or adjusted under 35
`US.(.'. 154(1)) by 0 days.
`
`(21) Appl. No.: 1l]_."419,286
`
`(22)
`
`l-‘iled:
`
`Apr. 18, 2003
`
`(65)
`
`Prior Publication Data
`
`US 200470209821 Al Oct. 21, 2004
`
`Int. CL7
`(51)
`.2) US. Cl.
`(58) Field of Search
`
`A6'lK 317445
`5'l4,r’3'l7
`5147317
`
`(56)
`
`References Cited
`
`U.S. l’Al‘l:'.N'l‘ DUCUMl:LN'l'S
`
`5_.6lO_.l44 A
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`5,637,602 A
`5,712,279 A
`5,739,135 A
`5,760,246 A
`6,043,265 A
`6_.194_.4-37 Bl
`6_.423_.689 B1
`6,548,529 B1
`2003,-WI122890 A1
`
`371997 Capct et 211.
`371997 Murugcsan
`611097 Caper er al.
`171998 Biller et al.
`411998 Biller er al.
`671998 Biller et al.
`372000 Murugesan ct ill.
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`llorwcll et: al.
`772002 Booth ct al.
`412003 Rohl et al.
`172003 Atwal et al.
`
`l-UR].-lI(3N P/\'l‘ljN'l‘ [)(](TUMl_-'N'[‘S
`
`JP
`W0
`W0
`W0
`W0
`W0
`W(J
`W0
`
`2002173476
`WO 92104045
`W0 93101167
`WO 95735314
`W0 99765932
`W0 99767221
`WI) U1],-‘H1389
`WO 01309543
`
`6,-’2U(I2
`3,-"1992
`1,-"1993
`1271995
`1271999
`1271999
`l,-"2[]t'It']
`2,-"2C|(I(|
`
`0'l"l[l_-"R PUBI.[(T/(IIUNS
`
`Moody, et al., European Journal of Pharmacology 409 (200)
`pp. 133-142.
`Ashwood et al., Bioorganic S.’ Medicinal Chemistry Letters
`8 (1998) pp. 2589-2594.
`Eden et al., Bioorganic & Medicinal Chemistry Letters, vol.
`6, No. 21 pp. 2617-2622, no date available.
`Ashwood, V. et al., “PD l76252—The First High Alfinity
`Non—peptide (3astrin—Releasing Peptide (BB2) Receptor
`Antagonist“, Bioorganic & Medicinal Chemistry Letters,
`vol. 8, pp. 2589-2594 (1998).
`
`(1)
`Bundgaard, II., “((7) Means to Enhance Penetration:
`Prodrugs as a means to improve the delivery of peptide
`drugs”, Advanced Drug Delivery Reviews, vol. 8, pp. 1-38
`(1992).
`
`Cross, R.l.. et al., “The Mode of Inhibition of Oxidative
`Phosphorylation by Efrapeptin (A23871): Evidence for an
`Alternating Site Mechanism for ATP Synthesis”, The Jour-
`nal of Biological Chemistry, vol. 253, No. 4, pp. 4865-4873
`(1978).
`
`.l.M. et al., “PD l65929—'l‘he liirst Iligh Allinity
`Liden,
`Non—peptide Neuromedin—B (NMB) Receptor Selective
`Antagonist”, Bioorganic & Medicinal Chemistry Letters,
`vol. 6, No. 21, pp. 2617-2622 (1996).
`
`(iasnier, 15. et al., “Use ol‘ Percoll Gradients for isolation of
`Human Placenta Mitochondria Suitable for Investigating
`Outer Membrane Proteins”, Analytical Biochemistry, vol.
`212, pp. 173-178 (1993).
`
`Kakeya, N. et al., “Studies on Prodrugs of (.'ephalosporins.
`1. Synthesis and Biological Properties of Glycyloxybenzoy-
`loxymethyl and Glycylaminobenzoyloxymethy Esters of 7
`B—[2—(2-/\minothiazol—4-yl)—(Z)—2—methoxyiminoacet
`amido]—3—methyl—3—cephem—4-carboxylic Acid”, Chem.
`Pharm. Bull., vol. 32, No. 2, pp. 692-698 (1984).
`
`Matsuno-Yagi, A. et al., “Studies on the mechanism of
`oxidative phosphorylation: ElIecLs of specilic l-‘O modifiers
`on ligand-induced conformation changes of E,", Proc. Natl.
`Acarl. Sci. USA, vol. 82, pp. 7550-7554 (1985).
`
`Maughfling, E..l.R. et al., “Construction of chimeric human
`bombesin receptors to identify neuromedin B and gasrrin-
`releasing peptide receptor binding sites", Biochemical Soci-
`ety Transactions, vol. 25, p. 455S (1997).
`
`(List continued on next page.)
`
`1’rr'.ura'ry Exm.In'ner—Raymond J. llenley, III
`(74) Attorney, /tgem‘, or F.irm—Laurelee A. Duncan
`
`(57)
`
`ABSTRACT
`
`Compounds having the formula (I),
`
`,
`R"
`
`1
`
`R
`
`R,
`
`x
`J'l\
`
`N
`I
`R“
`
`N
`I
`R7
`
`A
`
`3*
`R“
`
`0
`
`N
`
`(I)
`
`R4
`
`R5
`
`t
`
`1|’.
