HK1072938A - Novel mandelate salts of substituted tetracyclic tetrahydrofuran derivatives - Google Patents

Description

Novel mandelate compounds of substituted tetracyclic tetrahydrofuran derivatives

Technical field and background

The present invention relates to mandelate salts of novel substituted tetracyclic tetrahydrofuran derivatives of formula (I)

N-oxides and stereochemically isomeric forms thereof, wherein R¹And R²Each independently is hydrogen or C_1-6Alkyl and R³And R⁴Each independently hydrogen or halogen, and pharmaceutical compositions comprising the mandelate salts of the invention, the use of the mandelate salts of the invention as a medicament, a process for preparing the mandelate salts of the invention and the use of the mandelate salts of the inventionMandelates and pharmaceutical compositions comprising mandelates of the invention for use in the treatment or prevention of CNS disorders, cardiovascular disorders and gastrointestinal disorders.

The compounds of formula (I) are reported in WO99/19317 and WO97/38991, which also report the acid addition salts of the compounds of formula (I), including the salts with tartaric (D and L-forms), hydrochloric, hydrobromic and malic acids thereof, however, the acid addition salts of the compounds of formula (I) known in the prior art have the disadvantage of poor physicochemical stability, and the known salts, after storage or formulation, are observed to decompose gradually, with increasing amounts and numbers of impurities. Obviously, this problem is more severe in harsh environmental conditions (e.g., light, heat, humidity, acidity, alkalinity, and oxygen, etc.). WO99/19317 and WO97/38991 make no mention of the stability of the compounds disclosed and how to obtain or improve their stability.

Surprisingly, it has now been found that the above-mentioned problems can be solved by the use of mandelic acid salts of compounds of the formula (I), their N-oxides and their stereochemically isomeric forms. The mandelate salts are not sensitive to light and are far more stable at room temperature, elevated temperature and relatively high humidity and in aqueous media than the prior art salts.

The compounds of the invention may be represented generally by the following formula (II), the N-oxide forms thereof and the stereoisomeric forms thereof

Wherein R is¹And R²Each independently is hydrogen or C_1-6Alkyl and R³And R⁴Each independently hydrogen or halogen. In the foregoing definition, C_1-6Alkyl represents straight-chain and branched saturated hydrocarbon groups having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, butyl, 1-methylpropyl, 1, 1-dimethylethyl, pentyl and hexyl.

Halogen in the above definitions refers to fluorine, chlorine, bromine and iodine.

Preferred compounds are those wherein R is¹And R²Each independently hydrogen or methyl.

Preferred compounds are those wherein R is³And R⁴Each independently hydrogen or fluorine.

The following compounds are particularly preferred, among them:

·R¹is hydrogen, R²Is methyl, R³Is fluorine and R⁴Is hydrogen (11-fluoro-3, 3a, 8, 12 b-tetrahydro-N-methyl-2H-dibenzo- [3, 4: 6, 7)]Cyclohepta [1, 2-b ]]Mandelate salt of furan-2-methanamine);

·R¹is hydrogen, R²Is methyl, R³Is hydrogen and R⁴Is hydrogen (3, 3a, 8, 12 b-tetrahydro-N-methyl-2H-dibenzo- [3, 4: 6, 7)]Cyclohepta [1, 2-b ]]Mandelate salt of furan-2-methanamine);

·R¹is methyl, R²Is methyl, R³Is fluorine and R⁴Is hydrogen (5, 11-difluoro-3, 3a, 8, 12 b-tetrahydro-N, N-dimethyl-2H-dibenzo- [3, 4: 6, 7)]Cyclohepta [1, 2-b ]]Mandelate salt of furan-2-methanamine);

·R¹is methyl, R²Is methyl, R³Is fluorine and R⁴Is hydrogen (11-fluoro-3, 3a, 8, 12 b-tetrahydro-N, N-dimethyl-2H-dibenzo- [3, 4: 6, 7)]Cyclohepta [1, 2-b ]]Mandelate salt of furan-2-methanamine);

·R¹is methyl, R²Is methyl, R³Is hydrogen and R⁴Is hydrogen (3, 3a, 8, 12 b-tetrahydro-N, N-dimethyl-2H-dibenzo- [3, 4: 6, 7)]Cyclohepta [1, 2-b ]]Mandelate salt of furan-2-methanamine);

the N-oxide forms of the compounds of the formulae (I) and (II) mean that the nitrogen atoms in the compounds of the formula (I) contained are oxidized to the so-called N-oxides.

The term "stereochemically isomeric forms" as used herein is intended to define all the isomeric forms which the compounds of formula (I) and (II) may possess. Unless otherwise stated or indicated, the chemical formula of a compound represents a mixture of all possible stereochemically isomeric forms, said mixture comprising all diastereomers and enantiomers of the basic molecular structure, more particularly stereogenic centers which may have the R-or S-configuration (configuration); the substituent on the bivalent cyclic (partially) saturated group may have a cis or trans configuration.

The stereochemically isomeric forms of the compounds of formula (I) and (II) are expressly intended to be embraced within the scope of the present invention.

