CA1074319A - 4,4-diphenylcyclohexylpiperidine compounds and analogs thereof - Google Patents
4,4-diphenylcyclohexylpiperidine compounds and analogs thereofInfo
- Publication number
- CA1074319A CA1074319A CA246,241A CA246241A CA1074319A CA 1074319 A CA1074319 A CA 1074319A CA 246241 A CA246241 A CA 246241A CA 1074319 A CA1074319 A CA 1074319A
- Authority
- CA
- Canada
- Prior art keywords
- bis
- fluorophenyl
- chloro
- cyclohexyl
- benzimidazolinone
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
- C07D211/66—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4 having a hetero atom as the second substituent in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/40—Oxygen atoms
- C07D211/44—Oxygen atoms attached in position 4
- C07D211/52—Oxygen atoms attached in position 4 having an aryl radical as the second substituent in position 4
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
4,4-Diphenylcyclohexylpiperidine compounds and their analogs of the formula:
wherein the dotted line in Ring A indicates an optional bond;
R1, R2, R3 and R4 are independently a hydrogen atom, a halogen atom, a trifluoromethyl group or a lower alkyl group;
n is 1 or 2; m is 0 or 1; and Am is a piperidino group of the formula:
,
4,4-Diphenylcyclohexylpiperidine compounds and their analogs of the formula:
wherein the dotted line in Ring A indicates an optional bond;
R1, R2, R3 and R4 are independently a hydrogen atom, a halogen atom, a trifluoromethyl group or a lower alkyl group;
n is 1 or 2; m is 0 or 1; and Am is a piperidino group of the formula:
,
Description
10743~9 1 This invention relates to novel 4,4-diphenylcyclo-hexylpiperidine compounds and their analogs of the formula:
R ~ (CH2)m - Am (I) wherein the dotted line in Ring A indicates an optional bond;
Rl, R2, R3 and R4 are independently a hydrogen atom, a halogen atom (e.g. F, Cl, Br or I), a trifluoromethyl group or a lower alkyl group (e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl or pentyl); n is 1 or 2; m is 0 or 1; Am is a piperidino group of the formula:
R6 5 ~ 6 -11~5 where the dotted line in Ring B indicates an optional bond;
and RS and R6 are independently a hydrogen atom; a halogen atom, a trifluoromethyl group or a lower alkyl group; and pharmaceutically acceptable acid addition and quaternary ammonium ~, ~074319 1 salts thereof, pharmaceutical compositions containing the said compounds and the use thereof.
Preferred classes of compounds (I) are those wherein R is F, R is H or F, R is F, R is H or F, n is 2, and m is 0.
The compounds of formula (I) can be produced by one of the following methods:
METHOD I
Reaction of a compound of the formula:
~ ~ ) (CH2~m - X (II) with a compound of the formula:
H - Am (III) wherein R , R , R , R , n, m, the dotted line in Ring A and Am are as defined above, and X is a reactive atom or group such as a halogen atom (e.g. Cl, Br or I) or an organic sulfonyloxy group (e.g. mesyloxy or tosyloxy).
The reaction is usually carried out in an inert sol-vent such as methanol, ethanol, acetone, methyl ethyl ketone, tetrahydrofuran, dioxane, methylene chloride, chloroform, benzene, toluene, xylene, dimethylformamide, dimethyl sulfoxide, hexamethylphosphoric triamide or N-methylpyrrolidone or a mixture thereof, in the presence of an acid acceptor such as potassium carbonate, sodium carbonate, sodium hydrogen carbonate, calcium hydrogen carbonate, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide, sodium acetate, potassium acetate, pyridine 1 or triethylamine, if desired in the presence of a catalyst such as potassium iodide, at a temperature of from about 40C to about 90C, for a period of from about 30 minutes to about 100 hours.
METHOD _ This method, to be applied for the production of compounds of formula (I) wherein m is 0, comprises subjecting to dehydration reaction a compound of the formula:
~ -o ~IV) with a compound of formula (III), and subjecting to reduction the resulting compound of the formula:
R 1~ Am (V ) R3 ~ (CH2)a R ~
Wherein Rl, R2, R3, R4, n, the dotted line in Ring A and Am are as defined above, and a is O or 1.
The dehydration reaction is usually carried out in an inert solvent such as mentioned for Method I, preferably benzene, toluene or xylene, in the presence of an acid catalyst such as hydrogen chloride, sulfuric acid or p-toluene-sulfonic acid, at a temperature of from room temperature to a boiling point of the solvent employed, for a period of from several hours to several days.
The emanine intermediate of formula (V) can be 1~743~9 1 isolated and purified by a conventional method such as dis-tillation, recrystallization or chromatography. The isolation is, however, not always necessary.
The reduction includes catalytic and chemical re-ductions. The catalytic reduction is carried out over a metal (e.g. palladium, platinum, rhodium, nickel, ruthenium or cobalt) on a carrier (e.g. active carbon, alumina, barium sulfate, calcium carbonate or strontium carbonate), in an inert solvent such as mentioned for Method I. The reaction time is dependent on reaction conditions such as pressure and temperature, and many hours are required at room temperature and atmospheric pressure. The chemical reduction is carried out by the use of formic acid (or its derivative) or a complex metal hydride. The reduction by the use of formic acid is usually carried out by adding formic acid to a compound of formula (V), and maintaining the resulting mixture at an elevated temperature. The reduction by the use of a complex metal hydride is carried out in an inert solvent such as mentioned for Method I, at a temperature of from 0 C to a boiling point of the solvent employed, for a period of from several minutes to 10 hours. The complex metal hydride includes, for example, lithium aluminum hydride, sodium boro-hydride, boron hydride (borane) and NaAl(OCH2CH20CH3)2H2, and a combination of, for example, lithium aluminum hydride - aluminum chloride or sodium borohydride - aluminum chloride may also be used.
In case a double bond is existent in Ring A or B, the chemical reduction is preferred.
The compounds of formula (I) can also be produced by one of the following methods III to V, however, from the economical point of view, they are not so advanta~eous as Methods I and II as mentioned above.
This method, to be applied for the production of compounds of formula (I) wherein Am is the group of the formula:
- ~ ~ NH
R5 ~ R6 and m is O, comprises reacting a compound of the formula:
R~N~ooR7 with a compound of the formula:
R5 NH2 (VII) in an inert solvent having a relatively high boiling point such as benzene or xylene, at about 80C to about 200C for 5 to 24 hours.
I the above formulas Rl R2 R3 R4 R5 R6 n and the dotted line in Ring A are as defined above, and R7 is a lower alkyl group (preferably methyl or ethyl).
METHOD IV
This method, to be applied for the production of com-pounds of formula ~I) wherein Am is the group of the formula:
~074319 ~ NH
- N ~ ~
R5 ~ R6 eomprises reacting a eompound of the formula:
~ ~ (CEI2)m - N (VIII) with a compound-of the formula:
~H2 R5 ~ R6 (IX) in an inert solvent sueh as water, acetic acid or metha.nol at OC to 100C for 1 to 48 hours, and subjecting to hydrolysis the resulting compound of the formula:
R ~ (CH2)m ~ ~ E (X) R4 R5 ~ R6 in the presence of a catalyst, preferably hydrochloric acid, sulfuric acid, sodium hydroxide or potassium hydroxide, at OC to ~074319 1 150C for 10 minutes to 24 hours, and then subjecting to ring closure the resulting compound of the formula:
R~ ~ (C~2)m ~ ~ 2 R
R5 ~ R6 10 in the presence of a condensing agent, preferably formamide or an aqueous solution of formaldehyde, at 100C to 250C for 1 to 48 hours.
In the above formulas, R , R , R , R , R , R , n, m and the dotted line in Ring A are as defined above, and M is an r alkali metal (e.g. K or Na).
METHOD V
This method, to be applied for the production of compounds of formula (I) wherein Am is the group of the 20 formula:
~ H
- N ~ R
~ R
comprises reacting a compound of the formula:
~ ~ 2)m ~ (VIII) 1 with a compound of the formula:
R ~ ~ y (XII) in an inert solvent, preferably ether, tetrahydrofuran or dioxane, at -30C to 150C for 0.5 to 10 hours.
In the above formulas, R , R , R , R , R , R , n, m and the dotted line in Ring A are as defined above, and Y is -Mg-Hal (Hal is a halogen atom) or Li.
The Starting compounds of formulas (II) and (IV) wherein, for example, n is 2 and m is O can be prepared by such a conventional method as described in the following reaction scheme:
Arl CH3COCH=CH2Arl H2/Pd-C Arl
R ~ (CH2)m - Am (I) wherein the dotted line in Ring A indicates an optional bond;
Rl, R2, R3 and R4 are independently a hydrogen atom, a halogen atom (e.g. F, Cl, Br or I), a trifluoromethyl group or a lower alkyl group (e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl or pentyl); n is 1 or 2; m is 0 or 1; Am is a piperidino group of the formula:
R6 5 ~ 6 -11~5 where the dotted line in Ring B indicates an optional bond;
and RS and R6 are independently a hydrogen atom; a halogen atom, a trifluoromethyl group or a lower alkyl group; and pharmaceutically acceptable acid addition and quaternary ammonium ~, ~074319 1 salts thereof, pharmaceutical compositions containing the said compounds and the use thereof.
Preferred classes of compounds (I) are those wherein R is F, R is H or F, R is F, R is H or F, n is 2, and m is 0.
The compounds of formula (I) can be produced by one of the following methods:
METHOD I
Reaction of a compound of the formula:
~ ~ ) (CH2~m - X (II) with a compound of the formula:
H - Am (III) wherein R , R , R , R , n, m, the dotted line in Ring A and Am are as defined above, and X is a reactive atom or group such as a halogen atom (e.g. Cl, Br or I) or an organic sulfonyloxy group (e.g. mesyloxy or tosyloxy).
The reaction is usually carried out in an inert sol-vent such as methanol, ethanol, acetone, methyl ethyl ketone, tetrahydrofuran, dioxane, methylene chloride, chloroform, benzene, toluene, xylene, dimethylformamide, dimethyl sulfoxide, hexamethylphosphoric triamide or N-methylpyrrolidone or a mixture thereof, in the presence of an acid acceptor such as potassium carbonate, sodium carbonate, sodium hydrogen carbonate, calcium hydrogen carbonate, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide, sodium acetate, potassium acetate, pyridine 1 or triethylamine, if desired in the presence of a catalyst such as potassium iodide, at a temperature of from about 40C to about 90C, for a period of from about 30 minutes to about 100 hours.
METHOD _ This method, to be applied for the production of compounds of formula (I) wherein m is 0, comprises subjecting to dehydration reaction a compound of the formula:
~ -o ~IV) with a compound of formula (III), and subjecting to reduction the resulting compound of the formula:
R 1~ Am (V ) R3 ~ (CH2)a R ~
Wherein Rl, R2, R3, R4, n, the dotted line in Ring A and Am are as defined above, and a is O or 1.
The dehydration reaction is usually carried out in an inert solvent such as mentioned for Method I, preferably benzene, toluene or xylene, in the presence of an acid catalyst such as hydrogen chloride, sulfuric acid or p-toluene-sulfonic acid, at a temperature of from room temperature to a boiling point of the solvent employed, for a period of from several hours to several days.
The emanine intermediate of formula (V) can be 1~743~9 1 isolated and purified by a conventional method such as dis-tillation, recrystallization or chromatography. The isolation is, however, not always necessary.
The reduction includes catalytic and chemical re-ductions. The catalytic reduction is carried out over a metal (e.g. palladium, platinum, rhodium, nickel, ruthenium or cobalt) on a carrier (e.g. active carbon, alumina, barium sulfate, calcium carbonate or strontium carbonate), in an inert solvent such as mentioned for Method I. The reaction time is dependent on reaction conditions such as pressure and temperature, and many hours are required at room temperature and atmospheric pressure. The chemical reduction is carried out by the use of formic acid (or its derivative) or a complex metal hydride. The reduction by the use of formic acid is usually carried out by adding formic acid to a compound of formula (V), and maintaining the resulting mixture at an elevated temperature. The reduction by the use of a complex metal hydride is carried out in an inert solvent such as mentioned for Method I, at a temperature of from 0 C to a boiling point of the solvent employed, for a period of from several minutes to 10 hours. The complex metal hydride includes, for example, lithium aluminum hydride, sodium boro-hydride, boron hydride (borane) and NaAl(OCH2CH20CH3)2H2, and a combination of, for example, lithium aluminum hydride - aluminum chloride or sodium borohydride - aluminum chloride may also be used.
In case a double bond is existent in Ring A or B, the chemical reduction is preferred.
The compounds of formula (I) can also be produced by one of the following methods III to V, however, from the economical point of view, they are not so advanta~eous as Methods I and II as mentioned above.
This method, to be applied for the production of compounds of formula (I) wherein Am is the group of the formula:
- ~ ~ NH
R5 ~ R6 and m is O, comprises reacting a compound of the formula:
R~N~ooR7 with a compound of the formula:
R5 NH2 (VII) in an inert solvent having a relatively high boiling point such as benzene or xylene, at about 80C to about 200C for 5 to 24 hours.
I the above formulas Rl R2 R3 R4 R5 R6 n and the dotted line in Ring A are as defined above, and R7 is a lower alkyl group (preferably methyl or ethyl).
