AU730659B2

AU730659B2 - Substituted 1, 3-benzodioxoles

Info

Publication number: AU730659B2
Application number: AU30067/97A
Authority: AU
Inventors: Gerardo De La Cruz Francisco; Adam Matthew Gilbert; George Theodore Grosu; Michael Sotirios Malamas; Fuk-Wah Sum; Aranapakam Mudumbai Venkatesan
Original assignee: American Home Products Corp
Current assignee: Wyeth LLC
Priority date: 1996-05-14
Filing date: 1997-05-09
Publication date: 2001-03-08
Anticipated expiration: 2017-05-09
Also published as: AU3006797A; HUP9902088A2; IL126780A0; JP2000510150A; KR20000011001A; BR9708948A; CA2254120A1; EP0901484A1; NZ332713A; WO1997043273A1

Description

WO 97/43273 PCT/US97/08148 SUBSTITUTED 1.3-BENZODIOXOLES This invention relates to novel substituted 1,3-benzodioxole compounds which have antidiabetic, antihyperglycemic, and antiobesity properties. The present invention also relates to pharmaceutical compositions containing these compounds, methods for the preparation of these compounds, and methods for the use of these compounds in treating diabetes and/or hyperglycemia and/or obesity in mammals.

BACKGROUND OF THE INVENTION Bloom, et al., U.S. Patent 5,061,727, disclose substituted 5-(2-((2-aryl-2hydroxyethyl)amino)propyl)- 1,3-benzodioxoles of general formula (I) R R 2

R

3

(I)

R4 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, Cl 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 Ci 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 Cl to C4 alkyl; R5 and R6 are selected from the group consisting of hydrogen, carboxy, alkoxycarbonyl, hydroxymethyl, -CH20CH2COOR 7 and CH20CH2CH20R 7 where R7 is hydrogen or Cl to C4 alkyl; with the provision that and R6 may not both be hydrogen; which have antihyperglycemic and antiobesity activity.

-2- The synthesis, antidiabetic effects, and antiobesity effects of 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 the Future, 1994, 19, 23.

The compounds of the present invention possess greatly increased potency at human 33 receptors in comparison to the compounds in Bloom, et al., U.S. Patent 5,061,727. They retain high selectivity for the P3 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 33 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 R5 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 minimal side effects such as heart rate increase :and muscle tremor in humans and animals, when formulated into pharmaceutical compositions.

-3- Throughout the description and claims of the specification the word "comprise" and variations of the word, such as "comprising" and "comprises", is not intended to exclude other additives, components, integers or steps.

The discussion of the background to the invention herein is included to explain the context of the invention. This is not to be taken as an admission that any of the material referred to was published, known or part of the common general knowledge in Australia as at the priority date of any of the claims.

DESCRIPTION OF THE INVENTION The compounds of the present invention achieve their antidiabetic, antihyperglycemic, and antiobesity effects by acting as selective agonists at 33 adrenergic receptors. The stimulation of these receptors on white and brown adipocytes promotes both lipolysis (breakdown of fat) and energy expenditure.

15 Selective stimulation of P3 adrenergic receptors is important for chronic treatment.

Stimulation of other p-receptors could cause side effects such as increased heart rate (p1 effect) and muscle tremor (p2 effect). The compounds of the present 00 invention show high selectivity for 33 adrenergic receptors.

According to the present invention there are provided new compounds of 20 the formula (II): 0 0•

OR

2

R

3 O

I

N

O R7 R and R ar indpndntly hydrogn, Ci to C alky, trifluoromethyl, RP is hydrogen or Co to Cg trialkylsilyl; R6

O

wherein: R, and R 6 are independently hydrogen, C1 to C6 alkyl, trifluoromethyl, cyano, C, to C6 alkoxy, or halogen;

R

2 is hydrogen or C, to C 6 trialkylsilyl;

R

3 is hydrogen or C, to C6 alkoxycarbonyl; or R 2 and R 3 are joined to form a ring: 0

N

W:\fonaNKI\Spcis\30067.doc -4wherein R' is hydrogen, C, to C6 alkyl, or aryl;

R

4 and R 5 are independently hydrogen or Ci to C6 alkyl;

R

7 and R 8 are independently OR 9 or NRioR 11

R

9 in each instance is independently selected from hydrogen, Ci to C12 alkyl, C, to C12 cycloalkyl, Ci to C12 silylalkyl, aryl, arylalkyl, alkoxyalkyl, heteroaryl, -CHR 1 2COOR 13

-CHR

1 2C(O)R 13

-CHR

1 2CONRoR 11

-CHR

1 2 0COOR 13 or -CHR 12 0C(O)R 13 with the provision that R 9 is not hydrogen in both R 7 and R 8 Rio and R 11 are independently hydrogen, C1 to C12 alkyl, aralkyl, aryl, furanylalkyl, or alkoxycarbonylalkyl;

R

12 and R 13 are independently hydrogen, Ci to C12 alkyl, aryl, or aralkyl; further providing that when R 2 is hydrogen or Ci to C6 trialkylsilyl and R 3 is hydrogen or C, to C6 alkoxycarbonyl, then R 7 and R 8 are each OR 9 when R 9 in each instance is other than C1 to C12 alkyl; 15 or a pharmaceutically acceptable salt thereof, enantiomer thereof, racemic mixture thereof, or diastereomeric mixture thereof.

In the description above, aryl may be phenyl or naphthyl; arylalkyl ay be phenyl C1 to C6 alkyl or naphthyl C1 to C6 alkyl; alkoxy alkyl may be Ci to C6 alkoxy Ci to C6 alkyl; and heteroaryl may be pyridyl, thiophenyl, furanyl, 20 imidazolyl, oxazolyl, or thiazolyl. The aryl, arylalkyl and heteroaryl groups referred to above may be optionally substituted with one or more moieties selected from halogens, CI-C6 alkyl, CI-C6 alkoxy, -CF 3 -CN, or -OH groups. In a more preferred embodiment of this invention, the phenyl C1 to C6 alkyl group may be optionally substituted by one or more substituents selected from F, CI, Br, CH 3 or S- 25 CF 3 This invention also provides processes for preparing the compounds of the invention which comprise one of the following: a) reacting a compound of formula:

OR

2

R

3

I

N O CO 2 Ag R,

R

4

R

5 X wherein R-R 6 are as defined in laim and R 8 is OAg or R as defined above R A wherein Ri-R6 are as defined in Claim 1 and Re is OAg or Ra as defined above W:fiona\NKI\Spcics\30067.doc excepting OH with a compound of formula:

I-CHR

12 0C(O)R 13 wherein R 12 and R 13 are as defined in claim 1 to give a compound of formula II wherein R 9 is

-CHR

12 0C(O)R 13 or b) reacting a compound of formula: wherein R 1

-R

6 and R 8 are as defined above with compound of formula R 9

OH

where R 9 is as defined above excepting hydrogen to give a corresponding compound of formula II; or c) hydrolysing a compound for formula:

COR

7

COR

8 wherein R 1

R

4

R

5

R

6

R

7 and R 8 are as defined in claim 1 and R 2 is trialkylsilyl and R 3 is (C 1

-C

6 alkoxy)-carbonyl to give a corresponding compound of formula I wherein R 2 and R 3 are both hydrogen; or d) reacting a compound of formula I wherein R 2 and R 3 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 R 2 and R 3 are joined to form a ring: W:\fol\NKI\Spcies\30067.doc -6- 0' ;or e) reacting a compound of formula: wherein R 1

R

4

R

5 and R 8 are as defined in claim 1 with the proviso that neither

R

2 or R 3 is hydrogen with a compound of formula:

Z-R

9 wherein Z is Cl, Br, 1, methanesulfonate or p-toluenesulfonate and R 9 is as defined in claim 1 excepting hydrogen, to give a corresponding compound of formula 11; or f) hydrolysing a compound of formula:

COOR

9

COR

8 wherein Ri, R 2

R

3

R

4

R

5 and R 6 are as defined in claim 1, R 8 is OR 9 and R 9 is Cl-C1 2 cycloalkyl, C1-012 silylalkyl, aryl, arylalkyl, alkoxyalkyl or heteroaryl to give 15 a compound of formula: wherein R 1

-R

6 and R 8 are as defined above providing that R 2 and R 3 are both hydrogen or joined to form a ring: W:\fionW\NISpis\30067.doc N ;or g) reacting a compound of formula:

OR

2

R

3 01N 0 C00R 9 R,

R

4

R

5

I

wherein R 1

-R

6 and R 8 are as defined in claim 1 and R 9 as defined above, with a compound of formula: HNRjjR 12 wherein R 1 1 and R 12 are as defined in Claim I to give a compound of formula: 2 3* N 0 C0NRjjR 12 O> 0 OR 8 wherein R 1

-R

6

R

1 1 and R 12 are as defined in Claim 1.

The most preferred compounds of this invention are the following and the pharmaceutically acceptable salts thereof: 5-{2-[2-(3-chloro-phenyl)-2-hyd roxy-ethylamino]-propyl}-benzo[1 ioxole- 2 ,2-d icarboxyl ic acid bis-(2-methoxy-ethyl )ester; i 5-{2-[2-(3-chloro-phenyl)-2-hyd roxy-ethylamino]-propyl}-benzo[1 ioxole- 2,2-dicarboxylic acid diphenethyl ester; 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[I ,31-d ioxole- 2,2-dicarboxylic acid bis-(2-butoxy-ethyl) ester; 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[I ,31-d ioxole- 2,2-dicarboxylic acid bis-(2-phenoxy-ethyl) ester; 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[I ,3]-dioxole- 2,2-dicarboxylic acid bis-(2-ethoxy-ethyl) ester; W:\iom\NKlSpdi\3O67.doc WO 97/43273 WO 9743273PCT/US97/08148 -8- (3-chloro-phenyl)-2-hYdroxy-ethylamino] -propyl) -benzo[ 1 ,3]dioxole- 2,2-dicarboxylic acid bis-(2-tert-butoxy-ethyl) ester; (3-chloro-phenyl)-2-hydroxy-ethylamino] -propyl)I-benzor 1,3]dioxole- 2,2-dicarboxylic acid (2-tert-butoxy-ethyl) ester; 5-f 2- (3-chloro-phenyl)-2-hydroxy-ethylamino] -propyl )-benzo[1I,3]dioxole- 2,2-dicarboxylic acid bis-(2-isobutoxy-ethyl) ester; (3-chloro-phenyl)-2-hydroxy-ethylamino] -propyl)I-benzo[ 1,3]dioxole- 2,2-dicarboxylic acid bis-(benzyl) ester; 2- (3-chloro-phenyl)-2-hydroxy-ethylamino] -propyl)I-benzo[ 1,3]dioxole- 2,2-dicarboxylic acid bis-(cyclohexyl) ester; 2- (3-chloro-phenyl)-2-hydroxy-ethylamino] -propyl }-benzo[ 1,3]dioxole- 2,2-dicarboxylic acid bis-(cyclopentyl) ester; 2- (3-chloro-phenyl)-2-hydroxy-ethylamino] -propyl )-benzo[ 1,3] dioxole- 2,2-dicarboxylic acid dioctyl ester; 5-f (3-chloro-phenyl)-2-hydroxy-ethylamino] -propyl)I-benzo[ 1,3]dioxole- 2,2-dicarboxylic acid dipentyl ester; 2- 2- (3-chloro-phenyl)-2- hydroxy-ethylamino] -propyl I -ben zo[ 1,3] dioxole- 2,2-dicarboxylic acid dihexyl ester; carbonic acid 3-chloro-benzyl ester 2- (3-chloro-benzyloxycarbonyloxy)-4- {2- [2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl)}-phenyl ester; 2- [2-(3-chloro-phenyl)-2-hydroxy-ethylamino] -propyl)}-benzo[ 1,3]dioxole- 2,2-dicarboxylic acid bis-( 1-phenyl-ethyl) ester; 2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino] -propyl) -benzo[ 1,3ldioxole- 2,2-dicarboxylic acid diheptyl ester; 5-f( 2- (3 -chloro-phenyl) -2-hydroxy-ethyl amino] -propyl I -benzo[ 1 dioxole- 2,2-dicarboxylic acid dinonyl ester; 2- (3-chloro-phenyl)-2-hydroxy-ethylamino] -propyl)I-benzo[l1,3]dioxole- 2,2-dicarboxylic acid bis-decyl ester; 2- (3-chloro-phenyl)-2-hydroxy-ethylamino] -propyl)}-benzo[ 1,3]dioxole- 2,2-dicarboxylic acid didodecyl ester; 2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino] -propyl)I-benzo[ 1,3]dioxole- 2,2-dicarboxylic acid bis-(2-isopropoxy-ethyl) ester; 2- (3-chloro-phenyl)-2-hydroxy-ethylamino] -propyl)I-benzo[ 1,3]dioxole- 2,2-dicarboxylic acid isopropyl ester; WO 97/43273 WO 9743273PCT/US97/08148 -9- 3 -chloro-phenyl)-2-hydroxy-ethylamino] -propyl)7 -benzo[ 1 ,3]dioxole- 2,2-dicarboxylic acid ethyl ester; 3 -chloro-phenyl)-2-hydroxy-ethylamino]-propyl)I-benzo[ 1,3]dioxole- 2,2-dicarboxylic acid bis-methoxycarbonylmethyl ester; 5- 3 -chloro-phenyl)-2-hydroxy-ethylamino] -propyl)I-benzo[ 1,3jdioxole- 2,2-dicarboxylic acid bis-propoxycarbonylmethyl ester; 2 2 3 -chloro-phenyl)-2-hydroxy-ethylamino] -propyl 71-benzo[ 1,3]dioxole- 2,2-dicarboxylic acid bis-( 1-methoxycarbonyl-ethyl) ester; 2 2 3 -chloro-phenyl)-2-hydroxy-ethylaminol-propyl)}-benzo[ 1,3]dioxole- 2,2-dicarboxylic acid bis-isopropoxycarbonylmethyl ester; f 2 2 3 -chloro-phenyl)-2-hydroxy-ethylamino]-propyl 71-benzo[ 1,3jdioxole- 2,2-dicarboxylic acid bis-ethoxycarbonylmethyl ester; 2- 3 -chloro-phenyl) hydroxy-ethyl amino] -propyl)7 -benzo[ 1, ,31dioxole- 2,2-dicarboxylic acid bis-(1 -ethoxycarbonyl-ethyl) ester; 5-f 2 2 -(3-chloro-phenyl)-2-hydroxy-ethylamino] -propyl 71-benzo[ 1,3]dioxole- 2,2-dicarboxylic acid bis-trimethylsilanylmethyl ester; 2- 2 -(3-chloro-phenyl)-2-hydroxy-ethylamino] -propyl 71-benzo[ 1,3]dioxole- 2,2-dicarboxylic acid bis- (2-trimethylsilanyl-ethyl) ester; 3 -chloro-phenyl)-2-hydroxy-ethylamino] -propyl )-benzo[ 1,3]dioxole- 2,2-dicarboxylic acid bis-(3-trimethylsilanyl-propyl) ester; (3-chloro-phenyl)-2-hydroxy-ethylamino] -propyl 71-benzo[ 1,3]dioxole- 2,2-dicarboxylic acid bis-(3 ,3-dimethyl-butyl) ester; (3-chloro-phenyl)-2-hydroxy-ethylamino] -propyl 71-benzo[ 1,3]dioxole- 2,2-dicarboxylic acid bis-cyclohexylmethyl ester; 5- (3-chloro-phenyl)-2- hydroxy-ethylaminol -propyl I -ben zo[ 1,3] dioxole- 2,2-dicarboxylic acid bis-(4-methyl-pentyl) ester; (3-chloro-phenyl)-2-hydroxy-ethylamino] -propyl)I-benzo[ 1,3]dioxole- 2,2-dicarboxylic acid bis-(2-cyclohexyl-ethyl ester; 2 2 3 -chloro-phenyl)-2-hydroxy-ethylamino] -propyl)I-benzo[ 1,3]dioxole- 2,2-dicarboxylic acid bi s- (3-cycl open tyl-propyl ester; 2 2 3 -chloro-phenyl)-2-hydroxy-ethylamino]-propyl I-benzo[ 1 ,3]dioxole- 2,2-dicarboxylic acid bis-cyclopropylmethyl ester; 5-1 2- 2- (3 -chl oro-phenyl)-2- hydroxy-ethyl amino] -propyl -benzo[ 1 dioxole- 2,2-dicarboxylic acid hi 1-niethyl-cyclopropylmethyl) ester; WO 97/43273 WO 9743273PCTIUS97/08148 {2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino] -propyl )-benzo[ 1,3ildioxole- 2,2-dicarboxylic acid his-cyclohutylmethyl ester; Q3-chloro-phenyl) -2-hydroxy-ethylamino] -propyl -ben zo[ 1 dioxole- 2,2-dicarboxylic acid bis-(2-cyclopentyl-ethyl) ester; 5- 2 2 -(3-chloro-phenyl)-2-hydroxy-ethylaminolpropyl benzo[ I ,3ljdioxole- 2,2-dicarboxylic acid his-acetoxymethyl ester; (3-chloro-phenyl)-2-hydroxy-ethylamino]propyl benzo[ 1 ,3]dioxole- 2,2-dicarboxylic acid bis-propionyloxymethyl ester; 2 2 -(3-chloro-phenyl)-2-hydroxy-ethylaminolpropyl henzo[ 1 ,3]dioxole- 2,2-dicarhoxylic acid bis-butyryloxymethyl ester; 2- (3-chloro-pherlyl)-2-hydroxy-ethylaninojpropyl benzo[ 1 ,3lldioxole- 2,2-dicarboxylic acid his-isobutyryloxymethyl ester; 2 2 -(3-chloro-phenyl)-2-hydroxy-ethylamino]propyl benzo[ 1 ,3]dioxole- 2,2-dicarboxylic acid bis-heptanoyloxymethyl ester; 5- 2- (3 -chloro-phenyl)-2-hydroxy-ethylamino]propyl benzo[ 1 ,3]dioxole- 2,2-dicarboxylic acid bis-(4-methyl-pentanoyloxymethyl) ester; (3-chloro-phenyI)-2-hydroxy-ethylamino~propyl) benzo[ 1 ,3]dioxole- 2,2-dicarhoxylic acid bis-hexanoyloxymethyl ester; 2- (3-chloro-phenyl)-2-hydroxy-ethylanminolpropyl I benzo[ 1 ,3]dioxole- 2,2-dicarhoxylic acid bis- (2,2-dimethyl-propionyloxymethyl) ester; 2 2 -(3-chloro-phenyl)-2-hydroxy-ethylaminojpropyl benzo[ 1 ,3]dioxole- 2,2-dicarboxylic acid bis cyclohexanecarhonyloxymethyl ester; (3-chloro-phenyl)-2-hydroxy-ethylan-iino]propyl benzo[ 1 ,3]dioxole- 2,2-dicarhoxylic acid his-( 1-propionyloxy-ethyl) ester; 5- 2 2 3 -chloro-phenyl)-2-hydroxy-ethylaniino]propyl )benzo[ 1,3]dioxole- 2,2-dicarboxylic acid his- [1-(2,2-dimethyl-propionyloxy-ethyl) ester; 3 -chloro-phenyl)-2-hydroxy-ethylaniino~propyl enzo[ 1,3]dioxole- 2,2-dicarhoxylic acid bis-(3,3-dimethyl-butyryloxyniethyl) ester; 2 2 -(3-chloro-phenyl)-2-hydroxy-ethylan-linolpropyl benzo[ 1 ,3]dioxole- 2,2-dicarboxylie acid hi 1- (3,3-dimethyl-butyryloxy)-ethyl) )ester; f 2 2 -(3-chloro-phenyl)-2-hydroxy-ethylaminolpropyI I benzo[ 1 ,3]dioxole- 2,2-dicarboxylic acid his-(3-cyclopentyl-propionyloxymethyl) ester; 2 2 -(3-chloro-phenyl)-2-hydroxy-ethylamino]propyl henzo[ 1 ,3]dioxole- 2,2-dicarhoxylic acid his-benzoyloxyrnethyl ester; WO 97/43273 PCT/US97/08148 -11- 2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]propyl )benzo[1,3]dioxole- 2,2-dicarboxylic acid bis-(benzoyloxy-ethyl) ester; 5-1 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)-benzo[ 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; 12-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl -benzo[1,3]dioxole- 2,2-dicarboxylic acid bis-n-butyl amide; 5-(2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl)-benzo[l,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; 5-12-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl)-benzo[1,3]dioxole- 2,2-dicarboxylic acid bis-(glycine ethyl ester) amide; 5-1 2-[2-(3-chloro-phenyl)-3-oxazolidinyl] -propyl) -benzo[1,3]dioxole-2,2dicarboxylic 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 mammals which comprises administering to a human or other mammal 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 utilized, the mode of administration, 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 administered 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 administered in divided doses two to six times per day, or in a sustained release form. For most large mammals, 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.

WO 97/43273 PCT/US97/08148 -12- When treating obesity, in conjunction with diabetes and/or hyperglycemia, or alone, generally satisfactory results can be obtained when the compounds of this invention are administered at a daily dosage of from about 0.1 mg to about 1 mg per kg of body weight, preferably given in divided doses two to six times per day or in a sustained release form. For most large mammals, the total daily dosage is from about 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 gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating 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.

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 as 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 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 pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation 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 contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol glycerol, WO 97/43273 PCTIUS97/08148 -13propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable 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 animals, i.e. ungulate animals 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 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, cottonseed 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 important 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 medicated swine, cattle, sheep and goat feed generally contain from 0.01 to 400 grams of active ingredient per ton of feed, the optimum amount for these animals usually being about 50 to 300 grams per ton of feed. The preferred poultry and domestic pet feed usually contain about 0.01 to 400 grams and preferably to 400 grams of active ingredient per ton of feed.

