JPH0474349B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention provides 4-aryl-4-
Regarding piperidine carbinol. Mental illnesses include both psychoses and neuroses. Symptoms requiring treatment include depression, anxiety, agitation and hallucinations. Drugs specifically used to treat both reactive and endogenous depression include monoamine oxidase (MAO) inhibitors such as iproniazid, tranylcypromine, niaramid, phenelzine and pargyline, and the non-MAO inhibitory tricyclics. aromatic dibenzazepines such as imipramine and dibenzocycloheptenes such as amitriptyline. All of these drugs have adverse side effects that limit their usefulness. Although MAO inhibitors may be useful in milder forms of depression, their use is highly controversial due to the risk of severe toxic effects. They can cause liver damage and acute hypertension, especially when administered with cheese, bananas or other amine-containing foods. MAO inhibitors may also cause tremor, insomnia, hyperhidrosis, agitation, severe manic behavior, confusion, hallucinations, convulsions, and orthostatic hypotension. They often cause dizziness, dizziness, headache, ejaculation inhibition, difficulty urinating, weakness, fatigue, dry mouth, constipation and blurred vision. Imipramine can cause blurred vision, dry mouth, constipated urine retention, orthostatic hypotension, respiratory depression, myocardial infarction, and congestive heart palsy. Similar difficulties are experienced with amitriptyline. There continues to be a need for psychotherapeutic agents that have fewer side effects than currently used drugs, and also have a mode of action that is different from currently used drugs. This is because none of these can be said to be completely effective. British Patent No. 888657 and Canadian Patent No.
No. 1079734 discloses formulas useful as analgesics and cough suppressants. where X is phenyl, Y is hydroxymethyl, 1-hydroxyethyl or 1-hydroxypropyl, alk is alkylene with up to 6 carbon atoms, and R contains oxygen or nitrogen. piperidine carbinols of the heterocyclic group tetrahydrofurfuryloxyethyl, aryl, aryloxy, aralkoxy, alkoxy having up to 6 carbon atoms or alkoxy substituted by hydroxy, ethoxy or phenoxy are disclosed. . Compounds of such structure, where Y is alkanoyl and the other substituents are similarly defined, are also known from GB 841,120. “Helvetica Chimica Acta” Volume No.
2489 (1949) discloses the synthesis of various analgesics, and the formula (wherein _R2 is methyl or n-propyl) are disclosed. "J.Chem.Soc.(C)" page 1074 (1970) Compounds have been disclosed. The present invention is based on the formula However, in the formula, a) R ¹ is hydrogen, alkyl having 1 to 12 carbon atoms, cycloalkyl or benzyl having 3 to 8 carbon atoms, and b)
R ² and R ³ are each independently hydrogen and 1-
selected from lower alkyl having 4 carbon atoms, R ¹ and R ² together being a branched or unbranched alkylene bridge (the alkylene bridge having 3 or 4 carbon atoms) or R ² and R ³ together form a branched or unbranched alkylene bridge (the alkylene bridge may contain 3 to 6
c) R ⁴ is 1)
phenyl or 2-naphthyl or the same or different fluorine, chlorine, alkyl, perfluoroalkyl, alkoxy, aryloxy, alkylthio, arylthio, perfluoroalkoxy, perfluoroalkylthio and dialkylamino, the alkyl and alkoxy moieties of which are 1-
phenyl or 2-naphthyl substituted with one or two substituents selected from 12 carbon atoms and whose aryl part has 6 to 12 carbon atoms, 2) 2) -, 3- or 4-
biphenylyl or one or both aromatic moieties are the same or different and fluorine, chlorine, alkyl, perfluoroalkyl, alkoxy, aryloxy, alkylthio, arylthio, perfluoroalkoxy, perfluoroalkylthio and dialkylamino (those alkyl and alkoxy moieties are 2-, 3- or 4 substituted with 1 or 2 substituents selected from 1 to 12 carbon atoms and whose aryl part has 6 to 12 carbon atoms) -diphenylyl, 3)
2-pyrrolyl or 2-pyrrolyl substituted with 1 to 3 lower alkyl groups having 1 to 4 carbon atoms, 4) 2-, 3- or 4-pyridyl, or 5) 1- to 2-thienyl substituted with lower alkyl having 4 carbon atoms, and d) R ⁵ and R ⁶ are each independently 1-12
selected from alkyl containing 3 to 8 carbon atoms and cycloalkyl containing 3 to 8 carbon atoms, or R ⁵ and R ⁶ together are branched or unbranched alkylene bridges (the alkylene bridge contains 3 to 11 carbon atoms), provided that R ¹ , R ⁵ and R ⁶ are methyl and R ² and R ³ are hydrogen, then R ⁴ is p- tertiary butylphenyl or
4-aryl-4-piperidine carbinol (not 2'-biphenylyl). The present invention also relates to esters of the piperidine carbinols described above and aliphatic mono- and dicarboxylic acids having from 1 to 8 carbon atoms, amino salts of the piperidine carbinols described above and pharmaceutically compatible inorganic acids, and N-oxide of piperidine carbinol. The 4-aryl-4-piperidine carbinol of the present invention can be produced by a series of reactions performed in the following order. i.e. 1) R ⁴
Br is lithiated with n-butyllithium to form R ⁴ Li
and then convert it into the expression (wherein R ¹ , R ² , R ³ and R ⁴ are as defined above) with piperidinone. and dehydrate 2) to obtain a mixture of olefins.

[expression] and

3) is lithiated with n-butyllithium and then reacted with the ketone R ⁵ COR ⁶ where R ⁵ and R ⁶ are as defined above. Oxazabicyclooctane

[expression] and/or

[Formula] is generated, and 4) is reduced to generate . Alternatively, after lithiation of the ester R ⁵ COOR ⁷ where R ⁵ is as defined above and R ⁷ is lower alkyl having 1 to 4 carbon atoms. react with ketone

[expression] and/or

[Formula] and then convert it to R ⁶ Li or R ⁶ MgX, where R ⁶ is as defined above,
and X is chlorine, bromine or iodine) to produce. Obviously, this alternative cannot be used when R ⁵ and R ⁶ together represent alkylene. The reactions described above are described in more detail below. The above summary should not be construed as limiting the invention. 1 is manufactured as follows. ^R4
Lithiation of Br is carried out in an ethereal solvent such as diethyl ether or tetrahydrofuran.
It can be carried out at 100°C to 50°C. Commonly used known lithiation agents include, for example, n-butyllithium, methyllithium, and secondary and tertiary butyllithium. As is known in the art, a magnesium (Grinnard) reagent can be used in place of the alkyllithium compound, in which case the resulting intermediate is an organomagnesium compound. Also, as is known in the art and disclosed, for example, in Organic Reactions, Volume 26, certain compounds R ⁴ H, where R ⁴ is as defined above, Intermediate R ⁴
It can be lithiated directly rather than via Br. Tetramethylethylenediamine can be used with alkyllithium compounds. Compounds that are so directly lithiated include alkoxybenzenes (in which case the lithiation occurs in the ortho position to the alkoxy substituent) and pyrrole and 5-alkylthiophene (in which case the lithiation occurs in the 2-position). (occurs in). In the second step of the preparation, the organolithium or organomagnesium compound is prepared either without solvent or in an ethereal solvent such as diethyl ether or tetrahydrofuran at -70°C.
React with piperidinone above at ~50°C. 2 is manufactured as follows. The reaction to dehydrate is carried out in the presence of a catalyst such as hydrochloric acid, hydrobromic acid, methanesulfonic acid/phosphorous pentoxide, trifluoroacetic acid or an arylsulfonic acid, in a solvent such as an aromatic hydrocarbon, or in the presence of a solvent such as an aromatic hydrocarbon. Can be done in the absence. Depending on the nature of the substituents R ¹ , R ² , R ³ and R ⁴ , dehydration can be carried out at any suitable temperature within the range of 0°C to 200°C. After dehydration, the acid catalyst is neutralized to convert the amine salt to the free amine. 3 is manufactured as follows. The compound can be metallized as described above for the production of. Lithiation is carried out in the absence of oxygen and water at -70°C to 70°C, preferably -
It can be carried out at 10°C to -20°C. The metal salt in solution thus produced is dissolved in an ethereal solvent such as diethyl ether or tetrahydrofuran at -100°C to 50°C with the above ketone R ⁵ COR ⁶
can be reacted with. The resulting lithium or magnesium salt is hydrolyzed to obtain . 4 is manufactured as follows. By reducing , we get . The reduction can be carried out using borohydride reagents such as sodium borohydride in alcohol or sodium cyanoborohydride in alcohol/acetic acid mixtures, or by catalytic hydrogenation such as palladium in the presence of mineral acids in acetic acid or alcoholic solvents. This can be done using a catalyst. An alternative method to the above involves reacting the metallized in solution with the ester R ⁵ COOR ⁷ to form R ⁶ Li or R ⁶ at −20°C to 50°C in an ethereal solvent.
