CA2254120A1 - Substituted 1, 3-benzodioxoles - Google Patents

Substituted 1, 3-benzodioxoles Download PDF

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CA2254120A1
CA2254120A1 CA002254120A CA2254120A CA2254120A1 CA 2254120 A1 CA2254120 A1 CA 2254120A1 CA 002254120 A CA002254120 A CA 002254120A CA 2254120 A CA2254120 A CA 2254120A CA 2254120 A1 CA2254120 A1 CA 2254120A1
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propyl
phenyl
chloro
dioxole
benzo
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Aranapakam M. Venkatesan
George T. Grosu
Fuk-Wah Sum
Adam M. Gilbert
Michael S. Malamas
Gerardo D. Francisco
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Wyeth LLC
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing three or more hetero rings
    • 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
    • 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
    • A61P3/04—Anorexiants; Antiobesity agents
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1896—Compounds having one or more Si-O-acyl linkages

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Abstract

The present invention provides new compounds having anti-diabetic and/or antihyperglycemia and/or anti-obesity activity, as well as pharmaceutical compositions and methods of treatment utilizing the compounds and processes for making the compounds, the compounds having 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 a ring (a): wherein R' is hydrogen, C1 to C6 alkyl or aryl; 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, aryl, arylakyl, alkoxyalkyl, heteroaryl, -CHR12COOR13, -CHR12C(O)R13, -CHR12CONR10R11, -CHR12OCOOR13, or -CHR12OC(O)R13, with the provision that R9 is not hydrogen in both R7 and R8; R10 and R11 are independently hydrogen, C1 to C12 alkyl, aralkyl, aryl, furanylalkyl, or alkoxycarbonylalkyl; R12 and R13 are independently hydrogen, C1 to C12 alkyl, aryl, or aralkyl; and their pharmaceutically acceptable salts thereof, the enantiomers thereof, the racemic mixtures thereof, and the diastereomeric mixtures thereof.

Description

CA 022~4120 1998-ll-lO

SUBSTITUTF.D 1.3-BEN7,0n~0XO~,FS

This invention relates to novel substituted 1,3-benzodioxole compounds which have ~nti~ hetic, antihyperglycemic, and antiobesity properties. The present invention also relates to pharm~eutic~l compositions cont~ining 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 ~ ls BACKGROUND OF THF INVE~TION
Bloom, et al., U.S. Patent 5,061,727, disclose substituted 5-(2-((2-aryl-2-hydroxyethyl)amino)propyl)- 1 ,3-benzodioxoles of general formula (I) R1 ~ X (I) 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, C1 to C4 thioalkyl, sulfonyl and sulfinyl; X is a divalent radical consisting of OR' R' O-y ~,N~ or ~'N

wherein R' is selected from the group consisting of hydrogen, Cl to C4 alkyl and C1 to C4 acyl and Y is selected from the group consisting of carbonyl and thiocarbonyl; R2 and R3 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, alkoxycarbonyl, hydroxymethyl, -CH2OCH2COOR7 and -CH2OCH2CH2OR7, where R7 is hydrogen or C1 to C4 alkyl; with the provision that ~ Rs and R6 may not both be hydrogen; which have antihyperglycemic and antiobesity activity.

CA 022~4120 1998-11-10 Wo 97/43273 PCT/US97/08148 The synthesis, anti~ betic effects, and antiobesity effects of (R,R)-5-[2-[[2-(3-chlorophenyl)-2-hydroxyethyl~amino]propyl)- 1,3-benzodioxole-2,2-dicarboxylate (which is one of the compounds 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. Drugs of ~he Future, 1994, 19, 23.

The compounds of the present invention possess greatly increased potency at human ,B3 receptors in comparison to the compounds in Bloom, et al., U.S. Patent5,061,727. They retain high selectivity for the ,B3 receptor and show much higher 10 antiobesity and antihyperglycemic activity in animal models than the compounds of the prior art. The compounds have intrinsic activity at human ,~3 receptors and can directly bring about antihyperglycemic and antiobesity effects, but may also be hydrolyzed in vivo to deliver a compound of the type disclosed in Bloom, et al., U.S. Patent 5,061,727 where Rs and R6 are carboxy. Thus the compounds may act as prodrugs.
15 Therefore, the compounds of this invention are useful in treating diabetes, hyperglycemia, and obesity, exhibiting minim~l side effects such as heart rate increase and muscle tremor in humans and animals, when form~ t~d into phann~euti~l compositions.

l)ESCR~PT~ON OF THE INVFNT~ON

The compounds of the present invention achieve their ~ntirli~betic, antihyperglycemic, and antiobesity effects by acting as selective agonists at ,B3 adrenergic receptors. The stim~ tion of these receptors on white and brown 25 adipocytes promotes both lipolysis (breakdown of fat) and energy expenditure.Selective stimulation of ,B3 adrenergic ~~c~lol~ is important for chronic tre~t~n.o.nt.
Stimulation of other ,~-receptors could cause side effects such as increased heart rate (,Bl effect) and muscle tremor (~2 effect). The compounds of the present invention show high selectivity for ,B3 adrenergic receptors.
According to the present invention there are provided new compounds of the formula (II):

CA 022~4120 1998-ll-lO

WO 97/43273 PCT/~S97/08148 R1 ~~ R?'~[~~<~R7 (II) R6 o wherein:
R1 and R6 are independently hydrogen, C1 to C6 alkyl, trifluoromethyl, cyano, Cl to C6 alkoxy, or halogen;
R2 is hydrogen or Cl to C6 trialkylsilyl;
R3 is hydrogen or Cl to C6 alkoxycarbonyl;
or R2 and R3 are joined to form a ring:

~ N~

wherein R' is hydrogen, Cl to C6 alkyl, or aryl;
R4 and Rs are independently hydrogen or C1 to C6 alkyl;
R7 and R8 are independently ORg or NR1oR1 1;
Rg is hydrogen, C1 to C12 alkyl, Cl to C12 cycloalkyl, Cl to C12 silylalkyl, aryl, arylallcyl, alkoxyalkyl, heteroaryl, -CHR12COOR13, -CHR12C(O)R13, -CHR12CONRloRll, -CHR12OCOOR13, or -CHR12OC(O)R13, with the provision that Rg is not hydrogen in both R7 and R8;
R1o and R11 are independently hydrogen, C1 to C12 alkyl, arylalkyl, aryl, furanylalkyl, or alkoxycarbonylalkyl;
R12 and R13 are independently hydrogen, Cl to C12 alkyl, aryl, or aralkyl;
and the pharmaceutically acceptable salts thereof, the enantiomers thereof, the racemic mixtures thereof, and the diastereomeric mixtures thereof.

In the description above, aryl may be phenyl or napthyl; arylalkyl may be phenyl Cl to C6 alkyl or naphthyl C1 to C6 alkyl; alkoxy alkyl may be C1 to C6 alkoxy C1 to C6 alkyl; and heteroaryl may be pyridyl, thiophenyl, furanyl, imi~i~7.r)1yl, oxazolyl, or thiazolyl. The aryl, arylalkyl and heteroaryl groups referred to above may be optionally substituted with one or more moieties select~d from halogens, Cl-C6 alkyl, C,-C6 alkoxy, -CF3, -CN, or -OH groups. In a more preferred embo~lim~nt of this invention, the phenyl Cl to C6 alkyl group may be optionally substituted by one or more substituents selected from F, Cl, Br, CH3 or CF3.
s This invention also provides processes for preparing the compounds of the invention which comprise one of the following:

a) reacting a compound of formula:

Rl ~ R~oXco2RAo wherein R2 - R6 are as defined above and Rg~ is OAg or R8 as defined above excepting OH with a compound of formula:

I-CHR1 2oc(o)Rl3 wherein R12 and R13 are as defined above to give a compound of formula II wherein Rg is -CHR12OC(O)R13 or b) reacting a compound of formula:

R ~J ~N ~OxCO2H
R4 R5 ~ o COR8 25 wherein Rl-R6 and R8 are as defined above with compound of formula RgOH whereRg is as defined above excepting hydrogen to give a corresponding compound of formula II;

CA 02254120 1998-ll-lO

or c) hydrolysing a compound for formula:

R1--~ I ~[ OXCOR, wherein Rl, R4, Rs, R6, R7 and R8 are as defined above and R2 is trialkylsilyl and R3 is (Cl-C6 alkoxy)carbonyl to give a corresponding compound of formula 1 wherein R2 and R3 are both hydrogen, or d) reacting a compound of formula II wherein R2 and R3 are both hydrogen with an aldehyde of forrnula:

R'CHO

wherein R' is as defined above to give a corresponding compound of forrnula I wherein R2 and R3 are joined to forrn a ring:

o~R' ~N

or e) reacting a compound of formula:

R ~ '~Ooxco2RH

CA 02254120 1998-ll-lO

wherein Rl, R4, Rs and R8 are as defined above with the proviso neither R2 or R3 is hydrogen with a compound of formula:

s wherein Z is Cl, Br, I, methanesulfonate or p-toluenesulfonate and Rg is as defined in above excepting hydrogen, to give a corresponding compound of formula II;

or f) hydrolysing a compound of formula:

R g3r,~ ~0XCoOR9~

wherein R1, R2, R3~ R4, Rs and R6 are as defined in Claim 1, R8 is ORg' or NR1oRl 1 and Rg~ is Cl-C12 alkyl, C1-C12 cycloalkyl, C1-C12 silyalkyl, aryl, 15 arylalkyl, alkoxyalkyl or heteroaryl to give a compound of formula:

R ~/ ~ ~ OXCOOH

wherein RI-R6 and R8 are as defined above providing that R2 and R3 are both 20 hydrogen or joined to form a ring:

or g) reacting a compound of formula:

CA 022~4120 1998-11-10 wo 97/43273 PCT/US97/08148 N~O~COORg R1 ~ R4 5 ~ ~ COR8 wherein R1-R6 and R8 are as defined above and Rg~ is as defined above, with a 5 compound of forrnula:

wherein Rl I and R12 are as defined above to give a compound of formula:
~I R2 R3 R~ OXCONRllRl2 wherein RI-R6, Rg, Rll and R12 are as defined above.

The most ~l~fell~d compounds of this invention are the following and the pharmaceutically acceptable salts thereof:
5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl)-benzo[1 ,3~dioxole-2,2-dicarboxylic acid bis-(2-methoxy-ethyl) ester;
5- ~ 2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino] -propyl ~ -benzo[ 1 ,3]dioxole-2,2-dicarboxylic acid diphenethyl ester;
5- { 2-~2-(3-chloro-phenyl)-2-hydroxy-ethylamino] -propyl } -benzo[ 1 ,3]dioxole-2,2-dicarboxylic acid bis-(2-butoxy-ethyl) ester;
5- {2-~2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl~-benzo[1,3]dioxole-- 2,2-dicarboxylic acid bis-(2-phenoxy-ethyl) ester;
5- { 2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino] -propyl ) -benzo[ 1 ,3]dioxole-2,2-dicarboxylic acid bis-(2-ethoxy-ethyl) ester;

CA 022~4120 1998-11-10 5- ~ 2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl ) -benzo[ 1 ,3]dioxole-2,2-dicarboxylic acid bis-(2-tert-butoxy-ethyl) ester;
5- { 2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino~-propyl ) -benzo[ 1 ,3]dioxole-2,2-dicarboxylic acid (2-tert-butoxy-ethyl) ester;
55-(2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl)-benzo[1,3]dioxole-2,2-dicarboxylic acid bis-(2-isobutoxy-ethyl) ester;
5-~2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl)-benzo[1,3]dioxole-2,2-dicarboxylic acid bis-(benzyl) ester;
5-~2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-102,2-dicarboxylic acid bis-(cyclohexyl) ester;
5- { 2-12-(3-chloro-phenyl)-2-hydroxy-ethylamino] -propyl } -benzo[ 1 ,3]dioxole-2,2-dicarboxylic acid bis-(cyclopentyl) ester;
5- ( 2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl ) -benzo[ 1 ,3]dioxole-2,2-dicarboxylic acid dioctyl ester;
155- ( 2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl ~ -benzo[ 1 ,3]dioxole-2,2-dicarboxylic acid dipentyl ester;
5- { 2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl ) -benzo[ 1 ,3]dioxole-2,2-dicarboxylic acid dihexyl ester;
carbonic acid 3-chloro-benzyl ester 2-(3-chloro-benzyloxycarbonyloxy)-4-(2-20[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl3-phenyl ester;
5-~2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid bis-(1-phenyl-ethyl) ester;
5- { 2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino] -propyl ) -benzo[ 1 ,3]dioxole-2,2-dicarboxylic acid diheptyl ester;
255- ~ 2- [2- (3-chloro-phenyl)-2-hydroxy-ethylamino] -propyl ) -benzo[ 1 ,3]dioxole-2,2-dicarboxylic acid dinonyl ester;
5- ~ 2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl ) -benzo[ 1 ,3]dioxole-2,2-dicarboxylic acid bis-decyl ester;
5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-302,2-dicarboxylic acid didodecyl ester;
5- { 2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl } -benzo[ 1 ,3]dioxole-2,2-dicarboxylic acid bis-(2-isopropoxy-ethyl) ester;
5- { 2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl } -benzo[ 1 ,3]dioxole-2,2-dicarboxylic acid isopropyl ester;

CA 022~4120 1998-11-10 5- ~ 2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino] -propyl) -benzo[ 1 ,3]dioxole-2,2-dicarboxylic acid ethyl ester;
5-(2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl)-benzo[1,3]dioxole-2,2-dicarboxylic acid bis-methoxycarbonylmethyl ester;
55-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl)-benzo~1,3]dioxole-2,2-dicarboxylic acid bis-propoxycarbonylmethyl ester;
5-(2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1 ,3]dioxole-2,2-dicarboxylic acid bis-(1-methoxycarbonyl-ethyl) ester;
5-(2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl)-benzo[1 ,3]dioxole-102,2-dicarboxylic acid bis-isopropoxycarbonylmethyl ester;
5-(2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid bis-ethoxycarbonylmethyl ester;
5- ( 2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl } -benzo[ 1 ,3]dioxole-2,2-dicarboxylic acid bis-(1-ethoxycarbonyl-ethyl) ester;
155- ( 2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl} -benzo[1 ,3]dioxole- 2,2-dicarboxylic acid bis-trimethylsilanylmethyl ester;
5-(2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1 ,3]dioxole-2,2-dicarboxylic acid bis-(2-trimethylsilanyl-ethyl) ester;
5- ( 2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl ) -benzo[ 1 ,3]dioxole-202,2-dicarboxylic acid bis-(3-trimethylsilanyl-propyl) ester;
5-(2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid bis-(3,3-dimethyl-butyl) ester;
5-(2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl~-benzo[1,3]dioxole-2,2-dicarboxylic acid bis-cyclohexylmethyl ester;
255- ( 2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl ) -benzo[ 1 ,3]dioxole-2,2-dicarboxylic acid bis-(4-methyl-pentyl) ester;
5- ( 2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino] -propyl ) -benzo[ 1 ,3]dioxole-2,2-dicarboxylic acid bis-(2-cyclohexyl-ethyl ) ester;
5- ( 2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino] -propyl ) -benzo[ 1 ,3~dioxole-- 302,2-dicarboxylic acidbis-(3-cyclopentyl-propyl )ester;
5-(2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid bis-cyclopropylmethyl ester;
5-(2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl)-benzo[1 ,3]dioxole-2,2-dicarboxylic acid bis-(l-methyl-cyclopropylmethyl) ester;

CA 022~4120 1998-11-10 5-(2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl)-benzo[1,3]dioxole-2,2-dicarboxylic acid bis-cyclobutylmethyl ester;
5- { 2-~2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl ) -benzo[ I ,3]dioxole-2,2-dicarboxylic acid bis-(2-cyclopentyl-ethyl) ester;
55- { 2-[2-(3-chloro-phenyl)-2-hydroxy-ethylarnino]propyl 3 benzo[ 1 ,3]dioxole-2,2-dicarboxylic acid bis-acetoxymethyl ester;
5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]propyl}benzo~1,3]dioxole-2,2-dicarboxylic acid bis-propionyloxymethyl ester;
5-{2-~2-(3-chloro-phenyl)-2-hydroxy-ethylamino]propyl)benzo[1,3]dioxole-102,2-dicarboxylic acid bis-butyryloxymethyl ester;
5- { 2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]propyl l benzo[ 1 ,3]dioxole-2,2-dicarboxylic acid bis-isobutyryloxymethyl ester;
5- { 2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]propyl ) benzo[ 1 ,3]dioxole-2,2-dicarboxylic acid bis-heptanoyloxymethyl ester;
155- { 2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]propyl } benzo[ 1 ,3]dioxole- 2,2-dicarboxylic acid bis-(4-methyl-pentanoyloxymethyl) ester;
5-(2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]propyl)benzo[1,3]dioxole-2,2-dicarboxylic acid bis-hexanoyloxymethyl ester;
5 - ~ 2- [2- (3 -chloro-phenyl)-2-hydroxy-ethylamino]propyl ) benzo[ 1 ,3]dioxole-202,2-dicarboxylic acid bis- (2,2-dimethyl-propionyloxymethyl) ester;
5- { 2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]propyl ) benzo[ 1 ,3]dioxole-2,2-dicarboxylic acid bis cyclohexanecarbonyloxymethyl ester;
5- { 2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]propyl ) benzo[ 1 ,3]dioxole-2,2-dicarboxylic acid bis-(l-propionyloxy-ethyl) ester;
255-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]propyl~benzo~1,3]dioxole-2,2-dicarboxylic acid bis-[1-(2,2-dimethyl-propionyloxy-ethyl) ester;
5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]propyl)benzo[1,3]dioxole-2,2-dicarboxylic acid bis-(3,3-dimethyl-butyryloxymethyl) ester;
5-~2-[2-(3-chloro-phenyl)-2-hydroxy-ethylarnino]propyl~benzo[1,3]dioxole-302,2-dicarboxylic acid bis-[1-(3,3-dimethyl-butyryloxy)-ethyl)}ester;
5- { 2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]propyl ) benzo[ 1 ,3]dioxole-2,2-dicarboxylic acid bis-(3-cyclopentyl-propionyloxymethyl) ester;
5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]propyl)benzo[1,3]dioxole-2,2-dicarboxylic ~cid bis-benzoyloxymethyl ester;

CA 022~4120 1998-ll-lO

5-~2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino~propyl}benzo[1,3]dioxole-2,2-dicarboxylic acid bis-(benzoyloxy-ethyl) ester;
5- ~ 2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]propyl ) benzo[ 1 ,3]dioxole-2,2-dicarboxylic acid bis-(2,2-dimethyl-butyryloxymethyl) ester;
5- ~ 2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl ) -benzol 1 ,3]dioxole-2,2-dicarboxylic acid bis-amide;
5- { 2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino] -propyl ) -benzo[ 1 ,3]dioxole-2,2-dicarboxylic acid bis-2-propyl amide;
5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl)-benzo[l ,3]dioxole-2,2-dicarboxylic acid bis-n-butyl amide;
5- { 2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino] -propyl } -benzo[ 1 ,3]dioxole-2,2-dicarboxylic acid bis-phenylmethyl amide;
5-{2-~2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl~-benzo[1,3]dioxole-2,2-dicarboxylic acid bis-(2-furanylmethyl) amide;
5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl)-benzo[1,3]dioxole-2,2-dicarboxylic acid bis-(glycine ethyl ester) amide;
5- ( 2-[2-(3-chloro-phenyl)-3-oxazolidinyl] -propyl } -benzo[ 1 ,3]dioxole-2,2-dicarboxylic acid;

Also according to the present invention there is provided a method of treating diabetes and/or hyperglycemia and/or obesity in humans or other .~ s which comprises administering to a human or other m:~mm~l an antiobesity effective amount or an antihyperglycemia effective amount of a compound of the present invention.
It is understood that the effective dosage of the active compounds of this invention may vary depending upon the particular compound ntili7sd, the mode of a(lmini~tration, the condition, and severity thereof, of the condition being treated, as well as the various physical factors related to the individual being treated. For treating diabetes mellitus and/or hyperglycemia generally satisfactory results may be obtained when the compounds of this invention are ~rlmini~tered to the individual in need at a daily dosage of from about 0.1 mg to about 1 mg per kilogram of body weight, ~ preferably ~rlmini~tered in divided doses two to six times per day, or in a sustained release form. For most large m~mm~ls, the total daily dosage is from about 3.5 mg to about 140 mg. This regimen may be adjusted to provide the optimal therapeutic response.

CA 022~4120 1998-ll-lO

When treating obesity, in conjunction with diabetes and/or hyperglycemia, or alone, generally satisfactory results can be obtained when the com~oullds of this invention are ;~-imini~tered at a daily dosage of from about 0.1 mg to about 1 mg per kg 5 of body weight, preferably given in divided doses two to six times per day or in a sustained release form. For most large m~mm~ls, the total daily dosage is from about 3.5 to about 140 mg, preferably from about 3.5 to about 5 mg. In the case of a 70 kg human adult, the total daily dose will generally be from about 7 mg to about 70 mg and may be adjusted to provide the optimal therapeutic result.
The tablets, pills, capsules, and the like may also contain a binder such as gumtrag~canth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a rli~integrating agent such as corn starch, potato starch, alginic acid; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin.
15 When a dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil. Various other materials may be present as coatings or to modify the physical form of the dosage unit. For instance, tablets may be coated with shellac, sugar or both. A syrup or elexir may contain, in addition to the active ingredients, sucrose as a sweetening agent, methyl and propyl parabens as20 preservatives, a dye and a flavoring such as cherry or orange flavor.

These active compounds may also be administered parenterally. Solutions or suspensions of these active compounds can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in 25 glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, there preparations contain a preservative to prevent the growth of micoorganisms.

The pharn~ eutic~l forms suitable for injectable use include sterile aqueous 30 solutions or dispersions and sterile powders for the extemporaneous plep~ on of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the corl~n~ g action of microorganisms such as bacteria and fungi. The carrier can be a solvent or 35 dispersion medium containing, for example, water, ethanol, polyol (e.g. glycerol, CA 022~4120 1998-ll-lO

propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, andvegetable oils.

The compounds of the present invention also possess utility for increasing lean meat deposition and/or improving lean meat to fat ratio in edible ~nim~lc, i.e. ungulate ~nim:3l.c and poultry.

Animal feed compositions effective for increasing lean meat deposition and for improving lean meat to fat ratio in poultry, swine, sheep, goats, domestic pets and cattle are generally prepared by mixing the compounds of the present invention with a sufficient amount of animal feed to provide from about 1 to 1000 ppm of the compound in the feed. Animal feed supplements can be prepared by admixing about 75% to 95%
by weight of a compound of the present invention with about 5% to about 25% by weight of a suitable carrier or diluent. Carriers suitable for use to make up the feed supplement compositions include the following: alfalfa meal, soybean meal, cottonceed oil meal, linseed oil meal, sodium chloride, cornmeal, cane molasses, urea, bone meal, corncob meal and the like. The carrier promotes a uniform distribution of the active ingredients in the finished feed into which the supplement is blended. It thus performs an illJyOl ~U1t function by ensuring proper distribution of the active ingredient throughout the feed. The supplement is used as a top dressing for the feed, it likewise helps to ensure uniformity of distribution of the active material across the top of the dressed feed.

The preferred m~ ted swine, cattle, sheep and goat feed generally contain from 0.01 to 400 grams of active ingredient per ton of feed, the c~lilllulll amount for these animals usually being about 50 to 300 grams per ton of feed. The pn~e.lcd poultry and domestic pet feed usually contain about 0.01 to 400 grams and preferably 10 to 400 grams of active ingredient per ton of feed.

- 30 For parenteral administration the compounds of the present invention may be prepared in the form of a paste or a pellet and administered as an implant, usually under ~ the skin of the head or ear of the animal in which increase in lean meat deposition and improvement in lean mean to fat ratio is sought. In general, parenteral ~imini~ration involves injection of a sufficient amount of the compounds of the present invention to provide the animal with 0.001 to 100 mg/kg/day of body weight of the active CA 022~4120 1998-ll-lO

ingredient. The preferred dosage for swine, cattle, sheep and goats is in the range of from 0.001 to 50 mg~g/day of body weight of active ingredient; whereas, the preferred dose level for poultry and domestic pets is usually in the range of from 0.001 to 35 mgJlcg/day of body weight.

Paste formulations can be prepared by dispersing the active compounds in a ph~rtn~reutic~lly acceptable oil such as peanut oil, sesame oil, corn oil or the like.
Pellets containing an effective amount of the compounds of the present invention can be prepared by admixing the compounds of the present invention with a diluent such as 10 carbowax, carnuba wax, and the like, and a lubricant, such as m~gnecillm or calcium stearate, can be added to improve the pelleting process. It is, of course, recognized that more than one pellet may be administered to an animal to achieve the desired dose level which will provide the increase in lean meat deposition and improvement in lean meat to fat ratio desired. Moreover, it has been found that implants may also be made 15 periodically during the animal treatment period in order to ."~inl~i" the proper drug level in the animal's body. The method of the present invention has several advantages;
for the pet owner or veterinarian who wishes to increase leanness and trim unwanted fat from pet ~nim~, the present invention provides the means by which this can be accomplished. For the poultry and swine raisers, using the method of the present20 invention yields leaner animals which command higher prices from the meat industry.

Further, according to the present invention there are provided pharm~rell~ic~l compositions of matter comprising an effective amount of the compounds of the present invention in combination with a pharmaceutically acceptable carrier; as well as a method 25 for increasing the content of lean meat in edible ~nim~l~, which comprises administering to edible m~mm~I~ an effective amount of the compound.

Also according to the present invention there are provided processes for producing the compounds of the present invention.
PROCE~ OF THE INVI~NTION

The compounds of the present invention may be prepared according to one of the general processes outlined below.

As outlined in Scheme I, a disodium carboxylate 1 is converted to a disilver carboxylate and treated with an iodo derivative 2 to yield the diester compounds 3 wherein R1, R4, Rs, R6, R12, and R13 are as defined above.

