(12) United States Patent
`Robl et al.
`
`(10) Patent N0.:
`(45) Date of Patent:
`
`US 6,812,345 B2
`Nov. 2, 2004
`
`USU0681 2345132
`
`(54) HMG-C0/\ REl)UCTASE lNH[BI'l‘()RS ANI)
`METHOD
`
`up
`Iii’
`EP
`
`0491225 A
`0444533 A
`0818197 A
`
`enooz
`W199?
`M1998
`
`(7.5)
`
`inventors: Jelfrey A. Rohl, Newtown, PA (US);
`Bang-Chi Chen, Plainsboro, NJ (US);
`Chong-Qing Sun, East Windstir, NJ
`(U5)
`(73) Assignee: Bristol-Myers Squibb Company,
`I
`Princeton, NJ (US)
`
`[ ’* ) Notice:
`
`Subject to any disclaimer, the term oithis
`patent is extended or adjusted under 35
`U30 154$) by 0 dam‘
`
`1
`.
`(Zl) Appl' No“ l0'f602’752
`(22)
`Filed;
`Jun, 24, 2003
`
`(65)
`
`Print‘ Publication Data
`US 2004,-"UU92573 Al May [3, 2004
`
`OTHER PUBLICATIONS
`Rob] el al, J. Med. Chem, 34, 2804-2815, 1991.
`* cited by examiner
`
`Prirrrary Exar.wTn'er—Evelyn Mei Huang
`(74) Attorney, /tgem‘, or F.irm—Burton Rodney
`
`(57)
`
`ABSTRACT
`‘
`Compounds ofthe following structure are HMG CoA reduc-
`tasc inhibitors and thus are active in inhibiting cholesterol
`biosynlhesis, modulating blood serum lipids such as lower-
`ing I.I)I. cholesterol andfor increasing IIDI cholesterol, and
`treating hyperlipidemia, hypereholesterolemia, hypertrig—
`1
`-
`‘d
`‘-- d -1h
`.--1
`yum cm” ‘in
`d cm“. arm“
`
`Related U.S. Application Data
`
`tiled on Dec. 4,
`lF],."T]U7,4F]7,
`(60) Division of application No.
`2001, now Pat. No. 6_.627_.636_. wlliclt is a conliuualiuu—in—
`part of application No. 09,:"875__l55, tiled on Jun. 6, 2001,
`now abandoned.
`
`2000.
`
`Provisional application No. 60,-"211_.59:3_. filed on 11:11. 15,
`
`(60)
`
`(51)
`
`Int. CL7
`
`C[|7D 491E044; CUYD 4954114;
`C0'r'D 4714114; C[I7F 9.-"28; A(j1K 3114353
`54-6f89; 546/23; 546/80;
`(52) U.S. Cl.
`546193; 5444542; 5444577; 514E291; 5l4f2]3.U]
`(58) Field of Search
`546,589, St}, 23;
`5404542, 577
`
`and pharmaoeutically acceptable salts thereof, wherein X is
`O, S, so, S03 or NR7;
`Z is
`
`(56)
`
`References Cited
`
`U.S. P/X11.-'N'l‘ [)()(IUMt_-'N'[‘S
`
`”"
`
`.
`3
`(.0 R
`
`3
`
`or
`
`"
`
`.
`"“_
`
`>>>>>ZD*ZD*
`
`.3,-"1990 Chuchnlowski et al.
`4,906,624
`5,-"1990 Kesseler et al.
`4,925,852
`411991 Angerbaucr et at.
`5_.tJU6_.53U
`1211992 Angerbaucr et at.
`5_.16.9_.35?
`M1993 Angerhaucr et a1.
`5,lT’,I'J8O
`111199?’ Rot‘-I
`5,686,433
`511998 Wattanasin
`5_.753_.6?5
`2I'JD3.-’I'JI'Jl8l.9.9 Al * M2003 Brodtuehrer el al.
`FOREIGN PATENT DOCUMENTS
`
`"jp
`LP
`I-Ll’
`I.-‘P
`
`0306929 A2
`U3U?'34-2 A2
`EJ325129 A2
`0325130 A2
`
`33989
`3,-‘I989
`"#1989
`"#1989
`
`on
`
`0
`
`S48/1?[}
`
`11 is 0 or 1;
`RI and R“ an Ihc Same or dj]]'cmm and are fr-1dcp3nd3m|y
`selected from alkyl, arylalkyl, eycloalkyl, alkenyl,
`cycloalkenyl, aryl, heteroaryl or cyeloheteroalkyl; and
`R3 to R10 are as defined herein.
`
`'12 Claims, No Drawings
`
`1 Of 37
`
`PENN EX. 2099
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`CFAD V. UPENN
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`

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`US 6,812,345 B2
`
`1
`HMG-COA REDUCTASE INHIBITORS AND
`METHOD
`
`This application is the divisional of U.S. application Ser.
`No. 10;’007,407", filed on Dec. 4, 2001, now U.S. Pat. No.
`6,627,636, which is a continuation—in—part of U.S. applica-
`tion Ser. No. U9;’875,155 filed Jun. 6, 2001 abandoned which
`application claims priority from U.S. provisional application
`No. ti0f2'11,595, filed Jun. 15, 2000.