React with MgX. The resulting lithium or magnesium salt is hydrolyzed to obtain . In any of the above methods, the compounds of the invention have a piperidine moiety, but the N-substituent may be benzyl in place of R ¹ , in which case the final product is but with the proviso that N-
The substituent is benzyl in place of R ¹ . The N benzylated product is an important intermediate and can be prepared by catalytic hydrolysis using palladium solvent in acetic acid solvent to prepare secondary amines i.e.
When R ¹ is hydrogen, it can be converted to: Secondary amines can be alkylated with a suitable alkyl or cycloalkyl halide, where R ¹ is an alkyl having 1 to 12 carbon atoms or a cycloalkyl halide having 3 to 8 carbon atoms. alkyl) is produced. R ¹
Some of the groups can be introduced in another way, namely by first acylating the secondary amine with an acyl chloride, the acyl group of which corresponds to the desired R ¹ group upon reduction. The amide formed by the acylation can be reduced with a hydride reducing agent such as borane or lithium aluminum hydride to provide the desired amine. Pharmacologically acceptable acids such as hydrochloric acid, sulfuric acid,
Suitable salts with phosphoric and maleic acids can be prepared from all free bases. Such salts are preferred when the free base is an oil. Salts of bases will also be more stable on storage than the free base and will be better absorbed orally. In the following examples all temperatures are expressed in degrees Celsius (°C). Table 1 summarizes the compounds produced in the Examples. In that table, Me is methyl, Et is ethyl,
Ph is phenyl, _PhCH2 is benzyl,
and Cp is cyclopentyl.

【table】

Table IA further shows preferred compounds of the invention, but these compounds are not described in the Examples herein.

[Table] Example 1 4-phenyl-α,α-1-trimethyl-4-
Piperidine methanol n-butyllithium (1.5M solution in hexane 15
ml) in 50 ml of tetrahydrofuran under nitrogen, commercially available 1-methyl-4-phenyl-1,
2,3,6-tetrahydropyridine (, R ¹ =
Me, R ² , R ³ = H, R ⁴ = phenyl) 4.7 g of −10°
Add to the solution held in. This deep red solution is stirred at -10° for 15 minutes and then poured slowly into a stirred mixture of 15 ml of acetone and 25 ml of tetrahydrofuran held at -70°. 5 at -70°
After stirring for a minute, add excess 10% hydrochloric acid. The mixture is allowed to warm up to room temperature and then washed with toluene. The aqueous layer is made basic with sodium hydroxide and extracted with methylene chloride. The solvent was removed from this dried solution, and the residue was subjected to short-path distillation [bath temperature 90-135°, 5 × 10 ^-4 mmHg].
(0.07Pa)], 5-phenyl-2,6,6-
Trimethyl-7-oxa-2-azabicyclo[3,2,1]octane (, R ¹ , R ⁵ , R ⁶ =Me,
R ² , R ³ = H, R ⁴ = phenyl) 2.79g has a purity of approximately 85
% oil. A solution of 1.47 g of the above product in a mixture of 10 ml of methanol and 2 ml of acetic acid is ice-cooled and treated with 0.76 g of sodium cyanoborohydride. The mixture is stirred at room temperature for 2 hours and the excess borohydride is destroyed by adding 8 ml of concentrated hydrochloric acid with ice cooling. After stirring for 0.5 h at room temperature, the mixture is made basic using aqueous sodium hydroxide solution and extracted with methylene chloride.
Removal of the solvent from the dried solution and crystallization of the residue from ethyl acetate yielded 4-phenyl-
0.98 g of α,α,1-trimethyl-4-piperidine methanol (mp 146-147°) is obtained. NMR
(in 220 MHz CDCl ₃ ): τ2.7~2.8 (m, 5H), 7.0
~8.2 (m, 9H), 8.0 (s, 3H) and 8.9 (s,
6H). Elemental analysis (as C ₁₅ H ₂₃ NO) C H N calculated value: 77.21 9.94 6.00 Actual value: 77.12 9.89 6.00 Example 2 4-(3'-trifluoromethylphenyl)-α,
α,1-Trimethyl-4-piperidine methanol and its hydrochloride A 1.5 M solution (150 ml) of n-butyllithium in hexane was heated under nitrogen at −70° with 300 ml of tetrahydrofuran.
Add to a stirred solution of 50 g of 3-bromobenzotrifluoride in ml. The mixture is stirred at -70° for 15 minutes and then allowed to warm to -20°. 1 freshly distilled in 50 ml of tetrahydrofuran
- A solution of 30 g of methyl-4-piperidone is slowly added while maintaining the temperature at -20°. The mixture is then stirred for 0.5 hours at 0° and for 3 hours at room temperature. Water and methylene chloride are added and the aqueous layer is extracted several times with methylene chloride. The solvent was removed from the combined and dried methylene chloride solutions and the residue was subjected to short-circuit distillation [bath temperature 110~
130°, 5×10 ^-4 mmHg (0.07 Pa)], 1-methyl-4-(3'-trifluoromethylphenyl)-
4-Piperidinol (, R ¹ = Me, R ² , R ³ =
H, R ⁴ = m-trifluoromethylphenyl) 41.6
g is obtained as a solid content. 28.1 g of this product and trifluoroacetic acid
Heat 100 ml of the mixture to reflux for 24 hours. Excess acid is removed under vacuum, the residue is dissolved in methylene chloride, and the solution is made basic with 10% aqueous sodium carbonate solution. The solvent is removed from the dried organic phase and the residue is subjected to short path distillation to give 1-
Methyl-4-(3'-trifluoromethylphenyl)
-1,2,3,6-tetrahydropyridine (
24.06 g of a, ^R1 =Me, ^R2 , ^R3 =H, ^R4 =m-trifluoromethylphenyl) are obtained. To a solution of this product a in 150 ml of tetrahydrofuran are added 80 ml of a 1.5 M solution of n-butyllithium in hexane at -10°. This red solution at −10°
Stir for 15 minutes and then slowly pour into a stirred mixture of 60 ml acetone and 60 ml tetrahydrofuran held at -20°. The mixture is allowed to warm up to 10° and then treated with 10% aqueous sodium chloride solution. The layers are separated and the aqueous phase is extracted repeatedly with methylene chloride. Removal of the solvent from the combined and dried organic phases yields the crude 5
-(3'-trifluoromethylphenyl)-2,6,
6-trimethyl-7-oxa-2-azabicyclo[3,2,1]octane (, R ¹ , R ⁵ , R ⁶ =Me,
34.35 g of R ² , R ³ =H, R ⁴ =m-trifluoromethylphenyl) are obtained. Dissolve this product in a mixture of 150 ml methanol and 25 ml acetic acid,
The ice-cooled solution is then treated with 9 g of sodium cyanoborohydride. After stirring at room temperature for 2 hours and standing for an additional 0.5 hours, concentrated hydrochloric acid (50 ml) was added.
is added, the mixture is made basic with aqueous sodium hydroxide solution and extracted with methylene chloride. Removal of the solvent from the dried organic phase gives 31.74 g of product, which is partitioned between dilute hydrochloric acid and ether/toluene. The aqueous layer is made basic again and then extracted with methylene chloride to produce the product.