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 administration 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 WO 97/43273 PCT/US97/08148 -14ingredient. The preferred dosage for swine, cattle, sheep and goats is in the range of from 0.001 to 50 mg/kg/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 mg/kg/day of body weight.

Paste formulations can be prepared by dispersing the active compounds in a pharmaceutically 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 carbowax, carnuba wax, and the like, and a lubricant, such as magnesium 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 periodically during the animal treatment period in order to maintain 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 animals, the present invention provides the means by which this can be accomplished. For the poultry and swine raisers, using the method of the present invention yields leaner animals which command higher prices from the meat industry.

Further, according to the present invention there are provided pharmaceutical 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 for increasing the content of lean meat in edible animals, which comprises administering to edible mammals an effective amount of the compound.

Also according to the present invention there are provided processes for producing the compounds of the present invention.

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

WO 97/43273 PCT/US97/08148 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, R5, R6, R12, and R13 are as defined above.

Scheme I

OH

R,-

1) AgNO 3 2)

R

1 2 0 1I 0 3 2 O R 13 OH H 0 R2 N O> 11 0 0

R

13 4 3 0 o Y O O R 3

R

1 2 Alternatively, a dicarboxylic acid 4 (Scheme H) is treated with an alcohol and an acid catalyst to yield the diester compounds 5 wherein RI, R4, R5, R6, and R9 are as defined above.

Scheme II

OH

N0 c o 2 H

R

9 0 H, H R- I r I U- WO 97/43273 PCT/US97/08148 -16- As outlined in Scheme III, the diester compounds 5 can also be produced by 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-R9, and removing the protecting groups R2 and R3, wherein RI, R2, R3, R4, R5, R6, and R9 are as defined above and Z is Cl, Br, I, methanesulfonate, trifluoromethanesulfonate, or para-toluenesulfonate.

Scheme III -OEt *OEt 1) add R2 and R 3 2) OH- 1) base,Z-R 9 2) remove

R

2 and R 3 As outlined in Scheme IV, a dicarboxylate 1 is treated with an aldehyde R'CHO to yield the oxazaline compounds 8, wherein R1, R4, R 5 R6, and R' are as defined above.

WO 97/43273 WO 9743273PCTIUS97/08148- 17 Scheme IV ONa ONa

R'CHO

As outlined in Scheme V the diester compounds 5 can be hydrolyzed under basic conditions to a monoester 9a and/or 9b, wherein Rl, R4, R5, R6, and R9 are as defined above. One or both of the diastereomers 9a and 9b may be produced in the hydrolysis reaction.

Scheme V 0 .oILOR 9 -0 OR 9 0

OH'

0 OH H 0 T~r~LOR 9 NjL OH 0 OH and/or R R t R I)'R

R

6 0R 6 0 WO 97/43273 PCT/US97/08148 18- As illustrate in Scheme VI, a diester compound 5 is reacted with an amine HNR11R12 to yield the diamide compounds 10, wherein R1, R4, R5, R6, R9, R11, and R12 are as defined above.

Scheme VI

OH

N

OR

9 R4 Rg5

OR

9 6 0

OH

R

H

R ,P I HNRllRl 2 NRjjR 12 NRjjR 12 The compounds of this invention were tested for antihyperglycemic and antiobesity activity according to the following procedures.

Human Beta Adrenergic Receptor Selectivity The activity of the test compounds on human 3-adrenergic receptors was determined with Chinese hamster ovary (CHO) cells transfected with human P2, or p1 adrenergic receptors. Agonist activity is indicated by increased cAMP levels in the CHO cells. Selectivity of the test compounds for the 03 receptor was assessed by comparison with results in 32 and 13 adrenergic receptor transfected cells.

Procedure: Chinese hamster ovary (CHO) cells transfected with human 12, or 13 adrenergic receptors were used in the assay.

Cells were grown to confluent conditions in 24 well plates.

WO 97/43273 PCT/US97/08148 19- Drugs were dissolved in DMSO at a concentration of 10 p.M.

Cells were incubated with drug at 10 nM concentration for 10 min at 370 C.

Isoproterenol (Standard 1) was used as the standard compound and assayed at 10 p.M which gives a maximal cAMP elevation in all 3 cell types.

Cell cAMP concentrations were assayed using a scintillation proximity assay kit from Amersham Corp., Chicago, IL.

Activities for the test compounds are expressed as a percentage of the isoproterenol response.

Production of the CHO cells transfected with human P2, or P1 adrenergic receptors, and compound test procedures utilizing the CHO cells, are described by Emorine et al. in their article "Molecular Characterization of the Human Beta3- Adrenergic Receptor", Science 1989, 245(8), 1118-1121 and by Muzzin et al. in the article "An Adipose Tissue-Specific Beta3-Adrenergic Receptor", J. Biol. Chem. 1991, 266, 24053-24058.

Effects on Free Fatty Acid Levels in Rats Rats respond to a single oral dose of P3 agonists by increasing plasma free fatty acids (FFA) in response to p3 receptor stimulation on the plasma membrane of the fat cell. 5- {2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl) -benzo[ 1,3]dioxole- 2,2-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: Drugs were dissolved in DMSO at 10 mg/ml.

Twenty p1 of the DMSO-drug solution was added to 10 mL methyl cellulose:tween- 80 for a final concentration of 20 p.g/mL.

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.

Plasma was analyzed for free fatty acids using a kit supplied by Biochemical Diagnostics Inc. (Brentwood, WO 97/43273 PCT/US97/08148 Drug response was calculated from the formula below.

FFA Response= FFA (compound) FFA vehicle x 100 FFA (Standard 2) FFA vehicle Effects on Hyperglycemia in Mice On the morning of Day 1 (baseline), 35 mice (male, db/db (C57BL/KsJ), Jackson Laboratories, 2 to 7 months of age and 35 to 60 g) were fasted for 4 h, weighed, and a baseline blood sample was collected from the tail-tip of each mouse without anesthesia, placed directly into a fluoride-containing tube, mixed, and maintained on ice. Food was then returned to the mice. The plasma was seperated and the levels of glucose in the plasma were dertermined by an Abbot VP Analyzer.

Because of the variable plasma glucose levels of the db/db mice, the 5 mice having the most extreme highest or lowest) plasma glucose levels were excluded and the remaining 30 mice were randomly assigned into 7 groups of equivalent mean plasma glucose level (vehicle control, ciglitazone (Standard and 5 test compound groups).

On the afternoon of Days 1, 2, and 3 the vehicle (0.2 mL of 2% Tween 80/saline w/v) or test compounds were administered to the ad libitum fed mice. On the morning of Day 4, the food was removed from the cages for 3 h, a blood sample was collected, and the mice were then given the fourth administration of test compound or vehicle.

Additional blood samples were collected at 2 and 4 h after test compound administration. Plasma glucose levels were determined. To assess test compound activity, the percent change of an animal's plasma glucose level on Day 4 (mean of 2 and 4 h values) from its level before test compound administration (Day 1 baseline sample) was determined as follows: 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 db/db mice represents a normalization of glucose levels.

WO 97/43273 PCTIUS97/08 148 21 Table I Compound aa Rat Free db/db Mice (Example) i 02 Fatty Plasma GlucoseC 1 4% 2 0. 02 2 g M 0. 07 1 mj "g/k T. 1289- mg/ kg 3 0%___2077 0 4 1% 2% 4% 115% 6 3% 14% 7 2% 22% 8 1% 9 16% 22% 0% 59% 11 _nt 118% 1 48% 14 5% 18% 46% 16I;, nt 17 _nt nt_ 18 19 2% 36% 0% 48% 21 2% 22 0.015 4M 23 nt 57% 24 nt_ 6% 30% 26 7% 42% 27 28 2% 22% 29- 2% 9% 0% 75% 31 5% 32- 2% 33% 5.90 g.M 0. 100 gM 0.8 m-7g 0.201 mg/kg 34 2% 74% 4% 69% 36 2% 37% 37 3% 33% 38 0.274 tM 0.086 mg/kWg 39 1% 71% 8.4 4iM 0.420 .M 0.071 mg/kg 41 22% 36% _01o__ WO 97/43273 PCTfUS97/08 148 22 Compound Rat Free db/db Mice (Example) pla 2 a Fatty Plasma Acidb GlucoseC 42 0% 39% 43 0% 44 0% 24% 1% 26% 46 23% 47 0% 37% 48 4% 29% 49 4% 50% 0% 19% 51 0% 52 2% 23% 53 2% 20% 54 7% 24% 0% 31% 56 8% 31% 57 0% 58 8% 35% 59 10% 17% 3% 22% 66 3% 40% 68 5% 5% 69 0.079 4,M 42% 3.00 4.M 0.048 p.M 39% 71 14% 72 13%43 73 0% 83% 74 0% 755.4 4.M 0.058 4.M 0.026 mg/kg 0.110 mg/kg 760.980 4.M 0.074 4.M 42% 77 5% 78 5.0 4.M 0.325 4.M 0.027 mg/kg 0.028 mg/kg 79 0% 61% 2.4 4.M 0.055 4.M 81% 81 0.380 p.M 0.059 4M 61% 82 nt 84% 83 nt 13% 84 60% 86 nt WO 97/43273 WO 9743273PCTIUS97/08148 23 Compound aaRat Free db/db Mice (Example) 02 1 Fatty Plasma Acidb GlucoseC 87 nt 68% 89 nt 7% 11% 91 7% 27% 92 nt 93 nt 94 nt 78% 0% 73% 96 1% 71% 97 4% 39% 98 7% 86% 99 16% 58% 100 2% 1 10% 101 3% 104 2% 83% a Human f3receptors expressed in Chinese hamster ovary cells, compounds tested at nM, results expressed as of isoproterenol activity (increase in cAMP) at 10 tLIM.

EC

50 (tiM) 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 3 -Chloro-phenyl)-2-hydroxy-ethylamino]-propyl 1benzo[ 1,31-dioxole-2,2-dicarboxylic acid diisopropyl ester response (78% increase) at 0.1 mg/kg. ED 50 (mg/kg) values determined for selected compounds.

C ED 50 (mg/kg/day) values for lowering of plasma glucose.

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

EXAMPLE 1 2 2 -(3-Chloro-phenyl)-2-hydroxy-ethylaiuinop-propyl1..

benzo[1 ,3]dioxole-2,2-dicarboxylic acid bi s-(2 -methoxy- ethyl) ester hydrochloride salt To a stirred mixture of 5-f 2 2 -(3-chloro-phenyl)-2-hydroxy-ethylamino.

propyl I-benzo[1,3]dioxole.2,2-dicarboxylic acid (1.0 g, 2.37 mmol), and 2-methoxy- WO 97/43273 WO 9743273PCTIUS97/08148 24 1-ethanol (10 m-L) was added excess HCl(g). The mixture became homogeneous and was stirred at 23 After 12 h, the solution was concentrated, and chromatographed on silica gel, eluting with CHCl 3 /MveOH then 40/1, 20/1 and 10/1) to give fractions containing 5- 3 -chloro-phenyl)-.2-hydroxy-ethylaminoy-propyl) benzo[1,3ijdioxole-2,2-dicarboxylic acid bis-(2-methoxy-ethyl) ester (Rf=-0.37 (10/1 CHCl 3 /MeOH)) as a viscous oil. This oil was dissolved in Et 2 O (10 mL) 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[1I,3]dioxole-2,2-dicarboxylic acid bis-(2-methoxy-ethyl) ester hydrochloride salt as a white solid; 1 H NMR (300 MHz, CDCl 3 8 1.33 (brm, 3H), 2.75-2.88 (brm, lH), 3.10-3.30 (bin, 2H), 3.35 6H), 3.40-3.53 (bn 2H), 3.63-3.68 (complexm, 4H), 4.40-4.48 (brm, 4H), 5.40-5.50 (brd, IH), 5.50-5.75 (brs, 1H), 6.70-6.91 (complex mn, 4H), 7.18-7.38 (mn, 2H), 7.43 lH), 8.60-8.85 (brs, lH), 9.90-10.15 (brs, 1H); MS (ES) mlz (relative intensity): 538 (M+-HCl, 100).

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

WO 97/43273 WO 9743273PCTIUS97/08148 25 EXAMPLE 3

S-{

2 2 3 -Chloro..phenyl)-2-hydroxy-ethylamino1..propyI}.

benzo[1,3]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-hydroxyethylamino] -propyl)}-benzo[1I,3ldioxole-2,2-dicarboxylic acid and 2-butoxyethanol accord-ing to the procedure of Example I as a colorless oil; IH NMR (300 MHz, CDCl 3 580.78-0.93 (in, 6H), 1. 15-1.78 (in, 12H), 2.70-3.62 (bin, 3.31-3.47 (in, 4H), 3.57-3.73 (mn, 4H), 4.29-4.53 (in, 4H), 5.47-5.57 (bns, 1H), 6.70-6.95 (in, 3H), 7.20-7.49 (in, 4H); MIS (ES) m/z (relative intensity): 622 (M+-HCI, 20), 214 158 EXAMPLE 4

S-{

2 2 3 -Chloro-phenyl)-2-hydroxy-ethylamino..propyl}..

benzo[1,3]dioxole-2,2..dicarboxylic acid bis-(2-phenoxy-ethyl) ester hydrochloride salt The title compound was prepared from 5-f 2-1i2-(3-chloro-phenyl)-2-hydroxyethylamino] -propyl )-benzo[1I,3]dioxole-2,2-dicarboxylic acid and 2-phenoxyethanol according to the procedure of Example 1 as an off-white gummy solid; IH NMR (300 MHz, CDCl 3 8 1.23-1.40 (brs, 3H), 2.70-2.90 (bin, 1H), 3.05-3.30 (brm, 2H), 3.31-3.52 (brm, 2H), 4.12 J 4.4 Hz, 4 4.57 J 4.8 Hz, 4 5.38-5.60 (bns, 2H), 6.70-7.0 (coinplexm, IOH), 7.15-7.47 (complex m, 7 8.60-8.80 (brs, 1H), 9.90-10.20 (brs, I MIS (ES) ml z (relative intensity): 662 (M+-HC1, (100), 594 498 EXAMPLE 2 2 3 -Chloro-phenyl)-2-hydroxy-ethylamino]..propyl}.

benzo[l,3]dioxole-2,2-dicarboxylic acid bis-(2-ethoxy-ethyl) ester hydrochloride salt The title compound was prepared from 5-f 2 2 -(3-chloro-phenyl)-2-hydroxyethylam-ino] -propyl)}-benzo[1I,3]dioxole-2,2-dicarboxylic acid and 2-ethoxyethanol according to the procedure of Example 1 as an oily off-white gummy solid; IH NMR WO 97/43273 WO 9743273PCTIUS97/08148 26 (300 MHz, CDCl 3 8 1.10-1.20 (t overlaps with d, J 6.9 Hz, 9H), 1.3 1-1.41 (brm, 2 2.75-2.90 (brm, lH), 3.10-3.30 (brm, 3.50 (brq, J 6.9 Hz, 4H), 3.62- 3.71 (brm, 4H), 4.37-4.47 (brm, 4H), 5.30-5.70 (brm, 2H), 6.70-6.90 (brm, 4H), 7.19-7.50 (brm, 3H), 8.50-8.85 (brs, 1H), 9.90-10.30 (brs, 1H); MS (ES) m/z (relative intensity): 566 (M+-HC1, EXAMPLE 6 and EXAMPLE 7 5-{2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]..propyllbenzo[1,3]dioxole-2,2-dicarboxylic acid bis-(2-tert-butoxy-ethyl) ester and 2 -12-(3-Chloro-phenyl)-2-hydroxy-ethylaminol-propyl}.

benzo[1,3]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-dicarboxylic acid (1.0 g, 2.37 mmol), and 2-t-butoxy- 1-ethanol (10 mL) was added p-toluenesulfonic acid (451 mg, 2.37 mmol). The mixture became homogeneous and was stirred at 23 0 C. After 12 h, an additional portion of p-toluenesulfonic acid (351 mg, 1.84 mmol) was added. After a total of h, the solution was concentrated, and chromatographed on silica gel, eluting with CHC13/MeOH then 40/1, 20/1 and 10/1) to give 100 mg (7 of chloro-phenyl)-2-hydroxy-ethylamino]-propyl)I-benzo[ 1,3]dioxole-2,2-dicarboxylic acid bis-(2-tert-butoxy-ethyl) ester (Rf'=0.25 (10/1 CHCl3IMeOH)) 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 CHCl 3 /MeOH)) as an off-white solid.

{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, CDCI 3 8 1.15 3H), 1.68 18 1.85-2.40 (brn, 2H), 2.50-2.75 (in, 2H), 2.8 1-2.96 (mn, 1H), 3,41-3.51 (mn, 4H), 3.56-3.64 (in, 2H), 3.65-3.76 (mn, 4H), 4.30-4.41 (in, 2H), 6.61-6.87 (in, 4H), 7.15-7.33 (mn, 2H), 7.44 1H); MS (ES) ml z (relative intensity): 622 90), 522 (M+-t-BuOCH 2

CH

3 60), 352 266 (100).

WO 97/43273 WO 9743273PCTIUS97/08148- 27 2- (3-chloro-phenyl)-2-hydroxy-ethylamino] -propyl -benzo[ 1 ,3]dioxole- 2,2-dicarboxylic acid (2-tert-butoxy-ethyl) ester; IH NMIR (300 MHz, CDCl 3 8 1.-10 (brm, 12H), 2.25-2.70 (brm, 2H), 3.00-3.30 (brm, 5H), 3.51-3.61 2H), 4.25- 4.47 (mn, 2H), 5.20-5.35 (brm, 114), 6.50-6.70 (brm, 4H), 7.15-7.44 (in, 3H), 8.70- 9.70 (brs, 1H). MIS (ES) m/z (relative intensity): 522 100).

EXAMPLE 8

S-{

2 2 -(3-Chloro-phenyl)-2-hydroxy-ethylamino]..propyl}.

benzolll,3]dioxole-2,2-dicarboxylic acid bis-(2-isobutoxy-ethyl) ester The titde compound was prepared from 5- {2-12-(3-chloro-phenyl)-2-hydroxyethylainino]-propyl }-benzo[ 1,3]dioxole-2,2-dicarboxylic acid and 2-isobutoxyethanol according to the procedure of Example 1 as a colorless oil; IH NMR (300 MHz, CDCl 3 8 0.70-0.95 (mn, 12H), 1. 10-2.0 (coinplexin, I1IH), 3.09-3.29 (in, 4H), 3.51 3.58 (in, 1H), 3.60-3.72 (mn, 4H), 4.3 1-4.48 (in, 2H), 6.70-7.00 (in, 4H), 7.15-7.50 (in, 4H); MS (ES) mlz (relative intensity): 622 (M±-HCl, 100).

EXAMPLE 9 5-{2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}.

benzolll,3]dioxole-2,2-dicarboxylic acid bis-(benzyl) ester hydrochloride salt The title compound was prepared from 5- {2-[2-(3-chloro-phenyl)-2-hydroxyethylainino]-propyl)I-benzo[ 1,3]dioxole-2,2-dicarboxylic acid and benzyl alcohol according to the procedure of Example 1 as a gummy white solid: I HNMR (300 MHz, CDCl 3 8 1.26-1.32 (in, 3H), 2.76 (brt, 1H), 3.01-3.21 (bin, 2H), 3.36-3.49 (bin, 2H), 5.24 4H), 5.41 J=9.5 Hz, 1H), 6.70-6.88 (in, 7.12-7.44 (complex in, 14H), 8.70-8.83 (brs, lH), 9.95-10.10 (brs, IH); MIS (ES) m/z (relative intensity): 602 100).

WO 97/43273 WO 9743273PCT/US97/08148 28 EXAMPLE

S-{

2 2 -(3-Chloro-phenyl)-2-hydroxy-ethylamino].propyl}.

benzotll,3ldioxole-2,2-dicarboxylic acid bis-(cyclohexyl) ester hydrochloride salt The tide compound was prepared from 5-f 2 -1 2 3 -chloro-phenyl)-2-hydroxyethylamino] -propyl -ben zo[ 1 dioxole-2,2-dicarboxylic acid and cyclohexanol.

according to the procedure of Example 1 as a yellow gum: IH NMR (300 MHz, CDC1 3 8 1.10-1.40 (complex m, 7H), 1.45-1.60 (brmn, 4H), 1.63-1.81 (brm, 8H), 1.82-1.95 (brm, 4H), 2.72-2.90 (brm, IH), 3.10-3.30 (brm, 2H), 3.37-3.55 (in, 2H), 4.90-5.03 (mn, 5.37-5.52 (brs, IH), 6.7 1-6.90 (complex m, 4H), 7.20-7.32 (in, 2H), 7.44 1H), 8.55-8.80 (brs, 1H), 9.90-10.20 (brs, 1H); MIS (ES) m/z (relative intensity): 585 HCl), 532 EXAMPLE 11 2 -[2-(3-Chloro-phenyI)-2-hydroxy-ethylamino-propy}..

benzo[1,3]dioxole-2,2-dicarboxylic acid bis-(cyclopentyl) ester The fitle compound was prepared from 5-f 2-[2-(3-chloro-phenyl)-2-hydroxyethylainino] -propyl)}-benzo[1I,3]dioxole-2,2-dicarboxylic acid and cyclopentanol as a yellow gum according to the procedure of Example 1, leaving out the final HCl~gEt 2

O

hydrochloride salt forming step: 1 H NMR (300 MHz, CDCl 3 8 1.07 J=6.2 Hz, 3H), 1.50-2.00 (complex in, 16H), 2.52-2.70 (complex m, 3H), 2.85-2.95 (in, 2 H), 4.55-4.65 (in, 1H), 5.29-5.38 (in, 2H), 6.65-6.72 (in, 1H), 6.76 1H), 6.84 (d, Hz, 1H), 7.18-7.30 (in, 3H), 7.37 IH); MIS (ES) m/z (relative intensity): 558 100), 518 490 EXAMPLE 12

S-{

2 -12-(3-Chloro-phenyl)-2hydroxy-ethylaminol-propyl}.

benzojll,3]dioxole-2,2-dicarboxylic acid dioctyl ester The title compound was prepared from 5-f 2- [2-(3-chloro-phenyl)-2-hydroxyethylamino] -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 final HCl(g)/t2O hydrochloride salt forming step: IH NMR (300 MHz, CDCl 3 8 0.78- 0.90 (in, 6H), 0.95-1.40 (bin, 23H), 1.52-1.87 (mn, 6H), 2.55-2.75 (brs, 1H), 2.89- WO 97/43273 WO 9743273PCTIUS97/08 148 29 3.30 (brm, 4H), 4.12-4.33 (in, 4H), 5.15-5.35 (brs, 1H), 6.60-6.81 (in, 3H), 7.12- 7.45 (in, 4H); MS (El) m/z (relative intensity): 645 504 (100), 348 (100), 319 (100), 180 (100).

