US3542783A - Isoquino(1,2-b)quinazolines - Google Patents

Description

United States Patent Int. Cl. C07d 51/48 US. Cl. 260-251 4 Claims 10 ABSTRACT OF THE DISCLOSURE Compounds from the class of tetrahydro and decahydro-8H-isoquino[1,2-b]quinazolines. The compounds are useful as central nervous system depressants, antipyretic agents and antiinflammatory agents.

This apphcatlon 1s a dlVlSIOIl applicatlon of Ser. No.

623,238, filed Mar. 15, 1967, now Pat. No. 3,497,499, issued Feb. 24, 1970.

This invention relates to the' componds of the formula: 2

wherein R R R A A and ring A are as defined be- 3,542,783 Patented Nov. 24, 1970 ICC wh'erein R R R ring A, A and A are as defined below; and

' R X R R N W wherein ring A is a member selected from the group consisting of ortho-phenylene and ortho-cyclohexylene;

R is a member selected from the group consisting of a hydrogen atom, 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 (OCH O) R is a member selected from the group consisting of a hydrogen atom, 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 and methyl;

R is a linear alkyl having from 1 to 4 carbon atoms;

A is a member selected from the group consisting of a hydrogen atom, fluoro, chloro, linear alkyl having from 1 to 4 carbon atoms, linear alkoxy having from 1 to 4 carbon atoms and, taken together with A methylenedioxy;

A is a member selected from the group consisting of a hydrogen atom, fluoro, chloro, linear alkyl having from 1 to 4 carbon atoms, linear alkoxy having from 1 to 4 carbon atoms and, taken together with A methylenedioxy;

B is a member selected from the group consisting of a hydrogen atom, linear alkyl having from 1 to 4 carbon atoms, linear alkoxy having from 1 to 4 carbon atoms and, taken together with B methylenedioxy;

B is a member selected from the group consisting of a hydrogen atom, linear alkyl having from 1 to 4 carbon atoms, linear alkoxy having from 1 to 4 carbon atoms and, taken together with B methylenedioxy; and

X is a member selected from the group consisting of chloro, bromo and iodo,

provided that each of A A B and B is a hydrogen atom where ring A is ortho-cyclohexylene.

Compounds I include the classes of Compounds Ia, Ib, Ic and Id:

Ha I 1b Illa Compounds III include classes of Compounds IIIa, 111b, IIIc and HM:

Id R

and

wherein R R R B and B are as defined above.

Compounds 11 include classes of Compounds 11a, 11b, He and Hd:

m q R N IVa OHa-N wherein R R A and A are as defined above IVb CHz-N monium salt, by treatment with R X, i.e., a lower alkyl 7 halide, e.g., CH I in ether. X In Step ((1) the Compound IV is reduced with sodium in liquid ammonia to the corresponding Compound I. It is noted that where A or A of the Compound IV is a hydrogen atom, alkyl, alkoxy or a methylenedioxy then upon reduction, the B and B substituents of the resulting Compound I, correspond to A and A of Compound IV. However, if any of A and A of Compound IV is halo, i.e., fluoro or chloro, then such halo is converted to a hydrogen in Step (d). Hence, where any of A and A is H I IVc halo, then the corresponding B or B of the resulting Compound I, will be a hydrogen. It is preferred to use Compounds IV wherein A and A correspond to the desired B and B substitutents of the Compound I.

Since Step (a) of the reaction scheme is an idealized illustration, it shows the preparation of Compounds II. However, it has been found that in carrying our Step (a) that where R is a hydrogen atom, Compounds VII, are

, also formed, i.e., compounds of the formula u': I i I R1 I I E V .1 Ivd Ram N wherein R R ,-R ,'A A and X are as defined'above. 2 I T Compounds I maybe obtained bythe following reaction scheme (R R R R A A X and ringA being as defined above): i 1

wherein R R A A and ring A are as defined above. Subjection of a Compound IIIa or IIIc to a hydrogen atmosphere, e.g., 20 to 100 p.s.i., in the presence of PtO preferably in a solvent, e.g., ethanol, with agitation, results in the preparation of a Compound VIII, i.e., a compound of the formula:

VIII q wherein R R A A and ring A are as defined above.