27.40g is obtained. Short path distillation [bath temperature up to 210°,
10 ^-3 mmHg (0.1 Pa)] and the distillate was crystallized from cyclohexane to yield 7.59 g of 4-(3'-trifluoromethylphenyl)-α,α,1-trimethyl-4-piperidinemethanol. (mp111
~112°) is obtained. NMR (90MHz, CDCl ₃
Medium): τ2.3 to 2.6 (m, 4H), 7.1 to 8.3 (m, 9H),
7.8 (s, 3H) and 8.8 (s, 6H), 19F NMR
(in CDCl ₃ ): Singlet at −63.02 ppm from CFCl ₃ . The hydrochloride salt (denoted as Example 2A in Table 2) has a mp of 240-241° after crystallization from isopropyl alcohol. Elemental analysis (as C ₁₆ H ₂₃ ClF ₃ NO) C H N calculated value: 56.89 6.86 4.15 Actual value: 57.03 6.78 4.07 Example 3 1-[1′-Methyl-4′-(2″,3″-dimethoxyf) enyl)-4'-piperidinyl]cyclopentanol Veratrol in 400 ml of anhydrous tetrahydrofuran
Cool 138 g of the solution in a dry ice/acetone bath and add 500 g of a 1.6 M solution of n-butyllithium at such a rate that the temperature of the reaction mixture is maintained at 0°.
Process using ml. After the addition is complete, the reaction mixture is stirred at room temperature for 3 hours. The white slurry that forms at the end of this period is cooled in a dry ice/acetone bath and the temperature of the reaction mixture is reduced to -10°.
Add 90.4 g of 1-methyl-4-piperidone at a rate such that: After the addition is complete, the reaction mixture is stirred at 0° C. for 2 hours, quenched with 400 ml of water and diluted with 400 ml of ether. The organic layer was separated and the aqueous layer was treated with methylene chloride (3x
Extract with 400ml). The combined organic layers were dried (potassium carbonate) and concentrated under reduced pressure to an oil.
270.9g is obtained. This oil is heated under reduced pressure to remove all materials boiling below 150°/0.025 mm Hg (3.3 Pa). The residue (97.55 g) was the desired 4-(2',3'-dimethoxyphenyl)-1-
Methyl-4-piperidinol (, R ¹ = Me,
R ² , R ³ = H, R ⁴ = 2,3-dimethoxyphenyl)
contains, which is used in the next step without further purification. A solution of 79.49 g of this product in 238 ml of concentrated hydrochloric acid
Heat at 65° for 3 hours. At the end of this period the reaction mixture is cooled to room temperature, made basic with 20% aqueous sodium hydroxide solution and extracted with methylene chloride (3 x 200 ml). The combined organic layers are dried (potassium carbonate) and concentrated under reduced pressure. The product thus obtained was distilled under reduced pressure to give 4-(2',3'-dimethoxyphenyl)-1
-Methyl-1,2,3,6-tetrahydropyridine (a: R ¹ = Me, R ² , R ³ = H, R ⁴ = 2,3
-dimethoxyphenyl) is obtained as a colorless oil. bp100~120°/0.05mmHg (7Pa), 73.56g
(yield 84.8%). 4.7 g of this product in 50 ml of tetrahydrofuran
is treated with n-butyllithium as described in Example 1 and the solution of the lithium salt is added at -70° to a mixture of 20 ml of cyclopentanone and 30 ml of tetrahydrofuran. Example 1
and crystallization of the crude product from ethyl acetate yielded 2'-methyl-5'-
(2″,3″-dimethoxyphenyl)spiro[cyclopentane-1,6′-[7]-oxy[2]azabicyclo[3,2,1]octane (:R ¹ =Me,
R ² , R ³ = H, R ⁴ = 2,3-dimethoxyphenyl,
R ⁵ , R ⁶ = (CH ₂ ) ₄ ) 3.29 g (mp 110°) is obtained. Elemental Analysis (as C ₁₉ H ₂₇ NO ₃ ) C H N Calculated: 71.89 8.57 4.41 Found: 72.24 8.45 4.52 Immediate reduction of the above product with sodium cyanoborohydride as described in Example 1 1-[1'-Methyl-4'-(2'',3''-dimethoxyphenyl)-4'-piperidinyl]cyclopentanol (mp 114-115°) is obtained. Elemental analysis (as C ₁₉ H ₂₉ NO ₃ ) C H N calculated value: 71.44 9.15 4.38 Actual value: 71.49 9.01 4.41 Example 4 4-(3'-fluorophenyl)-α,α,1-trimethyl-4- Piperidine methanol 4-(3'-fluorophenyl)-α,α,1-trimethyl-4-piperidine methanol is Example 2
is prepared from 3-bromofluorobenzene by the procedure described in . mp158~159°. NMR
(in CDCl ₃ ): τ2.5~3.2 (m, 4H), 7.2~8.3 (m,
12H) and 8.8(s, 6H). 19F NMR (CDCl ₃
(Middle): Singlet at -117.4 ppm from CFCl ₃ (after H-decoupling). Elemental analysis (as C ₁₅ H ₂₂ FNO) C H N calculated value: 71.68 8.82 5.57 Actual value: 71.68 8.77 5.69 Example 5 4-(4'-fluorophenyl)-α,α,1-trimethyl-4-piperidine Methanol 4-(4′-fluorophenyl)-α,α,1-trimethyl-4-piperidine methanol is Example 2
It is prepared from 4-bromofluorobenzene by the procedure described in . mp165~166°. NMR
(in CDCl ₃ ): τ2.6~3.1 (m, 4H), 7.2~8.7 (m,
12H) and 8.9(s, 6H). 19F NMR (CDCl ₃
(Middle): Singlet at -117.6 ppm from CFCl ₃ (after H-decoupling). Elemental analysis (as C ₁₅ H ₂₂ FNO) C H N calculated value: 71.68 8.82 5.57 Actual value: 71.26 8.70 5.67 Example 6 4-(3'-chlorophenyl)-α,α,1-trimethyl-4-piperidinemethanol 4 -(3'-Chlorophenyl)-α,α,1-trimethyl-4-piperidinemethanol is prepared from 3-bromofluorobenzene (mp 149-150°) using the procedure described in Example 2. NMR
(in CDCl ₃ ), τ2.6~2.8 (m, 4H) 7.1~8.3 (m,
12H) and 8.8(s, 6H). Elemental analysis (as C ₁₅ H ₂₂ ClNO) C H N calculated value: 67.28 8.28 5.23 Actual value: 67.34 8.15 5.24 Example 7 4-(4'-chlorophenyl)-α,α,1-trimethyl-4-piperidinemethanol 4 -(4'-chlorophenyl)-α,α,1-trimethyl-4-piperidinemethanol is prepared from 4-bromofluorobenzene using the procedure described in Example 2. mp192~194°. Elemental analysis (as C ₁₅ H ₂₂ ClNO) C H N calculated value: 67.28 8.28 5.23 Actual value: 67.34 8.13 5.25 Example 8 4-(3'-chlorophenyl)-α,α-diethyl-1-methyl-4-piperidine Methanol and its hydrochloride 4-(3'-chlorophenyl)-α,α-diethyl-1-methyl-4-piperidine Methanol was prepared according to the procedure described in Example 2, except that diethyl ketone was used instead of acetone in the preparation. (3
