EP0901484A1 - Substituted 1, 3-benzodioxoles - Google Patents

Substituted 1, 3-benzodioxoles

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Publication number
EP0901484A1
EP0901484A1 EP97924720A EP97924720A EP0901484A1 EP 0901484 A1 EP0901484 A1 EP 0901484A1 EP 97924720 A EP97924720 A EP 97924720A EP 97924720 A EP97924720 A EP 97924720A EP 0901484 A1 EP0901484 A1 EP 0901484A1
Authority
EP
European Patent Office
Prior art keywords
propyl
phenyl
chloro
dioxole
hydroxy
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP97924720A
Other languages
German (de)
French (fr)
Inventor
Adam Matthew Gilbert
George Theodore Grosu
Michael Sotirios Malamas
Fuk-Wah Sum
Aranapakam Mudumbai Venkatesan
Gerardo De La Cruz Francisco
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Wyeth LLC
Original Assignee
American Home Products Corp
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Filing date
Publication date
Application filed by American Home Products Corp filed Critical American Home Products Corp
Publication of EP0901484A1 publication Critical patent/EP0901484A1/en
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1896—Compounds having one or more Si-O-acyl linkages

Definitions

  • 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.
  • Ri and R4 may be one or more groups which may be the same or different and are selected from the group consisting of hydrogen, Cl to C4 alkyl, Ci to C4 alkoxy, hydroxy, halogen, trifluoromethyl, carboxy, hydroxyalkyl, alkoxycarbonyl, Ci to C4 thioalkyl, sulfonyl and sulfinyl;
  • X is a divalent radical consisting of
  • 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, -CH2OCH2COOR7 and - CH2OCH2CH2OR7, where R7 is hydrogen or Cl to C4 alkyl; with the provision that R5 and R6 may not both be hydrogen; which have antihyperglycemic and antiobesity activity.
  • the compounds of the present invention possess greatly increased potency at human ⁇ 3 receptors in comparison to the compounds in Bloom, et al., U.S. Patent 5,061 ,727. They retain high selectivity for the ⁇ 3 receptor and show much higher antiobesity and antihyperglycemic activity in animal models than the compounds of the prior art.
  • the compounds have intrinsic activity at human ⁇ 3 receptors and can directly bring about antihyperglycemic and antiobesity effects, but may also be hydrolyzed in vivo to deliver a compound of the type disclosed in Bloom, et al., U.S. Patent 5,061,727 where R5 and R6 are carboxy. Thus the compounds may act as prodrugs. 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.
  • the compounds of the present invention achieve their antidiabetic, antihyperglycemic, and antiobesity effects by acting as selective agonists at ⁇ adrenergic receptors.
  • the stimulation of these receptors on white and brown adipocytes promotes both lipolysis (breakdown of fat) and energy expenditure.
  • Selective stimulation of ⁇ 3 adrenergic receptors is important for chronic treatment. Stimulation of other ⁇ -receptors could cause side effects such as increased heart rate ( ⁇ l effect) and muscle tremor ( ⁇ 2 effect).
  • the compounds of the present invention show high selectivity for ⁇ 3 adrenergic receptors.
  • Rl and R6 are independently hydrogen, Ci to C6 alkyl, trifluoromethyl, cyano, Cl to C6 alkoxy, or halogen;
  • R2 is hydrogen or Cl to C6 trialkylsilyl
  • R3 is hydrogen or Cl to C6 alkoxycarbonyl
  • R2 and R3 are joined to form a ring:
  • R' is hydrogen, Ci to C6 alkyl, or aryl
  • R4 and R5 are independently hydrogen or Ci to C ⁇ alkyl
  • R7 and Rs are independently OR9 or NRioRl i;
  • Ro is hydrogen, Ci to C12 alkyl, Ci to C12 cycloalkyl, Ci to C12 silylalkyl, aryl, arylalkyl, alkoxyalkyl, heteroaryl, -CHR12COOR13, -CHRi2C(O)Ri3, - CHR12CONR10RH, -CHR12OCOOR13, or -CHRi2OC(O)Ri3, with the provision that R9 is not hydrogen in both R7 and Rs;
  • RlO and Rn are independently hydrogen, Q to C12 alkyl, arylalkyl, aryl, furanylalkyl, or alkoxycarbonylalkyl;
  • Rl2 and R13 are independently hydrogen, Ci to C12 alkyl, aryl, or aralkyl; and the pharmaceutically acceptable salts thereof, the enantiomers thereof, the racemic mixtures thereof, and the diastereomeric mixtures thereof.
  • aryl may be phenyl or napthyl; arylalkyl may be phenyl Cl to Co alkyl or naphthyl Ci to C ⁇ alkyl; alkoxy alkyl may be Ci to C(, alkoxy Ci to C6 alkyl; and heteroaryl may be pyridyl, thiophenyl, furanyl, imidazolyl, oxazolyl, or thiazolyl.
  • aryl, arylalkyl and heteroaryl groups referred to above may be optionally substituted with one or more moieties selected from halogens, C,-C 6 alkyl, C j -C 6 alkoxy, -CF 3 , -CN, or -OH groups.
  • the phenyl Cl to Co alkyl group may be optionally substituted by one or more substituents selected from F, Cl, Br, CH3 or CF3.
  • This invention also provides processes for preparing the compounds of the invention which comprise one of the following:
  • R2 - R ⁇ are as defined above and Rs' is OAg or Rs as defined above excepting OH with a compound of formula:
  • R12 and R13 are as defined above to give a compound of formula II wherein R9 is -CHRi2OC(O)Ri3 or b) reacting a compound of formula:
  • Ri, R.1 , Rs , R ⁇ , R7 and Rs are as defined above and R2 is trialkylsilyl and R3 is (Ci-C ⁇ alkoxy)carbonyl to give a corresponding compound of formula 1 wherein R2 and R3 are both hydrogen,
  • R' is as defined above to give a corresponding compound of formula I wherein R 2 and R3 are joined to form a ring:
  • Ri, R2, R3 ' R4, R5 and R6 are as defined in Claim 1
  • Rs is OR9' or NRloRl l an( * ⁇ 9' * s ⁇ 12 a ⁇ yl.
  • Rl-R6 and R8 are as defined above and R9' is as defined above, with a compound of formula:
  • R ⁇ -R6 R ⁇ > Rll and R12 are as defined above.
  • 2,2-dicarboxylic acid bis-(2-ethoxy-ethyl) ester 5- ⁇ 2-f 2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl ⁇ -benzof 1 ,3 Jdioxole- 2,2-dicarboxylic acid bis-(2-tert-butoxy-ethyl) ester;
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the total daily dosage is from about 3.5 to about 140 mg, preferably from about 3.5 to about 5 mg.
  • 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.
  • 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.
  • 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.
  • 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 (e.g. glycerol, propylene 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 95% by weight of a compound of the present invention with about 5% to about 25% by weight of a suitable carrier or diluent.
  • Carriers suitable for use to make up the feed supplement compositions include the following: alfalfa meal, soybean meal, 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
  • 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.
  • 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 ingredient.
  • 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 35 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.
  • 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.
  • 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.
  • the compounds of the present invention may be prepared according to one of the general processes outlined below. As outlined in Scheme I, a disodium carboxylate 1 is converted to a disilver carboxylate and treated with an iodo derivative 2 to yield the diester compounds 3 wherein Ri, R4, R5, R6, Rl2, and R13 are as defined above.
  • a dicarboxylic acid 4 (Scheme II) is treated with an alcohol R9OH and an acid catalyst to yield the diester compounds 5 wherein R ⁇ , R4, R5, R6, and R9 are as defined above.
  • 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» &6. and R9 are as defined above and Z is Cl, Br, I, methanesulfonate, trifluoromethanesulfonate, or para-toluenesulfonate.
  • the diester compounds 5 can be hydrolyzed under basic conditions to a monoester 9a and/or 9b, wherein Ri, R4, R5, R6, and R9 are as defined above.
  • One or both of the diastereomers 9a and 9 b may be produced in the hydrolysis reaction.
  • the compounds of this invention were tested for antihyperglycemic and antiobesity activity according to the following procedures.
  • test compounds on human ⁇ -adrenergic receptors were determined with Chinese hamster ovary (CHO) cells transfected with human ⁇ 2, or ⁇ l adrenergic receptors. Agonist activity is indicated by increased cAMP levels in the CHO cells. Selectivity of the test compounds for the ⁇ 3 receptor was assessed by comparison with results in ⁇ 2 and ⁇ l adrenergic receptor transfected cells.
  • Activities for the test compounds are expressed as a percentage of the isoproterenol response.
  • Rats respond to a single oral dose of ⁇ 3 agonists by increasing plasma free fatty acids (FFA) in response to ⁇ 3 receptor stimulation on the plasma membrane of the fat cell.
  • FFA plasma free fatty acids
  • 5- ⁇ 2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl ⁇ -benzof 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.
  • Methyl cellulose:tween-80 drug suspension was given via gavage (1 mL/200g body weight; or 0.1 mg/kg) to rats and blood was collected 50 min later. 4). Plasma was analyzed for free fatty acids using a kit supplied by Biochemical Diagnostics Inc. (Brentwood, N.Y.). 5). Drug response was calculated from the formula below.
  • mice Male, db/db (C57BL/KsJ), Jackson Laboratories, 2 to 7 months of age and 35 to 60 g
  • 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.
  • mice having the most extreme (i.e., highest or lowest) plasma glucose levels were excluded and the remaining 30 mice were randomly assigned into 7 groups of equivalent mean plasma glucose level (vehicle control, ciglitazone (Standard 3), and 5 test compound groups).
  • vehicle 0.2 mL of 2% Tween 80/saline w/v
  • test compounds were administered (p.o.) to the ad libitum fed mice.
  • 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.
  • 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:
  • EXAMPLE 6 and EXAMPLE 7 5- ⁇ 2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl ⁇ - benzo[l,3]dioxole-2,2-dicarboxylic acid bis-(2-tert-butoxy-ethyl) ester and
  • Step 1 5-(2- ⁇ tert-ButoxycarbonyI- [2- (3-chloro- phenyl )-2-hydroxy-ethyl]- amino ⁇ -propyl)-benzo[l,3]dioxole-2,2-dicarboxylic acid bis-ethyl ester
  • Step 4 5- ⁇ 2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl ⁇ -benzo[l,3]- dioxole-2,2-dicarboxylic acid bis-methoxycarbonylmethyl ester
  • Step 2 5- ⁇ 2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl ⁇ - benzofl ,3]dioxole-2,2-dicarboxylic acid bis-(l-methoxycarbonyl- ethyl)ester
  • Step 1 5-(2- ⁇ tert-Butoxycarbonyl-[2-(3-chloro-phenyl)-2-hydroxy-ethyl]- amino ⁇ -propyl)-benzofl,3]dioxole-2,2-dicarboxylic acid bis- isopropoxycarbonyl-methyl ester
  • the title compound was prepared from 5-(2- ⁇ tert-buto ⁇ ycarbonyl-[2-(3-chloro- phenyl)-2-hydroxy-ethyl]-amino)-propyl)-benzofl,3]dioxole-2,2-dicarboxylic acid and isopropyl 2-bromoacetate according to the procedure of Example 24, step 3 as a colorless oil: J H NMR (300 MHz, CDCI3): ⁇ 1.15-1.30 (m, 15H), 1.40 (s, 9H), 2.45- 2.70 (m, 2H), 3.06-3.15 (m, IH), 3.45-3.60 (m, IH), 4.
  • Step 2 5- ⁇ 2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl ⁇ -benzo [l,3]dioxole-2,2-dicarboxylic acid bis-isopropoxycarbonylmethyl ester
  • Step 1 5-(2- ⁇ tert-Butoxycarbonyl-[2-(3-chloro-phenyl)-2-hydroxy-ethyl]- amino ⁇ -propyl)-benzof l,3]dioxole-2,2-dicarboxylic acid bis-(l- ethoxycarbonyl-ethyl) ester
  • Acetyl chloride (0.59 g, 7.5 mmol) was added to trimethylsilylmethanol (4.03 g, 37.5 mmol) with stirring at room temperature. After 0.5 h, 5- ⁇ 2-[2-(3-chloro- phenyl)-2-hydroxy-ethylamino] -propyl) -benzof 1 ,3]dioxole-2,2-dicarboxylic acid
  • 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, K., Ishihara, S., Yanagisawa, H., Ide, J., Nakayama, E., Nakao, H. , Sugawara, S., Iwata, M. J. Antibiotics 1987, 19, 370.
  • reaction mixture 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 1 x 100 IN HCI, 1 x 100 mL brine, dried over MgSO 4 , filtered and evaporated to a yellow oil.
  • Step 5 5- ⁇ (2R)-2-[[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethyl]-(2,2,2- trichloro-ethoxycarbonyl)-amino]-propyl ⁇ -benzofl,3]dioxole-2,2- dicarboxylic acid diallyl ester
  • Step 2 5- ⁇ (2R)-2-[[(2R)2-(3-Chloro-phenyl)-2-hydroxy-ethyl]-(2,2,2- trichloro-ethoxycarbonyl)-amino]-propyl ⁇ -benzo[l,3]dioxole-2,2- dicarboxylic acid bis-(3-phenyl-allyl) ester

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Abstract

The present invention provides new compounds having anti-diabetic and/or antihyperglycemia and/or anti-obesity activity, as well as pharmaceutical compositions and methods of treatment utilizing the compounds and processes for making the compounds, the compounds having formula (II), wherein: R1 and R6 are independently hydrogen, C1 to C6 alkyl, trifluoromethyl, cyano, C1 to C6 alkoxy, or halogen; R2 is hydrogen or C1 to C6 trialkylsilyl; R3 is hydrogen or C1 to C6 alkoxycarbonyl; or R2 and R3 are joined to form a ring (a): wherein R' is hydrogen, C1 to C6 alkyl or aryl; R4 and R5 are independently hydrogen or C1 to C6 alkyl; R7 and R8 are independently OR9 or NR10R11; R9 is hydrogen, C1 to C12 alkyl, C1 to C12 cycloalkyl, C1 to C12 silylalkyl, aryl, arylakyl, alkoxyalkyl, heteroaryl, -CHR12COOR13, -CHR12C(O)R13, -CHR12CONR10R11, -CHR12OCOOR13, or -CHR12OC(O)R13, with the provision that R9 is not hydrogen in both R7 and R8; R10 and R11 are independently hydrogen, C1 to C12 alkyl, aralkyl, aryl, furanylalkyl, or alkoxycarbonylalkyl; R12 and R13 are independently hydrogen, C1 to C12 alkyl, aryl, or aralkyl; and their pharmaceutically acceptable salts thereof, the enantiomers thereof, the racemic mixtures thereof, and the diastereomeric mixtures thereof.

