CA2271885A1 - Substituted benzo[1,4]dioxanes as antiobesity agents - Google Patents
Substituted benzo[1,4]dioxanes as antiobesity agents Download PDFInfo
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- CA2271885A1 CA2271885A1 CA002271885A CA2271885A CA2271885A1 CA 2271885 A1 CA2271885 A1 CA 2271885A1 CA 002271885 A CA002271885 A CA 002271885A CA 2271885 A CA2271885 A CA 2271885A CA 2271885 A1 CA2271885 A1 CA 2271885A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
- C07D319/14—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems
- C07D319/16—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D319/20—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring with substituents attached to the hetero ring
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Abstract
This invention relates to novel substituted 1,4-benzodioxane compounds having antidiabetic, antihyperglycemic, and antiobesity properties represented by formula (II) wherein R1 and R6 are independently hydrogen, C1 to C6 alkyl, trifluoromethyl, cyano, C1 to C6 alkoxy, or halogen; R2 is hydrogen or C1 to C6 trialkylsilyl; R3 is hydrogen or C1 to C6 alkoxycarbonyl; or R2 and R3 are joined to form the oxazolidinone ring (III); R4 and R5 are independently hydrogen or C1 to C6 alkyl; R7 and R8 are independently OR9 or NR10R11; R9 is hydrogen, C1 to C12 alkyl, C1 to C12 cycloalkyl, C1 to C12 silylalkyl, phenyl, naphthyl, phenyl C1 to C6 alkyl, C1 to C6 alkoxy C1 to C6 alkyl, pyridyl, thiophenyl, furanyl, imidazolyl, oxazolyl, -CHR12COOR13, -CHR12C(O)R13, -CHR12CONR10R11, -CHR12OCOOR13, or -CHR12OC(O)R13; R10 and R11 are independently hydrogen, C1 to C12 alkyl, phenyl, naphthyl, phenyl-C1 to C6 alkyl, furanylalkyl, or alkoxycarbonylalkyl; R12 and R13 are independently hydrogen, C1 to C12 alkyl, phenyl, naphthyl, or phenyl-C1 to C6 alkyl; and the pharmaceutically acceptable salts thereof, a salt thereof; an enantiomer thereof, the racemic mixtures thereof, and the diastereomeric mixtures thereof.
Description
SUBSTITUTED BENZO[1,4]DIOXANES AS ANTIOBESITY AGENTS
This invention relates to novel substituted 1,4-benzodioxane compounds which have antidiabetic, antihyperglycemic, and antiobesity properties. The present invention also s relates to pham~aceutical compositions comprising these compounds) methods for the preparation of these compounds) and methods for the use of these compounds in treating diabetes and/or hyperglycemia and/or obesity in mammals. The antiobesity compounds may find further use in reducing the fat content in domestic edible animals.
to BACKGROUND OF THE INVEN'j'ION
It is well known that medicinal agents are employed in the treatment of persons suffering from diabetes, hyperglycemia, and obesity. The compounds of the present invention achieve their antidiabetic, antihyperglycemic, and antiobesity effects by acting as is selective agonists at (33 adrenergic receptors. The stimulation of these receptors on white and brown adipocytes promotes both lipolysis (breakdown of fat) and energy expenditure.
Selective stimulation of ~i3 adrenergic receptors is important for chronic treatment.
Stimulation of other (3-receptors could cause side effects such as increased heart rate (ail effect) and/or muscle tremor ((32 effect). The compounds of the present invention show 2o high selectivity for (33 adrenergic receptors.
Bloom, et al., U.S. Patent 5,061,727, disclose substituted 5-(2-((2-aryl-2-hydroxyethyi)amino)propyl)-1,3-benzodioxoles of general formula (I) ~RS
R~ ~ ~ R2 R3 ~// ~ s R
R
wherein R1 and R4 may be one or more groups which may be the same or different and are selected from the group consisting of hydrogen) C1 to C4 alkyl, C1 to C4 alkoxy, hydroxy, halogen, trifluoromethyl, carboxy, hydroxyalkyl, alkoxycarbonyl, C 1 to C4 thioalkyl, sulfonyl and sulfinyl; X is a divalent radical consisting of OR' R' 0-Y
i ~N~ or ~N..
wherein R' is selected from the group consisting of hydrogen, C 1 to C4 alkyl and C 1 to C4 aryl and Y is selected from the group consisting of carbonyl and thiocarbonyl;
R2 and R3 SUBSTITUTE SHEET (RULE 26) may be the same or different and are selected from the group consisting of hydrogen and C1 to C4 alkyl; RS and R6 are selected from the group consisting of hydrogen, carboxy, allcoxycarbonyl, hydroxymethyl, -CH20CH2COOR7 and -CH20CH2CH20R7, where R7 is hydrogen or C 1 to C4 alkyl; with the provision that RS and R6 may not both be hydrogen;
s which have antihyperglycemic and antiobesity activity.
The synthesis, antidiabetic effects, and antiobesity effects of (R,,R)-5-[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]-1,3-benzodioxole-2,2-dicarboxylate, disclosed by Bloom, et al. in U.S. Patent 5,061,727, are detailed in Bloom, et al. J. Med.
Chem:, 1992, 35, 3081, Largis, et al. Drug Dev. Res., 1994 ) 32, 69, and Bloom, et al.
to Drugs of the Future,1994, l9, 23.
The compounds of the present invention contain a 1,4-benzodioxane ring) whereas the compounds in Bloom, et al., U.S. Patent 5,061,727 contain a 1,3-benzodioxole. They retain high selectivity for the (33 receptor and show much higher antiobesity and antihyperglycemic activity in animal models. Therefore, the compounds of this invention 1 s are useful in treating diabetes, hyperglycemia, and obesity, exhibiting minimal side effects such as heart rate increase and/or muscle tremor in humans and animals) when formulated into pharmaceutical compositions. Health-conscious individuals today are making an effort to reduce body fat through exercise and low fat diet. An invention compound can help a human reduce body fat and through treatment of domestic edible animals such as cattle, 2o swine, sheep, goats, turkeys and chickens can provide leaner meats for human consumption.
2s This invention provides new compounds of formula (II):
i i ~ ~ O R7 O
U
II
wherein Rl and R6 are independently hydrogen, Cl to C6 alkyl, trifluoromethyl, cyano, 3o CI to C6 alkoxy, or halogen;
R2 is hydrogen or C1 to C6 trialkylsilyl; R3 is hydrogen or Cl to C6 allcoxycarbonyl; or R2 and R3 are joined to form the oxazolidinone ring SUBSTITUTE SHEET (RULE 26) O
O--' ~N~
R4 and RS are independently hydrogen or Ci to C6 allryl;
R7 and R8 are independently OR9 or NRl°R";
s R9 is hydrogen, Cl to C12 alkyl, C~ to C~2 cycloalkyl) C1 to C12 silyiallcyl, phenyl, naphthyl, phenyl Cl to C6 alkyl, C, to C6 alkoxy C1 to C6 alkyl, pyridyl, thiophenyl, furanyl, imidazolyl, oxazolyl, -CHR'zCOOR'3, _ CHR'iC(O)R'3, -CIaR'2CONR'°R", -CHR'20COOR'3, or -CHR'20C(O)R'3;
to R'° and R" are independently hydrogen, Cl to C12 alkyl, phenyl, naphthyl) phenyl-Cl to C6 alkyl, furanylalkyl, or alkoxycarbonylalkyl;
R'2 and R'3 are independently hydrogen, Cl to C~2 alkyl, phenyl) naphthyl, or phenyl-Cl to C6 alkyl; and the pharmaceutically acceptable salts thereof, the salts thereof;
1 s the enantiomers thereof, the racemic mixtures thereof, and the diastereomeric mixtures thereof.
R' is preferably a halogen, more preferably chlorine and is preferably located at the meta-position of the benzene ring. R2 and R3 are each independently preferably hydrogen 20 or are joined to form the oxazolidinone ring. R4 and RS are each independently preferably hydrogen or C, to C6 alkyl; more preferably hydrogen or methyl. In particularly preferred embodiments one of R4 and RS is hydrogen and the other is methyl. R6 is preferably hydrogen. R9 is preferably hydrogen) C, to C,2 alkyl, C, to C12 cycloalkyl, phenyl) phenyl C~ to C6 alkyl or C~ to C6 alkoxy Cl to C6 alkyl; more preferably hydrogen, methyl, ethyl) 2s isopropyl, isobutyl) octyl, cyclopropyl, cyclohexyl, benzyl or 2-ethyloxyethyl.
When used herein, as a definition or part of a definition, the term alkyl includes both straight and branched chain alkyl groups, e.g. methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, s-butyl) pentyl and hexyl. When used herein, as a definition or part of a definition, the term halogen includes chlorine, bromine, fluorine and iodine.
When used 3o herein, as a definition or part of a definition, the term cycloalkyl includes cyclopropyl, cyclobutyl, cycopentyi and cycolohexyl.
Acid addition salts on an invention compound where a basic nutrogen is present can be prepared using a pharmaceutically acceptable inorganic or organic acid such as, but not SUBSTITUTE SHEET (RULE 26) a limited to, hydrochloric, hydrobromic, sulfuric, phosphoric, acetic) fumaric, malefic) succinic, benzoic, methanesulfonic or toluenesulfonic acid. Base addition salts can be prepared where the invention compound has a carboxylic acid group from an alkali metal oxide or hyrdoxide or alkaline earth metal oxide or hydroxide such as NaOH, KOH, s Ca(OH)2.
The (33 selective compounds of this invention are useful for the treatment of non-insulin dependent diabetes mellitus, hyperglycemia and obesity in mammais. ~3 adrenergic receptors can be divided into (31, ~i2) and X33 subtypes. Activation of (31 receptors invokes increase in heart rate while activation of [32 receptors stimulates glycogen breakdown in i o muscle and therefore prevents glycogen synthesis. Activation of (33 receptors stimulates Iipolysis or the breakdown of brown adipose tissue triglycerides to glycerol and free fatty acids) and therby promotes the loss of fat mass. Compounds that stimulate ~i3 receptors will have anti-obesity activity. Brown adipose tissue may also play a role in glucose homeostasis and ~i3 adrenergic agonist may therefore also have hypoglycemic or anti-15 diabetic activity.
