(12) United States Patent
`Robl et al.
`
`(10) Patent No.:
`(45) Date of Patent:
`
`Us 7,358,254 B2
`Apr. 15, 2008
`
`US00?358254B2
`
`514-"365
`514-GT4
`514.-‘"376
`5485236
`
`.. 504-242
`514.-"355
`
`
`
`5.254.526 A
`5.262.540 A
`5.348.969 A
`5.3tEi2.87"9 A
`
`10.-"1993 Rominc et al.
`ll.-‘"1993 Meanwell
`9.-"1994 Romine ei at.
`ll.-‘"1994 Meanwell
`
`i
`j3"599'.;..J.5 '
`A
`...
`.
`5.512.359 A *
`
`.
`‘
`lxubota et :11.
`2:19‘)?
`3.-"1997 Nlilrugesan
`
`'
`
`FR
`l_.R
`RU
`SU
`WU
`W0
`W0
`
`FOREIGN PATENT DOCUMENTS
`2 1 S6 486
`l__l9_n
`,'(;”'6,m
`,M99(‘J
`Héo54'935
`4..-‘I994
`2033184
`fi.-"I990
`W092,-94334
`3,-1992
`w0l)5__-'173l)3
`5_.-1995
`WO..-'96..-35678
`1|.-‘I996
`
`OTHER l’UBLlCA'l‘IONS
`
`Klcmcn C1 all. J'Cc1lBiochcmSupp1_' VOL 15' No 8! p‘ m
`(-Xpwzzugmg) “gm )_
`Me-lki ct
`.11..
`J." Lipid Rcs.. vol. 34. No. 9. pp. 152?-1534
`(_X1"0'0l0‘)4445) (I993).
`Baxa. ct .11. Biocheinistiy. vol. 225. No. 22. 1989 pp. 8683-8690.
`Hotainisligil. GS. el al. "Uneoupling of Obesity from Insulin
`Resistance Thi'oug.l1aTa.i'geIed Mutationm aP2. lheAdip0eyleFal1y
`Acid Binding Protein”. Science. V0. 2?4._ Nov. 22. 1996. pp.
`l3TF—l3?9.
`\»Ia'.A.
`.l.“D'hd a]k]h'
`'. hthl hl
`'
`11'
`-:
`'i\"0l\l«'el
`;i:i)d—l\'iicle*{)isil:l)tE iilinlliie
`S—DABO % ' 3”, J. M '1. Ch
`., 1997, 40,
`|447—l454.
`Dialog AlerIr1t)‘“l:§l)l{‘)2§:iiJm1.t2TI‘)97, Phanmprpjecis No. 5149.
`8
`_
`_
`‘med 130’ 33311111131’
`Jon Weber
`Priiiiari’ ;"5'.raniim3r
`Assi'.s.faiii‘ I£.ra.miJrer Abdel A Mohamed
`(74)‘.1_q,,,.,,q,,’ /;gL,,,,: Onyx.-,._.” R0Scma[.yM_Mianofloscpll
`(_~_ Wang: lflumlcc A_ ])u]]Ca,]
`
`(57)
`
`ABSTRACT
`
`Aiiietliod is provided iortreatiiig atherosclerosis and related
`diseases. eiiiployiiig an aP2 inhibitor or a combinatioii of an
`al-’2 l]']l']il)llt)[' and another amiatliemsclemtie agent.
`for
`example. an llM(i C0./\ reduetase inhibitor such as pravas-
`Hun
`‘
`'
`
`2 Claims, 1 Drawing Sheet
`
`(54) METIIOD FOR TREATING
`ATIll4IR()S(II.ER()S[S ENlPI.()YING AN AP2
`]_\‘H[]3[']"0RAN]) (303/[B[NAT[0‘\'
`
`(75)
`
`lnventnrsz Jefirey A. Robl, Newluwii, PA (US):
`Rex A. Parker, Tilusville. NJ (US);
`‘
`,
`.
`.
`.
`5”“ *'‘- B11"-'1‘~_ Le-“m1?=‘°”= M’*[U5)~
`Haris Jamil. Libertyville, IL (US);
`Bruce L. Jacobson. Carlsbad, CA
`(US); Krishna Kodukula. Priiieeluli.
`NJ (US): Gokhan Hotamisligil.
`w‘°-‘”‘°"51°'Y= MA (US)
`1
`_
`‘
`_
`I
`_
`(73) Assignees: Bristol-Myers Squibb Company.
`Princeton. NJ (US); President &
`Fellows of Harvard College.
`Cambridge. MA (US)
`
`(“ 3 Notice:
`
`Subjectto any disclaimer,‘ the term of this
`patent 15 extended or acliusted under 35
`U5-(1 154(5) W314 d"‘3’5-
`
`_
`(21J APPL N04 10/371731
`
`(221
`
`l:ill3d1
`
`J1111- 21: 2004
`
`(65)
`
`(51)
`
`Prior Publication Data
`Us 200450229807 Al
`NOV‘ 18-' 2004
`Int. Cl.
`(2()U(:.()l)
`AMKJL/505
`(2006.01)
`A6IK 38/00
`(20U(“0l)
`C07” 275m6
`(200601)
`C070 1”3/00
`Sl4f2S6;5I4ll2:5]4f374:
`(52) U.S. Cl.
`548E210: 548E232: 548E235; 548F236: 530F324
`(58) Field of Classification Search
`514E256.
`514-i'12_. 374; 548E210, 232, 235, 236; 530F324
`See application file for complete search history.
`
`(56)
`
`References cited
`U.S. l-‘A'l‘l-'.N'l‘ |)()(.‘UM|-'.N'l‘S
`
`4.001.223 A
`4.051.250 A
`5.l8?.l88 A
`5.218.124 A
`
`15197? NlaJ.L:i.lia
`9319?‘? Dahin et al.
`2.-"1993 Nleanwell
`6-"1993 Failli et al.
`
`260.-"2411 M
`424.-"2?2
`514.-"3?4
`548.-"180
`
`1 of 17
`
`PENN EX. 2100
`CFAD V. UPENN
`[PR2015-0 1836
`
`

`
`U.S. Patent
`
`Apr. 15,2008
`
`US 7,358,254 B2
`
`léuflfi
`
`2 of 17
`
`PENN EX. 2100
`CFAD V. UPENN
`[PR20l5-01836
`
`

`
`US 71,358,254 B2
`
`1
`METIIOD FOR '[‘REA'[‘I_‘{(I
`ATIIEROSCLEROSIS EMPLOYING AN AP2
`INHIBITOR AND (I()NlB[NA'['I()N
`
`FIELD OF THE INVENTION
`
`2
`
`The method of the invention also encompasses prevent-
`ing. inhihitiiig or reducing risk of cardiovascular and cere-
`brovasculer diseases resulting from atherosclerosis, such as
`cardiac andfor cerebral
`ischemia.