METHOD IV
This method, to be applied for the production of com-pounds of formula ~I) wherein Am is the group of the formula:
~074319 ~ NH
- N ~ ~
R5 ~ R6 eomprises reacting a eompound of the formula:
~ ~ (CEI2)m - N (VIII) with a compound-of the formula:
~H2 R5 ~ R6 (IX) in an inert solvent sueh as water, acetic acid or metha.nol at OC to 100C for 1 to 48 hours, and subjecting to hydrolysis the resulting compound of the formula:
R ~ (CH2)m ~ ~ E (X) R4 R5 ~ R6 in the presence of a catalyst, preferably hydrochloric acid, sulfuric acid, sodium hydroxide or potassium hydroxide, at OC to ~074319 1 150C for 10 minutes to 24 hours, and then subjecting to ring closure the resulting compound of the formula:
R~ ~ (C~2)m ~ ~ 2 R
R5 ~ R6 10 in the presence of a condensing agent, preferably formamide or an aqueous solution of formaldehyde, at 100C to 250C for 1 to 48 hours.
In the above formulas, R , R , R , R , R , R , n, m and the dotted line in Ring A are as defined above, and M is an r alkali metal (e.g. K or Na).
METHOD V
This method, to be applied for the production of compounds of formula (I) wherein Am is the group of the 20 formula:
~ H
- N ~ R
~ R
comprises reacting a compound of the formula:
~ ~ 2)m ~ (VIII) 1 with a compound of the formula:
R ~ ~ y (XII) in an inert solvent, preferably ether, tetrahydrofuran or dioxane, at -30C to 150C for 0.5 to 10 hours.
In the above formulas, R , R , R , R , R , R , n, m and the dotted line in Ring A are as defined above, and Y is -Mg-Hal (Hal is a halogen atom) or Li.
The Starting compounds of formulas (II) and (IV) wherein, for example, n is 2 and m is O can be prepared by such a conventional method as described in the following reaction scheme:
Arl CH3COCH=CH2Arl H2/Pd-C Arl
2~,CHCHO ~1,NaE~H4 Ar ~NaBH4 OH Ar1 esterifying ~ agent A 1 agent Ar ~ Ar ~
Ar , Ar = ~ R ~ ; esterifying agent = PC15, p-CH3C6H4S02Cl, CH3S02Cl, etc, The compounds of formula (I), in case Ring A is cyclohexene ring, cyclopentene ring or cyclopentane ring, are optically active compounds or racemic modifications, which, if desired, can be separated in a conventional manner each into two enantiomers.
The compounds of formula (I) can be converted into 1 acid addition salts with various inorganic and organic acids (e.g. hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, maleic, fumaric, succinic, citric, or tartaric acid), and also into quaternary ammonium salts with dimethyl sulfate, diethyl sulfate, methyl iodide, ethyl bromide, etc.
The compounds of formula (I) and salts thereof exhibit potent and long-lasting psychotropic effects such as anti-apomorphine effect, effect on conditioned avoidance response, anti-methamphethamine effect, taming effect and analgesic effect.
ANTI-APOMORPHINE EFFECT
Test Compounds A: 1-[4,4-bis(p-fluorophenyl)cyclohexyl]-4-(4-chloro-3-trifluoromethylphenyl)-4-piperidinol hydrochloride B: 8-[4,4-bis(p-fluorophenyl)cyclohexyl]-1-(p-fluorophenyl)-1,3,8-triazaspiro[4.5]decan-4-one C: 1-[1-(4,4-bis~p-fluorophenyl)cyclohexyl~-4-piperidyl]-5-chloro-2-benzimidazolinone D: 1-[1-(4,4-bis(p-fluorophenyl)-2-cyclohexenyl)-4-piperidyl]-5-chloro-2-benzimidazolinone E: 8-[4,4-bis(p-fluorophenyl)cyclohexyl]-1-(p-chlorophenyl)-1,3,~-triazaspiro[4.5]decan-4-one F: 1-[1-(4,4-bis(p-fluorophenyl)cyclohexyl)-4-piperidyl]-5-fluoro-2-benzimidazolinone G: 1-[1-(4,4-bis(p-fluorophenyl)-2-cyclohexenyl)-4-piperidyl]-5-fluoro-2-benzimidazolinone hydrochloride hemihydrate Haloperidol (comparison): 1-[3-(p-fluorobenzoyl)propyl]-4-(p-chlorophenyl)-4-piperidinol Pimozide (comparison): 1-[1-(4,4-bis(p~fluorophenyl)butyl)-4-piperidyl]-2-benzimidazolinone 1 Metho and Results The test was performed essentially by the method described by Paul A.J. Janssen et al in "Arzneimittel-Forschung", vol. 17, 841 (1967), using groups of 5-7 female rats. The results are summarized in Table I.
TABLE I
Test Compound ED50 mg/kg~ P.-A 2.46 B 0.10 . _ ._ C 0.18 . .
0.51 E 0.28 . .
F 0.14 .. . .. __ I
G 0.17 Haloperidol 0.50 .
Pimo~ide 0.25 Anti-apomorphine effect was examined in respect of its durability at a dose of ED50 value obtained by the above method. The results are summarized in Table II.
_ 10 -1~74319 ~ .
\ \ Inhibition (%) C(EDSp5o0ùmg/k~ 1 ~ 24 48 72 96 120 144 (? 46~ 7.1 ¦21.4 = 57.1 35.7 ~ 0 = =
(0'C0). . 50~0 ~ 35.7 14.3 7.1 (0.18) 14.350.0 64.3 64.3 64.3 35.7 21.4 0 (0.51) __ 21.450.0 71.4 71.4 64.3 71.4 71.4 64.3 35.7 (0.28) 0 21.4 50.0 50.0 50.0 35.7 7.1 (0.14) - 10 0 50 0 _ 20.0 _ 10.0 ___ .. ... _ (0.17) 20.050.0 40.0 10.0 Haloperidol . .
(0.50) 57.1 ;0.0 21.4 14.3 7.1 _ . .. , . .
Pimozide _(0.25) . 57.1 50.0 35.7 7.1 The data in Table II shows the compounds of the invention exhibit more long-lasting action than Haloperidol and Pi.mozide.
ACUTE TOXICITY
Acute toxicity (LD50~ female mouse, ~ os) was measured by Litchfield-Wilcoxon method (The Journal of Phar-macology and Experimental Therapeutics, vol. 96, 99 (1949)).
The results are summarized in Table III.
1~74319 Test Compound LD50 mq/kg .
A _ 464 C >1000 . ...
D >1000 E _ 464 Haloperidol > 100 Pimozide >1000 The compounds of formula (I), in base or salt form, are useful as long-lasting psychotropie drugs, anti-anxiety drugs, sedatives, analgesies and so on, in the form of a pharmaeeutical preparation with a suitable and conventional pharmaceutically aceeptable carrier, without adversely affecting the patients.
The pharmaceutical preparations can take any con-ventional form such as tablets, capsules, granules, powders o~
injectable solutions.
FORMULATION E~A~PLES
The following is an example of formulations when a compound of the invention is administered for pharmaceutical purposes:
(a) Tablets are prepared from the following eompositions:
5 mg 25 mg 50 mg Tablets Tablets Tablets Compound (I) or its salt5 mg 25 mg 50 mg Lactose 43.6 58.6 51.4 Microcrystalline Cellulose 25.0 25.0 30.0 Corn Stareh 20.0 30.0 30.0 Methyl Cellulose 0.4 0.4 0.6 Tale 6.0 6.0 8.0 Total 100 mg 145 mg 170 mg t (b) Injectable solutions (5 mg/ 2 ml) are prepared from the following compositions:
Compound (I) or its salt0.25%
Benzyl alcohol 2.0 Propylene glycol 30.0 Sodium chloride 0.9 Water for Injectiona sufficient amount to make 2 ml The dose of compound (I) or a salt thereof for human adults usually ranges from 2.5 to 50 mg per week for oral administration, in single or multiple dose, but it may vary depending upon the age, body weight, and/or severity of the conditions to be treated as well as the response to the medication.
The present invention will be better understood from the following examples, but they are not to be construed as limiting the present invention.
A mixture of 4.1 g of 4,4-diphenylcyclohexyl tosylate, 2.2 g of 4-piperidyl-2-benzimidazolinone, 1.5 g of potassium car~onate, 1.5 g of potassium iodide and 50 ml of dimethyl-formamide is stirred at 55C for 47 hours. The reaction mixture is cooled to room temperature and poured into ice water. The precipitate is collected by filtration and dissolved in chloroform under warming. The solution is washed with water and dried over sodium sulfate, and the chloroform is removed under reduced pressure. To the residue is added ether, and the mixture is cooled. The precipitated crystals are collected by filtration and recrystallized twice from a mixture of methanol and chloroform. The crystals are dried at 100C under reduced pressure for many hours, because the solvent is not easily 1 removable. Thus is obtained 1-[1-(4,4-diphenylcyclohexyl)-4-piperidyl]-2-benzimidazolinone as light gray crystals, melting at 289-293C.
A mixture of 13.5 g of 3,3-bis(p-fluorophenyl)cyclo-pentyl tosylate (nD 1.5691), 7.5 g of 1-(4-piperidyl)-5-chloro-2-benzimidazolinone hydrochloride, 8.6 g of potassium carbonate and 70 ml of dimethylformamide is stirred at 70C
for 52 hours. The reaction mixture is poured into ice water, and the aqueous layer is removed by decantation. The pre-cipitated semi-solid is dissolved in chloroform. The solution is washed with water and dried over sodium sulfate, and the solvent is removed. The crude crystals are recrystallized from a mixture of chloroform and ethanol (20:1) to give 1-[1-(3,3-bis(p-fluorophenyl)cyclopentyl)-4-piperidyl]-5-chloro-2-benzimidazolinone as white crystals, melting at 131-134C.
_ _ ____ A mixture of 11 g of 4,4-bis(p-fluorophenyl)cyclohexyl tosyLate, 6 g of 1-(4-piperidyl)-5-chloro-2-benzimidazolinone,
Ar , Ar = ~ R ~ ; esterifying agent = PC15, p-CH3C6H4S02Cl, CH3S02Cl, etc, The compounds of formula (I), in case Ring A is cyclohexene ring, cyclopentene ring or cyclopentane ring, are optically active compounds or racemic modifications, which, if desired, can be separated in a conventional manner each into two enantiomers.
The compounds of formula (I) can be converted into 1 acid addition salts with various inorganic and organic acids (e.g. hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, maleic, fumaric, succinic, citric, or tartaric acid), and also into quaternary ammonium salts with dimethyl sulfate, diethyl sulfate, methyl iodide, ethyl bromide, etc.
The compounds of formula (I) and salts thereof exhibit potent and long-lasting psychotropic effects such as anti-apomorphine effect, effect on conditioned avoidance response, anti-methamphethamine effect, taming effect and analgesic effect.
ANTI-APOMORPHINE EFFECT
Test Compounds A: 1-[4,4-bis(p-fluorophenyl)cyclohexyl]-4-(4-chloro-3-trifluoromethylphenyl)-4-piperidinol hydrochloride B: 8-[4,4-bis(p-fluorophenyl)cyclohexyl]-1-(p-fluorophenyl)-1,3,8-triazaspiro[4.5]decan-4-one C: 1-[1-(4,4-bis~p-fluorophenyl)cyclohexyl~-4-piperidyl]-5-chloro-2-benzimidazolinone D: 1-[1-(4,4-bis(p-fluorophenyl)-2-cyclohexenyl)-4-piperidyl]-5-chloro-2-benzimidazolinone E: 8-[4,4-bis(p-fluorophenyl)cyclohexyl]-1-(p-chlorophenyl)-1,3,~-triazaspiro[4.5]decan-4-one F: 1-[1-(4,4-bis(p-fluorophenyl)cyclohexyl)-4-piperidyl]-5-fluoro-2-benzimidazolinone G: 1-[1-(4,4-bis(p-fluorophenyl)-2-cyclohexenyl)-4-piperidyl]-5-fluoro-2-benzimidazolinone hydrochloride hemihydrate Haloperidol (comparison): 1-[3-(p-fluorobenzoyl)propyl]-4-(p-chlorophenyl)-4-piperidinol Pimozide (comparison): 1-[1-(4,4-bis(p~fluorophenyl)butyl)-4-piperidyl]-2-benzimidazolinone 1 Metho and Results The test was performed essentially by the method described by Paul A.J. Janssen et al in "Arzneimittel-Forschung", vol. 17, 841 (1967), using groups of 5-7 female rats. The results are summarized in Table I.
TABLE I
Test Compound ED50 mg/kg~ P.-A 2.46 B 0.10 . _ ._ C 0.18 . .
0.51 E 0.28 . .
F 0.14 .. . .. __ I
G 0.17 Haloperidol 0.50 .
Pimo~ide 0.25 Anti-apomorphine effect was examined in respect of its durability at a dose of ED50 value obtained by the above method. The results are summarized in Table II.
_ 10 -1~74319 ~ .
\ \ Inhibition (%) C(EDSp5o0ùmg/k~ 1 ~ 24 48 72 96 120 144 (? 46~ 7.1 ¦21.4 = 57.1 35.7 ~ 0 = =
(0'C0). . 50~0 ~ 35.7 14.3 7.1 (0.18) 14.350.0 64.3 64.3 64.3 35.7 21.4 0 (0.51) __ 21.450.0 71.4 71.4 64.3 71.4 71.4 64.3 35.7 (0.28) 0 21.4 50.0 50.0 50.0 35.7 7.1 (0.14) - 10 0 50 0 _ 20.0 _ 10.0 ___ .. ... _ (0.17) 20.050.0 40.0 10.0 Haloperidol . .
