JPS58500714A - Therapeutically useful tetralin derivatives 3, processes for the preparation of such compounds and pharmaceutical formulations - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] name of invention Therapeutically useful tetralin derivatives ■, processes for the preparation and pharmaceutical formulations of such compounds Technical field The present invention provides a novel 1,2,3,4-tetra-hydro-2-naphthylamine, such Processes for making compounds, pharmaceutical formulations of such compounds and uses of such compounds in therapy. Regarding.

The object of the present invention is to provide compounds for therapeutic use, particularly those with therapeutic activity in the central nervous system. An object of the present invention is to provide a compound having the following properties.

Background technology formula (In the formula, YIl and R■ are H, YI is CH30, Bl and RII is H or CH3 and Hllll is CH3 or phenyl) The compound is ``Chemical and Pharmaceutical Pretans'' (Chem, Ph arm, Bull) J Vol. 20, p. 1321 (1972) and [Chemical ・Abstracts (Chemical Abstracts) J Vol. 81 No. 1 20417, respectively. Furthermore, 81% R1 and RRI is H, YI and YI are CH30, and R1 is phenyl The item is "Chemical and Pharmaceutical Pretans" Volume 21, Page 459 (1973). The above compounds have analgesic activity.

[Journal of Pharmaceutical Sciences (ff’, Phar m, 5ci) J Vol. 60, p. 201 (1971) and “Journal of ・Medicinal Chemistry (J, Med, 'C'hem) J No. 14 Volume 60 (1971) indicates that -Yl is H or CH3,O, and yl is H. , B and R11 are H or C) (3, and R111 is CH3 or Ben and 'BY' is C'H3 as a compound having analgesic activity. It is written as follows.

Mr. W, H, 5helver [1762] Dissertation (ThesiS), Dissertation Abstracts (Diss, Abstr,) J Vol. 25, p. 7444 (1965) 2 “Chemical Abstr. Structures, Vol. 63, p. 14901g] is the formula (In the formula, R11 is C'OOH, C00CH3, COCH3, C0C6H5, CH2 0H and CH20COC6H5).

This compound has been tested for analgesic activity.

German Patent No. 2,752,659 specifically describes the formula (wherein Y1 is 5-0 H16-OH and 7-OH, R is H1CH3, n-c'3'n7.1 -c3I(7 or (endil) and R[l is H, CH3 or C3H7 Some compounds have been described.

The compounds have effects on alpha- and beta-adrenoceptors and dopamine receptors. It has been described that it has a stimulating effect.

“Biomedical mass chromometry (Biomed, Mass Spectrom,) J Vol. 8, p. 90 (1981), Nie Hacksell ( U. Hacksell et al. have reported several types of 2-aminotetralin, among others formula Mass fragmentation analysis of the compound sis).

Disclosure of invention According to the invention, the formula [In the formula, Y is OH, R4COO, (R5)2NCOO or R60 (where R4 is Alkyl radicals having 1 to 5 carbon atoms or optionally substituted phenyl radicals and R5 is an alkyl group having 1 to 5 carbon atoms, and R6 is an alkyl group having 1 to 5 carbon atoms. or benzyl group), R1 is an atom having 1 to 3 carbon atoms; an alkyl group j), R2 is an alkyl group having 1 to 6 carbon atoms, and and R6 is an alkyl group having 1 to 3 carbon atoms. or its pharmaceutically acceptable acid addition salts and which can be used therapeutically for said purposes. It was found to have unexpected pharmacological properties that satisfy the following criteria: Process for making such compounds , their pharmaceutical and medical uses and pharmaceutical preparations and employing such compounds Treatment methods constitute another aspect of the invention.

The alkyl group can be a straight chain alkyl group or a branched chain alkyl group.

The optionally substituted phenyl group R4 is phenyl, 2,6-dimethylphenyl or or is a 3- or 4-hydroxyphenyl group or has the formula (wherein R7 is an alkyl group having 1 to 6 carbon atoms) can be a 4-alkanoyloxyphenyl group.

Symbols for numbers, atoms or groups mentioned below are specified in advance unless otherwise specified. shall have the broadest meaning given.

Non-toxic pharmaceutically acceptable acid addition of compounds of the invention with both organic and inorganic acids Can be used to form salts. Examples of acids are sulfuric acid, nitric acid, phosphoric acid, hydrochloric acid, and citric acid. , acetic acid, lactic acid, tartaric acid, pamoic acid (pamolc aal), ethanedisulfo cyclohexylsulfamic acid, sulfamic acid, succinic acid, cyclohexylsulfamic acid, fumaric acid, Marein i oyohi cheap! ``Froic acid.'' These salts are prepared by methods known in the art. Easily prepared.

In a specified embodiment, Y is OH, R4COO1(R5), NCO O and R60 (where R4 is an optionally polysubstituted phenyl group, and R 5 is CH3 and R6 is an allyl group), and R1, R2 and and R3 relate to compounds of formula 1 above as defined above. further identified In embodiments, the invention provides that Y is OH-R4COO and R60, where R4 is is a polysubstituted phenyl group and R6 is an allyl group), and and R1, R2 and R3 relate to compounds of formula 1 as defined above.

In still further specified embodiments, the invention provides that Y is 0H1R4C00, (R5 )2NCOO and R60 (where R4 is methyl, phenyl, t or 4-alkaline noyloxyphenyl (where the alkyl group has 1 to 4 carbon atoms) , R5 is methyl, R6 is allyl), and R1 is 1 to 3 alkyl having carbon atoms, 6D, R2 is alkyl having 3 to 6 carbon atoms; and R3 is methyl or ethyl.

Among the compounds of formula 1 in which Y is R4COO, R4 is preferably 4-alkanoyl Oxyphenyl group, where the alkyl group (R7) has 4 to 6 carbon atoms It is a compound that is

According to a preferred embodiment, the present invention relates to compounds in which R1 is n-C3H7. Ru.

