Patent Application
20230105412
The present disclosure relates to a serotonin type-3 (5-HT3) receptor modulator, (S)-7-(quinuclidine-3-yl)-8,9-dihydro-2H-azepino[5,4,3-cd]indazol-6(7H)-one, its compositions, free form of, and the salts, and their use in the treatment of disease in which the 5-HT3 receptor is implicated, for example, in the treatment of Irritable Bowel Syndrome (IBS), chemotherapy-induced nausea and vomiting (CINV), post-operative nausea and vomiting (PONV) and symptoms due to carcinoid syndrome. The present disclosure also relates to methods of preparation of the salts of 5-HT3 receptor modulator.
Irritable bowel syndrome (IBS) is a group of intestine functional disorders characterized by continual or interval attack and clinical situations of abdominal pain, abdominal distension, bowel evacuation habit and/or stool trait change, without gastrointestinal tract structure abnormality. IBS is classified as one of functional bowel disorders in Rome IV, and young and middle-aged people are the main patients. The age of onset usually is 20-50 years old, more women than men are diagnosed, and it has a tendency of familial aggregation. IBS is generally accompanied by other diseases of gastrointestinal tract functional disturbance such as functional dyspepsia.
Nausea and vomiting caused by chemotherapy remain among the most distressing side effects for patients undergoing treatment for cancer. Depending upon the chemotherapy agents or regimens given, up to 90% of patients may suffer from some form of chemotherapy-induced nausea and vomiting (CINV). Symptoms from CINV can be severely debilitating and often result in patients refusing further courses of chemotherapy, with obviously unfavorable consequences as regards to progression of the cancer. Furthermore, CINV is burdensome on the medical system, consuming time from the healthcare staff, who could otherwise attend to other patients or medical issues.
Postoperative nausea and vomiting (PONV) is the phenomenon of nausea, vomiting or retching experienced by a patient following a surgical procedure using anesthesia. It is an unpleasant complication that affects about 10% of the population undergoing general anesthesia each year.
Carcinoid syndrome is comprised of symptoms that occur secondary to carcinoid tumors. The syndrome includes diarrhea, flushing and vomiting and is associated with secretion of copious amounts of serotonin.
Studies indicate that 5-hydroxytryptamine (5-HT) is a key neurotransmitter in gastrointestinal tract, and the 5-hydroxytryptamine (5-HT3) receptor is a key target point of developing drugs for treatment of irritable bowel syndrome, carcinoid syndrome, emesis, etc. The applicant's early studies show compounds with structure of formula (I) can effectively modulate the activity of the 5-HT3 receptor, and have a very good application prospect in preparation of drugs for treatment of irritable bowel syndrome, carcinoid syndrome, emesis, etc.
The compound, (S)-7-(quinuclidin-3-yl)-8,9-dihydro-2H-azepino[5,4,3-cd]indazol-6(7H)-one or formula (I), may be useful in the treatment of inflammatory bowel disease (including but not limited to ulcerative colitis, pyoderma gangrenosum and Crohn's disease), irritable bowel syndrome, chemotherapy-induced nausea and vomiting, post-operative nausea and vomiting, carcinoid syndrome, spastic dystonia, chronic pain, acute pain, celiac sprue, pouchitis, vasoconstriction, anxiety, panic disorder, depression, bipolar disorder, autism, sleep disorders, jet lag, amyotrophic lateral sclerosis (ALS), cognitive dysfunction, drug/toxin-induced cognitive impairment (e.g., from alcohol, barbiturates, vitamin deficiencies, recreational drugs, lead, arsenic, mercury), disease-induced cognitive impairment (e.g., arising from Alzheimer's disease (senile dementia), vascular dementia, Parkinson's disease, multiple sclerosis, AIDS, encephalitis, trauma, renal and hepatic encephalopathy, hypothyroidism, Pick's disease, Korsakoff's syndrome and frontal and subcortical dementia), hypertension, bulimia, anorexia, obesity, cardiac arrhythmias, gastric acid hypersecretion, ulcers, pheochromocytoma, progressive supramuscular palsy, chemical dependencies and addictions (e.g., dependencies on, or addictions to nicotine (and/or tobacco products), alcohol, benzodiazepines, barbiturates, opioids or cocaine), headache, migraine, stroke, traumatic brain injury (TBI), obsessive-compulsive disorder (OCD), psychosis, Huntington's chorea, tardive dyskinesia, hyperkinesia, dyslexia, schizophrenia, multi-infarct dementia, age-related cognitive decline, epilepsy, including petit mal absence epilepsy, attention deficit hyperactivity disorder (ADHD), Tourette's Syndrome, particularly, nicotine dependency, addiction and withdrawal; including use in smoking cessation therapy.
The compounds of this disclosure may also be used in a pharmaceutical composition in combination with an antidepressant such as, for example, a tricyclic antidepressant or a serotonin reuptake inhibiting antidepressant (SRI), in order to treat both the cognitive decline and depression associated with AD, PD, stroke, Huntington's chorea or traumatic brain injury (TBI); in combination with muscarinic agonists in order to stimulate both central muscarinic and nicotinic receptors for the treatment, for example, of ALS, cognitive dysfunction, age-related cognitive decline, AD, PD, stroke, Huntington's chorea and TBI; in combination with neurotrophic factors such as NGF in order to maximize cholinergic enhancement for the treatment, for example, of ALS, cognitive dysfunction, age-related cognitive decline, AD, PD stroke, Huntington's chorea and TBI; or in combination with agents that slow or arrest AD such as cognition enhancers, amyloid aggregation inhibitors, secretase inhibitors, tau kinase inhibitors, neuronal anti-inflammatory agents and estrogen-like therapy.
Compounds that relate to a serotonin type-3 (5-HT3) receptor modulator, including (S)-7-(quinuclidin-3-yl)-8,9-dihydro-2H-azepino[5,4,3-cd]indazol-6(7H)-one or formula (I) are referred to in U.S. patent application Ser. No. 13/941,304, filed Jul. 12, 2013, now U.S. Pat. No. 8,710,047, which is a continuation of U.S. patent application Ser. No. 13/372,967, filed Feb. 14, 2012, now U.S. Pat. No. 8,501,729, which is a continuation of U.S. patent application Ser. No. 12/473,940, filed May 28, 2009, now U.S. Pat. No. 8,124,600, which claims benefit of U.S. Provisional Patent Application Ser. No. 61/057,014, filed May 29, 2008. The foregoing applications, owned in common with the present application and incorporated herein by reference in their entirety, generically recite pharmaceutically acceptable salts for the compounds referred to therein.
The present disclosure relates to the free form and salts of (S)-7-(quinuclidin-3-yl)-8,9-dihydro-2H-azepino[5,4,3-cd]indazol-6(7H)-one. The salts of the present disclosure comprise one or more of adipate, benzenesulphonate, hydrobromide, fumarate, benzoate, methanesulfonate, L-malate, d-glyconate, sorbate, phosphate, sulfate, L-tartrate, p-methylbenzenesulphonate, citrate, hydrochloride, ethanesulfonate, 1-hydroxy-2-naphthoate, succinate, acetate, glutarate or L-pyroglutamate salt.
