IE52642B1 - Morpholine derivatives,process for preparing them and use of said morpholine derivatives in pharmaceutical preparations - Google Patents
Morpholine derivatives,process for preparing them and use of said morpholine derivatives in pharmaceutical preparationsInfo
- Publication number
- IE52642B1 IE52642B1 IE1729/80A IE172980A IE52642B1 IE 52642 B1 IE52642 B1 IE 52642B1 IE 1729/80 A IE1729/80 A IE 1729/80A IE 172980 A IE172980 A IE 172980A IE 52642 B1 IE52642 B1 IE 52642B1
- Authority
- IE
- Ireland
- Prior art keywords
- formula
- compound
- acid
- salt
- morpholine
- Prior art date
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
- C07D295/027—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring
- C07D295/03—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring with the ring nitrogen atoms directly attached to acyclic carbon atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Morpholine derivatives of the formula:- wherein R represents ethyl or phenyl, as well as their salts and N-oxides, possesses fungicidal activity and can be used as antimycotics, especially for combating Candida albicans.
Description
The present invention relates to heterocyclic compounds More particularly, the Invention is concerned with heterocyclic compounds, a process for the manufacture thereof, fungicidal compositions containing said compounds and a process for the production of said compositions. The invention is also concerned with the use of the present heterocyclic compounds.
The present invention provides a heterocyclic compound of the formula as well as salts and N-oxides of said compound.
The compounds of formula I according to the invention are distinguished from the compounds known from Patent Specification No. 45748 in that they represent the cis isomers of said known compounds.
The process provided by the present invention for the manufacture of the compound of formula I and of salts and N-oxides thereof comprises (a) reacting a halide of the general formula II II CH2-Y wherein R has the significance given above and Y represents chlorine, bromine or iodine, with a compound of the formula or (b) III reducing a compound of the formula OAO4<5 wherein R has the significance given above and one of the two broken lines represents an additional bond, or (c) reacting a compound of the formula with a compound which yields a carbonium ion of the formula R.
H3C © >c-ch3 VI wherein R has the significance given above, or (d) reacting a compound of the formula wherein R has the significance given above, under hydrogenating conditions with a compound of formula III 10 or, for the manufacture of a N-oxide, treating a compound of formula I with hydrogen peroxide or a peracid, or, for the manufacture of a salt, converting the base of formula I into a salt with an acid in a manner known per se.
In accordance with embodiment (a) of the foregoing 15 process, a halide of formula II is reacted with an amine of formula III, conveniently in an inert solvent (for example, in an ether such as diethyl ether, tetrahydrofuran or dioxan, in dimethyl sulphoxide, or, preferably, in a high-boiling alcohol such as ethyleneglycol or glycerine) in the presence of a base (for example, triethylamine or an excess of amine of formula III). The reaction is preferably carried out in a temperature range between 50°C and 150°C. Ethyleneglycol is especially preferred as the inert solvent and a temperature of 100°-110°C is also especially preferred.
In accordance with embodiment (b) of the foregoing process, a compound of formula IV is reduced. When a compound of formula IV in which the double-bond is situated in the α-position to the morpholine ring is used as the starting material, then the reduction can be carried out catalytically or by using-formic acid.
Especially suitable catalysts are noble metal catalysts such as, for example, platinum, palladium (optionally precipitated on charcoal) and Raney nickel. Palladium-on-charcoal is the preferred catalyst. Suitable solvents for the catalytic reduction are hydrocarbons such as benzene, toluene or xylene, and alcohols such as methanol or ethanol.
Toluene is the preferred solvent. The catalytic reduction is advantageously carried out at a temperature between 0°C and 50°C, preferably at room temperature. The reduction of a compound of formula IV with formic acid is preferably carried out in the absence of a solvent, the formic acid being added dropwise to the compound of formula IV at a temperature of from 0°C to 100’C, preferably at 5O°-7O’C, if necessary whilst cooling.
When a compound of formula IV in which the double-bond is situated in the α-position to the phenyl ring is used as the starting material, the reduction can be carried out catalytically. Platinum or palladium is preferably used as the catalyst, with water or alcohol being used as the solvent. In order to avoid a possible hydrogenolysis, at least one equivalent of acid, preferably hydrochloric acid, is added to the reduction mixture.
