CA2047195A1 - .beta.-methoxyacrylates, their production and use - Google Patents
.beta.-methoxyacrylates, their production and useInfo
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- CA2047195A1 CA2047195A1 CA002047195A CA2047195A CA2047195A1 CA 2047195 A1 CA2047195 A1 CA 2047195A1 CA 002047195 A CA002047195 A CA 002047195A CA 2047195 A CA2047195 A CA 2047195A CA 2047195 A1 CA2047195 A1 CA 2047195A1
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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
- C07D407/02—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
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- 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
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- 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
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Abstract
Novel .beta.-methoxyacrylates, the preparation and use thereof Abstract of the Disclosure .beta.-methoxyacrylates of the formula in which R1, R2 and R3 have the meanings indicated in the description, and the preparation thereof are described.
The compounds are suitable for controlling diseases.
The compounds are suitable for controlling diseases.
Description
- 2 ~
O.Z. 00~0~40598 Novel ~-methoxyacrylates, the preparation and use thereof Description The present invention relates to novel ~-methoxy-acrylates, a process for the preparation thereof and the use thereof for controlling di6ea6es.
The Journal of Antibiotics, 32 (1979) 1113 and 36 (1983) 661, and "Cellular Regulation and Malignant Growth", Springer Verlag, Berlin 1985, pages 169-176 describe certain ~-methoxyaclylates, namely strobilurin and oudemansin and derivatives thereof. These compounds are distinguished by a high antifungal and cytostatic activity.
Strobilurins A, B and C and oudemansins A and B
have been isolated from the genera Strobilurus, Oudeman-siella, Xerula, Cyphellopsis, Hydropus and Mycena. All compGunds inhibit the respiration of eukaryotes and thus the growth of fungi and cells. The strobilurins and oudemansins bind reversibly to the bt center of cytochrome b in complex III of the mitochondrial respiratory chain.
It has now been found that ~-methoxyacrylates of the formula I
R~CH--OCH 3 I ~ .
OCH 3 . ~ .
in which R1 is hydrogen or an optionally unsaturated hydrocarbon radical with up to 10 carbon atoms, which can be substi-tuted by fluorine, chlorine, bromine, C16-alkoxy, C26-alkenoxy or Ca6-alkynoxy or by a phenyl or phenoxy radical which is optionally substituted by fluorine, chlorine, bromine, iodine, trifluoromethyl, Cl4-alkyl or Cl4-alkoxy, R2 and R9 are identical or different and are hydrogen atomg, Cl-6~ alkyl groups or C37-cycloalkyl groups or R2 and R3 together are a C2B-alkylene group, have an : :
~"1~ "1, ~
- 2 - O.Z. 0050/40598 improved action.
The compounds of the formula I have two center~
of chirality in the dioxolane ring (only one when R1 = H).
They can therefore occur in vaxious enantiomeric and/or diastereomeric configurations which can be fractionated and isolated in a conventional manner. The fxactionation of the configurational isomers can also expediently be carried out at the stage of intermediates of the formula II Isee below). Fractionation of the configurational isomers is unnecessary for the use of the compounds according to the invention.
Furthermore, the ~-methoxyacrylate group can be in the E or Z configuration. Compounds of the formula I
with the E configuration are preferred.
The compounds of the formula I according to the invention are prepared by reacting an aldehyde of the formula II
Rl` O
R 2~:HO I I
in which R1, R2 and R3 have the abovementioned meanings, with a phosphonic ester of the formula III
( R40 ) 2--O~CH-OCH 3 I I I
in which R4 is a C1~-alkyl radical, in the presence of a base, and, where appropriate, hydrogenating the compounds obtained in this way if R1 is an unsaturated radical.
The reaction of the compounds II with III takes place in the sense of a Wittig-Horner reaction in the presence of a solvent and of a base such as lithium diisopropylamide, phenyllithium, butyllithium, sodium alcoholate, sodamide, sodium hydride or potassium t-butylate. Suitable solvents for the reaction are .~ . .
.:
'~ . . , , . , ~. ' . A , ' :~ ' ' , . i' ' '; ' ' . :
, ' . : . ' ' ' ' , ' :
. ' ' ' ' , ' ' ~ ~ 7 ~ r ~ g~
O.Z. 00~0~40598 Novel ~-methoxyacrylates, the preparation and use thereof Description The present invention relates to novel ~-methoxy-acrylates, a process for the preparation thereof and the use thereof for controlling di6ea6es.
The Journal of Antibiotics, 32 (1979) 1113 and 36 (1983) 661, and "Cellular Regulation and Malignant Growth", Springer Verlag, Berlin 1985, pages 169-176 describe certain ~-methoxyaclylates, namely strobilurin and oudemansin and derivatives thereof. These compounds are distinguished by a high antifungal and cytostatic activity.
Strobilurins A, B and C and oudemansins A and B
have been isolated from the genera Strobilurus, Oudeman-siella, Xerula, Cyphellopsis, Hydropus and Mycena. All compGunds inhibit the respiration of eukaryotes and thus the growth of fungi and cells. The strobilurins and oudemansins bind reversibly to the bt center of cytochrome b in complex III of the mitochondrial respiratory chain.
It has now been found that ~-methoxyacrylates of the formula I
R~CH--OCH 3 I ~ .
OCH 3 . ~ .
in which R1 is hydrogen or an optionally unsaturated hydrocarbon radical with up to 10 carbon atoms, which can be substi-tuted by fluorine, chlorine, bromine, C16-alkoxy, C26-alkenoxy or Ca6-alkynoxy or by a phenyl or phenoxy radical which is optionally substituted by fluorine, chlorine, bromine, iodine, trifluoromethyl, Cl4-alkyl or Cl4-alkoxy, R2 and R9 are identical or different and are hydrogen atomg, Cl-6~ alkyl groups or C37-cycloalkyl groups or R2 and R3 together are a C2B-alkylene group, have an : :
~"1~ "1, ~
- 2 - O.Z. 0050/40598 improved action.
The compounds of the formula I have two center~
of chirality in the dioxolane ring (only one when R1 = H).
They can therefore occur in vaxious enantiomeric and/or diastereomeric configurations which can be fractionated and isolated in a conventional manner. The fxactionation of the configurational isomers can also expediently be carried out at the stage of intermediates of the formula II Isee below). Fractionation of the configurational isomers is unnecessary for the use of the compounds according to the invention.
