Anti-inflammatory androstane derivatives

Details Anti-inflammatory androstane derivatives Anti-inflammatory androstane derivatives

2002-02-04

2003-03-25

Qazi, Sabiha (Department: 1616)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Cyclopentanohydrophenanthrene ring system doai

C514S171000, C514S169000, C514S177000, C540S107000, C540S108000, C540S110000, C540S112000, C540S114000, C540S115000, C424S045000

Reexamination Certificate

active

06537983

ABSTRACT:

The present invention relates to novel anti-inflammatory and anti-allergic compounds of the androstane series and to processes for their preparation. The present invention also relates to pharmaceutical formulations containing the compounds and to therapeutic uses thereof, particularly for the treatment of inflammatory and allergic conditions.
Glucocorticoids which have anti-inflammatory properties are known and are widely used for the treatment of inflammatory disorders or diseases such as asthma and rhinitis. For example, U.S. Pat. No. 4,335,121 discloses 6&agr;, 9&agr;-Difluoro-17&agr;-(1-oxopropoxy)-11&bgr;-hydroxy-16&agr;-methyl-3-oxo-androsta-1,4-diene-17&bgr;-carbothioic acid S-fluoromethyl ester (known by the generic name of fluticasone propionate) and derivatives thereof. The use of glucocorticoids generally, and especially in children, has been limited in some quarters by concerns over potential side effects. The side effects teat are feared with glucocorticoids include suppression of tile Hypothalamic-Pituitary-Adrenal (HPA) axis, effects on bone growth in children and on bone density in the elderly, ocular complications (cataract formation and glaucoma) and skin atrophy. Certain glucocorticoid compounds also have complex paths of metabolism wherein the production of active metabolites may make the pharmacodynamics and pharmacokinetics of such compounds difficult to understand. Whilst the modern steroids are very much safer than those originally introduced it remains an object of research to produce new molecules which have excellent anti-inflammatory properties, with predictable pharmacokinetic and pharmacodynamic properties, with an attractive side effect profile, and with a convenient treatment regime.
We have identified a novel series of glucocorticoids, which substantially meets these objectives.
Thus, according to one aspect of the invention, there is provided a compound of formula (I)
wherein
R
1
represents C
1-6
alkyl or C
1-6
haloalkyl;
R
2
represents —C(═O)-aryl or —C(═O)-heteroaryl;
R
3
represents hydrogen, methyl (which may be in either the &agr;or &bgr; configuration) or methylene;
R
4
and R
5
are the same or different and each represents hydrogen or halogen; and {overscore (-----)} represents a single or a double bond;
and salts and solvates thereof.
References to the term “aryl” include references to phenyl which may be optionally substituted with one or more substituents.
References to the term “heteroaryl” include references to 5 or 6 membered heterocyclic aromatic rings containing 1-3 hetero atoms selected from N, O and S (e.g. pyridinyl, pyrimidinyl, thienyl (eg thien-2-yl or thien-3-yl), furanyl (eg furan-2-yl or furan-3-y), pyrrolyl (eg 1H-pyrrol-2-yl), oxazolyl, thiadiazolyl (eg 1,2,3-thiadiazol-5-yl, 1,2,5-thiadiazol-3-yl or 1,2,3-thiadiazol-4-yl)). In one respect the heterocycle is preferably thiophenyl, pyrrolyl or furanyl, more preferably thiophenyl or furanyl. Further examples include thiazolyl (eg 1,3-thiazolyl-5-yl or 1,3-thiazolyl-4-yl), isoxazolyl (eg isoxazol-5-yl or isoxazol-4-yl), isothiazolyl (eg isothiazol-3-yl or isothiazol-5-yl), pyrazolyl (eg 1H-pyrazol-5-yl) and imidazolyl (eg 1H-imidazol-5-yl).
All of the previously named heterocycles may be optionally substituted with one or more (e.g. 1 or 2) substituents.
Examples of substituents for aryl and heteroaryl include C
1-6
alkyl (e.g. methyl) or halogen (e.g. chlorine or bromine). Other examples include C
1-6
alkoxy (e.g. methoxy or ethoxy).
