l||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
`
`USUU6 1 944-54131
`
`(12; United States Patent
`Dow
`
`(111) Patent No.:
`(45) Date of Patent:
`
`US 6,194,454 B1
`Feb. 27., 2001
`
`(54) CYANO L‘(}N'1'AIN1NG UXAMIC ACIDS ANI)
`IJERIVATIVES AS 'l"HYR()II) RI€CICI’1"()R
`I.I(}ANI)S
`
`(75)
`
`Inventor: Robert 1.. Dow, Waterford, Cl‘ (US)
`
`(73) Assignee: Pfizer Inc., New York, NY (US)
`
`(*) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`USC. 154(b) by [1 days.
`
`(21) App]. No.: 09/514,696
`
`(22
`
`Filed:
`
`1:91;. 28, 20110
`
`Related U.S. Application Data
`Provisional application No. 61],-'122,1l9,
`liled on Man.
`1999.
`
`1,
`
`(60)
`
`(51)
`
`Int. Cl.7 ____________________ __ A6IK 311275; ("(176 253360;
`A611’ 3106; A611’ 3/04
`........................ .. 5144522; 5587413; 553E416;
`5581’-‘-I I7
`........................... .. 514E523; 558E413,
`5583417
`
`(52) U.S. Cl.
`
`(58) Field of Searcll
`
`(56)
`
`References Cited
`U.S. P/K1‘1_'LN'1' DUCUMl_iN'1'S
`
`................... .. 424K319
`5141487
`5147247
`5143535
`5443239
`544K239
`5141549
`562.4129
`51471539
`514.1539
`560x43
`
`
`
`..
`
`fntewtafiortai Corigrefiiortat’ Service
`l{.I:'.. et al.,
`Steele,
`(;‘\1herosc|erosis X) 1066: 321-324 (1995).
`
`Stephan, ZJ-‘. et al., /11‘!1¢=ro.s“c1'er0.s'is, 126: 53—63 (1996).
`
`Underwood, A.I1. et al., Nr1t11r‘e, V01. 324: pp. 425-429
`(1986).
`
`Webb, K.S. & levy. 1)..
`S'l17—51'18 (1995).
`
`'1'E:1'1'ahedr'(Jr1
`
`I.e£!., 36 (29):
`
`Wright, s.w. at 111., OPP! B1‘ief9, 29 (1): 128-131 (1997).
`
`Yokoyama, N. C1 111., Jozovmf ofMedt'c.'.'1tr1I C1'1e1m‘.s1‘r'__v, 38 (4):
`695-707 ( 1995).
`
`Pr1‘ma.-‘,1-' J'Jxc1r111‘r1cr—Michael (3. Ambrose
`(74) /l.1“f0H11‘_7 ', /1 gent‘, or Fim1—Peter C. Rich ardson; Gregg
`C. Benson; Jennifer A. Kispert
`
`(57)
`
`AHS'1"1{AC'1"
`
`The present invention provides novel compounds of the
`Formula
`
`([1
`
`11‘
`
`R"
`
`115
`K’
`3
`R?
`‘tr 4
`'
`5
`4'&F .~J1“(o)r'(o1R“
`.1
`|,R
`R]
`
`and prodrugs thereof, geometric and optical isomers thereof,
`and pliariiiaccutically acceptable salts of such (:(ll'11p01..ll'1(15,
`prodrugs and isomers, wherein R1 R3 and X are as
`described herein. Pharmaceiltical compositions containing
`such compounds, prodrugs,
`isomers or pharmaceutically
`acceptable salts thereof, and methods, pharmaceutical com-
`positions and kits for treating obesity, Iiyperlipidemia, thy-
`roid disease, laypolhyroidism and related disorders and dis-
`eases such as diabetes mellitus, atherosclerosis,
`hypertension, coronary heart disease, h_vperc|1olesteremia,
`depression and osteoporosis are also provided.
`
`45 Claims, Nu Drawings
`
`171978 Scilstcdt cl: al.
`4,[J69_.343
`11.91985 Hilfiger el :11.
`4,554,290
`371988 17-.11is el al.
`£I,7f16_.|}‘.I
`571989 Hllis el al.
`4,826,876
`351990 Ellis ct al.
`4_.EJlU_.3EJ5
`11171991 Hliinictt et a1.
`5_,[J61__798
`871993 Sam C1 211.
`5,232,947
`271994 Walker el al.
`5,284,971
`371995 Yokoyatna ct £11.
`5,401,772
`1ll.r'199t'1 Yokoyatiia et al.
`5_.569_.674
`8_:'|99'.r Yokoyatita et :11.
`5,o'54__=1(18
`F()R1:LIGN l’Pt'I']:LN'I' DOCUMI:'N1'S
`[]58[J_":5U
`
`.
`[I-L1’)
`1271993
`01111:-1R PUBLICAHONS
`
`Casiraghi, G. et
`(1980).
`Chain, D.M.'1". et
`(1998).
`
`211., J.C.S.
