NO883674L - 5-HYDROXY-3-AMINOCROMAN COMPOUNDS, PROCEDURES ARE REQUIRED FOR PREPARATION, PHARMACEUTICAL PREPARATIONS CONTAINING THE COMPOUNDS AND METHODS OF TREATMENT THEREOF. - Google Patents

Description

The present invention relates to new 5-hydroxy-3-amino-chromans, enantiomers and salts thereof, methods for the production of such compounds, as well as new intermediates which are useful in the production of 5-hydroxy-3-amino-chromans. The invention further relates to pharmaceutical preparations containing the compounds and the use of the compounds in therapy.

An object of the invention is to provide compounds for therapeutic use, especially compounds which have a therapeutic activity via the central nervous system (CNS). Another purpose is to provide compounds which have a selective effect on the 5-hydroxytryptamine receptors in mammals, including humans.

In J. Med. Chem. Vol. 27, 1340-1343 (1984), 6,7-dihydroxy-3-aminochroman is described and stated to possess dopaminergic activity in the central nervous system.

In EP 0.041.488 tetralines are described with the formula:

where Y is hydroxy, and R<1> is alkyl with 1-8 carbon atoms, benzyl or phenethyl, and R<2> is hydrogen or alkyl with 1-5 carbon atoms. Such compounds are reported to have an effect on the 5-hydroxytryptamine neurons.

It has been found that compounds of the formula:

(I) where R<1>is a saturated or unsaturated alkyl group with 1-5 carbon atoms or a phenylalkyl group where the phenyl ring may be substituted or unsubstituted, and the alkyl group has 1-4 carbon atoms, R<2>is hydrogen or an alkyl group with 1- 5 carbon atoms, or R<1>and R22 together form a saturated or unsaturated 5- or 6-membered ring containing 1-2 hetero-atoms selected from N, 0 and S and enantiomers as well as physiologically acceptable salts thereof, possessing unexpected pharmacological properties that make them useful in central nervous system therapy, particularly in the serotonergic system and closely related systems.

The invention also provides compounds, enantiomers and physiologically acceptable salts thereof, which are useful in the therapeutic treatment of 5-hydroxytryptamine-mediated conditions and disorders such as depression, anxiety, anorexia, senile dementia, Alzheimer's disease, hypertension, thermo-regulatory and sexual disorders disturbances. A further feature of the invention relates to the use of the compounds and their salts in combating pain. Alkyl groups in formula (I) represent straight, branched and cyclic alkyl groups with 1-5 carbon atoms, e.g. methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, n-pentyl, i-pentyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, allyl, butenyl or pentenyl.

Possible substituted phenylalkyl group in formula (I) represents substituted or unsubstituted phenylalkyl, where the alkyl group is straight or branched alkyl with 1-4 carbon atoms, and the aromatic ring may be substituted with one or more of fluorine, chlorine, bromine, trifluoromethyl, methyl, ethyl, hydroxy, methoxy or ethoxy, preferably in the meta and/or para positions.

Examples of suitable 5- or 6-membered ring structures formed by R 1 , R 2 and the nitrogen atoms and containing N, O and S are piperazine and morpholine.

The compounds in the present invention have an asymmetric carbon atom in the oxygen-containing ring part, i.e. the ring carbon atom adjacent to the nitrogen atom. Thus, the compounds exist as two optical isomers, i.e. enantiomers. Both the pure enantiomers, racemic mixtures (50$ of each enantiomer) and various mixtures of the two are covered by the invention. The therapeutic properties of the compounds can be attributed to a greater or lesser extent to one or both of the two enantiomers present.

Both organic and inorganic acids can be used to form non-toxic, physiologically acceptable acid addition salts of the compounds of the invention. Illustrative acids are sulfuric acid, nitric acid, phosphoric acid, oxalic acid, hydrochloric acid, hydrobromic acid, citric acid, acetic acid, lactic acid, tartaric acid, pamoic acid, ethanedisulfonic acid, sulfamic acid, succinic acid, cyclohexylsulfamic acid, fumaric acid, maleic acid and benzoic acid. These salts can be readily prepared by methods known in the art.

Preferred compounds are those where R<*> is an alkyl group with 2-3 carbon atoms, and R<2> is hydrogen or an alkyl group with 2-3 carbon atoms. Further preferred are compounds where R<*> is n-propyl, and R<2> is hydrogen, ethyl or n-propyl.

Intermediate products

Some of the starting materials intermediates mentioned above and their pentaposition are known. However, intermediates for starting materials are novel and constitute a further aspect of the invention. Thus, according to one aspect, the invention relates to novel compounds of the formula:

where R<4> is hydrogen or saturated or unsaturated alkyl containing 1-5 carbon atoms or a phenylalkyl where the phenyl ring may be substituted or unsubstituted, and the alkyl group has 1-4 carbon atoms, R^ is hydrogen or saturated or unsaturated alkyl containing 1- 5 carbon atoms or a phenylalkyl where the phenyl ring may be substituted or unsubstituted and the alkyl group has 1-4 carbon atoms, R<2> is hydrogen or alkyl containing 1-5 carbon atoms, or R<2> and R^ together form a 5- or 6- membered ring containing one or two heteroatoms selected from N, O and S, provided that when R<4>is hydrogen, then R^ is hydrogen, as well as enantiomers and salts of said compounds, and methods for preparing said compounds or salts. Preferred intermediates are those where R<4> is a methyl group.

Some of the compounds of formula (IA) have activity on the 5-HT system in the CNS and are useful as therapeutic agents in the diseases indicated for compounds of formula (I).