Description

SUBSTITUTED 1.3-BENZODTOXOLES
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-2- hydroxyethyl)arnino)propyl)-l,3-benzodioxoles of general formula (I)
wherein Ri and R4 may be one or more groups which may be the same or different and are selected from the group consisting of hydrogen, Cl to C4 alkyl, Ci to C4 alkoxy, hydroxy, halogen, trifluoromethyl, carboxy, hydroxyalkyl, alkoxycarbonyl, Ci to C4 thioalkyl, sulfonyl and sulfinyl; X is a divalent radical consisting of
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, -CH2OCH2COOR7 and - CH2OCH2CH2OR7, where R7 is hydrogen or Cl to C4 alkyl; with the provision that R5 and R6 may not both be hydrogen; which have antihyperglycemic and antiobesity activity. The synthesis, antidiabetic effects, and antiobesity effects of (R ,R)-5-[2-[[2-(3- chlorophenyl)-2-hydroxyethyl]amino]propyl]-l,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 β3 receptors in comparison to the compounds in Bloom, et al., U.S. Patent 5,061 ,727. They retain high selectivity for the β3 receptor and show much higher antiobesity and antihyperglycemic activity in animal models than the compounds of the prior art. The compounds have intrinsic activity at human β3 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. 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.
DESCRIPTION OF THE INVENTION
The compounds of the present invention achieve their antidiabetic, antihyperglycemic, and antiobesity effects by acting as selective agonists at ββ adrenergic receptors. The stimulation of these receptors on white and brown adipocytes promotes both lipolysis (breakdown of fat) and energy expenditure. Selective stimulation of β3 adrenergic receptors is important for chronic treatment. Stimulation of other β-receptors could cause side effects such as increased heart rate (βl effect) and muscle tremor (β2 effect). The compounds of the present invention show high selectivity for β3 adrenergic receptors.
According to the present invention there are provided new compounds of the formula (II):
wherein:
Rl and R6 are independently hydrogen, Ci to C6 alkyl, trifluoromethyl, cyano, Cl to C6 alkoxy, or halogen;
R2 is hydrogen or Cl to C6 trialkylsilyl; R3 is hydrogen or Cl to C6 alkoxycarbonyl; or R2 and R3 are joined to form a ring:
wherein R' is hydrogen, Ci to C6 alkyl, or aryl;
R4 and R5 are independently hydrogen or Ci to Cβ alkyl;
R7 and Rs are independently OR9 or NRioRl i; Ro, is hydrogen, Ci to C12 alkyl, Ci to C12 cycloalkyl, Ci to C12 silylalkyl, aryl, arylalkyl, alkoxyalkyl, heteroaryl, -CHR12COOR13, -CHRi2C(O)Ri3, - CHR12CONR10RH, -CHR12OCOOR13, or -CHRi2OC(O)Ri3, with the provision that R9 is not hydrogen in both R7 and Rs;
RlO and Rn are independently hydrogen, Q to C12 alkyl, arylalkyl, aryl, furanylalkyl, or alkoxycarbonylalkyl;
Rl2 and R13 are independently hydrogen, Ci to C12 alkyl, aryl, or aralkyl; and the pharmaceutically acceptable salts thereof, the enantiomers thereof, the racemic mixtures thereof, and the diastereomeric mixtures thereof.
In the description above, aryl may be phenyl or napthyl; arylalkyl may be phenyl Cl to Co alkyl or naphthyl Ci to Cβ alkyl; alkoxy alkyl may be Ci to C(, alkoxy Ci to C6 alkyl; and heteroaryl may be pyridyl, thiophenyl, furanyl, 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, C,-C6 alkyl, Cj-C6 alkoxy, -CF3, -CN, or -OH groups. In a more preferred embodiment of this invention, the phenyl Cl to Co alkyl group may be optionally substituted by one or more substituents selected from F, Cl, Br, CH3 or CF3.
This invention also provides processes for preparing the compounds of the invention which comprise one of the following:
a) reacting a compound of formula:
wherein R2 - Rβ are as defined above and Rs' is OAg or Rs as defined above excepting OH with a compound of formula:
I-CHRi2OC(O)Rl3
wherein R12 and R13 are as defined above to give a compound of formula II wherein R9 is -CHRi2OC(O)Ri3 or b) reacting a compound of formula:
wherein Ri-Rβ and R% are as defined above with compound of formula R9OH where R9 is as defined above excepting hydrogen to give a corresponding compound of formula II; or c) hydrolysing a compound for formula:
wherein Ri, R.1, Rs, Rό, R7 and Rs are as defined above and R2 is trialkylsilyl and R3 is (Ci-Cβ alkoxy)carbonyl to give a corresponding compound of formula 1 wherein R2 and R3 are both hydrogen,
or d) reacting a compound of formula II wherein R2 and R3 are both hydrogen with an aldehyde of formula:
R'CHO
wherein R' is as defined above to give a corresponding compound of formula I wherein R2 and R3 are joined to form a ring:
or e) reacting a compound of formula:
wherein Ri, R4, R5 and Rs are as defined above with the proviso neither R2 or R3 is hydrogen with a compound of formula:
Z-R9
wherein Z is Cl, Br, I, methanesulfonate or p-toluenesulfonate and R9 is as defined in above excepting hydrogen, to give a corresponding compound of formula II;
or 0 hydrolysing a compound of formula:
wherein Ri, R2, R3' R4, R5 and R6 are as defined in Claim 1 , Rs is OR9' or NRloRl l an(* ^9' *s ^Γ^12 a^yl. CJ-CJ 2 cycloalkyl, Cj-C^ silyalkyl, aryl, arylalkyl, alkoxyalkyl or heteroaryl to give a compound of formula:
wherein and Rs are as defined above providing that R2 and R3 are both hydrogen or joined to form a ring:
or g) reacting a compound of formula:
wherein Rl-R6 and R8 are as defined above and R9' is as defined above, with a compound of formula:
HNR11R12
wherein R\ 1 and R12 are as defined above to give a compound of formula:
wherein Rι-R6» Rδ> Rll and R12 are as defined above.
The most preferred compounds of this invention are the following and the pharmaceutically acceptable salts thereof:
5- { 2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl } -benzof 1 ,3]dioxole- 2,2-dicarboxylic acid bis-(2-methoxy-ethyl) ester;
5- { 2-f 2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl } -benzof 1 ,3]dioxole- 2,2-dicarboxylic acid diphenethyl ester;
5- { 2-f 2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl } -benzof 1 ,3]dioxole- 2,2-dicarboxylic acid bis-(2-butoxy-ethyl) ester;
5- { 2-f 2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl } -benzof 1 ,3]dioxole- 2,2-dicarboxylic acid bis-(2-phenoxy-ethyl) ester; 5- { 2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino] -propyl } -benzof 1 ,3]dioxole-
2,2-dicarboxylic acid bis-(2-ethoxy-ethyl) ester; 5- { 2-f 2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl } -benzof 1 ,3 Jdioxole- 2,2-dicarboxylic acid bis-(2-tert-butoxy-ethyl) ester;
5- { 2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl } -benzof 1 ,31dioxole- 2,2-dicarboxylic acid (2-tert-butoxy-ethyl) ester; 5- {2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl} -benzof l,3]dioxole-
2,2-dicarboxylic acid bis-(2-isobutoxy-ethyl) ester;
5- { 2-f 2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl } -benzof 1 ,3]dioxole- 2,2-dicarboxylic acid bis-(benzyl) ester;
5- { 2-f 2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl } -benzof 1 ,3]dioxole- 2,2-dicarboxylic acid bis-(cyclohexyl) ester;
5-{2-l2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[l,3]dioxole- 2,2-dicarboxylic acid bis-(cyclopentyl) ester;
5- { 2-l2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl } -benzof 1 ,31dioxole- 2,2-dicarboxylic acid dioctyl ester; 5- { 2-f 2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl } -benzof 1 ,3]dioxole-
2,2-dicarboxylic acid dipentyl ester;
5- {2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl } -benzofl ,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;
5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[l,3]dioxole- 2,2-dicarboxylic acid bis-(l-phenyl-ethyl) ester;
5-{2-f2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzofl ,3]dioxole- 2,2-dicarboxylic acid diheptyl ester; 5-{2-f2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl)-benzo[l,3]dioxole-
2,2-dicarboxylic acid dinonyl ester,
5- {2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl} -benzof l,3]dioxole- 2,2-dicarboxylic acid bis-decyl ester;
5-{2-f2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzofl,3]dioxole- 2,2-dicarboxylic acid didodecyl ester;
5- {2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl} -benzof 1,3 Jdioxole- 2,2-dicarboxylic acid bis-(2-isopropoxy-ethyl) ester;
5- {2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl} -benzof l,3]dioxole- 2,2-dicarboxylic acid isopropyl ester; 5-(2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl } -benzof 1 ,3]dioxole- 2,2-dicarboxylic acid ethyl ester;
5- { 2-f 2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl } -benzof 1 ,3]dioxole- 2,2-dicarboxylic acid bis-methoxycarbonylmethyl ester; 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl } -benzof 1 ,3]dioxole-
2,2-dicarboxylic acid bis-propoxycarbonylmethyl ester;
5- { 2-f 2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl } -benzof 1 ,3]dioxole- 2,2-dicarboxylic acid bis-(l-methoxycarbonyl-ethyl) ester;
5- { 2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl } -benzof 1 ,3]dioxole- 2,2-dicarboxylic acid bis-isopropoxycarbonylmethyl ester;
5-{2-{2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl } -benzof 1 ,3]dioxole- 2,2-dicarboxylic acid bis-ethoxycarbonylmethyl ester;
5-{2-f2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl } -benzof 1 ,31dioxole- 2,2-dicarboxylic acid bis-(l-ethoxycarbonyl-ethyl) ester; 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl } -benzof 1 ,3]dioxole-
2,2-dicarboxylic acid bis-trimethylsilanylmethyl ester;
5- ( 2-f 2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl } -benzof 1 ,3]dioxole- 2,2-dicarboxylic acid bis-(2-rrimethylsilanyl-ethyl) ester;
5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl } -benzof 1 ,3]dioxole- 2,2-dicarboxylic acid bis-(3-trimethylsilanyl-propyl) ester;
5- ( 2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl } -benzof 1 ,3]dioxole- 2,2-dicarboxylic acid bis-(3,3-dimethyl-butyl) ester;
5- { 2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl } -benzof 1 ,3]dioxole- 2,2-dicarboxylic acid bis-cyclohexylmethyl ester; 5- { 2-f 2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl } -benzof 1 ,3]dioxole-
2,2-dicarboxylic acid bis-(4-methyl-pentyl) ester;
5- { 2-f 2-(3-chloro-phenyl)-2-hydroxy-ethylamino] -propyl } -benzof 1 ,3]dioxole- 2,2-dicarboxylic acid bis-(2-cyclohexyl-ethyl ) ester;
5- { 2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl } - benzo f 1 , 3 ] dioxole - 2,2-dicarboxylic acid bis-(3-cyclopentyl-propyl ) ester;
5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl } -benzof 1 ,3]dioxole- 2,2-dicarboxylic acid bis-cyclopropylmethyl ester;
5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl } -benzof 1 ,3]dioxole- 2,2-dicarboxylic acid bis-(l-methyl-cyclopropylmethyl) ester; 5- { 2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl } -benzof 1 ,3]dioxole- 2,2-dicarboxylic acid bis-cyclobutylmethyl ester;
5- { 2-f 2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl } -benzof 1 ,3]dioxole- 2,2-dicarboxylic acid bis-(2-cyclopentyl-ethyl) ester; 5- { 2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]propyl } benzof 1 ,31dioxole-
2,2-dicarboxylic acid bis-acetoxymethyl ester;
5-{2-f2-(3-chloro-phenyl)-2-hydroxy-ethylamino]propyl}benzo[l,3]dioxole- 2,2-dicarboxylic acid bis-propionyloxymethyl ester;
5- { 2-f 2-(3-chloro-phenyl)-2-hydroxy-ethylamino]propyl ) benzof 1 ,3]dioxole- 2,2-dicarboxylic acid bis-butyryloxymethyl ester;
5- { 2-f 2-(3-chloro-phenyl)-2-hydroxy-ethylamino]propyl } benzof 1 ,3]dioxole- 2,2-dicarboxylic acid bis-isobutyryloxymethyl ester;
5- { 2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]propyl } benzof 1 ,3]dioxole- 2,2-dicarboxylic acid bis-heptanoyloxymethyl ester; 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]propyl} benzof l ,3]dioxole-
2,2-dicarboχylic acid bis-(4-methyl-pentanoyloxymethyl) ester ;
5- { 2-f 2-(3-chloro-phenyl)-2-hydroxy-ethylamino]propyl} benzof l,3]dioxole- 2,2-dicarboxylic acid bis-hexanoyloxymethyl ester;
5- { 2-[2- (3-chloro-phenyl)-2-hydroxy-ethylamino]propyl } benzof 1 ,3]dioxole- 2,2-dicarboxylic acid bis- (2,2-dimethyl-propionyloxymethyl) ester;
5- {2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]propyl} benzof l,3]dioxole- 2,2-dicarboxylic acid bis cyclohexanecarbonyloxymethyl ester;
5- {2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]propyl } benzof 1 ,3]dioxole- 2,2-dicarboxylic acid bis-(l-propionyloxy-ethyl) ester; 5- {2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]propyl} benzof l,3]dioxole-
2,2-dicarboxylic acid bis-[l-(2,2-dimethyl-propionyloxy-ethyl) ester;
5-{2-f2-(3-chloro-phenyl)-2-hydroxy-ethylamino]propyl}benzo[l,3]dioxole- 2,2-dicarboxylic acid bis-(3,3-dimethyl-butyryloxymethyl) ester;
5- { 2- f 2- (3-chloro-pheny l)-2-hydroxy-ethylamino]propyl } benzof 1 ,3]dioxole- 2,2-dicarboxylic acid bis-[l-(3,3-dimethyl-butyryloxy)-ethyl)}ester;
5- {2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]propyl} benzof l,3]dioxole- 2,2-dicarboxylic acid bis-(3-cyclopentyl-propionyloxymethyl) ester;
5- {2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]propyl} benzof l,3]dioxole- 2,2-dicarboxylic acid bis-benzoyloxymethyl ester; 5- { 2-[2- (3-chloro-phenyl)-2-hydroxy-ethylamino]propyl } benzof 1 ,3]dioxole- 2,2-dicarboxylic acid bis-(benzoyloxy-ethyl) ester,
5- { 2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]propyl } benzof 1 ,3]dioxole- 2,2-dicarboxylic acid bis-(2,2-dimethyl-butyryloxymethyl) ester; 5- { 2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino] -propyl } -benzof 1 ,3]dioxole-
2,2-dicarboxylic acid bis-amide;
5- { 2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl } -benzof 1 ,3]dioxole- 2,2-dicarboxylic acid bis-2-propyl amide;
5- { 2-f 2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl } -benzof l,3]dioxole- 2,2-dicarboxylic acid bis-n-butyl amide;
5- {2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino] -propyl} -benzof l,3]dioxole- 2,2-dicarboxylic acid bis-phenylmethyl amide;
5- { 2-f 2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl} -benzof l,3]dioxole- 2,2-dicarboxylic acid bis-(2-furanylmethyl) amide; 5- {2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl} -benzof l,3]dioxole-
2,2-dicarboxylic acid bis-(glycine ethyl ester) amide;
5-{2-[2-(3-chloro-phenyl)-3-oxazolidinyl]-propyl}-benzo[l,3]dioxole-2,2- dicarboxylic acid;
Also according to the present invention there is provided a method of treating diabetes and/or hyperglycemia and/or obesity in humans or other 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. 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 3.5 to about 140 mg, preferably from about 3.5 to about 5 mg. In the case of a 70 kg human adult, the total daily dose will generally be from about 7 mg to about 70 mg and may be adjusted to provide the optimal therapeutic result.
The tablets, pills, capsules, and the like may also contain a binder such as 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 (e.g. glycerol, propylene 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 95% by weight of a compound of the present invention with about 5% to about 25% by weight of a suitable carrier or diluent. Carriers suitable for use to make up the feed supplement compositions include the following: alfalfa meal, soybean meal, 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
10 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 ingredient. 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 35 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. 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 Ri, R4, R5, R6, Rl2, and R13 are as defined above.
Scheme I
Alternatively, a dicarboxylic acid 4 (Scheme II) is treated with an alcohol R9OH and an acid catalyst to yield the diester compounds 5 wherein R\, R4, R5, R6, and R9 are as defined above.
Scheme II
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» &6. and R9 are as defined above and Z is Cl, Br, I, methanesulfonate, trifluoromethanesulfonate, or para-toluenesulfonate.
Scheme III
1 ) base, Z-R9
2) remove R2 and R3
As outlined in Scheme IV, a dicarboxylate 1 is treated with an aldehyde R'CHO to yield the oxazaline compounds 8, wherein R\ , R4, R5, Rβ, and R' are as defined above. Scheme IV
As outlined in Scheme V the diester compounds 5 can be hydrolyzed under basic conditions to a monoester 9a and/or 9b, wherein Ri, R4, R5, R6, and R9 are as defined above. One or both of the diastereomers 9a and 9 b may be produced in the hydrolysis reaction.
Scheme V
9a 9b As illustrate in Scheme VI, a diester compound 5 is reacted with an amine HNR11R12 to yield the diamide compounds 10, wherein Ri, R4, R5, R6, R9, Rl l, and R 12 are as defined above.
Scheme VI
The compounds of this invention were tested for antihyperglycemic and antiobesity activity according to the following procedures.
Human Beta Adrenerpic Receptor Selectivity
The activity of the test compounds on human β-adrenergic receptors was determined with Chinese hamster ovary (CHO) cells transfected with human β2, or βl adrenergic receptors. Agonist activity is indicated by increased cAMP levels in the CHO cells. Selectivity of the test compounds for the β3 receptor was assessed by comparison with results in β2 and βl adrenergic receptor transfected cells.
Procedure:
1). Chinese hamster ovary (CHO) cells transfected with human β2, or βi adrenergic receptors were used in the assay. 2). Cells were grown to confluent conditions in 24 well plates. 3). Drugs were dissolved in DMSO at a concentration of 10 μM. 4). Cells were incubated with drug at 10 nM concentration for 10 min at 37° C. Isoproterenol (Standard 1) was used as the standard compound and assayed at 10 μM which gives a maximal cAMP elevation in all 3 cell types. 5). Cell cAMP concentrations were assayed using a scintillation proximity assay kit from Amersham Corp., Chicago, IL.
6). Activities for the test compounds are expressed as a percentage of the isoproterenol response.
Production of the CHO cells transfected with human β2, or βi adrenergic receptors, and compound test procedures utilizing the CHO cells, are described by Emorine et al. in their article "Molecular Characterization of the Human Betay Adrenergic Receptor" , Science 1989, 245(8), 1118-1 121 and by Muzzin et al. in the article "An Adipose Tissue-Specific BetayAdrenergic Receptor", J. Biol. Chem.1991, 266, 24053-24058.
Effects on Free Fattv Acid Levels in Rats
Rats respond to a single oral dose of β3 agonists by increasing plasma free fatty acids (FFA) in response to β3 receptor stimulation on the plasma membrane of the fat cell. 5- { 2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl } -benzof 1 ,3]dioxole- 2,2-dicarboxylic acid diisopropyl ester (Standard 2) was used as a standard compound. All test compounds were dosed at 0.1 mg/kg and compared to the response by Standard 2.
Procedure:
1). Drugs were dissolved in DMSO at 10 mg/ml.
2). Twenty μl of the DMSO-drug solution was added to 10 mL methyl cellulose:tween- 80 (0.5%:0.1 %) for a final concentration of 20 μg/mL.