In one embodiment, the present disclosure relates to the free form of (S)-7-(quinuclidin-3-yl)-8,9-dihydro-2H-azepino[5,4,3-cd]indazol-6(7H)-one. As set forth
In diffraction angle (28) values, errors sometimes occur, for example, attributable to the purity of crystal in powder applied to the powder X-ray diffraction analysis, particle size of the powder, an error derived from measure limit of the powder X-ray diffraction apparatus and the like. In this specification, when the crystal is specified by using diffraction angles (28), the diffraction angles are not limited to the measured values per se indicated as having peaks in the column of the examples. The diffraction angles are generally understood to have a variability of ±0.2° based upon recommendations outlined in the discussion of variability in the general chapter on X-ray powder diffraction in the United States Pharmacopeia, USP <941>. These are true to crystals, which will be described later, other than crystals of the free form, for example, methanesulfonate, phosphate, hydrochloride, succinate, 1-hydroxy-2-naphthoate and L-pyroglutamate salts.
As set forth
In one embodiment, the present disclosure relates to methanesulfonate salt. As set forth
As set forth
In one embodiment, the present disclosure relates to phosphate salt. As set forth
As set forth
In another embodiment, the present disclosure relates to hydrochloride salt. As set forth
As set forth
In another embodiment, the present disclosure relates to the succinate salt. As set forth
As set forth
In another embodiment, the present disclosure relates to 1-hydroxy-2-naphthoate salt. As set forth
As set forth
In another embodiment, the present disclosure relates to L-pyroglutamate salt. As set forth
As set forth
Another embodiment of the invention relates to a pharmaceutical composition comprising at least one of polymorphic Forms A, B, C, or other forms of certain salts of (S)-7-(quinuclidin-3-yl)-8,9-dihydro-2H-azepino[5,4,3-cd]indazol-6(7H)-one and a pharmaceutically acceptable carrier or excipient, for use in the treatment of inflammatory bowel disease (including but not limited to ulcerative colitis, pyoderma gangrenosum and Crohn's disease), irritable bowel syndrome, chemotherapy-induced nausea and vomiting, post-operative nausea and vomiting, carcinoid syndrome, spastic dystonia, chronic pain, acute pain, celiac sprue, pouchits, vasoconstriction, anxiety, panic disorder, depression, bipolar disorder, autism, sleep disorders, jet lag, amyotrophic lateral sclerosis (ALS), cognitive dysfunction, drug/toxin-induced cognitive impairment (e.g., from alcohol, barbiturates, vitamin deficiencies, recreational drugs, lead, arsenic, mercury), disease-induced cognitive impairment (e.g., arising from Alzheimer's disease (senile dementia), vascular dementia, Parkinson's disease, multiple sclerosis, AIDS, encephalitis, trauma, renal and hepatic encephalopathy, hypothyroidism, Pick's disease, Korsakoff's syndrome and frontal and subcortical dementia), hypertension, bulimia, anorexia, obesity, cardiac arrhythmias, gastric acid hypersecretion, ulcers, pheochromocytoma, progressive supramuscular palsy, chemical dependencies and addictions (e.g., dependencies on, or addictions to nicotine (and/or tobacco products), alcohol, benzodiazepines, barbiturates, opioids or cocaine), headache, migraine, stroke, traumatic brain injury (TBI), obsessive-compulsive disorder (OCD), psychosis, Huntington's chorea, tardive dyskinesia, hyperkinesia, dyslexia, schizophrenia, multi-infarct dementia, age-related cognitive decline, epilepsy, including petit mal absence epilepsy, attention deficit hyperactivity disorder (ADHD), and Tourette's Syndrome. Another more preferred embodiment of the invention is wherein the pharmaceutical composition is useful in the treatment of nicotine dependency, addiction and withdrawal; most preferably, for use in smoking cessation therapy.
The present invention further relates to pharmaceutical compositions for the uses described in the foregoing paragraph comprising any one of the salts of (S)-7-(quinuclidin-3-yl)-8,9-dihydro-2H-azepino[5,4,3-cd]indazol-6(7H)-one.
The present invention further relates to a method of treating inflammatory bowel disease (including but not limited to ulcerative colitis, pyoderma gangrenosum and Crohn's disease), irritable bowel syndrome, chemotherapy-induced nausea and vomiting, post-operative nausea and vomiting, carcinoid syndrome, spastic dystonia, chronic pain, acute pain, celiac sprue, pouchitis, vasoconstriction, anxiety, panic disorder, depression, bipolar disorder, autism, sleep disorders, jet lag, amyotrophic lateral sclerosis (ALS), cognitive dysfunction, drug/toxin-induced cognitive impairment (e.g., from alcohol, barbiturates, vitamin deficiencies, recreational drugs, lead, arsenic, mercury), disease-induced cognitive impairment (e.g., arising from Alzheimer's disease (senile dementia), vascular dementia, Parkinson's disease, multiple sclerosis, AIDS, encephalitis, trauma, renal and hepatic encephalopathy, hypothyroidism, Pick's disease, Korsakoff's syndrome and frontal and subcortical dementia), hypertension, bulimia, anorexia, obesity, cardiac arrhythmias, gastric acid hypersecretion, ulcers, pheochromocytoma, progressive supramuscular palsy, chemical dependencies and addictions (e.g., dependencies on, or addictions to nicotine (and/or tobacco products), alcohol, benzodiazepines, barbiturates, opioids or cocaine), headache, migraine, stroke, traumatic brain injury (TBI), obsessive-compulsive disorder (OCD), psychosis, Huntington's chorea, tardive dyskinesia, hyperkinesia, dyslexia, schizophrenia, multi-infarct dementia, age-related cognitive decline, epilepsy, including petit mal absence epilepsy, attention deficit hyperactivity disorder (ADHD), and Tourefte's Syndrome comprises administering to a subject in need of treatment a therapeutically effective amount of any of Forms A, B, C or other forms of the salt of formula (I) or (S)-7-(quinuclidin-3-yl)-8,9-dihydro-2H-azepino[5,4,3-cd]indazol-6(7H)-one.
The invention also relates to a process for the preparation of the Forms A, B or C of salts of (S)-7-(quinuclidin-3-yl)-8,9-dihydro-2H-azepino[5,4,3-cd]indazol-6(7H)-one comprising the steps of (i) contacting (S)-7-(quinuclidin-3-yl)-8,9-dihydro-2H-azepino[5,4,3-cd]indazol-6(7H)-one with between 1 and 2 equivalents of acid in a suitable solvent; and (ii) collecting the crystals formed.
