US3209007A - (dibenzo (a, d) 1, 4-cycloheptene-5-yloxy) amines - Google Patents

Description

United States Patent 3,209,007 (DIBENZO (a,d) 1,4-CYCLOHEPTENE-- YLOXY)AMINES August F. Harms, Amsterdam, Netherlands, assignor to N.V. Koninklijke Pharmaceutische Fabrieken v/ h Brocades-Stheeman & Pharmacia Meppel, Netherlands, a corporation of the Netherlands No Drawing. Filed Apr. 30, 1963, Ser. No. 277,013 Claims priority, application Netherlands, Apr. 1,1959, 237,664 5 Claims. (Cl. 260-294) This is a continuation-in-part of my copending application Serial No. 16,660, filed March 22, 1960, now US. Patent No. 3,119,829, and reference is also made to the application entitled Therapeutically-Active Dibenzocycloheptane Derivatives filed concurrently herewith which is also a continuation-in-part of said copending application Serial No. 16,660.

Reference is also made to my copending application Serial No. 90,153, filed May 2, 1960, now abandoned, and Serial No. 141,590, filed September 29, 1961, now US. Patent 3,138,660 with respect to the preparation of the intermediate carbinols from the corresponding ketones referred to above. Both of these last-named applications are based upon Netherlands application No. 237,663, filed April 1, 1959.

The invention relates to therapeutically active dibenzocycloheptane derivatives, to processes for their preparation, and to pharmaceutical compositions containing them. According to the present invention there are provided new compounds of the general formula I.

in which:

X is a radical selected from the group consisting of CH -CH and -CH=CH R and R are each selected from the group consisting of a hydrogen atom, a halogen atom and a lower alkyl group, preferably an alkyl group having at most 4 carbon atoms,

R, is a member of the group consisting of a hydrogen atom, an alkyl group, preferably a lower alkyl group such as methyl, ethyl, and propyl, and an aralkyl group, preferably a phenyl-lower alkyl group such as benzyl, phenethyl, alphamethylphenethyl, and the like, n being an integar having the value 1 or 2, and the salts thereof.

In the foregoing, the term lower alkyl is used in its conventional sense as designating alkyl groups of up to 7 carbon atoms.

The particularly preferred compounds are those of Formu a I wherein X represents the CH -CH group, R

is in the 3-position and represents hydrogen, chloro or methyl, R is hydrogen, and R is methyl.

The salts of the dibenzocycloheptane derivatives coming within the purview of this invention include the acidaddition salts, more particularly the non-toxic acid addition salts, i.e., salts, which are not harmful to the animal organism when used in therapeutic doses. Acids useful for preparing the acid addition salts include, inter alia, inorganic acids, such as the hydrohalic acids (e.g., hydrochloric and hydrobromic acid) and organic acids, such as oxalic, maleic, tartaric, citric, acetic, and succinic acid.

The compounds of this invention are therapeutically active compounds which have utility as stimulants. Apart from their stimulating activity, the compounds also exhibit anti-histaminic and atropine-like properties.

The toxicity of the compounds according to the invention, expressed in LD on mice, is about 30 mg./kg. after intravenous, and about 600 mg./kg. after oral administration. The novel compounds of this invention can be administered orally or parenterally in conventional dosage forms such as tablets, capsules, injection solutions, or the like, by incorporating the appropriate dose of the compound with carriers according to accepted pharmaceutical practice.

The compounds of this invention can be prepared from the corresponding ketone having the general formula wherein X, R and R have the meaning hereinbefore defined, and this ketone first being converted into a carbinol intermediate of the general formula by reduction of the ketone of general Formula H, by treatment with a reducing agent such as sodium borohydride, sodium amalgam, aluminum isopropoxides and lithium aluminum hydride. The resulting alcohol is then interacted with a halide (preferably chloride) of the formula hlalogen R3 IV the reaction preferably being conducted in the presence of a basic condensation reagent such as sodamide. This series of reactions is shown by the following equations:

X RIQ GR:

Compounds of Formula II, wherein X represents a CH:CH group, are preferably obtained by conversion of the CH -CH group into the -CH CH group by conventional methods such as bromination followed by removal of H131".

