WO2004055034A1

WO2004055034A1 - Polymorph

Info

Publication number: WO2004055034A1
Application number: PCT/EP2003/014489
Authority: WO
Inventors: Richard Freer; Paula Saklatvala; Mark Ralph Shipton
Original assignee: Glaxo Group Limited
Priority date: 2002-12-18
Filing date: 2003-12-16
Publication date: 2004-07-01
Also published as: AU2003292255A1

Abstract

(2S,3S,4R,5R)-2-(5-tert-butyl-[1,3,4]-oxadiazol-2-yl)-5-[6-(4-chloro-2-fluorophenylamino)-purin-9-yl]-tetrahydrofuran-3,4-diol in polymorphic form III.

Description

POLYMORPH

The present invention relates to heterocyclyl substituted adenosine derivatives. More particularly the invention is concerned with particular physical forms of (2S,3S,4R,5R)-2-(5- tert-butyl-[1 ,3,4]-oxadiazol-2-yl)-5-[6-(4-chloro-2-fluorophenylamino)-purin-9-yl]- tetrahydrofuran-3,4-diol, pharmaceutical formulations thereof and their use in therapy.

(2S,3S,4R,5R)-2-(5-tert-butyl-[1,3,4]-oxadiazol-2-yl)-5-[6-(4-chloro-2-fluorophenylamino)- purin-9-yl]-tetrahydrofuran-3,4-diol has activity at the adenosine A1 receptor.

WO99/67262 (Glaxo Group Limited) discloses certain heterocyclyl adenosine derivatives including (2S,3S,4R,5R)-2-(5-tert-butyl-[1,3,4]-oxadiazol-2-yl)-5-[6-(4-chloro-2- fluorophenylamino)-purin-9-yl]-tetrahydrofuran-3,4-diol, Example 14 of WO99/67262, the structure of which is indicated below as the compound of formula (A):

(A) The preparation of the compound of formula (A) is described in WO99/67262. The compound of formula (A) may be prepared by the reaction of 4-chloro-2-fluoroaniline with an appropriate purinyl derivative having a suitable leaving group in the 6-position of the purine ring, optionally in the presence of a solvent at elevated temperatures. Alternatively the compound of formula (A) may be prepared by treating 9-{(3aR,4R,6S,6aR)-6-[5-tert- butyl-1 ,3,4-oxadiazol-2-yl]-2,2-dimethyltetrahydrofuro[3,4-d][1 ,3]dioxol-4-yl}-N-(4-chloro-2- fluorophenyl)-9H-purin-6-amine with trifluoroacetic acid followed by treatment with sodium bicarbonate. Extraction of the product into ethyl acetate followed by evaporation in vacuo provides the compound of formula (A) as a buff solid.

We have now surprisingly found that the compound of formula (A) can be obtained in polymorphic forms.

We have further found that the compound of formula (A) may be obtained by crystallisation under certain conditions in the form of polymorphic form III (hereinafter Polymorph III). There is thus provided as a first aspect of the invention (2S,3S,4R,5R)-2-(5-tert-butyl- [1 ,3,4]-oxadiazol-2-yl)-5-[6-(4-chloro-2-fluorophenylamino)-purin-9-yl]-tetrahydrofuran-3,4- diol in polymorphic form III.

Polymorph III is obtained in an easily handleable crystal habit and is particularly suitable for bulk preparation and handling and thus may be useful in the preparation of pharmaceutical formulations.

In a preferred aspect the invention provides (2S,3S,4R,5R)-2-(5-tert-butyl-[1,3,4]- oxadiazol-2-yl)-5-[6-(4-chloro-2-fluorophenylamino)-purin-9-yl]-tetrahydrofuran-3,4-diol in the form of Polymorph III as herein defined substantially free of any other polymorph.

In a further aspect the invention provides (2S,3S,4R,5R)-2-(5-tert-butyl-[1 ,3,4]-oxadiazoI-2- yl)-5-[6-(4-chloro-2-fluorophenylamino)-purin-9-yl]-tetrahydrofuran-3,4-diol in the form of Polymorph III as herein defined substantially free of impurities.

(2S,3S,4R,5R)-2-(5-tert-Butyl-[1,3,4]-oxadiazoI-2-yl)-5-[6-(4-chloro-2-fluorophenylamino)- purin-9-yl]-tetrahydrofuran-3,4-diol may be prepared in polymorphic form III by crystallisation of the compound under suitable conditions.