`
`FIELD OF THE INVENTION
`
`The present invention relates to compounds and pharma-
`ceutical compositions useful as hypocholesterolemic and
`hypolipidemic agents. More particularly, this invention con-
`cerns (l) certain inhibitors of the enxyme 3-hydroxy-3-
`rnethylglutaryl—coenzynie A reductase (EIM(j—CoA
`reductase)
`that
`include a pyridine containing nucleus
`attached by means of a linker to an HMG—binding domain
`sidechain, (2) pharmaceutical compositions containing such
`compounds and
`a method of lowering blood serum
`cholesterol levels and modulating blood serum lipid levels
`employing such pharmaceutical compositions.
`
`BACKGROUND OF THE INVENTION
`
`U.S. Pat. No. 5,686,433 to Rohl-discloses the structure
`
`Am
`
`L
`
`R‘
`
`R-|
`
`R?
`
`DN
`
`R3
`
`“-.(O)m
`
`wherein:
`
`Am is a binding domain sidechain;
`X is a linker;
`R1 and R2 are the same or different and are each inde-
`pendently selected from
`hydrogen,
`01,? alkyl-
`(iii) aryl,
`(iv) cycloalkyl,
`(v) aralkyl,
`(vi) aralkoxy,
`(vii) alkenyl,
`(viii) cycloalkenyl, and
`(ix) heterocyclo (e.g., thienyl, benzodioxolyl);
`R3 is selected from
`(i) hydrogen,
`(ii) lower alkyl,
`(iii) aryl,
`(iv) cycloalkyl,
`(v) alkoxy,
`(vi) aralkyl,
`(vii) aralkoxy,
`(viii) alkenyl,
`(ix) cycloalkenyl,
`(x) halo-substituted alkyl,
`(xi) adamantyl, and
`(xii) heterocyclo (e .g., thienyl, hemodioxolyl);
`
`R" is selected from
`(i) hydrogen,
`(ii) lower alkyl,
`(iii) ‘aryl,
`(iv) cycloalkyl,
`(v) alkoxy,
`(vi) aralkyl,
`(vii) aralkoxy,
`(viii) alkenyl,
`(ix) eyeloalkenyl,
`(x) adamantyl,
`(xi) halogen,
`(xii) halo-substituted alkyl (e.g., trilluoroniethyl), and
`(xiii) heterocyclo (e.g., thienyl, bcnzodioxolyl); or R3
`and R4 taken together can be
`
`T(CI I3)pr
`
`(CIIg),1
`
`(C113),
`
`01'
`
`(t'.TH:CH)3_.
`
`but when Am is
`
`RI’:
`
`IIO*CII*CII3*C*ClIg—COgRB
`()H
`
`or a 6 lactone thereof, R3 and R‘ cannot be (CH=CH)2;
`
`R“ is hydrogen or lower alkyl;
`R3 is hydrogen, lower alkyl, alkali metal, or alkaline earth
`metal;
`n is 0 or 1;
`p is 3, 4 or 5;
`q is O, 1, 2, or 3; and
`r is 0,1, 2, or 3.
`is an HM(}—bincling
`In preferred embodiments (Am)
`domain sidechain having a dihydroxy or a phosphinic acid
`function.
`
`5
`
`10
`
`"I5
`
`ll]
`
`35
`
`30
`
`35
`
`4E]
`
`The phosphinic (or phosphonic when X is CII2—()—)
`acid HMG—binding domain sidechain (A,) is
`
`45
`
`R5
`
`o
`H
`k5o— P—(?H3—c:—c?Hg—t?o3R7
`I()H
`]
`
`wherein R5 and R7 are independently selected from
`hydrogen, lower alkyl, alkali metal ion and alkaline earth
`metal ion; and R“ is hydrogen or lower alkyl.
`The dihydroxy acid binding domain sidechain (A,_._ is
`
`R6
`
`H0—cH—cH3—c— CH3 —c031-:3
`OII
`
`wherein Rf’ is hydrogen or lower alkyl, R” is hydrogen or
`lower alkyl in free acid form or in the fonn of a physiologi-
`cally acceptable and hydrolyzable ester or 6 lactone thereof
`(i.e., when Am is
`
`PENN EX. 2099
`
`5;;
`
`35
`
`an
`
`65
`
`20f3'}'
`
`CFAD V. UPENN
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`IPR2015-01836
`
`

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`US 6,812,345 B2
`
`In addition, R” can be alkali metal ion or alkaline earth metal
`ion.
`
`is —(CH7),7—, —CH=CH—,
`A suitable linker (X)
`—(.‘E(T , —CII3()—, wherein O is linked to the phos-
`phorous atom or the aromatic anchor when Am is Al, and
`wherein O is linked to the aromatic anchor when Am isA7,
`and wherein "a" is I, 2, or 3.
`
`BRIEF DESCRIPTION OF THE INVENTION
`
`In accordance with the present invention, there are pro-
`vided certain pyridine—containing compounds that are potent
`inhibitors of cholesterol biosynthesis by virtue of their
`ability to inhibit the enzyme 3-methyl-glutaryl-coenzyme A
`rcductase (HMG—CoA reductase).