`
`I’erkt'r1 Ii'rm.s. 1: 1862-1865
`
`111., Tetrrdiedrori Letters, 39: 2933-2936
`
`10117
`
`PENN EX. 2133
`
`CFAD V. UPENN
`IPR2015-01836
`
`

`
`US 6,194,454 B1
`
`1
`CYANO C()N'l"AININ(} (IXAMIC ACIDS AND
`DERIVATIVES AS THYROID RECEl'll()R
`LIGANDS
`
`(?R()SSRl:'l~'ERl:'N(?E '11] RE! .A'l‘l:‘.I)
`APPl.lCATl0N
`
`2
`T3 may be produced directly from the thyroid gland, or,
`in peripheral tissues, by the removal of the 5'
`iodine by
`deiodinase enzytnes. Thyromimetic analogs are often
`designed to be structurally similar to T3. In addition, natu-
`rally occurring metabolites of 'l‘3 are known.
`
`This application claims priority from U.S. Provisional
`Patent Application No.
`t’1tl,’l22,l'l‘) filed Mar. 1, 199*), the
`lienelit of which is hereby claimecl under 3'? C.I"'.R. §l.T8
`(a)t3)-
`
`FIELD or THE INVENTION
`
`thyroid receptor
`invention relates to novel
`The present
`ligands and, more particularly, relates to novel cyano con-
`taining oxamic acids, and derivatives thereof, which are
`useful in the treatment of obesity, ltyperlipidernia, thyroid
`disease, hypothyroidism and related disorders and diseases
`such as diabetes mellitus, atherosclerosis, hypertension,
`coronary heart disease, hypercholesterernia, depression and
`osteoporosis. Also provided are methods, pharmaceutical
`compositions and kits for treating such diseases and disor-
`ders.
`
`BACKEERUUNIJ ()I-' THE. [N\-"I:'N'l'l()N
`
`thyroid hormones,
`is generally accepted that
`It
`specifically, biologically active iotlothyronines, are critical
`to normal development and to maintaining metabolic
`homeostasis. Thyroid hormones stimulate the metabolism of
`cholesterol to bile acids and enhance the lipolytic responses
`of fat cells to other hormones.
`
`Thyroid hormones also alfect cardiac function both
`directly and indirectly, e.g.,by increasingthc metabolic rate.
`For example,
`tachycardia,
`increased stroke volume,
`increased cardiac index, cardiac hypertrophy, decreased
`peripheral vascular resistance and increased pulse pressure
`are observed in patients with hyperthyroidism.
`Disorders of the thyroid are generally treated with hor-
`mone replacement by administering either naturally occur-
`ring thyroid hormones or thyromimetic analogues thereof
`which mimic the effects of thyroid hormones.
`Two naturally occurring thyroid hormones, namely, thy-
`roxine or 3,5,3',5'—telraiodo—L—thyrouine (commonly
`referred to as "'l',,"') and 3,5,3'—triiodo—L—thyronine
`(cotmnorily referred to as “'1'_-,”), are shown below:
`
`I
`
`“° 0 ° 9 CH“?-*°°“
`
`H
`
`I
`
`I
`
`I
`
`I
`
`Till-3
`IIU (J (‘Iig‘|I|'*E'l')()I[
`
`H
`
`I
`
`l0
`
`15
`
`thyroid hormones affect cardiac
`As discussed above,
`functioning, for example, by causing an increase in the heart
`rate and, accordingly, an increase in oxygen consumption.
`While the increase in oxygen consumption may result
`in
`certain desired metabolic effects, nonetheless, it does place
`an extra burden on the heart, which in some situations, may
`give rise to damaging side elIects. Therefore, as is known in
`the art, such as described by A. H. Underwood et al. in an
`article published in Nnmre, Vol. 324: pp. 425-429 (1986),
`efforts have been made to synthesilie thyroid hormone
`analogs which function to lower lipids and serum eholeste rol
`without generating the adverse cardiac effects referred to
`above.
`
`US. Pat. Nos. 4,766,121; 4,826,876; 4,910,305; and
`5,(l'61,'798 disclose certain thyroid hormone mimetics,
`namely, 3,5—dibromo—3'—[ti—oxo—3(lH)—pyrida2inylmethy|]—
`thyronines.
`
`30
`
`US. Pat. No. 5,284,971 discloses certain thyromimetic
`cholesterol
`lowering agents, namely, 4—(3—cyclohexyl—4—
`hydroxy or —rncthoxy phenylsulfonyl)—3,5 dibromopheny—
`lacetic compounds.
`
`US. Pat. Nos. 5,401,772; 5,654,468; and 5,569,674 dis-
`close certain lipid lowering agents, namely, hete roaeetie acid
`derivatives, which compete with radiolabeled T3 in binding
`assays using rat liver nuclei and plasma membrane prepa-
`rations.
`
`40
`
`45
`
`50
`
`SS
`
`Certain oxamic acids and derivatives thereofare known in
`
`the art, e.g., U.S. Pat. No. 4,069,343 describes the use of
`certain oxaruie acids to prevent immediate type hypersen-
`sitivity reaelions; U.S. Pat. No. 4,554,290 describes the use
`of certain oxamic acids to control pests on animals and
`plants; US. Pat. No. 5,232,947 describes the use of certain
`oxaruie acids to improve damaged cerebral functions of the
`brain; and European Patent Specification published as EP
`St-itl,55tl discloses oertain oxamic acid derivatives as hypo-
`eholesteremic agents.
`
`111 additiort, certain oxamic acid derivatives of thyroid
`hormones are known in the art. For example, N. Yokoyama
`et al.
