llllllIllllllllllllllllllllllllllllllllllllllliIIIIIlllllllllllllllllllllll
`
`USOO5321036A
`[11] Patent Number:
`[45] Date of Patent:
`
`' 5,321,036
`Jun. 14, 1994
`
`United States Patent [191
`Sher
`
`[54] THIAZOLE AND OXAZOLE-BASED B3
`ADRENERGIC RECEPTOR AGONISTS
`[75] Inventor:
`Philip M. Sher, Plainsboro, NJ.
`[73] Assignee: Bristol-Myers Squibb Company,
`Princeton, NJ.
`[21] Appl. No.: 15,940
`[22] Filed:
`Feb. 10, 1993 _
`
`[51] Int. Cl.5 ................... .. A61K 31/42; C07D 261/08
`[52] US. Cl. .................................. .. 514/365; 514/378;
`548/201; 548/204; 548/236
`[58] Field of Search .............. .. 514/365, 378; 548/201,
`548/204, 236
`
`[56]
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`3,631,055 12/1971 Posselt et a1. .
`4,385,066 5/ 1983 Ainsworth et a1. .
`4,391,826 7/1983 Mills et a1. .
`4,438,128 3/1984 Wiedernann et a1. ......... .. 544/277 X
`4,585,796 4/1986 Alig et a1. .
`4,608,383 8/1986 Wiedernann et a1. .
`4,629,737 12/1986 Cantello .
`4,652,679 3/1987 Alig et al. .
`4,743,604 5/1988 Alig et al. .
`4,753,962 6/1988 Ainsworth et al. .
`4,845,127 7/1989 Mills et al. .
`4,871,755 10/1989 Alig et a1. .
`5,064,863 11/1991 Alig et a1. .
`
`FOREIGN PATENT DOCUMENTS
`
`6766 l/1980 European Pat. Off. .
`7204 1/1980 European Pat. Off. .
`28105 5/1981 European Pat. Off. .
`63004 10/1982 European Pat. Off. .
`85514 8/1983 European Pat. Off. .
`170121 2/1986 European Pat. Off. .
`2531312 5/1976 Fed. Rep. of Germany .
`
`OTHER PUBLICATIONS
`R. Howe et al., Selective B3—Adrenergic Agonists of
`Brown Adipose Tissue and Thermogenesis, 1. [4-[2—[(
`2-Hydroxy-3—phenoxypropy1)arnino]ethoxy]—
`phenoxy]acetates, J. Med. Chem., 1992; 35:1751-1759.
`R. Howe et al., Selective B3—Adrenegeric Agonists of
`Brown Adipose Tissue and Thermogenesis. 2. [4-[2—[(
`
`2-Hydroxy-3-phenoxypropyl)amino]ethoxy]—phenox
`y]acetamides, J. Med. Chem, 1992; 35:1759-1764.
`J. Simiand et al., Antidepresent pro?le in rodents of SR
`58611A, a new selective agonist for a typical b-a
`drenoceptors, Eur. J. of PharmacoL, 1992; 219:193-201.
`D. C. Humber et al., “Disodiurn (R,R)—5-[2—(3-Chlor0
`pheny)-2-hydroxyethy1]amino]pr0pyl]-1,3-benzodiox
`ole-2,2-dicarboxylate (CL 316,243). A Potent B-A
`drenergic Agonist Virtually Speci?c for B3 Receptors.
`A Promising Antidiabetic and Antiobesity Agent”, J.
`Med. Chem, 1992; 35:3081-3084.
`Primary Examiner-Mary C. Lee
`Assistant Examiner-Jacqueline Haley
`Attorney, Agent, or Firm-Ellen K. Park
`[57]
`ABSTRACT
`Compounds having the formula
`
`OH
`
`ll
`0
`
`and pharmaceutically acceptable salts thereof where
`A is
`
`(Abstract continued on next page.)
`
`SAWAI EX. 1011
`Page 1 of 20
`
`

`

`5,321,036
`Page 2
`
`R3 is —(CH2),|—- 01' in the case where R2 is
`
`\
`
`s
`
`,,
`
`Y Z ,
`
`N
`
`R5’
`
`R3 in addition to the above may be
`
`R7’
`-'(CH2)p_(‘:— ;
`COR4
`
`R4 is hydroxy, alkoxy, amino, alkylamino or dialkyl
`amino;
`R5 is hydrogen, ?uorine, chlorine, bromine, iodine,
`
`—CN, CF3, lower alkyl, lower alkoxy, cycloalkyl
`or aryl;
`R6 is lower alkyl, cycloalkyl or aryl;
`R7, R7’, R8 and R3’ are independently hydrogen or a
`lower alkyl or R7 and R8 may together be CHZCHZ;
`Z is hydrogen or
`
`m is an integer of l or 2;
`n is zero or an integer of l to 6; and
`p is an integer of l to 5. These compounds are beta 3
`adrenergic receptor agonists and are useful, there
`fore for example, in the treatment of diabetes, obe
`sity and gastrointestinal diseases.
`
`31 Claims, No Drawings
`
`SAWAI EX. 1011
`Page 2 of 20
`
`

