`Rob]
`
`(10) Patent N0.:
`(45) Date of Patent:
`
`US 6,627,636 B2
`Sep. 30, 2003
`
`US[}U6627636l32
`
`(54) HMG-C0/\ RlCl)UCTASE INHIBITORS AND
`METHOD
`
`EP
`Iii’
`
`04445.33 A
`081819".-" A
`
`W199?
`H1998
`
`(75)
`
`II1Vl.:I1lUl'I
`
`.Iefl‘rI:y A. Rubi, Newtown, PA (US)
`
`(73) Assignee: Bristol-Myers Squibb Company,
`Princeton, NJ (US)
`
`[ "‘ ) Notice:
`
`Subject to any disclaiiner, the term of this
`patent is extended or adjusted under 35
`U'5‘(" 154”) by 0 d"3‘5‘
`
`(31) APPL N0-i 10«"007a407
`(22) Film:
`net 4, 2001
`(65)
`Prior‘ Pllllllcation llata
`US 2[JU2,.'l'lI1‘_J49'.|"i' Al Jul. 18, 2002
`
`Related U.S. Application Data
`
`[(53)
`
`[(30)
`
`(?onlinuation—in—parl of application No. U9,-'8".I'5_,l55_, filed on
`Jun. 6, 2UU1_. now abandoned.
`Provisional application No. 60,.-"21 L595, filed on Jun.
`ZUUU.
`
`[5,
`
`UFIIER PUm‘I(:‘N”0NS
`I ‘l, J. M (1. Ch
`., 34, 2804-2815. 1991.
`R bl
`gm
`C d
`6
`0
`1’rr.'rm:r__v Ex(miinei'—l_ivelyn Mei Iluzlng
`(74) Attorney, Agem, or l"‘.=Trm—Burton Rodnev
`_
`i
`V ‘
`V ‘
`1
`(37)
`AB51RA('l
`Compounds of the following structure are HMG COA reduc-
`tase inhibitors and thus are active in inhibiting cholesterol
`biosynthcsis, modulating blood serum lipids such as lower-
`mg IDI. cholesterol and,-"or increasing IIDI cholesterol. and
`treating hyperlipidemia, hypereholesterolemia, hypertrig—
`lyceridernia and atherosclerosis
`
`
`
`(52) U.S. CI.
`
`(51)
`
`Int. CL?
`
`A6lI( 3'l,t'4353; /\61K 31;’-4365;
`C071’) 49'la’0-14; C071) 495104; A6'lP 3;’06
`5141291; 51415292; 514213.01;
`540577; 546180; 546.81; 546189; 546f93
`(58) Field of Search
`514E291, 292,
`5l4i’213.Ul; 546.-"30, 81, 89, 93; 540577
`
`(55)
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`and pharmaceulically aoceptable salts thereof, wherein X is
`O, S, S0, S0“ or NR ; Z is
`"
`7
`
`4_.906_.624 A
`4,925,852 A
`5_.UU6_.53U A
`5,169.85? A
`521 T7-',fJ8(J A
`5_.fi86,4_33 A
`5_.7.‘i3,675 A
`
`351900 Chucholowski cl al.
`5,r'l‘J9U Kesseler el ill.
`4i'1‘J‘J1 Angerbaucr ct al.
`l2x'1‘J02 Angerbaucr ct al.
`l,.I'l‘J93 Arigerhaiicr at al.
`H.319‘)? Robl
`5,."199S Watlallasiii
`
`‘
`
`'
`Hp
`I51-’
`tap
`
`FOREIGN pAl~EN'[~DO(_=UMEN'1‘S
`‘E
`4.
`..
`I
`[B25129 A2
`l']32513f] A2
`0491225 A
`
`.
`.
`..'
`wwgg
`7,-"1989
`6;'1<.J‘J2
`
`H0
`
`0
`
`0"
`
`[f()1]{3
`
`or
`
`0
`
`OH
`
`n is 0 or "l; R, and 1:12 fare thenfalrrie or iliitfprent andlkare
`independently selccte mm a
`3-’
`, aryla ky, cycloa yl,
`alkenyl, eyeloalkeriyl, aryl, heteroaryl or cyclohetcroalkyl;
`.
`__
`.
`1
`‘
`'
`and R) to Rm are as refined herein
`
`25 Claims, No Drawings
`
`luf36
`
`PENN EX. 2098
`
`CFAD V. UPENN
`lPR20l5-01836
`
`
`
`US 6,627,636 B2
`
`1
`HMG-COA RlCl)UCTASl<l INH[BI'll()RS AND
`METHOD
`
`This application is a continuation—in—part of US. appli-
`cation Ser. No. O9,-'875,l55 filed Jun. 6, 200], abandoned
`which application claims priority lironi U.S. provisional
`application No. 6[l;?.ll,595, illed Jun. 15, 2000.