`in an article published in the Jourmnl 0f'Medt'cr'mn'
`CJ'rerm'sn'y, 38 (4): 695-707 (1995) describe replacing a
`—CH: aroup in a naturally occurring metabolite of '1}, with
`an —Nll group resulting in —IlNCOCO:I I. Likewise, R. Li.
`Steele et al. in an article published in lntemational Congres-
`sional Servioe (.4fIten::srrIr’r0sis' X) "1066: 321-3224 (1995)
`and Z.
`I"-. Stephan et al.
`in an article published in
`r1ffIf!lT).$Cf€!I13'f.$__. 126: 53-63 (1996), describe certain oxamic
`acid derivatives useful as lipid—lowering thyromimetic
`agents yet devoid of undesirable cardiac activities.
`
`T3 is the more biologically active of the two and, as will be
`appreciated from the structural formulae provided above,
`differs from T4 by the absence of the 5‘ iodine.
`
`including the
`All of the documents cited herein,
`foregoing, are incorporated by reference herein in their
`entiret.ics.
`
`20fl7
`
`PENN EX. 2133
`CFAD V. UPENN
`IPR2015-01836
`
`

`
`US 6,194,454 B1
`
`3
`SUMMARY OF THE INVENTION
`
`The present invention provides compounds of Formula I:
`
`R4
`—\< R3
`
`4'“
`I"
`5|
`RJ
`
`R2
`3
`9
`
`R‘
`
`_
`[[3
`\‘c(o)c(o)i<3
`
`U)
`
`10
`
`15
`
`prodmgs thereof, geometric and optical isomers thereof, and
`pharmaceutically acceptable salts of said compounds, said
`prodmgs, and said isomers, wherein:
`R1 and R3 are independently halogen, CH, al.kyl,—CN or
`CH, pcrfluoroalkyl; provided that at least one of R‘ and
`R3 is —CN;
`R3 is hydrogen or (‘H5 alkyl;
`R”
`is halogen, CH, pcrfluoroalkyl, CH5 alkyl, CH,
`alkanoyl, hydro:-ty-(CM, alkyl], aryl optionally substi-
`tuted with Y and Z, aryl—((",_,, alkyl), carhocyclic aroyl
`optionally substituted with Y and Z, C340 eyeloalkyl
`optionally substituted with Y and Z, or
`(THU -
`cycloalkyl-(CH, alkyl];
`or R4 is the radical
`
`30
`
`40
`
`4-5
`
`50
`
`S5
`
`of‘!
`
`wherein: R5’ is hydrogen, C,_,, alkyl, aryl optionally substi-
`tuted with Y and Z,
`aryl—(C‘.__,, alkyl),
`(.‘_.,_,0 cyeloalkyl
`optionally substituted with Y and Z, or CH0 cycloalkyl—
`(CH, alkyl); Rm is —OR”; R '1 is hydrogen or (“,3 alkyl;
`or R10 and R“ may be taken together with the carbon atom
`I.o which I.hey are attached to form a carbonyl group;
`R5 is hydroxy, esterified bydroxy or etherifietl hydroxy;
`R” is hydrogen, halogen, C, 5 alkyl or C, Rperfluoroalkyl;
`R7 is hydrogen, CH, alkyl or CH, periluoroalkyl;
`R6 is OR” or NRDIIH;
`R” and R” are each independently hydrogen or CH,
`alkyl;
`R” is hydrogen, CH, alkyl or C,_,, acyl;
`X is 0, 8(0),, C=0 or NR15;
`a is [1,
`'1 or 2;
`R15 is hydrogen or CH, alkyl;
`Y and Z for each occurrence are independently (a)
`hydrogen, (b) halogen, (c) trifiuoromethyl, (d) —OCl7'3,
`[e] —CN, [f) CH, all-(yl optionally substituted with one
`or more suhstitucnts independently selected from the
`group consisting of halogen, —OCF3, —CF_, and
`phcnyl, (g) (TH, alkoxy, {hl aryl optionally substituted
`with one or more substituents independently selected
`from the group consisting of halogen, —()CI"3, —CI"3,
`C,_,, alkyl and C,__, alkoxy, (I) —C'(O_)3R”‘, (i) _—C[O)
`NR"’R”, (k) —(I(()]Rl°, (1) —NR"'(?([)]NR"'R'7 or
`[m) —NR1°C‘(O)R”; or Y and Z for any occurrence
`may be taken together to form (a) at carbocycle of the
`formula —((‘H2),,, or (b) a hcterocycle selected from
`the group consisting of —U(CIl;._)_.O—, (CII,),,NII—
`and —C‘II=C‘IINII—;
`
`4
`
`b is 3, 4, 5, 6 or 1';
`c and cl are each independently 2, 3, 4, 5 or ti;
`R1" and R” for each occurrence are independently
`hydrogen, CH, alkyl, CH, alkenyl, —(C,_d alkyl)—C_‘,_c,
`alkoxy, aryl optionally substituted with Y and Z, het
`optionally substituted with Y and Z, —(C,__, alkyl)-aryl
`optionally substituted with Y and 2, —(C,_,, all-tyl)—
`heterocyele optionally substituted with Y and 2,
`—(C,_,, alkyl)-hydroxy, —(C,_4 alkyl)-halo, —(C,_,,
`all-{yl)—poly—halo, _(t:,_,, a1ky1)-t:t)N1113u1-° or c,_,,,
`cyeloalkyl;
`bet for each occurrence is a 4-, 5-, 6-, 'i''- or 8-mcmbcred
`partially or fully saturated, or unsaturated, ring con-
`taining from one to four heteroatoms independently
`selected from the group consisting of N, (J and S, and
`including any bicyclic group in which any of the above
`heterocyclic rings is fused to a benzene ring or another
`heterocycle which is a 4-, 5-, 6-, 7- or 8—membered
`partially or fully saturated, or unsaturated, ring con-
`taining from one to four heteroatoms independently
`selected from the group consisting of N, O and S; and
`R13 and R1"
`for each occurrence are independently
`hydrogen, C“, alkyl, C340 cycloalkyl or aryl option-
`ally substituted with Y and Z.
