CA1127655A - N-benzoyl-retinylamines, their preparation and pharmaceutical formulations containing these compounds - Google Patents
N-benzoyl-retinylamines, their preparation and pharmaceutical formulations containing these compoundsInfo
- Publication number
- CA1127655A CA1127655A CA336,669A CA336669A CA1127655A CA 1127655 A CA1127655 A CA 1127655A CA 336669 A CA336669 A CA 336669A CA 1127655 A CA1127655 A CA 1127655A
- Authority
- CA
- Canada
- Prior art keywords
- benzoyl
- retinylamine
- formula
- parts
- preparation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
- C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
-
- 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
- C07C403/18—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 nitrogen atoms
-
- 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
- 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
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
O.Z.0050/033447 Abstract of the disclosure: Novel N-benzoyl-retinyl-amines of the formula I
Description
~Z7655 - 1 O.Z. 0050/033447 N-Benzoyl-retinylamines, their preparation, and pharma-ceutical formulations containing these com~ounds The present invention relates to novel N-ben~oyl-retinylamines of the formula I
where R is hydrogen or methyl, their preparation, pharma-ceutical formulations containing these compounds, and their use as drugs.
The synthesis of N-acetyl-retinylamine and N-formyl-retinylamine, for example, is known from the literature (F. Kienzle, Helv. Chim. Acta 56 (1973), 1662 et seq.).
Further, it has been disclosed that N-acetyl-retinylamine may be used for the systemic and topical therapy of pre-cancerous conditions and carcinomas and ~or the systemic and topical prophylaxis o~ carcinomas (M.B. Sporn et al. Nature 263 (1976), 110-113).
The cellular toxicity threshold, namely in res-pect o~ the toxicity to tracheal cartilage in vitro, of N-acetyl-retinylamine is above a molar concentration of 10 5 (Nature 263 (1976), 110-113), but this retinoid, in biological experiments on hamster tracheal tissue keratinized by vitamin A hypovitaminosis, exhibits an activity only in molar concentrations as high as 9xlO 9.
The methods used are described by G.H. Clamon et al.,
where R is hydrogen or methyl, their preparation, pharma-ceutical formulations containing these compounds, and their use as drugs.
The synthesis of N-acetyl-retinylamine and N-formyl-retinylamine, for example, is known from the literature (F. Kienzle, Helv. Chim. Acta 56 (1973), 1662 et seq.).
Further, it has been disclosed that N-acetyl-retinylamine may be used for the systemic and topical therapy of pre-cancerous conditions and carcinomas and ~or the systemic and topical prophylaxis o~ carcinomas (M.B. Sporn et al. Nature 263 (1976), 110-113).
The cellular toxicity threshold, namely in res-pect o~ the toxicity to tracheal cartilage in vitro, of N-acetyl-retinylamine is above a molar concentration of 10 5 (Nature 263 (1976), 110-113), but this retinoid, in biological experiments on hamster tracheal tissue keratinized by vitamin A hypovitaminosis, exhibits an activity only in molar concentrations as high as 9xlO 9.
The methods used are described by G.H. Clamon et al.,
2 - O.Z. 0050/033447 Nature 250, (1974), 64-66 and ~.B Sporn et al., Nature 253, (1975), 47-50. The keratinization is regarded as a pre-cancerous process.
We have found that the N~benzoyl-retinylamines of the formula I exhibit particularly valuable pharmaco-logical properties, since they have a substantially higher therapeutic index Whilst having a comparably low cellular toxicity, the compounds according to the invention still inhibit the keratinization of hamster tracheal tissue in lO lO
molar solution and are therefore more active, by from l to 2 powers of ten, than N-acetyl-retinylamine Accordingly, the invention further relates to pharmaceutical formulations which contain, as the active ingredient, a compound of the formula I, in addition to conventional pharmaceutical carriers or diluents, with or without conventional pharmaceutical excipients, and to the use of a compound of the formula I for the prepara-tion of a drug Formulations which contain a compound according to the inven1;ion, of the formula I, may be used prefer-entially for the topical and systemic therapy of pre-cancerous conditions and carcinomas of the skin, mucous membranes and internal organs, and for the systemic and topical therapy of acne, psoriasis and other dermato-logical disorders accompanied by intensified or pathologi-cally modified keratinization In contrast to free retinic acid, the compounds according to the invention do not irritate the skin and do not cause any A-hyper-~lZ765~
We have found that the N~benzoyl-retinylamines of the formula I exhibit particularly valuable pharmaco-logical properties, since they have a substantially higher therapeutic index Whilst having a comparably low cellular toxicity, the compounds according to the invention still inhibit the keratinization of hamster tracheal tissue in lO lO
molar solution and are therefore more active, by from l to 2 powers of ten, than N-acetyl-retinylamine Accordingly, the invention further relates to pharmaceutical formulations which contain, as the active ingredient, a compound of the formula I, in addition to conventional pharmaceutical carriers or diluents, with or without conventional pharmaceutical excipients, and to the use of a compound of the formula I for the prepara-tion of a drug Formulations which contain a compound according to the inven1;ion, of the formula I, may be used prefer-entially for the topical and systemic therapy of pre-cancerous conditions and carcinomas of the skin, mucous membranes and internal organs, and for the systemic and topical therapy of acne, psoriasis and other dermato-logical disorders accompanied by intensified or pathologi-cally modified keratinization In contrast to free retinic acid, the compounds according to the invention do not irritate the skin and do not cause any A-hyper-~lZ765~
- 3 - O.Z. 0050/033447 vitaminosis.
