PCT
`
`WORLD INTELLECTUAL PROPERTY ORGANIZATION
`International Bureau
`
`
`
`INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`(51) International Patent Classification 5 :
`(11) International Publication Number:
`WO 94/18161
`CO7C 311/21, 311/46, 311/47, CO7D
`213/30, 213/38, 215/36, A61K 31/18,
`31/44, 31/47
`att
`:
`ti
`(21) International Application Number
`i
`iling Date:
`1
`(22) International Filing
`Date
`
`.
`3
`
`PCT/US94/00766
`1994
`(19.01.94
`9 January 1994
`(19.01.94)
`
`Hoboken, NJ 07030 (US). WEBER, Ann, E. [US/US]; 1974
`Duncan Drive, Scotch Plains, NJ 07076 (US).
`(74) Agent: ROSE, David, L.; 126 East Lincoln Avenue, Rahway,
`NJ 07065 (US).
`
`(43) International Publication Date:
`
`18 August 1994 (18.08.94)
`
`.
`
`a7
`
`
`
`
`
`compounds can also be used to reduce triglyceride levels and cholesterol levels or raise high density lipoprotein levels or to reduce gut
`
`
`
`
`
`(30) Priority Data:
`US
`9 February 1993 (09.02.93)
`015,689
`
`
`08/168,105 US|(81) Designated States: BB, BG, BR, BY, CN, CZ, FI, HU, KR,15 December 1993 (15.12.93)
`KZ, LK, LV, MG, MN, MW, NO, NZ, PL, RO, RU, SD,
`SK, UA, US, UZ, OAPI patent (BF, BJ, CF, CG, CI, CM,
`GA, GN, ML, MR, NE, SN, TD, TG).
`
`(60) Parent Application or Grant
`,
`(63) Related by Continuation
`08/168,105 (CON)
`US
`
`Filed on 15 December 1993 (15.12.93)|Published
`With international search report.
`
`(71) Applicant (for all designated States except US)} MERCK &
`CO., INC. [US/US]; 126 East Lincoln Avenue, Rahway, NJ
`07065 (US).
`
`(72) Inventors; and
`(75) Inventors/Applicants (for US only): FISHER, Michael, H.
`[US/US]; 80 Old York Road, Ringoes, NJ 08551 (US).
`
`MATHVINK, Robert, J. [US/US]; Apartment No. 1908, 45
`River Drive South, Jersey City, NJ 07310 (US). OK, Hyun,
`
`O. [US/US]; 48 Laura Avenue, Edison, NJ 08820 (US).
`
`PARMEE, Emma, R. [GB/US]; Apartment 1, 406 4th Street,
`
`
`(54) Title: SUBSTITUTED PHENYL SULFONAMIDES AS SELECTIVE 63 AGONISTS FOR THE TREATMENT OF DIABETES
`AND OBESITY
`
`“or
`fbpoateOHHEeOL \ N-SOp(CHa\-R7
`=|=
`(R’),
`R AS
`
`3
`
`*
`
`:
`
`(57) Abstract
`
`Substituted phenylsulphonamides having formula (1) where the variables are as defined in Claim 1; are selective beta-3 adrenergic
`receptor agonists with very little beta-1 and beta-2 adregenic receptoractivity and as such the compoundsare capableof increasinglipolysis
`and energy expenditure in cells. The compounds thus have very potent activity in the treatment of Type II diabetes and obesity. The
`
`In addition, the compounds can be used to reduce neurogenic inflammation or as antidepressant agents. The compoundsare
`| motility.
`prepared by coupling an aminoalkylphenylsulphonamide with an appropriately substituted alkyl epoxide. Compositions and methodsfor the
`use of the compoundsin the treatment of diabetes and obesity and for the reduction of triglyceride levels and cholesterol levels or raising
`high density lipoprotein levels or for increasing gut motility are also disclosed.
`
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`FOR THE PURPOSES OF INFORMATION ONLY
`
`Codes used to identify States party to the PCT on the front pages of pamphlets publishing international
`applications under the PCT.
`
`Mauritania
`MR
`United Kingdom
`GB
`Austria
`AT
`
`
`
`
`AU MWs-MalawiAustralia GE Georgia
`BB
`Barbados
`GN
`Guinea
`NE
`Niger
`BE
`Belgium
`GR
`Greece
`NL
`Netherlands
`BF
`Burkina Faso
`HU
`Hungary
`NO
`Norway
`BG
`Bulgaria
`IE
`Ireland
`NZ
`New Zealand
`BJ
`Benia
`IT
`Italy
`PL
`Poland
`BR
`Brazil
`JP
`Japan
`PT
`Portugal
`BY
`Belarus
`KE
`Kenya
`RO
`Romania
`CA
`Canada
`KG
`Kyrgystan
`RU
`Russian Federation
`CF
`Central African Republic
`KP
`Democratic People’s Republic
`SD
`Sudan
`CG
`Congo
`of Korea
`SE
`Sweden
`CH
`Switzerland
`Republic of Korea
`SI
`Slovenia
`cI
`Cate d'Ivoire
`Kazakhstan
`SK
`Slovakia
`CM
`Cameroon
`Liechtenstein
`SN
`Senegal
`CN
`China
`Sri Lanka
`TD
`Chad
`cs
`Czechoslovakia
`Luxembourg
`TG
`Togo
`CZ
`Czech Republic
`Latvia
`TJ
`Tajikistan
`DE
`Germany
`Monaco
`TT
`Trinidad and Tobago
`DK
`Denmark
`Republic of Moldova
`UA
`Ukraine
`ES
`Spain
`Madagascar
`US
`United States of America
`FI
`Finland
`Mali
`UZ
`Uzbekistan
`FR
`France
`Mongolia
`VN
`Viet Nam
`GA
`Gabon
`
`KR
`KZ
`LI
`LK
`LU
`LV
`MC
`MD
`MG
`ML
`MN
`
`
`
`
`
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`WO 94/18161
`
`PCT/US94/00766
`
`-l-
`
`TITLE OF THE INVENTION
`SUBSTITUTED PHENYL SULFONAMIDESAS SELECTIVE £3
`AGONISTS FOR THE TREATMENTOF DIABETES AND OBESITY
`
`CROSS REFERENCE TO RELATED APPLICATIONS
`This application is a continuation-in-part of our copending
`application Serial Number 08/015689 filed February 9, 1993.
`
`BACKGROUND OF THE INVENTION
`B-Adrenoceptors have been subclassified as B] and 82 since
`Increased heart rate is the primary consequence of B]-receptor
`1967.
`stimulation, while bronchodilation and smooth muscle relaxation
`typically result from B2 stimulation. Adipocyte lipolysis wasinitially
