CN1257504A - Salts of aromatic sulphonic acids - Google Patents
Salts of aromatic sulphonic acids Download PDFInfo
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- CN1257504A CN1257504A CN98805420A CN98805420A CN1257504A CN 1257504 A CN1257504 A CN 1257504A CN 98805420 A CN98805420 A CN 98805420A CN 98805420 A CN98805420 A CN 98805420A CN 1257504 A CN1257504 A CN 1257504A
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- salt
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- hexichol
- tetrahydrochysene
- pyrroles
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- 150000003839 salts Chemical class 0.000 title claims abstract description 36
- 125000003118 aryl group Chemical class 0.000 title claims abstract description 14
- 239000002253 acid Substances 0.000 title description 4
- 150000007513 acids Chemical class 0.000 title description 2
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 12
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 claims abstract description 9
- 238000002347 injection Methods 0.000 claims abstract description 5
- 239000007924 injection Substances 0.000 claims abstract description 5
- 150000003233 pyrroles Chemical class 0.000 claims description 14
- 150000001875 compounds Chemical class 0.000 claims description 13
- 239000003814 drug Substances 0.000 claims description 11
- 239000000203 mixture Substances 0.000 claims description 9
- 229940077388 benzenesulfonate Drugs 0.000 claims description 8
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims description 7
- 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 description 6
- ODQWQRRAPPTVAG-GZTJUZNOSA-N doxepin Chemical compound C1OC2=CC=CC=C2C(=C/CCN(C)C)/C2=CC=CC=C21 ODQWQRRAPPTVAG-GZTJUZNOSA-N 0.000 claims description 6
- 229960005426 doxepin Drugs 0.000 claims description 6
- 230000000694 effects Effects 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- PSZYNBSKGUBXEH-UHFFFAOYSA-M naphthalene-1-sulfonate Chemical group C1=CC=C2C(S(=O)(=O)[O-])=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-M 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 238000009472 formulation Methods 0.000 claims 2
- 125000005490 tosylate group Chemical group 0.000 claims 2
- 238000002360 preparation method Methods 0.000 abstract description 10
- 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 abstract description 2
- 230000002349 favourable effect Effects 0.000 abstract description 2
- 239000003874 central nervous system depressant Substances 0.000 abstract 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-N sulfonic acid Chemical compound OS(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-N 0.000 abstract 1
- 235000002639 sodium chloride Nutrition 0.000 description 23
- 239000013078 crystal Substances 0.000 description 9
- 238000002425 crystallisation Methods 0.000 description 9
- 230000008025 crystallization Effects 0.000 description 9
- 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 6
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-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
- 201000010099 disease Diseases 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 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
- 239000000739 antihistaminic agent Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 229950005627 embonate Drugs 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 3
- 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 2
- IOYNGCZNYGEZRO-UHFFFAOYSA-N 3-ethyl-n,n,2-trimethyl-1h-indol-5-amine Chemical compound C1=C(N(C)C)C=C2C(CC)=C(C)NC2=C1 IOYNGCZNYGEZRO-UHFFFAOYSA-N 0.000 description 2
- 208000019901 Anxiety disease Diseases 0.000 description 2
- 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
- 230000001387 anti-histamine Effects 0.000 description 2
- 230000036506 anxiety Effects 0.000 description 2
- 229960005245 asenapine Drugs 0.000 description 2
- 210000003169 central nervous system Anatomy 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 230000002045 lasting effect Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 208000020016 psychiatric disease Diseases 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- LODHFNUFVRVKTH-ZHACJKMWSA-N 2-hydroxy-n'-[(e)-3-phenylprop-2-enoyl]benzohydrazide Chemical class OC1=CC=CC=C1C(=O)NNC(=O)\C=C\C1=CC=CC=C1 LODHFNUFVRVKTH-ZHACJKMWSA-N 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
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- CTENFNNZBMHDDG-UHFFFAOYSA-N Dopamine hydrochloride Chemical compound Cl.NCCC1=CC=C(O)C(O)=C1 CTENFNNZBMHDDG-UHFFFAOYSA-N 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
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 1
- 208000028017 Psychotic disease Diseases 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-N Salicylic acid Natural products OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical group [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 230000002973 anti-dopamine Effects 0.000 description 1
- 229940125715 antihistaminic agent Drugs 0.000 description 1
- 239000003420 antiserotonin agent Substances 0.000 description 1
- 239000012752 auxiliary agent Substances 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
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 231100000457 cardiotoxic Toxicity 0.000 description 1
- 230000001451 cardiotoxic effect Effects 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000001035 drying Methods 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
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 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 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical compound C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 1
- -1 naphthoate 2-methoxyphenyl--acetate Chemical compound 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000001291 vacuum drying Methods 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)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Biomedical Technology (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 salt-forming 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
The present invention relates to compound anti--5-chloro-2,3,3a, 12b-tetrahydrochysene-2-methyl isophthalic acid H-hexichol (2,3:6,7) doxepin (4,5-c) pyrroles (trans-5-chloro-2,3,3a, 12b-tetrahydro-2-methyl-1H-dibenz[2,3:6,7] oxepino[4,5-c] pyrrole) and the salt of salt forming agent.