`
`FIELD OF Till} [N VLiN'l‘ION
`
`Tlie prcsciil iiiveiitioii relates to ooiiipouiids and pharma-
`ceutical compositions useful as hypecholesterolcmic and
`hypolipidernic agents. More particularly, this invention con-
`cerns ('1) certain inhibitors of the enzyme 3-hydroxy-3-
`methylglutary1—cocnzyme A rcrluctase (HMU—CoA
`rediictase) that
`include a pyridine containing micleiis
`attached by means of a linker to an IIMG-binding domain
`sidechain, (2) pharmaceutical compositions containing such
`compounds and (3) a method of lowering blood serum
`cholesterol levels and modulating blood serum lipid levels
`employing such pharmaceutical compositions.
`BACKGROUND OF THE INVENTION
`
`US. Pat. No. 5,686,433 to Robl discloses the structure
`
`Am
`
`
`
`wherein:
`
`Arn is a binding domain sidechain;
`X is a linker;
`R‘ and R2 are the same or different and are each inde-
`pendently selected from
`(i) hydrogen,
`alkylv
`(gm) aryl.
`(H3) eyfilozlilkyl,
`V‘ ara 'y ,
`(vi) aralkoxy,
`(vii) alkenyl,
`(viii) cyeloalkenyl, and
`n(ix) heterocyclo (e.g., thienyl, benzodioxolyl);
`R" is selected from
`
`hYd"0g'-7"»
`low“ ‘ilkylv
`Q") aryl’
`(iv) cycloalkyl,
`(V) amoxy,
`(vi) aralkyl,
`(vii) aralkoxy,
`(viii) alkenyl,
`Cycloalkcnylj
`(x) halo—substitutcd alkyl,
`(xi) adamantyl, and
`(xii) lieterocyclo (e.g., tliieiiyl, lieiimdioxolyl);
`R4 is Sc]cc1c(] from
`(i) hydrogen’
`(ii) lower alkylj
`(iii) aryl,
`
`(iv) eycloalkyl,
`(v) alkoxy,
`(vi) aralkyl,
`(vii) aralkoxy,
`(viii) alkenyl,
`(ix) eycloalkenyl,
`(x) adarnantyl,
`(xi) halogen,
`(xii) halo—siihsIituted alkyl (e_g_, trifiuoromcthyl), and
`(xiii) hcterocyclo (e.g., thienyl, benzoclioxolyl); or R3
`and R" taken together can he
`
`IU
`
`I5
`
`:0‘-11:J,.,
`
`‘(I-‘Hziq
`
`EC-‘Half:
`
`01'
`
`((TH:(Tt-I)-3
`
`but when Am is
`
`R6
`
`iio—cti—c:ii3—ct—cii3—c7o3iz*3
`OH
`
`30
`
`35
`
`4U
`
`45
`
`50
`
`55
`
`6”
`
`or a 5 lactone thereof, R3 and R4 cannot be
`(CH=CH)3;
`R“ is hydroguii or lower alkyl;
`R3 is hydrogen, lower alkyl, alkali metal, or alkaline earth
`metal;
`
`11 is 0 or 1;
`p is 3, 4 or S;
`q is 0, 1, 2, or 3; and
`I’ isfl, 1, 2, or 3.
`is an HMG-binding
`In preferred embodiments (Am)
`domain sidechain having a dihydroxy or a phosphinie acid
`fiinction.
`
`The phosphinic (or phosphonic when X is CII;—O—)
`acid IIMG-binding domain sidechain (A,) is
`5
`
`Fl‘
`fi
`_
`i<”o—i'—c:ii;—:::—ciig—cog1<
`l
`l
`OH
`
`7
`
`wherein R5 and R7 are independently selected from
`hydrogen, lower alkyl, alkali metal ion and alkaline earth
`metal ion; and R6 is hydrogen or lower allcyl.
`‘
`_
`_
`_
`_
`_
`‘
`I
`The dihydroxy acid binding domain sidechain (A2 is
`
`1|<"
`_ _ _ _ _
`CH
`CH;
`CH2
`
`on
`
`HO
`
`COZRB
`
`8 ‘
`6 ‘
`'
`wherein R is hydrogen or lower alkyl, R is hydrogen or
`65 lower a|.k.yl in free acid form or 1.11 the form oi a physiologi-
`cally acceptable and Iiydrolyxable ester or 6 lactone thereof‘
`(i.e., when Am is
`
`2 BT36
`
`PENN Ex. 2093
`CFAD V. UPENN
`lPR20l5-01836
`
`
`
`US 6,627,636 B2
`
`4
`alkenyl, eycloalkenyl,
`cycloheteroalkyl,
`
`aryl, heteroaryl or
`
`R“, and R7”, and RV and R73, and RM are the same or
`dilTerent and are independently selected from H, alkyl,
`arylalkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, het-
`eroaryl or cycloheteroalkyl; or R7,, and Rh may be
`taken together with the nitrogen to which they are
`attached to form El stable 3 to 8 membered heterocyclic
`ring, which where applicable, includes :1 total of 1 to 3
`heteroatorns in the ring, which helerozttoms may be N,
`O or S; or RV and R73 may be taken together with the
`nitrogen to which they are attached to form a stable 3
`to 8 membered hcterocyclic ring which, where
`applicable, includes a total of "l
`to 3 heteroatoms in the
`ring, which heteroatoms may be N, O or S;
`R,, is II or lower alkyl;
`R9 and Rm are the same or dilIerent and are independently
`selected from I] or alkyl, or where at least one of R9 and
`Rm is alkyl, R,, and Rm may be taken together with the
`carbon or carbons to which they are attached to form a
`3 to 7 membered carbocyclic ring, which may include
`a spirocyclic ring;
`and If represents a single bond or a double bond (which
`may be eis or trans);
`and including pharmaceutically acceptable salts thereof
`where R3 is II, esters thereof, prodrug esters thereof, and all
`slereoisomers thereof.