EXAMPLE 13 54{2- 2 3 -Chloro-phenyl).2- hydroxy-ethylamino]..propyllbenzo[ 1,3ldioxole-2,2-dicarboxylic acid dipentyl ester The title compound was prepared from 5- 2 -[2-(3-chloro-phenyl)-2-hydroxyethylamino]-propyl)}-benzo[~1 ,3lldioxole-2,2-dicarboxylic acid and 1 -pentanol as a brown gum according to the procedure of Example 1, leaving out the final HC1(gy/Eit2O hydrochloride salt formning step: IH NMR (300 MI-z, CDC 3 8 0.90 J=6.9 Hz, 3H), 1.21-1.41 (bin, IOH), 1.67 J=7.0 Hz, 4H), 1.80-2.10 (brs, 11H), 2.80 (t, Hz, 3.05-3.19 (brm, 2H), 3.45 J=10.4 Hz, 2H1), 4.28 J 6.7 Hz, 4H), 5.46 J=9.6 Hz, 1H), 5.50-5.90 (bins, 1H), 6.7 1-6.90 (mn, 3H), 7.20-7.35 (in, 311), 7.43 IN), 8.76 (brs,. 1H), 1.05 (brs, 1H); MS (ES) m/z (relative intensity): 562 100).

EXAMPLE 14

S-{

2 -[2-(3-Chloro-phenyl)-2-hydroxy-ethylaminoI..propyI}.

benzo[1,3]dioxole-2,2-dicarboxylic acid dihexyl ester The title compound was prepared from 5- 2 -[2-(3-chloro-phenyl)-2-hydroxyethylainino]-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 HCI~gEt 2

O

hydrochloride salt forming step: IH NMR (300 MI-z, CDC 3 8 0.75-0.90 (mn, 6H), 1.00-1.41 (brm, 15H), 1.47-1.85 (in, 6H), 2.60-3.50 (bin, 5H), 4.15-4.30 (in, 4H), 5.18-5.35 (brs, IH), 6.67-6.82 (in, 7.15-7.45 (mn, 4H); MS (ES) m/z (relative intensity): WO 97/43273 WO 9743273PCTIUS97/08148 30 EXAMPLE Carbonic acid 3-chloro-benzyl ester 2-(3-chlorobenzyioxycarbonyloxy)-4-{2-[2-(3-chloro.phenyl).2hydroxy.

ethylamino]-propyl}-phenyl ester The title compound was prepared from 5-{ 2 -12-(3-chloro-phenyl)-2-hydroxyethylami~no]-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 formning step: III NMR (300 MHz, CDCl 3 8 1.28 (d, J=6.3 Hz, 1.80-2.40 (brs, IH), 2.79 J=8.8 Hz, IH), 3.05-3.17 (brm, 2H), 3.37-3.49 (in, 2H), 5.23 4H), 5.43 (in, LH), 6.72-6.88 (in, 3H), 7.10-7.44 (complexin, 12H), 8.76 (brs, 1H), 10.02 (brs, 1H); MS (ES) ml z (relative intensity): 670 100) EXAMPLE 16 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-hydroxyethylainino]-propyl )-benzo[1I,3]dioxole-2,2-dicarboxylic acid and 1 -phenylethanol as a gummy tan solid according to the procedure of Example 1, leaving out the final HC1(g~ft2O hydrochloride salt forming step: IH NMR (300 MHz, CDCl 3 5 0.90- 1.22 (in, 6H), 1.30-1.61 (in, 6H), 2.39-2.70 (brm, IH), 2.83-3.19 (brm, 2H), 3.20- 3.50 (brm, 2H), 5.15-5.35 (brs, I 5.90-6.02 (bin, 1H), 6.45-6.82 (in, 3H), 7.11- 7.40 (in, 8.64 (bins, IH), 9.45 (brs, 1H); MS (ES) m/z (relative intensity): 630 100).

EXAMPLE 17 2 2 -(3-Chloro-phenyl)-2-hydroxy-ethylaminol..propyl}.

benzo[1,3]dioxole-2,2-dicarboxylic acid diheptyl ester The title compound was prepared from 2 2 -(3-chloro-phenyl)-2-hydroxyethyl amino] -propyl ben zo dioxole-2,2-dicarboxylic acid and 1-heptanol as a brown gum according to the procedure of Example 1, leaving out the final HCI~gEt 2

O

hydrochloride salt formning step: IH NMR (300 M~z, CDCL 3 8 0.80-0.92 (in, 6H), WO 97/43273 WO 9743273PCTfUS97/08148 31 1.23-1.40 (brm, 19H), 1.60-1.75 (in, 4H), 2.80 J=8.8 Hz, IR), 3.05-3.30 (bin, 2H), 3.38-3.50 (in, 211), 4.27 J=6.7 Hz, 4H), 5.43 J=8.4 Hz, IR), 6.72-6.90 (in, 4H), 7.20-7.33 (in, 2H), 7.44 IH), 8.70 (brs, 1H), 10.10 (brs, 1H); MS (ES) m/z (relative intensity): 618 100).

EXAMPLE 18 2 -12-(3-Chloro-phenyl)-2-hydroxyethylamino]-propyl}.

benzolll,3]dioxole-2,2-dicarboxylic acid dinonyl ester The title compound was prepared from 5-(2-[2-(3-chloro-phenyl)-2-hydroxyethylamino]-propyl}-benzo[1,3ldioxole-2,2-dicarboxylic acid and 1-nonanol as a brown gum according to the procedure of Example 1, leaving out the final HCIlg/Et 2

O

hydrochloride salt forming step: IH NMR (300 MHz, CDCI 3 8 0.88 J=6.8 Hz, 9H), 1.25-1.40 (mn, 22H), 1.54-1.60 (mn, 2H), 1.63-1.74 (in, 4H), 2.79 (brt, J 8.8 Hz, 1H), 3.08-3.30 (mn, 2H), 3.40-3.55 (in, 2H), 4.28 J=6.8 Hz, 4H), 5.46 (d, J=8.7 Hz, 1H), 6.70-6.90 (in, 3H), 7.15-7.35 (mn, 3H), 7.43 1H), 8.72 (brs, 1H), 9.98 (brs, 1H); MS (ES) m/z (relative intensity): 674 100), 548 (M+-C 9

H

2 0 EXAMPLE 19 5-{2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}.

benzo[1,3]dioxole-2,2-dicarboxylic acid bis-decyl ester The title compound was prepared from 5-f 2-12-(3-chloro-phenyl)-2-hydroxyethylainino] -propyl)I-benzo[ 1,3]dioxole-2,2-dicarboxylic acid and and I -decanol as a brown gum according to the procedure of Example 1, leaving out the final HClIy/Et 2

O

hydrochloride salt form-ing step: IH NMR (300 Mffz, CDCl 3 8 0.88 J=6.8 Hz, 9H), 1.15-1.40 (mn, 24H), 1.52-1.60 (in, 4H), 1.62-1.74 (in, 4H1), 2.80 (brt, J 8.8 Hz, 11H), 3.08-3.28 (in, 2H1), 3.35-3.52 (in, 2H), 4.28 J=6.7 Hz, 4H), 5.45 (d, J=8.8 Hz, 6.70-6.90 (mn, 3H), 7.18-7.35 (mn, 3H), 7.43 IH), 8.71 (brs, 1H), 10.02 (brs, IR); MS (ES) m/z (relative intensity): 702 100).

WO 97/43273 WO 9743273PCT/US97/08 148 32 EXAMPLE 5-{2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylaminoj-propyl}.

benzo[1,3]dioxole-2,2-dicarboxylic acid didodecyl ester The title compound was prepared from 5-(2-[2-(3-chloro-phenyl)-2-hydroxyethylaininoli-propyl )-benzo[ 1,3]dioxole-2,2-dicarboxylic acid and 1 -dodecanol as a brown gum according to the procedure of Example 1, leaving out the final HClI>/Et 2

O

hydrochloride salt forming step: 1 H. NMR (300 MHz, CDCl 3 8 0.88 J=6.8 Hz, 9H), 1.20-1.40 (in, 30H), 1.51-1.60 (mn, 4H), 1.62-1.73 (in, 4H), 2.75-2.85 (in, 1H), 3.05-3.25 (mn, 2H), 3.35-3.52 (mn, 2H), 4.28 J=6.8 Hz, 4H), 5.45 J=8.8 Hz, 1H), 6.60-6.90 (in, 3H), 7.17-7.40 (mn, 3H), 7.43 1H), 8.78 (brs, 1H), 10.05 (brs, 1H); MS (ES) m/z (relative intensity): 594 100).

EXAMPLE 21 S-{2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylaminol-propyl}benzo[1,3]dioxole-2,2-dicarboxylic acid bis-(2-isopropoxy-ethyl) ester The title compound was prepared from 5-12-[2-(3-chloro-phenyl)-2-hydroxyethylamino]-propyl )-benzo[1,3ildioxole-2,2-dicarboxylic acid and 2-isopropoxyethanol as a brown solid according to the procedure of Example 1, leaving out the final HCl(g~ft2O hydrochloride salt forming step: 1 H NMR (300 MHz, CDCl 3 8 1 .11 (d, J=6.1 Hz, 12H), 1.30 J=6.2 Hz, 3H), 2.79 J=8.7 Hz, 1H), 3.06-3.28 (in, 2H), 3.40-3.60 (in, 2H), 3.62-3.70 (comnplexin, 4H), 3.90-4.12 (brm, 2H), 4.35- 4.45 (complexin, 4H), 5.43 J 8.7 Hz, IH), 6.61-6.90 (mn, 3H), 7.11-7.32 (mn, 3H), 7.44 (in, lH), 8.70 (brs, 1H), 9.92 (brs, lH); MS (ES) m/z (relative intensity): 758 30), 546 (100).

EXAMPLE 22 [2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}benzo[1,3]dioxole-2,2-dicarboxylic acid isopropyl ester To a stirred solution of 5-f 2-[2-(3-chloro-phenyl)-2-hydroxy-ethylaminopropyl) -benzo[ 1 ,3]dioxole-2,2-dicarboxylic acid bis-isopropyl ester hydrochloride salt g, 5.53 iniol) and 20 mL of i-PrOH was added was added IN NaOH (11. 1 nL, 11.1 inmol). After stirring at 23 0 C for 3 days, the mixture was concentrated to WO 97/43273 WO 9743273PCTIUS97/08148 33 dryness, dissolved in 1 0 MeOH/CH 2

CI

2 and filtered through a small pad of silica gel. The filtrate was concentrated to a colorless gum, and triturated with Et 2 O to give 1 .0 g (39 of 2 -1 2 -(3-chloro-phenyl)-2-hydroxy-ethylaminol-propyl) benzo[ 1 3]dioxole-2,2-dicarboxylic acid isopropyl ester as a white solid; ~IH NMR (300 MHz, CDCl 3 8 0.93 J=6.1 Hz, 3H), 1.17 J=6.3 Hz, 6H), 2.30-2.53 (in, 2H), 2.67-2.80 (in, 2H), 2.85-3.00 (in, 1H), 4.65-4.75 (brs, IH), 4.91 (hept, J=6.3 Hz, 1H), 6.52-6.80 (complexin, 3H), 7.17-7.45 (complexm, 4H); MS (ES) m/z (relative intensity): 464 100).

EXAMPLE 23

S-{

2 2 3 -Chloro-phenyl)-2-hydroxy-ethylamino]..propyl).

benzo[1,3ldioxole-2,2-dicarboxylic acid ethyl ester The title compound was prepared from 5- (2-[2-(3-chloro-phenyl)-2-hydroxyethylamino] -propyl)}-benzo[1I,3]dioxole-2,2-dicarboxylic acid bis-ethyl ester hydrochloride according to the procedure of Example 22 as a brown solid: IH NMR (300 MHz, CDCI 3 8 1.20 J=6.7 Hz, 3H)l 1.33 J=7.1 Hz, 3H), 2.70 (in, 1H), 2.90-3.22 (in, 4H), 3.23-3.48 (in, IH), 4.34 J=7.1 Hz, 2H), 5.30 (in, 1H), 6.55- 6.90 (mn, 3H), 7.10-7.45 (in, 4H); MIS (ES) m/z (relative intensity): 450 1, EXAMPLE 24 2 2 3 Chloro-p henyl) hyd roxy-ethylaminol propy 11 benzo[1,3ldioxole-2,2-dicarboxylic acid bis-methoxycarbonylmethyl ester Step 1

S-(

2 -{tert-Butoxycarbonyl2(3.chloro.pheny).2hydroxy.ethyl]amino} -propyl)- benzo[ 1,3] dioxole.2,2..dica rboxyl ic acid bis-ethyl ester To a stirred solution of 5-{ 2 2 3 -chloro-phenyl)-2-hydroxy-ethylanino].

propyl)-benzo[1,3]dioxole-2,2-dicarboxylic acid diethyl ester hydrochloride salt g, 9.72 minol), and THF (90 ml-) was added i-Pr 2 NEt (4.23 mL, 3.14 g, 24.3 minol) and (Boc) 2 0 (2.12 g, 9.72 minol). After 6 h, an additional portion of (1300 2 0 (200 mng, 0.92 inmol) is added. After a total of 22 h, the solution was quenched with 10 mrL of sat. aq. NaHCO 3 and extracted with 3 x 100 mL Et 2 O. The combined organics WO 97/43273 WO 9743273PCTIUS97/08148 34 were washed with 1 x 150 mL of brine, dried over MgSO 4 filtered and concentrated to a yellow oil. Flash chromatography on silica gel, eluting with hexanes/EtOAc (2/1) gave 5.07 g (90 of product as a sticky, off-white solid; IH NMR (300 MHz, CDCl 3 8 1.22 J 6.9 Hz, 3H), 1.30-1.47 (in, 15H), 2 4 7-2.54(m, 1H), 2.57- 2.70 (in, 1H), 3.05-3.15 (in, 1H), 3.46-3.68 (mn, lH), 4.08-4.18 (in, 1H), 4.29-4.42 (mn, 4H), 4.75 (brd, J 8.6 Hz, 1H), 5.51 (brs, IH), 6.55-6.88 (complexm, 4H), 7.20-7.44 (in, 3H); MIS (ES) m/z (relative intensity): 578 504 336 298 198 (100), 180 Step 2

S-(

2 -{tert-Butoxycarbonyl.[2.(3chloro-pheny).2hydroxy.ethyl] amino}.propyl)-benzo[1,3ldioxole..2,2-dicarboxylic acid To a stirred solution of (tert-butoxycarbonyl- [2-(3-chloro-phenyl)-2hydroxy-ethyl] -amino)} -propyl)-benzo[ I,3]dioxole-2,2-dicarboxylic acid bis-ethyl ester (4.42 g 7.65 mmol), MeOH (100 mL) and H 2 0 (25 inL) was added 5 N NaGH (7.64 inL, 38.2 minol). After 19 h, the solution was concentrated to an aqueous mixture and acidified to pH I with I N aq. HCl which turns the solution milky-white. Extraction with 3 x 100 mL EtOAc, washing the combined organics with 1 x 200 mL brine, drying over Na 2

SO

4 filtration and concentration gave 3.96 g (99 of product as a white solid; IH NMR (300 MHz, DMSO-d 6 8 1.16 J 6.7 Hz, 3H), 1.31 (s, 9H), 2.55-2.70 (in, lH), 2.80-2.92 (mn, 1H), 3.05-3.23 (in, 2H), 3.71-3.93 (mn, 2H), 4.62-4.87 (in, 2H), 5.30-5.90 (brs, 1H), 6.59-6.99 (complexin, 4H), 7.14-7.47 (complexm, 3H), 8.60-8.80 (brs, 1H); MIS (ES) m/z (relative intensity): 522. (M+ H, Step 3

S-(

2 -{tert-Butoxycarbonyl.[2.(3chloro.phenyl).2hydroxy-ethyl]arnino}- propyl)- benzo[1,3]dioxole2,2 dicarboxyl ic acid bismethoxycarbonyl-methyl ester To a stirred solution of {tert-butoxycarbonyl-[2-(3-chloro-phenyl)-2hydroxy-ethyl] -amino) -propyl)-benzo[ 1 ,3]dioxole- 2,2-dicarboxylic acid (500 ing, 0.96 inmol) and DMF (10 rnL) was added K 2 C0 3 (132 ing, 0.96 inmol) and inethyl-2bronioacetate (0.23 mL, 366 ing, 2.40 niiol). After stirring at 50 TC for 4 h, the WO 97/43273 WO 9743273PCTIUS97/08148 35 reaction mixture was cooled to 23 quenched with 5 mnL sat. aq. NaHCO 3 and extracted with 3 x 30 ml- of EtOAc. The combined organics were washed with 2 x mL brine, dried over MgSO 4 filtered and concentrated to a yellow oil. Flash chromatography on silica gel, eluting with hexane/EtOAc (4/1 to gave 508 mg (79 of product as a colorless oil; IH NMR (300 MHz, CDCl 3 8 1.22 J 6.9 Hz, 3 1.41 (brs, 9H), 2.50-2.60 (brm, 1H), 2.60-2.75 (brm, 1H), 3.06-3.15 (brm, 1H), 3.45-3.60 (brm, 1H), 3.76 3H), 3.77 3H), 4.05-4.20 (brm, 1H), 4.70- 4.79 (brm, 4.79(s, 2H), 4.80(s, 211), 5.42-5.51 (brs, 1H), 6.60-6.91 (complexm, 4H), 7.20-7.43(complexm, 3H); MS (ES) m/z (relative intensity): 666 (100), 610 Step 4 2 -(3-Chloro-phenyl)-2-hydroxy-ethylamino-propyl}..benzo[1,3).

dioxole-2,2-dicarboxylic acid bis-methoxycarbonylmethyl ester To a stirred solution of (tert-butoxycarbonyl- [2-(3-chloro-phenyl)-2hydroxy-ethyl] -amino) -propyl)-benzo[ 1,31 dioxole-2,2-dicarboxylic acid bismethoxycarbonyl-methyl ester (330 mg, 0.50 mmol) and CH 2 Cl 2 (10 mL) was added trifluoroacetic acid (0.08 mL, 113 mg, 0.99 mmol). After stirring at 23 T( 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. NaHCO 3 and extracted with 3 x 30 mnL of EtOAc. The combined organics were washed with I x 50 mL of brine, dried over MgSO 4 filtered and concentrated to a yellow oil. Flash chromatography on silica gel, eluting with CHCI 3 /MeOH (20/1 to 10/1) gave 145 mg (52 of product as a white gum; IH NMR (300 MI-z, CDCI 3 8 1.33 (in, 3H), 1.70-2.40 (brm, 2H), 2.73-2.90 (brt, 1H), 3.04-3.30 (in, 2H), 3.37-3.53 (mn, 2H), 3.75 3H), 3.76 (s, 3H), 4.80 2H), 4.81 5.40 (in, 1H), 6.73-6.93 (complexm, 4H), 7.15- 7.32 (in, 2H0, 7.43 MS (ES) m/z (relative intensity): 566 80), 508

CO

2

CH

3 100), 450 2C0 2

CH

3 +2H, WO 97/43273 WO 9743273PCT/US97/08148 -36- EXAMPLE

S-{

2 -[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino..propyl}..

benzo[1,3ldioxole-2,2-dicarboxylic acid bis-propoxycarbonylmethyl ester Step 1

S-(

2 -{tert-Butoxycarbonyl.[2-(3-chloro-phenyl).2hydroxy..ethyl].

anhino}-propyl)-benzo[1,3]dioxole-2,2-dicarboxylic acid bispropoxycarbonylmethyl ester The title compound was prepared from 5-(2-1 tert-butoxycarbonyl- [2-(3-chlorophenyl)-2-hydroxy-ethyl] -amino Ii -propyl)- benzof 1 ,3]dioxole-2,2-dicarboxylic acid and propyl 2-bromoacetate according to the procedure of Example 24, step 3 as a colorless oil: IH NMR (300 MHz, CDC1 3 8 0.91 J=7.4 Hz, 6H), 1.21 J=6.9 Hz, 3H), 1.40 9H), 1.55-1.72 (in, 4H), 2.47-2.70 (in, 1H), 3.05-3.17 (mn, 1H), 3.46-3.60 (mn, 1H), 4.11 J=6.6 Hz, 4H), 4.70-4.85 (in, 4H), 5.47 1H), 6.60-6.92 (in, 3H), 7.20-7.35 (in, 3H), 7.41 1H); MS (ES) m/z (relative intensity): 722 100).

Step 2 5-{2-12-(3-Clloro-phenyl )-2-hydroxy-ethylarnino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid bis-propoxycarbonylmethyl ester The title compound was prepared from 5-(2-{tert-butoxycarbonyl-[2-(3-chlorophenyl)-2-hydroxy-ethyl]-amino I-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: I H NMR (300 MHz, CDCI 3 8 0.80-0.95 (in, 9H),1.40-1.80 bin, 6H), 2.80-3.74 (brm, 7H), 4.05-4.20 (in, 4H), 4.70-4.85 (in, 2H), 5.10 (brs, 1H), 6.70-6.95 (brm, 3H), 7.15-7.40 (bin, 4H); MS (ES) m/z (relative intensity): 622 100).