This class salt is known.Therefore, for example maleate of above-claimed cpd (Org 5222) and preparation thereof have been described in US4, and in 145,434, it is for referencial use that the disclosure of the document is incorporated this paper into.
This compound is described as has CNS inhibition activity and anti-histamine activity and medmain activity.
De Boer etc. has summarized instead-5-chloro-2,3,3a, 12b-tetrahydrochysene-2-methyl isophthalic acid H-hexichol (2,3:6,7) doxepin (4,5-c) pharmacology distribution, its kinetics and the metabolism of pyrroles in people volunteer and schizophreniac, and first security and efficient studies (following medicine (Drugs of the Future) 1993,18 (12), 1117～1123).Confirmed the i.e. anti--5-chloro-2 of Org5222,3,3a, 12b-tetrahydrochysene-2-methyl isophthalic acid H-hexichol (2,3:6,7) doxepin (4,5-c) pyrroles (Z)-2-butylene diacid salt (1: 1) is a kind of effectively Dopamine HCL and 5-hydroxytryptamine antagonist and has potential and suppress psychoactive antihistaminic agent.
In view of the effectiveness of this compound, wish it is mixed various pharmaceutical compositions, particularly those compositions of advantageously using to the patient who suffers from mental disorder.Because their disease character has nothing in common with each other, these patients often refusal take medicine, and perhaps only for example forget and take medicine owing to apathy.In view of this, especially for example above-claimed cpd is applied with the form of slow release type preparation, described slow release type preparation promptly is the pharmaceutical composition that contains the doses medicine, it is enough to for a long time (for example several weeks) and uses, and by continuing release, it will fulfil its function required to central nervous system.
Yet this class known compound not really is applicable to such slow release type preparation.To the major requirement of this purposes is that this compound is that crystal (otherwise this compound will be metastable, owing to be metastable state, just can not predict how many compound amounts at the biological needs of regular hour point is) and it should have low water solubility.The latter is important for reaching required lasting release.For example, described maleate (i.e. (Z)-2-butylene diacid salt, Org 5222) (it is a crystal) has the solubleness of 3mg/ml (21 ℃), and this means also will have higher dosage (the lasting release that is used to control) is directly scooped up into patients'blood.Free alkali (Org 33254) have less than 0.1mg/ml than low solubility, but it is unsettled.Embonate (Org 33388) is unbodied, and half embonate (hemipamoate) (Org 39058) is the mixture of amorphous substance and crystalline substance.In addition, require the fusing point can not too low (preferably being higher than 80 ℃), because the problem that it can cause temperature to cause when making tablet or granula.
For a long time, people recognize the Effect on Performance that does not have reliable method to predict the salt pair parent compound of concrete kind in this field, for example referring to pharmaceutical science magazine (J.Pharm.Sci.) 66,1～19,1977.Therefore, generally select salt forming agent by rule of thumb, and (for example international journal of Practical Pharmacy (International Journal ofPharmaceutics) in recent document, 33 (1986) 201～217), people recognize, particularly, be difficult to selected in advance salt forming agent for the such performance of moisture absorptivity, stability and solvability.