(0.50) 57.1 ;0.0 21.4 14.3 7.1 _ . .. , . .
Pimozide _(0.25) . 57.1 50.0 35.7 7.1 The data in Table II shows the compounds of the invention exhibit more long-lasting action than Haloperidol and Pi.mozide.
ACUTE TOXICITY
Acute toxicity (LD50~ female mouse, ~ os) was measured by Litchfield-Wilcoxon method (The Journal of Phar-macology and Experimental Therapeutics, vol. 96, 99 (1949)).
The results are summarized in Table III.
1~74319 Test Compound LD50 mq/kg .
A _ 464 C >1000 . ...
D >1000 E _ 464 Haloperidol > 100 Pimozide >1000 The compounds of formula (I), in base or salt form, are useful as long-lasting psychotropie drugs, anti-anxiety drugs, sedatives, analgesies and so on, in the form of a pharmaeeutical preparation with a suitable and conventional pharmaceutically aceeptable carrier, without adversely affecting the patients.
The pharmaceutical preparations can take any con-ventional form such as tablets, capsules, granules, powders o~
injectable solutions.
FORMULATION E~A~PLES
The following is an example of formulations when a compound of the invention is administered for pharmaceutical purposes:
(a) Tablets are prepared from the following eompositions:
5 mg 25 mg 50 mg Tablets Tablets Tablets Compound (I) or its salt5 mg 25 mg 50 mg Lactose 43.6 58.6 51.4 Microcrystalline Cellulose 25.0 25.0 30.0 Corn Stareh 20.0 30.0 30.0 Methyl Cellulose 0.4 0.4 0.6 Tale 6.0 6.0 8.0 Total 100 mg 145 mg 170 mg t (b) Injectable solutions (5 mg/ 2 ml) are prepared from the following compositions:
Compound (I) or its salt0.25%
Benzyl alcohol 2.0 Propylene glycol 30.0 Sodium chloride 0.9 Water for Injectiona sufficient amount to make 2 ml The dose of compound (I) or a salt thereof for human adults usually ranges from 2.5 to 50 mg per week for oral administration, in single or multiple dose, but it may vary depending upon the age, body weight, and/or severity of the conditions to be treated as well as the response to the medication.
The present invention will be better understood from the following examples, but they are not to be construed as limiting the present invention.
A mixture of 4.1 g of 4,4-diphenylcyclohexyl tosylate, 2.2 g of 4-piperidyl-2-benzimidazolinone, 1.5 g of potassium car~onate, 1.5 g of potassium iodide and 50 ml of dimethyl-formamide is stirred at 55C for 47 hours. The reaction mixture is cooled to room temperature and poured into ice water. The precipitate is collected by filtration and dissolved in chloroform under warming. The solution is washed with water and dried over sodium sulfate, and the chloroform is removed under reduced pressure. To the residue is added ether, and the mixture is cooled. The precipitated crystals are collected by filtration and recrystallized twice from a mixture of methanol and chloroform. The crystals are dried at 100C under reduced pressure for many hours, because the solvent is not easily 1 removable. Thus is obtained 1-[1-(4,4-diphenylcyclohexyl)-4-piperidyl]-2-benzimidazolinone as light gray crystals, melting at 289-293C.
A mixture of 13.5 g of 3,3-bis(p-fluorophenyl)cyclo-pentyl tosylate (nD 1.5691), 7.5 g of 1-(4-piperidyl)-5-chloro-2-benzimidazolinone hydrochloride, 8.6 g of potassium carbonate and 70 ml of dimethylformamide is stirred at 70C
for 52 hours. The reaction mixture is poured into ice water, and the aqueous layer is removed by decantation. The pre-cipitated semi-solid is dissolved in chloroform. The solution is washed with water and dried over sodium sulfate, and the solvent is removed. The crude crystals are recrystallized from a mixture of chloroform and ethanol (20:1) to give 1-[1-(3,3-bis(p-fluorophenyl)cyclopentyl)-4-piperidyl]-5-chloro-2-benzimidazolinone as white crystals, melting at 131-134C.
_ _ ____ A mixture of 11 g of 4,4-bis(p-fluorophenyl)cyclohexyl tosyLate, 6 g of 1-(4-piperidyl)-5-chloro-2-benzimidazolinone,
3.5 g of potassium carbonate, 4.1 g of potassium iodide and 80 ml of dimethylformamide is stirred at 70-80C for 64 hours.
The reaction mixture is poured into water, ether is added to the separated semi-solid, and the whole is stirred for 30 minutes. The substance insoluble in water and ether is collected by filtration, washed with ether and dried. The obtained crystals are dissolved in a mixture of chloroform and methanol (9:1), and the solution is concentrated to some degree and cooled. The precipitated crystals are collected by filtration and purified in the same manner to give 1-[1-~4,4-10743~9 1 bis(p-fluorophenyl)cyclohexyl)-4-piperidyl]-5-chloro-2-benzimidazolinone as white crystals, melting at 279-284C.
A mixture of 6.1 g of 4,4-bis(p-fluorophenyl)-1-chloro-2-cyclohexene (m.p. 39-42C), 5.0 g of 1-(4-piperidyl)-5-chloro-2-benzimidazolinone, 2.8 g of potassium carbonate, 3.3 g of potassium iodide and 50 ml of dimethylformamide is stirred at 65-70C for 3 hours. The reaction mixture is poured into water, and the precipitated powder is collected by filtration, dried and dissolved in a mixture of chloroform and methanol t9:1). The solvent is then removed, and the precipitate is collected by filtration and purified in the same manner to give l-[l-(4,4-bis(p-fluorophenyl)-2-cyclo-hexenyl)-4-piperidylJ-5-chloro-2-benzimidazolinone as white crystalline powder, melting at 153-157C. This white crystalline powder, when recrystallized from a mixture of ethanol and methanol (7:3), turns into white crystals showing a melting point of 217-219C.
A mixture of 6.1 g of 4,4-bis(p-fluorophenyl)-1-chloro-2-cyclohexene, 4.4 g of 1-(1,2,3,6-tetrahydro-4-pyridyl)-2-benzimidazolinone, 4.4 g of potassium carbonate and 50 ml of dimethylformamide is stirred at 55-60C for 4 hours. The reaction mixture is poured into water, and the aqueous mixture is extracted with chloroform. The extract is washed with water and dried over sodium sulfate, and the solvent is removed. The residual oil is purified by column chromatography on silica gel using a mixture of chloroform and methanol (9:1) as an eluent. The purified product (base) is converted in a 1 conventional manner into the hydrochloride, and the hydro-chloride thus obtained is again converted into the base. The solid (base) is recrystallized from a mixture of acetone and methanol to give 1-[1-(4,4-bis(p-fluorophenyl)-2-cyclohexenyl)-1,2,3,6-tetrahydro-4-pyridyl]-2-benzimidazolinone as white crystals, melting at 200-202C.
-A mixture of 10 g of 4,4-bis(p-fluorophenyl)cyclo-hexanone, 6.6 g of 1-(4-piperidyl)-2-benzimidazolinone, 0.2 g of p-toluenesulfonic acid and 80 ml of xylene is stirred under reflux for 34 hours, the water formed being removed. The xylene is then removed under reduced pressure, and to the residue is added 200 ml of methanol and 10 ml of water. To the resulting mixture is added dropwise 15 g of sodium borohydride at about 20C with cooling. After the addition is complete, the mixture is stirred under reflux for 3 hours.
The reaction mixture is concentrated Completely under reduced pressur~, water is added to the residue, and the aqueous mixture is extracted with chloroform. The extract is washed with water and dried over sodium sulfate, and the solvent is removed. The residual viscous oil is purified by column chromatography using methylene chloride and then a mixture of methylene chloride and methanol ~9:1) as an eluent. Thus is obtained 1-[1-(4,4-bis(p-fluorophenyl)cyclohexyl)-4-piperidyl]-2-benzimidazolinone as colourless crystals, melting at 235-238C.
A solution of 8.6 g o~ methyl 1-[4,4-bis(p-fluoro-phenyl)cyclohexyl]-4-oxo-3-piperidinecarboxylate (its oxalate 1 monohydrate: m.p. 122-126C) in 40 ml of xylene is added dropwise to a solution of 2.2 g of o-phenylenediamine in 50 ml of xylene under reflux for 7 hours. During the addition about 40 ml of the solvent (equal amount of the addition) is removed over 7 hours. After the addition is complete, the resulting mixture is stirred under reflux for 3 hours. After cooling the solvent is removed under reduced pressure, and the residual oil is dissolved in ethanol and cooled. The precipitated crystals are collected by filtration and re- -crystallized from a mixture of methanol and ethanol to give 1-[1-(4,4-bis(p-fluorophenyl)cyclohexyl)-1,2,3,6-tetrahydro-
The reaction mixture is poured into water, ether is added to the separated semi-solid, and the whole is stirred for 30 minutes. The substance insoluble in water and ether is collected by filtration, washed with ether and dried. The obtained crystals are dissolved in a mixture of chloroform and methanol (9:1), and the solution is concentrated to some degree and cooled. The precipitated crystals are collected by filtration and purified in the same manner to give 1-[1-~4,4-10743~9 1 bis(p-fluorophenyl)cyclohexyl)-4-piperidyl]-5-chloro-2-benzimidazolinone as white crystals, melting at 279-284C.
A mixture of 6.1 g of 4,4-bis(p-fluorophenyl)-1-chloro-2-cyclohexene (m.p. 39-42C), 5.0 g of 1-(4-piperidyl)-5-chloro-2-benzimidazolinone, 2.8 g of potassium carbonate, 3.3 g of potassium iodide and 50 ml of dimethylformamide is stirred at 65-70C for 3 hours. The reaction mixture is poured into water, and the precipitated powder is collected by filtration, dried and dissolved in a mixture of chloroform and methanol t9:1). The solvent is then removed, and the precipitate is collected by filtration and purified in the same manner to give l-[l-(4,4-bis(p-fluorophenyl)-2-cyclo-hexenyl)-4-piperidylJ-5-chloro-2-benzimidazolinone as white crystalline powder, melting at 153-157C. This white crystalline powder, when recrystallized from a mixture of ethanol and methanol (7:3), turns into white crystals showing a melting point of 217-219C.
A mixture of 6.1 g of 4,4-bis(p-fluorophenyl)-1-chloro-2-cyclohexene, 4.4 g of 1-(1,2,3,6-tetrahydro-4-pyridyl)-2-benzimidazolinone, 4.4 g of potassium carbonate and 50 ml of dimethylformamide is stirred at 55-60C for 4 hours. The reaction mixture is poured into water, and the aqueous mixture is extracted with chloroform. The extract is washed with water and dried over sodium sulfate, and the solvent is removed. The residual oil is purified by column chromatography on silica gel using a mixture of chloroform and methanol (9:1) as an eluent. The purified product (base) is converted in a 1 conventional manner into the hydrochloride, and the hydro-chloride thus obtained is again converted into the base. The solid (base) is recrystallized from a mixture of acetone and methanol to give 1-[1-(4,4-bis(p-fluorophenyl)-2-cyclohexenyl)-1,2,3,6-tetrahydro-4-pyridyl]-2-benzimidazolinone as white crystals, melting at 200-202C.
-A mixture of 10 g of 4,4-bis(p-fluorophenyl)cyclo-hexanone, 6.6 g of 1-(4-piperidyl)-2-benzimidazolinone, 0.2 g of p-toluenesulfonic acid and 80 ml of xylene is stirred under reflux for 34 hours, the water formed being removed. The xylene is then removed under reduced pressure, and to the residue is added 200 ml of methanol and 10 ml of water. To the resulting mixture is added dropwise 15 g of sodium borohydride at about 20C with cooling. After the addition is complete, the mixture is stirred under reflux for 3 hours.
The reaction mixture is concentrated Completely under reduced pressur~, water is added to the residue, and the aqueous mixture is extracted with chloroform. The extract is washed with water and dried over sodium sulfate, and the solvent is removed. The residual viscous oil is purified by column chromatography using methylene chloride and then a mixture of methylene chloride and methanol ~9:1) as an eluent. Thus is obtained 1-[1-(4,4-bis(p-fluorophenyl)cyclohexyl)-4-piperidyl]-2-benzimidazolinone as colourless crystals, melting at 235-238C.
A solution of 8.6 g o~ methyl 1-[4,4-bis(p-fluoro-phenyl)cyclohexyl]-4-oxo-3-piperidinecarboxylate (its oxalate 1 monohydrate: m.p. 122-126C) in 40 ml of xylene is added dropwise to a solution of 2.2 g of o-phenylenediamine in 50 ml of xylene under reflux for 7 hours. During the addition about 40 ml of the solvent (equal amount of the addition) is removed over 7 hours. After the addition is complete, the resulting mixture is stirred under reflux for 3 hours. After cooling the solvent is removed under reduced pressure, and the residual oil is dissolved in ethanol and cooled. The precipitated crystals are collected by filtration and re- -crystallized from a mixture of methanol and ethanol to give 1-[1-(4,4-bis(p-fluorophenyl)cyclohexyl)-1,2,3,6-tetrahydro-
4-pyridyl]-2-benzimidazolinone as white crystals, melting at 23S-238C.