=Compounds 11a, 11b, 11c and 11d may be prepared according to the reaction scheme by using as Compound VI as'isatoic anhydride, an -N-methyl isatoic anhydride, hexahydroisatoic anhydride and N-methyl 'hexahydroisatoic anhydride, respectively. I

Compounds 11a and 11b can be converted to Compounds He and IId, respectively, by hydrogenation by well-known methods. Where any of A or A of Compounds IIa or 11b is halo then such halo is converted to a hydrogen atom during the hydrogenation. Example 9, presented hereinafter, illustrates such a conversion.

Compounds I, II, III, VII and VIII are active upon the central nervous system. Compounds I are useful as Awording t0 the reaction Scheme, p is a 0011- central nervous system stimulants and also hypotensive densation of a dihydroisoquinoline (V) with an isatoic agents. They may be administered to mammals either anhydride (VI), e.g., by admixing and heating Comorally or parenterally in daily doses of from 1 to 10 pounds V and VI, to form a Compound 11 (a isoquino mg./kg. of body weight, e.g., from 50 to 600 mg. per

[1,2-b1quinazolin-8-one). diern, preferably administered in divided doses from 2 to Step (b) is a reduction of the Compound II to the 4timesaday.

corresponding Compound III, e.g., by heating with lithium Compounds II, III, VII and VIII are useful as central aluminum hydride (LAH) in a suitable solvent, e.g., dinervous system depressants, antiinfiammatories and antiethyl ether (ether). pyretics. They are administered to mammals either orally Step (c) is a conversion of the Compound III to a or parenterally in daily doses of from 5 to 30 mg./kg. of Compound IV, i.e., its corresponding quaternary ambody weight, e.g., from 300 to 1800 milligrams per diern,

preferably administered in divided doses 2 to 4 times a day.

Pharmaceutically acceptable acid addition and quaternary ammonium salts of Compounds I, III and VIII are equally as effective as Compounds I, III and VIII, respectively and may be used in a similar manner. The acid addition and quaternary ammonium salts may be prepared according to well-known procedures from Compounds I, III and VIII, respectively. 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 critic acid; saturated acids, e.g., acetic acid; ethylenically unsaturated acids, e.g., maleic acid and fumaric acid; and aromatic acids, e.g., salicylic acid and arylsulfonic acids, such as phenylsulfonic acid. The only limitation on this 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 10 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 4 50. Tragacanth 2. Lactose 39. Corn starch 5.

Talcum 3. Magnesium stearate 0.5

Alcohol SD-30, q.s. Purified water, q.s.

Examples illustrative of this invention follow. In the example all temperatures are in degrees centigrade and r 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 .2,3-dimethoxy-5,6, 13 ,13a-tetrahydro-8H-isoquino[ 1,2-b] quinazolin-S-one Gang W CHaO- N Example 2.2,3-dimethoXy-5,6, l 3 ,13 a-tetrahydro-SH-isoquino 1,2-b] quinazoline CHaO omo- L This example illustrates the preparation of a Compound III which is useful in preparing Compounds IV, as is illustrated in Example 3.

Add 45 parts of 2,3-dimethoxy-5,6,13,13a-tetrahydro- 8H-isoquino[l,2-b]quinazolin-8-one suspended in 1500 parts by volume of tetrahydrofuran (THF) to a solution of 14 parts of lithium aluminum hydride (LAH) in 1300 parts by volume of ether and heat under reflux for 40 hours. Cool the reaction mixture, wash with parts by volume of water and filter. Evaporate the filtrate under vacuum to obtain a residue which is then crystalized from ether to obtain the title compounds, M.P. to 172.

Replace the 2,3-dimethoxy-5,6,13,l3a-tetrahydro 8H- isoquino[l,2-b]quinazolin-8 one with 5,6,8a,9,10,l1,12, l2a,l3,l3a-decahydroisoquino[1,2-b]quinazolin 8 one results in the preparation, in a similar manner, of the corresponding Compound III.

emo-

$N H-N W This example illustrates the preparation of the title compound is'a Compound IV which is useful for preparing a Compound I as is illustrated in Example 4.

