NEW CHROMAN AND THIOCHROMAN DERIVATIVES

Abstract: Compounds of formula (I), processes for their preparation, pharmaceutical preparations, use of and method of treatment of disorders in CNS by using compounds of formula (I).

Description: New chroman and thiochroman derivatives Description Field of the Invention The present invention relates to new substituted-3-amino- chromans and thiochromans, enantio ers and salts thereof, processes for their preparation, pharmaceutical compositions containing said therapeutically active compounds as well as new intermediates useful in the preparation of the thera¬ peutically active compounds and to the use of said active compounds in therapy. An object of the invention is to provide compounds for therapeutic use, especially compounds having a therapeutic activity via the central nervous system (CNS). A further object is to provide compounds having a selective effect on the 5-hydroxy-tryptamine receptors in mammals including man. Prior art Therapeutically useful 3-amino-dihydro-[l]-benzopyran and benzothiopyran having effect on 5-hydroxy tryptamine neurons in mammals are disclosed in EP 0222 996. These compounds are defined by the formula wherein Z is 0 or S; R is hydrogen or loweralkyl; R.. is hydrogen, loweralkyl or arylloweralkyl; R- is hydrogen, loweralkyl or arylloweralkyl; or R. and R~ together form a ring with 4 - 6 carbon atoms; R- is hydrogen, hydroxy, loweralkoxy, aryllower- alkoxy, acyloxy or aryloxy when Z is S and R- is hydroxy, loweralkoxy, arylloweralkoxy, acyloxy or aryloxy when Z is O and R.- is in 5- or 8-position when Z is O; R. and R^ are independently hydrogen, lower alkyl or halogen, and mono- or di-S-oxide thereof when Z is S, and pharmaceutically acceptable salts thereof. 3-Chromanamine hydrochlorides with two alkyl groups in the aromatic ring having central stimulating activities are described in J. Med. Chem. 1^, p. 863-65 (1972). Disclosure of the Invention The object of the present invention is to obtain new com¬ pounds which have a high affinity to the 5-hydroxy-tryptami receptors in the central nervous system at the same time as they act as agonists, partial agonists or antagonists on th serotonin receptors. Thus, a group of new compounds of the formula I of the present invention as well as the enantiomers and salts thereof are useful in therapeutic treatment of 5-hydroxy- tryptamine mediated states and disorders such as depression, anxiety, anorexia, senile dementia, Alzheimer's disease, migraine, termoregulator and sexual disturbances. Further aspects of the invention are related to the use of the compounds, enantiomers and salts thereof in pain control an in modulation of the cardiovascular system. Thus, the invention provides compounds of the formula I wherein (0 ii ) PD X is O or S; p is an integer 0, 1 or 2; R is hydrogen, fluoro or C^-C, alkyl; R. is hydrogen, C,-C- alkyl or C--C- alkenyl; R 2 is hydrogen, c ι " c c alkyl, C--C- alkenyl, C.-C. alkylaryl where aryl may contain 1 or 2 heteroatoms selected from N, O or S optionally substituted by halogen, CN, CF.,, --C, alkyl, C--C- alkenyl or c i~ C 4 a lk° χ Y' R. and R 2 may together form a 5- or 6- membered ring which may contain 1 or 2 heteroatoms selected from N, O or S; R 3 is halogen, CN, CF 3 , SO..CF.-, N_ , NO-, C 1 -C 8 alkyl, C 2 - _ alkenyl, NH-, NR-R-, COR-,, 5- or 6-membered aryl which may contain 1 or 2 heteroatoms selected from N, O or S and being either (i) optionally substituted by one or more substituents indepen¬ dently selected from halogen, CN, CF J-, C1, -CD- alkyl, C 6 -C- alkenyl or C..-C. alkoxy or either (ii) fused at two adjacent carbon atoms to an aryl ring, said aryl ring being optionally substituted by one or more substituents independently selected from halogen, CN, CF 3 , C.-C- alkyl, C--C 8 alkenyl or C,-C. alkoxy; R. is hydrogen or halogen; R e is. ydrogen, C.-C- alkyl or C--C- alkenyl; R 6 is 1 ~C 6 alkyl or C-,-Cg alkenyl; or R- and R fi may together form a 5- or 6- membered ring which may contain 1 or 2 heteroatoms selected from N, O or S; R 7 is hydrogen, hydroxy, chloro, bromo, C.-C- alkyl, C--C- alkenyl, C-^C. alkoxy; NR g R 9 or 5- or 6- membered aryl which may contain 1 or 2 heteroatoms selected from N, O or S optionally substituted by one or more of halogen, CN, CF_, C.-C β alkyl, C~-C 8 alkenyl or C,-C 4 alkoxy; R R and R Q are each independently hydrogen, C.-C 8 alkyl, C--Cg alkenyl, 5- or 6- membered aryl which may contain 1 or 2 heteroatoms selected from N, O or -S optionally substituted by halogen, CN, CF,, C.-C 8 alkyl, 2 ~Cg alkenyl, C--C. alkoxy, or may together form a 5- or 6- membered ring containing 1 or 2 heteroatoms selected from N, O or S; enantiomers or salts thereof. A further aspect of the invention is a pharmaceutical preparation containing as active ingredient a compound according to formula I wherein 0 or ( ?S';P is p is an integer 0, 1 or 2; R is hydrogen, fluoro or .-C 8 alkyl; R, is hydrogen, C.,-Cg alkyl or C^-Cg alkenyl; R-, is hydrogen, C.-C 8 alkyl, C-,-Cg alkenyl, C^-C . alkylaryl where aryl may contain 1 or 2 hetero¬ atoms selected from N, O or S optionally substitut¬ ed by halogen, CN, CF 3 , C.-Cg alkyl, C 2 ~Cg alkenyl or C.-C. alkoxy; or R. and R 2 may together form a 5- or 6- membered ring which may contain 1 or 2 heteroatoms R 3 is halogen, CF 3 , C.-Cg alkyl, C_-Cg alkenyl, NR t -R g , COR-,, 5- or 6-membered aryl which may contain 1 or 2 heteroatoms selected from N, O or S and being either (i) optionally substituted by one or more substituents independently selected from halogen, CN, CF 3 , C.-Cg alkyl, C~,-Cg alkenyl or C.-C. alkoxy or either (ii) fused at two adjacent carbon atoms to an aryl ring, said aryl ring being optionally substituted by one or more substituents independently selected from halogen, CN, CF-., C. - Cg alkyl, C 2 ~ C 6 alkenyl or C.-C. alkoxy; R. is hydrogen or halogen; R- is hydrogen, C--Cg alkyl or 2 -C 8 alkenyl; _ g is C.-C 8 alkyl or C-,-Cg alkylen; or R- and Rg may together form a 5- or 6- membered ring which may contain 1 or 2 heteroatoms selected from N, O or S; R-, is hydrogen, C.-Cg alkyl, C_,-Cg alkenyl, C.-C. alkoxy, NR g R Q or 5- or 6- membered aryl which may contain 1 or 2 heteroatoms selected from N, O or S optionally substituted by one or more of halogen, CN, CF-, C.-Cg alkyl, C--Cg alkenyl or C.-C, alkoxy; g and g are each independently hydrogen, C.-C 8 alkyl, C 2 ~Cg alkenyl, 5- or 6- membered aryl which may contain 1 or 2 heteroatoms selected from N, O or S optionally substituted by halogen, CN, CF-, C.-Cg alkyl, C--Cg alkenyl, C.-C. alkoxy or may together form a 5- or 6- membered ring containing 1 or 2 heteroatoms selected from N, O or S; an enantiomer or a pharmaceutically acceptable salt there¬ of. A preferred group of therapeutically active compounds of formula I are those wherein R. and R 2 are each independent¬ ly hydrogen, n-propyl, i-propyl or cyclopropyl and R- is a carbonylgroup COR-. Among these groups are the de inition of R 7 as alkyl, aminoalkyl e.g. methyl, ethyl, n-propyl, i-propyl, cyclopropyl, n-butyl, i-butyl, t-butyl and cyclobutyl or aryl, a inoaryl e.g. phenyl, thienyl, fluoro¬ phenyl and furanyl. Another preferred group is when R, is aryl e.g. phenyl, thienyl, furanyl, or fluorophenyl. Another preferred group is when R~ is alkyl e.g. n-propyl, i-propyl or alkenyl e.g. i-propenyl and allyl. Another preferred group of active compounds are those wherein R. is halogen in 8 position as well as enantiomers thereof. Compounds of formula I wherein R 3 is CN, COOH, COCl, COBr, NH-,, N 3 , N0 2 or SO^CF- are new intermediates for prepara¬ tion of the therapeutically active compounds of formula I. C j -Cg alkyl in formula I representing straight, branched and cyclic alkyl groups having 1 to 6 carbon atoms, for example methyl, ethyl, n-propyl, i-propyl, n-butyl, i- butyl, t-butyl, n-pentyl, i-pentyl, t-pentyl, neo-pentyl, n-hexyl, i-hexyl, cyclopropyl, cyclobytyl, cyclopentyl, cyclohexyl, methylcyclopropyl, ethylcyclopropyl, methyl- cyclobutyl. Preferred alkyl groups have 1 to 4 carbon atoms. 