NO160365B - ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY ACTIVE PHENYLAZACYCLYCLANES. - Google Patents

Description

The present invention relates to the production of new, substituted phenylazacycloalkanes for therapeutic use, particularly with therapeutic activity in the central nervous system.

In Chemical Abstracts 69:86776S (1968) (Julia, M. et al.,' Bull. Soc. Chim. Fr. 1968, (3), 1000-7) compounds of the general formula are described:

Among the compounds mentioned are compounds in which R<1> is m-OCH3 and R<11> is H, <CH>3, C2H5, CH2CgH5, CH_CH2C6H5 or CH2CH2CgH4N02(p) and in which R<1> is m-OH and R is CH2CH2CgH5 or CH2CH2CgH4N02(p). Said compounds were prepared for investigation of pharmaceutical properties.

Swiss patent 526,536 describes compounds of the formula:

where R<1> is H or OH and R11 is H. The compounds are said to have useful pharmacological properties especially as broncholytic agents.

DE explanatory document 2,621,536 describes compounds with the formula:

where X<1> is hydrogen or an acyl group, and R<1> is an alkyl, alkenyl or phenylalkyl group. The compounds are stated to have dopaminergic properties.

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

where n is 2; Y is OH, R<1>COO, R2R3NCOO- or R40, where R1

is an alkyl group with 1-5 carbon atoms, phenyl or phenyl substituted with alkyl with 1-5 carbon atoms or alkylcarbonyl with 1-5 carbon atoms, R 2 is an alkyl group with 1-5 carbon atoms, a phenethyl, benzyl or phenyl group,

3 4

R is H or an alkyl group with 1-5 carbon atoms, and R

is an allyl or benzyl group; and R is an alkyl group with 1-5 carbon atoms, a hydroxyalkyl, dimethylaminoalkyl or methylthioalkyl group with 2-6 carbon atoms in the alkyl part and with the heteroatom bonded in a position other than the 1-position, or an alkenyl group with 3-5 carbon atoms other than 1 -alkenyl group, as bases, pharmaceutically acceptable acid addition salts or esters thereof, as well as their enantiomers and mixtures thereof, are effective neuropharmacological agents. Said compounds are thus active as presynaptic dopamine receptor agonists administered to animals including man. The compounds are thus useful for the treatment of disturbances in the central nervous system, especially psychotic conditions in humans. Among the compounds according to the invention, there are also compounds that have a positive inotropic cardiac effect, and lack significant chrono-

tropical effect. Such compounds are useful for the treatment of heart failure.

An alkyl group can be a straight alkyl group or a branched alkyl group.

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

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

Symbols for numbers, atoms or groups mentioned in

the following has the broadest meaning previously stated unless otherwise specified.

Both organic and inorganic acids can be used

for the formation of non-toxic pharmaceutically acceptable acid addition salts of the present compounds. 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 can be easily prepared by known methods.

In a limited embodiment, the invention relates to the preparation of compounds of formula I where Y is OH,

2 3

R C00- or R R NCOO-, : where R is an alkyl group with 1-5 carbon atoms, or a phenyl group, and R 2 is an alkyl group with 1-5 carbon atoms, a phenethyl, benzyl or phenyl group, and R 3 is H or an alkyl group of 1-5 carbon atoms, and R is an alkyl group of 1-5 carbon atoms, a hydroxyalkyl group of 2-6 carbon atoms in the alkyl part other than a 1-hydroxyalkyl group, or an alkenyl group of 3-5 carbon atoms other than a 1-alkenyl group .

Preferred compounds of formula I are those where

Y and R have the above meaning. Preferred are

1 4

also those in which Y is OH or R C00 or R 0. Further preferred are compounds in which R is an alkyl group with 3-5 carbon atoms.

The compounds of formula I 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 present. The pure enantiomers, as well as mixtures thereof, are thus covered by the invention.

Certain compounds of formula I can be metabolized

to other connections with. formula I before they exert their effect.

1 2 3

Compounds of formula I wherein Y is R C00, R R NCOO or

R^O is thus assumed to exert its main activity after the metabolism of compounds where Y is OH.

The compounds with formula I are prepared according to the invention by carrying out the methods specified below a)-

d) :

a) An ether or ester with the formula:

where Ra is a hydrocarbon or acyl residue, preferably a

alkyl group with 1-5 carbon atoms, or an alkylcarbonyl group with 2-6 carbon atoms, and n and R have the meaning given above, is cleaved to form a compound of formula I where Y is a hydroxy group.

When Ra 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/CH3C00H, BBr3, AlCl3, pyridine-HCL or (CH3)3 Sil, or with a basic nucleophilic reagent such as CH^gH^-S6 or C2H,--see.

When R<3> is an acyl residue, the cleavage can be carried out by hydrolysis in an aqueous acid or base or by reduction, preferably with LiAlH4..

b) In connection with the formula:

where Z is SO^H, Cl or NH2, and n and R have the meanings given above, the Z group is replaced by a hydroxy group to form a compound of formula I wherein Y

is a hydroxy group. When Z is SO 3 H or Cl, the reaction can be carried out by treatment with a strong alkali under heating, conveniently with an alkali melt such as KOH when Z is SO 3 H, and with a strong aqueous alkali such as NaOH or KOH when Z is Cl. When Z 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.

c) A compound of formula I:

r

where Y is OH, and R is different from hydroxyalkyl, and n is as indicated below, is converted into a compound with the same

