NZ750772B2 - Crystalline forms - Google Patents
Crystalline forms Download PDFInfo
- Publication number
- NZ750772B2 NZ750772B2 NZ750772A NZ75077217A NZ750772B2 NZ 750772 B2 NZ750772 B2 NZ 750772B2 NZ 750772 A NZ750772 A NZ 750772A NZ 75077217 A NZ75077217 A NZ 75077217A NZ 750772 B2 NZ750772 B2 NZ 750772B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- crystalline form
- amino
- compound
- methoxy
- pyrrolidinyl
- Prior art date
Links
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- ATADHKWKHYVBTJ-UHFFFAOYSA-N hydron;4-[1-hydroxy-2-(methylamino)ethyl]benzene-1,2-diol;chloride Chemical compound Cl.CNCC(O)C1=CC=C(O)C(O)=C1 ATADHKWKHYVBTJ-UHFFFAOYSA-N 0.000 claims description 5
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- 231100000759 toxicological effect Toxicity 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
- C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
Abstract
The invention relates to crystalline forms of 4-((R)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylic acid butyl ester hydrochloride, processes for the preparation thereof, pharmaceutical compositions comprising said crystalline forms, pharmaceutical compositions prepared from such crystalline forms and their use as a medicament, especially as a P2Y12 receptor antagonist.
Description
Crystalline Forms The invention relates to novel crystalline forms of {[6-((S)methoxy-pyrrolidinyl)- yl-pyrimidinecarbonyl]-amino}phosphono-propionyl)-piperazinecarboxylic acid butyl ester hydrochloride (hereinafter also referred to as "COMPOUND·HCl"), processes for the preparation thereof, pharmaceutical compositions comprising said crystalline forms, pharmaceutical compositions sing 4-((R){[6-((S)methoxy-pyrrolidinyl) phenyl-pyrimidinecarbonyl]-amino}phosphono-propionyl)-piperazinecarboxylic acid butyl ester (hereinafter also referred to as "COMPOUND") wherein COMPOUND is obtained from said crystalline forms of ND·HCl, pharmaceutical compositions prepared from such lline forms of COMPOUND·HCl, use of the crystalline forms of COMPOUND·HCl as P2Y12 receptor antagonists in the treatment of s P2Y12 receptor-mediated diseases and disorders and use of COMPOUND as P2Y12 receptor antagonist in the treatment of various P2Y12 receptor-mediated diseases and disorders wherein COMPOUND is obtained from said lline forms of COMPOUND·HCl.
Background of the invention: The circulation of blood from and to organs guarantees the supply of oxygen, nutrients, as well as the disposal of catabolic products. Therefore, the integrity of blood vessels is essential at all times. When the vascular integrity is compromised, a highly efficient repair mechanism is activated at the site of injury resulting in the formation of a repair seal to prevent further blood loss. This fundamental biological process is defined as hemostasis.
Thrombosis is the result of a pathological deviation of one or several components involved in asis leading to uncontrolled platelet thrombus formation and vessel occlusion. ets have been described to contribute to hemostasis and thrombosis since their discovery (Coller BS, Historical perspective and future directions in platelet research. J Thromb Haemost. 2011;9 Suppl 1:374-395). More recently, atherosclerotic s in combination with occlusive platelet thrombi have been found in ts with ischemic cardiac death (Davies MJ et al., Intramyocardial platelet aggregation in ts with unstable angina suffering sudden ischemic cardiac death. Circulation. 1986;73:418-427).
Inhibition of platelet aggregation is recognized as an ive gy for the prevention of thrombosis in patients with atherosclerotic e in the coronary (Jneid H et al., 2012 accf/aha focused update of the guideline for the management of patients with unstable angina/non-st-elevation myocardial infarction (updating the 2007 guideline and replacing the 2011 focused update): A report of the american college of cardiology foundation/american heart association task force on practice guidelines. J Am Coll Cardiol. 2012;60:645-681; O'Gara PT et al., 2013 accf/aha guideline for the management of st-elevation myocardial tion: A report of the american college of cardiology tion/american heart association task force on practice guidelines. Circulation. 2013;127:e362-425), peripheral (Jagroop IA et al., The effect of clopidogrel, aspirin and both antiplatelet drugs on platelet function in patients with peripheral arterial e. ets. 2004;15:117-125; as M et al., The effect of a loading dose (300 mg) of clopidogrel on platelet function in patients with peripheral arterial disease. Clin Appl Thromb Hemost. 2003;9:115-120), and cerebrovascular circulation (Liu F et al., P2Y12 receptor inhibitors for secondary prevention of ischemic stroke.
Expert Opin Pharmacother. 2015;16:1149-1165). tion of P2Y 12 as an antiplatelet approach was ted in multiple clinical s. Several P2Y12 nists have been demonstrated to effectively reduce the risk of e cardiovascular events in patients with acute coronary syndromes (ACS) and patients undergoing percutaneous coronary intervention (PCI) (Cattaneo M, The platelet P2Y12 or for adenosine diphosphate: Congenital and drug-induced s. Blood. 2011;117:2102-2112; Thomas MR et al., The future of P2Y12 receptor nists. Platelets. 2015;26:392-398; Wiviott SD et al., Clinical evidence for oral antiplatelet therapy in acute coronary syndromes. Lancet. 2015;386:292- 302; Wallentin L, P2Y12 inhibitors: Differences in properties and mechanisms of action and potential consequences for clinical use. Eur Heart J. 2009;30:1964-1977). In current treatment guidelines, P2Y12 nists define the cornerstone therapy for patients with ACS (Jneid H et al., 2012 accf/aha focused update of the guideline for the management of patients with unstable angina/non-st-elevation myocardial infarction (updating the 2007 guideline and replacing the 2011 focused update): A report of the american e of cardiology tion/american heart association task force on practice guidelines. J Am Coll Cardiol. 2012;60:645-681; O'Gara PT et al., 2013 ha guideline for the management of st-elevation myocardial infarction: A report of the american college of cardiology foundation/american heart association task force on practice guidelines. Circulation. 2013;127:e362-425).
Three indirect P2Y12 antagonists of the thienopyridine family, which block the ADP-induced platelet activation and aggregation, have reached the market: the orally active ticlopidine, clopidogrel and prasugrel. In addition, two direct P2Y12 antagonists, which do not require metabolic activation and therefore display faster on- and offset of action, have received market approval: the nucleotide analogues ticagrelor and cangrelor. 4-((R){[6-((S)methoxy-pyrrolidinyl)phenyl-pyrimidinecarbonyl]-amino} phosphono-propionyl)-piperazinecarboxylic acid butyl ester is a potent, reversible, and selective P2Y12 receptor antagonist (Caroff E et al., J. Med. Chem . 2015;58:9133-9153; WO 69100). Its hydrochloride salt was used as a powder in a first-in-man clinical trial (Baldoni et al., Clinical Drug Investigation 2014;34:807-818). e the fact that many ts failed to crystallize ND·HCl from several solvents in a mono-phase solvent system, it surprisingly has been found that a crystallization took place in certain heterogeneous solvent systems. The obtained lline forms of COMPOUND·HCl may have advantageous ties in view of the potential use of COMPOUND·HCl or COMPOUND as active ceutical ingredient. Such advantages may include higher purity; better storage stability; better flow properties; less hygroscopicity; better reproducibility in cturing (for example better filtration ters, better reproducibility of formation, and/or better sedimentation); and/or defined morphology. Such crystalline forms of COMPOUND·HCl may be particularly suitable in a process of manufacturing certain ceutical compositions. It is an object of the present invention to go at least some way to achieving one or more of the abovementioned advantages, and/or to at least provide the public with a useful choice.
Summary of the Invention In a first aspect, the invention provides a crystalline form of 4-((R){[6-((S)methoxypyrrolidinyl )phenyl-pyrimidinecarbonyl]-amino}phosphono-propionyl)-piperazine carboxylic acid butyl ester hloride, characterized by the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2?: 4.0°, 5.0°, and 15.3°, wherein the X-ray powder diffraction diagram is obtained by using combined Cu Ka1 and Ka2 radiation, without Ka2 stripping.
In a second aspect, the invention provides a crystalline form of 4-((R){[6-((S)methoxypyrrolidinyl )phenyl-pyrimidinecarbonyl]-amino}phosphono-propionyl)-piperazine carboxylic acid butyl ester hydrochloride according to claim 1, characterized by the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2?: 4.0°, .0°, 11.7°, 15.3°, and 19.3°, wherein the X-ray powder diffraction diagram is obtained by using combined Cu Ka1 and Ka2 ion, without Ka2 stripping.