A preferred embodiment of this disclosure relates to the above process wherein about 1.1 equivalents of acid is employed and the acid is added to a solution containing the free base. A preferred mode of practicing this process is wherein the contact step is allowed to proceed for less than 2 hours. A more preferred embodiment of this invention relates to the above process wherein the contact step (i.e., step “(i)” above) is allowed to proceed between 30-120° C.
Another preferred embodiment of this invention relates to the above process wherein the suitable solvent is selected from the group consisting of an (C1-C6)alkyl alcohol, an (C1-C6)alkyl ketone, an (C1-C6)alkyl ether, acetonitrile and an (C1-C6)alkyl ester (e.g., ethyl acetate, isopropyl acetate, etc.). More preferably, the suitable solvent is ethanol.
Further another embodiment relates to a polymorph of a compound having a structure represented by formula (I). Optionally, the polymorph is characterized substantially by at least one of the following powder x-ray diffraction pattern peak angles expressed in terms of 2θ (°) (±0.20°) as measured with copper Kα radiation chosen from 11.3, 14.6, 17.2, 18.57, 21.8 and 23.6.
Still another embodiment relates to a method for preparing a polymorph of a compound having a structure represented by formula (I). The method may comprise steps of subjecting to such compound to a temperature, such as room temperature, for example, in the presence of a medium selected from one or more of diisopropyl ether, ethanol, or isopropyl alcohol.
Optionally in any embodiment, the medium may comprise isopropyl alcohol.
Yet another embodiment relates to a pharmaceutical formulation. The pharmaceutical composition may comprise a polymorph of a compound having a structure represented by formula (I), and a pharmaceutically acceptable excipient.
Another embodiment relates to a method of treating a disease. The method may comprise steps of administering to a subject in need of such treatment a therapeutically effective amount of a polymorph of a compound having a structure represented by formula (I).
Still another embodiment relates to a polymorph of a compound having a structure represented by formula (I) for use as a medicament.
The free form and salts of (S)-7-(quinuclidin-3-yl)-8,9-dihydro-2H-azepino[5,4,3-cd]indazol-6(7H)-one, such as adipate, benzenesulphonate, hydrobromide, fumarate, benzoate, methanesulfonate, L-malate, d-glyconate, sorbate, phosphate, sulfate, L-tartrate, p-methylbenzenesulphonate, citrate, hydrochloride, ethanesulfonate, 1-hydroxy-2-naphthoate, succinate, acetate, glutarate or L-pyroglutamate are relatively inert towards common excipients, making them highly suitable for pharmaceutical formulation use.
The object of the present disclosure is to provide free form and salts of relatively stable and soluble 5-HT3 receptor modulator (formula (I)), as well as its crystal form, and the object of the present disclosure is also to provide the use of above salts or crystals in the preparation of drugs for prevention and/or treatment of 5-HT3 receptor related diseases such as irritable bowel syndrome, carcinoid syndrome, emesis, etc.
The present disclosure provides the free form and salts of formula (I):
As used above, and throughout the description of the disclosure, the following terms, unless otherwise indicated, shall be understood to have the following meanings.
The term “alkyl” means an aliphatic or cyclic hydrocarbon group which may be straight or branched having about 1 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl are attached to a linear alkyl chain. Example alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, n-pentyl, and 3-pentyl.
The term “compound”, and equivalent expressions, are meant to embrace compounds of general formula (I) as hereinbefore described, which expression includes the prodrugs, the pharmaceutically acceptable salts, the oxides, and the solvates, e.g. hydrates, where the context so permits. Similarly, reference to intermediates, whether or not they themselves are claimed, is meant to embrace their salts, and solvates, where the context so permits. For the sake of clarity, particular instances when the context so permits are sometimes indicated in the text, but these instances are purely illustrative and it is not intended to exclude other instances when the context so permits.
The term “method of treating” means amelioration or relief from the symptoms and/or effects associated with the disorders described herein. As used herein, reference to “treatment” of a patient is intended to include prophylaxis.
Compounds described herein may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms. Each chiral center may be defined, in terms of absolute stereochemistry, as (R)- or (S)-. The present disclosure is meant to include all such possible isomers, as well as mixtures thereof, including racemic and optically pure forms. Optically active (R)- and (S)-, (−)- and (+)-, or (0)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included.
As used herein, and as would be understood by a person of skill in the art, the recitation of “a compound” is intended to include salts, solvates, oxides, and inclusion complexes of that compound as well as any stereoisomeric form, or a mixture of any such forms of that compound in any ratio. Thus, in accordance with some embodiments of the disclosure, a compound as described herein, including in the contexts of pharmaceutical compositions, methods of treatment, and compounds per se, is provided as the salt form.
The term “solvate” refers to a compound of formula (I) in the solid state, wherein molecules of a suitable solvent are incorporated in the crystal lattice. A suitable solvent for therapeutic administration is physiologically tolerable at the dosage administered.
Examples of suitable solvents for therapeutic administration are ethanol and water.
When water is the solvent, the solvate is referred to as a hydrate. In general, solvates are formed by dissolving the compound in the appropriate solvent and isolating the solvate by cooling or using an antisolvent. The solvate is typically dried or azeotroped under ambient conditions.
Inclusion complexes are described in Remington, The Science and Practice of Pharmacy, 19th Ed. 1:176-177 (1995), which is hereby incorporated by reference in its entirety. The most commonly employed inclusion complexes are those with cyclodextrins, and all cyclodextrin complexes, natural and synthetic, are specifically encompassed within the claims.
The term “salt” refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases including inorganic acids and bases and organic acids and bases. Since the compounds of formula (I) contain a basic nitrogen, salts may be prepared from pharmaceutically acceptable non-toxic acids including inorganic and organic acids.
Suitable pharmaceutically acceptable acid addition salts for the compounds of the present disclosure include acetic, benzenesulfonic (besylate), benzoic, camphorsulfonic, citric, ethenesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, and the like. When the compounds contain an acidic side chain, suitable pharmaceutically acceptable base addition salts for the compounds of the present disclosure include metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from lysine, N,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine.
The configuration of any carbon-carbon double bond appearing herein is selected for convenience only and is not intended to designate a particular configuration; thus a carbon-carbon double bond depicted arbitrarily herein as E may be Z, E, or a mixture of the two in any proportion.
The term “therapeutically effective amount” is meant to describe an amount of compound of the present disclosure effective in modulating 5-HT3 activity and thus producing the desired therapeutic effect. Such amounts generally vary according to a number of factors well within the purview of ordinarily skilled artisans given the description provided herein to determine and account for. These include, without limitation: the particular subject, as well as its age, weight, height, general physical condition, and medical history, the particular compound used, as well as the carrier in which it is formulated and the route of administration selected for it; and, the nature and severity of the condition being treated.
