Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
  • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
• • 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
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5375—1,4-Oxazines, e.g. morpholine
  • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/24—Antidepressants
• • 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

• This invention relates to novel salt forms of 5-ethyl-4-methyl-N-[4-[(2S) morpholin- 2-yl]phenyl]-1H-pyrazole-3-carboxamide (hereinafter referred to as compound of Formula I), to pharmaceutical compositions comprising said salt forms, to processes for forming the salt forms and to their use in medical treatment.
• compound of Formula I 5-ethyl-4-methyl-N-[4-[(2S) morpholin- 2-yl]phenyl]-1H-pyrazole-3-carboxamide
• the present invention also relates to particular polymorphic forms of the new salt forms of the compound of Formula I described herein, as well as to pharmaceutical compositions comprising these polymorphic forms, to processes for obtaining them, and their use in medical treatment.
• WO2017157873 discloses the TAAR1 agonist 5-ethyl-4-methyl-N-[4-[(2S) morpholin-2-yl]phenyl]-1H-pyrazole- 3-carboxamide (Formula I), which is useful for the treatment of certain diseases and disorders of the central nervous system.
• the structure of 5-ethyl-4-methyl-N-[4-[(2S) morpholin-2- yl]phenyl]-1H-pyrazole-3-carboxamide (Formula I) is shown below.
• the present invention provides a pharmaceutically acceptable salt of 5-ethyl-4-methyl-N-[4-[(2S) morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide (Formula I) wherein the pharmaceutically acceptable salt is selected from a hydrochloric acid salt, a sulfuric acid salt, a methanesulfonic acid salt, a phosphoric acid salt, a tartaric acid salt, a fumaric acid salt, a citric acid salt, an adipic acid salt, a glycolic acid salt and a p-toluenesulfonic acid salt.
• the pharmaceutically acceptable salt is selected from a hydrochloric acid salt, a sulfuric acid salt, a methanesulfonic acid salt, a phosphoric acid salt, a tartaric acid salt, a fumaric acid salt, a citric acid salt, an adipic acid salt, a glycolic acid salt and a p-toluene
• the present invention provides a crystalline polymorph form A of 5-ethyl-4-methyl-N-[4-[(2S) morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide, mono hydrochloric acid salt, wherein the crystalline form is as described herein.
• the present invention provides a crystalline polymorph form A of 5-ethyl-4-methyl-N-[4-[(2S) morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide, hemi sulfuric acid salt, wherein the crystalline form is as described herein.
• the present invention provides a crystalline polymorph form A of 5-ethyl-4-methyl-N-[4-[(2S) morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide, mono phosphoric acid salt, wherein the crystalline form is as described herein.
• the present invention provides a crystalline polymorph form A of 5-ethyl-4-methyl-N-[4-[(2S) morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide, mono p- toluenesulfonic acid salt, wherein the crystalline form is as described herein.
• the present invention provides 5-ethyl-4-methyl-N-[4-[(2S) morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide, mono hydrochloric acid salt that is in amorphous form.
• the present invention provides a process for manufacturing 5- ethyl-4-methyl-N-[4-[(2S) morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide, mono hydrochloric acid salt, wherein the process is as described herein.
• the present invention provides a crystalline polymorph form A of 5-ethyl-4-methyl-N-[4-[(2S) morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide, mono hydrochloric acid described herein, when obtained by the process described herein.
• the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable salt described herein.
• the present invention provides the pharmaceutically acceptable salts described herein for use as a medicament.
• the present invention provides the pharmaceutically acceptable salts described herein for use in the treatment of depression, anxiety disorders, bipolar disorder, attention deficit hyperactivity disorder (ADHD), stress-related disorders, schizophrenia, Parkinson’s disease, Alzheimer’s disease, epilepsy, migraine, hypertension, substance abuse, addiction, eating disorders (e.g. binge eating), diabetes, diabetic complications, obesity, dyslipidemia, disorders of energy consumption and assimilation, disorders and malfunction of body temperature homeostasis, disorders of sleep and circadian rhythm, cardiovascular disorders, attenuated psychotic syndrome, psychosis in neurodegenerative diseases, and apathy in neurodegenerative diseases.
• ADHD attention deficit hyperactivity disorder
• stress-related disorders schizophrenia, Parkinson’s disease, Alzheimer’s disease, epilepsy, migraine, hypertension, substance abuse, addiction, eating disorders (e.g. binge eating), diabetes, diabetic complications, obesity, dyslipidemia, disorders of energy consumption and assimilation, disorders and malfunction of body temperature homeostasis, disorders of sleep and circadian rhythm, cardiovascular disorders, attenuated psychotic
• Figure 1 illustrates the XRPD of a crystalline polymorph form A of 5-ethyl-4-methyl- N-[4-[(2S) morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide, mono hydrochloric acid salt, with characteristic peaks at 3.4, 6.7, 10.1, 13.5, 15.4, 15.6, 15.8, 16.6, 18.0, 19.0, 20.3, 20.8, 21.1, 22.1, 23.1, 23.225.0, 25.2 and 25.9 [° 2 Theta ⁇ 0.2° 2 Theta, Cu K ⁇ radiation (1.5406 ⁇ )].
• Figure 2 illustrates the XRPD of a crystalline polymorph form A of 5-ethyl-4-methyl- N-[4-[(2S) morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide, hemi sulfuric acid salt, with characteristic peaks at 3.4, 6.8, 10.2, 13.6, 14.5, 15.4, 16.9, 17.3, 17.4, 18.2, 19.5, 21.3, 21.7, 21.9, 22.2, 22.5, 23.5, 23.9 and 25.1 [° 2 Theta ⁇ 0.2° 2 Theta, Cu K ⁇ radiation (1.5406 ⁇ )].
• Figure 3 illustrates the XRPD of A crystalline polymorph form A of 5-ethyl-4- methyl-N-[4-[(2S) morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide, mono phosphoric acid salt, with characteristic peaks at 3.4, 10.3, 14.8, 14.9, 17.3, 18.4, 19.3, 21.1, 21.3, 21.5, 21.8, 25.8 and 27.3 [° 2 Theta ⁇ 0.2° 2 Theta, Cu K ⁇ radiation (1.5406 ⁇ )].
