I
`
`LNITF:I) !·nxn:s Ill:PAKTMl:NT OF COl\I.Vn:KCE
`Cnitcd States I'atcnt and Trademark Office
`
`NOHmbCI" 02, 2017
`
`nIlS IS TO CI:;RTl}:,Y TlIAT AKKI:;XED lS A TRUl: COPY t:ROM TIn;
`RECORDS OF TIllS OFFICE OF TIlE FILE 'YR4.PI'l!:R Arm CONTE~TS
`OF:
`
`APPLICATION NUMBER: 081233,166
`FILING DATE: Apl'il26, 1994
`
`By Autbority of the
`Lnder Seertlary of Commerce for Intellectual Property
`and Dircctor "fthe Lnitcd States P. lent and Trad mark Office
`
`ASTELLAS 2006
`Sawai v. Astellas
`IPR2018-00079
`
`Page 1 of 108
`
`
`
`LNITF:I) !·nxn:s Ill:PAKTMl:NT OF COl\I.Vn:KCE
`Cnitcd States I'atcnt and Trademark Office
`
`NOHmbCI" 02, 2017
`
`nIlS IS TO CI:;RTl}:,Y TlIAT AKKI:;XED lS A TRUl: COPY t:ROM TIn;
`RECORDS OF TIllS OFFICE OF TIlE FILE 'YR4.PI'l!:R Arm CONTE~TS
`OF:
`
`APPLICATION NUMBER: 081233,166
`FILING DATE: Apl'il26, 1994
`
`By Autbority of the
`Lnder Seertlary of Commerce for Intellectual Property
`and Dircctor "fthe Lnitcd States P. lent and Trad mark Office
`
`ASTELLAS 2006
`Sawai v. Astellas
`IPR2018-00079
`
`Page 1 of 108
`
`
`
`"~'""'~
`
`rICr>
`'2-"-
`
`liE
`__
`
`,.
`
`•
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`I~ERCk ~ ?:'., 1M..
`P.O. 'Bl'X ,~ou
`n"'o~,:! ',,;ili
`fll1l!>il\Y, tH
`
`Page 2 of 108
`
`
`
`T
`
`..
`
`u.s. PATENT APPUCATION
`
`08/233,l66
`
`'"
`MICHAIIL M. VISKIIR. RINGOIS. HJI ~G OK. IIDI80N. HJ, I LIZ ABETH M. KA!LOR,
`SC01CR PLAI NS. IIJI ANN II. llBeER, &OOTCH ~IIS. IIJ.
`
`"CQnDW I IiG DATA···.·· •• ••••• ••• •••••
`Vl:l\trIIi:!l
`
`"ro~IG"fPCT APPLICATI~ II " """" "
`VERIrl lW
`
`l'ORBIGN nLlttG LI CllIISII QMJlTKII OS/23/'14
`
`"
`
`,
`
`"
`
`fAlIG
`MOLL Ul K.
`1'1\TB/fI' IlIPT.
`MEJ\CI( Ii 00., l11e.
`P .O. IIOX 2000
`RAJIMAY,
`IIJ 07C~ 5-O'107
`
`S110.00
`
`InOJ
`
`"""'"-
`,
`
`,
`
`SUaSTITUTtO SULFONAMIDES AS SELICTIVE B1T1\J AQONIST S FOR THI
`TfiSATllElIT OF OIIIIlITJ:S 11110 OIIl!:SITY
`
`Thl. io 10 _tifv tlMl an"e~ed MlelO I, .. true copy lrOl'l'lltle r..:cnds 01 "'. United Stales
`Patent W>d T m ....... rk OIlioe of 11M 'ppliClltion which It Identified 1Ibov ••
`8v ou tl>otity of ,.,.
`COMMISSION~ 01' p..,n NTS "'NO TRADE ...... RKS
`
`Page 3 of 108
`
`
`
`1111233166
`
`PA'J":II'I' HPU['\TIOl! SERI AL NO,. ____ ~--
`
`u.s. DEPARTMENT OF COMHERCE
`PAT Illi'l' KND TRADEMARK OFFICE
`n;1 RECORD SHEET
`
`I
`
`PTO-1556
`(5(87)
`
`Page 4 of 108
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`
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`- 1 -
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`19203
`
`TITLE OF THE INVENTION
`SUBSTITUTED SULFONAMIDES AS SELECTIVE)33 AGONISTS
`fOR TIlE TREATMENT OF DIABETES AND OBESITY
`
`BACKGROUND OF THE INVENTION
`j3-Adrenoceptors have been subclassified as 131 and 132 since
`1967. Increased heart rate is the primary consequence of )3I-receptor
`stimulation, while bronchodilation and smooth muscle relaxation
`typically result from 132 stimulation. Adipocyte lipuiysis was initia!ly
`thought to be solely a )31-mediated process. However, more recent
`results indicate that the receptor-mediating lipolysis is atypical in
`nature. These atypical receptors, later called J33-adrenoceptors, are
`found on the cell surface of both white and brown adipocytes where
`their stimulation promotes both lipolysis (breakdown of fat) and energy
`expenditure.
`Early developments in this area produced compounds with
`greater agonist activity for the stimulation of lipolysis (133 activity) than
`for stimulation of atrial rate (!31 ) illld tracheal relaxation (132). These
`early developments disclosed in Ainsworth.m.aL U.S. Patents 4,478,849
`and 4,396,627, were derivatives of phenylethanoiamines .