`
`DLII
`
`-'
`
`2
`
`1"-[F0 ATP
`are useful as inhibitors of mitochondrial
`hydrolase, wherein R‘-R”, X, A, Z, n and m are defined
`h
`'
`.
`cl-cm
`
`I of 15
`
`21 Claims, No Drawings
`
`PENN EX. 2230
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`
`

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`US 6,846,836 B2
`Page 2
`
`OTHER PUBLICATIONS
`
`'l‘.W. et al., “Nonpeplicle neuromedin ll receptor
`Moody,
`antagonists inhibit the proliferation of C6 cells”, European
`Journal of Pharmacology, vol. 409, pp. 133-142 (2000).
`Nielsen, NM. et al., “Glycolamide Esters as Biolabile
`Prodrugs of Carhoxylic Acid Agents: Synthesis, Stability,
`Bioconversion, and Physicochemical Properties”, Journal of
`Pharmaceutical Sciences, vol. 77, No. 4, pp. 285-298
`(1988).
`
`Pullman, ME. et al., "Partial Resolution of the Enzymes
`
`Catalyzing Oxidative Phosphorylation”, The Journal of Bio-
`logical Chemistry, vol. 235, No. 11, pp. 3322-3329 (19(j[|).
`
`Salomon, A,R. et al., "Understanding and exploiting the
`
`mechanistic basis for selectivity of polykelide inhibitors o I‘
`
`F[,F,—ATPase", PNAS, vol. 97, No. 26, pp. 14766-14771
`
`(2000).
`
`2ofl5
`
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`US 6,846,836 B2
`
`1
`N-SUBSTITUTED PHENYLUREA
`INHIBITORS OF MITOCHONDRLAL F IF"
`ATP HYDROLASE
`
`IiIl_".I_l) OF 'l'IIl_-l INVt_-'NT[()N
`
`This invention relates to N-substituted phenylurea com-
`pounds that inhibit mitochondrial F,F,, ATP hydrolase, and
`are therefore potentially useful for the treatment of a variety
`ofischemia—related diseases and disorders, including periph-
`eral occlLLsive arterial disease,
`intermittent claudication,
`chronic stable angina pectoris, stroke, myocardial infarction
`BACKGROUND OF THE INVENTION
`
`Ischemic heart disease is a common and serious health
`problem. Every year,
`large numbers of patients die from
`ischemic heart disease and its complications. Many others
`experience acute myocardial infarcation, congestive heart
`failure, cardiac arrhythmias, or other disorders.
`Myocardial ischemia exists when the heart tissue experi-
`ences a demand for oxygen and substrates that exceed the
`supply. Imbalanees between oxygen supply and demand
`span a large range, and thus, there are various syndromes
`and biochemical pathways involved in the pathogenesis of
`ischemia, e.g., from low-grade to severe ischemic condi-
`tions.
`Iior example, chronic stable angina pectoris is a
`low-grade condition, in which the resting coronary blood
`llood may be normal but the blood llow reserve is insulli—
`cient to meet an increased energy demand. In more extreme
`situations, the ischemic muscle can develop an impaired
`contractile function and potential to generate arrhythmias.
`Major consequences of myocardial
`ischemia include
`mechanical and elec1rical dysfunction, muscle cell damage,
`and development of necrosis. Acute ischemic events may
`develop where there is coronary atherosclerosis. Ultimately,
`if the ischemia is sufficiently severe there will be an imme-
`diate reduction (or cessation] of contractile function in the
`heart.
`
`The impairment of contractile function in ischemic
`rnuscle is associated with mitochondrial levels of adenosine
`
`triphosphate (ATP) and adenosine triphosphatases
`(ATPases). ATPases are enzymes that typically catalyze the
`hydrolysis of ATP,
`the main energy currency in cells,
`to
`adenosine monophosphate (AMP) or adenosine diphosphate
`(ADP), plus phosphate ions and energy. The contractile
`function ofthe heart is regulated by the transport of calcium,
`sodium, and potassium ions, which in turn is modulated by
`ATP and ATPases. More particularly, intracellular ATP is
`split by Na+, K+ ATPase, an enzyme that is responsible for
`maintaining a gradient of sodium and potassium ions across
`the cell membrane. The splitting of ATP by Na+, K+ ATPase
`releases the energy needed to transport K+ and Na+ ions
`against concentration gradients. This enables the existence
`of a resting potential in the membrane (i.e, Na+ out, K+ in)
`which initiates the contractile response. Contraction is trig-
`gered by Na,=‘Ca exchange and Ca2+ transport, the energy for
`which is generated by the hydrolysis of ATP by Ca2+
`ATPase.
`
`To maintain homeostasis, the cells’ supply of ATP must be
`replenished as
`it
`is consumed (e.g., with muscle
`contraction). During the steady state, the rate of ATP syn-
`thesis needs to be closely matched to its rate ofoonsumption.