• Figure 4 illustrates the XRPD of a crystalline polymorph form A of 5-ethyl-4-methyl- N-[4-[(2S) morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide, mono p-toluenesulfonic acid salt, with characteristic peaks at 6.6, 13.1, 16.1, 16.3, 18.3, 19.0, 19.7, 20.5, 22.1, 22.4, 23.4, 24.7 and 27.6 [° 2 Theta ⁇ 0.2° 2 Theta, Cu K ⁇ radiation (1.5406 ⁇ )].
• Pharmaceutically acceptable salts of 5-ethyl-4-methyl-N-[4-[(2S) morpholin-2- yl]phenyl]-1H-pyrazole-3-carboxamide include, but are not limited to: acid addition salts, formed by reacting the compound with a pharmaceutically acceptable inorganic acid, such as, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, metaphosphoric acid, and the like; or with an organic acid, such as, for example, acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, trifluoroacetic acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid,
• the present invention provides a pharmaceutically acceptable salt of 5-ethyl-4-methyl-N-[4-[(2S) morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide (Formula I)
• the pharmaceutically acceptable salt is selected from a hydrochloric acid salt, a sulfuric acid salt, a methanesulfonic acid salt, a phosphoric acid salt, a tartaric acid salt, a fumaric acid salt, a citric acid salt, an adipic acid salt, a glycolic acid salt and a p-toluenesulfonic acid salt.
• the present invention provides a pharmaceutically acceptable salt of the compound of Formula (I), wherein the pharmaceutically acceptable salt is selected from a hydrochloric acid salt, a sulfuric acid salt, a phosphoric acid salt, and a p-toluenesulfonic acid salt.
• the present invention provides a pharmaceutically acceptable salt of the compound of Formula (I), wherein the pharmaceutically acceptable salt is the mono hydrochloric acid salt. [0025] In one embodiment, the present invention provides a pharmaceutically acceptable salt of the compound of Formula (I), wherein the pharmaceutically acceptable salt is the hemi sulfuric acid salt. [0026] In one embodiment, the present invention provides a pharmaceutically acceptable salt of the compound of Formula (I), wherein the pharmaceutically acceptable salt is the mono phosphoric acid salt. [0027] In one embodiment, the present invention provides a pharmaceutically acceptable salt of the compound of Formula (I), wherein the pharmaceutically acceptable salt is the mono p- toluenesulfonic acid salt.
• the present invention provides a pharmaceutically acceptable salt of the compound of Formula (I) described herein, wherein the salt is in crystalline form.
• the present invention provides a crystalline polymorph form A of 5-ethyl- 4-methyl-N-[4-[(2S) morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide, mono hydrochloric acid salt that is characterized as having: (a) an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 3.4, 6.7, 10.1, 13.5, 15.4, 15.6, 15.8, 16.6, 18.0, 23.1, 23.2, 25.0, and 25.9 [° 2 Theta ⁇ 0.2° 2 Theta, Cu K ⁇ radiation (1.5406 ⁇ )
• said crystalline form is characterized as having property (a). [0031] In one embodiment, said crystalline form is characterized as having property (b). [0032] In one embodiment, said crystalline form is characterized as having property (c). 5-ethyl-4-methyl-N-[4-[(2S) morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide, hemi sulfuric acid salt [0033] In one aspect, the present invention provides a crystalline polymorph form A of 5- ethyl-4-methyl-N-[4-[(2S) morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide, hemi sulfuric acid salt that is characterized as having: (a) an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 3.4, 6.8, 10.2, 13.6, 14.5, 15.4, 16.9, 17.3, 17.4, 18.2, 21.3, 23.5, and 25.1 [° 2 Theta ⁇
• said crystalline form is characterized as having property (a). [0035] In one embodiment, said crystalline form is characterized as having property (b). [0036] In one embodiment, said crystalline form is characterized as having property (c). 5-ethyl-4-methyl-N-[4-[(2S) morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide, mono phosphoric acid salt [0037] In one aspect, the present invention provides a crystalline polymorph form A of 5- ethyl-4-methyl-N-[4-[(2S) morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide, mono phosphoric acid salt that is characterized as having: (a) an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 3.4, 10.3, 14.8, 14.9, 17.3, 18.4, 21.1, 21.5, 25.8 and 27.3 [° 2 Theta ⁇ 0.2° 2 Theta
• said crystalline form is characterized as having property (a). [0039] In one embodiment, said crystalline form is characterized as having property (b). [0040] In one embodiment, said crystalline form is characterized as having property (c). 5-ethyl-4-methyl-N-[4-[(2S) morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide, mono p- toluenesulfonic acid salt [0041] In one aspect, the present invention provides a crystalline polymorph form A of 5- ethyl-4-methyl-N-[4-[(2S) morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide, mono p- toluenesulfonic acid salt that is characterized as having: (a) an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 6.6, 13.1, 16.1, 18.3, 19.0, 20.5, 23.4, and 24.7 [°
• XRPD
• said crystalline form is characterized as having property (a). [0043] In one embodiment, said crystalline form is characterized as having property (b). [0044] In one embodiment, said crystalline form is characterized as having property (c). Amorphous 5-ethyl-4-methyl-N-[4-[(2S) morpholin-2-yl]phenyl]-1H-pyrazole-3- carboxamide, mono hydrochloric acid salt [0045] In a further aspect, the present invention provides 5-ethyl-4-methyl-N-[4-[(2S) morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide, mono hydrochloric acid salt that is in amorphous form.
• the amorphous form of 5-ethyl-4-methyl-N-[4-[(2S) morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide, mono hydrochloric acid salt has an XRPD pattern showing a lack of crystallinity.
• Preparation of Crystalline Forms [0046]
• a crystalline form of a pharmaceutically acceptable salt of 5- ethyl-4-methyl-N-[4-[(2S) morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide is prepared as outlined in the Examples. It is noted that solvents, temperatures and other reaction conditions presented herein may vary.
