United States Patent [191
`Fisher et al.
`
`US005451677A
`Patent Number:
`Date of Patent:
`
`[11]
`[45]
`
`5,451,677
`Sep. 19, 1995
`
`[54]
`
`[75]
`
`[73]
`[21]
`[22]
`
`[63]
`
`[51]
`
`[52]
`
`[58]
`
`[56]
`
`SUBSTITUTED PHENYL SULFONAMIDES
`As SELECI‘IVE B s AGONISTS FOR THE
`TREATMENT OF DIABETES AND OBESITY
`
`Inventors: Michael H. Fisher, Ringoes; Robert
`J. Mathvink, Jersey City; Hyun 0.
`0k, Edison; Emma R. Parmee,
`Hoboken; Ann E. Weber, Scotch
`Plains, all of NJ.
`
`Assignee: Merck & C0,, Inc., Rahway, NJ.
`
`Appl. No.: 168,105
`
`Filed:
`
`Dec. 15, 1993
`
`Related US. Application Data
`Continuation-impart of Ser. No. 15,689, Feb. 9, 1993,
`abandoned.
`
`Int. Cl.6 ................ .. CO7D 455/ 00; C07D 307/10;
`C07C 311/01
`US. Cl. .................................. .. 546/ 138; 546/290;
`548/3164; 548/469; 548/541; 549/33; 549/416;
`549/475; 564/80; 564/82; 564/ 83; 564/84;
`564/85; 564/86; 564/87; 564/ 88; 564/ 89;
`564/90; 564/92; 564/96; 564/99
`Field of Search ................ .. 514/ 604, 605; 564/ 80,
`564/82, 83, 84, 85, 86, 87, 88, 89, 90, 92, 96, 99;
`546/290, 138; 548/469, 541, 316.4; 549/33, 475,
`416
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`4,083,992 4/ 1978 Smith .
`4,396,627 8/1983 Ainsworth et a1. ............... .. 514/533
`4,478,849 10/1984 Ainsworth et al. ..
`..... .. 514/445
`4,959,366 9/ 1990 Cross et a1. ..... ..
`514/239.5
`4,999,377 3/1991 Caulkett et al.
`.... .. 514/507
`5,017,619 5/1991 Alig et al. ...... ..
`.. 514/653
`
`5,066,678 11/1991 Skidmore et a1. . . . .
`. . . . . .. 514/597
`5,153,210 10/1992 Ainsworth et al. ............... .. 514/369
`
`FOREIGN PATENT DOCUMENTS
`
`091749 10/1983
`European Pat. Off. .
`455006 4/1991
`European Pat. Off. .
`427480 5/ 1991
`European Pat. Off. .
`9000548 1/ 1990
`WIPO .
`90/ 15203 12/1990 WIPO .
`WO94/ 03425 2/1994 WIPO .
`
`OTHER PUBLICATIONS
`Lis, et a1, Abstract to “Synthesis of novel (aryloxy)
`propanolamines and related compounds possessing both
`class II and class III antiarrhythmic activity” J. Med,‘
`Chem, (1990), 33(10), pp. 2883-2891.
`Bloom, et al., J. Med. Chem, 35 3081-3084 (1992).
`Still, et al., J. Org. Chem, 43, 2923 (1978).
`Primary Examiner-Jose 'G. Dees
`Assistant Examiner-Dwayne C. Jones
`Attorney, Agent, or Firm-Mollie M. Yang; David L.
`Rose
`ABSTRACT
`[57]
`Substituted phenylsulfonamides are selective B3 adren
`ergic receptor agonists with very little B1 and B2 adren
`ergic receptor activity and as such the compounds are
`capable of increasing lipolysis and energy expenditure
`in cells. The compounds thus have potent activity in the
`treatment of Type II diabetes and obesity. The com
`pounds can also be used to lower triglyceride levels and
`cholesterol levels or raise high density lipoprotein lev
`els or to decrease gut motility. In addition, the com
`pounds can be used to reduced neurogenic in?amma
`tion or as antidepressant agents. The compounds are
`prepared by coupling an aminoalkylphenyl-sulfonamide
`with an appropriately substituted alkyl epoxide. Com
`positions and methods for the use of the compounds in
`the treatment of diabetes and obesity and for lowering
`triglyceride levels and cholesterol levels or raising high
`density lipoprotein levels 01' for increasing gut motility
`are also disclosed.
`
`18 Claims, No Drawings
`
`SAWAI EX. 1009
`Page 1 of 35
`
`