-pentanone) from 3-bromochlorobenzene. Convert the free base to the hydrochloride salt. It has a mp of 249-250° (decomposed) after crystallization from ethanol. NMR
(during CDCl ₃ ): τ2.6 (m, 4H), 6.3~8.0 (m, 12H)
,
8.3-8.6 (quartet, 4H) and 9.2 (t, 6H). Elemental analysis (as C ₁₇ H ₂₇ Cl ₂ NO) C H N calculated value: 61.44 8.19 4.21 Actual value: 61.19 8.19 4.19 Example 9 4-(2'-tolyl)-α,α,1-trimethyl-
4-piperidinemethanol 4-(2'-tolyl)-α,α,1-trimethyl-
4-Piperidinemethanol is prepared from 2-bromotoluene by the procedure described in Example 2. mp104~105. NMR (in CDCl ₃ ): τ2.5~3.0
(m, 4H), 7.0-8.3 (m, 15H) and 8.9 (s,
6H). Elemental analysis (as C ₁₆ H ₂₅ NO) C H N calculated value: 77.68 10.19 5.66 Actual value: 77.69 10.19 5.76 Example 10 4-(3'-tolyl)-α,α,1-trimethyl-
4-piperidinemethanol 4-(3'-tolyl)-α,α,1-trimethyl-
4-Piperidinemethanol is prepared from 3-bromotoluene by the procedure described in Example 2. mp139~140°, NMR (in CDCl ₃ ): τ2.6~3.1
(m, 4H), 7.2-8.5 (m, 15H) and 8.9 (s,
6H). Elemental analysis (as C ₁₆ H ₂₅ NO) C H N calculated value: 77.68 10.19 5.66 Actual value: 77.68 10.12 5.83 Example 11 4-(4′-tolyl)-α,α,1-trimethyl-
4-piperidinemethanol 4-(4'-tolyl)-α,α,1-trimethyl-
4-Piperidinemethanol is prepared from 4-bromotoluene by the procedure described in Example 2. mp172~174°, NMR (in CDCl ₃ ): τ2.6~3.0
(m, 4H), 7.2-8.5 (m, 15H) and 8.9 (s,
6H). Elemental analysis (as C ₁₆ H ₂₅ NO) C H N calculated value: 77.68 10.19 5.66 Actual value: 77.80 10.23 5.67 Example 12 4-(5'-m-xylyl)-α,α,1-trimethyl-4-piperidine Methanol 4-(5'-m-xylyl)-α,α,1-trimethyl-4-piperidinemethanol is prepared from 5-bromo-m-xylene by the procedure described in Example 2. mp123~125°, NMR (CDCl ₃
middle): τ3.0-3.2 (m, 3H), 7.2-8.6 (m, 18H) and 8.9 (s, 6H). Elemental analysis (as C ₁₇ H ₂₇ NO) C H N calculated value: 78.11 10.41 5.36 Actual value: 78.21 10.19 5.48 Example 13 4-(4′-o-xylyl)-α,α,1-trimethyl-4-piperidine Methanol 4-(4'-o-xylyl)-α,α,1-trimethyl-4-piperidinemethanol is prepared from 4-bromo-o-xylene by the procedure described in Example 2. mp127~128°, NMR (CDCl ₃
middle): τ2.8-3.1 (m, 3H), 7.2-8.3 (m, 18H) and 8.9 (s, 6H). Elemental analysis (as C ₁₇ H ₂₇ NO) C H N calculated value: 78.11 10.41 5.36 Actual value: 78.43 10.11 5.40 Example 14 4-(3'-methoxyphenyl)-α,α-dimethyl-4-piperidinemethanol and Its hydrochloride 1-benzyl-4-(3'-methoxyphenyl)-
α,α-Dimethyl-4-piperidine methanol was prepared by the procedure described in Example 2, but by using 1-benzyl-4-piperidone in place of 1-methyl-4-piperidone in the first step. - Manufactured from bromoanisole. This product (2.90 g) is dissolved in 20 ml of acetic acid, 0.49 g of 10% palladium on carbon is added, and the mixture is stirred for 25 hours under a stream of hydrogen. The mixture is filtered, concentrated, made basic, and extracted with methylene chloride to yield the crude free base (,
R ¹ , R ² , R ³ = H, R ⁴ = m-MeOC ₆ H ₄ , R ⁵ , R ⁶
=Me) 1.88g is obtained. Convert it to hydrochloride. After it is crystallized from acetonitrile
Has mp232-233° (decomposition). NMR ( _D2O
Medium): τ2.6~3.3 (m, 4H), 6.3 (s, 3H), 6.6~
8.3 (m, 9H) and 9.0 (s, 6H). Elemental analysis (as C ₁₅ H ₂₄ ClNO ₂ ) C H N calculated value: 63.04 8.46 4.90 Actual value: 63.19 8.41 4.87 Example 15 4-(2'-methoxyphenyl)-α,α,1-trimethyl-4- Piperidine methanol 4-(2'-methoxyphenyl)-α,α,1-trimethyl-4-piperidine methanol is Example 3
is prepared from anisole by substituting acetone for cyclopentanone in its preparation according to the procedure described in . m.
p.110~111°, NMR (in CDCl ₃ ): τ2.6~3.1 (m,
4H), 6.2 (s, 3H), 6.7-8.5 (m, 9H), 7.9 (s,
3H) and 8.9 (broad s, 6H). Elemental analysis (as C ₁₆ H ₂₅ NO ₂ ) C H N calculated value: 72.96 9.57 5.32 Actual value: 73.02 9.56 5.41 Example 16 4-(3'-methoxyphenyl)-α,α,1-trimethyl-4- Piperidine methanol 4-(3'-methoxyphenyl)-α,α,1-trimethyl-4-piperidine methanol is Example 2
is prepared from 3-bromoanisole by the procedure described in . mp100°, NMR (in CDCl ₃ ): τ2.6
~3.3 (m, 4H), 6.1 (s, 3H), 7.1~8.3 (m,
12H), 8.9(s, 6H). Elemental analysis (as C ₁₆ H ₂₅ NO ₂ ) C H N calculated value: 72.96 9.57 5.32 Actual value: 72.52 9.42 5.29 Example 17 4-(3'-methoxyphenyl)-α,1-dimethyl-α-ethyl- 4-Piperidinemethanol 4-(3'-Methoxyphenyl)-α,1-dimethyl-α-ethyl-4-piperidinemethanol was prepared by the procedure described in Example 2, except that methyl ethyl ketone was used instead of acetone in the preparation. (2-butanone) from 3-bromoanisole. mp134~135°,
NMR (in CDCl ₃ ): τ2.6~3.3 (m, 4H), 6.2 (s,
3H), 7.2-8.3 (m, 12H), 8.6 (quartet, 2H),
9.0 (s, 3H) and 9.2 (t, 3H). Elemental analysis (as C ₁₇ H ₂₇ NO ₂ ) C H N calculated value: 73.61 9.81 5.05 Actual value: 73.73 9.69 5.17 Example 18 4-(3'-methoxyphenyl)-α,α-diethyl-1-methyl- 4-Piperidinemethanol and its hydrochloride 4-(3'-methoxyphenyl)-α,α-diethyl-1-methyl-4-piperidinemethanol was prepared by the procedure described in Example 2, except that acetone was used in the preparation. is prepared from 3-bromoanisole by using diethyl ketone instead of 3-bromoanisole. The product is converted to the hydrochloride salt. It has a mp 197-198° (decomposition) after crystallization from isopropyl alcohol. NMR (CDCl ₃
Medium): τ2 (wide s, 1H), 2.5-3.2 (m, 4H),
6.1 (s, 3H), 6.3-8.6 (m, 16H), and 9.2
(t, 6H). Elemental analysis (as C ₁₈ H ₃₀ ClNO ₂ ) C H N calculated value: 65.93 9.22 4.27 Actual value: 65.91 9.14 4.72 Example 19 4-(4'-methoxyphenyl)-α,α,1-trimethyl-4- Piperidine methanol 4-(4'-methoxyphenyl)-α,α,1-trimethyl-4-piperidine methanol is Example 2
is prepared from 4-bromoanisole by the procedure described in . mp114~115°, NMR (CDCl ₃
Medium): τ2.6~3.2 (m, 4H), 6.2 (s, 3H), 7.2~
