CA2290070A1 - Salts of aromatic sulphonic acids - Google Patents

Salts of aromatic sulphonic acids Download PDF

Info

Publication number
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
Authority
CA
Canada
Prior art keywords
salt
aromatic
methyl
oxepino
dibenz
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.)
Abandoned
Application number
CA002290070A
Other languages
French (fr)
Inventor
Gerardus Johannes Heeres
Franciscus Hermanus Antonius Adreana Van Bakel
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Akzo Nobel NV
Original Assignee
Individual
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Individual filed Critical Individual
Publication of CA2290070A1 publication Critical patent/CA2290070A1/en
Abandoned legal-status Critical Current

Links

Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D491/00Heterocyclic 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
    • C07D491/02Heterocyclic 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
    • C07D491/04Ortho-condensed systems
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/24Antidepressants
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Landscapes

  • 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 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
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
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

Claims (10)

Claims:
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.
CA002290070A 1997-05-26 1998-05-19 Salts of aromatic sulphonic acids Abandoned CA2290070A1 (en)

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)

Families Citing this family (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NL7605526A (en) * 1976-05-24 1977-11-28 Akzo Nv NEW TETRACYCLICAL DERIVATIVES.

Also Published As

Publication number Publication date
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

Similar Documents

Publication Publication Date Title
US6348456B1 (en) Method of treating chemical dependency in mammals and a composition therefor
CA2290070A1 (en) Salts of aromatic sulphonic acids
JPH02104573A (en) Production of cys, end-2-azabicyclo(3, 3, 0) octane-3-carboxylic acid derivative
AU1186795A (en) Inhibition of smooth muscle migration and proliferation with hydroxy carbazole compounds
SK167698A3 (en) Polymorphs of donepezil hydrochloride and process for production
US5426106A (en) Pyrrolo-pyridazinone derivatives
PT87716B (en) PROCESS FOR THE PREPARATION OF (8-BETA) CYCLOALQUILAMIDES -1-ALKYL-6- (SUBSTITUTED) ERGOLINS
SK284362B6 (en) 1,7,7-Trimethyl-bicyclo[2.2.1]heptane derivatives, a process for the preparation thereof and use thereof
GB2372036A (en) Aspartate derivative of amlodipine
JP2974351B2 (en) Carbamate of 6-chloro-7,8-dihydroxy-1- (4&#39;-hydroxyphenyl) -2,3,4,5-tetrahydro-1H-3-benzazepine as a prodrug
US4528299A (en) 1-(2,3-Dimethyl-4-methoxyphenyl)-2-methyl-3-(1-pyrrolidinyl)-1-propanone and anti-spastic use thereof
DE69925250T2 (en) ACTIVATORS OF THE KALIUM CHANNELS
FR2570701A1 (en) FURO (3,2-C) PYRIDINE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC USE
MXPA99010901A (en) Salts of aromatic sulphonic acids
MXPA03005884A (en) Amlodipine hemimaleate.
CZ286649B6 (en) 2-(Aminomethyl)-3,4,7,9-tetrahydro-2H-pyrano/2,3-e/indol-8-one derivatives and pharmaceutical preparation in which they are comprised
EP1749817A1 (en) Neurogenic pain control agent composition
JPH10152438A (en) Stabilization of 1-azaxanthone derivative or its salt and 1-azaxanthone derivative-containing composition
NZ249346A (en) 2,6-methano-2h-quinolizine ester derivatives and medicaments thereof
CZ423099A3 (en) Salts of aromatic sulfonic acids
KR100220878B1 (en) Composition for treating cognitive disorders containing certain esters of hexahydro-8-hydroxy-2,6-methano-2h-quinolizin-3(4h)-one and related compounds
US3128278A (en) Substituted l
WO1999020623A1 (en) Indole derivative useful as endothelin receptor antagonist
US4318909A (en) Benzoxazocines
SE441447B (en) 2-HYDROXI-5- / 1-HYDROXI-2- / 4- (2-OXO-1-BENZIMIDAZOLINYL) -PIPERIDINO / ETHYL / BENZOIC ACID DERIVATIVE AND SET TO PREPARE THESE

Legal Events

Date Code Title Description
FZDE Discontinued