PCT
`
`WORLD INTELLECTUAL PROPERTY ORGANIZATION
`International Bureau
`
`
`
`
`INTERNATIONAL APPLICATION PUBLISHED. UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(51) Internatlonal Patent Classrficatlon 5 i
`C07C 311/21 311/46 311/47 C07D
`213/30, 213/58, 215/33, A61K’ 31/18,
`31/44, 31/47
`
`(11) International Publication Number:
`
`W0 94/18161
`
`(43) International Publication Date:
`
`18 August 1994 (18.08.94)
`
`,
`
`~
`.
`-
`tl
`(21) International Apphca on Number
`'
`‘ '
`D :
`1
`(22) International Fflmg
`ate
`
`.
`.
`
`PCT/USQ4/00766
`1
`4
`. 1. 4
`9 January 99 (19 0 9 )
`
`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).
`
`(30) Priority Data:
`015,689
`08/168,105
`
`9 February 1993 (09.02.93)
`15 December 1993 (15.12.93)
`
`US
`US
`
`(81) Designated States: BB, BG, BR, BY, CN,CZ, Fl, HU, KR,
`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, TO).
`
`(60) Parent Application or Grant
`(63) Related by Continuation
`US
`Filed on
`
`.
`
`'
`08/168,105 (CON)
`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).
`MATI-IVINK, 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]; Aparunent 1, 406 4th Street,
`
`
`(54) Title: SUBSTITUTED PHENYL SULFONAMIDES AS SELECTIVE H3 AGONISTS FOR THE TREATNEENT OF DIABETES
`AND OBESITY
`
`O
`
`H
`
`HR
`
`2
`
`@OCHz—CHCHZNCl-(X)m—<:_:>—RN-),-RSOZ(CH2
`
`(8‘).
`
`m
`
`(57) Abstract
`
`Substituted phenylsulphonamides having formula (I) where the variables are as defined in Claim 1; are selective beta-3 adrenergic
`receptor agonists with very little beta-l and beta-2 adregenic receptor activity and as such the compounds are capable of increasing lipolysis
`and energy expenditure in cells. The compounds thus have very potent activity in the treatment of Type II diabetes and obesity. The
`compounds can also be used to reduce triglyceride levels and cholesterol levels or raise high density lipoprotein levels or to reduce gut
`' motility.
`In addition, the compounds can be used to reduce neurogenic inflammation or as antidepressant agents. The compounds are
`prepared by coupling an aminoalkylphenylsulphonamide with an appropriately substituted alkyl epoxide. Compositions and methods for the
`use of the compounds in 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.
`
`SAWAI EX. 1012
`
`Page 1 of 104
`
`SAWAI EX. 1012
`Page 1 of 104
`
`

`

`
`
`FOR THE PURPOSES OF INFORMATION ONLY
`
`Codes used to identify States party to the PCI‘ on the front pages of pamphlets publishing international
`applications under the PCI‘.
`
`AT
`AU
`BB
`BE
`BF
`36
`3.]
`BR
`BY
`CA
`CF
`CG
`CH
`CI
`CM
`CN
`CS
`CZ
`DE
`DK
`E
`Fl
`FR
`GA
`
`Austria
`Australia
`Barbados
`Belgium
`Burkina Faso
`Bulgaria
`Benin
`Brazil
`Belarus
`Canada
`Cenrral African Republic
`Congo
`Switzerland
`com d'Ivoire
`Cameroon
`Giina
`Czechoslovakia
`Czech Republic
`Germany
`Denmark
`Spain
`Finland
`France
`Gabon
`
`GB
`GE
`GN
`GR
`BU
`[E
`IT
`JP
`KE
`KG
`KP
`
`KR
`KZ
`LI
`LK
`LU
`LV
`MC
`MD
`MG
`ML
`MN
`
`United Kingdom
`Georgia
`Guinea
`Greece
`Hungary
`Ireland
`Italy
`Japan
`Kenya
`Kyrgystan
`Democratic People's Republic
`of Korea
`Republic of Korea
`Kazakhstan
`Liechtenstein
`Sri Lanka
`Luxembourg
`Latvia
`Monaco
`Republic of Moldova
`Madagascar
`Mali
`Mongolia
`
`MR
`MW
`NE
`NL
`N0
`NZ
`PL
`PT
`R0
`RU
`SD
`SE
`SI
`SK
`SN
`TD
`TG
`TJ
`'IT
`UA
`US
`UZ
`VN
`
`Mauritania
`Malawi
`Niger
`Netherlands
`Norway
`New Zealand
`Poland
`Portugal
`Romania
`Russian Fedu'ation
`Sudan
`Sweden
`Slovenia
`Slovakia
`Senegal
`Quad
`Togo
`Tajikistan
`Iiinidad and Tobago
`Ukraine
`United States of America
`Uzbekistan
`Viet Nam
`
`SAWAI EX. 1012
`
`Page 2 of 104
`
`
`
`SAWAI EX. 1012
`Page 2 of 104
`
`