According to CAS-nomenclature principles, when two stereogenic centers of known absolute configuration are present in a molecule, the chiral (chiral) center with the smallest number is assigned (based on Cahn-Ingold-Prelog order rules) with the descriptor of R or S (descriptor) as the control center, and the second stereogenic center is identified with the associated descriptor [ R^*，R^*]Is shown in which R^*Always as a control center and [ R ]^*，R^*]Represents a center having the same chirality, and [ R ]^*，S^*]Representing centers of different chirality, e.g. if the least numbered chiral center in the molecule has S configuration and the second center is R, the stereodescriptor will be denoted S- [ R [ ]^*，S^*](ii) a If "α" and "β" are used: the position of the most preferred substituent at the asymmetric carbon atom in the ring system having the lowest ring number is always arbitrarily designated as "α" in the mean plane defined by the ring system, while the position of the most preferred substituent at other asymmetric carbon atoms in the ring system is designated as "α" when the position of the most preferred substituent on the reference atom is on the same side of the mean plane of the ring system, and as "β" when on different sides.

Some of the compounds of formulae (I) and (II) and intermediates used in their preparation have not been tested for their absolute stereochemical configuration, in which case the first isolated compound is designated "a" and the second isolated compound is designated "B", and no further reference is made to their true stereochemical configuration. However, if "a" and "B" have an enantiomeric relationship, the so-called "a" or "B" isomeric forms may still differ significantly in, for example, their optical activity. The absolute configuration of such compounds can be determined by those skilled in the art using methods known in the art, such as X-ray diffraction.

For example, a compound with the stereochemical descriptor a- (2 α, 3a β, 12b α) represents a pure enantiomer with one of the following two configurations: (a) the configuration is [2R- (2 alpha, 3a beta, 12b alpha.)]In which carbon atom 2 is a reference atom of R configuration and-CH₂-NR¹R²The substituents being alpha-sides lying in the mean plane, the carbon atom 3a having the S configuration, since the hydrogen substituents are relative to-CH₂-NR¹R²The substituents being on the other side of the mean plane and the carbon atom 12b having the R configuration, since the hydrogen substituent is opposite to the-CH₂-NR¹R²The substituents being on the same side of the mean plane, or (b) having the configuration [2S- (2 α, 3a β, 12b α)]Wherein carbon atom 2 has the S configuration, carbon atom 3a has the R configuration and carbon atom 12b has the S configuration.

Similarly, a compound with the stereochemical descriptor a- (2 α, 3a α, 12b β) represents a pure enantiomer having one of the following two configurations: (a) the configuration is [2R- (2 alpha, 3a alpha, 12b beta)]Wherein carbon atom 2 is a reference atom having the R configuration and-CH₂-NR¹R²The substituents being on the alpha-side of the average plane, carbon atom 3a having the R configuration and carbon atom 12b having the S configuration, or (b) having the configuration [2S- (2 alpha, 3a alpha, 12b beta)]Wherein carbon atom 2 has the S configuration, carbon atom 3a has the S configuration and carbon atom 12b has the R configuration.

We note that the furan moiety in formula (I) contains three stereogenic carbon atoms at positions 2, 3a and 12b, respectively, and thus formula (I) contains 8 different isomers. Most preferred are the isomers designated (2 α, 3a α, 12b β).

Since mandelic acid exists in two isomeric forms (the R and S forms), it is understood that the salts of both isomeric forms, including any mixtures thereof, are encompassed by the present invention, with the S-form of the mandelate salt being particularly preferred.

The compounds of the invention exhibit p-5 HT₂Affinity of receptors, especially for 5-HT_2AAnd 5-HT_2CReceptors [ named as D, as described in "Serotonine (5-HT) in neurological and psychiatric disorders" by Hoyer, edited by M.D Ferrari, BoerhaaveC administration of the University of Leiden 1994]. The serotonin (sertonine) antagonistic properties of the compounds of the invention can be demonstrated by their inhibitory effect in the mouse 5-hydroxytryptophan assay, which is described in drug dev.res., 13, 237-244 (1988); furthermore, the mandelate salts according to the invention show interesting pharmacological activities in the "mouse mCPP test" described in WO99/19317 and the "mouse mixed Apomorphine (Apomorphine), Tryptamine (Tryptamine), Norepinephrine (ATN) test" described in Arch. int. Pharmacodyn, 227, 238-253 (1977).

The invention therefore also relates to the use of the mandelate salts according to the invention as defined above as pharmaceuticals, in particular the compounds of formula (II) may be used for the manufacture of a medicament for the treatment of CNS disorders such as e.g. pyro-filtration, psychosis, schizophrenia, depression, migraine, sleep-eye disorders and addiction to drugs of abuse.

In particular, the mandelate salts according to the invention are useful as therapeutic agents for the treatment or prevention of disorders of the central nervous system such as anxiety, depression and depression, bipolar disorders, sleep-and sexual dysfunction, psychosis, borderline schizophrenia, migraine, personality or obsessive-compulsive disorder, social phobia or panic attacks, organic psychotic disorders, childhood psychotic disorders, aggressive behavior, senile memory and posture disorders, addiction, obesity, bulimia and similar disorders.

