Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-04-18
2001-04-03
Powers, Fiona T. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S454000
Reexamination Certificate
active
06211223
ABSTRACT:
This invention relates to an indole derivative useful in the treatment of a variety of diseases including acute renal failure, restenosis, and pulmonary hypertension, and to pharmaceutical formulations containing the compound.
International Patent Application WO 94/14434 discloses indole derivatives which are indicated as endothelin receptor antagonists. European Patent Application 617001 discloses a large number of phenoxyphenylacetic acid derivatives which are also indicated as endothelin receptor antagonists.
Bergman et al, Tetrahedron, Vol. 31, N° 17, 1975, pages 2063-2073, disclose a number of indole-3-acetic acids. Similar compounds are disclosed by Rusinova et al., Khim. Geterotsikl. Soedin., 1974, (2), 211-213 (see also Chemical Abstracts, Vol. 81, N° 7, Aug. 19, 1974, abstract N° 37455a), and Yarovenko et al, J. Gen. Chem. USSR (English translation), Vol. 39, 1969, page 2039 (see also Beilstein, Registry Number 431619).
These compounds are not indicated in any kind of therapy.
Julian et al., J. Chem. Soc., Chemical Communications, N° 1, 1973, disclose an N-p-chlorobenzoylindole derivative as a by-product of a photo-addition reaction. The compound is not indicated in any kind of therapy.
Yamamoto et al, Japanese Patent N° 70 041 381 (see also Chemical Abstracts, Vol. 75, N° 3, 1971, abstract N° 20189v), disclose an N-p-chlorobenzoylindole derivative which is indicated as an anti-inflammatory agent.
International Patent Application N° PCT/EP97/01882 (filed Apr. 11, 1997, published as WO 97/43260) discloses a group of indole derivatives indicated in the treatment of a variety of diseases including restenosis, renal failure and pulmonary hypertension. Example 17 discloses 3-{1-(1,3-benzodioxol-5-yl)-2-[(2-methoxy-4-methylphenyl)sulfonylamino]-2-oxoethyl}-1-methyl-1H-indole-6-carboxylic acid.
It has now been found that the (+)-enantiomer of 3-{1-(1,3-benzodioxol-5-yl)-2-[(2-methoxy-4-methylphenyl)sulfonylamino]-2-oxoethyl}-1-methyl-1H-indole-6-carboxylic acid possesses significant advantages over the (−)-enantiomer. X-ray studies indicate that the absolute configuration of the (+)-enantiomer of this compound is S.
Thus, according to the present invention, there is provided (S)-(+)-3-{1-(1,3-benzodioxol-5-yl)-2-[(2-methoxy-4-methylphenyl)sulfonylamino]-2-oxoethyl}-1-methyl-1H-indole-6-carboxylic acid,
which is substantially free from its (R)-(−)-enantiomer, and pharmaceutically acceptable derivatives thereof (referred to herein as “the compounds of the invention”).
In accordance with normal practice, the designation “(+)” indicates that an enantiomer rotates the plane of plane-polarized light in the clockwise direction, for example when in a methanol solution at a concentration of around 1 mg/ml. The designation “(−)” should be construed accordingly.
By “substantially free from its (−)-enantiomer” is meant that a sample of a (+)-enantiomer contains less than 10% by weight of its (−)-enantiomer (i.e. it is more than 90% enantiopure), more preferably less than 5% by weight of its (−)-enantiomer, and most preferably less than 1% by weight of its (−)-enantiomer, for example pure (+)-enantiomer. “Substantially free from its (+)-enantiomer” should be construed accordingly.
Pharmaceutically acceptable derivatives include compounds which are suitable bioprecursors (prodrugs) of (S)-(+)-3-{1-(1,3-benzodioxol-5-yl)-2-[(2-methoxy-4-methylphenyl)sulfonylamino]-2-oxoethyl}-1-methyl-1H-indole-6-carboxylic acid, and pharmaceutically acceptable salts.
Suitable bioprecursors are discussed in Drugs of Today, Vol. 19, 499-538 (1983) and Annual Reports in Medicinal Chemistry, Vol. 10, Ch 31 p306-326, and include C
1-6
alkyl esters of the carboxylic acid group. Suitable pharmaceutically acceptable salts include alkali metal salts, for example sodium salts.