2~ c _ a ^kenyl in formula I representing straight or branched carbon atoms chains having 2 to 6 carbon atoms and containing one or two double bond, for example allyl, propenyl, isopropenyl, butenyl, isobutenyl, pentenyl, isopentenyl. Preferred alkenyl groups have 2 to 4 carbon atoms and one double bond. C.-C. alkoxy in formula I representing a straight alkoxy group having 1 to 4 carbon atoms, for example methoxy, ethoxy, propoxy or butoxy, preferably methoxy and ethoxy. C.-C. alkylaryl where aryl may contain 1 or 2 heteroatoms selected from N, O or S in the definition of R-, in formula I representing an aryl residue having 3 to 12 carbon atoms in the aromatic ring and optionally 1 or 2 heteroatoms selected from N, 0 or S in the aromatic ring, bond by a straight or branched alkylen chain having 1 to 4 carbon atoms in the aliphatic chain. The aromatic ring may be substituted by one or more of nitrile, trifluoromethyl, halogen such as fluoro, chloro, bromo, iodo, C. -C 8 alkyl, e.g. methyl, ethyl, propyl, _-Cg alkenyl e.g. allyl, propenyl, or C.-C. alkoxy preferably in meta and/or para position. Examples of suitable aryl groups in C.-C. alkyl- aryl are phenyl, naphtyl, biphenyl, thienyl, furyl, pyryl, pyri idyl and pyrridinyl. Preferred C.-C, alkylaryl groups are unsubstituted and substituted phenylalkyl groups wherein the alkyl group is a straight or branched alkyl having 1 to 4 carbon atoms and the aromatic ring may be substituted by one or more of fluoro, chloro, bromo, iodo, nitrile, trifluoromethyl, methyl or ethyl in meta and/or para position. For example benzyl, phenethyl and phenyl- propyl, especially preferred is phenylpropyl. Halogen in formula I representing fluoro, chloro, bromo, iodo, preferably fluoro, chloro and bromo. 5- or 6-membered aryl which may contain 1 or 2 heteroatoms selected from N, O or S and being either (i) optionally substituted by one or more substituents independently selected from halogen, CN, CF 3 , C.-Cg alkyl, C 2 -C 8 alkenyl or C.-C. alkoxy or either (ii) fused at two adjacent carbon atoms to an aryl ring, said aryl ring being optionally substituted by one or more substituents independently selected from halogen, CN, CF 3 , C.-C 8 alkyl, C 2 -C β alkenyl or C.-C. alkoxy; in the definition of R-. in formula I representing either (i) substituted or unsubstituted phenyl, thienyl, furyl, pyridyl, pyrimidyl, pyrazinyl, pyradazinyl, thiozolyl, isothiozolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, piperazinyl or orpholinyl or either (ii) substituted or unsubstituted quinolyl, isoquinolyl, quinazolyl, quinaxazolyl or indolyl. 5- or 6-membered aryl which may contain 1 or 2 heteroatoms selected from N, O or S in the definition of R_, R- and R- in formula I representing phenyl, thienyl, furyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, piperazinyl, morpholinyl. Examples of suitable 5- or 6-membered ring structures formed by R. and R 2 or Re and R-, or R-. and R- respectively and the nitrogen atom and which may contain a ~ further heteroatom selected from N, 0 or S are piperazine, morpholine, pyrrolidine, pyrrole, pyrroline, imidazole, imidazoline, i idazolidine, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine. The compounds of the invention have one or two assymetric carbon atoms. When R is hydrogen the compounds have an assymetric carbon atom adjacent to the nitrogen atom i.e. C 3 and when R is C.-Cg alkyl the compounds have an assymetric carbon atom adjacent to the nitrogen atom and an assymetric carbon atom adjacent to the alkyl group i.e. C.. Thus, the compounds exist as two or four optical isomers i.e. enantiomers. Both the pure enantiomers, racemic mixtures are within the scope of the present invention. The therapeutic properties of the compounds may to a greater or lesser degree be ascribed to the racemate or to the enantiomers occurring. Both organic and inorganic acids can be employed to form non-toxic pharmaceutically acceptable acid addition salts of the compounds of this invention. Illustrative acids are sulfuric, nitric, phosphoric, oxalic, hydrochloric, formic, hydrobromic, citric, acetic, lactic, tartaric, pamoic, ethanedisulfonic, εulfamic, succinic, methylsulphonic, propionic, glycollic, malic, gluconic, pyruvic, phenyl- acetic, 4-aminobenzoic, anthranilic, salicylic, 4-amino- salicylic, 4-hydroxybenzoic, nicotinic, methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, benzenesulfonic, p- toluenesulfonic, sulfanilic, naphtalenesulfonic, ascorbinic, cyclohexylsulfa ic, fumaric, aleic and benzoic acids. These salts are readily prepared by methods known in the art. Methods of Preparation The compounds of the formula I may be prepared by the following processes constituting a further aspect of the invention. a. Converting a compound of formula II II IA wherein Y is a leaving group such as trifluoro ethane sulfonate (OS0 2 CF 3 ), halide e.g. Cl or Br, and X, R, R-, R 2 and R. are defined as above by substitution of the group Y to a carboxy group COZ, wherein Z is Cl, Br, OH, OR where R is C.-Cg alkyl to formation of a compound of formula I wherein R 3 is COZ, (IA) . The compound of formula II can be converted to the compound of formula IA by the following catalytic cycle. Metal M° should be a zerovalent transition metal, such as Pd or Ni with ability to undergo oxidative addition to aryl-Y-bonds e.g. the aryl-SO-.CF 3 bonds. M° may be generated in situ II II from M . The aryl-CO-M -Y are formed by treatment with carbon monoxide (CO). Further reagants are an alcohol such as alkanol e.g. ethanol, ethanol, an a ine base such as a trialkylamine e.g. triethylamine in an inert organic solvent preferen- tially a polar aprotic solvent such as dimethylformamide (DMF), dimethylsulfoxide (DMSO), aceton, acetonitrile etc. The reaction is normally performed at a temperature between +40 to + 120°C and at a pressure between 100 to 500 KPa. Optionally followed by hydrolyze and treatment with a thionyl halide e.g. thionylchloride to obtain the corresponding acid halide derivative. b. Compound of formula I wherein R~. is COZ (IA) can also be formed by the reversed process: A reaction as the catalytic cycle using a zerovalent transition metal M , such as Pd, or Ni with ability to undergo an oxidation addition to Z-Y, wherein Z is defined Cl, Br, OH or ORp where Rp is C.1-C6- alkyl and Y is a leaving group such as SO-.CF.. and halide, treatment with carbon monoxide followed by addition of a compound of formula III, wherein X, R, R-, R 2 and R. are as defined under formula I. The Z-CO-M -Y can also be formed from Z-COCl directly. The reaction conditions and reagant are the same as described in method a. above. Hydrolyze of suitable carbo- xylic acid ester forms the free acid, which can be con¬ verted to its acid halide derivative. c. Converting a compound of formula II II IB wherein X, R, R. , R~ and R. are as defined above and Y is a leaving group such as Cl, Br or SO-.CF-. by treatment with a cyanide reagant such as cupper cyanide (CuCN) to obtain a compound of formula I wherein R, is CN. The reaction with cyanide reagant is performed in an inert organic solvent such as dimethylformamide, hexamethylenphosphotriamide etc. at a temperature between 20° to 200°C preferrably between 50° to 150°C and at normal temperature. d. Amination of a compound of formula IA IA IC wherein X, R, R. , R 2 and R. are as defined above and Z is Cl, Br, OH or ORp where Rp_ is C.1-C6- alkyl. If the compound of formula IA is a carboxylic acid ester it must first be hydrolyzed to form the free acid. The free acid is then transformed into the amide IC via its acid chloride derivative by reaction of the corresponding amine NR-R-, where R- and R g are as defined under formula I, in a nonpolar aprotic solvent e.g. toluene, benzen at reflux temperature between 0 to 100°C. e. Wittig reaction to formation of a compound of formula I where R 3 is a C 2 ~Cg alkenyl group (IE), ID IE A 5-carboxy chroman/thiochroman derivative, where X, R, R. , R- and R. are defined as above and R-, is alkyl defined as above (ID) is converted by using a dipolar reagant such as alkyltriphenylphosphonium halide to formation of a corresponding alkenyl group (IE). f. Catalytic hydrogenation of a 5-alkene chroman/thio¬ chroman derivative of formula I wherein R 3 is a C 2 -C 8 alkenyl group by using H 2 /Pd, H 2 /Pt or H 2 /Raney Ni to formation of corresponding chroman/thiochroman derivative of formula I wherein R 3 is C..