CA1127170A - Retinic acid n-(carboxy)-phenylamides and 7,8-dehydro-retinic acid n-(carboxy)-phenylamides, their preparation and pharmaceutical formulations containing these compounds - Google Patents
Retinic acid n-(carboxy)-phenylamides and 7,8-dehydro-retinic acid n-(carboxy)-phenylamides, their preparation and pharmaceutical formulations containing these compoundsInfo
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- CA1127170A CA1127170A CA336,670A CA336670A CA1127170A CA 1127170 A CA1127170 A CA 1127170A CA 336670 A CA336670 A CA 336670A CA 1127170 A CA1127170 A CA 1127170A
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- Prior art keywords
- acid
- carboxy
- retinic acid
- retinic
- phenylamide
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- 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
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- 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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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
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- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Dermatology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
O.Z. 0050/033446 Abstract of the disclosure: all-E- and 13-Z-retinic acid compounds of the formulae I and II
II
where the broken line is a chemical bond or two hydrogen atoms and the carboxyl group in the aromatic ring may be in the ortho-, meta- or para-position, the preparation of these compounds, pharmaceutical formulations contain-ing these compounds, and their use as drugs in the topical and systemic therapy and prophylaxis of pre-cancerous conditions and carcinomas, and of dermatologi-cal disorders
II
where the broken line is a chemical bond or two hydrogen atoms and the carboxyl group in the aromatic ring may be in the ortho-, meta- or para-position, the preparation of these compounds, pharmaceutical formulations contain-ing these compounds, and their use as drugs in the topical and systemic therapy and prophylaxis of pre-cancerous conditions and carcinomas, and of dermatologi-cal disorders
Description
1~717() ; . O.Z. 0050/033446 R`etinic acid N~carboxy)-phenylamides and 7,8-dehydro-retinic acid N-(carboxy)-phenylamides, their preparation, and pharmaceutical formulations containing these com-pounds The present invention relates to all-E- and 13-Z-retinic acid compounds of the formulaeI and II
~ ~Co2lI
where the broken line is a chemical bond or two hydrogen atoms and the carboxyl group in the aromatic ring may be in the ortho-, meta- or para-position, the preparation of these compounds, pharmaceutical formulations containing these compounds,-and their use as drugs.
German Laid-Open Application DOS 2,102,586 dis-closes that retinic acid amides which, for example, are 10 substituted by a benzyl or phenyl group at the amide nitrogen, exhibit a pharmacPlogical action, It states that these compounds may be used for the topical and sys-temic therapy of pre-cancerous conditions and carcinomas, and for the topical and systemic prophylaxis of carcin-omas. They may also be employed for the therapy of acne, psoriasis and other dermatological disorders accompanied by intensified or pathologically modified keratinization, and in cases of eczema and of disorders '~
~ ~Co2lI
where the broken line is a chemical bond or two hydrogen atoms and the carboxyl group in the aromatic ring may be in the ortho-, meta- or para-position, the preparation of these compounds, pharmaceutical formulations containing these compounds,-and their use as drugs.
German Laid-Open Application DOS 2,102,586 dis-closes that retinic acid amides which, for example, are 10 substituted by a benzyl or phenyl group at the amide nitrogen, exhibit a pharmacPlogical action, It states that these compounds may be used for the topical and sys-temic therapy of pre-cancerous conditions and carcinomas, and for the topical and systemic prophylaxis of carcin-omas. They may also be employed for the therapy of acne, psoriasis and other dermatological disorders accompanied by intensified or pathologically modified keratinization, and in cases of eczema and of disorders '~
- 2 - o.z. 0050/033446 of the mucous membranes, Examples of specific compounds mentioned, inter alia, in German Laid-Open Application DOS 2,102,586 are retinic acid N-ethylamide, retinic acid N-benzylamide and retinic acid N-phenylamide.
German Laid-Open Application DOS 2,300,107 dis-closes retinic acid amides, especially with substituted phenyl radicals, for roughly the same applications.
Examples of specific compounds described are retinic acid (p-ethoxy)-anilide and retinic acid N-(p-ethoxy-carbonyl)-phenylamide.
A disadvantage of these known retinic acid amides is their narrow therapeutic range. The substances either exhibit a relatively low activity, or are toxic even at relatively low doses. For example, retinic acid N-ethylamide can reverse keratinization of hamster tracheal tissue, induced by vit min A hypovitaminosis, at molar concentrations of as low as 2 x lO 9. The relevant methods are described by G.H. Clamon et al., Nature 250 (1974), 64-66 and M.B. Sporn et al., Nature ~53 (1975), 47-50. The keratinization is regarded as a pre-cancerous process. Retinic acid N-ethylamide however has a toxic effect on hamster tracheal carti-lage tissue in a culture at a molar concentration o~ as little as 9 x lO 7, as described by M.B. Sporn et al., Nature 263 (1976), 110-113. On the other hand, retinic acid N-(p-ethoxycarbonyl)-phenylamide has a low cellular toxicity, but requires a molar concentration of 10 8 to heal the keratinization of hamster tracheal tissue.
,7~
We have found that the all-E- and 13-Z-retinic acid N-(carboxy)-phenylamides of the formulae I and II
exhibit particularly valuable pharmacological properties, since they have a substantially higher therapeutic index.
For example, all-E-retinic acid N-(p-carboxy)-phenylamide exhibits as low a toxicity as the corresponding ethyl ester. However, in the prophylaxis of precancerous conditions of keratinized hamster tracheal tissue the free acid is still active at a molar concentration of 10 and is thus substantially more active than the ethyl ester.