Too, and the earlier selected salt forming agent of difficult matter more is because also require crystallinity concerning compound of the present invention.Therefore, an object of the present invention is to be the selected a kind of salt forming agent of above-claimed cpd that it causes this medicament is water-insoluble basically, and is crystal.
By the present invention, selected salt forming agent is an aromatic sulfonic acid.
Though any in principle pharmaceutically acceptable aromatic sulfonic acid all is suitable, some aromatics part obviously is preferred.For example, this aromatics part may advantageously have this class of single benzyl ring.Such preferred acid is Phenylsulfonic acid and toluenesulphonic acids, and the preferred salt of the present invention is benzene sulfonate and tosylate.Alternatively, not replacing for the aromatics part may be favourable (certainly except that sulfonic group).In this respect, not only benzene sulfonate is the preferred salt of the present invention, and naphthene sulfonic acid also is this sour suitable candidate, and it causes forming corresponding naphthalenesulfonate.But the most preferred salt of the present invention is benzene sulfonate.
Salt of the present invention can be described in US4 with being similar to, the method preparation in 145,434.As for compound anti--5-chloro-2,3,3a, 12b-tetrahydrochysene-2-methyl isophthalic acid H-hexichol (2,3:6,7) doxepins (4,5-c) pyrroles's preparation can be with reference to the document.In order to obtain required salt, described compound can be dissolved in the suitable solvent (for example ethanol), then its is mixed with suitable solution of aromatic sulfonic acid, preferably in identical solvent or can with the miscible solvent of the solvent of described compound in mix.Again this mixture is placed time enough and made corresponding salt crystallization of the present invention (it spontaneously carries out).If necessary, can make the crystal of acquisition further experience conventional washing and drying and/or purification step, for example simple recrystallization, then dry.
As known maleate, composition of the present invention be applicable to the treatment suffer from for instead-5-chloro-2,3,3a, and 12b-tetrahydrochysene-2-methyl isophthalic acid H-hexichol (2,3:6,7) Mammals (comprising the people) of all diseases of doxepin (4,5-c) pyrroles's treatment sensitivity.These diseases comprise mental disorder, for example anxiety, excitement, anxiety, psychosis and schizophrenia.Described composition also can be used for the relevant disease of anti-Dopamine HCL, antihistamine and medmain.
Therefore, salt of the present invention self useful as drug, and they can use in any form, and but, described in WO95/23600, oral administration can cause cardiotoxic side effect.So other administration form is preferred, for example subcutaneous administration, injection is perhaps by means of the pharmaceutical composition hypogloeeis or cheek (as described in WO95/23600).
All these one-pack type pharmaceutical compositions that contain salt of the present invention all comprise the anti--5-chloro-2,3 as a dose unit of activeconstituents, 3a, 12b-tetrahydrochysene-2-methyl isophthalic acid H-hexichol (2,3:6,7) doxepins (4,5-c) pyrroles.A dose unit may contain 0.005mg～15mg activeconstituents.Preferably, this dose unit contain the 0.03～0.50mg that has an appointment anti--5-chloro-2,3,3a, 12b-tetrahydrochysene-2-methyl isophthalic acid H-hexichol (2,3:6,7) doxepins (4,5-c) pyrroles.Any suitable, pharmaceutically acceptable carrier substance all can be used, and also can add pharmaceutically acceptable assistant agent.All these pharmaceutically acceptable vehicle (for example carrier and assistant agent) all are well known by persons skilled in the art, so need not explanation at this.
Preferably, and only may described salt be used by the form of slow release type injection liquid (promptly to be higher than the dosage of one-pack type) owing to cause of the present invention.The standard dose of this class preparation comprises 10～40mg activeconstituents.Slow release type preparation of the present invention can comprise water as carrier with its simple form, and the low water solubility of described salt makes it preferably be disperseed certainly rather than be dissolved.For the ease of preparing stable dispersion liquid, can use conventional auxiliary agent, for example tween (tensio-active agent), propylene glycol, Yelkin TTS etc.Acceptable carrier also is suitable on the other medicines, for example carboxymethyl cellulose, gelatin, polyvinylpyrrolidone, perhaps other vehicle of knowing.As for the background knowledge of slow release type preparation, can be with reference to Leiberman, Rieger, Bunker, pharmaceutical dosage form: dispersion system (Pharmaceutical Dosage Forms:DisperseSystem), the 2nd volume.
