FI89796B - Intermediates of oxysalicylamido derivatives - Google Patents

Abstract

The invention relates to an intermediate for the preparation of oxysubstituted salicyl derivatives of the formula <IMAGE> wherein Z1 is OH, OR1 or NH2, Z2 is OR4, Z3 is OH, OR4 or OR1, R2 is a hydrogen atom, a halogen atom, R4 or F3C- (CH2)n-, R3 is a hydrogen atom, R4, straight or branched hydrocarbon chain having a double or triple bond and 2-3 carbon atoms, phenyl or phenyl substituted with methylene dioxy or one or more selected from the following: fluoro, chloro, bromo, trifluoromethyl, methyl, ethyl, methoxy or ethoxy in the ortho, meta, or para positions. R1 is an alkyl-CO, wherein the alkyl is a straight or branched hydrocarbon chain having 1-17 carbon atoms, R4 is an alkyl group having 1-4 carbon atoms, and n is 0, 1 or 2, or salts thereof. The intermediate has the structural formula <IMAGE>

Description

Γ Ο r ’> / - ύ

Intermediates of oxysalicylamide derivatives Separated from application 850398.

The invention relates to intermediates for novel pharmacologically active oxy-substituted salicylamides.

It is an object of the invention to provide a substituted neuroleptic benzamide useful for blocking dopamine receptors in the brain. Such compounds are useful in the treatment of emesis, anxiety disorders, psychosomatic illnesses and psychotic conditions such as schizophrenia and depression, alcohol related illnesses, confusion states and sleep disorders caused by aging.

"Remoxipride" (U.S. Patent 4,232,037) having the formula

Br OCH3 ^ nnch2-C ^ och3 c2h5 is a fairly new antipsychotic agent. This compound has been reported to be a potent antibody to apomorphine syndrome in rats.

EP patent application 60,235 discloses benzamide derivatives which are potent inhibitors of apomorphine syndrome in rats, e.g. a compound of the formula

Cl OH

The compounds of U.S. Patent 4,232,037 and EP Patent Application 60,235 are less potent in antidopaminergic activity than the compounds of the invention. C / Vconhch2-1 ^ n ^ ci och3 c2h5 2 rn '' '-. / · Υ> /, υ

The present invention relates to intermediates of compounds of formula R2 Z1 ÖCONHCH -, - ^, I, ZJ z2 ch2r3 wherein Z1 is OH, OR1 or NH2, Z2 is OR4, Z3 is OH, OR4 or OR1, R2 is a hydrogen atom, halogen atom, R4 or F3C- (CH2) n-, R3 is a hydrogen atom, R4, a straight or branched hydrocarbon chain having a double or triple bond and 2-3 carbon atoms, phenyl, or phenyl substituted by methylenedioxy or one or more of fluorine, chlorine, bromine, trifluoromethyl, methyl, ethyl, methoxy or ethoxy in the ortho, meta or para positions, R 1 is alkyl-CO, wherein alkyl represents a straight or branched hydrocarbon chain having 1 to 17 carbon atoms, R 4 is an alkyl group having 1 to 4 carbon atoms and n is 0, 1 or 2; or their salts.

It has been found that these compounds have valuable therapeutic properties, in particular they are more potent in their antidopaminergic effects than the previous compounds mentioned above, and they also have fewer drug-induced extrapyramidal side effects.

The invention thus provides compounds and their physiologically acceptable salts which are useful in the treatment of emesis, anxiety disorders, psychosomatic diseases such as gastric and duodenal ulcers, and psychotic disorders. in the treatment of conditions such as schizophrenia, depression, alcohol-related illnesses, confusion states, and sleep disorders in the elderly.

Highly preferred compounds are the following:

Br / ° H, C 'VCONHCH2 ^ -n' K u H3co 0CH3

Br OH

(f VcONHCHj ^^ »\ - / £ h2ch = ch2 ch3o OCH3

Cl OH

^ CONHCH, ^ H3CO OCH3

Br OH

J-X

X c * ‘iJ

CH3o OCH3

H5C2 OH

$ ^ -CONHCH2 h3co och3

4 >> ·. ' U

0

II

Br OC- (CH 2) 14 -CH,

x x Γ — H

\ VcONHCHj — L / s \? ch3o och3 c2hs These compounds can be used therapeutically as racemic mixtures containing the (+) and (-) forms obtained synthetically. They can also be separated into the corresponding enantiomers, which can likewise be used therapeutically. The (+) and (-) forms can also be obtained by reacting the corresponding enantiomeric 2-aminomethylpyrrolidine derivative with a benzoic acid group.

The compounds of the invention may be administered in the form of the free bases or their salts with non-toxic acids. Some typical examples of such salts are hydrobromide, hydrochloride, phosphate, sulfate, sulfonate, sulfamate, citrate, lactate, maleate, tartrate and acetate.

The compounds are prepared with intermediates characterized by what is stated in the characterization of claims 1 and 2.

Pharmaceutical preparations

In clinical practice, the compounds of the invention are normally administered orally, rectally or by injection in the form of pharmaceutical preparations containing the active ingredient either as the free base or as a pharmaceutically acceptable non-toxic acid addition salt, for example as a hydrobromide, hydrochloride, sulphate, phosphate, , tartrate, acetate and the like together with a pharmaceutically acceptable carrier. Thus, the terms relating to the novel compounds of the invention, both generally and specifically, mean both 5 * · · "·

JS! . U

free amine base and acid addition salts of this free base, unless the context in which such terms are used, for example in specific examples, limits the use of such a broader term.

The carrier may be a solid, semi-solid, or liquid diluent or capsule. These pharmaceutical preparations are also within the scope of the invention. The active substance usually comprises 0.1 to 99% by weight of the preparation, in particular 0.5 to 20% by weight in preparations intended for injection and 2 to 50% by weight in preparations suitable for oral administration.

To prepare pharmaceutical preparations containing a compound of the invention in unit dosage form for oral administration, the selected compound may be admixed with a solid powdered carrier such as lactose, sucrose, sorbitol, mannitol, starches such as potato starch, corn starch, corn starch, or amyllo and a lubricant such as magnesium stearate, calcium stearate, polyethylene glycol waxes and the like, and then compressed into tablets. If coated tablets are desired, the core portions prepared in the present manner may be coated with a concentrated sugar solution which may contain, for example, acacia, gelatin, talc, titanium dioxide and the like.

Alternatively, the tablet may be coated with a varnish dissolved in a volatile organic solvent or solvent mixture. Dyestuffs may be added to these coatings in order to readily separate tablets containing different active ingredients or different amounts of active compound.

To prepare soft gelatin capsules (bead-shaped sealed capsules) containing gelatin and, for example, glycerol, or similar sealed capsules, the active ingredient can be mixed with vegetable oil. Hard gelatin capsules may contain granules of the active ingredient together with solid powdered carriers such as lactose, sucrose, sorbitol, mannitol, starches (e.g. potato starch, corn starch or amylopectin), cellulose derivatives or gelatin.

Dosage units for rectal administration may be prepared in the form of suppositories containing the active ingredient in admixture with a neutral base fat, or in gelatinous rectal capsules containing the active ingredient in admixture with vegetable oil or paraffin oil.

Liquid preparations for oral use may be in the form of syrups or suspensions, for example, solutions containing from about 0.2% to about 20% by weight of active ingredient, the remainder being sugar and a mixture of ethanol, water, glycerol and propylene glycol. Such liquid preparations may also contain coloring agents, flavoring agents, saccharin and carboxymethylcellulose as a thickening agent.

Injectable solutions for parenteral use may be prepared in the form of an aqueous solution containing a water-soluble pharmaceutically acceptable salt of the active ingredient, preferably at a concentration of about 0.5 to 10% by weight. These solutions may also contain stabilizers and / or buffers and may conveniently be presented in ampoules of different dosage units.

Compounds of formula I in which R 1 is an acyl group, an alkoxycarbonyl group or a mono- or dialkylcarbamoyl group may be advantageously used in pharmaceutical preparations intended for intramuscular administration in order to obtain a long-lasting relieving effect, i.e. continuous effect.

i J. I V '7

Suitable daily doses for oral administration of a compound of the invention are in the range of 1 to 50 mg, preferably 5 to 20 mg.

methods of Preparation

Compounds of formula I may be obtained using any of the following methods.

Compounds of formula Ör ~ 9.

z3 z2 ch2r3 wherein Z1 is OH, OR1 or NH2, Z2 is OR4, Z3 is OH, OR4 or OR1, R2 is a hydrogen atom, a halogen atom, R4 or F3C- (CH2) n-, R3 is a hydrogen atom, R4, straight or branched a hydrocarbon chain having a double or triple bond and 2-3 carbon atoms, phenyl, or phenyl substituted by methylenedioxy or one or more of fluorine, chlorine, bromine, trifluoromethyl, methyl, ethyl, methoxy or ethoxy ortho-, meta - or in the para-positions, R 1 is alkyl-CO, in which alkyl represents a straight or branched hydrocarbon chain having 1 to 17 carbon atoms, R 4 is an alkyl group having 1 to 4 carbon atoms and n is 0, 1 or 2, or physiologically suitable salts can be obtained by a process comprising a) a compound of formula 8 '·' R 2 Z 1 r y -cooti z 3 z 2 wherein Z 1, Z 2, Z 3 and R 2 are as defined above and -COOH is a reactive group which capable of reacting with an amino group to form an amide group with a compound of formula ch2r3 wherein R3 is as defined above, or a reactive derivative thereof, to form a compound of formula I.

The reaction is carried out in a suitable solvent such as diethyl ether, THF, dichloromethane, chloroform or toluene at a temperature between -20 ° C and the boiling point of the reaction mixture. The resulting amine can be separated as a salt, e.g. by filtration. Alternatively, the resulting amine can be converted to the free base using conventional methods, such as adding aqueous ammonia or sodium hydroxide solution and extracting with an organic solvent.

According to the invention, the following compounds can be used as reactive derivatives of the above cyclic amine:

Reaction products of the amine with phosphorus chloride, phosphorus oxychloride, dialkyl, diaryl or o-phenylene chlorophosphites or alkyl or aryl dichlorophosphites or isothiocyanate or amine isocyanate. Said reactive derivatives may be reacted with an acid in situ or after prior separation.

It is also possible to react the free acid and the free amine with a condensing agent, e.g. silicon tetrachloride, diphosphorus pentoxide, phosphine or hexamethylphosphoric triamide plus carbon tetrahalide, diphenylphosphite, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, , such as dicyclohexylcarbodiimide, N, N'-carbonyldiimidazole, N, N'-thionyldiimidazole or diethyldiazodicarboxylate.

Compounds of formula I may also be prepared by a process comprising b) deprotecting a compound of formula R 2 Z 1 'ÖCONHCH, -L.

>> Z2 CH2R3 wherein Z2, R2 and R3 have the same meaning as in the preamble of claim 1, Z1 "is OH, OR1 or a suitably protected hydroxy group when Z2 = Z3 = OH and Z3" is OH, OR4, OR1 or a suitably protected hydroxy group when the product Z2 = Z3 = OH, and at least one of Zin and Z3 "is a suitably protected hydroxy group, of the formula R2 Z1 ÖCONHCH -, - L.

. Γ, z · 3 z2 for the preparation of a compound according to ch2r3, wherein Z1, Z2, Z3, R2 and R3 have the same meaning as in the preamble of claim 1 and at least one of Z1 and Z3 is OH.

10

Suitable conventional phenol protecting groups include, for example, groups such as trimethylsilyl, t-butyldimethylsilyl, tetrahydropyranyl, benzyl, methoxyethoxymethyl, methoxymethyl, methylthiomethyl, aliphatic or aromatic esters, carbonates or cyclic acetals, Z, or esters, ketals or esters. The protecting groups can be removed by conventional methods (T. W. Greene: "Protective Groups in Organic Synthesis", Wiley, New York, 1981, pp. 87-113).

A special form of protecting group is Z1 or Z2 when alkoxy.

The invention therefore relates to intermediates of the formulas R2 Z1 "V '/ -CO - nhch9-L.

v == \ t z3 "z2 ch2r3 wherein Z2, R2 and R3 are the same as above and Z1" is OH, OR1 or a suitably protected hydroxyl group when the product Z2 = Z3 = OH, and Z3 is OH, OR4, OR1 or suitably protected a hydroxyl group when the product Z2 = Z3 = OH, and at least one of Z1 and Z3 is a suitably protected hydroxyl group and V1

r 'y — COOH

Z3, z2 wherein Z1, Z2, Z3 and R2 are the same as in claim 1. They are thus intermediates of process variants a) and b).

V. '11

The former intermediate is prepared by the method described in a).

Intermediates of the invention of formula R2 ^ Z1

^ ^ -COOH

Z3 Z2 wherein R2, Z1, Z2 and Z3 are as defined above can be prepared by: i) treating a compound of formula R2 Z1 C 'y-COOH Z3 Z2 wherein R2 is as defined above and Z1, Z2 and Z3 are OR4, wherein R 4 is as defined above, with a Lewis acid such as boron tribromide, boron trichloride or aluminum chloride or hydrobromic acid, ii) treating a compound of formula '8 "Z 3 Z 2 wherein R 2 is as defined above, except that they are not Br or I, Z1, Z2 and Z3 are alkoxy, dialkylamino or alkylthio, or alternatively Z1, Z2 and 12 Z3 may be suitably protected derivatives such as methoxymethyl ether, tetrahydropyranyl ether, t-butoxycarbonylamine or t-butylcarbonylamine after deprotection alkyl or aryllithium followed by reaction with carbon dioxide and acidification, iii) by treating a compound of formula Z1--COOH Z3 Z2 wherein Z1, Z 2 and Z 3 are as defined above, with halogen, sulfuryl halide (preferably SO 2 Cl 2) or halogenated dioxane complex to give compounds wherein R 2 is halogen.

