I ||||| |||||||| Ill lllll ||||| ||||| ||||| ||||| Illll |l||| lllll ||ll|| Ill I|l|| ||||
`US0055 1 0379A
`
`United States Patent
`
`719;
`
`[11]
`
`Patent Number:
`
`5,510,379
`
`Lee et al.
`
`[45] Date of Patent:
`
`Apr. 23, 1996
`
`[54]
`
`SULFUNATE ACAT INHIBITORS
`
`[58] Field of Search
`
`558749, 50; 514-7517,
`514-7510
`
`['75]
`
`Inventors: Helen T. Lee, Ann Arbor; Joseph A.
`Picard, Canton; Drago R. Sliskovic,
`Ypsilanti, an of Mich.
`
`[56]
`
`_
`References Cited
`
`[73] Assignoc: Wamer-Lambert Company, Morris
`P1”""" NJ‘
`
`U.S. PATENT DOCUMENTS
`171986 314111; et 41.
`
`4,557,004
`
`2607465 R
`
`[22]
`['51]
`
`[21] Appl. No.: 359,144
`*.
`‘
`Dec’ 19’ 1994
`Filed’
`Int. Cl.5 .................... .. COYC 309769; C07C 309770;
`A61K 31.-‘O95; CUTD 487704
`........................ .. 5147517; 5147510; 5147513;
`[52] U.S. Cl.
`5147300; 5147404; 5147312; 5147457; 5147341;
`5147256; 5147252; 5147314; 5147246; 5147248;
`5147259; 5147274; 5147351; 5147387; 5147445;
`5147443; 5147473; 5147470; 5147469; 5147247;
`5147255; 5147424; 5147407; 5147372; 5147365;
`5147376; 5147380; 5147384; 5147359; 5147392;
`5147386; 5147367; 5147418; 5147415; 5147311;
`5147309; 5147307; 558750; 558749; 558752;
`5467122; 5467153; 5467294; 5467157; 5467172;
`5467141; 5467147; 5467146; 5487370.1;
`5487370.4; 5487550; 5487551; 5487213;
`5487187; 5487228; 5487229; 5487243; 5487255;
`5487264.4; 54873241; 5487166; 5487178;
`5487180; 5487251; 5487486; 5487484; 5487510;
`54872654; 5497471; 5497399; 5497410;
`549765; 549766; 549752; 549751; 5497479;
`5497466; 5447215; 5447237; 5447235; 5447283;
`5447315; 5447319; 5447298; 5447239; 5447408
`
`Primary Exami7:er—CeciIia Tsang
`As.1'r'sta7zt Exa1m'ner—Kjng Lit Wong
`A"_0m9)5 7489'“; 0?‘ F5"?1—Ch31"1CS W- AShbTD0k; T0915 M-
`C1155’-W
`
`[57]
`
`ABSTRACT
`
`B—Carboxy sulfonates of 1111: formula
`
`9
`0
`1|
`||
`R;—0—5—C—C—Y—R;
`11
`/ \
`0 R3
`
`R4
`
`wherein R1 is aryl, R3 and R4 are hydrogen or alkyl, Y is -0-,
`—S—, or —NR2—, and R5 is alkyl or aryl axe p01en11'nhibi10rs of
`the enzyme acyl CoA:choIesterol acyltransfcrase (ACAT)
`and are thus useful for treating hypercholesterolernia and
`atherosclerosis.
`
`13 Claims, No Drawings
`
`Iofl3
`
`PENN EX. 2201
`
`CFAD V. UPENN
`lPR20l5-01836
`
`

`
`1
`SULFONATE ACAT INHIBITORS
`
`5,510,379
`
`113451031?»
`halo,
`
`2
`
`Him,’
`0l'3-I10,
`u-iflugl-gm¢my1_
`_COOH
`
`,
`-
`’
`’C00a]ky_1 w!m°m_alky1 has from 1 to 4 carbon atoms
`and which 13 Straight °r branched‘
`—(CH7),,,NR,R), wherein In is O or 1, and each of Rx and
`Ry i5 indcpcndcnfly hYd1'°SC“ 01" C1'C4 alkyli
`[Cl W3 ETD‘-1P
`
`
`
`(d) the 3m"?
`
`N
`f x.
`Rm-N
`
`R
`
`3
`
`R
`
`9
`
`5
`
`25
`
`35
`
`BACKGROUND OF THE INVENTION
`This invention provides new chemical compounds char-
`acterizcd as being fi—carboxy sulfonates. The compounds
`inhibit acyl-CoA: cholesterol acyltransferase (ACATJ, the
`enzyme responsible for the esterification ofdietaiy choles-
`terol. Such agents thus decrea.se the absorption of dietary
`cholesterol and tlierefore provide a therapy for individuals 10
`with hyperehelesterolemia and atherosclerosis.
`High levels of cholesterol have been associated with
`heightened risk for development of several disease states,
`most notably coronary heart disease. A great deal of efl'ort
`has been devoted to finding ways to lower cholesterol levels 15
`in biological systems. The approach of lowering cholesterol
`intake by modifying diet has met with only limited success.
`The ACAT enzyme is known to catalyze the esterification of
`dietary cholesterol, and has been implicated in several
`aspects of the atherosclerotic process in animals. One 20
`approach to lowering cholesterol then is to inhibit the ACAT
`enzyme. While several ACAT inhibitors have been identified
`(see for example EP 0570245), the need continues to identify
`and develop new ACAT inhibitors having improved Ihera-
`pcutic properties.
`_
`An object of this invention is therefore to provide a new
`series of compounds which are B-carboxy sulfonate de1'iva—
`tives and which have demonstrated excellent ACAT inhibi-
`to
`ro erties. Another ob'ect is to provide pharmaceutical
`_
`_
`forriiriiilagons comprising the sulfonates and a carrier or 3” w:“;$RB m:mR9r']:'d°I:“dggg :r°dE)l'CE aikyior I'§1°"_y1‘
`excipient, and a method for inhibiting the ACAT enzyme by
`3“
`15 3 5
`3
`or
`Ian
`_
`3'_ C“ 0“ gm“? avmg
`admim-Staring a compound of the I-nvcntiong
`fnomdl to 18. carbon atoéns ;1.rhitt:Jh 1: saturated or 1sdunsat-
`urate
`containing one
`ou e
`on
`or two nona JECCIII.