In addition to the [33 stimulating compounds, this invention provides for a method of treating obesity, hyperglycemia, and diabetes in mammals as well as a pharmaceutical composition. In addition to treating obesity in humans for health benefit, the invention compounds may offer further health benefit in humans by use in reducing fat in meat of 2o animals raised for human consumption such as cattle, poultry, swine, sheep and goats.
Detailed Description of the Invention The compounds of the present invention may be prepared according to one of the general processes outlined below.
2s As outlined in Scheme I, a catechol 1 is treated with a base and a dibromosuccinate ester 2 to afford an oxazolidinone 3, which is hydrolyzed to yield a 1,4-benzodioxane dicarboxylic acid 4) wherein R1, R4, R5, and R6, are as defined above. Syntheses of the starting catechol 1 is described in U. S. patent 5,061,727 and U. S. patent 5,420,291.
SUBSTITUTE SHEET (RULE 26) N ~ OH B~ OEt R~ ' ~ R5 ~~ / + B~ OEt R OH O
base R2.Rs O
i N ~ O OEt R ~ / R4 RS I~ / O Et Rs hydrolysis N ~ O
R~ ~ , 4 R5~~ / 'OH
R O
a o As outlined in Scheme II below, a disodium carboxylate 4 is converted to a disilver carboxylate and treated with an iodo derivative 5 to yield the diester compounds 6 wherein s R1, R4, R5, R6, R12, and R13 are as defined above.
SUBSTITUTE SHEET (RULE 26) a i i Scheme II
N ~ O ONa > > A~N03 R~ ~ / a Rs ~ / Na Rs O O 2) R12 OII
4 Na salt I~O~R~3 R2 R3 O R12 O'I
N ~ O O~O~R13 R ~ / ~ R5 I/ / O O R13 s O
g R O R2 O
Scheme III below illustrates an alternative procedure for diester preparation wherein s a dicarboxylic acid 4 is treated with an alcohol R90H and an acid catalyst to yield the diester compounds 7 wherein R1, Ra, R5, R6, and R9 are as defined above.
Scheme III
R~ , ~ N ~ O ONa RsOH~ H+
' / Ra R5 ~ / O ONa Rs O
N . ~ O s , ~OR
R ~ / Ra R5 s~ / ~ OR9 R O
This invention relates to novel substituted 1,4-benzodioxane compounds which have antidiabetic, antihyperglycemic, and antiobesity properties. The present invention also s relates to pham~aceutical compositions comprising these compounds) methods for the preparation of these compounds) and methods for the use of these compounds in treating diabetes and/or hyperglycemia and/or obesity in mammals. The antiobesity compounds may find further use in reducing the fat content in domestic edible animals.
to BACKGROUND OF THE INVEN'j'ION
It is well known that medicinal agents are employed in the treatment of persons suffering from diabetes, hyperglycemia, and obesity. The compounds of the present invention achieve their antidiabetic, antihyperglycemic, and antiobesity effects by acting as is selective agonists at (33 adrenergic receptors. The stimulation of these receptors on white and brown adipocytes promotes both lipolysis (breakdown of fat) and energy expenditure.
Selective stimulation of ~i3 adrenergic receptors is important for chronic treatment.
Stimulation of other (3-receptors could cause side effects such as increased heart rate (ail effect) and/or muscle tremor ((32 effect). The compounds of the present invention show 2o high selectivity for (33 adrenergic receptors.
Bloom, et al., U.S. Patent 5,061,727, disclose substituted 5-(2-((2-aryl-2-hydroxyethyi)amino)propyl)-1,3-benzodioxoles of general formula (I) ~RS
R~ ~ ~ R2 R3 ~// ~ s R
R
wherein R1 and R4 may be one or more groups which may be the same or different and are selected from the group consisting of hydrogen) C1 to C4 alkyl, C1 to C4 alkoxy, hydroxy, halogen, trifluoromethyl, carboxy, hydroxyalkyl, alkoxycarbonyl, C 1 to C4 thioalkyl, sulfonyl and sulfinyl; X is a divalent radical consisting of OR' R' 0-Y
i ~N~ or ~N..
wherein R' is selected from the group consisting of hydrogen, C 1 to C4 alkyl and C 1 to C4 aryl and Y is selected from the group consisting of carbonyl and thiocarbonyl;
R2 and R3 SUBSTITUTE SHEET (RULE 26) may be the same or different and are selected from the group consisting of hydrogen and C1 to C4 alkyl; RS and R6 are selected from the group consisting of hydrogen, carboxy, allcoxycarbonyl, hydroxymethyl, -CH20CH2COOR7 and -CH20CH2CH20R7, where R7 is hydrogen or C 1 to C4 alkyl; with the provision that RS and R6 may not both be hydrogen;
s which have antihyperglycemic and antiobesity activity.
The synthesis, antidiabetic effects, and antiobesity effects of (R,,R)-5-[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]-1,3-benzodioxole-2,2-dicarboxylate, disclosed by Bloom, et al. in U.S. Patent 5,061,727, are detailed in Bloom, et al. J. Med.
Chem:, 1992, 35, 3081, Largis, et al. Drug Dev. Res., 1994 ) 32, 69, and Bloom, et al.
to Drugs of the Future,1994, l9, 23.
The compounds of the present invention contain a 1,4-benzodioxane ring) whereas the compounds in Bloom, et al., U.S. Patent 5,061,727 contain a 1,3-benzodioxole. They retain high selectivity for the (33 receptor and show much higher antiobesity and antihyperglycemic activity in animal models. Therefore, the compounds of this invention 1 s are useful in treating diabetes, hyperglycemia, and obesity, exhibiting minimal side effects such as heart rate increase and/or muscle tremor in humans and animals) when formulated into pharmaceutical compositions. Health-conscious individuals today are making an effort to reduce body fat through exercise and low fat diet. An invention compound can help a human reduce body fat and through treatment of domestic edible animals such as cattle, 2o swine, sheep, goats, turkeys and chickens can provide leaner meats for human consumption.
2s This invention provides new compounds of formula (II):
i i ~ ~ O R7 O
U
II
wherein Rl and R6 are independently hydrogen, Cl to C6 alkyl, trifluoromethyl, cyano, 3o CI to C6 alkoxy, or halogen;
R2 is hydrogen or C1 to C6 trialkylsilyl; R3 is hydrogen or Cl to C6 allcoxycarbonyl; or R2 and R3 are joined to form the oxazolidinone ring SUBSTITUTE SHEET (RULE 26) O
O--' ~N~
R4 and RS are independently hydrogen or Ci to C6 allryl;
R7 and R8 are independently OR9 or NRl°R";
s R9 is hydrogen, Cl to C12 alkyl, C~ to C~2 cycloalkyl) C1 to C12 silyiallcyl, phenyl, naphthyl, phenyl Cl to C6 alkyl, C, to C6 alkoxy C1 to C6 alkyl, pyridyl, thiophenyl, furanyl, imidazolyl, oxazolyl, -CHR'zCOOR'3, _ CHR'iC(O)R'3, -CIaR'2CONR'°R", -CHR'20COOR'3, or -CHR'20C(O)R'3;
to R'° and R" are independently hydrogen, Cl to C12 alkyl, phenyl, naphthyl) phenyl-Cl to C6 alkyl, furanylalkyl, or alkoxycarbonylalkyl;
R'2 and R'3 are independently hydrogen, Cl to C~2 alkyl, phenyl) naphthyl, or phenyl-Cl to C6 alkyl; and the pharmaceutically acceptable salts thereof, the salts thereof;
1 s the enantiomers thereof, the racemic mixtures thereof, and the diastereomeric mixtures thereof.
R' is preferably a halogen, more preferably chlorine and is preferably located at the meta-position of the benzene ring. R2 and R3 are each independently preferably hydrogen 20 or are joined to form the oxazolidinone ring. R4 and RS are each independently preferably hydrogen or C, to C6 alkyl; more preferably hydrogen or methyl. In particularly preferred embodiments one of R4 and RS is hydrogen and the other is methyl. R6 is preferably hydrogen. R9 is preferably hydrogen) C, to C,2 alkyl, C, to C12 cycloalkyl, phenyl) phenyl C~ to C6 alkyl or C~ to C6 alkoxy Cl to C6 alkyl; more preferably hydrogen, methyl, ethyl) 2s isopropyl, isobutyl) octyl, cyclopropyl, cyclohexyl, benzyl or 2-ethyloxyethyl.
When used herein, as a definition or part of a definition, the term alkyl includes both straight and branched chain alkyl groups, e.g. methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, s-butyl) pentyl and hexyl. When used herein, as a definition or part of a definition, the term halogen includes chlorine, bromine, fluorine and iodine.
When used 3o herein, as a definition or part of a definition, the term cycloalkyl includes cyclopropyl, cyclobutyl, cycopentyi and cycolohexyl.
Acid addition salts on an invention compound where a basic nutrogen is present can be prepared using a pharmaceutically acceptable inorganic or organic acid such as, but not SUBSTITUTE SHEET (RULE 26) a limited to, hydrochloric, hydrobromic, sulfuric, phosphoric, acetic) fumaric, malefic) succinic, benzoic, methanesulfonic or toluenesulfonic acid. Base addition salts can be prepared where the invention compound has a carboxylic acid group from an alkali metal oxide or hyrdoxide or alkaline earth metal oxide or hydroxide such as NaOH, KOH, s Ca(OH)2.