A preferred indication is the prophylacticand therapeutic treatment of pre-cancerous conditions and tumors of the bladder, the rnammary gland, the skin and the mucous membranes.
11~7~5S
_4 _ O . Z . 0050/033447 f20 ~0 a o .
o a ~ L~ .r1 n~ _ (n tnbO ~: ~I)1~.111~r~ ~
S~ ~ (~1 ~ O E 3 O
rt a) rl ~ ~rl L~1 L L E ~S/n L
~ a~ 5 ~ rl a) S~r-t hO ~ ~\l r-t ~~L) ~r1O L 0J :~ r-l(I)(I) ~ ~: ~ L( )~ ^ a~
L~r1 r-l ~ O(L~~:( )~ L
O N 3 O O Q.
E S:: L ~ O
~ O Ou~ O L:~: L
t~ tn .o r-l ~ ~ . O
(.) L O I O EC ) tD L r-t E L ~3 ~~ ~10 ~> ~~r1 ~~ct ~
L (~ ~r1 ~ ~ ~ E L ~rt t~tl) O ~, ~r1 )~t ~ O
~3L O u~ a) r-t S O ~ ~rl 0~
d . ~) ~ ~ Lr-t ~ ~rl J->1`--~3tL ~ ~ ¢ E~ g L
~rl'~
~:E3 ~I ~ ' 3 rl~ ~ t~5 ~a.)_Crlt~
~:E-l ~ L a~ ~1J~ ~1 _ a~ ~ s ~rl ~I) L O S: ~ I
(n r-tt;Q ~ ~1) ~) ~ 0 3r1 ~ ~- ~S ~) s~ a) La~ g~\1 E
~rl ln ~ ~J->~) 0 0 o ~2 o 3 ~
tl~t;q 'O S~t ~ rl ~) r-t L :~ O
~rt~11 0 a) (1) L ~ ~1) S
~3~ ~ O O r-l 5 ~ O ~ L
0 O ~ ~ ~ ~0 ~ O ~ I ~-- L
E--~ ~ ~ ~ _ r-l ~
r-l ~rl L S Cl t~ ~ tl) ~ In a) r1 S ~) ~ ~n o ~J-)a)~ t a~ ~D
N ~ 1 C~0 ~ S S
,-1 0 0 Il) ~t (.)1~ L :>.L~
D m L~> L a~ O
H tn ~r1 ~d O L O un L S~
-~ a) ~ )Cl~ t (11 ~ - OU) ~ ,:`,C,) ~rL un L O ~ O L
O L a)51: M (~
L O e u) ~ ,1 ~ ~ ~ ~d _ ~ _ ~ ~ ~r I L
L J~ ~\J `Oe~ aS~ tll bO
O O ~ r~ ~ ~)L ~
0 C~ 0 0 ~ ~) _ O~rl~ ~ S
e ~ ~ ~a) ~ ~ o - r-t ~
~rl r-l SbOrl O L nl Z 3 8 ~rl (~ .5~ r1 O O La) ~) r-l ~1 3 L C~ O L
~-:>~ :~ L ~; r-l L
o a) ~In ~ :~ o N r-l O a~J~ ~ S ~ ~I
~: Dr l~(n ~) U~ (, a> 0 0rd D
D ~ ~I E D ~3 m ~
~t I O~rtun ~ m ~rl r_l a) r-t ~ L r-t r-l 0 O ~.:~ bOr-l O ~ ~ O a) C a) bO ~rl a) 1~ ttl L
~rt a)~1 S (~ E 3 r1 S D
,~ ~ ,1 L L ~ ~ ~ a) r1 ~1 ; ~U~ ~ O L ~ O
` 1127ti55 - 5 - O.Z. 0050/033447 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 National Cancer Institute 60 (1978), 1035-1041. The compounds also inhibit the proliferation of spontaneously chemically or virally transformed cells in tissue culture, the preferred culture being S 91 melanoma cells.
The compounds of the formula I, according to the ¦ invention, are prepared in the conventional manner by reacting all-E-retinylamine with a reactive deri~ative of benzoic acid or of p-toluic acid. Suitable re~ctive acid derivatives are esters, anhydrides and, preferably, acid halides, especially the acid chlorides. The re-action is advantageously carried out in the presence of a base, especially a tertiary amine, preferably pyridine, in an inert solvent, such as a dialkyl ether or chlorohydrocarbon,preferably in diethyl ether or methylene chloride. Advantageously, it is carried out in the absence of oxygen and moisture, for example under nitro-gen as a blanketing gas.
