Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1997-12-16
2000-07-25
Moezie, Minna
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
514347, C07D21172, C07D21184, C07D21362, A61K 3144
Patent
active
060938285
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to a novel physical form of the (E)-3-[6-[[(2,6-dichlorophenyl)-thio]methyl]-3-(2-phenylethoxy)-2-pyridiny l]-2-propenoic acid, pharmaceutical compositions containing it and its use in therapy.
(E)-3-[6-[[(2,6-dichlorophenyl)-thio]methyl]-3-(2-phenylethoxy)-2-pyridinyl ]-2-propenoic acid, that is to say, the compound of the following structure: ##STR2## is known in the art as a compound which is useful as a leukotriene antagonist. In particular, the compound is disclosed in WO94/00437 as being useful for the treatment of psoriasis. Patients suffering from psoriasis are often exposed to sunlight as part of their therapy, and such exposure can potentially cause degradation of pharmaceutically active compounds. There is therefore a need for topical formulations containing this compound which are resistant to exposure to sunlight.
(E)-3-[6-[[(2,6-dichlorophenyl)-thio]methyl]-3-(2-phenylethoxy)-2-pyridinyl ]-2-propenoic acid can exist in a number of different physical forms (also known as polymorphs).
The present invention therefore provides, in a first aspect (E)-3-[6-[[(2,6-dichlorophenyl)-thio]methyl]-3-(2-phenylethoxy)-2-pyridiny l]-2-propenoic acid in the form identified by the following characteristics: 142.2.degree. C.) as identified by differential scanning calorimetry. degrees
Hereinafter the form having these characteristics will be referred to as (E)-3-[6-[[(2,6-dichlorophenyl)-thio]methyl]-3-(2-phenylethoxy)-2-pyridiny l]-2-propenoic acid Form II.
For the avoidance of doubt, the above infra-red absorption bands above are those obtained from a nujol mull.
(E)-3-[6-[[(2,6-dichlorophenyl)-thio]methyl]-3-(2-phenylethoxy)-2-pyridinyl ]-2-propenoic acid in the polymorphic form disclosed in WO 94/00437 has the following physical characteristics: 138.degree. C. and a melting endotherm with onset at about 140.degree. C. as identified by differential scanning calorimetry. degrees.
The polymorphic form having the above characteristics is designated as Form I.
(E)-3-[6-[[(2,6-dichlorophenyl)-thio]methyl]-3-(2-phenylethoxy)-2-pyridinyl ]-2-propenoic acid Form II has certain surprising advantages when compared with the previously identified physical forms. For example (E)-3-[6-[[(2,6-dichlorophenyl)-thio]methyl] -3-(2-phenylethoxy)-2-pyridinyl]-2-propenoic acid Form II exhibits much greater stability to light compared with the Form I polymorph.
The invention also provides in a further aspect (E)-3-[6-[[(2,6-dichlorophenyl)-thio]methyl]-3-(2-phenylethoxy)-2-pyridiny l]-2-propenoic acid Form II for use in therapy, in particular in the treatment of psoriasis. When used in therapy, (E)-3-[6-[[(2,6-dichlorophenyl)-thio]methyl]-3-(2-phenylethoxy)-2-pyridiny l]-2-propenoic acid Form II can be formulated in a standard pharmaceutical composition using techniques well known in the art of pharmacy.
In further aspect, the present invention provides a pharmaceutical composition comprising (E)-3-[6-[[(2,6-dichlorophenyl)-thio]methyl]-3-(2-phenylethoxy)-2-pyridiny l]-2-propenoic acid Form II in association with a pharmaceutical carrier.
It will be apparent to those skilled in the art that a pharmaceutical composition comprising (E)-3-[6-[[(2,6-dichlorophenyl)-thio]methyl]-3-(2-phenylethoxy)-2-pyridiny l]-2-propenoic acid Form II in substantially pure form will exhibit the above advantages. By `substantially pure form` is meant at least 50% pure, preferably 80-90% pure, and most preferably greater than 95% pure.
Compositions comprising mixtures of Form I and Form II polymorphs form a further aspect of the invention.
In a further aspect, the present invention provides the use of (E)-3-[6-[[(2,6-dichlorophenyl)-thio]methyl]-3-(2-phenylethoxy)-2-pyridiny l]-2-propenoic acid Form II in the manufacture of a medicament for the treatment of psoriasis. The invention also provides a method of treatment of psoriasis which comprises administration to a host in need thereof an effective amount of (E)-3-[6-[[(2,6-dichlorophenyl)-thio]methyl]-3-(2-phenylethoxy)-2-pyridiny l]-2-propenoic acid Form II.
The dosage r
Anderson Richard Keith
Harris Michael Anthony
Jacewicz Victor Witold
Kanagy James M.
Kinzig Charles M.
Moezie Minna
SmithKline Beecham p.l.c.
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