`

`1
`
`5,321,036
`
`THIAZOLE AND OXAZOLE-BASED B3
`ADRENERGIC RECEPTOR AGONISTS
`
`BRIEF DESCRIPTION OF THE INVENTION
`The present invention is directed to compounds of
`the formula
`
`5
`
`OH
`
`and pharmaceutically acceptable salts thereof. As used
`in formula I, and throughout the speci?cation, the sym
`bols have the following meanings:
`
`RéSOZNH
`
`or
`
`;
`
`HO
`
`25
`
`2
`DESCRIPTION OF THE INVENTION
`The present invention provides for compounds of
`formula I, pharmaceutical compositions employing
`such compounds and for methods of using such com
`pounds. Listed below are de?nitions of various terms
`used to describe the compounds of the instant invention.
`These de?nitions apply to the terms as they are used
`throughout the speci?cation (unless they are otherwise
`limited in speci?c instances either individually or as part
`of a larger group.
`The term “alkyl” refers to both straight and branched
`chain groups having 1 to 12 carbon atoms in the normal
`chain, preferably 1 to 7 carbons, such as methyl, ethyl,
`propyl, isopropyl, butyl, t-butyl, isobutyl, pentyl, hexyl,
`isohexyl, heptyl, 4,4-dirnethylpentyl, octyl, 2,2,4
`trimethylpentyl, nonyl, decyl, undecyl, dodecyl, the
`various branched chain isomers thereof, and the like.
`The term “lower alkyl” as employed herein includes
`such alkyl groups as described above containing 1 to 6
`carbon atoms in the normal chain.
`The term “alkoxy” refers to any of the above alkyl
`groups linked to an oxygen atom.
`The term “lower alkoxy” refers to any of the above
`lower alkyl groups linked to an oxygen atom.
`The term “aryl” refers to monocyclic or bicyclic
`aromatic groups containing from 6 to 10 carbons in the
`ring portion, such as phenyl, naphthyl, substituted
`phenyl or substituted naphthyl wherein the substituent
`on either the phenyl or naphthyl may be 1, 2 or 3 lower
`alkyl groups, halogens (e.g., chlorine, bromine or ?uo
`rine), or 1, 2 or 3 lower alkoxy groups.
`The term “cycloalkyl” refers to saturated cyclic hy
`drocarbon groups containing one or more rings of 3 to
`12 ring carbons, preferably 3 to 8 ring carbons,>which
`include cyclopropyl, cyclobutyl, cyclopentyl, cyclo
`hexyl, cycloheptyl, cyclooctyl, cyclodecyl, and ada
`mantyl.
`The compounds of formula I can be present as salts,
`in particular pharmaceutically acceptable salts. If the
`compounds of formula I have, for example, at least one
`basic center, they can form acid addition salts. These
`are formed, for example, with strong inorganic acids,
`such as mineral acids for example sulfuric acid, phos
`phoric acid or a hydrohalic acid, with strong organic
`carboxylic acids, such as alkanecarboxylic acids of l to
`4 carbon atoms which are unsubstituted or substituted,
`for example, by halogen, for example acetic acid, such
`as saturated or unsaturated dicarboxylic acids, for ex
`ample oxalic, malonic, succinic, maleic, fumaric,
`phthalic or terephthalic acid, such as hydroxycarboxy
`lic acids, for example ascorbic, glycolic, lactic, malic,
`tartaric or citric acid, such as amino acids, for example
`aspartic or glutamic acid, or such as benzoic acid, or
`with organic sulfonic acids, such as alkane- (of 1 to 4
`carbon atoms) or arylsulfonic acids which are unsubsti
`tuted or substituted, for example by halogen, for exam
`ple methane- or p-toluenesulfonic acid. Corresponding
`acid addition salts can also be formed having, if desired,
`an additionally present basic center. The compounds of
`formula I having at least one acid group (for example
`COOH) can also form salts with bases. Suitable salts
`with bases are, for example, metal salts, such as alkali
`metal or alkaline earth metal salts, for example sodium,
`potassium or magnesium salts, or salts with ammonia or
`an organic amine, such as morpholine, thiomorpholine,
`piperidine, pyrrolidine, a mono-, di- or tri-lower alkyla
`mine, for example ethyl-, tert-butyl-, diethyl-, diisopro
`
`35
`
`R3 is —(CI-IZ),,— or in the case where R; is I‘
`
`.
`
`N
`
`_
`
`S
`
`1
`
`I ,
`
`R3’
`
`R3 in addition to the above may be —(CH2)p-—(II— ;
`COR4
`
`R4 is hydroxy, alkoxy, amino, alkylamino or dialkyl
`amino;
`R5 is hydrogen, ?uorine, chlorine, bromine, iodine,
`—CN, —CF3, lower alkyl, lower alkoxy, cycloal
`kyl or aryl;
`R6 is lower alkyl, cycloalkyl or aryl;
`R7, R7’, R3 and R3’, are independently hydrogen or
`lower alkyl or R7 and R3 may together be CHZCHZ;
`Z is hydrogen or
`
`55
`
`m is an integer of 1 or 2;
`n is zero or an integer of l to 6; and
`p is an integer of l to 5.
`These compounds possess activity at the beta 3 adren
`ergic receptor. The compounds are useful in the treat
`ment of diabetes, obesity, and intestinal hypermotility
`disorders. The invention also provides processes for
`their preparation.
`
`65
`
`SAWAI EX. 1011
`Page 3 of 20
`
`

