WO2012061576A1 - Crystalline forms of ( s ) - 2 - amino - 3 - (4 - ( 2 - amino - 6 - ( (r) - 1 - (4 - ch loro-2- (3 -methyl- 1h- pyrazol- 1 -yl) phenyl) - 2, 2, 2 - trifluoroethoxy) pyrimidin- 4 - yl) phenyl) propanoic acid - Google Patents
Crystalline forms of ( s ) - 2 - amino - 3 - (4 - ( 2 - amino - 6 - ( (r) - 1 - (4 - ch loro-2- (3 -methyl- 1h- pyrazol- 1 -yl) phenyl) - 2, 2, 2 - trifluoroethoxy) pyrimidin- 4 - yl) phenyl) propanoic acid Download PDFInfo
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- WO2012061576A1 WO2012061576A1 PCT/US2011/059107 US2011059107W WO2012061576A1 WO 2012061576 A1 WO2012061576 A1 WO 2012061576A1 US 2011059107 W US2011059107 W US 2011059107W WO 2012061576 A1 WO2012061576 A1 WO 2012061576A1
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- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
Definitions
- Compounds may exist in one or more crystalline forms, but the existence and characteristics of those forms cannot be predicted with any certainty. And even after one polymorph has been identified, the existence and characteristics of other forms can only be determined by additional experimentation. Id.
- One em bodiment of the invention encompasses pharmaceutical compositions comprising the solid forms described herein. Another encompasses methods of their use. 4. BRIEF DESCRIPTION OF THE FIGURES
- Figure 1 is an X-ray diffraction pattern of a crystalline solid form of anhydrous (S)-2- amino-3-(4-(2-amino-6-(( )-l-(4-chloro-2-(3-methyl-lH-pyrazol-l-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid besylate, referred to herein as Form C.
- the diffractogram was obtained using a Bruker D8 Advance system (Cu Ka radiation).
- This invention is d irected, in part, to solid (e.g., crystalline) forms of (S)-2-amino-3-(4-(2- amino-6-((R)-l-(4-chloro-2-(3-methyl-lH-pyrazol-l-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4- yl)phenyl)propanoic acid and salts (e.g., pharmaceutically accepta ble salts) thereof.
- the compound is an inhibitor of tryptophan hydroxylase, and may be used to treat a wide range of diseases and disorders mediated by serotonin. See, e.g., U.S. patent nos. 7,553,840 and 7,709,493.
- This invention is also d irected to dosage forms comprising solid forms of (S)-2-amino-3-
- the phrases "disease or disorder med iated by peripheral serotonin” a nd “disease a nd disorder mediated by peripheral serotonin” mean a disease and/or disorder having one or more symptoms, the severity of which is or are affected by peripheral serotonin levels.
- the terms “manage,” “managing” and “management” encompass preventing the recurrence of the specified disease or disorder in a patient who has already suffered from the disease or disorder, and/or lengthening the time that a patient who has suffered from the disease or disorder remains in remission.
- the terms encompass modulating the threshold, development and/or duration of the disease or disorder, or cha nging the way that a patient responds to the disease or disorder.
- a “prophylactically effective amou nt” of a compound is an amount sufficient to prevent a disease or condition, or one or more symptoms associated with the d isease or condition, or to prevent its recurrence.
- a prophylactically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of the disease or condition.
- the term “prophylactically effective amount” can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.
- a "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit in the treatment or management of a d isease or condition, or to delay or minimize one or more symptoms associated with the d isease or cond ition.
- a therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment or management of the disease or condition.
- the term "therapeutically effective amount” can encompass a n amount that improves overall therapy, red uces or avoids symptoms or causes of a disease or condition, or enhances the therapeutic efficacy of another therapeutic agent.
- the terms “treat,” “treating” a nd “treatment” contemplate an action that occurs while a patient is suffering from the specified disease or disorder, which reduces the severity of the disease or disorder or one or more of its symptoms, or retards or slows the progression of the disease or disorder.
