NZ788605A - Polymorphs of n-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide and salts thereof - Google Patents

Polymorphs of n-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide and salts thereof

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NZ788605A
NZ788605A NZ788605A NZ78860517A NZ788605A NZ 788605 A NZ788605 A NZ 788605A NZ 788605 A NZ788605 A NZ 788605A NZ 78860517 A NZ78860517 A NZ 78860517A NZ 788605 A NZ788605 A NZ 788605A
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New Zealand
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methyl
methoxymethyl
phenyl
pyrazolecarboxamide
oxopyridinyl
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NZ788605A
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Haydn Beaton
David Malcolm Crowe
Hannah Joy Edwards
Haynes Nicholas James Griffiths
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Kalvista Pharmaceuticals Limited
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Publication of NZ788605A publication Critical patent/NZ788605A/en

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Abstract

The invention provides new polymorphs of N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide and salts thereof, pharmaceutical compositions containing them and their use in therapy.

Description

POLYMORPHS OF FLUOROMETHOXYPYRIDINYL)METHYL](METHOXYMETHYL)({4-[(2- IDINYL)METHYL]PHENYL}METHYL)PYRAZOLECARBOXAMIDE AND SALTS THEREOF The present invention relates to new polymorphs of a plasma kallikrein inhibitor, a pharmaceutical composition containing them and their use in therapy. ound to the Invention Inhibitors of plasma kallikrein have a number of therapeutic applications, particularly in the treatment of retinal ar permeability associated with diabetic retinopathy, diabetic macular edema and hereditary angioedema.
Plasma kallikrein is a trypsin-like serine protease that can liberate kinins from kininogens (see K. D.
Bhoola et al., krein-Kinin Cascade", Encyclopedia of Respiratory Medicine, p483-493; J. W. Bryant et al., "Human plasma kallikrein-kinin system: physiological and biochemical ters" Cardiovascular and ological agents in medicinal chemistry, 7, p234-250, 2009; K. D. Bhoola et al., Pharmacological Rev., 1992, 44, 1; and D. J. Campbell, "Towards tanding the kallikrein-kinin system: insights from the measurement of kinin peptides", ian Journal of Medical and Biological Research 2000, 33, 665-677). It is an ial member of the intrinsic blood coagulation cascade although its role in this cascade does not involve the release of bradykinin or enzymatic cleavage.
Plasma prekallikrein is encoded by a single gene and synthesized in the liver. It is secreted by hepatocytes as an inactive plasma prekallikrein that circulates in plasma as a heterodimer complex bound to high molecular weight gen which is activated to give the active plasma kallikrein. Kinins are potent mediators of inflammation that act h G protein-coupled receptors and antagonists of kinins (such as bradykinin antagonists) have previously been investigated as potential therapeutic agents for the treatment of a number of disorders (F. Marceau and D. Regoli, Nature Rev., Drug Discovery, 2004, 3, 845-852).
Plasma kallikrein is thought to play a role in a number of inflammatory disorders. The major tor of plasma kallikrein is the serpin C1 esterase inhibitor. Patients who present with a genetic deficiency in C1 esterase inhibitor suffer from hereditary angioedema (HAE) which results in intermittent swelling of face, hands, throat, gastro-intestinal tract and genitals. rs formed during acute episodes contain high levels of plasma kallikrein which cleaves high molecular weight kininogen liberating bradykinin leading to increased vascular permeability. Treatment with a large protein plasma kallikrein inhibitor has been shown to effectively treat HAE by preventing the release of bradykinin which causes increased vascular permeability (A. Lehmann "Ecallantide (DX-88), a plasma kallikrein inhibitor for the treatment of hereditary dema and the prevention of blood loss in on-pump cardiothoracic surgery" Expert Opin. Biol. Ther. 8, p1187-99).
The plasma kallikrein-kinin system is abnormally abundant in patients with advanced diabetic macular edema. It has been recently published that plasma kallikrein contributes to retinal vascular dysfunctions in diabetic rats (A. Clermont et al. "Plasma kallikrein mediates retinal vascular dysfunction and induces retinal thickening in diabetic rats" Diabetes, 2011, 60, p1590-98). rmore, stration of the plasma kallikrein inhibitor ASP-440 ameliorated both retinal vascular permeability and retinal blood flow abnormalities in diabetic rats. Therefore a plasma kallikrein inhibitor should have utility as a treatment to reduce retinal vascular permeability associated with diabetic retinopathy and diabetic macular edema.
Plasma kallikrein also plays a role in blood coagulation. The intrinsic coagulation cascade may be activated by factor XII (FXII). Once FXII is ted (to FXIIa), FXIIa triggers fibrin formation through the activation of factor XI (FXI) thus ing in blood coagulation. Plasma kallikrein is a key component in the intrinsic coagulation cascade because it activates FXII to FXIIa, thus resulting in the activation of the intrinsic ation pathway. Furthermore, FXIIa also activates further plasma prekallikrein resulting in plasma kallikrein. This s in positive feedback amplification of the plasma kallikrein system and the intrinsic coagulation y (Tanaka et al. bosis Research 2004, 113, 333-339); Bird et al.
(Thrombosis and Haemostasis, 2012, 107, 1141-50).
Contact of FXII in the blood with vely charged surfaces (such as the es of external pipes or the membrane of the ator that the blood passes during cardiopulmonary bypass surgery) induces a conformational change in n FXII ing in a small amount of active FXII (FXIIa). The formation of FXIIa triggers the formation of plasma kallikrein ing in blood coagulation, as described above.
Activation of FXII to FXIIa can also occur in the body by contact with negatively charged surfaces on various sources (e.g. bacteria during sepsis, RNA from degrading cells), thus resulting in disseminated intravascular coagulation (Tanaka et al. (Thrombosis Research 2004, 113, 333-339)).
Therefore, inhibition of plasma kallikrein would inhibit the blood coagulation cascade described above, and so would be useful in the treatment of disseminated ascular coagulation and blood coagulation during cardiopulmonary bypass surgery where blood coagulation is not desired. For example, ra et al. (Thrombosis ch, 1996, 82, 361–368) showed that administration of a plasma kallikrein inhibitor, PKSI-527, for LPS-induced disseminated intravascular coagulation significantly suppressed the decrease in platelet count and ogen level as well as the increase in FDP level which usually occur in disseminated intravascular coagulation. Bird et al. (Thrombosis and Haemostasis, 2012, 107, 1141-50) showed that clotting time increased, and thrombosis was significantly reduced in plasma kallikrein-deficient mice. Revenko et al. , 2011, 118, 5302-5311) showed that the reduction of plasma prekallikrein levels in mice using antisense oligonucleotide treatment resulted in antithrombotic effects. Tanaka et al. (Thrombosis Research 2004, 113, 333-339) showed that ting blood with DX-88 (a plasma kallikrein inhibitor) resulted in an increase in activated clotting time (ACT). Lehmann et al. (Expert Opin. Biol. Ther. 2008, 1187-99) showed that Ecallantide (a plasma kallikrein inhibitor) was found to delay contact activated induced coagulation. n et al. conclude that Ecallantide “had in vitro anticoagulant effects as it inhibited the intrinsic pathway of ation by inhibiting plasma kallikrein”.
Plasma kallikrein also plays a role in the inhibition of platelet tion, and therefore the cessation of bleeding. Platelet activation is one of the earliest steps in hemostasis, which leads to platelet plug formation and the rapid cessation of bleeding ing damage to blood vessels. At the site of vascular injury, the interaction between the exposed collagen and platelets is critical for the retention and activation of platelets, and the subsequent cessation of bleeding.
Once activated, plasma kallikrein binds to collagen and thereby interferes with collagen-mediated activation of ets mediated by GPVI receptors (Liu et al. (Nat Med., 2011, 17, 206–210)). As discussed above, plasma kallikrein inhibitors reduce plasma likrein activation by inhibiting plasma kallikrein-mediated tion of factor XII and thereby reducing the positive feedback amplification of the kallikrein system by the contact activation system.
Therefore, inhibition of plasma kallikrein reduces the binding of plasma kallikrein to collagen, thus reducing the interference of plasma kallikrein in the cessation of bleeding. Therefore plasma kallikrein tors would be useful in the treatment of treating cerebral haemorrhage and bleeding from post operative surgery. For example, Liu et al. (Nat Med., 2011, 17, 206–210) demonstrated that systemic stration of a small molecule PK inhibitor, ASP-440, reduced hematoma expansion in rats. Cerebral hematoma may occur following intracerebral rhage and is caused by bleeding from blood vessels into the surrounding brain tissue as a result of vascular injury. Bleeding in the cerebral haemorrhage model reported by Liu et al. was induced by surgical intervention involving an incision in the brain parenchyma that d blood vessels. These data demonstrate that plasma rein inhibition reduced bleeding and hematoma volume from post operative surgery. Björkqvist et al. (Thrombosis and Haemostasis, 2013, 110, 399- 407) demonstrated that aprotinin (a protein that inhibits serine proteases including plasma kallikrein) may be used to decrease postoperative bleeding.
Other complications of diabetes such as cerebral haemorrhage, nephropathy, cardiomyopathy and neuropathy, all of which have associations with plasma kallikrein may also be considered as targets for a plasma kallikrein inhibitor.
Synthetic and small molecule plasma kallikrein inhibitors have been described usly, for example by Garrett et al. ("Peptide aldehyde…." J. Peptide Res. 52, p62-71 ), T. Griesbacher et al.
("Involvement of tissue kallikrein but not plasma kallikrein in the development of symptoms mediated by endogenous kinins in acute pancreatitis in rats" British Journal of cology 137, p692-700 (2002)), Evans ("Selective dipeptide inhibitors of kallikrein" WO03/076458), Szelke et al. ("Kininogenase inhibitors" WO92/04371), D. M. Evans et al. (Immunolpharmacology, 32, p115-116 (1996)), Szelke et al. nogen inhibitors" WO95/07921), Antonsson et al. ("New peptides derivatives" WO94/29335), J.
Corte et al. (”Six membered heterocycles useful as serine protease inhibitors” /123680), J.
Stürzbecher et al. lian J. Med. Biol. Res 27, p1929-34 (1994)), Kettner et al. (US 5,187,157), N. Teno et al. (Chem. Pharm. Bull. 41, p1079-1090 (1993)), W. B. Young et al. ("Small molecule inhibitors of plasma kallikrein" Bioorg. Med. Chem. Letts. 16, p2034-2036 (2006)), Okada et al. lopment of potent and selective plasmin and plasma kallikrein inhibitors and studies on the structure-activity relationship" Chem. Pharm. Bull. 48, p1964-72 (2000)), Steinmetzer et al. ("Trypsin-like serine protease inhibitors and their preparation and use" WO08/049595), Zhang et al. ("Discovery of highly potent small molecule rein inhibitors" Medicinal Chemistry 2, p545-553 ), Sinha et al. ("Inhibitors of plasma kallikrein" 16883), Shigenaga et al. (“Plasma Kallikrein Inhibitors” WO2011/118672), and Kolte et al. (“Biochemical terization of a novel high-affinity and specific kallikrein inhibitor”, British Journal of Pharmacology (2011), 162(7), 1639-1649). Also, Steinmetzer et al. (“Serine protease inhibitors” WO2012/004678) describes cyclized peptide analogs which are tors of human plasmin and plasma kallikrein.
To date, no small molecule tic plasma kallikrein inhibitor has been approved for medical use.
Many of the molecules described in the known art suffer from limitations such as poor selectivity over related enzymes such as KLK1, thrombin and other serine proteases, and poor oral availability. The large protein plasma rein inhibitors present risks of anaphylactic reactions, as has been ed for Ecallantide. Thus there remains a need for compounds that selectively inhibit plasma kallikrein, that do not induce anaphylaxis and that are orally ble. Furthermore, the vast majority of molecules in the known art feature a highly polar and ionisable ine or amidine functionality. It is well known that such functionalities may be limiting to gut permeability and therefore to oral availability. For example, it has been reported by Tamie J. te and Sukanto Sinha (“ASP-634: An Oral Drug Candidate for Diabetic MacularEdema”, ARVO 2012 May 6th – May 9th, 2012, Fort Lauderdale, Florida, Presentation 2240) that ASP-440, a benzamidine, suffers from poor oral availability. It is further reported that absorption may be improved by creating a prodrug such as 4. However, it is well known that prodrugs can suffer from several drawbacks, for example, poor chemical ity and potential toxicity from the inert carrier or from unexpected lites. In another report, indole amides are claimed as compounds that might overcome problems associated with drugs possessing poor or inadequate ADME- tox and physicochemical properties although no inhibition against plasma kallikrein is presented or claimed (Griffioen et al, “Indole amide derivatives and related compounds for use in the treatment of neurodegenerative diseases”, WO2010/142801).
BioCryst Pharmaceuticals Inc. have reported the discovery of the orally available plasma kallikrein inhibitor BCX4161 (“BCX4161, An Oral Kallikrein Inhibitor: Safety and cokinetic Results Of a Phase 1 Study In Healthy Volunteers”, Journal of Allergy and Clinical Immunology, Volume 133, Issue 2, Supplement, February 2014, page AB39 and “A Simple, Sensitive and Selective genic Assay to Monitor Plasma rein Inhibitory Activity of 1 in Activated Plasma”, Journal of Allergy and al logy, Volume 133, Issue 2, Supplement February 2014, page AB40). However, human doses are relatively large, tly being tested in proof of concept studies at doses of 400 mg three times daily.
There are only few reports of plasma kallikrein inhibitors that do not feature guanidine or amidine functionalities. One example is Brandl et al. (“N-((6-amino-pyridinyl)methyl)-heteroaryl-carboxamides as inhibitors of plasma kallikrein” WO2012/017020), which describes compounds that e an amino- pyridine functionality. Oral efficacy in a rat model is demonstrated at relatively high doses of 30 mg/kg and 100 mg/kg but the pharmacokinetic profile is not reported. Thus it is not yet known whether such compounds will provide sufficient oral availability or efficacy for progression to the clinic. Other examples are Brandl et al. (“Aminopyridine derivatives as plasma kallikrein inhibitors” WO2013/111107) and Flohr et al. (“5-membered heteroarylcarboxamide derivatives as plasma kallikrein inhibitors” WO2013/111108). However, neither of these documents report any in vivo data and therefore it is not yet known whether such compounds will provide sufficient oral availability or cy for progression to the clinic. Another example is Allan et al. “Benzylamine derivatives” WO2014/108679.
In the manufacture of pharmaceutical ations, it is important that the active compound be in a form in which it can be conveniently handled and processed in order to obtain a commercially viable manufacturing process. Accordingly, the chemical stability and the physical stability of the active compound are important factors. The active compound, and formulations containing it, must be capable of being effectively stored over appreciable s of time, without exhibiting any significant change in the physico-chemical teristics (e.g. chemical composition, density, hygroscopicity and solubility) of the active nd.
