US3449498A - Analgesic compositions of a 4-aminoal-kylamino-quinazoline and 1-amino-alkoxybenzimidazole - Google Patents

Description

Unite il US. Cl. 424251 3 Claims ABSTRACT OF THE DISCLOSURE Pharmaceutical compositions comprising essentially compounds of the Formulae I and II P h I and P by C R:|

| O-alkyl-amino NH-alkyl-amino in which each of Ph and Ph stands for a 1,2-phenylene radical, R for hydrogen or an aromatic radical and R for an aliphatic, araliphatic or aromatic radical, their N- oxides and quaternaries and the salts of these compounds. The compositions of the invention are useful, inter alia, as analgesic agents.

The present invention concerns and has for its object the provision of pharmaceutical compositions comprising essentially a 4-aminoalkylamino-quinazoline and a 1- aminoalkoxy-benzimidazole.

More particularly the compositions of the invention contain as the active main ingredients compounds of the Formulae I and II -alkylamino NH-alkyl-amino in which each of Ph; and Ph stands for a 1,2-phenylene radical, R for hydrogen or an aromatic radical and R for an aliphatic araliphatic or aromatic radical, their N-oxides and quaternaries and the salts of these compounds.

The 1,2-phenylene radicals Ph and Ph may be unsubstituted or substituted by one or more than one of the same or of different substituents attached to any of the four positions available for substitution. Such substituents are primarily the following: lower alkyl, e.g. methyl, ethyl, nor i-propyl or -butyl, etherified hydroxyl, especially lower alkoxy, e.g. methoxy, ethoxy, nor i-propoxy, nor tert. -butoxy, lower alkenyloxy, e.g. allyloxy, lower alkylenedioxy, e.g. methylenedioxy, esterified hydroxyl, particularly halogeno, e.g. fluoro, chloro or bromo, trifluoromethyl, nitro, unsubstituted or substituted amino, such as di-lower alkylamino, e.g. dimethylamino or diethylamino, acyl, such as lower alkanoyl, e.g. acetyl, propionyl or pivalyl, benzoyl or pyridoyl, e.g. p-toluoyl or nicotinoyl, or sulfamyl.

Above all the 1,2-phenylene radicals Ph and Ph stand for 1,2-phenylene, (lower alkyl)-l,2-phenylene, (lower alkoxy)-1,2-phenylene, (halogeno)-l,2-phenylene, (trifluoromethyl) 1,2 phenylene, (nitro)-1,2-pheny1ene,

States Patent (amino)-l,2-phenylene, (di-lower alkylamino)-l,2-phenylene, (lower alk-anoyl)-l,2-phenylene or (sulfamyl)-l,2- phenylene.

An aliphatic or araliphatic radical representing R is, for example, lower alkyl, e.g. methyl, ethyl, nor i-propyl, straight or branched chain butyl, pentyl, hexyl or heptyl bound in any position, lower alkenyl, e.g. allyl or methallyl, cycloalkyl or cycloalkyl-lower alkyl having from three to eight, preferably from five to six, ring carbon atoms, e.g. cyclopropyl, cyclopentyl, cyclohexyl or cycloheptyl; cyclopropyl-methyl, cyclopentyl-methyl, 3-cyclopentyl-propyl, cyclohexyl-methyl, 2-cyclohexyl-ethyl or cycloheptylmethyl, cycloalkenyl or cycloalkenyl-lower alkyl having from five to eight, preferably from five to six, ring carbon atoms, e.g. l-cyclopentenyl, l-cyclohexenyl, 3-cyclohexenyl, l-cycloheptenyl, 3-cycloheptenyl or l-cyclooctenyl; l-cyclopentenyl-methyl, l-cyclohexenyl-methyl or 2-(3-cyclohexenyl)-ethyl, or monocyclic carbocyclic aryllower alkyl, e.g. benzyl, lor 2-phenyl-ethyl. Said aralkyl radicals may be unsubstituted or substituted in the aromatic moiety by one or more than one of the same or of different substituents attached to any of the positions available for substitution. Such substituents are exemplified by those listed for the 1,2-phenylene radicals Ph and Ph Above all an aliphatic radical R stands for alkyl with 1 to 4 carbon atoms.

An aromatic radical R and R more especially stands for a monocyclic carbocyclic or heterocyclic aryl radical, the latter of which is preferably an azacyclic aryl radical, e.g. a 2-, 3-, or 4-pyridyl radical. These aryl radicals may be unsubstituted or substituted by one or more than one of the same or of different substituents attached to any of the positions available for substitution. Such substituents are exemplified by those listed for the 1,2-phenylene radicals Ph and Ph,,.

Above all an aromatic radical R and R stands for phenyl, (lower aIkyD-phenyl, (lower alkoxy)-phenyl, (halogeno) phenyl, (trifluoromethyl) phenyl, (nitro)- phenyl, (amino)-phenyl, (di-lower alkylamino)-phenyl, (lower alkanoyl)-phenyl or (sulfamyD-phenyl; pyridyl or (lower alkyl)-pyridyl or thienyl.