`thought to be solely a B]-mediated process. However, more recent
`results indicate that the receptor-mediating lipolysis is atypical in
`nature. These atypical receptors, later called B3-adrenoceptors, are
`found on the cell surface of both white and brown adipocytes where
`their stimulation promotes both lipolysis (breakdown of fat) and energ
`expenditure.
`
`Early developments in this area produced compoundswith
`greater agonist activity for the stimulation of lipolysis (B3 activity) than
`for stimulation of atrial rate (81) and tracheal relaxtion (62). These
`early developments disclosed in Ainsworth et al., U.S. Patents 4,478,849
`and 4,396,627, were derivatives of phenylethanolamines.
`Such selectivity for B3-adrenoceptors could make
`In
`compoundsofthis type potentially useful as antiobesity agents.
`addition, these compoundshavebeen reported to show antihypergly-
`cemic effects in animal models of non-insulin-dependent diabetes
`mellitus.
`
`A major drawback in treatment of chronic diseases with B3
`agonists is the potential for stimulation of other B-receptors and
`subsequentside effects. The most likely of these include muscle tremor
`(82) and increased heart rate (B]). Although these phenylethanolamine
`derivatives do possess some [33 selectively, side effects of this type have
`
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`WO 94/18161
`
`PCT/US94/00766
`
`-2-
`
`been observed in human volunteers. It is reasonable to expect that these
`side effects resulted from partial Bj and/or B2 agonism.
`Morerecent developmentsin this area are disclosed in
`Ainsworth et al., U.S. Patent 5,153,210, Caulkett et al., U.S. Patent
`4,999,377, Alig et al., U.S. Patent 5,017,619, Lecountet al., European
`Patent 427480 and Bloom et al., European Patent 455006.
`Even though these more recent developments purport to
`describe compounds with greater B3 selectively over the Bj and B2
`activities, this selectively was determined using rodents, in particular,
`rats as the test animal. Because even the most highly selective
`compounds,as determined by theseassays, still show signs ofside
`effects due to residual B} and B2 agonist activity when the compounds
`are tested in humans,it has become apparentthat the rodent is not a
`good model for predicting human §3selectivity.
`|
`Recently, assays have been developed which more
`accurately predict the effects that can be expected in humans. These
`assays utilize cloned human $3 receptors which have been expressed in
`Chinese hamster ovary cells. The agonist and antagonist effects of the
`various compoundsonthe cultivated cells provide an indication of the
`antiobesity and antidiabetic effects of the compoundsin humans.
`
`SUMMARY OF THE INVENTION
`The instant invention is concerned with substituted phenyl
`sulfonamides whichare 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
`stereoisomers of the substituted phenylsulfonamides. 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
`compoundsas the active ingredient thereof. Further objects will
`become apparent from reading the following description.
`
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`
`PCT/US94/00766
`
`-3-
`
`DESCRIPTION OF THE INVENTION
`The compoundsofthe instant invention are best realized in
`the following structural formula:
`
`Ge
`
`where
`
`nis
`
`m is
`
`ris
`
`Ais
`
`Rl is
`
`10
`
`15
`
`20
`
`25
`
`30
`
`OH
`H R?
`eee
`OCHCHCHEN-C-00)
`R3
`
`im
`px
`c
`
`,
`
`N-SO2(CHa)rR
`R®
`:
`
`0 to 7;
`0 or 1;
`0 to 3;
`phenyl, naphthyl, a 5 or 6-membered heterocyclic ring
`with from | to 4 heteroatomsselected from oxygen, sulfur
`or nitrogen, a benzene ring fused to a C3-Cg cycloalkyl
`ring, a benzene ring fused to a 5 or 6-membered
`heterocyclic ring with from | to 3 heteroatoms selected
`from oxygen, sulfur or nitrogen or a 5 or 6-membered
`heterocyclic ring with from | to 3 heteroatoms selected
`from oxygen, sulfur or nitrogen fused to a 5 or 6-
`memberedheterocyclic ring with from 1 to 3 heteroatoms
`selected from oxygen, sulfur or nitrogen;
`hydroxy, oxo,halogen, cyano, nitro, NR8R8, SR8,
`trifluoromethyl, C]-Cé6 alkyl, Cj-C6 alkoxy, C3-Cg
`cycloalkyl, phenyl, SO2R9, NR8COR9, CORY, NR8SO2R9,
`NR&CO2R8or Cj -Cé6alkyl substituted by hydroxy, nitro,
`halogen, cyano, NR8R8, SR8, trifluoromethyl, C1-C6
`alkoxy, C3-Cg cycloalkyl, phenyl, NR8SCORY, COR9,
`SO2R9, NR8SO2R9, NR8CO2R8, or R! is a5 or 6-
`memberedheterocycle with from 1 to 3 heteroatoms
`selected from oxygen, sulfur or nitrogen;
`
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`WO 94/18161
`
`PCT/US94/00766
`
`-4-
`
`RO is
`R7 is
`
`Bis
`
`R2 and R3 are independently hydrogen, C]-C6 alkyl or Cj-C6 alkyl
`substituted by | to 3 of hydroxy, C]-C6 alkoxy, or
`halogen;
`-CH?-, -CH2-CH?2- , -CH=CH- or -CH20-;
`X 1S
`R4 and R5 are independently hydrogen, Cj-C¢6alkyl, halogen, NHR8,
`ORg, SO2R9 or NHSO2R9;
`hydrogen or C]-C6 alkyl;
`C1-Cé6alkyl, C3-Cg cycloalkyl, or B-(R1)n;