`SLMMARY OF THE INVENTION
`double b[)I1ClS; phenyl; phenyl substituted with f1‘01Tl l I0 3
`substituents selected from
`C _C alkyl
`C1_C" alkali
`1
`4
`hydroxy.
`
`This invention concerns new compounds which are |3-car-
`boxy sulfonates and which inhibit die ACAT enzyme.
`The compounds of the invention have the Formula I
`
`Y’
`
`I 4'!)
`
`5°
`
`55
`
`ltll
`fl)
`Rl—0—fi———-—C--C--Y—R5
`0 R3
`m
`wherein R1 is selected from
`(a) phenyl which is unsubstituted or is substituted with from 45
`l to 3 substituents selected from
`CFC“ aim’
`C1434 alkoxy,
`CFC‘ alkyl [him
`hydroxy’
`halo»
`nitro,
`cyano,
`trifluoromethyl.
`-COOH,
`-C0Oalkyl wherein alkyl has from I
`and which is straight or branched,
`-(cH,),,,NR,s, wherein m is 0 or 1, and each of R, and 5°
`Ry is independently hydrogen or C1-C4 alkyl;
`(13) l- or 2—naphthy] which is unsubstituted or substituted
`with from 1
`to 3 substituents selected from
`
`to 4 carbon atoms
`
`halo,
`Ditto,
`fditaiiitdromem 1
`C00
`y '
`_
`'
`H’
`-C0g3_1kY1 “fhfiieln :]kY1£1¢':§ fmm 1 10 4 C3-Tho“ 3101115
`dii
`lstsiitrmg mi; Him 3 is
`:1
`d ti
`:1
`-( abéfiz. 01,11), pw erein In,
`,, an R, are as
`e ne
`3. heterodyclic group selected from 2-, 3-, or 4—pyt'idyl, 2-,
`4-, or 5-pyrimidinyl, 2-, or 3-pyrazinyl, 2-, 3-, 4-, 5-, 6-,
`7-. or 8-quinolinyl, 3- or 4-pyridazinyl, and the N—ox-
`ides thereof;
`(6) [115 810119
`
`
`
`C1-C4 alkyl,
`C1-C4 alkoxy,
`C1_C4 ajkylmio,
`
`65
`
`(f) a straight or branched hydrocarbon group having from 1
`to 18 carbon atoms which is saturated or is unsaturated
`
`2 of 13
`
`PENN Ex. 2201
`CFAD V. UPENN
`lPR20l5-01836
`
`

`
`3
`
`4
`
`5,510,379
`
`containing one double bond or two nortadjacent double
`bonds;
`(g) a cycloalkyl group having front 3 to 10 carbon atoms;
`(h) the group
`
`
`
`or R3 and R4 taken together with the carbon to which they
`are attached complete a C3-C3 earbocyelie ring;
`Y is -0-, -S-, or -NR1-, wherein R2 is hydrogen, C1-C4
`alkyl, pheny], C1-C4 alkyl, phenyl, wherein the phenyl may
`be substituted with l, 2, or 3 groups selected from C1-C4
`alkyl, C1-C4 alkoxy. C1-C4 alkylthio, hydmxy, halo, nitro,
`cyano, trifluoromethyl, and COOH;
`R5 is R6_ C1-C-411 alkyl. C2—C,41 alkenyl. C2-C241 alkynyl
`and alkyl, alkenyl and alkcnyl substituted with one or two
`groups defined by
`where R6 is hydrogen, C3-C6
`l
`cycloalkyl, phenyl,
`— or 2 - naphthyl, and phenyl and
`naphthyl substituted with from 1 to 3 substituents selected
`front:
`
`C1-C4 alkyl,
`C1-C4 alkoxy,
`C1-C4 alkylthio,
`phenyl,
`hydmxy,
`halo,
`nilro,
`cyano,
`
`trifluoromethyl,
`-C001-I,
`-C00al.kyl wherein alkyl has from 1 to 4 carbon atoms
`and which is straight or branched,
`-(CH2),,,NRIR1, wherein m is 0 or 1, and each of R1, and
`R4, is hydrogen or a straight chain alkyl group having 1
`to 4 carbon atoms; and
`R15 is hcteroary] selected from a 5- or fiwmembered mono-
`cyelic or fused bicyclic heterocyclic group eontairiing
`at least
`1 to 4 heteroaloms in at least one ring,.said
`heteroatoms being nitrogen, oxygen, or sulfur and
`combinations thereof, said hctcrocyelic group being
`unsubstituted or substituted with amino, halo, nitro,
`hydroxy, cyano,
`trifluoromethyl, or an alkyl group
`having from 1 to 20 carbon atoms and the N-oxides
`thereof.
`
`Preferred compounds of the invention have the Formula H
`
`if
`ii‘
`R.—0—fi—CH;—C—Y—R5
`0
`
`"
`
`wherein R1, Y, and R5 are as defined above. Further pre-
`ferred are those of the above formula in which Y is -0-, -S-,
`or -NH-, and especially where Y is -NH-. Additionally
`preferred are eompounds of Formula 11 wherein R1 is phenyl
`or substituted phenyl, Y is -0- or S, and R5 is C5-C1, alkyl,
`phenyl, or substituted phenyl. Preferred substituted phenyl
`groups are di- and trialkyl, such as diisopropyl and triiso—
`propyl-
`Particnlarly preferred compounds have Formula II
`wherein:
`
`A. R1 is phenyl or phenyl substituted with l or 2 C1-C4
`alkyl groups;
`A{l) Y is NH and R5 is C5-C211 alkyl;
`A(2) Y is NH and R5 is phenyl or phenyl substituted with
`l or 2 C1-C4 alkyl or C1-C4 alkoxy groups;
`A{3J Y is NH and R5 is pyridy] or pyridyl substituted with
`1 or 2 C1-C4 alkyl groups;
`A{4J Y is S and R5 is C11-C24, alkyl;
`A{5) Y is O and R5 is C4-C411 alkyl;
`A(6) Y is O and R5 is phenyl or phenyl substituted with
`l or 2 C1-C4 alkyl groups;
`
`wherein — denotes a single or double bond; Q and Z are
`each independently hydrogen, C1-C4 alkyl, C1-C4 alkoxy,
`or halo;
`
`15
`
`20
`
`25
`
`35
`
`45
`
`50
`
`55
`
`60
`
`6S
`
`W is oxygen or two hydrogen atoms;
`R“ is hydrogen or C1-C4 alkyl, and n’ is 0 or I;
`[i) is selected from the group
`Rm
`R11
`
`‘V D
`
`IE
`
`E
`
`RI3
`
`R13
`
`R12
`
`R1:
`
`RM
`
`N '~~...
