US3496165A - Octahydro-3-benzazecines - Google Patents
Octahydro-3-benzazecines Download PDFInfo
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- US3496165A US3496165A US623799A US3496165DA US3496165A US 3496165 A US3496165 A US 3496165A US 623799 A US623799 A US 623799A US 3496165D A US3496165D A US 3496165DA US 3496165 A US3496165 A US 3496165A
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- octahydro
- dimethoxy
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D455/00—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
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- the compounds can be prepared by first treating a polyhydrocycloalkano [i] quinolizine with a lower linear alkyl halide, e.g., methyliodide to form the quaternary ammonium salt thereof and then reducing the salt with sodium in liquid ammonia to form the corresponding compound, e.g., 10,11-dimethoxy-3-methyl-7,8- trimethylene-1,2,3,4,5,6,7,8-octahydro-3-benzazecine.
- a polyhydrocycloalkano [i] quinolizine with a lower linear alkyl halide, e.g., methyliodide to form the quaternary ammonium salt thereof and then reducing the salt with sodium in liquid ammonia to form the corresponding compound, e.g., 10,11-dimethoxy-3-methyl-7,8- trimethylene-1,2,3,4,5,6,7,8-octahydro-3-benzazecine.
- This invention relates to compounds of the formula:
- n 0, 1 or 2;
- R is a member selected from the group consisting of a hydrogen atom, hydroxy, linear alkyl having from 1 to 4 carbon atoms, e.g. methyl, ethyl, propyl and butyl, linear alkoxy having from 1 to 4 carbon atoms, e.g. methoxy, ethoxy, propoxy and butoxy and, taken together with R methylenedioxy
- R is a member selected from the group consisting of a hydrogen atom, hydroxy, linear alkyl having from 1 to 4 carbon atoms, linear alkoxy having from 1 to 4 carbon atoms and, taken together with R methylenedioxy;
- each of R and R is independently selected from the group consisting of a hydrogen atom, methyl and ethyl;
- R is a linear alkyl having from one to four carbon atoms
- Compounds I include three classes of compounds:
- Step (a) is effected by treatment of a polyhydrocycloalkano [i] quinolizine (Compound II) with a lower alkyl halide (R X), e.g., CH I, preferably in a solvent, e.g., ethanol, to obtain Compound III, i.e., the quaternary ammonium salt of Compound II.
- R X lower alkyl halide
- Step (b) the Compound III is reduced by sodium in liquid ammonia to obtain the corresponding Compound I.
- Compounds I and their pharmaceuticalfiy acceptable acid addition and quaternary ammonium salts are useful as central nervous. system stimulants. They are administered to mammals either orally or parenterally in daily doses of from 0.5 to 5 mg./kg. of body weight, e.g. from 30 to 300 milligrams per diem, preferably administered in divided doses from 2 to 4 times a day; a single daily oral dose is also acceptable.
- the pharmaceutically acceptable acid addition salts are salts of organic acids, e.g. tartaric acid; inorganic acids, e.g. hydrochloric acid, hydrobromic acid and sulfuric acid; monobasic acids, e.g. an alkylsulfonic acid, such as methylsulfonic acid (H C-SO H); dibasic acids, e.g. succinic acid; tribasic acids, e.g. phosphoric acid and citric acid; saturated acids, e.g. acetic acid; ethylenically unsaturated acids, e.g. maleic acid and fumaric acid; and aromatic acids, e.g. salicyclic acid and arylsulfonic acids, such as phenylsulfonic acid.
- the only limitation on the acid is that the resulting salt be pharmaceutically acceptable; it is preferred, however, that the acid addition salt be water-soluble.
- Each of the pharmaceutically active compounds of this invention may be, e.g. incorporated, for oral administration, in a tablet as the sole active ingredient.
- a typical tablet is constituted by from 1 to 3 percent binder, e.g. tragacanth; from 3 to percent disintegrating agent, e.g. corn starch; from 2 to 10 percent lubricant, e.g. talcum; from 0.25 to 1.0 percent lubricant, e.g. magnesium stearate; an average dosage of active ingredient; and q.s. 100 percent of filler, e.g. lactose; all percentages being by weight.