`phenyl, naphthyl, a 5 or 6-memberedheterocyclic ring
`with from | to 4 heteroatomsselected from oxygen, sulfur
`or nitrogen, a benzene ring fused to a C3-Cg cycloalky!
`ring, a benzene ring fused to a 5 or 6-membered
`heterocyclic ring with from | to 3 heteroatomsselected
`from oxygen, sulfur or nitrogen or a 5 or 6-membered
`heterocyclic ring with from | to 3 heteroatomsselected
`from oxygen, sulfur or nitrogen fused to a 5 or 6-
`memberedheterocyclic ring with from | to 3 heteroatoms
`selected from oxygen, sulfur or nitrogen;
`hydrogen, C]-C10 alkyl, C3-Cg cycloalkyl, phenyl
`optionally substituted by | to 3 of halogen, C1-C6 alkyl or
`C1-C6 alkoxy, or C1-C10 alkyl substituted by | to 3 of
`hydroxy, halogen, CO2H, CO2-C1-C6 alkyl, C3-Cg
`cycloalkyl, Cj-C6 alkoxy, or phenyl optionally substituted
`by from | to 3 of halogen, C1-C6 alkyl or Ci-C6 alkoxy;
`R8, NHR8 or NR8R8.
`In the abovestructural formula and throughoutthe instant
`specification, the following terms have the indicated meanings:
`The alkyl groups specified above are intended to include
`those alkyl groups of the designated length in either a straight or
`branched configuration. Exemplary of such alkyl groups are methyl,
`ethyl, propyl, isopropyl, butyl, sec-butyl, tertiary butyl, pentyl,
`isopentyl, hexyl, isohexyl, and the like.
`The alkoxy groups specified above are intended to include
`those alkoxy groups of the designated lengthin either a straight or
`
`R8 is
`
`R9 is
`
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`WO 94/18161
`
`PCT/US94/00766
`
`5.
`
`branched configuration. Exemplary of such alkoxy groups are
`methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary
`butoxy, pentoxy, isopentoxy, hexoxy, isohexoxy andthe like.
`The term "halogen"is intended to include the halogen
`atoms fluorine, chlorine, bromine andiodine.
`Certain of the above defined terms may occur more than
`once in the above formula and upon such occurrence each term shall be
`defined independently of the other.
`The preferred 5 and 6-membered heterocycles and fused
`heterocycles of A, B and R] are those heterocycles with from | to 4
`heteroatoms independently selected from one of oxygenorsulfur or |
`to 4 nitrogen atoms.
`The preferred values of A and B are phenyl, naphthyl! or
`the foregoing preferred 5 and 6-membered heterocycles and fused
`heterocycles.
`|
`The morepreferred values of A are phenyl, naphthyl,
`pyridyl, quinolinyl, pyrimidinyl, pyrrollyl, thienyl, imidazolyl, and
`thiazolyl.
`
`The more preferred values of B are phenyl, naphthyl,
`quinolinyl, thieny!, benzimidazolyl, thiadiazolyl, benzothiadiazolyl,
`indolyl, indolinyl, benzodioxolyl, benzodioxany]l, benzothiophenyl,
`benzofuranyl, benzisoxazolyl, benzothiazolyl, tetrahydronaphthy],
`dihydrobenzofuranyl, and tetrahydroquinolinyl.
`Further preferred compoundsof the instant invention are
`realized when in the above structural formula:
`R2 and R3 are hydrogen or methyl;
`X is
`-CH?-
`m is
`1;
`ris
`0-2; and
`R4, RS and R6 are hydrogen.
`Still further preferred compoundsof the instant invention
`are realized when in the abovestructural formula:
`Als
`phenyl, quinolinyl, or a 6-membered heterocyclic ring with
`1 or 2 nitrogen atoms;
`
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`PCT/US94/00766
`
`-6-
`
`B is
`R1 is
`
`ris
`
`phenyl or quinohiny];
`NH2,hydroxy, halogen, cyano, trifluoromethyl, phenyl,
`NR8COR9, NR8CO2R8, C1-C6 alkyl optionally substituted
`by hydroxy; and
`0 or 2.
`
`Representative preferred antiobesity and antidiabetic
`compoundsof the present invention include the following:
`
`N-[4-[2-[[2-hydroxy-3-(4-hydroxyphenoxy)propyl]JaminoJethyl|]pheny]]-
`benzenesulfonamide
`N-[4-[2-[[2-hydroxy-3-(4-hydroxyphenoxy)propy]Jamino]ethyl]pheny]]-
`4-iodobenzenesulfonamide
`.
`N-[4-[2-[[2-hydroxy-3-(4-hydroxyphenoxy)propy]Jamino]ethyl]phenyl]-
`2-naphthalenesulfonamide
`N-[4-[2-[[2-hydroxy-3-(4-hydroxyphenoxy)propy]Jamino]ethyl]pheny!]-
`4-(benzo-2,1,3-thiadiazole)sulfonamide
`N-[4-[2-[[2-hydroxy-3-(4-hydroxyphenoxy)propyl]amino]ethy]]pheny]]-
`2-phenylethanesulfonamide
`N-[4-[2-[[3-(4-fluorophenoxy)-2-hydroxypropy]|amino]ethyl|pheny]]-
`4-benzenesulfonamide
`N-[4-[2-[[3-[(2-amino-5-pyridinyl)oxy]-2-hydroxypropy]aminoJethy!]-
`phenyl]-2-naphthalenesulfonamide
`N-[4-[2-[[2-hydroxy-3-(4-hydroxyphenoxy)propy] Jamino]ethyl]pheny!J-
`3-quinolinesulfonamide
`N-[4-[2-[[2-hydroxy-3-(4-hydroxyphenoxy)propy]|aminoJethyl]pheny]]-
`4-[(5-methoxycarbony])pentanoyl]amino]benzenesulfonamide
`N-[4-[2-[[2-hydroxy-3-(4-hydroxyphenoxy)propylaminoJethy]]pheny!-
`4-[(5-hydroxycarbony])pentanoy]]amino]benzenesulfonamide
`N-[4-[2-[[2-hydroxy-3-(4-hydroxyphenoxy)propy]JaminoJethyl|pheny]]-
`4-(hexylaminocarbonylamino)benzenesulfonamide
`N-[4-[2-[(2-hydroxy-3-phenoxypropyl)aminoJethyl]pheny!]-4-
`chlorobenzenesulfonamide
`
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`WO 94/18161
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`PCT/US94/00766