The alkylation of a compound of formula VI in accordance with embodiment (o) of the foregoing process is carried out in the presence of a suitable amount of a Friedel-Crafts catalyst. Suitable catalysts are the known Friedel-Crafts catalysts such as, for example, aluminium chloride, iron chloride, zinc chloride, boron trifluoride, tin chloride, hydrogen fluoride, sulphuric acid and phosphoric acid. Sulphuric acid is especially preferred for the purpose of the present invention.
The use of an inert organic solvent in embodiment (c) is not essential, but is preferred. Especially suitable inert organic solvents are alkanes such as hexane and cyclohexane as well as chlorinated hydrocarbons such as chloroform, ethylene dichloride and methylene chloride, with methylene chloride being especially preferred. The temperature at which the alkylation is carried out is not critical, but generally lies between 0°C and 50°C, preferably between 18°C and 20°C.
Preferably, and especially when sulphuric acid is used as the catalyst in embodiment (c), after completion of the alkylation the product obtained in the salt form is extracted with an inert organic solvent such as, for example, methylene chloride. If desired, the free amine can be obtained with a suitable base such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate or calcium hydroxide.
Preferred compounds which yield the carbonium ion of general formula VI are the corresponding tertiary alcohol; that is, 2-methyl-2-butanol or tertiary chlorides such as 2-chloro-2-methyl-butane, The reaction of a substituted cinnamaldehyde of formula VII with the cis-2,6-dimethyl-morpholine of formula III in accordance with embodiment (d) of the foregoing process is carried out under hydrogenating conditions, for example using a palladium catalyst (e.g. in methanol).
In order to manufacture a N-oxide of the compound of formula I, the compound of formula I is treated with hydrogen peroxide or a peracid. When hydrogen peroxide is used as the oxidising agent, an alcohol such as methanol, ethanol or, preferably, isopropanol is used as the solvent. This oxidation is preferably carried out at a temperature between 0°C and 50°C, especially at 40°C. Examples of peracids which can be used are peracetic acid, perbenzoic acid, metachloroperbenzoic acid and peradipic acid. Preferred solvents for the peracids are halogenated hydrocarbons such as methylene chloride, chloroform or ethylene chloride.
The oxidation with a peracid is suitably carried out at the same temperature as that previously mentioned in connection with the oxidation using hydrogen peroxide.
The carpound of formula I forms salts with organic and inorganic acids. Preferred salts of the compound formula I are salts formed with physiologically compatible acids. These include, in particular, the salts formed with hydrohalic acids (e.g. hydrochloric acid and hydrobromic acid), phosphoric acid, nitric acid, monofunctional and bifunctional carboxylic acids and hydroxycarboxylic acids (e.g. acetic acid, maleic acid, succinic acid, fumaric acid, tartaric acid, citric acid, salicylic acid, sorbic acid and lactic acid), and sulphonic acids (e.g. 1,5-naphthalene-disulphonic acid). The preparation of. such salts is carried out in a manner known per se.
The starting materials of formulae II and VI are known compounds. The starting materials of formulae III and IV are known as the cis/trans mixture. The cis starting materials of formulae III and IV can be prepared in analogy . to the process for the manufacture of the cis/trans mixture.
The starting material of formula XV in which the double-bond is situated in the α-position to the morpholine ring can be prepared, for example, by reacting a corresponding ly substituted phenyl-2-methyl-propionaldehyde with cis-2.6-dimethyl-morpholine. The hydrogenation of a thus-obtained compound of formula IV is conveniently carried out in situ.
The starting material of formula IV in which the double-bond is situated in the α-position to the phenyl ring can be prepared, for example, by reacting a halide which corresponds to formula II, but which carries a double-bond in the α-position to the phenyl ring, with cis-2,6-dimethyl-morpholine.
The starting material of formula V can be prepared by mixing a compound of the formula CHO VIII with a compound of formula XII and catalytically hydrogenating the mixture.
An organic solvent (e.g. an alcohol such as methanol) is preferably used as the solvent. The temperature is not critical, but generally lies between 0°C and 50°C.
The catalytic hydrogenation can be carried out using a customary hydrogenation catalyst such as, for example, platinum, Raney nickel or palladium, with 5% palladium/charcoal being especially preferred.
