Corticoid 17,21-dicarboxylic esters and corticosteroid...

Details Corticoid 17,21-dicarboxylic esters and corticosteroid... Corticoid 17,21-dicarboxylic esters and corticosteroid...

1997-07-22

2004-12-28

Badio, Barbara P. (Department: 1616)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Cyclopentanohydrophenanthrene ring system doai

C514S180000, C514S181000, C552S574000, C552S576000

Reexamination Certificate

active

06835724

ABSTRACT:

The invention relates to corticoid 17,21-dicarboxylic esters and corticoid 17-carboxylic ester 21-carbonic esters of the formula I:
in which:
A is CHOH and CHCl in arbitrary steric arrangement, CH
2
, C═O or 9(11) double bond,
Y is hydrogen, fluorine or chlorine,
Z is hydrogen, fluorine or methyl,
R(1) is optionally substituted or fused aryl or hetaryl
(C
1
-C
4
)-alkyl is saturated, unsaturated once or more than once, branched by further alkyl groups, unsubstituted or inserted or substituted by heteroatoms O, S or N,
n is zero or 1,
m is zero or 1,
R(2) is linear or branched (C
1
-C
8
)-alkyl
R(3) is hydrogen or &agr;- or &bgr;-methyl.
Corticoid 17,21-dicarboxylic esters and corticoid 17-carboxylic ester 21-carbonic esters of the formula I are preferred in which:
R(1), A, Y, Z and R(3) are defined as above,
R(2) is linear or branched (C
1
-C
8
)-alkyl
The invention also relates to a process for preparing a compound I, in which process
a) a compound of the formula II:
in which R(5) is OH and the remaining substituents have the abovementioned meanings,
a1) is reacted with an activated carboxylic acid of the formula III, preferably a halide or anhydride or azolide,
R(6)-CO—(O)
n
—[(C
1
-C
4
)-alkyl]
m
-R(1)  III
in which:
n is zero,
m is zero or 1, and
[(C
1
-C
4
)-alkyl] and R(1) have the abovementioned meanings, and
R(6) is Cl, Br, O[—CO—(O)
n
—](C
1
-C
4
)-alkyl]
m
-R(1)
1
, —O—C(O)CF
3
, or another activated acid radical, or
a2) is reacted with a haloformate of the formula III, in which
n is 1,
m is zero or 1,
[(C
1
-C
4
)-alkyl] and R(1) have the abovementioned meanings and R(6) is Cl, Br or I, or
a3) is reacted with a carboxylic acid of the formula III itself, in which
R(6) is OH, and
n is zero,
and the other substituents are given in formula III, in the presence of water-eliminating reagents (DCCI, etc.),
or in which
b) compounds of the formula II:
in which R(5) is Br, I, or a sulfonic aryl ester group or sulfonic alkyl ester group, and the other substituents have the meaning given in formula I, are reacted with a salt, preferably a K or Na salt or a trialkylammonium salt, of a carboxylic acid of the formula III:
R(6)-CO—(O)
n
—[(C
1
-C
4
)-alkyl]
m
-R(1)  III
in which
R(6) is —[O
−
Me
+
], and
n is zero,
and the other substituents have the meanings given in formula III,
Me preferably being the cation of an alkali metal salt or of a trialkylammonium salt.
The steroid 17-carboxylic esters with a free 21-hydroxyl group of the formula II [R(5)=OH], which are required as starting substances, are as a rule known or are prepared by known methods.
The stippled line between carbon atoms 1 and 2 indicates that this bond can be a single bond or an unsaturated bond.
The steroid 17-carboxylic esters with R(5) being Br, I, —OSO
2
-aryl or —OSO
2
-alkyl in formula II are known as a rule or are prepared by known methods, e.g. in analogy with corresponding corticoid 17-alkyl carbonate 21-compounds in accordance with U.S. Pat. No. 4,377,575 (HOE 78/F 082) and EP-A-470 617 (HOE 90/F 241). The 17-carboxylic esters of the following corticosteroids come into consideration in this context:
prednisolone, prednisone, 6&agr;-methylprednisolone, 6&agr;,61&agr;-dimethylprednisolone, 16&agr;-methylprednisolone, hydrocortisone (cortisol), cortisone, 6&agr;-methylcortisol, Reichstein's substance S, 11-desoxy-9(11)-dehydroprednisolone, 6&agr;-fluoroprednisolone, dexamethasone, 6&agr;-fluorodexamethasone, 9&agr;-fluoroprednisolone, 6&agr;,9&agr;-difluoroprednisolone, 6&agr;-methyl-9&agr;-fluoroprednisolone, betamethasone and clobetasol.