• the present invention provides a crystalline form of the mono hydrochloride salt of 5-ethyl-4-methyl-N-[4-[(2S) morpholin-2-yl]phenyl]-1H-pyrazole-3- carboxamide described herein, wherein the crystalline form is obtained using seed crystals of said crystalline form. It has been found that the present process using seed crystals is more reliable than a process whereby the resulting salt precipitates spontaneously or is brought out of a solution by adding a non-solvent. For example, it has been found that the present process using seed crystals allows control over the desired polymorphic form.
• the present invention provides a crystalline form of the mono hydrochloride salt of 5-ethyl-4-methyl-N-[4-[(2S) morpholin-2-yl]phenyl]-1H-pyrazole-3- carboxamide described herein, wherein the crystalline form is obtained from a mixture of an alcohol and water, in particular from a mixture of 1-propanol and water.
• the process of the present invention is well suited for industrial scale production of 5-ethyl-4-methyl-N-[4-[(2S) morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide, mono hydrochloric acid salt.
• the present invention provides a process for manufacturing 5-ethyl-4- methyl-N-[4-[(2S) morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide, mono hydrochloric acid salt comprising: (a) reacting 5-ethyl-4-methyl-N-[4-[(2S) morpholin-2-yl]phenyl]-1H-pyrazole-3- carboxamide with hydrochloric acid; and (b) adding seed crystals of 5-ethyl-4-methyl-N-[4-[(2S) morpholin-2-yl]phenyl]-1H- pyrazole-3-carboxamide, mono hydrochloric acid salt to the mixture obtained from step a).
• steps (a) and (b) of the process of the invention are performed in a solvent mixture of an alcohol and water.
• the alcohol solvent used in steps (a) and (b) of the process of the invention is 1-propanol.
• the ratio of alcohol to water in the solvent mixture used in step (a) of the process of the invention is about 15:1 vol/vol.
• the hydrochloric acid in step (a) of the process of the invention is added as an aqueous solution.
• said aqueous solution of hydrochloric acid comprises about 25% wt/wt of hydrochloric acid.
• the process of the invention further comprises step (c): reducing the water content of the reaction mixture by distillation. It has surprisingly been found that this process step increases the final yield of 5-ethyl-4-methyl-N-[4-[(2S) morpholin-2-yl]phenyl]-1H- pyrazole-3-carboxamide, mono hydrochloric acid.
• the water content after said reducing the water content of the reaction mixture is about 2% wt/wt.
• the volume of the reaction mixture during said reducing the water content of the reaction mixture is kept constant by continuous addition of an organic solvent, in particular an alcohol, most preferably 1-propanol.
• the process of the invention further comprises step (d): cooling. In one embodiment, said cooling is cooling to 0°C +/- 5 C [0055] In one embodiment, the process of the invention further comprises step (e): ageing. In one embodiment, said ageing is ageing at 0°C +/- 5 C. In one embodiment, said ageing is ageing for at least 4 h. [0056] In one embodiment, said seed crystals in step (b) of the process of the invention are added as a suspension in an organic solvent. In one embodiment, said organic solvent is 1- propanol.
• the present invention provides a crystalline polymorph form A of 5-ethyl- 4-methyl-N-[4-[(2S) morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide, mono hydrochloric acid described herein, when obtained by the process of the invention described herein.
• Suitable Solvents [0058] Therapeutic agents that are administrable to mammals, such as humans, must be prepared by following regulatory guidelines. Such government regulated guidelines are referred to as Good Manufacturing Practice (GMP). GMP guidelines outline acceptable contamination levels of active therapeutic agents, such as, for example, the amount of residual solvent in the final product. Preferred solvents are those that are suitable for use in GMP facilities and consistent with industrial safety concerns.
• Solvents are categorized into three classes. Class 1 solvents are toxic and are to be avoided. Class 2 solvents are solvents to be limited in use during the manufacture of the therapeutic agent. Class 3 solvents are solvents with low toxic potential and of lower risk to human health. Data for Class 3 solvents indicate that they are less toxic in acute or short-term studies and negative in genotoxicity studies.
• Class 1 solvents which are to be avoided, include: benzene; carbon tetrachloride; 1,2- dichloroethane; 1,1-dichloroethene; and 1,1,1-trichloroethane.
• Class 2 solvents are: acetonitrile, chlorobenzene, chloroform, cyclohexane, 1,2-dichloroethene, dichloromethane, 1,2-dimethoxyethane, N,N- dimethylacetamide, N,N-dimethylformamide, 1,4-dioxane, 2-ethoxyethanol, ethyleneglycol, formamide, hexane, methanol, 2-methoxyethanol, methylbutyl ketone, methylcyclohexane, N- methylpyrrolidine, nitromethane, pyridine, sulfolane, tetralin, toluene, 1,1,2-trichloroethene and xylene.
• Class 3 solvents which possess low toxicity, include: acetic acid, acetone, anisole, 1- butanol, 2-butanol, butyl acetate, tert-butylmethyl ether (MTBE), cumene, dimethyl sulfoxide, ethanol, ethyl acetate, ethyl ether, ethyl formate, formic acid, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1-butanol, methylethyl ketone, methylisobutyl ketone, 2- methyl-1-propanol, pentane, 1-pentanol, 1-propanol, 2-propanol, propyl acetate, and tetrahydrofuran.
• acetic acid acetone
• anisole 1- butanol
• 2-butanol butyl acetate
• MTBE tert-buty
• compositions comprising a crystalline form of a pharmaceutically acceptable salt of 5-ethyl-4-methyl-N-[4-[(2S) morpholin-2-yl]phenyl]-1H- pyrazole-3-carboxamide (e.g. 5-ethyl-4-methyl-N-[4-[(2S) morpholin-2-yl]phenyl]-1H-pyrazole- 3-carboxamide, mono hydrochloric acid salt) include a residual amount of an organic solvent(s).
• compositions comprising a crystalline form of a pharmaceutically acceptable salt of 5-ethyl-4-methyl-N-[4-[(2S) morpholin-2-yl]phenyl]-1H-pyrazole-3- carboxamide (e.g. 5-ethyl-4-methyl-N-[4-[(2S) morpholin-2-yl]phenyl]-1H-pyrazole-3- carboxamide, mono hydrochloric acid salt) include a detectable amount of an organic solvent(s).
