CA2290070A1 - Salts of aromatic sulphonic acids - Google Patents
Salts of aromatic sulphonic acids Download PDFInfo
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- CA2290070A1 CA2290070A1 CA002290070A CA2290070A CA2290070A1 CA 2290070 A1 CA2290070 A1 CA 2290070A1 CA 002290070 A CA002290070 A CA 002290070A CA 2290070 A CA2290070 A CA 2290070A CA 2290070 A1 CA2290070 A1 CA 2290070A1
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- Prior art keywords
- salt
- aromatic
- methyl
- oxepino
- dibenz
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- 150000003839 salts Chemical class 0.000 title claims abstract description 28
- 125000003118 aryl group Chemical class 0.000 title claims abstract description 17
- 239000002253 acid Substances 0.000 title description 5
- 150000007513 acids Chemical class 0.000 title description 4
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 claims abstract description 10
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 9
- BDHFUVZGWQCTTF-UHFFFAOYSA-N sulfonic acid Chemical compound OS(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-N 0.000 claims abstract description 8
- 238000002360 preparation method Methods 0.000 claims abstract description 6
- 239000007924 injection Substances 0.000 claims abstract description 5
- 238000002347 injection Methods 0.000 claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims description 16
- VSWBSWWIRNCQIJ-HUUCEWRRSA-N (S,S)-asenapine Chemical compound O1C2=CC=CC=C2[C@H]2CN(C)C[C@@H]2C2=CC(Cl)=CC=C21 VSWBSWWIRNCQIJ-HUUCEWRRSA-N 0.000 claims description 11
- 239000003814 drug Substances 0.000 claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- JXLHNMVSKXFWAO-UHFFFAOYSA-N azane;7-fluoro-2,1,3-benzoxadiazole-4-sulfonic acid Chemical compound N.OS(=O)(=O)C1=CC=C(F)C2=NON=C12 JXLHNMVSKXFWAO-UHFFFAOYSA-N 0.000 claims 4
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 abstract description 8
- 239000003874 central nervous system depressant Substances 0.000 abstract description 2
- 230000002349 favourable effect Effects 0.000 abstract 1
- 235000002639 sodium chloride Nutrition 0.000 description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 4
- 239000003405 delayed action preparation Substances 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- GMDCDXMAFMEDAG-CHHFXETESA-N (S,S)-asenapine maleate Chemical compound OC(=O)\C=C/C(O)=O.O1C2=CC=CC=C2[C@H]2CN(C)C[C@@H]2C2=CC(Cl)=CC=C21 GMDCDXMAFMEDAG-CHHFXETESA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 230000001387 anti-histamine Effects 0.000 description 3
- 239000000739 antihistaminic agent Substances 0.000 description 3
- 239000003420 antiserotonin agent Substances 0.000 description 3
- 229960005245 asenapine Drugs 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 238000013268 sustained release Methods 0.000 description 3
- 239000012730 sustained-release form Substances 0.000 description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 3
- GUGOEEXESWIERI-UHFFFAOYSA-N Terfenadine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 GUGOEEXESWIERI-UHFFFAOYSA-N 0.000 description 2
- 230000000794 anti-serotonin Effects 0.000 description 2
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 208000020016 psychiatric disease Diseases 0.000 description 2
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- VOPNAHNLWOLODK-UHFFFAOYSA-N 4-methylbenzenesulfonic acid;phenylmethanesulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1.OS(=O)(=O)CC1=CC=CC=C1 VOPNAHNLWOLODK-UHFFFAOYSA-N 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- 206010002942 Apathy Diseases 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 208000028017 Psychotic disease Diseases 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical group [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- VJHCJDRQFCCTHL-UHFFFAOYSA-N acetic acid 2,3,4,5,6-pentahydroxyhexanal Chemical compound CC(O)=O.OCC(O)C(O)C(O)C(O)C=O VJHCJDRQFCCTHL-UHFFFAOYSA-N 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000002973 anti-dopamine Effects 0.000 description 1
- 230000000561 anti-psychotic effect Effects 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 231100000457 cardiotoxic Toxicity 0.000 description 1
- 230000001451 cardiotoxic effect Effects 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000002178 crystalline material Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 229960003638 dopamine Drugs 0.000 description 1
- 239000003210 dopamine receptor blocking agent Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- -1 excitation Diseases 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-M hexadecanoate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 150000002688 maleic acid derivatives Chemical class 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical group C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229940049953 phenylacetate Drugs 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
- 230000000698 schizophrenic effect Effects 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed 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
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Pain & Pain Management (AREA)
- Psychiatry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention is a salt of the CNS-depressant trans-5- chloro-2,3,3a,12b-tetrahydro-2- methyl-1H-dibenz¢2,3:6,7! oxepino¢4,5-c!pyrrole and a saltforming agent, the latter being an aromatic sulphonic acid. The disclosed salt, preferably the besylate, has favourable properties. Thus it has the required insolubility and crytallinity in order to be suitable for use in depot injection preparations.
