CA1136638A - N-hydroxylpropylamides of all-e retinic acid and 13-z-retinic acid, their preparation, and pharmaceutical formulations containing these compounds - Google Patents

N-hydroxylpropylamides of all-e retinic acid and 13-z-retinic acid, their preparation, and pharmaceutical formulations containing these compounds

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CA1136638A
CA1136638A CA000336668A CA336668A CA1136638A CA 1136638 A CA1136638 A CA 1136638A CA 000336668 A CA000336668 A CA 000336668A CA 336668 A CA336668 A CA 336668A CA 1136638 A CA1136638 A CA 1136638A
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retinic acid
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retinic
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Joachim Paust
Axel Nuerrenbach
Horst Koenig
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BASF SE
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
    • C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D317/28—Radicals substituted by nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C403/00—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone
    • C07C403/20—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone having side-chains substituted by carboxyl groups or halides, anhydrides, or (thio)esters thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/10—Oxygen atoms
    • C07D309/12—Oxygen atoms only hydrogen atoms and one oxygen atom directly attached to ring carbon atoms, e.g. tetrahydropyranyl ethers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/09—Geometrical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated

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  • General Health & Medical Sciences (AREA)
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  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
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  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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Abstract

Abstract of the disclosure: Novel N-hydroxypropyl-amides of all-E-retinic acid and 13-Z-retinlc acid of the general formulae I and II,

Description

o.Z~ 0050/033449 N-Hydroxylpropylamides of all-E-retinic acid and 13-Z-retinic acid, their preparation, and pharmaceutical formulations containin~ these compounds The present invention relates to novel N-hydroxy-propylamides of all-E-retinic acid and 13-Z-retinic acid, of the general formulae I and II

-- I HN ~ Y- I
~ X

II
N ~ y X

where X and Y are hydrogen or hydroxyl, but at least one is hydroxyl, or X and Y together with the carbon atoms linking them form a 2,2-dimethyl-1,3-dioxolane ring, the preparation of these compounds, pharmaceutical formula-tions containing the compounds and their use as drugs.
German Laid-Open Application DOS 2,102,586 dis-closes that retinic acid amides substituted at theamide nitrogen by, for example, alkoxy- or alkylamino-substituted alkyl or by hydroxy-lower alkyl, phenyl or benzyl, exhibit pharmacological effects.
It is stated that these compounds may be used for the topical and systemic therapy of carcinomas and pre-cancerous conditions and for the topical and systemic prophylaxis of carcinomas. They can also be used for the therapy of acne, psoriasis and other dermatological 113~63~
- 2 - -Z~ 0050/033449 disorders accompanied by intensified or pathologically modified keratinization, and of eczemas and disorders of the mucous membranes. Examples of individual com-pounds described in German Laid-Cpen Application DOS
2,102,586, inter alia, are retinic acid N-ethylamide and retinic acid N-(~-hydroxy)-ethylamide We have found that the compounds of the formulae I and II exhibit particularly valuable pharmacological properties.
lo The compounds according to the invention are prepared in the conventionaI manner by reacting a func-tional derivative of all-E- or 13-Z-retinic acid with an amine of the general formula III

~2N ~ y III
X

where X and Y have the meanings given for formulae I and II and the hydroxyl groups present are advantageously pro-vided with a protective group which is subsequently split off in the conventional manner by acid hydrolysis.
Suitable functional derivatives of all-E-retinic acid and 13-Z-retinic acid are in particular the acid halides, preferably the acid chlorides, as well as the esters of the said acids, for example the methyl or phenyl esters.
2- or 3-Hydroxy-propyl-l-amine is preferably employed in the form of the tetrahydropyranyl ether (IV, V), whilst 2,3-dihydroxypropyl-1-amine is advantageously ~136638
- 3 - O.Z. 0050/033449 employed in the form of the acetonide VI.

