N-(2-aminocycloheptyl)N-alkanoylanilides and their 2-N-oxides of the formula ##STR1## e.g., trans-3,4-dichloro-N-[2-(allylamino)cycloheptyl]propionanilide, and their pharmacologically acceptable salts, have been found to possess potent Central Nervous System antidepressant properties. Many of them are new.
These compounds are promising antidepressant drugs which are characterized by lower toxicity than imipramine, and long acting activity which may allow longer durations between administrations, e.g., once a day. pharmaceutical compositions containing these compounds and a process for treating conditions of depression with these compositions are disclosed.
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21. 3,4-Dichloro-N-[2-(N-allyl-N-methylamino)cyloheptyl]propionanilide and the acid addition salts thereof.
23. 3,4-Dichloro-N-[2-(N-benzyl-N-methylamino)cycloheptyl]propionanilide, and the acid addition salts thereof.
22. 3,4-Dichloro-N-[2-(N-β-p
henethyl-N-methylamino)cycloheptyl]propionanilide and the acid addition salts thereof.
18. A compound of the formula ##STR24## wherein the wavy line (∼) in the 1-position of the cyclopentyl cycloheptyl ring indicates cis or transconfiguration of the substituents in the 1- and 2-positions of the cyclopentyl cycloheptyl ring;
p is zero or 1; Q is oxygen or sulfur; R is C1 to C3 -alkyl, vinyl C3 to C6 -cycloalkyl, ethoxy, or methoxymethyl; R1 is hydrogen or C1 to C3 -alkyl; R2 is C3 to C6 -(allylic)alkenyl; each of Y and Z is selected from the group consisting of hydrogen, a halogen having an atomic number of from 9 to 35, trifluoromethyl, C1 to C2 -alkyl, and C1 to C2 -alkyloxy and when Y is trifluoromethyl, Z is hydrogen; when Y is C1 to C2 -alkyloxy and Z is hydrogen, the C1 to C2 -alkyloxy is in the 3-position; when Y and Z are both halogens or C1 to C2 -alkyloxy, they are present in the 3- and 4- or 3- and 5-positions, or an acid addition salt thereof.
24. A compound of the formula ##STR25## wherein the wavy line (∼) in the 1-position of the cycloheptyl ring indicates cis or trans configuration of the substituents in the 1- and 2-positions of the cyclopentyl cycloheptyl ring;
P p is zero or 1; Q is oxygen or sulfur; R is vinyl, C3 to C6 -cycloalkyl, ethoxy, or methoxymethyl; R1 is hydrogen or C1 to C3 -alkyl; R2 is C3 to C6 -(allylic)alkenyl), benzyl or phenylethyl, each of Y and Z is selected from the group consisting of hydrogen, a halogen having an atomic number of from 9 to 35, trifluoromethyl, C1 to C2 -alkyl, and C1 to C2 -alkyloxy and when Y is trifluoromethyl, Z is hydrogen,; when Y is C1 to C2 -alkyloxy and Z is hydrogen, the C1 to C2 -alkyloxy is in the 3-position,; when Y and Z are both halogens or C1 to C2 -alkyloxy, they are present in the 3- and 4- or 3- and 5-positions, or a pharmacologically acceptable salt thereof.
1. A process for treating depression which comprises administering to a depressed human a compound of the formula ##STR22## wherein the wavy line (∼) in the 1-position of the cycloheptyl ring indicates cis or trans configuration of the substituents in the 1- and 2-positions of the cyclopentyl cycloheptyl ring;
p is zero or 1; Q is oxygen or sulfur; R is C1 to C3 -alkyl, vinyl, C3 to C6 -cycloalkyl, ethoxy, or methoxymethyl; R1 is hydrogen or C1 to C3 -alkyl; R2 is: --CH2 C6 H5, --CH2 CH2 --C6 H5, or C3 -C6 (allylic)alkenyl; each of Y and Z is selected from the group consisting of hydrogen, a halogen having an atomic number of from 9 to 35, trifluoromethyl, C1 to to C2 -alkyl, and C1 to C2 -alkyloxy and when Y is trifluoromethyl, Z is hydrogen; when Y is C1 to C2 -alkyloxy and Z is hydrogen, the C1 to C2 -alkyloxy is in the 3-position; when Y and Z are both halogens or C1 to C2 -alkyloxy, they are present in the 3-and 4- or 3- and 5-positions, or a pharmacologically acceptable salt thereof, in an amount ranging from about 4 to about 400 mg. per dosage unit to alleviate the conditions of depression, in association with a pharmaceutical carrier.