The (33 selective compounds of this invention are useful for the treatment of non-insulin dependent diabetes mellitus, hyperglycemia and obesity in mammais. ~3 adrenergic receptors can be divided into (31, ~i2) and X33 subtypes. Activation of (31 receptors invokes increase in heart rate while activation of [32 receptors stimulates glycogen breakdown in i o muscle and therefore prevents glycogen synthesis. Activation of (33 receptors stimulates Iipolysis or the breakdown of brown adipose tissue triglycerides to glycerol and free fatty acids) and therby promotes the loss of fat mass. Compounds that stimulate ~i3 receptors will have anti-obesity activity. Brown adipose tissue may also play a role in glucose homeostasis and ~i3 adrenergic agonist may therefore also have hypoglycemic or anti-15 diabetic activity.
In addition to the [33 stimulating compounds, this invention provides for a method of treating obesity, hyperglycemia, and diabetes in mammals as well as a pharmaceutical composition. In addition to treating obesity in humans for health benefit, the invention compounds may offer further health benefit in humans by use in reducing fat in meat of 2o animals raised for human consumption such as cattle, poultry, swine, sheep and goats.
Detailed Description of the Invention The compounds of the present invention may be prepared according to one of the general processes outlined below.
2s As outlined in Scheme I, a catechol 1 is treated with a base and a dibromosuccinate ester 2 to afford an oxazolidinone 3, which is hydrolyzed to yield a 1,4-benzodioxane dicarboxylic acid 4) wherein R1, R4, R5, and R6, are as defined above. Syntheses of the starting catechol 1 is described in U. S. patent 5,061,727 and U. S. patent 5,420,291.
SUBSTITUTE SHEET (RULE 26) N ~ OH B~ OEt R~ ' ~ R5 ~~ / + B~ OEt R OH O
base R2.Rs O
i N ~ O OEt R ~ / R4 RS I~ / O Et Rs hydrolysis N ~ O
R~ ~ , 4 R5~~ / 'OH
R O
a o As outlined in Scheme II below, a disodium carboxylate 4 is converted to a disilver carboxylate and treated with an iodo derivative 5 to yield the diester compounds 6 wherein s R1, R4, R5, R6, R12, and R13 are as defined above.
SUBSTITUTE SHEET (RULE 26) a i i Scheme II
N ~ O ONa > > A~N03 R~ ~ / a Rs ~ / Na Rs O O 2) R12 OII
4 Na salt I~O~R~3 R2 R3 O R12 O'I
N ~ O O~O~R13 R ~ / ~ R5 I/ / O O R13 s O
g R O R2 O
Scheme III below illustrates an alternative procedure for diester preparation wherein s a dicarboxylic acid 4 is treated with an alcohol R90H and an acid catalyst to yield the diester compounds 7 wherein R1, Ra, R5, R6, and R9 are as defined above.
Scheme III
R~ , ~ N ~ O ONa RsOH~ H+
' / Ra R5 ~ / O ONa Rs O
N . ~ O s , ~OR
R ~ / Ra R5 s~ / ~ OR9 R O
i o As outlined in Scheme IV below, the diester compounds 7 can be hydrolyzed under basic conditions to a monoester 8a and/or 8 b, wherein R 1, R4, R5, R6, and R9 are as defined above. One or both of the regioisomers 8a and 8b may be produced in the hydrolysis reaction.
SUBSTITUTE SHEET (RULE 26) Scheme IV
w N4 I "~ O ORs OH
R R5 ~ / O R9 Rs O
R~ ~ ~ N I ~ O OR9 R4 R5 ~ / O OH
Rs O
8a and/or R~ ~ ~ N '~ O OH
/ R4 R5 ~ / O OR9 Rs O
8b As illustrated in Scheme V which follows, a diester compound 7 is reacted with an amine HNR~°RI1 to yield the diamide compounds 9, wherein R', R4, R5, R6, R9, R'°, and Rll are as defined above.
Scheme V
R2 ~3 O
O OR9 HNRf°Rti R ' / R4 R5 s~ / O OR9 R O
R i ~ I ~ O NR~°R1~
R4 R5.s~/ O NR1°R»
R O
As illlustrated in Scheme VI which follows, a mono ester compound 8a or 8b may be suitably converted to a mono ester/mono acid halide derivative, e.g., the conversion to SUBSTITUTE SHEET (RULE 26) n i i the corresponding acid chloride may conveniently be achieved with oxalyl chloride in dimethylforn~amide and methylene chloride. The mono ester/mono acid halide derivative l0a or lOb may then be converted to the corresponding formula II mono ester/mono amide, e.g.) by reaction with an amine of the formula HNRI~Rn.
SUBSTITUTE SHEET (RULE 26) Scheme VI
8a (COC1)2/DMF/CH2C12 O
~OR9 R
~CI
l0a , p HNR1°R11/ THF/
N ~ O ORs R' ' ~ R4 R5 ~ ~ NRI~Rt~
R O
O
8b (COC1)2/DMF/CH2C12 R3 0 °C/ RT O
\ N ~ O
.- 'cl R i R4 R5 / s / lOb R6 / O OR
yoRy ~/ O
OR2 i 3 O
N \ O NR~~Ro t R ~ / R4 R5 ~/ / ORs Rs O
O
SUBSTITUTE SHEET (RULE 26) n i i The following specific examples are included for illustration of the preparative procedures and are not to be construed as limiting to this disclosure in any way. The reagents and intermediates are either commercially available or readily prepared according to standard literature procedures by those skilled in the art of organic synthesis. Those skilled s in the art may be aware of still other procedures for preparing compounds of this invention.
Example 1 6-{(2R)-2-[(5R)-5-(3-Chloro-phenyl)-2-oxo-oxazolidin-3-yl]-propyl}-2, 3 -dihydro-benzo[1,4] dioxane-2,3-dicarboxylic acid dimethyl ester A mixture of (R,R)-(~)-5-(3-chlorophenyl)-3-(2-(3,4-dihydroxyphenyl)-1 1 o methylethyl)-2-oxazoldinone (3.47 g, 10 mmol), meso I,2-dibromo dimethyl succinate (3,06 g, 10 mmol) and anhydrous K2C03 was refluxed in acetone for six hours.
The reaction mixture was then filtered and the residue was washed with acetone.
The combined acetone filtrate was concentrated and the crude product obtained was purified by silica-gel column chromatography by eluting it with 3:1 hexane: ethylacetate. Pale yellow liquid.
is Yield 2.8 g (57%) M+H.
Example 2 6-{2-5-(3-Chloro-phenyl)-2-oxo-oxazolidin-3-yl]-propyl}-2,3-dihydro-benzo[1,4]dioxane-2,3-dicarboxylic acid 3-methyl ester 2o To a stirred ethanolic solution of 6-((2R)-2-[(SR)-5-(3-chloro-phenyl)-2-oxo-oxazolidin-3-yl]-propyl } -2, 3-dihydro-benzo[ 1,4] dioxane-2,3-dicarboxylic acid dimethyl ester, (2.4 g, 5 mmol) sodium hydroxide ( 1.0 g, 25 mmol) was added. The reaction mixture was stirred for 8 hrs at room temperature. The reaction mixture was then concentrated and dissolved in water ( 100 ml). Concentrated hydrochloric acid was added 2s and the separated compound was extracted with chloroform; washed well with water, dried over anhydrous magnesium sulfate; filtered and concentrated. The product was purified by silica-gel column chromatography by eluting it with chloroform.
Yield: 2.0 g solid; mp 198°C; M+H 476.
so Example 3 (2,3-cis)-6-{(2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-2,3-dihydro-benzo[1,4]dioxane-2,3-dicarboxylic acid 6-{ (2R)-2-[(SR)-5-(3-Chloro-phenyl)-2-oxo-oxazolidin-3-yl]-propyl } -2, 3 dihydro-benzo[1,4] dioxane-2,3-dicarboxylic acid dimethyl ester, (2.4 g, 5 mmol) and 3 s sodium hydroxide ( 1.0 g, 25 mmol) were refluxed in ethanol: water (9: I , 50 ml) for seventy-two hours. The reaction mixture was concentrated and the residue was dissolved in water (50 ml). It was neutralized with 1 N HCl and the separated solid was filtered;
SUBSTITUTE SHEET (RULE 26) washed well with water and air dried. It was found to be pure enough for further transformations.
Yield: 2.0 g; mp 220°C; M'~H 436.
s Example 4 (2,3-cis)-6-{(2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl-2,3-dihydro-benzo[1,4] dioxane-2,3-dicarboxylic acid diisopropyl ester to Example 5 (2,3-cis)-6-{ (2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-2,3-dihydro-benzo[1,4]dioxane-2,3-dicarboxylic acid 3-isopropyl ester Hydrogen chloride gas was passed through isopropanol ( 100 ml) at 0°C
for fifteen is minutes and the (2,3-cis)-6-{(2R)-2-[(2R)-2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl } 2,3-dihydro-benzo[ 1,4] dioxane-2,3-dicarboxylic acid (2.15 g) 5 mmol) was added. The reaction mixture was refluxed for twenty-four hours and it was concentrated.
The residue obtained was neutralized with sodium bicarbonate solution and extracted with chloroform. It was dried over anhydrous sodium sulfate; filtered and concentrated. The 2o product obtained was purified by silica-gel column chromatography by eluting it initially with chloroform and then with chloroform:methanol (9:1). The diester eluted out first and was followed by the monoester.
(2,3-cis)-6-{ (2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl-2,3-2s dihydro-benzo[1,4] dioxane-2,3-dicarboxylic acid diisopropyl ester.
Amorphous; Yield 850 mg( 32%); M+H 520.
(2,3-cis)-6- ( (2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyi }-2, 3-dihydro-benzo[1,4]dioxane-2,3-dicarboxylic acid-3-isopropyl ester.
3o Amorphous; Yield 700 mg (29%) M'~H 478.
