CA1110246A - Method of producing cyclic-aminophenyl ether compound - Google Patents
Method of producing cyclic-aminophenyl ether compoundInfo
- Publication number
- CA1110246A CA1110246A CA356,441A CA356441A CA1110246A CA 1110246 A CA1110246 A CA 1110246A CA 356441 A CA356441 A CA 356441A CA 1110246 A CA1110246 A CA 1110246A
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- Prior art keywords
- alkyl group
- lower alkyl
- phenyl
- piperidine
- prepared
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Abstract
ABSTRACT OF THE DISCLOSURE
Method of producing cyclic-aminophenyl ether compounds or the pharmacologically acceptable salts thereof having the formula:
wherein R1 represents hydrogen atom or a lower alkyl group, R2 represents a cyclohexyl group which may have been substituted by lower alkyl group(s), an alkyl group containing 1 to 20 carbon atoms, A phenyl group or a benzyl group, R3 represents hydrogen atom, a lower alkyl group, or a cyclohexyl group which may have been substituted by lower alkyl group(s); said R2 and R3 may, however, form together with the adjacent carbon atom a cyclohexane ring which may have been substituted by lower alkyl group(s) and n is 4 or 5.
The above compounds have a hypolipemic activity, a cholesterol and a triglyceride reducing activity, and an activity increasing high density lipoprotein (HDL) cholesterol, selectively.
Method of producing cyclic-aminophenyl ether compounds or the pharmacologically acceptable salts thereof having the formula:
wherein R1 represents hydrogen atom or a lower alkyl group, R2 represents a cyclohexyl group which may have been substituted by lower alkyl group(s), an alkyl group containing 1 to 20 carbon atoms, A phenyl group or a benzyl group, R3 represents hydrogen atom, a lower alkyl group, or a cyclohexyl group which may have been substituted by lower alkyl group(s); said R2 and R3 may, however, form together with the adjacent carbon atom a cyclohexane ring which may have been substituted by lower alkyl group(s) and n is 4 or 5.
The above compounds have a hypolipemic activity, a cholesterol and a triglyceride reducing activity, and an activity increasing high density lipoprotein (HDL) cholesterol, selectively.
Description
2~;
1 DETAILED_DESC_IPTION_OF_THE INVENTION
This invention relates to a method of producing the novel cyclicaminophenyl ether compounds or the pharmacologically acceptable salts thereof shown by formula I
R2-- C -- O ~ N (CH2)
1 DETAILED_DESC_IPTION_OF_THE INVENTION
This invention relates to a method of producing the novel cyclicaminophenyl ether compounds or the pharmacologically acceptable salts thereof shown by formula I
R2-- C -- O ~ N (CH2)
- 3 :
;~ 10 wherein Rl represents hydrogen atom or a lower alkyl group; R2 represents a cyclohexyl group which may have been substituted by lower alkyl group(s), an alkyl group containing from 1 to 20 carbon atoms, a phenyl group or a benzyl group; R3 represents hydrogen atom, a lower alkyl group or a cyclohexyl group which may have been : substituted by lower alkyl group(s); said R2 and R3 : may, however, form together with the adjacent carbon atom a cyclohexane ring which may have been substituted by lower alkyl group(s) and n is 4 or 5.
When in the cyclicaminophenyl ether compounds shown R
by formula I, the moiety shown by R2 ~ ~ ~ has a disubstituted cyclohexane ring, there exists the cis and trans stereoisomers of them, and hence the compounds in this invention include these stereoisomers.
Now, "lower alkyl group" used in this invention includes straight chain or branched alkyl group(s) containing from 1 to 6 carbon atoms, such as methyl group, ethyl group, isopropyl group, butyl group, isopentyl group hexyl group, etc.
, ~
i~ 24~
1 As the pharmacologically acceptable salts of the compounds of formula I in this invention, there are salts with an inorganic acid such as hydrochloric acid, hydrobromic acid, phosphoric acid, etc.; salts with an organic acid such as formic acid, acetic acid, lactic acid, oxalic acid, succinic acid, fumaric acid, benzoic acid, benzenesulfonic acid, etc.; and also the quaternary ammonium salts obtained by the reaction with an alkyl halide such as methyl iodide, etc.
The compounds of formula I in this invention have a hypolipermic activity and also a particularly excellent cholesterol and triglyceride reducing activity and are effective for the prophylaxis and the medical treatment of arteriosclerosis such as coronary heart disease.
It is said that arteriosclerosis is caused partially ~, by unusually excessive amount of lipids such as cholesterol, triglyceride, etc., in blood. A hypolipemic ~;; agent, p-chloropenoxy-iso-butyric acid ethyl ester (Clofibrate) has hitherto been used frequently but it has further been desired to develope medicaments having more effective hypolipemic activity and less side effect.
As the result of the inventors' earnest investigations, it has now been found that the compounds described in formula I have a cholesterol and triglyceride reducing activity and an effect of elevating high density lipoprotein (HDLJ cholesterol, selectively.
It is known that the amount of HDL in blood is lower in arteroisclerosis than in normal state in human and also HDL prevents the excessive accumulation of cholesterol on the arterial wall and promotes the removal of cholesterol 2~6 1 from the arterial wall in experimental animals.
Therefore, the increase of HDL cholesterol may be effective for the prophylaxis and the medical treatment of arteriosclerosis. However, the conventional hypolipemic agent such as Clofibrate, etc., does not show an activity of increasing HDL cholesterol, selectively.
As a compound having the activity increasing HDL
cholesterol, N-[p-(l-adamantyloxy)phenyl]piperidine (U-41,972) as described in U.S. Patent No. 4,036,977 is known, but the activity of the compounds in this invention is clearly superior to that of the known compound, as shown below.
Ex_erime_t_l.
Three weeks old male Sprague-Dawley rats were fed for 7 days semipurified diet containing 1.5% cholesterol and 0.5~ bile aid to induce hypercholesterolemia.
A compound in this invention suspended in an aqueous solution containing 0.25~ methyl cellulose was administered to them once a day by oral gavage for final four days.
After fasted overnight, the animals were anesthetized with ether, and the blood was obtained from the peripheral vascular, and the HDL cholesterol (cholesterol of HDL~ in the serum were determined. The results are shown in the following tables. In addition, the determination of the total cholesterol was practiced by the method described in Schettler G. & Nussel; "Arbeitsmed. Sozialmed.
Praventivmed.", 10, 25(1975) and the determination of HDL
cholesterol was practiced by the method described in T.T. Ishikawa et al; "Lipids", 11, 628(1976).
-Z:~6 . 1 Table_l_ Compound Dose Decrease Increase of (A) (mg/kg/day) of choles- cholesterol (Control =l) - terol (%) of HDL(%) Known . Compound : U-41,792 1 25 -73 210 19.7 Compounds in this invention (Example No.) 1 25 -80 370 47.3 . 10 17 25 -80 460 47.7 (A): Cholesterol of HDL/cholesterol of (VLDL + LDL) 2 ~, .
""',;
.
' :1 ~$~
.
Table_2 Compound Dose Cholesterol /
(mg/kg/day) of HDL / cholesterol / of (VLDL + LDL)*2 : (control = 1) :~ Known Compound U-41,972 25 19.7 Compounds in the Invention (Example No.) 1 25 47.3 10 17 25 47.7 *1: N- p-(l-adamantyloxy)phenyl piperidine (U.S.
` patent No. 4,036,977).
o *2: VLDL: very low density lipoprotein LDL: low density lipoprotein.
:
.~
z~
Experiment 2 __ _________ By following the same procedure as in Experiment 1 using five weeks old male Sprague-Dawley rats and the total cholesterol in the serum and the HDL cholesterol were determined, by the same manner as in Experiment 1.
The results are shown in the following tables.