In particular, the mandelate salts of the invention may also be used as anxiolytics, antipsychotics, anti-depression agents, anti-migraine agents and as agents having the potential to overcome addiction to drugs of abuse.

The mandelate salts of the invention may also be useful as therapeutic agents for the treatment of movement disorders, and it may be advantageous to use the mandelate salts of the invention in combination with typical therapeutic agents used in the treatment of such diseases.

The mandelate salts of the invention may also be useful in the treatment or prevention of the following diseases: damage to the nervous system caused by trauma, stroke, neurodegenerative diseases, and the like; cardiovascular diseases such as hypertension, thrombosis, stroke, etc.; and gastrointestinal disorders such as motor dysfunction of the gastrointestinal system.

In view of the above-mentioned use of the mandelate salt according to the invention, the invention also provides a method of treating a warm-blooded animal having such a disease comprising the systemic administration of a therapeutically effective amount of a compound of formula (II), an N-oxide thereof or a stereoisomer thereof, which is effective in the treatment of the above-mentioned diseases, in particular in the treatment of anxiety, psychosis, schizophrenia, depression, migraine, sleep disorders and addiction to drugs of abuse.

The daily amount of therapeutically effective agent will be determined by those skilled in the art of treatment of such diseases from the test results set forth hereinafter and may range from about 0.01 mg/kg to about 10 mg/kg body weight, more preferably from about 0.05 mg/kg to about 1 mg/kg body weight.

For ease of administration, the compounds of the present invention may be formulated for administration in a variety of pharmaceutical dosage forms. To prepare the pharmaceutical compositions of this invention, a therapeutically effective amount of a particular compound, as the active ingredient, is intimately admixed with a pharmaceutically acceptable carrier, which may take a wide variety of forms depending on the form of preparation to be administered. These pharmaceutical compositions are preferably in unit dosage form suitable for oral, rectal, transdermal or parenteral administration by injection. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed, e.g., water, glycerol, oils, alcohols, and the like for preparing liquid preparations for oral administration (e.g., suspensions, syrups, elixirs, and solutions); or the use of solid carriers (e.g., starches, sugars, kaolin, lubricants, binders, disintegrants, and the like) for the preparation of powders, pills, capsules, and tablets, and the like, which represent the most advantageous oral dosage unit forms for ease of administration, among which solid pharmaceutical carriers are obviously employed; for compositions intended for parenteral administration, the carrier will typically comprise sterile water, at least in large part, although other ingredients, for example, co-solvents; injectable solvents, for example, can be prepared in which the carrier comprises saline solution, glucose solution or a mixed solution of saline and glucose; injectable solutions containing a mandelate salt according to the invention may be formulated as oil solutions for protracted action, oils suitable for this purpose being, for example, peanut oil, sesame oil, cottonseed oil, corn oil, soybean oil, synthetic glycerol esters of long chain fatty acids and mixtures thereof with other oils; also can be prepared into injectable suspensions in which case appropriate liquid carriers, suspending agents and the like can be employed; the carrier in a composition suitable for transdermal administration may optionally comprise penetration aids and/or suitable wetting agents, and may optionally be combined with suitable minor additives of any nature that do not cause any significant adverse effect on the skin, which additives facilitate the ease of application of the formulation to the skin and/or aid in the preparation of the desired composition. These compositions may be administered in a variety of ways, for example, as a transdermal patch, as a spot-on or as an ointment; mandelate salts, which are acid addition salts of the compounds of formula (I), are more suitable for preparing aqueous compositions due to their higher aqueous solubility than the corresponding bases or acids.

In order to increase the solubility and/or stability of the compounds of the formula (II) in the pharmaceutical compositions, it may be advantageous to use α -, β -or γ -cyclodextrins or derivatives thereof, in particular hydroxyalkyl-substituted cyclodextrins, such as 2-hydroxypropyl- β -cyclodextrin, and, in addition, cosolvents, such as alcohols, may also be used for improving the solubility and/or stability of the compounds of the formula (II) in the pharmaceutical compositions.

Other convenient methods for increasing the solubility of the compounds of the invention in pharmaceutical compositions are disclosed in WO 97/44014.

More particularly, the compounds of the present invention may be formulated in a pharmaceutical composition comprising a therapeutically effective amount of particles which comprise a solid dispersion comprising:

(a) a compound of formula (II), with

(b) One or more pharmaceutically acceptable water-soluble polymers.

The term "solid dispersion" denotes a solid (as opposed to liquid or gaseous) system comprising at least two components, one of which is more or less uniformly dispersed in the other component, when the dispersion of these components is such that the system is chemically and physically completely homogeneous or thermodynamically in phase, such dispersion being referred to as a "solid solution", which is a preferred physical system because the components are readily bioavailable by the organism of the intended user.

The term "solid dispersion" also encompasses dispersions that are not as homogeneous as solid solutions, such dispersions are not chemically or physically completely homogeneous, or they comprise more than one phase.