By "substantially free" is meant containing less than 10%, preferably less than 5%, more preferably less than 2%, of alternative polymorph or impurity.

Polymorph III may be prepared substantially free from alternative polymorphs by controlling crystallisation conditions.

In general, (2S,3S,4R,5R)-2-(5-tert-butyl-[1 ,3,4]-oxadiazol-2-yl)-5-[6-(4-chloro-2- fluorophenylamino)-purin-9-yl]-tetrahydrofuran-3,4-diol in the form of Polymorph III may be obtained by treatment of 9-{(3aR,4R,6S,6aR)-6-[5-tert-butyl-1 ,3,4-oxadiazoI-2-yl]-2,2- dimethyltetrahydrofuro[3,4-d][1 ,3]dioxol-4-yl}-N-(4-chloro-2-fluorophenyl)-9H-purin-6-amine (less than 98% pure, preferably 96-98% pure) with trifluoroacetic acid followed by treatment with aqueous ammonia/methanol allowing the mixture to reach a temperature greater than 30°C, preferably 35-60°C, more preferably 42-52°C.

The conversion of Polymorph III to other polymorph or polymorphs can occur under certain circumstances.

The methods for the preparation of Polymorph 111, described herein, constitute further aspects of the present invention.

Description of Figures:

Figure 1 shows X-Ray diffraction data obtained for Polymorph Figure 2 shows a Raman spectrum of Polymorph 111. Figure 3 shows an infrared spectrum of Polymorph III. Figure 4 shows a photographic image of Polymorph III.

Polymorph III has been characterised by X-ray powder diffraction (XRPD) studies, Raman spectroscopy and infrared spectroscopy.

Polymorph III is characterised by having signals in its Infrared spectra substantially at 3434, 3414, 858 and 852 cm-1.

Infrared peaks are quoted to the nearest cm-1.

Polymorph 111 is characterised by having peaks in its Raman spectra substantially at 3434, 3414, 1618, 1585 and 1298 cm-1.

Raman peaks are quoted to the nearest cm-1.

Polymorph III is characterised by having an XRPD pattern with signals substantially at 4.28, 5.43, 8.16, 8.59, 9.97, 10.22, 11.90, and 13.86 (degrees 2-theta).

The skilled person will recognise that XRPD peak positions are affected by differences in sample height. The peak positions quoted herein are thus subject to a variation of +/- 0.15 degrees 2-theta.

It will be recognised that spectra and diffraction data will vary slightly according to various factors such as the temperature, concentration and instrumentation used. In order to account for this variability, signals and peak positions are quoted herein as being "substantially" at specific values.

The present invention also provides (2S,3S,4R,5R)-2-(5-tert-butyl-[1 ,3,4]oxadiazol-2-yl)-5- [6-(4-chloro-2-fluorophenylamino)-purin-9-yl]-tetrahydrofuran-3,4-diol characterised in that it: i) provides an XRPD spectrum substantially as illustrated in Figure 1 :and/or ii) provides a Raman spectrum substantially as illustrated in Figure 2; and/or iii) provides an infrared spectrum substantially as illustrated in Figure 3.

The present invention further provides (2S,3S,4R,5R)-2-(5-tert-butyl-[1 ,3,4]oxadiazol-2-yl)- 5-[6-(4-chloro-2-fluorophenylamino)-purin-9-yl]-tetrahydrofuran-3,4-diol characterised in that it: i) provides an XRPD spectrum with signals substantially at 4.28, 5.43, 8.16, 8.59,

9.97, 10.22, 11.90, and 13.86 (degrees 2-theta); and/or ii) provides a Raman spectrum with signals substantially at 3434, 3414, 1618, 1585 and 1298 cm-1; and/or iii) provides an infrared spectrum with signals substantially at 3434, 3414, 858 and 852 cm-1.

This invention further provides for a pharmaceutical composition comprising (2S,3S,4R,5R)-2-(5-tert-butyl-[1,3,4]oxadiazol-2-yl)-5-[6-(4-chloro-2-fluorophenylamino)- purin-9-yl]-tetrahydrofuran-3,4-diol in polymorphic form 111, and a pharmaceutically acceptable carrier and/or excipient.

Suitable pharmaceutically acceptable carriers and excipients are described in WO 99/67262.