`Such selectivity for !33-adrenoceptors could make
`compounds of this type potentially useful as antiobesity agents. hI
`addition, these compounds have been reported to show
`antihypergiycemic effects in animal models of non-insulin-dependent
`diabetes mellitus.
`A major drawback in treatment of chronic diseases with 133
`agonists is the potential for stimulation of other l3-receptors and
`subsequent side effects, Thc mo~t likely of these include muscle tremor
`(~2) and increased heart rate (131). Although these phenylethanoiamine
`derivatives do possess some 133 sekctivity, side -effects of this type have
`been observed in human volunteers. It is reasonable to expect that these
`side effects resulted from partial 131 and/or 132 agonism.
`More n:eent developments in this area are disclosed in
`Ainsworth g, .ill" U.S. Patent 5,153,210, Canlkett.tl ill., U.S. Patent
`
`Page 5 of 108
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`- 2 -
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`19203
`
`4,999,377, Alig .tll!1-. U.S. Patent 5,017,619, Lecount tl.aJ.., European
`Patent 427480 and Bloom !<tal.. European Patent 455006.
`Even though these more recent developments purport to
`describe compound~ with greater ~3 selectivity over the Pl and 132
`activities, this selectivity was detennined using rodents, in particular,
`rats as the test animal. Because even the most highly selective
`compounds, as detennined by these assays. still show signs of side
`effects due to residual 131 and l32 agonist activity when the compounds
`are tested in humans, it has become apparent that the rodent is not a
`good model for predicting human 133 selectivity.
`Recently, assays have been developed which more
`accurately predict the effects that can be expected in humans. These
`assays utilize cloned human 133 receptors which have been expressed in
`Chinese hamster ovary cells. See Emorine et aI, Scjence, 1989,
`245:1118-1121; and Liggett, Mol. Pharmacol., 1992,42:634-637. The
`agonist and antagoni~t effects of the vari(}Us compounds on the
`cultivated cells provide an indication of the antiobesity and antidiabetic
`effects of the compounds in humans.
`
`SUMMARY OF THE INVENTION
`The instant invention is concerned with substituted
`sulfonanlides which are useful as antiobesity and antidiabetic
`compounds. Thus, it is an object of this invention to describe such
`compounds. It is a further object to describe the specific preferred
`stereoisomern of the substituted sulfonamides. A still further object is
`to describe processes for the preparation of such compounds. Another
`object is to describe methods and compositions which use the
`compounds as the active ingredimt thereof. Further objects will
`become apparent from reading the following description ..
`
`30
`
`DESCRIPTION OF WE INVENTIO N
`The present invention provides compounds having the
`
`fonnula I:
`
`I
`
`I
`
`Page 6 of 108
`
`
`
`·3 ·
`
`19203
`
`•
`
`,
`
`J
`
`where
`n Jill
`
`0105;
`o or I ;
`o to 3;
`phenyl, a 5 or 6 -membered heterocyclic ring with from 1
`to 4 heteroatoms ~elected from oxygen, sulfur and
`nitrogen, It benzene ring fused to a C3-CS cycloalkyJ ring,
`a benzene ring fused to a 5 or 6-membered heterocyclic
`ring with from 1 to 3 heteroatoms selected from ollygen,
`sulfur and nitrogen, or a 5 or 6-membered heterocyclic
`ring with from I to 3 heteIoatoms selected from oXY8en,
`ruIfur and nilrogeo fu~ to a 5 or 6-membered
`beterocydic ring wit h f rom I 10 3 hetcroilioms se lected
`from oxygen , sulfur and nillugen;
`hydrox y, oxo, halogen, cyanu, NRRRB, SRg
`trlfluoromelhy1. C }.C6 alkyl, C]--Qj alkoxy. S02R9,
`GeOR9, NRRcoR9, COR9, NR8S02R9, NRRC02RB, or
`C J-C6 alkyl mb~tituted by hydroxy, halogen, cyano,
`NRRRB, SRR, trifJuoromethyl, C l-C6 alkoxy, C3-C8
`cycloalkyl, phenyl, NRBCOR9, COR9, S02R9, OCOR9,
`NR8S02R9 or NRAC02RA;
`R2 and RJ are independently hydrogen, CI-C6 alkyl or C I -C6 alkyl
`with I to 3 subsliluenls selected from hydroxy, Cl-C6
`alkollY, and halogen ;
`-CH2-, -CH2-CH2- ,-CB:=CH- or -CH20-;
`X is
`R4 and R5 are independently hydrogen, C l-C6 alkyl, halogen, NHR8,
`ORA, S02R9 or NHS02R9;
`hydrogen or CI-C6 alkyl;
`
`" In III
`
`r IS
`A is
`
`"
`
`25
`
`30
`
`R6 is
`
`Page 7 of 108
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`- 4 -
`
`19203
`
`R7 i.~
`RIa is
`
`Z is
`
`R8 is
`
`Z-(RIa)n;
`Ri, C3-eR cycloalky\, phenyl, or 5 or 6-membered
`heterocycle with from 1 to 3 heteroatoms selected from
`oJ[ygen, sulfur and nitrogen, optionally substinned with up
`to three groups independently selected from OllO, R8 and
`NRRR8;
`pheny l. naphthyl. a 5 or 6 -membered heterocyclic ring
`with from 1 to 4 heteroatoms selected from oxygen, sulfur
`and nitrogen, II benzene ring fused to a C3-CS cycloa\kyJ
`ring, II benzene ring fu sed 10 a 5 or 6-membered
`heterocyclic ring with from I to 3 heleroatoms ~e1ected
`from oxygen, ~ulfur and nitrogen. or a 5 or 6·membered
`heterocyclic ri ng with from I to 3 hete maloms selected
`from oxygen, sulfur and nitrogen fused to a 5 or 6-
`membered heterocyclic ring with from I to 3 heteroatOlllS
`selected from oxygen, sulfu r and nitrogen;
`hydrogen. C, -ClO alkyl, C3-Cg cycloaIkyl. Z optionally
`having 1 to 3 substituent~ ~!ected from halogen. CI-C6
`alkyl and CI -C6 alkoxy_ o r C ]-C]O alkyl having I to 3
`subsliruents selected from hydroxy, halogen, C02H, C02-
`e l-C6 alkyl, S02-CI-C6 alkyl, C3-CS cyclvalkyJ, CI -C6
`alko,-y, and Z oplionally su ~li tutcd by from I 10 3 of
`halogen, Cl-C6 alkyl or C J -C6 alkoxy;
`R8 or NR8R8; or
`R9 i~
`a phannaceutically acceptable ~alt thereof.
