19-Nor-steroids

Details 19-Nor-steroids 19-Nor-steroids

1995-05-17

2004-09-14

Badio, Barbara P. (Department: 1616)

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

Organic compounds

Cyclopentanohydrophenanthrene ring system containing

C552S648000

Reexamination Certificate

active

06790971

ABSTRACT:

OBJECTS OF THE INVENTION
It is an object of the invention to provide the novel compounds of formulae I and IA and a novel process and novel intermediates for their preparation.
It is another object of the invention to provide novel hormonal compositions and novel methods of inducing hormonal reactions in warm-blooded animals.
These and other objects and advantages of the invention will become obvious from the following detailed description.
THE INVENTION
The novel compounds of the invention are 19-nor-steroids of the formula
wherein the A and B rings have a structure selected from the group consisting of
are individually selected from the group consisting of hydrogen and alkyl of 1 to 4 carbon atoms, R
3
is selected from the group consisting of hydrogen, alkyl of 1 to 4 carbon atoms and acyl of an organic carboxylic acid of 1 to 7 carbon atoms, R
17
and R′
17
together form ═O or R
17
is —OH or acyloxy and R′
17
is selected from the group consisting of hydrogen, alkyl of 1 to 8 carbon atoms and alkenyl and alkynyl of 2 to 8 carbon atoms, all optionally substituted, X is selected from the group consisting of —CH
2
— or —CH
2
O—, arylene and arylenoxy linked to the C ring through a carbon atom, Y is selected from the group consisting of a simple bond and saturated and unsaturated aliphatic of 1 to 18 carbon atoms optionally interrupted with at least one member of the group consisting of arylene, —O— and optionally oxidized —S— and optionally terminated with aryl, Z is a simple bond or —CH
2
O— linked to Y by a carbon atom, R
A
and R
A
′ being individually selected from the group consisting of hydrogen and alkyl of 1 to 8 carbon atoms optionally substituted with at least one member of the group consisting of aryl, alkylamino, dialkylamino, —OH, halogen and esterified carboxyl or R
A
and R
A
′ taken together with the nitrogen to which they are attached form 5 to 6 ring heterocycle optionally containing at least one heteroatom selected from the group consisting of —S—, —O— and —N— optionally substituted with alkyl of 1 to 4 carbon atoms with the proviso 1) that both R
A
and R
A
′ are not hydrogen, and 2) when Z and Y are both simple bonds, X is not —CH
2
— or —CH
2
O—, A) wherein n is 1, K is oxygen, R
18
is —OH or optionally salified
R
B
′ is methyl, R
B
is isopropyl or n-butyl or heptafluorobutyl, X′ is selected from the group consisting of methylene, phenylene and phenoxy attached to the steroid by a carbon atom, Y′ is selected from the group consisting of —(CH
2
)
7
—, —(CH
2
)
8
—, —(CH
2
)
5
—C≡C—, —(CH
2
)
q
—O——CH
2
— and
q is an integer from 5 to 7, n′ is 0, 1 or 2 and Z is a simple bond and B) wherein n is 1 or 2, K is —O— or —S—, R
18
and R′
18
form ═O or R
18
is —OH or acyloxy, and R′
18
is selected from the group consisting of hydrogen and optionally substituted alkyl, alkenyl and alkynyl of up to 8 carbon atoms, X′ is selected from the group consisting of —CH
2
—, —CH
2
O—, arylene and arylenoxy and arylenethio connected to the steroid by a carbon atom, Y′ is selected from the group consisting of a simple bond and optionally unsaturated aliphatic of 1 to 18 carbon atoms optionally interrupted with arylene or —O— or —S—, —SO— or —SO
2
— and optionally terminated with arylene, Z′ is a simple bond with the proviso that when Y′ and Z′ are both a simple bond, X′ is not —CH
2
— or —CH
2
O— and R
B
and R′
B
are individually selected from the group consisting of hydrogen and alkyl of 1 to 8 carbon atoms optionally substituted with a member of the group consisting of aryl, alkylamino, dialkylamino, —OH, halogen and esterified carboxy or taken together with the nitrogen to which they are attached form an optionally unsaturated 5- or 6-member heterocycle optionally containing at least one additional heteroatom of —O—, —S— or nitrogen optionally substituted with a member of the group consisting of alkyl of 1 to 4 carbon atoms, aryl of 6 to 10 carbon atoms and aralkyl of 7 to 10 carbon atoms with the proviso that at least one of R