Table_3 'Compound in the Dose Decrease of Increase of : Invention (mg/kg/day) cholesterol(%) HDL (%) . 10 (Example No.) 1 12.5 -43 119 ~,~
' 18 12.5 -54 212 , 25 -68 308 . 19 12.5 -36 154 - Table 4 _______ Compound in the Dose Cholesterol .20 Invention (mg/kg/day) of HDL / Cholesterol ; / of (VLDL -~ / LDL) (Example No) (control = 1) 1 12.5 2.2 16.5 18 12.5 5.7 18.8 19 12.5 2.5 '':
~ 1 As is clear from the above-described experimental - results, the compounds of formula I in this invention have not only an excellent cholesterol reducing activity but also make the amount of HDL increasing greatly which is known to promote the removal of cholesterol from the arterial wall. Therefore, the compounds in this invention are very effective for the prophylaxis and the medical treatment of arteriosclerosis.
The compounds of formula I in this invention can be formed into various formulations such as powders, granules, tablets, capsules, injections, etc., using additives for formulation generally used. It is preferred , .
that the compounds are administered orally. The doses of the compounds depend upon the condition, age, etc., of the patient but in a case of oral administration, the dose is usually 1-100 mg/kg, preferably about 5-25 mg/kg a day per an adult.
The compounds of formula I in this invention can be prepared by reacting the compound shown by formula II:
R
R - C - ~ NH2 II
~ R
with the compound shown by formula III:
X- (CH2) - X III
wherein Rl, R2 and R3 have the same significance as above and X represents a halogen atom.
Preferred examples of the halogen atom in the ; process are bromine atom and iodine atom. It is preferred to perform the reaction at room temperature or under 24~i 1 heating in an organic solvent such as benzene, toluene, xylene, dimethylformamide, dimethylsulfoxide, dioxane, tetrahydrofuran, pyridine, methanol, ethanol, etc., or a mixed solvent of them, in the presence of a basic agent such as sodium carbonate, potassium carbonate. etc.
The starting material shown by formula II can be prepared by reacting the compound shown by formula IV:
R
~ _R
wherein Rl, R2 and R3 have the same significance as above, with the p-halogenonitrobenzene shown by formula V:
X ~ 2 :~' ~ wherein X represents halogen atom, in the presence of a - strong base and then reducing the product.
- It is preferred that the reaction is carried out under heating in an organic solvent such as benzene, toluene, xylene, dimethylformamide, dimethylsulfoxide, tetrahydrofuran, dioxane, etc., or a mixed solvent thereof. Preferred examples of the strong base used in this invention are sodium, potassium, litium, sodium hydride, potassium hydride, lithium hydride, etc. In this case, it is preferred that the alcohol compound of formula IV is reacted with the strong base beforehand and then the product is reacted with the p-halogenonitrobenzene of formula V.
The reduction can be performed by an ordinary manner, i24~i 1 for example, by the catalyst reduction in hydrogen atmosphere using a catalyst such as Raney nickel catalyst, platinum, palladium, etc., or by the reduction under an acidic condition using a metal such as iron, zinc, tin.
etc. The catalyst reduction can perform not only the reduction of nitro group but also the hydrogentation of the double bond existing in the group:
;- R
R - -C -~2 ` - R
In the above-mentioned process, if the cis-compound of the alcohol compound of formula IV is used, the cis-isomer of the compound of formula I is obtained and if the trans-compound of the alcohol compound of formula IV
is used, the trans-isomer of the compound of formula I is obtained. Also, if a mixture of the eis-trans-isomer of the aleohol eompound of formula IV is used, a mixture of the eis-trans-isomer of the eompound of formula I is obtained and in this ease, the eis-eompound or the trans-eompound ean be isolated eaeh other by an ordinaryseparation proeedure sueh as fraetional erystallization.
Then the produetion method of the eompounds of this invention are deseribed by referring to the following examples.
Exa_ple_l CH ~ CH3 NH2 ~q' ~ ~,<, 1 In 120 ml of a mixture of dimethylformamide and benzene in 1:2 by volume ratio was dissolved 5.1 g. of ; p-methen-8-ol and after adding thereto 1.6 of sodium hydride (50% suspension in a mineral oil), the mixture was refluxed for 30 minutes. Then after cooling the reaction mixture, 4.7 g of p-fluoronitrobenzene was added, dropwise to the mixture and the resultant mixture was refluxed for 6 hours. After cooling the reaction mixture, 200 ml of benzene was added thereto, the mixture was washed with water and then an aqueous sodium chloride solution successively.
The benzene layer was separated and dried over anhydrous sodium sulfate. The solvent was distilled off - under reduced pressure. The residue was applied to a silica gel column chromatography and the desired product was eluted using an equivalent mixture of benzene and hexane. Then, by distilling off the solvent from the ; eluate under reduced pressure, 7.2 9 of
;~ 10 wherein Rl represents hydrogen atom or a lower alkyl group; R2 represents a cyclohexyl group which may have been substituted by lower alkyl group(s), an alkyl group containing from 1 to 20 carbon atoms, a phenyl group or a benzyl group; R3 represents hydrogen atom, a lower alkyl group or a cyclohexyl group which may have been : substituted by lower alkyl group(s); said R2 and R3 : may, however, form together with the adjacent carbon atom a cyclohexane ring which may have been substituted by lower alkyl group(s) and n is 4 or 5.
When in the cyclicaminophenyl ether compounds shown R
by formula I, the moiety shown by R2 ~ ~ ~ has a disubstituted cyclohexane ring, there exists the cis and trans stereoisomers of them, and hence the compounds in this invention include these stereoisomers.
Now, "lower alkyl group" used in this invention includes straight chain or branched alkyl group(s) containing from 1 to 6 carbon atoms, such as methyl group, ethyl group, isopropyl group, butyl group, isopentyl group hexyl group, etc.
, ~
i~ 24~
1 As the pharmacologically acceptable salts of the compounds of formula I in this invention, there are salts with an inorganic acid such as hydrochloric acid, hydrobromic acid, phosphoric acid, etc.; salts with an organic acid such as formic acid, acetic acid, lactic acid, oxalic acid, succinic acid, fumaric acid, benzoic acid, benzenesulfonic acid, etc.; and also the quaternary ammonium salts obtained by the reaction with an alkyl halide such as methyl iodide, etc.
The compounds of formula I in this invention have a hypolipermic activity and also a particularly excellent cholesterol and triglyceride reducing activity and are effective for the prophylaxis and the medical treatment of arteriosclerosis such as coronary heart disease.
It is said that arteriosclerosis is caused partially ~, by unusually excessive amount of lipids such as cholesterol, triglyceride, etc., in blood. A hypolipemic ~;; agent, p-chloropenoxy-iso-butyric acid ethyl ester (Clofibrate) has hitherto been used frequently but it has further been desired to develope medicaments having more effective hypolipemic activity and less side effect.
As the result of the inventors' earnest investigations, it has now been found that the compounds described in formula I have a cholesterol and triglyceride reducing activity and an effect of elevating high density lipoprotein (HDLJ cholesterol, selectively.
It is known that the amount of HDL in blood is lower in arteroisclerosis than in normal state in human and also HDL prevents the excessive accumulation of cholesterol on the arterial wall and promotes the removal of cholesterol 2~6 1 from the arterial wall in experimental animals.
Therefore, the increase of HDL cholesterol may be effective for the prophylaxis and the medical treatment of arteriosclerosis. However, the conventional hypolipemic agent such as Clofibrate, etc., does not show an activity of increasing HDL cholesterol, selectively.
As a compound having the activity increasing HDL
cholesterol, N-[p-(l-adamantyloxy)phenyl]piperidine (U-41,972) as described in U.S. Patent No. 4,036,977 is known, but the activity of the compounds in this invention is clearly superior to that of the known compound, as shown below.
Ex_erime_t_l.
Three weeks old male Sprague-Dawley rats were fed for 7 days semipurified diet containing 1.5% cholesterol and 0.5~ bile aid to induce hypercholesterolemia.
A compound in this invention suspended in an aqueous solution containing 0.25~ methyl cellulose was administered to them once a day by oral gavage for final four days.
After fasted overnight, the animals were anesthetized with ether, and the blood was obtained from the peripheral vascular, and the HDL cholesterol (cholesterol of HDL~ in the serum were determined. The results are shown in the following tables. In addition, the determination of the total cholesterol was practiced by the method described in Schettler G. & Nussel; "Arbeitsmed. Sozialmed.