Description
SALTS OF AROMATIC SULPHONIC ACIDS
The invention pertains to a salt of the compound trans-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole and a salt forming agent.
Such salts are known. Thus, e.g., the maleate of the above compound (Org 5222), as well as the preparation thereof, has been described in US 4,145,434, the disclosure of which is incorporated herein by reference.
The compound is described as having CNS-depressant activity and antihistamine and antiserotonin activities.
IS The pharmacological profile of trans-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole, its kinetics and metabolism, as well as the first safety and efficacy studies in human volunteers and in schizophrenic patients were reviewed by De Boer et al. (Drugs of the Future 1993, 18(12), 1117-1123). It has been established that Org 5222, which is traps-5-chloro-2,3,3a, l2b-tetrahydro-2-methyl-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole(Z)-2-butenedio.ae (1:1), is a very potent dopamine and serotonin antagonist and antihistaminic with potential antipsychotic activity.
In view of the compound's utility, it is desired for it to be incorporated into pharmaceutical compositions of all kind and, notably, those that are advantageous with regard to administering to patients suffering from mental disorders. Due to the vary nature of their disease, these patients frequently refuse to take their medicine or simply forget to take it, e.g. as a result of apathy. In view hereof, it is highly desired for compounds such as the above, to be administered in the form of a depot preparation, i.e. a pharmaceutical composition containing a dose of the medicine sufficient for a prolonged time, e.g. several ;0 weeks, and which by means of sustained release will perform its desired function to the central nervous system.
The invention pertains to a salt of the compound trans-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole and a salt forming agent.
Such salts are known. Thus, e.g., the maleate of the above compound (Org 5222), as well as the preparation thereof, has been described in US 4,145,434, the disclosure of which is incorporated herein by reference.
The compound is described as having CNS-depressant activity and antihistamine and antiserotonin activities.
IS The pharmacological profile of trans-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole, its kinetics and metabolism, as well as the first safety and efficacy studies in human volunteers and in schizophrenic patients were reviewed by De Boer et al. (Drugs of the Future 1993, 18(12), 1117-1123). It has been established that Org 5222, which is traps-5-chloro-2,3,3a, l2b-tetrahydro-2-methyl-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole(Z)-2-butenedio.ae (1:1), is a very potent dopamine and serotonin antagonist and antihistaminic with potential antipsychotic activity.
In view of the compound's utility, it is desired for it to be incorporated into pharmaceutical compositions of all kind and, notably, those that are advantageous with regard to administering to patients suffering from mental disorders. Due to the vary nature of their disease, these patients frequently refuse to take their medicine or simply forget to take it, e.g. as a result of apathy. In view hereof, it is highly desired for compounds such as the above, to be administered in the form of a depot preparation, i.e. a pharmaceutical composition containing a dose of the medicine sufficient for a prolonged time, e.g. several ;0 weeks, and which by means of sustained release will perform its desired function to the central nervous system.
The known compounds, however, are not very well suitable for use in such depot preparations. The main requirements for such a use are that the compound is crystalline (otherwise the compound will be metastable, due to which it cannot be predicted what, at a certain point in time, the amount of biologically desired compound is) and that it has a low solubility in water. The latter is important for attaining the required sustained release.