- the term “include” has the same meaning as “include, but are not limited to,” and the term “includes” has the same meaning as “includes, but is not limited to.” Similarly, the term “such as” has the same meaning as the term “such as, but not limited to.”
- one or more adjectives immediately preceding a series of nouns is to be construed as applying to each of the nouns.
- the phrase "optionally su bstituted alky, aryl, or heteroaryl” has the same meaning as “optionally su bstituted alky, optionally su bstituted aryl, or optionally su bstituted heteroaryl.”
- any atom shown in a drawing with unsatisfied valences is assumed to be attached to enough hydrogen atoms to satisfy the valences.
- chemical bonds depicted with one solid line parallel to one dashed line encompass both single and dou ble (e.g., aromatic) bonds, if valences permit.
- names of compounds having one or more chiral centers that do not specify the stereochemistry of those centers encompass pure stereoisomers and mixtures thereof.
- This invention is directed to solid forms of (S)-2-amino-3-(4-(2-amino-6-((R)-l-(4-chloro- 2-(3-methyl-lH-pyrazol-l l)phenyl)propanoic acid:
- One embodiment of the invention encompasses crystalline (S)-2-amino-3-(4-(2-amino-6- ((R)-l-(4-chloro-2-(3-methyl-lH-pyrazol-l-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4- yl)phenyl)propanoic acid.
- a particular form has a differential scanning calorimetry (DSC) peak at about 126°C.
- DSC differential scanning calorimetry
- Another embodiment of the invention encompasses crystalline besylate salts of (S)-2- amino-3-(4-(2-amino-6-((R)-l-(4-chloro-2-(3-methyl-lH-pyrazol-l-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid.
- Form A is anhydrous (S)-2-amino-3-(4-(2-amino- 6-((R)-l-(4-chloro-2-(3-methyl-lH-pyrazol-l-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4- yl)phenyl)propanoic acid besylate having a melting point of about 234°C as determined by DSC (onset temperature).
- a specific form has a DSC peak at about 238°C.
- a specific form provides an X-ray diffraction (XRPD) pattern with peaks at one or more of about 9.2, 15.9, 16.8, 18.4, 19.8, and/or 20.8 degrees 2 ⁇ . When used herein in connection with XRPD data, the term "about” means ⁇ 0.3 degrees.
- One embodiment of the invention encompasses Form A having an XRPD pattern with peaks at about 15.9, 16.8, and 18.4 degrees 2 ⁇ .
- Form B Another form (“Form B”) is (S)-2-amino-3-(4-(2-amino-6-((R)-l-(4-chloro-2-(3-methyl-lH- pyrazol-l-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid besylate monohydrate.
- a particular form has a melting point of about 218°C (DSC onset temperature).
- a specific form has a DSC peak at about 230°C.
- a specific form provides an XRPD pattern with peaks at one or more of about 8.7, 9.1, 13.4, 18.3, and/or 20.2 degrees 2 ⁇ .
- Form B encompasses Form B having an X PD pattern with peaks at about 8.7, 9.1, and 13.4 degrees 2 ⁇ .
- Form C is anhydrous (S)-2-amino-3-(4-(2-amino-6-((R)-l-(4-chloro-2-(3- methyl-lH-pyrazol-l-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid besylate having a melting point of about 228°C (DSC onset temperature).
- DSC onset temperature melting point of about 228°C
- a specific form has a DSC peak at a bout 233°C.
- a specific form provides an XRPD pattern with peaks at one or more of about 8.7, 9.5, 16.9, 17.5, 19.1, 19.7, 20.1, 20.4, 21.8, 22.1, and/or 26.4 degrees 2 ⁇ .
- one embodiment of the invention encompasses Form C having an XRPD pattern with peaks at about 8.7 and 9.5 degrees 2 ⁇ .
- Another embodiment encompasses Form C having an XRPD pattern with peaks at about 8.7, 9.5, and 19.1 degrees 2 ⁇ .
- Another embodiment encompasses Form C having an XRPD pattern with peaks at about 16.9, 19.1, and 26.4 degrees 2 ⁇ .