EXAMPLE g A mixture of 3.7 g of 4,4-bis(p-fluorophenyl)-1-chloro-2-cyclohexene, 3.1 g of 1-(p-bromophenyl)-1,3,8-triazaspiro~4.5]decan-4-one (m.p. 204 207C), 1.7 g of potassium carbonate, 2 g o~ potassium iodide and 25 ml of dimethyl-formamide is stirred at 65-75C for 3.5 hours. The reaction mixture is then poured into water. The precipitated powder is collected by filtration and dissolved in methanol. The solution is concentrated to some degree, and acetone is added thereto, and the whole mixture is cooled. The pre-cipitated crystals are collected by filtration and purified in the same manner to give 8-[4,4-bis(p-fluorophenyl~-2-cyclohexenyl]-l-(p-bromophenyl)-1,3,8-triazaspiro[4.5~decan-4-one as white crystals, melting at 219-221C.
A mixture of 16 g of 4,4-bis(p-fluorophenyl)cyclohexyl 1 mesylate, 10 g of 1-(p-fluorophenyl)-1,3,8-triazaspiro[4.5]-decan-4-one (m.p. 234-234.5C), 6.1 g of potassium carbonate, 7.3 g of potassium iodide and 100 ml of dimethylformamide is stirred at 70-80C for 50 hours. The reaction mixture is poured into water, isopropyl ether is added to the a~ueous mixture, and the resulting mixture is stirred for some time.
The precipitated crystals are collected by filtration and dissolved in a mixture of chloroform and methanol (9:1). The solvent is removed to some degree and cooled in an ice bath.
The precipitated crystals are collected by filtration and purified in the same manner to give 8-[4,4-bis(p-fluorophenyl)-cyclohexyl]-l-(p-fluorophenyl)-1,3,8-triazaspiro[4.5]decan-4-one as white crystals, melting at 237~240C.
A mixture of 10.6 g of 4,4-bis(p-fluorophenyl)-cyclohexyl tosylate, 5.7 g of 1-(3-chloro-4-fluorophenyl)-1,3,8-triazaspiro[4.5]decan-4-one (m.p. 194.S-196.5C), 3.3 g of potassium carbonate, 4 g of potassium iodide and 50 ml of dimethylformamide is stirred at 75-80 C for 5 hours. The reaction mixture is poured into water, and the precipitated crystals are collected by filtration, dried in a desiccator and dissolved in a mixture of chloroform and methanol (9:11.
The solution is concentrated to some degree and cooled. The precipitated crystals are collected by filtration and purified in the same manner to give 8-[4,4-bis(p-fluorophenyl)-cyclOhexyl]-1-(3-chloro-4-fluorophenyl)-1,3,8-triazaspiro-[4.5]decan-4-one as white crystals, melting at 201-203C.
3 A mixture of 8.85 g of 4,4-bis(p-fluorophenyl)cyclohexyl tosylate, 4.5 g of 1-(p-chlorophenyl)-1,3,8-triazaspiro[4.5]decan-1 4-one, 2.8 g of potassium carbonate, 3.3 g of potassium iodide and 50 ml of dimethylformamide is stirred at 70-75C for 72 hours.
The reaction mixture is poured into water, and the precipitated powder is collected by filtration and dried. The powder is dissolved in a mixture of chloroform and methanol (9:1), and the solvent is concentrated. The precipitated crystals are collected by filtration and purified in the same manner to give 8-~4,4-bis-(p-fluorophenyl)cyclohexyl]-l-(p-chlorophenyl)-1,3,8-triazaspiro-14.5]decan-4-one as white crystals, melting at 258-261C.
A solution of 2.9 g of potassium cyanide in 8 ml of water is added dropwise to a mixture of 16.3 g of 1-[4,4-bis(p-fluorophenyl)cyclohexyl]-4-piperidone (oil; its hydrochloride:
m.p. 214-217C), 4.1 g of aniline and 40 ml of acetic acid at room temperature with stirring. The resulting mixture is stirred at room temperature for 6 hours and allowed to stand at room temperature overnight. The reaction mixture is poured into ice water, t:he aqueous mlxture is made alkaline with potassium carbonate, and the alkaline mixture is extracted with chloroform.
The extract is washed with water and dried over sodium sulfaie, and the solvent is removed. The residual oil is dissolved in acetone, and 20% ethanolic hydrochloric acid is added thereto.
After cooling the precipitated hydrochloride is collected by filtration and converted in a conventional manner into the base.
The obtained crystals are recrystallized from a mixture of acetone and petroleum ether to give l-[4,4-bis(p-fluorophenvl)cyclohexyl~-4-cyano-4-anilinopiperidine as white crystals, melting at 139-140 C.
To 16.5 g of 1-~4,4-bis~p-fluorophenyl)cyclohexyl~-4-cyano-4-anilinopiperidine is added gradually a solution of 180 g of concentrated sulfuric acid and 20 ml of water under 3~ cooling. After the addition is complete, the resulting mixture is stirred at 70C for 1 hour and then cooled. The reaction 1 mixture is poured into water, and the precipitated powder is collected by filtration. Then water is added to the powder, the aqueous mixture is made alkaline with potassium carbonate, and the alkaline solution is extracted with chloroform. The extract is washed with water and dried over sodium sulfate, and the solvent is removed. The precipitated crystals are collected by filtration and recrystallized from a mixture of chloroform and acetone to give l-[4,4-bis(p-fluorophenyl)-cyclohexyl]-4-carbamoyl-4-anilinopiperidine as white crystals, melting at 224-227C.
To 16 g of 1-[4,4-bis(p-fluorophenyl)cyclohexyl]-4-carbamoyl-4-anilinopiperidine is added 30 g of formamide, the temperature is raised slowly, and the mixture is heated at 170C for 14 hours. After cooling water is added to the reaction mixture, and the aqueous mixture ~s extracted with chloroform. The extract is washed with water and dried over sodium sulfate, and the solvent is removed. The precipitated cry~t~ls are collected by filtration and recrystallized from chloroform to give 8-[4,4-bis(p-fluorophenyl)cyclohexyl]-1-phenyl-1,3,8-triazaspiro[4.51decan-4-one as white crystals, melting at 249-253C.
A mixture of 4.1 g of 4,4-diphenylcyclohexyl tosylate, 2.8 g of 4-(4-chloro-3-trifluoromethylphenyl)-4-piperidinol, 1.1 g of sodium carbonate and 400 ml of toluene is stirred under reflux for 48 hours. The reaction mixture is concentrated completely under reduced pressure, water is added to the residue, and the aqueous mixture i-s-extracted with chloroform. The extract is washed with water and dried over sodium sulfate, and the solvent is removed. The residual viscous 1 oil is purified by column chromatography on silica gel using chloroform and then chloroform - methanol (9:1) as an eluent.
The purified base is converted in a conventional manner into the hydrochloride. Thus is obtained 1-(4,4-diphenylcyclohexyl)-4-(4-chloro~3-trifluoromethylphenyl)-4-piperidinol hydro-chloride monohydrate as white crystals, melting at 270-273C.
A mixture of 14.3 g of 4,4-bis(p-fluorophenyl~-cyclohexanone, 14 g of 4-~4-chloro-3-trifluoromethylphenyl)-4-piperidinol, 0.5 g of p-toluenesulfonic acid and 100 ml of toluene is stirred under reflux for 145 hours, water formed being removed as an azeotropic mixture with toluene. ~he toluene is then removed, and the residual oil is dissolved in 100 ml of 90~ methanol. To the solution is added slowly 19 g of sodium borohydride under cooling. After the addition is complete, the methanol is removed under reduced pressure, water is added to the residue, and the aqueous mixture is extracted with chloroform. The extract is washed with water and dried over sodium sulfate. The residual oil is purified by column chromatography on silica gel using a mixture of chloroform and methanol (9:1) as an eluent. The objective base thus obtained is converted in a conventional manner into the hydrochloride. Thus is obtained 1-[4,4-bis(p-fluorophenyl)-cyclohexyl]-4-(4-chloro-3-trifluoromethylphenyl)-4-piperidinol hydrochloride as colourless crysta]s, melting at 274-277C.
E~AMPLE 15 A solution of 6.3 g of 3-trifluoromethyl-4-chloro-l-bromobenzene in 16 ml of tetrahydrofuran is added dropwise to a mixture of 0.6 g of magnesium turnings, a few crystals of -- ~1 --1 iodine and 5 ml of tetrahydrofuran at room temperature with stirring by occasional cooling. After refluxing for 30 minutes, to the cooled Grignard reagent is added dropwise a solution of 7.3 g of 1-[4,4-bis(p-fluorophenyl)-2-cyclohexenyl]-4-piperidone (m.p. 112-114C) in 25 ml of tetrahydrofuran by occasional cooling. After the addition is complete, the resulting mixture is stirred at room temperature for 1 hour and then under reflux for an additional hour. After cooling a saturated aqueous solution of ammonium chloride is added dropwise to the reaction mixture, and the whole is extracted with ethyl acetate. The extract is washed with water and dried over sodium sulfate, and the solvent is removed. The residual oil is dissolved in acetone. To the acetone solution is added 20% ethanolic hydrochloric acid, and the whole is cooled. The precipitated crystals are collected by filtration and recrystallized from a mixture of methanol and acetone to give 1- r4 ~ 4-bis(p-fluorophenyl~-2-cyclohexenyl]-4-(4-chloro-3-trifluoromethylphenyl)-4-piperidinol hydrochloride as white crystals, melting at 252-254C.
2~ Using the procedure set forth in the above examples, the following compounds are also producible:
(16) 1-[1-(4,4-bis(p-tolyl)-2-cyclohexenyl)-4-piperidyl]-5-chloro-2-benzimidazolinone, m.p. 151-153 C
(17) 1-[1-(3,3-bis(p-fluorophenyl)cyclopentylmethyl)-4-piperidyl]-
EXAMPLE g A mixture of 3.7 g of 4,4-bis(p-fluorophenyl)-1-chloro-2-cyclohexene, 3.1 g of 1-(p-bromophenyl)-1,3,8-triazaspiro~4.5]decan-4-one (m.p. 204 207C), 1.7 g of potassium carbonate, 2 g o~ potassium iodide and 25 ml of dimethyl-formamide is stirred at 65-75C for 3.5 hours. The reaction mixture is then poured into water. The precipitated powder is collected by filtration and dissolved in methanol. The solution is concentrated to some degree, and acetone is added thereto, and the whole mixture is cooled. The pre-cipitated crystals are collected by filtration and purified in the same manner to give 8-[4,4-bis(p-fluorophenyl~-2-cyclohexenyl]-l-(p-bromophenyl)-1,3,8-triazaspiro[4.5~decan-4-one as white crystals, melting at 219-221C.
A mixture of 16 g of 4,4-bis(p-fluorophenyl)cyclohexyl 1 mesylate, 10 g of 1-(p-fluorophenyl)-1,3,8-triazaspiro[4.5]-decan-4-one (m.p. 234-234.5C), 6.1 g of potassium carbonate, 7.3 g of potassium iodide and 100 ml of dimethylformamide is stirred at 70-80C for 50 hours. The reaction mixture is poured into water, isopropyl ether is added to the a~ueous mixture, and the resulting mixture is stirred for some time.
The precipitated crystals are collected by filtration and dissolved in a mixture of chloroform and methanol (9:1). The solvent is removed to some degree and cooled in an ice bath.
The precipitated crystals are collected by filtration and purified in the same manner to give 8-[4,4-bis(p-fluorophenyl)-cyclohexyl]-l-(p-fluorophenyl)-1,3,8-triazaspiro[4.5]decan-4-one as white crystals, melting at 237~240C.
A mixture of 10.6 g of 4,4-bis(p-fluorophenyl)-cyclohexyl tosylate, 5.7 g of 1-(3-chloro-4-fluorophenyl)-1,3,8-triazaspiro[4.5]decan-4-one (m.p. 194.S-196.5C), 3.3 g of potassium carbonate, 4 g of potassium iodide and 50 ml of dimethylformamide is stirred at 75-80 C for 5 hours. The reaction mixture is poured into water, and the precipitated crystals are collected by filtration, dried in a desiccator and dissolved in a mixture of chloroform and methanol (9:11.
The solution is concentrated to some degree and cooled. The precipitated crystals are collected by filtration and purified in the same manner to give 8-[4,4-bis(p-fluorophenyl)-cyclOhexyl]-1-(3-chloro-4-fluorophenyl)-1,3,8-triazaspiro-[4.5]decan-4-one as white crystals, melting at 201-203C.
3 A mixture of 8.85 g of 4,4-bis(p-fluorophenyl)cyclohexyl tosylate, 4.5 g of 1-(p-chlorophenyl)-1,3,8-triazaspiro[4.5]decan-1 4-one, 2.8 g of potassium carbonate, 3.3 g of potassium iodide and 50 ml of dimethylformamide is stirred at 70-75C for 72 hours.
The reaction mixture is poured into water, and the precipitated powder is collected by filtration and dried. The powder is dissolved in a mixture of chloroform and methanol (9:1), and the solvent is concentrated. The precipitated crystals are collected by filtration and purified in the same manner to give 8-~4,4-bis-(p-fluorophenyl)cyclohexyl]-l-(p-chlorophenyl)-1,3,8-triazaspiro-14.5]decan-4-one as white crystals, melting at 258-261C.
A solution of 2.9 g of potassium cyanide in 8 ml of water is added dropwise to a mixture of 16.3 g of 1-[4,4-bis(p-fluorophenyl)cyclohexyl]-4-piperidone (oil; its hydrochloride:
m.p. 214-217C), 4.1 g of aniline and 40 ml of acetic acid at room temperature with stirring. The resulting mixture is stirred at room temperature for 6 hours and allowed to stand at room temperature overnight. The reaction mixture is poured into ice water, t:he aqueous mlxture is made alkaline with potassium carbonate, and the alkaline mixture is extracted with chloroform.