-Cg alkyl (IF). g. Substitution of a 5-bromo-chroman/thiochroman derivative by treatment with an appropriate stannic tri- alkyl reagant in presence of a zerovalent metal preferrably palladium (Pd ) to obtain a compound of formula I wherein R 3 is C.-Cg alkyl, C.-C. alkenyl or aryl, in presence of carbonmonoxide (CO) is formed a compound of formula I wherein R 3 is COR 7 wherein R 7 is C.-Cg alkyl, C_,-C fi alkylen or aryl. The substitution may be performed by one of the following ways: 1) 2) Sn(alkyl)-R 3 /Pd o ,C0 e.g. Sn(CH-)-R-/Pd o ,C0 SUBSTITUTE SHEET h. Converting the 5-carboxy chroman/thiochroman deriva¬ tive of formula I where X, R, R-, 2 and R. are defined as above and Z is Cl, Br by using R 7 Li wherein R 7 is alkyl, alkenyl or aryl as a cuprate reagant to obtain corresponding 5-keto- chroman/thiochroman derivative. Suitable R 7 i used is alkyllithium e.g. CH 3 Li, alkenyllithium e.g. CH 2 CHLi or aryllithiu e.g. phenyl-Li. The reaction is performed in an inert organic solvent preferrably a nonpolar aprotic solvent such as ethers e.g. diethyl ether, tetrahydrofuran at a temperature between -50° - +50°C. 1. Hydrolysis of a compound of formula I, wherein R 3 is CN (IB) IB IA SUBSTITUTESHEET wherein X, R, R. , R-, and R. are as defined above optionally followed by treatment with a thionyl halide e.g. thionyl- chloride, thionylbromide to obtain a compound of formula I wherein R 3 is COZ where Z is OH, Cl or Br. j. Substitution of a compound of formula I, wherein R 3 is CN (IB) IB ID wherein X, R, R. , R 2 and R. are defined as above by treat¬ ment with an appropriate organometallic reagant pre- ferentially an organolithium such as R 7 Li or a Gringard reagent such as R 7 Mg halide in an inert organic solvent preferentially a nonpolar aprotic solvent such as bensen, ethers e.g. diethylether, tetrahydrofuran followed by hydrolysis of the intermediate complex to obtain a compound of formula I wherein R 3 is COR 7 where R ? is C.-Cg alkyl, C 2~ C 6 alken Y! or aryl. k. Hydrogeneration of a 5-alkene thiochroman/chroman derivative of formula I wherein R 3 is a C~-C fi alkenyl group by using H 2 /Pd, H 2 /Pt or H 2 /Raney Ni or potassium azodicar- boxylate to formation of corresponding thiochroman/chroman derivative of formula I wherein R 3 is C.-Cg alkyl. SUBSTITUTE SHEET 1. Converting a compound of the formula (II) (ID (IE) wherein Y is a leaving group such as trifluoromethanesul- phonate (Tf), phosphonate, halide such as Br or J and R, R. and R 2 are defined as above by substitution of the group Y to R 3 where R 3 is a 2 -C 8 alkenyl group (IE). The compound (II) may be converted to (IE) by reaction with a transition metal, such as Pd or Ni with ability to form ligand complex and undergo oxidative addition. A suitable alkenyl-substituent can be introduced via a suitable tri- alkylalkenylstannane. Further reagents are an a ine such as triethylamine and lithiumsalt e.g. lithium chloride. The reaction is preferen¬ tially carried out in a polar aprotic solvent such as di- methylformamide, dioxane, acetonintril or dimethylsulfoxide at a temperature between +40 to +120°C. . Converting a compound of the formula (II) SUBSTITUTESHEET wherein Y is a leaving group such as trifluoromethanesul- phonate (Tf), phosphonate, halide such as Br or J and R, R. and R 2 are defined as above by substitution of the group Y to 5- or 6-membered aryl (Ar) which may contain 1 or 2 heteroatoms selected from N, O, or S being either substitute or fused at two adjacent carbon atoms to an aryl ring as defined above to formation of a compound of formula IF. The compound (II) may be converted to (IF) by reaction with a transition metal, such as Pd or Ni with ability to form ligand complex and undergo oxidative addition. A suitable aryl-substituent can be introduced via a suitable trialkyl- arylstannane or aryl-boric acid reagents. Further reagents are an a ine such as triethylamine and lithiumsalt e.g. lithium chloride. The reaction is preferen¬ tially carried out in a polar aprotic solvent such as di¬ methylformamide, dioxane, acetonitril or dimethylsulfoxide at a temperature between +40 to +120°C. The following method describes one way of obtaining the intermediate of formula IB wherein R. , R2 and R4 are defined as in formula I Pharmaceutical preparations According to the present invention the compounds of the formula I 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 a pharmaceutically acceptable non-toxic acid addition salt, e.g. the hydrochloride, hydrobromide, lactate, acetate, phosphate, sulphate, sulpha ate, citrate, tartrate, oxalate and the like in a pharmaceutically acceptable dosage form. The dosage form may be a solid, semisolid or liquid prepara¬ tion. Usually the active substance will constitute between 0.1 and 99% by weight of the preparation, more specifically between 0.5 and 20% by weight for preparations intended for injection and between 0.2 and 50% by weight for preparations suitable for oral administration. To produce pharmaceutical preparations containing a compound of the formula I in the form of dosage units for oral application, the selected compound may be mixed with a solid excipient, e.g. lactose, saccharose, sorbitol, mannitol, starches such as potato starch, corn starch or amylopectin, cellulose derivatives, a binder such as gelatine or poly- vinylpyrrolidone, and a lubricant such as magnesium stearate, calcium stearate, polyethylene glycol, waxes, paraffin, and the like, and then compressed into tablets. If coated tablets are required, the cores, prepared as described above, may be coated with a concentrated sugar solution which may contain e.g. gum arabic, gelatine, talcum, titanium dioxide, and the like. Alternatively, the table can be coated with a polymer known to the man skilled in the art, dissolved in a readily volatile organic solvent or mixture of organic solvents. Dyestuffs may be added to these coatings in order to readily distinguish between tablets containing different active substances or different amounts of the active compounds. For the preparation of soft gelatine capsules, the active substance may be admixed with e.g. a vegetable oil or poly¬ ethylene glycol. Hard gelatine capsules may contain granules of the active substance using either the abovementioned excipients for tablets e.g. lactose, saccharose, sorbitol, mannitol, starches (e.g. potato starch, corn starch or amylopectin) , cellulose derivatives or gelatine. Also liquid or semisolids of the drug can be filled into hard gelatine capsules. Dosage units for rectal application can be solutions or suspensions or can be prepared in the form of suppositories comprising the active substance in admixture with a neutral fatty base, or gelatine rectal capsules comprising the activ substance in admixture with vegetable oil or paraffin oil. Liquid preparations for oral application may be in the form of syrups or suspensions, for example solutions containing from about 0.2% to about 20% by weight of the active sub¬ stance herein described, the balance .being sugar and mixtur of ethanol, water, glycerol and propylene glycol. Optionall such liquid preparations may contain colouring agents, flavouring agents, saccharine and carboxymethyl-cellulose a a thickening agent or other excipients known to the man in the art. Solutions for parenteral applications by injection can be prepared in an aqueous solution of a water-soluble