- Form D is anhydrous (S)-2-amino-3-(4-(2-amino-6-((R)-l-(4-chloro-2-(3- methyl-lH-pyrazol-l-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid besylate having a melting point of about 234°C (DSC onset temperature).
- a specific form has a DSC peak at a bout 238°C.
- a specific form provides an XRPD pattern with peaks at one or more of about 7.6, 8.6, 12.9, 15.0, 15.3, 17.3, 19.2, 19.5, 20.2, and/or 23.1 degrees 2 ⁇ .
- one embodiment of the invention encompasses Form D having an XRPD pattern with peaks at about 8.6, 12.9, and 15.0 degrees 2 ⁇ .
- Another embodiment encompasses Form D having an XRPD pattern with peaks at about 15.3, 17.3, and 19.2 degrees 2 ⁇ .
- Another embodiment encompasses Form D having an XRPD pattern with peaks at about 15.3, 17.3, and 19.2 degrees 2 ⁇ .
- Form D having an XRPD pattern with peaks at about , 19.2, 19.5, and 20.2 degrees 2 ⁇ .
- Another embodiment of the invention encompasses crystalline dibesylate salts of (S)-2- amino-3-(4-(2-amino-6-((R)-l-(4-chloro-2-(3-methyl-lH-pyrazol-l-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid.
- a particular form has a melting point of about 223°C (DSC onset temperature).
- a specific form has a DSC peak at about 227°C.
- a specific form provides an XRPD pattern with peaks at one or more of about 4.7, 13.8, 18.3, 20.0, 20.3,
- one embodiment of the invention encompasses a crystalline dibesylate salt of the compound having an XRPD pattern with peaks at about 18.3, 20.0, and 20.3 degrees 2 ⁇ .
- Another embodiment of the invention encompasses crystalline edisilate salts of (S)-2- amino-3-(4-(2-amino-6-(( )-l-(4-chloro-2-(3-methyl-lH-pyrazol-l-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid.
- a particular form has a melting point of about 252°C (DSC onset temperature).
- a specific form has a DSC peak at about 259°C.
- a specific form provides an XRPD pattern with peaks at one or more of about 4.4, 8.9, 12.8, and/or 16.1 degrees 2 ⁇ .
- one embodiment of the invention encompasses a crystalline edisilate salt of the compound having an XRPD pattern with peaks at about 4.4, 8.9, and 12.8 degrees 2 ⁇ .
- Another embodiment of the invention encompasses crystalline esylate salts of (S)-2- amino-3-(4-(2-amino-6-((R)-l-(4-chloro-2-(3-methyl-lH-pyrazol-l-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid.
- a particular form has a melting point of about 214°C (DSC onset temperature).
- a specific form has a DSC peak at about 223°C.
- a specific form provides an XRPD pattern with peaks at one or more of about 8.1, 8.7, 13.0, 16.2, 18.3, and/or 20.2 degrees 2 ⁇ .
- one embodiment of the invention encompasses a crystalline esylate salt of the compound having an XRPD pattern with peaks at about 13.0, 16.2, and 18.3 degrees 2 ⁇ .
- Another embodiment of the invention encompasses crystalline isopropyl sulfate salts of (S)-2-amino-3-(4-(2-amino-6-((R)-l-(4-chloro-2-(3-methyl-lH-pyrazol-l-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid.
- a particular form has a melting point of about 194°C (DSC onset temperature).
- a specific form has a DSC peak at about 204°C.
- a specific form provides an XRPD pattern with peaks at one or more of about 7.8, 15.6, 19.6, 23.6, and/or 31.6 degrees 2 ⁇ .
- one embodiment of the invention encompasses a crystalline isopropyl sulfate salt of the compound having an XRPD pattern with peaks at about 7.8, 15.6, and 19.6 degrees 2 ⁇ .
- This invention encompasses solids that are mixtures of both amorphous and crystalline forms.
- Certain such solids comprise crystalline (S)-2-amino-3-(4-(2-amino-6-((R)-l-(4-chloro-2- (3-methyl-lH-pyrazol-l-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid or a pharmaceutically salt thereof in an amount of at least about 50, 75, 80, 85, 90, 95 or 99 weight percent.