(2S,3S,4R,5R)-2-(5-tert-Butyl-[1,3,4]-oxadiazol-2-yl)-5-[6-(4-chloro-2-fluorophenylamino)- purin-9-yl]-tetrahydrofuran-3,4-diol in polymorphic form III may be used for decreasing plasma free fatty acid concentration; reducing heart rate; or treating ischemic heart disease, peripheral vascular disease, stroke, pain (for example inflammatory pain and neuropathic pain), migraine, CNS disorder, or sleep apnoea, as described in WO 99/67262.

In a further aspect the present invention therefore provides (2S,3S,4R,5R)-2-(5-tert-butyl- [1 ,3,4]-oxadiazol-2-yl)-5-[6-(4-chloro-2-fluorophenylamino)-purin-9-yl]-tetrahydrofuran-3,4- diol in polymorphic form III for use in decreasing plasma free fatty acid concentration; reducing heart rate; or treating ischemic heart disease, peripheral vascular disease, stroke, pain, migraine, CNS disorder, or sleep apnoea.

(2S,3S,4R,5R)-2-(5-tert-butyl-[1 ,3,4]-oxadiazol-2-yl)-5-[6-(4-chloro-2-fluorophenylamino)- purin-9-yl]-tetrahydrofuran-3,4-diol in polymorphic form III may be used in the manufacture of a medicament for use in decreasing plasma free fatty acid concentration; reducing heart rate; or treating ischemic heart disease, peripheral vascular disease, stroke, pain (for example inflammatory pain and neuropathic pain), migraine, CNS disorder, or sleep apnoea, as described in WO 99/67262.

In a yet further aspect the present invention provides the use of (2S,3S,4R,5R)-2-(5-tert- butyl-[1 ,3,4]-oxadiazol-2-yl)-5-[6-(4-chloro-2-fluorophenylamino)-purin-9-yl]- tetrahydrofuran-3,4-diol in polymorphic form III in the manufacture of a medicament for use in decreasing plasma free fatty acid concentration; reducing heart rate; or treating ischemic heart disease, peripheral vascular disease, stroke, pain (for example inflammatory pain and neuropathic pain), migraine, CNS disorder, or sleep apnoea.

In another aspect the present invention also provides a method of treating a patient suffering from a condition where there is an advantage in decreasing plasma free fatty acid concentration; or reducing heart rate; or treating a patient suffering from ischemic heart disease, peripheral vascular disease, stroke, pain (for example inflammatory pain and neuropathic pain), migraine, CNS disorder, or sleep apnoea comprising administering a therapeutically effective amount of of (2S,3S,4R,5R)-2-(5-tert-butyl-[1 ,3,4]-oxadiazol-2- yl)-5-[6-(4-chloro-2-fluorophenylamino)-purin-9-yl]-tetrahydrofuran-3,4-dioI in polymorphic form III.

WO 99/67262 (Glaxo Group Limited) is incorporated by reference herein as though fully set forth.

The following examples illustrate the invention but are not intended as a limitation thereof.

EXAMPLES

9-{(3aR,4R,6S,6aR)-6-[5-(tert-butyl)-1 ,3,4-oxadiazol-2-yl]-2,2-dimethyltetrahydrofuro[3,4- d][1 ,3]dioxol-4-yl)-N-(4-chloro-2-fluorophenyl)-9H-purin-6-amine was prepared according to the methods described in WO99/67262, in particular intermediate 63.

Example 1 - Preparation of Polymorph III

A 3L conical flask fitted with stirrer bar was charged with trifluoroacetic acid (1.45L, 18.86mol) and water (0.161L, 8.94mol) and the mixture stirred, resulting in a rise in temperature to 30°C. Solid 9-{(3aR,4R,6S,6aR)-6-[5-(tert-butyl)-1 ,3,4-oxadiazol-2-yl]-2,2- dimethyltetrahydrofuro[3,4-d][1 ,3]dioxol-4-yl}-N-(4-chloro-2-fluorophenyl)-9H-purin-6-amine (96.6% pure, 421 g, 0.795mol) was added as a single portion with stirring and the mixture stirred at ambient temperature for VΛ hours when the reaction was adjudged complete by HPLC. The mixture was filtered via filter paper under vacuum to remove particulate matter. The resulting filtrate was added to a stirred mixture of 880 ammonia (1.18L, 23.64mol), methanol (5.30L) and water (3.54L) in a steady stream such that the temperature at the end of the addition was 51 °C. The pH at the end of the addition was 8. The mixture was then stirred and cooled to 5°C over a period of 214 hours and a further V hour at this temperature to complete the crystallisation of the product. The product was then filtered via a Buchner funnel and sucked dry before being washed with water (2 x 0.74L), sucked dry as possible and then dried in vacuo at 55°C for 20 hours to give crude (2S,3S,4R,5R)-2-(5-t-butyl-1 ,3,4-oxadiazol-2-yl)-5-{6-[(4-chloro-2-fluorophenyl)amino]9H- purin-9-yl}tetrahydrofuran-3,4-diol (285g, 87%) [Relative assay: 98.17%, Polymorph III].

