GB2056454A - 2,6-dimethyl morpholine derivatives - Google Patents
2,6-dimethyl morpholine derivatives Download PDFInfo
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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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Description
1 GB 2 056 454 A 1
SPECIFICATION Heterocyclic compounds
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 5 invention is also concerned with the use of the present heterocyclic compounds.
The present invention provides heterocyclic compounds of the general formula R CH3 H3C>< 1 CH3 wherein R represents ethyl or phenyl, as well as salts and Noxides of these compounds.
C H3 H3 1 The process provided by the present invention for the manufacture of the compounds of formula I and of salts and N-oxides thereof comprises ' (a) reacting a halide of the general formula R CH3 H3C 1 CH3 CH2-Y wherein R has the significance given earlier and Y represents chlorine, bromine or iodine, with a'compound of the formula or HN (b) reducing a compound of the general formula C H,3 H3 R CH3 H3C CH3 N 11 Ill CH3 CH3 IV wherein R has the significance given earlier and one of the two broken lines represents an additional bond, or (c) reacting a compound of the formula 2 GB 2 056 454 A 2 CH3 / - - 1 \- CH3 CH3 with a compound which yields a carbonium ion of the general formula R (D H,C wherein R has the significance given earlier, or / C-CH3 (d) reacting a compound of the general formula R CH3 H3C CH3 - 1 CHO wherein R has the significance given earlier, v VII v[ 1 under hydrogenating conditions with a compound of formula Ill hereinbefore, or, for the manufacture of a N-oxide, treating a compound of formula 1 with hydrogen peroxide or a peracid, or, for the manufacture of a salt, converting a base of formula 1 into a salt with an acid in a manner known per se.
In accordance with embodiment (a) of the foregoing process. a halide of formula 11 is reacted with an amine of formula Ill, 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 15 of formula 111). The reaction is preferably carried out in a temperature range between 501C and 1 501C. Ethyleneglycol is especially preferred as the inert solvent and a temperature of 1001-11 O'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 a-posi tion to the morpholine ring is used as the starting material, then the reduction can be carried out catalytically or using formic acid.
Especially suitable catalysts are noble metal catalysts such as, for example, platinum, palladium (optionally precipitated on charcoal) and Raney nickel. Pal ladiu rn-on-charcoal is the preferred catalyst. Suitable solvents for the catalytic reduction are hydrocarbons such as benzene, toluene or xzy[ene and alcohols such as methanol or ethanol. Toluene is the preferred solvent. The catalytic reduction is advantageously carried out at a temperature between OIC and 501C, 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 O'C to 1 OOOC, preferably at 500-701C, if necessary whilst cooling.
When a compound of formula [V in which the doublebond is situated in the a-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 (c) 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 40, acid is especially preferred for the purpose of the present invention.
3 GB 2 056 454 A 3 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 5 generally lies between 01C and 5WC, preferably between 1 80C and 200C.
Preferably, and especially when sulphuric acid 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 ions of general formula VI are the corresponding tertiary alcohols such as 2-methyl-2-butanol or tertiary chlorides such as 2-chloro-2-methyl-butane.
The reaction of a substituted cinnamaidehyde of formula Vil with the cis2,6-dimethyi-morpholine of formula Ill 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 a compound of formula 1, a compound of formula 1 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 0c1C and 500C, especially at 400C. Examples of peracids which can be used are peracetic acid, perbenzoic acid, metachloroperbenzoic acid and peradipic acid. 20 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.
Compounds of formula 1 form salts with organic and inorganic acids. Preferred salts of the compounds of formula 1 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 11 and VI are known compounds. The starting materials of formulae Ill and IV are known as the cis/trans mixture. The cis starting materials of formulae Ill and IV can be prepared in analogy to the process for the manufacture of the cis/trans mixture.
The starting materials of formula IV in which the double-bond is situated in the a-position to the morpholine ring can be prepared, for example, by reacting a correspondingly substituted phenyl-2- 35 methyl-proplonaldehyde with cis-2,6-dimethyi-morpholine. The hydrogenation of a thus-obtained compound of formula IV is conveniently carried out in situ.
