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Patent 3013411 Summary

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(12) Patent Application: (11) CA 3013411
(54) English Title: NOVEL BIAROMATIC PROPYNYL COMPOUNDS, PHARMACEUTICAL AND COSMETIC COMPOSITIONS CONTAINING SAME, AND USES THEREOF
(54) French Title: NOUVEAUX COMPOSES PROPYNYL BI-AROMATIQUES, COMPOSITIONS PHARMACEUTIQUES ET COSMETIQUES LES CONTENANT ET UTILISATIONS
Status: Dead
Bibliographic Data
(51) International Patent Classification (IPC):
  • C07D 213/80 (2006.01)
  • A61K 31/192 (2006.01)
  • A61K 31/44 (2006.01)
  • C07C 65/19 (2006.01)
(72) Inventors :
  • PORTAL, THIBAUD (France)
(73) Owners :
  • GALDERMA RESEARCH & DEVELOPMENT (France)
(71) Applicants :
  • GALDERMA RESEARCH & DEVELOPMENT (France)
(74) Agent: BENOIT & COTE INC.
(74) Associate agent:
(45) Issued:
(86) PCT Filing Date: 2017-02-03
(87) Open to Public Inspection: 2017-08-10
Availability of licence: N/A
(25) Language of filing: English

Patent Cooperation Treaty (PCT): Yes
(86) PCT Filing Number: PCT/IB2017/000075
(87) International Publication Number: WO2017/134513
(85) National Entry: 2018-08-01

(30) Application Priority Data:
Application No. Country/Territory Date
62/290,707 United States of America 2016-02-03

Abstracts

English Abstract

The invention relates to novel compounds of general formula (I), as well as the use of said compounds in pharmaceutical compositions intended for use in human or veterinary medicine (dermatological, rheumatic, respiratory, cardiovascular and ophthalmologic disorders, in particular), or in cosmetic compositions.


French Abstract

L'invention concerne de nouveaux composés de formule générale (I) : ainsi que l'utilisation de ces derniers dans des compositions pharmaceutiques destinées à un usage en médecine humaine ou vétérinaire (affections dermatologiques, rhumatismales, respiratoires, cardiovasculaires et ophtalmologiques notamment), ou bien encore dans des compositions cosmétiques.

Claims

Note: Claims are shown in the official language in which they were submitted.


13
CLAIMS
1- Bi-aromatic propynyl compounds, characterized by the fact that they
correspond
to general formula (l) below:
Image
in which:
*Ar represents a radical chosen from among the radicals of formulas (a)-(e)
below:
Image
R5 having the meaning given below,
* R1 represents: (i) a hydrogen atom
(ii) a -CH3 radical
(ii) a -CH2-O-R6 radical
(iv) an -O-R6 radical
(v) a -CO-R7 radical,
(vi) an -S(O)t R9 radical
R6, R7, R9 and t having the signification given below,
* R2 and R3 represent a hydrogen atom, a linear or branched alkyl radical
having 1 to
20 carbon atoms, an -OR6 radical or an -SR6 radical, R6 having the meaning
given
below, given that R2 and R3, taken together, can form with the adjacent
aromatic ring
a 5- or 6-member ring optionally substituted by methyl groups and/or
optionally
interrupted by an oxygen or sulfur atom,

14
* R4 represents a hydrogen atom, a halogen atom, a lower alkyl radical or an -
0R6
radical, R6 radical having the meaning given below,
given that in all of the preceding:
- R6 represents a hydrogen atom, a lower alkyl radical, linear or branched
alkyl radical having 1 to 20 carbon atoms, an -O-CH3-R9 radical or a -CO-R9
radical,
R9 having the meaning given below,
- R7 represents:
(a) a hydrogen atom
(b) a lower alkyl radical
(c) a radical of formula:
Image
R' and R" having the meaning given below,
(d) an -OR8 radical, R8 having the meaning given below,
- R8 represents a hydrogen atom, a linear or branched alkyl radical having 1
to 20 carbon atoms, an alkenyl radical, a mono- or polyhydroxyalkyl radical,
an
optionally substituted aryl or aralkyl radical or a sugar residue or an amino
acid or
peptide residue,
- R9 represents a lower alkyl radical, or a linear or branched alkyl radical
having 1 to 20 carbon atoms,
- R' and R" represent a hydrogen atom, a lower alkyl radical, a mono- or
polyhydroxyalkyl radical, an optionally substituted aryl radical or an amino
acid or
peptide residue or sugar residue, or even, taken together, form a heterocycle,
- t is a whole number equal to 0, 1 or 2.
as well as salts and optical and geometric isomers thereof.