Preferred compounds are those in which R1 is n-C4H7 and R2 contains 5 to 6 carbon atoms. and R3 is CH5 or CII (5) . More preferably, R1 is n-C3H7 and R2 has 3 to 5 carbon atoms. and R3 is CH3.

Examples of compounds of formula I according to the invention are shown in the table below.

OHCH3n-C3H7CH3 0Hn-C3H7n-C3H7CH3 0Hn-C3H7n-C4H9CH3 0Hn-C3H7n-C3H11CH30Hn-C4H71-C3H7CH3 0H, n-C3H7-CH2CH(CH3)2 CH30Hn-C3H7n C 3H7C2H50Hn-C3H7n-C3H7n-C3H700CCH3n-C 3H7n-C3H7CH30obe◇n-C3H7n-C3H7CH300Ce' 0OCC(CH3)3 n-C3H7n-C3H7CH30CH2CH=CH2 n-C3H7n C3H7-CH500CN(CH3)2 n-C3H7n-C 3H7''H33 The compound of the present invention contains an asymmetric carbon atom in the heterocyclic moiety. The therapeutic properties of a compound may be expressed in more or less than one of the two enantiomers that exist. or both. Therefore, pure enantiomers as well as mixtures thereof are covered by the present invention. is within the range of

Of the two pure enantiomeric forms, preferred is the levorotatory (-)-5-hydroxy- Same feed configuration as 2-methyl-2-(di-n-propylamine)tetralin (nitrogen carbon atom at the 2-position).

A compound that structurally deviates from Formula I is converted into a compound of Formula II after being administered to an organism. The present invention also takes into consideration how these functions function in this structural form. be done. This consideration is another aspect of the invention. Similarly, certain formulations of formula I A compound may be metabolized to other Formula I compounds before exerting its effect. Y is R4 Compounds of the invention which are COO1(R5)2NCOOt or R60 therefore have Y It is believed that the main effects of the present invention occur after being metabolized into compounds that are H. The compounds may be obtained and prepared by one of the following methods which constitute another aspect of the invention.

a) Formula with RO in the 5th position (wherein R is a hydrocarbon or an acyl residue, preferably an acyl residue having 1 to 5 carbon atoms) Alkyl group, or benzyl group, or alkyl group having 2 to 6 carbon atoms bonyl group, and R1, R2 and R5 are as defined above) Ethers or esters cleave to form compounds of formula ■ where Y is a hydroxy group I can do it.

When R is a hydrocarbon residue, the cleavage is to convert the compound of formula r/CH3COOH, BBr3, AlCl2, pyridine-HCl or (CH 3) With acidic nucleophiles such as 3Sj or CH2O, 5R4-8o or This can be accomplished by treatment with a basic nucleophile such as C2H5-8○.

When R is a benzyl group, the cleavage is preferably carried out using Pa or pto2 as a catalyst. It can also be carried out by reduction with fresh hydrogen.

When R is an acyl residue, cleavage can be achieved by hydrolysis in aqueous acid or base. Alternatively, it can be preferably carried out by reduction with L:1AtH54.

Compound 2) can be obtained by the following synthetic route.

Therefore, the compound of formula uA can be diluted by reaction with methyl carbonate in the presence of NaH. Methylcarboxylation yields ketoester IIB, which is NaOC2H5 followed by cyc-alkylation by R3X (X=Br, ■) in the presence of a base such as dicarboxylic acid by hydrogenolysis of the keto function and hydrolysis of the ester function. It produces Ilc. Compound Ilc (10) Reaction with C7COOC2H5 in the presence of ethylamine followed by NaN3 Amine-containing compounds are converted to azides and subjected to Curtius rearrangement and acid hydrolysis. +1D and in the presence of a base KRXCOCt (in the formula, RX is Rx-CH2-7 5'' is defined by the relationship that R1 is equal to !11N-acylated, L jAtHA reduction and H3'C0Ct (wherein R7 is R7- (defined by the relationship that CH2- is equal to R2) After final reduction with LiA/, H4, a compound of formula (2) is obtained.

The pure enantiomer of compound ■ was first prepared by UK(-)-0-methylmandelic acid. Conversion to amide nF followed by chromatographic separation of the two diastereomers and then potassium using trace amounts of water and CH3Li in tetrahydrofuran. cleaved by reacting with tert-butoxide, and then the two enantiomers prepared by alkylation of the desired body (lB'$- and E") It can be done.

The compound (wherein R1, R2 and R5 are as defined above) is this compound. a base like triethylamine or pyridine or H2so4 or CF3 a suitable carboxylic acid halide R4C0X or anhydride in the presence of an acid such as COOH. (R4CO)20 or a suitable carbamoylparite (R effect NC0X(1 1) or triethylamine, pyridine or potassium tert-butoxide with a suitable allyl halide or benzyl halide R''X in the presence of a base such as Formulas in which Y becomes R4COO, (R5)2NCOO or R60 by processing I can be converted into a compound of I. X represents halogen, preferably Ct or Br.

Alternatively, conversion of Y=OH to R4COO is contemplated and R4 is R7C0 If 0C6HA-, then the formula! (In the formula, Y is OH) (wherein Y is HOC6H4CC)O-) and then convert it to a base or or an appropriate carboxylic acid halide R7C0X or anhydride (R7C0X) in the presence of an acid. O) Can be treated with 20.

(In the formula, Ha is either R1 or R2, and R1, R2, R3 and Y is as defined above) whose nitrogen atom is replaced with a suitable alkylating agent. It can be converted to a compound of formula I by alkylation. Therefore, Ra is R1 Certain starting compounds are dissolved in organic solvents such as acetonitrile or acetone and Alkyl halide or tosilane in the presence of a base such as 2CO3 or NaOH. -) R2X1 (in the formula, X1 is CL, Br, engineering or -0302-C6HACH3 ) or the starting compound is treated with carboxylic acid/NaBH4 complex, namely RbC00H-NaBH4 (wherein Rb is RbC'H2 (12) is equal to R2).