The starting materials of formula IV in which the double-bond is situated in the a-position to the phenyl ring can be prepared, for example, by reacting a halide which corresponds to formula 11, but which carries a double-bond in the a-position to the phenyl ring, with cis-2,6-di methyl-morpho line. 40 The starting materials of formula V can be prepared by mixing a compound of the formula I CH3 CHO Vill with a compound of formula Ill hereinbefore 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 01C to 501C.
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 contain an asymmetric carbon atom in the propylene chain linking the morpholine ring with the p-substituted phenyl ring and can therefore occur 50 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, (+)-camphor1 0-sulphonic acid, 0,01dibenzoyitartaric acid (L- of D- form), L(+Martaric 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.
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 4 GB 2 056 454 A _4 1.
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 stfliformia (stripea rust of wheat), Puccinia recondita (leaf rust of cereals), Uromyces 5 fabae and appendiculatus (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), Ophlobolus 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, Helminthosporium as well as to some extent also against Peronospora, Conlophora, Lenzites, Corticlum, Theilaviopsis and Fusarium.
Furthermore, compounds of formula 1 are also active against phytopathogenic bacteria such as, for example, Xanthomonas vesicatoria, Xanthomonas oryzae and other Xanthomonades as well as against 15 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 com.pounds then being used as therapeutically active preparations in the form of salves, cones, suppositories, ovules or other suitable dosage forms.
The pharmaceutical p ' reparations can be produced in a manner known per se by mixing the 25' 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 30 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 03-5%, 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 compounds provided by the invention were tested for their activity against Candida albicans in the vaginai candidiasis test on rats described in Path. Microbiol. 23: 62-68 (1960), the following results being obtained:
Compound Concentration in % at which an "ED 50" activity occurred Cis-4-[3-(p-tert.amyl-phenyl) 2-methylphenyll-2,6-dimethyl- 0.01 morpholine Cis-4-[3-[p- (a,a-dimethyl benzyl)-phenyl]-2-methyl- 0.01 propyll-2,6-dimethyl morpholine The following Examples illustrate the process provided by the present invention:
EXAMPLE 1
230 g of 3-(p-tert.amyi-phenyi)-2-methyi-propionaidehyde and 137 g of cis2,6-d i methyl- morpholine are heated at reflux in 1000 m[ of toluene using a water separator and while gassing with nitrogen for 16 hours until the cleavage of water has been completed. 17. 5 g of 5% pailadiumon charcoal are added at room temperature while gassing with nitrogen and subsequently the mixture is 45 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.amyi-phenyi)-2 methyi-propyll-2,6-dimethyi-morpholine of boiling point 1201C/0.1 Torr.
GB 2 056 454 A 5 1 ' 1 EXAMPLE 2
In a manner analogous to that described in Example 1, by reaction of 3-[p(a,ce-dimethyi-benzyi)phenyl]-2-methyi-propionaidehyde with cis-2,6dimethyi-morpholine and subsequent hydrogenation there is obtained cis-4[3-(p-(cv, a-d imethyibenzyl)-phenyll-2-methyf-propyll-2,6-dimethy(morpho fine of boiling point 162 'C/0.04 Torr.
EXAMPLE 3
To 1223 g of cis-4-(2-methyi-3-phenyi-propyi)-2,6-dimethyi-morpholine in 4 litres of methylene chloride are added dropwise at -51C 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 10 extracts are washed with sodium hydroxide and subsequently with water, dried, evaporated and the oily cis4-[3-(p-tert.amyi-phenyi)-2-methylpropyll-2,6-dimethyi-morphofine is distilled in vacuo; boiling point 120'C/0.1 Torr.