The extract is washed with water and dried over sodium sulfaie, and the solvent is removed. The residual oil is dissolved in acetone, and 20% ethanolic hydrochloric acid is added thereto.
After cooling the precipitated hydrochloride is collected by filtration and converted in a conventional manner into the base.
The obtained crystals are recrystallized from a mixture of acetone and petroleum ether to give l-[4,4-bis(p-fluorophenvl)cyclohexyl~-4-cyano-4-anilinopiperidine as white crystals, melting at 139-140 C.
To 16.5 g of 1-~4,4-bis~p-fluorophenyl)cyclohexyl~-4-cyano-4-anilinopiperidine is added gradually a solution of 180 g of concentrated sulfuric acid and 20 ml of water under 3~ cooling. After the addition is complete, the resulting mixture is stirred at 70C for 1 hour and then cooled. The reaction 1 mixture is poured into water, and the precipitated powder is collected by filtration. Then water is added to the powder, the aqueous mixture is made alkaline with potassium carbonate, and the alkaline solution is extracted with chloroform. The extract is washed with water and dried over sodium sulfate, and the solvent is removed. The precipitated crystals are collected by filtration and recrystallized from a mixture of chloroform and acetone to give l-[4,4-bis(p-fluorophenyl)-cyclohexyl]-4-carbamoyl-4-anilinopiperidine as white crystals, melting at 224-227C.
To 16 g of 1-[4,4-bis(p-fluorophenyl)cyclohexyl]-4-carbamoyl-4-anilinopiperidine is added 30 g of formamide, the temperature is raised slowly, and the mixture is heated at 170C for 14 hours. After cooling water is added to the reaction mixture, and the aqueous mixture ~s extracted with chloroform. The extract is washed with water and dried over sodium sulfate, and the solvent is removed. The precipitated cry~t~ls are collected by filtration and recrystallized from chloroform to give 8-[4,4-bis(p-fluorophenyl)cyclohexyl]-1-phenyl-1,3,8-triazaspiro[4.51decan-4-one as white crystals, melting at 249-253C.
A mixture of 4.1 g of 4,4-diphenylcyclohexyl tosylate, 2.8 g of 4-(4-chloro-3-trifluoromethylphenyl)-4-piperidinol, 1.1 g of sodium carbonate and 400 ml of toluene is stirred under reflux for 48 hours. The reaction mixture is concentrated completely under reduced pressure, water is added to the residue, and the aqueous mixture i-s-extracted with chloroform. The extract is washed with water and dried over sodium sulfate, and the solvent is removed. The residual viscous 1 oil is purified by column chromatography on silica gel using chloroform and then chloroform - methanol (9:1) as an eluent.
The purified base is converted in a conventional manner into the hydrochloride. Thus is obtained 1-(4,4-diphenylcyclohexyl)-4-(4-chloro~3-trifluoromethylphenyl)-4-piperidinol hydro-chloride monohydrate as white crystals, melting at 270-273C.
A mixture of 14.3 g of 4,4-bis(p-fluorophenyl~-cyclohexanone, 14 g of 4-~4-chloro-3-trifluoromethylphenyl)-4-piperidinol, 0.5 g of p-toluenesulfonic acid and 100 ml of toluene is stirred under reflux for 145 hours, water formed being removed as an azeotropic mixture with toluene. ~he toluene is then removed, and the residual oil is dissolved in 100 ml of 90~ methanol. To the solution is added slowly 19 g of sodium borohydride under cooling. After the addition is complete, the methanol is removed under reduced pressure, water is added to the residue, and the aqueous mixture is extracted with chloroform. The extract is washed with water and dried over sodium sulfate. The residual oil is purified by column chromatography on silica gel using a mixture of chloroform and methanol (9:1) as an eluent. The objective base thus obtained is converted in a conventional manner into the hydrochloride. Thus is obtained 1-[4,4-bis(p-fluorophenyl)-cyclohexyl]-4-(4-chloro-3-trifluoromethylphenyl)-4-piperidinol hydrochloride as colourless crysta]s, melting at 274-277C.
E~AMPLE 15 A solution of 6.3 g of 3-trifluoromethyl-4-chloro-l-bromobenzene in 16 ml of tetrahydrofuran is added dropwise to a mixture of 0.6 g of magnesium turnings, a few crystals of -- ~1 --1 iodine and 5 ml of tetrahydrofuran at room temperature with stirring by occasional cooling. After refluxing for 30 minutes, to the cooled Grignard reagent is added dropwise a solution of 7.3 g of 1-[4,4-bis(p-fluorophenyl)-2-cyclohexenyl]-4-piperidone (m.p. 112-114C) in 25 ml of tetrahydrofuran by occasional cooling. After the addition is complete, the resulting mixture is stirred at room temperature for 1 hour and then under reflux for an additional hour. After cooling a saturated aqueous solution of ammonium chloride is added dropwise to the reaction mixture, and the whole is extracted with ethyl acetate. The extract is washed with water and dried over sodium sulfate, and the solvent is removed. The residual oil is dissolved in acetone. To the acetone solution is added 20% ethanolic hydrochloric acid, and the whole is cooled. The precipitated crystals are collected by filtration and recrystallized from a mixture of methanol and acetone to give 1- r4 ~ 4-bis(p-fluorophenyl~-2-cyclohexenyl]-4-(4-chloro-3-trifluoromethylphenyl)-4-piperidinol hydrochloride as white crystals, melting at 252-254C.
2~ Using the procedure set forth in the above examples, the following compounds are also producible:
(16) 1-[1-(4,4-bis(p-tolyl)-2-cyclohexenyl)-4-piperidyl]-5-chloro-2-benzimidazolinone, m.p. 151-153 C
(17) 1-[1-(3,3-bis(p-fluorophenyl)cyclopentylmethyl)-4-piperidyl]-
5-chloro-2-benzimidazolinone, m.p. 203-206 C
(18) 1-[1-(4,4-bis(p-fluorophenyl)-2-cyclohexenyl)-4-piperidyl]-2-benzimidazolinone hydrochloride,m.p. 213-215C
(19) 1-[1-(4,4-bis~p-chlorophenyl)-2-cyclohexenyl)-4-piperidyl]-2-benzimidazolinone hydrochloride, m.p. 268-272C
0 (20) 1-[1-(4,4-bis(p-chlorophenyl)cyclohexyl)-4-piperidyl~-2-benzimidazolinone, m.p. 256-261 C
1 (21) 1-[1-(3,3-bis(p-fluorophenyl)cyclopentyl)-4-piperidyl]-2-benzimidazolinone, m.p. 142-145C
(22) 1-[1-(4,4-bis(p-tolyl)-2-cyclohexenyl)-4-piperidyl]-2-benzimidazolinone, m.p. 218-220C
(23) 1-[1-(4,4 bis(p-fluorophenyl)cyclohexyl)-4-piperidyl]-5-fluoro-2-benzimidazolinone, m.p. 256-259 C
(24) 1-[1-(4,4-bis(p-fluorophenyl)-2-cyclohexenyl)-4-piperidyl]-5-fluoro-2-benzimidazolinone hydrochloride hemihydrate, m.p, 257-259C
10 (25) 8-[4,4-bis(p-chlorophenyl)-2-cyclohexenyl]-1-phenyl-1,3,8-triaæaspiro[4.5]decan-4-one, m.p. 217-220C; its hydrochloride: m.p. 257-260C
(26) 8-[4,4-bis(p-fluorophenyl)cyclohexyl]-1-(2,4-difluoro-phenyl)-1,3,8-triazaspiro[4.5]decan-4-one, m.p. 214-217C; its hydrochloride: m.p. 274-276C
(27) 8-~4,4-bis(p-fluorophenyl)-2-cyclohexenyl]-1-(3,4-dichlorophenyl)-1,3,8-triazaspiro[4.5]decan-4-one, m.p. 226-227C
(28) 8-[4,4-bis(p-fluorophenyl)cyclohexyl]-1-(3,4-dichloro-phenyl)-1,3,8-triazaspiro[4.5]decan-4-one, m.p. 241-244C
(29) 8-[4,4-bis(p-fluorophenyl)cyclohexyl]-l~(p-bromophenyl)-1,3,8-triazaspiro[4.5]decan-4-one, m.p. 255-259C
(30) 8-[4,4-bis(p-fluorophenyl)-2-cyclohexenyl]-1-(p-fluorophenyl)-1,3,8-triazaspiro[4.5]decan-4-one, m.p. 194-196C
(31) 8-[4,4-bis(p-trifluoromethylphenyl)cyclohexyl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one hydrochloride, m.p.
268-271~
(32) 8-[4,4-bis(p-fluorophenyl)-2-cyclohexenyl]-1-(p-chloro-phenyl)-1,3,8-triazaspiro[4.5]decan-4-one, m.p. 266-269C
1 (33) 8-~4,4-bis(p-fluorophenyl)-2-cyclohexenyl]-1-(3-ehloro-4-fluorophenyl)-1,3,8-triazaspiro[4.5]decan-4-one, m.p.
(34~ ~-[4,4-bis(p-fluorophenyl)-2-cyclohexenyl]-1-phenyl-1,3,8-triazaspiro[4.51decan-4 one, m.p. 193-196C
(35) 8-[3,3-bis(p-fluorophenyl)cyclopentylmethyl]-1-(p-fluorophenyl)-1,3,8-triazaspiro[4.5]decan-4-one hydro-ehloride, m.p. 250-253C
(36) 1-(4,4-diphenyleyelohexyl)-4-(p-chlorophenyl)-4-piperidinol, m.p. 187-190C
(37) 1-[4,4-bis(p-fluorophenyl)eyelohexyl]-4-(p-tolyl)-4-piperidinol, m.p. 182-183C
(38) 1-[4,4-bis(p-fluorophenyl)eyelohexyl]-4-(p-chlorophenyl)-4~piperidinol, m.p. 185-189C
(39) 1-[4,4-bis(p-chlorophenyl)-2-cyclohexenyl]-4-(4-ehloro-3-trifluoromethyl-phenyl)-4-piperidinol hydro-chloride, m.p. 269-271C
(40) 1-[4,4-bis(p-ehlorophenyl)eyelohexyl]-4-(4-ehloro-3-trifluoromethylphenyl)-4-piperidinol hydrochloride, m.p. 274-276C
(41) 1-[4,4-bis(p-tolyl)-2-eyelohexenyl]-4-(4-ehloro-3-tri-fluoromethylphenyl)-4-piperidinol hydrochloride, m.p.
(42) 1-~3,3~bis(p-fluorophenyl)eyclopentyl]-4-(4-ehloro-3-trifluoromethylphenyl)-4-piperidinol hydroehloride, m.p.
t43) 1-[1-t4,4-bis(3,4-difluorophenyl)cyclohexyl)-4-piperidyll-5-chloro-2-benzimidazolinone, m.p. 265-269 C
(44) 1 [1-(4,4-bis(2,4-difluorophenyl)cyclohexyl)-4-piperidyl]-5-chloro-2-benzimidazolinone hydroehloride, m.p. 302-305 C
iO74319 1 t45) 1-[1-(4,4-bis(2,4-difluorophenyl)-2-cyclohexenyl)-4-piperidyl]-5-chloro-2-benzimidazolinone hydrochloride, m.p. 251-253C
(46) 8-[4,4-bis(3,4-difluorophenyl)-2-cyclohexenyl]-1-(p-fluorophenyl)-1,3,8-triazaspiro[4.5]decan-4-one, m.p.
(47) 1-~1-(4,4-bis(3,4-difluorophenyl)cyclohexyl)-4-piperidyl]-5-fluoro-2-benzimidazolinone (48) 1-[1-(4,4-bis(2,4-difluorophenyl)cyclohexyl)-4-piperidyl]-5-fluoro-2-benzimi.dazolinone (49) 1-[1-(4,4-bis(2,4-difluorophenyl)-2-cyclohexenyl)-4-piperidyl~-5-fluoro-2-benzimidazolinone (50) 1-[1-(4,4-bis(p-bromophenyl)cyclohexyl)-4-piperidyl]-5-chloro-2-benzimidazolinone (51) 1-[1-(4,4-bis(p-fluorophenyl)cyclohexyl)-4-piperidyl]-5,6-difluoro-2-benzimidazolinone (52) 1-[1-(4,4-bis(p-fluorophenyl)cyclohexyl)-4-piperidyl]-5-trifluoromethyl-2-benzimidazolinone (53) 1-[1-(4,4-bis(p-fluorophenyl)-2-cyclohexenyl)-4-piperidyl]-5-tri.fluoromethyl-2-benzimidazolinone (54) 1-[1-(4,4-bis(p-fluorophenyl)cyclohexyl)-4-piperidyl]-5,6-dichloro-2-benzimidazolinone (55) 1-[1-(4,4-bis(p-fluorophenyl)cyclohexyl)-4-piperidyl]-5-methyl-2-benzimidazolinone (56) 1-[1-(4,4-bis(p-fluorophenyl)cyclohexyl)-4-piperidyl~-5-bromo-2-benzimidazolinone (57) 8-[4,4-bis(3,4-difluorophenyl3cyclohexyl]-1-(p-fluoro-phenyl)-1,3,8-triazaspiro~4.5]decan-4-one (58) 8-[4,4-bis(2,4-difluorophenyl)cyclohexyl]-1-(p-fluoro-phenyl)-1,3,8-triazaspiro[4A5]decan-4-one 10743~9 1 (59) 8-[4,4-bis(2,4-difluorophenyl)cyclohexyl]-1-(p-chlorophenyl)-1,3,8-triazaspiro[4.5]decan-4-one (60) 8-[4,4-bis(3,4-difluorophenyl)cyclohexyl]-1-tp-chloro-phenyl)-1,3,8-triazaspiro[4.5]decan-4-one (61) 8-[4,4-bis(2,4-difluorophenyl)-2-cyclohexenyl]-1-(p-fluorophenyl)-1,3,8-triazaspiro[4.5]decan-4-one (62) 1-[4,4-bis(2,4-difluorophenyl)cyclohexyl]-4-(4-chloro-3-trifluoromethylphenyl)-4-piperidinol (63) 8-[4,4-bis(p-fluorophenyl)cyclohexyl]-1-(p-tolyl)-1,3,8-triazaspiro[4.5]decan-4-one Although the present invention has been ade~uately discussed in the foregoing specification and examples included therein, one readily recognizes that various changes and modifications may be made without departing from the spirit and scope thereof.