Similar results were obtained with all-E-retinic acid N-(m-carboxy)-phenylamide, all-E-retinic acid N-(o-carboxy)-phenyl-amide, all-E-7,8-dehydro-retinic acid N-(p-carboxy)-phenylamide, all E-7,8-dehydro-retinic acid N-(m-carboxy)-phenylamide, all-E-7,8-dehydro-retinic acid N-(o-carboxy)-phenylamide, 13-Z-retinic acid N-(p-carboxy)-phenylamide, 13-Z-retinic acid N-(m-carboxy)-phenylamide and 13-Z-retinic acid N-(o-carboxy)-phenylamide.
Amongst the compounds according to the invention, all-E~retinic acid N-(p-carboxy)-phenylamide, all-E-7,8-dehydro-retinic acid N-~p-carboxy)-phenylamide and 13-Z-retlnic acid N-(p-carboxy)-phenylamide, and in particular all-E-retirlic acid N-(o-carboxy)-phenylamide are preferred~
The compounds according to the invention are prepared in the conventional manner by reacting a reactive acid derivative of all-E- or 13-Z-retinic acid or all-E- or 13-Z-7,8-dehydroxy-retinic acid with ortho-, meta- or para-aminobenzoic acid or one of its acid derivatives, the resulting derivative, in the latter case, being subsequently hydrolyzed to the acid in the conventional manner.
The reactive acid derivatives of all-E- or 13-Z-retinic acid or o~ all-E- or 13-Z-7,8-dehydro-retinic acid Bi are in particular the esters or acid halides, preferably the acid chlorides. Derivatives of ortho-, meta- or para-aminobenzoic acid which may be employed are in particular the corresponding esters, for example ethyl esters. The retinic acid N-~alkoxycarbonyl)-phenylamide first produced on reacting the retinic acid chloride with the aminobenzoic acid esters càn be converted to the phenylcarboxylic acid in the conventional manner by alkali-catalyzed hydrolysis of the ester groups.
The preparation of the retinic acld chlorides, and their further reaction with an aminobenzoic acid or one of its esters, is preferably carried out in an inert organic solvent, such as a dialkyl ether or an aliphatic chlorohydrocarbon, eg. diethyl ether or methylene chloride, or in a mixture of these solvents, in the presence of a base at from -25 to +25C.
Preferably, ther eaction is carried out in diethyl ether or in a solvent mixture, using from one to two moles of pyridine, per mole of reactant, as the base. The reaction is advantageously carried out in the abs~nce of oxygen and moisture, for example under nitrogen as a blanketing gas.
/
~ .
~ ~ -4-1~L ~71~
_ 5 _ o.z. oOSo/033446 The end product is worked up in the conventional manner. However, a preferred method of purification is recrystallization.
By virtue of the pharmacological properties mentioned, the compounds according to the invention can be employed in the topical and systemic therapy and pro-phylaxis of pre-cancerous conditions and carcinomas of the skin, mucous membranes and internal organs, and in the topical and systemic therapy of acne, psoriasis and other dermatological disorders accompanied by pathologic-ally modified keratinization.
A preferred 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 de-tected by the method described by R. Lotan et al in Jour-nal of the National Cancer Institute 60, pages 1035-1041.
The compounds also lnhibit the prolireration of spontane-ous chemioally or virally transformed cells in tlssue culture, the pre~erred culture being S 91 melanoma cells.
Accordingly, the invention also relates to pharmaceutical formulations which contain a c.ompound of the formula I or II as the active co~pound , 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 ~lso embraces the prepara-_ 6 -- O.Z. 0050/03~4~a6 tion of therapeutic agents or formulations which are obtained in the c~nventional manner, in parti-cular by mixing a dose of the active compound approp-riate for the part cular application with conventiona carriers or diluents, with or withcut conventional pharmaceutical excipients , in accord~nce wi~h the desired route of administration.
For t~cal application the therapeutic agents contain the compounds, to be used according to the inven-lo tion, at a concentration of from 0.001 to 1.0%, 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 mg, and can vary in accordance with the nature and severity of the disorder, the formulation used, and the route of administration.
The conventional galenical formulations are employed, for example, for oral administration, tablets, film tablets, dragees, capsules, pills, powders, gran-ules, solutions or suspensions. For external use, - suitable forms are in particular pastes, olntments,jell;es, creams, lotions, powders, solutions or emulsions and sprays.
The drugs according to the invention may be employed eith~r intel~lally or externally~ Preferably, they are administered orally or applied topically.
Examples of conventional pharmaceutical auxili-aries for t~cal application are alcohols, eg. isoprcpanol, oxye~hylated castor oil or oxyethylated hydr~genated castor oil, polyacrylic acid, glycerol monosteara+e, pa~;affin oil, vaseline, wool grease, polyethylene glycol 400, polyethylene glycol 400 stearate and oxyethylated 7~7~) _ 7 _ o.z. 0050/033446 fatty alcohols, whilst examples for systemic administra-tion are sucrose, lactose, propylene glycol, ethanol, starch, talc and polyvinylpyrrolidone.
EXamples of further conventional additives are preservatives, antioxidants, flavorings, stabilizers, emulsifiers, lubri.cants, wetting agents and the like.
It is a precondition that ali materials used in the preparation of pharmaceutical formulatiolls should be non-toxic and compatible with the active compounds employed (cf. L.G Goodman and A. ~ilman, The Pharma-cological Basis of Therapeutics).