- To form a compound of formula I where at least one of R1 and R2 is CH3 , the alkylation reaction is carried out by converting the compound of formula (1) into formaldehyde-Na(ON)BH3 It can be carried out with a mixture or by treatment with formaldehyde and formic acid.

(wherein Y is OH or R60, and R6 is as defined above, R Q is an algorithm defined by the relationship that Re-CH2- is equal to R1 or R2. The amide of (Kyl group and Hd is the other of R1 and R2) is e.g. LiAtH4 or tetrahydrofuran in ether or tetrahydrofuran Compounds of formula I are reduced by treatment with a hydride reducing agent such as BH3 in Can form things.

(In the formula, M1 and M2 are the same or different, and -CH, >CH- Zl or nC==0, M5 is Ml and M3 otherwise is R3, zl is hydroxy at the benzylic position (Ml or M2) or a group sensitive to hydrogenolysis such as halogen, Ip, RZ is hydrogen, metal thyl or ethyl, Y is other than allyloxy, and R1, R2 and R3 is as defined above) is converted into a compound of formula (■) by reduction. sell. Therefore, keto functionalities can be treated with hydrazine under alkaline conditions, for example. or by intermediate formation of hydroxyl groups and Catalytic hydrogenation, which may also include the process of breaking double bonds and forming double bonds if possible. It can be reduced stepwise and converted to CH2 by using CH2. Basic CH-21 reduction using nuclear hydride reducing agents such as LiAtH4 or catalytic hydrogenation. It can be implemented by

(In the formula, Y is 6D other than allyloxy, and R1 and R2 are as defined above. aziridinium salts (e.g. cto4- or BF4-) with Preferably by catalytic hydrogenation formula! Converted to the compound (in the formula, R5 is CH3) It can be done.

(14) (wherein X represents 5O3H, CL or NH2), hydroxyl The group X is substituted with the group X to form a compound of formula I, where Y represents a hydroxy group. I can do it. When X is 5O3H or Ct, the above reaction is performed when X is So3H If so, treat with a strong alkali under heat, or suitably an alkali melt such as KOH. and if X is Ct, an aqueous strength such as NaOH or KOH. This can be carried out by treatment with alkali. If X is NH2, this reaction is treated with aqueous nitrous acid to form an intermediate diazonium compound, which is then treated with aqueous nitrous acid. This can be carried out by hydrolysis in a medium.

A racemic mixture or a mixture partially enriched in one of the enantiomers of the compound is Enantiomeric resolution may be performed to obtain pure enantiomers of formula (1). This is known in the art industry This can be done by a method. These methods include tartaric acid, 0.0-dibenzoyltartaric acid , with the pure enantiomers of acids such as mandelic acid and camphor-10-sulfonic acid. Recrystallization of diastereomeric salts is included.

The free bases formed can then be converted to their acid addition salts, and the acid addition salts formed The salt addition can then be converted to the corresponding base or other acid addition salt.

(15) pharmaceutical formulations Pharmaceutical formulations of the compounds of the invention constitute another aspect of the invention.

In clinical practice, the compounds of the present invention are typically administered as free bases or as pharmaceutical agents. Acceptable non-toxic acid addition salts such as hydrochloride, lactate, acetate, sulfamate of pharmaceutical formulations comprising the active ingredient as such in combination with a pharmaceutically acceptable carrier. The form may be administered orally, rectally or by injection.

Therefore, the terms relating to the novel compounds of the present invention, whether general or specific, For example, in an example where such a term is used, the context is consistent with the broader concept. It is intended to include both free amine bases and acid addition salts of free bases. be done. The carrier may be a solid, semisolid or liquid diluent or capsule. Ru. These pharmaceutical formulations constitute another aspect of the invention. Usually the active substance is 0.1-99% by weight of the preparation, more specifically 0.5-20% by weight of the preparation for injection. , and will constitute 0.2-95% by weight of a formulation suitable for oral administration.

Pharmaceutical formulations containing compounds of the invention in dosage unit solid form for oral administration may preferably contain from 2 to 95% by weight of active substance; in such formulations the selected Selected compounds can be transferred to solid, finely divided carriers such as lactose, sucrose, sorbitol, mannitol, etc. Thor, starch such as potato starch, corn starch or amylo, cutin, cell Loose derivative (16) or Seratin, and lubricants such as magnesium stearate, stearic acid Mixed with calcium, polyethylene glycol socks, etc., and then compressed Tablets can be formed. If coated tablets are required, proceed as above. The prepared core contains e.g. gum arabic, gelatin, talc, titanium dioxide, etc. It can be coated with a concentrated sugar solution. Alternatively, tablets may be prepared using readily volatile organic solvents or It can be coated with a lacquer dissolved in a solvent mixture. Contains different active substances These tablets can be easily distinguished from each other or tablets containing different amounts of active substance. Dyes may be added to the coating.

Soft gelatin capsules (pearl-shaped closed caps) consisting of gelatin and, for example, glycerin. To prepare capsules) or similar sealed capsules, the active substance is mixed with vegetable oil. sell.

Hard gelatin capsules contain granules of active substances such as lactose, sucrose, sorbitol and mannitol. starch (e.g. potato starch, corn starch or amylo-cutin), may be contained in combination with solid fine particle carriers such as ululose derivatives or gelatin. Ru.

Liquid form preparations for oral administration include syrups or suspensions, such as those described herein. Contains about 0.2 to about 20 liters of active substance, with the remainder being sugar, ethanol, and water. , can be in the form of a solution that is a mixture of glycerin and propylene glycol . In some cases, such liquid preparations contain coloring agents, flavoring agents, saccharin and thickening agents. Carboxy (17) Special Table 58-500714 (7) Methylcellulose may contain.