E.g. the maleate, (the (Z}-2-butenedioate Org 5222), which is crystalline, has a solubility of 3 mg/ml (21°C) which means that also higher doses, intended for controlled sustained release, will be taken up in the patient's blood immediately. The free base (Org 33254) has a relatively low solubility of Less then 0.1 mg/ml, but is instable. The pamoate (Org 33388) is amorphous, the hemipamoate (Org 39058) is a mixture of amorphous and crystalline material. Further, it is desired that the melting point is not too low (preferably above 80°C), as this may lead to temperature-induced problems when making tablets or granules.
For long it has been recognized in the art that there is no reliable way of predicting the influence of a particular salt species on the behaviour of the parent compound, see e.g.
J.Pharm.Sci. 66, 1-19, 1977. Salt-forming agents are therefore generally chosen empirically, and also in later literature, e.g. International Journal of Pharmaceutics, 33 (1986) 201-217, it has been recognized that, notably for properties such as hygroscopicity, stability and solubility, it is difficult to select the salt fornung agent beforehand.
The same holds for the present compounds, all the more since also crystallinity is required.
Hence it is an object of the present invention to select a salt-forming agent for the above compound which leads to this pharmacon being substantially water-insoluble, and crystalline.
According to the invention the salt-forming agent selected is an aromatic sulphonic acid.
Although in principle any pharmaceutically acceptable aromatic sulphonic acid is suitable, some aromatic moieties are clearly preferred. Thus the aromatic moiety may advantageously be of the type having a single phenyl ring. Preferred acids of this type being benzene sulphonic acid and toluene sulphonic acid, the preferred salts of the invention are the besylate and the tosylate. In the alternative, it may be advantageous for i T
E.g. the maleate, (the (Z}-2-butenedioate Org 5222), which is crystalline, has a solubility of 3 mg/ml (21°C) which means that also higher doses, intended for controlled sustained release, will be taken up in the patient's blood immediately. The free base (Org 33254) has a relatively low solubility of Less then 0.1 mg/ml, but is instable. The pamoate (Org 33388) is amorphous, the hemipamoate (Org 39058) is a mixture of amorphous and crystalline material. Further, it is desired that the melting point is not too low (preferably above 80°C), as this may lead to temperature-induced problems when making tablets or granules.
For long it has been recognized in the art that there is no reliable way of predicting the influence of a particular salt species on the behaviour of the parent compound, see e.g.
J.Pharm.Sci. 66, 1-19, 1977. Salt-forming agents are therefore generally chosen empirically, and also in later literature, e.g. International Journal of Pharmaceutics, 33 (1986) 201-217, it has been recognized that, notably for properties such as hygroscopicity, stability and solubility, it is difficult to select the salt fornung agent beforehand.
The same holds for the present compounds, all the more since also crystallinity is required.
Hence it is an object of the present invention to select a salt-forming agent for the above compound which leads to this pharmacon being substantially water-insoluble, and crystalline.
According to the invention the salt-forming agent selected is an aromatic sulphonic acid.
Although in principle any pharmaceutically acceptable aromatic sulphonic acid is suitable, some aromatic moieties are clearly preferred. Thus the aromatic moiety may advantageously be of the type having a single phenyl ring. Preferred acids of this type being benzene sulphonic acid and toluene sulphonic acid, the preferred salts of the invention are the besylate and the tosylate. In the alternative, it may be advantageous for i T
the aromatic moiety to be unsubstituted (apart from the sulphonic acid group of course).
In this respect not only the besylate is the preferred salt of the invention, but naphthalene sulphonic acid is also a suitable candidate for the acid, resulting in the corresponding napsylate. However, the most preferred salt of the invention is the besylate.
The salts of the present invention can be prepared analogously to those described in US
In this respect not only the besylate is the preferred salt of the invention, but naphthalene sulphonic acid is also a suitable candidate for the acid, resulting in the corresponding napsylate. However, the most preferred salt of the invention is the besylate.