• compositions comprising a crystalline form of a pharmaceutically acceptable salt of 5-ethyl-4-methyl-N-[4-[(2S) morpholin-2-yl]phenyl]-1H-pyrazole-3- carboxamide (e.g. 5-ethyl-4-methyl-N-[4-[(2S) morpholin-2-yl]phenyl]-1H-pyrazole-3- carboxamide, mono hydrochloric acid salt) include a residual amount of a Class 3 solvent.
• the Class 3 solvent is selected from the group consisting of acetic acid, acetone, anisole, 1-butanol, 2-butanol, butyl acetate, tert-butylmethyl ether, cumene, dimethyl sulfoxide, ethanol, ethyl acetate, ethyl ether, ethyl formate, formic acid, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1-butanol, methylethyl ketone, methylisobutyl ketone, 2-methyl-1-propanol, pentane, 1-pentanol, 1-propanol, 2-propanol, propyl acetate, and tetrahydrofuran.
• the Class 3 solvent is selected from the group consisting of 1-butanol, 2-butanol, ethanol, 3-methyl-1-butanol, 2-methyl-1-propanol, 1-pentanol, 1-propanol, and 2-propanol. In some embodiments, the Class 3 solvent is 1-propanol.
• compositions described herein include the use of a crystalline form of a pharmaceutically acceptable salt of 5-ethyl-4-methyl-N-[4-[(2S) morpholin-2-yl]phenyl]- 1H-pyrazole-3-carboxamide (e.g.5-ethyl-4-methyl-N-[4-[(2S) morpholin-2-yl]phenyl]-1H- pyrazole-3-carboxamide, mono hydrochloric acid salt).
• the crystalline forms of the pharmaceutically acceptable salt of 5-ethyl-4-methyl-N-[4-[(2S) morpholin-2-yl]phenyl]-1H- pyrazole-3-carboxamide e.g.
• 5-ethyl-4-methyl-N-[4-[(2S) morpholin-2-yl]phenyl]-1H-pyrazole- 3-carboxamide, mono hydrochloric acid salt) described herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, 1-propanol, ethanol, and the like.
• pharmaceutically acceptable solvents such as water, 1-propanol, ethanol, and the like.
• Detectable amount refers to an amount that is measurable using standard analytic methods (e.g.
• an “effective amount” for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms.
• therapeutically effective amount includes, for example, a prophylactically effective amount. The effective amount will be selected based on the particular patient and the disease level.
• an effect amount or “a therapeutically effective amount” varies from subject to subject, due to variation in metabolism of drug, age, weight, general condition of the subject, the condition being treated, the severity of the condition being treated, and the judgment of the prescribing physician.
• an appropriate “effective” amount in any individual case is determined using techniques, such as a dose escalation study.
• the term “effective amount” or “therapeutically effective amount,” is used in reference to 5-ethyl-4-methyl-N-[4-[(2S) morpholin-2-yl]phenyl]- 1H-pyrazole-3-carboxamide, or a pharmaceutically acceptable salt thereof, and refers to a sufficient amount of 5-ethyl-4-methyl-N-[4-[(2S) morpholin-2-yl]phenyl]-1H-pyrazole-3- carboxamide, or a pharmaceutically acceptable salt thereof, being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated.
• kit and “article of manufacture” are used as synonyms.
• compositions are formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which are used pharmaceutically.
• suitable techniques, carriers, and excipients include those found within, for example, Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed.
• the present invention relates to a pharmaceutical composition
• a pharmaceutically acceptable of salt 5-ethyl-4-methyl-N-[4-[(2S) morpholin-2- yl]phenyl]-1H-pyrazole-3-carboxamide described herein e.g. 5-ethyl-4-methyl-N-[4-[(2S) morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide, mono hydrochloric acid salt
• at least one additional ingredient selected from pharmaceutically acceptable carriers, diluents and excipients are examples of the addition ingredient selected from pharmaceutically acceptable carriers, diluents and excipients.
• the present invention relates to a pharmaceutical composition
• a pharmaceutical composition comprising a crystalline form of a pharmaceutically acceptable of salt 5-ethyl-4-methyl-N-[4- [(2S) morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide described herein (e.g. a crystalline polymorph form A of 5-ethyl-4-methyl-N-[4-[(2S) morpholin-2-yl]phenyl]-1H-pyrazole-3- carboxamide, mono hydrochloric acid salt) and at least one additional ingredient selected from pharmaceutically acceptable carriers, diluents and excipients.
• a pharmaceutically acceptable of salt 5-ethyl-4-methyl-N-[4- [(2S) morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide described herein (e.g. a crystalline polymorph form A of 5-ethyl-4-methyl-N-[4-[(2S)
• a crystalline form of a pharmaceutically acceptable salt of 5- ethyl-4-methyl-N-[4-[(2S) morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide described herein e.g.5-ethyl-4-methyl-N-[4-[(2S) morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide, mono hydrochloric acid salt
• a crystalline form of a pharmaceutically acceptable salt of 5-ethyl-4-methyl-N-[4- [(2S) morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide described herein e.g. a crystalline polymorph form A of 5-ethyl-4-methyl-N-[4-[(2S) morpholin-2-yl]phenyl]-1H-pyrazole-3- carboxamide, mono hydrochloric acid salt
• a crystalline form of a pharmaceutically acceptable salt of 5-ethyl-4-methyl-N-[4- [(2S) morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide described herein e.g. a crystalline polymorph form A of 5-ethyl-4-methyl-N-[4-[(2S) morpholin-2-yl]phenyl]-1H-pyrazole-3- carboxamide, mono hydrochloric acid salt
• a pharmaceutically acceptable salt of 5-ethyl-4-methyl-N-[4- [(2S) morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide described herein e.g. a crystalline polymorph form A of 5-ethyl-4-methyl-N-[4-[(2S) morpholin-2-yl]phenyl]-1H-pyrazole-3- carboxamide, mono hydrochloric acid salt
• a crystalline form of a pharmaceutically acceptable salt of 5-ethyl-4-methyl-N-[4- [(2S) morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide described herein e.g. a crystalline polymorph form A of 5-ethyl-4-methyl-N-[4-[(2S) morpholin-2-yl]phenyl]-1H-pyrazole-3- carboxamide, mono hydrochloric acid salt
• Contemplated pharmaceutical compositions provide a therapeutically effective amount of a crystalline form of a pharmaceutically acceptable salt of 5-ethyl-4-methyl-N-[4- [(2S) morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide described herein (e.g. a crystalline polymorph form A of 5-ethyl-4-methyl-N-[4-[(2S) morpholin-2-yl]phenyl]-1H-pyrazole-3- carboxamide, mono hydrochloric acid salt), enabling, for example, once-a-day, twice-a-day, three times a day, etc. administration.