B
and R′
B
is not hydrogen and at least one of the following conditions is met, n is 2 or K is —S— or X′ is arylenethio attached to the steroid by a carbon atom or R
B
and R′
B
with the nitrogen is a 5- or 6-member heterocycle substituted by aryl or aralkyl.
Examples of R
3
, R
2
and/or R′
2
as alkyl are methyl, ethyl, propyl, isopropyl, butyl, tert.-butyl and isobutyl, preferably methyl. Examples of R
3
as acyl are acetyl, propionyl, butyryl and benzoyl.
When R
17
or R
18
is an acyloxy, it is derivative of an aliphatic or cycloaliphatic carboxylic acid, saturated or unsaturated and especially alkanoic acids such as for example, acetic acid, propionic acid, butyric acid or isobutyric acid, valeric acid or undecylic acid; a hydroxyalkanoic acid such as hydroxyacetic acid; cycloalkylcarboxylic acids or cycloalkylalkanoic acids such as cyclopropylcarboxylic acid, cyclopentylcarboxylic acid or cyclohexyl carboxylic acid, cyclopentyl or cyclohexyl acetic acid or propionic acid, benzoic acid, salicylic acid or a phenylalkanoic acid such as phenylacetic acid or phenylpropionic acid, an amino acid such as diethylaminoacetic acid or aspartic acid or formic acid. It is preferably a derivative of acetic acid, propionic acid, butyric acid or butanedioic acid.
When R
17
or R
18
is alkyl, it is preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, 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 and most preferably, methyl.
When R
17
or R
18
is alkenyl, it is preferably vinyl, propenyl, isopropenyl, allyl, 2-methylallyl, butenyl or isobutenyl and most preferably vinyl or propenyl. When R
17
or R
18
is alkynyl, it is preferably ethynyl, propynyl, propargyl, butynyl or isobutynyl and most preferably ethynyl or propynyl.
The expression optionally substituted applied to the alkyl, alkenyl or alkynyl includes at least one member of the group consisting of halogen, such as fluorine, chlorine, bromine or iodine, alkoxy such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, alkylthio such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, amino, alkylamino such as methylamino or ethylamino, dialkylamino such as dimethylamino, diethylamino or methyl ethylamino, each of the dialkylaminos being optionally in the oxidized form; aminoalkyl such as aminomethyl or aminoethyl, dialkylaminoalkyl such as dimethylaminomethyl or ethyl, dialkylaminoalkoxy such as dimethylaminoethoxy, optionally acylated hydroxyl, for example acetoxy or
in which n=2 to 5, such as acetyl, propionyl, butyryl, benzoyl, free or esterified carboxy and alkoxycarbonyl, for example methoxycarbonyl or ethoxycarbonyl, cyano, trifluoromethyl, aryl such as phenyl, furyl, thienyl or aralkyl such as benzyl, these being optionally substituted by alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl or by alkoxy, alkylthio, alkylamino or di-alkylamino indicated above.
When X or X′ is arylene it is preferably phenylene and when X or X′ is arylenoxy, it is preferably phenylenoxy.
When Y or Y′ is saturated or unsaturated linear or branched aliphatic chain, it can be methylene, ethylene, propylene, isopropylene, butylene, isobutylene or tert.-butylene, n-pentylene, n-hexylene, 2-methyl pentylene, 2,3-dimethyl butylene, n-heptylene, 2-methylhexylene, 2,2-dimethylpentylene, 3,3-dimethylpentylene, 3-ethylpentylene, n-octylene, 2,2-dimethylhexylene, 3,3-dimethylhexylene, 3-methyl 3-ethylpentylene, nonylene, 2,4-dimethyl heptylene, n-decylene, n-undecylene, n-dodecylene, n-tridecylene, n-tetradecylene, n-penta-decylene, n-hexadecylene n-heptadecylene or n-octadecylene, preferably n-nonylene or n-decylene. Equally it can be one of the following; vinylene, isopropylene, allylene, 2-methylallylene or isobutenylene, and when the chain

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