5 Scheme I
OH H
~ N ~ OxCO2Na 1 ) AgNO3 R~ ~ R6 1 ~OJ~R

~ >~ R~2 13 Alternatively, a dicarboxylic acid 4 (Scheme II) is treated with an alcohol RgOHand an acid catalyst to yield the diester compounds 5 wherein Rl, R4, Rs, R6, and Rg 10 are as defined above.

Scheme II

OH H

R~--~ R~/~oXCO H RgOH, H+

R~ R?~;;~O>~OR9 R6 o CA 02254l20 l998-ll-lO

As outlined in Scheme III, the diester compounds 5 can also be produced by 5 protecting the hydroxy and amino groups of compound 6 with R2 and R3 groups, respectively, basic hydrolysis of the ethyl esters, alkylation of the carboxyl groups of compound 7 with an alkylating agent Z-Rg, and removing the protecting groups R2 and R3, wherein Rl, R2, R3, R4, R5, R6, and Rg are as defined above and Z is Cl, Br, I, methanesulfonate, trifluoromethanesulfonate, or para-toluenesulfonate.

Scheme III

OH H O>~OEt 1) add R2 and R3 4 5 o OEt 2) OH-OR2 ,R3 N>~.~O~,~LOH
R 1--~1 R4 R5 ~/~ O~ OH
7 6 o 1) base,Z-Rg ~N~[O~ LoR9 2) remove R2and R3 RlR4 R6 o~OR9 lS 5 4 o As outlined in Scheme IV, a dicarboxylate 1 is treated with an aldehyde R'CHO
to yield the oxazaline compounds 8, wherein Rl, R4, Rs, R6, and R' are as defined above.

Scheme IV

OH H o R1 ~ R~Oo><~oNa R'CHO

R6 o R' OX~ OH
R6 o As outlined in Scheme V the diester compounds 5 can be hydrolyzed under basic conditions to a monoester 9a and/or 9b, wherein R1, R4, Rs, R6, and Rg are as defined above. One or both of the diastereomers 9a and 9b may be produced in the hydrolysis reaction.
Scheme V

H O
R--~ RX;~ o~lL OR9 OH-4 5 /~o ~rORg R6 o R,~ and/or R,~ OR

9a 9b Wo 97/43273 PC~/USg7/08148 As illustrate in Scheme VI, a diester compound 5 is reacted with an amine HNRllR12toyieldthediamide compounds 10, wherein Rl, R4, R5, R6, Rg, Rll, and R12 are as defined above.

Scheme VI

H O
,~1 N ~ O~ ~L ORg R~ ~;~ R4 Rs ~ ~O~OR9 HNRl1R12 6 o H O
R ~--R~CO~NRl1R12 R6 o The compounds of this invention were tested for antihyperglycemic and antiobesity activity according to the following procedures.

Hum~n Beta Adrener~ic ReceDtor Selectivity The activity of the test compounds on human ,B-adrenergic r~ce~to.~ was determined with Chinese ha~ er ovary (CHO) cells transfected with human ,B2, or ,B1 adrenergic receptors. Agonist activity is in~lic~te~ by increased cAMP levels in the CHO cells. Selectivity of the test compounds for the ,B3 receptor was assessed by comparison with results in ~2 and ~1 adrenergic receptor transfected cells.
Procedure:

1). Chinese hamster ovary (CHO) cells transfected with human ,~2, or ,B1 ad,,_.lcl~,ic receptors were used in the assay.
25 2). Cells were grown to confluent conditions in 24 well plates.

CA 022~4120 1998-11-10 3). Drugs were dissolved in DMSO at a concentration of 10 ~M.
4). Cells were incubated with drug at 10 nM conrentration for 10 rnin at 37~ C.
- Isoproterenol (Standard 1) was used as the standard compound and assayed at 10 ~lM
which gives a maximal cAMP elevation in all 3 cell types.
5 5). Cell cAMP concentrations were assayed using a scin~ill~tion proximity assay kit from Amersham Corp., Chicago, IL.
6). Activities for the test compounds are expressed as a percentage of the isoproterenol response.

Production of the CHO cells transfected with human ~2. or ,B1 adlen~ly,ic receptors, and compound test procedures utili7ing the CHO cells, are described by Emorine et al. in their article "Molecular Characterizanon of the ~llrnan Beta3-AdrenergicReceptor", Science 1989, 245(8), 1118-1121 and by Muzzin et al. in thearticle "AnAdiposeTissue-SpecificBeta3-AdrenergicReceptor", J. Biol. Chem.l991, 266, 24053-24058.

Fffects on Free Fatty Acid l,evels in Rats Rats respond to a single oral dose of ,B3 agonists by increasing plasma free fatty acids (FFA) in response to ,B3 receptor stim~ tion on the plasma membrane of the fat cell. 5-~2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl)-benzo[1,3]dioxole-2,2-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.
Procedure:

1). Drugs were dissolved in DMSO at 10 mg/ml.
2). Twenty ~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 ~lg/mL.
3). Methyl cellulose:tween-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.
4). Plasma was analyzed for free fatty acids using a kit supplied by Biochçntic~l Diagnostics Inc. (Brentwood, N.Y.).

CA 022~4120 1998-11-10 WO 97143273 rCT/US97/08148 5). Drug response was calculated from the formula below.

% FFA Response= FFA (compound) - FFA vehicle x 100 FFA (Standard 2) - FFA vehicle s Effects on Hyperglycemia in Mice On the morning of Day 1 (baseline), 35 mice (male, db/db (C57BLtKsJ), Jackson Laboratories, 2 to 7 months of age and 35 to 60 g) were fasted for 4 h, 10 weighed, and a baseline blood sample was collected from the tail-tip of each mouse without anesthesia, placed directly into a fluoride-cont~ining tube, mixed, and mz-int~ined on ice. Food was then returned to the mice. The plasma was seperated and the levels of glucose in the plasma were d~e..-~ined by an Abbot VP Analyzer.
Because of the variable plasma glucose levels of the db/db mice, the 5 mice having the 15 most extreme (i.e., highest or lowest) plasma glucose levels were excluded and the re.~ g 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 ~Aminist~ed (p.o.) to the ad libitum fed mice. On the morning 20 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 ~lmini~ration of test compound or vehicle.
Additional blood samples were collected at 2 and 4 h after test coml)ound ~dministration. 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 25 and 4 h values) from its level before test compound administration (Day 1 b~celine sample) was determined as follows:
Mean of 2 and 4 h samples (Day 4) x 100 Baseline sample (Day 1) A 50-60% reduction of plasma glucose levels in the hyperglycemic dbtdb mice represents a normalization of glucose levels.

CA 02254l20 l998-ll-lO

W097/43273 PCTrUS97/08148 Table I
Compound a Rat Freedb/db Mice (Example) ~la ~2 Fatty Plasma Acidb GlucoseC
1 4% 65%
0.022 ~M0-071 mg/kg 0.128 mg/kg 3 ocj 2070 - O77 2C,~
~C 7 ll5~o 6 ~C/o 14%
7 2~,o 22%
8 1 ~,'~ 50~,7 9 16~/~ 22C,~
0% 59C,~
1 n: 113 2 1 ~77 4~C~o 5~~'~ 6~07~
' 5 18% 46~,o :.6 n- 0.128 mg/kg 7 n- nt 60,7~ 25%
2~ 3n%
, ~ oO7~ 4 %
~ 1 2~ 0.086 mg/kg 22 0.015 ~M 45%
23 nt 57%
24 nt nt 6% 30C~o 26 7C~ 42%
27 5% 7~C,j 28 2~,'~ 2 ~ CYo 29 2C ~ 9 ~'~
0~,7J 75O7~
31 5O7~ 0.090 mg/kg 32 2% 33%
33 5.90 ~M0.100 ~M0-080 mglkg 0.201 m~g 34 207~ 74c.j ~% 69~,'~
36 'C,~ 37C,j 37 '~% 33%
38 0.274 ~M0-086 mg/kg 39 1% 71%
8.4 ~M0.420 ~M0.071 m~g 41 22% 36%

CA 02254120 1998-ll-lO

Compound Rat Free db/db Mice (Example) ~1a ~2a Fatty Plasma Al~idb GlucoseC
42 0~,S ~9C,~
43 007J ~C j 44 OCaJ 4C~aJ
1% 6C~
46 ln% 23~,7J
47 C,~ 37~,~
48 ' ~ 29C/o 49 ~ 50%
CC,~ 19%
51 0% 2%
52 2% 23%
53 2% 20%
54 7C,j 24%
0~S 31%
56 8~,7J 31%
57 C C~ 30~,S
5 3 c,O 35c,o 5~ o _7C~o 3C j r 2~,S
~n 3% ~OC,O
5O~J 5%
0.079 ~M 42%
3.00 ~M 0.048 lM 39%
71 14Cr~ 0.076 mg~kg 72 13O~7J 43%
73 0% 3%
74 0% 6%
5.4 ~M 0.058 ~M 0.02~. mg/kg 0.110 mglkg 76 0.980 ~M 0.074 ~M 42%
77 5% 25%
78 5.0 ~M 0.325 ~M 0-027 mg~kg 0-028 mg/kg 79 0% 61%
2.4 ~M 0.055 ~M 81%
81 0.380 ~M 0.059 ~M 61%
2 n: 84c~j 3 n 3~,~J
J4 n: ~iS~,~
n: ~0%
,6 n ~0%

Wo 97l43273 PcT/us97losl48 Compound Rat Free db/db Mice ~ (Example) ~la ~2a Fatty Plasma Ac db GlucoseC
87 n- r~ %
89 n- ' J%
7~ 1 ~1 7~ ~707J
32 nt ~0%
~3 n: 7 5~
~4 n- 78%
~5 OC~ 73C~o ~6 1% 71C~o ~7 4% 3~C~o ~8 7% 8~-%
~9 16% 5 %
00 2% 10%
01 3% 38%
- 04 2% 83t,'~o a Human ,B receptors expressed in Chinese hamster ovary cells, compounds tested at 10 nM, results expressed as % of isoproterenol activity (increase in cAMP) at 10 IlM.
S EC50 (~lM) values determined for selected compounds.
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)-benzo~1,3]-dioxole-2,2-dicarboxylic acid diisopropyl ester response (78% increase) at 0.1 mg/kg. EDso (mg/kg) values determined for selected compounds.
10 C ED50 (mg/kg/day) values for lowering of plasma glucose.

The following non-limiting specific examples further illustrate the present invention.

5-{2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[l,3]dioxole-2,2-dicarboxylic acid bis-(2-methoxy-ethyl) ester hydrochloride salt 20To a stirred mixture of 5- l 2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl)-benzo[1,3]dioxole-2,2-dicarboxylic acid (1.0 g, 2.37 mmol), and 2-methoxy-CA 022~4120 1998-ll-lO

1-ethanol (10 mL) was added excess HCl(g). The rnixture became homogeneous and was stirred at 23 ~C. After 12 h, the solution was concentrated, and cnro~,natographed on silica gel, eluting with CHC13/MeOH (1/0, then 40/1, 20/1 and 10/1) to give fractions con~ining 5- ~ 2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl } -benzo[1,3]dioxole-2,2-dicarboxylic acid bis-(2-methoxy-ethyl) ester (RpO.37 (10/1 CHC13/MeOH)) as a viscous oil. This oil was dissolved in Et20 (10 rnL) and HCl(g) was bubbled through the solution for 1 min. The resulting solution was evaporated to give 1.06 g (78 %) of 5-(2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl)-benzo[1,3]dioxole-2,2-dicarboxylic acid bis-(2-methoxy-ethyl) ester hydrochloride salt as a white solid; IH NMR (300 MHz, CDC13): ~ 1.33 (brm, 3H), 2.75-2.88 (brm, lH), 3.10-3.30 (brm, 2H), 3.35 (s, 6H), 3.40-3.53 (brm 2H), 3.63-3.68 (complexm,4H), 4.40-4.48 (brm, 4H), 5.40-5.50 (brd, IH), 5.50-5.75 (brs, lH), 6.70-6.91 (complex m, 4H), 7.18-7.38 (m, 2H), 7.43 (s, lH), 8.60-8.85 (brs, lH), 9.90-10.15 (brs, lH); MS (ES) m/z (relative intensity): 538 (M+-HCI, 100).

~-{2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[l,3]dioxole-2,2-dicarboxylic acid diphenethyl ester hydrochloride salt The title compound was prepared from 5-~2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl }-benzol l ,3]dioxole-2,2-dicarboxylic acid and 2-phenylethanol accord-ing to the procedure of Example 1 as a colorless oil; lH NMR (300 MHz, CDC13): d 1.30-1.45 (brs, 3H), 2.80-2.90 (brm, lH), 2.89 (t, J = 6.9 Hz, 4H), 3.10-3.30 (brm, 2H), 3.39-3.69 (brm, H), 4.40 (t, J = 6.8 Hz, 4H), 5.45-5.61 (brs, 2 H), 6.70-6.91 (brm, 3 H), 7.10-7.35 (complex m, 13H), 7.40-7.51 (brs, lH), 8.60-8.85(brs, lH), 9.91-10.20 (brs, lH); MS (ES) m/z (relative intensity): 630 (M+-HCI, 40), 144 (100).

CA 02254120 1998-ll-lO

5-{2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzoll,3]dioxole-2,2-dicarboxylic acid bis-(2-butoxy-ethyl) ester hydrochloride salt The title compound was prepared from 5-(2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino] -propyl ~ -benzo[1,3]dioxole-2,2-dicarboxylic acid and 2-butoxyethanol accord-ing to the procedure of Example 1 as a colorless oil; lH NMR (300 MHz, CDCl3): ~ 0.78-0.93 (m, 6H), 1.15-1.78 (m, 12H), 2.70-3.62 (brm, 5H), 3.31 -3.4710(m, 4H), 3.57-3.73 (m, 4H), 4.29-4.53 (m, 4H), 5.47-5.57 (brs, lH), 6.70-6.95 (m, 3H), 7.20-7.49 (m, 4H); MS (ES) m/z (relative intensity): 622 (M+-HCl, 20), 214 (10), 158 (1()).

155-{2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[l,3]dioxole-2,2-dic~rboxylic acid bis-(2-phenoxy-ethyl) ester hydrochloride salt The title compound was prepared from 5-~2-[2-(3-chloro-phenyl)-2-hydroxy-20ethylamino]-propyl )-benzo[1,3]dioxole-2,2-dicarboxylic acid and 2-phenoxyethanol according to the procedure of Example 1 as an off-white gummy solid; lH NMR (300MHz, CDC13): o 1.23-1.40 (brs, 3H), 2.70-2.90 (brm, lH), 3.05-3.30 (brrn, 2H), 3.31-3.52 (brm, 2H), 4.12 (t, J = 4.4 Hz, 4 H), 4.57 (t, J = 4.8 Hz, 4 H), 5.38-5.60 (brs, 2H), 6.70-7.0 (complexm, IOH), 7.15-7.47 (complex m, 7 H), 8.60-8.80 (brs,25lH), 9.90-10.20 (brs, 1 H).; MS (ES) m/z (relative intensity): 662 (M~-HCl, (100), 594 (20), 498 (35).

5-{2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-- 30benzo[1,3]dioxole-2,2-dicarboxylic acid bis-(2-ethoxy-ethyl) ester hydrochloride salt The title compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl l -benzo~ 1,3]dioxole-2,2-dicarboxylic acid and 2-ethoxyethanol 35according to the procedure of Example I as an oily off-white gummy solid; lH NMR

CA 022~4120 1998-ll-lO

(300 MHz, CDC13): ~ 1.10-1.20 (t overlaps with d, J = 6.9 Hz, 9H), 1.31-1.41 (brm, 2 H), 2.75-2.90 (brm, lH), 3.10-3.30 (brm, 2H), 3.50 (brq, J = 6.9 Hz, 4H), 3.62-3.71 (brm, 4H), 4.37-4.47 (brm, 4H), 5.30-S.70 (brm, 2H), 6.70-6.90 (brm, 4H), 7.19-7.50 (brm, 3H), 8.50-8.85 (brs, lH), 9.90-10.30 (brs, lH); MS (ES) mlz (relative intensity): 566 (M~-HCI, (60).

EXAMPLE 6 and EXAMPLE 7 5-{2-~2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[lj3]dioxole-2,2-dicarboxylic acid bis-(2-tert-butoxy-ethyl) ester and 5-{2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[l,3]dioxole-2,2-dicarboxylic acid (2-tert-butoxy-ethyl) ester To a stirred mixture of 5- (2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl~-benzo[1,3]dioxole-2,2-dicarboxy}ic acid (1.0 g, 2.37 mmol), and 2-t-butoxy-l-ethanol (10 mL) was added p-toluenesulfonic acid (451 mg, 2.37 mmol). The mixture became homogeneous and was stirred at 23 ~C. After 12 h, an additional portion of p-toluenesulfonic acid (351 mg, 1.84 mmol) was added. After a total of 90 h, the solution was concentrated, and chromatographed on silica gel, eluting with CHC13/MeOH (1/0, then 40/1, 20/1 and 10/1) to give 100 mg (7 %) of 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl ~ -benzo[1,3]dioxole-2,2-dicarboxylic acid bis-(2-tert-butoxy-ethyl) ester (Rf~0.25 (10/1 CHC13/MeOH)) as a yellow oil and 320 mg (26 %) of 5-(2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl~-benzo[1,3]dioxole-2,2-dicarboxylic acid (2-tert-butoxy-ethyl) ester (Rf=0.09 (10/1 CHCl3/MeOH)) as an off-white solid.

5- ~ 2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl ) -benzo[1,3]dioxole-2,2-dicarboxylic acid bis-(2-tert-butoxy-ethyl) ester; IH NMR (300 MHz, CDC13): ~
1.15 (d, 3H), 1.68 (s, 18 H), 1.85-2.40 (brm, 2H), 2.50-2.75 (m, 2H), 2.81-2.96 (m, lH), 3,41-3.51 (m, 4H), 3.56-3.64 (m, 2H), 3.65-3.76 (m, 4H), 4.30-4.41 (m, 2H), 6.61-6.87 (m, 4H), 7.15-7.33 (m, 2H), 7.44 (s, lH); MS (ES) m/z (relative intensity): 622 (M+, 90),522 (M+-t-BuOCH2CH3, 60), 3S2 (40), 266 (100).

- 5- (2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl ) -benzo[1,3]dioxole-2,2-dicarboxylic acid (2-tert-butoxy-ethyl) ester; lH NMR (300 MHz, CDCl3): ~ 1.10 - (brm, 12H), 2.25-2.70 (brm, 2H), 3.00-3.30 (brm, SH), 3.51-3.61 (m, 2H), 4.25-4.47 (m, 2H), 5.20-5.35 (brm, lH), 6.50-6.70 (brm, 4H), 7.15-7.44 (m, 3H), 8.70-9.70 (brs, lH). MS (ES) m/z (relative intensity): 522 (M+, 100).

S-{2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl~
ben~o[1,3]dioxole-2,2-dicarboxylic acid bis-(2-isobutoxy-ethyl) ester The title compound was prepared from 5-~2-~2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl }-benzo[1,3]dioxole-2,2-dicarboxylic acid and 2-isobutoxyethanol according to the procedure of Example 1 as a colorless oil; lH NME~ (300 MHz, CDCl3): ~ 0.70-0.95 (m, 12H), 1.10-2.0 (complexm, 1 lH), 3.09-3.29 (m, 4H), 3.51-3.58 (m, lH), 3.60-3.72 (m, 4H), 4.31-4.48 (m, 2H), 6.70-7.00 (m, 4H), 7.15-7.50(m, 4H); MS (ES) m/z (relative intensity): 622 (M+-HCl, 100).

5 {2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benYol1,3]dioxole-2,2-dic~rboxylic acid bis-(benzyl) ester hydrochloride salt The title compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylarnino]-propyl ) -benzo[1,3]dioxole-2,2-dicarboxylic acid and benzyl alcohol according to the procedure of Example 1 as a gummy white solid: lH NMR (300 MHz,CDCl3): ~ 1.26-1.32 (m, 3H), 2.76 (brt, lH), 3.01-3.21 (brrn, 2H), 3.36-3.49 (brrn, 2H), 5.24 (s, 4H), 5.41 (d, J=9.5 Hz, lH), 6.70-6.88 (m, 3H), 7.12-7.44 (complexm, 14H), 8.70-8.83 (brs, lH), 9.95-10.10 (brs, lH); MS (ES) m/z (relative intensity):
602 (M+, 100).

5-{2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo~l,3]dioxole-2,2-dicarboxylic acid bis-(cyclohexyl) ester hydrochloride salt s The title compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl)-benzo~1,3]dioxole-2,2-dicarboxylic acid and cyclohex~nc-l according to the procedure of Example 1 as a yellow gum: lH NMR (300 MHz, CDC13): ~ 1.10-1.40 (complex m, 7H), 1.45-1.60 (brrn, 4H), 1.63-1.81 (brm, 8H), 101.82-1.95 (brm, 4H), 2.72-2.90 (brm, lH), 3.10-3.30 (brm, 2H), 3.37-3.55 (m, 2H), 4.90-5.03 (m, 2H), 5.37-5.52 (brs, lH), 6.71-6.90 (complex m, 4H), 7.20-7.32 (m, 2H), 7.44 (s, lH), 8.55-8.80 (brs, lH), 9.90-10.20 (brs, lH); MS (ES) m/z (relative intensity): 585 (M+- HCl), 532 (10).

5-{2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[l,3]dioxole-2,2-dicarboxylic acid bis-(cyclopentyl) ester The title compound was prepared from 5-(2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl)-benzo[1,3]dioxole-2,2-dicarboxylic acid and cyclopentanol as a 20 yellow gum according to the procedure of Example 1, leaving out the final HCl(g~/Et20 hydrochloride salt forming step: IH NMR (300 MHz, CDC13): ~ 1.07 (d, J=6.2 Hz, 3H), 1.50-2.00 (complex m, 16H), 2.52-2.70 (complex m, 3H), 2.85-2.95 (m, 2 H), 4.55-4.65 (m, lH), 5.29-5.38 (m, 2H), 6.65-6.72 (m, lH), 6.76 (s, lH), 6.84 (d, J=8.0 Hz, lH), 7.18-7.30 (m, 3H), 7.37 (s, lH); MS (ES) mtz (relative intensity):
25558 (M+, 100), 518 (10), 490 (20).

5-{2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl~-benzo[l,3]dioxole-2,2-dicarboxylic acid dioctyl ester The title compound was prepared from 5-~2-~2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl ~ -benzo[1,3]dioxole-2,2-dicarboxylic acid and 1 -octanol as a gummy white solid according to the procedure of Example 1, leaving out the finalHCl(g)/Et20 hydrochloride salt forming step: IH NMR (300 MHz, CDC13): ~ 0.78-350.90 (m, 6H), 0.95-1.40 (brm, 23H), 1.52-1.87 (m, 6H), 2.55-2.75 (brs, lH), 2.89-CA 02254l20 l998-ll-lO

~ 3.30 (brm, 4H), 4.12-4.33 (m, 4H), 5.15-5.35 (brs, lH), 6.60-6.81 (m, 3H), 7.12-7.45 (m, 4H); MS (EI) m/z (relative intensity): 645 (M+, 5), 504 (100), 348 (100), 319 ~ (100), 180 (100).

5-{2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[l,3]dioxole-2,2-dicarboxylic acid dipentyl ester The title compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl } -benzo[1,3]dioxole-2,2-dicarboxylic acid and 1 -pentanol as a brown gum according to the procedure of Example 1, leaving out the final HCl(g)/Et20 hydrochloride salt forrning step: IH NMR (300 MHz, CDC13): ~ 0.90 (t, J=6.9 Hz, 3H), 1.21-1.41 (brm, lOH), 1.67 (t, J=7.0 Hz, 4H), 1.80-2.10 (brs, lH), 2.80 (t,J=6.5 Hz, lH), 3.05-3.19 (brm, 2H), 3.45 (d, J=10.4 Hz, 2H), 4.28 (t, J = 6.7 Hz, 4H), 5.46 (d, J=9.6 Hz, lH), 5.50-5.90 (brs, lH), 6.71-6.90 (m, 3H), 7.20-7.35 (m, 3H), 7.43 (s, lH), 8.76 (brs, lH), 1.05 (brs, lH); MS (ES) m/z (relative intensity):
562 (M+, 100).

5-{2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl~-benzo[l,3]dioxole-2,2-dicarboxylic acid dihexyl ester The title compound was prepared from 5-(2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl~-benzo[1,3]dioxole-2,2-dicarboxylic acid and 1-hexanol as a white solid according to the procedure of Example 1, leaving out the final HCl(g)/Et20hydrochloride salt forming step: lH NMR (300 MHz, CDC13): ~ 0.75-0.90 (m, 6H), 1.00-1.41 (brm, l5H), 1.47-1.85 (m, 6H), 2.60-3.50 (brm, SH), 4.15-4.30 (m, 4H),5.18-5.35 (brs, lH), 6.67-6.82 (m, 3H), 7.15-7.45 (m, 4H); MS (ES) m/z (relativeintensity):

CA 02254120 1998-ll-lO

Carbonic acid 3~chloro-benzyl ester 2-(3-chloro-benzyloxycarbonyloxy)-4-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino3-propyl}-phenyl ester The title compound was prepared from 5-{2-~2-(3-chloro-phenyl)-2-hydroxy-ethylarnino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid and 3-chlorobenzyl alcohol as a tan solid according to the procedure of Example 1, leaving out the final HCl(g)/Et2O hydrochloride salt forming step: lH NMR (300 MHz, CDCl3): ~ 1.28 (d,10J=6.3 Hz, 3H), 1.80-2.40 (brs, lH), 2.79 (t, J=8.8 Hz, lH), 3.05-3.17 (brm, 2H), 3.37-3.49 (m, 2H), 5.23 (s, 4H), 5.43 (m, lH), 6.72-6.88 (m, 3H), 7.10-7.44 (complexm, 12H), 8.76 (brs, lH), 10.02 (brs, lH); MS (ES) m/z (relative intensity):
670 (M+, 100) 5-{2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylaminol-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid bis-(1-phenyl-ethyl) ester The title compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-20ethylamino]-propyl)-benzo[1,3]dioxole-2,2-dicarboxylic acid and 1-phenylethanol as a gummy tan solid according to the procedure of F~mple 1, leaving out the final HCl(g)/Et20 hydrochloride salt forming step: IH NMR (300 MHz, CDCl3): ~ 0.90-1.22 (m, 6H), 1.30-1.61 (m, 6H), 2.39-2.70 (brm, lH), 2.83-3.19 (brm, 2H), 3.20-3.50 (brm, 2H), 5.15-5.35 (brs, lH), 5.90-6.02 (brm, lH), 6.45-6.82 (m, 3H), 7.11-257.40 (m, 4H), 8.6~ (brs, IH), 9.45 (brs, lH); MS (ES) m/z (relative intensity): 630 (M+, 100).

