US20020173530A1 - Single morphic forms of metalloproteinase inhibitors - Google Patents
Single morphic forms of metalloproteinase inhibitors Download PDFInfo
- Publication number
- US20020173530A1 US20020173530A1 US10/105,956 US10595602A US2002173530A1 US 20020173530 A1 US20020173530 A1 US 20020173530A1 US 10595602 A US10595602 A US 10595602A US 2002173530 A1 US2002173530 A1 US 2002173530A1
- Authority
- US
- United States
- Prior art keywords
- dosage form
- form according
- morphic
- morphic form
- single morphic
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 239000003475 metalloproteinase inhibitor Substances 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 17
- 150000001408 amides Chemical class 0.000 claims abstract description 6
- 239000002552 dosage form Substances 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 7
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 7
- 239000000203 mixture Substances 0.000 claims description 5
- 238000003801 milling Methods 0.000 claims description 4
- 239000002775 capsule Substances 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 3
- 239000007891 compressed tablet Substances 0.000 claims 2
- FGKJLKRYENPLQH-UHFFFAOYSA-N isocaproic acid Chemical compound CC(C)CCC(O)=O FGKJLKRYENPLQH-UHFFFAOYSA-N 0.000 abstract description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- 229940126062 Compound A Drugs 0.000 description 3
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 3
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 3
- 229940011051 isopropyl acetate Drugs 0.000 description 3
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000012298 atmosphere Substances 0.000 description 2
- 238000007906 compression Methods 0.000 description 2
- 230000006835 compression Effects 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 238000001938 differential scanning calorimetry curve Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 238000003109 Karl Fischer titration Methods 0.000 description 1
- 102000002274 Matrix Metalloproteinases Human genes 0.000 description 1
- 108010000684 Matrix Metalloproteinases Proteins 0.000 description 1
- 102000018594 Tumour necrosis factor Human genes 0.000 description 1
- 108050007852 Tumour necrosis factor Proteins 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 229940124606 potential therapeutic agent Drugs 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
- C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
- C07K5/06052—Val-amino acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- This invention relates to new crystalline forms of known compounds, having therapeutic utility, that are metalloproteinase inhibitors.
- This invention is based on the surprising discovery that Compounds A and B exists in more than one morphic form. Further, it has been found that, by comparison with the produces 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.
- XRPD X-ray powder diffraction
- 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.
- 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.
- a compound of the invention is mixed with a pharmaceutically acceptable carrier.
- 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.
- 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 acetateheptane, 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.
- 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.
Abstract
The present invention pertains to single morphic forms 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-[2S-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
- This invention relates to new crystalline forms of known compounds, having therapeutic utility, that are metalloproteinase inhibitors.
- 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-mercaptobutyrylamino]4-methylpentanoic acid (2,2-dimethyl-1S-methylcarbamoylpropyl)amide (herein Compound A) and 2S-[2S-mercapto-4-(3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl)butyrylamino]-4methylpentanoic acid (2,2-dimethyl-1S-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).
- This invention is based on the surprising discovery that Compounds A and B exists in more than one morphic form. Further, it has been found that, by comparison with the produces 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.
- The accompanying drawings are XRPD traces obtained for Compounds A and B, respectively.
- 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.
- 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 acetateheptane, 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.
- 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 (12)
1. A single morphic form of a compound selected from the group consisting of 2S-[4-(2,5-dioxopyrrolidin-1-yl)-2S-mercaptobutyrylamino]-4-methylpentanoic acid (2,2-dimethyl-1S-methylcarbamoylpropyl)amide and 2S-[2S-mercapto-4-(3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl)butyrylamino]-4-methylpentanoic acid (2,2-dimethyl-1S-methylcarbamoylpropyl)amide, isolable as such.
2. The single morphic form according to claim 1 , which is non-hygroscopic.
3. The single morphic form according to claim 1 , which is solvent-free.
4. The 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. The 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 claim 1 , obtainable by milling, and a pharmaceutically-acceptable carrier.