The carboxylic acids of the formula III [R(6) is OH and n is zero] which are used as reaction partners, and their activated derivatives, such as the halides [R(6)═Cl, Br or I, or their anhydrides], or their azolides [R(6) is imidazolide or triazolide], or their salts [R(6) is (MeO)—, preferably (KO)— or (NaO)—], are as a rule known and are prepared, where appropriate, by general preparative methods. Examples of carboxylic acids according to formula III [R(6) is OH and n is zero] which can be used in accordance with the invention are to be found in the list at the end of the text prior to the claims.
All carboxylic acids coming into this category carry, in their acid radical, an aryl or hetaryl group which is optionally substituted by methylenedioxy, halogen, alkyl, alkoxyl, acyl, thioalkyl, thioacyl, nitro, amino, aminoalkyl, amido, cyano, oxyacyl, oxyaryl, etc., or is optionally fused. The aryl and hetaryl groups are essential constituents of the invention.
As is demonstrated in the pharmacological section, corticoid 17,21-dicarboxylic esters of this type (=21-aryl ester or 21-hetaryl ester type), in particular, often exhibit qualities of effect which are clearly superior, as regards the local/systemic ratio of antiinflammatory effect, to those of structurally related corticoid 17,21-dicarboyxlic esters or structurally related corticoid 17-alkyl carbonate 21-carboxylic esters which do not carry any aryl or hetaryl group in the 21-acid residue.
Detailed description of the conduct of the individual reactions in the processes for preparing the products according to Formula I according to the invention:
Regarding process variant a:
In order to prepare 21-carboxylic esters of the abovementioned type, either carbonyl halides or carboxylic azolides of the formula IV
R(6)-OC—[(C
1
-C
4
-alkyl]
m
-R(1)  IV,
in which:
R(6) is Cl, Br, I,
m is zero or 1, and
R(1) and (C
1
-C
4
)-alkyl have the meanings given for formula III,
or carboxylic anhydrides of the formula V:
O{—OC—[(C
1
-C
4
)-alkyl]
m
-R(1)}
2
  V,
in which
m is zero or 1, and
R(1) and (C
1
-C
4
)-alkyl have the meanings given for formula III, are preferably used. In both cases, the carboxylic acids on which they are based, and which are given in the list, can be used, preferably their carbonyl chlorides, carboxylic anhydrides, carboxylic imidazolides and carboxylic triazolides.
R(6) in formula IV can also comprise other groups which activate the carboxyl group in carboxylic acids for esterification, such as, for example, —O—CO—CF
3
, or the activated carboxylic acids which can be prepared from phosphonic or phosphinic anhydrides (e.g. propylphosphonic anhydride) or polyphosphoric anhydride (PPA).
Additional phosphorus reagents which can bring about mild esterification of organic carboxylic acids with the 21-alcohol group of corticoid 17-alkyl carbonates are cited or described in the literature references Synth. Commun. 13, 471 ff (1983) and Synth. Commun. 14, 515 ff (1984).
In order to carry out the esterification using a carbonyl halide or carboxylic anhydride or a haloformate, the steroid component is dissolved in an inert solvent, for example in an ether, such as dioxane, tetrahydrofuran or diglyme, or in optionally halogenated hydrocarbons, such as benzene, toluene, cyclohexane, methylene chloride or chloroform, or in acetone, or in a mixture of these solvents. In order to remove the hydrohalic acid which is produced in the reaction, 1 to 1000 molar equivalents of a tertiary base, such as pyridine, quinoline, triethylamine, dimethylaniline, dimethylaminopyridine, etc., are added. However, an inorganic base, such as sodium hydrogen carbonate or calcium carbonate, can also be used for removing the acid. 1 to 200 molar equivalents, preferably 1-3 molar equivalents, of one of the above-listed acylating agents, optionally dissolved in one of the above-listed solvents, are then added dropwise at a temperature of −40° C. up to the boiling point of the solvent used, preferably at a temperature of 0° C. to 25° C. Subsequently, the reaction mixture is left to stand for one to 120 hours at a temperature of −40° C. up to the boiling point of the solvent, preferably at a temperature of 0° C. to 25° C.
When using carboxylic anhydrides as acylating agents, it is now and then advanta

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