Use of fumaric acid derivatives

Details Use of fumaric acid derivatives Use of fumaric acid derivatives

1999-07-08

2002-08-20

Travers, Russell (Department: 1617)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Ester doai

C514S546000, C514S549000

Reexamination Certificate

active

06436992

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention relates to the use of certain fumaric acid monoalkyl esters as salt either alone or in combination with a dialkyl fumarate for preparing pharmaceutical compositions for the treatment of poly-arthritis, multiple sclerosis and graft-versus-host reactions. The invention also relates to medicaments containing one or several fumaric acid monoalkyl esters in the form of free acids, optionally in combination with dialkyl fumarate, as active ingredient for the treatment of polyarthritis, multiple sclerosis, graft-versus-host reactions and other auto-immune diseases. These compositions do not contain fumaric acid per se. The use according to the invention also extends to the treatment of juvenile diabetes, Hashimoto's thyroiditis, Grave's disease, systemic Lupus erythematosus (SLE), Sjogren's syndrome, pernicious anaemia and chronically active (=lupoid) hepatitis.
Pharmaceutical compositions which end in the citric acid cycle when decomposed after administration or which belong to the citric acid cycle are increasingly gaining therapeutic value, especially when given in high dosages, because they help relieve or heal diseases with cryptogenetic causes.
Fumaric acid, for example, inhibits the growth of the Ehrlich ascites tumour in mice, reduces the toxic effects of mitomycin C and aflatoxin [K. Kuroda, M. Akao, Biochem. Pharmacol. 29, 2839-2844 (1980)/Gann. 72, 777-782 (1981)/Cancer Res. 36, 1900-1903, (1976)] and displays a anti-psoriatic and anti-microbial activity [C. N. Huhtsnen, J. Food Sci. 48, 1574 (1983)/M. N. Islam, U.S. Pat. No. 4,346,118 dated Aug. 24, 1982/C. A. 97, 161317b (1982)].
When administered parenterally, dermally and especially perorally, high dosages of fumaric acids or its derivatives known so far such as dihydroxy fumaric acid, fumaramide and fumaronitrile have such unacceptably severe side effects and high toxicity [P. Holland, R. G. White, Brit. Dermatol. 85, 259-263 (1971)/M. Hagedorn, K. W. Kalkoff, G. Kiefer, D. Baron. J. Hug, J. Petres, Arch. Derm. Res. 254, 67-73 (1975)] that, in most cases, such a therapy had to be abandoned in the past.
European Patent Application 18 87 49 already describes fumaric acid derivatives and pharmaceutical compositions containing the same for the treatment of psoriasis. Pharmaceutical compositions for the treatment of psoriasis containing a mixture of fumaric acid and other fumaric acid derivatives are known from DE-A-25 30 372. The content of free fumaric acid is obligatory for these medicaments.
DE-A-26 21 214 describes medicaments containing the fumaric acid monoethyl ester and its mineral salts as active ingredient for the treatment of psoriasis. The publication “Hautarzt (Dermatologist) (1987) 279-285” discusses the use of fumaric acid monoethyl ester salts (Ca, Zn, Mg) and of the fumaric acid dimethyl ester for the treatment of psoriasis. Pharmaceutical compositions containing a mixture of fumaric acid monoalkyl ester salts and a fumaric acid diester for the treatment of psoriasis, psoriatic arthritis, neurodermitis and enteritis regionalis Crohn are known from EP 0 312 697 B1.
Surprisingly, we have now found in in vitro tests and in animal experiments that it is possible to treat polyarthritis, multiple sclerosis and graft-versus-host reactions with pharmaceutical compositions using one or several compounds from the group consisting of calcium, magnesium, zinc and iron salts of fumaric acid monoalkyl esters of the general formula
optionally in admixture with dialkyl fumarate of the formula
 wherein A is a bivalent cation from the series consisting of Ca, Mg, Zn or Fe or a monovalent cation from the series consisting of potassium or sodium, respectively, and n denotes the numeral 1 or 2 depending on the type of cation,
optionally together with commonly used pharmaceutical excipients.