`

`SUBSTITUTED PHENYL SULFONAMIDES AS
`SELECTIVE B 3 AGONISTS FOR THE
`TREATMENT OF DIABETES AND OBESITY
`
`5
`
`CROSS REFERENCE TO RELATED
`APPLICATIONS
`This application is a continuation-in-part of our ap
`plication Ser. No. 08/015,689 ?led Feb. 9, 1993, aban
`doned on May 12, 1994.
`
`15
`
`25
`
`35
`
`BACKGROUND OF THE INVENTION
`B-Adrenoceptors have been subclassi?ed as B1 and
`8; since 1967. Increased heart rate is the primary conse
`quence of B1-receptor stimulation, while bronchodila
`tion and smooth muscle relaxation typically result from
`[32 stimulation. Adipocyte lipolysis was initially thought
`to be solely a B1-mediated process. However, more
`recent results indicate that the receptor-mediating lipol
`ysis 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 stimula
`tion promotes both lipolysis (breakdown of fat) and
`energy expenditure.
`Early developments in this area produced com
`pounds with greater agonist activity for the stimulation
`of lipolysis (B3 activity) than for stimulation of atrial
`rate (B1) and tracheal relaxtion (5'2)- These early devel
`opments disclosed in Ainsworth et al., US. Pat. Nos.
`4,478,849 and 4,396,627, were derivatives of phenyle
`thanolarnines.
`Such selectivity for ?g-adrenoceptors could make
`compounds of this type potentially useful as antiobesity
`agents. In addition, these compounds have been re
`ported to show antihyperglycemic effects in animal
`models of non-insulin-dependent diabetes mellitus.
`A major drawback in treatment of chronic diseases
`with B 3 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 ([31). Although these phenylethanolamine deriva
`tives do possess some B3 selectively, side effects of this
`type have been observed in. human volunteers. It is
`45
`reasonable to expect that these side effects resulted from
`partial B1 and/or 3; agonism.
`More recent developments in this area are disclosed
`in Ainsworth et al., US. Pat. No. 5,153,210, Caulkett
`etal., US. Pat. No. 4,999,377, Alig et al., US. Pat. No.
`5,017,6 l9, Lecount et al., European Patent 427480 and
`Bloom et al., European Patent 455006.
`Even though these more recent developments pur
`port to describe compounds with greater B3 selectively
`over the B1 and B2 activities, this selectively was deter
`mined using rodents, in particular, rats as the test ani
`mal. Because even the most highly selective com
`pounds, as determined by these assays, still show signs
`of side effects due to residual B1 and 3; agonist activity
`when the compounds are tested in humans, it has be
`come 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 B3 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
`
`55
`
`65
`
`1
`
`5,451,677
`
`2
`of the antiobesity and antidiabetic effects of the com
`pounds in humans.
`
`SUMMARY OF THE INVENTION
`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 ac
`tive ingredient thereof. Further objects will become
`apparent from reading the following description.
`DESCRIPTION OF THE INVENTION
`The compounds of the instant invention are best real
`ized in the following structural formula:
`
`A is phenyl, naphthyl, a 5 or 6-membered heterocy
`clic ring with from 1 to 4 heteroatoms selected
`from oxygen, sulfur or nitrogen, a benzene ring
`fused to a C3-C3 cycloalkyl ring, a benzene ting
`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 heterocy
`clic ring with from 1 to 3 heteroatoms selected
`from oxygen, sulfur or nitrogen fused to a 5 or
`6-membered heterocyclic ting with from 1 to 3
`heteroatoms selected from oxygen, sulfur or nitro
`gen;
`R1 is hydroxy, oxo, halogen, cyano, nitro, NR8R3’
`SR3, tri?uoromethyl, C1-C6 alkyl, C1-C6 alkoxy,
`C3-C8 cycloalkyl, phenyl, SO2R9’ NR3COR9,
`COR9, NR3SO2R9» NR3CO2R3 or C1-C6 alkyl sub
`stituted by hydroxy, nitro, halogen, cyano, NR8R3,
`SR3, tri?uoromethyl, C1-C6 alkoxy, C3-C3 cycloal
`kyl, phenyl, NR3COR9' COR9’ SO2R91 NR3SO2R9,
`NR8CO2R8, or R1 is a 5 or 6-membered heterocycle
`with from 1 to 3 heteroatoms selected from oxy
`gen, sulfur or nitrogen;
`R2 and R3 are independently hydrogen, C1-C6 alkyl
`or C1-C6 alkyl substituted by l to 3 of hydroxy,
`C1-C6 alkoxy, or halogen;
`
`R4 and R5 are independently hydrogen, C1-C6 alkyl,
`halogen, NHRg, 0R3, SO2R9 or NHSO2R9;
`R6 is hydrogen or C1-C6 alkyl;
`R7 is C1-C6 alkyl, C3-C3 cycloalkyl, or B-(RI)n;
`B is phenyl, naphthyl, a 5 or 6-membered heterocy
`clic ring with from 1 to 4 heteroatoms selected
`from oxygen, sulfur or nitrogen, a benzene ring
`fused to a C3-C3 cycloalkyl ring, a benzene ting
`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 heterocy
`
`SAWAI EX. 1009
`Page 2 of 35
`
`