3). Methyl cellulose:tween-80 drug suspension was given via gavage (1 mL/200g body weight; or 0.1 mg/kg) to rats and blood was collected 50 min later. 4). Plasma was analyzed for free fatty acids using a kit supplied by Biochemical Diagnostics Inc. (Brentwood, N.Y.). 5). Drug response was calculated from the formula below.
% FFA Response= FFA (compound) - FFA vehitig x 10o 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 (i.e., highest or lowest) plasma glucose levels were excluded and the remaining 30 mice were randomly assigned into 7 groups of equivalent mean plasma glucose level (vehicle control, ciglitazone (Standard 3), and 5 test compound groups). On the afternoon of Days 1, 2, and 3 the vehicle (0.2 mL of 2% Tween 80/saline w/v) or test compounds were administered (p.o.) to the ad libitum fed 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 ioo Baseline sample (Day 1)
A 50-60% reduction of plasma glucose levels in the hyperglycemic db/db mice represents a normalization of glucose levels. Table I
a Human β receptors expressed in Chinese hamster ovary cells, compounds tested at 10 nM, results expressed as % of isoproterenol activity (increase in cAMP) at 10 μM. EC50 (μM) values determined for selected compounds.
* Elevation of plasma free fatty acids in rats, compounds tested at 0.1 mg/kg, results expressed as % of 5-{2-f2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}- benzof l,3]-dioxole-2,2-dicarboxylic acid diisopropyl ester response (78% increase) at 0.1 mg/kg. ED50 (mg/kg) values determined for selected compounds. c ED50 (mg/kg/day) values for lowering of plasma glucose.
The following non-limiting specific examples further illustrate the present invention.
EXAMPLE 1
5-{2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}- benzo[l,3]dioxole-2,2-dicarboxylic acid bis-(2-methoxy-ethyl) ester hydrochloride salt
To a stirred mixture of 5-{2-f2-(3-chloro-phenyl)-2-hydroxy-ethylamino]- propyl } -benzof l ,3]dioxole-2,2-dicarboxylic acid (1.0 g, 2.37 mmol), and 2-methoxy- 1-ethanol (10 mL) was added excess HCl(g). The mixture became homogeneous and was stirred at 23 °C. After 12 h, the solution was concentrated, and chromatographed on silica gel, eluting with CHCl3/MeOH (1/0, then 40/1, 20/1 and 10/1) to give fractions containing 5- { 2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl } - benzof l,3]dioxole-2,2-dicarboxylic acid bis-(2-methoxy-ethyl) ester (Rf=0.37 (10/1 CHCl3/MeOH)) as a viscous oil. This oil was dissolved in Et2θ (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[l,3]dioxole-2,2-dicarboxylic acid bis-(2-methoxy-ethyl) ester hydrochloride salt as a white solid; JH NMR (300 MHz, CDC13): δ 1.33 (brm, 3H), 2.75-2.88 (brm, IH), 3.10-3.30 (brm, 2H), 3.35 (s, 6H), 3.40-3.53 (brm 2H), 3.63-3.68 (complexm, 4H), 4.40-4.48 (brm, 4H), 5.40-5.50 (brd, IH), 5.50-5.75 (brs, IH), 6.70-6.91 (complex m, 4H), 7.18-7.38 (m, 2H), 7.43 (s, IH), 8.60-8.85 (brs, IH), 9.90-10.15 (brs, IH); MS (ES) m/z (relative intensity): 538 (M+-HC1, 100).
EXAMPLE 2
5-{2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}- benzo[l,3]dioxole-2,2-dicarboxylic acid diphenethyl ester hydrochloride salt
The title compound was prepared from 5-{2-f2-(3-chloro-phenyl)-2-hydroxy- ethylamino]-propyl) -benzof l,3]dioxole-2,2-dicarboxylic acid and 2-phenylethanol accord-ing to the procedure of Example 1 as a colorless oil; *H NMR (300 MHz, CDCI3): d 1.30-1.45 (brs, 3H), 2.80-2.90 (brm, IH), 2.89 (t, J = 6.9 Hz, 4H), 3.10- 3.30 (brm, 2H), 3.39-3.69 (brm, H), 4.40 (t, J = 6.8 Hz, 4H), 5.45-5.61 (brs, 2 H), 6.70-6.91 (brm, 3 H), 7.10-7.35 (complex m, 13H), 7.40-7.51 (brs, IH), 8.60-8.85 (brs, IH), 9.91 -10.20 (brs, IH); MS (ES) m/z (relative intensity): 630 (M+-HC1, 40), 144 (100). EXAMPLE 3
5-{2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}- benzo[l,3]dioxo!e-2,2-dicarboxylic acid bis-(2-butoxy-ethyl) ester hydrochloride salt
The title compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy- ethylamino]-propyl}-benzo[l,3]dioxole-2,2-dicarboxylic acid and 2-butoxyethanol accord-ing to the procedure of Example 1 as a colorless oil; 'H NMR (300 MHz, CDCI3): δ 0.78-0.93 (m, 6H), 1.15-1.78 (m, 12H), 2.70-3.62 (brm, 5H), 3.31-3.47 (m, 4H), 3.57-3.73 (m, 4H), 4.29-4.53 (m, 4H), 5.47-5.57 (brs, IH), 6.70-6.95 (m, 3H), 7.20-7.49 (m, 4H); MS (ES) m/z (relative intensity): 622 (M+-HC1, 20), 214 (10), 158 (10).
EXAMPLE 4 5-{2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}- benzo[l,3]dioxole-2,2-dicarboxy!ic acid bis-(2-phenoxy-ethyl) ester hydrochloride salt
The title compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy- ethylamino]-propyl}-benzo[l,3]dioxole-2,2-dicarboxylic acid and 2-phenoxyethanol according to the procedure of Example 1 as an off-white gummy solid; }H NMR (300 MHz, CDCI3): δ 1.23-1.40 (brs, 3H), 2.70-2.90 (brm, IH), 3.05-3.30 (brm, 2H), 3.31-3.52 (brm, 2H), 4.12 (t, J = 4.4 Hz, 4 H), 4.57 (t, J = 4.8 Hz, 4 H), 5.38-5.60 (brs, 2H), 6.70-7.0 (complexm, 10H), 7.15-7.47 (complex m, 7 H), 8.60-8.80 (brs, IH), 9.90-10.20 (brs, 1 H).; MS (ES) m/z (relative intensity): 662 (M+-HC1, (100), 594 (20), 498 (35).
EXAMPLE 5 5-{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-{2-[2-(3-chloro-phenyl)-2-hydroxy- ethylamino]-propyl) -benzof 1 ,3]dioxole-2,2-dicarboxylic acid and 2-ethoxyethanol according to the procedure of Example 1 as an oily off-white gummy solid; *H NMR (300 MHz, CDCI3): δ 1.10-1.20 (t overlaps with d, J = 6.9 Hz, 9H), 1.31-1.41 (brm, 2 H), 2.75-2.90 (brm, IH), 3.10-3.30 (brm, 2H), 3.50 (brq, J = 6.9 Hz, 4H), 3.62- 3.71 (brm, 4H), 4.37-4.47 (brm, 4H), 5.30-5.70 (brm, 2H), 6.70-6.90 (brm, 4H), 7.19-7.50 (brm, 3H), 8.50-8.85 (brs, IH), 9.90-10.30 (brs, IH); MS (ES) m/z (relative intensity): 566 (M+-HC1, (60).
EXAMPLE 6 and EXAMPLE 7 5-{2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}- benzo[l,3]dioxole-2,2-dicarboxylic acid bis-(2-tert-butoxy-ethyl) ester and
5-{2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}- benzo[l,3]dioxole-2,2-dicarboxylic acid (2-tert-butoxy-ethyl) ester
To a stirred mixture of 5- {2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]- propyl } -benzof l,3]dioxole-2,2-dicarboxylic acid (1.0 g, 2.37 mmol), and 2-r-butoxy-
1-ethanol (10 mL) was added /Moluenesulfonic acid (451 mg, 2.37 mmol). The mixture became homogeneous and was stirred at 23 °C. After 12 h, an additional portion of /Moluenesulfonic acid (351 mg, 1.84 mmol) was added. After a total of 90 h, the solution was concentrated, and chromatographed on silica gel, eluting with CHC13/MeOH (1/0, then 40/1, 20/1 and 10/1) to give 100 mg (7 %) of 5-{2-[2-(3- chloro-phenyl)-2-hydroxy-ethylamino]-propyl} -benzof l,3]dioxole-2,2-dicarboxylic acid bis-(2-tert-butoxy-ethyl) ester (Rf=0.25 (10/1 CHCl3/MeOH)) as a yellow oil and
320 mg (26 %) of 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}- benzof l,3]dioxole-2,2-dicarboxylic acid (2-tert-butoxy-ethyl) ester (Rf=0.09 (10/1 CHCb/MeOH)) as an off-white solid.
5- {2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl} -benzof l,31dioxole- 2,2-dicarboxylic acid bis-(2-tert-butoxy-ethyl) ester; ]H NMR (300 MHz, CDCI3): δ 1.15 (d, 3H), 1.68 (s, 18 H), 1.85-2.40 (brm, 2H), 2.50-2.75 (m, 2H), 2.81-2.96 (m, IH), 3,41-3.51 (m, 4H), 3.56-3.64 (m, 2H), 3.65-3.76 (m, 4H), 4.30-4.41 (m, 2H), 6.61 -6.87 (m, 4H), 7.15-7.33 (m, 2H), 7.44 (s, IH); MS (ES) m/z (relative intensity): 622 (M+, 90), 522 (M+-r-BuOCH2CH3, 60), 352 (40), 266 (100). 5- { 2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl } -benzof 1 ,3]dioxole- 2,2-dicarboxylic acid (2-tert-butoxy-ethyl) ester; *H NMR (300 MHz, CDCI3): δ 1.10 (brm, 12H), 2.25-2.70 (brm, 2H), 3.00-3.30 (brm, 5H), 3.51-3.61 (m, 2H), 4.25- 4.47 (m, 2H), 5.20-5.35 (brm, IH), 6.50-6.70 (brm, 4H), 7.15-7.44 (m, 3H), 8.70- 9.70 (brs, IH). MS (ES) m/z (relative intensity): 522 (M+, 100).
EXAMPLE 8
5-{2-{ 2- (3-Ch!oro-phenyl)-2-hydroxy-ethylamino]- propyl }- benzo[l,3]dioxole-2,2-dicarboxy!ic acid bis-(2-isobutoxy-ethyl) ester
The title compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy- ethylamino]-propyl} -benzof l,3]dioxole-2,2-dicarboxylic acid and 2-isobutoxyethanol according to the procedure of Example 1 as a colorless oil; *H NMR (300 MHz, CDCI3): δ 0.70-0.95 (m, 12H), 1.10-2.0 (complexm, 1 1H), 3.09-3.29 (m, 4H), 3.51- 3.58 (m, IH), 3.60-3.72 (m, 4H), 4.31-4.48 (m, 2H), 6.70-7.00 (m, 4H), 7.15-7.50 (m, 4H); MS (ES) m/z (relative intensity): 622 (M+-HC1, 100).
EXAMPLE 9
5-{2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]- propyl} - benzo[l,3]dioxole-2,2-dicarboxylic acid bis-(benzyl) ester hydrochloride salt
The title compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy- ethylamino]-propyl} -benzof l,3]dioxole-2,2-dicarboxylic acid and benzyl alcohol according to the procedure of Example 1 as a gummy white solid: Η NMR (300 MHz, CDCI3): δ 1.26-1.32 (m, 3H), 2.76 (brt, IH), 3.01-3.21 (brm, 2H), 3.36-3.49 (brm, 2H), 5.24 (s, 4H), 5.41 (d, J=9.5 Hz, IH), 6.70-6.88 (m, 3H), 7.12-7.44 (complex m, 14H), 8.70-8.83 (brs, IH), 9.95-10.10 (brs, IH); MS (ES) m/z (relative intensity): 602 (M+, 100). EXAMPLE 10
5-{2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyI}- benzo[l,3]dioxole-2,2-dicarboxylic acid bis-(cyclohexyl) ester hydrochloride salt
The title compound was prepared from 5-{2-f2-(3-chloro-phenyl)-2-hydroxy- ethylamino]-propyl}-benzofl,3]dioxole-2,2-dicarboxylic acid and cyclohexanol according to the procedure of Example 1 as a yellow gum: lH NMR (300 MHz, CDCI3): δ 1.10-1.40 (complex m, 7H), 1.45-1.60 (brm, 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 (m, 2H), 4.90-5.03 (m, 2H), 5.37-5.52 (brs, IH), 6.71-6.90 (complex m, 4H), 7.20-7.32 (m, 2H), 7.44 (s, IH), 8.55-8.80 (brs, IH), 9.90-10.20 (brs, IH); MS (ES) m/z (relative intensity): 585 (M+- HCI), 532 (10).
EXAMPLE 11
5-{2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}- benzo[l,3]dioxole-2,2-dicarboxylic acid bis-(cyclopentyl) ester
The title compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy- ethylamino] -propyl} -benzof 1 ,3]dioxole-2,2-dicarboxy lie acid and cyclopentanol as a yellow gum according to the procedure of Example 1, leaving out the final HCl(g)/Et2θ hydrochloride salt forming step: ]H NMR (300 MHz, CDCI3): δ 1.07 (d, J=6.2 Hz, 3H), 1.50-2.00 (complex m, 16H), 2.52-2.70 (complex m, 3H), 2.85-2.95 (m, 2 H), 4.55-4.65 (m, IH), 5.29-5.38 (m, 2H), 6.65-6.72 (m, IH), 6.76 (s, IH), 6.84 (d, J=8.0 Hz, IH), 7.18-7.30 (m, 3H), 7.37 (s, IH); MS (ES) m/z (relative intensity): 558 (M+, 100), 518 (10), 490 (20).
EXAMPLE 12
5-{2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}- benzof l,3]dioxole-2,2-dicarboxyIic acid dioctyl ester
The title compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy- ethylamino] -propyl) -benzof 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)/Et2θ hydrochloride salt forming step: *H NMR (300 MHz, CDCI3): δ 0.78- 0.90 (m, 6H), 0.95-1.40 (brm, 23H), 1.52-1.87 (m, 6H), 2.55-2.75 (brs, IH), 2.89- 3.30 (brm, 4H), 4.12-4.33 (m, 4H), 5.15-5.35 (brs, IH), 6.60-6.81 (m, 3H), 7.12- 7.45 (m, 4H); MS (EI) m/z (relative intensity): 645 (M+, 5), 504 (100), 348 (100), 319 (100), 180 (100).
EXAMPLE 13
5-{2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}- benzo[l,3]dioxole-2,2-dicarboxylic acid dipentyl ester
The title compound was prepared from 5-{2-f2-(3-chloro-phenyl)-2-hydroxy- ethylamino]-propyl}-benzof l,3]dioxole-2,2-dicarboxylic acid and 1-pentanol as a brown gum according to the procedure of Example 1, leaving out the final HCl(g)/Et2θ hydrochloride salt forming step: lU NMR (300 MHz, CDCI3): δ 0.90 (t, J=6.9 Hz, 3H), 1.21 -1.41 (brm, 10H), 1.67 (t, J=7.0 Hz, 4H), 1.80-2.10 (brs, IH), 2.80 (t, J=6.5 Hz, IH), 3.05-3.19 (brm, 2H), 3.45 (d, J=10.4 Hz, 2H), 4.28 (t, J = 6.7 Hz, 4H), 5.46 (d, J=9.6 Hz, IH), 5.50-5.90 (brs, IH), 6.71-6.90 (m, 3H), 7.20-7.35 (m, 3H), 7.43 (s, IH), 8.76 (brs, IH), 1.05 (brs, IH); MS (ES) m/z (relative intensity): 562 (M+, 100).
EXAMPLE 14 5-{2-f 2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}- benzo[l,3]dioxole-2,2-dicarboxylic acid dihexyl ester
The title compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy- ethylamino]-propyl) -benzof 1 ,3]dioxole-2,2-dicarboxylic acid and 1-hexanol as a white solid according to the procedure of Example 1, leaving out the final HCl(gyΕt2θ hydrochloride salt forming step: *H NMR (300 MHz, CDCI3): δ 0.75-0.90 (m, 6H), 1.00-1.41 (brm, 15H), 1.47-1.85 (m, 6H), 2.60-3.50 (brm, 5H), 4.15-4.30 (m, 4H), 5.18-5.35 (brs, IH), 6.67-6.82 (m, 3H), 7.15-7.45 (m, 4H); MS (ES) m/z (relative intensity): EXAMPLE 15
Carbonic acid 3-chloro-benzyl ester 2-(3-chloro- benzyloxycarbonyloxy)-4-{2-[2-(3-chloro-phenyl)-2-hydroxy- ethylamino]-propyl}-phenyl ester
The title compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy- ethylamino] -propyl) -benzof l,3]dioxole-2,2-dicarboxy lie acid and 3-chlorobenzyl alcohol as a tan solid according to the procedure of Example 1, leaving out the final HCl(g)/Et2θ hydrochloride salt forming step: JH NMR (300 MHz, CDCI3): δ 1.28 (d, J=6.3 Hz, 3H), 1.80-2.40 (brs, IH), 2.79 (t, J=8.8 Hz, IH), 3.05-3.17 (brm, 2H), 3.37-3.49 (m, 2H), 5.23 (s, 4H), 5.43 (m, IH), 6.72-6.88 (m, 3H), 7.10-7.44 (complexm, 12H), 8.76 (brs, IH), 10.02 (brs, IH); MS (ES) m/z (relative intensity): 670 (M+, 100)
EXAMPLE 16
5-{2-[2-(3-ChIoro-phenyl)-2-hydroxy-ethylamino]-propyl}- benzo[l,3]dioxole-2,2-dicarboxylic acid bis-(l-phenyl-ethyl) ester
The title compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy- ethylamino] -propyl) -benzof 1 ,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 HCl(gyΕt2θ hydrochloride salt forming step: ]H NMR (300 MHz, CDCI3): δ 0.90- 1.22 (m, 6H), 1.30-1.61 (m, 6H), 2.39-2.70 (brm, IH), 2.83-3.19 (brm, 2H), 3.20- 3.50 (brm, 2H), 5.15-5.35 (brs, IH), 5.90-6.02 (brm, IH), 6.45-6.82 (m, 3H), 7.11- 7.40 (m, 4H), 8.64 (brs, IH), 9.45 (brs, IH); MS (ES) m/z (relative intensity): 630 (M+, 100).
EXAMPLE 17 5-{2-[2-(3-Chloro-phenyI)-2-hydroxy-ethylamino]-propyl}- benzo[l,3]dioxole-2,2-dicarboxylic acid diheptyl ester
The title compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy- ethylamino]-propyl)-benzo[l,3]dioxole-2,2-dicarboxylic acid and 1-heptanol as a brown gum according to the procedure of Example 1, leaving out the final HCl(g)/Et2θ hydrochloride salt forming step: *H NMR (300 MHz, CDCI3): δ 0.80-0.92 (m, 6H), 1.23-1.40 (brm, 19H), 1.60-1.75 (m, 4H), 2.80 (t, J=8.8 Hz, IH), 3.05-3.30 (brm, 2H), 3.38-3.50 (m, 2H), 4.27 (q, J=6.7 Hz, 4H), 5.43 (d, J=8.4 Hz, IH), 6.72-6.90 (m, 4H), 7.20-7.33 (m, 2H), 7.44 (s, IH), 8.70 (brs, IH), 10.10 (brs, IH); MS (ES) m/z (relative intensity): 618 (M+, 100).
EXAMPLE 18
5-{2-f2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}- benzo[l,3]dioxo!e-2,2-dicarboxyIic acid dinonyl ester
The title compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy- ethylamino] -propyl) -benzof 1 ,3]dioxole-2,2-dicarboxylic acid and 1-nonanol as a brown gum according to the procedure of Example 1, leaving out the final HCl(g)/Et2θ hydrochloride salt forming step: *H NMR (300 MHz, CDC13): δ 0.88 (t, J=6.8 Hz, 9H), 1.25-1.40 (m, 22H), 1.54-1.60 (m, 2H), 1.63-1.74 (m, 4H), 2.79 (brt, J = 8.8 Hz, IH), 3.08-3.30 (m, 2H), 3.40-3.55 (m, 2H), 4.28 (t, J=6.8 Hz, 4H), 5.46 (d, J=8.7 Hz, IH), 6.70-6.90 (m, 3H), 7.15-7.35 (m, 3H), 7.43 (s, IH), 8.72 (brs, IH), 9.98 (brs, IH); MS (ES) m/z (relative intensity): 674 (M+, 100), 548 (M+-C9H20, 5).
EXAMPLE 19 5-{2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyI}- benzo[l,3]dioxole-2,2-dicarboxylic acid bis-decyl ester
The title compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy- ethylamino]-propyl)-benzo[l,3]dioxole-2,2-dicarboxylic acid and and 1-decanol as a brown gum according to the procedure of Example 1, leaving out the final HCl(g)/Et2θ hydrochloride salt forming step: lH NMR (300 MHz, CDCI3): δ 0.88 (t, J=6.8 Hz, 9H), 1.15-1.40 (m, 24H), 1.52-1.60 (m, 4H), 1.62-1.74 (m, 4H), 2.80 (brt, J = 8.8 Hz, IH), 3.08-3.28 (m, 2H), 3.35-3.52 (m, 2H), 4.28 (t, J=6.7 Hz, 4H), 5.45 (d, J=8.8 Hz, IH), 6.70-6.90 (m, 3H), 7.18-7.35 (m, 3H), 7.43 (s, IH), 8.71 (brs, IH), 10.02 (brs, IH); MS (ES) m/z (relative intensity): 702 (M+, 100). EXAMPLE 20
5-{2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}- benzo[l,3]dioxole-2,2-dicarboxylic acid didodecyl ester
The title compound was prepared from 5-{2-f2-(3-chloro-phenyl)-2-hydroxy- ethylamino]-propyl) -benzof l,3]dioxole- 2,2-dicarboxylic acid and 1-dodecanol as a brown gum according to the procedure of Example 1, leaving out the final HCl(g)/Et2θ hydrochloride salt forming step: 'H NMR (300 MHz, CDCI3): δ 0.88 (t, J=6.8 Hz, 9H), 1.20-1.40 (m, 30H), 1.51-1.60 (m, 4H), 1.62-1.73 (m, 4H), 2.75-2.85 (m, IH), 3.05-3.25 (m, 2H), 3.35-3.52 (m, 2H), 4.28 (t, J=6.8 Hz, 4H), 5.45 (d, J=8.8 Hz, IH), 6.60-6.90 (m, 3H), 7.17-7.40 (m, 3H), 7.43 (s, IH), 8.78 (brs, IH), 10.05 (brs, IH); MS (ES) m/z (relative intensity): 594 (M+, 100).
EXAMPLE 21 5-{2-[2-(3-Chloro-phenyl)-2-hydroxy-ethyIamino]-propyl}- benzofl,3]dioxole-2,2-dicarboxylic acid bis-(2-isopropoxy-ethyl) ester
The title compound was prepared from 5-{2-f2-(3-chloro-phenyl)-2-hydroxy- ethylamino]-propyl } -benzof 1 ,3]dioxole-2,2-dicarboxy lie acid and 2-isopropoxyethanol as a brown solid according to the procedure of Example 1, leaving out the final HCl(g)/Et2θ hydrochloride salt forming step: ]H NMR (300 MHz, CDCI3): δ 1.11 (d, J=6.1 Hz, 12H), 1.30 (d, J=6.2 Hz, 3H), 2.79 (t, J=8.7 Hz, IH), 3.06-3.28 (m, 2H), 3.40-3.60 (m, 2H), 3.62-3.70 (complexm, 4H), 3.90-4.12 (brm, 2H), 4.35- 4.45 (complexm, 4H), 5.43 (d, J = 8.7 Hz, IH), 6.61-6.90 (m, 3H), 7.11-7.32 (m, 3H), 7.44 (m, IH), 8.70 (brs, IH), 9.92 (brs, IH); MS (ES) m/z (relative intensity): 758 (M+, 30), 546 (100).
EXAMPLE 22 5-{2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}- benzo[l,3]dioxole-2,2-dicarboxylic acid isopropyl ester
To a stirred solution of 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]- propyl)-benzo[l,3]dioxole-2,2-dicarboxylic acid bis-isopropyl ester hydrochloride salt
(3.0 g, 5.53 mmol) and 20 mL of /-PrOH was added was added IN NaOH (11.1 mL, 11.1 mmol). After stirring at 23 °C for 3 days, the mixture was concentrated to dryness, dissolved in 10 % MeOH/CH2Cl2, and filtered through a small pad of silica gel. The filtrate was concentrated to a colorless gum, and triturated with Et2θ to give 1.0 g (39 %) of 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}- benzo[l,3]dioxole-2,2-dicarboxylic acid isopropyl ester as a white solid; *H NMR (300 MHz, CDC13): δ 0.93 (d, J=6.1 Hz, 3H), 1.17 (d, J=6.3 Hz, 6H), 2.30-2.53 (m, 2H), 2.67-2.80 (m, 2H), 2.85-3.00 (m, IH), 4.65-4.75 (brs, IH), 4.91 (hept, J=6.3 Hz, IH), 6.52-6.80 (complexm, 3H), 7.17-7.45 (complexm, 4H); MS (ES) m/z (relative intensity): 464 (M+, 100).
EXAMPLE 23
5-{2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}- benzo[l,3]dioxole-2,2-dicarboxylic acid ethyl ester
The title compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy- ethylamino]-propyl)-benzo[l,3]dioxole-2,2-dicarboxylic acid bis-ethyl ester hydrochloride according to the procedure of Example 22 as a brown solid: *H NMR (300 MHz, CDCI3): δ 1.20 (d, J=6.7 Hz, 3H)1 1.33 (t, J=7.1 Hz, 3H), 2.70 (m, IH), 2.90-3.22 (m, 4H), 3.23-3.48 (m, IH), 4.34 (q, J=7.1 Hz, 2H), 5.30 (m, IH), 6.55- 6.90 (m, 3H), 7.10-7.45 (m, 4H); MS (ES) m/z (relative intensity): 450 (M++1, 50 ).
EXAMPLE 24