`

`3
`pyl-, triethy1-, tributyl- or dimethylpropylamine, or a
`mono-, di- or trihydroxy lower alkylamine, for example
`mono-, di- or triethanolarnine. Corresponding internal
`salts may furthermore be formed. Salts which are un
`suitable for pharmaceutical uses but which can be em
`ployed, for example, for the isolation or puri?cation of
`free compounds I or their pharmaceutically acceptable
`salts, are also included.
`All stereoisomers of the compounds of the instant
`invention are contemplated, either in admixture or in
`pure or substantially pure form.
`It should be understood that the present invention
`includes prodrug forms of the compounds of formula l
`such as aldehyde addition products of formula
`
`10
`
`15
`
`cg,
`
`OPro
`
`A,‘
`
`NZ‘
`
`I‘
`
`sect-12mm; N \/<ch'1>n
`R3
`
`S
`
`R7
`
`iv
`
`3
`
`0R9
`
`q
`
`I
`
`_
`
`WLere Z is hydrogen or
`
`$7.9m
`
`A was) a
`4 frat‘ \r/ CH2“
`
`<
`\
`Ow
`R
`
`2
`
`ll
`O
`
`Compounds of formula EV are then deprotected with,
`20 for example, fluoride to form compounds of the formula
`
`where R is alkyl or aryl such that RCHO is a suitable,
`for example, non-toxic aldehyde.
`The compounds of the instant invention may, for
`example, be in the free or hydrate form, and may be
`obtained by methods exempli?ed by the following de
`scriptions.
`Compounds of formula l where A is
`
`30
`
`35
`
`R7
`
`RB
`
`5
`
`where Z" is hydrogen or
`
`(|)H
`a» / \cn2—
`
`40 which are themselves compounds of formula I where
`R4 is alkoxy. Compounds of formula V may be deesteri
`?ed such as by saponi?cation to form the compounds of
`formula I where R4 is hydroxy.
`Alternatively, compounds of formula V may be ami
`dated, for example with ammonia or a mono or dialkyla~
`mine, to form compounds of formula l Where R4, is
`amino, alkylamino or diallcylamino.
`Compounds of formula ll may also be coupled with
`an epoxide of formula
`
`45
`
`and R3 is —(Cl*lz)n—— may be prepared by coupling a
`compound of formula
`
`II
`A
`(CHZM
`0R9
`
`Where R9 is a lower alkyl, with a compound of the
`
`formula
`
`‘
`
`to form compounds of formula V. Use of epoxide Illa
`would obviate the need for the deprotection step as is
`necessary after coupling compounds of formula H with
`compounds of formula ill.
`To prepare compounds or formula 1 where A is
`
`,
`
`.
`
`60
`
`where Pro is a suitable oxygen protecting group such as
`t-butyldimethylsilyl and L is a leaving group such as
`tri?ate, mesylate, tosylate, nosylate, bromide or iodide,
`optionally in the presence of an acid scavenger such as
`diisopropylethylamine to form a compound of formula
`
`and R2 is
`
`SAWAI EX. 1011
`Page 4 of 20
`
`

`

`a compound of formula
`
`NHz
`
`II
`
`5,321,036
`
`R2 iS
`
`III
`
`VI
`
`15
`
`20
`
`and R3 is -—(CI-I2),,— a compound of formula
`
`is coupled with a compound of the formula III option
`ally in the presence of an acid scavenger such as diiso
`propylethylamine to form a compound of formula
`
`is coupled with a compound of formula III optionally in
`the presence of an acid scavenger such as diisopropyle
`thylamine to form a compound of formula
`
`OPro
`
`l
`
`VII
`
`Compounds of formula X are then deprotected, for
`example, with fluoride to form compounds of the for
`mula
`
`0
`
`Compounds of formula VII are then deprotected, for
`example, with ?uoride to form compounds of the for
`mula
`
`35
`
`VIII
`
`0
`
`45
`
`50
`
`which are themselves compounds of formula I where
`R4 is alkoxy. Compounds of formula VIII may be dees
`teri?ed such as by saponi?cation to form the com
`pounds of formula I where R4 is hydroxy.
`Alternatively, Compounds of formula VIII may be
`amidated, for example with ammonia or a mono or
`dialkylamine, to form compounds of formula I where
`R4 is amino, alkylamino or dialkylamino.
`Compounds of formula VI may also be coupled with
`an epoxide of formula IIIa to form compounds of for
`mula VIII.
`To prepare compounds of formula I where A is
`
`which are themselves compounds of formula I where
`R4 is alkoxy. Compounds of formula XI may be dees
`teri?ed such as by saponi?cation to form the com
`pounds of formula I where R4 is hydroxy.
`Alternatively, Compounds of formula XI may be
`amidated, for example with ammonia or a mono or
`dialkylamine, to form compounds of formula I where
`R4 is amino, alkylamino or dialkylamino.
`Compounds of formula IX may also be coupled with
`an epoxide of formula H121 to form compounds of for
`mula XI.
`To prepare the compounds of formula I where A is
`
`55
`
`65
`
`R2 IS
`
`Rs
`
`Y
`
`\
`
`N
`
`,,
`
`I J7’ ,
`
`S
`
`and R3 is —(CI-I2),,—, a compound of formula II is
`coupled with a compound of formula
`
`4
`
`Rs
`
`,
`
`SAWAI EX. 1011
`Page 5 of 20
`
`