(18) 1-[1-(4,4-bis(p-fluorophenyl)-2-cyclohexenyl)-4-piperidyl]-2-benzimidazolinone hydrochloride,m.p. 213-215C
(19) 1-[1-(4,4-bis~p-chlorophenyl)-2-cyclohexenyl)-4-piperidyl]-2-benzimidazolinone hydrochloride, m.p. 268-272C
0 (20) 1-[1-(4,4-bis(p-chlorophenyl)cyclohexyl)-4-piperidyl~-2-benzimidazolinone, m.p. 256-261 C
1 (21) 1-[1-(3,3-bis(p-fluorophenyl)cyclopentyl)-4-piperidyl]-2-benzimidazolinone, m.p. 142-145C
(22) 1-[1-(4,4-bis(p-tolyl)-2-cyclohexenyl)-4-piperidyl]-2-benzimidazolinone, m.p. 218-220C
(23) 1-[1-(4,4 bis(p-fluorophenyl)cyclohexyl)-4-piperidyl]-5-fluoro-2-benzimidazolinone, m.p. 256-259 C
(24) 1-[1-(4,4-bis(p-fluorophenyl)-2-cyclohexenyl)-4-piperidyl]-5-fluoro-2-benzimidazolinone hydrochloride hemihydrate, m.p, 257-259C
10 (25) 8-[4,4-bis(p-chlorophenyl)-2-cyclohexenyl]-1-phenyl-1,3,8-triaæaspiro[4.5]decan-4-one, m.p. 217-220C; its hydrochloride: m.p. 257-260C
(26) 8-[4,4-bis(p-fluorophenyl)cyclohexyl]-1-(2,4-difluoro-phenyl)-1,3,8-triazaspiro[4.5]decan-4-one, m.p. 214-217C; its hydrochloride: m.p. 274-276C
(27) 8-~4,4-bis(p-fluorophenyl)-2-cyclohexenyl]-1-(3,4-dichlorophenyl)-1,3,8-triazaspiro[4.5]decan-4-one, m.p. 226-227C
(28) 8-[4,4-bis(p-fluorophenyl)cyclohexyl]-1-(3,4-dichloro-phenyl)-1,3,8-triazaspiro[4.5]decan-4-one, m.p. 241-244C
(29) 8-[4,4-bis(p-fluorophenyl)cyclohexyl]-l~(p-bromophenyl)-1,3,8-triazaspiro[4.5]decan-4-one, m.p. 255-259C
(30) 8-[4,4-bis(p-fluorophenyl)-2-cyclohexenyl]-1-(p-fluorophenyl)-1,3,8-triazaspiro[4.5]decan-4-one, m.p. 194-196C
(31) 8-[4,4-bis(p-trifluoromethylphenyl)cyclohexyl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one hydrochloride, m.p.
268-271~
(32) 8-[4,4-bis(p-fluorophenyl)-2-cyclohexenyl]-1-(p-chloro-phenyl)-1,3,8-triazaspiro[4.5]decan-4-one, m.p. 266-269C
1 (33) 8-~4,4-bis(p-fluorophenyl)-2-cyclohexenyl]-1-(3-ehloro-4-fluorophenyl)-1,3,8-triazaspiro[4.5]decan-4-one, m.p.
(34~ ~-[4,4-bis(p-fluorophenyl)-2-cyclohexenyl]-1-phenyl-1,3,8-triazaspiro[4.51decan-4 one, m.p. 193-196C
(35) 8-[3,3-bis(p-fluorophenyl)cyclopentylmethyl]-1-(p-fluorophenyl)-1,3,8-triazaspiro[4.5]decan-4-one hydro-ehloride, m.p. 250-253C
(36) 1-(4,4-diphenyleyelohexyl)-4-(p-chlorophenyl)-4-piperidinol, m.p. 187-190C
(37) 1-[4,4-bis(p-fluorophenyl)eyelohexyl]-4-(p-tolyl)-4-piperidinol, m.p. 182-183C
(38) 1-[4,4-bis(p-fluorophenyl)eyelohexyl]-4-(p-chlorophenyl)-4~piperidinol, m.p. 185-189C
(39) 1-[4,4-bis(p-chlorophenyl)-2-cyclohexenyl]-4-(4-ehloro-3-trifluoromethyl-phenyl)-4-piperidinol hydro-chloride, m.p. 269-271C
(40) 1-[4,4-bis(p-ehlorophenyl)eyelohexyl]-4-(4-ehloro-3-trifluoromethylphenyl)-4-piperidinol hydrochloride, m.p. 274-276C
(41) 1-[4,4-bis(p-tolyl)-2-eyelohexenyl]-4-(4-ehloro-3-tri-fluoromethylphenyl)-4-piperidinol hydrochloride, m.p.
(42) 1-~3,3~bis(p-fluorophenyl)eyclopentyl]-4-(4-ehloro-3-trifluoromethylphenyl)-4-piperidinol hydroehloride, m.p.
t43) 1-[1-t4,4-bis(3,4-difluorophenyl)cyclohexyl)-4-piperidyll-5-chloro-2-benzimidazolinone, m.p. 265-269 C
(44) 1 [1-(4,4-bis(2,4-difluorophenyl)cyclohexyl)-4-piperidyl]-5-chloro-2-benzimidazolinone hydroehloride, m.p. 302-305 C
iO74319 1 t45) 1-[1-(4,4-bis(2,4-difluorophenyl)-2-cyclohexenyl)-4-piperidyl]-5-chloro-2-benzimidazolinone hydrochloride, m.p. 251-253C
(46) 8-[4,4-bis(3,4-difluorophenyl)-2-cyclohexenyl]-1-(p-fluorophenyl)-1,3,8-triazaspiro[4.5]decan-4-one, m.p.
(47) 1-~1-(4,4-bis(3,4-difluorophenyl)cyclohexyl)-4-piperidyl]-5-fluoro-2-benzimidazolinone (48) 1-[1-(4,4-bis(2,4-difluorophenyl)cyclohexyl)-4-piperidyl]-5-fluoro-2-benzimi.dazolinone (49) 1-[1-(4,4-bis(2,4-difluorophenyl)-2-cyclohexenyl)-4-piperidyl~-5-fluoro-2-benzimidazolinone (50) 1-[1-(4,4-bis(p-bromophenyl)cyclohexyl)-4-piperidyl]-5-chloro-2-benzimidazolinone (51) 1-[1-(4,4-bis(p-fluorophenyl)cyclohexyl)-4-piperidyl]-5,6-difluoro-2-benzimidazolinone (52) 1-[1-(4,4-bis(p-fluorophenyl)cyclohexyl)-4-piperidyl]-5-trifluoromethyl-2-benzimidazolinone (53) 1-[1-(4,4-bis(p-fluorophenyl)-2-cyclohexenyl)-4-piperidyl]-5-tri.fluoromethyl-2-benzimidazolinone (54) 1-[1-(4,4-bis(p-fluorophenyl)cyclohexyl)-4-piperidyl]-5,6-dichloro-2-benzimidazolinone (55) 1-[1-(4,4-bis(p-fluorophenyl)cyclohexyl)-4-piperidyl]-5-methyl-2-benzimidazolinone (56) 1-[1-(4,4-bis(p-fluorophenyl)cyclohexyl)-4-piperidyl~-5-bromo-2-benzimidazolinone (57) 8-[4,4-bis(3,4-difluorophenyl3cyclohexyl]-1-(p-fluoro-phenyl)-1,3,8-triazaspiro~4.5]decan-4-one (58) 8-[4,4-bis(2,4-difluorophenyl)cyclohexyl]-1-(p-fluoro-phenyl)-1,3,8-triazaspiro[4A5]decan-4-one 10743~9 1 (59) 8-[4,4-bis(2,4-difluorophenyl)cyclohexyl]-1-(p-chlorophenyl)-1,3,8-triazaspiro[4.5]decan-4-one (60) 8-[4,4-bis(3,4-difluorophenyl)cyclohexyl]-1-tp-chloro-phenyl)-1,3,8-triazaspiro[4.5]decan-4-one (61) 8-[4,4-bis(2,4-difluorophenyl)-2-cyclohexenyl]-1-(p-fluorophenyl)-1,3,8-triazaspiro[4.5]decan-4-one (62) 1-[4,4-bis(2,4-difluorophenyl)cyclohexyl]-4-(4-chloro-3-trifluoromethylphenyl)-4-piperidinol (63) 8-[4,4-bis(p-fluorophenyl)cyclohexyl]-1-(p-tolyl)-1,3,8-triazaspiro[4.5]decan-4-one Although the present invention has been ade~uately discussed in the foregoing specification and examples included therein, one readily recognizes that various changes and modifications may be made without departing from the spirit and scope thereof.
Claims (49)
- Claim 1 continued.....
optional bond; R1, R2, R3 and R4 are independently a hydrogen atom, a halogen atom, a trifluoromethyl group, or an alkyl group containing 1 to 4 carbon atoms; n is 1 or 2; m is 0 or 1; a is 0 or 1; X is a reactive atom or group;
and Am is a piperidine group of the formula:
, or where the dotted line in Ring B indicates an optional bond, and R5 and R6 are independently a hydrogen atom, a halogen atom, a trifluoromethyl group or an alkyl group containing 1 to 4 carbon atoms. - 2. A method of producing a compound of formula (I) of claim 1 wherein R1 is F, R2 is H or F, R3 is F, R4 is H or F, n is 2 and m is 0 and a pharmaceutically acceptable salt thereof comprising the process in sub-paragraph (i) or (ii) of claim 1.
- 3. A method of producing a compound of formula (I) of claim 1 wherein R1 is F at para-position, R2 is H, R3 is F at para-position, R4 is H, n is 2 and m is 0 and a pharmaceutically acceptable salt thereof comprising the process in sub-paragraph (i) or (ii) of claim 1.
- 4. A method according to claim 1 of producing 1-[1-(4,4-diphenyl-cyclohexyl)-4-piperidyl]-2-benzimidazolinone which comprises reacting 4,4-diphenylcyclohexyl tosylate with 1-(4-piperidyl)-2-benzimidazolinone.
- 5. A method according to claim 1 of producing 1-[1-(3,3-bis(p-fluoro-phenyl)cyclopentyl)-4-piperidyl]-5-chloro-2-benzimidazolinone which comprises reacting 3,3-bis(p-fluorophenyl)cyclopentyl tosylate with 1-(4-piperidyl)-5-chloro-2-benzimidazolinone.
- 6. A method according to claim 1 of producing 1-[1-(4,4-bis(p-fluoro-phenyl)cyclohexyl)-4-piperidyl]-5-chloro-2-benzimidazolinone which comprises reacting 4,4-bis(p-fluorophenyl)cyclohexyl tosylate with 1-(4-piperidyl)-5-chloro-2-benzimidazolinone, or reducing 1-[1-(4,4-bis(p-fluorophenyl)-1-cyclohexenyl)-4-piperidyl]-5-chloro-2-benzimidazolinone.
- 7. A method according to claim 1 of producing 1-[1-(4,4-bis(p-fluoro-phenyl)-2-cyclohexenyl)-4-piperidyl]-5-chloro-2-benzimidazolinone which comprises reacting 4,4-bis(p-fluorophenyl)-1-chloro-2-cyclohexene with 1-(4-piperidyl)-5-chloro-2-benzimidazolinone.
- 8. A method according to claim 1 of producing 1-[1-(4,4-bis(p-fluoro-phenyl)-2-cyclohexenyl)-1,2,3,6-tetrahydro-4-pyridyl]-2-benzimidazolinone which comprises reacting 4,4-bis(p-fluorophenyl)-1-chloro-2-cyclohexene with 1-(1,2,3,6-tetrahydro-4-pyridyl)-2-benzimidazolinone.
- 9. A method according to claim 1 of producing 1-[1-(4,4-bis(p-fluoro-phenyl)cyclohexyl)-4-piperidyl]-2-benzimidazolinone which comprises reducing 1-[1-(4,4-bis(p-fluorophenyl)-1-cyclohexenyl)-4-piperidyl]-2-benzimidazolinone.
- 10. A method according to claim 1 of producing 1-[1-(4,4-bis(p-fluoro-phenyl)cyclohexyl)-1,2,3,6-tetrahydro-4-pyridyl]-2-benzimidazolinone which comprises reacting 4,4-bis(p-fluorophenyl)cyclohexyl tosylate with 1-(1,2,3,6-tetrahydro-4-pyridyl)-2-benzimidazolinone.