• a pharmaceutically acceptable salt of 5-ethyl-4-methyl-N-[4- [(2S) morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide described herein e.g. a crystalline polymorph form A of 5-ethyl-4-methyl-N-[4-[(2S) morph
• compositions provide an effective amount of a crystalline form of a pharmaceutically acceptable salt of 5-ethyl-4- methyl-N-[4-[(2S) morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide described herein (e.g. a crystalline polymorph form A of 5-ethyl-4-methyl-N-[4-[(2S) morpholin-2-yl]phenyl]-1H- pyrazole-3-carboxamide, mono hydrochloric acid salt), enabling once-a-day dosing.
• a pharmaceutically acceptable salt of 5-ethyl-4- methyl-N-[4-[(2S) morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide described herein e.g. a crystalline polymorph form A of 5-ethyl-4-methyl-N-[4-[(2S) morpholin-2-yl]phenyl]-1H- pyrazole-3-carbox
• the amount of a crystalline form of a pharmaceutically acceptable salt of 5-ethyl-4-methyl-N-[4-[(2S) morpholin-2-yl]phenyl]-1H-pyrazole-3- carboxamide described herein e.g. a crystalline polymorph form A of 5-ethyl-4-methyl-N-[4- [(2S) morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide, mono hydrochloric acid salt
• the pharmaceutical compositions is about 0.5mg to about 1000mg per dose, preferably about 0.5mg to about 100mg per dose, more preferably about 0.5mg to about 20mg per dose.
• the amount of a crystalline form of a pharmaceutically acceptable salt of 5-ethyl-4-methyl-N-[4-[(2S) morpholin-2-yl]phenyl]-1H-pyrazole-3- carboxamide described herein e.g. a crystalline polymorph form A of 5-ethyl-4-methyl-N-[4- [(2S) morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide, mono hydrochloric acid salt
• in the pharmaceutical compositions is about 20mg to about 400mg per dose, prefereably about 30mg to about 350mg per dose, more preferably about 45mg to about 300mg per dose.
• the amount of a crystalline form of a pharmaceutically acceptable salt of 5-ethyl-4-methyl-N-[4-[(2S) morpholin-2-yl]phenyl]-1H-pyrazole-3- carboxamide described herein e.g.
• a crystalline polymorph form A of 5-ethyl-4-methyl-N-[4- [(2S) morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide, mono hydrochloric acid salt), in the pharmaceutical compositions is about 1mg, about 2mg, about 3mg, about 4mg, about 5mg, about 6mg, about 7mg, about 8mg, about 9mg, about 10mg, about 11mg, about 12mg, about 13mg, about 14mg, about 15mg, about 16mg, about 17mg, about 18mg, about 19mg or about 20mg.
• the desired dose is conveniently presented in a single dose or in divided doses administered simultaneously (or over a short period of time) or at appropriate intervals, for example as two, three, four or more sub-doses per day.
• a crystalline polymorph form A of 5-ethyl-4- methyl-N-[4-[(2S) morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide, mono hydrochloric acid salt), is from about 0.01 to about 30mg, in particular from about 10 to about 20mg, most particularly 18mg.
• the daily dosage or the amount of active in the dosage form are lower or higher than the ranges indicated herein.
• the present invention provides a pharmaceutically acceptable salt of 5- ethyl-4-methyl-N-[4-[(2S) morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide described herein (e.g. a crystalline polymorph form A of 5-ethyl-4-methyl-N-[4-[(2S) morpholin-2-yl]phenyl]-1H- pyrazole-3-carboxamide, mono hydrochloric acid salt) for use as a medicament.
• a pharmaceutically acceptable salt of 5- ethyl-4-methyl-N-[4-[(2S) morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide described herein e.g. a crystalline polymorph form A of 5-ethyl-4-methyl-N-[4-[(2S) morpholin-2-yl]phenyl]-1H- pyrazole-3-carboxamide, mono hydrochloric acid salt
• the present invention provides a pharmaceutically acceptable salt of 5-ethyl-4-methyl-N-[4-[(2S) morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide described herein (e.g.
• the present invention provides a pharmaceutical composition described herein for use in the treatment of depression, anxiety disorders, bipolar disorder, attention deficit hyperactivity disorder (ADHD), stress-related disorders, schizophrenia, Parkinson’s disease, Alzheimer’s disease, epilepsy, migraine, hypertension, substance abuse, addiction, eating disorders (e.g.
• the present invention provides a method of treating depression, anxiety disorders, bipolar disorder, attention deficit hyperactivity disorder (ADHD), stress- related disorders, schizophrenia, Parkinson’s disease, Alzheimer’s disease, epilepsy, migraine, hypertension, substance abuse, addiction, eating disorders (e.g.
• the present invention provides a method of treating depression, anxiety disorders, bipolar disorder, attention deficit hyperactivity disorder (ADHD), stress- related disorders, schizophrenia, Parkinson’s disease, Alzheimer’s disease, epilepsy, migraine, hypertension, substance abuse, addiction, eating disorders (e.g.
• the present invention provides the use of a pharmaceutically acceptable salt of 5-ethyl-4-methyl-N-[4-[(2S) morpholin-2-yl]phenyl]-1H-pyrazole-3- carboxamide described herein (e.g.
• the present invention provides the use of a pharmaceutical composition described herein in a method of manufacturing a medicament for the treatment of depression, anxiety disorders, bipolar disorder, attention deficit hyperactivity disorder (ADHD), stress-related disorders, schizophrenia, Parkinson’s disease, Alzheimer’s disease, epilepsy, migraine, hypertension, substance abuse, addiction, eating disorders (e.g.