`

`-
`
`'
`
`optionally in the presence of a solvent such as 2-
`propanol or dimethylsulfonide to form compounds of 10
`Um formula
`
`which may then be converted to compounds or iormula
`
`I
`
`“ g
`
`Where Z’” is hydrogen or
`
`which may then be converted to the compounds of
`formula I as described above ‘for compounds of formula
`"V.
`Compounds of formula 1 where A is
`
`35
`
`R21S
`
`N
`O
`
`,
`
`,
`
`R5
`
`X”,
`
`/O\,/
`
`_
`
`40 and R3 is ‘-—(CH2),,——, a compound ofvformula EX '15
`coupled with a compound of formula Xll optionally 1n
`the presence of a solvent such as Z-propanol or dimeth
`ylsull'oxide to form compounds of the formula
`
`_
`
`and R2 is
`
`5
`
`which may then be converted to the compounds or"
`tormula l. as described above for compounds or tormula
`n
`_
`_
`n r
`T7”
`Jul.
`Compounds of formula 1 Where A is
`
`may be prepared by coupling a compound of formula 65
`Xll with a compound of formula Vl optionally in the
`presence of a solvent such as 2-propanol or dirnethyl-
`sulfoxide to form compounds of formula
`
`HO
`
`may be prepared by coupling compounds of formulae
`ll, Vl or IX with compounds of formula
`
`SAWAI EX. 1011
`Page 6 of 20
`
`

`

`9
`
`5,321,036
`
`XVI
`
`10
`
`where Rlois benzyl or hydrogen, to form compounds of
`formula
`
`R100
`
`where Z"" is hydrogen or
`
`I?
`
`2
`
`R100
`
`and subsequent procedures as outlined immediately
`above and using methods known in the art (R. H. Uloth,
`et al., J. Med. Chem. 9, 88 (1966)).
`Compounds of formula II are prepared by reacting
`compounds of formula
`
`BOC
`\
`NH
`
`O
`"
`
`R7
`
`R3
`
`XIX
`
`with a thionating reagent such as Lawesson’s reagent or
`Belleau’s reagent prepared as described in Lecher, H.
`2., et al., JACS 78, 5018 (1956) and Belleau, B., et al.,
`Tet. Letr. 24, 3815 (1983) to form compounds of formula
`
`15
`
`20
`
`25
`
`Compounds of formula XVII are subjected to subse
`quent ketone reduction, and where Rlois benzyl, phenol
`deprotection to form compounds of the formula
`
`BOC
`
`NH
`
`Isl
`
`XX
`
`XVIII
`0R9
`
`35
`
`where Z""' is hydrogen or
`
`R SO NH
`
`OH
`
`6
`
`2 ]@/kCH2_
`
`HO
`
`45
`
`Compounds of formula XVI and subsequent chemical
`methods are known in the art as disclosed in A. A.
`Larsen et al., J. Med. Chem. 10, 462 (1967).
`Compounds of formula XVIII themselves are com
`pounds of formula I where R4 is alkoxy. Compounds of
`formula XVIII may be deesteri?ed, for example by
`saponi?cation to form compounds of formula I where
`R4 is hydroxy. Alternatively, compounds of formula
`XVIII may be amidated, for example with ammonia or
`a mono or dialkylamine, to form compounds of formula
`I where R4 is amino, alkylamino or dialkylamino.
`Compounds of formula I where A is
`
`50
`
`which are then reacted with a haloketone of the formula
`
`COZRQ
`
`O
`
`XXI
`
`where X is chlorine, bromine or iodine, preferably bro
`mine, in a solvent such as ether to form compounds of
`formula
`
`OH
`
`XXII
`
`BOC
`N
`\
`NH A (CHZ)n_COZR9
`l
`X-(CHZM
`R7
`R3
`
`5
`
`~
`
`Compounds of formula XXII are then reacted with a
`dehydrating agent such as methanesulfonyl chloride
`and triethylamine in an organic solvent such as methy
`lene chloride to form compounds of formula
`
`55
`
`(cant-002R‘;
`
`XXI"
`
`N
`
`A
`
`RéSOzNH
`
`R7
`
`R3
`
`may be prepared from compounds of formulae II, VI,
`or IX by coupling with compounds of formula
`
`65
`
`which are then reacted with a deprotecting agent such
`as trifluoroacetic acid in an organic solvent such as
`methylene chloride to form the formula II compounds.
`
`SAWAI EX. 1011
`Page 7 of 20
`
`

