Aromatic tetracyclic compounds of the retinoid type method...

Details Aromatic tetracyclic compounds of the retinoid type method... Aromatic tetracyclic compounds of the retinoid type method...

1999-07-15

2001-05-29

Higel, Floyd D. (Department: 1613)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C549S405000, C562S008000, C562S490000, C562S491000

Reexamination Certificate

active

06239284

ABSTRACT:

This invention relates to tetracyclic aromatic compounds of the retinoid type of general formula:
in which:
R
1
is chosen from among a hydrogen atom, a lower alkyl group, a group of formula —PO
3
H
2
, —CH
2
OH, —OH, —CHO, —COOH, —COR
8
, —CH
2
OCOR
9
, —SH, —S-alkyl, —NH
2
, —NHCOOR
10
, p-hydroxyphenylaminocarbonyl, tetrazol-5-yl-aminocarbonyl, tetrazol-5-yl, 5-trifluoromethyl-tetrazoyl, and when it is possible their salts with physiologically tolerated acids, where R
10
is a lower alkyl or aralkyl group and R
8
and R
9
are chosen from among:
a hydrogen atom, an —OH group, a lower alkyl group, or a group of formula —OR
11
, where R
11
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
is chosen from among 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
12
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
12
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
is chosen from among a hydrogen atom, a lower alkyl group, a halogen atom, a fluoroalkyl group having from 1 to 6 carbon atoms and from 3 to 7 fluorine atoms, or a group of formula —OR
13
where R
13
represents a hydrogen atom, a lower alkyl group, an aryl group, 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 sulfur, and
R
5
and R
6
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 sulfur,
one or two atoms of oxygen in the case where X
1
is an atom of sulfur (the case of a sulphoxide —SO— or a sulphone —SO
2
—).
R
4
is chosen from among a hydrogen atom, a halogen atom and more particularly a fluorine atom, a trifluoromethyl group, an aryl group, an aralkyl group, or a lower alkyl group, possibly substituted with a hydroxyl group, one or more atoms of fluorine, a lower alkoxy group or by a group with the formula —(C═O)R
14
in which R
14
represents a hydrogen atom, a lower 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.
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 sulfur, oxygen or nitrogen. Hence the nucleus carrying X
2
and X
3
can be a benzene, pyridine, thiophene, furane, or pyrrole nucleus.
R
7
is chosen from among a hydrogen atom, a trifluoromethyl group, a lower alkyl group, possibly substituted with one or more atoms of fluorine, or a —OR
15
where R
15
represents a hydrogen atom or a lower alkyl group.
X
4
represents a carbon atom or a nitrogen atom
X
5
is chosen from among a carbon, oxygen, sulfur or nitrogen atom, a sulfide of formula —S—, a sulfoxide of formula —SO—, a sulfone of formula —SO
2
—, an amine of formula —NR
16
— where R
16
represents a hydrogen atom or a lower alkyl group, a group of formula —COR
17
— or —CO
2
R
17
— where R
17
is a lower alkyl group or a benzyl group.
n is 0 or 1.
As examples of pharmaceutically acceptable salts of the previous compounds, one may mention, in a non-limitative way: the salts of acetic, hydrochloric, cinnamic, citric, formic, hydrobromic, hydriodic, hydrofluoric, malonic, methanesulfonic, oxalic, picric, maleic, lactic, nicotinic, phenylacetic, phosphoric, succinic, sulfuric 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 synthesized 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.,
Ciba. 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 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 that show retinoid type activity are used in the treatment of mammals and more particularly man by 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 that show retinoid type activity are also useful in 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, interference with the lipid balance, and are even teratogens, which makes their clinical use a delicate matter (Kistler, A. et al. Arch Toxicol., 64: 616-622; “Retinoids in Oncology”, edited by Waun Ki Hong & Reuben Lotan, The University of Texas M. D. Anderson Cancer Center, Houston, Tex., USA, Marcel Decker 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 compounds of the retinoid type which are active notably in the treatment and prevention of the diseases mentioned previously but do not show any secondary effects.
The applicant has devised and then studied the properties of new compounds of the retinoid type corresponding to formula I, notably in comparison with the reference arotinoid (E)-4-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-naphthalenyl)-1-propenyl]benzoic acid (TTNPB).
The compounds of formula (I) of the invention include a double bond between the aromatic groups and can therefore exit in cis (Z) or trans (E) configurations or can be in the form of a mixture of cis/trans isomers.
So as to facilitate the

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