`
`Preferably, the 2. group will be in form of a free acid, a
`physiologically acceptable and hydrolymble ester or 5 lac-
`tune thereof, or an alkali metal salt, alkaline earth metal salt
`or an amino acid salt.
`It is preferred that X is 0, S0: or NR7 where R,
`R-,,,SO3—.
`Preferretl are compounds oli formula I ol the invention
`wherein
`
`is
`
`R1 and R; are independently selected from alkyl,
`cycloalkyl and aryl;
`R4 is H, alkyl or halogen;
`X is (J; and
`n is 0.
`More preferred are compounds of formula I of the inven-
`tion wherein R1 is aryl [especially substituted aryl as defined
`hereinafter);
`R2 is alkyl or cyeloalkyl;
`R4 is H;
`R9 and Rm are H;
`X is 0;
`It is 0; and
`f is a double bond.
`Still more preferred are compounds of formula I of the
`invention wherein
`
`R, is substituted aryl, preferably 4—fluorophenyl, 4—fluoro—
`3-methylphenyl or 3,5 -dimethylphenyl;
`R2 is alkyl or cycloalkyl, preferably isopropyl, t-butyl or
`eyclopropyl;
`R4 is II;
`X is O;
`n is o;
`
`4’
`
`is a double bond, preferably "trans"; and
`
`1U
`
`I5
`
`30
`
`35
`
`4U
`
`45
`
`SU
`
`55
`
`6E]
`
`65
`
`In addition, R“ can be alkali metal ion or alkaline earth metal
`ion.
`
`is —((TH2)a—, —ClI=Cll—,
`(X)
`A suitable linker
`—C.EC , —CH30—, wherein O is linked to the phos-
`phorous atom or the aromatic anchor when Am is Al, and
`wherein () is linked to the aromatic anchor when Am is A2,
`and wherein “a” is ‘l, 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 t.'I1'.{.)'II1U 3—n1ctlIyl—glutaryl—eocnzyInc A
`reductase (HMG—CoA reduetase).
`In particular, in its broadest chemical compound aspect,
`the present invention provides compounds ol‘ the fomtula I
`
`
`
`wherein
`
`X is U, S, SE), S03 or NR7;
`Z is
`
`0
`
`OH
`
`Rs
`
`on
`
`C-02RJ
`
`or
`
`0
`
`n is 0 or 1;
`R1 and R3 are the same or different and are independently
`selected from alky], arylalkyl, cycloalkyl, alkenyl,
`cyeloalkenyl, aryl, heteroaryl or eyeloheteroalkyl;
`R3 is II, or lower alkyl or a metal ion {such as an alkali
`metal or an alkaline earth metal);
`R,, is H, halogen, CF3, hydroxy, alkyl, alkoxy, earboxyl,
`carboxylalkyl—, aniinoalkyl, amino, alkanoylaniino,
`aroylamino, cyano, alkoxy(f(]N(R,(,}-, R7,R7RN(f()—,
`R,J,R,HNCO;—, R,,.SO_._N(R_7,_,)—, R,IR7,,NSO2N(R,,_,)—,
`R—,,.()CO;._— or R-,E.OCO—;
`is II, alkyl, aryl, alkanoyl, aroyl, alkoxycarbonyl,
`R.,“S():,_—, R.,.,,ll,‘.NS()2— or R,bR,rN(?()—;
`R7,, and R7,, are the same or different and are indepen-
`dently selected from alkyl, arylalkyl, eycloalkyl,
`
`R,
`
`30f36
`
`PENN EX. 2098
`
`CFAD V. UPENN
`lPR20l5-01836
`
`
`
`US 6,627,636 B2
`
`6
`reducing the risk of undergoing myocardial revasculariza—
`tion procedures, or preventing or treating mierovaseular
`diseases such as nephropatliy, neuropathy, retitiopathy atid
`nephrotic syndrome or preventing or treating hypertension
`in a patient in need of such treatment by administering a
`phaririaceutical composition in accordance with the present
`itivetitioti as defined above.