WO 97/43273 WO 9743273PCT/US97/08148 37 EXAMPLE 26 5-{2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino].propyl}benzo[1,3]dioxole-2,2-dicarboxylic acid bis-(I-methoxycarbonyl-ethyl) ester Step 1

S-(

2 -{tert-Butoxycarbonyl-[2-(3-chloro-phenyl).2Iiydroxy.ethyl].

amhino)}-propyl)-benzo[ 1,3]ldioxole-2,2-dicarboxylic acid bis-(1.

methoxyca rbonyl-ethyl)ester The title compound was prepared from tert-butoxycarbonyl-[2-(3-chlorophenyl)-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 H NMR (300 MHz, CDCl 3 8 1.22 J=6.9 Hz, 3H), 1.38 9H), 2.50-2.70 (in, 2H), 2.89 3H), 2.96 3H), 3.07-3.15 (in, 1H), 3.45-3.60 (in, 1H), 3.70-3.83 (in, 8H), 4.05-4.18 (in, IH), 4.72-4.80 (in, 1H), 5.22-5.32 (in, 1H), 6.60-6.90 (in, 3H), 7.20-7.32 (mn, 3H), 7.41 IH); MS (ES) m/z (relative intensity): 694 100), 638 20), 594 (M+-Boc, Step 2 5-{2-[2-(3-Chloro-phenyI)-2-hydroxy-ethylaminoI-propyI}.

benzo[I ,3ldioxole-2,2-dicarboxylic acid bis-(1-methoxycarbonyl- Sethyl)ester The title compound was prepared from tert-butoxycarbonyl-[2-(3-chlorophenyl)-2-hydroxy-ethyl] -amino) -propyl)-benzo[ I ,3]dioxole-2,2-dicarboxylic acid bis-methoxycarbonyl-1I-ethyl ester according to the procedure of Example 24, step 4 as a colorless gum: I H NMR (300 MHz, CDC1 3 5 1.28 J=6.7 Hz, 3H), 1.30-2.00 (bin, 2H), 1.55-1.65 (in, 6H), 2.70-2.80 (mn, 1H), 3.05-3.30 (mn, 2H), 3.35-3.69 (in, 2H), 3.68-3.80 (in, 5.10-5.18 (in, 1H), 5.22-5.31 (in, 2H), 6.70-6.95 (in, 3H), 7.15-7.30 (mn, 3H), 7.36 1H); MS (ES) mlz (relative intensity): 594 100).

WO 97/43273 WO 9743273PCTIUS97/08148 38 EXAMPLE 27 2 -(3-Chloro-phenyl)-2-hydroxy-ethylamino]..propyl}.

benzo[l,3]dioxole-2,2-dicarboxylic acid bis-isopropoxycarbonylmethyl ester Step 1

S-(

2 -{tert-Butoxycarbonyl-[2-(3-chloro-phenyl)2.hydroxy.ethyJ..

amino}-propyl)-benzo[1,3]dioxole-2,2-dicarboxylic acid bisisopropoxycarbonyl-niethyl ester The title compound was prepared from 5-( 2 -(tert-butoxycarbonyl-[2-(3-chlorophenyl) -2-hydroxy-ethyl] -amino)} -propyl)-benzo[1I,3]dioxole-2,2-dicarboxylic acid and isopropyl 2-bromoacetate according to the procedure of Example 24, step 3 as a colorless oil: IH NMR (300 MHz, CDCl 3 8 1.15-1.30 (in, 15H), 1.40 2.45- 2.70 (in, 2H), 3.06-3.15 (mn, IH), 3.45-3.60 (in, lH), 4.05-4.18 (mn, 2H), 4.70-4.80 (mn, 4H), 5.06 (sept, J=6.3 Hz, 2H), 5.46 (brs, IR), 6.60-6.90 (in, 3H), 7.20-7.35 (in, 3H), 7.41 MIS (ES) m/z (relative intensity): 722 100).

Step 2 2 2 -(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo II1,3]dioxole-2,2-dicarboxylic acid bis-isopropoxycarbonylmethyl ester The title compound was prepared from tert-butoxycarbonyl-[2-(3-chlorophenyl)-2- hydroxy-ethyl] -amino) -propyl)-benzol 1 ,3]dioxole-2,2-dicarboxylic acid bis-isopropoxycarbonylmethyl ester according to the procedure of Example 24, step 3 as a brown gum: IH NMR (300 MHz, CDCl 3 8 1.17-1.30 (mn, 15H), 2.72-2.82 9m, 1H), 3.10-3.29 (mn, 3H), 3.38-3.50 (mn, 1H), 4.70-4.80 (mn, 4H), 4.95-5.18 (complexin, 3H), 6.72-6.95 (mn, 3H), 7.15-7.30 (mn, 3H), 7.36 1H), 8.73 (brs, 1H), 9.86 (brs, IH); MIS (ES) m/z (relative intensity): 622 100).

WO 97/43273 WO 9743273PCTIUS97/08148 39 EXAMPLE 28 2 3 -Chloro-phenyl)-2-hydroxy.ethylaminol.propyl..

ben zo dioxole-2,2.

dicarboxylic acid bis-ethoxycarbonylmethyl ester Step 1

S-(

2 -{tert-Butoxycarbonyl-[2.(3-chloro.phenyl)..2-hydroxy..ethyl]amino) -propyl). benzo[ l,3]dioxole-2,2.dicarboxylic acid bisethoxycarbonyl methylester The title compound was prepared from 5-(2-1 tert-butoxycarbonyl-[2-(3-chloro.

phenyl)-2-hydroxy-ethyll amino) -propyl )-benzo[ 1 ,3ldioxole-2,2-dicarboxylic acid and ethyl bromoacetate according to the procedure of Example 24, Step 3 as a colorless oil; IH NMR (300 MHz, CDCI 3 8 1.17-1.30 (in, 9H), 1.39 9H), 2.48-2.54 (brm, 1H), 2.55-2.61(brm, lH), 3.07-3.13 (mn, 2H), 3.47-3.55 (brm, 1H), 4.05-4.20 (brm, 1H), 4.21 J =7.0 Hz, 4H), 4.20-4.33 (brm, 1H), 4.78 2H), 4.79 2 H), 5.45-5.50 (bin, 1 6.61-6.85 (mn, 4H), 7.20-7.43 (in, 3H); MIS (ES) m/z (relative intensity): 694 (100), 638 594 Step 2 hloro-phenyl)-2-hyd roxy-ethylamino]-propyl..benzo[1,3] dioxole-2,2-dicarboxylic acid bis-ethoxycarbonylmethyl ester The title compound was prepared from 5-( 2 -{tert-butoxycarbonyl-[2-(3-chlorophenyl)-2-hydroxy-ethyl]-ainino) -propyl)-benzo[ 1 3 ]dioxole-2,2-dicarboxylic acid bis-ethoxycarbonylinethyl ester according to the procedure of Example 24, Step 4 as a white gum; I H NMR (300 MHz, CDCl 3 8 1.15-1.27 (mn, 3H), 1.3 1-1.41 J=6.8 Hz, 6H), 2.53-3.51 (in, 6H), 3.60-3.80 (in, 4H), 4.00-4.10 (brs, 1H), 4.15-4.30 (q, J=6.7 Hz, 4H), 4.70-4.85 (brm, 1H), 6.60-6.95 (in, 3H), 7.10-7.50 (in, 4H); MS (ES) m/z (relative intensity): 594 10), 522 508 436 (100).

WO 97/43273 WO 9743273PCTIUS97/08148 EXAMPLE 29 S-{2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylaxninol-propyl..

benzo[1,3ldioxole-2,2-dicarboxylic acid bis- (1 -ethoxyca rbonylI-ethyl) ester Step 1 S-(2-{tert-Butoxycarbonyl.[2-(3-chloro-phenyl).2hydroxy..ethyl].

amino) -propyl)-benzo[ 1,31]dioxole-2,2-d ica rboxyli c acid bis-(1ethoxycarbonyl -ethyl) ester The title compound was prepared from tert-butoxycarbonyl-[2-(3-chlorophenyl)-2-h ydroxy-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, CDCl 3 8 1.15-1.30 (complex m, 9H), 1.40 (brs, 9H), 1.52-1.69 (in, 6H), 2.47-2.58 (in, 1H), 2.58-2.70 (in, 1H), 3.05-3.16 (mn, 1H), 3.42-3.54 (mn, 1H), 4.05-4.30 (complexin, 4.77 (in, 1H), 5.19-5.30 (in, 2H), 5.49 (brs, 6.57-6.67 (in, IH), 6.71-6.80 (in, 1H), 6.82-6.91 (in, 2H), 7.20- 7.35 (in, 2H), 7.41 (brs, 1H); MS (ES) m/z (relative intensity): 722 100).

Step 2 5-{2-12-(3-Chloro-phenyl)-2-hydroxy-ethylarnino].propyl}.

benzoI[l,3]dioxole-2,2-dicarboxylic acid bi s- (I-eth oxyca rbon yl -ethyl) ester The title compound was prepared from {tert-butoxycarbonyl-[2-(3-chlorophenyl)-2-hydroxy-ethyl]-amino -propyl)-benzol 1,3] dioxole-2,2-dicarboxylic acid bis-ethoxycarbonyl- 1 -ethyl ester according to the procedure of Example 24, Step 4 as a colorless oil; IH NMR (300 MHz, CDCI 3 8 very complex due to 4 diastereoiners present; MS (ES) m/z (relative intensity): 622 40), 522 (M+-CH 3

CHCO

2 Et, 100).

WO 97/43273 WO 9743273PCT/US97/08148 41 EXAMPLE 2 3 -Chloro-phernyI)-2-hydroxy-ethylamino]..propyI}.

benzo[1,3]dioxole-2,2-dicarboxylic acid bis-trimethylsilanylmethyl ester Acetyl chloride (0.59 g, 7.5 mmol) was added to trimethylsilylmethanol (4.03 g, 37.5 mmrol) with stirring at room temperature. After 0.5 h, 5-{2-[2-(3-chlorophenyl)-2-hydroxy-ethylamino] -propyl )-benzo[ 1, 3 ldioxole-2,2-dicarboxylic acid (1.05 g, 2.5 mmol) was added in portions. The resulting solution was stirred 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/1 :1 until no more trimethylsilylmethanol 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; I H NMR (CDC1 3 8 0.06 18 1. 33 J 6.5 Hz, 3 2.80 (mn, I 3.15 (mn, I 3.20 (in, 1 3.48 (in, 2 4.014 (s, 2 4.015 2 5.45 (bd, J 9.7 Hz, 1 5.60 (bs, 1 6.80 (in, 3 7.25 (in, 2 7.45 I 8.70 (bs, 1 10.10 (bs, 1 IR (KBr): 1763 cm-1 MS (ES) in/z 594 25 23' 1.0, CHC1 3 Anal. Calcd. for C28H40C1NO 7 Si 2 .HCl: 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.

EXAMPLE 31 2 2 3 -Chloro-phenyl).2-hydroxy..ethylaminol.propyl}.

benzo[1,3ldioxole-2,2-dicarboxylic acid bis-(2-trimethylsilanyl-ethyl) ester The title compound was prepared from 2 2 3 -chloro-phenyl)-2-hydroxyethylamino] propyl -ben zo[ I ,3]dioxole-2,2-dicarboxylic acid and 2triinethylsilylethanol according to the procedure of Example 30 as a white foam (HCl salt); IH NMIR (CDCI 3 850.03 18 1.06 J 8.6 Hz, 4 1.33 (bs, 3 H), 1.90 (bs, lH), 2.80 (bs, 1H), 3.18 (bs, 2H), 3.48 (bs, 2 4.37 J 8.6 Hz, 4 5.45 (bs, I 6.80 (mn, 3 7.26 (in, 2 7.43 1 8.70 (bs, 1 H), 10.10 (bs, I IR (KBr): 1763 cnv t MS (ES) in/z 622 [a]25 _23' (c, WO 97/43273 WO 9743273PCTIUS97/08148 42

CHCI

3 Anal. Calcd. for C 30

H

4 4 C1NO 7 Si 2 .HCI: 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.

EXAMPLE 32

S-{

2 2 -(3-Chloro-phenyl).2-bydroxy-ethylamino]..propyl)benzo[1,3]dioxole-2,2.dicarboxylic acid bis-(3-trimethylsilanyl-propyl) ester The title compound was prepared from 5- 2 -(3-chloro-phenyl)-2-hydroxyethylami no] -propyl -ben zo[ 1 dioxole- 2,2-dicarboxylic acid and 3trimethylsilyipropanol according to the procedure of Example 30 as a white foam (HCl salt); IH NMR (CDCI 3 8 0.01 18 0.46 (in, 4 1.33 J =6.3 Hz, 3 H), 1.70 (mn, 4 2.80 (mn, IH), 3.18 (in, 2H), 3.46(mn 2 4.24(t, J 7.0 Hz, 4 H), 5.47 (bd, J =9.7 Hz, I 5.70 (bs, I 6.80 (in, 3 7.25 (mn, 2 7.43 1 8.70 (bs, 1 10.10 (bs, I JR (KBr): 1765 cm- 1 MS (ES) n/z 650 (MHI); [cxi 25-22' 1.0, CHCI 3 Anal. Calcd. for C 32

H

48 C1NO 7 Si 2 .HCl: C, 55.96; H, 7.04; N, 2.04 Cl, 10.32; Si, 8.18. Found: C, 55.82; H, 7.21; N, 1.87; Cl, 10.22; Si, 7.76.

EXAMPLE 33 5-{2-[2-(3-Chloro-phenyI)-2-hydroxy-ethylaminoI-propyI}.

benzo[1,3]dioxole-2,2-dicarboxylic acid bis-(3,3-dimethyl-butyl) ester The title compound was prepared from 5- [2-(3-chloro-phenyl)-2-hydroxyethylainino] -propyl )-benzo[1I,3]dioxole-2,2-dicarboxylic acid and 3 ,3-dimethylbutanol according to the procedure of Example 30 as a white foam (HCl salt); IH NMR (CDCl 3 8 0.90 18 1.33 (bs, 3 1.62 J 7.4 Hz, 4 2.80 (bs, 1H), 3.18 (bs, 2H), 3.48 (bs, 2 4.35 J 7.4 Hz, 4 5.45 (bs, 1 6.80 (in, 3 7.26 (in, 2 7.43 1 8.70 (bs, 1 10.10 (bs, 1 IR (KBr): 1765 c-1 n/z 90 _4 c .,CC3.Aa.Cld o m 1 CI m/ 50 (I- 4 );rQD-2(c10,C l).Aa.acdfo C32H4 4 C1N0 7 -HCl: 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.

WO 97/43273 WO 9743273PCT/JS97/08148 43 EXAMPLE 34

S-{

2 2 -(3-Chloro-phenyl)-2-hydroxy-ethylamino]..propyl}.

benzo[1,3ldioxole.2,2-dicarboxylic acid bis-cyclohexylmethyl ester The fide compound was prepared from 5-{ 2 2 -(3-chloro-phenyl)-2-hydroxyethylamino] -propyl )-benzo[ 1,3]dioxole-2,2-dicarboxylic acid and cyclohexylmethanol according to the procedure of Example 30 as a white foam (HCI salt); III NMR (CDCl 3 8 0.80-1.80 (in, 22 1.33 (bs, 3 2.80 (mn, 111), 3.18 (mn, 2H1), 3.48 (mn, 2 4. 10 (mn, 4 5.50 (bs, 1 6.80 (in, 3 7.25 (in, 2 7.43 1 H), 8.70 (bs, 1 10.10 (bs, 1 IR (KBr): 1765 cm- 1 MS (CI) m/z 614 (MHW); [a]r 2522' 1.0, CHC1 3 Anal. Calcd. for C 34

H-

44 C1N0 7 *HCl: 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.

EXAMPLE 5-{ 2 2 -(3-Chloro-plienyl)-2-hydroxy-ethylamino.propyl}.

benzo[1,3]dioxole-2,2..dicarboxylic acid bis- (4-methyl -pen tyl) ester The tide compound was prepared from 2 -[2-(3-chloro-phenyl)-2-hydroxyethylamino] -propy 1) -ben zo 1 ,3]dioxole- 2,2-dicarboxylic acid and 4-methylpentanol according to the procedure of Example 30 as a colorless gum (HCl salt); IH NMR (CDC1 3 8 0.87 J 6.5 Hz, 12 1.33 (bs, 3 1.10-2.0 (mn, 10 2.80 (bs, 1H), 3.18 (bs, 2H), 3.48 (bs, 2 4.28(m, 4 5.60 (bs, 2 6.80 (in, 3 H), 7.25 (in, 2 7.43 1 8.70 (bs, 1 10.10 (bs, 1 IR (KBr): 1765 cm- 1 MS (CI) rr/z 590 [a]I 25 24' 1.0, CHCl 3 Anal. Calcd. for C32H44C1NO 7 .HCl: 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.

EXAMPLE 36 (3-Chloro-phenyl)-2-hydroxy-ethylamino]..propyl}.

benzo[1,3]dioxole-2,2-dicarboxylic acid bis-(2-cyclohexyl-ethyl ester The tide compound was prepared from 5- 2 2 -(3-chloro-phenyl)-2-hydroxyethylamino] -propyl benzo[ 1,3]dioxole-2,2-dicarboxylic acid and 2 -cyclohexylethanol according to the procedure of Example 30 as an off-white foam (HCl salt); III NMR WO 97/43273 WO 9743273PCTIUS97/08148 44 (CDCl 3 8 0.80-1.80 (in, 26 1.32 J 6.3 Hz, 3 2.80 (in, 1H), 3.18 (in, 2H), 3.48 (mn, 2 4.32 J 6.9 Hz, 4 5.45 (bd, J 9.7 Hz, 1 6.80 (mn, 3 7.25 (in, 2 7.45 1 8.70 (bs, 1 10.0 (bs, 1 JR (KBr): 1765 cm- 1 MIS (CI) m/z 642 5 _24' 1.0, CHCI 3 Anal. Caled. for C3"H8C1N0 7 *HCl: 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.

EXAMPLE 37 S-{2-[2-(3-Chloro-phenyl)-2-hyd roxy-ethylamino].propyl}.

benzo[1,3ldioxole-2,2-dicarboxylic acid bis-(3-cyclopentyl-propyl) ester The tide compound was prepared from 5-12- 2 3 -chloro-phenyl)-2-hydroxyethylainino]-propyl )-benzo[1 ,3]dioxole-2,2-dicarboxylic acid and 3cyclopentylpropanol according to the procedure of Example 30 as a colorless gumi (HCI salt); IH NMR (CDCI 3 8 0.80-1.80 (in, 26 1.33 J 6.3 Hz, 3 2.80 (mn, 11H), 3.18 (in, 2H), 3.48 (in, 2 4.28 J 6.8 Hz, 4 5.45 (bd, J 9.7 Hz, 1 6.80 (mn, 3 7.25 (in, 2 7.45 1 8.70 (bs, 1 10.10 (bs, 1 JR (KBr): 1765 cm- 1 MS (CI) in/z 642 2 5 _21' 1.0, CHCl 3 Anal. Calcd. for C36H4 8

CINO

7 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.

EXAMPLE 38 2 3 -Chloro-phenyI)-2-hydroxy-ethylaminoI..propyI}.

benzolll,3ldioxole-2,2-dicarboxylic acid bis-cyclopropylniethyl ester The tide compound was prepared from 5-( 2 -1 2 -(3-chloro-phenyl)-2-hydroxy.

ethylainino] -propyl )-benzo[ 1,3] dioxole-2,2-dicarboxylic acid and cyclopropylinethanol according to the procedure of Example 30 as a white solid (HCl salt); IH NMR (CDC1 3 8 0.33 (mn, 4 0.61 (mn, 4 1.21, (in, 2 1.32 (bs, 3 2.80 (mn, 11H), 3.19 (mn, 2H), 3.48 (mn, 2 4.15 J 7.3 Hz, 4 5.50 (bd, 1 5.70 (bs, 1 6.80 (in, 3 7.25 (mn, 2 7.45 1 8.70 (bs, 1 10.10 (bs, 1 IR (KBr): 1757, 1778 cnv 1 MS (ES) nVz 530 25 260 WO 97/43273 WO 9743273PCTIUS97/08 148 45 CHC1 3 Anal. Calcd. for C 2 8 H1 3 2 C1N0 7 *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.

EXAMPLE 39

S-{

2 2 3 -Chloro-phenyl)-2-hydroxy-ethylamino]..propyl}.

benzo[1,3]dioxole.2,2-dicarboxylic acid bis-(1-methylcyclopropylmethyl) ester The title compound was prepared from 5- 2 2 -(3-chloro-phenyl)-2-hydroxyethylami no] -propyl) -ben zo 1,3]Jdioxole- 2,2-dicarboxylic acid and 1methylcyclopropyl-methanol according to the procedure of Example 30 as a white solid (HCl salt); 1 H NMR (CDCI 3 8 0.39 (in, 4 0.52 (in, 4 1.10, 6 1.32 (d, J 6.5 Hz, 3 2.80 (mn, I 3.19 (in, 2H), 3.48 (in, 2 4. 10 4 5.50 (bd, 1 5.70 (bs, 1 6.80 (in, 3 7.25 (in, 2 7.45 1 8.70 (bs, 1 10.10 (bs, 1 IR (KBr): 1763 cm- 1 MIS (ES) m/z 558 [cx]2 _250 1.0, CHCl 3 Anal. Calcd. for C3 0

H

3 6 C1N0 7 -HCl: 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.