`Preferred compounds of the instant invention are realized
`when in the above structural fonnula I:
`R2 and R3 are bydrogen o r methyl;
`X is
`-CH2-;
`nlS
`010 3;
`I-•
`'" "
`ti s
`Oto2; and
`R4, R5 and]{6 are hydrogen.
`
`Page 8 of 108
`
`
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`•
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`,
`..
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`30
`
`- 5 -
`
`J9203
`
`RI is
`
`Other preferred compounds of the instant invention are
`realized when in the above structural fannula I:
`A is
`phenyl or II. 6·membcred heterocyclic ring with 1 or 2
`nitrogen atoms;
`hydroxy, balogen, cyano, trifluoromethyl, NRRRR,
`, NR8S02R9, NRSCOR9, NR8C:02R8, Cl -<:6 alkyl
`optionally substituted by hydroxy; and
`00r2.
`More prefe rred compounds are represented by the fonn ula
`
`ri ~
`
`La:
`
`wherein
`
`"" m"
`
`RI is
`Ria is
`
`0(0 3;
`I
`halogen or NRRR8;
`halogen, Cl -C6 alkyl, NN.8RS, NR8COR9, NRRco2RS,
`OCOR9, or 5 or 6-membered heterocycle with from I to 3
`heteroatoms selected from oxygen, mlfur and nitrogen,
`optionally subMiruted with up to three groups independently
`selected from oxo, R8 and NRRR8;
`phenyl, naphthyl or benzene ring fu sed to a :5 or 6·
`membered heterocyclic ring with from I 10 3 helerootoms
`selected from oxygen. sulfur and nitrogen;
`-CHZ-; and
`X is
`R2, R3 are independently hydrogen or methyl.
`Other more prefelTed ccmpound.~ are rep!e~ nted by
`
`Z is
`
`fonnulll Ib:
`
`Page 9 of 108
`
`
`
`2
`
`,
`
`"
`
`- 6 -
`
`19203
`
`Ib
`
`wherein
`n IS
`m IS
`Rl is
`Ria is
`
`Z is
`
`o to 3;
`I
`hydroxy, NRRRR or halogen;
`halogen, C1-C6 alkyl, NRSRS, NRSCOR9, NRRC02RR,
`DeOR 9, or 5 or 6-membered heterocycle with from 1 to 3
`heteroatoms selected from oxygen, sulfur and nitmgen,
`optionally substituted with up to three groups independently
`selected from ax~, R8 and NRSR8;
`phenyl. naphthyl or benzene ring fused to a 5 or 6-
`membered heterocyclic ring with from I to 3 heteroatoms
`selected from oxygen, sulfur and nitrogen;
`-CH2-; and
`X is
`R2 and R3 are independently hydrogen or methyl.