Furthermore, the ~-methoxyacrylate group can be in the E or Z configuration. Compounds of the formula I
with the E configuration are preferred.
The compounds of the formula I according to the invention are prepared by reacting an aldehyde of the formula II
Rl` O
R 2~:HO I I
in which R1, R2 and R3 have the abovementioned meanings, with a phosphonic ester of the formula III
( R40 ) 2--O~CH-OCH 3 I I I
in which R4 is a C1~-alkyl radical, in the presence of a base, and, where appropriate, hydrogenating the compounds obtained in this way if R1 is an unsaturated radical.
The reaction of the compounds II with III takes place in the sense of a Wittig-Horner reaction in the presence of a solvent and of a base such as lithium diisopropylamide, phenyllithium, butyllithium, sodium alcoholate, sodamide, sodium hydride or potassium t-butylate. Suitable solvents for the reaction are .~ . .
.:
'~ . . , , . , ~. ' . A , ' :~ ' ' , . i' ' '; ' ' . :
, ' . : . ' ' ' ' , ' :
. ' ' ' ' , ' ' ~ ~ 7 ~ r ~ g~
- 3 - O.~. 0050/40598 benzene, dimethylformamide, tetrahydrofuran, diethyl ether and dimethoxyethane. The reaction is expediently carried out at a temperature of 0-25DC.
A subsequent hydrogenation where appropriate is carried out in a conventional catalytic manner.
The preparation of compounds of the formula III
i8 described in EP 20 360.
The intermediates of the formula II according to the invention are prepared in accordance with the follow-10ing synthetic scheme:
o H~X ~3 IV
O HO~CHO
THP~ X HO~
R2 R3 ' :
V
HO
THP~CHO R 1--CHO
VI
Rl~O
R 2~ CHO
Il For this, a known ketone of the formula IV inwhich X is Br or Cl, Liebigs Anm. Chem. 724 (1969) 128, is initially reacted in a conventional manner with acid catalysis at 0-30C to give the protected tetrahydro-pyranyl(2) derivative V, and the latter is reacted with3,4-dihydroxybenzaldehyde in the presence of 0.2-1.2 equivalents of an auxiliary base and, preferably, of a .. . . . .
~ J~trlj - 4 - O.Z. 0050/40598 protic or dipolar aprotic solvent to give VI.
Particularly suitable as auxiliary base for the reaction V ~ VI are sodium carbonate, potassium car-bonate, sodium hydroxide, potassium hydroxide, 1,8-diaza-bicyclo[5,4,0]undec-7-ene, diisopropylmethylamine and diisopropylethylamine. Suitable and preferred 601vents are dimethylformamide, tetrahydrofuran, diethyl ether, methanol, ethanol, acetonitrile and acetone. The reaction V , VI takes place ~atisfactorily at temperatures between 0 and 30C.
The elimination of the THP protective group and cyclization to give the dioxolanes of the formula II i6 then carried out with aldehydes of the formula R1-CH0 in the presence of acid with removal of the water produced in the reaction by distillation. Suitable examples of entraining agents are benzene, toluene and chloroform and - tetrachloromethane.
The example~ which follow illustrate the preparation:
A. Preparation of the starting material:
a) Preparation of the chloro ketone of the formula V
(R2, R3 = CH3, X = Cl) 683 mg (5 mmol) of 1-chloro-3-hydroxy-3-methyl-2-butanone IV (R2, R3 = CH3) were dissolved in 20 ml of absolute dichloromethane and, after addition of 630 mg (7 mmol) of 3,4-dihydro-2H-pyran and 125 mg (0.7 mmol) of pyridinium tosylate, stirred at room tempexature.
After 3 h, the reaction mixture was diluted with diethyl ether and washed 1 x with semi-saturated NaCl solution in order to remove the catalyst. The ether phase was dried over MgS04 and then concentrated in vacuo.
980 mg (4.5 mmol) of a colorless oil were obtained.
Yield: 90%
;.. : . - .: . ~ . .
A subsequent hydrogenation where appropriate is carried out in a conventional catalytic manner.
The preparation of compounds of the formula III
i8 described in EP 20 360.
The intermediates of the formula II according to the invention are prepared in accordance with the follow-10ing synthetic scheme:
o H~X ~3 IV
O HO~CHO
THP~ X HO~
R2 R3 ' :
V
HO
THP~CHO R 1--CHO
VI
Rl~O
R 2~ CHO
Il For this, a known ketone of the formula IV inwhich X is Br or Cl, Liebigs Anm. Chem. 724 (1969) 128, is initially reacted in a conventional manner with acid catalysis at 0-30C to give the protected tetrahydro-pyranyl(2) derivative V, and the latter is reacted with3,4-dihydroxybenzaldehyde in the presence of 0.2-1.2 equivalents of an auxiliary base and, preferably, of a .. . . . .
~ J~trlj - 4 - O.Z. 0050/40598 protic or dipolar aprotic solvent to give VI.
Particularly suitable as auxiliary base for the reaction V ~ VI are sodium carbonate, potassium car-bonate, sodium hydroxide, potassium hydroxide, 1,8-diaza-bicyclo[5,4,0]undec-7-ene, diisopropylmethylamine and diisopropylethylamine. Suitable and preferred 601vents are dimethylformamide, tetrahydrofuran, diethyl ether, methanol, ethanol, acetonitrile and acetone. The reaction V , VI takes place ~atisfactorily at temperatures between 0 and 30C.
The elimination of the THP protective group and cyclization to give the dioxolanes of the formula II i6 then carried out with aldehydes of the formula R1-CH0 in the presence of acid with removal of the water produced in the reaction by distillation. Suitable examples of entraining agents are benzene, toluene and chloroform and - tetrachloromethane.
The example~ which follow illustrate the preparation:
A. Preparation of the starting material:
a) Preparation of the chloro ketone of the formula V
(R2, R3 = CH3, X = Cl) 683 mg (5 mmol) of 1-chloro-3-hydroxy-3-methyl-2-butanone IV (R2, R3 = CH3) were dissolved in 20 ml of absolute dichloromethane and, after addition of 630 mg (7 mmol) of 3,4-dihydro-2H-pyran and 125 mg (0.7 mmol) of pyridinium tosylate, stirred at room tempexature.