`

`WO 94/18161
`
`PCT/US94/00766
`
`-1-
`
`TITLE OF THE INVENTION
`
`SUBSTITUTED PHENYL SULFONAMIDES AS SELECTIVE B3
`AGONISTS FOR THE TREATMENT OF 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.
`
`10
`
`15
`
`BACKGROUND OF THE INVENTION
`B-Adrenoceptors have been subclassified as B] and B2 since
`Increased heart rate is the primary consequence of B1-receptor
`
`1967.
`
`stimulation, while bronchodilation and smooth muscle relaxation
`typically result from B2 stimulation. Adipocyte lipolysis was initially
`thought to be solely a Bl—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 energy
`
`expenditure.
`
`20
`
`Early developments in this area produced compounds with
`greater agonist activity for the stimulation of lipolysis (B3 activity) than
`for stimulation of atrial rate (B1) and tracheal relaxtion (B2). These
`
`early developments disclosed in Ainsworth gt a_l., US. Patents 4,478,849
`and 4,396,627, were derivatives of phenylethanolamines.
`Such selectivity for B3-adrenoceptors could make
`
`25
`
`In
`compounds of this type potentially useful as antiobesity agents.
`addition, these compounds have been reported to show antihypergly-
`cemic effects in animal models of non-insulin-dependent diabetes
`
`mellitus.
`
`3O
`
`A major drawback in treatment of chronic diseases with B3
`
`agonists‘is the potential for stimulation of other B-receptors and
`subsequent side effects. The most likely of these include muscle tremor
`(B2) and increased heart rate (B1). Although these phenylethanolamine
`derivatives do possess some B3 selectively, side effects of this type have
`
`SAWAI EX. 1012
`
`Page 3 of 104
`
`SAWAI EX. 1012
`Page 3 of 104
`
`

`

`W0 94/ 18161
`
`PCT/US94/00766
`
`-2-
`
`been observed in human volunteers. It is reasonable to expect that these
`side effects resulted from partial [31 and/or [32 agonism.
`
`More recent developments in this area are disclosed in
`Ainsworth _e_tfl., US. Patent 5,153,210, Caulkett _e_t_al., US. Patent
`
`4,999,377, Alig e_t_al., US. Patent 5,017,619, Lecount e_t;a_l., European
`Patent 427480 and Bloom _e_t_ al., European Patent 455006.
`
`Even though these more recent developments purport to
`describe compounds with greater B3 selectively over the B] and [32
`activities, this selectively was determined using rodents, in particular,
`rats as the test animal. Because even the most highly selective
`compounds, as determined by these assays, still show signs of side
`effects due to residual [31 and [32 agonist activity when the compounds
`
`are tested in humans, it has become apparent that the rodent is not a
`good model for predicting human B3 selectivity.
`'
`Recently, assays have been developed which more
`accurately predict the effects that can be expected in humans. These
`assays utilize cloned human [33 receptors which have been expressed in
`Chinese hamster ovary cells. The agonist and antagonist effects of the
`various compounds on the cultivated cells provide an indication of the
`antiobesity and antidiabetic effects of the compounds in humans.
`
`SUMMARY OF THE TNVENTION
`
`The instant invention is concerned with substituted phenyl
`
`sulfonamides 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
`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
`compounds as the active ingredient thereof. Further objects will
`become‘apparent from reading the following description.
`
`10
`
`15
`
`20
`
`25
`
`3O
`
`SAWAI EX. 1012
`
`Page 4 of 104
`
`SAWAI EX. 1012
`Page 4 of 104
`
`

`

`W0 94/ 18161
`
`PCT/US94/00766
`
`-3-
`
`DESCRIPTION OF THE INVENTION
`
`The compounds of the instant invention are best realized in
`
`the following structural formula:
`
`@ocm-FDHCHCHZNcl-(xRam—<:::\>—RN630?}CH2)-R
`
`H R2
`
`(R )n
`
`where
`
`n is
`
`m is
`
`r is
`
`A is
`
`R1 is
`
`10
`
`15
`
`20
`
`25
`
`3O
`
`l
`
`0 to 7;
`
`0 or 1;
`
`0 to 3;
`
`phenyl, naphthyl, a 5 or 6—membered heterocyclic ring
`with from 1 to 4 heteroatoms selected from oxygen, sulfur
`or nitrogen, a benzene ring fused to a C3—C8 cycloalkyl
`
`ring, a benzene ring fused to a 5 or 6-membered
`
`heterocyclic ring with from 1 to 3 heteroatoms selected
`
`from oxygen, sulfur or nitrogen or a 5 or 6-membered
`
`heterocyclic ring with from 1 to 3 heteroatoms selected
`
`from oxygen, sulfur or nitrogen fused to a 5 or 6-
`
`membered heterocyclic ring with from 1 to 3 heteroatoms
`
`selected from oxygen, sulfur or nitrogen;
`hydroxy, oxo, halogen, cyano, nitro, NR8R8, SR8,
`trifluoromethyl, C1-C6 alkyl, C1-C6 alkoxy, C3-C8
`cycloalkyl, phenyl, 802R9, NR8c0R9, COR9, NR8302R9,
`NR8C02R8 or C1-C6 alkyl substituted by hydroxy, nitro,
`halogen, cyano, NR8R8, SR8, trifluoromethyl, C1-C6
`alkoxy, C3-C8 cycloalkyl, phenyl, NR8C0R9, COR9,
`SOzR9, NR8802R9, NR8C02R8, or R1 is a 5 or 6—
`
`membered heterocycle with from 1 to 3 heteroatoms
`
`selected from oxygen, sulfur or nitrogen;
`
`SAWAI EX. 1012
`
`Page 5 of 104
`
`SAWAI EX. 1012
`Page 5 of 104
`
`