15
2- The compounds according to claim 1, further characterized in that they are
in the
form of alkali metal or alkaline earth metal salts, or even zinc or an organic
amine.
3- The compounds according to one of claims 1 or 2, further characterized in
that the
lower alkyl radicals are chosen in the group made up of methyl, ethyl,
isopropyl,
butyl, tert-butyl and hexyl radicals.
4- The compounds according to any one of the preceding claims, further
characterized in that the linear or branched alkyl radicals having 1 to 20
carbon
atoms are chosen in the group made up of methyl, ethyl, propyl, cyclopropyl,
cyclobutyl and cyclopentyl radicals.
5- The compounds according to any one of the preceding claims, further
characterized in that the monohydroxyalkyl radicals are chosen in the group
made
up of 2-hydroxyethyl, 2-hydroxypropyl, or 3-hydroxypropyl radicals.
6- The compounds according to any one of the preceding claims, further
characterized in that the polyhydroxyalkyl radicals are chosen in the group
made up
of 2,3-dihydroxypropyl, 2,3,4-trihydroxybutyl, 2,3,4,5-tetrahydroxypentyl
radicals or
the pentaerythritol residue.
7- The compounds according to any one of the preceding claims, further
characterized in that the aryl radical is a phenyl radical optionally
substituted with at
least one halogen atom, a hydroxyl, or a nitro function.
8- The compounds according to any one of the preceding claims, further
characterized in that the aralkyl radicals are chosen in the group made up of
benzyl
or phenethyl radicals optionally substituted by at least one halogen atom, a
hydroxyl,
or a nitro function.

16
9- The compounds according to any one of the preceding claims, further
characterized in that the alkenyl radicals are chosen in the group made up of
radicals
containing 1 to 5 carbon atoms and having one or more ethylene unsaturations,
in
particular, the allyl radical.
10- The compounds according to any one of the preceding claims, further
characterized in that the sugar residues are chosen in the group made up of
glucose,
galactose, mannose or glucuronic acid residues.
11- The compounds according to any one of the preceding claims, further
characterized in that the amino acid residues are chosen in the group made up
of
residues deriving from lysine, glycine or aspartic acid.
12- The compounds according to any one of the preceding claims, further
characterized in that the peptide residues are chosen in the group made up of
dipeptide or tripeptide residues.
13- The compounds according to any one of the preceding claims, further
characterized in that the heterocyclic radicals are chosen in the group made
up of
piperidino, morpholino, pyrrolidino or piperazino radicals, optionally
substituted in
position 4 by a C1-C6 alkyl or mono- or polyhydroxyalkyl radical.
14- The compounds according to any one of the preceding claims, further
characterized in that the halogen atoms are chosen in the group made up of
fluorine,
chlorine and bromine.
15- The compounds according to claim 1, further characterized by the fact that
they
are taken in the group made up of:

17
Image
- Compound 1:
Image
- Compound 2:
16- The compounds according to claim 1, further characterized in that R4
represents
the hydrogen atom, an -OH group or an -OR6 group, R5 represents the hydrogen
atom or -OH group, R1 a -CO-R7 radical, R7 represents an OR8 radical.
17- The compounds according to any one of the preceding claims for use as a
medicament.

Description

Note: Descriptions are shown in the official language in which they were submitted.