The compounds provided by the present invention 10 contain an asymmetric carbon atom in the propylene chain linking the morpholine ring with the p-substituted phenyl ring and can therefore occur in the form of racemates and in the form of optical antipodes. The latter can be obtained from the racemates by resolution with optically active acids, for example with (+)-camphoric acid, (+)-camphor-10-sulphonic acid, Ο,Ο'-dibenzoyltartaric acid (L- or D-form), I(+)-tartaric acid, D(-)-tartaric acid, L(+)-glutamic acid 4-sulphonate, L(-)-malic acid or D(+)-malic acid. This resolution can be carried out according to conventional resolution methods. 2642 The compounds provided by the present invention possess fungicidal activity and can accordingly be used for combating fungi in agriculture and in horticulture. The compounds are especially suitable for combating powdery mildew fungi such as, for example, Erysiphe graminis (powdery mildew of cereals), Erysiphe cichoracearum (powdery mildew of cucumbers), Podosphaera leucotricha (powdery mildew of apples), Sphaerotheca pannosa (powdery mildew of roses), Oidium tuckeri (powdery mildew of vines), rust diseases such as, for example, those of the genera Puccinia, Uromyces and Hemileia, especially Puccinia graminis (stem rust of cereals), Puccinia coronata (crown rust of oats), Puccinia sorghi (corn rust), Puccinia striiformia (stripe rust of wheat), Puccinia recondita (leaf rust of cereals), Uromyces fabae and append!culatus (bean rusts), as well as against Hemileia vastatrix (coffee rust) and Phragmidium mucronatum (leaf rust of roses).
Furthermore, the present compounds are also active against the following phytopathogenic fungi: Ustilago avenae (loose smut of oats), Venturia inaequalis (apple scab), Cercospora arachidicola (peanut early leaf spot), Ophiobolus graminis (cereal take-all), Septoria nodorum (cereal leaf spot) or Marssonina rosae (rose blackspot). Certain of the present compounds possess pronounced subsidiary activities against various species of the following genera: Rhizoctonia, Tilletia, Helminthospo52642 rium as well as to some extent also against Peronospora, Coniophora, Lenzites, Corticium, Thielavlopsis and Fusarium.
Furthermore, compounds of formula I are also active against phytopathogenic bacteria such as, for example, Xanthomonas vesicatoria, Xanthomonas oryzae and other Xanthomonades as well as against various species of Erwinia such as Erwinia tracheiphila.
Primarily,’ however, on the basis of their fungistatic and fungicidal activity the compounds provided by the present invention are suitable for combating infections which are caused by fungi and yeasts; for example, those of the genera Candida, Trichophytes or Histoplasma. They are especially active against Candida species such as Candida albicans and are particularly suitable for the local therapy of superficial infections of the skin and of the mucous membranes, particularly of the genital tract (e.g. vaginitis, especially that caused by Candida). The chosen route of administration is local, the compounds then being used as 'therapeutically active preparations in the form of salves, cones, suppositories, ovules or other suitable dosage forms.
The pharmaceutical preparations can be produced in a manner known per se by mixing the compounds provided by this invention with customary organic or inorganic inert carrier materials and/or adjuvant substances such as water, gelatine, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkyleneglycols, petroleum jelly, preserving, stabilising, wetting or emulsifying agents, salts for the variation of the osmotic pressure or buffers.
The dosage administered will vary according to individual requirements, but a daily administration of 1-2 tablets which contain 50-100 mg of active ingredient (i.e. a compound of this invention) for a few days can be a preferred dosage. The salves conveniently contain 0.3-5%, preferably 0.5-2% and especially preferably 0.5-1%, of active ingredient. The following experimental report and the results given in the Table hereinafter also provide an expert with appropriate information appertaining to the dosage of the active ingredient.
