EP4171233A1 - Crystal forms of 2-[4-[(2,3,4-trimethoxyphenyl)methyl]piperazin -1-yl]ethyl pyridine-3-carboxylate and methods of synthesis - Google Patents

Crystal forms of 2-[4-[(2,3,4-trimethoxyphenyl)methyl]piperazin -1-yl]ethyl pyridine-3-carboxylate and methods of synthesis

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Publication number
EP4171233A1
EP4171233A1 EP21833175.9A EP21833175A EP4171233A1 EP 4171233 A1 EP4171233 A1 EP 4171233A1 EP 21833175 A EP21833175 A EP 21833175A EP 4171233 A1 EP4171233 A1 EP 4171233A1
Authority
EP
European Patent Office
Prior art keywords
compound
formula
composition
free base
crystal
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP21833175.9A
Other languages
German (de)
English (en)
French (fr)
Other versions
EP4171233A4 (en
Inventor
Neil Buckley
Dan BELMONT
Sarah Bethune
Krista DIAZ
Bryan HAUSER
Myoung Goo Kim
Kumar Kannan
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Imbria Pharmaceuticals Inc
Original Assignee
Imbria Pharmaceuticals Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Imbria Pharmaceuticals Inc filed Critical Imbria Pharmaceuticals Inc
Publication of EP4171233A1 publication Critical patent/EP4171233A1/en
Publication of EP4171233A4 publication Critical patent/EP4171233A4/en
Pending legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C07D213/80—Acids; Esters in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the invention relates to crystallographic forms of 2-[4-[(2,3,4- trimethoxyphenyl)methyl]piperazin-l-yl]ethyl pyridine-3 -carboxylate and method of chemical synthesis of that compound.
  • Heart disease is the leading cause of death worldwide, accounting for 15 million deaths across the globe in 2015. In many forms of heart disease, decreased cardiac efficiency stems from changes in mitochondrial energy metabolism. Mitochondria are sub-cellular compartments in which metabolites derived from glucose and fatty acids are oxidized to produce high-energy molecules. Increasing fatty acid oxidation in the heart decreases glucose oxidation, and vice versa. Glucose oxidation is a more efficient source of energy, but in certain types of heart disease, such as heart failure, ischemic heart disease, and diabetic cardiomyopathies, fatty acid oxidation predominates in cardiac mitochondria. As a result, the pumping capacity of the heart is reduced.
  • CV-8972 which has the IUPAC name 2-[4-[(2,3,4-trimethoxyphenyl)methyl]piperazin- l-yl]ethyl pyridine-3 -carboxylate and the following structure: was recently identified as a promising therapeutic candidate for treating or preventing cardiac conditions due to its pharmacokinetic profile.
  • crystallographic forms of CV-8972 and compositions containing them are provided herein.
  • the invention recognizes that crystals of CV-8972 exist in multiple polymorphic forms and that one polymorph, Form A, is the most stable under conditions of ambient temperature and relative humidity. Therefore, Form A crystals of CV-8972 are useful for the manufacture of pharmaceutical compositions.
  • pharmaceutical compositions that contain the Form A polymorph do not require special handling during storage or distribution.
  • such compositions may retain their efficacy better than compositions containing other polymorphs or mixtures of polymorphs.
  • the invention also provides methods of treating cardiac conditions in subject using CV-8972 polymorphs, such as Form A.
  • the invention also provides methods of synthesis of CV-8972.
  • Prior schemes for synthesis of CV-8972 require formation of a free base form of 2-[4-[(2,3,4- trimethoxyphenyl)methyl]piperazin-l-yl]ethanol, also called CV-8814, and conversion of the free base form of CV-8814 to a hydrochloride salt.
  • CV-8814 must then be converted back to its free base form for coupling to nicotinic acid to form the free base form of CV-8972.
  • the invention provides a CV-8972 synthesis scheme that bypasses the reversible conversion of CV-8814 between the free base and HC1 salt forms.
  • the free base form of CV-8814 is formed in a reductive amination reaction, and the free base product is used directly as a substrate for coupling to nicotinic acid to form CV-8972. Because fewer steps are required, the synthesis schemes of the invention are simpler, faster, and provide better yields than prior methods of making CV-8972.
  • the invention provides crystals comprising a polymorph of a compound of Formula (X):
  • the polymorph may be Form A, Form B, Form C, Form D, or Form E.
  • the crystal may be substantially free of one or more other polymorphs.
  • the crystal may include a Form A polymorph and be substantially free of polymorphs of Form B, Form C, Form D, and Form E.
  • the crystal may include a hydrochloride salt of the compound of Formula (X).
  • the crystal may include the compound of Formula (X) and the hydrochloride ion in a defined stoichiometric ratio.
  • the crystal may include the compound and the hydrochloride ion in a 1 :3 stoichiometric ratio.
  • the crystal may include a hydrated form of the compound of Formula (X).
  • the crystal may include a monohydrate form of the compound.
  • the crystal may include an anhydrous form of the compound.
  • the invention provides pharmaceutical compositions that include a polymorph of the compound of Formula (X).
  • the polymorph may be Form A, Form B, Form C, Form D, or Form E.
  • the composition may be substantially free of one or more other polymorphs.
  • the composition may include a Form A polymorph and be substantially free of polymorphs of Form B, Form C, Form D, and Form E.
  • the composition may include a hydrochloride salt of the compound of Formula (X).
  • the composition may include the compound of Formula (X) and the hydrochloride ion in a defined stoichiometric ratio.
  • the composition may include the compound and the hydrochloride ion in a 1:3 stoichiometric ratio.
  • the composition may include a hydrated form of the compound of Formula (X).
  • the composition may include a monohydrate form of the compound.
  • the composition may include an anhydrous form of the compound.
  • the composition may be formulated for any route or mode of administration.
  • the composition may be formulated for buccal, dermal, enteral, intraarterial, intramuscular, intraocular, intravenous, nasal, oral, parenteral, pulmonary, rectal, subcutaneous, topical, or transdermal administration.
  • the composition may be formulated for administration by injection or with or on an implantable medical device (e.g., stent or drug-eluting stent or balloon equivalents).
  • the composition may be formulated as a single unit dosage.
  • the composition may be formulated as divided dosages.
  • the composition may contain a defined dose of the compound.
  • the dose may contain from about 10 mg to about 2000 mg, from about 10 mg to about 1000 mg, from about 10 mg to about 800 mg, from about 10 mg to about 600 mg, from about 10 mg to about 400 mg, from about 10 mg to about 300 mg, from about 10 mg to about 200 mg, from about 25 mg to about 2000 mg, from about 25 mg to about 1000 mg, from about 25 mg to about 800 mg, from about 25 mg to about 600 mg, from about 25 mg to about 400 mg, from about 25 mg to about 300 mg, about 25 mg to about 200 mg, from about 50 mg to about 2000 mg, from about 50 mg to about 1000 mg, from about 50 mg to about 800 mg, from about 50 mg to about 600 mg, from about 50 mg to about 400 mg, from about 50 mg to about 300 mg, about 50 mg to about 200 mg, from about 100 mg to about 2000 mg, from about 100 mg to about 1000 mg, from about 100 mg to about 800 mg, from about 100 mg to about 600 mg, from about 100 mg to about 400 mg, from about 100 mg
  • the composition may contain a crystal of the compound of Formula (X).
  • the crystal may have any of the properties described above in relation to crystals of the compound.
  • the invention provides methods of treating a condition in a subject by providing to a subject having, or at risk of developing, a condition a composition containing a therapeutically effective amount of a polymorph of a compound of Formula (X).
  • the polymorph may be Form A, Form B, Form C, Form D, or Form E.
  • composition may have any of the properties described above in relation to compositions that include the compound of Formula (X), including crystals of the compound.
  • the composition may be provided by any suitable route or mode of administration.
  • the composition may be provided buccally, dermally, enterally, intraarterially, intramuscularly, intraocularly, intravenously, nasally, orally, parenterally, pulmonarily, rectally, subcutaneously, topically, transdermally, by injection, or with or on an implantable medical device (e g., stent or drug-eluting stent or balloon equivalents).
  • an implantable medical device e g., stent or drug-eluting stent or balloon equivalents.
  • the composition may be provided as a single unit dosage.
  • the composition may be provided as divided dosages.
  • the composition may be provided in one dose per day.
  • the composition may be provided in multiple doses per day.
  • the composition may be provided in two, three, four, five, six, eight, or more doses per day.
  • composition may contain a defined dose of the compound, such as any of the doses described above.
  • the dose or doses may be provided for a defined period.
  • One or more doses may be provided daily for at least one week, at least two weeks, at least three weeks, at least four weeks, at least six weeks, at least eight weeks, at least ten weeks, at least twelve weeks or more.
  • the condition may be a cardiovascular condition.
  • the cardiovascular condition may be aneurysm, angina, atherosclerosis, cardiomyopathy, cerebral vascular disease, congenital heart disease, coronary artery disease, coronary heart disease, diabetic cardiomyopathy, heart attack, heart disease, heart failure, hypertension, ischemic heart disease, pericardial disease, peripheral arterial disease, rheumatic heart disease, stroke, transient ischemic attacks, or valvular heart disease.
  • the angina may be refractory to other medical interventions.
  • the condition may be a rheumatic condition.