1 2 3 4 <; >formula where Y is R C00, R R NCOO or R 0 by treating the former compound with a suitable carboxylic acid halide R<1>COX or anhydride (R<1>CO)„0 or with a suitable 2 3 2 carbamoyl halide R R NCOX or isocyanate R NCO in the presence of a base such as triethylamine or pyridine, or an acid such as H 2 SO 4 or CF 3 COOH 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 is a halogen, preferably Cl or Br. When the conversion of Y = OH to R1COO is desired and R1 is , alternatively a compound of formula I where Y is OH can first be converted into a compound of formula I where Y is

which is then treated with a

suitable carboxylic acid halide R 5 COX or anhydride (R 5CO) 20 in the presence of a base or an acid.

d) A compound with the formula:

where n and Y have the meanings given above, are converted

a to compound of formula I by alkylating the nitrogen atom with a suitable alkylating agent. The starting compound can thus be treated with an alkyl, hydroxyalkyl, dimethylaminoalkyl, methylthioalkyl, alkenyl or benzyl halide or tosylate RX1, where x1 is Cl, Br, I or

in an organic solvent such as

acetonitrile or acetone and in the presence of a base such as K-CO-, or NaOH, or the starting compound can be treated with a carboxylic acid NaBH4 complex R COOH-NaBH4, where R is defined through the ratio R^-ci^-like R. For the formation of a compound of formula I where R is CH^, which cannot be obtained by the latter reaction, alkylation reaction can be carried out by treatment with a formaldehyde-Na(CN)BH^ mixture. For the formation of a compound of formula I where R is hydroxyalkyl, dimethylaminoalkyl or methylthioalkyl, the synthesis can also be carried out by alkylation with a suitable dihaloalkane which gives a monohaloalkyl derivative of formula I followed by acid or alkaline hydrolysis and reaction with dimethylamine or CH^S ø. In particular, for the formation of a compound of formula I where R is 2-hydroxyalkyl, the alkylation can also be carried out by reaction with a 1,2-epoxyalkane.

Formed free bases can afterwards be converted into

their acid addition salts, and acid addition salts formed can subsequently be converted into the corresponding bases or other acid addition salts, and/or dissolved into their enantiomers.

Starting materials for the production methods described above can be obtained using several known methods or as described below.

The starting material for method a) according to formula II above, can be prepared using one of the following methods: Al)

A compound of formula IX where Ra is an alkyl group with 1-5 carbon atoms is reduced, e.g. with LiAlH^. In the compound X formed, an R group can then be introduced analogously to the procedure in method d) above.

In a compound of formula XI, which can be obtained by method E2) below, the methoxy group is split off with HBr, whereby a protecting group Ra which is an alkyl group with 1-5 carbon atoms or an acyl group with 2-6 carbon atoms is substituted in the hydroxy group by reaction with a halide R<a>X in the presence of a base. The compound thus formed is then hydrogenated to form a compound of formula II where n is 2 and Ra has the meaning just stated with subsequent (method A1) introduction of a group, R.

The starting material in method b) can be produced by one of the following methods:

In a compound of formula XIII, a group R can be introduced as described earlier whereby the compound is treated with Cl2 or f^SO^ to form an isomeric mixture XIV, from which the compound III in which Z is Cl or SO^H is obtained by chroinatographic separation.

The compound of formula XV is hydrogenated under acidic conditions in the presence of Pt00 to form a phenylpiperidine which is N-acylated with an appropriate carboxylic acid chloride R COC1 where R f is an alkyl group of 1-4 carbon atoms or an ethoxy group, in the presence of a base such as triethylamine, giving an amide, which undergoes mild acid or basic hydrolysis of the ester function to give a compound of formula XVI. Said compound XVI is treated with ClCOOC2H5 and triethylamine and then with sodium azide which gives a carboxylic acid-

azide which on heating gives the isocyanate XVII.; The isocyanate is treated with an excess of boiling benzyl alcohol to give a carbamate which is then hydrogenated in the presence of Pd/C

to form a compound of formula XVIII. A connection

of formula III where Z is NH 2 and n is 2 is then formed by subjecting the amide group in compound XVIII to cleavage with an aqueous acid or base when an N-unsubstituted compound is desired, to reduction with e.g. LiAlH^ when R= an alkyl group with 2-5 carbon atoms is desired. When R = CH, is desired, a compound of XVIII where R f is an ethoxy group can be treated with LiAlH^.

The following examples further illustrate the invention.

Production of intermediate products

Example II. N-butyl-3-(3-methoxyphenyl)piperidine hydrochloride

(method Al)

Butyryl chloride (2.0 g, 0.019 mol) in dry toluene (5 mL) was slowly added to a solution of 3-methoxyphenylpiperidine (2.45 g, 0.013 mol) and triethylamine (1.92 g, 0.013 mol) in dry toluene at 5°C. The mixture was stirred at room temperature for 30 minutes, whereby the formed triethylammonium chloride was filtered off and the solvent evaporated. The crude N-butyryl-3-(3-methoxyphenyl)piperidine (2.82 g) dissolved in dry tetrahydrofuran (30 mL) was added to a suspension of LiAlH 2 (2.0 g) in dry tetrahydrofuran (30 mL) under nitrogen. After refluxing for 3 hours, the mixture was hydrolyzed, the precipitate filtered off and the solvent evaporated. The residue dissolved in light petroleum was passed through an alumina column. (The remainder could alternatively be distilled in vacuo.) The product was precipitated as the hydrochloride and recrystallized from ethanol/ether and this gave the pure product (3.6 g, 88%), m.p. 130-131°C.