It is also possible, though not preferred, first to prepare compounds of the formula CH=CH R1 l R2 COOH v by reacting a compound of the formula CHO R1 1 with a compound of the formula wherein R and R are as hereinbefore defined, and thereupon effecting cyclization by treatment with phosphorus pentoxide at an elevated temperature.

If a substituted phthalic anhydride is used as a reactant in the above series of reactions, the position of the substituent on the resulting benzalphthalide will depend on the position of the substituent on the phthalic anhydride. Thus, when ortho-substituted phthalic anhydride is condensed with phenylacetic acid, a mixture of 4- and 7- substituted 3-benzalphthalides is obtained. These products .are then separated by fractional crystallization and the separated products treated with phosphorus and bydroiodic acid, followed by phosphorous pentoxide, to yield a l-substituted-dibenzo (a,d) '1,4-cycloheptadienone-(5) and a 4-substituted dibenzo (a,d) 1,4-cycloheptadienone- (5), respectively. Where a meta-substituted phthalic anhydride is used, a mixture of 5- and 6-substituted 3-benzalphthalides is obtained. These products are then separated by fractional crystallization and then treated with phosphorus and hydroiodic acid followed by phosphorus pentoxide, to yield 2-substituted dibenzo (a,d) 1,4-cycloheptadienone-(S) and 3-substituted dibenzo (a,d) 1,4- cycloheptadienone- 5 respectively.

If a substituted phenylacetic acid is used as a reactant in the above series of reactions, the position of the substituent on the resulting benzalphthalide will depend on the position of the substituent on the phenylacetic acid. Thus, if an ortho-substituted phenylacetic acid is condensed with phthalic anhydride and the remaining steps of the process are carried out, a l-substituted dibenzo (a,d) 1,4-cycloheptadienone-(5) is obtained. If :1 metasubstituted phenylacetic acid is used, a mixture of 2- substituted and 4-substituted dibenzo (a,d) 1,4-cycloheptadienones-(S) is prepared, which can be separated by fractional crystallization. If a para-substituted phenylacetic acid is used, a 3-substituted dibenzo (a,d) 1,4- cycloheptadienone-(5) is obtained.

Among the suitable phthalic anhydrides utilizable as initial reagents in these reactions may be mentioned: phthalic anhydride, halophthalic anhydrides, such as 3- and 4-chlorophthalic anhydride, 3- and 4-bromophthalic anhydride, and 3- and 4-fiuorophthalic anhydride, alkylphthalic anhydrides, such as 3- and 4-methyl phthalic anhydride, 3- and 4-ethylphthalic anhydride, 3- and 4-isopropylphthalic anhydride, and 3- and 4-tertiary butylphthalic anhydride.

Among the suitable phenylacetic acids utilizable as initial reagents in these reactions may be mentioned: phenylacetic acid, halo-phenylacetic acids, such as 2-, 3- and 4-chlorophenylacetic acid, 2-, 3- and 4-bromopheny1- acetic acid, and 2-, 3- and 4-fluorophenylacetic acid, alkyl phenylacetic acids, such as 2-, 3- and 4-methyl phenylacetic acid, 2-, 3- and 4-ethylphenylacetic acid, 2-, 3- and 4-isopropylphenylacetic acid, and 2-, 3- and 4-tertiary butylphenyl acetic acid.

According to another feature of the invention, a compound having the formula Rl R2 is reacted with a compound of the general formula I Ra Wherein A and B are different and each represents a halogen (preferably chlorine) atom or. the group-OM, in which M is an alkali metal atom, or A represents a halogen atom or a hydroxyl group and B represents a hydroxyl group and R R and X are as hereinbefore defined. The reaction can be carried out in the presence or absence of an inert organic solvent. When A represents a halogen atom and B an OH-group, the reaction can be carried out while using an excess of the amino alcohol or with the addition of another acid-binding substance. Preferably, the chloride of the tri-cyclic alcohol is reacted with an excess of the aminoalcohol at a temperature of about 140-160 C., whereby the hydrochloride of the aminoalcohol and the free base of the desired compound are formed.