The ccnpound of formula I provided hy the inventicn was tested for its activity against Candida albicans in the vaginal candidiasis test on rats described in Path. Microbiol. 23; 62-68 (1960), the following result being obtained: Compound Concentration in % at which an ED 50 activity occurred Cis-4-[3-(p-tert.amyl-phenyl)-2-methylpropyl] -2,6-dimethyl-morphollne 0.01 i6 The following Examples illustrate the process provided by the present invention: Example 1 230 g of 3-(p-tert.amyl-phenyl)-2-methyl-propionalde5 hyde and 137 g of cis-2,6-dimethyl-morpholine are heated at reflux in 1000 ml of toluene using a water separator and while gassing with nitrogen for 16 hours until the cleavage of water haa been completed. 17.5 g of 5% palladium-on-oharcoal are added at room temperature while gassing with nitrogen and subsequently the mixture is hydrogenated until the hydrogen uptake is complete. The catalyst is filtered off and the toluene is evaporated in vacuo. By distillation of the residue there is obtained pure cis-4-[3-(p-tert.amyl-phenyl)-2-methyl-propyl]-2,6-dimethyl-morpholine of boiling point 120°C/0.1 Torr. )7 Example 2 To 1223 g of cis-4-(2-methvl-3-phenyl-propyl)-2,6-dimethyl-morpholine in 4 litres of methylene chloride are added dropwise at -5°C within 45 minutes 4941 g of concentrated sulphuric acid and subsequently within 60 minutes 520 g of 2-methyl-2-butanol. The solution is treated with water while cooling with ice and the aqueous phase is extracted several times with methylene chloride. The organic extracts are washed with sodium hydroxide and subsequently with water, dried, evaporated and the oily cis-4-[3-(p-tert.amyl-phenyl)-2-methyl-propyl]-2,6-dimethyl-morpholine is distilled in vacuoj boiling point 120°C/0.1 Torr.
The cis-4-(2-methyl-3-phenyl-propyl)-2,6-dimethyl-morpholine used as the starting material can be prepared as follows: 1000 g of a-methyl-cinnamaldehyde, 10 litres of methanol and 789 g of cls-2,6-dimethyl-morphollne are treated under a nitrogen atmosphere with 50 g of. 5% palladium-on-charcoal. Subsequently, the mixture is hydrogenated while cooling with water at 30°C until the hydrogen uptake is complete. The catalyst is filtered off, the methanol is distilled off under reduced pressure and then the crude cis-4-(2-methyl-3-phenyl-propyl)-2,6-dimethyl-morpholine is distilled. The product, which is 99% pure, boils at 109°C/0.055 Torr.
' Example 3 .0 g of p-( tert.amy])-—·-—o'-methyl-cinnamaldehyde and 9.6 g of cis-2,6-dimethyl-morpholine are treated in 60 ml of methanol while gassing with argon with 1 g of 5% palladium-on-charcoal and subsequently the mixture is hydrogenated until the hydrogen uptake is complete. The solution, freed from catalyst, is evaporated under reduced pressure, chromatographed on aluminium oxide (activity grade II) with chloroform and subsequently distilled in a high vacuum.
There is obtained cls-4-/~3- (p- (tert, amv 1-phenvl) -2-methyl-propyl]-2,6-dimethyl-morpholine of boiling point 120°C/0.1 Torr.
Example 4 44.3 g of 3-(p-tert.amyl-phenyl)-2-methyl-propyl bromide are slowly added dropwise at 125°C to a solution of 22.7 g of cis-2,6-dimethyl-morpholine in 70 ml of ethyleneglycol and the mixture is stirred at this temperature for 48 hours. After cooling, the mixture is treated with 2N hydrochloric acid and the neutral constituents are extracted with ether. Subsequently, the hydrochloric acid solution is made alkaline with 5N sodium hydroxide solution and extracted with ether. The ether extract is washed with water, dried over sodium sulphate and evaporated. By distillation there is obtained pure cis-4-[3-(p-tert.aroyl-phenyl)-2-methyl-propyl]-2,6-dlmethyl-morpholine of boiling point 120°C/0.1 Torr.
Example 5 266 g of cis-4-[3-(p-tert.amyl-phenyl)-2-methyl-propyl]-2,6-dimethyl-morpholine are dissolved in·500 ml of absolute ethanol and at room temperature there are added dropwise 500 ml of a 28% hydrogen chloride/ethanol solution. The homogeneous solution is concentrated to dryness on a rotary evaporator and the residue is recrystallised from 100 ml of water. The crystallisate is washed with water and dried at 55°C in a vacuum drying oven. There is obtained cis-4-[3-(p-tert.amyl-phenyl)-2-methyl-propyl]-2,6-dimethyl-morpholine hydrochloride in the form of white, slightly hygroscopic crystals of melting point 2O4°-2O6°C.
