CA1110634A - 1-dimethyl substituted alkyl-2-or 4-substituted phenylimidazoles, their production and their use as anti-obesity agents - Google Patents
1-dimethyl substituted alkyl-2-or 4-substituted phenylimidazoles, their production and their use as anti-obesity agentsInfo
- Publication number
- CA1110634A CA1110634A CA318,825A CA318825A CA1110634A CA 1110634 A CA1110634 A CA 1110634A CA 318825 A CA318825 A CA 318825A CA 1110634 A CA1110634 A CA 1110634A
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- Prior art keywords
- formula
- compound
- hydrogen
- acceptable salt
- production
- Prior art date
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Abstract
PHENYLIMIDAZOLES, THEIR PRODUCTION AND THEIR USE
AS ANTI-OBESITY AGENTS
Abstract of the Disclosure:
This disclosure describes novel compounds of the formula (I) wherein R1 and R2 each represent hydrogen, or.
AS ANTI-OBESITY AGENTS
Abstract of the Disclosure:
This disclosure describes novel compounds of the formula (I) wherein R1 and R2 each represent hydrogen, or.
Description
;39~
This application relates to l-dimethyl-substituted alkyl-2- or 4-substituted phenylimidazoles which are useful as anti-obesity agents. In particular, it relates to 1-dimethyl-substituted alkyl-2- or 4-substituted-phenylimidazoles and their pharmaceutically acceptable acid addition salts.
The compounds of this invention may be represented by the following structural formula:
J, ~ .
( CH2 ) n~CH2~NL=,~
1 R2 (I) wherein Rl and R2 each represent hydrogen, or R~ ~ and R3 is hydrogen or fluoro, and n is 1, 2 or 3, and provided that one of Rl and R2 is other than hydrogen.
The compounds of formula (I) may be prepared according to the following reaction scheme:
[J (CH2)nCH2X + ~ CH2)n CU2 (II) (III) (I) 3~
where X is halo having an atomic weight of about 35 to 127 or OSO2~,R4 wherein R4 is hydrogen, chlorine, or methyl, Z is sodium, potassium or lithium, and Rl, R2, n and the proviso are as defined above.
The compounds of formula (I) are prepared by treating a compound of the formula (II) with a compound of the formula (III) under an inert atmosphere preferably nitrogen in the presencq of an inert organic solvent. Although the particular solvent employed is not critical, the preferred solvents include the aromatic hydrocarbons such as benzene, toluene and the like, the ethers such as dioxane, tetrahydro-furan and the like, dimethylacetamide and dimethylformamide, the latter being especially preferred. The temperature of the reaction is not critical, but it is preferred that the reaction be carried out between about 15 to 60C., preferably from about 20 to 30C. The reaction may be run from about 8 to 36 hours, preferably from about 12 to 20 hours. The pro-duct is recovered using conventional techniques, e.g., dis-tillation or crystallization or when necessary, column chro-matography followed by distillation or crystallization.
The compounds of formulae (II) and (III) are known and may be prepared by methods described in the literature.
It will be understood that the compounds of formula (I) may exist in the form of optically active isomers which can be separated and recovered by conventional techniques, and such isomeric forms are also included within the scope ~-of this invention.
The compounds of formula (I) are useful because they possess pharmacological activity in animals. In par-ticular, the compounds of formula (I) are useful as anti-obesity agents in the treatment of obesity as indicated by preventing an increase in the blood sugar level in male Wistar rats in groups of 4 which are fasted for 16 hours and then are given an initial dose of 200 milligrams per kilogram of animal body weight of the test compound orally. One hour later, the rats are given 2.5 grams per kilogram of animal body weight of starch load. Thirty minutes after admin-istration of the starch, the rats are anesthetized with 120 milligrams per kilogram of animal body weight of sodium hexobarbital after which blood is collected via cardiac puncture. The blood samples are placed in an autoanalyzer cup containing 0.1 milliliters of heparin (1,000 units per milliliter). The heaprinized blood is used to determine the blood sugar level with an autoanalyzer. The blood sugar content is compared to the control group which receives 0.5% carboxmethyl cellulose and are run concurrently. The blood sugar levels are calculated and compared to the control.