After 3 h, the reaction mixture was diluted with diethyl ether and washed 1 x with semi-saturated NaCl solution in order to remove the catalyst. The ether phase was dried over MgS04 and then concentrated in vacuo.
980 mg (4.5 mmol) of a colorless oil were obtained.
Yield: 90%
;.. : . - .: . ~ . .
- 5 - O.Z. 0050/40598 CloH~7C103 (MW 220) IR:
2990, 2950, 2860, 1730 (cm~1) lH NMR ( 9 0 MHz, CDCl3 ):
1.30-1.96 (12) m; 3.20-3.50 (1) m; 3.73-4.07 (1) m;
4.47_4.73 (3) m (~ ppm) b) Preparation of the compound of the formula VI
440 mg (2 mmol) of chloro ketone V (R2, R3 = CH3) and 276 mg (2 mmol) of 3,4-dihydroxy-benzaldehyde were dissolved in 10 ml of absolute acetone and, after addition of 13 mg (1 mmol) of K2CO3, heated under reflux overnight. The solvent was stripped off, the residue was taken up in water and extracted with ether. The combined ether pha6es were washed with saturated Na2CO3 solution and water and dried over MgSO4. Concentration in vacuo was followed by chromatography of the crude product mixture on silica gel with petroleum ether/ethyl acetate (3:1) as mobile phase.
402 mg (62%) of the compound of the formula VI (R2, R3 = CH3) were obtained in the form of a colorless viscous oil which crystallized at 0-5C, melting point 86-90C.
lH NNR (200 MHz, CDCl3):
9.81 (1) s; 7.50-7.35 (2) m; 7.10-6.90 (1) m;
5.85-5.70 (1) m; 5.05-4.95 (1) m; 4.40-4.20 (1) m;
4.10-3.90 (1) m; 3.60-3.45 (1) m; 1.95-1.30 (12) m (~ ppm) IR ( CHCl3 ):
3500, 3250, 2995, 2940, 2840, 2710, 1680, 1600, 1580, 1500 cm~1 c) Preparation of the diasteromeric compounds of the formula II ( Rl = 2,2-dimethylvinyl, R2, R3 = CH3 ) -:
1.15 g (3.6 mmol) of the compound of the formula VI (R2, R3 = CH3) and 90 mg (0.45 mmol) of pyridinium tosylate were dissolved in 50 ml of benzene and, after addition of 0.5 ml (5 mmol) of . .
:. . - :; - ,. :.
.. ..
2990, 2950, 2860, 1730 (cm~1) lH NMR ( 9 0 MHz, CDCl3 ):
1.30-1.96 (12) m; 3.20-3.50 (1) m; 3.73-4.07 (1) m;
4.47_4.73 (3) m (~ ppm) b) Preparation of the compound of the formula VI
440 mg (2 mmol) of chloro ketone V (R2, R3 = CH3) and 276 mg (2 mmol) of 3,4-dihydroxy-benzaldehyde were dissolved in 10 ml of absolute acetone and, after addition of 13 mg (1 mmol) of K2CO3, heated under reflux overnight. The solvent was stripped off, the residue was taken up in water and extracted with ether. The combined ether pha6es were washed with saturated Na2CO3 solution and water and dried over MgSO4. Concentration in vacuo was followed by chromatography of the crude product mixture on silica gel with petroleum ether/ethyl acetate (3:1) as mobile phase.
402 mg (62%) of the compound of the formula VI (R2, R3 = CH3) were obtained in the form of a colorless viscous oil which crystallized at 0-5C, melting point 86-90C.
lH NNR (200 MHz, CDCl3):
9.81 (1) s; 7.50-7.35 (2) m; 7.10-6.90 (1) m;
5.85-5.70 (1) m; 5.05-4.95 (1) m; 4.40-4.20 (1) m;
4.10-3.90 (1) m; 3.60-3.45 (1) m; 1.95-1.30 (12) m (~ ppm) IR ( CHCl3 ):
3500, 3250, 2995, 2940, 2840, 2710, 1680, 1600, 1580, 1500 cm~1 c) Preparation of the diasteromeric compounds of the formula II ( Rl = 2,2-dimethylvinyl, R2, R3 = CH3 ) -:
1.15 g (3.6 mmol) of the compound of the formula VI (R2, R3 = CH3) and 90 mg (0.45 mmol) of pyridinium tosylate were dissolved in 50 ml of benzene and, after addition of 0.5 ml (5 mmol) of . .
:. . - :; - ,. :.
.. ..
- 6 - O . Z . 0050/40598 3-methylcrotonaldehyde, heated to xeflux under an Ar atmosphere with a water trap for 15 h. The reaction mixture was worked up by addin~ it to semisaturated NaCl solution, extracting with ether and drying over MgSO4.
The two diastereomers were produced approximately in the ratio 1:1 according to an NMR
check on the crude product.
Th~ crude product was chromatographed on silica gel with hexane/ethyl acetate (10:1) as mobile phase, which separated the two diastereomers.
Yield:
Diastereomer 1: 330 mg of colorless crystals Diastereomer 2: 308 mg of colorless crystals Diastereomer 1 (Cl,H20O5) (MM 304):
H NMR (200 MHz, benzene-d6) 9.60 (1) s; 7.51 (1) d, J = 2 Hz; 7.10 (1) dd, Jl =
2 HZ, J2 = 8 Hz; 6-81 (1) d, J = 8 Hz; 6.12 (1) d, J = 7 Hz; 5.35 (1) d/septet, Jl = 7 Hz~ J2 = 1 Hz;
3.98 (1), J = 11 Hz; 3.40 (1), J = ll Hz; 1.43 (3) d, J = 1 Hz; 1.32 (3) d, J = 1 Hz; 1.31 (3) s; 0.94 (3) s (~ ppm) IR (K~r):
3040, 2980, 2940, 2910, 2830, 2800, 2730, 1680, 1580, 1500 cm~l Diastereomer 2 ( Cl7H20O5) (MM 304):
H NNR (200 MHz, benzene-d6) 9.56 (1) s; 7.49 (1) d, J = 2 Hz; 7.09 (1) dd, Jl =
2 Hz, J2 = 8 Hz; 6-79 (1) d, J = 8 Hz; 5.92 (1) d, J - 7 Hz; 5.53 (1) d/~eptat, J1 ~ 7 Hz, J2 ' l Hz;
3.86 (1) d, J = 11 Hz; 3.48 (1) d, J = 11 Hz; 1.41 (3) d, J = l Hz; 1.38 (3) d, J = 1 Hz; 1.26 (3) s;
0.83 (3) s (ppm) IR (KBr):
3060, 2990, 2940, 2840, 2740, 1680, 1600, 1580, 1500 cm B. Preparation of the diastereomeric final product .,~
, .. . .