`A preferred group of compounds and pharmaceutically
`acceptable salts of such compounds, designated the A
`Group, contains those compounds of Formula I and phar-
`maceutically acceptable salts of such compounds, as shown
`above, wherein X is oxygen.
`A preferred group of compounds and pharmaceutically
`acceptable salts of such compounds, of the A Group, des-
`ignated the B Group, contains these compounds of I-'onnula
`I and phannaceutically acceptable salts of such compounds,
`as shown above, wherein R3 is located at the 2' position, R"
`is located at the 3" position, R5 is located at the 4' position
`and R“ is located at the 5' position.
`A preferred group of compounds and pharmaceutically
`acceptable salts of such corrtpouncls, of the B Group, des-
`ignated the C Group, contains those compounds of Formula
`I and phannaceutically acceptable salts of such compounds,
`as shown above, wherein R“, R5 and R7 are hydrogen, and
`R“ is hydroxy.
`A preferred group of compounds and pharmaeeutically
`acceptable salts of such compounds, of the C Group, des-
`ignated the D Group, contains those compounds of Formula
`I and phannaceutically acceptable salts of such compounds,
`as shown above, wherein R1 and R3 are each independently
`—CN, methyl or chloro, provided that at least one of R‘ and
`R2 is —CN.
`A preferred group of compounds and pharmaccutically
`acceptable salts of such compounds, of the D Group, des-
`ignated the IE. Group, contains those compounds of Formula
`I and phan'naceutical.ly acceptable salts of such compounds,
`as shown above, wherein R3 is —OR”.
`A preferred group of compounds and pharmaceutically
`acceptable salts of such compounds, of the E Group, des-
`ignated the F Group, contains those compounds of Formula
`I and pharmaceutically acceptable salts of such compounds,
`as shown above, wherein R” is hydrogen, methyl or ethyl,
`and R4 is —CH(CH_,,):.
`A preferred group of compounds and pharmaceutically
`acceptable salts of such compounds, of the D Group, des-
`ignated the G Group, contains those compounds of Formula
`I and pharmaceutically acceptable salts of such com pounds,
`as shown above, wherein R8 is NRERJ3.
`Apreferred group of the pharmaceutically acceptable salts
`ofthe compounds of Formula I, and the prodrugs, geometric
`
`30fl7
`
`PENN EX. 2133
`CFAD V. UPENN
`IPR2015-01836
`
`

`
`US 6,194,454 B1
`
`5
`6
`which comprise administering to said mammal obesity treat-
`and optical isomers thereof, containsthose pharmaccutically
`ing elfcctive amoun s of a compound of Formula I, or a
`acccptable salts of the compounds, prodrugs, and geometric
`prndrugthcfoofioragcomctrjc or an optical isomer thereof,
`and optical
`iS.0I"I'1Cl'S wherein lIl'IC salt
`is
`3 potassium OI‘
`or a pharmaceutical y accept.able salt of such compound,
`S0514-lm 5311-
`5 Such pmdmg, or See},
`isomer, as described above’ and a
`Apreferred group of C()mp()1Itl(lt-‘. of Formula I, prodrugs
`lilmee inhJ'himr_
`and geometric and optical isomers thereof, and phan'naceu-
`In another aspect, this invention provides pharmaceutical
`Elcally aCc°pl;abl° 5315 0t the C°mp_°"ml3’ pmdmgs all-‘Ed
`compositions. comprising a compound of Formula 1, or :1
`“"me”” dfslgnalcd The H Gmup’
`I"‘"'l"de'v'
`the ”'pcc'l'C
`prodrugthereof, or a geometric or an optical isomer thereof,
`compounds N'[3'CyaU0'4'{4Thydi0xy'3"S0pmpyI"
`l0 or a pharmaceutical y acceptable salt of such compound,
`Ehcnoxyys'm°thy1'ph°ny1]T"“m1c and and N'[3'chl0m'
`.
`.
`1
`_
`_ —cyano—4—[4—hydroxy-3—isopropyl—pbenoxy)—pheny|]—
`Rmdmg‘ or lmmc!‘ ail dcScI.1h('d abow” imd a pharmaccw
`oxamic acid, and the ethyl esters thereof.
`“filly flmuplahlu V°1'(.flu.’ d11u°.m M miner‘
`.