The water-soluble polymer in the particles means a polymer having an apparent viscosity of 1 to 100mpa.s when dissolved in a 2% aqueous solution of water at 20 ℃.

Preferred water-soluble polymers are hydroxypropyl methylcellulose or HMPC. HMPC having a molar substitution of methoxy from about 0.8 to about 2.5 and hydroxypropyl from about 0.05 to about 3.0 are generally water soluble. The degree of substitution by methoxy groups refers to the average number of methyl ether groups present per anhydroglucose unit of the cellulose molecule, and the degree of substitution by hydroxypropyl moles refers to the average number of moles of propylene oxide that have reacted with each anhydroglucose unit of the cellulose molecule.

The particles as defined above may be prepared by first preparing a solid dispersion of the components and then optionally milling the dispersion. Various prior art techniques for preparing solid dispersions include melt extrusion, spray drying and solution-evaporation, with melt extrusion being the preferred mode.

It is particularly advantageous to formulate the aforementioned pharmaceutical compositions in dosage unit form for ease of administration and uniformity of dosage, where dosage unit form is intended in the specification and claims to mean physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect, in association with the required pharmaceutical carrier. Examples of such dosage unit forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions, teaspoonfuls, tablespoonfuls and the like, segregated multiples thereof.

The mandelate salt of formula (II) is prepared by dissolving the compound of formula (I) in its free base form in a suitable solvent, optionally heating the mixture, adding a sufficient amount of mandelic acid, cooling the reaction mixture and collecting the crystalline material. The corresponding salt thus obtained can be purified by recrystallization from a suitable solvent.

Suitable solvents for the preparation and recrystallization of mandelate salts herein are any lower alkanol or ketone based solvent which dissolves the compounds of formula (I) including primary, secondary and tertiary alcohols having 1 to 6 carbon atoms and the corresponding ketones, and suitable lower alkanol solvents include methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-methyl-1-propanol, 1, 1-dimethyl-ethanol, cyclohexanol and the like. Mixtures of two or more of the above solvents, as well as solutions of said solvents or mixtures thereof with water, are also useful in the preparation of mandelates of the invention. Specifically, water may comprise up to about 25% to 35% by volume of the solution. The solvents used are preferably lower alcohols, in particular 2-propanol.

The compounds of formula (I) of the present invention may be prepared according to the methods described in WO99/19317 and WO97/38991, those methods being disclosed herein by reference.

In general, the compounds of formula (I) mayBy N-alkylation of intermediates of formula (III) using intermediates of formula (IV) wherein W is a suitable leaving group, e.g. halogen, in which intermediates (III) and (IV) R¹To R⁴Are as defined for the compounds of formula (I). The N-alkylation reaction is conveniently carried out in a reaction-inert solvent (e.g. methanol, tetrahydrofuran, methyl isobutyl ketone, N-dimethylformamidone or dimethylsulfoxide), optionally in the presence of a suitable base, and stirring and raising the temperature (e.g. at reflux temperature) increases the rate of reaction; alternatively, this N-alkylation reaction may be carried out using the method described by Monkovic et al (j.med.chem. (1973), 16(4), p.403-407), which involves the use of a pressurized reaction vessel.

The compounds of formula (I) may also be interconverted according to art-known transformations.

Furthermore, the compounds of formula (I) may be converted into the corresponding N-oxide form by methods known in the art for converting trivalent nitrogen into its N-oxide, which N-oxidation reaction may generally be carried out by reacting the starting materials of formula (I) with a suitable organic or inorganic peroxide. Suitable inorganic peroxides include, for example, hydrogen peroxide, alkali or alkaline earth metal peroxides, such as sodium peroxide, potassium peroxide; suitable organic peroxides may comprise peroxy acids, such as peroxybenzoic acid or halogen-substituted peroxybenzoic acids, such as 3-chloroperoxybenzoic acid, peroxy alkanoic acids, such as peroxyacetic acid, alkyl hydroperoxides, such as t-butyl hydroperoxide; suitable solvents are, for example, water, lower alkanols, such as ethanol and the like, hydrocarbons, such as toluene, ketones, such as 2-butanone, halogenated hydrocarbons, such as methylene chloride, and mixtures of such solvents.

Pure stereochemically isomeric forms of the compounds of formula (I) may be prepared by employing procedures known in the art, and the diastereomers may be separated by physical methods, e.g. by selective crystallization and chromatographic techniques, e.g. reflux distribution, liquid chromatography, etc.

The compounds of formula (I) prepared in the above-described manner are usually racemic mixtures of enantiomers, which can be separated from each other using the following resolution methods known in the art. Compounds of formula (I) which are sufficiently basic or acidic in nature can be converted to the corresponding diastereomeric salt forms by reaction with an appropriate chiral acid and an appropriate chiral base, respectively, followed by separation of the diastereomeric salts, for example, by selective or fractional crystallization, and liberation of the enantiomers therefrom by base or acid. Further methods for separating the enantiomers of compound (I) include liquid chromatography using a chiral stationary phase; pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs in a stereospecific manner. If a particular stereoisomer is desired, this compound is preferably synthesized by stereospecific methods of preparation, which advantageously employ the starting materials in enantiomerically pure form.