It is known that manufacturing a particular solid-state form of a ceutical ingredient can affect many aspects of its solid state properties and offer advantages in aspects of solubility, dissolution rate, chemical stability, mechanical properties, cal feasibility, processability, pharmacokinetics and bioavailability. Some of these are described in ook of Pharmaceutical Salts; Properties, Selection and Use", P. Heinrich Stahl, Camille G. Wermuth (Eds.) (Verlag Helvetica Chimica Acta, Zurich). Methods of cturing solid-state forms are also described in "Practical s ch and Development", Neal G. Anderson (Academic Press, San Diego) and "Polymorphism: In the Pharmaceutical ry", Rolf Hilfiker (Ed) (Wiley VCH). Polymorphism in pharmaceutical ls is described in Byrn (Byrn, S.R., Pfeiffer, R.R., Stowell, J.G., "Solid-State Chemistry of Drugs", SSCI Inc., West Lafayette, Indiana, 1999), Brittain,H.G., "Polymorphism in Pharmaceutical Solids", Marcel , Inc., New York, Basel, 1999) or Bernstein (Bernstein, J., "Polymorphism in Molecular Crystals", Oxford University Press, 2002).
The applicant has developed a novel series of compounds that are inhibitors of plasma kallikrein, which are disclosed in WO2016/083820 (). These compounds demonstrate good selectivity for plasma kallikrein and are ially useful in the treatment of diabetic retinopathy, macular edema and hereditary angioedema. One such compound is N-[(3-fluoromethoxypyridin yl)methyl](methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide.
Initial attempts to prepare N-[(3-fluoromethoxypyridinyl)methyl](methoxymethyl)({4-[(2- idinyl)methyl]phenyl}methyl)pyrazolecarboxamide were med by evaporation of the 1% ammonia-methanol/DCM solvent used during chromatography to yield a foam with XRPD data (recorded using Method B) that shows mainly amorphous content consistent with the solid form referred to herein as ‘Form A’ (Figure 1a). The applicant has now developed novel crystalline forms of this compound, which are herein referred to as ‘Form 1’, ‘Form 2’, ‘Form 3’ and ‘Form 4’. The novel solid forms have advantageous physico-chemical properties that render them suitable for development.
The applicant has also developed novel crystalline salt forms of N-[(3-fluoromethoxypyridin yl)methyl](methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide, specifically novel crystalline hloride, sulfate, phosphate, mesylate, tosylate, ate and besylate salts of N-[(3-fluoromethoxypyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide. The novel solid forms have advantageous physicochemical properties that render them suitable for development, in particular, they have a low copicity and their preparation by crystallisation is simple and le.
Description of the Invention Thus, in accordance with an aspect of the present invention, there is provided crystalline polymorphs of N-[(3-fluoromethoxypyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide. In the present application these polymorphs may be referred to as ‘Form 1’, ‘Form 2’, ‘Form 3’ and ‘Form 4’.
The crystalline polymorphs of the present invention have advantageous physico-chemical properties that render them suitable for development. For example, Gravimetric Vapour Sorption (GVS) data of ‘Form 1’ of N-[(3-fluoromethoxypyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide, Figure 5, under normal conditions (for example, up to 70% relative ty) there is only a relatively gradual increase in water content. This is consistent with the absence of significant hygroscopicity. In st, amorphous materials are typically significantly hygroscopic, or even deliquescent, often rendering the material into an unworkable gum. Furthermore, the absence of weight loss before melt of the sample of Form 1 (see STA data, Figure 3) indicates that Form 1 is not hydrated or solvated. Stable hydrates may be unsuitable for pharmaceutical development because they may induce an rable transformation of the administered anhydrous form of the drug once the drug meets the aqueous environment of the human body. Another advantage of the lline polymorphs is that they are more easily processable. That is, their preparation by crystallisation (see Examples) is a common and easily scalable procedure to remove undesirable impurities.
Further evidence of the suitability of the crystalline forms of N-[(3-fluoromethoxypyridin yl)methyl](methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide for pharmaceutical development is provided by the stability data disclosed herein. Two samples of Form 1 of N-[(3-fluoromethoxypyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide were stored at 25°C/60% RH and 40°C/75% RH packed in double polyethylene bags and sealed in a HDPE bottle. At the initial timepoint, XRPD showed the sample to be crystalline and consistent with the Form 1 polymorph. Under the e conditions of °C/60% RH and 40°C/75% RH, XRPD showed no change after 1 month and after 3 months es 46 and 47).
The solubility of the free base in water of fluoromethoxypyridinyl)methyl] (methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide was relatively low (<0.5 mg/mL), and therefore salts of N-[(3-fluoromethoxypyridinyl)methyl] (methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide were investigated.
In a further aspect of the present invention, there is provided crystalline polymorphs of N-[(3-fluoro methoxypyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide salts, ically crystalline polymorphs of N-[(3- fluoromethoxypyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide hloride; N-[(3-fluoromethoxypyridin yl)methyl](methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide sulfate; N-[(3-fluoromethoxypyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide phosphate; N-[(3-fluoromethoxypyridin yl)methyl](methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide mesylate; N-[(3-fluoromethoxypyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide te; N-[(3-fluoromethoxypyridinyl)methyl]- 3-(methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide edisylate; and N-[(3-fluoromethoxypyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide besylate.
Furthermore, the present invention provides specific crystalline polymorphs of N-[(3-fluoro methoxypyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide hydrochloride which are herein referred to as ‘Form ’, ‘Form 6’, ‘Form 7’, and ‘Form 18’.
Furthermore, the present invention es a specific crystalline polymorph of N-[(3-fluoro methoxypyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide sulfate which is herein referred to as ‘Form 8’.
Furthermore, the present invention es specific crystalline polymorphs of N-[(3-fluoro ypyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide phosphate which are herein referred to as ‘Form 9’, ‘Form 10’, and ‘Form 11’.
Furthermore, the present invention provides specific crystalline rphs of N-[(3-fluoro methoxypyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin hyl]phenyl}methyl)pyrazolecarboxamide mesylate which are herein referred to as ‘Form 12’, and ‘Form 13’.
Furthermore, the present invention provides a ic crystalline polymorph of N-[(3-fluoro methoxypyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide tosylate which is herein referred to as ‘Form 14’.
Furthermore, the present invention provides specific crystalline polymorphs of fluoro methoxypyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide edisylate which are herein referred to as ‘Form 15’, and ‘Form 16’.
Furthermore, the present invention provides a specific crystalline polymorph of N-[(3-fluoro methoxypyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide besylate which is herein referred to as ‘Form 17’.
The novel crystalline salts of the present invention have advantageous physico-chemical properties that render them suitable for development. For example Form 8 of N-[(3-fluoromethoxypyridin yl)methyl](methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide sulfate shows excellent aqueous solubility, and can be reproducibly scaled-up. For example, Gravimetric Vapour Sorption (GVS) data of Form 8 of fluoromethoxypyridinyl)methyl] xymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide sulfate, Figure 33, under normal conditions (for example, up to 70% relative humidity), show that there is only a relatively gradual increase in water content and that the hydration is reversible. This is consistent with the absence of icant hygroscopicity. Furthermore, the sulfate salt of N-[(3-fluoro methoxypyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide shows a low tendency for rphism, as demonstrated by the single polymorph that was identified during the rph screens disclosed herein.
The name fluoromethoxypyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide denotes the structure depicted in Figure A.
Figure A Four lline polymorphs of N-[(3-fluoromethoxypyridinyl)methyl](methoxymethyl)({4-[(2- oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide have been isolated and characterised to date, which are herein referred to as ‘Form 1’, ‘Form 2’, ‘Form 3’, and ‘Form 4’. Preferably, the crystalline form is Form 1.
Four crystalline polymorphs of N-[(3-fluoromethoxypyridinyl)methyl](methoxymethyl)({4-[(2- oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide hydrochloride have been isolated and characterised to date, which are herein referred to as ‘Form 5’, ‘Form 6’, ‘Form 7’, and ‘Form 18’.
One crystalline polymorph of N-[(3-fluoromethoxypyridinyl)methyl](methoxymethyl)({4-[(2- idinyl)methyl]phenyl}methyl)pyrazolecarboxamide sulfate have been isolated and characterised to date, which is herein referred to as ‘Form 8’.
The term te” as used herein when referring to a salt of N-[(3-fluoromethoxypyridin yl)methyl](methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide is intended to encompass both a mono-sulfate salt and a hemi-sulfate salt. In one embodiment, Form 8 of N-[(3-fluoromethoxypyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide is a mono-sulfate salt. In an alternative embodiment, Form 8 of N-[(3-fluoromethoxypyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide is a ulfate salt.
Three crystalline polymorphs of N-[(3-fluoromethoxypyridinyl)methyl](methoxymethyl)({4- [(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide phosphate have been isolated and characterised to date, which are herein referred to as ‘Form 9’, ‘Form 10’, and ‘Form 11’.
The term “phosphate” as used herein when referring to a salt of N-[(3-fluoromethoxypyridin yl)methyl](methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide is intended to encompass both a mono-phosphate salt and a hemi-phosphate salt. In one embodiment, Forms 9, 10 and 11 of N-[(3-fluoromethoxypyridinyl)methyl](methoxymethyl)({4-[(2- oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide are each independently a monophosphate salt. In an alternative embodiment, Forms 9, 10 and 11 of N-[(3-fluoromethoxypyridin hyl](methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide are each independently a hemi-phosphate salt.
Two crystalline polymorphs of fluoromethoxypyridinyl)methyl](methoxymethyl)({4-[(2- idinyl)methyl]phenyl}methyl)pyrazolecarboxamide mesylate have been ed and characterised to date, which are herein referred to as ‘Form 12’, and ‘Form 13’.
One crystalline polymorph of fluoromethoxypyridinyl)methyl](methoxymethyl)({4-[(2- oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide tosylate has been isolated and characterised to date, which is herein referred to as ‘Form 14’.
Two crystalline polymorphs of N-[(3-fluoromethoxypyridinyl)methyl](methoxymethyl)({4-[(2- oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide edisylate have been isolated and characterised to date, which are herein referred to as ‘Form 15’, and ‘Form 16’.
The term “edisylate” as used herein when referring to a salt of N-[(3-fluoromethoxypyridin hyl](methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide is intended to encompass both a mono-edisylate salt and a hemi-edisylate salt. In one embodiment, Forms 15 and 16 of N-[(3-fluoromethoxypyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin- 1-yl)methyl]phenyl}methyl)pyrazolecarboxamide are each independently a mono-edisylate salt. In an ative embodiment, Forms 15 and 16 of N-[(3-fluoromethoxypyridinyl)methyl] (methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide are each independently a hemi-edisylate salt. Preferably, Forms 15 and 16 of N-[(3-fluoromethoxypyridin yl)methyl](methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide are each independently a mono-edisylate salt.
One crystalline polymorph of N-[(3-fluoromethoxypyridinyl)methyl](methoxymethyl)({4-[(2- oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide besylate has been isolated and characterised to date, which is herein referred to as ‘Form 17’.
The present invention encompasses solvates (e.g. hydrates) of the crystalline forms of N-[(3-fluoro methoxypyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide and salts thereof described herein.
In an aspect of the invention, Form 1 of N-[(3-fluoromethoxypyridinyl)methyl](methoxymethyl)- 1-({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide is not a solvate or a hydrate.
In an aspect of the invention, Form 18 of N-[(3-fluoromethoxypyridinyl)methyl] (methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide hydrochloride is a solvate or a hydrate, preferably a e, more preferably a hemi-hydrate, monohydrate or dihydrate, most preferably a dihydrate.
In an aspect of the invention, Form 8 of fluoromethoxypyridinyl)methyl](methoxymethyl)- 1-({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide sulfate is a solvate or a hydrate, ably a hydrate, more preferably a hemi-hydrate, monohydrate or dihydrate, most preferably a hemi-hydrate.
In an aspect of the invention, Form 15 of fluoromethoxypyridinyl)methyl] (methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide edisylate is a solvate or a hydrate, preferably a hydrate, more preferably a hemi-hydrate, monohydrate or dihydrate.
In an aspect of the invention, Form 16 of fluoromethoxypyridinyl)methyl] (methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide edisylate is a solvate or a hydrate, preferably a hydrate, more ably a hemi-hydrate, monohydrate or dihydrate.
In the present specification, X-ray powder ction peaks (expressed in degrees 2θ) are measured using Cu Kα radiation.
The present invention provides a crystalline form (Form 1) of N-[(3-fluoromethoxypyridin yl)methyl](methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide, which exhibits at least the following characteristic X-ray powder diffraction peaks (Cu Kα radiation, expressed in degrees 2θ) at approximately: (1) 11.2, 12.5, 13.2, 14.5 and 16.3; or (2) 11.2, 12.5, 13.2, 14.5, 16.3, 17.4 and 17.9; or (3) 11.2, 12.5, 13.2, 14.5, 16.3, 17.4, 17.9, 21.2 and 22.0.
The term ximately" means in this context that there is an uncertainty in the measurements of the degrees 2θ of ± 0.3 (expressed in degrees 2θ), preferably ± 0.2 (expressed in degrees 2θ).
The present invention also provides a crystalline form (Form 1) of N-[(3-fluoromethoxypyridin yl)methyl](methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide, having an X ray powder diffraction pattern comprising teristic peaks (expressed in degrees 2θ) at approximately 4.4, 11.2, 12.5, 13.2, 14.5, 16.3, 17.4, 17.9, 21.2, 22.0 and 22.6.
The present invention also es a crystalline form (Form 1) of N-[(3-fluoromethoxypyridin yl)methyl](methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide having an X-ray powder diffraction pattern substantially the same as that shown in Figure 2a.
The X-ray powder diffraction pattern of a polymorphic form may be described herein as "substantially" the same as that depicted in a Figure. It will be appreciated that the peaks in X-ray powder diffraction patterns may be slightly shifted in their positions and ve intensities due to various factors known to the skilled . For example, shifts in peak positions or the relative intensities of the peaks of a n can occur because of the equipment used, method of sample preparation, preferred g and orientations, the ion source, and method and length of data collection. However, the skilled person will be able to compare the X-ray powder diffraction patterns shown in the figures herein with those of an unknown polymorph to confirm the ty of the rph.
The present invention also provides a crystalline form (Form 2) of N-[(3-fluoromethoxypyridin yl)methyl](methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide having an X-ray powder diffraction pattern substantially the same as that shown in Figure 7.