`
`5
`
`Of alkaline Ciiflh ITlCl3.l
`0]’ an
`31111110 110111 3311-
`M051 pI01UIIO(1 C01Tlp01|l'l(1S 0110ITflU1fl 1 011110 1DV'CDli0H 111
`will have the structure
`
`thereof or an
`
`R5
`
`In addition, in accordance with the present invention, a
`rncthgd
`provided for prgvgnting gr trgating diabgtgg’
`especially Type 2 diabetes, and related diseases such as
`insulin resistance, hypcrglycciiiia,
`liyperinsuliiictiiia,
`elevated blood levels of fatty acids or glycerol, obesity,
`Syndrome X, diabetic complications, dysmetabolic
`syndrome, and related diseases, and sexual dysfunction,
`wherein a tlicrapeutically eticctive atiiouiit of a compound of
`15 structure [ 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—
`tlielial
`iicoplasia (PIN), gastrointestinal
`tiialigiiciicies,
`liposarcomas and various other epithelial tumors (including
`breast, prostate, colon, ovarian, gastric and lung), cancer-
`indueed asthenia (fatigue),
`irritable bowel syndrome,
`35 (frohn’s disease, gastric ulceritis, and gallstones, and lllV
`infection, other
`infectious diseases, drug-induced
`lipgdystrophy’ and prolifgrativc diggascs sugh a5 psoriasis’
`Still
`OI’ 3ll\'.'iliI'l6 earth ITlt'.-T..'1l (SLlCl'l as Na, K [IF
`or an
`wherein a therapeutically effective amount of a compound of
`11117117111} 01 311 311111111 *1‘-'1‘-1 55111 (511911 315 31t=’.111111")= 11111131131" Rs
`slructitre I
`is administered to a human patient
`in need of
`111111 Re: (110 1110 53-1110 01 111111310111 111101 111C10l1011d01111Y 501001130
`from II, halogen andfor alkyl (preferably 4-lluoro, 4-iluoro- so treatment‘
`3'“"°111Y1 01 3»5'111'1"10111Y1l; 111111
`In addition, in accordance with the present invention, a
`R: 15 3111311 111 13113101111"-Y1: 11115113111111)? 1-°*11i1111l1Y1a 1-11111311 111
`method is provided for improving, coagulation homeostasis
`t—‘)’€-‘10PIOP}'1-
`including reducing PA]-1 activity, reducing fibrinogen, and}
`In another aspect, the present invention provides pliarma-
`or rcductng plat;-,]ct aggregation, rmdgor improving ¢ndorh¢_
`01‘-11110111 00111005111011-‘3, 11501111 ‘<15 11}’D011D100I1110 01 11311300110‘ 35 lial function, wherein a therapeutically etfeetive amount of
`lesterolemic agents. or hypelriglycenclemic agents. or anli-
`acompound of structure I is administered to apatient in need
`Alzheimer's agents, or anti—osteoporosis agents as well as
`of U-c3tm;;m_
`other uses as described herein, comprising a hypolipidcmic
`In addition, in accordance with the present invention, a
`or hypoeholesterolernic or hypetriglyceridelnie or anli-
`method is provided for treating cholesterol related diseases,
`11111110111101“ 11150350 01' 31111'0-51000010313 3111011111: 01 011101 411 diabetes and related diseases, cardiovascular diseases, cere-
`1h0I'r'lPOU11Cc'l11Y 01f0C11V'0 c'|Y1'101|1’11 (depending UPOU 1150) 013
`brovascular diseases as defined above and hereinafter and
`compound Of formula l in accordance
`illlS l[]VCflll0fl, in
`other digcascg 35 gct out alxyvc, wherein a therapeutically
`‘31111111111a111111 W1111 3 l111"11111a"'31111C5111Y ELCCCP11111111 '311111C1-
`elIective amount of a coiiibiiiatioii of a compound of struc-
`In another aspect, the present invention provides a method
`mm ] and 3 hypgtjpjdemtc agent, andgrtr ttptd rngdulating
`inhibiting cholesterol biosynthesis or ltiwering blood 45 agent andfor ar1tidia[)ctic agent andgor cardiovascular agar-rt,
`oi‘
`SCF1-lm C1101CS1Cl'01 1CVC15 EIFICHOF modulating 1110001 901"-1111
`cerebrovascular agent, andfor other
`type of therapeutic
`cholesterol levels such as lowering IDI. cholesterol andfor
`agent, ti; adminjstcrgd to a pattcm in nccrt 0f tr¢arm¢nt_
`11113113151118 1'1D1— 13110105113101: 0111133111118 C1y311D1dC1111a» 111111011
`In the above methods of the invention wherein a combi-
`dyslipidcmia. hypcrlipidcmia. hypcrcholcstcrolcmia. hypo
`nation is administered, the oompourid of structure I will be
`11'11t10P10117111011"1'r1a 1131- 1'1i11“=111 11: 11111 P1111111“ /1: 1131101‘
`511 employed in a weight ratio to the other therapeutic agent
`11I10P1‘11"311'131'1113 01 11Yl1131111g1)"5111'111171111i1a 111111 1111101 11110113‘
`(depending upon its mode of operation] within the range
`lions of apolipoprotein B metabolism, or reducing levels of
`from about u.oi:i
`to about 5ou:i, preferably from about
`l.p(a), or treating or preventing other cholesterol-related
`(]_5;1to about 100;},
`diseases,
`treating or preventing or reversing progressio’n
`DL,:[,AILED [)ESCRIP,l,I0N OF “IE
`of atherosclerosis, or preventing or treating Alzheimer s 55
`INVENTION
`disease, or preventing or
`treating osteoporosis andfor
`111 31313011131100 ‘V1111 11115 111050111 11110311111111: 111010 15 P111‘
`osteopenia, or
`reducing inflammatory markers such as
`\t"i(.lC(.l
`t.Zt.l|'I‘It'J()lll'l(l‘~‘a useful ll‘!