CA 03013411 2018-08-01
1
NOVEL BIAROMATIC PROPYNYL COMPOUNDS, PHARMACEUTICAL AND
COSMETIC COMPOSITIONS CONTAINING SAME, AND USES THEREOF
The invention relates to bi-aromatic compounds as novel and useful industrial
products. lt also relates to the use of these novel compounds in
pharmaceutical
compositions intended for use in human or veterinary medicine, or in cosmetic
compositions.
The compounds according to the invention have marked activity in the domains
of
cellular differentiation and proliferation, and find applications more
particularly in the
topical and systemic treatment of dermatological conditions related to a
keratinization disorder, dermatological (or other) conditions with an
inflammatory
and/or immunoallergic component, and dermal or epidermal proliferations,
whether
benign or malignant. These compounds may also be used in the treatment of
connective-tissue degeneration disorders, to combat skin aging, whether photo-
induced or chronological, and to treat healing disorders. They can also be
applied in
the ophthalmological field, especially in the treatment of corneal diseases.
The compounds according to the invention can also be used in cosmetic
compositions for body and hair hygiene.
The compounds according to the invention can be represented by general formula
(I)
below:
R3 R4
R2
ArRi
(I)
in which:
* Ar represents a radical chosen from among the radicals of formulas (a) or
(b)
below:
KN
(a) (b)

CA 03013411 2018-08-01
2
R5 having the meaning given below,
* R1 represents: (i) a hydrogen atom
(ii) a -0H3 radical
(ii) a -CH2-0-R6 radical
(iv) an -0-R6 radical
(y) a -00-R7 radical,
(vi) an -S(0)tR9 radical
R6, R7, R9 and t having the meaning given below,
* R2 and R3 represent a hydrogen atom, a linear or branched alkyl radical
having 1
ta 20 carbon atoms, an -0R6 radical or an -SR6 radical, R6 having the meaning
given below, given that R2 and R3, taken together, can form with the adjacent
aromatic ring a 5- or 6-member ring optionally substituted by methyl groups
and/or
optionally interrupted by an oxygen or sulfur atom,
* R4 represents a hydrogen atom, a halogen atom, a lower alkyl radical or
an -0R6
radical, R6 having the meaning given below,
given that in ail of the preceding:
- R6 represents a hydrogen atom, a lower alkyl radical, a linear or branched
alkyl radical having 1 ta 20 carbon atoms, an -0-0H3-R9 radical or a -00-R9
radical,
R9 having the meaning given below,
- R7 represents:
(a) a hydrogen atom
(b) a lower alkyl radical
(c) a radical of formula:
lil
Rfi

CA 03013411 2018-08-01
3
R' and R" having the meaning given below,
(d) an -0R8 radical, R8 having the meaning given below,
- R8 represents a hydrogen atom, methyl, ethyl, propyl, cyclopropyl,
cyclobutyl, or cyclopentyl, an alkenyl radical, a mono- or polyhydroxyalkyl
radical, an
optionally substituted aryl or aralkyl radical or a sugar residue or an amino
acid or
peptide residue,
_ R9 represents a lower alkyl or methyl, ethyl, propyl, cyclopropyl,
cyclobutyl,
cyclopentyl radical,
- R' and R" represent a hydrogen atom, a lower alkyl radical, a mono- or
polyhydroxyalkyl radical, an optionally substituted aryl radical or an amino
acid or
peptide or sugar residue, or aven, taken together, form a heterocycle,
- t is a whole number equal to 0, 1 or 2.
The invention also pertains to salts of compounds of formula (I) aboya in the
case
where Ri represents a carboxylic acid function, as well as the optical and
geometric
isomers of said compounds. When compounds according to the invention are
present in the form of salts, they are preferably alkali matai or alkaline-
earth metal
salts, or aven zinc or an organic amine compound.
According to the present invention, lower alkyl radical means a radical having
1 to 6
carbon atoms, preferably methyl, ethyl, isopropyl, butyl, tert-butyl and hexyl
radicals.
Linear or branched alkyl radical having 1 to 20 carbon atoms means, in
particular,
methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, 2-ethylhexyl,
octyl,
dodecyl, hexadecyl, and octadecyl radicals.
Monohydroxyalkyl radical means a radical preferably having 2 or 3 carbon
atoms,
notably a 2-hydroxyethyl, 2-hydroxypropyl, or 3-hydroxypropyl radical.
Polyhydroxyalkyl radical means a radical preferably containing 3 to 6 carbon
atoms
and 2 to 5 hydroxyl groups such as 2,3-dihydroxypropyl, 2,3,4-trihydroxybutyl,