When A and B both represent an OH-group, both reaction components are preferably heated, either dry or in solution, in the presence of an organic sulphonic acid, e.g., paratoluene sulphonic acid. 1

1 When A represents an O-alkali metal group or a halogen atom, the compounds can be produced from the corresponding alcohols in a manner known per se.

The preparation of the acid addition salts from the base suitably takes place by methods known per se, for example, by mixing equivalent quantities of base and acid in an inert organic solvent followed by filtration of the salt.

Typical compounds of the Formula II which may be used for the manufacture of the compounds according to the invention, e.g. dibenzo-(a,d) 1,4-cycloheptadienone-5 (boiling at 203204) (7 mm. Hg) and dibenzo-(a,e) 1,3,5-cycloheptatrienone-5 (melting point 90-91 C.) are known from the literature. The first mentioned compound has been described by W. Treibs and H. J. Klinkhammer, Ber. 83, 367371 (1950) the latter by E. D. Bergmanu et al., Bull. Soc. Chem. Fr., 18, 684-692 (1951). While the compounds of this invention are produced directly from compounds of the Formula III, these latter compounds are, in efiect, intermediates in producing the compounds of the invention from the corresponding ketones of the Formula II.

The term methods known per se as used in the specification means methods heretofore employed or described in the chemical literature.

The fol-lowing examples illustrate the invention (all temperatures being in centigrade). The first ten examples are directed to the preparation of the ketones of the Formula II and the remaining examples are directed to the preparation of the carbinol intermediates and the final compounds of this invention.

EXAMPLE 1 Dibenzo (a,d) 1,4-cycloheptadienone-5 (a) Preparation of 3-benzalphthalide.-In a 500 cc. round bottom flask are placed 100 grams of phthalic anhydride, 110 grams of phenylacetic acid and 2.6 grams of fused sodium acetate.

The reaction mixture is heated rapidly in an oil-bath until the internal temperature reaches 230. During'the next three hours the internal temperature is slowly raised to 240, during which the water formed in the reaction is allowed to distill out. The mixture is then cooled to 90 and the product dissolved in 400 ml. of boiling alcohol, the solution being filtered to separate a small amount of insoluble material and allowed to cool. The benzalphthalide is filtered and washed with cold alcohol. It is sufliciently pure vfor use in the next step.

(b) Preparation of aibenzyl-o-carbo nic acid.A mixture of 289 g. of benzalphthalide, 113.3 g. of hydrogen iodide (sp. gravity 1.7) and 113.3 g. of red phosphorus is refluxed with stirring for ten hours and the resulting mixture poured into ice water. A red crystalline mass is obtained which is filtered off and dried. The dried solid is extracted with one liter of boiling acetone and filtered while hot. The acetone filtrate is concentrated to about 300 cc. and cooled. One liter of water is added and the mixture is again cooled. The solid which crystallizes is filtered to yield about 243 g. of product, melting at about 115118. Recrystallization from aqueous acetone gives the pure product of a constant melting point of about 121122.

(c) Preparation of dibenzo (a,d) 1,4-cycl0heptadienone-5.-To 260 cc. of phosphoric acid at 80 is added 377 g. of phosphorus pentoxide. The temperature is kept at 80-90 by slowly adding the phosphorus pentoxide. At the end of the addition, the reaction is kept at for one hour, then heated to C., and 118 g. of dibenzyl-o-carbonic acid is added portionwise. The mixture is heated at 170 for 2 /2 hours and then poured with stirring into four liters of ice water and allowed to stand overnight. The dark oil is extracted with 3 x 700 cc. of ether. The ether is washed with sodium bicarbonate and dried over magnesium sulfate. After removal of the ether, the residue is distilled to yield about 81 g. of product, boiling at about 180/3.5 mm., 12 216315.

EXAMPLE 2 1- and 4-chl0r0 dibenzo (a,d) 1,4-cycl0heptadien0ne-5 EXAMPLE 3 3-chl0r0 dibenzo (a,d) 1,4-cycl0heptadien0ne-5 Following the procedure of Example 1, but substituting an equivalent amount of 4-chlorophenyl acetic acid for the phenyl acetic acid in Step a, 3-chloro dibenzo (a,d) 1,4-cycloheptadienone-5, melting point 5557 is obtained. The melting point can be increased to 62.5- 63.5 by further crystallization from petroleum ether.