We also found an effect when polyarthritis, multiple sclerosis and graft-versus-host reactions were treated with pharmaceutical compositions containing one or several compounds of alkyl hydrogen fumaric acid of the general formula
optionally in admixture with dialkyl fumarate of the formula
 wherein R, R
1
, R
2
may be the same or different and each of R, R
1
and R
2
is an alkyl group having 1 to 5 carbon atoms (C
1
-C
5
alkyl);
and, optionally, commonly used pharmaceutical excipients and carriers.
Preferred compositions according to the invention contain the calcium salt of the fumaric acid monomethyl ester, the calcium salt of the fumaric acid monomethyl ester in admixture with dimethyl fumarate or the relevant salts of the fumaric acid monoethyl ester.
Preparations containing the calcium salt of the fumaric acid monoalkyl ester or the fumaric acid alkyl ester in the form of the free acid in an amount of 10 to 300 mg are especially suitable for administration, the total weight of the active ingredients being 10 to 300 mg.
Other preferred oral forms of administration contain 10 to 290 parts by weight of the calcium salt of the fumaric acid monoalkyl ester and 290 to 10 parts by weight of dimethyl fumarate as well as 1 to 50 parts by weight of the zinc salt of the fumaric acid monoalkyl ester or 1 to 250 parts by weight of the calcium salt of the fumaric acid monoalkyl ester, 250 to 10 parts by weight of dimethyl fumarate, 1 to 50 parts by weight of the magnesium salt of the fumaric acid monoalkyl ester and 1 to 50 parts by weight of the zinc salt of the fumaric acid monoalkyl ester or the monomethyl ester, respectively, the total weight of the active ingredients being 30 to 300 mg.
Preferred compositions according to the invention also contain the methyl hydrogen fumarate in an amount of 10 to 300 mg.
For commencement of a systemic therapy and, vice versa, termination of the treatment by gradual reduction of the dosage, low doses containing, for example, 30.0 mg of dimethyl fumarate, 20.0 mg of the calcium salt of monoethyl fumarate and 3.0 mg of the zinc salt of monoethyl fumarate or monomethyl fumarate, respectively, are advantageous.
For therapeutic dosing after an initial phase, for example, a dosage of 120.0 mg of dimethyl fumarate, 87.0 mg of the calcium salt of the monoethyl fumarate and 3.0 mg of the zinc salt of the mono ethyl fumarate or the monomethyl fumarate may be used.
The fumaric acid derivatives contained in the compositions according to the invention, are obtained by
a) condensation of a compound of the formula
 with 2 moles of alkyl alcohol (ROH) by a known method to obtain a diester, followed by controlled hydrolysation to obtain a monoester, or
b) condensation of 1 mole of the relevant alkyl alcohol (ROH) in the usual manner followed by hydrolysis of the monoacid chloride thus obtained to obtain an acid, or
c) direct condensation of the fumaric acid with 2 moles of alkyl alcohol (ROH) by a known method to obtain the relevant diester followed by controlled hydrolysation to obtain the monoester, or
d) direct condensation of maleic acid or maleic anhydride with 1-2 moles of the relevant alkyl alcohol (ROH) by a known method to obtain a mono- or diester followed by catalytic isomerisation to obtain the respective fumaric acid derivative.
The salts of the fumaric acid monoalkyl esters may also be obtained by reacting a compound of the general formula
wherein R is a C
1
-C
5
alkyl group with equivalent mole amounts of Na, K, Fe, Ca, Mg or Zn hydroxide or oxide in toluene and removing the water generated during the reaction.
For particularly preferred applications, preparations containing the following active ingredients in the stated dosages and proportions are used:
as a pharmaceutical composition for oral administration in the form of tablets or capsules, characterised in that they contain the calcium salt of the fumaric acid monomethyl ester in an amount of 10 to 300 mg, the total weight of the active ingredients being 10 to 300 mg; or
as a pharmaceutical composition for oral administration in the form of tablets or capsules, characterised in that they contain 10 to 290 parts by weight of the c

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