WO2009130263A1 - PROCESS FOR PREPARING A CRYSTALLINE FORM COMPOUND OF 3-BENZYL-2-METHYL-2,3,3a,4,5,6,7,7a-OCTAHYDROBENZO[d]ISOXAZOL-4-ONE - Google Patents
PROCESS FOR PREPARING A CRYSTALLINE FORM COMPOUND OF 3-BENZYL-2-METHYL-2,3,3a,4,5,6,7,7a-OCTAHYDROBENZO[d]ISOXAZOL-4-ONE Download PDFInfo
- Publication number
- WO2009130263A1 WO2009130263A1 PCT/EP2009/054859 EP2009054859W WO2009130263A1 WO 2009130263 A1 WO2009130263 A1 WO 2009130263A1 EP 2009054859 W EP2009054859 W EP 2009054859W WO 2009130263 A1 WO2009130263 A1 WO 2009130263A1
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- WO
- WIPO (PCT)
- Prior art keywords
- methyl
- oxalic acid
- crystal
- solvent
- octahydrobenzo
- Prior art date
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- ALQXIMVNPRVWQA-UHFFFAOYSA-N 3-benzyl-2-methyl-3,3a,5,6,7,7a-hexahydro-1,2-benzoxazol-4-one Chemical compound CN1OC2CCCC(=O)C2C1CC1=CC=CC=C1 ALQXIMVNPRVWQA-UHFFFAOYSA-N 0.000 title claims abstract description 26
- 150000001875 compounds Chemical class 0.000 title claims abstract description 23
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 14
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims abstract description 160
- 239000013078 crystal Substances 0.000 claims abstract description 59
- 235000006408 oxalic acid Nutrition 0.000 claims abstract description 52
- 239000002904 solvent Substances 0.000 claims abstract description 35
- 238000000034 method Methods 0.000 claims abstract description 23
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 6
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 3
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 27
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 24
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 18
- 239000003814 drug Substances 0.000 claims description 13
- 239000000843 powder Substances 0.000 claims description 10
- 239000007810 chemical reaction solvent Substances 0.000 claims description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 claims description 6
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 6
- 238000010992 reflux Methods 0.000 claims description 6
- 208000000044 Amnesia Diseases 0.000 claims description 4
- 208000031091 Amnestic disease Diseases 0.000 claims description 4
- 208000019901 Anxiety disease Diseases 0.000 claims description 4
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 4
- 208000019022 Mood disease Diseases 0.000 claims description 4
- 230000006986 amnesia Effects 0.000 claims description 4
- 238000006243 chemical reaction Methods 0.000 claims description 4
- 230000002920 convulsive effect Effects 0.000 claims description 4
- 229940079593 drug Drugs 0.000 claims description 4
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 claims description 4
- 208000011580 syndromic disease Diseases 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- 238000001816 cooling Methods 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 229940044613 1-propanol Drugs 0.000 claims description 2
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 2
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 claims description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 2
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 claims description 2
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 claims description 2
- 238000013019 agitation Methods 0.000 claims description 2
- 229960004132 diethyl ether Drugs 0.000 claims description 2
- 239000012429 reaction media Substances 0.000 claims description 2
- 239000000243 solution Substances 0.000 description 16
- 239000012458 free base Substances 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 6
- 239000000203 mixture Substances 0.000 description 4
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 3
- 238000012512 characterization method Methods 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 238000002441 X-ray diffraction Methods 0.000 description 2
- 238000002447 crystallographic data Methods 0.000 description 2
- 238000013480 data collection Methods 0.000 description 2
- 238000002050 diffraction method Methods 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000011159 matrix material Substances 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- -1 oxalic acid compound Chemical class 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 238000013341 scale-up Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000011200 topical administration Methods 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 229910016523 CuKa Inorganic materials 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 229920000881 Modified starch Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 238000012926 crystallographic analysis Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000006196 drop Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000003365 glass fiber Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 239000010439 graphite Substances 0.000 description 1
- 229910002804 graphite Inorganic materials 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 229940001470 psychoactive drug Drugs 0.000 description 1
- 239000004089 psychotropic agent Substances 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000010963 scalable process Methods 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/20—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings condensed with carbocyclic rings or ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
- A61P25/36—Opioid-abuse
Definitions
- the present invention concerns a process for preparing a crystalline form compound of 3-benzyl-2-methyl-2,3,3a,4,5,6,7,7a-octahydrobenzo[d]isoxazol-4- one of formula
- a co-crystal obtained by said process comprising 3-benzyl-2-methyl-2,3,3a,4,5,6,7,7a-octahydrobenzo[d]isoxazol-4-one and oxalic acid, and its use for the treatment of mood disorders, anxiety disorders, depression, convulsive states, in the improvement of learning ability, in the reversal of amnesia, in resolving abstinence syndrome from medicaments and drugs.