Examples of substituted furanyl include 3-Me-furan-2-yl, 5-Br-furan-2-yl, 2-Me-furan-3-yl and 2,5-diMe-furan-3-yl. Examples of substituted thienyl include 3-Me-thien-2-yl, 5-Me-thien-2-yl, 5-Cl-thien-2-yl, 3-Cl-thien-2-yl, 3-Br-thien-2-yl, 3-Ethoxy-thien-2-yl, 4-methoxy-thien-3-yl, 2,5-diCl-thien-3-yl and 4-methoxy-5-Cl-thien-3-yl. Examples of substituted pyrrolyl include 1-Me-1H-pyrrol-2-yl. Examples of substituted thiazolyl include 4-Me-1,3-thiazol-5-yl, 2,4-diMe-1,3-thiazol-5-yl and 2-Me-1,3-thiazol4-yl. Examples of substituted thiadiazolyl include 4-Me-1,2,3-thiadiazol-5-yl. Examples of substituted isoxazolyl include 3-Me-isoxazol-5-yl, 5-Me-isoxazol-3-yl, 5-Me-isoxazol-4-yl and 3,5-diMe-isoxazol-4-yl. Examples of substituted pyrazolyl include 1,3-diMe-1H-pyrazol-5-yl and 1-Et-3-Me-1H-pyrazol-5-yl. Examples of substituted imidazolyl include 1-Me-1H-imidazol-5-yl.
Examples of Solvates Include Hydrates
Examples of salts of compounds of formula (I) include physiologically acceptable salts which may be formed with basic compounds (such as when heteroaryl is basic) eg. acetate, benzoate, citrate, succinate, lactate, tartrate, fumarate and maleate.
References hereinafter to a compound according to the invention includes both compounds of formula (I) and salts and solvates thereof, particularly pharmaceutically acceptable salts and solvates.
It will be appreciated that the invention includes within its scope all stereoisomers of the compounds of formula (I) and mixtures thereof. Preferably, the absolute stereochemistry will be as shown in the representation of compounds of formula (I).
Examples of C
1-6
haloalkyl that R
1
may represent include C
1-6
alkyl substituted by 1-3 halogen atoms, preferably 1 halogen atom. Preferred halogen atoms are selected from bromine, chlorine and fluorine. Examples of C
1-6
alkyl that R
1
may represent include methyl.
We prefer R
1
to represent fluoromethyl, chloromethyl, bromomethyl or 2′-fluoroethyl, especially fluoromethyl.
We prefer R
2
to represent —C(═O)-heteroaryl. Preferably the heteroaryl is a 5-membered heterocyclic aromatic ring containing 1 to 3 heteroatoms selected from O, N and S which may optionally be substituted. In one respect, preferably heteroaryl represents furanyl, pyrrolyl or thiophenyl, more preferably furanyl or thiophenyl eg 2-furanyl, 3-furanyl, 2-thiophenyl or 3-thiophenyl, especially furanyl, particularly 2-furanyl. However it may also be preferred that heteroaryl represents pyrrolyl or thiophenyl, more preferably thiophenyl eg 2-thiophenyl or 3-thiophenyl which pyrrolyl or thiophenyl may be optionally substituted.
Of particular interest are compounds in which the heteroaryl is a 5-membered heterocyclic aromatic ring containing 2 heteroatoms selected from O, N and S. Thus a further set of preferred compounds is that in which R
2
represents optionally substituted thiazolyl. A further set of preferred compounds is that in which R
2
represents optionally substituted isothiazolyl. A further set of preferred compounds is that in which R
2
represents optionally substituted pyrazolyl. A further set of preferred compounds is that in which R
2
represents optionally substituted isoxazolyl. A further set of preferred compounds is that in which R
2
represents optionally substituted isothiazolyl. A further set of preferred compounds is that in which R
2
represents optionally substituted imidazolyl.
Of particular interest is compounds in which the heteraryl is a 5-membered heterocyclic aromatic ring containing 3 heteroatoms selected from O, N and S. Thus a further set of preferred compounds is that in which R
2
represents optionally substituted thiadiazolyl.
Compounds in which R
2
represents —C(═O)-aryl (preferably aryl represents phenyl) are also of particular interest.
We prefer R
3
to represent methyl, especially methyl in the &agr; configuration. Compounds in which R
3
represents methyl in the &ggr; configuration are also of particular interest.
Compounds of formula (I) in which R
4
and R
5
, which can be the same or different, each represents hydrogen, fluorine or chlorine, particularly hydrogen or fluorine, are preferred. Especially preferred are compounds in which both R
4
and R
5
are fluorine.
Preferably, {overscore (-----)} represents a double bond. Compounds in which {overscore (-----)} represents a single bond are also of particular interest.
A particularly preferred group of compounds of the present invention are compounds of formula (I) in which R
1
is fluoromethyl; R
2
is —C(═O)-2-furanyl; R
3
is methyl; R
4
and R
5
, w

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