The term “pharmaceutical composition” means a composition comprising a compound of formula (I) and at least one component comprising pharmaceutically acceptable carriers, diluents, adjuvants, excipients, or vehicles, such as preserving agents, fillers, disintegrating agents, wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents, perfuming agents, antibacterial agents, antifungal agents, lubricating agents and dispensing agents, depending on the nature of the mode of administration and dosage forms.
As used herein, the term “pharmaceutically acceptable carrier” is used to mean any carrier, diluent, adjuvant, excipient, or vehicle, as described herein. Examples of suspending agents include ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin. Examples of suitable carriers, diluents, solvents, or vehicles include water, ethanol, polyols, suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate. Examples of excipients include lactose, milk sugar, sodium citrate, calcium carbonate, and dicalcium phosphate. Examples of disintegrating agents include starch, alginic acids, and certain complex silicates, Examples of lubricants include magnesium stearate, sodium lauryl sulphate, talc, as well as high molecular weight polyethylene glycols.
The term “pharmaceutically acceptable” means it is, within the scope of sound medical judgment, suitable for use in contact with the cells of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
One embodiment of the present disclosure relates to pharmaceutically acceptable salts, or non-salt forms, of any of the compounds of formula (d) described herein.
Single enantiomers, any mixture of enantiomers, including racemic mixtures, or diastereomers (both separated and as any mixtures) of the compounds of the present disclosure are also included within the scope of the disclosure.
The scope of the present disclosure also encompasses active metabolites of the present compounds.
Compounds of the present disclosure as described herein are useful as 5-HT3 receptor modulators. It may be found upon examination that compounds that are not presently excluded from the claims are not patentable to the inventors in this application. In that case, the exclusion of species and genera in applicants' claims are to be considered artifacts of patent prosecution and not reflective of the inventors' concept or description of their disclosure. The disclosure, in a compound aspect, is all compounds of formula (I), except those that are in the public's possession.
While it may be possible for compounds of formula (I) to be administered as the raw chemical, it will often be preferable to present them as part of a pharmaceutical composition. Accordingly, another aspect of the present disclosure is a pharmaceutical composition containing a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier. The carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
Furthermore, when reference is made in an independent claim to a compound or a pharmaceutically acceptable salt thereof, it will be understood that claims which depend from that independent claim which refer to such a compound also include pharmaceutically acceptable salts of the compound, even if explicit reference is not made to the salts.
In one embodiment of the present disclosure, the pharmaceutical composition further comprises one or more other therapeutic ingredients, e.g., other compounds effective in the treatment of IBS, CINV or PONV, that are known to persons of skill in the art. Such other therapeutic agents are described below.
Another aspect of the present disclosure relates to a method of treating a disease or condition which is susceptible to treatment with a 5-HT3 receptor modulator. This method involves selecting a patient with a disease or condition which is susceptible to treatment with a 5-HT, receptor modulator and administering to the patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
Diseases or conditions which are susceptible to treatment with a 5-HT, receptor modulator in accordance with the present disclosure include, but are not limited to, general anxiety disorders, social phobias, vertigo, obsessive-compulsive disorders, panic disorders, post-traumatic stress disorders, bulimia nervosa, drug withdrawal effects, alcohol dependency, pain (including visceral pain), sleep related central apneas, chronic fatigue syndrome, Parkinson's Disease Psychosis, schizophrenia, cognitive decline and defects in schizophrenia, Parkinson's Disease, Huntington's Chorea, presenile dementias, Alzheimer's Disease, psychological disorders, obesity, substance abuse disorders, dementia associated with neurodegenerative disease, cognition deficits, fibromyalgia syndrome (see US. Patent Application Publication No 2004/0204467, which is hereby incorporated by reference in its entirety), rosacea (see PCT Publication No. WO 2007/138233, which is hereby incorporated by reference in its entirety), cardiovascular disorders mediated by serotonin, chemotherapy induced nausea and vomiting (CINV), post-operative induced nausea and vomiting (PONV), radiation induced nausea and vomiting (RINV), gastrointestinal disorders (e.g. of the esophagus, stomach and both large and small intestines), including irritable bowel syndrome (IBS) and gastroesophageal reflux disease (GERD) (see European Patent No. EP0430190, U.S. Pat. Nos. 6,967,207, and 5,352,685, which are hereby incorporated by reference in their entirety), bronchial asthma, pruritus, migraine (see Costall et al., Current Drug Targets—CNS & Neurological Disorders, 3:27-37 (2004) and Israili, Current Med. Chem.—CNS Agents, 1:171-199 (2001), which are hereby incorporated by reference in their entirety), and epilepsy (see PCT Publication No. WO 2007/010275, which is hereby incorporated by reference in its entirety).
In another embodiment of the present disclosure, the above method further involves administering a therapeutically effective amount of one or more schizophrenia or Parkinson's Disease adjuncts. Suitable schizophrenia adjuncts include, but are not limited to, vaiproate and levomepromazine. Suitable Parkinson's Disease adjuncts include, but are not limited to, transdermal rotigatine, rotigatine and/or rasagiline as a levodopa adjunct, levodopa, carbidopa, doparnine agonists (brornocriptine, prarnipexole, or ropinirole), COMT inhibitors (entacapone or tolcapone), MAO-B inhibitors (rasagiline or selegiline), amantadine, anticholinergic agents (benztropine or trihexyphenidyl), and salfinamide. The compositions may additionally comprise aiprazolam, haloperidol, chlorpromazine, risperidone, paliperidone, olanzapine, ziprasidone, quetiapine, clozapine, lithium carbonate, diazepam, carbamazepine, selective serotonin re-uptake inhibitors (SSRI's) (ZOLOFT® or CELEXA®) or tricyclic antidepressants, such as PAMELOR®.
A further aspect of the present disclosure relates to a method of treating irritable bowel syndrome (IBS). This method involves selecting a patient with IBS and administering to the patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
In another embodiment of the present disclosure, the above method further involves administering a therapeutically effective amount of other serotonin 5-HT3 receptor modulators and/or serotonin 5-HT4 receptor modulators, some of which are indicated below. Suitable other serotonin 5-HT; receptor modulators and/or serotonin 5-HT4 receptor modulators include, but are not limited to, Alosetron (LOTRONEX®), renzapride, cilansetron, Tegaserod (ZELNORM®), Prucalopride, ondansetron; somatostatin analogs such as Octreotide; muscarinic receptor antagonists such as Darifenacin, and Zamifenacin; laxatives such as methylcellulose (CITRUCEL®), Psyllium (METAMUCIL®, FIBERALL®, REGULOID®, KONSYL®), malt soup extract, polyacrylic resins (e.g., hydrophilic forms such as polycarbophil and calcium polycarbophil), plantago seeds, dioctyl calcium sulfosuccinate, dioctyl potassium sulfosuccinate, dioctyl sodium sulfosuccinate, mineral oil, magnesium citrate, magnesium hydroxide, magnesium sulfate, dibasic sodium phosphate, monobasic sodium phosphate, sodium biphosphate, glycerin, anthraquinones or anthracene laxatives (such as aloe, cascara sagrada, danthron, senna, aloin, casanthranol, frangula, and rhubarb), diphenylmethanes (such as bisacodyl and phenolphthalein), and castor oil and the like; antispasmodics, such as the anticholinergic agents dicyclomine HCl (BENTYL®), hyoscyamine sulfate (LEVSIN®), and the like; antidepressants such as imipramine (TOFRANIL®), amitriptylin (ELAVIL®); antidiarrheal agents such as diphenoxylate HCl+atropine sulfate (LOMOTILD), loperamide (IMODILMO), natural or synthetic opiates (such as difenoxin, diphenoxylate, pargoric, opium tincture, and loperamide), anticholinergics (such as belladonna aikoloids-atropine hyoscyamine, and hyosine), acetyltannic acid, albumin tannate, alkofanone, aluminum salicylates, catechin, lidamidine, mebiquine, trillium, and uzarin, and the like; prokinetic agents, peripheral opiate narcotic antagonists such as fedotozine, trimebutine, and the like. Suitable prokinetic agents include, but are not limited to, cisapride monohydrate (PROPULSID®), metoclopromide, domperidone, and the like.
