# US 5,702,710 A · Dibenzofuran compounds and pharmaceutical/cosmetic compositions comprised thereof

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- Number: US 5,702,710 A
- Document ID: US5702710A
- Status: Granted
- Kind: A
- Application number: 08/539,222
- Filed: 1995-10-04
- Granted: 1997-12-30
- Earliest claimed: 1994-10-04
- Assignees: Centre International de Recherches Dermatologiques Galderma
- Inventors: Bruno Charpentier; Michele Vion; Bruno Bernard; Jean Maignan
- Web page: https://patentgrep.com/patent/US5702710A

## CPC

- C07D 407/04: directly linked by a ring-member-to-ring-member bond
- A61K 8/4973: {with oxygen as the only hetero atom}
- A61K 8/671: {Vitamin A; Derivatives thereof, e.g. ester of vitamin A acid, ester of retinol, retinol, retinal}
- A61Q 19/00: Preparations for care of the skin
- C07D 307/93: condensed with a ring other than six-membered
- A61Q 7/00: Preparations for affecting hair growth
- A61Q 17/04: Topical preparations for affording protection against sunlight or other radiation; Topical sun tanning preparations
- A61Q 19/08: Anti-ageing preparations
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61Q: SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS

## Abstract

Novel pharmaceutically/cosmetically-active dibenzofuran compounds have the structural formula (I): ##STR1## wherein A is a radical having one of the formulae (IIa), (IIb) or (IIc): ##STR2## and are useful for the treatment of a wide variety of disease states, whether human or veterinary, for example dermatological, rheumatic, respiratory, cardiovascular and ophthalmological disorders, as well as for the treatment of mammalian skin and hair conditions/disorders.

## Claims

### Claim 1

A dibenzofuran compound having the structural formula (I): ##STR11## in which R is a hydrogen atom, a halogen atom, a lower alkyl radical having 1 to 6 carbon atoms, a lower acyl radical having 1 to 10 carbon atoms or an OR' radical; A is a radical selected from the group consisting of the following formulae (IIa-IIc): ##STR12## wherein R.sub.1 is (i) a hydrogen atom,
(ii) the --CH.sub.3 radical,
(iii) an --CH.sub.2 --O--R.sub.5 radical,
(iv) an --OR.sub.5 radical
(v) a ##STR13## radical, or (vi) an --S(O).sub.t R.sub.6 radical; R.sub.2 is a hydrogen atom or an --OR.sub.5 radical; R.sub.3 and R.sub.4 are independently a hydrogen atom, a lower alkyl radical having 1 to 6 carbon atoms or a --(X).sub.n --(CH.sub.2).sub.m --R.sub.7 radical, or R.sub.3 and R.sub.4 may together form an oxo (.dbd.O) group, a thioxo (.dbd.S) group, an oxime group or a group derived from the oxime (R.sub.6 --O--N.dbd.), an epoxy group, or a dioxolane group (--O--(CH.sub.2).sub.q --O--) wherein q is equal to 2 or 3; R.sub.3 ' and R.sub.4 ' are independently a hydrogen atom, a lower alkyl radical having 1 to 6 carbon atoms or a lower acyl radical having 1 to 6 carbon atoms; t is equal to 0, 1 or 2; R.sub.5 is a hydrogen atom, a lower alkyl radical having 1 to 6 carbon atoms, or a lower acyl radical having 1 to 6 carbon atoms; R.sub.6 is a hydrogen atom, an --N(R',R'") radical, or an --OR.sub.8 radical; R.sub.6 is a hydrogen atom or a --(CO).sub.p --R.sub.9 radical, wherein p is 0 or 1; R.sub.8 and R' are independently a hydrogen atom, an alkyl radical having from 1 to 20 carbon atoms, a mono- or polyhydroxyalkyl radical respectively having 1 to 6 or 2 to 6 carbon atoms, an optionally substituted phenyl radical or optionally substituted benzyl or phenethyl radical wherein the substituents on said phenyl, benzyl or phenethyl radical, if present, are selected from the group consisting of halogen, hydroxyl, nitro and methoxy groups; R.sub.9 is a hydrogen atom, an alkyl radical, having 1 to 20 carbon atoms, an alkenyl radical which is a linear or branched radical having 1 to 20 carbon atoms and having at least one ethylenic double bond, an alkynyl radical, which is a linear or branched radical having 1 to 20 carbon atoms and having at least one acetylenic double bond, a phenyl radical, an --OR.sub.7 radical wherein m is other than 0, or an --N(R',R'") radical; R' and R'", which may be identical or different, are each a hydrogen atom, a lower alkyl radical having 1 to 6 carbon atoms, a mono- or polyhydroxyalkyl radical respectively having 1 to 6 or 2 to 6 carbon atoms, an optionally substituted phenyl radical, an optionally substituted benzyl or phenethyl radical wherein the substituents on said phenyl, benzyl or phenethyl radical, if present, are selected from the group consisting of halogen, nitro, hydroxyl and methoxy group; X is an oxygen or sulfur atom; and n ranges from 0 to 1 and m from 0 to 10; or a pharmaceutically/cosmetically acceptable salt or optical or geometric isomer thereof.