`
`-7-
`
`N-[4-[2-[[2-hydroxy-3-(3-cyanophenoxy)propy]]amino]ethy]]phenyl]-3-
`quinolinesulfonamide
`N-[4-[2-[[3-(4-amino-3-cyanophenoxy)-2-hydroxypropy]Jamino]ethyl]-
`pheny!]-3-quinolinesulfonamide
`N-[4-[2-[[2-hydroxy-3-[(3-hydroxymethy]l)phenoxy]propyl |amino]-
`ethyl]pheny!]-3-quinolinesulfonamide
`N-[4-[2-[[2-hydroxy-3-(3-pyridyloxy)propyl]aminoJethylphenyl]]}-3-
`quinolinesulfonamide
`N-[4-[2-[[2-hydroxy-3-(3-pyridyloxy)propy]]aminoethyl]]pheny]!]-4-
`iodobenzenesulfonamide
`N-[4-[2-[[3-[(2-amino-5-pyridinyl)oxy]-2-hydroxypropy]amino]Jethy]]-
`phenyl]-4-isopropylbenzenesulfonamide.
`|
`
`The compoundsof the instant inventionall have at least one
`asymmetric center as noted bythe asterisk in structural Formulae I and
`la. Additional asymmetric centers may be present on the molecule
`depending uponthe nature of the various substituents on the molecule,
`in particular, R2 and R3. Each such asymmetric center will produce
`two optical isomersandit 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 instant invention.
`In the case of the asymmetric center represented by the asterisk in
`FormulaI, it has been found that the compound in which the hydroxy
`substituent is above the plane ofthe structure, as seen in FormulaIa,is
`more active and thus more preferred over the compound in which the
`hydroxy substituent is below the plane of the structure.
`Compoundsof the general Formula I may be separated into
`diastereoisomeric pairs of enantiomers by, for example, fractional
`crystallization from a suitable solvent, for example methanol or ethy]
`acetate or a mixture thereof. The pair of enantiomers thus obtained
`may be separated into individual stereoisomers by conventional means,
`for example by the use of an optically active acid as a resolving agent.
`
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`-8-
`
`Alternatively, any enantiomer of a compoundofthe
`general Formula I may be obtained by stereospecific synthesis using
`optically pure starting materials of known configuration.
`The following stereospecific structure represents the
`preferred stereoisomers of the instant invention.
`
`Re
`OHH
`H
`y'*
`an
`OCH,-C-CHoN-C-(X),,
`* 4 =|=
`Re
`R3
`R°
`
`1
`(R')n
`
`N-SO2(CHa),-R
`t3
`
`la
`
`wherethe various substituents are as defined above.
`The instant compoundscan beisolated in the form of their
`pharmaceutically acceptable acid addition salts, such as the salts derived
`from using inorganic and organic acids. Examples of such acids are
`hydrochloric, nitric, sulfuric, phosphoric, formic, acetic,
`In
`trifluoroacetic, propionic, maleic, succinic, malonic and the like.
`addition, certain compoundscontaining an acidic function such as a
`carboxyortetrazole, can be isolated in the form of their inorganicsalt
`in which the counterion can be selected from sodium, potassium,
`lithium, calcium, magnesium andthe like, as well as from organic bases.
`The compounds(I) of the present invention can be
`prepared from epoxide intermediates such as those of formula II and
`amine intermediates such as those of formula IJ. The preparation of
`these intermediates is described in the following schemes.
`
`O
`oOX<]
`
`R2
`R4
`|
`-|-
`HANG0g PrNsoutCHale
`R?
`AF
`R®
`
`1]
`
`IH
`
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`-9-
`
`where n, m, r, A, RJ, R2, R3, R4, R5, R6, R7 and X are as defined
`above.
`
`Compounds I] can be conveniently prepared by a variety of
`methods familiar to those skilled in the art. One commonroute is
`illustrated in Scheme |. Alcohol 1 is treated with base such as sodium
`hydride or potassium t-butoxide in a polar solvent such as anhydrous
`dimethylformamide. The resultant anion is alkylated with epoxide
`derivative 2, wherein "L" is a leaving group such as a sulfonate ester or
`a halide, for 0.5 to 24 hours at temperatures of 20-100°C to provide
`compound II. The epoxide derivative 2 is conveniently the
`commercially available, enantiomerically pure (2S) or (2R)-glycidyl 3-
`nitrobenzene sulfonate or (2R) or (2S)-glycidy] 4-toluenesulfonate, thus
`both the (S) and (R) enantiomers of epoxide II are readily available.
`
`SCHEME 1
`
`
`
`Ino
`
`Manyof the alcohols 1 are commercially available or
`readily prepared by methods described in the literature and knownto
`those skilled in the art. R1 substituents on the alcohol 1 may need to be
`protected during the alkylation and subsequent procedures. A
`description of such protecting groups may be found in: Protective
`Groups in Organic Synthesis, 2nd Ed., T. W. Greene and P. G. M.
`Wuts, John Wiley and Sons, New York, 1991. A useful method for
`protecting the preferred alchohol 1 wherein A (R1)py is 4-hydroxy-
`pheny]asits tert-butyldimethylsily! (TBS) derivative is illustrated in
`Scheme 2. Commercially available phenol 3 is treated with a silylating
`
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`15
`
`20
`
`25
`
`30
`
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`