Another aspect of the present disclosure relates to a method of treating emesis. This method involves selecting a patient with emesis and administering to the patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
In another embodiment of the present disclosure, the above method further involves administering a therapeutically effective amount of one or more other anti-emetic compounds. Suitable anti-emetic compounds include, but are not limited to, alosetron, aiprazolam, aprepitant, dexamethasone, dimenhydrinate, diphenhydramine, dolasetron, tetrahydrocannabinol, nabilone, dronabinol, droperidol, granisetron, haloperidol, lorazepam, metoclopramide, midazolam, olanzapine, ondansetron, palonosetron, proclorperazine, promethazine, and tropisetron.
Yet another aspect of the present disclosure relates to a method of treating CNS diseases or conditions. This method involves selecting a patient with a CNS disease or condition and administering to the patient an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. Suitable CNS diseases or conditions include, but are not limited to, schizophrenia and Parkinson's disease. Beneficial effects of 5-HT, modulators have been reported in clinical studies of Parkinson's disease (Zoidan J et al., Advances in Neurology, 69:541-544 (1996), which is hereby incorporated by reference in its entirety) and schizophrenia (Zhang-Jin et al., Schizophrenia Research, 83: 102-110 (2006): Alder et al., Am, J, Psychiatry, 162:386-388 (2005), which are hereby incorporated by reference in their entirety). Brain responses in humans have been altered upon treatment with alosetron in IBS patients (Mayer et al., Aliment Pharmacol. Ther, 16:1357-1366 (2002), which is hereby incorporated by reference in its entirety). A 5-HT3 modulator may be used as an adjunct or in combination with another medication.
It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.
Another aspect of the present invention relates to a process of preparing a salt of formula (i). This process involves (i) contacting formula (i) or (S)-7-(quinuclidin-3-yl)-8,9˜dihydro-2H-azepino[5,4,3-cd]indazol-6(7H)-one in a suitable solvent with between about 1 and about 2 equivalents of acid; and (ii) collecting the crystals formed. Further another aspect of the present invention relates various salt polymorphs. The salt of formula (I) may exist as multiple polymorphs: anhydrous form, solvate form, or some other unsolvated form.
In some embodiments, one polymorph may convert to another polymorph under appropriate conditions.
Salts may be further purified by crystallization or recrystallization. The crystallization or recrystallization process may be standing or stirring. More specifically, the crystallization process may be preferably stirring. The temperature of the crystallization process may be −10˜60° C., preferably room temperature.
The solid state thermal behavior of Forms A, B, C or other forms of the salt of (S)-7-(quinuclidin-3-yl)-8,9-dihydro-2H-azepino[5,4,3-cd]indazol-6(7H)-one were investigated by differential scanning calorimetry (DSC). The DSC thermograms were obtained on a Mettler Toledo DSC 822e. Generally, samples between 1 and 10 mg were prepared in crimped aluminum pans with a small pinhole. The measurements were run at a heating rate of 10° C. per minute in the range of 30 to 400° C.
One of skill in the art will however note that in DSC measurements there is a certain degree of variability in actual measured onset and peak temperatures which is dependent on rate of heating, crystal shape and purity, and a number of measurement parameters.
The powder x-ray diffraction patterns for Forms A, B, C or other forms of the salts were collected using a PANalytical CubiX-Pro XRD equipped with copper Kα radiation (CuKV, 45 kV), divergent slit (automatic 1.0 mm), and a Kevex solid state detector. Data was collected from 3.0 to 40.0 degrees in two theta (28) using a step size of 0.03 degrees and a step time of 10 seconds.
The x-ray powder diffraction pattern of the salt was conducted with a copper anode. The range for 26 was between 3.0 to 45.0 degrees with a step size of 0.03 degrees, a step time of 1.00 s, a smoothing width of 0.300° and a threshold of 1.0.
The diffraction peaks at diffraction angles (28) in a measured powder X-ray diffraction analysis for the Form A are shown in Table I. The relative intensities, however, may change depending on the crystal size and morphology.
The salts of the disclosure (hereafter “the active salts”) can be administered via either the oral, transdermal (e.g., through the use of a patch), intranasal, sublingual, rectal, parenteral or topical routes. Transdermal and oral administration are preferred. These salts are, most desirably, administered in dosages ranging from about 0.01 mg up to about 1500 mg per day, preferably from about 0.1 to about 300 mg per day in single or divided doses, although variations will necessarily occur depending upon the weight and condition of the subject being treated and the particular route of administration chosen. However, a dosage level that is in the range of about 0.001 mg to about 10 mg per kg of body weight per day is most desirably employed. Variations may nevertheless occur depending upon the weight and condition of the persons being treated and their individual responses to said medicament, as well as on the type of pharmaceutical formulation chosen and the time period and interval during which such administration is carried out. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effects, provided that such larger doses are first divided into several small doses for administration throughout the day.
The active salts can be administered alone or in combination with pharmaceutically acceptable carriers or diluents by any of the several routes previously indicated. More particularly, the active salts can be administered in a wide variety of different dosage forms, e.g., they may be combined with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, transdermal patches, lozenges, troches, hard candies, powders, sprays, creams, salves, suppositories, jellies, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups, and the like. Such carriers include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents. In addition, oral pharmaceutical compositions can be suitably sweetened and/or flavored. In general, the active compound is present in such dosage forms at concentration levels ranging from about 5.0% to about 70% by weight.
