(12; United States Patent
`ltohl
`
`(10) Patent N0.:
`
`(45) Date of Patent:
`
`US 6,620,821 B2
`Sep. 16, 2003
`
`US[)(]662[)821B2
`
`(54) HMG-C0/\ RICl)UCT/\SlC INHIBITORS AND
`METHOD
`
`(5 7)
`
`ABSTRACI"
`
`(75)
`
`Inventor:
`
`.Iefl‘rey A. Robl, Newtown, PA (US)
`
`(73) Assignee: Bristol-Myers Squibb Company,
`Princeton, NJ (US)
`
`[ "‘ ) Notice:
`
`Subject lo any disclairner, lhe term of this
`patent is extended or adjusted under 35
`USC. 154(b) by 0 days.
`
`(21) App]. No.: l0f0l]8,l54
`
`(22) Filed:
`
`Dec. 4, 2001
`
`(65)
`
`Prior Publication Data
`
`US 2[J[]2,.'l'lII6l9I]l Al Mai}-' 23, 2002
`
`Related U.S. Application Data
`
`[(53)
`
`[(30)
`
`(?onlinuation—in—parl of application No. (19,-'875_,2l8_, filed on
`Jun. 6, 2UU1_. now abandoned.
`Provisional application No. 60,.-"21|,.'394, filed on Jun.
`ZUUU.
`
`[5,
`
`[5l)
`
`Int. CL?
`
`(52) U.S. Cl.
`
`(58) Field Of Search
`
`_/\6'lK 31,3435; /\6lK 31,3473;
`COTD 221,"'06; C071) 405306; A6'lP 3,506
`514-,u"29l]; 546393; 546K101;
`546K111
`546,393, 101, 111;
`514;"29U
`
`(56)
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`3r'lCJ00 Chaeholowski. cl 221.
`4_.906_.624 A
`5,r'1‘J9U Keeseler el :1[.
`4,925,852 A
`4x'1‘J‘J1 Angerbauer el al.
`5_.UU6_.53U A
`l2x'1‘J02 Angerbauer el al.
`5,169.85? A
`l,.I'1‘J93 Angerhauer et al.
`fi_,1??,[J8(J A
`11,519‘)? Rohl
`5_,o8E'1,433 A
`FORILIGN l’Pil‘IiN'I' DO(.‘UML£N'l‘S
`
`IE1‘
`I-‘II’
`EP
`I-El‘
`
`[]3ll6‘J2‘J A2
`f]3EI?'3r-I2 A2
`U32'.f12‘J A2
`[B25130 A2
`
`3,r'1‘.JS‘.J
`3,-‘1‘.J8‘.J
`7.-"I989
`7,-"l‘.J8‘.J
`
`()'I'IIl_-lR PUIl[.[(I/\'l'IUNS
`
`Rohl et al, J. Med. Chem, 34, 2804—28I5, I991.
`
`I’J‘imm}‘ E.\'rmIiner—l_ivelyn Mei Iluang
`(74) Arrorrre}-3, Agent, or Fim1—I!urton Rodney
`
`Compounds of the following structure are IIMU Co/\ reduc-
`tase inhibitors and thus are active in inhibiting cholesterol
`biosynlhcsis, modulating blood serum lipids, for example,
`lowering l.|)I. cholesterol andfor
`increasing I[l)I.
`cholesterol, and treating hyperlipidemia, dyslipidemia, hor-
`nlunc replaeemcnl tllcrupy, hypcrcholestcrolemia, hyperlrig—
`lycerideniia and atherosclerosis as well as Alzheimer‘s dis-
`ease and osteoporosis
`
`
`
`Una,
`
`(CH3),
`
`'''''~-~--.
`
`\
`
`>< R:
`
`and pharmaceulically acceptable salts thereof,
`
`no
`
`7. is
`
`:1,
`
`.ruvu'~
`
`01]
`
`OOER3
`
`or
`
`0
`
`on;
`
`I1 is 0 or 1;
`x is0, 1,2,3 or4;
`y is U, 1, 2, 3 or 4, provided that at least one of x and y
`is other than 0; and optionally one or more carbons of
`(CH3), andfor (CH3), together wilh additional carbons
`form a 3 to 7 me-mbe-red spiroeyelie ring;
`R1 and R3 arc the smile or r.lilIcrcnl and are independently
`selected from alkyl, arylalkyl, cyclozllkyl, alkenyl,
`eyeloalkenyl, aryl, heteroaryl or cyeloheteroalkyl;
`R3 is H or lower alkyl;
`R, and R7 are as defined herein.
`
`18 Clailns, No Drawings
`
`1of38
`
`PENN EX. 2097
`
`CFAD V. UPENN
`lPR20l5-01836
`
`

`

`US 6,620,821 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. 093875218 filed Jun. 6, 200], abandoned
`which application claims priority lironi U.S. provisional
`application No. 6[l;?.ll,594, illed Jun. 15, 2000.
`
`FIELD OF Till} [N VLiN'l‘ION
`
`Tlie preseiit invent ioii relates to ooiiipouiids and pharma-
`ceutical compositions useful as hypocholesterolcmic and
`hypolipidernic agents. More particularly, this invention con-
`cerns ('1) certain inhibitors of the enzyme 3-hydroxy-3-
`methylglutary1—cocnzyme A rcductase (HMU—CoA
`rediictase) that
`include a pyridine containing nucleus
`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 lipids
`employing such pharmaceutical compositions.