The end products are worked up in the convention-al manner, The starting compound, all-E-retinylamine, can be prepared according to F. Kienzle (loc. cit ) from all-E-retinol via all-E-retinyl-phthalimide. A
further advantageous method of synthesis of N-retinyl-phthalimide is the Wittig olefinization of the known Cl5-phosphonium salt II with 2-methyl-4-phthalimido-but-2-en-l-al III.
E~;
11;~765S
- 6 - O.Z. 0050/033447 N ~ III
II Wittig olefinization ; r isomerization H2H-~, CH30H
. ' 1 X~
F~ .
The present invention also embraces the prepara-tion of therapeutic agents or formu~ations which are obtained in the conventi.onal manner, in parti-cular by mixing a dose of the active compGund approp-riate for the particular application with conventional carriers or diluents, with or without conventional pharmaceutical excipients, in accordance with the desired route of administration~
l~Z~655 - 7 - O.Z. 0050/033447 For topical application the therapeutic formula-tions contain the compounds, to be used according to the invention, at a concentration of from 0.001 to 1.0%, pre-ferably from 0.01 to 0.1%, whilst for systemic administra-tion a single dose is pre~erably from 0.1 to 5 mg Suit-able daily dosages are from 50 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, ~owders, gran-ules, solutions or suspensions For external use, suitable forms are in particular pastes, ointments,je1lies, creams, lotions, powders, sol1tions or ernulsions and sprays.
~he drugs according to the invention may be employed either internally or externally. Preferably, they are adminis-tered orally or applied topically.
Examples of conventional pharmaceutical auxili-ariesfortopical application are alcohols, eg. isoPropanol, oxyethylated castor oil or oxyethylated hydrogenated castor oil, polyacrylic acid, glycerol monostearate, paraffin oil, vaseline, wool grease, polyethylene glycol 400, polyethylene glycol 400 stearate and oxyethylated fatty alcohols, whilst examples for systemic administra-tion are lactose, sucrose, propylene glycol, ethanol, ~1~7655 - 8 ~ O.Z. 0050/033447 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 formulations should be non-toxic and compatible with the active compounds employed (cf. L.G. Goodman and A. Gilman, The Pharmaco-logical Basis of Therapeutics).
N-(E-3-Formyl-but-2-en-1-yl)-phthali,mide:
210 parts by weight of 4-chloro-2-methyl-but-2-enal-diethylacetal are added dropwise to a solution of 343.2 parts by weight of,ethyl orthoformate in 151 parts by weight of ethanol. The solution is stirred for 1 hour at 40C and is concentrated on a rotary evaporator at 16 mm Hg/40C. 400 parts by weight of dimethylformamide and 300 parts by weight of potassium phthalimide are added, and the mixture is heated for 1 hour at 120C)C and filtered after it has cooled. The fil-trate is concentrated on a rotary evaporator at 50C ~nder2 mm Hg and the residue is taken up in 1,500 parts by volume of diisopropyl ether and 200 parts by volume of ethanol. At about 0C, 172 parts by wei.ght of N-(E-
A preferred indication is the prophylacticand therapeutic treatment of pre-cancerous conditions and tumors of the bladder, the rnammary gland, the skin and the mucous membranes.
11~7~5S
_4 _ O . Z . 0050/033447 f20 ~0 a o .
o a ~ L~ .r1 n~ _ (n tnbO ~: ~I)1~.111~r~ ~
S~ ~ (~1 ~ O E 3 O
rt a) rl ~ ~rl L~1 L L E ~S/n L
~ a~ 5 ~ rl a) S~r-t hO ~ ~\l r-t ~~L) ~r1O L 0J :~ r-l(I)(I) ~ ~: ~ L( )~ ^ a~
L~r1 r-l ~ O(L~~:( )~ L
O N 3 O O Q.