`

`W0 94/ l 8161
`
`PCT/US94/00766
`
`-4-
`
`R2 and R3 are independently hydrogen, C1-C6 alkyl or C1-C6 alkyl
`substituted by l to 3 of hydroxy, C1—C6 alkoxy, or
`
`X is
`
`halogen;
`-CH2-, -CH2—CH2- , —CH=CH- or -CH20-;
`
`R4 and R5 are independently hydrogen, C1 -C6 alkyl, halogen, NHRg,
`0R8, $02129 or'NHsozR9;
`hydrogen or C1-C6 alkyl;
`C1-C6 alkyl, C3-C8 cycloalkyl, or B-(R1)n;
`
`R6 is
`R7 is
`
`10
`
`B is
`
`15
`
`20
`
`R8 is
`
`25
`
`R9 is
`
`phenyl, naphthyl, a 5 or 6-membered heterocyclic ring
`with from 1 to 4 heteroatoms selected from oxygen, sulfur
`or nitrogen, a benzene ring fused to a C3-C8 cycloalkyl
`
`ring, a benzene ring fused to a 5 or 6-membered
`heterocyclic ring with from 1 to 3 heteroatoms selected
`from oxygen, sulfur or nitrogen or a 5 or 6—membered
`heterocyclic ring with from 1 to 3 heteroatoms selected
`from oxygen, sulfur or nitrogen fused to a 5 or 6-
`membered heterocyclic ring with from 1 to 3 heteroatoms
`
`selected from oxygen, sulfur or nitrogen;
`hydrogen, C1-C10 alkyl, C3-C8 cycloalkyl, phenyl
`optionally substituted by 1 to 3 of halogen, C1-C6 alkyl or
`C1-C6 alkoxy, or C1-C 10 alkyl substituted by 1 to 3 of
`hydroxy, halogen, C02H,.C02-C1-C6 alkyl, C3-C8
`cycloalkyl, C1-C6 alkoxy, or phenyl optionally substituted
`by from 1 to 3 of halogen, C1-C6 alkyl or C1-C6 alkoxy;
`R8, NHR8 or NR8R8.
`
`1n the above structural formula and throughout the instant
`
`30
`
`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 length in either a straight or
`
`SAWAI EX. 1012
`
`Page 6 of 104
`
`SAWAI EX. 1012
`Page 6 of 104
`
`

`

`W0 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 and the like.
`The term "halogen" is intended to include the halogen
`
`atoms fluorine, chlorine, bromine and iodine.
`
`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 R1 are those heterocycles with from 1 to 4
`
`heteroatoms independently selected from one of oxygen or sulfur or 1
`
`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 more preferred values of A are phenyl, naphthyl,
`pyridyl, quinolinyl, pyrimidinyl, pyrrollyl, thienyl, imidazolyl, and
`
`thiazolyl.
`
`The more preferred values of B are phenyl, naphthyl,
`quinolinyl, thienyl, benzimidazolyl, thiadiazolyl, benzothiadiazolyl,
`indolyl, indolinyl, benzodioxolyl, benzodioxanyl, benzothiophenyl,
`benzofuranyl, benzisoxazolyl, benzothiazolyl, tetrahydronaphthyl,
`
`dihydrobenzofuranyl, and tetrahydroquinolinyl.
`Further preferred compounds of the instant invention are
`
`realized when in the above structural formula:
`
`R2 and R3 are hydrogen or methyl;
`X is
`-CH2-
`
`m is
`
`r is
`
`l;
`
`0-2; and
`
`R4, R5 and R6 are hydrogen.
`
`Still further preferred compounds of the instant invention
`are realized when in the above structural formula:
`
`A is
`
`phenyl, quinolinyl, or a 6-membered heterocyclic ring with
`
`1 or 2 nitrogen atoms;
`
`10
`
`15
`
`20
`
`25
`
`3O
`
`SAWAI EX. 1012
`
`Page 7 of 104
`
`SAWAI EX. 1012
`Page 7 of 104
`
`