- Tablets are prepared according to standard tabletting techniques, which are well-known in the art, employing the necessary amounts of conventional granulating liquids, e.g. alcohol SD-30 and purified water.
- An exemplary tabletting formulation for the instant active compounds is:
- Example 1 30 Tragacanth 2 Lactose 59.5 Corn starch 5 Talcum 3 Magnesium stearate 0.5 Alcohol SD-30, purified water, q.s.
- This example illustrates the preparation of a compound 1b according to the reaction scheme presented above.
- Step (a) replacing the methyl iodide with propyl bromide results in the preparation, in a similar manner, of the corresponding compound III and the corresponding compound I, according to Step (b).
- EXAMPLE 2 10, l 1-dimethoxy-3-methyl-7,8-trimethylene-l ,2,3,4,5,6,7, 8-octahydro-3-benzazecine bimaleate CHaO CHaO N Jig-C0011 HC-COOH (a) Preparation of 11,l2-dimethoxy-2,3,3a,4,5,6,8,9-octahydro-lH-benzo[a]cyclopenta[i] quinolizine methiodide cr-no Dissolve 20 parts of 11,12-dimethoxy-2,3,3a,4,5,6,8, 9-octahydro-1H-benzo[a]cyclopenta[ilquinolizine in 80 parts by volume ethanol and 50 parts by volume methyl iodide.
- Step (a) replacing the 1l,12-dimethoxy-2,3,3a,4,5,6, 8,9-octahydrolH-benzo [a] cyclopenta [i] quinolizine with 11,12-dibutylor 11-hydroxy-2,3,3a,4,5,6,8,9-octahydro- 1H-benzo[a]cyclopenta[i]quinolizine results in the preparation, in a similar manner, of the corresponding compound II from which the corresponding compound I may be obtained according to Step (b). In a similar manner, by selecting appropriate starting materials compounds Ic may be prepared, e.g. 10,11-dimethoxy-3-methyl-7,8- pentamethylene-1,2,3,4,5,6,7,8-octahydro-3-benzazacine.
- n 0, 1 or 2;
- R is a member selected from the group consisting of a hydrogen atom, hydroxy, linear alkyl having from 1 to 4 carbon atoms, linear alkoxy having from 1 to 4 carbon atoms and, taken together with R methylenedioxy;
- R is a member selected from the group consisting of a hydrogen atom, hydroxy, linear alkyl having from 1 to 4 carbon atoms, linear alkoxy having from 1 to 4 carbon atoms and, taken together with R methylenedioxy;
- each of R and R is independently selected from the group consisting of a hydrogen atom, methyl and ethyl;
- R is a linear alkyl having from one to four carbon atoms.
- a compound according to claim 2 which is 10, 11 dimethoxy 3 methyl 7,8 trimethylene-1,2,3,4,5,6, 7,8-octahydro-3-benzazecine bimaleate.
- a compound according to claim 4 which is 10, 11 dimethoxy 3 methyl-7,8-tetramethylene-1,2,3,4,5,6, 7,8-octahydro-3-benzazecine.
- a compound according to claim 6 which is 10, 11 dimethoxy 3 methyl-7,8-pentamethylene-l,2,3,4,5, 6,7,8-octahydro-3-benzazecine.
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Description
United States Patent ()flice 3,496,165 Patented Feb. 17, 1970 3,496,165 OCTAHYDRO-3-BENZAZECINES William J. Houlihan, Mountain Lakes, and Robert E. Manning, Parsippany, N.J., assignors t Sandoz Wander, Inc., Hanover, NJ. No Drawing. Filed Mar. 17, 1967, Ser. No. 623,799
Int. Cl. C07d 41/00, 35/00; A61k 27/00 U.S. Cl. 260-239 7 Claims ABSTRACT OF THE DISCLOSURE The compounds are 3-1ower alkyl-7,8-polymethylene- 1,2,3,4,5,6,7,8-octahydro-3-benzazecines (the polymethylene having from 3 to 5 carbon atoms). The compounds and their pharmaceutically acceptable acid addition and quaternary ammonium salts are useful as central nervous system stimulants. The compounds can be prepared by first treating a polyhydrocycloalkano [i] quinolizine with a lower linear alkyl halide, e.g., methyliodide to form the quaternary ammonium salt thereof and then reducing the salt with sodium in liquid ammonia to form the corresponding compound, e.g., 10,11-dimethoxy-3-methyl-7,8- trimethylene-1,2,3,4,5,6,7,8-octahydro-3-benzazecine.