The present invention also provides a crystalline form (Form 3) of N-[(3-fluoromethoxypyridin yl)methyl](methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide having an X-ray powder diffraction pattern substantially the same as that shown in Figure 8.
The present invention also provides a crystalline form (Form 4) of N-[(3-fluoromethoxypyridin yl)methyl](methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide having an X-ray powder diffraction pattern substantially the same as that shown in Figure 9.
The present invention also provides a crystalline form (Form 5) of N-[(3-fluoromethoxypyridin yl)methyl](methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide hydrochloride having an X-ray powder diffraction pattern substantially the same as that shown in Figure The present invention also provides a crystalline form (Form 6) of N-[(3-fluoromethoxypyridin yl)methyl](methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide hydrochloride having an X-ray powder diffraction pattern substantially the same as that shown in Figure The present ion also provides a crystalline form (Form 7) of N-[(3-fluoromethoxypyridin yl)methyl](methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide hydrochloride having an X-ray powder diffraction pattern substantially the same as that shown in Figure The present invention also provides a crystalline form (Form 8) of N-[(3-fluoromethoxypyridin yl)methyl](methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide sulfate, which exhibits at least the ing characteristic X-ray powder diffraction peaks (Cu Kα ion, expressed in degrees 2θ) at approximately: (1) 5.1, 7.5, 12.0, 15.2, and 17.9; or (2) 5.1, 7.5, 12.0, 15.2, 17.9, 20.1 and 22.8; or (3) 5.1, 7.5, 12.0, 15.2, 17.9, 20.1, 22.8, 24.4 and 25.8.
The present invention also es a crystalline form (Form 8) of N-[(3-fluoromethoxypyridin yl)methyl](methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide e, having an X ray powder diffraction pattern comprising characteristic peaks (expressed in degrees 2θ) at imately 5.1, 7.5, 12.0, 13.2, 15.2, 17.9, 18.2, 19.3,20.1, 22.3, 22.8, 24.4 and 25.8.
The present invention also provides a crystalline form (Form 8) of N-[(3-fluoromethoxypyridin yl)methyl](methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide sulfate having an X-ray powder diffraction pattern substantially the same as that shown in Figure 13 or Figure 30 (top).
The present ion also provides a crystalline form (Form 9) of N-[(3-fluoromethoxypyridin yl)methyl](methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide phosphate, which exhibits at least the following teristic X-ray powder diffraction peaks (Cu Kα radiation, expressed in degrees 2θ) at approximately: (1) 4.5, 13.4, 16.3, 17.3 and 18.9; or (2) 4.5, 13.4, 16.3, 17.3, 17.8, 18.9 and 19.3; or (3) 4.5, 13.4, 16.3, 17.3, 17.8, 18.9, 19.3, 20.5 and 23.0.
The present invention also provides a crystalline form (Form 9) of N-[(3-fluoromethoxypyridin yl)methyl](methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide phosphate, having an X ray powder diffraction pattern comprising characteristic peaks (expressed in degrees 2θ) at approximately 4.5, 7.2, 10.1, 13.4, 16.3, 17.3, 17.8, 18.9, 19.3, 20.5, 21.2, 23.0, 25.4 and 27.2.
The present invention also provides a crystalline form (Form 9) of N-[(3-fluoromethoxypyridin yl)methyl](methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide phosphate having an X-ray powder diffraction pattern substantially the same as that shown in Figure 14.
The present invention also provides a crystalline form (Form 10) of N-[(3-fluoromethoxypyridin yl)methyl](methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide phosphate having an X-ray powder diffraction pattern ntially the same as that shown in Figure 15.
The t invention also provides a crystalline form (Form 11) of N-[(3-fluoromethoxypyridin yl)methyl](methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide phosphate having an X-ray powder diffraction pattern substantially the same as that shown in Figure 16.
The present invention also provides a crystalline form (Form 12) of N-[(3-fluoromethoxypyridin hyl](methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide te, which exhibits at least the following characteristic X-ray powder ction peaks (Cu Kα radiation, expressed in degrees 2θ) at approximately: (1) 5.0, 10.0, 14.8, 16.4 and 23.3; or (2) 5.0, 10.0, 14.8, 16.4, 19.2, 20.3 and 23.3; or (3) 5.0, 10.0, 14.8, 16.4, 19.2, 20.3, 21.5, 23.3, and 26.2.
The present invention also provides a crystalline form (Form 12) of N-[(3-fluoromethoxypyridin yl)methyl](methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide mesylate, having an X ray powder diffraction pattern sing characteristic peaks (expressed in degrees 2θ) at approximately 5.0, 10.0, 13.8, 14.8, 16.4, 19.2, 20.3, 21.5, 23.3, 24.0, 26.2 and 27.6.
The present invention also provides a crystalline form (Form 12) of N-[(3-fluoromethoxypyridin yl)methyl](methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide te having an X-ray powder diffraction pattern substantially the same as that shown in Figure 17.
The present invention also provides a lline form (Form 13) of N-[(3-fluoromethoxypyridin yl)methyl](methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide te having an X-ray powder diffraction pattern substantially the same as that shown in Figure 18.
The present invention also provides a crystalline form (Form 14) of N-[(3-fluoromethoxypyridin yl)methyl](methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide tosylate, which exhibits at least the following characteristic X-ray powder ction peaks (Cu Kα radiation, expressed in degrees 2θ) at approximately: (1) 5.0, 9.6, 13.7, 17.8 and 23.3; or (2) 5.0, 9.6, 13.7, 17.8, 20.1, 23.3 and 23.6; or (3) 5.0, 9.6, 13.7, 14.9, 17.8, 18.8, 20.1, 23.3 and 23.6.
The present invention also provides a crystalline form (Form 14) of fluoromethoxypyridin yl)methyl](methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide tosylate, having an X ray powder diffraction pattern comprising characteristic peaks (expressed in degrees 2θ) at approximately 5.0, 9.6, 13.7, 14.9, 17.8, 18.8, 19.0, 20.1, 23.3, 23.6 and 24.2.
The present invention also provides a crystalline form (Form 14) of N-[(3-fluoromethoxypyridin yl)methyl](methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide tosylate having an X-ray powder diffraction pattern substantially the same as that shown in Figure 19.
The present invention also provides a crystalline form (Form 15) of N-[(3-fluoromethoxypyridin yl)methyl](methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide ate, which exhibits at least the following characteristic X-ray powder diffraction peaks (Cu Kα radiation, expressed in s 2θ) at approximately: (1) 7.7, 10.3, 18.3, 19.4 and 20.7; or (2) 7.7, 10.3, 15.7, 18.3, 19.4, 20.7 and 25.7; or (3) 7.7, 10.3, 15.7, 18.3, 19.4, 20.7, 24.1, 25.1 and 25.7.; The present invention also es a crystalline form (Form 15) of N-[(3-fluoromethoxypyridin yl)methyl](methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide edisylate, having an X ray powder diffraction pattern comprising teristic peaks (expressed in degrees 2θ) at approximately 7.7, 10.3, 15.7, 18.3, 19.4, 20.7, 24.1, 25.1, 25.7, 28.2 and 30.7.
The present invention also provides a lline form (Form 15) of N-[(3-fluoromethoxypyridin yl)methyl](methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide ate having an X-ray powder diffraction pattern substantially the same as that shown in Figure 20 or in Figure 37 (top).
The present invention also provides a crystalline form (Form 16) of N-[(3-fluoromethoxypyridin yl)methyl](methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide edisylate, which exhibits at least the following characteristic X-ray powder diffraction peaks (Cu Kα radiation, expressed in degrees 2θ) at approximately: (1) 10.4, 18.5, 19.5, 22.4 and 25.2; or (2) 10.4, 18.5, 19.5, 20.8, 22.4, 24.2 and 25.2; or (3) 5,2, 10.4, 16.5, 18.5, 19.5, 20.8, 22.4, 24.2 and 25.2.
The present invention also provides a crystalline form (Form 16) of N-[(3-fluoromethoxypyridin yl)methyl](methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide edisylate, having an X ray powder diffraction pattern sing characteristic peaks (expressed in degrees 2θ) at approximately 5.2, 10.4, 16.1, 16.5, 18.5, 19.5, 20.8, 22.4, 23.3, 24.2 and 25.2.
The present invention also provides a crystalline form (Form 16) of N-[(3-fluoromethoxypyridin yl)methyl](methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide edisylate having an X-ray powder diffraction pattern substantially the same as that shown in Figure 21 or Figure 42 (top).
The present invention also provides a crystalline form (Form 17) of N-[(3-fluoromethoxypyridin yl)methyl](methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide besylate, which ts at least the following characteristic X-ray powder diffraction peaks (Cu Kα radiation, expressed in degrees 2θ) at approximately: (1) 5.3, 9.8, 14.9, 19.9, and 23.1; or (2) 5.3, 9.8, 14.9, 19.2, 19.9, 23.1 and 24.6; or (3) 5.3, 9.8, 14.9, 16.4, 17.4, 19.2, 19.9, 23.1 and 24.6.
The present invention also provides a crystalline form (Form 17) of fluoromethoxypyridin yl)methyl](methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide besylate, having an X ray powder diffraction pattern comprising characteristic peaks (expressed in degrees 2θ) at approximately 5.3, 9.8, 14.9, 16.4, 17.4, 19.2, 19.9, 21.0, 22.3, 23.1, 24.6 and 25.8.
The present invention also provides a lline form (Form 17) of N-[(3-fluoromethoxypyridin hyl](methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide besylate having an X-ray powder diffraction pattern substantially the same as that shown in Figure 22.
The t invention also provides a crystalline form (Form 18) of N-[(3-fluoromethoxypyridin yl)methyl](methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide hydrochloride, which exhibits at least the following characteristic X-ray powder diffraction peaks (Cu Kα radiation, expressed in degrees 2θ) at approximately: (1) 5.5, 8.5, 11.6, 17.0 and 19.0; or (2) 5.5, 8.5, 11.6, 17.0, 19.0, 22.8 and 26.1; or (3) 5.5, 8.5, 11.6, 13.2 17.0, 19.0, 22.8, 23.8 and 26.2.
The present invention also provides a crystalline form (Form 18) of N-[(3-fluoromethoxypyridin yl)methyl](methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide hydrochloride, having an X ray powder diffraction pattern comprising characteristic peaks (expressed in degrees 2θ) at approximately 5.5, 7.3, 8.5, 11.6, 13.2 17.0, 19.0, 20.6, 22.8, 23.8 and 26.2.
The present ion also provides a crystalline form (Form 18) of fluoromethoxypyridin yl)methyl](methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide hydrochloride having an X-ray powder ction pattern substantially the same as that shown in Figure 24 (top).
The d person is familiar with techniques for measuring XRPD patterns. In particular, the X-ray powder diffraction pattern of the sample of compound may be recorded using a Philips X-Pert MPD diffractometer with the following experimental conditions: Tube anode: Cu; Generator tension: 40 kV; Tube current: 40 mA; ngth alpha1: 1.5406 Å; Wavelength alpha2: 1.5444 Å; Sample: 2 mg of sample under analysis gently compressed on the XRPD zero back ground single obliquely cut silica sample .
The present invention provides a crystalline form (Form 1) of N-[(3-fluoromethoxypyridin yl)methyl](methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide, which exhibits an endothermic peak in its DSC thermograph at 151 ± 3 °C, preferably 151 ± 2 °C, more ably 151 ± 1 °C.
The present invention provides a crystalline form (Form 1) of N-[(3-fluoromethoxypyridin yl)methyl](methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide, having a DSC graph substantially the same as that shown in Figure 4.
The present invention provides a crystalline form (Form 18) of N-[(3-fluoromethoxypyridin yl)methyl](methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide hloride, which exhibits an endothermic peak in its DSC thermograph at 149 ± 3 °C, preferably 149 ± 2 °C, more preferably 149 ± 1 °C.
The present invention provides a crystalline form (Form 18) of N-[(3-fluoromethoxypyridin yl)methyl](methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide hydrochloride, having a DSC thermograph substantially the same as that shown in Figure 26.
The present invention provides a crystalline form (Form 8) of N-[(3-fluoromethoxypyridin yl)methyl](methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide sulfate, which exhibits an endothermic peak in its DSC thermograph at 110 ± 3 °C, preferably 110 ± 2 °C, more preferably 110 ± 1 °C.
The present invention es a crystalline form (Form 8) of N-[(3-fluoromethoxypyridin yl)methyl](methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide sulfate, having a DSC thermograph substantially the same as that shown in Figure 32.
The present invention provides a crystalline form (Form 16) of N-[(3-fluoromethoxypyridin yl)methyl](methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide edisylate, which exhibits an endothermic peak in its DSC thermograph at 110 ± 3 °C, preferably 110 ± 2 °C, more preferably 110 ± 1 °C.
The present ion provides a crystalline form (Form 16) of N-[(3-fluoromethoxypyridin yl)methyl](methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide edisylate, having a DSC thermograph substantially the same as that shown in Figure 44.
The skilled person is familiar with ques for measuring DSC thermographs. In particular, the DSC thermograph of the sample of compound may be recorded by (a) weighing 5 mg of the sample into an ium DSC pan and sealing non-hermetically with an aluminium lid; (b) g the sample into a Perkin-Elmer Jade DSC and holding the sample at 30°C until a stable heatflow response is ed while using a 20 cm3/min helium purge; (c) heating the sample to a temperature of between 200 and 300°C at a scan rate of 10°C/min and monitoring the resulting heat flow response while using a 20 cm3/min helium purge.
The present ion provides a crystalline form (Form 1) of N-[(3-fluoromethoxypyridin hyl](methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide having an X-ray powder diffraction pattern as described above, and a DSC thermograph as described above.
The present invention provides a crystalline form (Form 18) of N-[(3-fluoromethoxypyridin yl)methyl](methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide hloride having an X-ray powder diffraction pattern as described above, and a DSC graph as described above.
The present invention provides a crystalline form (Form 8) of fluoromethoxypyridin yl)methyl](methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide sulfate having an X-ray powder diffraction pattern as described above, and a DSC thermograph as described above.
The present invention provides a crystalline form (Form 16) of N-[(3-fluoromethoxypyridin yl)methyl](methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide edisylate having an X-ray powder diffraction pattern as bed above, and a DSC thermograph as described above.
The crystalline form of the present invention can exist in both unsolvated and solvated forms. The term 'solvate' is used herein to describe a molecular complex comprising the compound of the invention and an amount of one or more pharmaceutically acceptable solvents, for example, methanol. The term 'hydrate' is employed when the solvent is water.
A reference to a particular compound also includes all isotopic ts.