`Representative antiobesity and antidiabetic compounds of
`the present invention include the following:
`N -[4-L 2-ll2-hydrox y-2-( 4-aminopyridin-3-y l)elhylJamino ]etbyl]phenylJ-
`4-(hexylaminocarbony lamina )benzcnesulfonamide
`N -[4-[2-[[2 -hydroxy-2-( 4-aminopyridin-3-yl)ethy ljamino lethyl]phen ylJ-
`4-iodobenzenesulfonamide
`1:1-[ 4-[2-[[2-hydroxy-2-( 4-aminopyridin-3-y\)ethy I]amino lethyl]phen y Ij(cid:173)
`bellZen es ulf 0 narnide
`,tl-14-[2-[[2-hydroxy-2-( 4-aminopyridin-3-yJ)ethyIJ amino jethyljphenyl J-
`2-naphthall:J1eSulfonamide
`N-[ 4-[2 -[[2-hydroV-2-( 4-aminopyridin-3-y l)ethy !lamino ]eth yl]phenyIJ -
`3-quinolinesulfonamide
`
`Page 10 of 108
`
`
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`•
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`•
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`- 7 -
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`19203
`
`s
`
`"
`
`20
`
`"
`
`30
`
`Ii-[4-[2-[[Z-hydroxy-2-(4-amlnopyridin-3-yl)ethyllamino]ethyllphenylJ-
`5-benzisoxazolesulfonf1lnide
`N-14-[2-([2-hydroJly-2-(4 .aminopyridin-3-yJ)etbyl)arninoJethyl Jphenyll
`4.[(beJly lmethylammocarbonyl)amlno lbenzcnesulfonamide
`N -[4-[2-{! 2.hydroxy-2-( 4-aminopyridin-3-yl)etbyl]amino lethylJphenyl]-
`4- [( dimethyiarninocarbonyl)amino ]benzenesulfonamide
`Ii -[4- [2-1 12-hydrox y-2-{ 4-aminopyridin-3-y l)ethy ljamino }ethyJ)phenyJJ-
`4-(3-hell yl-2-imidawlidon- l -yl)benzenesulfonamide
`Ii -r 4-[2-[(2-hydro!\y-2 -(3-pyridinyl)elhyl]amino lelhyl] phenyll-4-
`(hexylaminocarbonylamino )benzencsulfonamide
`N -14- [2-[[2-hydroxy-2-(3-pyridin yl)cthyl]amino loth y l]pheny! ]-4-
`ioopropylbenzenesul fonamide
`N-l 4-12 -[(2-hydroxy-2-(3-pyridin yl)ethyljamino Jetb)' l}phenyIJ-2-
`naphthalcnesulfonamido
`N-[4-[2-rrZ-bydroxy-2-(3-pyridinyl)ethylJamino]ethyllphenylj-3-
`qujnollne~lI lfonamide
`li -L 4-12-UZ-hydrox y-2-(3-pyridinyl)elbyl jamino ]ethyllphenyl )-4-
`{(hex y lmeth ylaminocarbonyl)ammo l~nzenesulfonamjoo
`H -{ 4-fZ- 11 2-hydroxy-2-(3-pyridinyl)eth yl] amino ]eth y ]Iphen ylJ -4-(3-
`hex y I-2-im idazolidon-I-yl)benzenerulfonamide
`li-{4-{2-f [2-hydrox y-2-(3-pyridin yl)ethyllamino)eth y I Jphenyl}-4-
`jodobenzen~ll lfonamide
`N-[4-IZ-[C2-hydroxy-2-phenyJethyJ)aminoJethyl]phenylJ-4-
`iodobenzene~ulfonarni de
`li-I4-12-1 C2-hydroxy-2-phen yletb yJ)amino Jethyl Jphenylj-2-
`naphthalenesulfonamide
`N-14-12-fC2-hydroxy-2-phenylethyJ)amino lelbyl lphenyIJ-3-
`quinolinesulfomunide
`N-I4-I2-1 f 2-hydroxy-2-{ 4-ammopyridin-3-y J)ethylJamino Jpropyl J-
`phenylJ-4-(hexylaminocarbonylamino )benzeoesulfonamide
`Ii -[4-[2-[ [2-hydrox y-2-( 4-aminopyridin-3-yl )ethyl] amino ]propy J J(cid:173)
`phenyl]-4-iodobenzene~ ulfonamide
`N-14-IZ-11 2-hydroxy-2-(4-aminopyridin-3-yl}elhyIJaminoJpropyl)(cid:173)
`phenyl"lbenzcnesulfOlwnide
`
`Page 11 of 108
`
`
`
`p
`
`,
`
`"
`
`20
`
`"
`
`30
`
`- R-
`
`19203
`
`N -[ 4-[2-[(2-hydwlIY-2-( 4-aminopyridin-3-y l)ethyl Jamino]propyll (cid:173)
`phcnyl1-2-naphthaleuesulfonamide
`.N -l4- [2-[[2-hydrolly-2-( 4-aminopyridin-3-y l)ethyljaminojpropyl] (cid:173)
`pheny 1]-3 -quinolinesulfomurude
`N -[ 4-[2-[[2-hydrox y-2-(3-chloropheny J)elhy l]amino lethy 1]phen yl ]-3-
`isoprapylbenzenesulfonamide
`N -[4-[2-([2-hydroxy-2-(3-chlorophenyJ)ethyJJamino]ethyllphenyl J-2-
`napbthaienesulfonalllide
`N-[ 4-[2-[[2-hydroJl. y-2-(3-chloropheny l)ethyIJamino ]ethyl)phenyJ J-3-
`q uinolinesulfonamidc
`The compounds of the instant inventi~ all have MI!ea st one
`asymmetric center itS nOled by the asterisk in structural Formula 1.
`Additional asymmetric center~ may be pment on the molecule
`depending upon the nature of the various substituents on the molecule.
`in particular, R2 and R3. Each such asymmetric center will produce ·
`two optical iSQmenl and it is intended that all such optical isomers, as
`separated, pure or partially purified optical isomers or racemic
`mixtures thereof, be included within the ambit of the in~tant invention.
`Tn the case of the asymmetric cente r represented by the asterisk in
`FomlUla I, it has been found that the compound in which the hydroxy
`subSliruenl i~ aoove the phtOe of the structure, as seen in Formu", Ie, i ~
`more active and thus more preferred over the compound in which the
`hydroxy substituent is below the plane of the structure.
`The following stereospedfic structure represents the
`preferred stereo isomers of the instant invention:
`
`Page 12 of 108
`
`
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`- 9 -
`
`19203
`
`,
`
`where n, m, r, A, R I, Rl, R3, R4, R5, R6, R7 and X are as defined
`above under fannula L
`Throughout the instant application, the following tenns
`have the indicated meanings:
`The alkyl groups specified above are intended to include
`tho~e alkyl groups of the designated length in either a straight or
`branched configuration, E~emplary of such alkyl groups are methyl,
`ethyl, propyl, isopropyl, butyl, sec-butyl, tertiary butyl, pentyl,
`isopentyi, hexyl, isohexyl, and the like.