Preparation Examples Example 1 (S) - (-) - N - [(1-ethyl-2-pyrrolidinyl) methyl] -3-bromo-2,5,6-trimethoxybenzamide. method a__

A solution of 3-bromo-2,5,6-trimethoxybenzoic acid (4.5 g; 0.015 mol) in 60 ml of toluene was treated with thionyl chloride (4.5 g; 0.038 mol) at 65 ° C for 1 h. The solvent was evaporated and the residue was dissolved in 20 ml of CHCl 3. A solution of (S) - (-) - 2-aminomethyl-1-ethylpyrrolidine in 40 mL of CHCl 3 was added. The temperature rose to 45 ° C. After 0.5 h, the solvent was removed and the residue was neutralized with 100 mL of 1 M NaOH. Extraction three times with 100 ml of ether, drying and evaporation gave 5.8 g of the title compound. Crystallization from diisopropyl ether gave 4.8 g (79%) of product. Sp. 106-107 ° C; NMR: one aromatic line at 7.07 ppm and three methoxy lines at 3.86, 3.85 and 3.84 ppm. Carbon-13- 1 3 f f- · r 'l signals at 164.6 (7), respectively; 149.9 (5); 147.6 (2); 145.9 (6); 128.6 (1), 117.0 (4) and 111.1 (3) ppm.

Analysis (C 17 H 21 BrN 2 O 4)% C: calculated 50.88; found 50.84%; H: calculated 6.28; found 6.27%; N: calculated 6.98; found 6.96.

Example 2 (S) - (-) - N - [(1-ethyl-2-pyrrolidinyl) methyl] -3-chloro-2,5,6-trimethoxybenzamide., Method α-3-chloro -2,5,6-trimethoxybenzoic acid 2, 5,6-Trimethoxybenzoic acid, 5.0 g (0.024 mol), was suspended in 75 mL of CHCl 3 and cooled to 0 ° C. 1.9 ml (0.024 mol) of SO 2 Cl 2 in the N 2 ring were then added. The reaction mixture was stirred for 2 h and allowed to slowly reach room temperature. The reaction mixture was diluted with 100 mL of CHCl 3 and washed with 200 mL of H 2 O. The aqueous layer was washed with 50 mL of CHCl 3 and the combined organic layer was dried (Na 2 SO 4) and the solvent was evaporated. Yield 5.5 g (95%) of 3-chloro-2,5,6-trimethoxybenzoic acid (oil). Sp. 246.7.

(S) - (-) - N - [(1-ethyl-2-pyrrolidinyl) methyl] -3-chloro-2,5,6-trimethoxybenzamide

A solution of 3-chloro-2,5,6-trimethoxybenzoic acid, 5.5 g (0.023 mol), DMF and SO 2 in toluene was stirred at 50 ° C under N 2 until gas evolution ceased. The solvent was evaporated and the residue was dissolved in 100 ml of CHCl 3 and evaporated again. The residue was dissolved in 75 mL of CHCl 3 and stirred with a solution of (S) - (-) - 2-aminoethyl-1-ethylpyrrolidine in 10 mL of CHCl 3. The mixture was stirred at room temperature for 3 h and then extracted with 2 x 100 mL of 1M HCl. The combined aqueous layer was basified with 45% NaOH (aq) and then extracted with 3 x 150 mL CH 2 Cl 2. The combined organic layer was dried (Na 2 SO 4) and the solvent was evaporated. 4.8 g (60%) of a crystallizing residue were obtained. Recrystallization from 50 ml of iPR 2 O gave 2.1 g of the title compound, m.p. 118-120 ° C (26%).

14

Example 3 (S) - (-) - N - [(1-ethyl-2-pyrrolidinyl) methyl] -2,3,6-trimethoxybenzamide. method α-2,3,6-trimethoxybenzoic acid, (4.2 g; 0.020 mol) was treated with thionyl chloride (7.1 g; 0.060 mol) in toluene (150 ml) at 65 ° C for 1 h. The solvent was removed in vacuo and the residue was dissolved in 50 ° C. to chloroform. A solution of (S) - (-) - N-ethyl-2-aminomethylpyrrolidine (3.8 g; 0.030 mol) in 50 ml of chloroform was added and stirred at 40 ° C for 30 min. Addition of sodium hydroxide dia (20 ml; 2N), separation and evaporation of the organic layer gave 4.5 g of the title compound. The properties of the magnetic resonance spectra of the atoms of this compound are shown below.

1 H-NMR (CDCl 3) δ ppm, 6.87 (d, 1H), 6.58 (d, 1H, J = 9.1 Hz), 3.88 (s, 3H), 3.82 (s, 3H ), 3.78 (s, 3 H).

13 C-NMR (CDCl 3) δ ppm, 165.6, 150.2, 147.0, 146.9, 114.3, 113.4, 106.5.

Example 4 (S) - (-) - N - [(1-Ethyl-2-pyrrolidinyl) methyl] -3-ethyl-2,5,6-trimethoxybenzamide Method of reaction α-3-ethyl-2,5,6-trimethoxybenzoic acid (2.0 g; 0.0083 mol) was treated with thionyl chloride (1.2 g; 0.010 mol) in 20 ml of toluene containing 3 drops of dimethylformamide as a catalyst at 50 ° C for 1.5 h. The solvent was removed. The residue of crude 3-ethyl-2,5,6-trimethoxybenzoyl chloride was dissolved in 20 ml of chloroform and mixed with a solution of (S) - (-) - 1-ethyl-2-aminomethylpyrrolidine (1, 3 g; 0.010 mol) in 20 ml of chloroform. After 16 h, the reaction mixture was extracted with 2 x 50 mL of 1N HCl. The aqueous layer was made alkaline with 30% NaOH. Extraction with 2 x 75 ml of chloroform, drying (Na 2 SO 4) and evaporation of the solvent gave 2.0 g of product. Yield 71%. Sp. 85-87 ° C from diisopropyl ether. = -71 ° C (c = 0.74, acetone).

13 C-NMR (CDCl 3) δ 166.0 (CONH), 149.1 (C-2), 148.2 (C-6), 144.3 (C-5), 133.0 (C- 3), 127.2 (Cl), 113.8 (C-4) (aromatic signals only) ppm.

Example 5 (S) - (-) - N - [(1-ethyl-2-pyrrolidinyl) methyl] -3-propyl-2,5,6-trimethoxybenzaroid. Method α-3-Propyl-2,5,6-trimethoxybenzoic acid (23 g; 0.09 mol) was treated with thionyl chloride and (2S) - (-) - 1-ethyl-2-aminomethylpyrrolidine as described in Example 4. Yield 10.6 g (32%). Sp. 68-70 ° C (i-Pr 2 O).

1 H-NMR (CDCl 3): δ 6.73 (s, 1H), 6.40 (b, 1H), 3.85 (s X 2.6H), 3.76 (s, 3H), 0.9- 3.8 (m, 21 H) ppm.

Example 6 (R) - (+) - N - [(1-Benzyl-2-pyrrolidinyl) methyl] -3-bromo-2,5,6-trimethoxybenzamide, Method α-3-Bromo-2,5,6-trimethoxybenzoyl chloride (8 mmol) was reacted with (2R) -1-benzyl-2-aminomethylpyrrolidine (6.5 mmol) in 15 mL of dichloromethane as described in Example 1. Purification by evaporation chromatography on SiO 2 using i-Pr 2 O / MeOH / NH 3 100: 10: 1 as eluent gave 1.17 g (39%) of product. Sp. 112-114 ° C. [α] = + 57 ° C (c = 0.52, acetone). 1 H-NMR (CDCl 3):

Three methoxy signals 3.85, 3.84 and 3.83 ppm. 13 C-NMR (CDCl 3): δ 164.7 (CONH, 149.9, 147.7, 146.1, 139.3, 128.9, 128.7, 128.3, 127.0, 117.3, 111.1 (aromatic) ppm Mass spectrum (EI, 70 eV): m / z 464/462 (M, 0.14% / 0.1%), 160 (100%), 91 (52%).

Example 7 (S) - (-) - N - [(1-ethyl-2-pyrrolidinyl) methyl] -2-amino-3-bromo-5,6-dimethoxybenzamide. method a_

To a solution of 2-amino-3-bromo-5,6-trimethoxybenzoic acid (0.96 g, 3 mmol) and triethylamine (0.58 mL; 4.2 mmol) in 15 mL of tetrahydrofuran / dichloromethane (1 : 1), ethyl chloroformate (0.32 mL; 3.4 mmol) was added at -20 ° C. After stirring for 45 min at -20 ° C, a solution of (2S) - (-) - 1-ethyl-2-aminomethylpyrrolidine in 10 mL of dichloromethane was added at -20 ° C. After stirring for 3 h at room temperature, the mixture was washed with water and extracted with 0.5 M HCl. The aqueous phase was made alkaline and extracted twice with dichloromethane. Drying (Na 2 SO 4) and evaporation gave 0.45 g of crude material which was purified by chromatography on a C18 reverse phase column using H 2 O / MeOH / NH 3 40: 60: 0.3 as eluent to give 0.25 g (22%) of pure product as an oil. .

Analysis (C 16 H 24 BrN 3 O 3): Calculated C 49.75; H 6.26; N 10.88. Found: C, 49.90; H 6.31; N 10.69.

1 H-NMR (CDCl 3): δ 1.11 (t, CH 3), 1.7-3.9 (multiline, 11 H), 3.80 and 3.82 (two s, (Ome) 2), δ, 80 (b, HN 2), 7.14 (s, 4-H), 7.9 (b, NH) ppm. 13 C-NMR (CDCl 3): δ 167.0 (CONH), 148.1, 143.7, 140.9, 120, 113.0, 104.9 (aromatic) ppm.

Example 8 (S) - (-) - N - [(1-ethyl-2-pyrrolidinyl) methyl] -3-bromo-5-hydroxy-2,6-dimethoxybenzamide. Method α-3,5-Dibromo-2,6-dimethoxybenzoic acid (10.0 g, 0.036 mol) was dissolved in 200 mL of 10% sodium hydroxide. 1.0 g of copper-bronze powder was added and the mixture was heated at 100 ° C for 6 h. After cooling, the mixture was neutralized with concentrated hydrochloric acid and extracted with 2 x 200 ml of methylene chloride. Drying and evaporation of the solvent gave 3.5 g of a brown residue of 3-bromo-5-hydroxy-1,6-dimethoxybenzoic acid.

The residue was treated with thionyl chloride (3.5 g; 0.03 mol) in 50 ml of toluene at 65 ° C for 1 h. The solvent was evaporated in vacuo and the residue was dissolved in 30 ml of chloroform. A solution of (S) - (-) - 1-ethyl-2-aminomethylpyrrolidine in 15 ml of chloroform was then added and the mixture was stirred at 35 ° C for 1 h. Water and 20 mL of 2N NaOH were then added. The product was extracted with chloroform and treated on a chromatographic column (Si-gel, Merck V '17

Lichrosorb, CH 2 Cl 2 -C 2 H 5 OH-NH 3, 90: 9: 1). 0.35 g of the title compound was obtained as an oil.

Mass spectrum: Molecular peak 386/388, corresponding to C16H23BrN2O4.

NMR: (CDCl 3) proton: δ ppm 7.56 (b, 5-OH), 7.03 (s, H 4), 6.83 (b, NH), 3.80 (s, CH 3 O), 3.77 (s, CH 3 O), 1.7-3.8 (m, 11H), 1.11 (t, CH 3). Carbon -13: δ ppm 165.4 CONH, 147.2 C5OH, 146.6 C2-OMe, 144.4 C6OMe, 127.0 C1-CONH, 121.2 C4-H, 111.3 C3-Br.

Example 9 (S) - (-) - N - [(1-ethyl-2-pyrrolidinyl) methyl] -3-bromo-2-hydroxy-5,6-dimethoxybenzamide and (S) - (-) - 3-bromo -N - [(1-ethyl-2-pyrrolidinyl) methyl] -6-hydroxy-2,5-dimethoxybenzamide. method b____________.

a) The compound (S) - (-) - N - [(1-ethyl-2-pyrrolidinyl) methyl] -3-bromo-2,5,6-trimethoxybenzamide (8.1 g; 0.020 mol) was dissolved in 100 ml: aan CH2Cl2. 3M HCl ether (7.7 mL; 0.022 mol) was added at room temperature followed by a solution of boron tribromide (5.5 g; 0.022 mol) in 40 mL of CH 2 Cl 2. After standing for 1 h at 25 ° C, 2M ammonia (50 ml) was added and the organic layer was separated, dried and evaporated. The residue (6.1 g) showed two peaks in GC analysis with retention times of 8.5 and 6.8 min, and two points in the TLC (silica-methanol-diisopropyl ether 1: 4) ratio 2: 1. The major part of the product was separated in a chromatographic column to give 3.0 g of the title product. The hydrochloride was crystallized from 15 ml of acetone-ether, m.p. 135-137 ° C.