`BACKGROUND OF THE INVENTION
`
`US. Pat. No. 5,686,433 to Rohl cliscloscs the structiirct
`
`
`
`(iv) cycloalkyl,
`(v) alkoxy,
`(vi) aralkyl,
`(vii) aralkoxy,
`(viii) alkenyl,
`(ix) cycloalkenyl,
`(x) adariiantyl,
`(xi) halogen,
`(xii) halo—siihsIituted alkyl (e_g_, trifiuoromcthyl), and
`(xiii) heterocyclo (e.g., thienyl, benzodioxolyl);
`or R3 and R" taken together can he:
`
`IU
`
`I5
`
`*(.{3H2Jp.-“((3H3)q
`
`WHJX‘
`
`or
`
`[C[I:C-mg:
`
`but when Am is:
`
`R6
`
`15
`
`tiU—(;ii—L:tig—(i—L:ttg—L:og1(“
`OH
`
`m or a 6 lactone thereof, R3 and R4 cannot be (CII=C[I)2;
`R“ is hydrogen or lower alkyl;
`R3 is hydrogen, lower alkyl, alkali metal, or alkaline earth
`metal;
`
`wherein:
`
`Arn is a binding domain sidechain;
`X is a linker;
`
`35
`
`n is 0 or 1;
`P l-5 3: 4 0|‘ 5;
`
`q is U, 1, 3, 01' 3; and
`I’ is 0, 1, 2, or 3.
`
`R‘ and R2 are the same or different and are each inde- 40
`pendently selected from:
`(i) hydrogen,
`(11) alkylv
`(iii) aryl.
`(kg) eyfilozlilkyl,
`v ara 'y ,
`(vi) aralkoxy,
`(vii) alkenyl,
`(viii) cycloalkenyl, and
`n(ix) heterocyclo (e.g., thienyl, benzotlioxolyl);
`R" is selected from:
`
`45
`
`50
`
`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
`
`T
`(F
`R-‘o:i'—c:iig—C—r;ng—cogi<7
`Li)“
`
`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 alkyl.
`‘
`_
`_
`_
`_
`_
`‘
`I
`The dihydroxy acid binding domain sidechain (A2 is:
`
`R“
`Ho—cH—CH —rl:—CH —CO R3
`'
`2
`I
`'
`2
`'
`1
`()[-1
`
`hYd"0g'-7"»
`low“ ‘ilkylv
`(111) aryl’
`(iv) cycloalkyl,
`(V) amoxy,
`(vi) aralkyl,
`(vii) aralkoxy,
`(viii) amcnyl’
`(ix) cycloalkenyl,
`(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,
`
`55
`
`6;;
`
`8 ‘
`6 ‘
`'
`wherein R is hydrogen or lower alkyl, R is hydrogen or
`65 lower alkyl in free acid form or m the form oi a physiologi-
`cally acceptable and Iiydrolyzahle ester or Ft lactone thereof‘
`(i.e., when Am is:
`
`2 BT33
`
`PENN EX. 2097
`CFAD V. UPENN
`lPR20l5-01836
`
`

`

`US 6,620,821 B2
`
`OII
`
`‘1-LL
`
`0
`
`o
`
`In addition, R3 can be alkali metal ion or alkaline earth metal
`ion.
`
`is —((fI[2)a—, —CII=(fII—,
`(X)
`A suitable linker
`—(‘EC—, —(TH2(J—, wherein () 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 '1, 2, or 3.
`BRIEF DILSCRIPTION OI’ 'I'IIL-l INVENTION
`
`In accordance with the present invention, there are pro-
`vided certain p yridi[1c—coutait1iug, compounds that are potent
`inhibitors of cholesterol biosynthesis by virtue of their
`ability to inhibit the enzyme 3-methyl-glutaryl-coenzyme A
`reductase (I IMO-CoA reductase).
`In particular, in its broadest chemical compound aspect,
`the present invention provides compounds of the formula I:
`
`
`
`wherein
`Zis
`
`HO
`
`R7
`
`.n.rvv'
`
`OH
`
`0033-‘
`
`or
`
`0
`
`on;
`R_F
`
`0
`
`\I\I\f\I‘
`
`n is U or 1;
`xisU,1,2,3or4;
`y is 0, '1, 2, 3 or 4, provided that at least one of x and y
`is other then o;
`and optionally one or more carbons of (CH2), anclfor
`[CIl:),. may form part ofa 3 to 7 membered spirocyclie
`ring;
`R1 and R3 are the same or diifercnt and are independently
`selected from alkyl, arylalkyl, cycloalkyl, alkenyl,
`cycloalkenyl, aryl, heteroaryl or cycloheteroalkyl;
`R3 is H or lower alkyl;
`R4 is H, halogen, (TF3, hydroxy, alkyl, alkoxy, earboxyl,
`carboxylalkyl-, aminoalkyl, amino, alkanoylamirto,
`
`rm
`
`1U
`
`I5
`
`EU
`
`4
`aroylamino, cyano, alkoxyCON(R,o)—,
`RIIRIZNCOT’ R11.R12NC02T' R13S02N(Rl0)T!
