AU650972B2 - Aromatic compounds derived from imine, their preparation and their use in human and veterinary medicine and in cosmetics - Google Patents
Aromatic compounds derived from imine, their preparation and their use in human and veterinary medicine and in cosmetics Download PDFInfo
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- C07C327/00—Thiocarboxylic acids
- C07C327/58—Derivatives of thiocarboxylic acids, the doubly-bound oxygen atoms being replaced by nitrogen atoms, e.g. imino-thio ethers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/136—Amines having aromatic rings, e.g. ketamine, nortriptyline having the amino group directly attached to the aromatic ring, e.g. benzeneamine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
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- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
- A61K31/24—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group having an amino or nitro group
- A61K31/245—Amino benzoic acid types, e.g. procaine, novocaine
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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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- A61P17/00—Drugs for dermatological disorders
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
- C07C251/02—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton containing imino groups
- C07C251/24—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton containing imino groups having carbon atoms of imino groups bound to carbon atoms of six-membered aromatic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C257/00—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines
- C07C257/04—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines without replacement of the other oxygen atom of the carboxyl group, e.g. imino-ethers
- C07C257/08—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines without replacement of the other oxygen atom of the carboxyl group, e.g. imino-ethers having carbon atoms of imino-carboxyl groups bound to carbon atoms of six-membered aromatic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C257/00—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines
- C07C257/10—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines
- C07C257/18—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines having carbon atoms of amidino groups bound to carbon atoms of six-membered aromatic rings
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- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/04—One of the condensed rings being a six-membered aromatic ring
- C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/56—Ring systems containing bridged rings
- C07C2603/58—Ring systems containing bridged rings containing three rings
- C07C2603/70—Ring systems containing bridged rings containing three rings containing only six-membered rings
- C07C2603/74—Adamantanes
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Abstract
Diaromatic compounds corresponding to the following general formula: <IMAGE> in which: R1 is H, OH, -CH3, -CH2OH, -COR7, -CH(OH)CH3, -CH2OCOR8, and the like, R7 is H, OH, -OR10, N(r'r"), lower alkyl, and the like, R8 is linear or branched alkyl, or a sugar residue, R9 is OH, lower alkyl or N(r'r"), R10 being alkyl or alkenyl, r' and r" are H, a lower alkyl, an aryl, aralkyl, and the like, or r' and r" form a heterocycle, R2 and R6 are H, OH, lower alkyl, and the like, R3 and R5 are alpha , alpha '-disubstituted alkyl or cycloalkyl, R4 is H, OH, alkoxy, or alpha , alpha '-disubstituted alkyl, R3 and R4 or R4 and R5, taken together, can form a ring containing 5 or 6 C, Z is O, S, -CH=CR11- or -N=CR12-, R11 being H, OH or lower alkyl, R12 being H or lower alkyl, X is (i) -CR13=N-, (ii) -N=CR13-, <IMAGE> <IMAGE> R13 being R16, OR16, -SR16 or NR16R17 R16 and R17 being H, a lower alkyl, a fluoroalkyl and the like, R14 being alkyl R15 being lower alkyl or lower fluoroalkyl, with the exception of the compounds of the formula (I) when R3 and R5 are identical and X represent the -CR13=N- radical, R13 being H, and the salts of the said compounds of formula (I).
Description
6 50 5 7
AUSTRALIA
PATENTS ACT 1990 COMPLETE SPECIFICATION NAME OF APPLICANT(S): Centre International De Recherches Dermatologlques Galderma (CIRD Galderma) ADDRESS FOR SERVICE: DAVIES COLLISON CAVE Patent Attorneys 1 Little Collins Street, Melbourne, 3000.
INVENTION TITLE: Aromatic compounds derived from imine, their preparation and their use in human and veterinary medicine and in cosmetics The following statement is a full description of this invention, including the best method of performing it known to me/us:o ii o iii r ii r ri r ii r.
r ~II II i
I
ii ct ii i -la- The present invention relates to new aromatic compounds, to their preparation and to their use in human and veterinary medicine and in cosmetic compositions.
These new compounds are usefully employed in the topical and systemic treatment of dermatologic ailments linked to a keratinization disorder (differentiation-proliferation) and dermatologic disorders, or others having an inflammatory and/or immuno-allergic component and in conjunctinve tissue degenerative diseases. They also exhibit an anti-tumoral activity. Moreover, these compounds can be employed in the treatment of atopy be it cutaneous or respiratory, and in the treatment of rheumatoid psoriasis.
The compounds are also useful in the ophthalmological field and in particular in the treatment of corneopathies.
The compounds according to the invention can be represented by the following general formula R1 4 R 6
(I)
R
wherein
R
1 represents hydrogen, OH, -CH 3
-CH
2 OH, -COR 7
-CH(OH)CH
3 -CH20COR 8 -S02R9, -SOR9 or SRg S0 p -2r
R
7 represents hydrogen, OH, -OR10, -N lower alkyl, monohydroxyalkyl, polyhydroxyalkyl or the residue of a sugar,
R
8 represents linear or branched alkyl having 1-20 carbon atoms, alkenyl having 2 to 20 carbon atoms or the residue of a sugar, r
R
9 represents OH, lower alkyl or -N r"
R
10 represents alkyl having 1-20 carbon atoms or alkenyl having 2-20 carbon atoms, r' and each independently, represent hydrogen, lower alkyl, aryl, aralkyl, the residue of an amino acid, the residue of a sugar, the residue of an aminated sugar or a heterocycle, or S r' and r" taken together form a heterocycle, R2 and R6 represent hydrogen, OH, lower alkyl, alkoxy having S*1-6 carbon atoms, fluorine, chlorine or CF3, S: R 3 and R 5 represent a,a'-disubstituted alkyl having 4-12 carbon atoms or mono or polycyclic cycloalkyl having 5 to 12 S".i carbon atoms whose linking carbon is trisubstituted,
R
4 represents hydrogen, OH, alkoxy having 1-6 carbon atoms or a,a'-disubstituted alkyl having 4-12 carbon atoms, i l -3-
R
3 and R 4 or R 4 and R 5 taken together form, with the adjacent benzene ring, a ring having 5 or 6 carbon atoms substituted by 2 to 6 methyl groups, Z represents oxygen or sulfur, the divalent radical
-CH=CR
11 or the divalent radical -N=CR 12
R
11 represents hydrogen, OH or lower alkyl,
R
12 represents hydrogen or lower alkyl, X is selected from the group consisting of
-CR
13 (ii) -N=CR 13 (iii) -C-NR 14 and
N-R
1 (iv) -NR 1 4
-C-
N-R
15 /R16
R
13 represents R 16
OR
16
-SR
16 or -N i R17
R
16 and R 17 represent hydrogen, lower alkyl, fluoro lower alkyl, alkenyl having 2-6 carbon atoms, alkynyl having 2-6 carbon atoms,-aryl or aralkyl,
R
14 represents lower alkyl,
R
15 represents lower alkyl or fluoro lower alkyl, with the exclusion of compounds of Formula in which R 3 and R 5 are identical when X represents -CR 13 wherein R 13 represents hydrogen.
1 ~a.an~~ -4- The present invention also relates to the salts of these compounds formed from bases as well as from acids and the optical isomers of the said compounds of Formula When the compounds according to the invention are provided in salt form, by the addition of a base, it is a question of salts of an alkali or alkaline earth metal or even of zinc or an organic amine.
When the compounds are provided in salt form by the addition of an acid, it is a question of pharmaceutically or cosmetically acceptable salts obtained by the addition of a mineral or organic acid, in particular, hydrochloric acid, sulfuric acid, acetic acid, citric acid, fumaric acid, hemisuccinic acid, maleic acid and mandelic acid.
By lower alkyl is meant alkyl having from 1 to 6 carbon atoms and preferably methyl, ethyl, isopropyl, butyl and tert.
butyl.
S.t" By alkoxy having 1 to 6 carbon atoms is meant, preferably, S. methoxy, ethoxy, isopropoxy or butoxy.
By a,a'-disubstituted alkyl having 4-12 carbon atoms is S: meant, principally, tert. butyl, 1,1-dimethyl propyl, 1-methyl- 1-ethyl propyl, 1-methyl-i-ethyl hexyl or 1,1-dimethyl decyl.
So By mono or polycyclic cycloalkyl having 5-12 carbon atoms whose linking carbon is trisubstituted is meant 1-methyl cyclohexyl or 1-adamantyl.
9 By monohydroxyalkyl is meant a radical having 1-6 carbon atoms, principally, 2-hydroxyethyl, 2-hydroxypropyl or 3hydroxypropyl.
By polyhydroxyalkyl is meant a radical containing 2-6 carbon atoms and 2-5 hydroxyl groups such as 2,3-dihydroxypropyl, 2,3,4trihydroxybutyl, 2,3,4,5-tetrahydroxypentyl or the residue of pentaerythritol.
By aryl is meant phenyl, optionally substituted by at least one halogen, hydroxyl or nitro function.
By aralkyl is meant benzyl or phenylethyl optionally substituted by at least one halogen, hydroxyl or nitro function.
By alkenyl having 2-6 carbon atoms is meant principally vinyl, propenyl, 2-methylpropenyl or buten-2-yl.
By alkynyl having 2-6 carbon atoms is meant principally propargyl.
By fluoro lower alkyl is meant a radical having 1-6 carbon I atoms and 3-7 fluorine atoms, such as -CF 3 and C 2
F
5 When R S or R 10 represent alkyl having 1-20 carbon atoms or e alkenyl having 2 to 20 carbon atoms, they are linear or branched radicals optionally substituted by one or more hydroxyl groups or one or more fluorine atoms.
By amino acid residue is meant a residue derived, for example, from one of the 20 amino acids having L or D configuration (or their racemic mixture) constitutive of mammalian proteins.
-6- By sugar residue is meant a residue derived, for example, from glucose, galactose or mannose.
