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WO1990010006A2 - NOUVEAUX β-METHOXYACRYLATES, LEUR PRODUCTION ET LEUR UTILISATION - Google Patents

NOUVEAUX β-METHOXYACRYLATES, LEUR PRODUCTION ET LEUR UTILISATION Download PDF

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Publication number
WO1990010006A2
WO1990010006A2 PCT/EP1990/000280 EP9000280W WO9010006A2 WO 1990010006 A2 WO1990010006 A2 WO 1990010006A2 EP 9000280 W EP9000280 W EP 9000280W WO 9010006 A2 WO9010006 A2 WO 9010006A2
Authority
WO
WIPO (PCT)
Prior art keywords
formula
compounds
cells
methoxyacrylates
compound
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.)
Ceased
Application number
PCT/EP1990/000280
Other languages
German (de)
English (en)
Other versions
WO1990010006A3 (fr
Inventor
Lothar Daum
Gerhard Keilhauer
Hubert Sauter
Gunda Bertram
Timm Anke
Wolfgang Weber
Wolfgang Steglich
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.)
BASF SE
Original Assignee
BASF SE
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by BASF SE filed Critical BASF SE
Publication of WO1990010006A2 publication Critical patent/WO1990010006A2/fr
Publication of WO1990010006A3 publication Critical patent/WO1990010006A3/fr
Anticipated expiration legal-status Critical
Ceased 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
    • C07D407/02—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 two hetero rings
    • C07D407/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/10—Spiro-condensed systems

Definitions

  • the present invention relates to new ⁇ -methoxyacrylates, processes for their preparation and their use in combating
  • R 1 represents hydrogen or an optionally unsaturated hydrocarbon radical having up to 10 carbon atoms, which is represented by fluorine, chlorine, bromine, C 1-6 alkoxy, C 2-6 alkenoxy or C 2-6 alkynoxy or by an optionally fluorine, Chlorine, bromine, iodine, trifluoromethyl, C 1-4 -alkyl or C 1-4 -alkoxy substituted phenyl or phenoxy may be substituted,
  • R 2 and R 3 are the same or different and are hydrogen atoms
  • R 2 and R 3 together represent a C 2-8 alkylene group, have a better effect
  • the compounds of formula I have two centers of chirality in
  • the configuration isomers can expediently also be separated at the stage of intermediates of the formula II (see below). A separation of the configuration isomers is not necessary for the use of the compounds according to the invention.
  • the ⁇ -methoxyacrylate group can be in the E or Z configuration.
  • the compounds of formula I are preferred with
  • R 4 is a C 1-8 alkyl radical, reacted in the presence of a base and the compounds thus obtained - if R 1 is an unsaturated radical - optionally hydrogenated.
  • the reaction of the compounds II with III takes place in the sense of a Wittig-Homer reaction in the presence of a solvent and a base, such as lithium diisopropylamide, phenyllithium, butyllithium, sodium alcoholate, sodium amide, sodium hydride or potassium t-butoxide.
  • a solvent and a base such as lithium diisopropylamide, phenyllithium, butyllithium, sodium alcoholate, sodium amide, sodium hydride or potassium t-butoxide.
  • Suitable solvents for the reaction are benzene, dimethylformamide, tetrahydrofuran, diethyl ether and dimethoxyethane.
  • the reaction is useful in a
  • Sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, 1,8-diazabicyclo [5,4,0] undec-7-ene, diisopropylmethylamine and diisopropylethylamine are particularly suitable as auxiliary bases for the reaction V ⁇ VI.
  • Preferred solvents are dimethylformamide, tetrahydrofuran, diethyl ether, methanol, ethanol, acetonitrile and acetone.
  • the reaction V ⁇ VI works well at temperatures between 0 and 30 ° C.
  • THP protective group is then split off and the cyclization to the dioxolanes of the formula II then takes place with aldehydes of the formula R 1 -CHO in the presence of acid with removal of the water of reaction formed by distillation.
  • suitable entraining agents are benzene, toluene and chloroform and carbon tetrachloride. The following examples explain the production:
  • reaction mixture was diluted with diethyl ether and washed 1x with semi-saturated NaCl solution to remove the catalyst. After drying over MgSO 4, the ether phase was concentrated in vacuo.
  • reaction mixture was poured into semi-saturated NaCl solution, extracted with ether and dried over MgSO 4 .
  • the two diasteromers were formed in a ratio of about 1: 1.
  • Diastereomer 1 330 mg of colorless crystals
  • Diastereomer 2 308 mg colorless crystals
  • Diastereomer 1 (C 17 H 20 O 5 ) (MW 304):
  • Diastereomer 2 (C 17 H 20 O 5 ) (MW 304): 1 H-NMR (200 MHz, benzene-d 6 ):
  • the mixture was allowed to warm to room temperature and stirred for 24 h.
  • the reaction solution was poured into 15 ml of ether, washed twice with 3 ml of water and once with 3 ml of saturated NaCl solution. After drying over MgSO 4 , the mixture was evaporated.
  • the raw product was with
  • Diastereomer 1 (C 29 H 32 O 7 , MW 492):
  • Diastereomer 1 (C 32 H 36 O 7 , MW 532):
  • Distereomer 2 (C 32 H 36 O 7 , MW 532):
  • the new compounds in particular the compounds of Examples 1 to 16 - show good antiviral, antiproliferative and cytotoxic activity.
  • the following examples explain the effects of the new substances:
  • the oxygen consumption was measured polarographically in an airtight container (3 ml volume, with magnetic stirrer) with an oxygen electrode.
  • the test mushroom was grown from a spore suspension to a mycelium weight of 10-20 mg mycelium wet weight / ml. The measurements were carried out with a mycelium concentration of 25-30 mg mycelium wet weight / ml in 1% glucose solution. After a short constant course of breathing, the compounds (0.3 mg / ml) dissolved in methanol were added to the suspension and the 02 consumption was recorded. The experiment was carried out using strobilurin A as a comparative compound. The results of the percent breathing inhibition are shown in Table 1. Table 1
  • HeLa-S3 cells were on a 96-well titer plate with a cell density of 4 x 105 cells / ml in medium F12 with 10% fetal calf serum
  • the cells were spread out on the surface and the medium was changed.
  • the cells were incubated with the medium containing the test compounds (10, 1, 0.1 or 0.01 ⁇ g per ml medium) for 72 h (37 ° C., 5% CO 2 ). After 72 hours, the normally epithelial-like growing cells were fibroblast-like
  • Morphology From a 45% growth inhibition, the change in morphology is significantly visible through the action of the substances.
  • the experiment was carried out using strobilurin A as a comparative compound.
  • the cell density was measured by determining the total protein content per hole.
  • the values given show the results after three days of incubation with the test substances and are listed in Table 2 as a percentage of the total protein of the untreated control.
  • Antiviral effect in HEp-2 cells on VSV The determination of the antiviral activity of a test compound is based on the measurement of the protection of human HEp-2 cells as indicator cells against the cytopathic effect (CPE) of Vesicular Stomatitis Virus (VSV).
  • CPE cytopathic effect
  • the percentage of protected cells in the cultures treated with the test compounds and subsequently infected with VSV was determined by means of crystal violet staining / the measure of the antiviral activity based on 0 and 100% protection was determined as the sample concentration, which leads to 50% protection.
  • Table 3 lists the test substances with the concentration which 50% protects the HEp-2 cells against the cytopathic effect of VSV.
  • Example 1 In contrast to rHuIFN- ⁇ , the substance of Example 1 also showed an antiproliferative effect under these test conditions compared to cell control. The antiviral and antiproliferative activities The substances of Example 1 ran in parallel and correlated with a morphological change in the cells, ie the cells were elongated compared to the cell control and had neurite-like processes.
  • Example D The substances of Example 1 ran in parallel and correlated with a morphological change in the cells, ie the cells were elongated compared to the cell control and had neurite-like processes.
  • tumor cells of different tissue origin 5637-6: human bladder carcinoma; HT-29: human colon carcinoma; B-16: murine melanoma
  • 1 to 2 ⁇ 103 exponential growth tumor cells were plated in 96-well plates in complete growth medium (RPMI 1640 x 10% fetal calf serum) and incubated overnight under standard culture conditions (37 ° C, 5% carbon dioxide, water vapor-saturated atmosphere). The substance was added the next day, serial titrations of substances 1 B1 and 1 B2 being carried out over a concentration range of 10 -4 to 10 -9 M. After a further incubation of 72 h under standard conditions, the cell number was determined by staining with crystal violet and a subsequent photometric