`R,,RuNSO:N[R,,,)—, R,_.4OC02— or R,_40CO—;
`R13 is alkyl, arylalkyl, eycloalkyl, alkenyl, Cycloallcenyl,
`aryl, heteroaryl or cyclolleteroalkyl,
`R4, and R42, and Rm are the same or different and are
`independently selected from II, alkyl, arylalkyl,
`cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl or
`cycloheteroalkyl; or R” and RR 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 oil to 3 heteroatoms in the
`ring, which heteroatoms may be N, O or S;
`R, is H or lower alkyl; and
`
`3/
`
`represents a single bond or a double bond (which may be cis
`or trans);
`and including pharmaceutically acceptable salts thereof
`when R3 is H, esters thereof, prodrug esters thereof, and
`all stereoisomers thereof.
`Preferably, the 2. group will be in form of a free acid, a
`physiologically acceptable and hydrolyzable ester or E: lac-
`tone thereof, or an alkali metal salt, alkaline earth metal salt
`or an amino acid salt.
`
`Preferred are compounds of formula I of the invention
`wherein
`
`30
`
`R, and R2 are independently selected from alkyl,
`cycloalkyl and aryl;
`R4 is II, alkyl, or halogen;
`x is 2 or 3;
`y is o; and
`It is o.
`
`More preferred are compounds of formula I of the inven-
`tion wherein R, is aryl (especially substituted aryl as defined
`hereinafter);
`R2 is alkyl or cyeloalkyl;
`R4 is II;
`x is 3;
`y is o;
`11 is o; and
`
`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—methylphcnyl or 3,5—dimethylphenyl;
`R2 is alkyl or cycloalkyl, preferably isopropyl, t—butyl or
`cyclopropyl;
`R4 is II;
`x is 3;
`y is o;
`It is o;
`
`35
`
`4U
`
`5U
`
`55
`
`(SE!
`
`is a double bond, preferably “trans”; and
`
`3uf38
`
`PENN EX. 2097
`
`CFAD V. UPENN
`lPR20l5-01836
`
`

`

`US 6,620,821 B2
`
`6
`preventing, or treating peripheral arterial disease, or prevent-
`ing or treating acute vascular syndromes, or preventing or
`reducing the risk of undergoing myocardial revasculariza-
`lion procedures, or preventing or treating microvascular
`5 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 delined above.
`
`m
`
`\,.()H;
`
`0
`
`Jvuv
`
`
`
`or an alkali metal salt thereof, alkaline earth metal salt or an
`amino acid gall‘
`Most preferred compounds of formula I of the invention
`will have [he Slmcmrc IA: [A
`
`R
`
`5
`
`accordance with the present‘ invention, a
`In addition,
`m°lhU.d
`Pmvldud. tor pwvullllng‘ or m'.""“ug dlabclus’
`especially type 2 diabetes, and related diseases such as
`"mull" nmslancc’ hylicrglycaillla’ hypc“”"""1'mm.1a’
`elevated blood levels or fatty acids ‘or glycerol, obesity,
`byndroiiie X, diabetic coiiiplicatioiis, dysmetabolic
`'5 syndrome, and related diseases, and sexual dysfunction,
`wherein a therapeutically effective 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
`an lesions (such as ductal carcinoma in situ of the breast and
`lobular carcinoma in situ of the breast), premalignant lesions
`(such as Iibroadeiionia oi‘ the breast and prostatic iiitracpi—
`thelial neoplasia (PIN), gastrointestinal malignencies,
`liposarcomas and various other epithelial tumors (including
`15 breast, prostate, colon, ovarian, gastric and lung), cancer-
`induced asthenia (fatigue),
`irritable bowel syndrome,
`(_'rohn’s disease, gastric ulceritis, and gallstones, and lllV
`infection, other
`infectious diseases, drug-induced
`lipodyslrophy, and proliferative diseases such as psoriasis,
`or an alkali or alkaline earth metal (such as Na, K or (fa) salt m wherein a tlierapeutically effective amount of a L‘0lTlp0lll'ltl of
`thereof, or amino acid salt (such as arginine), wherein R,
`'
`structure 1
`is administered to a human patient in need of
`and R‘; are the same or different and independently selected
`treatment.
`from H, halogen andlor alkyl (preferably 4—Iluoro, 4—iluoro—
`In addition, in accordance with the present invention, a
`3-methyl or 3,5-dirnetliyl); and
`method is provided for improving coagulation homeostasis
`R3 is alkyt or cycloalkyt, pt-cfembly isgpropyl, 1_bu1y1o;
`including reducing plasminogen activating inhibitor (l’Al]—1
`cyclopropyl,
`35 activity,
`reducing fihrinogen, andfor reducing platelet
`In another aspect, the present invention provides pharma-
`aggregation, «'lflCli"0I'impI'0Vi1'1g01'1d01h91i3I function. WI1|3F|3i1’1
`ccutica] compositions, useful as hypolipidemic or hypo-r;ho—
`El therapeutically {:lTut.'li\-“I: uIT‘ItJLlI1l. of a compound of struc-
`lcstcrgjlcmic agents, of [1yp(3[rig]y;_;cridcmi[_; aggn[s, Ur a[1[i—
`ll.l]'€
`I is administered II.)