- (S)-2-Amino-3-(4-(2-amino-6-((R)-l-(4-chloro-2-(3-methyl-lH-pyrazol-l-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid can be prepared from methods described herein and known in the art. See, e.g., U.S. patent nos. 7,553,840 and 7,709,493. Crystalline salts of the compound can be prepared by heating a solution comprising the compound and a pharmaceutically acceptable acid, reducing the solubility of the resulting salt, and isolating the crystalline salt. 5.3. Methods of Treatment
- This invention encompasses a method of inhibiting tryptophan hydroxylase (TPH), which comprises contacting TPH with a compound of the invention (i.e., a compou nd disclosed herein).
- TPH tryptophan hydroxylase
- This invention encompasses methods of treating, preventing, and managing va rious diseases and disorders mediated by peripheral serotonin, which comprise inhibiting TPH (e.g., the TPH 1 isoform) activity in a patient in need of such treatment, prevention or management.
- TPH e.g., the TPH 1 isoform
- Particular d iseases and disorders include carcinoid syndrome and gastrointestinal diseases and disorders.
- diseases and disorders include a bdominal pain (e.g., associated with medullary carcinoma of the thyroid), anxiety, carcinoid syndrome, celiac disease, constipation (e.g., constipation having an iatrogenic cause, and idiopathic constipation), depression, diabetes, diarrhea (e.g., bile acid diarrhea, enterotoxin-induced secretory diarrhea, diarrhea having an iatrogenic cause, idiopathic diarrhea (e.g., idiopathic secretory diarrhea), and traveler's diarrhea), emesis, functional a bdominal pain, functional dyspepsia, irrita ble bowel disease (IBD, including Crohn's disease and ulcerative colitis), irrita ble bowel syndrome (IBS), lactose intolerance, M EN types I and II, Ogilvie's syndrome, Pancreatic Cholera Syndrome
- cardiovascular and pulmonary diseases and disorders include acute and chronic hypertension, chronic obstructive pulmonary d isease (COPD), pulmonary embolism (e.g., bronchoconstriction and pulmonary hypertension following pulmonary embolism), pulmonary hypertension (e.g., pulmonary hypertension associated with portal hypertension), a nd radiation pneumonitis (including that giving rise to or contributing to pulmonary hypertension).
- COPD chronic obstructive pulmonary d isease
- pulmonary embolism e.g., bronchoconstriction and pulmonary hypertension following pulmonary embolism
- pulmonary hypertension e.g., pulmonary hypertension associated with portal hypertension
- a nd radiation pneumonitis including that giving rise to or contributing to pulmonary hypertension.
- a DS adult respiratory distress syndrome
- CREST syndrome calcinosis, Raynaud's phenomenon, esophageal dysfunction, sclerodactyly, telangiectasia
- Gilbert's syndrome nausea, serotonin syndrome, su barachnoid hemorrhage, a nd ulcerative colitis.
- Still others include functional anorectal d isorders, functional bloating, and functional gall bladder and sphincter of Odd i disorders.
- compositions and dosage forms comprising solid form of the invention.
- Pharmaceutical compositions and dosage forms of this invention may optionally contain one or more pharmaceutically accepta ble carriers or excipients.
- Certain pharmaceutical compositions are single unit dosage forms suita ble for oral, topical, mucosal (e.g., nasal, pulmonary, su blingual, vaginal, buccal, or rectal), parenteral (e.g., su bcutaneous, intravenous, bolus injection, intramuscular, or intraarterial), or transdermal administration to a patient.
- dosage forms include, but are not limited to: ta blets; caplets; capsules, such as soft elastic gelatin capsules; cachets; troches; lozenges; d ispersions; suppositories; ointments; cataplasms (poultices); pastes; powders; dressings; creams; plasters; solutions; patches; aerosols (e.g., nasal sprays or inhalers); gels; liquid dosage forms suita ble for oral or mucosal administration to a patient, including suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions, or a water-in-oil liquid emulsions), solutions, and elixirs; liquid dosage forms suita ble for parenteral administration to a patient; and sterile solids (e.g., crystalline or amorphous solids) that can be reconstituted to provide liquid dosage forms suita ble for parenteral administration to a
- the formulation should suit the mode of administration.