Praventivmed.", 10, 25(1975) and the determination of HDL
cholesterol was practiced by the method described in T.T. Ishikawa et al; "Lipids", 11, 628(1976).
-Z:~6 . 1 Table_l_ Compound Dose Decrease Increase of (A) (mg/kg/day) of choles- cholesterol (Control =l) - terol (%) of HDL(%) Known . Compound : U-41,792 1 25 -73 210 19.7 Compounds in this invention (Example No.) 1 25 -80 370 47.3 . 10 17 25 -80 460 47.7 (A): Cholesterol of HDL/cholesterol of (VLDL + LDL) 2 ~, .
""',;
.
' :1 ~$~
.
Table_2 Compound Dose Cholesterol /
(mg/kg/day) of HDL / cholesterol / of (VLDL + LDL)*2 : (control = 1) :~ Known Compound U-41,972 25 19.7 Compounds in the Invention (Example No.) 1 25 47.3 10 17 25 47.7 *1: N- p-(l-adamantyloxy)phenyl piperidine (U.S.
` patent No. 4,036,977).
o *2: VLDL: very low density lipoprotein LDL: low density lipoprotein.
:
.~
z~
Experiment 2 __ _________ By following the same procedure as in Experiment 1 using five weeks old male Sprague-Dawley rats and the total cholesterol in the serum and the HDL cholesterol were determined, by the same manner as in Experiment 1.
The results are shown in the following tables.
Table_3 'Compound in the Dose Decrease of Increase of : Invention (mg/kg/day) cholesterol(%) HDL (%) . 10 (Example No.) 1 12.5 -43 119 ~,~
' 18 12.5 -54 212 , 25 -68 308 . 19 12.5 -36 154 - Table 4 _______ Compound in the Dose Cholesterol .20 Invention (mg/kg/day) of HDL / Cholesterol ; / of (VLDL -~ / LDL) (Example No) (control = 1) 1 12.5 2.2 16.5 18 12.5 5.7 18.8 19 12.5 2.5 '':
~ 1 As is clear from the above-described experimental - results, the compounds of formula I in this invention have not only an excellent cholesterol reducing activity but also make the amount of HDL increasing greatly which is known to promote the removal of cholesterol from the arterial wall. Therefore, the compounds in this invention are very effective for the prophylaxis and the medical treatment of arteriosclerosis.
The compounds of formula I in this invention can be formed into various formulations such as powders, granules, tablets, capsules, injections, etc., using additives for formulation generally used. It is preferred , .
that the compounds are administered orally. The doses of the compounds depend upon the condition, age, etc., of the patient but in a case of oral administration, the dose is usually 1-100 mg/kg, preferably about 5-25 mg/kg a day per an adult.
The compounds of formula I in this invention can be prepared by reacting the compound shown by formula II:
R
R - C - ~ NH2 II
~ R
with the compound shown by formula III:
X- (CH2) - X III
wherein Rl, R2 and R3 have the same significance as above and X represents a halogen atom.
Preferred examples of the halogen atom in the ; process are bromine atom and iodine atom. It is preferred to perform the reaction at room temperature or under 24~i 1 heating in an organic solvent such as benzene, toluene, xylene, dimethylformamide, dimethylsulfoxide, dioxane, tetrahydrofuran, pyridine, methanol, ethanol, etc., or a mixed solvent of them, in the presence of a basic agent such as sodium carbonate, potassium carbonate. etc.
The starting material shown by formula II can be prepared by reacting the compound shown by formula IV:
R
~ _R
wherein Rl, R2 and R3 have the same significance as above, with the p-halogenonitrobenzene shown by formula V:
X ~ 2 :~' ~ wherein X represents halogen atom, in the presence of a - strong base and then reducing the product.
- It is preferred that the reaction is carried out under heating in an organic solvent such as benzene, toluene, xylene, dimethylformamide, dimethylsulfoxide, tetrahydrofuran, dioxane, etc., or a mixed solvent thereof. Preferred examples of the strong base used in this invention are sodium, potassium, litium, sodium hydride, potassium hydride, lithium hydride, etc. In this case, it is preferred that the alcohol compound of formula IV is reacted with the strong base beforehand and then the product is reacted with the p-halogenonitrobenzene of formula V.
The reduction can be performed by an ordinary manner, i24~i 1 for example, by the catalyst reduction in hydrogen atmosphere using a catalyst such as Raney nickel catalyst, platinum, palladium, etc., or by the reduction under an acidic condition using a metal such as iron, zinc, tin.
etc. The catalyst reduction can perform not only the reduction of nitro group but also the hydrogentation of the double bond existing in the group:
;- R
R - -C -~2 ` - R
In the above-mentioned process, if the cis-compound of the alcohol compound of formula IV is used, the cis-isomer of the compound of formula I is obtained and if the trans-compound of the alcohol compound of formula IV
is used, the trans-isomer of the compound of formula I is obtained. Also, if a mixture of the eis-trans-isomer of the aleohol eompound of formula IV is used, a mixture of the eis-trans-isomer of the eompound of formula I is obtained and in this ease, the eis-eompound or the trans-eompound ean be isolated eaeh other by an ordinaryseparation proeedure sueh as fraetional erystallization.
Then the produetion method of the eompounds of this invention are deseribed by referring to the following examples.
Exa_ple_l CH ~ CH3 NH2 ~q' ~ ~,<, 1 In 120 ml of a mixture of dimethylformamide and benzene in 1:2 by volume ratio was dissolved 5.1 g. of ; p-methen-8-ol and after adding thereto 1.6 of sodium hydride (50% suspension in a mineral oil), the mixture was refluxed for 30 minutes. Then after cooling the reaction mixture, 4.7 g of p-fluoronitrobenzene was added, dropwise to the mixture and the resultant mixture was refluxed for 6 hours. After cooling the reaction mixture, 200 ml of benzene was added thereto, the mixture was washed with water and then an aqueous sodium chloride solution successively.
The benzene layer was separated and dried over anhydrous sodium sulfate. The solvent was distilled off - under reduced pressure. The residue was applied to a silica gel column chromatography and the desired product was eluted using an equivalent mixture of benzene and hexane. Then, by distilling off the solvent from the ; eluate under reduced pressure, 7.2 9 of
4-(1-p-menthen-8-yloxy) nitrobenzene was obtained. A
mixture of this product and 0.7 g of 10% palladium carbon in 100 ml of ethyl acetate was shaken under hydrogen until the theoretical amount of hydrogen had been absorbed.
After filtering away palladium carbon, the solvent was distilled off under reduced pressure and the residue was distilled under reduced pressure to provide 5.07 g of 4-(p-menthan-8-yloxy)aniline.
Boiling point: 146-148~C./0.3 mm Hg Elemental Analysis for C16H25NO:
.,.
.
``` 1~ 6 ;
1 C(~) H(~) N(%) Calculated 77.68 10.19 5.66 Eound: 77.73 10.20 5.64 Example 2 ~3 ~ I _ O _ ~, To 150 ml of anhydrous ethanol were added successively 6.2 g of 4-(p-menthan-8-yloxy)aniline, 7 g of anhydrous potassium carbonate, and 5.75 g of 1,5-dibromopentane and the mixture was refluxed for 40 hours. After cooling the reaction mixture, the solvent was distilled off under reduced pressure and to the residue were added 200 ml of dichloromethane and 150 ml of water. The dichloromethane layer was separated, washed with water and then an aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was - applied to a silica gel column chromatography. The desired product was then eluted using benzene saturated with ammonia and then the solvent was distilled off under reduced pressure from the eluate to provide 5.77 g of crystalline 1-[4-(p-menthan-3-yloxy)phenyl]piperidine.
When the product was recrystallized from ethanol, the white crystals having a melting point of 53-54 C. were obtained.
Elemental analysis for C21~33NO:
:
1 C(%) H(~) N(%) Calculated 79.95 10.54 4.44 Found 79.90 10.83 4.37 ~ y the similar procedure as in Example 1 using other alcohol compounds instead of p-menthan-8-ol in Example 1, aniline derivatives were obtained and they were reacted with 1,5-dibromopentane by the similar procedure as in Example 1 to provide the compounds in Examples 3-17.