`
`\ N
`
`and
`
`R13
`
`R
`
`R14
`
`b X 5
`"-..
`
`N
`
`RI2
`
`wherein R12, R13, R”, and R15 are each independently
`hydrogen.
`halo,
`C1-C4 allcyl,
`C1-C4 alkoxy,
`C1-C4 alkylthio,
`cycloalkylthio of 5 to 7 carbon atoms,
`phcnylalkylthio in which alkyi is 1 to 4 carbon atoms,
`substituted phenylthio, heteroarylthio, or heteroaryloxy;
`and B, D, E. and G are nitrogen or carbon where one or more
`of B, D, and E is nitrogen; with the proviso that when G
`_ =N, the group is attached to the nitrogen atom of Formula
`I at the four or five position of the pyrimidine ring (a and b);
`or
`
`(j) a 5- or 6—membered monocyelie or fused bicyclic het-
`erocycle containing from 1 to 4 heteroatoms selected from
`nitrogen, oxygen, and sulfur; R3 and R4 independently are
`C3-C1, cycloalkyl. hydroxy-C1-C4 alkyl, C1-C4 alkoxy,
`hydrogen, C1-C4 alkyl, phenyl, 1- or 2 -naphthyl, or phcnyl
`or naphthyl substituted with from I to 3 substituents selected
`from C1-C4 alkyl, C1-C4 alkoxy. C1-C4 alkylthio, halo,
`nitro, cyano, trifluoromethyl, phcnyl, or C3-C3 cyeloalkyl,
`
`sons
`
`PENN EX. 2201
`
`CFAD V. UPENN
`lPR20l5-01836
`
`

`
`5
`
`6
`
`5,510,379
`
`AU) Y is NH and R5 is tetrazioly] or tetrazolyl substituted
`with a Ci;-Coo alkyl group;
`E. R1 is phenyl substituted with l, 2, or 3 C1-C4 alkoxy
`groups;
`
`Pharmaeeutically acceptable salts of the compounds of
`Formula I are also included as a part of the present invention.
`Suitable acids for forming salts of the compounds of For-
`mula ] containing a basic group such as amino or pyridyl
`include. but are not necessarily limited to acetic, benzoic,
`benzenesulfonic, hydrobromic,hydroeliloric, citi-ic,_furnar-lc,
`
`13(1) Y is ism and R5 is phony] or oiiooyi soooiioiioo with 5
`i, 2_ or 3 C1_C4 oikoxy gi-oops;
`Bo Y
`and Rs eon
`tartaric acid: Additional gcicls for use to forni acid salts of
`B8) Y is S and R5 is C°"C?-0 alkyli
`the compounds of Formula I include, but are not necessarily
`3(4) Y is 0 and R5 is Cc'C2.o alkyl:
`limited to, those acids found in Tables 3 and 4 of Grant &
`B(5) Y is 0 and R5 is phenyl or phcnyl substituted with
`I-lacl<h’s Chemical Dictionary, Fifth Edition, l98?:ll—l3.
`l. 2, or 3 C,—C,, allroxy groups;
`The acid addition salts are formed by procedures well
`C. R, is l- or 2-naphthyl or 1- or 2—naphthyl substituted
`known in the art.
`with l, 2, or 3 groups selected from C1-C4 alkyl or C1——C_,
`Certain compounds of the present invention may also
`alkoxy;
`exist in different isomeric forms, specifically stereoisomeric
`Cg) Y is N}; and R5 is C6_Cm oikyh phony], o; phony]
`forms, by virtue of the presence of asymmetric centers in the
`sobommod with ], 2’ or 3 groups soioolod from CFC‘
`compound. The present invention contemplates all stereoi—
`3119:] or C1_C4 aikoxy;
`somers that may be obtained, if desired, by methods known
`Ctz) Y is 5 and R5 is C6_Cm alkyl;
`[11 the art as, for example, the separation 0fSl.Cl'C01SD1'i’lC.I5 by
`.
`.
`Chiral Chromatographic columns
`C[3) Y is O and R, is C6-C2.) alkyl, phenyl, tetrazolyl, or
`Further, the compounds of this invention may exist in
`Phenyl substituted whh 1’ 2’ or 3 C1-C4 alky] gmupsi
`unsolvated as well as solvated forms with pharmaccutically
`0:4) Y is 0 and R5 is hYdT°B31'13
`acceptable solvents such as water, ethanol, and the like. in
`13- R1 is Crczo fllkltlé
`M1) Y is O and R5 is phenyl or phenyl substituted with 25 general. the solvated forms are considered equivalent to the
`l or 2 C1-C4 alkyl groups;
`unsolvated forms for the purposes of this invention.