Solutions for parenteral administration by injection preferably have a concentration of about 5 to about 10% by weight. may be prepared as an aqueous solution of a water-soluble pharmaceutically acceptable salt of the active substance.

These solutions may also contain stabilizers and/or buffers and advantageously contain species. The drug may be provided in individual dosage unit ampoules.

For therapeutic treatment, a suitable daily dose of a compound of the invention is 100 to 100 mg for oral administration. 500'Org, preferably 500-300011117 and For oral administration, the dose is 0.5 to 500 Mg, preferably 25 to 250 Mg.

Example The following examples further illustrate the invention.

Preparation of intermediates Example 1 ω-5-methoxy-2-methyl-2-(di-n-brobylamino)te tralin 5-methoxy-2-methyltetralin-2-carboxylic acid dry EtoH (125 m ) in methyl 5-methoxy-1-oxotetralin-2-carboxylate ( A solution of 25r, 1oo mmol) was mixed with 80% NaH (3,3r, 110 mmol). ＃　　　　、　.

A freshly prepared solution consisting of dry benzene (125m) and dry EtOH (125mg) was added gradually into the prepared mixture. The resulting slurry was refluxed under a nitrogen stream for 20 hours. I let it happen. After cooling, methyl iodide was added 6 times in 10-hour increments (68.4r, -465 mmol). ) was added. The reaction mixture was refluxed for 1 hour, then it was neutralized with acetic acid. Vol. The starting material was evaporated under vacuum and the residue (18) First, the official materials are passed through a short alumina column using ether as the eluent, and then chromatography on a silica column using ether/petroleum ether (1:2) as eluent. Methyl 5-methoxy-2-methyl-1-oxotetralin- 2-Carboxylate 242 was obtained as an oil. This oil was mixed with acetic acid (500y nl), perchloric acid (1+++74) was added and the resulting solution was dissolved in pa Hydrogenated over /c (4M) at atmospheric pressure. After 24 hours the reaction is complete and the catalyst is Filtered (through Celite) and added CHCL3 (10DDrnI!).

The organic layer was washed several times with 100 ml of H2O, followed by evaporation of CHCL3 under vacuum. An oily substance was obtained, which was mixed with MeOH (100mJ), N20 (125-) and KoH Barrett (50F) for 4 hours. Evaporate MeOH under vacuum and by adding ice-cold 10% HCt to the resulting solution. The product precipitated. Recrystallization twice from EtOH/H20 yields pure 5-methoxy 9.6 r (44%) of cy-2-methyltetralin-2-carboxylic acid was obtained. . Melting point: The compound is 2,6-simethoxy-9,10-dihydrophenanthrene- 9-carboxylic acid to 2,3-dimethoxy-9-amino-9,10-dihydrof Nichols et al. used it to treat henanthrene. Methods [Journal of Medicinal Chemistry (J.

Med, Chem) J Vol. 21, p. 395 (1978)] 19) Methoxy-2-methyltetralin-2-carboxylic acid (8,7!M, 38 mmol ) was prepared from Convert the amine to the hydrochloride salt and from EtoH/ether It was recrystallized twice. Yield 5.89 (76%), melting point 2495-2515°C (decomposition) .

Propionyl chloride (4,6'?, 49 ml) in dry ether (60 rnl) 2-amino-5-methoxy-2-methyl in dry ether (750 mJ) Tiltetralin (63t, 33 mmol) and triethylamine (4,9r, 49 mmol). After 60 minutes at room temperature, the reaction mixture was filtered and evaporated. evaporated. The resulting crude amide was passed through an alumina column and purified with ether. eluted. The purified amide remaining in the dry THF (100 m7) was removed with a N2 stream. Below is LiALH4 (7,2t, 187 mmol) in dry 1”HF (200-) ) was added to the suspension. After stirring under reflux for 6 hours, the reaction mixture was hydrolyzed and the precipitate was removed. Filter and evaporate the solvent. The oily residue was evaporated with ether/petroleum ether as eluent. Pure 5 was purified by chromatography on an alumina column using ether (1:1). -Methoxy-2-methyl-2-(n-propylamine)tetralin 6, 49 ( 83%).

This base was converted to its hydrochloride. Melting point 239-239.5℃ (decomposition) (Et oH/from ether).

(20) 5-methoxy-2-methyl-2-(n-propylamino)tetralin (45t, 19 mmol), propionyl chloride (2,7f, 29 mmol), trie A mixture of thylamine (2,9r, 29 mmol) and benzene (15M) was added to the room. The mixture was stirred at room temperature for 10 hours. Filter the precipitate, evaporate the solvent under vacuum and remove the resulting The crystals were rinsed with ether. The resulting pure amide (3,81) was evaluated for complete reaction by TLC. LiA7H4 (1.5t, 39 mmol) and and dioxane (10o7) and heated to 80°C. Disrupt the reaction mixture, followed by water and 15% NaOH, filter the precipitate, and evaporate the volatiles to form an oil. A similar substance was obtained. When this is passed through an alumina column and eluted with ether, pure 5- Methoxy-2-methyl-2-(di-n-propylamino)tetralin 3.6r (68%) was obtained.

The base was converted to the hydrochloride salt. Melting point 145-145.5°C (from EtOH/ether ).