..
:
:: . ~ , . - .
.
:: ' ' ~ ' . ' .
The two diastereomers were produced approximately in the ratio 1:1 according to an NMR
check on the crude product.
Th~ crude product was chromatographed on silica gel with hexane/ethyl acetate (10:1) as mobile phase, which separated the two diastereomers.
Yield:
Diastereomer 1: 330 mg of colorless crystals Diastereomer 2: 308 mg of colorless crystals Diastereomer 1 (Cl,H20O5) (MM 304):
H NMR (200 MHz, benzene-d6) 9.60 (1) s; 7.51 (1) d, J = 2 Hz; 7.10 (1) dd, Jl =
2 HZ, J2 = 8 Hz; 6-81 (1) d, J = 8 Hz; 6.12 (1) d, J = 7 Hz; 5.35 (1) d/septet, Jl = 7 Hz~ J2 = 1 Hz;
3.98 (1), J = 11 Hz; 3.40 (1), J = ll Hz; 1.43 (3) d, J = 1 Hz; 1.32 (3) d, J = 1 Hz; 1.31 (3) s; 0.94 (3) s (~ ppm) IR (K~r):
3040, 2980, 2940, 2910, 2830, 2800, 2730, 1680, 1580, 1500 cm~l Diastereomer 2 ( Cl7H20O5) (MM 304):
H NNR (200 MHz, benzene-d6) 9.56 (1) s; 7.49 (1) d, J = 2 Hz; 7.09 (1) dd, Jl =
2 Hz, J2 = 8 Hz; 6-79 (1) d, J = 8 Hz; 5.92 (1) d, J - 7 Hz; 5.53 (1) d/~eptat, J1 ~ 7 Hz, J2 ' l Hz;
3.86 (1) d, J = 11 Hz; 3.48 (1) d, J = 11 Hz; 1.41 (3) d, J = l Hz; 1.38 (3) d, J = 1 Hz; 1.26 (3) s;
0.83 (3) s (ppm) IR (KBr):
3060, 2990, 2940, 2840, 2740, 1680, 1600, 1580, 1500 cm B. Preparation of the diastereomeric final product .,~
, .. . .
..
:
:: . ~ , . - .
.
:: ' ' ~ ' . ' .
- 7 - O.Z. 0050/40598 (formula I, R1 z 2,2-dimethylvinyl, R2, R3 = CH3) a) 60 mg (2 mmol~ of NaH were suspended under a protective ga~ atmosphere (Ar) in 1 ml of absolute tetrahydrofuran.
Then, at 0C, a solution of 608 mg (2 mmol) of diastereomer 1 of the compound of the formula II tR = 2,2-dimethylvinyl, R2, R3 = CH3) [cf. 1 Ac] and 6.28 g (2 mmol) of the phosphonic ester of the formula III (R~ = -CH3) in 5 ml of absolute tetrahydrofuran was added dropwise.
The mixture was allowed to warm to room temperature and was stirred for 24 h. The reaction solution was worked up by adding it to 15 ml of ether and washing 2 x with 3 ml of water and 1 x with 3 ml of saturated NaCl solution. Drying over MgSO4 was followed by concentration in a rotary evaporator. The crude product was chromatographed on a silica gel column with hexane/ethyl acetate (5:1) as mobile phase.
540 mg (55~) of a white solidified oil which contained only diastereomer 1 w2re obtained.
Diastereomer 1 (C2~H32O7) (MM 492):
H NMR ( 200 MHz, benzene-d6) 7.65-7.25 (6) m; 7.05-6.90 (4) m; 6.18 (1) d, J = 7.5 Hz; 5.39 (1) d/septet, J1 = 7.5 Hz, J2 = 1 Hz; 4.05 (1) d, J = 11 Hz; 3.59 (1) d, J = 11 Hz; 3.40 (3) 8; 2.80 (3) 8; 1.46 (3) d, J = 1 Hz; 1.36 (3) 8; 1.35 (3) d, J - 1 Hz; 1.01 (3) ~ (6 ppm) IR (K~r): :
3060, 3020, 2980, 2940, 1710, 1630, 1585, 1510, 1435 cm~
b) In a corresponding manner, diastereomer 2 (C2~H32O" MW 492) was prepared from diastereomer 2 of the compound of the formula II (R = 2,2-dimethyl-vinyl, R2, R3 = CH3 ) .
lH NMR ( 200 MHz, benzene-d6 ) . ~ : . . -;., ~ . .. . , . . - ............... :
.
. - - . , - - , . - .. ~ .,. ; -- : :
.,.. : , . . .. . . .. .... . . .
7 ~ ~ ~
.
Then, at 0C, a solution of 608 mg (2 mmol) of diastereomer 1 of the compound of the formula II tR = 2,2-dimethylvinyl, R2, R3 = CH3) [cf. 1 Ac] and 6.28 g (2 mmol) of the phosphonic ester of the formula III (R~ = -CH3) in 5 ml of absolute tetrahydrofuran was added dropwise.
The mixture was allowed to warm to room temperature and was stirred for 24 h. The reaction solution was worked up by adding it to 15 ml of ether and washing 2 x with 3 ml of water and 1 x with 3 ml of saturated NaCl solution. Drying over MgSO4 was followed by concentration in a rotary evaporator. The crude product was chromatographed on a silica gel column with hexane/ethyl acetate (5:1) as mobile phase.
540 mg (55~) of a white solidified oil which contained only diastereomer 1 w2re obtained.