`Apre-ferred group of the pharmaceutically acceptable salts
`In another aspect, this invention provides pharmaceutical
`the Compounds’ prodrugs, and geomelric and Optical
`01-
`°Ump°5“‘°']5 ‘{°mp“5‘“«’='-
`*1 ‘fumpounfl ‘ff lufmnula 1’ "I 3‘
`isomers of the II Group, designated the I Group, contains
`‘5 Pmdmglhcfmfs ‘fl’ 3 8°0m°11"‘3 01' 3“ Opncal 150m“ Ih"'1'°°fo
`those pharmacetitically acceptable salts of the compounds,
`or a pharmaceutical y acceptable salt of such compound,
`prodrugs, and geometric and eptieeiisomel-S wherein the ea“
`prodrug, or isomer, as described above, an anorectic agent
`1'5 3 potassium or wdium 5,111_
`and a pharmaceutically acceptable vehicle, diluentor carrier.
`This invention provides methods, of [mating a condiiion
`In another aspect, this invention provides pharmaceutical
`selected from obesity, hyperlipidemia,
`thyroid disease,
`Io compositions comprising a compound of Formula 1, or a
`hypothyroidism, diabetes mellitus, atherosclerosis,
`prodrug thereof, or a geometric or an optical isomer thereof,
`hypertension, coronary heart disease, hypercholesteremia,
`or a pharmaceutically acceptable salt of such compound,
`depression and osteoporosis,
`in a inammal (including a
`prodrug, or isomer, as described above, a lipase inhibitor and
`human being) which comp rise administering to said mam-
`a pharmaceutically acceptable vehicle, diluent or carrier.
`mat an effective treating amount of a compound of Formula
`In another aspect, this invention provides pharmaceutical
`I, or a prodrug thereof, or a geometric or an optical isomer “:5
`compositions for treating a condition selected from obesity,
`thereof, or a pharmaceutically acceptable salt of such
`hyperlipidemia, thyroid disease, hypothyroidism, diabetes
`compound, such prodrug, or such isomer, as described
`mellitus, atherosclerosis, hypertension, coronary heart
`above.
`disease,hypercholesteremia,depression and osteoporosis,in
`this invention provides methods of
`In another aspect,
`treating a condition selected from obesity, hyperlipidemia, 30 a mammal (including a human being) comprising a com-
`thyroid disease, hypothyroidism, diabetes mellilus,
`pound of Formula I, or a prodrug thereof, or a geometric or
`atherosclerosis, hypertension, coronary heart disease,
`an optical isomer thereof, or a pharmaceutically acceptable
`hypercholesteremia, depression and osteoporosis, in a mam-
`salt of such compound, prodrug, or isomer, as described
`mal (including a human being) which comprise administcr-
`above, and a pharmaccutically acceptable vehicle, diluent or
`ing to said mammal elfective treating amounts of a com— 35 carrier.
`pound of l"ormula l, or a prodrug thereof, or a geometric or
`In another aspect, this invention provides pharmaceutical
`an optical isomer thereof, or a pharmaceutically acceptable
`compositions for treating a condition selected from obesity,
`salt of such compound, such prodrug, or such isomer, as
`hypcrlipidcmia, thyroid disease, hypothyroidism, diabetes
`described above, and an anorectic agent.
`mellitus, atherosclerosis, hypertension, coronary heart
`In another aspect,
`this invention provides methods of 40 disease,hypcrcholestcrcmia,depression and osteoporosis, in
`treating a condition selected from obesity, hyperlipidemia,
`a mammal (including a human being) comprising a com-
`thyroid disease, hypothyroidism, diabetes mcllilus,
`pound of Formula I, or a prodrug thereof, or a geometric or
`atherosclerosis, hypertension, coronary heart disease,
`an optical isomer thereof, or a pharmaceutically acceptable
`hypercholcstcremia, depression and osteoporosis, in a mam—
`salt of such compound, prodrug, or isomer, as described
`mal (including a human being) which comprise administcr- 443 above, an anorectic agent, and a pharmaceutically accept-
`ing to said mammal effective treating amounts of a com—
`able vehicle, diluent or carrier.
`pound of Formula I, or a prodrug thereof, or a geometric or
`In another aspect, this invention provides pharmaceutical
`an optical isomer thereof, or a pharmaceutically acceptable
`compositions for treating a condition selected from obesity,
`salt of such compound, such prodrug, or such isomer, as
`hypcrlipidcmia, thyroid disease, hypothyroidism, diabetes
`described above, and a lipase inhibitor.
`50 mellitus, atherosclerosis, hypertension, coronary heart
`In a preferred aspect, this invention provides methods of
`disease,hypercholesteremia,depression and osteoporosis,in
`treating obesity in mammals (including a human being]
`21 mammal (including a human being] comprising a com—
`which comprise administering to said mammal an obesity
`pound of Formula I, or a prodrug thereof, or a geometric or
`treating effective amount of compound of Formula I, or a
`an optical isomer thereof, or a pharmaceutically acceptable
`prodrug thereof, ora geometric or an optical isomer thereof,
`55 salt of such compound, prodrug, or isomer, as described
`or a pharmaceutically acceptable salt of such compound,
`above, a lipase inhibitor, and a pharmaceutically acceptable
`prodnig, or isomer, as described above.
`vehicle, diluent or carrier.