`

`5,32I,036
`azole in a solvent such as chloroform, to form com
`pounds of the formula
`
`11
`In some instances reaction of compounds of formula
`XX as described above may give compounds of formula
`XXIII or even compounds of formula 11 directly.
`Compounds of formula XIX are prepared by reacting
`the appropriate aminoalkanoic acid ester salt, such as
`(R)-3-aminobutanoic acid methyl ester hydrochloride
`(prepared as described in US. Pat. No. 4,585,887), with
`a base such as triethylamine and a t-butoxycarbonylat
`ing reagent such as di-tert-butyl dicarbonate ((BOC)2U)
`in an organic solvent such as methylene chloride to
`form
`
`soc
`
`XXIV
`
`NH
`1
`cwwcngm
`
`ll)
`
`.
`
`OCI-I3
`
`which is then deesteri?ed with, for example, aq. sodium
`hydroxide in an organic solvent such as tetrahydrofuran
`to form compounds of formula
`
`20
`
`BOC
`
`XXV
`25
`
`R7
`
`Rs
`
`35
`
`Compounds of formula XXV are then reacted with
`ammonia in the presence of a coupling reagent such as
`l-hydroxybenzotriazole/ 1-(3-dimethylaminopropyl)-3
`ethylcarbodiimide hydrochloride (WSC) in a solvent
`such as acetonitrile to form the formula XIX com
`pounds. Compounds of formula XXV may be derived
`from the appropriate aminoalkanoic acid by t-butox
`ycarbonylation as described in 0. Keller et al., Org.
`Synzh. 63, 160 (1984).
`Compounds of formula III are prepared by reacting
`an R5-substituted benzaldehyde with a haloform such as
`CI-IBr3 or CHI3 and a lithium salt such as lithium chlo
`ride or lithium bromide and an alkali metal hydroxide
`such as potassium hydroxide or sodium hydroxide in a ,_
`solvent such as aqueous 1,4-dioxane to form compounds
`of formula
`
`tlltPro
`
`XXVIII
`
`Compounds of formula XXVIII are then reacted
`with a reducing agent such as diisobutylaluminum hy
`dride in a solvent such as toluene to form
`
`which are then activated converting the hydroxyl
`group into a leaving group, for example by reaction
`with a tritlating agent such as "l‘fzO, in the presence of
`a base such as pyridine in a solvent such as methylene
`chloride, to form the compounds of formula III.
`Compounds of formula IIIa are prepared from com
`pounds of formula XXVII by standard methods.
`Compounds of formula VI may be prepared by react
`ing a compound of formula
`
`0
`
`(when R3’ is —(CH2),,— and n is zero, it is preferred
`that X is chlorine) with a compound of formula XX in
`the presence of a solvent such as dimethylformamide or
`1,2-dichloroethane to form compounds of formula
`
`which are then reacted with a deprotecting agent such
`as trifluoroacetic acid in a solvent such as methylene
`chloride to form the formula VI compounds.
`Compounds of formula XXX where R3’ is (CH;),,
`where n is zero or 1 and R3’ is hydrogen or methyl are
`all known in the literature. Compounds of formula
`XXX where R8’ is hydrogen and R3’ is (CH2),, where n
`is 2, 3, 4-, 5 or 6 may be prepared by reacting the lactone
`of formula
`
`0
`
`XFIXII
`
`(ltnown in the art) in an alcohol such as ethanol under
`acid catalysis with, for example, sulfuric acid followed
`by treatment with an oxidizing agent such as pyridinium
`
`OH
`I
`@” COZH
`
`XX VI
`
`.
`
`i
`
`R5
`
`/
`
`m)
`
`Compounds of formula XXVI are then reacted with a
`methylating agent such as Mel, in the presence ofa base
`such as potassium carbonate in a solvent such as acetone
`to form
`
`XXVEI
`
`55
`
`65
`
`which are then protected, for example by reaction with
`tert-butyldimethylsilyl chloride and a base such as imid
`
`SAWAI EX. 1011
`Page 8 of 20
`
`