Example 20→- and (-)-5-methoxy-2-methyl-2(';-n-di-n -R dissolved in propylaminoline CH2Cl2 (5mZ) -(-) -o-Methylmandelic acid chloride (60f, 0033 mol) (R-(-) -〇-Methylmandelic acid to thionyl chloride and 2[treated at 1°C for 10 hours] ω-5-methoxy-2-methyl-2-(n-propyl) Amino) Tetrali (21) Special table 1984-500714 (8) N (7,0″?, 0.026 mol), CH2Cl2 (50ml), N20 (50m) and 5 Added to a stirred mixture of polyhydric NaOH (80 ml) at room temperature. 15 minutes After stirring for a while, the phases were separated and the organic phase was washed once with water and then dried (Na2SO4). , filtered and evaporated. Ether/Petroleum Ether (Ni3) (15rn1.) was added to the residue. The mixture was cooled to about -70°C and diastereomeric One of the midos precipitated (0.91). Evaporate the P solution and remove the oily residue by 5j O2 (4(), 63 um) on column with ether/petroleum ether (1 :3). The first eluted diastereomer ( 0,71) is the diastereomeric amide that first comes out as crystals from the mixture. was shown to be the opposite. The second diastereomer (0,5 1) was shown to be identical to the diastereomeric amide originally crystallized. . crystals (above) and the second eluting diastereomer (0,9S'+0. 59, total 142) were stereochemically pure by HPLC. This jias Teleomeramide (1,1', 0.0037 mol) was dissolved in THF (50me). The mixture was allowed to cool and maintained at -15°C. Add potassium 6th ptoxide (0,1') The mixture was then kept at this temperature under stirring for 5 hours. ether and N20 was added and the phases were separated. The ether phase was extracted with 10% HCl and dried (Na2 SO4) and evaporated to give an oil, which was dissolved in dry THF(20-). Dissolved and diluted with a 1.6 M solution of CH3Li in ether (50 g) at -15 °C. Stirred for a minute and then extracted with 10% HCt. The aqueous phase was mixed with the above 10% HC1 extract. The mixture was made alkaline with Na2CO3 and extracted with ether. Aete Treatment of the ethanol phase with HCl in ether resulted in a precipitate, which was removed with ethanol/ether. Recrystallized from (5-methoxy-2-(n-propylamino)tetraly) Colorless crystals (0.75P, 28 mmol) of N-hydrochloride were obtained.

Melting point 218-222°C, [α]j'=+19.6° (C02, MeOH).

CH2Cl2 (10m) and triethylamine ((→-5-methyl) in 2m7 Toxi-2-methyl-2-(n-propylamino)tetralin (0,25r, 1 propionyl chloride in CH2Cl2 (10d) in a solution of (020), 2.1 mmol) was gradually added. This mixture was heated at room temperature for 1 hour. Stir for a while, add water and separate the organic layer, dry (Na2SO4) and dissolve. The medium was evaporated. The residue (0,, 25r) in ether (25d) is converted into ether (25 m) to a stirring suspension of L]AtH4 (0,25?) in The mixture was refluxed for 1 hour. When treated in a conventional manner, the base is obtained as an oil. This was converted to the hydrochloride using ethereal HC1 to give (th)-5-methoxy -2-methyl-2-(n-propylamino)tetralin hydrochloride (0,20f) Obtained.

Others (7) Surdiastereo-7-R-0-0-mer containing diastereomeric amide Using ether/petroleum ether (1:3) with tilmandelamide as eluent Separated on 5102 (23) The first fractions (supra) were combined and evaporated. Oily residue ( 071,18 mmol) in THF (20 rn!) at -15°C. Toki, Cyto (2,09) and then treated with CH3Li (ether 2.5 ml of a 1.6 M solution in Ru-2-(n-propylamino)tetralin hydrochloride (o,3oy, 11 mmol ) was obtained. Melting point: 215-219°C, [α]-21,0 (C02, MeOH).

This product (0.30f, 11 mmol) was dissolved in CH2O, 2 (10 ml.) and and propionyl chloride (0,21f, 2-) in triethylamine (1,5-) ．． 2 mmol) to give the amide, which was dissolved in LjAIH4 (0 , 25f) to give (-)-5-methoxy-2-methyl-2-(di- -n-propylamino)tetralin hydrochloride (0,2(1) Example E1 (a)-5- Hydroxy-2-methyl-2-(di-n-propylamino)tetralin C+J-5-methoxy-2-methyl-2-(di-n-propylamino)tetrali hydrochloride (0.75r, 2.4 mmol) in 48% water-polluted HBr at 0°C. Heated under a stream of N2 for 2 hours. The volatiles were removed under reduced pressure and the residue was dissolved in EtOH. / ether to give (t)-5-hydroxy-2-methyl-2-(di-n -Propylamino)tetralin hydrobromide 0.4 Or (58%) was obtained. melting point 217-218°C.

Example E2 ←)-5-hydroxy-2-methyl-2-(di-(24) n-propylamino)tetralin (Th)-5-methoxy-2-methyl-2-(dimethyl) in CH2Cl, (5 m/) -n-propylamine)tetralin hydrochloride (0,20f-0,65 mmol) Treated with BBr3 (2 ml) at -70°C for 5 minutes and then at room temperature for 30 minutes. . This mixture was extracted with 10% Na2CO3, and the organic layer was dried (Na2SO4 ) L and the solvent was evaporated. Using MeOH as the eluent for the oily residue Chromatography was performed on a 5jO2 (40-63 um) column. ether Treatment with HC1 gave crystals which were recrystallized from MeOH/ether ( )-5-hydroxy-2-methyl-2-(di-n-propylamino) tetrali ion hydrochloride (80 mg) was obtained. Melting point: 212-215°C, [1-+195°CQ] o, 2, MeOH).

Example E3 (-)-5-hydroxy-2-methyl-2-(di-n-propylamino) Tetralin (-)-5-methoxy-2-methyl-2-(dimethyl) in CH2Cl2 (5 mA) -n-propylamine) tetralin hydrochloride (0202,0.65 mmol) as an example. Treated with 13Br5 (2 ml) as described above in E2 (-) -5-hydroxy-2-methyl-2-(di-n-propylamino)tetralin salt The acid salt (1001 g) was obtained. Melting point 211~2゛17℃1, [α) M14 21. 3° (co, 1, MIIIOH).