EXAMPLE 1 '.
all-E-Retinic acid N-(p-carboxy)-phenylamide:
75 parts by weight of retinic acid are suspended in 1,000 parts by volume of diethyl ether, 21.9 parts by weight of pyridine are added and a solution of 33 parts by weight of thionyl chloride in 150 parts by volume of diethyl ether is introduced dropwise at 0C. Stirring is continued for 2 hours at 0C, the crystalline pyridinium hydrochloride is separated off by filtration, and the filtrate is run into a suspension of 34 parts by volume of p-aminobenzoic acid in 41.8 parts by weight of pyridine, 250 parts by volume of diethyl ether and 250 parts by volume of methylene chloride at a rate such that the reaction temperature does not exceed -20C.
The mixture is then stirred for 2 hours at about 25C
To obtain the product, the reaction mixture is washed with 250 parts by volume of ice-cold 1 N hydro-chloric acid and with 250 parts by volume of saturated sodium chloride solution and worked up in the convention-1~L27~7~
- 8 - O.Z. 0050/033446 al manner, and the residue is recrystallized from 1,200 parts by volume of acetone After drying at 50C
and 0.1 mm Hg for 5 hours, 75 parts by weight of all-E-retinic acid N-(p-carboxy)-phenylamide, melting point 199 to 201C, are obtained.
By working in accordance with the instructions given in Example 1, the following compounds are obtained in comparable yields:
all-E-Retinic acid N-(m-carboxy)-phenylamide, o melting point 193-194C after recrystallization from acetone.
all-E-Retinic acid N-(o-carboxy)-phenylamide, melting point 172-173C after recrystallization from acetonitrile.
13-Z-Retinic acid N-(p-carboxy)-phenylamide, melting point 165-166C after recrystallization from ethyl acetate, 13-Z-Retinic acid N-(m-carboxy)-phenylamide, melting point 152-154C after recrystallization from ; 20 ethyl acetate.
13-Z-Retinic acid N-(o-carboxy)-phenylamide, melting point 144-146C after recrystallization from ethyl acetate.
all-E-7,8-Dehydro-retinic acid N-(p-aarboxy)-phenylamide, melting point 235-237C after recrystalliza-tion from acetonitrile/methanol.
all-E-7,8-Dehydro-retinic acid N-(m-carboxy)-phenylamide, melting point 211-213C after recrystalliza-1~2,7~7~
- 9 - o.Z. 0050/033446 tion from acetonitrile/methanol.
all--E-7,8-Dehydro-retinic acil N-(o-carboxy)-phenylamide, melting point 202-205C after recrystalliza-tion from acetonitrile/methanol.
The isomer purity of the compounds prepared can be determined by high pressure liquid chromatography and is as a rule > 960/o. The structure ascribed is based on H-NMR spectroscopy.
Examples of suitable pharmaceutical f~rmulations or drug compositions for external application are:
Solution all-E-retinic acid N-(p-carboxy)-phenylamide 0.25 g oxyethylated hydrogenated castor oil 35.0 g tCremophor RH 40, from BASF AG, Ludwigshafen) Polyethylene glycol 400 35.0 g oxyethylated castor oil (Softigen 767, 10.0 g from Chemische Werke Witte~
deionized water 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 stirring and the poly-ethylene glycol 400 is added. The solutian is then c~oled to 40C and water at 40C is added slcwly, whilst stirring. The finished solution is filtered and packaged in, for example, 100 ml flasks.
Cream ail-E-7,8-dehydro-retinic acid N-(p-carboxy~- 0.1 g phenylamide butylhydrox~toluene 0.1 g . ..
1~717~) - 10 - o.Z. ooso/033446 glycerol monostearate 11.0 g polyethylene glycol 400 stearate 6.o g oxyethylated fatty alcohol 4,0 g paraffin oil . . - .10.0 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 lo active compound and butylhydroxytoluene are dispersed therein whilst stirring at 65C (~olution I). The , water is boiled up with the Nipasteril and then 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 i~ tubes carrying an inte~1al protective coating.
:~ EXAMP$E 3 20 Jelly 13-Z-retinic acid.N-(p-carboxy)-phenylamide 0.01 g butylhydroxytoluenc 0.1 g oxyethylated castor oil ~Cremophor EL, from BASF AG, Ludwigshafen) 35.0 g isopropanol 20.0 g polyacrylic acid (Carbopol, from Goodrich Hamburg) 1.5 g triethanolamine 0.002 g p-hydroxybenzoic acid ester (Nipasteril, 30 from Nipalaboratorium Hamburg) 0.2 g Tr~de~n~ ~
l~7~7n ~ o.z. oo50/033~46 deionized water to give 100.0 g The Cremophor EL is heated to 60C, the active compound and the butylhydroxytoluene are dissolved therein, whilst stirring, and the isopropanol, in which the Nipasteril has been dissolved are admixed (solution I). The Carbo-pol is dispersed in the water, with vigorous s~irring tSolution II). Solution II is added, a little at a - time, to solution I, with thorough stirring. The pH
o~ the mixture is brought to 4.5 with triethanola~ine.
The finished jelly is packaged in tubes carrying an - internal protective coating.
Examples of formulations or drug compositions particuIarly suitable for systemic use are the following:
Drops a~1-E-retinic-acid N-(p-carboxy)-phenylamide 0.1 g propylene glycol 25.0 g ethyl alcohol to give 50.0 g The ethyl alcohol and propylene glycol are mixed .~
and the active compound is dissolved in the mixture by heating at 35C and stirring. After filtration, the solution is packaged in dark-colored drop bottles.
B AMP$E 5 Hard gelatin capsules 13-Z-retinic acid N-(p-carboxy)-phenylamide 1 mg lactose to give 0.25 g The constituents are sieved, mixed and used to l~7l7n - 12 - O.Z. 0050/033446 fill hard gelatin capsules of size 2 on a suitable cap-sule filling and sealing machine.