`Arguably, the most important ATPase is the mitochondrial
`F117;,-ATPase. Unlike other ATPases which function typi-
`cally to hydrolyze ATP and release energy, the F,F[,-ATPase
`has both hydrolytic and synthetic states. As “ATP synthase”,
`
`10
`
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`
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`the mitochondrial [5,]-in-A'l‘Pase catalyzes the production of
`ATP via oxidative phosphorylation of ADP and P,-. Thus,
`li1I"0-A'I'Pase is responsible for producing the cell's main
`energy source, ATP. In normoxic conditions, mitochondrial
`li,I"0-A'I'Pase modulates this ATP production via its two
`units, the F, and F0 complexes. F0 is the inner membrane
`domain, and Ii,
`is a catalytic domain consisting of five
`subunits (oLBxfie—the catalytic site is on the F1 unit), that
`protrude from the F0 domain into the mitochondrial matrix.
`When sufiicient levels of oxygen are present, electrons from
`ATPase substrates are transferred to oxygen, and protons are
`transported out of the mithcondrial matrix. This proton!
`electron transport creates an electrochemical proton gradient
`across the mitochondrial membrane and through the ['0
`domain which drives the 171 domain to synthesize ATP.
`
`this electrochemical
`In ischemic conditions, however,
`gradient collapses, and F,F0—ATPase switches to its hydro-
`lytic state. This hydrolysis of ATP seems to serve no useful
`purpose. Also, as F,F0-ATPase operates in its hydrolytic
`state there is a down—regulation of F ,F0—PCl"P synthase.
`F,F0—ATP synthase activities in vesicles from ischemic
`muscle typically are substantially (up to -50-80%) less than
`those ofcontrol muscle. A native peptide called IF, inhibitor
`protein (or IF.) may be bound to the F, unit under ischemic
`conditions to inhibit
`the ATP hydrolase activity of the
`enzyme; however, IF, is highly pII dependent and in severe
`conditions can provide only a modicum of control. The
`conversion of F,F0—ATP synthase to F,F0—ATP hydrolase is
`reversible, as addition of substrate and oxygen to the mito-
`chondria of ischemic muscle can reactivate the F lF0—ATPase
`and ATP levels to control levels.
`
`As may be appreciated, in ischemic conditions the activity
`of I",li[;,-/\'l'Pa.se produces a futile cycling and waste ofATP.
`It is believed that this depletion of ATP and;’or ATP synthase
`may suppress the Na+K+ pump to increase cardiac
`eontraetility, vasoeonstrietion, sensitivity to vasoactivc
`agents, and arterial blood pressure. Several inhibitors of
`F,F,,—ATPase have been described,
`including efrapeptin,
`oligomycin, autovertin B, and azide. Oligomycin targets F0
`and reportedly postpones cell
`injury by preserving ATP
`during ischemia. However,
`the only known inhibitors of
`li,I"0-A'I'Pase are large proteins or peptides which are not
`orally bioavailable.
`
`Accordingly, there is an ongoing need for useful inhibitors
`of F,F0—ATPase inhibitors, especially those that are orally
`bioavailable.
`
`SUMMARY OF THE INVENTION
`
`In accordance with the present invention, a method of
`treating a mitochondrial FIFO ATP hydrolase associated
`disorder in a mammal is described comprising administering
`to the patient in need of such treatment an effective amount
`of at least one compound having the formula (I):
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`US 6,846,836 B2
`
`(U
`
`3
`
`R
`
`1
`
`R
`
`R3
`
`x
`A
`i '
`8R
`1|?
`R7
`
`R“
`
`0
`
`N
`
`R"
`
`R5
`
`(
`
`)1.
`
`)Ill
`
`their enantiomers, diastereomers, and pharmaceutically
`acceptable salts, prodru gs and solvares thereof, wherein:
`X is selected from O or S;
`
`A is selected from hydrogen, alkyl, substituted alkyl,
`cycloalkyl, heterocycle, aryl, and heteroaryl;
`n and m are U, 1, or 2
`
`R1 through R5 are independently selected from hydrogen,
`halogen, N03, CN, Cmalkyl, substituted C1_,3alkyl,
`L.‘3_,3cycloalky1, aryl, heterocyclo, heteroaryl, UR9,
`SR9, coir“, (.‘cJ,R“, (T()NR°R‘° or NR°R‘°,
`R“ and R7 are independently hydrogen, alkyl or substi-
`tuted alkyl;
`(.',_,,alkyl, substituted C,_Ralkyl, aryl,
`R“ is hydrogen;
`heterocyclo or heteroaryl,
`Z is hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl,
`heterocyclo, heteroaryl, COR“, COZR“, SO2R“, S(O)
`R” or (T()NR9Rm;
`R9 and Rm are independently hydrogen, C,_Ralkyl, sub-
`stituted C1_,,alkyl, C3_mcycloalkyl, aryl, heterocyclo,
`heteroaryl, COR”, SOZRIE or S(U)R'3; and
`R“, R13 and R13 are independently hydrogen, C,_,,alkyl,
`substituted C1_3alkyl, Cmocycloalkyl, aryl, heterocy-
`clo or heteroaryl;
`wherein each occurrence of R9—R” is chosen indepen-
`dently.