Example E4 (t)-5-acetoxy-2-'methyl-2-(di-n-propylamine c) Tetralin (t)-5-hydroxy-2-methyl-2-(di-n-propylamino)tetra Phosphorus was dissolved in acetic anhydride (10m). Add triethylamine (o, sy) and the solution was refluxed for 1.5 hours. Add gtoH (25d) and solvent was evaporated to give an oil. Using diluted NaOH while cooling this oily substance externally, The mixture was made alkaline to pH 10 and then extracted with ether. Dry the organic phase and evaporation to give the desired compound as an oil. Desired for ethereal HCL The hydrochloride of the compound was obtained. Melting point °C.

Example E5 (t)-5-benzoyloxy-2-methyl-2=(di-n-propyl amino)tetralin ω-5-hydroxy-2-methyl-2-(di-n-propyl) Amino)tetralin (0.20r, 60mmol) in CH2Cl2 (10m) and dissolved in pyridine (1-).

Benzoyl chloride (0.98F, 7.0 mmol) was added and the mixture was stirred at room temperature for 6 hours. Water (15 ml.) was added, the organic layer was separated and dried (N a2SO+) L and evaporated to obtain an oil, which was evaporated using ethereal HC1. and converted to its hydrochloride. Melting point °C.

Following the method of the example above, the combination compound was prepared and added to ethanol as an acid addition salt. It was recrystallized from alcohol/ether or isolated as a base.

(27) The following examples illustrate how compounds of the invention can be included in pharmaceutical formulations. .

Example P1 Preparation of soft gelatin capsules 500t of active substance is mixed with corn oil 5002 and the mixture is then added to each capsule. soft gelatin so that the mixture contains 100η (i.e. 5019 active substances). Fill into capsules.

Example P2 Preparation of tablets Active substance 0.5~ ．． Mix with 2 increments. Mix this with 0.45 Kf of potato starch and 0.5 Kf of lactose. and mix this mixture with starch paste prepared from 5°t of potato starch and distilled water. and pass the mixture through a sieve to form granules. Dry the granules sieve and mix 20 f of magnesium stearate thereto. At the end The mixture is compressed into tablets each weighing 17 Cy.

Example P5 Preparation of syrup 100 g of active substance is dissolved in 300 f of 95% ethanol, where it is dissolved in glycerin. 300? , flavoring and coloring agents (as appropriate) and water 1000 ml.

You will get syrup.

Example P4 Preparation of injection solution Active substance (hydrobromide) (1f), chloride) + Jum (0,89) and a Dissolve 100m (7) of scorbic acid (0,1?) (28) Dissolve in enough distilled water to obtain a liquid. 17! Contains 10mg of this active substance. Use this solution for filling ampoules and heat the ampule at 120°C for 20 minutes. Drugs that affect neural humoral transmission are associated with various diseases of central and peripheral origin. It is of great interest in the treatment of symptoms. For example, monoaminergic systems Compounds with specific effects can be used, for example, in Parkinson's syndrome, schizophrenia, psychosis. Depression, geriatric mental and motor disorders, hypotensive and hypertensive symptoms, and other It is of great therapeutic value.

During the search for novel nadopamine (DA') receptor activators, we predicted that Unexpectedly, some compounds of formula I have been found to be effective in stimulating central serotonin (5-HT) and DA synthesis. scales that significantly alter production, turnover, and metabolism, while related to behavioral effects. discovered that it exhibits a unique pharmacological profile. Evaluation of the activity of compounds of formula I For evaluation, the following biochemical and behavioral tests were performed.

Behavioral and biochemical activities in rats a) Reserpine-induced in rats Antagonism of neuroleptic syndrome (overall behavior) Decreased monoamine stores by reserpine can lead to akinesia, catalepsy, muscle stiffness, and kyphosis. by central and peripheral symptoms of postural and numerous other monoamine depletions. Characteristic .

This results in the ``neuroleptic syndrome,'' which is associated with This reserpine-induced syndrome is often used as an animal model to mimic Parkinson's disease and psychotic depression. It will be done.

This syndrome, in whole or in part, is directly or indirectly linked to DA or 5-HT receptors. can be reversed by administering drugs that stimulate

b) Rat brain tyrosine and tryptophan in vivo Measurement of droxylation rates (biochemical demonstration of DA- and 5-HT receptor activity) ) The compound being evaluated is biochemically linked to its central DA and 5-HT receptors ( Preganglionic and/or tubular) stimulatory activity was tested. This biochemical screen The concept of the DA or 5-HT receptor antagonist is to stimulate the receptor. tyrosine or tryptopyl, respectively, via a controlled action feedback system. preganglionic (synaptic) neurons and then preganglionic (synaptic) neurons I) decrease the synthesis rate for A and 5-HT. N SD 1015' (3-hydroxybenzylhydrazine hydrochloride) for aromatic L- Donoξ and 5 measured after in vivo inhibition of amino acid decarboxylase - Taking the formation of HTP as an indirect measure of the rate of DA and 5-HT synthesis, respectively .

Similar conditions also exist for central NA neurons. supine dominant hemisphere (main DOPA formation in the cortex (30) Therefore, the effect on I can do it.