E S:: L ~ O
~ O Ou~ O L:~: L
t~ tn .o r-l ~ ~ . O
(.) L O I O EC ) tD L r-t E L ~3 ~~ ~10 ~> ~~r1 ~~ct ~
L (~ ~r1 ~ ~ ~ E L ~rt t~tl) O ~, ~r1 )~t ~ O
~3L O u~ a) r-t S O ~ ~rl 0~
d . ~) ~ ~ Lr-t ~ ~rl J->1`--~3tL ~ ~ ¢ E~ g L
~rl'~
~:E3 ~I ~ ' 3 rl~ ~ t~5 ~a.)_Crlt~
~:E-l ~ L a~ ~1J~ ~1 _ a~ ~ s ~rl ~I) L O S: ~ I
(n r-tt;Q ~ ~1) ~) ~ 0 3r1 ~ ~- ~S ~) s~ a) La~ g~\1 E
~rl ln ~ ~J->~) 0 0 o ~2 o 3 ~
tl~t;q 'O S~t ~ rl ~) r-t L :~ O
~rt~11 0 a) (1) L ~ ~1) S
~3~ ~ O O r-l 5 ~ O ~ L
0 O ~ ~ ~ ~0 ~ O ~ I ~-- L
E--~ ~ ~ ~ _ r-l ~
r-l ~rl L S Cl t~ ~ tl) ~ In a) r1 S ~) ~ ~n o ~J-)a)~ t a~ ~D
N ~ 1 C~0 ~ S S
,-1 0 0 Il) ~t (.)1~ L :>.L~
D m L~> L a~ O
H tn ~r1 ~d O L O un L S~
-~ a) ~ )Cl~ t (11 ~ - OU) ~ ,:`,C,) ~rL un L O ~ O L
O L a)51: M (~
L O e u) ~ ,1 ~ ~ ~ ~d _ ~ _ ~ ~ ~r I L
L J~ ~\J `Oe~ aS~ tll bO
O O ~ r~ ~ ~)L ~
0 C~ 0 0 ~ ~) _ O~rl~ ~ S
e ~ ~ ~a) ~ ~ o - r-t ~
~rl r-l SbOrl O L nl Z 3 8 ~rl (~ .5~ r1 O O La) ~) r-l ~1 3 L C~ O L
~-:>~ :~ L ~; r-l L
o a) ~In ~ :~ o N r-l O a~J~ ~ S ~ ~I
~: Dr l~(n ~) U~ (, a> 0 0rd D
D ~ ~I E D ~3 m ~
~t I O~rtun ~ m ~rl r_l a) r-t ~ L r-t r-l 0 O ~.:~ bOr-l O ~ ~ O a) C a) bO ~rl a) 1~ ttl L
~rt a)~1 S (~ E 3 r1 S D
,~ ~ ,1 L L ~ ~ ~ a) r1 ~1 ; ~U~ ~ O L ~ O
` 1127ti55 - 5 - O.Z. 0050/033447 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 National Cancer Institute 60 (1978), 1035-1041. The compounds also inhibit the proliferation of spontaneously chemically or virally transformed cells in tissue culture, the preferred culture being S 91 melanoma cells.
The compounds of the formula I, according to the ¦ invention, are prepared in the conventional manner by reacting all-E-retinylamine with a reactive deri~ative of benzoic acid or of p-toluic acid. Suitable re~ctive acid derivatives are esters, anhydrides and, preferably, acid halides, especially the acid chlorides. The re-action is advantageously carried out in the presence of a base, especially a tertiary amine, preferably pyridine, in an inert solvent, such as a dialkyl ether or chlorohydrocarbon,preferably in diethyl ether or methylene chloride. Advantageously, it is carried out in the absence of oxygen and moisture, for example under nitro-gen as a blanketing gas.
The end products are worked up in the convention-al manner, The starting compound, all-E-retinylamine, can be prepared according to F. Kienzle (loc. cit ) from all-E-retinol via all-E-retinyl-phthalimide. A
further advantageous method of synthesis of N-retinyl-phthalimide is the Wittig olefinization of the known Cl5-phosphonium salt II with 2-methyl-4-phthalimido-but-2-en-l-al III.
E~;
11;~765S
- 6 - O.Z. 0050/033447 N ~ III
II Wittig olefinization ; r isomerization H2H-~, CH30H
. ' 1 X~
F~ .
The present invention also embraces the prepara-tion of therapeutic agents or formu~ations which are obtained in the conventi.onal manner, in parti-cular by mixing a dose of the active compGund approp-riate for the particular application with conventional carriers or diluents, with or without conventional pharmaceutical excipients, in accordance with the desired route of administration~
l~Z~655 - 7 - O.Z. 0050/033447 For topical application the therapeutic formula-tions contain the compounds, to be used according to the invention, at a concentration of from 0.001 to 1.0%, pre-ferably from 0.01 to 0.1%, whilst for systemic administra-tion a single dose is pre~erably from 0.1 to 5 mg Suit-able daily dosages are from 50 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, ~owders, gran-ules, solutions or suspensions For external use, suitable forms are in particular pastes, ointments,je1lies, creams, lotions, powders, sol1tions or ernulsions and sprays.
~he drugs according to the invention may be employed either internally or externally. Preferably, they are adminis-tered orally or applied topically.
Examples of conventional pharmaceutical auxili-ariesfortopical application are alcohols, eg. isoPropanol, oxyethylated castor oil or oxyethylated hydrogenated castor oil, polyacrylic acid, glycerol monostearate, paraffin oil, vaseline, wool grease, polyethylene glycol 400, polyethylene glycol 400 stearate and oxyethylated fatty alcohols, whilst examples for systemic administra-tion are lactose, sucrose, propylene glycol, ethanol, ~1~7655 - 8 ~ O.Z. 0050/033447 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 formulations should be non-toxic and compatible with the active compounds employed (cf. L.G. Goodman and A. Gilman, The Pharmaco-logical Basis of Therapeutics).