EXAMPLE

S-{

2 -[2-(3-Chloro-phenyl)-2-hydroxy-ethylaminol-propyl}.

benzo[1,3]dioxole-2,2-dicarboxylic acid bis-cyclobutylmethyl ester The title compound was prepared from 5- 2 -(3-chloro-phenyl)-2-hydroxyethylami~no]-propyl )-benzo[ 1,3]dioxole-2,2-dicarboxylic acid and cyclobutylinethanol according to the procedure of Example 30 as an off-white solid (HCl salt); IH NMR (CDCl 3 8 1.32 J 6.5 Hz, 3 1.85 (in, 8 2.05 (in, 4 2.69 (in, 2 H), 2.80 (in, 1H), 3.19 (in, 2H), 3.48 (in, 2 4.10 4 5.50 (bd, 1 5.70 (bs, 1 6.80 (mn, 3 7.25 (mn, 2 7.45 1 8.70 (bs, I 10.10 (bs, 1 H); JR (KBr): 1759, 1779 cin 1 MS (ES) n/z 558 [a]25 _27' CHCl 3 Anal. Calcd. for C30H- 3 6 ClN0 7 .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.

WO 97/43273 WO 9743273PCTIUS97/08148 46 EXAMPLE 41 5-{2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylaminol-propyl}.

benzo[1,3]dioxole-2,2-dicarboxylic acid bis-(2-cyclopentyl-ethyl) ester The tide compound was prepared from 5- (2-[2-(3-chloro-phenyl)-2-hydroxyethylamino]-propyl )-benzo[ 1,3]dioxole-2,2-dicarboxylic acid and 2-cyclopentylethanol according to the procedure of Example 30 as an amber gum (HCl salt); 1 H NMR

(CDCI

3 8 1.32 J 6.3 Hz, 3 1.60 (in, 20 2.80 (in, 1H), 2.90 (in, 2 H), 3.15 (mn, 1H1), 3.20 (in, 3.48 (in, 2 4.30 J 6.9 Hz, 4 5.50 (bd, 1 6.80 (in, 3 7.25 (in, 2 7.43 1 8.70 (bs, 1 10.10 (bs, 1 IR (KBr): 1765 cm- 1 MS (CI) m/z 614 [cx 25240 1.0, CHC1 3 Anal.

Calcd. for C34H 44 C1NO 7 .HCI: 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-hydroxyethylaminol-propyll-benzo[1,3]dioxole-2,2-dicarboxylic acid bisacetoxy-alkyl esters Step 1 Preparation of Acyloxyalkyl Iodides These esters were prepared by reacting the appropriate acid chlorides with formaldehyde or acetaldehyde in the presence of a catalytic amount of anhyrous ZnCl2 according to Ulich, L. H. and Adams, R. J. Amer. Chem. Soc. 1921, 43 660- 666.

The resultant acyloxyalkyl chlorides were converted in to the corresponding acyloxyalkyl iodide derivatives by reacting them with Nal in boiling benzene according to Fujimoto, Ishihara, Yanagisawa, Ide, Nakayama, Nakao, H., Sugawara, Iwata, M. J. Antibiotics 1987, 19, 370.

WO 97/43273 PCT/US97/08148 -47- Step 2 2 -[2-(3-Chlorophenyl)-2-hydroxyethylamino]-propyl}benzo[1,3]dioxole-2,2-dicarboxylic acid disilver salt To a stirred solution of 5-{ 2 2 3 -chlorophenyl)-2-hydroxyethylamino]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 mmol) was added dropwise. 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 under vacuum to give a colorless solid; yield 100%; mp 183-185; M+H 422.1.

Step 3 2 2 -(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}benzo[1,3]dioxole-2,2-dicarboxylic acid bis-acetoxyalkyl esters To a stirred suspension of 5-{ 2 2 3 -chlorophenyl)-2-hydroxyethylamino]propyl)-benzo[l,3]dioxole-2,2-dicarboxylic acid disilver salt (2.0 gms, 3 mmol) in anhydrous chloroform the appropriately substituted acyloxyalkyl 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 Na2S203 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. The compounds of Examples 42-58 below were prepared according to this general procedure.

EXAMPLE 42 2 -(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-hydroxyethylamino]propyl}-benzo[l,3]dioxole-2,2-dicarboxylic acid disilver salt (2.0 gms, 3 mmol) in anhydrous chloroform, acetoxymethyl iodide (9 mmol) dissolved in chloroform 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% Na2S203 solution in WO 97/43273 PCT/US97/08148 -48distilled 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 an ivory color solid; mp 132-134; yield 97%; M+H 566.

EXAMPLE 43 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[l,3]dioxole-2,2-dicarboxylic acid disilver salt (2.0 gms, 3 mmol) in anhydrous chloroform, propionyloxymethyl iodide (9 mmol) dissolved in chloroform 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% Na2S203 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.

EXAMPLE 44 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]propyl)-benzo[l,3]dioxole-2,2-dicarboxylic acid disilver salt (2.0 gms, 3 mmol) in anhydrous chloroform butyryloxymethyl iodide (9 mmol) dissolved in chloroform 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% Na2S203 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.

WO 97/43273 WO 9743273PCTIUS97/08148 49 EXAMPLE

S-{

2 -[2-(3-Chloro-phenyl)-2-hydroxyethylaminolpropyl~benzo[1,3] dioxole-2,2-dicarboxylic acid bis-isobutyryloxymethyl ester To a stirred suspension of 2 2 3 -chlorophenyl)-2-hydroxyethylaniino].

propyl)-benzoll,3]dioxole-2,2-dicarboxylic acid disilver salt (2.0 gins, 3 inmol) in anhydrous chloroform isobutyryloxymethyl iodide (9 inmol) dissolved in chloroform inL) 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 chloroformn 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 rnL of hexane was added. The separated solid was filtered and washed with hexane to yield a white solid; mp 114-116 (dec); yield 78%; M+H 622.

EXAMPLE 46

S-{

2 -1 2 3 -Chloro-phenyl)-2-hydroxyethylaminolpropyl) benzo[1,3] dioxole-2,2-dicarboxylic acid bis-heptanoyloxymethyl ester To a stirred suspension of 5-f 2 2 3 -chlorophenyl)-2-hydroxyethylamino..

propyl )-ben zo[ 1,3]dioxole- 2,2-dicarboxylic acid disilver salt (2.0 gins, 3 inol) in anhydrous chloroform heptanoyloxymethyl iodide (9 ininol) dissolved in chloroform 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 rrL 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.

EXAMPLE 47 5-{ 2 2 3 -Chloro-phenyl)-2-hydroxyethylaminolpropyl}benzo[1,3] dioxole-2,2-dicarboxylic acid bis-(4-methyl-pentanoyloxyniethyl) ester To a stirred suspension of 5-f 2-[ 2 3 -chlorophenyl)-2-hydroxyethylarino].

propyl}-benzo[1,3)dioxole.2,2.dicarboxylic acid disilver salt (2.0 gins, 3 mmol) in anhydrous chloroform pentanoyloxymethyl iodide (9 mmol) dissolved in chloroform WO 97/43273 PCT/US97/08148 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% Na2S203 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 105-108 (dec); yield 19%; M+H 679.

EXAMPLE 48 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[l,3]dioxole-2,2-dicarboxylic acid disilver salt (2.0 gms, 3 mmol) in anhydrous chloroform hexanoyloxymethyl 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% Na2S203 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 106-109; yield 20%; M+H 679.

EXAMPLE 49 5-{2-[2-(3-Chloro-phenyl)-2-hydroxyethylamino]propyl}benzo[1,3] dioxole-2,2-dicarboxylic acid bis- (2,2-dimethyl-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 mmol) in anhydrous chloroform 2,2-dimethylpropionyloxymethyl 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% Na2S203 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 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 72 (dec); yield, 48%; M+H 651.

WO 97/43273 PCT/US97/08148 -51 EXAMPLE 2 2 3 -Chloro-phenyl)-2-hydroxyethylamino]propyl}benzo[1,3] dioxole-2,2-dicarboxylic acid bis-cyclohexanecarbonyloxymethyl 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 chloroform cyclohexanecarbonyloxymethyl 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% Na2S203 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 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.

EXAMPLE 51 2 2 -(3-Chloro-phenyl)-2-hydroxyethylamino]propyl}benzo[1,3] dioxole-2,2-dicarboxylic acid bis-(l-propionyloxy-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 mmol) in anhydrous chloroform 1-propionyloxyethyl iodide (9 mmol) dissolved in chloroform 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% Na2S203 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 130-132 (dec); yield, 68%; M+H 622 WO 97/43273 PCT/US97/08148 -52- EXAMPLE 52 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 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 temperature, under dark for 16 h. The reaction mixture was filtered and washed with 5% Na2S203 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 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.

EXAMPLE 53 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 chloroform 3,3-dimethylbutyryloxymethyl 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% Na2S203 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 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+H 678.

WO 97/43273 PCTIUS97/08148 -53- EXAMPLE 54 2 -[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]propyl}benzo[1,3] dioxole-2,2-dicarboxylic acid bis-[l-(3,3-dimethyl-butyryloxy)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 mmol) in anhydrous chloroform 3,3-dimethylbutyryloxyethyl 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% Na2S203 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 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.

EXAMPLE 5-{2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino] propyl}benzo[l,3]dioxole-2,2-dicarboxylic acid bis-(3-cyclopentylpropionyloxymethyl) 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 chloroform 3-cyclopentylpropionyloxy 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% Na2S203 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 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+H 730.

WO 97/43273 PCT/US97/08148 -54- EXAMPLE 56 5-{2-[2-(3-Chloro-phenyl)-2-hydroxyethylamino]propyl}benzo[1,3]dioxole-2,2-dicarboxylic acid bisbenzoyloxymethyl 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 chloroform benzoyloxymethyl iodide (9 mmol) dissolved in chloroform 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% Na2S203 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.

EXAMPLE 57 2 3 -Chloro-phenyl)-2-hydroxyethylamino]propyl}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[l,3]dioxole-2,2-dicarboxylic acid disilver salt (2.0 gms, 3 mmol) in anhydrous chloroform 1-benzoyloxyethyl iodide (9 mmol) dissolved in chloroform 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% Na2S203 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 an ivory solid; mp 82-83 (dec); yield 96%; M+H 718.

WO 97/43273 WO 9743273PCTIUS97/08148 55 EXAMPLE 58

S-{

2 2 3 -Chloro-phenyl)-2-hydroxyethylaminolpropyl}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-hydroxyethylamino].

propyl }-benzo[ 1,3]dioxole-2,2-dicarboxylic acid disilver salt (2.0 gins, 3 mmnol) in anhydrous chloroform 2,2-dimethylbutyryloxymethyl iodide (9 inmol) dissolved in chloroformn (30 nl was added. The reaction mixture was stirred at room temperature, under dark for 16 h. The reaction mixture was filtered and washed with 5% Na2S 203 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 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.

EXAMPLE 59 [(2R)-2-(3-Chloro-phenyl)-2-hyd roxy-ethylamino]-propyl}benzo[1,3]dioxole-2,2-dicarboxylic acid bis-[1- (cyclohexyloxycarbonyloxy)-ethyl] ester Cyclohexyl l-iodoethyl carbonate (5.6 g, 18 8 mmol) in CHC13 (10 mL) was added dropwise into a cold (0 suspension of R)-5-[2-[2-(3-chlorophenyl)-2hydroxyethylamino]propyl]-1I 3-benzodioxole-2,2-dicarboxylic acid disilver salt g, 6.3 mmol) and CHC13 (100 riL). 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 filtr-ate 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): mnp 78-81 0 Q (+)FAB m/e 762 Analysis for: C38H-48C1N0 13: Calcd: C, 59.89; H, 6.35; N, 1.84; Found: C, 60.88; H, 6.53; N, 1.99 WO 97/43273 WO 9743273PCTfUS97/08148 -56- EXAMPLE S-{2-[2-(3-Chloro-phenyl)-2-hydroxy..ethylaminoj.

propyll benzo[1,3]dioxole-2,2-dicarboxylic acid bis-amide A mixture of 5- 3 -chloro-phenyl)-2-hydroxy-ethylaminoy-propyl)Ibenzo[ 1,3]dioxole-2,2-dicarboxylic acid bis-ethyl ester (2.4 g, 5 mmol) and ammonia (excess) was stirred for 48 h. The reaction mixture was concentrated and the residue obtained was extracted with chloroform :methanol 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 98; yield. 1.0 g; 45%; M+H 420.

EXAMPLE 61 2 -[2-(3-Chloro-phenyl).2-hydroxy-etaylamino..propyl}..

benzo[1,3]dioxole-2,2-dicarboxylic acid bis-2-propyl amide A mixture of 5- (3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl I-benzo- [1 ,3]dioxole-2,2-dicarboxylic acid bis-ethyl ester (2.4 g, 5 mmol) and isopropylamnine mL, excess) was refluxed in ethanol for 48 h. The reaction mixture was concentrated and the residue obtained was extracted with chloroform methanol 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 60; yield g; 60%; M+H 504.

EXAMPLE 62 2 -(3-Chloro-phenyl)-2-hydroxy-ethylaminol..propyl}.

benzo[1,3]dioxole-2,2-dicarboxylic acid bis-n-butyl amnide A mixture of 5- 2 2 3 -chloro-phenyl)-2-hydroxy-ethylamino]-propyl)}-benzo- II1,3]dioxole-2,2-dicarboxylic acid bis-ethyl ester (2.4 g, 5 mmol) and n-butylamine ml-, excess) was refluxed in ethanol for 48 h. The reaction mixture was concentrated and the residue obtained was extracted with chloroform methanol 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 WO 97/43273 WO 9743273PCTIUS97/08148 57 eluted with 9:1 chloroform methanol to yield a brown semi solid; yield 1.6 g; 61%; M+H 532.

EXAMPLE 63

S-{

2 -1 2 -(3-Chloro-phenyl)-2-hydroxy-ethylamino..propyl..

benzolil,3]dioxole-2,2.dicarboxylic acid bis-phenylmethyl amide A mixture of 5- 2 2 -(3-chloro-phenyl)-2-hydroxy-ethylaminoj-propyl 1benzo[1,3]dioxole-2,2-dicarboxylic acid bis-ethyl ester (2.4 g, 5 mmol) and benzylamine (10 ml-, excess) was refluxed in ethanol for 48 h. The reaction mixture was concentrated and the residue obtained was extracted with chloroform methanol 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; yield 2.0 g; 67%; M+H- 600.

EXAMPLE 64 [2-(3-Chloro-phenyl).2-hyd roxy-ethylaniino].propyl}benzo[1,3]dioxole-2,2-dicarboxylic acid bis-(2-furanylmethyl) amide A mixture of 5- {24[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 2furanylmethylamine (10 mL, excess) was refluxed in ethanol for 48 h. The reaction mixture was concentrated and the residue obtained was extracted with chloroform: methanol 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 el uted with 9: 1 chloroform methanol to yield a brown solid; mp 50; yield 400 mg; 14%; M+H 58 1.

EXAMPLE [2-(3-Chloro-phenyl)-2-hyd roxy-ethylamino]-propyl}benzo[1,3ldioxole-2,2-dicarboxylic acid bis-(glycine ethyl ester) amide A mixture of glycine ethyl ester.HCl (1 .1I gin, 8 mol) and sodium methoxide (424 mng, 8 inmol) was stirred at room temperature in ethanol for fifteen minutes. At WO 97/43273 WO 9743273PCT/US97/08148 58 the end, 5- 2

-II

2 3 -chloro-phenyl)-2-hydroxy-ethylamino]-propyI 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.

EXAMPLE 66 Ioro-phenyl)-3-oxazolidinyl]-.propyl-benzo[1,3ldioxole.

2,2-dicarboxylic acid 2 2 3 -Chloro-phenyl)-2-hydroxy-ethylamino]-propyl)I-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; 1 H NMR (CDC1 3 5 1.02 J 6.4 Hz, 3 2.50 (in, 1 H), 3.00 (in, 2H), 3.20 (in, 1 3.80 (in, I 4.75 J 4.5 Hz, 1 4.90 J= Hz, 1 5.12 (t J 7.3 Hz, 1 6.70 (in, 1 6.86 (in, 2 7.40 (mn, 2 H), 7.50 1 IR (KBr): 1740 cm- 1 MS (CI) nVz 433 Anal. Calcd. for C2jH2OCINO 7 .HCl: C, 58.14; H, 4.65; N, 3.23; Cl, 8.17. Found: C, 57.08; H, 4.78; N, 3.32; Cl, 7.5 1.

EXAMPLE 67 2

R)-

2 -{tert-Butoxycarbonyl.[(2R)..2.(3-chloro.phenyI)2.hydroxyethylII-ami no}.p ropyI)- benzo[ 1,3]d ioxoe2,2-dicarboxylic acid bisdiethylcarbamoylmethyl ester A mixture of (tert-butoxycarbonyl- 2 R)-2-(3-chloro-phenyl)-2hydroxy-ethyl] -amino) -propyl)-benzo[ 1,3] dioxole-2,2-dicarboxylic acid (0.26 g, minol) and anhydrous potassium carbonate (0.28 g) in an hydrous diinethyl formainide was treated with 2 -bromo-N,N-diethylacetamide (0.39 g, 2 inmol), 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; 1

H

WO 97/43273 WO 9743273PCTIUS97/08148 59 NMR (CDC1 3 8 1.0-1.5 (nm, 24 2.6 (in, 2H), 3.0-3.5 (in, 10H), 4.0 (in, 1 H), 4.7-5.0 (in, 4H), 5.5, 6.0 (in, 1 6.80 (in, 3 7.26 (mn, 2 IR (KBr): 1772, 1668 cm- 1 MS (ES) n/z 748 EXAMPLE 68 2

R)-

2 2 R)-2-(3-Chloro.pheny1)..2-hydroxy.ethylamino..propy}..

benzo[1,3ldioxole-2,2-dicarboxylic acid bis- diet hylca rbamoylmethyl ester A solution of {tert-butoxycarbonyl-[ (2R)-2-(3-chloro-phenyl)-2hydroxy-ethyl] -amino) -prop yl) -benzo[ 1, 3] dioxole- 2,2-dicarboxylic acid bis-diethylcarbanioylmethyl ester (0.16 g, 0.2 nmol) in methylene chloride (2 mil) was treated with 0.08 nil of trifluoroacetic acid at room temperature for 18 h. The mixture was then evaporated, and the residue washed with ether to give 0. 12 g of white solid (TFA salt); IH NMR (DMSO-d 6 5 1.0-1.2 (mn, 15 2.6 (in, 2H), 3.0-4.0 (in, Il1H), 5.0 (mn, 4 6.1 (in, 1 6.80 (mn, 3 7.26 (in, 2 8.7 (bs, I H),9.2 (bs, 1 IR (KBr): 1765, 1654 cm- 1 MVS (ES) in/z 648 EXAMPLE 69 5-{ 2 -[2-(3-Chloro-phenyI)-2-hydroxy-ethylanino1..propyI}.

benzo[1,3ldioxole-2,2-dicarboxylic acid cyclopropylmethyl ester The title compound was prepared from 5-f 2 2 -(3-chloro-phenyl)-2-hydroxyethylaininol-propyl )-benzo[1I,3]dioxole-2,2-dicarboxylic acid and cyclopropylinethanol according to the procedure of Example 1 as an off-white solid; IH NMR (DMSO) 8 0.25 0.49 1.01 1.10 (in,1H), 2.49 (in, 1H), 2.85-3.20 (in,4H), 3.94 2H) 4.85 (bt, 1H), 6.58 1H), 6.76 7.35(in,3H), 7.46(s,1H); IR (KBr): 1653 cmin(C=O), 1747 cm- 1 MIS (CI) ni/z 476 Anal. Calcd. for C 24

H

26 C1N0 7 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.

WO 97/43273 WO 9743273PCT/US97/08 148 EXAMPLE 2 -(3-Chloro-phenyl)-2-hydroxy-ethylamino]..propyl}.

benzo[l,3]dioxole-2,2-dicarboxylic acid cyciobutylmethyl ester The title compound was prepared from 5-( 2 -[2-(3-chloro-phenyl)-2-hydroxyethylami no] propyl I -ben zo[ 1 ,3]ldioxole- 2,2-dicarboxylic acid and cyclobutylmethanol according to the procedure of Example 1 as an off-white solid; IH NMR (DMS0) 81.01 1.75(m,4H), 1.92(m,2H), 2.49 (in, IR), 2.65 2.85-3.20 4.09 4.85 (bt, IH), 6.58 1H), 6.76 7.35(m,3H), 7.46(s,IH); JR (KBr): 1652 cm-I(C=O), 1761 cm- 1 MS (CI) n/z 490 Anal. Calcd. for C2 5 H2 8 C1N0 7 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.

EXAMPLE 71

S-{

2 2 -(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl)benzo[1,3]dioxole-2,2-dicarboxylic acid bis 2-(3-Thienyl)ethyl- ester The tidle compound was prepared from 5-f 2-[2-(3-chloro-phenyl)-2-hydroxyethylami no] -propyl -ben zo[ 1 ,3]d ioxole- 2,2-dicarboxylic acid and 2-(3-thienyl)ethanol according to the procedure of Example 1 as yellow crystals (HCl salt); IH NMR (CDCl 3 81.33 3 2.82 (in, IH), 2.95 3.20(m, 2H1), 3.48 (bd, 2 H), 4.45 4 5.50 (bd, 1 5.60(bs,JH), 6.75-7.00(m, 7H), 7.

2 1-7.32(m, 7.45(s,1H), 8.70 (bs, 1 10.10 (bs, 1 IR (KBr): 1765 cm- 1 MS (CI) m/z642(MB); (x]25 _1(,10 H1) nl ac.frC43CSN7HI m/ 62 M1l~; 2oc,10CHI)AnlCac.frCH 3

CSN

7

CL

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.