- oral administration may require enteric coatings to protect the active ingredient from degradation within the gastrointestinal tract.
- the active ingredient may be administered in a liposomal formulation to shield it from degradative enzymes, facilitate transport in circulatory system, and/or effect delivery across cell membranes to intracellular sites.
- composition, shape, and type of dosage forms of the invention will typically vary depending on their use.
- a dosage form used in the acute treatment of a disease may contain larger amounts of one or more of the active ingredients it comprises than a dosage form used in the chronic treatment of the same disease.
- a parenteral dosage form may contain smaller amounts of one or more of the active ingredients it comprises than an oral dosage form used to treat the same disease.
- Crystalline free-base (neutral form) was obtained by mixing amorphous (S)-2-amino-3- (4-(2-amino-6-((R)-l-(4-chloro-2-(3-methyl-lH-pyrazol-l-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid (101.2 mg) with 1 ml MeCN/H 2 0.
- the resulting suspension was shaken with an Eppendorf Thermomixer for five days using the following temperature program: four hours at 20°C, heating to 40°C in two hours, two hours at 40°C, cooling to 20°C in four hours.
- the resulting solid was filtered off to afford crystalline needles.
- the volume of the mixture was adjusted by adding 51 kg of methyl THF at 50-55°C.
- the mixture was stirred at 50-55°C for 2 hours and then cooled to 20-25°C and stirred for 10 hours.
- the solid was filtered through a centrifuge. The reactor and the centrifuge were washed with 2-methyl THF twice (2x30 kg). The wet cake of free base was dried at 50- 60°C under vacuum for 10 hours.
- the free base was charged into a 300 L glass lined reactor containing 13 kg benzenesulfonic acid in acetonitrile solution (prepared by adding 3.45 kg benzenesulfonic acid hydrate (assay 87.1%, assay adjusted weight 3.00 kg) in 32 kg of acetonitrile), 7.5 kg of acetic acid and 7 kg of acetonitrile.
- acetonitrile solution prepared by adding 3.45 kg benzenesulfonic acid hydrate (assay 87.1%, assay adjusted weight 3.00 kg) in 32 kg of acetonitrile), 7.5 kg of acetic acid and 7 kg of acetonitrile.
- the mixture was heated to 58-63°C and stirred for 2.5 hours until all solid was dissolved. Additional 4.9 kg of benzenesulfonic acid acetonitrile solution was added and the mixture was stirred at 58-63°C for 10-15 minutes.
- the containers of the benzenesulfonic acid acetonitrile solution was rinsed with 32 kg of acetonitrile and the rinse was slowly added into the reactor in 2 hours.
- the slurry was stirred at 58-63°C for 3 hours before slowly cooled to 20-25°C in 2-4 hours.
- the slurry was stirred at 20- 25°C for 12 hours and then filtered with a centrifuge.
- the reactor and the wet cake were washed with acetonitrile three times (3x20 kg).
- the wet cake (15.44 kg) was dried at 50-60°C under vacuum for 40 hours.
- the product (besylate Form C) was unloaded and sieved.
- the crystallinity of the solid was confirmed by XRPD.
- the DSC exhibited a sharp peak at 222.8°C.
- TGA showed 41.7% weight loss up to a bout 390°C; the combustion of the
- ethanesulfonic acid produced 16% weight loss up to 570°C.
- SEM imaging of the solid showed needle-like crystals.
- the crystallinity of the solid was confirmed by XRPD.
- the DSC exhibited a sharp peak at 203.98°C.
- TGA showed a bout 1.3% weight loss up to a bout 200°C.
- SEM imaging of the solid showed rod-like crystals.