Example 6 A solution of 60 ml of 30% hydrogen peroxide in 60 ml of acetic acid anhydride is added dropwise to 21 g of cis-4-[3-(p-tert.amyl-phenyl)-2-methyl-propyl]-2,6-dimethyl-morpholine while cooling with acetone/dry-ice in such a manner that the temperature does not exceed 50°C and the mixture is subsequently left to react at room temperature for 16 hours. The course of the oxidation is checked by thin-layer chromatography (hexane/ether 1:1). In order to destroy the excess peroxide, the solution is cooled to -10°C and treated with 200 ml of 40% potassium hydroxide.
After stirring for 20 hours, the mixture is diluted with 500 ml of water and exhaustively extracted with chloroform. The combined chloroform extracts are washed neutral, dried and evaporated. By recrystallisation of the residue from 100 ml of pentane there is obtained pure cis-4-Γ3-(p-tert. amyl-phenyl)-2-methyl-propyl]-2,6-dimethyl-morpholine 4-oxide 5264-2 The following Examples describe the pharmaceutical preparations provided by the present invention: Example 7 Vaginal tablets containing the following ingredients 5 are produced in the usual manner: Cis-4-[3-(p-tert.amyl-phenyl)-2-methyl-propylJ-2,6-dimethyl- -morpholine 50 mg Secondary calcium phosphate dihydrate 400 mg Directly pressable starch (STA-RX 1500) 261 mg Lactose (spray-dried, 100 mg Polyvinylpyrrolidone 25 mg Citric acid 5 mg Magnesium stearate 6 mg 847 mg 58642 Example S A cream containing the following ingredients is produced: Cis-4-[3-(p-tert.amyl-phenyl)-2-methyl-propyl]-2,6-dimethyl-morpholine Polyoxyethylene stearate Stearyl alcohol Viscous paraffin oil Vaseline (white) Carboxyvinylpolymer CARBOPOL 934 Ph Sodium hydroxide (pure) Water (deionised) 0.7 g 3.3 g 8.0 g .0 g 10.0 g 0.3 g 0.07g ad 100.0 ·
Claims (13)
1. A compound of the formula wherein R represents ethyl 5 or a salt or N-oxide thereof.
2. Cis-4-[3-(p-tert. amyl-phenyl)-2-methyl-propyl]-2,6dimethyl-morpholine or a salt or the N-oxide thereof.
3. A compound according to claim 1 or 2 as an antimycotic. 10
4. A process for the manufacture of a compound of the formula wherein R represents ethyl or a salt or N-oxide thereof, which process comprises (a) reacting a halide of the general formula CHg—Y II wherein R has the significance given above and Y represents chlorine, bromine or iodine, with a compound of the formula S2642 III, or (b) reducing a compound of the formula 5. Wherein R has the significance given above and one of the two broken lines represents an additional bond, 32642 ?6 or (c) reacting a compound of the formula with a compound which yields a carbonium ion of the 5 formula h 3 c· >c-ch 3 VI wherein R has the significance given above r or 10 (d) reacting a compound of the formula /7 wherein R has the significance given above, under hydrogenating conditions with a compound of formula III 5 or, for the manufacture of a N.-oxide, treating a compound of formula I with hydrogen peroxide or a peracid, or, for the manufacture of a salt, converting a base of formula I into a salt with an acid in a manner known per se.
5. A process according to claim 4, wherein a compound 10 of formula IV in which the double-bond is situated in the α-position to the morpholine ring is reduced catalytically or by using formic acid.
6. A process according to claim 4, wherein a compound of formula IV in which the double-bond is situated in the 15 α-position to the phenyl ring is reduced catalytically.
7. A process according to claim 4, 5 or 6, wherein a racemate obtained is resolved into the optical antipodes.
8. A process for the production of a pharmaceutical preparation, which process comprises mixing at least one of the compounds set forth in claim 1 or 2 with a ηαη-toxic, inert, solid and/or liquid carrier customary in 5 such preparations and suitable for therapeutic administration and bringing the mixture into a suitable dosage form.