`In particular, in its broadest chemical compound aspect,
`the present invention provides compounds of the formula
`
`
`
`4
`alkenyl, cycloalkenyl, aryl, heteroaryl or
`cycloheteroalkyl,
`
`R7,, and R76, and R7, and R73, and R77, are the same or
`diiferent and are independently selected from H, alkyl,
`arylalkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, het-
`eroaryl or cycloheteroalkyl; or R77, and R7: may be
`taken together with the nitrogen to which they are
`attached to form a stable 3 to 8 membered heterocyclic
`ring, which where applicable, includes a total of 1 to 3
`heteroatoms in the ring, which heteroatoms may be N,
`O or S; or R7, and R73 may be taken together with the
`nitrogen to which they are attached to form a stable 3
`to 8 membered heterocyclic ring which, where
`applicable, includes a total of 1 to 3 heteroatoms in the
`ring, which hetcroatoms may be N, U or S;
`
`R3 is H or lower alkyl;
`
`R9 and R 10 are the same or dilferent and are independently
`selected from H or alkyl, or where at least one of R9 and
`Rm is alkyl, R9 and Rm may be taken together with the
`carbon or carbons to which they are attached to form a
`3 to 7 membered carboeyclic ring, which may include
`a spirocyclic ring;
`
`represents a single bond or a double bond (which
`and ,9’
`may be cis or trans);
`
`and including phannaceutically acceptable salts thereof
`where R3 is I], esters thereof, prodrug esters thereof,
`and all stereoisomers thereof.
`
`Preferably, the Z group will be in form of a free acid, a
`physiologically acceptable and hydrolyzable ester or E3 lac-
`tone thereof, or an alkali metal salt, alkaline earth metal salt
`or an amino acid salt.
`
`is preferred that X is 0, S07 or NR7 where R7 is
`It
`R7,,S02—.
`Preferred are compounds of formula I of the invention
`wherein
`
`R7
`
`and R7 are independently selected from alkyl,
`cycloalkyl and aryl;
`
`10
`
`"I5
`
`ll]
`
`L
`
`35
`
`4E]
`
`R4 is H, alkyl or halogen;
`X is O; and
`n is o.
`
`Sf]
`
`More preferred are compounds of formula I of the inven-
`tion wherein R1 is aryl (especially substituted aryl as defined
`hereinafter);
`
`R3 is alkyl or cycloalkyl;
`
`R,, is II;
`
`R9 and R”, are H;
`X is 0;
`
`n is 0; and
`
`60
`
`/’ is a double bond.
`
`is 0 or 1;
`R1 and R3 are the same or different and are independently
`selected from alkyl, arylalkyl, cycloalkyl, alkenyl,
`eycloalkenyl, aryl, heteroaryl or cycloheteroalkyl;
`R3 is H, or lower alkyl or a metal ion (such as an alkali
`metal or an alkaline earth metal);
`R4 is H, halogen, CF3, hydroxy, alkyl, alkoxy, carboxyl,
`carboxylalkyl-. aminoalkyl, amino, alkanoylamino,
`aroylamino, cyano, alkoXyCON(R77,)—,
`R7,R7gN(I()—, R7fR7gN(I()2—, R77,_S()7N(R7_,.)—,
`R7}R7xNS07N(R7,,) —, R7,.0CO7— or R7,0O0 ;
`R7 is H, alkyl, aryl, alkanoyl, aroyl, alkoxycarbonyl,
`R7,,SO3—, R7£,R7(.NSO7— or R7bR7cNCO—;
`R7‘, and R7_, are the same or dilferent and are indepen-
`dently selected from alkyl, arylalkyl, cycloalkyl,
`3 Of 37
`
`Still more preferred are compounds of formula I of the
`invention wherein
`
`R1 is substituted aryl, preferably 4-Iluorophenyl, 4-fluoro-
`3-methylphenyl or 3,5-dimethylphenyl;
`
`55
`
`R: I5 iilkyl 0‘ CYC]"31k}’1sl7T3fcrab1Y I-"""l7ml7)’1a l'h1llYl or
`cyclopropyl;
`PENN EX. 2099
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`
`US 6,812,345 B2
`
`R4 is II;
`X is 0;
`1'1 is o;
`.3 is a double bond, preferably “trans”; and
`
`HO
`
`7. is
`
`[I
`
`OIIIIIII
`
`['_‘( )2[.1
`
`or
`
`‘,\OII
`
`“‘
`
`O
`
`0
`
`or an alkali or alkaline earth metal salt thereof or an amino
`acid salt.
`
`Most preferred compounds of formula I of the invention
`will have the structure
`
`
`
`or an alkali or alkaline earth metal (such as Na, K or Ca) salt
`thereof, or an amino acid salt (such as arginine), wherein R5
`and R5 are the same or different and independently selected
`from II, halogen andfor alkyl (preferably 4-Iluoro, 4-fluoro-
`3—methyl or 3,5—dimcthyl); and
`R2 is alkyl or cycloalkyl, preferably isopropyl, t-liutyl or
`cyclopropyl.