`
`DI.-"l'AIl_l_-"D DI.-'S(TRIP'[‘[(}N
`
`The instant invention provides N-substituted phenylurea
`compounds that are potent and selective inhibitors of FIFO-
`ATP hydrolase. The compounds of the present invention are
`useful in treating or preventing conditions associated with
`ischemia, particularly myocardial ischemia and associated
`conditions, such as muscle cell damage, necrosis, and car-
`diac arrhythmias. Also, in view of their inhibitory activity,
`the inventive compounds may be used to treat cancer and
`tumor growth.
`listed below are definitions of various terms used to
`
`describe this invention. These definitions apply to the terms
`as they are used throughout this specification, unless other-
`wise limited in specific instances, either individually or as
`part of a larger group.
`The term “alkyl” refers to straight or branched chain
`unsubstituted hydrocarbon groups of 1 to 20 carbon atoms,
`preferably '1
`to 8 carbon atoms. The expression "lower
`alkyl" refers to unsubstituted alkyl groups of l to 4 carbon
`atoms.
`
`'I'he term “substituted alkyl" refers to an alkyl group as
`defined above having one, two, three, or four substituents
`selected from the group consisting of halogen,
`trifluoromethyl, alkenyl, alkynyl, nitro, cyano, keto (=0),
`OR”, SR“: NR,,R_:,, NR,,S02, NR,,SO2R,_., S02Rr_.,
`
`4
`s(),NR,,R,,, (:o,R,,, c(=o)R,,, (?(=())NR,,R,,, ()(?(=())
`Ra’ —0C(=0)NR..Rz,= NR“?-(=0)Rg.. NRJ“-02Ri.,
`=N—()II, =N—()-alkyl, aryl, heteroaryl, heterocyclo and
`cycloalkyl, wherein R” and Rh are selected from hydrogen,
`alkyl, alkenyl, cycloalkyl, heterocyclo, aryl, and heteroaryl,
`and RC is selected from hydrogen, alkyl. cycloalkyl, hetero-
`cyclo aryl and heteroaryl, When a substituted alkyl includes
`an aryl, heterocyclo, heteroaryl, or cycloalkyl substituent,
`said ringed systems are as defined below and thus may in
`turn have zero to four substituents (preferably 0-2
`substituents), also as defined below. When either R”, R,, or
`RC is an alkyl or alkenyl, said alkyl or alkenyl may option-
`ally be substituted with l—2 of halogen,
`trifluoromethyl,
`nitro, cyano, keto (=0), OH, O[alkyl], phenyloxy,
`benzyloxy, Sll, S(alkyl), NII2, Nllfalkyl], N(alkyl]2,
`NHSO2, NHSO:(alkyl), S02[alkyl), S02NH2’ S02NH
`(alkyl), COZH, CO3(alkyl), C(=0)H, C(=O)alkyl, C(=O)
`NH3, C(=O)NH(alkyl), C(=0)N(alkyl)3, OC(—O)alkyl,
`—o(:(=o)NI1,, —()r:(=r))N11(a1ky1), NII(I(=(J)alkyl,
`andfor NI I(T()2(alkyl).
`“Alkyl” when used in conjunction with another group
`such as in arylalkyl refers to a substituted alkyl in which at
`least one of the substituents is the specifically—named group.
`For example, the term arylalkyl includes benzyl, or any
`other straight or branched chain alkyl having at least one aryl
`group attached at any point of the alkyl chain.
`The term “alkenyl” refers to straight or branched chain
`hydrocarbon groups of 2 to 20 carbon atoms, preferably 2 to
`15 carbon atoms, and most preferably 2 to 8 carbon atoms,
`having one to four double bonds.
`The term “substituted alkenyl” refers to an alkenyl group
`substituted by, for example, one to two substituents, such as,
`halo, hydroxy, alkoxy, alkanoyl, alkanoyloxy, amino,
`alkylamino, dialkylamino, alkanoylamino, thiol, alkylthio,
`alkylthiono, alkylsulfonyl, sulfonamido, nitro, cyano,
`carboxy, carbamyl, substituted carbamyl, guanidino and
`heterocyclo, e.g.
`indolyl,
`imidazolyl,
`furyl,
`thienyl,
`thiazolyl, pyrrolidyl, pyridyl, pyrimidyl and the like.
`The term “alkynyl” refers to straight or branched chain
`hydrocarbon groups of 2 to 20 carbon atoms, preferably 2 to
`15 carbon atoms, and most preferably 2 to 8 carbon atoms,
`having one to four triple bonds.
`The term “substituted alkynyl” refers to an alkynyl group
`substituted by, for example, a substituent, such as, halo,
`hydroxy, alkoxy, alkanoyl, alkanoyloxy, amino, alkylamino,
`dialkylamino, alkanoylamino, thiol, alkylthio, alkylthiono,
`allrylsullonyl, sulfonamido, nitro, cyano. carboxy, carbamyl,
`substituted carbamyl, guanidino and heterocyclo, e.g.
`imidamlyl,
`fury],
`thienyl,
`thiazolyl, pyrrolidyl, pyridyl,
`pyrimidyl and the like.