- the BTG 1640 compound is prepared as a yellow oil then salified as a hydrochloride salt.
- Said preparation which comprises use of the oily free base to form the hydrochloride salt, requires a complicated crystallization and purification step to obtain a pharmaceutical grade salt.
- the object of the present invention is therefore to provide the compound BTG 1640 in crystalline form which responds to the need for an industrially scalable process.
- the invention therefore concerns a process for preparing a crystalline form compound of 3-benzyl-2-methyl-2,3,3a,4,5,6,7,7a-octahydrobenzo[d]isoxazol-4- one which comprises the step of reacting 3-benzyl-2-methyl-2,3,3a,4,5,6,7,7a- octahydrobenzo[d]isoxazol-4-one with oxalic acid in one or more solvents, wherein at least one solvent is a solvent having a carbon atom number of from 3 to 6, said solvent being non-halogenated and having a dielectric constant ⁇ in the range from 4 to 25.
- the invention concerns a process for preparing a crystalline form compound of 3-benzyl-2-methyl-2,3,3a,4,5,6,7,7a- octahydrobenzo[d]isoxazol-4-one which comprises the step of reacting 3-benzyl-2- methyl-2,3,3a,4,5,6,7,7a-octahydrobenzo[d]isoxazol-4-one with oxalic acid in a 2:1 molar ratio, in one or more solvents, wherein at least one solvent is a solvent having a number of carbon atoms from 3 to 6, said solvent being non-halogenated and having a dielectric constant ⁇ in the range from 4 to 25.
- the crystalline form BTG 1640 compound obtained by the process of the invention is a co-crystal.
- Another aspect of the invention concerns a co-crystal comprising 3- benzyl-2-methyl-2,3,3a,4,5,6,7,7a-octahydrobenzo[d]isoxazol-4-one and oxalic acid.
- the co-crystal comprising 3-benzyl-2-methyl- 2,3,3a,4,5,6,7,7a-octahydrobenzo[d]isoxazol-4-one and oxalic acid is used as a medicament.
- FIG. 1 shows the observed experimental x-ray powder diffractogram of the 3- benzyl-2-methyl-2,3,3a,4,5,6,7,7a-octahydrobenzo[d]isoxazol-4-one and oxalic acid co-crystal of the invention
- - Figure 2 shows the experimental diffractogram calculated from information obtained from X-ray diffractography on a single crystal of the 3-benzyl-2-methyl- 2,3,3a,4,5,6,7,7a-octahydrobenzo[d]isoxazol-4-one and oxalic acid co-crystal of the invention;
- the at least one reaction solvent is chosen from the group consisting of t-butyl-methyl-ether (MTBE), 1 -butanol, acetone.
- the yield of the crystalline form compound is in the range from 80% to 99%.
- the reaction between BTG 1640 and oxalic acid can be conducted with decidedly moderate amounts of solvents, i.e. a ratio of solvent quantity/mmol of reacting oxalic acid within the range from 2 to 10, and preferably within the range from 2.5 tO 5.
- the at least one reaction solvent is acetone or 1 -butanol
- a clear solution of the two reagents BTG 1640 and oxalic acid can be obtained while under agitation even at room temperature, without needing to reach solution reflux temperature.
- the diffractogram relating to the co-crystal of the invention exhibits characteristic peaks at the following diffractometer angles:
- the co-crystal is therefore obtained by a simple procedure, easily scalable to industrial levels and avoiding the use of lengthy and costly crystallization and purification steps, to obtain high yields of a pharmaceutical grade stable crystalline form.
- the tablets will preferably comprise an amount from 1 to 100 mg, even more preferably from 1 to 50 mg, of the co-crystal comprising oxalic acid and BTG 1640.
- the tablets could also contain suitable excipients in common pharmaceutical use such as pre-gelatinized starch, microcrystalline cellulose, sodium starch glycolate, talc, lactose, magnesium stearate, sucrose, stearic acid, mannitol.
- suitable excipients such as pre-gelatinized starch, microcrystalline cellulose, sodium starch glycolate, talc, lactose, magnesium stearate, sucrose, stearic acid, mannitol.
- Compositions for parenteral administration will conveniently comprise sterile preparations.
- Preparations for topical administration will preferably comprise an amount from 1 to 100 mg of co-crystal comprising oxalic acid and BTG 1640.
- Example 2 Process for preparing the BTG 1640 and oxalic acid co-crystal in tert-butyl-methyl- ether (MTBE)
- the co-crystal obtained in example 1 was analysed to determine its structure.
- a colourless needle crystal of the co-crystal of example 1 being 0.2 x
- the cell parameters and an orientation matrix for data collection were obtained by the least-squares method using the setting angles of 25 reflections within the range 7° ⁇ 15°.
- the space group was determined by means of the XPREP programme.
- the space group was P21 /n.