  • the rheumatic condition may be acute kidney injury, alcoholic cardiomyopathy, angina (e.g., refractory angina and angina associated with heart failure), ankylosing spondylitis, autoimmune-related lung disease, Behcet’s Disease, bursitis, cachexia, cardiac fibrosis, chemotherapy chronic fatigue syndrome, claudication (e.g., peripheral claudication), contrast nephropathy, cyanotic heart disease, dermatomyositis, dilated cardiomyopathy, disequilibrium, fibromyalgia, frailty, gout, Gulf War syndrome, heart failure, hypertrophic cardiomyopathy, induced nephropathy, infectious arthritis, inflammatory arthritis, inflammatory eye disease, inflammatory myositis, ischemic cardiomyopathy, juvenile idiopathic arthritis, left ventricular dysfunction, lupus, muscle myopathy, myofascial pain syndrome, myositis, osteo
  • the condition may fibrosis.
  • the fibrosis may be associated with another disease, disorder, or condition.
  • the fibrosis may include or be associated with adhesive capsulitis, aneurysm, angina, arterial stiffness, arthrofibrosis, atherosclerosis, atrial fibrosis, cardiomyopathy, cerebral vascular disease, cirrhosis, congenital heart disease coronary artery disease, coronary heart disease, Crohn's disease, cystic fibrosis, diabetic cardiomyopathy, Dupuytren's contracture, endomyocardial fibrosis, glial scar, heart attack, heart failure, high blood pressure (hypertension), idiopathic pulmonary fibrosis, ischemic heart disease, keloid, mediastinal fibrosis, myelofibrosis, nephrogenic systemic fibrosis, old myocardial infarction, pericardial disease, peripheral arterial disease, Peyronie's disease, progressive massive fibrosis, pulmonary
  • the condition may be cancer.
  • the cancer may be bladder cancer, brain cancer, breast cancer, carcinoma, cervical cancer, colon cancer, colorectal cancer, gastric cancer, glioblastoma, glioma, head and neck cancer, kidney cancer, leukemia, liposarcoma, liver cancer, lung cancer, lymphoma, medullablastoma, melanoma, muscle cancer, neuroblastoma, oligoastrocytoma, oligodendroglioma, osteosarcoma, ovarian cancer, pancreatic cancer, paraganglioma, prostate cancer, sarcoma, or thyroid cancer.
  • the invention provides methods of altering cardiac remodeling by providing to a subject that has developed, or is at risk of developing, cardiac remodeling a composition containing a therapeutically effective amount of a polymorph of a compound of Formula (X).
  • the polymorph may be Form A, Form B, Form C, Form D, or Form E.
  • composition may have any of the properties described above in relation to compositions that include the compound of Formula (X), including crystals of the compound.
  • the composition may be provided by any suitable route or mode of administration.
  • the composition may be provided buccally, dermally, enterally, intraocular intravenously, nasally, orally, parenterally, pulmonarily, subcutaneously, topically, transdermally, by injection, or with or on an implantable medical device (e.g., stent or drug-eluting stent or balloon equivalents).
  • an implantable medical device e.g., stent or drug-eluting stent or balloon equivalents.
  • the composition may be provided as a single unit dosage.
  • the composition may be provided as divided dosages.
  • the composition may be provided in one dose per day.
  • the composition may be provided in multiple doses per day.
  • the composition may be provided in two, three, four, five, six, eight, or more doses per day.
  • composition may contain a defined dose of the compound, such as any of the doses described above.
  • the dose or doses may be provided for a defined period.
  • One or more doses may be provided daily for at least one week, at least two weeks, at least three weeks, at least four weeks, at least six weeks, at least eight weeks, at least ten weeks, at least twelve weeks or more.
  • the cardiac remodeling may be associated with a disease, disorder, or condition.
  • the cardiac remodeling may be associated with a cardiovascular disease.
  • the cardiac remodeling may be associated with aberrant subclavian artery, aortic regurgitation, aortic stenosis, arteriovenous malformation and fistula, atrial septal defect, atrioventricular septal defect, bicuspid aortic valve, cardiomegaly, cardiomyopathy, coarctation of the aorta, complete heart block, concentric hypertrophy, congenital heart defects, congenital heart disease, coronary artery disease, dextrocardia, dextro-transposition of the great arteries, diabetes, diet, double aortic arch, double inlet left ventricle, double outlet right ventricle, Ebstein's anomaly, giant hepatic hemangioma, heart failure, high cholesterol, high-output hemodialysis fistula, hypertension, hypertension, hypoplastic left heart syndrome, hypoplastic right heart
  • the invention provides uses of crystals containing a polymorph of a compound of Formula (X) for making a medicament.
  • the polymorph is Form A, Form B, Form C, Form D, or Form E.
  • the crystal is substantially free of one or more other polymorphs.
  • the crystal includes a Form A polymorph and is substantially free of polymorphs of Form B, Form C, Form D, and Form E.
  • the crystal includes a hydrochloride salt of the compound of Formula (X). In embodiments of the use, the crystal includes the compound of Formula (X) and the chloride ion in a defined stoichiometric ratio. In embodiments of the use, the crystal includes the compound and the chloride ion in a 1 :3 stoichiometric ratio.
  • the medicament includes a hydrated form of the compound of Formula (X). In embodiments of the use, the medicament includes a monohydrate form of the compound. In embodiments of the use, the medicament includes an anhydrous form of the compound.
  • the medicament is formulated for buccal, dermal, enteral, intraarterial, intramuscular, intraocular, intravenous, nasal, oral, parenteral, pulmonary, rectal, subcutaneous, topical, or transdermal administration.
  • the medicament is formulated for administration by injection or with or on an implantable medical device (e.g., stent or drug-eluting stent or balloon equivalents).
  • the medicament is formulated as a single unit dosage. In embodiments of the use, the medicament is formulated as divided dosages.
  • the medicament contains from about 10 mg to about 2000 mg, from about 10 mg to about 1000 mg, from about 10 mg to about 800 mg, from about 10 mg to about 600 mg, from about 10 mg to about 400 mg, from about 10 mg to about 300 mg, from about 10 mg to about 200 mg, from about 25 mg to about 2000 mg, from about 25 mg to about 1000 mg, from about 25 mg to about 800 mg, from about 25 mg to about 600 mg, from about 25 mg to about 400 mg, from about 25 mg to about 300 mg, about 25 mg to about 200 mg, from about 50 mg to about 2000 mg, from about 50 mg to about 1000 mg, from about 50 mg to about 800 mg, from about 50 mg to about 600 mg, from about 50 mg to about 400 mg, from about 50 mg to about 300 mg, about 50 mg to about 200 mg, from about 100 mg to about 2000 mg, from about 100 mg to about 1000 mg, from about 100 mg to about 800 mg, from about 100 mg to about 600 mg, from about 100 mg to about 400 mg, from about 100 mg to about 300 mg, about 100 mg to about 100 mg to about 200
  • the step of reacting 2,3,4-trimethoxybenzaldehyde and 2-(piperazin-l-yl)ethan-l-ol may include one or more solvents, catalysts, or other chemicals.
  • the step of reacting 2,3,4- trimethoxybenzaldehyde and 2-(piperazin-l-yl)ethan-l-ol may include one or more of sodium triacetoxyborohydride, acetic acid, and 2-methyltetrahydrofuran.
  • the step of reacting 2,3,4-trimethoxybenzaldehyde and 2-(piperazin-l-yl)ethan-l-ol may be performed at a defined temperature.
  • the step of reacting 2,3,4-trimethoxybenzaldehyde and 2-(piperazin-l-yl)ethan-l-ol may be performed at from about 10°C to about 30°C, from about 15°C to about 30°C, from about 20°C to about 30°C, from about 25°C to about 30°C, from about 10°C to about 25°C, from about 15°C to about 25°C, from about 20°C to about 25°C, from about 10°C to about 20°C, or from about 15°C to about 20°C.
  • the step of reacting 2,3,4-trimethoxybenzaldehyde and 2-(piperazin-l-yl)ethan-l-ol may not include a specific solvent, catalyst, or other chemical.
  • the step of reacting 2,3,4- trimethoxybenzaldehyde and 2-(piperazin-l-yl)ethan-l-ol may not include di chi orom ethane.
  • the step of reacting the free base form of the compound of Formula (IX) with nicotinic acid may produce a free base form of the compound of Formula (X).
  • the step of reacting the free base form of the compound of Formula (IX) with nicotinic acid may include one or more solvents, catalysts, or other chemicals.
  • the step of reacting the free base form of the compound of Formula (IX) with nicotinic acid may include one or more of 1 -ethyl-3 -(3 -dimethylaminopropyl)carbodiimide, 4-(dimethylamino)pyridine, and dichloromethane.
  • the step of reacting the free base form of the compound of Formula (IX) with nicotinic acid may be performed at a defined temperature.
  • the step of reacting the free base form of the compound of Formula (IX) with nicotinic acid may be performed at from about 15°C to about 30°C, from about 20°C to about 30°C, from about 25°C to about 30°C, from about 15°C to about 25°C, from about 20°C to about 25°C, or from about 15°C to about 20°C.
  • the method may include converting the free base form of the compound of Formula (X) to a salt form of the compound of Formula (X).
  • the salt form of the compound of Formula (X) may be a HC1 salt.
  • the salt form of the compound of Formula (X) may be monohydrate.