- 11. A method according to claim 1 of producing 8-[4,4-bis(p-fluoro-phenyl)-2-cyclohexenyl]-1-(p-bromophenyl)-1,3,8-triazaspiro[4.5]decan-4-one which comprises reacting 4,4-bis(p-fluorophenyl)-1-chloro-2-cyclohexene with 1-(p-bromophenyl)-1,3,8-triazaspiro[4.5]decan-4-one.
- 12. A method according to claim 1 of producing 8-[4,4-bis(p-fluoro-phenyl)cyclohexyl]-1-(p-fluorophenyl)-1,3,8-triazaspiro[4.5]decan-4-one which comprises reacting 4,4-bis(p-fluorophenyl)cyclohexyl mesylate with 1-(p-fluorophenyl)-1,3,8-triazaspiro[4.5]decan-4-one.
- 13. A method according to claim 1 of producing 8-[4,4-bis(p-fluoro-phenyl)cyclohexyl]-1-(3-chloro-4-fluorophenyl)-1,3,8-triazaspiro[4.5]decan-4-one which comprises reacting 4,4-bis(p-fluorophenyl)cyclohexyl tosylate with 1-(3-chloro-4-fluorophenyl)-1,3,8-triazaspiro[4.5]decan-4-one.
- 14. A method according to claim 1 of producing 8-[4,4-bis(p-fluoro-phenyl)cyclohexyl]-1-(p-chlorophenyl)-1,3,8-triazaspiro[4.5]decan-4-one which comprises reacting 4,4-bis(p-fluorophenyl)cyclohexyl tosylate with 1-(p-chlorophenyl)-1,3,8-triazaspiro[4.5]decan-4-one.
- 15. A method according to claim 1 of producing 8-[4,4-bis(p-fluoro-phenyl)cyclohexyl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one which comprises reacting 4,4-bis(p-fluorophenyl)cyclohexyl tosylate with 1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one.
- 16. A method according to claim 1 of producing 1-(4,4-diphenylcyclohexyl)-4-(4-chloro-3-trifluoromethylphenyl)-4-piperidinol which comprises reacting 4,4-diphenylcyclohexyl tosylate with 4-(4-chloro-3-trifluoromethylphenyl)-4-piperidinol.
- 17. A method according to claim 1 of producing 1-[4,4-bis(p-fluoro-phenyl)cyclohexyl]-4-(4-chloro-3-trifluoromethylphenyl)-4-piperidinol which comprises reducing 1-[4,4-bis(p-fluorophenyl)-1-cyclohexenyl]-4-(4-chloro-3-trifluoromethylphenyl)-4-piperidinol.
- 18. A method according to claim 1 of producing 1-[4,4-bis(p-fluoro-phenyl)-2-cyclohexenyl]-4-(4-chloro-3-trifluoromethylphenyl)-4-piperidinol which comprises reacting 4,4-bis(p-fluorophenyl)-1-chloro-2-cyclohexene with 4-(4-chloro-3-trifluoromethylphenyl)-4-piperidinol.
- 19. A method according to claim 1 of producing 1-[1-(4,4-bis(p-tolyl)-2-cyclohexenyl)-4-piperidyl]-5-chloro-2-benzimidazolinone which comprises reacting 4,4-bis(p-tolyl)-1-chloro-2-cyclohexene with 1-(4-piperidyl)-5-chloro-2-benzimidazolinone.
- 20. A method according to claim 1 of producing 1-[1-(3,3-bis(p-fluoro-phenyl)cyclopentylmethyl)-4-piperidyl]-5-chloro-2-benzimidazolinone which comprises reacting 3,3-bis(p-fluorophenyl)-1-chloromethyl-cyclopentane with 1-(4-piperidyl)-5-chloro-2-benzimidazolinone.
- 21. A method according to claim 1 of producing 1-[1-(4,4-bis(p-fluoro-phenyl)-2-cyclohexenyl)-4-piperidyl]-2-benzimidazolinone which comprises reacting 4,4-bis(p-fluorophenyl)-1-chloro-2-cyclohexene with 1-(4-piperidyl)-2-benzimidazolinone.
- 22. A method according to claim 1 of producing 1-[1-(4,4-bis(p-chloro-phenyl)-2-cyclohexenyl)-4-piperidyl]-2-benzimidazolinone which comprises reacting 4,4-bis(p-chlorophenyl)-1-chloro-2-cyclohexene with 1-(4-piperidyl)-2-benzimidazolinone.
- 23. A method according to claim 1 of producing 1-[1-(4,4-bis(p-chloro-phenyl)cyclohexyl)-4-piperidyl]-2-benzimidazolinone which comprises reacting 4,4-bis(p-chlorophenyl)cyclohexyl tosylate with 1-(4-piperidyl)-2-benz-imidazolinone.
- 24. A method according to claim 1 of producing 1-[1-(3,3-bis(p-fluoro-phenyl)cyclopentyl)-4-piperidyl]-2-benzimidazolinone which comprises reacting 3,3-bis(p-fluorophenyl)cyclopentyl tosylate with 1-(4-piperidyl)-2-benz-imidazolinone.
- 25. A method according to claim 1 of producing 1-[1-(4,4-bis(p-tolyl)-2-cyclohexenyl)-4-piperidyl]-2-benzimidazolinone which comprises reacting 4,4-bis(p-tolyl)-1-chloro-2-cyclohexene with 1-(4-piperidyl)-2-benzimidazol-inone.
- 26. A method according to claim 1 of producing 1-[1-(4,4-bis(p-fluoro-phenyl)cyclohexyl)-4-piperidyl]-5-fluoro-2-benzimidazolinone which comprises reacting 4,4-bis(p-fluorophenyl)cyclohexyl tosylate with 1-(4-piperidyl)-5-fluoro-2-benzimidazolinone.
- 27. A method according to claim 1 of producing 1-[1-(4,4-bis(p-fluoro-phenyl)-2-cyclohexenyl)-4-piperidyl]-5-fluoro-2-benzimidazolinone which comprises reacting 4,4-bis(p-fluorophenyl)-1-chloro-2-cyclohexene with 1-(4-piperidyl)-5-fluoro-2-benzimidazolinone.
- 28. A method according to claim 1 of producing 8-[4,4-bis(p-chloro-phenyl)-2-cyclohexenyl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one which comprises reacting 4,4-bis(p-chlorophenyl)-1-chloro-2-cyclohexene with 1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one.
- 29. A method according to claim 1 of producing 8-[4,4-bis(p-fluoro-phenyl)cyclohexyl]-1-(2,4-difluorophenyl)-1,3,8-triazaspiro[4.5]decan-4-one which comprises reacting 4,4-bis(p-fluorophenyl)cyclohexyl tosylate with 1-(2,4-difluorophenyl)-1,3,8-triazaspiro[4.5]decan-4-one.
- 30. A method according to claim 1 of producing 8-[4,4-bis(p-fluoro-phenyl)-2-cyclohexenyl]-1-(3,4-dichlorophenyl)-1,3,8-triazaspiro[4.5]decan-4-one which comprises reacting 4,4-bis(p-fluorophenyl)-1-chloro-2-cyclohexene with 1-(3,4-dichlorophenyl)-1,3,8-triazaspiro[4.5]decan-4-one.
- 31. A method according to claim 1 of producing 8-[4,4-bis(p-fluoro-phenyl)cyclohexyl]-1-(3,4-dichlorophenyl)-1,3,8-triazaspiro[4.5]decan-4-one which comprises reacting 4,4-bis(p-fluorophenyl)cyclohexyl tosylate with 1-(3,4-dichlorophenyl)-1,3,8-triazaspiro[4.5]decan-4-one.
- 32. A method according to claim 1 of producing 8-[4,4-bis(p-fluoro-phenyl)cyclohexyl]-1-(p-bromophenyl)-1,3,8-triazaspiro[4.5]decan-4-one which comprises reacting 4,4-bis(p-fluorophenyl)cyclohexyl tosylate with 1-(p-bromophenyl)-1,3,8-triazaspiro[4.5]decan-4-one.
- 33. A method according to claim 1 of producing 8-[4,4-bis(p-fluoro-phenyl)-2-cyclohexenyl]-1-(p-fluorophenyl)-1,3,8-triazaspiro[4.5]decan-4-one which comprises reacting 4,4-bis(p-fluorophenyl)-1-chloro-2-cyclohexene with 1-(p-fluorophenyl)-1,3,8-triazaspiro[4.5]decan-4-one.
- 34. A method according to claim 1 of producing 8-[4,4-bis(p-trifluoro-methylphenyl)cyclohexyl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one which comprises reacting 4,4-bis(p-trifluoromethylphenyl)cyclohexyl tosylate with 1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one.
- 35. A method according to claim 1 of producing 8-[4,4-bis(p-fluoro-phenyl)-2-cyclohexenyl]-1-(p-chlorophenyl)-1,3,8-triazaspiro[4.5]decan-4-one which comprises reacting 4,4-bis(p-fluorophenyl)-1-chloro-2-cyclohexene with 1-(p-chlorophenyl)-1,3,8-triazaspiro[4.5]decan-4-one.
- 36. A method according to claim 1 of producing 8-[4,4-bis(p-fluoro-phenyl)-2-cyclohexenyl]-1-(3-chloro-4-fluorophenyl)-1.3,8-triazaspiro[4.5]-decan-4-one which comprises reacting 4,4-bis(p-fluorophenyl)-1-chloro-2-cyclohexene with 1-(3-chloro-4-fluorophenyl)-1,3,8-triazaspiro[4.5]decan-4-one.
- 37. A method according to claim 1 of producing 8-[4,4-bis(p-fluoro-phenyl)-2-cyclohexenyl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one which comprises reacting 4,4-bis(p-fluorophenyl)-1-chloro-2-cyclohexene with 1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one.
- 38. A method according to claim 1 of producing 8-[3,3-bis(p-fluoro-phenyl)cyclopentylmethyl]-1-(p-fluorophenyl)-1,3,8-triazaspiro[4.5]decan-4-one which comprises reacting 3,3-bis(p-fluorophenyl)-1-chloromethyl-cyclopentane with 1-(p-fluorophenyl)-1,3,8-triazaspiro[4.5]decan-4-one.
- 39. A method according to claim 1 of producing 1-(4,4-diphenylcyclohexyl)-4-(p-chlorophenyl)-4-piperidinol which comprises reacting 4,4-diphenylcyclohexyl tosylate with 4-(p-chlorophenyl)-4-piperidinol.
- 40. A method according to claim 1 of producing 1-[4,4-bis(p-fluoro-phenyl)cyclohexyl]-4-(p-tolyl)-4-piperidinol which comprises reacting 4,4-bis(p-fluorophenyl)cyclohexyl tosylate with 4-(p-tolyl)-4-piperidinol.
- 41. A method according to claim 1 of producing 1-[4,4-bis(p-fluoro-phenyl)cyclohexyl]-4-(p-chlorophenyl)-4-piperidinol which comprises reacting 4,4-bis(p-fluorophenyl)cyclohexyl tosylate with 4-(p-chlorophenyl)-4-piperidinol.
- 42. A method according to claim 1 of producing 1-[4,4-bis(p-chloro-phenyl)-2-cyclohexenyl]-4-(4-chloro-3-trifluoromethylphenyl)-4-piperidinol which comprises reacting 4,4-bis(p-chlorophenyl)-1-chloro-2-cyclohexene with 4-(4-chloro-3-trifluoromethylphenyl)-4-piperidinol.
- 43. A method according to claim 1 of producing 1-[4,4-bis(p-chloro-phenyl)cyclohexyl]-4-(4-chloro-3-trifluoromethylphenyl)-4-piperidinol which comprises reacting 4,4-bis(p-chlorophenyl)cyclohexyl tosylate with 4-(4-chloro-3-trifluoromethylphenyl)-4-piperidinol.
- 44. A method according to claim 1 of producing 1-[4,4-bis(p-tolyl)-2-cyclohexenyl]-4-(4-chloro-3-trifluoromethylphenyl)-4-piperidinol which comprises reacting 4,4-bis(p-tolyl)-1-chloro-2-cyclohexene with 4-(4-chloro-3-trifluoromethylphenyl)-4-piperidinol.
- 45. A method according to claim 1 of producing 1-[3,3-bis(p-fluoro-phenyl)cyclopentyl]-4-(4-chloro-3-trifluoromethylphenyl)-4-piperidinol which comprises reacting 3,3-bis(p-fluorophenyl)cyclopentyl tosylate with 4-(4-chloro-3-trifluoromethylphenyl)-4-piperidinol.
- 46. A method according to claim 1 of producing 1-[1-(4,4-bis(3,4-difluorophenyl)cyclohexyl)-4-piperidyl]-5-chloro-2-benzimidazolinone which comprises reacting 4,4-bis(3,4-difluorophenyl)cyclohexyl tosylate with 1-(4-piperidyl)-5-chloro-2-benzimidazolinone.
- 47. A method according to claim 1 of producing 1-[1-(4,4-bis(2,4-difluorophenyl)cyclohexyl)-4-piperidyl]-5-chloro-2-benzimidazolinone which comprises reacting 4,4-bis(2,4-difluorophenyl)cyclohexyl tosylate with 1-(4-piperidyl)-5-chloro-2-benzimidazolinone.
- 48. A method according to claim 1 of producing 1-[1-(4,4-bis(2,4-difluorophenyl)-2-cyclohexenyl)-4-piperidyl]-5-chloro-2-benzimidazolinone which comprises reacting 4,4-bis(2,4-difluorophenyl)-1-chloro-2-cyclohexene with 1-(4-piperidyl)-5-chloro-2-benzimidazolinone.