This invention relates to compounds of the formula:
n is either 0, 1 or 2;
R is a member selected from the group consisting of a hydrogen atom, hydroxy, linear alkyl having from 1 to 4 carbon atoms, e.g. methyl, ethyl, propyl and butyl, linear alkoxy having from 1 to 4 carbon atoms, e.g. methoxy, ethoxy, propoxy and butoxy and, taken together with R methylenedioxy R is a member selected from the group consisting of a hydrogen atom, hydroxy, linear alkyl having from 1 to 4 carbon atoms, linear alkoxy having from 1 to 4 carbon atoms and, taken together with R methylenedioxy;
each of R and R is independently selected from the group consisting of a hydrogen atom, methyl and ethyl;
R is a linear alkyl having from one to four carbon atoms;
and to pharmaceutically acceptable acid addition salts thereof and pharmaceutically acceptable quaternary ammonium salts thereof.
Compounds I include three classes of compounds:
I R4 R4 R5 RUAr/ R N a wherein R R R R and R are as defined above.
Compounds I may be prepared according to the following reaction scheme wherein n, R R R R and R are as defined above, and X is a chloro, bromo and iodo.
According to the reaction scheme, Step (a) is effected by treatment of a polyhydrocycloalkano [i] quinolizine (Compound II) with a lower alkyl halide (R X), e.g., CH I, preferably in a solvent, e.g., ethanol, to obtain Compound III, i.e., the quaternary ammonium salt of Compound II.
In Step (b) the Compound III is reduced by sodium in liquid ammonia to obtain the corresponding Compound I.
Compounds II, e.g., 11,l2-dimethoxy-2,3,3a,4,5,6,8,9- octahydro-lH-benzo[a]cyclopenta[i]quinolizine may be obtained according to the procedures described in United States Patent 3,210,357 of William I. Taylor et al. issued Oct. 5, 1965.
Compounds I and their pharmaceuticalfiy acceptable acid addition and quaternary ammonium salts are useful as central nervous. system stimulants. They are administered to mammals either orally or parenterally in daily doses of from 0.5 to 5 mg./kg. of body weight, e.g. from 30 to 300 milligrams per diem, preferably administered in divided doses from 2 to 4 times a day; a single daily oral dose is also acceptable.
The acid addition and quaternary ammonium salts of Compounds I are prepared according to well-known procedures from Compounds I. They are all useful, in accord with recognized procedures, for the preparation of corresponding pharmaceutically acceptable salts.
Among the pharmaceutically acceptable acid addition salts are salts of organic acids, e.g. tartaric acid; inorganic acids, e.g. hydrochloric acid, hydrobromic acid and sulfuric acid; monobasic acids, e.g. an alkylsulfonic acid, such as methylsulfonic acid (H C-SO H); dibasic acids, e.g. succinic acid; tribasic acids, e.g. phosphoric acid and citric acid; saturated acids, e.g. acetic acid; ethylenically unsaturated acids, e.g. maleic acid and fumaric acid; and aromatic acids, e.g. salicyclic acid and arylsulfonic acids, such as phenylsulfonic acid. The only limitation on the acid is that the resulting salt be pharmaceutically acceptable; it is preferred, however, that the acid addition salt be water-soluble.