  • the step of converting the free base form of the compound of Formula (X) to the salt form of the compound of Formula (X) may include one or more solvents, catalysts, or other chemicals.
  • the step of converting the free base form of the compound of Formula (X) to the salt form of the compound of Formula (X) may include one or more of HC1 and methyl ethyl ketone.
  • the step of converting the free base form of the compound of Formula (X) to the salt form of the compound of Formula (X) may be performed at a defined temperature.
  • the step of converting the free base form of the compound of Formula (X) to the salt form of the compound of Formula (X) may be performed at from about 40°C to about 60°C, from about 45°C to about 60°C, from about 50°C to about 60°C, from about 55°C to about 60°C, from about 40°C to about 55°C, from about 45°C to about 55°C, from about 50°C to about 55°C, from about 40°C to about 50°C, from about 45°C to about 50°C, from about 40°C to about 50°C, about 40°C, about 45°C, about 50°C, about 55°C, or about 60°C.
  • the method may include converting the salt form of the compound of Formula (X) from a first crystal form to a second crystal form.
  • Each of the first and second crystal forms may independently be Form A, Form B, Form C, Form D, or Form E.
  • the step of converting the salt form of the compound of Formula (X) from a first crystal form to a second crystal form may include one or more of changing the solvent of the salt form of the compound of Formula (X) and incubating the salt form of the compound of Formula (X), at about 60°C.
  • the method may be performed without the use of one or more solvents, catalysts, or other chemicals.
  • the method may be performed without the use of one or more of dioxane, ethylacetate, or potassium carbonate.
  • the method may include purifying the free base form of the compound of Formula (IX).
  • the method may include crystallizing the free base form of the compound of Formula (IX).
  • the invention provides methods of preparing a compound of Formula (X) by performing the steps of: reacting a compound of Formula (1): with a compound of Formula (2): to produce a free base form of a compound of Formula (IX): reacting the free base form of a compound of Formula (IX) with a compound of Formula
  • the method may include purifying the free base form of the compound of Formula (IX).
  • the method may include crystallizing the free base form of the compound of Formula (IX).
  • FIG. 1 is a space-filling three-dimensional model of the crystal structure of the Form D polymorph of CV-8972.
  • FIG. 2 is a space-filling three-dimensional model of the crystal structure of the Form D polymorph of CV-8972 at room temperature.
  • FIG. 3 is a space-filling three-dimensional model of the crystal structure of the Form A polymorph of CV-8972.
  • FIG. 4 is an XRPD diffractogram of the CV-8972 starting material.
  • FIG. 5 shows TGA and DSC thermograms of the CV-8972 starting material.
  • FIG. 6 shows XRPD diffractograms of various forms of CV-8972.
  • FIG. 7 is a polarized microscopic image of CV-8972 starting material.
  • FIG. 8 is a dynamic vapor sorption isotherm plot.
  • FIG. 9 shows XRPD diffractograms of CV-8972 before and after dynamic vapor sorption.
  • FIG. 10 shows XRPD diffractograms of CV-8972 in its dehydrated and rehydrated forms.
  • FIG. 11 shows XRPD diffractograms of various polymorphs of CV-8972.
  • FIG. 12 is a PLM image of a batch of single crystals of C22H34CI3N3O6 (CV-8972).
  • FIG. 13 shows PLM images of a crystal used for single-crystal diffractometer.
  • FIG. 14 shows images of a crystal mounted on a 100 micro Mitegen loop on the diffractometer.
  • FIG. 15 is an Ortep diagram of an asymmetric unit of the C22H34Q3N3O6 crystal.
  • FIG. 16 shows one unit cell of the C22H34CI3N3O6 crystal.
  • FIG. 17 is a diagram of hydrogen bonds networks and counter-ion pairs in the C22H34CI3N3O6 crystal.
  • FIG. 18 shows calculated and measured XRPD diagrams of the C22H34CI3N3O6 crystal.
  • FIG. 19 shows PLM images of single anhydrous crystals from recrystallized CV-8972.
  • FIG. 20 is an image of a single anhydrous crystal from recrystallized CV-8972 mounted on a tip of a glass fiber.
  • FIG. 21 is a thermal ellipsoid diagram of an asymmetric unit of the C22H32CI3N3O5 crystal.
  • FIG. 22 shows one unit cell of the C22H32CI3N3O5 crystal.
  • FIG. 23 is a diagram of hydrogen bonds networks and counter-ion pairs in the C22H32CI3N3O5 crystal.
  • FIG. 24 shows calculated and measured XRPD diagrams of the C22H34CI3N3O6 crystal.
  • CV-8972 holds promise as a therapeutic agent for treating a variety of conditions, including cardiovascular conditions, rheumatic diseases, fibrosis, and cancer.
  • CV-8972 which has the IUPAC name 2-[4-[(2,3,4- trimethoxyphenyl)methyl]piperazin-l-yl]ethyl pyridine-3 -carboxylate and the following structure: is metabolized in the body into two sets of products that increase mitochondrial energy production in different ways. In an initial reaction, the molecule is split into CV-8814, which has the following structure: and nicotinic acid. Over time, CV-8814 converted in the body to trimetazidine.
  • CV-8814 and trimetazidine inhibit beta-oxidation of fatty acids and therefore shift mitochondrial metabolism toward oxidation of glucose, a more oxygen-efficient source of energy.
  • Nicotinic acid serves as precursor for synthesis of nicotinamide adenine dinucleotide (NAD + ).
  • NAD + promotes mitochondrial respiration to drive ATP synthesis, regardless of whether glucose or fatty acids are used as the carbon source.
  • the two sets of products that result from breakdown of CV-8972 in vivo act synergistically to stimulate energy production in mitochondria in cardiac tissue and other cell types.
  • CV-8972 and its mechanism of action are described in U.S. Patent No. 10,556,013, the contents of which are incorporated herein by reference.
  • U.S. Patent No. 10,556,013 also provides a scheme for synthesis of CV-8972.
  • the scheme entails formation of a free base form of CV-8814 by reductive amination of 2,3,4- trimethoxybenzaldehyde and 2-(piperazin-l-yl)ethan-l-ol. Due to the difficulty of isolating CV- 8814 in a solid form in this prior method, the product of this reaction is then converted to a hydrochloride salt of CV-8814. However, CV-8814 must be converted back to its free base form for use in the esterification reaction with nicotinic acid that produces CV-8972.
  • the present invention recognizes that crystals of CV-8972 exist in multiple polymorphic forms.
  • One polymorph, Form A is most stable under conditions of ambient temperature and relative humidity and therefore has particular utility for the manufacture of pharmaceutical compositions. Due to the stability of Form A, compositions containing this polymorph can readily be stored and distributed without loss of therapeutic efficacy.
  • the invention provides compositions containing polymorphs of crystalline CV-8972, methods of making such compositions, and methods of using them to treat various conditions in a subject.
  • crystals of CV-8972 may exist in at least five polymorphic forms: Form A, Form B, Form C, Form D, and Form E.
  • Form A is monohydrate
  • Forms B, D, and E are anhydrous.
  • Form C was not obtained in purified form, so its hydration state could not be determined.
  • Crystals may be formed as salts of CV-8972.
  • crystals may be formed as hydrochloride salts of CV-8972.
  • FIG. 1 is a space-filling three-dimensional model of the crystal structure of the Form D polymorph of CV-8972.
  • the polymorph is a trihydrochloride salt, and chloride ions are shown in green.
  • FIG. 2 is a space-filling three-dimensional model of the crystal structure of the Form D polymorph of CV-8972 at room temperature.
  • the polymorph is a trihydrochloride salt, and chloride ions are shown in green.
  • FIG. 3 is a space-filling three-dimensional model of the crystal structure of the Form A polymorph of CV-8972.
  • the polymorph is a trihydrochloride salt, and chloride ions are shown in green.
  • the invention provides pharmaceutical compositions that contain crystals of a polymorph of CV-8972.
  • the composition may contain CV-8972 crystals in Form A, Form B, Form C, Form D, or Form E.
  • the composition may be substantially free of one or more other polymorphs.
  • the composition may include a Form A polymorph and be substantially free of polymorphs of Form B, Form C, Form D, and Form E.
  • a composition containing a polymorph of CV-8972 may be substantially free of one or more other polymorphic forms of CV-8972 if the composition contains the predominant polymorph at a defined level of purity. Purity may be expressed as the amount of predominant polymorph as a percentage of the total weight of two of more polymorphs of CV-8972.
  • the total weight is the weight of all polymorphs of CV-8972 in the composition.
  • a composition that contains the Form A polymorph and is substantially free of other polymorphs may contain Form A at a defined weight percentage of all polymorphs of CV-8972 in the composition.
  • the composition may contain Form A at at least 95% by weight, at least 96% by weight, at least 97% by weight, at least 98% by weight, at least 99% by weight, at least 99.5% by weight, at least 99.6% by weight, at least 99.7% by weight, at least 99.8% by weight, or at least 99.9% by weight of all polymorphs of CV-8972 in the composition.
  • the total weight is the weight of selected polymorphs of CV- 8972 in the composition.
  • a composition that contains the Form A polymorph and is substantially free of the Form B polymorph may contain Form A at a defined weight percentage of Forms A and B.