• the present invention provides the use of a pharmaceutically acceptable salt of 5-ethyl-4-methyl-N-[4-[(2S) morpholin-2-yl]phenyl]-1H-pyrazole-3- carboxamide described herein (e.g.
• the present invention provides the use of a pharmaceutical composition described herein in a method of treating described herein.
• Diseases or conditions that may be treated using a pharmaceutically acceptable salt of 5-ethyl-4-methyl-N-[4-[(2S) morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide described herein e.g.
• a crystalline polymorph form A of 5-ethyl-4-methyl-N-[4-[(2S) morpholin-2- yl]phenyl]-1H-pyrazole-3-carboxamide, mono hydrochloric acid salt) include all diseases that are associated with TAAR1 activity.
• the pharmaceutically acceptable salts and pharmaceutical compositions described herein are useful for treating diseases or conditions selected from bipolar disorder, schizophrenia, substance abuse, addiction, eating disorders (e.g. binge eating), diabetes, attenuated psychotic syndrome, psychosis in neurodegenerative diseases, and apathy in neurodegenerative diseases.
• the pharmaceutically acceptable salts and pharmaceutical compositions described herein are useful for treating schizophrenia.
• the pharmaceutically acceptable salts and pharmaceutical compositions described herein are useful for treating schizophrenia and manic episodes associated with bipolar disorders with reduced incidence of metabolic syndrome. In a further preferred embodiment, the pharmaceutically acceptable salts and pharmaceutical compositions described herein are useful for treating schizophrenia and manic episodes associated with bipolar disorders with antidiabetic efficacy. In a further preferred embodiment, the pharmaceutically acceptable salts and pharmaceutical compositions described herein are useful for treating schizophrenia and manic episodes associated with bipolar disorders with antidiabetic efficacy, which results in lowering blood glucose excursion.
• the pharmaceutically acceptable salts and pharmaceutical compositions described herein are useful for treating schizophrenia and manic episodes associated with bipolar disorders with antidiabetic efficacy, which results in lowering fat mass and body weight.
• the pharmaceutical compositions described herein comprising a crystalline form of a pharmaceutically acceptable salt of 5-ethyl-4-methyl-N-[4-[(2S) morpholin- 2-yl]phenyl]-1H-pyrazole-3-carboxamide described herein (e.g.
• compositions are administered for prophylactic and/or therapeutic treatments.
• the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest at least one of the symptoms of the disease or condition.
• amounts effective for this use depend on the severity and course of the disease or condition, previous therapy, the patient's health status, weight, and response to the drugs, and/or the judgment of the treating physician.
• compositions described herein comprising a crystalline form of a pharmaceutically acceptable salt of 5-ethyl-4-methyl-N-[4- [(2S) morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide described herein (e.g. a crystalline polymorph form A of 5-ethyl-4-methyl-N-[4-[(2S) morpholin-2-yl]phenyl]-1H-pyrazole-3- carboxamide, mono hydrochloric acid salt) are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder or condition.
• a pharmaceutically acceptable salt of 5-ethyl-4-methyl-N-[4- [(2S) morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide described herein e.g. a crystalline polymorph form A of 5-ethyl-4-methyl-N-[4-[(2S) morpholin-2-yl]phenyl]-1H-
• administration of the compound, compositions or therapies as described herein includes chronic administration.
• chronic administration includes administration for an extended period of time, including, e.g., throughout the duration of the patient’s life in order to ameliorate or otherwise control or limit the symptoms of the patient’s disease or condition.
• chronic administration includes daily administration.
• administration of the compound, compositions or therapies described herein is given continuously.
• the dose of drug being administered is temporarily reduced or temporarily suspended for a certain length of time (i.e., a “drug holiday”).
• the length of the drug holiday varies between 2 days and 1 year, including by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, and 365 days.
• the dose reduction during a drug holiday is from 10%-100%, including by way of example only 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, and 100%.
• a maintenance dose is administered if necessary.
• the dosage or the frequency of administration, or both is reduced, as a function of the symptoms, to a level at which the improved disease, disorder or condition is retained. In certain embodiments, however, the patient requires intermittent treatment on a long-term basis upon any recurrence of symptoms.
• the amount of a given agent that corresponds to such an amount varies depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight, sex) of the subject or host in need of treatment, but can nevertheless be determined according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated.
• Combination Treatments [0097] In certain instances, it is appropriate to administer a crystalline form of a pharmaceutically acceptable salt of 5-ethyl-4-methyl-N-[4-[(2S) morpholin-2-yl]phenyl]-1H- pyrazole-3-carboxamide described herein (e.g.
• the other therapeutic agent is an antipsychotic.
• the other therapeutic agent is an atypical antipsychotic.
• the other therapeutic agent is an antipsychotic selected from the group consisting of olanzapine (Zyprexa®), clozapine (Clorazil®), risperidone (Risperdal®), aripiprazole (Abilify®) and ziprasidone (Geodon®).
• the other therapeutic agent is olanzapine (Zyprexa®).
• the compositions and methods described herein are also used in conjunction with other therapeutic reagents that are selected for their particular usefulness against the condition that is being treated.
• other agents do not have to be administered in the same pharmaceutical composition, and are, because of different physical and chemical characteristics, administered by different routes.
• the initial administration is made according to established protocols, and then, based upon the observed effects, the dosage, modes of administration and times of administration, further modified.
• a crystalline form of a pharmaceutically acceptable salt of 5- ethyl-4-methyl-N-[4-[(2S) morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide described herein e.g. a crystalline polymorph form A of 5-ethyl-4-methyl-N-[4-[(2S) morpholin-2-yl]phenyl]-1H- pyrazole-3-carboxamide, mono hydrochloric acid salt
• is administered concurrently e.g., simultaneously, essentially simultaneously or within the same treatment protocol
• sequentially depending upon the nature of the disease and the condition of the patient.
• the determination of the order of administration, and the number of repetitions of administration of each therapeutic agent during a treatment protocol is based upon evaluation of the disease being treated and the condition of the patient.
• dosages of the co-administered compounds vary depending on the type of co-drug employed, on the specific drug employed, on the disease or condition being treated and so forth.