Example 12. N-pentyl-3-(3-methoxyphenyl)piperidine

(method Al and d)

To a solution of 3-(3-methoxyphenyl)piperidine

(3.92 g, 0.02 mol) in CH 3 CN (100 mL), solid K 2 CO 3 (5 g) was added and then the mixture was refluxed. A solution of pentyl iodide (4.5 g, 0.021 mol) in CH 3 CN (10 mL) was added dropwise over 30 min and then the mixture was refluxed for a further 30 min. The

the solid was filtered off from the cooled mixture and the solvent evaporated to give an oil which was chromatographed on a silica gel column with methanol as eluent. Yield 1.3 g (25%) of pure N-pentyl-3-(3-methoxyphenyl)piperidine (NMR) as an oil.

Example 13. N-propyl-3-(3-methoxyphenyl)piperidine hydrochloride

(method Al and d)

NaBH4 (6.08 g, 0.16 mol) was added portionwise with stirring to a solution of propionic acid (38 g, 0.51 mol)

1 dry benzene (150 ml). The temperature was kept below 15°C i

2 hours and then 3-(3-methoxyphenyl)-piperidine (6.1 g, 0.032 mol) dissolved in dry benzene (100 ml) was added and the mixture was refluxed for 3 hours. The reaction mixture was now brought to room temperature and was then extracted with 2.5 M NaOH (200 mL). The aqueous phase was extracted with benzene, all the benzene phases combined, dried (Na 2 SO 4 ) and the solvent evaporated to give an oily residue (6.6 g). The product was precipitated as hydrochloride and recrystallized from methanol/isopropyl ether to give the pure product (6.2 g, 72%), m.p. 191°C.

Example ^ 4• N-propyl-3-(3-methoxyphenyl)piperidine hydrobromide

(method A2)

3-(3-pyridinyl)methoxybenzene (3.0 g, 0.016 mol) and propyl bromide (2.0 g) were dissolved in dry acetone (50 mL) and allowed to react at 110°C in a high pressure steel vessel. After 20 hours, the reaction was stopped and the solvent was evaporated. The remaining quaternary N-propyl-3-(3-methoxyphenyl)-pyridinium bromide was hydrogenated (PtCl 2 ) in methanol at room temperature and 760 mmHg. H^ uptake ceased after 24 hours. The catalyst was filtered off and the solvent evaporated. The hydrobromide was recrystallized from ethanol/ether and this gave 2.63 g (70%) of the pure product, m.p. 155-156°C.

Example 15. 3-(3-pyridinyl)methoxybenzene

(method A2)

This substance was prepared by a dichlorbis-(triphenyl-phosphine)nickel(II)-catalyzed reaction between 3-methoxy-phenylmagnesium bromide (from 50 g of 3-bromo-anisole and 5.9 g of Mg in THF) and 31.8 g of 3 -bromopyridine. Yield 23.1 g (62%), b.p. 102°C/ 0.15 mmHg, m.p. (HC1) 187.5-189°C.

Example 16. 3-(3-Methoxyphenyl)piperidine hydrochloride

(method A2 )

To a solution of 3-(3-pyridinyl)methoxybenzene (22.0 g, 0.099 mol) in methanol (250 mL), PtO 2 (2 g) and concentrated HCl (30 mL) were added and the mixture was hydrogenated at 0.34 MPa in a Parr apparatus. After complete hydrogenation, the catalyst was filtered off. Most of the solvent was evaporated, the remainder was made alkaline with 1M NaOH and extracted with ether. The ether phase was dried (Na^O^)

and the solvent evaporated to give 18 g of the amine product. The hydrochloride was prepared and then recrystallized from ethanol/ether to yield 20.9 g (93%), m.p. 137-138.5°C.

Example 17. N-n-propyl-3-(3-aminophenyl)piperidine hydrochloride

(method B2)

3-|3-methyl.phen^1^-gy^idine

3-(3-Methylphenyl)-pyridine was prepared from 81.5 g (0.52 mol) of 3-bromopyridine and 120 g (0.70 mol) of 3-bromotoluene as described for the preparation of 3-(3-methoxyphenyl)- pyridine.

(example 15) . K.p. 87°C/0.05 mmHg, yield 61.7 g (69%) Methyl-3-^3-p_y.ridY<l>]_-<ben>zoate

A mixture of 3-(3-methylphenyl)-pyridine (30 g, 0.177 mol),

potassium permanganate (67.5 g, 0.427 mol) and water (825 mL) were refluxed overnight with stirring. The hot mixture was filtered, acidified (conc. HCl) and evaporated in vacuo. After drying in air, the solid was dissolved in HCl-saturated methanol (2500 mL), and the resulting solution was refluxed for 24 hours. The methanol was evaporated and the residue made alkaline with saturated potassium carbonate solution. Extraction with ether followed by drying, I^CO^)

and evaporation of the ether gave an oil which was distilled in vacuo. The fraction which distilled from 90°C to 135°C at

0.2 mm was then filtered through a SiC^ column with ether as eluent. Evaporation of the ether gave the pure product (21 g, 55%) as a solid.

The hydrochloride was prepared by dissolving the amino ester in ether followed by addition of HCl-saturated ether. The salt was recrystallized from methanol/ether, m.p. 208-209°C.

3ilIiEE2Ei22YiEiE2Ei£i2l3z¥iLll2§2£2§¥E§

A solution of the HCl salt of methyl 3-(3-pyridyl)benzoate (5.54 g, 0.022 mol) in methanol was hydrogenated (atm. pressure) at room temperature using PtCl 2 as catalyst. After filtration and evaporation, the residue was partitioned between a saturated potassium carbonate solution and ether. The ether layer was dried (^CO 2 ), cooled and treated with triethylamine (2.23 g, 0.022 mol) and propionyl chloride (2.05 g, 0.033 mol). Stirring at room temperature for one hour followed by filtration and evaporation gave an oil which was eluted twice through an A₂O₂ column with ether. Evaporation of the ether gave 4.8 g

pure methyl 3-(1-propionylpiperidin-3-yl)benzoate as an oil, which could not be crystallized.