`it pEiT.lCI]T.
`lI'l I'l66(.l Oi‘ ll'C2il|'I'lCI]T..
`Alzheimer's agents, or anti-osteoporosis agents as well as
`In addition,
`ifi
`flCCOI'flanCC With lhc [tI'CSC11l
`invflnfififl, 5|
`other uses as described herein, comprising a hypolipidemic 40 method is provided for treating cholesterol related diseases,
`or hypocholcs-,1¢ro]cmjc or hy*pg[['ig[ycc[i(]c[nic of anti.
`diabetes and related diseases, cardiovascular diseases, cere-
`Alzheimer"s disease or anti-osteoporosis amount, or other
`hTU“'3-‘9C_1lIi” dI5*73-‘*5 3-"3 defined 3l"'5“"c {ind hcrflinalltcf and
`Ihm-apcmically effective amount (dcpmding upnn use) of a
`other _diseases as set out above, wherein a therapeutically
`compound of formula I in accordance with this invention, in
`°II"“"""° “mount “F "_ “°m,b‘“‘“‘°“ °[ ‘‘ ‘-‘°m,Pf’““‘1 “f 5”E""'
`combination with a pharmaceutically acceptable carrier.
`45 "mi I and ‘‘ hYl?”_hP1d‘?m1° agcmv a”‘l”°r Ilpld modulaung
`In another aspect, the present invention provides a method
`agent a"(‘I’iF)_r afnlfihabctlc agfirnl andfor cmdlmrasculalt "*5-‘=‘°“.‘j
`of inhibiting cholesterol biosynthesis or lowering blood
`f'*’r"t‘r"_“'d-‘~(‘]~l'1ftr_‘dgei11t, ai‘.tt.or other
`typie pf therapeutic.
`serum cholesterol
`levels andior modulating blood serum
`‘lgfim’ D’
`‘1 mlmbwm 1? ‘1.p‘““?m 1" pee‘ ,0 t[?“IFI1‘fnl'
`.
`cholesterol levels such as lowering LDL cholesterol andfor
`P the abmi-C -mclhudb OI [he mwmlori “herein d L0-mbh
`.
`.
`.
`.
`.
`.
`.
`nation is administered, the compound oi structure I will be
`lncwadlng I,IDI‘Ch0h?St,cml’,m lrcallng dysllpldcmlfhmlxcd 50 employed in a weight ratio to the other therapeutic agent
`dy5_I'p1d°m1_a’ h¥P°F11P1d°m1a= hypcrCh0l°5IcmI°m1a' hypo
`(depending upon its mode of operation] within the range
`°_"11P°P"‘f‘°”‘°_m‘“« IDL p?“°"“ IF II)" P3“'3"" A= hyllc"
`from about 0.01:1 to about 500:1, preferably from about
`lipoprrttteineiiiia or liyiirlgtriglygerlideinia, an|d othei abulzrrag
`05:1 [0 about 100;]
`tions 0 apo ipoprotein meta o ism, or re( ucing eve s o
`,,
`_
`,
`_
`_
`,
`,
`,
`,
`Lp(a), or treating or preventing other cholesterol-related 55
`DI"‘IAII‘I"‘D m"5’['RIPlI0N OI‘ “IL”
`diseases, or treating or preventing or reversing progression
`INVENTION
`is Pm‘
`1l‘1'~‘-I"?
`of atherosclerosis, or preventing or treating Alzheirner’s
`In «'iCC0l'd«'i00C Wllh "19 PFCSCUI
`i1'|V0Y1li0T1s
`disease, or preventing or
`treating osteoporosis andior
`Vidcd ‘-'UmP0““d-"3 Useful in inhibiling ‘ht’ 3"?’-Ymc HMO‘
`osteopenia, or
`reducing iiirlaininatory markers such as
`CD/\ l'Cd1lC1-350. Which Inhibllofi 31"? 11-“'»°fi11 35 hYl"°"h0IC-3'
`C—reactive protein, or preventing or
`treating low grade on lefillttfltit-'
`iigtilllé‘-i dyslipidemic agtifll-‘is
`l'1)‘P01iPid€ml‘-'
`vascular inflammation, or preventing or treating stroke, or
`335'"-*5:
`I"YllU“'igI)’CcrId‘5miC agcnlsa mil‘/\13"h‘7im9rI5 ‘ii-*5‘
`prcvcnting or treating dcmcntia’ gr prcvgnling and [mating
`ease agents,and antiosteoporosis agents as well as other uses
`coronary heart disease (including primary and secondary
`35 U’-»‘5CfilJ‘—'il
`Il*5WiI1-
`prevention of myocardial infarction), or preventing or treat-
`The term “coronary events" as employed herein refers to
`ing stable and unstable angina, or primary prevention of 65 myocardial
`infarction, myocardial
`revascularization
`coronary events, or secondary prevention of cardiovascular
`procedures, angina, cardiovascular death and acute coronary
`events, or preventing or treating peripheral vascular disease,
`syndrome.