The salts of the present invention can be prepared analogously to those described in US
4,145,434. For the preparation of the compound trans-S-chloro-2,3,3a,12b-tetrahydro-2-methyl-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole reference is made to said document. In order to obtain the desired salt, said compound can be dissolved in a suitable solvent, such as ethanol and then be mixed with a solution of the appropriate aromatic sulphonic acid, preferably in the same solvent or in a solvent miscible with the solvent for said compound.
The mixture then can be allowed to stand for sufficient time to let the corresponding salt according to the invention crystallize (which occurs spontaneously). If desired the obtained crystals can further undergo conventional washing and drying and/or purifying steps, e.g. simple recrystallization followed by drying.
Just as the known maleates, the compositions of the invention are useful in treating mammals, including humans, suf~'ering from all diseases susceptible to treatment by trans-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-1H-dibenz[2,3:6,7)oxepino[4,5-c]pyrrole. These diseases include mental disorders, such as tension, excitation, anxiety, psychosis, and schizophrenia. The compositions may also be used for antidopamine, antihistamine and for antiserotonin related diseases.
Hence, the salts of the present invention have a utility as a medicine per se, and they may be administered in any form, although, as described in WO 95/23600, peroral administration may lead to cardiotoxic side-effects. Thus other forms of administration are preferred, e.g. subcutaneous administration, injection, or by means of sublingual or buccal pharmaceutical composition as described in WO 95/23600.
All of these single dosage forms of pharmaceutical compositions containing the salt of the present invention comprise one dosage unit of trans-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole as an active ingredient. A
dosage unit may contain between 0.005 mg and I S mg of the active ingredient. Preferably the dosage unit contains of from about 0.03 to 0.50 mg of trans-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole. Any suitable, pharmaceutically acceptable carrier material may be applied, and pharmaceutically acceptable auxiliaries be added. All of these pharmaceutically acceptable excipients such as carriers and auxiliaries are known to the person skilled in the art and do not require elucidation here.
It is preferred, and only possible as a result of the present invention, that the salt be administered by means of a depot injection, i.e. at a dose higher than that in a single dosage form. Typical doses for such preparations comprise 10 to 40 mg of the active ingredient. The depot preparations of the present invention in its simplest form may comprise water as a carrier, the low aqueous solubility of the salt of course making it preferable for it to be dispersed rather than dissolved. To facilitate making a stable dispersion, conventional adjuvants may be used, e.g. Tween (surfactant), propylene glycol, lecithin, etc. Other pharmaceutically acceptable carriers are also suitable, e.g. carboxy methyl cellulose, gelatin, poly(vinyi pyrrolidone), or other well-known excipients. For background knowledge of depot preparations reference is made to Leiberman, Rieger, Bunker, Pharmaceutical Dosage Forms: Disperse System Volume 2.
The invention is further illustrated with reference to the following examples.
EXAMPLE I
A solution of 940 mg of benzene sulphonic acid in 15 ml of ethanol was added to a solution of 1.7 g of trans-S-chloro-2,3,3a,12b-tetrahydro-2-methyl-1H-dibenz[2,3:6,7]-oxepino[4,5-c]pyrrole. Crystallization occurred, and the crystals obtained were collected and recrystallized from 75 ml of boiling ethanol. After cooling to 20°C
the crystals were collected and dried in vacuo over calcium chloride and potassium hydroxide.
Yield: 1.9 g (72%) of trans-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-1H-dibenz[2,3:6,7)oxepino[4,5-c]pyrrole benzene sulphonate (besylate). This salt was found to have a melting point of 227.8°C and a solubility in water measured at 20°C of « 1 mg/ml.
r , T
COMPARATIVE EXAMPLE
The procedure of Example 1 was repeated, employing a great many different acids, all known for their suitability as a salt-forming agent for a pharmacon. The results attained 5 are given in the following table:
TABLE
Salt Form Melting Solubility in water point (C) (mg/ml) maieate crystalline 141-145 3 fumarate crystalline 185.5-187 1 1-hydroxy no crystallization- -naphthoate palmitate no crystallization- -pamoate amorphous 23 0-240 <0.3 5 hemipamoate amorphous /crystalline167-168 <0.25 benzoate no crystallization- -2-hydroxy no crystallization- -benzoate 4-acetyl aminono crystallization- -benzoate 3-hydroxy-2- no crystallization- -naphthoate 2-methoxy no crystallization- -phenyl acetate Clearly, the aromatic sulphonates of the invention form an exception in combining the desired properties of being crystalline, having a high melting point and displaying such a low solubility in water as to be held water-insoluble.
i i i EXAMPLE II
The procedure of Example I was repeated, substituting toluene-4-sulphonic acid for benzene sulphonic acid. Thus the corresponding toluene sulphonate (tosylate) was obtained.