`

`WO 94/18161
`
`PCT/US94/00766
`
`-10-
`
`agent such as fert-butyldimethylsilyl chloride in the presence of a base
`such as imidazole in an aprotic solvent such as dimethylformamide. The
`benzyl group is then removedby catalytic hydrogenation to give the
`desired alcohol 5.
`
`SCHEME2
`
`10
`
`15
`
`20
`
`25
`
`30
`
`(tert-Bu)Me2SiCl
`OBn WW»
`
`cy imidazole, DMF
`
`(tert-Bu)MeoSiO
`
`HO
`
`3
`
`OBn
`
`4
`
`Pd catalyst
`
`(tert
`
`tert-Bu)Me,SiO
`
`Bu)Mep
`
`5
`
`CompoundsII] 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 hydrogenis illustrated in Scheme 3.
`Compound6 is selectively protected as a suitable carbamate derivative
`6a with, for example, di-tert-butyl] dicarbonate or carbobenzyloxy
`chloride. This compoundis then treated with a sulfony] halide,
`—
`preferably the sulfonyl chloride 7, 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, preferably O°C, to provide the
`sulfonamide 8. The protecting group is then removed with, for
`example, trifluoracetic acid in the case of Bocor catalytic
`hydrogenation in the case of Cbz, to give the desired amine 9.
`
`SAWAI EX. 1012
`Page 12 of 104
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`

`

`WO 94/18161
`
`PCT/US94/00766
`
`SCHEME3
`
`-ll-
`
`or CbzCl/base
`
`ii ae“ = Boc2O
`GNH-c—“at>
`R(CH>),SO2CI(Z) “reH
`————>
`HEN- so()CH
`
`10
`
`15
`
`20
`
`25
`
`30
`
`6a28 Ge= aoc or Cbz
`
`7
`
`pyridine, CH2Cl,
`
`=I
`
`R
`
`R
`
`TFA, CHoCl>
`or H./Pd catalyst
`
`.
`
`alCh alr
`
`9
`
`CompoundsIII where R® is not hydrogen may be
`conveniently preparedasillustrated in Scheme 4. Sulfonamide 8,
`prepared as described above,is alkylated with an appropriate alkylating
`agent 10 in the presence of base to provide sulfonamide 11. Removal of
`the protecting group as above gives the desired compound III.
`
`SAWAI EX. 1012
`Page 13 of 104
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`