Methods of manufacture

The compounds in the present invention can be prepared by one of the following methods which constitute a further aspect of the invention.

a) Cleavage of an ether with the formula:

where Ra represents a hydrocarbon residue, preferably an alkyl group having 1-5 carbon atoms, a benzyl or aryl group, and R<1> and R<2> have the meaning as indicated in formula (I), to form a compound with formula (I). The cleavage can be carried out by treating the compound of formula (II) with an acidic nucleophilic reagent such as aqueous HBr, or HI, HBr/CH3COOH, BBr3, AlCl3, pyridine-HCl or (CH3)3SiI, with a basic nucleophilic reagent such as CH3C^H4-S~ or C2H5-S<-.>

When Ra is a benzyl group, the cleavage can also be carried out by reduction, preferably with hydrogen using Pd or PtC>2 as catalyst.

b) N-alkylation of a compound of the formula:

where Ra is as defined in formula (II), R<b>is either R<1>or

R 2 , and R<1> and R<2> are as defined under formula (I), to a compound of formula (II), by alkylating the nitrogen atom with a suitable alkylating agent. Thus, the starting compound where ~ bP is R<2> can be treated with an alkyl, benzyl or phenethyl halide or tosylate R<1>X<1>, where X<1> represents Cl, Br, I or in an organic solvent such as acetonitrile or acetone and in the presence of a base such as K2CO3 or NaOH, or said starting compound can be treated with a carboxylic acid-NaBH^j complex R<e>C00HNaBH4, where Re is defined by the relation Re<->CH2~like R <1>. For the formation of a compound of formula (I) where at least one of R<1> and R<2> is CH3, the alkylation reaction can be carried out by treating the compound of formula (III) with a formaldehyde-Na(CN)BH3 mixture, or with formaldehyde and formic acid.

c) Reduction of an amide with the formula:

Jivor R<4>is hydrogen or R1 t R<c>is hydrogen or R<1>, where

R<1> is as defined in formula (I), and Rd is hydrogen or an alkyl group with 1-4 carbon atoms, e.g. by treatment with a hydride reducing agent such as LiAlH4i ether or tetrahydrofuran or BH<3>i tetrahydrofuran, to form a compound of formula (I) or (IA).

d) Catalytic reduction of a compound with the formula:

where R<4> and R<b> have the meanings given above, for the formation of a compound of formula (III) by treatment with e.g. H2/Pd. With appropriate values for R4 and bP, the obtained product also satisfies formula (I) or (IA).

e) Transformation of a compound with the formula:

where X represents SO 3 H, Cl or NH 2 , and R^- and R<2> have them

meanings given above, by substitution of the group X to a hydroxy group to form a compound of formula (I). When X is SO3H or Cl, said reaction can be carried out by treatment with a strong alkali under heating, suitably with an alkali melt such as KOH when X is SO3H, and with a strong aqueous alkali such as NaOH or KOH when X is Cl.

When X is NHg, the reaction can be carried out by treatment with aqueous sodium peracid to form a dizonium intermediate which is then subjected to hydrolysis in water.

f) Conversion with an enamine with either a C^-C2~ or a C2-C3 double bond or an imine base (without R2) or

immonium salt (e.g. CIO4- or BF4-) with a C2-N double bond of the formula:

where R<4>, r! and R<2> have the meanings given above, upon reduction to a compound of formula (I) or (IA), preferably by catalytic hydrogenation using PtO 2 or Pd as catalyst.

Free bases formed can then be converted into their acid addition salts, and acid addition salts formed can then be converted into the corresponding bases or other acid addition salts.

Production of intermediate products

The new intermediates of the general formula (IA) can be obtained by the methods described below or by methods known in the art.

i) The starting material for method a) with formula (II) can i.a. produced by the following procedure:

A compound of formula (IIA) is reacted by phenolic alkylation with L- or D-chlorocysteine to form a compound of formula (IIB), which is reacted with a phthalic anhydride to form a compound of formula (IIC). Compound (IIC) is cyclized by a Friedel-Craft acylation, preferably using aluminum chloride and thionyl chloride (AlC13/SO2C12) to a compound of formula (HD), which is reduced by catalytic hydrogenation preferably using Hg/Pd to form a connection with (HE). Then the compound (HE) is dephthaloylated using hydrazine (HgN-NHg) to form the L or D form of compound (HF). If a secondary or tertiary amine is desired, the compound (HF) is alkylated preferably with an alkyl halide such as alkyl bromide to a compound (II).

The intermediate product of formula (III) in the form of a primary amine can be prepared by the following methods. Corresponding secondary or tertiary amines included in formula (III) can be prepared from the primary amine of formula (II) by alkylation with an alkyl halide such as alkyl bromide to form the desired amine or by the methods indicated below. A compound of formula (HIA) is reacted with alkyl vinyl ether such as ethyl vinyl ether in the presence of trichloroacetic acid as a catalyst to form a compound of formula (UIB), which is reacted with butyllithium in dimethylformamide (BuLi/DMF) to form a compound of formula ( IIIC), whose protection is deprotected using HC1. Compound (IIID) is reacted by 1,4-addition of acrylonitrile in DABCO<®> followed by an intramolecular condensation to form a compound of formula (HIE), the compound is then alkali hydrolyzed to a compound (IIIF) and esterified with R ^OH, where R^ is a suitable alkyl group, followed by reduction preferably with Hg/ to form a compound of formula (IIIH). Compound (IIIH) is then reacted by a Curtius rearrangement, preferably using diphenyl phosphorazidate in the presence of trialkylamine, followed by addition of benzyl alcohol and reduction (Hg/Pd) to form a primary amine of formula

(III).