`inyocardial
`infarction,
`angina. peripheral vascular disease and stroke.
`The aP2 inhibitors suitable for use in the method of the
`
`The present invention relates to a method for treating
`atherosclerosis and related diseases. employing an aP2
`inhibitor alone or in combination with another type ant iath-
`311159131"01113 112e111-
`
`invention are compounds which bind to the aP2 protein and
`inhibits its function andfor its ability to bind free fatty acids.
`The compounds will preferably contain less than 60 carbon
`10 atoms, more preferably less than 45 carbon atoms, and will
`contain less than 20 hetcroatoins, more preferably less than
`l2 hetcroatoins. They contain a hydrogen bond donator or
`BACKGROUND OF T11“ 1NV1—1NT10N
`acceptor grotip, preferably acidic in nature. which include).
`_
`‘
`‘
`_
`but is not limited to. co,11, tctrazole, so,11, 110,11, Pat‘)
`11111)’ 1115111 1111111119 P10161115 (F-‘1B_1’S) are 5111311 °¥10P15"S-
`mic proteins which bind to fatty acids stich as oleic acids 15 (ololl (wllmc R is lower alkyl or lower allmxy). Oll.
`which are important metabolic fuels and cellular regulators.
`l-tll [S()__Rf 0,. (;0Nll501l{a lwllcm lg ls lower alkylll and
`D3'51'eB1111111011 01 11111)’ 1113151 111“~‘111-1311115111 111 1111111111“ 1155113 15
`thiazolidindione. and interacts (directly or through an iiiter—
`a prominent feature ol: insulin resistance and the transition
`Yelling water molecule): either bylonlc Orllydmgen bondlng
`1111111
`11119311)’
`111
`111111'1115111111
`d'~'I1C1111‘~‘111
`111111113195
`1111311111111
`interactions, with one. two, or three of the three amino acid
`1111111131111 111' 11131119 11 1111111911351
`residues, designated
`Arg l[)(, Arg l2( and Tyr 128 in
`aP2, an abundant I-4.6 KDa cytosolic protein in adipo—
`hulmm al)2_ Within the aP2 pmlzeinl
`1
`cytcs, and one ofa family ofhomologous intracellular fatty
`vl-he mmbmmds Suilablc for use lmmln preferably comain
`a1i:_i;,ibindi11(1;5pr§:1l°i:15 [F:ABc1rS1' is 1111111131311 iglhc 1§31"“‘1‘?:;
`an additional substituent, preferably hydrophobic in nature.
`0
`‘'111'.‘‘‘’‘ m C .mg 1n‘ 3. ‘1f°°1’1e‘ al?
`.m.e laws ,";‘"1’ am
`which include the following groups: alkyl. cycloalkyl. aryl.
`fluxes in adipose tissue. (1. S. Ilotamisligil et al. Ui1coti- 35 helemaryl
`cyclohetemalkyl
`benzO_l-used aryl
`,md het_
`1'0 fOb’”
`F
`I
`‘
`l‘ R‘‘‘‘'
`'*'I‘Iiro
`"Ii “d
`1
`-
`-
`1
`-1
`1;/I1lfi:T1i)0nin1':g§ tIl'::11:kcll1i1’1:J"1JI1te1]'-:1,’21]‘;’1‘5‘ltL'id Bh?d€ll:dP:0I:1;flj,
`eroaryl, and their substituted counterparts. Ftspccially pre-
`S _. _
`_ _ V. 1‘ 2.l."4 N‘
`£12 fggl,
`ty‘HW H79 E _
`ha-‘
`ferred are aryl and substituted aryl groups. More especially
`‘ uLm’L;'
`,0 ‘
`,' W‘
`’
`1' 111?‘
`‘
`_
`'
`‘_
`’_m1mn1
`preferred is phenyl and halo or methyl substituted phenyl.
`1
`aP2-delicient mice placed on a high [at diet
`[or several
`.
`.
`.
`.
`.
`weeks developed dietary obesity. but. unlike control—11iice on 30
`.Theh.ydmph°b1c 5"b1.1m."em binds 10 (“.11 andfor Interacts
`‘.
`.
`.
`.
`.
`.
`.
`.
`with a discrete pocket within the al-12 protein defined roughly
`a similar diet, did not develop insulin resistance or diabetes.
`b tl
`.
`.d
`.d
`Pl
`16 T
`19 M t 20 V 1 23
`Hotamisligil et al conclude that “aP2 is central
`to the
`‘B11 :;‘1:;a21l1_I19l;?c]]J]r_e1°151,l11.fi 5:
`if A‘
`11” :’
`111
`’ ‘
`‘1
`‘.
`’
`pathway that links obesity to insulin resistance” (Abstract.
`‘1
`“ ,d i
`I
`’
`11'
`’ W
`1’
`rg 1
`"1
`page 1377}
`human al 2.
`I111: throttgli space distance from the hydrogen
`DIALOG ALERT DBDR928 dates Jam 2‘ 1997‘ I,hm__ 35 bond donorfacceptor group and the additional substittient
`maprojects No. 5149 (Knight—Ridder Informatioii) discloses
`ffijxtliqls wlthm the dlsmnce 01 about 7 to about 15 Ang-
`that a major drug company “is using virttial screening
`‘
`“
`_
`l
`‘
`techniques to identify potential new antidiabetic com-
`The ab0V_e compounds may be 1-‘111P1°}’ed In 1116 ion“ 01
`pmmdgfv ll ls mplmcd lhal -slhc company is Screening “sing
`pharmaceutically acceptable salts thereof and prodrug esters
`aI-’2_. a protein related to adipocyte fatty acid binding pro-
`11113111111‘
`ieinf‘
`The term “antiatlierosclerotic agent“ as employed herein
`refers to antihyperlipidemic agents including I-IMG C‘oA
`reductase inhibitors, rnicrosomal triglyceride transfer pro-
`tein (MTP] inhibitors. fibric acid derivatives. squalene syn-
`In accordance with the present invention, a method is 45 thetase inhibitors and other known cholesterol
`lowering
`provided for treating atherosclerosis wherein a tlierapeuti-
`agents. lipoxygenase inhibitors, _/\_(.'AI‘ inhibitors. and I-’l-’AR
`cally elI‘ective amount of a drug which inhibits al-12 (aP2
`(1117 dual agonists as disclosed hereinafter.