A mixture of methyl 3-(1-propionylpiperidin-3-yl)-benzoate (4.8 g, 0.017 mol), sodium hydroxide pellets (5 g), methanol (80 mL) and water (20 mL) was stirred until TLC indicated that no starting material was left (4 hours). The methanol was evaporated and the alkaline aqueous layer was washed with ether, acidified with hydrochloric acid and extracted with chloroform. Evaporation gave the product (4.0 g, 69% yield from methyl 3-(3-pyridyl)-benzoate) as an oil which crystallized after several weeks on standing. (Mp. 125-126°C.)

SzEE2EZiz2rl2zaSiD°<£>§DYiilEiE§Ei^iDi}YÉE23si2Ei§

To a cooled (-10°C) solution of 3-(1-propionyl-piperidin-3-yl)benzoic acid (9.75 g, 0.036 mol) and triethylamine (3.56 g, 0.033 mol) in acetone (115 mL) ), ethyl chloroformate (4.34 g, 0.040 mol) was slowly added. After stirring by

-10°C for one and a half hours, a solution of sodium azide (3 g, 0.046 mol) in water (10 ml) was added dropwise and the mixture was stirred at -10°C for another hour. The reaction mixture was poured into ice water and extracted with toluene. The toluene extract was dried (MgSO 4 ) and heated until a small sample by IR analysis indicated that the reaction (conversion of the acyl azide to the isocyanate) was complete. -Evaporation of the toluene gave the isocyanate as an oil. The isocyanate was boiled with benzyl alcohol (20 mL) until the reaction was complete (IR; 24 h). Evaporation of unreacted benzyl alcohol gave an oil (1/5 g) which was dissolved in methanol and hydrogenated at room temperature and atmospheric pressure with 10% Pd/C as catalyst. Filtration and evaporation gave an oil which was further reacted with LiAlH 2 (1.0 g, 0.026 mol) in tetrahydrofuran. Refluxing for 3 hours followed by hydrolysis of the reaction mixture, filtration and evaporation of the solvent gave the crude N-n-propyl-3-(3-aminophenyl)-piperidine which was converted to its dihydrochloride by dissolving the base in methanol and saturating the solution with HC1. Evaporation of the methanol gave the salt as an oil. Yield: 0.40 g (4%, calculated on 3-(1-propionylpiperidin-3-yl)benzoic acid). A sample of the oil was reconstituted into the base and dissolved in CDCl 3 for NMR (see table).

Production of end connections

Example El. N-n-propyl-3-(3-hydroxyphenyl)piperidine hydrobromide

(method a)

N-propyl-3-(3-methoxyphenyl)piperidine hydrochloride (7.0 g, 0.026 mol) was suspended in 48% HBr (200 mL). The mixture was refluxed under nitrogen for 3 hours. The hydrobromic acid was evaporated and the residue was recrystallized from ethanol/ether,

and this gave the pure product (6.7 g, 86%) m.p. 146-147.5°C. Example E2. N-pentyl-3-(3-hydroxyphenyl)piperidine hydrochloride

(method a)

N-pentyl-3-(3-methoxyphenyl)piperidine (1.3 g, 0.005 mol) in CH 2 Cl 2 (20 mL) was cooled with dry ice and BBr 2 (1.6 g,

0.006 mol) was added dropwise. The mixture was then kept at -78°C for 1 hour and then allowed to reach room temperature overnight. The solution was made alkaline with aqueous N<a>2 CO 3 , extracted with CH 2 Cl 2 and the organic phase dried with Na 2 SO 4 . Evaporation of the solvent gave an oily residue which was treated with HCl-saturated ethanol (5 mL). After evaporation of the solvent, purification by extractions and recrystallization (ethanol/ether), the desired product (0.40 g, 29%) was obtained, m.p. 70-80°C.

Example E3. N-n-propyl-3-(3-acetoxyphenyl)piperidine hydrochloride (method c)

N-n-propyl-3-(3-hydroxyphenyl)piperidine (0.8 g,

0.0037 mol) was dissolved in acetic anhydride (20 mL). Triethylamine (1 ml) was added and the solution was refluxed for 1.5 hours, ethanol (50 ml) was added and the volatiles were evaporated to give a residual oil. The residue was separated between ether and water. Separation of the two phases and evaporation of the ether gave an oily residue (700 mg). This was dissolved in dry ether (100 ml) and HCl-saturated ether was added which gave the desired compound as a crystalline precipitate which was filtered off and recrystallized from methanol/isopropyl ether. Yield 0.60 g (55%), m.p. 173-175°C.

Example E4. N-n-propyl-3-(3-benzoyloxyphenyl)piperidine hydrochloride (method c)

N-n-propyl-3-(3-hydroxyphenyl)piperidine (0.5 g,

0.0023 mol) was dissolved in CH 2 Cl 2 (50 mL). Triethylamine (1 mL) and benzoyl chloride (0.5 mL, 0.004 mol) were added and the mixture was stirred at room temperature for 48 hours. The solvent was evaporated and the residue was separated between ether and water. The ether phase was dried (Na 2 SO 4 ) and the solvent evaporated to give an oily residue which was eluted through a short silica gel column with methanol as eluent. Evaporation of the solvent gave an oily residue (300 mg). The oil was dissolved in ether and HCl-saturated ether was added. Filtration and drying gave the desired compound in a crystalline form. Yield 13%, m.p. 170°C.

Example E5. 2-[3-(3-hydroxyphenyl)-piperidino]ethanol hydrochloride (method d)

Ethylene oxide (0.36 mL, 7.0 mmol) was added to a stirred solution of 3-(3-hydroxyphenyl)piperidine (1.0 g,

5.6 mmol) in methanol (150 ml), the temperature being maintained at -30°C, after which the reaction mixture was allowed to reach room temperature.