A compound of formula (IIIAa) is brominated to form a compound of formula (IIIJ) which is reacted by Friedel-Craft acylation, e.g. with CICOCHgCHgCl to form a compound of formula (HIK). The compound (HIK) is then cyclized in the presence of potassium carbonate to a compound (HIL) which is then treated with tert-butyl nitrite in the presence of t-BuO~K<+> to form a compound of formula (HIM) followed by reduction, preferably by use of Pd/BaSC^, HAIH 4 , to form a primary amine of formula (IA). Alternatively, the compound (HIL) can be reacted by a Neber reaction using e.g. of iso-CsHyONa and HAIH4 to form the compound of formula (IA), directly.

A compound of formula (IIIJ) is reacted by a 1,4-addition with equivalent vinylnitrile to form a compound (HIN) which is hydrolyzed (NaOH/KOH) to compound (UIO). Compound (UIO) is reacted by a Friedel-Craft acylation using PCI5/AICI3 to form a compound of formula (HIL) which is then reacted with tert-butylnitrile and tert.Bu~K<+> followed by reduction or by Neber- reaction described in method iii) to form a primary amine of formula (IA).

A compound of formula (HIP) is reacted with one equivalent of chloroethyl nitrite (C1CH2CH2N02) to form compound of formula (IIIQ) which is then catalytically hydrogenated to form the primary amine of formula (IA).

A compound of formula (HIR) is diazotized using diazomethane in the presence of thionyl chloride to form compound of formula (HIS), which is reacted with C2H50BF3 to form compound (HIT) which is reductively aminated to form the primary amine of formula (III) .

A compound of formula (UIO) is reacted with a Tl<3+> salt under alkaline conditions to form the adduct (IIIU) which is cyclized to (IIIY) and transferred to (IA) via tosylate and azide.

A compound of formula (VIIIA) is reacted with a nitrate to form a compound of formula (VIIIB) which is reduced to a primary amine of formula (IA).

The compound of formula (VIIIC) where L is a leaving group such as chloride, bromide or tosylate, reacts via a reaction with potassium phthalimide and subsequent formation of a primary amine of formula (IA) by treatment with hydrazirf and H2/Pd.

x) The starting material for method c) according to formula (IV) can be produced by the following methods:

A compound of formula (IVA) is reacted by a Neber rearrangement in three steps, e.g. in step a) NH20HXHC1 , in step b) tosyl chloride and in step c) CgHsONa, HC1 to form a compound of formula (IVB), which is then acylated with an acyl halide to compound (IVC). Compound (IVC) is catalytically hydrogenated (H2/Pd) to form a compound of formula (IV).

A compound of formula (HIT) is reacted with an amine such as R<C>H2 in the presence of acetic acid and molecular sieves or methylamine hydrochloride in the presence of NaOH to form an intermediate Imine which is reduced by catalytic reduction, preferably using PtO2 or Pd to form a primary or a secondary amine of formula (IA). When a tertiary amine is desired, compound (IA) is acylated with a carboxylic acid chloride in the presence of triethylamine, and then reduced to form the compound of formula (IV).

xii) The starting material for method d) according to formula (V) can be prepared as described above by benzylation of a primary amine of formula (IA) with a benzyl halide such as benzyl bromide or benzyl chloride followed by subsequent reduction with LIAIH4.

xiii) The starting material for method f) according to formula (VII) is five-staged as described in method xi) above.

Pharmaceutical preparations

Pharmaceutical preparations of the compounds in the present invention constitute a further aspect of the invention.

In clinical practice, the compounds of the present invention will normally be administered orally, rectally or by injection, in the form of pharmaceutical preparations comprising the active ingredient either as a free base or as a pharmaceutically acceptable, non-toxic acid addition salt, e.g. the hydrochloride, lactate, acetate, sulfamate, etc., in conjunction with a pharmaceutically acceptable carrier.

The designations relating to the new compounds in the present invention, either generically or specifically, are therefore intended to include both the free amine base and the acid addition salts of the free base, unless the context in which such designations are used, e.g. in the specific examples, would be inconsistent with the broad concept. The carrier may be a solid, semi-solid or liquid diluent or capsule. These preparations constitute a further aspect of the present invention. Generally, the active substance will constitute between 0.1 and 99% by weight of the preparation, more particularly between 0.5 and 20% by weight for preparations for injection, and between 0.2 and 95% by weight for preparations suitable for oral administration.

Pharmaceutical preparations containing a compound of the present invention in solid form of dosage units for oral use can preferably contain between 2 and 95% by weight of the active substance. In such preparations, the selected compound can be mixed with a solid, fine-grained carrier, e.g. lactose, sucrose, sorbitol, mannitol, starches such as potato starch, corn starch or amylopectin, cellulose derivatives or gelatin and lubricants such as magnesium stearate, calcium stearate, polyethylene glycol wax, etc., and then compressed to form tablets. If coated tablets are desired, the cores, prepared as described above, can be coated with a concentrated sugar solution which may contain e.g. gum arabic, gelatin, talc, titanium dioxide, etc. Alternatively, the tablet can be coated with a varnish dissolved in a slightly volatile organic solvent or mixture of solvents. Dyes can be added to these coatings to easily distinguish between tablets containing different active substances or different amounts of the active compound.

For the production of soft gelatin capsules (bead-shaped, closed capsules) consisting of gelatin and e.g. glycerol, or similar closed capsules, the active substance can be mixed with a vegetable oil. Hard gelatin capsules may contain granules of the active substance in combination with solid, fine-grained carriers such as lactose, sucrose, sorbitol, mannitol, starches (e.g. potato starch, corn starch or amylopectin), cellulose derivatives or gelatin.