`

`5,451,677
`4
`3
`Representative preferred antiobesity and antidiabetic
`clic ring with from 1 to 3 heteroatoms selected
`compounds of the present invention include the follow
`from oxygen, sulfur or nitrogen fused to a 5 or
`ing: N-[4-[2-[[2-hydroxy-3-(4-hydroxyphenoxy)propyl
`6-membered heterocyclic ring with from 1 to 3
`]amino]ethyl]phenyl]benzenesulfonarnide N-[4-[2-[[2
`heteroatoms selected from oxygen, sulfur or nitro
`hydroxy-3-(4-hydroxyphenoxy)propyl]amino]ethyl]
`gen;
`R8 is hydrogen, C1—C1() alkyl, C3-C3 cycloalkyl,
`phenyl]-4-iodobenzenesulfonamide
`N-[4-[2-[[2
`hydroxy-3-(4-hydroxyphenoxy)propyl]amino]ethyl]
`phenyl optionally substituted by l to 3 of halogen,
`phenyl]-2-naphthalenesulfonamide N-[4-[2-[[2-hydroxy
`C1-C6 alkyl or C1-C6 alkoxy, or C1-C1() alkyl sub
`3-(4-hydroxyphenoxy)propyl]amino]ethyl]phenyl]4
`stituted by l to 3 of hydroxy, halogen, COZH,
`CO2—-C1—C6 alkyl, C3-C8 cycloalkyl, C1-C6 alk
`(benzo-Z, l,3-thiadiazole)sulfonamide
`N- [4- [2-[[2
`hydroxy-3-(4-hydroxyphenoxy)propyl]amino]ethyl]
`oxy, or phenyl optionally substituted by from 1 to
`3 of halogen, C1-C6 alkyl or C1-C6 alkoxy;
`phenyl]-2-phenylethanesulfona.mide
`N-[4-[2-[[3-(4
`
`35
`
`In the above structural formula and throughout the
`instant speci?cation, the following terms have the indi
`cated meanings:
`The ‘alkyl groups speci?ed above are intended to
`include those alkyl groups of the designated length in
`either a straight or branched con?guration. Exemplary
`of such alkyl groups are methyl, ethyl, propyl, isopro
`pyl, butyl, sec-butyl, tertiary butyl, pentyl, isopentyl, _
`hexyl, isohexyl, and the like.
`The alkoxy groups speci?ed above are intended to
`include those alkoxy groups of the designated length in
`either a straight or branched con?guration. Exemplary
`25
`of such alkoxy groups are methoxy, ethoxy, propoxy,
`isopropoxy, butoxy, isobutoxy, tertiary butoxy, pen
`toxy, isopentoxy, hexoxy, isohexoxy and the like.
`The term “halogen” is intended to include the halo
`gen atoms ?uorine, chlorine, bromine and iodine.
`30
`Certain of the above de?ned terms may occur more
`than once in the above formula and upon such occur
`rence each term shall be de?ned independently of the
`other.
`The preferred 5 and 6-membered heterocycles and
`fused heterocycles of A, B and R1 are those heterocy
`cles with from 1 to 4 heteroatoms independently se
`lected from one of oxygen or sulfur or 1 to 4 nitrogen
`atoms.
`The preferred values of A and B are phenyl, naphthyl'
`40
`or the foregoing preferred 5 and 6-membered heterocy
`cles and fused heterocycles.
`The more preferred values of A are phenyl, naphthyl,‘ .
`pyridyl, quinolinyl, pyrimidinyl, pyrrollyl, thienyl, im
`idazolyl, and thiazolyl.