pharma- ceutically acceptable salt of the active substance, prefer¬ ably in a concentration of from about 0.5% to about 10% by weight. These solutions may also contain stabilizing agents and/or buffering agents and may conveniently be provided in various dosage unit ampoules. Suitable daily doses of the compounds of the invention in therapeutical treatment of humans are about 0.01-100 g/kg bodyweight at peroral administration and 0.001-100 g/kg bodyweight at parenteral administration. Working examples The following examples will further illustrate the inven¬ tion. Example 1 3-Dipropylamino-5-trif luoromethanesulfonylchroman 3-Dipropylamino-5-hγdroxychroman (Thorberg et al. Acta Pharm. Suec. 24(1987)) (1.4 g, 4.0 mmol) and N,N-dimethylamino- pyridine (0.1 g, 0.75 mmol) were dissolved in 50 mL methylene dichloride (CH-C1-. and cooled to -30°C. 2,4,6-Collidine (0.75 mL, 5.7 mmol) was added followed by trifluoromethane sulfonic anhydride (1.0 mL, 6.0 mmol). The solution was stirred at -20°C for 3 hours and then allowed to reach ambient temperature. The solution was washed with aqueous NaHC0 3 , dried with Na 2 SO. and evaporated to dryness. The pale yellow oil was finally purified by flash chromatography (silica gel) by elution with ethyl acetate/hexane 1:9. Yield: 55%, Mp 125-127°C (oxalate). Example 2 3-Dipropylamino-5-methyloxycarbonyichroman 3-Dipropylamino-5-trifluoromethanesulfonylchroman (Example 1; 4.43 g, 11.6 mmol) was dissolved in 80 mL dimethylforma- mide/methanol 6:2 and the solution was degassed (10 mm Hg, 20°C, 15 min). PdOAc 2 (76 mg, 0.34 mmol), 1,3-bis-diphenyl- phosphinopropane (141 mg, 0.34 mmol) and triethylamine (3.5 mL, 25 mmol) were then added. The mixture was heated to 70°C under CO atmosphere and stirred for 5 hours. The solution was cooled, diluted with toluene (200 mL), washed with aqueous NaHC0 3 , dried with Na 2 SO. and evaporated to dryness. The oil was purified by flash chromatography (silica gel) by elution with ethyl acetate/hexane 1:8. Yield: 76%, Mp 150-152°C (HCl-salt) . Example 3 3-Dipropylamino-5-carbamoylchroroan 3-Dipropylamino-5-methyloxychroman (Example 2; 400 mg, 1.37 mmol) was dissolved in 10 ml methanol and NaOH (60 mg, 1.5 mmol) in 2 mL H-.0 was added. The mixture was refluxed for 5 * II hours, cooled, filtered through Celite and evaporated to dryness. The residue was refluxed in SOC1-, (5 mL, 68 mmol) for 30 minutes. The excess SOC1-, was then removed in vacuo to give 3-dipropylamino-5-chloroformylchroman*HCL as a gum. The pale brown gum was dissolved in CH-Cl- (50 L), and a stream of NH- (g) was introduced during 2 minutes. The solution was washed with aqueous NaHCO- , dried with Na-SO, and evaporated to dryness. The oil was purified by flash chromatography (silica gel) by elution with ethyl acetate- /hexane 1:4. Yield 80%, 13 C-NMR: 172.0 154.9 136.5 126.9 120.4 119.1 118.6 67.8 53.0 52.6 26.1 22.4 21.9 14.1 11.7 Example 4 3-dipropylamino-5-N,N-dimethylcarbamoylchroman The title compound was prepared analogous to the procedure used in Example 3 starting from 3-dipropylamino-5-methγl- oxycarbonylσhroman and substituting dimethylamine (g) in place of NH-. (g) . 13 C-NMR: 189.3 170.3 149.9 137.4 126.7 126.1 124.9 65.8 64.7 48.2 47.7 30.7 26.0 15.1 10.9. Example 5 3-Dipropylamino-5-N,N-diisopropylcarbamoylchroman The title compound was prepared analogous to the procedure used in Example 3 starting from 3-dipropylamino-5-methyloxy- chro an. Mp 228-230°C (HCl-salt). Example 6 3-Dipropylamino-5-N-methylcarbamoylchroman The title compound was prepared analogous to the procedure used in Example 3 starting from 3-dipropylamino-5-methyl- oxycarbonylchro an and substituting methyla ine (g) in place of NH 3 (g). Mp 95-97°C (oxalate). Example 7 3-Dipropylamino-5-acetylchroman 3-Dipropylamino-5-chloroformylchroman*HCl (4.42 g, 13.4 mmol), prepared from 3-dipropylamino-5-methyloxycarbonyl- chroman (Example 2) analogous to the procedure used in Example 3, in dry tetrahydrofuran (20 ml), was added to a pre-formed solution of lithium dimethylcuprate; prepared from MeLi and Cul, in 200 mL tetrahydrofuran at -78°C. The solution was stirred for 15 minutes at -78°C and was then allowed to reach room temperature during 10 minutes. Then, 30 L H 2 0 was slowly added. The organic phase was decanted, dried with Na 2 SO. and evaporated to dryness. The residue was purified by flash chromatography (silica gel) by elution with ethyl acetate/hexane 1:8. The title compound was crystallized as salt from ethyl acetate. Mp 106-108°C (oxalate). Example 8 3-Dipropylamino-5-cyclopropylcarbonylchroman The title compound was prepared analogous to the procedure used in Example 7 substituting lithium dicyclopropylcuprate (J. Org. Che ., 41 (22), 1976) in place of lithium dimethyl¬ cuprate. Mp 100-102°C (oxalate). Example 9 3-Dipropylamino-5-tertbutylcarbonylchroman The title compound was prepared analogous to the procedure used in Example 7 substituting lithium di-tertbutylcuprate (from tertbutyllithium and CuBr*Me-S) in place of lithium di ethylcuprate. Mp 118-120°C (oxalate). Example 10 3-Dipropylamino-5-isopropylcarbonylchroman The title compond was prepared analogous to the procedure used in Example 7 substituting magnesium diisopropylcuprate (from isopropylmagnesium chloride and CuBr*Me 2 S) in place of lithium dimethylcuprate. Mp 60-62°C (oxalate). Example 11 3-Dipropylamino-5-(4-fluorophenylcarbonyDchroman The title compound was prepared analogous to the procedure in Example 7, substituting magnesiumdi(4-fluorophenyDcuprat (from 4-fluorophenyl magnesium bromide and Cul) in place of lithium dimethylcuprate. Mp 98.3-98.4°C (oxalate). Example 12 3-Dipropylamino-5-(2-thienylcarbonyl)chroman The title compound was prepared analogous to the procedure used in Example 7 substituting lithium di(2-thienyl)cuprate (from 2-thienyllithium and Cul) in place of lithium dimethyl cuprate. Mp 87-88.5 (oxalate). Example 13 3-Dipropylamino-5-isopropenylchroman Methyltriphenylphosphoniumbromide (0.62 g, 1.74 mmol) was dissolved in dry ethyl ether (20 ml) under nitrogen at ambient temperature and n-BuLi (0.7 ml, 2.5 M, 1.74 mmol) was added and the solution was stirred for 4 hours. 3-Dipropylamino-5-acetylchroman (Example 7; 0.40 g, 1.45 mmol) was dissolved in dry diethyl ether (2.0 ml) and this solution was added to the previously formed Wittig-reagent. The mixture was stirred at ambient temperature overnight. The solution was diluted with toluene and washed with water. Drying of the organic phase with Na-SO. and evaporation to dryness gave a solid, which was finally purified by flash chromatography by elution with ethyl acetate/hexane 1:4. The collected fractions were evaporated and gave the title 13 compound as a colourless oil. C-NMR: 11.82 21.94 24.28 26.69 52.79 53.64 67.70 115.03 115.13 118.73 120.07 126.83 144.88 145.27 154.03. Example 14 3-Dipropylamino-5-aminochroman 3-Dipropylamino-5-methyloxycarbonylchroman (Example 2; 1.0 g, 3.4 mmol) was dissolved in methanol (20 ml). Sodium hydroxide (0.16 g, 4.1 mmol) in water (1.0 ml) was added and the solution was refluxed with nitrogen overnight. The solution was evaporated to dryness, toluene (20 ml) was added and again the solution was evaporated to dryness. The residue was dissolved in toluene 20 ml, diphenylphosphoryl azid (1.87 g, 6.8 mmol) was added and the solution was refluxed for 2 hours. Methanol (2.0 ml) was added and reflux was continued for 4 hours. The solution was cooled, washed with water and extracted with dilute HCl (aq.). The acidic water phase was neutralized NaOH (aq.) and extracted with toluene. The toluene-phase was dried with sodium sulphate and evaporated to dryness. The residue was dissolved in ethanol containing 10% NaOH (20 ml) and the solution was refluxed overnight. The solution was cooled and diluted with toluene. Washing with water, drying of the organic phase and evaporation to dryness afforded the title compound as an oil, which was converted to a dihydrochloride salt. Mp 173- 174°C. Example 