• the individual compounds of such combinations are administered either sequentially or simultaneously in separate or combined pharmaceutical formulations. In one embodiment, the individual compounds will be administered simultaneously in a combined pharmaceutical formulation. Appropriate doses of known therapeutic agents will be appreciated by those skilled in the art.
• kits/Articles of Manufacture For use in the therapeutic methods of use described herein, kits/articles of manufacture are also described herein. Such kits include a carrier, package, or container that is optionally compartmentalized to receive one or more doses of a pharmaceutical composition of a crystalline form of a pharmaceutically acceptable salt of 5-ethyl-4-methyl-N-[4-[(2S) morpholin- 2-yl]phenyl]-1H-pyrazole-3-carboxamide described herein (e.g.
• kits contain packaging materials.
• Packaging materials for use in packaging pharmaceutical products include, but are not limited to those described in e.g., U.S. Patent No.5,323,907.
• Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, bags, containers, bottles, and any packaging material suitable for a selected formulation and intended mode of administration and treatment.
• a wide array of formulations of a crystalline form of a pharmaceutically acceptable salt of 5-ethyl-4-methyl-N-[4-[(2S) morpholin-2- yl]phenyl]-1H-pyrazole-3-carboxamide described herein e.g. a crystalline polymorph form A of 5-ethyl-4-methyl-N-[4-[(2S) morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide, mono hydrochloric acid salt
• compositions thereof are contemplated as are a variety of treatments for any disease, disorder, or condition that would benefit by treatment with an TAAR1 agonist.
• the container(s) include a crystalline form of a pharmaceutically acceptable salt of 5-ethyl-4-methyl-N-[4-[(2S) morpholin-2-yl]phenyl]-1H-pyrazole-3- carboxamide described herein (e.g. a crystalline polymorph form A of 5-ethyl-4-methyl-N-[4- [(2S) morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide, mono hydrochloric acid salt), optionally in a composition or in combination with another agent as disclosed herein.
• kits optionally include an identifying description or label or instructions relating to its use in the methods described herein.
• a kit typically includes labels listing contents and/or instructions for use, and package inserts with instructions for use. A set of instructions will also typically be included.
• a label is on or associated with the container.
• a label is on a container when letters, numbers or other characters forming the label are attached, molded or etched into the container itself; a label is associated with a container when it is present within a receptacle or carrier that also holds the container, e.g., as a package insert.
• a label is used to indicate that the contents are to be used for a specific therapeutic application. The label also indicates directions for use of the contents, such as in the methods described herein.
• the pharmaceutical compositions are presented in a pack or dispenser device which contains one or more unit dosage forms containing a compound provided herein.
• the pack for example, contains metal or plastic foil, such as a blister pack.
• the pack or dispenser device is accompanied by instructions for administration.
• the pack or dispenser is also accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration.
• a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration.
• Such notice for example, is the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert.
• compositions containing a crystalline form of a pharmaceutically acceptable salt of 5-ethyl-4-methyl-N-[4-[(2S) morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide described herein e.g. a crystalline polymorph form A of 5-ethyl-4-methyl-N-[4-[(2S) morpholin-2- yl]phenyl]-1H-pyrazole-3-carboxamide, mono hydrochloric acid salt
• a compatible pharmaceutical carrier are also prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.
• Example 1 Salt Forms of 5-ethyl-4-methyl-N-[4-[(2S) morpholin-2-yl]phenyl]-1H- pyrazole-3-carboxamide
• 5-ethyl-4-methyl-N-[4-[(2S) morpholin-2- yl]phenyl]-1H-pyrazole-3-carboxamide (approx.450 mg) was dissolved in dioxane (approx.90 mL) at elevated temperature (approx. 90 °C) in a 100 mL glass vial.
• the clear solution was then cooled to 60 °C (to approx.40 °C for adipic acid) prior to the addition of approx.1.1 equivalents (approx.0.55 equivalents for sulfuric acid) of a 0.5 M (0.2 M for fumaric acid) stock solution in dioxane of the respective acid under agitation.
• the reaction mixture was then allowed to reach ambient temperature passively and further agitated overnight.
• the solvent was partially evaporated at this stage to increase the yield.
• the solid residue was collected by filtration and rinsed with approx.2 mL of dioxane.
• a sample of the wet product was analyzed by XRPD.
• Supersaturation was generated by a first cooling step to 60 °C. Seeding was performed with milled mono hydrochloride salt of 5-ethyl-4-methyl-N-[4-[(2S) morpholin-2- yl]phenyl]-1H-pyrazole-3-carboxamide, mono hydrochloric acid salt crystals (crystal Form A). The water content was then reduced to less than 2% by distillation. During this operation, the volume in the reactor was kept constant by adding fresh 1-propanol. After distillation, the suspension was cooled to the isolation temperature of 0 °C, followed by final ageing and filtration.
• Example 4 Preparation of Crystalline Form A of 5-ethyl-4-methyl-N-[4-[(2S) morpholin-2- yl]phenyl]-1H-pyrazole-3-carboxamide, hemi sulfuric acid salt
• 5-ethyl-4-methyl-N-[4-[(2S) morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide 700 mg, 2.23 mmol
• Sulfuric acid (96 %, 68 ⁇ L, 1.22 mmol, 0.55 equivalents) was added dropwise.
• the resulting rich suspension was agitated for 2 days at ambient temperature.
• the product was then isolated by filtration using a filter nutsche with a paper filter.
• the residue was rinsed with ethanol (5 mL) and then dried in a vacuum tray dryer at 50 °C / ⁇ 10 mbar for two days yielding a colorless solid (690 mg, 85% yield) of the hemi sulfuric acid salt of 5-ethyl-4-methyl-N-[4-[(2S) morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide.
• Melting temperature >260 ° (melting under decomposition)
• DVS n.d.