`In another aspect, the present invention provides phan'na-
`ceutical compositions, useful as hypolipidemic or hypoeho—
`lesterolemic agents, or hypotriglyceridemic agents, or anti-
`Alzheimer’s agents, or anti—osteoporosis agents as well as
`other uses as described herein, comprising a hypolipidemic
`or hypocholesterolemic or hypotriglyceridemic or anti-
`Alzhein'ter’s disease or anti-osteoporosis amount, or other
`therapeutically elfec1ive amount (depending upon use) of a
`compound of formula I in accordance with this invention, in
`combination with a pharmaceutically acceptable carrier.
`In another aspect, the present invention provides a method
`of inhibiting cholesterol biosynthesis or
`lowering blood
`serum cholesterol
`levels andfor modulating blood serum
`cholesterol levels such as lowering LDL cholesterol andfor
`increasing HDL cholesterol, or treating dyslipidemia, mixed
`dyslipidemia, hyperlipidemia, hypercholesterolemia, hypo
`o.—lipoproteinemia, LDL Pattern B, LDL Pattern A, hyper-
`lipoproteinemia or hypertriglyceridemia, and other aberra-
`tions of apolipoprotein B metabolism, or reducing levels of
`I.p[a), or treating or preventing other cholesterol-related
`diseases, or treating or preventing or reversing progression
`of atherosclerosis, or preventing or treating /\lv.heimer’s
`disease, or preventing or
`treating osteoporosis andfor
`osteopenia, or reducing inflammatory markers such as
`C—reactive protein, or preventing or
`treating low grade
`vascular inflammation, or preventing or treating stroke, or
`preventing or treating dementia, or preventing and treating
`coronary heart disease (including primary and secondary
`prevention of myocardial infarction), or preventing or treat-
`ing stable and unstable angina, or primary prevention of
`coronary events, or secondary prevention of cardiovascular
`
`10
`
`"I5
`
`ll]
`
`35
`
`4E]
`
`45
`
`Sf]
`
`60
`
`65
`
`6
`events, or preventing or treating peripheral vascular disease,
`preventing or treating peripheral arterial disease, or prevent-
`ing or treating acute vascular syndromes, or preventing or
`reducing the risk of undergoing myocardial revasculariza-
`tion procedures, or preventing or treating microvascular
`diseases such as nephropathy, neuropathy, retinopathy and
`nephrotic syndrome or preventing or treating hypertension
`in a patient in need of such treatment by administering a
`pharmaceutical composition in accordance with the present
`invention as defined above.
`In addition, in accordance with the present invention, a
`method is provided for preventing or treating diabetes,
`especially Type 2 diabetes, and related diseases such as
`insulin resistance, hyperglycemia, hyperinsulinermia,
`elevated blood levels of fatty acids or glycerol, obesity,
`Syndrome X, diabetic complications, dysmetabolic
`syndrome, and related diseases, and sexual dysfunction,
`wherein a therapeutically eifective amount of a compound of
`structure I is administered to a patient in need of treatment.
`In addition, in accordance with the present invention, a
`method is provided for preventing and treating malignant
`lesions (such as ductal carcinoma in situ of the breast and
`lobular carcinoma in situ of the breast), premalignant lesions
`(such as fibroadenoma of the breast and prostatic intraepi—
`thelial neoplasia (PIN), gastrointestinal malignencies,
`liposareomas and vaiious other epithelial tumors (including
`breast, prostate, colon, ovarian, gastric and lung), cancer-
`induced asthenia (fatigue),
`irritable bowel syndrome,
`Crohn's disease, gastric ulceritis, and gallstones, and HIV
`infection, other
`infectious diseases, drug—induced
`lipodystrophy, and proliferative diseases such as psoriasis,
`wherein a therapeutically effective amount of a compound of
`structure I
`is administered to a human patient in need of
`treatment.
`
`In addition, in accordance with the present invention, a
`method is provided for improving coagulation homeostasis
`including reducing PAI—1 activity, reducing fibrinogen, and!
`or reducing platelet aggregation, andfor improving endothe-
`lial function, wherein a therapeutically elfective amount of
`a compound of structure I is administered to a patient in need
`of treatment.
`
`In addition, in accordance with the present invention, a
`method is provided for treating cholesterol related diseases,
`diabetes and related diseases, cardiovascular diseases, cere-
`brovascular diseases as defined above and hereinafter and
`
`other diseases as set out above, wherein a therapeutically
`effective amount of a combination of a compound of struc-
`ture I and a hypolipidemic agent, andfor lipid modulating
`agent andfor antidiabetic agent andfor cardiovascular agent,
`cerebrovascular agent, andfor other type of therapeutic
`agent, is administered to a patient in need of treatment.
`In the above methods of the invention wherein a combi-
`
`nation is administered, the compound of structure I will be
`employed in a weight ratio to the other therapeutic agent
`{depending upon its mode of operation) within the range
`from about 0.01:] to about 500:1, preferably from about
`05:1 to about l0[l:l.