For such usage, the compounds of formula (1) may be combined with a pharmaceutically acceptable carrier or adjuvant and may be administered orally or parenterally as such or admixed with conventional pharmaceutical carriers.
They may be administered in such forms as tablets, disper-sible powders, granules, capsules, syrups and elixirs, and parenterally as solutions, suspensions and the like, e.g., a 6~4 sterile injectable aqueous solution. The dosage will vary depending ~pon the mode of administration utilized and the particular compound employed.
The compounds of formula (I) may be similarly admin-istered in the form of their non-toxic pharmaceutically accept-able salts. Such salts possess the same order of activity as the free base and are readily prepared by reacting the base with an appropriate acid and accordingly, are included within the scope of this invention. Representative of such salts are the mineral acid salts such as the hydrochloride, hydrobromide, sulfate, phosphate and the like and the organic salts such as the succinate, benzoate, acetate, p-toluene-sulfonate and the like.
The anti-obesity effective dosage of active ingredient employed for the treatment of obesity may vary depending on the particular compound employed, the mode of administration and the severity of the condition being treated. However, in general, satisfactory results are ` obtained when the compounds of formula (I) are administered at a daily dosage of from about 2 milligrams to about 400 milligrams per kilogram of animal body weight, p.o., preferably given in divided doses two to four times a day, or in sustained release form. For most large mammals, the total daily dosage is from about 25 to about 1000 milligrams.
Dosage forms suitable for internal use comprise from about 7.S to about 500 milligrams of the active compound in intimate admixture with a solid or liquid pharmaceutically acceptable carrier or diluent.
A representative formulation suitable for oral administration two to four times a day for the treatment of i34 obesity is a capsule prepared by standard encapsulating techniques which contains the following:
INGREDIENTS WEIGHT (mg.) -(+)-1-(3,7-dimethyloctyl)-2-phenylimidazole 100 inert solid diluent (starch, lactose, kaolin) 200 (+)-1-(3,7-dimethyloctyl)-2-phenylimidazole.
To a solution of 21.5 q (0.14 mole) of 2-phenyl-imidazole in 60 ml. dry dimethylformamide and 300 ml. dry tetrahydrofuran under nitrogen atmosphere there is added at room temperature 9.0 g. (0.19 mole) of 50% sodium hydride/
mineral oil suspension. The resulting mixture is stirred and heated to 50C. for about 3 hours. After cooling to room temperature the resulting mixture is treated dropwise with a solution of 40.5g. (0.18 mole) of (+)-1-bromo-3,7-dimethyloctane in dry tetrahydrofuran. The reaction mixture is stirred over night at room temperature and the resulting mixture is filtered and the residue washed with tetrahydro-furan. The combined filtrate is concentrated in vacuo to an oil, the oil is than dissolved in methylene chloride, washed with water, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to yield an oily product.
Distillation gave (+) 1-(3,7-dimethyloctyl)-2-phenylimidazole;
b.p. 150 to 157C. at 0.2 - 0.16 mm.
Following the above procedure and using in place of 2-phenylimidazole an equivalent amount of a) 2-(p-fluorophenyl)imidazole, or b) 4-phenylimidazole r' 1~1~634 there is obtained a) (+)-1-(3,7-dimethyloctyl)-2-(p-fluorophenyl) imidazole or b) (+)-l-(3,7-dimethyloctyl)-4-phenyl imidazole b.p. 155 to 165C at 0.2 mm respectively.
Also following the above procedure and using in place of (+)-l-bromo-3,7-dimethyloctane an equivalent amount of c) (+)-l-bromo-4,8-dimethylnonane, or d) (+)-1-bromo-5,9-dimethyldecane, there is obtained c) (+)-l-(4,8-dimethylnonyl)-2-phenylimidazole, or d) (+)-l-(5,9-dimethyldecyl)-2-phenylimidazole, b.p. 142-148 at 0.7 mm.