`

`13
`chlorochromate in a solvent such as methylene chloride
`to form a compound of formula
`
`5,321,036
`
`14
`
`XXXIII
`
`5
`
`which is then reacted with a halogenating agent such as
`bromine in a solvent such as a mixture of diethyl ether
`and 1,4-dioxane.
`Likewise, compounds of formula XXX where R3’ is a
`lower alkyl and R3’ is (CI-I2)” where n is 2, 3, 4, 5 or 6
`may be prepared by halogenation of compounds of
`formula
`
`15
`
`0
`ll
`
`XXXIV
`
`with a halogenating agent such as bromine in a solvent
`such as a mixture of diethyl ether and l,4-dioxane.
`Compounds of formula XXXIV may be made by
`modifying procedures disclosed in R. Majee et al.,
`Chemistry and Industry 167, (1983) and R. Finke et al.,
`Org. Synth. 59, 102 (1979).
`Compounds of formula XXX where R3’ is hydrogen
`and R3’ is
`
`may be prepared analogously to those where R3’ is
`hydrogen by substituting a lower alkyl vinyl ketone for
`acrolein.
`Compounds of formula IX are prepared by reacting a
`compound of formula XXV with an amino alcohol of
`formula
`
`HZN
`
`(CHZ)n—CO2R9
`
`7
`
`XXXVI
`
`in the presence of a coupling agent such as WSC in the
`optional presence of a catalyst such as l-hydroxybenzo
`triazole in a solvent such as MeCN and optionally a base
`such as triethylamine, to form a compound of formula
`
`BOC
`
`OH
`
`XXXVII
`
`which is then reacted with a cyclodehydrating agent
`such as triphenylphosphine/carbon tetrachloride in the
`presence of a base such as diisopropylethylamine, in a
`solvent such as MeCN to form compounds of formula
`
`35
`
`0
`
`XXXVIII
`
`may be prepared by similar halogenation of aldehydes
`of formula
`
`BOC
`
`XXXV
`
`45
`
`0
`
`Where p is l, the aldehyde of formula XXXV is pre
`pared by base catalyzed addition of
`
`50
`
`N
`
`A O
`
`R7
`
`R3
`
`Compounds of formula XXXVIII are then reacted
`with an oxidizer such as CuBrz in the presence of a base
`such as l,8-diazabicyclo[5.4.0]undec-7-ene in a solvent
`such as ethyl acetate/ chloroform mixtures to form com
`pounds of formula
`
`0
`
`XXXIX
`
`BOC
`
`55
`
`(known in the art) to acrolein. Where p is 2, the alde
`hyde of formula XXXV is prepared from the aldehyde
`of formula XXXV where p is l by standard aldehyde
`homologation procedures such as methoxymethylene
`Wittig reaction followed by acid catalyzed hydrolysis.
`Likewise, the aldehyde of formula XXXV where p is 3
`may be prepared from the aldehyde of formula XXXV
`where p is 2. Further repetition of the homologation
`sequence will provide aldehydes of formula XXXV
`wherein p is 4 or 5.
`Compounds of formula XXX where R3’ is a lower
`alkyl and R3’ is
`
`R7
`
`Rs
`
`An alternative method includes nickel peroxide oxida
`tion in a solvent such as methylene chloride. Com
`pounds of formula XXXIX are then reacted with a
`deprotecting agent such as tri?uoroacetic acid, option
`ally in a solvent such as methylene chloride to form the
`compounds of formula IX.
`Compounds of formula XII may be prepared by re
`acting an activated glycidyl alcohol such as (2S)-(+)
`
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`
`

