WO1996031512A1

WO1996031512A1 - Benzopyranopyrrole compounds, their preparation and use

Info

Publication number: WO1996031512A1
Application number: PCT/DK1996/000157
Authority: WO
Inventors: Marit Kristiansen; Mark Scheideler
Original assignee: Novo Nordisk A/S
Priority date: 1995-04-06
Filing date: 1996-04-01
Publication date: 1996-10-10
Also published as: AU5272296A

Abstract

Benzopyranopyrrole compounds of formula (I) wherein R1 is hydrogen, alkyl optionally substituted, cycloalkyl, alkenyl or allyl optionally substituted; and R2, R3 are the same or different and independently are hydrogen, alkyl, aralkyl or phenyl; and R4 is hydrogen, halogen, trifluoromethyl, alkyl or cyano; and R?5, R6, R7¿ are the same or different and independently are hydrogen, hydroxy, alkoxy, O-acyl, halogen, trifluoromethyl, alkyl, triflate, cyano, carbamoyl or amine optionally substituted, are useful in the treatment of central nervous system ailment related to dysfunction of the central dopamine system.

Description

Benzopyranopyrrole compounds, their preparation and use

The present invention relates to the therapeutically active benzopyrano¬ pyrrole compounds, a method of preparing the same, pharmaceutical compositions comprising the compounds, and their use in therapy, e.g. in treatment of central nervous system ailments, more precisely diseases related to dysfunction of the central dopamine system, for example Parkinson's disease, psychoses, depression, drug abuse, pain, neurode- generative diseases, schizophrenia, appetite regulation and obesity control.

Dopamine receptors may be divided into D1 -dopamine and D2-dopamine receptor families. The D2s and D3 dopamine receptors are subtypes of the D2-dopamine receptor family. Compounds capable of binding selec¬ tively to D3 receptors are well known in the art (see, e.g. Sokoloff et al. , ature 347 ( 1 990) 146).

It has now been found that members of a novel group of benzopyrano- pyrroles have high affinity for dopamine D3-receptors, which makes them useful in psychopharmaceutical preparations.

Accordingly, the present invention relates to benzopyranopyrrole com¬ pounds of the general formula I

(I)

and pharmaceutically acceptable acid addition salts and hydrates thereof, wherein R¹ is hydrogen, C _β-alkyl optionally substituted with phenyl, thiophene or naphthalene, or R¹ is cycloalkyl, alkenyl or ally! optionally substituted with halogen; and R², R³ are the same or different and independently are hydrogen, C,^- alkyl, aralkyl or phenyl; and

R⁴ is hydrogen, halogen, trifluoromethyl, C-,._β-alkyl or cyano; and R⁵, R⁶, R⁷ are the same or different and independently are hydrogen, hydroxy, C-.g-alkoxy, O-acyl, halogen, trifluoromethyl, C,._e-alkyl, triflate, cyano, carbamoyl or amine optionally substituted with C-.g-alkyl.

Pharmaceutically acceptable acid addition salts include inorganic salts such as hydrochloride, hydrobromide, sulphate, phosphate and nitrate, and organic salts such as maleate, fumarate, benzoate, and tartrate. If desirable, selected salts may be subjected to further purification by recrystallization.

The compounds of this invention have asymmetric carbon atoms as well as cis and trans-isomers. The present invention includes within its scope all such eπantiomers, stereoisomers, and mixtures, including racemic mixtures.

The term

as used herein refers to a straight or branched, saturated hydrocarbon chain having 1 -6 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert. butyl, n-pentyl, sec-pentyl, n-hexyl, 2,2-dimethylpropyl, and the like.

The term "cycloalkyl" as used herein refers to a saturated carbocyclic ring having from 3 to 7 carbon atoms such as cyclopropane, cyclobu- tane, cyclopentane, cyclohexane or cycloheptane, and the like. The term "alkenyl" as used herein refers to straight or branched carbon chains having at least one carbon-carbon double bond and containing from 2 to 6 carbon atoms such as ethenyl, 1 -propenyl, 2-butenyl, etc.