`inhibitor) is administered to a human patient
`in need ol‘
`treatment.
`
`311
`
`411
`
`DESCRIPTION OF THE INVENTION
`
`BRIEF DESCRIPTION OF FIGURE
`
`is 3 wmplllcr g,_.m_.ml,_.d
`'l'h,_. acwlllpanylllg l.‘](}UR][
`image of 3 partial X_ra}' Sn-ucml-e of compound XV-‘IA
`(d,_.5m-[bed lmmjnaflcrl hmmd ll», human ap2_
`
`l_)]:‘,'l‘Al]_l:‘]_) DESCR[l)']‘ION Q1: 'l‘l—lE
`INVENTION
`
`In addition, in accordance with the present invention, a 50
`method is provided for treating atherosclerosis. wherein a
`therapeutically eifective amount ofa combination of an aP2
`inhibitor and another type of antiatherosclerotic agent
`is
`administered to a human patient in need of treatment.
`l-‘urtlicriiiore. in accordance with the present invention, a 35
`novel antiatherosclerotic combination is provided which is
`formed of a drug which inhibits al-’2 and an aiitiatlieroscle-
`Examples ofaP2 inhibitors suitable for use herein include
`1011.1: .d15cm_wlm,h 1111161111115 11.11.11 mm_ihan"1lu_°1l1Cr 1111111 by
`l
`.
`.
`.
`inhibiting al-12.
`Iht. al-12 inhibitor will be employed in a
`compounds which include an oxazole or analogous ring.
`_.
`.
`.
`.
`.
`\M..lgl1I ratio to the antiatherosclerotic agent (dependingupon can Thm U l; Pat No 5 218 124 10 Failli at al (the diliclomm
`its mode ofoperation) within the range from about 0.01:] to
`l.
`C _
`'
`°
`l
`_
`_.
`b
`ll.’
`,
`__
`about l00:l_. preferably from about 0.511 to about 10:].
`E01: (1: \£_:;'L1l?1£;r:£LaC1lt;1L1nas lip; alga
`11 will be appreciawd that the, method 01-,th9_ 11‘‘’e‘"i°‘‘ 11”
`suitafhlc for‘. use herein. which iynclude substituted benmyl-
`treatmg mherosclerosls employmg an aP2 mhlbnor alone or
`benvenc bipheny- and 2-oxayole-alkanoic acid derivatives
`in combination with an antiatherosclerotic agent eiicom-
`65 h,
`-I
`l~ ll
`_-
`,
`_
`1
`passes treating, redticiiig risk of. inhibiting. preventing and!
`“mg 1 L 0 Owing Hruuurh
`or reducing or causing regression of atherosclerosis.
`A(CII2},,O—B
`
`3 of 1?
`
`I
`PENN EX. 2100
`CFAD V. UPENN
`[PR2015-01836
`
`

`
`wherein
`
`A is a group having the fonnula
`
`3
`
`US 75,358,254 B2
`
`4
`
`-c0n‘['in]_]ed
`
`R‘
`1*‘
`YE of
`
`s
`
`R‘: :‘<
`| Y
`
`3
`
`11-
`
`wherein
`X is
`
`N
`
`or
`
`}’_ is
`
`R3
`I
`:53‘;
`
`R3
`l
`
`R3
`l
`
`
`
`PE“.
`
`‘
`
`R3
`l
`
`_
`
`l
`
`R3
`l
`
`i
`
`‘i
`PC‘ 0
`0
`LITII3
`(1!
`R4
`I
`I
`I
`II
`—cirNHcI|x*I15_ —tH—cToH or —r.-HCNIOHIR5;
`
`on
`
`R3
`
`R“ is lower alkyl;
`m is 0-3;
`
`—
`
`10
`
`and the pharmaoologically acceptable salts thereof.
`The grouping A embraces, inter alia, 5- or 6-111embered
`15 unsaturated nitrogen, sulfur or oxygen containing n1ono- or
`benzofused-heterocycles, optionally substituted with lower
`alkyl or phenyl. The foregoing definition embraces the
`following heterocyclic 111oieties;
`furyl, pyrrolyl,
`thienyl,
`oxamlyl, thiazolyl, imidamlyl, pyridyl, pyrazinyl, pyrim-
`2n idinyl, henzofllranyl, benzothienyl, henzothia'/olyl. indolyl.
`bcnzoxazolyl, quinazolinyl, belncimidazolyl, quinoxalinyl,
`quinazolinyl and the like.
`Preferred are the examples where A is defined as above
`and l! is
`
`re: '4:
`
`and R7 is
`
`R1 is hydrogen, lower alkyl or phenyl;
`R3 is hydrogen or lower allqrl; or
`R‘ and R3 taken together form a benzene ring, with the
`proviso that when X is
`N , Z is other than
`
`30
`
`:CHCO:H-
`1;,
`
`R3
`R-"
`_
`l
`l
`TCZCT‘
`
`invention. com-
`In another embodiment of the present
`pounds which have activity
`aP2 inhibitors suitable for use
`,5 herein are disclosed in US. Pat. No. 5.403.852 to Barreau et
`" al (which is incorporated herei11 by reference) which are
`oxamle derivatives and have tl1e structure
`
`R3 is hydrogen or lower alkyl:
`n is 1-2;
`B
`
`4”
`
`\\
`
`F2
`ll
`0
`
`/
`T ‘
`\
`
`Cl-ICOT Y or
`
`R7
`
`W-]]m-gin
`Y is ()R5 Gr N(()11)R";
`R4 a11d R5 are each. independently, hydrogen or lower
`alkyl;
`R“ is hydrogen, halo or nitro;
`R7 is
`
`R4
`
`:C?HC00R5.
`
`0
`
`R4
`R4
`|
`|
`:C11NE0111C-‘N112. —CHNt01I}CR*=
`
`0
`
`R,
`
`
`RI
`
`1~'/
`
`II
`
`O
`
`1\'II—N
`
`L
`LII]
`l
`l‘- 211T"/\ <\
`1\'— N
`
`R’
`
`R
`
`_
`so _
`in which;
`R and R‘ are identical or dillerent and represent a hydro-
`gen atom or an alkyl radical containing 1 or 2 carbon atoms,
`R, and R2 are identical or dillerent a11d represent hydro-
`)5 gen or halogen atoms or alkyloxy radicals i11 which the alkyl
`portion contains
`1
`to 4 carbon atoms iii a straight or
`branched cllain. and
`n equals 3 to 6,
`
`5“
`
`as
`
`as well to their salts, to their isomers where they exist and
`to pharmaceutical oonipositions containing them.