By aminated sugar residue is meant a residue derived, for LI example, from glucosamine, galactosamine or mannosamine.
By heterocycle is meant, preferably, piperidino, morpholino, F pyrrolidino or piperazino, optionally substituted in position 4 by a Cl-C 6 alkyl or a mono or polyhydroxyalkyl such as defined above.
I Principal among the compounds of Formula given above, are the following: I (N-methyl-5, 6,7, 8-tetrahydro-5, 5,8, 8-tetramethyl-2naphthylcarboxamidino) benzoic acid, 4- 8-tetrahydro-5,5,8, 8-tetramethyl-2naphthylcarboxamidino) benzoic acid, (1-adamantyl) -2-hycroxy-4-methoxybenzylideneamino] benzoic acid, 4-(3-(1-adamantyl)-4-methoxybenzamidino) benzoic acid, i~ ,the hydrochloride of 4-(N-methyl-3-(l-adamantyl)-4methoxybenzamidinoj benzoic acid, 4- (1-adamantyl) -4-methoxyphenylformamidinomethylthioetherj benzoic acid, (1-adamantyl) -4-methoxyphenylformamidino-methylether) benzoic acid, methyl 4-[3-(l-adamantyl)-4-methoxybenzylideneamino] benzoate, -7- 4-f 3- (1-adamantyl) -4-methoxybenzylideieamino] benzoic acid, 4 -(3-tert.butyl-4-methoxybenzamidino) benzoic acid, methyl 4-(5,6,7,8-tetrahydro-5, 5,8,8-tetramethyl-2naphthylcarboxamidino) benzoate, 4- 6, 7,8-tetrahydro-5, 5, 8,8-tetramethyl-2naphthylcarboxamidino) benzyl al(.-ohol, 4- 6,7, 8-tetrahydro-5, 5,8, 8-tetramethyl-2naphthylcarboxamidino) toluene, N 6,7, 8-tetrahydro-5, 5,8, 8-tetramethyl-2naphthylcarboxamidino) benzamide, 2-hydroxy-4-(5, 6,7, 8-tetrahydro-5, 5,8, 8-tetramethyl-2naphthylcarboxamidino) benzoic acid, allyl 4-(a-chloro-5, 6,7,8-tetrahydro-5, 5,8, 8-tetramethyl-2naphthylmethylimino) benzoate, 6,7, 8-tetrahydro-5, 5,8, 8-tetramethyl-2naphthylcarboxamidino) benzoic acid, the hydrochloride of 4-(Nl-phenyl-5,6,7,8-tetrahydro- A 5,5,8,8-tetramethyl-2-naphthylcarboxamidino) benzoic acid, 4-.(Nl-benzyl-5, 6,7, 8-tetrahydro-5,5,8,8-tetramethyl-2naphthylcarboxamidino) benzoic acid, 4- (N 1 N-dimethyl-5,6,7, 8-tetrahydro-5,5,8, 8-tetramethyl-2k1 naphthylcarboxamidino) benzoic acid, 4-CN 2 6,7,8-tetrahydro-5,5,8, 8-tetramethyl-2-naphthyl) amidino] benzoic acid, 4-(Nl-phenyl-N 2 -(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2naphthyl) arnidino~benzoic acid, the hydrochloride of 4-(5,6,7,8-tetrahydro-5,5,8,8tetramethyl-2-naphthylarboxanidino) phenol, tctramethyl-2-naphthylcarboxamidino) benzoic acid and 4-[N-(3,3,3-trifluoroethyl)-5,6,7,8-tetrahydro-5,5,8,8tetramethyl-2-naphthylcarboxamidino) benzoic acid.
The present invention also relates to, as intermediate compounds, those of the formula R2.
R
3 R 13II Vwherein
PIS
of:W represents a radical selected from the group consisting I (iii)-C-NH- and i -9- (iv) -NH-C-, Z and R2 to R 6 have the same meanings given above for Formula
R
1 has the same meaning given above for Formula when W is either the radical or the radical or R 1 represents the radical -COOCH 2
-CH=CH
2 when W is either the radic". (iii) or the radical (iv).
The present invention also relates to the process for preparing the compounds of Formula When X represents an imine link with the compounds are obtained by the reaction of a benzaldehyde substituted with a para-amino allyl benzoate, optionally substituted, in an anhydrous solvent such as methylene chloride in the presence of dehydrating agent, for example, basic alumina.
When X represents an imine link with X=(ii) the compounds S. are obtained by the reaction of a substituted aniline on an aromatic aldehyde substituted by an acid function which is protected in the form of an allylic ester under the same ai preceding conditions.
When X represents an imidate, thioimidate or amidine link "i with the compounds according to the invention are prepared in accordance with the following reaction scheme: R 2 N CO 2CHi CHi CH 2 z _C O l CHi CH 2 NH 3 C 2CH2z Soc' 2 N-4 Z RCO2CH CH -CH2 S. it St Sr S A
S
hAStE it 4 a C
S
{Alcohol Amine or Thjo 1 CHi CH 2
IS
I -11- The first step consists in reacting in an anhydrous medium, in an organic solvent such as tetrahydrofuran or methylene chloride containing a tertiary amine (pyridine or triethylamine) an activated form of a substituted benzoic acid, for example, an acid chloride or a mixed anhydride on a para-amino allyl benzoate optionally substituted The reaction is conducted at ambient temperature and with stirring.
The amide thus obtained is converted into an iminochloride by the action of thionyl chloride, phosphorus pentachloride or phosgene.
By the reaction of compound with an amine, an alcohol or a thiol in the presence of a tertiary amine and an alkaline hydride in an organic solvent such as tetrahydrofuran or methylene chloride, the compound of formula is obtained.
When X represents an imidate, thioimidate or amidine link with X=(ii) the preparation is carried out in the same manner as above by starting with the following compounds and
R
2 Cl COOCH- CH CH
R
S (7) (6) The passage of the ester to the free acid can be effected in the 4 cases above by means of a catalyst, such as certain S' transition metal complexes, for example, tetrakis triphenyl fr' -12- 2phosphine palladium in the presence of a secondary amine or the sodium salt of diethyl malonate or in an alkaline medium, preferably in the presence of a methanolic soda solution.
When X represents an amidine link corresponding to formulas (iii) and (iv) the synthesis is carried out in accordance with the conventional Pinner process by condensing a substituted aniline with an aromatic nitrile.
The present invention also relates to, as a medicine, the compounds of Formula as defined above.
The compounds according to the invention exhibit good stability to light and oxygen.
These compounds exhibit an activity in the differentiation test of embryonic teratocarcinoma cells of mice (F9) (Cancer Research 43 p. 5268, 1983) and/or in the inhibition test of ornithine decarboxylase after induction by TPA in mice (Cancer Research 38, p. 793-801, 1978). These tests show the activity of the compounds, respectively, in the areas of differentiation and proliferation.
The compounds according to the invention are indeed S particularly appropriate in the following treatment areas: to treat dermatologic ailments linked to a keratinization disorder causing differentiation and proliferation and principally for treating acne vulgaris, comedones, polymorphs, nodulokystic acne, conglobata, senile acne, secondary acne such as solar, medicinal or professional acne; acne such as solar, medicinal or professional acne; i i (Ii
I
-13to treat other types of keratinization disorders, principally ichtyoses, ichthyosiform conditions, Darrier malady, leucoplasiforms, cutaneous or mucous lichen; to treat dermatologic ailments linked to a keratinization disorder having an inflammatory and/or immunoallergic component and, principally, all forms of psoriasis be they cutaneous, mucous or ungual, and even psoriatic rheumatism, or again cutaneous atopy, such as eczema, or respiratory atopy or gingival hypertrophy; the compounds can also be employed in certain inflammatory conditions not exhibiting any keratinization disorder; to treat all dermic or epidermic proliferations that are benign or malignant, that are of viral origin such as common warts, planar warts and epidermodysplasie verruciform, florid oral papillomatosis, the proliferation being able also to be induced by ultraviolet radiation, principally in the case of baso epithelioma and cellular spino; to treat other dermatologic disorders such as blistery S dermatoses and collagen maladies; to treat certain ophthalmologic disorders, and principally, corneopathies; to restore or combat against skin aging be it S. chronologic or photoinduced or to reduce pigmentation and actinic S* keratosis; i
I
s -14to prevent or heal the scars of epidermic and/or dermic atrophy induced by local or systemic corticosteroids, or any other form of cutaneous atrophy; to prevent or restore cicatrization disorders or vergetures; to combat against disorders of the sebaceous function, such as hyper seborrhea of acne or simple seborrhea; (11) in the treatment of cancerous or precancerous situations in particular at the cutaneous level; and (12) in the treatment of inflammatory conditions, such as arthritis.
The present invention also related to medicinal compositions containing at least one compound of Formula such as defined above, or one of its salts.
The present invention relates then to a new medicinal composition intended principally for the treatment of the abovementioned conditions comprising, in a pharmaceutically acceptable support, at least one compound of Formula and/or one of its salts.
The compounds according to the invention are generally administered at a daily dosage of about 0.01 mg/kg to 100 mg/kg of body weight in 1 or 3 doses.
The administration can be effected enterally, parenterally, topically or ocularly. When administered enterally, the medicine can be provided in the form of tablets, gelules, dragees, syrups, suspensions, solutions, powders, granules and emulsions. When rro r r r
I
a r n c Ir r i administered parenterally, the compositions 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 invention are intended for the treatment of the skin and mucous membranes and are provided in the form of an ointment, cream, milk, pomade, powder, impregnated pads, solutions, gels, sprays, lotions or suspensions. They can also be provided in the form of microspheres or nanospheres or ionic or nonionic or polymeric lipidic vesicles or polymeric patches or hydrogels which permit controlled release.
These topically applied compositions can be provided either under anhydrous form or under aqueous form in accordance with clinical indications.