- the structure was solved by direct methods and refined using the full-matrix least-squares method on F 2 with the SHELX-97 programme.
- Table 2 Crystalloqraphic data of the compound of the invention in crystalline form.
- Figures 2 and 3 show respectively the calculated experimental diffractogram for the co-crystal and the corresponding table listing the values of the various peaks in said diffractogram.
- Example 5
- Example 6 The same analyses as in examples 4 and 5 were carried out on the samples obtained from preparative examples 2-3. The results obtained are in agreement with the results given in examples 4 and 5, confirming the fact that all the preparative conditions of examples 2-3 have led to the BTG 1640 and oxalic acid co-crystal of the invention being obtained.
- the process of the invention being simple and of immediate industrial scale-up, has hence provided a new crystalline form which is a co-crystal comprising BTG 1640 and oxalic acid.
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- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Psychiatry (AREA)
- Addiction (AREA)
- Pain & Pain Management (AREA)
- Anesthesiology (AREA)
- Hospice & Palliative Care (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
A process for preparing a crystalline form compound of 3-benzyl-2-methyl-2,3,3a,4,5,6,7,7a-octahydrobenzo[d]isoxazol-4-one is described, comprising the step of reacting 3-benzyl-2-methyl-2,3,3a,4,5,6,7,7a-octahydrobenzo[d]isoxazol-4-one with oxalic acid in one or more solvents, wherein at least one solvent is a solvent having a carbon atom number of from 3 to 6, said solvent being non-halogenated and having a dielectric constant ε within the range from 4 to 25. The process of the invention enables a co-crystal comprising 3-benzyl-2-methyl-2,3,3a,4,5,6,7, 7a-octahydrobenzo[d]isoxazol-4-one and oxalic acid to be obtained.
Description
PROCESS FOR PREPARING A CRYSTALLINE FORM COMPOUND OF 3-
BENZYL-2-METHYL-2,3,3a,4,5,6,7,7a-OCTAHYDROBENZO[d]ISOXAZOL-4-
ONE
FIELD OF THE INVENTION
The present invention concerns a process for preparing a crystalline form compound of 3-benzyl-2-methyl-2,3,3a,4,5,6,7,7a-octahydrobenzo[d]isoxazol-4- one of formula
in all its stereochemical configurations, a co-crystal obtained by said process comprising 3-benzyl-2-methyl-2,3,3a,4,5,6,7,7a-octahydrobenzo[d]isoxazol-4-one and oxalic acid, and its use for the treatment of mood disorders, anxiety disorders, depression, convulsive states, in the improvement of learning ability, in the reversal of amnesia, in resolving abstinence syndrome from medicaments and drugs.
STATE OF THE ART
The compound rel-(3R,3aS,7aS)-3-benzyl-2-methyl-2,3,3a,4,5,6,7,7a- octahydrobenzo[d]isoxazol-4-one, also known as BTG 1640, is described in international patent application WO93/17004 and pertains to a new family of psychoactive agents.
According to this document, the BTG 1640 compound is prepared as a yellow oil then salified as a hydrochloride salt. Said preparation, which comprises use of the oily free base to form the hydrochloride salt, requires a complicated crystallization and purification step to obtain a pharmaceutical grade salt.
Thus, there is still a need for a BTG 1640 compound in crystalline form which is
easy to prepare, that is to say not requiring difficult and lengthy crystallizations and can hence be easily scaled-up to industrial levels.
The object of the present invention is therefore to provide the compound BTG 1640 in crystalline form which responds to the need for an industrially scalable process. SUMMARY
As the hydrochloride salt of BTG 1640 presented not only preparation problems, but was also unstable at temperatures above 30QC, the inventors of the present invention have turned their attention to the preparation of compounds alternative to BTG 1640 hydrochloride.
The aforementioned object was hence achieved through the selection of oxalic acid and the selection of reaction solvent(s).
The invention therefore concerns a process for preparing a crystalline form compound of 3-benzyl-2-methyl-2,3,3a,4,5,6,7,7a-octahydrobenzo[d]isoxazol-4- one which comprises the step of reacting 3-benzyl-2-methyl-2,3,3a,4,5,6,7,7a- octahydrobenzo[d]isoxazol-4-one with oxalic acid in one or more solvents, wherein at least one solvent is a solvent having a carbon atom number of from 3 to 6, said solvent being non-halogenated and having a dielectric constant ε in the range from 4 to 25. In a preferred aspect, the invention concerns a process for preparing a crystalline form compound of 3-benzyl-2-methyl-2,3,3a,4,5,6,7,7a- octahydrobenzo[d]isoxazol-4-one which comprises the step of reacting 3-benzyl-2- methyl-2,3,3a,4,5,6,7,7a-octahydrobenzo[d]isoxazol-4-one with oxalic acid in a 2:1 molar ratio, in one or more solvents, wherein at least one solvent is a solvent having a number of carbon atoms from 3 to 6, said solvent being non-halogenated and having a dielectric constant ε in the range from 4 to 25. The inventors of the present invention have surprisingly found that the crystalline form BTG 1640 compound obtained by the process of the invention is a co-crystal. Another aspect of the invention, therefore, concerns a co-crystal comprising 3- benzyl-2-methyl-2,3,3a,4,5,6,7,7a-octahydrobenzo[d]isoxazol-4-one and oxalic acid. In a further aspect of the invention the co-crystal comprising 3-benzyl-2-methyl-
2,3,3a,4,5,6,7,7a-octahydrobenzo[d]isoxazol-4-one and oxalic acid is used as a medicament.