`
`4 BT33
`
`PENN EX. 2097
`CFAD V. UPENN
`lPR20l5-01836
`
`

`

`US 6,620,821 B2
`
`8
`Such salts include ammonium salts; alkali metal salts, such
`as lithium, sodium and potassium salts (which are
`preferred]; alkaline earth metal salts, such as calcium and
`magnesium salts; salts with organic bases, such as amine
`
`7
`The term "eardiovascu lar diseases or events” as employed
`herein refers to atherosclerosis of the coronary arteries,
`myocardial infarction, including primary MI and secondary
`MI,
`recurrent myocardial
`infarction, angina pectoris
`(including stable and unstable angina), congestive heart
`l3CI'l.’.d.[l'l1l'lG,
`like salts (e.g., d-icyclohexylamine‘ salt,
`l-ailum’ and Sudden cardiac deallm
`N:m¢1hy'l'D'l-3hfC“m'1“e' am} ljydrabajmlnc Sans); a_“d Sans
`The term "cerebrovascular diseases or events” as
`Wllh 310100 3C1Cl5 111“? arglnlncs 135105 and ll“? 113°? and
`employed herein refers to cerebral
`infarction or stroke
`zwitterions, the so-called “inner salts". Nontoxic, pharma-
`(caused by vessel blockage or hernrnorage), or transient
`In ceutically acceptable salts are preferred, although other salts
`l~‘5‘5h°1T1ir"_ “U3-‘-‘k (TIA): SYQCUPC,
`‘f1ll'lCF0SC10l'0S_i5 Of
`111“
`are alnn nnnfnl on“ in lmlnllnn or nnnfylnn Inn nrnnncn
`intracranial andlor extracranial arteries, and the like.
`_
`The term “cholesterol-related diseases” as employed
`1110 ICIITI pharrnaccullcally £lCCC1JlEll’!1C “-S2111" and “Stills”
`herein refers to diseases involving elevated levels of l.|)I.
`also includes acid addition salts. These are formed, for
`elioleslerol, diseases involving regulation of LDL receptors,
`‘ll5°'f15f55 l'{V0lVi“8 fF‘l_U°‘3Cl‘
`l°V¢l5 Of HDL Cl10l'35lCf0L '5 example, with strong inorganic acids, such as mineral acids,
`dyfillpldcmm hyp°rl'p1dCm'a' elevated LDL Patter" B’
`for example sulfuric acid, phosphoric acid or a liydrolialic
`elevated I.DI_ Pattern A, hypercholesterolemia, hypo
`.d
`h
`Hcl
`HB w.n_1
`1
`0
`.
`b
`1.
`or
`as
`Sue
`tit—lipoproteiiieiiiia (low I-IDI. cliolesterol syiidroiiie),
`acl
`r’
`,1
`Strong 01-“amc car Oxy [C
`n}. nnrll-nnn mwlncm la, clnvalnd llnlal
`lnvcln,
`acids, such asalkanecarboxylic acids ofl to 4 carbon atoms
`hypertriglyceridemia, other aberrations of apolipoprotein B n which ?1Tf3‘1ll1-‘illh-‘$1111-llfld UT’ S1113-"l111U1Cd. 1'1” Cxamplfla bl?
`metabolism, heterozygous familial, presumed familial eom-
`*0 halogen, mi’ example =1C0l1C Mild. Such 35 Salllfalcd 0!’
`bined and non—familial (non—l~'H] forms of primary hylJcrc—
`unsaturated diearboxylic acids, for example oxalic, malonic,
`holestcrolcmia (including Frederickson Types Ila and lib),
`suecinie, maleic, fumaric, phthalic or tcrcphthalic acid, such
`cholesterol ester storage disease, and cholesterol ester trans-
`as hydn,xycnIl,0,n,llC acidjnj for nxnmnlg nnmrbln, gl).-Colic’
`15
`f5‘-1' l31'0l°iY1 (ll?-935°: <'m(l 1"31alC(l (li5‘3a5°5-
`lactic, malic, tartaric or citric acid, such as amino acids, (for
`The conditions, diseases, and maladies collectively refer- " cxamnlc asnanln or glnlan-nc acld or lyslnc or al-glnlnnl’ or
`5nC°_d l0_ 35 "SY"d1'“1"“' X’? 0" D)"5m‘.’-‘3l’0ll'3 SY“d"°'“° (35
`benzoic acid, or with organic sulfonic acids, such as ((31-4)
`dclmlcdm Johansonvl C‘r"_”' "f_”d0C'f’”Ol'Mremb" 19918:)’
`alkyl or arylsulfonic acids which are unsubstituted or
`727_734’ and mher pl"bl“”'au0n5)
`lndudfl hypflrglyccmw
`substituted for example by halogen for example methane-
`andfor prediabetie_ins_ulin_resistance‘syndrome, and is char- Sn Sulfom-C acid or pnolucncsulfonlc aéld
`acterized by an initial
`insulin resistant state generating
`The term “spirocyclic ring” as used in reference to ((T[[2)_,_
`hyperinsiilinemia, dyslipidemia, and impaired glucose
`andlor (CH3)? refers to a 3 to 7' membered spiroeyelic ring
`tolerance, which can progress to Type [I diabetes, eharac-
`formed from one or more of the carbons in ((71-12), ancllor
`terized by hyperglycemia, which can progress to diabetic
`as one or more carbons in (CI 11).,
`together with additional
`C0fIl}JllC‘c1ll0I1‘S-
`The term "diabetes and related diseases" refers to Type II " carbons to make up a 3 to 7 membered ring.