Diastereomer 1 (C2~H32O7) (MM 492):
H NMR ( 200 MHz, benzene-d6) 7.65-7.25 (6) m; 7.05-6.90 (4) m; 6.18 (1) d, J = 7.5 Hz; 5.39 (1) d/septet, J1 = 7.5 Hz, J2 = 1 Hz; 4.05 (1) d, J = 11 Hz; 3.59 (1) d, J = 11 Hz; 3.40 (3) 8; 2.80 (3) 8; 1.46 (3) d, J = 1 Hz; 1.36 (3) 8; 1.35 (3) d, J - 1 Hz; 1.01 (3) ~ (6 ppm) IR (K~r): :
3060, 3020, 2980, 2940, 1710, 1630, 1585, 1510, 1435 cm~
b) In a corresponding manner, diastereomer 2 (C2~H32O" MW 492) was prepared from diastereomer 2 of the compound of the formula II (R = 2,2-dimethyl-vinyl, R2, R3 = CH3 ) .
lH NMR ( 200 MHz, benzene-d6 ) . ~ : . . -;., ~ . .. . , . . - ............... :
.
. - - . , - - , . - .. ~ .,. ; -- : :
.,.. : , . . .. . . .. .... . . .
7 ~ ~ ~
.
- 8 - O.Z. 0050/40598 7.60-7.20 ~6) m;7.00-6.88 (4) m; 5.97 (1) d, J = 7.5 Hz; 5.61 (1) d/septet, J1 = 7.5 Hz, J2 = 1 Hz; 3.94 (1) d, J = 11 Hz; 3.67 (1) d, J = 11 Hz; 3.40 (3) s; 2.81 (3) s; 1.45 (3) d, J = 1 Hz; 1.42 (3) d, J = 1 Hz; 1.32 (3) s; 0.92 (3) 8 (~ ppm) IR (KBr):
3060, 3020, 2980, 2940, 2840, 1710, 1630, 1585, 1510, 1435 cm~l The corresponding diastereomers of the formula I
were obtained from the diastereomers of the formula II
(R1 = 2,2-dimethylvinyl, R2 R3 a ~ ) in analogy to Example 1:
Diastereomer 1 (C32H36O~, MW 532):
H NMR (200 MHZ, benzene-d6) 7.64-7.31 (6) m; 7.15-6.94 (5) m; 6.18 (1) d, J = 7.5 Hz;
5.39 (1) d/septet, J1 = 7.5 Hz, J2 = 1 Hz; 4.06 (1) d, J = 11 Hz; 3.68 (1) d, J = 11 Hz; 3.40 (3) s; 2.80 (3) s;
2.39-2.25 (1) m; 1.90-1.45 (5) m; 1.44 (3) d, J = 1 Hz;
1.33 (3) d, J = 1 Hz; 1.27-0.85 (4) m.
IR (KBr):
3060, 3020, 2930, 2860, 1700, 1630, 1580, 1505, 1450, 1430 cm~1 Diastereomer 2 (C32H36O~, MM 532):
H NNR (200 NHZ, benzene-d~) 7.62-7.28 (4) m; 7.20-6.92 (6) m; 5.94 (l) d, J - 7.5 Hz;
5.63 (1) d/septet, J1 ~ 7.5 Hz, J2 ~ 1 Hz; 3.98 (1) d, J = 11 Hz; 3.77 (1) d, J = 11 Hz; 3.40 (3) s; 2.81 (3) s;
2.38-2.22 (1) m; 1.85-1.50 (5) m; 1.45 (3) d, J = 1 Hz;
1.42 (3) d, J = 1 Hz; 1.37-0.80 (4) m.
IR (KBr):
30S0, 3020, 2930, 2860, 1700, 1630, 1580, lSOS, 1450, 1430 cm~l .. .
.,'`'~ :: ` ' : ': ........................... . .
~, -~ . :.
3060, 3020, 2980, 2940, 2840, 1710, 1630, 1585, 1510, 1435 cm~l The corresponding diastereomers of the formula I
were obtained from the diastereomers of the formula II
(R1 = 2,2-dimethylvinyl, R2 R3 a ~ ) in analogy to Example 1:
Diastereomer 1 (C32H36O~, MW 532):
H NMR (200 MHZ, benzene-d6) 7.64-7.31 (6) m; 7.15-6.94 (5) m; 6.18 (1) d, J = 7.5 Hz;
5.39 (1) d/septet, J1 = 7.5 Hz, J2 = 1 Hz; 4.06 (1) d, J = 11 Hz; 3.68 (1) d, J = 11 Hz; 3.40 (3) s; 2.80 (3) s;
2.39-2.25 (1) m; 1.90-1.45 (5) m; 1.44 (3) d, J = 1 Hz;
1.33 (3) d, J = 1 Hz; 1.27-0.85 (4) m.
IR (KBr):
3060, 3020, 2930, 2860, 1700, 1630, 1580, 1505, 1450, 1430 cm~1 Diastereomer 2 (C32H36O~, MM 532):
H NNR (200 NHZ, benzene-d~) 7.62-7.28 (4) m; 7.20-6.92 (6) m; 5.94 (l) d, J - 7.5 Hz;
5.63 (1) d/septet, J1 ~ 7.5 Hz, J2 ~ 1 Hz; 3.98 (1) d, J = 11 Hz; 3.77 (1) d, J = 11 Hz; 3.40 (3) s; 2.81 (3) s;
2.38-2.22 (1) m; 1.85-1.50 (5) m; 1.45 (3) d, J = 1 Hz;
1.42 (3) d, J = 1 Hz; 1.37-0.80 (4) m.
IR (KBr):
30S0, 3020, 2930, 2860, 1700, 1630, 1580, lSOS, 1450, 1430 cm~l .. .
.,'`'~ :: ` ' : ': ........................... . .
~, -~ . :.
- 9 - O.Z. 0050/40598 The compound of the formula I (Rl = 2,6-dimethyl-1,5-heptadienyl (1), R2, R3 = CH3, C34H4007, MW 560) was obtained in analogy to Example lB. a).
lH NMR (200 H2, benzene-d6):
7.65-6.90 (10) m; 6.22 (1) d, J = 7.5 Hz; 5.48 (1) d/septet, J1 = 7.5 Hz, J2 = 1 Hz; 5.15-5.02 (1) m; 4.04 (1) d, J = 11 Hz; 3.59 (1) d, J = 11 Hz; 3.45 (3) s; 2.81 (3) s; 2.08-1.85 (4) m; 1.61 (3) d, J = 11 Hz; 1.47 (3) s; 1.43 (3) d, J = 1 Hz; 1.36 (3) s; 1.02 (3) s.