~;~ oJ~ ~2N--~ ~2N o~C
IV V Vl The reaction is preferably carried out in an inert organic solvent, such as a dialkyl ether, a satu-rated cyclic ether or an aliphatic chlorohydrocarbon, eg. diethyl ether, tetrahydrofurar or methylene chloride, or in a mixture of these solvents, at from -20C to 40C, preferably from -20C to 0C. Advantageously, the reaction is carried out in the absence of oxygen and moisture, for example under nitrogen as a blanketing gas.
It is advantageous to trap the hydrogen chloride, formed on reaction of an acid chloride, with an HCl acceptor Tertiary amines, eg. triethylamine or, preferably, pyridine, are used for this purpose.
The protective groups are removed in the conven-tional manner, for example in sulfuric acid solution, advantageously in an aqueous tetrahydrofuran/methanol mixture at a pH of from 1 to 2, and at from 30 to 50C.
The end product is worked up in the conventional manner, advantageously, for example, by column chromato-graphy over alumina or silica gel, or by recrystallization.
The biological activity of the compounds accor-ding to the invention is roughly comparable to that of the retinic acid amides disclosed in German Laid-Open _ 4 _ o.z. 0050/033449 Application DOS 2,102,586 For example, both retinic acid N-(~-hydroxy)-ethylamide and the retinoids according to the invention are still able, in solutions of a molar concentration as low as 10 8, completely to reverse the keratinization of hamster tracheal tissue~induced by vitamin A hypovitaminosis. The relevant methods are described by G.H. CLAMON et a~., Nature 250 (1974), 64-66 and M.B. SPORN et al., Nature 253 (1975), 47-50. The keratinaztion is regarded as a pre-cancerous process.
However, the practical usefulness of retinoids in the prophylaxis and therapy of cancer is by no means dependent only on the biological activity. Rather, other critical factors are the toxicity and pharmaco-kinetics in vivo of the various active compounds. For example, in using a retinoid it can be a disadvantage if the latter is stored in certain organs, during the treat-- ment, at such a high concentration that toxic side-effects manifest themselves. On the other hand, the concentration of a retinoid or of its active metabolites in certain organs affected by pre-cancerous conditions or carcinomas may be so low that the desired healing action does not occur in these organs. In these respects, the compounds I and II of the invention are clearly superior, in a way which could not be foreseen, to retinic acid N-(~-hydroxy)-ethylamide and to the retinic acid N-hydroxybutylamide isomers, eg. retinic acid N-(3,4-dihydroxy)-n-butylamide, N-(3-hydroxy)-n-butylamide and N-(4-hydroxy)-n-butylamide, ie they exhibit a sub-stantially larger therapeutic range The preferred 113663~

_ 5 _ O.Z. OoSO/033449retinic acid N-hydroxypropylamides are the dihydroxy compounds of the formulaeI (X = Y = OH) and II (X = Y =
OH) and their acetonides, By virtue of the pharmacological properties mentioned, the compounds according to the invention can be used in the topical and systemictherapy and prophylaxis of pre-cancerous conditions and carcinomas of the skin, mucous membranes and internal organs, and in the topical and sy~ic therapy of acne, psoriasis and other dermato-logical disorders accompanying pathologically modifiedkeratinization.
A preferred field of indication is the prophyl-actic and therapeutic treatment of pre-cancerous con-ditions and tumors of the bladder, the mammary gland, the skin:and the mucous membranes.
.. _..... ____ . _ .. . _ . ._ .............. _ _ . , _ The compounds according to the invention have significant tumor-inhibiting action. Growth control may be observed in cells cultivated in vitro and may be detected by the method described by R. Lotan et al in Journal of the Na-tional Cancer Institute60. 10~5-1041. The compounds also inhibit the proliferation of spontaneousl~ chemicall~J or virally transformed cells in tissue culture, thepre~erred culturebeing S 91 melanoma cells.
Accordingly, the invention also relates to pharmaceutical formulations which contain a compound of the formula I or II as the active ingredient, in addition to conventional carriers or diluents, with or without pharmaceutical excipients , and to the use of a compound of the formula I or II for the preparation of a drug The present invention also embra-ces the prepara-~ 6 _ o.z. 0050/033449 tion of therapeutic agents or formulations which are obtained in the conventional manner, in parti-cular by mixing a dose of the active compound approp-riate for the particular application with conventional carriers or diluents, with or without conventional' pharmaceutical excipi2nts , in accordance with the desired route of administration.
Fort~pical application the therapeutic agents contain the compounds, to be used according to the inven-tion, at a concentration of from 0.001 to l.oY~ prefer-ably from 0.01 to 0.1%, whilst for systemic administra-tion a single dose is preferably from 0.1 to 5 mg.
Suitable daily dosages are from 5 to 100 mgj and can-~ary in accordance with the nature and severity of the disorder, the formulation used, and the route of admini-stration The conventional galenical formulations are employed, for example, for oral a~ministration, tablets, film tablets, dragees, capsules, pills, powders, gran-- 20 ules, solutions or suspensions. For external use, suitable forms are in particular pastes, ointments,jellies, creams, lotions, powders, solutionsor emulsions and~sprays.
'The''~drugs according to the invention may be employed either internally or externally, Preferably, they are administered orally or applied topically Examples Gf conventional pharmaceutical auxili-aries for topical application are alcohols, eg. iso~ropanol, oxyethylated castor oil or ox~ethylated hydrogenated castor oil, polyac.ylic acid, glycerol monostearate, paraffin oil, vaseline, wool grease, polyethylene glycol 400, polyethylene glycol 40Q stearate and oxyethylated fatty alcohols, whilst examples for systemic administra-_ 7 _ o.z. 0050/033449 tion are sucrose, lactose, propylene glycol, ethanol,starch, talc and polyvinylpyrrolidone.
Examples of further conventional additives are preservatives, antioxidants, flavorings, stabilizers, emulsifiers, lubricants, wetting agents and the like.
It is a precondition that all materials used in the preparation of pharmaceutical fo~mulations should be non-toxic and compatible with the active compounds employed (cf. L.G. Goodman and A. ~ilman, The Pharmaco-lo logical Basis of Therapeutics).
The isomer purity of the novel compounds preparedcan be determined by analysis by high pressure liquid chromatography and is as a rule ~ 96%. The struct-ures-ascribed are based on H-NMR spectroscopy.