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`PCT/US94/00766
`
`_j2-
`
`SCHEME4
`
`10
`
`15
`
`20
`
`25
`
`30
`
`R°-Y
`
`10
`
`GNH-+atpe(CHa)-Robase
`ONE a>(CH)
`TFA,CHCl,
`
`or H,/Pd catalyst
`
`Re
`|
`
`HoN-1(X)mi aCHa)
`
`G = Boc or Cbz
`
`Y= Cl, Br, or |
`
`The sulfonyl chlorides 7, many of which are commercially
`available, can also be readily prepared by a numberof methods familiar
`to those skilled in the art. One suitable method involves the addition of
`an organolithium reagent or a Grignard reagent to sulfuryl chloride
`following the procedure of S. N. Bhattacharya,et. al., J. Chem. Soc.
`(C), 1265-1267 (1968). Another convenient method involves the
`treatment of a thiol with sulfuryl chloride and a metal nitrate according
`to the procedure of Y. J. Park, et. al., Chemistry Letters, 1483-1486
`(1992). Sulfonic acids are also conveniently converted to the
`corresponding sulfonyl chloride by treatment with PC1I5, PCl3 or SOCI2
`(J. March, Advanced Organic Chemistry, 4th Ed., John Wiley and Sons,
`New York: 1992, p1297 and references cited therein). Alternatively,
`aromatic compounds maybetreated with chlorosulfonic acid according
`
`to the procedure of Albert, et. al., J. Het. Chem. 15, 529 (1978), to
`provide the sulfonyl! chlorides.
`
`SAWAI EX. 1012
`Page 14 of 104
`
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`
`

`

`WO 94/18161
`
`PCT/US94/00766
`
`-13-
`
`The diamines 6 are commercially available or readily
`prepared by methodsdescribed in the literature or knownto those
`skilled in the art. Compound 6 where R2 or R3 is methyl can be
`prepared from the corresponding amino acid following the method of J.
`D. Bloom,et. al., J. Med. Chem., 35, 3081-3084 (1992). As illustrated
`in Scheme 5 for R3 = methyl, the appropriate (R) amino acid 12 is
`esterified, conveniently by treatment with methanolic hydrochloric acid,
`and then treated with di-tert-butyl dicarbonate to give compound 13.
`The ester group is reduced with a hydride source suchaslithium
`borohydride and the resultant alcohol is converted to a leaving group
`such as a mesylate. Removalof the Boc protecting groups gives
`diamine 14. This compoundis subjected to catalytic hydrogenation in
`the presence of base such as sodium acetate to give the desired o-methy]
`amine 15. The other enantiomeris available through an analogous
`sequencestarting with the corresponding (S) aminoacid.
`
`10
`
`15
`
`20
`
`25
`
`30
`
`SAWAI EX. 1012
`Page 15 of 104
`
`SAWAI EX. 1012
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`

`

`WO 94/1816!
`
`PCT/US94/00766
`
`SCHEME5
`
`-14-
`
`1)MeOH,HCIHCl
`
`HO;ae2)°2)Boc,0,NaHCCNaHCO,
`
`Me0,C“oh
`2)MeSO.Cl,Et,N
`BocNA
`13 Re
`HNal
`Ho,NaQAcsci
`A,5
`
`10
`
`15
`
`20
`
`12
`
`R®
`
`re
`
`S
`
`1) LiBH,
`
`NHBoc
`
`3) TFA, CH2Cl,
`
`NH2
`14 R° L906F,CO.H
`
`cat. Pd
`
`HN
`
`i5 AR
`
`295
`
`39
`
`Diamines6 or sulfonamide amines 9 where X is -CH20-
`and m is | are also readily prepared by methods describedin the
`literature or knownto those skilled in the art. For example, as shown
`in Scheme6, the sodium salt of 4-nitrophenol 16 is alkylated with !-
` bromo-2-chloroethane, conveninetly in refluxing 2-butanone with a base
`such as potassium carbonate, to give chloro derivative 17. The chloride
`is converted to the corresponding amine by treatment with lithium azide
`followed by reduction with, for example, triphenylphosphine in aqueous
`tetrahydrofuran. Protection of the resultant amine, conveniently asits
`t-butyl carbamate by treatment with di-tert-butyldicarbonate, gives
`
`SAWAI EX. 1012
`Page 16 of 104
`
`SAWAI EX. 1012
`Page 16 of 104
`
`

`

`WO 94/1816]
`
`PCT/US94/00766
`
`-15-
`
`derivative 18. The nitro group is then reduced, for example, by
`catalytic hydrogenation to provide amine 19. Acylation of intermediate
`19 with sulfonyl chloride 7, followed by deprotection with acid such as
`trifluoroacetic acid gives the desired intermediate 20.
`
`SCHEME 6
`
`10
`
`15
`
`20
`
`25
`
`30
`
`NaO
`
`CO.
`
`NO
`
`2
`
`16
`
`1. LiN3, DMF, 60°
`
`2. PPhg, THF/H2O,
`3. BOC anhydride,
`CHCl.
`
`ClBIT
`
`
`
`K5CO3,
`2-butanone,
`reflux, 24h
`
`c7~
`
`NO>
`
`17
`
`BOCNH7~C*S cS
`18
`
`~
`NO2
`
`
`
`Hy, Pa/C
`
`BOCNH~O NH, 2 TRAICH2Ch (1:3)
`
`1. R7(CH,),SO>Cl(2), pyridine, CHCl,
`
`
`19
`
`“Co. NHSO.(CH,),-R’
`
`20
`
`SAWAI EX. 1012
`Page 17 of 104
`
`SAWAI EX. 1012
`Page 17 of 104
`
`