`T.l']6 fll']ZyITI6 llM(i-
`("_rca;3tivc -pr()tc[r1, or preventing or
`treating low grade
`C0/1 101111011150» W1111311 1111111111015 511° 1151131111 35 11Yl111"11111C-‘9'
`vascular inflammation, or preventing or treating stroke, or
`preventing or treating dementia, or preventing and treating on lemlernic agents, dyslipidemic agents, hypolipidemic
`cnrnnnry heart rligcagc (jnclttding primary and gconnrlary
`ilgCI']L*§, hypotriglyceridemic 2igG1']TS, anti-/\l;r.heimer’s Lil};-
`prevention of myocardial infarction), or preventing or treat-
`0350 32,0015. 3-1111 3I1110S100P0I'0S1S 39,0015 «'15 W011 35 011101’ 1-1505
`ing stable and unstable angina, or primary prevention of
`H5 1105011111511 11010111-
`coronary events, or secondary prevention of cardiovascular
`The term “coronary events" as employed herein refers to
`events, or preventing ortreatingperipheral vascular disease, 65 myocardial
`infarction, myocardial
`revascularization
`preventing or treating peripheral arterial disease, or prevent-
`procedures, angina, cardiovascular death and acute coronary
`ing or treating acute vascular syndromes, or preventing or
`syndrome.
`
`
`
`311
`
`4 0136
`
`PENN EX. 2093
`CFAD V. UPENN
`lPR20l5-01836
`
`
`
`US 6,627,636 B2
`
`15
`
`8
`7
`The terms pharmaeeutically acceptable “salt” and "salts”
`The term "cardiovascular diseases or events” as employed
`herein refers to atherosclerosis of the coronary arteries,
`refer to basic salts formed with inorganic and organic bases.
`Such salts include ammonium salts; alkali metal salts, such
`myocardial infarction, including primary MI and secondary
`MI,
`recurrent myocardial
`infarction, angina peetoris
`as lithium, sodium and potassium salts (which are
`5 preferred], alkaline earth metal salts, such as calcium and
`(including “able and Unstable angina): Congemve hear‘
`magnesium salts; salts with organic bases, such as amine
`fall‘-‘ms and Sudden Cardiac d‘7‘1lh-
`like Sang,
`(c_g_, djcycjghcxylamjm-, Salt’ bcnzathtnc’
`The term "cerebrovasciilar diseases or events" as
`N—nietliyl—D—glucainiiie, and hydrabainine salts); and salts
`employed h0I0il'1 IUIUIFS 10 Ocrfibfal
`illfflft-'li0l'l Ur SIFORC
`with amino acids like arginine.
`lysine and the like; and
`[caused by vessel blockage or hcmmoragc), or transient
`ischemia attack (TIA), syncope, atherosclerosis of the 1” zwitterions, the so—ealled “inner salts”. Nontoxic, pharma-
`i1'lTIr'lCI<'|1'1ir'l1 i1l'ld»"0f Cxlfiicfillliiil ilflcflcs, and 1l'l<—' 1ik<—'-
`ceutieally acceptable salts are preferred, although other salts
`The term “cholesterol-related diseases” as employed
`are also useful, eg.. in isolating or purifying the product.
`,,
`herein refers to diseases involving elevated levels of LDL
`.l.h
`.
`H
`1 __
`,,
`..
`salt
`_
`._
`_
`_
`.
`.
`.
`_
`e term pharmaeeutically acccptablc
`and salts
`cholesterol, diseases involving regulation of LDL receptors,
`alm include; acid addition ‘am The“ am formed for
`diseases involving reduced levels of lll)I. cholesterol,
`'5 méam 10 with gm“ mm am; aéiag ‘Mich ac1mincrala’cid5
`dysllpldcmla’
`llypclllpldcmla’ clcvalcd l'Dl' Panel" B’
`for eiilairiple stilfurif acidg phosphoric acid or a hvdrohalic
`clcvalcd LDL Pallcm A‘
`llypclcllolcslerolemla’ hypo
`acid such asillfll or llBi with strong organic carboxvlic
`tit-lipoproteinemia (low lllJ[. cholesterol syndrome),
`.
`'
`l
`'
`’
`.
`I
`'
`.
`.
`.
`acids, such as alkanecarboxylic acids of 1 to 4 carbon atoms
`llypcrllpopmlclncmla’ Clcvalcd l'p(a)
`levels’
`which are unsubstituted or substituted for exam le b
`y
`hypertriglyceridcmia, other aberrations of apolipoprotein B 3“ h
`.