The present invention also encompasses a s for the preparation of Form 1 of the present invention, said process comprising the crystallisation of said crystalline form from a solution of N-[(3- fluoromethoxypyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide in a solvent or a mixture of solvents. ably the solvent is selected from acetonitrile and isopropanol (IPA). More ably the solvent is isopropanol.
After adding the N-[(3-fluoromethoxypyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide to a solvent or a mixture of solvents (e.g. acetonitrile or isopropanol), the combined mixture (compound plus solvent(s)) may be heated to a temperature of imately 60-85°C. Alternatively, the combined mixture may be heated to a temperature of approximately 70-85°C. Alternatively, the combined mixture may be heated to a temperature of approximately 80-85°C. Alternatively, the combined mixture may be heated to a ature of approximately 80, 81, 82, 83, 84 or 85°C. Alternatively, the combined e may be heated to a temperature of approximately 82°C. Alternatively, the combined mixture may be heated to reflux.
Following heating, the combined mixture may be cooled. Alternatively, the combined mixture may be cooled to a temperature of approximately 0-40 °C. Alternatively, the combined mixture may be cooled to a temperature of approximately 10-30 °C. Alternatively, the combined mixture may be cooled to room temperature. Alternatively, the combined mixture may be cooled to approximately 0 °C.
The present invention also encompasses a process for the preparation of Form 18 of the present invention, said s comprising the crystallisation of said crystalline form from a on of N-[(3- fluoromethoxypyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide hydrochloride in a solvent or a mixture of ts.
Optionally, said solution of fluoromethoxypyridinyl)methyl](methoxymethyl)({4-[(2- oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide hydrochloride may be formed by adding hydrochloric acid to a solution of N-[(3-fluoromethoxypyridinyl)methyl](methoxymethyl)({4- [(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide in a solvent or a mixture of solvents.
Preferably, the solution of N-[(3-fluoromethoxypyridinyl)methyl](methoxymethyl)({4-[(2- oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide in a solvent or a e of solvents may be heated such that the solid is dissolved before the hydrochloric acid is added. ably, the t is ethyl acetate or itrile. More preferably, the solvent is acetonitrile. The crystallisation may be performed by ultrasonication and/or temperature cycling of the mixture. Preferably the crystallisation is performed by ultrasonication followed by temperature cycling of the mixture. The temperature cycling may comprise cycling the ature of the mixture between about 30-50 °C and t temperature, optionally between about 40 °C and ambient temperature. Preferably, the temperature cycling is carried out for between about 18 to about 24 hours.
The present invention also encompasses a process for the preparation of Form 8 of the present invention, said process comprising the crystallisation of said crystalline form from a solution of N-[(3- fluoromethoxypyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide e in a solvent or a mixture of solvents.
Optionally, said solution of N-[(3-fluoromethoxypyridinyl)methyl](methoxymethyl)({4-[(2- idinyl)methyl]phenyl}methyl)pyrazolecarboxamide sulfate may be formed by adding sulfuric acid to a solution of N-[(3-fluoromethoxypyridinyl)methyl](methoxymethyl)({4-[(2- oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide in a solvent or a mixture of solvents.
Preferably, the solution of N-[(3-fluoromethoxypyridinyl)methyl](methoxymethyl)({4-[(2- oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide in a t or a mixture of solvents may be heated such that the solid is dissolved before the sulfuric acid is added. Preferably, the solvent is acetonitrile or acetone. More preferably, the solvent is acetonitrile. The crystallisation may be performed by ultrasonication and/or temperature cycling of the mixture. Preferably the crystallisation is performed by onication followed by ature g of the mixture. The temperature cycling may comprise cycling the temperature of the mixture between about 30-50 °C and ambient temperature, optionally between about 40 °C and ambient temperature. Preferably, the temperature cycling is carried out for between about 18 to about 24 hours.
The present invention also encompasses a process for the preparation of Form 15 of the present invention, said process comprising the crystallisation of said crystalline form from a suspension of N-[(3- fluoromethoxypyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide edisylate in a solvent or a mixture of solvents.
Optionally, said suspension of N-[(3-fluoromethoxypyridinyl)methyl](methoxymethyl)({4-[(2- oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide edisylate may be formed by adding a solvent or a mixture of solvents to a mixture of ethane honic acid (e.g. ethane honic acid hydrate) and N-[(3-fluoromethoxypyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide. Preferably, the solvent is acetone or ethyl acetate.
More preferably, the solvent is acetone. The crystallisation may be performed by ultrasonication and/or ature g of the suspension. Preferably the crystallisation is performed by ultrasonication followed by temperature cycling of the suspension. The temperature cycling may comprise cycling the temperature of the suspension between about 30-50 °C and ambient temperature, ally between about 40 °C and t temperature. Preferably, the temperature cycling is carried out for between about 18 to about 24 hours.
The present invention also encompasses a process for the preparation of Form 16 of the present invention, said process comprising the crystallisation of said crystalline form from a solution of N-[(3- fluoromethoxypyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide edisylate in a solvent or a e of ts.
Optionally, said solution of N-[(3-fluoromethoxypyridinyl)methyl](methoxymethyl)({4-[(2- oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide edisylate may be formed by adding a solvent or a mixture of solvents to a mixture of ethane honic acid (e.g. ethane disulphonic acid hydrate) and N-[(3-fluoromethoxypyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide. Optionally ethane disulphonic acid and the mixture of N-[(3-fluoromethoxypyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide is heated until to dissolve the solid. Preferably, the solvent is tetrahydrofuran or acetonitrile. More preferably, the solvent is acetonitrile. The crystallisation may be performed by ultrasonication and/or temperature cycling of the mixture. Preferably the crystallisation is performed by ultrasonication followed by temperature cycling of the e. The temperature cycling may comprise cycling the temperature of the suspension between about 30-50 °C and ambient temperature, optionally between about 40 °C and ambient temperature. Preferably, the temperature g is carried out for between about 18 to about 24 hours.
The processes of the present invention may also comprise the addition of crystalline seeds of the lline form of the invention.
In an aspect, the present invention es the crystalline form of the invention when manufactured by a process according to the invention.
As previously mentioned, the crystalline form of the present invention has a number of eutic applications, particularly in the treatment of diseases or conditions mediated by plasma rein.
Accordingly, the present invention provides a crystalline form of N-[(3-fluoromethoxypyridin yl)methyl](methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide and salts thereof, as hereinbefore defined, for use in therapy. In a red embodiment, the crystalline form is Form 1. In another preferred embodiment, the crystalline form is Form 8.
The present invention also provides for the use of a crystalline form of N-[(3-fluoromethoxypyridin yl)methyl](methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide and salts thereof, as hereinbefore defined, in the manufacture of a ment for the ent of a disease or condition mediated by plasma rein. In a preferred embodiment, the crystalline form is Form 1. In r preferred ment, the crystalline form is Form 8.
The present ion also provides a crystalline form of N-[(3-fluoromethoxypyridinyl)methyl] (methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide and salts thereof, as hereinbefore defined, for use in a method of treatment of a disease or condition mediated by plasma kallikrein. In a preferred embodiment, the crystalline form is Form 1. In another preferred embodiment, the crystalline form is Form 8.
The present invention also provides a method of ent of a disease or condition mediated by plasma kallikrein, said method comprising administering to a mammal in need of such treatment a therapeutically effective amount of a crystalline form of fluoromethoxypyridinyl)methyl] (methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide and salts thereof, as hereinbefore defined. In a preferred embodiment, the crystalline form is Form 1. In another preferred embodiment, the crystalline form is Form 8.
In an aspect, the disease or condition mediated by plasma kallikrein is selected from impaired visual acuity, diabetic retinopathy, retinal vascular permeability associated with diabetic retinopathy, ic macular edema, hereditary angioedema, diabetes, pancreatitis, cerebral rhage, nephropathy, cardiomyopathy, neuropathy, inflammatory bowel disease, arthritis, inflammation, septic shock, hypotension, cancer, adult respiratory distress syndrome, disseminated intravascular coagulation, blood ation during cardiopulmonary bypass surgery, and ng from post-operative y. In a preferred embodiment, the disease or condition mediated by plasma kallikrein is diabetic macular edema. In another preferred embodiment, the disease or condition mediated by plasma kallikrein is hereditary angioedema.
In another aspect, the e or condition in which plasma kallikrein activity is implicated is l vein occlusion.
Alternatively, the disease or condition ed by plasma kallikrein may be selected from retinal vascular permeability associated with diabetic retinopathy, diabetic macular edema and hereditary dema. Alternatively, the disease or condition mediated by plasma kallikrein may be retinal vascular bility associated with diabetic retinopathy or ic macular edema. The crystalline forms of N-[(3-fluoromethoxypyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide and salts thereof may be administered in a form suitable for injection into the ocular region of a patient, in particular, in a form suitable for vitreal injection.
In the context of the present invention, references herein to "treatment" e references to curative, palliative and prophylactic treatment, unless there are specific indications to the contrary. The terms "therapy", "therapeutic" and "therapeutically" should be construed in the same way.
The crystalline form of the present invention may be administered alone or in combination with one or more other drugs. Generally, it will be administered as a formulation in association with one or more pharmaceutically acceptable excipients. The term “excipient” is used herein to describe any ingredient other than the compound(s) of the invention which may impart either a functional (i.e., drug release rate controlling) and/or a non-functional (i.e., processing aid or diluent) characteristic to the ations. The choice of excipient will to a large extent depend on factors such as the particular mode of administration, the effect of the excipient on solubility and ity, and the nature of the dosage form.
In another aspect, the compounds of the present invention may be administered in combination with laser treatment of the retina. The combination of laser therapy with itreal injection of an inhibitor of VEGF for the treatment of diabetic macular edema is known (Elman M, Aiello L, Beck R, et al.
“Randomized trial evaluating ranibizumab plus prompt or ed laser or triamcinolone plus prompt laser for diabetic macular .Ophthalmology. 27 April 2010). ceutical compositions suitable for the delivery of the crystalline form of the present invention and s for their preparation will be readily apparent to those skilled in the art. Such compositions and s for their preparation may be found, for example, in Remington’s Pharmaceutical Sciences, 19th Edition (Mack Publishing Company, 1995).
For administration to human patients, the total daily dose of the crystalline form of the invention is typically in the range 0.1 mg and 10,000 mg, or between 1 mg and 5000 mg, or between 10 mg and 1000 mg depending, of course, on the mode of stration. If stered by intra-vitreal injection a lower dose of between 0.0001 mg (0.1 µg) and 0.2 mg (200 µg) per eye is envisaged, or between 0.0005 mg (0.5 µg) and 0.05 mg (50 µg) per eye.
The total daily dose may be administered in single or divided doses and may, at the physician's discretion, fall outside of the typical range given herein. These s are based on an average human subject having a weight of about 60kg to 70kg. The physician will readily be able to determine doses for subjects whose weight falls outside this range, such as s and the elderly.
Accordingly, the present invention provides a pharmaceutical composition comprising a crystalline solid form of N-[(3-fluoromethoxypyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide, as hereinbefore defined, and a pharmaceutically acceptable carrier, diluent or excipient. In a preferred ment, the crystalline solid form is Form 1.
In another red embodiment, the crystalline form is Form 8. It will be appreciated that the reference to crystalline solid forms of N-[(3-fluoromethoxypyridinyl)methyl](methoxymethyl) ({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide as hereinbefore defined includes both the free base and the salts f which have hereinbefore been described.
The pharmaceutical itions may be administered topically (e.g. to the eye, to the skin or to the lung and/or airways) in the form, e.g., of ops, creams, solutions, suspensions, heptafluoroalkane (HFA) aerosols and dry powder formulations; or systemically, e.g. by oral stration in the form of tablets, capsules, syrups, powders or granules; or by parenteral administration in the form of solutions or suspensions; or by subcutaneous administration; or by rectal administration in the form of suppositories; or transdermally. In a further embodiment, the pharmaceutical composition is in the form of a suspension, tablet, capsule, powder, granule or suppository.
In an embodiment of the invention, the active ingredient is stered orally. Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, and/or buccal, lingual, or sublingual administration by which the compound enters the blood stream ly from the mouth.
Formulations le for oral administration include solid plugs, solid microparticulates, semi-solid and liquid (including multiple phases or dispersed systems) such as tablets; soft or hard capsules containing multi- or nano-particulates, liquids, emulsions or powders; lozenges ding -filled); chews; gels; fast dispersing dosage forms; films; ovules; sprays; and buccal/mucoadhesive s. ations suitable for oral administration may also be designed to deliver the crystalline form in an immediate release manner or in a rate-sustaining manner, wherein the release profile can be delayed, pulsed, controlled, sustained, or delayed and sustained or modified in such a manner which optimises the therapeutic efficacy of the said crystalline form. Means to deliver compounds in a rate-sustaining manner are known in the art and include slow release polymers that can be formulated with the said compounds to control their release.
Liquid (including multiple phases and dispersed systems) formulations include emulsions, suspensions, ons, syrups and elixirs. Such formulations may be presented as fillers in soft or hard capsules.
Liquid formulations may also be ed by the reconstitution of a solid, for example, from a sachet.
The crystalline form of the ion may also be used in fast-dissolving, fast-disintegrating dosage forms such as those described in Liang and Chen, Expert Opinion in Therapeutic Patents, 2001, 11 (6), 981-986.
The ation of s is discussed in Pharmaceutical Dosage Forms: Tablets, Vol. 1, by H. Lieberman and L. Lachman (Marcel Dekker, New York, 1980).
The invention will now be illustrated by the following non-limiting examples. In the examples the following figures are presented: Figure 1a: X-ray powder diffraction pattern of Form A of N-[(3-fluoromethoxypyridinyl)methyl] xymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide (Example 41 of WO2016/083820 ()).
Figure 1b: X-ray powder diffraction pattern of Form A of N-[(3-fluoromethoxypyridinyl)methyl] (methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide (Example 1).
Figure 2a: X-ray powder diffraction pattern of Form 1 of N-[(3-fluoromethoxypyridinyl)methyl] (methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide (Example 2).
Figure 2b: X-ray powder diffraction pattern of Form 1 of fluoromethoxypyridinyl)methyl] (methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide le 3).
Figure 2c: X-ray powder diffraction pattern of Form 1 of N-[(3-fluoromethoxypyridinyl)methyl] (methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide (Example 4).
Figure 3: STA of Form 1 of N-[(3-fluoromethoxypyridinyl)methyl](methoxymethyl)({4-[(2- oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide (Example 2).
Figure 4: DSC thermograph of Form 1 of N-[(3-fluoromethoxypyridinyl)methyl] (methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide (Example 2).
Figure 5: Gravimetric vapour on isotherms (adsorption and desorption) of Form 1 of N-[(3-fluoro- 4-methoxypyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide (Example 2).