7. The dosage form according to claim 6 , which is a filled capsule.
8. The dosage form according to claim 6 , which is a compressed tablet.
9. A method for the manufacture of a dosage form according to claim 6 , 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.
10. The method for the manufacture of a dosage form according to claim 9 , wherein the dosage form is a filled capsule.
11. The method for the manufacture of a dosage form according to claim 9 , wherein the dosage form is a compressed tablet.
12. The single morphic form according to claim 2 , which is solvent free.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US10/105,956 US20020173530A1 (en) | 1998-10-23 | 2002-03-21 | Single morphic forms of metalloproteinase inhibitors |
Applications Claiming Priority (7)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB9823335.6A GB9823335D0 (en) | 1998-10-23 | 1998-10-23 | Compounds |
| GB9823335.6 | 1998-10-23 | ||
| GB9823336.4 | 1998-10-23 | ||
| GBGB9823336.4A GB9823336D0 (en) | 1998-10-23 | 1998-10-23 | Compounds |
| US09/425,572 US6277827B1 (en) | 1998-10-23 | 1999-10-22 | Single morphic forms of metalloproteinase inhibitors |
| US09/924,839 US20020025980A1 (en) | 1998-10-23 | 2001-08-08 | Single morphic forms of metalloproteinase inhibitors |
| US10/105,956 US20020173530A1 (en) | 1998-10-23 | 2002-03-21 | Single morphic forms of metalloproteinase inhibitors |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US09/924,839 Continuation US20020025980A1 (en) | 1998-10-23 | 2001-08-08 | Single morphic forms of metalloproteinase inhibitors |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| US20020173530A1 true US20020173530A1 (en) | 2002-11-21 |
Family
ID=26314567
Family Applications (3)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US09/425,572 Expired - Fee Related US6277827B1 (en) | 1998-10-23 | 1999-10-22 | Single morphic forms of metalloproteinase inhibitors |
| US09/924,839 Abandoned US20020025980A1 (en) | 1998-10-23 | 2001-08-08 | Single morphic forms of metalloproteinase inhibitors |
| US10/105,956 Abandoned US20020173530A1 (en) | 1998-10-23 | 2002-03-21 | Single morphic forms of metalloproteinase inhibitors |
Family Applications Before (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US09/425,572 Expired - Fee Related US6277827B1 (en) | 1998-10-23 | 1999-10-22 | Single morphic forms of metalloproteinase inhibitors |
| US09/924,839 Abandoned US20020025980A1 (en) | 1998-10-23 | 2001-08-08 | Single morphic forms of metalloproteinase inhibitors |
Country Status (6)
| Country | Link |
|---|---|
| US (3) | US6277827B1 (en) |
| EP (1) | EP1123308A1 (en) |
| JP (1) | JP2002528461A (en) |
| AU (1) | AU6352199A (en) |
| CA (1) | CA2347911A1 (en) |
| WO (1) | WO2000024763A1 (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2001860A2 (en) * | 2006-04-06 | 2008-12-17 | Wisconsin Alumni Research Foundation | 19-nor-vitamin d analogs with 1,2,or 3,2 heterocyclic ring |
| ES2700117T3 (en) * | 2010-08-31 | 2019-02-14 | Chimerix Inc | Derivatives of phosphonate ester and methods of synthesis thereof |
| ES2685819T3 (en) | 2013-11-15 | 2018-10-11 | Chimerix, Inc. | Morphic forms of hexadecyloxypropyl phosphonate esters |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CZ288436B6 (en) * | 1994-10-05 | 2001-06-13 | Darwin Discovery Ltd | Peptidyl derivatives, their therapeutic use as inhibitors of metalloproteinases and pharmaceutical preparation in which they are comprised |