  • the composition may contain Form A at at least 95% by weight, at least 96% by weight, at least 97% by weight, at least 98% by weight, at least 99% by weight, at least 99.5% by weight, at least 99.6% by weight, at least 99.7% by weight, at least 99.8% by weight, or at least 99.9% by weight of Forms A and B of CV-8972 in the composition.
  • compositions that contains the Form A polymorph and is substantially free of the Form B and C polymorphs may contain Form A at a defined weight percentage of Forms A, B, and C.
  • the composition may contain Form A at at least 95% by weight, at least 96% by weight, at least 97% by weight, at least 98% by weight, at least 99% by weight, at least 99.5% by weight, at least 99.6% by weight, at least 99.7% by weight, at least 99.8% by weight, or at least 99.9% by weight of Forms A, B, and C of CV-8972 in the composition.
  • a composition containing a polymorph of CV-8972 may be substantially free of one or more other polymorphic forms of CV-8972 if the composition contains the secondary polymorphs at levels below a defined level. Presence of a secondary polymorphs may be defined as the amount of one or more secondary polymorphs as a percentage of the total weight of two of more polymorphs of CV-8972.
  • the total weight is the weight of all polymorphs of CV-8972 in the composition.
  • a composition that contains the Form A polymorph and is substantially free of other polymorphs may contain all polymorphs other than Form A at a defined weight percentage of all polymorphs of CV-8972 in the composition.
  • the composition may contain all polymorphs other than Form A at below 5% by weight, below 4% by weight, below 3% by weight, below 2% by weight, below 1% by weight, below 0.5% by weight, below 0.4% by weight, below 0.3% by weight, below 0.2% by weight, or below 0.1% by weight of all polymorphs of CV-8972 in the composition.
  • the total weight is the weight of selected polymorphs of CV- 8972 in the composition.
  • a composition that contains the Form A polymorph and is substantially free of the Form B polymorph may contain Form B at a defined weight percentage of Forms A and B.
  • the composition may contain Form B at below 5% by weight, below 4% by weight, below 3% by weight, below 2% by weight, below 1% by weight, below 0.5% by weight, below 0.4% by weight, below 0.3% by weight, below 0.2% by weight, or below 0.1% by weight of Forms A and B of CV-8972 in the composition.
  • compositions that contains the Form A polymorph and is substantially free of the Form B and Form C polymorphs may contain Forms B and C at a defined weight percentage of Forms A, B, and C.
  • the composition may contain Forms B and C at below 5% by weight, below 4% by weight, below 3% by weight, below 2% by weight, below 1% by weight, below 0.5% by weight, below 0.4% by weight, below 0.3% by weight, below 0.2% by weight, or below 0.1% by weight of Forms A , B, and C of CV-8972 in the composition.
  • the composition may include a hydrochloride salt of a CV-8972 polymorph.
  • the composition may include CV-8972 and the chloride ion a defined stoichiometric ratio.
  • the composition may include CV-8972 and the chloride ion in a 1 :3 stoichiometric ratio.
  • the composition may include a hydrated form of CV-8972.
  • the composition may include a monohydrate form of CV-8972, such as the Form A polymorph.
  • the composition may include an anhydrous form of CV-8972, such as a Form B, Form D, or Form E polymorph.
  • the composition may be formulated for any route or mode of administration.
  • the composition may be formulated for buccal, dermal, enteral, intraarterial, intramuscular, intraocular, intravenous, nasal, oral, parenteral, pulmonary, rectal, subcutaneous, topical, or transdermal administration.
  • the composition may be formulated for administration by injection or with or on an implantable medical device (e.g., stent or drug-eluting stent or balloon equivalents).
  • the composition may be formulated as a single unit dosage.
  • the composition may be formulated as divided dosages.
  • the composition may contain a defined dose of CV-8972.
  • the dose may contain from about 10 mg to about 2000 mg, from about 10 mg to about 1000 mg, from about 10 mg to about 800 mg, from about 10 mg to about 600 mg, from about 10 mg to about 400 mg, from about 10 mg to about 300 mg, from about 10 mg to about 200 mg, from about 25 mg to about 2000 mg, from about 25 mg to about 1000 mg, from about 25 mg to about 800 mg, from about 25 mg to about 600 mg, from about 25 mg to about 400 mg, from about 25 mg to about 300 mg, about 25 mg to about 200 mg, from about 50 mg to about 2000 mg, from about 50 mg to about 1000 mg, from about 50 mg to about 800 mg, from about 50 mg to about 600 mg, from about 50 mg to about 400 mg, from about 50 mg to about 300 mg, about 50 mg to about 200 mg, from about 100 mg to about 2000 mg, from about 100 mg to about 1000 mg, from about 100 mg to about 800 mg, from about 100 mg to about 600 mg, from about 100 mg to about 400 mg, from about
  • a pharmaceutical composition containing a polymorph of CV-8972 may be in a form suitable for oral use, such as tablets, troches, lozenges, fast-melts, dispersible powders or granules, or capsules.
  • Compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the polymorph in admixture with non-toxic pharmaceutically acceptable excipients.
  • excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid, or talc.
  • inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate
  • granulating and disintegrating agents for example corn starch, or alginic acid
  • binding agents for example starch, gelatin or acacia
  • lubricating agents for example magnesium stearate, stearic acid, or talc.
  • Formulations for oral use may also be presented as hard gelatin capsules in which the compounds are mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate or kaolin.
  • the formulation may allow controlled release of the polymorph of CV-8972 in the gastrointestinal tract by encapsulating the polymorph in an enteric coating.
  • Dispersible powders and granules provide the compounds in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
  • a dispersing or wetting agent for example sweetening, flavoring and coloring agents, may also be present.
  • compositions may contain mixtures that include erodible polymers that promote swelling of the mixture in an aqueous environment.
  • An erodible polymer is any polymer that breaks down inside the body within a physiologically relevant time frame.
  • the erodible polymer may have other characteristics that promote the gradual release of the polymorphic form of CV-8972 from the mixture.
  • the polymer may be one or more of the following: biocompatible, i.e., not harmful to living tissue; hydrophilic; hygroscopic; tending to form a hydrogel.
  • the polymer-containing mixtures may promote gradual release by one or more mechanisms. For example, swelling of the mixture by absorption of water may facilitate diffusion of the polymorphic form of CV-8972 from the mixture. Degradation of the polymer may also allow the polymorphic form of CV-8972 to be released from the mixture. Osmotic pressure due the high concentration gradient of compound between the inside and outside of the mixture may also contribute to diffusion of the polymorphic form of CV-8972 from the mixture.
  • the polymer may be a cellulose derivative, a gelatin derivative, e.g., a cross-linked gelatin derivative, or a polyester derivative.
  • Derivatives of cellulose is a linear chain b(1®4) linked D-glucose units, include polymers that contain substitutions on one of more of the hydroxyl groups of each glucose unit. Substituents may be organic or inorganic and are typically attached via ester or ether linkages.
  • Cellulose ester derivatives include carboxymethyl cellulose (CMC), e.g., sodium carboxymethyl cellulose, ethyl cellulose, ethyl hydroxyethyl cellulose, ethyl methyl cellulose, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), and methylcellulose.
  • CMC carboxymethyl cellulose
  • HPMC hydroxypropyl methylcellulose
  • Cellulose ether derivatives include cellulose acetate, cellulose acetate butyrate, cellulose acetate propionate, cellulose propionate, cellulose sulfate, cellulose triacetate, and nitrocellulose.
  • cellulose-based polymers to form biodegradable hydrogels is known in the art and described in, for example, Sannino, et al., Biodegradable Cellulose-based Hydrogels: Design and Applications, Materials 2009, 2, 353-373; doi:10.3390/ma2020353, the contents of which are incorporated herein by reference.
  • the mixture may contain multiple polymers or multiple polymeric forms of the same polymer.
  • HPMC polymeric forms may differ in a variety of physical properties, including viscosity, degree of methoxyl substitution, degree of hydroxypropoxyl substitution, or average molecule weight.
  • the viscosity of a HMPC polymeric form may be determined by testing under standard conditions, including the concentration of HMPC in the solution and the temperature of the solution.
  • the HPMC concentration may be 1%, 1.5%, 2%, 2.5%, or 3%.
  • the temperature of the solution may be 15°C, 16°C, 17°C, 18°C, 19°C, 20°C, 21°C, 22°C, 23°C, 24°C, or 25°C.
  • a polymeric form of a cellulose derivative, such as HPMC may have a defined viscosity.
  • a polymeric form of HPMC may have a viscosity of from about 2 cP to about 4 cP, from about 4 cP to about 6 cP, from about 5 cP to about 8 cP, from about 12 cP to about 18 cP, from about 40 cP to about 60 cP, from about 80 cP to about 120 cP, from about 300 cP to about 500 cP, from about 1200 cP to about 2400 cP, from about 2500 cP to about 5000 cP, from about 9000 cP to about 18,000 cP, from about 12,000 cP to about 24,000 cP, from about 12,000 cP to about 24,000 cP, from about 75,000 cP to about 150,000 cP, at least about 2 cP at least about 4 cP at least about 5 cP at least about 12
  • Polymeric forms of cellulose derivatives may vary in their degree of substitution of the glucose units.
  • the degree of substitution may be expressed as a weight percentage of the substituent or as a molar ratio of substituent to glucose unit.