9. . A pharmaceutical preparation containing at least one of the compounds set forth in claim·.. 1 or 2 and a non-toxic, inert carrier material.
10. 10. A pharmaceutical preparation according to claim 9 for combating infections caused by pathogenic fungi or yeasts.
11. A compound according to Claim 1 or 2 for use as an antinycotic.
12. . A compound according to · Claim 1 or 2
13. 15 for use in combating Candida albicans. Dated this the 15th day of-August, 1980
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CH756079A CH644113A5 (en) | 1979-08-17 | 1979-08-17 | N-substituted 2,6-dimethylmorpholine compounds |
CH418780 | 1980-05-29 |
Publications (2)
Publication Number | Publication Date |
---|---|
IE801729L IE801729L (en) | 1981-02-17 |
IE52642B1 true IE52642B1 (en) | 1988-01-06 |
Family
ID=25694874
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
IE1729/80A IE52642B1 (en) | 1979-08-17 | 1980-08-15 | Morpholine derivatives,process for preparing them and use of said morpholine derivatives in pharmaceutical preparations |
Country Status (31)
Country | Link |
---|---|
EP (1) | EP0024334B1 (en) |
AR (1) | AR225318A1 (en) |
AT (1) | ATE4206T1 (en) |
AU (1) | AU530398B2 (en) |
BG (1) | BG60798B2 (en) |
CA (1) | CA1128943A (en) |
CS (1) | CS402091A3 (en) |
CU (1) | CU35298A (en) |
DE (3) | DE19375077I2 (en) |
DK (1) | DK150509C (en) |
ES (2) | ES494314A0 (en) |
FI (1) | FI69455C (en) |
FR (1) | FR2463767B1 (en) |
GB (1) | GB2056454B (en) |
HR (1) | HRP930340B1 (en) |
HU (1) | HU182189B (en) |
IE (1) | IE52642B1 (en) |
IL (1) | IL60813A (en) |
IT (1) | IT1220970B (en) |
LU (1) | LU82713A1 (en) |
MC (1) | MC1345A1 (en) |
MY (1) | MY8500272A (en) |
NL (1) | NL8004537A (en) |
NO (1) | NO153176C (en) |
NZ (1) | NZ194628A (en) |
PH (1) | PH15480A (en) |
PT (1) | PT71708B (en) |
SE (1) | SE447730B (en) |
SI (1) | SI8011754A8 (en) |
YU (1) | YU43475B (en) |
ZW (1) | ZW15780A1 (en) |
Families Citing this family (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE3421810A1 (en) * | 1984-06-12 | 1985-12-12 | Basf Ag, 6700 Ludwigshafen | PHENYLALKYLAMINE - BIOREGULATORS |
CA2008775C (en) * | 1989-02-24 | 1998-12-22 | Alberto Ferro | Nail lacquer |
EP0446585A1 (en) * | 1990-03-12 | 1991-09-18 | F. Hoffmann-La Roche Ag | Control of fungal infections in aquaculture |
EP1749826A1 (en) * | 2005-07-28 | 2007-02-07 | Galderma S.A. | Process of producing bepromoline |
EP1749825A1 (en) * | 2005-07-28 | 2007-02-07 | Galderma S.A. | Process of producing amorolfine |
EP1842848A1 (en) * | 2006-04-03 | 2007-10-10 | Galderma S.A. | Process for producing 3-[4-(1,1-dimethyl-propyl)-phenyl]2-methyl-propionaldehyde and cis-4{3-[4-(1,1-dimethyl-propyl)-phenyl]2-methyl-propyl}-2,6-dimethyl-morpholine (amorolfine) |
EP1935889A1 (en) * | 2006-12-21 | 2008-06-25 | Galderma S.A. | Process of producing amorolfine |
ITFI20090032A1 (en) | 2009-02-20 | 2010-08-21 | Synteco S P A Prodotti Di Sintesi Per L Ind | INDUSTRIAL PRODUCTION PROCESS OF CHLORIDATED AMOROLFIN |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AT354187B (en) * | 1976-11-22 | 1979-12-27 | Hoffmann La Roche | FUNGICIDE AGENT |
DE2656747C2 (en) * | 1976-12-15 | 1984-07-05 | Basf Ag, 6700 Ludwigshafen | Morpholine derivatives |