`Dig) Y is 3 and R5 Cfi_Cm aiioyi;
`In Fonriula I, R5 can be C,—c,o alkyl, C2-C3, allcenyl, or
`E. R, is pyridyl or pyridyl substituted with 1 or 2 (:,_c,,
`C2~Ciu alkynyl. Each of these groups can have one or two
`aikyi groups;
`grouigs defingdlllny R16 uttacheéd, ‘for edxample £lI.JSLll)Sl1ll.(;ll.ECl fir
`‘Y is O or S and R5 C6_C2o
`30 Llflsll Stltute P en)! , 01' 3511 Slltute 01' llnsu Sl.1t1.l(E: nap -
`E R1
`at state 2::
`F“) Y is NH and R5 CFC20 alkyh
`branched saturatedlhydrocarbon cliainsphaving from I to 20
`F0) Y is 5 and R515 Phenyl OT Phfinyl Substituted W11“ is
`carbon atoms include methyl, ethyl, 2-cyclohutyl-2-phenyh
`2a “T 3 CFC4 alklil gmuflsi
`ethyl. n—propyl.
`isopropyl, n—butyl,
`iso—butyl,
`tert—butyl,
`G. R] is 4-[2-chlorophenyl)-5,7—dirnethyltiuinolin—2-yl;
`mpemyl’ 5_pheny]pemyI‘
`2_cyc10p1-opyl_5_Pheny1pen[yL
`G(l) Y is O and R5 is C6
`o alkyl;
`isopentyl, ii-heityl, n-heptyl, n—ocIyl, n—undccyl, n—dodccyl,
`Ga} Y is NH and R5 is phony] or phony] substituted with
`n-hexadecyl, 2,2-dimcthyldodecyl, 2—tet1'adecyl, and n—0cta—
`], 2, or 3 Ci—C,, alkoxy groups;
`d0C)’1 g1'011_P3-
`_
`G6) Y is S and R5 is Q4320 alkmyl;
`Illustrative examples of straight or branched hydrocarbon
`The most prcfcrmd Compounds of the imcnu-on are
`alkenylchains having from2to_20 carbon atoms a.nd‘hav1ng
`defined by Formula H when R]
`is phcny] or gubsmmed
`one double bond or two nonadiacent double bonds include
`phcnyl, Y is _NH_ and R5 is phcnyl or dialk},Iphcny1_
`ethcnyl,
`2—pi'openyl,
`2—butenyl, 4-eyclobutyl-2-butenyl,
`Also provided by this invention am phammcemjcal fm,_
`3—penLenyl, 2—oetcnyl, 5—nonenyl, 4—undecenyl, 5—heptade—
`mulations comprising a compound of Formula I togctllcr 45 Cenyl‘ 3'°F1adecenyl‘ 9.-ocladccenyl‘ 9_phcny]'9.'0ctadccc'
`WM]
`:3 phanljaceuucally acccpmblc mcipicm’ Carder’ Ur
`nyl, 2.2—dimethyl-l l-eicosenyl, 9.12-octadecadienyl, and
`diluent. Preferred formulations are those having a compound
`hexadeoenfl Typical all,“/my] gmilps are those having from
`of Formula II or any of the preferred compounds of A-G as
`to 20 (Eamon atoms mlh one’ mph: bond or two momma‘
`the active ingredient. The invention also provides a method
`-laoem mple bonds and mchlde Zflclynyl’ 5'hepm'3'decy'
`of treating hypercholesterolemia, atherosclerosis. and inhib- 5° W1‘ aild 4'ph°“yI'2.'b"w“yl‘
`_
`_
`in-ng the ACAT enzyme’ comp“-sing adml-nislefing to a
`R, in Formulal includes phenyl substituted with l, 2, or
`subject an elfective amount of a compound of Formula l to
`3 groups Such. as C‘-C‘ alkyl’ CVC‘ alkoxy and.C‘_C“
`-
`-
`-
`-
`-
`alkylthto. Straight or branched C —C alkyl groups include
`treat such conditions and to inhibit such enzyme.
`methyl and isopmpyl Straight 0; branched alkoxy groups
`55 having l to 4 carbon atoms include methoxy, ethoxy, n—pr0—
`poxy, ii-butoxy, and isopropoxy. C1-C4 alkylthio includes
`groups such as methylthio. ethylthio, isopropylthio, and the
`llk°-
`_
`C!r'C1031kYl STWPS hflwflfi ffom 3 10 10 C3-1‘b0T1 3101113
`50 which R1 and R4 ‘WY 1'5P1'353nT-
`incl‘-l‘3l°
`°)’°1°PT°I3Y1o
`cyclobutyl,
`cyclopentyl,
`cyclohexyl,
`cycloheptyl,
`and
`cyclooctyl.
`
`1:}
`
`15
`
`20
`
`35
`
`40 _
`
`DETAILED DESCRIPTION
`The compounds of this invention are named as sulfonates,
`and more specifically as carbonylmethyl sulfonates. For
`example, the invention compound of the formula
`
`0
`
`0
`
`0_:S|[_CH2_g_0_CH3
`
`0
`
`will be named phenyl methoxycarbonylmethyl sulfonate.
`
`65
`
`hr;-Intliloo llgogpé chloro, bromo, or iodo, but preferably
`
`A 5- or 6-membered rnonocyclic or fused bicyclic het-
`eroeycle is a monocyclic or fused bicyclic aromatic ring
`containing at least one to four heteroatorns in at least one
`
`4 of 13
`
`PENN Ex. 2201
`CFAD V. UPENN
`lPR20l5-01836
`
`

`
`5,510,379
`
`7
`
`ring, such as nitrogen, oxygen, or sulfur, or a combination
`thereof. Such a heterocyelic group includes, for example,
`thienyl, benzothienyl, furanyl, bcnzofuranyl, pyridyl, pyri-
`midinyl, pyridazinyl, pyrazinyl, pyrrolyl, pyrazolyl,isotl1ia-
`zolyl,
`thiazolyl, oxazolyl, isoxaziolyl, uiazolyl, tetrazolyl,
`imidazolyl, benzothiazolyl, indolyl, quinolinyl, isoquiI1uli-
`ny]. or N-oxides of heterocycles containing a nitrogen atom.