For oral administration, tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine may be employed along with various disintegrants such as starch (preferably corn, potato or tapioca starch), alginic acid and certain complex silicates, together with granulation binders like polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc can be used for tabletting purposes. Solid compositions of a similar type may also be employed as fillers in gelatin capsules; preferred materials in this connection also include lactose or milk sugar, as well as high molecular weight polyethylene glycols. When aqueous suspensions and/or elixirs are desired for oral administration the active ingredient may be combined with various sweetening or flavoring agents, coloring matter and, if so desired, emulsifying and/or suspending agents, together with such diluents as water, ethanol, propylene glycol, glycerin and various combinations thereof.
For parenteral administration, a solution of an active salt in either sesame or peanut oil or in aqueous propylene glycol can be employed. The aqueous solutions should be suitably buffered (preferably pH greater than 8), if necessary, and the liquid diluent first rendered isotonic. These aqueous solutions are suitable for intravenous injection purposes. The oily solutions are suitable for intraarticular, intramuscular and subcutaneous injection purposes. The preparation of all these solutions under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.
It is also possible to administer the active salts topically and this can be done by way of creams, a patch, jellies, gels, pastes, ointments and the like, in accordance with standard pharmaceutical practice.
The invention disclosure discloses that experiments were conducted through a series of salt formation investigation using multiple solvent and counterion combinations. The project proceeded in a multi-tiered approach to probe for crystalline salts of formula (I) including an initial screen at a 4 mg scale utilizing a diverse array of conditions and subsequent scale-up experiments. Formula (I) was confirmed to form crystalline and/or semi-crystalline salts with the following counterions: adipic acid, benzenesulfonic acid, hydrobromic acid, fumaric acid, benzoic acid, methanesulfonic acid, L-malic acid, sorbic acid, phosphoric acid, sulfuric acid, L-tartaric acid, p-toluenesulfonic acid, citric acid, hydrochloric acid, ethanesulfonic acid, 1-hydroxy-2-napthoic acid, succinic acid, glutaric acid and 2-pyrrolidine-5-carboxylic acid. Following the initial characterization, six salt candidates were identified for further assessment of physical properties including: methanesulfonic acid, phosphoric acid, hydrochloric acid, succinic acid, 1-hydroxy-2-napthoic acid and 2-pyrrolidine-5-carboxylic acid. The selections were made based on the following considerations: improved solubility over the free form, crystallinity, thermal stability (Mp), and safety. Each of the six salts was further characterized including an assessment of stability under slurry conditions and at elevated temperature/humidity. Based on the results from the analysis, a mono-HCl salt of formula (I) was recommended as the final salt form of formula (I). The hydrochloride exhibited the most desirable physical properties of the salts investigated including high solubility in water as well as form stability at elevated temperature, humidity and under slurry conditions. The phosphate and glutamate were also observed to be viable salts.
The phosphate was found to be slightly hygroscopic and showed improved aqueous solubility in comparison to the free form. The glutamate also showed good solubility, however, deliquesced at relative humidity (RH) conditions above 80% which potentially resulted in the formation of a stable monohydrate. The mesylate salt was not recommended due additional testing requirements that would be required for genotoxic impurities if isolated from an alcoholic solvent. The succinate and naphthoate were not recommended as these salts showed conversion to hydrate forms with limited RH stability. A summary of the experimental conditions used to generate all materials, evaluation at each stage of the salt screen and characterization of the salt species are provided herein.
Forty-one conditions that afforded solids which either showed birefringence, a unique Raman spectrum in comparison to the free form, or improved aqueous solubility were scaled up to 70 mg to provide additional material for confirmation of salt formation and further characterization. Crystalline or semi-crystalline solids recovered from these experiments were analyzed by XRPD, Raman, Optical Microscopy, DSC, TGA, ICP/OES, 1H-NMR, and gravimetric solubility in water. Of the counterions investigated, crystalline and/or semi-crystalline salts of formula (I) were observed with adipic acid, benzenesulfonic acid, hydrobromic acid, fumaric acid, benzoic acid, methanesulfonic acid, L-malic acid, sorbic acid, phosphoric acid, sulfuric acid, L-tartaric acid, p-toluenesulfonic acid, citric acid, hydrochloric acid, ethanesulfonic acid, 1-hydroxy-2-napthoic acid, succinic acid, glutaric acid and L-pyroglutamic acid (2-pyrrolidine-5-carboxylic acid). Six salt forms were identified for further assessment of physical properties including: methanesulfonic acid, phosphoric acid, hydrochloric acid, succinic acid, 1-hydroxy-2-napthoic acid and 2-pyrrolidine-5-carboxylic acid (Table 7).
These salts were selected based on the following characteristics: improved water solubility compared to the free form, crystallinity, thermal stability as predicted by melting point(MP), and safety. Of these counterions, succinic acid, L-pyroglutamic acid and hydrochloric acid were scaled up to 200 mg to produce additional material for further characterization. The stability of each salt was assessed via room temperature slurries in organic solvent and water, storage at elevated temperature (60° C.), and exposure to elevated relative humidity by gravimetric moisture sorption. From the water slurries, the solubility of each salt was determined at ambient conditions. With the exception of the naphthoate, each of the six salts was observed to be stable following the slurry experiments and exposure to elevated temperature. The naphthoate was confirmed to be the least soluble salt exhibiting comparable water solubility to the free form. From the gravimetric moisture sorption experiments, the succinate, glutamate and naphthoate showed a propensity to form hydrates. Of these salts, only the glutamate exhibited a potential hydrate that was stable across a wide humidity range. The mesylate was observed to be moderately hygroscopic while the phosphate and hydrochloride showed the least affinity for water sorption. Overall there were many viable crystalline salt candidates identified; however, it was concluded that the hydrochloride possessed the most desirable physical properties including: stability, low hygroscopicity and substantially improved solubility over the formula (I) free form (Table 7).
Obviously, based on above content of the present disclosure, according to the common technical knowledge and the conventional means in the field, without department from above basic technical spirits, other various modifications, alternations or changes can further be made.
By following specific examples of said embodiments, above content of the present disclosure is further illustrated. But it should not be construed that the scope of above subject of the present disclosure is limited to following examples. The techniques realized based on above content of the present disclosure are all within the scope of the present disclosure.
The following examples illustrate the methods and compounds of the present disclosure. It will be understood, however, that the disclosure is not limited to the specific Examples.
Unless otherwise noted, reagents and solvents were used as received from commercial suppliers. Formula (I) was synthesized according to US2009298809.
Albany Molecular Research, Inc. (AMRI) performed a salt screen of formula (I). The investigation was conducted through a series of salt-formation experiments using multiple solvent and counter ion combinations. The selected crystalline salt forms generated during the screen were analyzed by XRPD, the crystal form of each salt was classified into A, B, or C according to the XRPD results.