When administered ocularly, they are principally eyewashes.
These compositions contain at least one compound of formula such as defined above or one of its salts, in an amount preferably ranging from 0.001 to 5 percent by weight relative to the total weight of the composition.
also find use in the cosmetic field, in particular, in body and hair hygiene, and principally for the treatment of skin having acne tendencies, for hair growth, to combat hair loss, to combat S: against the oily appearance of the skin or hair, in the protection against the harmful effects of the sun or in the treatment of physiologically dry skin.
t t -16- The present invention thus also envisions a cosmetic composition containing in a cosmetically acceptable support at least one compound of Formula or one of its salts, this composition being provided principally in the form of a cream, a milk, a lotion, a gel, microspheres or nanospheres or lipidic or polymeric vesicles, a soap or a shampoo composition.
The concentration of the compound of Formula in the cosmetic compositions ranges, principally, from 0.001 to 3 percent by weight based on the total weight of the composition.
The medicinal and cosmetic compositions according to the invention can also contain inert or even pharmacodynamic or cosmetically active additives or combinations thereof and principally: wetting agents; depigmenting agents such as hydroquinone, azelaic acid, caffeic acid, kojic acid; emollient agents; hydrating agents such as glycerol, PEG 400, thiamorpholinone and its derivatives or urea; antiseborrhea or anti-acne agents, such as S-carboxymethylcysteine, S-benzylcysteamine, their salts and their derivatives, tioxolone or a Sc.. benzoyl peroxide; antibiotics such as erythromycin and its S' esters, neomycin, clindamycin and its esters and tetracyclines; antifungus agents such as ketoconazole or 4,5-polymethylene-3isothiazolinones; agents promoting hair growth such as "Minoxidil" (2,4-diamino-6-piperidino-pyrimidine-3-oxide) and its derivatives, Diazoxide (7-chloro-3-methyl-l,2,4-benzothiadiazine- 1,1-dioxide) and Phenytoin (5,5-diphenyl-imidazolidine-2,4dione); steroidal and non-steroidal anti-inflammatory agents; 4 4 I niugsaet uha eocnzl r45plmtyee3 -17carotenoids and principally, B-carotene; anti-psoriatic agents such as anthralin and its derivatives and 5,8,11,14eicosatetraynoic and 5,8,11-eicosatriynoic acids, their esters and their amides; or anti-irritant agents such as derivatives of a-hydroxy acids and more particularly the derivatives of mandelic acid.
The compositions according to the invention can also contain flavor improving agents, preservatives such as esters of parahydroxybenzoic acid, stabilizers, humidity regulating agents, pH regulating agents, osmotic pressure modifying agents, emulsifying agents, UV-A and UV-B filters, and antioxidants such as a-tocopherol, butylhydroxyanisole and butylhydroxytoluene.
The following non-limiting examples illustrate the preparation of the active compounds of Formula according to the invention as well as examples of compositions containing these compounds.
Sxample 1 4-(N-methyl-5,6,7,8-tetrahydro-5,5,8,8- I tetramethyl-2-naphthylcarboxamidino) benzoic acid allyl 4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl- 2-naphthylcarboxamido) benzoate In a round bottom flask, there are introduced 2.8 g (16 mmoles) of allyl 4-aminobenzoate, 2.5 ml (16 mmoles) of triethylamine and 50 ml of THF. A solution of 4.3 g (16 mmoles) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthoyl chloride dissolved in 50 ml of THF is slowly added and the mixture is t L i: i -18stirred at ambient temperature for 2 hours. The reaction medium is poured into water and extracted with ethyl ether. The organic phase is decanted, dried on magnesium sulfate and evaporated.
The resulting residue is purified by chromatography on a silica column, eluted with a 60/40 mixture of dichloromethane and hexane. After evaporation of the solvents 5.7 g of the expected ester having a melting point of 148-149'C are obtained.
allyl 4-(a-chloro-5,6,7,8-tetrahydro-5,5,8,8tetramethyl-2-naphthylmethylimino) benzoate In a round bottom flask, there are introduced 3.9 g mmoles) of the ester obtained in Example 1 and 50 ml of thionyl chloride. The mixture is heated at reflux for 24 hours and is then evaporated to dryness. 4.4 g (100%) of the expected crude product is recovered and is employed, as such, for the following synthesis.
allyl 4-(N-methyl-5,6,7,8,-tetrahydro-5,5,8,8tetramethyl-2-naphthylcarboxamidino) benzoate In a round bottom flask, there are introduced 2.2 g (0.05 Smole) of the iminochloride obtained above in l(b) and while cooling to 0'C, 50 ml of methylamine (40% in water) are slowly added.- The mixture is stirred at ambient temperature for 1 hour.
The reaction medium is poured into water and extracted with ethyl ether. The organic phase is decanted, dried on magnesium sulfate S and evaporated. The resulting residue is purified by chromatography on a silica column, eluted with a 90/10 mixture of dichloromethane and ethyl ether. After evaporation of the solvents, 1.6 g of a slightly yellow oil is obtained.
Ii -19- IJ(d) 4-(N-methyl-5, 6,7-8-tetrahydro-5,5,8, 8-tetramethyl- 2-naphthylcarboxamidino) benzoic acid In a round bottom flask, there are introduced 1.4 g (3.4 mmoles)* of the allylic ester obtained above in 1(c) and 50 ml of THF. Under nitrogen 400 mg (0.35 mmole) of tetrakis (triph~nylphosphine) palladium are introduced and 3 ml (34 mmoles) of morpholine are slowly added. The mixtrure is stirred at ambient temperature for 4 hours and the reaction medi.um is evaporated to dryness. The resulting residue is taken up in is filtered and dried on phosphorus pentoxide. The solid is K purified by chromatography on a silica column, by eluting with an 80/20 mixture of dichloromethane and methanol. 850 mg of the expected acid having a melting point of 164-167'C (with Examle 2 4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2alylnaphthylcarboxamidino) benzoic acid llyl4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl- Ina2-naphthylcarboxamidino) benzoate In a manner analogous to Example 1(c) by reacting 22 g (0.05 mole) of-the iminochloride obtained in Example 1 with 50 ml of ammonia 1.8 g of the expected allylic ester are obtained in the form of a yellow oil.
4: 4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2naphthylcarboxamidino) -benzoic acid *In a manner analogous to Example 1(d) starting with 1.6 g (4.1 mmoles) of allyl 4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl- M O1 e ii 2-naphthylcarboxamidino) benzoate 710 mg of the expected acid having a melting point of 192-195'C (with decomposition) are obtained.
Example 3 4-[5-(1-adamantyl)-2-hydroxy-4-methoxybenzylideneamino] benzoic acid 2-hydroxy-4-methoxybenzyaldehyde In a round bottom flask, there are introduced 6 g (0.2 mole) of sodium hydride (80% in oil) and 50 ml of DMF. A solution of 27.6 g (0.2 mole) of 2,4-dihydroxybenzaldehyde in 100 ml of DMF is slowly added and the mixture is stirred until the cessation of gaseous emission. There are then slowly added 12.5 ml (0.2 mole) of methyliodide and the mixture is stirred at ambient temperature for 12 hours. The reaction medium is poured into water and extracted with ethyl ether. The organic phase is decanted, dried on magnesium sulfate and evaporated. The resulting residue is purified by chromatography on a silica column by eluting with a 70/30 mixture of dichloromethane and hexane. After evaporation of the solvents, 20.3 g of the expected product whose melting point is 38-40'C are recovered.
5-(1-adamantyl)-2-hydroxy-4-methoxy-benzaldehyde In a round bottom flask, there are introduced 10.4 g (68 mmoles) of the aldehyde obtained in Example 10 g (68 mmoles) of 1-adamantanol and 300 ml of dichloromethane. 3.6 ml of sulfuric acid are slowly added and the mixture is stirred at ambient temperature for 24 hours. The reaction medium is poured 45 55 i su, -21into water and extracted with dichloromethane. The organic phase is decanted, washed with water, driel on magnesium sulfate and evaporated. The residue is pulverized in ethanol and filtered.
The resulting solid is dried under a vacuum. 14.8 g of the expected product whose melting point is 191-193'C are recovered.
4-[5-(1-adamantyl)-2-hydroxy-4-methoxybenzylideneamino] benzoic acid In a round bottom flask, there are introduced 2.86 g (0.01 mole) of the aldehyde obtained above in 1.37 g (0.01 mole) of 4-aminobenzoic acid and 500 ml of ethanol. 540 mg (0.01 mole) of sodinm methylate are added and the mixture is heated at reflux and the ethanol is distilled off. The remainder is taken up in water and the pH is adjusted to 5 with citric acid. The resulting solid is filtered, washed with water and dried on phosphorus pentoxide. The solid is ground in 50 ml of ethyl ether and after filtration, 2.9 g of the expected acid whose melting point is 333-335'C are recovered.
Example 4 4-[3-(1-adamantyl)-4-methoxy benzamidino] benzoic acid allyl 4-[3-(1-adamantyl)-4-methoxybenzamido] benzoate In a manner analogous to Example 1(a) starting with 12.6 g (71 mmoles) of allyl 4-aminobenzoate and 21.6 g (71 mmoles) of 3- S.i (l-adamantyl)-4-methoxy benzoyl chloride, 32 g of the expected amide whose melting point is 191-192C are isolated.
-22ii. allyl 4-ct-chloro-i-(l-adamantyl)-4- Starting with 8.9 g (19.2 mmoles) of the derivative obtained 4 above in a synthesis is carried out following the procedures of Example The resulting crude product is washed with ether and 6.5 g of allyl 4-(a-chloro-3-(l-adamantyl)-4- 4 methoxyphenylmethylimino) benzoate whose melting point is 108are obtained.
allyl 4-[3-(l-adamantyl) -4-methoxybenzamidino] benzoate In a manner analogous to Example by reacting 5 g (107 mmoles) of the iminochloride obtained above in with 10 ml of amoi 3% n fe hoaogah ftecuepouto silica column eluted with a 40/60 mixture of ethylacetate and petroleum ether, 2.4 g if the expected product whose melting point is 173-174*C are obtained.
4-[3-(l-adamantyl)-4-methoxybenzamidinoJ benzoic acid 4 In a manner analogous to Example 1(d) starting with 2 g mmoles) of allyl 4-[3-(l-adamantyl) -4-methoxybenzamidino] benzoate, 950 mg of the expected acid whose melting point is 263-265 4 Carobind Exa~l 5- The hydrochloride of 4-(N-methyl-3-(l- 4 adamantyl)-4-methoxybenzamidino] benzoic acid allyl 4-[N-methyl-3-(l-adamantyl) benzamidino] benzoate In a manner analogous to Excample 1 by reacting 3.8 g of the iminochloride prepared in Example 4(b) with 44 4 -23ml of methylamine (40% in water), and after chromatography on a silica column eluted with a 40/60 mixture of ethylacetate and petroleum ether, 2.3 g of the expected product whose melting point is 77-79C are obtained.
the hydrochloride of 4-[N-methyl-3-(1-adamantyl)- 4-methoxybenzamidino] benzoic acid In a round bottom flask, there are introduced 2 g (4.4 mmoles) of the allylic ester prepared previously and 43 ml of THF. There are then added, under nitrogen, 437 mg (0.44 mmoles) of tetrakis (triphenylphosphine) palladium 8.8 mmole3 of base prepared starting with 1.4 g (8.8 mmoles) of diethyl malonate and 262 mg (8.8 mmoles) of sodium hydride (80% in oil) in 30 ml of THF are slowly added. After stirring the mixture at ambient temperature for 2 hours, the medium is acidified with ml of 1 N hydrochloric acid. The recovered precipitate is washed with ether, then recrystallized in ethanol. 1.63 g of the hydrochloride of 4-[N-methyl-3-(l-adamantyl)-4methoxybenzamidino] benzoic acid whose melting point is 205- 207*C are obtained.
Examle 4-[3-(1-adamantyl)-4-methoxyphenyl formamidinomethylthioether] benzoic acid allyl 4-[3-(1-adamantyl)-4-methoxyphenylformani- Sdinomethylthioether] benzoate In a round bottom flask, 700 mg (10 mmoles) of sodium thiomethylate are suspended in 25 ml of dimethoxymethane. At ambient temperature and under a nitrogen stream, there are slowly S -cC~ c -24introduced 3.5 g (7.6 mmoles) of allyl 4-[a-chloro-3-(1adamantyl)-4-methoxyphenylmethylimino] benzoate obtained in Example 4(b) and dissolved in 50 ml of DME. After 3 hours of reaction, the mixture is poured into water and extracted with ethyl ether. The organic phase is dried on sodium sulfate, then evaporated under a vacuum; the resulting crude product is chromatographed on a silica column eluted with a 20/80 mixture of ethyl ether and hexane. After evaporation of the solvents 2.6 g of the expected product whose melting point is 50-53'C are obtained.
4-[3-(1-adamantyl)-4-methoxyphenylformamidinomethylthioether] benzoic acid In a manner analogous to Example 5(b) starting with 1.5 g (3.2 mmoles) of the allylic ester obtained above in 1.05 g of 4-[3-(1-adamantyl)-4-methoxyphenylformamidinomethylthioether] benzoic acid whose melting point is 235-237"C are obtained.
Example 7 4-3-(1-adamantyl)-4-methoxyphenylformamidino- S. methylether] benzoic acid allyl 4-[3-(l-adamantyl)-4-methoxyphenylformamidinomethylether] benzoate In a three-necked flask, there are introduced, under an inert atmosphere, 30 ml of dichloromethane, 1.43 ml (10 mmoles) Sof triethylamine and 324 Al (8 mmoles) of methanol. The mixture is heated to 50'C, then 3.7 g (8 mmoles) of the iminochloride obtained in Example 4(b) and dissolved in 35 ml of *1
S
*4
-I
dichloromethane are slowly added. At the end of the addition, one equivalent of methanol, or 324 Am is added. After 4 hours of reaction, the reaction mixture poured into water, then extracted with dichloromethane. The organic phase is decanted, dried on magnesium sulfate and evaporated to dryness. The resulting liquid residue is chromatographed on a silica column Ieluted with the aid of a 10/90 mixture of ethyl ether and hexane.
SAfter evaporation of the solvents, 1.7 g of the expected product whose melting point is 85-87*C are recovered.
4-[3-(1-adamantyl)-4-methoxyphenylformamidinomethylether] benzoic acid In a manner analogous to Example 5(b) starting with 1.08 g (2.6 mmoles) of the allylic ester obtained above in 720 mg of 4-[3-(l-adamantyl)-4--iethoxyphenylformamidinomethylether] benzoic acid whose melting point is 224- 225'C are obtained Example 8 Methyl 4-[3-(l-adamantyl)-4-methoxybenzylideneamino] benzoate 3 g of basic alumina and 1.94 g (12.9 mmoles) of methyl 4r e aminobenzoate are mixed in a mortar, then introduced into a round bottom flask. 3 g (11.1 mmoles) of 3-(l-adamantyl)-4methoxybenzaldehyde in 50 ml of anhydrous dichloromethane are -"Ai added with stirring. After heating at reflux for 24 hours, the reaction medium is extracted with dichloromethane and evaporated to dryness. The crude product is recrystallized in a mixture of i
I
LL J 1 1 1 1 -26ethyl acetate and acetone. After filtration, 3.4 g of the expected product whose melting point is 180-182*C are obtained.
Exap~ 9- 4-(3-(l-adamantyl)-4-methoxybenzylideneamino] benzoic acid allyl 4-(3-(1-adamantyl) -4-methoxybenzylidene amino] benzoate Starting with 3.4 g (12.6 mmoles) of 3-(l-adamantyl)-4metho~iybenzaldehyde and 2.6 g (14.4 mmoles) of allyl 4aminobenzoate the synthesis is effected following the procedures described in Example 8. The resulting crude product is recrystallized in ethyl acetate. After filtration and drying, 4.1 g of the allylic ester whose melting point is 160- 1620C are obtained.
4- (1-adamantyl) -4-methoxybenylideneamino] benzoic acid In a manner analogous to Example 1(d) starting with 2 g (4.7 mmoles) of the allylic ester prepared above in 1.4 g (77%) of 4-[3-(1-adamantyl)-4-methoxybenylideneamino] benzoic acid whose melting point is 299-3OV*C are obtained.
Exam~e 10 4-(3-tert.butyl-4-methoxybenzamidino) benzoic acid allyl 4-(3-tert.butyl-4-methoxybenzamido) benzoate :In a round bottom flask, there are introduced 5.92 g (33.4 S S mmoles) of allyl 4-aminobenzoate, 5.6 ml (40.25 mmoles) of triethylamine and 100 ml of THF. A solution of 8 g (38.4 mmoles) of 3-tert.butyl-4-methoxybenzoyl chloride dissolved in 50ml o
A',
-27- THF are slowly added and the mixture is stirred at ambient temperature for 4 hours. The reaction medium is poured into water and extracted with dichloromethane. The organic phase is decanted, washed with demineralized water up to pH 6, dried on Na 2
SO
4 and filtered. The solvents are evaporated under reduced pressure. The resulting maroon oil is crystallized in hexane.
The solid is filtered and recrystallized in absolute ethanol.
After filtration on fritted glass and drying for 48 hours at 5.1 g of the expected ester are obtained in the form of white crystals whose melting point is 180-182'C.
allyl 4-(a-chloro-3-tert.butyl-4-methoxyphenyl methylimino) benzoate Starting with 2 g (5.44 mmoles) of the derivative obtained above in the synthesis is carried out following the procedures of Example After evaporation to dryness, 2.3 g (100%) of the expected crude product are recovered which is employed as such in the following synthesis.
allyl 4-(3-tert.butyl---ethoxybenzamidino) benzoate '4 In a manner analogous to Example by reacting 2.3 g (5.44 mmoles) of the iminochloride obtained above in with ml of ammonia then extracting with ethyl acetate, and chromatographing on a silica column by eluting with a 50/50 mixture of ethyl acetate and hexane, 1.06 g of the expected product whose melting point is 120-122C are obtained.
SV 4-(3-tert.butyl-4-methoxybenzamidino) benzoic acid tV V r -28- In a round bottom flask, there are introduced 300 mg (0.82 mmole) of the derivative obtained above in 180 mg mmoles) of soda and 10 ml of methanol. After 24 hours of reaction at reflux of the methanol, the mixture is evaporated and the remainder is taken up in water. The reaction mixture is neutralized to pH 5-6 by acetic acid. The resulting precipitate is filtered, washed with demineralized water and then dried for 48 hours at 80'C. 210 mg of the expected acid whose melting point is 170-172C are obtained Examle 11 Methyl 4-(5,6,7,8-tetrahydro-5,5,8,8tetramethyl-2-naphthylcarboxamidino) benzoate Methyl 4-(a-chloro-5,6,7,8-tetrahydro-5,5,8,8tetramethyl-2-naphthylmethylimino) benzoate Starting with 4.94 g (13.5 mmoles) of methyl 4-(5,6,7,8tetrahydro-5,5,8,8-tetramethyl-2-naphthyl carboxamido) benzoate, the synthesis is carried out following the procedure of Example After evaporation to dryness, 5.7 g (100%) of the expected J crude product are obtained which is used as such for the t y following synthesis.
IC
act 2(b) Methyl 4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl- 2-naphthylcarboxamidino) benzoate In a manner analogous to Example 1(c) by reacting 5.7 g (13.5 mmoles) of the iminochloride obtained above in with 125 I I ml of ammonia an oily crude proauct is recovered which is chromatographed on a silica column in a 30/70 ethylacetate- 4i
CI
I L I _LI I i a i; ia -29hexane system. 600 mg of the expected ester whose melting point is 196-198"C are recovered.