N-Formyl-3-hydroxy-propyl-1-amine:
60,5 parts by weight of methyl formate are added dropwise in the course of 5 minutes to 75.1 parts by weight of 3-hydroxy-propyl-1-amine, whilst stirring the mixture and cooling it in a waterbath. During the addition, the temperature rises to about 70C. The mixture is then stirred for 1 hour at 80C. On sub-sequent distillation, 75.5 parts by weight of N-formyl-3-hydroxy-propyl-l-amine, boiling point 134-137 C/0.02 mm Hg, are obtained.
2-(3-N-Formylamino-propoxy)-tetrahydro-2H-pyran :
171.7 parts by weight of 3,4-dihydro-2H-pyran are added to a solution of 103.0 parts by weight of N-formyl-3-hydroxy-propyl-1-amine in 220 parts by volume - 8 - O.Z. 0050/033449 of diethyl ether and 220 parts by volume of methylene chloride, and gaseous hydrogen chloride is passed into this solution at room temperature for 2 minutes The mix-ture is refluxed for 1 hour and then cooled to room temperature, and 450 parts by volume of 5% strength by weight aqueous sodium bicarbonate solution are added.
~ After working up the organic phase in the conventional m~nner, 135 parts by weight of 2-(3-formylamino-propoxy)-tetrahydro-2H-pyran, boiling point 122C/0.01 mm Hg, are obtained.
2-(3-Amino-propoxy)-tetrahydro-2H-pyran :
172 parts by weight of 85 per cent strength potassium hydroxide and 850 parts by volume of ethanol are added to 187.2 parts by weight of 2-(3-N-formylamino-propoxy)-tetrahydro-2H-pyran and the mixture is refluxed for 30 minutes. It is then cooled, 650 parts by vol-ume of water are added and the batch is extracted with four times 500 parts by volume of diethyl ether. me combined ether . ~~ -solutions are washed with water , dried over potassiumcarbonate and worked up in the conventional manner.
Fractional distillation gives 119 parts by weight of 2-(3-aminopropoxy)-tetrahydro-2H-pyran~ boiling point 104-106C/12 mm Hg; according to analysis by gas chromatography, the product is 92% pure.
Retinic acid N-3-(2-tetrahydro-2H-pyranyloxy)-n-propyl-~m; de:
120 parts by weight of all-E-retinic acid are suspended in 1,600 parts by volume of diethyl ether and ~13663B
_ g _ o.z. 0050/033449 34 parts by volume of pyridine are added. A solution of 32,5 parts by volume of thionyl chloride in 200 parts by volume of diethyl ether is added dropwise at -5C and the mixture is then stirred for 2 hours in an icebath.
The mixture is filtered in the absence of oxygen and moisture, the crystals (pyridinium hydrochloride) are washed with 200 parts by volume of ~iethyl ether, and the combined ice-cooled filtrate is run into a solution of 69.2 parts by weight of 2-(3-amino-propoxy)-tetra-hydro-2H-pyran and 34 parts by volume of pyridine in 300 parts by volume of diethyl et~er at a rate such that the temperature does not exceed -20C. The mixture is then stirred ~or 2 hours without cooling, after which it is allowed to settle, the supernatant solution is decanted, the residue is boiled for 10 minutes with 500 parts by volume of diisopropyl ether, and the mixture is again allowed to settle and decanted. me ether phase~diisopropyl ether phase are combined, washed twice with cold 2.5 per cent strength sodium bicarbonate solution and worked up in the conventional manner.
117.9 parts by weight of crude retinic acid N -3-(2-tetrahydro-2H-pyranyloxy)-n-propylamide are obtained.
On recrystallizing this material from 350 parts by vol-ume of diisopropyl ether at -10C, 92.2 parts by weight, of melting point 73-74C, are obtained.
all-E-Retinic acid N-(3-hydroxy)-propylamide:
82.2 parts by weight of retinic acid N-3-(2-tetrahydro-2H-pyranyloxy)-n-propylamide are dissolved in 11000 parts by volume of 80 per cent strength aqueous 113~63~3 - 10 - O.Z. 0050/033449 tetrahydrofuran and 100 parts by volume of methanol, and the solution is brought to pH 2 with 10 parts by volume of 65 per cent strength sulfuric acid and is stirred for 30 minutes at 45C 800 parts by weight of ice are added, the mixture is extracted with four times 200 parts by volume of methylene chloride, and the organic phase is washed with 500 parts by volume of cold 2.5 per cent strength sodium bicarbonate solution and worked up in the conventional manner to give 102 parts by weight of crude product; on recrystallizing this material from 3 liters of diisopropyl ether at 0C, 55 parts by weight of retinic acid N-(3-hydroxy)-propylamide, of melting point 109-110C, are obtained.