N-(E-3-Formyl-but-2-en-1-yl)-phthali,mide:
210 parts by weight of 4-chloro-2-methyl-but-2-enal-diethylacetal are added dropwise to a solution of 343.2 parts by weight of,ethyl orthoformate in 151 parts by weight of ethanol. The solution is stirred for 1 hour at 40C and is concentrated on a rotary evaporator at 16 mm Hg/40C. 400 parts by weight of dimethylformamide and 300 parts by weight of potassium phthalimide are added, and the mixture is heated for 1 hour at 120C)C and filtered after it has cooled. The fil-trate is concentrated on a rotary evaporator at 50C ~nder2 mm Hg and the residue is taken up in 1,500 parts by volume of diisopropyl ether and 200 parts by volume of ethanol. At about 0C, 172 parts by wei.ght of N-(E-
4,4-diethoxy-3-methyl-but-2-en-1-yl)-phthalimide crystallize out overnight and are filtered off and dried in a stream of nitrogen. The crystals are then taken up in 1,500 parts by volume of 80% strength aqueous methanol, about 8 parts by volume of concentrated ~12~655 _ ~ _ O.Z. 0050/033447 sulfuric acid are added (resulting in pH 2) and the mix-ture is stirred for 30 minutes at 50C. It is then worked up in the conventional manner by partition between methylene chloride and water, and recrystallization of the residue from diisopropyl ketone gives 102 parts by weight of N-(E-3-formyl-but-2-en-1-yl)-phthalimide, melting point 112C.
N-all-E-Retinyl-phthalimide:
142.6 parts by weight of N-(E-3-formylbut-2-en-l-yl)-phthalimide are added to 1,1~0 parts by volume of a 30% strength by weight solution of ~-ionylidene-ethyl~
triphenyl-phosphonium bisulfate in dimethylformamide, and ammonia is passed into the mixture at -20C until saturation is reached. The mixture is allowed to come to about 25C, 1,500 parts by volume of n~hexane are added and the batch is washed with three times 650 parts by volume of 60% strength aqueous methanol. The n-hexane solution is concentrated to about 700 parts by volume. After it has cooled in an ice bath, 115 parts by weight of N-all-E-retinyl-phthalimide precipi-tate as crystals of melting point 103.5C. A further 88 parts by weight can be obtained, after isomerization, from the mother liquor.
N-Benzoyl-all-E-retinylamine:
16.8 parts by weight of N-all-E-retinyl-phthali-mide and 6.2 parts by volume of hydrazine hydrate are dissolved in 234 parts by volume of methanol, the solu-;:
11;~76i~5~10 _ O.Z. 0050J033447 tion is refluxed for 2 hours, and 78 parts by volume of 2 N hydrochloric acid are subsequently added at 0C
The phthalic acid hydrazide whichhas precipitated is fil-tered off, 1,500 parts by volume of water are added to the filtrate, the mixture is extracted twice with 250 parts by volume of ether, and 80 parts by volume of con-centrated ammonia are then added to the aqueous phase.
The resulting aqueous alkali phase is extracted with four times 250 parts by volume of ether. Convention-al working up of the ether phase gives 11 parts byweight of crude all-E-retinylamine as a red oil.
The crude retinylamine is dissolved in 50 parts by volume of pyridine at -20C and 5 parts by weight of benzoyl chloride are added dropwise. The mixture is allowed to come to 20C, 80 parts by weight of ice are added, and the batch is extracted with five times 80 parts by volume of methylene chloride. Conventional working up gives 16.8 parts by weight of a red viscous oil which is taken up in 50 parts by volume of diiso-propyl ether, 5,5 parts by welght of N-benzoyl-all-E-retinylamine, melting point 105.5C, crystallize at -10C. The mother liquor is concentrated (11 parts by weight) and chromatographed over 300 parts by weight of silica gel The fractions which are pure accord-ing to analysis by thin layer chromatography are crystallized from ~5 parts by volume of diisopropyl ether, to give a further 3 ~ parts by weight of pure product; melting point 104C.
~lZ~6SS
~ O.Z. 0050/033447 Following instructions similar to those in Example 3, with p-toluyl chloride as the starting material, N-p-toluyl-all-E-retinylamine, melting point ll9.5C, is obtained.
Examples of suitable pharmaceutical formulations or drug compositions for external application are the following:
Solution N-Benzoyl-all-E-retinylamine 0.25 g oxyethylate~ hydrogenated castor oil35.0 g (Cremophor RH 40, from ~ASF AG, Ludwigshafen) Polyethylene glycol 400 35.0 g oxyethylated castor oil (Softigen 767,lO.0 g from Chemische Wer:~e ~tten) deionized water to give lO0.0 g The Cremophor r~H 40 and Softiger. 767 are mixed and the mixture is heated to 70C, The active com-pound is dissol~ed therein whilst stirring and the poly-ethylene glycol 400 i5 added, The solution is then cooled to 40C and water at 40C is added slowly, whilst stirring. The fin.ished solution .is filtered and packaged in, for example, lO0 ml flask.s.