`

`WO 94/18161
`
`PCT/US94/00766
`
`—6-
`
`B is
`R1 is
`
`phenyl or quinolinyl;
`NH2, hydroxy, halogen, cyano, trifluoromethyl, phenyl,
`NR8COR9, NR8C02R8, C1-C6 alkyl optionally substituted
`
`by hydroxy; and
`
`r is
`
`0 or 2.
`
`Representative preferred antiobesity and antidiabetic
`compounds of the present invention include the following:
`
`10
`
`15
`
`fl-[4—[2-[[2-hydroxy-3-(4-hydroxyphenoxy)propyllamino]ethyl]phenyl]-
`
`benzenesulfonamide
`
`_l\l—[4-[2—[[2—hydroxy-3-(4-hydroxyphenoxy)propyl]amino]ethyl]phenyl]-
`
`4-iodobenzenesulfonamide
`
`'
`
`_N_-[4-[2-[ [2—hydroxy-3-(4-hydroxyphenoxy)propyl]amino]ethyl]phenylj -
`
`2-naphthalenesulfonamide
`_l\_I-[4—[2—[ [2-hydroxy-3-(4-hydroxyphenoxy)propy1]amino]ethyl]phenyl] -
`
`4-(benzo-2, l ,3-thiadiazole)sulfonamide
`
`_N_-[4-[2-[ [2—hydroxy—3-(4—hydroxyphenoxy)propyl]amino]ethyl]phenyl]—
`
`20
`
`2-phenylethanesulfonamide
`fl-[4—[2—[[3-(4-fluorophenoxy)—2—hydroxypropyl]amino]ethyl]phenyl] -
`
`4—benzenesulfonamide
`
`25
`
`3O
`
`fl-[4-[2-[[3—[(2-amino-5-py1idinyl)oxy]-2-hydroxypropyl]amino]ethylil-
`
`phenyl]—2-naphthalenesulfonamide
`fl-[4-[2-[[2-hydroxy-3-(4-hydroxyphenoxy)propyl]amino]ethyl]phenyl]-
`
`3-quinolinesulfonamide
`fl-[4—[2-[ [2-hydroxy-3-(4-hydroxyphenoxy)propyl]amino]ethyl]phenyl]—
`4—[(5—methoxycarbonyl)pentanoyl]amino]benzenesulfonamide
`_N_-[4-[2-[ [2-hydroxy-3-(4-hydroxyphenoxy)propyl]amino]ethyl]phenyli] —
`4—[(5—hydroxycarbonyl)pentanoyl]amino]benzenesulfonamide
`_I\_I—[4—[2-[ [2—hydroxy-3-(4-hydroxyphenoxy)propyl]amino]ethyl]phenyl] -
`4-(hexylaminocarbonylamino)benzenesulfonamide
`fl-[4-[2— [(2-hydroxy-3-phenoxypropyl)amino]ethyl]phenyl] -4-
`
`chlorobenzenesulfonamide
`
`SAWAI EX. 1012
`
`Page 8 of 104
`
`SAWAI EX. 1012
`Page 8 of 104
`
`

`

`W0 94/ 18161
`
`PCT/US94/00766
`
`-7-
`
`fl-[4—[2-[[2-hydroxy—3-(3-cyanophenoxy)propyl]amino]ethyl]phenyl]—3-
`
`quinolinesulfonamide
`fl—[4-[2-[[3-(4-amino-3-cyanophenoxy)—2-hydroxypropyl]amino]ethyl]-
`
`phenyl]-3—quinolinesulfonamide
`fl-[4-[2-[[2-hydroxy-3-[(3~hydroxymethyl)phenoxy]propyl]amino]-
`
`ethyl]phenyl]—3-quinolinesulfonamide
`fl—[4—[2—I[2-hydroxy-3—(3—pyridyloxy)propyl]amino]ethyl]phenyl]—3-
`
`quinolinesulfonamide
`fl-[4—[2-[[2-hydroxy-3-(3-pyridyloxy)propyl]amino]ethyl]phenyl]—4-
`
`iodobenzenesulfonamide
`
`N-[4-[2-[[3-[(2—amino—5-pyridinyl)oxy]—2—hydroxypropy1]amino]ethyl]-
`
`phenyl]-4-isopropylbenzenesulfonamide.
`
`.
`
`The compounds of the instant invention all have at least one
`asymmetric center as noted by the asterisk in structural Formulae I and
`la. Additional asymmetric centers may be present 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 isomers 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 instant invention.
`
`In the case of the asymmetric center represented by the asterisk in
`Formula I, it has been found that the compound in which the hydroxy
`substituent is above the plane of the structure, as seen in Formula la, is
`more active and thus more preferred over the compound in which the
`
`hydroxy substituent is below the plane of the structure.
`Compounds of 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 ethyl
`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.
`
`10
`
`15
`
`20
`
`25
`
`3O
`
`SAWAI EX. 1012
`
`Page 9 of 104
`
`SAWAI EX. 1012
`Page 9 of 104
`
`