13-Z-Retinic acid N-3-(2-tetrahydro-2H-pyranyloxy)-pro-pylamide:
Using the method described in Example 1, 60 parts by weight of 13-Z-retinic acid are converted to the acid chloride, and the latter is reacted with 34.6 parts by - weight of 2-(3-aminopropoxy)-tetrahydro-2H-pyran .
60.6 parts by weight of crude product are obtained and are chromatographed over 800 parts by weight of basic alumina (activity level III, diisopropyl ether as the mobile phase). Concentrating the fractions which are pure according to analysis by gas chromatography gives 48 parts by weight of 13-Z-retinic acid N-3-(2-tetrahydro-2H-pyranyloxy)-propylamide as a yellow oil, the structure and configuration of which was confirmed by H-NMR spectroscopy. Examples of characteristic 1~366313 aspects of the spectrum are the chemical shift of the C20-methyl group (2.0 ppm) and of the C14-vinyl proton ~5.45 ppm) compared to the corresponding signals of the all-E compound (2.3 ppm and 5.65 ppm).
13-Z-Retinic acid N-(3-hydroxy)-propylamide:
Following the instructions for the all-E com-pound given in Example 1, 40 parts by weight of 13-Z-retinic acid N-3-(2-tetrahydro-2H-pyranyloxy)-propylamide are subjected to acid-catalyzed hydrolysis. The lo crude product is chromatographed over 900 parts by weight of silica gel, with diisopropyl ether/ethyl acetate as the mobile phase. 29 parts by weight of 13-Z-retinic acid N-(3-hydroxy)-propylamide are obtained as a yellow oil. The structure and configuration are confirmed by H-NMR analysis: C20-methyl protons 2.0 ppm, C14-vinyl proton 5.45 ppm.