The cis-4(2-methyl-3-phenyl-propyi)-2,6-dimethyl-morpholin-e used as the starting material can be prepared as follows:
1000 g of a-methyicinnamaidehyde, 10 litres of methanol and 789 g of cis2,6-d 1 methylmorpholine are treated under a nitrogen atmosphere with 50 g of 5% palladium-on-charcoal. Subsequently, the mixture is hydrogenated while cooling with water at 3WC 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-methyi-3-phenyl-propyi)-2,6-dimethyt-morpholine is distilled. The product, which is 99% 20 pure, boils at 1090C/0.55 Torr.
EXAMPLE 4
20.0 g of p-(a,a-dimethyi-benzyi)-a-methyl-cinnamaidehyde and 9.6 g of cis-2,6-di m ethylmorpholine are treated in 60 mi 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 11) with chloroform and subsequently distilled in a high vacuum. There is obtained cis-4[3-[p-(at,a-dimethyf-benzyi)-phenyi-2-methyi-p ropyll-2,6-d imethylmorpho line of boiling point 162 0 C/0.04 Torr.
EXAMPLE 5
In a manner analogous to that described in Example 4, from p-(tert.amyiphenyi)-a'-methyicinnamaidehyde and cis-2,6-dimethyl-morpho(ine there is obtained cis-4-[3-(p-tert.amyi-phenyi)-2methyi-propyll-2,6-dimethyimorpholine.
EXAMPLE 6
44.3 g of 3-(p-tert.amyf-phenyf)-2-methyi-propyI bromide are slowly added dropwise at 125 'C 35 to a solution of 22.7 9 of cis-2,6-dimethyl-morpholine in 70 mi 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-4-13- '40 (p-tert.amyi-phenyi)-2-methyi-propyll-2,6-dimethyi-morpholine of boiling point 1201C/0.1 Torr.
EXAMPLE 7
51.8 9 of 3-[p-(a,a-dimethyi-benzyi)-phenyll-2-methyi-propyI bromide are slowly added dropwise at 1251C to a solution of 22.7 9 of 2,6-cis-dimethyi-morpholine in 80 mi of ethyleneglycol and the mixture is stirred at this temperature for 48 hours. The working-up is carried out in a manner analogous 45 to that described in Example 6. By distillation there is obtained pure cis-4-[3-[p-(a,cv-dimethyi-benzyi)phenyll-2-methylpropyll-2,6-dimethyimorpholine of boiling point 1621C/0.04 Torr.
EXAMPLE 8
266 g of cis-4-[3-(p-tert.amyl-phenyl)-2-methyl-propyll-2,6-dimethylmorpholine are dissolved in 500 ml of absolute ethanol and at room temperature there are added dropwise 500 ml of a 28% hydrogen 50 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 551C in a vacuum drying oven. There is obtained cis-4-(3-(p-tert.amylphenyl)-2-methyl-propyll-2,6- dim ethyl-morpho line hydrochloride in the form of white, slightly hygroscopic crystals of melting point 204'-2060C.
55- EXAMPLE 9
A solution of 60 mI of 30% hydrogen peroxide in 60 mi of acetic acid anhydride is added dropwise to 21 9 of cis-4-[3-(p-tert.amyi-phenyl)-2methyl-propyll-2,6-dimethyi-morpholine while cooling with 6 GB 2 056 454 A 6 acetone/dry-ice in such a manner that the temperature does not exceed 501C 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 -1 OOC and treated with 200 mi of 40% potassium hydroxide. After stirring for 20 hours, the 5- mixture is diluted with 500 m] of water and exhaustively extracted with chloroform. The combined chloroform extracts are washed neutral, dried and evaporated. By recrystallisation of the residue from 100 mi of pentane there is obtained pure cis-4-[3-(p-tert.a myi-phe nyi)-2-methyi- propyll-2,6-di methylmorphorine-4-oxide.