`

`W0 94/ 18161
`
`PCT/US94/00766
`
`-8-
`
`Alternatively, any enantiomer of a compound of the
`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.
`
`10
`
`1
`(R )n
`
`H\
`
`OH H
`“’
`'
`OCHg-C-CHzN-C-(X)m
`~k
`/\‘\
`R2
`
`R3
`
`7
`
`N'SOZ(CH2)r'R
`FIKB
`
`R4
`/' \
`_|_
`R5
`
`Ia
`
`15
`
`where the various substituents are as defined above.
`
`20
`
`25
`
`3O
`
`The instant compounds can be isolated 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 compounds containing an acidic function such as a
`carboxy or tetrazole, can be isolated in the form of their inorganic salt
`in which the counterion can be selected from sodium, potassium,
`
`lithium, calcium, magnesium and the 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 III. The preparation of
`
`these intermediates is described in the following schemes.
`
`0
`O\/<l
`
`R2
`R4
`I
`—|—
`HzN—Cls—<X>m< / Issoz<CH2)r-R7
`R3
`Flt!)
`R6
`
`(Ran
`
`II
`
`III
`
`SAWAI EX. 1012
`
`Page 10 of 104
`
`SAWAI EX. 1012
`Page 10 of 104
`
`

`

`W0 94/ 1 8161
`
`PCT/US94/00766
`
`-9-
`
`where n, m, r, A, R], R2, R3, R4, R5, R6, R7 and X are as defined
`
`above.
`
`Compounds 11 can be conveniently prepared by a variety of
`
`methods familiar to those skilled in the art. One common route is
`
`illustrated in Scheme 1. Alcohol L 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 (25) or (2R)-glycidyl 3-
`
`nitrobenzene sulfonate or (2R) or (2S)-glycidyl 4-toluenesulfonate, thus
`
`both the (S) and (R) enantiomers of epoxide II are readily available.
`
`SCHEME 1
`
`
`
`IN
`
`Many of the alcohols l are commercially available or
`
`readily prepared by methods described in the literature and known to
`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)n is 4-hydroxy—
`
`phenyl as its tert-butyldimethylsilyl (TBS) derivative is illustrated in
`
`Scheme 2. Commercially available phenol _3_ is treated with a silylating
`
`SAWAI EX. 1012
`
`Page 11 of 104
`
`10
`
`15
`
`20
`
`25
`
`3O
`
`SAWAI EX. 1012
`Page 11 of 104
`
`

`

`W0 94/ 18161
`
`PCT/US94/00766
`
`-10-
`
`agent such as tert-butyldimethylsilyl chloride in the presence of a base
`such as imidazole in an aprotic solvent such as dimethylformamide. The
`benzyl group is then removed by catalytic hydrogenation to give the
`
`desired alcohol i.
`
`W
`
`10
`
`15
`
`20
`
`25
`
`3O
`
`(tert—Bu)MeZSiC|
`OBn ________.
`
`O imidazole, DMF
`
`(tert-Bu)M928iO
`
`HO
`
`.3
`
`H2—-—-———>
`Pd catalyst
`
`trt—B M 90
`
`u) 92'
`
`(e
`
`OBn
`
`A
`
`s
`
`OH
`
`§
`
`Compounds 111 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 Q is selectively protected as a suitable carbamate derivative
`Q with, for example, di—tcrt—butyl dicarbonate or carbobenzyloxy
`chloride. This compound is then treated with a sulfonyl 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 0°C, to provide the
`sulfonamide 3. The protecting group is then removed with, for
`example, trifluoracetic acid in the case of Boc or catalytic
`hydrogenation in the case of Cbz, to give the desired amine 2.
`
`SAWAI EX. 1012
`
`Page 12 of 104
`
`SAWAI EX. 1012
`Page 12 of 104
`
`

`

`WO 94/ l 8161
`
`PCT/US94/00766
`
`-11-
`
`SEEM
`
`ft.“
`w
`r
`H2N—clz—(X)m—<\ / NH2
`R3
`A;
`R25
`GNH—c—3:)m—<:>—NH2
`
`—a=G 800 or Cbz
`
`30020 ,
`orCszI/base
`
`7
`
`<__>_____<.>
`
`pyridine, CH2C|2
`
`R2
`I
`
`R3
`
`(aw—09%,}1802<CH2>rR7
`
`4—
`
`5
`
`H
`
`TFA, 01—12012
`
`————>
`
`or H2/Pd catalyst
`
`HzN-C:—(X)m’<:>Nso2((-CHZ),R7
`
`.9
`
`Compounds 11] where R6 is not hydrogen may be
`
`conveniently prepared as illustrated in Scheme 4. Sulfonamide {L
`
`prepared as described above, is alkylated with an appropriate alkylating
`agent m in the presence of base to provide sulfonamide fl. Removal of
`
`the protecting group as above gives the desired compound HI.
`
`SAWAI EX. 1012
`
`Page 13 of 104
`
`10
`
`15
`
`20
`
`25
`
`3O
`
`SAWAI EX. 1012
`Page 13 of 104
`
`