Analysis (C 16 H 24 BrClN 2 O 4):% C: calculated 45.35, found 45.22; % H: calculated 5.71, found 5.67; % N: calculated 6.61, found 6.56; % Br: calculated 18.86, found 18.75; % Cl: calculated 8.37, found 8.47.

1 H-NMR: (CDCl 3, δ ppm) 7.28 (s, 1H), 3.93 (s, 3H), 3.84 (s, 3H), 3.70 (dd, 1H), 3.30 ( m, 2H), 2.84 (dq, 1H), 2.6 (m, 1H), 2.20 (m, 2H), 1.4-1.8 (m, 4H), 1.13 (t , 3H).

13 C-NMR: aromatic range 169.2, 153.5, 147.9, 144.6, 121.9, 109.0, 105.5.

·· w 18

From the above recovered fractions, which also contained the second title compound, 0.93 g, m.p. 97-99 ° C, from hexane-ethanol (20: 1).

1 H-NMR: (CDCl 3): δ 8.9 (b, HN), 7.06 (s, H-4), 3.86 (s, OCH 3), 3.84 (s, OCH 3), 1.6 -3.9 (m, 12H), 1.13 (t, CH 3) ppm.

13 C-NMR: (CDCl 3): δ 169.1 (CONH), 153.4 (C-2), 148.8 (C-6), 146.7 (C-5), 118.2 (C-4) ), 108.9 (Cl), 103.8 (C-3) (aromatic) ppm. [α] D = -53 ° C (c = 1.52, acetone).

b) 0.5 mmol of the anhydrous stock solution containing (S) -N - [(1-ethyl-2-pyrrolidinyl) methyl] -3-bromo-5,6-dimethoxy-2-trimethylsilyloxybenzamide was removed and treated with water at room temperature to rapidly form the first title compound having similar NMR values and GC retention times to the compound described in a).

Example 10 (S) - (-) - N - [(1-ethyl-2-pyrrolidinyl) methyl] -3-chloro-2-hydroxy-5,6-dimethoxybenzamide and (S) - (-) - 3-chloro -N - [(1-ethyl-2-pyrrolidinyl) methyl] -6-hydroxy-2,5-dimethoxybenzamide. method b_

To a solution of 2.0 g of (S) - (-) - N - [(1-ethyl-2-pyrrolidinyl) methyl] -3-chloro-2,5,6-trimethoxybenzamide (0.0056 mol) and 1.9 ml of 3M HCl ether (0.0056 mol) in 20 ml of CH 2 Cl 2, a solution of 1.4 g of BBr 3 in 10 ml of CH 2 Cl 2 was added over 1 hour. After standing for 1 hour at room temperature, the reaction mixture was extracted with concentrated ammonia. The alkaline aqueous layer was extracted with 2 x 100 mL of CH 2 Cl 2. The organic layer was dried (Na 2 SO 4) and evaporated to give a residue of 1.3 g. The TLC assay (silica iPR 2 O: MeOH in NH 3 89: 10: 1) had two spots at Rf 0.45 and Rf 0.30, respectively. 0.9 g of the mixture was separated in a chromatographic column to give 0.4 g of the title compound. The mesylate was crystallized from acetone. Sp. 165-166 ° C.

Analysis (C 16 H 23 ClN 2 O 4):% C: calculated 46.52, found 46.53; % H: calculated 6.20, found 6.14; % Cl: calculated 8.08 found.

19 tu 7.89; % N: calculated 6.38, found 6.30; % 0: calculated 25.52, found 25.39; % S: calculated 7.31, found 7.38.

From the recovered fractions containing a smaller amount of the second title compound, 0.10 g was prepared as an oil, [α] = = -62 ° C (c = 0.18, acetone).

1 H-NMR: (CDCl 3): δ 8.9 (b, NH), 6.92 (s, H-4), 3.8 ^ 6 (s, (OCH 3) 2), 1.6-3.8 (m, UH), [.alpha.] D @ 20 (t, CH3 D @ 13 13 C-NMR: (CDCl3): δ 169.4 (CONH), 153.1 (C-6), 148.0 (C-2) 146.6 (C-5), 115.9 (C-4), 115.7 (C-3), 108.8 (Cl) (aromatic) ppm.

Example 11 (S) - (-) - N - [(1-ethyl-2-pyrrolidinyl) methyl] -3-ethyl-2-hydroxy-5,6-dimethoxybenzamide and (S) - (-) - N - [ (1-Ethyl-2-pyrrolidinyl) methyl] -3-ethyl-6-hydroxy-2,5-dimethoxybenzamide, Method b_

A solution of (S) - (-) - N - [(1-ethyl-2-pyrrolidinyl) methyl] -3-ethyl-2,5,6-trimethoxybenzamide (0.80 g; 0.002 mol) in 25 ml: in CH 2 Cl 2, treated with 3N HCl-ether (1 mL; 0.003 mol) and then a solution of boron tribromide (0.6 g, 0.0023 mol) in 10 mL of CH 2 Cl 2 at ambient temperature was added. Further work-up and chromatography according to Example 9 gave 0.4 g (54%) of the title compound as an oil.

Proton NMR: (CDCl 3) δ ppm: 9.2 (b, NH), 6.92 (s, H 4), 3.90 (S, CH 3 O), 3.84 (s, CH 3), 1.7- 3.8 (m, 13H), 1.17 (t, CH 3), 1.13 (t, CH 3).

Carbon 13 NMR: (CDCl 3) δ ppm: 170.2 CONH, 154.7 C2-OH, 146.3 C6-OCH3, 143.8 C5-OCH3, 128.3 C3-C2H5, 119.0 C4- H, 107.5 Cx-CONH.

GC: retention time 6.6 min, temp. 260 ° C, 10 m SE 54. The smaller isomer has an RT of 7.8 m.

The mesylate was prepared from ether by stirring 1 equivalent of methanesulfonic acid in acetone and crystallizing from

20 '·' 'U

from acetone. Sp. 153-155 ° C (from acetone). Yield 0.32 g (38%).

Analysis (C 19 H 32 N 2 O 7 S):% C: calculated 52.76, found 52.69; % H: calculated 7.46, found 7.33; % N: calculated 6.48, found 6.44; % 0: calculated 25.89, found 25.76; % S: calculated 7.41, found 7.27.

From the recovered fractions containing a smaller amount of isomers, 0.3 g of the second title compound was prepared as the methanesulfonate. Sp. 137-138 ° C from acetone. [ar] p® (base) = -48 ° C (c = 1.0, acetone).

1 H-NMR: (CDCl 3): δ 8.9 (b, NH), 6.79 (s, H-4), 3.87 (s, OCH 3), 3.71 (s, OCH 3), 1.6 -3.9 (m, 13H), 1.23 (t, CH 3), 1.13 (t, CH 3) ppm.

13 C-NMR: (CDCl 3): δ 170.2 (CONH), 151.9 (C-6), 149.8 (C-2), 146.1 (C-5), 125.5 (C-3) ), 115.8 (C-4), 108.0 (Cl) (aromatic) ppm.

Example 12 (S) - (-) - 5,6-Dimethoxy-N - [(1-ethyl-2-pyrrolidinyl) methyl] -2-hydroxy-3-propylbenzamide. method b_

A solution of 10.0 g (0.027 mol) of (S) - (-) - N - [(1-ethyl-2-pyrrolidinyl) methyl] -3-propyl-2,5,6-trimethoxybenzamide , was treated with 16 mL (0.027 mol) of 1.6 M HCl ether in 250 mL of methylene chloride. A solution of 6.8 g (0.027 mol) of boron tribromide in 50 ml of methylene chloride was added slowly at 10 ° C. The reaction mixture was stirred at 20 ° C for 2 h and 100 mL of 2M NH 3 was added. Extraction with 2 x 300 ml of CH 2 Cl 2, drying (Na 2 SO 4) and evaporation of the solvent gave 9.2 g of the two components in a ratio of 4: 1. The residue was dissolved in 300 mL of ether and shaken with 2 x 50 mL of 1N NaOH, which completely removed the minor component from the ether layer. Drying and evaporation of the solvent gave 6.0 g of the title compound as an oil. GC 5.5 min at 250 ° C (SE-54). S.iant o 65%.

13 C-NMR: (CDCl 3): δ 170.2 (CONH), 154.9 (C-2), 146.3 (C-6), 143.6 (C-5), 126.7 (C-3) ), 119.9 (C-4), 107.5 (Cl), 62.2 21 (OCH3), 62.1 (OCH3), 61.2 (C1-2), 572, 53.4, 47, 7, 40.5, 32.0, 28.4, 22.6, 14.0, 13.9, (9 carbons) ppm.

The oil was dissolved in 75 ml of acetone. A hot solution of 2.6 g of L (+) - tartaric acid in 95 ml of 98% (aq) acetone was then added to give 4.5 g of the tartrate salt. Sp.

84-85 ° C.

Example 13 (S) - (-) - 2,5-Dimethoxy-N - [(1-ethyl-2-pyrrolidinyl) methyl] -6-hydroxy-3-propylbenzamide. method b_

The combined alkaline aqueous layer obtained in Example 12 was washed with 50 ml of ether and neutralized with ammonium chloride to pH 8.5. Extraction with 2 x 50 ml of ether gave 1.3 g of pure smaller isomer as an oil. GC (SE-54, 250 ° C) 6.0 min.

1 H-NMR: (CDCl 3): δ 8.5 (b, NH), 6.77 (s, H-4), 3.86 (s, OCH 3), 3.71 (s, OCH 3), 1.6 -3.9 (m, 15H), 1.13 (t, 3H), 0.98 (t, 3H) ppm.

13 C-NMR: (CDCl 3): δ 170.1 (CONH), 151.8 (C-6), 149.9 (C-2), 145.8 (C-5), 123.9 (C-3) ), 115.8 (C-4), 107.9 (Cl) (aromatic) ppm.

Example 14 (S) - (-) - N - [(1-allyl-2-pyrrolidinyl) methyl] -3-bromo-2-hydroxy-5,6-dimethoxybenzamide and (S) - {-) - N - [ (1-Allyl-2-pyrrolidinyl) methyl] -3-bromo-6-hydroxy-2,5-dimethoxybenzamide. method b_

By the method described in Example 9, the (S) - (-) - N - [(1-allyl-2-pyrrolidinyl) methyl] -3-bromo-2,5,6-trimethoxybenzamide prepared in Example 21 was modified in the title to the former compound. Yield 48% of a colorless oil. [α] D 20 = (c = 1.8, acetone).

1 H-NMR: (CDCl 3): δ 9.05 (b, NH), 7.27 (s, H-4), 5.91 (m, vinyl-H), 5.19 (dd, 1H) , 5.12 (d, 1H), 3.92 (s, OCII3), 3.83 (s, OCH3), 1.6-3.8 (m, 11H) ppm.

13 C-NMR: (CDCl 3): δ 169.3 (CONH), 153.6 (C-2), 148.0 (C-6), 144.6 (C-5), 135.9 (C-4) ), 122.0 (vinyl-CH), 117.0 (vinyl-N / 22i-CH2), 109.1 (Cl), 105.6 (C-3), 61.5 (CH-2- ), 61.4 (OCH3-5), 57.2 (OCH3-6), 56.9 (NHCH2), 54.2 (NCH2), 40.6 (CH2-5 ') f 28.4 (CH2- 3 '), 22.8 (CH2-4r) ppm.

From the fractions containing the smaller component, 0.06 of the second title compound was isolated as an oil.

[α] D 20 = -5 ° C (c = 0.18, acetone).

1 H-NMR: (CDCl 3): δ 8.9 (b, NH), 7.07 (s, H-4), 5.90 (m, 1H), 5.20 (dd, 1H, J = 22 Hz) , 1.5 Hz), 5.16 (d, 1H, J = 16 Hz), 3.87 (s, OCH 3), 3.84 (s, OCH 3), 1.6-3.8 (m, UH ) ppm.

Example 15 (R) - (+) - N - [(1-benzyl-2-pyrrolidinyl) methyl] -3-bromo-2-hydroxy-5,6-dimethoxybenzamide and (R) - (+) - N - [ (1-Benzyl-2-pyrrolidinyl) methyl] -3-bromo-6-hydroxy-2,5-dimethoxybenzamide. Method b__ (R) - (+) - N - [(1-benzyl-2-pyrrolidinyl) methyl] -3-bromo-2,5,6-trimethoxybenzamide (950 mg; 2.05 mmol) was dissolved in 30 mL dichloromethane and cooled with ice. A solution of 4M HCl in ether (0.5 mL; 2 mmol) was then added followed by 3.2 mL of 0.65 M boron tribromide in trichloromethane (2.1 mmol). After stirring for 1 h, 30 mL of 0.7 M NH 3 was added and the mixture was extracted with dichloromethane. The solvent was evaporated, the residue was dissolved in Et 2 O, washed with brine, dried (MgSO 4) and evaporated to give 923 mg (100%) of the two isomeric phenols. GC (SE-30, capillary column, 270 ° C): retention times 10.1 min and 12.4 min (ratio 3: 7).

The phenols were separated by evaporation chromatography using SiO 2 and Et 2 O / MeOH / NH 3 100: 3: 0.3 as eluent to give 495 mg (54%) of the title compound as an oil, [α]] ρ0 = + 94 ° (c = 0 , 52, acetone).

