Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/04—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
  • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
  • C07D513/04—Ortho-condensed systems

Definitions

• This invention relates to methods for separation of enantio ers of heterocyclic organic compounds, and in particular to methods for separation of enantiomers of mianserin and related compounds .
• racemic mixtures of enantiomers during the synthesis of pharmacologically-active agents is a significant problem in the pharmaceutical industry. It is well known in the art that in many cases there is differential activity between the two enantiomers, and that in some cases deleterious side-effects are associated with one optical isomer but not with the other.
• the complex structure of such molecules also means that their synthesis involves many steps, and consequently where chiral centres are present the compounds are usually prepared in the form of racemic mixtures.
• the pharmacological activity is mediated by the binding of the pharmacological agent to a target site, which may be extracellular or intracellular .
• the 3- dimensional interaction between the pharmaceutical agent and its target site results in the pharmacological action, either by stimulating a biological activity, or by blocking a biological activity which is mediated by the target site.
• the more accurate the 3-dimensional fit between the pharmacological agent and its target site the more potent will be the pharmacological activity which results, and the lower the likelihood of unwanted side-effects.
• Mianserin, ( ⁇ ) -1,2, 3,4, 10, 14b-hexahydro-2- methyldibenzo[c,f.pyrazino [1, 2- ⁇ ] azepine is an anti- depressant drug marketed under the name of Tolvin by Organon. Its synthesis was originally described in US Patent No.3534041 by Organon, and derivatives of mianserin are disclosed in British Patents No. 1498632 and No. 1498633. Normianserin (Chemical Abstracts No. 71936-92-0), also known as desmethylmianserin, has similar pharmacological activity to that of mianserin but is less potent (Pinder, 1985; Doggrell, 1985; Przegalinski et al, 1986).
• a related class of dibenzo-pyrazino-azepines was disclosed in U.S. Patent No. 3,701,778 (van der Burg) . These compounds were selected to have anti-inflammatory, anti-serotonergic, anti-histamine and cardiovascular effects, while certain intermediates in their preparation were also pharmacologically active.
• the compounds included oxazepines, thiazepines and diazepines, and a variety of synthetic routes for obtaining the desired products was set forth.
• Mianserin and the closely related compound normianserin are serotonin antagonists, and in addition to their anti-depressant activity have anti-histamine activity, and therefore are useful in the treatment of allergies.
• Synthetic methods for production of mianserin and normianserin result in a racemic mixture.
• the (+) enantiomer of mianserin is either the active component of such mixtures, or has higher activity than the (-) enantiomer as a result of preferential binding to cell membranes .
• anti-histamine agents which do not cross the blood-brain barrier, and consequently are non-sedating, for example terfenadine (Seldane; Hoechst Marion Roussel), astemizole (Hismanal; Janssen Pharmaceutica) and loratadine (Claritin; Schering Corporation) .
• terfenadine Shieldane; Hoechst Marion Roussel
• astemizole Hismanal; Janssen Pharmaceutica
• loratadine loratadine
• terfenadine interacts with certain anti-fungal drugs and antibiotics to cause life-threatening abnormalities of cardiac ventricular rhythm, as a result of inhibition by the anti-fungal agent or antibiotic of conversion of terfenadine to its active metabolite, terfenadine carboxylate (fexofenadine) .
• Astemizole requires approximately a week to become effective, and therefore patients frequently exceed the recommended dose. This can result in abnormal heart rhythms or even cardiac arrest.
• astemizole also interacts with certain anti- fungal agents and antibiotics in a similar manner to terfenadine, resulting in increased blood levels of atemizol. Elevated blood levels of loratadine can also result from such interactions, but so far no adverse cardiac effects have been reported. Thus there is a also a considerable need in the art for further non-sedating anti- histamine agents .
• agents of this type which are currently in clinical use, only terfenadine and its metabolite fexofenadine, marketed under the name Allegra by Hoechst Marion Roussel, are chiral compounds, and both of these are marketed as racemates.
• a method for separation of the enantiomers of terfenadine is described in International patent publication No. W095/31436 by Merrell Dow Pharmaceuticals Inc.