Further set forth the present invention with reference to following embodiment.
Example I
With the solution of 940mg Phenylsulfonic acid in 15ml ethanol be added to 1.7g anti--5-chloro-2,3,3a is in 12b-tetrahydrochysene-2-methyl isophthalic acid H-hexichol (2,3:6,7) doxepins (4,5-c) pyrroles's the solution.Crystallization has taken place, and has collected the crystal of acquisition and recrystallization from 75ml ebullient ethanol.After being cooled to 20 ℃, collecting this crystal and on calcium chloride and potassium hydroxide, carry out vacuum-drying.Anti--5-chloro-2,3 of productive rate: 1.9g (72%), 3a, 12b-tetrahydrochysene-2-methyl isophthalic acid H-hexichol (2,3:6,7) doxepins (4,5-c) pyrroles's benzene sulfonate.The fusing point of finding this salt is 227.8 ℃, under 20 ℃, record its solubleness in water＜＜1mg/ml.
The comparative example
Repeated the operation of embodiment 1, wherein used a large amount of different acid, they all are known as the suitability of the salt forming agent of medicine.The result who obtains is given in the following table:
The solubleness of table salt form fusing point in water
(℃), (mg/ml) maleate crystal 141～145 3 fumarate crystal, 185.5～187 not crystallizations of 11-Hydroxynaphthoate--not crystallization of palmitate--amorphous 230～240＜0.35 half embonates of embonate are amorphous/the not crystallization of crystal 167～168＜0.25 benzoate--the not crystallization of 2 hydroxybenzoic acid salt--the not crystallization of 4-acetylamino--not crystallization of benzoate 3-hydroxyl-2---the not crystallization of naphthoate 2-methoxyphenyl--acetate
Obviously, aromatic sulphonate of the present invention constitutes an exception having following required aspect of performance concurrently: crystallinity, have high-melting-point and show as such low water solubility so that keep water-insoluble.
Example II
Replace Phenylsulfonic acid to repeat the operation of example I with toluene-4-sulfonic acid.Therefore, obtain corresponding tosylate.
EXAMPLE III
Replace Phenylsulfonic acid to repeat the operation of example I with naphthalene-1-sulfonic acid and naphthalene-2-sulfonic acid.Therefore, obtain corresponding naphthalenesulfonate.
Claims (10)
1. anti--5-chloro-2,3,3a, the salt of 12b-tetrahydrochysene-2-methyl isophthalic acid H-hexichol (2,3:6,7) doxepin (4,5-c) pyrroles and salt forming agent is characterized in that described salt forming agent is an aromatic sulfonic acid.
2. the salt of claim 1 is characterized in that, the aromatics of described aromatic sulfonic acid partly is single benzyl ring.
3. the salt of claim 2 is characterized in that, this salt is tosylate or benzene sulfonate.
4. the salt of claim 1 is characterized in that, the aromatics of described aromatic sulfonic acid partly is unsubstituted.
5. the salt of claim 4 is characterized in that, this salt is naphthalenesulfonate or benzene sulfonate.
6. as anti--5-chloro-2,3 of medicine, 3a, 12b-tetrahydrochysene-2-methyl isophthalic acid H-hexichol (2,3:6,7) doxepins (4,5-c) pyrroles's aromatic sulphonate.
7. as anti--5-chloro-2-methyl-2,3 of medicine, 3a, 12b-tetrahydrochysene-1H-hexichol (2,3:6,7) doxepins (4,5-c) pyrroles's benzene sulfonate.
8. pharmaceutical composition, it comprises the anti--5-chloro-2,3 as medicinal activity compound, 3a, 12b-tetrahydrochysene-2-methyl isophthalic acid H-hexichol (2,3:6,7) doxepin (4,5-c) pyrroles's salt and pharmaceutically acceptable carrier is characterized in that, described salt is aromatic sulphonate.
9. the pharmaceutical composition of claim 8 is characterized in that, described aromatic sulphonate is selected from tosylate, benzene sulfonate, naphthalenesulfonate and composition thereof.