49. A method according to claim 1 of producing 8-[4,4-bis(3,4-difluoro-phenyl)-2-cyclohexenyl]-1-(p-fluorophenyl)-1,3,8-triazaspiro[4.5]decan-4-one which comprises reacting 4,4-bis(3,4-difluorophenyl)-1-chloro-2-cyclohexene with 1-(p-fluorophenyl)-1,3,8-triazaspiro[4.5]decan-4-one.
50. A compound of formula (I) of claim 1 and a pharmaceutically acceptable salt thereof, whenever produced by the method of claim 1.
51. A compound of formula (I) of claim 1 wherein R1 is F, R2 is H or F, R3 is F, R4 is H or F, n is 2 and m is 0 and a pharmaceutically acceptable salt thereof, whenever produced by the method of claim 2.
52. A compound of formula (I) of claim 1 wherein R1 is F at para-position, R2 is H, R3 is F at para-position, R4 is H, n is 2 and m is 0 and a pharmaceuti-cally acceptable salt thereof, whenever produced by the method of claim 3.
53. 1-[1-(4,4-Diphenylcyclohexyl)-4-piperidyl]-2-benzimidazolinone, whenever produced by the method of claim 4.
54. 1-[1-(3,3-Bis(p-fluorophenyl)cyclopentyl)-4-piperidyl]-5-chloro-2-benzimidazolinone, whenever produced by the method of claim 5.
55. 1-[1-(4,4-Bis(p-fluorophenyl)cyclohexyl)-4-piperidyl]-5-chloro-2-benzimidazolinone, whenever produced by the method of claim 6.
56. 1-[1-(4,4-Bis(p-fluorophenyl)-2-cyclohexenyl)-4-piperidyl]-5-chloro-2-benzimidazolinone, whenever produced by the method of claim 7.
57. 1-[1-(4,4-Bis(p-fluorophenyl)-2-cyclohexenyl)-1,2,3,6-tetrahydro-4-pyridyl]-2-benzimidazolinone, whenever produced by the method of claim 8.
58. 1-[1-(4,4-Bis(p-fluorophenyl)cyclohexyl)-4-piperidyl]-2-benzimidazolinone, whenever produced by the method of claim 9.
59. 1-[1-(4,4-Bis(p-fluorophenyl)cyclohexyl)-1,2,3,6-tetrahydro-4-pyridyl]-2-benzimidazolinone, whenever produced by the method of claim 10.
60. 8-[4,4-Bis(p-fluorophenyl)-2-cyclohexenyl]-1-(p-bromophenyl)-1,3,8-triazaspiro[4.5]decan-4-one, whenever produced by the method of claim 11.
61. 8-[4,4-Bis(p-fluorophenyl)cyclohexyl]-1-(p-fluorophenyl)-1,3,8-triazaspiro[4.5]decan-4-one, whenever produced by the method of claim 12.
62. 8-[4,4-Bis(p-fluorophenyl)cyclohexyl]-1-(3-chloro-4-fluorophenyl)-1,3,8-triazaspiro[4.5]decan-4-one, whenever produced by the method of claim 13.
63. 8-[4,4-Bis(p-fluorophenyl)cyclohexyl]-1-(p-chlorophenyl)-1,3,8-triazaspiro[4.5]decan-4-one, whenever produced by the method of claim 14.
64. 8-[4,4-Bis(p-fluorophenyl)cyclohexyl]-1-phenyl-1,3,8-triazaspiro-[4.5]decan-4-one, whenever produced by the method of claim 15.
65. 1-(4,4-Diphenylcyclohexyl)-4-(4-chloro-3-trifluoromethylphenyl)-4-piperidinol, whenever produced by the method of claim 16.
66. 1-[4,4-Bis(p-fluorophenyl)cyclohexyl]-4-(4-chloro-3-trifluoromethyl-phenyl)-4-piperidinol, whenever produced by the method of claim 17.
67. 1-[4,4-Bis(p-fluorophenyl)-2-cyclohexenyl]-4-(4-chloro-3-trifluoro-methylphenyl)-4-piperidinol, whenever produced by the method of claim 18.
68. 1-[1-(4,4-Bis(p-tolyl)-2-cyclohexenyl)-4-piperidyl]-5-chloro-2-benzimidazolinone, whenever produced by the method of claim 19.
69. 1-[1-(3,3-Bis(p-fluorophenyl)cyclopentylmethyl)-4-piperidyl]-5-chloro-2-benzimidazolinone, whenever produced by the method of claim 20.
70. 1-[1-(4,4-Bis(p-fluorophenyl)-2-cyclohexenyl)-4-piperidyl]-2-benzimidazolinone, whenever produced by the method of claim 21.
71. 1-[1-(4,4-Bis(p-chlorophenyl)-2-cyclohexenyl)-4-piperidyl]-2-benzimidazolinone, whenever produced by the method of claim 22.
72. 1-[1-(4,4-Bis(p-chlorophenyl)cyclohexyl)-4-piperidyl]-2-benzimidazolinone, whenever produced by the method of claim 23.
73. 1-[1-(3,3-Bis(p-fluorophenyl)cyclopentyl)-4-piperidyl]-2-benzimidazolinone, whenever produced by the method of claim 24.
74. 1-[1-(4,4-Bis(p-tolyl)-2-cyclohexenyl)-4-piperidyl]-2-benzimidazol-inone, whenever produced by the method of claim 25.
75. 1-[1-(4,4-Bis(p-fluorophenyl)cyclohexyl)-4-piperidyl]-5-fluoro-2-benzimidazolinone, whenever produced by the method of claim 26.
76. 1-[1-(4,4-Bis(p-fluorophenyl)-2-cyclohexenyl)-4-piperidyl]-5-fluoro-2-benzimidazolinone, whenever produced by the method of claim 27.
77. 8-[4,4-Bis(p-chlorophenyl)-2-cyclohexenyl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one, whenever produced by the method of claim 28.
78. 8-[4,4-Bis(p-fluorophenyl)cyclohexyl]-1-(2,4-difluorophenyl)-1,3,8-triazaspiro[4.5]decan-4-one, whenever produced by the method of claim 29.
79. 8-[4,4-Bis(p-fluorophenyl)-2-cyclohexenyl]-1-(3,4-dichlorophenyl)-1,3,8-triazaspiro[4.5]decan-4-one, whenever produced by the method of claim 30.
80. 8-[4,4-Bis(p-fluorophenyl)cyclohexyl]-1-(3,4-dichlorophenyl)-1,3,8-triazaspiro[4.5]decan-4-one, whenever produced by the method of claim 31.
81. 8-[4,4-Bis(p-fluorophenyl)cyclohexyl]-1-(p-bromophenyl)-1,3,8-triazaspiro[4.5]decan-4-one, whenever produced by the method of claim 32.
82. 8-[4,4-Bis(p-fluorophenyl)-2-cyclohexenyl]-1-(p-fluorophenyl)-1,3,8-triazaspiro[4.5]decan-4-one, whenever produced by the method of claim 33.
83. 8-[4,4-Bis(p-trifluoromethylphenyl)cyclohexyl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one, whenever produced by the method of claim 34.
84. 8-[4,4-Bis(p-fluorophenyl)-2-cyclohexenyl]-1-(p-chlorophenyl)-1,3,8-triazaspiro[4.5]decan-4-one, whenever produced by the method of claim 35.
85. 8-[4,4-Bis(p-fluorophenyl)-2-cyclohexenyl]-1-(3-chloro-4-fluoro-phenyl)-1,3,8-triazaspiro[4.5]decan-4-one, whenever produced by the method of claim 36.
86. 8-[4,4-Bis(p-fluorophenyl)-2-cyclohexenyl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one, whenever produced by the method of claim 37.
87. 8-[3,3-Bis(p-fluorophenyl)cyclopentylmethyl]-1-(p-fluorophenyl)-1,3,8-triazaspiro[4.5]decan-4-one, whenever produced by the method of claim 38.
88. 1-(4,4-Diphenylcyclohexyl)-4-(p-chlorophenyl)-4-piperidinol, whenever produced by the method of claim 39.
89. 1-[4,4-Bis(p-fluorophenyl)cyclohexyl]-4-(p-tolyl)-4-piperidinol, whenever produced by the method of claim 40.
90. 1-[4,4-Bis(p-fluorophenyl)cyclohexyl]-4-(p-chlorophenyl)-4-piperidinol, whenever produced by the method of claim 41.
91. 1-[4,4-Bis(p-chlorophenyl)-2-cyclohexenyl]-4-(4-chloro-3-trifluoro-methylphenyl)-4-piperidinol, whenever produced by the method of claim 42.
92. 1-[4,4-Bis(p-chlorophenyl)cyclohexyl]-4-(4-chloro-3-trifluoro-methylphenyl)-4-piperidinol, whenever produced by the method of claim 43.
93. 1-[4,4-Bis(p-tolyl)-2-cyclohexenyl]-4-(4-chloro-3-trifluoromethyl-phenyl)-4-piperidinol, whenever produced by the method of claim 44.
94. 1-[3,3-Bis(p-fluorophenyl)cyclopentyl]-4-(4-chloro-3-trifluoro-methylphenyl)-4-piperidinol, whenever produced by the method of claim 45.
95. 1-[1-(4,4-Bis(3,4-difluorophenyl)cyclohexyl)-4-piperidyl]-5-chloro-2-benzimidazolinone, whenever produced by the method of claim 46.
96. 1-[1-(4,4-Bis(2,4-difluorophenyl)cyclohexyl)-4-piperidyl]-5-chloro-2-benzimidazolinone, whenever produced by the method of claim 47.
97. 1-[1-(4,4-Bis(2,4-difluorophenyl)-2-cyclohexyl)-4-piperidyl]-5-chloro-2-benzimidazolinone, whenever produced by the method of claim 48.
98. 8-[4,4-Bis(3,4-difluorophenyl)-2-cyclohexenyl]-1-(p-fluorophenyl)-1,3,8-triazaspiro[4.5]decan-4-one, whenever produced by the method of - claim 49.
1. A method of producing a compound of the formula (I):
(I) and a pharmaceutically acceptable salt thereof, which comprises:
(i) reacting a compound of the formula (II):
(II) with a compound of the formula:
H - Am (III) or (ii) reducing a compound of the formula (V):
(V) and, if desired, isolating the resulting compound as a pharmaceutically acceptable salt thereof, wherein the dotted line in Ring A indicates an
Applications Claiming Priority (7)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP50025170A JPS51100084A (en) | 1975-02-28 | 1975-02-28 | |
| JP8796175A JPS5212171A (en) | 1975-07-17 | 1975-07-17 | Process for preparation of cyclohexane derivatives |
| JP8856675A JPS5212174A (en) | 1975-07-18 | 1975-07-18 | Preparation of cyclohexane derivatives |
| JP8953975A JPS5214776A (en) | 1975-07-21 | 1975-07-21 | Process for preparing cyclohexane derivatives |
| JP8953775A JPS5214774A (en) | 1975-07-21 | 1975-07-21 | Process for preparing cyclohexane derivatives |
| JP8953875A JPS5214775A (en) | 1975-07-21 | 1975-07-21 | Process for preparing cyclohexane derivatives |
| JP50111387A JPS5236672A (en) | 1975-09-13 | 1975-09-13 | Process for preparation of cyclohexane derivatives |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1074319A true CA1074319A (en) | 1980-03-25 |
Family
ID=27564056
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA246,241A Expired CA1074319A (en) | 1975-02-28 | 1976-02-20 | 4,4-diphenylcyclohexylpiperidine compounds and analogs thereof |
Country Status (7)
| Country | Link |
|---|---|
| CA (1) | CA1074319A (en) |
| CH (1) | CH613203A5 (en) |
| DE (1) | DE2607300A1 (en) |
| FR (1) | FR2313057A1 (en) |
| GB (1) | GB1486546A (en) |
| GR (1) | GR59877B (en) |
| NL (1) | NL7601980A (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| PT921125E (en) * | 1997-12-05 | 2002-06-28 | Hoffmann La Roche | DERIVATIVES OF 1,38-TRIAZA-ESPIRO 4,5 DECAN-4-ONA |
| JP2006507301A (en) * | 2002-10-30 | 2006-03-02 | メルク エンド カムパニー インコーポレーテッド | Piperidinylcyclopentylarylbenzylamide modulators of chemokine receptor activity |
-
1976
- 1976-02-18 GB GB630376A patent/GB1486546A/en not_active Expired
- 1976-02-19 CH CH221076A patent/CH613203A5/en not_active IP Right Cessation
- 1976-02-20 CA CA246,241A patent/CA1074319A/en not_active Expired
- 1976-02-20 GR GR50109A patent/GR59877B/en unknown
- 1976-02-23 FR FR7604879A patent/FR2313057A1/en active Granted
- 1976-02-23 DE DE19762607300 patent/DE2607300A1/en not_active Withdrawn
- 1976-02-26 NL NL7601980A patent/NL7601980A/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| NL7601980A (en) | 1976-08-31 |
| DE2607300A1 (en) | 1976-09-09 |
| GR59877B (en) | 1978-03-09 |
| FR2313057A1 (en) | 1976-12-31 |
| GB1486546A (en) | 1977-09-21 |
| CH613203A5 (en) | 1979-09-14 |
| FR2313057B1 (en) | 1981-12-18 |
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