5-{2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}- benzo[l,3]diυxole-2,2-dicarboxylic acid bis-methoxycarbonylmethyl ester
Step 1 5-(2-{tert-ButoxycarbonyI- [2- (3-chloro- phenyl )-2-hydroxy-ethyl]- amino}-propyl)-benzo[l,3]dioxole-2,2-dicarboxylic acid bis-ethyl ester
To a stirred solution of 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]- propyl) -benzof l,3]dioxole-2,2-dicarboxylic acid diethyl ester hydrochloride salt (5.0 g, 9.72 mmol), and THF (90 mL) was added /-Pr2NEt (4.23 mL, 3.14 g, 24.3 mmol) and (Boc)2θ (2.12 g, 9.72 mmol). After 6 h, an additional portion of (Boc^O (200 mg, 0.92 mmol) is added. After a total of 22 h, the solution was quenched with 10 mL of sat. aq. NaHCO3, and extracted with 3 x 100 mL Et2θ. The combined organics were washed with 1 x 150 mL of brine, dried over MgSO4, 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; !H NMR (300 MHz, CDC13): δ 1.22 (d, J = 6.9 Hz, 3H), 1.30-1.47 (m, 15H), 2.47-2.54(m, IH), 2.57- 2.70 (m, IH), 3.05-3.15 (m, IH), 3.46-3.68 (m, IH), 4.08-4.18 (m, IH), 4.29-4.42 (m, 4H), 4.75 (brd, J = 8.6 Hz, IH), 5.51 (brs, IH), 6.55-6.88 (complexm, 4H), 7.20-7.44 (m, 3H); MS (ES) m/z (relative intensity): 578 (M+, 1), 504 (20), 336 (60), 298 (20), 198 (100), 180 (40).
Step 2
5-(2-{tert-Butoxycarbonyl-[2-(3-chloro-phenyl)-2-hydroxy-ethyl]- amino)-propyl)-benzo[l ,3]dioxole-2,2-dicarboxylic acid
To a stirred solution of 5-(2-{tert-butoxycarbonyl-[2-(3-chloro-phenyl)-2- hydroxy-ethyl]-amino)-propyl)-benzo[l,3]dioxole-2,2-dicarboxylic acid bis-ethyl ester
(4.42 g , 7.65 mmol), MeOH (100 mL) and H2O (25 mL) was added 5 N NaOH (7.64 mL, 38.2 mmol). After 19 h, the solution was concentrated to an aqueous mixture and acidified to pH = 1 with 1 N aq. HCI 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 Na2SO4, filtration and concentration gave 3.96 g (99 %) of product as a white solid; *H NMR (300 MHz, DMSO-dό): δ 1.16 (d, J = 6.7 Hz, 3H), 1.31 (s,
9H), 2.55-2.70 (m, IH), 2.80-2.92 (m, IH), 3.05-3.23 (m, 2H), 3.71-3.93 (m, 2H),
4.62-4.87 (m, 2H), 5.30-5.90 (brs, IH), 6.59-6.99 (complexm, 4H), 7.14-7.47
(complexm, 3H), 8.60-8.80 (brs, IH); MS (ES) m/z (relative intensity): 522. (M++ H, 50).
Step 3 5-(2-{tert-Butoxycarbonyl-[2-(3-chloro-phenyl)-2-hydroxy-ethyl]- amino}-propyl)-benzofl,3]dioxole-2,2-dicarboxylic acid bis- methoxycarbonyl-methyl ester
To a stirred solution of 5-(2- {tert-butoxycarbonyl-[2-(3-chloro-phenyl)-2- hydroxy-ethyl]-amino)-propyl)-benzof l,3]dioxole-2,2-dicarboxylic acid (500 mg,
0.96 mmol) and DMF (10 mL) was added K2CO3 (132 mg, 0.96 mmol) and methyl-2- bromoacetate (0.23 mL, 366 mg, 2.40 mmol). After stirring at 50 °C for 4 h, the reaction mixture was cooled to 23 °C, quenched with 5 mL sat. aq. NaHCO3, and extracted with 3 x 30 mL of EtOAc. The combined organics were washed with 2 x 50 mL brine, dried over MgSO4, filtered and concentrated to a yellow oil. Flash chromatography on silica gel, eluting with hexane/EtOAc (4/1 to 2/1), gave 508 mg (79 %) of product as a colorless oil; »H NMR (300 MHz, CDC13): δ 1.22 (d, J = 6.9 Hz, 3 H), 1.41 (brs, 9H), 2.50-2.60 (brm, IH), 2.60-2.75 (brm, IH), 3.06-3.15 (brm, IH), 3.45-3.60 (brm, IH), 3.76 (s, 3H), 3.77 (s, 3H), 4.05-4.20 (brm, IH), 4.70- 4.79 (brm, IH), 4.79(s, 2H), 4.80(s, 2H), 5.42-5.51 (brs, IH), 6.60-6.91 (complexm, 4H), 7.20-7.43(complexm, 3H); MS (ES) m/z (relative intensity): 666 (M+, (100), 610 (25).
Step 4 5-{2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[l,3]- dioxole-2,2-dicarboxylic acid bis-methoxycarbonylmethyl ester
To a stirred solution of 5-(2-{tert-butoxycarbonyl-[2-(3-chloro-phenyl)-2- hydroxy-ethy l]-amino } -propyl)-benzof 1 ,3]dioxole-2,2-dicarboxylic acid bis- methoxycarbonyl-methyl ester (330 mg, 0.50 mmol) and CH2CI2 (10 mL) was added trifluoroacetic acid (0.08 mL, 113 mg, 0.99 mmol). After stirring at 23 °C for 1 h, additional trifluoroacetic acid (0.08 mL, 113 mg, 0.99 mmol) was added. After a total of 22 h, the mixture was quenched with 5 mL of sat. aq. NaHCO3, and extracted with 3 x 30 mL of EtOAc. The combined organics were washed with 1 x 50 mL of brine, dried over MgSO4, filtered and concentrated to a yellow oil. Flash chromatography on silica gel, eluting with CHCl3/MeOH (20/1 to 10/1) gave 145 mg (52 %) of product as a white gum; Η NMR (300 MHz, CDCI3): δ 1.33 (m, 3H), 1.70-2.40 (brm, 2H), 2.73-2.90 (brt, IH), 3.04-3.30 (m, 2H), 3.37-3.53 (m, 2H), 3.75 (s, 3H), 3.76 (s, 3H), 4.80 (s, 2H), 4.81 (s, 2H), 5.40 (m, IH), 6.73-6.93 (complexm, 4H), 7.15- 7.32 (m, 2H0, 7.43 (s, IH); MS (ES) m/z (relative intensity): 566 (M+, 80), 508 (M+ - CO2CH3+H, 100), 450 (M+ - 2CO2CH3+2H, 30). EXAMPLE 25
5-{2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}- benzo[l,3]dioxole-2,2-dicarboxylic acid bis-propoxycarbonylmethyl ester
Step 1 5-(2-{tert-ButoxycarbonyI-[2-(3-chloro-phenyl)-2-hydroxy-ethyl]- amino}-propyl)-benzo[l,3]dioxo!e-2,2-dicarboxylic acid bis- propoxycarbonylmethyl ester
The title compound was prepared from 5-(2-{tert-butoxycarbonyl-[2-(3-chloro- phenyl)-2-hydroxy-ethylJ-amino)-propyl)-benzo[l,3]dioxole-2,2-dicarboxylic acid and propyl 2-bromoacetate according to the procedure of Example 24, step 3 as a colorless oil: ]H NMR (300 MHz, CDCI3): δ θ.91 (t, J=7.4 Hz, 6H), 1.21 (d, J=6.9 Hz, 3H), 1.40 (s, 9H), 1.55-1.72 (m, 4H), 2.47-2.70 (m, IH), 3.05-3.17 (m, IH), 3.46-3.60 (m, IH), 4.11 (t, J=6.6 Hz, 4H), 4.70-4.85 (m, 4H), 5.47 (s, IH), 6.60-6.92 (m, 3H), 7.20-7.35 (m, 3H), 7.41 (s, IH); MS (ES) m/z (relative intensity): 722 (M+, 100).
Step 2
5-{2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzoll,3]- dioxole-2,2-dicarboxy!ic acid bis-propoxycarbonylmethyl ester
The title compound was prepared from 5-(2-{tert-butoxycarbonyl-[2-(3-chloro- phenyl)-2-hydroxy-ethyl]-amino) -propyl)-benzo[l ,3]dioxole-2,2-dicarboxylic acid bis-propoxyoxycarbonylmethyl ester according to the procedure of Example 24, step 4 as a brown gum: *H NMR (300 MHz, CDCI3): δ 0.80-0.95 (m, 9H),1.40- 1.80 brm, 6H), 2.80-3.74 (brm, 7H), 4.05-4.20 (m, 4H), 4.70-4.85 (m, 2H), 5.10 (brs, IH), 6.70-6.95 (brm, 3H), 7.15-7.40 (brm, 4H); MS (ES) m/z (relative intensity): 622 (M+, 100). EXAMPLE 26
5-{2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}- benzo[l,3]dioxole-2,2-dicarboxylic acid bis-(l-methoxycarbonyl-ethyl) ester Step 1
5-(2-{tert-ButoxycarbonyI-[2-(3-chloro-phenyl)-2-hydroxy-ethyl]- amino}-propyl)-benzof l,3]dioxole-2,2-dicarboxylic acid bis-(l- methoxycarbonyl-ethyl)ester
The title compound was prepared from 5-(2-{tert-butoxycarbonyl-[2-(3-chloro- phenyl)-2-hydroxy-ethyl]-amino)-propyl)-benzo[l,3]dioxole-2,2-dicarboxylic acid and methyl 1 -bromopropionate according to the procedure of Example 24, step 3 as a colorless oil : lH NMR (300 MHz, CDCI3): δ 1.22 (d, J=6.9 Hz, 3H), 1.38 (s, 9H), 2.50-2.70 (m, 2H), 2.89 (s, 3H), 2.96 (s, 3H), 3.07-3.15 (m, IH), 3.45-3.60 (m, IH), 3.70-3.83 (m, 8H), 4.05-4.18 (m, IH), 4.72-4.80 (m, IH), 5.22-5.32 (m, IH), 6.60-6.90 (m, 3H), 7.20-7.32 (m, 3H), 7.41 (s, IH); MS (ES) m/z (relative intensity): 694 (M+, 100), 638 (M+-r-Bu, 20), 594 (M+-Boc, 20).
Step 2 5-{2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}- benzofl ,3]dioxole-2,2-dicarboxylic acid bis-(l-methoxycarbonyl- ethyl)ester
The title compound was prepared from 5-(2-{tert-butoxycarbonyl-[2-(3-chloro- phenyl)-2-hydroxy-ethyl]-amino ) -propyl)-benzo[ 1 ,3]dioxole-2,2-dicarboxylic acid bis-methoxycarbonyl- 1 -ethyl ester according to the procedure of Example 24, step 4 as a colorless gum: *H NMR (300 MHz, CDCI3): δ 1.28 (d, J=6.7 Hz, 3H), 1.30-2.00 (brm, 2H), 1.55-1.65 (m, 6H), 2.70-2.80 (m, IH), 3.05-3.30 (m, 2H), 3.35-3.69 (m, 2H), 3.68-3.80 (m, 6H), 5.10-5.18 (m, IH), 5.22-5.31 (m, 2H), 6.70-6.95 (m, 3H), 7.15-7.30 (m, 3H), 7.36 (s, IH); MS (ES) m/z (relative intensity): 594 (M+, 100). EXAMPLE 27
5-{2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}- benzo[l,3]dioxole-2,2-dicarboxylic acid bis-isopropoxycarbonylmethyl ester
Step 1 5-(2-{tert-Butoxycarbonyl-[2-(3-chloro-phenyl)-2-hydroxy-ethyl]- amino}-propyl)-benzofl,3]dioxole-2,2-dicarboxylic acid bis- isopropoxycarbonyl-methyl ester The title compound was prepared from 5-(2-{tert-butoχycarbonyl-[2-(3-chloro- phenyl)-2-hydroxy-ethyl]-amino)-propyl)-benzofl,3]dioxole-2,2-dicarboxylic acid and isopropyl 2-bromoacetate according to the procedure of Example 24, step 3 as a colorless oil: JH NMR (300 MHz, CDCI3): δ 1.15-1.30 (m, 15H), 1.40 (s, 9H), 2.45- 2.70 (m, 2H), 3.06-3.15 (m, IH), 3.45-3.60 (m, IH), 4.05-4.18 (m, 2H), 4.70-4.80 (m, 4H), 5.06 (sept, J=6.3 Hz, 2H), 5.46 (brs, IH), 6.60-6.90 (m, 3H), 7.20-7.35 (m, 3H), 7.41 (s, IH).; MS (ES) m/z (relative intensity): 722 (M+, 100).
Step 2 5-{2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo [l,3]dioxole-2,2-dicarboxylic acid bis-isopropoxycarbonylmethyl ester
The title compound was prepared from 5-(2-f tert-butoxycarbonyl-f2-(3-chloro- phenyl)-2-hydroxy-ethyl]-amino)-propyl)-benzo[l,3]dioxole-2,2-dicarboxylic acid bis-isopropoxycarbonylmethyl ester according to the procedure of Example 24, step 3 as a brown gum: lH NMR (300 MHz, CDCI3): δ 1.17-1.30 (m, 15H), 2.72-2.82 9m, IH), 3.10-3.29 (m, 3H), 3.38-3.50 (m, IH), 4.70-4.80 (m, 4H), 4.95-5.18 (complexm, 3H), 6.72-6.95 (m, 3H), 7.15-7.30 (m, 3H), 7.36 (s, IH), 8.73 (brs, IH), 9.86 (brs, IH); MS (ES) m/z (relative intensity): 622 (M+, 100). EXAMPLE 28
5-{2-[2-(3-Chloro-phenyl)-2-hydroxy-ethyIamino]-propyl}- benzo[l,3]dioxole-2,2- dicarboxylic acid bis-ethoxycarbonylmethyl ester
Step 1
5-(2-{tert-Butoxycarbonyl-[2-(3-chloro-phenyl)-2-hydroxy-ethyl]- amino}-propyl)-benzo[l,3]dioxole-2,2-dicarboxylic acid bis- ethoxycarbonyl methylester
The title compound was prepared from 5-(2-{ tert-butoxycarbonyl-[2-(3-chloro- phenyl)-2-hydroxy-ethyl]-amino) -propyl)- benzof l,3]dioxole-2,2-dicarboxylic acid and ethyl bromoacetate according to the procedure of Example 24, Step 3 as a colorless oil; lH NMR (300 MHz, CDC13): δ 1.17-1.30 (m, 9H), 1.39 (s, 9H), 2.48-2.54 (brm, IH), 2.55-2.61 (brm, IH), 3.07-3.13 (m, 2H), 3.47-3.55 (brm, IH), 4.05-4.20 (brm, IH), 4.21 (q, J = 7.0 Hz, 4H), 4.20-4.33 (brm, IH), 4.78 (s, 2H), 4.79 (s, 2 H), 5.45-5.50 (brm, 1 H), 6.61 -6.85 (m, 4H), 7.20-7.43 (m, 3H); MS (ES) m/z (relative intensity): 694 (M+ , (100), 638 (15), 594 (15).
Step 2
5-{2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[l,3] dioxole-2,2-dicarboxylic acid bis-ethoxycarbonylmethyl ester
The title compound was prepared from 5-(2-{tert-butoxycarbonyl-[2-(3-chloro- phenyl)-2-hydroxy-ethy l]-amino } -propyl)-benzo[ 1 ,3]dioxole-2,2-dicarboxylic acid bis-ethoxycarbonylmethyl ester according to the procedure of Example 24, Step 4 as a white gum; 'H NMR (300 MHz, CDCI3): δ 1.15-1.27 (m, 3H), 1.31-1.41 (t, J=6.8 Hz, 6H), 2.53-3.51 (m, 6H), 3.60-3.80 (m, 4H), 4.00-4.10 (brs, IH), 4.15-4.30 (q, J=6.7 Hz, 4H), 4.70-4.85 (brm, IH), 6.60-6.95 (m, 3H), 7.10-7.50 (m, 4H); MS (ES) m/z (relative intensity): 594 (M+, 10), 522 (80), 508 (80), 436 (100). EXAMPLE 29
5-{2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}- benzo[l,3]dioxole-2,2-dicarboxyIic acid bis-(l-ethoxycarbonyl-ethyl) ester
Step 1 5-(2-{tert-Butoxycarbonyl-[2-(3-chloro-phenyl)-2-hydroxy-ethyl]- amino}-propyl)-benzof l,3]dioxole-2,2-dicarboxylic acid bis-(l- ethoxycarbonyl-ethyl) ester
The title compound was prepared from 5-(2-{tert-butoxycarbonyl-[2-(3-chloro- phenyl)-2-hydroxy-ethyl]-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; Η NMR (300 MHz, CDCI3): δ 1.15-1.30 (complex m, 9H), 1.40 (brs, 9H), 1.52-1.69 (m, 6H), 2.47-2.58 (m, IH), 2.58-2.70 (m, IH), 3.05-3.16 (m, IH), 3.42-3.54 (m, IH), 4.05-4.30 (complexm, 5H), 4.77 (m, IH), 5.19-5.30 (m, 2H), 5.49 (brs, IH), 6.57-6.67 (m, IH), 6.71-6.80 (m, IH), 6.82-6.91 (m, 2H), 7.20- 7.35 (m, 2H), 7.41 (brs, IH); MS (ES) m/z (relative intensity): 722 (M+, 100).
Step 2
5-{2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyI}- benzofl,3]dioxole-2,2-dicarboxylic acid bis-(l-ethoxycarbonyl-ethyl) ester The title compound was prepared from 5-(2- { tert-butoxycarbonyl-[2-(3-chloro- phenyl)-2-hydroxy-ethyl]-amino) -propyl)-benzo[ 1 ,3]dioxole-2,2-dicarboxylic acid bis-ethoxycarbonyl-1 -ethyl ester according to the procedure of Example 24, Step 4 as a colorless oil; lH NMR (300 MHz, CDCI3): δ very complex due to 4 diastereomers present; MS (ES) m/z (relative intensity): 622 (M+, 40), 522 (M+-CH3CHCO2Et, 100). EXAMPLE 30
5-{2-[2-(3-Chloro-phenyI)-2-hydroxy-ethylamino]-propyl}- benzo[l,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 mmol) with stirring at room temperature. After 0.5 h, 5-{2-[2-(3-chloro- phenyl)-2-hydroxy-ethylamino] -propyl) -benzof 1 ,3]dioxole-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/l :l 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 HCI salt yielded 1.16 g of white foam; 5H NMR (CDC13) δ 0.06 (s, 18 H), 1.33 (d, J = 6.5 Hz, 3 H), 2.80 (m, IH), 3.15 (m, IH), 3.20 (m, 1 H), 3.48 (m, 2 H), 4.014 (s, 2 H), 4.015 (s, 2 H), 5.45 (bd, J = 9.7 Hz, 1 H), 5.60 (bs, 1 H), 6.80 (m, 3 H), 7.25 (m, 2 H), 7.45 (s, 1 H), 8.70 (bs, 1 H), 10.10 (bs, 1 H); IR (KBr): 1763 cnr1 (C=O); MS (ES) m/z 594 (MH+); [α]p5 -23° (c, 1.0, CHCI3). Anal. Calcd. for C28H4θClNO7Si2 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 5-{2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}- benzo[l,3]dioxole-2,2-dicarboxylic acid bis-(2-trimethylsilanyl-ethyl) ester
The title compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy- ethylamino]-propyl) -benzof 1 ,3]dioxole-2,2-dicarboxylic acid and 2- trimethylsilylethanol according to the procedure of Example 30 as a white foam (HCI salt); lH NMR (CDCI3) δ θ.03 (s, 18 H), 1.06 (t, J = 8.6 Hz, 4 H), 1.33 (bs, 3 H), 1.90 (bs, IH), 2.80 (bs, IH), 3.18 (bs, 2H), 3.48 (bs, 2 H), 4.37 (t, J = 8.6 Hz, 4 H), 5.45 (bs, 1 H), 6.80 (m, 3 H), 7.26 (m, 2 H), 7.43 (s, 1 H), 8.70 (bs, 1 H), 10.10 (bs, 1 H); IR (KBr): 1763 cm"1 (C=O); MS (ES) m/z 622 (MH+); [α]£5 -23° (c, 1.0, CHCI3). Anal. Calcd. for C3oH44ClNO7Si2 HCl: C, 54.70; H, 6.88; N, 2.13; Cl, 10.76; Si, 8.53. Found: C, 53.96; H, 7.05; N, 1.86; Cl, 8.84; Si, 10.33.
EXAMPLE 32 5-{2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}- benzo[l,3]dioxole-2,2-dicarboxylic acid bis-(3-trimethylsilanyl-propyl) ester
The title compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy- ethylamino]-propyl) -benzof 1 ,3]dioxole-2,2-dicarboxylic acid and 3- trimethylsilylpropanol according to the procedure of Example 30 as a white foam (HCI salt); !H NMR (CDCI3) δ θ.01 (s, 18 H), 0.46 (m, 4 H), 1.33 (d, J = 6.3 Hz, 3 H), 1.70 (m, 4 H), 2.80 (m, IH), 3.18 (m, 2H), 3.46(m 2 H), 4.24(t, J = 7.0 Hz, 4 H), 5.47 (bd, J = 9.7 Hz, 1 H), 5.70 (bs, 1 H), 6.80 (m, 3 H), 7.25 (m, 2 H), 7.43 (s, 1 H), 8.70 (bs, 1 H), 10.10 (bs, 1 H); IR (KBr): 1765 cm-* (C=O); MS (ES) m/z 650 (MH+); [α]p5 -22° (c, 1.0, CHCI3). Anal. Calcd. for C32H48ClNO7Si2-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-f2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}- benzo[l,3]dioxole-2,2-dicarboxylic acid bis-(3,3-dimethyl-butyl) ester
The title compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy- ethylamino]-propyl)-benzo[l,3]dioxole-2,2-dicarboxylic acid and 3,3-dimethylbutanol according to the procedure of Example 30 as a white foam (HCI salt); *H NMR (CDCI3) δ 0.90 (s, 18 H), 1.33 (bs, 3 H), 1.62 (t, J = 7.4 Hz, 4 H), 2.80 (bs, IH), 3.18 (bs, 2H), 3.48 (bs, 2 H), 4.35 (t, J = 7.4 Hz, 4 H), 5.45 (bs, 1 H), 6.80 (m, 3 H), 7.26 (m, 2 H), 7.43 (s, 1 H), 8.70 (bs, 1 H), 10.10 (bs, 1 H); IR (KBr): 1765 cm-1 (c=0); MS (CI) m/z 590 (MH+); [α]^5 -24° (c, 1.0, CHCI3). Anal. Calcd. for
C32H44ClNO7-HCl: C, 61.34; H, 7.08; N, 2.24; Cl, 1 1.32. Found: C, 60.79; H, 7.46; N, 2.09; Cl, 11.95. EXAMPLE 34
5-{2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyI}- benzo[l,3]dioxole-2,2-dicarboxylic acid bis-cyclohexylmethyl ester
The title compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy- ethylamino] -propyl) -benzof 1 ,3]dioxole-2,2-dicarboxyIic acid and cyclohexylmethanol according to the procedure of Example 30 as a white foam (HCI salt); lH NMR (CDC13) δ 0.80-1.80 (m, 22 H), 1.33 (bs, 3 H), 2.80 (m, IH), 3.18 (m, 2H), 3.48 (m, 2 H), 4.10 (m, 4 H), 5.50 (bs, 1 H), 6.80 (m, 3 H), 7.25 (m, 2 H), 7.43 (s, 1 H), 8.70 (bs, 1 H), 10.10 (bs, 1 H); IR (KBr): 1765 cm-1 (C=0); MS (CI) m/z 614 (MH+); [α]^5 -22° (c, 1.0, CHCI3). Anal. Calcd. for C34H44CINO7 HCI: C, 62.77;
H, 6.82; N, 2.15; Cl, 10.90. Found: C, 61.83; H, 7.27; N, 2.07; Cl, 10.25.
EXAMPLE 35 5-{2-[2-(3-Chloro-phenyl)-2-hydroxy-ethyIamino]-propyl}- benzo[l,3]dioxole-2,2-dicarboxylic acid bis-(4-methyl-pentyl) ester
The title compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy- ethylamino] -propyl) -benzof l,3]dioxole- 2,2-dicarboxylic acid and 4-methylpentanol according to the procedure of Example 30 as a colorless gum (HCI salt); Η NMR (CDCI3) δ 0.87 (d, J = 6.5 Hz, 12 H), 1.33 (bs, 3 H), 1.10-2.0 (m, 10 H), 2.80 (bs, IH), 3.18 (bs, 2H), 3.48 (bs, 2 H), 4.28(m, 4 H), 5.60 (bs, 2 H), 6.80 (m, 3 H), 7.25 (m, 2 H), 7.43 (s, 1 H), 8.70 (bs, 1 H), 10.10 (bs, 1 H); IR (KBr): 1765 cm"1 (C=O); MS (CI) m/z 590 (MH+); [α£5 -24° (c, 1.0, CHCI3). Anal. Calcd. for C32H44CINO7-HCI: C, 61.34; H, 7.08; N, 2.24; Cl, 1 1.32. Found: C, 60.50; H, 7.36; N, 2.13; Cl, 11.66.
EXAMPLE 36 5-{2- [2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyI}- benzo[l,3]dioxole-2,2-dicarboxylic acid bis-(2-cyclohexyl-ethyl ) ester
The title compound was prepared from 5-{2-f2-(3-chloro-phenyl)-2-hydroxy- ethylamino]-propyl}-benzo[l,3]dioxole-2,2-dicarboxylic acid and 2-cyclohexylethanol according to the procedure of Example 30 as an off-white foam (HCI salt); 'H NMR (CDC_3) δ 0.80-1.80 (m, 26 H), 1.32 (d, J = 6.3 Hz, 3 H), 2.80 (m, IH), 3.18 (m, 2H), 3.48 (m, 2 H), 4.32 (t, J = 6.9 Hz, 4 H), 5.45 (bd, J = 9.7 Hz, 1 H), 6.80 (m, 3 H), 7.25 (m, 2 H), 7.45 (s, 1 H), 8.70 (bs, 1 H), 10.0 (bs, 1 H); IR (KBr): 1765 cm-1 (C=O); MS (CI) m/z 642 (MH+); [α]^5 -24° (c, 1.0, CHC13). Anal. Calcd. for C36H48CINO-7 HCI: C, 63.71; H, 7.13; N, 2.06; Cl, 10.45. Found: C, 63.07; H, 7.54; N, 2.07; Cl, 12.81.
EXAMPLE 37 5-{2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}- benzo[l,3]dioxole-2,2-dicarboxylic acid bis-(3-cyclopentyl-propyl ) ester
The title compound was prepared from 5-{2-[2-(3-chloro~phenyl)-2-hydroxy- ethylamino]-propyl) -benzof 1 ,3]dioxole-2,2-dicarboxylic acid and 3- cyclopentylpropanol according to the procedure of Example 30 as a colorless gum (HCI salt); ]H NMR (CDCI3) δ 0.80-1.80 (m, 26 H), 1.33 (d, J = 6.3 Hz, 3 H), 2.80 (m, IH), 3.18 (m, 2H), 3.48 (m, 2 H), 4.28 (t, J = 6.8 Hz, 4 H), 5.45 (bd, J = 9.7 Hz, 1 H), 6.80 (m, 3 H), 7.25 (m, 2 H), 7.45 (s, 1 H), 8.70 (bs, 1 H), 10.10 (bs, 1 H); IR (KBr): 1765 cm-1 (OO); MS (CI) m/z 642 (MH+); [α£5 -21° (c, 1.0, CHCI3). Anal. Calcd. for C36H48C1N07 HC1: 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 5-{2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyI}- benzo[l,3]dioxole-2,2-dicarboxylic acid bis-cyclopropylmethyl ester