Prepare a solution of 1 part 2,3-dimethoxy-5,6,13,13atetrahydro-8H-isoquino[1,2-b]quinazoline in 7 parts by volume of CH CI 3 parts by volume of ether and 3 parts by volume of methyl iodide and allow the solution to stand at room temperature (20 C.) for /2 hour. Evaporate the solution to dryness under vacuum and recrystallize the residue from ethanol to obtain the title compound, M.P. 245 to 250 C.

Replacing the methyl iodide with ethyl bromide results in the preparation, in a similar, of the corresponding Compound IV.

Example 4.8,9-dimethoxy-13-methyl-5,6,11,12,13,14- hexahydrodibenzo [b,h] [1,5] diazecine CHaO N CH8 CHaO Example 5.-l-chloro-2,3-dimethoxy-13-methyl-5,6,13

1 3 a-tetrahydro-8H-isoquino[ 1,2-b] quinolin-S-one C He 0 l I CHaN This example illustrates the preparation of a Compound II, which is useful in preparing a Compound III, as is illustrated in. Example 6.

Heat under reflux a mixture of 50 parts of 6,7-dimethoxy-3,4-dihydroisoquinoline and 55 parts of 6- chloro-N-methyl isatoic anhydride in 500 parts by volume for 16 hours. Treat the mixture with carbon black and filter. Evaporate the filtrate under vacuum and crystallize the residue from methanol. Recrystallize the product from methylene chloride-methanol to obtain the title compound, MI. 167 to 170 C.

Replacing the 6,7 methoxy 3,4 dihydroisoquinoline with 6,7-diethoxy-3,4-dihydroisoquinolinoline results in the preparation, in a similar manner, of the corresponding Compound II.

Example 6.10-chloro-2,3-dimethoxy-13-methyl-5,6,13, 1 3 a-tetrahydro-SH-iso quino 1,2-b] quinazoline Add 30 parts .of l0-chloro-2,3- dimethoxy-lS-methyl- 5,6,13,13a-tetrahydro 8H isoquino[1,2-b]quinazolin-8- one in 1500 parts by volumeof ether to a refluxing solution of 9 parts of LAI-I in 1500 parts by volume of ether. Reflux the mixture for 18 hours. Cool the mixture and add 70 parts by volume of water. Filter t'hemixture and evaporate the filtrate under vacuum. Crystallize the residue from ether to obtain the title compound, M.P. 138 to 140 C.

Replacing the 10-chloro-2,3-dimethoxy-13-methy1-5 ,6, 13,13a-tetrahydro-SH-isoquino[l,2-b]quinazolin 8 one with 10,11-difluoro-2,3-dimethyl 13 methyl-5,6,13,13atetrahydro-8H-isoquino 1,2-b] quinazolin-8-one results in the preparation, in a similar manner, of the corresponding Compound III.

1 0 Example 7.--10-chloro 13-methy1-5,6,13,l3a-tetrahydro- SH-isoquino 1,2-b1quinazolin-8-one T CHa-N This example also illustrates the preparation of a Compound II.

Reflux 29.5 parts of 3,4-dihydroisoquinoline and 32 parts of 6-chloro-N-methyl isatoic anhydride in 250 parts by volume of toluene for 18 hours. Treat the mixture with carbon black and filter. Evaporate the filtrate under vacuum and crystallize the resultant residue from ether to obtain the title compound, MP. to 132 C.

Replacing the 6-chloro-N-methyl-isatoic anhydride with S-butoxy-6-methyl-N-methyl isatoic anhydride results in the preparation, in a similar manner, of the corresponding Compound II.

Example 8.-5,6, l 3, 13a-tetrahydro-8H-isoquino 1 ,2-b1

quinolin-8-one This example also illustrates the preparation of a Compound H.

Reflux under nitrogen for 16 hours a mixture of 19 parts of 3,4-dihydroisoquinoline and 21 parts of isatoic anhydride in 250 parts by volume of toluene. Treat the reaction mixture with carbon black and filter. Evaporate the filtrate under vacuum to obtain a residue, crystallize the residue from ether and recrystallize from benzene to obtain the title compound, M.P. 161 to 163 C.