10. slow release type injection formulations, it comprises instead-5-chloro-2,3,3a, 12b-tetrahydrochysene-2-methyl isophthalic acid H-hexichol (2,3:6,7) doxepins (4,5-c) pyrroles's aromatic sulphonate and be applicable to the pharmaceutically acceptable carrier of slow release type injection formulations.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP97201596 | 1997-05-26 | ||
| EP97201596.0 | 1997-05-26 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1257504A true CN1257504A (en) | 2000-06-21 |
Family
ID=8228372
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN98805420A Pending CN1257504A (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) |
Families Citing this family (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1578664A (en) | 2001-10-30 | 2005-02-09 | 诺瓦提斯公司 | Depot formulations of iloperidone and a 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 |
| KR20070084123A (en) * | 2004-10-15 | 2007-08-24 | 엔.브이.오가논 | Treatment of bipolar disorders and associated symptoms |
| RU2012102247A (en) * | 2009-06-24 | 2013-07-27 | Мсд Осс Б.В. | INJECTION COMPOSITIONS CONTAINING ASENAPINE AND METHOD OF TREATMENT WITH THEIR APPLICATION |
| ITMI20110734A1 (en) | 2011-05-02 | 2012-11-03 | Olon Spa | CRYSTALLINE ASENAPINE SALTS |
| EP2524921A1 (en) | 2011-05-17 | 2012-11-21 | Sandoz AG | Novel Crystalline Salts of Asenapine |
| 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 |
| CN115813887A (en) | 2016-12-20 | 2023-03-21 | 罗曼治疗系统股份公司 | Transdermal therapeutic system comprising asenapine |
| US11337932B2 (en) | 2016-12-20 | 2022-05-24 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine and polysiloxane or polyisobutylene |
| CA3067938A1 (en) | 2017-06-26 | 2019-01-03 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine and silicone acrylic hybrid polymer |
| KR20210022656A (en) | 2018-06-20 | 2021-03-03 | 에르테에스 로만 테라피-시스테메 아게 | Transdermal treatment system containing acenapine |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NL7605526A (en) * | 1976-05-24 | 1977-11-28 | Akzo Nv | NEW TETRACYCLICAL DERIVATIVES. |
-
1998
- 1998-05-19 TR TR1999/02727T patent/TR199902727T2/en unknown
- 1998-05-19 KR KR1019997010957A patent/KR20010012985A/en not_active Application Discontinuation
- 1998-05-19 PL PL98337027A patent/PL337027A1/en unknown
- 1998-05-19 CN CN98805420A patent/CN1257504A/en active Pending
- 1998-05-19 EP EP98925632A patent/EP0984968A1/en not_active Withdrawn
- 1998-05-19 AU AU77675/98A patent/AU7767598A/en not_active Abandoned
- 1998-05-19 WO PCT/EP1998/003022 patent/WO1998054186A1/en not_active Application Discontinuation
- 1998-05-19 CA CA002290070A patent/CA2290070A1/en not_active Abandoned
- 1998-05-19 HU HU0002106A patent/HUP0002106A3/en unknown
- 1998-05-19 BR BR9809162-0A patent/BR9809162A/en not_active Application Discontinuation
- 1998-05-19 JP JP50020299A patent/JP2001526702A/en active Pending
-
1999
- 1999-11-25 NO NO995770A patent/NO995770D0/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| JP2001526702A (en) | 2001-12-18 |
| HUP0002106A3 (en) | 2001-11-28 |
| KR20010012985A (en) | 2001-02-26 |
| BR9809162A (en) | 2000-08-01 |
| CA2290070A1 (en) | 1998-12-03 |
| HUP0002106A2 (en) | 2000-11-28 |
| AU7767598A (en) | 1998-12-30 |
| EP0984968A1 (en) | 2000-03-15 |
| TR199902727T2 (en) | 2000-07-21 |
| NO995770L (en) | 1999-11-25 |
| WO1998054186A1 (en) | 1998-12-03 |
| PL337027A1 (en) | 2000-07-31 |
| NO995770D0 (en) | 1999-11-25 |
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