EP0901484A1 - 1,3-benzodioxoles substitues - Google Patents

1,3-benzodioxoles substitues

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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Withdrawn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)
English (en)
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/fr
Withdrawn legal-status Critical Current

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Classifications

    • 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 System
    • 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

Abstract

Nouveaux composés présentant une activité antidiurétique et/ou antihyperglycémique et/ou anti-obésité, et compositions pharmaceutiques et méthodes de traitement utilisant les composés et procédés de fabrication de ces composés, qui sont de formule (II), dans laquelle R1 et R6 sont indépendamment hydrogène, alkyle en C1-C6, trifluorométhyle, cyano, alcoxy en C1-C6, ou halogène; R2 est hydrogène ou trialkylsilyle en C1-C6; R3 est hydrogène ou alcoxycarbonyle en C1-C6; ou R2 et R3 ensemble forment un noyau (a) dans lequel R' est hydrogène, alkyle en C1-C6 ou aryle; R4 et R5 sont indépendamment hydrogène ou alkyle en C1-C6; R7 et R8 sont indépendamment OR9 ou NR10R11; R9 est hydrogène, alkyle en C1-C12, cycloalkyle en C1-C12, silylalkyle en C1-C12, aryle, arylakyle, alcoxyalkyle, hétéroaryle, -CHR12COOR13, -CHR12C(O)R13, -CHR12CONR10R11, -CHR12OCOOR13, ou -CHR12OC(O)R13, à condition que R9 ne soit pas hydrogène à la fois dans R7 et R8; R10 et R11 sont indépendamment hydrogène, alkyle en C1-C12, aralkyle, aryle, furanylalkyle, ou alcoxycarbonylalkyle; R12 et R13 sont indépendamment hydrogène, alkyle en C1-C12, aryle, ou aralkyle; leurs sels pharmaceutiquement acceptables, leurs énantiomères, les mélanges racémiques correspondants et les mélanges diastéréomériques correspondants.
EP97924720A 1996-05-14 1997-05-05 1,3-benzodioxoles substitues Withdrawn EP0901484A1 (fr)

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

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JP (1) JP2000510150A (fr)
KR (1) KR20000011001A (fr)
AU (1) AU730659B2 (fr)
BR (1) BR9708948A (fr)
CA (1) CA2254120A1 (fr)
HU (1) HUP9902088A2 (fr)
IL (1) IL126780A0 (fr)
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IL126780A0 (en) 1999-08-17
HUP9902088A2 (hu) 2001-04-28
NZ332713A (en) 2000-07-28
JP2000510150A (ja) 2000-08-08
BR9708948A (pt) 1999-08-03
AU3006797A (en) 1997-12-05
WO1997043273A1 (fr) 1997-11-20
CA2254120A1 (fr) 1997-11-20
AU730659B2 (en) 2001-03-08
KR20000011001A (ko) 2000-02-25

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