WO1982004042A1

WO1982004042A1 - Therapeutically useful tetralin derivatives iii,processes for preparation and pharmaceutical preparations for such compounds

Info

Publication number: WO1982004042A1
Application number: PCT/SE1982/000160
Authority: WO
Inventors: Folke Lars Erik Arvidsson; Per Arvid Emil Carlsson; Uli Alf Hacksell; John Stephan Mikael Hjorth; Anette Margareta Johansson; Per Lennart Lindberg; John Lars Gunnar Nilsson; Domingo Sanchez; Hakan Vilhelm Wikstroem
Original assignee: Folke Lars Erik Arvidsson; Per Arvid Emil Carlsson; Uli Alf Hacksell; John Stephan Mikael Hjorth; Anette Margareta Johansson; Per Lennart Lindberg; John Lars Gunnar Nilsson; Domingo Sanchez; Hakan Vilhelm Wikstroem
Priority date: 1981-05-11
Filing date: 1982-05-10
Publication date: 1982-11-25
Also published as: EP0091437A1; FI832108A0; DK576182A; NO830040L; AU8455082A; JPS58500714A; FI832108L

Abstract

Compounds of the formula <IMAGE> wherein Y is OH, R<4>COO, (R<5>)2NCOO or R<6>O, whereby R<4> is an alkyl group having 1-5 carbon atoms or a possibly substituted phenyl group, R<5> is an alkyl group having 1-5 carbon atoms and R<6> is an allyl or benzyl group, R<1> is an alkyl group having 1-3 carbon atoms, R<2> is an alkyl group having 1-6 carbon atoms, and R<3> is an alkyl group having 1-3 carbon atoms, processes and intermediates for their preparation, pharmaceutical preparations and methods of treatment employing such compounds. The compounds are useful for therapeutic purposes, especially for treatment of disorders in the central nervous system.

Description

THERAPEUTICALLY USEFUL TETRALIN DERIVATIVES III, PROCESSES FOR PREPARATION AND PHARMACEUTICAL PREPARATIONS FOR SUCH COMPOUNDS.

DESCRIPTION

Technical Field

The present invention is related to new 1,2,3,4-tetra-hydro-2- -naphtyl amines, to processes for preparing such compounds, pharmaceutical preparation of such compounds and the use of such compounds in therapy.

An object of the invention is to provide compounds for therapeutic use, especially compounds having a therapeutic activity in the central nervous system.

Background Art

Compounds of the formula

wherein Y^II and R^IV are H, Y^I is CH₃O, R^I and R^II are H or CH₃ and R^{I I I} is either CH₃ or phenyl have been described in Chem. Pharm.

Bull., 20, 1321 (1972) and Chemical Abstracts 81 : 120417 K, respectively . Further, a compound wherein R , R¹' and R are H, Y^I and Y^II are CH₃O and R^III is phenyl has been described in Chem. Pharm. Bull., 21, 439 (1973). The above mentioned compounds possess analgesic activity.

In J. Pharm. Sci., 60, 201 (1971) and J. Med. Chem. 14 , 60 (1971) compounds wherein Y^I is H or CH₃O, Y^{I I} is H, R^I and R^II are H or CH₃, R^III is CH₃ or benzyl and R^IV is CH₃ have been described as compounds possessing analgesic activity. W.H. Shelver (Thesis, 1962; Diss. Abstr. 25, 7444 (1965); CA 63 : 14901 g) describes compounds of the formula

wherein R^III is COOH, COOCH₃, COCH₃, COC₆H₅, CH₂OH and CH₂OCOC₆H₅. The compounds have been tested for analgesic activity.

German Patent 2,752,659 describes i.a. compounds of the formula

wherein Y^I is 5-OH, 6-OH and 7-OH, R^I is H, CH₃, n-C₃H₇, i-C₃H₇ or benzyl and R^{I I} is H, CH₃ or C₃H₇. The compounds are stated to have stimulating effects on α- and β-adrenoreceptors as well as on dopamine receptors.

In Biomed. Mass Spectrom., 8, 90 (1981) U. Hacksell et al. presents mass fragmentation analyses of several 2-aninotetralins, i.a. a compound of the formula

Disclosure of Invention

According to the present invention it has been found that novel compounds of the formula

wherein Y is OH, R⁴COO, (R⁵)₂NCOO or R⁶O, whereby R⁴ is an alkyl group having 1-5 carbon atoms or a possibly substituted phenyl group, R⁵ is an alkyl group having 1-5 carbon atoms and R⁶ is an allyl or benzyl group, R is an alkyl group having 1-3 carbon atoms, R² is an alkyl group having 1-6 carbon atoms, and R³ is an alkyl group having 1 -3 carbon atoms, as bases and pharmaceutically acceptable acid addition salts thereof, possess unexpected pharmacological properties rendering them useful in therapy and full- filling the objects stated above. Processes for preparation of such compounds, their pharmaceutical and medical use and pharmaceutical preparations and methods of treatment employing such compounds constitute further aspects of the invention.

The alkyl groups may be straight alkyl groups or branched alkyl groups .

A possibly substituted phenyl group R⁴ may be a phenyl, 2,6-dϊmethyl- phenyl or 3- or 4-hydroxyphenyl group or a 3- or 4-alkanoyloxypnenyl group with the formula

wherein R⁷ is an alkyl group having 1-6 carbon atoms.

Symbols for numbers, atoms or groups referred to below have the broadest meaning previously assigned unless specified otherwise.