In yet a further aspect of the invention, the co-crystal comprising 3-benzyl-2- methyl-2,3,3a,4,5,6,7,7a-octahydrobenzo[d]isoxazol-4-one and oxalic acid is used for the production of a medicament for treating mood disorders, anxiety disorders, depression, convulsive states, in the improvement of learning ability, in the reversal of amnesia, in resolving abstinence syndrome from medicaments and drugs.
DESCRIPTION OF THE FIGURES The characteristics and advantages of the invention will be evident from the detailed description that follows and from the accompanying figures, in which:
- Figure 1 shows the observed experimental x-ray powder diffractogram of the 3- benzyl-2-methyl-2,3,3a,4,5,6,7,7a-octahydrobenzo[d]isoxazol-4-one and oxalic acid co-crystal of the invention; - Figure 2 shows the experimental diffractogram calculated from information obtained from X-ray diffractography on a single crystal of the 3-benzyl-2-methyl- 2,3,3a,4,5,6,7,7a-octahydrobenzo[d]isoxazol-4-one and oxalic acid co-crystal of the invention; and
- Figure 3 shows the table containing a list of the characteristic peaks of the calculated experimental diffractogram shown in Figure 2.
DETAILED DESCRIPTION OF THE INVENTION
The invention therefore concerns a process for preparing a crystalline form compound of 3-benzyl-2-methyl-2,3,3a,4,5,6,7,7a-octahydrobenzo[d]isoxazol-4- one which comprises the step of reacting 3-benzyl-2-methyl-2,3,3a,4,5,6,7,7a- octahydrobenzo[d]isoxazol-4-one with oxalic acid in one or more solvents, wherein at least one solvent is a solvent having a number of carbon atoms of from 3 to 6, said solvent being non-halogenated and having a dielectric constant ε in the range from 4 to 25. The reaction between 3-benzyl-2-methyl-2,3,3a,4,5,6,7,7a- octahydrobenzo[d]isoxazol-4-one and oxalic acid takes place in the presence of one or more solvents. In this respect, the inventors of the present invention perceived they had obtained a compound in crystalline form by means of a
process suitable for industrial scale-up, through the selection of at least one reaction solvent according to specific physical and structural characteristics. Said reaction solvent is therefore a non-halogenated solvent, having a number of carbon atoms from 3 to 6 and having a dielectric constant ε in the range from 4 to 25.
The at least one solvent of the invention is preferably selected from the group consisting of diethylether, t-butyl-methyl-ether (MTBE), 1 ,2-dimethoxyethane, tetrahydrofuran (THF), diisopropylether, 4-methyl-2-pentanone, 2-methoxyethanol, 2-butanol, 2-methyl-1 -propanol, 2-propanol, 2-butanone, 1 -propanol, 1 -butanol, acetone.
In the most preferred embodiment of the invention the at least one reaction solvent is chosen from the group consisting of t-butyl-methyl-ether (MTBE), 1 -butanol, acetone. In said embodiment, advantageously, the yield of the crystalline form compound is in the range from 80% to 99%. Advantageously, by using at least one solvent of the invention chosen from the group consisting of t-butyl-methyl-ether (MTBE), 1 -butanol and acetone, the reaction between BTG 1640 and oxalic acid can be conducted with decidedly moderate amounts of solvents, i.e. a ratio of solvent quantity/mmol of reacting oxalic acid within the range from 2 to 10, and preferably within the range from 2.5 tO 5.
In a preferred aspect, the invention concerns a process for preparing a crystalline form compound of 3-benzyl-2-methyl-2,3,3a,4,5,6,7,7a- octahydrobenzo[d]isoxazol-4-one which comprises the step of reacting 3-benzyl-2- methyl-2,3,3a,4,5,6,7,7a-octahydrobenzo[d]isoxazol-4-one with oxalic acid in a 2:1 molar ratio, in one or more solvents, wherein at least one solvent is a solvent having a number of carbon atoms of from 3 to 6, said solvent being non- halogenated and having a dielectric constant ε in the range from 4 to 25. In the process of the invention oxalic acid is hence reacted with the BTG 1640 free base, preferably in a 1 :2 ratio. Preferably in the process of the invention oxalic acid is added under reflux to the solution consisting of the BTG 1640 free base dissolved in one or more solvents, said reflux conditions being maintained until a clear solution is obtained. The
solution is then cooled to a temperature in the range from room temperature to - 25Q C for a time varying from 2 to 24 hours.