`The more preferred values of B are phenyl, naphthyl,
`quinolinyl, thienyl, benzimidazolyl, thiadiazolyl, benzo
`thiadiazolyl, indolyl, indolinyl, benzodioxolyl, benzodi
`oxanyl, benzothiophenyl, benzofuranyl, benzisoxazolyl,
`benzothiazolyl, tetrahydronaphthyl, dihydrobenzofura
`nyl, and tetrahydroquinolinyl.
`Further preferred compounds of the instant invention
`are s realized when in the above structural formula:
`R2 and R3 are hydrogen or methyl;
`X is ---CH;—
`111 is 1;
`r is 0-2; and -
`R4, R5 and R5 are hydrogen.
`Still further preferred compounds of the instant in
`vention are realized when in the above structural for
`mula:
`A is phenyl, quinolinyl, or a 6-membered heterocy
`clic ring with l or 2 nitrogen atoms;
`B is phenyl or quinolinyl;
`R1 is NHZ, hydroxy, halogen, cyano, tri?uoromethyl,
`phenyl, NR8COR9' NR8CO2R8, C1—C6 alkyl op
`tionally substituted by hydroxy; and
`r is 0or2.
`
`60
`
`N-[4-[2-[[3-[(2-amino-5
`4-benzenesulfonamide
`pyridiny1)oxy]-2-hydroxyptopyl]amino]ethyl]phenyl]
`Z-naphthalenesulfonamide
`N-[4-[2-[[2-hydroxy-3-(4
`hydroxyphenoxy)propyl]amino]ethyl]pheny1]-3
`quinolinesulfonamide N-[4-[2-[[2-hydroxy-3-(4-hydrox
`yphenoxy)propyl]amino]ethyl]phenyl]-4—[(5-methox
`ycarbonyl)pentanoyl]amino]benzenesulfonamide N-[4
`[2-[[2-hydroxy-3-(4-hydroxyphenoxy)propyl]amino]e
`thyl]pheny1]-4-[(5-hydroxycarbonyl)pentanoyl]amino]
`benzenesulfonamide N-[4-[2-[[2-hydroxy-3-(4-hydroxy
`phenoxy)propyl]amino]ethyl]phenyl]-4~(hex
`N-[4~[2
`ylaminocarbonylamino)benzenesulfonamide
`[(Z-hydroxy-3-phenoxypropyl)amino]ethyl]phenyl]~4
`chlorobenzenesulfonamide
`N-[4-[2-[[2-hydroxy-3-(3
`cyanophenoxy)propyl]amino]ethyl]phenyl]-3
`quinolinesulfonamide
`N-[4-[2-[[3-(4-amino-3-cyano
`phenoxy)-2-hydroxypropyl]amino]ethyl]phenyl
`]-3
`~quinolinesu1fonamide
`N-[4-[2-[[2-hydroxy-3-[(3
`hydroxymethyl)phenoxy]propyl]amino]ethyliphenyl]
`3-quinolinesulfonamide
`N-[4-[2-[[2-hydroxy-3-(3
`pyridyloxy)propyl]amino]ethyl]phenyH-B-quinolinesul
`fonamide N-[4-[2-[[2-hydroxy-3-(3-pyridyloxy)propyl
`lamino]ethyl]phenyl]-4-iodobenzenesulfonamide N-[4
`[2-[[3-[(Z-amino-S-pyridinyDoxy]-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 Ia. 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
`puri?ed 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 com
`pound 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 sepa
`rated into diastereoisomeric pairs of enantiomers by, for
`example, fractional crystallization from a suitable sol
`vent, 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.
`Alternatively, any enantiomer of a compound of the
`general Formula I may be obtained by stereospeci?c
`synthesis using optically pure starting materials of
`known con?guration.
`
`50
`
`55
`
`65
`
`SAWAI EX. 1009
`Page 3 of 35
`
`