AU4690979A (en) * | 1978-05-16 | 1979-11-29 | F. Hoffmann-La Roche Ag | Heterocyclic compounds |
DE2830127A1 (en) * | 1978-07-08 | 1980-01-17 | Basf Ag | N-ARYL PROPYL SUBSTITUTED CYCLIC AMINES |
DE2830999A1 (en) * | 1978-07-14 | 1980-01-31 | Basf Ag | METHOD FOR PRODUCING STEREOISOMERS N-ARALKYL-2,6-DIMETHYLMORPHOLINES |
DE2965247D1 (en) * | 1978-08-08 | 1983-05-26 | Hoffmann La Roche | Synthesis of phenyl-propyl morpholine and piperidine derivatives |
DE2907614A1 (en) * | 1979-02-27 | 1980-09-04 | Basf Ag | OPTICAL ACTIVE SHAPES OF THE 1- CORNER CLAMP ON 3- (P-TERT.-BUTHYLPHENYL) -2- METHYLPROPYL CORNER CLAMP ON -CIS-3,5- DIMETHYLMORPHOLINS |
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1980
- 1980-07-07 ZW ZW157/80A patent/ZW15780A1/en unknown
- 1980-07-07 IT IT23283/80A patent/IT1220970B/en active
- 1980-07-08 YU YU1754/80A patent/YU43475B/en unknown
- 1980-07-08 SI SI8011754A patent/SI8011754A8/en unknown
- 1980-07-11 CA CA356,038A patent/CA1128943A/en not_active Expired
- 1980-07-25 AR AR281915A patent/AR225318A1/en active
- 1980-07-30 CU CU8035298A patent/CU35298A/en unknown
- 1980-08-01 FI FI802418A patent/FI69455C/en not_active IP Right Cessation
- 1980-08-05 PH PH24406A patent/PH15480A/en unknown
- 1980-08-07 AT AT80104656T patent/ATE4206T1/en active
- 1980-08-07 DE DE1993175077 patent/DE19375077I2/en active Active
- 1980-08-07 EP EP80104656A patent/EP0024334B1/en not_active Expired
- 1980-08-07 DE DE8080104656T patent/DE3064267D1/en not_active Expired
- 1980-08-07 DE DE19803029966 patent/DE3029966A1/en not_active Withdrawn
- 1980-08-08 NL NL8004537A patent/NL8004537A/en not_active Application Discontinuation
- 1980-08-11 AU AU61321/80A patent/AU530398B2/en not_active Expired
- 1980-08-11 NZ NZ194628A patent/NZ194628A/en unknown
- 1980-08-11 IL IL60813A patent/IL60813A/en unknown
- 1980-08-14 MC MC801466A patent/MC1345A1/en unknown
- 1980-08-14 PT PT71708A patent/PT71708B/en unknown
- 1980-08-14 FR FR8017977A patent/FR2463767B1/en not_active Expired
- 1980-08-14 LU LU82713A patent/LU82713A1/en unknown
- 1980-08-15 GB GB8026709A patent/GB2056454B/en not_active Expired
- 1980-08-15 NO NO802453A patent/NO153176C/en unknown
- 1980-08-15 SE SE8005784A patent/SE447730B/en not_active IP Right Cessation
- 1980-08-15 IE IE1729/80A patent/IE52642B1/en not_active IP Right Cessation
- 1980-08-15 DK DK355180A patent/DK150509C/en not_active IP Right Cessation
- 1980-08-15 HU HU802034A patent/HU182189B/en unknown
- 1980-08-16 ES ES494314A patent/ES494314A0/en active Granted
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1981
- 1981-03-02 ES ES499957A patent/ES499957A0/en active Granted
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1985
- 1985-12-30 MY MY272/85A patent/MY8500272A/en unknown
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1991
- 1991-12-23 CS CS914020A patent/CS402091A3/en unknown
-
1993
- 1993-03-12 HR HRP-1754/80A patent/HRP930340B1/en not_active IP Right Cessation
-
1994
- 1994-02-25 BG BG98580A patent/BG60798B2/en unknown
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Legal Events
Date | Code | Title | Description |
---|---|---|---|
MM9A | Patent lapsed through non-payment of renewal fee |