`The alkoxy groups specified above are intended to indude
`those alkoxy groups of the designated length in either a straight or
`bmnched configuration. Exemplary of such alkoxy groups are
`methoxy, ethoxy, propoxy, isopropoxy, 11utoxy, isobutoxy, tertiary
`buloxy, pentoxy, isopentoxy, hcxoxy, isohexoxy and the like.
`The term "halogen" is intended to include the halogen
`atoms fluorine. chlorine, bromine and iodine.
`Examples of 5 and 6-membered heterocycles and fused
`heterocycles of A, Z and Ria include pyridyl, quinolinyl, pyrimidinyl,
`pyrroJyJ, Ihienyl, imidazolyl, thiazolyl, benzimidazolyl, Ihiadiazolyl,
`benwlhiadiazolyl, indolyl, indolinyJ, benzodioxolyl, benzodioxanyJ,
`henzothiophenyl. benzofuranyl, benzoxazinyl, benzisoxazoJyl,
`benzothiazol yl, tetrahydronaphthy I, dihydrobenzofuran yl,
`tetrahydroquinolinyl, furopyridine and thienopyridine.
`The preferred value~ of A and Z are phenyl, naphthyl or
`heterocycles with from I to 4 heteroatoms independently selected from
`one of oxygen or sulfur, and/ur I to 4 nitrogen atoms.
`The more preferred values of A are phenyl, pyridyl,
`quinolinyJ, pyrimidinyl, pyrrolyl, thienyJ, imidazolyl, and thiazolyl.
`The more preferred values of Z are phenyl, naphthyl,
`quinolinyl, thienyl, benzimidazolyl, thiadiazolyl, benzothiadiazolyl,
`indolyl, indolinyl, benzodioxolyl, henzodioxanyl, benzothiophenyl,
`benzofuranyl, benzoxazinyl, benzisoxazolyl, benzothiazolyJ,
`tetrahydronaphlhyl. dihydrobenzofuranyl, and letrahydroquinolinyl.
`
`Page 13 of 108
`
`
`
`• 10 .
`
`1920)
`
`,
`
`,.
`
`Certain of the above dermed tenns may occur more than
`once in the ~bove fannula and upon such occurrence: each tenn shall be
`defined indepecdently of the other; thus for example, NR8R8 may
`represent NH2 . NHCH3. N(CH3)CH1CH3. and the like .
`1be following abbreviations are used throughout the
`specification:
`
`"oc em
`
`OTP·Cl
`OMF
`OMSO
`HPLC
`Mo
`MPLC
`M,
`NBS
`NCS
`oH"
`TFA
`THF
`
`: tert-butyloxycarbonyl
`: carbobenzyloxy
`: diisopinocampheylchlorobomne
`: dimethylfonn~mide
`: dimethyl~lI lfoxide
`: high pressure liquid chromalOgraphy
`: methyl
`: medium pressure liquid chromatography
`: rnethanesulfonyl (mesy1)
`: N-bromoltuccinimide
`: N-chlorO$uccinirnide
`: n.hexyl
`: trifluoroacetic ,cid
`: tetrahyd rofuran
`The compowlds (1) of the present invention eRn be
`prepared from epoxide intemlediales such as tho~e of fonnula II ,md
`amulc intermediates such a~ those of fonnula TTl. The preparation of
`llIese intennediates is described in the following schemes.
`
`o
`
`A
`
`n
`where n, m, r. A. R i, R2, R3, R4, RS. R6, R7 and X are as de fined
`above.
`
`III
`
`Page 14 of 108
`
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`19203
`
`Compounds n are known in the literature or may be
`conveniently prepare<! by It variety of methods famili ar to those skilled
`in the art. One common route is illustrated in Scheme 1. Acid chloride
`1. which may be commercially available or readily prepared from the
`corresponding acid by treatment with, for example, thiony l chloride or
`oxalyl chloride, is treated with diazomethane in a solvent such as diethyl
`ether. The resultant diazoketone is then treated with hydrogen chloride
`to give chloroketonc.2 (X = CO, The haloketone 2. is then reduced with
`" reduci ng age nt ~-uch a.~ sodium borohydride. The resultant alcohol ..1 is
`treated with bru;e such as potassium carbonate in refluxing acetooe to
`provide the desired epoxide II , The enantiomerically enriched (R) and
`(5) epoxides II are readily available by asymmetric redu ction of
`baloketones 2. us ing chirn] redUcing agents such as (-) or (+ )-DlP-Cl,
`(R) or (S)-Alpine bomne or (R) or (S)-tetrahydro-l-methyl-3.3 -
`diphenyl-lH,JH-pyrro\o[1.2·c:J t I ,3,2Joxazaborole-ooranc «(R) or (S)(cid:173)
`OABoBH3).
`
`,
`
`10
`
`20
`
`"
`
`JO
`
`I
`
`Page 15 of 108
`
`
`
`- 12 -
`
`19203
`
`SCHEME 1
`
`.
`
`2) HCI
`
`2. (X _ CI, Brl
`
`[HI
`
`.