`

`5,451,677
`5
`The following stereospeci?c structure represents the
`preferred stereoisomers of the instant invention.
`
`6
`-continued
`SCHEME 1
`
`10
`
`pos where the various substituents are as defined above.
`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 or
`ganic acids. Examples of such acids are hydrochloric,
`nitric, sulfuric, phosphoric, formic, acetic, tri?uoroace
`tic, propionic, maleic, succinic, malonic and the like. In
`addition, certain compounds containing an acidic func
`tion 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
`25
`described in the following schemes.
`
`(111)”
`
`II
`
`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 alky
`lation 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-hydroxyphenyl as its tert-butyldimethylsi
`lyl (TBS) derivative is illustrated in Scheme 2. Com
`mercially available phenol 3 is treated with a silylating
`agent such as tert-butyldimethylsilyl chloride in the
`presence of a base such as imidazole in an aprotic sol
`vent such as dimethylformamide. The benzyl group is
`then removed by catalytic hydrogenation to give the
`desired alcohol 5.
`
`30
`
`35
`
`HO
`
`3
`
`SCHEME 2
`
`OBn
`
`(tert-Bu)MegSiCl
`imidazole, DMF 5
`
`45
`
`where n, m, r, A, R1, R2, R3, R4, R5, R6, R7 and X are as
`de?ned above.
`Compounds II 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
`1 is treated with base such as sodium hydride or potas
`sium 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°—l00° C. to provide com
`pound II. The epoxide derivative 2 is conveniently the
`commercially available, enantiomerically pure (2S)or
`(2R)-glycidyl S-nitrobénzene sulfonate or (2R) or (2S)
`glycidyl 4-toluenesulfonate, thus both the (S) and (R)
`enantiomers of epoxide II are readily available.
`
`SCHEME 1
`
`llbase
`0 ;
`ak/Q
`
`Q...
`
`(111)”
`
`l
`
`65
`
`OBn
`
`H2
`Pd catalyst
`
`5
`
`(tert-Bu)Me2SiO
`
`4
`
`OH
`
`(tert-Bu)Me2SiO
`
`5
`
`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 hy
`drogen is illustrated in Scheme 3. Compound 6 is selec
`tively protected asia suitable carbamate derivative 60
`with, for example, di-tert-butyl dicarbonate or car
`bobenzyloxy 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 8. The protecting group
`is then removed with, for example, tri?uoracetic acid in
`the case of Boc or catalytic hydrogenation in the case of
`Cbz, to give the desired amine 9.
`
`SAWAI EX. 1009
`Page 4 of 35
`
`

`

`5,451,677
`
`7
`
`SCHEME 3
`
`8
`-continued
`SCHEME 4
`
`R4
`
`R5
`
`R5
`
`R4
`
`B0020
`
`NHZ
`
`pyridine, CHZCIZ >
`
`10
`
`20
`
`G = Boc or Cbz
`
`R3
`
`H
`
`TFA,
`CHzClz
`O
`Pd catalyst
`
`R5
`
`9
`
`Compounds III where R6 is not hydrogen may be
`conveniently prepared as illustrated in Scheme 4. Sul
`fonamide 8, prepared as described above, is alkylated
`with an appropriate alkylating agent 10 in the presence 45
`of base to provide sulfonamide 11. Removal of the pro
`tecting group as above gives the desired compound III.
`
`G = Boc or Cbz
`Y = Cl, Br, or I
`
`III
`
`The sulfonyl chlorides 7, many of which are commer
`cially available, can also be readily prepared by a num
`ber of methods familiar to those skilled in the art. One
`suitable method involves the addition of an organoli
`thium reagent or a Grignard reagent to sulfuryl chlo
`ride following the procedure of S. N. Bhattacharya, et.
`al., J. Chem. Soc. (C), 1265-1267 (1968). Another con
`venient 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 PCl5, PCl3 or SOClz (J. March, Ad
`vanced Organic Chemistry, 4th Ed., John Wiley and
`Sons, New York: 1992, p 1297 and references cited
`therein). Alternatively, aromatic compounds may be
`treated with chlorosulfonic acid according to the proce
`dure of Albert, et. al., J. Het. Chem 15, 529 (1978), to
`provide the sulfonyl chlorides.
`The diamines 6 are commercially available or readily
`prepared by methods described in the literature or
`known to those skilled in the art. Compound 6 where
`R2 or R3 is methyl can be prepared from the corre
`sponding 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=methy1, the appropriate
`(R) amino acid 12 is esteri?ed, conveniently by treat
`ment with methanolic hydrochloric acid, and then
`treated with di-tert-butyl dicarbonate to give com
`pound 13. 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 mesyl
`ate. Removal of the Boo protecting groups gives di
`amine 14. This compound is subjected to catalytic hy- ,
`drogenation in-the presence of base such as sodium
`acetate to give the desired a-methyl amine 15. The other
`enantiomer is available through an analogous sequence
`starting with the corresponding (S) amino acid.
`
`?lm
`R4
`
`HZNV (X)m
`E
`HOZC
`
`l MeOI-I I-ICl
`2) B0020, NaHCOj;
`
`SAWAI EX. 1009
`Page 5 of 35
`
`