`More specifically, such a heterocycle may be a 2- or
`3—thienyl; 2- or 3-furanyl; 2-, 3-, or 4-pyridyl or 2-, 3-. or
`4-pyridinyl-N-oxide; 2-, 4-, or 5-pyrimidinyl; 3- or 4-pv-
`ridazinyl; 2-pyrazinyl; 2-pyrazinyl—N—oxide; 2- or 3-pyrro-
`13;]; 3-, 4-, or 5-pyrazolyl; 2-, 4-, or 5-thiazolyl; 3-, 4-, or
`5-isoxazolyl; 2-, 4-, or 5-oxazolvl; 3-, 4-, or 3-isothiazolyl;
`S-tetrazolyl; 3- or 5-{1,2,4)-Lriazolyl; 4- or 5-[1,2,3)-trIaz-
`olyl; 2-, 4-, or 5-irnidazolyl; 2-, 3-, 4-, 5-, 5-, or 7-indolyl;
`2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolinyl; l-, 3-, 4-, 5-, 6-, 7-, or
`8—isoquinc-linyl; 2-, 4-, 5-, 6-, or 7-benzothiazolyl; or 2-, 3-,
`4-, 5-, 6-, or 7-bcnzothienyl.
`A preferred embodiment of this invention includes com-
`pounds having the formula.
`
`Ct—C-e 2!-l1<)~'1
`
`is
`if
`0—i:i—(..‘Hg-C—Y—Cs-Can alkyl
`0
`
`where Y is O, S, or NH, and especially NH.
`Also preferned are compounds of the formula
`0
`0
`C1-C4 3-lk)'l
`||
`H
`ED-°+C“=+%3E
`E
`
`C1-C4 alkyl
`
`C1—C-tillklfl
`
`C1—C-I3]-k}"1
`
`where Y is O, S, or NH, and especially NH.
`Another class of compounds provided by the invention
`have the fonnula
`
`0
`D
`||
`|[
`xx:-Cl *-fi'-Cl-I3—C—Y —Ce—(h,cm.l.kyl
`Cl
`
`‘
`
`C1-C1 alkyl
`
`C1-C1 alkyl
`
`8
`Another preferred group of compounds of the invention
`have the formula
`
`0—S—CH;—C—Y—C5—C'qg alkyl
`
`‘ii’
`
`ii
`
`Q._
`
`15
`
`30
`
`35
`
`40
`
`45
`
`
`
`0—fi—CH;—C—Y—C,<,-Cmallcyl
`0
`
`wherein R2_ R3_ R,’ R, ,, W, 11', Q, and Z are as defined above,
`and Y is 0. S. or NH.
`
`The compounds of this invention are prepared by any of
`several synthetic routes utilizing routine methodology well
`known to those skilled in the art of organic chernistry. The
`compounds are prepared from readily available starting
`materials and reactants.
`
`In a preferred embodiment, compounds of Formula H
`O
`0
`ll
`ll
`
`R.—O—fi—CHg—C—Y—R5
`o
`
`are prepared by reacting an alcohol, thiol, or amine of the
`formula H-Y-R5 with an sulfonic acetyl halide of the for-
`mula
`
`Another class of invention compounds have the formula
`
`
`
`0
`O
`II
`II
`0 -5-—CH2-C—Y—C¢—C2u alkyl or phenyl
`H
`or substituted
`0
`phcnyl
`
`0
`0
`II
`II
`R1-—D-—S—Cl-I-g—C-l1a]n,
`I
`
`Io
`
`where R, is as defined above and halo is preferably brorno
`or ehloro. The sulfonic acetyl halides are readily prepared by
`starting with a sulfonic acetic acid, which can be reacted
`with an alcohol to give the corresponding sulfonic acetic
`acid ester, which reacts with a hale-genating agent to give the
`
`60
`
`65
`
`where Y is O, S, or NH, and substituted phenyl is phenyl
`having 1, 2, or 3 substitucnts as defined above.
`
`5ofl3
`
`PENN EX. 2201
`
`CFAD V. UPENN
`lPR20l5-01836
`
`

`
`5,510,379
`
`10
`
`compounds in which one or both of R3 and R4 of Formula
`1 are other than hydrogen. For example, a preferred class of
`invention compounds have the formula
`
`9
`corresponding sulfonyl halide The sulfonyl halide is reacted
`with an alcohol R1 OH to provide the corresponding sulfonic
`acetic acid ester. The ester is readily hydrolyzed to the acid,
`which is then converted to the corresponding sulfonic aoetyl
`halide. The above reaction is depicted by the general scheme 5
`of Chart 1 as follows:
`
`CHART 1
`
`O
`
`0
`
`0
`
`0
`
`II
`II
`mm,
`ll
`II
`Ho—fi—CH;—c—0H —--—-> H0-fi-CI-I;—C—O alkyl
`0
`O
`A
`2
`
`Hnlogenaoon
`
`0
`O
`0
`0
`N
`H
`R103
`ll
`ll
`R;—-O—fi—CH;—C—0 allryl (T ha.lo—T‘l[—CH2—C—0a]kyl
`0
`0 .
`.
`E
`E
`
`Hydrolysis to acid
`.
`
`gfigiitsian
`React wilh HYR5 and coupling agent
`
`0
`O
`0
`0
`II
`ll
`HYR5
`ll
`ll
`Rg—0—fi—CH2—C-halo T R1—0—fi—C[-l;g—~C-—Y—R5
`O
`0
`lU!
`
`Formula 1[
`
`In atypical synthesis, for example, sulfoacetic acid (1) is
`reacted with ethanol at about 56° C. for 2 hours to give the
`acetic acid ethyl ester (2 where alkyl is ethyl). The ethyl
`ester is reacted with a halogenating agent such as phospho-
`rus oxychloride to give the corresponding sulfonylchloride
`(3 where halo is chloro).