Liquid preparations for oral use can be in the form of syrups or suspensions, e.g. solutions containing from approx. 0.2 to approx. 20% by weight of the active substance described herein, the rest being sugar and a mixture of ethanol, water, glycerol and propylene glycol. Optionally, such liquid preparations may contain dyes, flavourings, saccharin and carboxymethyl cellulose as a thickening agent.

Solutions for parenteral applications by injection can be prepared in an aqueous solution of a water-soluble, pharmaceutically acceptable salt of the active substance, preferably in a concentration from approx. 0.5 to approx. 10 weight #. These solutions can also contain stabilizing agents and/or buffering agents, and can suitably be provided in different dosage unit ampoules.

For therapeutic treatment, the suitable daily doses of the compounds of the present invention are 100-5,000 mg for oral use, preferably 500-3,000 mg, and 0.5-500 mg for parenteral use, preferably 25-250 mg.

The following examples further illustrate the invention.

Example 1

2- hydroxy- 6- methoxybenzaldehyde ( 4)

A mixture of 3-methoxyphenol (1) (114.5 g, 0.92 mol), ethyl vinyl ether (99.8 g, 1.38 mol), trichloroacetic acid (3.01, 0.18 mol) and chloroform (550 mL ) was stirred at room temperature for 1 20 hours. The reaction mixture was diluted with ether and extracted twice with 0.5 M NaOH and once with brine. The organic layer was dried (K2CO3) and evaporated. The obtained 1-[(1-ethoxy )-ethoxy]-3-methoxybenzene (2) was "lithiated" without further purification.

BuLi (1.6-M in n-hexane; 76 mL, 0.122 mol) was added dropwise at room temperature over 1 h to a mixture of 1-[(1-ethoxy)]-3-methoxybenzene (2) (12 .0 g, 0.061 mol) in dry ether (120 mL) whereby the mixture was stirred for 2 h under N 2 . Dimethylformamide (14.3 g, 0.02 mol) in dry ether (25 mL) was added slowly at 10°C over 1 hour, and stirring was continued for 2 hours. The reaction mixture was poured onto crushed ice and extracted three times with ether. The organic layer was dried (Na 2 SO 4 ) and evaporated to give 2-[(1-ethoxy)-ethoxy]-6-methoxy-benzaldehyde (3) as an oil. 2-M HCl was added dropwise to a stirred mixture of the obtained oil (11.9 g, 53 mmol) 1 MeOH. The precipitated product 2-hydroxy-6-methoxybenzaldehyde was filtered and recrystallized from n-hexane. Temp. 72-73°C, yield 10.6 g (78%).

Example 2

3- cyano- 5- methoxy- l. 2- benzopyrin ( 5)

A mixture of 2-hydroxy-6-methoxybenzaldehyde (4) (1.0 g, 66.6 mmol), acrylonitrile (1.74 g, 33.0 mmol) and DABCO® (0.16 g, 1.5 mmol) was refluxed for 2 hours. The reaction mixture was diluted with chloroform (10 mL) and extracted twice with saturated NaHCO 3 , once with dilute HCl and once with H 2 O. The organic layer became dried (Na 2 SO 4 ) and evaporated to give the desired compound which was recrystallized from EtOH-H 2 O (1:1), yield: 0.73 g (60$), m.p. 70.5-72.0°C.

Example 3

5- methoxy-l. 2- benzopyrln- 3- carboxylic acid ( 6)

3-cyano-5-methoxy-1,2-benzopyran (5) (25.0 g, 0.0133 mol) in 60 mL of 10% aqueous NaOH was refluxed for 2 h under a stream of nitrogen. Cooling the solution followed by acidification with hydrochloric acid (6M) gave 25.1 g (92$) of the desired compound. Recrystallization from ethanol-H 2 O gave yellow needles. Temp. 220-222°C.

Example 4

5- methoxyromane- 3- carboxylic acid ( 7 )

5-Methoxy-1,2-benzopyran-3-carboxylic acid (6) (30 g; 0.145 mol) was esterified by boiling in ethanol (400 mL) with sulfuric acid (5 mL) as catalyst. The excess of ethanol was evaporated and the ester obtained was extracted with ether. After drying and evaporation, 5-methoxy-1,2-benzopuran-3-carboxyethyl ether was obtained and characterized by NMR, and was used in the next step without further purification. A solution of the obtained ester (10% in ethanol) was then hydrogenated over 5% Pd/C at normal pressure and room temperature. When the calculated amount of H 2 had been absorbed (4 hours), the mixture was filtered and the solvent evaporated. The ester was treated with boiling KOH (122 g; 0.213 mol in ethanol/water 50+50) for 1 hour. On acidifying the alkaline solution, the saturated acid (7) was isolated as white crystals in 6% total yield (24 g). Temp. 171-173°C (from ethanol-H 2 O).

Example 5

3- amlno- 5- methoxyroman ( 8)

A mixture of 5-methoxy-chroman-3-carboxylic acid (7) (10.0 g; 0.048 mol), diphenyl phosphorazidate (16.6 g; 0.0603 mol), triethylamine (6.10 g; 0.0603 mol) In benzene (150 mL) was stirred under reflux for 2 hours. Benzyl alcohol (6.52 g; 0.0603 mol) was added and reflux was continued for another 24 hours. The mixture was evaporated and the residue was dissolved in toluene. The solution was washed successively with 5% citric acid, water, saturated NaHCO 3 and brine. Drying and evaporation gave an oil which crystallized from an ether solution. The crystalline 3-benzyloxycarbonyl-5-methoxychroman (6 g; 0.0192 mol) was dissolved in 1 methanol. A solution of hydrogen chloride gas in methanol (33 ml; 0.58-M) and a catalyst 5$ Pd/C (3 g) was added, the mixture was hydrogenated at room temperature and atmospheric pressure (3 hours). After filtration and evaporation, the remaining product is a colorless, viscous oil. The product was dissolved in water and after alkalization the free base was extracted with methylene chloride. After drying and evaporating the methylene chloride solution, the oil was converted to its hydrochloride and recrystallized from ethanol-ether. Temp. 237-238°C, yield 6.0 g ($70).