`

`5,321,036
`16
`creased protein breakdown such as during convales
`cence after surgery, treatment of triglyceridemia, hy
`percholesterolemia, atherosclerotic and cardiovascular
`diseases, and increasing high density lipoprotein levels.
`In addition, it is expected that these compounds may be
`useful as feed additives for fattening or improving
`weight gain or increasing lean body mass in animals and
`may therefore be used to decrease birth mortality and
`increase post-natal survival rates in animals.
`The following examples and preparations describe
`the manner and process of making and using the inven
`tion and are illustrative rather than limiting. It should be
`understood that there may be other embodiments which
`fall within the spirit and scope of the invention as de
`fined by the claims appended hereto.
`
`15
`glycidyl 3-nitrobenzenesulfonate with a phenoxide such
`as sodium phenoxide in an organic solvent such as di
`methylformamide.
`Compounds of formula XXI for n=0, 1, 2, or 3 are
`known compounds. In general, compounds of formula
`XXI may be prepared by halogenation of ketones of
`formula
`
`which are known in the art, with, for example, bromine
`in methanol as described in S. F. MacDonald, Can. J.
`Chem. 52, 3258 (1974).
`Compounds of formula XXXVI where n is 0, 1, or 2
`are known compounds. Higher homologues of the com
`pounds of formula XXXVI may be prepared from the
`corresponding carboxylic acids HOCH2C(NH2)(CH2)
`nCOzH by acid catalyzed esteri?cation. The carboxylic
`acids, HOCH2C(NH2)(CH2),,CO2H, may be prepared
`from the aminoacids of formula
`
`15
`
`20
`
`HZN
`
`(cam-com,
`
`XU
`25
`
`COZI-I
`
`30
`
`35
`
`EXAMPLE 1
`2-[(R)-2-[[2-(3-chlorophenyl)-2-hydroxyethy1]amino]
`propyl]-4-thiazolecarboxylic acid
`(R)-3-[[(l,1-Dimethylethoxy)carbonyl]amino]
`A.
`butanoic acid, methyl ester
`To a solution of (R)-3-aminobutanoic acid, methyl
`ester (US. Pat. No. 4,585,887) in methylene chloride at
`room temperature under argon was added triethylamine
`(11.0 g, 109 mmol, 1.1 eq) and di-tert-butyl dicarbonate
`(23.76 g, 109 mmol, 1.1 eq). The resulting solution
`warmed upon mixing and was cooled in an ice bath
`which was then allowed to warm to room temperature.
`After 16 hours the reaction mixture was concentrated to
`70 g and dissolved in a biphasic mixture of ethyl acetate
`(~50O mL) and water (~500 mL). The organic layer
`was removed, washed once more with water (~5OO
`mL), dried over sodium sulfate, and concentrated to a
`yellow oil (29.9 g) which by NMR was shown to consist
`of 69% desired product. TLC (10% (10% concentrated
`aq. ammonium hydroxide/methanol)/methylene chlo
`ride): 0.83, p-anisaldehyde.
`13C NMR (67.7 MHz in CDC13): 820.1, 28.0, 40.3,
`43.2, 51.2, 78.7, 154.8, 171.5.
`E.
`(R)-3-[[(1,1-Dimethylethoxy)carbonyl]amino]
`butanoic acid
`To a solution of the title A compound (13.1 g, 60
`mmol) in methanol at room temperature under argon
`was added ~1M sodium hydroxide (100 mL). After
`stirring for 60 hours, the solution was acidi?ed at 0° C.
`to pH 3 by addition of ~ 1M hydrochloric acid. The
`resulting solution was extracted four times with ethyl
`acetate (150 mL). The combined organic layers were
`dried over sodium sulfate and then concentrated to
`yield the title compound (12.98 g) as a crystallizing
`colorless oil, which by proton NMR was shown to be
`97% pure title compound.
`TLC (2% acetic acid/48% ethyl acetate/50% hex
`ane)‘: 0.6, p-anisaldehyde.
`13C NMR (67.8 MHZ in CDClg): 620.4, 28.3, 40.1,
`43.3, 79, 155.6, 176.8.
`C.
`(R)-3-[[(l,1-Dimethylethoxy)carbonyl]amino]
`
`by methods employed in K. Barlos, et al., J. Chem. Soc.
`Chem. Commun. 1583 (1987) and R. B. Silverman and
`M. A. Levy, J. Org. Chem. 45, 815 (1980).
`The present compounds of formula I have activity at
`the beta 3 adrenergic receptor and are therefore useful,
`for example, in the treatment of diabetes, obesity, and
`gastrointestinal diseases such as inflammatory bowel
`disease, irritable bowel syndrome, nonspeci?c diarrhea,
`and peptic ulcer.
`Thus a composition containing one (or a combina
`tion) of the compounds of this invention, may be admin
`istered to a species of mammal (e. g., humans) suffering
`from diabetes, obesity or an intestinal hypermotility
`disorder as treatment therefor.
`A single dose, or two to four divided daily doses,
`provided on a basis of about 0.1 to 100 mg per kilogram
`of body weight per day, preferably about 1 to 15 mg per
`45
`kilogram of body weight per day is appropriate. The
`substance is preferably administered orally, but intrana
`sal, transdermal and parenteral routes such as the subcu
`taneous, intramuscular, intravenous or intraperitoneal
`routes can also be employed.
`The compounds of this invention can also be formu
`lated in combination with betal/betag adrenergic block
`ers or stimulants.
`The compounds of formula I can be formulated for
`use in compositions such as tablets, capsules or elixirs
`for oral administration, in sterile solutions or suspen
`sions for parenteral or intranasal administration, or in
`transdermal patches. About 10 to 500 mg of a com
`pound of formula I is compounded with a physiologi
`cally acceptable vehicle, carrier, excipient, binder, pre
`servative, stabilizer, flavor, etc., in a unit dosage form as
`called for by accepted pharmaceutical practice. The
`amount of active substance in these compositions or
`preparations is such that a suitable dosage in the range
`indicated is obtained.
`Based on the literature, it is expected that these com
`pounds may be useful for other indications such as treat
`ment of depression and stress, regulation of intraocular
`pressure, treatment of conditions associated with in
`
`SS
`
`butanamide
`_
`To a solution of the title B compound (4.0 g, 19.7
`mmol) in acetonitrile (125 mL) at room temperature
`under argon was added l-hydroxybenzotriazole hy
`drate (2.9 g, 21.7 mmol, 1.1 eq), and WSC (4.1 g, 21.7
`mmol, 1.1 eq). After four hours, concentrated aq. am
`monium hydroxide (8.1 mL, 118.8 mmol, 6 eq) was
`added. After stirring overnight the mixture was concen
`trated to white solid. The solid was chromatographed
`
`65
`
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`