`When reference is made to a substituted alkylene,
`alkenylene, or alkynylene group,
`these groups are substi-
`tuted with one to four substitutents as defined above for alkyl
`groups. A substituted alkylene, alkenylene, or alkynylene
`may have a ringed substituent attached in a spiro fashion.
`The term “alkoxy” refers to an alkyl, alkenyl, or substi-
`tuted alkyl or alkenyl group bonded through an oxygen atom
`(—0—). For example,
`the term "alkoxy" includes the
`groups —O—C,_,2all<yl, —O—C:_,,all\'enyl, and so forth.
`The term “alkylthio” refers to an alkyl or alkenyl or
`substituted alkyl or alkenyl group bonded through a sulfur
`(%—) atom. For example, the term “alkylthio” includes
`the groups —S—(CH,._)CH3, —S—CH,._aryl. etc.
`The len'n “alkylamino” refers to an alkyl or alkenyl or
`substituted alkyl or alkenyl group bonded through a nitrogen
`(—NR'—) group. For example,
`the term “aminoalkyl”
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`5
`includes the groups —NR'—C,_2alkyl and —NR"—(fII2-
`aryl, etc. (where R‘ is hydrogen, alkyl or substituted alkyl as
`defined above.) "Amino” refers to the group —NII2.
`When a subscript is used, as in Cusalkyl, the subscript
`refers to the number of carbon atoms the group may contain.
`Zero when used in a subscript denotes a bond, e.g., (f0__,alkyl
`refers to a bond or an alkyl of l to 4 carbon atoms. When
`used with alkoxy, thioalkyl, or alkylamino (or aminoalkyl),
`a subscript refers to the number of carbon atoms that
`the
`group may contain in addition to heteroatoms. Thus, for
`example, monovalent Cmatkylamino includes the groups
`—NIl—CII3, —NII—CII2—CII3, and —N—(ClI3]2. A
`lower aminoalkyl comprises an aminoalkyl having one to
`four carbon atoms.
`
`thioalkyl, or aminoalkyl groups may be
`The alkoxy,
`monovalent or bivalent. By "monovalent” it is meant that the
`group has a valency (i.e., power to corrrbinc with another
`group), of one, and by "bivalent” it is meant that the group
`has a valency of two.
`l-‘or example, a monovalent alkoxy
`includes groups such as —O—C,_,2alkyl, whereas a biva-
`lent alkoxy includes groups such as —O—C,_,2alkylene—,
`etc.
`
`The term "acyl" refers to a carbonyl
`
`"
`||
`(‘C’)
`
`linked to an organic group i.e.,
`
`0
`
`—(7—R,,_.
`
`wherein Rd may be selected from alkyl, alkenyl, substituted
`alkyl, substituted alkenyl, aryl, heterocyclo, cyeloalkyl, or
`heteroaryl, as defined herein.
`The term “alkoxycarbonyl” refers to a group having
`
`O
`
`jcjoj
`
`linked to an organic radical, Rd, i.e.,
`
`O
`
`—C—o—R.._.
`
`wherein R, is as defined above for aeyl.
`The term "halo" or "halogen” refers to chloro, bromo,
`lluoro and iodo.
`
`The term "haloalkyl" means a substituted alkyl having
`one or more halo substituents. For example, “haloalkyl”
`includes mono, bi, and triftuoromethyl.
`The term “haloalkoxy” means an alkoxy group having
`one or more halo substituents.
`l-‘or example, “haloalkoxy”
`includes OCF3.
`The term “sulfonyl” refers to a sulphoxide group (i.e.,
`—S(O),_2) linked to an organic radical RC, as defined above.
`The term “sulfonamidyl” or "sulfonarnido” refers to the
`group —S(0)2NReRJ,, wherein R, and R, are as defined
`above. Preferably when one of RE and Rf is optionally
`substituted heteroaryl or heterocycle (as defined below), the
`other of R__, and Rfis hydrogen, alkyl, or substituted alkenyl.
`The term “cycloalkyl” refers to fully saturated and par-
`tially unsaturated hydrocarbon rings of 3 to 9, preferably 3
`
`6
`to 7 carbon atoms. The term “cycloalkyl" includes such
`rings having zero to four substituents (preferably 0-2
`substituents), selected from the group consisting of halogen,
`alkyl, substituted alkyl (e.g., trilluoroniethyl), alkenyl, sub-
`stituted alkenyl, alkynyl, nitro, cyano, keto, OR,,, SR“,
`NR,,R,.NR,.SO2, NRCSO;._R,., C(=O)H, acyl,
`COQH’
`alkoxyearbonyl, carbamyl, sulfonyl, sulfonamidc, —0C
`(=O)R,,, =N OH, =N—0—alkyl, aryl, hetcroaryl,
`heterocyclo, a 4 to 7 membered carbocyclic ring, and a five
`or six membered ketal, e,g., 1,3—dioxolane or 1,3—dioxane,
`wherein Re, R”, and R‘, are delined as above. The term
`“cycloalkyl” also includes such rings having a phenyl ring
`fused thereto or having a carbon-carbon bridge of 3 to 4
`carbon atoms. Additionally, when a cycloalkyl is substituted
`with a
`further
`ring,
`i.e., aryl, arylalkyl, heteroaryl,
`heteroarylalkyl, heterocyclo, heterocycloalkyl,
`cycloalkylalkyl, or a further cycloalkyl ring, such ring in
`turn may be substituted with one to two of C0__,alkyl
`optionally substituted with halogen,
`trilluoromethyl,
`alkenyl, alkynyl, nitro, cyano, keto (=0), OII, (](alkyl),
`phenyloxy, benzyloxy, SH, S(alkyl), NH3, NH(alkyl),
`N(a]kyl):, NHS02,
`l\I]lSO:(alkyl), S():(alkyl), S()2N[I:,
`S()3Nl](a]ky]), (Z0311, (T()2(alkyl), (I(=())II, (T(—O)alkyl,
`C(=O)NH3, C(=0)NH(alkyl), C(=O)N(alkyl)3,
`OC(=O)alkyl, —OC(=O)NH3,
`OC(=O)NH(alkyl),
`NlIC(=())alkyl, and NllCO;._(al.kyl).