2,3,4,5-tetrahydroxypentyl radicals or pentaerythritol residue.
Aryl radical means, preferably, a phenyl radical optionally substituted with
at least
one halogen atom, a hydroxyl, or a nitro function.
Aralkyl radical means, preferably, the benzyl or phenethyl radical optionally
substituted with at least one halogen atom, hydroxyl, or a nitro function.

CA 03013411 2018-08-01
4
Alkenyl radical means a radical containing preferably 1 ta 5 carbon atoms and
having one or more ethylene unsaturations, such as, more particularly, the
any'
radical.
Sugar residue means a residue particularly deriving from glucose, galactose or
mannose, or even glucuronic acid.
Amino acid residue particularly means a residue deriving from lysine, glycine
or
aspartic acid, and peptide residue means, more particularly, a dipeptide or
tripeptide
residue resulting from the combination of amino acids.
Finally, heterocycle particularly means, preferably, a piperidino, morpholino,
pyrrolidino or piperazino radical, possibly substituted in position 4 by a C1-
C6 alkyl
radical or mono- or polyhydroxyalkyl such as defined above.
When R4 and R5 represent a halogen atom, this is preferably a fluorine,
chlorine or
bromine atom.
The compounds of general formula (I) above within the scope of the present
invention notably include the following compounds:
According to the present invention, the compounds of formula (I) more
particularly
preferred are those for which R5 represents -OH, R7 represents an OR8 radical,
and
R1 1 represents an -0R6 radical, R6 and R11 having the meaning given above.
The compounds according ta the invention are particularly well suited in the
following
treatment fields:
O.
0
Compound 1:

CA 03013411 2018-08-01
. 7
el*
..-
N I el
Compound 2: 0
1) to treat dermatological conditions linked to a keratinization disorder
pertaining to cellular differentiation and proliferation, especially to treat
acne vulgaris,
comedonic or polymorphic acne, rosacea, nodulocystic acne, acne conglobata,
5 senile
acne, and secondary acnes such as solar, drug-induced or occupational acne;
2) to treat keratinization disorders, especially ichthyosis, ichthyosiform
states,
Darier's disease, palmoplantar keratoderma, leukoplakia and leukoplakiform
conditions, cutaneous or mucosal (buccal) lichen;
3) to treat other dermatological conditions associated with a keratinization
disorder with an inflammatory and/or immunoallergic component and, in
particular,
ail forms of psoriasis whether cutaneous, mucosal or nail, and psoriatic
arthritis, or
cutaneous atopy, such as eczema or respiratory atopy or gingival hypertrophy;
the
compounds may also be used in certain inflammatory conditions which do not
present a keratinization disorder,
(4) to treat dermal or epidermal proliferations, whether benign or malignant,
whether of viral origin or not such as common warts, flat warts and
verruciform
epidermodysplasia, oral or florid papillomatoses and proliferations that can
be
induced by UV radiation, in particular basal and prickle cell epithelioma,
5) to treat other dermatological disorders such as bullous dermatosis and
collagen diseases,
6) to treat certain ophthalmological problems, especially corneal diseases,
7) to repair or combat aging of the skin, whether photo-induced or
chronological or to reduce pigmentation and actinic keratosis, or any
pathologies
associated with chronological or actinic aging,
8) to prevent or treat stigmata of epidermal and/or dermal atrophy induced by
local or systemic corticosteroids, or any other form of cutaneous atrophy,
9) to prevent or treat healing disorders or to prevent or repair stretch
marks,

