Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1998-07-15
2001-07-24
Oswecki, Jane C. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S378000, C514S381000, C514S438000, C514S456000, C514S784000, C546S322000, C548S248000, C548S250000, C549S071000, C549S399000, C549S402000, C562S490000
Reexamination Certificate
active
06265423
ABSTRACT:
This invention relates to aromatic polycyclic derivatives of the retinoid type of general formula:
in which the groups R
3
and R
4
carried by the double bond between the 11 and 12 carbon are in a cis arrangement and R
1
, R
2
, R
3
, R
4
, R
5
, R
6
, R
7
, X
1
, X
2
and X
3
have the following meanings:
R
1
represents a hydrogen atom, a lower alkyl group, or a group of formula —CH
2
OH, —OH, —CHO— —COOH, —COR
8
, —CH
2
OCOR
9
, —SH, —S-alkyl, —PO
3
H
2
, p-hydroxyphenylaminocarbonyl, tetrazol-5-ylaminocarbonyl, tetrazol-5-yl, 5-trifluoromethyl-tetrazoyl, and when it is possible their salts with physiologically tolerated acids, where R
8
and R
9
are:
a hydrogen atom, an —OH group, a lower alkyl group, or a group of formula —OR
10
, where R
10
represents an alkyl group, which may be branched or not, having from 1 to 20 carbon atoms, an alkenyl group which may be branched or not, having from 2 to 20 carbon atoms, an aryl or aralkyl group, or
an amine group of formula:
in which r and r′, identical or different, represent a hydrogen atom, a lower alkyl group, an aryl or aralkyl group, an &agr;-aminoacid group, a sugar group or a heterocyclic group in which r and r′ taken together form a heterocyclic ring.
R
2
represents a hydrogen atom, a halogen atom and more particularly a fluorine atom, a lower alkyl group, a group of formula —COOH, OR
11
, —SR
11
, —(CF
2
)
n
CF
3
where n is a whole number between 0 and 10, or a OCOR
11
group, and when this is possible their salts with physiologically tolerated acids, or an amine group of formula:
in which r and r′ have the same meaning as previously, and R
11
represents a hydrogen atom, a lower alkyl group, a fluoroalkyl group having 1 to 6 carbon atoms and from 3 to 7 fluorine atoms, an aryl group or an aralkyl group.
R
3
represents a hydrogen atom, a trifluoromethyl group, an aryl group, an aralkyl group or a lower alkyl group, possibly substituted with a hydroxyl group or with one or more atoms of fluorine, with a lower alkoxy group or with a group of formula —(C═O)R
12
, in which R
12
represents a hydrogen atom, a lower alkyl group, a hydroxyl group, a lower alkoxy group, or an amine group of formula:
in which r and r′ have the same meaning as previously,
R
4
represents a hydrogen atom or an aryl group,
R
5
represents a hydrogen atom, a lower alkyl group, a halogen atom, a fluoroalkyl group having 1 to 6 carbon atoms and from 3 to 7 atoms of fluorine, or a group of formula —OR
13
where R
13
represents a hydrogen atom, a lower alkyl group, an aryl group or an aralkyl group or a trifluoromethyl group,
X
1
is chosen from among an atom of carbon, an atom of oxygen or an atom of sulphur, and
R
6
and R
7
are:
methyl or ethyl groups, in the case where X
1
is an atom of carbon,
nothing in the case where X
1
is an atom of oxygen or an atom of sulphur,
one or two atoms of oxygen in the case where X
1
is an atom of sulphur (the case of a sulphoxide —SO— or a sulphone —SO
2
—).
X
2
and X
3
, identical or different, represent an atom of carbon, an atom of oxygen or an atom of nitrogen, or X
2
-X
3
may be a single atom of sulphur, oxygen or nitrogen so the nucleus carrying X
2
and X
3
can be a benzene, pyridine, thiophene, furane, pyrrole nucleus or in the case where X
2
is an atom of oxygen and X
3
an atom of carbon, C
13
and C
14
represent a single, one and the same carbon atom, and then the nucleus carrying X
2
and X
3
can be an iso-oxazole nucleus.