Cream N-p-Toluyl-all-E-retinylamine O.l g butylhydroxytoluene O.l g glycerol monostearate ll.0 g polyethylene glycol 400 stearate 6.o g 2-~ 55 -12 ~ O.Z. 0050/033447 oxyethylated fatty alcohol 4.0 g paraffin oil lO.0 g p-hydroxybenzoic acid ester (Nipasteril, from Nipalaboratorium Hamburg) 0.2 g perfume oil O.l g deionized water to gi~e lO0.0 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 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 ~emperature, whilst stirring. The finished cream is packaged in tubes carrying an internal protective coating.
EXA~LE 3 Jelly N-Benzoyl~all-E-retlnylamine O.Ol g butylhydroxytoluene O.l g oxyethylated castor oil (Cremophor EL, from BASF AG, Ludwigshafen) 35.0 g isopropanol , 20.0 g polyacrylic acid (Carbopol, from Goodrich Hamburg) l,5 g triethanolamine 0.002 g p-hydroxybenzoic acid ester (Nipasteril, from Nipalaboratorium Hamburg) 0,2 g deionized water to give lO0.0 g The Cremophor EL is heated to 60C, the active I r~lerr a Y ~
- llZ76SS
- 13 - O.Z. 0050/033447 compound and the butylhydroxytoluene are dissolved therein, whilst stirring, and the isopropanol, in which the Nipaesters have 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, to 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:
~XAMPLE 4 Drops N-Benzoyl-all-E-retinylamine 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 ~5C and stirring After filtration, the solution is packaged in dark-colored drop bottles.
Hard gelatin capsules N-p-Toluyl-all-E-retinylamine 1 mg lactose 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 ~ ' ~r~enl~ y k
N-all-E-Retinyl-phthalimide:
142.6 parts by weight of N-(E-3-formylbut-2-en-l-yl)-phthalimide are added to 1,1~0 parts by volume of a 30% strength by weight solution of ~-ionylidene-ethyl~
triphenyl-phosphonium bisulfate in dimethylformamide, and ammonia is passed into the mixture at -20C until saturation is reached. The mixture is allowed to come to about 25C, 1,500 parts by volume of n~hexane are added and the batch is washed with three times 650 parts by volume of 60% strength aqueous methanol. The n-hexane solution is concentrated to about 700 parts by volume. After it has cooled in an ice bath, 115 parts by weight of N-all-E-retinyl-phthalimide precipi-tate as crystals of melting point 103.5C. A further 88 parts by weight can be obtained, after isomerization, from the mother liquor.
N-Benzoyl-all-E-retinylamine:
16.8 parts by weight of N-all-E-retinyl-phthali-mide and 6.2 parts by volume of hydrazine hydrate are dissolved in 234 parts by volume of methanol, the solu-;:
11;~76i~5~10 _ O.Z. 0050J033447 tion is refluxed for 2 hours, and 78 parts by volume of 2 N hydrochloric acid are subsequently added at 0C
The phthalic acid hydrazide whichhas precipitated is fil-tered off, 1,500 parts by volume of water are added to the filtrate, the mixture is extracted twice with 250 parts by volume of ether, and 80 parts by volume of con-centrated ammonia are then added to the aqueous phase.
The resulting aqueous alkali phase is extracted with four times 250 parts by volume of ether. Convention-al working up of the ether phase gives 11 parts byweight of crude all-E-retinylamine as a red oil.
The crude retinylamine is dissolved in 50 parts by volume of pyridine at -20C and 5 parts by weight of benzoyl chloride are added dropwise. The mixture is allowed to come to 20C, 80 parts by weight of ice are added, and the batch is extracted with five times 80 parts by volume of methylene chloride. Conventional working up gives 16.8 parts by weight of a red viscous oil which is taken up in 50 parts by volume of diiso-propyl ether, 5,5 parts by welght of N-benzoyl-all-E-retinylamine, melting point 105.5C, crystallize at -10C. The mother liquor is concentrated (11 parts by weight) and chromatographed over 300 parts by weight of silica gel The fractions which are pure accord-ing to analysis by thin layer chromatography are crystallized from ~5 parts by volume of diisopropyl ether, to give a further 3 ~ parts by weight of pure product; melting point 104C.
~lZ~6SS
~ O.Z. 0050/033447 Following instructions similar to those in Example 3, with p-toluyl chloride as the starting material, N-p-toluyl-all-E-retinylamine, melting point ll9.5C, is obtained.