`

`5,451,677
`
`9
`-continued
`w
`R4
`
`10
`-continued
`SCHEME 6
`
`O
`
`BocNH
`
`(X),,,
`
`MeOZC
`
`1) LiBH4
`2) MeSOgCl, Et3N
`3)TFA,CH;C12 9
`
`NHBoc
`
`R5
`
`13
`
`R4
`
`1O BOCNH/\/o
`
`N02
`
`18
`
`1. R7(CH2),SO2Cl (7),
`pyridine, CHZCIZ
`A/CHZCIZ (1:3) 5
`
`2.
`NH2
`
`(X)!!!
`HZN
`H2,NaOAc
`Y
`MSO/ W
`NH;
`
`15
`
`19
`
`H2N/\/O
`
`R .ZCF3COZH
`
`14
`
`20
`
`NHSO2(CH2)r—R7
`
`20
`
`R4
`
`H2N\=/<X)m
`lire
`
`N'Hz
`
`R
`
`Alternatively, diamine 6 where X is —-CHzO— and
`25 m is 1 is available from intermediate 19 by treatment
`with tri?uoroacetic acid. This diamine may then be
`modi?ed as illustrated in Scheme 3.
`Diamines 6 and sulfonamide amines 9 where X is
`—CH2CH2— and m is I are also readily prepared by
`30 methods described in the literature or known 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 re
`duced by treatment with hydrogen and catalytic palla
`dium to provide amine 23. Amine 23 is acylated with
`sulfonyl chloride 7 to give the corresponding sulfona
`mide 24. Reduction of compound 24 with cobalt chlo
`ride and sodium borohydride provides the desired
`amine 25.
`
`35
`
`Diamines 6 or sulfonamide amines 9 where X is
`—CH2O— and m is l are also readily prepared by meth
`ods 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 16 is alkylated with l
`bromo-Z-chloroethane, conveninetly in re?uxing 2
`butanonewith a base 0 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, triphen
`ylphosphine in aqueous tetrahydrofuran. Protection of
`the resultant amine, conveniently as its t-butyl carba
`45
`mate by treatment with di-tert-butyldicarbonate, gives
`derivative 18. The nitro group is then reduced, for ex
`ample, by catalytic hydrogenation to provide amine 19.
`Acylation of intermediate 19 with sulfonyl chloride 7,
`followed by deprotection with acid such as tri?uoro
`acetic acid gives the desired intermediate 20.
`
`SCHEME 7
`
`NC
`
`Hz, Pd/C
`MeOI-I 5
`
`N02
`
`22
`
`50
`
`5 B0cNH/\/ 0 H2, Pd/
`
`
`
`SCHEME 6
`
`Cl
`
`Br
`
`K2C03,
`N02 Z-butanone,
`
`;
`
`N30
`
`16
`
`1. LiN3, DMF, 60°
`2. PPh3, THF/HzO,
`3. BOC anhydride,
`NO;
`
`5
`
`NC
`
`55
`
`60
`
`NC
`
`R7(CH2);$02C1(7) E
`pyridine, CHZCIZ
`
`NH;
`
`23
`
`65
`
`24
`
`Na-BH4,
`MeOH
`
`CoClZ.6l-I2O5
`
`SAWAI EX. 1009
`Page 6 of 35
`
`