a-(2-Tetrahydro-2H-pyranyloxy)-propionitrile:
71.1 parts by weight of acetaldehyde-cyanohydrin are dissolved in 200 parts by volume of methylene chlor-ide, 0.2 part by volume of concentrated aqueous hydrochloricacid and 168 parts by weight of dihydropyran are added (whereupon the temperature rises to 50C) and the mix-ture is then stirred for 3 hours at 25C.
1,000 parts by volume of 5% strength by weight sodium carbonate solution are added to the solution ob-tained above and the batch is extracted with three times 300 parts by volume of methylene chloride and wor~ed up in the conventional manner. Rectification of the 113~i63~
- 12 - -Z~ 0050/033449 residue at 48-49C/0.3 mm Hg gives 138 parts by weight of a-(2-tetrahydro-2H-pyranyloxy)-propionitrile; accor-ding to analysis by gas chromatography, the product is a mixture of two diastereomers in the ratio of 1.25:1.
2-(2-Tetrahydro-ZH-pyranyloxy)-propyl-l-amine:
A solution of 129 5 parts by weight of a-(2-tetrahydro-2H-pyranyloxy)-propionitrile in 250 parts by volume of diethyl ether is added dropwise in the course of 35 minutes to a gently boiling suspension of 27 parts by weight of lithium aluminum hydride in 1,200 parts by volume of diethyl ether, the mixtl-re is then re-fluxed for 2 hours and the excess reducing agent is cautiously hydrolyzed in an icebath. The ether phase is separated from the aluminum hydroxide by filtration and is worked up in the conventional manner, giving 116.4 parts by weight of crude product. Rectification of the latter at 60-64C/0.4 mm Hg gives 104.5 g of 2-(2-tetrahydro-2H-pyranyloxy)-propyl-l-amine, which is 96%
pure.
Retinic acid N-(2-tetrahydro-2H-pyranyloxy)-propylamide:
A s~lution of retinic acid chloride in ether, prepared as described in Example l from 120 parts by weight of retinic acid, is added to a solution of 66.9 parts by weight of 2-(2-tetrahydro-2H-pyranyloxy)-propyl-l-amine and 34 parts by volume of pyridine in 500 parts by volume of diethyl ether at a rate such that the temperature does not exceed -20C, and the batch is then allowed to come to 25C in the course of 2 hours.
600 parts by volume of n-hexane are added and the mixture - 13 - O.Z. 0050/033449 is washed with twice ~00 parts by volume of 5% strength by weight sodium bicarbonate solution. 109 parts by weight of crude product are isolated in the conventional manner from the organic phase, and are dissolved in 1,000 parts by volume of diisopropyl ether and filtered over 400 parts by weight of alumina (activity level III) to remove retinic acid. The filtrate is concentrated and gives 88 parts by weight of retinic acid N-2-(2-tetrahydro-2H-pyranyloxy)-propylamide as a yellow oil which is pure according to analysis by gas chromatography and H-NMR spectroscopy.
Retinic acid N-(2-hydroxy)-propylamide:
80 parts by weight of retinic acid N-2-(2-tetra-hydro-2H-pyranyloxy)-propylamide are dissolved in 900 parts by volume of 80% strength aqueous tetrahydrofuran and 100 parts by volume of methanol, and the solution is brought to pH 2 with 20 parts by volume of 65 per cent strength sulfuric acid and stirred for 1 hour at 45C.
It is then cooled to 20C, 800 parts by weight of ice are added, the mixture is extracted with three times ~50 parts by volume of methylene chloride, and the organic phase is washed with 100 parts by volume of 2.5% strength by weight sodium bicarbonate solution and worked up in the conven-tional manner. ~his gives 81 parts by weight of crude product which after recrystallization from 150 parts by volume of diisopropyl ether at 0C gives 51 parts by weight of retinic acid N-(2-hydroxy)-propylamide, of melting point 115.8C. A further 15 parts by weight of the active compound can be isolated from the mother 113~i638 - 14 - o.Z~ oOso/o33449 liquor by concentrating it and subjecting it to chromatography over 800 parts by weight of alumina (activity level III, diisopropyl ether/ethyl acetate as the mobile phase).

13-Z-Retinic acid N-2-(2-tetrahydro-2H-pyranyloxy)-propylamide:
Using the method described in Example 3, 60 parts by weight of 13-Z-retinic acid are converted into the acid chloride, and the latter is reacted with 33 5 parts by weight of 2-(2-tetrahydro-2H-pyranyloxy)-propylamine 54 5 parts by weight of crude product are obtained and are purified by chromatography over 500 parts by weight of basic alumina (activity level III, diisopropyl ether as the mobile phase) This gives 46 parts by weight of 13-Z-retinic acid N-2-(2-tetra-hydro-2H-pyranyloxy)-propylamide as a yellow oil. The structure is supported by H-NMR spectroscopic results:
C20-methyl protons 2.05 ppm, C14 vinyl proton 5 5 ppm.
13-Z-Retinic acid N-(2-hydroxy)-propylamide:
Using the method described in Example 3, 40 parts by weight of 13-Z-retinic acid N-2-(2-tetrahydro-2H-pyranyloxy)-propylamide are subjected to acid-catalyzed hydrolysis. The crude product (38 parts by weight) is purified by colllmn chromatography over 800 parts by weight of silica gel (diisopropyl ether/ethyl acetate as the mobile phase), to give 29 parts by weight of 13-Z-retinic acid N-(2-hydroxy)-propylamide as a yellow oil.
The structure and configuration are confirmed by H-NMR