### Claim 2 (depends on 1)

A dibenzofuran compound as defined by claim 1, wherein formula (I), A has the structure (IIa).

### Claim 3 (depends on 1)

A dibenzofuran compound as defined by claim 1, wherein formula (I), A has the structure (IIb).

### Claim 4 (depends on 1)

A dibenzofuran compound as defined by claim 1, wherein formula (I), A has the structure (IIc).

### Claim 5 (depends on 1)

A dibenzofuran compound as defined by claim 1, comprising a pharmaceutically acceptable salt thereof.

### Claim 6 (depends on 1)

A dibenzofuran compound as defined by claim 1, wherein formula (I), the lower alkyl radical substituents are selected from the group consisting of methyl, ethyl, isopropyl, butyl, tert-butyl and hexyl radicals.

### Claim 7 (depends on 1)

A dibenzofuran compound as defined by claim 1, wherein formula (I), the lower acyl radical is selected from the group consisting of acetyl, propionyl and pivaloyl radicals.

### Claim 8 (depends on 1)

A dibenzofuran compound as defined by claim 1, wherein formula (I), the monohydroxyalkyl radical substituents are selected from the group consisting of 2-hydroxyethyl, 2-hydroxypropyl and 3-hydroxypropyl radicals.

### Claim 9 (depends on 1)

A dibenzofuran compound as defined by claim 1, wherein formula (I), the polyhydroxyalkyl radical substituents are selected from the group consisting of 2,3-dihydroxypropyl, 2,3,4-trihydroxybutyl, 2,3,4,5-tetrahydroxypentyl and pentaerythritol radicals.

### Claim 10 (depends on 1)

A dibenzofuran compound as defined by claim 1, selected from the group consisting of methyl 6-›(1,2,3,4-tetrahydro-1,4a,9b-trimethyl-1,4-methanodibenzofuran-8-yl)carb onyl!-2-naphthoate; 6-›(1,2,3,4-tetrahydro-1,4a,9b-trimethyl-1,4-methanodibenzofuran-8-yl)carb onyl!-2-naphthoic acid; 6-›(1,2,3,4-tetrahydro-1,4a,9b-trimethyl-1,4-methanodibenzofuran-8-yl)meth yl!-2-naphthoic acid; methyl 6-›(1,2,3,4-tetrahydro-1,4a,9b-trimethyl-1,4-methanodibenzofuran-8-yl)hydr oxymethyl!-2-naphthoate; 6-›(1,2,3,4-tetrahydro-1,4a,9b-trimethyl-1,4-methanodibenzofuran-8-yl)hydr oxymethyl!-2-naphthoic acid; methyl 4-›(1,2,3,4-tetrahydro-1,4a,9b-trimethyl-1,4-methanodibenzofuran-8-yl)carb onyl!benzoate; 4-›(1,2,3,4-tetrahydro-1,4a,9b-trimethyl-1,4-methanodibenzofuran-8-yl)carb onyl!benzoic acid; 4-›(1,2,3,4-tetrahydro-1,4a,9b-trimethyl-1,4-methanodibenzofuran-8-yl)hydr oxymethyl!phenylcarbinol; 4-›(1,2,3,4-tetrahydro-1,4a,9b-trimethyl-1,4-methanodibenzofuran-8-yl)carb onyl!benzaldehyde; 2-(1,2,3,4-tetrahydro-1,4a,9b-trimethyl-1,4-methanodibenzofuran-8-yl)-2-(4 -methoxycarbonylphenyl)-1,3-dioxolane; 2-(1,2,3,4-tetrahydro-1,4a,9b-trimethyl-1,4-methanodibenzofuran-8-yl)-2-(4 -carboxyphenyl)-1,3-dioxolane; 1,2,3,4-tetrahydro-1,4a,7,9b-tetramethyl-1,4-methanodibenzofuran; methyl 4-›(1,2,3,4-tetrahydro-1,4a,7,9b-tetramethyl-1,4-methanodibenzofuran-8-yl) carbonyl!benzoate; and 4-›(1,2,3,4-tetrahydro-1,4a,7,9b-tetramethyl-1,4-methanodibenzofuran-8-yl) carbonyl!benzoic acid.

### Claim 11 (depends on 3)

A dibenzofuran compound as defined by claim 3, wherein formula (IIb), R.sub.1 is the radical: ##STR14##

### Claim 12 (depends on 1)

A dibenzofuran compound having the structural formula (X): ##STR15## in which R is as defined in claim 1; and R.sub.10 has the definition of R.sub.1 in claim 1, with the proviso that R.sub.10 can not be a hydrogen atom, and wherein R.sub.1 further can be a moiety selected from the group consisting of a halogen atom, a --C(O)--R.sub.8 radical, a --C(O)--CH.sub.2 -halogen radical, or a (CH.sub.2).sub.n N(R',R'") radical, wherein R.sub.8, R', R'" and n are also as defined in claim 1.