Each of the pharmaceutically active compounds of this invention may be, e.g. incorporated, for oral administration, in a tablet as the sole active ingredient. A typical tablet is constituted by from 1 to 3 percent binder, e.g. tragacanth; from 3 to percent disintegrating agent, e.g. corn starch; from 2 to 10 percent lubricant, e.g. talcum; from 0.25 to 1.0 percent lubricant, e.g. magnesium stearate; an average dosage of active ingredient; and q.s. 100 percent of filler, e.g. lactose; all percentages being by weight. Tablets are prepared according to standard tabletting techniques, which are well-known in the art, employing the necessary amounts of conventional granulating liquids, e.g. alcohol SD-30 and purified water. An exemplary tabletting formulation for the instant active compounds is:
Parts Title compound of Example 1 30 Tragacanth 2 Lactose 59.5 Corn starch 5 Talcum 3 Magnesium stearate 0.5 Alcohol SD-30, purified water, q.s.
Examples illustrative of this invention follow. In the examples all temperatures are in degrees centigrade and all percents and parts are by weight, unless specified otherwise. Parts by weight are related to parts by volume as a kilogram is related to a liter.
EXAMPLE 1 10,1 1-dimethoxy-3-methyl-7,8-tetramethylene-1,2,3,4,5,6 7,8-octahydro-3-benzazecine CHaO /CHa CHaO N---:
This example illustrates the preparation of a compound 1b according to the reaction scheme presented above.
4 (a) Preparation of 12,13-dimethoxy-l,2,3,4,4a,5,6,7,9,10- decahydro-benzo[a]cyclohexa[i]quinolizine methiodide on o CHaO
(b) Preparation of 10,11-dimethoxy-3-methyl-7,8-tetramethylene-1,2,3,4,5,6,7,8-octahydro-3-benzazecine Add 8 parts of sodium to a stirred suspension of 30 parts of compound (a) (12,13-dimthoxy-l,2,3,4,4a,5,6,7, 9,10 decahydro benzo[a]cyclohexa[ilquinolizine methiodide) in 500 parts by volume liquid ammonia cooled in a Dry Ice-acetone mixture. Stir the mixture for one hour, then allow to evaporate for 16 hours. Add to the residue aqueous methanol and extract with chloroform. Dry the chloroform extract over sodium sulfate and evaporate under vacuum. Crystallize the residue twice from ethanol to obtain the title product, melting point (M.P.), to 86 C.
In Step (a) replacing the methyl iodide with propyl bromide results in the preparation, in a similar manner, of the corresponding compound III and the corresponding compound I, according to Step (b).
Replacing the 12,13 dimethoxy 1,2,3,4,4a,5,6,7,9,l0- decahydrobenzo[a]cyclohexa[i]quinolizine in Step (a) with 12,13-dipropylor l2,l3-methylenedioxy-l,2,3,4,4a,5,6,7, 9,10-decahydrobenzoIa]cyclohexa[i]quinolizine results in the preparation, in a similar manner, of the corresponding compounds III, and from which the corresponding compounds I, may be prepared according to Step (b).
EXAMPLE 2 10, l 1-dimethoxy-3-methyl-7,8-trimethylene-l ,2,3,4,5,6,7, 8-octahydro-3-benzazecine bimaleate CHaO CHaO N Jig-C0011 HC-COOH (a) Preparation of 11,l2-dimethoxy-2,3,3a,4,5,6,8,9-octahydro-lH-benzo[a]cyclopenta[i] quinolizine methiodide cr-no Dissolve 20 parts of 11,12-dimethoxy-2,3,3a,4,5,6,8, 9-octahydro-1H-benzo[a]cyclopenta[ilquinolizine in 80 parts by volume ethanol and 50 parts by volume methyl iodide. Heat solution under reflux for 3 days. Concentrate the reaction mixture and recover the solids. Triturate the solids with ethanol-ether and collect by filtration. Recrystallize from ethanol to obtain the methiodide (compound (a)), M.P. 213 to 215 C.
11,12 dimethoxy 2,3,3a,4,5,6,8,9 octahydro-lH-benzo[a]cyclopenta[i]quinolizine is obtainable by the procedure of Example 1 of United States Patent 3,210,357 noted above.