`diabetes, Type 1 diabetes,
`impaired glucose tolerance,
`.
`.
`.
`__
`Hr. Unliiss
`5
`lowlili alkyl
`the “inn
`obesity, hyperglycemia, Syndrome X, dysmetaholic
`lndlualcd’
`‘ilkyl Or
`syndrome, diabetic complications and hyperinsulinemia.
`an“ ‘Li’ amployed harm“ ‘flame or ‘*5’ pd“ (if
`The conditions, diseases and maladies collectively 40 another gm"? ""°"',‘l‘f'-“ both ftrajght and hr,a'lCh”d cham
`ml-erred [0 as vvdiabetic Compncanonst, include rcnnopznhy’
`hydrocarbons, containing 1 to -0 carbons, prelerably l to ‘I0
`iieuropatliy and nepliropathy, and other known coiiiplica-
`carbons’ more pmfflably 1 To 8 Car_b°”S’ 1“ [he normal sham’
`nnns nf dlnbclcS_
`such as methyl, ethyl, propyl,
`isopropyl, butyl,
`t-butyl,
`lyPe(S) of lnerannnllc agenln-s an
`-lwha
`[arm vnolhen.
`isohutyl,pentyl,-hexyl,isohexyl,heptyl,4,4-dimethylpentyl,
`employed herein refers to one or more antidiabetic agents 45 Uclylv 2-2-4'"}m°lh3"1'P°“lYL ‘”"‘”3'1-
`‘l°°3’1v undecyls
`lnlllcr than compounds of formula l}, 0,19 0, mow am-
`clodecyl, the variousbranched chain isomers thereof, and the
`obesity agel-115,, amjgor one 01' mg“: 1fpid.10weri1-lg agel-.15,
`like as well as such groups including I
`to 4 substituents such
`one or more lipid modulating agents (including aiiti—
`35 lilillfl. 10f OKEIIDPIG V. BL Cl Of I 0T CV3, alkyl, alkoxy, aryl,
`atherosclerosis agents], other types of anti-atherosclerosis
`aryloxy, aryl(aryl) or diaryl, arylalkyl, arylalkyloxy, alkenyl,
`agents, andfor one or more antiplatelet agents, one or more Sn cycloalkyl, cycloalkylalkyl, cycloalkylalkyloxy, amino,
`agents for treating hypertension, one or more anti—caneer
`liydroxy, liydroxyalkyl, aeyl, cycluheteroalkyl,
`lieteroaryl,
`drugs, one or more agents [or treating arthritis, one or more
`ht;-,1;-,-,1oa ryloxy-_ hctcroarylalkyl, heieroarylalkgxy,
`anti—osteoporosis agents, one or more agents for treating
`3,-yloxyalkyll alkylthion 3,-ylalkyllhlol 3,-yloxyal-yl,
`11T'mUn0m°¢lUl?ll0F)” d1-'5‘5*l-'5°5-
`alkylamido, alkanoylamino, arylcarbonylamino, nitro,
`The term “lipid-modulating” agent as employed hcrcin 55 cyano, thiol, haloalkyl, trihaloalkyl anclfor alkylthio_
`refers to agents which lower LDL andior raise HUI. andfor
`_
`_
`_
`as
`term ncyclflalkyl
`lower triglycerides zindfor
`lower total cholesterol andfor
`Unlcm mhcfwmc md"mlcd= the‘
`nllnn known nwnnnnlnmn l-or lnnrnnnnllnnlly lrcnnnn lnnn
`employed herein alone or as part of another group includes
`dim,-dc,-S_
`saturated orpartially unsaturated (containing 1 or 2 double
`The term "other types of anti-atherosclerosis agents” as an l’°“d-9)’ ‘Wcllc hydrqcarbofl 3Tf3uP5"3°nl3m1n8 ]~_ I0 3 W189»
`employed herein refers to conventional anti-atherosclerosis
`1"‘-'l“d1_“g 'T_“"“"’C}’Cl‘C 3lk)'_'1a_l"1CYC11C alkyl (“T h1‘5)"510all\')’l)
`agents including lipoxygenase inhibitors, ACAT inhibitors,
`and 1_"C)'Cl"-'
`fill‘)-‘la C0T|li“"“'|g 3 Tmal Of 3 10 20 ‘farhfin-‘i
`aiiiiuxiilauis, PPAR aguiiisis, ptiusptiulipase inliibiturs
`forming the ring. preferably 3 I0 10 carbons, formmg the
`[including PI_.A-2 inhibitors], andfor other known anti-
`ring and which may be fused to l or 2 aromatic rings as
`atherosclerosis agents.
`65 described for aryl, which includes cyclopropyl, Cyclobutyl,
`The terms pharmaceutically acceptable “salt” and “salts"
`eyelopentyl, eyelohexyl, eycloheptyl, eyelooetyl, eye-lode-
`refer to basic salts formed with inorganic and organic bases.