5-{2.[2-(3-Chloro~phenyl)-2-hydroxy-ethylamino]-propyl}-30benY.o[1,3]dioxole-2,2-dicarboxylic acid diheptyl ester The title compound was prepared from 5-(2-[2-(3-chloro-phenyl)-2-hydroxy-ethylarnino]-propyl ) -benzo[1,3]dioxole-2,2-dicarboxylic acid and 1 -heptanol as a brown gum according to the procedure of Example 1, leaving out the final HCl(g)/Et20 35hydrochloride salt forming step: IH NMR (300 MHz, CDCl3): o 0.80-0.92 (m, 6H), CA 02254l20 l998-ll-lO

~ 1.23-1.40 (brm, l9H), 1.60-1.75 (m, 4H), 2.80 (t, J=8.8 Hz, lH), 3.05-3.30 (brm, 2H), 3.38-3.50 (m, 2H), 4.27 (q, J=6.7 Hz, 4H), 5.43 (d, J=8.4 Hz, lH), 6.72-6.90 ~ (m, 4H), 7.20-7.33 (m, 2H), 7.44 (s, lH), 8.70 (brs, lH), 10.10 (brs, lH); MS (ES) m/z (relative intensity): 618 (M+, 100).
s 5-{2-~2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2~dicarboxylic acid dinonyl ester The title compound was prepared from 5-~2-[2-(3-chloro-phenyl)-2-hydroxy-ethylaminol-propyl ~ -benzo[1,3]dioxole-2,2-dicarboxylic acid and 1 -nonanol as a brown gum according to the procedure of Example 1, leaving out the final HCl~,)/Et20 hydrochloride salt forming step: IH NMR (300 MHz, CDC13): S 0.88 (t, J-6.8 Hz, 9H), 1.25-1.40 (m, 22H), 1.54-1.60 (m, 2H), 1.63-1.74 (m, 4H), 2.79 (brt, J = 8.8 15Hz, lH), 3.()8-3.30 (m, 2H), 3.40-3.55 (m, 2H), 4.28 (t, J=6.8 Hz, 4H), 5.46 (d, J=8.7 Hz, lH), 6.70-6.90 (m, 3H), 7.15-7.35 (m, 3H), 7.43 (s, lH), 8.72 (brs, lH), 9.98 (brs, lH); MS (ES) m/z (relative intensity): 674 (M+, 100), 548 (M+-CgH20, 5).

205-{2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[l,3]dioxole-2,2-dicarboxylic acid bis-decyl ester The title compound was prepared from 5-(2-~2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid and and 1-decanol as a 25brown gum according to the procedure of Example 1, leaving out the final HCl~,)/Et20 hydrochloride salt forming step: lH NMR (300 MHz, CDCl3): ~ 0.88 (t, J=6.8 Hz, 9H), 1.15-1.40 (m, 24H), 1.52-1.60 (m, 4H), 1.62-1.74 (m, 4H), 2.80 (brt, J = 8.8 Hz, lH), 3.08-3.28 (m, 2H), 3.35-3.52 (m, 2H), 4.28 (t, 1=6.7 Hz, 4H), 5.45 (d, J=8.8 Hz, lH), 6.70-6.90 (m, 3H), 7.18-7.35 (m, 3H), 7.43 (s, lH), 8.71 (brs, lH), 3010.02 (brs, lH); MS (ES) m/z (relative intensity): 702 (M+, 100).

5-{2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[l,3]dioxole-2,2-dicarboxylic acid didodecyl ester S The title compound was ~ par~d from 5-~2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl)-benzo[1,3]dioxole-2,2-dicarboxylic acid and 1-clodec~nc-l as a brown gum according to the procedure of Example 1, leaving out the final HCl(g)/Et20 hydrochloride salt forming step: lH NMR (300 MHz, CDCl3): o 0.88 (t, J=6.8 Hz, 9H), 1.20-1.40 (m, 30H), 1.51-1.60 (m, 4H), 1.62-1.73 (m, 4H), 2.75-2.85 (m, 10lH), 3.05-3.25 (m, 2H), 3.35-3.52 (m, 2H), 4.28 (t, J=6.8 Hz, 4H), 5.45 (d, J=8.8 Hz, lH), 6.60-6.90 (m, 3H), 7.17-7.40 (m, 3H), 7.43 (s, lH), 8.78 (brs, lH), 10.05 (brs, lH); MS (ES) m/z (relative intensity): 594 (M+, 100).

155-{2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[l,3]dioxole-2,2-dicarboxylic acid bis-(2-isopropoxy-ethyl) ester The title compound was prepared from 5-(2-~2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo~1,3]dioxole-2,2-dicarboxylic acid and 2-isopropoxyethanol 20as a brown solid according to the procedure of Fy;~mrle 1, leaving out the final HCl(g,~/Et2O hydrochloride salt forming step: lH NMR (300 MHz, Cl)Cl3): ~ 1.11 (d, J=6.1 Hz, 12H), 1.30 (d, J=6.2 Hz, 3H), 2.79 (t, J=8.7 Hz, lH), 3.06-3.28 (m, 2H), 3.40-3.60 (m, 2H), 3.62-3.70 (complexm, 4H), 3.90-4.12 (brm, 2H), 4.35 4.45 (complexm, 4H), 5.43 (d, J = 8.7 Hz, lH), 6.61-6.90 (m, 3H), 7.11-7.32 (m, 253H), 7.44 (m, lH), 8.70 (brs, lH), 9.92 (brs, lH); MS (ES) m/z (relative intensity):
758 (M+, 30), 546 (100).

5-{2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-30benzo[l,3]dioxole-2,2-dicarboxylic acid isopropyl ester To a stirred solution of 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl~-benzo[1,3]dioxole-2,2-dicarboxylic acid Ws-isopropyl ester hydrochloride salt (3.0 g, 5.53 mmol) and 20 mL of i-PrOH was added was added lN NaOH (11.1 mL, 11.1 mmol). After stirring at 23 ~C for 3 days, the mixture was con-~e~ ed to - dryness, dissolved in 10 % MeOHJCH2C12, and filtered through a small pad of silica gel. The filtrate was concentrated to a colorless gum, and ¢iturated with Et20 to give - 1.0 g (39 ~o) of 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl)-benzo~1,3]dioxole-2,2-dicarboxylic acid isopropyl ester as a white solid; lH NMR(300 MHz, CDC13): o 0.93 (d, J=6.1 Hz, 3H), 1.17 (d, J=6.3 Hz, 6H), 2.30-2.53 (m, 2H), 2.67-2.80 (m, 2H), 2.85-3.00 (m, lH), 4.65-4.75 (brs, lH), 4.91 (hept, J=6.3 Hz, lH), 6.52-6.80 (complexm, 3H), 7.17-7.45 (complexm, 4H); MS (ES) m/z (relative intensity): 464 (M+, 100).

5-{2-[2-(3-Chloro-phenyl)~2-hydroxy-ethylamino]-propyl}-ben~.o[l,3]dioxole-2t2-dicarboxylic acid ethyl ester The title compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzoL1,3]dioxole-2,2-dicarboxylic acid bis-ethyl ester hydrochloride according to the procedure of Example 22 as a brown solid: lH NMR
(300 MHz, CDC13): o 1.20 (d, J=6.7 Hz, 3H)1 1.33 (t, J=7.1 Hz, 3H), 2.70 (m, lH), 2.90-3.22 (m, 4H), 3.23-3.48 (m, lH), 4.34 (q, J=7.1 Hz, 2H), 5.30 (m, lH), 6.55-6.90 (m, 3H), 7.10-7.45 (m, 4H); MS (ES) m/z (relative intensity): 450 (M++1, 50 ).

5-{2-~2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[l,3]dioxole-2,2-dicarboxylic acid bis-methoxycarbonylmethyl ester Step 1 5-(2-{tert-Butoxycarbonyl-[2-(3-chloro-phenyl)-2-hydroxy-ethyl]-amino}-propyl)-ben~.o[1,3]dioxole-2,2-dicarboxylic acid bis-ethyl ester ~ 30 To a stirred solution of 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylarnino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid diethyl ester hydrochloride salt (5.0 g, 9.72 mmol), and THF (90 mL) was added i-Pr2NEt (4.23 mL, 3.14 g, 24.3 mmol) and (Boc)2O (2.12 g, 9.72 mmol). After 6 h, an additional portion of (Boc)2O (200 mg, 0.92 mmol) is added. After a total of 22 h, the solution was quenched with 10 mL
of sat. aq. NaHC03, and extracted with 3 x 100 rnL Et20. The combined organics were washed with 1 x 150 mL of brine, dried over MgSO4, filtered and concentrat~d to a yellow oil. Flash chromatography on silica gel, eluting with hex~ne~/EtOAc (V1) gave 5.07 g (90 %) of product as a sticky, off-white solid; IH NMR (300 MHz, CDC13): ~ 1.22 (d, J = 6.9 Hz, 3H), 1.30-1.47 (m, l5H), 2.47-2.54(m, lH), 2.57-2.70 (m, lH), 3.05-3.15 (m, lH), 3.46-3.68 (m, lH), 4.08-4.18 (m, lH), 4.29-4.42(m, 4H), 4.75 (brd, J = 8.6 Hz, lH), 5.51 (brs, lH), 6.55-6.88 (complexm, 4H), 7.20-7.44 (m, 3H); MS (ES) m/z (relative intensity): 578 (M+, 1), 504 (20), 336 (60), 298 (20), 198 (100), 180 (40).

Step 2 5-(2-{tert-Butoxycarbonyl-~2-(3-chloro-phenyl)-2-hydroxy-ethyl]-amino}-propyl)-benzo[1,3]dioxole-2,2-dicarboxylic acid To a stirred solution of 5-(2-{tert-butoxycarbonyl-[2-(3-chloro-phenyl)-2-hydroxy-ethyl]-amino)-propyl)-benzo[1,3]dioxole-2,2-dicarboxylic acid bis-ethyl ester (4.42 g, 7.65 mmol), MeOH (100 mL) and H20 (25 mL) was added S N NaOH (7.64 mL, 38.2 mmol). After 19 h, the solution was concentrated to an aqueous mixture and acidifîed to pH = I with I N aq. HCI which turns the solution rnilky-white. Extraction with 3 x 100 rnL EtOAc, washing the combined organics with 1 x 200 mL brine, drying over Na2SO4, filtration and concentration gave 3.96 g (99 %) of product as a white solid; IH NMR (300 MHz, DMSO-d6). ~ 1.16 (d, J = 6.7 Hz, 3H), 1.31 (s, 9H), 2.55-2.70 (m, lH), 2.80-2.92 (m, lH), 3.05-3.23 (m, 2H), 3.71-3.93 (m, 2H),4.62-4.87 (m, 2H), 5.30-5.90 (brs, lH), 6.59-6.99 (complexm, 4H), 7.14-7.47 (complexm, 3H), 8.60-8.80 (brs, lH); MS (ES) m/z (relative intensity): 522. (M++25 H, 50).

Step 3 5-(2-{tert-Butoxycarbonyl-[2-(3-chloro-phenyl3-2-hydroxy-ethyl]-amino}-propyl)-benzo[1,3]dioxole-2,2-dicarboxylic acid bis-30 methoxycarbonyl-methyl ester To a stirred solution of 5-(2- ~ tert-butoxycarbonyl-[2-(3-chloro-phenyl)-2-hydroxy-ethyl3-amino } -propyl)-benzo[1,3]dioxole-2,2-dicarboxylic acid (500 mg,0.96 mmol) and DMF (10 mL) was added K2C03 (132 mg, 0.96 mmol) and methyl-2-bromo~cet~te (0.23 mL, 366 mg, 2.40 mmol). After stining at 50 ~C for 4 h, the CA 02254120 1998-ll-lO

W O 97/43273 PCTrUS97/08148 ~ reaction mixture was cooled to 23 ~C, quenched with 5 mL sat. aq. NaHCO3, and extracted with 3 x 30 mL of EtOAc. The combined organics were washed with 2 x 50~ mL brine, dried over MgSO4, filtered and concentrated to a yellow oil. Flash chromatography on silica gel, eluting with hexane/EtOAc (4/1 to 2/1), gave 508 mg (79 %) of product as a colorless oil; IH NMR (300 MHz, CDCl3): ~ 1.22 (d, J = 6.9 Hz, 3 H), 1.41 (brs, 9H), 2.50-2.60 (brm, lH), 2.60-2.75 (brm, lH), 3.06-3.15 (brm, lH), 3.45-3.60 ~brm, lH), 3.76 (s, 3H), 3.77 (s, 3H), 4.05-4.20 (brm, lH), 4.70-4.79 (brm, lH), 4.79(s, 2H), 4.80(s, 2H), 5.42-5.51 (brs, lH), 6.60-6.91 (complexm, 4H), 7.20-7.43(complexm, 3H); MS (ES) m/z (relative intensity): 666 (M+, (100), 610 (25).

Step 4 5-~2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3}-dioxole-2,2-dicarboxylic acid bis-methoxycarbonylmethyl ester To a stirred solution of 5-(2- ~tert-butoxycarbonyl-[2-(3-chloro-phenyl)-2-hydroxy-ethyl]-amino3-propyl)-benzo[1,3]dioxole-2,2-dicarboxylic acid bis-methoxycarbonyl-methyl ester (330 mg, 0.50 mmol) and CH2C12 (10 mL) was added trifluoroacetic acid (0.08 mL, 113 mg, 0.99 mmol). After stirring at 23 ~C for 1 h, additional trifluoroacetic acid (0.08 mL,113 mg,0.99 mmol) was added. After a total of 22 h, the mixture was quenched with 5 mL of sat. aq. NaHCO3, and extracted with 3 x 30 mL of EtOAc. The combined organics were washed with 1 x 50 mL of brine, dried over MgSO4, filtered and concentrated to a yellow oil. Flash chromatography on silica gel, eluting with CHC13/MeOH (20/1 to 10/1) gave 145 mg (52 %) of product as a white gum; lH NMR (300 MHz, CDC13): o 1.33 (m, 3H), 1.70-2.40 (brm, 2H), 2.73-2.90 (brt, lH), 3.04-3.30 (m, 2H), 3.37-3.53 (m, 2H), 3.75 (s, 3H), 3.76 (s, 3H), 4.80 (s, 2H), 4.81 (s, 2H), 5.40 (m, lH), 6.73-6.93 (complexm, 4H), 7.15-7.32 (m, 2H(), 7.43 (s, lH); MS (ES) m/z (relative intensity): 566 (M+, 80), 508 (M+ -CO2CH3+H, 100), 450 (M+ - 2CO2CH3+2H, 30).

Wo 97143273 PCT/USg7/08148 5-{2- [2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo~l,3]dioxole-2,2-dicarboxylic acid bis-propoxycarbonylmethyl ester s Step 1 5-(2-{tert-Butoxycarbonyl-[2-(3-chloro-phenyl)-2-hydroxy-ethyl]-amino}-propyl)-benzo[1,3]dioxole-2,2-dicarboxylic acid bis-propoxycarbonylmethyl ester The title compound was prepared from 5-(2-{tert-butoxycarbonyl-[2-(3-chloro-phenyl)-2-hydroxy-ethyl]-amino}-propyl)-benzo[1,3]dioxole-2,2-dicarboxylic acid and propyl 2-bromoacetate according to the procedure of Example 24, step 3 as a colorless oil: lH NMR (300 MHz, CDC13): ~ 0.91 (t, J=7.4 Hz, 6H), 1.21 (d, J=6.9 Hz, 3H), 1.40 (s, 9H), 1.55-1.72 (m, 4H), 2.47-2.70 (m, lH), 3.05-3.17 (m, lH), 3.46-3.60(m, lH), 4.11 (t, J=6.6 Hz, 4H), 4.70-4.85 (m, 4H), 5.47 (s, lH), 6.60-6.92 (m, 3H), 7.20-7.35 (m, 3H), 7.41 (s, lH); MS (ES) m/z (relative intensity): 722 (M+,100).

Step 2 5-~2-[2-(3-Chloro-phenyl)-2-hydroxy~ethylamino]-propyl}-benzo[1,31-dioxole-2,2-dicarb~xylic acid bis-propoxycarbonylmethyl ester The title compound was plGpared from 5-(2-~tert-butoxycarbonyl-[2-(3-chloro-phenyl)-2-hydroxy-ethyl]-amino}-propyl)-benzo[1,3]dioxole-2,2-dicarboxylic acid bis-propoxyoxycarbonylmethyl ester according to the procedure of Example 24, step 4 as a brown gum: IH NMR (300 MHz, CDCl3): ~ 0.80-0.95 (m, 9H),1.40-1.80 brm, 6H), 2.80-3.74 (brm, 7H), 4.05-4.20 (m, 4H), 4.70-4.85 (m, 2H), 5.10 (brs, lH), 6.70-6.95 (brm, 3H), 7.15-7.40 (brm, 4H); MS (ES) m/z (relative intensity): 622 (M+, 100).

CA 02254l20 l998-ll-lO

~ EXAMPLE 26 5-{2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-- benzo[l,3]dioxole-2,2-dic~rboxylic acid bis-(l-methoxycarbonyl-ethyl) ester Step 1 5-(2-{tert-Butoxycarbonyl-[2-(3-chloro-phenyl)-2-hydroxy-ethyl]-amino}-propyl)-ben~.oll,3]dioxole-2,2-dicarboxylic acid bis-(l-methoxycarbonyl-ethyl~ester The title compound was ~repa-~d from 5-(2- ~ tert-butoxycarbonyl-[2-(3-chloro-phenyl)-2-hydroxy-ethyl]-amino ) -propyl)-benzo[1,3]dioxole-2,2-dicarboxylic acid and methyl 1-bromopropionate according to the procedure of Example 24, step 3 as a colorless oil: IH NMR (300 MHz, CDC13): o 1.22 (d, J=6.9 Hz, 3H), 1.38 (s, 9H), 2.50-2.70 (m, 2H), 2.89 (s, 3H), 2.96 (s, 3H), 3.07-3.15 (m, lH), 3.45-3.60 (m, lH), 3.70-3.83 (m, 8H), 4.05-4.18 (m, lH), 4.72-4.80 (m, lH), 5.22-5.32 (m, lH),6.60-6.90 (m, 3H), 7.20-7.32 (m, 3H), 7.41 (s, lH); MS (ES) m/z (relative intensity):
694 (M+, 10()), 638 (M+-t-Bu, 20), 594 (M+-Boc, 20).

Step 2 5-{2-12-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[l,31dioxole-2,2-dicarboxylic acid bis-(l-methoxycarbonyl-ethyl)ester The title compound was prepared from 5-(2-ttert-butoxycarbonyl-[2-(3-chloro-phenyl)-2-hydroxy-ethyl]-amino)-propyl)-benzo[1,3]dioxole-2,2-dicarboxylic acid bis-methoxycarbonyl- l-ethyl ester according to the procedure of Fy~mple 24, step 4 as a colorless gum: IH NMR (300 MHz, CDCl3): o 1.28 (d, J=6.7 Hz, 3H), 1.30-2.00 (brm, 2H), 1.55-1.65 (m, 6H), 2.70-2.80 (m, lH), 3.05-3.30 (m, 2H), 3.35-3.69 (m, 2H), 3.68-3.80 (m, 6H), 5.10-5.18 (m, lH), 5.22-5.31 (m, 2H), 6.70-6.95 (m, - 30 3H), 7.15-7.30 (m, 3H), 7.36 (s, lH); MS (ES) m/z (relative intensity): 594 (M+, 100).

CA 02254120 1998-ll-lO

5-{2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[l,3]dioxole-2,2-dicarboxylic acid bis-isopropoxycarbonylmethyl ester Step 1 5-(2-{tert-Butoxycarbonyl-[2-(3-chloro-phenyl)-2-hydroxy-ethyl]-amino}-propyl)-benzo[1,3]dioxole-2,2-dicarboxylic acid bis-isopropoxycarbonyl-methyl ester 10The title compound was prepared from 5-(2-{tert-butoxycarbonyl-[2-(3-chloro-phenyl)-2-hydroxy-ethyl]-amino)-propyl)-benzo[1,3]dioxole-2,2-dicarboxylic acid and isopropyl 2-bromoacetate according to the procedure of Example 24, step 3 as a colorless oil: lH NMR (300 MHz, CDC13): ~ 1.15-1.30 (m, 15H), 1.40 (s, 9H), 2.45-2.70 (m, 2H), 3.06-3.15 (m, lH), 3.45-3.60 (m, lH), 4.05-4.18 (m, 2H), 4.70-4.8015(m, 4H), 5.06 (sept, J=6.3 Hz, 2H), 5.46 (brs, lH), 6.60-6.90 (m, 3H), 7.20-7.35 (m, 3H),7.41 (s, lH).; MS (ES) m/z (relative intensity): 722 (M+, 100).

Step 2 5-{2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]~propyl}-benzo 20[1,3]dioxole-2,2-dicarboxylic acid bis-isopropoxycarbonylmethyl ester The title compound was plcpa~,d from 5-(2-~tert-butoxycarbonyl-[2-(3-chloro-phenyl)-2-hydroxy-ethyl]-amino)-propyl)-benzo[1,3]dioxole-2,2-dicarboxylic acid bis-isopropoxycarbonylmethyl ester according to the procedure of Example 24, step 3 25as a brown gum: IH NMR (300 MHz, CDC13): ~ 1.17-1.30 (m, 15H), 2.72-2.82 9m, lH), 3.10-3.29 (m, 3H), 3.38-3.50 (m, lH), 4.70-4.80 (m, 4H), 4.95-5.18 (complexm, 3H), 6.72-6.95 (m, 3H), 7.15-7.30 (m, 3H), 7.36 (s, lH), 8.73 (brs, lH), 9.86 (brs, lH); MS (ES) m/z (relative intensity): 622 (M+, 100).

CA 022~4120 1998-11-10 5-{2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzoll,3]dioxole-2,2 dicarboxylic acid bis-ethoxycarbonylmethyl ester s Step 1 5-(2-{tert-Butoxycarbonyl-[2-(3-chloro-phenyl)-2-hydroxy-ethyll-amino}-propyl)-benzo[1,3]dioxole-2,2-dicarboxylic acid bis-ethoxycarbonyl methylester The tit~e compound was prepared from 5-(2-(tert-butoxycarbonyl-[2-(3-chloro-phenyl)-2-hydroxy-ethyl]-amino}-propyl)-benzo~1,3]dioxole-2,2-dicarboxylic acid and ethyl bromoacetate according to the procedure of Example 24, Step 3 as a colorless oil;
1H NMR (300 MHz, CDC13): ~ 1.17-1.30 (m, 9H), 1.39 (s, 9H), 2.48-2.54 (brm, lH), 2.55-2.61(brm, lH), 3.07-3.13 (m, 2H), 3.47-3.55 (brm, lH), 4.05-4.20 (brrn, lH), 4.21 (q, J = 7.0 Hz, 4H), 4.20-4.33 (brm, lH), 4.78 (s, 2H), 4.79 (s, 2 H),5.45-5.50 (brm, 1 H), 6.61-6.85 (m, 4H), 7.20-7.43 (m, 3H); MS (ES) m/z (relative intensity): 694 (M+, (100), 638 (15), 594 (15).

Step 2 5-{2-~2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl~-benzo[1,3]
dioxole-2,2-dic~rboxylic acid bis-ethoxycarbonylmethyl ester The title compound was prepared from 5-(2-{tert-butoxycarbonyl-[2-(3-chloro-phenyl)-2-hydroxy-ethyll-amino~-propyl)-benzo[1,3]dioxole-2,2-dicarboxylic acid bis-ethoxycarbonylmethyl ester according to the procedure of Example 24, Step 4 as a white gum; lH NMR (300 MHz, CDC13): ~ 1.15-1.27 (m, 3H), 1.31-1.41 (t, J=6.8 Hz, 6H), 2.53-3.51 (m, 6H), 3.60-3.80 (m, 4H), 4.00-4.10 (brs, lH), 4.15-4.30 (q, J=6.7 Hz, 4H), 4.70-4.85 (brm, lH), 6.60-6.95 (m, 3H), 7.10-7.50 (m, 4H); MS
(ES) m/z (relative intensity): 594 (M+, 10), 522 (80), 508 (80), 436 (100).

CA 022~4l20 l998-ll-lo Wo 97/43273 PCT/USg7/08148 S-{2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[l,3]dioxole-2,2-dicarboxylic acid bis-(l-ethoxycarbonyl-ethyl) ester s Step 1 5-(2-{tert-Butoxycarbonyl-[2-(3-chloro-phenyl)-2-hydroxy-ethyl]-amino}-propyl)-ben~o[1,3]dioxole-2,2-dicarboxylic acid bis-(l-ethoxycarbonyl-ethyl) ester The title compound was prepared from 5-(2- ( tert-butoxycarbonyl-[2-(3-chloro-phenyl)-2-hydroxy-ethyl]-amino)-propyl)-benzo[1,3]dioxole-2,2-dicarboxylic acid and ethyl 2-bromopropionate according to the procedure of Example 24, Step 3 as a colorless oil; IH NMR (300 MHz, CDC13): ~ 1.15-1.30 (complex m, 9H), 1.40 (brs, 9H), 1.52-1.69 (m, 6H), 2.47-2.58 (m, lH), 2.58-2.70 (m, lH), 3.05-3.16 (m, lH),3.42-3.54 (m, lH), 4.05-4.30 (complexm, 5H), 4.77 (m, lH), 5.19-5.30 (m, 2H), 5.49 (brs, lH), 6.57-6.67 (m, lH), 6.71-6.80 (m, lH), 6.82-6.91 (m, 2H), 7.20-7.35 (m,2H),7.41 (brs, lH); MS (ES) m/z (relative intensity): 722 (M+, 100).