`ln addition, other compounds which have activity as al-’2
`inhibitors suitable for use in the method of the invention are
`
`Pat. No. 4.001.228 to Mattalla
`compounds disclosed in U
`(which is
`incorporated herein by reference) which are
`2—thiol—4,5-diphenyloxazole S—derivatives which have the
`structure
`
`4 of 1?
`
`PENN EX. 2100
`CFAD V. UPENN
`[PR2015-01836
`
`

`
`U1
`
`US 75,358,254 B2
`
`C
`
`C—S—(‘I-t3—[Cl-I3}m—((.‘0),,—l1
`
`111
`
`'4:
`
`l or 2, n is I and R represents hydroxy,
`wherein m is 0,
`alkoxy or amino. Also i11cl11ded within the scope of this
`invention are salts of the co111pounds of formula III above,
`. ..
`-.
`particularly pl']dITl’1dCl.Lll1Ldlly acccplablc
`addition salts
`thereof.
`Preferred are S—(4,5—dipl1enyloxazoI—2—yl)—mercaptocar— 15
`boxylic acids of the formula:
`
`10
`
`N
`II
`c—s—c11;—:c113;,,,—coo11
`
`‘7fi”5-tC
`||
`c
`t.‘5II,/ ~\()/
`
`3”
`
`25
`
`1 or 2, and pltarmaeeulically acceptable
`wherein m is 0,
`lower alkyl esters and salts thereof.
`In another embodiment of the present invention, com-
`pounds which have activity as aP2 inhibitors suitable for use
`herein are disclosed i11 US. Pat. No. 4,051,250 to Dahm et 30
`al (the disclosure of which is incorporated herein by refer-
`ence) which discloses amle derivatives of the structure
`
`6
`
`—continued
`
`
`
`R‘
`
`h
`\
`
`/
`
`RI
`
`R‘
`
`/
`
`N
`\
`
`0
`
`01'
`
`R]
`
`.,
`‘
`_
`R is (.ll2R‘;
`R‘
`is l-‘h or Th;
`R2 is
`
`114
`\l-..___N
`_
`\
`l] “j
`31/
`
`H
`/l\'-..___ 11
`<
`l
`N’/"
`
`(,0 R3 _ d
`'3
`" dn
`R"
`15 ll! 01' C-1'C410wcr alkylé
`_
`or pharmaceutically acceptable salt thereof.
`Preferred are the compounds where R is CI-I3CO2I-I and
`
`R
`
`R
`
`_
`
`i
`3
`NYE.
`
`s—A—11.
`
`Iv 35
`
`4n
`
`CH3
`
`ll.
`
`L
`-
`
`'-aw
`
`.\I"'\l
`
`wherein R1 is carboxyl, esterified carboxyl or other fiJnc— _ 01' its l5'“l0me1’ and R1 I3 Ph-
`liflmlly m0dlfi9d 031"l3“XY1 310111‘; R: and R3 '-“Ch “"3 “U1 Ur 4’
`In yet another embodiment ofthe method ofthe invention,
`UP 10 10 °31’b“T1 3WT15i A is (-3.112.. 1“ Wlllch '1 is 3" l‘“‘~‘g‘3"
`compounds which have activity as aP2 inhibitors suitable for
`hum 1 l° 10-‘ inchlsive-i and Z 15 0 Gr S= and lhg physlologi’
`use l1erci11 are disclosed in PC'1‘ application W0 95i’l7'393
`Cally acceptable salts thereof‘
`which are diaryloxamle derivatives having the structure
`Preferred are preferred compounds as disclosed in the Sn
`Dahm et al patent.
`'
`In still another embodiment of the invention. compounds
`which have activity as aP2 inhibitors suitable for use herein
`are disclosed in US. Pat. No. 5,380,854 to Romine et al (the
`disclosure of wl1icl1 is incorporated herein by reference) and is
`are pl1enyl—heterocyclic oxazole derivatives which have the
`i
`structure
`
`1
`R‘
`
`1
`R‘
`
`i
`
`\
`3
`/J—‘i‘__Q
`’\o—r\'—R‘
`
`_\J
`
`\
`
`0
`
`VI
`
`X l
`TOR
`
`\“
`
`K
`
`:
`N\,_/O
`
`V 60
`
`65
`_
`
`.
`.
`wherein R1 is carboxy or protected carboxy.
`R2 is aryl which may have suitable substituent(s),
`R" is aryl which 111ay have suitable substit'uent(s).
`A‘ is lower alkylene,
`A2 is bond or lower alkylerie and
`—Q— is
`
`5 of 1?
`
`PENN EX. 2100
`CFAD V. UPENN
`[PR2015-01836
`
`

`
`US 75,358,254 B2
`
`7
`
`.
`
`1
`.-\'
`
`CH:
`
`‘
`(Jig:
`
`or
`
`A
`:
`j f .
`V \'
`
`(in which
`
`8
`
`VIII
`
`PI1
`
`Pl:
`
`5
`
`10
`
`
`
`3
`
`"
`
`wherein
`Y and Z are independently hydrogen or together term a
`15 bond‘,
`I
`2
`3
`X 15 CN.-I C023 01’ CONR R .1
`is cyclo (lowerjualkane or cycle(lower)alkene. each of which
`R and R are independently or together ll, Na, or C1-C5
`may have Suiwble 5ub51imem(5}},
`low‘? alky
`_
`1
`_
`Preferred are the preferred compounds of WO 95117393
`“(R1-and R are independently or together} I, or(.,-(.5 lower
`as illustrated by the working Examples thereoi
`Another embodiment of compounds which have activity an d y ‘ lk ].
`I
`1
`h Th
`f
`_ b H
`I. h ,
`d‘
`as aP2 inhibitors suitable for use l1erei11 are disclosed in U.S.
`gr ?I._ a _1dm_e
`id _
`IF‘ d “I”
`Pat. No. 5,362,879 to Meanwell (the disclosure of which is
`M H"
`‘:m"t1 L .fim‘tl‘n:‘d Eonhpoun bk?
`‘xmnp es
`incorporated herein by reference) which are 4.5-dipl1eny-
`hE_’af“}e
`pa en as 1 1"’ m e
`y
`1e W“ mg
`.