### Claim 13 (depends on 11)

A dibenzofuran compound as defined by claim 11, selected from the group consisting of 1,2,3,4-tetrahydro-1,4a,9b-trimethyl-1,4-methanodibenzofuran-8-yl methyl ketone; 1,2,3,4-tetrahydro-1,4a,9b-trimethyl-1,4-methanodibenzofuran-8-carboxaldeh yde; 1,2,3,4-tetrahydro-1,4a,9b-trimethyl-1,4-methanodibenzofuran-8-carboxylic acid; 1,2,3,4-tetrahydro-1,4a,9b-trimethyl-1,4-methanodibenzofuran-8-yl bromomethyl ketone; and 8-ethynyl-1,2,3,4-tetrahydro-1,4a,9b-trimethyl-1,4-methanodibenzofuran.

### Claim 14 (depends on 1)

A pharmaceutical composition of matter, comprising a therapeutically effective amount of a dibenzofuran compound as defined by claim 1, or pharmaceutically acceptable salt or isomer thereof, and a pharmaceutically acceptable carrier or diluent therefor.

### Claim 15 (depends on 14)

The pharmaceutical composition as defined by claim 14, further comprising a retinoid compound, a D vitamin a corticosteroid, an anti-free radical agent, an .alpha.-hydroxy or .alpha.-keto acid an ion channel blocker, or combination thereof.

### Claim 16 (depends on 14)

The pharmaceutical composition as defined by claim 14, selected from the group consisting of a tablet, a capsule, a syrup, a suspension, an elixir, a solution, a powder, granules, an emulsion, microspheres, nanospheres, lipid vesicles, polymeric vesicles, or a composition for injection.

### Claim 17 (depends on 14)

The pharmaceutical composition as defined by claim 14, selected from the group consisting of an ointment, a cream, a milk, a pommade, an impregnated pad, a gel, a spray, and a lotion.

### Claim 18 (depends on 14)

The pharmaceutical composition as defined by claim 14, for topical administration.

### Claim 19 (depends on 14)

The pharmaceutical composition as defined by claim 14, for systemic administration.

### Claim 20 (depends on 14)

The pharmaceutical composition as defined by claim 14, comprising from 0.001% to 5% by weight of said dibenzofuran compound, or salt or isomer thereof.

### Claim 21 (depends on 1)

A cosmetic composition of matter, comprising a cosmetically effective amount of a dibenzofuran compound as defined by claim 1, or cosmetically acceptable salt or isomer thereof, and a cosmetically acceptable carrier or diluent therefor.

### Claim 22 (depends on 21)

The cosmetic composition as defined by claim 21, selected from the group consisting of a cream, a milk, a lotion, a gel, microspheres, nanospheres, lipid vesicles, polymeric vesicles, a soap, and a shampoo.

### Claim 23 (depends on 21)

The cosmetic composition as defined by claim 21, comprising from 0.001% to 3% by weight of said dibenzofuran compound, or salt or isomer thereof.

### Claim 24 (depends on 21)

The cosmetic composition as defined by claim 21, further comprising a compound selected from the group consisting of retinoid compound, a D vitamin a corticosteroid, an anti-free radical agent, an .alpha.-hydroxy or .alpha.-keto acid an ion channel blocker, and combinations thereof.

### Claim 25 (depends on 14)

The pharmaceutical composition as defined by claim 14, further comprising a compound selected from the group consisting of a wetting agent, a depigmenting agent, a moisturizing agent, an antiseborrhoeic or antiacne agent, an antibiotic, an antifungal agent, a hair regrowth promoter, a non-steroidal anti-inflammatory agent, a carotenoid, an anti-psoriatic agent, 5,8,11,14-eicosatetraytnoic, 5,8,11-eicosatrynoic acid or a pharmaceutically acceptable ester or amide thereof, and combinations thereof.

### Claim 26 (depends on 14)

The pharmaceutical composition as defined by claim 14, further comprising a compound selected from the group consisting of a taste- or flavor-enhancing agent, a preservative, a stabilizer, a moisture regulating agent, a pH regulating agent, an osmotic pressure modifying agent, an emulsifying agent, a UV-A or UV-B screening agent, an antioxidant, and combinations thereof.

### Claim 27 (depends on 21)

The cosmetic composition by claim 21, further comprising a compound selected from the group consisting of a wetting agent, a depigmenting agent, a moisturizing agent, an antiseborrhoeic or antiacne agent, an antibiotic, an antifungal agent, a hair regrowth promoter, a non-steroidal anti-inflammatory agent, a carotenoid, an anti-psoriatic agent, 5,8,11-14-eicosatetraynoic, 5,8,11-eicosatrynoic acid or cosmetically acceptable ester or amide thereof, and combinations thereof.

### Claim 28 (depends on 21)

The cosmetic composition as defined by claim 21, further comprising a compound selected from the group consisting of a taste- or flavor-enhancing agent, a preservative, a stabilizer, a moisture regulating agent, a pH regulating agent, an osmotic pressure modifying agent, an emulsifying agent, a UV-A or UV-B screening agent, an antioxidant, and combinations thereof.