Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1998-12-14
2002-07-09
Rotman, Alan L. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S201000
Reexamination Certificate
active
06417197
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates to thalidomide prodrugs, to a method of producing them, and to the use of the same as a pharmaceutical active ingredient.
The excessive formation of the cytokinin TNF-&agr; (tumour necrosis factor &agr;) plays a central part in the pathogenesis of graft-versus-host syndrome, of multiple sclerosis, of transplant rejection, aphthous stomatitis, erythema nodosum leprosum, morbus Boeck, rheumatoid arthritis and a series of other diseases which are associated with inflammatory symptoms. One basis for the therapy of these diseases consists of the targeted suppression of the release of TNF-&agr;, by administering inmmunomodulating active ingredients, such as dexamethasone, pentoxifylline or thalidomide for example.
In the treatment of aphthous stomatitis, thalidomide has proved to be superior to classical immunosuppressants. Other examples of diseases in which thalidomide has exhibited good efficacy without resulting in a general imnmunosuppression include cutaneous lupus erythematosus, pyoderma gangrenosum and orogenital ulcers with morbus Behcet, as well as ulcerations in HIV-infected patients, which do not differ histologically from aphthous ulcers and in which—in contrast to the majority of HIV-associated mucocutaneous lesions—no microbial instigators can be detected. As distinct from stomatitis aphthosa, these lesions, which can be characterised as major aphthae, occur in the entire digestive tract, and when located in the pharyngeal space or the oesophagus make the absorption of food difficult, and also make the taking of oral medication difficult, due to the pain which they cause. The pathogenetic factors are endogenous mediators which have effects on the endothelium and on circulating leukocytes. Under the influence of locally-formed TNF-&agr; and other cytokinins, there is a marked increase in the adhesiveness of the endothelium in relation to leukocytes, which makes a definitive contribution to the development of venous vasculitis. Substances which, like thalidomide, suppress this alteration of the endothelium without at the same time blocking the specific cellular immune defence, can constitute an important advance in therapy.
In severe cases of pharyngeal or oesophageal ulcers, in which the taking of oral medication is made difficult, or in which this may even be impossible, and in cases of HIV-associated pathology in which severe symptoms of diarrhoea make the use of oral medication unpredictable, the parental administration of active ingredients is appropriate. However, the low solubility of thalidomide in water (0.012 mg/ml; Arch. Pharm. 321, 371 (1988)) constitutes an obstacle to the parenteral application of this active ingredient.
Thalidomide derivatives are known from DE 42 11 812 which comprise a benzoyloxymethyl group with an amine-bearing substituent on the nitrogen atom of the glutarimide residue. These thalidomide derivatives have a considerably higher solubility in water than that of thalidomide The pH values of aqueous solutions of these compounds are considerably lower than the physiological pH range, however, so that it is necessary to increase the pH before their application. In the course of this procedure, the corresponding bases are precipitated, with the consequence that the advantage of higher solubility in water is eliminated to a considerable extent or even completely.
SUMMARY OF THE INVENTION
The underlying object of the present invention was to develop thalidomide prodrugs which are water-soluble within the physiological pH range. The object was also that the compounds to be developed should not give rise to any toxicological effects due to the separation of non-physiological prodrug residues.
It has been found that the requirements imposed on the compounds to be developed are fulfilled by selected thalidomide prodrugs.
Accordingly, the present invention relates to thalidomide prodrugs of formula I
wherein R denotes —CHR
1
—NHR
2
or —(CH
2
)
n
COOH, R
1
denotes H or C
1-4
alkyl, R
2
denotes H, C
1-3
alkyl, C(O)—CH
2
—NHR
3
or an amino-protective group, R
3
denotes H or an amino-protective group, and n is an integer between 2 and 4, in the form of their bases or salts of physiological acids.