`

`WO 94/18161
`
`PCT/US94/00766
`
`- 12 _
`
`SCHEME4
`
`R4
`
`“
`
`I
`T2
`GNH—CIJ—(X)m‘<\:l:/>JTISOZ(CH2)FR7
`R3
`_8__
`R5
`H
`R4
`
`l
`t2
`GNH-CIJ —(X)m—< >l\|1802(CH2),-R7
`R3
`[L5
`R6
`
`.11
`
`4
`
`1o
`
`RG-Y
`_
`base
`
`TFA, CHZCIZ
`or H2/Pd catalyst
`
`t2
`H2N (I:
`.Fl3
`
`_ _ X
`
`()rn
`
`T
`\l / ITISOZ(CH2),R
`5
`R6
`
`_
`
`Ft
`
`7
`
`G=Bocor0bz
`Y=C|,Br,orl
`
`The sulfonyl chlorides 1, many of which are commercially
`available, can also be readily prepared by a number of 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, _e_t. a” 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, e_t. £11., Chemistry Letters, 1483-1486
`(1992). Sulfonic acids are also conveniently converted to the
`corresponding sulfonyl chloride by treatment with PC15, PC13 or SOC12
`
`(J. March, Advanced Organic Chemistry, 4th Ed., John Wiley and Sons,
`New York: 1992, p1297 and references cited therein). Alternatively,
`aromatic compounds may be treated with chlorosulfonic acid according
`to the procedure of Albert, _e_t._al., J. Het. Chem. _l_§, 529 (1978), to
`provide the sulfonyl chlorides.
`
`SAWAI EX. 1012
`
`Page 14 of 104
`
`10
`
`15
`
`20
`
`25
`
`30
`
`SAWAI EX. 1012
`Page 14 of 104
`
`

`

`W0 94/1816]
`
`PCT/US94/00766
`
`-13-
`
`The diamines _6_ are commercially available or readily
`
`prepared by methods described in the literature or known to those
`skilled in the art. Compound 9 where R2 or R3 is methyl can be
`prepared from the corresponding amino acid following the method of J.
`D. Bloom, e_t. 341., J. Med. Chem., _3_5_, 3081-3084 (1992). As illustrated
`in Scheme 5 for R3 = methyl, the appropriate (R) amino acid 1; is
`esten'fied, conveniently by treatment with methanolic hydrochloric acid,
`and then treated with di-tert-butyl dicarbonate to give compOund l_3_.
`The ester group is reduced with a hydride source such as lithium
`borohydride and the resultant alcohol is converted to a leaving group
`
`such as a mesylate. Removal of the Boc protecting groups gives
`diamine 1A. This compound is subjected to catalytic hydrogenation in
`
`the presence of base such as sodium acetate to give the desired OL-methyl
`amine 1;. The other enantiomer is available through an analogous
`
`sequence starting with the corresponding (S) amino acid.
`
`10
`
`15
`
`20
`
`25
`
`30
`
`SAWAI EX. 1012
`
`Page 15 of 104
`
`SAWAI EX. 1012
`Page 15 of 104
`
`

`

`W0 94/ 18161
`
`PCT/US94/00766
`
`-14-
`
`SEA/[Li
`
`R4
`Hquxlm ,/
`H020 E/
`E
`\
`12
`R5
`
`NH2
`
`1)MeOH,HC|
`2) Boczo, Ncho3
`
`1.0
`
`15
`
`20
`
`25
`
`30
`
`B NH
`0°
`
`\5/
`
`(X)
`
`m
`
`R4
`\/\
`
`1)LiBH4
`
`M9020 m 2) MeSOQCl, Et3N
`
`NHBOC
`
`3) TFA, CHZCIQ
`
`1.3 R5
`
`H2NO§(MU
`
`R5
`
`NH2
`°2CF3COZH
`
`1A
`
`H2,NaOAC
`
`_______._.._>
`
`cat. Pd
`
`4
`
`HgNymm f
`1319 I!”
`5// NH2
`
`15
`
`R
`
`Diamines Q or sulfonamide amines 2 where X is -CH20-
`
`and m is l are also readily prepared by methods described in the
`literature or known to those skilled in the art. For example, as shown
`
`in Scheme 6, the sodium salt of 4-nitrophenol _1_§ is alkylated with 1—
`bromo-2-chloroethane, conveninetly in refluxing 2-butanone with a base
`such as potassium carbonate, to give chloro derivative 1_7_. 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 as its
`t-butyl carbamate by treatment with di—tefi-butyldicarbonate, gives
`
`SAWAI EX. 1012
`
`Page 16 of 104
`
`SAWAI EX. 1012
`Page 16 of 104
`
`