As examples of pharmaceutically acceptable salts of the previous derivatives, one may mention, in a non-limitative way: the salts of acetic, hydrochloric, cinnamic, citric, formic, hydrobromic, hydriodic, hydrofluoric, malonic, methanesulphonic, oxalic, picric, maleic, lactic, nicotinic, phenylacetic, phosphoric, succinic, sulphuric and tartaric acids, ammonium salts, and salts of piperazine, diethylamine, nicotinamide, urea, sodium, potassium, calcium, magnesium, zinc, lithium, methylamine, dimethylamine, trimethylamine and tris(hydroxymethyl)aminomethane.
The term lower alkyl or alkoxy groups designates groups with 1 to 6 carbon atoms, straight chained or branched such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, methoxy, ethoxy, propoxy, isopropoxy, butyloxy, isobutyloxy and secondary butyloxy groups.
Totally trans retinoic acid, a metabolite of vitamin A exhibits a large number of biological properties. Several molecules constructed from chemical modifications of this acid have been synthesised and have been shown to be biologically active. These synthetic analogues and their derivatives are called retinoids according to the definition of Sporn M. B. and Roberts A. B., Found Symp., 113, 1-5, 1985. Among these compounds, one may mention those described in European Patent Applications published under numbers 350 846, 303 186, 253 302, in the PCT International Patent Application published under the number WO 93/11755, or in American Patents U.S. Pat. Nos. 5,300,522, 5,420,273, 4,578,498 and the German Patents 3602473 and 3715955 as well as in the articles by Marcia I. Dawson et al. (J. Med. Chem., 1989, 32, 1504-1517; J. Med. Chem. 1993, 36, 2605-2613).
The compounds of the retinoid type that show activity are used in the treatment of mammals and more particularly humans as chemoprevention and chemotherapy, notably in the treatment of numerous diseases such as dermatosis, acne, Darier's disease, psoriasis, icthyosis and eczema. These compounds are also used for the treatment and the prevention of cancerous diseases and numerous malignant hyperproliferative diseases such as cancers of the breast, the prostate, the lung, the head and the neck as well as certain types of cancer of epithelial origin and myelocytary leukaemias. The compounds of the retinoid type that show activity are also used for the treatment and the prevention of arteriosclerosis, restenosis stemming from neo-intimal hyperproliferation, benign hyperproliferative pathologies such as endometrial hyperplasis, benign hypertrophy of the prostate, proliferative retinopathy, for the treatment of auto-immune diseases and immunological disorders such as erythematic lupus, for the treatment and the prevention of diseases associated with the metabolism of lipids and for the treatment of the effects of the sun on the skin.
However, these compounds of the retinoid type exhibit important secondary effects, notably a strong irritation of the skin and of the mucous membranes, lipidic toxicity, and are even teratogens, which makes their clinical use delicate (Kistler, A. et al. Arch Toxicol., 64: 616-622; “Retinoids in Oncology”, edited by Waun Ki Hong & Reuben Lotan, The University of Texas M. F. Anderson Cancer Center, Houston, Tex., USA, Marcel Dekker Inc., pages 127-146; “Retinoids in Clinical Practice”, edited by Gideon Koren The Motherisk Program, The Hospital for Sick Children and The University of Toronto, Toronto, Ontario, Canada, Marcel Dekker Inc.).
The harmful effects reported above have led the applicant to look for aromatic polycyclic derivatives of the retinoid type which are active in the treatment and prevention of the preceding diseases but do not show any secondary effects.
In a surprising way, the applicant has provided evidence that the compounds of Formula I in which the groups R
3
and R
4
of the double bond between carbons 11 and 12 are in cis configuration, show activity greater than that of the corresponding trans isomers or a mixture of cis/trans isomers, and may not show the secondary effects notably teratogenic effects generally associated with the use of compounds of the retinoid type. The prior art and notably the patents and patent applications mentioned above indicate logically the existence of cis and trans isomers because of the double bond between carbon atoms 11 and 12, but concern themselves specifically with compounds with a trans configuration since this configuration is that met with in the reference arotinoid: the acid (E) 4-[21(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-naphthalenyl)-1-propenyllbenzoic acid (TTNPB
Darro Francis
Devine Abdallah
Duhamel Pierre
Germain Pierre
Kiss Robert
Centre Europeen de Bioprospective-CEB
Oswecki Jane C.
Schnader Harrison Segal & Lewis LLP
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