Figure 6: X-ray powder diffraction pattern (top) of fluoromethoxypyridinyl)methyl] (methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide following slurry of Form 1 with 90:10 IPA:water. The bottom X-ray powder diffraction pattern is of Form 1 as a reference (Example 2).
Figure 7: X-ray powder diffraction n of Form 2 of N-[(3-fluoromethoxypyridinyl)methyl] (methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide (Example 5).
Figure 8: X-ray powder ction pattern of Form 3 of N-[(3-fluoromethoxypyridinyl)methyl] (methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide le 6).
Figure 9: X-ray powder diffraction pattern of Form 4 of N-[(3-fluoromethoxypyridinyl)methyl] (methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide (Example 7).
Figure 10: X-ray powder diffraction pattern of Form 5 of N-[(3-fluoromethoxypyridinyl)methyl] (methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide hydrochloride (Example 8).
Figure 11: X-ray powder diffraction pattern of Form 6 of N-[(3-fluoromethoxypyridinyl)methyl] (methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide hydrochloride (Example 9).
Figure 12: X-ray powder diffraction pattern of Form 7 of N-[(3-fluoromethoxypyridinyl)methyl] (methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide hydrochloride (Example 10).
Figure 13: X-ray powder ction pattern of Form 8 of N-[(3-fluoromethoxypyridinyl)methyl] (methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide sulfate (Example 11).
Figure 14: X-ray powder diffraction n of Form 9 of N-[(3-fluoromethoxypyridinyl)methyl] (methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide phosphate (Example 12).
Figure 15: X-ray powder diffraction pattern of Form 10 of N-[(3-fluoromethoxypyridinyl)methyl] (methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide phosphate (Example 13).
Figure 16: X-ray powder diffraction pattern of Form 11 of N-[(3-fluoromethoxypyridinyl)methyl] (methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide phosphate (Example 14).
Figure 17: X-ray powder diffraction pattern of Form 12 of N-[(3-fluoromethoxypyridinyl)methyl] (methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide mesylate (Example 15).
Figure 18: X-ray powder ction pattern of Form 13 of N-[(3-fluoromethoxypyridinyl)methyl] (methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide mesylate (Example 16).
Figure 19: X-ray powder diffraction pattern of Form 14 of N-[(3-fluoromethoxypyridinyl)methyl] xymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide tosylate (Example 17).
Figure 20: X-ray powder diffraction pattern of Form 15 of N-[(3-fluoromethoxypyridinyl)methyl] xymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide edisylate (Example 18).
Figure 21: X-ray powder diffraction pattern of Form 16 of N-[(3-fluoromethoxypyridinyl)methyl] (methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide edisylate (Example 19).
Figure 22: X-ray powder diffraction n of Form 17 of N-[(3-fluoromethoxypyridinyl)methyl] (methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide besylate (Example 20).
Figure 23: NMR spectrum of fluoromethoxypyridinyl)methyl](methoxymethyl)({4-[(2- oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide hydrochloride (Example 21).
Figure 24: X-ray powder diffraction pattern of Form 18 (Example 21) (top) overlaid with Form 5 (Example 8) (bottom) of N-[(3-fluoromethoxypyridinyl)methyl](methoxymethyl) ({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide hydrochloride.
Figure 25: STA of Form 18 of N-[(3-fluoromethoxypyridinyl)methyl](methoxymethyl)({4-[(2- oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide hydrochloride le 21).
Figure 26: DSC thermograph of Form 18 of N-[(3-fluoromethoxypyridinyl)methyl] (methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide hydrochloride (Example 21).
Figure 27: Gravimetric vapour sorption isotherms (adsorption and desorption) of Form 18 of N-[(3- fluoromethoxypyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide hydrochloride (Example 21).
Figure 28: X-ray powder diffraction pattern (top) of N-[(3-fluoromethoxypyridinyl)methyl] (methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide hydrochloride following slurry of Form 18 with 90:10 IPA:water. The bottom X-ray powder diffraction pattern is of Form 18 as a reference (Example 21).
Figure 29: NMR spectrum of N-[(3-fluoromethoxypyridinyl)methyl](methoxymethyl)({4-[(2- oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide sulfate (Example 22).
Figure 30: X-ray powder diffraction pattern of scaled-up Form 8 (Example 22) (top) overlaid with the screening sample of Form 8 (Example 11) m) of N-[(3-fluoromethoxypyridin yl)methyl](methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazole carboxamide sulfate.
Figure 31: STA of Form 8 of N-[(3-fluoromethoxypyridinyl)methyl](methoxymethyl)({4-[(2- oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide sulfate (Example 22).
Figure 32: DSC thermograph of Form 8 of N-[(3-fluoromethoxypyridinyl)methyl] (methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide sulfate (Example 22).
Figure 33: Gravimetric vapour on isotherms (adsorption and desorption) of Form 8 of N-[(3-fluoro- 4-methoxypyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin hyl]phenyl}methyl)pyrazolecarboxamide sulfate le 22).
Figure 34: X-ray powder diffraction pattern (top) of N-[(3-fluoromethoxypyridinyl)methyl] (methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide sulfate following slurry of Form 8 with 90:10 ter. The bottom X-ray powder ction pattern is of Form 8 as a reference (Example 22).
Figure 35: X-ray powder diffraction pattern of Form 8 of fluoromethoxypyridinyl)methyl] (methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide sulfate in Example 23.
Figure 36: NMR spectrum of N-[(3-fluoromethoxypyridinyl)methyl](methoxymethyl)({4-[(2- oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide edisylate (Example 24).
Figure 37: X-ray powder diffraction pattern of scaled-up Form 15 (Example 24) (top) overlaid with the screening sample of Form 15 (Example 18) (bottom) of N-[(3-fluoromethoxypyridin yl)methyl](methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazole carboxamide edisylate.
Figure 38: STA of Form 15 of fluoromethoxypyridinyl)methyl](methoxymethyl)({4-[(2- oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide edisylate (Example 24).
Figure 39: DSC thermograph of Form 15 of N-[(3-fluoromethoxypyridinyl)methyl] xymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide edisylate (Example 24).
Figure 40: X-ray powder diffraction pattern (top) of N-[(3-fluoromethoxypyridinyl)methyl] (methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide edisylate ing slurry of Form 15 with 90:10 IPA:water. The bottom X-ray powder diffraction pattern is of Form 15 as a reference (Example 24).
Figure 41: NMR um of N-[(3-fluoromethoxypyridinyl)methyl](methoxymethyl)({4-[(2- oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide edisylate (Example 25).
Figure 42: X-ray powder diffraction pattern of scaled-up Form 16 (Example 25) (top) overlaid with the screening sample of Form 16 (Example 19) (bottom) of N-[(3-fluoromethoxypyridin yl)methyl](methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazole amide edisylate.
Figure 43: STA of Form 16 of N-[(3-fluoromethoxypyridinyl)methyl](methoxymethyl)({4-[(2- oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide edisylate (Example 25).
Figure 44: DSC thermograph of Form 16 of N-[(3-fluoromethoxypyridinyl)methyl] (methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide edisylate (Example 25).
Figure 45: etric vapour sorption isotherms (adsorption and desorption) of Form 16 of N-[(3- fluoromethoxypyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide edisylate le 25).
Figure 46: X-ray powder diffraction patterns of Form 1 of N-[(3-fluoromethoxypyridinyl)methyl] (methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide during a 25 °C / 60%RH stability study at 0 days (top), 1 month (middle) and 3 months (bottom).
Figure 47: X-ray powder diffraction patterns of Form 1 of N-[(3-fluoromethoxypyridinyl)methyl] (methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide during a 40 °C / 75%RH stability study at 0 days (top), 1 month (middle) and 3 months (bottom).
General Experimental Details In the following examples, the following abbreviations and definitions are used: aq Aqueous on DCM Dichloromethane DMF N,N-Dimethylformamide DMSO Dimethyl sulfoxide DSC Differential Scanning Calorimetry EtOAc Ethyl Acetate 2-(3H-[1,2,3]triazolo[4,5-b]pyridinyl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) hrs Hours HOBt Hydroxybenzotriazole IPA 2-Propanol / Propanol / Iso-propanol LCMS Liquid chromatography mass spectrometry Me Methyl MeCN Acetonitrile MeOH Methanol min Minutes MS Mass spectrum Nuclear magnetic resonance spectrum – NMR spectra were ed at a frequency of 400MHz unless otherwise ted Pet. Ether Petroleum ether fraction g at C Ph Phenyl STA Simultaneous Thermal Analysis SWFI Sterile water for injection rt room temperature THF Tetrahydrofuran TFA Trifluoroacetic acid XRPD X-ray powder diffraction All reactions were carried out under an atmosphere of nitrogen unless specified otherwise. 1H NMR a were recorded on a Bruker (400MHz) or on a JEOL (400MHz) spectrometer with reference to deuterium solvent and at rt.
Molecular ions were obtained using LCMS which was carried out using a Chromolith Speedrod RP-18e column, 50 x 4.6 mm, with a linear gradient 10% to 90% 0.1% HCO2H/MeCN into 0.1% HCO2H/H2O over 13 min, flow rate 1.5 , or using Agilent, X-Select, acidic, 5-95% MeCN/water over 4 min. Data was collected using a Thermofinnigan Surveyor MSQ mass spectrometer with electospray ionisation in conjunction with a Thermofinnigan Surveyor LC system.
Alternatively, molecular ions were obtained using LCMS which was carried out using an Agilent Poroshell 120 EC-C18 , 3.0 x 50mm) column with 0.1% v/v Formic acid in water t A]; MeCN [eluent B]; Flow rate min and 1.5 minutes equilibration time between samples, gradient shown below.
Mass detection was afforded with API 2000 mass spectrometer (electrospray).
Gradient: Time (min) Eluent A (%) Eluent B (%) 0.00 95 5 0.20 95 5 2.00 5 95 3.00 5 95 3.25 95 5 3.50 95 5 Where products were purified by flash chromatography, ‘silica’ refers to silica gel for chromatography, 0.035 to 0.070 mm (220 to 440 mesh) (e.g. Merck silica gel 60), and an applied pressure of nitrogen up to 10 p.s.i accelerated column elution. e phase preparative HPLC purifications were d out using a Waters 2525 binary gradient pumping system at flow rates of typically 20 mL/min using a Waters 2996 photodiode array detector.
All solvents and commercial reagents were used as received.
Chemical names were generated using automated software such as the Autonom software provided as part of the ISIS Draw package from MDL Information Systems or the Chemaxon software ed as a component of MarvinSketch or as a component of the IDBS E-WorkBook.
X-Ray Powder Diffraction patterns were collected on a Philips X-Pert MPD diffractometer and analysed using the following experimental conditions (Method A), unless otherwise specified: Tube anode: Cu tor tension: 40 kV Tube current: 40 mA Wavelength : 1.5406 Å Wavelength alpha2: 1.5444 Å Start angle [2θ]: 4 End angle [2θ]: 40 Continuous scan Approximately 2 mg of sample under analysis was gently compressed on the XRPD zero back ground single obliquely cut silica sample holder. The sample was then loaded into the diffractometer for analysis.
Where specified, X-Ray Powder Diffraction patterns were collected using the following method (Method X-ray powder ction studies were performed using a Bruker AXS D2 PHASER (D2-205355) in Bragg- Brentano configuration, equipment #2353. A Cu anode at 30kV, 10 mA, sample stage rd rotating (5/min) with beam stop and monochromatisation by a Kβ-filter (0.59% Ni) are used. The slits that are used are fixed divergence slits 1.0mm (=0.61°), primary axial Soller slit 2.5° and secondary axial Soller slit 2.5°. The detector is a linear detector E with receiving slit 5° detector opening. The standard sample holder (0.1mm cavity in (51O) silicon wafer) has a l contribution to the background signal. The measurement conditions: scan range 5 —45° 2θ, sample rotation 5 rpm, 0.5s/step, 0.010°/step, 3.0mm detector slit; and all ing conditions are logged in the instrument control file. The software used for data collection is Diffrac.Commander v4.0. Data analysis is performed using Diffrac.Eva V4.1 evaluation software. No background correction or smoothing is applied to the patterns.
DSC data were collected using the following method: Approximately 5 mg of each sample was weighed into an aluminium DSC pan and sealed non-hermetically with an aluminium lid. The sample was then loaded into a Perkin-Elmer Jade DSC and held at 30°C. Once a stable heat-flow response was ed, the sample was then heated to a temperature between 200 and 300°C at a scan rate of 10°C/min and the resulting heat flow response was monitored. A 20 cm3/min helium purge was used. Prior to analysis, the instrument was temperature and heat flow verified using an indium rd.
Gravimetric Vapour Sorption (GVS) data were collected using the following method: Approximately 10 mg of sample was placed into a wire-mesh vapour sorption balance pan and loaded into an ‘IgaSorp’ vapour on balance (Hiden Analytical ments). The sample was then dried by maintaining a 0% humidity environment until no r weight change was recorded. Subsequently, the sample was then subjected to a ramping profile from 0 – 90 % RH at 10 % RH increments, maintaining the sample at each step until equilibration had been attained (99% step completion). Upon reaching equilibration, the % RH within the tus was ramped to the next step and the equilibration procedure repeated.
After completion of the sorption cycle, the sample was then dried using the same procedure. The weight change during the sorption/desorption cycles were then monitored, allowing for the hygroscopic nature of the sample to be determined.
Simultaneous Thermal Analysis (STA) data were collected using the following method: Approximately 5 mg of sample was accurately weighed into a ceramic crucible and it was placed into the chamber of Perkin-Elmer STA 600 A analyzer at ambient temperature. The sample was then heated at a rate of 10°C/min, typically from 25°C to 300°C, during which time the change in weight was monitored as well as DTA signal. The purge gas used was nitrogen at a flow rate of 20 n.
Synthetic Examples Example 1 A. ydroxymethyl-benzyl)-1H-pyridinone 4-(Chloromethyl)benzylalcohol (5.0 g, 31.93 mmol) was dissolved in acetone (150 mL). 2-hydroxypyridine (3.64 g, 38.3 mmol) and potassium carbonate (13.24 g, 95.78 mmol) were added and the reaction mixture was stirred at 50 °C for 3 hrs after which time the solvent was removed in vacuo and the residue taken up in chloroform (100 mL). This solution was washed with water (30 mL), brine (30 mL), dried 4) and evaporated in vacuo. The residue was purified by flash chromatography (silica), eluent 3% MeOH / 97% CHCl3, to give a white solid identified as 1-(4-hydroxymethyl-benzyl)-1H-pyridinone (5.30g, 24.62mmol, 77% yield).