Example 6

5- methoxy- 3- propylaminochroman ( 9)

To a solution of 3-amino-5-methoxychroman (8) (2.0 g; 0.028) was added potassium carbonate (11.6 g; 0.084 mol) and a catalytic amount of sodium iodine. 1-Bromopropane (2.05 g, 0.017 mol) was added dropwise at 50°C with stirring. Stirring was continued for 5 hours at 50°C. The mixture was cooled and diluted with water (300 mL). The solution was extracted twice with ether. After drying (NagSO 4 ) and evaporation of the organic solvent, the desired product was obtained in 89% yield (6.6 g). The product was precipitated as the hydrochloride salt and recrystallized from ethanol/acetonitrile. Temp. 194-195°C.

Example 7

3- dlpropylamino- 5- methoxyromane ( 11)

This compound was obtained from 3-amino-5-methoxychroman (8) (2.8 g; 0.0156) in the same manner as described in Example 6. Yield: 3.28 g as base (80$). Its hydrochloride salt melted at 137-139°C (from ethanol-ether).

Example 8

5- hydroxy- 3- propylaminochroman ( 10)

A solution of BBr (500 mg; 1.0 mmol) in CH 2 Cl 2 was added dropwise to an ice-cooled solution of 5-methoxy-3-propylaminochroman (9) (150 mg; 0.569 mmol) in CH 2 Cl 2 (20 mL) over 10 min. . Stirring was continued for an additional 1 hour at 0°C. The mixture was poured onto ice, and NaCl, concentrated with NH 4 OH and NaCl, and extracted twice with CH 2 Cl 2 . The collected organic phases were dried and evaporated. The remaining colorless oil was crystallized as the hydrochloride salt. Yield: 90 mg ($76) (from ethanol-ether), m.p. 172-174°C.

Example 9

3- dipropylamino- 5- hydroxychroman ( 12)

This compound was prepared from 3-dipropylamino-5-methoxychroman (11) (1.85 g; 0.007 mol) in the same manner as described in Example 8. The demethylation was complete after 5 minutes of stirring at 0°C. Yield 1.5 g as base ($86).

Example 12

(+)- 3- di- propylamino- 5- hydroxychroman hydrochloride ( 23)

The hydrochloride was prepared by adding HCl-ether (3M) to the base (16) dissolved in acetonitrile.

Yield: 1.2 g ($74) of compound (22) as white crystals.

Temp. 237-238°C (decomposition) [α]D<5>= 22.8° [C = 0.5 methanol].

Example 13

(-)- 3- di- propylamino- 5- hydroxychromane hydrochloride ( 24)

Prepared from the (-)-base (15) which (23) gave.

Yield: 1.0 g ($71) as white crystals.

Temp. 235-236°C (decomposition) [α]D<5>= -23.0 [C = 0.5, methanol].

Example 14

3- ethylpropylamlno- 5- methoxyromane ( 17)

A mixture of 3-N-ethylpropylamino-5-methoxychroman (0.7 g; 3.2 mmol), bromoethane (1.0 g; 8.1 mmol), K2CO3 (2.9 g; 14 mmol), DMF ( 15 ml) and a catalytic amount of Kl, was stirred at 70°C overnight. 100 ml of ether was added to the product and washing was carried out with 5 x 25 ml of water. Flash chromatography (SiO 2 /diisopropyl ether) gave 0.5 g (63$) of compound (17) as a light brown oil. Gas chromatography showed 98$ purity. The hydrochloride did not crystallize and was therefore used directly in the demethylation step.

MS (70 eV): m/z 249 48$ M-29 100$.

Example 15

3- ethylpropylamino- 5- hydroxychroman ( 18)

0.6 g (2 mmol) of 3-N-ethylpropylamino-5-methoxyromane hydrochloride was dissolved in CHgClg, and to this was added 5 ml (5 mmol) of 1 M BBr3 solution in CHgClg. Conventional workup afforded 0.4 g ($80) of compound (18) as a colorless oil. The hydrochloride was crystallized from CH 3 CN to give 0.3 (60%) of white crystals. Temp. 194-196°C (decomposition).

Example 16

3- propylphenethylamino- 5- methoxyromane ( 19)

A mixture of 3-amino-5-methoxychroman (0.5 g; 3 mmol), (2-bromomethyl)benzene (0.5 g; 3 mmol), K 2 CO 3 (1 g; 7 mmol) and DMF (3.5 mL ) was stirred at 70°C overnight. Gas chromatography indicated 100% of new product, and workup gave 0.8 g of a brown oil. To the crude oil was added 1 g of 1-bromopropane, 1 g of KgCO;}, 3 ml of DMF and catalytic amounts of Kl. The mixture was stirred at 70°C. Extraction and flame chromatography (SiCl 2 diisopropyl ether) gave 0.5 g of compound (14) as a colorless oil with 98% purity by gas chromatography.

MS CI (70 eV): m/z + 1,326 ($100), 234 ($7).

Example 17

3- propylphenethylamino- 5- hydroxychroman ( 20 )

The oil (5) (0.5 g, 0.0015 mol) was dissolved in ether and an excess of 3.5 M HCl in ether was added. An oil was formed. The ether was distilled off, and the oil was dissolved in 1 CH 2 Cl 2 (3 mL) and 4.5 mL (0.0045 mol) of 1 M BBr in CH 2 Cl 2 was added.