8.5 (m, 12H) and 8.9 (s, 6H). Elemental analysis (as C ₁₆ H ₂₅ NO ₂ ) C H N calculated value: 72.96 9.57 5.32 Actual value: 72.63 9.47 5.39 Example 20 4-(2',3'-dimethoxyphenyl)-α, α,
1-trimethyl-4-piperidinemethanol 4-(2',3'-dimethoxyphenyl)-α,α,
1-Trimethyl-4-piperidinemethanol is prepared according to the procedure described in Example 3, but using acetone instead of cyclopentanone in the preparation. mp97°,
NMR (in CDCl ₃ ): τ2.9~3.3 (m, 3H), 6.2 (2s,
6H), 6.7-8.5 (12H) and 8.9 (broad, 6H). Elemental analysis (as C ₁₇ H ₂₇ NO ₃ ) C H N calculated value: 69.59 9.28 4.77 Actual value: 69.93 9.17 4.81 Example 21 4-(4'-methylthiophenyl)-α, α, 1-
Trimethyl-4-piperidinemethanol 4-(4'-methylthiophenyl)-α,α,1-
Trimethyl-4-piperidinemethanol is prepared from 4-bromothioanisole by the procedure described in Example 2. mp132~133°, NMR
(in CDCl ₃ ): τ2.7 (s, 4H), 7.2~8.5 (m+2s,
15H) and 8.9(s, 6H). Elemental analysis (as C ₁₆ H ₂₅ NOS) C H N calculated value: 68.77 9.02 5.01 Actual value: 68.82 8.93 5.12 Example 22 1-[1′-Methyl-4′-(3″-methoxyphenyl)
-4′-piperidinyl]-cyclobutanol 1-[1′-methyl-4′-(3″-methoxyphenyl)
-4'-Piperidinyl]-cyclobutanol is prepared from 3-bromoanisole by the procedure described in Example 2, but substituting cyclobutanone for acetone in the preparation. mp105°, NMR (in 360MHz CDCl ₃ ): τ2.5
(t, 1H), 3.1 (d, further split, 1H) 3.1
(t, 1H), 3.2 (d/d, 1H), 6.2 (s, 3H), 7.8
(s, 3H) and 7.2-8.8 (m, 15). Example 23 1-[1′-Methyl-4′-(2″,3″-dimethoxyphenyl)-4′-piperidinyl]cyclohexanol 1-[1′-Methyl-4′-(2″,3″) -dimethoxyphenyl)-4'-piperidinyl]cyclohexanol is prepared by the procedure described in Example 3, but using cyclohexanone in place of cyclopentanone in the synthesis. mp121~123°, NMR (in CDCl ₃ ): τ3.1 (t,
1H), 3.2 (m, 2H), 6.2 (2s, 6H), 7.0~7.3 (m,
4H), 7.7-9.1 (15H) and 7.9 (s, 3H). Elemental analysis (as C ₂₀ H ₃₁ NO ₃ ) C H N calculated value: 72.03 9.37 4.20 Actual value: 71.58 9.22 4.48 Example 24 4-(1'-Methyl-2'-pyrroline)-α, α, 1
-Trimethyl-4-piperidinemethanol 4-(1'-methyl-2'-pyrroline)-α,α,1
-Trimethyl-4-piperidinemethanol is prepared by the procedure described in Example 3, but using 1-methylpyrrole instead of veratrol in the preparation and acetone instead of cyclopentanone in the preparation of be done. mp110~111°, NMR (in CDCl ₃ ): τ3.5
(m, 1H), 4.0 (m, 2H), 6.2 (s, 3H), 7.1~
8.5 (m, 12H) and 8.8 (s, 6H). Example 25 4-(5'-methyl-2'-thienyl)-α,α,1
-Trimethyl-4-piperidinemethanol 4-(5'-methyl-2'-thienyl)-α,α,1
-trimethyl-4-piperidinemethanol according to the procedure described in Example 3, but using 2-methylthiophene instead of veratrol in the preparation and acetone instead of cyclopentanone in the preparation of Manufactured by. mp113~114°, NMR
(in 360MHz CDCl ₃ ): τ3.35 (AB quartet, J=
3.5Hz, low field compound splits into quartets, J=
0.7Hz, 2H), 7,3 (m, 2H), 7.5 (d, J=
0.7Hz, 3H), 7.8 (s, 3H), 8.0 (m, 6H), 8.4
(wide s, 1H) and 8.8 (s, 6H). Example 26 4-(3′-pyridyl)-α,α,1-trimethyl-4-piperidinemethanol 4-(3′-pyridyl)-α,α,1-trimethyl-4-piperidinemethanol was prepared as in Example 2. It is prepared from 3-bromopyridine by the procedure described, except that the carbinol is dehydrated by heating to 180° with trifluoroacetic acid instead of refluxing. mp131~133°, NMR
(in 360MHz CDCl ₃ ): τ1.4 (d, J = 2.5Hz,
1H), 1.5 (d/d, J=4.5/1.5Hz, 1H), 2.3
(d/t, J=8.5/2Hz, 1H), 2.7(d/d, J
=8.5/4.5Hz, 1H), 7.2(d, further split,
2H), 7.6 (d, 2H), 7.8-7.9 (m+s, 5H), 8.1
(wide s, 1H) and 8.8 (s, 6H). Example 27 1-[1′-methyl-4′-(3″-methoxyphenyl)
-4′-piperidinyl]cycloheptanol 1-[1′-methyl-4′-(3″-methoxyphenyl)
-4'-piperidinyl]cycloheptanol is prepared from 3-bromoanisole by the procedure described in Example 2, but substituting cycloheptanone for acetone in the preparation. mp139~140°, NMR (in CDCl ₃ ):
τ2.6~3.3 (m, 4H), 6.2 (s, 3H) and 7.2~
9.0 (m+s, 24H). Elemental analysis (as C ₂₀ H ₃₁ NO ₂ ) C H N calculated value: 75.67 9.84 4.41 Actual value: 76.23 9.64 4.28 Example 28 1-[1′-Methyl-4′-(3″-methoxyphenyl)
-4′-piperidinyl]cyclooctanol 1-[1′-methyl-4′-(3″-methoxyphenyl)
-4'-piperidinyl]cyclooctanol is prepared from 3-bromoanisole by the procedure described in Example 2, but substituting cyclooctanone for acetone in the preparation. mp120~122°, NMR (in CDCl ₃ ):
τ2.6~3.3 (m, 4H), 6.2 (s, 3H) and 7.2~
9.0 (m+s, 26H). Elemental analysis (as C ₂₁ H ₃₃ NO ₂ ) C H N calculated value: 76.09 10.03 4.33 Actual value: 76.11 9.70 4.09 Example 29 4-[2',5'-dimethoxyphenyl)-α, α,
1-trimethyl-4-piperidinetamenol 4-[2',5'-dimethoxyphenyl)-α,α,
1-Trimethyl-4-piperidinemethanol is prepared from 1,4-dimethoxybenzene by the procedure described in Example 3, but using acetone instead of cyclopentanone in the synthesis. mp139~140°, NMR
(during CDCl ₃ ): τ3.0~3.3 (m, 3H), 6.2 (2s, 6H),
6.6-8.5 (m+s, 12H) and 8.9 (wide,
6H). Elemental analysis (as C ₁₇ H ₂₇ NO ₃ ) C H N calculated value: 69.59 9.29 4.77 Actual value: 69.66 9.09 4.66 Example 30 1-[1′-Methyl-4′-(3″-trifluoromethylphenyl) -4′-Piperidinyl]cyclopentanol 1-[1′-Methyl-4′-(3″-trifluoromethylphenyl)-4′-piperidinyl]cyclopentanol was prepared according to the procedure described in Example 2. , but by using cyclopentanone in place of acetone in its preparation.
mp137~138°. Elemental analysis (as C ₁₈ H ₂₄ F ₃ NO) C H N calculated value: 66.04 7.34 4.09 Actual value: 66.14 7.23 4.09 Example 31 4-(3'-trifluoromethylphenyl)-α,
1-dimethyl-α-ethyl-4-piperidinemethanol and its hydrochloride 4-(3′-trifluoromethylphenyl)-α,
1-Dimethyl-α-ethyl-4-piperidinemethanol is prepared by the procedure described in Example 2, but using methyl ethyl ketone instead of acetone in the preparation.