.~ .
~ ' ' .
'^ .
:
German Laid-Open Application DOS 2,300,107 dis-closes retinic acid amides, especially with substituted phenyl radicals, for roughly the same applications.
Examples of specific compounds described are retinic acid (p-ethoxy)-anilide and retinic acid N-(p-ethoxy-carbonyl)-phenylamide.
A disadvantage of these known retinic acid amides is their narrow therapeutic range. The substances either exhibit a relatively low activity, or are toxic even at relatively low doses. For example, retinic acid N-ethylamide can reverse keratinization of hamster tracheal tissue, induced by vit min A hypovitaminosis, at molar concentrations of as low as 2 x lO 9. The relevant methods are described by G.H. Clamon et al., Nature 250 (1974), 64-66 and M.B. Sporn et al., Nature ~53 (1975), 47-50. The keratinization is regarded as a pre-cancerous process. Retinic acid N-ethylamide however has a toxic effect on hamster tracheal carti-lage tissue in a culture at a molar concentration o~ as little as 9 x lO 7, as described by M.B. Sporn et al., Nature 263 (1976), 110-113. On the other hand, retinic acid N-(p-ethoxycarbonyl)-phenylamide has a low cellular toxicity, but requires a molar concentration of 10 8 to heal the keratinization of hamster tracheal tissue.
,7~
We have found that the all-E- and 13-Z-retinic acid N-(carboxy)-phenylamides of the formulae I and II
exhibit particularly valuable pharmacological properties, since they have a substantially higher therapeutic index.
For example, all-E-retinic acid N-(p-carboxy)-phenylamide exhibits as low a toxicity as the corresponding ethyl ester. However, in the prophylaxis of precancerous conditions of keratinized hamster tracheal tissue the free acid is still active at a molar concentration of 10 and is thus substantially more active than the ethyl ester.
Similar results were obtained with all-E-retinic acid N-(m-carboxy)-phenylamide, all-E-retinic acid N-(o-carboxy)-phenyl-amide, all-E-7,8-dehydro-retinic acid N-(p-carboxy)-phenylamide, all E-7,8-dehydro-retinic acid N-(m-carboxy)-phenylamide, all-E-7,8-dehydro-retinic acid N-(o-carboxy)-phenylamide, 13-Z-retinic acid N-(p-carboxy)-phenylamide, 13-Z-retinic acid N-(m-carboxy)-phenylamide and 13-Z-retinic acid N-(o-carboxy)-phenylamide.
Amongst the compounds according to the invention, all-E~retinic acid N-(p-carboxy)-phenylamide, all-E-7,8-dehydro-retinic acid N-~p-carboxy)-phenylamide and 13-Z-retlnic acid N-(p-carboxy)-phenylamide, and in particular all-E-retirlic acid N-(o-carboxy)-phenylamide are preferred~
The compounds according to the invention are prepared in the conventional manner by reacting a reactive acid derivative of all-E- or 13-Z-retinic acid or all-E- or 13-Z-7,8-dehydroxy-retinic acid with ortho-, meta- or para-aminobenzoic acid or one of its acid derivatives, the resulting derivative, in the latter case, being subsequently hydrolyzed to the acid in the conventional manner.
The reactive acid derivatives of all-E- or 13-Z-retinic acid or o~ all-E- or 13-Z-7,8-dehydro-retinic acid Bi are in particular the esters or acid halides, preferably the acid chlorides. Derivatives of ortho-, meta- or para-aminobenzoic acid which may be employed are in particular the corresponding esters, for example ethyl esters. The retinic acid N-~alkoxycarbonyl)-phenylamide first produced on reacting the retinic acid chloride with the aminobenzoic acid esters càn be converted to the phenylcarboxylic acid in the conventional manner by alkali-catalyzed hydrolysis of the ester groups.
The preparation of the retinic acld chlorides, and their further reaction with an aminobenzoic acid or one of its esters, is preferably carried out in an inert organic solvent, such as a dialkyl ether or an aliphatic chlorohydrocarbon, eg. diethyl ether or methylene chloride, or in a mixture of these solvents, in the presence of a base at from -25 to +25C.
Preferably, ther eaction is carried out in diethyl ether or in a solvent mixture, using from one to two moles of pyridine, per mole of reactant, as the base. The reaction is advantageously carried out in the abs~nce of oxygen and moisture, for example under nitrogen as a blanketing gas.
/
~ .
~ ~ -4-1~L ~71~
_ 5 _ o.z. oOSo/033446 The end product is worked up in the conventional manner. However, a preferred method of purification is recrystallization.
By virtue of the pharmacological properties mentioned, the compounds according to the invention can be employed in the topical and systemic therapy and pro-phylaxis of pre-cancerous conditions and carcinomas of the skin, mucous membranes and internal organs, and in the topical and systemic therapy of acne, psoriasis and other dermatological disorders accompanied by pathologic-ally modified keratinization.
A preferred 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 de-tected by the method described by R. Lotan et al in Jour-nal of the National Cancer Institute 60, pages 1035-1041.
The compounds also lnhibit the prolireration of spontane-ous chemioally or virally transformed cells in tlssue culture, the pre~erred culture being S 91 melanoma cells.
Accordingly, the invention also relates to pharmaceutical formulations which contain a c.ompound of the formula I or II as the active co~pound , 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 ~lso embraces the prepara-_ 6 -- O.Z. 0050/03~4~a6 tion of therapeutic agents or formulations which are obtained in the c~nventional manner, in parti-cular by mixing a dose of the active compound approp-riate for the part cular application with conventiona carriers or diluents, with or withcut conventional pharmaceutical excipients , in accord~nce wi~h the desired route of administration.