Step 2 5-~2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[l,3]dioxole-2,2-dicarboxylic acid bis-(l-ethoxycarbonyl-ethyl) ester The title compound was prepared from 5-(2-(tert-butoxycarbonyl-~2-(3-chloro-phenyl)-2-hydroxy-ethyl]-arnino)-propyl)-benzo[1,3]dioxole-2,2-dicarboxylic acidbis-ethoxycarbonyl-1-ethyl ester according to the procedure of Example 24, Step 4 as a colorless oil; IH NMR (300 MHz, CDCl3): o very complex due to 4 dia~ Gom~
present; MS (ES) m/z (relative intensity): 622 (M+, 40), 522 (M+-CH3CHCO2Et, 100).

CA 022~4120 1998-11-10 5-{2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[l,3]dioxole-2,2-dicarboxylic acid bis-trimethylsilanylmethyl ester S Acetyl chloride (0.59 g, 7.5 mmol) was added to trimethylsilylmeth~ncl (4.03 g, 37.5 mmol) with stirring at room temperature. After 0.5 h, 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino] -propyl ) -benzo[1,3]dioxole-2,2-dicarboxylic acid(1.05 g, 2.5 mmol) was added in portions. The resulting solution was st~rred for 3 days, and then treated with 50 ml of 50% sodium bicarbonate solution, followed by extraction with ethyl acetate (50 ml). The organic extract was dried over anhydrous sodium sulfate, filtered, and evaporated. The residue was passed through a pad of silica gel, eluting with hexanes, and ether-hexanes/l:l until no more trimethylsilylmeth;~nol could be detected. The filter pad was then eluted with ethyl acetate, and the solvent was evaporated to give 1.14 g of the desired product as a colorless gum. Conversion to the HCl salt yielded 1.16 g of white foam; lH NMR (CDC13) ~ 0.06 (s, 18 H), 1.33 (d, J
= 6.5 Hz, 3 H), 2.80 (m, lH), 3.15 (m, lH), 3.20 (m, 1 H), 3.48 (m, 2 H), 4.014 (s, 2 H), 4.015 (s, 2 H), 5.45 (bd, J = 9.7 Hz, 1 H), 5.60 (bs, 1 H), 6.80 (m, 3 H), 7.25 (m, 2 H), 7.45 (s, I H), 8.70 (bs, 1 H), 10.10 (bs, 1 H); IR (KBr): 1763 cm-l (C=O);
MS (ES) m/z 594 (MH+); [a]2D5 -23~ (c, 1.0, CHC13). Anal. Calcd. for C2gH40ClNO7Si2HCI: C, 53.32; H, 6.39; N, 2.22; Cl, 11.24; Si, 8.91. Found: C, 52.65; H, 6.70; N, 2.11; Cl, 11.47; Si, 9.00.

5-~2- 12-(3-Chloro-phenyl)-2-hydroxy-ethylamino] -propyl}-benzo[l,3]dioxole-2,2-dicarboxylic acid bis-(2-trimethylsilanyl-ethyl) ester The title compound was prepared from 5-12-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino] -propyl ) -benzo[1,3]dioxole-2,2-dicarboxylic acid and 2-trimethylsilylethanol according to the procedure of Example 30 as a white foam (HCl salt); IH NMR (CDC13) ~0.03 (s, 18 H), 1.06 (t, J = 8.6 Hz, 4 H), 1.33 (bs, 3 H), 1.90 (bs, lH), 2.80 (bs, IH), 3.18 (bs, 2H), 3.48 (bs, 2 H), 4.37 (t, J = 8.6 Hz, 4 H), 5.45 (bs, 1 H), 6.80 (m, 3 H), 7.26 (m, 2 H), 7.43 (s, 1 H), 8.70 (bs, 1 H),10.10 (bs, 1 H); IR (KBr): 1763 cm-l (C=O); MS (ES) m/z 622 (MH+); [a]25 -23~ (c, CA 02254120 1998-ll-lO

WO 97143273 PCTfUS97/08148 1.0, CHCl3). Anal. Calcd. for C30H44ClNO7Si2-HCl: C, 54.70; H, 6.88; N, 2.13; Cl, 10.76; Si, 8.53. Found: C, 53.96; H, 7.05; N, 1.86; Cl, 8.84; Si, 10.33.

55-{2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid bis-(3-trimethylsilanyl-propyl) ester The title compound was prepared from 5-~2-[2-(3-chloro-phenyl)-2-hydroxy-10ethylamino]-propyl )-benzo[1,3]dioxole-2,2-dicarboxylic acid and 3-trimethylsilylpropanol according to the procedure of Example 30 as a white foam (HCl salt); IH NMR (CDCl3) ~ 0.01 (s, 18 H), 0.46 (m, 4 H), 1.33 (d, J = 6.3 Hz, 3 H), 1.70 (m, 4 H), 2.80 (m, lH), 3.18 (m, 2H), 3.46(m 2 H), 4.24(t, J = 7.0 Hz, 4 H), 5.47 (bd, J = 9.7 Hz, 1 H), 5.70 (bs, 1 H), 6.80 (m, 3 H), 7.25 (m, 2 H), 7.43 (s, 1 15H), 8.70 (bs, 1 H), 10.10 (bs, 1 H); IR (KBr): 1765 cm-l (C=O); MS (ES) m/z 650 (MH+); [a]2D5 -22~ (c, 1.0, CHCl3). Anal. Calcd. for C32H4gClNO7Si2-HCl: C, 55.96; H, 7.()4; N, 2.()4 Cl, 10.32; Si, 8.18. Found: C, 55.82; H, 7.21; N, 1.87; Cl, 10.22; Si, 7.76.

5-{2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylaminol-propyl}-benzo~1,3]dioxole-2,2-dicarboxylic acid bis-(3,3-dimethyl-butyl) ester The title compound was prepared from ~-{2-[2-(3-chloro-phenyl)-2-hydroxy-25ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid and 3,3-dimethylbutanol according to the procedure of Example 30 as a white foam (HCl salt); lH NMR
(CDC13) ~ 0.90 (s, 18 H), 1.33 (bs, 3 H), 1.62 (t, J = 7.4 Hz, 4 H~, 2.80 (bs, lH), 3.18 (bs, 2H), 3.48 (bs, 2 H), 4.35 (t, J = 7.4 Hz, 4 H), 5.45 (bs, 1 H), 6.80 (m, 3 H), 7.26 ~m, 2 H), 7.43 (s, 1 H), 8.70 (bs, 1 H), 10.10 (bs, 1 H); IR (KBr): 1765 30cm-l (C=O); MS (CI) m/z 590 (MH+); [~12DS -24~ (c, 1.0, CHCl3). Anal. Calcd. for C32H44ClNO7HCl: C, 61.34; H, 7.08; N, 2.24; Cl, 11.32. Found: C, 60.79; H, 7.46; N, 2.09; Cl, 11.95.

CA 02254120 1998-ll-lO

~ EXAMPLE 34 5-{2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[l,3]dioxole-2,2-dicarboxylic acid bis-cyclohexylmethyl ester S The title compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid and cyclohexylmeth~nc-l according to the procedure of Example 30 as a white foam (HCl salt); IH NMR
(CDC13) ~ 0.80-1.80 (m, 22 H), 1.33 (bs, 3 H), 2.80 (m, lH), 3.18 (m, 2H), 3.48 (m, 2 H), 4.10 (m, 4 H), 5.50 (bs, 1 H), 6.80 (m, 3 H), 7.25 (m, 2 H), 7.43 (s, 1 H), 8.70 (bs, 1 H), 10.10 (bs, 1 H); IR (KBr): 1765 cm-l (C=O); MS (Cl) m/z 614 (MH+); [o~]2D5 -22~ (c, 1.0, CHC13). Anal. Calcd. for C34H44ClNO7-HCI: C, 62.77;H, 6.82; N, 2.15; Cl, 10.90. Found: C, 61.83; H, 7.27; N, 2.07; Cl, 10.25.

5-{2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid bis-(4-methyl-pentyl) ester The title compound was prepared from 5-l2-[2-(3-chloro-phenyl)-2-hydroxy-ethylaminol-propyl)-benzo[1,3]dioxole-2,2-dicarboxylic acid and 4-methylpentanolaccording to the procedure of Example 30 as a colorless gum (HCI salt); IH NMR
(CDC13) ~ 0.87 (d, J = 6.5 Hz, 12 H), 1.33 (bs, 3 H), 1.10-2.0 (m, 10 H), 2.80 (bs, lH), 3.18 (bs, 2H), 3.48 (bs, 2 H), 4.28(m, 4 H), 5.60 (bs, 2 H), 6.80 (m, 3 H),7.25 (m, 2 H), 7.43 (s, 1 H), 8.70 (bs, 1 H), 10.10 (bs, 1 H); IR (KBr): 1765 crn~l (C=O); MS (Cl) rn/z 590 (MH+); [~12D5 -24~ (c, 1.0, CHCl3). Anal. Calcd. for C32H44CINO7-HCI: C, 61.34; H, 7.08; N, 2.24; Cl, 11.32. Found: C, 60.50; H, 7.36; N, 2.13; Cl, 11.66.

5-{2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo~1,3]dioxole-2,2-dicarboxylic acid bis-(2-cyclohexyl-ethyl ) ester The title compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino] -propyl } -benzo[1,3]dioxole-2,2-dicarboxylic acid and 2-cyclohexylethanol according to the procedure of Example 30 as an off-white foam (HCI salt); IH NMR

WO 97/43273 PCTtUS97/08148 (CDCl3) ~0.80-1.80 (m, 26 H), 1.32 (d, J = 6.3 Hz, 3 H), 2.80 (m, lH), 3.18 (m, 2H)7 3.48 (m, 2 H), 4.32 (t, J = 6.9 Hz, 4 H), 5.45 (bd, J = 9.7 Hz, 1 H), 6.80 (m, 3 H), 7.25 (m, 2 H), 7.45 (s, 1 H), 8.70 (bs, 1 H), 10.0 (bs, I H); IR (KBr): 1765 cm~l (C=O); MS (CI) m/z 642 (MH+); [~]2D5 -24~ (c, 1.0, CHC13). Anal. Calcd. for S C36H4gClNO7-HCI: C, 63.71; H, 7.13; N, 2.06; Cl, 10.45. Found: C, 63.07; H, 7.54; N, 2.07; Cl, 12.81.

I~:XAMPLE 37 5-{2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino~-propyl}-10benzo[1,31dioxole-2,2-dicarboxylic acid bis-(3-cyclopentyl-propyl ) ester The ~itle compound was prepared from 5-~2-[2-(3-chloro-phenyl)-2-hydroxy-ethylarnino]-propyl ) -benzo[1,3]dioxole-2,2-dicarboxylic acid and 3-15 cyclopentylpropanol according to the procedure of Example 30 as a colorless gum(HCI salt); lH NMR (CDC13) ~ 0.80-1.80 (m, 26 H), 1.33 (d, J = 6.3 Hz, 3 H), 2.80 (m, lH), 3.18 (m, 2H), 3.48 (m, 2 H), 4.28 (t, J = 6.8 Hz, 4 H), 5.45 (bd, J = 9.7 Hz, 1 H), 6.80 (m, 3 H), 7.25 (m, 2 H), 7.45 (s, I H), 8.70 (bs, 1 H), 10.10 (bs, 1 H); IR (KBr): 1765 cm-l (C=O); MS (CI) m/z 642 (MH+); [~]2D5 -21~ (c, 1.0, CHCl3).
Anal. Calcd. for C36H4~CINO7-HCI: C, 63.71; H, 7.13; N, 2.06; Cl, 10.45. Found:
C, 63.69; H, 7.64; N, 2.00; Cl, 10.13.

5-{2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo~l,3~dioxole-2,2-dicarboxylic acid bis-cyclopropylmethyl ester The title compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl)-benzo[1,3]dioxole-2,2-dicarboxylic acid and cyclopropylm~ h~nol according to the procedure of Example 30 as a white solid (HCl salt); IH NMR
(CDC13) ~ 0.33 (m, 4 H), 0.61 (m, 4 H), 1.21, (m, 2 H), 1.32 (bs, 3 H), 2.80 (m,lH), 3.19 (m, 2H), 3.48 (m, 2 H), 4.15 (d, J = 7.3 Hz, 4 H), 5.50 (bd, 1 H), 5.70 (bs, 1 H), 6.80 (m, 3 H), 7.25 (m, 2 H), 7.45 (s, l H), 8.70 (bs, 1 H), 10.10 (bs, 1 H); IR (KBr): 1757, 1778 cm~l (C=O); MS (ES) m/z 530 (MH+); [OL]2D5 -26~ (c, 1.0, CA 022~4l20 l998-ll-lO

~ CHC13). Anal. Calcd. for C2gH32ClNO7-HCI: C, 59.37; H, 5.69; N, 2.47; Cl, 12.53.
Found: C, 59.19; H, 5.88; N, 2.29; Cl, 12.87.

55-{2-12~(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-ben~o[1,3~dioxole-2,2-dicarboxylic acid bis-(l-methyl-cyclopropylmethyl) ester The ~tle compound was prepared from 5-(2-[2-(3-chloro-phenyl)-2-hydroxy-10ethylamino]-propyl ~-benzo[1,3]dioxole-2,2-dicarboxylic acid and 1-methylcyclopropyl-methanol according to the procedure of Example 30 as a white solid (HCl salt); 1H NMR (CDC13) ~ 0.39 (m, 4 H), 0.52 (m, 4 H), 1.10, (s, 6 H), 1.32 (d, J = 6.5 Hz, 3 H), 2.80 (m, IH), 3.19 (m, 2H), 3.48 (m, 2 H), 4.10 (s, 4 H), 5.50(bd, 1 H), 5.70 (bs, 1 H), 6.80 (m, 3 H), 7.25 (m, 2 H), 7.45 (s, 1 H), 8.70 (bs, 1 15H), 10.10 (bs, 1 H); IR (KBr): 1763 cm-l (C-O); MS (ES) m/z 558 (MH+); [a]2DS -25~
(c, 1.0, CHC13). Anal. Calcd. for C30H36CINO7HCI: C, 60.61; H, 6.10; N, 2.36;
Cl, 11.94. Found: C, 60.02; H, 6.58; N, 2.17; Cl, 11.20.

205-~2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid bis-cyclobutylmethyl ester The htle compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl ) -benzo[1,3]dioxole-2,2-dicarboxylic acid and cyclobutyl~ ol25according to the procedure of Example 30 as an off-white solid (HCl salt); lH NMR
(CDCl3) ~ 1.32 (d, J = 6.5 Hz, 3 H), 1.85 (m, 8 H), 2.05 (m, 4 H), 2.69 (m, 2 H), 2.80 (m, lH), 3.19 (m, 2H), 3.48 (m, 2 H), 4.10 (s, 4 H), 5.50 (bd, 1 H), 5.70 (bs, 1 H), 6.80 (m, 3 H), 7.25 (m, 2 H), 7.45 (s, 1 H), 8.70 (bs, 1 H), lO.10 (bs, 1 H);
IR (KBr): 1759, 1779 cm-l (C=O); MS (ES) m/z 558 (MH+); [oL]2D5 -27~ (c, 1.0, 30CHC13). Anal. Calcd. for C30H36CINO7-HCI: C, 60.61; H, 6.10; N, 2.36; Cl, 11.94.
Found: C, 60.68; H, 6.30; N, 2.31; Cl, 11.71.

CA 02254l20 l998-ll-lO

5-{2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[l,3]dioxole-2,2-dicarboxylic acid bis-(2-cyclopentyl-ethyl) ester The title compound was prepared from 5-(2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl~-benzo~1,3]dioxole-2,2-dicarboxylic acid and 2-cyclopentylethanol according to the procedure of Exarnple 30 as an amber gum (HCl salt); lH NMR
(CDC13) ~ 1.32 (d, J = 6.3 Hz, 3 H), 1.60 (m, 20 H), 2.80 (m, lH), 2.90 (m, 2 H), 3.15 (m, lH), 3.20 (m, lH), 3.48 (m, 2 H), 4.30 (t, J = 6.9 Hz, 4 H), 5.50 (bd, 1 H), 6.80 (m, 3 H), 7.25 (m, 2 H), 7.43 (s, 1 H), 8.70 (bs, 1 H), 10.10 (bs, 1 H); IR
(KBr): 1765 cm-l (C=O); MS (CI) m/z 614 (MH+); [OL]2D5 -24~ (c, 1.0, CHCl3). Anal.
Calcd. for C34H44CINO7-HCl: C, 62.77; H, 6.82; N, 2.15; Cl, 10.90. Found: C, 64.04; H, 8.24; N, 1.62; Cl, 8.99.

General Method to Prepare 5-{2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl~-ben~o~1,3]dioxole-2,2-dicarboxylic acid bis-acetoxy-alkyl esters Step 1 Preparation of Acyloxyalkyl Iodides These esters were prepared by reacting the appropriate acid chlorides with forrnaldehyde or acetaldehyde in the presence of a catalytic amount of anhyrous ZnC12 according to Ulich, L. H. and Adams, R. J. Amer. Chem. Soc. 1921, 43, 660- 666.
25 The resultant acyloxyalkyl chlorides were converted in to the co~ ,onding acyloxyalkyl iodide derivatives by reacting them with NaI in boiling benzene according to Fujimoto, K., Ishihara, S., Yanagisawa, H., Ide, J., Nakayama, E., Nakao, H.,Sugawara, S., Iwata, M. J. Antibiotics 1987,19, 370.

CA 022~4120 1998-ll-lO

WO 97/43273 PCT/US97tO8148 Step 2 5-{2- [2-(3-Chlorophenyl)-2-hydroxyethylamino]-propyl}-benzo[l,3]dioxole-2,2-dicarboxylic acid disilver salt To a stirred solution of 5- f 2-~2-(3-chlorophenyl)-2-hydroxyethylarnino]-propyl)-benzo[1,3]dioxole-2,2-dicarboxylic acid disodium salt (3.0 gm, 6.0 mmol) in distilled water, (in the dark) a solution of AgNO3 (2.3 g, 12.0 mrnol) was addeddropwise. After stirring at room temperature for 1 h the separated solid was filtered and washed with water and acetone. The solid was dried at room temperature undervacuum to give a colorless solid; yield 100%; mp 183-185; M+H 422.1.

Step 3 5-{2- [2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[l,3]dioxole-2,2-dicarboxylic acid bis-acetoxyalkyl esters To a stirred suspension of 5-(2-[2-(3-chlorophenyl)-2-hydroxyethylarnino]-propyl)-benzol1,3ldioxole-2,2-dicarboxylic acid disilver salt (2.0 gms, 3 mmol) in anhydrous chloroforrn the apl,lu,."iately substituted acyloxyalkyl iodide (9 rnmol) dissolved in chloroform (30 mL) was added. The reaction mixture was stirred at room 20 temperature, under dark for 16 h. The reaction mixture was filtered and washed with 5% Na2S2O3 solution in distilled water. The chloroform layer was dried over anhydrous MgSO4 and filtered. It was evaporated to dryness and the residue obtained was dissolved in 5 mL of ethyl acetate and 60 mL of hexane was added. The sep~edsolid was filtered and washed with hexane. The compounds of Exarnples 42-58 below 25 were prepared according to this general procedure.

5-{2-12-(3-Chloro-phenyl)-2-hydroxyethylamino]propyl}benzo[1,3]
dioxole-2,2-dicarboxylic acid bis-acetoxymethyl ester To a stirred suspension of 5-~2-[2-(3-chlorophenyl)-2-hydroxyethylaminol-- propyl)-benzo[1,3]dioxole-2,2-dicarboxylic acid disilver salt (2.0 gms, 3 mrnol) in anhydrous chloroforrn, acetoxymethyl iodide (9 mmol) dissolved in chloroform (30mL) was added. The reaction rnixture was stirred at room temperature, under dark for 16 h. The reaction rnixture was filtered and washed with 5% Na2S2O3 solution in CA 022~4120 1998-ll-lO

distilled water. The chloroform layer was dried over anhydrous MgSO4 and filtered.
It was evaporated to dryness and the residue obtained was dissolved in S mL of ethyl acetate and 60 mL of hexane was added. The separated solid was filtered and washed with hexane to yield an ivory color solid; mp 132-134; yield 97%; M+H 566.
s 5-{2-[2-(3-Chloro-phenyl)-2-hydroxyethylamino]propyl}benzo[1,3]
dioxole-2,2-dicarboxylic acid bis-propionyloxymethyl ester To a stirred suspension of 5-{2-[2-(3-chlorophenyl)-2-hydroxyethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid disilver salt (2.0 gms, 3 mrnol) in anhydrous chloroform, propionyloxymethyl iodide (9 mmol) dissolved in chloroform(30 mL) was added. The reaction mixture was stirred at room temperature, under dark for 16 h. The reaction mixture was filtered and washed with 5% Na2S2O3 solution in distilled water. The chloroform layer was dried over anhydrous MgSO4 and filtered.
It was evaporated to dryness and the residue obtained was dissolved in 5 mL of ethyl acetate and 60 mL of hexane was added. The separated solid was filtered and washed with hexane to yield a colorless solid; mp 118-20; yield 88%; M+H 594.

5-{2-[2-(3-Chloro-phenyl)-2-hydroxyethylamino]propyl}benzo[1,3]
dioxole-2,2-dicarboxylic acid bis-butyryloxymethyl ester To a stirred suspension of 5-{2-~2-(3-chlorophenyl)-2-hydroxyethylamino]-propyll-benzo[1,3]dioxole-2,2-dicarboxylic acid disilver salt (2.0 gms, 3 mmol) in anhydrous chloroform butyryloxymethyl iodide (9 mmol) dissolved in chlc,lorolln (30 mL) was added. The reaction mixture was stirred at room temperature, under dark for 16 h. The reaction mixture was filtered and washed with 5% Na2S2O3 solution in distilled water. The chloroform layer was dried over anhydrous MgSO4 and filtered.
It was evaporated to dryness and the residue obtained was dissolved in 5 mL of ethyl acetate and 60 mL of hexane was added. The separated solid was filtered and washed with hexane to yield a white solid; mp 70-72 (dec); yield 85%; M+H 622.

CA 02254120 1998-ll-lO

5-{2-[2-(3-Chloro-phenyl)-2-hydroxyethylamino]propyl}benzo[1,3]
~ dioxole~2,2-dic~rboxylic acid bis-isobutyryloxymethyl ester 5To a stirred suspension of 5-~2-[2-(3-chlorophenyl)-2-hydroxyethylamino]-propyl}-benzo[1,3~dioxole-2,2-dicarboxylic acid disilver salt (2.0 gms, 3 rnrnol) in anhydrous chloroform isobutyryloxymethyl iodide (9 mrnol) dissolved in chloroforrn (30 rnL) was added. The reaction mixture was stirred at room temperature, under dark for 16 h. The reaction mix~ure was filtered and washed with 5% Na2S2O3 solution in 10~lictilled water. The chloroform layer was dried over anhydrous MgSO4 and ~ltered.
It was evaporated to dryness and the residue obtained was dissolved in 5 rnL of ethyl acetate and 60 mL of hexane was added. The separated solid was filtered and washed with hexane to yield a white solid; mp 1 14-116 (dec); yield 78%; M+H 622.

5-{2-[2-(3-Chloro-phenyl)-2-hydroxyethylamino]propyl}benzoll,3]
dioxole-2,2-dicarboxylic acid bis-heptanoyloxymethyl ester To a stirred suspension of 5-12-[2-(3-chlorophenyl)-2-hydroxyethylamino]-20propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid disilver salt (2.0 gms, 3 mmol) in anhydrous chloroforrn heptanoyloxymethyl iodide (9 mmol) dissolved in chlororc,~(30 mL) was added. The reaction mixture was stirred at room temperature, under dark for 16 h. The reaction mixture was filtered and washed with 5% Na2S2O3 solution in distilled water. The chlu~of~.n~ layer was dried over anhydrous MgSO4 and filtered.
25It was evaporated to dryness and the residue obtained was dissolved in 5 mL of ethyl acetate and 60 mL of hexane was added. The separated solid was filtered and washed with hexane to yield a white solid; mp 94-96; yield 18%; M+H 707.

305-{2-[2-(3-Chloro-phenyl)-2-hydroxyethylamino]propyl}benzo[1,3]
dioxole-2,2-dica~rboxylic acid bis-(4-methyl-pentanoyloxymethyl) ester To a stirred suspension of 5-~2-[2-(3-chlorophenyl)-2-hydroxyethylarnino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid disilver salt (2.0 gms, 3 mmol) in 35anhydrous chloroforrn pentanoyloxymethyl iodide (9 rnrnol) dissolved in chlc~rorol.

CA 02254120 1998-ll-lO

(30 mL) was added. The reaction mixture was stirred at room temperature, under dark for 16 h. The reaction mixture was filtered and washed with 5% Na2S2O3 solution in distilled water. The chloroform layer was dried over anhydrous MgSO4 and filtered.
It was evaporated to dryness and the residue obtained was d~ssolved in 5 mL of ethyl acetate and 60 rnL of hexane was added. The separated solid was filtered and washed with hexane to yield a white solid; mp 105-108 (dec); yield 19%; M+H 679.

5-{2-[2-(3-Chloro-phenyl~-2-hydroxyethylamino]propyl}benzo[1,3]
dioxole-2,2-dicarboxylic acid bis-hexanoyloxymethyl ester To a stirred suspension of 5-{2-[2-(3-chlorophenyl)-2-hydroxyethylamino]-propyl)-benzo[1,3]dioxole-2,2-dicarboxylic acid disilver salt (2.0 gms, 3 mrnol) in anhydrous chloroforrn hexanoyloxymethyl iodide (9 mmol) dissolved in chlolol~
(30 mL) was added. The reaction mixture was stirred at room temperature, under dark for 16 h. The reaction mixture was filtered and washed with 5% Na2S2O3 solution in distilled water. The chloroform layer was dried over anhydrous MgSO4 and filtered.
It was evaporated to dryness and the residue obtained was dissolved in 5 rnL of ethyl acetate and 60 mL of hexane was added. The separated solid was filtered and washed with hexane to yield a white solid; mp 106-109; yield 20%; M+H 679.