CA 03013411 2018-08-01
6
10) to combat disorders of sebaceous function, such as hyperseborrhea
associated with acne or simple seborrhea,
11) in the treatment or prevention of cancerous or precancerous conditions,
12) in the treatment of inflammatory disorders such as arthritis,
13) in the treatment of any skin or general condition of viral origin,
14) in the prevention or treatment of alopecia,
15) in the treatment of dermatological or general conditions with an
immunological component,
16) in the treatment of cardiovascular system disorders such as
atherosclerosis.
In the abovementioned therapeutic fields, the compounds according to the
invention
can advantageously be used in combination with other compounds with retinoid
activity, with D vitamins or derivatives thereof, with corticosteroids, with
anti-free
radicals, a-hydroxy or a-keto acids or derivatives thereof, or with ion
channel
blockers. D vitamins or derivatives thereof means, for example, vitamin D2 or
D3
derivatives and in particular 1,25-dihydroxyvitamin D3. Anti-free radicals
means, for
example, a-tocopherol, superoxide dismutate, ubiquinol or certain metal
chelators.
a-hydroxy or a-keto acids or derivatives thereof means, for example, lactic,
malic,
citric, glycolic, mandelic, tartaric, glyceric or ascorbic acids or salts
thereof, amides
or esters. Finally, ion channel blockers means, for example, minoxidil (2,4-
diamino-6-
piperidino-pyrimidine-3-oxide) and its derivatives.
The present invention also has for a subject medicinal compositions containing
at
least one compound of formula (I) such as defined above, one of its optical or

geometric isomers or one of its salts.
The present invention therefore also has for a subject a novel medicinal
composition
intended in particular for treatment of the abovementioned conditions, which
is
characterized by the fact that it comprises, in a pharmaceutically-acceptable
carrier
and compatible with the selected mode of administration thereof, at least one
compound of formula (I), one of the optical isomers thereof or one of the
salts
thereof.
The composition according to the invention can be administered enterally,
parenterally, topically or ocularly.

CA 03013411 2018-08-01
7
For enterai administration, the composition may be in the form of tablets,
hard
capsules, dragées, syrups, suspensions, solutions, powders, granulates,
emulsions,
microspheres or nanospheres or lipid or polymer vesicles permitting controlled

release. For parenteral administration, the compositions can advantageously be
in
the form of solutions or suspensions for infusion or for injection.
The compounds according to the invention are generally administered at a daily
dosage of approximately 0.01 mg/kg to 100 mg/kg of bodyweight, in 1 to 3
doses.
For topical administration, the pharmaceutical compositions based on compounds

according to the invention are more particularly intended for treatment of the
skin
lo and mucosa and may then be in the form of ointments, creams, milks,
pomades,
powders, swabs, solutions, gels, sprays, lotions or suspensions. They may also
be in
the form of microspheres or nanospheres or lipid or polymer vesicles, or
polymer
patches and hydrogels permitting controlled release. These topical
compositions
may also be in the anhydrous or the aqueous form, depending on the clinical
indication.
For ocular administration, they are mainly eye drops.
These compositions for topical or ocular use contain at least one compound of
formula (I) such as defined above, or one of the optical or geometric isomers
thereof
or one of the salts thereof, at a concentration preferably comprised between
0.001%
and 5% by weight relative to the total weight of the composition.
Compounds of formula (I) according to the invention also find application in
the
cosmetic field, in particular in body and hair hygiene and especially for the
treatment
of acne-prone skin, for hair regrowth and loss prevention, to treat oily skin
or hair, to
protect against the harmful aspects of the sun or in the treatment of
physiologically
dry skin, to prevent and/or to combat photo-induced or chronological aging.
In the cosmetic field, the compounds according to the invention can further
advantageously be used in combination with other compounds with retinoid
activity,
with D vitamins or derivatives thereof, with corticosteroids, with anti-free
radicals, a-
hydroxy or oc-keto acids or derivatives thereof, or with ion channel blockers,
ail these
various products being as defined above.
The present invention therefore also relates to a cosmetic composition which
is
characterized by the fact that it comprises, in a cosmetically-acceptable
carrier and
suitable for topical application, at least one compound of formula (I) as
defined
above or one of the optical or geometric isomers thereof or one of the salts
thereof;
this cosmetic composition may be in the form of a cream, a milk, a lotion, a
gel,
microspheres or nanospheres or lipid or polymer vesicles, a soap or a shampoo.