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Communicable Diseases (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Oncology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Abstract

Des beta-méthoxyacrylates ayant la formule (I), dans laquelle R1, R2 et R3 ont la signification donnée dans la description, sont utiles pour traiter des maladies. L'invention concerne également leur production.
PCT/EP1990/000280 1989-02-25 1990-02-20 NOUVEAUX β-METHOXYACRYLATES, LEUR PRODUCTION ET LEUR UTILISATION Ceased WO1990010006A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE3905911A DE3905911A1 (de) 1989-02-25 1989-02-25 Neue ss-methoxyacrylate, ihre herstellung und verwendung
DEP3905911.1 1989-02-25

Publications (2)

Publication Number Publication Date
WO1990010006A2 true WO1990010006A2 (fr) 1990-09-07
WO1990010006A3 WO1990010006A3 (fr) 1990-11-01

Family

ID=6374929

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1990/000280 Ceased WO1990010006A2 (fr) 1989-02-25 1990-02-20 NOUVEAUX β-METHOXYACRYLATES, LEUR PRODUCTION ET LEUR UTILISATION

Country Status (5)

Country Link
EP (1) EP0460084A1 (fr)
JP (1) JPH04503671A (fr)
CA (1) CA2047195A1 (fr)
DE (1) DE3905911A1 (fr)
WO (1) WO1990010006A2 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007113170A1 (fr) * 2006-03-29 2007-10-11 Basf Se Utilisation de strobilurine pour le traitement de troubles du metabolisme du fer

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE4443648C2 (de) * 1994-12-08 1999-01-21 Akzo Nobel Nv Verfahren zur Herstellung von Polyestern und Copolyestern

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3815484A1 (de) * 1988-05-06 1989-11-16 Basf Ag Neue strobilurinderivate, ihre herstellung und verwendung

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007113170A1 (fr) * 2006-03-29 2007-10-11 Basf Se Utilisation de strobilurine pour le traitement de troubles du metabolisme du fer

Also Published As

Publication number Publication date
CA2047195A1 (fr) 1990-08-26
JPH04503671A (ja) 1992-07-02
WO1990010006A3 (fr) 1990-11-01
EP0460084A1 (fr) 1991-12-11
DE3905911A1 (de) 1990-08-30

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