`In another aspect,
`this invention provides methods of
`In another preferred aspect, this invention provides phar-
`t.reating obesity in mammals (including a human being)
`maceutical compositions for treating obesity in a mammal
`which comprise administering to said mammal obesity trcat- 50 (including a human being) comprising a compound of
`ing effective amounts of a compound of Formula I, or a
`Formula I, or a prodnig thereof, or a geometric or an optical
`prodrug thereof, or a geometric or an optical isonicr thereof,
`isomer thereof, or a pharmaceutically acceptable salt of such
`or a pharmaccutically acceptable salt of such compound,
`compound, prodrug, or isomer, as described above, and a
`prodrug, or isomer, as described above, and an anorectic
`pharmaceutically acceptable vehicle, diluent or carrier.
`agent.
`In yet another aspect, this invention provides pharmaceu-
`this invention provides methods of
`In another aspect,
`tical compositions for
`treating obesity in a mammal
`treating obesity,
`in a mammal (including a human being)
`(including a human being) comprising a compound of
`
`tuft
`
`4 of 17
`
`PENN EX. 2133
`CFAD V. UPENN
`IPR2015-01836
`
`

`
`US 6,194,454 B1
`
`7
`Formula I, or a prodrug thereof, or a geometric or an optical
`isomer thereof, or a pharmaceutically acceptable salt of such
`compound, prodrug, or
`isomer, as described above, an
`anorectic agent, and a pharmaceutically acceptable vehicle,
`diluent or carrier.
`in yet another aspect, this invention provides phan'naceu-
`tical compositions for
`treating obesity in a mammal
`(including a human being) comprising a compound of
`Formula I, or a prodrug thereof, or a geometric or an optical
`isomer thereof, or a pharmaccutically acceptable salt of such
`compound, prodrug, or isomer, as described above, a lipase
`inhibitor, and a pharmaceulically acceptable vehicle, diluent
`or carrier.
`this invention provides kits for the
`In another aspect,
`treatment of
`a condition selected from obesity,
`hypeilipidemia,
`thyroid disease, hypothyroidism, diabetes
`mellitus, atherosclerosis, hypertension, coronary heart
`disease, hypercholesterernia, depression and osteoporosis
`which comprise: a
`first compound, said first compound
`being a compound of Formula I, or a prodrug thereof, or a
`geometric or an optical isomer thereof, or a pharmaceuti-
`cally acceptable salt of such compound, prodrug, or isomer,
`as described above, and a pharmaceutically acceptable
`vehicle, carrier or diluent,
`in a first unit dosage form; a
`second compound, said second compound being an anorec-
`tic agentor a lipase inhibitor, and a pharmaceutically acoept-
`able vehicle, carrier or diluent, in a second unit dosage form;
`and a container.
`In another preferred aspect, this invention provides kits
`for
`the treatment of
`a obesity which comprise:
`a
`first
`compound, said tirst com pound being a compound of For-
`mula l, or a prodrug thereol, or a geometric or an optical
`isomer thereof, or a pharmaceutically acceptable salt of such
`compound, prodrug, or isomer, as described above, and a
`pharmaceutically acceptable vehicle, carrier or diluent, in a
`first unit dosage form; a second compound, said second
`compound being an anorectic agent or a lipase inhibitor, and
`a pharmaceutically acceptable vehicle, carrier or diluent, in
`a second unit dosage form; and a container.
`Unless otherwisu- provided herein:
`“acyl" means an organic radical derived from an organic
`acid by the removal of the hydroxyl group, including,
`as the case may be, for example, acetyl, CH, aikanoyl,
`carbocyclic aryl-CH, alkanoyl or carbocyclic aroyl;
`“alkanoyl"’ means a univalent or bivalent acyl
`radical
`tormed by removal of hydroxyl
`irom the carboxyl
`group which replaced the methyl group at the end of the
`main chain of the acyclic hydrocarbon; "(_‘,_,, alkanoyl”
`includes, as the case may be for example, acetyl,
`propionyl, butyryl or pivaloyl;
`"alkanoylamino” of “CH, alkanoylamino” includes, as
`the case may be, for example, acetamido or propiona—
`mido;
`“alkoxy” means an alkyl radical which is attached to the
`reicnainder of the molecule by oxygen, including as the
`case may be, for example, methoxy, ethoxy, propoxy,
`isopropoxy or butoxy;
`“a]koxyearbonyl"' of “C.__,, alkoxycarbonyl" preferably
`contains one to four carbon atoms in the aikoxy moiety
`and includes, as the case may be, For example,
`methoxycarbonyl, ethoxycarbonyl, propoxycarbony]
`and isopropoxycarhonyl;
`“alkyl" means a straight or branched hydrocarbon chain
`radical, including as the case may be, for example,
`methyl, ethyl, n-propyl, isopropyl, n-butyl and the like;
`“aroyl” means aryl acyl, including, as the case may be, for
`example, benzencsulfonyl, benzoyl and naphthoyl;
`
`10
`
`15
`
`-
`
`30
`
`40
`
`4-5
`
`50
`
`of‘!