Advantageously, if the at least one reaction solvent is acetone or 1 -butanol, a clear solution of the two reagents BTG 1640 and oxalic acid can be obtained while under agitation even at room temperature, without needing to reach solution reflux temperature.
Advantageously, if the at least one reaction solvent is methyl-t-butyl-ether (MTBE) or acetone, yields exceeding 80% can already be obtained by cooling the solution of the two reagents to ambient temperature. The compound in crystalline form which separates as a colourless compound can be optionally subjected to further purification cycles according to the known art. The mother liquors can possibly be evaporated and subjected to prolonged cooling with the aim of recovering more of the BTG 1640 and oxalic acid compound in crystalline form. The compound in crystalline form which separates from the process of the invention is a co-crystal comprising oxalic acid and BTG 1640 free base. As will be demonstrated in the experimental part, the co-crystal of the invention is a crystalline molecular complex, i.e. a combination of the two molecules BTG 1640 and oxalic acid spatially disposed to create a single crystal form. The co-crystal of the invention was characterized by X-ray diffractometry carried out on both the powders and the single crystal.
X-ray powder diffractometry was used to obtain the observed experimental diffractogram shown in Figure 1 , from which it is inferred that the co-crystal of the invention exhibits peaks at the diffraction degrees (±0.2 °2Θ) shown in Table 1 below: Table 1
8.15 18.31 22.80 28.80 36.17
1 1 .26 18.59 23.39 29.1 1 36.47
15.80 19.38 24.62 29.64 36.57
16.19 19.56 25.14 31 .67 36.80
16.74 21 .52 25.59 32.64 39.03
16.96 21 .67 26.79 33.75 39.66
More specifically, the diffractogram relating to the co-crystal of the invention exhibits characteristic peaks at the following diffractometer angles:
1 1 .26 °2Θ 15.80 °2Θ
17.46 °2Θ
18.31 °2Θ
19.55 °2Θ
24.62 °2Θ Single crystal X-ray diffractometry was used to obtain information on the structure and on the interatomic distances of the molecules involved, which confirmed the fact that the crystalline solid is a co-crystal consisting of two molecules of BTG
1640 and one of oxalic acid. Calculations on the data obtained from the single crystal diffraction analysis on the BTG 1640 and oxalic acid co-crystal, have generated the calculated experimental diffractogram, which is devoid of any of the imperfections and background noise typical of microcrystalline powders. The calculated experimental diffractogram is given in Figure 2, the characteristic peaks of which are given in the subsequent Figure 3.
According to the invention, the co-crystal is therefore obtained by a simple procedure, easily scalable to industrial levels and avoiding the use of lengthy and costly crystallization and purification steps, to obtain high yields of a pharmaceutical grade stable crystalline form.
The co-crystal comprising BTG 1640 and oxalic acid of the invention can be used as a medicament. It can then be combined with a pharmaceutically acceptable carrier and, optionally, with suitable excipients, to obtain pharmaceutical compositions. The term
"pharmaceutically acceptable carrier" includes solvents, diluents and the like which are used in the administration of the co-crystals of the invention.
Said pharmaceutical compositions can be parenterally, orally or topically administered.
Compositions of the present invention suitable for oral administration will be conveniently in the form of discrete units such as tablets, capsules, cachets, as powders or granules, or as a suspension in a liquid.
More preferably the compositions of the invention for oral administration will be in the form of tablets.
The tablets will preferably comprise an amount from 1 to 100 mg, even more preferably from 1 to 50 mg, of the co-crystal comprising oxalic acid and BTG 1640.
Preferably the tablets will contain from 1.7% to 40% by weight of the co-crystal comprising BTG 1640 and oxalic acid, and even more preferably the co-crystal comprising BTG 1640 and oxalic acid will constitute from 2.1 % to 34.7% of the total tablet weight.
The tablets could also contain suitable excipients in common pharmaceutical use such as pre-gelatinized starch, microcrystalline cellulose, sodium starch glycolate, talc, lactose, magnesium stearate, sucrose, stearic acid, mannitol. Compositions for parenteral administration will conveniently comprise sterile preparations.
Preparations for parenteral administration will preferably comprise an amount from
0.1 to 100 mg of co-crystal comprising oxalic acid and BTG 1640.
Compositions for topical administration will be conveniently in the form of creams, pastes, poultices, oils, ointments, emulsions, foams, gels, drops, aqueous solutions, spray solutions and transdermal patches.
Preparations for topical administration will preferably comprise an amount from 1 to 100 mg of co-crystal comprising oxalic acid and BTG 1640.