EXAMPLE III
The procedure of Example I was repeated, substituting naphthalene-I-sulphonic acid and naphthalene-2-sulphonic acid for benzene sulphonic acid. Thus the corresponding naphthalene sulphonates (napsylates) were obtained.
~ r
The mixture then can be allowed to stand for sufficient time to let the corresponding salt according to the invention crystallize (which occurs spontaneously). If desired the obtained crystals can further undergo conventional washing and drying and/or purifying steps, e.g. simple recrystallization followed by drying.
Just as the known maleates, the compositions of the invention are useful in treating mammals, including humans, suf~'ering from all diseases susceptible to treatment by trans-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-1H-dibenz[2,3:6,7)oxepino[4,5-c]pyrrole. These diseases include mental disorders, such as tension, excitation, anxiety, psychosis, and schizophrenia. The compositions may also be used for antidopamine, antihistamine and for antiserotonin related diseases.
Hence, the salts of the present invention have a utility as a medicine per se, and they may be administered in any form, although, as described in WO 95/23600, peroral administration may lead to cardiotoxic side-effects. Thus other forms of administration are preferred, e.g. subcutaneous administration, injection, or by means of sublingual or buccal pharmaceutical composition as described in WO 95/23600.
All of these single dosage forms of pharmaceutical compositions containing the salt of the present invention comprise one dosage unit of trans-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole as an active ingredient. A
dosage unit may contain between 0.005 mg and I S mg of the active ingredient. Preferably the dosage unit contains of from about 0.03 to 0.50 mg of trans-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole. Any suitable, pharmaceutically acceptable carrier material may be applied, and pharmaceutically acceptable auxiliaries be added. All of these pharmaceutically acceptable excipients such as carriers and auxiliaries are known to the person skilled in the art and do not require elucidation here.
It is preferred, and only possible as a result of the present invention, that the salt be administered by means of a depot injection, i.e. at a dose higher than that in a single dosage form. Typical doses for such preparations comprise 10 to 40 mg of the active ingredient. The depot preparations of the present invention in its simplest form may comprise water as a carrier, the low aqueous solubility of the salt of course making it preferable for it to be dispersed rather than dissolved. To facilitate making a stable dispersion, conventional adjuvants may be used, e.g. Tween (surfactant), propylene glycol, lecithin, etc. Other pharmaceutically acceptable carriers are also suitable, e.g. carboxy methyl cellulose, gelatin, poly(vinyi pyrrolidone), or other well-known excipients. For background knowledge of depot preparations reference is made to Leiberman, Rieger, Bunker, Pharmaceutical Dosage Forms: Disperse System Volume 2.
The invention is further illustrated with reference to the following examples.
EXAMPLE I
A solution of 940 mg of benzene sulphonic acid in 15 ml of ethanol was added to a solution of 1.7 g of trans-S-chloro-2,3,3a,12b-tetrahydro-2-methyl-1H-dibenz[2,3:6,7]-oxepino[4,5-c]pyrrole. Crystallization occurred, and the crystals obtained were collected and recrystallized from 75 ml of boiling ethanol. After cooling to 20°C
the crystals were collected and dried in vacuo over calcium chloride and potassium hydroxide.