(The reaction was monitored by TLC.) More ethylene oxide (0.5 mL, 9.8 mmol) was added in portions until the reaction was complete (two weeks). An excess of ethereal hydrogen chloride was added and the solvent was evaporated. The oily residue was passed through a silica gel

column with 10% methanol in chloroform. After evaporation, the hydrochloride was recrystallized from ethanol/ether and this gave 0.6 g (41%) of 2-[3-(3-hydroxyphenyl)-piperidino]ethanol hydrochloride, m.p. 116.5-120°C.

Example E6. N-n-propyl-3-(3-hydroxyphenyl)piperidine hydrochloride (method b)

To a solution of N-n-propyl-3-(3-aminophenyl)-piperidine (0.74 g, 0.0034 mol) in 6M H 2 SO 4 (2 mL), NaNO 2 (0.23 g, 0.0034 mol) was dissolved in water (0.6 ml) added dropwise at 5°C and then the mixture was stirred at 5°C

for 1 hour. The resulting mixture was added dropwise

to refluxing 10% H 2 SO 4 (3.5 mL) and refluxing was continued for 5 min. Cooling, alkalization (Na 2 CO 3 ), extraction with ether, drying and evaporation of the organic phase gave the desired product as a free base. Conversion of the hydrochloride followed by recrystallization gave 0.22 g (25%) of N-n-propyl-3-(3-hydroxyphenyl)piperidine hydrochloride,

m.p. 14 3.5-14 6°C.

Example E7. N-n-propyl-3-(3-benzyloxyphenyl)piperidine hydrochloride (method c)

A mixture of N-n-propyl-3-(3-hydroxyphenyl)-piperidine hydrobromide (1.0 g, 0.0033 mol), potassium t-butoxide (1.0 g, 0.009 mol) and benzyl chloride (1.0 g, 0.009 mol) in t-butanol (25 mL), was refluxed for 1 hour. Water was added and the mixture extracted with ether. The organic phase was dried with Na 2 SO 4 and evaporated to dryness to give a pale yellow oily residue. The residue was chromatographed through a silica gel column with methanol as eluent. The relevant fractions were collected and evaporated to dryness. The oily residue was dissolved in ether and HCl-saturated ether was added to give white crystals. Evaporation and treatment of the residue with acetone gave 0.60 g (52%) of the desired product as white crystals, m.p. 171°C.

Example E8. N-n-propyl-3-[3-(phenylcarbamoyloxy)phenyl]-piperidine hydrochloride (method c)

A mixture of N-n-propyl-3-(3-hydroxyphenyl)-piperidine hydrobromide (0.76 g, 0.0025 mol), phenyl isocyanate

(5.45 g, 0.046 mol), triethylamine (0.5 g, 0.049 mol) and methylene chloride (2 mL) were stirred at room temperature for 18 h. The mixture was partitioned between water and ether. The ether phase was dried and evaporated and this gave a partially crystalline residue. The residue was dissolved in methanol and chromatographed on a silica gel column (200 g SiO 2 ) with methanol as eluent. The fractions which according to GLC contained the desired product in pure form were collected and the solvent evaporated. The residue was dissolved in ether and treated with HCl-saturated ether and this gave a crystalline precipitate. Filtration and washing gave 0.18 g (20%) of the desired hydrochloride, m.p. 184-190°C.

Example E9. N-n-propyl-3-[3-(2,6-dimethylbenzoyloxy)-phenyl]piperidine hydrochloride (method c)

A mixture of N-n-propyl-3-(3-hydroxyphenyl)piperidine hydrobromide (1.0 g, 0.0033 mol), 2,6-dimethylbenzoyl chloride (2.15 g, 0.0127 mol) and distilled dry pyridine ( 7 ml) was stirred at room temperature under a ^-atmosphere for 24 hours.

Aqueous NaHCO 3 was added and the mixture was extracted with ether. The organic phase was dried and all the solvents evaporated to give an oily residue. The residue was eluted through an alumina column with ether and then through a silica gel column with light petroleum

ether (1:1) as eluent. The product was then precipitated by addition of HCl-saturated ether. Filtration and drying gave 1.2 g (93%) of the pure desired hydrochloride, m.p. 190-191°C.

According to the methods in the examples given above, the following compounds were prepared and recrystallized as acid addition salts from ethanol/ether or isolated as the bases.

Footnotes

*) Subject to elemental analysis (C,H,N); all analyzes were satisfactory.

a) Calculated on the phenylpiperidine or pyridinylbenzene starting compounds. b) 6(CDCl 3 ) 0.7-3.2 (2oH,m), 3.75 (3H,s), 6.6-7.0 (%h,m), 7.0-7.4 ( 1H,m) c) 6(CDCl 3 ) 0.7-3.2 (26H,m), 3.75 (3H,s), 6.6-6.95 (3H,m), 6.95-7 .35 (lH,m). d) S(CDCl 3 ) 1.0 (6H,d), 1.0-3.1 (10H,m), 3.7 (3H,s), 6.55-6.95 (3H,m), 6.95-7.35 (1H,m). e) 6(CDCl 3 ) 1.2 (9H,s), 1.2-3.1 (11H,m), 3.7 (3H,s), 6.6-6.9 (3H,m), 6.9-7.35 (1H,m). f) <5(CDC13) 1.3-3.3 (HH,m), 3.8 (3H,s), 4.9-5.4 (2H,m) , 5.55-6.3 ( 1H,m), 6.6-7.0 (3H,m), 7.0-7.4 (1H,m).