IR (CHCl3):
3020, 2980, 2940, 2850, 1700, 1625, 1585, 1505, 1430 cm~
The following intermediates of the formula II
(R2, R3 = CH3) can be prepared in analogy to Example lAc:
Rl = H, Methyl, n-Butyl, Methoxymethyl, Trifluoromethyl, Trichloromethyl, 2,2-Dimethylpropyl, 3,3-Dimethylbutenyl(l), 1,3-Pentadienyl(l), 2,6-Dimethyl-5-heptenyl(l), 2-Methylpropyl, 2-Phenyl-vinyl, Phenoxymethyl.
The following active substances of the formula I
30 can be prepared therefrom in analogy to Example lB
(R2, R3 = CH3):
Example Rl 4 H, Methyl, 6 n-Butyl, 7 E-Methoxymethyl, 8 Trifluoromethyl, .: . . - ~ .. . . .
lH NMR (200 H2, benzene-d6):
7.65-6.90 (10) m; 6.22 (1) d, J = 7.5 Hz; 5.48 (1) d/septet, J1 = 7.5 Hz, J2 = 1 Hz; 5.15-5.02 (1) m; 4.04 (1) d, J = 11 Hz; 3.59 (1) d, J = 11 Hz; 3.45 (3) s; 2.81 (3) s; 2.08-1.85 (4) m; 1.61 (3) d, J = 11 Hz; 1.47 (3) s; 1.43 (3) d, J = 1 Hz; 1.36 (3) s; 1.02 (3) s.
IR (CHCl3):
3020, 2980, 2940, 2850, 1700, 1625, 1585, 1505, 1430 cm~
The following intermediates of the formula II
(R2, R3 = CH3) can be prepared in analogy to Example lAc:
Rl = H, Methyl, n-Butyl, Methoxymethyl, Trifluoromethyl, Trichloromethyl, 2,2-Dimethylpropyl, 3,3-Dimethylbutenyl(l), 1,3-Pentadienyl(l), 2,6-Dimethyl-5-heptenyl(l), 2-Methylpropyl, 2-Phenyl-vinyl, Phenoxymethyl.
The following active substances of the formula I
30 can be prepared therefrom in analogy to Example lB
(R2, R3 = CH3):
Example Rl 4 H, Methyl, 6 n-Butyl, 7 E-Methoxymethyl, 8 Trifluoromethyl, .: . . - ~ .. . . .
- 10 - O.Z. 0050/40538 9 Trichloromethyl, 2,2-Dimethylpropyl, 11 3,3-Dimethylbutenyl(l), 12 1,3-Pentadienyl(l), 13 2,6-Dimethyl-5-heptenyl(l), 14 2-Methylpropyl, 2-Phenyl-vinyl, 16 Phenoxymethyl.
The novel compounds - especially the compounds of 10Examples 1 to 16 - show good antiviral, antiproliferative and cytotoxic activity. - -The following examples iliustrate the action of the novel substances:
EXAMPLE A
15Inhibitory action on respiration in Penicillium notatum The oxygen consumption was measured by polaro-graphy in a vessel (volume 3 ml, with magnetic stirrer) which was closed air-tight and had an oxygen electrode.
The test fungus was cultured from a spore suspension to 20a mycelium weight of 10-20 mg wet weight of mycelium/ml. .
The measurements were carried out with a mycelium con-centration of 25-30 mg wet weight of mycelium/ml in 1%
strength glucose solution. After a brief constant course of respiration, the compounds dissolved in methanol 25(0.3 mg/ml) were added to the suspension, and the 2 consumption was recorded. The test was carried out using strobilurin A as comparison compound. The results of the percentage inhibition of respiration are stated in Table 1.
Compound Inhibition of respiration as % of the control Example 1 Bl 95 Example 1 B2 95 Strobilurin A 93 EXAMPLE B
Cytostatic and morphological action on HeLa-S3 cells . .
: . . , . . ... . : . . - :
''' .,:: . . ~'. ' , - :, .: :, , .
~ ~ 3 J~ rj ~ O.Z. 0050/40598 On incubation of HeLa-S3 and other cells with the compounds according to the inventLon, cell division was inhibited within a short time. In addition, the morpho-logy of the cells was changed.
HeLa-S3 cells were placed on a 96-well titer plate at a cell density of 4 x 10$ cells/ml in medium F12 with 10% fetal calf serum. After 24 h the cells had spread over the surface, and the medium was changed. The cells were incubated with the medium containing the test compounds (10, 1, 0.1 and 0.01 ~g per ml of medium) for 72 h (37C, 5% CO2). After 72 h the normally epithelioid growing cells had a fibroblast-like morphology. The change in morphology is significantly visible at and above a 45% inhibition of growth by the action of the substances.
The test was carried out using strobilurin A as comparison compound. The cell density was measured by determining the total protein content per well. The stated values show the results after three-active incuba-tion with the test substances and are listed in Table 2 as a percentage of the total protein of the untreated control.
Compound Protein content as percentage of the control (~g/ml) -10 ~g 1 ~g 0.1 ~g 0.01 ~g Example 1 91 20 21 23 55 Example 1 B2 38 38 50- 70 Strobilurin A 23 55 92 100 EXAMPLE C
Antiviral action on VSV in HEp-2 cells The determination of the antiviral activity of a test compound is based on measurement of the protection of human HEp-2 cells ac indicator cells from the cyto-pathic effect (CPE) of vesicular stomatitis virus (VSV).
For this, 100 ~l of culture medium with 2 x 104 ... .. : : ., . . , : ~ . . ~
: ,: -- . :-. .
- 12 - O.Z. 0050/40598 HEp-2 cells were placed in the wells of a 96-well flat-bottomed plate and incubated at 37C and 5% (V/V) earbon dioxide overnight. The next day 100 ~1 of the sample solution was added to the confluent cell cultures, and serial 2 x titration was carried out. Also made up on the culture plate were a cell control (= untreated cells not infected with virus) and a virus control (= untreated cells infected with virus). After further incubation at 37C and 5% (V/V) C02 for 24 h, the cultures were infected with 50 ~1 of a VSV suspension in culture medium and ineubated at 37C and 5% (V/V) C02. After two days, the eell destruetion eaused by the virus (CPE) in the unpro-teeted eultures (- virus eontrol) was eomplete. The pereentage of proteeted eells in the cultures treated with test eompounds and subsequently infected with VSV
was determined by staining with crystal violet. The sample concentration which leads to 50% protection, based on 0 and 100% protection, was determined as a measure of the antiviral activity. Reeombinant human interferon-~
(rHuIFN-~) was also investigated as eontrol for the antiviral aetivity of a compound.
