Claims
- 1. A process for the treatment of a dermatologic, rheumatismal, respiratory or ophtalmologic disease comprising administering to a person suffering from said disease an effective amount of a composition containing, in a pharmaceutically acceptable vehicle, as the active ingredient thereof a benzonaphthalene compound of the formula ##STR11## wherein R.sub.1 represents ##STR12## or (ii)--CH.sub.2 OH, R.sub.6 represents ##STR13## or OR.sub.7 wherein R.sub.7 represents hydrogen, alkyl having 1-20 carbon atoms, monohydroxyalkyl or polyhydroxyalkyl, r' and r" represent hydrogen, lower alkyl, mono or polyhydroxyalkyl aryl or a residue of an amino acid, glucosamine, galactosamine or mannosamine, or together form a heterocycle selected from the group consisting of piperidino, piperazino, morpholino and pyrrolidino,
- R.sub.2 represents hydrogen, branched or straight chain alkyl having 1-15 carbon atoms, alkoxy having 1-4 carbon atoms or a cycloaliphatic radical,
- R.sub.3 represents hydrogen, hydroxy, branched or straight chain alkyl having 1-4 carbon atoms, alkoxy having 1-10 carbon atoms, a cycloaliphatic radical selected from the group consisting of 1- methylcyclohexyl and 1-adamantyl, a thiocycloaliphatic radical, or --O--Si(CH.sub.3).sub.2 --R.sub.8 wherein R.sub.8 represents linear or branched alkyl,
- R.sub.4 and R.sub.5 each independently represent hydrogen, lower alkyl.Iadd., hydroxy .Iaddend.or lower acyloxy. or salt thereof.
- 2. A cosmetic composition for both and hair hygiene comprising a cosmetically acceptable vehicle and an effective amount of as the active ingredient at least one benzonaphthalene compound of the formula ##STR14## wherein R.sub.1 represents ##STR15## or (ii) --CH.sub.2 OH, R.sub.6 represents ##STR16## OR.sub.7 wherein R.sub.7 represents hydrogen, alkyl having 1-20 carbon atoms, monohydroxyalkyl or polyhydroxyalkyl, r' and r" represent hydrogen, lower alkyl, mono or polyhydroxyalkyl, aryl or a residue of an amino acid, glucosamine, galactosamine or mannosamine, or together form a heterocycle selected from the group consisting of piperidino, piperazino, morpholino and pyrrolidino,
- R.sub.2 represents hydrogen, branched or straight chain alkyl having 1-15 carbon atoms, alkoxy having 1-4 carbon atoms or a cycloaliphatic radical.
- R.sub.3 represents hydrogen, hydroxy, branched or straight chain alkyl having 1-4 carbon atoms, alkoxy having 1-10 carbon atoms, a cycloaliphatic radical selected from the group consisting of 1-methylcyclohexyl and 1- adamantyl, a thiocycloaliphatic radical, or --O--Si(CH.sub.3).sub.2--R.sub.8 wherein R.sub.8 represents linear or branches alkyl,
- R.sub.4 and R.sub.5 each independently represent hydrogen, lower alkyl.Iadd., hydroxy .Iaddend.or lower acyloxy, or a salt thereof.
- 3. The cosmetic composition of claim 2 wherein said active ingredient is present in an amount ranging from 0.0005 to 2 weight percent based on the total weight of said composition.
- 4. The cosmetic composition of claim 2 wherein said active ingredient is present in an amount ranging from 0.01 to 1 weight percent based on the total weight of said composition.
Priority Claims (1)
| Number |
Date |
Country |
Kind |
| 85849 |
Apr 1985 |
LUX |
|
Parent Case Info
This is a division of application Ser. No. 07/120,958, filed Nov. 16, 1987, now U.S. Pat. No. 4,940,696, which is a division of Ser. No. 06/850,145, filed Apr. 10, 1986, now U.S. Pat. No. 4,717,720.
The present invention relates to benzonaphthalene derivatives, to a process for preparing them and to their use in therapeutic and cosmetic compositions.
These new benzonaphthalene derivatives are usefully employed in the topical and systemic treatment of dermatological diseases linked to keratinization disorders (differentiation--proliferation) and dermatological diseases, or others, with inflammator and/or immunoallergic components and in the treatment of diseases attributable to the degeneration of conjuctive tissue, The benzonophthalene derivatives of the present invention also exhibit anti-tumor activity. Moreover, these derivatives can be employed in the treatment of atopy be it cutaneous or respiratory.
The benzonaphthalene derivatives of the present invention are also usefully employed in the field of ophthalmology and principally in the treatment of corneopathies.
A number of compounds have already been proposed for the various treatments noted above and principally compounds known under the designation of "retinoids" of which the most well-known ones are the trans and cis retonic acids (tretinoin and isotretinoin) and etretinate.
Compared to these known compounds, the benzonaphthalene derivatives according to the present invention exhibit a strong activity and better stability to light and to oxygen of the air.