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 a re sulfuric, nitric, phosphoric, hydrochloric, citric, acetic, lactic, tartaric, pamoic, ethanedisulfonic, sulfamic, succinic, cyclohexylsulfamic, fumaric, maleic and benzoic acid. These salts are readily prepared by methods known in the art.

In a restricted embodiment the invention is related to compounds of the formula I above wherein Y is OH, R⁴COO, (R⁵)₂NCOO and R⁶O, wherebv R⁴ is a possibly substituted phenyl group, R⁵ is CH₃ and R⁶ is an allyl group, and R¹, R² and R³ are as specified above. In a further restricted embodiment the invention is related to compounds of the formula I above wherein Y is OH, R⁴COO and R⁶O, whereby R⁴ is a possibly substituted phenyl group and R⁶ is an allyl group, and R¹, R² and R³ are as specified above. In a still further restricted embodiment the invent ion is related to compounds of the formula I above wherein Y is OH, R⁴COO, (R⁵)₂NCOO and R⁶O wherein R⁴ is methyl, phenyl, or 4-alkanoyloxyphenyl wherein the alkyl group has 1-4 carbon atoms, R⁵ is methyl, R⁶ is ally], R¹ is alkyl having 1-3 carbon atoms, R² is alkyl having 3-6 carbon atoms, and R³ is methyl or ethyl.

Preferred among the compounds of the formula 1 wherein y represents R⁴COO are those wherein R⁴ is a 4-alkainoyloxyphenyl group wherein the alkyl group (R⁷) has 4-6 carbon atoms.

According to a preferred embodiment the invention is related to compounds of the formula 1 wherein R¹ is n-C₃H₇.

Preferred compounds are those wherein R¹ is n-C₃H₇, R² is an alkyl group containing 3~6 carbon atoms and R³ is CH₃ or C₂H₅. Further preferred are compounds wherein R¹ is n-C₃H₇, R² is an alkyl group with 3-5 carbon atoms and R³ is CH³.

Examples of compounds of the formula I according to the invention ace given in the fol lowing Table.

The compounds of the invention contain an asymm atric carbon atom in the heterocyclic ring moiety. The therapeutic properties of the compounds may to a greater or lesser degree be ascribed to either or both of the two enantiomers occurring. Thus the pure enantiomers as well as mixtures thereof are within the scope of the invention.

Preferred among the two pure enantiomeric forms is that form which has the same absolute configuration (at the nitrogen - carrying 2-carbon atom) as the levorotameric (-)-5-hydroxy-2-methyl-2-(di-n-propylamino) tetralin.

The invention takes into consideration that compounds which structurally deviates from the formula I, after administration to a living organism may be transformed to a compound of the formula I and in this structural form exert their effects. This consideration is a further aspect of the invention. Likewise, certain compounds of formula I may be metabolized into other compounds of formula I before exerting their effect. Compouuds of the invention wherein Y is R⁴COO, ( R⁵) ₂NCOO or R⁶O are thus believed to exert their main activity after metabolism to compounds wherein Y is OH.

Methods of Preparation

The compounds of the invention may be obtained by one of the following methods constituting a further aspect of the invention.

An ether or ester of the formula

with RO in position 5 and wherein R represents a hydrocarbon or acyl residue, preferably an alkyl group having 1-5 carbon atoms or a benzyl group, or an alkylcarbonyl grouo having 2-6 carbon atoms, and R¹, R² and R³ are as defined above, may be cleaved to form a compoundof formula I wherein Y is a hydroxy group

When R is a hydrocarbon residue the cleavage may be carried out by treating the compound of formula II with an acidic nucleophilic reagent such as aqueous HBr, or HI, HBr/CH₃OOH, BBr₃, AlCl₃, pyridine-HCl or

(CH₃)₃ SiI, or with a basic nucleophilϊc reayent such as CH₃C₆H₄ -S or C₂H₅-S

. When R is a benzyl group the cleavage may also be carried out by reduction, preferably with hydrogen using Pd or PtO₂ as catalyst.

When R is an acyl residue the cleavage may be carried out by hydrolysis in an aqueous acid or base or by reduction, preferably by LiAlH₄.

The compound of formula II is obtainable by the following synthetic route:

Thus, a compound of formula IIA is methyl carboxyl ated by reaction with methyl carbonate in the presence of NaH giving the keto-ester IIB, which is C-alkylated by R³X (X=Br, l) in the presence of a base such as NaOC₂H₅ followed by hydrogenolysis of the keto function and hydrolysis of the ester function giving the caboxylic acid IIC. Reaction of compound IIC with CICOOC₂H₅ in the presence of tr iethyl ami ne fo-1 lowed by convertion to an azide by NaN₃ and Curt ius-rearrangemeπt and acid hydrolysis to a amino-containing compound II D, N-acylation by R^XCOCl (wherein R^X is defined by the relation R^X-CH₂-equals R¹) in the presence of a base,

LiAlH₄-reduction, once again N-acylation by R^yCOCl (wherein R^y is defined by the relation R^y-CH₂ -equals R²) in the presence of a base and finally tiAlii_*-redaction give a compound of the formula II.

A pure enantiomer of compound II may be prepared by first conversion of II E into the (-)-0-methylmandelic acid amide II F followed by chromatographic separation of the two diastereomers and cleavage by subsequent reaction with potassium tert-butoxide in tetrahydrofuran with traces of water and CH₃Li, and then the desired of the two enantiomers (II E 'and E") is alkylated.