In a third aspect, the invention provides a crystalline form of 4-((R){[6-((S)methoxypyrrolidinyl )phenyl-pyrimidinecarbonyl]-amino}phosphono-propionyl)-piperazine carboxylic acid butyl ester hydrochloride according to the first aspect of the invention, characterized by the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2?: 4.0°, 5.0°, 5.9°, 11.7°, 15.3°, 16.9°, 19.3°, 19.7°, and 20.7°, wherein the X-ray powder ction diagram is ed by using combined Cu Ka1 and Ka2 radiation, without Ka2 ing.
In a fourth aspect, the invention relates to a process for the preparation of 4-((R){[6-((S) methoxy-pyrrolidinyl)phenyl-pyrimidinecarbonyl]-amino}phosphono-propionyl)- piperazinecarboxylic acid butyl ester hloride in a crystalline form according to any one of the first to third aspect of the invention, wherein the process comprises the following steps: a. addition of acetone (10 to 30 vol.) to a on comprising 4-((R){[6-((S) methoxy-pyrrolidinyl)phenyl-pyrimidinecarbonyl]-amino}phosphonopropionyl )-piperazinecarboxylic acid butyl ester hydrochloride and a non-polar solvent (0.5 to 3.0 vol.) at 45 to 60°C, wherein the non-polar solvent is selected from (C1-2)chloroalkane; b. addition of water (0.3 to 0.7 vol.) at 45 to 60°C; c. stirring of the mixture under cooling from a temperature of 45 to 60°C to a temperature at or below 30°C for at least 1h; and d. ion of the obtained crystalline material.
In a fifth aspect, the invention provides a crystalline form of 4-((R){[6-((S)methoxy- pyrrolidinyl)phenyl-pyrimidinecarbonyl]-amino}phosphono-propionyl)-piperazine carboxylic acid butyl ester hydrochloride according to any one of the first to third aspects of the invention, for use as a medicament.
In a sixth aspect, the invention es a pharmaceutical composition comprising as active ingredient a crystalline form of {[6-((S)methoxy-pyrrolidinyl)phenylpyrimidinecarbonyl ]-amino}phosphono-propionyl)-piperazinecarboxylic acid butyl ester hydrochloride ing to any one of the first to third aspects of the invention, and at least one pharmaceutically acceptable carrier.
In a seventh aspect, the invention provides a crystalline form of 4-((R){[6-((S)methoxypyrrolidinyl )phenyl-pyrimidinecarbonyl]-amino}phosphono-propionyl)-piperazine carboxylic acid butyl ester hydrochloride according to any one of the first to third aspects of the invention, for use in the manufacture of a pharmaceutical composition, wherein said pharmaceutical composition comprises as active ingredient 4-((R){[6-((S)methoxypyrrolidinyl )phenyl-pyrimidinecarbonyl]-amino}phosphono-propionyl)-piperazine carboxylic acid butyl ester hydrochloride, and at least one pharmaceutically acceptable carrier material.
In an eighth aspect, the invention relates to ase of a crystalline form of 4-((R){[6-((S) methoxy-pyrrolidinyl)phenyl-pyrimidinecarbonyl]-amino}phosphono-propionyl)- piperazinecarboxylic acid butyl ester hloride according to any one of the first to third aspects of the invention, in the preparation of a medicament for the prevention or treatment of diseases ed from the group consisting of acute coronary syndromes, peripheral ischaemia, amaurosis, ischaemic stroke and transient ischaemic attack.
The invention is defined in the claims. r, the disclosure preceding the claims may refer to additional methods and other subject matter outside the scope of the t claims.
This disclosure is retained for technical es.
Description of the Figures Fig. 1 shows the X-ray powder diffraction diagram of COMPOUND·HCl in the lline form 1, wherein the X-ray powder diffraction diagram is displayed against Cu Ka radiation. The X- ray diffraction diagram shows peaks having a relative intensity, as compared to the most intense peak in the m, of the following percentages (relative peak intensities given in parenthesis) at the ted angles of refraction 2theta (selected peaks from the range 3-30° 2theta with ve intensity larger or equal than 10% are reported): 4.0° (100%), 5.0 (60%), .9° (23%), 11.7° (10%), 15.3° (13%), 19.3° (15%), 19.7° (11%), and 20.7° (10%).
Fig. 2 shows the X-ray powder diffraction diagram of COMPOUND·HCl in the lline form 2, wherein the X-ray powder diffraction diagram is yed against Cu Ka radiation. The X- ray diffraction diagram shows peaks having a ve intensity, as compared to the most intense peak in the diagram, of the following percentages (relative peak intensities given in hesis) at the indicated angles of refraction 2theta (selected peaks from the range 3-30° 2theta with relative intensity larger or equal than 10% are reported): 5.2° (100%), 6.8° (26%), 8.0° (14%), 10.3° (66%), 10.8° (66%), 12.7° (10%), 15.4° (18%), 16.2° (13%), 20.3° (40%), .5° (28%), and 21.7° (13%).
Fig. 3 shows the X-ray powder diffraction diagram of COMPOUND·HCl in the crystalline form 3, wherein the X-ray powder diffraction diagram is displayed against Cu Ka ion. The X- ray diffraction diagram shows peaks having a ve ity, as compared to the most intense peak in the diagram, of the following percentages (relative peak intensities given in parenthesis) at the indicated angles of refraction 2theta (selected peaks from the range 8-30° 2theta with relative intensity larger or equal than 10% are reported): 5.5° (100%), 7.2 (43%), 11.0° (51%), 11.5° (45%), 13.0° (10%), 14.4° (15%), 16.6° (51%), 18.1° (39%), 18.5° (27%), 21.1° (32%), 22.0° (37%), 23.1° (17%), 24.3° (16%) and 26.1° (10%).
In the X-ray diffraction diagrams of Fig. 1 to Fig. 3 the angle of refraction 2theta (2?) is plotted on the horizontal axis and the counts on the vertical axis.
For avoidance of any doubt, the above-listed peaks describe the experimental results of the X-ray powder diffraction shown in Figures 1 to 3. It is understood that, in contrast to the above peak list, only a selection of characteristic peaks is ed to fully and unambiguously characterize COMPOUND·HCl in the respective crystalline form of the present invention.
Fig. 4 shows the etric vapour sorption behaviour in the range of 20 to 75% RH at 25°C (coming from low %RH and going to high %RH, i.e., sorption cycle) of COMPOUND·HCl in the crystalline form 1 as obtained from Example 1A.
Fig. 5 shows the gravimetric vapour on behaviour in the range of 20 to 75% RH at 25°C (coming from high %RH and going to low %RH, i.e., desorption cycle) of COMPOUND·HCl in the crystalline form 2 as obtained from Example 2.
Fig. 6 shows the etric vapour sorption behaviour in the range of 20 to 75% RH at 25°C (coming from low %RH and going to high %RH, i.e., on cycle) of COMPOUND·HCl in the crystalline form 3 as obtained from Example 3A.
In the gravimetric vapour on diagrams of Figs. 4, 5, and 6 the relative humidity (% RH) is plotted on the horizontal axis and the mass change (% dm, dry basis) on the vertical axis.
Detailed Description of the Invention 1) A first embodiment of the invention relates to crystalline forms of 4-((R){[6-((S) methoxy-pyrrolidinyl)phenyl-pyrimidinecarbonyl]-amino}phosphono-propionyl)- piperazinecarboxylic acid butyl ester hydrochloride (COMPOUND·HCl), characterized by: a. the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2?: 4.0°, 5.0°, and 15.3° (form 1); or b. the presence of peaks in the X-ray powder ction diagram at the following angles of tion 2?: 5.2°, 6.8°, and 10.3° (form 2); or c. the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2?: 5.5°, 11.0°, and 16.6° (form 3).