Yield 0.2 g (40$) of compound (20) as hydrochloride in the form of white crystals.

MS EI (70 eV): 220 (m/z-91) ($100)

Temp. 258-260°C.

Example 18

3-(4-Fluorobenzyl)propylamino-5-methoxycromane (21)

0.5 g (0.002 mol) of 3-propylamino-5-methoxyromane hydrochloride was mixed with 0.5 g (0.003 mol) of 4-fluorobenzyl bromide, 3 ml of DMF, 0.7 g (0.005 mol) of K2CO3 and catalytic amounts of Kl. The mixture was stirred at 70°C for 6 hours. The yield after work-up was 0.7 g of a light brown oil (21). Gas chromatography indicates 100$ purity. The oil was used directly without any further purification in the demethylation step.

Example 19

, 3-(4-fluorobenzyl)propylamino-5-hydroxychroman (22)

Demethylation according to standard methods gave 0.5 g (63$) of a colorless oil with a purity of 100$ according to gas chromatography.

MS EI (70 eV): m/z 315 (12$), 109 (100$), 286 (29$).

Example 20

3- butylpropylamino- 5- methoxyromane ( 23)

A mixture of 5-methoxy-3-propylaminochroman (9) (0.43 g; 1.9 mmol), iodobutane (0.54 g; 2.9 mmol), K 2 CO 3 (0.54 g; 3.9 mmol) and DMF (1 mL) was stirred at 50°C for 26 h. To the mixture was added 20 ml of H 2 O, and extraction was carried out three times with ether (dried and evaporated). Chromatotron chromatography (S102:chloroform/n-hexane/ethanol/NH3(aq), 60:38:2:0.05) gave 0.51 g (95$) of compound (23) as an oil. Gas chromatography showed 98$ purity, and NMR confirmed the correct structure. The base was used directly in the demethylation step.

Example 21

3- butylpropylamino- 5- hydroxychroman ( 24)

0.49 g (1.8 mmol) of 3-butylpropylamino-5-methoxyromane was dissolved in CH 2 Cl 2 (50 mL) and BBr 3 (4.9 mL; 5.3 mmol) in CH 2 Cl 2 (55 mL) was added to an ice-cooled solution of 3-amino-butylpropyl-8-methoxyromane in CH 2 Cl 2 (50 ml). After stirring for 3 hours, a conventional workup afforded 0.48 g ($100) of the desired compound (24) as a brown oil. The hydrochloride was recrystallized from isopropanol/isopropyl ether to give 0.49 g, m.p. 166.9-168.1°C.

Pharmacology

Pharmacological treatment of depression in humans

There is evidence that nerve transmission in the central nervous system (CNS) in depressed patients can be disrupted. These disturbances appear to involve the neurotransmitters norepinephrine (NA) and 5-hydroxytryptamine (5-HT). The drugs most commonly used in the treatment of depression are considered to work by improving the neurotransmission of one or both of these physiological agonists. Available data suggest that the increase in 55-HT neurotransmission will primarily improve the depressed mood and anxiety, while the increase in norepinephrine neurotransmission will instead improve the retardation symptoms that occur in depressed patients. In recent years, efforts have been made to develop new drugs with high selectivity for the preparation of 5-HT neurotransmission in the CNS.

The mechanism of action of the drugs generally used today in the therapy of mental depression is indirect, i.e. they work by blocking the reuptake of the neurotransmitters (NA and/or 5-HT) released from nerve terminals in the CNS, thus increasing the concentration of these transmitters in the synaptic cleft and therefore restores an adequate neurotransmission.

A fundamentally different way to improve neurotransmission in the central 5-HT neurons would be to use a direct 5-HT receptor agonist. In order to minimize side effects, a high selectivity for this type of receptor would then be preferable.

Surprisingly, it has been found that a group of compounds of formula (I) has a selective, direct stimulating effect on central 5-HT receptors. To assess the 5-HT receptor-stimulating effect and selectivity, the effects on pre-; different receptors in rat brain measured in vitro using receptor assays (IC50nM).

In vitro test: Receptor binding assay

Method

The method of Peroulka & Snyder (Mol. Pharmacol. 16, 687-699, 1979) was used. Male Sprague-Dawley rats weighing 150-200 g were euthanized, and their brains were rapidly removed. Striata were dissected, pooled, and homogenized in 50 mM Tris-HCl buffer (pH 7.6). The membrane fraction was collected by centrifugation (48,000 g 1 10 min.), washed once with the buffer, and resuspended in 50 mM tris-HCl (pH 7.6) containing 0.1% ascorbic acid, 10 mM paragyline, 120 mM NaCl , 5 mM KCl, 2 mM CaCl 2 and 1 mM MgCl 2 . The suspension was preincubated at 37°C for 1 10 min. and then kept on ice until use.

The analyzes were performed using a cell harvesting device. Incubations were performed in 4 replicates, each containing membrane suspension<3>H-spiperone (0.4 nM) or<3>H-5-HT (5 nM), and test compound in a final volume of 0.5 ml. After incubation for 10 min. at 37°C, the contents of the wells were rapidly filtered and washed on Whatman GF/B filters using the cell harvester. The specific binding was defined as the difference for radioligand bound in the presence and in the absence of a specific displacer (d-LSD, 1 pM and 5-HT, 10 µM for<3>4-spiperone and<3>H-5-HT, respectively). The test results are expressed as IC50. The ICso value is given in nM, and indicates the concentration of the test substance which reduces the amount of specific bound radioligand by 50%.