CA 03013411 2018-08-01
8
The concentration in compound of formula (1) in cosmetic compositions
according to
the invention is advantageously comprised between 0.001% and 3% by weight
relative to the whole composition.
The medicinal and cosmetic compositions according to the invention may also
contain inert additives or even pharmacodynamically or cosmetically-active
additives,
or combinations of these additives, and in particular: wetting agents;
depigmenting
agents such as hydroquinone, azelaic acid, caffeic acid or kojic acid;
emollients;
hydrating agents such as glycerol, PEG 400, thiamorpholinone, and derivatives
thereof or urea; anti-seborrheic or anti-acne agents, such as S-
carboxymethylcysteine, S-benzyl-cysteamine, salts or derivatives thereof, or
benzoyl
peroxide; antibiotics such as erythromycin and esters thereof, neomycin,
clindamycin
and esters thereof, tetracyclines; antifungal agents such as ketoconazole or
polymethylene-4,5-isothiazolidones-3; agents promoting regrowth of hair such
as
minoxidil (2,4-diamino-6-piperidino-pyrimidine-3-oxide) and derivatives
thereof,
diazoxide (7-chloro-3-methy1-1,2,4-benzothiadiazine 1,1-dioxide) and phenytoin
(5,4-
diphenyl-imidazolidine 2,4-dione); non-steroidal anti-inflammatory agents;
carotenoids and, in particular, p-carotene; anti-psoriatic agents such as
anthralin and
derivatives thereof; and finally eicosa-5,8,11,14-tetraynoic and eicosa-5,8,11-
trynoic
acids, esters and amides thereof.
The compositions according to the invention may also contain flavors,
preservatives
such as para-hydroxybenzoic acid esters, stabilizers, moisture regulators, pH
regulators, osmotic pressure modifiers, emulsifiers, UV-A and UV-B filters,
antioxidants such as cx-tocopherol, butylhydroxyanisole or
butylhydroxytoluene.
We will now give several examples, for illustration purposes and non-limiting,
to
validate the activity of active compounds of formula (1) according to the
invention, as
well as various concrete formulations based on such compounds.
Example 1 : Transactivation test
a) Test principle:
Activation of receptors by an agonist (activator) in HeLa cells leads to the
expression
of a reporter gene, luciferase, which generates light in the presence of a
substrate.
Therefore the activation of receptors can be measured by quantifying the
luminescence produced after incubation of the cells in the presence of a
reference
antagonist. The activator products displace the antagonist from its site, thus
permitting the receptor to be activated. The activity is measured by
quantifying the
increase in light produced. This measurement determines the activating
activity of
the useful compound in the invention.

CA 03013411 2018-08-01
9
In this study, a constant is determined that represents the affinity of the
molecule for
the receptor. This value can fluctuate according to the basal activity and
expression
of the receptor; it is designated apparent Kd (KdApp).
To determine this constant, cross curves are created of the product to be
tested (4'-
(3-hydroxy-propy1)-3'-(5,5,8,8-tetramethy1-5,6,7,8-tetrahydro-naphthalen-2-y1)-

bipheny1-4-carboxylic acid and 4'-(2,3-dihydroxy-propy1)-3'-(5,5,8,8-
tetramethy1-
5,6,7,8-tetrahydro-naphtalen-2-y1)-biphenyl-4-carboxylic) acid versus a
reference
antagonist also called reference ligand, 4-(5,5-dimethy1-8-p-toly1-5,6-dihydro-