Examples of suitable pharmaceutical formulations or drug compositions for external application are the following:
Solution N-Benzoyl-all-E-retinylamine 0.25 g oxyethylate~ hydrogenated castor oil35.0 g (Cremophor RH 40, from ~ASF AG, Ludwigshafen) Polyethylene glycol 400 35.0 g oxyethylated castor oil (Softigen 767,lO.0 g from Chemische Wer:~e ~tten) deionized water to give lO0.0 g The Cremophor r~H 40 and Softiger. 767 are mixed and the mixture is heated to 70C, The active com-pound is dissol~ed therein whilst stirring and the poly-ethylene glycol 400 i5 added, The solution is then cooled to 40C and water at 40C is added slowly, whilst stirring. The fin.ished solution .is filtered and packaged in, for example, lO0 ml flask.s.
Cream N-p-Toluyl-all-E-retinylamine O.l g butylhydroxytoluene O.l g glycerol monostearate ll.0 g polyethylene glycol 400 stearate 6.o g 2-~ 55 -12 ~ O.Z. 0050/033447 oxyethylated fatty alcohol 4.0 g paraffin oil lO.0 g p-hydroxybenzoic acid ester (Nipasteril, from Nipalaboratorium Hamburg) 0.2 g perfume oil O.l g deionized water to gi~e lO0.0 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 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 ~emperature, whilst stirring. The finished cream is packaged in tubes carrying an internal protective coating.
EXA~LE 3 Jelly N-Benzoyl~all-E-retlnylamine O.Ol g butylhydroxytoluene O.l g oxyethylated castor oil (Cremophor EL, from BASF AG, Ludwigshafen) 35.0 g isopropanol , 20.0 g polyacrylic acid (Carbopol, from Goodrich Hamburg) l,5 g triethanolamine 0.002 g p-hydroxybenzoic acid ester (Nipasteril, from Nipalaboratorium Hamburg) 0,2 g deionized water to give lO0.0 g The Cremophor EL is heated to 60C, the active I r~lerr a Y ~
- llZ76SS
- 13 - O.Z. 0050/033447 compound and the butylhydroxytoluene are dissolved therein, whilst stirring, and the isopropanol, in which the Nipaesters have 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, to 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:
~XAMPLE 4 Drops N-Benzoyl-all-E-retinylamine 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 ~5C and stirring After filtration, the solution is packaged in dark-colored drop bottles.
Hard gelatin capsules N-p-Toluyl-all-E-retinylamine 1 mg lactose 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 ~ ' ~r~enl~ y k
Claims (10)
1. A process for the preparation of a benzoyl-retiny-lamine of the formula I
wherein R is hydrogen or methyl, characterized in that all-E-retinylamine is reacted with a reactive derivative of benzoic acid or p-toluic acid to obtain a compound of formula I as defined above.
wherein R is hydrogen or methyl, characterized in that all-E-retinylamine is reacted with a reactive derivative of benzoic acid or p-toluic acid to obtain a compound of formula I as defined above.
2. A benzoyl-retinylamine of the formula I
wherein R is hydrogen or methyl whenever prepared by a process as claimed in claim 1 or an obvious chemical equivalent thereof.
wherein R is hydrogen or methyl whenever prepared by a process as claimed in claim 1 or an obvious chemical equivalent thereof.
3. A process for the preparation of benzoyl-retinylamine of the formula I' characterized in that a reactive derivative of benzoic acid is reacted with all-E-retinylamine to obtain the compound of formula I'.
4. A process as claimed in claim 3, characterized in that the reactive derivative of benzoic acid is benzoyl chloride.
5. Benzoyl-retinylamine of the formula I' I' whenever prepared by a process as claimed in claim 3 or an obvious chemical equivalent thereof.
6. Benzoyl-retinylamine of the formula I' I' whenever prepared by a process as claimed in claim 4 or an obvious chemical equivalent thereof.
7. A process for the preparation of benzoyl-retiny-lamine of the formula I"
I"
characterized in that a reactive derivative of p-toluic acid is reacted with all-E-retinylamine to obtain the compound of formula I" .
I"
characterized in that a reactive derivative of p-toluic acid is reacted with all-E-retinylamine to obtain the compound of formula I" .
8. A process as claimed in claim 7, characterized in that the reactive derivative of p-toluic acid is p-toluyl chloride.
9. Benzoyl-retinylamine of the formula I"
I"
whenever prepared by a process as claimed in claim 7 or an obvious chemical equivalent thereof.
I"
whenever prepared by a process as claimed in claim 7 or an obvious chemical equivalent thereof.
10. Benzoyl-retinylamine of the formula I"
I"
whenever prepared by a process as claimed in claim 8 or an obvious chemical equivalent thereof.