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Abstract
Description
Claims
Priority Applications (11)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
MX2013004921A MX2013004921A (en) | 2010-11-05 | 2011-11-03 | Crystalline forms of ( s ) - 2 - amino - 3 - (4 - ( 2 - amino - 6 - ( (r) - 1 - (4 - ch loro-2- (3 -methyl- 1h- pyrazol- 1 -yl) phenyl) - 2, 2, 2 - trifluoroethoxy) pyrimidin- 4 - yl) phenyl) propanoic acid. |
BR112013011015A BR112013011015A2 (en) | 2010-11-05 | 2011-11-03 | solid forms of -2-amino-3- (4- (2-amino-6 - ((r) -1- (4-chloro-2- (3-methyl-1h-pyrazol-1-yl) acid) ) phenyl) -2,2,2-trifluoroethoxy) pyrimidin-4-yl) phenyl) propanoic |
EP11787757.1A EP2635569A1 (en) | 2010-11-05 | 2011-11-03 | Crystalline forms of ( s ) - 2 - amino - 3 - (4 - ( 2 - amino - 6 - ( (r) - 1 - (4 - ch loro-2- (3 -methyl- 1h- pyrazol- 1 -yl) phenyl) - 2, 2, 2 - trifluoroethoxy) pyrimidin- 4 - yl) phenyl) propanoic acid |
JP2013537814A JP2013541589A (en) | 2010-11-05 | 2011-11-03 | (S) -2-amino-3- (4- (2-amino-6-((R) -1- (4-chloro-2- (3-methyl-1H-pyrazol-1-yl) phenyl)- Crystal form of 2,2,2-trifluoroethoxy) pyrimidin-4-yl) phenyl) propanoic acid |
CA2816963A CA2816963A1 (en) | 2010-11-05 | 2011-11-03 | Solid forms of (s)-2-amino-3-(4-(2-amino-6-((r)-1-(4-chloro-2-(3-methyl-1h-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid |
CN2011800534249A CN103228648A (en) | 2010-11-05 | 2011-11-03 | Crystalline forms of (s)-2-amino-3-(4-(2-amino-6-((r)-1-(4-chloro-2-(3-methyl-1h-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl) propanoic acid |
SG2013032156A SG189535A1 (en) | 2010-11-05 | 2011-11-03 | Crystalline forms of ( s ) - 2 - amino - 3 - (4 - ( 2 - amino - 6 - ( (r) - 1 - (4 - ch loro-2-(3 -methyl- 1h- pyrazol- 1 -yl) phenyl) - 2, 2, 2 - trifluoroethoxy) pyrimidin- 4 - yl) phenyl) propanoic acid |
AU2011323302A AU2011323302A1 (en) | 2010-11-05 | 2011-11-03 | Crystalline forms of ( S ) - 2 - amino - 3 - (4 - ( 2 - amino - 6 - ( (R) - 1 - (4 - ch loro-2- (3 -methyl- 1H- pyrazol- 1 -yl) phenyl) - 2, 2, 2 - trifluoroethoxy) pyrimidin- 4 - yl) phenyl) propanoic acid |
RU2013125756/04A RU2013125756A (en) | 2010-11-05 | 2011-11-03 | SOLID FORMS ) -2,2,2-TRIFTORETOXY) PYRIMIDIN-4-IL) Phenyl) PROPANIC ACID |
KR1020137014387A KR20130141572A (en) | 2010-11-05 | 2011-11-03 | Crystalline forms of (s)-2-amino-3-(4-(2-amino-6-((r)-1-(4-chloro-2-(3-methyl-1h-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid |
ZA2013/03049A ZA201303049B (en) | 2010-11-05 | 2013-04-25 | Crystalline forms of (s)-2-amino-3-(4-(2- amino-6-((r)-1(4-chloro-2-(3-methyl-1h-pyrazol-1-yl) phenyl)- 2, 2, 2-trifluoroethoxy)pyrimidin-4- yl)phenyl)propanoic acid |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US41042110P | 2010-11-05 | 2010-11-05 | |
US61/410,421 | 2010-11-05 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2012061576A1 true WO2012061576A1 (en) | 2012-05-10 |
Family
ID=45023872
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2011/059107 WO2012061576A1 (en) | 2010-11-05 | 2011-11-03 | Crystalline forms of ( s ) - 2 - amino - 3 - (4 - ( 2 - amino - 6 - ( (r) - 1 - (4 - ch loro-2- (3 -methyl- 1h- pyrazol- 1 -yl) phenyl) - 2, 2, 2 - trifluoroethoxy) pyrimidin- 4 - yl) phenyl) propanoic acid |