Replacing the isatoic acid with 5,6-dipropylisatoic anhydride results in the preparation, in a similar manner, of the corresponding Compound H.

Example 9. 2,3,-dimethy1-13-methyl-5,6,8a,9,10,11,12, 12a,13,13a-decahydro-8H isoquino 1,2-b] quinazolin-8- one OIIaO This example illustrates the preparation of a Compound IId from a Compound IIb.

Shake a solution of 18 parts of 10-chloro-2,3-dimethoxy-l3-methyl-5,6,l3,l3a-tetrahydro 8H isoquino [1,2-b1quinazolin-8-one in parts by volume of glacial acid containing 0.5 part of PtO in an atmosphere of hydrogen (at 50 psi.) for 20 hours. Filter the reaction mixture through Celite (diatomaceous earth) and evaporate the filtrate under vacuum. Mix the residue with sodium carbonate solution and methylene chloride, re-

cover the methylene chloride layer and dry over sodium sulfate, then evaporate to obtain a residue. Crystallize the residue from ether to obtain the title compound, MP. 146 to 148 C.

Replacing the -chloro-2,3-dimethoxy-13-methyl-5,6, 13,l3a-tetrahydro-8H-isoquino[l,2-b]quinazolin '8 one with 2-propoxy-l3-methyl 5,6,13,13a-tetrahydro-8H-isoquinol[1,2-a] quinazolin-S-one results in the preparation, in a similar manner, of the corresponding Compound Hd.

Example 10.10-chloro-2,3-dimethoxy-5,6-di'hydro-8H- isoquino 1,2-b] quinazolin-8-one CHaO CHaO

This example illustrates the preparation of a Compound VII.

Heat under reflux for 16 hours a mixture of 19 parts of 6,7-dimethoxy-3,4-dihydroisoquinoline and 17.5 parts of 6-chloro isatoic anhydride in 200 parts by volume of toluene. Treat the reaction mixture with carbon black and filter. Evaporate the filtrate under vacuum to a thick paste and triturate with 20 parts by volume of methanol and 100 parts by volume ether and filter to obtain the title compound, M.P. 255 to 257 C.

Replacing the 6,7-dimethoxy-3,4 dihydroisoquinoline with 6,7-dimethyl-3,4-dihydroisoquinoline results in the preparation, in a similar manner, of the corresponding Compound VH.

Example l1.2,3 dimethoxy-5,6-dihydro 8H isoquino 1,2-b1quinazoline CHaO- CHaO 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 quarternry ammonium salt thereof; the free base being of the formula:

R1 q R wherein ring A is a member selected from the group consisting of ortho-phenylene and ortho-cyclohexylene R is a member selected from the group consisting of a hydrogen atom, 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, 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 and methyl;

A is a member selected from the group consisting of a hydrogen atom, fluoro, chloro, linear alkyl having from 1 to 4 carbon atoms, linear alkoxy having from 1 to 4 carbon atoms and, taken together with A methylenedioxy;

A is a member selected irom the group consisting of a hydrogen atom, fluoro, chloro, linear alkyl having from 1 to 4 carbon atoms, linear alkoxy having from 1 to 4 carbon atoms and, taken together with A methylenedioxy;

provided that each of A A is a hydrogen atom where ring A is ortho-cyclohexylene.

2. A compound according to claim 1 which is 2,3-dimethoxy 5,6,13,13a-tetrahydro 8H isoquino-[1,2-b] quinozoline.

3. A compound according to claim 1 which is 10-chloro- 2,3-dimethoxy 13 methyl 5,6,13,13a-tetrahydro-8H- isoquino[ 1,2-b] quinazoline.

4. A compound according to claim 1 which is the methyl iodide quaternary ammonium salt of 2,3-dimethoxy 5,6,13,13a tetrahydro 8H isoquino[1,2-b] quinazoline.

References Cited UNITED STATES PATENTS 3,297,696 1/1967 Ott 260247.5

ALEX MAZEL, Primary Examiner R. V. RUSH, Assistant Examiner US. Cl. X.R. 424-251