SINGLE MORPHIC FORMS OF KNOWN PEPTIDE METALLOPROTEINASE INHIBITORS

Abstract: A single morphic form of a compound selected from 2S- [4- (2, 5 -dioxopyrrolidin- 1-yl)- 2S- mercaptobutyrylamino] -4- methylpentanoic acid (2,2- dimethyl- 1S- methylcarbamoylpropyl) amide and 2S- [2 DOLLAR I(S)mercapto- 4-(3, 4, 4- trimethyl- 2, 5- dioxoimidazolidin- 1-yl) butyrylamino] -4- methylpentanoic acid (2, 2-dimethyl -1S- methylcarbamoylpropyl) amide, isolable as such.

Description: SINGLE MORPHIC FORMS OF KNOWN PEPTIDE METALLOPROTEINASE INHIBITORS Field of the Invention This invention relates to new crystalline forms of known compounds, having therapeutic utility, that are metalloproteinase inhibitors. Background of the Invention As potential therapeutic agents, in the treatment of inflammatory and other conditions, there is considerable interest in compounds that have the ability to inhibit matrix metalloproteinases and also the release of tumour necrosis factor. Two known compounds of this type are 2S'-[4-(2,5-dioxopyrrolidin- 1 -yl)-2S-mercaptobutyrylarnino]-4- methylpentanoic acid (2,2-dimethyl-15'-methylcarbamoylpropyl)amide (herein Compound A)and25-[2S-mercapto-4-(3,4,4-trimethyl-2,5-dioxoinridazoUdin-l-yl)butyrylamino]-4- methylpentanoic acid (2,2-dimethyl- 15-methylcarbamoylpropyl)amide (herein Compound B). Compound A is disclosed in WO-A-96/11209 and WO-A-98/39024. Compound B is disclosed in WO-A-97/12902 (generically) and WO-A-98/39024 (specifically). Summary of the Invention This invention is based on the discovery that Compounds A and B exists in more than one morphic form. Further, it has been found that, by comparison with the products whose preparation has previously been reported, novel compounds can be isolated as a single morphic form (this term is used herein to describe a crystalline form having a single morphology). A novel morphic form according to the present invention is reproducibly isolable as a single crystalline species. It may be characterised by its crystalline structure, its X-ray powder diffraction (XRPD) pattern, its DSC thermogram, and/or by a different melting point from that previously reported. It may be essentially free of bound solvent, non- hygroscopic, and more thermodynamically stable, i.e. both more chemically and physically stable than the compound as previously reported. This stability makes the novel species particularly suitable for formulation into pharmaceutical formulations, following milling and, if appropriate, compression. It may also provide improved bioavailability. Description of the Drawings The accompanying drawings are XRPD traces obtained for Compounds A and B, respectively. Description of the Invention The present invention depends in part on the solvent chosen for the crystallisation. Suitable procedures are shown in the Examples, below. Other procedures have produced other morphic forms of the same compounds, but these generally have properties that are unsuitable for the purposes of the present invention, e.g. not being isolable as a single morphic form. One criterion for choosing the desired product is by observation of a single sharp peak in the DSC thermogram. Another may be a high melting point, depending on the desire for increased solubility or stability. As indicated above, compounds of the invention have a morphic or crystalline form that is unchanged on milling. They are therefore particularly suitable for use in solid, discrete pharmaceutical unit dosage forms such as filled capsules, etc. Further, they are unchanged under compression used in a tableting process. For the purposes of formulation, a compound of the invention is mixed with a pharmaceutically acceptable carrier. Examples of suitable carriers and also suitable doses can readily be determined by one skilled in the art or are known; see also the PCT publications identified above, the contents of which are incorporated herein by reference. The following Examples illustrate how single morphic forms according to the present invention may be prepared. Example 1 Compound A is dissolved with heating to 50° C in 1.5 volumes of isopropyl acetate under an atmosphere of nitrogen. To this solution is added 0.56 volumes of heptane, and the mixture is slowly cooled to 10°C. The solid is isolated by filtration, washed with 1:1 isopropyl acetate/heptane, and dried in vacuo at approximately 65 °C. The melting point of the product is 148°C. The XRPD trace is shown in Fig. 1. The major peaks are at 8.0, 9.1, 10.7, 12.4, 13.6 and 17.0. Example 2 Compound B is dissolved with heating in 3 volumes of isopropyl acetate under an atmosphere of nitrogen, and the water content assessed by Karl Fischer titration to be less than approximately 0.5%. The solution is heated to reflux with stirring and 2.5 volumes of heptane is added slowly. Crystallisation is initiated by the addition of seed crystals at 80-85 °C. The suspension is allowed to cool to ambient temperature and the solid isolated by filtration. The filter cake is washed with a mixture of isopropyl acetate (1.6 volumes) and heptane ( 1.25 volumes) and dried in vacuo at approximately 50°C. The melting point of the product is 164°C. The XRPD trace is shown in Fig. 2. The major peaks are at 7.6, 8.0, 15.3, 16.1, 16.5 and 17.8.

Claims: CLAIMS 1. A single morphic form of a compound selected from 2Λ'-[4-(2, 5-dioxopyrrolidin- 1 - yl)-2S-mercaptobutyrylamino]-4-methylpentanoic acid (2, 2-dimethyl- 1S- methylcarbamoylpropyl)amide and 2S-[2.S'-mercapto-4-(3,4,4-trimethyl-2,5- dioxoimidazolidin- l-yl)butyrylamino]-4-methylpentanoic acid (2,2-dimethyl-lS- methylcarbamoylpropyl)amide, isolable as such. 2. A single morphic form according to claim 1, which is non-hygroscopic. 3. A single morphic form according to either preceding claim, which is solvent-free. 4. A single morphic form of the first compound according to claim 1, having peaks at 8.0, 9.1, 10.7, 12.4, 13.6 and 17.0, by X-ray powder diffraction. 5. A single morphic form of the second compound according to claim 1 , having peaks at 7.6, 8.0, 15.3, 16.1, 16.5 and 17.8, by X-ray powder diffraction. 6. A pharmaceutical unit dosage form comprising a single morphic form according to any preceding claim, obtainable by milling, and a pharmaceutically-acceptable carrier. 7. A dosage form according to claim 6, which is a filled capsule. 8. A dosage form according to claim 6, which is a compressed tablet. 9. A method for the manufacture of a dosage form according to any of claims 6 to 8, which comprises milling the morphic form, mixing it with the carrier, and optionally also compressing the mixture, wherein the structure of the morphic form is unchanged by the method.

Inventors: EVANS GRAHAM ROBERT, KATZ RUTH BERNICE, EVANS, GRAHAM, ROBERT, KATZ, RUTH, BERNICE
Applicants: DARWIN DISCOVERY LTD, DARWIN DISCOVERY LIMITED
Application year: 1999
Main classification: C07K5
IPC codes: A61K9, A61K31, A61P31, A61P43, C07D207, C07D233, C07K5, C12N9