`The term “aryl” refers to phenyl, biphenyl, 1—naphthyl,
`2-naphthyl, and anthracenyl, with phenyl being preferred.
`The term “aryl” includes such rings having zero to four
`substituents (preferably 0-2 substituents), selected from the
`group consisting of halo, alkyl, substituted alkyl (e.g.,
`trifluoromethyl), alkenyl, substituted alkenyl, alkynyl, nitro,
`cyano, OR,,., SR,,., NR,,.R,,, NR,,S03, NRGSOZRC, C(=0)H,
`acyl, —C()2lI, alkoxycarbonyl, carbamyl, sulfonyl,
`sulfonamide, —0C(=O)R,,, heteroaryl, heterocyclo,
`cycloalkyl, phenyl, benzyl, napthyl, including phenylethyl,
`phenyloxy, and phenylthio, wherein Rt, Rd and R‘. are
`defined as above. Additionally, two substituents attached to
`an aryl, particularly a phenyl group, may join to form a
`further ring such as a fused or spiro-ring, e.g., cyclopentyl or
`cyclohexyl or fused heteroeycle or heteroaryl. When an aryl
`is substituted with a further ring, such ring in turn may be
`substituted with one to two of CD_,,alkyl optionally substi-
`tuted with halogen, trifluoromethyl, alkenyl, alkynyl, nitro,
`cyano, keto (=0), OH, O(a1kyl), phenyloxy, benzyloxy,
`SH, S(al.kyl), NH3, NH(al.kyl), N(alkyl)3, NHS03, NHSO2
`(alkyl), S()2(aIkyl), SOZNII2, S()2NII(alkyl), (T0211, (T0:
`(alkyl), C(=0)Il, C(=0)alkyl, C(=0)NII2, C(=O)NIl
`(alkyl), C(=O)N(alkyl):, OC(=O)alkyl, —OC(=O)NH:,
`—0C(—O)NH(alkyl), NHC(=O)alkyl, and NHC02
`(alkyl).
`The term “heterocyclo” refers to substituted and unsub-
`stituted non-aromatic 3 to 7 membered monocyclic groups,
`7 to 11 membered bicyclic groups, and 10 to 15 membered
`tricyclic groups, in which at least one of the rings has at least
`one heteroatom ((), S or N). Each ring of the heterocyclo
`group containing a heteroatom can contain one or
`two
`oxygen or sulfur atoms andfor from one to four nitrogen
`atoms provided that the total number of heteroatoms in each
`ring is four or
`less, and further provided that
`the ring
`contains at least one carbon atom. The fused rings complet-
`ing bicyclic and tricyclic groups may contain only carbon
`atoms and may be saturated, partially saturated, or unsatur-
`ated. The nitrogen and sulfur atoms may optionally be
`oxidized and the nitrogen atoms may optionally be quater-
`nized. The heterocyclo group may be attached at any avail-
`able nitrogen or carbon atom. The heterocyclo ring may
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`contain zero to four substituents (preferably 0-2
`substituents), selected from the group consisting of halo,
`alkyl, substituted alkyl (e.g., trifluoromethyl}, alkenyl, sub-
`stituted alkenyl, alkynyl, nitro, cyano, keto, OR,” SR4,
`NR,,R,., NR,,S03, NR,,SO3Rc, SO3R,_,, C(—O)H, acyl,
`—C03H, alkoxycarbonyl, carbamyl, sulfonyl, sulfonamide,
`OC(—0)R,,., —N OH, —N 0—alkyl, aryl, heteroaryl,
`cycloalkyl, a five or six membered ketal, e.g., 1,3—dioxolane
`or 1,3-dioxane, or a monocyclic 4 to 7 membered non-
`aromatic ring having one to four hetcroatoms, wherein R,__,
`R,, and R_, are defined as above. The term “heterocyclo" also
`includes such rings having a phenyl ring fused thereto or
`having a carbon-carbon bridge of 3 to 4 carbon atoms.