SUBSTITUTE SHEET (RULE 26) a i i i WO 98/29405 PCT/US9?/24019 General Procedure to Prepare (2,3-cis)-6-{(2R)-2-[(2R)-2-(3-Chloro-phenyt)-2-hydroxy-ethylamino]-propyl}-2, 3-dihydro-benzo[1,4]dioxane-2,3-dicarboxylic acid alkyl and cycioalkyl esters.
s Hydrogen chloride gas was passed through the appropriate alcohol (100 ml) at 0°C
for fifteen minutes and the (2,3-cis)-6- { (2R)-2-[(2R)-2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl } 2,3-dihydro-benzo[ 1,4] dioxane-2,3-dicarboxylic acid (2.15 g, 5 mmol) was added. The reaction mixture was heated to 100°C for forty-eight hours. At the end, excess alcohol was removed under reduced pressure and the residue was neutralized 1 o with sodium bicarbonate solution. The product obtained was extracted with chloroform;
washed well with water, dried over anhydrous magnesium sulfate; filtered and concentrated. The products were purified by silica-gel column chromatography.
Initially the column was eluted with chloroform and later with 9:1 chlorofornl:methanol.
1 s Example 6 (2,3-cis-)-6-{(2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-2,3-dihydro-benzo[1,4]dioxane-2,3-dicarboxylic acid dibutyl ester The tide compound was prepared from (2,3-cis)-6-{(2R)-2-((2R)-2-(3-chloro phenyl)-2-hydroxy-ethylamino]-propyl } 2,3-dihydro-benzo( 1,4] dioxane-2,3-dicarboxylic 2o acid (2.15 g, 5 mmol) and n-butanol according to the General Procedure above to yield a brown oil: 1.1 g (40%); M~'H 548.
Example 7 (2,3-cis)-6-{(2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-2s propyl}-2, 3-dihydro-benzo[1,4]dioxane-2,3-dicarboxylic acid bis-(2-ethoxy-ethyl) ester The title compound was prepared from (2,3-cis)-6- { (2R)-2-[(2R)-2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl ) 2,3-dihydro-benzo[ 1,4] dioxane-2,3-dicarboxylic 3o acid (2.15 g, 5 mmol) and 2-ethoxyethanol. Two diastereomers were obtained as amorphous solids: diastereomer 1: Yield 800 mg (33%) M+H 480.
diasteromer 2: Yield 600 mg (25%) M+H 480.
SUBSTITUTE SHEET (RULE 26) Example 8 (2,3-cis)-6-{(2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-2,3-dihydro-benzo[1,4]dioxane-2,3-dicarboxylic acid diethyl ester The title compound was prepared from (2,3-cis)-6-{(2R)-2-[(2R)-2-(3-chloro s phenyl)-2-hydroxy-ethylamino]-propyl } 2,3-dihydro-benzo[ 1,4] dioxane-2,3-dicarboxylic acid (2.15 g, 5 mmol) and ethanol according to the General Procedure above to yield a brown oil: 600 mg (24%); M+H 492.
Example 9 to (2,3-cis)-6-{(2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-2,3-dihydro-benzo[1,4]dioxane-2,3-dicarboxylic acid dicyclohexyl ester The title compound was prepared from (2,3-cis)-6-{ (2R)-2-[(2R)-2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl ) 2,3-dihydro-benzo[ 1,4] dioxane-2,3-dicarboxylic i s acid (2.15 g, 5 mmol) and cyclohexanol according to the General Procedure above to yield a brown foam: 750 mg (40%); M+H 600.
Example 10 (2,3-cis)-6-{ (2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-2o propyl}-2,3-dihydro-benzo[1,4]dioxane-2,3-dicarboxylic acid dicyclopentyl ester The title compound was prepared from from (2,3-cis)-6-( (2R)-2-[(2R)-2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl ) 2,3-dihydro-benzo[ 1,4] dioxane-2,3-dicarboxylic acid (2.15 g, 5 mmol) and cyclopentanol according to the General Procedure above to yield 2s an amorphous solid: 1.4g (49%); M+ H 572.
Example 11 (2,3-cis)-6-{(2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-2,3-dihydro-benzo[1,4]dioxane-2,3-dicarboxylic acid dioctyl ester so The title compound was prepared from from (2,3-cis)-6-( (2R)-2-[(2R)-2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl ) 2,3-dihydro-benzo[ 1,4] dioxane-2,3-dicarboxylic acid (2.15 g, 5 mmol) and 1-octanol according to the General Procedure above to yield a brown foam: 1.3 g (39%); M+H 660.
SUBSTITUTE SHEET (RULE 26) n i i Example 12 (2,3-cis)-6-{ (2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyi}-2,3-dihydro-benzo[1,4]dioxane-2,3-dicarboxylic acid dibenzyl ester s The title compound was prepared from from (2,3-cis)-6-{ (2R)-2-[(2R)-2-(3-chloro-phenyi)-2-hydroxy-ethylamino]-propyl } 2,3-dihydro-benzo[ 1,4] dioxane-2,3-dicarboxylic acid (2:15 g) 5 mmol) and benzyl alcohol according to the General Procedure above to yield a brown oil: 1.0 g(32%); M+H 616.
to Human Beta Adrenergic Receptor Selectivity The activity of the test compounds on human (3-adrenergic receptors was determined with Chinese hamster ovary (CHO) cells transfected with human X33, ~i2, or ~1 adrenergic receptors. The preparation of these cells has been described in Emorine, L.J.) Marullo, S., Briend-Sutren, M.) Patey, G., Tate, K., Delavier-Klutchko, C., Strosberg, 1 s A.D. Molecular Characterization of the Human Beta 3-Adrenergic Receptor Science 1989, 245(8), 1118-1121 and in Muzzin, P., Revelli, J.-P., Kuhne, F., Gocayne, J.D., McCombie, W.R., Venter, J.C., Giacobino, J.-P., Fraser, C.M. An Adipose Tissue-Specific Beta 3-Adrenergic Receptor. Molecular Cloning and Down-Regulation in Obesity J. Biol. Chem. 1991, 226, 24053-24058. Agonist activity is indicated by increased cAMP
20 levels in the CHO cells. Selectivity of the test compounds for the j33 receptor was assessed by comparison with results in {i2 and (31 adrenergic receptor transfected cells.
Procedure:
2s 1 ). Chinese hamster ovary (CHO) cells transfected with human (33, (32, or (31 adrenergic receptors were used in the assay.
2). Cells were grown to confluent conditions in 24 well plates.
3). Drugs were dissolved in DMSO at a concentration of 10 ~tM.
4). Cells were incubated with drug at 10 nM concentration for 10 min at 37~ C
.
3o Isoproterenol (Standard 1) was used as the standard compound and assayed at 10 ~M
which gives a maximal cAMP elevation in all 3 cell types.
5). Cell cAMP concentrations were assayed using a scintillation proximity assay from Amersham Corp (Chicago, IL).
6). Activities for the test compounds are expressed as a percentage of the isoproterenol 3s response.
SUBSTITUTE SHEET (RULE 26) __ . __ _.___ _ __ Effects on Free Fatty Acid Levels in Rats Rats respond to a single oral dose of (33 agonist by increasing plasma free fatty acids (FFA) in response to (33 receptor stimulation on the plasma membrane of the fat cell.
5-{ 2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl }-benzo[ 1,3]dioxole-2,2-s dicarboxylic acid diisopropyl ester (Standard 2) was used as a standard compound. All test compounds were dosed at 0.1 mg/kg and compared to the response by Standard 2.
10 1 ). Drugs were dissolved in DMSO at 10 mg/mL.
2). Twenty N.1 of the DMSO-drug solution was added to 10 mL methyl cellulose:Tween-80 (0.5%:0.1%) for a final concentration of 20 ltg/mL.
3). Methyl celluloseaween-80 drug suspension was given via gavage (1 mL/200g body weight; or 0.1 mg/kg) to rats and blood was collected 50 min later.
is 4). Plasma was analyzed for free fatty acids using a kit supplied by Biochemical Diagnostics Inc. (Brentwood, N.Y.).
5). Drug response was calculated from the formula below.
% FFA Response= ~A ~compoun~ - FFA veh;~iP x 100 FFA (Standard 2) - FFA vehicle Effects on Hyperglycemia in Mice On the morning of Day 1 (baseline), 35 mice (male, db/db (C57BL/KsJ), Jackson 2s Laboratories) 2 to 7 months of age and 35 to b0 g) were fasted for 4 h) weighed, and a baseline blood sample was collected from the tail-tip of each mouse without anesthesia, placed directly into a fluoride-containing tube, mixed, and maintained on ice.
Food was then returned to the mice. The plasma was seperated and the levels of glucose in the plasma were dertermined by an Abbot VP Analyzer. Because of the variable plasma glucose levels of the db/db mice, the 5 mice having the most extreme (i.e., highest or lowest) plasma glucose levels were excluded and the remaining 30 mice were randomly assigned into 7 groups of equivalent mean plasma glucose level (vehicle control, ciglitazone (Standard 3), and 5 test compound groups). On the afternoon of Days 1) 2, and 3 the vehicle (0.2 mL of 2% Tween 80/saline w/v) or test compounds were administered (p.o.) to the ad libitum fed s s mice. On the morning of Day 4, the food was removed from the cages for 3 h, a blood sample was collected, and the mice were then given the fourth administration of test compound or vehicle. Additional blood samples were collected at 2 and 4 h after test SUBSTITUTE SHEET (RULE 26) n i i i t6 compound administration. Plasma glucose levels were determined. To assess test compound activity, the percent change of an animal's plasma glucose level on Day 4 (mean of 2 and 4 h values) from its level before test compound administration (Day 1 baseline sample) was determined as follows:
s Mean of 2 and 4 h samples lDay 47 x 100 Baseline sample (Day 1) A 50-60% reduction of plasma glucose levels in the hyperglycemic db/db mice represents a 1 o normalization of glucose levels.
Table I
Compound ~2a (~3a Rat Free Fatty (Exam le) Acidb 4 9% 4% 32%
11 % 50% 6%
6 16% 51% 0%
7 33% 40% 7%
8 19%
SUBSTITUTE SHEET (RULE 26) Scheme IV
w N4 I "~ O ORs OH
R R5 ~ / O R9 Rs O
R~ ~ ~ N I ~ O OR9 R4 R5 ~ / O OH
Rs O
8a and/or R~ ~ ~ N '~ O OH
/ R4 R5 ~ / O OR9 Rs O
8b As illustrated in Scheme V which follows, a diester compound 7 is reacted with an amine HNR~°RI1 to yield the diamide compounds 9, wherein R', R4, R5, R6, R9, R'°, and Rll are as defined above.