  • the polymeric form may be described by the degree of substitution for each substituent.
  • Each polymeric form of HPMC may independently have a defined degree of methoxyl substitution.
  • the degree of methoxyl substitution may be from about 19% to about 24%, from about 22% to about 24%, from about 27% to about 30%, from about 27% to about 30%, or from about 28% to about 32%.
  • Each polymeric form of HPMC may independently have a defined degree of hydroxypropoxyl substitution.
  • the degree of hydroxypropoxyl substitution may be from about 4% to about 8%, from about 7% to about 10%, from about 7% to about 12%, from about 8% to about 10%, from about 8% to about 11%, or from about 9% to about 12%.
  • Each polymeric form of HPMC may independently have a defined average molecular weight.
  • the average molecular weight may be about 10 kDa, about 13 kDa, about 20 kDa, about 26 kDa, about 41 kDa, about 63 kDa, about 86 kDa, about 110 kDa, about 120 kDa, about 140 kDa, about 180 kDa, or about 220 kDa.
  • a polymer such as HPMC
  • a polymer such as HPMC
  • Pharmaceutical compositions may include modified-release formulations that contain one or more polymorphic forms of CV-8972.
  • the formulations contain mixtures that include one or more polymorphic forms of CV-8972 and one or more erodible polymers that promote swelling of the mixture in an aqueous environment.
  • the hygroscopic and erodible properties of the polymers may allow the mixture to form a hydrogel that slowly breaks down in the digestive tract of the subject. Consequently, the mixture promotes the steady release of the polymorphic form of CV-8972 and metabolic products thereof into circulation.
  • the mixture may contain a defined amount of the polymorphic form of CV-8972.
  • the mixture may contain at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, or at least 80% by weight of the polymorphic form of CV-8972.
  • the mixture may contain the polymorphic form of CV-8972 and the polymer in a defined weight ratio.
  • the mixture may contain the polymorphic form of CV-8972 and the polymer in a weight ratio of about 1:5, about 1 :4, about 1:3, about 1 :2, about 1:1, about 3:2, about 2:1, about 3:1, about 4:1, about 5:1, from about 1:100 to about 100:1, from about 1 : 100 to about 50:1, from about 1 : 100 to about 20: 1, from about 1 : 100 to about 10: 1, from about 1:100 to about 5:1, from about 1:100 to about 2:1, from about 1:50 to about 100:1, from about 1:50 to about 50:1, from about 1:50 to about 20:1, from about 1:50 to about 10:1, from about 1:50 to about 5:1, from about 1 :50 to about 2:1, from about 1 :20 to about 100: 1, from about 1 :20 to about 50:1, from about 1 :20 to about 20: 1, from about 1 :20 to about 10:
  • the pharmaceutical composition may be formulated for a particular route of administration.
  • the pharmaceutical may be formulated for oral, enteral, intravenous, or rectal administration.
  • the pharmaceutical composition may be formulated as a unit dosage containing a defined amount of the polymorphic form of CV-8972.
  • the unit dosage may contain about 5 mg, about 10 mg, about 20 mg, about 50 mg, about 100 mg, about 200 mg, about 500 mg, from about 5 mg to about 10 mg, from about 5 mg to about 20 mg, from about 5 mg to about 50 mg, from about 5 mg to about 100 mg, from about 5 mg to about 200 mg, from about 5 mg to about 500 mg, from about 10 mg to about 20 mg, from about 10 mg to about 50 mg, from about 10 mg to about 100 mg, from about 10 mg to about 200 mg, from about 10 mg to about 500 mg, from about 20 mg to about 50 mg, from about 20 mg to about 100 mg, from about 20 mg to about 200 mg, from about 20 mg to about 500 mg, from about 50 mg to about 100 mg, from about 50 mg to about 200 mg, from about 50 mg to about 500 mg, from about 100 mg to about 200 mg, from about 100 mg to about 500 mg, or from about 200 mg to about 500 mg
  • the pharmaceutical composition may be formulated such that it produces a defined value for one or more parameters, as described below in relation to methods of the invention.
  • the parameter may be Cm®, the interval between administration and achieving Cm ® , T 1/2, or AUC.
  • compositions of the invention may contain excipients.
  • the composition may contain sweetening agents, flavoring agents, coloring agents, or preserving agents.
  • the compositions may contain one or more of mannitol, starch, and magnesium stearate.
  • the invention provides methods of treating a condition in a subject by providing a polymorph of CV-8972.
  • the polymorph may be Form A, Form B, Form C, Form D, or Form E.
  • the polymorph of CV-8972 may be provided in a pharmaceutical composition, as described above. In certain embodiments of the methods, only a polymorph of Form A is provided.
  • the polymorph of CV-8972 may be provided by any suitable route or mode of administration.
  • the polymorph of CV-8972 may be provided buccally, dermally, enterally, intraarterially, intramuscularly, intraocularly, intravenously, nasally, orally, parenterally, pulmonarily, rectally, subcutaneously, topically, transdermally, by injection, or with or on an implantable medical device (e.g., stent or drug eluting stent or balloon equivalents).
  • an implantable medical device e.g., stent or drug eluting stent or balloon equivalents.
  • the polymorph of CV-8972 may be provided according to a dosing regimen.
  • a dosing regimen may include a dosage, a dosing frequency, or both.
  • Doses may be provided at any suitable interval. For example and without limitation, doses may be provided once per day, twice per day, three times per day, four times per day, five times per day, six times per day, eight times per day, once every 48 hours, once every 36 hours, once every 24 hours, once every 12 hours, once every 8 hours, once every 6 hours, once every 4 hours, once every 3 hours, once every two days, once every three days, once every four days, once every five days, once every week, twice per week, three times per week, four times per week, or five times per week.
  • the dose may contain a defined amount of CV-8972 that improves cardiac mitochondrial function, such as any of the doses described above in relation to pharmaceutical compositions containing a polymorph of CV-8972.
  • the dose may be provided in a single dosage, i.e., the dose may be provided as a single tablet, capsule, pill, etc.
  • the dose may be provided in a divided dosage, i.e., the dose may be provided as multiple tablets, capsules, pills, etc.
  • the dosing may continue for a defined period.
  • doses may be provided for at least one week, at least two weeks, at least three weeks, at least four weeks, at least six weeks, at least eight weeks, at least ten weeks, at least twelve weeks or more.
  • the subject may be a human.
  • the subject may be a human that has a cardiovascular condition, rheumatic condition, fibrosis, or cancer.
  • the subject may be a human that is at risk of developing a cardiovascular condition, rheumatic condition, fibrosis, or cancer.
  • a subject may be at risk of developing a condition if the subject does not meet established criteria for diagnosis of the condition but has one or more symptoms, markers, or other factors that indicate the subject is likely to meet the diagnostic criteria for the condition in the future.
  • the subject may be a pediatric, a newborn, a neonate, an infant, a child, an adolescent, a pre-teen, a teenager, an adult, or an elderly subject.
  • the subject may be in critical care, intensive care, neonatal intensive care, pediatric intensive care, coronary care, cardiothoracic care, surgical intensive care, medical intensive care, long-term intensive care, an operating room, an ambulance, a field hospital, or an out-of-hospital field setting.
  • Conditions that may be treated with a polymorph of CV-8972 may be treated with a polymorph of CV-8972
  • the invention provides methods of treating a condition in a subject by providing a polymorph of CV-8972.
  • the condition may be any disease, disorder, or condition for which increasing mitochondrial energy production provides a therapeutic benefit.
  • the condition may be a cardiac condition.
  • the cardiac condition may be aneurysm, angina, atherosclerosis, cardiomyopathy, cerebral vascular disease, congenital heart disease coronary artery disease (CAD), coronary heart disease, diabetic cardiomyopathy, heart attack, heart disease, heart failure, high blood pressure (hypertension), ischemic heart disease, pericardial disease, peripheral arterial disease, refractory angina, rheumatic heart disease, stable angina, stroke, transient ischemic attack, unstable angina, or valvular heart disease.
  • CAD congenital heart disease coronary artery disease
  • CAD congenital heart disease coronary artery disease
  • CAD congenital heart disease coronary artery disease
  • CAD congenital heart disease coronary artery disease
  • CAD congenital heart disease
  • Angina pectoris is chest pain or pressure that is typically due to insufficient blood flow to the heart muscle.
  • the pain or discomfort is retrosternal or left-sided and may radiate to the left arm, neck, jaw, or back.
  • Stable angina also called effort angina, is related to myocardial ischemia.
  • chest discomfort and associated symptoms are usually triggered by some physical activity, such as running or walking, but symptoms are minimal or non-existent when the patient is at rest or has taken sublingual nitroglycerin. Symptoms typically abate several minutes after activity and recur when activity resumes. Symptoms may also be induced by cold weather, heavy meals, and emotional stress.
  • Unstable angina is angina that changes or worsens. Unstable angina has at least one of the following features: (1) it occurs at rest or with minimal exertion, usually lasting more than 10 minutes, (2) it is severe and of new onset, i.e., within the prior 4-6 weeks, and (3) it occurs with a crescendo pattern, i.e., distinctly more severe, prolonged, or frequent than before.
  • Cardiac syndrome X also called microvascular angina, is angina-like chest pain, in the context of normal epicardial coronary arteries on angiography. Its primary cause is unknown, but factors apparently involved are endothelial dysfunction and reduced flow in the tiny resistance blood vessels of the heart.