g) vmax 1680 (c=0), 1260 (ArOCH3)

h) vmax 1640 (C=0), 1250 (ArOCHj)

i) vmax 1638 (C=0), 1255 (ArOCH3)

j) 6(CDCl 3 ) 1.3 (9H,s), 1.4-3.0 (9H,m), 3.8 (3H,s),

6.65-6.95 (3H,m), 7.1-7.45 (1H,m); vmax 1650 cm"1.

k) 6(CDC13) 0.9 (3H,t), 1.15-3.25 (13H,m), 3.5 (2H, br.s),

6.4-6.75 (3H,m), 6.95-7.3 (1H,m). 1) <5(CDCl3) 0.7-3.5 (2oH,m), 6.6-6.9 (3H,m) , 6.9-7.35 (1H,m) ,

9.8 (1H, br.s).

m) 6(CDCl 3 ) 0.7-3.4 (26H,m), 6.55-6.9 (3H,m) 6.9-7.3 (1H,m),

9.55 (1H, br.s).

n) <S(CD3OD) 1.1 (9H,s), 1.7-3.6 (HH,m) , 5.1 (1H, br.s),

6.6-6.95 (3H,m), 6.95-7.35 (1H,m).

o) When using dimethyl-2-chloroethylamine hydrochloride as

alkylating agent.

p) 6CDC13 0.92 (3H,t), 1.2-3.2 (16H,m), 4.45-4.65 (2H,m),

5.15-5.30 (lH,m), 5.30-5.60 (2H,m), 5.80-6.40 (lH,m),

6.55-6.90 (3H,m), 7.00-7.35 (1H,m).

q) Methods A1 and d modified by using a w-haloalkylcarboxylalkyl ester namely 3-bromomethylpropionate as alkylating agent, and carrying out reduction of the ester intermediate.

Pharmacological assessment

Medicines that act on central dopamine (DA) transmission have long been known to be clinically effective for a number of illnesses that arise from the CNS, e.g. parkinsonism and schizophrenia. In the former condition, the nigro-neostriatal hypofunction can be restored by an increase in postsynaptic DA receptor stimulation, while, on the other hand, the latter condition can be normalized by achieving a decrease in postsynaptic DA receptor stimulation. So far, this reduction has mainly been achieved either by a) direct blockade of the postsynaptic DA receptors (considered to

be the mode of action of classic antipsychotic agents such as e.g. haloperidol and chlorpromazine), or b) inhibition of intraneuronal presynaptic pathways essential for the maintenance of adequate neurotransmission, e.g. granular uptake and storage (cf. the neuroleptic reserpine which is known to deplete monoamine stores via its effects on granular structures), transport mechanisms and transmitter synthesis.

In recent times, a large amount of pharmacological, biochemical and electrophysiological material has accumulated,

which provides significant support for the existence of a specific population of central autoregulatory DA receptors, so-

called autoreceptors, which are located on the dopaminergic neuron itself (i.e. presynaptically located). These receptors are part of a homeostatic mechanism that modulates nerve impulse flow and transmitter synthesis and thus the amount of DA released from the nerve endings.

The well-known DA receptor agonist apomorphine can

activate the DA autoreceptors, as well as the postsynaptic DA receptors. At low doses, however, the effects of autoreceptor stimulation appear to be dominant, whereas at higher doses (autoreceptor-mediated) attenuation of DA transmission is offset by the increase in postsynaptic receptor stimulation. The "paradoxical" antipsychotic and antidyskinetic effects demonstrated in humans after low doses of apo-

morphine is thus most likely due to the autoreceptor-stimulating properties of this DA receptor agonist. IN

consistent with this and in consideration of the known disadvantages associated with the use of DA receptor antagonists in the therapy of schizophrenia and other psychotic disorders, it has been proposed that DA receptor stimulants with a high selectivity for CNS DA autoreceptors would provide new therapeutic principles of great value in psychiatric medicine. At the moment, no such drug is commonly known. In the search for new postsynaptic DA receptor agonists (anti-Parkinson agents), a group of substances with selective DA autoreceptor agonist properties has surprisingly been discovered. In order to investigate this new pharmacological profile, the following experiments were carried out. For connection numbers, refer to the table of "end connections" above.

Pharmacological methods

1. Antagonism of the reserpine-induced "neuroleptic syndrome" in the rat

Depletion of the monoamine stores with reserpine works

a "neuroleptic syndrome" which is characterized by hypo-motility, catalepsy, muscle stiffness, chromic stiffness, as well as a number of other central and peripheral signs of monoamine depletion. This syndrome can be reversed by administration of drugs that stimulate postsynaptic DA receptors directly or indirectly, e.g. apomorphine, L-Dopa.

Rats (150-300 g) pretreated with reserpine (10 mg/kg i.p., 6 hours earlier) were given compound £ subcutaneously at various doses. However, no antagonism of the reserpine-induced syndrome was observed, not even near lethal doses. In a similar way, compound 1_ was tested at 20 mg/kg s.c., i.e. at a dose of approx.

100 times the ED5Q value in Table I. No antagonism of the reserpine-induced syndrome was observed.

2. In-vivo determination of tyrosine hydroxylation in rat brain

The compounds evaluated were tested biochemically for central DA receptor (pre- and/or postsynaptic) stimulatory activity. The essential thing about this biochemical assessment method is that a DA receptor agonist will stimulate the receptor and through regulatory "feedback" systems cause a decrease in tyrosine hydroxylase activity and thus a subsequent reduction in the synthesis rate for DA in the presynaptic neuron. Formation of Dopa determined after in vivo inhibition of aromatic L-amino acid decarboxylase with NSD 1015 (3-hydroxybenzylhydrazine hydrochloride) is taken as an indirect measure of DA synthesis rate.