I"
whenever prepared by a process as claimed in claim 8 or an obvious chemical equivalent thereof.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE19782843915 DE2843915A1 (en) | 1978-10-07 | 1978-10-07 | N-BENZOYL RETINYLAMINE |
DEP2843915.8 | 1978-10-07 |
Publications (1)
Publication Number | Publication Date |
---|---|
CA1127655A true CA1127655A (en) | 1982-07-13 |
Family
ID=6051730
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA336,669A Expired CA1127655A (en) | 1978-10-07 | 1979-09-28 | N-benzoyl-retinylamines, their preparation and pharmaceutical formulations containing these compounds |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP0010209B1 (en) |
JP (1) | JPS5551060A (en) |
AT (1) | ATE582T1 (en) |
CA (1) | CA1127655A (en) |
DE (2) | DE2843915A1 (en) |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CH529742A (en) * | 1970-02-02 | 1972-10-31 | Hoffmann La Roche | Process for the production of vitamin A acid amides |
FR2138211B1 (en) * | 1971-05-19 | 1973-05-11 | Rhone Poulenc Sa | |
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 |
-
1978
- 1978-10-07 DE DE19782843915 patent/DE2843915A1/en active Pending
-
1979
- 1979-09-28 AT AT79103683T patent/ATE582T1/en active
- 1979-09-28 EP EP79103683A patent/EP0010209B1/en not_active Expired
- 1979-09-28 CA CA336,669A patent/CA1127655A/en not_active Expired
- 1979-09-28 DE DE7979103683T patent/DE2961892D1/en not_active Expired
- 1979-10-05 JP JP12811479A patent/JPS5551060A/en active Pending
Also Published As
Publication number | Publication date |
---|---|
DE2843915A1 (en) | 1980-04-24 |
ATE582T1 (en) | 1982-02-15 |
JPS5551060A (en) | 1980-04-14 |
DE2961892D1 (en) | 1982-03-04 |
EP0010209B1 (en) | 1982-01-20 |
EP0010209A1 (en) | 1980-04-30 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
DK172070B1 (en) | Benzonaphthalene derivatives, processes for their preparation and use, and their pharmaceutical and cosmetic preparations | |
USRE39706E1 (en) | Crystalline form of a vitamin D analogue | |
EP0667330B1 (en) | Cyclohexanol derivative, agent and composition containing the same for imparting pleasantly cool feeling, process for producing the derivative, and intermediate therefor | |
DE3851262T2 (en) | Benzoylaminophenoxybutyric acid derivatives. | |
CA1294971C (en) | Benzofurannic derivatives, process for preparing such and medicated compoundsand cosmetics containing said derivatives | |
BE1001203A3 (en) | COMPOSITION BASED ON DERIVATIVES hydroxypyridone TO REDUCE HAIR LOSS. | |
JP2634394B2 (en) | Method for producing 5,8,11-eicosatriic acid | |
FI96201C (en) | Process for preparing new therapeutically useful retinoid | |
GB1603904A (en) | Hydroxyurea derivatives | |
DE68902772T2 (en) | SULFURED EICOSANOIDS AND THEIR USE IN MEDICINAL PRODUCTS AND COSMETICS. | |
BE898315A (en) | Anti-acne composition containing as active compound an isothiazolo-(5,4b)pyridine one-3 derivative. | |
CH674930A5 (en) | ||
CA1127170A (en) | Retinic acid n-(carboxy)-phenylamides and 7,8-dehydro-retinic acid n-(carboxy)-phenylamides, their preparation and pharmaceutical formulations containing these compounds | |
SE500215C2 (en) | New aromatic naphthyl compounds, their preparation and their use in human and veterinary medicine and in cosmetics | |
US4512985A (en) | N-carbamoyl derivatives of (5,4b)-isothiazolo pyridine-3-one and anti-acne cosmetic compositions containing the same | |
CA1127655A (en) | N-benzoyl-retinylamines, their preparation and pharmaceutical formulations containing these compounds | |
CA1143657A (en) | Pharmaceutical agent containing all-e- or 13-z-7,8-dehydroretinic acid, processes for its preparation, and its use | |
US4755530A (en) | 1-hydroxy-8-acyloxy-10-acyl anthrones, process for their preparation and their use in human or veterinary medicines and in cosmetic formulations | |
EP0008665B1 (en) | Furyl-nonatetraene derivatives and the pharmaceutically acceptable salts thereof, processes for their preparation, starting compounds used in these processes, and pharmaceutical compositions containing them | |
EP0009776B1 (en) | N-monohydroxypropylamides, n-dihydroxypropylamides and their acetonoides of all-e and 13-z retinoic acid, process for their preparation and pharmaceutical compositions containing them | |
JP2554683B2 (en) | Eicosatetrainamide compound, method for producing the same, and pharmaceutical / cosmetic composition | |
CA2110336A1 (en) | Nonatetraenoic acid derivative | |
US4810694A (en) | Benzonorbornene derivatives process, for their preparation and medicinal and cosmetic compositions comprised thereof | |
EP0427625B1 (en) | Internal salts of 2,4-diamino-6-alkoxy-3-sulphooxypyrmidium hydroxide and their use in the treatment and prevention of hair-loss | |
SU1731043A3 (en) | Process for preparing ethyl-p-[(e)-2-(6,7,8,9-tetrahydro-7,7-dimethyl-5h- benzocyclohepten -2-yl)propenyl]benzoate |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
MKEX | Expiry |