  • Microvascular angina may be part of the pathophysiology of ischemic heart disease.
  • Refractory angina is a chronic condition (> 3 months in duration) in which angina (1) occurs in the context of coronary artery disease (CAD), (2) cannot be controlled by a combination of optimal medical therapy, angioplasty, or bypass surgery, and (3) in which reversible myocardial ischemia has been clinically established to be the cause of the symptoms.
  • CAD coronary artery disease
  • Providing a polymorph of CV-8972 may improve cardiac efficiency in the subject.
  • cardiac efficiency A variety of definitions of cardiac efficiency exist in the medical literature. See, e.g., Schipke, J.D. Cardiac efficiency, Basic Res. Cardiol. 89:207-40 (1994); and Gibbs, C.L. and Barclay, C.J. Cardiac efficiency, Cardiovasc. Res. 30:627-634 (1995), incorporated herein by reference.
  • One definition of cardiac mechanical efficiency is the ratio of external cardiac power to cardiac energy expenditure by the left ventricle. See Lopaschuk G.D., et al., Myocardial Fatty Acid Metabolism in Health and Disease, Phys. Rev. 90:207-258 (2010), incorporated herein by reference.
  • Another definition is the ratio between stroke work and oxygen consumption, which ranges from 20-25% in the normal human heart. Visser, F., Measuring cardiac efficiency: is it useful? Hear Metab. 39:3-4 (2008), incorporated herein by reference. Another definition is the ratio of the stroke volume to mean arterial blood pressure. Any suitable definition of cardiac efficiency may be used to measure the effects of compounds of the invention
  • a polymorph of CV-8972 may be used to treat a rheumatic disease, disorder, or condition.
  • a rheumatic disease, disorder, or condition is any condition that affects the joints, tendons, ligaments, bones, muscles, or connective tissue or is associated with pain in or more of such tissues.
  • the rheumatic disease, disorder, or condition may primarily affect the joints, tendons, ligaments, bones, muscles, or connective tissue.
  • Examples of such conditions include ankylosing spondylitis, autoimmune-related lung disease, Behcet’s Disease, bursitis, chronic fatigue syndrome, dermatomyositis, fibromyalgia, gout, Gulf War syndrome, infectious arthritis, inflammatory arthritis, inflammatory eye disease, inflammatory myositis, juvenile idiopathic arthritis, lupus, myofascial pain syndrome, osteoarthritis, osteonecrosis of the jaw, osteoporosis, polymyalgia rheumatica, polymyositis, psoriatic arthritis, rheumatoid arthritis, sarcoidosis, scleroderma, Sjogren’s syndrome, tendinitis, and vasculitis.
  • the rheumatic disease, disorder, or condition may primarily affect the cardiovascular system and have secondary effects on the joints, tendons, ligaments, bones, muscles, or connective tissue.
  • the condition may be alcoholic cardiomyopathy, aneurysm, angina (including refractory angina and angina in the context of heart failure), atherosclerosis, cardiac fibrosis, cardiomyopathy, cerebral vascular disease, claudication (e.g., peripheral claudication) congenital heart disease coronary artery disease, coronary heart disease, cyanotic heart disease, diabetic cardiomyopathy, dilated cardiomyopathy, heart attack, heart failure, high blood pressure (hypertension), hypertrophic cardiomyopathy, ischemic cardiomyopathy, ischemic heart disease, left ventricular dysfunction, pericardial disease, peripheral arterial disease, rheumatic heart disease, stroke, transient ischemic attacks, or valvular heart disease.
  • the rheumatic disease, disorder, or condition may be a rare muscle disease.
  • the condition may be CAV3-related distal myopathy, Duchenne Muscular Dystrophy, hypertrophic cardiomyopathy, isolated hyperCKemia, limb-girdle muscular dystrophy 1C, muscle myopathy, myositis, or rippling muscle disease.
  • the rare muscle disease may be associated with a mutation in BICD2, CAV3, or DMD.
  • the rheumatic disease, disorder, or condition may be a glycogen storage disease.
  • the glycogen storage disease may be aldolase A deficiency, Andersen disease, Cori's disease, Fanconi-Bickel syndrome, Hers' disease, Lafora disease, McArdle disease, Pompe's disease, Tarui's disease, or von Gierke's disease.
  • the glycogen storage disease may be associated with a deficiency in an enzyme or protein, such as acid alpha-glucosidase, aldolase A, b-enolase, glucose transporter, glucose-6-phosphatase, glycogen branching enzyme, glycogen debranching enzyme, glycogen synthase, glycogenin-1, liver glycogen phosphorylase, muscle glycogen phosphorylase, muscle lactate dehydrogenase, muscle phosphofructokinase, muscle phosphoglycerate mutase, phosphoglycerate mutase, or phosphorylase kinase.
  • an enzyme or protein such as acid alpha-glucosidase, aldolase A, b-enolase, glucose transporter, glucose-6-phosphatase, glycogen branching enzyme, glycogen debranching enzyme, glycogen synthase, glycogenin-1, liver glycogen phosphorylase, muscle glycogen phosphorylase, muscle lactate dehydrogenase,
  • the glycogen storage disease may be associated with a mutation in a gene, such as AGL, ALDOA, EN03, G6PC, GAA, GBE1, GLUT2, GYG1, GYS2, LDHA, PGAM2, PGAM2, PHKA1, PHKA2, PHKB, PHKG2, PKFM, PYGL, PYGM, or SLC37A4.
  • a gene such as AGL, ALDOA, EN03, G6PC, GAA, GBE1, GLUT2, GYG1, GYS2, LDHA, PGAM2, PGAM2, PHKA1, PHKA2, PHKB, PHKG2, PKFM, PYGL, PYGM, or SLC37A4.
  • the rheumatic disease, disorder, or condition may be another condition that affects the joints, tendons, ligaments, bones, muscles, or connective tissue, such as acute kidney injury, cachexia, chemotherapy induced nephropathy, contrast nephropathy, disequilibrium, frailty, pulmonary arterial hypertension, pulmonary fibrosis, sarcopenia, tinnitus, or vertigo.
  • a polymorph of CV-8972 may be used to treat fibrosis or a disease, disorder, or condition associated with fibrosis.
  • the methods are useful for treating diseases, disorders, or conditions in which fibrosis in an organ or tissue is associated with reduced energy production by that organ or tissue.
  • the fibrosis may affect any organ or tissue, such as the heart, lungs, liver, brain, cardiovascular system, joints, gastrointestinal system, limbs, digits, skin, bone marrow, or penis.
  • the fibrosis may be associated with another condition, e.g., it may be secondary to another condition, or it may lead to the other condition.
  • the fibrosis may include or be associated with adhesive capsulitis, aneurysm, angina, arterial stiffness, arthrofibrosis, atherosclerosis, atrial fibrosis, cardiomyopathy, cerebral vascular disease, cirrhosis, congenital heart disease coronary artery disease, coronary heart disease, Crohn's disease, cystic fibrosis, diabetic cardiomyopathy, Dupuytren's contracture, endomyocardial fibrosis, glial scar, heart attack, heart failure, high blood pressure (hypertension), idiopathic pulmonary fibrosis, ischemic heart disease, keloid, mediastinal fibrosis, myelofibrosis, nephrogenic systemic fibrosis, old myocardial infarction, pericardial disease, peripheral arterial disease, Peyronie's
  • a polymorph of CV-8972 may be used to treat cancer.
  • the cancer may be bladder cancer, brain cancer, breast cancer, carcinoma, cervical cancer, colon cancer, colorectal cancer, gastric cancer, glioblastoma, glioma, head and neck cancer, kidney cancer, leukemia, liposarcoma, liver cancer, lung cancer, lymphoma, medullablastoma, melanoma, muscle cancer, neuroblastoma, oligoastrocytoma, oligodendroglioma, osteosarcoma, ovarian cancer, pancreatic cancer, paraganglioma, prostate cancer, sarcoma, or thyroid cancer.
  • the invention also provides CV-8972 synthesis schemes in which the free base form of CV-8814 formed as a product in the reductive amination reaction can be used directly as a substrate in the esterification reaction.
  • the invention is based in part on the identification of conditions that improve the stability of CV-8814 free base and allow the free base form to be crystallized.
  • the schemes provided herein obviate the need to convert CV-8814 from its free base form to a HC1 salt and then back to the free base form. Consequently, the invention provides simpler, quicker, and higher-yield methods for making CV-8972.
  • the invention provides methods for preparing a compound of Formula (X): (X), by performing the steps of: reacting 2,3,4-trimethoxybenzaldehyde and 2-(piperazin-l-yl)ethan-l-ol to produce a free base form of a compound of Formula (IX): reacting the free base form of the compound of Formula (IX) with nicotinic acid to produce the compound of Formula (X), wherein the method does not comprise producing a salt form of the compound of Formula (IX).
  • 2,3,4-trimethoxybenzaldehyde has the following structure:
  • 2-(piperazin-l-yl)ethan-l-ol has the following structure:
  • Nicotinic acid has the following structure:
  • the step of reacting 2,3,4-trimethoxybenzaldehyde and 2-(piperazin-l-yl)ethan-l-ol may include one or more solvents, catalysts, or other chemicals.