9. A pharmaceutical preparation in dosage unit form adapted for administration to obtain an anti-depression effect comprising per dosage unit an anti-depressant effective, non-toxic amount of a compound of the formula ##STR23## wherein the wavy line (∼) in the 1-position of the cyclopentyl cycloheptyl ring indicates cis or trans configuration of the substituents in the 1- and 2-positions of the cyclopentyl cycloheptyl ring;
P p is zero or 1; Q is oxygen or sulfur; R is C1 to C3 -alkyl, vinyl, C3 to C6 -cycloalkyl, ethoxy, or methoxymethyl; R1 is hydrogen or C1 to C3 -alkyl; R2 is: --CH2 C6 H5, --CH2 CH2 C6 H5, or C3 to C6 -(allylic)alkenyl; each of Y and Z is selected from the group consisting of hydrogen, a halogen having an atomic number of from 9 to 35, trifluoromethyl, C1 to to C2 -alkyl, and C1 to C2 -alkyloxy and when Y is trifluoromethyl, Z is hydrogen; when Y is C1 to C2 -alkyloxy and Z is hydrogen, the C1 to C2 -alkyloxy is in the 3-position; when Y and Z are both halogens or C1 to C2 -alkyloxy, they are present in the 3- and 4- or 3- and 5-positions, or a pharmacologically acceptable salt thereof, in an amount ranging from about 4 to about 400 mg. per dosage unit to alleviate the conditions of depression, in association with a pharmaceutical carrier.
2. A process in accordance with
3. A process according to
4. A process according to
5. A process according to
6. A process according to
7. A process according to
8. A process according to
10. A pharmaceutical preparation according to
11. A pharmaceutical preparation according to
12. A pharmaceutical preparation according to
13. A pharmaceutical preparation according to
14. A pharmaceutical preparation according to claim .Badd.13.Baddend. 12 wherein the compound of formula I therein is 3,4-dichloro-N-[2-(N-allylamino)cycloheptyl]propionanilide, or a pharmacologically acceptable salt thereof.
15. A pharmaceutical preparation according to
16. A pharmaceutical preparation according to
17. A pharmaceutical preparation according to
19. A compound according to
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This is a cycloheptane cycloheptene oxide IIIa with an aniline under conditions well known in the art gives the N-(2hydroxycyclopentyl)aniline N-(2-hydroxycycloheptyl)aniline IX which, when reacted with chlorosulfonic acid in a non-polar organic solvent, e.g., methylene chloride, at 20°-30°C followed by heating with a selected R2 -amine (aqueous) at 100°-150°C for 40-55 hours at elevated pressure (2-10 atm.), gives the diamine X. Reaction of diamine X with 2,2,2-trichloroethyl chloroformate, or equivalent N-blocking compound, at 20°-30°C for 1-5 hours proceeds in the presence of an acid scavenger, e.g., triethylamine, to give the 2-(N-blocked amino) compound XI. Acylation of the N-blocked compound XI with the selected acid anhydride, ##STR19## by heating at 90°-120°C for 12 to 30 hours gives the N-blocked anilide XII. Deprotection of the 2-amino function of the 2-N-blocked anilide XII is then accomplished by reaction with an N-deblocking agent such as metal dust in acid, e.g., zinc in acetic acid, in a polar organic solvent, e.g., methanol, at 20°-100°C for 2 to 6 hours. Work-up, isolation and purification procedures are those standard in the art of organic chemistry.
Preparation of the cis isomeric compound XIV is carried out as described previously ##STR20## in this specification by oxidation of the -hydroxycy clopentylanilide 2-hydroxycycloheptylanilide XV with a known oxidizing agent, e.g., Jones Reagent, to the ketone XVI, which, when reacted with a C3 to C6 -(allylic)alkenyl, benzyl or β-phenethyl amine in the presence of a reducing agent, e.g., sodium cyanoborohydride, gives mixed isomer amino anilide XVII. ##STR21## Chromatographic separation of the two isomers can be effected to give the cis amino anilide XIV, wherein R2 is the C2 to C6 -(allylic)alkenyl, benzyl or phenethyl group.