`

`11
`-continued
`SCHEME 7
`
`HZN
`
`5,451,677
`
`12
`-continued
`SCHEME 8
`
`R4
`
`__ 1
`NHSOXCHZ)’ R
`
`25
`
`5
`
`R2
`|
`H2N—c—(X)m
`R3
`
`N$0z(CH2)r-R7 —>
`1L6
`
`R5
`
`m
`
`‘:2
`[OH 1|‘!
`mCHCmN_C.(.x)
`l3
`"'
`R
`
`1
`(R )"
`
`R4
`
`R5
`
`I
`
`Nsodmrrkv
`| 5
`r
`R
`
`Alternatively, diamine 6 where X is —-CH2CH2— 10
`and m is l is available from intermediate 23 by reduction
`of the nitrile group with, for example, cobalt chloride
`and sodium borohydride. This diamine may then be
`modi?ed as illustrated in Scheme 3.
`Intermediates II and III are coupled by heating them 15
`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 20
`re?uxing methanol. Alternatively, a salt of amine III,
`_
`such as the tri?uoroacetate or hydrochloride salt, may
`_ In some cases, the eoupllng Prod?!“ I from t_he l'eae'
`be used. In these cases, a base such as sodium bicarbon-
`"on desel'lbed 1n Scheme 3 may be fufthef modl?ed’ f0!‘
`ate or diisopropylethylamine is added to the reaction
`mixture. The product is puri?ed from unwanted side 25 exan‘lplei PS’ the femeval of Pmteetmg groups 01' the
`products by recrystallization, trituration, preparative
`mampulatlon Qf subetltuents e11, 111 pamculfiri R1 find
`thin layer chromatography, ?ash chromatography on
`IU- These mampulations may include reduction, oxida
`silica gel as described by W. c. Still, et. al., J. Org.
`Hon, alkylation, acylation, and hydrolysis reactions
`Chem. 43, 2923 (1978), medium pressure liquid chroma-
`which are commohbf known to_ those skilled in the art
`tography, ‘or HPLC. Compounds which are puri?ed by 30 one sueh example 15 Illustrated 111 scheme 9- Compound
`HPLC may be isolated as the corresponding salt. Puri?~
`25, Whleh 1-5 Prepared as eutlllled "1 fhe Scheme 8 frefn
`cation of intermediates is achieved in the same manner.
`the corresponding epoxlde! 15 subleeted t0 eatalytle
`hydrogenation in a polar solvent such as 1:] acetic
`acid/methanol to provide compound 27. Other exam
`35 ples of substituents on compound I which may be re
`SCHEME 8
`— duced to the corresponding amine by catalytic hydro
`genation and methods commonly known to those
`skilled in the art include nitro groups, nitriles, and
`azides.
`
`SCHEME 9
`
`OH H
`
`\ Q\/\/N-C'-'X
`R2‘ 1(R33
`
`/
`N
`
`R4
`
`R5
`II‘ISOZ(CH2)II_R7
`R6
`
`i
`
`N
`ll
`N
`
`OZN
`
`26
`
`H2, Pd catalyst
`AcOH-MeOI-I
`
`.
`OH H
`\ 0\/\/N—c_—X
`
`R5
`
`N502(CH2)u-R7
`
`O
`o
`W +
`
`HZN
`
`N I
`
`R4
`
`27
`
`65
`
`Scheme 10 illustrates an example of another such
`modi?cation of the coupling product I. Acetamido
`derivative 28, which is prepared as outlined in the
`Scheme 8 from the corresponding epoxide, is subjected
`
`SAWAI EX. 1009
`Page 7 of 35
`
`

`

`5,451,677
`13
`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.
`
`14
`chloride in the presence of a base such as pyridine fol
`lowed by removal of the protecting group with, in the
`case of a tert-butylcarbamate, acid such as tri?uoroace
`tic acid or methanolic hydrogen chloride, provides the
`
`SCHEME 10
`
`2
`R
`
`is
`
`.
`
`OH
`
`1
`
`l
`
`AcNH
`
`/
`
`y
`
`(Y = CH, N)
`
`28
`
`HCl or NaOH
`
`1
`(R )n
`
`O
`
`2
`
`H I
`
`\ 0\)\/N—?_(X)m
`
`R3
`
`H2N
`
`/
`Y
`
`(Y = CH, N)
`
`29
`
`R4
`
`R5
`
`R5
`
`An alternate method for the synthesis of compound I
`
`sulfonamide I.
`
`is illustrated in Scheme 11. Epoxide II is coupled to
`amine 6 as described above for coupling intermediates
`II and III (Scheme 8) to give aniline derivative 31:; The
`secondary amine is selectively protected, for example,
`as a carbamate by treatment with di-tert-butyldicarbon
`ate to provide carbamate 32. Alternatively, nitro amine
`30 is used in the coupling reaction to provide 3112. Fol
`lowing protection as described above, the nitro group is
`reduced, for example, by catalytic hydrogenation, to
`provide intermediate 32. Treatment with a sulfonyl
`
`65
`
`In some cases, sulfonamide I from the reaction se
`quence illustrated in Scheme 11 may be further modi
`?ed, 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 I 1 may occur. An exam—
`ple of. this is illustrated in Scheme 12. N-Boc 4
`
`SAWAI EX. 1009
`Page 8 of 35
`
`