The aforementioned intermediates, which are commercially available or can be prepared according to methods known in the art, for example, the intermediates of formula (III) can be prepared according to the methods described by Monkovic et al (J.Med.chem. (1973), 16(4), p.403-407).

The following examples are intended to illustrate but not limit the scope of the invention.

Experiment of

A. Preparation of intermediate compounds

a) Mixing LiAlH₄(0.0686 mol) AlCl suspended in tetrahydrofuran (75 ml) was added dropwise₃(0.0718 mol) to a suspension, the suspension was cooled on an ice bath under a nitrogen atmosphere, the mixture was stirred at 0 ℃ for ten minutes, and 2-fluoro-5H-dibenzo [ a, d ] dissolved in tetrahydrofuran (75 ml) was added dropwise]Cycloheptene-5- (0.0653 mol, prepared according to the process described in DE3,644,462) solution, and the resulting solutionThe reaction mixture was warmed to room temperature, then the reaction mixture was stirred and refluxed for 2 hours, the mixture was cooled on an ice bath, water and dichloromethane were added, the organic layer was washed with saturated aqueous sodium bicarbonate solution, dried, filtered, and the solvent was evaporated to yield 13.16 g (96%) of 2-fluoro-5H-dibenzo [ a, d ] -5]Cycloheptene (intermediate 1).

b) M-chloroperbenzoic acid (0.0501 mol dissolved in chloroform (40 ml), the organic solution dried, filtered, and the filter was added dropwise to a solution of intermediate 1(0.0417 mol) and 1, 4-benzenediol (0.26 g) in chloroform (70 ml) with stirring at 60 ℃; after stirring the reaction mixture at 60 ℃ for 2.5 hours, it was cooled on an ice bath, washed with 10% aqueous sodium carbonate and brine, dried, filtered, and the filtrate was concentrated to yield 10.42 g of 3-fluoro-6, 10 b-dihydro-1 aH-dibenzo [3, 4: 6, 7] cyclohepta [1, 2-b ] oxirane (intermediate 2).

c) Bromo-2-propenyl-magnesium (0.0542 mol) was added dropwise under nitrogen to a solution of intermediate 2(0.04956 mol) dissolved in tetrahydrofuran (120 ml), the reaction mixture was stirred at room temperature for 30 minutes, then stirred under reflux for 2 hours, cooled on an ice bath, and 20% HN₄After discontinuation of the reaction with Cl solution, extraction with ethyl acetate, separation of the organic layer, drying, filtration and evaporation of the solvent, purification of the residue by HPLC on silica gel and separation into two regioisomeric eluents: hexane/ethyl acetate 9/1) and the two pure fractions were collected and the solvent was evaporated off to yield 4.79 g (36%) of (±) -trans 8-fluoro-10, 11-dihydro-11- (2-propenyl) -5H-dibenzo [ a, d ],]cyclohepten-10-ol (intermediate 3) with 2.52 g (19%) of (trans) -2-fluoro-10, 11-dihydro-11- (2-propenyl) -5H-dibenzo [ a, d ]]Cyclohepten-10-ol (intermediate 4).

d) Pyridinium tribromide (0.0175 mol) was added in portions to a solution of intermediate 3(0.0175 mol) dissolved in chloroform (80 ml), cooled on an ice bath, the reaction mixture was stirred for one hour at room temperature, water was added, stirring was continued for 5 minutes, the organic layer was separated, washed with water, dried, filtered and the solvent was evaporated, and the residue was purified by short column chromatography over silica gel (eluent: hexane/dichloromethane 4: 1 followed by 1: 1), the pure fractions were collected and the solvent was evaporated off, yielding 5.02 g (83%) of (±) [ (2 α, 3a β, 12b α) + (2 α, 3a α, 12b β) ] -2- (bromomethyl) -11-fluoro-3, 3a, 8, 12 b-tetrahydro-2H-dibenzo- [3, 4: 6, 7] -cyclohepta [1, 2-b ] furan (intermediate 5).

Can be prepared by similar method

(±) [ (2 α, 3a β, 12b α) + (2 α, 3a α, 12b β) ] -2- (bromomethyl) -5-fluoro-3, 3a, 8, 12 b-tetrahydro-2H-dibenzo- [3, 4: 6, 7] -cyclohepta [1, 2-b ] furan (intermediate 6).