Example 12 4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2naphthylcarboxamidino) benzylic alcohol In a round bottom flask, there are introduced 420 mg (1.15 mmole) of the ester obtained in Example 11 and 25 ml of THF.
There are then introduced, by portions, 110 mg (2.88 mmoles) of the double lithium and aluminum hydride. The mixture is stirred for 8 hours at ambient temperature. The reaction medium is hydrolyzed with hydrated sodium sulfate. The resulting precipitate is filtered and the filtrate is evaporated. 350 mg of the expected alcohol whose melting point is 171-172*C are obtained.
Example13 4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2naphthylcarboxamidino) toluene 4-(a-chloro-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl- 2-naphthylmethylimino) toluene Starting with 2 g (6.22 moles) of 4-(5,6,7,8-tetrahydro- 5,5,8,8-tetramethyl-2-naphthylcarboxamido) toluene, the synthesis is carried out by following the procedures of Example 1(b).
After evaporation to dryness, 2.34 g (100%) of the expected crude product are obtained which is used as such in the following synthesis.
it t
I
4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2naphthylcarboxamidino) toluene In a manner analogous to Example l(c) by reacting 2.34 g (6.22 mmoles) of the iminochloride obtained above in with ml of ammonia then extraction with ethyl acetate and chromatography on a silica column using a 40/60 ethyl acetatehexane eluant system, 740 mg of the expected product whose melting point is 147-149'C are obtained.
Example 14 4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2naphthylcarboxamidino) benzamide 4-(a-chloro-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl- 2-naphthylmethylimino) benzoyl chloride In a round bottom flask, there are introduced 1 g (2.84 mmoles) of 4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2naphthylcarboxamidino) benzoic acid and 10 ml of thionyl chloride. The mixture is heated at reflux for 24 hours and evaporated to dryness. 1.2 g of the expected crude product (100%) are recovered which is used as such in the following synthesis.
I 4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2naphthylcarboxamidino) benzamide SIn a round bottom flask, there are introduced 1.2 g (2.84 M i mmoles) of the derivative obtained in above and 15 ml of THF.
J The mixture is stirred while maintaining the reaction medium at 0*C. 40 ml of ammonia are slowly added and the mixture is Sstirred for 4 hours and then extracted with ethyl acetate. The organic phase is washed until neutralized, dried on sodium i: r -31sulfate and filtered. The solvents are evaporated under reduced pressure. 1 g of the crude product is recovered which is taken up in hot ethyl acetate. After filtration, 470 mg of the expected amide whose melting point is 247-249"C are obtained.
Example 15 2-hydroxy-4-(5,6,7,8-tetrahydro-5,5,8,8tetramethyl-2-naphthylcarboxamidino) benzoic acid allyl 2-hydroxy-4-aminobenzoate In a round bottom flask, there are introduced 50 ml of allyl alcohol and 460 mg (0.02 mole) of sodium while cooling with an ice bath. There is then added a solution of 8.3 g (0.05 mole) of methyl 2-hydroxy-4-amino benzoate in 100 ml of allyl alcohol.
The mixture is heated while distilling the methanol formed. The mixture is evaporated to dryness, and the residue is taken up in water, acidified with IN hydrochloric acid and, extracted with ethyl ether. The organic phase is decanted, dried on magnesium sulfate and evaporated. The residue is taken up in hexane, filtered and dried. 8.6 g of the allyl ester whose melting point is 58-59*C are recovered.
allyl 2-hydroxy-4-(5,6,7,8-tetrahydro-5,5,8,8tetramethyl-2-naphthylcaboxamido) benzoate In a manner analogous to Example l(a) by reacting 6.7 g (34.7 mmole) of allyl 2-hydroxy-4-aminobenzoate with 8.7 g (34.7 mmoles) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthoyl chloride, 12.7 g of the expected allyl ester which melts at 129-130'C are obtained.
:I
-32allyl 2-hydroxy-4-[a-chloro-(5,6,7,8-tetrahydro- 5,5,8, 8-tetramethyl-2-naphthyl) methylimino] benzoate In a round bottom flask, there are introduced 4 g (0.01 mole) of the preceding product and 50 ml of thionyl chloride.
The mixture is heated at reflux for 24 hours. The reaction medium is evaporated to dryness and 4.2 g (100%) of the expected crude product is recovered which is used as such for the following synthesis.
allyl 2-hydroxy-4-(5,6,7,8-tetrahydro-5,5,8,8tetramethyl-2-naphthylcarboxamidino) benzoate In a manner analogous to Example by reacting 4.2 g mmoles) of the preceding iminochloride with 50 ml of ammonia B 2.1 g of the expected allyl ester are obtained in the form of a yellow oil.
2-hydroxy-4-(5, 6,7,8-tetrahydro-5, 5, 8,8-tetramethyl- 2-naphthylcarboxamidino) benzoic acid In a manner analogous to Example 1(d) starting with 2.1 g r~ mmoles) of allyl 2-hydroxy-4-(5,6,7,8-tetrahydro-5,5,8,8tetramethyl-2-naphthylcarboxamidino) benzoate, 1.1 g of the 4 expected acid whose melting point is 209-210*C are obtained.
Exam;le 1 allyl 4-(a-chloro-5,6,7,8-tetrahydro-5,5,8,8- V tetramethyl-2-naphthylmethylimino) benzoate j~ ~In a round bottom flask, there are introduced 40.5 (0.103 mole) of allyl 4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2naphthylcarboxamido)benzoate and 500 ml of thionylchloride. The mixture is heated at reflux for 48 hours. The reaction mixture is evaporated to dryness. The residue is crystallized in hexane, -33filtered, washed with hexane and dried under a vacuum. 16.86 g of the expected product whose melting point is 80'C are recovered.
Examle 17 4-(N 1 -phenyl-5,6,7,8-tetrahydro-5,5,8,8tetramethyl-2-naphthylcarboxamidino) benzoic acid allyl 4-(N 1 -phenyl-5,6,7,8-tetrahydro-5,5,8,8tetramethyl-2-naphthylcarboxamidino) benzoate In a round bottom flask, there are introduced 4.08 ml (44.8 mmoles) of aniline and 10 ml of THF. 4 g (8.97 mmoles) of the iminochloride obtained in Example 16, dissolved in 40 ml of THF are slowly added. The mixture is stirred at ambient temperature for 24 hours. The reaction medium is poured into water, acidified to pH 5 with 1N hydrochloric acid, extracted with ethyl acetate and washed with water. The organic phase is decanted, dried on sodium sulfate and evaporated. The resulting residue is purified by chromatography on a silica column eluted with an 85/15 mixture of hexane and ethyl acetate. After evaporation of the solvents, 3.6 g of a yellow oil are obtained.
S(b) 4-(N-phenyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl- S2-naphthylcarboxamidino) benzoic acid In a round bottom flask, there are introduced 3.55 g (7.62 mmoles) of the allyl ester obtained in Example 17(a) and 70 ml of S. THF. 880 mg (0.76 mmole) of tetrakis (triphenyl-phosphine) palladium are added and then 6.64 ml (76.2 mmoles) of morpholine are slowly added. The mixture is stirred at ambient temperature for 1 hour. The reaction medium is poured into -34water, acidified to pH 5 with acetic acid, extracted with ethyl acetate, washed with water, dried on sodium sulfate and evaporated. The resulting residue is purified by chromatography on a silica column eluted with a 50/50 mixture of ethyl acetate and hexane. After evaporation of the solvents 3.05 g of the expected acid whose melting point is 125-130'C are obtained.
Example 18 The hydrochloride of 4-(NT 1 -phenyl-5,6,7,8tetrahydro-5,5,,8,8-tetraethyl-2-naphthylcarboxamidino) benzoic acid In a round bottom flask, there are introduced 500 mg (1.17 mmole) of the acid obtained in Example 17(b) and 15 ml of acetone. 1.12 ml of hydrochloric acid (1.045 N) are added. The precipitate is filtered, washed with acetone and dried. 490 mg of the expected hydrochloride whose melting point is 297'C (with decomposition) are recovered.
Example 19 4-(N 1 -benzyl-5,6,7,8-tetrahydro-5,5,8,8i tetramethyl-2-naphthylcarboxamidino) benzoic acid allyl 4-(N 1 -benzyl-5,6,7,8-tetrahydro-5,5,8,8tetramethyl-2-naphthylcarboxamidino) benzoate In a manner analogous to Example 17(a) starting with 5 g :1 i '(11.2 mmoles) of the iminochloride obtained in Example 16 and 5.67 ml (52 mmoles) of benzylamine, 3.5 g of the expected allyl ester are obtained in the form of a yellow oil.
4-(N 1 -benzyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl- 2-naphthylcarboxamidino) benzoic acid In a manner analogous to Example 17(b) starting with 3.5 g (7.3 mmoles) of the allyl ester obtained in Example 19(a) there are obtained, after chromatography on a silica column eluted with a 60/40 mixture of ethyl acetate and hexane, and evaporation of the solvents, 2.45 g of the expected acid whose melting point is 105'C.
Example 20 4-(N1,N1-dimethyl-5,6,7,8-tetrahydro-5,5,8,8tetramethyl-2-naphthylcarboxamidino) benzoic acid allyl 4-(N 1
,N
1 -dimethyl-5,6,7,8-tetrahydro-5,5,8,8tetramethyl-2 -naphthy1carboxamidino) benzoate In a manner analogous to Example 17(a) starting with 4 g (8.97 mmoles) of the iminochloride obtained in Example 16 and 5.63 ml (0.452 mole) of dimethylamine (40% in water) 3.33 g *(89 of the expected allyl ester are obtained in the form of a yellow oil.