Convert the product to the hydrochloride. It is mp227 ~
228° (decomposed). NMR (360MHz CDCl ₃
Medium): τ2.4~2.5 (m, 4H), 6.5 (m, 2H), 7.0~
7.6 (m, 10H), 8.5 (m, 1H), 8.8 (m, 1H), 8.9
(s, 3H) and 9.1 (t, 3H). Example 32 4-(4'-phenoxyphenyl)-α,α,1-
Trimethyl-4-piperidinemethanol 4-(4'-phenoxyphenyl)-α,α,1-
Trimethyl-4-piperidine methanol is prepared from p-bromophenyl phenyl ether by the procedure described in Example 2. mp148°. Elemental analysis (as C ₂₁ H ₂₇ NO ₂ ) C H N calculated value: 77.50 8.36 4.30 Actual value: 77.25 8.13 4.33 Example 33 4-(4'-dimethylaminophenyl)-α, α,
1-trimethyl-4-piperidinemethanol 4-(4'-dimethylaminophenyl)-α,α,
1-Trimethyl-4-piperidinemethanol was prepared by the procedure described in Example 2 to prepare p-bromo-N,
It is prepared from N-dimethylaniline, except that the carbinol is dehydrated by heating to 140° with trifluoroacetic acid in a sealed tube instead of refluxing. mp142~143°. Elemental analysis (as C ₁₇ H ₂₈ N ₂ O) C H N calculated value: 73.87 10.21 10.13 Actual value: 73.89 10.15 10.27 Example 34 1-[1′-Methyl-4′-(3″-methoxyphenyl)
-4′-piperidine]cyclopentanol 1-[1′-methyl-4′-(3″-methoxyphenyl)
-4'-Piperidine]cyclopentanol is prepared from m-bromoanisole by the procedure described in Example 2, but substituting cyclopentanone for acetone in the preparation. mp108~109°. Elemental analysis (as C ₁₈ H ₂₇ NO ₂ ) C H N calculated value: 74.70 9.40 4.84 Actual value: 74.99 9.12 5.03 Example 35 1-[1′-Methyl-4′-(3″-methoxyphenyl)
-4′-piperidine]cyclohexanol 1-[1′-methyl-4′-(3″-methoxyphenyl)
-4'-Piperidine]cyclohexanol is prepared from m-bromoanisole by the procedure described in Example 2, but substituting cyclohexanone for acetone in the preparation. Convert the product to the hydrochloride salt. it is
Has mp255° (decomposition). NMR (in CDCl ₃ ):
τ2.5~2.8 (m, 1H), 3.0~3.3 (m, 2H), 6.2 (s
，
3H) and 6.4-9.3 (m, 22H). Example 36 4-(3'-biphenylyl)-α,α,1-trimethyl-4-piperidinemethanol and its hydrochloride 4-(3′-biphenylyl)-α,α,1-trimethyl-4-piperidinemethanol is Prepared from 3-bromobiphenyl by the procedure described in Example 2. When the product is converted to hydrochloride, it is
Has mp221-223° (decomposition). NMR (CDCl ₃
middle): τ2.2-2.7 (m, 9H), 6.3-7.7 (m, 12H) and 8.7 (s, 6H). Example 37 4-(2′,3′-dimethoxyphenyl)-1-benzyl-α,α-dimethyl-4-piperidinemethanol and its hydrochloride 4-(2′,3′-dimethoxyphenyl)-1 -benzyl-α,α-dimethyl-4-piperidine methanol according to the procedure described in Example 3, but using 1-benzyl-4-piperidone instead of 1-methyl-4-piperidone in the preparation; and is produced by using acetone instead of cyclopentanone in the production of. When the product is converted into the hydrochloride, it has a mp of 236-237° (decomposition) after crystallization from acetonitrile. Elemental analysis (as C ₂₃ H ₃₂ ClNO ₃ ) C H N calculated value: 68.05 7.95 3.45 Actual value: 68.37 7.80 3.69 Example 38 1-[1′-benzyl-4′-(2″,3″-dimethoxyphenyl) )-4′-piperidinyl]cyclopentanol and its hydrochloride 1-[1′-benzyl-4′-(2″,3″-dimethoxyphenyl)-4′-piperidinyl]cyclopentanol was prepared in Example 3. It is prepared according to the procedure described but using 1-benzyl-4-piperidone instead of 1-methyl-4-piperidone in the first step. Convert the product to the hydrochloride salt. After it was crystallized from 90% ethanol
It is mp235 (disassembled). Elemental analysis (as C ₂₅ H ₃₄ ClNO ₃ ) C H N calculated value: 69.51 7.93 3.24 Actual value: 69.29 7.71 3.59 Example 39 4-(6'-methoxy-2'-naphthyl)-α, α,
1-trimethyl-4-piperidinemethanol 4-(6'-methoxy-2'-naphthyl)-α,α,
1-Trimethyl-4-piperidinemethanol was converted to 2-bromo-6-methanol by the procedure described in Example 2.
Manufactured from methoxynaphthalene. mp170~
171°. Elemental analysis (as C ₂₀ H ₂₇ NO ₂ ) C H N calculated value: 76.64 8.68 4.47 Actual value: 76.59 8.73 4.38 Example 40 4-(3'-ethoxyphenyl)-α,α,1-trimethyl-4- Piperidine methanol and its hydrochloride 4-(3'-ethoxyphenyl)-α,α,1-trimethyl-4-piperidine methanol is Example 2
It is prepared from 3-ethoxybromobenzene by the procedure described in . Convert the free base to the hydrochloride salt. It has a mp of 229-230° after crystallization from isopropyl alcohol. Elemental analysis (as C ₁₇ H ₂₈ ClNO ₂ ) C H N calculated value: 65.05 8.99 4.46 Actual value: 65.19 9.03 4.64 Example 41 4-(3'trifluoromethylphenyl)-α,α
-dimethyl-1-ethyl-4-piperidinemethanol 4-(3'-trifluoromethylphenyl)-α,
α-Dimethyl-1-ethyl-4-piperidinemethanol is prepared as described in Example 2, except that in the first step 1-ethyl-4-piperidone is replaced with 1-ethyl-4-piperidone. is used. mp110°. Elemental analysis (as C ₁₇ H ₂₄ F ₃ NO) C H N calculated value: 64.74 7.67 4.44 Actual value: 64.73 7.90 4.55 Example 42 4-(4'-biphenylyl)-α,α,1-trimethyl-4-piperidine Methanol 4-(4'-biphenylyl)-α,α,1-trimethyl-4-piperidinemethanol is prepared from 4-bromobiphenyl by the procedure described in Example 2. mp192~193°, NMR (in CDCl ₃ ):
τ2.2-2.8 (m, 9H), 7.1-8.5 (m+s, 12H) and 8.8 (s, 6H). Example 43 4-(3'-methoxyphenyl)-α,α,1,3
-Tetramethyl-4-piperidinemethanol 4-(3'-methoxyphenyl)-α,α,1,3
-Tetramethyl-4-piperidinemethanol was prepared according to the procedure of Example 2, except that 1,3-tetramethyl-4-piperidone was replaced with 1-methyl-4-piperidone.
Prepared from 3-bromoanisole by using dimethyl-4-piperidone. The product is heated to a bath temperature of 130 to 160° under a vacuum of 5 × 10 _-4 torr (0.07 Pa).
Obtained as an oil by distillation. it is
It is a mixture (83/17 ratio) of two isomers (R ³ is cis or trans to the aryl group) as determined by the 360 MHz NMR spectrum. The main isomer has a C-3 methyl group at τ 8.5 as a doublet (J=7.2 Hz) and two α-methyl groups at 8.7 and 8.9. Calculated value for C ₁₇ H ₂₇ NO ₂ MS: m/z 277.204 Actual value: 277.204 Example 44 4-(3'-tolyl)-α,α,1,2-tetramethyl-4-piperidinemethanol 4- (3'-Tolyl)-α,α,1,2-tetramethyl-4-piperidinemethanol was prepared according to the procedure of Example 2, except that 1-methyl-4-piperidone was replaced with 1,2-dimethyl −
Prepared from 3-bromotoluene by using 4-piperidone. mp139°, NMR
(360MHz CDCl ₃ ): τ2.8~2.9 (m, 3H), 3.0
(d, further split, 1H), 7.0 (m, 1H), 7.4
(m, 2H), 7.5-7.9 (m+2s, 10H), 8.0 (wide s, 1H), 8.9 (2 s, 6H) and 9.4 (d, J
=7Hz, 3H). Elemental analysis (as C ₁₇ H ₂₇ NO) C H N calculated value: 78.11 10.41 5.36 Actual value: 78.23 10.31 5.30 Example 45 7-(3'-trifluoromethylphenyl)-α,
α-dimethyl-7-indolizidinemethanol 7-(3′-trifluoromethylphenyl)-α,
α-Dimethyl-7-indolizidine methanol is prepared according to the procedure of Example 2, except that 7-indolizidinone is used in place of 1-methyl-4-piperidone in the preparation. The product is a mixture containing two stereoisomers in a ratio of 3:2. Elemental analysis (as C ₁₈ H ₂₄ F ₃ NO) C H N calculated value: 66.04 7.39 4.28 Actual value: 65.99 7.48 4.39 Example 46 (±)-cis and trans-3-methyl-1
-[1′-Methyl-4′-(3″-trifluoromethylphenyl)-4′-piperidinyl]cyclopentanol (±)-cis and trans-3-methyl-1
-[1′-Methyl-4′-(3″-trifluoromethylphenyl)-4′-piperidinyl]cyclopentanol was prepared by the procedure described in Example 2, except that in the preparation instead of acetone ( ±)-3
-Prepared as a 60/40 mixture of two racemic diastereomers by using methylcyclopentanone. mp112~113°. Especially 19F
NMR spectrum: −62.6ppm (Freon
Singlet at _11CFCl3 ). 1H-NMR spectrum: two doublets at 9.0 and 9.1 in a 2:3 ratio (J=7Hz). Example 47 (−)-cis and trans-3-methyl-1
-[1'-Methyl-4'-(3''-trifluoromethylphenyl)-4'-piperidinyl]cyclopentanol (-)-cis and trans-3-methyl-1
-[1'-Methyl-4'-(3''-trifluoromethylphenyl)-4'-piperidinyl]cyclopentanol was prepared by the procedure described in Example 2, except that in the preparation of (-)-3 -Produced as a mixture of two optically active diastereomers by using methylcyclopentanone. m.
p.103-104°. [α] _D −6.7° (c=1.07, CHCl ₃ ).