X-Ray Powder Diffraction

The sample preparation and acquisition conditions were as follows:

Samples were lightly ground and packed (top-filling) into sample cups. Instrumentation consisted of a Bruker D8 Advance X-Ray powder diffractometer configured with a Cu anode (40 kV 40 mA), variable divergence slit, primary and secondary Soller slits, and a position sensitive detector. Data were acquired over the range 2 - 35 degrees 2-theta using a step size of 0.0145 degrees 2-theta (time per step: 1 s). Samples were rotated.

Data obtained for Polymorph III are shown in Figure I.

Raman Spectroscopy

Raman spectra were acquired using a Nicolet 960 ESP FT-Raman spectrometer. Samples were held in glass vials; spectra of 5 different points on a sample were averaged. Data collection parameters include: Laser power: 400 mW, Resolution: 4 cm-^'', Sample gain: 1.0, Detector: InGaAs, Beamsplitter: CaF2, Correction: none, Zero filling: none, Apodization: Happ-Genzel, Phase correction: Power spectrum.

A Raman spectrum of Polymorph III is shown in Figure 2.

Infrared Spectroscopy

Infrared spectra of the samples were obtained as Nujol mulls using a Perkin-Elmer 2000 FT-IR spectrometer. Spectra were recorded by averaging 2 scans and using a resolution of 2cm-1 , scan interval of 0.5cm-1 and a spectral range of 4000-450cm-1.

An infrared spectrum of Polymorph III is shown in Figure 3.

Photographic Image

Photographic images of the solid were acquired by suspending approx. 1 mg of the crystalline solid in a single drop of Zeiss 518N immersion oil on a microscope slide. The solid was gently dispersed and the suspension covered with a cover slip and compressed to produce a thin film.

The crystal habit was examined using an Olympus BX51 optical microscope using reflected light. Image capture was achieved using a Media Cybernetics Cool-snap pro digital camera.

A photographic image of Polymorph III is shown in Figure 4.

Claims

1. (2S,3S,4R,5R)-2-(5-tert-Butyl-[1 ,3,4]-oxadiazol-2-yl)-5-[6-(4-chloro-2- fluorophenylamino)-purin-9-yl]-tetrahydrofuran-3,4-diol in polymorphic form III.

2. A pharmaceutical formulation comprising a polymorphic form according to claim 1 , and a pharmaceutically acceptable carrier and/or excipient.

3. A polymorphic form according to claim 1 for use in decreasing plasma free fatty acid concentration; reducing heart rate; or treating ischemic heart disease, peripheral vascular disease, stroke, pain, migraine, CNS disorder, or sleep apnoea.

4. Use of a polymorphic form according to claim 1 in the manufacture of a medicament for use in decreasing plasma free fatty acid concentration; reducing heart rate; or treating ischemic heart disease, peripheral vascular disease, stroke, pain, migraine, CNS disorder, or sleep apnoea.

5. A method of treating a patient suffering from a condition where there is an advantage in decreasing plasma free fatty acid concentration; or reducing heart rate; or treating a patient suffering from ischemic heart disease, peripheral vascular disease, stroke, pain, migraine, CNS disorder, or sleep apnoea comprising administering a therapeutically effective amount of a polymorphic form according to claim 1.

6. (2S,3S,4R,5R)-2-(5-tert-butyl-[1 ,3,4]-oxadiazol-2-yl)-5-[6-(4-chloro-2- fluorophenylamino)-purin-9-yl]-tetrahydrofuran-3,4-diol in polymorphic form III substantially as described herein in the specification and/or examples.