The term "aralkyl" as used herein refers to an alkyl chain of 1 to 6 carbon atoms substituted with phenyl or naphthyl. Examples of such aralkyl groups are benzyl, phenethyl, 1 -naphtylmethyl, etc.

The term

as used herein refers to a substituent comprising a

group linked through an ether oxygen. Examples of such

alkoxy groups are methoxy, ethoxy, propoxy, butoxy, pentoxy, etc.

The term O-acyl as used herein refers to groups R⁸-C( = O)- wherein R⁸ is C_1-β-alkyl. Examples of such O-acyl groups are acetoxy, propionyloxy, butyryloxy, and the like.

The term halogen as used herein refers to fluorine, chlorine, bromine or iodine.

• In a preferred embodiment of the invention, R¹ represents propyl or allyl, 'Λ² and R³ represent hydrogen and R⁴ represents hydrogen or halogen.

In another preferred embodiment of the invention at least one of R⁵, R^β or R⁷ is hydroxy and the others or R⁵, R⁶ and R⁷ are selected from halogen or hydrogen.

Preferred compounds of the invention are:

Cis-8-Methoxy-3-propyl-1 ,2,3,3a,4,9b-hexahydro-_1 _benzopyrano[3,4-b]- pyrrole,

6-Methoxy-3-propyl-1 ,2,3,3a,4,9b-hexahydro-[1 ]benzopyrano[3,4-b_pyr- role, Cis-8-Hydroxy-3-propyl-1 ,2,3,3a,4,9b-hexahydro-[1 ]benzopyrano[3,4-b]- pyrrole,

6-Hydroxy-3-propyl- 1 ,2, 3,3a, 4,9b-hexahydro-_1 _benzopyrano[3,4-b]pyr- role, and salts hereof.

The invention also relates to methods of preparing the above-mentioned compounds. These methods comprise:

a) reacting a compound of formula II

wherein R⁴, R⁵, R⁶ and R⁷ are as defined above, with an amine NH₂R\ wherein R¹ is as defined above to form a compound of formula III

wherein R\ R⁴, R⁵, R^β and R⁷ are as defined above. The reaction is generally carried out in a non-protic solvent e.g. dichloromethane in the presence of a dehydrating agent such as molecular sieve or a Lewis' acid such as titanium(IV) chloride, and reacting the compound of formula III with a compound of formula IV:

R² R³

(IV)

X

wherein R² and R³ have the meaning set forth above and X and Y repre¬ sent leaving groups, to form a compound of the general formula V

wherein R\ R², R³, R⁴, R⁵, R⁶ and R⁷ are as defined above.

Each of the leaving groups X and Y, may be any suitable leaving group, for example halogen. The reaction is preferably carried out under alkaline conditions, i.e. , in the presence of a base, and among bases magnesium halogen alkyles are preferred.

Subsequently, the compound of formula V may be reduced to form a compound of the general formula I. The reduction is generally carried out using a reducing catalyst such as Platinum(IV) oxide in a hydrogen atmosphere.

b) Halogen-substituted compounds of formula I can be made by substitu- tion of one or more hydrogen atoms by action of a halogenating agent, such as bromine, chlorine or iodine in acetic acid, or such as sulphuryl chloride, to give the compounds of formula I, wherein one or more of the substituents R⁴, R⁵, R⁶ and R⁷ are chlorine, bromine or iodine.

c) Reacting a compound of formula VI

wherein R², R³, R\ R⁵, R⁶ and R⁷ are as defined above, with R¹Y, where¬ in R¹ is as defined above and Y is a leaving group, to form a compound of formula I.

