NEW FORM OF (E)-3-[6-[[(2,6-DICHLOROPHENYL)-THIO]METHYL]-3-(2-PHENYLETHOXY)-2-PYRIDINYL]-2-PROPENOIC ACID

Abstract: A novel physical form of (E)-3-[6-[[(2,6-dichlorophenyl)-thio]methyl]-3-(2-phenylethoxy)-2-pyri dinyl]-2-propenoic acid and its use in therapy is disclosed.

Description: NEW FORM OF (E)-3-[6-[[(2,6-DICHLOROPHE^^τX)-ππO]METHY 3 2■■PHE^rτXETHOXYV2- PYRIDINYL1-2-PROPENOIC ACID The present invention relates to a novel physical form of the (E)-3-[6-[[(2,6- dichlorophenyl)-thio]methyl]-3-(2-phenylethoxy)-2-pyridinyl]-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: 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-pyridinyl]-2-propenoic acid in the form identified by the following characteristics: • infra-red absorption bands at about 697, 743 and 884 cm . • a single melting endothenn with onset at about 140°C (minimum at 142.2°C) as identified by differential scanning calorimetry. • x-ray diffraction scattering (Cu source) at 9.2, 16.4, 23.3, 26.8 & 27.3 degrees Hereinafter the form having these characteristics will be referred to as (E)-3-[6- [[(2,6-dichlorophenyl)-thio]methyl]-3-(2-phenylethoxy)-2-pyridinyl]-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: • infra-red absorption bands at about 704, 758 and 896 cm . • a small endodierm followed by a small exotherm from 118°C to 138°C and a melting endotherm with onset at about 140°C as identified by differential scanning calorimetry. • x-ray diffraction scattering (Cu source) at 10.1, 20.0, 23.0, 24.0 and 25.4 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-pyridinyl]-2-propenoic acid Form LI 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-pyridinyl]-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- pyridinyl]-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- pyridinyl]-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-pyridinyl]-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-pyridinyl]-2-propenoic acid Form II. The dosage range for the compound of the present invention is expected to be in the range of from about 5 to about lOOOmg daily, preferably about 10 to about 200mg daily. For topical use for the treatment of psoriasis the dosage range will depend on the size of the affected area and the severity of the disease. When administered in accordance with the invention, no unacceptable toxicological effects are expected with the compounds of the invention. The following examples illustrate the invention. Example 1 A foil covered 50mL conical flask was charged with crude (E)-3-[6-[[(2,6- dichlorophenyl)-thio]methyl]-3-(2-phenylethoxy)-2-pyridinyl]-2-propenoic acid (prepared according to the method disclosed in WO/95/00487) (5.0g) and propan- 2-ol (25mL). The suspension was heated to reflux and the resultant solution filtered through paper under reduced pressure into a foil-covered vial containing a magnetic follower. The vial was sealed and the filtrate stirred for 3 hours allowing to cool to ambient temperature. The white solid was filtered, drained well, top washed with diethyl ether (3mL) (see note) and dried under vacuum to give (E)-3-[6-[[(2,6-dichlorophenyl)-thio]methyl]-3-(2-phenylethoxy)-2- pyridinyl]-2-propenoic acid as a snow-white solid (4.36g, 88% recovery). Note: Diethyl ether was used to aid the vacuum drying, it may be omitted or replaced by a wash with cold propan-2-ol without affecting the yield. The product had the following characteristics: • infra-red absorption bands at about 697, 743 and 884 cm . • a single melting endotherm with onset at about 140°C (minimum at 142.2°C) as identified by differential scanning calorimetry. • x-ray diffraction scattering (Cu source) at 9.2, 16.4,23.3, 26.8 and 27.3 degrees. Example 2 Comparison of light stability of crystalline forms. Samples of form I and form II were exposed to xenon light (85,0001ux) in a Heraeus Sun Test CPS light cabinet for 4 hours. The samples were analysed before .and after exposure to light by HPLC for relative response and impurity profile. Sa le Relative Area % of Area % of response to main peak Dimer unexposed Form I unexposed 100% 99.5% 0.1% Form I exposed 0.7% 1.1% 75.8% Form II unexposed 100% 97.7% nd Form II exposed 96.5% 98.1% <0.1% nd = not detected. The dimer refers to a cyclobutane dimer of (E)-3-[6-[[(2,6-dichlorophenyl)- thio]methyl]-3-(2-phenylethoxy)-2-pyridinyl]-2-propenoic acid, which is the principle degradation product of the form I compound. The results clearly show that the form II is considerably more stable than form I on exposure to xenon light. After 4 hours exposure form I degrades almost completely.

Claims: Claims 1. (E)-3-[6-[[(2,6-dichlorophenyl)-thio]methyl]-3-(2-phenylethoxy)-2- pyridinyl]-2-propenoic acid in the form identified by the following characteristics: • infra-red absorption bands at about 697, 743 and 884 cm . • a single melting endotherm with onset at about 140°C (minimum at 142.2°C) as identified by differential scanning calorimetry. • x-ray diffraction scattering (Cu source) at 9.2, 16.4,23.3, 26.8 and 27.3 degrees. 2. A pharmaceutical composition comprising the form of (E)-3-[6-[[(2,6- dichlorophenyl)-thio]methyl]-3-(2-phenylethoxy)-2-pyridinyl]-2-propenoic acid as described in claim 1 in association with a pharmaceutically acceptable carrier. 3. The form of (E)-3-[6-[[(2,6-dichlorophenyl)-thio]methyl]-3-(2- phenylethoxy)-2-pyridinyl]-2-propenoic acid as described in claim 1 for use in therapy. 4. The form of (E)-3-[6-[[(2,6-dichlorophenyl)-thio]methyl]-3-(2- phenylethoxy)-2-pyridinyl]-2-propenoic acid as described in claim 1 for use in the treatment or prophylaxis of psoriasis. 5. A pharmaceutical composition comprising (E)-3-[6-[[(2,6-dichloro- phenyl)-thio]methyl]-3-(2-phenylethoxy)-2-pyridinyl]-2-propenoic acid form I and (E)-3-[6-[[(2,6-dichloro-phenyl)-thio]methyl]-3-(2-phenylethoxy)-2- pyridinyl]-2-propenoic acid form II in association with a pharmaceutically acceptable carrier.

Inventors: ANDERSON RICHARD KEITH, HARRIS MICHAEL ANTHONY, JACEWICZ VICTOR WITOLD, ANDERSON, RICHARD, KEITH, HARRIS, MICHAEL, ANTHONY, JACEWICZ, VICTOR, WITOLD
Applicants: ANDERSON RICHARD K, HARRIS MICHAEL A, JACEWICZ VICTOR W, SMITHKLINE BEECHAM PLC, ANDERSON, RICHARD, KEITH, HARRIS, MICHAEL, ANTHONY, JACEWICZ, VICTOR, WITOLD
Application year: 1996
Main classification: C07D213
IPC codes: A61K31, A61P17, C07D213