• a substantially optically pure (+) -mianserin comprising the steps of:
• a substantially optically pure (-) -mianserin comprising the steps of :
• (+) -di-p-toluoyl-D-tartaric acid is referred to throughout the specification as the (+) -di- p-toluoyl-D-tartrate salt of mianserin, or simply as the (+) -di-p-toluoyl-D-tartrate salt .
• the initial crystallisation step in either is performed using a ratio of mianserin to (-)-di-p- toluoyl-L-tartaric acid or (+) -di-p-toluoyl-D-tartaric acid (as appropriate) of 1:2-2.2.
• the crystallisation steps are performed using hot absolute ethanol as solvent.
• a method wherein the mother liquor remaining after the substantially optically pure crystals of the (-)-di-p- toluoyl-L-tartrate or (+) -di-p-toluoyl-D-tartrate salt form is subjected to treatment to isolate (+) -mianserin or (-)- mianserin, respectively.
• Treatment of the mother liquor typically involves a molar ratio of mianserin to the tartaric acid enantiomer of about 1:1.1.
• treatment to isolate (-)- mianserin comprises the steps of :
• the treatment to isolate (+) -mianserin comprises the steps of :
• the basification step is performed using 10% sodium hydroxide.
• the final purification step may suitably be performed by extraction with ethyl acetate,
• the method is also applicable to the preparation of mianserin-like compounds in optically pure form.
• a mianserin-like compound is a compound prepared from mianserin as a precursor.
• a purified enantiomer of mianserin prepared by the method of the invention may be used as starting material for preparation of a substantially pure (+) or (-) enantiomer, as appropriate, of a mianserin-like compound.
• the mianserin- like compound is selected from the group consisting of compounds of general formula I :
• Y H, CN or —(CH.) n — 1C.N .
• R 3 H or lower alkyl
• R 4 H, lower alkyl, or lower acyl.
• a substantially optically pure (+)- or (-) -mianserin-like compound comprising the steps of:
• (+)- or (-) -mianserin can be converted to (+) or (-) 2- cyanonormianserin by reaction with a cyanogen halide, preferably cyanogen bromide. Typically this reaction is conducted in dry benzene under an atmosphere of nitrogen. The product may be extracted with a 1:1 mixture of benzene and ether. - li ⁇
• (+) or (-)-2- cyanonormianserin can be converted to (+)- or (-)-2- carboxamidino-1, 2,3,4,10, 14b-hexahydrodibenzo [c, f] pyrazino- [1,2- ⁇ ] azepine by reaction with an alkylhaloaluminium amide.
• the alkylhaloaluminium amide is methylchloroaluminium amide generated in situ from trimethylaluminium and ammonium chloride.
• (+) or (-)-2- cyanonormianserin can be converted to (+)- or (-)- normianserin, where necessary, and (+)- or (-) -mianserin- like compounds of the general formula I are prepared by:
• R 1 is as defined above, and L is a leaving group selected from the group consisting of CH 3 0, CH 3 S, CH 3 S0 2 , S0 3 H, and 3,5-dimethylpyrazol-l-yl,
• step (f) reacting N-cyanonormianserin with H 2 S as in step (c), reacting the thus-formed product with methyl iodide in a second step, and reacting the product of the second step with R ⁇ NH,
• a substantially optically pure (+)- or (-) -mianserin-like compound Preferably the mianserin-like compound is FCC-5. More preferably, the compound is the (-) -enantiomer of FCC-5.
• a pharmaceutical composition comprising (+)- or (-) -mianserin or a (+)- or (-)- mianserin-like compound and a pharmaceutically acceptable carrier .
• a method for the treatment of disturbances of 5-hydroxytryptamine metabolism and/or h stamine metabolism in a mammal comprising the step of administering to a mammal suffering from such disturbance a pharmacologically effective amount of a substantially optically pure (+)- or (-) -mianserin-like compound.
• a substantially optically pure (+) or (-) -mianserin-like compound in the treatment of disturbances of 5-hydroxytryptamine metabolism and/or histamine metabolism.