1 H-NMR: (CDCl 3): δ 7.25 (s, overlap with Ph, 4-H), 3.81 and 3.75 (two s, (0ME) 2).

Mass spectrum (EI, 70 eV): m / z 449/447 (MH, 0.57 / 0.61%), 261/259 (ArCO, 1.3 / 1.3%), 160 (100%), 91 ( 51%).

23 'Λ · /. · I.

From the fractions containing the smaller component, 0.06 g of the second title compound was isolated as an oil.

[α] = + 81 ° C (c = 1.1, acetone).

1 H-NMR: (CDCl 3): δ 7.12 (s, 4-H), 3.79 and 3.84 (two s, (OME) 2).

Mass spectrum (EI, 70 eV): m / z 449/447 (MH, 0.31 / 0.33%), 261/259 (ArCO, 0.86 / 0.91%), 160 (100%), 91 (54%).

Example 16 (S) - (-) - N - [(1-ethyl-2-pyrrolidinyl) methyl] -3,6-dibenzyloxy-2-methoxybenzamide. method a_

A solution of 3,6-dibenzyloxy-2-methoxybenzoic acid (120 mg; 0.33 mmol), thionyl chloride (120 mg; 1 mmol) and two drops of dimethylformamide as catalyst in 5 mL of toluene was stirred at 60 ° C for 1.5 h. The solvent was evaporated and the residue was dissolved in CH 2 Cl 2 and evaporated again. This residue was dissolved in 8 mL of CH 2 Cl 2 and a solution of (S) - (-) - 1-ethyl-2-aminomethylpyrrolidine (65 mg; 0.5 mmol) in 2 mL of CH 2 Cl 2 was added. After stirring overnight at room temperature, the solvent was evaporated and the residue partitioned between 2M HCl and ether. The aqueous phase was made alkaline, extracted with CH 2 Cl 2, dried (Na 2 SO 4) and evaporated to give the crude product. Chromatographic purification on SiO 2 using iPR 2 O / hexane / -MeOH / NH 3 69: 20: 10: 1 as eluent gave 145 mg (93%) of pure title compound. Sp. 121-123 ° C.

[α] D 20 = -42 ° (c = 2.8, acetone).

1 H-NMR: (CDCl 3): δ 7.39 and 7.38 (two s, CH 2 Ph), 6.89 and 6.59 (AB, 4-H and 5-H), 5.06 and 5.03 ( two s, CH 2 Ph), 3.95 (s, OMe), ppm.

Mass spectrum (EI, 70 eV): m / z 474 (M, 0.13%), 347 (ArCO, 0.33%), 98 (100%), 91 (12%).

24 .... - ·. / "s ^. ·. \ .i

Example 17 (S) - (-) - [(1-ethyl-2-pyrrolidinyl) methyl] -3,6-dihydroxy-2-methoxybenzamide (Method b)

A mixture of (S) - (-) - [(1-ethyl-2-pyrrolidinyl) methyl] -3,6-dibenzyloxy-2-methoxybenzamide (130 mg; 0.27 mmol), 5% Pd / C ( 50 mg), 0.5 ml of 4M HCl in ether and 5 ml of ethanol were shaken under a hydrogen atmosphere for 1 h. Filtration and evaporation of the solvent gave 90 mg of pure title compound as an oily hydrochloride.

1 H-NMR: (CDCl 3 / CD 3 OD): δ 7.13 and 6.67 (AB, 4-H and 5-H), 3.99 (s, OMe), ppm.

Mass spectrum (EI, 70 eV): m / z 294 (M, 0.64%), 167 (ArCO, 1.4%), 98 (100%)

Example 18

The following compounds can be prepared by any of the methods described in the above examples: (S) - (-) - N - [(1-ethyl-2-pyrrolidinyl) methyl] -2-hydroxy-5,6-dimethoxy-3-methylbenzamide, ( S) - (-) - N - [(1-ethyl-2-pyrrolidinyl) methyl] -5-bromo-2,3-dihydroxy-6-methoxybenzamide, (S) - (-) - N - [(1- Ethyl-2-pyrrolidinyl) methyl] -3-ethyl-2,5-dihydroxy-6-methoxybenzamide, (S) - (-) - N - [(1-ethyl-2-pyrrolidinyl) methyl] -5-amino -3-ethyl-2-hydroxy-6-methoxybenzamide, (S) - (-) - N - [(1-ethyl-2-pyrrolidinyl) methyl] -3-bromo-5,6-diethoxy-2-hydroxybenzamide .

Example 19

The following examples illustrate the preparation of the pharmaceutical compositions of the invention. The phrase "active ingredient" means a compound of the invention or a salt thereof.

Preparation A. Soft gelatin capsules 500 g of active substance were mixed with 500 g of corn oil, after which the mixture was filled into soft gelatin capsules, each capsule containing 100 mg of mixture (i.e. 50 mg of active substance).

25 ~

Preparation B. Soft Gelatin Capsules 500 g of active substance were mixed with 750 g of peanut oil, after which the mixture was filled into soft gelatin capsules, each capsule containing 125 mg of mixture (i.e. 50 mg of active substance).

Preparation C, Tablets 50 kg of active substance were mixed with 20 kg of silica bearing the trademark "Aerosil". To this were mixed 45 kg of potato starch and 50 kg of lactose, and the mixture was moistened with a starch paste prepared from 5 kg of potato starch and distilled water, after which the mixture was granulated through a sieve. The granulate was dried and screened, followed by mixing with 2 kg of magnesium stearate. The mixture was finally compressed into tablets each weighing 172 mg.

Preparation D. Effervescent tablets 100 g of active substance, 140 g of finely divided citric acid, 100 g of finely divided sodium bicarbonate, 3.5 mg of magnesium stearate and flavors (q.s.) were mixed together and the mixture was compressed into tablets each containing 100 mg of active substance.

Preparation E. Long-acting tablet 200 g of active substance were melted together with 50 g of stearic acid and 50 g of carnauba wax. The mixture thus obtained was cooled and ground to a particle size of not more than 1 mm in diameter. The mixture thus obtained was mixed with 5 g of magnesium stearate and compressed into tablets each weighing 305 mg. Each tablet thus contains 200 mg of active substance.

Preparation F. Solution for injection

3,000 mg of active substance

Sodium pyrosulfate 0.500 mg

Disodium edetate 0.100 mg

Sodium chloride 8,500 mg

Sterile water for injections ad 1.00 ml

26 l. C

Preparation G. Hard gelatin capsules 10 g of active substance were mixed with 400 g of lactose and finally 2 g of magnesium stearate were added. The mixture was then filled into hard gelatin capsules, each capsule containing 206 mg of mixture (i.e. 5 mg of active ingredient).

Preparation H. Tablets 50 g of active substance were mixed with 1500 g of lactose, 200 g of microcrystalline cellulose and 10 g of magnesium stearate. Tablets containing 5 mg of active substance with a core weight of 176 mg were finally coated.

Preparation I. Storage preparation (S) -N - [(1-ethyl-2-pyrrolidinyl) methyl] -3-bromo-2-hexadecanoyl-5,6-dimethoxybenzamide 200 mg

1 ml of peanut oil ad

Pharmacology

A number of studies indicate that the antipsychotic effect of neuroleptic drugs is due in some way to a decrease in catecholamine migration in the brain caused by these drugs, and more specifically to blockade of the central dopamine (DA) receptor in the cortical and sub-cortical regions of the brain.

Most compounds with antipsychotic activity affect several DA systems in the brain. There is evidence that the antipsychotic effect may be related to the blockade of DA receptors in subcortical and cortical limbic structures (J. Pharm. Pharmacol. 25, 346, 1973, Lancet, 1027, 1976), while the well-known extrapyramidal side effects of neuroleptic drugs are due to the blockade of DA receptors in the nigro-neostriatic DA system (Intern. J. Neurol. 6, 27-45, 1967).

- 'V ..' 27 A. In vivo experiments

Several different methods are currently available for studying DA receptor blockade in the brain in vivo. One method is based on the ability of antipsychotic drugs to block the behavioral effects of DA antibody apomorphine in rats. Several studies show an excellent correlation between the in vivo DA receptor blockade measured by the apomorphine assay and the therapeutic effect of various antipsychotic drugs. Apomorphine causes a characteristic syndrome in rats and other animal species, consisting of repetitive movements (stereotypes) and overactivity that appears to be due to activation of postsynaptic DA receptors in the brain (J. Pharm. Pharmacol. 19, 627, 1967; J. Neurol. Transm. 40. 97-113, 1977). Such stereotypes (chewing, licking, biting) appear to be mainly due to activation of DA receptors that bind to the nigroneo-striatal DA system (J. Psychiat. Res. 11, 1, 1974), whereas increased mobility (hyperactivity) appears to be mainly due to DA activation of receptors in subcortical mesolimbic structures (nucleus oi-factorium, nucleus accumbens), i.e. in a mesolimbic DA system (J. Pharm. Pharmacol. 25, 1003, 1973).

Several studies have shown that neuroleptics belonging to different structural classes block the apomorphine stereotype in rats and that this blockade is closely related to the inhibition of DA transmission as measured by biochemical or neurophysiological methods. Thus, the antiapomorphine effect corresponds well to changes in DA mobility induced by neuroleptic drugs (Eur. J. Pharmacol. 11, 303, 1970), DA receptor binding studies (Life Science, 17, 993-1002, 1976), and most importantly most importantly, antipsychotic efficacy (Nature, 2.63, 388-341, 1976).

.► · - y, 28 · °

Methods Male Sprague-Dawley rats (weight 225-275 g) were used. These rats were observed in Perspex cages (length 40, width 25 and height 30 cm) and behavior was recorded 5, 20, 40 and 60 minutes after apomorphine administration, and compounds were injected 60 minutes before apomorphine hydrochloride (1 mg / kg). injected subcutaneously (sc) into the neck, this dosage form and dosage form was found to produce a very constant response and a very low variability in the magnitude of the reaction, and apomorphine when administered sc also produced very constant hyperactivity.

Immediately after injection, the animals were placed in cages, one for each. Evaluation of stereotypes was performed by two different methods. The first review system was a modification of the system proposed by Costall and Naylor (1973). The magnitude of the stereotype was rated on a scale of 0-3 as follows:

Value Description of Stereotypic Behavior 0 No change in behavior compared to the comparative salt-salt test 1 Continuous sniffing 2 Continuous sniffing 3 Continuous sniffing, chewing, biting, and widowing

In the second system, the number of animals with apomorphine-induced hyperactivity was recorded. Each group comprised 6-8 animals. Saliva experiments were always performed simultaneously. ED50 values in the first grading system (scale 0-3) are those doses that reduce the intensity of stereotypes by 50% during a 60-minute observation period. The ED50 values for the second grading system are those doses that reduce the number of animals showing hyperactivity by 50% during the 60-minute observation period. ED50 values were calculated from logarithmic dose-response curves by the least four-night method using 4-6 different dose amounts and 6-8 animals at each dose level.

B. In vitro test. Receptor binding assay

The clinical efficacy of antipsychotic drugs has been found to be consistent with their ability to displace tritiated spiperone from dopamine receptor preparations [Seeman Biochem. Pharmacol. 26, 1741 (1977)].

Method The method of Burt et al. [Proc. Nat. Acad. Sci. USA 72, 4655 (1975)]. Male Spraque-Dawley rats weighing 150-200 g were decapitated and their brains were rapidly removed. The striatum was separated, pooled and homogenized in 50 mM Tris-HCl buffer (pH 7.6). The membrane fraction was collected by centrifugation (48,000 g; 10 minutes), washed once with buffer and resuspended in 50 mM Tris-HCl (pH 7.6) containing 0.1% ascorbic acid, 10 mM pargyline, 120 mM NaCl, 5 mM KCl , 2 mM CaCl 2 and 1 mM MgCl 2. The suspension was pre-incubated at 37 ° C for 10 minutes and then kept on ice until use.

The experiments were performed using a cell harvester. Incubation was performed using four test batches each containing a membrane suspension (2.5 mg / 0.5 ml), 3 H-spiperone (0.4 nM) and test compound in a final volume of 0.5 ml.

After incubation for 10 minutes at 37 ° C, the contents of the test batches were rapidly filtered and washed by Whatman GF / B filtration using a cell harvester. Specific binding was determined as the difference in ligand binding in the presence and absence of 1 μΜ (+) - butaclamol. The experimental results are presented as an estimate of the IC50. IC50 values, expressed in μΜ, indicate the concentration of test substance that reduces the amount of specifically bound spiperone by 50%.

Test results

The test results are shown in the following table.

30 'j'

Test compound In vivo__ In vitro

Reduction of hyperactive 3H-spi? Ercn of stereotypes Inhibition of low binding (.mu.mol / kg i.p.) of thymir en0ς_, ...... IC50 (, μM) _ _ (μmol / kg i.o.) _ / _

Known compounds:

Br OCH 3 6.5 0.3, -, 1.57

\ I

Och. r II

3 L2 ^ ("remoxipride", U.S. Patent 4,232,037)

Cl OH

V-C0NHCH_ --nJ

\ - / 2 2.4 0.11 0.025

/ 'I

Cl OCH -, C_, H „3d (compound according to EP 60235)

Compounds of the invention:

CH CH9CH OH

J z \ ~ _ / ____ ^ -CONHCI ^ l ^ J 2 6-10 <LO · 10 24-10 CH30 XOCH3 C2 H5

Br OH

^^ - C0NHCH2L_nJ 4.2-10 ~ 2 5 -10 ~ 3 10-10-4 ch3o och3 c2h5

C-, OHς OH

Δ \ 3 / Q.O, HCH2r3 5.8-10-2 0.7-10-3 7-10- ^ C1I3 ° X ° C! T3 c2 „5) 31

Review of test results

The compounds of the invention have antidopamine activity that is superior to the previously known compounds tested, both in vivo and in vitro. The ability to inhibit the stereotypes induced by apomorphine in rats is about 50-150 times more potent than the previously known compounds tested. In addition, there is a large difference between the ED50 doses that block apomorphine-induced hyperactivity and the ED50 doses that block stereotypes, indicating a highly selective effect on specific dopamine neurons. These properties could not be predicted from the properties of the previously known compounds.