Approximately 70 mg of formula (I), lot LMA-U-133(2) was weighed to an 8-mL or 20-mL vial containing a magnetic stir bar. To the vial, primary solvent (MeOH, EtOH, IPA or THF) was added to ensure dissolution at elevated temperature. Following dissolution, 1.05 equivalent of acid was added drop-wise as a 0.25, or 0.50 M solution (Table 1). All mixtures were allowed to stir at elevated temperature for ˜10-15 min, followed by cooling to room temperature at a rate of 20° C./h and stirring at room temperature overnight. Solids observed following cooling were isolated by filtration and dried overnight under vacuum at room temperature. Samples without solids following cooling were evaporated under nitrogen and dried overnight under vacuum at room temperature. An analysis summary of the resulting solids is provided in Table 1.
1H-NMR
)
),
acid
, IPA
, EtOH
THF
indicates data missing or illegible when filed
To generate more material for further characterization, additional salt formations were performed for the HCl, glutamate and succinate salts of formula (I) at an increased scale. Approximately 200 mg of formula (I), lot LMA-U-133(2) was weighed to an 8 mL or 40 mL vial containing a magnetic stir bar. To the vial, primary solvent (EtOH or THE) was added to ensure dissolution at elevated temperature. Following dissolution, 1.05 equivalent of acid was added drop-wise as 0.5 M solution. All mixtures were allowed to stir at elevated temperature for ˜10-15 min, followed by cooling to room temperature at a rate of 20° C./h and stirring at room temperature overnight. Solids observed following cooling were isolated by filtration and dried overnight under vacuum at room temperature. See Table 2 for experimental details and results.
The formula (I) free base starting material [lot LMA-U-133(2)] supplied by AMRI and select crystalline salt forms generated during the screen were analyzed by XRPD, Raman, Microscopy, DSC, and TGA. 1H NMR and/or ICP/OES were performed to determine salt stoichiometry and to determine if degradation had occurred during the salt formation.
The water solubility of select salts afforded from the 70 mg scale experiments was estimated using the following gravimetric method. Approximately 20 mg of each confirmed salt was weighed into a 2 mL HPLC vial. 50 μL increments of deionized H2O were then added to each vial along with a small magnetic stir bar. If dissolution was observed, the samples were stored in a hood overnight and examined the next day for precipitation. Samples affording slurries after a maximum of 250 μl of water were left stirring at ambient conditions overnight to equilibrate. These samples were then centrifuge filtered, and 50 μL of each saturated solution was aliquoted into tared TGA pans. On the TGA, each sample was heated and held at elevated temperature until all solvent was dried off. Resulting dry weight and aliquoted volume for each saturated solution was then utilized in estimating solubility. Refer to Table 3 for results of this study.
at RT
indicates data missing or illegible when filed
Approximately 20 mg of the free form, mesylate, hydrochloride, succinate, glutamate, naphthoate and phosphate salts of formula (I) were weighed to individual HPLC vials equipped with a magnetic stir bar and 0.05 mL increments of deionized water added. If dissolution was observed, the approximate solubility was recorded. If no dissolution had occurred, the slurries were stirred overnight at ambient temperature. The supernatant from each slurry was obtained using centrifuge filters. Each solution was tested for pH and by HPLG versus a calibration curve (
Approximately 10 mg of the free form, mesylate, hydrochloride, succinate, glutamate, naphthoate and phosphate salts of formula (I) were weighed to individual 4 mL vials and stored uncovered in an oven at 60° C. and ambient pressure. After seven days of exposure, the solids were analyzed by XRPD to check for form conversion and 1H-NMR for signs of degradation (Table 5).
1H-NMR
Approximately 30 mg of the free form, mesylate, hydrochloride, succinate, glutamate, naphthoate and phosphate salts of formula (I) were weighed to individual HPLG vials equipped with a magnetic stir bar. Either THF or IPA was added to obtain a free flowing slurry. After seven days of ambient equilibration, solid from each slurry was obtained using centrifuge filtration with 0.45 μm nylon centrifuge filters, and dried at ambient temperature and ˜30 in Hg. After drying overnight, each was analyzed by XRPD to check for form conversion and 1H-NMR for signs of degradation (Table 6).
Approximately 30 mg of Form A mono-glutamate salt [lot HAL-G-29(2)] was stored uncovered in a small glass container in a desiccator containing an aqueous saturated solution of Na2HPO4.12H2O to achieve a relative humidity of 95%. After five hours of exposure the solid had deliquesced and the sample was exposed to the lab environment (20% RH) overnight. The resulting dried solid was characterized by XRPD, DSC, and TGA.
The formula (I) free form [Lot LMA-U-133(2)] obtained from the Medicinal Chemistry Department at AMRI, afforded a crystalline diffraction pattern by XRPD and was designated as Form A (
Lot HAL-G-32(7) obtained following a 7-day room temperature slurry of Form A in IPA, afforded a unique XRPD pattern which showed differences in comparison to the diffraction pattern of Form A (
(2) Adipic acid
Lots HAL-G-26(1) isolated from EtOH and lot HAL-G-26(2) from IPA at a 70 mg scale, afforded the same crystalline XRPD pattern which was unique as compared to formula (I) free form and all other synthesized salts (
Lots HAL-G-26(3) isolated from THE at a 70 mg scale, afforded a crystalline XRPD pattern which was unique in comparison to the diffraction pattern of formula (I) free form and all other synthesized salts (
Lots HAL-G-26(4) isolated from IPA at a 70 mg scale, afforded a crystalline XRPD pattern which was unique in comparison to the diffraction pattern of formula (I) free form and the Form A besylate salt (
The results obtained from the characterization of the formula (I) besylate indicated the presence of two crystalline mono-salt forms (Forms A and B). This counter ion was not selected for further characterization due to additional testing requirements which would be required for genotoxic impurities if isolated from an alcoholic solvent. A summary of the results obtained from the characterization of Form B is presented in Table 7.