Also following the above procedure and using in place 2-phenylimidazole an equivalent amount of 4-phenyl-imidazol-e and using in place of (+)-l-bromo-3,7-dimethyl-octane an equivalent amount of (+)-l-bromo-5,9-dimethyl-20~ decane there is obtained c) (+)-1-(5,9-dimethyldecyl)-4-phenylimidazole b.p. 195 to 205C at 0.5 mm.
The (+)-1-(3,7-dimethyloctyl)-2-phenylimidazole of ;~ this example is an effective anti-obesity agent when orally administered to an animal in need of said treatment at a dosage of 150 mg. two to four times a day.
:: :
, . .
This application relates to l-dimethyl-substituted alkyl-2- or 4-substituted phenylimidazoles which are useful as anti-obesity agents. In particular, it relates to 1-dimethyl-substituted alkyl-2- or 4-substituted-phenylimidazoles and their pharmaceutically acceptable acid addition salts.
The compounds of this invention may be represented by the following structural formula:
J, ~ .
( CH2 ) n~CH2~NL=,~
1 R2 (I) wherein Rl and R2 each represent hydrogen, or R~ ~ and R3 is hydrogen or fluoro, and n is 1, 2 or 3, and provided that one of Rl and R2 is other than hydrogen.
The compounds of formula (I) may be prepared according to the following reaction scheme:
[J (CH2)nCH2X + ~ CH2)n CU2 (II) (III) (I) 3~
where X is halo having an atomic weight of about 35 to 127 or OSO2~,R4 wherein R4 is hydrogen, chlorine, or methyl, Z is sodium, potassium or lithium, and Rl, R2, n and the proviso are as defined above.
The compounds of formula (I) are prepared by treating a compound of the formula (II) with a compound of the formula (III) under an inert atmosphere preferably nitrogen in the presencq of an inert organic solvent. Although the particular solvent employed is not critical, the preferred solvents include the aromatic hydrocarbons such as benzene, toluene and the like, the ethers such as dioxane, tetrahydro-furan and the like, dimethylacetamide and dimethylformamide, the latter being especially preferred. The temperature of the reaction is not critical, but it is preferred that the reaction be carried out between about 15 to 60C., preferably from about 20 to 30C. The reaction may be run from about 8 to 36 hours, preferably from about 12 to 20 hours. The pro-duct is recovered using conventional techniques, e.g., dis-tillation or crystallization or when necessary, column chro-matography followed by distillation or crystallization.
The compounds of formulae (II) and (III) are known and may be prepared by methods described in the literature.
It will be understood that the compounds of formula (I) may exist in the form of optically active isomers which can be separated and recovered by conventional techniques, and such isomeric forms are also included within the scope ~-of this invention.
The compounds of formula (I) are useful because they possess pharmacological activity in animals. In par-ticular, the compounds of formula (I) are useful as anti-obesity agents in the treatment of obesity as indicated by preventing an increase in the blood sugar level in male Wistar rats in groups of 4 which are fasted for 16 hours and then are given an initial dose of 200 milligrams per kilogram of animal body weight of the test compound orally. One hour later, the rats are given 2.5 grams per kilogram of animal body weight of starch load. Thirty minutes after admin-istration of the starch, the rats are anesthetized with 120 milligrams per kilogram of animal body weight of sodium hexobarbital after which blood is collected via cardiac puncture. The blood samples are placed in an autoanalyzer cup containing 0.1 milliliters of heparin (1,000 units per milliliter). The heaprinized blood is used to determine the blood sugar level with an autoanalyzer. The blood sugar content is compared to the control group which receives 0.5% carboxmethyl cellulose and are run concurrently. The blood sugar levels are calculated and compared to the control.
For such usage, the compounds of formula (1) may be combined with a pharmaceutically acceptable carrier or adjuvant and may be administered orally or parenterally as such or admixed with conventional pharmaceutical carriers.
They may be administered in such forms as tablets, disper-sible powders, granules, capsules, syrups and elixirs, and parenterally as solutions, suspensions and the like, e.g., a 6~4 sterile injectable aqueous solution. The dosage will vary depending ~pon the mode of administration utilized and the particular compound employed.
The compounds of formula (I) may be similarly admin-istered in the form of their non-toxic pharmaceutically accept-able salts. Such salts possess the same order of activity as the free base and are readily prepared by reacting the base with an appropriate acid and accordingly, are included within the scope of this invention. Representative of such salts are the mineral acid salts such as the hydrochloride, hydrobromide, sulfate, phosphate and the like and the organic salts such as the succinate, benzoate, acetate, p-toluene-sulfonate and the like.
The anti-obesity effective dosage of active ingredient employed for the treatment of obesity may vary depending on the particular compound employed, the mode of administration and the severity of the condition being treated. However, in general, satisfactory results are ` obtained when the compounds of formula (I) are administered at a daily dosage of from about 2 milligrams to about 400 milligrams per kilogram of animal body weight, p.o., preferably given in divided doses two to four times a day, or in sustained release form. For most large mammals, the total daily dosage is from about 25 to about 1000 milligrams.
Dosage forms suitable for internal use comprise from about 7.S to about 500 milligrams of the active compound in intimate admixture with a solid or liquid pharmaceutically acceptable carrier or diluent.
A representative formulation suitable for oral administration two to four times a day for the treatment of i34 obesity is a capsule prepared by standard encapsulating techniques which contains the following:
INGREDIENTS WEIGHT (mg.) -(+)-1-(3,7-dimethyloctyl)-2-phenylimidazole 100 inert solid diluent (starch, lactose, kaolin) 200 (+)-1-(3,7-dimethyloctyl)-2-phenylimidazole.
To a solution of 21.5 q (0.14 mole) of 2-phenyl-imidazole in 60 ml. dry dimethylformamide and 300 ml. dry tetrahydrofuran under nitrogen atmosphere there is added at room temperature 9.0 g. (0.19 mole) of 50% sodium hydride/
mineral oil suspension. The resulting mixture is stirred and heated to 50C. for about 3 hours. After cooling to room temperature the resulting mixture is treated dropwise with a solution of 40.5g. (0.18 mole) of (+)-1-bromo-3,7-dimethyloctane in dry tetrahydrofuran. The reaction mixture is stirred over night at room temperature and the resulting mixture is filtered and the residue washed with tetrahydro-furan. The combined filtrate is concentrated in vacuo to an oil, the oil is than dissolved in methylene chloride, washed with water, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to yield an oily product.
Distillation gave (+) 1-(3,7-dimethyloctyl)-2-phenylimidazole;
b.p. 150 to 157C. at 0.2 - 0.16 mm.
Following the above procedure and using in place of 2-phenylimidazole an equivalent amount of a) 2-(p-fluorophenyl)imidazole, or b) 4-phenylimidazole r' 1~1~634 there is obtained a) (+)-1-(3,7-dimethyloctyl)-2-(p-fluorophenyl) imidazole or b) (+)-l-(3,7-dimethyloctyl)-4-phenyl imidazole b.p. 155 to 165C at 0.2 mm respectively.
Also following the above procedure and using in place of (+)-l-bromo-3,7-dimethyloctane an equivalent amount of c) (+)-l-bromo-4,8-dimethylnonane, or d) (+)-1-bromo-5,9-dimethyldecane, there is obtained c) (+)-l-(4,8-dimethylnonyl)-2-phenylimidazole, or d) (+)-l-(5,9-dimethyldecyl)-2-phenylimidazole, b.p. 142-148 at 0.7 mm.
Also following the above procedure and using in place 2-phenylimidazole an equivalent amount of 4-phenyl-imidazol-e and using in place of (+)-l-bromo-3,7-dimethyl-octane an equivalent amount of (+)-l-bromo-5,9-dimethyl-20~ decane there is obtained c) (+)-1-(5,9-dimethyldecyl)-4-phenylimidazole b.p. 195 to 205C at 0.5 mm.
The (+)-1-(3,7-dimethyloctyl)-2-phenylimidazole of ;~ this example is an effective anti-obesity agent when orally administered to an animal in need of said treatment at a dosage of 150 mg. two to four times a day.
:: :
, . .