It is understood, that the lline forms according to embodiment 1) comprise COMPOUND·HCl in form of the hydrochloric acid (hydrochloride) salt. Furthermore, said crystalline form may comprise non-coordinated and / or coordinated solvent (especially noncoordinated and / or coordinated water). Coordinated solvent ially coordinated water) is used herein as term for a lline solvate (especially a crystalline hydrate). For the avoidance of doubt, in this application the term "crystalline e" encompasses nonstoichiometric hydrates. Likewise, non-coordinated solvent is used herein as term for physiosorbed or physically entrapped solvent (definitions according to Polymorphism in the Pharmaceutical Industry (Ed. R. er, VCH, 2006), Chapter 8: U.J. Griesser: The ance of Solvates). It is further understood, that the crystalline form may contain ent amounts of coordinated water as a function of relative humidity and that the X-ray powder diffraction diagram may thus vary with relative ty. Crystalline form 1 in ular comprises about 0 to 3% of coordinated and/or non-coordinated water. Cystalline form 2 in particular comprises about 5 to 10% of coordinated and/or non-coordinated water.
Crystalline form 3 in particular comprises about 2.5 to 8% of coordinated and/or non- coordinated water. 2) Another embodiment relates to crystalline forms of COMPOUND·HCl according to embodiment 1), characterized by a. the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2?: 4.0°, 5.0°, 11.7°, 15.3°, and 19.3° (form 1); or b. the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2?: 5.2°, 6.8°, 10.3°, 10.8°, and 15.4° (form 2); or c. the ce of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2?: 5.5°, 7.2°, 11.0°, 11.5°, and 16.6° (form 3). 3) Another embodiment relates to crystalline forms of COMPOUND·HCl according to embodiment 1), characterized by a. the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2?: 4.0°, 5.0°, 5.9°, 11.7°, 15.3°, 16.9°, 19.3°, 19.7°, and 20.7° (form 1); or b. the ce of peaks in the X-ray powder ction diagram at the following angles of refraction 2?: 5.2°, 6.8°, 8.0°, 10.3°, 10.8°, 12.7°, 15.4°, 16.2°, 20.3°, and 21.7° (form 2); or c. the presence of peaks in the X-ray powder diffraction m at the following angles of refraction 2?: 5.5°, 7.2°, 11.0°, 11.5°, 14.4°, 16.6°, 18.1°, 21.1°, and 22.0° (form 3). 4) Another embodiment relates to a crystalline form of COMPOUND·HCl according to embodiment 1), characterized by the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2?: 4.0°, 5.0°, and 15.3°.
) Another embodiment relates to a crystalline form of COMPOUND·HCl according to embodiment 1), characterized by the presence of peaks in the X-ray powder ction diagram at the following angles of refraction 2?: 4.0°, 5.0°, 11.7°, 15.3°, and 19.3°. 6) r embodiment relates to a crystalline form of COMPOUND·HCl according to embodiment 1), characterized by the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2?: 4.0°, 5.0°, 5.9°, 11.7°, 15.3°, 16.9°, 19.3°, 19.7°, and 20.7°. 7) Another embodiment relates to a crystalline form of ND·HCl according to embodiment 1), which essentially shows the X-ray powder diffraction pattern as depicted in Fig. 1. 8) Another embodiment relates to a crystalline form of COMPOUND·HCl according to ment 1), characterized by the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2?: 5.2°, 6.8°, and 10.3°. 9) r embodiment relates to a crystalline form of COMPOUND·HCl ing to embodiment 1), characterized by the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2?: 5.2°, 6.8°, 10.3°, 10.8°, and 15.4°. 10) Another embodiment relates to a crystalline form of ND·HCl according to ment 1), characterized by the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2?: 5.2°, 6.8°, 8.0°, 10.3°, 10.8°, 12.7°, 15.4°, 16.2°, 20.3°, and 21.7°. 11) Another embodiment s to a crystalline form of COMPOUND·HCl according to embodiment 1), which essentially shows the X-ray powder diffraction pattern as depicted in Fig. 2. 12) Another embodiment relates to a crystalline form of COMPOUND·HCl according to embodiment 1), characterized by the presence of peaks in the X-ray powder diffraction diagram at the following angles of tion 2?: 5.5°, 11.0°, and 16.6°. 13) Another embodiment relates to a lline form of COMPOUND·HCl according to embodiment 1), characterized by the presence of peaks in the X-ray powder diffraction diagram at the ing angles of refraction 2?: 5.5°, 7.2°, 11.0°, 11.5°, and 16.6°. 14) Another embodiment relates to a crystalline form of COMPOUND·HCl according to embodiment 1), characterized by the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2?: 5.5°, 7.2°, 11.0°, 11.5°, 14.4°, 16.6°, 18.1°, 21.1°, and 22.0°.
) Another embodiment relates to a crystalline form of COMPOUND·HCl according to embodiment 1), which essentially shows the X-ray powder ction pattern as depicted in Fig. 3. 16) Another embodiment relates to a crystalline form, such as an essentially pure crystalline form, of 4-((R){[6-((S)methoxy-pyrrolidinyl)phenyl-pyrimidinecarbonyl]-amino}- 3-phosphono-propionyl)-piperazinecarboxylic acid butyl ester hydrochloride (COMPOUND·HCl) obtainable by: a. addition of aq. 33% HCl (5.1 vol.) to a solution of butyl 4-((R)(diethoxyphosphoryl)- (S)methoxypyrrolidinyl)phenylpyrimidine carboxamido)propanoyl)piperazinecarboxylate in a mixture of DCM and THF (5.5 vol.); b. stirring for 4 to 12h at a temperature of 20 to 30°C; c. addition of water (8.2 vol.) and DCM (8.2 vol.) at a temperature of 20 to 30°C; d. separation of layers and extraction with DCM (8.2 vol.); e. removal of solvent by distillation at Ti = 50°C, on of acetone (8.7 vol.) and r removal of solvent by distillation at Ti = 50°C until a final amount of 7.0 vol. s; f. addition of acetone (18.5 vol.) at Ti = 50°C; g. addition of water (0.5 vol.) at Ti = 50°C within 30 min and stirring at Ti = 56°C for 3.5h; h. cooling to 20 to 30°C within 2h and stirring at 20 to 30°C for 1.5h; and i. ion of the obtained solid residue. 17) Another ment relates to a crystalline form of COMPOUND·HCl ing to embodiment 16), characterized by the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2?: 4.0°, 5.0°, and 15.3°. 18) Another embodiment relates to a crystalline form of COMPOUND·HCl according to embodiment 16), characterized by the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2?: 4.0°, 5.0°, 11.7°, 15.3°, and 19.3°. 19) Another embodiment relates to a crystalline form of COMPOUND·HCl according to embodiment 16), characterized by the presence of peaks in the X-ray powder ction diagram at the following angles of refraction 2?: 4.0°, 5.0°, 5.9°, 11.7°, 15.3°, 16.9°, 19.3°, 19.7°, and 20.7°.
) Another embodiment relates to a crystalline form of COMPOUND·HCl according to embodiment 16), which essentially shows the X-ray powder diffraction pattern as depicted in Fig. 1. 21) Another ment relates to the crystalline form of COMPOUND·HCl according to any one of embodiments 4) to 7), obtainable by the process of embodiment 16). 22) Another embodiment relates to a crystalline form, such as an essentially pure crystalline form, of 4-((R){[6-((S)methoxy-pyrrolidinyl)phenyl-pyrimidinecarbonyl]-amino}- 3-phosphono-propionyl)-piperazinecarboxylic acid butyl ester hloride (COMPOUND·HCl) obtainable by: a) equilibration of a sample of ND·HCl in a lline form according to any one of embodiments 4) to 7) at RH > 90% and at about RT; and b) equilibration of the obtained sample at about RH = 40% and at about RT.
Especially, the first equilibration step requires about 3 days and the second equilibration step requires about 1 day. 23) Another embodiment relates to a lline form of COMPOUND·HCl ing to embodiment 22), characterized by the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2?: 5.2°, 6.8°, and 10.3°. 24) Another embodiment relates to a crystalline form of COMPOUND·HCl according to ment 22), characterized by the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2?: 5.2°, 6.8°, 10.3°, 10.8°, and 15.4°.
) Another embodiment relates to a lline form of ND·HCl according to embodiment 22), characterized by the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2?: 5.2°, 6.8°, 8.0°, 10.3°, 10.8°, 12.7°, 15.4°, 16.2°, 20.3°, and 21.7°. 26) r embodiment relates to a crystalline form of COMPOUND·HCl ing to embodiment 22), which essentially shows the X-ray powder diffraction pattern as depicted in Fig. 2. 27) Another embodiment relates to the crystalline form of COMPOUND·HCl according to any one of embodiments 8) to 11), obtainable by the processes of embodiment 22). 28) Another embodiment s to a crystalline form, such as an essentially pure crystalline form, of 4-((R){[6-((S)methoxy-pyrrolidinyl)phenyl-pyrimidinecarbonyl]-amino}- 3-phosphono-propionyl)-piperazinecarboxylic acid butyl ester hydrochloride (COMPOUND·HCl) obtainable by: a) equilibration of a sample of COMPOUND·HCl in a lline form according to any one of embodiments 8) to 11) in a dry nitrogen gas stream at about RT; b) equilibration of the obtained sample at about RH = 40% and at about RT.