4-(N1,N1-dimethyl-5,6,6,7-tetrahydro-5,5,8,8tetramethyl-2-naphthylcarboxamidino) benzoic acid In a manner analogous to Example 17(b) starting with 3.3 g (7.92 mmoles) of the allyl ester obtained in Example 20(a) 2.5 g of the expected acid whose melting point is 240*C are obtained
T
1
R
-36- Exaple21- 4-(N2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl- 2-naphthyl) amidino] benzoic acid methyl 4-(N 2 -(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl- 2-naphthyl) amidino] benzoate In a manner analogouis to Example 11(b) by reacting 2.5 g (6.9 mmoles) of methyl 4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl- 2-naphthylcarbamoyl) benzoate with 25 ml of thionyl chloride, there is recovered, after evaporation, the corresponding fj iminochioride which is directly reacted with 100 ml of ammonia After recrystallization in a mixture of ethyl acetate and hexane, 1.5 a of the expected ester whose melting point is 218-2209C are obtained.
4-[N 2 -(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl- 2-naphthyl) amidino] benzoic acid In a manner analogous to Example 10(d) starting with 500 mg (1.37 mmole) of the ester obtained previously in 300 mg of the expected acid whose melting point Is 281-284*C are obtained.
Example.22 .4-[Nl-phenyl-N 2 -(5,6,7,8-tetrahydro-5,5,s,8- ~i tetramethyl-2-naphthyl) amidino] ben~zoic acid (a)amty -N-hnlN-5,,,-erhdo5588 b -37of the expected ester whose melting point is 163-1640C are isolated.
4-[Nl-phenyl-N 2 -(5,6,7,8-tetrahydro-5,5,8,8tetramethyl-2-naphthyl) amidino] benzoic acid jIn a manner analogous to Example 10(d) starting with 300 mg (0.68 mmole) of the derivative obtained above in 230 mg of the expected acid whose melting point is 281-2840C are isolated.
Examle 2 The hydrochloride of 4-(5,6,7,8-tetrahydro- 5,5,8, 8-tetramethyl-2-naphthylcarboxamidino) 4 phenol 4-(a-chloro-5, 6,7,8-tetrahydro-5,5,8,8-tetramethyl- 2 -naphthylmethyl imino) anisole In a manner analogous to Example 1(b) by reacting 3 g (8.9 inmoles) of 4-(5,6,7,8-tetrahydro-5,5,8,S-tetramethyl-2naphthylcarboxamido) anisole with 30 W~ of thionyl chloride, the expected iminochloride is recovered and used as such in the S following synthesis.
L 4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2naphthylcarboxamidinv) anisole in a manner analogous to Example 1(c) by reacting 8.9 %moles of the iminochloride obtained above in with 62 ml of ammonia and after recrystallization in hexane, 1.22 g of the expected product whose melting point is 138-1400C are isolated.
~I aThe hydrochloride of 4-(5,6,7,8-tetrahydro-5,5,8,8tetramethyl-2 -naphthylcarboxanidino) phenol CInC round bottom flask, there are introduced 800 mg (2.38 C mmoles) of the derivative previously obtained in and 5 g -38- (43.3 mmoles) of pyridine hydrochloride. The reaction mixture is progressively heated to 190-200'C with vigorous stirring and this temperature is maintained for 1 hour. The reaction mixture is returned to 100*C and a large excess of water is added. The resulting precipitate is filtered, washed abundantly with demineralized water and dried for 48 hours at 80'C. 500 mg (59%) of the expected phenol whose melting point is 255-256*C are Sobtained.
Example 24 4-(N 1 -methyl-N 2 -methyl-5,6,7,8-tetrahydro-5,5,8,8tetramethyl-2-naphthylcarboxamidino) benzoic acid N-methyl-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl- 2-naphthyl) amide In a round bottom flask, there are introduced 0.75 g (43 mmoles) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthoyl chloride and 70 ml of THF. 10 ml of N-methylamine (40% in water) are slowly added and the mixture is stirred for 8 hours at c ambient temperature. The reaction mixture is poured into water.
The resulting precipitate is filtered, washed until neutral and dried for 24 hours at 80'C. 10.16 g of the expected amide whose melting point is 136-140'C are obtained.
methyl 4-(N 1 -methyl-N 2 -methyl-5,6,7,8-tetrahydroj 5,5,8,8-tetramethyl-2-naphthylcarboxamidino) benzoate SIn a manner analogous to Example 11(b) by reacting 1.5 g
C
c V (6.12 mmoles) of the derivative previously obtained in with ml of thionyl chloride, there is recovered, after evaporation, C I i i i -39the corresponding iminochloride that is diluted in 25 ml of THF.
There are then added, at ambient temperature, 2 g (12.12 mmoles) of methyl 4-(N-methylamino) benzoate dissolved in 20 ml of THF and the mixture is stirred for 8 hours. After chromatography on casilica column eluted with ethyl acetate 380 mg of the expected ester whose melting point is 225-230'C are isolated.
4-(N 1 -methyl-N 2 -methyl-5,6,7,8-tetrahydro-5,5,8,8tetramethyl-2-naphthylcarboxamidino) benzoic acid In a round bottom flask, there are introduced 250 mg (0.64 mmole) of the ester previously obtained in 630 mg (15.8 mmoles) of soda and 12 ml of methanol. The reaction medium is maintained at reflux for 4 hours and the methanol is then evaporated. The residue is taken up in water, neutralized with acetic acid and evaporated to dryness. The residue is taken up in THF and filtered. The filtrate is evaporated and an oil which precipitates in hexane is obtained. After filtration, 35 mg of the expected acid whose melting point is 275-280'C are isolated V t Examples of Compositions A. Oral Compositions 0.2 g tablet t i Compound of Example 1 0.001 g Starch 0.114 g Dicalciumphosphate 0.020 g Silica 0.020 g r c i i
F
I
I
Lactose 0.030 g Talc 0.010 g Magnesium stearate 0.005 g In this example, the compound of Example 1 can be replaced by the same amount of the compound of Example 2.
Drinkable suspension in 5 ml ampoules Compound of Example 3 0.500 g Glycerine 0.500 g Sorbitol, 70% 0.500 g Sodium saccharinate 0.010 g Methyl parahydroxybenzoate 0.040 g Flavor, sufficient amount Purified water, sufficient amount for 5 ml In this example, the compound of Example 3 can be replaced by the same amount of the compound of Example 4.
0.8 g tablet Compound of Example 7 0.500 g Pregelatinized starch 0.100 g Microcrystalline cellulose 0.115 g Lactose 0.075 g Magnesium stearate 0.010 g In this example the compound of Example 7 can be replaced by the same amount of the compound of Example 9.
Drinkable suspension in 10 ml ampoules Compound of Example 5 0.200 g Glycerine 1.000 g 6*
A
A S. A .4.666
SR
I~
A I
C
lit I~ -41- Sorbitol, 70% 1.000 g Sodium saccharinate 0.010 g Methyl parahydroxybenzoate 0.080 g Flavor, sufficient amount Purified water, sufficient amount for 10 ml B. Topical Compositions Ointment Compound of Example 1 0.020 g Isopropyl myristate 81.700 g Fluid petrolatum oil 9.100 g Silica, sold under the trade name "AEROSIL 200" by Degussa 9.180 g In this example, the compound of Example 1 can be replaced by the same amount of the compound of Example 2.
Ointment Compound of Example 3 0.300 g White petrolatum codex, sufficient S..amount for 100 g In this example, the compound of Example 3 can be replaced by the same amount of the compound of Example 4.
Nonionic water-in-oil cream SCompound of Example 7 0.100 g S, Mixture of emulsive lanolin alcohols, waxes and raffinated oils, sold under the trade name "EUCERINE ANHYDRE" by BDF 39.900 g I Methyl parahydroxybenzoate 0.075 g c\ C¢ C, Sc -42- Propyl parahydroxybenzoate 0.075 g Sterile, demineralized water, sufficient amount for 100 g In this example the compound of Example 7 can be replaced by the same amount of the compound of Example 9.
Lotion Compound of Example 5 0.100 g Polyethylene glycol (PEG 400) 69.900 g Ethanol, 95% 30.000 g Hydrophobic ointment Compound of Example 6 0.300 g Isopropyl myristate 36.400 g Silicone oil, sold under the trade name S• "RHODORSIL 47 V 300" by Rhone Poulenc 36.400 g Beeswax 13.600 g S: Silicone oil, sold under the trade name "ABIL 300.000 cst" by Goldschmidt, in an amount sufficient for 100 g Nonionic oil-in-water cream Compound of Example 8 1.000 g Cetyl alcohol 4.000 g Glycerol monostearate 2.500 g Stearate of "PEG 50" 2.500 g Karite butter 9.200 g Propylene glycol 2.000 g Methyl parahydroxybenzoate 0.075 g Propyl parahydroxybenzoate 0.075 g -43- Sterile, demineralized water, sufficient amount for 100 g Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers.