Claims (6)
1. A process for the production of a compound of the formula I
wherein R1 and R2 each represent hydrogen, or , and R3 is hydrogen or fluoro, and n is 1, 2 or 3, and provided that at least one of R1 and R2 is other than hydrogen or a non-toxic pharmaceutically acceptable salt thereof, characterized by reacting a compound of formula II
II
in which n is as defined above, and X is chlorine, bromine or , in which R4 is hydrogen chloride or methyl, with a compound of formula III, III
in which R1 and R2 are as defined above, and Z is sodium, potassium or lithium and if required converting a compound of formula I thus obtained into a non-toxic pharmaceutically acceptable salt thereof.
wherein R1 and R2 each represent hydrogen, or , and R3 is hydrogen or fluoro, and n is 1, 2 or 3, and provided that at least one of R1 and R2 is other than hydrogen or a non-toxic pharmaceutically acceptable salt thereof, characterized by reacting a compound of formula II
II
in which n is as defined above, and X is chlorine, bromine or , in which R4 is hydrogen chloride or methyl, with a compound of formula III, III
in which R1 and R2 are as defined above, and Z is sodium, potassium or lithium and if required converting a compound of formula I thus obtained into a non-toxic pharmaceutically acceptable salt thereof.
2. A compound of formula I as defined in Claim 1 or a non-toxic pharmaceutially acceptable salt thereof whenever prepared by a process as claimed in Claim 1 or by an obvious chemical equivalent thereof.
3. A process as claimed in Claim 1 wherein in the formula I R2 represents hydrogen and R1 represents the group .
4. A compound of the formula I as illustrated in Claim 1 wherein R2 represents hydrogen and R1 represents the group or a non-toxic pharmaceutically acceptable salt thereof whenever prepared by a process as claimed in Claim 3 or by an obvious chemical equivalent thereof.
5. A process as claimed in Claim 1 wherein in the formula I R2 represents hydrogen and R1 represents phenyl.
6. A compound of the formula I as illustrated in Claim 1 wherein R2 represents hydrogen and R1 represents phenyl or a non-toxic pharmaceutically acceptable salt thereof whenever prepared by a process as claimed in Claim 5 or by an obvious chemical equivalent thereof.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US90315578A | 1978-05-05 | 1978-05-05 | |
| US903,155 | 1992-06-24 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1110634A true CA1110634A (en) | 1981-10-13 |
Family
ID=25417025
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA318,825A Expired CA1110634A (en) | 1978-05-05 | 1978-12-29 | 1-dimethyl substituted alkyl-2-or 4-substituted phenylimidazoles, their production and their use as anti-obesity agents |
Country Status (8)
| Country | Link |
|---|---|
| JP (1) | JPS54145664A (en) |
| AU (1) | AU4305579A (en) |
| CA (1) | CA1110634A (en) |
| DK (1) | DK585878A (en) |
| ES (1) | ES476564A1 (en) |
| FI (1) | FI783953A (en) |
| IL (1) | IL56308A0 (en) |
| PT (1) | PT69182A (en) |
-
1978
- 1978-12-21 FI FI783953A patent/FI783953A/en not_active IP Right Cessation
- 1978-12-26 IL IL56308A patent/IL56308A0/en unknown
- 1978-12-28 DK DK585878A patent/DK585878A/en unknown
- 1978-12-28 JP JP16129978A patent/JPS54145664A/en active Pending
- 1978-12-29 CA CA318,825A patent/CA1110634A/en not_active Expired
-
1979
- 1979-01-02 AU AU43055/79A patent/AU4305579A/en not_active Abandoned
- 1979-01-03 ES ES476564A patent/ES476564A1/en not_active Expired
- 1979-02-06 PT PT6918279A patent/PT69182A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| JPS54145664A (en) | 1979-11-14 |
| DK585878A (en) | 1979-11-06 |
| FI783953A (en) | 1979-11-06 |
| PT69182A (en) | 1979-03-01 |
| AU4305579A (en) | 1979-11-08 |
| IL56308A0 (en) | 1979-03-12 |
| ES476564A1 (en) | 1979-12-01 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKEX | Expiry |