`'
`The sulfouyl chloride 3 is reacted with an alcohol (pref-
`erably a phenol, especially a di- or trisubstiurted phenol) to
`produce the sulfonate acetic acid ester 4. The ester 4 is
`readily converted to an acid halide by first hydrolyzing the
`ester, for instance by reaction with an alkaline base such as
`sodium hydroxide or potassium hydroxide to give the sol-
`fonatc acetic acid, and then reacting the acid with a halo-
`genating agent such as oxalyl chloride or the like to give an
`acid halide 5. The acid chloride 5 is reacted with about an
`
`equimolar quantity of an alcohol, thiol, or amine of the
`formula HYR5 to give the invention compound of Formula
`II. This latter reaction typically is carried out in an unreac-
`tivc organic solvent such as methylene chloride or toluene,
`and normally is complete in about 2 to 24 hours when
`carried out at about 2f]°—6£]° C. The product of Formula II
`is readily isolated by mutine—methods, and purified if
`desired by crystallization or chromatography over solid
`supports such as silica. eluting with common solvents such
`as ethyl acetate, acetone, and the like.
`An alternative method for preparing compounds of the
`invention comprises reacting a sulfonate acetic acid with an
`amine, alcohol, or thiol in the presence of a coupling reagent
`such as those commonly utilized in peptide synthesis. Typi-
`cal peptide coupling reagents include N.N—dicyclohexylcar—
`bodiimide (DCC), l\l—ethoxyca:bonyl-2-ethoxy-I ,2-dihydro-
`quinoline (EEDQ) and carbonyldiimidazole (CD1). This
`direct coupling reaction is preferred for preparing invention
`
`0
`II
`
`0
`II
`
`a,—o—i=.|—r|:a—c—NH-R,
`0 R3
`
`wherein R3 is phenyl or naphthyl, or substituted phenyl or
`substituted naphthyl as defined above.
`The use of a coupling reagent is depicted in Chart 1, and
`is given in more detail in Chart 11 below:
`casarn
`
`ii’
`s.—ou +ci——is|—tEH2
`1_
`o R4
`
`3
`
`———-%-
`
`if
`R; —0—fi—(|:H2
`0 R4
`
`9.
`
`l)HlJ.Li
`33002
`
`ii
`i’
`it
`it
`nfo—"#pn—c—ras R1—o—fi—pH—c—oa
`0 R4
`0 to
`
`E
`
`E
`
`In the above Scheme H, a sulfonyl -halide, such as the
`chloride (2), is reacted with an alcohol R,OI-i to give the
`sulfonate 3. The sulfonate is reacted with a strong base such
`as n—butyl lithium. generally in a solvent such as teu‘ahy-
`
`6ofl3
`
`PENN EX. 2201
`
`CFAD V. UPENN
`lPR20l5-01836
`
`

`
`5,5 10,379
`
`11
`drofuran at a reduced temperature of about -70“ C., to
`produce a lithio salt, which generally is not isolated but is
`reacted directly with carbon dioxide to give the acetic acid
`(4). The acetic acid is reacted with an amine HZNR5, an
`alcohol HORE, or a thiol HSR5, in the presence of a coupling
`reagent to alford the invention compound (5). The coupling
`reaction generally is conducted in an unreactivc organic
`solvent such as dichloromethane and normally is complete
`in about 2 to 24 hours when carried out at about 20° C. to
`about 60° C. The product (5) is readily isolated by routine
`procedures such as filtration and evaporation of solvents,
`and it is further purified if desired by crystallization, chro-
`matography, or the like.
`Compounds of Formula 1 wherein one or both of R3 and '
`15
`R4 are other than hydrogen can alternatively be prepared
`simply by reacting a Formula 1 compound in which one or
`both of R3 and R4 are hydrogen with a strong base such as
`sodium hydride to form an anion. followed by reaction with
`a compound of the formula RBL or R4L, where L is a leaving
`group such as halogen, especially chloro, iodo, or bromo.
`This reaction scheme is depicted in Chart III as follows:
`
`20
`
`5
`
`10
`
`12
`POCI3 (30.67 g, 200 mM) was heated at 125° C. for 5 hours.
`The rnixnire was cooled and filtered, and excess POC13 was
`removed to give ethyl chlorosulfonylacetate. The ethyl chlo-
`rosulfonylacetatc (18.66 g, 100 mM) was added dnopwise
`with stirring to a solution of 2,4,6-triisopropylphenol (22.1
`g, 100 mM) in 50 mL CH2Cl2 maintained at 0° C. The
`mixture was stirred at room temperature for an additional 18
`hours. The solvent was removed and the residue was redis-
`solved in 100 ml. ethyl acetate and washed with 1 N HCl and
`brine. The ethyl acetate was evaporated to provide ethyl
`(2,4,6-triisopropylphenoxysulfony1)acetate.
`This product was used for the next step without further
`purification.
`Ethyl 2,4,6-triisopropylphenoxysulfonyl}acetate (20 g,
`52.63 mM) and KOH (3.91 g, 100 mM) were mixed in 30
`mL H20 and 12 ml. Et01-I. The mixture was stirred at room
`temperature until all starting material dissolved. The solvent
`was evaporated, and the residue was redissolved in water.
`The aqueous solution was washed with diethyl ether, and the
`aqueous portion was acidified by pH 2 by addition of 1N
`hydrochloric acid. The acidic solution was extracted three
`
`CHART 111
`
`o
`o
`o
`o
`II
`II
`II
`I
`R1—O— —cna_—r:—r—a_.; “$4 R;—O—S—CI-I—C-—‘r"—R5
`!
`ll 9
`0
`0
`Na*
`
`I I
`
`1
`
`2
`
`R3L
`
`CI
`0
`ll
`II
`n.—o—s—c—c—-Y R,
`H / \
`OR;
`R4
`
`< UNQH
`2)R4L
`
`0
`0
`II
`II
`R1 0 s CH C—Y—R5
`]
`R3
`
`I-A
`
`Lu
`
`The invention compound (1) is reacted with about 1 M
`equivalent of sodium hydride to give anion (2), which is not
`isolated but rather is reacted directly with R3L, for example
`methyl chloride, 1-naphthyl chloride, cyclopropyl iodide,
`phenyl iodide, or the like, to give the tr-substituted sulfona-
`mide acetic acid derivative (3). If desired, the compound (3)
`can be Further reacted with a molar equivalent of sodium
`hydride, followed by reaction with R4L, to give the (1.02-
`dlsubstituted compound (4).