Especially, the first equilibration step requires about 1 day for a 100 mg sample at a gas stream of about 400 mL/min and the second equilibration step requires about 1 day. 29) Another embodiment relates to a crystalline form of COMPOUND·HCl according to embodiment 28), characterized by the ce of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2?: 5.5°, 11.0°, and 16.6°. ) r embodiment relates to a crystalline form of ND·HCl according to embodiment 28), characterized by the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2?: 5.5°, 7.2°, 11.0°, 11.5°, and 16.6°. 31) Another embodiment relates to a crystalline form of COMPOUND·HCl according to embodiment 28), characterized by the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2?: 5.5°, 7.2°, 11.0°, 11.5°, 14.4°, 16.6°, 18.1°, 21.1°, and 22.0°. 32) Another embodiment relates to a crystalline form of COMPOUND·HCl according to embodiment 28), which essentially shows the X-ray powder diffraction pattern as depicted in Fig. 3. 33) Another embodiment s to the crystalline form of COMPOUND·HCl according to any one of embodiments 12) to 15), obtainable by the processes of embodiment 28). 34) r ment relates to a crystalline form of COMPOUND·HCl according to any one of embodiments 4) to 7) or 16) to 21), which essentially shows a gravimetric moisture on profile (sorption cycle) as depicted in Fig. 4, wherein the gravimetric moisture sorption e is measured at 25°C.
) Another embodiment relates to a crystalline form of COMPOUND·HCl according to any one of embodiments 8) to 11) or 22) to 27), which ially shows a gravimetric moisture sorption profile (desorption cycle) as depicted in Fig. 5, wherein the gravimetric moisture sorption profile is measured at 25°C. 36) r embodiment relates to a crystalline form of COMPOUND·HCl according to any one of embodiments 12) to 15) or 28) to 33), which essentially shows a etric re sorption profile (sorption cycle) as depicted in Fig. 6, wherein the gravimetric moisture sorption profile is ed at 25°C. 37) A process for the preparation of COMPOUND·HCl in a crystalline form according to any one of embodiments 1) to 7), wherein the process comprises the following steps: a. addition of acetone (10 to 30 vol.) to a solution comprising COMPOUND·HCl and a non-polar solvent (0.5 to 3.0 vol.; 0.5 to 3.0 L per kg COMPOUND·HCl) at 45 to 60°C, wherein the non-polar solvent is selected from (C1-2)chloroalkane; b. on of water (0.3 to 0.7 vol.) at 45 to 60°C; c. stirring of the mixture under cooling from a temperature of 45 to 60°C to a temperature at or below 30°C for at least 1h; and d. isolation of the obtained crystalline material. 38) A process according to embodiment 37), wherein the amount of added acetone in step a. is about 20 vol.. 39) A s according to any one of embodiments 37) or 38), wherein the amount of the non-polar t in step a. is 1.0 to 2.0 vol. and wherein the non-polar solvent is dichloromethane. 40) A process according to any one of embodiments 37) to 39), wherein the amount of the added water in step b. is 0.4 to 0.6 vol. (and especially 0.5 vol.). 41) A process according to any one of embodiments 37) to 40), wherein the e is stirred in step c. between 1 and 4h at a temperature of 45 to 60°C and is uently cooled to a temperature between 20 and 30°C (especially 25°C) during 1 to 2h. 42) A process according to any one of embodiments 37) to 41), wherein the isolation in step d. is done by filtration. 43) A process according to any one of ments 37) to 42), wherein the solution comprising COMPOUND·HCl and a non-polar solvent used in step a. is obtained by a process comprising the steps: a. coupling of (S)(3-methoxypyrrolidinyl)phenylpyrimidinecarboxylic acid, or a salt thereof ially a sodium salt thereof), with butyl (R)(2-amino (diethoxyphosphoryl)propanoyl)piperazinecarboxylate in the presence of an amide coupling agent; b. extraction with a solvent mixture comprising (C1-2)chloroalkane (especially dichloromethane); and water or an aqueous solution of an inorganic salt (especially an aqueous sodium hydrogencarbonat solution) c. addition of aqueous hloric acid and stirring of the mixture; d. extraction with a solvent mixture comprising (C1-2)chloroalkane (especially dichloromethane); and water or an aqueous solution of an inorganic salt (especially water); and e. removal of solvents until the amount of (C1-2)chloroalkane equals 0.5 to 3.0 L per kg (especially 1.0 to 2.0 L per kg) COMPOUND·HCl.
Based on the dependencies of the ent ments 1) to 43) as disclosed hereinabove, the following embodiments are thus possible and intended and th specifically disclosed in individualised form: 1, 2+1, 3+1, 4+1, 5+1, 6+1, 7+1, 8+1, 9+1, 10+1, 11+1, 12+1, 13+1, 14+1, 15+1, 16, 17+16, 18+16, 19+16, 20+16, 21+4+1, , 21+6+1, 21+7+1, 22, 23+22, 24+22, 25+22, 26+22, 27+8+1, 27+9+1, 27+10+1, 1, 28, 29+28, 30+28, 31+28, 32+28, 33+12+1, 33+13+1, 33+14+1, 33+15+1, 34+4+1, 34+5+1, 34+6+1, 34+7+1, 34+16, 34+17+16, 34+18+16, 34+19+16, 34+20+16, 4+1, 34+21+5+1, 34+21+6+1, 7+1, 35+8+1, 35+9+1, +10+1, 35+11+1, 35+22, 35+23+22, 22, 35+25+22, 35+26+22, 35+27+8+1, +27+9+1, 35+27+10+1, 35+27+11+1, 36+12+1, 36+13+1, 36+14+1, 36+15+1, 36+28, 36+29+28, 28, 36+31+28, 36+32+28, 36+33+12+1, 36+33+13+1, 36+33+14+1, 36+33+15+1, 37, 38+37, 39+37, 39+38+37, 40+37, 40+38+37, 40+39+37, 40+39+38+37, 41+37, 41+38+37, 41+39+37, 41+39+38+37, 41+40+37, 41+40+38+37, 41+40+39+37, 41+40+39+38+37, 42+37, 42+38+37, 42+39+37, 42+39+38+37, 42+40+37, 42+40+38+37, 42+40+39+37, 42+40+39+38+37, 42+41+37, 42+41+38+37, 42+41+39+37, 39+ 38+37, 42+41+40+37, 40+38+37, 42+41+40+39+37, 42+41+40+39+38+37, 43+37, 43+38+37, 43+39+37, 43+39+38+37, 43+40+37, 38+37, 43+40+39+37, 43+40+39+38+37, 43+41+37, 43+41+38+37, 39+37, 43+41+39+38+37, 43+41+40+37, 43+41+40+38+37, 43+41+40+39+37, 43+41+40+39+38+37, 43+42+37, 43+42+38+37, 43+42+39+37, 43+42+39+38+37, 43+42+40+37, 43+42+40+38+37, 43+42+40+39+37, 43+42+40+39+38+37, 43+42+41+37, 43+42+41+38+37, 43+42+41+ 39+37, 43+42+41+39+38+37, 43+42+41+40+37, 43+42+41+40+38+37, 41+40+ 39+37, 43+42+41+40+39+38+37; in the list above the numbers refer to the embodiments according to their numbering provided hereinabove whereas "+" indicates the dependency from another embodiment. The different individualised embodiments are separated by commas. In other words, "21+4+1" for example refers to embodiment 21) depending on ment 4), depending on embodiment 1), i.e. embodiment "21+4+1" corresponds to embodiment 1) further terised by the es of the embodiments 4) and 21).
For avoidance of any doubt, whenever one of the above embodiments refers to "peaks in the X-ray powder diffraction diagram at the ing angles of refraction 2?", said X-ray powder diffraction diagram is obtained by using combined Cu Ka1 and Ka2 ion, t Ka2 stripping; and it should be tood that the cy of the 2? values as provided herein is in the range of +/- 0.1-0.2°. Notably, when specifying an angle of refraction 2theta (2?) for a peak in the invention ments and the claims, the 2? value given is to be understood as an interval from said value minus 0.2° to said value plus 0.2° (2? +/- 0.2°); and preferably from said value minus 0.1° to said value plus 0.1° (2? +/- 0.1°).