The leaving group Y, may be any suitable leaving group as for example halogen.

d) Reacting the compound of formula II

wherein R⁴, R⁵, R^β and R⁷ are as defined above, with pyrrolidine to form a compound of formula VII

wherein R⁴, R⁵, R⁶ and R⁷ are as defined above. The reaction is generally carried out in a non-protic solvent, e.g. toluene in the presence of a dehydrating agent, such as p-toluenesulphonic acid, and reacting the compound of formula VII with a compound of formula VIM

wherein R² and R³ has the meaning set forth above, to form a compound of formula IX

wherein R², R³, R⁴, R⁵, R⁶ and R⁷ are as defined above.

The leaving group Y, may be any suitable leaving group as for example halogen.

Subsequently the compound of formula IX may be reduced to form a compound of the formula VI, wherein R², R³, R⁴, R⁵, R⁶ and R⁷ are as defined above. The reduction is generally carried out using Lithium aluminum hydride and a reducing catalyst such as Platinum(IV) oxide in a hydrogen atmosphere. The formed compound of formula VI is hereafter treated as described in method c) .

When a compound of formula I is obtained as a mixture of enantiomers these may be separated by conventional methods such as crystallization in the presence of a resolving agent or chromatography, for example using a chiral HPLC column.

When the reaction products contain protective groups, these may be removed by catalytic reduction (e.g. catalytic hydrogenation) or by treatment with lithium diphenylphosphide, boron tribromide, hydrobromic acid, trimethylsilyl iodide or hydroiodic acid.

The starting materials employed in the syntheses of the compounds of formula I are either known or may be prepared in conventional manner from commercially available materials, e.g. according to Wise et al.,

J.Med.Chem. 3J_ (1988) 688.

In another aspect the invention relates to a compound of the general formula I or a pharmaceutically acceptable acid addition salt thereof for use as a therapeutically acceptable substance, preferably for use as a therapeutically acceptable substance in the treatment of central nervous system ailments. Furthermore, the invention also relates to the use of the inventive com¬ pounds of formula I as medicaments useful in the treatment of central nervous system ailments, especially related to dysfunctions of the central dopamine system, such as Parkinson's disease, psychoses, depression, drug abuse, pain, neurodegenerative diseases and schizo¬ phrenia.

The pharmacological properties of the compounds of the invention can be illustrated by determining their ability to bind at Dopamine D3- and D2s-receptors.

Detailed conditions for the assays are described below:

In Vitro Assay of Dopamine-D2s Receptor Binding

The structural gene for the human Dopamine-D2s receptor has previously been cloned and stably expressed in a mammalian Ltk^" cell line (Bunzow,

J.R. et al. (1988) Nature 316, 783-787; Neve, K.A. et al. (1989) Mol.

Pharm. 3_6, 446-451 ). The dopamine-D2s receptor is stably expressed to high levels as a single binding site for the dopamine-D2 ligand [³H]Spipe- rone. Further, the expressed receptor is negatively coupled to adenylyl cyclase.

In order to stably transfect Ltk^" cells the dopamine-D2s structural gene was cloned into the pZEM3 plasmid and co-transfected into Ltk^' cells with the plasmid pRSVneo. The antibiotic G-418 is used to maintain selection for the Neomycin resistance gene on the pRSVneo plasmid and is normally included (0.5 mg/ml) in the cell growth media (Dulbeccos Modified Eagles Media containing 10% fetal bovine serum (v/v) and 1 % Pencillin/Streptomycin (w/v)).

Cell membranes used in measurements of specific [³H]Spiperone binding are prepared from confluent plates of cells at 0-4°C by hypotonic lysis as previously described by Scheideler, M.A. and R.S. Zukin ( 1 990) J. Biol. Chem. 265. 1 5176-1 5182. Cells are harvested cells by scraping in physiologic saline and then collected by centrifugation at low speed (600-800 X g for 5 min). The cell pellets are washed by gentle resuspen- sion in low ionic strength buffer ( 10 mM K-phosphate, pH 7.5), collected by high-speed centrifugation (30,000 X g for 10 min) and then resus- pended in 30 vol of the low ionic strength buffer for 20 min to initiate hypo-osmotic swelling and breakage. Unbroken cells are removed by centrifugation at low speed and cell membranes collected by high-speed centrifugation. The resulting cell pellets are homogenized in Resuspen- sion buffer (25 mM K-Phosphate, pH 7.5, containing 0.32 M Sucrose and 5 mM EDTA) and stored at -80°C.