`
`X
`
`base
`
`(Al ln
`
`.a {X = CI, Brl
`
`0
`
`(R'I~
`
`An alternate route to the desired haloketones 2. is illustrated
`in Scheme 2, Methylketone 5. may be converted to the correspondiug
`haloketone usiug a variety of reagents known to those in the art and
`swnmarized in Larock Comprehensive Organic Transformatiom; VCH:
`New York, 1989, 369-372. Conveniently, methylketone.4 is treated
`with chlorine or N-chlorosuccinimide in acetic acid with an additional
`acid source such as hydrogen chloride or aluminum chloride, For the
`synthesis of 2. (X '" Br), bromine or NBS with hydrogen bromide or
`alwninum bromide may be used. In some cases, the chloro or
`bromoketones 2 may be commercially available,
`
`"
`
`"
`
`20
`
`25
`
`30
`
`Page 16 of 108
`
`
`
`,
`
`- 13 -
`
`19203
`
`SCHEME 2
`
`.
`
`A
`
`2. (X . CI, Sr)
`
`Many of the methylketones ± are commercially available or
`readily prepared by methods described in the literature and known to
`those skilled in the art. R l substituents on the acid chlorides 1 or
`methylketones :l may need to be protected during the subsequent
`procedures. A description of such protecting groups may be found in:
`Pmtective Groups in Ori:anic S~mlhCl:ii~, 2nd Ed., T . W. Greene and P.
`G. M. Wuts, John Wiley and Sons, New York, 1991.
`Compounds III can be conveniently prepared by a variety
`of methods familiar to those skilled in the art. A convenient route for
`their preparation when R6 is hydrogen is illustrated in Scheme 3.
`Compound.5. is selectively protected as a suitable carbamate derivative.6.
`with, for example, di-tert-butyl dicarbonate or carbobenzyloxy
`chloride. This compOlUld is then treated with a sulfonyl halide,
`preferably the sulfonyl chloride L. and a base such as pyridine in an
`anhydrous solvent such as dichloromethane or chloroform for 0.5 to 24
`hours at temperatures of -20 to 50°C, prefembly O"C, to provide the
`sulfonamide 8..
`'I1le protecting gruup is then removed with, for
`example, tritluoracetic acid in the case of Boc or catalytic
`hydrogenation in the case of Cbz, to give the desired amine 2..
`
`I
`
`Page 17 of 108
`
`
`
`19203
`
`SCHEME 3.
`
`or CbzCl/base
`
`•
`or H2"Pd catalyst
`
`CompoWld ~ rn where R6 is not hydrogen mlly be
`conveniently prepared as illustrated in Scheme 4. SulJommide .s.
`prepared as described above, is alkylated with an appropriate alkylating
`agent lil in the presence of base to provide sulJonamide ll. Removal of
`the protecting group as above gi";e.~ the def-ired compowld 21.
`
`,
`
`10
`
`20
`
`"
`
`JO
`
`Page 18 of 108
`
`
`
`,
`
`"
`
`· l.~ .
`
`SCHEME 4
`
`19203
`
`A1k-Y
`10
`
`""', •
`
`or H?,Pd catalyst
`
`G .. Boc or Cbz
`y ", CI, 8J, or I
`AI<: .. C"Ce alkyl
`
`The sulfonyl chloride~ 1, many of which are commercially
`available, can also be readily prepared by a number of methods familiar
`to those ~killed in the art. One suitable method involves the addition of
`an organo]ithiwn reagent or a Grignard reagent to sulfuryl chloride
`following the procedure of S. N. Bhattacharya, tl.l!L 1. Chern. Soc.
`(C), J265· I 267 ( 1969). Another convenient method involve!> the
`treatmem of a thiol with rulfuryl chluride and a melal nitrate according
`to the procedure of Y. 1. Park,.Ill. al., Chemistry Letten;, 1483.1486
`(1992). Sulfonic acids are also conveniently converted to the
`corresponding sulfo!1yl chloride by trea tment with PCIS. PCI3 or SOCIZ
`(1. March. Advanced Organic Chemistry, 4th Ed .• 101m Wiley and Son.~.
`New York: 1992, pl297 and refertn~s I>ite<i therein). Aromatic lUld
`heu:roaIOlnatic compounds may be ch!ofOli;ulfonylated directly by
`treatment with Vilsmeier's reagent or choro~lJlfonj e acid (Organi(;
`S)llthe~i s . I. 8).
`
`Page 19 of 108
`
`
`
`- 16 -
`
`19203
`
`,
`
`"
`
`'fhe diamine~ ,illre commercially available or readily
`pn:pared hy methods described in the lirerature or k.nown to those
`sk.iIled in the art. Compound l where R2 or R3 is methyl can be
`prepared from the corresponding amino acid following the method of 1.
`D. Bloom, n. JlL 1. Med. Chem.,Jl, 3081-3084 (1992). A'i> illustrated
`in Scheme 5 for R3 : methyl, the appropriate (N) amino acid 12. is
`esterified, wnveniently by treatment with methllnolic hydrochloric acid ,
`and then treated with di-tert-butyl dicarbonate to give compound U.
`The eSler group is reduced with a hydride source such as lithium
`horohydridc and Ihe resu itanlllicohol is converted 10 a leaving group
`such u~ a mesylate. Removal of the Boc protecting groups give~
`diamine 1.1.. Thi~ compound is subjected 10 catulYlic hydrogenation in
`Ihe pre~ence of ba~ sudt as sodium acelate 10 give the desired a-methyl
`amine U. The other enantiomer is available thI'IXlgh an analogous
`sequence starting with the corresponding (S) amino acid.
`
`"
`
`30
`
`Page 20 of 108
`
`
`
`- 17 -
`
`SCHEMES
`
`19203
`
`R'
`H2N'f(X)"'().