- Table 3 lists the test substanees with the eoneentration whieh 50% protected HEp-2 eells from the eytopathie effeet of VSV.
Compound Antiviral aetivity (ng/ml) Example 1 Bl 3 Example 1 B2 3-Control (rHuIFN-~) 0.6 In eontradistinetion to rHuIFN-~, the substance of Exsmple 1 also showed an antiproliferative effeet under these test eonditions by eomparison with the cell eontrol. The antiviral and antiproliferative aetivities of the substances of Example 1 ran in parallel and eorrelated with a morphologieal change in the cells, ie.
the eells were, by eomparison with the eell eontrol, : -: " ~ ~ ~ ' .
. . ~ . ,: . . . :.- - .
~ : ~ .. ~ .: ' : . . . ' .
- 13 - O.Z. 0050/40598 elongate and displayed neurite-like projections.
EXAMPLE D
Cytotoxic and antiproliferative action on human tumor cells Tumor cells derived from different tissues (5637-6: human bladder carcinoma; HT-29: human colon carcinoma; B-16: murine melanoma) were used to determine the antitumor properties of compounds 1 B1 and 1 B2.
1 to 2 x 103 tumor cells undergoing exponential growth were plated out in complete growth medium (RPMI 1640 x 10% fetal calf serum) in 96-well plates and incubated under standard culture conditions (37C, 5%
carbon dioxide, atmosphere saturated with water vapor) overnight. The substance was added the next day, making up serial titrations of substances 1 B1 and 1 B2 over a concentration range from 10-4 to 10-~ M. After further incubation under standard conditions for 72 h, the cell count was determined by staining with crystal violet and subsequent photometric evaluation at 540 nm using a multiphotometer.
Only at the very high concentration of 10-4 M was cytolysis of the treated cells to be seen under the microscope. At the other concentrations investigated there was found to be a strong, dose-dependent inhibition of cell proliferation so that even at the lowest con-centration investigated of 10-~ M the number of treated cells showed a value of less than 50% of the untreated cell control.
Thi8 great decrease in the proliferative activity of the cells treated with the substances of Example 1 was associated with a morphological change characterized by an elongation of the cell bodies and by the formation of cell pro~ections.
The novel compounds - especially the compounds of 10Examples 1 to 16 - show good antiviral, antiproliferative and cytotoxic activity. - -The following examples iliustrate the action of the novel substances:
EXAMPLE A
15Inhibitory action on respiration in Penicillium notatum The oxygen consumption was measured by polaro-graphy in a vessel (volume 3 ml, with magnetic stirrer) which was closed air-tight and had an oxygen electrode.
The test fungus was cultured from a spore suspension to 20a mycelium weight of 10-20 mg wet weight of mycelium/ml. .
The measurements were carried out with a mycelium con-centration of 25-30 mg wet weight of mycelium/ml in 1%
strength glucose solution. After a brief constant course of respiration, the compounds dissolved in methanol 25(0.3 mg/ml) were added to the suspension, and the 2 consumption was recorded. The test was carried out using strobilurin A as comparison compound. The results of the percentage inhibition of respiration are stated in Table 1.
Compound Inhibition of respiration as % of the control Example 1 Bl 95 Example 1 B2 95 Strobilurin A 93 EXAMPLE B
Cytostatic and morphological action on HeLa-S3 cells . .
: . . , . . ... . : . . - :
''' .,:: . . ~'. ' , - :, .: :, , .
~ ~ 3 J~ rj ~ O.Z. 0050/40598 On incubation of HeLa-S3 and other cells with the compounds according to the inventLon, cell division was inhibited within a short time. In addition, the morpho-logy of the cells was changed.
HeLa-S3 cells were placed on a 96-well titer plate at a cell density of 4 x 10$ cells/ml in medium F12 with 10% fetal calf serum. After 24 h the cells had spread over the surface, and the medium was changed. The cells were incubated with the medium containing the test compounds (10, 1, 0.1 and 0.01 ~g per ml of medium) for 72 h (37C, 5% CO2). After 72 h the normally epithelioid growing cells had a fibroblast-like morphology. The change in morphology is significantly visible at and above a 45% inhibition of growth by the action of the substances.
The test was carried out using strobilurin A as comparison compound. The cell density was measured by determining the total protein content per well. The stated values show the results after three-active incuba-tion with the test substances and are listed in Table 2 as a percentage of the total protein of the untreated control.
Compound Protein content as percentage of the control (~g/ml) -10 ~g 1 ~g 0.1 ~g 0.01 ~g Example 1 91 20 21 23 55 Example 1 B2 38 38 50- 70 Strobilurin A 23 55 92 100 EXAMPLE C
Antiviral action on VSV in HEp-2 cells The determination of the antiviral activity of a test compound is based on measurement of the protection of human HEp-2 cells ac indicator cells from the cyto-pathic effect (CPE) of vesicular stomatitis virus (VSV).
For this, 100 ~l of culture medium with 2 x 104 ... .. : : ., . . , : ~ . . ~
: ,: -- . :-. .
- 12 - O.Z. 0050/40598 HEp-2 cells were placed in the wells of a 96-well flat-bottomed plate and incubated at 37C and 5% (V/V) earbon dioxide overnight. The next day 100 ~1 of the sample solution was added to the confluent cell cultures, and serial 2 x titration was carried out. Also made up on the culture plate were a cell control (= untreated cells not infected with virus) and a virus control (= untreated cells infected with virus). After further incubation at 37C and 5% (V/V) C02 for 24 h, the cultures were infected with 50 ~1 of a VSV suspension in culture medium and ineubated at 37C and 5% (V/V) C02. After two days, the eell destruetion eaused by the virus (CPE) in the unpro-teeted eultures (- virus eontrol) was eomplete. The pereentage of proteeted eells in the cultures treated with test eompounds and subsequently infected with VSV
was determined by staining with crystal violet. The sample concentration which leads to 50% protection, based on 0 and 100% protection, was determined as a measure of the antiviral activity. Reeombinant human interferon-~
(rHuIFN-~) was also investigated as eontrol for the antiviral aetivity of a compound.
- Table 3 lists the test substanees with the eoneentration whieh 50% protected HEp-2 eells from the eytopathie effeet of VSV.