5-{2-[2-(3-Chloro-phenyl)-2-hydroxyethylaminolpropyl}benzo[1,3]
dioxole-2,2-dicarboxylic acid bis- (2,2-dimethyl-propionyloxymethyl) ester To a stirred suspension of 5-(2-l2-(3-chlorophenyl)-2-hydroxyethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid disilver salt (2.0 gms, 3 mmol) in anhydrous chloroform 2,2-dimethylpropionyloxymethyl iodide (9 rnmol) dissolved in chlolofo~ (30 mL) was added. The reaction mixture was stirred at room temperature, under dark for 16 h. The reaction mixture was filtered and washed with 5% Na2S2O3 solution in distilled water. The chloroform layer was dried over anhydrous MgSO4and filtered. It was evaporated to dryness and the residue obtained was dissolved in 5 rnL of ethyl acetate and 60 mL of hexane was added. The separated solid was filtered and washed with hexane to yield a ivory solid; mp 72 (dec); yield, 48%; M+H 651.

CA 022~4120 lsss-ll-lo wo 97/43273 PCT/USg7/08148 5-{2-12-(3-Chloro-phenyl)-2-hydroxyethylamino]propyl}benzo[1,3]
dioxole-2,2-dicarboxylic acid bis-cyclohexanecarbonyloxymethyl ester s To a stirred suspension of 5-(2-[2-(3-chlorophenyl)-2-hydroxyethylamino]-propyl}-benzol1,3]dioxole-2,2-dicarboxylic acid disilver salt (2.0 gms, 3 mmol) in anhydrous chloroform cyclohexanecarbonyloxymethyl iodide (9 mmol) dissolved in chloroforrn (30 mL) was added. The reaction mixture was stirred at room ~ p~ ture, under dark for 16 h. The reaction mixture was filtered and washed with 5% Na2S2O3 solution in distilled water. The chloroform layer was dried over anhydrous MgSO4and filtered. It was evaporated to dryness and the residue obtained was dissolved in 5 mL of ethyl acetate and 60 mL of hexane was added. The separated solid was filtered and washed with hexane to yield a white solid; mp 86 (dec); yield 52%; M+H 703.

5-~2-~2-(3-Chloro-phenyl)-2-hydroxyethylamino]propyl}benzo[1,3]
dioxole-2,2-dicarboxylic acid bis-(1-propionyloxy-ethyl) ester To a stirred suspension of 5-12-[2-(3-chlorophenyl)-2-hydroxyethylamino]-propyl)-benzo[1,3]dioxole-2,2-dicarboxylic acid disilver salt (2.0 gms, 3 mmol) in anhydrous chloroform 1-propionyloxyethyl iodide (9 mmol) dissolved in chloroform(30 mL) was added. The reaction mixture was stirred at room temperature, under dark for 16 h. The reaction mixture was filtered and washed with 5% Na2S2O3 solution in distilled water. The chlorofo,lll layer was dried over anhydrous MgSO4 and filtered.
It was evaporated to dryness and the residue obtained was dissolved in 5 mL of ethyl acetate and 6() rnL of hexane was added. The separated solid was filtered and washed with hexane to yield a white solid; mp 130-132 (dec); yield, 68%; M+H 622 CA 022~4120 1998-11-10 WO 97/43273 rCT/US97/08148 5-{2-[2-(3-Chloro-phenyl)-2-hydroxyethylamino]propyl}benzo[1,3]
dioxole- 2,2-dicarboxylic acid bis-[1-(2,2-dimethyl-propionyloxy-ethyl) ester s To a stirred suspension of 5-~2-[2-(3-chlorophenyl)-2-hydroxyethylamino]-propyl)-benzo[1,3]dioxole-2,2-dicarboxylic acid disilver salt (2.0 gms, 3 mmol) in anhydrous chloroform 1-(2,2-dimethylpropionyloxy)ethyl iodide (9 mmol) dissolved in chloroform (30 mL) was added. The reaction mixture was stirred at room telllp~latul~, under dark for 16 h. The reaction mixture was filtered and washed with 5% Na2S2O3 solution in distilled water. The chloroform layer was dried over anhydrous MgSO4and filtered. It was evaporated to dryness and the residue obtained was dissolved in 5 mL of ethyl acetate and 60 mL of hexane was added. The separated solid was filtered and washed with hexane to yield a white solid; mp 92; yield, 58%; M+H 679.

5-{2-[2-(3-Chloro-phenyl)-2-hydroxyethylamino]propyl}benzo~1,3]
dioxole-2,2-dicarboxylic acid bis-(3,3-dimethyl-butyryloxymethyl) ester To a stirred suspension of 5-{2-[2-(3-chlorophenyl)-2-hydroxyethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid disilver salt (2.0 gms, 3 mmol) in anhydrous chlolofolln 3,3-dimethylbutyryloxymethyl iodide (9 mmol) dissolved in chloroform (30 mL) was added. The reaction mixture was stirred at room l~m~e-~lure, under dark for 16 h. The reaction mixture was filtered and washed with 5% Na2S2O3 solution in distilled water. The chloroform layer was dried over anhydrous MgSO4and filtered. It was evaporated to dryness and the residue obtained was dissolved in 5 mL of ethyl acetate and 60 mL of hexane was added. The separated solid was filtered and washed with hexane to yield a white solid; mp 104-105 (dDec); yield 98%; M+H678.

CA 022~4l20 l998-ll-lo Wo 97143273 PCT/USg7/08148 ~ EXAMPLE 54 5-{2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]propyl}benzo[1,3]
dioxole-2,2-dicarboxylic acid bis-[1-(3,3-dimethyl-butyryloxy)-ethyl)}ester s To a stirred suspension of 5-(2-[2-(3-chlorophenyl)-2-hydroxyethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid disilver salt (2.0 gms, 3 mmol) in anhydrous chloroform 3,3-dimethylbutyryloxyethyl iodide (9 mrnol) dissolved in chlolofc)r-~l (30 mL) was added. The reaction mixture was stirred at room tenl~e.~u~e, under dark for 16 h. The reaction mixture was filtered and washed with 5% Na2S2O3 solution in distilled water. The chloroform layer was dried over anhydrous MgSO4and filtered. It was evaporated to dryness and the residue obtained was dissolved in 5 mL of ethyl acetate and 60 mL of hexane was added. The separated solid was filtered and washed with hexane to yield a white solid; mp 96-98 (dec); yield, 72%; M+H 706.
EXAMPLI: 55 5-{2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]
propyl}benzo[1,3~dioxole-2,2-dicarboxylic acid bis-(3-cyclopentyl-propionyloxymethyl~ ester To a stirred suspension of 5-{2-[2-(3-chlorophenyl)-2-hydroxyethylarnino]-propyl)-benzo[1,3]dioxole-2,2-dicarboxylic acid disilver salt (2.0 gms, 3 rnmol) in anhydrous chloroform 3-cyclopentylpropionyloxy iodide (9 nunol) dissolved in chloroform (30 mL) was added. The reaction mixture was stirred at room tell~pel~lul~, under dark for 16 h. The reaction mixture was filtered and washed with 5% Na2S2O3 solution in distilled water. The chloroform layer was dried over anhydrous MgSO4and filtered. It was evaporated to dryness and the residue obtained was dissolved in 5 mL of ethyl acetate and 60 mL of hexane was added. The separated solid was filtered and washed with hexane to yield a white solid; mp 155-157 (dec); yield, 98%; M+H730.

5-{2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]propyl}benzo[1,3]dioxole-2,2-dicarboxylic acid bis-benzoyloxymethyl ester s To a stirred suspension of 5-(2-[2-(3-chlorophenyl)-2-hydroxyethylamino]-propyl)-benzo[1,3]dioxole-2,2-dicarboxylic acid disilver salt (2.0 gms, 3 rnrnol) in anhydrous chloroform benzoyloxymethyl iodide (9 rnmol) dissolved in chloroform (30 rnL) was added. The reaction mixture was stirred at room temperature, under dark for 16 h. The reaction mixture was filtered and washed with 5% Na2S2O3 solution in distilled water. The chloroform layer was dried over anhydrous MgSO4 and filtered.
It was evaporated to dryness and the residue obtained was dissolved in 5 mL of ethyl acetate and 60 mL of hexane was added. The separated solid was filtered and washed with hexane to yield a white solid; mp 150-153 (dec); yield 98%; M+H 690.

5-{2-[2-~3-Chloro-phenyl)-2-hydroxyethylaminolpropyl}benzo[1,3]
dioxole-2,2-dicarboxylic acid bis-(benzoyloxy-ethyl) ester To a stirred suspension of 5-(2-[2-(3-chlorophenyl)-2-hydroxyethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid disilver salt (2.0 gms, 3 mrnol) in anhydrous chloroform 1-benzoyloxyethyl iodide (9 rnmol) dissolved in chlo -~rc)~ (30 mL) was added. The reaction mixture was stirred at room temperature, under dark for 16 h. The reaction mixture was filtered and washed with ~% Na2S2O3 solution in (li.ctilled water. The chloroform layer was dried over anhydrous MgSO4 and filtered.
It was evaporated to dryness and the residue obtained was dissolved in S mL of ethyl acetate and 60 mL of hexane was added. The separated solid was filtered and washed with hexane to yield an ivory solid; mp 82-83 (dec); yield 96%; M+H 718.

CA 022~4120 1998-ll-lO

5-{2~[2-(3-Chloro-phenyl)-2-hydroxyethylamino]propyl}benzo[1,3~
dioxole-2,2-dicarboxylic acid bis-(2,2-dimethyl-butyryloxymethyl) ester To a stirred suspension of 5-{2-[2-(3-chlorophenyl)-2-hydroxyethylarnino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid disilver salt (2.0 gms, 3 mmol) in anhydrous chloroform 2,2-dimethylbutyryloxymethyl iodide (9 rnmol) dissolved in chloroform (30 mL) was added. The reaction mixture was stirred at room temperature, under dark for 16 h. The reaction mixture was filtered and washed with 5% Na2S2O3 solution in distilled water. The chloroform layer was dried over anhydrous MgSO4and filtered. It was evaporated to dlyness and the residue obtained was dissolved in 5 mL of ethyl acetate and 60 mL of hexane was added. The separated solid was filtered and washed with hexane to yield a ivory solid; mp 121-123 (dec); yield 37%; M+H
679.

5-{(2R)~2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid bis-[l-(cyclohexyloxycarbonyloxy)-ethyl] ester Cyclohexyl 1-iodoethyl carbonate (5.6 g, 18 8 mmol) in CHCl3 (10 mL) was added dropwise into a cold (0 ~C) suspension of (R, R)-5-[2-[2-(3-chlorophenyl)-2-hydroxyethylamino]propyl]-1,3-benzodioxole-2,2-dicarboxylic acid disilver salt (4.0 g, 6.3 mmol) and CHC13 (100 mL). After the addition, the mixture was allowed to come to room temperature and stirred for 24 h. Diethyl ether (300 mL) was added into the reaction mixture and the precipitated solids were filtered and discarded. The filtrate was concentrated in vaccuo at room temperature and the residue was quickly chromatographed through silica gel, eluting anhydrous solvent (EtOAc / hexane, 1/1), to give a light yellow solid (1.25 g, 26% yield): mp 78-81 ~C; (+)FAB m/e 762 - 30 (M+H)+. Analysisfor: C3gH4gClNO13: Calcd: C, 59.89; H, 6.35; N, 1.84; Found:
C, 60.88; H, 6.53; N, 1.99 CA 02254120 1998-ll-lO

5-{2 [2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}benzo[l,3~dioxole-2,2-dicarboxylic acid bis-amide S A mixture of 5-~2-[2-(3-ehloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic aeid bis-ethyl ester (2.4 g, 5 mrnol) and ~.. ,.-;~
(excess) was stirred for 48 h. The reaction mixture was ccnce~ dted and the residue obtained was extracted with chloroform: methanol (3:1). It was washed with waterand dried over anhydrous MgSO4. The organic layer was filtered and coneentrated.
10 The residue obtained was chromatographed over silica gel eluted with 9:1 chloroform:
methanol to yield a brown solid; mp 98; yield. 1.0 g; 45%; M+H 420.

I :XAMPLE 61 5-{2-12-(3-Chloro-phenyl)-2-hydroxy~ethylamino]-propyl}-benzo[l,3]dioxole-2,2-dicarboxylic acid bis-2-propyl amide A mixture of 5-{2-[2-(3-ehloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo-[1,3]dioxole-2,2-diearboxylic acid bis-ethyl ester (2.4 g, 5 mmol) and isopropylamine (10 mL, excess) was refluxed in ethanol for 48 h. The reaetion mixture was 20 eoneentrated and the residue obtained was extracted with chloroform: methanol (3:1).
It was washed with water and dried over anhydrous MgSO4. The organic layer was filtered and concentrated. The residue obtained was chromatographed over silica gel eluted with 9:1 chloroforrn: methanol to yield a colorless spongy solid; mp 60; yield 1.5 g; 60%; M+H 504.

5-{2-[2-(3-Chloro-phenyl)-2-hydroxy~ethylamino]-propyl}-benzo[l,3]dioxole-2,2-dicarboxylic acid bis-n-butyl amide A mixture of 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo-[1,3]dioxole-2,2-dicarboxylic acid bis-ethyl ester (2.4 g, 5 mmol) and n-butylamine (10 mL, excess) was refluxed in ethanol for 48 h. The reaction mixture was eoncentrated and the residue obtained was extracted with chloroform: methanol (3:1).
It was washed with water and dried over anhydrous MgSO4. The organic layer was filtered and concentrated. The residue obtained was chromatographed over siliea gel ~ eluted with 9:1 chloroform: methanol to yield a brown semi solid; yield 1.6 g; 61%;
M+H 532.

55-{2-~2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid bis-phenylmethyl amide A mixture of 5-{2-~2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl)-benzo[ 1 ,3]dioxole-2,2-dicarboxylic acid bis-ethyl ester ~2.4 g, 5 rnmol) and 10benzylamine (10 mL, excess) was refluxed in ethanol for 48 h. The reaction mixture was concentrated and the residue obtained was extracted with chloroform: methanol (3:1). It was washed with water and dried over anhydrous MgSO4. The organic layer was filtered and concentrated. The residue obtained was chromatographed over silica gel eluted with 9:1 chloroform: methanol to yield a colorless spongy solid; mp 101;
15yield 2.0 g; 67%; M+H 600.

5-~2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[l,3]dioxole-2,2-dicarboxylic acid bis-(2-furanylmethyl) amide A mixture of 5- { 2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl } -benzo[1,3]dioxole-2,2-dicarboxylic acid bis-ethyl ester (2.4 g, 5 mmol) and 2-furanylmethylamine (10 mL, excess) was refluxed in ethanol for 48 h. The reaction mixture was concentrated and the residue obtained was extracted with chloroform:25 meth~nQl (3:1). It was washed with water and dried over anhydrous MgSO4. The organic layer was filtered and concentrated. The residue obtained was chromatographed over silica gel eluted with 9:1 chloroform: methanol to yield a brown solid; mp 50; yield 400 mg; 14%; M+H 581.

5-{2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[l,3]dioxole-2,2-dicarboxylic acid bis-(~lycine ethyl ester) amide A mixture of glycine ethyl ester.HCI (1.1 gm, 8 mmol) and sodium methoxide 35(424 mg, ~ mmol) was stirred at room temperature in ethanol for fifteen minutes. At CA 022~4120 1998-11-10 the end, 5- l 2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl } -benzo[1,3]dioxole-2,2-dicarboxylic acid bis-ethyl ester (970 mg, 2 mmol) was added to the reaction mixture and refluxed for 48 hours. At the end ethanol was removed.
The residue obtained was added to ice cold water and seperated solid was filtered. The solid was dried and purified by silica gel column chromatography by eluting it with 3:1 chloroform:methanol to yield a colorless solid; yield 500 mg; 42%; M+H 592.

5-{2-[2-(3-Chloru-phenyl)-3-oxazolidinyl~-propyl}-benzo[1,31dioxole-2,2-dicarboxylic acid 5- (2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl } -benzo[1,3]dioxole-2,2-dicarboxylic acid sodium salt (0.46 g, 1.0 mmol) was dissolved in 4 mL of 37%
formaldehyde, and stirred at room temperature for 0.5 h. Trifluoroacetic acid (0.23 g, 2.0 mmol) was then added dropwise, and the resulting white suspension was stirred for 24 h. The precipitate was filtered, washed with water, and dried in vacuo to give 0.40 g of white solid; IH NMR (CDC13) ~ 1.02 (d, J = 6.4 Hz, 3 H), 2.50 (m, 1 H), 3.00 (m, 2H), 3.20 (m, 1 H), 3.80 (m, 1 ~I), 4.75 (d, J = 4.5 Hz, 1 H), 4.90 (d, J =
4.5 Hz, 1 H), 5.12 (t J = 7.3 Hz, 1 H), 6.70 (m, 1 H), 6.86 (m, 2 H), 7.40 (m, 2 H), 7.50 (s, 1 H); IR (KBr): 1740 cm-l (C=O); MS (CI) n~/z 433 (M~). Anal. Calcd. for C21H20ClNO7-HCl: C, 58.14; H, 4.65; N, 3.23; Cl, 8.17. Found: C, 57.08; H, 4.78;N, 3.32; Cl, 7.51.

5-((2R)-2-{tert-Butoxycarbonyl-[(2R)-2-(3-chloro-phenyl)-2-hydroxy-ethyl]-amino}-propyl)-benzo[1,3]dioxole-2,2-dicarboxylic acid bis-diethylcarbamoylmethyl ester A mixture of 5-((2R)-2-~tert-butoxycarbonyl-[(2R)-2-(3-chloro-phenyl)-2-hydroxy-ethyl]-amino)-propyl)-benzo[1,3]dioxole-2,2-dicarboxylic acid (0.26 g, 0.5 mmol) and anhydrous potassium carbonate (0.28 g) in anhydrous dimethyl rc,~ .--ide was treated with 2-bromo-N,N-diethyl~cet~mide (0.39 g, 2 mmol), and stirred at room temperature for 3 days. It was then diluted with water and hexanes, and the resulting suspension was filtered. The precipitate was washed with saturated sodium bicarbonate solution, water, and hexanes, and then dried in vacuo to give 0.27 g of white solid; lH

Wo 97/43273 PCT/USg7/08148 NMR (CDCl3) ~ 1.0-1.5 (m, 24 H), 2.6 (m, 2H), 3.0-3.5 (m, lOH), 4.0 (m, 1 H~, 4.7-5.0 (m, 4H), 5.5, 6.0 (m, 1 H), 6.80 (m, 3 H), 7.26 (m, 2 H); IR (KBr): 1772, - 1668 cm-l (C=O); MS (ES) m/z 748 (MH+).

5-{(2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy~ethylamino]-propyl~-benzo[l,3]dioxole-2,2-dicarboxylic acid bis-diethylcarbamoylmethyl ester A solution of 5-((2R)-2- { tert-butoxycarbonyl-[(2R)-2-(3-chloro-phenyl)-2-hydroxy-ethyl]-amino) -propyl)-benzoL 1,3]dioxole-2,2-dicarboxylic acid bis-diethyl-c~ Joylmethyl ester (0.16 g, 0.2 mmol) in methylene chloride (2 ml) was treated with 0.08 ml of trifluoroacetic acid at room temperature for 18 h. The rnixture was then evaporated, and the residue washed with ether to give 0.12 g of white solid (TFA salt);
lH NMR (DMSO-d6) ~ 1.0-1.2 (m, 15 H), 2.6 (m, 2H), 3.0-4.0 (m, llH), 5.0 (m, 4 H), 6.1 (m, 1 H), 6.80 (m, 3 H), 7.26 (m, 2 H), 8.7 (bs, 1 H),9.2 (bs, 1 H); IR
(KBr): 1765, 1654 cm-l (C=O); MS (ES) m/z 648 (MH+).

5-{2-~2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid cyclopropylmethyl ester The title compound was prepared from 5-(2-[2-(3-chloro-phenyl)-2-hydroxy-ethylarnino]-propyl)-benzo[1,3]dioxole-2,2-dicarboxylic acid and cyclopropylm~th~nol according to the procedure of Example 1 as an off-white solid; IH NMR (DMSO) ~
0.25 (q,2H), 0.49 (q,2H), 1.01 (d,3H), 1.10 (m,lH), 2.49 (m, lH), 2.85-3.20 (m,4H), 3.94 (d, 2H) 4.85 (bt, lH), 6.58 (d, lH), 6.76 (m,2H), 7.35(m,3H), 7.46(s,1H); IR (KBr): 1653 cm-l(C=O), 1747 cm-l (C=O); MS (CI) m/z 476 (MH+).
Anal. Calcd. for C24H26ClNO7: C, 60.57; H, 5.51; N, 2.94; Cl, 7.46. Found: C, 56.38; H, 5.16; N, 2.61; Cl, 7.60.

CA 02254120 1998-ll-lO

5-{2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[l,3]dioxole-2,2-dicarboxylic acid cyclobutylmethyl ester S The title compound was prepared from 5-(2-[2-(3-chloro-phenyl)-2-hydroxy-ethylarnino]-propyl3-benzo[1,3]dioxole-2,2-dicarboxylic acid and cyclobutylm~.th~nol according to the procedure of Example 1 as an off-white solid; IH NMR (I)MSO) ~1.01 (d,3H), 1.75(m,4H), 1.92(m,2H), 2.49 (m, lH), 2.65 (m,lH), 2.85-3.20 (m,4H), 4.09 (d, 2H), 4.85 (bt, lH), 6.58 (d, lH), 6.76 (m,2H), 7.35(m,3H), 7.46(s,1H); IR (KBr): 1652 cm-l(C=O), 1761 cm-l (C=O); MS (CI) rn/z 490 (MH+).
Anal. Calcd. for C2sH28clNo7: C, 61.29; H, 5.76; N, 2.86; Cl, 7.24. Found: C, 57.13; H, 5.15; N, 2.43; Cl, 6.83.

5-{2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid bis 2-(3-Thienyl)ethyl- ester The title compound was prepared from 5-{2-[2- (3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid and 2-(3-thienyl)ethanol according to the procedure of Example 1 as yellow crystals (HCl salt); lH NMR
(CDC13) ~1.33 (d, 3 H), 2.82 (m, lH), 2.95 (t,4H), 3.20(m, 2H), 3.48 (bd, 2 H), 4.45 (t, 4 H), 5.50 (bd, 1 H), 5.60(bs,1H), 6.75-7.00(m, 7H), 7.21-7.32(m, 5H), 7.45(s,1H), 8.70 (bs, 1 H), 10.10 (bs, 1 H); IR (KBr): 1765 cm-l (C=O); MS (CI) rn/z 642 (MH+); [a]25 -21 ~ (c, 1.0, CHC13). Anal. Calcd. for C34H32ClS2NO7-HCl:
C, 56.63; H, 4.75; N, 2.06; S, 9.45; Cl, 10.46. Found: C, 55.89; H, 4.95; N, 1.87;
S, 9.45; Cl, 9.95.

~-{2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[l,3]dioxole-2,2-dicarboxylic acid 2~(3-Thienyl)ethyl ester The title compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl ~ -benzo[1,3]dioxole-2,2-dicarboxylic acid bis 2-(3-thienyl)ethyl-ester according to the procedure of Example 22 as an off-white solid; lH NMR

- (DMSO) ~i0.96 (d,3H), 2.45 (m, lH), 2.72-3.10 (m,6H), 4.25(t,2H), 4.80 (bt, lH), 5.92 (bs, lH), 6.60(d,1H), 6.79(d,2H), 7.05(d,1H), 7.17(s,1H), 7.30-7.50(5H); IR(KBr): 1652 cm-l(C=O), 17Sl cm~l (C=O); MS (CI) m/z 532 (MH+). Anal. Calcd.
for C26H26CISNO7: C, 58.70; H, 4.93; N, 2.63; S, 6.01; Cl, 5.98. Found: C, 54.17;
H, 4.44; N, 2.24; S, 5.13; Cl, 5.98.

5-{2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[l,3]dioxole-2,2-dicarboxylic acid bis 2-(Chloro)ethyl ester The title compound was prepared from 5-12-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl } -benzo[1,3]dioxole-2,2-dicarboxylic acid and 2-chloroethanol according to the procedure of Example 1 as yellow crystals (HCI salt); 1H NMR
(DMSO) ~1.13 (d, 3 H), 2.65 (m, lH), 3.15-3.52(m, 4H), 3.85 (t, 4 H), 4.60 (t, 4H), 5.55 (bd, I H), 6.40(bs,1H), 6.86(d,1H), 7.08(m,2H), 7.40-7.58(m,4H), 8.85 (bs, 1 H), 9.40 (bs, 1 H); IR (KBr): 1770 cm~l (C=O); MS (Cl) m/z 548 (MH+); [al25 -28~ (c, 1.0, DMSO). Anal. Calcd. for C24H26CI3NO7-HCI: C, 49.42; H, 4.67; N, 2.40;CI, 25.9. Found: C, 49.69; H, 4.38; N, 2.32; Cl, 23.20.

5-{(2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylaminol-propyl}-benzoll,3]dioxole-2,2-dicarboxylic acid bis-(2-ethylbutyl) ester The title compound was prepared from 5-(2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino] -propyl ) -benzo[1,3]dioxole-2,2-dicarboxylic acid and 2-ethylbutanol according to the procedure of Example I as an off-white gum (HCI salt); IH NMR
(CDC13~ ~ 0.80-0.95 (m, 12 H), 1.25-1.45 (m, 10 H), 1.50-1.65 (m, 3 H), 2.75-2.85 (m, lH), 3.10-3.40 (m, lH), 3.47-3.49 (m, 2 H), 4.25 (d, 5 H), 5.50 (d, 1 H), 6.70-6.80 (m, 1 H), 6.80-6.90 (m, 2 H), 7.20-7.45 (m, 3 H), 7.46 (s, 1 H), 8.74 (bs, 1 H), 10.06 (bs, 1 H); IR (KBr): 2964 cm~l (-OH), 1766 cm-l (C=O); MS (ES) m/z 590.4 (MH+); [a]2D5 -21~ (c, 1.0, CHCl3). Anal. Calcd. for C32H44ClNO7-HCl: C, 61.34; H, 7.08; N, 2.24; Cl, 11.32. Found: C, 61.09; H, 7.46; N, 2.12; Cl, 10.77.