In vitro receptor binding studies confirm the potent efficacy of the compounds of the invention in vivo. The activity of the compounds according to the invention displaces 3H-spiperone from rat striatal preparations prepared from rat brain is very much higher than the corresponding activity of the known compounds tested.

c 32

Mellanprodukter till oxisalicylamidoderivat Avdelat frän ansökan 850398 For the production of oxysalicylamides derived from oxy-substituted salicylamides.

The addition of these compounds to a benzamide neuroleptic, which is an alternative to blocking the dopamine receptor, is contemplated. Sädana substanser är användbara vid behandling av emesi, ängesttillständ, psykosomatiska sjukdomar och psykotiska tillständ säsom schizofreni och depression, alkoholrelaterade sjukdomar, förvirringstill-ständ och sömnrubbningar hos äldre.

Remoxipride (U.S. Pat. No. 4,232,037) is a formulation of Br 0 CH 3 (1-conhch 2 J) 0CH 3 C 2 H and is a highly antipsychotic mediator. The use of an upstream compound as a kraftig antagonist for apomorphine syndrome.

I European patent 60235 uppenbar benzene derivatives, vilka uppges Vara kraftiga inhibitorer av apomorfinsyndromet i rätta, varvid bland dessa hör föreningen med formuleln

Cl OH

O

Cl 0CH3 i2H5 33 For the purposes of U.S. Pat. No. 4,232,037 and EP 60235, an anti-dopaminergic network is used for the preparation of an upper ligand.

For example an upstream feed is produced in the form of a mixture of formulas R2 / Z1

C V- CONHCH- J

\ - / L N I

i '2 1 3 ZJ Z * CH ^ · 5 from Z1 to OH, OR1 or NH2, 7? is OR4, Z3 is OH, OR4 or OR1, R2 is an atom, not a halogen atom, R4 is an F3C- (CH2) n-, R3 is an atom, R4, is a linear or fused group with a double or triple bond and 2 accounts 3 cola-Tomer, phenyl or phenyl substituted with methylenedioxy or en fluorine of fluorine, chlorine, bromine, trifluoromethyl, methyl, ethyl, methoxy or ethoxy ortho-, meta-or para-substituted, R1 is alkyl-CO, of alkyl a reporter or linear group having 1 to 17 columns, R 4 and an alkyl group having 1 to 4 columns, 0 to 1 or 2 to another site.

Man har funnit att sAdana föreningar har värdefulla tera-peutiska egenskaper. Specifically, the anti-doped minerals are used in the form of a separate technical unit for the treatment and extraction of the extrapyramidal bifurcation.

The use of medical devices for the treatment of physiological and physiological conditions of the patient is limited to 34 years alcoholate grains, fresh-water distillates and blue-green algae.

Specifically, for example,

K / CH _ 8r. OH

Q- C0NHCH2 f ^ VcONHCH2 Λ.Ν)

HjCO OCHj C2H5 CHjO OCHj CH2CH = CH2

Cly, 0H _ 8rW ° H

\ y ~ CQNHCH2 ~ L HJ ^ y C0NHCH2 J

/> I / 'I // λ

HjCO 0CH3 * 2H5 Cm3 ° 0CH3 Ch2 0 HSC2 0H Br 0 (! - (CH2) 14-ch3 / V conhch2 -C n) X ^ y conhch2 \ n ^ H3CO OCHj C2H5 CH3 ° ^ 3 C2H5

The present invention provides a therapeutic approach to racemic derivatives of the (+) - and (-) - former, with a strong genomic synthesis. The enantiomer is enriched in the molten envelope, with a high potency. The (+) - and (-) - forms of the genomic reaction of the enantiomer of the 2-aminomethyl-pyrrolidine derivative with benzoic acid are used.

In particular, the administration of the application is carried out in the form of free or controlled use of highly toxic syrups. Typical exemptions include hydrogen bromide, hydrochloride, phosphate, sulfate, sulfonate, sulfamate, citrate, lactate, maleate, tartrate and acetate.

35 r · "- * ** · χ * 'v> Föreningarna framställs medelst mellanprodukter, vilka kän-netecknas av vad som szges i kännetecknande delen av krav 1 och 2.

In the case of clinical trials, the use of the active compound is normally administered orally, rectally or by genomic injection in the form of a pharmaceutical preparation which is active in the form of an active ingredient or a pharmaceutical formulation which is toxic, toxic. hydrobromides, hydrochlorides, phosphates, sulphates, sulphonates, sulphates, citrates, lactates, malates, tartrates, acetates and the like and other pharmaceutical preparations. In particular, the utilization of the utilization is to be determined by means of a specific or specific specification of the utilization of the amber base and the safety of the utilization of the utilization, for example, by means of the utilization of the utilization, e.g. and the specific nature of the sample is determined by the nature of the mixture.

Bäraren kan vara ett fast, halvfast eller flytande utspäd-ningsmedel eller en kapsel. This pharmaceutical practice is the most important aspect of the uptake. There are currently only 90% of the active substance at the time of injection, from 0.5% to 20% at the time of injection and 2% of the 50% at the time of administration of the oral administration. ring.

For use in the manufacture of pharmaceutical products in the form of oral dosage forms for oral administration, the use of bleaching agents in the form of a fast powder form, e.g. lactose, sackose, sorbitol, mannitol, starch sdsom potatisstarch, maize starch or amylopectin, cellulosic derivatives or gelatin and smoking agents containing magnesium stearate, calcium stearate, polyethylene glycol and other pressed matter. For the purposes of this Regulation, the third paragraph of this Regulation does not apply to products of the same type, including the t.ex. gum arabicum, gelatin, talc, titanium dioxide and oil.

Alternatively, the tablets may be present with a lack of lost organic matter or bleached organic tablets. For the purposes of this Regulation, the following Member States have indicated that they were active in the assets or in their assets.

For the production of solid gelatine capsules (pearl capsule capsules), the gelatin and glycerol-free capsules may be used as active ingredients in the presence of a vegetable. The gelatin capsule may contain granules of the active substance in combination with a powder, lactose, lactose, sardose, sorbitol, mannitol, starch (i.e. potassium starch, starch or amylopectin), cellulose adsorbent.

The dosage form for rectal application can be used in the form of a suppository of active substances in bleaching with neutral fats or rectal capsules of gelatin of active substances in bleaching with vegetable oils or paraffins.

For the purpose of oral administration, the active ingredient may be in the form of a syrup or a suspension, the release of which is limited to 0.2 to 20% by weight of the active substance in the form of glycerol and propylene glycol. Occasionally, the fly ash may be treated with friedmedels, arommedel, sackarin och carboxymethylcellulosa as part of the flaxseeds.

The solution for parenteral application of the genomic injection can be used in the form of a pharmaceutical formulation and a 37-fold formulation of the active substance in the form of an active substance in a concentration of 0.5 to 10% by weight. In this case, the stabilized rings and / or buffers and heaters are heated to the same level.

Formulations of formula I, wherein R1 is an acyl group, may be used in the manufacture of a pharmaceutical composition for the administration of a compound having the same effect, for example, as a depressant.

The dosage unit dose for oral administration is 1-50 mg, up to 5-20 mg.

Framställningsmetoder Föreningar enligt formulel I kan erhällas genom nägon av föl-jande metoder.

A. Formation of the form / V-conhch2 - [) lZ> 3

CHZRJ

wherein Z1 is OH, OR1 or NH2, Z2 is OR4, Z3 is OH, OR4 or OR1, R2 is a hydrogen atom, an halogen atom, R4 is an FjC-ClCl2, ,, R3 is a hydrogen atom, R4 is a linear atom or a ring atom flasks with double or triple bonding and 2 to 3 columns, phenyl, phenyl or phenyl substituted with methylenedioxy or fluorine, fluorine, bromine, trifluoromethyl, methyl, ethyl, methoxy or ethoxy and orco, meta-eller in the case of a substituent, 38 R1 is alkyl-CO, an alkyl repenteric and linear group having 1 to 17 cholaters, R4 is an alkyl group of 1 to 4 cholatomers, 0 to 1 or 2, which is a genome and a group, in which case: (a) reaction to form ** 2 '

C00H

z3 z2 of Z1, Z2, Z3 and R2 have a definitive group and -C00H is a reactive group, which can react with an amino group under the image of an amide group, with a formulation of V-CHrS? oyR3 is that R3 is defined as such that the reactants are derived.

The reaction mixture is heated to dryness with diethyl ether, THF, dichloromethane, chloroform or toluene at -20 ° C and the reaction mixture is heated to reflux. The result is that it is isolated that you have received t.ex. genome filtration. Alternatively, the reaction can be carried out on a conventional basis using conventional techniques for the production of ammonia or sodium hydroxide solution and extraction with organic solvents.

in the case of uptake of the above-mentioned cyclical method 2, the reactive derivatives are derived from the following cycles: J - ,,.

39

The reaction products are phosphorus chloride, phosphorus oxychloride, dialkyl, diaryl or o-phenylchlorophosphite or alkyl or aryl chlorophosphite or isothiocyanate or isocyanate. These reactive derivatives can be reacted with syrup in situ or after isolation.

It is possible to disclose the effect of the condensation and the condensation of the condensate, t.ex. disacchloride, diphosphorus pentoxide and phosphine or hexamethylphosphoric triamide plus enol tetrahydride, diphenylphosphite, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, titantetrachloride or carbodiimide carbamimide, dicyclohexylcarbide , N'-thionyldiimidazole and diethyldiazodicarboxylate.

(B) Formation of formula R2 Z1

rV CONHCH, -ΓJ

M Ϊ z3 z2 ch2-r3 for Z1, Z2, Z3, R2 and R3 are defined by the ingredients of claims 1 and the same as in Z1 and Z3 are OH, which is the genome of the genome which is derived from the form of R2 z '" Z, Z2: h, -r3 are Z2, R2 and R3 are defined by the ingredients of claims 1 and Z1 "or OH, OR1 or a hydroxyl group, and Z2 = Z3 = OH, and Z3 OH, OR4, OR1 or a heated hydroxyl group 40 and a minimum of Z1 "and Z3" are also a hydroxyl group.

The standard hydrolytic group for the phenol group can be trimethylsilyl, t-butyldimethylsilyl, tetrahydropyranyl, benzyl, methoxyethoxymethyl, methoxymethyl, methylthiomethyl, aliphatic or aromatic esters, carbonates or cyclic acetates, ketals, A group of standard genomic processors (T.W. Greene in Protective Groups in Organic Synthesis, Wiley,

New York, 1981, pp. 87-113).

In a specific form, the group is represented by a group Z1 and Z2, which is alkoxy.

The transfer of all products with the formulation R2 R2 Z1 "

G) - CONRCH2-G

., / \ I

Z3 Z2 ch2-r3 is Z2, R2 and R3 are selected from the group consisting of Z1 "or OH, OR1 or a protected hydroxyl group, and the products Z2 = Z3 = OH, and Z3 'are OH, OR4, OR1 or a heated hydroxyl group , the products Z2 = Z3 = OH and the equivalents of Z1 'and Z3 "are heated by a hydroxyl group, and in the form of: R2 Z1 Z3 Z2 of Z1, Z2, Z3 and R2 are the same as in patent claim 1. i forfarandealternativen a) och b).

41

The genomic products of the present invention are described in (a).

Mellanprodukter med formeIn R2 Z1

// \ V_COOH

Z * V

in which R2, Z1, Z2 and Z3 are defined above, the genome being the same as that of the form R2 R21

// \ V_C00H

Z 2 Z 2 is R 2 is defined as O and Z1, Z 2 and Z 3 are OR 4, R 4 is R 4 is defined as boron tribromide, boron trichloride or aluminum chloride or Bromine chloride, ii) a mixture of R2 in the form of Z1 and 'V - cooh z) zz to R2 is somewhere between br and I; Z1, Z2 and X3 are alkoxy, dialkylamino or alkylthio; Alternatively, Z1, Z2 and Z3 may be substituted with methoxymethyl ether or tetrahydropyranyl ether, t-butoxycarbonylamine or t-butylcarbonylamine, which may be reacted with alkyl or aryllithium to give a reaction with colloidal oxides and surgical agents.

- - ν '42 (iii) in the case of form Z1

// \ V__C00H

/ pj Γ Zz for Z1, Z2 and Z3 are defined as halogen, en sulfuryl halides (for the first time S02C12) or halogen-dioxane complex, for example with R2 = halogen.