On the day of the assay the needed amount of protein is thawed at room temperature and diluted into 20-30 ml of Assay buffer (20mM Hepes, pH 7.4, containing 2 mM MgCI₂) in order to wash the cell membranes. After centrifugation for 10 min at 1 6,000 rpm (Beckman JA-20) the cell membrane pellet is re-homogenized in Assay buffer with a teflon Dounce homogenizer to yield a typical concentration in the assay of 0.1 mg/ml.

The affinity of a test substance for the dopamine-D2s receptor is deter¬ mined by measuring its ability to compete for specific [³H]Spiperone binding.

To initiate the assay the tissue and test substance are preincubated at 25°C for 1 5 min. Then [³H]Spiperone (New England Nuclear) is added to yield a final concentration in the assay of 0.3 nM and the incubation continued at 25°C for 40 min. The samples are then passed through Whatman GF/B filters under vacuum and immediately washed twice with

4 ml ice-cold 20 mM Hepes, pH 7.4, containing 0.1 M NaCI. Filters are placed in counting vials, 4ml of Ultima Gold (Packard) is added, and total dpm estimated by scintillation counting.

Non-specific binding is evaluated by including D-Butaclamol (3 μM) in the assay instead of test substance. Data were fit to competititon curves and analyzed using non-linear least squares fitting procedures. Results are reported as I , values.

In Vitro Assay of Dopamine-D3 Receptor Binding

Dopamine-D3 receptor binding is performed essentially as described by D. Levesque et al. ( 1 992) Proc. Natl. Acad. Sci (USA) 89 , 81 55-81 59. The concentration of Dopamine-D3 receptors in striatum is high relative to Dopamine-D2 receptor expression. The two receptor subtypes can be distinguished in a radioreceptor binding assay which employs striatal membranes by measuring the specific binding of the selective dopamine- D3 ligand [³H]7-OH-DPAT. The affinity of a test substance for the dopamine-D3 receptor can then be determined by measuring its ability to compete for specific [³H]7-OH-DPAT binding.

All membrane preparation steps are performed at 0-4°C. Frozen cow otriatum purchased from Pel Freeze (USA) is thawed in Resuspension buffer (25mM Tris/HCI, pH 7.4, containing 0.32M Sucrose and 5mM EDTA), homogenized with a Ultra-turrax homogenizer and centrifuged at 3000 rpm (Beckman JA-20) for 10 min. The supernatant is saved and and the pellet homogenized a second time in the Resuspension buffer and centrifuged at 3000 rpm (Beckman JA-20). This procedure is repeat¬ ed 3 times, each time saving the supernatant. The 3 low-speed superna- tants are then pooled and centrifuged at high speed 1 6,000 rpm (Beck- man JA-20) for 10 min. The final pellet is homogenized with a teflon

Dounce homogenizer in Resuspension buffer to a final concentration of 1 mg tissue/ml and frozen at -80°C in 1 ml aliquots. On the day of the assay, the needed amount of protein is thawed at room temperature, diluted 1 : 10 (v/v) in assay buffer and centrifuged for 10 min. at 1 6,000 rpm (Beckman JA-20) in order to wash the mem¬ branes. The pellet is then re-homogenized in Assay buffer (50mM Tris/ HCI, pH 7.4) with a teflon Dounce homogenizer to yield a final assay concentration of 1 mg/ml.