The title compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy- ethylamino]-propyl ) -benzof 1 ,3]dioxole-2,2-dicarboxy lie acid and cyclopropylmethanol according to the procedure of Example 30 as a white solid (HCI salt); *H NMR (CDCI3) δ 0.33 (m, 4 H), 0.61 (m, 4 H), 1.21 , (m, 2 H), 1.32 (bs, 3 H), 2.80 (m, IH), 3.19 (m, 2H), 3.48 (m, 2 H), 4.15 (d, J = 7.3 Hz, 4 H), 5.50 (bd, 1 H), 5.70 (bs, 1 H), 6.80 (m, 3 H), 7.25 (m, 2 H), 7.45 (s, 1 H), 8.70 (bs, 1 H), 10.10 (bs, 1 H); IR (KBr): 1757, 1778 cm"1 (C=O); MS (ES) m/z 530 (MH+); [α]" -26° (c, 1.0, CHCI3). Anal. Calcd. for C28H32CINO7HCI: 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 5-{2-[2-(3-ChIoro-phenyl)-2-hydroxy-ethylamino]-propyl}- benzo[l,3]dioxole-2,2-dicarboxylic acid bis-(l-methyl- cyclopropylmethyl) ester
The title compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy- ethylamino]-propyl)-benzo[l,3]dioxole-2,2-dicarboxylic acid and 1- methylcyclopropyl-methanol according to the procedure of Example 30 as a white solid (HCI salt); >H NMR (CDCI3) δ 0.39 (m, 4 H), 0.52 (m, 4 H), 1.10, (s, 6 H), 1.32 (d, J = 6.5 Hz, 3 H), 2.80 (m, IH), 3.19 (m, 2H), 3.48 (m, 2 H), 4.10 (s, 4 H), 5.50 (bd, 1 H), 5.70 (bs, 1 H), 6.80 (m, 3 H), 7.25 (m, 2 H), 7.45 (s, 1 H), 8.70 (bs, 1 H), 10.10 (bs, 1 H); IR (KBr): 1763 cm-1 MS (ES) m/z 558 (MH+); fα]*5 -25°
(c, 1.0, CHCI3). Anal. Calcd. for C30H36CINO-7 HCI: 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 40 5-{2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}- benzo[l,3]dioxole-2,2-dicarboxylic acid bis-cyclobutylmethyl ester
The title compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy- ethylamino] -propyl) -benzof 1 ,3]dioxole-2,2-dicarboxylic acid and cyclobutylmethanol according to the procedure of Example 30 as an off-white solid (HCI salt); !H NMR (CDCI3) δ 1.32 (d, J = 6.5 Hz, 3 H), 1.85 (m, 8 H), 2.05 (m, 4 H), 2.69 (m, 2 H), 2.80 (m, IH), 3.19 (m, 2H), 3.48 (m, 2 H), 4.10 (s, 4 H), 5.50 (bd, 1 H), 5.70 (bs, 1 H), 6.80 (m, 3 H), 7.25 (m, 2 H), 7.45 (s, 1 H), 8.70 (bs, 1 H), 10.10 (bs, 1 H); IR (KBr): 1759, 1779 cm-1 (c=0); MS (ES) m/z 558 (MH+); [α]^5 -27° (c, 1.0, CHCI3). Anal. Calcd. for C30H36C1NO7 HC1: 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. EXAMPLE 41
5-{2-f2-(3-Chloro-phenyl)-2-hydroxy-ethylaminoJ-propyl}- benzo[l,3]dioxole-2,2-dicarboxyIic acid bis-(2-cyclopentyl-ethyl) ester
The title compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy- ethylamino] -propyl) -benzof 1 ,3]dioxole-2,2-dicarboxy lie acid and 2-cyclopentylethanol according to the procedure of Example 30 as an amber gum (HCI salt); *H NMR (CDCI3) δ 1.32 (d, J = 6.3 Hz, 3 H), 1.60 (m, 20 H), 2.80 (m, IH), 2.90 (m, 2 H), 3.15 (m, IH), 3.20 (m, IH), 3.48 (m, 2 H), 4.30 (t, J = 6.9 Hz, 4 H), 5.50 (bd, 1 H), 6.80 (m, 3 H), 7.25 (m, 2 H), 7.43 (s, 1 H), 8.70 (bs, 1 H), 10.10 (bs, 1 H); IR (KBr): 1765 cm"1 (C=O); MS (CI) m/z 614 (MH+); [α]^5 -24° (c, 1.0, CHCI3). Anal.
Calcd. for C34H44CINO7 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-hydroxy- ethylamino]-propyl}-benzo[l,3]dioxole-2,2-dicarboxylic acid bis- acetoxy-alkyl esters
Step 1 Preparation of Acyloxyalkyl Iodides
These esters were prepared by reacting the appropriate acid chlorides with 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, K., Ishihara, S., Yanagisawa, H., Ide, J., Nakayama, E., Nakao, H. , Sugawara, S., Iwata, M. J. Antibiotics 1987, 19, 370. Step 2
5-{2-[2-(3-Chlorophenyl)-2-hydroxyethylamino]-propyl}- benzo[l,3]dioxole-2,2-dicarboxylic acid disilver salt
To a stirred solution of 5-{2-f2-(3-chlorophenyl)-2-hydroxyethylamino]- propyl) -benzof l,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
5-{2-[2-(3-ChIoro-phenyl)-2-hydroxy-ethyIamino]-propyl}- benzof l,3]dioxole-2,2-dicarboxylic acid bis-acetoxyalkyl esters
To a stirred suspension of 5-{2-f2-(3-chlorophenyl)-2-hydroxyethylamino]- propyl) -benzof 1 ,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 5% Na2S2θ3 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
5-{2-[2-(3-Chloro-phenyl)-2-hydroxyethylamino]propyl}benzo[l,3] dioxole-2,2-dicarboxylic acid bis-acetoxymethyl ester
To a stirred suspension of 5-{2-[2-(3-chlorophenyl)-2-hydroxyethylamino]- propyl) -benzof 1 ,3]dioxole-2,2-dicarboxy lie acid disilver salt (2.0 gms, 3 mmol) in anhydrous chloroform, acetoxymethyl 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% Na2S2θ3 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 color solid; mp 132-134; yield 97%; M+H 566.
EXAMPLE 43
5-{2-[2-(3-Chloro-phenyl)-2-hydroxyethylamino]propyl}benzo[l,3] dioxole-2,2-dicarboxylic acid bis-propionyloxymethyl ester
To a stirred suspension of 5-{2-[2-(3-chlorophenyl)-2-hydroxyethylamino]- propyl) -benzof 1 ,3]dioxole-2,2-dicarboxylic acid disilver salt (2.0 gms, 3 mmol) in anhydrous chloroform, propionyloxymethyl iodide (9 mmol) dissolved in chloroform
(30 mL) was added. The reaction mixture was stirred at room temperature, under dark for 16 h. The reaction mixture was filtered and washed with 5% Na2S2θ3 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[l,3] dioxole-2,2-dicarboxylic acid bis-butyryloxymethyl ester
To a stirred suspension of 5-{2-f2-(3-chlorophenyl)-2-hydroxyethylamino]- propyl ) -benzof l,3]dioxole-2,2-dicarboxylic acid disilver salt (2.0 gms, 3 mmol) in anhydrous chloroform butyryloxymethyl 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% Na2S2θ3 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. EXAMPLE 45
5-{2-[2-(3-Chloro-phenyl)-2-hydroxyethylamino]propyl}benzo[l,3] dioxυle-2,2-dicarboxylic acid bis-isobutyryloxymethyl ester
To a stirred suspension of 5-{2-[2-(3-chlorophenyl)-2-hydroxyethylamino]- propyl } -benzof l,3]dioxole-2,2-dicarboxylic acid disilver salt (2.0 gms, 3 mmol) in anhydrous chloroform isobutyryloxymethyl 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% Na2S2θ3 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 114-116 (dec); yield 78%; M+H 622.
EXAMPLE 46
5-{2-f2-(3-Chloro-phenyl)-2-hydroxyethylamino]propyl}benzo[l,3] dioxo!e-2,2-dicarboxylic acid bis-heptanoyloxymethyl ester
To a stirred suspension of 5-{2-[2-(3-chlorophenyl)-2-hydroxyethylamino]- propyl) -benzof 1 ,3]dioxole-2,2-dicarboxylic acid disilver salt (2.0 gms, 3 mmol) in anhydrous chloroform heptanoyloxymethyl 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% Na2S2θ3 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 94-96; yield 18%; M+H 707.
EXAMPLE 47 5-{2-[2-(3-Chloro-phenyl)-2-hydroxyethylamino]propyl}benzo[l,3] dioxole-2,2-dicarboxylic acid bis-(4-methyl-pentanoyloxymethyl) ester
To a stirred suspension of 5-{2-[2-(3-chlorophenyl)-2-hydroxyethylamino)- propyl) -benzof l ,3)dioxole-2,2-dicarboxylic acid disilver salt (2.0 gms, 3 mmol) in anhydrous chloroform pentanoyloxymethyl 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% Na2S2θ3 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[l,3] dioxole-2,2-dicarboxylic acid bis-hexanoyloxymethyl ester
To a stirred suspension of 5-{2-f2-(3-chlorophenyl)-2-hydroxyethylamino]- propyl) -benzof 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% Na2S2θ3 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-phenyI)-2-hydroxyethylamino]propyl}benzo[l,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)-benzof l,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% Na2S2θ3 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 ivory solid; mp 72 (dec); yield, 48%; M+H 651. EXAMPLE 50
5-{2-[2-(3-Chloro-phenyI)-2-hydroxyethylamino]propyl}benzo[l,3] dioxole-2,2-dicarboxylic acid bis-cyclohexanecarbonyloxymethyl ester
To a stirred suspension of 5-{2-[2-(3-chlorophenyl)-2-hydroxyethylamino]- propyl) -benzof l,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% Na2S2θ3 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 86 (dec); yield 52%; M+H 703.
EXAMPLE 51
5-{2-[2-(3-Chloro-phenyI)-2-hydroxyethylamino]propyl}benzo[l,3] dioxole-2,2-dicarboxylic acid bis-(l-propionyloxy-ethyl) ester
To a stirred suspension of 5-{2-f2-(3-chlorophenyl)-2-hydroxyethylamino]- propyl) -benzof l,3]dioxole-2,2-dicarboxylic acid disilver salt (2.0 gms, 3 mmol) in anhydrous chloroform 1-propionyloxyethyl iodide (9 mmol) dissolved in chloroform (30 mL) was added. The reaction mixture was stirred at room temperature, under dark for 16 h. The reaction mixture was filtered and washed with 5% Na2S2θ3 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 EXAMPLE 52
5-{2-[2-(3-Chloro-phenyI)-2-hydroxyethylamino]propyl} benzof 1,3] dioxole- 2,2-dicarboxylic acid bis-[l-(2,2-dimethyl-propionyloxy-ethyl) ester
To a stirred suspension of 5-{2-[2-(3-chlorophenyl)-2-hydroxyethylamino]- propyl) -benzof l,3]dioxole-2,2-dicarboxylic acid disilver salt (2.0 gms, 3 mmol) in anhydrous chloroform l-(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% Na2S2θ3 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 92; yield, 58%; M+H 679.
EXAMPLE 53
5-{2-[2-(3-Chloro-phenyl)-2-hydroxyethylamino]propyl}benzo[l,3] dioxole-2,2-dicarboxylic acid bis-(3,3-dimethyl-butyryloxymethyI) ester
To a stirred suspension of 5-{2-[2-(3-chlorophenyl)-2-hydroxyethylamino]- propyl) -benzof 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% Na2S2θ3 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 104-105 (dDec); yield 98%; M+H 678. EXAMPLE 54
5-{2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylami no] propyl} benzof 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) -benzof 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% Na2S2θ3 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 96-98 (dec); yield, 72%; M+H 706.
EXAMPLE 55
5-{2-[2-(3-Chloro-phenyI)-2-hydroxy-ethylamino] propyl} benzo[l,3]dioxole-2,2-dicarboxy lie acid bis-(3-cyclopentyl- propionyloxymethyl) ester
To a stirred suspension of 5-(2-[2-(3-chlorophenyl)-2-hydroxyethylamino]- propyl) -benzof l,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% Na2S2θ3 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 155-157 (dec); yield, 98%; M+H 730. EXAMPLE 56
5-{2-[2-(3-Chloro-phenyl)-2-hydroxy- ethylamino]propyl}benzo[l,3]dioxole-2,2-dicarboxylic acid bis- benzoyloxymethyl ester
To a stirred suspension of 5-{2-[2-(3-chlorophenyl)-2-hydroxyethylamino]- propyl) -benzof l,3]dioxole-2,2-dicarboxylic acid disilver salt (2.0 gms, 3 mmol) in anhydrous chloroform benzoyloxymethyl 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% Na2S2θ3 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
5-{2- [2- (3-Chloro-phenyl)-2-hydroxyethylamino]propyl} benzof 1,3] dioxole-2,2-dicarboxylic acid bis-(benzoyloxy-ethyl) ester
To a stirred suspension of 5-{2-[2-(3-chlorophenyl)-2-hydroxyethylamino]- propyl) -benzof 1 ,3]dioxole-2,2-dicarboxylic acid disilver salt (2.0 gms, 3 mmol) in anhydrous chloroform 1 -benzoyloxyethyl 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% Na2S2θ3 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. EXAMPLE 58
5-{2-[2-(3-Chloro-phenyl)-2-hydroxyethylamino]propyl}benzo[l,3] dioxole-2,2-dicarboxylic acid bis-(2,2-dimethyl-butyryloxymethyI) ester
To a stirred suspension of 5-{2-[2-(3-chlorophenyl)-2-hydroxyethylamino]- propyl)-benzof l,3]dioxole-2,2-dicarboxylic acid disilver salt (2.0 gms, 3 mmol) in anhydrous chloroform 2,2-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% Na2S2θ3 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 ivory solid; mp 121-123 (dec); yield 37%; M+H 679.
EXAMPLE 59
5-{(2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}- benzo[l,3]dioxole-2,2-dicarboxylic acid bis-[l-
(cyclohexyloxycarbonyloxy)-ethyl] ester
Cyclohexyl 1-iodoethyl carbonate (5.6 g, 18 8 mmol) in CHCI3 (10 mL) was added dropwise into a cold (0 °C) suspension of (R, R)-5-[2-f2-(3-chlorophenyl)-2- hydroxyethylamino]propyl]-l,3-benzodioxole-2,2-dicarboxylic acid disilver salt (4.0 g, 6.3 mmol) and CHCI3 (100 mL). After the addition, the mixture was allowed to come to room temperature and stirred for 24 h. Diethyl ether (300 mL) was added into the reaction mixture and the precipitated solids were filtered and discarded. The filtrate was concentrated in vaccuo at room temperature and the residue was quickly chromatographed through silica gel, eluting anhydrous solvent (EtOAc / hexane, 1/1), to give a light yellow solid (1.25 g, 26% yield): mp 78-81 °Q (+)FAB m/e 762 (M+H)+. Analysis for: C38H48CINO13: Calcd: C, 59.89; H, 6.35; N, 1.84; Found:
C, 60.88; H, 6.53; N, 1.99 EXAMPLE 60
5-{2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]- propyl}benzof l,3]dioxole-2,2-dicarboxylic acid bis-amide
A mixture of 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylarnino]-propyl}- benzo[l,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 (3: 1). It was washed with water and dried over anhydrous MgSO4. The organic layer was filtered and concentrated. The residue obtained was chromatographed over silica gel eluted with 9: 1 chloroform : methanol to yield a brown solid; mp 98; yield. 1.0 g; 45%; M+H 420.
EXAMPLE 61 5-{2-[2-(3-ChIoro-phenyl)-2-hydroxy-ethylamino]-propyl}- benzo[l,3]dioxole-2,2-dicarboxylic acid bis-2-propyI amide
A mixture of 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl)-benzo-
[l,3]dioxole-2,2-dicarboxylic acid bis-ethyl ester (2.4 g, 5 mmol) and isopropylamine
(10 mL, excess) was refluxed in ethanol for 48 h. The reaction mixture was concentrated and the residue obtained was extracted with chloroform : methanol (3:1).
It was washed with water and dried over anhydrous MgSO4. The organic layer was filtered and concentrated. The residue obtained was chromatographed over silica gel eluted with 9:1 chloroform : methanol to yield a colorless spongy solid; mp 60; yield 1.5 g; 60%; M+H 504.
EXAMPLE 62
5-{2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}- benzo[l,3]dioxole-2,2-dicarboxylic acid bis-n-butyl amide
A mixture of 5- { 2-f 2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl ) -benzo- f l,3]dioxole-2,2-dicarboxylic acid bis-ethyl ester (2.4 g, 5 mmol) and n-butylamine (10 mL, excess) was refluxed in ethanol for 48 h. The reaction mixture was concentrated and the residue obtained was extracted with chloroform : methanol (3: 1). It was washed with water and dried over anhydrous MgSO4. The organic layer was filtered and concentrated. The residue obtained was chromatographed over silica gel eluted with 9:1 chloroform : methanol to yield a brown semi solid; yield 1.6 g; 61%; M+H 532.
EXAMPLE 63 5-{2-[2-(3-Chloro-phenyI)-2-hydroxy-ethylamino]-propyl}- benzof l,3]dioxole-2,2-dicarboxylic acid bis-phenylmethyl amide
A mixture of 5-{2-f2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}- benzo[l,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
(3:1). It was washed with water and dried over anhydrous MgSO4. The organic layer was filtered and concentrated. The residue obtained was chromatographed over silica gel eluted with 9: 1 chloroform : methanol to yield a colorless spongy solid; mp 101; yield 2.0 g; 67%; M+H 600.
EXAMPLE 64
5-{2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyI}- benzo[l,3]dioxole-2,2-dicarboxylic acid bis-(2-furanylmethyl) amide
A mixture of 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}- benzo[l,3]dioxole-2,2-dicarboxylic acid bis-ethyl ester (2.4 g, 5 mmol) and 2- furanylmethylamine (10 mL, excess) was refluxed in ethanol for 48 h. The reaction mixture was concentrated and the residue obtained was extracted with chloroform : methanol (3: 1). It was washed with water and dried over anhydrous MgSO4. The organic layer was filtered and concentrated. The residue obtained was chromatographed over silica gel eluted with 9: 1 chloroform : methanol to yield a brown solid; mp 50; yield 400 mg; 14%; M+H 581.
EXAMPLE 65
5-{2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyI}- benzofl,3]dioxole-2,2-dicarboxylic acid bis-(glycine ethyl ester) amide
A mixture of glycine ethyl ester.HCl (1.1 gm, 8 mmol) and sodium methoxide (424 mg, 8 mmol) was stirred at room temperature in ethanol for fifteen minutes. At the end, 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}- benzo[l,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 5-{2-f2-(3-Chloro-phenyl)-3-oxazolidiny I] -propyl }-benzo[l, 3]dioxole- 2,2-dicarboxylic acid
5- {2-f 2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl) -benzof l,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; JH NMR (CDCI3) δ 1.02 (d, J = 6.4 Hz, 3 H), 2.50 (m, 1 H), 3.00 (m, 2H), 3.20 (m, 1 H), 3.80 (m, 1 H), 4.75 (d, J = 4.5 Hz, 1 H), 4.90 (d, J = 4.5 Hz, 1 H), 5.12 (t J = 7.3 Hz, 1 H), 6.70 (m, 1 H), 6.86 (m, 2 H), 7.40 (m, 2 H), 7.50 (s, 1 H); IR (KBr): 1740 cm l (C=O); MS (CI) m/z 433 (M+). Anal. Calcd. for C2iH2oClNO7-HCl: C, 58.14; H, 4.65; N, 3.23; Cl, 8.17. Found: C, 57.08; H, 4.78;
N, 3.32; Cl, 7.51.
EXAMPLE 67 5-((2R)-2-{tert-Butoxycarbonyl-[(2R)-2-(3-chloro-phenyl)-2-hydroxy- ethyl]-amino}-propyl)-benzo[l,3]dioxole-2,2-dicarboxylic acid bis- diethylcarbamoylmethyl ester
A mixture of 5-((2R)-2-{tert-butoxycarbonyl-[(2R)-2-(3-chloro-phenyl)-2- hydroxy-ethyl]-amino}-propyl)-benzo[l,3]dioxole-2,2-dicarboxylic acid (0.26 g, 0.5 mmol) and anhydrous potassium carbonate (0.28 g) in anhydrous dimethyl formamide was treated with 2-bromo-N,N-diethylacetamide (0.39 g, 2 mmol), and stirred at room temperature for 3 days. It was then diluted with water and hexanes, and the resulting suspension was filtered. The precipitate was washed with saturated sodium bicarbonate solution, water, and hexanes, and then dried in vacuo to give 0.27 g of white solid; *H NMR (CDCI3) δ 1.0-1.5 (m, 24 H), 2.6 (m, 2H), 3.0-3.5 (m, 10H), 4.0 (m, 1 H), 4.7-5.0 (m, 4H), 5.5, 6.0 (m, 1 H), 6.80 (m, 3 H), 7.26 (m, 2 H); IR (KBr): 1772, 1668 cm-1 (C=O); MS (ES) m/z 748 (MH+).
EXAMPLE 68
5-{(2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}- benzofl,3]dioxole-2,2-dicarboxylic acid bis-diethylcarbamoylmethyl ester
A solution of 5-((2R)-2-{tert-butoxycarbonyl-[(2R)-2-(3-chloro-phenyl)-2- hydroxy-ethyl]-amino)-propyl)-benzo[ l,3]dioxole-2,2-dicarboxylic acid bis-diethyl¬ carbamoylmethyl ester (0.16 g, 0.2 mmol) in methylene chloride (2 ml) was treated with 0.08 ml of trifluoroacetic acid at room temperature for 18 h. The mixture was then evaporated, and the residue washed with ether to give 0.12 g of white solid (TFA salt); *H NMR (DMSO-d6) δ 1.0-1.2 (m, 15 H), 2.6 (m, 2H), 3.0-4.0 (m, 11H), 5.0 (m, 4 H), 6.1 (m, 1 H), 6.80 (m, 3 H), 7.26 (m, 2 H), 8.7 (bs, 1 H),9.2 (bs, 1 H); IR (KBr): 1765, 1654 cm"1 (C=O); MS (ES) m/z 648 (MH+).
EXAMPLE 69 5-{2-[2-(3-ChIoro-phenyl)-2-hydroxy-ethylamino]-propyl}- benzo[l,3]dioxole-2,2-dicarboxylic acid cyclopropylmethyl ester
The title compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy- ethylamino]-propyl)-benzo[l,3]dioxole-2,2-dicarboxylic acid and cyclopropylmethanol according to the procedure of Example 1 as an off-white solid; ]H NMR (DMSO) δ 0.25 (q,2H), 0.49 (q,2H), 1.01 (d,3H), 1.10 (m,lH), 2.49 (m, IH), 2.85-3.20 (m,4H), 3.94 (d, 2H) 4.85 (bt, IH), 6.58 (d, IH), 6.76 (m,2H), 7.35(m,3H), 7.46(s,lH); IR (KBr): 1653 cm-l(C=O), 1747 cm-1 (c=0); MS (CI) m/z 476 (MH+). Anal. Calcd. for C24H26CINO7: 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. EXAMPLE 70
5-{2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}- benzo[ l,3]dioxole-2,2-dicarboxylic acid cyclobutylmethyl ester