`cyl and cyclododecyl, cyclohexenyl,
`
`,,
`
`”
`
`5 BT33
`
`PENN EX. 2097
`CFAD V. UPENN
`lPR20l5-01836
`
`

`

`US 6,620,821 B2
`
`9
`
`as
`oo
`
`any of which groups may be optionally substituted with "l to
`4 substituents such as halogen, alkyl, alkoxy, hydroxy, aryl,
`aryloxy, arylalkyl, cycloalkyl, alkylamido, alkanoylarnino,
`oxo, acyl, 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 10 carbons and 1 or 2
`double bonds. Exemplary eyeloalkenyl groups include
`ttyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl,
`cyclohexadienyl, and cycloheptadienyl, 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 alkenyl” or
`“alkenyl" as used herein by itself or as part of another group
`refers to straight or branched chain radicals of 2 to 20
`carbons, preferably 2 to 12 carbons, and more preferably "l
`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-penlenyl, 2-hexenyl,
`3-hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 3-octenyl,
`3—nonenyl, 4—deccnyl, 3—undeoenyl, 4—dodeeenyl, 4,8,12-
`tetradeeatnenyl, and the like, and which may be optionally
`substituted with "l
`to 4 siihstitlients, namely, halogen,
`haloalkyl, alkyl, alkoxy, alkenyl, alkynyl, aryl, arylalkyl,
`cycloalkyl, amino, hydroxy, heteroaryl, cycloheteroalkyl,
`alkanoylamino, alkylamido, ary|carbonyl—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 itselfor as part of another group
`refers to straight or branched chain radicals of 2 to 20
`carbons, preferably 2 to 12 carbons and more preferably 2 to
`8 carbons in the normal chain, which include one triple bond
`in the normal chain, such as 2-propynyl, 3-butynyl,
`2-butynyl, 4-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl,
`2—heptynyl, 3—heptynyl, 4—heptynyl, 3—octyny|, 3—nonynyl,
`4—Lleeyt1yl, 3—ut1decyt1yl, 4—dodeeyuyl and the like, and
`which may be optionally substituted with l to 4 substituents,
`namely, halogen, haloalkyl, alkyl, alkoxy, alkenyl, alkynyl,
`aryl, arylalkyl, cyeloalkyl, amino,
`lieteroaryl,
`cycloheteroalkyl, hydroxy, alkanoylarnino, alkylamido,
`arylcarbonylamino, nitro, cyano,
`thiol, andfor alkylthio,
`andfor any of the- alkyl substituents set out herein.
`'Ihe terms “arylalkenyl” and "arylalkynyl" as used alone
`or as pan 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 “alkylenc” groups and may optionally be
`substituted with l or 2 substituents as defined above for
`
`“alkyl", such as, for example alkyl, halo, hydroxy, alkoxy
`andlor cycloalkyl.
`Where alkenyl groups as defined above and alkynyl
`groups as defined above, respectively, have single bonds for
`
`1U
`
`I5
`
`30
`
`35
`
`4U
`
`45
`
`SU
`
`55
`
`till
`
`65
`
`10
`attachment at two different carbon atoms, they are termed
`“alkonylene groups” and “alkynylcne groups", respectively,
`and may optionally be substituted with l or 2 substituents as
`defined above for "alkenyl” and "alkynyl”_
`
`includes alkylene groups as defined
`(C112), or (C112),
`herein, which may optionally include 1, 2, or 3 substituents
`which include alkyl, alkenyl, halogen, aryl, hydroxy, alkoxy,
`or C3—C,_ cycloalkyl.
`
`Examples of (CH2), or (CHQJV, alkylene groups include
`_(:H,_, —(.‘H2(.‘H2—,
`
`—ct13—ct1—ct1g—,:ct1
`(CH2):
`,
`
`_.
`'lCH3]-I
`
`KCII-_3
`
`:(cti3,t-_.—_.
`
`(11,
`
`(ctt,}3—c—c113Ci12—__ —ctI;tcrt—,
`
`Cit,
`
`ctr,
`
`—L:i13t|;i1t;1i3
`C_1‘H§
`
`_,
`
`(|.'IlCiI-_3
`CH3
`
`_,
`
`(|.‘ll.L‘ll3{_Illg
`(EH5
`
`—cnCtICn2
`CH,
`I
`'
`CH,
`
`T
`
`F
`
`CH3
`
`(CH3);
`
`(|iH3
`, —cn,—c—rn,—_
`t
`
`C"3
`(‘l
`CH.
`CH3
`
`Ct-lg
`CH3
`
`CH3
`
`,
`
`(Cllglg
`
`(|..Il
`(EH;
`
`CH3
`
`(ITH
`(‘H3
`
`{ITH
`(‘H3
`
`CH‘
`
`CH-_3
`
`CH
`
`CH;
`
`(|Tl-I
`(‘H3
`
`f|_‘
`(TI-l_,
`
`(Tl-I3
`
`(|iH
`CH,
`
`(I_‘.lI_1
`cit
`
`TCII3
`cu
`__
`cngczng
`:(ClI2}3—CF_:* .
`
`([13:11;
`
`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 (IF3, with chlorine or fluorine being
`preferred.