The benzonaphthane derivatives of the present invention can be represented by the following formula: ##STR4## wherein
R.sub.1 represents; ##STR5## or (ii) --CH.sub.2 OH,
R.sub.6 represents ##STR6## or --OR.sub.7 represents hydrogen, alkyl having 1-20 carbon atoms, monohydroxyalkyl or polyhydroxyalkyl, r' and r" represent hydrogen, lower alkyl, mono- or polyhydroxyalkyl, aryl optionally substituted or a residue of an amino acid or aminated sugar or r' and R" taken together form a heterocycle.
R.sub.2 represents hydrogen, branched or straight chain alkyl having 1.carbon atoms, alkoxy having 1-4 carbon atoms or a cycoaliphatic group,
R.sub.3 represents hydrogen, hydroxy, straight or branched chain alkyl having 1-4 carbon atoms, alkoxy having 1-10 carbon atoms, a cycloaliphatic group substituted or not, a thio-cycloaliphatic group of the formula --O--Si(CH.sub.3).sub.2 --R.sub.8 wherein R.sub.8 represents linear or branched lower alkyl.
R.sub.4 and R.sub.5 each independently represent hydrogen, lower alkyl, hydroxy or a lower acyloxy group, and the salts of the said benzonaphthalene derivatives of Formula I.
By the expression "lower alkyl" is meant alkyl radicals having from 1-6 carbon atoms and principally methyl, ethyl, isopropyl, butyl and tert.butyl.
The term "alkoxy" is intended to include radicals having 1-10 carbon atoms and principally methoxy, ethoxy, isopropoxy, hexyloxy and decyloxy radicals.
By the expression "lower acyloxy"is meant radicals having 1-4 carbon atoms and principally acetyloxy and propionyloxy radicals.
By the term "monohydroxyalkyl" is meant a monohydroxy substituted radical having 2 or 3 carbon atoms, principally, 2-hydroxy ethyl and 2- hydroxypropyl.
Representative residues of aminated sugars include those derived from glucosamine, galactosamine and mannosamine.
By the terms "polyhydroxyalkyl" is meant an alkyl radical having 3-6 carbon atoms substituted 2-5 hydroxyl groups, such as 2,3-dihydroxy propyl, 1,3-dihydroxy propyl, or the residue of pentaerythritol.
The term "cycloaliphatic" is meant to include a mono or polycyclic radical such as, for example, 1-methyl cyclohexyl or 1-adamantyl.
The preferred thiocycloaliphatic radical is, principally, 1-adamantylthio.
r' and r" together form a heterocycle, it is preferably a piperidino, piperazino, morphilino or pyrrolidino radical.
The preferred compounds of Formula I are more particularly those having the following formula: ##STR7## wherein
R'.sub.6 represents ##STR8## or --OR'.sub.7,
r' and r" each independently represent hydrogen or lower alkyl, or r' and r" taken together form a morpholino radical,
R'.sub.7 represents hydrogen or lower alkyl,
R'.sub.2 represents hydrogen, alkyl, alkoxy or 1 -adamantyl, and
R'.sub.3 represent hydrogen, hydroxy, alkyl, alkoxy or 1 -adamantylthio.
Representative compounds of the present invention include:
The present invention also relates to a process for preparing the compounds of Formula I.
According to this process the compounds of Formula I are obtained by a coupling reaction between a halogenated compound of Formula III and a halogenated derivative of naphthalene of Formula IV: ##STR9## wherein
R.sub.1 to R.sub.5 have the same meanings as those given above for Formula I and
X and Y represent Cl, Br, F or I.
According to this coupling reaction, the halogenated compound of Formula III is transformed into its magnesium, lithium or zinc form in accordance with methods described in the literature and is coupled with the halogenated naphthalene derivative of Formula IV by employing, as a reaction catalyst, a transition metal or one of its complexes.
Particularly preferred catalysts are those derived from nickel or palladium and more particularly the compounds of NiII (NiCl.sub.2) with various phosphines.
The coupling reaction is generally carried out at a temperature between -20.degree. and +30.degree. C. in an anhydrous solvent such as, for example, dimethylformamide or tetrahydrofuran.
The resulting product can be purified by recrystallization or silica column chromatography.
Obviously, the choice of the halogenated naphthalene derivative of Formula IV, for use in the coupling reaction with the halogenated compound of Formula III, must be such that it can lead, by subsequent reaction, to the various meanings of the R.sub.1 radical given above.
When the compounds according to the present invention are provided in salt form, it is a question of salts of an alkali or alkaline earth metal or of an organic amine when the compounds have at least one free acid function.
The present invention also relates to a medicinal composition comprising as the active principle thereof the compounds of Formula I as defined above.
These compounds exhibit excellent activity in the test for inhibiting ornithine decarboxylase after induction, by "tape stripping" the body of a nude rat. This test is considered a measure of the activity of the retinoids with regard to cellular proliferation phenomenon.
For instance, it has been noted that in this test, 6-[3(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid exhibits an effective dose between 5 and 22 nmoles applied per cm.sup.2.
The compounds according to the invention also exhibit a strong activity in the differentiation test of embryonic tetracarcinoma F9 rat cells (Cancer Research 43, page 5268, 1983).