`loxazole derivatives having the structures
`l “mu '
`.
`.
`Wm j_
`In another embodiment of the invention, compounds
`*3 which have activity as al-’2 inhibitors suitable for use herein
`are disclosed in U.S. Pat. No. 5,348,969 to Romine et al (the
`disclosure of which is incorporated herein by reference)
`which are phenyloxamlyloxamle derivatives having the
`structure
`
`Pb
`
`/
`
`_
`1‘
`\§
`
`ph
`
`0
`
`_
`3
`/
`Y
`
`o
`
`CU3R
`
`wherein
`R is H or C1-C5 lower alkyl,
`X is N or (Tl l,
`Y is H or CO2R‘, or CORE,
`R‘ is C1-C5 lower alkyl. or phcnylmethyl, and
`R3 is C1-C5 alkyl;
`
`Pb
`
`\ ‘\
`0
`
`Plt
`
`0
`V
`x\‘C.‘O1R
`
`‘
`
`wherein
`
`R is H or C1-C5 lower alkyl,
`X is ((5113),, or para or meta substituted phenyl
`_
`1
`_
`7
`“"1‘°:°“‘ ‘he 5"b5l””°m 15 OR:
`R“ is C1-C5 alkyl, and
`n is an integer of 4 to 8,
`
`30
`
`_
`I
`W “'""m
`X is
`
`VIII?»
`
`35
`
`4,,
`
`4)
`
`5n
`
`J
`
`R
`
`/
`
`N
`)\
`
`0
`
`x
`
`11'
`
`IX
`
`‘
`on-
`
`j or
`R‘
`
`R"
`
`R‘
`
`I
`
`\V
`.\I\R_s R5
`H
`
`0
`
`N
`
`\~
`
`Y
`
`Y is (I3, Ph, or 0]], provided that when Y is ()1 l,
`55 compound exists an the kero-enol tautaumerisni for111
`
`the
`
`and pharrnaceutically acceptable salts thereof.
`Preferred are the preferred compounds of the Meanwell 50
`patent as illustrated by the working Examples thereof.
`ln still another enibodinient of the present
`invention.
`compounds which have activity as al-’2 inhibitors suitable [hr
`use herein are disclosed in U.S. Pat. No. 5,187,188 to
`
`HN
`
`O
`\n/
`0
`
`0
`
`I\'\
`Y
`OH
`
`Meanwell (the disclosure of which is incorporated herein by 65
`reference) which are oxamle carboxylic acid derivatives
`having the structure
`
`_
`I
`R I5 P11 0l'Tl1:
`R1 is (.'l l2R3:
`
`6 of 17
`
`PENN EX. 2100
`CFAD V. UPENN
`[PR2015-01836
`
`

`
`US 75,358,254 B2
`
`9
`
`11-‘ is (10,114;
`R4 is II or C1-C5 lower alkyl;
`R5 is ll or CII3; R5 is OI ICIIN or HEN: and
`R7 is II or Oil;
`
`10
`ln another embodiment of the invention, compounds
`which have activity as aP2 inhibitors suitable for use herein
`are disclosed in PC!‘ application WO 92ft)-4334 which are
`substituted 4,5-diary] heterocycles having tl1e formula
`
`or pharmaceutically acceptable salt thereof.
`Preferred are the preferred compounds as delineated in the
`Roniine et al patent a11d in the working lflxamples thereof.
`especially where X is
`
`XI
`
`
`
`10
`
`in which
`
`15
`
`each group Ar is the same or different a11d is optionally
`substituted phenyl or eptieiially substituted heteroaryl;
`X is nitrogen or CR '.
`Y is nitrogen, N(CHg),.-A Or C (C H2),.A;
`and R3 is cH,co,H.
`Z is nilmgcn. OX)/E011 01' Na-‘I 13),,-’\s and lhll d0W~‘d lint‘
`In addition, co111pou11ds which have activity as aP2 inhibi-
`tors which 111ay be employed herein include those disclosed 2n ifldicalcfi 1110 0P1i0T13] I31'C5l311Cl3 Of 3 d0Ul31C bimd 30 35 T0
`in U .S. Pat. No. 5,262,540 to Meanwell (the disclosure of
`f0l‘II1 3 fully llllsflfflfaled heterocyclic ring;
`which is incorporated herein by reference) and are 2-[4,5-
`R1 ishydrogen, (I1_,alkyl_. optionally substituted phenyl or
`diaryl)—2—oxazoly1 substituted phenoxyalkanoic acids and
`optionally substituted heteroaryl;
`esters having the structure
`11 is 4 to 12; and
`A is COEH era yup hydrolysable to C031-I, 5—tetrazolyl,
`3
`_
`_
`SO 1-], P 0] OR)“ P 0) 0H),, or P O R) OR in which R
`
`25
`
`N
`\>:[cH,}n(_-0,11
`0
`
`l
`
`Ph
`
`“‘
`
`X91
`
`KB
`
`ph
`
`PJ1
`
`I \%S—[CI-E3},,(.‘tT}_1R
`
`N
`
`0
`
`(wherein n is 7-9 and R is hydrogen or lower alkyl: or when
`R is hydrogen. the alkali metal salt thereof).
`
`is hydrogen or C1__,alkyl_. or a pharmaceutically acceptable
`salt thereof.
`Preferred are preferred compotmds of WO 92304334.
`ln yet another embodiment of the invention. compounds
`which have activity as al’2 inhibitors suitable for use herein
`are disclosed in French Patent 2156486 which have the
`structure
`
`XII
`
`R3
`
`RI
`
`0
`R3
`I
`/>—X—CH—C:OOH
`\]
`‘
`
`|
`
`30
`
`35
`
`4n
`
`R,
`
`R1
`
`1311
`
`P11
`
`‘
`
`N
`
`0
`
`X
`
`\
`i /
`
`‘_*—r.-oak,
`
`'
`
`' m
`
`N
`\
`
`l %3—CH-*
`0
`
`l
`
`\_OCHm1R
`X '
`‘
`'
`‘
`
`Xe
`
`X1)
`
`_
`Where X is O or S;
`“(R1 is ll, phenyl or phenyl substituted with 1-‘, (Tl or Br or
`45 “ ‘my’
`R2 is H, allcyl, phenyl or phenyl substituted with F. C1 or
`
`Br or alkoxy, and
`.
`R3 is H or alkyl.
`Preferred are those preferred compounds as set out
`
`50 French Patent No. 2156486.