Exempel 1 (S) - (-) - N - [(1-ethyl-2-pyrrolidinyl) methyl] -3-bromo-2,5,6-trimethoxybenzamide. förfarande a

The best yields of 3-bromo-2,5,6-trimethoxybenzoic acid (4.5 g; 0.015 mol) in 60 ml of toluene were added to give thionyl chloride (4.5 g; 0.038 mol) at 65 ° C. timmes tid. The solution was stirred and rested in 20 ml of CHCl 3. The loan was carried out with (S) - (-) - 2-aminomethyl-1-ethylpyrrolidine in 40 ml of CHCl 3. The temperature is maintained at 45 ° C. After 0.5 h, the solution is stirred and the mixture is neutralized with 100 ml of 1-M NaOH. In the case of extraction with 100 ml of ether, purification and addition of 5.8 g of the title compound. Crystallization from diisopropyl ether gave 4.8 g (79%) of product. Sp. 106-107 ° C; NMR: the aromatic band was 7.07 ppm and the methoxy band was 3.86, 3.85 and 3.84 ppm. Koi-13 signaler vid 164.6 (7); 149.9 (5); 147.6 (2); 145.9 (6); 128.6 (1); 117.0 (4) and 111.1 (3) ppm.

Analys: (C 11 H 12 BrN 3 O 3)% C: 50.88; constituent 50.84%; H: beräknat 6.28; constituent 6.27%; N: beräknat 6.98; constatate 6.96.

Exempel 2 (S) - (-) - N - [(1-ethyl * 2-pyrrolidinyl) methyl] -3-chloro-2,5,6-trimethoxybenzamide. To give 3-chloro-2,5,6-trimethoxybenzoyl is dissolved in 5.0 ml (0.024 mol) of 2,5,6-trimethoxybenzoyl, 75 ml of CHCl3 are added and the mixture is cooled to 0 [deg.] C. The sedan was charged with 1.9 mL (0.024 mol) of SO 2 Cl 2 under a nitrogen atmosphere. Reaction of the reaction mixture was carried out for 2 hours and then cooled to room temperature. The reaction mixture is taken up in 100 ml of CHCl3 and treated with 200 ml of H2O. Dilute with water 50 ml of CHCl 3 and give organic organic solvents (Na 2 SO 4) and give a solid solution. 5.5 g (95%) of 3-chloro-2,5,6-trimethoxybenzoic acid (oil) are obtained. The melting point is 246.7 ° C.

(S) - (-) - N - [(1-ethyl-2-pyrrolidinyl) methyl] -3-chloro-2,5,6-trimethoxybenzamide

5.5 g (0.023 mol) of 3-chloro-2,5,6-trimethoxybenzoic acid, DMF and SO 2 in toluene are then added at 50 ° C in a gas atmosphere. The reaction mixture was stirred and rested in 100 ml of CHCl 3 and dried. The residue was taken up in 75 ml of CHCl 3 and bleached with the addition of (S) - (-) - 2-amino-ethyl-1-ethylpyrrolidine in 10 ml of CHCl 3. The mixture is stirred for 3 h at room temperature and extra times with 2 x 100 ml of 1M HCl. The mixture was quenched with 45-% NaOH (aq) and extracted with 3x150 mL CH 2 Cl 2. The organic organic compound is added (Na2SO4) and dissolved in water. 4.8 g (60%) of crystals are obtained. Crystallization from 50 ml of iPR20 yields 2.1 g of the title compound, m.p. mp 118-120 ° C (26%).

Exempel 3 (S) - (-) - N - [(1-ethyl-2-pyrrolidinyl) methyl] -2,3,6-trimethoxybenzamide. To give 2,3,6-trimethoxybenzoic acid (4.2 g; 0.02 mol) was added thionyl chloride (7.1 g; 0.060 mol) in toluene (150 ml) at 65 ° C. . The solution was stirred under vacuum and refluxed with 50 ml of chloroform. The (S) - (-) - N-ethyl-2-aminomethylpyrrolidine (3.8 g; 0.030 mol) was added in 50 ml of chloroform and stirred at 40 ° C for 30 minutes. The genome was obtained with sodium hydroxide (20 ml; 2N), separation and addition of organic solvents to give 4.5 g of the title compound. Egenskaperna hos kärnresonansspektrumet för atomerna i denna förening var följande.

1 H-NMR (CDCl 3) δ ppm, 6.87 (d, 1H), 6.58 (d, 1H, J = 9.1 Hz), 3.88 (s, 3H), 3.82 (s, 3H), 3.78 (s, 3H). 13 C-NMR (CDCl 3) δ ppm, 165.6, 150.2, 147.0, 146.9, 114.3, 113.4, 106.5.

Exempel 4 (S) - (-) - N - [(1-ethyl-2-pyrrolidinyl) methyl] -3-ethyl-2,5,6-trimethoxybenzamide to give 3-ethyl-2,5,6-trimethoxybenzoic acid (2 0.0 g; 0.0083 mol) of thionyl chloride (1.2 g; 0.010 mol) in 20 ml of toluene are added to 3 parts of dimethylformamide as a catalyst at 50 ° C and 1.5 times. Lösningsmedlet avlägsnades. The 3-ethyl-2,5,6-trimethoxybenzoyl chloride was diluted with 20 ml of chloroform and treated with (S) - (-) - 1-ethyl-2-aminomethylpyrrolidine (1.3 g; 0.010 mol). ) in 20 ml of chloroform. After 16 minutes of additional reaction reactions with 2x50 ml of 1N HCl. The water was quenched with 30% NaOH. After extraction with 2x75 ml of chloroform, purification (Na 2 SO 4) and addition of a solution of 2.0 g of product are obtained. Utbytet var 71%. Sp. 85-87 ° C with diisopropyl ether. [α] D = -71 ° C (c = 0.74, acetone).

13 C-NMR (CDCl 3) δ 166.0 (CONH), 149.1 (C-2), 148.2 (C-6), 144.3 (C-5), 133.0 (C-3), 127.2 (Cl), 113.8 (C-4), (as aromatic signal) ppm.

Exempel 5 (S) - (-) - N - [(1-ethyl-2-pyrrolidinyl) methyl] -3-propyl-2,5,6-trimethoxybenzamide. to give 3-propyl-2,5,6-trimethoxybenzoic acid (23 g; 0.09 mol) was treated with medion thionyl chloride and (2S) - (-) - 1-ethyl-2-aminomethylpyrrolidine. exempel 4.

Yield 10.6 g (32%). Sp. 68-70 ° C (i-Pr 2 O).

1 H-NMR (CDCl 3): δ 6.73 (s, 1H), 6.40 (b, 1H), 3.85 (s X 2.6H), 3.76 (s, 3H), 0.9 -3.8 (m, 21 H) ppm.

i 45

Exempel 6 (R) - (+) - N - [(1-benzyl-2-pyrrolidinyl) methyl] -3-bromo-2,5,6-trimethoxybenzamide. 3-Bromo-2,5,6-trimethoxybenzoyl chloride (8 mmol) was treated with (2R) -1-benzyl-2-aminomethylpyrrolidine (6.5 mmol) in 15 mL of dichloromethane. samma sätt som beskrivits i exempel l.

The residue was chromatographed on SiO 2 eluting with PrO 2 / MeOH / NH 3 100: 10: 1 to give 1.17 g (39%) of product as eluent. Sp. 112-114 ° C. [α] D = + 57 ° C (c = 0.52, acetone).

1 H-NMR (CDCl 3): Tre methoxy signal 3.85, 3.84 and 3.83 ppm. 13 C-NMR (CDCl 3): δ 164.7 (CONH, 149.9, 147.7, 146.1, 139.3, 128.9, 128.7, 128.3, 127.0, 117.3, 111.1 (aromatic) ppm Mass spectrum (EI, 70 eV): m / z 464/462 (M, 0.14% / 0.1%), 160 (100%), 91 (52%).

Exempel 7 (S) - (-) - N - [(1-ethyl-2-pyrrolidinyl) methyl] -2-amino-3-bromo-5,6-dimethoxybenzamide. forfarande a_

This gave 2-amino-3-bromo-5,6-trimethoxybenzoic acid (0.96 g, 3 mmol) and triethylamine (0.58 mL, 4.2 mmol) in 15 mL of tetrahydrofuran / dichloromethane (1: 1) was added ethyl chloroform (0.32 mL; 3.4 mmol) at -20 ° C. After stirring for 45 minutes at -20 ° C, (2S) - (-) - 1-ethyl-2-aminomethylpyrrolidine is added in 10 ml of dichloromethane at -20 ° C. After this time, the mixture is heated to room temperature with water and extra 0.5 M HCl. The watten halide is alkaline and extra green with dichloromethane. After working up (Na 2 SO 4) and yielding 0.45 g of a flash product, chromatographed on a Cu-hydrogen phase phase column with H 2 O / MeOH / NH 3 40: 60: 0.3 as eluent, colors 0.25 g (22%) of ren product and oil form.

Analysis (C 16 H 24 BrN 3 O 3): found C 49.75; H 6.26; N 10.88. Constants: C 49.90; H 6.31; N 10.69.

1 H-NMR (CDCl 3): δ 1.11 (t, CH 3), 1.7-3.9 (multiplex, 11 H), 3.80 and 3.82 (internal s, (Ome) 2), δ .80 (b, HN 2), 7.14 (s, 4-H), 7.9 (b, NH) ppm. 13 C-NMR (CDCl 3): δ 167.0 (CONH), 148.1, 143.7, 140.9, 120, 113.0, 104.9 (aromatic) ppm.

', · - c- 46

Exempel 8 (S) - (-) - N - [(1-ethyl-2-pyrrolidinyl) methyl] -3-bromo-5-hydroxy-2,6-dimethoxybenzamide. For 3,5-dibromo-2,6-dimethoxybenzoic acid (10.0 g, 0.036 mol) was added 200 ml of 10% sodium hydroxide. 1.0 g of coprarbron powder was added and bleached at 6 ° C. After neutralization, neutralize the mixture with chlorinated chlorine and extract with 2x200 ml of methylene chloride.

3.5 g of the brown product are preferably obtained from 3-bromo-5-hydroxy-1,6-dimethoxybenzoic acid.

The product was treated with thionyl chloride (3.5 g; 0.03 mol) in 50 ml of toluene at 65 ° C. The solution was stirred under vacuum and dried in 30 ml of chloroform. To this end, (S) - (-) - 1-ethyl-2-aminomethylpyrrolidine was added in 15 ml of chloroform and bleached at 1 ° C for 1 hour. The sedan was added with water and 20 mL of 2N NaOH. The products are extracted with chloroform and chromatographed on a column (Si-gel, Merck Lichrosorb, CH2Cl2-C2H50H-NH3, 90: 9: 1). 0.35 g of oil is obtained as an oil.

Mass spectrum: Molecular band 386/388, m / z C 2 H 2 BrN 2 Cl 2.

NMR: (CDCl 3) proton: δ ppm 7.56 (b, 5-OH), 7.03 (s, H 4), 6.83 (b, NH), 3.80 (s, CH 3 O), 3.77 (s, CH 3 O), 1.7-3.8 (m, 1H), 1.11 (t, CH 3). Koi -13: δ ppm 165.4 CONH, 147.2 C5OH, 146.6 C2-OMe, 144.4 C6OMe, 127.0 CrCONH, 121.2 C4-H, 111.3 C3Br.

Exempel 9 2-Hydroxy-5,6-dimethoxybenzamide and (S) - (-) - 3-Bromo-N - [(1-ethyl-2-pyrrolidinyl) methyl] -6-hydroxy-2,5-dimethoxybenzamide, formate ba) Formation of (S) - {-) - N - [(1-ethyl-2-pyrrolidinyl) methyl] -3-bromo-2,5,6-trimethoxybenzamide (8.1 g, 0.020 mol) in 100 ml CH2C12. 3-M HCl-ether (7.3 mL, 0.022 mol) was added dropwise at room temperature to give boron tribromide (5.5 g, 0.022 mol) in 40 mL of CH 2 Cl 2. After 1 h at 25 ° C, 2-M ammonia (50 ml) is added and the organic phase is refluxed, eluting with 47 ml. Intermediates (6.1 g) were added to the top of the GC with a retention solution of 8.5 resp. 6.8 min and then on TLC (silica gel in methanol-diisopropyl ether, 1: 4) for 2: 1. The product was isolated by genomic column chromatography to give 3.0 g of the title product. The hydrochlorides crystallized from 15 ml of acetone-ether. Smp. 135-137 ° C. Analyzes (C ^ H ^ BrClNp ^:

Beräknat: 45.35% C 5.71% H 6.61% N 18.86% Br 8.37% Cl

Funnet: 45.22% C 5.67% H 6.56% N 18.75% Br 8.47% C 1 H-NMR: (CDCl 3, δ ppm) 7.28 (S, 1H), 3.93 (s, 3H), 3.84 (s, 3H), 3.70 (dd, 1H), 3.30 (m, 2H), 2.84 (dq, 1H), 2.6 (m, 1H) , 2.20 (m, 2H), 1.4-1.8 (m, 4H), 1.13 (t, 3H).

13 H-NMR: aromatic spectrum 169.2, 153.5, 147.9, 144.6, 121.9, 109.0, 105.5.

(b) Free of water from (S) -N - [(1-ethyl-2-pyrrolidinyl) methyl] -3-bromo-5,6-dimethoxy-2-trimethylsilyloxybenzamide 0.5 mmol and more vatten vid rumstemperatur, vilket orsakade snabb bildning av rubrikens förening, somhade identical NMR and GC-retentionstid med den förening som beskrivits ia).