C) Experimental method Males pretreated or reserpine pretreated (5i+g/Kp, 18 hours before) Sprague-Dawley system (200-300F) is given the compound to be evaluated. I got it. Observation of overall behavior (motility, body posture, chronic illness, and other changes) and movement Exercise activity recording (electronic exercise meter, Motron Products) was performed. body Temperature was measured with a rectal probe (Yellow Spring Instruments). established. Subsequently (administration of NSD 1015, decapitation, brain dissection (striatum, forebrain) limbus, cortex, diencephalon, brainstem), homogenization, centrifugation, ion-exchange cloning Matography and fluorescein are measured by Book of Medicinal Chemistry (J, Med, Chem,) J Volume 21 864-867 (1978) and references cited therein] Actual dopa and 5-HTP levels were given. In one experiment, the test drug is given without any other treatment, and monoamines, their precursors and High performance liquid chromatography using electrochemical detection method to detect brain levels of and metabolites It was measured by HPLC.

d) Results Compound 2 significantly antagonizes reserpine-induced akinesia (Table 1). But long Complete ``neuroleptic syndrome'' (61) There is no reversal. The animal remained in a kyphotic position while exhibiting forward locomotion. Furthermore, that They often have generalized tremors [wet-dog shakes]. 5hakes) J) was shown. The motor stimulation induced by compound 2 is (10*y/Ky, ip, 6 hours before) + tyrosine hydroxylase inhibitor α -Methyl-p-tyrosine (250 μ/Ky, i, p, 1 hour before) Since it is not inhibited, it releases catecholamines (data not shown). It can be concluded that it is not mediated by any other means. Furthermore, DA receptor stimulation Agents 5-hydroxy-2-(di-n-propylamine)tetralin and apomol In contrast to fins, the locomotor activity exhibited by compound 2 is due to DA receptor stimulation. without any of the typical symptoms of chronic illness (licking, sniffing, biting, etc.) This was given at a dose that produced efficient blocking of DA receptors. Completely resistant to pretreatment with loharidol. Methoxy homolog of compound 2 5-methoxy-2-methyl-2-(di-n-propylamino)tetralin ( 20■/Y14, s, c,) failed to antagonize reserpine-induced akinesia. .

Measurements of monoamine synthesis rates performed simultaneously after Compound 2 also showed significant changes. did. That is, the rate of 5-HT synthesis in all brain regions examined was higher than that of compound 2. After that, it rose 20-60 inches above the control value. This increase was caused by reserpine pretreatment. observed both in the absence and in the presence of (Table III). Change tyrosine and to(62) Lyptophan levels increased significantly after Compound 2. Slightly no DA synthesis rate However, a significant increase was also observed in the brainstem (Table ■). These biochemical changes At least in rats not treated with reserpine, it was accompanied by a significant increase in body temperature. (Table ■).

Compound 2 also produced significant locomotor activity and “ ``Wet Dog Shake'' (Table ■). brain stuff that follows Analysis of amines, their precursors and metabolites showed that norad Renarin (NA) and 5-HT levels remain unchanged, while homovanillic acid ( HVA) levels were shown to be significantly elevated compared to controls. Furthermore, 5-hydroxy Cyindoleacetic acid (5-H-AA) levels are slightly but significant in the limbic forebrain. DA and 3,4-dihydroxyphenylacetic acid (DOPAC) Levels were significantly decreased in the striatum. As in the previous experiment, tryptophore There was an increase in tryptophan and tyrosine levels, but no statistical significance was observed. achieved only for fans.

All the results obtained for compound 2 above also indicate that the pure levorotatory enantiomer (- It was also obtained for 1-2, but dextrorotation (not obtained for +-1-2) Ta.

Conclusion Pharmacological data show that the compounds of the invention have significant pharmacological effects. ing. Simultaneous behavioral and biological effects induced by the compounds under consideration Scientific (33) Special Table of Publication 58-50071461) Changes have been previously described. constitute a unique pharmacological profile. Said compound is mentioned in the introduction part above. affected pathological conditions such as Parkinson's disease, psychotic depression and geriatric It is of great clinical interest in the treatment of nervous system disorders.

Table 1. Compound 2 antagonizes reserpine-induced akinesia (as a dopaminergic stimulant) comparison) B, R + eight haloridol (6) 4.0 ± 1.5 4 NS vs, AC, R 10 Compound 2 121±144 D, R ten H ten compounds 2 130±14 4 NS ve, CF, R+H+5-0 H=DPAT 5.0±1.7 4 0.001 vs, EG, R+apomorph In　299 ± 674 reserpine pre-treated (5 ■轡, 1.pl, 18 hours ago) Halo was administered to ridol (0,5 iy/9, i-p,) and compound 2 (2 0 kan g/suke, e, c,), s -OH-DPAT (0,1119/ni 9, s, c, ) or apomorphine (0,1119/Kg, s, c,), respectively, during exercise. It was given 30 minutes and 0 minutes before entering the meter. Controls are applied to corresponding time intervals. given an injection of vehicle. Track and record open locomotor activity for the next 50 minutes. Ta. Shown are mean values±s.e.m. For statistical comparisons, Student's test was used. NS indicates significant and critical (p>0.05) .

(34) Effect of surface compound 2 on rat rectal temperature and in vivo rat brain DA- and 5-HT synthesis rate P <0.025 <0.001 <0.025 <0 ．． 001P <0.001 (35) Reserpine treatment (5119/Kr, i, p, 18 hours before) or no pretreatment Rats were given compound 2 (9, s, c, in 201197) 60 minutes before death. Ta. Controls received vehicle. N5D101 for all animals 30 minutes before death 5 (100 my/Ky, j, p,) was given. Kill this rat by decapitation. , the brain was dissected and DOPA, 5-HTP, tyrosine and and to measure tryptophan levels. Body temperature measured by rectal probe determined. Shown are mean values±sen. statistics student Depends on the test. P indicates significance level. n8 indicates not significant (p>0.05) vinegar.

(36) BEST MODE FOR CARRYING OUT THE INVENTION The compound 5-hydroxy-2-methyl-2-(di-n-propylamino)tet Larin and its salts, processes for the preparation of said compounds, and treatments of said compounds, especially for psychosis. Use in the treatment of depression is the best mode of carrying out the invention currently known. represents.