DETAILED DESCRIPTION
The definition of the R
1
wherein R
1
is a C
1-4
alkyl radical includes both straight chain and branched hydrocarbon radicals, which may be substituted with OH, COOH, —C(O)NH
2
, NH
2
, —NHC(O)NH
2
, —NHC(NH)NH
2
or S—C
1-3
—-alkyl, or with a substituted or unsubstituted phenyl group.
The definition of R
2
wherein R
2
is a C
1-3
alkyl radical includes straight chain and branched hydrocarbon radicals.
Compounds which are suitable as thalidomide prodrugs of formula I, wherein R denotes —CHR
1
—NHR
2
, are those in which the R
1
radical denotes H, CH
3
, —CH(CH
3
)
2
, —CH
2
CH(CH
3
)
2
or —CH(CH
3
)CH
2
CH
3
, particularly those compounds in which the R
1
radicals denote H, CH
3
or —CH(CH
3
)
2
and R
2
denotes H, CH
3
, C(O)—OC(CH
3
)
3
or C(O)—O—CH
2
—C
6
H
5
.
Of the thalidomide prodrugs of formula I in which R denotes —(CH
2
)
n
COOH, the compound in which n is 2 is particularly suitable.
The present invention further relates to a method of producing thalidomide prodrugs of formula I, wherein R denotes —CHR
1
—NHR
2
, R
1
denotes H or C
1-4
alkyl, R
2
denotes H, C
1-3
alkyl, C(O)—CH
2
—NHR
3
or an amino-protective group, R
3
denotes H or an amino-protective group, and R
3
denotes H or an amino-protective group, which is characterised in that N-hydroxymethylthalidomide is reacted with an amino acid, the amino function of which is protected, in the presence of a carbodiimide or carbonyldiimidazole, and the protective group for the amino function is subsequently split off by acidolysis if desired.
The t-butyloxycarbonyl radical and the benzyloxycarbonyl radical are particularly suitable as a protective group for the amino function. The reaction of N-hydroxymethylthalidomide with a protected amino acid is conducted in the presence of equimolar to double equimolar amounts of a carbodiimide, for example dicyclohexylcarbodiimide, or of a carbonyldiimidazole, in an organic solvent, for example dichloromethane, chloroform, acetone, dimethylformamide and/or pyridine. The reactions can be conducted in the presence of a catalyst, for example 4-pyrrolidinopyridine or 4-dimethylaminopyridine.
Acidolytic cleavage of the amino-protective group is preferably effected with trifluoroacetic acid, optionally in the presence of an organic solvent, for example dichloromethane.
The present invention also relates to a method of producing thalidomide prodrugs of formula I wherein R denotes —(CH
2
)
n
COOH, which is characterised in that N-hydroxymethylthalidomide is reacted with an acid anhydride in the presence of an amine.
Succinic anhydride is preferably used as the acid anhydride. Triethylamine and/or pyridine are suitable as the amines which are usually used in equimolar to double equimolar amounts with respect to N-hydroxymethylthalidomide. The reactions are usually conducted in an organic solvent, for example dichloromethane, chloroform, pyridine and/or dimethylformamide, in the presence of a catalyst, for example 4-pyrrolidinopyridine or 4-dimethylamino-pyridine.
Salts of compounds according to the invention with physiologically compatible acids, for example hydrochloric acid, hydrobromic acid, sulphuric acid, methanesulphonic acid, formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid, citric acid, glutamic acid and aspartic acid, are obtainable either from the corresponding bases or from trifluoroacetates. For the production of hydrochlorides, the corresponding trifluoroacetates are preferably converted into hydrochlorides with the aid of a weakly basic anion exchanger. Short chain aliphatic alcohols, for example methanol, are preferred as solvents.
The compounds according to the invention can be applied as substances which are soluble in water in the physiological pH range between 70 and 75, and are toxicologically har
Akermann Michaela
Eger Kurt
Schneider Johannes
Winter Werner
Wnendt Stephan
Crowell & Moring LLP
Gruenenthal GmbH
Robinson Binta
Rotman Alan L.
LandOfFree
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