For t~cal application the therapeutic agents contain the compounds, to be used according to the inven-lo tion, at a concentration of from 0.001 to 1.0%, 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 mg, and can vary in accordance with the nature and severity of the disorder, the formulation used, and the route of administration.
The conventional galenical formulations are employed, for example, for oral administration, tablets, film tablets, dragees, capsules, pills, powders, gran-ules, solutions or suspensions. For external use, - suitable forms are in particular pastes, olntments,jell;es, creams, lotions, powders, solutions or emulsions and sprays.
The drugs according to the invention may be employed eith~r intel~lally or externally~ Preferably, they are administered orally or applied topically.
Examples of conventional pharmaceutical auxili-aries for t~cal application are alcohols, eg. isoprcpanol, oxye~hylated castor oil or oxyethylated hydr~genated castor oil, polyacrylic acid, glycerol monosteara+e, pa~;affin oil, vaseline, wool grease, polyethylene glycol 400, polyethylene glycol 400 stearate and oxyethylated 7~7~) _ 7 _ o.z. 0050/033446 fatty alcohols, whilst examples for systemic administra-tion are sucrose, lactose, propylene glycol, ethanol, starch, talc and polyvinylpyrrolidone.
EXamples of further conventional additives are preservatives, antioxidants, flavorings, stabilizers, emulsifiers, lubri.cants, wetting agents and the like.
It is a precondition that ali materials used in the preparation of pharmaceutical formulatiolls should be non-toxic and compatible with the active compounds employed (cf. L.G Goodman and A. ~ilman, The Pharma-cological Basis of Therapeutics).
EXAMPLE 1 '.
all-E-Retinic acid N-(p-carboxy)-phenylamide:
75 parts by weight of retinic acid are suspended in 1,000 parts by volume of diethyl ether, 21.9 parts by weight of pyridine are added and a solution of 33 parts by weight of thionyl chloride in 150 parts by volume of diethyl ether is introduced dropwise at 0C. Stirring is continued for 2 hours at 0C, the crystalline pyridinium hydrochloride is separated off by filtration, and the filtrate is run into a suspension of 34 parts by volume of p-aminobenzoic acid in 41.8 parts by weight of pyridine, 250 parts by volume of diethyl ether and 250 parts by volume of methylene chloride at a rate such that the reaction temperature does not exceed -20C.
The mixture is then stirred for 2 hours at about 25C
To obtain the product, the reaction mixture is washed with 250 parts by volume of ice-cold 1 N hydro-chloric acid and with 250 parts by volume of saturated sodium chloride solution and worked up in the convention-1~L27~7~
- 8 - O.Z. 0050/033446 al manner, and the residue is recrystallized from 1,200 parts by volume of acetone After drying at 50C
and 0.1 mm Hg for 5 hours, 75 parts by weight of all-E-retinic acid N-(p-carboxy)-phenylamide, melting point 199 to 201C, are obtained.
By working in accordance with the instructions given in Example 1, the following compounds are obtained in comparable yields:
all-E-Retinic acid N-(m-carboxy)-phenylamide, o melting point 193-194C after recrystallization from acetone.
all-E-Retinic acid N-(o-carboxy)-phenylamide, melting point 172-173C after recrystallization from acetonitrile.
13-Z-Retinic acid N-(p-carboxy)-phenylamide, melting point 165-166C after recrystallization from ethyl acetate, 13-Z-Retinic acid N-(m-carboxy)-phenylamide, melting point 152-154C after recrystallization from ; 20 ethyl acetate.
13-Z-Retinic acid N-(o-carboxy)-phenylamide, melting point 144-146C after recrystallization from ethyl acetate.
all-E-7,8-Dehydro-retinic acid N-(p-aarboxy)-phenylamide, melting point 235-237C after recrystalliza-tion from acetonitrile/methanol.
all-E-7,8-Dehydro-retinic acid N-(m-carboxy)-phenylamide, melting point 211-213C after recrystalliza-1~2,7~7~
- 9 - o.Z. 0050/033446 tion from acetonitrile/methanol.
all--E-7,8-Dehydro-retinic acil N-(o-carboxy)-phenylamide, melting point 202-205C after recrystalliza-tion from acetonitrile/methanol.
The isomer purity of the compounds prepared can be determined by high pressure liquid chromatography and is as a rule > 960/o. The structure ascribed is based on H-NMR spectroscopy.
Examples of suitable pharmaceutical f~rmulations or drug compositions for external application are:
Solution all-E-retinic acid N-(p-carboxy)-phenylamide 0.25 g oxyethylated hydrogenated castor oil 35.0 g tCremophor RH 40, from BASF AG, Ludwigshafen) Polyethylene glycol 400 35.0 g oxyethylated castor oil (Softigen 767, 10.0 g from Chemische Werke Witte~
deionized water 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 stirring and the poly-ethylene glycol 400 is added. The solutian is then c~oled to 40C and water at 40C is added slcwly, whilst stirring. The finished solution is filtered and packaged in, for example, 100 ml flasks.
Cream ail-E-7,8-dehydro-retinic acid N-(p-carboxy~- 0.1 g phenylamide butylhydrox~toluene 0.1 g . ..
1~717~) - 10 - o.Z. ooso/033446 glycerol monostearate 11.0 g polyethylene glycol 400 stearate 6.o g oxyethylated fatty alcohol 4,0 g paraffin oil . . - .10.0 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 lo active compound and butylhydroxytoluene are dispersed therein whilst stirring at 65C (~olution I). The , water is boiled up with the Nipasteril and then 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 i~ tubes carrying an inte~1al protective coating.