`

`W0 94/1816]
`
`PCT/US94/00766
`
`-15-
`
`derivative _1_§. The nitro group is then reduced, for example, by
`catalytic hydrogenation to provide amine 12. Acylation of intermediate
`12 with sulfonyl chloride 1, followed by deprotection with acid such as
`trifluoroacetic acid gives the desired intermediate 1Q.
`
`NaO
`
`SCHEME 6
`
`CI
`
`. Br/\/
`
`
`O K2003,
`NO
`2—butanone,
`reflux, 24h
`
`2
`
`lfi
`
`C|/\/O
`
`N02
`
`17
`
`1. LiN3, DMF, 60°
`2. PPha, THF/HZO,
`
`
`3. 300 anhydride,
`CHQCIZ
`
`BOCNHNO
`
`18
`
`0
`
`~
`
`H2, Pd/C
`
`
`N02
`
`BOCNHNOO NH2
`
`B
`
`1. R7(CH2),302CI (z), pyridine, CH2012
`
`
`2. TFA/CH2C|2 (1:3)
`
`”WOO
`
`2_Q
`
`NHSO2(CH2),-Fl7
`
`10
`
`15
`
`20
`
`25
`
`3O
`
`SAWAI EX. 1012
`
`Page 17 of 104
`
`SAWAI EX. 1012
`Page 17 of 104
`
`

`

`W0 94/ l 8161
`
`PCT/US94/00766
`
`-16-
`
`Alternatively, diamine Q where X is —CH20- and m is l is
`available from intermediate 12 by treatment with trifluoroacetic acid.
`This diamine may then be modified as illustrated in Scheme 3.
`Diamines Q and sulfonamide amines 2 where X is
`—CH2CH2- and m is l are also readily prepared by methods described in
`the literature or known to those skilled in the art. For example, as
`
`shown in Scheme 7, bromo derivative 2_1_ is treated with sodium cyanide
`
`to provide nitrile Q. The nitro group is selectively reduced by
`treatment with hydrogen and catalytic palladium to provide amine 23.
`Amine 21 is acylated with sulfonyl chloride 1 to give the corresponding
`sulfonamide 29;. Reduction of compound 23 with cobalt chloride and
`
`sodium borohydride provides the desired amine _2_5_.
`
`10
`
`15
`
`20
`
`25
`
`30
`
`SAWAI EX. 1012
`
`Page 18 of 104
`
`SAWAI EX. 1012
`Page 18 of 104
`
`

`

`W0 94/ 18161
`
`PCT/US94/00766'
`
`_ 17 _
`
`SCHEME 7
`
`Br\/\©\
`
`a
`
`N02
`
`
`
`NaCN
`
`RT, 6 h
`
`NC
`
`22
`
`N02
`
`10
`
`15
`
`20
`
`25
`
`30
`
`
`
`H2, Pd/C NCVU R7(CH2).8020I (2)
`
`MeOH
`
`NH
`
`pyridine, CH2012
`
`
`
` NC\/\©\ C0C|2°6H20
`
`NHSOZ(CH2)r-R7
`
`NaBH4,MeOH
`
`24
`
`2-5
`
`NHSO CH -R7
`2(
`2)r
`
`Alternatively, diamine Q where X is -CH2CH2- and m is 1
`
`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 Scheme 3.
`
`Intermediates H and III are coupled by heating them neat
`
`or as a solution in a polar solvent such as methanol, acetonitrile,
`
`tetrahydrofuran, dimethylsulfoxide or N—methyl pyrrolidinone for l to
`
`24 hours at temperatures of 30 to 150°C to provide compounds I as
`
`shown in Scheme 8. The reaction is conveniently conducted in
`
`refluxing methanol. Alternatively, a salt of amine 111, 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
`
`