To initiate the assay the tissue and test substance are preincubated at 25°C for 1 5 min. Then [³H]7-OH-DPAT (Amersham) is added to yield a final concentration in the assay of 2 nM and the incubation continued at

25°C for 40 min. The samples are then passed through Whatman GF/B filters under vacuum and immediately washed once with 5ml ice-cold Assay buffer containing 0.1 M NaCI. Filters are placed in counting vials, 4ml of Ultima Gold (Packard) is added, and total dpm estimated by scintillation counting.

Non-specific binding is evaluated by including quinpirole (5 μWΛ) in the assay instead of test substance. Data were fit to competititon curves and analyzed using non-linear least squares fitting procedures. Results are reported as K, values.

The compounds of the present invention had K, values lower than 1 μM at the human Dopamine D3 receptors.

The compounds of the invention, together with a conventional adjuvant, carrier or diluent, and if desired a pharmaceutically acceptable acid addi^¬ tion salt thereof, may be placed into the form of pharmaceutical compo¬ sitions and unit disages thereof, and in such form may be employed as solids, such as tablets or filled capsules, or liquids, such as solutions, suspensions, emulsions, elixirs, or capsules filled with the same, all for oral use, in the form of suppositories for rectal administration, or in the form of sterile injectable solutions for parenteral (including subcutaneous) use. Such pharmaceutical compositions and unit dosage forms thereof may comprise conventional ingredients in conventional proportions, with or without additional active compounds or principles, and such unit dosage forms may contain any suitable effective central nervous system ailment alleviating amount of the active ingredient commensurate with the intended daily dosage range to be employed. Tablets containing 0.05-100 mg of active ingredient or, more specified 1 -50 mg per tablet are accordingly suitable representative unit dosage forms.

The compounds of this invention can thus be used for the formulation of pharmaceutical preparations e.g. for oral and parenteral administration to mammals including humans in accordance with conventional methods of galenic pharmacy.

Conventional excipients are such pharmaceutically acceptable organic or inorganic carrier substances suitable for parenteral or oral application which do not deleteriously react with the active compound.

Examples of such carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, gelatin, lactose, amylose, magnesium stearate, talc, silicic acid, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, hydroxymethylcellu- lose and polyvinylpyrrolidone.

The pharmaceutical preparations can be sterilized and mixed, if desired, with auxiliary agents, such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salt for influencing osmotic pressure, buffers and/or colouring substances and the like, which do not deleteriously react with the active compound.

For parenteral application, particularly suitable are injectable solutions or suspensions, preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil.

Ampoules are convenient unit dosage forms.

For oral applications, particularly suitable are tablets, dragees, or cap¬ sules having talc and/or a carbohydrate carrier or binder or the like, the carrier preferably being lactose and/or corn starch and/or potato starch. A syrup, elixir or like can be used when a sweetened vehicle can be employed. Generally, as to broader ranges, the compound of the inven- tion is dispensed in unit dosage form comprising 0.05-100 mg in a pharmaceutically acceptable carrier per unit dosage.

A typical tablet which may be prepared by conventional tabletting tech¬ niques contains:

Active compound 1 .0 mg

Lactosum 67.9 mg ph.Eur

Avicel^* 31 .4 mg

Amberlite^* IRP 88 1 .0 mg Magnesii stearas 0.25 mg Ph. Eur.

The invention will now be described in further detail with reference to the following examples, which may not be construed as limiting:

EXAMPLE 1

Cis-8-Methoxy-3-propyl-1 ,2,3,3a,4,9b-hexahydro-[1 ]benzoρyrano[3,4-b]- pyrrole (Compound 1 )

To a stirred solution of 6-methoxy-3,4-dihydro-2H-1-benzopyran-3-one (20 g, 0.1 1 mol) and n-propylamine (13 ml, 0.1 5 mol) in dry diethyl ether (300 ml) under nitrogen was added molecular sieve, 4A (43 g). The mixture was stirred at room temperature for 17 h, filtered and evaporated to dryness in vacuo. The desired enamine was obtained as a brown oil (23.8 g, yield 99 %). The resulting oxygen-sensitive oil was shown by HPLC to have a purity greater than 92 %. Because of the instability of this material, subsequent reactions were carried out with the crude enamine.