  • the step of reacting 2,3,4- trimethoxybenzaldehyde and 2-(piperazin-l-yl)ethan-l-ol may include one or more of sodium triacetoxyborohydride, acetic acid, and 2-methyltetrahydrofuran.
  • the step of reacting 2,3,4-trimethoxybenzaldehyde and 2-(piperazin-l-yl)ethan-l-ol may be performed at a defined temperature.
  • the step of reacting 2,3,4-trimethoxybenzaldehyde and 2-(piperazin-l-yl)ethan-l-ol may be performed at from about 10°C to about 30°C, from about 15°C to about 30°C, from about 20°C to about 30°C, from about 25°C to about 30°C, from about 10°C to about 25°C, from about 15°C to about 25°C, from about 20°C to about 25°C, from about 10°C to about 20°C, or from about 15°C to about 20°C.
  • the step of reacting 2,3,4-trimethoxybenzaldehyde and 2-(piperazin-l-yl)ethan-l-ol may not include a specific solvent, catalyst, or other chemical.
  • the step of reacting 2,3,4- trimethoxybenzaldehyde and 2-(piperazin-l-yl)ethan-l-ol may not include di chi orom ethane.
  • the step of reacting the free base form of the compound of Formula (IX) with nicotinic acid may produce a free base form of the compound of Formula (X).
  • the step of reacting the free base form of the compound of Formula (IX) with nicotinic acid may include one or more solvents, catalysts, or other chemicals.
  • the step of reacting the free base form of the compound of Formula (IX) with nicotinic acid may include one or more of 1 -ethyl-3 -(3 -dimethylaminopropyl)carbodiimide, 4-(dimethylamino)pyridine, and dichloromethane.
  • the step of reacting the free base form of the compound of Formula (IX) with nicotinic acid may be performed at a defined temperature.
  • the step of reacting the free base form of the compound of Formula (IX) with nicotinic acid may be performed at from about 15°C to about 30°C, from about 20°C to about 30°C, from about 25°C to about 30°C, from about 15°C to about 25°C, from about 20°C to about 25°C, or from about 15°C to about 20°C.
  • the method may include converting the free base form of the compound of Formula (X) to a salt form of the compound of Formula (X).
  • the salt form of the compound of Formula (X) may be a HC1 salt.
  • the salt form of the compound of Formula (X) may be monohydrate.
  • the step of converting the free base form of the compound of Formula (X) to the salt form of the compound of Formula (X) may include one or more solvents, catalysts, or other chemicals.
  • the step of converting the free base form of the compound of Formula (X) to the salt form of the compound of Formula (X) may include one or more of HC1 and methyl ethyl ketone.
  • the step of converting the free base form of the compound of Formula (X) to the salt form of the compound of Formula (X) may be performed at a defined temperature.
  • the step of converting the free base form of the compound of Formula (X) to the salt form of the compound of Formula (X) may be performed at from about 40°C to about 60°C, from about 45°C to about 60°C, from about 50°C to about 60°C, from about 55°C to about 60°C, from about 40°C to about
  • 50°C from about 45°C to about 50°C, from about 40°C to about 50°C, about 40°C, about 45°C, about 50°C, about 55°C, or about 60°C.
  • the compound of Formula (X) may exist in at least five crystal forms: Form A, Form B, Form C, Form D, and Form E.
  • Form A is monohydrate
  • Forms B, D, and E are anhydrous.
  • the method may include converting the compound of Formula (X) from a first crystal form to a second crystal form.
  • Each of the first and second crystal forms may independently be Form A, Form B, Form C, Form D, or Form E.
  • the method may include one or more of the following conversions of the compound of Formula (X): from an anhydrous form to a hydrated form; from a hydrated form to an anhydrous form; from one anhydrous form to another; and from one hydrated form to another.
  • the step of converting the salt form of the compound of Formula (X) from a first crystal form to a second crystal form may include one or more of changing the solvent of the salt form of the compound of Formula (X) and incubating the salt form of the compound of Formula (X), at about 60°C.
  • the method may be performed without the use of one or more solvents, catalysts, or other chemicals.
  • the method may be performed without the use of one or more of dioxane, ethylacetate, or potassium carbonate.
  • the method may include purifying the free base form of the compound of Formula (IX).
  • the method may include crystallizing the free base form of the compound of Formula (IX).
  • CV-8972 which has the structure of Formula (X)
  • the CV-8972 starting material was characterized by X-ray powder diffraction (XRPD), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), dynamic vapor sorption (DVS), and polarized light microscopy (PLM).
  • XRPD X-ray powder diffraction
  • TGA thermogravimetric analysis
  • DSC differential scanning calorimetry
  • DVS dynamic vapor sorption
  • PLM polarized light microscopy
  • the data showed that the material is crystalline in nature and has similar XRPD pattern to that of the Form A.
  • polymorph/single crystal screening experiments were set up under 34 conditions using methods of vapor diffusion, slow evaporation, and cooling crystallization. Five unique XRPD patterns were observed, which include Form A, Form B, Forms A + C, Form D, and Form E.
  • Form A is monohydrate form as confirmed by single crystal structure.
  • Form D is anhydrous, and it was also confirmed by single crystal structure.
  • Form E is an anhydrous form produced through dehydration of Form A at ⁇ 90 °C.
  • Form B is a known anhydrate from a separate study.
  • Form C was not obtained in the pure form during the study but rather appeared as a mixture of Forms A + C.
  • Water activity analysis indicated that Form E converts to Form A under all conditions tested.
  • Form E was exposed to ambient temperature and humidity, it showed partial conversion to Form A.
  • the results from slurry competition between both anhydrous Forms D and E also indicated that both forms converted to Form A during the experiments. These results suggest that the Form A is the most stable form at the ambient temperature and humidity.
  • the starting material of CV-8972 was characterized using X-ray powder diffraction (XRPD), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), and polarized light microscopy (PLM).
  • XRPD X-ray powder diffraction
  • TGA thermogravimetric analysis
  • DSC differential scanning calorimetry
  • PLM polarized light microscopy
  • FIG. 4 is an XRPD diffractogram of the CV-8972 starting material.
  • the XRPD results suggested high crystallinity of the starting material.
  • FIG. 5 shows TGA and DSC thermograms of the CV-8972 starting material.
  • TGA thermogram is shown in green, and DSC thermogram is shown in blue.
  • TGA and DSC data about 3.46% weight loss was observed up to 150 °C before decomposition.
  • DSC showed a small endotherm at 85.3 °C (peak) and a possible melting endotherm at 214.6 °C (onset), followed by decomposition and a melting point at 131.7 °C (peak) was observed.
  • FIG. 6 shows XRPD diffractograms of various forms of CV-8972.
  • CV-8972 starting material is shown in blue; CV-8972 following incubation at 90 °C for 8 hours is shown in red; and CV-8972 following incubation at 65 °C in a vacuum for 2 hours is shown in purple.
  • XRPD was performed on Form A after storing it in an oven at 90 °C for 8 hours. The data showed that the Form A converts to Form E.
  • FIG. 7 is a polarized microscopic image of CV-8972 starting material. Very platy "mica like" morphology of the crystals was observed by PLM.
  • FIG. 8 is a dynamic vapor sorption isotherm plot. Cycle sorption is shown in red; cycle 1 desorption is shown in blue; and cycle 2 sorption is shown in green. DVS results showed that water uptake of CV-8972 is ⁇ 0.2% at 25°C and 80% relative humidity (RH) indicated that starting material was non hygroscopic. However, there is a drastic increase in the mass change beyond 80% RH, which indicates there could be deliquescence.
  • FIG. 9 shows XRPD diffractograms of CV-8972 before and after dynamic vapor sorption. Pre-DVS data is shown in red; and post-DVS data is shown in blue. The XRPD of the sample after DVS indicated weak crystalline peaks but was mostly similar to the starting material.
  • FIG. 10 shows XRPD diffractograms of CV-8972 in its dehydrated and rehydrated forms. Data from starting material is shown in blue; data following incubation for 2 hours in vacuum oven are shown in red; and data from heated material that was exposed to ambient relative humidity is shown in green. To monitor Form A in its dehydrated state, it was placed in a vacuum oven at 65°C for 2 hours followed by its XRPD analysis. The XRPD results showed that this process created a new anhydrous form of the material and assigned as Form E. Rehydration of Form E when exposed to ambient RH resulted in its partial conversion to Form A.
  • FIG. 11 shows XRPD diffractograms of various polymorphs of CV-8972.
  • Form A is shown in blue;
  • Form B is shown in green;
  • a mixture of Forms A and C is shown in navy;
  • Form D is shown in orange;
  • Form E is shown in purple.
  • Form A was successfully characterized to understand its form behavior.
  • a comprehensive polymorph screening in 34 different conditions was performed. Five polymorph of the CV-8972 were identified during the screening, including Form A, Form B, a mixture of Forms A + C, Form D, and Form E.
  • Form D and E are anhydrous, Form A is a monohydrate, and Form B is a hydrate with unknown stoichiometry.
  • Phase origin of Form C is not known since it was not obtained it in pure form; it always crystallized as mixture with Form A.
  • CV-8972 has a tendency to form multiple polymorphs. Current studies have concluded that Form A is the best form for development of CV-8972 and is a stable monohydrate form, and is the most stable form under conditions of ambient temperature and humidity.