A compound of formula

wherein R¹, R² and R³ a re as defined above may be converted into a compound of formula I wherein Y is R⁴COO, ( R⁵)₂NCOO or R⁶O by treating the. first mentioned compound with an appropriate carboxylic acid halide R⁴COX or anhydride ( R⁴CO)₂O or with an appropriate carbaπoyl halide (R KNCOX in the presence of a base such as tr iethylamine or pyridine or an acid such as H₂SO₄ or CF₃COOH or with an appropriate allyl or benzyl halide R⁶X in the presence of a base such as triethylamϊne, pyridine or potassium t-butoxide. X represents a halogen, preferably Cl or Br.

Alternatively, when conversion of Y = OH into R⁴COO is intended and R⁴ is R⁷COOC₆H₄- a compound of formula I wherein Y is OH may first be converted to a compound of formula I wherein Y is HOC₆ H₄COO- which is then treated with an appropriate carboxylic acid halide R⁷COX or anhydride (R⁷CO)₂O in the presence of a base or an acid. c) A compound of the formu l a

wherein R^a is either R¹ or R², and R¹, R², R³ and Y are as defined above, may be converted into a compound of formula 1 by alkylation of the nitrogen atom with an appropriate alkylating agent. Thus, the starting compound wherein R^a is R¹ may be treated with an alkyl halide or tosylate R¹X¹, wherein X represents C1 , Br, I or -OSO₂- C₆H₄CH₃ 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 may be treated with a carboxylic acid NaBH₄ complex R^bCOOH-NaBH₄, wherein R^b is defined by the relation R^b-CH₂ equals R².

To the formation of a compound of formula 1 wherein at least one of R¹ and R² is CH₃, the alkylation reaction may be carried out by treatment of the compβund of formula IV with a formaldehyde - Na(CN)8H₃ mixture, or with formaldehyde and formic acid.

d) An amide of the formula

wherein Y is OH or R⁶O, and R⁶ is as def ined above, R^C is an alkyl group defined by the relation R^C-CH₂- equals either R¹ or R² and R^d is the other of R¹ and R², may be reduced, e.g. by treatment with a hydride reducing agent such as LiAlH₄ in ether or tetrahydrofuran or BH₃ in tetrahydro furan, to the formation of a compound of formula I.

e) A compound of the formula

wherein M¹ and M² are the same or different and each represents -CH₂-,

when M¹ and M² are -CH₂- and in other cases M³ is R³ , Z¹ is a group sensitive to hydrogenolys is such as hydroxy in benzyl ic position (M¹ or M²) or halogen, R is hydrogen, methyl or ethyl, Y is other than allyloxy and R¹, R² and R³ are as defined above may be converted to a compound of formula I by reduction. Thus, a keto function may be either directly converted to CH„ by treatment with e.g. hydrazine under alkaline conditions or by a stepwise reduction by using e.g. catalytic hydrogenatϊon which may involve an intermediary formation of an hydroxy group and,where possible, also an elimination to a double bond. Reduction of a group ^CH-Z' may be carried out by using a nucleophilic hydride reducing agent such as LiAlH₄, or catalytic hydro genat ion.

f) An aziridinium salt (e.g. C10-₄ or BF-₄ ) with the formula

wherein Y is other than allyloxy and R¹ and R² are as defined above may be converted by reduction, preferably by catalytic hydrogenation, into a compound of the formula I wherein R³ is CH₃.

g) In a compound of the formula

wherein X represents SO₃H, Cl or NH₂ a hydroxy group may be substituted for the group X to the formation of a compound of formula I wherein Y represents a hydroxy group. When X is SO₃H or Cl said reaction may 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 NH₂ the reaction may be carried out by treatment with aqueous nitrous acid to the formation of an intermediate diazoπϊum compound which is then subjected to hydro lysis in water. A racemic mixture or a mixture partly enriched on one of the enantiomers of a compound of formula

may be subjected to enantiomeric separation to obtain a pure enantiomer of compound I. This may be done by methods known in the art. These methods include recrystallization of diastereomeric saltswith pure enantiomers of acids such as tartaric acid, 0,0- -dibenzoyltartaric acid, mandelic acid and camphor-10-sulphonic acid.

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

Pharmaceutical Preparations

Pharmaceutical preparations of the compounds of the 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, and the like, in association with a pharmaceutically acceptable carrier.

Accordingly, terms relating to the novel compounds of this invention, whether geπerically or specifically, are intended to include both the free amlne base and the acid addition salts of the free base, unless the context in which such terms are used, e.g. in the specific examples, would be inconsistent with the broad concept. The carrier may be a solid, semlsolid or liquid diluent or capsule. These pharmaceutical preparations constitute a further aspect of this invention. 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 preparation intended for injection and between 0.2 and 95% by weight for preparations sui table for oral administration. Pharmaceutical preparations containing a compound of the invention in a solid form of dosage units for oral application may preferably contain between 2 and 95% by weight of the active substance, in such preparations the selected compound may be mixed with a solid fine grain carrier, e.g. lactose, saccharose, sorbitol, mannitol, starches such as potato starch, corn starch or amylopect in, cellulose derivatives, or gelatin and a lubricant such as magnesium stearate, calcium stearate, polyethylene glycol waxes, and the like, and then compressed to form 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, gelatin, talcum, titanium dioxide, and the like. Alternatively the tablet can be coated with a lacquer 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 compound.

For the preparation of soft gelatin capsules (pearl-shaped closed capsules) consisting of gelatin and, for example, glycerol, or similar closed capsules, the active substance may be admixed with a vegetable oil. Hard gelatin capsules may contain granulates of the active substance in combination with solid, fine grain carriers such as lactose, saccharose, sorbitol, mannitol, starches (e.g. potato starch, corn starch or amylopectin), cellulose derivatives or gelatin.

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 substance herein described, the balance being sugar and a mixture of ethanol, water, glycerol and propylene glycol. Optionally such liquid preparations may contain colouring agents, flavouring agents, saccharine and carboxymethylcellulose as a thickening agent.

Solutions for parenteral applications by injection can be prepared in a aqueous solution of a water-soluble pharmaceutically acceptable salt of the active substance preferably 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.

In therapeutical treatment the suitable daily doses of the compounds of the invention are 100-5000 mg for oral application, preferentially 500-3000 mg, and 0.5-500 mg for parenteral application, preferentiaIly 25-250 mg. Working examples

The following examples will further illustrate the invention.

preparation of intermediates

Example-11 (±)-5-Methoxy-2-methyl-2-(di-n-propylamino) tetralin

5-Hethoxy-2-methyltetralin-2-carboxylic acid

A solution of methyl 5-methoxy-1-oxotetralin-2-carboxylate (25 g, 100 mmol) in dry EtOH (125 mL) was slowly added to a freshly prepared mixture of 80% NaH (3.3 g, 110 mmol), dry benzene (125 mL), and dry EtOH (125 mL). The resulting slurry was refluxed for 20 h under N₂ After cooling, three 10 mL portions of methyl iodide (68.4 g, 465 mmol) was added. The reaction mixture was refluxed for 1 h, whereafter It was neutralized with acetic acid. The volatiles were evaporated in vacuo and the residue was first passed through a short alumina column with ether as eluant and then chromatographed on a silica column with ether- - light petroleum (1:2) as eluant affording 24 g of methyl 5-methoxy- -2-methyl-1-oxotetralin-2-carboxylate as an oil. The oil was dissolved in acetic acid (500 mL), perchloric acid (1 mL) was added and the resulting solution was hydrogenated at atmospheric pressure over Pd/C (5 g). After 24 h the reaction was complete, the catalyst was filtered (Celite) and CHCl₃ (1000 mL) was added. Washing the organic layer several times with 100 mL portions of H₂O followed by evaporation of the CHCl₃ in vacuo gave on oil which was refluxed for k h with HeOH ( 100 mL) , H₂O (125 mL) and KOH pellets (50 g). The HeOH was evaporated in vacuo, and the product was precipitated by addition of ice-cold 10% HCl to the resulting solution. Two recrystallisations from EtOH-H₂O gave 9.6 g (44%) of pure 5-methoxy- -2-methyltetralin-2-carboxylic acid , mp 138-149^ο C.

(+)-2-Amino-5-methoxy-2-nethyltetralin

This compound was prepared from 5-methoxy-2-methyltetralIn-2-carboxylic acid (8.75 g, 38 mmol) according to the method used by Nichols et al. (J. Med. Chem. 21 , 395 (1978) for the preparation of 2,3-dimethoxy-9- amIno-9, 10-dihydrophenantrene from 2,3-dimethoxy-9, 10-dihydrophenantrene- -9-carboxylic acid. The amine was converted to the hydrochlor ide and recrystallized twice from EtOH-ether. Yield 5.8 g (76%), mp 249.5 - 251-5^οC ^(decomp.) ( ±)-5-Methoxy-2-methyl -2- (n -propyla min o ) tetral i n

Propionyl chloride (4.6 g, 49 mmol) in dry ether (60 mL) was added to a solution of 2-amino-5-methoxy-2-rnethyltetralin (6.3 g, 33 mmol) and triethylamine (4.9 g, 49 mmol) in dry ether (750 mL). After 30 min at room temperature the reaction mixture was filtered and the ether was evaporated. The resulting crude amide was passed through an alumina column eluted with ether. The purified amide dissolved in dry THF (100 mL) was added to a suspension of LiAlH₄ (7.2 g, 187 mmol) in dry THF (200 mL) under N«. After stirring under reflux for 3 h, the reaction mixture was hydrolyzed, the precipitate was filtered off and the solvent was evaporated. The oily residue was chromatographed on an alumina column with ether-light petroleum (1:1) as eluant yielding 6.4 g (83%) of pure 5-methoxy-2-methyl-2-(n-propylamino) tetralin. The base was converted to its hydrochlor ide, mp 239 - 239-5^ο C (decomp.) (from EtOH-ether).

(±)-5-Methoxy-2-methyl-2-(di-n-propylamino) tetralin

A mixture of 5-methoxy-2-methyl-2-(n-propylamino) tetral in (4.5 g, 19 mmol), propionyl chloride (2.7 g, 29 mmol), triethylamine (2.9 g, 29 mmol), and benzene (150 mL) was stirred at room temperature for 10 h. The precipitate was filtered off, the solvent was evaporated In vacuo, and the resulting crystal Is were rinsed with ether. The resulting pure amide (3.8 g) was heated with LiAlH, (1.5 g, 39 mmol) and dioxane (100 mL) at 80^ο C until TLC indicated that the reaction was complete (19 h) . Destruction of the reaction mixture followed by addition of water and 15% NaOH, filtration of the precipitate, and evaporation of the volatiles gave an oil. This was passed through an alumina column eluted with ether affording 3.6 g (68%) of pure 5-mεthoxy-2-methyl-2-(di-n-propylamino) tetralin . The base was converted into the hydrochlorIde, mp 145 - 145-5^ο C (from EtOH-ether).

Example 1 2 (+)- and (-)-5-Methoxy-2-methyl-2(di-n-propylamino) tetralin

(+)-5-Methoxy-2-methy1-2-(di-n-propyIamino) tetralin.

R-(-)-0-Methylmandelic acid chloride (6,0 g, 0.033 mol), prepared from R-(-)-0-methylmandelic acid by treatment with thionyl chloride at 20^οC for 10 hours, dissolved in CH₂Cl₂ (5 ml) was added at room temperature to a stirred mixture of (+)-5-methoxy-2-methyl-2-(n-proρylamino) tetralin (7.0 g, 0.026 mol), CH₂C1₂ (50 ml), H₂O (50 ml) and 5% aqueous NaOH (80 ml). After stirring for 15 h the phases were separated and the organic phase was washed once with water then dried (Na₂SO₄), filtered and evaporated. Ether/light petroleum (1:3) (15 ml) was added to the residue. The mixture was cooled to about -70^οC and one of the diastereomeric amides precipitated (0.9 g) . The filtrate was evaporated and the oily residue was chromatographed on a SiO₂ (40.63 um) column with ether/light petroleum (1:3) as eluant. The diastereomer which was first eluated (0.7 g) showed to be the opposite to the diastereomeric amide which first came out as crystals from the mixture. The diastereomer which was secondly eluated (0.5 g) showed to be the same as the diastereomeric amide which first crystallized. The crystals (see above) and the diastereomer which was secondly eluated (0.9 + 0.5 g;totally: 1.4 g) were stereochemical ly pure according to HPLC. This diastereomeric amide (1.4 g, 0.0037 mol) was dissolved in THF (50 ml) and kept at -15^οC. Potassium tert-butoxide (4.0 g) was added and the mixture was kept at this temperature and under stirring for 5 hours. Ehter and H₂O were added and the phases were separated. The ether phase was extracted with 10% HCl, dried (Na₂SO₄) and evaporated giving an oil which was dissolved in day THF (20 ml) and stirred with 1.6 M solution of CH₃Li in ether (5 ml) for 30 minutes at -15^οC and then extracted with 10% HCl. The aqueous phase was combined with the 10% HCl-extract of above, alkalized with Na₂CO ₃, extracted with ether. The ether phase was treated with HCl in ether, yielding a precipitate which was recrystallized from ethanol/ether giving colorless crystals of (+)-5-methoxy-2-(n-propylamino) tetralin hydrochloride (0.75 g,2,8mmol), mp 218-222 °C,[α]_D ²¹ = + 19.6° (c 0.2 ,MeOH).

Propionylchloride (0,20g , 2.1 mmol) in CH₂Cl₂ (10 ml) was slowly added to a solution of (+)-5-methoxy-2-methyl-2-(n-proρylamfno) tetral in (0,25g, 1.1 mmol) in CH₂Cl₂ (10 ml) and triethylamine (2 ml).The mixture was stirred at room temperature for 1 h ,water was added and the organic layer was separated, dried (Na₂SO₄) and the solvent was evaporated.The residue (0.25 g) in ether (25 ml) was added to a stirred suspension of LiAlH₄ (0.25 g) in ether (25 ml) and the mixture was refluxed for 1 h. Usual workup afforded the base as an oil,which was converted to the hydrochloride with ethereal HCl, giving (+)-5-methoxy-2-methyl-2- (n-propylamino) tetral in hydrochloride (0.20 g). (-) -5-Methoxy-2-methy l -2- (d i -n-propyl am i no) tet ra l i n

The first fractions from the separation of the diastereomeric R-(-)-0-metylmandelamϊdes on SiO₂ with ether/light petroleum (1:3) as eluant (see above) containing the other diastereomeric amide, were combined and evaporated.The oily residue (0,7 g , 1.8 mmol) was treated with potassium tert-butoxϊde (2,0 g) in THF (20 ml) at -15 °C and then with CH₃Li (2.5 ml of a solution being 1.6 H in ether)as described above, to give (-)-5-methoxy-2-methyl-2-(n propylamino) tetralin hydrochloride (0.30 g , 1.1 mmol),mp 215-219 °C, [α]²¹ = -21.0 ^ο(c 0.2,MeOH) .

This product (0.30 g,1,1 mmol) was acylated with propionylchlor ide (0.21 g,2.2 mmol) In CH₂CL₂ (10 ml) and triethylamine (1.5 ml) , yielding an amide which was reduced with LiAlH, (0,25 g) in ether (see above) giving (-)-5-methoxy-2-methyl-2-(di-n-propylamino) tetralin hydrochloride (0.20 g).

Preparationof end compounds

Example E1. (±)-5-Hydroxy-2-methyl-2-(di-n-propylamino) tetralin

(±)-5-Methoxy-2-methyl-2-(di-n-propylamino) tetralin hydrochloride (0.75 g, 2.4 mmol) was heated in 48 % aqueous HBr for 2 h at 120°C N₂.The volatiles were removed under reduced pressure and the residue was recrystal 1 ized from EtOH/ether giving 0,40 g (58%) of (+) -5-hydroxy- 2-methyl-2-(di-n-propyl amino) tetral in hydrobromide,mp 217-218^οC .