To a dry, nitrogen-filled flask equipped with a reflux condenser was added the above prepared enamine (23.8 g, 0.1 1 mol) and dry tetrahy- drofuran (50 ml). A 2 M solution of isopropylmagnesium chloride in tetrahydrofuran (75 ml) was added slowly at a rate which maintained a gentle reflux. 1 -Bromo-2-chloroethane (13 ml, 0.16 mol) was added to the warm reaction mixture, again at such a rate that the reflux tempera¬ ture was maintained. On completion of the addition of the alkyl halide, an additional solution of Grignard reagent (30 ml) was added to the reaction. The reaction mixture was heated at reflux temperature for 1 h after which an additional solution of Grignard reagent (30 ml) was added. The reaction mixture was heated at reflux temperature for addi¬ tionally 1 h. The cooled mixture was diluted with 10 % aqueous ammo- nium chloride (100 ml) and extracted twice with toluene (75 ml). The combined organic phases was washed twice with water and evaporated to dryness to give 8-methoxy-3-propyl-1 ,2,3,4-tetrahydro-[1 ]benzopyra- no[3,4-b]pyrrole (23.4 g, yield 88 %) as a red oil. Because of the insta¬ bility of this material, subsequent reactions were carried out with the crude enamine.

A mixture of 8-methoxy-3-propyl-1 ,2,3,4-tetrahydro-_1 ]benzopyrano[3,4- blpyrrole (23.4 g, 0.097 mol), Platinum(IV) oxide hydrate (0.5 g), and absolute ethanol (500 ml) was hydrogenated at 30 psi for 1 h. The reaction mixture was filtered and the solvent was removed in vacuo. The residue was dissolved in methylene chloride (150 ml) and extracted twice with 0.5 N hydrochloric acid (150 ml). The combined aqueous extracts were washed twice with methylene chloride (100 ml), made alkaline with 25 % ammonium hydroxide and extracted twice with ethyl acetate (100 ml). The organic phase was dried over magnesium sulphate and evaporated in vacuo. This base was dissolved in dry tetrahydrofuran (100 ml) and treated with etheral hydrogen chloride to give cis-8-meth- oxy-3-propyl-1,2,3,3a,4,9b-hexahydro-[1]benzopyrano[3,4-b]pγrrole hydrochloride (8.3 g, yield 31 %). M.p. 175-177°C.

¹H-NMR(CDCI₃) (of the base) in ppm: δ 6.6-6.9 (3H,phenyl), 4.0 (1H,d.d,CH in 0CH₂), 3.75 (3H,s,CH₃0), 3.65 (1H,d.d.CH in 0CH₂),

3.4-2.3 (7H,m), 1.7-1.9 (1H,m,CH), 1.6 (2H,sept., CH₂CH₃), 0.9 (3H,t,CH₃).

In the same manner the following compound was prepared:

6-Methoxy-3-propyl- 1,2, 3,3a, 4,9b-hexahydro-[1]benzopyrano[3,4-b]pyr- role (Compound 2) from 8-methoxy-3,4-dihydro-2H-1-benzopyran-3-one.

¹H-NMR(CDCI₃)in ppm: δ 6.7-6.9 (3H, phenyl), 4.15 (1H,d.d,CH in 0CH₂), 3.9 (3H,s,CH₃O), 3.7 (1H,d.d.CH in OCH₂), 3.4-2.3 (7H,m), 1.7-

1.9 (1H,m,CH), 1.6 (2H,sept., CH₂CH₃), 0.9 (3H,t,CH₃).