(±) [ (2 α, 3a β, 12b α) + (2 α, 3a, 12b β) ] -2- (bromomethyl) -3, 3a, 8, 12 b-tetrahydro-2H-dibenzo- [3, 4: 6, 7] -cyclohepta [1, 2-b ] furan (intermediate 7) with (±) [ (2 α, 3a β, 12b α) + (2 α, 3a α, 12b β) ] -2- (bromomethyl) -5, 11-difluoro-3, 3a, 8, 12 b-tetrahydro-2H-dibenzo- [3, 4: 6, 7] -cyclohepta [1, 2-b ] furan (intermediate 8).

e) A mixture of intermediate 5(0.073 mol), dimethylamine gas (170 g) and CaO (26 g) in THF (400 ml) was heated in an autoclave at 125 ℃ for 16 hours (reaction x 2), the mixture was washed with saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, the separated organic layer was dried, filtered and the solvent was removed by evaporation, the residue was dissolved in diethyl ether, converted to the hydrochloride salt with HCl/2-propanol (pH < 4) (1: 1), the solvent was removed by evaporation, the residue was stirred into boiling 2-propanone, filtered and dried: 20.5 grams of (±) [ (2 α, 3a β, 12b α) -11-fluoro-3, 3a, 8, 12 b-tetrahydro-N, N-dimethyl-2H-dibenzo- [3, 4: 6, 7] -cyclohepta [1, 2-b ] furan-2-methanamine (intermediate 9).

f) Evaporating the solvent from the mother liquor, purifying the residue by high performance liquid chromatography on RP-18 to obtain an eluate (0.5% ammonium acetate in water)/methanol/CH₃CN gradient eluent) was collected and the solvent was evaporated off, yield: 0.400 g of (±) - [ (2 α, 3a α, 12b β) -11-fluoro-3, 3a, 8, 12 b-tetrahydro-N, N-dimethyl-2H-dibenzo-, [2 ]3，4：6，7]-cyclohepta [1, 2-b ]]Furan-2-methanamine (intermediate 10).

g) Chiral column chromatography was performed on the column purified by chromatography on chirala 1pak AD (eluent: hexane/2-propanol 97/3) intermediate 10(0.00128 moles) was separated into its enantiomers, two pure fractions were collected and the solvent was evaporated, yield: 0.201 g of a- (2 α, 3a α, 12b β) -11-fluoro-3, 3a, 8, 12 b-tetrahydro-N, N-dimethyl-2H-dibenzo- [3, 4: 6, 7] -cyclohepta [1, 2-B ] furan-2-methanamine (intermediate 11) with 0.170 g of B- (2 α, 3a α, 12B β) -11-fluoro-3, 3a, 8, 12B-tetrahydro-N, N-dimethyl-2H-dibenzo- [3, 4: 6, 7] -cyclohepta [1, 2-b ] furan-2-methanamine (intermediate 12).

The following intermediates were also prepared in analogy to example 10:

(±) [ (2 α, 3a α, 12b β) -5-fluoro-3, 3a, 8, 12 b-tetrahydro-N, N-dimethyl-2H-dibenzo- [3, 4: 6, 7] -cyclohepta [1, 2-b ] furan-2-methanamine (intermediate 13),

(±) [ (2 α, 3a α, 12b β) -3, 3a, 8, 12 b-tetrahydro-N, N-dimethyl-2H-dibenzo- [3, 4: 6, 7] -cyclohepta [1, 2-b ] furan-2-methanamine (intermediate 14) with

(±) [ (2 α, 3a α, 12b β) -5, 11-difluoro-3, 3a, 8, 12 b-tetrahydro-N, N-dimethyl-2H-dibenzo- [3, 4: 6, 7] -cyclohepta [1, 2-b ] furan-2-methanamine (intermediate 15).

h) The monomethyl equivalents of intermediates 13, 14 and 15 can be prepared in a similar manner using methylamine (gas) instead of N, N-dimethylamine (gas) to give

(±) [ (2 α, 3a α, 12b β) -11-fluoro-3, 3a, 8, 12 b-tetrahydro-N-methyl-2H-dibenzo- [3, 4: 6, 7] -cyclohepta [1, 2-b ] furan-2-methanamine (intermediate 16),

(±) [ (2 α, 3a α, 12b β) -5-fluoro-3, 3a, 8, 12 b-tetrahydro-N-methyl-2H-dibenzo- [3, 4: 6, 7] -cyclohepta [1, 2-b ] furan-2-methanamine (intermediate 17),

(±) [ (2 α, 3a α, 12b β) -5, 11-fluoro-3, 3a, 8, 12 b-tetrahydro-N-methyl-2H-dibenzo- [3, 4: 6, 7] -cyclohepta [1, 2-b ] furan-2-methanamine (intermediate 18) with

(±) [ (2 α, 3a α, 12b β) -3, 3a, 8, 12 b-tetrahydro-N-methyl-2H-dibenzo- [3, 4: 6, 7] -cyclohepta [1, 2-b ] furan-2-methanamine (intermediate 19).

B. Preparation of mandelate salts

Compound 1

0.00025 mol of the B-enantiomer of intermediate 16 and 0.00025 mol of S-mandelic acid were dissolved in 4 ml of 2-propanol and then allowed to crystallize, the precipitate was filtered off and dried (under vacuum, 50 ℃ C.), yield: 0.096 g of the mandelate salt (Compound 1). Compound 1, 5 mg, was placed in 1 ml of 2-propanol (containing 3 drops of ethanol) and recrystallized to obtain a sample suitable for X-ray analysis.