The following Examples -de-scrib^e- the pharma c-euica' fprepa rations provided by the present 10 invention:
EXAMPLE 10
Vaginal tablets containing the following ingredients are produced in the usual manner:
Cis-4-[3-(p-tert.amyl-phenyf)-2- methyi-propyll-2,6-dimethyimorpholine 50 mg Secondary calcium phosphate dihydrate 400 mg 15 Directly pressable starch (STA-RX 1500) 261 mg Lactose (spray-dried) 100 mg Polyvinylpyrrolidone 25 mg Citric acid 5 mg Magnesium stearate 6 mg 20 847 mg EXAMPLE 11
A salve containing the following ingredients is produced:
Cis-4-[3-[p-(a,a-dimethyl-benzyi- phenyl]-2-methyi-propyll-2,6dimethyi-morpholine 0.7 mg Cetyl alcohol 3.6 g Lanolin 9.0 g Vaseline (white) 79.3 g Paraffin oil 7.4 g 3G' 100.0 g 7 GB 2 056 454 A 7 1. 1 - 1 EXAMPLE 12
A cream containing the following ingredients is produced:
Cis-4-[3-(p-tert.amyl-phenyl) 2-methyl-p ropyll -2,6-di methyl-morpho line 0.7 g Polyoxyethylene stearate 3.3 g 5 Stearyl alcohol 8.0 g Viscous paraffin oil 10.0 g Vaseline (white) 10.0 g Carboxyvinylpolymer CARBOPOL 934 Ph 0.3 g Sodium hydroxide (pure) 0.07 g 10 Water (deionised) ad 100.0 g
Claims (12)
1. Compounds of the general formula CH3 R CH3 H3C CH3 CH3 wherein R represents ethyl or phenyl, as well as salts and N-oxides of these compounds. 15
2. Cis-4-[3-(p-tert.amyi-phenyi)-2-methyi-propyll-2,6-dimethyi-morpholine as well as its salts and N-oxide.
3. Cis-4-[3-[p-(a,a-dimethyi-benzyi)-2-methyi-propyll-2,6-dimethyimorpholine as well as its salts and N-oxide.
4. Compounds according to any one of claims 1 to 3 as antimycotics.
5. A process for the manufacture of compounds of the general formula R CH3 H3C 1 CH3 Ill,' \ wherein R represents ethyl or phenyl, and of salts and N-oxides, thereof, which process comprises (a) reacting a halide of the general formula R CH3 H3C 1 CH3 CH2-Y CH3 CH3 1 11 wherein R has the significance given earlier in this claim and Y represents chlorine, bromine or iodine, with a compound of the formula 8 GB 2 056 454 A 8 1 1 1 HN \- CH3 ill CH3 or (b) reducing a compound of the general formula R CH3 H3C N IV CH3 CH3 CH wherein R has the significance given earlier in this claim and one of the two broken lines represents an additional bond, or (c) reacting a compound of the formula -- CH3 - 1 U N CH3 CH3 v with a compound which yields a carbonium ion of the general formula R \ (D / C-CH3 V1 H,C wherein R has the significance given earlier in this claim, z or (d) reacting a compound of the general formula R CH3 H3C I CH3 CHO V11 wherein R has the significance given earlier in this claim, under hydrogenating conditions with a compound of formula Ill hereinbefore, or, for the manufacture of a N-oxide, treating a compound of formula 1 with hydrogen peroxide or a peracid, or, for the manufacture of a salt, converting a base of formula 1 into a salt with an acid in a manner known per se.
GB 2 056 454 A 9 9
6. A process according to claim 5, wherein a compound of formula IV in which the double-bond is situated in the a-position to the morpholine ring is reduced catalytically or using formic acid.
7. A process according to claim 5, wherein a compound of formula IV in which the double-bond is situated in the a-position to the phenyl ring is reduced catalytically.
8. A process according to claim 5, claim 6 or claim 7, wherein a racernate obtained is resolved into 5 the optical antipodes.
9. A process for the production of a pharmaceutical preparation, which process comprises mixing at least one of the compounds set forth in claims 1 to 3 is mixed with non-toxic, inert, solid and/or liquid carriers customary in such preparations and suitable for therapeutic administration and bringing the mixture into a suitable dosage form.