S-{(2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[l,3]dioxole-2,2-dicarboxylic acid bis-(3-methylbutyl)ester S The title compound was prepared from 5-l2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl 1 -benzo[1,3]dioxole-2,2-dicarboxylic acid and 3-methylbutanol accord-ing to the procedure of Example 1 as an off-white foam (HCl salt); lH NMR(CDC13) ~ 0.90 (d, 12 H), 1.35 (d, 2 H), 1.55-1.80 (m, 6H), 2.70-2.85 (m, lH), 3.45-3.55 (m, 3 H), 4.30 (t, 4 H), 5.45 (bd, 1 H), 5.65 (bs, 1 H), 6.70-6.80 (m, 1 H), 6.80-6.9() (m, 3 H), 7.25-7.35 (m, 3H), 7.43 (s, lH), 8.74 (bs, 1 H), 10.08 (bs, 1 H); IR (KBr): 3303 cm-l (-OH), 1765 cm-l (C=O); MS (ES) m/z 562.4 (MH+); [~325 -24~ (c, 1.0, CHC13). Anal. Calcd. for C30H40ClNO7-HCI: C, 60.20; H, 6.74; N, 2.34; Cl, 11.85. Found: C, 59.98; H, 7.04; N, 2.24; Cl, 12.09.

5-{(2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-ben~o[l,3]dioxole-2,2-dicarboxylic acid (3-methylbutyl)ester The title compound was prepared from 5-1(2R)-2-[(2R)-2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl)-benzo[},3]dioxole-2,2-dicarboxylic acid bis-(3-methyl-butyl)ester according tO the procedure of Example 22 as an off-white solid; lH NMR
(DMSO) ~ 0.80-0.85 (m, 6H), 1.02-1.09 (m, 3H), 1.45 (q, 2H), 1.55-1.70 (m, lH), 3.01-3.05 (m, 2H), 3.15-3.25 (m, lH), 3.26-3.40 (m, 2H), 4.15 (t, 2H), 5.00-5.08(m, lH), 6.45 (bs, lH), 6.55-6.65 (m, lH), 6.75-6.90 (m, 2H), 7.45-7.49 (m, SH),7.51 (s, lH); ~R (Kbr): 3394 cm~l (-OH), 1651 cm~l (C=O); MS (ES) rn/z 492.0 (MH+); 1~]2DS -22~ (c, 1.0, CHC13). Anal. Calcd. for C2sH30ClNO7: C, 61.04; H, 6.15; N, 2.85; Cl, 7.20. Found: C, 59.80; H, 6.10; N, 2.89; Cl, 7.10.

5-{(2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[l,3]dioxole-2,2-dicarboxylic acid bis-adamantan-l-ylmethyl ester The title compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid and a~ m~nt~n-l-CA 022~4120 1998-11-10 W O 97/43273 PCT~US97/08148 ylm--th~nol according to the procedure of Example 1 as a white solid (HCI salt); lH
NMR (CDCl3) ~ 1.25 (m, 2H), 1.35 (d, 3 H), 1.51 (s, 12 H), 1.55-1.61 (m, 2H), 1.61-1.67 (m, 4 H), 1.67-1.75 (m, 6 H), 1.97 (s, 4 H), 3.20 (s, 2H), 3.42-3.49 tm, 2H), 3.88 (s, 4H), 4-11-4.16 (q, lH), 5.45 (bd, lH), 5.65 (bd, lH), 6.75 (m, lH), 56.78-6.89 (m, 2H), 7.23-7.30 (m, 3H), 7.44 (s, lH), 8.74 (bs, lH), 10.115 (bs, lH); IR (KBr) 3418 cm~l (-OH), 1767 cm~1 (C=O); MS (ES) m/z 718.4 (MH+); ~o~]25 -15~ (c, 1.0, CHCl3). Anal. Calcd. for C42Hs2ClNO7: C, 68.94; H, 9.22; N, 1.90; Cl, 9.40. Found: C, 67.48; H, 7.49; N, 1.48; Cl, 8.10.

5-{(2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino~-propyl}-benzo[l,3]dioxole-2,2-dicarboxylic acid bis-(2,2-dimethyl-propyl) ester 15The title compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl ~-benzol 1,3]dioxole-2,2-dicarboxylic acid and 2,2-dimethylpropanol according to the procedure of Fx~mple I as an off-white foam (HCl salt); IH NMR (CDC13) ~ .924 (s, 18 H), 1.45 ~d, 2H), 1.75 (s, 2H), 2.80 (m, lH), 3.17 (m, lH), 3.45 (m, lH), 3.98 (s, 4H), 5.45-5.55 (bd, lH), 5.63-5.67 (bs, lH), 206.75-6.80 (m, 2H), 6.80-6.89 (m, 2H), 7.25-7.35 (m, 3H), 7.440 (s, lH), 8.75 (bs, lH), 10.10 (bs, lH); IR (KBr) 3355 cm-l (-OH), 1767 cm-l (C=O); MS (ES) m/z 562.3 (MH+); [~12DS -23~ (c, 1.0, CHC13). Anal. Calcd. for C30H40ClNO7: C, 60.20;
H, 6.90; N, 2.34; Cl, 11.85. Found: C, 59.74; H, 6.97; N, 2.23; Cl, 11.60.

5-{(2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid adamantan-1-ylmethyl ester The title compound was prepared from 5- ( (2R)-2-[(2R)-2-(3-chloro-phenyl)-2-30hydroxy-ethylamino]-propyl ) -benzo[1,3]dioxole-2,2-dicarboxylic acid bis-~m~nt~n-1-ylmethyl ester according to the procedure of Example 22 as an off-white solid; lH
NMR (DMSO) ~ 1.03-1.09 (m, 3H), 1.44 (s, 6 H), 1.45-1.64 (m, 8H), 1.86 (s, 4H), 3.02-3.15 (m, lH), 3.25-3.55 (m, 2H), 3.70-3.80 (m, 2H), 4.58 (s, 2H), 5.06-5.10(m, lH), 6.52-6.65 (m, lH), 6.79-6.88 (m, 2H), 7.32-7.49 (m, 3H), 7.49 ~s, lH);

CA 02254120 1998-ll-lO

IR (KBr) 3384 cm~l (-OH), 1758 cm~l (C=O), 1651 cm~l (C=O); MS (ES) m/z 570.3 (MH+); [a]2D5 -29~ (c, 1.0, CHCl3). Anal. Calcd. for C31H36ClNO7: C, 65.31; H, 6.37; N, 2.46; Cl, 6.39. Found: C, 64.19; H, 6.20; N, 2.33; Cl, 6.33.

5-{(2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl~-benzo[l,3]dioxole-2,2-dicarboxylic acid (2,2-dimethyl-propyl)ester The title compound was prepared from 5- { (2R)-2-[(2R)-2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl)-benzo[1,3]dioxole-2,2-dicarboxylic acid bis-(2,2-dimethyl-propyl) ester according to the procedure of Example 22 as a white solid; IH
NMR (DMSO) ~ 0.868 (s, 9 H), 1.02-1.06 (m, 3H),3.00-3.02 (m, lH), 3.24-3.30 (m, lH), 3.35 (s, 5H), 3.80 (t, 2H), 4.55 (s, lH), 5.03 (m, lH), 6.52 (m, lH), 6.61 (m, lH), 6.79 (m, lH), 7.34 (m, 3H), 7.48 (s, lH); IR (KBr) 3398 cm-1 (-OH), 1748 cm-l (C=O), 1654 cm-1 (C=O); MS (ES) rn/z 492.3 (MH~; [o~l25 - 93~ (c, 1.0, CHCl3). Anal. Calcd. for C2sH30ClNO7: Ct 61.04; H, 6.15; N, 2.85; Cl, 7.21.
Found: C, 56.96; H,5.65; N, 2.63; Cl, 7.05.

5-{(2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]- propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid (3,3-dimethylbutyl) ester The title compound was prepared from 5- ~ (2R)-2-[(2R)-2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl)-benzo[1,3]dioxole-2,2-dicarboxylic acid bis-(3-methyl-butyl)ester according to the procedure of Example 22 as an off-white solid; lH NMR
(DMSO) ~ 0.87 (s, 9 H), 1.04 (m, 3H), 1.50 (t, 2 H), 3.34 (s, 8H), 4.20 (t, 2H),4.95-5.05 (m, lH), 6.35 (m, lH), 6.60 (m, lH), 6.75 (m, lH), 7.34-7.46 (m, 3H), 7.48 (s, lH); IR (KBr) 3410 cm-l (-OH), 1745 cm-l (C=O), 1651 cm-l (C=O); MS
(ES) m/z 506.4 (MH+); Anal. Calcd. for C26H32CINO7: C, 61.72; H, 6.37; N, 2.77;
Cl, 7.01. Found: C, 60.69; H, 6.20; N, 2.63; Cl,7.06.

W O 97143273 PCTrUS97/08148 5-{(2R)-2-[(2R)-2-(3~Chloro~phenyl)-2-hydroxy-ethylamino]-propyl}-~ ben~o[l,3]dioxole-2,2-dicarboxylic aicd bis-(l-methyl-cyclohexylmethyl) ester.
s The title compound was prepared from 5-~2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino] -propyl } -benzo[1,3]dioxole-2,2-dicarboxylic acid and 1 -methylcyclohexyl-methanol according to the procedure of Example 1 as an off-white solid; IH NMR
(DMSO-d6,400MHz) ~ 0.84 (s, 6H, CH3, CH3), 1.09 (d, J = 6.4 Hz, 3H, CH3), 1.1-1.4 (m, 20H, cyclohexyl), 2.6 (m, lH, CH), 3-3.3 (m, 3H, CH, CH2), 3.4 (brs, lH,CH), 4.04 (s, 4H, OCH2, OCH2), 5.05 (m, lH, CH), 6.35 (d, J = 4.17 Hz, lH, OH), 6.85 (dd, J = 7.9, 1.32 Hz, lH, Ar-H), 7.07 (s, lH, Ar-H), 7.09 (d, J = 8.35 Hz, Ar-H), 7.38-7.42 (m, 3H, Ar-H), 7.5 (s, lH, Ar-H), 8.8 (brs, lH, NH), 9.4 (brs, lH, NH); IR (KBr, cm~~) 3400 (OH), 2900 (NH), 1760 (CO); MS mle 641 (M+); Analysis for: C36H48ClNO7xHCI: Calc'd: C, 63.71; H, 7.28; N, 2.06; Found: C, 63.72; H, 7.03; N, 1.91.

5-{(2R)-2-1(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[l,3~dioxole-2,2-dicarboxylic aicd bis-(2-cyclohexyl-2-methyl-propyl) ester.

The title compound was prepared from 5-(2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl } -benzo[1,3]dioxole-2,2-dicarboxylic acid and 2-cyclohexyl-2-methyl~r~anol according to ~he procedure of Example 1 as an off-white solid; lH
NMR (DMSO-d6,400MHz) ~ 1.1 (s, 6H, CH3, CH3), 1.45 (s, 6H, CH3, CH3), 1.5 (s, 6H, CH3, CH3), 2,6 (m, lH, CH), 3-3.3 (m, 3H, CH, CH2), 3.4 (brs, lH, CH), 4.04 (s, 4H, OCH2, OCH2), 5.05 (m, lH, CH), 6.35 (d, J = 4.17 Hz, lH, OH), 6.85 (dd, J = 7.9, 1.32 Hz, lH, Ar-H), 7.07 (m, 2H, Ar-H), 7.38-7.42 (m, 3H, Ar-H), 7.5 (s, lH, Ar-H), 8.8 (brs, lH, NH), 9.4 (brs, lH, NH); IR (KBr, cm~l) 3400 (OH), 2900 (NH), 1760 (CO); MS mle 698 (M+H)+; Analysis for: C40Hs6ClNO7xHCl:
Calc'd: C, 65.38; H, 7.82; N, 1.91; Found: C, 65.32; H, 7.96; N, 1.94.

CA 02254l20 l998-ll-lO

5-{(2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo~l,3]dioxole-2,2-dicarboxylic aicd bis-(2-methyl-2-nitro-propyl) ester.
s The title compound was prepared from 5-{2-[2-(3-ehloro-phenyl)-2-hydroxy-ethylamino]-propyl } -benzo[1,3]dioxole-2,2-diearboxylie aeid and 2-methyl-2-ni~ upanol according to the procedure of Example 1 as an off-white solid; IH NMR(DMSO-d6,400MHz) ~i 0.78 (s, 12H, 4 x CH3), 0.8-1.0 (m, 4H, CH2), 1- 1.2 (m, llH, eyelohexyl, CH3), 1.5-1.65 (m, 10 H, cyclohexyl), 2.6 (m, lH, CH), 3-3.3 (m, 3H, CH, CH2), 3.4 (brs, lH, CH), 4.04 (s, 4H, OCH2, OCH2), 5.05 (m, lH, CH), 6.35 (d, J = 4.17 Hz, lH, OH), 6.83 (dd, J = 7.9, 1.32 Hz, lH, Ar-H), 7.06 (s lH, Ar-H), 7.09 (d, J = 8.35 Hz), 7.38-7.42 (m, 3H, Ar-H), 7.5 (s, lH, Ar-H), 8.8 (brs, lH, NH), 9.4 (brs, lH, NH); IR (KBr, cm~~) 3400 (OH), 2900 (NH), 1760 (CO);
Analysis for: C28H34ClN3O~IxHCl: Cale'd: C, 50.92; H, 5.34; N, 6.36; Found: C, 50.72; H, 5.42; N, 5.96.

5-{(2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[l,3]dioxole-2,2-dicarboxylic aicd bis-(2,2,4-trimethyl-pentyl) ester.

The title compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl ~ -benzo[1,3]dioxole-2,2-diearboxylie aeid and 2,2,4-~imethylpentanol aeeording to the proeedure of Example 1 as an off-white solid; IH
NMR (DMSO-d6,400MHz) ~ 0.65-0.9 (m, 24H, 8 x CH3), 1.09 (d, J = 6.4 Hz, 3H, CH3), 1.1- 1.4 (m, 4H, CHz, CH2), 2.62 (m, IH, CH), 3-3.3 (m, 3H, CH, CH2), 3.4 (brs, lH, CH), 4.04 (s, 4H, OCH2, OCHz), 5.05 (m, lH, CH), 6.34 (d, J = 3.95 Hz,lH, OH), 6.85 (dd, J = 7.9, 1.32 Hz, lH, Ar-H), 7.07 (m, 2H, Ar-H), 7.38-7.42 (m, 3H, Ar-H), 7.5 (s, lH, Ar-H), 8.7 (brs, lH, NH), 9.1 (brs, lH, NH); IR (KBr, em~1~ 3300 (OH), 2900 (NH), 1760 (CO); MS m/e 646 (M+H)+; Analysis for:
C36HszClNO7xHCl: Calc'd: C, 63.33; H, 7.83; N, 2.05; Found: C, 62.96; H, 7.71; N, 2.44.

CA 02254l20 l998-ll-lO

5-{(2R)-2-[(2R~-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]~propyl}-- benzo[1,3]dioxole-2,2-dicarboxylic aicd bis-(2,2-dimethyl-pentyl) ester.
s The tide compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl)-benzo[1,3]dioxole-2,2-dicarboxylic acid and 2,2-dimethylpentanol according to the procedure of Example 1 as an off-white solid; lH
NMR(DMSO-d6,400MHz)~0.8 (m, 18H, 6xCH3), 1.1-1.2 (m, llH, CH2CH3), 2.6 (m, lH, CH), 3-3.3 (m, 3H, CH, CH2), 3.4 (brs, lH, CH), 4.0 (s, 4H, OCH2, OCH2), 5.09 (m, lH, CH), 6.36 (d, J= 4.17 Hz, lH, OH), 6.86 (dd, J= 7.9, 1.32 Hz, lH, Ar-H), 7.07 (s lH, Ar-H), 7.09 (d, J = 8.35 Hz, Ar-H), 7.35-7.42 (m, 3H,Ar-H), 7.48 (s, lH, Ar-H), 8.84 (brs, lH, NH), 9.48 (brs, lH, NH); IR (KBr, cm~l) 3300 (OH), 2900 (NH), 1760 (CO); MS mle 617 (M+); Analysis for:
C34H48ClNO7xHCl: Calc'd: C, 62.38; H, 7.55; N, 2.14; Found: C, 62.47; H, 7.51; N, 2.31.

5-{(2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylaminol~propyl}-benzo[l,3]dioxole-2,2-dicarboxylic aicd bis-(tetrahydro-furan-3-ylmethyl) ester.

The title compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl ) -benzo[1,3]dioxole-2,2-dicarboxylic acid and tetrahydrofuran-3-ylmethanol according to the procedure of Example 1 as an off-white solid; lH NMR(DMSO-d6,400MHz) ~ 1.03 (d, J = 6.37 Hz, 3H, CH3), 1.5 (m, 2H, CH2), 1.9 (m, 2H, CH2), 2.6 (m, 3H, CH), 3-3.3 (m, 3H, CH, CH2), 3.4 (brs, lH, CH), 3.6-3.7 (m, 6H, CH2), 4.1-4.15 (m, 6H, CH2), 5.09 (m, lH, CH), 6.36 (brs, lH, OH), 6.86 (m, lH, Ar-H), 7.07 (m, 2H, Ar-H), 7.38-7.42 (m, 3H, Ar-H), 7.47 (s, lH, Ar-H), 8.84 (brs, 2H, NH, NH); IR (KBr, cm~l) 3300 (OH~, 2900 (NH), 1760 (CO); MS
mle 590 (M+H)+; Analysis for: C30H36ClNO9xHCl: Calc'd: C, 57.51; H, 5.95; N, 2.24; Found: C, 57.80; H, 6.30; N, 2.21.

. . .. ~. ~ . .

CA 02254120 1998-ll-lO

5-{(2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-ben~o~1,3]dioxole-2,2-dicarboxylic aicd bis-(3-hydroxy-2,2,4-trimethyl-pentyl) ester.

The ti~e compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl)-benzo[1,3~dioxole-2,2-dicarboxylic acid and cyclopropylmetl,allol according to the procedure of Example 1 as an off-white solid; IH NMR (DMSO-d6,400MHz) ~0.7-0.95 (m, 27H, 9 x CH3), 1.8 (m, lH, CH), 2.1 (m, lH, CH), 2.6 (m, lH, CH), 3-3.4 (m, 6H, OH, CH, CH2), 3.6-3.8 (brs, 2H, CH), 4.04 (m, 2H, OCH2, OCH2), 4.6 (m, lH, CH), 4.85 (m, lH, CH), 5.05 (m, lH, CH), 6.35 (d, J =
3.7 Hz, lH, OH), 6.85 (dd, J = 7.9, 1.32 Hz, lH, Ar-H), 7.09 (m, 2H, Ar-H), 7.38-7.42 (m, 3H, Ar-H), 7.5 (s, lH, Ar-H), 8.78 (brs, lH, NH), 9.2 (brs, lH, NH); IR(KBr, cm~l) 3400 (OH), 2900 (NH), 1750 (CO); MS mle 678 (M+H)~; Analysis for:
C36H52ClNO9xHCl: Calc'd: C, 60.50; H, 7.47; N, 1.95; Found: C, 60.30; H, 8.09; N, 1.62.

5-{(2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[l,3]dioxole-2,2-dicarboxylic aicd bis-(2,2-dimethyl-3-phenyl-propyl) ester.

The title compound was prepared from 5-(2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl l -benzo[1,3]dioxole-2,2-dicarboxylic acid and 2,2-dimethyl-3-phenylpropanol according to the procedure of Example 1 as an off-white solid; lHNMR (DMSO-d6,400MHz) ~0.82 (s, 12H, 4 x CH3~, 1.08 (d, J = 6.37 Hz, 3H, CH3), 2.6 (m, lH, CH), 3-3.3 (m, 3H, CH, CH2), 3.4 (brs, lH, CH), 3.96 (s, 4H, OCH2, OCH2), 5.04 (m, lH, CH), 6.35 (d, J= 4.17 Hz, lH, OH), 6.89 (dd, J =
8.13, 1.53 Hz, lH, Ar-H), 7.05 (m, 4H, Ar-H), 7.14 (m, 8H, Ar-H), 7.38-7.42 (m, 3H, Ar-H), 7.5 (s, lH, Ar-H), 8.81 (brs, lH, NH), 9.38 (brs, lH, NH); IR (KBr, cm~~) 3400 (OH), 2900 (NH), 1760 (CO); MS mle 714 (M+H)+; Analysis for:
C42H48ClNO7xHCI: Calc'd: C, 67.19; H, 6.58; N, 1.87; Found: C, 66.69; H, 6.53; N, 1.83.

CA 02254l20 l998-ll-lO

5~{(2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[l,3]dioxole-2,2-dicarboxylic aicd bis-(tetrahydro-pyran-2-ylmethyl) ester.
s The tide compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl)-benzo~1,3]dioxole-2,2-dicarboxylic acid and tetrahydropyran-2-ylmethanol according to the procedure of Example 1 as an off-white solid; IH NMR(DMSO-d6,400MHz) ~ 1.10 (d,J = 6.37 Hz, 3H, CH3), 1.1-1.2 (m, 2H, CH2), 1.3-1.6 (m, 8H, CH2), 1.7-1.8 (m, 2H, CH2), 2.6 (m, lH, CH), 3-3.5 (m, 9H, CH, CH2), 3.8 (m, 2H, CH), 4.19-4.2 (s, s, 4H, OCH~, OCH2), 5.04 (m, lH, CH), 6.35 (d, J = 4.17 Hz, IH, OH), 6.85 (d, J = 8.13 Hz, lH, Ar-H), 7.07 (m, 2H, Ar-H), 7.36-7.42 (m, 3H, Ar-H), 7.48 (s, lH, Ar-H), 8.76 (brs, lH, NH), 9.18 (brs, lH, NH); IR (KBr, cm~l) 3400 (OH), 2900 (NH), 1760 (CO); MS m/e 618 (M+H)+;
Analysis for: C32H40ClNOgxHCI: Calc'd: C, 58.72; H, 6.31; N, 2.14; Found: C, 57.97; H, 6.46; N, 2.08.

5-{(2R)-2~[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[l,3]dioxole-2,2-dicarboxylic aicd bis-(tetrahydro-furan-2-ylmethyl) ester.

The title compound was prepared from 5-(2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl ) -benzo[1,3]dioxole-2,2-dicarboxylic acid and tetrahydrofuran-2-ylmethanol according to the procedure of Example 1 as an off-white solid; IH NMR(DMSO-d6,400MHz) ~ 1.1 (d, J = 6.37 Hz, 3H, CH3), 1.43-1.6 (m, 2H, CH2) 1.65-1.8 (m, 4H, CH2), 1.98-2.0 (m, 2H, CH2), 2.6 (m, lH, CH), 3-3.3 (m, 3H, CH, CH2), 3.4 (brs, lH, CH), 3.57-3.7 (m, 4H, CH2), 4.05 (m, 2H, CH2), 4.2 (m, 2H, CH2), 4.3 (m, 2H, CH2), 5.04 (m, lH, CH), 6.34 (d, J = 3.95 Hz, lH, OH), 6.84 ~ 30 (dd, J = 8.13, 1.32 Hz, lH, Ar-H), 7.07 (m, 2H, Ar-H), 7.36-7.44 (m, 3H, Ar-H~, 7.48 (s, lH, Ar-H), 8.77 (brs, lH, NH), 9.2 (brs, lH, NH); IR (KBr, cm~~) 3400 (OH), 2900 (NH), 1760 (CO); MS mle 590 (M+H)+; Analysis for: C30H36ClNO9xHCl:
Calc'd: C, 57.51; H, 5.95; N, 2.24; Found: C, 56.37; H, 5.90; N, 2.20.

WO ~7/43273 PCT/US97/08148 5~{(2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic aicd bis-(5-methyl-[1,3]dioxan-5-ylmethyl) ester.

The title compound was l~r~ .,d from 5-~2-~2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl ~ -benzo[1,3]dioxole-2,2-dicarboxylic acid and S-methyl-[1,3]dioxan-5-ylmethanol according to the procedure of Example 1 as an off-whitesolid; ~H NMR (DMSO-d6,400MHz) ~ 0.7 (s, 3H, CH3), 0.74 (s, 3H, CH3), 1.1 (d, J = 6.59 Hz, 3H, CH3), 2.6 (m, lH, CH), 3-3.3 ~m, 8H, CH, CH2), 3.6-3.7 (m, 4H, CH2), 4.6-4.8 (m, 4H, CH2), 5.04 (m, lH, CH), 6.34 (brs, lH, OH), 6.84 (dd, J=
8.13, 1.32 Hz, lH, Ar-H), 7.07 (m, 2H, Ar-H), 7.36-7.44 (m, 3H, Ar-H), 7.48 (s, lH, Ar-H), 8.77 (brs, lH, NH), 9.2 (brs, lH, NH); IR (KBr, cm~l) 3400 (OH), 2900 (NH), 1760 (CO); MS mle 650 (M+H)+; Analysis for: C32H40ClNOllxHCl:
lS Calc'd: C, 55.98; H, 6.02; N, 2.04; Found: C, 54.67; H, 6.58; N, 2.05.

5-{(2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[l,33dioxole-2,2-dicarboxylic aicd bis-(1-methyl-cyclohex-3-enylmethyl) ester.