Where the plural form is used for compounds, , ceutical compositions, diseases and the like, this is intended to mean also a single compound, solid, pharmaceutical composition, disease or the like.
Definitions provided herein are intended to apply uniformly to the subject matter as defined in any one of embodiments 1) to 43), and, mutatis mutandis, throughout the description and the claims unless an otherwise expressly set out definition provides a broader or narrower definition. It is well understood that a definition or preferred definition of a term or expression defines and may e the respective term or expression independently of (and in combination with) any definition or preferred definition of any or all other terms or expressions as defined herein.
The term "(C1-2)chloroalkane" refers to an alkane group containing one or two carbon atoms in which one or more (and possibly all) hydrogen atoms have been replaced with chlorine.
For example a (C1-2)chloroalkane group contains one or two carbon atoms in which one to six (especially two) hydrogen atoms have been replaced with chlorine. Preferred examples of (C1-2)chloroalkane groups are romethane and 1,2-dichloroethane (and especially dichloromethane).
The term "amide coupling agent" refers to a compound that promotes the formation of a chemical bond (amide bond) between the -COOH group of a carboxylic acid and the -NH2 group of an amine. Representative examples of amide coupling agents are carbodiimides (such as dicyclohexylcarbodiimide, diisopropylcarbodiimide or 1-ethyl(3-dimethylaminopropyl diimide) in the ce or absence of an additive such as 1-hydroxybenzotriazole , oxyaza-1H-benzotriazole or N-hydroxysuccinimide; phosphonium reagents (such as benzotriazolyloxy-tris(dimethylamino)-phosphonium hexafluoro- phosphate or benzotriazolyloxy-tripyrrolidino-phosphonium hexafluorophosphate); aminium reagents (such as 2-(1H-benzotriazolyl)-N,N,N’,N’-tetramethylaminium tetrafluoroborate , benzotriazolyl)-N,N,N’,N’-tetramethylaminium hexafluorophosphate or 2-(7-aza-1H-benzotriazolyl)-N,N,N’,N’-tetramethylaminium hexafluorophosphate); and 2- propanephosphonic acid anhydride; preferred is 1-ethyl(3-dimethylaminopropyl) carbodiimide in the presence of 1-hydroxy-benzotriazole.
The term "enantiomerically enriched" is understood in the context of the present invention to mean especially that at least 90, preferably at least 95, and most preferably at least 99 per cent by weight of the COMPOUND (or of COMPOUND·HCl) are present in form of one enantiomer of the COMPOUND (or of COMPOUND·HCl). It is tood that any reference to "COMPOUND" (or to " COMPOUND·HCl") refers to {[6-((S)methoxy-pyrrolidin- 1-yl)phenyl-pyrimidinecarbonyl]-amino}phosphono-propionyl)-piperazinecarboxylic acid (or to its HCl salt) in enantiomerically enriched or in pure form.
The term tially pure" is understood in the context of the present invention to mean especially that at least 90, preferably at least 95, and most preferably at least 99 per cent by weight of the crystals of COMPOUND·HCl are present in a crystalline form according to the present invention.
When defining the presence of peak in e.g. an X-ray powder diffraction diagram, a common approach is to do this in terms of the S/N ratio (S = signal, N = noise). According to this definition, when stating that a peak has to be present in a X-ray powder diffraction diagram, it is understood that the peak in the X-ray powder diffraction diagram is defined by having an S/N ratio (S = signal, N = noise) of greater than x (x being a numerical value greater than 1), usually greater than 2, especially greater than 3.
In the context with stating that the crystalline form essentially shows an X-ray powder ction pattern as depicted in Fig. 1, 2, or 3, respectively, the term "essentially" means that at least the major peaks of the diagram depicted in said figures, i.e. those having a relative intensity of more than 20%, especially more than 10%, as compared to the most intense peak in the diagram, have to be present. r, the person d in the art of X-ray powder diffraction will recognize that relative intensities in X-ray powder diffraction ms may be subject to strong ity variations due to preferred orientation effects.
The term "equilibration", as used in the context of "equilibration of a sample of COMPOUND·HCl", refers to a process step of keeping a sample for an equilibration time under specific conditions, such as a specifically given ve humidity, a specifically given gas stream and/or a specifically given temperature, wherein the term "equilibration time" refers to the time that is required to obtain an ially constant content of water in the sample. The content of water is "essentially nt" if the change in the water content is less than 5% if the sample is kept for 24 h under the given specific conditions.
Unless used regarding temperatures, the term "about" placed before a numerical value "X" refers in the current application to an interval extending from X minus 10% of X to X plus 10% of X, and preferably to an interval extending from X minus 5% of X to X plus 5% of X; most preferred is X. In the particular case of temperatures, the term "about" placed before a temperature "Y" refers in the current application to an interval extending from the ature Y minus 10 ºC to Y plus 10 ºC, preferably to an interval extending from Y minus 3 ºC to Y plus 3 ºC; most preferred is Y. Room temperature means a temperature of about 25 ºC. er the word "between" or "to" is used to describe a numerical range, it is to be understood that the end points of the indicated range are explicitly included in the range. For example: if a temperature range is bed to be between 40ºC and 80ºC (or 40ºC to 80ºC), this means that the end points 40ºC and 80ºC are included in the range; or if a variable is defined as being an integer between 1 and 4 (or 1 to 4), this means that the variable is the integer 1, 2, 3, or 4.
The term "comprising" as used in this specification and claims means "consisting at least in part of". When interpreting statements in this specification and claims which include the term "comprising", other features besides the features prefaced by this term in each statement can also be present. Related terms such as "comprise" and "comprised" are to be reted in similar manner.
It is tood that {[6-((S)methoxy-pyrrolidinyl)phenyl-pyrimidine- 4-carbonyl]-amino}phosphono-propionyl)-piperazinecarboxylic acid butyl ester hydrochloride (or ND·HCl) refers to a hydrochloride salt of COMPOUND wherein the salt contains about 1 molar equivalent of HCl per molar equivalent of COMPOUND, especially 0.98 to 1.02 molar equivalent of HCl per molar equivalent of COMPOUND and notably 1.00 molar equivalent of HCl per molar lent of COMPOUND.
The expression % w/w refers to a tage by weight compared to the total weight of the composition considered. Likewise, the expression v/v refers to a ratio by volume of the two components considered.
The crystalline forms, ally the essentially pure crystalline forms, of COMPOUND·HCl according to any one of embodiments 1) to 36) can be used as medicaments, e.g. in the form of pharmaceutical compositions for enteral (such especially oral) or parenteral administration (including topical application or tion). 44) Another embodiment thus relates to a crystalline form of 4-((R){[6-((S)methoxypyrrolidinyl )phenyl-pyrimidinecarbonyl]-amino}phosphono-propionyl)-piperazine carboxylic acid butyl ester hydrochloride according to any one of embodiments 1) to 36) for use as a medicament. 45) Another embodiment s to COMPOUND, or a pharmaceutically able salt thereof, for use as a medicament, wherein COMPOUND, or a pharmaceutically acceptable salt thereof, is obtained from a crystalline form of COMPOUND·HCl according to any one of embodiments 1) to 36).
The term "pharmaceutically acceptable salt" refers to a salt that retains the desired biological activity of the subject nd and ts minimal undesired toxicological effects. Such salts include inorganic or organic acid and/or base addition salts depending on the presence of basic and/or acidic groups in the subject compound. For reference see for example ook of Pharmaceutical Salts. Properties, Selection and Use.’, P. Heinrich Stahl, Camille G. Wermuth , Wiley-VCH, 2008, and ‘Pharmaceutical Salts and stals’, Johan Wouters and Luc Quéré (Eds.), RSC Publishing, 2012.
The lline solid, especially the essentially pure crystalline solid, of COMPOUND·HCl according to any one of embodiments 1) to 36) may be used as single component or as mixture with other crystalline forms or amorphous form of COMPOUND·HCl.