The title compound was prepared from 5-{2-f2-(3-chloro-phenyl)-2-hydroxy- ethylamino]-propyl) -benzof 1 ,3]dioxole-2,2-dicarboxylic acid and cyclobutylmethanol according to the procedure of Example 1 as an off-white solid; *H NMR (DMSO) δl.01 (d,3H), 1.75(m,4H), 1.92(m,2H), 2.49 (m, IH), 2.65 (m,lH), 2.85-3.20 (m,4H), 4.09 (d, 2H), 4.85 (bt, IH), 6.58 (d, IH), 6.76 (m,2H), 7.35(m,3H), 7.46(s,lH); IR (KBr): 1652 cm'l(C=O), 1761 cm-1 (C=O); MS (CI) m/z 490 (MH+). Anal. Calcd. for C25H28CINO7: 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 5-{2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}- benzo[l,3]dioxole-2,2-dicarboxylic acid bis 2-(3-Thienyl)ethyl- ester
The title compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy- ethylamino]-propyl) -benzof l,3]dioxole-2,2-dicarboxylic acid and 2-(3-thienyl)ethanol according to the procedure of Example 1 as yellow crystals (HCI salt); lH NMR (CDCl3) δl.33 (d, 3 H), 2.82 (m, IH), 2.95 (t,4H), 3.20(m, 2H), 3.48 (bd, 2 H), 4.45 (t, 4 H), 5.50 (bd, 1 H), 5.60(bs,lH), 6.75-7.00(m, 7H), 7.21-7.32(m, 5H), 7.45(s,lH), 8.70 (bs, 1 H), 10.10 (bs, 1 H); IR (KBr): 1765 cm-l (C=0); MS (CI) m/z 642 (MH+); [α]^5 -21° (c, 1.0, CHCI3). Anal. Calcd. for C34H32ClS2NO7 HCl: C, 56.63; H, 4.75; N, 2.06; S, 9.45; Cl, 10.46. Found: C, 55.89; H, 4.95; N, 1.87; S, 9.45; Cl, 9.95.
EXAMPLE 72 5-{2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}- benzo[l,3]dioxole-2,2-dicarboxylic acid 2-(3-Thienyl)ethyl ester
The title compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy- ethylamino]-propyl) -benzof l,3]dioxole- 2,2-dicarboxylic acid bis 2-(3-thienyl)ethyl- ester according to the procedure of Example 22 as an off-white solid; lH NMR (DMSO) δθ.96 (d,3H), 2.45 (m, IH), 2.72-3.10 (m,6H), 4.25(t,2H), 4.80 (bt, IH), 5.92 (bs, IH), 6.60(d,lH), 6.79(d,2H), 7.05(d,lH), 7.17(s,lH), 7.30-7.50(5H); IR (KBr): 1652 cm-l(C=O), 1751 cm-1 (c=0); MS (CI) m/z 532 (MH+). Anal. Calcd. for C26H26ClSNO7: 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
5-{2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}- benzo[l ,3]dioxole-2,2-dicarboxylic acid bis 2-(Chloro)ethyl ester
The title compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy- ethylamino]-propyl }-benzofl,3]dioxole-2,2-dicarboxylic acid and 2-chloroethanol according to the procedure of Example 1 as yellow crystals (HCI salt); iH NMR (DMSO) δl.13 (d, 3 H), 2.65 (m, IH), 3.15-3.52(m, 4H), 3.85 (t, 4 H), 4.60 (t, 4 H), 5.55 (bd, 1 H), 6.40(bs,lH), 6.86(d,lH), 7.08(m,2H), 7.40-7.58(m,4H), 8.85 (bs, 1 H), 9.40 (bs, 1 H); IR (KBr): 1770 cm"1 (C=O); MS (CI) m/z 548 (MH+); [a]^
-28° (c, 1.0, DMSO). Anal. Calcd. for C24H26C13NO7 HCl: C, 49.42; H, 4.67; N, 2.40;C1, 25.9. Found: C, 49.69; H, 4.38; N, 2.32; Cl, 23.20.
EXAMPLE 74
5-{(2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}- benzof l,3]dioxole-2,2-dicarboxylic acid bis-(2-ethylbutyl) ester
The title compound was prepared from 5-{2-f2-(3-chloro-phenyl)-2-hydroxy- ethylamino]-propyl) -benzof 1 ,3]dioxole-2,2-dicarboxylic acid and 2-ethylbutanol according to the procedure of Example 1 as an off-white gum (HCI salt); lH NMR (CDCI3) δ 0.80-0.95 (m, 12 H), 1.25-1.45 (m, 10 H), 1.50-1.65 (m, 3 H), 2.75-2.85 (m, IH), 3.10-3.40 (m, IH), 3.47-3.49 (m, 2 H), 4.25 (d, 5 H), 5.50 (d, 1 H), 6.70- 6.80 (m, 1 H), 6.80-6.90 (m, 2 H), 7.20-7.45 (m, 3 H), 7.46 (s, 1 H), 8.74 (bs, 1 H), 10.06 (bs, 1 H); IR (KBr): 2964 crrr1 (-OH), 1766 cm"1 (C=O); MS (ES) m/z 590.4 (MH+); [α]^5 -21° (c, 1.0, CHCI3). Anal. Calcd. for C32H44ClNO7 HCl: C,
61.34; H, 7.08; N, 2.24; Cl, 1 1.32. Found: C, 61.09; H, 7.46; N, 2.12; Cl, 10.77. EXAMPLE 75
5-{(2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}- benzo[l,3]dioxole-2,2-dicar boxy lie acid bis-(3-methylbutyl)ester
The title compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy- ethylamino] -propyl) -benzof 1 ,3]dioxole-2,2-dicarboxylic acid and 3-methylbutanol accord-ing to the procedure of Example 1 as an off-white foam (HCI salt); *H NMR (CDCl3) δ 0.90 (d, 12 H), 1.35 (d, 2 H), 1.55-1.80 (m, 6H), 2.70-2.85 (m, IH), 3.45-3.55 (m, 3 H), 4.30 (t, 4 H), 5.45 (bd, 1 H), 5.65 (bs, 1 H), 6.70-6.80 (m, 1 H), 6.80-6.90 (m, 3 H), 7.25-7.35 (m, 3H), 7.43 (s, IH), 8.74 (bs, 1 H), 10.08 (bs, 1 H); IR (KBr): 3303 cm-1 (.QH), 1765 cm-1 (C=0); MS (ES) m/z 562.4 (MH+); [α]Jf
-24° (c, 1.0, CHCI3). Anal. Calcd. for C3υH4θClNO7-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
5-{(2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}- benzo[l,3]dioxole-2,2-dicarboxylic acid (3-methylbutyl)ester
The title compound was prepared from 5-{(2R)-2-[(2R)-2-(3-chloro-phenyl)-2- hydroxy-ethylamino]-propyl) -benzof l,3]dioxole-2,2-dicarboxy lie acid bis-(3-methyl- butyl)ester according to the procedure of Example 22 as an off-white solid; ]H NMR (DMSO) δ 0.80-0.85 (m, 6H), 1.02-1.09 (m, 3H), 1.45 (q, 2H), 1.55-1.70 (m, IH), 3.01-3.05 (m, 2H), 3.15-3.25 (m, IH), 3.26-3.40 (m, 2H), 4.15 (t, 2H), 5.00-5.08 (m, IH), 6.45 (bs, IH), 6.55-6.65 (m, IH), 6.75-6.90 (m, 2H), 7.45-7.49 (m, 5H), 7.51 (s, IH); IR (Kbr): 3394 cnr1 (-OH), 1651 cπr1 (C=O); MS (ES) m/z 492.0 (MH+); [α]^5 -22° (c, 1.0, CHCI3). Anal. Calcd. for C25H3oClNO7: 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 5-{(2R)-2-f(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}- benzo[l,3]dioxole-2,2-dicarboxy!ic acid bis-adamantan-1-ylmethyl ester
The title compound was prepared from 5-{2-f2-(3-chloro-phenyl)-2-hydroxy- ethylamino]-propyl) -benzof 1 ,3]dioxole-2,2-dicarboxy lie acid and adamantan-1- ylmethanol according to the procedure of Example 1 as a white solid (HCI salt); *H NMR (CDCI3) δ 1.25 (m, 2H), 1.35 (d, 3 H), 1.51 (s, 12 H), 1.55-1.61 (m, 2H), 1.61-1.67 (m, 4 H), 1.67-1.75 (m, 6 H), 1.97 (s, 4 H), 3.20 (s, 2H), 3.42-3.49 (m, 2H), 3.88 (s, 4H), 4-11-4.16 (q, IH), 5.45 (bd, IH), 5.65 (bd, IH), 6.75 (m, IH), 6.78-6.89 (m, 2H), 7.23-7.30 (m, 3H), 7.44 (s, IH), 8.74 (bs, IH), 10.115 (bs, IH); IR (KBr) 3418 cm-1 (_QH), 1767 cm-1 (C=O); MS (ES) m/z 718.4 (MH+); [α]£5
-15° (c, 1.0, CHCI3). Anal. Calcd. for C42H52ClNO7: C, 68.94; H, 9.22; N, 1.90; Cl, 9.40. Found: C, 67.48; H, 7.49; N, 1.48; Cl, 8.10.
EXAMPLE 78
5-{(2R)-2-[(2R)-2-(3-Chloro-phenyI)-2-hydroxy-ethyIamino]-propyl}- benzo[l,3]dioxole-2,2-dicarboxylic acid bis-(2,2-dimethyl-propyI) ester
The title compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy- ethylamino]-propyl) -benzof 1 ,3]dioxole-2,2-dicarboxylic acid and 2,2- dimethylpropanol according to the procedure of Example 1 as an off-white foam (HCI salt); 1H NMR (CDCI3) δ .924 (s, 18 H), 1.45 (d, 2H), 1.75 (s, 2H), 2.80 (m, IH), 3.17 (m, IH), 3.45 (m, IH), 3.98 (s, 4H), 5.45-5.55 (bd, IH), 5.63-5.67 (bs, IH), 6.75-6.80 (m, 2H), 6.80-6.89 (m, 2H), 7.25-7.35 (m, 3H), 7.440 (s, IH), 8.75 (bs, IH), 10.10 (bs, IH); IR (KBr) 3355 cm-l (-OH), 1767 cm-1 (C=O); MS (ES) m/z 562.3 (MH+); [a]2^ -23° (c, 1.0, CHCI3). Anal. Calcd. for C30H40CINO7: C, 60.20;
H, 6.90; N, 2.34; Cl, 1 1.85. Found: C, 59.74; H, 6.97; N, 2.23; Cl, 11.60.
EXAMPLE 79
5-{(2R)-2- [(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}- benzofl,3]dioxole-2,2-dicarboxylic acid adamantan-1-ylmethyl ester
The title compound was prepared from 5-{(2R)-2-f(2R)-2-(3-chloro-phenyl)-2- hydroxy-ethylamino]-propyl ) -benzof l,3]dioxole-2,2-dicarboxylic acid bis-adamantan- 1-ylmethyl ester according to the procedure of Example 22 as an off-white solid; lH NMR (DMSO) δ 1.03-1.09 (m, 3H), 1.44 (s, 6 H), 1.45-1.64 (m, 8H), 1.86 (s, 4H), 3.02-3.15 (m, IH), 3.25-3.55 (m, 2H), 3.70-3.80 (m, 2H), 4.58 (s, 2H), 5.06-5.10 (m, IH), 6.52-6.65 (m, IH), 6.79-6.88 (m, 2H), 7.32-7.49 (m, 3H), 7.49 (s, IH); IR (KBr) 3384 cm"1 (-OH), 1758 cm"1 (C=O), 1651 cm"1 (C=O); MS (ES) m/z 570.3 (MH+); [α]p5 -29° (c, 1.0, CHC13). Anal. Calcd. for C3ιH36ClNO7: 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 80
5-{(2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethyIamino]-propyl}- benzo[l,3]dioxole-2,2-dicarboxylic acid (2,2-dimethyl-propyl)ester
The title compound was prepared from 5-{(2R)-2-[(2R)-2-(3-chloro-phenyl)-2- hydroxy-ethylamino]-propyl } -benzof l,3]dioxole-2,2-dicarboxylic acid bis-(2,2- dimethyl-propyl) ester according to the procedure of Example 22 as a white solid; *H NMR (DMSO) δ 0.868 (s, 9 H), 1.02-1.06 (m, 3H),3.00-3.02 (m, IH), 3.24-3.30 (m, IH), 3.35 (s, 5H), 3.80 (t, 2H), 4.55 (s, IH), 5.03 (m, IH), 6.52 (m, IH), 6.61 (m, IH), 6.79 (m, IH), 7.34 (m, 3H), 7.48 (s, IH); IR (KBr) 3398 cm"' (-OH), 1748 cm-1 (C=O), 1654 cm-1 (C=O); MS (ES) m/z 492.3 (MH+); [α]^5 - 93° (c, 1.0,
CHCI3). Anal. Calcd. for C25H30CINO-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 5-{(2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]- propyl}- benzo[l,3]dioxole-2,2-dicarboxylic acid (3,3-dimethylbutyI) ester
The title compound was prepared from 5-{(2R)-2-[(2R)-2-(3-chloro-phenyl)-2- hydroxy-ethylamino]-propyl } -benzof 1 ,3]dioxole-2,2-dicarboxylic acid bis-(3-methyl- butyl)ester according to the procedure of Example 22 as an off-white solid; *H NMR (DMSO) δ 0.87 (s, 9 H), 1.04 (m, 3H), 1.50 (t, 2 H), 3.34 (s, 8H), 4.20 (t, 2H), 4.95-5.05 (m, IH), 6.35 (m, IH), 6.60 (m, IH), 6.75 (m, IH), 7.34-7.46 (m, 3H), 7.48 (s, IH); IR (KBr) 3410 cm-1 (-OH), 1745 cm"1 (C=O), 1651 cm-1 (C=0); MS (ES) m/z 506.4 (MH+); Anal. Calcd. for C26H32ClNO7: 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. EXAMPLE 82
5-{(2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}- benzo[l,3]dioxole-2,2-dicarboxyIic aicd bis-(l-methyl- cyclohexylmethyl) ester.
The title compound was prepared from 5- { 2-[2-(3-chloro-phenyl)-2-hydroxy- ethylamino]-propyl } -benzof 1 ,3]dioxole-2,2-dicarboxylic acid and 1-methylcyclohexyl- methanol according to the procedure of Example 1 as an off-white solid; Η NMR (DMSO-rf5,400MHz) 50.84 (s, 6H, CH3, CH3), 1.09 (d, J = 6.4 Hz, 3H, CH3), 1.1- 1.4 (m, 20H, cyclohexyl), 2.6 (m, IH, CH), 3-3.3 (m, 3H, CH, CH2), 3.4 (brs, IH, CH), 4.04 (s, 4H, OCH2, OCH2), 5.05 (m, IH, CH), 6.35 (d, / = 4.17 Hz, IH, OH), 6.85 (dd, J = 7.9, 1.32 Hz, IH, Ar-H), 7.07 (s, IH, Ar-H), 7.09 (d, J = 8.35 Hz, Ar-H), 7.38-7.42 (m, 3H, Ar-H), 7.5 (s, IH, Ar-H), 8.8 (brs, IH, NH), 9.4 (brs, IH, NH); IR (KBr, cm"1) 3400 (OH), 2900 (NH), 1760 (CO); MS mle 641 (M+); Analysis for: C36H48ClNO7xHCl: Calc'd: C, 63.71; H, 7.28; N, 2.06; Found: C, 63.72; H, 7.03; N, 1.91.
EXAMPLE 83 5-{(2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}- benzo[l,3]dioxole-2,2-dicarboxylic aicd bis-(2-cyclohexyI-2-methyl- propyl) ester.
The title compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy- ethylamino]-propyl) -benzof 1 ,3]dioxole-2,2-dicarboxylic acid and 2-cyclohexyl-2- methylpropanol according to the procedure of Example 1 as an off-white solid; 1H NMR (DMSO-d6,400MHz) <5 1.1 (s, 6H, CH3, CH3), 1.45 (s, 6H, CH3, CH3), 1.5 (s, 6H, CH3, CH3), 2.6 (m, IH, CH), 3-3.3 (m, 3H, CH, CH2), 3.4 (brs, IH, CH), 4.04 (s, 4H, OCH2, OCH2), 5.05 (m, IH, CH), 6.35 (d, J = 4.17 Hz, IH, OH), 6.85 (dd, 7 = 7.9, 1.32 Hz, IH, Ar-H), 7.07 (m, 2H, Ar-H), 7.38-7.42 (m, 3H, Ar-H), 7.5 (s, IH, Ar-H), 8.8 (brs, IH, NH), 9.4 (brs, IH, NH); IR (KBr, cm"1) 3400 (OH), 2900 (NH), 1760 (CO); MS mle 698 (M+H)+; Analysis for: C40H56ClNO7xHCl: Calc'd: C, 65.38; H, 7.82; N, 1.91; Found: C, 65.32; H, 7.96; N, 1.94. EXAMPLE 84 5-{(2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}- benzo[l,3]dioxole-2,2-dicarboxylic aicd bis-(2-methyl-2-nitro-propyl) ester.
The title compound was prepared from 5-{2-f2-(3-chloro-phenyl)-2-hydroxy- ethylamino] -propyl) -benzof l,3]dioxole-2,2-dicarboxylic acid and 2-methyl-2- nitropropanol according to the procedure of Example 1 as an off-white solid; Η NMR (DMSO-d6,400MHz) δ 0.78 (s, 12H, 4 x CH3), 0.8-1.0 (m, 4H, CH2), 1- 1.2 (m, 11H, cyclohexyl, CH3), 1.5-1.65 (m, 10 H, cyclohexyl), 2.6 (m, IH, CH), 3-3.3 (m, 3H, CH, CH2), 3.4 (brs, IH, CH), 4.04 (s, 4H, OCH2, OCH2), 5.05 (m, IH, CH), 6.35 (d, J = 4.17 Hz, IH, OH), 6.83 (dd, J = 7.9, 1.32 Hz, IH, Ar-H), 7.06 (s IH, Ar-H), 7.09 (d, J = 8.35 Hz), 7.38-7.42 (m, 3H, Ar-H), 7.5 (s, IH, Ar-H), 8.8 (brs, IH, NH), 9.4 (brs, IH, NH); IR (KBr, cm"1) 3400 (OH), 2900 (NH), 1760 (CO); Analysis for: C28H34ClN3OπxHCl: Calc'd: C, 50.92; H, 5.34; N, 6.36; Found: C, 50.72; H, 5.42; N, 5.96.
EXAMPLE 85 5-{(2R)-2-f(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}- benzo[l,3]dioxole-2,2-dicarboxylic aicd bis-(2,2,4-trimethyl-pentyl) ester.
The title compound was prepared from 5-{2-f2-(3-chloro-phenyl)-2-hydroxy- ethylamino] -propyl) -benzof 1 ,3]dioxole-2,2-dicarboxylic acid and 2,2,4- mmethylpentanol according to the procedure of Example 1 as an off-white solid; Η NMR (DMSO-d6,400MHz) 50.65-0.9 (m, 24H, 8 x CH3), 1.09 (d, J = 6.4 Hz, 3H, CH3), 1.1- 1.4 (m, 4H, CH2, CH2), 2.62 (m, IH, CH), 3-3.3 (m, 3H, CH, CH2), 3.4 (brs, IH, CH), 4.04 (s, 4H, OCH2, OCH2), 5.05 (m, IH, CH), 6.34 (d, / = 3.95 Hz, IH, OH), 6.85 (dd, J = 7.9, 1.32 Hz, IH, Ar-H), 7.07 (m, 2H, Ar-H), 7.38-7.42 (m, 3H, Ar-H), 7.5 (s, IH, Ar-H), 8.7 (brs, IH, NH), 9.1 (brs, IH, NH); IR (KBr, cm" ') 3300 (OH), 2900 (NH), 1760 (CO); MS mle 646 (M+H)+; Analysis for: C36H52ClNO7xHCl: Calc'd: C, 63.33; H, 7.83; N, 2.05; Found: C, 62.96; H, 7.71; N, 2.44. EXAMPLE 86
5-{(2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}- benzofl,3]dioxole-2,2-dicarboxylic aicd bis-(2,2-dimethyl-pentyl) ester.
The title compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy- ethylamino]-propyl}-benzo[l,3]dioxόle-2,2-dicarboxylic acid and 2,2- dimethylpentanol according to the procedure of Example 1 as an off-white solid; 1H NMR (DMSO-rf6,400MHz) <50.8 (m, 18H, 6 x CH3), 1.1-1.2 (m, 11H, CH2 CH3), 2.6 (m, IH, CH), 3-3.3 (m, 3H, CH, CH2), 3.4 (brs, IH, CH), 4.0 (s, 4H, OCH2, OCH2), 5.09 (m, IH, CH), 6.36 (d, J = 4.17 Hz, IH, OH), 6.86 (dd, J = 7.9, 1.32 Hz, IH, Ar-H), 7.07 (s IH, Ar-H), 7.09 (d, J = 8.35 Hz, Ar-H), 7.35-7.42 (m, 3H, Ar-H), 7.48 (s, IH, Ar-H), 8.84 (brs, IH, NH), 9.48 (brs, IH, NH); IR (KBr, cm"1) 3300 (OH), 2900 (NH), 1760 (CO); MS mle 617 (M+); Analysis for: C34H48ClNO7xHCl: Calc'd: C, 62.38; H, 7.55; N, 2.14; Found: C, 62.47; H, 7.51; N, 2.31.
EXAMPLE 87 5-{(2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}- benzo[l ,3]dioxole-2,2-dicarboxylic aicd bis-(tetrahydro-furan-3- ylmethyl) ester.
The title compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy- ethylamino] -propyl) -benzof 1 ,3]dioxole-2,2-dicarboxylic acid and tetrahydrofuran-3- ylmethanol according to the procedure of Example 1 as an off-white solid; Η NMR (DMSO-d6,400MHz) 5 1.03 (d, J = 6.37 Hz, 3H, CH3), 1.5 (m, 2H, CH2), 1.9 (m, 2H, CH2), 2.6 (m, 3H, CH), 3-3.3 (m, 3H, CH, CH2), 3.4 (brs, IH, CH), 3.6-3.7 (m, 6H, CH2), 4.1-4.15 (m, 6H, CH2), 5.09 (m, IH, CH), 6.36 (brs, IH, OH), 6.86 (m, IH, Ar-H), 7.07 (m, 2H, Ar-H), 7.38-7.42 (m, 3H, Ar-H), 7.47 (s, IH, Ar-H), 8.84 (brs, 2H, NH, NH); IR (KBr, cm"1) 3300 (OH), 2900 (NH), 1760 (CO); MS mle 590 (M+H)+; Analysis for: C30H36ClNO<,xHCl: Calc'd: C, 57.51; H, 5.95; N, 2.24; Found: C, 57.80; H, 6.30; N, 2.21. EXAMPLE 88
5-{(2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}- benzo[l,3]dioxole-2,2-dicarboxylic aicd bis-(3-hydroxy-2,2,4- trimethyl-pentyl) ester.
The title compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy- ethylamino] -propyl) -benzof 1 ,3]dioxole-2,2-dicarboxy lie acid and cyclopropylmethanol according to the procedure of Example 1 as an off-white solid; Η NMR (DMSO- <4,400MHz) 50.7-0.95 (m, 27H, 9 x CH3), 1.8 (m, IH, CH), 2.1 (m, IH, CH), 2.6 (m, IH, CH), 3-3.4 (m, 6H, OH, CH, CH2), 3.6-3.8 (brs, 2H, CH), 4.04 (m, 2H, OCH2, OCH2), 4.6 (m, IH, CH), 4.85 (m, IH, CH), 5.05 (m, IH, CH), 6.35 (d, J = 3.7 Hz, IH, OH), 6.85 (dd, J = 7.9, 1.32 Hz, IH, Ar-H), 7.09 (m, 2H, Ar-H), 7.38- 7.42 (m, 3H, Ar-H), 7.5 (s, IH, Ar-H), 8.78 (brs, IH, NH), 9.2 (brs, IH, NH); IR (KBr, cm'1) 3400 (OH), 2900 (NH), 1750 (CO); MS mle 678 (M+H)+; Analysis for: C36H52ClNO9xHCl: Calc'd: C, 60.50; H, 7.47; N, 1.95; Found: C, 60.30; H, 8.09; N, 1.62.
EXAMPLE 89 5-{(2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}- benzo[l,3]dioxole-2,2-dicarboxylic aicd bis-(2,2-dimethyl-3-phenyl- propyl) ester.
The title compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy- ethylamino]-propyl) -benzof l,3]dioxole- 2,2-dicarboxylic acid and 2,2-dimethyl-3- phenylpropanol according to the procedure of Example 1 as an off-white solid; H NMR (DMSO-d6,400MHz) 50.82 (s, 12H, 4 x CH3), 1.08 (d, J = 6.37 Hz, 3H, CH3), 2.6 (m, IH, CH), 3-3.3 (m, 3H, CH, CH2), 3.4 (brs, IH, CH), 3.96 (s, 4H, OCH2, OCH2), 5.04 (m, IH, CH), 6.35 (d, J = 4.17 Hz, IH, OH), 6.89 (dd, J = 8.13, 1.53 Hz, IH, Ar-H), 7.05 (m, 4H, Ar-H), 7.14 (m, 8H, Ar-H), 7.38-7.42 (m, 3H, Ar-H), 7.5 (s, IH, Ar-H), 8.81 (brs, IH, NH), 9.38 (brs, IH, NH); IR (KBr, cm 1) 3400 (OH), 2900 (NH), 1760 (CO); MS mle 714 (M+H)+; Analysis for: C42H48ClNO7xHCl: Calc'd: C, 67.19; H, 6.58; N, 1.87; Found: C, 66.69; H, 6.53; N,
1.83. EXAMPLE 90
5-{(2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethyIamino]-propyI}- benzofl,3]dioxole-2,2-dicarboxylic aicd bis-(tetrahydro-pyran-2- ylmethyl) ester.
The title compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy- ethylamino]-propyl)-benzo[l,3]dioxole-2,2-dicarboxylic acid and tetrahydropyran-2- ylmethanol according to the procedure of Example 1 as an off-white solid; H NMR (DMSO-4,400MHz) 5 1.10 (d, 7 = 6.37 Hz, 3H, CH3), 1.1-1.2 (m, 2H, CH2), 1.3- 1.6 (m, 8H, CH2), 1.7-1.8 (m, 2H, CH2), 2.6 (m, IH, CH), 3-3.5 (m, 9H, CH, CH2), 3.8 (m, 2H, CH), 4.19-4.2 (s, s, 4H, OCH2, OCH2), 5.04 (m, IH, CH), 6.35 (d, J = 4.17 Hz, I H, OH), 6.85 (d, J = 8.13 Hz, IH, Ar-H), 7.07 (m, 2H, Ar-H), 7.36-7.42 (m, 3H, Ar-H), 7.48 (s, IH, Ar-H), 8.76 (brs, IH, NH), 9.18 (brs, IH, NH); IR (KBr, cm"1) 3400 (OH), 2900 (NH), 1760 (CO); MS mle 618 (M+H)+; Analysis for: C32H40ClNO9xHCl: Calc'd: C, 58.72; H, 6.31; N, 2.14; Found: C, 57.97; H, 6.46; N, 2.08.
EXAMPLE 91 5-{(2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}- benzofl,3]dioxole-2,2-dicarboxylic aicd bis-(tetrahydro-furan-2- ylmethyl) ester.
The title compound was prepared from 5-{2-f2-(3-chloro-phenyl)-2-hydroxy- ethylamino]-propyl)-benzo[l,3]dioxole-2,2-dicarboxylic acid and tetrahydrofuran-2- ylmethanol according to the procedure of Example 1 as an off-white solid; 1H NMR (DMSO-d6,400MHz) 5 1.1 (d, J = 6.37 Hz, 3H, CH3), 1.43-1.6 (m, 2H, CH2) 1.65- 1.8 (m, 4H, CH2), 1.98-2.0 (m, 2H, CH2), 2.6 (m, IH, CH), 3-3.3 (m, 3H, CH, CH2), 3.4 (brs, IH, CH), 3.57-3.7 (m, 4H, CH2), 4.05 (m, 2H, CH2), 4.2 (m, 2H, CH2), 4.3 (m, 2H, CH2), 5.04 (m, IH, CH), 6.34 (d, J = 3.95 Hz, IH, OH), 6.84 (dd, J = 8.13, 1.32 Hz, IH, Ar-H), 7.07 (m, 2H, Ar-H), 7.36-7.44 (m, 3H, Ar-H), 7.48 (s, IH, Ar-H), 8.77 (brs, IH, NH), 9.2 (brs, IH, NH); IR (KBr, cm"1) 3400 (OH), 2900 (NH), 1760 (CO); MS mle 590 (M+H)+; Analysis for: C30H36ClNO9xHCl: Calc'd: C, 57.51; H, 5.95; N, 2.24; Found: C, 56.37; H, 5.90; N, 2.20. EXAMPLE 92 5-{(2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}- benzo[l,3]dioxole-2,2-dicarboxylic aicd bis-(5-methyl-f l,3]dioxan-5- ylmethyl) ester.
The title compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy- ethylamino] -propyl) -benzof 1 ,3]dioxole-2,2-dicarboxylic acid and 5-methyl- fl,3]dioxan-5-ylmethanol according to the procedure of Example 1 as an off-white solid; 1H NMR (DMSO-d6,400MHz) 5 0.7 (s, 3H, CH3), 0.74 (s, 3H, CH3), 1.1 (d, J = 6.59 Hz, 3H, CH3), 2.6 (m, IH, CH), 3-3.3 (m, 8H, CH, CH2), 3.6-3.7 (m, 4H, CH2), 4.6-4.8 (m, 4H, CH2), 5.04 (m, IH, CH), 6.34 (brs, IH, OH), 6.84 (dd, / = 8.13, 1.32 Hz, IH, Ar-H), 7.07 (m, 2H, Ar-H), 7.36-7.44 (m, 3H, Ar-H), 7.48 (s, IH, Ar-H), 8.77 (brs, IH, NH), 9.2 (brs, IH, NH); IR (KBr, cm"1) 3400 (OH), 2900 (NH), 1760 (CO); MS mle 650 (M+H)+; Analysis for: C^H^ClNOπxHCl: Calc'd: C, 55.98; H, 6.02; N, 2.04; Found: C, 54.67; H, 6.58; N, 2.05.