`
`8
`preferably benmyl and benzoyl substituted on the
`be-n'.»:ene ring by CH, alkyl, CH, alkoxy, halogen or
`trifluoromethyl;
`“aryl” includes earooeyelie aryl and heterocyclic aryl, and
`is preferably phenyl optionally substituted by one or
`two of (.‘,_,, alkyl,
`(.',_,, alkoxy, hydroxy,
`(_',_,,
`alkanoyloxy, halogen,
`trilluoromethyl, eyano, CH2
`alkanoylamino or (TH, alkoxycarbonyl; "aryl” oi""aryl—
`CH, all-tyl” is preferably benzyl or phenethyl optionally
`substituted by one or two oi" (I,_,, alkyl, (I,_,, alkoxy,
`hydroxy, CH, alkanoyloxy, halogen or trilluoromethyl;
`“carliocyclic” (carbocycle) Ineans an unsaturated, or a
`partially or fully saturated, ring having only carbon
`atoms in its nucleus, including, as the case may he, an
`aryl (an organic radical derived from an aromatic
`hydrocarbon by the removal of one atom, c.g., phenyl
`from benzene, also including, for example, naphthyl);
`“carbocyclic aryl" includes, as the case may be,
`for
`example, optionally substituted phenyl or optionally
`substituted naphthyl;
`a saturated, monocyctic
`“cycloalkanc” means
`hydrocarbon,
`including, as the case may be,
`for
`example, cyclohexane;
`“(f_,__w cycloalkyl” means a monocyclic or polycyclic
`radical derived from a cycloalkane, including as the
`case may be, for example, cyclopentyl and cyclohexyl;
`“(f_,,_”, cyeloalkyl—((.‘,_,, alkyl) includes, as the case may
`be, for example, 1- or 2—[cyclopentyl or cyclohexyl)
`ethyl, "l —, 2- or 3—(cyclopentyl or cyclohexyl)propyl, or
`1-, 2-, 3- or 4—(cyelopentyl or cyclohexyl)butyl;
`“esterified hydroxy" means acyloxy, e.g., acyloxy derived
`from an organic carboxylic acid, preferably CH2
`aikanoyloxy. aroyloxy, or aryl—(C,
`,, alkanoyloxy);
`also, 3,7,12(3ct., Sli, 7ot,
`lZot)-trihydroxy-cholan-24-
`oyloxy (derived from cholic acid), and the like;
`“etherilied hydroxy” includes, as the case may be, for
`example, CH, alkoxy, C,_,,. alkenyloxy, C_,_,
`cycloalkyloxy, carbocyclic aryl—C1_8 alkoxy,
`tetrahydropyranyloxy, C‘5_, cycloalkyl-(‘H alkoxy, and
`the like;
`“halo” and “halogen” mean a radical derived from the
`elements lluorine, chlorine, bromine or iodine;
`“heterocyclic” (“he-terocycle”) means a radical derived
`from an unsaturated, or a partially or fully saturated,
`ring of ditferent types of atoms, and includes aromatic
`and non—aromatic heterocyclic groups containing one
`or more lieteroatoms each selected from O, S and N;
`examples of heterocyclic groups include, as the case
`may be, for example, benzimidazolyl, benzofuranyl,
`benzothiophenyl, benzoxazolyl,
`furyl,
`imidazolyl,
`indolyl,
`isoquinolyl,
`isothiazolyl,
`isoxazolyl,
`morpholinyl, oxarliazolyl, oxazolyl, piperazinyl,
`pipcridyl, pyranyl, pyrazinyl, pyrazolyl, pyridyl,
`pyrimidyl, pyrroly], quinolyl,
`tetrahydroisoquinoly,
`tetrahydroquinolyl,
`tctrahydrothicnyl,
`tetrazolyl,
`thiadiazolyl,
`thiazolyl,
`thienyl,
`thiomorpholinyl,
`thiophcnyl and triazoly]; whcrc heterocyclic groups are
`specilicaily recited or covered as substituents for the
`compounds of formula I, it is understood that, unless
`specifically noted otherwise, all suitable isomers of
`such heterocyclic groups are intended;
`“heterocyclic aryl” includes, as the case may be, for
`example, monoeyclic heterocyclic aryl, e.g., optionally
`substituted thienyl,
`furanyl, pyridyl, pyrrolyl or
`N—((T,_,, alkyljpyrrolyl; optionally substituted thienyl
`
`S0fl7
`
`PENN EX. 2133
`CFAD V. UPENN
`IPR2015-01836
`
`

`
`US 6,194,454 B1
`
`10
`(C2 C.,)alkanoyloxymethyl,
`(C, C,,}all<y|,
`1—(al.kanoyloxy)ethyl having from 4 to 9 carbon atoms,
`l-methyl-l-{alkat1oyloxy)-ethyl having from 5 to [0
`carbon atoms, alkoxycarbonyloxymethyl having from
`3 to 6 carbon atonis, l—(alkoxycar|'mnyloxy)ethyl hav-
`‘
`‘"3 [mm 4 I" 7 ‘-‘3rb"“_ “mm-"’v _1'm‘71hYl'I'
`(al.koxycarbon}rloxy)ethyl having from 3 to_ 8 carbon
`atoms, N-(alkoxycarbonyDaminometbyl having lrom 3
`to 9 _a[_bm atom‘; 1_(N_(alk0x
`1
`1
`.
`L.
`.