Exempel 10 (S) - {-) - N - [(1-ethyl-2-pyrrolidinyl) methyl] -3-chloro-2-hydroxy-5,6-dimethoxybenzamide and (S) - (-) - 3-chloro -N - [(1-ethyl-2-pyrrolidinyl) methyl] -6-hydroxy-2,5-dimethoxybenzamide. 2.0 g of (S) - (-) - N - [(1-ethyl-2-pyrrolidinyl) methyl] -3-chloro-2,5,6-trimethoxybenzamide (0.0056 mol) are obtained. ) and 1.9 ml of 3-M HCl-ether (0.0056 mol) in 20 ml of CH2Cl2 are added in the form of 1.4 g of BBr3 and 10 ml of Cl2Cl2 are added for 1 h. After 1 h at room temperature extraction reactions with concentrated ammonia. The mixture was then washed with 2x100 ml CH 2 Cl 2. The organic phase is quenched (Na 2 SO 4) and induced, preferably 1.3 g.

TLC (silica dioxide iPr 2 O: MeOH: NH 3 89: 10: 1) gave a flash Rf 0.45 and a corresponding Rf 0.30. 0.9 g of the mixture is separated by genomic column chromatography and 0.4 g of the title compound is obtained. The mesylate crystallized from acetone. Smp. 165-166 ° C.

Analysis: (C 16 H 23 ClN 2 O 4):

Beräknat: 46.52% C 6.20% H 8.08% Cl 6.38% N 25.52% 0 7.31% S

Funnet: 46.53% C 6.14% H 7.89% Cl 6.30% N 25.39% 0 7.38% S

This fraction of the residue is determined to give 0.10 g of the product as an oil [cx] q ° = -62 ° C (c = 0.18, acetone). 1 H-NMR: (CDCl 3): δ 8.9 (b, NH), 6.92 (s, H-4), 3.86 (s, (OCH 3) 2), 1.6-3.8 (m , 11H), 1.13 (t, CH 2) ppm. 13 C-NMR: (CDCl 3): δ 169.4 (CONM), 153.1 (C-6), 148.0 (C-5), 115.9 (C-4), 115.7 (C- 3), 108.8 (Cl) (aromatic) ppm.

Exempel 11 (S) - (-) - N - [(1-ethyl-2-pyrrolidinyl) methyl] -3-ethyl-2-hydroxy-5,6-dimethoxybenzamide and (S) - (-) - N - [ (1-ethyl-2-pyrrolidinyl) methyl] -3-ethyl-6-hydroxy-2,5-dimethoxybenzamide, method b

To give (S) - (-) - N - [(1-ethyl-2-pyrrolidinyl) methyl] -3-ethyl-2,5,6-trimethoxybenzamide (0.80 g, 0.002 mol) in 25 mL of CH 2 Cl 2 Add 3-N HCl-ether (1 mL, 0.003 mol) to a solution of boron tribromide (0.6 g, 0.0023 mol) in 10 mL of CH 2 Cl 2 at reflux. The work-up and chromatography are carried out with an additional 9 g of 0.4 g (54%) of the title compound.

Proton NMR: (CDCl 3) δ ppm: 9.2 (b, NH), 6.92 (s, H 4), 3.90 (s, CH 2 O), 3.84 (s, CH 2 O), 1.7- 3.8 (m, 13H), 1.17 (t, CH 3), 1.13 (t, CH 3).

Col-13 NMR: (CDCl 3) δ ppm: 170.2 CONH, 154.7 C 2 -OH, 146.3 C 6 -OCH 3, 143.8 C 5 -C 20, 128.3 C 3 -C 2 H 5, 119.0 CH 4 -. H, 107.5 ° C, -CONH. GC: Retention conditions 6.6 min at 260 ° C at 10 m SE 54. The min isomer at RT 7.8 min.

The mesylate is converted from the ether genome to the equivalent of methanesulfonic acid in acetone and crystallized from acetone. Smp. 153-155 ° C (acetone). 0.32 g (38%) was obtained.

Analysis (C19 H32N2O7S):

Beräknat: 52.76% C, 7.46% H, 6.48% N, 25.89% O, 7.41% S

i. 'J O

49

Funnet: 52.69% C, 7.33% H, 6.44% N, 25.76% O, 7.27% S

In this case, the fraction obtained from the isomeric fractions is 0.3 g in the form of a methane sulfonate. Smp. 137-138 ° C in acetone. [α] D (bas) = -48 ° C (c = 1.0, acetone). 1 H-NMR: (CDCl 3): δ 8.9 (b, NH), 6.79 (S, H-4), 3.87 (s, OCH 3), 3.71 (s, OCH 3), 1, 6-3.9 (m, 13H), 1.23 (t, CH 3), 1.13 (t, CH 3) ppm. 13 C-NMR: (CDCl 3): δ 170.2 (CONH), 151.9 (C-6), 149.8 (C-2), 146.1 (C-5), 125.5 (C-3) ), 115.8 (C-4), 108.0 (Cl) (aromatic) ppm.

Exempel 12 (S) - (-) - 5,6-dimethoxy-N - [(1-ethyl-2-pyrrolidinyl) methyl] -2-hydroxy-3-propylbenzamide. förfarande b

10.0 g (0.027 mol) of (S) - (-) - N - [(1-ethyl-2-pyrrolidinyl) methyl] -3-propyl-2,5,6-trimethoxybenzamide are obtained 16 ml (0.027 mol) of 1.6M HCl-ether in 250 ml of methylene chloride. To a solution of 6.8 g (0.027 mol) of boron tribromide in 50 ml of methylene chloride was added at 10 ° C. The reaction mixture was stirred at 20 ° C for 2 h. 100 ml of 2M NH3 are added. Extraction with 2x300 ml of CH2Cl2, purification (Na2SO4) and addition of a solution of 9.2 g of the component are obtained in a ratio of 4: 1. The mixture was diluted with 300 ml of ether and brine with 2x50 ml of 1N NaOH to give a complete mixture of ether. Torkning and indunstning av lösningsmedlet get 6,0 g of rubricens somorn oijija. GC

5.5 min at 250 ° C (SE-54). Utbyte 63%.

13 C-NMR (CDCl 3) δ 170.2 (CONH), 154.9 (C-2), 146.3 (C-6), 143.6 (C-5), 126.7 (C-3) , 119.9 (C-4), 107.5 (Cl), 62.2 (OCH3), 62.1 (OCH3), 61.2 (C'-2), 57.2, 53.4, 47 .7, 40.5, 32.0, 28.4, 22.6, 14.0, 13.9 (9 koi) ppm.

The oil was poured into 75 ml of acetone. A solution of 2.6 g of L (+) - vinyl in 95 ml of 98% (wattage) acetone is added to give 4.5 g of tartrate salt. Smp. 84-85 ° C.

50 ·>

Exempel 13 (S) - (-) - 2,5-dimethoxy-N - [(1-ethyl-2-pyrrolidinemethyl] -6-hydroxy-3-propylbenzamide.

The alkaline water mixture is dissolved in 50 ml of ether and neutralized with ammonium chloride to a pH of 8.5. Extraction with 2x50 ml of ether gave 1.3 g of each of the isomeric forms as an oil. GC (SE-54, 250 ° C) 6.0 min.

1 H-NMR: (CDCl 3): δ 8.5 (b, NH), 6.77 (s, H-4), 3.86 (s, OCH 3), 3.71 (s, OCH 2), 1, 6-3.9 (m, 15H), 1.13 (t, 3H), 0.98 (t, 3H) ppm.

13 C-NMR: (CDCl 3): δ 170.1 (CONH), 151.8 (C-6), 149.9 (C-2), 145.8 (C-5), 123.9 (C-3) ), 115.8 (C-4), 107.9 (Cl) (aromatic disc) ppm.

Exempel 14 (S) - (-) - N - [(1-allyl-2-pyrrolidinyl) methyl] -3-bromo-2-hydroxy-5,6-dimethoxybenzamide and (S) - (-) - N - [ (1-allyl-2-pyrrolidinedimethyl-3-bromo-6-hydroxy-2,5-dimethoxybenzamide.

The same method is used to exempt (1) - (-) - N - [(1-allyl-2-pyrrolidinyl) methyl] -3-bromo-2,5,6-trimethoxybenzamide to give the title compound. Utbyte 48% färglös oil. [α] D = -62 ° (c = 1.8, acetone).

1 H-NMR: (CDCl 3): δ 9.05 (b, NH), 7.27 (s, H-4), 5.91 (m, vinyl-H), 5.19 (dd, 1H ), 5.12 (d, 1H), 3.92 (s, OCH 3), 3.83 (s, OCH 3), 1.6-3.8 (m, 11H), ppm.

13 C-NMR: (CDCl 3): δ 169.3 (CONH), 153.6 (C-2), 148.0 (C-6), 144.6 (C-5), 135.9 (C-4) ), 122.0 (vinyl-CH), 117.0 (vinyl-CH2), 109.1 (Cl), 105.6 (C-3), 61.5 (CH-2 '), 61.4 ( OCH3-5), 57.2 (OCH2-6), 56.9 (NHCH2), 54.2 (NCH2), 40.6 (CH2-5 '), 28.4 (CH2-3'), 22, Δ (CH 2 - 4 ') ppm.

In this fraction, all components are separated into 2 0 mg of 0.06 g of the desired oil. [α] D = -51 ° C (c = 0.18, acetone).

51 1 H-NMR: (CDCl 3): δ 8.9 (b, NH), 7.07 (9, H-4), 5.90 (m, 1H) , 5.20 (dd, 1H, J = 22¾. 1.5¾). 5.16 (d, 1H, J = 16). 3.87 (s, OCH 2), 3.84 (s, OCH 2), 1.6-3.8 (m, 1H) ppm.

Exempel 15 (R) - (+) - N - [(1-benzyl-2-pyrrolidinyl) methyl] -3-bromo-2-hydroxy-5,6-dimethoxybenzamide and (R) - (+) - N - [ (1-Benzyl-2-pyrrolidin-dimethyl-3-bromo-6-hydroxy-2,5-dimethoxybenzamide. Formula b (R) - (+) - N - [(1-benzyl-2-pyrrolidinyl) methyl] -3- Bromo-2,5,6-trimethoxybenzamide (950 mg, 2.05 mmol) was added to 30 mL of dichloromethane and brine, and a solution of 4M HCl in ether (0.5 mL, 2 mmol) was added over 3.2. ml of 0.65 M boron tribromide in dichloromethane (2.1 mmol) was added dropwise, followed by addition of 30 ml of 0.7M NH3 and further extraction with dichloromethane for 1 h. Addition of the reaction mixture, addition of Et 2 O, addition of a salt solution MgSO 4) and starting from 923 mg (100%) of the isomeric phenol GC (SE 30, capillary column, 270 ° C): Retention solution 10.1 min and 12.4 min (for 3: 7) .

The phenol was separated by genomic flash chromatography on SiO 2 with Et 2 O / MeOH / NH 3 100: 3: 0.3 to give 495 mg (54%) of the title compound.

[α] D 20 = + 94 ° (c = 0.52, acetone).

1 H-NMR (CDCl 3): 7.25 (s, spread over Ph, 4-H), 3.81 and 3.75 (s, (OMe) 2).

Mass spectrum (EI, 70 eV): m / z 449/447 (MH, 0.57 / 0.61%), 261/259 (ArCO, 1.3 / 1.3%), 160 (100%), 91 (51%).

The fraction is separated from each component by separating 0.06 g of the desired rubric with some oil. = + 81 ° C (c = 1.1, acetone).

1 H-NMR (CDCl 3): δ 7.12 (s, 4-H), 3.79 and 3.84 (tvs, (OMe) 2) -

Mass spectrum (EI, 70 eV): m / z 449/447 (MH, 0.31 / 0.33%), 261/259 (ArCO, 0.86 / 0.91%), 160 (100%), 91 (54%).

52

Exempel 16 (S) - (-) - N - [(1-ethyl-2-pyrrolidinyl) methyl] -3,6-dibenzyloxy-2-methoxybenzamide. förfarande a

3,6-Dibenzyloxy-2-methoxybenzoic acid (120 mg; 0.33 mmol), thionyl chloride (120 mg; 1 mmol) and dimethylformamide are added dropwise to the catalyst in 5 ml of toluene for 1.5 h at 60 ° C. ° C. The solution was prepared and treated with CH 2 Cl 2 and treated. To this solution was added 8 mL of CH 2 Cl 2 and the solution was added (S) - (-) - 1-ethyl-2-aminomethylpyrrolidine (65 mg; 0.5 mmol) in 2 mL of CH 2 Cl 2 and then added dropwise. The rum base is treated with 2M HCl and ether. The water is alkalized, extracts with CH 2 Cl 2, pierced (Na 2 SO 4) and treated, colored and ashydrous. Chromatography on SiO 2 with iPR 2 O / hexane / MeOH / NH 3 69: 20: 10: 1 gave 145 mg (93%) of the title compound as an eluent. Sp.

121-123 ° C.

[α] D = -42 ° (c = 2.8, acetone).

1 H-NMR: (CDCl 3): δ 7.39 and 7.38 (t, CH-, Ph). 6.89 and 6.59 (AB, 4 - H and 5-H), 5.06 and 5.03 (tvd s, CH 2 Ph), 3.95 (s, OMe), ppm.

Mass spectrum (EI, 70 eV): m / z 474 (M, 0.13%), 347 (ArCl, 0.33%), 98 (100%), 91 (12%).