`

`5,451,677
`15
`16
`nitrobenzenesulfonamide 33, which is prepared from
`nous insulin, oral administration of drugs and dietary
`therapies.
`intermediate 32 and 4-nitrobenzenesulfonyl chloride, is
`subjected to catalytic hydrogenation and the resultant
`Two major forms of diabetes mellitus are now recog
`aniline is acylated with, for example, an acid chloride in
`nized. Type I diabetes, or insulin-dependent diabetes, is
`the presence of base to give N-Boc intermediate 34.
`the result of an absolute de?ciency of insulin, the hor
`mone which regulates glucose utilization. Type II dia
`Deprotection with acid such as tri?uoroacetic acid or
`methanolic hydrogen chloride provides the desired
`betes, or insulin-independent diabetes, often occurs in
`sulfonamide 35.
`the face of normal, or even elevated levels of insulin and
`
`5
`
`SCHEME 12
`R4
`
`OH Boc R2
`
`OCH2CHCHZN— C- (X)m
`R3
`
`OH Boc R2
`OCl-I2CHCH2N— ([3- OO»:
`R3
`
`OH H R2
`l
`I
`l
`OCl-IzCI-ICI-lzN-f-(XM
`R3
`
`H
`N\ ||
`ll
`0
`
`R5
`
`33
`
`1) H2, catalytic Pd/C
`2) RBCOC], pyridine
`
`R4
`
`R5
`
`34
`
`H
`N\ I]
`ll
`0
`
`\l/TFA or HCl/MeOH
`R4
`
`H 0
`N\ H S
`ll
`0
`
`R5
`
`N02
`
`NHCOR8
`
`NHcoR8
`
`(R1)n
`
`(R1)n
`
`-
`
`(R1)n
`
`As previously indicated, the compounds of the pres- 4S
`ent invention have valuable pharmacological proper
`ties.
`The present invention also provides a compound of
`the general Formula I or a pharmaceutically acceptable
`salt thereof for use as an active therapeutic substance.
`In one aspect, the present invention provides a com
`pound of the general Formula I or a pharmaceutically
`acceptable ester thereof: or a pharmaceutically accept
`able salt thereof for use in the treatment of obesity in
`human or non-human animals.
`55
`The present invention further provides a compound
`of the general Formula I, or a pharmaceutically accept
`able ester thereof; or pharmaceutically acceptable salt
`thereof, for use in the treatment of hyperglycemia (dia
`betes) in human or non-human animals.
`The disease diabetes mellitus is characterized by met
`abolic defects in production and utilization of glucose
`which result in the failure to maintain appropriate blood
`sugar levels. The result of these defects is elevated
`blood glucose or hyperglycemia. Research on the treat
`ment of diabetes has centered on attempts to normalize
`fasting and postprandial blood glucose levels. Treat
`ments have included parenteral administration of exoge
`
`65
`
`appears to be the result of the inability of tissues to
`respond appropriately to insulin. Most of the Type II
`diabetics are also obese.
`In addition the compounds of the present invention
`lower triglyceride levels and cholesterol levels and raise
`high density lipoprotein levels and are therefore of use
`in combatting medical conditions wherein such lower
`ing (and raising) is thought to be beneficial. Thus they
`may be used in the treatment of hyper-triglyceridaemia,
`hypercholesterolaemia and conditions of low HDL
`(high density lipoprotein) levels in addition to the treat
`ment of atherosclerotic disease such as of coronary,
`cerebrovascular and peripheral arteries, cardiovascular
`disease and related conditions.
`Accordingly, in another aspect the present invention
`provides a method of lowering triglyceride and/or
`cholesterol levels and/or increasing high density lipo
`protein levels which comprises administering, to an
`animal in need thereof, a therapeutically effective
`amount of a compound of the formula (I) or pharmaceu
`tically acceptable salt thereof. In a further aspect the
`present invention provides a me