`Additionally, when a heterocyclo is substituted with a fur-
`ther ring, i.e., aryl, arylalkyl, heteroaryl, heteroarylalkyl,
`cycloalkyl, cycloalkylalkyl, heterocycloalkyl, or a further
`heterocyclo ring, such ring in tu rn may be substituted with
`one to two of C0__,alkyl optionally substituted with halogen,
`trifluoromethyl, alkenyl, alkynyl, nitro, cyano, keto (=0),
`()lI, ()(alkyl), phenyloxy, benzyloxy, SII, S(alkyl), NII2,
`NH(alkyl), N(alkyl):, NHSOS, NHS03(alkyl), SO2(alkyl),
`S():l\lll2, S[)2NII(alkyl),
`(T0211,
`(I()2(alkyl), (3(=())Il,
`(I[=())alkyl, (I(=()]NII:,
`(T(=())Nll(alkyl),
`(T(=())N
`[alkyl);._, OC(=O)alkyl, —OC(=O)NH3, —OC(=O)NH
`[alkyl), NHC(=O)alkyl, and NHCO:(al.kyl).
`Exemplary monocyclie groups include azetidinyl,
`pyrrolidinyl, oxetanyl,
`imidazolinyl, oxazolidinyl,
`isoxazolinyl,
`thiaxolidinyl,
`isothiazolidinyl,
`tetrahydrofuranyl, piperidinyl, piperazinyl,
`2—oxopiperazinyl, 2—oxopiperidinyl, 2—oxopyrrolodinyl,
`2-oxoazepinyl, azepinyl, 4-piperidonyl, tetrahydropyranyl,
`morpholinyl,
`thiamorpholinyl,
`thiamorpholinyl sulfoxide,
`thiamorpholinyl sulfone, 1,3—dioxolane and tetrahydro—1,1—
`dioxothienyl and the like. Exemplary bicyclic heterocyclo
`groups include quinuclidinyl.
`the term "heteroaryl" refers to substituted and unsubsti-
`tuted aromatic 5 to 7 membered monocyclic groups, 9 or 10
`membered bicyclic groups, and 1 l to 14 membered tricyclic
`groups which have at least one heteroatom (O, S or N) in at
`least one of the rings. Each ring of the heteroaryl group
`containing a heteroatom can contain one or two oxygen or
`sulfur atoms andfor from one to four nitrogen atoms pro-
`vided that the total number of heteroatoms in each ring is
`four or less and each ring has at least one carbon atom. The
`fused rings completing the bicyclic and tricyelie groups may
`contain only carbon atoms and may be saturated, partially
`saturated, or unsaturated. The nitrogen and sulfur atoms may
`optionally be oxidized and the nitrogen atoms may option-
`ally be qu aternized. Heteroaryl groups which are bicyclic or
`tricyclic must include at least one fully aromatic ring but the
`other fused ring or rings may be aromatic or non-aromatic.
`The heteroaryl group may be attached at any available
`nitrogen or carbon atom of any ring. The heteroaryl ring
`system may contain zero to four substituents (preferably 0-2
`substituents), selected from the group consisting of halo,
`alkyl, substituted alkyl (e.g., trifluoromethyl}, alkenyl, sub-
`stituted alkenyl, alkynyl, nitro, cyano, UR,” SR,,, NR,,R,_,,
`NR,,SO;._, NR,,SO3R,., S03R,,, C(=O)H, acyl, —CD3H,
`alkoxycarbonyl, carbamyl, sulfonyl, sulfonamide, —()(f
`[=O)R,,, heterocyclo, cycloalkyl, aryl, or a monocyclic 4 to
`7 membered aromatic ring having one to four heteroatoms,
`including phenylethyl, phenyloxy, and phenylthio, wherein
`Re, R,, and R‘, are defined as above. Additionally, when a
`heteroaryl
`is substituted with a
`further
`ring,
`i.e., aryl,
`arylalkyl, heterocyclo, heterocycloalkyl, cycloalkyl,
`cycloalkylalkyl, heteroarylalkyl, or a further heteroaryl ring,
`such ring in turn may be substituted with one to two of
`
`8
`(f0_,,alkyl optionally substituted with halogen,
`trifluoromethyl, alkenyl, alkynyl, nitro, cyano, keto (=0),
`()II, ()(alkyl), phenyloxy, benzyloxy, SII, S(alkyl), NII._.,
`NlI(al.kyl). Nfalkyl)-_,. l\lIISO._,, NIISO2[alkyl),n SO._._(alkyl),
`SO3NH3, SO3NH[alkyl), COZH, CO3(alkyl), C(=O)H,
`C(=O)alkyl, C(=O)NH;._, C[—O)NH(alkyl), C(=O)N
`{al.kyl)2, OC(=O)alkyl, —OC(=())NH2, —OC(=O)NI-I
`(alkyl), NHC(=0)alkyl, and NHCO;._[alkyl).
`Exemplary rnonocyclic heteroaryl groups include
`pyrrolyl, pyrazolyl, pyrazolinyl,
`imidazolyl, oxazolyl,
`isoxazolyl, thiamlyl [i.e.,
`
`s
`
`(I-e-. K E J,
`
`N
`
`10
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`"I5
`
`thienyl, oxadiazolyl,
`furanyl,
`isothiazolyl,
`thiadiazolyl,
`pyridyl, pyrazinyl, pyrimidinyl, pyridaxinyl, triazinyl and
`the like.