Test result

3-Di-propylamino-5-hydroxychroman was inactive in <3>H-spiro7peridol (Dopamine-D2) and <3>H-Ketanserin (5-HT2) receptor binding studies, while it was active in <3>H-5 -HT (5-HT}), showing an IC50 of 0.083 pM.

These pharmacological data confirm that the aminochromans of the present invention are very effective centrally acting 5-HT receptor stimulants with high selectivity for certain 5-HT receptors in relation to DA and NA receptors. Because of. this unique pharmacological profile is the compounds of great clinical interest in the treatment of certain disorders of the CNS such as depression and anxiety. Further potential uses of the new compounds are the fight against pain, where 5-HT has been shown to be involved, and 1 senile disturbances of movement and metal function, e.g. senile dementia, where a reduced level of cardiac 5-HT has been demonstrated.

Best method for carrying out the invention

The compounds 3-(di-propylamino)-5-hydroxychroman and 3-ethylpropylamino-5-hydroxychroman and their optical enantiomers and salts, methods for producing said compounds and methods for using said compounds in therapy represent the best way of carrying out the invention as the inventors of which time knows.

Claims (28)

1. Compound, characterized by the formula: where R <1> is a saturated or unsaturated alkyl group with 1-5 carbon atoms or a phenylalkyl group, where the phenyl ring may be substituted or unsubstituted, and the alkyl group has 1-4 carbon atoms, R <2> is hydrogen or an alkyl group of 1-5 carbon atoms, or R* and R <2> together form a 5- or 6-membered ring Containing one or two heteroatoms selected from N, 0 and S, and enantiomers and physiological acceptable salts thereof. 2. Compound according to claim 1, characterized in that R <*> and R <2> are the same or different and selected from ethyl and n-propyl. 3. Compound, characterized in that it consists of 3-dipropylamino-5-hydroxychroman, enantiomers and physiologically acceptable salts thereof. 4. Process for producing a compound with formula (1) according to claim 1, characterized in that: a) cleaving an ether with the formula: where R a represents a hydrocarbon residue, and R 2 and R 22 have the same meanings as defined under formula (I), to form a compound of formula (I), b) N-alkylates a compound with the formula: where Ra has the same meaning as stated under formula (II), R <b> is either R <1> or R <2> , where R21 and R <2> have the same meanings as stated under formula (I), to a compound of formula Jl) with a suitable alkylating agent, c) reduces a compound with the formula: where R<4> is hydrogen, orR<1>, R<c> is hydrogen orR<1>, where R<1> has the same meaning as under formula (I), and Rd is hydrogen or an alkyl group with 1- 4 carbon atoms, formation of a compound with (I) with a suitable reducing agent, d) catalytically reduces a compound of the formula: where R <4> and R*1 have the meanings given above, to form a compound of formula (I), e) transforms a compound with: where X represents SO3 H, NH2 or Cl, and R<1> and R<2> are as defined under formula (I) by substitution of the group X to a hydroxy group to form a compound of formula (I), f) converts an enamine with either a C^ -Cg or a C2 -Cs double bond or an imine base (without R <2> ) or immonium salt (e.g. C104 or BF4 ) with a C2 -N double bond with the formula : where R <4> , R21 and R <2> have the meanings given above, by reduction to a compound of formula (I) or (IA), preferably by catalytic hydrogenation, after which an obtained base is optionally converted to a physiologically acceptable acid addition salt or an obtained salt is converted to the base or to a different, physiologically acceptable acid addition salt, and an obtained isomeric mixture is optionally separated into a pure isomer. 5. Pharmaceutical preparation, characterized in that it contains as active ingredient a compound according to any one of claims 1-3, an enantiomer or a physiologically acceptable salt thereof. 6. Method for treating disorders in the central nervous system, in particular 5-hydroxytryptamine-mediated disorders, characterized in that a compound as defined in claims 1-3, an enantiomer or a physiologically acceptable salt thereof is administered to mammals and humans. 7. Method according to claim 6, characterized in that it is performed for the treatment of depression, anxiety, anorexia, hypertension, senile dementia, thermoregulatory and sexual disorders. 8. Method according to claim 6, characterized in that it is carried out for the treatment of pain. 9. Compound according to any one of claims 1-3, characterized in that it is an enantiomer or a physiologically acceptable salt thereof, for use in therapy. 10. Compound according to claim 9, characterized in that it is intended for use in the treatment of depression, anxiety, anorexia, senile dementia, hypertension, thermoregulator and sexual disorders. 11. Compound according to claim 9, characterized in that it is intended for use in the treatment of pain. 12. Use of a compound according to claims 1-3 for the production of a medicinal product for the treatment of disorders in the central nervous system, in particular 5-hydroxytryptamine-mediated disorders. 13. Use according to claim 12, for the production of a medicine for the treatment of depression, anxiety, anorexia, senile dementia, hypertension, thermoregulatory and sexual disorders. 14. Use according to claim 12 for the production of a drug for the treatment of pain. 15. Compound, characterized by^ the formula; where R <4> is hydrogen, saturated or unsaturated alkyl containing 1-5 carbon atoms or a phenylalkyl where the phenyl ring may be substituted or unsubstituted, and the alkyl group has 1-4 carbon atoms, R <3> is hydrogen or saturated or unsaturated alkyl containing 1-5 carbon atoms, or a phenylalkyl, where the phenyl ring may be substituted or unsubstituted, and the alkyl group has 1-4 carbon atoms, R <2> is hydrogen or alkyl containing 1-5 carbon atoms or R <2> and R <3> together form a 5- or 5-membered ring contain 1 or 2 heteroatoms selected from N, 0 S, provided that when R <4> is hydrogen, then R <3> is hydrogen, enantiomers and salts thereof. 16. Compound according to claim 15, characterized in that R<4> is methyl. 