[M+Na]+ = 238 B. 1-(4-Chloromethyl-benzyl)-1H-pyridinone 1-(4-Hydroxymethyl-benzyl)-1H-pyridinone (8.45 g, 39.3 mmol), dry DCM (80 mL) and triethylamine (7.66 ml, 55.0 mmol) were cooled in an ice bath. M ethanesulfonyl de (3.95 ml, 51.0 mmol) was added and stirred in ice bath for 15 min. The ice bath was removed and stirring continued at rt temperature overnight. The reaction mixture was partitioned between DCM (100 mL) and saturated aqueous NH4Cl solution (100 mL). The aqueous layer was extracted with further DCM (2 x 50 mL) and the combined organics washed with brine (50 mL), dried over Na2SO4, filtered and concentrated to give 1-(4- chloromethyl-benzyl)-1H-pyridinone (8.65 g, 36.6 mmol, 93 % yield) as a pale yellow solid.
[MH]+ = 234.1 C. Methyl 3-(methoxymethyl)(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H-pyrazolecarboxylate Potassium carbonate (519 mg, 3.76 mmol) was added to a solution of methyl 3-(methoxymethyl)-1H- pyrazolecarboxylate (320 mg, 1.88 mmol; CAS no. 318496 1 (synthesised according to the method described in DMF (5 mL) and heated at 60 °C ght. The on mixture was diluted with EtOAc (50 mL) and washed with brine (2 x 100 mL), dried over magnesium sulfate, filtered and reduced in vacuo. The crude product was ed by flash chromatography (40 g , 0-100% EtOAc in isohexanes) to afford two regioisomers. The second isomer off the column was collected to afford methyl 3-(methoxymethyl)(4- ((2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H-pyrazolecarboxylate (378 mg, 1.01 mmol, 53.7 % yield) as a colourless gum.
[MH]+ = 368.2 D. 3-(Methoxymethyl)(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H-pyrazolecarboxylic acid To methyl 3-(methoxymethyl)(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H-pyrazolecarboxylate (3.77 g, 10.26 mmol) in THF (5 mL) and MeOH (5 mL) was added 2M NaOH solution (15.39 ml, 30.8 mmol) and stirred at rt overnight. 1M HCl (50 mL) was added and extracted with EtOAc (50 mL). The organic layer was washed with brine (50 mL), dried over magnesium sulfate, ed and reduced in vacuo to give 3- (methoxymethyl)(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H-pyrazolecarboxylic acid (1.22 g, 3.45 mmol, 33.6 % yield) as a white powder.
[MH]+ = 354.2 E. 3-Fluoromethoxy-pyridinecarbonitrile To a large microwave vial, copper (I) cyanide (1.304 g, 14.56 mmol) was added to a solution of 2-bromo- romethoxypyridine (1 g, 4.85 mmol) in DMF (5 mL). The on vial was sealed and heated to 100 °C for 16 hrs. The reaction mixture was diluted with water (20 mL) and EtOAc (20 mL). The thick suspension was sonicated and required additional water (40 mL) and EtOAc (2 x 50 mL) with tion to break-up the solid precipitated. The combined layers were filtered through a plug of celite and the organic layer ed, washed with brine (50 mL), dried over magnesium sulfate, filtered and the solvent d under reduced pressure to give a pale green solid identified as the desired compound 3-fluoro- 4-methoxy-pyridinecarbonitrile (100 mg, 0.578 mmol, 12 % yield) F. (3-Fluoromethoxy-pyridinylmethyl)-carbamic acid tert-butyl ester 3-Fluoromethoxy-pyridinecarbonitrile (100 mg, 0.578 mmol) was dissolved in anhydrous methanol (10 mL, 247 mmol) and nickel chloride hexahydrate (14 mg, 0.058 mmol) was added followed by di-tertbutyl dicarbonate (255 mg, 1.157 mmol). The resulting pale green on was cooled in an ice-salt bath to -5 °C and then sodium borohydride (153 mg, 4.05 mmol) was added portionwise maintaining the reaction temperature ~0 °C. The deep brown solution was left to stir at 0 °C and slowly allowed to warm to rt and then left to stir at rt for 3 hrs. The reaction mixture was evaporated to dryness at 40 °C to afford a black residue which was diluted with DCM (10 mL) and washed with sodium hydrogen carbonate (10 mL). An emulsion formed so the organics were separated via a phase separating cartridge and concentrated. The crude liquid was purified by chromatography g with EtOAc / iso-Hexane to afford the title compound, (3-fluoromethoxy-pyridinylmethyl)-carbamic acid tert-butyl ester as a clear yellow oil (108 mg, 62 % yield) [MH]+ = 257 G. C-(3-Fluoromethoxy-pyridinyl)-methylamine hydrochloride salt (3-Fluoromethoxy-pyridinylmethyl)-carbamic acid tert-butyl ester (108mg, 0.358mmol) was taken up in iso-propyl alcohol (1 mL) and then HCl (6N in iso-propyl alcohol) (1 mL, 0.578 mmol) was added at rt and left to stir at 40 °C for 2 hrs. The reaction mixture was concentrated under reduced pressure and then triturated with ether, sonicated and then decanted to give a cream coloured solid (75 mg, 55% yield) identified as C-(3-fluoromethoxy-pyridinyl)-methylamine hydrochloride salt.
[MH]+ = 157 H. N-[(3-Fluoromethoxypyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide (Form A) 3-(Methoxymethyl)(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H-pyrazolecarboxylic acid (825 mg, 2.34 mmol) and C-(3-fluoromethoxy-pyridinyl)-methylamine hydrochloride salt (450 mg, 2.34 mmol) were ved in DCM while cooling to 0°C. 1-Ethyl(3-dimethylaminopropyl)carbodiimide hydrochloride (627.0 mg, 3.27 mmol), HOBt (378.8 mg, 2.80 mmol) and triethylamine (1.63 mL, 1182 mmol) were added while stirring, the mixture allowed to warm to rt and stirring continued for 20 hrs.
Chloroform (50 mL) was added, the mixture was washed with saturated NaHCO3(aq) and reduced in vacuo. The crude al was purified by chromatography eluting with methanol/DCM. The resulting solid was dissolved in hot MeCN, allowed to cool and itate, and the resulting solids were removed by filtration. The filtrate was reduced in vacuo then freeze dried from MeCN/water to afford the title compound as a white solid (720 mg, 62% yield).
[MH]+ = 492.0 NMR (CD3OD) δ: 3.41 (3H, s), 4.03 (3H, s), 4.65 (2H, s), 4.72 (2H, d, J=2.3Hz), 5.24 (2H, s), 5.37 (2H, s), 6.44 (1H, td, J = 1.4, 6.8Hz), 6.62 (1H, d, J = , .22 (1H, m), .38 (4H, m), 7.56-7.60 (1H, m), 7.75 (1H, dd, J = 1.9, 7.1Hz), 8.18 (1H, s), 8.27 (1H, d, J = 5.6Hz) ppm.
An XRPD diffractogram of N-[(3-fluoromethoxypyridinyl)methyl](methoxymethyl)({4-[(2- oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide (Form A) is shown in Figure 1b. Form A was found to be mostly ous.
Example 2 - N-[(3-Fluoromethoxypyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide (Form 1) 3-(Methoxymethyl)(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H-pyrazolecarboxylic acid (825 mg, 2.34 mmol) and C-(3-fluoromethoxy-pyridinyl)-methylamine hydrochloride salt (450 mg, 2.34 mmol) were ved in DCM while cooling to 0°C. 1-Ethyl(3-dimethylaminopropyl)carbodiimide hloride (627.0 mg, 3.27 mmol), HOBt (378.8 mg, 2.80 mmol) and triethylamine (1.63 mL, 1182 mmol) were added while stirring, the mixture allowed to warm to rt and stirring continued for 20 hrs.
Chloroform (50 mL) was added, the mixture was washed with saturated NaHCO3(aq) and reduced in vacuo. The crude material was purified by tography eluting with methanol/DCM. The solvent was removed in vacuo and the resulting solid triturated with diethyl ether. The resulting solids were collected by filtration to afford the title compound.
An XRPD diffractogram of N-[(3-fluoromethoxypyridinyl)methyl](methoxymethyl)({4-[(2- oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide (Form 1) is shown in Figure 2a.
Peak position table: No. Pos. [°2Th.] Rel. Int. [%] 1 4.436 32.36 2 5.0471 58.74 3 10.2255 43.07 4 11.2061 48.44 12.0101 16.4 6 12.5494 37.17 7 13.165 67.26 8 14.4984 38.94 9 15.8919 23.54 16.2983 34.56 11 2 36.63 12 17.8564 71.49 13 18.6888 21.9 14 20.285 26.12 21.1598 100 16 22.04 87.76 17 22.5857 36.38 18 23.4408 14.33 19 24.3045 31.11 25.1655 78.97 21 25.3728 93.91 22 6 56.79 23 27.991 76.91 24 28.7495 22.99 30.7611 13.4 26 32.413 17.2 27 37.2144 14.13 28 38.1171 14.14 Simultaneous Thermal Analysis (STA) The STA data for Form 1 are shown in Figure 3. ential Scanning Calorimetry (DSC) The DSC data for Form 1 are shown in Figure 4.
Gravimetric Vapour Sorption (GVS) The GVS data for Form 1 are listed in the table below and shown in Figure 5.
%-RH %-Wt(dry basis) 0.0335 0.047222 9.9791 0.229954 9 18 .0091 0.712554 39.9998 04 49.991 1.206867 59.9808 37 70.0195 1.912025 80.0136 2.186122 90.0039 3.226288 85.0063 2.546901 75.0151 2.115841 64.9759 1.86517 54.9837 1.684781 44.9954 1.525476 .0052 1.017107 .0135 0.70084 .0203 0.501709 4.9801 0.126875 0.0335 68 Slurry studies Form 1 (20 mg) was suspended in 90/10 IPA/water (200µL or 300µL) and shaken at ambient temperature for 72 hrs. The supernatant was evaporated rather than filtered due to the small volume and the resulting solid was examined by XRPD (Figure 6). The resulting XRPD (Figure 6) was different to that of Figure 2a which indicated that the free base probably has a tendency to form hydrate(s).
Visual aqueous solubility Form 1 (10mg) was weighed into a glass vial and water was added in 100µL portions up to 3mL then 1mL portions thereafter. lity was assessed visually following a brief period of equilibration.
Form 1 did not give any indication it was ving at all in 20mL water (<< 0.5mg/mL).
Example 3 - N-[(3-Fluoromethoxypyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide (Form 1) 3-(Methoxymethyl)(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H-pyrazolecarboxylic acid (825 mg, 2.34 mmol) and C-(3-fluoromethoxy-pyridinyl)-methylamine hydrochloride salt (450 mg, 2.34 mmol) were dissolved in DCM while cooling to 0°C. 1-Ethyl(3-dimethylaminopropyl)carbodiimide hydrochloride (627.0 mg, 3.27 mmol), HOBt (378.8 mg, 2.80 mmol) and triethylamine (1.63 mL, 1182 mmol) were added while stirring, the mixture allowed to warm to rt and stirring continued for 20 hrs.
Chloroform (50 mL) was added, the mixture was washed with saturated NaHCO3(aq) and reduced in vacuo. The crude material was purified by chromatography eluting with ol/DCM. The resulting solid was dissolved in hot MeCN, allowed to cool and precipitate, and the ing solids were collected by filtration to afford the title compound as a white solid (130 mg, 11% yield).
An XRPD diffractogram (recorded using Method B) of N-[(3-fluoromethoxypyridinyl)methyl] (methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide (Form 1) is shown in Figure 2b. The XRPD diffractogram (Figure 2b) of the isolated solids confirmed that they were of the same polymorphic form as Form 1 (Example 2) (Figure 2a).
Peak position table: No. Pos. [°2Th.] Rel. Int. [%] 1 4.3928 34.22 2 11.108 43.43 3 8 29.35 4 13.1205 36.63 13.3366 100 6 14.4197 49.36 7 15.5175 14.68 8 15.8379 17.4 9 16.2139 51.86 17.3752 44.76 11 17.7813 72.85 12 18.6993 39.41 13 20.2369 23.49 14 21.126 95.26 22.012 39.31 16 22.5384 38.64 17 23.3774 25.27 18 24.2866 80.45 19 8 52.68 25.0623 70.87 21 6 37.33 22 26.5143 48.56 23 27.9517 49.02 24 28.7252 17.67 30.7541 34.12 26 34.8799 20.8 27 37.1548 15.95 28 38.1305 28 Example 4 - Fluoromethoxypyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide (Form 1) 3-(Methoxymethyl)(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H-pyrazolecarboxylic acid (61 g, 0.173 mol) was dissolved in DMF (400 mL) and 1,1’-carbonyldiimidazole (27.99 g, 0.173 mol) was added portion wise. Once the addition was complete, the reaction was heated to 50 °C for 2 hrs. C-(3-fluoro methoxy-pyridinyl)-methylamine (26.95 g, 0.17 3mol) was added to the on mixture portion wise. The reaction was heated to 50 °C overnight. The reaction was cooled to rt and added dropwise to a 3:1 mixture of water and saturated (aq) (4000 mL). The resulting suspension was stirred for 30 min before isolating the solids by filtration. The solids were washed with water (2x500 mL) before drying in a vacuum oven to give 119 g of the crude product. The crude product was combined with two other separate batches (starting with 0.173 mol and 0.0874 mol of the acid ng material respectively) and slurried together in IPA (1400 mL) and heated to reflux. Additional portions of IPA were added until all of the material had dissolved at reflux (total of 2000 mL IPA added). The solution was held at reflux for 30 min before it was cooled to rt. The mixture was cooled further with an ter bath for 30 min before the product was collected by filtration. The solids were washed with IPA and dried to give 167.2 g of the title product (78.5% yield).
[MH]+ = 491.9 NMR (CD3OD) spectrum conformed to the NMR spectrum of Example 1.
An XRPD diffractogram (recorded using Method B) of the isolated solids e 2c) confirmed that they were of the same polymorphic form as Form 1 (Example 2 and Example 3) (Figures 2a and 2b).