EXAMPLE 2

Cis-8-Hydroxy-3-propyl-1 ,2,3,3a,4,9b-hexahydro[1 ]benzopyrano[3,4-b]- pyrrole (Compound 3)

To a solution of diphenylphosphine (1.2 ml, 7 mmol) in dry tetrahydro- furan (10 ml) was added 2.5 M n-butyllithium in hexane (2.4 ml, 6 mmol) at 0°C. Cis-8-methoxy-3-propyl-1,2,3,3a,4,9b-hexahydro-[1]ben- zopyrano[3,4-b]pyrrole (0.8 g, 3.2 mmol) dissolved in dry tetrahydro- furan ( 10 ml) was added to the above mentioned solution of lithium diphenylphosphide. The resulting mixture was refluxed for 6 hours. Ice- water (25 ml) was added and the mixture was extracted twice with diethyl ether (20 ml). The water phase was treated first with 1 2 N hydrochloric acid to acidic pH and secondly with 25% ammonium hydroxide to basic pH, and extracted twice with ethyl acetate (20 ml). The organic phase was dried over magnesium sulphate and evaporated in. vacuo to give the title compound as base. The residue was dissolved in tetrahydrofuran and treated with etheral hydrogen chloride to give cis-8- hydroxy-3-propyl-1 ,2,3,3a,4,9b-hexahydro-[1 ]benzopyrano[3,4-b]pyrrole hydrochloride (0.3 g, yield 35 %), M.p. 192-1 96°C.

¹H-NMR (CD₃OD) in ppm: δ 6.5-6.8 (3H, phenyl), 4.45 ( 1 H, d .d, CH in OCH₂), 4.1 ( 1 H, d .d.CH in OCH₂), 3.9-2.6 (7H,m), 1 .7-2.0 ( 1 H,m,CH), 1 .7 (2H, sept., CH₂CH₃), 1 .1 (3H,t,CH₃).

In the same manner the following compound was prepared from the corresponding 6-methoxy analogue:

6-Hydroxy-3-propyl-1 ,2,3,3a,4,9b-hexahydro-[1 ]benzopyrano[3,4-b]- pyrrole hydrochloride (Compound 4).

^-NMR (CDCI₃) (of the base) in ppm: δ 6.65-6.85 (3H, phenyl), 4. 1 ( 1 H, d.d, CH in OCH₂), 3.8 ( 1 H, d.d.CH in OCH₂), 3.4-2.3 (7H, m), 1 .7-1 .9 (1 H, m, CH), 1 .6 (2H, sept., CH₂CH₃), 0.9 (3H, t, CH₃).

Claims

It A compound of the general formula I

and pharmaceutically acceptable acid addition salts and hydrates thereof, wherein R¹ is hydrogen,

optionally substituted with phenyl, thiophene or naphthalene, or R¹ is cycloalkyi, alkenyl or allyl optionally substituted with halogen; and

R², R³ are the same or different and independently are hydrogen, C_h¬ alky!, aralkyl or phenyl; and R⁴ is hydrogen, halogen, trifluoromethyl,

or cyano; and R⁵, R^β, R⁷ are the same or different and independently are hydrogen, hydroxy, Ci.g-alkoxy, O-acyl, halogen, trifluoromethyl, C_1-β-alkyl, triflate, cyano, carbamoyl or amine optionally substituted with C_1-β-alkyl.

2_. A compound according to claim 1 wherein R² and R³ represent hydrogen.

3_ A compound according to claims 1 or 2 wherein R¹ represents propyl or allyl.

4,. A compound according to any of the claims 1 -3 wherein R⁴ represents hydrogen or halogen. E A compound according to any of the claims 1 -4 wherein at least one of R⁵, R⁶ or R⁷ is hydroxy and the others of R⁵, R⁶ or R⁷, are selected from halogen or hydrogen.

f A compound according to any of the claims 1 -5 which is

Cis-8-Methoxy-3-propyl-1 ,2,3,3a,4,9b-hexahydro-[1 ]benzopyrano[3,4-b_- pyrrole,

6-Methoxy-3-propyl-1 ,2,3,3a,4,9b-hexahydro-[1 ]benzopyrano[3,4-b]pyr- role, Cis-8-Hydroxy-3-propyl- 1 ,2, 3,3a, 4,9b-hexahydro-[1 ]benzopyrano[3,4-b]- pyrrole,

6-Hydroxy-3-propyl-1 ,2,3,3a,4,9b-hexahydro-[1 ]benzopyrano[3,4-b_pyr- role, and salts hereof.