`
`ll]
`
`Exemplary bicyclic heteroaryl groups include indolyl,
`benmthiamlyl, benzodioxolyl, benzoxaxolyl, benmthienyl,
`quinolinyl,
`tetrahydroisoquinolinyl,
`isoquinolinyl,
`benzimidazolyl, benzopyranyl,
`indolizinyl, benzofuranyl,
`chromonyl, coumarinyl, benzopyranyl, cinnolinyl,
`quinoxalinyl,
`indazolyl, pyrrolopyridyl,
`furopyridinyl,
`dihydroisoindolyl, tetrahydroquinolinyl and the like.
`Exemplary tricyclic heteroaryl groups include carbazolyl,
`benzindolyl, phenanthrollinyl, acridinyl, phenanthridinyl,
`xanthenyl and the like.
`When the term “unsaturated” is used herein to refer to a
`
`ring or group, the ring or group may be fully unsaturated or
`partially unsaturated.
`Throughout
`the specillcation, groups and substituents
`thereofmay be chosen by one skilled in the field to provide
`stable moieties and compounds. The phrase "optionally
`substituted” is intended to include substituted or unsubsti-
`
`tuted possibilities. Accordingly, the phrase “each group of
`which may be optionally substituted means that each group
`includes both substituted and unsubstituted groups.
`The use of the phrase “where valence allows" means that
`the groups may be substituted only to the degree and nature
`allowed by valency of the group. This is commonly under-
`stood by those of skill in the art. For example, a hydrogen
`substituent cannot be further substituted nor can a phenyl
`group be directly substituted by an oxo group due to limits
`on valency.
`The compounds of formula I form salts which are also
`within the scope of this invention. Reference to a compound
`of the formula I herein is understood to include reference to
`
`salts thereof, unless otherwise indicated. The term "salt(s]”,
`as employed herein, denotes acidic andfor basic salts formed
`with inorganic andfor organic acids and bases. In addition,
`when a compound of formula I contains both a basic moiety,
`such as, but not
`limited to an amine or
`a pyridine or
`imidazole ring, and an acidic moiety, such as, but not limited
`to a carboxylic acid, zwitterions ("inner salts") may be
`formed and are included within the term “salt(s)” as used
`herein. Phannaceutically acceptable (i.e., non-toxic, physi-
`ologically acceptable) salts are preferred, although other
`salts are also useful, e.g., in isolation or purification steps
`which may be employed during preparation. Salts of the
`compoundsofthe formula I may be formed, for example, by
`reacting a compound of the formula I with an amount of acid
`or base, such as an equivalent amount, in a medium such as
`one in which the salt precipitates or in an aqueous medium
`followed by lyophilization.
`
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`US 6,846,836 B2
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`to
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`‘IS
`
`10
`9
`a) i')e.s'igri oft"ir)drrig.s, edited by II. Bundgaard, (Elsevier,
`'I'he compounds of formula I which contain a basic
`1985) and Methods in Enzyim;-logy, Vol. 42, p. 309-396,
`moiety, such as, but not limited to an amine or a pyridine or
`edited by K. Widder, et. al. (Academic Press, 1985).
`imidazole ring, may form salts with a variety oforganic and
`b)A Textbook ofDi'rtgDe.s'ign and Dewlopriierit, edited by
`inorganic acids. Exemplary acid addition salts include
`acetates (such as these formed with acetic acid or trihalo— 5 Krosgaard—Larsen and H. Bundgaard, Chapter 5, "Design
`acetic acid,
`for example,
`trifluoroacetic acid), adipates,
`and Application of Prodrugs," by H.Bundgaard, p. 113-191
`alginates, ascorbates, aspartates, benzoates,
`(1991).
`benzenesulfonates, bisulfates, borates, butyrates, citrates,
`c) H. Bundgaard, Advanced Drug De.-'i'verjv Reviews, 8,
`camphorates, camphorsulfonates, cyclopentanepropionates,
`1-38 (1992).
`digluconates, dodecylsulfates, ethanesulfonates, fumarates,
`d) H. Bundgaard, et. al., Jourria.-' of Pfiarriinceirricni
`glucoheptanoates, glycerophosphates, hemisulfates,
`Sciences, 77, 285 (1988).
`heplanoates, hexanoates, hydrochlorides (formed with
`e) N. Kakeya, et. al., Chant Pfiar Brill, 32, 692 (1984).
`hydrochloric acid), hydrobromides (formed with hydrogen
`It should further be understood that solvates (e.g.,
`bromide), hydroiodides, 2—hydroxyethanesulfonates,
`hydrates) of the compounds of formulas I—IV are also with
`lactates, maleates (formed with maleic acid), methane-
`the scope of the present invention. Methods of solvation are
`sulfonates (formed with methanesulfonic acid),
`generally known in the art.
`2—naphthalenesulfonates, nicotinates, nitrates, oxalates,
`Preferred M°lh"d"’
`pectinates, persulfates, 3—phenylpropionates, phosphates,
`Preferred methods