The production of the pharmaceutical compositions can be effected in a manner which will be familiar to any person skilled in the art (see for example Remington, The Science and Practice of Pharmacy, 21st Edition (2005), Part 5, "Pharmaceutical Manufacturing" [published by Lippincott Williams & Wilkins]) by bringing the lline form of the t invention, optionally in combination with other therapeutically valuable substances, into a galenical administration form together with suitable, non-toxic, inert, pharmaceutically acceptable solid or liquid carrier materials and, if desired, usual pharmaceutical adjuvants. 46) A further embodiment of the invention relates to pharmaceutical compositions comprising as active ingredient a crystalline form of COMPOUND·HCl according to any one of embodiments 1) to 36), and at least one pharmaceutically acceptable r al. 47) A further embodiment of the invention relates to ceutical compositions comprising as active ingredient COMPOUND, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier material, wherein COMPOUND, or a pharmaceutically acceptable salt thereof, is obtained from a crystalline form of COMPOUND·HCl according to any one of embodiments 1) to 36). 48) A further embodiment of the invention relates to a crystalline form of COMPOUND·HCl according to any one of embodiments 1) to 36), for use in the manufacture of a pharmaceutical composition, wherein said pharmaceutical composition comprises as active ingredient the COMPOUND·HCl, and at least one pharmaceutically acceptable carrier material. 49) A further embodiment of the ion relates to COMPOUND, or a pharmaceutically able salt thereof, for use in the manufacture of a pharmaceutical composition, n said pharmaceutical composition comprises as active ingredient the COMPOUND, or a pharmaceutically acceptable salt f, and at least one pharmaceutically acceptable carrier material, wherein the ND is obtained from a crystalline form of COMPOUND·HCl according to any one of embodiments 1) to 36). 50) A further embodiment of the invention relates to a lline form of COMPOUND·HCl according to any one of embodiments 1) to 36), for use in the prevention/prophylaxis or treatment of diseases selected from the group consisting of acute arterial thrombosis. 51) A preferred embodiment of the invention relates to a crystalline form of ND·HCl according to any one of embodiments 1) to 36), for use in the prevention/prophylaxis or treatment of diseases ed from the group consisting of acute coronary mes, peripheral ischaemia, amaurosis, ischaemic stroke and transient ischaemic attack. 52) A most preferred embodiment of the invention relates to a crystalline form of COMPOUND·HCl according to any one of embodiments 1) to 36), for use in the prevention/prophylaxis or treatment of acute coronary syndromes. 53) A r embodiment of the invention relates to ND, or a pharmaceutically acceptable salt thereof, for use in the prevention/prophylaxis or treatment of a disease selected from the diseases ing to any one of embodiments 50) to 52), wherein the COMPOUND, or a pharmaceutically able salt thereof, is obtained from a crystalline form of COMPOUND·HCl according to any one of embodiments 1) to 36). 54) A further embodiment of the invention s to a lline form of COMPOUND·HCl according to any one of embodiments 1) to 36), for use in the manufacture of a pharmaceutical composition for the prevention/prophylaxis or treatment of diseases selected from the group consisting of acute arterial thrombosis. 55) A red embodiment of the invention s to a crystalline form of COMPOUND·HCl according to any one of embodiments 1) to 36), for use in the cture of a pharmaceutical composition for the prevention/prophylaxis or treatment of diseases selected from the group consisting of acute coronary syndromes, eral ischaemia, amaurosis, ischaemic stroke and transient ischaemic attack. 56) A most preferred embodiment of the invention relates to a lline form of COMPOUND·HCl according to any one of embodiments 1) to 36), for use in the manufacture of a pharmaceutical composition for the prevention/prophylaxis or treatment of acute coronary syndromes. 57) A further embodiment of the invention relates to COMPOUND, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a ceutical composition for the prevention/prophylaxis or treatment of a disease selected from the diseases according to any one of embodiments 54) to 56), wherein the COMPOUND, or a pharmaceutically acceptable salt thereof, is obtained from a crystalline form of COMPOUND·HCl ing to any one of embodiments 1) to 36). 58) A further embodiment of the invention relates to pharmaceutical compositions according to ment 46), for use in the prevention/prophylaxis or treatment of diseases selected from the group ting of acute al thrombosis. 59) A preferred embodiment of the invention relates to pharmaceutical compositions according to embodiment 46), for use in the prevention/prophylaxis or treatment of diseases selected from the group consisting of acute coronary syndromes, peripheral ischaemia, amaurosis, ischaemic stroke and transient ischaemic attack. 60) A most preferred embodiment of the invention relates to pharmaceutical compositions according to embodiment 46), for use in the prevention/prophylaxis or treatment of acute coronary syndromes. 61) A further embodiment of the invention relates to pharmaceutical compositions according to ment 47), for use in the tion/prophylaxis or treatment of a disease selected from the es according to any one of embodiments 58) to 60).
The present invention also relates to a method for the prevention/prophylaxis or treatment of a disease or disorder mentioned herein, comprising administering to a t a pharmaceutically active amount of a crystalline form of COMPOUND·HCl according to any one of embodiments 1) to 36), or of a pharmaceutical ition ing to embodiment The present invention also relates to a method for the prevention/prophylaxis or treatment of a disease or disorder mentioned herein, comprising administering to a subject a pharmaceutically active amount of the COMPOUND, or a pharmaceutically acceptable salt thereof, wherein the COMPOUND, or a pharmaceutically acceptable salt thereof, is ed from a crystalline form of COMPOUND·HCl according to any one of embodiments 1) to 36), or of the pharmaceutical composition according to embodiment 47).
In this specification where reference has been made to patent specifications, other external documents, or other sources of information, this is generally for the purpose of providing a context for discussing the features of the invention. Unless specifically stated otherwise, reference to such al documents is not to be construed as an admission that such documents, or such sources of information, in any jurisdiction, are prior art, or form part of the common general knowledge in the art.
Experimental ures: Abbreviations (as used hereinbefore or hereinafter): AP Aqueous layer aq. Aqueous Bu Butyl such as in n-Bu = n-butyl conc. Concentrated DCM Dichloromethane EDCl 1-Ethyl(3-dimethylaminopropyl)carbodiimide eq Equivalent(s) Et Ethyl EtOAc Ethyl acetate EtOH Ethanol Fig Figure h Hour(s) 1H-NMR Nuclear magnetic resonance of the proton HOBt 1-Hydroxy-benzotriazole mono e HPLC High mance liquid chromatography IPC cess control LC-MS Liquid chromatography – Mass Spectrometry Me Methyl MeCN Acetonitrile MeOH Methanol mW milli-Watt min Minute(s) MS Mass spectrometry N Normality NMR Nuclear magnetic resonance prep. Preparative RH relative humidity RT Room temperature sat. Saturated sec Second(s) Te External ature Ti Internal temperature TFA trifluoroacetic acid THF Tetrahydrofuran tR Retention time UPLC Ultra Performance Liquid Chromatography UV Ultra violet vol. L solvent per kg starting material XRPD X-ray powder diffraction All solvents and reagents are used as obtained from commercial sources unless otherwise Temperatures are indicated in degrees Celsius (°C). Unless otherwise indicated, the reactions take place at room temperature (RT).
In mixtures, relations of parts of solvent or eluent or t mixtures in liquid form are given as volume relations (v/v), unless indicated ise.
Compounds described in the invention are characterized by UPLC and chiral HPLC (retention time tR is given in min using the conditions listed below).
Analytical UPLC conditions as used in the Examples below: UPLC analyses are performed using the following elution condition: Analytical UPLC on YMC Triart ExRS (Part. No. TAR08S03-1003PTH) column (100mm x 3.0 mm, 3µm); nt of 20mM Ammonium acetate + 10 mM NH4PF6 buffer / Acetonitrile 95/5 (A) and Acetonitrile / Ammonium acetate 10 mM (B) from 8% to 100% B over 19 min; flow rate 0.5 ml/min, detection at 210 nm.
Analytical HPLC over a chiral stationary phase are med on a Chiralpak AD-H (4.6 X 250 mm, 5 µm) column. Typical conditions of chiral HPLC are an isocratic mixture of Hexane/Ethanol/TFA (80:20:0.1 v/v/v), at a flow rate of 0.8 mL/min., at 40 °C; detection at 247 nm.
X-ray powder diffraction analysis (XRPD) X-ray powder diffraction patterns were collected on a Bruker D8 Advance X-ray diffractometer equipped with a Lynxeye detector operated with CuKa-radiation in reflection mode (coupled two Theta). Typically, the X-ray tube was run at of 40kV/40mA. A step size of 0.02° (2?) and a step time of 76.8 sec over a scanning range of 3 - 50° in 2? were applied. The divergence slits were set to fixed 0.3°. Powders were slightly pressed into a silicon single crystal sample holder with depth of 0.5 mm and samples were rotated in their own plane during the measurement. Diffraction data are reported without application of Ka2 stripping. The accuracy of the 2? values as provided herein is in the range of +/- 0.1-0.2° as it is lly the case for conventionally recorded X-ray powder diffraction patterns.