The title compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl }-benzo[1,3]dioxole-2,2-dicarboxylic acid and 1-methylcyclohex-3-enylmethanol according to the procedure of Example 1 as an off-white solid; ~H NMR
(DMSO-d6,4()0MHz) ~0.84 (s, 6H, 2 x CH3), 1.09 (d, J = 6.4 Hz, 3H, CH3), 1.25-1.4 (m, 4H, CH2), 1.6-1.65 (m, 2H, CH2), 1.8-2.0 (m, 6H, CH2), 2.6 (m, lH, CH), 3-3.3 (m, 3H, CH, CH2), 3.4 (brs, lH, CH), 4.04 (m, 4H, OCH2, OCH2), 5.05 (m, lH, CH), S.SS-5.65 (m, 4H, CH), 6.35 (d, J = 4.17 Hz, lH, OH), 6.85 (dd, J = 7.9, 1.32 Hz, lH, Ar-H), 7.07 (m, 2H, Ar-H), 7.38-7.42 (m, 3H, Ar-H), 7.5 (s, lH, Ar-H), 8.8 (brs, lH, NH), 9.4 (brs, lH, NH); IR (KBr, cm~~) 3400 (OH), 2900 (NH), 1760 (CO); MS mle 638 (M+H)+; Analysis for: C36H44ClNO7xHCI: Calc'd: C, 64.09;
H, 6.72; N, 2.08; Found: C, 64.69; H, 7.19; N, 1.67.

.

CA 022~4120 1998-11-10 5-{(2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-~benzo[l,3]dioxole-2,2-dicarboxylic aicd bis-(3-hydroxy-2,2-dimethyl-propyl) ester.
s The title compound was prepared from 5-(2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl ) -benzo[1,3]dioxole-2,2-dicarboxylic acid 3-hydroxy-2,2-dimethyl-propanol according to the procedure of Example 1 as an off-white solid; IH NMR
(DMSO-d6,400MHz) ~0.78 (s, 12H, 4 x CH3), 1.09 (d, J = 6.4 Hz, 3H, CH3), 2.6 (m, lH, CH), 3-3.3 (m, 7H, CH, CH2), 3.4 (brs, lH, CH), 4.04 (s, 4H, OCH2, OCH2),4.65 (m, 2H, OH), 5.05 (m, lH, CH), 6.34 (d, J = 4.17 Hz, lH, OH), 6.85 (dd, J = 7.9, 1.53 Hz, lH, Ar-H), 7.07 (m, 2H, Ar-H), 7.37-7.42 (m, 3H, Ar-H), 7.48 (s, lH, Ar-H), 8.78 (brs, lH, NH), 9.2 (brs, lH, NH); IR (KBr, cm~l) 3400 (OH), 2900 (NH), 1760 (CO); MS mle 594 (M+H)+; Analysis for: C30H40ClNO9xHCl:
Calc'd: C, 57.14; H, 6.55; N, 2.22; Found: C, 56.44; H, 6.62; N, 2.38.

EXAMPI,E 95 5-{(2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid (2-ethoxy-ethyl) ester Through a stirred room te.llpc,.at-lre solution of 8.0 g (0.019 mole) 5-(2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl ) -benzo[1,3]dioxole-2,2-dicarboxylic acid and 30 mL of 2-ethoxyethanol was bubbled HCl(g) for 5 min. After heating at 100 ~~C for 12 h, TLC (9/1 CH2Cl2/MeOH) indicated the formation of both 5-12-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl 3 -benzo[1,3]dioxole-2,2-dicarboxylic acid bis-(2-ethoxy-ethyl) ester (R~ = 0.8; 9/1 CH2Cl2/MeOH) and 5-1(2R)-2-[(2R)-2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl } -benzo[1,3]dioxole-2,2-dicarboxylic acid (2-ethoxy-ethyl) ester (Rf = 0.2; 9/1 CH2Cl2/MeOH). After cooling to room t~,..pel~ture, excess 2-ethoxyethanol was removed via Kugelrohr ~ 3tion (0.05 mm, oven teml)eldture = 95 ~C), and the brown residue was chromatographed on silica gel, eluting with 0 to 10% MeOH in CH2Cl2, to give 1.0 g (0.002 mole, a 10% yield) of the title compound as an off-white solid; IH NMR (300 MHz, DMSO-d6): ~ 1.12 (m, J =
6.3 Hz, 3H), 2.5 (m, 3H) 3.35 (m, 8H), 5.06 (m, lH), 6.3 (s, lH, OH) 6.5 (m, lH), 6.6 (m, lH), 6.8 (m, 2H), 7.0 (m, lH), 7.5 (m, 2H), 8.0 (m, lH, NH), d 9.2 (m, lH, COOH); MS (ES) m/z (relative intensity): 494 (M++H, 100).

CA 02254120 1998-ll-lO

5-{(2R)-2- [(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[l,3]dioxole-2,2-dicarboxylic acid bis-[2-(3-bromo-phenyl)-ethyl]ester hydrochloride salt The title compound was plepal~d as a brown oil from 5-(2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino] -propyl } -benzo[1,3]dioxole-2,2-dicarboxylic acid and 2-(3-bromophenyl)ethanol according to the procedure of Example 1; IH NMR (300 MHz, CDCI3): ~ 1.12 (m, J = 6.3 Hz, 3H), 2.79 (m, 8H), 3.5 (m 2H), 4.18 (s, lH, OH), 5.56 (m, lH), 6.8 (m, 3H), 7.0 (m, 4H), 7.33 (m, 4H), 7.5 (m, 4H), 8.5 (m, lH, NH); MS (ES) m/z (relative intensity): 788 (M'+H, 100).

5-{(2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[l,3]dioxole-2,2-dic~rboxylic acid bis-(2-m-tolyl-ethyl) ester hydrochloride salt The title compound was prepared as a brown oil from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino~-propyl ) -benzo[1,3]dioxole-2,2-dicarboxylic acid and 2-(3-methylphenyl)ethanol according to the procedure of Example l; yield: 81%; IH
NMR (300 MHz, CDCI3): ~ 1.12 (m, J = 6.3 Hz, 3H),2.27 (s, 6H), 2.79 (m, 7H), 3.19 (m, lH), 3.48 (m, 2H), 4.29 (m, J = 6.6 Hz, 4H), 5.49 (m, lH,) 6.75 (m, J =8.1 Hz, lH), 6.83 (m, lH), 7.05 (m, 8H), 7.20 (m, lH), 7.27 (m, lH), 7.43 (s, lH), 7.5 (m, 2H); MS (ES) m/z (relative intensity): 658 (M++H, 100).

EXAMPLE 9~
5-{(2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[l,3]dioxole-2,2-dicarboxylic acid diallyl ester Step I
(R,R)-5-{2-[[2-(3-Chloro-phenyl)-2-hydroxy-ethyl]-(2,2,2-trichloro-ethoxycarbonyl)-amino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid diethyl ester 10To a 0 ~C solution of 3.0 g (5.83 mmol) (R,R)-5-~2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl } -benzo[1,3]dioxole-2,2-dicarboxylic acid diethyl ester hydrochloride salt and 60 mL CH2CI2 was added 2.54 rnL (1.88 g, 14.57 rnmol) of i-Pr2NEt followed by 0.84 mL (1.30 g, 6.12 mmol) of 2,2,2-trichloroethyl chloroformate. After stirring at room temperature for 6 h, the reaction mixture was 15quenched with 10 mL sat. aq. NaHCO3, and extracted with 3 x 100 mL Et2O. The combined organics were washed with I x 100 lN HCI, 1 x 100 mL brine, dried over MgSO4, filtered and evaporated to a yellow oil. Flash chromatography on silica gel, eluting with hexanes/EtOAc (4/1 to 2/1), gives 3.46 g (5.30 mrnol, a 91% yield) of the title compound (R~ = 0.32; 2/1 hexanes/EtOAc) as an oily, off-white solid; IH NMR
20300 MHz, CDCI3): ~ 1.20-1.39 (complex m, 9H), 2.60-2.80 (m, lH), 2.80-2.91 (m,lH), 3.01-3.19 (m, lH), 3.23-3.31 (m, lH), 3.40-3.53 (m, lH), 4.10-4.23 (m, lH),4.30-4.42 (complex m, 4H), 4.70-4.89 (m, 3H), 6.65-6.88 (complex m, 4H), 7.15-7.39 (complex m, 3H); MS (ES) m/z (relative intensity): 654 (M+ + H, 100).

25Step 2 5-{(2R)-2-[[(2R)-2-(tert-Butyl-dimethyl-siloxy)-2-(3-chloro-phenyl)-ethyl~-(2,2,2-trichloro-ethoxycarbonyl)-amino]-propyl}-benzo[l,3]dioxole-2,2-dicarboxylic acid diethyl ester 30To a -78 ~C solution of 3.75 g (5.47 mmol) (R,R)-5-~2-[[2-(3-chloro-phenyl)-2-hydroxy-ethyl] -(2,2,2-trichloro-ethoxycarbonyl)-amino]-propyl ~ -benzo[1,3]dioxole-2,2-dicarboxylic acid diethyl ester and 60 mL of CH2CI2 was added 1.27 mL (1.17 g, 10.94 mmol) of 2,6-lutidene followed by 1.38 mL (1.59 g, 6.03 mmol) of TBSOTf.
After stirring at -78 ~C for 1.5 h, the reaction mixture was quenched with 50 rnL sat.
aq. NaHCO3 and warmed to room temperature. After extraction with 3 x 150 mL Et2O, CA 022~4120 lsss-ll-lo WO 97/43273 PcTluss7/o8l48 the combined organics were washed with 1 x 200 mL sat. CuSO4, 1 x 200 mL brine, dried over MgSO4, filtered and evaporated to a cloudy white oil. Flash chromatography on silica gel, eluting with hexanes/EtOAc (8/1 to 4/1) gave 3.42 g (4.46 mmol, an 82% yield) of the title compound (Rf = 0.31; 4/1 hexanes/EtOAc) as a 5gummy colorless solid; IH NIVIR (300 MHz, CDCl3): ~ -0.13-(-0.08) (m, 3H), 0.00-0.06 (m, 3H), 0.85-0.91 (m, 9H), 1.05 (d, J=6.7 Hz, 3H), 1.33 (t, J=7.1 Hz, 6H),2.60-2.75 (m, lH), 2.77-2.96 (m, lH), 3.00-3.31 (m, 2H), 3.77-4.00 (m, lH), 4.35(q, J=7.1 Hz, 4H), 4.65-4.88 (m, 2H), 5.02-5.20 (m, lH), 6.60-6.85 (m, 4H), 7.15-7.37 (m, 3H); MS (ES) m/z (relative intensity): 790 (M++Na, 100), 768 (M++H, 20).
Step 3 5-{(2R)-2-[[(2R)-2-(tert-Butyl-dimethyl-siloxy)-2-(3-chloro-phenyl)-ethyl]-(2,2,2-trichloro-ethoxycarbonyl)-amino]-propyl}-benzo[l,3]dioxole-2,2-dic~rboxylic acid To a room temperature solution of 3.31 g (4.31 mmol) 5-~(2R)-2-[~(2R)-2-(tert-butyl-dimethyl-siloxy)-2-(3-chloro-phenyl)-ethyl]-(2,2,2-trichloro-ethoxycarbonyl)-amino]-propyl~-benzo[1,3]dioxole-2,2-dicarboxylic acid diethyl ester, 100 mL MeOH and 25 mL H20 was added 4.31 mL (21.56 mmol) of a 5N NaOH
20solution. After stirring at room temperature for 80 h, the solvent was evaporated, and the resulting slurry was acidifled to pH 1 with 1 N HCI. The reaction mixture isextracted with 3 x 100 mL EtOAc, and the combined organics were washed with 2 x 30 mL brine, dried over Na2SO4, filtered and evaporated to give 3.01 g (4.23 mmol, a 98% yield) of the title compound (R~ = 0.0; 10/1 CHCI3/MeOH) as an off-white solid;
25IH NMR (300 MHz, CDCl3): ~ -0.19-(-0.11) (m, 3H), 0.01 -0.09 (m, 3H), 0.81 -0.91 (m, 9H), 0.93-0.97 (m, 3H), 2.55-2.97 (complex m, 3H), 3.07-3.35 (m, 2H), 3.80-4.40 (br m, 2H), 4.60-4.83 (m, 2H), 5.03-5.18 (m, lH), 6.60-6.92 (m, 4H), 7.15-7.39 (m, 3H); MS (ES) m/z (relative intensity): 734 (Mt+Na, 30), 712 (M++H, 100).

CA 022~4120 1998-11-10 wo 97/43273 PCT/US97/08148 Step 4 5-{(2R)-2-[[(2R)-2-(tert-Butyl~dimethyl-siloxy)-2-(3-chloro-phenyl)-- ethyll-(2,2,2-trichloro-ethoxycarbonyl)-amino]-propyl}-benzo[l,3]dioxole-2,2-dicarboxylic acid diallyl ester s To a room temperature solution of 950 mg (1.34 mmol) 5-{(2R)-2-[[(2R)-2-(tert-butyl-dimethyl-siloxy)-2-(3-chloro-phenyl)-ethyl]-(2,2,2-trichloro-ethoxycarbonyl)-amino]-propyl } -benzo[1,3]dioxole-2,2-dicarboxylic acid and 15 rr~
DMF was added 267 mg (2.67 mmol) of KHCO3 and 0.26 mL (471 mg, 2.80 mrnol) of allyl iodide. After stirring at room temperature for 16 h, the reaction was quenched with 10 mL sat. aq. NaHCO3 and extracted with 3 x 100 mL Et2O. The combined organics were washed with I x 150 mL brine, dried over MgSO4, filtered and evaporated to a colorless oil. Flash chromatography on silica gel, eluting with hex~n~c/EtOAc (8/1 to 4tl), gave 670 mg (0.85 mmol, a 63% yield) of the title compound (R~ = 0.62; 2/1 hexaneslEtOAc) as a colorless oil; IH NMR (300 MHz, CDCI3): ~-0.19-(-0.11) (m, 3H), 0.00-0.08 (m, 3H), 0.87 (s, 9~1), 1.04 (d, J=6.7Hz, 3H), 2.60-2.74 (m, lH), 2.77-2.98 (m, lH), 3.03-3.17 (m, lH), 3.18-3.30 (m, lH), 3.75-3.98 (m, lH), 4.65-4.87 (m, 6H), 5.03-5.18 (m, lH), 5.29 (d, J=17.3 Hz, 2H), 5.34 (d, ~=23.7 Hz, 2H), 5.82-5.97 (complex m, 2H), 6.60-6.88 (m, 4H), 7.15-7.37 (m, 3H); MS (ES) m/z (relative intensity): 814 (M++Na, 100).

Step 5 5-{(2R)-2-1[(2R)~2-(3-Chloro-phenyl)-2-hydroxy-ethyl]-(2,2,2-trichloro-ethoxycarbonyl)-amino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid diallyl ester To a 0 ~C solution of 650 mg (0.82 mmol) 5-~(2R)-2-[[(2R)-2-(tert-butyl-dimethyl-siloxy)-2-(3-chloro-phenyl)-ethyl]-(2,2,2-trichloro-ethoxycarbonyl)-amino]-propyl~-benzo[1,31dioxole-2,2-dicarboxylic acid diallyl ester and 20 rnL THF was30 added 1.0 mL of HF-pyridine, and the reaction mixture was warmed to room temperature. After 22 h, TLC indicated that some starting material remained (Rf = 0.62 (Vl hexanes/EtOAc), and an additional 1.0 mL of HF-pyridine was added. After a total of 26 h, TLC indicated the disappearance of starting material and the formation of the title compound (Rf = 0.28 (2/1 hexanes/EtOAc). The reaction mixture was slowly quenched with 30 mL of sat. aq. NaHCO3, extracted with 2 x 75 mL Et2O and then CA 022~4120 1998-11-10 with 1 x 75 mL EtOAc. The combined organics were washed with 1 x 100 mL brine, dried over MgSO4, filtered and evaporated to a colorless oil. Flash chromatography on silica gel, eluting with hexanes/EtOAc (2/1), gave 460 mg (0.68 mmol, an 83% yield) of the title compound (Rf = 0.28; 2/1 hexanes/EtOAc) as a colorless oil; lH NMR (300 S MHz, CDCl3): ~ 1.20-1.37 (m, 3H), 2.60-2.78 (m, 2H), 2.80-2.91 (m, lH), 2.98-3.18 (m, lH), 3.23-3.40 (m, lH), 3.41-3.54 (m, 2H), 4.10-4.26 (br m, lH), 4.73-4.92 (SH), 5.22-5.40 (complex m, 4H), 5.81-5.98 (complex m, 2H), 6.62-6.87 (m, 4H),7.17-7.41 (m, 3H); MS (ES) m/z (relative intensity): 700 (M++ Na, 100).

Step 6 5-{(2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylaminol-propyl}-benzo[l,3]dioxole-2,2-dicarboxylic acid diallyl ester A mixture of 370 mg (0.55 mmol) 5-~(2R)-2-~[(2R)-2-(3-chloro-phenyl)-2-hydroxy-ethyl]-(2,2,2-trichloro-ethoxycarbonyl)-amino] -propyl } -benzo[1,3]dioxole-2,2-dicarboxylic acid diallyl ester,10 mL glacial acetic acid and 357 mg (5.46 mmol) of Zn dust were stirred at room temperature for 40 h. The reaction mixture was filtered through celite, poured into 50 rnL brine, and extracted with 3 x 50 mL EtOAc. The combined organics were washed with 3 x 75 mL sat. NaHCO3,1 x 75 mL brine, dried over Na2SO4, filtered and evaporated to a colorless oil. Flash chromatography on silica gel, eluting with CHCl3/MeOH (20/1 to 10/1), gave 180 mg (0.36 mmol, a 66% yield) of the title compound (Rf = 0.35; 10/1 CHCI3/MeOH) as a colorless gum; lH NMR
(300 MHz, CDCI3): o 1.20-1.33 (m, 3H), 2.70-2.81 (m, lH), 3.00-3.19 (m, 2H), 3.36-3.45 (m, 2H), 4.50-5.50 (br s, 2H), 4.70-4.80 (m, 4H), 5.10-5.20 (m, lH), 5.25-5.40 (m, 4H), 5.82-6.00 (complex m, 2H), 6.70-6.91 (m, 3H), 7.17-7.30 (m, 3H),7.41 (s, lH); MS (ES) m/z (relative intensity): 502 (M+,100).

CA 022~4120 1998-11-10 ~ EXAMPLE 99 5-{(2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-- benzo[l ,3]dioxole-2,2-dicarboxylic acid bis-(3-phenyl-allyl)ester Step 1 5-{(2R)-2-[[(2R)-2-(tert-Butyl-dimethyl-siloxy)-2-(3-chloro-phenyl)-ethyll-(2,2,2-trichloro-ethoxycarbonyl)-amino]-propyl}-benzo[l,3]dioxole-2,2-dicarboxylic acid bis-(3-phenyl-allyl) ester The title compound was prepared as a colorless oil according to the procedure of Example 4, Step 4 except that cinnamyl bromide was used in place of allyl iodide;
yield 66%; Rf = 0.68 (2/1 hexanes/EtOAc); IH NMR (300 MHz, CDCl3): ~ -0.19-(-0.11) (m, 3H), -0.01-0.05 (m, 3H), 0.83-0.90 (m, 9H), 1.02 (d, J=6.7 Hz, 3H), 2.60-2.75 (m, IH), 2.77-2.96 (m, IH), 3.04-3.33 (m, 2H), 3.76-4.00 (m, lH), 4.65-4.85 (m, 2H), 4.90-4.98 (m, 4H), 5.02-5.20 (m, lH), 6.20-6.33 (m, 2H), 6.60-6.85(m, 5H), 7.15-7.45 (m, 14H); MS (ES) m/z(relative intensity) 944 (M+, 100).

Step 2 5-{(2R3-2-[[(2R)2-(3-Chloro-phenyl)-2-hydroxy-ethyl]-(2,2,2-trichloro-ethoxycarbonyl)-amino]-propyl}-benzoll,3]dioxole-2,2-dicarboxylic acid bis-(3-phenyl-allyl) ester The title compound was prepared as a colorless oil according to the procedure of Example 4, Step 5 except that 5- { (2R)-2-[[(2R)-2-(tert-butyl-dimethyl-siloxy)-2-(3-chloro-phenyl)-ethyl]-(2,2,2-trichloro-ethoxycarbonyl)-amino]-propyl } -benzo[1,3]dioxole-2,2-dicarboxylic acid bis-(3-phenyl-allyl) ester was used in place of 5- ( (2R)-2-[~(2R)-2-(tert-butyl-dimethyl-siloxy)-2-(3-chloro-phenyl)-ethyl]-(2,2,2-trichloro-ethoxycarbonyl)-amino]-propyl ) -benzo[1,3]dioxole-2,2-dicarboxylic acid diallyl ester; yield 78%; R~ = 0.31 (2/1 hexanes/EtOAc); IH NMR (300 MHz, CDC13):
~ 1.20-1.35 (m, 3H), 2.58-2.80 (m, lH), 2.81-3.20 (m, 2H), 3.22-3.56 (m, 2H), 4.10-4.31 (m, 3H), 4.70-4.95 (m, SH), 6.17-6.43 (m, 2H), 6.60-6.90 (m, SH), 7.15-7.45 (m, 14H).; MS (ES) m/z (relative intensity): 830 (M++H, 100).

Step 3 5-{(2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid bis-(3-phenyl-allyl)ester The title compound was prepared as a colorless oil according to the procedure 5of Example 4, Step 6 except that 5-{(2R)-2-[[(2R)2-(3-chloro-phenyl)-2-hydroxy-ethyl]-(2,2,2-trichloro-ethoxycarbonyl)-amino]-propyl ) -benzo[1,3]dioxole-2,2-dicarboxylic acid bis-(3-phenyl-allyl) ester was used in place of 5- ~ (2R)-2-[~(2R)-2-(3-chloro-phenyl)-2-hydroxy-ethyl]-(2,2,2-trichloro-ethoxycarbonyl)-amino]-propyl } -benzo[1,3]dioxole-2,2-dicarboxylic acid diallyl ester; yield 59%; Rf = 0.35 (10/1 10CHCl3/MeOH); IH NMR (300 MHz, CDCl3): ~ 1.15 (d, J=6.3 Hz, 3H), 2.50-3.70 (brs, 2H), 2.60-2.71 (m, IH), 2.80-2.92 (m, 2H), 2.95-3.15 (m, 2H), 4.83-4.95 (m, 5H), 5.25-5.40 (m, 4H), 6.08-6.30 (complex m, 2H), 6.66-6.91 (m, 5H), 7.15-7.40 (m, 14H); MS (ES) m/z (relative intensity): 654 (M+, 100).

5-{(2R) 2-~(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino~-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid dicyclooctyl ester The title compound was prepared as a white gum from 5-(2-[2-(3-chloro-20phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid and cyclooctanol according to the procedure of Example l; yield 84 %; Rf = 0.30 (10/1 CHCI3/MeOH); lH NMR (300 MHz, CDCI3): ~ 1.30-1.39 (brd, 3H), 1.40-1.92 (m, 28H), 2.72-2.~7 (m, lH), 3.06-3.30 (m, 2H), 3.39-3.52 (m, 2H), 3.80-3.91 (m, lH), 5.02-5.13 (m, lH), 5.40-5.80 (m, lH), 6.71-6.89 (m, 4H), 7.21-7.37 (m, 2H),257.44 (s, lH), 8.73 (brs, lH), 10.11 (brs, lH); MS (ES) m/z (relative intensity). 679 (M+, 100).

5-{(2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl~-30benzo[1,3]dioxole-2,2-dicarboxylic acid bis-(4-benzyloxy-but-2-enyl)ester To a room temperature solution of 110 mg (0.25 mmol) of 5-~2-[2-(3-chloro-phenyl)-3-oxazolidinyl]-propyl }-benzo[1,3ldioxole-2,2-dicarboxylic acid and 5 rnL of 35DMF was added 69 mg (0.69 mmol) of K2CO3 followed by 195 mg (0.76 mmol) of Wo 97/43273 PCT/US97/08148 ~ cis-4-benzyloxy-2-buten-1-methane sulfonate. After heating at 50 ~C for 20 h, the reaction mixture was cooled to room temperature, poured into 50 mL of brine and - extracted with 2 x 50 mL EtOAc. The combined organics were washed with 1 x 50 n~
sat. aq. NaHCO3, 1 x 50 mL brine, dried over Na2SO4, filtered and evaporated to a S yellow oil. Flash chromatography on silica gel, eluting with CHCI3/MeOH (40/1 to 10/1), gave 89 mg (0.12 mmol, a 47% yield) of the title compound (R~ = 0.30 (10/1 CHCI3/MeOH) as a yellow oil. IH NMR (300 MHz, CDCl3): ~ 0.98-1.10 (m, 3H), 2.44-2.78 (m, 3H), 2.82-3.00 (m, 2H), 4.11-4.20 (m, 4H), 4.40-4.70 (m, 2H), 4.85-4.95 (m" 4H), 5.70-5.79 (m, 2H), 5.81-5.92 (m, 2H), 6.72-6.90 (m, 3H), 7.17-7.47(m, 14H); MS (ES) m/z (relative intensity): 742 (M+, 100).

5-{(2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}ben~o[l,3]dioxole-2,2-dicarboxylic acid phenethyl ester To a 0 ~C solution of 0.630 g (1.0 mmol) of 5-1(2R)-2-[(2R)-2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl ) -benzo~ 1,3]dioxole-2,2-dicarboxylic acid bis-(2-phenethyl) ester in 12 mL CH3CN was added 5.6 mL 1 N NaOH (5.6 mmol), and the resulting solution was stirred at room temperature for 12 h. The solution was concentrated, 10 mL of water and 10 mL of ether were added, the pH of the rnixture was adjusted to pH 8 with sat. aq. NH4Cl, and the resulting white precipitate was collected by filtration. After washing with sat. aq. NaHCO3, water and ether, the resulting solid was dried under vacuum to give 0.4 g (0.76 mmol, a 76% yield) of the title compound (Rf = 0.39; 9/1 CHCI3/MeOH) as a tan solid; mp 75-82 ~C; ~H NMR
(300 MHz, DMSO-d6): â 1.00 (d, 3H), ~ 2.5 (br m, 4H), ~ 2.84-3.10 (m, SH), 3.35 (br, water), ~ 4.28 (t, 2H), ~ 4.90 (m, lH), ~ 6.6 (d, lH), ~ 6.76 (d, 2H), ~
7.21 (br s, 6H), ~ 7.36 (m, 3H), o 7.46 (s, lH); MS (ES) m/z (relative intensity): 526 (M+, 100).