| CN1145637C (en) * | 1995-10-05 | 2004-04-14 | 达尔文发现有限公司 | Thio-substituted peptides as inhibitors for metalloproteinases and tnfliberation |
| AU741903C (en) * | 1997-03-03 | 2002-09-05 | Darwin Discovery Limited | Selective MMP inhibitors having reduced side-effects |
-
1999
- 1999-10-20 EP EP99950931A patent/EP1123308A1/en not_active Withdrawn
- 1999-10-20 AU AU63521/99A patent/AU6352199A/en not_active Abandoned
- 1999-10-20 JP JP2000578333A patent/JP2002528461A/en active Pending
- 1999-10-20 WO PCT/GB1999/003464 patent/WO2000024763A1/en not_active Application Discontinuation
- 1999-10-20 CA CA002347911A patent/CA2347911A1/en not_active Abandoned
- 1999-10-22 US US09/425,572 patent/US6277827B1/en not_active Expired - Fee Related
-
2001
- 2001-08-08 US US09/924,839 patent/US20020025980A1/en not_active Abandoned
-
2002
- 2002-03-21 US US10/105,956 patent/US20020173530A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| JP2002528461A (en) | 2002-09-03 |
| US6277827B1 (en) | 2001-08-21 |
| AU6352199A (en) | 2000-05-15 |
| EP1123308A1 (en) | 2001-08-16 |
| WO2000024763A1 (en) | 2000-05-04 |
| US20020025980A1 (en) | 2002-02-28 |
| CA2347911A1 (en) | 2000-05-04 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA2350956C (en) | New crystals of celecoxib | |
| EP2540704B1 (en) | Benethamine salt forms of atorvastatin | |
| EP0579681B1 (en) | Crystalline tiagabine hydrochloride monohydrate, its preparation and use | |
| SK95699A3 (en) | Novel modifications to 2-amino-4-(4-fluorobenzylamino)-1- -ethoxycarbonyl-aminobenzene and processes for preparing said compound | |
| NO320047B1 (en) | Composition for oral administration | |
| JPH0655739B2 (en) | Novel 8α-acylaminoergolines | |
| US6277827B1 (en) | Single morphic forms of metalloproteinase inhibitors | |
| US20040063782A1 (en) | Bicalutamide forms | |
| EP4303212A1 (en) | Hydroxytyrosol nicotinamide eutectic crystal, and preparation method therefor and composition thereof | |
| CA2164296C (en) | Heterocyclic chemistry | |
| AU679094B2 (en) | Crystals of antimicrobial compound | |
| KR100476606B1 (en) | Polymorphs of a Crystalline Azabicyclo(2,2,2)Octan-3-Amine Citrate and Their Pharmaceutical Compositions | |
| EP1051398B1 (en) | Thermodynamically stable form of (r)-3- (4-fluorophenyl) sulphonyl]amino] -1,2,3,4- tetrahydro -9h-carbazole -9-propanoic acid (ramatroban) | |
| CA2372236A1 (en) | Polymorphs of crystalline (2-benzhydryl-1-azabicyclo¬2,2,2|oct-3-yl)-(5-isopropyl-2-methoxybenzyl)-amine citrate as nk-1 receptor antagonists | |
| JP2707012B2 (en) | Crystal polymorph of N-tert-butyl-1-methyl-3,3-diphenylpropylamine hydrochloride and method for producing the same | |
| EA006245B1 (en) | 4-[4-(2-pyrrolylcarbonyl)-1-piperazinyl]-3-trifluoromethyl-benzoylguanidine hydrochloride | |
| WO2006051340A1 (en) | Novel form of celecoxib | |
| EP1713769B1 (en) | Amorphous tamsulosin hydrochloride | |
| AU2001100436A4 (en) | Amlodipine hemimaleate | |
| CN116462610A (en) | Crystal form of optically active diamine derivative salt and preparation method thereof | |
| AU720753B2 (en) | New polymorphic form of doxazosin mesylate (Form I) | |
| WO2013054146A1 (en) | New co crystals useful in the preparation of pharmaceutical compositions |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| STCB | Information on status: application discontinuation |
Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION |