NO830040L - THERAPEUTIC USEFUL TETRALIN DERIVATIVES III, PROCEDURES FOR THEIR PREPARATION AND PHARMACEUTICAL PREPARATIONS FOR SUCH COMPOUNDS - Google Patents

Description

The present invention relates to new 1,2,3,4-tetrahydro-2-naphthylamines, methods for producing such compounds, pharmaceutical preparations 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 which have a therapeutic activity in the central nervous system.

Connections with the formula:

where Y11 and RIV are H, Y1 is CrUO, R1 and R11 are H or CH., and

III

R is either CH 3 or phenyl, is described in Chem. Pharm. Bull., 20, 1321 (1972) and Chemical Abstracts 81: 120417K, respectively. Furthermore, a compound has where R1, R11 and RIV

are H, Y<1> and Y<11> are CH30 and R<1>11 is phenyl, have been described in Chem, Pharm. Bull., 21, 439 (1973). The above-mentioned compounds have analgesic activity.

In J. Pharm. Sei., 60, 201 (1971) and J. Med. Chem. 14, 60 (1971) have compounds where Y<1> is H or CH30, Y<11> is H, R<1>bgR<11> is H or CH3, R111 is CH3 or benzyl and RIV is CH3,

have been described as compounds having analgesic activity.

W.H. Shelver (Thesis, 1962; Diss. Abstr. 25, 7444 (1965); CA 63 : 14901 g) describes compounds of the formula:

where R<111> is COOH, COOCH3, COCH3, COCgH^ CH2OH and CH2OCOC6H5. The compounds have been tested for analgesic activity.

German patent no. 2,752,659 describes i.a. compounds with the formula:

where Y<1> is 5-OH, 6-OH and 7-OH, R<1> is H, CH3, n-C3H7, i-C3H7 or benzyl and R<11> is H, CH3 or C-jH2. The compounds are reported to have stimulating effects on a- and 3-adrenoreceptors, as well as on dopamine receptors.

In Biomed. Mass Speetrom., 8, 90 (1981) U. Hacksell et al. mass fragmentation analyzes of several 2-aminotetra-lines are indicated, i.a. a compound with the formula:

According to the present invention, it has been found that new compounds with the formula:

where Y is OH, R<4>COO, (R<5>)2NCOO or R<6>0, where R4 is an alkyl group with 1-5 carbon atoms or an optionally substituted

ert phenyl group, R 5 is an alkyl group with 1-5 carbon atoms

6 1

and R is an allyl or benzyl group, R is an alkyl group with 1-3 carbon atoms, R 2 is an alkyl group with 1-6 carbon atoms

atoms, and R 3 is an alkyl group of 1-3 carbon atoms, as bases and pharmaceutically acceptable acid addition salts thereof, have unexpected pharmacological properties that make them useful in therapy and fulfill the above stated purposes. Methods for the production of such compounds, their pharmaceutical and medical use and pharmaceutical preparations and treatment methods using such compounds constitute further features of the invention.

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

An optionally substituted phenyl group R 4 can be a phenyl, 2,6-dimethylphenyl or 3- or 4-hydroxyphenyl group or a 3- or 4-alkanoyloxyphenyl group with the formula:

where R 7 is an alkyl group with 1-6 carbon atoms.

Symbols for numbers, atoms or groups indicated below have

the widest meaning previously given unless otherwise specified.

Both organic and inorganic acids can be used to form non-toxic pharmaceutically acceptable acid addition salts of the compounds according to the invention. Illustrative acids are sulfuric acid, nitric acid, phosphoric acid, hydrochloric acid, citric

acid, acetic acid, lactic acid, tartaric acid, pamoic acid, ethanedisulfonic acid, sulfamic acid, succinic acid, cyclohexylsulfamic acid, fumaric acid, maleic acid and benzoic acid. These salts are easily produced by known methods.

In a limited embodiment, the invention relates to compounds of formula I as indicated above, where Y is OH, R 4 C00, (R 5 )«NCOO

6 4 5

and R 0, where R is an optionally substituted phenyl group, R is

6 12 3

CH-j and R is an allyl group, and R , R , and R have the meaning given above. In a further limited embodiment an-

the invention relates to compounds of formula I as indicated above

4 6 4

where Y is OH, R C00 and RO, where R is an optional sub-

6 12

substituted phenyl group and R is an allyl group, and R , R and R 3 have the meaning indicated above. In yet another limited embodiment, the invention relates to compounds of formula I which

4 5 6 4 indicated above where Y is OH, R C00, (R )2NCOO and R 0 where R

is methyl, phenyl or 4-alkanoyloxyphenyl where the alkyl group

5 6 1

has 1-4 carbon atoms, R is methyl, R is allyl, R is alkyl of 1-3 carbon atoms, R<2> is alkyl of 3-6 carbon atoms, and

3

R is methyl or ethyl.

Preferred among the compounds of formula I wherein Y is R 4C00

are those where R 4 is a 4-alkanoyloxyphenyl group where the alkyl group (R 7 ) has 4-6 carbon atoms.

According to a preferred embodiment, the invention relates to compounds of formula I where R is n-C^H^.

1 2

Preferred compounds are those where R is n-C,H7, R is an alkyl group of 3-6 carbon atoms, and R is CH_. or C9H,- .

1 2

Further preferred are compounds where R is n-C-.H7, R

3 3

is an alkyl group with 3-5 carbon atoms and R is CH.

Examples of compounds with formula I according to the invention

are indicated in the following table.

The compounds according to the invention contain an asymmetric carbon atom in the heterocyclic ring part. The therapeutic properties of the compounds can be attributed to a greater or lesser extent to one or both of the two enantiomers that arise. The pure enantiomers, as well as mixtures thereof, are thus covered by the invention.

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

The invention takes into account that compounds which structurally deviate from formula I can, after administration to a living organism, be transformed into a compound of formula I and exert their effects in this structural form. This constitutes a further feature of the invention. Likewise, certain compounds of formula I may be metabolized to other compounds of formula I before exerting their effect. Compounds 4 5 6 according to the invention where Y is R C00, (R ) 2 NCOO or R 0 are thus assumed to exert their main activity after metabolism to the compounds where Y is OH.

Manufacturing methods

The compounds according to the invention can be obtained by one of the following methods which constitute a further feature of the invention.

a) An ether or ester with the formula:

with RO in position 5 and where R is a hydrocarbon or acyl residue, preferably an alkyl group with 1-5 carbon atoms or a benzyl group, or an alkylcarbonyl group with 2-6 carbon-12 3

atoms, and R , R , and R have the meanings given above, can be cleaved to form a compound of formula I where Y is a hydroxy group.

When R is a hydrocarbon residue, the cleavage can be effected by treating the compound of formula II with an acidic nucleophilic reagent such as aqueous HBr, or HI, HBr/CH-jOOH, BBr^, AlCl-., pyridine-HCl or (CH-J Si, or with a basic nucleophilic reagent such as CH^C^-H^-S 0 or C2H^-S 0. When R is a benzyl group, the cleavage can also be carried out by reduction, preferably with hydrogen using Pd or PtO 2 as catalyst .

When R is an acyl residue, the cleavage can be carried out by hydrolysis

in an aqueous acid or base or by reduction, preferably with LiAlH^.

The compound of formula II can be obtained in the following synthetic way:

Thus, a compound of formula I IA is methylcarboxylated by reaction with methyl carbonate in the presence of NaH to give the ketoester IIB, which is C-alkylated with R 3X (X=Br, I) in the presence of a base such as NaOC^H^ followed by hydrogenolysis of the keto function and hydrolysis of the ester function which gives the carboxylic acid IIC. Reaction of compound IIC with ClCOOC^Hj. in the presence of triethylamine followed by conversion to an azide with NaN^ and Curtius rearrangement and acid hydrolysis to an amino-containing compound IID, N-acylation with R COC1 (where

x' x 1

R is defined by the ratio R -CH~-like R ) in the presence of a base, LiAIH.-reduction, again N-acylation with R YC0C1

Y Y 2

(where R is defined by the ratio R -Cr^ equal to R ) in the presence of a base and final LiAlH^ reduction, gives a compound of formula II.

A pure enantiomer of compound II can be prepared by first converting IIE to the (-)-O-methylmandelic acid amide IIF followed by chromatographic separation of the two diastereomers and resolution with subsequent reaction with calcium tert-butoxide in tetrahydrofuran with traces of water and CH^Li, and then the desired of the two enantiomers (IIE<1>

and E") alkylated.

b) A compound with the formula:

12 3

where R , R and R have the meaning given above, can be converted into a compound of formula I where Y is R 4C00,

5 6

(R )-NCOO or R 0 by treating the first-mentioned compound with a suitable carboxylic acid halide R COX or a(nR h5v)d2NrCi0d X (R i 4CnæOr)v0æ0 r ealv leer n mbed ase et splaik ssesnom de tkraierbtyamloamyilhn aelolgleenrid

pyridine or an acid such as f^SO^ or CF3COOH or with an appropriate allyl or benzyl halide R^X in the presence of a base such as triethylamine, pyridine or potassium t-butoxide. X represents a halogen, preferably Cl or Br.

Alternatively, when conversion of Y = OH to R 4C00 is the objective

4 7

and R is R COOCgH^-, a compound of formula I where Y is OH can first be converted into a compound of formula I where Y is HOCgH^COO- which is then treated with a suitable

7 7

carboxylic acid halide R COX or anhydride (R CO)20 in the presence of a base or an acid.

c) A compound with the formula:

where Ra is either R1 or R2, and R1, R2, R3 and Y have it

meaning given above, can be converted into a compound of formula I by alkylating the nitrogen atom with a suitable alkylating agent. Thus, the output connection where Ra

1 2 1

is R is treated with an alkyl halide or tosylate R X , where X<1> is Cl, Br, I or -OS02-CgH4CH3 in an organic solvent such as acetonitrile or acetone and in the presence of a base such as K2CO3 or NaOH, or said starting compound can be treated with a carboxylic acid NaBH^-complex R<b>COOH-NaBH4, where R<b>is defined by R<b->CH2like R<2.>

For the formation of a compound of formula I where at least one of R 1 and R 2 is CH^, the alkylation reaction can be carried out by treating the compound of formula IV with a formaldehyde-Na(CN)BH^ mixture, or with formaldehyde and formic acid.

d) An amide of the formula:

where Y is OH or R 6 O, and R 6 has the above meaning,

c c 1

R is an alkyl group defined by R -CH„-like either R or

2 d 12

R and R is the second of R and R , can be reduced e.g. by treatment with a hydride reducing agent such as LiAlH^

in ether or tetrahydrofuran or BH^in tetrahydrofuran,

to form a compound of formula I.

e) A compound with the formula:

1 2

hydroxy in the benzyl position (M or M ) or halogen,

R is hydrogen, methyl or ethyl, Y is different from

12 3

allyloxy and R , R and R have the meaning given above, can be converted into a compound of formula I by reduction. A keto function can thus either be directly converted to CH2 by treatment with e.g. hydrazine under alkaline conditions or by a stepwise reduction using e.g. catalytic hydrogenation which may involve an intermediate formation of a hydroxy group and, where possible,

also an elimination to a double bond. Reduction of a

group

can be carried out using a nucleophile

hydride reducing agent such as LiAlH^, or by cata-

lytic hydrogenation.

f) An aziridinium salt (e.g. C104 or BF^ ) with ■ the formula: 1 2 where Y is different from allyloxy and R and R have the meaning given above, can be converted by reduction, preferably by catalytic hydrogenation, into a compound of formula In which R<3> is CH^. g) In connection with the formula:

where X is SO₂H, Cl or NH₂, a hydroxy group can replace the group X to form a compound of formula I where Y is a hydroxy group. When X is SO^H or Cl, said reaction can be carried out by treatment with a strong alkali under heating, conveniently with an alkali melt such as KOH when X is SO^H, and with a strong aqueous alkali such as NaOH or KOH when X is Cl. When X is NH 2 , the reaction can be carried out by treatment with aqueous nitric acid to form a diazonium intermediate which is then subjected to hydrolysis in water. h) A racemic mixture or a mixture partially enriched in one of the enantiomers of a compound of the formula:

is subjected to enantiomeric separation to obtain a pure enantiomer of compound I. This can be done using known methods. These methods include recrystallization of diastereomeric salts with pure enantiomers of acids such as tartaric acid, 0,O-dibenzoyltartaric acid, mandelic acid and camphor-10-sulfonic acid.

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

Pharmaceutical Pararates

Pharmaceutical preparations of the compounds according to the invention constitute further features of the invention.

In clinical practice, the compounds according to 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, the lactate, the acetate, the sulfamate, and the like, in association with a pharmaceutically acceptable carrier.

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

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

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

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

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

For therapeutic treatment, suitable daily doses of the compounds according to the invention are 100-5000 mg for oral use, preferably 500-3000 mg, and 0.5-500 mg for parenteral use, preferably 25-250 mg.

Work examples

The following examples further illustrate the invention.

Ex empe1 II ( ±)- 5- methoxy- 2- methyl1- 2-( di- n- propylamino)-tetralin

5- methoxy- 2- methyltetralin- 2- carboxylic acid

A solution of methyl 5-methoxy-1-oxotetralin-2-carboxy-

lat (25 g, 100 mmol) in dry EtOH (125 mL) was slowly added

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

hours under N2. After cooling, three 10 mL portions of methyl iodide (68.4 g, 465 mmol) were added. The reaction mixture was refluxed for 1 hour, after which it was neutralized

seasoned with acetic acid. The volatile substances were evaporated in vacuo and the residue was first passed through a short alumina column with ether as eluent and then chromatographed on a silica column with ether-light petroleum (1:2) as eluent, which gave 24 g of methyl 5-methoxy-2-methyl -I-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 hydrogenated at atmospheric pressure over Pd/C (5 g). After 24 hours the reaction was complete, the catalyst was filtered (Celite) and CHCl^

(1000 mL) was added. Washing the organic layer several times with 10 mL portions of H 2 O followed by evaporation of CHCl 2 in vacuo gave an oil which was refluxed for 4 hours

with MeOH (100 mL), H 2 O (125 mL) and KOH pellets (50 g).

The MeOH was evaporated in vacuo and the product was precipitated by adding ice-cold 10% HCl to the resulting solution.

Two recrystallizations from EtOH-H 2 O gave 9.6 g (44%) of pure 5-methoxy-2-methyltetralin-2-carboxylic acid, m.p. 138-149°C.

( ±)- 2- amino- 5- methoxy- 2- methyltetralin

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 producing

ing of 2,3-dimethoxy-9-amino-9,10-dihydrophenanthrene from 2,3-dimethoxy-9,10-dihydrophenanthrene-9-carboxylic acid. The amine was converted to the hydrochloride and recrystallized twice from EtOH-ether. Yield 5.8 g (76%), m.p. 249.5-251.5°C (decomp.).

( ±)- 5- methoxy- 2- methyl- 2-( n- propylamino) tetralin

Propionyl chloride (4.6 g, 49 mmol) in dry ether (60 mL) was added to a solution of 2-amino-5-methoxy-2-methyltetralin (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 N2 • After stirring and refluxing 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 eluent, which gave 6.4 g (83%) of pure 5-methoxy-2-methyl-2-(n-propylamino)tetralin. The base was converted to its hydrochloride,

m.p. 239-239.5°C (decomp.) (from EtOH-ether).

( l )- 5- methoxy- 2- methyl- 2-( di- n- propylamino) tetralin

A mixture of 5-methoxy-2-methyl-2-(n-propylamino)tetralin

(4.5 g, 19 mmol), propionyl chloride (2.7 g, 29 mmol), triethylamine (2.9 g, 29 mmol), and benzene (150 mL) were stirred at room temperature for 10 h. The precipitate was filtered off and the solvent was evaporated in vacuo and the resulting crystals were rinsed with ether. The resulting pure amide (3.8 g) was heated with LiAlH 2 (1.5 g, 39 mmol) and dioxane (100 mL) at 80°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 eluted through an alumina column

with ether to give 3.6 g (68%) of pure 5-methoxy-2-methyl-2-(di-n-propylamino)tetralin. The base was converted to the hydrochloride, m.p. 145-145.5°C (from EtOH-ether).

Example 12 (+)- and (-)-5-methoxy-2-methyl-2(di-n-propylamino)-tetralin

(+)- 5- methoxy- 2- methyl- 2-( di- n- propylamino) tetralin R-(-)-O-methylmandelic acid chloride (6.0 g, 0.033 mol), prepared from R-(-)-O -methylmandelic acid by treatment with thionyl chloride at 20°C for 10 hours, dissolved in CH2Cl2 (5 ml)- was added at room temperature to a stirred mixture of (±)-5-methoxy-2-methyl-2-(n-propylamino) tetralin (7.0 g, 0.026 mol), CH 2 Cl 2

(50 mL), H 2 O (50 mL) and 5% aqueous NaOH (80 mL).

After stirring for 15 hours, the phases were separated and the organic phase was washed once with water and then dried (Na-pSO 4 ), filtered and evaporated. Ether/light petroleum (1:3) (15 ml)

was added to the rest. The mixture was cooled to approx.

-70°C and one of the diastereomeric amides precipitated (0.9 g). The filtrate was evaporated and the oily residue was chromatographed on a SiO 2 (40.63 µm) column with ether/light petroleum (1:3) as eluent. The diastereomer that eluted first (0.7 g) turned out to be the opposite of the diastereomeric amide that first came out as crystals from the mixture. The diastereomer that eluted second (0.5 g) was found to be the same as the diastereomeric amide that crystallized first. The crystals (see above) and the diastereomer eluted as number 2 (0.9 + 0.5 g; total: 1.4 g) were stereochemically pure according to HPLC. This diastereomeric amide (1.4 g, 0.0037 mol) was dissolved in THF (50 mL) and kept at -15°C. Potassium tert-butoxide (4.0 g) was added and the mixture stirred at this temperature for 5 hours. Ether and H 2 O were added and the phases were separated. The ether phase was extracted with 10% HCl, dried (Na 2 SO 4 ) and evaporated to give an oil which was dissolved in dry THF

(20 mL) and stirred with 1.6 M solution of CH 2 Li in ether (5 mL) for 30 min at -15°C and then extracted with 10% HCl. The aqueous phase was combined with the 10% HCl extract above

for, alkalized with Na^^CO^, extracted with ether. The ether phase was treated with HCl in ether to give a precipitate which was recrystallized from ethanol/ether to give colorless crystals of (+)-5-methoxy-2-(n-propylamino)tetralin hydrochloride (0.75 g, 2 .8'mmol), m.p. 218-222°C, [α]2<1>= +19.6°

(c 0.2, MeOH).

Propionyl chloride (0.20 g, 2.1 mmol) in CH 2 Cl 2 (10 mL) was slowly added to a solution of (+)-5-methoxy-2-methyl-2-(n-propylamino)tetralin (0.25 g , 1.1 mmol) in CH 2 Cl 2 (10 mL) and triethylamine (2 mL). The mixture was stirred at room temperature for 1 hour, water was added and the organic layer was separated, dried (Na 2 SO 4 ) and the solvent was evaporated. The residue (0.25 g) in ether (25 ml) was added to a stirred suspension of LiAlH 2 (0.25 g) in ether (25 ml) and the mixture was refluxed for 1 hour. Usual workup gave the base as an oil, which was converted to the hydrochloride with ethereal HCl to give (+)-5-methoxy-2-methyl-2-(n-propylamino)tetralin hydrochloride (0.20 g).

(-)- 5- methoxy- 2- methyl- 2-( di-n- propylamino) tetralin The first fractions from the separation of the diastereomeric R-(-)-O-methylmandelamides on SiO2 with ether/light petroleum (1:3) as eluent (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-butoxide (2.0 g) in THF (20 mL) at -15°C and then with CH 2 Li (2.5 mL of a 1.6 M ether solution) as described above gave (- )-5-methoxy-2-methyl-2-(n-propylamino)-tetralin hydrochloride (0.30 g, 1.1 mmol), m.p. 215-219°C,

[α]21 = -21.0° (c 0.2, MeOH). This product (0.30 g,

1.1 mmol) was acylated with prop-Lonyl chloride (0.21 g, 2.2 mmol) in CH 2 Cl 2 (10 mL) and triethylamine (1.5 mL) to give an amide which was reduced with LiAlH^ (0.25 g) in ether (see above)

and this gave (-)-5-methoxy-2-methyl-2-(di-n-propylamino)-tetralin hydrochloride (0.20 g).

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Example El. (±)-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 N 2 . The volatile substances were removed during redu-

pressure and the residue was recrystallized from EtOH/ether to give 0.40 g (58%) of (±)-5-hydroxy-2-methyl-2-(di-n-propylamino)tetralin hydrobromide, m.p. 217-218°C.

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

(+)-5-methoxy-2-methyl-2-(di-n-propylamino)tetralin hydrochloride (0.20 g, 0.56 mmol) in CH 2 Cl 2 (5 mL) was treated with BBr-j

(2 mL) at -70°C for 5 minutes and then at room temperature

for 30 minutes. The mixture was extracted with 10% Na 2 CO 3 ,

the organic layer was dried (Na 2 SO 4 ) and the solvent was evaporated. The oily residue was chromatographed on a SiO 2 (40-6 3 µm) column with MeOH as eluent. "Treatment with ethereal HCl gave crystals which were recrystallized

separated from MeOH/ether, and this gave (+)-5-hydroxy-2-methyl-2-(di-n-propylamino)tetralin hydrochloride (80 mg), m.p. 212-

215°C, [α]2<1>= +19.5° (c 0.2, MeOH).

Example E3. (-)-5-hydroxy-2-methyl-2-(di-n-propylamino)-tetralin

(-)-5-Methoxy-2-methyl-2-(di-n-propylamino)tetralin hydrochloride (0.20 g, 0.65 mmol) in CH 2 Cl 2 (5 mL) was treated with BBr 3 (2 mL) as described above in example E2 and this

gave (-)-5-hydroxy-2-methyl-2-(di-n-propylamino)tetralin hydrochloride (100 mg), m.p. 211-217°C, [α]<21>-21.3°

(c 0.1, MeOH).

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 refluxed for 1.5 hours. EtOH

(25 mL) was added and the solvents were evaporated to give an oil. The oil was made alkaline with dilute NaOH to pH 10 under external cooling and then extracted with ether. The organic phase was dried and evaporated to give the desired compound as an oil. Etheric HCl gave the hydrochloride of the desired compound,

m.p. °C.

Example E5. (±)-5-benzoyloxy-2-methyl-2-(di-n-propylamino)-tetralin

(±)-5-Hydroxy-2-methyl-2-(di-n-propylamino)tetralin (0.20 g, 6.0 mmol) was dissolved in CP^Cl^ (10 mL) and pyridine (1 mL) . Benzoyl chloride (0.98 g, 7.0 mmol) was added and the mixture was stirred at room temperature for 3 hours. Water (15 ml) was added, the organic layer was separated, dried (Na 2 SO 4 ) and evaporated to give an oil which was converted to its hydrochloride with ethereal HCl, m.p. °C.

According to the methods in 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 according to the present invention can be included in pharmaceutical preparations.

Example P 1. Production of soft gelatin capsules

500 g of active substance is mixed with 500 g of corn oil, whereby the mixture is filled into soft gelatin capsules, each capsule containing 100 mg of the mixture (ie 50 mg of active substance).

Example P 2. Production of tablets

0.5 kg of active substance is mixed with 0.2 kg of silicic acid with the trade name Aerosil. 0.45 kg of potato starch and 0.5 kg of lactose are thus mixed and the mixture is moistened with a starch paste prepared from 50 g of potato starch and distilled water, whereby the mixture is granulated through a sieve. The granulate is dried and sieved, whereby 20 g of magnesium stearate is 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 is dissolved in 300 g of 95% ethanol, whereby 300 g of glycerol, aroma and coloring agents (q.s.) and 1000 ml of water are mixed into it. A syrup is obtained.

Example P 4. Preparation of an injection solution ■ Active substance (hydrobromide) (1 g), sodium chloride (0.8 g) and ascorbic acid (0.1 g) are dissolved in a sufficient amount of distilled water to give 100 ml of solution. This solution, which contains 10 mg of active substance per ml is used when filling ampoules which are sterilized by heating at 120°C for 20

minutes.

Pharmacological assessment

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Drugs that affect neurohumoral transmission are of considerable interest in the treatment of a number of different disease states of central and peripheral origin. For example, compounds which have specific effects on the monoaminergic systems are of great value in the therapy of e.g. parkinsonism, schizophrenia, mental depression, senile mental and motor disorders, hypo- and hypertensive states, etc.

In the search for new dopamine (DA) receptor-active agents

surprisingly, a group of compounds of formula I was found to be capable of significantly altering central serotonin (5-HT) and DA synthesis, clearance and metabolism, while exhibiting a unique pharmacological profile with respect to behavioral effects. In order to assess the effects of the compounds of formula I, the following biochemical and behavioral studies were carried out.

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a) Antagonism of the reserpine-induced "neuroleptic syndromes" in the rat (behavior for bulk).

Depletion of the monoamine stores with reserpine causes a "neuro-leptic syndrome" characterized by akinesia, catalepsy, muscle stiffness, hunchback posture, as well as several other central and peripheral signs of monoamine depletion. The reserpine-induced syndrome has often been used as an animal model for mimicking Parkinson's disease and mental depression. All or part of this syndrpmjcan be reversed by administration of drugs that stimulate DA or 5-HT receptors directly or indirectly.

b) Determination of tyrosine and tryptophan hydroxylation rates of the rat brain in vivo (biochemical evidence of

DA and 5HT receptor activity).

The compounds to be evaluated were tested biochemically for central DA and 5-HT receptor (pre- and/or postsynaptic) stimulatory activity. The concept of this biochemical sorting method is that a DA or 5-HT receptor agonist will stimulate the receptor and through regulatory feedback systems cause a decrease in tyrosine or tryptophan hydroxylating activity, respectively, and a subsequent reduction in the synthesis rate for DA and 5 -HT in the pre-synaptic 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), is taken as an indirect measure of DA and 5-HT synthesis rate. named, respectively.

Analogous conditions also exist for central NA neurons. Effects on dopa formation in the NA-dominant hemispheric parts (mainly cortex) can thus be considered to reflect NA-recpetor-mediated changes.

c) Experimental methods.

Male Spragué-Dawley rats (200-300 g), non-pretreated

or reserpine-pretreated (5 mg/kg, 18 h earlier), were given the compounds to be tested. Main behavioral observations (changes in locomotion, posture, stereotypies, etc.) and recordings of locomotor activity (electronic motility meters; Motron Products) were made. Body temperature was measured using a rectal probe (Yellow Springs Instr.). Subsequent administration of NSD 1015, decapitation, brain dissection (corpora striata, limbic forebrain, cortex, midbrain, brainstem), homogenization, centrifugation, ion exchange chromatography and spectrofluorometric measurements (all as described in detail by Wikstrom et al., J. Med. Chem., 21, 864-867, 1978 and references therein) provided the relevant dopa and 5-HTP levels. In one experiment, the test drug was given without any other treatment and the brain levels of the monoamines,

their precursors and metabolites were determined by high-performance liquid chromatography (HPLC) with electrochemical detection.

d) Results.

Compound 2 significantly antagonized the reserpine-induced

akinesia (Table I). However, there was no complete reversal of the "neuroleptic syndrome". The animals remained in a hunchback position while exhibiting a forward-directed locomotion. They also showed shaking of the whole body ("wet-dog-shaking"). Since the motor stimulation induced by compound 2 was not prevented by pretreatment with reserpine (10 mg/kg i.p., 6 h earlier) plus the tyrosine hydroxylase inhibitor α-methyl-para-tyrosine (250 mg/kg i.p., 1 h earlier) , it can be concluded that it is not mediated via catecholamine release (data not shown).

Moreover, in contrast to the DA receptor stimulants 5-hydroxy-2-(di-n-propylamino)tetralin and apomorphine, the locomotor activity elicited by compound 2 was never accompanied by any signs of stereotypy typical of DA receptor stimulation (licking, sniffing , gnawing, etc.) and was completely resistant to pretreatment with halo-peridol, given at a dose which produced an effective blockade of the DA receptors (Table I). The methoxy analogue 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.

Simultaneous measurements of the monoamine synthesis rates following compound 2 also showed significant changes. Thus, the 5-HT synthesis rate—in all—examined brain areas 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, tyrosine - and tryptophan levels were constantly elevated following compound 2. A slight but significant increase in DA synthesis rate was also noted in the brainstem (Table II). These biochemical changes were, at least in non-reserpinized rats, accompanied by a significant rise in body temperature (Table II).

Compound 2 induced a clear increase in locomotor activity and "wet-dog-shaking" also in otherwise untreated rats (Table III). Subsequent analysis of the brain monoamines, their precursors and metabolites showed that norepinephrine (NA) and 5-HT levels in the examined brain areas remained unchanged, while homovanillic acid (HVA) levels were significantly increased compared to controls. Moreover, 5-hydroxyindoleacetic acid (5-HIAA) levels were slightly, though significantly, increased in the limbic forebrain and DA and 3,4-dihydroxyphenylacetic acid (DOPAC) levels were significantly decreased in the striatum. As in previous experiments, an increase in tryptophan and tyrosine levels was obtained, although statistical significance was only achieved for tryptophan.

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

Conclusion

The pharmacological data demonstrate that compounds according to the present invention have clear pharmacodynamic effects. The accompanying behavioral and biochemical changes induced by the compounds in question constitute a unique pharmacological profile not previously described. Said compounds are of great clinical interest in the therapy of phatological conditions as referred to in the introduction, e.g. Parkinson's disease, mental depression and senile disorders of the nervous system.

Best mode of carrying out the invention

The compound 5-hydroxy-2-methyl-2-(di-n-propylamino)tetralin and its salts, methods for preparing said compound and methods for using said compound in therapy, especially in the therapy of mental depression, represent the present best mode of carrying out the invention.

Claims (17)

1. Compound, characterized by the formula: where Y is OH, R4COO, (R <5> )pNCOO or R60, where R4 is an alkyl group with 1-5 carbon atoms or an optionally substituted phenyl group, R^ is an alkyl group with 1-5 carbon atoms and R^ is an allyl- or benzyl group, R 1 " is an alkyl group of 1-3 carbon atoms, R 2 is an alkyl group of 1-6 carbon atoms, and R 3 is an alkyl group of 1-3 carbon atoms, as the base and pharmaceutically acceptable acid addition salts thereof. 2. Compound according to claim 1, characterized 4 5 in that R is an optionally substituted phenyl group, R 6 12 is a methyl group, and R is an allyl group, and R , R and R 3 have the meaning specified in claim 1. 3. Compound according to claim 1, characterized 4 6 4 in that Y is OH, R C00 or R 0, where R is an optionally 6 12 substituted phenyl group and R is an allyl group, and R , R 3 and R has the meaning specified in claim 1. 4. Compound according to claim 1, characterized in that R <4> is methyl, phenyl or 4-alkanoyloxyphenyl where the alkyl group has 1-4 carbon atoms, R <5> is methyl, R 6 is allyl, R 1 is alkyl with 1-3 carbon atoms, _R 2 is alkyl with 3-6 carbon atoms, and R 3 is methyl or ethyl. 5. Compound according to claim 1, characterized in that Y is R 4 C00, and where R 4 is a 4-alkanoyloxyphenyl group where the alkyl group has 4-6 carbon atoms, and R 1 , R 2 and R 3 have the meaning specified in clause 1. 6. Compound according to any one of claims 1-5, characterized in that R is n-propyl. 7. Compound according to claim 6, characterized 2 in that R is an alkyl group with 3-6 carbon atoms and R is methyl or ethyl. 8. Compound according to any one of claims 1-7, characterized in that R<3> is methyl. 9. Compound according to any one of claims 1-4 and 6-8, characterized by atYer OH. 10. Compound according to any one of claims 1-9, characterized in that it exists in its pure enantiomeric form which has the same absolute configuration as the levorotomer (-)-5-hydroxy-2-methyl-2-(di-n -propylamino)tetralin. 11. Compound according to any one of the preceding claims, characterized in that R 4 is an alkyl group with 1-5 carbon atoms, a phenyl, 2,6-dimethylphenyl or 3- or 4-hydroxyphenyl group or one 3- or 4- alkanoyloxyphenyl group with the formula: where R <7> is an alkyl group with 1-6 carbon atoms. 12. Compound, characterized in that it consists of 5-hydroxy-2-methyl-2-(di-n-propylamino)-tetralin. 13. Procedure for preparing a compound of the formula: 4 5 6 4 where Y is OH, R C00, (R )^COO or R 0, where R is an alkyl group with 1-5 carbon atoms or an optionally substituted phenyl group, R^ is an alkyl group with 1-5 carbon atoms and R 6 is an allyl or benzyl group, R 1 is an alkyl group with 1-3 carbon atoms, R 2 is an alkyl group with 1-6 carbon atoms, and R 3 is an alkyl group with 1-3 carbon atoms, as the base and pharmaceutically acceptable acid addition salts thereof, characterized by ata) an ether or ester of the formula: 12 3 where R is a hydrocarbon or acyl residue and R , R and R have the above meaning, is cleaved to form a compound of formula I where Y is a hydroxy group, or b) a compound of the formula: 12 3 where R , R and R have the meaning given above, if "" ' ' 4 is formed into a compound of formula I wherein Y is R C00, (R 5 )„NC00 or R 60, by treating the former compound with a carboxylic acid halide R 4 COX or anhydride (R 4 CO) 20 or with a carbamoyl halide (R 5 ) 2 NC0X in the presence of a base or an acid, or with an allyl or benzyl halide R X in the presence of a base, where X is halogen, or c) a compound of the formula: where Ra is either R or R <2> , and R , R , R and Y have the above meaning, is converted to a compound of formula I by alkylation of nitrogen atoms with an alkylating agent, or d) an amide of the formula: 6 6 where Y is OH or RO, and R has the above meaning, R c is an alkyl group defined by the ratio R c- o j CH2 - equal to either R"*" or R2 and R^ is the other of R"*" and R2, is reduced with a reducing agent to form a compound of formula I, or e) a compound of the formula: htveorer r M -1 CoHg 2-M , 2 XeHr -Zl1 ikee lelelr le>r C=fo0r, skMj3 eelr lig-Ce HoCg|z ^hveelr ler rep-Cre^s°ezn- 1 2 3 3 1 when M and M~ CH2~°9 1 .an<3re cases M is R , Z is a group sensitive to hydrogenolysis, R is hydrogen, methyl or ethyl, Y is different from allyloxy and R 1 , R <2> and R 3 have the above meaning, are converted into a compound of formula I by reduction, or f) an aziridinium salt (e.g. CIO4 . or BF4 .) of the formula: 1 2 where Y is different from allyloxy and R and R have the meaning stated above, is converted by reduction to a compound of formula I where R 3 is CH-j, or g) the group X in a compound of the formula: where X represents SO^ H, Cl or NH2 , is replaced by a hydroxy group to form a compound of formula I where Y is a hydroxy group, or h) a racemic mixture or a mixture partially enriched in one of the enantiomers of a compound of the formula: subjected to enantiomeric separation to obtain a pure enantiomer of compound I; after which an isomeric mixture obtained is optionally separated into a pure isomer. 14. Method according to claim 13, characterized 1 2 3 in that Y, R , R and R have the meaning as defined in any of claims 1-12. 15. Pharmaceutical preparation, characterized in that it comprises as active ingredient a compound according to one or more of claims 1-12, in connection with a pharmaceutically acceptable carrier. 16. Use of a compound according to any one of claims 1-12 as an active ingredient in the preparation of pharmaceutical preparations for the treatment of disorders in the central nervous system. 17. Compound according to any one of claims 1-12, for use in the treatment of disorders of the central nervous system. 1. Compound, characterized by the formula: where Y is OH, R4COO, (R <5> )2 NCOO or R60, where R4 is an alkyl group with 1-5 carbon atoms or an optionally substituted 5-6 phenyl group, R is an alkyl group with 1-5 carbon atoms and R is an allyl - or benzyl group, R is an alkyl group of 1-3 carbon atoms, R 2 is an alkyl group of 1-6 carbon atoms, and R 3 is an alkyl group of 1-3 carbon atoms, as the base and pharmaceutically acceptable acid addition salts thereof. 2. Compound according to claim 1, characterized in that R 4 is an optionally substituted phenyl group, R <5> 6 12 is a methyl group, and R is an allyl group, and R , R and 3 R has the meaning specified in claim 1. 3. Compound according to claim 1, characterized in that Y is OH, R <4> COO or R <6> 0, where R <4> is an optionally 6 12 substituted phenyl group and R is an allyl group, including R ,' R and R 3 has there. in the meaning specified in claim 1. 4. Compound according to claim 1, characterized in that R <4> is methyl, phenyl or 4-alkanoyloxyphenyl where the alkyl group has 1-4 carbon atoms, R <5> is methyl, R <6> is allyl, R 1 is alkyl with 1-3 carbon atoms, R 2 is alkyl with 3-6 carbon-3 atoms, and R is methyl or ethyl. 5. Compound according to claim 1, characterized4 4 in that Y is R C00, and where R. is a 4-alkanoyloxyphenyl group where the alkyl group has 4-6 carbon atoms, and R <1> , R <2> and 3 R has the meaning specified in claim 1. 6. Compound according to any one of claims 1-5, characterized in that R<1> is n-propyl. 7. Compound according to claim 6, characterized in that R 2 is an alkyl group with 3-6 carbon atoms and R <3> is methyl or ethyl. 8. Compound according to any one of claims 1-7, characterized in that R<3> is methyl. 9. Compound according to any one of claims 1-4 and 6-8, characterized by atYer OH. 10. Compound according to any one of claims 1-9, characterized in that it exists in its pure enantiomeric form which has the same absolute configuration as the levorotomer (-)-5-hydroxy-2-methyl-2-(di-n -propylamino)tetralin. 11. Compound according to any one of the preceding claims, characterized in that R 4 is an alkyl group with 1-5 carbon atoms, a phenyl-, 2,6-dimethylphenyl- or 3- or 4-hydroxyphenyl group or a 3- or 4- alkanoyloxyphenyl group with the formula: where R 7 is an alkyl group with 1-6 carbon atoms. 12. Compound, characterized in that it consists of 5,'ydr6"xy-2-mécyI"-2-(di^rT-propylamino)-tetralin. 13. Procedure for preparing a compound of the formula: 4 5 6 4 where Y is OH, R C00, (R )^COO or R 0, where R is an alkyl group with 1-5 carbon atoms or an optionally substituted phenyl group, R <5> is an alkyl group with 1-5 carbon atoms and R^ is an allyl or benzyl group, R^" is an alkyl group with 1-3 carbon atoms, R 2 is an alkyl group with 1-6 carbon atoms, and R 3 is an alkyl group with 1-3 carbon atoms , as the base and pharmaceutically acceptable acid addition salts thereof, characterized by ata) an ether or ester of the formula: 12 3 where R is a hydrocarbon or acyl residue and R , R and R have the above meaning, is cleaved to form a compound of formula I where Y is a hydroxy group, or b) a compound of the formula: 12 3 where R , R and—R—have—the cven-f—Gr—indicated—meaning, is converted into a compound of formula I where Y is R 4C00, (R 5 ) NCOO or R 60, by treating the former compound with a carboxylic acid halide R 4COX or an-4 5 hydride (R CO) 2 0 or with a carbamoyl halide (R ) 2 NC0X in the presence of a base or an acid, or with an allyl or benzyl halide R^X in the presence of a base, wherein X is halogen, or c) a compound of the formula: a 1 2 12 3 where R is either R or R , and R , R , R and Y have the meanings given above, is converted into a compound of formula I by alkylation of nitrogen atoms with an alkylating agent, or d) an amide of the formula: where Y is OH or R <6> 0, and R <6> has the meaning indicated above. R c is an alkyl group defined by the ratio R c-CH2~ equal to either R <1> or R <2> and Rd is the other of R <1> and R <2> , is reduced with a reducing agent to form a compound with formula I, or e) a compound of the formula: 12 where M and M are the same or different and^each represents -CH2 -, XH-Z <1> or >C=0, M <3> is -CHC|z or~ C<°Z when M 1 and M 2~ CH2 - and in other cases M 3 is R 3 , Z 1 is a group sensitive to hydrogenolysis, R is hydrogen, methyl or ethyl, Y is different from allyloxy and R 1 , R <2> and R 3 have the above stated meaning, is converted into a compound of formula I by reduction, or f) an aziridinium salt (e.g. CIO^ or BF^ ) of the formula: 1 2 where Y is different from allyloxy and R and R have the above meaning, is converted by reduction to a compound of formula I where R <3> is CH^/ or g) the group X in a compound of the formula: where X represents SO^ H, Cl or NH^ , is replaced by a hydroxy group to form a compound of formula I where Y is a hydroxy group, or h) a racemic mixture or a mixture partially enriched in one of the enantiomers of a compound of the formula: subjected to enantiomeric separation to obtain a pure enantiomer of compound I; after which an isomeric mixture obtained is optionally separated into a pure isomer. 14. Method according to claim 13, characterized 12 3 in that Y, R , R and R have the meaning as defined in any of claims 1-12.