Mandelate salts of the B-enantiomers of intermediates 12, 13, 14, 15, 17, 18 and 19 can be prepared in a similar manner.

Stability test

The following salts were tested: b- (2 α, 3a α, 12B β) -11-fluoro-3, 3a, 8, 12B-tetrahydro-N-methyl-2H-dibenzo- [3, 4: tartrate, ditoluoyltartrate, citrate, malonate, succinate and mandelate salts of 6, 7-cyclohepta [1, 2-b ] furan-2-methanamine (Compound 1). These salts were tested for their water adsorption/desorption behavior, their crystal stability and their chemical stability.

a. Adsorption and desorption of water

The adsorption and desorption of water was studied for various salts in amounts of + -10 mg at 25 ℃ and various relative humidities, and the weight was recorded as a function of relative humidity, and the results are shown in FIG. 1. Mandelate salts are stable to moisture uptake throughout the humidity range. Malonate, succinate, tartrate, and (+) ditoluoyltartrate are less stable, but the weight changes little with relative humidity. Citrate is hygroscopic and liquefies at high relative humidity.

b. Stability of crystals

The stability of the crystal structure of the salts was investigated after storage of the compounds at Room Temperature (RT) and 5% or 75% Relative Humidity (RH) and 25 ℃/60% relative humidity for two weeks. The samples were analyzed by thermogravimetric analysis (TGA), Differential Scanning Calorimetry (DSC) and infrared spectroscopy (IR).

The test results are shown in Table 1.

Table 1: test results of crystal stability

Salt (salt)	Condition	TGA＜100℃	IR	DSCMax ΔH(℃) (J/g)		Appearance of the product
							Tartrate salt	Day 0	0.0	Ref	158.8	85.9	White colour
RT/＜5％RH	0.0	～Ref	160.3	86.4	White colour
						RT/＜56％RH		0.1	～Ref	159.0	86.2	White colour
RT/＜75％RH	0.0	～Ref	159.0	98.5	White colour
						Mandelate salt		Day 0	0.1	Ref	229.5	141.1	White colour
RT/＜5％RH	0.1	～Ref	229.1	140.2	White colour
							25℃/60％RH	0.1	～Ref	229.1	139.0	White colour
RT/75％RH	0.1	～Ref	229.4	137.6	White colour
							Citric acid salt	Day 0	(*)	Ref	Amorphous form		With yellow color
RT/＜5％RH	(*)	(*)	(*)		Liquid for treating urinary tract infectionTransforming
						(+) -ditoluoyltartrate salt		Day 0	0.2	Ref	173.7	71.9	White colour
RT/＜5％RH	0.3	～Ref	175.6	78.7	White colour
							25℃/60％RH	0.1	～Ref	177.6	74.7	White colour
RT/75％RH	0.2	～Ref	178.6	70.8	White colour

Not assay

-Ref: exactly the same as the reference

During storage at different relative humidities, no change was observed between the tartrate, mandelate and (+) ditoluoyltartrate, and the IR spectra and DSC curve remained the same before and after storage, indicating that the product was crystal stable. Citrate is amorphous and liquefies under conditions of RT/75% RH.

c. Chemical stability

In the chemical stability test procedure, salts were stored for 2, 4 and 8 weeks at 40 deg.C/75% RH, 50 deg.C, sunlight, RT/5% RH, RT/75% RH, 25 deg.C/60% RH and artificial light. Mandelate and ditoluoyltartrate were also stored under 0.3daICH light for 8 hours. After storage the compounds were analysed by HPLC and visual inspection.

The results of these tests are shown in Table 2.

Table 2: results of chemical stability

Salt (salt)	Condition	Sum of HPLC impurities			Appearance of the product
								2 weeks	4 weeks	8 weeks	2 weeks	4 weeks	8 weeks
		Tartrate salt	Reference value	0.72	-	-	White colour
Artificial light	0.79							-	-	White colour
			40℃/75％RH	0.72	0.83	0.93	White colour						White colour	Almost white in color
50℃	0.72							0.77	0.79	White colour	White colour	Almost white in color
			Sunlight	0.75	0.85	0.91	White colour						Almost white in color	Slightly yellow
RT/＜5％RH	-							0.73	0.75		White colour	White colour
			25℃/60％RH	-	0.75	0.77							White colour	White colour
RT/75％RH	-							0.72	0.80		White colour	White colour
			Mandelate salt	Reference value	1.72	-	-						White colour
Artificial light	1.70	-						-	White colour
				0.3DaICH light	1.70	-	-					White colour
40℃/75％RH	1.73	1.73						1.70	White colour	White colour	White colour
				50℃	1.74	1.75	1.70					White colour	White colour	White colour
Sunlight	1.73	1.71						1.72	White colour	White colour	White colour
				RT/＜5％RH	-	1.73	1.72						White colour	White colour
25℃/60％RH	-	1.71						1.69		White colour	White colour
				RT/75％RH	-	1.75	1.76						White colour	White colour