Its NMR spectrum is identical to that of the product of Example 46. The antidepressants of the present invention can be administered in the treatment of reactive and endogenous forms of psychotic depression by any means that brings the active agent into contact with the site of action of the drug within the mammalian body. can. They can be administered as individual therapeutic agents or in combination with therapeutic agents by any conventional means available for use with drugs. Although they can be administered alone, they will generally be administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice. The amount of drug administered will of course depend on known factors such as the pharmacodynamic properties of the particular drug and its mode of administration and route of administration, age, health and weight of the patient, nature and severity of symptoms, type of concurrent treatment, number of treatments and desired It will vary depending on the effect. The daily dosage of the active ingredient is usually approximately
It can be from 0.001 to 50 mg. To achieve the desired therapeutic results, a total of 0.01 to 1 kg body weight per day is usually required.
It is effective to administer 20 mg, preferably 0.1 to 10 mg, in divided doses 2 to 4 times a day or in sustained release form. Dosage forms (compositions) suitable for internal administration may contain from about 0.25 to about 10 mg of active ingredient per unit. In such pharmaceutical compositions, the active ingredient will normally be present in an amount of about 0.01 to 90% by weight, based on the total weight of the composition. The active ingredient can be administered orally in solid dosage forms such as capsules, tablets and powders or in liquid dosage forms such as elixirs, syrups and suspensions. It can also be administered parenterally in sterile liquid dosage form or rectally in the form of suppositories. Gelatin capsules can contain the active ingredient and powdered carriers such as lactose, sucrose, mannitol, starches, cellulose derivatives, magnesium stearate and stearic acid. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide continuous release of drug over an extended period of time.
Compressed tablets may be sugar-coated or coated to mask any unpleasant taste and protect the tablet from the atmosphere, and may be enteric-coated to allow selective disintegration in the intestinal tract. It can also be coated with Liquid dosage forms for oral administration can contain coloring and flavoring to enhance patient acceptance. In general, water, a suitable oil, saline, aqueous dextrose (glucose) and related sugar solutions and glycols such as propylene glycol or polyethylene glycol are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain an aqueous salt of the active ingredient, suitable stabilizing agents and, if necessary, buffering substances. Antioxidants such as sodium bisulfite, sodium sulfite and ascorbic acid, used alone or in combination, are suitable stabilizers. Also used are citric acid and its salts and sodium EDTA (ethylenediaminetetraacetic acid). Additionally, parenteral solutions can contain preservatives such as benzalkonium chloride, methyl or propyl parabens and chlorobutanol. Suppositories can contain the active ingredient in a suitable oily or water-soluble base. Oily bases include cocoa milk fat and other fats with similar properties, and water-soluble bases include polyethylene glycol. Suitable pharmaceutical carriers are discussed in the standard reference book in this field, Remington's by E. W. Martin.
Pharmaceutical Sciences”. Pharmaceutical dosage forms useful for administering the compounds of this invention are described below. Capsules (Hard) Hard capsules are made by filling standard two-pack hard gelatin capsules with the following mixture: 1 mg of active ingredient, 125 mg of lactose, 12 mg of talc, 3 mg of magnesium stearate, using conventional capsule manufacturing equipment. Can be manufactured. Capsules (Soft) A mixture of active ingredient in soybean oil can be prepared and injected into gelatin using a positive displacement pump to produce soft gelatin capsules containing 5 mg of active ingredient. The capsules can be washed with petroleum ether and dried. Tablets Tablets may be manufactured in a conventional manner such that each unit contains the following ingredients: 1 mg of active ingredient, 150 mg of spray-dried lactose, 35 mg of microcrystalline cellulose, 3 mg of magnesium stearate. Parenteral Compositions Parenteral compositions suitable for intramuscular administration contain in each ml the following ingredients: Active ingredient 1 mg Sodium carboxymethyl cellulose
0.75% by weight Polysorbate 80 0.04% by weight Benzyl alcohol 0.9% by weight Sodium chloride 0.9% by weight Water for injection It can be manufactured so as to contain an appropriate amount of 1 ml. Suspensions Aqueous suspensions are prepared for oral administration in each 5 ml containing the following ingredients: Active ingredient 5 mg Methylcellulose 5% by weight Carboxymethylcellulose 5% by weight Syrup 30% by weight Polysorbate 80 0.2% by weight Satucharin sodium 2 mg Thierry flavor 0.1% by weight % sodium benzoate 5 mg water (an appropriate amount to make a total of 5 ml). A standard method for discovering and comparing the antidepressant activity of compounds of the invention, which correlates well with efficacy in humans, is the inhibition of tetrabenazine-induced sedation and depression in mice. Described in "Antidepressant Drugs" (1967 First International Symposium Abstracts), edited by S. Garattini and MNG Dukes, pp. 164-167.
“The Dopa Response” by Mr. Everett
Potentiation Test and Its Use in Screening
for Antidepressant Drugs]. Groups of 10 Carworth CF ₁ S female mice, each weighing 18-21 g, were fasted for 1.5 hours and treated with e.g. 1% methocel (methyl cellulose).
Antagonist compounds are administered to the mice by intubation at oral doses of 0, 1, 3, 9, 27 and 81 mg/Kg in 0.20 ml. Thirty minutes later, 32 mg/Kg of tetrabenazine (as methanesulfonate) (dissolved in 0.05% aqueous potassium chloride, 0.20 ml, pH 2.0) is administered intraperitoneally to the mice. 1 hour after administration of antagonist (30 minutes after administration of tetrabenazine)
Test those mice for exploratory activity and blepharoptosis (closing of the eyelids). One mouse from a group of 10 in the test box was lifted by the tail and placed on the stainless steel test box lid [12.5 inches (31.8 cm) x 8 inches (20.3 cm), 0.33
Normal exploratory activity (from sedation to release) is recorded. Release from ptosis is recorded when eyelid closure is less than 50% in both eyes exactly 2 seconds after the mouse is placed facing the observer.
The table below shows the data obtained with the test compounds of the above examples (antagonistic effect on depression in mice induced by tetrabenazine 1 hour after oral administration of the drug).

【table】

[Table] (Note) *Peak value The following appetite-reducing effect data were obtained from the screening of central nervous system drugs. Weight 16-20g fasted for 17-21 hours overnight
of female mice are used in these studies. Oral dosage of compounds [aqueous Methocel (methyl cellulose, viscosity 100 CPS, grade MC, Dow Chemical Company) and 2.8% Tween
0.5 h after administration of 0.5 hours after administration of 0.5 hours after administration (produced in 80° C. and administered at 0.1 ml per 10 g of body weight), each mouse was placed in a separate transparent Lucite compartment with a wire mesh floor measuring 0.64 cm x 0.64 cm (Lucite, 13.3
cm x 12.7cm x 12.7cm). The five partitions are arranged linearly in each car.
Inside each compartment is a black Lucite rod (13cm x 1.2cm x 1.2cm) with 10 small indentations (0.8cm diameter) in its top, each indentation containing 50% sweetened condensate. milk 0.05
ml (a product of Borden's Eagle). After 30 minutes, mice are returned to the "Shubox" container and the number of milk spots consumed by each mouse is counted. It also evaluates and counts the portion of the spot consumed. Five mice per drug dose can drink up to 50 spots of milk (2.5 ml). Anorexia is considered to be indicative if the number of spots consumed by 5 mice is 9 or less. _ED50 values are evaluated based on the quantitative responses obtained. The data in Table 3 indicate that certain compounds of the present invention are useful as anorexia and, therefore, useful in the treatment of obesity. Table 3 Example ED for anorectic effect ₅₀ 2 60 mg/Kg 2A 36 4 60 6 60 7 20 8 20 10 20 16 60 17 60 30 60 31 20 32 60 37 60 39 60 41 60 Currently used to carry out the present invention The best mode contemplated is represented by the antidepressant of Example 2. As is clear from the description herein, the antidepressants and anorectic agents of the present invention are useful in the medical field, particularly in the areas of mental disorders and obesity. Although preferred embodiments of the invention have been described above, the invention is not limited to the specific configurations disclosed herein, and all changes and modifications are included within the scope of the invention. I want you to understand that it is something.