r oi
I
~o r r o e r i I r il_
Claims (16)
1. A bi-aromatic compound having the formula R 2 R4 R 6 (I) R wherein R 1 represents hydrogen, -OH, -CH 3 -CH20H, -COR 7 -CH(OH)CH 3 -CH 2 OCOR 8 -SO 2 Rg, -SOR 9 or -SRg, *"R 7 represents hydrogen, -OH, -OR 1 0 -N lower alkyl, monohydroxyalkyl, polyhydroxyalkyl or the residue of a sugar, R 8 represents linear or branched alkyl having 1-20 carbon atoms, alkenyl having 2-20 carbon atoms or the residue of a Ssugar, Rg represents -OH, lower alkyl or -N R 10 represents alkyl having 1-20 carbon atoms or alkenyl having 2-20 carbon atoms, r' and each independently, represent hydrogen, lower alkyl, aryl, aralkyl, an amino acid residue, a sugar residue, an aminated sugar residue or a heterocycle, or r' and r" taken together form a heterocycle, R 2 and R 6 represent hydrogen, OH, lower alkyl, alkoxy having 1-6 carbon atoms, fluorine, chlorine or CF3, R 3 and R 5 represent a,a'-disubstituted alkyl having 4-12 carbon atoms or mono or polycyclic cycloalkyl having 5-12 carbon atoms whose linking carbon is trisubstituted, R 4 represents hydrogen, OH, alkoxy having 1-6 carbon atoms, a,a'-disubstituted alkyl having 4-12 carbon atoms, R 3 and R 4 or R 4 and R 5 taken together form, with the adjacent benzene ring, a ring having 5 or 6 carbon atoms substituted by 2 to 6 methyl groups, S. Z represents an oxygen or sulfur atom, -CH=CR 11 or -N=CR12-, R represents hydrogen, OH or lower alkyl, ea 4 R 12 represents hydrogen or lower alkyl, X is selected form the group consisting of -CR13=N- -N=CR13 I iii) -C-NR1 4 and I (iv) -NR 1 4 -C- R16 R 13 represents R 16 OR 16 -SR 16 or N R17 i L r: -46- R16 and R 17 represent hydrogen, lower alkyl, fluoro lower alkyl, alkenyl having 2-6 carbon atoms, alkynyl having 2-6 carbon atoms, aryl or aralkyl, R 14 represents lower alkyl, R 1 5 represents lower alkyl or fluoro lower alkyl, with the exclusion of compounds of Formula wherein R 3 and R 5 are identical when X represents -CR 13 wherein R 13 represents hydrogen, and the salts of said compound of Formula obtained by the addition of a base when R 1 represents a carboxylic acid function or by the addition of an acid.
2. The compound of Claim 1 provided in the form of a salt 4 of an alkali metal, an alkaline earth metal, zinc or an organic amine.
3. The compound of Claim 1 provided in the form of a salt of a mineral or organic acid selected from the group consisting of hydrochloric acid, sulfuric acid, acetic acid, citric acid, fumaric acid, hemisuccinic acid, maleic acid and mandelic acid.
4. The compound of Claim 1 wherein said lower alkyl having 1-6 carbon atoms is selected from the group consisting of methyl, ethyl, isopropyl, butyl and tert.butyl. i -i I-1; C I_ a -47- The compound of Claim 1 wherein said alkoxy having 1-6 carbon atoms is selected from the group consisting of methoxy, ethoxy, isopropoxy and butoxy.
6. The compound of Claim 1 wherein said a,a'-disubstituted alkyl is selected from the group consisting of tert.butyl, 1,1- dimethylpropyl, l-methyl-l-ethylpropyl, 1-methyl-l-ethylhexyl and 1,1-dimethyldecyl.
7. The compound of Claim 1 wherein said mono or polycyclic cycloalkyl having 5-12 carbon atoms whose linking carbon is trisubstituted is 1-methyl cyclohexyl or 1-adamantyl.
8. The compound of Claim 1 wherein said monohydroxyalkyl is 2-hydroxyethyl, 2-hydroxypropyl or 3-hydroxypropyl. i
9. The compound of Claim 1 wherein said polyhydroxyalkyl has 2-6 carbon atoms and 2-5 hydroxyl groups and is selected from the group consisting of 2,3-dihydroxypropyl, 2,3,4- trihydroxybutyl, 2,3,4,5-tetrahydroxypentyl and the residue of pentaerythritol. The compound of Claim 1 wherein said aryl is phenyl or phenyl substituted by at least one of a halogen, hydroxyl or nitro function. i llrCI -48-
11. The compound of Claim 1 wherein said aralkyl is benzyl or phenethyl, optionally substituted by at least one of halogen, hydroxyl or a nitro function.
12. The compound of Claim 1 wherein said alkynyl having 2- 6 carbon atoms is propargyl.
13. The compound of Claim 1 wherein said alkenyl having 2- 6 carbon atoms is selected from the group consisting of vinyl, propenyl, 2-methyl propenyl and butene-2-yl.
14. The compound of Claim 1 wherein said fluoro lower alkyl has 1-6 carbon atoms and 3-7 fluorine atoms.
15. The compound of Claim 1 wherein said heterocycle is selected from the group consisting of piperidino, morpholino, pyrrolidino or piperazino, optionally substituted in the 4 position by a C 1 -C 6 alkyl or mono or polyhydroxyalkyl. i 16. The compound of Claim 1 selected from the group consisting of 4-(N-methyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2- naphthylcarboxamidino) benzoic acid, 4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2- naphthylcarboxamidino) benzoic acid, -49- I (1-adamantyl) -2-hydroxy-4-methoxybenzylideneamino] [I benzoic acid, 4-(3.-(l-adamantyl) -4-methoxybenzamidino] benzoic acid, the hydrochloride of 4-[N-methyl-3- (1-adamant. vi) -4- methoxybenzamidino] benzoic acid, 4- (3-C -adamantyl) -4-methoxyphenylformamidino- methyithioether] benzoic acid, (1-adamantyl) -4-methoxyphenylformamidinomethylether] benzoic acid, methyl 1-adamantyl) -4-methoxyberizylideneaminoJ benzoate, (l-adamantyl) -4-methoxybenzylideneamino] benzoic acid, 4-(3-tert.butyl-4-methoxybenzamidino) benzoic acid, methyl 8-tetra1ydro-5,5,8, 8-tetramethyl-2- naphthylcarboxamidino) benzoate, 4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2- naphthylcarboxamidino) benzyl alcohol, 6,7,8-tetrahydro-5,5,8,8-tetranethyl-2- naphthylcarboxamidino) toluene, 4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2- naphthiylcarboxamidino) benzamide, 2 -hydroxy-4 -tetrahydro-5 ,5,8,8 -tetramethyl -2- naphthylcarboxamidino) benzoic acid, allyl 4-(a-chloro-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2- naphthylmethylimino) benzoate, 6,7, 8-tetrahydro-5, 5,8,8-tetramethyl-2- naphthylcarboxamidino) benzoic acid, the hydrochloride of 4- (Nl-phenyl-5, 6,7, 8-tetrahydro- 5,5,8, 8-tetramethyl-2-naphthylarboxaidilo) benzoic acid, 4-(NI-beflzyl-5,6,7, 8-tetrahydro-5,5,8,8-tetramethyl-"2- naphthylcarboxamidino) benzoic acid, naphthylcarboxamidilo) benzoic acid, 4-(N 2 -(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) amidino] benzoic acid, 4IN-hnlN-5678ttayr-,,,-ermty,2 naphthyl) amidinojbenzoic acid, the hydrochloride of 4-(5,6,7,8-tetrahydro-5,5,8,8- tetramethy'l-2-naphthylcarboxamidino) phenol, 4 -(Nl-methyl-N 2 -methyl-5,6,7,8-tetrahydro-5,5,8,8- 'I a a''tetramethyl-2-naphthylcarboxamidilo) benzoic acid and 4-N(,,-rfIooty)-,,,-erhdo5588 tetramethyl-2-naphthylcarboxamidino) benzoic acid. A~N(,,-rfurehl-,,,-erhdO5588 ,4 A pharmaceutical composition comprising in a 11 pharmaceutically acceptable vehicle, for enteral, parenteral, a topical or ocular administration to a human or an animal, a I a therapeutically effective amount of at least one compound of formula of Claim 1. 'it -51-
18. The composition of Claim 17 wherein said compound of Formula is present in an amount ranging from 0.001 to about percent by weight based on the total weight of said composition.