Scheme V
R2 ~3 O
O OR9 HNRf°Rti R ' / R4 R5 s~ / O OR9 R O
R i ~ I ~ O NR~°R1~
R4 R5.s~/ O NR1°R»
R O
As illlustrated in Scheme VI which follows, a mono ester compound 8a or 8b may be suitably converted to a mono ester/mono acid halide derivative, e.g., the conversion to SUBSTITUTE SHEET (RULE 26) n i i the corresponding acid chloride may conveniently be achieved with oxalyl chloride in dimethylforn~amide and methylene chloride. The mono ester/mono acid halide derivative l0a or lOb may then be converted to the corresponding formula II mono ester/mono amide, e.g.) by reaction with an amine of the formula HNRI~Rn.
SUBSTITUTE SHEET (RULE 26) Scheme VI
8a (COC1)2/DMF/CH2C12 O
~OR9 R
~CI
l0a , p HNR1°R11/ THF/
N ~ O ORs R' ' ~ R4 R5 ~ ~ NRI~Rt~
R O
O
8b (COC1)2/DMF/CH2C12 R3 0 °C/ RT O
\ N ~ O
.- 'cl R i R4 R5 / s / lOb R6 / O OR
yoRy ~/ O
OR2 i 3 O
N \ O NR~~Ro t R ~ / R4 R5 ~/ / ORs Rs O
O
SUBSTITUTE SHEET (RULE 26) n i i The following specific examples are included for illustration of the preparative procedures and are not to be construed as limiting to this disclosure in any way. The reagents and intermediates are either commercially available or readily prepared according to standard literature procedures by those skilled in the art of organic synthesis. Those skilled s in the art may be aware of still other procedures for preparing compounds of this invention.
Example 1 6-{(2R)-2-[(5R)-5-(3-Chloro-phenyl)-2-oxo-oxazolidin-3-yl]-propyl}-2, 3 -dihydro-benzo[1,4] dioxane-2,3-dicarboxylic acid dimethyl ester A mixture of (R,R)-(~)-5-(3-chlorophenyl)-3-(2-(3,4-dihydroxyphenyl)-1 1 o methylethyl)-2-oxazoldinone (3.47 g, 10 mmol), meso I,2-dibromo dimethyl succinate (3,06 g, 10 mmol) and anhydrous K2C03 was refluxed in acetone for six hours.
The reaction mixture was then filtered and the residue was washed with acetone.
The combined acetone filtrate was concentrated and the crude product obtained was purified by silica-gel column chromatography by eluting it with 3:1 hexane: ethylacetate. Pale yellow liquid.
is Yield 2.8 g (57%) M+H.
Example 2 6-{2-5-(3-Chloro-phenyl)-2-oxo-oxazolidin-3-yl]-propyl}-2,3-dihydro-benzo[1,4]dioxane-2,3-dicarboxylic acid 3-methyl ester 2o To a stirred ethanolic solution of 6-((2R)-2-[(SR)-5-(3-chloro-phenyl)-2-oxo-oxazolidin-3-yl]-propyl } -2, 3-dihydro-benzo[ 1,4] dioxane-2,3-dicarboxylic acid dimethyl ester, (2.4 g, 5 mmol) sodium hydroxide ( 1.0 g, 25 mmol) was added. The reaction mixture was stirred for 8 hrs at room temperature. The reaction mixture was then concentrated and dissolved in water ( 100 ml). Concentrated hydrochloric acid was added 2s and the separated compound was extracted with chloroform; washed well with water, dried over anhydrous magnesium sulfate; filtered and concentrated. The product was purified by silica-gel column chromatography by eluting it with chloroform.
Yield: 2.0 g solid; mp 198°C; M+H 476.
so Example 3 (2,3-cis)-6-{(2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-2,3-dihydro-benzo[1,4]dioxane-2,3-dicarboxylic acid 6-{ (2R)-2-[(SR)-5-(3-Chloro-phenyl)-2-oxo-oxazolidin-3-yl]-propyl } -2, 3 dihydro-benzo[1,4] dioxane-2,3-dicarboxylic acid dimethyl ester, (2.4 g, 5 mmol) and 3 s sodium hydroxide ( 1.0 g, 25 mmol) were refluxed in ethanol: water (9: I , 50 ml) for seventy-two hours. The reaction mixture was concentrated and the residue was dissolved in water (50 ml). It was neutralized with 1 N HCl and the separated solid was filtered;
SUBSTITUTE SHEET (RULE 26) washed well with water and air dried. It was found to be pure enough for further transformations.
Yield: 2.0 g; mp 220°C; M'~H 436.
s Example 4 (2,3-cis)-6-{(2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl-2,3-dihydro-benzo[1,4] dioxane-2,3-dicarboxylic acid diisopropyl ester to Example 5 (2,3-cis)-6-{ (2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-2,3-dihydro-benzo[1,4]dioxane-2,3-dicarboxylic acid 3-isopropyl ester Hydrogen chloride gas was passed through isopropanol ( 100 ml) at 0°C
for fifteen is minutes and the (2,3-cis)-6-{(2R)-2-[(2R)-2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl } 2,3-dihydro-benzo[ 1,4] dioxane-2,3-dicarboxylic acid (2.15 g) 5 mmol) was added. The reaction mixture was refluxed for twenty-four hours and it was concentrated.
The residue obtained was neutralized with sodium bicarbonate solution and extracted with chloroform. It was dried over anhydrous sodium sulfate; filtered and concentrated. The 2o product obtained was purified by silica-gel column chromatography by eluting it initially with chloroform and then with chloroform:methanol (9:1). The diester eluted out first and was followed by the monoester.
(2,3-cis)-6-{ (2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl-2,3-2s dihydro-benzo[1,4] dioxane-2,3-dicarboxylic acid diisopropyl ester.
Amorphous; Yield 850 mg( 32%); M+H 520.
(2,3-cis)-6- ( (2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyi }-2, 3-dihydro-benzo[1,4]dioxane-2,3-dicarboxylic acid-3-isopropyl ester.
3o Amorphous; Yield 700 mg (29%) M'~H 478.
SUBSTITUTE SHEET (RULE 26) a i i i WO 98/29405 PCT/US9?/24019 General Procedure to Prepare (2,3-cis)-6-{(2R)-2-[(2R)-2-(3-Chloro-phenyt)-2-hydroxy-ethylamino]-propyl}-2, 3-dihydro-benzo[1,4]dioxane-2,3-dicarboxylic acid alkyl and cycioalkyl esters.
s Hydrogen chloride gas was passed through the appropriate alcohol (100 ml) at 0°C
for fifteen minutes and the (2,3-cis)-6- { (2R)-2-[(2R)-2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl } 2,3-dihydro-benzo[ 1,4] dioxane-2,3-dicarboxylic acid (2.15 g, 5 mmol) was added. The reaction mixture was heated to 100°C for forty-eight hours. At the end, excess alcohol was removed under reduced pressure and the residue was neutralized 1 o with sodium bicarbonate solution. The product obtained was extracted with chloroform;
washed well with water, dried over anhydrous magnesium sulfate; filtered and concentrated. The products were purified by silica-gel column chromatography.
Initially the column was eluted with chloroform and later with 9:1 chlorofornl:methanol.
1 s Example 6 (2,3-cis-)-6-{(2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-2,3-dihydro-benzo[1,4]dioxane-2,3-dicarboxylic acid dibutyl ester The tide compound was prepared from (2,3-cis)-6-{(2R)-2-((2R)-2-(3-chloro phenyl)-2-hydroxy-ethylamino]-propyl } 2,3-dihydro-benzo( 1,4] dioxane-2,3-dicarboxylic 2o acid (2.15 g, 5 mmol) and n-butanol according to the General Procedure above to yield a brown oil: 1.1 g (40%); M~'H 548.
Example 7 (2,3-cis)-6-{(2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-2s propyl}-2, 3-dihydro-benzo[1,4]dioxane-2,3-dicarboxylic acid bis-(2-ethoxy-ethyl) ester The title compound was prepared from (2,3-cis)-6- { (2R)-2-[(2R)-2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl ) 2,3-dihydro-benzo[ 1,4] dioxane-2,3-dicarboxylic 3o acid (2.15 g, 5 mmol) and 2-ethoxyethanol. Two diastereomers were obtained as amorphous solids: diastereomer 1: Yield 800 mg (33%) M+H 480.
diasteromer 2: Yield 600 mg (25%) M+H 480.
SUBSTITUTE SHEET (RULE 26) Example 8 (2,3-cis)-6-{(2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-2,3-dihydro-benzo[1,4]dioxane-2,3-dicarboxylic acid diethyl ester The title compound was prepared from (2,3-cis)-6-{(2R)-2-[(2R)-2-(3-chloro s phenyl)-2-hydroxy-ethylamino]-propyl } 2,3-dihydro-benzo[ 1,4] dioxane-2,3-dicarboxylic acid (2.15 g, 5 mmol) and ethanol according to the General Procedure above to yield a brown oil: 600 mg (24%); M+H 492.
Example 9 to (2,3-cis)-6-{(2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-2,3-dihydro-benzo[1,4]dioxane-2,3-dicarboxylic acid dicyclohexyl ester The title compound was prepared from (2,3-cis)-6-{ (2R)-2-[(2R)-2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl ) 2,3-dihydro-benzo[ 1,4] dioxane-2,3-dicarboxylic i s acid (2.15 g, 5 mmol) and cyclohexanol according to the General Procedure above to yield a brown foam: 750 mg (40%); M+H 600.
Example 10 (2,3-cis)-6-{ (2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-2o propyl}-2,3-dihydro-benzo[1,4]dioxane-2,3-dicarboxylic acid dicyclopentyl ester The title compound was prepared from from (2,3-cis)-6-( (2R)-2-[(2R)-2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl ) 2,3-dihydro-benzo[ 1,4] dioxane-2,3-dicarboxylic acid (2.15 g, 5 mmol) and cyclopentanol according to the General Procedure above to yield 2s an amorphous solid: 1.4g (49%); M+ H 572.
Example 11 (2,3-cis)-6-{(2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-2,3-dihydro-benzo[1,4]dioxane-2,3-dicarboxylic acid dioctyl ester so The title compound was prepared from from (2,3-cis)-6-( (2R)-2-[(2R)-2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl ) 2,3-dihydro-benzo[ 1,4] dioxane-2,3-dicarboxylic acid (2.15 g, 5 mmol) and 1-octanol according to the General Procedure above to yield a brown foam: 1.3 g (39%); M+H 660.
SUBSTITUTE SHEET (RULE 26) n i i Example 12 (2,3-cis)-6-{ (2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyi}-2,3-dihydro-benzo[1,4]dioxane-2,3-dicarboxylic acid dibenzyl ester s The title compound was prepared from from (2,3-cis)-6-{ (2R)-2-[(2R)-2-(3-chloro-phenyi)-2-hydroxy-ethylamino]-propyl } 2,3-dihydro-benzo[ 1,4] dioxane-2,3-dicarboxylic acid (2:15 g) 5 mmol) and benzyl alcohol according to the General Procedure above to yield a brown oil: 1.0 g(32%); M+H 616.
to Human Beta Adrenergic Receptor Selectivity The activity of the test compounds on human (3-adrenergic receptors was determined with Chinese hamster ovary (CHO) cells transfected with human X33, ~i2, or ~1 adrenergic receptors. The preparation of these cells has been described in Emorine, L.J.) Marullo, S., Briend-Sutren, M.) Patey, G., Tate, K., Delavier-Klutchko, C., Strosberg, 1 s A.D. Molecular Characterization of the Human Beta 3-Adrenergic Receptor Science 1989, 245(8), 1118-1121 and in Muzzin, P., Revelli, J.-P., Kuhne, F., Gocayne, J.D., McCombie, W.R., Venter, J.C., Giacobino, J.-P., Fraser, C.M. An Adipose Tissue-Specific Beta 3-Adrenergic Receptor. Molecular Cloning and Down-Regulation in Obesity J. Biol. Chem. 1991, 226, 24053-24058. Agonist activity is indicated by increased cAMP
20 levels in the CHO cells. Selectivity of the test compounds for the j33 receptor was assessed by comparison with results in {i2 and (31 adrenergic receptor transfected cells.
Procedure:
2s 1 ). Chinese hamster ovary (CHO) cells transfected with human (33, (32, or (31 adrenergic receptors were used in the assay.
2). Cells were grown to confluent conditions in 24 well plates.
3). Drugs were dissolved in DMSO at a concentration of 10 ~tM.
4). Cells were incubated with drug at 10 nM concentration for 10 min at 37~ C
.
3o Isoproterenol (Standard 1) was used as the standard compound and assayed at 10 ~M
which gives a maximal cAMP elevation in all 3 cell types.
5). Cell cAMP concentrations were assayed using a scintillation proximity assay from Amersham Corp (Chicago, IL).
6). Activities for the test compounds are expressed as a percentage of the isoproterenol 3s response.
SUBSTITUTE SHEET (RULE 26) __ . __ _.___ _ __ Effects on Free Fatty Acid Levels in Rats Rats respond to a single oral dose of (33 agonist by increasing plasma free fatty acids (FFA) in response to (33 receptor stimulation on the plasma membrane of the fat cell.
5-{ 2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl }-benzo[ 1,3]dioxole-2,2-s dicarboxylic acid diisopropyl ester (Standard 2) was used as a standard compound. All test compounds were dosed at 0.1 mg/kg and compared to the response by Standard 2.
10 1 ). Drugs were dissolved in DMSO at 10 mg/mL.
2). Twenty N.1 of the DMSO-drug solution was added to 10 mL methyl cellulose:Tween-80 (0.5%:0.1%) for a final concentration of 20 ltg/mL.
3). Methyl celluloseaween-80 drug suspension was given via gavage (1 mL/200g body weight; or 0.1 mg/kg) to rats and blood was collected 50 min later.
is 4). Plasma was analyzed for free fatty acids using a kit supplied by Biochemical Diagnostics Inc. (Brentwood, N.Y.).
5). Drug response was calculated from the formula below.
% FFA Response= ~A ~compoun~ - FFA veh;~iP x 100 FFA (Standard 2) - FFA vehicle Effects on Hyperglycemia in Mice On the morning of Day 1 (baseline), 35 mice (male, db/db (C57BL/KsJ), Jackson 2s Laboratories) 2 to 7 months of age and 35 to b0 g) were fasted for 4 h) weighed, and a baseline blood sample was collected from the tail-tip of each mouse without anesthesia, placed directly into a fluoride-containing tube, mixed, and maintained on ice.
Food was then returned to the mice. The plasma was seperated and the levels of glucose in the plasma were dertermined by an Abbot VP Analyzer. Because of the variable plasma glucose levels of the db/db mice, the 5 mice having the most extreme (i.e., highest or lowest) plasma glucose levels were excluded and the remaining 30 mice were randomly assigned into 7 groups of equivalent mean plasma glucose level (vehicle control, ciglitazone (Standard 3), and 5 test compound groups). On the afternoon of Days 1) 2, and 3 the vehicle (0.2 mL of 2% Tween 80/saline w/v) or test compounds were administered (p.o.) to the ad libitum fed s s mice. On the morning of Day 4, the food was removed from the cages for 3 h, a blood sample was collected, and the mice were then given the fourth administration of test compound or vehicle. Additional blood samples were collected at 2 and 4 h after test SUBSTITUTE SHEET (RULE 26) n i i i t6 compound administration. Plasma glucose levels were determined. To assess test compound activity, the percent change of an animal's plasma glucose level on Day 4 (mean of 2 and 4 h values) from its level before test compound administration (Day 1 baseline sample) was determined as follows:
s Mean of 2 and 4 h samples lDay 47 x 100 Baseline sample (Day 1) A 50-60% reduction of plasma glucose levels in the hyperglycemic db/db mice represents a 1 o normalization of glucose levels.
Table I
Compound ~2a (~3a Rat Free Fatty (Exam le) Acidb 4 9% 4% 32%
11 % 50% 6%
6 16% 51% 0%
7 33% 40% 7%
8 19%
9 1% 3% 3%
4% 3% 20%
11 38% 97% 5%
12 11% 27% 11%
is a Human ~3 receptors expressed in Chinese hamster ovary cells, compounds tested at 10 nNi, results expressed as % of isoproterenol activity (increase in cAMP) at 10 ~t.M.
b Elevation of plasma free fatty acids in rats, compounds tested at 0.1 mg/kg, results expressed as % of 5- { 2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl ) 2o benzo[1,3]dioxole-2,2-dicarboxylic acid diisopropyl ester response (78%
increase) at 0.1 mg/kg.
SUBSTITUTE SHEET (RULE 26) r_-___ Pharmaceutical Composition Compounds of this invention may be administered neat or with a pham~aceuticai carrier to a patient in need thereof. The pharmaceutical carrier may be solid or liquid.
s Applicable solid carriers can include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants) compression aids, binders or tablet-disintegrating agents or an encapsulating material. In powders, the carrier is a finely divided solid which is in admixture with the finely divided active ingredient. In tablets, the active ingredient is mixed with a carrier having the necessary 1 o compression properties n suitable proportions and compacted in the shape and size desired.
The powders and tablets preferably contain up to 99% of the active ingredient.
Suitable solid carriers include, for example) calcium phosphate, magnesium stearate) talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.
is Liquid carriers may be used in preparing solutions, suspensions, emulsions) syrups and elixirs. The active ingredient of this invention can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fat. The liquid carrier can contain other suitable pham~aceutical additives such a solubilizers, emulsifiers, buffers, preservatives, 2o sweeteners, flavoring agents, suspending agents, thickening agents) colors) viscosity regulators, stabilizers or osmo-regulators. Suitable examples of liquid carriers for oral and parenteral administration include water (particularly containing additives as above, e.g.) cellulose derivatives, preferable sodium carboxymethyl cellulose solution)) alcohols (including monohydric alcohols and polyhydric alcohols, e.g., glycols) and their 2s derivatives, and oils (e.g.) fractionated coconut oil and arachis oil). For parenteral administration the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration.
Liquid pham~aceutical compositions which are sterile solutions or suspensions can 3o be utilized by, for example, intramuscular, intraperitoneal or subcutaneous injection.
Sterile solutions can also be administered intravenously. Oral administration may be either liquid or solid composition form.
The compounds of this invention may be administered rectally in the form of a conventional suppository. For administration by intranasal or intrabronchial inhalation or ss insufflation, the compounds of this invention may be formulated into an aqueous or parnially aqueous solution, which can then be utilized in the form of an aerosol. The compounds of this invention may also be administered transdermally through the use of a SUBSTITUTE SHEET (RULE 26) transdernlal patch containing the active compound and a carrier that is inert to the active compound, is non-toxic to the skin, and allows delivery of the agent for systemic absorption into the blood stream via the skin. The carrier may take any number of forms such as creams and ointments, pastes, gels, and occlusive devices. The creams and s ointments may be viscous liquid or semi-solid emulsions of either the oil in wafer or water in oil type. Pastes comprised of absorptive powders dispersed in petroleum or hydrophilic petroleum containing the active ingredient may also be suitable. A variety of occlusive devices may be used to release the active ingredient into the blood stream such as a semipermeable membrane covering a reservoir containing the active ingredient with or to without a carrier, or a matrix containing the active ingredient. Other occlusive devices am known in the literature. Further, an invention compound may be incorporated into a controlled release subcutaneous implant for gradual release over a period of time eliminating the necessity of frequent dosing. An antiobesity invention compound may also be incorporated into animal feed for the use with livestock as a means of oral dosing.
1 s The dosage to be used in the treatment of a specific patient suffering obesity and/or diabetes and/or hyperglycemia must be subjectively determined by the attending physician.
The variables involved include the severity of the dysfunction, and the size) age, and response pattern of the patient. Treatment will generally be initiated with small dosages less than the optimum dose of the compound. Thereafter the dosage is increased until the 20 optimum effect under the circumstances is reached. Precise dosages for oral, parenteral) nasal, or inirabronchial administration will be determined by the administering physician based on experience with the individual subject treated and standerd madical principles.
Preferably the pharmaceutical composition is in unit dosage form, e.g., as tablets or capsules. In such form, the composition is sub-divided in unit dose containing appropriate 25 quantities of the active ingredient; the unit dosage form can be packaged compositions, for example packed powders, vials, ampoules, prefilled syringes or sachets containing liquids.
The unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions in package foam.
SUBSTITUTE SHEET (RULE 26) r_ --_-
4% 3% 20%
11 38% 97% 5%
12 11% 27% 11%
is a Human ~3 receptors expressed in Chinese hamster ovary cells, compounds tested at 10 nNi, results expressed as % of isoproterenol activity (increase in cAMP) at 10 ~t.M.
b Elevation of plasma free fatty acids in rats, compounds tested at 0.1 mg/kg, results expressed as % of 5- { 2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl ) 2o benzo[1,3]dioxole-2,2-dicarboxylic acid diisopropyl ester response (78%
increase) at 0.1 mg/kg.
SUBSTITUTE SHEET (RULE 26) r_-___ Pharmaceutical Composition Compounds of this invention may be administered neat or with a pham~aceuticai carrier to a patient in need thereof. The pharmaceutical carrier may be solid or liquid.
s Applicable solid carriers can include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants) compression aids, binders or tablet-disintegrating agents or an encapsulating material. In powders, the carrier is a finely divided solid which is in admixture with the finely divided active ingredient. In tablets, the active ingredient is mixed with a carrier having the necessary 1 o compression properties n suitable proportions and compacted in the shape and size desired.
The powders and tablets preferably contain up to 99% of the active ingredient.
Suitable solid carriers include, for example) calcium phosphate, magnesium stearate) talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.
is Liquid carriers may be used in preparing solutions, suspensions, emulsions) syrups and elixirs. The active ingredient of this invention can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fat. The liquid carrier can contain other suitable pham~aceutical additives such a solubilizers, emulsifiers, buffers, preservatives, 2o sweeteners, flavoring agents, suspending agents, thickening agents) colors) viscosity regulators, stabilizers or osmo-regulators. Suitable examples of liquid carriers for oral and parenteral administration include water (particularly containing additives as above, e.g.) cellulose derivatives, preferable sodium carboxymethyl cellulose solution)) alcohols (including monohydric alcohols and polyhydric alcohols, e.g., glycols) and their 2s derivatives, and oils (e.g.) fractionated coconut oil and arachis oil). For parenteral administration the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration.
Liquid pham~aceutical compositions which are sterile solutions or suspensions can 3o be utilized by, for example, intramuscular, intraperitoneal or subcutaneous injection.
Sterile solutions can also be administered intravenously. Oral administration may be either liquid or solid composition form.
The compounds of this invention may be administered rectally in the form of a conventional suppository. For administration by intranasal or intrabronchial inhalation or ss insufflation, the compounds of this invention may be formulated into an aqueous or parnially aqueous solution, which can then be utilized in the form of an aerosol. The compounds of this invention may also be administered transdermally through the use of a SUBSTITUTE SHEET (RULE 26) transdernlal patch containing the active compound and a carrier that is inert to the active compound, is non-toxic to the skin, and allows delivery of the agent for systemic absorption into the blood stream via the skin. The carrier may take any number of forms such as creams and ointments, pastes, gels, and occlusive devices. The creams and s ointments may be viscous liquid or semi-solid emulsions of either the oil in wafer or water in oil type. Pastes comprised of absorptive powders dispersed in petroleum or hydrophilic petroleum containing the active ingredient may also be suitable. A variety of occlusive devices may be used to release the active ingredient into the blood stream such as a semipermeable membrane covering a reservoir containing the active ingredient with or to without a carrier, or a matrix containing the active ingredient. Other occlusive devices am known in the literature. Further, an invention compound may be incorporated into a controlled release subcutaneous implant for gradual release over a period of time eliminating the necessity of frequent dosing. An antiobesity invention compound may also be incorporated into animal feed for the use with livestock as a means of oral dosing.
1 s The dosage to be used in the treatment of a specific patient suffering obesity and/or diabetes and/or hyperglycemia must be subjectively determined by the attending physician.
The variables involved include the severity of the dysfunction, and the size) age, and response pattern of the patient. Treatment will generally be initiated with small dosages less than the optimum dose of the compound. Thereafter the dosage is increased until the 20 optimum effect under the circumstances is reached. Precise dosages for oral, parenteral) nasal, or inirabronchial administration will be determined by the administering physician based on experience with the individual subject treated and standerd madical principles.
Preferably the pharmaceutical composition is in unit dosage form, e.g., as tablets or capsules. In such form, the composition is sub-divided in unit dose containing appropriate 25 quantities of the active ingredient; the unit dosage form can be packaged compositions, for example packed powders, vials, ampoules, prefilled syringes or sachets containing liquids.
The unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions in package foam.
SUBSTITUTE SHEET (RULE 26) r_ --_-
Claims (8)
1. A compound having the formula:
wherein R1 and R6 are independently hydrogen, C1 to C6 alkyl, trifluoromethyl, cyano, C1 to C6 alkoxy, or halogen;
R2 is hydrogen or C1 to C6 trialkylsilyl; R3 is hydrogen or C1 to C6 alkoxycarbonyl;
or R2 and R3 are joined to form the oxazolidinone ring R4 and R5 are independently hydrogen or C1 to C6 alkyl;
R7 and R8 are independently OR9 or NR10R11;
R9 is hydrogen, C1 to C12 alkyl, C1 to C12 cycloalkyl, C1 to C12 silylalkyl, phenyl, naphthyl, phenyl C1 to C6 alkyl, C1 to C6 alkoxy C1 to C6 alkyl, pyridyl, thiophenyl, furanyl, imidazolyl, oxazolyl, -CHR12COOR13, -CHR12C(O)R13, -CHR12CONR10R11, -CHR12OCOOR13, or -CHR12OC(O)R13;
R10 and R11 are independently hydrogen, C1 to C12 alkyl, phenyl, naphthyl, phenyl-C1 to C6 alkyl, furanylalkyl, or alkoxycarbonylalkyl;
R12 and R13 are independently hydrogen, C1 to C12 alkyl, phenyl, naphthyl, or phenyl-C1 to C6 alkyl; and the pharmaceutically acceptable salts thereof, an enantiomer or diastereomer thereof, or a pharmaceutically acceptable salt thereof.
wherein R1 and R6 are independently hydrogen, C1 to C6 alkyl, trifluoromethyl, cyano, C1 to C6 alkoxy, or halogen;
R2 is hydrogen or C1 to C6 trialkylsilyl; R3 is hydrogen or C1 to C6 alkoxycarbonyl;
or R2 and R3 are joined to form the oxazolidinone ring R4 and R5 are independently hydrogen or C1 to C6 alkyl;
R7 and R8 are independently OR9 or NR10R11;
R9 is hydrogen, C1 to C12 alkyl, C1 to C12 cycloalkyl, C1 to C12 silylalkyl, phenyl, naphthyl, phenyl C1 to C6 alkyl, C1 to C6 alkoxy C1 to C6 alkyl, pyridyl, thiophenyl, furanyl, imidazolyl, oxazolyl, -CHR12COOR13, -CHR12C(O)R13, -CHR12CONR10R11, -CHR12OCOOR13, or -CHR12OC(O)R13;
R10 and R11 are independently hydrogen, C1 to C12 alkyl, phenyl, naphthyl, phenyl-C1 to C6 alkyl, furanylalkyl, or alkoxycarbonylalkyl;
R12 and R13 are independently hydrogen, C1 to C12 alkyl, phenyl, naphthyl, or phenyl-C1 to C6 alkyl; and the pharmaceutically acceptable salts thereof, an enantiomer or diastereomer thereof, or a pharmaceutically acceptable salt thereof.
2. A compound according to claim 1 which is selected from:
6-{(2R)-2-[(5R)-5-(3-chloro-phenyl)-2-oxo-oxazolidin-3-yl]-propyl}-2,3-dihydro-benzo[1,4] dioxane-2,3-dicarboxylic acid dimethyl ester;
6-{2-5-(3-chloro-phenyl)-2-oxo-oxazolidin-3-yl]-propyl}-2,3-dihydro-benzo[1,4]dioxane-2,3-dicarboxylic acid 3-methyl ester, (2,3-cis)-6-{(2R)-2-[(2R)-2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-2,3-dihydro-benzo[1,4]dioxane-2,3-dicarboxylic acid;
(2,3-cis)-6-{(2R)-2-[(2R)-2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl-2,3-dihydro-benzo[1,4]dioxane-2,3-dicarboxylic acid diisopropyl ester;
(2,3-cis)-6-{(2R)-2-[(2R)-2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-2,3-dihydro-benzo[1,4]dioxane-2,3-dicarboxylic acid 3-isopropyl ester;
(2,3-cis-)-6-{(2R)-2-[(2R)-2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-2,3-dihydro-benzo[1,4]dioxane-2,3-dicarboxylic acid dibutyl ester;
(2,3-cis)-6-{(2R)-2-[(2R)-2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-2,3-dihydro-benzo[1,4]dioxane-2,3-dicarboxylic acid bis-(2-ethoxy-ethyl) ester;
(2,3-cis)-6-{(2R)-2-[(2R)-2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-2,3-dihydro-benzo[1,4]dioxane-2,3-dicarboxylic acid diethyl ester;
(2,3-cis)-6-{(2R)-2-[(2R)-2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-2,3-dihydro-benzo[1,4]dioxane-2,3-dicarboxylic acid dicyclohexyl ester;
(2,3-cis)-6-{(2R)-2-[(2R)-2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-2,3-dihydro-benzo[1,4]dioxane-2,3-dicarboxylic acid dicyclopentyl ester, (2,3-cis)-6-{(2R)-2-[(2R)-2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-2,3-dihydro-benzo[1,4]dioxane-2,3-dicarboxylic acid dioctyl ester, (2,3-cis)-6-{(2R)-2-[(2R)-2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-2,3-dihydro-benzo[1,4]dioxane-2,3-dicarboxylic acid dibenzyl ester and pharmaceutically acceptable salts thereof.