15 3-Dipropyla ino-5-nitrochroman 3-Dipropylamino-5-aminochroman (Example 14; 0.050 g, 0.20 mmol) was dissolved in a mixture of trifluoracetic acid (0.080 ml, 1.0 mmol) in water (5 ml). The clear solution was cooled to 0-4°C. Sodium nitrite (0.017 g, 2.5 mmol) in water (1.0 ml), was added dropwise with good stirring. The solutio was stirred for 15 minutes and neutralized with calcium carbonate. A solution of sodium nitrite (0.50 g, 7.2 mmol) in water (1.0 ml) was added followed by a mixture of copper sulfate (0.10 g, 0.62 mmol) and copper (1) oxide in water (1.0 ml). The solution was stirred at 0°C for 20 minutes and then at ambient temperature for 2 hours. The solution was extracted with diethyl ether. The organic phase was dried with sodium sulfate and evaporated to dryness. The residue was purified by flash chromatography on silica gel by elutio with ethyl acetate/hexane 1:9 to give the title compound. Mp 150-151°C (hydrochloride) . Example 16 3-Dipropylamino-5-azidochroman 3-Dipropylamino-5-aminochroman (Example 14; 0.050 g, 0.20 mmol) was diazotized according to the procedure of Example 15. After stirring for 15 minutes, sodium azide (0.026 g, 0.4 mmol) in water (1.0 ml) was added. After stirring at 5°C overninght the solution was worked-up and purified according to the procedure of Example 15 to give the title compound. Mp 167-168°C (oxalate). Example 17 - 3-Dipropylamino-5-(pyrrol-1-yl)chroman 3-Dipropylamino-5-aminochroman (Example 14; 0.60 g, 2.42 mmol) was dissolved in acetic acid (10 ml) and 2,5-dimethox tetrahydrofuran (0.40 g, 3.0 mmol) was added. The solution was refluxed for 1 hour. The solution was neutralized with NaOH (aq.) and extracted with toluene. The organic phase was dried with sodium sulfate and evaporated to dryness. The residue was purified by flash chromatography on silica gel by elution with ethyl acetate/hexane 1:9 to give the title compound. 13 C-NMR: 111.75 21.89 24.81 52.69 53.15 67.94 108.93 115.67 118.22 118.44 121.87 127.22 141.47 155.27 Example 18 3-(Methyl(3-phenylpropyl)amino)-5-hydroxychroman 3-Amino-5-methoxychroman (Thorberg et al. Acta Pharm. Suec. 24(1987)) (2.0 g, 9.28 mmol) was dissolved in methanol (50 ml) and pH was adjusted to 6.0 with acetic acid. The solution was cooled to 0°C and sodium cyanoborohydrid (0.87 g, 13.8 mmol) was added together with 3-phenylρropanal (1.22 ml, 9.28 mmol), the cooling was withdrawn and the solution was stirred at ambient temperature for 4 hours. Paraformaldehyde (0.42 g, 14 mmol) and sodium cyanoborohydride (0.87 g, 9.28 mmol) was added and stirring was continued overnight at ambient temperature. The solution was diluted with toluene and washed with water. Drying with sodium sulfate and evaporation to dryness gives an oil. The oil was purified by flash chromatography on silica gel by elution with ethylacete/hexane 1:4. The collected fractions were evaporated to give an oil. The oil was treated with HBr (47% aq. ) at 120°C for 1 hour. The solution was cooled and neutralised with sodium hydroxide and extracted with toluene. The organic phase was dried and evaporated to give the title compound as an oil. 13 C-NMR: 22.502 29.09 33.47 38.19 53.66 67.75 102.04 109.20 110.46 125.78 127.05 128.36 142.20 155.29 158.28. Example 19 3-(methyl(3-phenylpropyl) )amino-5-methyloxycarbonylchroman 3-(methyl(3-phenylpropyl) )amino-5-hydroxychroman (Example 18; 1.0 g, 3.37 mmol) was dissolved in CH-C1- (20 ml) at - 20°C. Pyridine (0.32 ml, 4 mmol), trifluoromethanesulfonic anhydride (0.65 ml, 5.9 mmol) and dimethylaminopyridine (DMAP), (0.041 g, 0.59 mmol) was added at -20°C under nitrogen. The solution was stirred for 3 hours at -20°C. Cooling was withdrawn and the solution was diluted with toluene, washed with sodium hydrogen carbonate (aq.), dried with sodium sulfate, filtered through silica gel and evaporated to dryness. The remaining oil was dissolved in 13 ml degassed methanol/DMF 3:10. Palladium acetate (0.056 g, 0.25 mmol), 1,3-bis(diphenylphosphino) ropane (0.103 g, 0.25 mmol) and triethyl amine (0.76 ml, 5 mmol) was added and the solution was flushed with CO(g) under vigorous stirring. The pressure in the reaction vessel was raised to 20.2 KPa(e) with the aid of a CO(g)-cylinder fitted with a regulator. Stirring was continued overnight at 75°C. The pressure and temperature was normalized and the solution was diluted with toluene and washed with water. The organic phase was dried and evaporated to dryness. The remaining oil was purified by flash chromatography on silica gel by elution with ethyl acetate/hexane 1:4. The collected fractions were evaporated to give the title compound as a colourless oil. C-NMR: 26.88 29.00 33.20 37.85 51.64 53.37 55.44 67.24 120.60 123.0 123.40 125.59 126.47 128.17 128.24 130.36 142.01 154.93 167.29. Example 20 3-(methyl(3-phenylpropyl) )amino-5-N-methylcarbamoyi chroman 3-(methyl(3-phenylpropyl) )amino-5-methyloxycarbonylchroman (Example 19; 0.32 g, 0.94 mmol) was dissolved in methanol (10 ml). NaOH (0.08 g, 2 mmol) in 1 ml water was added and the solution was refluxed overnight under nitrogen. The solution was evaporated to dryness and co-evaporated with toluene (10 ml) to dryness again. The remaining solid was refluxed in SOCl- for 30 minutes and evaporated to dryness. The pale brown gum was dissolved in tetrahydrofuran (THF) 2 ml and treated with methyl amine (g) for 1 minute under vigorous stirring. The solution was diluted with toluene and washed with sodium hydrogencarbonate (aq.). Drying and evaporation gave a gum, which was finally purified by flash chromatography on silica gel by elution with ethyl acetate- /hexane 1:2. The collected fractions were evaporated to give the title compound as a colourless gum. Crystallization from ethyl acetate as oxalate gave white needles. Mp 150-151°C. (oxalate) . Example 21 3-Dipropylamino-5-trifluoromethanesulfonylthiochroman 3-Dipropylamino-5-hydroxybenzothiopyran (EP 0222 996; 420 mg, 1.58 mmol) and collidine (0.27 g, 0.29 mL) were dissolved in 15 mL of CH-Cl- and cooled to -30°C. Trifluoromethanesulfonic anhydride (0.54 g, 0.32 mL) was added dropwise and allowed to reach ambient temperature, and after 20 minutes diluted with methylendichloride. The solution was washed with saturated NaHCO-, dried with Na 2 SO., and evaporated in vacuo. Chromatography on silica by elution with CHCl- gave 0.62 g of the title compound as the base. Yield: 98%. Mp. 37-8°C; 13 C NMR (200 MHz-CDCl 3 ) PPM 148.3, 136.7, 128.4, 127.2, 126.3, 122.0, 117.1, 115.2, 55.6, 52.5, 28.0, 26.6,- 22.6,11.8. Example 22 3-Dipropylamino-5-methyloxycarbonylthiochroman 3-Dipropylamino-5-hydroxybenzothiopyran (EP 0222 996; 620 mg, 1.6 mmol) was dissolved in 11 mL of dimethyl- formamide/methanol (6:2) and the solution was degassed (10 mm, 22°C, 15 min). Pd(OAc) 2 (llmg), 1,3-bis-diphenyl- phosphinopropane (19 mg), and triethylamine (0.48 mL, 0.35 g) were added to the reaction mixture. The mixture was heated to 70°C under carbonmonoxide atmos¬ phere and stirred for 5 hours. The solution was cooled, diluted with 30 mL of toluene, washed with saturated NaHCO-, dried with Na 2 SO., and evaporated in vacuo. Chromatography on silica by elution using a gradient CHC1- -> 10% EtOAc/CHCl 3 gave 310 mg of the title compound (base) as a slightly yellow oil; Yield: 64%. 