19. A process for the treatment of dermatologic, rheumatismal, respiratory or ophthalmologic ailments comprising administering to a human or animal host a therapeutically effective amount of the pharmaceutical composition of Claim 17. A cosmetic composition for body and hair hygiene comprising in a cosmetically acceptable vehicle a cosmetically effective amount of at least one compound of Formula of Claim 1. S,"21. The cosmetic composition of Claim 20 wherein said compound of Formula is present in an amount ranging from 0.001 to 3 percent by weight based on the total weight of said t composition. c 1 L- i 7- V -52-
22. A compound of claim 1, a process for the preparation or use thereof, or a pharmaceutical or cosmetic composition comprising a said compound, substantially as hereinbefore described with reference to the Examples. -93 T he steps, features, compositi- compounds disclosed herein or referred or indicated in the specification and/or aims of this application, individuall collectively, and any and all combinations olf ato r more oM rf s- or features. r 1 i t Cf DATED this TWENTY EIGHTH day of MAY 1992 Centre International De Recherches Dermatologiques Galderma (CIRD G;iderma) by DAVIES COLLISON CAVE Patent Attorneys for the applicant(s) 1/2 ABSTRACT A bi-aromatic compound has the formula R3 S r(I) R 1 is H, OH, -CH 3 -CH 2 OH, -COR 7 -CH(OH)CH 3 -CH20COR 8 -SO 2 R9, -SOR9 or -SRg, R 7 represents hydrogen, -OH, -OR 10 -N lower r" alkyl, monohydroxyalkyl, polyhydroxyalkyl or the residue of a sugar, R 8 represents linear or branched alkyl having 1-20 carbon atoms, alkenyl having 2-20 carbon atoms or the residue of a S* sugar, R 9 represents -OH, lower alkyl or -N represents alkyl having 1-20 carbon atoms or alkenyl I having 2-20 carbon atoms, r' and each independently, represent hydrogen, lower alkyl, aryl, aralkyl, an amino acid residue, a sugar residue, an aminated sugar residue or a heterocycle, or r' and r" taken together form a heterocycle, R 2 and R 6 represent hydrogen, OH, lover alkyl, alkoxy having 1-6 carbon atoms, fluorine, chlorine or CF 3 R 3 and R 5 represent a,a'-disubstituted alkyl having 4-12 carbon atoms or mono or polycyclic cycloalkyl having 5-12 carbon atoms whose linking carbon is trisubstituted, R 4 represents hydrogen, OH, alkoxy having 1-6 carbon atoms, a,a'-disubstituted alkyl having 4-12 carbon atoms, 2/2 R 3 and R 4 or R 4 and R 5 taken together form, with the adjacent benzene ring, a ring having 5 or 6 carbon atoms substituted by 2 to 6 methyl groups, Z represents an oxygen or sulfur atom, -CH=CR 11 or -N-CR 12 R 11 represents hydrogen, OH or lower alkyl, R 12 represents hydrogen or lower alkyl, X is selected form the group consisting of -CR 13 =N- (ii) -N=CR 13 (iii) -C-NR 14 and N-R 1 (iv) -NR 1 4 -C- N-R 1 i R16 S;R 13 represents R 1 6 OR 16 -SR 16 or N R17 R 16 and R 17 represent hydrogen, lower alkyl, fluoro lower alkyl, alkenyl having 2-6 carbon atoms, alkynyl having 2-6 carbon atoms, aryl or aralkyl, R 14 represents lower alkyl, R 15 represents lower alkyl or fluoro lower alkyl, with the exclusion of compounds of Formula wherein R 3 and R 5 are identical when X represents -CR 13 wherein R 13 represents hydrogen, and the salts of said compound of Formula obtained by the addition of a base when R 1 represents a carboxylic acid function or by the addition of an acid.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR9105883 | 1991-05-15 | ||
| FR9105883A FR2676440B1 (en) | 1991-05-15 | 1991-05-15 | NOVEL AROMATIC COMPOUNDS DERIVED FROM IMINE, THEIR PREPARATION PROCESS AND THEIR USE IN HUMAN AND VETERINARY MEDICINE AND IN COSMETICS. |
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| Publication Number | Publication Date |
|---|---|
| AU1627392A AU1627392A (en) | 1992-11-19 |
| AU650972B2 true AU650972B2 (en) | 1994-07-07 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU16273/92A Ceased AU650972B2 (en) | 1991-05-15 | 1992-05-15 | Aromatic compounds derived from imine, their preparation and their use in human and veterinary medicine and in cosmetics |
Country Status (10)
| Country | Link |
|---|---|
| EP (1) | EP0514269B1 (en) |
| JP (1) | JP3233451B2 (en) |
| AT (1) | ATE129698T1 (en) |
| AU (1) | AU650972B2 (en) |
| CA (1) | CA2068696A1 (en) |
| DE (1) | DE69205725T2 (en) |
| DK (1) | DK0514269T3 (en) |
| ES (1) | ES2080458T3 (en) |
| FR (1) | FR2676440B1 (en) |
| GR (1) | GR3018702T3 (en) |
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| US5648514A (en) | 1994-12-29 | 1997-07-15 | Allergan | Substituted acetylenes having retinoid-like biological activity |
| US5534641A (en) | 1994-12-29 | 1996-07-09 | Allergan | Acetylenes disubstituted with 2-tetrahydropyranoxyaryl and aryl or heteroaryl groups having retinoid-like biological activity |
| US5675033A (en) | 1995-06-06 | 1997-10-07 | Allergan | 2,4-pentadienoic acid derivatives having retinoid-like biological activity |
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| US5958954A (en) | 1995-09-01 | 1999-09-28 | Allergan Sales, Inc. | Synthesis and use of retinoid compounds having negative hormone and/or antagonist activities |
| US6008204A (en) | 1995-09-01 | 1999-12-28 | Allergan Sales, Inc. | Synthesis and use of retinoid compounds having negative hormone and/or antagonist activities |
| US5952345A (en) | 1995-09-01 | 1999-09-14 | Allergan Sales, Inc. | Synthesis and use of retinoid compounds having negative hormone and/or antagonist activities |
| US5675024A (en) | 1995-11-22 | 1997-10-07 | Allergan | Aryl or heteroaryl amides of tetrahydronaphthalene, chroman, thiochroman and 1,2,3,4,-tetrahydroquinoline carboxylic acids, having an electron withdrawing substituent in the aromatic or heteroaromatic moiety, having retinoid-like biological activity |
| US5965606A (en) | 1995-12-29 | 1999-10-12 | Allergan Sales, Inc. | Methods of treatment with compounds having RAR.sub.α receptor specific or selective activity |
| US5773594A (en) | 1996-06-21 | 1998-06-30 | Allergan | Alkyl or aryl substituted dihydronaphthalene derivatives having retinoid and/or retinoid antagonist-like biological activity |
| US5763635A (en) | 1996-06-21 | 1998-06-09 | Allergan | Tetrahydronaphthalene derivatives substituted in the 8 position with alkyhidene groups having retinoid and/or retinoid antagonist-like biological activity |
| US6555690B2 (en) | 1996-06-21 | 2003-04-29 | Allergan, Inc. | Alkyl or aryl substituted dihydronaphthalene derivatives having retinoid and/or retinoid antagonist-like biological activity |
| US5741896A (en) | 1996-06-21 | 1998-04-21 | Allergan | O- or S- substituted tetrahydronaphthalene derivatives having retinoid and/or retinoid antagonist-like biological activity |
| US5728846A (en) | 1996-12-12 | 1998-03-17 | Allergan | Benzo 1,2-g!-chrom-3-ene and benzo 1,2-g!-thiochrom-3-ene derivatives |
| US6037488A (en) | 1997-04-19 | 2000-03-14 | Allergan Sales, Inc. | Trisubstituted phenyl derivatives having retinoid agonist, antagonist or inverse agonist type biological activity |
| US5919970A (en) | 1997-04-24 | 1999-07-06 | Allergan Sales, Inc. | Substituted diaryl or diheteroaryl methanes, ethers and amines having retinoid agonist, antagonist or inverse agonist type biological activity |
| US6369261B1 (en) | 2000-08-29 | 2002-04-09 | Allergan Sales, Inc. | Compounds having activity as inhibitors of cytochrome P450RAI |
| US6369225B1 (en) | 2000-08-29 | 2002-04-09 | Allergan Sales, Inc. | Compounds having activity as inhibitors of cytochrome P450RAI |
| US6387951B1 (en) | 2000-08-29 | 2002-05-14 | Allergan Sales, Inc. | Compounds having activity as inhibitors of cytochrome P450RAI |
| US6380256B1 (en) | 2000-08-29 | 2002-04-30 | Allergan Sales, Inc. | Compounds having activity as inhibitors of cytochrome P450RAI |
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| FR2910321B1 (en) | 2006-12-21 | 2009-07-10 | Galderma Res & Dev S N C Snc | CREAM GEL COMPRISING AT LEAST ONE RETINOID AND BENZOLE PEROXIDE |
| FR2910320B1 (en) | 2006-12-21 | 2009-02-13 | Galderma Res & Dev S N C Snc | EMULSION COMPRISING AT LEAST ONE RETINOID AND BENZOLE PEROXIDE |
| FR2931661B1 (en) | 2008-05-30 | 2010-07-30 | Galderma Res & Dev | NOVEL DEPIGMENTING COMPOSITIONS IN THE FORM OF AN ANHYDROUS VASELIN - FREE AND ELASTOMER - FREE COMPOSITION COMPRISING A SOLUBILIZED PHENOLIC DERIVATIVE AND A RETINOID. |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4264505A (en) * | 1978-06-12 | 1981-04-28 | Usv Pharmaceutical Corporation | Substituted benzylidene imines |
| US4927928A (en) * | 1986-01-21 | 1990-05-22 | Centre International De Recherches Dermatologiques C.I.R.D. | Aromatic benzamido compounds, their preparation and their use in human or veterinary medicine or in cosmetic preparations |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3669974A (en) * | 1971-03-25 | 1972-06-13 | Usv Pharma Corp | N,n1-disubstituted benzamidines |
-
1991
- 1991-05-15 FR FR9105883A patent/FR2676440B1/en not_active Expired - Fee Related
-
1992
- 1992-05-14 DE DE69205725T patent/DE69205725T2/en not_active Expired - Fee Related
- 1992-05-14 AT AT92401320T patent/ATE129698T1/en not_active IP Right Cessation
- 1992-05-14 DK DK92401320.4T patent/DK0514269T3/en active
- 1992-05-14 EP EP92401320A patent/EP0514269B1/en not_active Expired - Lifetime
- 1992-05-14 CA CA002068696A patent/CA2068696A1/en not_active Abandoned
- 1992-05-14 ES ES92401320T patent/ES2080458T3/en not_active Expired - Lifetime
- 1992-05-15 AU AU16273/92A patent/AU650972B2/en not_active Ceased
- 1992-05-15 JP JP16529192A patent/JP3233451B2/en not_active Expired - Fee Related
-
1996
- 1996-01-17 GR GR960400103T patent/GR3018702T3/en unknown
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4264505A (en) * | 1978-06-12 | 1981-04-28 | Usv Pharmaceutical Corporation | Substituted benzylidene imines |
| US4927928A (en) * | 1986-01-21 | 1990-05-22 | Centre International De Recherches Dermatologiques C.I.R.D. | Aromatic benzamido compounds, their preparation and their use in human or veterinary medicine or in cosmetic preparations |
Also Published As
| Publication number | Publication date |
|---|---|
| FR2676440B1 (en) | 1993-07-30 |
| DE69205725T2 (en) | 1996-05-30 |
| DK0514269T3 (en) | 1996-03-04 |
| JP3233451B2 (en) | 2001-11-26 |
| GR3018702T3 (en) | 1996-04-30 |
| AU1627392A (en) | 1992-11-19 |
| EP0514269B1 (en) | 1995-11-02 |
| ES2080458T3 (en) | 1996-02-01 |
| FR2676440A1 (en) | 1992-11-20 |
| DE69205725D1 (en) | 1995-12-07 |
| ATE129698T1 (en) | 1995-11-15 |
| JPH05221951A (en) | 1993-08-31 |
| EP0514269A1 (en) | 1992-11-19 |
| CA2068696A1 (en) | 1992-11-16 |
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