113663~
- 15 - o.z. 0050/033449 spectroscopy: C20-methyl protons 2.05 ppm, C14-vinyl protons 5 5 ppm.

l-FormyLamino-2,3-dihydroxy-propane:
121 parts by weight of methyl formate are added dropwise to 91.1 parts by weight of 1-amino-2,3-di-hydroxy-propane. When the exothermic reaction subsides, the mixture is refluxed for 30 minutes and the excess methyl formate is then distilled off on a rotary evaporator.
N-(2,2-Dimethyl-1,3-dioxolan-4-yl!-methyl-formamide:
119 parts by weight of 1-formylamino-2,3-dihydroxy-propane are dissolved in 214 parts by volume of dimethylformamide and 1.8 parts by weight of p-toluenesulfonic acid and 210 parts by weight of 2,2-dimethoxypropane are added. The mixture is stirred for 30 minutes at 50C and is then left to stand over-night. Thereafter it is concentrated on a rotary evaporator at about 3 mm Hg and the residue is degassed at 80C/1.5 mm Hg and then subjected to molecular dis-tillation (boiling point 145C/0.02 mm Hg). This gives 109 parts by weight of N-2,2-dimethyl-1,3-dioxolan-
4-yl)-methyl-formamide, which according to analysis by gas chromatography is 96% pure.
2,2-Dimethyl-4-aminomethyl-1,3-dioxolane:
131.7 parts by weight of 85 per cent strength potassium hydroxide are dissolved in 900 parts by volume of methanol, 151.5 parts by weight of N~2,2-dimethyl-1,3-dioxolan-4-yl)-methyl-formamide are added and the mixture 1~3~63~

- 16 - O.Z. 0050/033449 is refluxed ~or 45 minutes The methanol is then distilled off through a Vigreux column until the tempera-ture at which material passes over reaches 80C The residue is partitioned between diethyl ether and saturated sodium chloride solution, the ether extract is concen-trated and the residue is subjected to fractional dis-tillation 105 parts by weight of 2,2-dimethyl-4-amino-methyl-1,3-dioxolane pass over at 72-73C/25 mm Hg Retinic acid N-(2,2-dimethyl-1,3-dioxolan-4-yl ? -methyl-amide:
A solution of retinic acid chloride in ether isprepared from 180 parts by weight of all-E-retinic acid, as described in Example 1. This solution is added to a solution of 67,5 parts by weight of 2,2-dimethyl-4-aminomethyl-1,3-dioxolane and 51 parts by volume of pyridine in 624 parts by volume of diethyl ether at a rate such that the temperature does not exceed -20C
The mixture is allowed to come to 25C in the course of 1 hour, 1,000 parts by volume of ice-cold 2.5% strength by weight sodium bicarbonate solution are added, and the batch is worked up in the conventional manner. The crude product (245 parts by weight) is chromatographed over 1,000 parts by weight of basic alumina (activity level III, diisopropyl ether/ethyl acetate as the mobile phase) to remove non-polar impurities and retinic acid The fractions which are pure according to analysis by gas chromatography conjointly give 187 parts by weight of retinic acid N-(2,2-dimethyl-1,3-dioxolan-4-yl)-methylamide A sample, after recrystallization from 113663~1 -- 17 - O.Z. 0050/033449 diisopropyl ether, melts at 106C
all-E-Retinic acid N-(2,3-dihydroxy)-propylamide:
50 parts by weight of retinic acid N-(2,2-dimethyl-1,3-dioxolan-4-yl)-methylamide are dissolved in 700 parts by volume of 80 per cent strength aqueous tetrahydrofuran and 100 parts by volume of methanol, and the mixture is brought to pH 1.5 with 4 parts by vol-ume of 65 per cent strength sulfuric acid and is stirred for 30 minutes at 45C. 500 parts by weight of ice are added and the mixture is wor~ed up in the conven-tional manner by partition between ether and water.
The crude product (52 parts by weight) is chromatographed over 400 parts by weight of silica gel (diisopropyl ether/
ethyl acetate as-the mobile phase) to remove small amounts of non-polar impurities and of retinic acid. The product obtained from the fractions (44 parts by weight) which are pure according to analysis by gas chromato-graphy is crystallized from ethyl acetate at -15C, to give 31.5 parts by weight of retinic acid N-(2,3-di-0 hydroxy)-propylamide, melting point 96C.