`
`I)I_-"I'AII.l_-ll) l)l_".S(TRIP'I'I[)N OI‘ 'I'III_-'
`INVENTION
`
`In accordance with the present invention, there is pro-
`vided eompounds useful in inhibiting the enzyme HMG—
`CoA reductase, which inhibitors are useful as hypocholes—
`terolemic agents, dyslipidemic agents, hypolipidemic
`agents, hypotriglyceridemic agents, anti-Al7.heimer’s dis-
`ease agents, and antiosteoporosis agents as well as other uses
`as described herein.
`
`PENN EX. 2099
`
`40f3'i'
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`CFAD V. UPENN
`
`IPR2015-01836
`
`

`
`US 6,812,345 B2
`
`,,
`
`,,
`
`‘
`‘ ii
`
`7
`8
`agents including lipoxygenase inhibitors, ACAT inhibitors,
`The term "coronary events" as employed herein refers to
`myocardial
`infarction, myocardial
`revascularization
`antioxidants, PPAR {*5 agonists, phospholipase inhibitors
`procedures, angina, cardiovascular death and acute coronary
`including PI./\-2 inhibitors andfor other known anti-
`syndrome.
`atherosclerotic agents.
`___
`__
`.
`,
`,
`The term “cardiovascular diseases or events” as employed 5
`and haiis
`"16 iflmsiiharmactiuiicaiiy acccpiablc Sail
`herein refers to atherosclerosis of the coronar
`arteries
`fer to basic salts forrned with inorvanic and 0 ianic bases
`’
`Y
`-
`-
`-
`v
`-
`-
`‘
`_
`,
`f9
`,
`ii=
`iii’
`myocardial infarction, including primary MI and secondary
`Such‘ salts include ammonium salts, alkali metal salts, such
`Mi,
`recurrent myocaidiai
`infaiciion’ angina pccioiis
`35 iiii““m' "”i_i"i"-' and liiiiassium Saiis (which are
`(including stable and unstable angina), congestive heart
`to preferred); alkaline earth metal salts, such as calcium and
`fai]-iii-3’ and Sudden cardiac dcam
`iiiagiicsium Saiisi Siiiis wiiii 0igaiiiC_ bases‘ Such as iiiiiiiii:
`The term "cerebrovascular diseases or events” as
`iii” Saiii‘ “"3” ii_i°3'i3i”i'ii”‘3’i‘”"iiii’, "’aii= iiiiiiiiiiiiiiiiiia
`employed herein refers to cerebral
`infarction or stroke
`N'mc1hy]'D'g1“C3m‘"5s and hydrabamlm 53115)} and 531115
`{caused by vessel blockage or hemmorage), or transient
`with amino acids like arginine,
`lysine and the like; and
`igchumia mack (TIA), syncope’ aiiwmscicmsis of ii“;
`"'5 ZWillCTiUl"-*5» [he 50'C3H‘4l “inmvr S311-‘ii N'5‘m'5‘xiCi Pha“T'a'
`intracranial andfor extracranial arteries, and the like.
`ceutically acceptable salts are preferred, although other salts
`Thg mrm iich01t,5ier01_re1;,it,d disflsgs" as employed
`arc 3150 Uscfuls cvgvs in lmlaling 01' Purifying the Product-
`herein refers to diseases involving elevated levels of LDL
`The [arm pharmacwii-caiiy awcpiabic ..Saii.. and ..SaiiS,,
`<(:iholestero_l, diseases involving regulation of LDL receptors,
`3;; also includes acid addition salts. These are formed, for
`isciiisiis iiivoiviiig‘ i.°d.uCi'd.
`icvcis oi HDL Ciioicsicioi’
`.
`.
`.
`.
`.
`.
`dyslipidemia, hyperlipidemia, elevated [.I)l. Pattern ll,
`example, with strong inorganic acids, such as mineral acids,
`.
`i.
`1
`i
`i
`ii.
`._ _ _.d
`h i h
`.‘
`‘.d
`i h d h i._
`elevated LDL Pattern A, hypercholesterolemia, hypo
`io_ldcx‘dri-'hi)_c‘5i'li(i'ilnL diiilii‘ ii
`[.)si1p_0rlL au fir.d_
`hm dii‘:
`r1—lipoproteinemia (low HUI. cholesterol syndrome),
`‘ii"i mi‘
`‘ii’
`' or
`i’ w_ii
`iiimiig Oigdiii‘ “ii my ii"
`hyperlipoproteinemia, elevated I,p{a)
`levels,
`aciiis’ Such as aikaiiiicaiboxyiic iiciiis of 1 ici 4 Carbon iiioiiis
`hypertriglyceridemia, other aberrations of apolipoprotein B
`metabolism, heterozygous familial, presumed familial com— 35 whwh 3“"_ ""5“b5m“i°‘i °r_ 5'ib5_'mi"°d-
`tor °xaml’i°= by
`bined and non-familial (non-l-‘I I) forms of primary hyperc-
`hamgcns 10" “X3-mplu “Wile aclds Such 35 Sillurillul Ur
`holesterolemia (including Frederickson Types Ha and Ilb),
`""531" Talcd ‘”Ca1'b0X)'1i‘3 acids» f01' cxamplc Oxallca m«'l10I1lC,
`cholesterol ester storage disease, and cholesterol ester trans-
`511003039: malcics fl-1m3FlC»I3hlh31l° 01' 191"-‘-Phlhalic acids Such
`fc; pi-01311-1 discglgci and fclatcd discascg‘
`as hydroxycarboxylic acids, for example ascorbic, glycolic,
`'[‘|-,3 a-,1-1di1i.;,1-15;,’ diseases, and maladieq, cgllgciivcly refer.
`lactic, malic, tartaric or citric acid, such as amino acids, (for
`cnccd to as "Syndrome X” or Dysmctabolic Syndrome (as,
`example aspartie or glutamic acid or lysine or arginine), or
`detailed in .Iohanson,J. Chin. Endocririoil. Mc.rab., 1997, 82,
`benzoic acid, or with organic sulfonic acids, such as
`727-734, and other publications) include hyperglycemia
`(C1-C4) alkyl or arylsulfonie acids which are unsubstituted
`andfor prediabetic insulin resistance syndrome, and is ehar— is or substituted, for example by halogen, for example meth-
`acterized by an initial
`insulin resistant state generating " ancsulfonic acid or p—t[)lucncs.ulfonic ;.cid_
`hyperinsulinemia, dyslipidemia, and impaired glucose
`,
`_
`,
`’
`‘iiiiyi
`iii°_ iiirm niowcii
`tolerance, which can progress to Type II diabetes, charac—
`Uiiicss Oihciwisc iiiiii°ai°ii'
`teriiced by hyperglycemia, which can progress to diabetic
`“alkyl” or nail‘? as cmpioycii h6_r°i" alone or a5 pan iii:
`compiiciiiionsi
`4“ another group includes both straight and branched chain
`The icim ssdiabcics and iciaicd discasgsss mfcis ii, 1-we ii
`hydrocarbons, containing 1 to 20 carbons. preferably 1 to l0
`diabcics’ Type i diabetes’
`impaired giucosc ioicmiicci
`carbons, more preferably I to8 carbons, in the normal chain,
`obesity, hyperglycemia, Syndrome X, dysmetabolic
`91"-'l" 35 mclhlda elhyls Pmllyls i5'5‘l7r'5‘l73’1a bmyla 1'bU1)‘ls
`syndrome, diabetic complications and hyperinsulinemia.
`l50bUl)'1s Pcmyls h‘3XY1~i50h°XY1- h’-3PlY1= 4-4‘(lim°lhY1P‘—'T1l}’1a
`The conditions, diseases and maladies collectively 45 “CW1: 2»3=4'”im*’1h)’l'l"’"1}’l» _“‘{“Y1» dccylr undccylo
`referred to as "diabetic complications” include retinopathy,
`dUd*"-'yla "73 Winn‘-'-“i hranchcd Chin“ 1-mmcm Ihcrwfa and [he
`1'1c11r()paT_hy and ncphr(3pa[[]yi and (flhcr kn()wn [_;[_)r|1i)[i(;a—
`likfl as Wtill 3.‘-i SLlCl'] g]'ULlpS including l TD 4 SLll'JST.illlBI'llS Slli..‘l'l
`tions of diabetes.
`as halo, for example F, Br, C1 or I or Cl’, alkyl, alkoxy, aryl,
`typ¢(,-3) of ihcmpc-uric agc-ms, as
`The,
`term “other
`aryloxy,aryl(aryl) or diaryl, arylalkyl,aryla1kyloxy, alkenyl,
`employed herein refers to one or more antidiabetic agents Sn cycloalkyl, cycloalkylalkyl, cycloalkylalkyloxy, amine,
`(other than compounds of formula I), one or more anti—
`hydroxy, hydroxyalkyl, acyl, cycloheteroalkyl, heteroaryl,
`obesity agents, andfor one or more lipid—lowering agents,
`heteroaryloxy, heteroarylalkyl, heteroarylalkoxy,
`one or more lipid modulating agents (including anti—
`aryloxyalkyl, alkylthio, arylalkylthio, aryloxyaryl,
`atherosclerosis agents), other types of anti-atherosclerosis
`3]ky]3mjdU, a]kam,y]amin0, ary1Carb0ny1arfiin(}, Him,’
`agem-‘h 3-T1d-’i0T 0173 0T W0“-5 iimil-"13-l51‘51 “gems: 055 Or more 55 cyano, thiol, haloalkyl, trihaloalkyl andfor alkylthio.
`agents for treating hypertension, one or more anti-cancer
`_
`_
`_
`drugs, one or more agents for treating arthritis, one or more
`Unlcsfi Olh‘-"_rW15°
`lndlcalcds ‘hi? lcrm “cycloalik-Y1” 33
`anti-osteoporosis agents, one or more anti-obesity agents,
`emplflyed harem 310173 “T 35" I33“ 01 anmher gmup lnclude-‘3
`one or more agents for treating immunomodulatory diseases,
`Siiiluniled 0‘ llamally llmialllraled lwnlaining 1 0‘ 2 dmlblfl
`andfor one or more agents for treating anorexia nervosa.
`fin btllilds) cyclic hydrocarbvn EJUUPS I-'Ul'll*1lI1l-Fig 1 10 3 H1135:
`The term “lipid—modulating” agent as employed herein
`including m0“0‘33'C1iC alkyl» blcycllc '<11k}'1(01' blCY°l0"l1kY1)
`refers to agents which lower LDL andfor raise HDL al1Cl;'i01‘
`and lrlC)'CllC alkyl. Conlflinirlg «'1 lolal Of 3 Y0 30 Carbflrls
`lower triglycerides andfor lower total cholesterol aiidfor
`forming the ring, preferably 3 to 10 carbons, forming the
`other known mechanisms for therapeutically treating lipid
`ring and which may be fused to 1 or 2 aromatic rings as
`disorders.
`55 described for aryl, which includes cyclopropyl, cyclobutyl,
`The term "other types of anti-atherosclerosis agents” as
`cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclode-
`employed herein refers to conventional anti-atherosclerosis
`cyl and cyclododecyl, cyclohexenyl,
`EX.
`5 Of 37
`CFAD V. UPENN
`IPR2015-01836
`
`_,
`
`

`
`US 6,812,345 B2
`
`wk
`o
`
`:10
`
`10
`attachment at two different carbon atoms, they are termed
`“alkenylene groups” and "alkynylene groups“, respectively,
`and may optionally be substituted with l or 2 substituents 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 C153, with chlorine or fluorine being
`prefened.
`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.
`
`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—n:Iphthyl) and may optionally include one
`to three additional rings fused to a carbocyclic ring or a
`heterocyclic ring (such as aryl, cyeloalkyl, heteroaryl or
`cycloheteroalkyl rings for example
`
`/
`
`\\
`Z
`
`‘q
`N//'
`
`|
`
`5-
`‘ /
`\\
`Z '
`
`| \:
`X
`
`"I5
`
`ll]
`
`any of which groups maybe optionally substituted with 1 to
`4 substituents such as halogen, alkyl, alkoxy, hydroxy, aryl,
`aryloxy, arylalkyl, cycloalkyl, alkylamido, alkanoylamino,
`oxo, acyl, arylcarbonylamino, heteroaryl, cycloheteroalkyl,
`amino, alkylamino, nitro, cyano, thiol andfor alkylthio and!’
`or any of the substituents for alkyl.
`The term "cycloalkenyll as employed herein alone or as
`part of another group refers to cyclic hydrocarbons contain-
`ing 3 to 12 carbons, preferably 5 to l() carbons and l or 2
`double bonds. Exemplary cycloalkenyl groups include
`cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl,
`cyclohexadienyl, and cyeloheptadienyl, which may be
`optionally substituted as defined for eycloalkyl.
`The term "alkanoyl" as used herein alone or as part of L
`another group refers to alkyl linked to a carbonyl group.
`Unless otherwise indicated, the term “lower alkenyl” or
`“alkenyl" as used herein by itselfor as part of another group
`refers to straight or branched chain radicals of '2 In 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-heplenyl. 3-heptenyl, 4-heptenyl, 3-oclenyl,
`3—nonenyl, 4—decenyl,
`3—u ndecenyl, 4—dodecenyl, 4,8,12-
`tetradecatrienyl, and the like, and which may be optionally --
`substituted with "l
`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 andfor any of the alkyl substituents set
`out herein.
`
`
`
`Unless otherwise indicated, the tenT| “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 l2 carbons and more preferably 2 to
`8 carbons in the normal chain, which include one triple bond
`in the normal chain, such as 2—propyny|, 3—h11tynyl,
`2-butynyl, 4-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl,
`2-heptynyl, 3-heptynyl, 4-heptynyl, 3-octynyl, 3-nonynyl,
`4-decynyl, 3-undecynyl, 4-dodecynyl and the like, and
`which may be optionally substituted with l to 4 substituents,
`namely, halogen, haloalkyl, alkyl, alkoxy, alkenyl, alkynyl,
`aryl, arylalkyl, cycloalkyl, amino, heteroaryl,
`cycloheteroalkyl, hydroxy, alkanoylamino, alkylamido,
`arylcarbonylamino, nitro, cyano,
`thiol, andfor alkyllhio,
`and;"or any of the alkyl substituents set out herein.
`The terms "arylalkenyl” and "arylalkynyll, 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 with l or 2 substituents as defined above for
`
`“alkyl”, such as, for example, alkyl, halo, hydroxy, alkoxy
`andfor cycloalkyl.
`Where alkenyl groups as defined above and atkynyl
`groups as defined above, respectively, have single bonds for
`
`45
`
`Sf]
`
`60
`
`65
`
`and may be optionally substituted through available carbon
`atoms with 1, 2, or 3 groups selected from hydrogen, halo,
`haloalkyl, alkyl, haloalkyl, alkoxy, halophenyl, benzoyloxy,
`haloalkoxy, alkenyl,
`trifluoromethyl,
`trilluoromethoxy,
`alkynyl, cycloalkyl— alkyl, cycloheteroalkyl,
`cycloheteroalkylalkyl, aryl, heteroaryl, arylalkyl, aryloxy,
`aryloxyalkyl, arylalkoxy, arylthio, arylazo, heteroarylalkyl,
`heteroarylalkenyl, heteroarylheteroaryl. heteroaryloxy,
`hydroxy, nitro, cyano, amino, substituted amino wherein the
`amino includes l or 2 substituents (which are alkyl,
`alkanoyl, aryl or any ofthe 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, arylsulfonylamino or arylsulfonaminocar—
`bonyl andfor any of the alkyl substituents set out herein.
`Unless otherwise indicated,
`the term “lower alkoxy",
`“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 SUlF ,EiCl2099
`
`5 Of 37
`
`CFAD V. UPENN
`IPR2015-01836
`
`

`
`US 6,812,345 B2
`
`5
`
`In
`
`alkyl, aralkyl or aryl groups linked to a sulfur atom.
`
`12
`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:
`
`N
`
`-"
`
`‘
`5’
`
`I"
`
`.\'
`
`0
`
`\_
`‘
`
`-"
`
`N
`
`N
`
`N
`
`Z
`
`IT,
`\ '
`
`O
`
`‘
`
`O
`
`0
`
`N,
`
`30 \_/
`
`N_N
`E
`\
`_. )=
`/3‘?
`l
`
`N
`Ly
`
`\
`/N:
`
`‘0
`
`51
`
`L
`I
`
`0
`
`I
`
`N
`
`0
`
`/
`1 -'
`N
`
`5
`
`L _
`
`‘
`
`0
`
`\I
`T’
`2
`0
`N\\
`.r‘'‘
`
`E 2 ' D ' D '
`
`11
`may be the same or different, such as alkyl, aryl, arylalkyl,
`heteroaryl, heteroarylalkyl, cycloheteroalkyl,
`cycloheteroalkylalkyl, cycloalkyl, cycloalkylalkyl,
`haloalkyl, hydroxyalkyl, alkoxyalkyl or thioalkyl. These
`substituents may be further substituted with a earboxylic
`acid and.-‘or any of the substituents for alkyl as set out above.
`In addition, the amino subslituents may be taken together
`with the nitrogen atom to which they are attached to form
`l-pyrrolidinyl,
`l-piperidinyl,
`l-axepinyl, 4-morpholinyl,
`4-thiamorpholinyl, 1-piperazinyl, 4-alkyl-"l-piperazinyl,
`4-ary1a1ky1—1—piperazinyl, 4-diarylalkyl-1-piperazinyl,
`l-pyrrolidinyl, 1-piperidinyl, or l-axiepinyl, optionally sub-
`stituted with alkyl, alkoxy, alkylthio, halo, trifluoromethyl or
`hydroxy.
`Unless otherwise indicated, the term “lower alkyllhio”, H
`alkylthio", “arylthio"' or aralkylthio" as employed herein '-
`\.\/\\.N=
`alone or as part of another group includes any of the above
`> ,
`/
`\=/
`Unless otherwise indicated, the term "lower alkylamino”,
`/K
`N \
`“alkylamino”, “arylamino", or “arylalkylamino” as
`< Z |T,
`employed herein alone or as part of another group includes 1:!
`“\/,
`l E,
`\\ l
`any of the above alkyl, aryl or arylalkyl groups linked to a
`)
`2
`nitrogen atom.
`S
`Unless otherwise indicated, the term “acyl" as employed
`i//1| ‘
`referstoyan organigradical linked%i)apcarbonyl
`25 lg ‘ F ‘W8 ‘
`‘\./\/O‘
`herein b itself or
`art of another
`ou , as defined herein,
`\ .\ M
`(0
`N,\/.\
`II)
`C
`/N‘‘'‘‘ K‘ . .
`0\ _____,
`(
`(
`'
`group; examples of aeyl groups include any of the R‘ groups
`N
`X
`/‘o
`attached to a carbonyl, such as alkanoyl, alkenoyl, aroyl,
`'N=N
`aralkanoyl, heteroaroyl, eyeloalkanoyl, cyeloheteroalkanoyl
`\.
`and the like.
`K
`/ .-
`Unless otherwise indicated, the term “cycloheteroalkyl” 3,5
`.5’
`as used herein alone or as part of another group refers to a
`5-, 6- or 7-membered saturated or partially unsaturated ring
`and mu like
`which includes 1
`to 2 hetero atoms such as nitrogen, oxygen
`The 1crm'a ccCvcluheleroalkvlalkylvv as used herein alum,
`andfor sulfur, linked through a carbon atom or a heteroatom,
`Wham possiblst Uptionally Via the linker (CI [2)r (Wham T is 4” or as part of another gorup refers to cycloheteroalkyl groups
`1! 2 "T 3)v Such as
`as defined above linked through a C atotn or lieteroalom to
`a (CH2), chain.
`The term "heteroarylalkyl” or "heteroarylalkenyl” as used
`herein alone or as part of another group refers to a heteroaryl
`2 I 45 group as defined above linked through a (3 atom or heteroa-
`tom to a —{(IlI:),— chain, alkylene or alkenylene as
`defined above.
`The term “polyhaloalkyl” as used herein refers to an
`E \|
`“alkyl” group as defined above which includes from 2 to 9,
`T=
`J an preferably from 2 to 5, halo substituents, such as 1-‘ or Cl,
`N
`_
`preferably I", such as Cl-‘3(TlI:,_, (TF3 or (Tl-‘3(.'li:._(TlI:._.
`The term “polyhaloalkox