:~ EXAMP$E 3 20 Jelly 13-Z-retinic acid.N-(p-carboxy)-phenylamide 0.01 g butylhydroxytoluenc 0.1 g oxyethylated castor oil ~Cremophor EL, from BASF AG, Ludwigshafen) 35.0 g isopropanol 20.0 g polyacrylic acid (Carbopol, from Goodrich Hamburg) 1.5 g triethanolamine 0.002 g p-hydroxybenzoic acid ester (Nipasteril, 30 from Nipalaboratorium Hamburg) 0.2 g Tr~de~n~ ~
l~7~7n ~ o.z. oo50/033~46 deionized water to give 100.0 g The Cremophor EL is heated to 60C, the active compound and the butylhydroxytoluene are dissolved therein, whilst stirring, and the isopropanol, in which the Nipasteril has been dissolved are admixed (solution I). The Carbo-pol is dispersed in the water, with vigorous s~irring tSolution II). Solution II is added, a little at a - time, to solution I, with thorough stirring. The pH
o~ the mixture is brought to 4.5 with triethanola~ine.
The finished jelly is packaged in tubes carrying an - internal protective coating.
Examples of formulations or drug compositions particuIarly suitable for systemic use are the following:
Drops a~1-E-retinic-acid N-(p-carboxy)-phenylamide 0.1 g propylene glycol 25.0 g ethyl alcohol to give 50.0 g The ethyl alcohol and propylene glycol are mixed .~
and the active compound is dissolved in the mixture by heating at 35C and stirring. After filtration, the solution is packaged in dark-colored drop bottles.
B AMP$E 5 Hard gelatin capsules 13-Z-retinic acid N-(p-carboxy)-phenylamide 1 mg lactose to give 0.25 g The constituents are sieved, mixed and used to l~7l7n - 12 - O.Z. 0050/033446 fill hard gelatin capsules of size 2 on a suitable cap-sule filling and sealing machine.
.~ .
~ ' ' .
'^ .
:
Claims (26)
1. A process for the preparation of retinic acid N-(carboxylic)-phenylamides and 7,8-dehydro-retinic acid N-(carboxy)-phenylamides of the formulae (I) and(II) :
(I) (II) wherein the broken line is a chemical bond or two hydrogen atoms and the carboxyl group in the aromatic ring may be in the ortho-, meta- or para-position, characterized in that a reactive acid derivative of all-E- or 13-Z-retinic acid or of all -E- or 13-Z-7,8-dehydro-retinic acid is reacted with o-, m- or p-aminobenzoic acid or an acid derivative thereof, and, where appropriate, the resulting acid derivative is hydrolyzed to the acid, to obtain a compound of formula (I) or formula (II) .
(I) (II) wherein the broken line is a chemical bond or two hydrogen atoms and the carboxyl group in the aromatic ring may be in the ortho-, meta- or para-position, characterized in that a reactive acid derivative of all-E- or 13-Z-retinic acid or of all -E- or 13-Z-7,8-dehydro-retinic acid is reacted with o-, m- or p-aminobenzoic acid or an acid derivative thereof, and, where appropriate, the resulting acid derivative is hydrolyzed to the acid, to obtain a compound of formula (I) or formula (II) .
2. Retinic acid N-(carboxy)-phenylamides and 7,8-dehydro-retinic acid N-(carboxy)-phenylamides of the formulae (I) and (II) :
(I) (II) wherein the broken line is a chemical bond or two hydrogen atoms and the carboxyl group in the aromatic ring may be in the ortho-, meta- or para-position, whenever prepared by a process as claimed in claim 1 or an obvious chemical equiva-lent thereof.
(I) (II) wherein the broken line is a chemical bond or two hydrogen atoms and the carboxyl group in the aromatic ring may be in the ortho-, meta- or para-position, whenever prepared by a process as claimed in claim 1 or an obvious chemical equiva-lent thereof.
3. A process for the preparation of retinic acid N-(carboxy)-phenylamides amd 7,8-dehydro-retinic acid N-(carboxy)-phenylamides of the formulae (I) and (II) (I) (II) wherein the broken line is a chemical bond or two hydrogen atoms and the carboxyl group in the aromatic ring may be in the ortho-, meta-, or para-position, characterized in that an acid halide of all-E- or 13-Z-retinic acid or of all-E-or 13-Z-7,8-dehydro-retinic acid is reacted with o-, m-,or p-aminobenzoic acid or a suitable corresponding alkyl ester derivative thereof, and, where appropriate, the resulting alkyl ester derivative is hydrolyzed to the acid, to obtain a compound of formula (I) or (II)
4. Retinic acid N-(carboxy)-phenylamides and 7,8-dehydro-retinic acid N-(carboxy)-phenylamides of the formulae (I) and (II) (I) (II) wherein the broken line is a chemical bond or two hydrogen atoms and the carboxyl group in the aromatic ring may be in the ortho-, meta- or para-position, whenever prepared by a process as claimed in claim 3 or an obvious chemical equivalent thereof.
5. A process for the preparation of a retinic acid N-(carboxy)-phenylamides and 7,8-dehydro-retinic acid N-(carboxy)-phenylamides of the formula (I) (I) wherein the broken line is a chemical bond or two hydrogen atoms and the carboxyl group in the aromatic ring may be in the ortho-, meta- or para-position, characterized in that an acid chloride of all-E-retinic acid or of all-E-7,8-de-hydro-retinic acid is reacted with o-, m-, or p-amino-benzoic acid to obtain a compound of formula (I).
