Steroids, their use as medicaments, their preparation...

Details Steroids, their use as medicaments, their preparation... Steroids, their use as medicaments, their preparation...

2001-06-25

2002-12-10

Qazi, Sabiha (Department: 1616)

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

Organic compounds

Cyclopentanohydrophenanthrene ring system containing

C552S610000, C552S633000, C552S646000, C552S647000

Reexamination Certificate

active

06492536

ABSTRACT:

The subject of the present invention is steroids, their use as medicaments, their preparation process and the intermediates of this process, and the pharmaceutical compositions containing them.
The subject of the invention is the products of general formula (I):
in which either R
1
represents a halogen atom, a hydroxyl radical, an alkyloxy radical containing 1 to 8 carbon atoms, an acyloxy radical containing 1 to 12 carbon atoms, and R
2
represents a halogen atom or a hydrogen atom, or R
1
and R
2
form together a second bond, Z is chosen from alkyloxy groups containing 1 to 8 carbon atoms, non-substituted or substituted alkylthio groups containing 1 to 8 carbon atoms, non-substituted or substituted arylthio groups containing 6 to 12 carbon atoms, halogen, cyano, mercapto, thiocyanato, CO
2
A and CH
2
CO
2
A groups, A being a hydrogen atom or an alkyl group containing 1 to 8 carbon atoms, Y represents a hydrogen atom or a methyl, the dotted line in position 1-2 or 5-6 optionally representing a second bond, as well as their addition salts with acids or bases, it being understood that 9&agr;-fluoro-11&bgr;-hydroxy-16&agr;-6-methyl-21-chloro-pregna-1,4-diene-3,20-dione is excluded and it being understood that when R
1
and R
2
form together a double bond, Z is not a halogen atom.
By halogen atom is meant fluorine, bromine, chlorine and iodine atoms.
By alkyloxy and alkylthio radical containing 1 to 8 carbon atoms is preferably meant methoxy, ethoxy, propoxy, butyloxy radicals and the corresponding sulphurated radicals.
By acyloxy radical containing 1 to 12 carbon atoms is preferably meant acetyloxy, propionyloxy, butyryloxy and benzoyloxy radicals.
By alkyl radical containing 1 to 8 carbon atoms is meant the following radicals: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, 2-methyl pentyl, 2,3-dimethyl butyl, n-heptyl, 2-methylhexyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 3-ethylpentyl, n-octyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 3-methyl-3-ethylpentyl. It is quite particularly the methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl radicals.
By arylthio radical is preferably meant thiophenyl.
When Z is a substituted alkylthio or arylthio radical, it can be one of the following substituents: fluorine, chlorine, bromine, iodine, an alkyl radical such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, an alkoxy radical such as methoxy, ethoxy, propyloxy, isopropyloxy, butyloxy, an alkylthio radical such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, an amino radical, an alkylamino radical such as methylamino or ethylamino, a dialkylamino radical such as dimethylamino, diethylamino, methylethylamino, an optionally acylated hydroxyl radical, for example acetoxy, or a radical of formula: —O—CO—(CH
2
)
n
CO
2
H in which n=2 to 5, an acyl radical containing 2 to 8 carbon atoms such as acetyl, propionyl, butyryl, benzoyl, a free carboxy radical, an esterified carboxy radical such as alkoxy carbonyl, for example methoxy carbonyl or ethoxy carbonyl, a cyano radical, a trifluoromethyl radical, or a phenyl radical. The alkyl term contains 1 to 12 carbon atoms.
Of course, the expression “optionally substituted” indicates that one or more substituents, identical or different, can be present.
The substitution on the aryl can be carried out in ortho, meta or para position.
When Z is an optionally substituted alkylthio radical, the S—CH
2
—CH
2
-A′ group is preferably meant in which A′ is a hydroxyl, a halogen atom or an acetyloxy group.
When ring B is saturated, Y is preferably in &agr; position.