`The synthesis of specific compounds provided by this
`invention is presented in Ihe following detailed examples.
`The examples are illustrative only, and the invention is not
`limited to the compounds actually made or the synthetic
`routes utilized.
`
`50
`
`EXAMPLE 1
`
`2,4,6-Triisopropylphenyl N,N-dibenzylea.rbamoylmeth-
`ylsulfonate
`A. Preparation of 2,-4,6-triisopropylphenoxysulfonyl
`acetic acid.
`
`.
`
`Sulfoacetic acid (52 g, 371 mM) and Et0H (500 mL)
`were heated under reflux for 20 hours. The reaction mixture
`was cooled, and the excess ethanol was removed under
`vacuum to give ethyl sulfoacetate.
`‘H NMR (CDCJ3): 51.35 (t, 3H), 4.1 (s, 2H), 4.25 (q, 2H}.
`A mixture of ethyl sulfoaeetate (16.82 g, 100 mM) and
`
`65
`
`times with 50 mL portions of diethyl ether. The ethereal
`extracts were combined and the solvent was removed by
`evaporation to give 2,4.6-triisopropylphcnoxysulfonyl ace-
`tic acid.
`
`tn);
`
`‘H NMR (CDCIS): 8 1.2 (18H, d); 2.';'5—‘2.9 (1H,
`3.2—3.35 (2H, m); 4.4 (2H, s); 6.98 (2H, s).
`B. Synthesis of 2,4,6—triisopropy1phenyl N,N-dibenzyl—
`earbamoylmethylsulfonate
`To a stirred solution of 2,4,6-triisopropylphenoxysulfonyl
`acetic acid (1.0 g, 2.92 mM) in 15 mLof methylene chloride
`at 0° C. was added a solution of dibenaylamirie (0.59 g, 2.92
`mM) and dicyclohexylcarbodiimide (0.62 g, 3 mM) in 10
`ml. of methylene chloride. The reaction mixture was stirred
`1 hour at 0° C., warmed to 24° C., and stirred at that
`temperature for 12 hours. The reaction mixture was filtered
`to remove the solid precipitate. The filtrate was concentrated
`to an oil by evaporation of the solvent under reduced
`pressure. The oil was purified by chromatography over a
`silica gel column, eluting with hexanezethyl acetate (l:1
`v.-’v). The fractions showed by thin layer chromatography to
`contain the major component were combined and the solvent
`was removed by evaporation under reduced pressure to
`provide 0.5 g (76%) of 2,4,6-triisopropylpheny] N,N—diben-
`zylearbamoylmethyl sulfonate, mp l07°—l10° C.
`
`7ofl3
`
`PENN EX. 2201
`
`CFAD V. UPENN
`lPR20l5-01836
`
`

`
`13
`EXAMPLE 2
`
`5,510,379
`
`14
`
`2,4.6—Tr'iisopropylphcr1y] N—dipher1ylmethylca.rbamoy]m-
`ethyl sulfonatc
`This compound was prepared by the procedure of
`Example 1, except the dibenzyl amine was replaced with
`diphenylmethyl amine, mp l65°—l66° C.
`
`EXAMPLE 3
`
`This compound was prepared by the procedure of
`Example 1, except the dibenzyl amine was replaced with
`. 2,6-diisopropylaniline, mp 193°—195° (2.
`EXAMPLE 10
`
`N-(2,6-diisopropy]phenyl)car—
`
`2.6—Diisopropylphenyl
`barnoylrnethylsulfonate
`This compound was prepared by the general procedure of
`Example 3, except the dibenzyl arninc was replaced with
`2-E*dfi9_“?l3r°ylanfli“""' mp 178?] 80° C‘
`.
`_
`_
`Additional compounds which can
`prepared utilizing
`the general methods described above 111elude:
`‘
`h
`3"3_5'3n°'4'mfl“°mm°mYlph°“¥1
`(2'°hl°r°'3'mU°p 5'
`“ylth‘°°“rb°ny])‘T1eu‘y1 9”1f°nate*
`2'“‘fPh'h5'l N"5°b'n}'1’N"(n‘°°Wl)°arba’“°y1m°fl1y1 3111'
`f°“ate'
`_
`_
`b0I(13'lhVE_/l$”‘l3''5l'%°d°t:"°arb°‘Y}“aPh‘2‘Yl
`Ph‘3nY1lh1°°3T'
`3’ m 3’ 5“ °"f“ ?
`‘
`f 4~p1ethoxy—2—pyndyl
`dodecylthiocarbonylmethyl
`sul-
`ona e;
`llf-n-pr{)pylpyraz0l—4—}'l
`l\',N—dibenzylcarbamoylmethyl
`su onate;
`2,4,6-triethoxyphenyl N-[3,4—diehlorophenylmethyl)car-
`bamoylmethyl sulfonate;
`3-methyl-2-pyridyl
`fonatc;
`cyclopropyl N-[phenylmethylkarbamoylusulfonateg
`4-octylphenyl
`[3—phenylbutoxycarbonyl}methyl
`fonate;
`N—isol1cpty]—N—(3—bron1opheny]rnethyl-
`2-t:yaJ:lDphE'.tlyl
`karbamoylmethyl Sulfonate’
`2,4,6-t1'iisopropylphenyl l—methy1dodecy1th.iocarbor1ylm-
`“"31 “””‘.’.‘““°‘
`..
`'
`.
`2.4.6—tr11sopropylphcnyl 2.6—d11sopropy]pl1enylth1ocarbo-
`35 nyl sulfonate,
`dodecylthioearbonylmethyl
`sul31'c':jr'p:tt‘l:1—yl-4—ethyl—l—pyridy]
`4-['2-chlorophenyl)-S.7-udimethylquinolin-2-yl N-methyl-
`N-(2-chlorophenylmethyl]carbamoylipcthyl sulfonate;
`4.6-dlmethyl-5-pyridmyl rnetliyllhiocarbonylmethyl sul-
`folla-l6;
`_
`_
`_
`l-(meth-
`4-(2-ch1orophenyl)—5 ,'?—d1methylq111nol1n—2-yl
`oxycarbot1yl)cthyl sulfonate; 4-Lrifluoromethylphenyl l—[N—
`n-hexpl-N-(3-ehlorophenylmetliyl)carbarnoyl]-3-phenyl-
`—l—
`tc;
`5 pngljdrninilinglltitlphenyl
`dodeeyloxycarbonylmethyl
`sul-
`t-(mate;
`4—ethoxycarbonylphcnyl N-methyl-N-tetradeeylcarbam—
`oylmcthyl sulfonatc;
`6—nitro—1—naphthyl 3—[4-nitrophenyl)-liexylthiocarbonyl—
`methyl gulf-Guam;
`trt.-bt
`b
`l
`ht.hl'd1' -2-1
`5,’.-’—d'
`thl
`e
`11 oxycar ony In
`y rt n
`ethyl 5H1113;21;pap
`y
`(2”m'_:thy1'3'Ch1°m'5'
`_4‘(3’Ph°nylPmp3']thi°)'?’pYfidy1
`55 mtaophbenyllthlilo) I:1a11;pogylr1:-1)’etl1yl pulfonatg,
`1
`th 1
`1
`f
`'n'_ my 9 my
`'( 3°" "Cm" “V kar amoy me 5' S” '
`I
`°“a[°'
`h
`3
`H
`b
`1 h
`1
`th
`4'h5'd‘l°xyli'1E]’n3’]f
`'[I_“°t‘°xy°ar On“) any me my’
`Jwfonyhmel 3" bsu llmgm’ 1 N 3
`h
`1) N (2 3 d,
`'1 "lift olxycag lonyg my 1‘
`'£h"‘]lya?Ep
`'
`'
`‘
`' 1'
`_
`10 in tiny last i'i)I:aI4a‘m0.y m: Y 15“ Eula 3’ b
`I
`1
`fmMa:“é;'l:pdr:?;lUfi'(§c:am1n°p any met 3' )Car army 9“ '
`3-cyano-4-nitrophcnyl
`(3,5-diarnénophenylmethoxyjcarv
`65 bonylmethyl sulfonaie diaeetate; an
`3,5 —diisobutylphcr1yl N-[2-(3-chlorophenyl)propylca.r—
`bamoyl sulfonate.
`
`2,6—Diisopropylphenyl N—dodecyl carbarnoylmethyl su]— 10
`X-‘mam
`The general procedure 0fExamp1e HA) was fonowcd tn
`react ethyl ehlorosulfonylaeetatc with 2,6--diisopropylphenol
`to give ethyl (2,fi—dijsopropylphenoxysulfonyI)acctate. The
`ethyl acetate derivative was hydrolyzed to 2,6-diisopropy-
`lphenoxysulfonyl acetic acid. The acetic acid derivative was
`reacted with dodecylamine and DCC according-to Example
`I(B) to provide 2.6-diisopropylphenyl N-dodecy]earbamoy]-
`mcthylsulfonam‘ mp 75o_-ms C_
`-
`EXAMPLE 4
`2,6—Diisopropy]phenyl N—diphenylmelhylearbamoylm-
`ethyl Slllfonalfi
`'Ihis compound was prepared by following the general 25
`procedure of Example 3, except
`the dodeeyl amine was
`replaced with diphenylmethyl amine, mp l20°—l22° C.
`
`20
`
`15
`
`EXAMPLE 5
`2’6_Dfis0pmpylphenoxysulfonyl acetic acid
`This coin ound was described in ex crimcntal section of
`Example 3 p
`13
`1H NM1i(cDC1 : 51.12 (12H, :1) , 3.15-3.22 (211. I11).
`422 (2H, S)’ 7_08_3_}'15 (3H, m), 94 OH, bf)’
`
`so
`
`EXAMPLE 6
`P PYP
`l henyl N-(2,3,6-triisopropy]pheny])ca_r.
`2,6-Diiso ro
`bamoylmcthylgulfonate
`This compound was prepared by the same procedure of 40
`Example 3, except the dibenzyl amine was replaced with
`2,4,5-u-iigop1-opylanjjine, mp 2]1“_213° C_
`
`4
`
`so
`
`EXAMPLE 7
`2=4v6'T‘fi5°PI°PYlPl‘e“3’1
`N'is°pr°133'l‘N'(4'Ihi°m°lh'
`ylphenylmethyllcarbamoylrriethyl sulfonate
`Tlfls C°ml3'3lmd W35 Prep’-‘Ted 1“ ‘-119 Sam“ _"‘3““5r 35 F0’
`the tltle compound of Example 1, except the dtbenzyl arnme
`was “591aC‘_3d with N‘i5°Pr°P5'1'N'
`(4'mi°methYlPhe“3’l)
`methyl) armne. mp l1{)‘’—] l2 “ C.
`EXAMPLE 8
`2,6—Diisopropylphcnyl
`(2.6~diisopropylphenoxyearbom
`y1}methylSL11fonatB
`2,6-Diisopropylphenoxysulfonyl acetic acid (prepared as
`described in Example 3] was reacted with oxalyl elflorideto
`provide 2,6—diis0propylphenoxysulfonyl
`aoety] chloride,
`The acid chloride was reacted with 2,6-diisopropylpheno] in
`diehloromcthane to provide, following evaporation of the 60
`reaction solvent, 2,6—diisopropylphenyl
`(2,6—diisopropy—
`lphenoxycarbonyl)methyl sulfonate, mp 9fJ°—92° C.
`EXAMPLE 9
`3,4,6—Triisopropylphenyl N-(2.6-diisop11opylphenyl)car-
`barnoylethyl snlfonate
`
`dodecylthiocarbonylmcthyl
`
`sul-
`
`sul-
`
`—
`
`3 of 13
`
`PENN Ex. 2201
`CFAD V. UPENN
`lPR20l5-01836
`
`

`
`5,510,379
`
`15
`
`The compounds of the presentinvention are potent inhibi-
`tors of the enzyme acyl—CoA: cholesterol acyltransferasc
`[AC1¥I'), and are thus effective in inhibiting the e