`

`WO 94/18161
`
`PCT/US94/00766
`
`- 16 -
`
`Alternatively, diamine 6 where X is -CH2O- and m is | is
`available from intermediate 19 by treatment with trifluoroacetic acid.
`This diamine may then be modified asillustrated in Scheme3.
`Diamines 6 and sulfonamide amines 9 where X is
`-CH»CH?2- and m is | are also readily prepared by methods described in
`the literature or knownto those skilled in the art. For example, as
`shown in Scheme7, bromo derivative 21 is treated with sodium cyanide
`to providenitrile 22. The nitro groupis selectively reduced by
`treatment with hydrogen andcatalytic palladium to provide amine 23.
`Amine 23 is acylated with sulfonyl chloride 7 to give the corresponding
`sulfonamide 24. Reduction of compound 24 with cobalt chloride and
`sodium borohydride provides the desired amine 25.
`
`10
`
`15
`
`20
`
`25
`
`30
`
`SAWAI EX. 1012
`Page 18 of 104
`
`SAWAI EX. 1012
`Page 18 of 104
`
`

`

`WO 94/18161
`
`PCT/US94/00766
`
`-17-
`
`SCHEME 7
`
`“CO.
`
`21
`
`NOz
`
`
`
`NaCN
`
`RT, 6h
`
`NC
`
`22
`
`NO>
`
`
`wenn
`NH,
`Pyridine, CHCl,
`
`23
`
`10
`
`15
`
`NHSO,(CH,)-R’?=NaBHy, MeOH
`24
`
`ODL
`
`CoCl.*6H,0
`
`20
`
`25
`
`30
`
`25
`
`NHSO2(CHp),-R’
`a(
`2)r
`
`Alternatively, diamine 6 where X 1s -CH2CH?- and m is |
`is available from intermediate 23 by reduction of the nitrile group with,
`for example, cobalt chloride and sodium borohydride. This diamine
`may then be modified as illustrated in Scheme3.
`Intermediates IJ and III are coupled by heating them neat
`or as a solution in a polar solvent such as methanol, acetonitrile,
`tetrahydrofuran, dimethylsulfoxide or N-methy! pyrrolidinonefor | to
`24 hours at temperatures of 30 to 150°C to provide compounds | as
`shown in Scheme 8. The reaction is conveniently conducted in
`refluxing methanol. Alternatively, a salt of amine II, such as the
`trifluoroacetate or hydrochloride salt, may be used.
`In these cases, a
`
`SAWAI EX. 1012
`Page 19 of 104
`
`SAWAI EX. 1012
`Page 19 of 104
`
`

`

`WO 94/18161
`
`PCT/US94/00766
`
`-18-
`
`base such as sodium bicarbonate or diisopropylethylamine is added to
`the reaction mixture. The productis purified from unwanted side
`products by recrystallization, trituration, preparative thin layer
`chromatography, flash chromatographyonsilica gel as described by W.
`C. Still, et. al., J. Org. Chem. 43, 2923 (1978), medium pressure liquid
`chromatography, or HPLC. Compounds which are purified by HPLC
`may beisolated as the corresponding salt. Purification of intermediates
`is achieved in the same manner.
`
`10
`SCHEME8
`
`!
`
`Owe +
`(R’)
`ia
`MENGOa|P-NBOsCH -—_—_o
`(Brocnacnons-g=0Lo{mom
`
`15
`
`20
`
`25
`
`30
`
`R?
`
`AS
`
`R®
`
`III
`
`OH
`
`|
`
`P
`
`(R’),
`
`|
`
`In somecases, the coupling product I from the reaction
`described in Scheme 8 may be further modified, for example, by the
`removal of protecting groups or the manipulation of substituents on, in
`particular, Rl and R7. These manipulations may include reduction,
`oxidation, alkylation, acylation, and hydrolysis reactions which are
`commonly known to those skilled in the art. One such exampleis
`illustrated in Scheme 9. Compound 26, which is prepared as outlined in
`the Scheme 8 from the corresponding epoxide, is subjected to catalytic
`
`SAWAI EX. 1012
`Page 20 of 104
`
`SAWAI EX. 1012
`Page 20 of 104
`
`

`

`WO 94/18161
`
`PCT/US94/00766
`
`-19-
`
`hydrogenation in a polar solvent such as 1:1 acetic acid/methanol to
`provide compound 27. Other examples of substituents on compound |
`which maybe reduced to the corresponding amine bycatalytic
`hydrogenation and methods commonly known to those skilled in the art
`include nitro groups, nitriles, and azides.
`
`SCHEME9
`
`OH 4
`af
`
`AcOH-MeOH
`
`0ALNA-C-AFiiaCHa)n-
`Zz
`|
`; ®
`NLy
`Ho, Pd catalyst
`~ 0ALN-C-OFNsOxCHe)p°
`
`OH y
`
`f
`
`A
`
`HoN~
`
`~N~
`
`10
`
`15
`
`ON
`
`20
`
`25
`
`30
`
`el
`
`Scheme 10 illustrates an example of another such
`modification of the coupling product I. Acetamido derivative 28, which
`is prepared as outlined in the Scheme 8 from the corresponding
`epoxide, is subjected to hydrolysis in a protic solvent such as
`methanol/water with added acid or base such as hydrochloric acid or
`sodium hydroxide to provide the corresponding aniline derivative 29.
`
`SAWAI EX. 1012
`Page 21 of 104
`
`SAWAI EX. 1012
`Page 21 of 104
`
`