`,
`year aony )amino]cthyl
`having from 4 to ll) carbon atoms, 3-phthalidyl,
`N—((.1—(.2)alkylaInino(C.2—(.,)alltyl
`(such as
`b-dimethylaIninoethyl),carbamoyl-(C,—C2)alkyl,N,N—
`di(C ,—C2)alkylcaIb am oy l-(C ,—C._.]alltyl and
`piperidino—, pyrrolidino— or morpholino{C:—C3)al.kyl;
`''T?|diCii1’’ 15 3 group Of 21101113 lhal b3h2W¢S RS 61 single
`010113 in 3 Cl10TI1i‘5?i1T*{?iC1i0T1- “-3-: 3“ 0Fg5lT1_iC_T?1dl‘3?11i3
`a group of atoms which co_n|"_ers characteristic proper-
`“es on a c0ml?0und_c0.m_ammg 1l’.0r_whlch Iemams
`unchanged during a series of reactions;
`__
`,__
`.
`.
`.1
`3 Snivatc
`isa ”“’1°°““‘.' or 1mm‘ complex (_)fn:01ccu1ef:
`or long’ ot a Solvent wlih those 0f.a SOIUEF‘ a’ Solliatc
`wherein the solvent
`is water,
`torms
`hydrates
`or
`hvdrated ions, and all suitable solvates are part of the
`p[.,,_Sem mvcmion; and
`inter alia,
`“treating,” "treat'” or "treatment" includes,
`preventative (e.g., prophylactic), palliative and curative
`lma1mcm_
`
`11
`
`S
`
`4,5
`
`,,
`
`h
`
`9
`includes 2- or 3-thienyl and 2- or 3-thienyl preferably
`su|)stit.ulcd by t'?l_,2 alkyl; optionally substituted |'ura—
`nyl includes 2- or 3-ruranyl and 2- or 3-furanyl pref-
`erably substituted by (“.142 alkyl; optionally substituted
`pyridyl
`includes 2-, 3- or 4-pyridyl and 2-, 3- or
`4-pyridyl preferably suhslittited by (“.,_F_, alkyl or halo-
`gun;
`.
`.
`\
`‘
`.
`‘
`.‘
`_,
`is a crystalline substance containing one or
`a hydrate
`.
`.
`.
`IT]?,r_c_ m_Oh=:C"lc::’
`,0‘: Wyéter _0f
`;¥yS:ja],]]Z":_I1'0n’ ll'c_"|_a 10
`_
`'_
`‘
`‘
`‘
`1“""'m1°“§
`"hydroxy-(CH, alkyl)" includes, as the case may be, for
`example, hydroxymcthyl;
`“perfluoroalkyl"’ means that all suitable hydrogen atoms 15
`are replaced with fluorine atoms, e.g., perlluoropenlyl,
`(j[.'3[(j1.'2)3(j1.-2
`;
`the carrier,
`"pharmaceutically acceptable" means that
`_
`_
`_
`-
`_
`_
`-
`_
`_
`_
`_-
`._
`_
`I
`__
`diluent, vehicle cxctpietits, atidfor salt must be coi:n— ,0
`patible with the other ingredients of the formulation,
`"
`and not deleterious to the recipient thereol‘;
`,
`H
`,
`ph‘°‘_"m_a°°““,°a113’ acccptablc 531"’ “t ‘h‘’ °°'“p°‘”'_d5 Of
`this invention may be formed of the compound itself,
`Pmdrug.-“v '3-Er C-filers: l_50m°r-5 and thc "kc: and [Inch-‘dc “J5
`311 of the pharmacliutlcally acccptflblc 53"?‘ Whlch am
`most often used in pharmaceutical chemistry;
`for
`example, salts may be formed with inorganic or organic
`DETAILED DESF‘F_{lPTI0N OF THE
`acids such as hydrochloric acid, hydroliromic acid,
`I-\'lV]-‘INHON
`hydroiodic acid, carboxylic acids, sullonic acids 30
`Unless otherwise noted, throughout this document: ° C. is
`including such agents as naphthalenesulfonic,
`degrees Centigrade,
`"o is percent, Ci
`is Curies, cm is
`ethanesulfonic, hydroxyethancsulfonic, methan-3-
`centimeter or centimeters, DEE is diethyl ether, DMF is
`sulfonic ("mesylate'”), benzenesulfonic ("besylate"]
`dimethylformamide, DMSO is dimethylsulfoxide, l;'t()H is
`antl
`toluenesulfonie acids,
`e_g_, p-toluenesulfonic
`(“tosylate”), sulfuric acid, nitric acid, phosphoric acid, 35 ethanol, Found is found data, g is gram or grams, h is hour
`tartaric acid, pyrosulfuric acid, metaphosphoric acid,
`or hours, kg is kilogram or kilograms, L is lit.er or liters, M
`succinic acid, formic acid, phthalic acid, malic acid,
`is molar (concentration), Me0II is methanol, mg is milli-
`maleic acid, lactic acid, ascorbic acid, glycollic acid,
`gram or milligrams, min is minute or minutes, ml. is
`gluconic acid, maridelic acid, glutamic acid, aspartic
`milliliter or milliliters, mmol ismillimole or millimolcs, mM
`acid, fumaric acid, pyruvic acid, phenylacctic acid, 40 is millimol