EXAMPLE 4 3-methyl dibenzo (a,d) 1,4-cycl0heptadien0ne-5 Following the procedure of Example 1, but substituting an equivalent amount of 4-methylphenylacetic acid for the phenyl acetic acid in Step a, 3-methyl dibenzo (a,d) 1,4-cycloheptadienone-5, boiling point 165167/ 2 mm. is obtained in 81% yield.

EXAMPLE 5 I 3-brom0 dibenzo (a,d) 1,4-cycZ0heptadien0n'e-5 Following the procedure of Example 1, but substituting an equivalent amount of 4-bromophenylacetic acid for the phenyl acetic acid in Step a, .3-bromodibenzo (a,d) 1,4-cycloheptadienone-5 is obtained in 53% yield. It has a melting point of 80-81 after crystallization from petroleum ether (boiling range 6080).

EXAMPLE 6 3-terliary butyl dibenzo (a,d) 1,4-cycl0heptadienone-5 Following the procedure of Example 1, but substituting an equivalent amount of 4-tertiary butylphenylacetic acid for the phenylacetic acid in Step 21, 3-tertiary butyl dibenzo (a,d) 1,4-cycloheptadienone-5 is obtained in 83% yield, boiling point 160162/1 mm.

4-tertiary butylphenylacetic acid of melting point 79.580.5 is prepared by converting tertiary butyl benzene into 4-tertiary butylbenzyl chloride. This compound in turn is converted into the corresponding cyanide as described by Skinner et al. I. Am. Chem. Soc. 73, 2230 (1951). The nitrile is saponified by treatment under reflux with potassium hydroxide in an aqueous ethanol solution.

EXAMPLE 7 I-methyl dibenzo (a,d) 1,4-cycloheptadienone-5 Following the procedure of Example 1, but substituting an equivalent amount of Z-methylphenylacetic acid for the phenylacetic acid in Step a, 1-methyl dibenzo (a,d) 1,4-cycloheptadienone-5, of melting point 6768, is obtained in 83% yield.

EXAMPLE 8 3-methyl dibenzo (a,d) 1,3,5-cyclheplatrienone-5 In a 100 ml. flask a mixture of 6.7 g. of 3-methyl dibenzo (a,d) 1,4-cycloheptadienone-5, 5.3 g. of N-bromosuccinimide and 0.1 g. of benzoylperoxide is boiled for 2 hours in 25 ml. of carbon tetrachloride under reflux cooling. After cooling, the succinimide is removed by filtration, whereupon the solvents are removed by evaporation. The resulting monobromo compound can be recrystallized from petroleum ether (boiling range 60- 80).

6.4 g. of the brominated product are heated with 20 ml. of pyridine and the mixture is poured into 250 ml. of 2 N hydrochloric acid. The precipitate is filtered and crystallized from petroleum ether (boiling range 60-80" There is obtained 3-methyl dibenzo (a,e) 1,3,5-cycloheptatrienone-S, melting point 80-81, in 78% yield.

EXAMPLE 9 3-br0m0dibenzo (a,e) 1,3,5-cycL0heptatrienone-5 Following the procedure of Example 8, but substituting an equivalent amount of 3-bromodibenzo (a,d) 1,4-cycloheptadienone-S for the 3-methyldibenzo (a,d) 1,4-cycloheptadienone-S, 3-bromo-dibenzo (a,e) 1,3,5-cycloheptatrienone-S, melting point 111-112", is obtained in 74% yield.

EXAMPLE 1O Dibenzo (a,e) 1,3,5-cycloheptatrienone- Following the procedure of Example 8, but substituting an equivalent amount of dibenzo (a,d) 1,4-cycloheptadienone-S for the 3-methyl dibenzo (a,d) 1,4-cycloheptadienone-S, dibenzo (a,e) 1,3,5-cycloheptatrienone- 5, melting point 89", is obtained.