Example E2. (+)-5-Hydroxy-2-methyl-2-(di-n-propylamino) tetralin

(+)-5-Methoxy-2-methy1-2-(di-n-propylamino) tetralin hydrochloride

(0.20 g,0.65 mmol) in CH₂Cl₂ (5 ml) was treated with 88r₃ (2 ml) at

- 70^οC for 5 min and then at room temperature for 30 min.The mixture was extracted with 10% Na₂CO₃, the organic layer was dried (Na₂SO₄) and the solvent was evaporated.The oily residue was chromatographed on a SiO₂ (40-63 um) column with MeOH as eluant.Treatment with ethereal HCl afforded crystals which were recrystallized from MeOH/ether, yielding (+)-5-hydroxy-2-methyl-2-(di-n-propylamino) tetralin hydrochloride

(80 mg), mp 212-215 °C ,[α] = +19.5 ^ο(c 0.2 ,HeOH). Example E3. (-)-5-Hydroxy-2-methyl-2-(di-n-propylamino) tetralin

(-)-5-Hethoxy-2-methyl-2-(di-n-peopylamiπo) tetral in hydrochloride (0,20g,0,65 mmol) in CH₂Cl₂ (5 ml) was treated with BBr₃ (2 ml) as described above in Example E2 to give (-)-5-hydroxy-2-methyl-2-(di- n-propylamino) tetral in hydrochloride (100 mg) , mp 211-217 °C , -

= - 21.3 °(c 0.1 ,HeOH)

Example E4. (+)-5-Acetoxy-2-methyl-2-(di-n-propylamino) tetralin

(+)-5-Hydroxy-2-methyl-2-(di-n-propylamino) tetralin was dissolved in acetic anhydride (10 ml).Triethylamine (0.5 ml) was added and the solution was refluxed for 1.5 h.EtOH ("25 'ml) was added and the solvents were evaporated giving an oil.The oil was made alkaline with diluted NaOH to pH 10 during external cooling and then extracted with ether. The organ'ic phase was dried and evaporated giving the desired compound as an oil. Ethereal HCl gave the hydrochloride of the desired compound, mp^οC ,

Example E5. (+)-5-Benzoyloxy-2-methyl-2-(di-n-propylamino) tetralin

(±)-5-Hydroxy-2-mathyl-2-(di-n-propylamϊno) tetralin ( 0.20 g, 6.0 mmol) was dissolved in CH₂Cl₂ (10 ml) and pyridine (1 ml). Benzoyl chloride (0.98 g , 7.0 mmol) was added and the mixture was stirred at room temerature for 3 h.Water (15 ml) was added, the organic layer was separated, dried (Na₂SO₄) and evaporated giving an oil,which was converted to its hydrochloride with ethereal HCl, mp ^οC .

According to the methods of the Examples above the following compounds were prepared and recrystallized as acid addition salts from ethanol/ ether or isolated as the bases.

Pharmaceutical Preparations

The following examples illustrate how the compounds of the present invention may be included into pharmaceutical preparations.

Example P 1. Preparation of soft gelatine capsules

500 g of active substance are mixed with 500 g of corn oil, whereupon the mixture is filled in soft gelatine capsules, each capsule containing 100 mg of the mixture (i.e. 50 mg of active substance).

Example P 2. Preparation of tablets

0.5 kg of active substance are mixed with 0.2 kg of silicic acid of the trade mark Aerosil. 0.45 kg of potato starch and 0.5 kg of lactose are mixed therewith and the mixture is moistened with a starch paste prepared from 50 g of potato starch and distilled water, whereupon the mixture is granulated through a sieves. The granulate is dried and sieved, whereupon 20 g of magnesium stearate are mixed into it. Finally the mixture is pressed into tablets each weighing 172 mg.

Example P 3. Preparation of a syrup

100 g of active substance are dissolved in 300 g of 95% ethanol, whereupon 300 g of glycerol, aroma and colouring agents (q.s.) and 1000 ml of wate are mixed therein. A syrup is obtained.

Example P 4. P reparation of an Injection solution

Active substance (hybrobromide) (1 g), sodiumchloride (0.8 g) and ascorbic acid (0.1 g) are dissolved in sufficient amount of distilled water to give 100 ml of solution. This solution, which contains 10 rng of active substance per ml, is used in filling ampoules, which are sterilized by heating at 120°C for 20 minutes. Pharmacological evaluation

Introduction

Drugs affecting neurohumoral transmission are of considerable interest in the treatment of a variety of disease states of central and peripheral origin. For example, compounds having specific effects on the monoamin ergic systems are of great value in the therapy of e.g. parkinsoni sm, schizophrenia, mental depression, senile mental and motor disturbances, hypo- and hypertensive states etc.

While searching for new dopamine (DA) -receptor active agents we surprisingly found that a group of compounds of the formula I were able to significantly alter the central serotonin (5"HT) and DA synthesis, turnover and metabolism while exhibiting a unique pharmacological profile with regard to behavioural effects. In order to evaluate the actions of compounds of the formula I the following biochemical and behavioural investigations were undertaken.

Behavioural andbiochemical activity in rats. a) Antagonism of the reserpine-induced "neuroleptic syndrome" In the rat (gross behaviour).

Depletion of the monoamine stores with reserpine brings about a "neuroleptic syndrome" characterized by akinesia, catalepsy, muscle rigidity, hunch-backed posture as well as a number of other central and peripheral signs of monoamine depletion. The reserpine-induced syndrome has been frequently used as an animal model mimicking Parkinson's disease as well as mental depression. The whole or parts of this syndrome can be reversed by the administration of drugs that stimulate DA or 5-HT receptors directly or indirectly.

b) Determination of tyrosine and tryptophan hydroxylat ion rates of the rat brain in vivo (biochemical evidence of DA- and 5-HT receptor activity).