Z_ A compound according to any of the claims 1 -6 or a pharma¬ ceutically acceptable salt thereof for use as a therapeutically acceptable substance.

8_j. A compound according to any of the claims 1 -6 or a pharma¬ ceutically acceptable salt thereof for use as a therapeutically acceptable substance in the treatment of central nervous system ailments related to dysfunction of the central dopamine system.

f A method of preparing a compound according to any of the claims 1 -6 which comprises:

a) reacting a compound of formula II

wherein R⁴, R⁵, R⁶ and R⁷ are as defined in claim 1 , with an amine NH₂R\ wherein R¹ is as defined in claim 1 to form a compound of formula III

wherein R¹, R\ R⁵, R⁶ and R⁷ are as defined above; and reacting the compound of formula III with a compound of formula IV

R² R³

(IV)

wherein R² and R³ have the meaning set forth in claim 1 , and X and Y represent leaving groups, to form a compound of the general formula V

wherein R¹ , R², R³, R⁴, R⁵, R⁶ and R⁷ are as defined above; and subsequently reducing the compound of formula V to form a compound of formula I; or

b) for halogen-substituted compounds of formula I, substitution of one or more hydrogen atoms by action of a halogenating agent to give a com¬ pound of formula I, wherein one or more of the substituents R⁴, R⁵, R⁶ and R⁷ are chlorine, bromine or iodine; or

c) reacting a compound of formula VI

wherein R², R³, R⁴, R⁵, R^β and R⁷ are as defined above, with R'Y, where¬ in R¹ is as defined above and Y is a leaving group, to form a compound of formula I; or

d) reacting a compound of formula II

wherein R⁴, R⁵, R⁶ and R⁷ are as defined above, with pyrrolidine to form a compound of formula VII

wherein R\ R⁵, R^β and R⁷ are as defined above; and reacting the com- pound of formula VII with a compound of formula VIII

(IX) wherein R², R\ R⁴, R⁵, R^β and R⁷ are as defined above, and subsequently reducing the compound of formula IX to form a compound of formula VI,

wherein R², R³, R⁴, R⁵, R^β and R⁷ are as defined above, and hereafter reacting said compound VI with R¹Y, wherein R¹ is as defined above and Y is a leaving group, to form a compound of formula I.

10. A pharmaceutical composition comprising as active component a compound according to any of the claims 1 -6 or a pharmaceutically acceptable salt thereof and a therapeutically inert excipient, carrier or diluent.

1 1 . A pharmaceutical composition for the treatment of central nervous system ailment related to dysfunction of the central dopamine system, which comprises a compound according to any of the claims 1 - 6 or a pharmaceutically acceptable salt thereof and a therapeutically inert excipient, carrier or diluent.

12. Use of a compound of formula I according to claim 1 or a phar¬ maceutically acceptable salt thereof for the manufacture of a pharma¬ ceutical composition for the treatment of a central nervous system ailment related to dysfunction of the central dopamine system. 13. A method of treating a central nervous system ailment related to dysfunction of the central dopamine system in a subject in need thereof, comprising administering an effective amount of a compound according to claim 1 .

14. A method of treating a central nervous system ailment related to dysfunction of the central dopamine system in a subject in need thereof comprising administering a pharmacaeutical composition according to claim 10.

15. A process for the manufacture of a medicament, particular to be used in the treatment of a central nervous system ailment related to dysfunction of the central dopamine system, which process comprises bringing a compound of formula I according to claim 1 or a pharmaceuti- cally acceptable salt thereof into a galenic dosage form.