Lots HAL-G-26(5) isolated from THF and lot HAL-G-26(6) from IPA at a 70 mg scale, afforded the same semi-crystalline XRPD pattern which was unique as compared to formula (I) free form and all other synthesized salts (
(5) Fumaric acid
Lots HAL-G-26(9) isolated from THF and lot HAL-G-26(10) from IPA at a 70 mg scale, afforded the same crystalline XRPD pattern which was unique as compared to formula (I) free form and all other synthesized salts (
Lots HAL-G-26(11) isolated from THF and lot HAL-G-26(12) from IPA at a 70 mg scale, afforded the same crystalline XRPD pattern which was unique as compared to formula (I) free form and all other synthesized salts (
Lots HAL-G-26(13) isolated from THF and lot HAL-G-26(14) from IPA at a 70 mg scale, afforded consistent crystalline XRPD patterns which showed differences in comparison to the diffraction pattern of the formula (I) free form (
Form A was observed to be moderately hygroscopic by gravimetric moisture sorption adsorbing up to 4.6 wt % water at 80% RH followed by a sharp increase to 8.8 wt % at 90% RH (
Lots HAL-G-26(15) isolated from THE and lot HAL-G-26(16) from IPA at a 70 mg scale, afforded the same crystalline XRPD pattern which was unique as compared to formula (I) free form and all other synthesized salts (
Lots HAL-G-26(20) isolated from IPA at a 70 mg scale, afforded a crystalline XRPD pattern which was unique as compared to formula (I) free form and all other synthesized salts (
Lots HAL-G-26(21) isolated from THE and lot HAL-G-26(22) from IPA at a 70 mg scale, afforded consistent crystalline XRPD patterns (
Lots HAL-G-26(23) isolated from THF at a 70 mg scale, afforded a crystalline XRPD pattern which was unique in comparison to the diffraction pattern of formula (I) free form and all other synthesized salts (
Lots HAL-G-26(24) isolated from IPA at a 70 mg scale, afforded a crystalline XRPD pattern which was unique in comparison to the diffraction pattern of formula (I) free form and the Form A sulfate salt (
Subsequent analysis of the sample by XRPD revealed conversion to an amorphous solid and the corresponding 1H-NMR spectrum showed signs of degradation. Given these findings, further investigation would be required to determine if the salt is solvated with water or EtOH. The results obtained from the characterization of the formula (I) sulfate indicated the presence of two crystalline mono-salt forms (Forms A and B). This counter ion was not selected for further characterization due to the potential for solvate formation. A summary of the results obtained from the characterization of Form B is presented in Table 7.
Lots HAL-G-26(25) isolated from THE at a 70 mg scale, afforded a crystalline XRPD pattern which was unique as compared to formula (I) free form and all other synthesized salts (
Lots HAL-G-26(26) isolated from IPA at a 70 mg scale, afforded a crystalline XRPD pattern which was unique as compared to formula (I) free form and the Form A tartrate salt (
This counter ion was not selected for further characterization due to the potential for hydrate formation which can often present stability challenges during long term storage. A summary of the results obtained from the characterization of Form B is presented in Table 7.
(13) p-Toluenesulfonic Acid
Lots HAL-G-26(27) isolated from THE and lot HAL-G-26(28) from IPA at a 70 mg scale, afforded similar crystalline XRPD patterns with the exception of an additional minor reflection at 6.5 degrees 2-theta (
Lots HAL-G-26(29) isolated from MeCOH and lot HAL-G-26(31) from IPA at a 70 mg scale, afforded the same crystalline XRPD pattern which was unique as compared to formula (I) free form and all other synthesized salts (
Lots HAL-G-26(30) isolated from THE at a 70 mg scale, afforded a unique XRPD pattern in comparison to the diffraction pattern of the formula (I) free form and the Form A citrate salt (
Lots HAL-G-26(32) isolated from EtOH, HAL-G-26(33) from IPA and HAL-G-26(34) from THF at a 70 mg scale, afforded consistent crystalline XRPD patterns which showed differences in comparison to the pattern of the formula (I) free form (
Form A was observed to be slightly hygroscopic adsorbing up to 0.8 wt % water at 60% RH and 1.3 wt % water at 90% RH (
Lots HAL-G-26(35) isolated from THF at a 70 mg scale, afforded a crystalline XRPD pattern which was unique as compared to formula (I) free form and all other synthesized salts (
Lots HAL-G-26(36) isolated from THE at a 70 mg scale, afforded a unique crystalline XRPD pattern which showed differences in comparison to the diffraction pattern of formula (I) free form (
Form A was observed to be moderately hygroscopic adsorbing up to 1.5 wt % water at 60% RH and 2.5 wt % water at 90% RH (
Form B was obtained from Form A after prolonged storage at 60° C., post moisture sorption analysis, and seven days of room temperature equilibration in IPA. Representative XRPD patterns of Form B are presented in
Form C was obtained following an overnight room temperature slurry of Form A in water (
Lots HAL-G-26(37) isolated from THF at a 70 mg scale and lot HAL-G-29(1) at a 200 mg scale, afforded consistent crystalline XRPD patterns which showed differences in comparison to the pattern of the formula (I) free form (
The Form A succinate salt showed a sharp increase in water sorption from 40%-50% RH by gravimetric moisture sorption (
Lots HAL-G-26(39) isolated from THF at a 70 mg scale afforded a crystalline XRPD pattern which was unique as compared to formula (I) free form and all other synthesized salts (
Lots HAL-G-26(40) isolated from THF at a 70 mg scale, afforded a crystalline XRPD pattern which was unique as compared to formula (I) free form and all other synthesized salts (
Form A was observed to be stable showing no signs of conversion following seven days of room temperature equilibration in IPA and storage at 60° C. (
As presented above, Form B was obtained following moisture sorption analysis of Form A and subsequent drying. In an effort to generate additional Form B for further characterization, a brief humidity study was performed as described below: approximately 30 mg of Form A mono-glutamate salt [lot HAL-G-29(2)] was stored uncovered in a small glass container in a desiccator containing an aqueous saturated solution of Na2HPO4.12H2O to achieve a relative humidity of 95%.
After five hours of equilibration at 95% RH, the solid had deliquesced. Following overnight exposure of the sample to the lab environment (˜20% RH), a dry solid was obtained which had adhered to the sample container. XRPD analysis of the solid afforded a crystalline XRPD pattern similar to that of Form B (
The above results indicate that the present disclosure has prepared various formula (I) salts of different crystal forms, compared with formula (I) methanesulfonate, phosphate, hydrochloride, succinate, 1-hydroxy-2-naphthoate and L-pyroglutamate have better properties with better crystallinity, solubility or stability. In each crystal forms, Form A has more excellent properties. Among the above various salts, the hydrochloride has the best overall performance due to its higher water solubility, better stability, and less hygroscopicity.
In summary, the present disclosure provides various salts of formula (I), as well as crystal forms and methods for their preparation. The inventors of the present invention conducted various researches under such a situation as mentioned above. As a result, they found that a hydrochloride salt of Formula (I) has at least one or more of such characteristics as (1) it has superior stability, (2) it shows superior crystallinity, (3) it shows high water solubility, (4) it does not show deliquescent property, (5) it shows superior flowability, (6) it shows superior tableting property, (7) it can be manufactured with less environmental load, (8) it shows less hygroscopicity, and (9) it can be manufactured in a large scale, and therefore it is useful as a bulk drug for medicaments than free base shown in formula (I), and thus they accomplished the present invention.
While the present invention has been particularly described, persons skilled in the art will appreciate that many variations and modifications can be made. Therefore, the invention is not to be construed as restricted to the particularly described embodiments, and the scope and concept of the invention will be more readily understood by reference to the claims, which follow.
Dprecipitation upon cooling all other ppt upon addition
additional
at 6.5 degrees 2-theta
indicates data missing or illegible when filed
This application claims the priority of a U.S. Provisional application filed on Mar. 16, 2020 in the U.S. Patent and Trademark Office and assigned Ser. No. 62/990,228, which is hereby incorporated by reference in their entirety.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/US2021/022595 | 3/16/2021 | WO |