6-{(2R)-2-[(5R)-5-(3-chloro-phenyl)-2-oxo-oxazolidin-3-yl]-propyl}-2,3-dihydro-benzo[1,4] dioxane-2,3-dicarboxylic acid dimethyl ester;
6-{2-5-(3-chloro-phenyl)-2-oxo-oxazolidin-3-yl]-propyl}-2,3-dihydro-benzo[1,4]dioxane-2,3-dicarboxylic acid 3-methyl ester, (2,3-cis)-6-{(2R)-2-[(2R)-2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-2,3-dihydro-benzo[1,4]dioxane-2,3-dicarboxylic acid;
(2,3-cis)-6-{(2R)-2-[(2R)-2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl-2,3-dihydro-benzo[1,4]dioxane-2,3-dicarboxylic acid diisopropyl ester;
(2,3-cis)-6-{(2R)-2-[(2R)-2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-2,3-dihydro-benzo[1,4]dioxane-2,3-dicarboxylic acid 3-isopropyl ester;
(2,3-cis-)-6-{(2R)-2-[(2R)-2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-2,3-dihydro-benzo[1,4]dioxane-2,3-dicarboxylic acid dibutyl ester;
(2,3-cis)-6-{(2R)-2-[(2R)-2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-2,3-dihydro-benzo[1,4]dioxane-2,3-dicarboxylic acid bis-(2-ethoxy-ethyl) ester;
(2,3-cis)-6-{(2R)-2-[(2R)-2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-2,3-dihydro-benzo[1,4]dioxane-2,3-dicarboxylic acid diethyl ester;
(2,3-cis)-6-{(2R)-2-[(2R)-2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-2,3-dihydro-benzo[1,4]dioxane-2,3-dicarboxylic acid dicyclohexyl ester;
(2,3-cis)-6-{(2R)-2-[(2R)-2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-2,3-dihydro-benzo[1,4]dioxane-2,3-dicarboxylic acid dicyclopentyl ester, (2,3-cis)-6-{(2R)-2-[(2R)-2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-2,3-dihydro-benzo[1,4]dioxane-2,3-dicarboxylic acid dioctyl ester, (2,3-cis)-6-{(2R)-2-[(2R)-2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-2,3-dihydro-benzo[1,4]dioxane-2,3-dicarboxylic acid dibenzyl ester and pharmaceutically acceptable salts thereof.
3. A method of treating obesity in an obese mammal or a method of treating diabetes and/or hyperglycemia in a mammal having diabetes or hyperglycemia which comprises administering to said mammal a therapeutically effective amount of a compound as claimed in Claim 1 or Claim 2.
4. A method of increasing the amount of lean meat in domestic animals raised for human consumption which comprises administering to said edible animals an effective amount of a compound as claimed in Claim 1 or Claim 2.
5. A pharmaceutical composition which comprises a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound as claimed in Claim 1 or Claim 2.
6. Use of a compound as claimed in Claim 1 or Claim 2 as a medicament.
7. Use of a compound as claimed in Claim 1 or Claim 2 in the preparation of a medicament for the treatment of obesity in an obese mammal or the treatment diabetes and/or hyperglycemia in a mammal having diabetes or hyperglycemia.
8. Process for the preparation of a compound as claimed in Claim 1 or Claim 2 which comprises:
a) reacting a catechol of formula 1 with a bromosuccinate ester of formula 2 wherein R14 is C1 to C12 alkyl, to provide a compound of formula II wherein R7 and R8 are both OR9 and R9 is C1 to C12 alkyl;
b) hydrolysing a compound of formula II, wherein R7 and R8 are both OR9 and R9 is C1 to C12 alkyl, to provide a compound of formula II wherein R7 and R8 are both OR9 and R9 is hydrogen;
c) reacting the appropriate dicarboxylic acid or its salt with an alcohol of formula R9OH, wherein R9 is as defined in Claim 1, to provide a compound of formula II
wherein R7 and R8 are both OR9;
d) hydrolysing a compound of formula II wherein R7 and R8 are both OR9 to provide one or both of the regioisomers 8a and 8b e) reacting a compound of formula II wherein R7 and R8 are both OR9 with an amine of formula NR11R12, wherein R11 and R12 are as defined in Claim 1, to provide a compound of formula II wherein R7 and R8 are both NR10R11;
or g) reacting an acid halide of the formula 10a or 10b wherein X is a halogen, with an amine of the formula HNR10R11 to obtain a compound of Formula II where one of R7 and R8 is OR9 and the other is -NR10R11.
a) reacting a catechol of formula 1 with a bromosuccinate ester of formula 2 wherein R14 is C1 to C12 alkyl, to provide a compound of formula II wherein R7 and R8 are both OR9 and R9 is C1 to C12 alkyl;
b) hydrolysing a compound of formula II, wherein R7 and R8 are both OR9 and R9 is C1 to C12 alkyl, to provide a compound of formula II wherein R7 and R8 are both OR9 and R9 is hydrogen;
c) reacting the appropriate dicarboxylic acid or its salt with an alcohol of formula R9OH, wherein R9 is as defined in Claim 1, to provide a compound of formula II
wherein R7 and R8 are both OR9;
d) hydrolysing a compound of formula II wherein R7 and R8 are both OR9 to provide one or both of the regioisomers 8a and 8b e) reacting a compound of formula II wherein R7 and R8 are both OR9 with an amine of formula NR11R12, wherein R11 and R12 are as defined in Claim 1, to provide a compound of formula II wherein R7 and R8 are both NR10R11;
or g) reacting an acid halide of the formula 10a or 10b wherein X is a halogen, with an amine of the formula HNR10R11 to obtain a compound of Formula II where one of R7 and R8 is OR9 and the other is -NR10R11.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US77474996A | 1996-12-30 | 1996-12-30 | |
| US08/774,749 | 1996-12-30 | ||
| PCT/US1997/024019 WO1998029405A1 (en) | 1996-12-30 | 1997-12-18 | Substituted benzo[1,4]dioxanes as antiobesity agents |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2271885A1 true CA2271885A1 (en) | 1998-07-09 |
Family
ID=25102168
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002271885A Abandoned CA2271885A1 (en) | 1996-12-30 | 1997-12-18 | Substituted benzo[1,4]dioxanes as antiobesity agents |
Country Status (10)
| Country | Link |
|---|---|
| EP (1) | EP0948494A1 (en) |
| JP (1) | JP2001507704A (en) |
| KR (1) | KR20000062404A (en) |
| AU (1) | AU5723098A (en) |
| BR (1) | BR9714109A (en) |
| CA (1) | CA2271885A1 (en) |
| HU (1) | HUP0000768A2 (en) |
| IL (1) | IL129715A0 (en) |
| NZ (1) | NZ336235A (en) |
| WO (1) | WO1998029405A1 (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6222050B1 (en) | 1998-07-31 | 2001-04-24 | Nisshin Flour Milling Co., Ltd. | Optically active 1,4-benzodioxine-2-carboxylic acid derivatives and process for producing the same |
| ES2291733T3 (en) * | 2002-10-22 | 2008-03-01 | Glaxo Group Limited | MEDICAL ARYLETHANOLAMINE COMPOUNDS. |
| PL377122A1 (en) | 2002-10-28 | 2006-01-23 | Glaxo Group Limited | Phenethanolamine derivative for the treatment of respiratory diseases |
| TW200732313A (en) | 2005-12-15 | 2007-09-01 | Astrazeneca Ab | Oxazolidinone compounds and their use as metabotropic glutamate receptor potentiators |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5061727A (en) * | 1990-05-04 | 1991-10-29 | American Cyanamid Company | Substituted 5-(2-((2-aryl-2-hydroxyethyl)amino)propyl)-1,3-benzodioxoles |
| US5482971A (en) * | 1993-10-01 | 1996-01-09 | American Cyanamid Company | Beta3 -adrenergic agents and their use in pharmaceutical compositions |
| ES2170855T3 (en) * | 1995-05-12 | 2002-08-16 | Nisshin Pharma Inc | DERIVATIVES OF 1,4-BENZODIOXINE. |
-
1997
- 1997-12-18 IL IL12971597A patent/IL129715A0/en unknown
- 1997-12-18 EP EP97953494A patent/EP0948494A1/en not_active Withdrawn
- 1997-12-18 CA CA002271885A patent/CA2271885A1/en not_active Abandoned
- 1997-12-18 HU HU0000768A patent/HUP0000768A2/en unknown
- 1997-12-18 KR KR1019997005997A patent/KR20000062404A/en not_active Application Discontinuation
- 1997-12-18 NZ NZ336235A patent/NZ336235A/en unknown
- 1997-12-18 BR BR9714109A patent/BR9714109A/en not_active Application Discontinuation
- 1997-12-18 AU AU57230/98A patent/AU5723098A/en not_active Abandoned
- 1997-12-18 WO PCT/US1997/024019 patent/WO1998029405A1/en not_active Application Discontinuation
- 1997-12-18 JP JP53026098A patent/JP2001507704A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| HUP0000768A2 (en) | 2001-05-28 |
| EP0948494A1 (en) | 1999-10-13 |
| AU5723098A (en) | 1998-07-31 |
| BR9714109A (en) | 2000-03-21 |
| IL129715A0 (en) | 2000-02-29 |
| WO1998029405A1 (en) | 1998-07-09 |
| JP2001507704A (en) | 2001-06-12 |
| KR20000062404A (en) | 2000-10-25 |
| NZ336235A (en) | 2000-11-24 |
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