13 C NMR (200 MHz-CDCl-) PPM 168.2, 136.6, 134.8, 131.6, 130.1, 126.5, 125.7, 56.7, 52.5, 52.1, 30.4, 28.0, 22.3, 11.9. Example 23 3-Dipropylamino-5-acetylthiochro an 3-Dipropylamino-5-methyloxycarbonylthiochroman (Example 22; 310 mg, 1.01 mmol) was dissolved in 8 mL metha¬ nol and 60 mg of sodium hydroxide in 2 mL water was added. After 5 hours reflux the mixture was cooled and evaporated in vacuo. The residue was dissolved in thionylchloride (5 ml) and refluxed for 1 hour. The excess thionylchloride was evaporated in vacuo to obtain a gum. The residual gum was dissolved in a minimal amount of tetra¬ hydrofuran and added dropwise to a cooled (-78°C) solution of lithium dimethyl cuprate (2.02 mmol) in 20 mL of tetra- hydrofuran. The reaction mixture was stirred for 15 minutes at -78°C, then allowed to reach ambient temperature and after 10 minutes the reaction was quenched with 0.9 L of water. II The reaction was filtered through Celite and evaporated to dryness. The residue were dissolved in ether, washed with saturated NaHCO-, treated with brine, dried with Na-SO., and evaporate in vacuo to afford the crude base as an oil. The crude residue was chromatographed on silica by elution using a gradient of CHCl 3 -> 5% EtOAc/CHCl-. The hydrc- hloride salt was obtained by dissolving the pure base in ether and dropping an excess of an ethereal HCl solution. Recrystallization in trichloromethane/diethylether gave 92 mg of the title compound as a white solid; Yield: 27%. Mp 141-2°C; 13 C NMR (200 MHz-CDCl-.) PPM 201.9, 138.4, 135.9, 13T.7, 131.2, 127.2, 127.0, 59.9, 54.1, 51.8, 29.9, 27.9, 26.1, 18.6, 18.2, 11.6. Example 24 5-Allyl-3-(dipropylamino)thiochroman To a solution of 3-(dipropylamino)-5-trifluoromethane¬ sulfonylthiochroman (Example 21; 1.28 g, 3.22 mmol), tetra- kis(triphenylphosphine)palladium(O) (76 mg, 0.064 mmol) and a few crystals of 2,6-di-t-butyl-4-methylphenol in 10 mL anhydrous toluene was 1.17 g (1.1 mL, 3.53 mmol) tributyl- allyltin added neat. The resulting solution was refluxed for 4 hours then pyridine (1 mL) was added to the cooled solution followed by 2.1 ml of a hydrogen fluoride-pyridine complex (Stille J.K. et al. JOC 52(1987) 422). After stirring for 1 hour at room temperature, the reaction mixture was diluted with 50 ml dietyl ether and treated, successively, with 50 mL 1 M NaOH solution, H 2 0 (x2), washed with a saturated NaCl solution and dried (NaSO.). After filtering and removal of the solvent in vacuo, the crude was obtained as a dark oil. Chromatography on silica by elution using a gradient hexane -> 5% EtOAc/hexane gave 0.85 g of the title compound (base) as a slightly yellow oil. Yield: 91%. 13 C NMR: (200 MHz-CDCl 3 ) PPM 139.0, 136.5, 134.0, 133.0, 126.1, 125.9, 125.0, 116.0, 57.0, 52.6, 37.7, 29.5, 27.7, 22.5, 11.9. A portion of the base was taken out and made into the hydro- chloride salt by dissolving the pure base in ether and dropping an excess of an ethereal HC1 solution. Recrystal- lizing (AcCN-Et20-hexane) gave a white solid. Mp 164-5°C. Example 25 3-(Dipropylamine)-5-propylthiochroman hydrochloride To a stirred suspension of potassium azodicarboxylate (0.76 g, 3.9 mmol) (made fresh from diethyl azbcarboxylate and potassium hydroxide) and 5-allyl-3-(N,N-dipropylamino)- thiochroman (Example 24; 0.4 g, 1.4 mmol) in 10 mL anhydrous methanol was added a solution of glacial acetic acid/methano (1:4) until the yellow color (from the potassium salt) disappeared. After 30 min stirring at room temperature more potassium azodicarboxylate (200 mg) was added and again decomposed as before. This process was continued until analysis (GC) showe no starting material remaining. Upon completion, (2 hours and 4 additions of the potassium salt) the solvent was removed in vacuo. To the remains, a 2 M NaOH solution was added which was extracted (x2) with diethyl ether and the combined organic portions were treated with a saturated NaCl solution, and dried (Na-SO.). The crude base was obtained as a light colored oil upon the removal of the solvent in vacuo. Chromatography on silica by elution using a gradient hexane - 5% EtOAc/hexane gave the title compound (base) as a clear oil. The hydrochloride salt was made by dissolvning the pure base in ether and dropping and an excess of an ethereal HCl solution. Recrystallizing (chloroform-Et-,0) gave 0.30 g of a white solid. Yield: 66%. Mp 150-151°C. C NMR: (on base, 200 MHz-CDCl 3 ) PPM 141.6 133.7 132.8, 125.8, 125.6, 124.5, 57.1, 52.6, 35.3, 29.5, 27.6, 23.6, 22.4, 14.3, 11.9. Pharmacology Pharmacological treatment of depression in man Evidence is available that in depressed patients the neuro- transmission in the central nervous system (CNS) may be disturbed. These disturbances appear to involve the neuro- transmitters noradrenaline (NA) and 5-hydroxytryptamine (5- HT) . The drugs most frequently used in the treatment of depression are considered to act by improving the neuro- transmission of either or both of these physiological agonists. Available data suggest that the enhancement of 5- HT neurotransmission will primarily improve the depressed mood and anxiety, whereas the enhancement of noradrenaline neurotransmission will rather improve the retardation symptoms occurring in depressed patients. In recent years many efforts have been made to develop new drugs with high selectivity for the improvement of the 5-HT neurotransmission in the CNS. The mechanism of action for the drugs generally used today in the therapy of mental depression is indirect, i.e. they act by blocking the reuptake of the neurotrans itters (NA and/or 5-HT) released from nerve terminals in the CNS, thus increasing the concentration of these transmitters in the synaptic cleft and hence restoring an adequate neurotrans¬ mission. A fundamentally different way to improve the neurotrans¬ mission 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 kind of receptors would then be preferable. Antagonisms of the inhibitory autoreceptors located on the cellbodies of 5-HT-neurons would be another fundamentally different way to improve the 5-HT neurotransmission. Surprisingly, we have found that a group of compounds of the formula I have selective, direct stimulating or inhibitory effect on a subgroup of central 5-HT receptors. Another observation is that some of those compounds have a particularly good oral bioavailability. In order to evaluate the 5-HT-receptor stimulating effect and selectivity, the affinity for various receptors in rat brain were measured in vitro using receptor assays (Ki nM) . In vitro test: Receptor binding assay 5HT. A binding assay. Cerebral cortex + hippocampus from each rat was dissected and homogenized in 15 ml ice-cold 50 mM Tris-HCl buffer 4.0 mM CaCl 2 and 5.7 mM ascorbic acid, pH 7.5 with an Ultra-Turrax (Janke & Kunkel, Staufen, FRG) for ten s. After centrifugation for 12.5 min at 17,000 rpm (39,800 x g in a Beckman centrifuge with a chilled JA-17 rotor (Beckman, Palo Alto, CA, USA), the pellets were re- suspended in the same buffer and homogenization and centri¬ fugation repeated. To each pellet 5 ml ice-cold 0.32 M sucrose were added and homogenized for 5 sec. These samples were kept frozen at -70°C. When used they were diluted with the buffer to 8 mg tissue/ml and homogenized for 10 sec. The tissue homogenates were incubated for ten minutes at 37°C and then supplied with 10 μM pargyline followed by reincubation for 10 minutes. The binding assay followed that described by Peroutka, J. Neurochem. 47, 529-540, (1986). The incubation mixture (2 ml) contained H-8-OH-DPAT (0.25 to 8 nM) , 5 mg/ml tissue ho ogenate in 50 mM Tris-HCl buffer containing 4.0 mM CaCl 2 and 5.7 mM ascorbic acid, pH 7.5. Six different concentra¬ tions of H-8-OH-DPAT were analyzed. Binding experiments were started by the addition of tissue homogenate and followed by incubation at 37°C for 10 minutes. The incuba¬ tion mixtures were filtered through Whatman GF/B glass filters with Brandel -Cell Harvester (Gaithersburg, MD, USA) The filters were washed twice with 5 ml ice-cold 50mM Tris- HC1 buffer, pH 7.5, and counted with 5 ml Ready-solv HP (Beckman) in a Beckman LS 3801 scintillation counter. Non¬ specific binding was measured by the addition of 10 μM 5-HT to the reaction mixture. The binding data was processed by non-linear least squares computer analysis (Munεon and Rodbard, Anal. Biochem. 107, 220-239, (1980). The test results are expressed as K. and are given in nM. For instance, 3-dipropylamino-5-acetylchroman has K. 1,0 (nM), 3-dipropylamino-5-carbamoylchroman has K. 3,1 (nM), 3-dipropylamino-5-N-methylcarbamoylchroman has K. 3,3 (nM) and 3-dipropylamino-5-(2-thienylcarbonylchroman has K L 1,7 (nM).