`

`WO 94/1816!
`
`PCT/US94/00766
`
`- 20 -
`
`SCHEME10
`
`(R'),
`\~e
`SL Z
`
`2
`
`R4
`
`=|=
`|
`yg
`OF
`0ALN—0—005-€ PrNsoucHae
`R?
`Ro
`R®
`
`(Y = CH, N)
`
`HCl or NaOH
`MeOH-H,0
`
`10
`
`15
`
`20
`
`25
`
`30
`
`ey + yy
`oLt —(X)
`SOxCH,)-R
`
`HsN~
`
`~Y
`(Y = CH, N)
`
`2
`
`An alternate method for the synthesis of compoundI is
`illustrated in Scheme 11. Epoxide II is coupled to amine 6 as described
`above for coupling intermediates I] and III (Scheme 8) to give aniline
`derivative 31a. The secondary amineis selectively protected, for
`example, as a carbamate by treatment with di-tert-butyldicarbonate to
`provide carbamate 32. Alternatively, nitro amine 30 is used in the
`coupling reaction to provide 31b. Following protection as described
`above, the nitro group is reduced, for example, by catalytic
`hydrogenation, to provide intermediate 32. Treatment with a sulfony!
`chloride in the presence of a basesuchas pyridine followed by removal
`of the protecting group with, in the case ofa tert-butylcarbamate, acid
`such astrifluoroacetic acid or methanolic hydrogen chloride, provides
`the sulfonamideI.
`
`SAWAI EX. 1012
`Page 22 of 104
`
`SAWAI EX. 1012
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`

`

`WO 94/18161
`
`PCT/US94/00766
`
`-2] -
`
`SCHEME11
`
`n
`
`¢ yo
`i
`R?
`H N=6-Oa py?
`
`|
`
`=|
`
`R?
`
`R®
`6 (Z = NHs)
`30 (Z = NO.)
`
`|
`
`10
`
`i
`R?
`H
`OH
`“I=
`|
`|
`|
`Boc,O or
`(A}-OCH.CHCHN—C— \|PZ
`| 3
`|
`1) Bocs0
`(R’)
`n
`saz ee |
`RS
`2) Ho, Pd/C
`
`4
`
`
`
`=
`2
`31b (Z = NO3)
`
`15
`
`20
`
`25
`
`30
`
`(Srocnschon—gbontew
`
`OH
`
`BrBoc .
`
`32
`
`(R'),
`
`1) R’(CH,),-SO,Cl, base
`
`
`2) TFA or HCI/MeOH
`
`In somecases, sulfonamide I from the reaction sequence
`illustrated in Scheme 11 may be further modified, for example, by the
`removal of protecting groups or the manipulation of substituents on, in
`particular, R1 and R7, as described above.
`In addition, manipulation of
`substituents on any of the intermediates in the reaction sequence
`illustrated in Scheme 11 may occur. An example of this is illustrated in
`
`SAWAI EX. 1012
`Page 23 of 104
`
`SAWAI EX. 1012
`Page 23 of 104
`
`

`

`WO 94/18161
`
`PCT/US94/00766
`
`22 -
`
`Scheme 12. N-Boc 4-nitrobenzenesulfonamide 33, which is prepared
`from intermediate 32 and 4-nitrobenzenesulfony! chloride, is subjected
`to catalytic hydrogenation andthe resultant aniline is acylated with, for
`example, an acid chloride in the presence of base to give N-Boc
`intermediate 34. Deprotection with acid such astrifluoroacetic acid or
`methanolic hydrogen chloride provides the desired sulfonamide 35.
`
`SCHEME 12
`
`NO
`
`NHCOR®
`
`NHCOR®
`
`HO
`
`Nol
`
`; O
`
`OH Boc Re
`(reonchonat¢é-(X)mn
`
`|
`
`(R'),
`
`3
`
`1) H», catalytic Pd/C
`2) R&COCI, pyridine
`
`O
`
`
`OH Boo Re
`(AS-OCH:CHCHN-G-Oa NLAUT
`o=Mm
`
`(R’),
`
`R?
`
`34
`
`| TFA or HCl/MeOH
`OHH R?
`i
`(AOCH:CHCH.N-G~0a DPSLI
`Re
`|
`(R’);
`S
`35
`R
`O
`
`4
`
`sy
`
`5
`
`Aspreviously indicated, the compoundsof the present
`invention have valuable pharmacological properties.
`
`SAWAI EX. 1012
`Page 24 of 104
`
`10
`
`15
`
`20
`
`25
`
`30
`
`SAWAI EX. 1012
`Page 24 of 104
`
`

`

`WO 94/18161
`
`PCT/US94/00766
`
`-23-
`
`The present invention also provides a compoundofth