Rats (150-300 g) pretreated with reserpine were given the compounds under investigation. Mass behavioral observations (changes in motility, stereotypy, etc.) were made to assess possible postsynaptic dopamine receptor activity. Subsequent administration of NSD 1015, decapitation, brain dissection (corpora striata and limbic forebrain), homogenization, centrifugation, ion-exchange chromatography and spectrofluorometric measurements (all as described in detail by Wikstrom et al., in J. Med. Chem . 21, 864-867, 1978 and references therein), provided relevant Dopa levels. Several doses (n=4-6) were tested to obtain a dose-response

curves for each connection and brain area. The dose of a compound which produced a half-maximal reduction in the Dopa level in the rat brain section was then determined. These values (ED^q) are given in Table I.

From studies of many other compounds with auto-receptor activity, as well as post-synaptic activity, it is known that at a dose that represents the ED5Q value, it is likely that only auto-receptor activation occurs. To achieve postsynaptic activation, higher doses are required.

(At the moment, no connection with selective postsynaptic DA stimulatory activity is known.) Regardless of other evidence (above or below) regarding receptor selectivity, the ED5Q values are therefore considered to represent doses that trigger selective autoreceptor stimulation.

All the compounds in Table I were biochemically active

with the exception of the two investigated reference compounds which were completely inactive even at 180 umol/kg and 90 umol/

kg, respectively. Most of the active compounds have an efficiency of approximately the same order of magnitude (ED^q 0.6-4.4). These compounds are considered to be the most suitable for medical use. Compounds with ED^g value of

IN

around 45 umol/kg which for N-propyl-3-(3-hydroxyphenyl)-pyrrolidine can be considered a borderline case of interest.

The absence of significant postsynaptic DA receptor activation at any tested dose indicates that all the active compounds have selectivity for the autoreceptors (further investigated only for compound A),

3. Antagonism of γ-butyrolactone (GBL)-induced increase of DA synthesis rate in rat brain j The administration of GBL in anesthetic doses inhibits the nerve impulse flow in central DA neurons, thus resulting in a loss that the impulse-mediated "feedback" control of tyrosine hydroxylase activity and in a subsequent increase

i i transmitter synthesis rate (which is determined as be-

in written under 2 above). Since the GBL inhibition precludes neuronal "feedback" effects, antagonistic effects can

exerted by DA receptor agonists on the GBL-induced increase in synthesis is most likely attributed to their stimulating DA autoreceptors found in the terminal area of the DA neurons.

Rats (150-300 g) were given compound A_ subcutaneously at various doses (n=7) followed by GBL (750 mg/kg i.p.,

5 minutes later) and NSD 1015 (100 mg/kg i.p., 10 minutes later). By a subsequent method according to 2 above, the Dopa levels (representing DA synthesis rates) were determined. In this model, compound £ dose-dependently antagonized the GBL-induced increase in DA synthesis rate (log-adjusted dose-response data in Table I). The maximal reversal of the GBL-induced increase in DA synthesis rate was approximately 160% in the limbic system and 110% in the corpus-striatum. Furthermore, the antagonism could be blocked by haloperidol and this thus confirmed that the effects are due to actions on DA autoreceptors (Table III). 4. Effect on spontaneous locomotor activity in the rat

Untreated animals exposed to a new environment show an initial high motor activity which then gradually decreases over a period of time. Administration of DA receptor agonists

(eg apomorphine) in doses where selective autoreceptor stimulation is likely to occur, causing a depression \

in the above-mentioned spontaneous motility, and this is thought to be due to the DA autoreceptor-mediated impairment of central DA transmission.

Rats (150-300 g) were injected subcutaneously with several doses of compounds 4 and after 5 minutes they were individually placed in motility containers ("M/P 4 0 Fc Electronic Motility Meter". Motron Products, Stockholm) and the motor activity (0-30 minutes) was quantified. Compound 4 exhibits a clear dose-dependent reduction of the initial high motor activity, the maximum effect being a 75% reduction from control values, achieved at approx. 8 mg/kg. No locomotor stimulation was ever observed regardless of the dose used. Pretreatment with a low dose of haloperidol (0.02 mg/kg i.p., 30 min beforehand), to selectively block DA autoreceptor sites, produced at least a partial reversal of the sedative effect obtained with a low dose (0 .5 mg/kg) of compound 4 (Table IV). There also appears to be a correlation between the decrease in spontaneous movement and the degree of antagonism of the GBL-induced increase in DA synthesis (cf. 3 above) in the limbic areas of the rat brain exerted by compound 4. The percentage decrease in motor activity is about 0.6 times the percentage reversal of GBL-induced increase in DA synthesis rate.

5. Turning behavior in rats with an acute unistriatal lesion

In animals with an acute unilateral KCl lesion (1 μl 25% KCl lesioned side, 1 μl 20% NaCl control side, administered through pre-implanted "guide cannulae") of the striatum, compensatory countervailing adjustments are effected in the intact contralateral striatum and therefore no significant asymmetry in body posture or twisting. Disturbances in balance produce, depending on the point of attack, ipsi- or alternating contralateral turning. In this model, postsynaptically active DA agonists (eg, apomorphine, high dose) elicit ipsilateral turning behavior and rotational behavior, whereas DA antagonists (eg, haloperidol) cause contralateral turning behavior. Consequently, it might be expected that agents acting exclusively on DA autoreceptors would produce contralateral turning in the injured animals.