• an eighth aspect of the present invention there is provided use of a substantially optically pure (+) or (-) -mianserin-like compound in the preparation of a medicament for the treatment of disturbances of 5-hydroxytryptamine metabolism and/or histamine metabolism.
• (+) Tartaric acid (0.30 g, 0.0019 ol) dissolved in hot absolute ethanol (5 ml) was added with stirring to a hot solution of racemic mianserin (0.5 g, 0.0018 mol) in absolute ethanol (10 ml) .
• the salt separated as white crystals.
• the salt was fractionally recrystallised, and after three recrystallisations material with almost constant rotation of [ ⁇ ] D +38.6° was obtained.
• the mother liquors yielded material of [ ⁇ ] D -20°.
• Liberation of free mianserin by base treatment of the salt with [ ⁇ ] D +38.6° gave material with [ ⁇ ] +48.8°.
• (+) and (-) isomers of FCC-5 were prepared in two steps from (+) and (-) isomers of mianserin.
• Each isomer of mianserin was first converted to 2-cyanonormianserin (2-Cyano-1,2,3,4,10, 14b-hexahydrodibenzo- [c, f]pyrazino [1,2- ⁇ ] azepine) using cyanogen bromide in benzene.
• 2-cyanonormianserin was then converted to FCC-5 according to the method of Garigipati (Garigipati, 1990) .
• the (+) and (-) isomers of FCC-5 were prepared as described in Example 4. Other compounds used were histamine diphosphate and mepyramine maleate (Sigma, MO, USA). Saline (NaCl, 0.9% w/v) was used as the vehicle for all drugs. FCC-5 was dissolved in saline at a concentration of 1 mM, and the solution was sonicated and slightly warmed to aid solubility. Concentrations of the test compounds are expressed as molar concentrations .
• Guinea pigs were killed instantly by exposure to halothane and exsanguination. An approximate 2 cm length of ileum was removed and mounted in a 15 mL organ bath containing Krebs solution of the following composition (mM) : NaCl 97.0, KC1 3.0, CaC12 1.89, MgSo4 1.0, KH2P04
• Figure 1 shows the time course for the recovery during washing of the antagonism of histamine by both FCC-5 isomers and mepyramine (15 min contact time) .
• the response of the ileum to histamine was significantly antagonised in the presence of either isomer of FCC-5 (10 nM) , after
• the antihistaminic properties of the isomers of FCC-5 have been demonstrated in vitro for the first time. Both isomers of FCC-5 produced potent antagonism of contractile responses to histamine in the isolated guinea pig ileum, an effect mediated by HI receptors.
• a distinguishing characteristic of the antihistaminic effect of FCC-5 (-) -isomer in the isolated ileum was the relatively rapid onset of this effect, within 15 min, and the subsequent lack of return of responses to histamine following washing of the tissue to remove the antagonist.
• the effect of FCC-5 (+) -isomer or mepyramine could be fully reversed with washing.
• FCC-5 (-) -isomer produces a non-competitive type of antagonism or a specific antihistaminic effect with slow dissociation of FCC-5 (-) -isomer from its Hi binding sites.
• FCC-5 (+) -isomer acts more like a competitive Hi receptor antagonist, similarly to mepyramine.
• racemic FCC-5 which also showed powerful and long-lasting antihistamine properties in vitro and in vivo, particularly in the .guinea pig respiratory system.
• Our results with FCC-5 (-) -isomer suggest that this compound is a nonsedating antihistamine which has significant therapeutic potential for the treatment of allergic disease.
• the purified enantiomers provided by the method of the invention are useful in the treatment of disturbances of 5-hydroxytryptamine and/or histamine metabolism in a mammal, hence they are useful as non- sedating anti-histamines for the treatment of asthma or an allergic condition and in the treatment of conditions such as depression, hypertension, congestive heart failure, migraine, anxiety, schizophrenia, gastrointestinal disturbances, diarrhoea and emesis.
• Przegalinski E., Rawlow, A., and Dohnal-Borak, L. Polish J. Pharmacol. Pharm., 1986 38 69-75.

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• 1998
  • 1998-09-25 EP EP98946144A patent/EP1017695A4/de not_active Withdrawn
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