6. Retinic acid N-(carboxy)-phenylamides and 7,8-dehydro-retinic acid N-(carboxy)-phenylamides of the formula (I) :
(I) wherein the broken line is a chemical bond or two hydrogen atoms and the carboxyl group in the aromatic ring may be in the ortho-, meta- or para-position, whenever prepared by a process as claimed in claim 5 or an obvious chemical equivalent thereof.
(I) wherein the broken line is a chemical bond or two hydrogen atoms and the carboxyl group in the aromatic ring may be in the ortho-, meta- or para-position, whenever prepared by a process as claimed in claim 5 or an obvious chemical equivalent thereof.
7. A process for the preparation of a retinic acid N-(carboxy)-phenylamides and 7,8-dehydro-retinic acid N-(carboxy)-phenylamides of the formula (II) :
(II) wherein the broken line is a chemical bond of two hydrogen atoms and the carboxyl group in the aromatic ring may be in the ortho-, meta- or para-position, characterized in that an acid chloride of 13-Z-retinic acid or 13-Z-7,8-dehydro-retinic acid is reacted with o-, m- or p-amino-benzoic acid to obtain a compound of formula (II).
(II) wherein the broken line is a chemical bond of two hydrogen atoms and the carboxyl group in the aromatic ring may be in the ortho-, meta- or para-position, characterized in that an acid chloride of 13-Z-retinic acid or 13-Z-7,8-dehydro-retinic acid is reacted with o-, m- or p-amino-benzoic acid to obtain a compound of formula (II).
8. Retinic acid N-(carboxy)-phenylamides and 7,8-dehydro-retininc acid N-(carboxy)-phenylamides of the formula (II) :
(II) wherein the broken line is a chemical bond or two hydrogen atoms and the carboxyl group in the aromatic ring may be in the ortho-, meta- or para-position, whenever prepared by a process as claimed in claim 7 or an obvious chemical equivalent thereof.
(II) wherein the broken line is a chemical bond or two hydrogen atoms and the carboxyl group in the aromatic ring may be in the ortho-, meta- or para-position, whenever prepared by a process as claimed in claim 7 or an obvious chemical equivalent thereof.
9. A process for the preparation of all-E-retinic acid-N-(o-carboxy)-phenylamide characterized in that all-E-retinic acid chloride is reacted with o-aminobenzoic acid to obtain all-E-retinic acid-N-(o-carboxy)-phenylamide.
10. All-E-retinic acid-N-(o-carboxy)-phenylamide whenever prepared by a process as claimed in claim 9 or an obvious chemical equivalent thereof.
11. A process for the preparation of 13-Z-retinic acid N-(o-carboxy)-phenylamide, characterized in that 13-Z-retinic acid chloride is reacted with o-aminobenzoic acid to obtain 13-Z-retinic acid N-(o-carboxy)-phenylamide.
12. 13-Z-retinic acid N-(o-carboxy)-phenylamide whenever prepared by a process as claimed in claim 11 or an obvious chemical equivalent thereof.
13. A process for the preparation of all-E-retinic acid-N-(p-carboxy)-phenylamide characterized in that all-E-retinic acid chloride is reacted with p-aminobenzoic acid to obtain all-E-retinic acid-N-(p-carboxy)-phenylamide.
14. All-E-retinic acid-N-(p-carboxy)-phenylamide whenever prepared by a process as claimed in claim 13 or an obvious chemical equivalent thereof.
15. A process for the preparation of 13-Z-retinic acid N-(p-carboxy)-phenylamide, characterized in that 13-Z-retinic acid chloride is reacted with p-aminobenzoic acid to obtain 13-Z-retinic acid N-(p-carboxy)-phenylamide.
16. 13-Z-retinic acid N-(p-carboxy)-phenylamide whenever prepared by a process as claimed in claim 15 or an obvious chemical equivalent thereof.
17. A process for the preparation of all-E-retinic aicd-N-(m-carboxy)-phenylamide characterized in that all-E-retinic acid chloride is reacted with m-aminobenzoic acid to obtain all-E-retinic acid-N-(m-carboxy)-phenylamide.
18. All-E-retinic acid-N-(m-carboxy)-phenylamide whenever prepared by a process as claimed in claim 17 or an obvious chemical equivalent thereof.
19. A process for the preparation of 13-Z-retinic acid N-(m-carboxy)-phenylamide, characterized in that 13-Z-retinic acid chloride is reacted with m-aminobenzoic acid to obtain 13-Z-retinic acid N-(m-carboxy)-phenylamide.
20. 13-Z-retinic acid N-(m-carboxy)-phenylamide whenever prepared by a process as claimed in claim 19 or an obvious chemical equivalent thereof.
21. A process for the preparation of all-E-7,8-dehydro-retinic acid-N-(o-carboxy)-phenylamide characterized in that all-E-7,8-dehydro-retinic acid chloride is reacted with o-aminobenzoic acid to obtain all-E-7,8-dehydro-retinic acid-N-(o-carboxy)-phenylamide.
22. All-E-7,8-dehydro-retinic acid-N-(o-carboxy)-phenylamide whenever prepared by a process as claimed in claim 21 or an obvious chemical equivalent thereof.
23. A process for the preparation of all-E-7,8-dehydro-retinic acid N-(p-carboxy)-phenylamide, characterized in that all-E-7,8-dehydro-retinic acid chloride is reacted with p-aminobenzoic acid to obtain all-E-7,8-dehydro-retinic acid N-(p-carboxy)-phenylamide.