Exa_ple_3 Alcohol compound used as starting material ~ OH MENTHOL
Desired compoundfH
O ~ N
~C ~
1-[4-(p-menthan-3-yloxy)phenyl]piperidine Melting point 93 - 94 C.
Elemental analysis for C21H33NO:
Ct%) H(%) N(%) Calculated 79.95 10.54 4.44 Found 79.91 10.75 4.41 Exa_ple_4 Alcohol compound used as starting material:
CH = ~ (CH2)3CH~CH2)2OH
3,7-dimethyl-7-octen-1-ol.
Desired compound:
,y.
f,~
"''" 1$1 .~
:
1 CH CH3 ~ N
. .
1-[4-(3,7-dimethyloctyloxy)phenyl]piperidine Boiling point 174-178 C/0.4mmHg Elemental analysis for C H NO:
C(%) H(%) N(~) Calculated 79.44 11.11 4.41 Found 79.40 11.43 4.19 Example 5 ____ ___ Alcohol compound used as starting material CH IOH
CH3C = CH(CH2)2C CH = CH2 ` 3,7-dimethyl-3-oxy-1,6-oxtadiene Desired compound:
. . .
N-[4-(3,7-dimethyloct-3-yloxy)phenyl]piperidine Boiling point 174-176 C/0.5mmHg Elemental analysis for C21H35NO:
C(%) H(%) N(%) Calculated 79.44 11.11 4.41 Found 79.74 11.23 4.13 Exam_le 6 _ _ : Alcohol compound used as starting material CH3(CH2)17 - OH
! ', ~ .
1 Octadecanol Desired compound '~' N-(4-octadecanyloxyphenyl)piperidine Melting point 54 - 55 C
Elemental analycis for C29H51NO:
C(%) H(%) N(%) Calculated 81.06 11.96 3.26 Found 80.92 12.27 3.00 - Exa_~le_7_ Alcohol compound used as starting material : CH3 ,.~. I
; l,l-dimethylpropanol .
Desired compound CH
20 3 2l ~ N
.
; CH
. ~;.
N-[4-(1,1-dimethylpropoxy)phenyl]piperidine Boiling point 120 - 122~ C/lmmHg Elemental analysis for C16H25NO:
C(%) H(%) N(%) Calculated 77.68 10.19 5.66 Found 77.32 10.24 5.39 Exa_~le_8 Alcohol compound used as starting material:
30 ~ CH2 OH
. .
1 Cyclohexylmethanol Desired compound:
~}
N- [ 4- ( cyclohexylmethoxy)phenyl]piperidine ; Melting point 63 - 64 C
Elemental analysis for C18H27NO:
C ( %) H ( %) N (%) Calculated 79.07 9.95 5.12 Found 78.88 10.22 5.00 Exa__le 9 Alcohol compound used as starting material:
CH
- ~ CH OH
"
l-cyclohexylethanol .:. Desired compound CH - O ~ ~
N-14-(1-cyclohexylethoxy)phenyl]piperidine Boiling point 147 - 148 C/0.3mmHg Elemental analysis ~or ClgH29NO:
C(%) H(%) N(%) Calculated 79.39 10.17 4.87 Found 79.28 10.51 4.87 Exam_le 10 ____ _____ Alcohol compound used as starting material . . .
~,'' ;
C OH
l-cyclohexyl-l-methylethanol Desired compound ~ IC- o ~3 ~
CH
N-[4-(1-cyclohexyl-1-methyloxy)phenyl]piperidine Melting point 66 - 67 C
Blemental analysis for C20H31NO:
C(%) H(%) N(~) Calculated 79.68 10.36 4.65 Found 79.54 10.58 4.41 Exa_ple_ll Alcohol compound used as starting material - CH
;` 20 l-Benzyl-l-methylethanol Desired compound ~: .
H2C -O ~ N
N-[4-(~,~-dimethylphenethyloxy)phenyl]piperidine I Melting point 68 - 69 C
Elemental analysis for C21H27NO:
' ~.
Z4~
1 C(%) H(%) N(~) Calculated 81.51 8.79 4.53 Found 81.33 8.95 4.52 Example_12 Alcohol compound used as starting material ~ OH
l-methylcyclohexanol Desired compound ~ CH3 ~ N~ . HCl , .
' N- [ 4-(1-methylcyclohexyloxy)phenyl~piperidine hydrochloride : Melting point 150 - 151 C
- Elemental analysis for C18H28NO:
C(%) H(~) N(%) Calculated 69.77 9.11 4.52 Found 69.39 9.42 4.64 Example 13 . , --________ : Alcohol compound used as starting compound CH
3-methylmenthol Desired compound ~' [~< o ~
CH\
: N-l4-(3-methyl-p-menthan-3-yloxy)phenyl]piperidine Boiling point 140 - 145C/0.3mmHg Elemental analysis for C22H35NO:
C(%) H(%) N(%) Calculated 80.19 10.71 4.25 Found 80.14 10.42 3.92 Exa_ple_14 . Alcohol compound used as starting material CH
C OH
., ~
~ .
a -cyclohexyl-~-methylbenzylalcohol Desired compound ~C_o ~
b N-[4-(~-cyclohexyl-~-methylbenzyloxy)phenyl]piperidine Boiling point 178 - 183 C/0.25mmHg Elemental analysis for C25H33NO:
C(%) H(%) N(%) Calculated 82.60 9.15 3.85 Found 82.66 9.35 3.65 .
:``` lil~29~6 1 Exa_~le_15 Alcohol compound used as starting material CH OH
Dicyclohexylmethanol - Desired compound . ~ CH _ .
N-(4-dicyclohexylmethoxyphenyl)piperidine . Melting point 57 - 58 C
: Elemental analysis for C24H37NO:
C(~) H(%) N(%) Calculated 81.07 10.49 3.94 Found 81.16 10.83 3.73 Exa ple_l6 . Alcohol compound used as starting material . CH
' ' ~}
.. CH3 -dimethylbenzylalcohol . Desired compound CH
CH
' , N-l4-(~,~-dimethylbenzyloxy)phenyl]piperidine Melting point 92 - 93C
Elemental analysis for C20H25NO:
C(%) H(%) N(%) Calculted 81.31 8.53 4.74 Found 81.09 9.69 4.98 Example 17 Alcohol compound used as starting material Cyclohexanol Desired compound :
O--- O ~--N~
N-(4-cyclohexyloxyphenyl)piperidine Melting point 50 - 51C
Elemental analysis for C17H25NO:
C(%) H(~) N(~) Calculated 78.72 9.71 5.40 30 Found 78.51 9.92 5.56 .: :
Zq~6 1 Exa_~le_18 C33 ~ ~ 3 1 To 50 ml of anhydrous ethanol were added successively 1.23 g of 4-(p-menthan-8-yloxy)aniline, 1.4 g. of anhydrous potassium carbonate and 1.1 g of ; 10 1,4-dibromobutane and the mixture was refluxed for 42 hours. Then, the reaction product was subjected to the extraction and purification procedures as in Example 1 to provide 1.1 g of crystalline N-[4-(p-menthan-8-yloxy)-phenyl]pyrrolidine. When the product was recrystallized from ethanol, the white crystals having a melting point of 92-93C were obtained.
Elemental analysis for C20H31NO:
C(%) H(%) N(%) Calculated 79.68 10.36 4.65 Found 79.43 10.65 4.37 Exam~le_l9 CH3 ~ I ~ N
CH
To 150 ml of anhydrous ethanol were added succesively 30 g of cis-4-(p-menthan-8-yloxy)aniline, 25.2 -~ g of anhydrous potassium carbonate and 33.5 g of 1,5-dibromopentane and the mixture was refluxed for 15 2~
:
1 hours. After cooling the reaction mixture, the solvent was distilled off under reduced pressure and to the residue were added 500 ml of dichloromethane and 500 ml of water. The dichloromethane layer was separated by decantation, washed with water and then an aqueous sodium chloride solution, and dried over anhydrous sodium sulfate.The sulfate was distilled off under reduced pressure and the residue formed was appiied to silica gel column chromatography. Then, the desired product was eluted using benzene saturated with ammonia and the solvent of the eluate was distilled off under reduced pressure to provide 23 g of cis-1-[4-(p-menthan-8-yloxy)-phenyl]piperidine. When the product was recrystallized from ethanol, the white crystals having a melting point of 78-79VC were obtained.
