CN1257504A - Aromatic Sulfonate - Google Patents
Aromatic Sulfonate Download PDFInfo
- Publication number
- 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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- CN
- China
- Prior art keywords
- salt
- chloro
- hexichol
- tetrahydrochysene
- pyrroles
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
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- 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
本发明涉及CNS抑制性的反－5－氯－2,3,3a,12b－四氢－2－甲基－1H－二苯[2,3:6,7]多塞平[4,5－c]吡咯和成盐剂的盐,所述成盐剂是芳族磺酸。公开的盐(优选是苯磺酸盐)具有有利的性能。因此,它具有需要的不溶性和结晶性以便适用于缓释型注射制剂。The present invention relates to CNS inhibitory trans-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-1H-diphenyl[2,3:6,7]doxepin[4,5- c] salts of pyrrole and a salt-forming agent which is an aromatic sulfonic acid. The disclosed salts, preferably besylate salts, have advantageous properties. Therefore, it has the required insolubility and crystallinity to be suitable for sustained-release injectable formulations.
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 | Aromatic Sulfonate |
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) | NO995770L (en) |
| PL (1) | PL337027A1 (en) |
| TR (1) | TR199902727T2 (en) |
| WO (1) | WO1998054186A1 (en) |
Families Citing this family (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003037337A1 (en) | 2001-10-30 | 2003-05-08 | Novartis Ag | 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 |
| BRPI0516000A (en) * | 2004-10-15 | 2008-05-06 | Pfizer | use of a compound or a pharmaceutically acceptable salt, solvate, hydrate or optical isomer thereof, method for treating bipolar disorder in a mammal in need thereof, and kit for use in treating bipolar disorder |
| 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 |
| ES3001152T3 (en) | 2016-12-20 | 2025-03-04 | Lts Lohmann Therapie Systeme Ag | Transdermal therapeutic system containing asenapine and polysiloxane or polyisobutylene |
| PL3338768T3 (en) | 2016-12-20 | 2020-05-18 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine |
| US11033512B2 (en) | 2017-06-26 | 2021-06-15 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine and silicone acrylic hybrid polymer |
| CN118806732A (en) | 2018-06-20 | 2024-10-22 | 罗曼治疗系统股份公司 | Transdermal therapeutic system containing asenapine |
| KR102802121B1 (en) | 2018-06-20 | 2025-05-02 | 에르테에스 로만 테라피-시스테메 아게 | Transdermal therapeutic system containing asenapine |
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 CN CN98805420A patent/CN1257504A/en active Pending
- 1998-05-19 TR TR1999/02727T patent/TR199902727T2/en unknown
- 1998-05-19 JP JP50020299A patent/JP2001526702A/en active Pending
- 1998-05-19 WO PCT/EP1998/003022 patent/WO1998054186A1/en not_active Ceased
- 1998-05-19 PL PL98337027A patent/PL337027A1/en unknown
- 1998-05-19 CA CA002290070A patent/CA2290070A1/en not_active Abandoned
- 1998-05-19 KR KR1019997010957A patent/KR20010012985A/en not_active Withdrawn
- 1998-05-19 HU HU0002106A patent/HUP0002106A3/en unknown
- 1998-05-19 AU AU77675/98A patent/AU7767598A/en not_active Abandoned
- 1998-05-19 EP EP98925632A patent/EP0984968A1/en not_active Withdrawn
- 1998-05-19 BR BR9809162-0A patent/BR9809162A/en not_active Application Discontinuation
-
1999
- 1999-11-25 NO NO995770A patent/NO995770L/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| NO995770D0 (en) | 1999-11-25 |
| TR199902727T2 (en) | 2000-07-21 |
| WO1998054186A1 (en) | 1998-12-03 |
| AU7767598A (en) | 1998-12-30 |
| HUP0002106A3 (en) | 2001-11-28 |
| KR20010012985A (en) | 2001-02-26 |
| NO995770L (en) | 1999-11-25 |
| JP2001526702A (en) | 2001-12-18 |
| PL337027A1 (en) | 2000-07-31 |
| HUP0002106A2 (en) | 2000-11-28 |
| BR9809162A (en) | 2000-08-01 |
| EP0984968A1 (en) | 2000-03-15 |
| CA2290070A1 (en) | 1998-12-03 |
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