Claims: Claims 1. A compound of the formula wherein (0 n ) Pn X is 0 or S; p is an integer 0, 1 or 2; R is hydrogen, fluoro or C.-C 8 alkyl; R. is hydrogen, C.-C 8 alkyl or C 2 -C 8 alkenyl; R 2 is hydrogen, C.-C 8 alkyl, C-,-C 8 alkenyl, C.-C. alkylaryl where aryl may contain 1 or 2 heteroatoms selected from N, O or S optionally substituted by halogen, CN, CF 3 , C.-Cg alkyl, C 2 -C 8 alkenyl or C.-C. alkoxy; or R. and R 2 may together form a 5- or 6- membered ring which may contain 1 or 2 heteroatoms selected from N, O or S; R 3 is halogen, CN, CF 3 , SO-.CF-,, N 3 , N0 2 , C 1 ~C g alkyl, C-,-Cg alkenyl, NH-,, NR 5 Rg, COR.-, 5- or 6-membered aryl which may contain 1 or 2 heteroatoms selected from N, 0 or S and being either (i) optionally substituted by one or more substituents independ¬ ently selected from halogen, CN, CF~, C^-C 8 alkyl, C 2 -Cg alkenyl or C^-C^ alkoxy or either (ii) fused at two adjacent carbon atoms to an aryl ring, said aryl ring being optionally substituted by one or more substituents independently selected from halogen, CN, CF 3 , C.-C, alkyl, C-,-Cg alkenyl or C.-C. alkoxy; R. is hydrogen, C.-C 8 alkyl or halogen; R ς is hydrogen C.-Cg alkyl or C 2 -C 8 alkenyl; Rg is C.-Cg alkyl or C 2 -C 8 alkenyl; or R. and R g may together form a 5- or 6-membered ring which may contain 1 or 2 heteroatoms selected from N, O or S; R 7 is hydrogen, hydroxy, chloro, bromo, C.-C 8 alkyl, C 2 -C 8 alkenyl, C.-C. alkoxy, NR- R- or 5- or 6- membered aryl which may contain 1 or 2 hetero¬ atoms selected from N, 0 or S optionally substitut¬ ed by one or more of halogen, CN, CF 3 , C.-C 8 alkyl, C 2 -C 8 alkenyl, or C.-C. alkoxy; R g and R g are each independently hydrogen, C..-Cg alkyl, C 2 -C 8 alkenyl, 5- or 6- membered aryl which may contain 1 or 2 heteroatoms selected from N, O or S optionally substituted by halogen, CN, CF 3 , C.-C 8 alkyl, C-,-C 8 alkenyl, C..-C. alkoxy or may together form a 5- or 6- membered ring containing 1 or 2 heteroatoms selected from N, O or S; an enantiomer or a salt thereof. 2. A compound according to claim 1 cherein X is O. 3. A compound according to claim 1 wherein ( 0 n ) D P X is S and p is 0, 1 or 2. 4. A compound according to claim 1 wherein X is S II p and p, R, R^ R-, R 3 , R 4 , R_, Rg, R 7 , R g and R g are defined as in claim 1 with the proviso that when R is hydrogen or C. -C 8 alkyl then R 3 cannot be halogen or C 1 -Cg alkyl. 5. A compound according to claim 1 wherein X is (0 D S II ) p and p is 0, R.. and R. is hydrogen, R and R- are propyl with the proviso that R- cannot be propyl. 6. A compound according to any of claims 1, 2, 3, 4 or 5 wherein R- is halogen, CF-, C.-Cg alkyl, C 2 ~Cg alkenyl, NR- R g , COR 7 , 5- or 6- membered aryl which may contain 1 or 2 heteroatoms selected from N, O or S and being either (i) optionally substituted by one or more substituents independently selected from halogen, CN, CF-, C. -C fi alkyl, C 2 ~C g alkenyl or C..-C. alkoxy or either (ii) fused at two adjacent carbon atoms to an aryl ring, said aryl ring being optionally substituted by one or more substituents independently selected from halogen, CN, CF-., C.-C fi alkyl, C 2 ~Cg alkenyl or C..-C. alkoxy; R 7 is hydrogen, C.-C 8 alkyl, C 2 ~Cg alkenyl, C.-C. alkoxy, NR g R- or 5- or 6- membered aryl which may contain 1 or 2 heteroatoms selected from N, O or S optionally substituted by one or more of halogen, CN, CF 3 , _-C 8 alkyl, C 2 -C 8 alkenyl, or C.-C. alkoxy; X, P, R, R " , R 2 , R., R J -, Rg, R g and R g are defined as in claim 1, an enantiomer or a pharmaceutically acceptable salt thereof for use in theraphy. 7 . A compound according to any of claims 1-6 , wherein R. and R- are the same or different and selected from hydro¬ gen, n-propyl, i-propyl and cyclopropyl. 8. A compound according to any of claims 1-7 wherein R- is COR 7 . 9. A compound according to claim 8 wherein R 7 is C.-C. alkyl, phenyl, furanyl or thienyl optionally substituted with halogen, NR g R g wherein R g and R g are each independently hydrogen or C.-C. alkyl, or C..-C. alkoxy. 10. A compound according to claim 8 wherein R and R. are hydrogen, R., and R_ are n-propyl and R 7 is methyl, ethyl, n-propyl, i-propyl, cyclopropyl, n-butyl, i-butyl, t-butyl, cyclobutyl, thienyl, furanyl, phenyl, a ino, N- methylamino, methoxy or fluorophenyl. 11. A compound according to any of claims 1-7 wherein R- is phenyl, furanyl, thienyl or fluorophenyl. 12. A compound according to any of claims 1-7 wherein R- is n-propyl, i-propyl, i-propenyl or allyl. 13. A compound according to any of claims 1-9, 11-12 wherein R. is halogen in 8 position. 14. A compound according to claim 1 which is 3-dipropylamino-5-acetylchroman, 3-dipropylamino-5-carbamoylchroman, 3-dipropylamino-5-N-methylcarbamoylchro an and 3-dipropy1-uτιino-5-(2-thienylcarbony1)chroman. 15. A compound according to claim 1 wherein R 3 is CN, COOH, COC1, COBr, Br, N 3 , NO-, SO.-CF.. or NH-, and X, R, R- ^ , R-. and R., are as defined in claim 1, an enantiomer or a salt thereof. 16. A compound according to claim 15 wherein R. and R- are 1 ,- the same or different and selected from hydrogen, -propyl, i-propyl and cyclopropyl. 17. A compound according to claim 16 wherein R and R. are hydrogen, R. and R 2 are n-propyl and R 3 is SO-CF-. 18. A pharmaceutical preparation containing as active ingredient a compound according to formula 7 wherein (O), X is O or S; p is an integer 0, 1 or 2; R is hydrogen, fluoro or C.-Cg alkyl; R. is hydrogen, C.-Cg alkyl or C 2 -C 8 alkenyl; R 2 is hydrogen, C.-Cg alkyl, C 2 ~Cg alkenyl, C..-C. alkylaryl where aryl may contain 1 or 2 heteroatom selected from N, O or S optionally substituted by halogen, CN, CF-., c ι~ c 6 alkyl, C 2 -Cg alkenyl or C l~ C 4 alkoxy; or R. and R 2 may together form a 5- or 6- membered ring which may contain 1 or 2 heteroatoms selected from N, O or S; R 3 is halogen, CF 3 , C--Cg alkyl, C 2 ~Cg alkenyl, R c Rg, COR 7 , 5- or 6- membered aryl which may contain 1 or 2 heteroatoms selected from N, 0 or S and being either (i) optionally substituted by one or more substituents independently selected from halogen, CN, CF 3 , C.-Cg alkyl, C 2 ~Cg alkenyl or c ι~ C 4 a lk° χ Y or either (ii) fused at two adjacent carbon atoms to an aryl ring, said aryl ring being optionally substituted by one or more substituents independently selected from halogen, CN, CF 3 , C.- Cg alkyl, C 2 -C 8 alkenyl or C.-C. alkoxy; R. is hydrogen alkyl or halogen; R. is hydrogen, C.-C 8 alkyl or C-,-C 8 alkylen; Rg is C.-C 8 alkyl or C 2 -C 8 alkylen; or R_ and R g may together form a 5- or 6- membered ring which may contain 1 or 2 heteroatoms selected from N, 0 or S; R 7 is hydrogen, C.-Cg alkyl, C 2 -C 8 alkenyl, C.-C. alkoxy, NR g R g or 5- or 6- membered aryl which may contain 1 or 2 heteroatoms selected from N, O or S optionally substituted by one or more of halogen, CN, CF 3 , C.-Cg alkyl, C-,-C 8 alkenyl, or C.-C. alkoxy; R o and R g are each independently hydrogen, C.-Cg alkyl, C_-C β alkenyl, 5- or 6- membered aryl which may contain 1 or 2 heteroatoms selected from N, O or S optionally substituted by halogen, CN, CF 3 , C.