The invention naturally extends to the salts of the compounds of formula (I), when these contain an amino function, with in particular the following acids: hydrochloric, hydrobromic, nitric, sulphuric, phosphoric, acetic, formic, propionic, benzoic, maleic, fumaric, succinic, tartaric, citric, oxalic, glyoxylic, aspartic, alkane sulphonic such as methane and ethane sulphonic, arylsulphonic, such as benzene and paratoluene sulphonic and arylcarboxylic, and when the compounds of formula (I) contain an acid function, to the optionally substituted alkali metal, alkaline-earth and ammonium salts.
A more particular subject of the invention is the products of formula (I) as defined previously in which R
1
is a hydroxyl radical and R
2
is a fluorine atom, as well as their addition salts with acids or bases.
Among the compounds of the invention, there can preferably be mentioned the compounds of formula (I) for which ring B is saturated and Y is a hydrogen atom, as well as their addition salts with acids or bases.
A more particular subject of the invention is the products of formula (I) as defined previously in which Z is a cyano radical or an alkylthio group containing 1 to 8 carbon atoms.
Among the preferred products of the invention the following products can be mentioned:
9&agr;-fluoro-11&bgr;-hydroxy-16&agr;-methyl-pregn-4-ene-3,20-dioxo-21-carbonitrile
methyl 3,20-dioxo-11&bgr;-hydroxy-16&agr;-methyl-21-nor cholane 1,4-diene-24-oate
21-fluoro-11&bgr;-hydroxy-16&agr;-methyl-pregna-1,4-diene-3,20-dione
21-thio-(2-hydroxyethylene)-9&agr;,11&bgr;-dichloro-16&agr;-methyl-pregna-1,4-diene-3,20-dione
21-thio-(2-acetyloxyethylene)-9&agr;,11&bgr;-dichloro-16&agr;-methyl-pregna-1,4-diene-3,20-dione
9&agr;,11&bgr;-dichloro-21-fluoro-16&agr;-methyl-pregna-1,4-diene-3,20-dione and quite particularly,
9&agr;-fluoro-11&bgr;-hydroxy-16&agr;-methyl-pregna-1,4-diene-3,20-dioxo-21-carbonitrile,
9&agr;-fluoro-11&bgr;-hydroxy-16&agr;-methyl-21-thiomethyl-pregna-1,4-diene-3,20-dione.
A subject of the invention is also a preparation process for the products of formula (I) characterized in that a product of general formula (II):
in which either R′
1
is a hydroxyl and R′
2
is a halogen or a hydrogen, or R′
1
is a halogen and R′
2
is a halogen or a hydrogen, or R′
1
and R′
2
form together a second bond and Y is as defined previously, is subjected to the action of an activation reagent of the alcohol of formula Hal-SO
2
—B, Hal being a bromine or chlorine atom and B being an alkyl radical containing 1 to 6 carbon atoms, non-substituted or substituted by 1 to 5 halogen atoms, or a phenyl or naphthyl group non-substituted or substituted by 1 to 5 alkyl groups, containing 1 to 6 carbon atoms, in order to obtain a compound of general formula (III):
which product of formula (III) is subjected, if appropriate, to one or more of the following reactions in a suitable order, in order to obtain a product of general formula (I):
action of a chlorination, iodination, bromination or fluorination reagent,
action of an optionally substituted alkylthiol or arylthiol,
action of a thioamide or of a thiourea followed by a hydrolysis,
action of KCN,
hydrolysis of the cyano group in acid medium then optionally esterification or salification
successive action of CH
2
(COOEt)
2
, a saponification reaction then a decarboxylation reaction optionally followed by an esterification reaction,
action of KSCN or NaSCN,
action of an alcohol or an alcoholate,
acylation reaction in position 11,
alkylation reaction in position 11,
reduction of the double bond in position 1-2,
formation of the double bond in position 1-2,
dehydration reaction in order to form a double bond in position 9-11,
salification.
By B is preferably meant the —CH
3
, —CF
3
, —Ph—Me radicals.
The mesylate, tosylate or triflate of formula (III) are formed by the action, cold, of methane sulphonyl chloride, tosyl chloride or triflic anhydride on the corresponding alcohol of formula (II) in the presence of a base such as pyridine.
The formation of the 21-chlorinated derivative from the corresponding mesylate of formula (III) is carried out according to methods known to a man skilled in the art, in particular by the action of lithium or potassium chloride.
The formation of the 21-brominated derivative from the corresponding mesylate of formula (III) is carried out according to methods known to a man skilled in the art, in particular by the action

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