`
`'l'he 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 pan of another group refers to monoeyclic
`and bicyclic aromatic groups containing 6 to ll) carbons in
`the ring portion (such as phcnyl or naphthyl
`including
`1—naphthyl and 2—naphthyl) and may optionally include one
`to three additional rings fused to a earbocyclic ring or a
`heterocyclie ring (such as aryl, cycloalkyl, heteroaryl or
`cycloheteroalkyl rings for example
`
`6uf38
`
`PENN EX. 2097
`
`CFAD V. UPENN
`lPR20l5-01836
`
`

`

`11
`
`US 6,620,821 B2
`
`\ '
`
`"i \ '
`
`"
`
`—\'i
`
`\
`% Y *
`<7» :—
`o=<,U <01}
`
`N
`
`\\
`
`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, henmyloxy,
`haloalkoxy, alkenyl,
`triiluoromethyl,
`triiluoromethoxy,
`alkynyl, eyeloalkylalkyl, cycloheteroalkyl,
`eyeloheteroalkylalkyl, aryl, heteroaryl, arylalkyl, aryloxy,
`aryloxyalkyl, arylalkoxy, arylthio, arylazo, heteroarylalkyl,
`heteroarylalkenyl, heteroarylheteroaryl, 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 com pounds mentioned
`in the definitions), thiol, alkylthio, arylthio, heteroarylthio,
`arylthioalkyl, alkoxyarylthio, alkylcarbonyl, arylearbonyl,
`alkyl-arninocarbonyl, arylaminoearbonyl, alkoxyearbony],
`aminocarbonyl, alkylcarbonyloxy, arylearbonyloxy,
`alkylcarbonylamino, arylcarbonylarnino, arylsulfinyl,
`arylsuliinylalkyl, arylsulfonylarnino or arylsul[on—
`aminoearbonyl andfor any of the alkyl substituents set out
`herein.
`the term “lower alkoxy”,
`Unless otherwise indicated,
`"alkoxy"', “aryloxy" or “aralkoxy” as employed herein alone
`or as part of another group includes any of the above alky],
`aralkyl or aryl groups linked to an oxygen atom.
`Unless otherwise indicated, the term "substituted amino"
`as employed herein alone or as part of another group refers
`to amino substituted with one or two substituents, which
`may be the same or diilierent, such as alkyl, aryl, arylalkyl,
`heteroaryl, heteroarylalkyl, eycloheteroalkyl,
`cyeloheteroalkylalkyl, eyeloalkyl, cyeloalkylalkyl,
`haloalkyl, hydroxyalkyl, alkoxyalkyl or thioalkyl. These
`substituents may be further substituted with a earboxylic
`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,
`l-piperidinyl,
`l-azepinyl, 4-morpholinyl,
`4-thiamorpholinyl, 1-piperazinyl, 4-alkyl-1-piperazinyl,
`4—arylalkyl—1—piperazinyl, 4—diarylalkyl—1—piperazinyl,
`l-pyrrolidinyl, 1-piperidinyl, or 1-azepinyl, optionally sub-
`stituted with alkyl, alkoxy, alkylthio, halo, triiluoromethyl or
`hydroxy.
`Unless otherwise indicated, the term "lower alkylthio”,
`alkylthio”, "arylthio” or "aralkylthio" as employed herein
`alone or as pan of another group includes any of the above
`alkyl, aralkyl or aryl groups linked to a sulfur atom.
`
`12
`Unless otherwise indicated, the term “lower alkylamino”,
`“alkylamino”, “arylamino", or “arylalkylamino” as
`employed herein alone or as part of another group includes
`any of the above alkyl, aryl or arylalkyl groups linked to a
`nitrogen atom.
`Unless otherwise indicated, the term “acyl" as employed
`herein by itself or part of another group, as defined herein,
`refers to an organic radical linked to a carbonyl
`
`(ii)
`
`group; examples of acyl groups include any of the R1 groups
`attached to a carbonyl, such as alkanoyl, alkenoyl, aroyl,
`aralkanoyl, heteroaroyl, cycloalkanoyl, eycloheteroalkanoyl
`and the like.
`
`Unless otherwise indicated, the term "cycloheteroalkyl”
`as used herein alone or as part of another group refers to a
`5-, 6- or 7—membered saturated or partially unsaturated ring
`which includes 1 to 2 hetero atoms such as nitrogen, oxygen
`andtor sulfur, linked through a carbon atom or a heteroatorn,
`where possible, optionally via the linker (CH2), (where r is
`"l, 2 or 3), such as
`
`and the like. The above groups may include 1 to 4 substitu-
`ents such as alkyl, halo, oxo andfor any of of the alkyl
`substituents set out herein. In addition, any oi" the cyclohet-
`eroalkyl rings can be fused to a eyeloalkyl, aryl, heteroaryl
`or cyclohcteroafkyl 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 sueh rings
`Fused to an aryl, cycloalkyl, heteroaryl or cycloheteroalkyl
`ring (e.g. benmthiophenyl, 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
`[or alkyl. Examples of heteroaryl groups include the fol-
`lowing:
`
`O
`
`
`
`5
`
`I5
`
`30
`
`35
`
`4U
`
`45
`
`SU
`
`55
`
`6E
`
`65
`
`7tJf38
`
`PENN EX. 2097
`
`CFAD V. UPENN
`lPR20l5-01836
`
`

`

`13
`
`_
`
`—continued
`
`US 6,620,821 B2
`
`14
`Examples of such prodrug esters include:
`
`E‘: <° / ._ 5
`N2 __
`Q
`\\ I
`:
`RN/H
`KY‘
`/“‘/t N/\