Yield: 1.9 g (72%) of trans-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-1H-dibenz[2,3:6,7)oxepino[4,5-c]pyrrole benzene sulphonate (besylate). This salt was found to have a melting point of 227.8°C and a solubility in water measured at 20°C of « 1 mg/ml.
r , T
COMPARATIVE EXAMPLE
The procedure of Example 1 was repeated, employing a great many different acids, all known for their suitability as a salt-forming agent for a pharmacon. The results attained 5 are given in the following table:
TABLE
Salt Form Melting Solubility in water point (C) (mg/ml) maieate crystalline 141-145 3 fumarate crystalline 185.5-187 1 1-hydroxy no crystallization- -naphthoate palmitate no crystallization- -pamoate amorphous 23 0-240 <0.3 5 hemipamoate amorphous /crystalline167-168 <0.25 benzoate no crystallization- -2-hydroxy no crystallization- -benzoate 4-acetyl aminono crystallization- -benzoate 3-hydroxy-2- no crystallization- -naphthoate 2-methoxy no crystallization- -phenyl acetate Clearly, the aromatic sulphonates of the invention form an exception in combining the desired properties of being crystalline, having a high melting point and displaying such a low solubility in water as to be held water-insoluble.
i i i EXAMPLE II
The procedure of Example I was repeated, substituting toluene-4-sulphonic acid for benzene sulphonic acid. Thus the corresponding toluene sulphonate (tosylate) was obtained.
EXAMPLE III
The procedure of Example I was repeated, substituting naphthalene-I-sulphonic acid and naphthalene-2-sulphonic acid for benzene sulphonic acid. Thus the corresponding naphthalene sulphonates (napsylates) were obtained.
~ r
Claims (10)
1. A salt of trans-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-1H-dibenz[2,3:6,7]oxepino-[4,5-c]pyrrole and a salt forming agent, characterized in that the salt forming agent is an aromatic sulphonic acid.
2. A salt according to claim 1, characterized in that the aromatic moiety of the aromatic sulphonic acid is a single phenyl ring.
3. A salt according to claim 2, characterized by being the tosylate or besylate.
4. A salt according to claim 1, characterized in that the aromatic moiety of the aromatic sulphonic acid is unsubstituted.
5. A salt according to claim 4, characterized by being the napsylate or besylate.
6. The aromatic sulphonate of trans-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole as a medicine.
7. Trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole besylate as a medicine.
8. A pharmaceutical composition comprising a salt of trans-5-chloro-2,3,3a,12b-tetra-hydro-2-methyl-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole as a medicinally active compound and a pharmaceutically acceptable carrier, characterized in that the salt is an aromatic sulphonate.
9. A pharmaceutical composition according to claim 8, characterized in that the aromatic sulphonate is selected from the group consisting of tosylate, besylate, napsylate, and mixtures thereof.
10.A depot injection preparation comprising an aromatic sulphonate of trans-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole and a pharmaceutically acceptable carrier suitable for use in depot injection preparations.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP97201596.0 | 1997-05-26 | ||
| EP97201596 | 1997-05-26 | ||
| PCT/EP1998/003022 WO1998054186A1 (en) | 1997-05-26 | 1998-05-19 | Salts of aromatic sulphonic acids |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2290070A1 true CA2290070A1 (en) | 1998-12-03 |
Family
ID=8228372
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002290070A Abandoned CA2290070A1 (en) | 1997-05-26 | 1998-05-19 | Salts of aromatic sulphonic acids |
Country Status (12)
| Country | Link |
|---|---|
| EP (1) | EP0984968A1 (en) |
| JP (1) | JP2001526702A (en) |
| KR (1) | KR20010012985A (en) |