Stability data A sample of Form 1 was packed in double polyethylene bags and sealed in a HDPE bottle and stored at conditions of 25 °C / 60%RH. The sample was reanalysed after 1 month and 3 months by XRPD (using Method B). The data is shown in Figure 46. No change in the XRPD diffractogram was observed when the sample was stored at 25 °C / 60%RH after either 1 month or 3 months. r tests on the sample of Form 1 stored at 25 °C / 60%RH were carried out as described in the table below: Testing intervals Test Initial 1 month 3 months Appearance Off-white solid Off-white solid ite solid Identity by retention ratio 1.00 1.00 1.00 Purity by HPLC (area %) 99.70 99.62 99.70 Total impurities (area %) 0.30 0.38 0.30 Assay by HPLC (on an anhydrous 101.0 99.5 99.6 and solvent free basis) (% w/w) HPLC assay (on an “as is” basis) (% 100.9 99.4 99.5 Water by Karl Fischer analysis (% < 0.1 < 0.1 < 0.1 Polymorph by XRPD Conforms to reference Conforms to ms to standard nce standard reference standard (Form 1) (Form 1) (Form 1) DSC Tpeak (C) 152.9 152.4 152.2 DSC Tonset (C) 151.3 151.1 150.8 A second sample of Form 1 was packed in double polyethylene bags and sealed in a HDPE bottle and stored under accelerated stability conditions of 40 °C / 75%RH. The sample was reanalysed after 1 month and 3 months by XRPD (using Method B). The data is shown in Figure 47. No change in the XRPD diffractogram was observed when the sample was stored at 40 °C / 75%RH after either 1 month or 3 months.
Further tests on the sample of Form 1 stored at 40 °C / 75%RH were d out as described in the table below: Testing intervals Test Initial 1 month 3 months Appearance Off-white solid Off-white solid ite solid Identity by retention ratio 1.00 1.00 1.00 Purity by HPLC (area %) 99.70 99.57 99.71 Total impurities (area %) 0.30 0.43 0.29 Assay by HPLC (on an anhydrous and 101.0 99.5 100.0 solvent free basis) (% w/w) HPLC assay (on an “as is” basis) (% 100.9 99.4 99.9 Water by Karl Fischer analysis (% < 0.1 < 0.1 0.1 Polymorph by XRPD Conforms to Conforms to Conforms to reference rd nce standard reference standard (Form 1) (Form 1) (Form 1) DSC Tpeak (C) 152.9 152.3 152.5 DSC Tonset (C) 151.3 151.1 150.6 Example 5 - N-[(3-Fluoromethoxypyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide (Form 2) N-[(3-fluoromethoxypyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide (19.5 mg) in 90/10 IPA/water (100 µL) was heated to dissolve the solid, filtering if necessary. The resulting solution was cooled by plunging the warm solution into a liquid en bath. The sample was then transferred into a freezer. The resulting solids were isolated to afford N-[(3-fluoromethoxypyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide (Form 2).
An XRPD diffractogram of N-[(3-fluoromethoxypyridinyl)methyl](methoxymethyl)({4-[(2- oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide (Form 2) is shown in Figure 7.
Peak position table: No. Pos. [°2Th.] Rel. Int. [%] 1 4.15 44.3 2 4.7421 100 3 9.463 55.02 4 10.8936 56.48 11.4363 21.16 6 14.2897 27.16 7 15.28 27.17 8 15.7912 20.99 9 18.6355 15.82 19.8599 41.02 11 21.389 20.04 12 21.9376 60.77 13 22.9962 20.48 14 23.6679 39 25.0948 29.42 16 26.465 33.13 17 29.2936 14.19 Example 6 - Fluoromethoxypyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide (Form 3) A suspension of N-[(3-fluoromethoxypyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide (30 mg) in 50/50 methanol/water (100 µL) was matured by temperature g for 2 days. The resulting solids were isolated to afford N-[(3-fluoro ypyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide (Form 3).
An XRPD diffractogram of N-[(3-fluoromethoxypyridinyl)methyl](methoxymethyl)({4-[(2- oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide (Form 3) is shown in Figure 8.
Peak position table: No. Pos. [°2Th.] Rel. Int. [%] 1 5.0236 100 2 10.0456 33.5 3 10.1526 38.94 4 5 6.8 14.8188 2.96 6 15.2588 2.89 7 16.3621 5.53 8 6 3.79 9 19.792 2.31 20.0456 3.56 11 20.6393 2.71 12 2 2.7 13 25.6434 1.49 14 1 8.57 27.6821 1.13 16 35.3459 3.38 Example 7 - N-[(3-Fluoromethoxypyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide (Form 4) A suspension of N-[(3-fluoromethoxypyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin hyl]phenyl}methyl)pyrazolecarboxamide (20 mg) in 50/50 methanol/water (100 µL) was heated. Not all of the solid dissolved and therefore the mixture was filtered. The filtrate was allowed to evaporate under nitrogen to afford N-[(3-fluoromethoxypyridinyl)methyl](methoxymethyl) ({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide (Form 4).
An XRPD diffractogram of N-[(3-fluoromethoxypyridinyl)methyl](methoxymethyl)({4-[(2- oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide (Form 4) is shown in Figure 9.
Example 8 to Example 20 - SALT SCREEN DATA A salt screen of N-[(3-fluoromethoxypyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide was carried out and XRPD diffractograms recorded of the products.
If the counter-ion was a solid (p-toluenesulphonic acid, ethanedisulphonic acid and benzene sulfonic acid), N-[(3-fluoromethoxypyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide (~ 15mg) was weighed into a vial with ~ 1.1 equivalents of the counter-ion as a physical solid mixture. 150 µL of the appropriate solvent was added.
If the counter ion was a liquid (5M hloric acid, 6M sulphuric acid, 85% orthophosphoric acid, methane sulphonic acid) the appropriate volume corresponding to ~ 1.1 equivalents was added to N-[(3- fluoromethoxypyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide (~ 15mg) in the chosen solvent (150µL) (mostly sion).
The mixture was shaken well by hand. All slurries or solutions were then temperature-cycled between ambient and 40°C for ~ 18-24 hrs.
If enough solid was present the atent was decanted off, if possible, and the solid dried by evaporation. If a solution was ed, the solvent was allowed to evaporate under nitrogen then dried. Any solids were examined by XRPD.
Example 8 - N-[(3-Fluoromethoxypyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide hydrochloride (Form 5) Obtained using the salt screen method described above when the solvent is EtOAc or MeCN. Acid is 5M hydrochloric acid.
An XRPD diffractogram of Form 5 is shown in Figure 10.
Example 9 - N-[(3-Fluoromethoxypyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide hydrochloride (Form 6) Obtained using the salt screen method described above when solvent is acetone. Acid is 5M hydrochloric acid.
An XRPD ctogram of Form 6 is shown in Figure 11.
Example 10 - Fluoromethoxypyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide hydrochloride (Form 7) Obtained using the salt screen method described above when solvent is THF. Acid is 5M hydrochloric acid.
An XRPD diffractogram of Form 7 is shown in Figure 12.
Example 11 – Sulfate salt of N-[(3-fluoromethoxypyridinyl)methyl](methoxymethyl)({4-[(2- oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide (Form 8) Obtained using the salt screen method described above when solvent is acetone or MeCN. Acid is 6M sulphuric acid.
An XRPD diffractogram of Form 8 is shown in Figure 13.
Example 12 – Phosphate salt of N-[(3-fluoromethoxypyridinyl)methyl](methoxymethyl)({4- [(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide (Form 9) Obtained using the salt screen method described above when solvent is acetone. Acid is 85% orthophosphoric acid.
An XRPD ctogram of Form 9 is shown in Figure 14.
Peak position table: No. Pos. [°2Th.] Rel. Int. [%] 1 4.4532 29.03 2 6.8089 6.4 3 7.2372 15.96 4 9.5928 22.07 10.0927 22.55 6 13.4475 31.38 7 14.4842 31.22 8 16.2685 77.62 9 17.2526 75.29 17.767 44.33 11 18.9329 76.89 12 19.2954 47.63 13 19.7409 29.56 14 8 100 21.1934 38.24 16 22.9919 68.51 17 23.6995 54.45 18 25.4212 55.32 19 27.1889 44.13 Example 13 – ate salt of N-[(3-fluoromethoxypyridinyl)methyl](methoxymethyl)({4- [(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide (Form 10) Obtained using the salt screen method described above when solvent is EtOAc. Acid is 85% hosphoric acid.
An XRPD diffractogram of Form 10 is shown in Figure 15.
Example 14 – Phosphate salt of N-[(3-fluoromethoxypyridinyl)methyl](methoxymethyl)({4- [(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide (Form 11) ed using the salt screen method described above when solvent is THF. Acid is 85% orthophosphoric acid.
An XRPD diffractogram of Form 11 is shown in Figure 16.
Example 15 - N-[(3-Fluoromethoxypyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide mesylate (Form 12) Obtained using the salt screen method described above when solvent is THF. Acid is methane sulphonic acid.
An XRPD diffractogram of Form 12 is shown in Figure 17.
Peak on table: No. Pos. [°2Th.] Rel. Int. [%] 1 4.9941 51.33 2 6.7123 7.1 3 10.0046 14.02 4 13.7899 14.91 14.7949 30.6 6 15.464 5.41 7 16.426 10.73 8 19.1813 31.02 9 20.3174 56.5 21.4928 32.46 11 23.2555 100 12 23.9691 26.22 13 25.0137 12.94 14 1 33.19 27.6423 14.16 16 28.8844 14.26 17 29.6868 4.92 18 30.6702 9.54 19 32.9271 4.06 Example 16 - N-[(3-Fluoromethoxypyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide mesylate (Form 13) ed using the salt screen method described above when solvent is acetone. Acid is methane sulphonic acid.
An XRPD diffractogram of Form 13 is shown in Figure 18.
Example 17 - N-[(3-Fluoromethoxypyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide tosylate (Form 14) Obtained using the salt screen method described above when solvent is acetone, EtOAc, THF or MeCN.
Acid is p-toluenesulfonic acid.
An XRPD diffractogram of Form 14 is shown in Figure 19.
Peak position table: No. Pos. [°2Th.] Rel. Int. [%] 1 4.9848 100 2 9.6143 25.67 3 12.7816 8.72 4 13.746 27.51 14.9399 14.77 6 16.3881 12.36 7 17.7628 37.11 8 18.7538 21.38 9 19.0483 19.01 20.058 29.04 11 21.0667 15.21 12 21.8804 11.45 13 23.2525 43.04 14 5 35.45 8 30.99 16 25.1144 13.88 17 28.6941 19.47 18 8 7.64 Example 18 – Edisylate salt of N-[(3-fluoromethoxypyridinyl)methyl](methoxymethyl)({4- [(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide (Form 15) Obtained using the salt screen method described above when solvent is acetone or EtOAc. Acid is ethanedisulfonic acid.
An XRPD diffractogram of Form 15 is shown in Figure 20.
Example 19 – Edisylate salt of N-[(3-fluoromethoxypyridinyl)methyl](methoxymethyl)({4- opyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide (Form 16) Obtained using the salt screen method described above when solvent is THF or MeCN. Acid is ethanedisulfonic acid.
An XRPD diffractogram of Form 16 is shown in Figure 21.
Example 20 - N-[(3-Fluoromethoxypyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide besylate (Form 17) Obtained using the salt screen method described above when solvent is acetone, EtOAc, THF or MeCN.
Acid is benzenesulfonic acid.
An XRPD diffractogram of Form 17 is shown in Figure 22.
Peak position table: No. Pos. [°2Th.] Rel. Int. [%] 1 5.3346 100 2 9.7624 59.63 3 10.6521 9.96 4 12.7094 6.69 14.2147 7.84 6 14.9024 31.52 7 15.5992 5.61 8 16.3806 26.39 9 17.4003 20.58 5 50.9 11 19.9071 58.63 12 20.9547 19.07 13 21.7211 13.78 14 22.261 24.2 23.1455 44.91 16 23.5866 19.8 17 24.5696 86.07 18 25.101 10.78 19 25.8617 22.03 26.6751 5.56 21 28.6473 10.33 22 29.1826 10.1 23 30.105 12.42 24 31.4456 4.01 38.5373 4.52 Example 21 to Example 25 - SCALE-UP MENTS Example 21 - N-[(3-Fluoromethoxypyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide hydrochloride (Form 18) N-[(3-Fluoromethoxypyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide (200mg) was heated in MeCN (2mL) so that the solid dissolved. A few crystals of primary screen sample (Form 5) were added to the warm solution followed by 5M hloric acid (90L) was added and mixed well. An oily solid separated and the mixture was ultrasonicated for ~ 1 min and the product was scratched with a spatula. The resulting sion was temperature-cycled between 40oC and t temperature overnight (18 - 24 hrs). The t amassed and MeCN (1mL) was added to mobilise before the product was filtered, washed with MeCN (2 x 1mL) and dried in a vacuum oven at 50oC for ~ 24 hrs to constant weight. (Yield 122mg) An NMR spectrum of the isolated product in O is shown in Figure 23.
An XRPD diffractogram of the isolated product (top) overlaid with Form 5 (Example 8) (bottom) is shown in Figure 24. The XRPD diffractograms showed that the isolated product (Form 18) was a different polymorphic form to that of Form 5.
Peak position table for Form 18: No. Pos. [°2Th.] Rel. Int. [%] 1 5.5212 100 2 7.2946 31.59 3 8.5234 46.13 4 11.6264 77.11 13.2243 35.95 6 14.6627 13.33 7 15.9994 10.62 8 17.0327 53.91 9 18.9939 47.87 20.6054 24.18 11 21.7408 18.27 12 22.8017 71.36 13 23.7665 40.19 14 26.1807 46.6 28.1871 19.34 16 6 16.04 17 30.6655 11.07 Simultaneous Thermal Analysis (STA) The STA data for Form 18 are shown in Figure 25. ential Scanning metry (DSC) The DSC data for Form 18 are shown in Figure 26.
Gravimetric Vapour Sorption (GVS) The GVS data for Form 18 are listed in the table below and shown in Figure 27.
%-RH %-Wt(dry basis) 0.034 0.000338 9.9796 0.236408 .0179 0.372259 .0076 0.503656 39.9983 0.661778 49.99 0.924572 59.9827 9.109051 70.02 59 80.0151 13.9262 90.0014 66.83245 85.0058 40.15885 75.0166 24.50478 64.9759 17.33807 54.9871 12.7659 44.9765 9.623504 .0013 7.124732 .013 4.993427 .0213 3.447841 4.9816 2.227407 0.0335 0.349988 Slurry studies Form 18 (20 mg) was suspended in 90/10 IPA/water (200µL or 300µL) and shaken at ambient temperature for 72 hrs. The supernatant was evaporated rather than filtered due to the small volume and the resulting solid was examined by XRPD (Figure 28). The resulting XRPD (Figure 28) showed that the resulting form after slurry with 90/10 IPA/water was different to that of Form 18.
Visual aqueous solubility Form 18 (10mg) was weighed into a glass vial and water was added in 100µL portions up to 3mL then 1mL portions thereafter. lity was assessed ly following a brief period of equilibration.
Form 18 appeared to dissolve initially in 0.1mL of water, but then reprecipitated. The solid did not then dissolve again up to 20mL.