EXAMPLE 93 5-{(2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}- benzo[l,3]dioxole-2,2-dicarboxylic aicd bis-(l-methyl-cyclohex-3- enylmethyl) ester.
The title compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy- ethylaminoj-propyl) -benzof 1 ,3]dioxole-2,2-dicarboxylic acid and l-methylcyclohex-3- enylmethanol according to the procedure of Example 1 as an off-white solid; 1H NMR (DMSO-ύf6,400MHz) 50.84 (s, 6H, 2 x CH3), 1.09 (d, J = 6.4 Hz, 3H, CH3), 1.25- 1.4 (m, 4H, CH2), 1.6-1.65 (m, 2H, CH2), 1.8-2.0 (m, 6H, CH2), 2.6 (m, IH, CH), 3-3.3 (m, 3H, CH, CH2), 3.4 (brs, IH, CH), 4.04 (m, 4H, OCH2, OCH2), 5.05 (m, IH, CH), 5.55-5.65 (m, 4H, CH), 6.35 (d, J = 4.17 Hz, IH, OH), 6.85 (dd, J = 7.9, 1.32 Hz, IH, Ar-H), 7.07 (m, 2H, Ar-H), 7.38-7.42 (m, 3H, Ar-H), 7.5 (s, IH, Ar- H), 8.8 (brs, IH, NH), 9.4 (brs, IH, NH); IR (KBr, cm'1) 3400 (OH), 2900 (NH), 1760 (CO); MS mle 638 (M+H)+; Analysis for: QeFLwClNO^HCl: Calc'd: C, 64.09; H, 6.72; N, 2.08; Found: C, 64.69; H, 7.19; N, 1.67. EXAMPLE 94 5-{(2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}- benzo[l,3]dioxole-2,2-dicarboxylic aicd bis-(3-hydroxy-2,2-dimethyl- propyl) ester.
The title compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy- ethylamino]-propyl ) -benzof 1 ,3]dioxole-2,2-dicarboxylic acid 3-hydroxy-2,2-dimethyl- propanol according to the procedure of Example 1 as an off-white solid; H NMR (DMSO-rf6,400MHz) 50.78 (s, 12H, 4 x CH3), 1.09 (d, J = 6.4 Hz, 3H, CH3), 2.6 (m, IH, CH), 3-3.3 (m, 7H, CH, CH2), 3.4 (brs, IH, CH), 4.04 (s, 4H, OCH2, OCH2),4.65 (m, 2H, OH), 5.05 (m, IH, CH), 6.34 (d, J = 4.17 Hz, IH, OH), 6.85 (dd, J = 7.9, 1.53 Hz, IH, Ar-H), 7.07 (m, 2H, Ar-H), 7.37-7.42 (m, 3H, Ar-H), 7.48 (s, IH, Ar-H), 8.78 (brs, IH, NH), 9.2 (brs, IH, NH); IR (KBr, cm"1) 3400 (OH), 2900 (NH), 1760 (CO); MS mle 594 (M+H)+; Analysis for: QoH^ClNO^HCl: Calc'd: C, 57.14; H, 6.55; N, 2.22; Found: C, 56.44; H, 6.62; N, 2.38.
EXAMPLE 95
5-{(2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethyIamino]-propyl}- benzo[l,3]dioxole-2,2-dicarboxylic acid (2-ethoxy-ethyl) ester
Through a stirred room temperature solution of 8.0 g (0.019 mole) 5-{2-[2-(3- chloro-phenyl)-2-hydroxy-ethylamino]-propyl) -benzof l,3]dioxole-2,2-dicarboxylic acid and 30 mL of 2-ethoxyethanol was bubbled HCl(g) for 5 min. After heating at 100 °C for 12 h, TLC (9/1 CH2Cl2/MeOH) indicated the formation of both 5-{2-[2-(3- chloro-phenyl)-2-hydroxy-ethylamino]-propyl) -benzof 1 ,3]dioxole-2,2-dicarboxylic acid bis-(2-ethoxy-ethyl) ester (Rf = 0.8; 9/1 CHjCl∑/MeOH) and 5-{(2R)-2-f(2R)-2-
(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl) -benzof 1 ,3]dioxole-2,2-dicarboxylic acid (2-ethoxy-ethyl) ester (Rf = 0.2; 9/1 CH2Cl2/MeOH). After cooling to room temperature, excess 2-ethoxyethanol was removed via Kugelrohr distillation (0.05 mm, oven temperature = 95 °C), and the brown residue was chromatographed on silica gel, eluting with 0 to 10% MeOH in CH2C12, to give 1.0 g (0.002 mole, a 10% yield) of the title compound as an off-white solid; Η NMR (300 MHz, DMSO-dg): δ 1.12 (m, J = 6.3 Hz, 3H), 2.5 (m, 3H) 3.35 (m, 8H), 5.06 (m, IH), 6.3 (s, IH, OH) 6.5 (m, IH), 6.6 (m, IH), 6.8 (m, 2H), 7.0 (m, IH), 7.5 (m, 2H), 8.0 (m, IH, NH), d 9.2 (m, IH, COOH); MS (ES) mlz (relative intensity): 494 (M++H, 100). EXAMPLE 96 5-{(2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethyIamino]-propyl}- benzofl,3]dioxole-2,2-dicarboxylic acid bis-[2-(3-bromo-phenyI)- ethyl]ester hydrochloride salt
The title compound was prepared as a brown oil from 5-{2-[2-(3-chloro- phenyl)-2-hydroxy-ethylamino]-propyl) -benzof l,3]dioxole-2,2-dicarboxylic acid and 2-(3-bromophenyl)ethanol according to the procedure of Example 1; 1H NMR (300 MHz, CDC13): δ 1.12 (m, J = 6.3 Hz, 3H), 2.79 (m, 8H), 3.5 (m 2H), 4.18 (s, IH, OH), 5.56 (m, I H), 6.8 (m, 3H), 7.0 (m, 4H), 7.33 (m, 4H), 7.5 (m, 4H), 8.5 (m, IH, NH); MS (ES) mlz (relative intensity): 788 (M++H, 100).
EXAMPLE 97 5-{(2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}- benzo[l,3]dioxole-2,2-dicarboxylic acid bis-(2-m-tolyl-ethyl) ester hydrochloride salt
The title compound was prepared as a brown oil from 5-{2-[2-(3-chloro- phenyl)-2-hydroxy-ethylamino]-propyl) -benzof l,3]dioxole-2,2-dicarboxylic acid and 2-(3-methylphenyl)ethanol according to the procedure of Example 1; yield: 81%; 1H NMR (300 MHz, CDC13): δ 1.12 (m, J = 6.3 Hz, 3H),2.27 (s, 6H), 2.79 (m, 7H), 3.19 (m, IH), 3.48 (m, 2H), 4.29 (m, J = 6.6 Hz, 4H), 5.49 (m, IH,) 6.75 (m, J = 8.1 Hz, IH), 6.83 (m, IH), 7.05 (m, 8H), 7.20 (m, IH), 7.27 (m, IH), 7.43 (s, IH), 7.5 (m, 2H); MS (ES) mlz (relative intensity): 658 (M++H, 100).
EXAMPLE 98
5-{(2R)-2-f (2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}- benzof l,3]dioxole-2,2-dicarboxylic acid diallyl ester
Step 1
(R,R)-5-{2-[[2-(3-Chloro-phenyl)-2-hydroxy-ethyl]-(2,2,2-trichloro- ethoxycarbonyl)-amino]-propyl}- benzof l,3]dioxole-2,2-dicarboxylic acid diethyl ester
To a 0 °C solution of 3.0 g (5.83 mmol) (R,R)-5-{2-f2-(3-chloro-phenyl)-2- hydroxy-ethylamino]-propyl } -benzof 1 ,3]dioxole-2,2-dicarboxylic acid diethyl ester hydrochloride salt and 60 mL CH2C12 was added 2.54 mL (1.88 g, 14.57 mmol) of i- Pr2NEt followed by 0.84 mL (1.30 g, 6.12 mmol) of 2,2,2-trichloroethyl chloroformate. After stirring at room temperature for 6 h, the reaction mixture was quenched with 10 mL sat. aq. NaHCO3, and extracted with 3 x 100 mL Et2O. The combined organics were washed with 1 x 100 IN HCI, 1 x 100 mL brine, dried over MgSO4, filtered and evaporated to a yellow oil. Flash chromatography on silica gel, eluting with hexanes/EtOAc (4/1 to 2/1), gives 3.46 g (5.30 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, CDC13): δ 1.20-1.39 (complex m, 9H), 2.60-2.80 (m, IH), 2.80-2.91 (m, IH), 3.01-3.19 (m, IH), 3.23-3.31 (m, IH), 3.40-3.53 (m, IH), 4.10-4.23 (m, IH), 4.30-4.42 (complex m, 4H), 4.70-4.89 (m, 3H), 6.65-6.88 (complex m, 4H), 7.15- 7.39 (complex m, 3H); MS (ES) mlz (relative intensity): 654 (M+ + H, 100).
Step 2
5-{(2R)-2-[[(2R)-2-(tert-Butyl-dimethyl-siloxy)-2-(3-chloro-phenyl)- ethyl]-(2,2,2-trichloro-ethoxycarbonyl)-amino]-propyl}- benzo[l,3]dioxole-2,2-dicarboxylic acid diethyl ester
To a -78 °C solution of 3.75 g (5.47 mmol) (R,R)-5-{2-[[2-(3-chloro-phenyl)-
2-hydroxy-ethyl]-(2,2,2-trichloro-ethoxycarbonyl)-amino]-propyl) -benzof l,3]dioxole- 2,2-dicarboxylic acid diethyl ester and 60 mL of CH2C12 was added 1.27 mL (1.17 g, 10.94 mmol) of 2,6-lutidene followed by 1.38 mL (1.59 g, 6.03 mmol) of TBSOTf. After stirring at -78 °C for 1.5 h, the reaction mixture was quenched with 50 mL sat. aq. NaHCO3 and warmed to room temperature. After extraction with 3 x 150 mL Et2O, the combined organics were washed with 1 x 200 mL sat. CuSO4, 1 x 200 mL brine, dried over MgSO4, filtered and evaporated to a cloudy white oil. Flash chromatography on silica gel, eluting with hexanes/EtOAc (8/1 to 4/1) gave 3.42 g (4.46 mmol, an 82% yield) of the title compound (Rf = 0.31; 4/1 hexanes/EtOAc) as a gummy colorless solid; 1H NMR (300 MHz, CDC13): δ -0.13-(-0.08) (m, 3H), 0.00- 0.06 (m, 3H), 0.85-0.91 (m, 9H), 1.05 (d, J=6.7 Hz, 3H), 1.33 (t, J=7.1 Hz, 6H), 2.60-2.75 (m, IH), 2.77-2.96 (m, IH), 3.00-3.31 (m, 2H), 3.77-4.00 (m, IH), 4.35 (q, J=7.1 Hz, 4H), 4.65-4.88 (m, 2H), 5.02-5.20 (m, IH), 6.60-6.85 (m, 4H), 7.15- 7.37 (m, 3H); MS (ES) mlz (relative intensity): 790 (M++Na, 100), 768 (M++H, 20).
Step 3
5-{(2R)-2-[[(2R)-2-(tert-Butyl-dimethyl-siloxy)-2-(3-chloro-phenyl). ethyl]-(2,2,2-trichloro-ethoxycarbonyI)-amino]-propyl}- benzo[l,3]dioxole-2,2-dicarboxylic acid
To a room temperature solution of 3.31 g (4.31 mmol) 5-{(2R)-2-ff(2R)-2- (tert-butyl-dimethyl-siloxy)-2-(3-chloro-phenyl)-ethyl]-(2,2,2-trichloro- ethoxycarbonyl)-amino]-propyl) -benzof 1 ,3]dioxole-2,2-dicarboxylic acid diethyl ester, 100 mL MeOH and 25 mL H2O 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 HCI. The reaction mixture is extracted with 3 x 100 mL EtOAc, and the combined organics were washed with 2 x 30 mL brine, dried over Na2SO4, filtered and evaporated to give 3.01 g (4.23 mmol, a 98% yield) of the title compound (Rf = 0.0; 10/1 CHCl3/MeOH) as an off-white solid; 1H NMR (300 MHz, CDC13): δ -0.19-(-0.11) (m, 3H), 0.01-0.09 (m, 3H), 0.81-0.91 (m, 9H), 0.93-0.97 (m, 3H), 2.55-2.97 (complex m, 3H), 3.07-3.35 (m, 2H), 3.80- 4.40 (br m, 2H), 4.60-4.83 (m, 2H), 5.03-5.18 (m, IH), 6.60-6.92 (m, 4H), 7.15- 7.39 (m, 3H); MS (ES) m/z (relative intensity): 734 (M++Na, 30), 712 (M++H, 100). Step 4
5-{(2R)-2-[[(2R)-2-(tert-Butyl-dimethyl-siloxy)-2-(3-chIoro-phenyl)- ethyl]-(2,2,2-trichloro-ethoxycarbonyl)-amino]-propyl}- benzo[l,3]dioxole-2,2-dicarboxylic acid diallyl ester
To a room temperature solution of 950 mg (1.34 mmol) 5-{(2R)-2-[f(2R)-2- (tert-butyl-dimethyl-siloxy)-2-(3-chloro-phenyl)-ethyl]-(2,2,2-trichloro- ethoxycarbonyl)-amino]-propyl) -benzof l,3]dioxole-2,2-dicarboxylic acid and 15 mL DMF was added 267 mg (2.67 mmol) of KHCO3 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. NaHCO3 and extracted with 3 x 100 mL Et2O. The combined organics were washed with 1 x 150 mL brine, dried over MgSO4, filtered and evaporated to a colorless oil. Flash chromatography on silica gel, eluting with hexanes/EtOAc (8/1 to 4/1), gave 670 mg (0.85 mmol, a 63% yield) of the title compound (Rf = 0.62; 2/1 hexanes/EtOAc) as a colorless oil; 1H NMR (300 MHz, CDC13): δ -0.19-(-0.1 1) (m, 3H), 0.00-0.08 (m, 3H), 0.87 (s, 9H), 1.04 (d, J=6.7 Hz, 3H), 2.60-2.74 (m, IH), 2.77-2.98 (m, IH), 3.03-3.17 (m, IH), 3.18-3.30 (m, IH), 3.75-3.98 (m, IH), 4.65-4.87 (m, 6H), 5.03-5.18 (m, IH), 5.29 (d, J=17.3 Hz, 2H), 5.34 (d, J=23.7 Hz, 2H), 5.82-5.97 (complex m, 2H), 6.60-6.88 (m, 4H), 7.15-7.37 (m, 3H); MS (ES) m/z (relative intensity): 814 (M++Na, 100).
Step 5 5-{(2R)-2-[[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethyl]-(2,2,2- trichloro-ethoxycarbonyl)-amino]-propyl}-benzofl,3]dioxole-2,2- dicarboxylic acid diallyl ester
To a 0 °C solution of 650 mg (0.82 mmol) 5-{(2R)-2-[[(2R)-2-(tert-butyl- dimethyl-siloxy)-2-(3-chloro-phenyl)-ethyl]-(2,2,2-trichloro-ethoxycarbonyl)-amino]- propyl) -benzof l,3]dioxole-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 an additional 1.0 mL of HF pyridine was added. After a total of 26 h, TLC indicated the disappearance of starting material and the formation of the title compound (Rf = 0.28 (2/1 hexanes/EtOAc). The reaction mixture was slowly quenched with 30 mL of sat. aq. NaHCO3, extracted with 2 x 75 mL Et2O and then with 1 x 75 mL EtOAc. The combined organics were washed with 1 x 100 mL brine, dried over MgSO4, filtered and evaporated to a colorless oil. Flash chromatography on silica gel, eluting with hexanes/EtOAc (2/1), gave 460 mg (0.68 mmol, an 83% yield) of the title compound (Rf = 0.28; 2/1 hexanes/EtOAc) as a colorless oil; 1H NMR (300 MHz, CDC13): δ 1.20-1.37 (m, 3H), 2.60-2.78 (m, 2H), 2.80-2.91 (m, IH), 2.98- 3.18 (m, IH), 3.23-3.40 (m, IH), 3.41-3.54 (m, 2H), 4.10-4.26 (br m, IH), 4.73- 4.92 (5H), 5.22-5.40 (complex m, 4H), 5.81-5.98 (complex m, 2H), 6.62-6.87 (m, 4H), 7.17-7.41 (m, 3H); MS (ES) mlz (relative intensity): 700 (M++ Na, 100).
Step 6
5-{(2R)-2- [(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}- benzυ[l,3]dioxole-2,2-dicarboxylic acid diallyl ester
A mixture of 370 mg (0.55 mmol) 5-{ (2R)-2-[f(2R)-2-(3-chloro-phenyl)-2- hydroxy-ethyI]-(2,2,2-trichloro-ethoxycarbonyl)-amino]-propyl)-benzof l,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. NaHCO3, 1 x 75 mL brine, dried over Na2SO4, filtered and evaporated to a colorless oil. Flash chromatography on silica gel, eluting with CHCl3/MeOH (20/1 to 10/1), gave 180 mg (0.36 mmol, a 66% yield) of the title compound (Rf = 0.35; 10/1 CHCyi MeOH) as a colorless gum; Η NMR
(300 MHz, CDC13): δ 1.20-1.33 (m, 3H), 2.70-2.81 (m, IH), 3.00-3.19 (m, 2H),
3.36-3.45 (m, 2H), 4.50-5.50 (br s, 2H), 4.70-4.80 (m, 4H), 5.10-5.20 (m, IH), 5.25-5.40 (m, 4H), 5.82-6.00 (complex m, 2H), 6.70-6.91 (m, 3H), 7.17-7.30 (m,
3H), 7.41 (s, IH); MS (ES) mlz (relative intensity): 502 (M+, 100).
EXAMPLE 99
5-{(2R)-2-[(2R)-2-(3-Chloro-phenyI)-2-hydroxy-ethylamino]-propyl}- benzo[l,3]dioxole-2,2-dicarboxylic acid bis-(3-phenyl-allyl)ester
Step 1
5-{(2R)-2-[f(2R)-2-(tert-Butyl-dimethyl-siloxy)-2-(3-chloro-phenyl)- ethyl]-(2,2,2-trichloro-ethoxycarbonyl)-amino]-propyl}- benzo[l ,3]dioxole-2,2-dicarboxylic acid bis-(3-phenyl-allyl) ester
The title compound was prepared as a colorless oil according to the procedure of Example 4, Step 4 except that cinnamyl bromide was used in place of allyl iodide; yield 66%; R, = 0.68 (2/1 hexanes/EtOAc); 1H NMR (300 MHz, CDC13): δ -0.19-(- 0.11) (m, 311), -0.01-0.05 (m, 3H), 0.83-0.90 (m, 9H), 1.02 (d, J=6.7 Hz, 3H), 2.60-2.75 (m, IH), 2.77-2.96 (m, IH), 3.04-3.33 (m, 2H), 3.76-4.00 (m, IH), 4.65- 4.85 (m, 2H), 4.90-4.98 (m, 4H), 5.02-5.20 (m, IH), 6.20-6.33 (m, 2H), 6.60-6.85 (m, 5H), 7.15-7.45 (m, 14H); MS (ES) m/z(relative intensity) 944 (M+, 100).
Step 2 5-{(2R)-2-[[(2R)2-(3-Chloro-phenyl)-2-hydroxy-ethyl]-(2,2,2- trichloro-ethoxycarbonyl)-amino]-propyl}-benzo[l,3]dioxole-2,2- dicarboxylic acid bis-(3-phenyl-allyl) ester
The title compound was prepared as a colorless oil according to the procedure of Example 4, Step 5 except that 5-{(2R)-2-f[(2R)-2-(tert-butyl-dimethyl-siloxy)-2-(3- chloro-phenyl)-ethyl]-(2,2,2-trichloro-ethoxycarbonyl)-amino]-propyl}- benzo[l,3]dioxole-2,2-dicarboxylic acid bis-(3-phenyl-allyl) ester was used in place of 5-{(2R)-2-[[(2R)-2-(tert-butyl-dimethyl-siloxy)-2-(3-chloro-phenyl)-ethyl]-(2,2,2- trichloro-ethoxycarbonyl)-amino]-propyl ) -benzof 1 ,3]dioxole-2,2-dicarboxylic acid diallyl ester; yield 78%; Rf = 0.31 (2/1 hexanes/EtOAc); 1H NMR (300 MHz, CDC13): δ 1.20-1.35 (m, 3H), 2.58-2.80 (m, IH), 2.81-3.20 (m, 2H), 3.22-3.56 (m, 2H), 4.10-4.31 (m, 3H), 4.70-4.95 (m, 5H), 6.17-6.43 (m, 2H), 6.60-6.90 (m, 5H), 7.15- 7.45 (m, 14H).; MS (ES) mlz (relative intensity): 830 (M++H, 100). Step 3
5-{(2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}. benzof l,3]dioxole-2,2-dicarboxylic acid bis-(3-phenyl-allyl)ester
The title compound was prepared as a colorless oil according to the procedure of Example 4, Step 6 except that 5-{(2R)-2-f[(2R)2-(3-chloro-phenyl)-2-hydroxy- ethyl]-(2,2,2-trichloro-ethoxycarbonyl)-amino]-propyl) -benzof l,3]dioxole-2,2- dicarboxylic acid bis-(3-ρhenyl-allyl) ester was used in place of 5-{(2R)-2-[[(2R)-2-(3- chloro-phenyl)-2-hydroxy-ethyl]-(2,2,2-trichloro-ethoxycarbonyl)-amino]-propyl)- benzo[l,3]dioxole-2,2-dicarboxylic acid diallyl ester; yield 59%; Rf = 0.35 (10/1 CHClVMeOH); 1H NMR (300 MHz, CDC13): δ 1.15 (d, J=6.3 Hz, 3H), 2.50-3.70 (brs, 2H), 2.60-2.71 (m, IH), 2.80-2.92 (m, 2H), 2.95-3.15 (m, 2H), 4.83-4.95 (m, 5H), 5.25-5.40 (m, 4H), 6.08-6.30 (complex m, 2H), 6.66-6.91 (m, 5H), 7.15-7.40 (m, 14H); MS (ES) mlz (relative intensity): 654 (M\ 100).
EXAMPLE 100
5-{(2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}- benzo[l,3]dioxole-2,2-dicarboxylic acid dicyclooctyl ester
The title compound was prepared as a white gum from 5-{2-[2-(3-chloro- phenyl)-2-hydroxy-ethylamino]-propyl) -benzof 1 ,3]dioxole-2,2-dicarboxylic acid and cyclooctanol according to the procedure of Example 1; yield 84 %; Rf = 0.30 (10/1 CHClVMeOH); IH NMR (300 MHz, CDC13): δ 1.30-1.39 (brd, 3H), 1.40-1.92 (m, 28H), 2.72-2.87 (m, IH), 3.06-3.30 (m, 2H), 3.39-3.52 (m, 2H), 3.80-3.91 (m, IH), 5.02-5.13 (m, IH), 5.40-5.80 (m, IH), 6.71-6.89 (m, 4H), 7.21-7.37 (m, 2H), 7.44 (s, IH), 8.73 (brs, IH), 10.1 1 (brs, IH); MS (ES) mlz (relative intensity): 679 (M+, 100).
EXAMPLE 101 5-{(2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}- benzo[l ,3]dioxole-2,2-dicarboxylic acid bis-(4-benzyloxy-but-2- enyl)ester
To a room temperature solution of 110 mg (0.25 mmol) of 5-{2-[2-(3-chloro- phenyl)-3-oxazolidinyl]-propyl}-benzo[l,3]dioxole-2,2-dicarboxylic acid and 5 mL of DMF was added 69 mg (0.69 mmol) of K2CO3 followed by 195 mg (0.76 mmol) of cis-4-benzyloxy-2-buten-l -methane sulfonate. After heating at 50 °C for 20 h, the reaction mixture was cooled to room temperature, poured into 50 mL of brine and extracted with 2 x 50 mL EtOAc. The combined organics were washed with 1 x 50 mL sat. aq. NaHCO3, 1 x 50 mL brine, dried over Na2SO4, 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 CHClVMeOH) as a yellow oil. 1H NMR (300 MHz, CDC13): δ 0.98-1.10 (m, 3H), 2.44-2.78 (m, 3H), 2.82-3.00 (m, 2H), 4.11-4.20 (m, 4H), 4.40-4.70 (m, 2H), 4.85- 4.95 (m„ 4H), 5.70-5.79 (m, 2H), 5.81-5.92 (m, 2H), 6.72-6.90 (m, 3H), 7.17-7.47 (m, 14H); MS (ES) mlz (relative intensity): 742 (M+, 100).
EXAMPLE 102
5-{(2R)-2-[(2R)-2-(3-Chloro-phenyI)-2-hydroxy-ethylamino]- propyl}benzo[l,3]dioxole-2,2-dicarboxylic acid phenethyl ester
To a 0 °C solution of 0.630 g (1.0 mmol) of 5-{(2R)-2-f(2R)-2-(3-chloro- phenyl)-2-hydroxy-ethylamino]-propyl)-benzo[l,3]dioxole-2,2-dicarboxylic acid bis- (2-phenethyl) ester in 12 mL CH3CN was added 5.6 mL 1 N NaOH (5.6 mmol), and the resulting solution was stirred at room temperature for 12 h. The solution was concentrated, 10 mL of water and 10 mL of ether were added, the pH of the mixture was adjusted to pH 8 with sat. aq. NH4C1, and the resulting white precipitate was collected by filtration. After washing with sat. aq. NaHCO3, water and ether, the resulting solid was dried under vacuum to give 0.4 g (0.76 mmol, a 76% yield) of the title compound (Rf = 0.39; 9/1 CHCl3/MeOH) as a tan solid ; mp 75-82 °Q 1H NMR (300 MHz, DMSO-d6): δ 1.00 (d, 3H), δ 2.5 (br m, 4H), δ 2.84-3.10 (m, 5H), δ 3.35 (br, water), δ 4.28 (t, 2H), δ 4.90 (m, IH), δ 6.6 (d, IH), δ 6.76 (d, 2H), δ 7.21 (br s, 6H), δ 7.36 (m, 3H), δ 7.46 (s, IH); MS (ES) mlz (relative intensity): 526 (M+, 100). EXAMPLE 103
5-{(2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]- propyl}benzυf l,3]dioxole-2,2-dicarboxylic acid (1-phenyl-ethyl) ester
The title compound was prepared as a tan solid according to the procedure of
Example 102 from 5-{(2R)-2-f(2R)-2-(3-chloro-phenyl)-2-hydroxy-ethylamino]- propyl) benzof 1 ,3]dioxole-2,2-dicarboxylic acid bis-(l-phenylethyl) ester; yield: 22 %; Rf = 0.39 (9/1 CHCVMeOH; mp 71-79 °C; Η NMR (300 MHz, DMSO-dβ): δ 1.00 (d, 3H), δ 1.5 (br m, 3H), δ 2.4-2.75 (m, IH), δ 3.15 -3.45(br m, 5H), δ 4.90 (br d, IH), δ 5.20 (br d, IH), δ 5.90 (q, IH), δ 6.6 (d, IH), δ 6.76 (d, 2H), δ 7.21 (br s, 6H), δ 7.36 (m, 3H), δ 7.46 (s, IH); MS (ES) mlz (relative intensity): 526 (M\ 100).
EXAMPLE 104 5-{(2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]- propyI}benzo[ l,3]dioxole-2,2-dicarboxylic acid bis-(3-benzyloxy- propy!)ester
The title compound was prepared as a yellow gum from 5-{2-[2-(3-chloro- phenyl)-2-hydroxy-ethylamino]-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 CHClVMeOH); 1H NMR (300 MHz, CDC13): δ 1.32 (d, 3H), δ 2.00 (m, 4H), δ 2.75 (m, IH), δ 3.30 (s, 2H), δ 3.50 (m, 4H), δ 4.40 (br m, 12H), δ 5.49 (s, IH), δ 6.68-6.85 (m, 3H), δ 7.24-7.40 (m, 13H), δ 7.43 (s, IH); MS (ES) mlz (relative intensity): 518 (M+-HC1, 100).