`Ho2e
`l /N
`.12 A5
`
`NH2
`
`'
`
`1, MeOH, HCI
`
`2) BOC20, NaHC03
`
`R'
`BoCNH'r(X)mc~'
`Msoi: I~
`
`.1J R
`
`NH Soc
`
`R'
`H2N'i(X)mV
`-
`I ,
`A'
`NH2
`R
`' 2CFaC0:2H
`
`/
`MsO
`
`H
`
`1) UBH,
`2) MeS02Cl. EI~ N
`•
`~) TFA, CH2CI2
`
`H2, NaOAc
`•
`cat Pd
`
`R'
`H2N,((X)mc:_
`
`Me !/J NH
`,.
`
`R'
`
`,
`
`Diamines i or ~nlfonam ide amincs.2 where X is -CH20-
`and III is I are also readily preperW by methods descri bed in the
`litentture or known 10 those skilled in the art. For example, as shown
`in Scheme 6, the sodium salt of -1 -nilfophenol l.Q is alk-ylated with 1-
`bromo-2-chloroethane, conveninetly in ref1uxing 2-butanooe with a base
`such as potassium carbonate 10 give chloro derivative ll. The chloride
`is converted to the con-e.~ponding amine by treatment with lithium azide
`followed by reduction with, for example, triphenylphosphine in aqueons
`tetnthydrofuran. Protection of the resultant amine, conveniently a~ its
`I-butyl carbamate by treatment with di-lt!.1-butyldicarbonate , gives
`derivative lJi. The ni tro group is then reduced, for example, by
`
`•
`
`5
`
`10
`
`"
`
`"
`
`"
`
`Page 21 of 108
`
`
`
`• J 8 .
`
`19203
`
`catalytic hydrogenation to provide amine 12. Acylation of intennediate
`12 with sulfonyl chloride 1, • .JIJowed by deprotection wi th acid such as
`uifluoroacetic ;\cid give~ the ~ired intennediate 22.
`
`SQjEME6
`
`CI
`B . ...............
`
`K~C~,
`2·blllanone,
`re flux, 24h
`
`NaO~
`
`V NO,
`
`1. LiNs• DMF, 60'
`2. PPh3, THF/H 20,
`
`3. Boc anhydride,
`CHzClz
`
`"
`
`H2N ...............
`
`Ovp
`~ NHS02(~H2)r·R1
`20
`
`Page 22 of 108
`
`
`
`- 19 -
`
`19203
`
`Alternatively, diamine .i where X is ,CH20- and m is I is
`available from intennediate 12 by treatment with trifluoroacetic acid.
`This diamine may then be modified as illustrated in Scheme 3.
`Diamines.i and sulfonamide amines 2. where X is
`-CH2CH2- and m is 1 are also readily prepared by methods described in
`the literature or kno\.VIl to those skilled in the art. For example, as
`shown in Scheme 7, bromo derivative 21 is treated with sodium cyanide
`to provide nitrile 22.. The nitro group is selectively reduced by
`treatment with hydrogen and catalytic palladium to provide amine n.
`Amine n is acylated with sulfonyl chloride 1 to give the corresponding
`sulfonamide 2:1. Reduction of compound 2:!. with cobalt chloride and
`sodium borohydride provides the desired ami ne 2,i.
`
`Page 23 of 108
`
`
`
`•
`
`J9203
`
`SCHEME?
`
`BC~
`
`NQ ...
`
`__ N::.,CN",, _ _ NC~
`•
`I
`~ 21
`DMSO
`A
`RT, 6 h
`
`.ll
`
`N02
`
`MoOH
`
`CoCI:z06HzO
`
`NaB~.MeOH
`
`Alternatively, diamine.5. where X is -CH:zCH2- and m is 1
`is available from intennedia(e n by reduction of the nitrile group with,
`for example, cobalt chloride and .~odium borohydride. This diamine
`may then be modified a.~ iltustnlteu in Scheme 3.
`I ntennediate.~ D and III are coupled by beat1ng the m neat
`or as a solution in a pular solvent such as methano l, acetonitrile,
`tettahydrofuran, dimeth y l ~u lfo-,; ide o r N·methyl pyrrolidinone for J 10
`24 hours at temperatures of 30 \n 150"C to provide compotlnds 1 as
`shown in Scheme 8. The reaction is conveniently conduct~d in
`refluxing methanol. Alternatively, a salt of amine lll, su ch as the
`
`,
`
`10
`
`"
`
`30
`
`Page 24 of 108
`
`
`
`- 21 -
`
`19203
`
`trifluoroacetate or hydrochloride sa lt, may be used. In these cases, a
`base such as sodium bicarbonate or dietbylisopropylami.ne is added \0
`tbe reaction mixture, 'The product is purified from unwanted side
`products by recry~talJization, trituration, preparative thin layer
`chromatography, flash chromatography on silica gel a~ described by W,
`C. Still,~. ilL J, Org. Chern. ~ 2923 (1978), medium pressu re liquid
`chromatography, or HPLC. Compounds which :u e purified by HPLC
`may be isolated a.~ the corresponding ~alt Purification of intermediates
`is achieved in the s!tITle manner.
`
`SCHEME R
`
`In some ca.~, the coupling product 1 from the reaction
`described in Scheme 8 may be further modified, for example, tiy the
`removal of protecting groups aT the manipulation of ~ubstitu ents on, in
`particular, Rl and R7. The . ..e manipulations may include, but are nOl
`limited to, reduction, oxidation. a tk ylation. acylation, and hydrolysis
`reactions which are commonly known 10 those ski lled in the an.