The compounds under evaluation were tested biochemically for central DA- and 5-HT-receptor (pre- and/or postsynaptic) stimulating activity. The concept of this biochemical screening method is that a DA- or 5-HT-receptor agonist will stimulate the receptor and through regulatory feedback systems effect a decline in tyrosine or tryptophan hydroxylating activity, respect ively, and a subsequent reduction in the synthesis rate for DA and 5-HT in the presynaptic neuron. Dopa and 5-HTP formation, as determined after in-vivo inhibition of the aromatic L-amino acid decarboxylase with NSD 1015

(3-hydroxybenzylhydrazine hydrochloride), are taken as ϊndi rect measures of DA- and 5-HT-synthesϊs rates, respectively.

Analogous conditions exist also for central NA-neurons. Effects on the dopa formation in the NA-predominated hemϊspheral parts (mainly cortex) may thus be considered to reflect NA-receptor-mediated changes.

c) Experimental procedures.

Male Sprague-Dawley rats (200-300 g), non-pretreated or reserpine-pretreated (5 mg/kg, 18 h before), were given the compounds under evaluation. Gross behavioural observations (changes in motility, body posture, stereotypies etc.) and locomotor activity recordings (electronic motility meters; Motron Products) were made. Body temperature was measured by means of a rectal probe (Yellow Springs Instr.). Subsequent administration of NSD 1015, decapitation, brain dissection (corpora striata, the limbic forebrain, cortex, diencephalon, brain stem), homogenization, centrifugation, ion-exchange chromatography and spectrofluorimetric measurements (all as described in detail by Wikström et al., J. Med. Chem., 21, 864-867, 1978 and references cited therein) gave the actual dopa and 5-HTP levels. In one experiment the test drug was given without any other treatment and the brain levels of the monoarnines , their precursors and metabol ites were determined by means of high performance liquid chromatography (HPLC) with electrochemical detection.

d) Results

Compound 2 markedly antagonized the reserpine-induced akinesia (Table I). However, there was no complete reversal of the "neuroleptϊc syndrome". The animals remained in a hunch-backed posture while exhibiting forward locomotion. Moreover, they frequently exhibited whole body shakes ("wei- -dog shakes"). Since the motor stimulation induced by compound 2 was not prevented by pretreatment with reserpϊne (10 mg/kg I. p., 6 h before) plus the tyrosine hydroxylase inhibitor α-methyl-para-tyrosiπe (250 mg/kg i.p., 1 h before) it can be concluded that it is not mediated via catechol amine release (data not shown). In addition, in contrast to the DA-re- receptor stimulants 5-hydroxy-2-(di-n-propylamino) tetral in and apo morphlne, the locomotor activity elicited by compound 2 was never accompanied by any signs of stereotypies typical of DA-receptor stimulation (licking, sniffing, gnawing etc.) and was totally resistant to pretreatment with haloperidol, given in a dose producing an efficient blockade of the DA receptors (Table 1). The methoxy-ana logue of compound 2, 5-methoxy-2-methyl-2-(di-n-propylamino) tetralin (20 mg/kg s.c.) was unable to antagonize the reserpine-induced akinesia.

Concomitant measurements of the monoamine synthesis rates following compound 2 a 1 so revealed significant alterations. Thus, the 5-HT-synthesis rate in all brain regions investigated was increased 20-30% above control values following compound 2. The increase was observed both In the absence and presence of reserpine-pretreatment (Table III). In addition, the tyrosine and tryptophan levels were consistently elevated following compound 2. A slight, though significant, increase of the DA-synthesis rate was also noted in the brain stem (Table II). These biochemical changes were, at least in non-reserpinized rats, accompanied by a signif icant rise in body temperature (Table II ).

Compound 2. induced a pronounced increase of the locomotor activity and "wet-dog shakes" also in otherwise non-treated rats (Table III). Subsequent analysis of the brain monoamines, their precursors and metabolites showed that, in the brain regions Investigated, the noradrenal ine (NA) and 5-HT levels remained unaltered whereas the homovanillic acid (HVA) levels were significantly increased as compared to controls. Furthermore, the 5-hydoxy ϊndoleacet ic acid (5-HlAA) level was slight, though significantly increased in the limbic forebrain and the DA and 3,4-di- -hydroxyphenylacetic acid (DOPAC) levels significantly decreased in striatum. As in previous experiments there was a rise in tryptophan and tyrosine levels although statistical significance was reached only for tryptophan.

All the results obtained for compound 2 as described above was also obtained for the pure levorotameric enantiomer ( - ) -2 , but not for the dextrorotameric (+)-2. CONCLUSION

The pharmacological data demonstrate that compounds of the present invention have pronounced pharmacodynamic actions. The concomitant behavioural and biochemical alterations Induced by the compounds under consideration constitute a unique pharmacological profile, not previously described. Said compounds are of great clinical interest in the therapy of pathological states referred to in the Introduction, for example Parkinson's disease, mental depression and senile disturbances in the nervous system.

i

Best mode of carrying out the invention

The compound 5-hydroxy-2-methyl-2-(di-n-propylamino) tetralin and its salts, processes for preparing said compound and methods of employing said compound in therapy, particularly in the therapy of mental depression, represent the best mode of carrying out the invention known to us at present.

Claims

C l a i ms

1. A compound of the formula

wherein Y is OH, R⁴COO, (R⁵)₂ NCOO or R⁶O, whereby R⁴ is an alkyl group having 1-5 carbon atoms or a possibly substituted phenyl group,

R⁵ is an alkyl group having 1-5 carbon atoms and R⁶ is an allyl or benzyl group, R¹ is an alkyl group having 1-3 carbon atoms, R² is an alkyl group having 1-6 carbon atoms, and R³ is an alkyl group having

1-3 carbon atoms, as the base and pharmaceutically acceptable acid addition salt thereof.