Compound Antiviral aetivity (ng/ml) Example 1 Bl 3 Example 1 B2 3-Control (rHuIFN-~) 0.6 In eontradistinetion to rHuIFN-~, the substance of Exsmple 1 also showed an antiproliferative effeet under these test eonditions by eomparison with the cell eontrol. The antiviral and antiproliferative aetivities of the substances of Example 1 ran in parallel and eorrelated with a morphologieal change in the cells, ie.
the eells were, by eomparison with the eell eontrol, : -: " ~ ~ ~ ' .
. . ~ . ,: . . . :.- - .
~ : ~ .. ~ .: ' : . . . ' .
- 13 - O.Z. 0050/40598 elongate and displayed neurite-like projections.
EXAMPLE D
Cytotoxic and antiproliferative action on human tumor cells Tumor cells derived from different tissues (5637-6: human bladder carcinoma; HT-29: human colon carcinoma; B-16: murine melanoma) were used to determine the antitumor properties of compounds 1 B1 and 1 B2.
1 to 2 x 103 tumor cells undergoing exponential growth were plated out in complete growth medium (RPMI 1640 x 10% fetal calf serum) in 96-well plates and incubated under standard culture conditions (37C, 5%
carbon dioxide, atmosphere saturated with water vapor) overnight. The substance was added the next day, making up serial titrations of substances 1 B1 and 1 B2 over a concentration range from 10-4 to 10-~ M. After further incubation under standard conditions for 72 h, the cell count was determined by staining with crystal violet and subsequent photometric evaluation at 540 nm using a multiphotometer.
Only at the very high concentration of 10-4 M was cytolysis of the treated cells to be seen under the microscope. At the other concentrations investigated there was found to be a strong, dose-dependent inhibition of cell proliferation so that even at the lowest con-centration investigated of 10-~ M the number of treated cells showed a value of less than 50% of the untreated cell control.
Thi8 great decrease in the proliferative activity of the cells treated with the substances of Example 1 was associated with a morphological change characterized by an elongation of the cell bodies and by the formation of cell pro~ections.
Claims (5)
1. A .beta.-methoxyacrylate of the formula I
I
in which R1 is hydrogen or an optionally unsaturated hydrocarbon radical with up to 10 carbon atoms, which can be substi-tuted by fluorine, chlorine, bromine, C1-6-alkoxy, C2-6-alkenoxy or C2-6-alkynoxy or by a phenyl or phenoxy radical which is optionally substituted by fluorine, chlorine, bromine, iodine, trifluoromethyl, C1-4-alkyl or C1-4-alkoxy, R2 and R3 are identical or different and are hydrogen atoms, C1-6-alkyl groups or C3-7-cycloalkyl groups or R2 and R3 together are a C2-8-alkylene group.
I
in which R1 is hydrogen or an optionally unsaturated hydrocarbon radical with up to 10 carbon atoms, which can be substi-tuted by fluorine, chlorine, bromine, C1-6-alkoxy, C2-6-alkenoxy or C2-6-alkynoxy or by a phenyl or phenoxy radical which is optionally substituted by fluorine, chlorine, bromine, iodine, trifluoromethyl, C1-4-alkyl or C1-4-alkoxy, R2 and R3 are identical or different and are hydrogen atoms, C1-6-alkyl groups or C3-7-cycloalkyl groups or R2 and R3 together are a C2-8-alkylene group.
2. A compound of the formula I as claimed in claim 1 for use for controlling diseases.
3. A process for preparing the .beta.-methoxyacrylates of the formula I as claimed in claim 1, which comprises reacting an aldehyde of the formula II
II
in which R1, R2 and R3 have the abovementioned meanings, with a phosphonic ester of the formula III
III
in which R4 is a C1-8-alkyl radical, in the presence of a base, and, where appropriate, hydrogenating the compounds obtained in this way if R1 is an unsaturated radical.
II
in which R1, R2 and R3 have the abovementioned meanings, with a phosphonic ester of the formula III
III
in which R4 is a C1-8-alkyl radical, in the presence of a base, and, where appropriate, hydrogenating the compounds obtained in this way if R1 is an unsaturated radical.
4. A compound of the formula II as claimed in claim 3.
5. A compound of the formula IV
IV
in which R2 and R3 have the abovementioned meaning.
IV
in which R2 and R3 have the abovementioned meaning.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE3905911A DE3905911A1 (en) | 1989-02-25 | 1989-02-25 | NEW SS-METHOXYACRYLATES, THEIR PREPARATION AND USE |
| DEP3905911.1 | 1989-02-25 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2047195A1 true CA2047195A1 (en) | 1990-08-26 |
Family
ID=6374929
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002047195A Abandoned CA2047195A1 (en) | 1989-02-25 | 1990-02-20 | .beta.-methoxyacrylates, their production and use |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP0460084A1 (en) |
| JP (1) | JPH04503671A (en) |
| CA (1) | CA2047195A1 (en) |
| DE (1) | DE3905911A1 (en) |
| WO (1) | WO1990010006A2 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE4443648C2 (en) * | 1994-12-08 | 1999-01-21 | Akzo Nobel Nv | Process for the production of polyesters and copolyesters |
| BRPI0710209A2 (en) * | 2006-03-29 | 2011-05-24 | Basf Se | use of strobilurin derivatives, drug, and process for the preparation of a drug |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3815484A1 (en) * | 1988-05-06 | 1989-11-16 | Basf Ag | NEW STROBILURINE DERIVATIVES, THEIR PREPARATION AND USE |
-
1989
- 1989-02-25 DE DE3905911A patent/DE3905911A1/en not_active Withdrawn
-
1990
- 1990-02-20 CA CA002047195A patent/CA2047195A1/en not_active Abandoned
- 1990-02-20 WO PCT/EP1990/000280 patent/WO1990010006A2/en not_active Ceased
- 1990-02-20 JP JP2504145A patent/JPH04503671A/en active Pending
- 1990-02-20 EP EP90904345A patent/EP0460084A1/en not_active Withdrawn
Also Published As
| Publication number | Publication date |
|---|---|
| JPH04503671A (en) | 1992-07-02 |
| WO1990010006A3 (en) | 1990-11-01 |
| EP0460084A1 (en) | 1991-12-11 |
| DE3905911A1 (en) | 1990-08-30 |
| WO1990010006A2 (en) | 1990-09-07 |
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