`‘
`‘
`x .
`‘
`I
`1’
`p ’
`.
`.
`.
`.
`alogen,
`tor example aCL-ltC acid, such as saturated or
`.
`mclabollsm’ llclcrozygous famlllal’ pres" mcd lamlllal com‘
`unsaturated dicarboxylic acids for example oxalic malonic
`hllwll and lmmllamlllal (ml-l'l:ll) lllrl-ml (ill plll-mlry l-lyllclC'
`succinic maleic fumaric phthialic or terephthalic acid sucli
`holcsterolemia [including Fredcrickson Types Ila and lib),
`‘as hydrolxycarbcixyhc acilds for cxqmplc ascorbic glygolic
`’
`cholesterol ester storage disease, and cholesterol ester trans—
`I
`_
`._
`,
`._
`,
`_
`._
`.
`.’_ _.
`‘,
`,
`,
`,
`,
`.
`f _.
`_
`.
`.
`.
`.1 1
`_
`1
`.1 1
`_
`_
`actic, malic, tartaric or citric acid, such as amino acids, (for
`lal pmlslll dlsedsc’ and leldlcd dl'i’tl‘l‘ill-T‘
`example aspartic or glutamic acid or lysine or arginine) or
`The conditions, diseases, and maladies collectively refer-
`bcnm,-C. acid‘ or wilh Organic Sulftfilic aL.idS1 Such’ as
`mccd l0 as “syndrome X” or Dysmclabolic Syndrome (a5
`(C1-C4) alkyl or arylsulfonic acids which are unsubstituted
`detailed in Johanson,J. Cliri. Eridocrimitl. Met(ib., 1997, 82,
`m 5uh5muwd1 for cxamplc by halogw’ for example m,,1lh_
`727-734, and other publications) include hyperglycemia m ,mC5uu-Um-C acid 0,. p_w1u,mC5un-onic acid
`andfor prediabetic insulin resistance syndrome, and is char— '
`_
`_
`_
`‘Wm “lower all‘-Ylli»
`acterized by an initial
`insulin resistant state generating
`U91‘-'55 Olhcfwfic lndlcalcds lh’-3
`hyperinsulincmia, dyslipidemia, and impaired glucose
`''3lk}'l” 0'' "3lk1" 35 3mPl0}'Cd h“'1“"i“ 3l'3‘1"‘7 '3“ 315 P31“ ‘ff
`10151-,mc,_~,1 whim can pl-Ogrcss to fypc [1 (|1'ab¢1c51 chat-ac-
`another group includes both straight and branched chain
`Ierized by hyperglycemia, which can progress to diabetic
`hydrocarbons. containing 1 to 20 carbons. preferably 1 to 1U
`mmp1iCati0n51
`35 carbons, more preferably '1 to 8 carbons, in the normal chain,
`The term "diabetes and related diseases" refers to Type I]
`such 35 mcthyl’ clllylf pmpyl’
`lsopmpyl’
`ljmyl’ Hnflyl’
`diabetes, Type I diabetes,
`impaired glucose tolerance,
`lmhmyl’ pcmyl’_hcxyl’ lsohcxyl’ hcptyl’ 4’4'dlmcth3llpcmyl’
`obesity,
`liyperglyceinia, Syndrome X, dysmetaholic
`llClyl' 2’2’4'”lmelhyl'pcmyl’ Flo," yl’
`flecyl’
`llmlccyl’
`syndrome, diabetic complications and hyperinsulinemia.
`40 Cl°d°_C1yl’ th°1 l’1la1r"3uS l’ranC1h,°d1°ha,m lsomcnl’ th‘1”',°°f’ ar_1d_ the
`The conditions, diseases and maladies collectively
`lll1“:_'l“’ wiill lli'_lllll('ll glljuljmiltludlng
`in 4 Sllbsllillcniii ifuch
`referred to as “diabetic complications” include retinopathy,
`‘lb l-llllll’ lm Bxdmplfi llblir’ ('l 0r I or ('ll3’ alkyl’ dlimxy’ dryl’
`neuropathy and nephropathy, and other known eomplica—
`alyl°x:{’_a.ryl(alyP °1lk‘lll"'lfi;l‘;llylalkyl‘1:ly1la1llElT°xy‘ alkcllyl’
`or
`:§::?.:;‘*i-,;2:;:::t,2a:2; ::::;':.:;.:::at3;r".2';.;:?:;:;;i
`emnlldi d(lirtrili:reii)1lEi:=fcrls}‘iJoc(rist)1eUelr
`irliciifdlihtnliidialiltiiidjlzii ed: 45 hclcmaryloxy’ hcmmarylalkyl’ hctcmarylalkoxy’
`p y _
`_
`'1
`,
`._
`aryloxyalkyl, alkylthio, arylalkylthio, aryloxyaryl,
`lolllel ll-ldll
`l'0mPol'll-l(l'i’ of llolmllld l)’ on or more ‘ll-lll
`alkylamido alkanovlamino arylcarbonylamino nitro
`obesity agents, andfor one or more lipid-lowering agents,
`C mo lhioll halOa]_k'1 Irihaléam 1 andmr alk hhiol
`one or more lipid modulating agents (including anti-
`y
`'
`'
`y '
`y
`y
`l
`atherosclerosis agents), other types of anti—atherosclerosis 50
`Unless otherwise indicated,
`the term “cycloalkylll as
`agents, andlor one or more antiplatelet agents, one or more
`employed herein alone or as part of another group includes
`agents for treating hypertension, one or more anti-eaneer
`saturated or partially unsaturated (containing 1 or 2 double
`drugs, one or more agents for treating arthritis, one or more
`bonds) cyclic hydrocarbon groups containing 1
`to 3 rings,
`anti—osteoporosis agents, one or more anti—obesity agents,
`including nionocyclic alkyl, bicyclic alkyl (or bicycloall<.yl)
`one ormon: agents for treatingimmunommlulatory diseases, 55 and tricyclic alkyl, containing a total of 3 to EU carbons
`andfor one or more agents for treating anorexia nervosa.