2. A compound according to claim 1 wherein R⁴ is a possibly substi tuted phenyl group, R⁵ is a methyl group, and R⁶ is an allyl group, and R¹, R² and R³ have the meaning specified in claim 1.

3. A compound according to claim 1 wherein Y is OH, R⁴COO or R⁶O, whereby R⁴ is a possibly substituted phenyl group and R⁶ is an allyl group, and R¹, R² and R³ have the meaning specified in claim 1.

4. A compound according to clain 1 wherein R⁴ is methyl, phenyl or

4-alkanoyloxyphenyl wherein the alkyl group has 1-4 carbon atoms, R⁵ is methyl, R⁶ is allyl, R¹is alkyl having 1-3 carbon atoms, R² is alkyl having 3-6 carbon atoms, and R³ is methyl or ethyl.

5. A compound according to claim 1 wherein Y is R⁴COO, and wherein

R⁴ is a 4-alkanoyloxyphenyl group wherein the alkyl grcjp has 4-6 carbon atoms, and R¹, R² and R³ have the meaning specified in claim 1.

6. A compound according to anyone of claims 1-5 wherein R¹ is n-propyl .

7. A compound according to claim 6 wherein R² is an alkyl group having 3-6 carbon atoms and R³ is methyl or ethyl.

8. A compound according to anyone of claims 1-7 wherein R is methyl.

9. A compound according to anyone of claims 1-4 and 6-8 wherein Y is OH.

10. A compound according to anyone of claims 1-9 in its pure enantiomeric form having the same absolute configuration as the levorotameric

(-)-5-hydroxy-2-methyl-2-(di-n-propylamino) tetralin.

11. A compound according to one or more of the preceding claims char acterized in that R⁴ Is an alkyl group having 1-5 carbon atoms, a phenyl, 2,6-dϊmethylphenyl or 3- or 4-hydroxyphenyl group or a 3- or

4-alkanoyloxyphenyl group with the formula

wherein R⁷ is an alkyl group having 1-6 carbon atoms.

12. The compound 5-hydroxy-2-methyl-2-(di-n-propylamino) tetralin.

13. A process for preparation of a compound of the formula

wherein Y is OH, R⁴COO, (R⁵)₁NCOG or R⁶O, whereby R⁴ is an alkyl group having 1-5 carbon atoms or a possibly substituted phenyl group, R⁵ is an alkyl group having 1-5 carbon atoms and R⁶ Is an allyl or benzyl group, R¹ is an alkyl group having 1-3 carbon atoms, R² Is an alkyl group having 1-6 carbon atoms, and R is an alkyl group having 1-3 carbon atoms, as the base and pharmaceutically acceptable acid addition salt thereof, characterized in that

a) an ehter or ester of the formula

wherein R represents a hydrocarbon or acyl residue and R¹, R² and

R³ are as defined above is cleaved, to form a compound of formula

I wherein Y is a hydroxy group, or

b) a compound of formula

wherein R¹, R² and R³ are as defined above is converted into a compound of formula I wherein Y is R⁴COO, ( R⁵)₂NCOO or R⁶O by treating the first mentioned compound with a carboxylic acid halide R⁴COX or anhydride (R⁴CO)₂O or with a carbamoyl halide (R⁵)₂NCOX in the presence of a base or an acid, or with an allyl or benzyl halide R⁶X in the presence of a base, wherein X represents halogen, or

c) a compound of the formula

wherein R^a Is either R¹ or R², and R¹, R², R³ and Y are as defined above, is converted Into a compound of formula I by alkylation of the nitrogen atom with an alkylating agent, or

d) an amide of the formula

wherein Y is OH or R⁶O, and R⁶ is a defined above, R^c is an alkyl group defined by the relation R^c-CH₂- equals either R¹ or R² and R^d is the other of R¹ and R², Is reduced with a reducing agent to the formation of a compound of formula I, or e) a compound of t he formu l a

wherein M and M are the same or different and each represents -CH₂-,

when M¹ and M² are -CH₂- and in other cases M³ is R³, Z¹ is a group sensitive to hydrogenolysis,

R^z is hydrogen, methyl or ethyl, Y is other than allyloxy and R¹, R² and R³ are as defined above is converted to a compound of formula I by reduction, or

f) an aziridinium salt (e.g. C10₄- or BF₄- ) with the formula

wherein Y is other than allyloxy and R and R are as defined above is converted by reduction into a compound of the formula I wherein

R³ is CH₃, or

g) in a compound of the formula

wherein X represents SO₃H, Cl or NH₂, a hydroxy group is substituted for the group X to the formation of a compound of formula I wherein Y represents a hydroxy group,or

h) a racemic mixture or a mixture partly enriched on one of the enantiomers of a compound of the formula

is subjected to enantiomeric separation to obtain a pure enantiomer of compound I ;whereupon optionally an isomeric mixture obtained is separated to a pure isomer.

14. A process according to claim 13 characterized in that Y, R¹,

R² and R³ are as defined In anyone of claims 1- 12.

15. A pharmaceutical preparation comprising as an active ingredient a compound according to one or more of claims 1 to 12, in conjunction with a pharmaceutically acceptable carr i er .

16. The use of a compound according to anyone of claims 1-12 as active ingredient in the preparation of pharmaceutical preparations for treatment of disorders in the central nervous system.

17 . A compound according to anyone of claims 1-12 for use in the treatment of disorders in the central nervous system.