I~:XAMPLE 103 5 {(2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}benzo[l,3]dioxole-2,2-dicarboxylic acid (l-phenyl-ethyl) ester S The title compound was prepared as a tan solid according to the procedure ofExample 102 from 5-~(2R)-2-[(2R)-2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}benzo[1,3]dioxole-2,2-dicarboxylic acid bis-(l-phenylethyl) ester; yield: 22 %;
Rf = 0.39 (9/1 CHCI3/MeOH; mp 71-79 ~C; lH NMR (300 MHz, DMSO-d6): ~ 1.00 (d, 3H), ~ l.S (br m, 3H), ~ 2.4-2.75 (m, lH), o 3.15 -3.45(br m, SH), â 4.90 (br d, 10lH), ~ 5.20 (br d, lH), ~ 5.90 (q, lH), o 6.6 (d, lH), â 6.76 (d, 2H), o 7.21 (br s, 6H), ~ 7.36 (m, 3H), ~ 7.46 (s, lH); MS (ES) m/z (relative intensity): 526 (M+, 100).

5-{(2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-15propyl}benzo~l,3]dioxole-2,2-dicarboxylic acid bis-(3-benzyloxy-propyl)ester The title compound was ~lepal~d as a yellow gum from 5-~2-[2-(3-chloro-phenyl)-2-hydroxy-ethylaminol-propyl ) -benzo[1,3]dioxole-2,2-dicarboxylic acid and 203-benzyloxy-propanol according to the procedure of Example 1; yield: 38 %; Rf = 0.52 (9/1 CHCI3/MeOH); 1H NMR (300 MHz, CDCI3): ~ 1.32 (d, 3H), o 2.00 (m, 4H), 2.75 (m, lH), ~ 3.30 (s, 2H), ~ 3.50 (m, 4H), o 4.40 (br m, 12H), ~ 5.49 (s, lH), ~
6.68-6.85 (m, 3H), ~ 7.24-7.40 (m, 13H), â 7.43 (s, lH); MS (ES) m/z (relative intensity): 5l8 (M+-HCI, 100).

Claims (109)

What is Claimed:
1) A compound of 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 a ring:

wherein R' is hydrogen, C1 to C6 alkyl, or aryl;
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, aryl, arylalkyl, alkoxyalkyl, heteroaryl, -CHR12COOR13, -CHR12C(O)R13, - CHR12CONR10R11, -CHR12OCOOR13, or -CHR12OC(O)R13, with the provision that R9 is not hydrogen in both R7 and R8;
R10 and R11 are independently hydrogen, C1 to C12 alkyl, aralkyl, aryl, furanylalkyl, or alkoxycarbonylalkyl;
R12 and R13 are independently hydrogen, C1 to C12 alkyl, aryl, or aralkyl; or a pharmaceutically acceptable salt thereof, enantiomer thereof, racemic mixture thereof, or diastereomeric mixture thereof.
2) A compound of Claim 1 which is 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid bis-(2-methoxy-ethyl) ester or a pharmaceutically acceptable salt thereof.
3) A compound of Claim 1 which is 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2.2-dicarboxylic acid diphenethyl ester or a pharmaceutically acceptable salt thereof.
4) A compound of Claim 1 which is 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid bis-(2-butoxy-ethyl)ester or a pharmaceutically acceptable salt thereof.
5) A compound of Claim 1 which is 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid bis-(2-phenoxy-ethyl) ester or a pharmaceutically acceptable salt thereof.
6) A compound of Claim 1 which is 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid bis-(2-ethoxy-ethyl)ester or a pharmaceutically acceptable salt thereof.
7) A compound of Claim 1 which is 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid bis-(2-tert-butoxy-ethyl) ester or a pharmaceutically acceptable salt thereof.
8) A compound of Claim 1 which is 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid (2-tert-butoxy-ethyl) ester or a pharmaceutically acceptable salt thereof.
9) A compound of Claim 1 which is 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid bis-(2-isobutoxy-ethyl) ester or a pharmaceutically acceptable salt thereof.
10)A compound of Claim 1 which is 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid bis-(benzyl) ester or a pharmaceutically acceptable salt thereof.
11) A compound of Claim 1 which is 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid bis-(cyclohexyl) ester or a pharmaceutically acceptable salt thereof.
12) A compound of Claim 1 which is 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid bis-(cyclopentyl) ester or a pharmaceutically acceptable salt thereof.
13) A compound of Claim 1 which is 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid dioctyl ester or a pharmaceutically acceptable salt thereof.
14) A compound of Claim 1 which is 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl)-benzo[1,3]dioxole-2,2-dicarboxylic acid dipentyl ester or a pharmaceutically acceptable salt thereof.
15) A compound of Claim 1 which is 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid dihexyl ester or a pharmaceutically acceptable salt thereof.
16) A compound of Claim 1 which is carbonic acid 3-chloro-benzyl ester 2-(3-chloro-benzyloxycarbonyloxy)-4-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-phenyl ester or a pharmaceutically acceptable salt thereof.
17) A compound of Claim 1 which is 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid bis-(1-phenyl-ethyl)ester or a pharmaceutically acceptable salt thereof.
18) A compound of Claim 1 which is 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid diheptyl ester or a pharmaceutically acceptable salt thereof.
19) A compound of Claim 1 which is 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid dinonyl ester or a pharmaceutically acceptable salt thereof.
20) A compound of Claim 1 which is 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid bis-decyl ester or apharmaceutically acceptable salt thereof.
21) A compound of Claim 1 which is 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid didodecyl ester or apharmaceutically acceptable salt thereof.
22) A compound of Claim 1 which is 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid bis-(2-isopropoxy-ethyl) ester or a pharmaceutically acceptable salt thereof.
23) A compound of Claim 1 which is 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid isopropyl ester or apharmaceutically acceptable salt thereof.
24) A compound of Claim 1 which is 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid ethyl ester or a pharmaceutically acceptable salt thereof.
25) A compound of Claim 1 which is 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid bis-methoxycarbonylmethyl ester or a pharmaceutically acceptable salt thereof.
26) A compound of Claim 1 which is 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylarnino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid bis-propoxycarbonylmethyl ester or a pharmaceutically acceptable salt thereof.
27) A compound of Claim 1 which is 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid bis-(1-methoxycarbonyl-ethyl) ester or a pharmaceutically acceptable salt thereof.
28) A compound of Claim 1 which is 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid bis-isopropoxycarbonylmethyl ester or a pharmaceutically acceptable salt thereof.
29) A compound of Claim 1 which is 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid bis-ethoxycarbonylmethyl ester or a pharmaceutically acceptable salt thereof.
30) A compound of Claim 1 which is 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid bis-(1-ethoxycarbonylethyl) ester or a pharmaceutically acceptable salt thereof.
31) A compound of Claim 1 which is 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid bis-trimethylsilanylmethyl ester or a pharmaceutically acceptable salt thereof.
32) A compound of Claim 1 which is 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid bis-(2-trimethylsilanylethyl) ester or a pharmaceutically acceptable salt thereof.
33) A compound of Claim 1 which is 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid bis-(3-trimethylsilanylpropyl) ester or a pharmaceutically acceptable salt thereof.
34) A compound of Claim 1 which is 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid bis-(3,3-dimethyl-butyl) ester or a pharmaceutically acceptable salt thereof.
35) A compound of Claim 1 which is 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid bis-cyclohexylmethylester or a pharmaceutically acceptable salt thereof.
36) A compound of Claim 1 which is 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylarnino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid bis-(4-methyl-pentyl) ester or a pharmaceutically acceptable salt thereof.
37) A compound of Claim 1 which is 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethy}amino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid bis-(2-cyclohexyl-ethyl) ester or a pharmaceutically acceptable salt thereof.
38) A compound of Claim 1 which is 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid bis-(3-cyclopentylpropyl) ester or a pharmaceutically acceptable salt thereof.
39) A compound of Claim 1 which is 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid bis-cyclopropylmethyl ester or a pharmaceutically acceptable salt thereof.
40) A compound of Claim 1 which is 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}benzo[1,3]dioxole-2,2-dicarboxylic acid bis-(1-methyl-cyclopropyl-methyl) ester or a pharmaceutically acceptable salt thereof.
41) A compound of Claim 1 which is 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylaminol-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid bis-cyclobutylmethylester or a pharmaceutically acceptable salt thereof.
42) A compound of Claim 1 which is 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid bis-(2-cyclopentyl-ethyl) ester or a pharmaceutically acceptable salt thereof.
43) A compound of Claim 1 which is 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]propyl}benzo[1,3]dioxole-2,2-dicarboxylic acid bis-acetoxymethyl ester or a pharmaceutically acceptable salt thereof.
44) A compound of Claim 1 which is 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]propyl}benzo[1,3]dioxole-2,2-dicarboxylic acid bis-propionyloxymethylester or a pharmaceutically acceptable salt thereof.
45) A compound of Claim 1 which is 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]propyl}benzo[1,3]dioxole-2,2-dicarboxylic acid bis-butyryloxymethyl ester or a pharmaceutically acceptable salt thereof.
46) A compound of Claim 1 which is 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]propyl}benzo[1,3]dioxole-2,2-dicarboxylic acid bis-isobutyryloxymethyl ester or a pharmaceutically acceptable salt thereof.
47) A compound of Claim 1 which is 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]propyl}benzo[1,3]dioxole-2,2-dicarboxylic acid bis-heptanoyloxymethylester or a pharmaceutically acceptable salt thereof.
48) A compound of Claim 1 which is 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]propyl}benzo[1,3]dioxole-2,2-dicarboxylic acid bis-(4-methyl-pentanoyloxy-methyl) ester or a pharmaceutically acceptable salt thereof.
49) A compound of Claim 1 which is 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]propyl}benzo[1,3]dioxole-2,2-dicarboxylic acid bis-hexanoyloxymethyl ester or a pharmaceutically acceptable salt thereof.
50) A compound of Claim 1 which is 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]propyl}benzo[1,3]dioxole-2,2-dicarboxylic acid bis- (2,2-dimethyl-propionyloxymethyl) ester or a pharmaceutically acceptable salt thereof.
51) A compound of Claim 1 which is 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]propyl}benzo[1,3]dioxole-2,2-dicarboxylic acid bis cyclohexanecarbonyloxymethyl ester or a pharmaceutically acceptable salt thereof.
52) A compound of Claim 1 which is 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]propyl}benzo[1,3]dioxole-2,2-dicarboxylic acid bis-(1-propionyloxy-ethyl) ester or a pharmaceutically acceptable salt thereof.
53) A compound of Claim 1 which is 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]propyl}benzo[1,3]dioxole-2,2-dicarboxylic acid bis-[1-(2,2-dimethyl-propionyloxyethyl) ester or a pharmaceutically acceptable salt thereof.
54) A compound of Claim 1 which is 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]propyl}benzo[1,3]dioxole-2,2-dicarboxylic acid bis-(3,3-dimethyl-butyryloxy-methyl) ester or a pharmaceutically acceptable salt thereof.
55) A compound of Claim 1 which is 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]propyl}benzo[1,3]dioxole-2,2-dicarboxylic acid bis-[1-(3,3-dimethyl-butyryl-oxy)ethyl)}ester or a pharmaceutically acceptable salt thereof.
56) A compound of Claim 1 which is 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]propyl}benzo[1,3]dioxole-2,2-dicarboxylic acid bis-(3-cyclopentyl-propionyl-oxymethyl) ester or a pharmaceutically acceptable salt thereof.
57) A compound of Claim 1 which is 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]propyl}benzo[1,3]dioxole-2,2-dicarboxylic acid bis-benzoyloxymethyl ester or a pharmaceutically acceptable salt thereof.
58) A compound of Claim 1 which is 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]propyl}benzo[1,3]dioxole-2,2-dicarboxylic acid bis-(benzoyloxy-ethyl)ester or a pharmaceutically acceptable salt thereof.
59) A compound of Claim 1 which is 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]propyl}benzo[1,3]dioxole-2,2-dicarboxylic acid bis-(2,2-dimethyl-butyryloxy-methyl) ester or a pharmaceutically acceptable salt thereof.
60) A compound of Claim 1 which is 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid bis-amide or a pharmaceutically acceptable salt thereof.
61) A compound of Claim 1 which is 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid bis-2-propyl amide or a pharmaceutically acceptable salt thereof.
62) A compound of Claim 1 which is 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid bis-n-butyl amide or a pharmaceutically acceptable salt thereof.
63) A compound of Claim 1 which is 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid bis-phenylmethyl amide or a pharmaceutically acceptable salt thereof.
64) A compound of Claim 1 which is 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid bis-(2-furanylmethyl) amide or a pharmaceutically acceptable salt thereof.
65) A compound of Claim 1 which is 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid bis-(glycine ethyl ester) amide or a pharmaceutically acceptable salt thereof.
66) A compound of Claim 1 which is 5-{2-[2-(3-chloro-phenyl)-3-oxazolidinyl]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid or a pharmaceutically acceptable salt thereof.
67) A compound of Claim 1 which is 5-((2R)-2-{tert-Butoxycarbonyl-[(2R)-2-(3-chloro-phenyl)-2-hydroxy-ethyl]-amino)-propyl)-benzo[1,3]dioxole-2,2-dicarboxylic acid bis-diethylcarbamoylmethyl ester or a pharmaceutically acceptable salt thereof.
68) A compound of Claim 1 which is 5-{(2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid bis-diethyl-carbamoylmethyl ester or a pharmaceutically acceptable salt thereof.
69) A compound of Claim 1 which is 5-{2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid cyclopropylmethyl ester or a pharmaceutically acceptable salt thereof.
70) A compound of Claim 1 which is 5-{2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid cyclobutylmethyl ester or a pharmaceutically acceptable salt thereof.
71) A compound of Claim 1 which is 5-{2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid bis 2-(3-Thienyl)ethyl-ester or a pharmaceutically acceptable salt thereof.
72) A compound of Claim 1 which is 5-{2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl)-benzo[1,3]dioxole-2,2-dicarboxylic acid 2-(3-Thienyl)ethyl ester or a pharmaceutically acceptable salt thereof.
73) A compound of Claim 1 which is 5-{2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid bis 2-(Chloro)ethyl ester or a pharmaceutically acceptable salt thereof.
74) A compound of Claim 1 which is 5-{(2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid bis-(2-ethylbutyl) ester or a pharmaceutically acceptable salt thereof.
75) A compound of Claim 1 which is 5-{(2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid bis-(3-methylbutyl)ester or a pharmaceutically acceptable salt thereof.
76) A compound of Claim 1 which is 5-{(2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid (3-methylbutyl)ester or a pharmaceutically acceptable salt thereof.
77) A compound of Claim 1 which is 5-{(2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid bis-adamantan-1-ylmethyl ester or a pharmaceutically acceptable salt thereof.
78) A compound of Claim 1 which is 5-{(2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid bis-(2,2-dimethyl-propyl) ester or a pharmaceutically acceptable salt thereof.
79) A compound of Claim 1 which is 5-{(2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid adamantan-1-ylmethyl ester or a pharmaceutically acceptable salt thereof.
80) A compound of Claim 1 which is 5-{(2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid (2,2-dimethyl-propyl)ester or a pharmaceutically acceptable salt thereof.
81) A compound of Claim 1 which is 5-{(2R)-2-1(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid (3,3-dimethylbutyl) ester or a pharmaceutically acceptable salt thereof.
82) A compound of Claim 1 which is) A compound of Claim 1 which is 5-{(2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic aicd bis-(1-methyl-cyclohexylmethyl) ester or a pharmaceutically acceptable salt thereof.
83) A compound of Claim 1 which is 5-{(2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylaminol-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic aicd bis-(2-cyclohexyl-2-methyl-propyl) ester or a pharmaceutically acceptable salt thereof.
84) A compound of Claim 1 which is 5-{(2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic aicd bis-(2-methyl-2-nitro-propyl) ester or a pharmaceutically acceptable salt thereof.
85) A compound of Claim 1 which is 5-{(2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic aicd bis-(2,2,4-trimethyl-pentyl) ester or a pharmaceutically acceptable salt thereof.
86) A compound of Claim 1 which is 5-{(2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic aicd bis-(2,2-dimethyl-pentyl) ester or a pharmaceutically acceptable salt thereof.
87) A compound of Claim 1 which is 5-{(2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic aicd bis-(tetrahydro-furan-3-ylmethyl) ester or a acceptable salt thereof.
88) A compound of Claim 1 which is 5-{(2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic aicd bis-(3-hydroxy-2,2,4-trimethyl-pentyl) ester or a pharmaceutically acceptable salt thereof.
89) A compound of Claim 1 which is 5-{(2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic aicd bis-(2,2-dimethyl-3-phenyl-propyl) ester or a pharmaceutically acceptable salt thereof.
90) A compound of Claim 1 which is 5-{(2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic aicd bis-(tetrahydro-pyran-2-ylmethyl) ester or a pharmaceutically acceptable salt thereof.
91) A compound of Claim 1 which is 5-{(2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic aicd bis-(tetrahydro-furan-2-ylmethyl) ester or a pharmaceutically acceptable salt thereof.
92) A compound of Claim 1 which is 5-{(2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic aicd bis-(5-methyl-[1,3]dioxan-5-ylmethyl) ester or a pharmaceutically acceptable salt thereof.
93) A compound of Claim 1 which is 5-{(2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic aicd bis-(1-methyl-cyclohex-3-enylmethyl) ester or a pharmaceutically acceptable salt thereof.
94) A compound of Claim 1 which is 5-{(2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic aicd bis-(3-hydroxy-2,2-dimethyl-propyl) ester or a pharmaceutically acceptable salt thereof.
95) A compound of Claim 1 which is 5-{(2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid (2-ethoxy-ethyl) ester or a pharmaceutically acceptable salt thereof.
96) A compound of Claim 1 which is 5-{(2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid bis-[2-(3-bromo-phenyl)-ethyl}ester hydrochloride salt.
97) A compound of Claim 1 which is 5-{(2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid bis-(2-m-tolyl-ethyl) ester hydrochloride salt.
98) A compound of Claim 1 which is 5-{(2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid diallyl ester or a pharmaceutically acceptable salt thereof.
99) A compound of Claim 1 which is 5-{(2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid bis-(3-phenyl-allyl)ester or a pharmaceutically acceptable salt thereof.
100) A compound of Claim 1 which is 5-{(2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid dicyclooctyl ester or a pharmaceutically acceptable salt thereof.
101) A compound of Claim 1 which is 5-{(2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid bis-(4-benzyloxy-but-2-enyl)ester or a pharmaceutically acceptable salt thereof.
102) A compound of Claim 1 which is 5-{(2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}benzo[1,3]dioxole-2,2-dicarboxylic acid phenethyl ester or a pharmaceutically acceptable salt thereof.
103) A compound of Claim 1 which is 5-{(2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}benzo[1,3]dioxole-2,2-dicarboxylic acid (1-phenyl-ethyl) ester or a pharmaceutically acceptable salt thereof.
104) A compound of Claim 1 which is 5-{(2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}benzo[1,3]dioxole-2,2-dicarboxylic acid bis-(3-benzyloxy-propyl)ester or a pharmaceutically acceptable salt thereof.
105) A method of treating diabetes in a mammal, the method comprising administering to a mammal in need thereof an effective amount of a compound of 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 a ring:

wherein R' is hydrogen, C1 to C6 alkyl, or aryl;
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, aryl, arylalkyl, alkoxyalkyl, heteroaryl, -CHR12COOR13, -CHR12C(O)R13, - CHR12CONR10R11, -CHR12OCOOR13, or -CHR12OC(O)R13, with the provision that R9 is not hydrogen in both R7 and R8;
R10 and R11 are independently hydrogen, C1 to C12 alkyl, aralkyl, aryl, furanylalkyl, or alkoxycarbonylalkyl;
R12 and R13 are independently hydrogen, C1 to C12 alkyl, aryl, or aralkyl; or a pharmaceutically acceptable salt thereof, enantiomer thereof, racemic mixture thereof, or diastereomeric mixture thereof.
106) A method of treating obesity in a mammal, the method comprising administering to a mammal in need thereof an effective amount of compound of theformula:

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 a ring:

wherein R' is hydrogen, C1 to C6 alkyl, or aryl;
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, aryl, arylalkyl, alkoxyalkyl, heteroaryl, -CHR12COOR13, -CHR12C(O)R13, - CHR12CONR10R11, -CHR12OCOOR13, or -CHR12OC(O)R13, with the provision that R9 is not hydrogen in both R7 and R8;
R10 and R11 are independently hydrogen, C1 to C12 alkyl, aralkyl, aryl, furanylalkyl, or alkoxycarbonylalkyl;
R12 and R13 are independently hydrogen, C1 to C12 alkyl, aryl, or aralkyl; or a pharmaceutically acceptable salt thereof, enantiomer thereof, racemic mixture thereof, or diastereomeric mixture thereof.
107) A method of treating hyperglycemia in a mammal, the method comprising administering to a mammal in need thereof an effective amount of compound of 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 a ring:

wherein R' is hydrogen, C1 to C6 alkyl, or aryl;
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, aryl, arylalkyl, alkoxyalkyl, heteroaryl, -CHR12COOR13, -CHR12C(O)R13, - CHR12CONR10R11, -CHR12OCOOR13, or -CHR12OC(O)R13, with the provision that R9 is not hydrogen in both R7 and R8;
R10 and R11 are independently hydrogen, C1 to C12 alkyl, aralkyl, aryl, furanylalkyl, or alkoxycarbonylalkyl;
R12 and R13 are independently hydrogen, C1 to C12 alkyl, aryl, or aralkyl; or a pharmaceutically acceptable salt thereof, enantiomer thereof, racemic mixture thereof, or diastereomeric mixture thereof.
108) A pharmaceutical composition comprising an effective amount of a compound of 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 a ring:

wherein R' is hydrogen, C1 to C6 alkyl, or aryl;
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, aryl, arylalkyl, alkoxyalkyl, heteroaryl, -CHR12COOR13, -CHR12C(O)R13, CHR12CONR10R11. -CHR12OCOOR13, or -CHR12OC(O)R13, with the provision that R9 is not hydrogen in both R7 and R8;
R10 and R11 are independently hydrogen, C1 to C12 alkyl, aralkyl, aryl, furanylalkyl, or alkoxycarbonylalkyl;
R12 and R13 are independently hydrogen, C1 to C12 alkyl, aryl, or aralkyl; or a pharmaceutically acceptable salt thereof, enantiomer thereof, racemic mixture thereof, or diastereomeric mixture thereof, in combination with a pharmaceutically acceptable carrier.
109) A process for preparing a compound of formula II as claimed in Claim 1 which comprises one of the following:

a) reacting a compound of formula:

wherein R2 - R6 are as defined in Claim 1 OH and R8 is OAg or R8 as defined above excepting OH with a compound of formula:

I-CHR12OC(O)R13 wherein R12 and R13 are as defined in Claim 1 to give a compound of formula II
wherein R9 is -CHR12OC(O)R13; or b) reacting a compound of formula:

wherein R1-R6 and R8 are as defined above with compound of formula R9OH where R9 is as defined above excepting hydrogen to give a corresponding compound of formula II, or c) hydrolysing a compound for formula:

wherein R1, R4, R5, R6, R7 and R8 are as defined in Claim 1 and R2 is trialkylsilyl and R3 is (C1-C6 alkoxy)-carbonyl to give a corresponding compound of formula 1 wherein R2 and R3 are both hydrogen; or d) reacting a compound of formula I wherein R2 and R3 are both hydrogen with an aldehyde of formula:

R'CHO

wherein R' is as defined in Claim 1 to give a corresponding compound of formula II
wherein R2 and R3 are joined to form a ring:

e) reacting a compound of formula:

wherein R1, R4, R5 and R8 are as defined in Claim 1 with the proviso neither R2 or R3 is hydrogen with a compound of formula:

wherein Z is Cl, Br, I, methanesulfonate or p-toluenesulfonate and R9 is as defined in Claim 1 excepting hydrogen, to give a corresponding compound of formula II; or f) hydrolysing a compound of formula:

wherein R1, R2, R3, R4, R5 and R6 are as defined in Claim 1, R8 is OR9' or NR10R11 and R9' is C1-C12 alkyl, C1-C12 cycloalkyl, C1-C12 silyalkyl, aryl, arylalkyl, alkoxyalkyl or heteroaryl to give a compound of formula:

wherein R1-R6 and R8 are as defined above providing that R2 and R3 are both hydrogen or joined to form a ring:

; or g) reacting a compound of formula:

wherein R1-R6 and R8 are as defined in Claim 1 and R9' as defined above, with a compound of formula:

wherein R11 and R12 are as defined in Claim 1 to give a compound of formula:

wherein R1-R6, R8, R11 and R12 are as defined in Claim 1.
CA002254120A 1996-05-14 1997-05-09 Substituted 1, 3-benzodioxoles Abandoned CA2254120A1 (en)

Applications Claiming Priority (2)

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US64597096A 1996-05-14 1996-05-14
US08/645,970 1996-05-14

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JP (1) JP2000510150A (en)
KR (1) KR20000011001A (en)
AU (1) AU730659B2 (en)
BR (1) BR9708948A (en)
CA (1) CA2254120A1 (en)
HU (1) HUP9902088A2 (en)
IL (1) IL126780A0 (en)
NZ (1) NZ332713A (en)
WO (1) WO1997043273A1 (en)

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EP3797108B1 (en) 2018-05-21 2022-07-20 Constellation Pharmaceuticals, Inc. Modulators of methyl modifying enzymes, compositions and uses thereof
CA3148444A1 (en) * 2019-07-24 2021-01-28 Constellation Pharmaceuticals, Inc. Ezh2 inhibition therapies for the treatment of cancers

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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

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IL126780A0 (en) 1999-08-17
BR9708948A (en) 1999-08-03
HUP9902088A2 (en) 2001-04-28
WO1997043273A1 (en) 1997-11-20
JP2000510150A (en) 2000-08-08
KR20000011001A (en) 2000-02-25
AU730659B2 (en) 2001-03-08
AU3006797A (en) 1997-12-05
EP0901484A1 (en) 1999-03-17
NZ332713A (en) 2000-07-28

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