EXAMPLE 72 [2-(3-Chloro-phenyl)-2-hydroxy-ethylamino].propyl}.

benzo[1 ,3]dioxole-2,2-dicarboxylic acid 2-(3-Thienyl)ethyl ester The title compound was prepared from 5-f 2-[2-(3-chloro-phenyl)-2-hydroxyethylam-i no]- propyl -ben zo[ 1 ,3]d ioxole- 2,2-dicarboxylic acid bis 2-(3-thienyl)ethylester according to the procedure of Example 22 as an off-white solid; III NMR WO 97/43273 WO 9743273PCTIUS97/08148 61 (DMISO) 80.96 2.45 (in, 111), 2.72-3.10 (m,611), 4.25(t,2H), 4.80 (bt, 1H), 5.92 (bs, 111), 6.60(d,1H), 6.79(d,2H), 7.05(d,1H), 7.17(s,11H), 7.30-7.50(5H1); IR (KBr): 1652 cm 1 1751 cm- 1 MS (CI) m/1z 532 Anal. Calcd.

for C26H26C1SN0 7 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.

EXAMPLE 73 2 4-( 3 Chloro-pheny)-2-Ihyd roxy..ethylami no] -propyI}.benzo[I ,3]dioxole-2,2-dicarboxylic acid bis 2-(Chloro)ethyl ester The title compound was prepared from 5- 2 -[2-(3-chloro-phenyl)-2-hydroxyethylamnino] -propyl )-benzo[1I,3]dioxole-2,2-dicarboxylic acid and 2-chloroethanol according to the procedure of Example 1 as yellow crystals (HCI salt); 111 NMR (DMSO) 81.13 3 2.65 (mn, 111), 3 .15-3.52(m, 4H1), 3.85 4 4.60 4 5.55 (bd, I 6.40(bs,IH), 6.86(d,1H), 7.08(m,2H), 7.40-7.58(in,4H), 8.85 (bs, 1 9.40 (bs, 1 IR (KBr): 1770 cm- 1 MS (CI) ni/z 548 -28' 1.0, DMSO). Anal. Calcd. for C24H2 6 C13N0 7 .HCl: C, 49.42; H, 4.67; N, 2.40;Cl, 25.9. Found: C, 49.69; H, 4.38; N, 2.32; Cl, 23.20.

EXAMPLE 74 2

R)-

2 3 -Chloro-phenyl)-2-hydroxy..ethylamino]-propyl}.

benzo[ 1,3]dioxole-2,2-dicarboxylic acid bis-(2-ethylbutyl) ester The title compound was prepared from 5-( 2 -[2-(3-chloro-phenyl)-2-hydroxyethylainino] -propyl ben zo[ 1 ,3]dioxole- 2,2-dicarboxylic acid and 2-ethylbutanol according to the procedure of Example 1 as an off-white gum (HCl salt); 111 NMR (CDCl 3 8 0.80-0.95 12 1.25-1.45 (in, 10 1.50-1.65 (in, 3 2.75-2.85 (in, 111), 3.10-3.40 (in, 1H), 3.47-3.49 (in, 2 4.25 5 5.50 1 6.70- 6.80 (in, I 6.80-6.90 (in, 2 7.20-7.45 (in, 3 7.46 1 8.74 (bs, 1 10.06 (bs, 1 IR (KBr): 2964 cm- 1 1766 cm- 1 MS (ES) n/z 590.4 25 21' 1.0, CHCI 3 Anal. Calcd. for C32H 44 C1N0 7 .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.

WO 97/43273 WO 9743273PCTIUS97/08148 62 EXAMPLE 2

R)-

2 -(3-Chloro-phenyI)-2-hydroxy..ethylamino]..propyI}.

benzo[1,3]dioxole-2,2-dicarboxylic acid bis-(3-methylbutyl)ester The title compound was prepared from 5-( 2 2 -(3-chloro-phenyl)-2-hydroxyethylamino] -propyl )-benzo[ 1,3ldioxole-2,2-dicarboxylic acid and 3-methylbutanol accord-ing to the procedure of Example 1 as an off-white foam (HCl salt); IH NMR

(CDCI

3 8 0.90 12 1.35 2 1.55-1.80 (in, 6H1), 2.70-2.85 (in, 1H), 3.45-3.55 (mn, 3 4.30 4 5.45 (bd, 1 5.65 (bs, 1 6.70-6.80 (in, 1 6.80-6.90 (mn, 3 7.25-7.35 (in, 3H), 7.43 1H1), 8.74 (bs, 1 10.08 (bs, 1 IR (KBr): 3303 cm- 1 1765 cm- 1 MS (ES) m/z 562.4 24' 1.0, CHCI 3 Anal. Calcd. for C30H40ClN0 7 HCl: 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.

EXAMPLE 76 [(2R)-2-(3-Chloro-phenyl)-2-hyd roxy-ethylamino]-propyl}.

benzo[1 ,3ldioxole-2,2-dicarboxylic acid (3-methylbutyl)ester The title compound was prepared from 5- [(2R)-2-(3-chloro-phenyl)-2hydroxy-ethylamino]-propyl)}-benzo[1 ,3ildioxole-2,2-dicarboxylic acid bis-(3-methylbutyl)ester according to the procedure of Example 22 as an off-white solid; IIH NMR (DMSO) 8 0.80-0.85 (mn, 6H), 1.02-1.09 (mn, 3H), 1.45 2H), 1.55-1.70 (in, 1H), 3.01-3.05 (in, 2H), 3.15-3.25 (mn, 1H1), 3.26-3.40 (in, 2H), 4.15 2H), 5.00-5.08 (mn, 1H), 6.45 (bs, 1H), 6.55-6.65 (in, 1H), 6.75-6.90 (in, 2H), 7.45-7.49 (in, 7.51 IIH); JR (Kbr): 3394 cm- 1 1651 cm- 1 MS (ES) n/z 492.0 [a]25 _22' 1.0, CHCl 3 Anal. Calcd. for C25H 3 0ClNO 7 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.

EXAMPLE 77 2

R)-

2 2 R)-2-(3-Chloro.pheny)-2-hydroxy.ethylaniino..propy}..

benzo[1,3]dioxole-2,2-dicarboxylic acid bis-adamantan- I-ylmethyl ester The title compound was prepared from 5-{ 2 2 -(3-chloro-phenyl)-2-hydroxyethylainino]-propyl -benzo[ I ,3]dioxole-2,2-dicarboxylic acid and adamantan- 1- WO 97/43273 WO 9743273PCTIUS97/08148 63 ylmethanol according to the procedure of Example 1 as a white solid (HCl salt); IH NMR (CDC1 3 8 1.25 (in, 2H), 1.35 3 1.51 12 1.55-1.61 (in, 2H), 1.61-1.67 (in, 4 1.67-1.75 (mn, 6 1.97 4 3.20 2H), 3.42-3.49 (in, 2H), 3.88 4H), 4-11-4.16 1H), 5.45 (bd, 1H), 5.65 (bd, 1H), 6.75 (mn, 1I), 6.78-6.89 (in, 7.23-7.30 (mn, 3H), 7.44 1H), 8.74 (bs, IH), 10.115 (bs, 1H); IR (KBr) 3418 cm- 1 1767 cin 1 MS (ES) ni/z 718.4

IU

1

D

1.0, CHCl 3 Anal. Calcd. for C 42

H

52 C1N0 7 C, 68.94; H, 9.22; N, 1.90; Cl, 9.40. Found: C, 67.48; H, 7.49; N, 1.48; Cl, 8. EXAMPLE 78 [(2R)-2-(3-Chloro-phenyl)-2-hyd roxy-ethylamino]-propyl}benzo[1,3ldioxole-2,2-dicarboxylic acid bis-(2,2-dimethyl-propyl) ester The tide compound was prepared from 5-12- [2-(3-chloro-phenyl)-2-hydroxyethylainino]-propyl )-benzo[1I,3]dioxole-2,2-dicarboxylic acid and 2,2dimethyipropanol according to the procedure of Example 1 as an off-white foam (HCl salt); IH NMR (CDCl 3 8 .924 18 1.45 2H), 1.75 2H), 2.80 (mn, 1H), 3.17 (in, 1H), 3.45 (mn, 1H), 3.98 4H), 5.45-5.55 (bd, 1H), 5.63-5.67 (bs, 1 H), 6.75-6.80 (in, 2H), 6.80-6.89 (in, 2H), 7.25-7.35 (in, 3H), 7.440 1H), 8.75 (bs, 1H), 10.10 (bs, 1H); IR (KBr) 3355 cm- 1 1767 cin 1 MS (ES) nvz 562.3 [ctl 25-23' 1.0, CHCI 3 Anal. Calcd. for C 30

H

40 C1NO 7 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.

EXAMPLE 79 [(2R)-2-(3-Chloro-phenyl)-2-hyd roxy-ethylamino]-propyl}.

benzo[1,3ldioxole-2,2-dicarboxylic acid adaiuantan-1-ylniethyl ester The title compound was prepared from 2 R)-2-[(2R)-2-(3-chloro-phenyl)-2hydroxy-ethyl amino] -propyl -benzo[ 1, 3] dioxole-2,2-dicarboxylic acid bis-adarnantan- 1-ylinethyl ester according to the procedure of Example 22 as an off-white solid; IH NMR (DMSO) 8 1.03-1.09 (in, 3H), 1.44 6 1.45-1.64 (mn, 8H), 1.86 4H), 3.02-3.15 (mn, IH), 3.25-3.55 (mn, 2H), 3.70-3.80 (in, 2H), 4.58 2H), 5.06-5.10 (in, 1H), 6.52-6.65 (in, 1H), 6.79-6.88 (in, 2H), 7.32-7.49 (mn, 3H), 7.49 1H); WO 97/43273 WO 9743273PCTIUS97/08148 64 IR (KBr) 3384 cm- 1 1758 cm- 1 1651 cm- 1 MIS (ES) n/z 570.3 (MHW); [cx 25 29' 1.0, CHCI 3 Anal. Calcd. for C3 1

H

36 C1N0 7 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.

EXAMPLE 2 R)-2-(3-Chloro-phenyl)-2.hydroxy-ethylamino..propyl..

benzo[1,3ldioxole-2,2-dicarboxylic acid (2,2-dimethyl-propyl)ester The title compound was prepared from 5- (2R)-2-[(2R)-2-(3-chloro-phenyl)-2hydroxy-eth yl amino] -propyl I -benzo[ 1,3ildioxole-2,2-dicarboxylic acid bis-(2,2dimethyl-propyl) ester according to the procedure of Example 22 as a white solid; IH NMR (DMS0) 8 0.868 9 1.02-1.06 (in, 3H),3.00-3.02 (in, 1H), 3.24-3.30 (mn, 11H), 3.35 5H), 3.80 2H), 4.55 5.03 (mn, 1H), 6.52 (mn, IH), 6.61 (in, 1H), 6.79 (mn, 7.34 (in, 3H), 7.48 IH); IR (KBr) 3398 cm- 1 1748 cm- 1 1654 cm- 1 MS (ES) in/z 492.3 (MI-It); [a 2 930 1. 0, CHC1 3 Anal. Calcd. for C2 5

H

3 OClNO 7 C, 61.04; H, 6.15; N, 2.85; Cl, 7.21.

Found: C, 56.96; H,5.65; N, 2.63; Cl, 7.05.

EXAMPLE 81 2 R)-2-[(2R)-2-(3-Chloro-phenyI)-2-hydroxy-ethylamino]. propyl}benzo[I ,3]dioxole-2,2-dicarboxylic acid (3,3-dimethylbutyl) ester The title compound was prepared from 5- ((2R)-2-[(2R)-2-(3-chloro-phenyl)-2hydroxy-ethylamino] -propyl )-benzo[1I,3]dioxole-2,2-dicarboxylic acid bis-(3-methylbutyl)ester according to the procedure of Example 22 as an off-white solid; IH NMR (DMSO) 8 0.87 9 1.04 (in, 3H1), 1.50 2 3.34 8H), 4.20 2H), 4.95-5.05 (in, 1H), 6.35 (in, 1H), 6.60 (mn, 6.75 (in, 11H), 7.34-7.46 (mn, 3H), 7.48 IH); IR (KBr) 3410 cm- 1 1745 cm- 1 1651 cm- 1

MS

(ES) m/z 506.4 Anal. Calcd. for C 2 6

H

3 2 CIN0 7 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.

WO 97/43273 WO 9743273PCTIUS97/08148 65 EXAMPLE 82 2 R)-2-(3-Chloro-pheny1).2-bydroxy-ethylamino]..propyI}.

benzo[1,3ldioxole-2,2-dicarboxylic aicd bis-(1-methylcyclohexylmethyl) ester.

The title compound was prepared from 5-{ 2 -[2-(3-chloro-phenyl)-2-hydroxyethylamino]-propyl -benzo[ I ,3]dioxole-2,2-dicarboxylic acid and 1 -methylcyclohexylmethanol according to the procedure of Example I as an off-white solid; I'H NMR (DM SO-d 6 ,400MHz) 860. 84 6H, CH 3

CH

3 1.09 J 6.4 Hz, 3H, CH 3 1.1 1.4 (in, 20H, cyclohexyl), 2.6 (in, I H, CH), 3-3.3 (in, 3H, CH, CHA) 3.4 (brs, I1H, CH), 4.04 4H, OCH 2

OCH

2 5.05 (mn, 1H, CH), 6.35 J 4.17 Hz, LH, OH), 6.85 (dd, J 7.9, 1.32 Hz, I1H, Ar-H), 7.07 I1H, Ar-H), 7.09 J 8.35 Hz, Ar-H), 7.38-7.42 (mn, 3H, Ar-H), 7.5 1H, Ar-H), 8.8 (brs, 1H, NH), 9.4 (brs, IH, NH); IR (KBr, cin' 3400 2900 1760 MS mWe 641 Analysis for: C 36

H

48 C1NO 7 xHCI: Calc'd: C, 63.71; H, 7.28; N, 2.06; Found: C, 63.72; H, 7.03; N, 1.91.

EXAMPLE 83 1(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino..propyl)benzo[1,3ldioxole-2,2-dicarboxylic aicd bis-(2-cyclohexyl-2-methylpropyl) ester.

The title compound was prepared from 5- (2-[2-(3-chloro-phenyl)-2-hydroxyethylainino] -propyl)I-benzo[ 1,3]dioxole-2,2-dicarboxylic acid and 2-cyclohexyl-2inethylpropanol according to the procedure of Example 1 as an off-white solid; 'H NMR (DMSO-d 6 ,400MHz) (5 1.1 6H, CM 3 Cl- 3 1.45 6H, CH 3

CM

3 6H, CM 3

CH

3 2.6 (in, IM, CH), 3-3.3 (in, 3M, CM, CHA) 3.4 (brs, IIH, CH), 4.04 4H, OCH 2

OCH

2 5.05 (in, IH, CH), 6.35 J 4.17 Hz, 1H, OH), 6.85 (dd, J 7.9, 1.32 Hz, IH, Ar-H), 7.07 (mn, 2H, Ar-H), 7.38-7.42 (mn, 3H, Ar-H), -7.5 1H, Ar-H), 8.8 (brs, IM, NH), 9.4 (brs, IH, NlI); IR (KBr, cm'1) 3400 2900 1760 MS Wle 698 Analysis for: C 4 oH 56 ClNO 7 xHCl: Calc'd: C, 65.38; H, 7.82; N, 1.91; Found: C, 65.32; H, 7.96; N, 1.94.

WO 97/43273 WO 9743273PCTIUS97/08148 66 EXAMPLE 84 2 R)-2-[(2R)-2-(3-Chloro-pheny)-2-liydroxy-ethylamino..propy}..

benzo[1,3]dioxole.2,2-dicarboxylic aicd bis-(2-methyl-2-nitro-propyl) ester.

The title compound was prepared from 5-{ 2 2 -(3-chloro-phenyl)-2-hydroxyethylamino] -propyl)}-benzo[ 1,3]dioxole-2,2-dicarboxylic acid and 2-methyl-2nitropropanol according to the procedure of Example 1 as an off-white solid; 'H NMR (DMSO-d, 6 ,400)MHz) &60.78 12H, 4 x Cl- 3 0.8-1.0 (in, 4H, CM 2 1- 1.2 (mn, 1H, cyclohexyl, CH 3 1.5-1.65 (mn, 10 H, cyclohexyl), 2.6 (in, I H, CH), 3-3.3 (in, 3H, CR, CM 2 3.4 (brs, IM, CH), 4.04 4H, OCR 2

OCH

2 5.05 (mn, 1H, CH), 6.35 J 4.17 Hz, 1H, OH), 6.83 (dd, J 7.9, 1.32 Hz, IIH, Ar-H), 7.06 (s 1H, Ar-H), 7.09 J 8.35 Hz), 7.38-7.42 (in, 3M, Ar-H), 7.5 1H, Ar-H), 8.8 (brs, 1H, NH), 9.4 (brs, 1H, NH); IR (KBr, cm'1) 3400 2900 1760 (CO); Analysis for: C 28

H

34 C1N 3

O

11 xMCI: Calc'd: C, 50.92; H, 5.34; N, 6.36; Found: C, 50.72; H, 5.42; N, 5.96.

EXAMPLE 2

R)-

2 -(3-Chloro-phenyl)-2-hydroxy.ethylamino..propyl}.

benzolll,3]dioxole-2,2-dica rboxylic aicd bis-(2,2,4-trimethyl-pentyl) ester.

The tide compound was prepared from 5-( 2 2 -(3-chloro-phenyl)-2-hydroxyethylamnino] -propyl -ben zo 1 ,3]d ioxole-2,2-dicarboxylic acid and 2,2,4trimethylpentanol according to the procedure of Example 1 as an off-white solid; H NMR (DMSO-d 6 ,400M~z) 8 0.65-0.9 (in, 24H, 8 x CM 3 1.09 J 6.4 Hz, 3H,

CM

3 1.4 (in, 4H, CM 2

CM

2 2.62 (in, III, CM), 3-3.3 (in, 3M, CM, CH 2 3.4 (brs, IM, CH), 4.04 4H, 0CM 2 0CM 2 5.05 (mn, IM, CM), 6.34 J 3.95 Hz, IM, OH), 6.85 (dd, J 7.9, 1.32 Hz, IM, Ar-H), 7.07 (in, 2H, Ar-H), 7.38-7.42 (in, 3M, Ar-H), 7.5 IM, Ar-H), 8.7 (brs, IM, NH), 9.1 (brs, IM, NH); JR (KBr, cm- I) 3300 2900 (NH)l, 1760 MIS mle 646 Analysis for:

C

36

H

52

CINO

7 xHCl: Calc'd: C, 63.33; H, 7.83; N, 2.05; Found: C, 62.96; H, 7.71; N, 2.44.

WO 97/43273 CUS7014 PCTIUS97/08148 67 EXAMPLE 86 2 -[(2R)-2-(3-Chloro-phenyl)-2-hydroxy..ethylamino]..propyl)benzolll,3ldioxole-2,2-dicarboxylic aicd bis-(2,2-dimethyl-pentyl) ester.

The title compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxyethylaininol-propyl )-benzo[ 1,3ldioxole-2,2-dicarboxylic acid and 2,2dimethylpentanol according to the procedure of Example 1 as an off-white solid; 1H NMR (DMSO-d 6 ,400MHz) 830.8 (in, 18H, 6 x CH 3 1.1-1.2 (in, 1 1H, CH 2

CH

3 2.6 (mn, 1H, CH), 3-3.3 (in, 3H, CH, CHA) 3.4 (brs, IR, CH), 4.0 4H, OCH 2

OCH

2 5.09 (mn, I H, CH), 6.36 J 4.17 Hz, 1iH, OH), 6.86 (dd, J 7.9, 1.32 Hz, 1H, Ar-H), 7.07 (s 1H, Ar-H), 7.09 J 8.35 Hz, Ar-H), 7.35-7.42 (in, 3H, Ar-H), 7.48 1H, Ar-H), 8.84 (brs, IH, NH), 9.48 (brs, IH, NH); IR (KBr, cm'1) 3300 2900 1760 MS ml e 617 Analysis for:

C

34

H

48 ClNO 7 xHCl: Calc'd: C, 62.38; H, 7.55; N, 2.14; Found: C, 62.47; H, 7.51; N, 2.3 1.

EXAMPLE 87 [(2R)-2-(3-Chloro-phenyl)-2-hyd roxy-ethyiaminol-propyl}benzolil,3ldioxole-2,2-dicarboxylic aicd bis- (tetra hyd ro-fu ran-3ylmethyl) ester.

The title compound was prepared from 5- (2-j12-(3-chloro-phenyl)-2-hydroxyethylainfino] -propyl )-benzo[ 1,3ildioxole-2,2-dicarboxylic acid and tetrahydrofuran-3ylinethanol according to the procedure of Example 1 as an off-white solid; 'H NMR (DMSO-d 6 ,400MHz) 8 1.03 J 6.37 Hz, 3H, CH 3 1.5 (mn, 2H, CHA) 1.9 (in, 2H, CHA) 2.6 (in, 3H, CR), 3-3.3 (in, 3H, CH, CHA) 3.4 (brs, 1H, CH), 3.6-3.7 (mn, 611, CR 2 4.1-4.15 (mn, 6H, CR 2 5.09 (in, I H, CR), 6.36 (brs, IH, OH), 6.86 (mn, 1H, Ar-H), 7.07 (mn, 2H, Ar-H), 7.38-7.42 (in, 3H, Ar-H), 7.47 1H, Ar-H), 8.84 (brs, 2H, NH, NH); IR (KBr, cm'1) 3300 2900 1760 MS Wle 590 Analysis for: C 3 0H 36 ClNO~xHCI: Calc'd: C, 57.51; H, 5.95; N, 2.24; Found: C, 57.80; H, 6.30; N, 2.21.

WO 97/43273 WO 9743273PCTIUS97/08148 68 EXAMPLE 88 2

R)-

2 3 -Chloro-phenyl)-2hydroxy-ethylamino..propyl.

benzo[1,3]dioxole-2,2-dicarboxylic aicd bis-(3-hydroxy-2,2,4triniethyl-pentyl) ester.