| CN (1) | CN1257504A (en) |
| AU (1) | AU7767598A (en) |
| BR (1) | BR9809162A (en) |
| CA (1) | CA2290070A1 (en) |
| HU (1) | HUP0002106A3 (en) |
| NO (1) | NO995770D0 (en) |
| PL (1) | PL337027A1 (en) |
| TR (1) | TR199902727T2 (en) |
| WO (1) | WO1998054186A1 (en) |
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| JP5067998B2 (en) | 2001-10-30 | 2012-11-07 | ノバルティス アーゲー | Depot formulation of iloperidone and star polymer |
| HRP20020440B1 (en) | 2002-05-21 | 2008-02-29 | GlaxoSmithKline istra�iva�ki centar Zagreb d.o.o. | 1-aza-dibenzoazulenes as inhibitors of tumor necrosis factor production and intermediates for the preparation thereof |
| HRP20020452A2 (en) | 2002-05-23 | 2004-02-29 | Pliva D D | 1,2-diaza-dibenzoazulen as inhibitor of production of tumor necrosis factors and intermediates for preparation thereof |
| GB0216416D0 (en) * | 2002-07-15 | 2002-08-21 | Novartis Ag | Organic compounds |
| MX2007004485A (en) * | 2004-10-15 | 2007-06-13 | Organon Nv | Treatment of bipolar disorders and associated symptoms. |
| TW201113018A (en) | 2009-06-24 | 2011-04-16 | Organon Nv | Injectable formulations containing asenapine and method of treatment using same |
| ITMI20110734A1 (en) | 2011-05-02 | 2012-11-03 | Olon Spa | CRYSTALLINE ASENAPINE SALTS |
| EP2524920A1 (en) | 2011-05-17 | 2012-11-21 | Sandoz AG | Novel Crystalline Asenapine Hydrochloride Salt Forms |
| EP2524919A1 (en) | 2011-05-17 | 2012-11-21 | Sandoz AG | Novel crystalline salts of Asenapine with organic Di-acids and Tri-acids |
| EP2524921A1 (en) | 2011-05-17 | 2012-11-21 | Sandoz AG | Novel Crystalline Salts of Asenapine |
| MX2019007391A (en) | 2016-12-20 | 2019-08-16 | Lts Lohmann Therapie Systeme Ag | Transdermal therapeutic system containing asenapine. |
| EP3558276A1 (en) | 2016-12-20 | 2019-10-30 | LTS Lohmann Therapie-Systeme AG | Transdermal therapeutic system containing asenapine and polysiloxane or polyisobutylene |
| WO2019002204A1 (en) | 2017-06-26 | 2019-01-03 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine and silicone acrylic hybrid polymer |
| WO2019243452A1 (en) | 2018-06-20 | 2019-12-26 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine |
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| NL7605526A (en) * | 1976-05-24 | 1977-11-28 | Akzo Nv | NEW TETRACYCLICAL DERIVATIVES. |
-
1998
- 1998-05-19 EP EP98925632A patent/EP0984968A1/en not_active Withdrawn
- 1998-05-19 CN CN98805420A patent/CN1257504A/en active Pending
- 1998-05-19 BR BR9809162-0A patent/BR9809162A/en not_active Application Discontinuation
- 1998-05-19 PL PL98337027A patent/PL337027A1/en unknown
- 1998-05-19 CA CA002290070A patent/CA2290070A1/en not_active Abandoned
- 1998-05-19 AU AU77675/98A patent/AU7767598A/en not_active Abandoned
- 1998-05-19 JP JP50020299A patent/JP2001526702A/en active Pending
- 1998-05-19 WO PCT/EP1998/003022 patent/WO1998054186A1/en not_active Application Discontinuation
- 1998-05-19 HU HU0002106A patent/HUP0002106A3/en unknown
- 1998-05-19 TR TR1999/02727T patent/TR199902727T2/en unknown
- 1998-05-19 KR KR1019997010957A patent/KR20010012985A/en not_active Application Discontinuation
-
1999
- 1999-11-25 NO NO995770A patent/NO995770D0/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
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| NO995770L (en) | 1999-11-25 |
| PL337027A1 (en) | 2000-07-31 |
| HUP0002106A2 (en) | 2000-11-28 |
| NO995770D0 (en) | 1999-11-25 |
| AU7767598A (en) | 1998-12-30 |
| WO1998054186A1 (en) | 1998-12-03 |
| HUP0002106A3 (en) | 2001-11-28 |
| BR9809162A (en) | 2000-08-01 |
| KR20010012985A (en) | 2001-02-26 |
| JP2001526702A (en) | 2001-12-18 |
| EP0984968A1 (en) | 2000-03-15 |
| CN1257504A (en) | 2000-06-21 |
| TR199902727T2 (en) | 2000-07-21 |
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