Claims

CLAIMS What is Claimed:
1 ) A compound of the formula:
wherein:
Rl and R6 are independently hydrogen, C\ to C6 alkyl, trifluoromethyl, cyano, Cl to C6 alkoxy, or halogen;
R2 is hydrogen or Cl to C6 trialkylsilyl; R3 is hydrogen or Cl to C6 alkoxycarbonyl; or R2 and R3 are joined to form a ring:
wherein R' is hydrogen, Ci to C6 alkyl, or aryl;
R4 and R5 are independently hydrogen or Cl to C6 alkyl; R7 and Rg are independently OR9 or NR10R11;
R9 is hydrogen, Ci to C12 alkyl, Ci to C12 cycloalkyl, C\ to C12 silylalkyl, aryl, arylalkyl, alkoxyalkyl, heteroaryl, -CHR12COOR13, -CHRi2C(O)Ri3, - CHR12CONR10R1 1, -CHR12OCOOR13, or -CHRi2OC(O)Ri3, with the provision that R9 is not hydrogen in both R7 and R8;
RlO and Rn are independently hydrogen, Ci to C12 alkyl, aralkyl, aryl, furanylalkyl, or alkoxycarbonylalkyl;
Rl2 and R13 are independently hydrogen, Ci to C12 alkyl, aryl, or aralkyl; or a pharmaceutically acceptable salt thereof, enantiomer thereof, racemic mixture thereof, or diastereomeric mixture thereof. 2) A compound of Claim 1 which is 5-{2-[2-(3-chloro-phenyl)-2-hydroxy- ethylamino]-propyl } -benzof 1 ,3]dioxole-2,2-dicarboxylic acid bis-(2-methoxy-ethyl) ester or a pharmaceutically acceptable salt thereof.
3) A compound of Claim 1 which is 5-{2-f2-(3-chloro-phenyl)-2-hydroxy- ethylamino]-propyl) -benzof 1 ,3]dioxole-2,2-dicarboxylic acid diphenethyl ester or a pharmaceutically acceptable salt thereof.
4) A compound of Claim 1 which is 5-{2-f2-(3-chloro-phenyl)-2-hydroxy- ethylamino] -propyl) -benzof 1 ,3]dioxole-2,2-dicarboxylic acid bis-(2-butoxy-ethyl) ester or a pharmaceutically acceptable salt thereof.
5) A compound of Claim 1 which is 5-{2-[2-(3-chloro-phenyl)-2-hydroxy- ethylamino]-propyl } -benzof 1 ,3]dioxole-2,2-dicarboxylic acid bis-(2-phenoxy-ethyl) ester or a pharmaceutically acceptable salt thereof.
6) A compound of Claim 1 which is 5- {2-f2-(3-chloro-phenyl)-2-hydroxy- ethylamino] -propyl } -benzof 1 ,3]dioxole-2,2-dicarboxylic acid bis-(2-ethoxy-ethyl) ester or a pharmaceutically acceptable salt thereof.
7) A compound of Claim 1 which is 5-{2-[2-(3-chloro-phenyl)-2-hydτoxy- ethylamino] -propyl) -benzof l,3]dioxole-2,2-dicarboxylic acid bis-(2-tert-butoxy-ethyl) ester or a pharmaceutically acceptable salt thereof.
8) A compound of Claim 1 which is 5- {2-[2-(3-chloro-phenyl)-2-hydroxy- ethylamino] -propyl } -benzof 1 ,3]dioxole-2,2-dicarboxylic acid (2-tert-butoxy-ethyl) ester or a pharmaceutically acceptable salt thereof.
9) A compound of Claim 1 which is 5- {2-[2-(3-chloro-phenyl)-2-hydroxy- ethylamino] -propyl ) -benzof l,3]dioxole-2,2-dicarboxylic acid bis-(2-isobutoxy-ethyl) ester or a pharmaceutically acceptable salt thereof.
10) A compound of Claim 1 which is 5-{2-[2-(3-chloro-phenyl)-2-hydroxy- ethylamino]-propyl) -benzof l,3]dioxole-2,2-dicarboxylic acid bis-(benzyl) ester or a pharmaceutically acceptable salt thereof. 11) A compound of Claim 1 which is 5- {2-[2-(3-chloro-phenyl)-2-hydroxy- ethylamino] -propyl) -benzof 1 ,3]dioxole-2,2-dicarboxylic acid bis-(cyclohexyl) ester or a pharmaceutically acceptable salt thereof.
12) A compound of Claim 1 which is 5-{2-[2-(3-chloro-phenyl)-2-hydroxy- e thy lamino] -propyl) -benzof 1 ,3]dioxole-2,2-dicarboxylic acid bis-(cyclopentyl) ester or a pharmaceutically acceptable salt thereof.
13) A compound of Claim 1 which is 5-{2-[2-(3-chloro-phenyl)-2-hydroxy- ethylamino]-propyl)-benzo[l,3]dioxole-2,2-dicarboxylic acid dioctyl ester or a pharmaceutically acceptable salt thereof.
14) A compound of Claim 1 which is 5-{2-[2-(3-chloro-phenyl)-2-hydroxy- ethylamino] -propyl) -benzof 1 ,3]dioxole-2,2-dicarboxylic acid dipentyl ester or a pharmaceutically acceptable salt thereof.
15) A compound of Claim 1 which is 5-{2-[2-(3-chloro-phenyl)-2-hydroxy- ethylamino]-propyl)-benzo[l,3]dioxole-2,2-dicarboxylic acid dihexyl ester or a pharmaceutically acceptable salt thereof.
16) A compound of Claim 1 which is carbonic acid 3-chloro-benzyl ester 2- (3-chloro-benzyloxycarbonyloxy)-4-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]- propyl) -phenyl ester or a pharmaceutically acceptable salt thereof.
17) A compound of Claim 1 which is 5-{2-[2-(3-chloro-phenyl)-2-hydroxy- ethylamino]-propyl)-benzo[l,3]dioxole-2,2-dicarboxylic acid bis-(l-phenyl-ethyl) ester or a pharmaceutically acceptable salt thereof.
18) A compound of Claim 1 which is 5-{2-[2-(3-chloro-phenyl)-2-hydroxy- ethylamino]-propyl) -benzof 1 ,3]dioxole-2,2-dicarboxylic acid diheptyl ester or a pharmaceutically acceptable salt thereof. 19) A compound of Claim 1 which is 5-{2-[2-(3-chloro-phenyl)-2-hydroxy- ethylamino]-propyl)-benzo[l,3]dioxole-2,2-dicarboxylic acid dinonyl ester or a pharmaceutically acceptable salt thereof.
20) A compound of Claim 1 which is 5-{2-[2-(3-chloro-phenyl)-2-hydroxy- ethylamino] -propyl) -benzof l,3]dioxole-2,2-dicarboxylic acid bis-decyl ester or a pharmaceutically acceptable salt thereof.
21) A compound of Claim 1 which is 5-{2-[2-(3-chloro-phenyl)-2-hydroxy- ethylamino] -propyl) -benzof 1 ,3]dioxole-2,2-dicarboxylic acid didodecyl ester or a pharmaceutically acceptable salt thereof.
22) A compound of Claim 1 which is 5-{2-[2-(3-chloro-phenyl)-2-hydroxy- ethylamino]-propyl ) -benzof 1 ,3]dioxole-2,2-dicarboxylic acid bis-(2-isopropoxy-ethyl) ester or a pharmaceutically acceptable salt thereof.
23) A compound of Claim 1 which is 5-{2-[2-(3-chloro-phenyl)-2-hydroxy- ethylami no] -propyl) -benzof 1 ,3]dioxole-2,2-dicarboxylic acid isopropyl ester or a pharmaceutically acceptable salt thereof.
24) A compound of Claim 1 which is 5- {2-[2-(3-chloro-phenyl)-2-hydroxy- ethylami no] -propyl) -benzof 1 ,3]dioxole-2,2-dicarboxylic acid ethyl ester or a pharmaceutically acceptable salt thereof.
25) A compound of Claim 1 which is 5-{2-[2-(3-chloro-phenyl)-2-hydroxy- ethylamino]-propyl)-benzofl,3]dioxole-2,2-dicarboxylic acid bis- methoxycarbonylmethyl ester or a pharmaceutically acceptable salt thereof.
26) A compound of Claim 1 which is 5-{2-[2-(3-chloro-phenyl)-2-hydroxy- ethylamino]-propyl)-benzof l,3]dioxole-2,2-dicarboxylic acid bis- propoxycarbonylmethyl ester or a pharmaceutically acceptable salt thereof.
27) A compound of Claim 1 which is 5-{2-[2-(3-chloro-phenyl)-2-hydroxy- ethylamino] -propyl } -benzof 1 ,3]dioxole-2,2-dicarboxylic acid bis-(l-methoxycarbonyl- ethyl) ester or a pharmaceutically acceptable salt thereof. 28) A compound of Claim 1 which is 5- {2-[2-(3-chloro-phenyl)-2-hydroxy- ethylamino] -propyl }-benzof 1 ,3]dioxole-2,2-dicarboxylic acid bis-isopropoxycarbonyl¬ methyl ester or a pharmaceutically acceptable salt thereof.
29) A compound of Claim 1 which is 5- {2-[2-(3-chloro-phenyl)-2-hydroxy- ethylamino] -propyl) -benzof 1 ,3]dioxole-2,2-dicarboxylic acid bis- ethoxycarbonylmethyl ester or a pharmaceutically acceptable salt thereof.
30) A compound of Claim 1 which is 5-{2-[2-(3-chloro-phenyl)-2-hydroxy- ethylamino] -propyl }-benzof 1 ,3]dioxole-2,2-dicarboxylic acid bis-(l -ethoxycarbonyl- ethyl) ester or a pharmaceutically acceptable salt thereof.
31) A compound of Claim 1 which is 5-{2-[2-(3-chloro-phenyl)-2-hydroxy- ethylamino] -propyl ) -benzof l,3]dioxole- 2,2-dicarboxylic acid bis- trimethylsilanylmethyl ester or a pharmaceutically acceptable salt thereof.
32) A compound of Claim 1 which is 5-{2-[2-(3-chloro-phenyl)-2-hydroxy- ethylamino] -propyl ) -benzof 1 ,3]dioxole-2,2-dicarboxylic acid bis-(2-trimethylsilanyl- ethyl) ester or a pharmaceutically acceptable salt thereof.
33) A compound of Claim 1 which is 5-{2-f2-(3-chloro-phenyl)-2-hydroxy- ethylamino]-propyl ) -benzof 1 ,3]dioxole-2,2-dicarboxylic acid bis-(3-trimethylsilanyl- propyl) ester or a pharmaceutically acceptable salt thereof.
34) A compound of Claim 1 which is 5-{2-[2-(3-chloro-phenyl)-2-hydroxy- ethylamino] -propyl } -benzof 1 ,3]dioxole-2,2-dicarboxylic acid bis-(3,3-dimethyl-butyl) ester or a pharmaceutically acceptable salt thereof.
35) A compound of Claim 1 which is 5-{2-f2-(3-chloro-phenyI)-2-hydroxy- ethylamino] -propyl ) -benzof 1 ,3]dioxole-2,2-dicarboxy lie acid bis-cyclohexylmethyl ester or a pharmaceutically acceptable salt thereof. 36) A compound of Claim 1 which is 5-{2-[2-(3-chloro-phenyl)-2-hydroxy- ethylamino]-propyl)-benzo[l,3]dioxole-2,2-dicarboxylic acid bis-(4-methyl-pentyl) ester or a pharmaceutically acceptable salt thereof.
37) A compound of Claim 1 which is 5-{2-f2-(3-chloro-phenyl)-2-hydroxy- ethylamino]- propyl) -benzof l,3]dioxole-2,2-dicarboxylic acid bis-(2-cyclohexyl-ethyl ) ester or a pharmaceutically acceptable salt thereof.
38) A compound of Claim 1 which is 5- {2-f2-(3-chloro-phenyl)-2-hydroxy- ethylamino] -propyl) -benzof 1 ,3]dioxole-2,2-dicarboxylic acid bis-(3-cyclopentyl- propyl ) ester or a pharmaceutically acceptable salt thereof.
39) A compound of Claim 1 which is 5-{2-[2-(3-chloro-phenyl)-2-hydroxy- ethylamino] -propyl }-benzo[ 1 ,3]dioxole-2,2-dicarboxylic acid bis-cyclopropylmethyl ester or a pharmaceutically acceptable salt thereof.
40) A compound of Claim 1 which is 5-{2-[2-(3-chloro-phenyl)-2-hydroxy- ethylamino]-propyl ) -benzof 1 ,3]dioxole-2,2-dicarboxylic acid bis-(l-methyl- cyclopropyl-methyl) ester or a pharmaceutically acceptable salt thereof.
41) A compound of Claim 1 which is 5- {2-[2-(3-chloro-phenyl)-2-hydroxy- ethylamino]-propyl ) -benzof 1 ,3]dioxole-2,2-dicarboxylic acid bis-cyclobutylmethyl ester or a pharmaceutically acceptable salt thereof.
42) A compound of Claim 1 which is 5-{2-f2-(3-chloro-phenyl)-2-hydroxy- ethylamino]-propyl)-benzo[l,3]dioxole-2,2-dicarboxylic acid bis-(2-cyclopentyl-ethyl) ester or a pharmaceutically acceptable salt thereof.
43) A compound of Claim 1 which is 5-{2-[2-(3-chloro-phenyl)-2-hydroxy- ethylamino]propyl ) benzof l,3]dioxole-2,2-dicarboxylic acid bis-acetoxymethyl ester or a pharmaceutically acceptable salt thereof.
44) A compound of Claim 1 which is 5- {2-f2-(3-chloro-phenyl)-2-hydroxy- ethylamino]propyl) benzof l,3]dioxole-2,2-dicarboxylic acid bis-propionyloxymethyl ester or a pharmaceutically acceptable salt thereof. 45) A compound of Claim 1 which is 5- {2-[2-(3-chloro-phenyl)-2-hydroxy- ethylamino]propyl) benzof l,3]dioxole-2,2-dicarboxylic acid bis-butyryloxymethyl ester or a pharmaceutically acceptable salt thereof.
46) A compound of Claim 1 which is 5-{2-[2-(3-chloro-phenyl)-2-hydroxy- ethylaminojpropyl ) benzof 1 ,3]dioxole-2,2-dicarboxylic acid bis-isobutyryloxymethyl ester or a pharmaceutically acceptable salt thereof.
47) A compound of Claim 1 which is 5- {2-[2-(3-chloro-phenyl)-2-hydroxy- ethylamino]propyl } benzof 1 ,3]dioxole-2,2-dicarboxylic acid bis-heptanoyloxymethyl ester or a pharmaceutically acceptable salt thereof.
48) A compound of Claim 1 which is 5- {2-f2-(3-chloro-phenyl)-2-hydroxy- ethylamino]propyl) benzof 1 ,3]dioxole-2,2-dicarboxylic acid bis-(4-methyl- pentanoyloxy-methyl) ester or a pharmaceutically acceptable salt thereof.
49) A compound of Claim 1 which is 5-{2-[2-(3-chloro-phenyl)-2-hydroxy- ethylamino]propyl } benzof 1 ,3]dioxole-2,2-dicarboxylic acid bis-hexanoyloxymethyl ester or a pharmaceutically acceptable salt thereof.
50) A compound of Claim 1 which is 5-{2-[2-(3-chloro-phenyl)-2-hydroxy- ethylamino]propyl) benzof l,3]dioxole-2,2-dicarboxy!ic acid bis- (2,2-dimethyl- propionyloxymethyl) ester or a pharmaceutically acceptable salt thereof.
51) A compound of Claim 1 which is 5-{2-f2-(3-chloro-phenyl)-2-hydroxy- ethylamino]propyl) benzof l,3]dioxole-2,2-dicarboxylic acid bis cyclohexanecarbonyl- oxymethyl ester or a pharmaceutically acceptable salt thereof.
52) A compound of Claim 1 which is 5- {2-[2-(3-chloro-phenyl)-2-hydroxy- ethylamino] propyl ) benzof l,3]dioxole-2,2-dicarboxylic acid bis-(l-propionyloxy-ethyl) ester or a pharmaceutically acceptable salt thereof. 53) A compound of Claim 1 which is 5-{2-[2-(3-chloro-phenyl)-2-hydroxy- ethylamino]propyl ) benzof 1 ,3]dioxole-2,2-dicarboxylic acid bis-[ 1 -(2,2-dimethyl- propionyloxyethyl) ester or a pharmaceutically acceptable salt thereof.
54) A compound of Claim 1 which is 5-{2-f2-(3-chloro-phenyl)-2-hydroxy- ethylamino]propyl) benzof 1, 3] dioxole- 2,2-dicarboxylic acid bis-(3,3-dimethyl- butyryloxy-methyl) ester or a pharmaceutically acceptable salt thereof.
55) A compound of Claim 1 which is 5- {2-[2-(3-chloro-phenyl)-2-hydroxy- ethylamino]propyl) benzof 1 ,3]dioxole-2,2-dicarboxylic acid bis-[l-(3,3-dimethyl- butyryl-oxy)ethyl)) ester or a pharmaceutically acceptable salt thereof.
56) A compound of Claim 1 which is 5-{2-[2-(3-chloro-phenyl)-2-hydroxy- ethylamino]propyl } benzof 1 ,3]dioxole-2,2-dicarboxylic acid bis-(3-cyclopentyl- propionyl-oxymethyl) ester or a pharmaceutically acceptable salt thereof.
57) A compound of Claim 1 which is 5- {2-[2-(3-chloro-phenyl)-2-hydroxy- ethylamino]propyl ) benzof 1 ,3]dioxole-2,2-dicarboxylic acid bis-benzoyloxymethyl ester or a pharmaceutically acceptable salt thereof.
58) A compound of Claim 1 which is 5-{2-[2-(3-chloro-phenyl)-2-hydroxy- ethylamino]propyl } benzof 1 ,3]dioxole-2,2-dicarboxylic acid bis-(benzoyloxy-ethyl) ester or a pharmaceutically acceptable salt thereof.
59) A compound of Claim 1 which is 5-{2-[2-(3-chloro-phenyl)-2-hydroxy- ethylamino]propyl ) benzof 1 ,3]dioxole-2,2-dicarboxylic acid bis-(2,2-dimethyl- butyryloxy-methyl) ester or a pharmaceutically acceptable salt thereof.
60) A compound of Claim 1 which is 5-{2-[2-(3-chloro-phenyl)-2-hydroxy- ethylamino]-propyl)-benzo[l ,3]dioxole-2,2-dicarboxylic acid bis-amide or a pharma¬ ceutically acceptable salt thereof.
61) A compound of Claim 1 which is 5- (2-f2-(3-chloro-phenyl)-2-hydroxy- ethylamino]-propyl)-benzo[l ,3Jdioxole-2,2-dicarboxylic acid bis-2-propyl amide or a pharmaceutically acceptable salt thereof. 62) A compound of Claim 1 which is 5-{2-[2-(3-chloro-phenyl)-2-hydroxy- ethylamino]-propyl) -benzof l,3]dioxole-2,2-dicarboxylic acid bis-n-butyl amide or a pharmaceutically acceptable salt thereof.
63) A compound of Claim 1 which is 5- {2-[2-(3-chloro-phenyl)-2-hydroxy- ethylamino] -propyl) -benzof l,3]dioxole- 2,2-dicarboxylic acid bis-phenylmethyl amide or a pharmaceutically acceptable salt thereof.
64) A compound of Claim 1 which is 5-{2-[2-(3-chloro-phenyl)-2-hydroxy- ethylamino]-propyl)-benzo[l ,3]dioxole-2,2-dicarboxylic acid bis-(2-furanylmethyl) amide or a pharmaceutically acceptable salt thereof.
65) A compound of Claim 1 which is 5-{2-[2-(3-chloro-phenyl)-2-hydroxy- ethylamino]-propyl) -benzof l,3]dioxole-2,2-dicarboxylic acid bis-(glycine ethyl ester) amide or a pharmaceutically acceptable salt thereof.
66) A compound of Claim 1 which is 5-{2-[2-(3-chloro-phenyl)-3- oxazolidinyl]-propyl) -benzof l,3]dioxole-2,2-dicarboxylic acid or a pharmaceutically acceptable salt thereof.
67) A compound of Claim 1 which is 5-((2R)-2-{tert-Butoxycarbonyl- f(2R)-2-(3-chloro-phenyl)-2-hydroxy-ethyl]-amino)-propyl)-benzo[l,3]dioxole-2,2- dicarboxylic acid bis-diethylcarbamoylmethyl ester or a pharmaceutically acceptable salt thereof.
68) A compound of Claim 1 which is 5-{(2R)-2-[(2R)-2-(3-Chloro- phenyl)-2-hydroxy-ethylamino]-propyl) -benzof l,3]dioxole-2,2-dicarboxylic acid bis- diethyl-carbamoylmethyl ester or a pharmaceutically acceptable salt thereof.
69) A compound of Claim 1 which is 5-{2-[2-(3-Chloro-phenyl)-2- hydroxy-ethylamino]-propyl } -benzof l,3]dioxole-2,2-dicarboxylic acid cyclopropylmethyl ester or a pharmaceutically acceptable salt thereof. 70) A compound of Claim 1 which is 5- {2-[2-(3-Chloro-phenyl)-2- hydroxy-ethylamino]-propyl } -benzof 1 ,3]dioxole-2,2-dicarboxylic acid cyclobutylmethyl ester or a pharmaceutically acceptable salt thereof.
71) A compound of Claim 1 which is 5-{2-[2-(3-Chloro-phenyl)-2- hydroxy-ethylamino]-propyl) -benzof l,3]dioxole-2,2-dicarboxylic acid bis 2-(3- Thienyl)ethyl- ester or a pharmaceutically acceptable salt thereof.
72) A compound of Claim 1 which is 5- { 2-[2-(3-Chloro-phenyl)-2- hydroxy-ethylamino]-propyl } -benzof 1 ,3]dioxole-2,2-dicarboxylic acid 2-(3-
Thienyl)ethyl ester or a pharmaceutically acceptable salt thereof.
73) A compound of Claim 1 which is 5-{2-[2-(3-Chloro-phenyl)-2- hydroxy-ethylamino]-propyl) -benzof 1 ,3]dioxole-2,2-dicarboxylic acid bis 2- (Chloro)ethyl ester or a pharmaceutically acceptable salt thereof.
74) A compound of Claim 1 which is 5- { (2R)-2-f (2R)-2-(3-Chloro- phenyl)-2-hydroxy-ethylamino]-propyl ) -benzof 1 ,3]dioxole-2,2-dicarboxylic acid bis- (2-ethylbutyl) ester or a pharmaceutically acceptable salt thereof.
75) A compound of Claim 1 which is 5- { (2R)-2-[(2R)-2-(3-Chloro- phenyl)-2-hydroxy-ethylamino]-propyl } -benzof 1 ,3]dioxole-2,2-dicarboxylic acid bis- (3-methylbutyl)ester or a pharmaceutically acceptable salt thereof.
76) A compound of Claim 1 which is 5- { (2R)-2-[(2R)-2-(3-Chloro- phenyl)-2-hydroxy-ethylamino]-propyl } -benzof 1 ,3]dioxole-2,2-dicarboxylic acid (3- methylbutyl)ester or a pharmaceutically acceptable salt thereof.
77) A compound of Claim 1 which is 5- { (2R)-2-f (2R)-2-(3-Chloro- phenyl)-2-hydroxy-ethylamino]-propyl ) -benzof 1 ,3]dioxole-2,2-dicarboxylic acid bis- adamantan-1-ylmethyl ester or a pharmaceutically acceptable salt thereof.
78) A compound of Claim 1 which is 5- { (2R)-2-f (2R)-2-(3-Chloro- phenyl)-2-hydroxy-ethylamino]-propyl)-benzo[l ,3]dioxole-2,2-dicarboxylic acid bis- (2,2-dimethyl-propyl) ester or a pharmaceutically acceptable salt thereof. 79) A compound of Claim 1 which is 5- { (2R)-2-f(2R)-2-(3-Chloro- phenyl)-2-hydroxy-ethylamino]-propyl } -benzof 1 ,3]dioxole-2,2-dicarboxylic acid adamantan-1-ylmethyl ester or a pharmaceutically acceptable salt thereof.
80) A compound of Claim 1 which is 5- { (2R)-2-[(2R)-2-(3-Chloro- phenyl)-2-hydroxy-ethylamino]-propyl)-benzo[l ,3]dioxole-2,2-dicarboxylic acid (2,2- dimethyl-propyl)ester or a pharmaceutically acceptable salt thereof.
81 ) A compound of Claim 1 which is 5- { (2R)-2-[(2R)-2-(3-Chloro- phenyl)-2-hydroxy-ethylamino]-propyl } -benzof 1 ,3]dioxole-2,2-dicarboxylic acid (3,3- dimethylbutyl) ester or a pharmaceutically acceptable salt thereof.
82) A compound of Claim 1 which is ) A compound of Claim 1 which is 5-{(2R)-2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}- benzof l,3]dioxole-2,2-dicarboxylic aicd bis-(l-methyl-cyclohexylmethyl) ester or a pharmaceutically acceptable salt thereof.
83) A compound of Claim 1 which is 5- { (2R)-2-[(2R)-2-(3-Chloro- phenyl)-2-hydroxy-ethylamino]-propyl ) -benzof 1 ,3]dioxole-2,2-dicarboxylic aicd bis- (2-cyclohexyl-2-methyl-propyl) ester or a pharmaceutically acceptable salt thereof.
84) A compound of Claim 1 which is 5- { (2R)-2-[(2R)-2-(3-Chloro- phenyl)-2-hydroxy-ethylamino]-propyl) -benzof 1 ,3]dioxole-2,2-dicarboxylic aicd bis- (2-methyl-2-nitro-propyl) ester or a pharmaceutically acceptable salt thereof.
85) A compound of Claim 1 which is 5- { (2R)-2-[(2R)-2-(3-Chloro- phenyl)-2-hydroxy-ethylamino]-propyl) -benzof l,3]dioxole-2,2-dicarboxylic aicd bis- (2,2,4-trimethyl-pentyl) ester or a pharmaceutically acceptable salt thereof.
86) A compound of Claim 1 which is 5- { (2R)-2-f(2R)-2-(3-Chloro- phenyl)-2-hydroxy-ethylamino]-propyl } -benzof 1 ,3]dioxole-2,2-dicarboxylic aicd bis- (2,2-dimethyl-pentyl) ester or a pharmaceutically acceptable salt thereof. 87) A compound of Claim 1 which is 5- { (2R)-2-[(2R)-2-(3-Chloro- phenyl)-2-hydroxy-ethylamino]-propyl ) -benzof 1 ,3]dioxole- 2,2-dicarboxylic aicd bis- (tetrahydro-furan-3-ylmethyl) ester or a pharmaceutically acceptable salt thereof.
88) A compound of Claim 1 which is 5- { (2R)-2-f (2R)-2-(3-Chloro- phenyl)-2-hydroχy-ethylamino]-propyl ) -benzof 1 ,3]dioxole-2,2-dicarboxylic aicd bis- (3-hydroxy-2,2,4-trimethyl-pentyl) ester or a pharmaceutically acceptable salt thereof.
89) A compound of Claim 1 which is 5- { (2R)-2-f (2R)-2-(3-Chloro- phenyl)-2-hydroxy-ethylamino]-propyl ) -benzof 1 ,3]dioxole-2,2-dicarboxylic aicd bis- (2,2-dimethyl-3-phenyl-propyl) ester or a pharmaceutically acceptable salt thereof.
90) A compound of Claim 1 which is 5- { (2R)-2-f (2R)-2-(3-Chloro- phenyl)-2-hydroχy-ethylamino]-propyl ) -benzof 1 ,3]dioxole-2,2-dicarboxylic aicd bis- (tetrahydro-pyran-2-ylmethyl) ester or a pharmaceutically acceptable salt thereof.
91) A compound of Claim 1 which is 5- { (2R)-2-[(2R)-2-(3-Chloro- phenyl)-2-hydroxy-ethylamino]-propyl) -benzof l,3]dioxole- 2,2-dicarboxylic aicd bis- (tetrahydro-furan-2-ylmethyl) ester or a pharmaceutically acceptable salt thereof.
92) A compound of Claim 1 which is 5- { (2R)-2-[(2R)-2-(3-Chloro- phenyl)-2-hydroxy-ethylamino]-propyl) -benzof 1 ,3]dioxole-2,2-dicarboxylic aicd bis- (5-methyl-[l,3]dioxan-5-ylmethyl) ester or a pharmaceutically acceptable salt thereof.
93) A compound of Claim 1 which is 5- { (2R)-2-f (2R)-2-(3-Chloro- phenyl)-2-hydroxy-ethylamino] -propyl) -benzof l,3]dioxole-2,2-dicarboxylic aicd bis- (l-methyl-cyclohex-3-enylmethyl) ester or a pharmaceutically acceptable salt thereof.
94) A compound of Claim 1 which is 5- { (2R)-2-f (2R)-2-(3-Chloro- phenyl)-2-hydroxy-ethylamino]-propyl } -benzof 1 ,3]dioxole-2,2-dicarboxylic aicd bis- (3-hydroxy-2,2-dimethyl-propyl) ester or a pharmaceutically acceptable salt thereof.
95) A compound of Claim 1 which is 5- { (2R)-2-f(2R)-2-(3-Chloro- phenyl)-2-hydroxy-ethylamino]-propyl) -benzof l,3]dioxole-2,2-dicarboxylic acid (2- ethoxy-ethyl) ester or a pharmaceutically acceptable salt thereof. 96) A compound of Claim 1 which is 5- { (2R)-2-[(2R)-2-(3-Chloro- phenyl)-2-hydroxy-ethylamino]-propyl } -benzof 1 ,3]dioxole-2,2-dicarboxy lie acid bis- [2-(3-bromo-phenyl)-ethyl]ester hydrochloride salt.
97) A compound of Claim 1 which is 5- { (2R)-2-[(2R)-2-(3-Chloro- phenyl)-2-hydroxy-ethylamino]-propyl } -benzof 1 ,3]dioxole-2,2-dicarboxylic acid bis- (2-m-tolyl-ethyl) ester hydrochloride salt.
98) A compound of Claim 1 which is 5- { (2R)-2-f(2R)-2-(3-Chloro- phenyl)-2-hydroxy-ethylamino]-propyl) -benzof l,3]dioxole-2,2-dicarboxylic acid diallyl ester or a pharmaceutically acceptable salt thereof.
99) A compound of Claim 1 which is 5- { (2R)-2-[(2R)-2-(3-Chloro- phenyl)-2-hydroxy-ethylamino]-propyl) -benzof l,3]dioxole-2,2-dicarboxylic acid bis- (3-phenyl-allyl)ester or a pharmaceutically acceptable salt thereof.
100) A compound of Claim 1 which is 5- { (2R)-2-[(2R)-2-(3-Chloro- phenyl)-2-hydroxy-ethylamino]-propyl } -benzof l,3]dioxole-2,2-dicarboxy lie acid dicyclooctyl ester or a pharmaceutically acceptable salt thereof.
101) A compound of Claim 1 which is 5-{(2R)-2-[(2R)-2-(3-Chloro- phenyl)-2-hydroxy-ethylamino]-propyl) -benzof l,3]dioxole-2,2-dicarboxylic acid bis- (4-benzyloxy-but-2-enyl)ester or a pharmaceutically acceptable salt thereof.
102) A compound of Claim 1 which is 5- { (2R)-2-f(2R)-2-(3-Chloro- phenyl)-2-hydroxy-ethylamino]-propyl } benzof l,3]dioxole-2,2-dicarboxylic acid phenethyl ester or a pharmaceutically acceptable salt thereof.
103) A compound of Claim 1 which is 5- { (2R)-2-f (2R)-2-(3-Chloro- phenyl)-2-hydroxy-ethylamino]-propyl) benzof l,3]dioxole-2,2-dicarboxylic acid (1- phenyl-ethyl) ester or a pharmaceutically acceptable salt thereof. 104) A compound of Claim 1 which is 5- { (2R)-2-[(2R)-2-(3-Chloro- phenyl)-2-hydroxy-ethylamino] -propyl) benzof 1 ,3]dioxole-2,2-dicarboxylic acid bis- (3-benzyloxy-propyl)ester or a pharmaceutically acceptable salt thereof.
105) A method of treating diabetes in a mammal, the method comprising administering to a mammal in need thereof an effective amount of a compound of the formula:
wherein:
Rl and R6 are independently hydrogen, Ci to C6 alkyl, trifluoromethyl, cyano, Cl to C6 alkoxy, or halogen;
R2 is hydrogen or Cl to C6 trialkylsilyl; R3 is hydrogen or Ci to C6 alkoxycarbonyl; or R2 and R3 are joined to form a ring:
R"
wherein R' is hydrogen, Ci to C6 alkyl,O or aryl;
R4 and R5 are independently hydrogen or Q to C6 alkyl; R7 and R8 are independently OR9 or NRioRl i;
R9 is hydrogen, Ci to C12 alkyl, Cl to C12 cycloalkyl, Cl to C12 silylalkyl, aryl, arylalkyl, alkoxyalkyl, heteroaryl, -CHR12COOR13, -CHRi2C(O)Ri3, -
CHR12CONR10RI L -CHR12OCOOR13, or -CHRi2OC(O)Ri3, with the provision that R9 is not hydrogen in both R7 and Rs; Rio and Rn are independently hydrogen, Ci to C12 alkyl, aralkyl, aryl, furanylalkyl, or alkoxycarbonylalkyl;
Rl2 and R13 are independently hydrogen, Ci to C12 alkyl, aryl, or aralkyl; or a pharmaceutically acceptable salt thereof, enantiomer thereof, racemic mixture thereof, or diastereomeric mixture thereof. 106) A method of treating obesity in a mammal, the method comprising administering to a mammal in need thereof an effective amount of compound of the formula:
wherein:
Rl and R6 are independently hydrogen, Ci to C6 alkyl, trifluoromethyl, cyano, Cl to C6 alkoxy, or halogen;
R2 is hydrogen or Ci to C6 trialkylsilyl; R3 is hydrogen or Cl to C6 alkoxycarbonyl; or R2 and R3 are joined to form a ring:
R'
wherein R' is hydrogen, Cl to Co alkyl,O or aryl;
R4 and R5 are independently hydrogen or Ci to C6 alkyl; R7 and Rs are independently OR9 or NR10R11;
R9 is hydrogen, Cl to C12 alkyl, Cl to C12 cycloalkyl, Ci to C12 silylalkyl, aryl, arylalkyl, alkoxyalkyl, heteroaryl, -CHR12COOR13, -CHRi2C(O)Ri3, - CHR12CONR10R1 1, -CHR12OCOOR13, or -CHRi2OC(O)Ri3, with the provision that R9 is not hydrogen in both R7 and R8;
RlO and Rn are independently hydrogen, Ci to C12 alkyl, aralkyl, aryl, furanylalkyl, or alkoxycarbonylalkyl;
Rl2 and R13 are independently hydrogen, Ci to C12 alkyl, aryl, or aralkyl; or a pharmaceutically acceptable salt thereof, enantiomer thereof, racemic mixture thereof, or diastereomeric mixture thereof. 107) A method of treating hyperglycemia in a mammal, the method comprising administering to a mammal in need thereof an effective amount of compound of the formula:
wherein:
Rl and R6 are independently hydrogen, Ci to C6 alkyl, trifluoromethyl, cyano, Cl to C6 alkoxy, or halogen;
R2 is hydrogen or Ci to Cβ trialkylsilyl;
R3 is hydrogen or Ci to Cβ alkoxycarbonyl; or R2 and R3 are joined to form a ring:
wherein R' is hydrogen, Cl to C6 alkyl, or aryl;
R4 and R5 are independently hydrogen or Ci to C6 alkyl;
R7 and R8 are independently OR9 or NRioRl i ;
R9 is hydrogen, Cl to C12 alkyl, Cl to C12 cycloalkyl, Cl to C12 silylalkyl, aryl, arylalkyl, alkoxyalkyl, heteroaryl, -CHR12COOR13, -CHRi2C(O)Ri3, - CHR12CONR10RH , -CHR12OCOOR13, or -CHRi2OC(O)Ri3, with the provision that R9 is not hydrogen in both R7 and R8;
RlO and Rn are independently hydrogen, Cl to C12 alkyl, aralkyl, aryl, furanylalkyl, or alkoxycarbonylalkyl;
Rl2 and R13 are independently hydrogen, Ci to C12 alkyl, aryl, or aralkyl; or a pharmaceutically acceptable salt thereof, enantiomer thereof, racemic mixture thereof, or diastereomeric mixture thereof. 108) A pharmaceutical composition comprising an effective amount of a compound of the formula:
wherein:
Rl and R6 are independently hydrogen, Ci to C6 alkyl, trifluoromethyl, cyano, Cl to C6 alkoxy, or halogen;
R2 is hydrogen or Ci to C6 trialkylsilyl;
R3 is hydrogen or Ci to Cβ alkoxycarbonyl; or R2 and R3 are joined to form a ring:
wherein R' is hydrogen, Cl to Co alkyl, or aryl;
R4 and R5 are independently hydrogen or C\ to C6 alkyl;
R7 and R8 are independently OR9 or NR10R11;
R9 is hydrogen, Ci to C12 alkyl, Ci to C12 cycloalkyl, Ci to C12 silylalkyl, aryl, arylalkyl, alkoxyalkyl, heteroaryl, -CHR12COOR13, -CHRi2C(O)Ri3, - CHR12CONR10RH , -CHR12OCOOR13, or -CHRi2OC(O)Ri3, with the provision that R9 is not hydrogen in both R7 and Rs;
RlO and Rn are independently hydrogen, C] to C12 alkyl, aralkyl, aryl, furanylalkyl, or alkoxycarbonylalkyl; R12 and R13 are independently hydrogen, Cl to C12 alkyl, aryl, or aralkyl; or a pharmaceutically acceptable salt thereof, enantiomer thereof, racemic mixture thereof, or diastereomeric mixture thereof, in combination with a pharmaceutically acceptable carrier.
109) A process for preparing a compound of formula II as claimed in Claim 1 which comprises one of the following:
a) reacting a compound of formula:
wherein R2 - Rβ are as defined in Claim 1 OH and Rs1 is OAg or Rs as defined above excepting OH with a compound of formula:
I-CHRi2OC(O)Rl3
wherein R12 and R13 are as defined in Claim 1 to give a compound of formula II wherein R9 is
-CHRi2OC(O)Ri3; or
b) reacting a compound of formula:
wherein Rj-R6 and R% are as defined above with compound of formula R9OH where R9 is as defined above excepting hydrogen to give a corresponding compound of formula II; or
c) hydrolysing a compound for formula:
wherein Ri, R^ Rs, Rό, R7 and Rβ are as defined in Claim 1 and R2 is trialkylsilyl and R3 is (C1-C6 alkoxy)-carbonyl to give a corresponding compound of formula 1 wherein R2 and R3 are both hydrogen; or
d) reacting a compound of formula I wherein R2 and R3 are both hydrogen with an aldehyde of formula:
R'CHO
wherein R' is as defined in Claim 1 to give a corresponding compound of formula 11 wherein R2 and R3 are joined to form a ring:
e) reacting a compound of formula:
wherein Rj, R4, R5 and Rs are as defined in Claim 1 with the proviso neither R2 or R3 is hydrogen with a compound of formula:
Z-R9
wherein Z is Cl, Br, I, methanesulfonate or p-toluenesulfonate and R9 is as defined in Claim 1 excepting hydrogen, to give a corresponding compound of formula II; or
0 hydrolysing a compound of formula:
wherein Rl, R2, R3' R4, R5 and R6 are as defined in Claim 1, R8 is OR9' or NRloR l l anc* *V *s C j -Cj 2 cycloalkyl, Cj-Cj2 silyalkyl, aryl, arylalkyl, alkoxyalkyl or heteroaryl to give a compound of formula:
wherein R1-R6 and Rs are as defined above providing that R2 and R3 are both hydrogen or joined to form a ring:
g) reacting a compound of formula:
wherein R1-R6 and R8 are as defined in Claim 1 and R9' as defined above, with a compound of formula: HNR11R 12
wherein Ry and R12 are as defined in Claim 1 to give a compound of formula:
wherein Ri-Rό, Rs. Rl l and R12 are as defined in Claim 1.
EP97924720A 1996-05-14 1997-05-05 Substituted 1, 3-benzodioxoles Withdrawn EP0901484A1 (en)

Applications Claiming Priority (3)

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US64597096A 1996-05-14 1996-05-14
US645970 1996-05-14
PCT/US1997/008148 WO1997043273A1 (en) 1996-05-14 1997-05-09 Substituted 1, 3-benzodioxoles

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

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CA3100977A1 (en) 2018-05-21 2019-11-28 Constellation Pharmaceuticals, Inc. Modulators of methyl modifying enzymes, compositions and uses thereof
PE20230253A1 (en) * 2019-07-24 2023-02-07 Constellation Pharmaceuticals Inc INHIBITION OF EZH2 IN COMBINED THERAPIES FOR THE TREATMENT OF CANCER

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US5061727A (en) * 1990-05-04 1991-10-29 American Cyanamid Company Substituted 5-(2-((2-aryl-2-hydroxyethyl)amino)propyl)-1,3-benzodioxoles
US5482971A (en) * 1993-10-01 1996-01-09 American Cyanamid Company Beta3 -adrenergic agents and their use in pharmaceutical compositions

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IL126780A0 (en) 1999-08-17
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BR9708948A (en) 1999-08-03
CA2254120A1 (en) 1997-11-20
HUP9902088A2 (en) 2001-04-28
JP2000510150A (en) 2000-08-08
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AU3006797A (en) 1997-12-05
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