10. A pharmaceutical preparation containing at least one of the compounds set forth in claims 1 to 3 and non-toxic, inert carrier material.
11. A pharmaceutical preparation according to claim 10 for combating infections caused by pathogenic fungi or yeasts.
12. Use of the compounds set forth in claims 1 to 3 as antimycotics, especially for combating 15 Candida albicans.
Printed for Her Majesty's Stationery Office by the Courier Press. Leamington Spa, 1981. Published by the Patent Office. 25 Southampton Buildings, London, WC2A lAY, from which copies may be obtained.
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 |
|---|---|
| GB2056454A true GB2056454A (en) | 1981-03-18 |
| GB2056454B GB2056454B (en) | 1983-11-09 |
Family
ID=25694874
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB8026709A Expired GB2056454B (en) | 1979-08-17 | 1980-08-15 | 2,6 - dimethyl morpholine derivatives |
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) | DE3029966A1 (en) |
| DK (1) | DK150509C (en) |
| ES (2) | ES8200355A1 (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) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4705553A (en) * | 1984-06-12 | 1987-11-10 | Basf Aktiengesellschaft | Method of reducing plant growth height using phenylalkylmorpholines |
| US5206243A (en) * | 1990-03-12 | 1993-04-27 | Hoffmann-La Roche Inc. | Control of fungal infections in aquaculture |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2008775C (en) * | 1989-02-24 | 1998-12-22 | Alberto Ferro | Nail lacquer |
| EP1749825A1 (en) * | 2005-07-28 | 2007-02-07 | Galderma S.A. | Process of producing amorolfine |
| EP1749826A1 (en) | 2005-07-28 | 2007-02-07 | Galderma S.A. | Process of producing bepromoline |
| 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 |
| ZA792242B (en) * | 1978-05-16 | 1980-05-28 | Hoffmann La Roche | 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 IT IT23283/80A patent/IT1220970B/en active
- 1980-07-07 ZW ZW157/80A patent/ZW15780A1/en unknown
- 1980-07-08 SI SI8011754A patent/SI8011754A8/en unknown
- 1980-07-08 YU YU1754/80A patent/YU43475B/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 DE DE19803029966 patent/DE3029966A1/en not_active Withdrawn
- 1980-08-07 DE DE1993175077 patent/DE19375077I2/en active Active
- 1980-08-07 EP EP80104656A patent/EP0024334B1/en not_active Expired
- 1980-08-07 AT AT80104656T patent/ATE4206T1/en active
- 1980-08-07 DE DE8080104656T patent/DE3064267D1/en not_active Expired
- 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 FR FR8017977A patent/FR2463767B1/en not_active Expired
- 1980-08-14 LU LU82713A patent/LU82713A1/en unknown
- 1980-08-14 MC MC801466A patent/MC1345A1/en unknown
- 1980-08-14 PT PT71708A patent/PT71708B/en unknown
- 1980-08-15 DK DK355180A patent/DK150509C/en not_active IP Right Cessation
- 1980-08-15 HU HU802034A patent/HU182189B/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 NO NO802453A patent/NO153176C/en unknown
- 1980-08-15 GB GB8026709A patent/GB2056454B/en not_active Expired
- 1980-08-16 ES ES494314A patent/ES8200355A1/en not_active Expired
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1981
- 1981-03-02 ES ES499957A patent/ES8201563A1/en not_active Expired
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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
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1993
- 1993-03-12 HR HRP-1754/80A patent/HRP930340B1/en not_active IP Right Cessation
-
1994
- 1994-02-25 BG BG098580A patent/BG60798B2/en unknown
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4705553A (en) * | 1984-06-12 | 1987-11-10 | Basf Aktiengesellschaft | Method of reducing plant growth height using phenylalkylmorpholines |
| US5206243A (en) * | 1990-03-12 | 1993-04-27 | Hoffmann-La Roche Inc. | Control of fungal infections in aquaculture |
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