Claims (1)

[Claims] 1 formula [wherein a) R ¹ is hydrogen, alkyl having 1 to 12 carbon atoms, cycloalkyl or benzyl having 3 to 8 carbon atoms,
b) R ² and R ³ are each independently selected from hydrogen or lower alkyl having 1 to 4 carbon atoms; R ¹ and R ² together represent a branched or unbranched alkylene bridge; (the alkylene bridge has 3 or 4 carbon atoms), or R ² and R ³ together form a branched or unbranched alkylene bridge (the alkylene bridge has 3 or 4 carbon atoms);
~6 carbon atoms) and c) R ⁴
1) phenyl or 2-naphthyl or the same or different fluorine, chlorine, alkyl, perfluoroalkyl, alkoxy, aryloxy, alkylthio, arylthio, perfluoroalkoxy, perfluoroalkylthio and dialkylamino (whose alkyl and alkoxy moieties are from 1 to 12 phenyl or 2-naphthyl substituted with one or two substituents selected from , 3- or 4-biphenylyl or one or both aromatic moieties are the same or different and fluorine, chlorine, alkyl, perfluoroalkyl, alkoxy, aryloxy, alkylthio, arylthio, perfluoroalkoxy, perfluoroalkylthio and dialkylamino (those alkyl 2-, substituted with one or two substituents selected from 3- or 4-biphenylyl, 3) 2-pyrrolyl or 2-pyrrolyl substituted with 1 to 3 lower alkyl groups having 1 to 4 carbon atoms, 4) 2-, 3- or 4-pyridyl, or 5) 2-thienyl substituted in the 5-position with lower alkyl having 1 to 4 carbon atoms, d) R ⁵ and R ⁶ are each independently 1 to
selected from alkyl having 12 carbon atoms and cycloalkyl having 3 to 8 carbon atoms, or R ⁵ and R ⁶ together are branched or unbranched alkylene bridges (that alkylene bridges having 3 to 11 carbon atoms), provided that R ¹ , R ⁵ and R ⁶ are methyl and R ² and R ³ are hydrogen, then R ⁴ is p- 4-aryl-4-piperidine carbinol, which is not tertiary-butylphenyl or 2'-biphenylyl, and its pharmacologically acceptable salts. 2 R ¹ , R ⁵ and R ⁶ are methyl, R ² and
4-aryl-4- according to claim 1, wherein R ³ is H and R ⁴ is m-CF ₃ C ₆ H ₄
Piperidine carbinol. 3. 4-aryl- according to claim 2
4-Piperidine carbinol hydrochloride. 4-Aryl-4-piperidine carbinol according to claim 1, wherein R ⁴ is meta-substituted phenyl. 4-Aryl-4-piperidine carbinol according to claim 1, wherein 5 R ¹ is benzyl. 6 formula [wherein a) R ¹ is hydrogen, alkyl having 1 to 12 carbon atoms, cycloalkyl or benzyl having 3 to 8 carbon atoms,
b) R ² and R ³ are each independently selected from hydrogen or lower alkyl having 1 to 4 carbon atoms; R ¹ and R ² together represent a branched or unbranched alkylene bridge; (the alkylene bridge has 3 or 4 carbon atoms), or R ² and R ³ together form a branched or unbranched alkylene bridge (the alkylene bridge has 3 or 4 carbon atoms);
~6 carbon atoms) and c) R ⁴
1) phenyl or 2-naphthyl or the same or different fluorine, chlorine, alkyl, perfluoroalkyl, alkoxy, aryloxy, alkylthio, arylthio, perfluoroalkoxy, perfluoroalkylthio and dialkylamino (whose alkyl and alkoxy moieties are from 1 to 12 phenyl or 2-naphthyl substituted with one or two substituents selected from , 3- or 4-biphenylyl or one or both aromatic moieties are the same or different and fluorine, chlorine, alkyl, perfluoroalkyl, alkoxy, aryloxy, alkylthio, arylthio, perfluoroalkoxy, perfluoroalkylthio and dialkylamino (those alkyl 2-, substituted with one or two substituents selected from 3- or 4-biphenylyl, 3) 2-pyrrolyl or 2-pyrrolyl substituted with 1 to 3 lower alkyl groups having 1 to 4 carbon atoms, 4) 2-, 3- or 4-pyridyl, or 5) 2-thienyl substituted in the 5-position with lower alkyl having 1 to 4 carbon atoms, d) R ⁵ and R ⁶ are each independently 1 to
selected from alkyl having 12 carbon atoms and cycloalkyl having 3 to 8 carbon atoms, or R ⁵ and R ⁶ together are branched or unbranched alkylene bridges (that alkylene bridges having 3 to 11 carbon atoms), provided that R ¹ , R ⁵ and R ⁶ are methyl and R ² and R ³ are hydrogen, then R ⁴ is p- A preparation as an antidepressant or anorectic agent containing 4-aryl-4-piperidine carbinol or a pharmacologically acceptable salt thereof as an active ingredient, which is not tertiary butylphenyl or 2'-biphenylyl. . 7 formula [wherein a) R ¹ is hydrogen, alkyl having 1 to 12 carbon atoms, cycloalkyl or benzyl having 3 to 8 carbon atoms,
b) R ² and R ³ are each independently selected from hydrogen and lower alkyl having 1 to 4 carbon atoms; R ¹ and R ² together represent a branched or unbranched alkylene bridge; (the alkylene bridge has 3 or 4 carbon atoms), or R ² and R ³ together form a branched or unbranched alkylene bridge (the alkylene bridge has 3 or 4 carbon atoms);
~6 carbon atoms) and c) R ⁴
1) phenyl or 2-naphthyl or the same or different fluorine, chlorine, alkyl, perfluoroalkyl, alkoxy, aryloxy, alkylthio, arylthio, perfluoroalkoxy, perfluoroalkylthio and dialkylamino (whose alkyl and alkoxy moieties are from 1 to 12 phenyl or 2-naphthyl substituted with one or two substituents selected from , 3- or 4-biphenylyl or one or both aromatic moieties are the same or different and fluorine, chlorine, alkyl, perfluoroalkyl, alkoxy, aryloxy, alkylthio, arylthio, perfluoroalkoxy, perfluoroalkylthio and dialkylamino (those alkyl 2-, substituted with one or two substituents selected from 3- or 4-biphenylyl, 3) 2-pyrrolyl or 2-pyrrolyl substituted with 1 to 3 lower alkyl groups having 1 to 4 carbon atoms, 4) 2-, 3- or 4-pyridyl, or 5) 2-thienyl substituted in the 5-position with lower alkyl having 1 to 4 carbon atoms, d) R ⁵ and R ⁶ are each independently 1 to
selected from alkyl having 12 carbon atoms and cycloalkyl having 3 to 8 carbon atoms, or R ⁵ and R ⁶ together are branched or unbranched alkylene bridges (that alkylene bridges containing 3 to 11 carbon atoms) provided that R ¹ , R ⁵ and R ⁶ are methyl and R ² and R ³ are hydrogen, then R ⁴ is p- tertiary butylphenyl or
In preparing 4-aryl-4-piperidine carbinol, which is not 2'-biphenylyl, the steps are carried out in the following order: 1) Lithiation of R ⁴ Br with n-butyllithium; Generate R ⁴ Li and then use it as the expression (wherein R ¹ , R ² , R ³ and R ⁴ are as defined above) with piperidinone. 2) is dehydrated to produce a mixture of olefins [formula] and [formula], 3) is lithiated with n-butyllithium, and then the ketone R ⁵ COR ⁶ (where R ⁵ and R ⁶ are as defined above to form oxazabicyclooctane and/or 4) and reduce 4) to form or alternatively is lithiated and then reacted with an ester R ⁵ COOR ⁷ where R ⁵ is as defined above and R ⁷ is lower alkyl having 1 to 4 carbon atoms. to form the ketone [formula] and/or [formula], which is then combined with R ⁶ Li or R ⁶ MgX, where R ⁶ is as defined above and X is chlorine, bromine or iodine. (but in this alternative method R ⁵ and R ⁶
cannot together represent alkylene).