Country Status (15)
Country | Link |
---|---|
US (1) | US8772483B2 (en) |
EP (1) | EP2635569A1 (en) |
JP (1) | JP2013541589A (en) |
KR (1) | KR20130141572A (en) |
CN (1) | CN103228648A (en) |
AR (1) | AR083755A1 (en) |
AU (1) | AU2011323302A1 (en) |
BR (1) | BR112013011015A2 (en) |
CA (1) | CA2816963A1 (en) |
MX (1) | MX2013004921A (en) |
RU (1) | RU2013125756A (en) |
SG (1) | SG189535A1 (en) |
TW (1) | TW201245183A (en) |
WO (1) | WO2012061576A1 (en) |
ZA (1) | ZA201303049B (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9199994B2 (en) | 2013-09-06 | 2015-12-01 | Karos Pharmaceuticals, Inc. | Spirocyclic compounds as tryptophan hydroxylase inhibitors |
US9611201B2 (en) | 2015-03-05 | 2017-04-04 | Karos Pharmaceuticals, Inc. | Processes for preparing (R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethanol and 1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethanone |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20120077831A1 (en) * | 2009-11-23 | 2012-03-29 | Philip Manton Brown | Methods and assays for the treatment of irritable bowel syndrome |
US20110124667A1 (en) * | 2009-11-23 | 2011-05-26 | Philip Manton Brown | Methods for the treatment of irritable bowel syndrome |
CN109180650A (en) * | 2018-08-28 | 2019-01-11 | 湖南华腾制药有限公司 | A kind of crystal form of deuterated tryptophan hydroxylase inhibitor |
AU2019382168A1 (en) * | 2018-11-16 | 2021-06-03 | Altavant Sciences Gmbh | A method for treating pulmonary arterial hypertension and associated pulmonary arterial hypertension |
Citations (1)
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WO2008073933A2 (en) * | 2006-12-12 | 2008-06-19 | Lexicon Pharmaceuticals, Inc. | 4-phenyl-6-(2,2,2-trifluoro-1-phenylethoxy)pyrimidine-based compounds and methods of their use |
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US7855291B2 (en) | 2005-12-29 | 2010-12-21 | Lexicon Pharmaceuticals, Inc. | Process for the preparation of substituted phenylalanines |
AU2006337137B2 (en) * | 2005-12-29 | 2012-06-14 | Tersera Therapeutics Llc | Multicyclic amino acid derivatives and methods of their use |
US7897763B2 (en) | 2005-12-29 | 2011-03-01 | Lexicon Pharmaceuticals, Inc. | Process for the preparation of substituted phenylalanines |
WO2009029499A1 (en) | 2007-08-24 | 2009-03-05 | Lexicon Pharmaceuticals, Inc. | Methods of preparing 4-phenyl-6-(2,2,2-trifluoro-1-phenylethoxy)pyrimidine-based compounds |
-
2011
- 2011-10-20 TW TW100138117A patent/TW201245183A/en unknown
- 2011-11-03 EP EP11787757.1A patent/EP2635569A1/en not_active Withdrawn
- 2011-11-03 CA CA2816963A patent/CA2816963A1/en not_active Abandoned
- 2011-11-03 RU RU2013125756/04A patent/RU2013125756A/en not_active Application Discontinuation
- 2011-11-03 AU AU2011323302A patent/AU2011323302A1/en not_active Abandoned
- 2011-11-03 MX MX2013004921A patent/MX2013004921A/en not_active Application Discontinuation
- 2011-11-03 US US13/288,366 patent/US8772483B2/en active Active
- 2011-11-03 BR BR112013011015A patent/BR112013011015A2/en not_active IP Right Cessation
- 2011-11-03 KR KR1020137014387A patent/KR20130141572A/en not_active Application Discontinuation