`15
`
`25
`
`30
`
`35
`
`17
`on silica gel in 75% ethyl acetate/hexane to yield a
`white solid (3.8 g).
`TLC (50% ethyl acetate/hexane): 0.2, p-anisalde
`hyde, UV.
`13C NMR (67.8 MHz in CDC13): 820.3, 28.2, 42.4,
`44.2, 79, 155.8,. 174.7.
`D.
`2,4-Bis(4-phenoxyphenyl)-2,4-dithioxo-l,3,2,4
`dithiadiphosphetane
`Made as per description in Lecher, H. Z., et al., JA CS
`78, 5018 (1956) and Belleau, B., et al., Tet. Lett., 24, 3815
`(1983).
`(R)-3-[[(l,l-Dimethylethoxy)carbony1]amino]
`E.
`butanethioamide
`(See Belleau, B., et al., Tet. Lett. 24, 3815, (1983) for
`examples of thionations involving BOC-protected am
`ides.)
`To a solution of the title C compound (~1 g, ~5.0
`mmol) in tetrahydrofuran (40 mL) under argon at room
`temperature was added the title D compound (1.45 g,
`20
`2.8 mmol, ~0.6 eq). The solution was stirred for two
`hours, after which another 480 mg (0.2 eq) of the title D
`compound was added. The reaction was complete by
`TLC at four hours. The solution was concentrated and
`then chromatographed on silica gel in ethyl acetate/
`hexane (1:1) to isolate the desired product as a white
`solid (750 mg).
`TLC (30% acetone/toluene): 0.6, p-anisaldehyde,
`UV.
`13C NMR (67.8 MHz in CDC13): 819.8, 28.0, 45.9,
`53.2, 78, 155.8, 206.8.
`F.
`(R)-4,5-Dihydro-2-[2-[[(1, l-dimethylethoxy)car
`bonyl]-amino]propyl]-4-hydroxy-4-thiazolecarboxy
`lic acid, ethyl ester
`See Houssin, R., et al., JOC, 50, 2788 (1985), for simi
`lar condensations. See US. Pat. No. 5,100,889 for exam
`ples of similar hydroxy-thiazoline-intermediates.
`A solution of the title E compound (310 mg, 1.4
`mmol) and ethyl bromopyruvate (0.18 mL, 1.4 mmol,
`1.0 eq) in diethyl ether (15 mL) stirred at room tempera
`ture under argon overnight yielded a white precipitate.
`The mixture was added to ice water (~40 mL) and
`basi?ed to pH 11 by addition of concentrated aq. ammo
`nium hydroxide. The organic layer was removed and
`the aqueous layer was extracted four times with methy
`lene chloride (30 mL). The combined organic layers
`were dried over sodium sulfate and then concentrated
`to give a clear, colorless oil (450 mg).
`TLC (10% concentrated aq. ammonium hydroxide/
`methanol)/methylene chloride): 0.6, p-anisaldehyde,
`UV.
`(R)-2-[2-[[(1,1-Dimethylethoxy)carbonyl]amino]
`G.
`propyl]-4-thiazolecarboxy1ic acid, ethyl ester
`To a solution of the title F compound (427.8 mg, 1.3
`mmol) in methylene chloride under argon at —78‘’ was
`added triethylamine (723 uL, 7.2 mmol, 5.5 eq). Me
`thanesulfonyl chloride (151 uL, 1.95 mmol, 1.5 eq) was
`added over one minute. The reaction was complete by
`TLC in 20 minutes. Methanol (~20 mL) was added and
`the resulting solution was concentrated and chromato
`graphed on silica gel in 30% ethyl acetate/hexane to
`yield a yellow oil (400 mg).
`TLC (50% ethyl acetate/hexane): 0.4, p-anisalde
`hyde, UV.
`13C NMR (67.8 MHz in CDC13): 814.0, 20.3, 28.0,
`39.8, 46.5, 61.0, 80.1, 127.4, 146.7, 154.8, 161.1, 167.7.
`H. (R)-2-(Z-Aminopropyl-4-thiazolecarboxylic acid,
`ethyl ester
`
`5,321,036
`18
`To a solution of the title G compound (384 mg, 1.2
`mmol) in methylene chloride (~15 mL) at room tem
`perature was added tri?uoroacetic acid (~15 mL).
`After three hours the solution was concentrated and
`redissolved in methylene chloride (~25 mL), to which
`was added ~ 1M sodium bicarbonate (25 mL) and brine
`(30 mL). The mixture was extracted three times with
`methylene chloride (25 mL), and the combined extracts
`were dried over sodium sulfate, and concentrated. The
`resulting oil was chromatographed in 8% (10% concen
`trated aq. ammonium hydroxide/methanoD/methylene
`chloride to isolate desired products as a clear oil (200
`mg).
`TLC (10% (10% concentrated aq. ammonium hy
`droxide/methanol)/methylene
`chloride):
`0.6,
`p
`anisaldehyde, UV.
`—C NMR (67.8 MHz in CDC13): 814.0, 23.3