The title compound was prepared from 5- 2 -[2-(3-chloro-phenyl)-2-hydroxyethylamninol-propyl )-benzo[1 ,3]dioxole-2,2-dicarboxylic acid and cyclopropylmethanol according to the procedure of Example 1 as an off-white solid; 'H NMR (DMS0d 6 ,400MHz) 860.7-0.95 (in, 27H, 9 x Cl- 3 1.8 (in, IlH, CH), 2.1 (in, I1H, CH), 2.6 (in, 1H, CH), 3-3.4 (mn, 6H, OH, CH, CHA) 3.6-3.8 (brs, 2H, CH), 4.04 (in, 2H,

OCH

2

OCH

2 4.6 (in, III, CH), 4.85 (mn, 1H, CH), 5.05 (mn, 1H, CH), 6.35 J 3.7 Hz, 1H, OH), 6.85 (dd, J 7.9, 1.32 Hz, 1H, Ar-H), 7.09 (mn, 2H, Ar-H), 7.38- 7.42 (in, 3H, Ar-H), 7.5 IH, Ar-H), 8.78 (brs, lH, NH), 9.2 (brs, 1H, NH); IR (KBr, cin') 3400 2900 1750 MS Wle 678 Analysis for:

C

36 H5 2 ClNOgxHCl: Calc'd: C, 60.50; H, 7.47; N, 1.95; Found: C, 60.30; H, 8.09; N, 1.62.

EXAMPLE 89 2

R)-

2 3 -Chloro-phenyl)-2-hydroxy.ethylaminol..propyl}.

benzo[1,3ldioxole-2,2-dicarboxylic aicd bis-(2,2-dimethyl-3-phenylpropyl) ester.

The title compound was prepared from 5- 2 2 -(3-chloro-phenyl)-2-hydroxyethylaiino] -propy I) -ben zo[ 1 ,3 ]dioxole- 2,2-dicarboxylic acid and 2,2-diinethyl-3phenyipropanol according to the procedure of Example 1 as an off-white solid; IH NMR (DMSO-d 6 ,400M1-z) 8 0.82 12H, 4 x Cl-IO, 1.08 J 6.37 Hz, 3H,

CH

3 2.6 (mn, I H, CH), 3-3.3 (in, 3H, CH, CHA) 3.4 (brs, 1H, CH), 3.96 4H,

OCH

2

OCH

2 5.04 (mn, 1H, CH), 6.35 J 4.17 Hz, 1H, OH), 6.89 (dd, J= 8.13, 1.53 Hz, IH, Ar-H), 7.05 (in, 4H, Ar-H), 7.14 (in, 8H, Ar-H), 7.38-7.42 (in, 3H, Ar-H), 7.5 IH, Ar-H), 8.81 (brs, 1H, NH), 9.38 (brs, 1H, IR (KBr, cin) 3400 2900 1760 MS Wle 714 Analysis for:

C

42

H

48

CINO

7 xHCl: Calc'd: C, 67.19; H, 6.58; N, 1.87; Found: C, 66.69; H, 6.53; N, 1.83.

WO 97/43273 WO 9743273PCTIUS97/08148 69 EXAMPLE 2

R)-

2 2

R)-

2 -(3-Chloro-pheny).2.hydroxy..ethylamino..propy}..

benzo[I ,3ldioxole-2,2-dicarboxylic aicd bis-(tetrahydro-pyran-2.

ylmethyl) ester.

The title compound was prepared from 5-( 2 2 -(3-chloro-phenyl)-2-hydroxyethylamino] -propyl )-benzo[ 1,3]dioxole-2,2-dicarboxylic acid and tetrahydropyran-2ylmethanol according to the procedure of Example 1 as an off-white solid; 'H NMR (DMSO-d 6 ,400MHz) 861. 10 J 6.37 Hz, 3H, CH 3 1.1-1.2 (in, 2H, CR 2 1.3- 1.6 (in, 8H, CR 2 1.7-1.8 (in, 2H, CR2), 2.6 (in, 1H, CH), 3-3.5 (in, 9H, CH, CHA) 3.8 2H, CR), 4.19-4.2 s, 4H, OCH 2

OCR

2 5.04 (in, 1H, CH), 6.35 J 4.17 Hz, IRH, OH), 6.85 J 8.13 Hz, I1H, Ar-H), 7.07 (in, 2H, Ar-H), 7.36-7.42 (mn, 3H, Ar-H), 7.48 IH, Ar-H), 8.76 (brs, 1H, NH), 9.18 (brs, 1H, NH); IR (KBr, cm-1 3400 2900 1760 MS mWe 618 Analysis for: C 32

H

4 0ClNOgxRCI: Calc'd: C, 58.72; H, 6.31; N, 2.14; Found: C, 57.97; H, 6.46; N, 2.08.

EXAMPLE 91 2

R)-

2 -(3-Chloro-phenyl).2-hydroxy.ethylamino..propyl}..

benzo[1 ,3ldioxole-2,2-dicarboxylic aicd bis-(tetrahydro-furan-2ylmethyl) ester.

The title compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxyethyl amino] propyl benzo I ,3ldioxole- 2,2-dicarboxylic acid and tetrahydrofuran-2ylmethanol according to the procedure of Example 1 as an off-white solid; 'H NMR (DMSO-d 6 ,400MHz) 8 1. 1 J 6.37 Hz, 3H, CR 3 .43-1.6 (in, 2H, CH 2 1.65- 1.8 (in, 4H, CR 2 1.98-2.0 (in, 2H, CHA) 2.6 (mn, 1H, CH), 3-3.3 (in, 3H, CH, CHA) 3.4 (brs, IRH, CR), 3.57-3.7 (mn, 4H, CR 2 4.05 (mn, 2H, CR 2 4.2 (in, 2H,

CH

2 4.3 (mn, 2H, CR 2 5.04 (in, I H, CR), 6.34 J 3.95 Hz, I H, OH), 6.84 (dd, J 8.13,1.32 Hz, 1H, Ar-H), 7.07 (in, 2H, Ar-H), 7.36-7.44 (mn, 3H, Ar-H), 7.48 IH, Ar-H), 8.77 (brs, IR, NH), 9.2 (brs, IR, NHi); IR (KBr, cin') 3400 2900 1760 MIS Wle 590 Analysis for: C 3 oR 36 C1NOgxHCI: Calc'd: C, 57.51; H, 5.95; N, 2.24; Found: C, 56.37; H, 5.90; N, 2.20.

WO 97/43273 WO 9743273PCTIUS97/08148 EXAMPLE 92 2

R)-

2 2

R)-

2 -(3-CIIloro-phenyI).2-hydroxy.ethylamino..propyl}.

benzo[1,3]dioxole-2,2-dicarboxylic aicd bis-(5-methyl-II1,3]dioxan-5.

ylmethyl) ester.

The title compound was prepared from 5-( 2 -1i 2 -(3-chloro-phenyl)-2-hydroxyethylamnino] -propyl }-benzo[ 1,3]dioxole-2,2-dicarboxylic acid and 1,3]dioxan- 5-yl methanol according to the procedure of Example 1 as an off-white solid; 1H NMR (DMSO-d 6 ,400MHz) 8 0.7 3H, CH 3 0.74 3H, CHA) 1.1 (d, J 6.59 Hz, 3H, CH 3 2.6 (in, I1H, CH), 3-3.3 (in, 8H, CH, CHA) 3.6-3.7 (in, 4H, CHA) 4.6-4.8 (in, 4H, CHA) 5.04 (in, IRH, CH), 6.34 (brs, IRH, OH), 6.84 (dd, J 8.13, 1.32 Hz, IH, Ar-H), 7.07 (in, 2H, Ar-H), 7.36-7.44 (in, 3H, Ar-H), 7.48 (s, 1H, Ar-H), 8.77 (brs, IR, 9.2 (brs, 1H, IR (KBr, cm'1) 3400 (OH), 2900 1760 MS mWe 650 Analysis for: C 32

H

4 oClNO, 1 xHCl: Calc'd: C, 55.98; H, 6.02; N, 2.04; Found: C, 54.67; H, 6.58; N, 2.05.

EXAMPLE 93 2

R)-

2 -(3-Chloro-phenyl)-2-hydroxy.ethylamino]..propyl}.

benzo[1,3ldioxole-2,2-dicarboxylic aicd bis-(1-niethyl-cyclohex-3enylmethyl) ester.

The title compound was prepared from 5- (2-[2-(3-chloro-phenyl)-2-hydroxyethylamino]-propyl -benzo[ I ,3]dioxole-2,2-dicarboxylic acid and I -inethylcyclohex-3enylmethanol according to the procedure of Example 1 as an off-white solid; 'H NMR (DMSO-d 6 ,400MHz) 860.84 6H, 2 x CHA) 1.09 J 6.4 Hz, 3H, CHA) 1.25- 1.4 (mn, 4H, CR 2 1.6-1.65 (mn, 2H, CH 2 1.8-2.0 (in, 6H, CH 2 2.6 (in, IR, CH), 3-3.3 (in, 3H, CH, CR 2 3.4 (brs, I1H, CH), 4.04 (in, 4H, OCR 2

OCH

2 5.05 (in, 1H, CH), 5.55-5.65 (mn, 4H, CR), 6.35 J 4.17 Hz, IR, OH), 6.85 (dd, J 7.9, 1.32 Hz, III, Ar-H), 7.07 (in, 2H, Ar-H), 7.38-7.42 (in, 3H, Ar-H), 7.5 1H, Ar- 8.8 (brs, IH, NH), 9.4 (brs, 1H, IR (KBr, cm-1) 3400 2900 (NH), 1760 MS nile 638 Analysis for: C 36 H44ClNO 7 xHCI: Calc'd: C, 64.09; H, 6.72; N, 2.08; Found: C, 64.69; H, 7.19; N, 1.67.

WO 97/43273 WO 9743273PCT/US97/08148 -71 EXAMPLE 94 2

R)-

2 -(3-Chloro-phenyl)-2-hydroxy.ethylamino]..propyi}.

benzo[1,3ldioxole-2,2-dicarboxylic aicd bis-(3-hydroxy-2,2-dimethyl.

propyl) ester.

The title compound was prepared from 5-I 2 2 -(3-chloro-phenyl)-2-hydroxyethylamrino]-propyl)I-benzo[ 1,3]dioxole-2,2-dicarboxylic acid 3-hydroxy-2,2-dimethylpropanol according to the procedure of Example 1 as an off-white solid; 'H NMR (DMSO-d 6 ,400MHz) 80.78 12H, 4 x CH 3 1.09 J 6.4 Hz, 3H, CR 3 2.6 (in, IIH, CR), 3-3.3 (in, 7H, CR, CHA) 3.4 (brs, 1H, CH), 4.04 4H, OCR 2 OCHA)4.65 (in, 2H, OH), 5.05 (mn, 11-, CH), 6.34 J 4.17 Hz, IH, OH), 6.85 (dd, J 7.9, 1.53 Hz, IRH, Ar-H), 7.07 (mn, 2H, Ar-H), 7.37-7.42 (in, 3H, Ar-H), 7.48 III, Ar-H), 8.78 (brs, lH, NH), 9.2 (brs, 1H, NH); IR (KBr, cm'1) 3400 2900 1760 MS mWe 594 Analysis for: C 3 "O1-C1NOgxHC1: Calc'd: C, 57.14; H, 6.55; N, 2.22; Found: C, 56.44; 6.62; N, 2.38.

EXAMPLE I(2R)-2-(3-Chloro-phenyI)-2-hydroxy-ethylaminoI-propyI}.

benzo[1,3ldioxole-2,2-dicarboxylic acid (2-ethoxy-ethyl) ester Through a stirred room temperature solution of 8.0 g (0.0 19 mole) 5- 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 TC for 12 h, TLC (9/1 CH 2 ClJ/MeOH) indicated the formation of both 5- chioro-phenyl)- 2-hydroxy-ethylam-ino] -propyl)I-benzo[ 1,3]dioxole-2,2-dicarboxylic acid bis-(2-ethoxy-ethyl) ester (Rf 0.8; 9/1 CH- 2 Cl 2 IMeOH) and 3 -chloro-phenyl)-2-hydroxy-ethylarnino] -propyl) -benzo[l1,3]dioxole-2,2-dicarboxylic acid (2-ethoxy-ethyl) ester (Rf 0.2; 9/1 CH 2 Cl 2 I/veOH). After cooling to room temperature, excess 2-ethoxyethanol was removed via Kugelrohr distillation (0.05 mm, oven temperature =95 'CQ, and the brown residue was chroinatographed on silica gel, eluting with 0 to 10% MeGH in CH 2 C1 2 to give 1.0 g (0.002 mole, a 10% yield) of the title compound as an off-white solid; I'H NMR (300 MHz, DMSO-d 6 8 1.12 (in, J 6.3 Hz, 3H), 2.5 (in, 3H) 3.35 (in, 8H), 5.06 (in, 1H), 6.3 11-, OH) 6.5 (mn, III), 6.6 (in, 111), 6.8 (in, 2H), 7.0 (mn, 7.5 (in, 211), 8.0 (in, 1H, NH), d 9.2 (mn, 1H, COOH); MS (ES) m/z (relative intensity): 494 100).

WO 97/43273 PCTIUS97/08148 72 EXAMPLE 96 2

R)-

2 3 -Chloro-phenyl)-2-hydroxy.ethylamino]..propyl}.

benzo[1,3ldioxole-2,2-dicarboxylic acid bis-[2-(3-bromno-phenyl)ethyllester hydrochloride salt The title compound was prepared as a brown oil from 5-f 2-[2-(3-chlorophenyl)-2-hydroxy-ethylami no] -propyl)}-benzo[ 1,3]dioxole-2,2-dicarboxylic acid and 2-(3-bromophenyl)ethanol according to the procedure of Example 1; 1 H NMR (300 MHz, CDC1 3 8 1.12 (in, J =6.3 Hz, 3H), 2.79 (in, 8H), 3.5 (m 2H), 4.18 I1H, OH), 5.56 (mn, 6.8 (mn, 3H), 7.0 (mn, 4H), 7.33 (in, 4H), 7.5 (in, 4H), 8.5 (in, 1H, MIS (ES) m/z (relative intensity): 788 100).

EXAMPLE 97 2

R)-

2 -[(2R)-2-(3-Chloro-pheny)-2-hydroxy.ethylamino..propy}.

benzo[1,3ldioxole.2,2-dicarboxylic acid b is- (2 -m-tolyl -ethyl) ester hydrochloride salt The title compound was prepared as a brown oil from 5- f2-[2-(3-chlorophenyl)-2-hydroxy-ethyl ami no] -propyl I -ben zo[ I ,3]dioxole-2,2-dicarboxylic acid and 2-(3-inethylphenyl)ethanol according to the procedure of Example 1; yield: 81%; 1H NMR (300 MHz, CDCI 3 8 1.12 (in, J 6.3 Hz, 3H),2.27 6H), 2.79 (in, 7H), 3.19 (in, 1H), 3.48 (in, 2H), 4.29 (in, J 6.6 Hz, 4H), 5.49 (in, 1H,) 6.75 (mn, J 8.1 Hz, 1H), 6.83 (in, 1H), 7.05 (in, 8H), 7.20 (rn, 1H), 7.27 (in, 1H), 7.43 1H), 7.5 (in, 2H); MIS (ES) m/z (relative intensity): 658 100).

WO 97/43273 WO 9743273PCTIUS97/08148 -73- EXAMPLE 98 2

R)-

2 -[(2R)-2-(3-Chloro-phenyl)-2-hydroxy..ethylamino].propy}..

benzolll,3ldioxole-2,2-dicarboxylic acid diallyl ester Step 1 [[2-(3-Chloro- phenyl).2-hydroxy-ethylI-(2,2,2..trichloroethoxyca rbonyl)-amino]-propyl}- benzo[1,3ldioxole-2,2-dicarboxylic acid diethyl ester To a 0 TC solution of 3.0 g (5.83 mmol) (R,R)-5-{2-[2-(3-chloro-phenyl)-2hydroxy-ethylamino]-propyl }-benzo[ 1,3] dioxole-2,2-dicarboxylic acid diethyl ester hydrochloride salt and 60 mL CH 2 Cl 2 was added 2.54 mL (1.88 g, 14.57 mmol) of i- Pr 2 NEt followed by 0.84 mL (1.30 g, 6.12 mmol) of 2,2,2-trichioroethyl chioroformate. After stirring at room temperature for 6 h, the reaction mixture was quenched with 10 m-fL sat. aq. NaHCO 3 and extracted with 3 x 100 mL Et 2 O. The combined organics were washed with I x 100 1N HCI, 1 x 100 mL brine, dried over MgSO 4 filtered and evaporated to a yellow oil. Flash chromatography on silica gel, eluting with hexanes/EtOAc (4/1 to gives 3.46 g (5.30 mmol, a 91% yield) of the title compound (Rf 0.32; 2/1 hexanes/EtOAc) as an oily, off-white solid; 1H NMR 300 MHz, CDCl 3 5 1.20-1.39 (complex m, 9H), 2.60-2.80 (in, 1H), 2.80-2.91 (mn, 1H), 3.01-3.19 (mn, 1H), 3.23-3.31 (mn, 1H), 3.40-3.53 (in, 1H), 4.10-4.23 (mn, 1H), 4.30-4.42 (complex m, 4H), 4.70-4.89 (in, 3H), 6.65-6.88 (complex m, 4H), 7.15- 7.39 (complex in, 3H); MS (ES) m/z (relative intensity): 654 H, 100).

Step 2 5-{(2R)-2-[jI(2R)-2-(tert-B utyI-dimethyl-siloxy)-2.(3-chloro-phenyl)ethyl]- (2,2,2-trichloro-et hoxyca rbony)-anino].propyl}..

benzolll,3]dioxole-2,2-dicarboxylic acid diethyl ester To a -78 TC solution of 3.75 g (5.47 mmol) (R,R)-5-12-[[2-(3-chloro-phenyl)- 2-hydroxy-ethyl] 2 2 2 -trich loro-ethox ycarbonyl)- amino] propyl I benzo[ 1, 3]dioxole- 2,2-dicarboxylic acid diethyl ester and 60 mL of CH 2

CI

2 was added 1.27 mL, 17 g, 10.94 inmol) of 2,6-lutidene followed by 1.38 mL (1.59 g, 6.03 iniol) of TBSOTf.

After stirring at -78 T( for 1.5 h, the reaction mixture was quenched with 50 m.L sat.

aq. NaHCO 3 and warmed to room temperature. After extraction with 3 x 150 mL Et 2

O,

WO 97/43273 WO 9743273PCTIUS97/08148 74the combined organics were washed with 1 x 200 mL. sat. CuSO0 4 1 x 200 -ML brine, dried over MgSO 4 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 0.3 1; 4/1 hexanes/EtOAc) as a gummy colorless solid; 'H NMR (300 MHz, CDCl 3 8 (in, 3H), 0.00- 0.06 (in, 3H), 0.85-0.91 (mn, 9H), 1.05 J=6.7 Hz, 3H), 1.33 J=7.1 Hz, 6H), 2.60-2.75 (mn, 2.77-2.96 (in, 1H), 3.00-3.31 (in, 2H), 3.77-4.00 (in, 1H), 4.35 J=7.1 Hz, 4H), 4.65-4.88 (in, 2H), 5.02-5.20 (in, 1H), 6.60-6.85 (in, 4H), 7.15- 7.37 (in, 3H); MIS (ES) m/z (relative intensity): 790 100), 768 Step 3 ethyl 2 2 ,2-trichloro-ethoxycarbonyl).amino]..propyl}Iben zo[ 1,3ldioxole-2,2-dica rboxylic acid To a room temperature solution of 3.31 g (4.31 mmol) (tr-uy-iity-ioy--3cloopey)ehl-222tihoo ethoxycarbonyl)- amino] -propyl )-benzo[ 1,3]dioxole-2,2-dicarboxylic acid diethyl ester, 100 nl MeOH and 25 ml- H 2 0 was added 4.31 mL. (21.56 mmol) of a 5N NaOH solution. After stirring at room temperature for 80 h, the solvent was evaporated, and the resulting slurry was acidified to pH 1 with 1 N HCL. The reaction mixture is extracted with 3 x 100 ml. EtOAc, and the combined organics were washed with 2 x ml brine, dried over Na 2

SO

4 filtered and evaporated to give 3.01 g (4.23 iniol, a 98% yield) of the title compound (Rf 0.0; 10/1 CHCI 3 IMeOH) as an off-white solid; 1 H NMR (300 MHz, CDCl 3 8 -0.19+(0.11) (in, 3H), 0.01 -0.09 (mn, 3H), 0. 81-0.91 9H), 0.93-0.97 (mn, 3H), 2.55-2.97 (complex mn, 3H), 3.07-3.35 (in, 2H), 3.80- 4.40 (br m, 2H), 4.60-4.83 (in, 2H), 5.03-5.18 (in, 1H), 6.60-6.92 (mn, 4H), 7.15- 7.39 (in, 3H); MIS (ES) ml z (relative intensity): 734 (M'4Na, 30), 712 100).