EXAMPLE 11 Dibenzo (a,d) 1,4-cycl0heptadien0l-5 To a solution of 50 g. of dibenzo (a,d) 1,4-cycloheptadienone-S in 500 ml. of methanol is added a solution of 9.1 g. of sodium borohydride in 100 ml. of water at room temperature. The temperature is not controlled and rises to 46. The resulting solution is refluxed for one hour. The pH adjusted to 4.0 with acetic acid and then the methanol is distilled off. A light yellow oil precipitates which is extracted with ether, the ether is dried over magnesium sulphate, filtered and allowed to evaporate at room temperature. The residue is triturated with a small amount of hexane to yield about 43 g. of a product melting at about 80-85". Recrystallization from hexane yields a pure compound, of constant melting point of about 89-90".

8 EXAMPLE 12 3-chl0r0 dibenzo (a,d) 1,4-cycl0heptadien0l-5 12.1 g. of 3-chlorodibenzo (a,d) 1,4-cycloheptadienone- 5 are dissolved in 190 ml. of ethanol (96%). The solution is boiled under reflux for 20 hours with 2.2 kg. of 0.5% sodium amalgam, and is then poured into ice-water acidified with 3 N acetic acid. The precipitate formed is filtered ofr, dried and crystallized from petroleum ether. 9.1 g. of 3-chloro dibenzo (a,d) 1,4-cycloheptadienol-S are obtained. The melting point is 117-118 and the yield 75%.

EXAMPLE 13 3-methyl dibenzo (a,e), 1,3,5-cycl0heptatrien0l-5 An etheral solution of 11.5 g. of 3-methyl dibenzo (a,e) 1,3,S-cycloheptatrienone-S is added to a solution of 1.0 g. of lithiumaluminumhydride in 200 ml. of ether. The mixture is then refluxed for 4 hours, after which it is decomposed by addition of moist ether and aqueous acetic acid. The ethereal layer is washed with water, dilute sodium hydroxide solution, and again with water, and subsequently dried on sodium sulphate. Evaporation of the solvent yields 8.5 g. of 3-methyldibenzo (a,e) 1,3, S-cycloheptatrienol-S, melting at 1181l9.5 after crystallization from ligroin (boiling range 6080).

EXAMPLE 14 S-methyldibenzo (a,d) 1,4-cycI0heptadien0l-5 Following the procedure of Example 12, but substituting an equivalent amount of 3-methyldibenzo (a,d) 1,4-cycloheptadienone-5 for the 3-chlorodibenzo (a,d) 1,4- cycloheptadienone-S, 3-methyl dibenzo (a,d) 1,4-cycloheptadienol-S, melting point 124125.5, is obtained in 87% yield.

EXAMPLE 15 Dibenao (a,e), 1,3,5-cycl0heptatrienol-5 Following the procedure of Example 11, but substituting an equivalent amount of dibenzo (a,e) 1,3,5-cycloheptatrienone-S for the dibenzo (a,d) 1,4-cycloheptadienone-5, dibenzo (a,e) 1,3,5-cycloheptatrienol-5, melting point 119120, is obtained.

EXAMPLE 16 I-methyl dibenzo (a,d) 1,4-cycl0heptadz'em0l-5 Following the procedure of Example 13, but substituting an equivalent amount of l-methyldibenzo (a,d) 1,4-cycloheptadienone-5 for the 3-methyl dibenzo (a,e) 1,3,5-cycloheptatrienone-5, l-methyl dibenzo (a,d) 1,4- cycloheptadienol-S, melting point 97100, is obtained in yield.

Similarly, by substituting an equivalent amount of each of the following substituted dibenzo (a,d) cycloheptadienone-S compounds for the l-methyl dibenzo (a,d) 1,4-cycloheptadienone-5 in Example 16, the indicated substituted dibenzo (a,d) 1,4-cycloheptadienol-5 is formed:

Substituted dibenzo (a,d) 1,4-cycloheptadienone-5:

Product 3-tertiary butyl 3-tertiary butyl. 3-bromo 3-bromo. l-chloro l-chloro.