- 2011-11-03 CN CN2011800534249A patent/CN103228648A/en active Pending
- 2011-11-03 SG SG2013032156A patent/SG189535A1/en unknown
- 2011-11-03 WO PCT/US2011/059107 patent/WO2012061576A1/en active Application Filing
- 2011-11-03 JP JP2013537814A patent/JP2013541589A/en not_active Withdrawn
- 2011-11-04 AR ARP110104110A patent/AR083755A1/en unknown
-
2013
- 2013-04-25 ZA ZA2013/03049A patent/ZA201303049B/en unknown
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WO2008073933A2 (en) * | 2006-12-12 | 2008-06-19 | Lexicon Pharmaceuticals, Inc. | 4-phenyl-6-(2,2,2-trifluoro-1-phenylethoxy)pyrimidine-based compounds and methods of their use |
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US7709493B2 (en) | 2006-12-12 | 2010-05-04 | Lexicon Pharmaceuticals, Inc. | 4-phenyl-6-(2,2,2-trifluoro-1-phenylethoxy)pyrimidine-based compounds and methods of their use |
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Cited By (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9199994B2 (en) | 2013-09-06 | 2015-12-01 | Karos Pharmaceuticals, Inc. | Spirocyclic compounds as tryptophan hydroxylase inhibitors |
US9512122B2 (en) | 2013-09-06 | 2016-12-06 | Karos Pharmaceuticals, Inc. | Spirocyclic compounds as tryptophan hydroxylase inhibitors |
US9750740B2 (en) | 2013-09-06 | 2017-09-05 | Kanos Pharmaceuticals, Inc. | Spirocyclic compounds as tryptophan hydroxylase inhibitors |
US10045988B2 (en) | 2013-09-06 | 2018-08-14 | Roivant Sciences Gmbh | Spirocyclic compounds as tryptophan hydroxylase inhibitors |
US10350208B2 (en) | 2013-09-06 | 2019-07-16 | Roivant Sciences Gmbh | Spirocyclic compounds as tryptophan hydroxylase inhibitors |
US10660893B2 (en) | 2013-09-06 | 2020-05-26 | ROIVANT SCIENCES, GmbH | Spirocyclic compounds as tryptophan hydroxylase inhibitors |
US10946018B2 (en) | 2013-09-06 | 2021-03-16 | Roivant Sciences Gmbh | Spirocyclic compounds as tryptophan hydroxylase inhibitors |
US11759462B2 (en) | 2013-09-06 | 2023-09-19 | Altavant Sciences Gmbh | Spirocyclic compounds as tryptophan hydroxylase inhibitors |
US9611201B2 (en) | 2015-03-05 | 2017-04-04 | Karos Pharmaceuticals, Inc. | Processes for preparing (R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethanol and 1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethanone |
US10710948B2 (en) | 2015-03-05 | 2020-07-14 | Roivant Sciences Gmbh | Processes for preparing (R)-1-(5-chloro-[1,1″-biphenyl] -2-yl)-2,2,2-trifluoroethanol and 1-(5-chloro-[1,1″-biphenyl]-2-yl)-2,2,2-trifluoroethanone |
Also Published As
Publication number | Publication date |
---|---|
TW201245183A (en) | 2012-11-16 |
SG189535A1 (en) | 2013-06-28 |
ZA201303049B (en) | 2014-07-30 |
CA2816963A1 (en) | 2012-05-10 |
AR083755A1 (en) | 2013-03-20 |
US8772483B2 (en) | 2014-07-08 |
US20120122904A1 (en) | 2012-05-17 |
EP2635569A1 (en) | 2013-09-11 |
KR20130141572A (en) | 2013-12-26 |
MX2013004921A (en) | 2013-06-28 |
CN103228648A (en) | 2013-07-31 |
JP2013541589A (en) | 2013-11-14 |
RU2013125756A (en) | 2014-12-10 |
BR112013011015A2 (en) | 2016-08-23 |
AU2011323302A1 (en) | 2013-05-30 |
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