These compounds, having a mono-C3 to C6 -(allylic)alkenyl, benzyl or β-phenethyl substituted amino group in the 2-position of the cyclopentyl cycloheptyl ring, have anti-depressant properties in standard laboratory animal tests such as the standard yohimbine toxicity potentiation and oxotremorine hypothermia antagonism tests, indicating quite potent anti-depressant properties of these compounds so that 2-(N-allylamino-, 2-(N-benzylamino- and 2-(N-phenethylamino)cycloheptyl anilides have similar properties and uses as the above-described N-[2-(N,N-disubstituted-amino)cycloheptyl]anilide compounds in about the same dosage ranges as indicated above.
PAC Trans-3,4-dichloro-N-[2-(N-allylamino)cycloheptyl]propionanilideA mixture of 0.20 mole of 3,4-dichloro-N-(2-sulfocycloheptyl)aniline and 250 ml. of a 50 percent allylamine in water solution is heated at 125°C in an autoclave for forty-eight hours. The resulting reaction mixture is washed from the autoclave 1500 ml. solution of methanol. This solution is evaporated until material therefrom oils out as a separate layer. The oil is extracted with 500 ml. of methylene chloride. The organic layer is washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated to an orange oil. The oil is chromatographed on 600 ml. of silica gel eluting with 2 liters of chloroform and 4 liters of ethyl acetate. The ethyl acetate fraction is separated and evaporated to an oil; the trans-3,4-dichloro-N-[2-(N-allylamino)cycloheptyl]aniline. This amine oil is converted to its hydrochloride salt with excess ether-hydrogen chloride mixture and recrystallized from a mixture of 450 ml. of methanol and about 2000 ml. of ethyl ether to obtain trans-3,4-dichloro-N-[2-(N-allylamino)cycloheptyl]aniline hydrochloride.
To a mixture of 0.05 mole of the above trans-3,4-dichloro-N-[2-(N-allylamino)cycloheptyl]aniline, released from its hydrochloride salt and 5.5 g. (0.05 mole) of triethylamine in 400 ml. of ethyl ether, there is added dropwise 10.6 g. (0.05 mole) of 2,2,2-trichloroethyl chloroformate in 50 ml. of ethyl ether while cooling the reaction vessel in ice in thirty minutes. The mixture is then stirred overnight at room temperature. The next day 250 ml. of saturated sodium bicarbonate solution is added. The organic layer is then separated and washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated to an oil. This is the crude sub-titled amine. A 1.0 g. portion of this amine oil is converted to its hydrochloride salt with excess ethereal hydrogen chloride and the salt is recrystallized from a mixture of 15 ml. of methanol and 80 ml. of ethyl ether to obtain the trans-3,4-dichloro-N-[2-(N-allyl-N-trichloroethoxycarbonylamino)cyclohepty l]anilide hydrochloride.
A mixture of 0.05 mole of trans-3,4-dichloro-N-[2-(N-allyl-N-trichloroethoxycarbonylamino)cyclohepty l]aniline and 50 ml. of propionic acid anhydride is heated on a steam bath overnight. Then 250 ml. of water is added and the heating is continued for 0.5 hours. The mixture is cooled, made basic with 15 percent sodium hydroxide solution and then extracted with ethyl ether. The organic layer is washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated to a brown oil weighing 24.5 g., the subtitled propionanilide, which is used without purification in the next step.
A mixture of the above prepared trans-3,4-dichloro-N-[2-N-allyl-N-trichloroethoxycarbonylamino)cycloheptyl ]propionanilide (about 0.05 mole) and 32.7 g. (0.50 mole) of zinc dust in 250 ml. of 5 percent acetic acid in methanol (v/v) is stirred overnight at room temperature. The resulting reaction mixture is then filtered through a filter aid (Celite ®) and evaporated to an oil. The oil residue is treated with 100 ml. of 15 percent sodium hydroxide solution and 300 ml. of methylene chloride. The mixture is then filtered to remove the excess zinc and zinc hydroxide. The organic layer is then washed with saturated sodium chloride, dried over magnesium sulfate and evaporated to a yellow oil, the named product which is then converted to its oxalic acid salt and analyzed as the salt.
| Patent | Priority | Assignee | Title |
| 4885027, | Apr 05 1985 | Chevron Research Company | Herbicidal arylmethylenesulfonamido-acetamide and thioacetamide derivatives |
| Patent | Priority | Assignee | Title |
| 3510492, |
| Executed on | Assignor | Assignee | Conveyance | Frame | Reel | Doc |
| Sep 24 1980 | The Upjohn Company | (assignment on the face of the patent) | / |
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