`
`Page 25 of 108
`
`
`
`- 22 -
`
`19203
`
`An alternate method for the synthesis of compound I is
`illustrated in Scheme 9. Epoxide II is coupled to amine 5. as described
`above for coupling intermediates II and III (Scheme 8) to give aniline
`derivative 21. The secondary amine is selectively protected, for
`example, as a carbamate by treatment with di-tert-butyldicarbonate to
`provide carbamate 22. Alternatively, nitro amine 2Q. is used in the
`coupling reaction to provide 28.. Following protection as described
`above, the nitro group is reduced, for example, by catalytic
`hydrogenation, to provide intermediate 22.. Treatment with a sulfonyl
`chloride in the presence of a base such as pyridine followed by removal
`of the protecting group with. in the case of a tert-butylcarhamate, acid
`such as trit1uoroacetic acid or methanolic hydrogen chloride, providl:s
`the sulfonamide 1.
`
`Page 26 of 108
`
`
`
`,
`
`"
`
`"
`
`•
`
`19203
`
`- 23 -
`
`SCHEME 9
`
`(R')~ •
`
`2) TFA or HCVMeOH
`
`[
`
`In some cases, compound I from the reactlo!l sequence
`illu~trated in Scheme 9 may be further modified, for example, by the
`removal of protecting groups or the mllIlipulation of substilUents on, in
`particul l1.T, R 1 and R7. a.o; described above. In addition, m:UlipulatioD of
`subsLiruelll& on any of the imermedimes in the reaction .seque.nce
`iIIum:l.led in Scheme 9 may occur. One such example is illust rated in
`Scheme 10, Compound}Q, which is prepared as outlined in Scheme 9
`from the corre~ponding epoxide, is subjected to reduction using lin (II)
`
`Page 27 of 108
`
`
`
`·24 ·
`
`19203
`
`chloride to provide compound ll. Other examples of substituents on
`compowld I which may be re<iuced to the corresponding amine by
`methods commonly known to those skilled in the an include nitro
`group.~. nilriles, and azides.
`
`SCHEME 10
`
`j SoC.
`
`aq. H'C~MeOH
`
`,
`
`"
`
`The compounds (I) of the present invention can also be
`prepared from amine intermediates such as those offonnula III and
`25 halokelone intcnnediates such as those of fonnula.t as shown in
`Scheme J I. Amine ill is alkylated with halokelone derivative 2.
`cooveniemly by trearment of a mixture o rID and 2 with ba!\e such as
`potassium carbonate or trietbyl~ine in a polar solvent such as
`acetonitrile, acetone or dimethylfonnamide. The re~'Ultant aminoketone
`30 12 is reduced with, for example, sodium borohydridc in methanol to
`give the cIe~ired aminoalcohol l.
`
`Page 28 of 108
`
`
`
`- 2~ -
`
`19203
`
`SCHEME 11
`
`[H]
`~.:..-.
`
`r
`
`In ~OOle cases, the product I from the reaction de.sc ri hed in
`Scneme I I m3Y be further modified, for example, by the removal of
`protecting group~ or the manipulaTion of substiruents on, in particular,
`Rl and R7. These mWlipulations may include, but are not limited to,
`reduction, oxidatioll, alk.ylation, acylation, and hydrolysis reaction~
`which are commonly known to those skilled in the an.
`Compounds of the general Formula I may be sepantted illlo
`dia~tereoisomeric pails of enantlomen; by, for example, fractional
`crystallization from a suitable solvent, for e.>;ampie methanol or ethyl
`acetate or a mixture thereof. The pair of enantiomers thus obtaiaed
`mhy be sepantted into individual stereoiwmers by conventional mean.,.
`for example by the use of an optically active acid as II resolving agent.
`
`I
`
`Page 29 of 108
`
`
`
`- 26 -
`
`19203
`
`Alternatively, any enantiomer of a compound of the
`ge~ral Fonnula I n1lIy be obtained by stereospecific synlbc!fls using
`optically pure starting materials of known configura.ion.
`'The instant compOlUlcl~ can be isolated in the fann of their
`pharmaceutically acceptable add ~ddition salts, such as the salts derived
`from using inorganic and organic acids. Examples of ~uch acids arc
`hydrochloric, nitric, sulfuric, phosphoric, fonnie, acetic.
`trinuomacetic. propionic, maleic. succinic. malonic and the like. 1n
`addition, certain compounds containing IiJl acidic function such as a
`carboxy or tetraloie, can be isolated in the fonn of their inorganic salt
`in which the cOlUlterion can be selected from sodium, pota~sjum,
`lithium, calcium, magnesium and the like, as well as from organic hases.
`As previollsly indicated. the compounds of the present
`invention have valuable phllrnIacological properties.
`TIle present invention "Iso provides a compound of the
`general Fonnula I or a pharmaceutically acceptable salt. thereof for usc
`as an active therapeutic ~ub,o;tance.
`In one aspect, the Pll:selil invent jOn provides a compound
`of the general Formula I or a phannaceutically acceptllble ester thereof:
`or a phannaceutiClllly acceptable salt !hereof for use in the treatment of
`obesity in human or non-human animals.
`TIle pre.sent invention further provides a compound of the
`general Formula 1. or a phannaceutically acceptable ester thereof; or
`phannaceutically acceptable sail thereof. for use in the trealDlem of
`hyperglycemia (diabetes) in hwnan or non-human animab.
`TIle disease dia
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