Rats (150-300 g) pretreated as above were given compound _4 subcutaneously at several dose levels and then the animals were observed for at least 4 hours. As predicted herein, it was demonstrated that compound 4, at each dose tested, caused the animals to turn to the side contralateral to the lesion (Table V). Their

overall behavior was also a sign of a sedative effect exerted by the compound thus confirming the previous findings (cf. 4 above). It was also shown that the ipsilateral turning response and rotary response after administration of postsynaptically effective doses of apomorphine (1.0 mg/kg s.c.) were not affected by pretreatment with compound 4 (Table V).

6. Other observations

Further preliminary investigations of the pharmacological profile of compound 4_ have shown that, unlike agents that stimulate postsynaptic DA receptors, it lacks emetic activity in dogs (at least at 1 mg/kg i.m.). In contrast to postsynaptically acting DA agonists, compound 4 (8 mg/kg s.c.) also did not lower the rectal temperature (0-30 minutes) in rats. It was missing

in fact any measurable temperature effect. 7. Comparative study of compound 4 and its 3,4-dihydroxy analogue known from DE specification no. 2,621,536

Rats (150-300 g) pretreated with reserpine (10 mg/kg i.p., 6 hours beforehand) were given either physiological saline, compound _4 (100 umol/kg), N-n-propyl-3-(3,4- dihydroxyphenyl)piperidine (100 umol/kg) or apomorphine

(2 umol/kg) subcutaneously and the locomotor activity (accumulated counts 0-60 minutes) was quantified using Motron containers (see 4 above). The results (Table VI) show that, apart from their DA autoreceptor effects (EDj.ø:s; cf. 2 above), N-n-propyl-3-(3,4-dihydroxy-phenyl)piperidine, as well as apomorphine exhibit strong central postsynaptic ' DA receptor stimulatory effects. In contrast to the last-mentioned agonists, compound £ was shown to act selectively

tively on the DA autoreceptors and thus lacked the effect of eliciting a motor response that differed more than slightly from control values.

Conclusion

The pharmacological data confirm the hypothesis that the compounds in question are centrally acting selective DA autoreceptor stimulants and thus of great clinical interest in the treatment of psychotic disorders such as schizophrenia and a number of other morbid conditions such as tardive dyskinesia, Huntington's chorea, hypoprolactinemia, alcoholism and drug abuse, as the aforementioned psychotic disorders and other morbid conditions are possibly associated with a pathological increase in central DA transmission.

Best embodiment of the invention

The compound N-n-propyl-3-(3-hydroxyphenyl)piperidine and its salts, methods for preparing said compound and methods for using the compound in therapy represent the best embodiment of the present invention currently known. Other compounds of great value are: N-butyl-3-(3-hydroxyphenyl)piperidine, N-pentyl-3-(3-hydroxyphenyl)piperidine, and N-isopropyl-3-(3-hydroxyphenyl)piperidine.

Claims (5)

1.. Analogy method for the production of therapy tically active phenylazacycloalkanes with the formula: where n is 2; Y is OH, R<1>COO, R<2>R<3>NCOO- or R<4>0, where R<1> is an alkyl group with 1-5 carbon atoms, phenyl or phenyl substituted with alkyl of 1-5 carbon atoms or alkylcarbonyl with 1-5 carbon atoms, R <2> is an alkyl group with 1-5 carbon atoms, a phenethyl, benzyl or phenyl group, R 3 is H or an alkyl group with 1-15 carbons atoms, and R 4 is an allyl or benzyl group; and R is one alkyl group with 1-5 carbon atoms, a hydroxyalkyl-, dimethylaminoalkyl or methylthioalkyl group with 2-6 carbon atoms in the alkyl part and with the heteroatom bound in a position other than the 1-position, or an alkenyl group of 3-5 carbon atoms other than a 1-alkenyl group, such as bases, pharmaceutically acceptable acid addition salts or esters thereof, as well as their enantiomers and mixtures thereof, characterized by that one a) splits a compound with the formula: where Ra is a hydrocarbon or acyl residue, and n and R have the meanings given above, for the formation of a conjunction group of formula I where Y is a hydroxy group; b) replaces the Z group in a compound with the formula: where Z is SO₂H, Cl or NH₂, and R and n are as defined above, with a hydroxy group; c) treats a compound with the formula: where Y is OH, R is different from hydroxyalkyl, and n has the above meaning, with a suitable carboxylic acid halide R^COX or anhydride (R^CO).,© or with a suitable carbamoyl halide R 2 R 3NCOX or isocyanate R 2 NCO in the presence of a base such as triethylamine or pyridine, or an acid such as H2SO4 or CF^COOH, or with an appropriate allyl or benzyl halide R X in the presence of a base such as triethylamine, pyridine, or potassium t-butoxide, to form 1 2 3 of a compound of formula I where Y is R C00, R R NCOO 4 or R 0; and d) alkylates a compound of the formula: where n and Y have the meanings given above, with et alkylating agent to form a compound of formula I, and, if desired, converting a compound thus obtained into a pharmaceutically acceptable salt or ester thereof, and/or, if desired, dissolving it into its enantiomers. in 2. Analogy method according to claim 1, for forward- ! position of N-n-propyl-3-(3-hydroxyphenyl)piperidine, or a salt thereof, characterized by using correspondingly substituted starting materials. t I 3. Analogous method according to claim 1, for the production of N-butyl-3-(3-hydroxyphenyl)piperidine, or a salt thereof, characterized in that similarly substituted starting materials are used. in 4. Analogous method according to claim 1, for the production of N-pentyl-3-(3-hydroxyphenyl)piperidine, or a salt thereof, characterized in that correspondingly substituted starting materials are used. 5. Analogous method according to claim 1, for the production of N-isopropyl-3-(3-hydroxyphenyl)piperidine, or a salt thereof, characterized in that correspondingly substituted starting materials are used. in