Gravimetric vapour on (GVS) analysis Measurements were performed on an IGASORP Model HAS080 moisture sorption instrument (Hiden ma, Warrington, UK) operated in stepping mode at 25°C. The sample was allowed to equilibrate at the starting relative humidity (RH) before starting a predefined humidity program in steps of 5% ?RH and with a l equilibration time of 24 hours per step. About 20 to 30 mg of each sample was used.
I-Chemistry (S)(3-methoxypyrrolidinyl)phenylpyrimidinecarboxylic acid, butyl (R)(2-amino (diethoxyphosphoryl)propanoyl)piperazinecarboxylate and 4-((R){[6-((S)methoxy- idinyl)phenyl-pyrimidinecarbonyl]-amino}phosphono-propionyl)-piperazine carboxylic acid butyl ester UND) can be prepared according to the procedures given in (S)(3-methoxypyrrolidinyl)phenylpyrimidinecarboxylic acid can be transferred into sodium (S)(3-methoxypyrrolidinyl)phenylpyrimidinecarboxylate in presence of aqueous sodium hydroxide.
II. Preparation of crystalline forms of COMPOUND·HCl Example 1A: Preparation and characterization of COMPOUND·HCl in crystalline form 1 A 15 L reactor was charged with sodium (S)(3-methoxypyrrolidinyl)phenylpyrimidine- 4-carboxylate (584 g, 1.82 mol) and 1-hydroxy-benzotriazole mono hydrate (HOBt) (274 g, 1.1 eq.). Water (1305 mL, 2.0 vol.) was added. The pH of the suspension was 5-6. Butyl (R)- 4-(2-amino(diethoxyphosphoryl)propanoyl)piperazinecarboxylate (665.7 g, 1.0 eq) was dissolved in tetrahydrofurane (THF) (1960 ml, 3.0 vol.). The solution was added to the reaction at 20 to 30 °C during 5 to 10 min. A solution of 1-ethyl(3- dimethylaminopropyl)carbodiimide (EDCl) (389 g, 1.2 eq.) in water (1305 ml, 2.0 vol.) was added to the reaction at 20 to 30 °C during 15 to 30 min. The pH of the reaction stayed between 6-7. The reaction was stirred during 4 h at 20 to 30 °C. An IPC showed 93% conversion. The reaction was diluted with dichloromethane (DCM) (3265 ml, 5.0 vol.) and ½ sat. aq. sodium hydrogencarbonat on (3265 ml, 5.0 vol.). The layers were separated.
The organic layer was washed again with ½ sat. aq. sodium hydrogencarbonat solution (3265 ml, 5.0 vol.). The layers were separated. An IPC showed the complete l of HOBt. The c layer was washed with aq. 10% citric acid (3265 ml, 5.0 vol.). In total 3.75 L of solvents were distilled off at minimal 800 mbar and Te = 75 to 80 °C during 40 min. The residual solution was cooled to 20 to 30 °C. Aq. 32% HCl (3 L, 19 eq.) was added during 5 to min at 20 to 30 °C. An IPC after 4 h of stirring showed complete hydrolysis. Water (5.2 L, 8 vol.) was added at 20 to 30 °C. The reaction was diluted with DCM (5.2 L, 8 vol.). The layers were separated. The s layer was extracted again 2 x with DCM (2x 5.2 L, 8 vol.). All DCM layers were combined and filtered h a polycap 75 HD filter. In total 14 L of solvents were distilled off during 2 h at atmospheric pressure and Te = 75 to 80 °C.
Acetone (21.6 L, 33 vol. ) was added to the refluxing reaction mixture at Te = 70 to 75 °C. To the refluxing fine suspension water (325 mL, 0.5 vol.) was added. The fine, pale suspension was stirred at reflux during 1.5 h and a thick white slurry was obtained. The slurry was cooled to Ti = 25 °C during 1 h (ramp). The solid product was isolated by filtration. The filter cake was rinsed with acetone (4.5 L, 7 vol.) and was dried by blowing nitrogen through it to give 750 g (69%) of 4-((R){[6-((S)methoxy-pyrrolidinyl)phenyl-pyrimidinecarbonyl]- amino}phosphono-propionyl)-piperazinecarboxylic acid butyl ester hydrochloride as a white solid.
Table 1: terisation data for COMPOUND·HCl in crystalline form 1 que Data Summary s XRPD Crystalline see Fig. 1 1H-NMR Consistent Elemental analysis Corresponds Purity (UPLC, Area %) 98.6% Moisture sorption at Profile measured from low RH to high RH see Fig. 4 Example 1B: Preparation and characterization of COMPOUND·HCl in crystalline form 1 An enamelled reactor was charged with water (10.5 L; 1.6 vol.), sodium (S)(3- methoxypyrrolidinyl)phenylpyrimidinecarboxylate (6.06 kg; 18.87 mol, 1.12 eq) and 1-hydroxy-benzotriazole mono hydrate (HOBt) (2.71 kg; 17.70 mol; 1.08 eq.). The ing white suspension was stirred during 60 min at 21 °C. A yellow solution of butyl (R)(2- amino(diethoxyphosphoryl)propanoyl)piperazinecarboxylate (6.47 kg, 16.45 mol, 1.0 eq.) in THF (41 kg, 46.6 L, 7.2 vol.) was transferred into a stirring tank via inline filter. After addition of this solution into the reactor within 12 min at 20 °C a solution of 1-ethyl(3- dimethylaminopropyl)carbodiimide (EDCl) (4.00 kg; 20.8 mol; 1.26 eq.) in water (13.5 L; 2.1 vol.) was added within 13 min at 20 °C. The reaction was stirred during 64 h at 20 °C. At 20 °C aq. 3.7% NaHCO3 (32 L; 5.0 vol.) was added into the reactor followed by dichloromethane (DCM) (32 L; 5.0 vol.). The mixture was stirred during 10 min at 20 °C. After layer separation the pH of the s layer (AP) was 8-9. The AP was extracted again with DCM (16 L; 2.5 vol.). The combined c layers were charged into the reactor (total volume = 94 L) and were washed with aq. 3.7% NaHCO3 (32 L; 5.0 vol.). After layer separation the pH was 10.
The resulting organic layer was washed with aq. 10% citric acid (32 L; 5.0 vol.). The yellow solution was concentrated to a final volume of 5.5 vol. of butyl 4-((R)(diethoxyphosphoryl)- 2-(6-((S)methoxypyrrolidinyl)phenylpyrimidinecarboxamido)propanoyl)piperazine- oxylate at 55 °C and not below a pressure of 585 mbar. 52 L solvent were removed within 5 h.
The concentrated organic solution was treated with aq. 33% HCl (33 L; 5.1 vol.). The reaction mixture was stirred during 12 h at 20 to 30 °C. An IPC showed complete conversion into free phosphonate. At 20 to 30 °C water (53 L; 8.2 vol.) was added into the reactor followed by DCM (53 L; 8.2 vol.). The layers were separated. The aqueous layer was ted 2 x with DCM (53 L; 8.2 vol.). The organic layers were ed and trated at Ti = 50 °C and a pressure not below 900 mbar. 76 L of solvents were removed. Acetone (56 L; 8.7 vol.) was added without interrupting the distillation. The distillation was continued at Ti = 50 °C until a final amount of 7 vol. remained. The re was not below 500 mbar.
The concentrated solution was diluted with acetone (120 L; 18.5 vol.). The concentrated solution was stirred at Ti = 50 °C. A white suspension was formed. Within 30 minutes the white suspension was diluted with water (3.4 L; 0.5 vol.) and was stirred during 3.5 h at Ti = 56 °C. The suspension was cooled to 20 to 30 °C within 2 h and stirred at this temperature for 1.5 h. The thick, white suspension was filtered off. The filter cake was washed twice with acetone (2x 24 L; 3.7 vol.) and was dried on the filter to give 7.67 kg of ((R)(4- (butoxycarbonyl)piperazinyl)(6-((S)methoxypyrrolidinyl)phenylpyrimidine amido)oxopropyl)phosphonic acid hydrochloride.