`forming the ring, preferably 3 to '10 carbons, forming the
`Thc [gym --1[pjd_modu1a1{ng” agcm 35 cmp].;~_.ycd hm-cjn
`ring and which may be fused to l or 2 aromatic rings as
`refers to agents which lower I.[)[. andfor raise I[|)I. andfor
`dc-‘it-'Tlh*3d rm “Yb ‘Vhich lncludas CYCl'5‘PmP)’la Wclflbulyla
`lower triglycerides andfor lower total cholesterol andfor
`C}'Cl0PC"‘}'l= Cyclflhcxylv Cyclahclllyla cyclrmctyl. CyCl0d*3'
`other known mechanisms for therapeutically treating lipid 5::
`“Y1 and ‘3)"310‘l0‘l°‘3Yl- ‘3Y‘5l°h°x°'“Yl:
`disorders.
`
`’
`
`The term “other types of anti-atherosclerosis agents” as
`employed herein refers to conventional anti—athereselerosis
`agents including lipoxygenase inhibitors, AC/\'I' inhibitors,
`antioxidants, PPAR 5 agonists, phospholipase inhibitors 65
`including l’LA—2 inhibitors andtor other known anti-
`atherosclerotic agents.
`
`3
`
`\
`
`'
`
`5 "T36
`
`PENN EX. 2098
`CFAD V. UPENN
`lPR20l5-01836
`
`
`
`US 6,627,636 B2
`
`10
`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 C173, 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.
`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
`l-naphlhyl and 2-naphthyl) and may optionally include one
`to three additional rings fused to a carbocyclic ring or a
`heterocyclic ring (such as aryl, cycloalkyl, heteroaryl or
`cycloheteroalkyl rings for example
`
`o=<I}s <B
`
`~ ~<\Nl / “xi /
`DO Z1/J)
`NX /
`0
`0 XI
`
`0
`\\
`
`N
`
`/
`X
`
`0
`
`\\
`
`/
`
`N
`
`\\
`
`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,
`trilluoromethyl,
`trifluoromethoxy,
`alkynyl, cycloalkylalkyl, cycloheteroalkyl,
`cycloheteroalkylalkyl, aryl, heteroaryl. arylalkyl, aryloxy,
`aryloxyalkyl, arylalkoxy, arylthio, arylaro, heteroarylalkyl,
`heteroarylalkenyl, heteroarylhetcroaryl, heteroaryloxy,
`hydroxy, nitro, eyano, amino, substituted amino wherein the
`amino includes 1 or 2 substituents (which are alkyl,
`alkanoyl, 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, arylearbonylamino, arylsulfinyl,
`arylsuliinylalkyl, 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 substituents, which
`may he the same or di|Terent, such as alkyl, aryl, arylalkyl,
`heteroaryl, hcteroarylalkyl, cyeloheteroalkyl,
`cyeloheteroalkylalkyl, eycloalkyl, eycloalkylalkyl,
`halnalkyl. hydroxyalkyl, alkoxyalkyl or thioalkyl. These
`
`6uf36
`
`PENN EX. 2098
`
`CFAD V. UPENN
`lPR20l5-01836
`
` N
`
`N
`
`\\
`
`\\
`
`9
`—continued
`
`any of which groups may be optionally substituted with 1 to
`4 substituents such
`halogen, alkyl, alkoxy, hydroxy, aryl,
`aryloxy, arylalkyl, cycloalkyl, alkylamido, alkanoylamino,
`oxo, aeyl, arylcarbonylamino, heteroaryl, cycloheteroalkyl,
`amino, alkylamino. nitro, cyano, thiol andfor alkyllhio and!