The co-crystal of the invention can be used for the production of a medicament for the treatment of mood disorders, anxiety disorders, depression, convulsive states, in the improvement of learning ability, in the reversal of amnesia, in resolving abstinence syndrome from medicaments and drugs.
The invention will now be described in greater detail in the following examples, given by way of non-limiting illustration of the invention, relative to the process of the invention and to the characterization of the co-crystal obtained by the process.
EXAMPLES
Example 1
Process for preparing BTG 1640 and oxalic acid co-crystal in acetone 0.8079 g of BTG 1640 free base (3.29 mmol) were placed in a 25 ml flask containing 5 ml of acetone; 0.148 g (1.64 mmol) of anhydrous oxalic acid were added at room temperature to the thus obtained solution to obtain a still clear solution.
From the solution kept at ambient temperature for 2 hours, the BTG 1640 and oxalic acid co-crystal (Tmelting from 127 to 130QC) was separated with a yield of 92%. Example 2 Process for preparing the BTG 1640 and oxalic acid co-crystal in tert-butyl-methyl- ether (MTBE)
0.8107 g of BTG 1640 free base (3.30 mmol) were placed in a 25 ml flask containing 5 ml of tert-butyl-methyl-ether (MTBE); 0.149 g (1.65 mmol) of anhydrous oxalic acid were then added at reflux to the solution thus obtained. Reflux conditions were maintained until a clear solution was obtained. From the solution cooled for 4 hours to ambient temperature, the BTG 1640 and oxalic acid co-crystal (Tmelting between 127 and 1305C) was separated with a yield of 82%. Example 3 Process for preparing the BTG 1640 and oxalic acid co-crystal in 1 -butanol 0.801 g of BTG 1640 free base (3.26 mmol) were placed in a 25 ml flask containing 5 ml of 1 -butanol; 0.147 g (1.63 mmol) of anhydrous oxalic acid were then added at room temperature to the thus obtained solution to obtain a still clear solution. From the solution cooled for 15 hours to a temperature of 45C, the BTG 1640 and oxalic acid co-crystal (Tmelting between 127 and 1305C) was separated with a yield of 95%.
In particular from examples 1 -3 the authors of the present invention have found that excellent yields of the BTG 1640 and oxalic acid co-crystal were obtained by mixing BTG 1640 and oxalic acid in a molar ratio of 2:1. These operating conditions enable reagent wastage, usually accompanying reactions not conducted under stoichiometric conditions, to be avoided, and to especially avoid the problem of managing the excesses which should in any case be removed from the reaction medium, and possibly recovered or reconverted.
Example 4
Characterization of the co-crystal by means of X-rav diffractometrv on the single crystal
The co-crystal obtained in example 1 was analysed to determine its structure.
Specifically, a colourless needle crystal of the co-crystal of example 1 , being 0.2 x
0.2 x 0.3 mm in size, was mounted onto a glass fibre in a random orientation. The crystallographic data were collected at room temperature using a Nonius CAD-4 diffractometer, Mo-kα radiation, α=0.71073 A, with a graphite monochromator.
The cell parameters and an orientation matrix for data collection were obtained by the least-squares method using the setting angles of 25 reflections within the range 7°<θ<15°.
The space group was determined by means of the XPREP programme. The space group was P21 /n. The structure was solved by direct methods and refined using the full-matrix least-squares method on F2 with the SHELX-97 programme.
The crystallographic data obtained are summarized in Table 2 below.
Table 2: Crystalloqraphic data of the compound of the invention in crystalline form.
The results of the crystallographic analysis have demonstrated that in samples of the substance obtained according to example 1 , there is no transfer of hydrogen between the oxalic acid carboxyl groups and the nitrogen atom of the BTG 1640 free base confirming that the compound of the invention is a co-crystal of oxalic acid and BTG 1640.
Figures 2 and 3 show respectively the calculated experimental diffractogram for the co-crystal and the corresponding table listing the values of the various peaks in said diffractogram. Example 5
Co-crystal characterization by determination of X-ray powder diffractogram An X-ray powder diffractogram was obtained from the same sample as example 4 by the X'Pert Pro analytical automated diffractometer equipped with X'Celerator, CuKa, using glass sample holders and 150 mg of substance, setting the voltage and amperage to 4OkV and 40mA respectively. The data collection programme used was set to obtain the data within the 2 theta range from 3Q to 40Q. The observed experimental diffractogram is shown in Figure 1. The peaks are given in table 1 below:
Table 1
8.15 18.31 22.80 28.80 36.17
1 1 .26 18.59 23.39 29.1 1 36.47
15.80 19.38 24.62 29.64 36.57
16.19 19.56 25.14 31 .67 36.80
16.74 21 .52 25.59 32.64 39.03
16.96 21 .67 26.79 33.75 39.66
17.46 22.06 27.38 34.28
17.84 22.36 27.73 34.70
Example 6 The same analyses as in examples 4 and 5 were carried out on the samples obtained from preparative examples 2-3. The results obtained are in agreement with the results given in examples 4 and 5, confirming the fact that all the preparative conditions of examples 2-3 have led to the BTG 1640 and oxalic acid co-crystal of the invention being obtained. The process of the invention, being simple and of immediate industrial scale-up, has hence provided a new crystalline form which is a co-crystal comprising BTG 1640 and oxalic acid.