naphthalen-2-ylethyny1)-benzoc acid. The product to be tested is used at 10
concentrations and the reference antagonist at 7 concentrations. ln each well
(of a
96-well plate), the cells are in contact with one concentration of the product
to be
tested and one concentration of the reference antagonist.
Full agonist contrais, also called 100% controls, (4-[2-(5,5,8,8 tetramethy1-
5,6,7,8
tetrahydronaphthalene-2-Apropenyl]-benzoic acid) and inverse agonist controls,
also called 0% controls, (4-{(E)-344-(4-tert-butyl-pheny1)-5,5,8,8-tetramethy1-
5,6,7,8-
tetrahydro-naphthalen-2-y1]-3-oxo-propenylFbenzoic acid) are also measured.
These cross curves allow determining the AC50 (concentration at which 50%
activation of the receptor is observed) of the reference ligand at different
concentrations of the product to be tested. These AC5Os are used to calculate
the
Schild regression by plotting a line conforming to the Schild equation
("Quantitation
in receptor pharmacology" Terry P. Kenakin, Receptors and Channels, 2001,7,
371-
385).
In the case of an agonist, the AC50 is calculated by plotting the curve of the
product
at the concentration of the reference ligand giving 80% activation. The
percentage of
activation that corresponds to the maximum level of activity obtained is also
measured.
b) Materials and Method:
The HeLa cell lines used are stable transfectants containing the plasmids ERE-
13Glob-Luc-SV-Neo (reporter gene) and RAR (a, [3, y) ER-DBD-puro. These cells
are
inoculated onto 96-well plates in an amount of 10,000 cells per well in 100 pl
DMEM
medium with no phenol red and supplemented with 10% delipidated fetal bovine
serum. The plates are then incubated at 37 C, 7% CO2 for 4 hours.

CA 03013411 2018-08-01
The different dilutions of the product to be tested, the reference ligand (4-
(5,5-
dimethy1-8-p-toly1-5,6-dihydro-naphthalen-2-ylethyny1)-benzoic acid), the 100%

control (100 nM 4-[2-(5,5,8,8 tetramethy1-5,6,7,8 tetrahydronaphthalene-2-
yppropeny1]-benzoic acid) and the 0% control (500 nM 4-{(E)-344-(4-tert-butyl-
5 pheny1)-5,5,8,8-tetramethy1-5,6,7,8-tetrahydro-naphthalen-2-y1]-3-oxo-
propenyll-
benzoic acid) are added in an amount of 5 pl per well. The plates are then
incubated
18 hours at 37 C, 7% CO2.
The culture medium is removed by turning over and 100 pl of a 1:1 PBS
(phosphate
buffer solution) /luciferin mixture is added to each well. After 5 minutes,
the plates
10 are read by the luminescence reader.
c) Results:
The apparent Kd constant values are indicated in the table below. These values
are
compared to those of the compounds of patent WO 99/10308 presenting the best
activities
RAR alpha RAR beta RAR
gamma
Kdapp (nM) Kdapp (nM)
Kdapp (nM)
Compound 1 120 4 4
Compound 2 30 2 4
EXAM P LE 2
In this example, various concrete formulations based on the compound according
to
the invention are illustrated.
A- ORAL ADMINISTRATION
(a) 0.2 g tablet
- Compound prepared in Example 7 0.001 g
- Starch 0.114g
- Dicalcium phosphate 0.020 g