Elemental analysis for C21H33NO:
C(%) H(%) N(%) Calculated 79.95 10.54 4.44 Found 79.83 10.98 4.36 20 Exam~le 20 ____ _____ CH
3 - a 1 3 N ~
By following the same procedure as in Example 19 using trans-4-(p-menthan-8-yloxy)aniline in place of cis-4-(p-menthan-8-yloxy)aniline, the crystals of trans-1-[4-(p-menthan-8-yloxy)phenyl]piperidine were obtained.
Melting point 62-63 C
1 Elemental analysis for C21H33NO;
C(~) H(%) N(%) Calculated 79.95 10.54 4.44 Found 80.00 10.87 4.39 Exa_ple_21 CH
3 _ O ~ C -- O ~ N
CH
In 47 ml of a 95% ethanol solution of 1 normal potassium hydroxide was dissolved 2.1 9 of trans-N-ethoxy-carbonyl-4-(p-menthan-B-yloxy)aniline and the solution was refluxed for 6 hours. Then, ethanol was distilled off under reduced pressure from the reaction mixture and to the residue formed were added 50 ml of ether and 50 ml of water followed by extraction with ether. The extract was washed with water and then an aqueous sodium chloride solution and after drying over anhydrous magnesium sulfate, ether was distilled off from the reaction mixture to provide 1.75 9 of trans-4-(p-menthan-8-yloxy)aniline.
To 50 ml of anhydrous ethanol was added 1.7 9 of the product together with 2 g of anhydrous postassium carbonate and 1.7 9 of 1,5-dibromopentane and the mixture was refluxed for 16 hours. Then~ by treating the reaction product as in Example 18, 0.95 9 of the crystals of trans-1-[4-(p-menthan-8-yloxy)phenyl]piperidine were obtained.
Melting point 62 - 63C
The infrared absorption spectra, nuclear magnetic resonance spectra ( H, C), and the mass spectra of the crystals coincided well with these spectra of the ~,' - 1 crystals obtained in Example 21.
Example_22 CH
CH3~ ~ ~ C O ~ N
. CH
'`
. By following the same procedure as in Example 20 .: .
using cis-N-ethoxycarbonyl-4-(p-menthan-8-yloxy)aniline in place of trans-N-ethoxycarbonyl-4-(p-menthan-8-yloxy)-aniline, the crystals of cis-1-[4-(p-menthan-8-yloxy)-phenyl]puperidine were obtained.
Melting point 78-79C
The infrared absorption spectra, nuclear magnetic resonance spectra ( H, C), and mass spectra of the crystals coincided well with those of the crystals obtained in Example 19.
Example 23 ___ ____ Tablets One thousand tablets for oral use, each containing . 100 mg of 1-[4-(p-menthan-8-yloxy)phenyl]piperidine, are ;. prepared from the following ingredients:
1-[4-(-p-menthan-8-yloxy)phenyl]piperidine: 100 Gm Methylcellulose J.P.: 6.5 Gm Lactotose: 25 Gm Talc: 5Gm Calcium Stearate: 3.5 GM
The 1-[4-(p-menthan-8-yloxy)phenyl]piperidine is granulated with 7.5% w/v aqueous solution of methylcellulose, passed through a No. 8 screen and dried ~ ~'~6 ,. 1 carefully. The dried gran~les are passed through a No. 12 screen, mixed with the talc, lactose and stearate and compressed into tablets.
:
~;' ', ~: 10 ';
. ,.
;
,, ,~
mixture of this product and 0.7 g of 10% palladium carbon in 100 ml of ethyl acetate was shaken under hydrogen until the theoretical amount of hydrogen had been absorbed.
After filtering away palladium carbon, the solvent was distilled off under reduced pressure and the residue was distilled under reduced pressure to provide 5.07 g of 4-(p-menthan-8-yloxy)aniline.
Boiling point: 146-148~C./0.3 mm Hg Elemental Analysis for C16H25NO:
.,.
.
``` 1~ 6 ;
1 C(~) H(~) N(%) Calculated 77.68 10.19 5.66 Eound: 77.73 10.20 5.64 Example 2 ~3 ~ I _ O _ ~, To 150 ml of anhydrous ethanol were added successively 6.2 g of 4-(p-menthan-8-yloxy)aniline, 7 g of anhydrous potassium carbonate, and 5.75 g of 1,5-dibromopentane and the mixture was refluxed for 40 hours. After cooling the reaction mixture, the solvent was distilled off under reduced pressure and to the residue were added 200 ml of dichloromethane and 150 ml of water. The dichloromethane layer was separated, washed with water and then an aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was - applied to a silica gel column chromatography. The desired product was then eluted using benzene saturated with ammonia and then the solvent was distilled off under reduced pressure from the eluate to provide 5.77 g of crystalline 1-[4-(p-menthan-3-yloxy)phenyl]piperidine.
When the product was recrystallized from ethanol, the white crystals having a melting point of 53-54 C. were obtained.
Elemental analysis for C21~33NO:
:
1 C(%) H(~) N(%) Calculated 79.95 10.54 4.44 Found 79.90 10.83 4.37 ~ y the similar procedure as in Example 1 using other alcohol compounds instead of p-menthan-8-ol in Example 1, aniline derivatives were obtained and they were reacted with 1,5-dibromopentane by the similar procedure as in Example 1 to provide the compounds in Examples 3-17.
Exa_ple_3 Alcohol compound used as starting material ~ OH MENTHOL
Desired compoundfH
O ~ N
~C ~
1-[4-(p-menthan-3-yloxy)phenyl]piperidine Melting point 93 - 94 C.
Elemental analysis for C21H33NO:
Ct%) H(%) N(%) Calculated 79.95 10.54 4.44 Found 79.91 10.75 4.41 Exa_ple_4 Alcohol compound used as starting material:
CH = ~ (CH2)3CH~CH2)2OH
3,7-dimethyl-7-octen-1-ol.
Desired compound:
,y.
f,~
"''" 1$1 .~
:
1 CH CH3 ~ N
. .
1-[4-(3,7-dimethyloctyloxy)phenyl]piperidine Boiling point 174-178 C/0.4mmHg Elemental analysis for C H NO:
C(%) H(%) N(~) Calculated 79.44 11.11 4.41 Found 79.40 11.43 4.19 Example 5 ____ ___ Alcohol compound used as starting material CH IOH
CH3C = CH(CH2)2C CH = CH2 ` 3,7-dimethyl-3-oxy-1,6-oxtadiene Desired compound:
. . .
N-[4-(3,7-dimethyloct-3-yloxy)phenyl]piperidine Boiling point 174-176 C/0.5mmHg Elemental analysis for C21H35NO:
C(%) H(%) N(%) Calculated 79.44 11.11 4.41 Found 79.74 11.23 4.13 Exam_le 6 _ _ : Alcohol compound used as starting material CH3(CH2)17 - OH
! ', ~ .
1 Octadecanol Desired compound '~' N-(4-octadecanyloxyphenyl)piperidine Melting point 54 - 55 C
Elemental analycis for C29H51NO:
C(%) H(%) N(%) Calculated 81.06 11.96 3.26 Found 80.92 12.27 3.00 - Exa_~le_7_ Alcohol compound used as starting material : CH3 ,.~. I
; l,l-dimethylpropanol .
Desired compound CH
20 3 2l ~ N
.
; CH
. ~;.
N-[4-(1,1-dimethylpropoxy)phenyl]piperidine Boiling point 120 - 122~ C/lmmHg Elemental analysis for C16H25NO:
C(%) H(%) N(%) Calculated 77.68 10.19 5.66 Found 77.32 10.24 5.39 Exa_~le_8 Alcohol compound used as starting material:
30 ~ CH2 OH
. .