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Claims (1)

[Claims] 1. Formula as a base or as a pharmaceutically acceptable acid addition salt thereof [In the formula, Y is OH, R4COO, (R5)2NCOO or R60 (here T R4 is an alkyl group having 1 to 5 carbon atoms or optionally substituted phenyl group, R5 is an alkyl group having 1 to 5 carbon atoms, and R6 is an alkyl group having 1 to 5 carbon atoms. lyl or benzyl group), and R1 is an alkyl group having 1 to 6 carbon atoms. kyl group, R2 is an alkyl group having 1 to 6 carbon atoms, and R 3 is an alkyl group having 1 to 6 carbon atoms. 2. R4 is an optionally di-substituted phenyl group, R5 is a methyl group, and and R6 is an allyl group, and R1, R2 and R5 are Compounds according to claim 1 having the meaning given in claim 1. 3, Y is OH, R4COO or R60 (where R4 is an optionally substituted fluorophore) and R6 is an allyl group), and R1, R2 and and R3 have the meanings given in claim 1. Compound. 4, R4 is methyl, phenyl or 4-alkanoyloxyphenyl (wherein has 1 to 4 carbon atoms), R5 is methyl, and R 6 is allyl (69) , R1 is alkyl having 1 to 3 carbon atoms, and R2 is alkyl having 3 to 6 carbon atoms. alkyl having a carbon atom, and R3 is methyl or ethyl; Compounds according to claim 1. 5, Y is R4COO (where R4 is an alkyl group with 4 to 6 carbon atoms) 4-alkanoyloxyphenyl group), and R1, R2 and and R5 has the meaning as defined in claim 1. compound. 6. According to any one of claims 1 to 5, wherein R1 is n-propyl. compound. 7, R2 is an alkyl group having 3 to 6 carbon atoms and R3 is methyl or A compound according to claim 6 which is ethyl or ethyl. 8. Compounds according to any one of claims 1 to 7, wherein R3 is methyl . 9. Any one of claims 1 to 4 and 6 to 8, wherein Y is OH. Compound by. 10, levorotatory (c)-5-hydroxy-2-methyl-2-(di-n-propyla mino)tetralin in its pure enantiomeric form with the same absolute configuration as A compound according to any one of claims 1 to 9. 11, R4 is an alkyl group having 1 to 5 carbon atoms, phenyl, 2,6-sime tylphenyl or 3- or 4-hydroxyphenyl group, or formula (40) (wherein R7 is an alkyl group having 1 to 6 carbon atoms) A claim characterized in that 4=alkanoyloxyphenyl group A compound according to one or more terms. 12, Compound 5-hydroxy-2-methyl-2-(di-n-propylamino)te Tolarin. 13. Formula as a base or as a pharmaceutically acceptable acid addition salt thereof [In the formula, Y is OH, R4C00, (R5)2NCOO or R60 (Kokote R4 is an alkyl group having 1 to 5 carbon atoms or optionally substituted phenyl In the group l), BS is an alkyl group having 1 to 5 carbon atoms and R6 is an allyl or benzyl group) and R1 has 1 to 6 carbon atoms f) is an alkyl group, R2 is an alkyl group having 1 to 6 carbon atoms; to produce a compound in which R5 is an alkyl group having 1 to 3 carbon atoms. Nitoshi, (42) (wherein R is a hydrocarbon or acyl residue and R1, R2 and R6 are Y is a hydroxy group by cleavage of the ether or ester of forming a compound of formula I, or (wherein R1, R2 and R3 are as defined above) with a base or Carboxylic acid...ride R4COX or anhydride (R4CO) in the presence of acid 20 or treated with carbamoylnolide (R5) 2NCOX, or with base In the presence of allyl or pendyl halide R6X (in the formula or representing halogen) By processing Y is R4COO, (R5)2NCOO or R60. or (wherein R is either R1 or R2) and R1, R2, R3 and Y are as defined above) By alkylating the nitrogen atom with an alkylating agent, the compound of formula ■ is obtained. Convert or d) Eq. (43) (In the formula, Y is OH or R60, R6 is as defined above, and RC is R an alkyl group defined by the relationship that C-CH2- is equal to R1 or R2 (and Rd is the other of R1 and R2) is reduced with a reducing agent. to form a compound of formula I, or (In the formula, M1 and M2 are the same or different, and each is -CH2-, /CH -21 or C-0, M3 is Ml and M5 otherwise is R3, J, zl is a group sensitive to hydrogenolysis, and Rz is hydrogen, methyl or or ethyl, Y is other than allyloxy, and R1, R2 and R3 is as defined above) is converted into a compound of formula (■) by reduction, or or (in the formula, Y is other than allyloxy, and IR12 and Ht are as defined above) aziridinium salts (e.g. C2O4- or BF,- ) is converted by reduction into a compound of formula ■ (wherein R3 is CH3), or 5 g) Formula (wherein X represents SO3H%Ct or NH2) substituting the group with the group X to form a compound of formula I, where Y represents a hydroxy group. or one of the racemic mixtures or enantiomers of the compound is partially enriched. The resulting mixture is subjected to enantiomeric resolution to obtain the pure enantiomer of formula ■, and then separation of the optionally obtained isomer mixture into pure isomers A method characterized by: 14. Y, R1, R2 and R3 are any of the claims 1 to 12 above. According to claim 13, the invention is as defined in claim 13. Method. 15. Claims 1 to 1 as the active ingredient together with a pharmaceutically acceptable carrier. Which of the two terms is one or more (44) Pharmaceutical formulations containing compounds according to section. 16. Use of active ingredients in the manufacture of pharmaceutical preparations for treating disorders in the central nervous system. Use of a compound according to any of the preceding claims 1 to 12 as a component. 1Z Claim No. 1 for use in treating disorders in the central nervous system A compound according to any one of items 1 to 12. (1) Special table Showa 58-500714 (3)