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11
- Silica 0.020 g
- Lactose 0.030 g
-Talc 0.010g
- Magnesium stearate
0.005 g
(b) Oral suspension in 5-ml ampoules
- Compound prepared in
Example 3 0.001 g
- Glycerin 0.500 g
- 70% sorbitol
0.500 g
- Sodium saccharin
0.010 g
- Methyl
parahydroxybenzoate 0.040 g
- Flavor qs
- Purified water qs 5 ml
(c) 0.8 g tablet
- Compound of Example 6 0.500 g
- Pregelatinized
starch 0.100 g
- Microcrystalline
cellulose 0.115 g
- Lactose 0.075 g
- Magnesium stearate
0.010 g
(d) Oral suspension in 10-ml ampoules
- Compound of Example 2 0.200 g
- Glycerin 1.000 g
- 70% sorbitol 1.000 g
- Sodium saccharin
0.010 g
- Methyl
parahydroxybenzoate 0.080 g
- Flavor qs
- Purified water qs 10 ml
B- TOPICAL ADMINISTRATION
(a) Ointment
- Compound of Example 9 0.020 g
- lsopropyl myristate 81.700 g
- Liquid Vaseline oil 9.100 g
- Silica ("Aerosil 200" sold by DEGUSSA) 9.180 g
(b) Ointment

CA 03013411 2018-08-01
12
- Compound of Example
10 0.300 g
- Codex white Vaseline
100 g
(c) Nonionic water-in-oil cream
- 2-hydroxy-443-hydroxy-3-(3-tert-buty1-4-
hydroxypheny1)]-1-propynylbenzoic acid 0.100 g
- Mixture of emulsive lanolin alcohols, waxes
and oils (anhydrous Eucerin) sold by BDF) 39.900 g
- Methyl
parahydroxybenzoate 0.075 g
- Propyl
parahydroxybenzoate 0.075 g
- Sterile demineralized water: qs
100 g
(d) Lotion
- Compound of Example 8 0.100 g
- Polyethylene glycol
(PEG 400) 69.900 g
- Ethanol (95%) 30.000 g
(e) Hydrophobic ointment
- Compound of Example 7 0.300 g
- lsopropyl myristate
36.400 g
- Silicone oil ("Rhodorsil 47 V 300" sold
by RHONE-POULENC) 36.400 g
- Beeswax 13.600g
- Silicone oil ("Abil 300.000 cst" sold
by GOLDSCHMIDT) 100 g
(f) Nonionic oil-in-water cream
- Compound of Example
3 1.000 g
- Cetyl alcohol
4.000 g
- Glycerol
monostearate 2.500 g
- PEG 50 stearate
2.500 g
- Shea butter 9.200 g
- Propylene glycol
2.000 g
- Methyl parahydroxybenzoate 0.075 g
- Propyl parahydroxybenzoate 0.075 g
- Sterile
demineralized water: 100 g

Representative Drawing
A single figure which represents the drawing illustrating the invention.
Administrative Status

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Administrative Status

Title Date
Forecasted Issue Date Unavailable
(86) PCT Filing Date 2017-02-03
(87) PCT Publication Date 2017-08-10
(85) National Entry 2018-08-01
Dead Application 2023-05-03

Abandonment History

Abandonment Date Reason Reinstatement Date
2022-05-03 FAILURE TO REQUEST EXAMINATION
2022-08-03 FAILURE TO PAY APPLICATION MAINTENANCE FEE

Payment History

Fee Type Anniversary Year Due Date Amount Paid Paid Date
Registration of a document - section 124 $100.00 2018-08-01
Application Fee $400.00 2018-08-01
Maintenance Fee - Application - New Act 2 2019-02-04 $100.00 2018-08-01
Maintenance Fee - Application - New Act 3 2020-02-03 $100.00 2020-01-06
Maintenance Fee - Application - New Act 4 2021-02-03 $100.00 2021-01-22
Owners on Record

Note: Records showing the ownership history in alphabetical order.

Current Owners on Record
GALDERMA RESEARCH & DEVELOPMENT
Past Owners on Record
None
Past Owners that do not appear in the "Owners on Record" listing will appear in other documentation within the application.
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Abstract 2018-08-01 1 10
Claims 2018-08-01 5 125
Description 2018-08-01 12 457
International Search Report 2018-08-01 6 201
Amendment - Abstract 2018-08-01 1 69
National Entry Request 2018-08-01 9 318
Cover Page 2018-08-13 1 37

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