Example 22 – Sulfate salt of N-[(3-fluoromethoxypyridinyl)methyl](methoxymethyl)({4-[(2- oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide (Form 8) N-[(3-Fluoromethoxypyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide (200mg) was heated in acetonitrile (2mL) so that the solid dissolved. 6M sulphuric acid (75L) was added to the warm solution, mixed well and ultrasonicated immediately after mixing. A slightly cloudy solution with a small quantity of oil was observed but no crystals were precipitated. A few crystals of primary screen sample were added at ambient temperature and solid rapidly amassed on further ultrasonication. The resulting suspension was temperature-cycled between 40oC and ambient ature overnight (18 - 24 hrs). The product was filtered, washed with MeCN (2 x 1mL) and dried in a vacuum oven at 50oC for ~ 24 hrs to constant weight. (Yield 133mg).
An NMR spectrum of the ed product in d6-DMSO is shown in Figure 29.
An XRPD diffractogram of the isolated product (top) overlaid with the screening sample of Form 8 (Example 11) (bottom) is shown in Figure 30. The XRPD ctograms showed that the rphic form of the isolated t was the same as the rphic form of the ing sample of Form 8 (Example 11).
Peak position table for Form 8: No. Pos. [°2Th.] Rel. Int. [%] 1 5.095 31.62 2 7.4926 14.43 3 11.3026 10.33 4 12.0297 35.43 12.6152 14.36 6 5 22.14 7 14.7487 13.8 8 15.1698 33.09 9 16.6928 11.02 17.8991 21.59 11 18.2272 22.27 12 19.2643 26.73 13 19.8687 38.21 14 20.1287 100 22.2453 32.59 16 22.7734 30.97 17 24.391 86.73 18 25.7855 29.06 19 27.3382 16.22 28.9485 9.94 21 30.1898 18.8 22 32.6891 11.46 23 3 4.92 Simultaneous Thermal is (STA) The STA data for Form 8 are shown in Figure 31.
Differential ng Calorimetry (DSC) The DSC data for Form 8 are shown in Figure 32.
Gravimetric Vapour Sorption (GVS) The GVS data for Form 8 are listed in the table below and shown in Figure 33.
%-RH %-Wt(dry basis) 0.034 0.039462 9.9777 0.440403 .0179 0.616343 .0076 0.777058 39.9993 0.638336 49.9891 0.873486 59.9817 1.213525 70.0229 2.0577 80.0122 3.989659 90.0029 14.16036 85.0092 6.295491 75.017 3.436462 4 1.643225 54.9837 0.949614 44.9949 0.563899 .0037 0.245853 .011 0.394726 .0203 0.228936 4.9806 0.078372 0.0335 0.000552 Slurry s Form 8 (20 mg) was suspended in 90/10 IPA/water (200µL or 300µL) and shaken at t temperature for 72 hrs. The supernatant was evaporated rather than filtered due to the small volume and the resulting solid was examined by XRPD (Figure 34). There was no change in the X-ray pattern ing slurry in 90/10 IPA/water.
Visual aqueous solubility Form 8 (10mg) was weighed into a glass vial and water was added in 100µL portions up to 3mL then 1mL portions fter. lity was assessed visually following a brief period of equilibration.
Form 8 completely dissolved in 0.1mL of water ( ~ >> 100mg/mL).
Example 23 - N-[(3-Fluoromethoxypyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide sulfate (Form 8) N-[(3-Fluoromethoxypyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide (2.00 g, 4.07 mmol) was stirred in MeCN (25 mL). The mixture was heated to 65 °C and held at this temperature until all of the starting material had dissolved.
To the warm solution, 6M aqueous sulphuric acid (0.75 mL, 4.5 mmol) was added. The mixture was stirred vigorously and a white solid was formed. The mixture was cooled to rt and the solids were isolated by filtration, washing with small portions of MeCN. The solids were dried for 24 hrs at 45 °C to give the title compound (2.6 g).
[MH]+ = 491.5 NMR (CD3OD) δ: 3.40 (3H, s), 4.26 (3H, s), 4.67 (2H, s), 4.82 (2H, d, J = 1.6Hz), 5.23 (2H, s), 5.35 (2H, s), 6.42-6.48 (1H, m), 6.61 (1H, d, J = 9.2Hz), 7.30 and 7.34 (each 2H, each d, J = 8.2 Hz), 7.54-7.62 (1H, m), 7.72-7.80 (2H, m), 8.18 (1H, d, J = 1.5 Hz), 8.54 (1H, d, J = 6.9Hz) ppm.
An XRPD diffractogram (recorded using Method B) of the isolated product is shown in Figure 35. The XRPD diffractogram showed that the polymorphic form of the isolated product was the same as the polymorphic form of the scaled-up sample of Form 8 in Example 22. e 24 - N-[(3-Fluoromethoxypyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide edisylate (Form 15) Ethane disulphonic acid hydrate (85mg) and N-[(3-fluoromethoxypyridinyl)methyl] (methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide (200mg) were weighed into a glass vial and acetone (2mL) was added to the physical solid e. The resulting suspension was heated but no dissolution was observed. Following onication, the mixture was ated with a spatula to dislodge slightly oily solid form the bottom of the vial. The resulting suspension was temperature-cycled between 40oC and ambient temperature ght (18 - 24 hours).
The product was filtered, washed with acetone (2 x 1mL) and dried in a vacuum oven at 50oC for ~ 24 hours to constant weight. (Yield 158mg).
An NMR spectrum of the ed product in d6-DMSO is shown in Figure 36.
An XRPD diffractogram of the isolated product (top) overlaid with the screening sample of Form 15 le 18) (bottom) is shown in Figure 37. The XRPD diffractograms indicated that the isolated product was not as crystalline as the primary screen sample (Form 15, Example 18) as revealed by intensity of peaks, but the pattern was consistent with that obtained in the primary screen (Example Peak position table for Form 15: No. Pos. [°2Th.] Rel. Int. [%] 1 5.1425 9.55 2 7.711 30.18 3 9.8944 8.48 4 10.2988 37.76 12.0881 11.57 6 5 25.73 7 14.4371 27.45 8 15.6664 26.3 9 18.3462 100 19.4459 84.42 11 20.6911 65.05 12 21.9894 18.54 13 23.2278 23.94 14 24.1041 62.77 25.0706 64.44 16 6 68.88 17 26.2107 27.72 18 28.2107 41.92 19 30.7149 38.27 32.0375 20.74 21 37.3892 11.25 22 3 16.23 23 34.1795 26.32 Simultaneous Thermal Analysis (STA) The STA data for Form 15 are shown in Figure 38. ential Scanning metry (DSC) The DSC data for Form 15 are shown in Figure 39.
Slurry studies An attempt to prepare a water slurry by mixing Form 15 (20mg) and deionised water (200µL) for 72 hrs resulted in complete dissolution of the sample.
Form 15 (20 mg) was suspended in 90/10 IPA/water (200µL or 300µL) and shaken at ambient temperature for 72 hrs. The supernatant was evaporated rather than filtered due to the small volume and the resulting solid was examined by XRPD (Figure 40). There were no differences in X-ray pattern following slurry in 90/10 IPA/water.
Visual aqueous solubility Form 15 (10mg) was weighed into a glass vial and water was added in 100µL portions up to 3mL then 1mL portions thereafter. Solubility was assessed visually following a brief period of equilibration.
Form 15 completely dissolved in 0.1mL of water ( ~ >> 100mg/mL) and then on repeat using even less water in 0.05mL (> mL).
Example 25 - N-[(3-Fluoromethoxypyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide edisylate (Form 16) Ethane disulphonic acid hydrate (85mg) and N-[(3-fluoromethoxypyridinyl)methyl] (methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide (200mg) were weighed into a glass vial and acetonitrile (2mL) was added to the physical solid mixture. The resulting suspension was heated and most of the solid dissolved except for a single agglomerate of acid.
Crystals precipitated at the higher ature before a completely clear solution was obtained. The slightly oily product was ultrasonicated and triturated with a spatula and remaining oil solidified and dispersed. The resulting suspension was temperature-cycled between 40oC and ambient temperature overnight (18 - 24 hrs). The product was filtered, washed with acetonitrile (2 x 1mL) and dried in a vacuum oven at 50oC for ~ 24 hrs to constant weight. (Yield 162mg).
An NMR spectrum of the isolated t in d6-DMSO is shown in Figure 41.
An XRPD ctogram of the isolated product (top) overlaid with the ing sample of Form 16 (Example 19) (bottom) is shown in Figure 42. The XRPD diffractograms indicated that the isolated product was not as crystalline as the primary screen sample (Form 16, e 19) as revealed by intensity of peaks, but the pattern was tent with that obtained in the primary screen (Example Peak position table for Form 16: No. Pos. ] Rel. Int. [%] 1 5.1694 14.42 2 6.0845 9.76 3 7.7237 13.84 4 10.4192 35.13 13.4025 19.6 6 14.5581 18.11 7 16.0635 32.97 8 8 31.4 9 18.4628 59.18 19.5103 65.78 11 20.8042 71.86 12 21.4525 52.29 13 22.4337 100 14 22.9305 39.42 23.2622 40.85 16 24.1582 82.29 17 25.2037 66.66 18 26.2617 35.09 19 28.2948 19.45 29.4186 15.75 21 32.1152 13.58 22 3 16.23 23 5 26.32 Simultaneous Thermal Analysis (STA) The STA data for Form 16 are shown in Figure 43.
Differential Scanning Calorimetry (DSC) The DSC data for Form 16 are shown in Figure 44.
Gravimetric Vapour Sorption (GVS) The GVS data for Form 16 are listed in the table below and shown in Figure 45.
%-RH %-Wt(dry basis) 0.0335 1.611676 9.9772 2.367329 .0183 2.626044 .0066 2.833529 40.0022 3.044856 49.9895 3.350959 59.9808 7.516016 70.0195 9.935387 80.0122 15.98189 89.9044 94.25731 3 57.40449 75.02 33.15955 64.9773 23.21695 54.9876 17.20631 44.9876 12.93879 .0032 65 .012 6.541352 .0203 4.494685 4.9811 2.865548 0.0335 0.00047 Visual aqueous solubility Form 16 (10mg) was weighed into a glass vial and water was added in 100µL portions up to 3mL then 1mL portions thereafter. Solubility was assessed visually following a brief period of equilibration.
Form 16 completely dissolved in 0.1mL of water ( ~ >> 100mg/mL) and then on repeat using even less water in 0.05mL (> 200mg/mL).
Example 26 - Biological Methods The ability of N-[(3-fluoromethoxypyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide to inhibit plasma kallikrein may be determined using the following biological assays: Determination of the IC50 for plasma kallikrein Plasma kallikrein inhibitory activity in vitro was determined using standard published methods (see e.g.
Johansen et al., Int. J. Tiss. Reac. 1986, 8, 185; Shori et al., Biochem. Pharmacol., 1992, 43, 1209; Stürzebecher et al., Biol. Chem. Hoppe-Seyler, 1992, 373, 1025). Human plasma kallikrein (Protogen) was incubated at 25 oC with the genic substrate H-DPro-Phe-Arg-AFC and various concentrations of the test compound. al enzyme activity (initial rate of on) was ined by measuring the change in optical absorbance at 410nm and the IC50 value for the test compound was ined.
When tested in this assay, N-[(3-fluoromethoxypyridinyl)methyl](methoxymethyl)({4-[(2- oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide showed an IC50 (human PKal) of 3.3 nM.
N-[(3-fluoromethoxypyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide was also screened for inhibitory activity against the related enzyme KLK1 using the following ical assay: Determination of the IC50 for KLK1 KLK1 inhibitory activity in vitro was determined using standard published methods (see e.g. Johansen et al., Int. J. Tiss. Reac. 1986, 8, 185; Shori et al., Biochem. Pharmacol., 1992, 43, 1209; Stürzebecher et al., Biol. Chem. Hoppe-Seyler, 1992, 373, 1025). Human KLK1 (Callbiochem) was incubated at 25 oC with the fluorogenic ate H-DVal-Leu-Arg-AFC and various concentrations of the test nd.
Residual enzyme activity (initial rate of reaction) was ined by measuring the change in optical absorbance at 410nm and the IC50 value for the test compound was determined.
When tested in this assay, N-[(3-fluoromethoxypyridinyl)methyl](methoxymethyl)({4-[(2- oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide showed an IC50 (human KLK1) of >40000 nM.
N-[(3-fluoromethoxypyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide was also ed for inhibitory activity t the related enzyme FXIa using the following biological assay: Determination of the % tion for FXIa FXIa inhibitory activity in vitro was determined using standard published methods (see e.g. Johansen et al., Int. J. Tiss. Reac. 1986, 8, 185; Shori et al., Biochem. Pharmacol., 1992, 43, 1209; Stürzebecher et al., Biol. Chem. Hoppe-Seyler, 1992, 373, 1025). Human FXIa (Enzyme Research Laboratories) was incubated at 25 oC with the fluorogenic substrate Z-Gly-Pro-Arg-AFC and 40 µM of the test compound.
Residual enzyme activity (initial rate of reaction) was determined by measuring the change in l absorbance at 410nm.
When tested in this assay, N-[(3-fluoromethoxypyridinyl)methyl](methoxymethyl)({4-[(2- oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide showed a % inhibition @ 40 µM (human FXIa) of 0%.
Example 27 - Pharmacokinetics A pharmacokinetic study of fluoromethoxypyridinyl)methyl](methoxymethyl)({4-[(2- oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide was performed to assess the pharmacokinetics following a single oral dose in male Sprague-Dawley rats. Two rats were given a single po dose of 5 mL/kg of a nominal 2 mg/mL (10 mg/kg) composition of test compound in vehicle.
Following dosing, blood samples were collected over a period of 24 hrs. Sample times were 5, 15 and 30 minutes then 1, 2, 4, 6, 8 and 12 hrs. Following collection, blood samples were fuged and the plasma fraction analysed for concentration of test compound by LCMS.
Oral exposure data acquired from this study for N-[(3-fluoromethoxypyridinyl)methyl] (methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide is shown below: e Dose po (mg/kg) Cmax (ng/mL) Tmax (min) % DMSO / 10% .5 1534 180 cremophor / 80% SWFI D-α-Tocopherol polyethylene glycol 1000 .1 1942 70 succinate (TPGS) solution (20% aq. w/v)

Claims (2)

1. A solid form of fluoromethoxypyridinyl)methyl](methoxymethyl)({4-[(2- idinyl)methyl]phenyl}methyl)pyrazolecarboxamide, which exhibits at least the following characteristic X-ray powder diffraction peaks (Cu Kα radiation, expressed in degrees 2θ) at approximately 11.2, 12.5, 13.2, 14.5 and 16.3.
2. The solid form according to claim 1 having an X-ray powder diffraction pattern substantially the same as that shown in
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