Claims
1. Process for preparing a crystalline form compound of 3-benzyl-2-methyl- 2,3,3a,4,5,6,7,7a-octahydrobenzo[d]isoxazol-4-one comprising the step of reacting 3-benzyl-2-methyl-2,3,3a,4,5,6,7,7a-octahydrobenzo[d]isoxazol-4-one with oxalic acid in one or more solvents wherein at least one solvent is a solvent having a carbon atom number of from 3 to 6, said solvent being non-halogenated and having a dielectric constant ε in the range from 4 to 25.
2. Process according to claim 1 wherein the 3-benzyl-2-methyl-2,3,3a,4,5,6,7,7a- octahydrobenzo[d]isoxazol-4-one is reacted with oxalic acid in a molar ratio of about 2:1.
3. Process according to claims 1 or 2 wherein the at least one solvent is chosen from the group consisting of diethylether, t-butyl-methyl-ether (MTBE), 1 ,2- dimethoxyethane, tetrahydrofuran (THF), diisopropylether, 4-methyl-2-pentanone, 2-methoxyethanol, 2-butanol, 2-methyl-1 -propanol, 2-propanol, 2-butanone, 1 - propanol, 1 -butanol, acetone.
4. Process according to claim 3 wherein the at least one reaction solvent is chosen from the group consisting of t-butyl-methyl-ether (MTBE), 1 -butanol, acetone.
5. Process according to claim 4 wherein the yield of the crystalline form compound is in the range 80% to 99%.
6. Process according to claim 4 wherein the reaction between BTG 1640 and oxalic acid is conducted with a solvent volume/mmol of oxalic acid ratio within the range from 2 to 10, preferably in the range from 2.5 to 5.
7. Process according to any one of claims from 1 to 6 wherein the oxalic acid is added at solvent reflux conditions until a clear solution is obtained.
8. Process according to claim 4 wherein if the at least one reaction solvent is acetone or 1 -butanol, the oxalic acid is added under agitation at room temperature until a clear solution is obtained.
9. Process according to any one of claims from 1 to 8 wherein the solution containing the oxalic acid and BTG 1640 is cooled to a temperature within the range from room temperature to -25QC for a time varying from 2 to 24 hours.
10. Process according to claim 4 wherein if the at least one reaction solvent is acetone or methyl-t-butyl-ether (MTBE), yields already exceed 80% by cooling the
reaction medium to ambient temperature
1 1. Co-crystal comprising oxalic acid and 3-benzyl-2-methyl-2,3,3a,4,5,6,7,7a- octahydrobenzo[d]isoxazol-4-one.
12. Co-crystal according to claim 1 1 wherein the co-crystal exhibits an X-ray powder diffractogram having characteristic peaks expressed in diffraction degrees (±0.2°2θ) at 1 1.26, 15.80, 17.46, 18.31 , 19.55 and 24.62 ±0.2° 2Θ.
13. Co-crystal according to claim 1 1 wherein the co-crystal exhibits an X-ray powder diffractogram having the following peaks expressed in diffraction degrees (±0.2 °2Θ):
8.15 18.31 22.80 28.80 36.17
1 1 .26 18.59 23.39 29.1 1 36.47
15.80 19.38 24.62 29.64 36.57
16.19 19.56 25.14 31 .67 36.80
16.74 21 .52 25.59 32.64 39.03
16.96 21 .67 26.79 33.75 39.66
17.46 22.06 27.38 34.28
17.84 22.36 27.73 34.70
14. Co-crystal according to claim 1 1 having an observed experimental X-ray powder diffractogram as shown in Figure 1.
15. Co-crystal according to claim 1 1 having a monocline space group P21/n, unit cell dimensions a=15.171 (6) A, alpha= 90°, b=5.9951 (3) A, beta=92.233(4)°, c= 15.995(5) A, gamma=90° and a volume of 1496.83(1 1 )A3.
16. Co-crystal according to claim 15 having an experimental diffractogram calculated from the single crystal X-ray diffractography as shown in Figure 2.
17. Pharmaceutical composition comprising the co-crystal according to any one of claims from 1 1 to 16 and a pharmaceutically acceptable carrier.
18. Co-crystal comprising oxalic acid and 3-benzyl-2-methyl-2,3,3a,4,5,6,7,7a- octahydrobenzo[d]isoxazol-4-one for use as a medicament.