-Cg alkyl, C 2 -C 8 alkenyl, C.-C. alkoxy or may together form a 5- or 6-membered ring containing 1 or 2 heteroatoms selected from N, 0 or S; an enantiomer or a pharmaceutically acceptable salt thereof. 19. A pharmaceutical preparation according to claim 18 wherein R, R. , R 2 , R- , R., R-,, R g and R g are defined as in any of claims 7-14. 20. A compound according to any of claims 6-14 for use in the treatment of disorders in the centralnervous system, especially 5-hydroxy tryptamine medicated disorders. 21. A compound according to claim 20 for use in the treat¬ ment of depression, anxiety, anorexia, senile dementia, migraine, Alzheimer's disease, hypertension, termoregulator and sexual disturbances, pain and disturbances in the cardiovascular system. 22. Use of a compound according to any of claims 6-14 for the manufacture of a medicament for treatment of disorders in the central nervous system, especially 5-hydroxy trypt¬ amine medicated disorders. 23. Use according to claim 22 for the manufacture of a medicament for treatment of depression, anxiety, anorexia, senile dementia, migraine, Alzheimer's disease, termo¬ regulator and sexual disturbances, pain and disturbances in the cardiovascular system. 24. A method for treatment of disorders in the central nervous system, especially 5-hydroxytryptamine mediated disorders by administering to mammals and man a compound defined in any of claims 6-14, an enantiomer or a physiologically acceptable salt thereof. 25. A method according to claim 24 for treatment of de¬ pression, anxiety, anorexia, senile dementia, migraine, Alzheimer's disease, termoregulator and sexual distur¬ bances, pain and disturbances in the cardiovascular system, 26. A process for the preparation of a compound of the formula I according to any of claims 1-17, by a) converting a compound of formula II wherein Y is a leaving group and X, R, R. , R- and R, are as defined under formula I by a catalytic cycle using a zerovalent transition metal (M) , which undergoes an oxi¬ dative addition to the aryl-Y-bonds, treatment with carbon monoxide followed by Z-H , where Z is Cl, Br, OH, OR , where R P is C±.-CD, alkyl, and the initially formed car- bonylated σ-aryl-metal-Y complex, to formation of a com¬ pound of formula I wherein R., is COZ (IA). b) reaction by a catalytic cycle using a zerovalent transition metal (M°) which undergoes an oxidative addition to Z-Y, . wherein Z is defined Cl, Br,. OH,. ORp.. where R_p. is C.-C 8 alkyl and Y is a leaving group, treatment with carbon monoxide, followed by addition of the compound of the formula III III 46 wherein X, R, R. , R 2 and R. are as defined under formula I and M is a transition metal to formation of a compound of formula I wherein R-. is COZ (IA). c) converting a compound of formula II wherein X, R, R- , R- and R. are as defined under formula I and Y is a leaving group such as SO..CF-, halide by treat¬ ment with a cyanide reagent, to formation of a compound of formula I wherein R 3 is CN (IB). d. amination of a compound of formula IA IA IC wherein X, R, R. , R-, and R., are as defined under formula I and Z is Cl, OH or ORp. where R_p is C.1-C6, alkyl by reaction with NHR g R g to give the corresponding amide of formula 1 , where R 3 is CONR g R g (IC). e) Wittig reaction of a 5-carboxy compound of formula I wherein R 3 is COR 7 (ID) ID IE and X, R, R.. , R_ and R. are as defined under formula I and R 7 is alkyl, alkenyl or aryl by using a dipolar reagant to formation of a compound of formula I wherein R 3 is a C--Cg alkenyl group, (IE). f) catalytic hydrogenation of a compound of formula I wherein R 3 is a C--C. alkenyl group to obtain a compound of the formula I where R 3 is a C--Cg alkyl group (IF). g) substitution of a 5-bromochroman/thiochroman deriva¬ tive wherein X, R, R. , R 2 and R. are as defined under formula I by treatment with a stannictrialkyl reagent in presence of a zerovalent mental e.g. Pd° to obtain a compound of formula I wherein R 3 is C.-Cg alkyl, 2 -C 8 alkylen or aryl or in presence of carbonmonoxide formed a compound where R 3 is COR 7 where R 7 is C.-C 8 alkyl, 2 -C 8 alkylen or aryl. h) converting the 5-carboxychroman/thiochroman derivative of formula IA IA ID wherein X, R, R. , R 2 and R. are defined as in formula I and Z is Cl, Br by using R.-Li to obtain corresponding compound of formula I when R is COR-, (ID) where R 7 is defined as C.-C 8 alkyl, C-,-C 8 alkenyl or aryl; i) hydrolysis of a compound of formula I wherein R- is CN (IB) IB wherein X, R, R. , R„ and R_ are as defined under formula I optionally followed by treatment with thionylhalide to obtain a compound of formula I wherein R-. is COZ, where Z is OH, Cl or Br (IA) j ) substitution of a compound of formula I wherein R 3 is IB wherein X, R, R. , R 2 and R. are as defined under formula I by treatment with an organometallic reagent followed .by hydrolysis to obtain a compound of formula I wherein R 3 is COR 7 , where R 7 is C.-Cg alkyl, C 2 ~Cg alkenyl or aryl (ID); k) Hydrogeneration of a 5-alkene thiochroman/chroman derivative of formula I wherein R 3 is a C 2 -C 8 alkenyl group by using H-/Pd, H 2 /Pt or H 2 /Raney Ni or potassium azodicarboxylate to formation of corresponding thio-chroma- n/chroman derivative of formula I wherein R- is C.-Cg alkyl; 1) converting a compound of formula II wherein Y is a leaving group and X, R, R. , R 2 and R. are as defined under formula I by reaction with a transition metal, to form a ligand complex which undergoes an oxi¬ dative addition by treatment with a trialkylalkenyl- stannane, to formation of a compound of formula I wherein R 3 is a C 2 ~Cg alkenyl group. m) converting a compound of formula II wherein Y is a leaving group and X, R, R. , R- and R. are as defined under formula I by a reaction with a transition metal to form a ligand complex, which undergoes an oxida¬ tive addition by treatment with a trialkylaryl stannane or aryl-boric acid reagants, to formation of a compound of formula I wherein R 3 is a 5-6-membered aryl which may contain 1 or 2 heteroatoms selected from N, 0 or S being either substituted or fused at two adjacent carbon atome; whereupon optionally a base obtained is converted to a acid addition salt or a salt obtained is converted to the base or to a different, acid addition salt, or optionally an isomeric mixture obtained is separated to a pure enantiomer. 27. Compounds, processes, pharmaceutical preparations, use of and method of treatment as claimed in any of claims 1- 26 and substantially described.

Inventors: LARSSON LARS-GUNNAR, NOREEN ROLF, RENYI LUCY ANNA, ROSS SVANTE BERTIL, SOHN DANIEL DUNGAN, SVENSSON BJOERN ERIC, THORBERG SETH OLOV, LARSSON, LARS-GUNNAR, NOREEN, ROLF, RENYI, LUCY, ANNA, ROSS, SVANTE, BERTIL, SOHN, DANIEL, DUNGAN, SVENSSON, BJOERN, ERIC, THORBERG, SETH, OLOV
Applicants: ASTRA AB, AKTIEBOLAGET ASTRA
Application year: 1990
Main classification: C07D335
IPC codes: A61K31, A61P25, C07D311, C07D335, C07D405, C07D407, C07D409, C07D413, C07D417