1 Cyclohexylmethanol Desired compound:
~}
N- [ 4- ( cyclohexylmethoxy)phenyl]piperidine ; Melting point 63 - 64 C
Elemental analysis for C18H27NO:
C ( %) H ( %) N (%) Calculated 79.07 9.95 5.12 Found 78.88 10.22 5.00 Exa__le 9 Alcohol compound used as starting material:
CH
- ~ CH OH
"
l-cyclohexylethanol .:. Desired compound CH - O ~ ~
N-14-(1-cyclohexylethoxy)phenyl]piperidine Boiling point 147 - 148 C/0.3mmHg Elemental analysis ~or ClgH29NO:
C(%) H(%) N(%) Calculated 79.39 10.17 4.87 Found 79.28 10.51 4.87 Exam_le 10 ____ _____ Alcohol compound used as starting material . . .
~,'' ;
C OH
l-cyclohexyl-l-methylethanol Desired compound ~ IC- o ~3 ~
CH
N-[4-(1-cyclohexyl-1-methyloxy)phenyl]piperidine Melting point 66 - 67 C
Blemental analysis for C20H31NO:
C(%) H(%) N(~) Calculated 79.68 10.36 4.65 Found 79.54 10.58 4.41 Exa_ple_ll Alcohol compound used as starting material - CH
;` 20 l-Benzyl-l-methylethanol Desired compound ~: .
H2C -O ~ N
N-[4-(~,~-dimethylphenethyloxy)phenyl]piperidine I Melting point 68 - 69 C
Elemental analysis for C21H27NO:
' ~.
Z4~
1 C(%) H(%) N(~) Calculated 81.51 8.79 4.53 Found 81.33 8.95 4.52 Example_12 Alcohol compound used as starting material ~ OH
l-methylcyclohexanol Desired compound ~ CH3 ~ N~ . HCl , .
' N- [ 4-(1-methylcyclohexyloxy)phenyl~piperidine hydrochloride : Melting point 150 - 151 C
- Elemental analysis for C18H28NO:
C(%) H(~) N(%) Calculated 69.77 9.11 4.52 Found 69.39 9.42 4.64 Example 13 . , --________ : Alcohol compound used as starting compound CH
3-methylmenthol Desired compound ~' [~< o ~
CH\
: N-l4-(3-methyl-p-menthan-3-yloxy)phenyl]piperidine Boiling point 140 - 145C/0.3mmHg Elemental analysis for C22H35NO:
C(%) H(%) N(%) Calculated 80.19 10.71 4.25 Found 80.14 10.42 3.92 Exa_ple_14 . Alcohol compound used as starting material CH
C OH
., ~
~ .
a -cyclohexyl-~-methylbenzylalcohol Desired compound ~C_o ~
b N-[4-(~-cyclohexyl-~-methylbenzyloxy)phenyl]piperidine Boiling point 178 - 183 C/0.25mmHg Elemental analysis for C25H33NO:
C(%) H(%) N(%) Calculated 82.60 9.15 3.85 Found 82.66 9.35 3.65 .
:``` lil~29~6 1 Exa_~le_15 Alcohol compound used as starting material CH OH
Dicyclohexylmethanol - Desired compound . ~ CH _ .
N-(4-dicyclohexylmethoxyphenyl)piperidine . Melting point 57 - 58 C
: Elemental analysis for C24H37NO:
C(~) H(%) N(%) Calculated 81.07 10.49 3.94 Found 81.16 10.83 3.73 Exa ple_l6 . Alcohol compound used as starting material . CH
' ' ~}
.. CH3 -dimethylbenzylalcohol . Desired compound CH
CH
' , N-l4-(~,~-dimethylbenzyloxy)phenyl]piperidine Melting point 92 - 93C
Elemental analysis for C20H25NO:
C(%) H(%) N(%) Calculted 81.31 8.53 4.74 Found 81.09 9.69 4.98 Example 17 Alcohol compound used as starting material Cyclohexanol Desired compound :
O--- O ~--N~
N-(4-cyclohexyloxyphenyl)piperidine Melting point 50 - 51C
Elemental analysis for C17H25NO:
C(%) H(~) N(~) Calculated 78.72 9.71 5.40 30 Found 78.51 9.92 5.56 .: :
Zq~6 1 Exa_~le_18 C33 ~ ~ 3 1 To 50 ml of anhydrous ethanol were added successively 1.23 g of 4-(p-menthan-8-yloxy)aniline, 1.4 g. of anhydrous potassium carbonate and 1.1 g of ; 10 1,4-dibromobutane and the mixture was refluxed for 42 hours. Then, the reaction product was subjected to the extraction and purification procedures as in Example 1 to provide 1.1 g of crystalline N-[4-(p-menthan-8-yloxy)-phenyl]pyrrolidine. When the product was recrystallized from ethanol, the white crystals having a melting point of 92-93C were obtained.
Elemental analysis for C20H31NO:
C(%) H(%) N(%) Calculated 79.68 10.36 4.65 Found 79.43 10.65 4.37 Exam~le_l9 CH3 ~ I ~ N
CH
To 150 ml of anhydrous ethanol were added succesively 30 g of cis-4-(p-menthan-8-yloxy)aniline, 25.2 -~ g of anhydrous potassium carbonate and 33.5 g of 1,5-dibromopentane and the mixture was refluxed for 15 2~
:
1 hours. After cooling the reaction mixture, the solvent was distilled off under reduced pressure and to the residue were added 500 ml of dichloromethane and 500 ml of water. The dichloromethane layer was separated by decantation, washed with water and then an aqueous sodium chloride solution, and dried over anhydrous sodium sulfate.The sulfate was distilled off under reduced pressure and the residue formed was appiied to silica gel column chromatography. Then, the desired product was eluted using benzene saturated with ammonia and the solvent of the eluate was distilled off under reduced pressure to provide 23 g of cis-1-[4-(p-menthan-8-yloxy)-phenyl]piperidine. When the product was recrystallized from ethanol, the white crystals having a melting point of 78-79VC were obtained.
Elemental analysis for C21H33NO:
C(%) H(%) N(%) Calculated 79.95 10.54 4.44 Found 79.83 10.98 4.36 20 Exam~le 20 ____ _____ CH
3 - a 1 3 N ~
By following the same procedure as in Example 19 using trans-4-(p-menthan-8-yloxy)aniline in place of cis-4-(p-menthan-8-yloxy)aniline, the crystals of trans-1-[4-(p-menthan-8-yloxy)phenyl]piperidine were obtained.
Melting point 62-63 C
1 Elemental analysis for C21H33NO;
C(~) H(%) N(%) Calculated 79.95 10.54 4.44 Found 80.00 10.87 4.39 Exa_ple_21 CH
3 _ O ~ C -- O ~ N
CH
In 47 ml of a 95% ethanol solution of 1 normal potassium hydroxide was dissolved 2.1 9 of trans-N-ethoxy-carbonyl-4-(p-menthan-B-yloxy)aniline and the solution was refluxed for 6 hours. Then, ethanol was distilled off under reduced pressure from the reaction mixture and to the residue formed were added 50 ml of ether and 50 ml of water followed by extraction with ether. The extract was washed with water and then an aqueous sodium chloride solution and after drying over anhydrous magnesium sulfate, ether was distilled off from the reaction mixture to provide 1.75 9 of trans-4-(p-menthan-8-yloxy)aniline.
To 50 ml of anhydrous ethanol was added 1.7 9 of the product together with 2 g of anhydrous postassium carbonate and 1.7 9 of 1,5-dibromopentane and the mixture was refluxed for 16 hours. Then~ by treating the reaction product as in Example 18, 0.95 9 of the crystals of trans-1-[4-(p-menthan-8-yloxy)phenyl]piperidine were obtained.
Melting point 62 - 63C
The infrared absorption spectra, nuclear magnetic resonance spectra ( H, C), and the mass spectra of the crystals coincided well with these spectra of the ~,' - 1 crystals obtained in Example 21.