19. Co-crystal comprising oxalic acid and 3-benzyl-2-methyl-2,3,3a,4,5,6,7,7a- octahydrobenzo[d]isoxazol-4-one for use in the treatment of mood disorders, anxiety disorders, depression, convulsive states, in the improvement of learning
ability, in the reversal of amnesia, in resolving abstinence syndrome from medicaments and drugs.
Priority Applications (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2009801145344A CN102015665A (en) | 2008-04-24 | 2009-04-23 | Process for preparing a crystalline form compound of 3-benzyl-2-methyl-2,3,3a,4,5,6,7,7a-octahydrobenzo[d]isoxazol-4-one |
| US12/989,069 US20110039902A1 (en) | 2008-04-24 | 2009-04-23 | PROCESS FOR PREPARING A CRYSTALLINE FORM COMPOUND OF 3-BENZYL-2-METHYL-2,3,3a,4,5,6,7,7a-OCTAHYDROBENZO[d]ISOXAZOL-4-ONE |
| EP09733825A EP2279180A1 (en) | 2008-04-24 | 2009-04-23 | PROCESS FOR PREPARING A CRYSTALLINE FORM COMPOUND OF 3-BENZYL-2-METHYL-2,3,3a,4,5,6,7,7a-OCTAHYDROBENZOÝd¨ISOXAZOL-4-ONE |
| JP2011505505A JP2011518802A (en) | 2008-04-24 | 2009-04-23 | Process for preparing crystalline compounds of 3-benzyl-2-methyl-2,3,3a, 4,5,6,7,7a-octahydrobenzo [d] isoxazol-4-one |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT000768A ITMI20080768A1 (en) | 2008-04-24 | 2008-04-24 | PROCEDURE FOR THE PREPARATION OF A COMPOUND IN CRYSTALLINE FORM OF 3-BENZYL-2-METHYL-2,3,3A, 4,5,6,7,7A-OCTODIDRO-BENZO [D] ISOSSAZOL-4-ONE |
| ITMI2008A000768 | 2008-04-24 |
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| WO2009130263A1 true WO2009130263A1 (en) | 2009-10-29 |
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|---|---|---|---|
| PCT/EP2009/054859 WO2009130263A1 (en) | 2008-04-24 | 2009-04-23 | PROCESS FOR PREPARING A CRYSTALLINE FORM COMPOUND OF 3-BENZYL-2-METHYL-2,3,3a,4,5,6,7,7a-OCTAHYDROBENZO[d]ISOXAZOL-4-ONE |
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| Country | Link |
|---|---|
| US (1) | US20110039902A1 (en) |
| EP (1) | EP2279180A1 (en) |
| JP (1) | JP2011518802A (en) |
| CN (1) | CN102015665A (en) |
| IT (1) | ITMI20080768A1 (en) |
| WO (1) | WO2009130263A1 (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1993017004A1 (en) * | 1992-02-19 | 1993-09-02 | British Technology Group Ltd. | Benzisoxazole derivatives and pharmaceutical compositions containing them |
| WO2008053325A1 (en) * | 2006-11-02 | 2008-05-08 | Abiogen Pharma S.P.A. | A salt of 3-benzyl-2-methyl-2,3,3a,4,5,6,7,7a-octahydrobenzo[d]isoxazol-4-one |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2445843A1 (en) * | 2001-05-01 | 2002-11-07 | H. Lundbeck A/S | The use of enantiomeric pure escitalopram |
-
2008
- 2008-04-24 IT IT000768A patent/ITMI20080768A1/en unknown
-
2009
- 2009-04-23 CN CN2009801145344A patent/CN102015665A/en active Pending
- 2009-04-23 WO PCT/EP2009/054859 patent/WO2009130263A1/en active Application Filing
- 2009-04-23 US US12/989,069 patent/US20110039902A1/en not_active Abandoned
- 2009-04-23 EP EP09733825A patent/EP2279180A1/en not_active Withdrawn
- 2009-04-23 JP JP2011505505A patent/JP2011518802A/en not_active Withdrawn
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1993017004A1 (en) * | 1992-02-19 | 1993-09-02 | British Technology Group Ltd. | Benzisoxazole derivatives and pharmaceutical compositions containing them |
| WO2008053325A1 (en) * | 2006-11-02 | 2008-05-08 | Abiogen Pharma S.P.A. | A salt of 3-benzyl-2-methyl-2,3,3a,4,5,6,7,7a-octahydrobenzo[d]isoxazol-4-one |
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| Publication number | Publication date |
|---|---|
| EP2279180A1 (en) | 2011-02-02 |
| JP2011518802A (en) | 2011-06-30 |
| US20110039902A1 (en) | 2011-02-17 |
| CN102015665A (en) | 2011-04-13 |
| ITMI20080768A1 (en) | 2009-10-25 |
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