EXAMPLE 17 4-(dibenz0 (a,d) 1,4-cycl0heptadien-5-yloxy) l-mctlzylpiperidine salt with maleic acid (a) Preparation of 4-(dibenz0 (a,d) 1,4-cycloheptadien-S-yloxy)-1-methyl-piperidine.-130 g. of dibenzo (a,d) l,4-cycloheptadienol-5 is dissolved in benzene and hydrogen chloride is then passed through the solution for half an hour. The solution is dried with calcium chloride, and after filtration, evaporated to dryness to remove all hydrogen chloride The residue (137.1 g. of dibenzo (a,d) 1,4-cycloheptadien-S-ylchloride) is dissolved in 500 ml. of anhydrous xylene and added to a boiling solution of 138.0 g. l-methyl piperidine-401 in 500 nrl. of anhydrous xylene under stirring. The reaction mixture is refluxed for 3 hours. It is then cooled, whereafter water is added. After separation the water layer is extracted with xylene and the combined organic layers are dried with sodium sulphate.

The solvents are then distilled off, leaving a residue which can be distilled under reduced pressure (boiling range l58l68/0.01 mm.).

(b) Preparation of the maleinate.-The maleic acid salt can be prepared either from the crude or the distilled base by dissolving the base in as little Warm alcohol as possible and adding to the solution the calculated amount of maleic acid in a small amount of alcohol. The solution is warmed at a temperature of 40 and then ether is added until an opalescence occurs. The salt precipitates on cooling; filtration yield 165 g. of 4-(dibenzo (a,d) 1,4-cycloheptadien--yloxy) 1 methylpiperidine maleinate (64%), melting at about 153-156.

Analysis-Calculated for C H NO C, 70.90%; H, 6.90%; N, 3.31%. Found: C, 71.39%; H, 6.87%; N,

EXAMPLE 18 3-(dibenzo (a,d) 1,4-cycloheptadien-5-yloxy)-1-methylpyrrolidz'ne salt with maleic acid Following the procedure of Example 17, but substituting an equivalent amount of 1-methylpyrrolidine-3-ol for the l-methyl piperidine-4-ol in Step a, 3-(dibenzo (a,d) 1,4-cycloheptadien-5-yloxy)-1-methy1 pyrrolidine maleinate is prepared in 71% yield. Melting point 106-107".

Analysis.--Calculated for C H NO C, 70.38%; H, 6.81%; N, 3.42%. Found: C, 70.40%; H, 6.67%; N, 3.41%.

As previously indicated, the product compounds of this invention are administered in conventional manner, either orally or parenterally, in suitable dosage quantities. In general, a typical dosage unit contains 25 to 50 mg. of the active compound and 75 to 125 mg. of a pharmacologically-acceptable inert carrier. The following are typical examples of compositions containing the product compounds of the invention.

EXAMPLE 19 A mixture of the following composition is prepared:

4-(dibenzo (a,d) 1,4-cycloheptadien-5 -yloxy)-1-methyl This mixture is made into tablets of 150 mg. If de-. sired the tablet may be provided with a coating.

1 0 EXAMPLE 20 A mixture of the following composition is prepared:

G 4-(dibenzo (a,d) 1,4-cycloheptadien-S-yloxy)-1-methy1 piperidine maleinate 50 Lactose Corn starch 15 Talcum 8 Stearic acid 2 The mixture is made into tablets of 135 mg. which are subsequently provided with a sugar coating, the weight of acid coating being about 35 mg. per tablet.

I claim:

1. A compound selected from the group consisting of free bases of the formula wherein X is selected from the and CH=CH-,

R and R are each selected from the group consisting of hydrogen, halogen, and lower alkyl,

R is a member of the group consisting of hydrogen, lower alkyl, and phenyl [lower alkyl],

12 is an integer having the value 1 to 2, and non-toxic acid addition salts thereof.

group consisting of -CH CH References Cited by the Examiner Mychajlyszyn et a1.: Collection of Czech. Chem. Communications, vol. 24, pages 3955- (December 1959).

WALTER A. MODANCE, Primary Examiner. NICHOLAS S, RIZZO, Examiner.

Claims (2)

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF FREE BASES OF THE FORMULA

3. A NON-TOXIC ACID ADDITION SALT OF 4-(DIBENZO (A,D) 1,4-CYCLOPHEPTADIEN-5-YLOXY)-1-METHYLPIPERIDINE.