Salt (salt)	Condition	Sum of HPLC impurities			Appearance of the product
								2 weeks	4 weeks	8 weeks	2 weeks	4 weeks	8 weeks
		Citric acid salt	Reference value	4.76	-	-	Yellow colour
Artificial light	8.99							-	-	Yellow brown
			40℃/75％RH	4.83	7.91	10.62	Liquefaction						Liquefaction	Liquefaction
50℃	6.29							7.47	9.07	Yellow brown	Yellow brown	Orange-brown
			Sunlight	5.81	5.99	6.31	Yellow brown						Yellow brown	Orange-brown
RT/75％RH	-							4.69	4.98	-	Liquefaction	Liquefaction
			(+) -ditoluoyltartrate salt	Reference value	1.01	-	-						White colour	-	-
Artificial light	1.57	-						-	White colour	-	-
				0.3DaICH light	1.41	-	-					White colour	-	-
40℃/75％RH	0.98	1.00						1.09	White colour	White colour	White colour
				50℃	1.06	1.22	1.25					White colour	White colour	White colour
Sunlight	1.26	1.65						1.74	White colour	White colour	White-yellow

Different versions of the chemical stability study gave the following observations:

the tartrate salt showed sensitivity to 40 ℃/70% RH and light as the total amount of impurities increased after storage at 40 ℃/70% RH and under both light conditions. Citrate showed degradation under all conditions studied.

(+) -ditoluoyltartrate showed sensitivity to temperature and light, as the total amount of impurities increased after storage at 50 ℃ and under both light conditions. Mandelate salts were chemically stable under all conditions studied.

In short, tartrate shows good adsorption and desorption properties, and the crystal is also stable but sensitive to higher humidity and light. Citrate is hygroscopic and liquefies at higher relative humidity during adsorption and desorption tests. Citrate is amorphous and chemically unstable and is sensitive to degradation under all storage conditions. (+) -ditoluoyltartrate, exhibits good adsorptive desquamation properties, is crystal stable but sensitive to temperature and light. Mandelate, on the other hand, shows good adsorption/desorption properties and is crystalline and chemically stable.

It has also been found that the stability of the salts increases with increasing purity, and furthermore, it is difficult to obtain a product of high purity from the prior art salts, and mandelate salts are often produced in high purity, so mandelate salts are preferred when selecting salts with sufficient stability.

Claims (10)

1. A mandelate salt of a compound of formula (I),

its N-oxide form and its stereochemically isomeric forms, wherein R¹And R²Each independently is hydrogen or C_1-6Alkyl radical, R³And R⁴Each independently of the other being hydrogen or halogen, C_1-6Alkyl represents straight-chain and branched-chain saturated hydrocarbon radicals having 1 to 6 carbon atoms and halogen represents fluorine, chlorineBromine and iodine.

2. Mandelate salt according to claim 1, characterized in that wherein R¹And R²Each independently hydrogen or methyl.

3. Mandelate salt according to any of claims 1 to 2, characterized in that wherein R³And R⁴Each independently hydrogen or fluorine.

4. A mandelate salt according to claim 1, characterized in that the compound is the mandelate salt of:

11-fluoro-3, 3a, 8, 12 b-tetrahydro-N-methyl-2H-dibenzo- [3, 4: 6, 7] cyclohepta [1, 2-b ] furan-2-methanamine;

3, 3a, 8, 12 b-tetrahydro-N-methyl-2H-dibenzo- [3, 4: 6, 7] cyclohepta [1, 2-b ] furan-2-methanamine;

5, 11-difluoro-3, 3a, 8, 12 b-tetrahydro-N, N-dimethyl-2H-dibenzo- [3, 4: 6, 7] cyclohepta [1, 2-b ] furan-2-methanamine;

11-fluoro-3, 3a, 8, 12 b-tetrahydro-N, N-dimethyl-2H-dibenzo- [3, 4: 6, 7] cyclohepta [1, 2-b ] furan-2-methanamine or

3, 3a, 8, 12 b-tetrahydro-N, N-dimethyl-2H-dibenzo- [3, 4: 6, 7] cyclohepta [1, 2-b ] furan-2-methanamine.

5. Mandelate salt according to any of claims 1 to 4, characterized in that the compound of formula (I) is the (2 α, 3a α, 12b β) isomer.

6. Mandelate salt according to any of claims 1 to 5, characterized in that the mandelate salt has the S-configuration.

7. Use of a mandelate salt according to any of claims 1 to 6 as a medicament.

8. The use of a compound according to any one of claims 1 to 7 for the manufacture of medicaments for the treatment of anxiety, psychosis, schizophrenia, depression, migraine, sleep disorders and addiction to drugs of abuse.

9. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and, as active ingredient, a therapeutically effective amount of a mandelate salt according to any of claims 1 to 7.

10. A process for the preparation of a mandelate salt according to any of claims 1 to 7, characterized in that the free base of the compound of formula (I) is dissolved in a suitable solvent, optionally the mixture is heated, sufficient mandelic acid is added, the reaction is cooled and the crystallized material is collected, optionally recrystallised in a suitable solvent to further purify the mandelate salt.