17. Compound according to claim 15-16, characterized in that R <2> and R <3> are the same or different, and selected from ethyl and n-propyl. 18. Pharmaceutical preparation, characterized in that it contains as active ingredient a compound according to claim 15, an enantiomer or a physiologically acceptable salt thereof. 19. Method for treating disorders in the central nervous system, especially 5-hydroxytryptamine-mediated disorders, characterized in that a compound according to claim 15, an enantiomer or a physiologically acceptable salt thereof is administered to mammals and humans. 20. Procedure According to claim 15, characterized in that it is intended for the treatment of depression, anxiety, anorexia, hypertension, senile dementia, thermoregulatory and sexual disorders. 21. Method According to claim 15, characterized in that it is intended for the treatment of pain. 22. Compound according to claim 15, characterized in that it consists of an enantiomer or a physiologically acceptable salt thereof, for use in therapy. 23. Compound according to claim 15, characterized in that it is intended for use in the treatment of depression, anxiety, anorexia, senile dementia, hypertension, thermoregulatory and sexual disorders. 24. Compound according to claim 15, characterized in that it is intended for use in the treatment of pain. 25. Use of a compound according to claim 15 for the production of a medicinal product for the treatment of disorders in the central nervous system, in particular 5-hydroxytryptamine-mediated disorders. 26. Use according to claim 15 for the manufacture of a drug for the treatment of depression, anxiety, anorexia, senile dementia, hypertension, thermoregulatory and sexual disorders. 27. Use according to claim 15 for the production of a medicine for the treatment of pain. 28. Compounds, methods, pharmaceutical preparations, use and methods of treatment as defined in any of claims 1-27, and substantially as described. Nve patent claim B 85607 1. Procedure for the preparation of a compound of formula: where R <1> is a saturated or unsaturated alkyl group with 1-5 carbon atoms or a phenylalkyl group, where the phenyl ring may be substituted or unsubstituted, and the alkyl group has 1-4 carbon atoms, R is hydrogen or an alkyl group with 1-5 carbon atoms, or R ^- and R <2> together form a 5- or 6-membered ring containing one or two heteroatoms selected from N, 0 and S, and enantiomers and physiologically acceptable salts thereof, characterized by the fact that mana) splits an ether with the formula: where Ra represents a hydrocarbon residue, and R<1> and R22 have the same meanings as defined under formula (I), to form a compound of formula (I), b) N-alkylates a compound with the formula: f where Ra has the same meaning as stated under formula (II), R <b> is either R <1> or R <2> , where R21 and R <2> have the same meanings as stated under formula (I), to a compound of formula (I) with a suitable alkylating agent, c) reduces a compound with the formula: where R <4> is hydrogen, or R <1>, R c is hydrogen or R3-, where R <1> has the same meaning as under formula (I), and Rd is hydrogen or an alkyl group with 1-4 carbon atoms , to form a compound with (I) with a suitable reducing agent, d) catalytically reduces a compound with the formula: where R<4> and R13 have the meanings given above, to form a compound of formula (I),e) converts a compound with: where X represents SO3 H, NHg or Cl, and R <1> and R <2> are as defined under formula (I) by substitution of the group X to a hydroxy group to form a compound of formula (I),f) converts an enamine with either a C^ -Cg- or a Cg-C3~ double bond or an imine base (without R <2> ) or immonium salt (e.g. CIO4 or BF4 ) with a Cg-N double bond of the formula: where R <4> , R21 and R <2> have the meanings given above, by reduction to a compound of formula (I) or (IA), preferably by catalytic hydrogenation, after which an obtained base is optionally converted to a physiologically acceptable acid addition salt or an obtained salt is converted to the base or to a different, physiologically acceptable acid addition salt, and an obtained isomeric mixture is optionally separated into a pure isomer. 2. Process according to claim 1, characterized in that R <1> and R <2> are the same or different and selected from ethyl or n-propyl. 3. Method, characterized in that it consists of 3-dipropylamino-5-hydroxychroman, enantiomers and physiologically acceptable salts thereof. 4. Use of a compound according to claims 1-3 for the production of a medicinal product for the treatment of disorders in the central nervous system, in particular 5-hydroxytryptamine-mediated disorders. 5. Use according to claim 4, for the production of a drug for the treatment of depression, anxiety, anorexia, senile dementia, hypertension, thermoregulatory and sexual disorders. 6. Use according to claim 4 for the production of a medicine for the treatment of pain. 7. Compound, characterized by the formula; where R <4> is hydrogen, saturated or unsaturated alkyl containing 1-5 carbon atoms or a phenylalkyl where the phenyl ring may be substituted or unsubstituted, and the alkyl group has 1-4 carbon atoms, R <3> is hydrogen or saturated or unsaturated alkyl containing 1-5 carbon atoms, or a phenylalkyl, where the phenyl ring may be substituted or unsubstituted, and the alkyl group has 1-4 carbon atoms, R <2> is hydrogen or alkyl containing 1-5 carbon atoms or R <2> and R <3> together form a 5- or 5-membered ring Contain 1 or 2 heteroatoms selected from N, OS, provided that when R <4> is hydrogen, then R <3> is hydrogen, enantiomers and salts thereof. 8. Compound according to claim 7, characterized in that R <4> is methyl. 9. Compound according to claim 7-8, characterized in that R<2> and R<3> are the same or different, and selected from ethyl and n-propyl. 10. Use of a compound according to claim 7 for the production of a medicinal product for the treatment of disorders in the central nervous system, especially in 5-hydroxytryptamine-formulated disorders, as well as for the treatment of depression, anxiety, anorexia, senile dementia, hypertension, thermoregulatory and sexual disorders, and pain.