  • TGA data was collected using a TA Discovery 550 TGA from TA Instrument.
  • DSC was performed using a TA Q2000 DSC from TA Instrument.
  • DSC was calibrated with Indium reference standard and the TGA was calibrated using nickel reference standard.
  • Detailed parameters used for TGA and DSC are listed in Table 9.
  • Polarized light microscopic (PLM) pictures were captured on a Nikon DS-Fi2 upright microscope at room temperature.
  • Low viscosity microscope immersion oil (Resolve®) was used to disperse powder crystals.
  • FIG. 12 is a PLM image of a batch of single crystals of C22H34CI3N3O6 (CV-8972). Bar represents 100 pm.
  • FIG. 13 shows PLM images of a crystal used for single-crystal diffractometer. Bars represent 100 pm. A thick needle was picked out and trimmed down to a size of 200 c 160 c 100 pm uniform block. This sample was mounted on a 100 mm MiTeGen MicroLoopTM with low viscosity cryo-oil (MiTeGen LV CryoOilTM).
  • FIG. 14 shows images of a crystal mounted on a 100 micro Mitegen loop on the diffractometer.
  • a total of 9576 frames were collected using Bruker Apex3 v2018-7.2.
  • the total exposure time was 18 hours (exposure times were adjusted based on 2Q).
  • the frames were integrated with the Bruker SAINT software package using a narrow-frame algorithm.
  • One asymmetric unit contains one whole API molecule.
  • the goodness-of-fit was 1.041.
  • the largest peak in the final difference electron density synthesis was 0.358 e-/A3 (0.81 A from Cli) and the largest hole was -0.438 e-/A3 (0.66 A from Cli).
  • FIG. 15 is an Ortep diagram of an asymmetric unit of the C22H34Q3N3O6 crystal.
  • the Ortep diagram of an asymmetric unit of the C22H34CI3N3O6 crystal demonstrates that this API is a monohydrate tris-HCl salt, as a ratio of 1:3:1 (APLHCFFLO) was observed.
  • FIG. 16 shows one unit cell of the C22H34CI3N3O6 crystal.
  • FIG. 17 is a diagram of hydrogen bonds networks and counter-ion pairs in the C22H34CI3N3O6 crystal.
  • the diagram shows that the three hydrochloride molecules are deprotonated, whereas the three nitrogens are protonated.
  • the water molecule serves as a hydrogen bond donor to bridging two chlorine anions.
  • Table 11 The crystallographic measurements of the hydrogen bonds and counter-ion pairs in the C22H34Q3N3O6 crystal are summarized in Table 11.
  • FIG. 18 shows calculated and measured XRPD diagrams of the C22H34CI3N3O6 crystal. Calculated XRPD diffractogram is shown in red; and measured XRPD diffractogram is shown in blue. Powder x-ray diffraction of this batch was obtained and compared with a calculated pattern based on this crystal structure using Mercury. The experimental peak positions and intensities fit well with the calculated pattern.
  • Polarized light microscopic picture was captured on Nikon DS-Fi2 upright microscope at room temperature.
  • XRPD was performed with a Panalytical X’Pert3 Powder XRPD on a Si zero-background holder. The 2Q position was calibrated against a Panalytical Si reference standard disc.
  • FIG. 20 is an image of a single anhydrous crystal from recrystallized CV-8972 mounted on a tip of a glass fiber. The colorless crystal was subsequently set up on the SCXRD instrument.
  • a colorless crystal was mounted on a tip of a glass fiber.
  • IpS Incoatec Microfocus Source
  • Atomic coordinates ( x 10 4 ) and equivalent isotropic displacement parameters (A 2 x 10 3 ) for j l a are provided in Table 13.
  • U(eq) is defined as one third of the trace of the orthogonalized Uij tensor Table 13.
  • Bond lengths [A] for j l a are provided in Table 14.
  • FIG. 21 is a thermal ellipsoid diagram of an asymmetric unit of the C22H32CI3N3O5 crystal. The diagram demonstrates that this form is an anhydrate, tris-HCl salt form.
  • FIG. 22 shows one unit cell of the C22H32CI3N3O5 crystal.
  • FIG. 23 is a diagram of hydrogen bonds networks and counter-ion pairs in the C22H32CI3N3O5 crystal.
  • FIG. 24 shows calculated and measured XRPD diagrams of the C22H34CI3N3O6 crystal. Calculated XRPD diffractogram is shown in red; and measured XRPD diffractogram is shown in green.
  • the compound crystallizes in tri clinic, space group P-1 (No. 2).
  • the asymmetric unit contains one molecule in the form of cation/anion salt (an anhydrate tri-HCl salt) with formula of C22H32O5N3CI3. There might be some intra-molecular H-bonding between N(1)-H(1)...C1(3)
  • Step 1 is a reductive amination using 2,3,4-trimethoxybenzaldehyde and 2-(piperazin-l- yl)ethan-l-ol starting materials, with sodium triacetoxyborohydride (STAB) as the reductant, in the presence of catalytic acetic acid (AcOH), and 2-methyltetrahydrofuran (2-MeTHF) as solvent.
  • STAB sodium triacetoxyborohydride
  • AcOH catalytic acetic acid
  • 2-MeTHF 2-methyltetrahydrofuran
  • CV-8814 Free Base (CV8814 Free Base) undergoes acid coupling with nicotinic acid in the presence of l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) and catalytic 4-(dimethylamino)pyridine (DMAP) in dichloromethane (DCM) solvent.
  • EDC l-ethyl-3-(3-dimethylaminopropyl)carbodiimide
  • DMAP catalytic 4-(dimethylamino)pyridine
  • MEK 2-butanone
  • MEK 2-butanone
  • MEK 2-butanone
  • Step 1 formation of CV8814 Free Base (2493-1903-00487), was performed according to Scheme 2.
  • reactor R-402 The contents of reactor R-402 were agitated for at least 5 minutes.
  • Phase cut was performed with the aqueous layer being transferred to R-402.
  • a phase cut was performed with the aqueous layer being transferred to a drum.
  • Heptane (56.3 kg; CHP Lot#: 233-190227) was charged over 8 min to R-401 while maintaining the temperature at 40°C ⁇ 5°C.
  • a FIO sample (FIO sample: 2493-1903-00484-100-01) was taken to observe the ratio of MTBE : Heptane of the contents in R-401. The ratio was 1.5 : 6.0.
  • Heptane (56.4 kg; CHP Lot#: 233-190227) was charged over 24 min to R-401 while maintaining the temperature at 30°C ⁇ 5°C.
  • CV-8814 Free Base (CY8814 Free Base) was double bagged, goose necked, and weighed.
  • CV-8814 Free Base (CV8814 Free Base) was removed from the bulk material double bagged, goose necked, and set aside for release under the Lot# 2493-1903- 00484.
  • Nicotinic Acid (17.1 kg, CHP Lot# 201-190222) and DCM (153.0 kg, CHP Lot# 328- 190326) were charged to reactor R-401.
  • R-401 The contents of R-401 were transferred to R-402 over approx. 1 hour while maintaining a temperature below 35 °C.
  • Tmax 27.2°C 43)
  • the temperature of the contents of R-402 was heated to 50 ⁇ 5°C and was agitated for at least 1 hour.
  • IPC sample 2479-1903-00489-87-01 was submitted to QC for KF.
  • Nicotinic Acid No Peak DMAP: No Peak CV8814: 0.1%
  • CV-8972 can be synthesized using Scheme 1.
  • the reductive amination in step 1 using 2,3,4-trimethoxybenzaldehyde and 2-(piperazin-l-yl)ethan-l- ol starting materials, sodium triacetoxyborohydride (STAB) as the reductant, catalytic acetic acid (AcOH), and 2-methyltetrahydrofuran (2-MeTHF) gave a 78.0% yield of CV-8814 Free Base (CV8814 Free Base) with 100.0% purity by HPLC after aqueous workup, solvent exchange, and crystallization. A 5 kg portion of CV-8814 Free Base (CV8814 Free Base) was diverted from the synthesis for release.
  • STAB sodium triacetoxyborohydride
  • AcOH catalytic acetic acid
  • 2-MeTHF 2-methyltetrahydrofuran
  • step 2 coupling of CV8814 Free Base with nicotinic acid in the presence of EDC and catalytic DMAP in DCM went to complete conversion to CV8972 Free Base by HPLC IPC. Solvent exchange to MEK and addition into concentrated HC1 in MEK afforded CV8972 Monohydrate in a 96.4% yield with 99.1% purity by HPLC.
  • the final form conversion in step 3 was completed by heating CV8972 Monohydrate to 60°C ⁇ 5°C in a mixture of water, methanol, and MEK and precipitating out with the addition of MEK.
  • the white solid CV-8972 was obtained as form A confirmed by XRPD analysis, in an 86.0% yield with 99.9% purity by HPLC.
  • the overall yield of the GMP synthesis of CV-8972 was 64.7%.
  • the final amount of CV-8972 produced was 41.7 kg.

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EP21833175.9A 2020-06-30 2021-06-28 CRYSTALLINE FORMS OF 2-[4-[(2,3,4-TRIMETHOXYPHENYL)METHYL]PIPERAZIN-1-YL]ETHYL PYRIDINE-3-CARBOXYLATE AND PROCESSES FOR SYNTHESIS Pending EP4171233A4 (en)

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