(S)-(+)-3-{1-(1,3-Benzodioxol-5-yl)-2-[(2-methoxy4-methylphenyl)sulfonylamino]-2-oxoethyl}-1-methyl-1H-indole-6-carboxylic acid may be separated from a racemic mixture using conventional means such as fractional crystallization.
Preferably, the separation is a dynamic resolution. This is possible because the proton attached to the chiral carbon atom is sufficiently acidic to exchange in the presence of base. Thus, the acid in solution epimerizes throughout the process, but the desired diastereomeric salt precipitates during the process, leaving a diminishing quantity of the unwanted enantiomer in solution. In this process the theoretical yield of the desired enantiomer is 100%, whereas conventional fractional crystallization can only yield a maximum of 50% of the desired enantiomer. Thus, according to a further aspect of the present invention, there is provided a process for the production of (S)-(+)-3-{1-(1,3-benzodioxol-5-yl)-2-[(2-methoxy-4-methylphenyl)sulfonylamino]-2-oxoethyl}-1-methyl-1H-indole-6-carboxylic acid as defined above, or a pharmaceutically acceptable derivative thereof, which comprises selective precipitation from a solution of 3-{1-(1,3-benzodioxol-5-yl)-2-[(2-methoxy-4-methylphenyl)sulfonylamino]-2-oxoethyl}-1-methyl-1H-indole-6-carboxylic acid of a diastereomeric salt formed between (S)-(+)-3-{1-(1,3-benzodioxol-5-yl)-2-[(2-methoxy-4-methylphenyl)sulfonylamino]-2-oxoethyl}-1-methyl-1H-indole-6-carboxylic acid and a chiral base.
Preferably, the chiral base is (S)-(−)-&agr;-methylbenzylamine.
Preferably, the solvent is a mixture of tetrahydrofuran and 1,2-dimethoxyethane, for example an approximately 1:1 mixture by volume, such as 9:11.
Preferably, the diastereomeric salt is formed by mixing the acid with the base in a molar ratio in the range 1:1.5 to 1:2.5.
Preferably, the temperature is initially in the range 55-60° C., and then reduced to 45° C. Preferably, the temperature reaches 45° C. 3 days after beginning the process.
Preferably, 10 ml of solvent is used for every gram of acid present.
Preferably, the reaction mixture is seeded with the desired diastereomeric salt, preferably at the beginning of the process. This can be obtained from a different synthetic route initially, but can be obtained from a previous batch of product when the process is run repeatedly.
The dynamic resolution described above can produce compound of sufficiently high enantiopurity for use in the clinic. However, the enantiopurity can be increased still further by preparing the disodium salt, crystallizing it, and converting it back to the free acid.
Alternatively, (S)-(+)-3-{1-(1,3-benzodioxol-5-yl)-2-[(2-methoxy-4-methylphenyl)-sulfonylamino]-2-oxoethyl}-1-methyl-1H-indole-6-carboxylic acid may be prepared according to Scheme 1 (described more fully in Example 1 below):
In International Patent Application WO 97/43260, Example 17 is prepared according to Scheme 2 below:
An acetic acid derivative is coupled with the appropriate sulphonamide, by means of a coupling agent (forming an activated ester) and a hindered base. The methyl ester in the resulting sulphonyl amide is then converted to the corresponding acid by basic hydrolysis. As mentioned above, it has been found that the proton attached to the chiral carbon atom in the intermediate activated ester is sufficiently acidic to exchange in the presence of base. This is a problem when chiral products are desired, because a chiral acetic acid derivative starting material would produce racemic coupled products.
The route in Scheme 1 has the advantage that the activated ester is not exposed to a base which allows racemization to take place, but only to ammonia, which is a good nucleophile. The proton attached to the chiral carbon atom in the resulting acetamide is not sufficiently acidic to exchange in the presence of base, and so reaction with the appropriate sulphonyl chloride in the presence of a hindered base leads to chiral products. The benzyl protecting group is then removed by catalytic hydrogenation
Challenger Stephen
Dack Kevin Neil
Derrick Andrew Michael
Dickinson Roger Peter
Ellis David
Benson Gregg C.
Goddard Carl J.
Pfizer Inc.
Powers Fiona T.
Richardson Peter C.
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