Table 2: Characterisation data for COMPOUND·HCl in crystalline form 1 Technique Data Summary Remarks XRPD Crystalline corresponds to Fig. 1 1H-NMR Consistent Purity (UPLC, Area %) 99.8% Moisture on at Profile measured from low RH to high RH corresponds to °C Fig. 4 e 2: Preparation and characterization of COMPOUND·HCl in crystalline form 2 COMPOUND·HCl in crystalline form 1 (100mg), as obtained by the s described in example 1A, was allowed to equilibrate at a relative humidity of >90% and room temperature for 3 days. The sample was then allowed to equilibrate at 40% RH and room temperature for 1 day to give COMPOUND·HCl in crystalline form 2.
Table 3: Characterisation data for COMPOUND·HCl in crystalline form 2 Technique Data Summary Remarks XRPD Crystalline see Fig. 2 1H-NMR Consistent Moisture sorption Profile measured from high RH to low RH see Fig. 5 at 25°C e 3A: Preparation and characterization of COMPOUND·HCl in crystalline form 3 ND·HCl in lline form 2 ), as obtained by the process described in example 2, was allowed to equilibrate in a dry en gas stream (400mL/min) at room temperature for 1 day. The sample was then d to equilibrate at 40% RH and room temperature for 1 day to give COMPOUND·HCl in crystalline form 3.
Table 4: Characterisation data for COMPOUND·HCl in crystalline form 3 Technique Data Summary Remarks XRPD Crystalline see Fig. 3 Moisture sorption Profile measured from low RH to high RH see Fig. 6 at 25°C Example 3B: Preparation and characterization of COMPOUND·HCl in crystalline form 3 by re-crystallization An enamelled reactor was rinsed with acetone (20 L). 4-((R){[6-((S)methoxy-pyrrolidin- 1-yl)phenyl-pyrimidinecarbonyl]-amino}phosphono-propionyl)-piperazinecarboxylic acid butyl ester hydrochloride (1.70 kg), water (1.28 L, 0.75 vol.) and acetone (8.5 L, 5 vol.) were charged and the mixture was heated to Ti = 40 °C for 34 min. Additional acetone (17 L, vol.) was added over 47 min. The mixture was further d for 37 min at Ti = 40 °C and cooled to Ti = 20 °C over 67 min. After 2 h at Ti = 20 °C the suspension was slowly filtered over 2h and the crystalline solid was washed twice with acetone (2x 10 L, 5.9 vol.).
Prolonged drying on the suction filter gave COMPOUND·HCl in crystalline form 3.
Table 5: Characterisation data for COMPOUND·HCl in crystalline form 3 que Data Summary Remarks XRPD Crystalline corresponds to Fig. 3 1H-NMR Consistent
Claims (15)
1. A crystalline form of 4-((R){[6-((S)methoxy-pyrrolidinyl)phenyl-pyrimidine- 4-carbonyl]-amino}phosphono-propionyl)-piperazinecarboxylic acid butyl ester hloride, characterized by the presence of peaks in the X-ray powder diffraction 5 diagram at the following angles of refraction 2?: 4.0°, 5.0°, and 15.3°, n the X-ray powder diffraction diagram is obtained by using combined Cu Ka1 and Ka2 radiation, without Ka2 stripping.
2. A crystalline form of 4-((R){[6-((S)methoxy-pyrrolidinyl)phenyl-pyrimidine- 10 4-carbonyl]-amino}phosphono-propionyl)-piperazinecarboxylic acid butyl ester hydrochloride according to claim 1, characterized by the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2?: 4.0°, 5.0°, 11.7°, 15.3°, and 19.3°, wherein the X-ray powder diffraction diagram is ed by using combined Cu Ka1 and Ka2 ion, without Ka2 ing.
3. A crystalline form of 4-((R){[6-((S)methoxy-pyrrolidinyl)phenyl-pyrimidine- 4-carbonyl]-amino}phosphono-propionyl)-piperazinecarboxylic acid butyl ester hydrochloride according to claim 1, terized by the presence of peaks in the X-ray powder diffraction diagram at the ing angles of refraction 2?: 4.0°, 5.0°, 5.9°, 11.7°, 20 15.3°, 16.9°, 19.3°, 19.7°, and 20.7°, wherein the X-ray powder diffraction diagram is obtained by using combined Cu Ka1 and Ka2 radiation, t Ka2 stripping.
4. A process for the preparation of 4-((R){[6-((S)methoxy-pyrrolidinyl)phenylpyrimidinecarbonyl ]-amino}phosphono-propionyl)-piperazinecarboxylic acid butyl 25 ester hydrochloride in a crystalline form according to any one of claims 1 to 3, wherein the process comprises the following steps: a. addition of acetone (10 to 30 vol.) to a solution comprising 4-((R){[6-((S) methoxy-pyrrolidinyl)phenyl-pyrimidinecarbonyl]-amino}phosphonopropionyl )-piperazinecarboxylic acid butyl ester hydrochloride and a non-polar 30 solvent (0.5 to 3.0 vol.) at 45 to 60°C, wherein the non-polar solvent is selected from (C1-2)chloroalkane; b. addition of water (0.3 to 0.7 vol.) at 45 to 60°C; c. stirring of the mixture under cooling from a temperature of 45 to 60°C to a temperature at or below 30°C for at least 1h; and d. ion of the obtained crystalline material.
5. A process according to claim 4, wherein the amount of the non-polar solvent in step a. is 5 1.0 to 2.0 vol. and wherein the non-polar solvent is dichloromethane.
6. A process according to any one of claims 4 or 5, wherein the mixture is stirred in step c. between 1 and 4h at a temperature of 45 to 60°C and is subsequently cooled to a temperature n 20 and 30°C during 1 to 2h.
7. A crystalline form of 4-((R){[6-((S)methoxy-pyrrolidinyl)phenyl-pyrimidine- 10 4-carbonyl]-amino}phosphono-propionyl)-piperazinecarboxylic acid butyl ester hydrochloride according to any one of claims 1 to 3, for use as a medicament.
8. A pharmaceutical composition comprising as active ingredient a crystalline form of 4-((R)- 2-{[6-((S)methoxy-pyrrolidinyl)phenyl-pyrimidinecarbonyl]-amino}phosphonopropionyl )-piperazinecarboxylic acid butyl ester hydrochloride according to any one of 15 claims 1 to 3, and at least one ceutically acceptable carrier.
9. A crystalline form of 4-((R){[6-((S)methoxy-pyrrolidinyl)phenyl-pyrimidine- onyl]-amino}phosphono-propionyl)-piperazinecarboxylic acid butyl ester hydrochloride according to any one of claims 1 to 3, for use in the manufacture of a pharmaceutical composition, wherein said ceutical composition ses as active 20 ient 4-((R){[6-((S)methoxy-pyrrolidinyl)phenyl-pyrimidinecarbonyl]- amino}phosphono-propionyl)-piperazinecarboxylic acid butyl ester hydrochloride, and at least one pharmaceutically acceptable carrier material.
10. Use of a crystalline form of 4-((R){[6-((S)methoxy-pyrrolidinyl)phenylpyrimidinecarbonyl ]-amino}phosphono-propionyl)-piperazinecarboxylic acid butyl 25 ester hydrochloride according to any one of claims 1 to 3, in the preparation of a ment for the prevention or treatment of diseases selected from the group consisting of acute coronary syndromes, peripheral ischaemia, amaurosis, ischaemic stroke and transient mic attack.
11. Use according to claim 10, wherein the disease is acute coronary syndromes. 30
12. A crystalline form of 4-((R){[6-((S)methoxy-pyrrolidinyl)phenyl-pyrimidine- 4-carbonyl]-amino}phosphono-propionyl)-piperazinecarboxylic acid butyl ester hydrochloride as claimed in any one of claims 1 to 3 substantially as herein described and with reference to any example thereof.
13. A process as claimed in any one of claims 4 to 6 substantially as herein described and with reference to any example thereof.
14. A pharmaceutical ition as d in claim 8 substantially as herein described and with reference to any example thereof. 5
15. A use as claimed in any one of claims 10 or 11 substantially as herein described and with reference to any example thereof.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP2016072562 | 2016-09-22 | ||
| PCT/EP2017/073858 WO2018055016A1 (en) | 2016-09-22 | 2017-09-21 | Crystalline forms |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| NZ750772A NZ750772A (en) | 2023-10-27 |
| NZ750772B2 true NZ750772B2 (en) | 2024-01-30 |
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