`Most preferred oxamle compotmds as aP2 inhibitors are
`the compounds
`
`in
`
`55
`
`wherein
`R,
`is pl1e11yl or tl1ienyl:
`R2 is hydrogen,
`lower alkyl or together with CO2 is
`tetraml- l-yl;
`X is a divalent connecting group selected from the group
`consisting of C II3C I13 , C II=ClI. and C‘II3O:
`Y is a divalent connecting group attached to the 3- or
`4-phenyl position selected from the group consisting of
`0CH2= CH2CH2 and CH=Cl-I.
`or when R3 is hydrogen, an alkali metal salt thereof.
`Preferred are the preferred compounds as set out in the as
`above Meanwell et al pate11t as illustrated in the working
`Examples thereof.
`
`fin
`
`7 of 1?
`
`_
`
`_
`R \ 0
`
`/-\
`
`0
`
`C-02H -'1-W1
`
`PENN EX. 2100
`CFAD V. UPENN
`[PR2015-01836
`
`

`
`US 75,358,254 B2
`
`1 2
`
`XIV)‘
`
`XIVB
`
`X5“.
`
`xivu
`
`xtvt‘
`
`
`
`CH5
`
`3:: R = SEC-l'l1i|1}-‘l
`3b R. ’ cyclopentyl
`3cR cvc]ohex_vl
`
`5 X CH
`X 0 3
`? X =3
`
`1 1
`
`-continued
`
`O O
`
`'\l\.
`
`O
`
`0
`
`C0311
`
`‘
`
`10
`
`15
`
`2n
`
`which may be prepared as disclosed in U.S. Pat. No.
`5,348,969 to Rominc et :11.
`
`Another class of aP2 inhibitors suitable for use in the 5_
`method of tlie invention i11cl11de pyrimidine derivatives. *3
`Thus, U.S. Pat. No. 5,599,770 to Kubota et al (the disclosure
`of which is incorporated herein by reference) disclose cum-
`pounds wl1icl1 have activity as am inhibitors and thus
`suitable for use herein include 2-benzyloxypyrin1idine
`derivatives having the following structure
`
`30
`
`T
`
`NT
`
`\
`
`II
`
`c:H,o—<\ /
`
`N
`
`RI
`
`R;
`
`xm 35
`
`45
`
`wherein
`
`R' and R1 are each independently [ l, a halogen. hydmxyl.
`C, -C4 alkyl, C,-C4l1aloalkyl,C5-C5 alkenyl. C5-C5 alkynyl,
`C,-C4 alkoxy, Cl-C5 haloalkoxy, C5-C5 alkenyluxy, C5-C5 5“
`alkynyloxy, C 1-C4 alkylthio. or phenyl. with the proviso that
`at least one ofR1 a11d R3 111ust be hydroxyl:
`I1 is an integer of 0 to 5; and
`_
`each X which may be identical or di[Terent ifn is greater
`than 1, is a halogen. C1-C4 allqrl. C._-C4 haloalkyl, C,-C4 35
`alkoxy, C1-C5
`alkylthio,
`(75.-(79
`aralkyloxy.
`phenyl.
`hydroxymethyl, hydroxycarbonyl, (71-C4 alkoxycarbonyl, or
`nitro.
`
`Preferred are tl1e compounds in which either R' or R2 is
`hydroxyl and the other R1 or R2 is C,-C4 alkyl and X is 5“
`halogen.
`ln another enibodiment of the method of the invention.
`compounds which have activity as aP2 inhibitors suitable for
`use herein are disclosed i11 A. Mai et al “Dihydro[alkylthio)-
`(naphtliylniethyl)oxopyrimidi11es: Novel Non-Nucleoside 65
`Reverse 'l'ranscriptase lnhihitors 01' the S-I )A|3(). Series”, J.
`Med. Chem._. 1997, 40, 1447-14-54 which have the structures
`
`8 of 1?
`
`PENN EX. 2100
`CFAD V. UPENN
`[PR2015-01836
`
`

`
`US 7,358,254 B2
`
`14
`
`where n is 0-3 and R3,, R31 a11d R33 are the same or
`diflbrent and are selected from
`II.
`
`C, -C,, alkyl,
`phenyl optionally substituted with 1_. 2 or 3—halo, C1-C6
`alkyl, C1-C5 alkoxy, —CF3_. —OH or —CN_.
`or where R_,, and R31 taken together with the attached
`nitrogen to form a ring selected from -pyrrolidinyl, —pip—
`eridinyl,
`-4-niorpholinyl,
`-4-thiolnorpholinyl,
`-4-pipera7i-
`nyl. —4—(1—C ,—C5alkyl)piperazinyl_. or a member selected
`from:
`
`13
`R'=sec-butyl, cyclopcntyl, cyclohexyl;
`
`R3 H, CH3. The structures X1\riA—XIV’E are depicted in their
`keto form. I-lowever. it will be apparent to one skilled in the
`art that they may also exist i11 their enol form to give
`structures of tlie type
`
`XIVF
`
`
`
`In yet another e111bodi111c11t of the method ofthe invention.
`compounds which have activity as al-’2 inhibitors suitable liar
`use herein are disclosed i11 l-‘CT application W0 9685678
`which are ot—substituted pyrin1idine—thioall<yl and alkylether
`compounds which have the structure
`
`XVI
`
`R6
`
`11,,
`
`R-1
`
`Z
`\ J\
`3'
`
`Y
`
`R12 R13
`
`R43
`Z in R1
`R4:
`
`where 111 is 0 or 1;
`R'
`is selected from C()1R5_,.
`
`( ()NR5_,R,.,,
`
`
`
`R25
`
`15
`
`re J:
`_
`
`30
`
`4o
`
`50
`
`where s is 0 or 1, a11d R3,, R3,. R23. R33. R24, and R,_.., are
`the same or difl'erent and are selected from —H. C , -C5 alkyl.
`C,-Ct, alkenyl, C,-C5 alkoxy. C,-(.',, alkylthio. C3-(7,,
`cycloalkyl, —CF3, —NO3. —l1alo, —Ol-I. —CN. phenyl,
`phenylthio_. -styryl,
`CO1[R_,,),
`(.‘(]N(R_,,,)[R32la
`CO
`(R31),
`((7112),, N(R3t)(R32)¢
`(-‘((311)
`(R3i(R_u}-
`—(C1Iz)uN(R31}(C0(R33ll= [CH2l,,N(R31)(SO2[R33))-
`01'
`where R20 and R2,, or R31 and R22. or R33 and R23 are taken
`together to form a live or six-nicnibered saturated or unsat-
`urated ring containing 0 or 1 oxygen. nitrogen or sulfur,
`where the unsaturated ring may be optionally substituted
`with 1, 2 or 3, C, -C,, alkyl, C 1 -C5 alkoxy. OH,
`CHZOH.
`—(cH,),,—N(R_, , )(R_,2)_. —C_,—C,, cycloalkyl, —CF_,, -halo,
`C-0z(R:.t)= —CON(R3t)(R3g)- —C0(R31}- —(CH2)..N(R_u)
`(CO(R33))= —(CH2),.N(R3t)(S02 (R3.-,)}, —CN, —CH20f
`—CI-l(CF3)2_. or phenyl
`a11d the saturated ring may be
`optionally substituted with 1.2 or 3,
`C4-C6 alkyl.
`C,-C,-, 55
`alkoxy, OIL Cll2Oll or
`(CII3)_, N(R3,)[R_,,2) or one
`oxo (=0);
`
`an
`
`l-cyclohexenyl, 2-pyri1nidinyl_. 4-pyriniidinyl. 5-pyr"im-
`idinyl, 2-imidayiolyl, 4-imidzmolyl, 2-bcnzotliiazolyl, 2-ben-
`zoxazolyl, 2—benzirnidazolyl_. 2—oxazolyl_. 4-—oxazolyl, 2—thia—
`mlyl, 3-isoxazolyl, 5-isoxazolyl, 5-111etl1yl-3-isoxazolyl.
`5—phenyl—3—isoxazolyl,
`4—thiazolyl,
`3—n1etl1yl—2—pyrazinyl,
`5—n1ethyl—2—pyrazinyl,
`6—n1etl1yl—2—pyrazinyl,
`5—chloro—2—
`thienyl, 3—furyl_. benzofuran—2—yl_. benzothien—2—yl, 2l-I-1-
`benzopymn-3-yl,
`2,3-dihydrobenzopyran-5-yl,
`l-nieth-
`yliniidazol-2-yl,
`quinoxalin-2-yl,
`pipcron-5-yl,
`4.7-
`dichlorobenzoxazol-2-yl,
`4,6-dintethylpyriinidin-2—yl.
`4-niethylpyrimidin-2-yl, 2,4-dimcthylpyriniidin-6-yl. 2-inc-
`thylpyrimidin-4-yl, 4-inethylpyrilnidin-6-yl, 6-chloropip-
`eron—5—yl_. 5-chloroirnidazol[l,2—a]pyridin—2—yl.
`1—H—inde11—
`3—yl_.
`1 —H—2—1nethyl—inden—2—yl.
`3,4—dihydronapl1th— l—yl,
`S-4-isopropcnylcyclol1exe11-l -yl or 4-diliydronaphth-2-yl:
`where
`R53
`is
`selected
`from —H, C ,—C Galkyl,
`(T3-Cficycloalkyl, phenyl (optionally substituted with 1.2. or
`3-lialo,C,-C6 alkyl, C1-C6 alkoxy,
`CF3, OII.
`CN), or
`a five or six—n1en1bered unsaturated ring containing 0 or 1
`oxygen, nitrogen or sulfur, where the unsaturated ring may
`be optionally substituted with
`II_. C1-C5 alkyl, C,-C5
`alkoxy, —OH, —C H301-l, or —(CI-l2),,—N[R_,1)(R32);
`where R54 and R55 being the same or different are selected
`from I], C1-C5 alkyl, ally], or phenyl (optionally substi-
`tuted with l_. 2 or 3—hale_. C1-C5 alkyl. C1-C5 alkoxy or
`—CF3)_. or taken together with the attached nitrogen to form
`a ring selected from -pyrrolidinyl, -pipcridinyl, -4-niorpholi-
`nyl, —4—tl1io1norpholinyl, —4—piperazinyl_.
`-4-—(1—C1—C5alkyl)
`piperazinylg
`R4, and R42, being the same or difiereiit, are selected from
`—H and C,—C,, alkyl;
`alkyl. —C_,,-C5
`Rm is
`selected from —H, C1-C5
`cycloalkyl,
`(IN,
`(.‘(())NI 1,,
`C(())_\I[C,-(T,,alkyl)(C,-
`CGalkyl), —CO2I-l_. —CO2(C,—C5alkyl)_. —CH3OH,
`—CH2NH3 or —CF3_:
`R,_, is selected |i“om
`Y is selected Ii'om S
`R4 is —OH;
`R5 is selected from —H, —C1H_,0l-l. —C1H_,—O-TR-
`DMS,
`halo,
`C3-Ct,
`cycloalkyl,
`C,-C3
`alkoxy.
`—CH2CH3Cl or C1-C4 alkyl, with the proviso that R5 is not
`isobutyl;
`or, when R6 is hydroxyl, R4 and R5 are taken together to
`form a five or six—rnen1ebered saturated or unsaturated ring
`which together with the pyri111idinc ring form the group
`consisting of7[ [-pyrrolo[2_.3-djpyrilnidine, 5,(:-dihydro-7[l-
`pyrrolo[2,3—d]pyrirnidine, furo[2,3—d]pyri1nidine. 5.6—dihy—
`dro-l‘uro[2,3-djpyriniidine, tl1ieno[2,3-djpyriniidinc, 5.6-di-
`hydro-thieno[2,3-d]pyrimidine,
`ll I-pyra7olo[3.4-d]
`pyrimidine,
`ll-l—purine,
`pyrin1ido[4_.5—d]pyrimidine,
`pteridine. pyrido[2,3—d]pyri1nidine. or quinazoline. where
`the unsaturated ring may be optionally substituted with 1, 2
`or 3. C1-C5 alkyl CICG alkoxy, —Ol-l_. —Cl-IEOH, or
`(Cll._,)n N(R_,,)(R_uj,
`C3-CR cycloalkyl.
`CF3, -halo.
`C03(R_;.),
`CUN(R3,)(Ry_:l.~
`C0[R3,).
`(Cll:,),,N
`(l{31)((7()(l{_,_,]],
`{Cll3),,N(R31)(S()3(R33)), a11d the satu-
`PENN EX. 2100
`CFAD V. UPENN
`[PR2015-01836
`
`Cl-‘3;
`ll, C1-C6 alkyl or
`,
`S(O)
`,
`S(O)2. or
`
`0
`
`9 of 1?
`
`

`
`US 75,358,254 B2
`
`1 5
`rated ring may be optionally substituted with 1. 2 or 3.
`C1-C6
`alkyl, C1-C6 alkoxy.
`O11,
`(T112011. or
`(Cl I2),,N(1{3,)(R_,2) or o11e oxo (=0): and
`R6 is selected from —11, —{)I1. halo. —CN, —C1"3.
`—CO2fRo1).~ —CfO.lRm or 4(0)N(Rfil)(Rfi2) Where Rm
`and R63 are the same or diiferent and are selected from
`lI_.
`C,-C5 alkyl,
`phenyl optionally substituted with 1, 2 or 3-halo. C1-C6
`alkyl, C1-C6 alkoxy, —LIl~',. —()H, —CN.
`or where R5, and R62 taken together with the attached
`nitrogen to form a ring selected from —pyrro1idinyl, —pip—
`eridinyl, —4—n1orpholinyl, —4—t11ion1orpho1iny1, —4—piperazi—
`nyl, or —4—(C,—C,, alky1)piperaziny1: or
`pharmaceutically acceptable salts. hydrates. N—oxides and
`solvates thereof.
`
`A preferred e111bodi111e11t is pyrin1idine—thioalkyl and alky-
`lether, where
`R_._ is
`O11; and
`R6 is selected from —l-1. halo. —CN. —C1~'_,. —CO3
`(Rm).
`C(0)RG, or
`(?(())l\l(R,,,)(l{,.,2). preferably (fl"_,.
`A preferred e111bodime11t are compounds of Formula XVI
`where s is U or 1, and Y is
`S
`or C): more preferably Y
`is —S—.
`
`Preferred are pyrimidine derivatives of the structures
`
`10
`
`15
`
`re '4:
`
`Xvm
`
`30
`
`Cl
`
`1 6
`
`—continued
`
`COOR5
`
`R
`
`I
`
`R:
`
`\ N
`_\J
`
`1
`
`7.
`
`V
`
`XVIIB
`
`where R, and R2 are 11, alkyl. aryl or arylalkyl. where the
`alkyl can include as substituents halogen. C173.
`(71130.
`(71 [_,S, N02, or R, and R1 with the carbons to which they are
`attached can form methylenedioxy, or
`R, and R2 can fonn a C3-C7 non—aro111atic ring. or a
`heterocycle which can be pyridine, pyrazine. pyrimidine.
`pyridazine,
`indol, or pyrazole, or a11 oxygen containing
`heteroeycle which can be pyran or furan, or a su1f11r con-
`taining heterocycle which can be thiopyran, or thiophene:
`the heterocycles being optionally substituted with halogen or
`alkyl,
`R3 and R4 are H, alkyl, halogen, CF}, CH,0, Cl-I38 or
`N02 or R3 and R, with the carbons to which t11ey are
`attached can form a niethylenedioxy group.
`R5 is H, and
`.7. is a heterocycle which can be pyridine, thiamle, ben-
`zothiamle, benziinidazole or quinoline, which 2’. group can
`optionally be substituted with halogen or alkyl.
`The preferred pyridazinone derivative is
`
`C0311
`
`01 1
`
`(:1-'_,
`
`ON
`1\'
`
`0
`
`and
`
`OH
`
` Ner;
`
`Ix‘/l\s
`
`xvns
`
`4o
`
`Br
`
`Cl
`
`C.‘ 1
`
`which may be prepared as disclosed in WO 96135678.
`Another embodiment of the method of the invention
`
`inhibitors which are pyridazinone
`includes use of a1-’2
`derivatives.
`lirench Patent No. 2.64?,676 discloses com-
`pounds which have activity as aP2 inhibitors and thus
`suitable for use herein which have the structures
`
`KVIIA
`
`coon,
`
`11:
`
`«
`
`50
`
`an
`
`65
`
`which may be prepared as disclosed in 1’rench Patent No.
`2,647,676.
`Preferred aP2 inhibitors for use herein will include an
`
`oxazole ring.
`the term “lower alkyl”.
`Unless otherwise indicated,
`“alk'yl" or “alk" as employed herein alone or as part of
`another group includes botl1 straight and branched chain
`hydrocarbons, containing 1 to 40 carbons, preferably 1 to 20
`carbons, more preferably 1
`to 12 carbons.
`iii the nonual
`chain, such as methyl, ethyl. propyl, isopropyl. butyl. t-bu-
`tyl, isobutyl, pentyl, hexyl, isohexyl. heptyl. 4,4—di111et11yl—
`pentyl, octyl, 2,2,4-—trirnethyl—pentyl, no11y1_. decyl. undecyl,
`dodecyl, the various 1)I'd]‘lC11t.‘d chain isomers thereof, and the
`like as well as such groups including 1 to 4 substituents such
`as halo, for example 1’, Br, C1 or 1 or C173. alkoxy, aryl.
`aryloxy, aryl(aryl) or diaryl, arylalkyl, arylalkyloxy. alkenyl,
`cycloalkyl,
`cycloalkylalkyl,
`cycloalkylalkyloxy.
`amino.
`hydroxy, acyl, heteroaryl, heteroaryloxy, heteroarylalkyl,
`PENN EX. 2100
`CFAD V. UPENN
`[PR2015-01836
`
`10 of 1'?
`
`

`
`US 75,358,254 B2
`
`18
`
`gr ggi (:6. Q,
`
`17
`heteroarylalkoxy, aryloxyalkyl, aryloxyaryl, alkylamido.
`alkanoylaniino, arylcarbonylaiiiino, nitro, cyaiio.
`Ihiol.
`haloalkyl, trihaloalkyl andfor alkylthio.
`Unless otherwise indicated,
`the term “cycloulkyl" as
`employed herein alone or as part of another group includes
`saturated or partially unsaturated (containing 1 or 2 double
`bonds) cyclic hydrocarbon groups containing 1 to 3 rings,
`including nionocyclicalkyl, bicyclicalkyl and tricyclicalkyl,
`containing a total of 3 to 20 carbons forming the rings.
`preferably 4 to 12 carbons, forming the ring and which may 10
`be fused to l or 2 aromatic rings as described fiir aryl, which
`inchide cyclopropyl. cyclobutyl, cyclopentyl, cyclohexyl.
`Cyc10hL.pIyL cyc]0oc1y1'
`cyclodccyl and cyc10d0dcCy]_
`Cyclohexenyls
`
`'4:
`
`\
`
`,
`1
`_
`_
`and the like. lhe above groups inay i