`or any of the substituents for alkyl,
`The term "cyeloalkenyl” as employed herein alone or as
`part of another group refers to cyclic hydrocarbons contain-
`ing 3 to 12 carbons, preferably 5 to H} carbons and l or 2
`double bonds. Exemplary eyeloalkenyl groups include
`cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl,
`cyclohexadienyl, and cyclohcptadicnyl, which may be
`optionally substituted as defined 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 alkcnyl" 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 "l
`to 8 carbons in the normal chain, which include one to six
`double bonds in the normal chain, such as vinyl, 2—propcnyl,
`3-butenyl, 2-butenyl, 4-pentenyl, 3-pentenyl, 2-hexenyl,
`3-hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 3-octenyl,
`3-nonenyl, 4-decenyl, 3-undecenyl, 4-dodecenyl, 4,8,12-
`tetradccatrienyl. and the like, and which may be optionally
`substituted with 1
`to 4 substiluenls, 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 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—heptyny1, 3—heptynyl. 4—heptynyl, 3—octynyl, 3—nonynyl,
`'1—decynyl,3—undecynyl, 4—dodecynyl and the like, and which
`may be optionally substituted with I
`to 4 substituents,
`namely, halogen, haloalkyl, alkyl, alkoxy, alkenyl, alkynyl,
`aryl, arylalkyl, eycloalkyl, amino, hcteroaryl,
`cyclolieteroalkyl, hydroxy, alkanuylamino, alkylamido,
`arylcarbonylamino, nitro, cyano,
`thiol, andfor alkylthio,
`and/or any of the alkyl substituents set out herein.
`Tlie 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 differe nt carbon atoms,
`they are termed “alkylene” groups and may optionally be
`substituted with "l or 2 substitucnts as defined above for
`
`"alkyl”, such as, for example, alkyl, halo, hydroxy, alkoxy
`andfor cyc|oalkyl_
`Where alkcnyl 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 with 1 or 2 substituents as
`defined above for "alkenyl" and “alkynyl”.
`
`5
`
`1U
`
`I5
`
`-
`
`30
`
`35
`
`4U
`
`45
`
`SU
`
`55
`
`oil
`
`65
`
`
`
`US 6,627,636 B2
`
`11
`substituents may be further substituted with a carboxylic
`acid andfor any of the substituents for alkyl as set out above.
`In addition, the amino substituents may be taken together
`with the nitrogen atom to which they are attached to form
`l—pyrrolidinyl. 1—piperidinyl,
`l—a2epinyl, 4—morpholinyl,
`4-thiarnorpholinyl,
`l-piperazinyl, 4-alkyl-1-piperazinyl,
`4-arylalkyl-1-piperazinyl, 4-diarylalkyl-1-piperazinyl,
`1—pyrrc-lidinyl, 'l—piperidinyl, or 1—azepinyl, optionally sub-
`stituted with alkyl, alkoxy. alkylthio, halo, trifluoromethyl or
`hydroxy.
`Unless otherwise indicated, the term “lower alkylthio",
`“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 "aeyl” as employed
`herein by itself or part of another group, as defined herein,
`refers to an organic radical linked to a carbonyl
`
`(ti)
`
`group; examples of acyl groups include any of the R‘ groups
`attached to a carbonyl, such as alkanoyl, alkenoyl, aroyl.
`aralkanoyl, heteroaroyl, cycloalkanoyl, eyeloheteroalkanoyl
`and the like.
`Unless otherwise indicated, the term “eyel-oheteroalkyl"
`as used herein alone or as part of another group refers to a
`5-, 6- or 7—mcnibered saturated or partially unsaturated ring
`which includes 1 to 2 hetero atoms such as nitrogen, oxygen
`andfor sulfur, linked through a carbon atom or a hctcroatom,
`where possible, optionally via the linker (CII2)r [where r is
`l, 2 or 3), such as
`
`O_
`
`and the like. The above groups may include 1 lo 4 substitu-
`ents such as alkyl, halo, oxo andfor any of of the alkyl
`substituents set out herein. in addition, any of the cyclohet-
`eroalkyl rings can be fused to a cycloalkyl, aryl, heteroaryl
`or eyeloheteroalkyl 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
`
`12
`fused to an aryl, cycloalkyl, heteroaryl or cycloheteroalkyl
`ring (e.g. benmthiophenyl, indolyl), and includes possible
`N-oxides. The heteroaryl group may optionally include I
`to
`4 substituents such as any of the substituents set out above
`for alkyl. Examples of heteroaryl groups include the fol-
`lowing:
`
`\N?—’
`
`\O?—t
`
`: :—’
`
`fa ti} <‘’ :+
`
`,.
`
`.,
`
`._ A
`
`and the like.
`
`The term "cyeloheteroalkylal.kyl” as used herein alone or
`as part of another gorup refers to cycloheteroalkyl groups as
`defined above linked through a C atom or heteroatom to a
`(CH2), chain.
`The term “heteroarylalkyl"‘ or “heteroarylalkenyl” as used
`herein alone or as part of another group refers to a heteroaryl
`group as defined above linked through a C atom or heteroa—
`tom to a —(CIl3),—chain, alkylene or alkcnylene as defined
`above.
`The term “polyhaloalkyl"’ as used herein refers to an
`“alkyl” group as defined above which includes from 2 to 9,
`prefe