Exempel 17 (S) - (-) - [(1-ethyl-2-pyrrolidinyl) methyl] -3,6-dihydroxy-2-methoxybenzamide, form b

The (S) - (-) - [(1-ethyl-2-pyrrolidinyl) methyl] -3,6-dibenzyloxy-2-methoxybenzamide (130 mg; 0.27 mmol), 5% Pd / C ( 50 mg), 0.5 ml of 4M HCl in ether and 5 ml of ethanol in a solid atmosphere. After filtration and addition, 90 mg of the hydrochloride are obtained.

1 H-NMR: (CDCl 3 / CD 3 OD): δ 7.13 and 6.67 (AB, 4-H and 5-H), 3.99 (s, OMe), ppm. Mass spectrum (EI, 70 eV): m / z 294 (M, 0.64%), 167 (ArCO, 1.4%), 98 (100%).

53 r r. r · ^ <-J st Li

Exempel 18

The genome of this method is described by the following methods: (S) - (-) - N - [(1-ethyl-2-pyrrolidinyl) methyl] -2-hydroxy-5,6- dimethoxy-3-methylbenzamide, (S) - (-) - N - [(1-ethyl-2-pyrrolidinyl) methyl] -5-bromo-2,3-dihydroxy-6-methoxybenzamide, (S) - ( -) - N - [(1-ethyl-2-pyrrolidinyl) methyl] -3-ethyl-2,5-dihydroxy-6-methoxybenzamide, (S) - (-) - N - [(1-ethyl- 2-pyrrolidinyl) methyl] -5-amino-3-ethyl-2-hydroxy-6-methoxybenzamide, (S) - {-) - N - [(1-ethyl-2-pyrrolidinyl) methyl] -3 - Bromo-5,6-diethoxy-2-hydroxybenzamide.

Exempel 19 Följande exempel illustrerar framställning av farmaceutiska kompositioner enligt uppfinningen. The entry "Active sub-funds" will be used for the purpose of up-to-date access to the site.

Formulation A. Miuka gelatin capsule 500 g of active substance in a blister pack containing 500 g of a capsule, which is filled with a gelatin capsule, the color of the capsule is 100 mg per blandningen (twice 50 mg of active substance).

Formulation B. Miuka gelatin capsule 500 g of the active substance in a blister containing 750 g of the active ingredient, which is filled with a gelatin capsule, the color of the capsule is 125 mg of the blister (twice 50 mg of the active substance).

Formulation C. Tablet 50 kg The active substance in the mixture contains 20 kg of the active ingredient AEROSIL. 45 kg of potash starch and 50 kg of lactose bleached starch and blanched fuktades med en starch 54 r. — rr - j .- /. L · ·

The granules are pierced and dried, and 2 kg of magnesium stearate are blown in place. Slurry was bleached to give 172 mg of tablets.

Formulation D. Brab blister 100 g of active substance, 140 g of finely divided lemon syrup, 100 g of finely divided sodium carbonate, 3.5 g of magnesium stearate and aromatic medals (q.s.) bleaching and bleaching presses to give a tablet of 100 mg of active substance.

Formulation E. Tablets with the addition of 200 g of active ingredients in the form of tablets with 50 g of stearin-syrup and 50 g of carnauba wax. The size of the bleaching side is reduced to a maximum of 1 mm in diameter. The mixture is bleached with 5 g of magnesium stearate and pressed to give 305 g of tablets. Shadow tablet innehctller contains 200 mg of active substance.

Formulation F. Injection system

Active substance 3,000 mg

Sodium pyrosulfite 0.500 mg

Edetate disodium 0.100 mg

Sodium chloride 8,500 mg

Sterile cotton wool for injection to 1.00 ml

Formulation G. Härda gelatin capsule 10 g of active substance in a mixture of 400 g of lactose and slurry in the form of 2 g of magnesium stearate. The gelatin capsule contains a gelatin capsule, which contains 206 mg of the capsule (twice 5 mg of active substance).

55 i 'r: r r' 3 3 y I. v

Formulation H. Tablet 50 g of active substance in a mixture of 1500 g of lactose, 200 g of microcrystalline cellulose and 10 g of magnesium stearate. Each tablet contains 5 mg of the active ingredient in a formulation containing 176 mg of the active ingredient.

Formula I. Depibrated (S) -N - [(1-ethyl-2-pyrrolidinyl) methyl] -3-bromo-2-hexadecanoyl-5,6-dimethoxybenzamide 200 mg

Jordens add 1 ml

pharmacologist

Inledning

For example, anti-psychotic drugs for neuroleptic drugs may be relayed to other and catecholamine transmissions in the environment and to the nerves to be administered to the central dopamine (DA) receptor block and the cortex. The use of anti-psychotic devices in the field of the DA system is effective. In addition, the antipsychotic network may be blocked by a DA receptor blocker in the subcortical and cortical limbic structures (J.Pharm.Pharmacol. 25, 346, 1973; Lancet, 1027, 1976). Medan de välkända extra-pyramidala biverkningar somewhat frambring of the neuroleptic pendulum is blocked by the DA receptor and the nigro-neostriatal DA system (Intern. J. Neurol. j6, 27-45, 1967).

A. In vivo test For nervous endpoints, the technician is shown in Figure 56. υ Studera DA receptor blockade in vivo. The method is based on antipsychotic pseudomedicts that block the uptake effect of the genomic DA-agonist apomorphine in the genome. In addition, the study of anti-correlation with DA receptor blockade in vivo has shown that apororphic tests and therapeutic networks have been performed with antipsychotic drugs. Apomorphine frambring and the arteries and arteries and the characteristic syndrome are best described by repetition (stereotyping) and hyperactivity, which also results in the activation of the postsynaptic DA receptor in the group (J. Pharm. Pharmacol. 627, 1967; J.

Neurol. Transm. 40, 97-113, 1977). Stereotype (tugg, ning, slickning, bitning) synthesized and interestingly induced by activation of the DA receptor mock-up with the nigro-neostriative DA system (J. Psychiat. Res., Γ1, 1, 1974), Medan den ökade förflyttningen ( hyperactivity) and interestingly, pA activation of the DA receptor in the subcortical fish mesolimbic structure (nucleus olfactorium, nucleus accumbens), dvs. det mesolimbiska DA systemet (J. Pharm. Pharmacol. 25, 1003, 1973).

In this study, neuroleptics have been shown to be structural blockers of the apomorphine stereotype host and have been shown to be blocked to block DA from the genomic biochemical or neurophysiological techniques. There are correlated anti-apomorphic effects in the field of DA in the production of genomic neuroleptic drugs (Eur. J. Pharmacol., 1, 303, 1970), DA receptor binding studies (Life Science, Γ7, 993-1002, 1976) and in other cases. antipsychotic network (Nature, 263, 338-341, 1976).

metoder

Sprague-Dawley-rAttor av procurement (weight 225-275 g) was obtained. RAttorna observerades i PERSPExi ^ -burar (40 (1) x 25 (b) x 30 (h) cm) and up to 5 minutes, 5, 40 and 60 min after apomorphine. For example, 60 minutes for c7 '· "· e

^ 'w ✓ t * O

apomorphine hydrochloride (1 mg / kg), injected subcutaneously (s.c.) into Nacken. Denna dos och administrationsform befanns ge ett mycket consistent weight and mycket liten variation i svaryrkan. Vidare gav apomorphine given s.c. även en mycket consistent hyperactivity.

Omedelbart is then injected placebo into the body and into the skin. Poängsättningen av stereotypierna ut-fördes genom tvA olika metoder. This modification system can be modified with the in-use method of Costall and Naylor (1973). Stereotypiernas styrka poängsattes i en Skala C-3 som feljer:

Poänq Beskrivning av stereotypiskt uppförande 0 Ingen förändring i uppförande i jämförelse med saltlösningskontroller elled sedaterade 1 Vädring med avbrott 2 Kontinuerlig vädring 3 Kontinuerlig vädring. Tuggning, bitning och slickning.

I have found that the system has been shown to increase hyperactivity or apomorphine. Varje grupp bestod av 6-8 djur. Koksaltlösningskontroller ködes alltid vel-tigigt. EDgg is also used for the control system (0-3 Scale) of the reducing styrene stereotype with a 50% observation period of 60 min. ED ^ g for this post-adjustment system is dosed with a reducing agent for which hyperactivity is observed with 50% over the observation period of 60 min. ED ^ g beräknades frän log dos-res-ponskurvor genom metoden med minsta quadraterna frän 4-6 dosniväer med 6-8 djur per dosnivA.

B. In vitro test: Receptor binding assays

The clinical network for antipsychotic medications has a viscosity of 58 r '- j>. - and correlates with a mixture of tritiated spiperones from the dopamine receptor (Seeman, Biochem. Pharmacol. 26, 1741 (1977)).

Metod

The method of Burt et al. (Proc. Nat. Acad. Sci. USA 72, 4655 (1975)). Sprague-Dawley rittor av hankön vägande 150-200 g halshöggs och deras hjärnor avlägsnades snabbt. The strands were mixed, homogenized and homogenized in 50 mM Tris-HCl buffer (pH 7.6). Membrane fractionation was performed by centrifugation of the genome (48,000 g for 10 min) in a buffer with 50 mM Tris-HCl (pH 7.6) containing 0.1% ascorbic acid, 10 mM pargyline, 120 mM NaCl, mM KCl, 2 mM CaCl 2 and 1 mM MgCl 2 · The suspension was preincubated at 37 ° C for 10 min and then added.

Uncertain utilization is limited to cellular utilization. The incubation was carried out in a solid phase, the colors being shaken with a brown membrane suspension (2.5 mg / 0.5 ml), 1 H-spiperone (0.4 nM) and tested in a volume of 0.5 ml. After incubation for 10 min at 37 ° C, the filtrate was dried and then placed on a Whatman GF / B filter with cell culture. The specificity of the binding is defined by the ability to use the ligand but also in the nerves and the fractions of 1 μM M (+) - butaclamol. Test results for the IC50. The IC50 values of Givet i / <M anger den concentration at a minimum of 50% spiperone in the game are determined.

Test results are shown in the table.

59 '' '-

Test in vivo In vitro

Reduction by Reduction by Blocker-sterile hyperactivity ring with ED50 ED50 3H-spiperon-binding _tyfmol / kg i.p.) (y / mol / kg i.p.) IC50 fyuM) For example, a technical point is used:

Br 0CH3

& ConhchJ ^ nJ

2 f 6.5 0.86 1.57 OCH 3 C 2 H 5 (remoxiprid, U.S. Patent 4,232,037)

Cl OH

2.4 0.11 0.026 (for EP 60235) For example:

CH3CH2C ^ JPH

^ [y-CONHCHj-1 ^ J 26.10'2 <10-10 "3 24.10'4 CH3 ° 0CH3 ^ h5

BW) of H

Γ _NV CONHCH ^ -k. ^ J

CH ^ OOCHj i2 „5 4 · ΣΊ0'2 5- '° · 3'« · «· 4 c2h5 oh ^^ C0NHCHfC ^ l 5.8ΊΟ *? 0.7 · 10'3 7ΊΟ * 4 ch3o och3 c2h5 60 ......

'J S l - U

Kcmmentarer_till_testresultäten For example, an uptake of an anti-dopant network is used, which may be used to test the use of a technical device in vivo and in vitro. In this case, the stereotype of the genome of the apomorphine is determined and the test is carried out with a maximum of 50-150 gangs and the test is carried out by a technician. In addition, the ED50 receptor may be used as a blocker for apomorphine frameworks with hyperactivity and the ED50 doser for blocker stereotyping, as well as the selective and mycket selective pA specificity of dopamine neuron. Dessa egenskaper kunde inte förutses frAn egenskaperna hos föreningarna enligt tehnikens stAndpunkt.

In vitro receptor studies have shown that these compounds can be used in vivo for uptake. For example, the use of H-spipers in the H-spiperone for the purpose of determining the level of activity and the activity of the test equipment.

Claims (2)

An intermediate in the preparation of oxy-substituted salicylic derivatives of the following formula R2 Z1 (f 'V-conhch2-L> .W, Z3 z2 ch2r3 in which formula Z1 is OH, OR1 or NH2, Z2 is OR4, Z3 is OH, OR4 or OR1, R2 is a hydrogen atom, a halogen atom, R4 or F3C- (CH2) n-, R3 is a hydrogen atom, R4, a linear or branched hydrocarbon chain containing a double or triple bond and 2-3 carbon atoms, a phenyl or a phenyl substituted in the modified fashion of Mylon dioxide or one or more of the following: tluoro, chloro, bromo, trifluoromethyl, methyl, ethyl, methoxy or ethoxy in ortho, meta or para position, R 1 is alkyl-CO wherein alkylene represents a linear or branched hydrocarbon chain of 1-17 carbon atoms, R4 is an alkyl group of 1-4 carbon atoms, and n is 0, 1 or 2; or salts thereof, characterized in that it has the formula R2 Z1 -nhch, -L., 3 zJ z2 ch2r3 where Ζ2, R2 and R3 are the same as above and Z1 "is OH, OR1 or a suitably protected hydroxyl group, where product Z2 = Z3 = OH, and Z3 "is OH, OR4, OR1 or a suitably protected hydroxyl group, where product Z2 = Z3 = OH, and at least one of Z1" and Z3 "is a suitably protected hydroxyl group. 2. An intermediate in the preparation of oxy-substituted salicyl derivatives according to the preamble of claim 1, characterized in that it has the formula R2 Z1 'V-COOH z3 z2 where Z1, Z2, Z3 and R2 are the same as in claim 1.