• Example 5 Preparation of Crystalline Form A of 5-ethyl-4-methyl-N-[4-[(2S) morpholin-2- yl]phenyl]-1H-pyrazole-3-carboxamide, mono phosphoric acid salt
• 5-ethyl-4-methyl-N-[4-[(2S) morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide 700 mg, 2.23 mmol
• Phosphoric acid 85 %, 165 ⁇ L, 2.45 mmol, 1.10 equivalents
• Example 6 Preparation of Crystalline Form A of 5-ethyl-4-methyl-N-[4-[(2S) morpholin-2- yl]phenyl]-1H-pyrazole-3-carboxamide, mono p-toluenesulfonic acid salt
• 5-ethyl-4-methyl-N-[4-[(2S) morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide 700 mg, 2.23 mmol
• ethanol 100 mL
• p-Toluenesulfonic acid 99.0 %, 426 mg, 2.45 mmol, 1.10 equivalents
• the resulting rich suspension was agitated for 3 days at ambient temperature.
• the product was isolated by filtration using a filter nutsche with a paper filter.
• the residue was rinsed with ethanol (5 mL) and then dried in a vacuum tray dryer at 50 °C / ⁇ 10 mbar for two days yielding a colorless solid (988 mg, 91% yield) of the mono p-toluenesulfonic acid salt of 5-ethyl-4-methyl-N-[4-[(2S) morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide.
• Melting temperature 272 °C (melting under decomposition)
• DVS n.d.
• Example 7 X-Ray Powder Diffraction (XRPD) Experimental Methodology
• X-ray diffraction patterns were recorded at ambient conditions in transmission geometry with a STOE STADI P diffractometer (Cu K ⁇ radiation (1.5406 ⁇ ), primary Ge- monochromator, Mythen 1K silicon strip detector, angular range 3° to 42° 2Theta, 20 seconds measurement time per step). The samples were prepared and analysed without further processing (e.g. grinding or sieving) of the substance. Measurement and evaluation of the X-ray diffraction data was done using WinXPOW software (STOE & Cie GmbH, Darmstadt, Germany).
• Example 8 Differential Scanning Calorimetry (DSC) and Thermogravimetric analysis (TGA) The DSC-thermograms were recorded using a Mettler-Toledo differential scanning calorimeter DSC1/2, DSC820/821e or a TA Instruments Discovery Series. For the measurements, approximately 2 to 6 mg of sample were placed in aluminum pans, accurately weighed and hermetically closed with perforation lids. Prior to measurement, the perforation lids were pierced resulting in approx.0.5 mm pin holes. In order to measure the sample under pressure, closed lids can also be used.
• DSC Differential Scanning Calorimetry
• TGA Thermogravimetric analysis
• thermogravimetric analyses were performed on a Mettler-Toledo thermogravimetric analyzer TGA/DSC1, TGA/DSC3+ or TGA851e/SDTA. For the thermogravimetric analyses, approximately 5 to 15 mg of sample were placed in aluminum pans, accurately weighed, and hermetically closed with perforation lids. Prior to measurement, the lids were automatically pierced resulting in approx.0.5 mm pin holes.
• Crystalline Form A of 5-ethyl-4-methyl-N-[4-[(2S) morpholin-2-yl]phenyl]-1H-20 pyrazole-3-carboxamide, hydrochloric acid salt [00117] A sample of Form A of 5-ethyl-4-methyl-N-[4-[(2S) morpholin-2-yl]phenyl]-1H- pyrazole-3-carboxamide, hydrochloric acid salt was analyzed by DSC and TGA.
• DSC analysis of Form A showed an endotherm having an onset at about 270 o C (melt and decomposition overlapping). TGA analysis showed continuous weight loss at ⁇ 260°C indicating beginning decomposition.
• Example 9 Dynamic Vapour Sorption (DVS) [00118] Moisture sorption/desorption data were collected on a DVS Advantage, a DVS Adventure, or a DVS Intrinsic (SMS Surface Measurements Systems) moisture balance system. The sorption/desorption isotherms were measured stepwise in a range from 0 %-RH to 90 %-RH at typically 25 °C.
• a weight change of typically ⁇ 0.001 %/min was chosen as criterion to switch to the next level of relative humidity (with a maximum equilibration time of typically 24 hours, if the weight change criterion was not met).
• the data were corrected for the initial moisture content of the samples by taking the weight after drying of the samples at 0 %-RH as zero point.
• the hygroscopicity of a given substance is characterized (by close analogy with the European Pharmacopoeia) by the increase in mass when the relative humidity is raised from 0 %-RH to 90 %-RH at 25 °C: non-hygroscopic: weight increase ⁇ m ⁇ 0.2% slightly hygroscopic: weight increase 0.2% ⁇ ⁇ m ⁇ 2.0% hygroscopic: weight increase 2.0% ⁇ ⁇ m ⁇ 15.0% very hygroscopic: weight increase ⁇ m ⁇ 15.0% deliquescent: sufficient water is adsorbed to form a liquid Crystalline Form A of 5-ethyl-4-methyl-N-[4-[(2S) morpholin-2-yl]phenyl]-1H- pyrazole-3-carboxamide, hydrochloric acid salt [00119] The DVS analysis of Form A of 5-ethyl-4-methyl-N-[4-[(2S) morpholin-2- yl]phenyl]-1
• Example 10 Aqueous Solubility Aqueous solubility was determined by suspending sufficient compound in water water to give a maximum final concentration of ⁇ 100 mg/mL. The solution was stirred for 24 hours at room temperature (25°C ⁇ 5°C) on a magnetic stirrer using a magnetic stir bar. The final pH of the suspension was measured after 24 hours with a standard pH meter. The suspension was filtered by centrifugation through a ⁇ 0.45 ⁇ m PVDF filter. The filtrate was then diluted 1:500 using a solution of ethanol : water (1:1). Quantification was by HPLC using a previously developed HPLC method (Table 4). A standard curve with a concentration range from 0.001 mg/mL – 0.3 mg/ml.
• Aqueous solubility was determined by suspending sufficient compound in water to give a maximum final concentration of ⁇ 10 mg/mL of the parent free-form of the compound. The suspension was equilibrated at 25°C for 24 hours then the pH was measured. The suspension was then filtered through a glass fibre C filter. The filtrate was then diluted by an appropriate factor e.g.101. Quantitation was by HPLC with reference to a standard solution of approximately 0.25 mg/mL in DMSO. Different volumes of the standard, diluted and undiluted sample solutions were injected.

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