Example_22 CH
CH3~ ~ ~ C O ~ N
. CH
'`
. By following the same procedure as in Example 20 .: .
using cis-N-ethoxycarbonyl-4-(p-menthan-8-yloxy)aniline in place of trans-N-ethoxycarbonyl-4-(p-menthan-8-yloxy)-aniline, the crystals of cis-1-[4-(p-menthan-8-yloxy)-phenyl]puperidine were obtained.
Melting point 78-79C
The infrared absorption spectra, nuclear magnetic resonance spectra ( H, C), and mass spectra of the crystals coincided well with those of the crystals obtained in Example 19.
Example 23 ___ ____ Tablets One thousand tablets for oral use, each containing . 100 mg of 1-[4-(p-menthan-8-yloxy)phenyl]piperidine, are ;. prepared from the following ingredients:
1-[4-(-p-menthan-8-yloxy)phenyl]piperidine: 100 Gm Methylcellulose J.P.: 6.5 Gm Lactotose: 25 Gm Talc: 5Gm Calcium Stearate: 3.5 GM
The 1-[4-(p-menthan-8-yloxy)phenyl]piperidine is granulated with 7.5% w/v aqueous solution of methylcellulose, passed through a No. 8 screen and dried ~ ~'~6 ,. 1 carefully. The dried gran~les are passed through a No. 12 screen, mixed with the talc, lactose and stearate and compressed into tablets.
:
~;' ', ~: 10 ';
. ,.
;
,, ,~
Claims (62)
PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A method of producing a cyclicaminophenyl ether compound represented by the formula:
wherein R1 represents hydrogen atom or a lower alkyl group; R2 represents a cyclohexyl group which may have been substituted by lower alkyl group(s), an alkyl group containing from 1 to 20 carbon atoms, a phenyl group, or a benzyl group; R3 represents hydrogen atom, a lower alkyl group, or a cyclohexyl group which may have been substituted by lower alkyl group(s) and n is 4 or 5; said R2 and R3 may form together with the adjacent carbon atom a cyclohexane ring which may have been substituted by lower alkyl group(s), which comprises reacting the compound represented by the formula:
wherein R1, R2 and R3 have the same significance as above and the compound represented by the formula:
X-(CH2)n-X
wherein X represents halogen atom.
wherein R1 represents hydrogen atom or a lower alkyl group; R2 represents a cyclohexyl group which may have been substituted by lower alkyl group(s), an alkyl group containing from 1 to 20 carbon atoms, a phenyl group, or a benzyl group; R3 represents hydrogen atom, a lower alkyl group, or a cyclohexyl group which may have been substituted by lower alkyl group(s) and n is 4 or 5; said R2 and R3 may form together with the adjacent carbon atom a cyclohexane ring which may have been substituted by lower alkyl group(s), which comprises reacting the compound represented by the formula:
wherein R1, R2 and R3 have the same significance as above and the compound represented by the formula:
X-(CH2)n-X
wherein X represents halogen atom.
2. The process as defined in claim 1, wherein n is 5.
3. The process as defined in claim 1, wherein each of R1 and R3 is lower alkyl, and R2 is cyclohexyl group which may have been substituted by lower alkyl group(s).
4. The process as defined in claim 2, wherein each of R1 and R3 is lower alkyl, and R2 is cyclohexyl which may have been substituted by lower alkyl group(s).
5. The process as defined in claim 1, wherein R1 is hydrogen or lower alkyl group and R2 and R3 form together within the adjacent carbon atom a cyclohexane ring which may have been substituted by lower alkyl group(s).
6. The process as defined in claim 2, wherein R1 is hydrogen or lower alkyl group and R2 and R3 form together within the adjacent carbon atom a cyclohexane ring which may have been substituted by lower alkyl group(s).
7. The process as defined in claim 1, wherein each of R1 and R3 is hydrogen atom or lower alkyl group, and R2 is alkyl group containing from 1 to 20 carbon atoms.
8. The process as defined in claim 2, wherein each of R1 and R3 is hydrogen atom or lower alkyl group, and R2 is alkyl group containing from 1 to 20 carbon atoms.
9. The process as defined in claim 1, wherein each of R1 and R3 is hydrogen atom or lower alkyl group, and R2 is benzyl group or cyclohexyl group which may have been substituted by lower alkyl group(s).
10. The process as defined in claim 2, wherein each of R1 and R3 is hydrogen atom or lower alkyl group, and R2 is benzyl group or cyclohexyl group which may have been substituted by lower alkyl group(s).
11. The process as defined in claim 1, wherein each of R1 and R3 is lower alkyl group or cyclohexyl group and R2 is phenyl group.
12. The process as defined in claim 2, wherein each of R1 and R3 is lower alkyl group or cyclohexyl group and R2 is phenyl group.
13. The process as defined in claim 1 for the preparation of 1-[4-(p-menthan-8-yloxy)phenyl]piperidine which comprises reacting 4-(P-menthan-8-yloxy)aniline and 1,5-dibromopentane.
14. The process as defined in claim 1 for the preparation of 1-[4-(p-menthan-3-yloxy)phenyl]piperidine which comprises reacting 4-(p-menthan-3-yloxy)aniline and 1,5-dibromopentane.
15. The process as defined in claim 1 for the preparation of 1-[4-(3,7-dimethyloctyloxy)phenyl]piperidine which comprises reacting 4-(3,7-dimethyloctyloxy)aniline and 1,5-dibromopentane.
16. The process as defined in claim 1 for the preparation of N-[4-(3,7-dimethyloct-3-yloxy)phenyl]piperidine which comprises reacting 4-(3,7-dimethyloct-3-yloxy)aniline and 1,5-dibromopentane.
17. The process as defined in claim 1 for the preparation of N-(4-octadecanyloxyphenyl)piperidine which comprises reacting 4-octadecanyloxyaniline and 1,5-dibromopentane.
18. The process as defined in claim 1 for the preparation of N-[4-(1,1-dimethylpropoxy)phenyl]piperidine which comprises reacting 4-(1,1-dimethylpropoxy)aniline and 1,5-dibromopentane.
19. The process as defined in claim 1 for the preparation of N-[4-(cyclohexylmethoxy)phenyl]piperidine which comprises reacting 4-(cyclohexylmethoxy)aniline and 1,5-dibromopentane.
20. The process as defined in claim 1 for the preparation of N-[4-(1-cyclohexylethoxy)phenyl]piperidine which comprises reacting 4-(1-cyclohexylethoxy)aniline and 1,5-dibromopentane.
21. The process as defined in claim 1 for the preparation of N-[4-(1-cyclohexyl-1-methyloxy)phenyl]piperidine which comprises reacting 4-(1-cyclohexyl-1-methyloxy)aniline and 1,5-dibrompentane.
22. The process as defined in claim 1 for the preparation of N-[-(.alpha.,.alpha.-dimethylphenethylxoy)phenyl]piperidine which comprises reaction 4-(.alpha.,.alpha.-dimethylphenetllyloxy)aniline and 1,5-dibrompentane.
23. The process as defined in claim 1 for the preparation of N-[4-(1-methylcyclohexyloxy)phenyl]piperidine which comprises reacting 4-(1-methylcyclophexyloxy)aniline and 1,5-dibromopentane.
24. The process as defined in claim 1 for the preparation of N-[4-(3-methyl-p-menthan-3-yloxy)phenyl]piperidine which comprises reacting 4-(3-methyl-p-menthan-3-yloxy)aniline and 1,5-dibromopentane.
25. The process as defined in claim 1 for the preparation of N-[4-(.alpha.-cyclohexyl-.alpha.-methylbenzyloxy)phenyl]piperidine which comprises reacting 4-(.alpha.-cyclohexyl-.alpha.-methylbenzyloxy)aniline and 1,5-dibromopentane.
26. The process as defined in claim 1 for the preparation of N-(4-dicyclohexylmethoxyphenyl)piperidine which comprises reacting 4-dicyclohexylmethoxyaniline and 1,5-dibromopentane.