`

`W0 94/ 18161
`
`PCT/US94/00766
`
`-18—
`
`base such as sodium bicarbonate or diisopropylethylamine is added to
`the reaction mixture. The product is purified from unwanted side
`products by recrystallization, trituration, preparative thin layer
`chromatography, flash chromatography on silica gel as described by W.
`C. Still, e_t. Q” J. Org. Chem. gl_3_, 2923 (1978), medium pressure liquid
`chromatography, or HPLC. Compounds which are purified by HPLC
`may be isolated as the corresponding salt. Purification of intermediates
`
`is achieved in the same manner.
`
`MM
`
`0
`
`$0..“ *
`
`(Ran
`
`T4
`r
`H2N_?—(X)m_<\:|:/>_[\IISOZ(CH2)r-R7
`
`R3
`
`R5
`
`R6
`
`—‘—>
`
`I”
`
`4
`
`T
`r
`.
`OH
`1"!
`@rOCHZCHCHzN—c—(X)m—<l:/>—TSOZ(CH2),R7
`
`3
`
`R
`
`R5
`
`R5
`
`In some cases, 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, R1 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 example is
`illustrated in Scheme 9. Compound 2Q, which is prepared as outlined in
`the Scheme 8 from the corresponding epoxide, is subjected to catalytic
`
`SAWAI EX. 1012
`
`Page 20 of 104
`
`10
`
`15
`
`20
`
`25
`
`3O
`
`SAWAI EX. 1012
`Page 20 of 104
`
`

`

`W0 94/ 18161
`
`PCT/US94/00766
`
`-19-
`
`hydrogenation in a polar solvent such as 1:1 acetic acid/methanol to
`provide compound ;7_. Other examples of substituents on compound I
`which may be reduced to the corresponding amine by catalytic
`
`hydrogenation and methods commonly known to those skilled in the art
`
`include nitro groups, nitriles, and azides.
`
`SCHEME9
`
`10
`
`15
`
`20
`
`02N
`
`_j/R5
`OH H
`\\ O\/J\V/N—Q—X \ /, NSOJCHQNR7
`“a |
`'6
`/
`R2
`R
`R4
`R
`
`N
`
`25
`
`1
`
`N
`
`N
`
`0
`H2, Pd catalyst
`/[ffj/OiN-Fe%X—<:::R5NSOZMH2-R7
`
`AcOH-MeOH
`
`l /
`
`R2]
`
`21
`
`Scheme 10 illustrates an example of another such
`
`25
`
`modification of the coupling product I. Acetamido derivative 3, 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 2_9_.
`
`30
`
`SAWAI EX. 1012
`
`Page 21 of 104
`
`SAWAI EX. 1012
`Page 21 of 104
`
`

`

`WO 94/18161
`
`PCT/US94/00766
`
`_ 20 -
`
`SCHEME 10
`
`R2
`R4
`(R )
`OH H
`l
`-l—
`\ o\/K/N—cl—(X)m-<I>—Nsog(CH2),-R
`i /
`R3
`R5
`R6
`
`7
`
`AcNH
`
`Y
`
`_2_§_
`
`10
`
`15
`
`20
`
`25
`
`30
`
`(Y CH, N)
`
`HCI or NaOH
`
`1R2MeOH-HZO
`OjiN— —(X)m
`H2N l/Y(Y = CH, N)
`Rgg
`
`N6802(CH2 ,--R7
`
`An alternate method for the synthesis of compound I is
`illustrated in Scheme 1 1. Epoxide II is coupled to amine Q as described
`above for coupling intermediates II and ID (Scheme 8) to give aniline
`derivative 11;. The secondary amine is selectively protected, for
`example, as a carbamate by treatment with di—tert—butyldicarbonate to
`provide carbamate 2. Alternatively, nitro amine 3—0 is used in the
`coupling reaction to provide ;l_b. Following protection as described
`above, the nitro group is reduced, for example, by catalytic
`hydrogenation, to provide intermediate 12. 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-butylcarbamate, acid
`such as trifluoroacetic acid or methanolic hydrogen chloride, provides
`
`the sulfonamide I.
`
`SAWAI EX. 1012
`
`Page 22 of 104
`
`SAWAI EX. 1012
`Page 22 of 104
`
`

`

`W0 94/ l 8161
`
`PCT/US94/00766
`
`_ 21 _
`
`SCHEME 11
`
`wow
`
`(PU)n
`
`“
`
`10
`
`15
`
`20
`
`25
`
`30
`
`T4
`R2
`H2N—?—(X)m—-<\:l>~2
`
`l
`
`R3
`
`_ _
`
`,.
`
`R5
`
`__.
`
`a (z = NH?)
`3Q (z = N02)
`
`T4
`R2
`H
`OH
`’ '
`I
`l
`l
`QB—OCHZCHCHQN—C—(XM \ / z
`(91)”
`I3
`I
`.
`ma —RNH )
`R5
`Bit; (2 = N02)
`
`Boc20 or
`
`
`1) 80020
`2) H2, Pd/C
`
`(R1)n@.'
`
`OCH CHCH N—-c—mm—<TR>NH
`OIHIBoc R2
`2
`2
`\ /
`
`32
`
`2
`
`1) R7(CH2)r-802Cl, base
`
`2) TFA or HCI/MeOH
`
`In some cases, 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
`
`

`

`W0 94/ 18161
`
`PCT/US94/00766
`
`-22-
`
`Scheme 12. fl-Boc 4—nitrobenzenesulfonamide 13;, which is prepar