24. All-E-7,8-dehydro-retinic acid N-(p-carboxy)-phenylamide whenever prepared by a process as claimed in claim 23 or an obvious chemical equivalent thereof.
25. A process for the preparation of all-E-7,8-dehydro-retinic acid-N-(m-carboxy)-phenylamide characterized in that all-E-7,8-dehydro-retinic acid chloride is reacted with m-aminobenzoic acid to obtain all-E-7,8-dehydro-retinic acid-N-(m-carboxy)-phenylamide.
26. All-E-7,8-dehydro-retinic acid-N-(m-carboxy)-phenylamide whenever prepared by a process as claimed in claim 25 or an obvious chemical equivalent thereof.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP2843811.1 | 1978-10-07 | ||
| DE19782843811 DE2843811A1 (en) | 1978-10-07 | 1978-10-07 | RETINIC ACID AND 7,8-DEHYDRO RETINIC ACID-N- (CARBOXY) -PHENYLAMIDE |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1127170A true CA1127170A (en) | 1982-07-06 |
Family
ID=6051651
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA336,670A Expired CA1127170A (en) | 1978-10-07 | 1979-09-28 | Retinic acid n-(carboxy)-phenylamides and 7,8-dehydro-retinic acid n-(carboxy)-phenylamides, their preparation and pharmaceutical formulations containing these compounds |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP0009777B1 (en) |
| JP (1) | JPS5551058A (en) |
| AT (1) | ATE964T1 (en) |
| CA (1) | CA1127170A (en) |
| DE (2) | DE2843811A1 (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5703130A (en) * | 1995-06-07 | 1997-12-30 | Institute Of Materia Medica, An Institute Of The Chinese Academy Of Medical Sciences | Chalcone retinoids and methods of use of same |
| US5716982A (en) * | 1995-06-07 | 1998-02-10 | Institute Of Materia Medica, An Institute Of The Chinese Academy Of Medical Sciences | Retinoids and methods of use of same |
| US5968940A (en) * | 1995-06-08 | 1999-10-19 | Institute Of Materia Medica | Retinoids and methods of use of same |
| CN102260186A (en) * | 2011-05-09 | 2011-11-30 | 北京吉科特科技有限责任公司 | N-(4-carboxyl phenyl)retinamide ethanol compound and preparation method thereof, and medicinal composition |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3002545A1 (en) * | 1980-01-25 | 1981-07-30 | Basf Ag, 6700 Ludwigshafen | 5-AMINO-TETRAZOLE DERIVATIVES OF RETINIC ACIDS, THEIR PRODUCTION AND THE PHARMACEUTICAL PREPARATIONS CONTAINING THEM |
| JP2589295B2 (en) * | 1986-11-14 | 1997-03-12 | キヤノン株式会社 | Image forming device |
| JP3431706B2 (en) * | 1994-12-16 | 2003-07-28 | 新日本石油化学株式会社 | Laminate, nonwoven fabric or woven fabric and reinforced laminate using them |
| US6054086A (en) * | 1995-03-24 | 2000-04-25 | Nippon Petrochemicals Co., Ltd. | Process of making high-strength yarns |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2300107C2 (en) * | 1973-01-03 | 1982-03-11 | Basf Ag, 6700 Ludwigshafen | Vitamin A acid anilide-4-carboxylic acid ethyl ester, process for its production and preparations containing it |
| DE2456959A1 (en) * | 1974-12-03 | 1976-06-16 | Basf Ag | 4- (E) - AND 4- (Z) -7-METHYL-9- (2,6,6TRIMETHYL-1-CYCLOHEXEN-1-YL) -NONA-2,4,6,8TETRAEN CARBONIC ACID, ITS DERIVATIVES AND CONTAINING THEM PREPARATIONS |
-
1978
- 1978-10-07 DE DE19782843811 patent/DE2843811A1/en active Pending
-
1979
- 1979-09-28 CA CA336,670A patent/CA1127170A/en not_active Expired
- 1979-09-28 DE DE7979103684T patent/DE2962720D1/en not_active Expired
- 1979-09-28 EP EP79103684A patent/EP0009777B1/en not_active Expired
- 1979-09-28 AT AT79103684T patent/ATE964T1/en not_active IP Right Cessation
- 1979-10-05 JP JP12811279A patent/JPS5551058A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5703130A (en) * | 1995-06-07 | 1997-12-30 | Institute Of Materia Medica, An Institute Of The Chinese Academy Of Medical Sciences | Chalcone retinoids and methods of use of same |
| US5716982A (en) * | 1995-06-07 | 1998-02-10 | Institute Of Materia Medica, An Institute Of The Chinese Academy Of Medical Sciences | Retinoids and methods of use of same |
| US5968940A (en) * | 1995-06-08 | 1999-10-19 | Institute Of Materia Medica | Retinoids and methods of use of same |
| CN102260186A (en) * | 2011-05-09 | 2011-11-30 | 北京吉科特科技有限责任公司 | N-(4-carboxyl phenyl)retinamide ethanol compound and preparation method thereof, and medicinal composition |
| CN102260186B (en) * | 2011-05-09 | 2014-03-12 | 北京吉科特科技有限责任公司 | N-(4-carboxyl phenyl)retinamide ethanol compound and preparation method thereof, and medicinal composition |
Also Published As
| Publication number | Publication date |
|---|---|
| DE2843811A1 (en) | 1980-04-24 |
| DE2962720D1 (en) | 1982-06-24 |
| EP0009777A1 (en) | 1980-04-16 |
| JPS5551058A (en) | 1980-04-14 |
| ATE964T1 (en) | 1982-05-15 |
| EP0009777B1 (en) | 1982-05-05 |
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