27. The process as defined in claim 1 for the preparation of N-[4-(.alpha., .alpha.-dimethylbenzyloxy)phenyl]piperidine which comprises reacting 4-(.alpha.,.alpha.-dimethylbenzyloxy)aniline and 1,5-dibromopentane.
28. The process as defined in claim 1 for the preparation of N-(4-cyclohexyloxyphenyl)piperidine which comprises reacting 4-cyclohexyloxyaniline and 1,5-dibromopentane.
29. The process as defined in claim 1 for the preparation of N-[4-(p-menthan-8-yloxy)phenyl]pyrrolidine which comprises reacting 4-(p-menthan-8-yloxy)aniline and 1,4-dibromobutane.
30. The process as defined in claim 1 for the preparation of cis-1-[4-(p-menthan-8-yloxy)phenyl]piperidine which comprises reacting cis-4-(p-menthan-8-yloxy)aniline and 1,5-dibromopentane.
31. The process for the preparation of trans-1-[4-(p-menthan-8-ylxoy)phenyl]piperidine which comprises reacting trans-4-(p-menthan-8-yloxy)aniline and 1,5-dibromopentane.
32. A compound of the formula:
wherein R1 represents hydrogen atom or a lower alkyl group;
R2 represents a cyclohexyl group which may have been substituted by lower alkyl group(s), an alkyl group containing from 1 to 20 carbon atoms, a phenyl group, or a benzyl group;
R3 represents hydrogen atom, a lower alkyl group, or a cyclohexyl group which may have been substituted by lower alkyl group(s) and n is 4 or 5; said R2 and R3 may form together with the adjacent carbon atom a cyclohexane ring which may have been substituted by lower alkyl group(s), when prepared by the process of claim 1.
wherein R1 represents hydrogen atom or a lower alkyl group;
R2 represents a cyclohexyl group which may have been substituted by lower alkyl group(s), an alkyl group containing from 1 to 20 carbon atoms, a phenyl group, or a benzyl group;
R3 represents hydrogen atom, a lower alkyl group, or a cyclohexyl group which may have been substituted by lower alkyl group(s) and n is 4 or 5; said R2 and R3 may form together with the adjacent carbon atom a cyclohexane ring which may have been substituted by lower alkyl group(s), when prepared by the process of claim 1.
33. A compound as defined in claim 32, wherein n is 5, when prepared by the process of claim 2.
34. A compound as defined in claim 32, wherein each of R1 and R3 is lower alkyl, and R2 is cyclohexyl group which may have been substituted by lower alkyl group(s) when prepared by the process of claim 3.
35. A compound as defined in claim 32, wherein n is 5, each of R1 and R3 is lower alkyl, and R2 is cyclohexyl group which may have been substituted by lower alkyl group(s) when prepared by the process of claim 4.
36. A compound as defined in claim 32, wherein R1 is hydrogen atom or lower alkyl group and R2 and R3 form together with the adjacent carbon atom a cyclohexane ring which may have been substituted by lower alkyl group(s), when prepared by the process of claim 5.
37. A compound as defined in claim 21, wherein n is 5, R1 is hydrogen atom or lower alkyl group and R2 and R3 form together with the adjacent carbon atom a cyclohexane ring which may have been substituted by lower alkyl group(s), when prepared by the process of claim 6.
33. A compound as defined in claim 32, wherein each of R1 and R3 is hydrogen atom or lower-alkyl group, and R2 is alkyl group containing from 1 to 20 carbon atoms, when prepared by the process of claim 7.
39. A compound as defined in claim 32, wherein n is 5, each of R1 and R3 is hydrogen atom or lower alkyl group, and R2 is alkyl group containing from 1 to 20 carbon atoms, when prepared by the process of claim 8.
40. A compound as defined in claim 32, wherein each of R1 and R3 is hydrogen atom or lower alkyl group, and R2 is benzyl group or cyclohexyl group which may have been substituted by lower alkyl group(s), when prepared by the process of claim 9.
41. A compound as defined in claim 32, wherein n is 5, each of R1 and R3 is hydrogen atom or lower alkyl group, and R2 is benzyl group or cyclohexyl group which may have been substituted by lower alkyl group(s), when prepared by the process of claim 10.
42. A compound as defined in claim 32, wherein each of R1 and R3 is lower alkyl group or cyclohexyl group, and R2 is phenyl group, when prepared by the process of claim 11.
43. A compound as defined in claim 32, wherein n is 5, each of R1 and R3 is lower alkyl group or cyclohexyl group, and R2 is phenyl group, when prepared by the process of claim 12.
44. 1-[4-(p-menthan-3-yloxy)phenyl]piperidine when prepared by the process of claim 13.
45. 1-[4-(p-menthan-3-yloxy)phenyl]piperidine when prepared by the process of claim 14.
46. 1-[4-(3,7-dimethyloctyloxy)phenyl]piperidine when prepared by the process of claim 15.
47. N-[4-(3,7-dimethyloct-3-yloxy)phenyl]piperidine when prepared by the process of claim 16.
48. N-(4-octadecanyloxyphenyl)piperidine when prepared by the process of claim 17.
49. N-[4-(1,1-dimethylpropoxy)phenyl]piperidine when prepared by the process of claim 18.
50. N-[4-(1-cyclohexylethoxy)phenyl]piperidine when prepared by the process of claim 19.
51. N-[4-(1-cyclohexylethoxy)phenyl]piperidine when prepared by the process of claim 20.
52. N-[4-(1-cyclohexyl-1-methyloxy)phenyl]piperidine when prepared by the process of claim 21.
53. N-[4-(.alpha.,.alpha.-dimethylphenethyloxy)phenyl]piperidine when prepared by the process of claim 22.
54. N-[4-(1-methylcyclohexyloxy)phenyl]piperidine when prepared by the process of claim 23.
55. N-[4-(3-methyl-p-menthan-3-yloxy)phenyl]piperidine when prepared by the process of claim 24.
56. N-[4-(.alpha.-cyclohexyl-.alpha.-methylbenzyloxy)phenyl]piperidine when prepared by the process of claim 25.
57. N-(4-dicyclohexylmethoxyphenyl)piperidine when prepared by the process of claim 26.
58. N-[4-(.alpha.,.alpha.-dimethylbenzyloxy)phenyl]piperidine when prepared by the process of claim 27.
59. N-(4-cyclohexyloxyphenyl)piperidine when prepared by the process of claim 28.
60. N-[4-(p-menthan-8-yloxy)phenyl[pyrrolodine when prepared by the process of claim 29.
61. cis-1-[4-(p-menthan-8-yloxy)phenyl]piperidine when prepared by the process of claim 30.
62. Trans-1-[4-(p-menthan-8-yloxy)phenyl]piperidine when prepared by the process of claim 31.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA356,441A CA1110246A (en) | 1977-12-29 | 1980-07-17 | Method of producing cyclic-aminophenyl ether compound |
Applications Claiming Priority (8)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP15809977A JPS5492926A (en) | 1977-12-29 | 1977-12-29 | Compound of aminophenyl ether and its preparation |
| JP158099/1977 | 1977-12-29 | ||
| JP3462478A JPS54128535A (en) | 1978-03-25 | 1978-03-25 | Aminophenyl ether compound and its preparation |
| JP34624/1978 | 1978-03-25 | ||
| JP9129278A JPS5519217A (en) | 1978-07-26 | 1978-07-26 | Aminophenyl ether derivative and its preparation |
| JP91292/1978 | 1978-07-26 | ||
| CA318,098A CA1110248A (en) | 1977-12-29 | 1978-12-18 | Method of producing aminophenyl ether compound |
| CA356,441A CA1110246A (en) | 1977-12-29 | 1980-07-17 | Method of producing cyclic-aminophenyl ether compound |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1110246A true CA1110246A (en) | 1981-10-06 |
Family
ID=27508130
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA356,441A Expired CA1110246A (en) | 1977-12-29 | 1980-07-17 | Method of producing cyclic-aminophenyl ether compound |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1110246A (en) |
-
1980
- 1980-07-17 CA CA356,441A patent/CA1110246A/en not_active Expired
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