As an illustration, 6-[3-(1-adamantyl)-4-methoxyphenyl]2-naphthoic acid, at a 0.01 micromolar concentration induces the differentiation of F9 carcinoma cells in endoderm cells. 6-(3-tert.butyl phenyl)-2-naphthoic acid acts in the same fashion at a concentration of 1 micromolar.
Moreover, the irritation test carried out on a rabbit has shown that the compounds of Formula I are less irritating than known retinoids of analogous structure. Moreover, their acute toxicity is weaker.
The compounds of the present invention are indeed particularly suitable for the treatment of dermatological diseases linked to a keratinization disorder (differentiation, proliferation), as well as dermatological diseases or others with inflammatory and/or immunoallergic components such as principally:
acne vulgaris, comedons or polymorphs, solar acne seniles and medicamental or professional acne;
extensive and/or severe forms of psoriasis, and other keratinization disorders, and principally ichtyosis and ichtyosiform states;
Darier disease;
palmo-plantary keratodermy;
leucplasies and leucoplasiform states, lichen plan;
all dermatological proliferations, benign or malignant, severe or extended.
They are also active for certain rheumatic diseases principally psoriasic rheumatism, for cutaneous or respiratory atopies, as well as for certain ophthalmologic disorders relative to the corneopathies.
The present invention also relates to medicinal compositions containing at least one compound of Formula I, as defined above and/or a salt thereof.
The present invention thus relates to a new medicinal composition, intended principally for the treatment of the above-mentioned diseases, comprising in a pharmaceutically acceptable support, at least one compound of Formula I and/or a salt thereof.
As has been indicated previously, the benzonaphthalene derivatives according to the present invention, relative to known retinoids, exhibit better stability against light and oxygen, this being essentially due to the fact that they do not possess any easily isimerized double bonds.
The compounds according to the present invention are generally administered at a daily dosage of about 2 .mu.g/kg to 2 mg/kg of body weight.
As vehicles or supports of these compositions, there can be employed any conventional support, the active compound being found either in the dissolved state or in the dispersed state in the vehicle or support.
The composition can be administered enterally, parenterally, topically or ocularly. When administered enterally, the medicinal composition can be provided in the form of tablets, gelules, lozenges, syrups, suspension, solutions, powders, granules or emulsions. When administered parenterally the medicinal composition can be provided in the form of solutions or suspensions for perfusion or injection.
When administered topically, the pharmaceutical compositions based on the compounds in accordance with the present invention can be provided in the form of ointments, tinctures, creams, pomrades, powders, impregnated pads, buffers, solutions, lotions, gels, sprays or even suspensions.
These compositions for topical application or administration can be provided either under anhydrous form, or in aqueous form according to clinical indications. When administered ocularly, the compositions are principally eyewashes.
The topical or ocular composition contains preferably between 0.0005 and 5 weight percent of the active compound based on the total weight of the composition.
The compounds of Formula I, according to the present invention also find use in the cosmetic field, in particular in body and hair hygiene and principally for acne, hairgrowth, preventing hair fallout, to combat against the oily appearance of the skin or hair, in the protection against harmful effects of the sun or in the treatment of physiologically dry skin.
The present invention then also envisages a cosmetic composition containing in a cosmetically acceptable support at least one compound of Formula I and/or a salt thereof, this composition being provided principally in the form of a lotion, gel, soap or shampoo.
The concentration of the compound(s) of Formula I in the cosmetic compositions is between 0.0005 and 2 weight percent, preferably between 0.01 and 1 weight percent, based on the total weight of the composition.
The medicinal and cosmetic compositions according to the present invention can contain inert or even pharmacodynamic or cosmetically active ad3uvants and principally: hydrating agents such as thiamorpholinone and its derivatives or urea; antiserbottheic agents such as S-carboxymethylcysteine, S-benzyl cysteamine and their derivatives, or tioxolone; antibiotics such as erythromycin, neomycin or the tetracyclines; agents favoring hair growth such as "Minoxidil" (2,4-diamino-6-piperdinopyrimidine-3-oxide) and its derivatives, Diazoxide and Phenytoin; steroidal anti-inflammatory agents; carotenoids and principally .beta.-carotene; and antipsoriasic agents such as anthralin and its derivatives, 5,8,11,14-eicosatetrainoic acid and 5,8,11-triynoic acid.
The compositions according to the present invention can also contain flavor improving agent, preservatives, stabilizers, humidity regulating agents, pH regulating agents, osmotic pressure modifying agents, emulsifiers, UV-A and UV-B filters and antioxidants such as .alpha.-tocopherol, butylhydroxy anisole or butylhydroxy toluene.
The following non-limiting examples illustrate several examples for the preparation of the active compounds of Formula I according to the present invention, as well as examples of compositions containing these active compounds.
US Referenced Citations (1)
| Number |
Name |
Date |
Kind |
| 4940696 |
Shroot et al. |
Jul 1990 |
|
Divisions (2)
|
Number |
Date |
Country |
| Parent |
120958 |
Nov 1987 |
|
| Parent |
850145 |
Apr 1986 |
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Reissues (1)
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Number |
Date |
Country |
| Parent |
502122 |
Mar 1990 |
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Patent Grant
RE34440