13-Z-Retinic acid N-(2,2-dimethyl-1,3-dioxolan-4-yl)-methylamide:
81 parts by weight of crude 13-Z-retinic acid N-(2,2-dimethyl-1,3-dioxolan-4-yl)-methylamide are first prepared from 60 parts by weight of 13-Z-retinic acid and 22.5 parts by weight of 2,2-dimethyl-4-aminomethyl-1,3-dioxolane, as described in Example 5. The pro-duct is purified by chromatography over 800 parts by weight - 18 - O.Z. 0050/033449 of basic alumina (activity level III, diisopropyl ether/
ethyl acetate as the mobile phase): yield 66 parts by weight of a yellow oil. H-NMR data: C20-methyl pro-tons 2.Q ppm, C14-vinyl protons 5.5 ppm.
13-Z-Retinic acid N-(2,3-dihydroxy)-propylamide:
25 parts by weight of 13-Z-retinic acid N-(2,2-dimethyl-1,3-dioxolan-4-yl)-methylamide are subjected to acid-catalyzed hydrolysis as described in Example 5;
22 parts by weight of crude product are obtained. This is purified by column chromatography over 600 parts by weight of silica gel (ethyl acette/methanol as the mobile phase). 18 parts by welght of 13-Z-retinic acid N-(2,~-dihydroxy)-propylamide are obtained as a yellow oil Characteristic H-NMR data: C20-methyl protons at 2.0 ppm, CI4-vinyl proton at 5.45 ppm.
Examples of suitable pharmaceutical formulations or drug compositlons for external application are:
E~A~ 1 Solution --all-E-retinic acid-N-(2,~-dihydroxy)- 0.25 g 20 propylamide oxyethylated hydrogenated castor oil35.0 g (Cremophor RH 40,* from BASF AG, Ludwigshafen) Polyethylene glycol 400 ~5.0 g oxyethylated castor oil (Softigen 767,* 10.0 g from Chemische ~Jerke Witten) deionized ~ater to give 100.0 g The Cremophor RH 40 and Softigen 767 are mixed and the mixture is heated to 70C. The active com-pound is dissolved therein whilst siirring and the poly-ethylene glycol 400 is added. The solution is then * Trademark ','` 113~63~3 . .
- 19 - .Z. 0050~033449 cooled to 40C and water at 40C is added slowly, whilst stirring. The finished solution is filtered and packaged in, for example, 100 ml flasks.

Cream 13-Z-retinic acid N-~2,3-dihydroxy)-propyl- 0.1 g amide butylhydroxytoluene 0.1 g glycerol monostearate 11.0 g polyethylene glycol 400 stearate 6.o g 10 oxyethylated fatty alcohol 4.0 g paraffin oil lO.0 g p-hydroxybenzoic acid ester (Nipasteril, from Nipalaboratorium Hamburg) 0.2 g perfume oil 0.1 g deionized water to giye 100.0 g The fats are melted and the very finely pulverized active compound and butylhydroxytoluene are dispersed therein whilst stirring at 65C (solution I). The water is boiled up with the Nipasteril*
and thèn cooled to 65C (solution II). Solution II
is then emulsified, a little at a time, in solution I, with thorough stirring. After the mixture has cooled to 45C, the perfume oil is added and the emulsion is cooled to room temperature, whilst stirring. The finished cream is packaged in tubes carrying an internal protective coating.
EXAMæLE 3 Jelly all-E-retinic acid N-(3-hydroxy)-prop~ylamide 0.01 g butylhydroxytoluene 0.1 g * Trademark 113663~
, - 20 -O.Z~ 0050/033449 oxyethylated castor oil (Cremophor EL, from BASF AG, Ludwigshafen) 35 0 g isopropanol 20.0 g polyacrylic acid (Carbopol, from Goodrich Hamburg) 1.5 g triethanolamine 0.002 g p-hydroxyber-oic acid ester (Nipasteri~, from Nipalaboratorium Hamburg) 0.2 g deionized water to give 100.0 g The Cremophor EL is heated to 60C, the active compound and the butylhydroxytoluene are dissolved therein, whilst stirring, and the isopropanol, in which the Nipasteril*h~s i -been dissolved are admixed (solution I). The Carbo-pol*is dispersed in the water, with vigorous stirring (solution II). Solution II is added, a little at a time, tG solution I, with thorough stirring. The pH
of the mixture is brought to 4.5 with triethanolamine.
The finished jelly is packaged in tubes carrying an internal protective coating.
Examples of formulations or drug compositions particularly suitable for systemic use are- the following:

Drops all-E-re~inic acid N-(2,3-dihydroxy)-0.1 g propylamide propylene glycol 25 0 g ethyl alcohol to give 50.0 g The ethyl alcohol and propylene glycol are mixed and the active compound is dissolved in the mixture by heating at 35C and stirring. After filtration, the *Trademark ~136638 - 21 - O.Z. 0050/03344g solution is pac~aged in dark-colored drop bottles, Hard gelatin capsules 13-Z-retinic acid N-(2,3-dihydroxy,)- l mg propylamide lac~ose to give 0.25 g The constituents are sieved, mixed and used to fill hard gelatin capsules of size 2 on a suitable cap-sule filling and sealing machine.

Claims (6)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:
1. Process for the preparation of a compound of the following formula I or II:

(I) (II) where X and Y are hydrogen or hydroxyl, but at least one is hydroxyl, or X and Y together with the carbon atoms linking them form a 2,2-dimethyl-1,3-dioxolane ring, said process which comprises reacting a functional derivative of all-E-retinic acid or of 13-Z-retinic acid with an amine of the formula III

(III) where X and Y have the meanings given above and advantageously providing the hydroxyl groups present with a protective group, after which, where required, removing the protective group by acid hydrolysis.
2. Process as claimed in claim 1, for the preparation of all-E-retinic acid N-(2,3-dihydroxy)-propylamide, which comprises reacting a solution of retinic acid chloride in ether with 2,2-dimethyl-4-aminomethyl-1,3-dioxolane and advantageously providing the hydroxyl groups present with a protective group, after which, removing the protective group by acid hydrolysis.
3. Process as claimed in claim 1, for the preparation of 13-Z-retinic acid N-(2,3-dihydroxy)-propylamide, which com-prises reacting 13-Z-retinic acid with 2,2-dimethyl-4-amino-methyl-1,3-dioxolane and advantageously providing the hydroxyl groups present with a protective group, after which, removing the protective group by acid hydrolysis.
4. Compounds of the formulae I and II

(I) (II) where X and Y are hydrogen or hydroxyl, but at least one is hydroxyl, or X and Y together with the carbon atoms linking them form a 2,2-dimethyl-1,3-dioxolane ring, whenever obtained by a process as claimed in claim 1 or its obvious chemical equivalents.
5. all-E-Retinic acid N-(2,3-dihydroxy)-propylamide, whenever obtained by a process as claimed in claim 2 or its obvious chemical equivalents.
6. 13-Z-Retinic acid N-(2,3-dihydroxy)-propylamide, whenever obtained by a process as claimed in claim 3 or its obvious chemical equivalents.
CA000336668A 1978-10-07 1979-09-28 N-hydroxylpropylamides of all-e retinic acid and 13-z-retinic acid, their preparation, and pharmaceutical formulations containing these compounds Expired CA1136638A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19782843870 DE2843870A1 (en) 1978-10-07 1978-10-07 N-HYDROXYPROPYLAMIDES OF ALL-E AND 13-Z RETINIC ACID
DEP2843870.2 1978-10-07

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EP (1) EP0009776B1 (en)
JP (1) JPS5551059A (en)
AT (1) ATE1382T1 (en)
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DE (2) DE2843870A1 (en)

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US4743400A (en) * 1986-09-22 1988-05-10 Mcneilab, Inc. Process for preparing retinoyl chlorides
EP0825286A3 (en) * 1992-11-18 2000-11-02 AQF Technologies LLC Fibrous structure containing immobilized particulate matter and process therefor
BR9606596A (en) * 1995-09-01 1997-10-28 Gist Brocades Nv Compound process for preparing a compound cosmetic or pharmaceutical composition and use of a compound
EP1241164B1 (en) * 1999-12-24 2004-05-06 Mitsubishi Rayon Co., Ltd. Process for preparation of tetrahydropyranyloxyamines
US7015225B1 (en) * 2003-06-26 2006-03-21 Larry Chen Anti-cancer agents and methods
KR100837186B1 (en) * 2006-09-29 2008-06-13 (주)아모레퍼시픽 Retinoic acid derivatives having anti-aging effect and preparation method thereof

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CH529742A (en) * 1970-02-02 1972-10-31 Hoffmann La Roche Process for the production of vitamin A acid amides

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ATE1382T1 (en) 1982-08-15
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EP0009776A1 (en) 1980-04-16
JPS5551059A (en) 1980-04-14

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