WO 97/43273 PCT/US97/08148 75 Step 4 ethyl]- (2,2,2-trichloro-ethoxyca rbonyl)-amino]. propyl}.benzo[1,3]dioxole-2,2-dicarboxylic acid diallyl ester To a room temperature solution of 950 mg (1.34 mmol) (tert-butyl-dimethyl- siloxy)-2-(Q3chloro-phenyl) -ethyl] (2,2,2-trichioroethoxycarbonyl)-amino] -propyl -ben zo[ 1, ,3]dioxole-2 ,2-dicarboxylic acid and 15 mL DMF was added 267 mg (2.67 mmol) of KHC0 3 and 0.26 mL (471 mg, 2.80 mmol) of allyl iodide. After stirring at room temperature for 16 h, the reaction was quenched with 10 mL sat. aq. NaHCO 3 and extracted with 3 x 100 mL Et 2 O. The combined organics were washed with I x 150 mL brine, dried over MgSO 4 filtered and evaporated to a colorless oil. Flash chromatography on silica gel, eluting with hexanes/EtOAc (8/1 to gave 670 mg (0.85 mnmol, a 63% yield) of the title compound (Rf 0.62; 2/1 hexanes/EtOAc) as a colorless oil; 'H NMR (300 NMz, CDC1 3 8 -0.19--11) (in, 3H), 0.00-0.08 (mn, 3H), 0.87 9H), 1.04 J=6.7 Hz, 3H), 2.60-2.74 (in, 1H), 2.77-2.98 (in, 111), 3.03-3.17 (mn, 1H), 3.18-3.30 (mn, 1H), 3.75-3.98 (in, 1H), 4.65-4.87 (in, 6H), 5.03-5.18 (in, 1H), 5.29 J=17.3 Hz, 2H), 5.34 J=23.7 Hz, 2H), 5.82-5.97 (complex m, 2H), 6.60-6.88 (in, 4H), 7.15-7.37 (in, 3H); MS (ES) m/z (relative intensity): 814 100).

Step 2

R)-

2 -II[(2R)..2.(3..Chloro..phenyl)..2.hydroxy..ethyIJ..(2,2,2trichioro-ethoxyca rbonyl)-amino]. propyl}-benzo[ 1,3]clioxole-2,2dicarboxylic acid diallyl ester To a 0 0 C solution of 650 mg (0.82 inmol) 5- {(2R)-2-[[(2R)-2-(tert-butyldiinethyl-siloxy)-2- 3 -chloro-phenyl)-ethyl]-(2,2,2-trichloro-ethoxycarbonyl)-am-ino] propyl I-ben zo[ 1,3]d ioxole- 2,2-dicarboxylic acid diallyl ester and 20 ml, THF was 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 (2/1 hexanes/EtOAc), and anl 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. NaHCO 3 extracted with 2 x 75 mL Et 2 O and then WO 97/43273 PCT/US97/08148 -76with 1 x 75 mL EtOAc. The combined organics were washed with 1 x 100 mL brine, dried over MgS04, filtered and evaporated to a colorless oil. Flash chromatography on silica gel, eluting with hexanes/EtOAc gave 460 mg (0.68 mmol, an 83% yield) of the title compound (Rf 0.28; 2/1 hexanes/EtOAc) as a colorless oil; 'H NMR (300 MHz, CDCl 3 8 1.20-1.37 3H), 2.60-2.78 2H), 2.80-2.91 1H), 2.98- 3.18 1H), 3.23-3.40 1H), 3.41-3.54 2H), 4.10-4.26 (br m, 1H), 4.73- 4.92 5.22-5.40 (complex m, 4H), 5.81-5.98 (complex m, 2H), 6.62-6.87 (m, 4H), 7.17-7.41 3H); MS (ES) m/z (relative intensity): 700 Na, 100).

Step 6 2 2 R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-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)-2hydroxy-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 mL brine, and extracted with 3 x 50 mL EtOAc. The combined organics were washed with 3 x 75 mL sat. NaHCO 3 1 x 75 mL brine, dried over Na 2

SO

4 filtered and evaporated to a colorless oil. Flash chromatography on silica gel, eluting with CHCI 3 /MeOH (20/1 to 10/1), gave 180 mg (0.36 mmol, a 66% yield) of the title compound (Rf 0.35; 10/1 CHCl3/MeOH) as a colorless gum; 'H NMR (300 MHz, CDCl 3 8 1.20-1.33 3H), 2.70-2.81 1H), 3.00-3.19 2H), 3.36-3.45 2H), 4.50-5.50 (br s, 2H), 4.70-4.80 4H), 5.10-5.20 1H), 5.25-5.40 4H), 5.82-6.00 (complex m, 2H), 6.70-6.91 3H), 7.17-7.30 (m, 3H), 7.41 1H); MS (ES) m/z (relative intensity): 502 100).

WO 97/43273 WO 7/4273PCTJUS97/08148 77 EXAMPLE 99 2 R)-2-(3-Chloro-phenyl)-2-hydroxy..ethylamino]..propyl}.

benzo[1 ,3]dioxole-2,2-dicarboxylic acid bis-(3-phenyl-allyI)ester Step 1 ethyl]- 2 ,2,2-t richloro-ethoxyca rbonyl).amino]..propylI}.

benzo[1 ,3]dioxole-2,2-dicarboxylic acid bis-(3-phenyl-aIlyl) 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); 'H NMR (300 MHz, CDC1 3 6 19+( 0.11) (in, 3H), -0.01-0.05 (in, 3H), 0.83-0.90 (in, 1.02 J=6.7 Hz, 3H), 2.60-2.75 (in, IH), 2.77-2.96 (mn, IM), 3.04-3.33 (in, 2H), 3.76-4.00 (mn, IH), 4.65- 4.85 (in, 4.90-4.98 (in, 4H), 5.02-5.20 (in, 1H), 6.20-6.33 (in, 2H), 6.60-6.85 (in, 5H), 7.15-7.45 (in, 14H); MS (ES) m/z(relative intensity) 944 100).

Step 2 [I(2R)2-(3-ChIloro-phenyl)-2-hydroxy-ethyj.(2,2,2.

trichloro-ethoxycarbonyI)-amino]-propyIl-benzo[1,3]dioxole.2,2dicarboxylic 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 2 R)-2-[[(2R)-2-(tert-butyl-dinethyl-siloxy..2(3.

chloro-phenyl)-ethyl]-(2,2,2-trichloro-ethoxycarbonyl)..aiino]-propyI I benzo[1,3]dioxole-2,2-dicarboxylic acid bis-(3-phenyl-allyl) ester was used in place of 2 R)-2-[[(2R)-2-(tert-butyl-dimethylsiloxy)2(3chlorophenyl)-ethyl]y(2,2,2 trichloro-ethoxycarbonyl)-amino] -propyl I -benzo[ 1,3]dioxole-2,2-dicarboxylic acid diallyl ester; yield 78%; Rf 0.31 (2/1 hexanes/EtOAc); I'H NMR (300 MHz, CDC 3 8 1.20-1.35 (mn, 3H), 2.58-2.80 (mn, 1H), 2.81-3.20 (in, 2H), 3.22-3.56 (in, 2H), 4.10-4.31 (in, 3M), 4.70-4.95 (mn, 5H), 6.17-6.43 (in, 2H), 6.60-6.90 (in, 5H), 7.15- 7.45 (mn, 14H).; MIS (ES) m/z (relative intensity): 830 100).

WO 97/43273 WO 9743273PCTIUS97/08148 78 Step 3 2 R)-2-[(2R)-2-(3-Chloro-pheny)-2-hydroxy.ethylamino..propy}..

benzo[1,3]dioxole-2,2.dicarboxylic acid bis-(3-phenyl-aIlyl)ester The title compound was prepared as a colorless oil according to the procedure of Example 4, Step 6 except that 5-f 2

R)-

2 -[[(2R)2-(3-chloro-phenyl)-2-hydroxyethyl] 2 2 2 -trichloro-ethoxycarbonyl)-amino] -propyl -benzo[ 1 ,3]dioxole-2,2dicarboxylic acid bis-(3-phenyl-allyl) ester was used in place of 5- chloro-phenyl1)-2- hydroxy-eth y] trichloro-ethoxycarbon yl) -amino] -propy I ben zo[l1,3]dioxole-2,2-dicarboxyl ic acid diallyl ester; yield 59%; Rf 0.35 (10/1 CHClJ/MeOH); 1H NMR (300 MHz, CDC1 3 8 1.15 J=6.3 Hz, 3H), 2.50-3.70 (brs, 2H), 2.60-2.7 1 (in, IH), 2.80-2.92 (in, 2H), 2.95-3.15 (in, 2H), 4.83-4.95 (in, 5.25-5.40 (in, 4H), 6.08-6.0 (complex mn, 2H), 6.66-6.9 1 (in, 5H), 7.15-7.40 (mn, 14H); MIS (ES) m/z (relative intensity): 654 100).

EXAMPLE 100 2

R)-

2 2 R)-2-(3-Chloro-plenyl)-2.hydroxy..ethylaminol..propyl}.

benzo[1 ,3]dioxole-2,2-dicarboxylic acid dicyclooctyl ester The title compound was prepared as a white gum from 5-[{2-1i2-(3-chlorophenyl)-2-hydroxy-ethylamino] -propyl) i-ben zo[ 1 ,3]dioxole-2,2-dicarboxylic acid and cyclooctanol according to the procedure of Example 1; yield 84 Rf 0.30 (10/1 CHCl 3 /MeOH); IH NMR (300 MHz, CDCl 3 8 1.30-1.39 (brd, 3H), 1.40-1.92 (in, 28H), 2.72-2.87 (in, 1H), 3.06-3.30 (mn, 2H), 3.39-3.52 (in, 2H), 3.80-3.91 (in, 1H), 5.02-5.13 (in, lH), 5.40-5.80 (in, IH), 6.7 1-6.89 (in, 4H), 7.21-7.37 (in, 2H), 7.44 1H), 8.73 (brs, lH), 10.11 (brs, 1H); MIS (ES) m/z (relative intensity): 679 100).

EXAMPLE 101 [(2R)-2-(3-Chloro-phenyl)-2-hyd roxy-ethylaminol-propyi}.

benzo[1 ,3]dioxole-2,2-dica rboxylic acid bis-(4- benzyloxy-but-2en y ester To a room temperature solution of 1 10 mng (0.25 inmol) of 5- (2-112-(3-chlorophenyl)- 3 -oxazolidinyl]..propyl)..benzo[1,3]dioxole-22.dicarboxylic acid and 5 mL of DMF was added 69 mng (0.69 inmol) of K 2 C0 3 followed by 195 mg (0.76 iniol) of WO 97/43273 PCT/US97/08148 -79cis-4-benzyloxy-2-buten-l-methane sulfonate. After heating at 50 OC 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 mL sat. aq. NaHCO 3 1 x 50 mL brine, dried over Na 2 SO4, filtered and evaporated to a yellow oil. Flash chromatography on silica gel, eluting with CHCl3/MeOH (40/1 to 10/1), gave 89 mg (0.12 mmol, a 47% yield) of the title compound (Rf 0.30 (10/1 CHCI3/MeOH) as a yellow oil. 'H NMR (300 MHz, CDCI3): 8 0.98-1.10 3H), 2.44-2.78 3H), 2.82-3.00 2H), 4.11-4.20 4H), 4.40-4.70 2H), 4.85- 4.95 4H), 5.70-5.79 2H), 5.81-5.92 2H), 6.72-6.90 3H), 7.17-7.47 14H); MS (ES) m/z (relative intensity): 742 100).

EXAMPLE 102 5-{(2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]propyl}benzo[l,3]dioxole-2,2-dicarboxylic acid phenethyl ester To a 0 OC solution of 0.630 g (1.0 mmol) of 5-{(2R)-2-[(2R)-2-(3-chlorophenyl)-2-hydroxy-ethylamino]-propyl)-benzo[ 3 ]dioxole-2,2-dicarboxylic acid bis- (2-phenethyl) ester in 12 mL CH 3 CN 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 mixture was adjusted to pH 8 with sat. aq. NH 4 C1, and the resulting white precipitate was collected by filtration. After washing with sat. aq. NaHC0 3 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 CHC13/MeOH) as a tan solid mp 75-82 OC; 'H NMR (300 MHz, DMSO-d 6 8 1.00 3H), 8 2.5 (br m, 4H), 8 2.84-3.10 5H), 8 3.35 (br, water), 8 4.28 2H), 8 4.90 1H), 8 6.6 1H), 5 6.76 2H), 8 7.21 (br s, 6H), 8 7.36 3H), 8 7.46 1H); MS (ES) m/z (relative intensity): 526 100).

4 4 WO 97/43273 PCTIUS97/08148 80 EXAMPLE 103 2

R)-

2 -[(2R).2-(3-Chloro-phenyl).2..bydroxy..ethylamino]propyllbenzo[1,3)dioxole-2,2-dicarboxylic acid phenyl -ethyl) ester The title compound was prepared as a tan solid according to the procedure of Example 102 from 5- 2

R)-

2 3 -chloro-phenyl)-2-hydroxy-ethylamino..

propyl) benzo[ 1,3]dioxole-2,2-dicarboxylic acid bis-( 1-phenylethyl) ester; yield: 22 Rf 0.39 (9/1 CHCl 3 /MeOH; mp 71-79 I1-H NMR (300 MHz, DMSO-dr 6 8 1.00 3H), 8 1.5 (br m, 3H), 8 2.4-2.75 (in, 1H), 8 3.15 -3.45(br m, 5H), 8 4.90 (br d, 1H), 8 5.20 (br d, 1H), 8 5.90 1H), 8 6.6 1H), 8 6.76 2H), 5 7.21 (br s, 6H), 8 7.36 (mn, 3H), 5 7.46 IH); MIS (ES) mlz (relative intensity): 526 100).

EXAMPLE 104 [(2R)-2-(3-Chloro-phenyl)-2- hydroxy-ethylamino]propyl}benzo[ 1,3ldioxole-2,2-dicarboxylic acid bis-(3-benzyloxypropyl)ester The title compound was prepared as a yellow gum from 5-[{2-[2-(3-chlorophenyl)-2-hydroxy-ethylami no] -propyl) -benzo[ 1,3]dioxole-2,2-dicarboxylic acid and 3-benzyloxy-propanol according to the procedure of Example 1; yield: 38 Rf 0.52 (9/1 CHClJ/MeOH); 1H NMIR (300 MHz, CDCl 3 8 1.32 3H), 8 2.00 (in, 4H), 8 2.75 (in, 1H), 8 3.30 2H), 8 3.50 (mn, 4H), 8 4.40 (br m, 12H), 8 5.49 1H), 8 6.68-6.85 (in, 3H), 8 7.24-7.40 (in, 13H), 8 7.43 1H); MS (ES) m/z (relative intensity): 518 (M+-HCl, 100).

Claims

5- {(2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino].propyl)}- benzo[1I,3ldioxole-2,2-dicarboxylic acid bis-(2-methyl-2-nitro-propyl) ester or a pharmaceutically acceptable salt thereof. 61) A compound of Claim 1 which is (2R)-2-[(2R)-2-(3-Chloro- phenyl)-2-hydroxy-ethylamrno]-propyl)}-benzo[ 1,3 Idioxole-2,2-dicarboxylic acid bi (tetrahydro-furan-3.ylmethyl) ester or a pharmaceutically acceptable salt thereof. 62) 5- {(2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyI I benzo[ 1,3ldioxole-2,2-dicarboxylic acid bis-(3-hydroxy-2,2,4-trimethyl-pentyl) ester a or a pharmaceutically acceptable salt thereof. 63) A compound of Claim 1 which is 5-{(2R)-2-[(2R)-2-(3-Chloro- phenyl)-2-hydroxy-ethylamino]-propyl)I-benzo[ 1,3 ]dioxole-2,2-dicarboxylic acid bis- (2,2-dimethyl-3-phenyl-propyl) ester or a pharmaceutically acceptable salt thereof. 64) A compound of Claim 1 which is Chloro- phenyl)-2-hydroxy-ethylamino]-propyll}-benzo[ 1,3ldioxole-2,2-dicarboxylic acid bis- (tetrahydro-pyran-2-ylmethyl) ester or a pharmaceutically acceptable salt thereof. AHP-95153 AU* -89- A compound of Claim 1 which is (2R)-2-[(2R)-2-(3-Chloro- phenyl)-2-hydroxy-ethylamino]-propyl }-benzo[ 1,3]dioxole-2,2-dicarboxylic acid bis- (tetrahydro-furan-2-ylmethyl) ester or a pharmaceutically acceptable salt thereof. 66) A compound of Claim 1 which is 5-{(2R)-2-[(2R)-2-(3-Chloro- phenyl)-2-hydroxy-ethylamino]-propyl I -benzo[ 1 ,3]dioxole-2,2-dicarboxylic acid bis- (5-methyl-[1,3]dioxan-5-ylmethyl) ester or a pharmnaceutically acceptable salt thereof. 67) 5- 2 R)- 2 -[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylaminol-propyI I benzo[ 1,3ldioxole-2,2-dicarboxylic acid bis-(l1-methyl-cyclohex-3-enylmethyl) ester or a pharmaceutically acceptable salt thereof. 68) 5- {(2R)-2-II(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylaino]-propyl benzo[ 1,3]dioxole-2,2-dicarboxylic acid bis-(3-hydroxy-2,2-dimethyl-propyl) ester or a pharmaceutically acceptable salt thereof. A compound of Claim 1 which is 5-{(2R)-2-[(2R)-2-(3-Chloro- phenyl)-2-hydroxy-ethylamino]-propyl }-benzo[ I,3]dioxole-2,2-dicarboxylic acid (2- ethoxy-ethyl) ester or a pharmaceutically acceptable salt thereof. *70) A compound of Claim I which is 5-1{(2R)-2-[(2R)-2-(3-Chloro- phenyl)-2-hydroxy-ethylaniino]-propyl I -benzo[ 1 ,3]dioxole-2,2-dicarboxylic acid bis- S 2 -(3-bromo-phenyl)-ethyljester hydrochloride salt. .71) A compound of Claim 1 which is 5-{(2R)-2-[(2R)-2-(3-Chloro- phenyl)-2-hydroxy-ethylamino]-propyl I -benzo[ 1 ,3]dioxole-2,2-dicarboxylic acid bis- :(2-m-tolyl-ethyl) ester hydrochloride salt. 72) 5- 2 R)- 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. 73) 5- 2 R)- 2 -II( 2 R)-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. AHP-95153 AU* 74) A compound of Claim 1 which is (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. 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 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 phenethyl 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 (1-phenyl- ethyl) 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-(3- benzyloxy-propyl)ester or a pharmaceutically acceptable salt thereof. 79) 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 any one of Claims 1 to 78 or a pharmaceutically acceptable salt thereof, enantiomer :e o: thereof, racemic mixture thereof, or diastereomeric mixture thereof. a 80) A method of treating obesity in a mammal, the method comprising administering to a mammal in need thereof an effective amount of a compound of any one of Claims 1 to 78 or a pharmaceutically acceptable salt thereof, enantiomer thereof, racemic mixture thereof, or diastereomeric mixture thereof. 81) A method of treating hyperglycemia in a mammal, the method comprising administering to a mammal in need thereof an effective amount of a compound of any one of Claims 1 to 78 or a pharmaceutically acceptable salt thereof, enantiomer thereof, racemic mixture thereof, or diastereomeric mixture thereof. S 82) A pharmaceutical composition comprising an effective amount of a compound as claimed in any one of claims 1 to 78 or a pharmaceutically acceptable salt thereof, AHP-95153 AU* -91- enantiomer thereof, racemic mixture thereof, or diastereomeric mixture thereof, in combination with a pharmaceutically acceptable carrier. 83) A process for preparing a compound of formula II as which comprises one of the following: claimed in Claim 1 a) reacting a compound of formula: OR 2 R3 I I CORg r wherein RI R 6 are as defined in Claim 1 and R 8 is OAg or Rg as defined above excepting OH with a compound of formula: I-CHRI2OC(O)R 13 wherein R 12 and RI 3 are as defined in Claim 1 to give a compound of formula II wherein R9 is -CHR120C(O)R13; or b) reacting a compound of formula: COR 8 wherein RI-R 6 and R 8 are as defined above with compound of formula R 9 OH where R 9 is as defined above excepting hydrogen to give a corresponding compound of formula II; or c) hydrolysing a compound for formula: AHP-95153 AU* wherein RI, R 4 R 5 R 6 R 7 and Rg are as defined in Claim 1 and R 2 is trialkylsilyl and R 3 is (Ci-C 6 alkoxy)-carbonyl to give a corresponding compound of formula 1 wherein R 2 and R 3 are both hydrogen; or d) reacting a compound of formula I wherein R 2 and R 3 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 R 2 and R 3 are joined to form a ring: 0 0 o o e) reacting a compound of formula: wherein RI, R 4 R 5 and R 8 are as defined in Claim 1 with the proviso neither R 2 or R 3 is hydrogen with a compound of formula: Z-R9 wherein Z is C1, Br, I, methanesulfonate or p-toluenesulfonate and R 9 is as defined in Claim 1 excepting hydrogen, to give a corresponding compound of formula II; or AHP-95153 AU* -93- f) hydrolysing a compound of formula: COR 8 wherein R1, R2, R3' R4, R5 and R6 are as defined in Claim 1, R8 is OR9' and R9' is CI-C 12 cycloalkyl, C1-C12 silylalkyl, aryl, arylalkyl, alkoxyalkyl or heteroaryl to give a compound of formula: 0 COOH r r r r r r wherein R 1 -R 6 and R 8 are as defined above providing that R 2 and R 3 are both hydrogen or joined to form a ring: R' ^^N or g) reacting a compound of formula: OR 2 R 3 SRN O COOR 9 R 1 RT Rh R n i R 1 R4 s O COR8 R6 wherein R1-R6 and R8 are as defined in Claim 1 and R9' as defined above, with a compound of formula: HNRIIR 12 -94- wherein R 11 and R 12 are as defined in claim 1 to give a compound of formula: OR 2 R 3 N O CONR 1 1 R 12 R, fz4 R5 X OCOR 8 wherein R 1 -R 6 R 11 and R 12 are as defined in claim 1.
84. A composition according to claim 1 substantially as hereinbefore described with reference to any of the examples.
85. A process according to claim 83 substantially as hereinbefore described. DATED: 20 December, 2000 PHILLIPS ORMONDE FITZPATRICK 15 Attorneys for: AMERICAN HOME PRODUCTS CORPORATION a