(b) Preparation of 10,11-dimethoxy-3-methyl-7,8-trimethylene-l,2,3,4,5,6,7,8-octahydro-3-benzazecine bimaleate CHaOX Following the procedure of Example 1, add 5 parts of sodium to 20 parts of compound (a), (11,12-dimethoxy- 2,3,3a,4,5,6,8,9 1H benzo[a]cyclopenta[i]quinolizine methiodide) in 400 parts by volume of liquid ammonia. Stir the mixture for one hour then allow to evaporate for 16 hours. Dissolve the residue in aqueous methanol and extract with chloroform. Dry the chloroform extract and evaporate under vacuum to obtain a residue, which then convert to the bimaleate salt by conventional procedure to obtain the title product, M.P. 170 to 172 C.
In Step (a) replacing the 1l,12-dimethoxy-2,3,3a,4,5,6, 8,9-octahydrolH-benzo [a] cyclopenta [i] quinolizine with 11,12-dibutylor 11-hydroxy-2,3,3a,4,5,6,8,9-octahydro- 1H-benzo[a]cyclopenta[i]quinolizine results in the preparation, in a similar manner, of the corresponding compound II from which the corresponding compound I may be obtained according to Step (b). In a similar manner, by selecting appropriate starting materials compounds Ic may be prepared, e.g. 10,11-dimethoxy-3-methyl-7,8- pentamethylene-1,2,3,4,5,6,7,8-octahydro-3-benzazacine.
What is claimed is:
1. A member selected from the group consisting of the free base, a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable quaternary ammonium salt thereof; the free base being of the formula:
I R4 R w l R N CH2)n+-l wherein:
n is either 0, 1 or 2;
R is a member selected from the group consisting of a hydrogen atom, hydroxy, linear alkyl having from 1 to 4 carbon atoms, linear alkoxy having from 1 to 4 carbon atoms and, taken together with R methylenedioxy;
R is a member selected from the group consisting of a hydrogen atom, hydroxy, linear alkyl having from 1 to 4 carbon atoms, linear alkoxy having from 1 to 4 carbon atoms and, taken together with R methylenedioxy;
each of R and R is independently selected from the group consisting of a hydrogen atom, methyl and ethyl; and
R is a linear alkyl having from one to four carbon atoms.
2. A compound according to claim 1 wherein n is 0.
3. A compound according to claim 2 which is 10, 11 dimethoxy 3 methyl 7,8 trimethylene-1,2,3,4,5,6, 7,8-octahydro-3-benzazecine bimaleate.
4. A compound according to claim 1 wherein n is 1.
5. A compound according to claim 4 which is 10, 11 dimethoxy 3 methyl-7,8-tetramethylene-1,2,3,4,5,6, 7,8-octahydro-3-benzazecine.
6. A compound according to claim 1 wherein n is 2.
7. A compound according to claim 6 which is 10, 11 dimethoxy 3 methyl-7,8-pentamethylene-l,2,3,4,5, 6,7,8-octahydro-3-benzazecine.
References Cited FOREIGN PATENTS 107,640 10/ 1965 Norway.
ALTON D. ROLLINS, Primary Examiner US. Cl. X.R.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US62379967A | 1967-03-17 | 1967-03-17 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| US3496165A true US3496165A (en) | 1970-02-17 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US623799A Expired - Lifetime US3496165A (en) | 1967-03-17 | 1967-03-17 | Octahydro-3-benzazecines |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| USB536935I5 (en) * | 1974-12-23 | 1976-01-13 | ||
| US3976634A (en) * | 1974-03-25 | 1976-08-24 | Sandoz, Inc. | Substituted 7,12-methano dibenzazocines and 8,13-methano dibenzazonines |
-
1967
- 1967-03-17 US US623799A patent/US3496165A/en not_active Expired - Lifetime
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3976634A (en) * | 1974-03-25 | 1976-08-24 | Sandoz, Inc. | Substituted 7,12-methano dibenzazocines and 8,13-methano dibenzazonines |
| USB536935I5 (en) * | 1974-12-23 | 1976-01-13 | ||
| US3985729A (en) * | 1974-12-23 | 1976-10-12 | Sandoz, Inc. | Substituted 7,12-methano dibenzazocines |
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