The amino-alkyl group in the compounds of the Formulae I and II, attached to the nitrogen or oxygen atom respectively, more particularly is a primary, secondary or preferably a tertiary amino-lower alkyl goup, in which the amino portion is separated from the hetero atom by at least two carbon atoms. The alkyl chain thereof may be straight or branched and preferably contains 2 to 4 carbon atoms. Examples for the amino-alkyl group are the following: l-amino-ethyl-(Z), -propyl-(2), -propyl (3), -butyl-(2), -butyl-(3), -butyl-(4), -per1tyl-(5 -hexyl- (6), -heptyl-(4) or -2-methyl-propyl-(2); Z-amino-propyl- (3), -butyl-(3), -bntyl-(4) or -pentyl-(5), 3-amino-butyl- (4) or -pentyl-(5 The amino-alkyl group preferably contains a secondary or especially a tertiary amino group. It may contain aliphatic, cycloaliphatic, araliphatic or aromatic radicals, such as lower alkyl, alkenyl, alkylene, aza-, oxa-, or thiaalkylene, mono-cyclic cyclo-lower alkyl or alkenyl, monocyclic cyclo-lower alkylor alkenyl-lower alkyl, monocyclic carbocyclic aryl-lower alkyl or monocyclic carbocyclic aryl. These radicals may be unsubstituted or substituted, the aliphatic radicals especially by free, esterified or etherified hydroxy groups, e.g. those mentioned above and the aryl radicals by those substituents mentioned for Ph and P112.

Examples for such amino groups are the following: monoor di-lower alkylamino, e.g. methylamino, dimethylamino, N-methyl-N-ethylamino, ethylamino, diethylamino, n-propylamino, di-n-propylamino, isopropylamino, di-isopropylamino, nabutylamino or di-n-butylamino, hy-

hydroxy-lower alkyl-amino, N-(hydroxy-lower alkyl)-N lower alkyl-amino or di-(hydroxylower alkyl)-amino, in which hydroxyl is separated from the amino nitrogen by at least two carbon atoms, e.g. Z-hydroxyethyl-amino, N- (2-hydroxyethyl) N-methylamino or di- (Z-hydroxyethyl) amino, lower alkyleneimino or hydroxy-alkyleneimino, e.g. ethyleneimino, pyroolidino, 2-methyl-pyroolidino, piperidino, 2- or 4-methyl-piperidino, 3-hydroxyor acetoxy-piperidino, 3-hydroxyrnethyl-piperidino, 1,6- or 2,5- hexamethyleneimino, 1,7- or 2,6-heptamethyleneimino, lower aza-alkyleneimino, preferably N-lower alkyl-azaalkyleneimino, e.g. piperazino, 4-methyl-, ethyl-, hydroxyethylor acetoxy-ethyl-piperazino, 3-aza-1,6-hexylene imino, 3-methyl-3-aza-1,6-hexyleneimino, 4-aza-1,7-heptyleneimino, 4-methyl-4-aza1,7-heptyleneimino, lower oxaor thia-alkyleneimino, e.g. morpholino, 3-methylmorpholino or thiomorpholino, monocyclic cyclo-lower alkyl-amino or N-cyclo-lower alkyl-N-lower alkyl-amino e.g. cyclopentylamino, cyclohexylamino, N-cyclopentyl-N- methylamino, N-cyclohexyl-N-methylamino or N-cyclohexyl-N-ethylamino, monocyclic cyclo-lower alkyl-lower alkyl-amino, e.g. cyclopentylmethylamino or 2-cyclopentyl-ethylamino, phenyl-lower alkyl-amino or N-lower alkyl-N-phenyl-lower alkyl-amino, e.g. benzylamino, N- methyl-N-benzylamino, N-ethyl-N-benzylamino, N-ethyl- N-(1-phenylethy1)-amino or N-rnethyl-N-(Z-phenylethyl)-amino, phenylor diphenyl-amino, e.g. p-tolylamino or di-p-anisylamino.

In the amino-alkyl group the alkyl portion, either partially or in toto, may also form part of a saturated heterocyclic ring system, of which the amino group is a ring member and is separated from the hetero atom by at least two carbon atoms. Such amino-alkyl groups are, for example, pyrrlidyl-(3), 1-methyl-pyrrolidyl-(3), piperidyl-(2) or (3)-methyl, piperidyl-(4), 1-ethylpiperidyl-(4) or 1-methyl-piperidyl-(2) or (3)-methyl.

The quaternaries of the present invention are those containing an additional lower alkyl or aralkyl group, e.g.

-one of those mentioned above, on any tertiary nitrogen atom present.

The salts of the above compounds are pharmacologically acceptable acid addition salts, derived, for example, from the following inorganic or organic acids, such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid or perchloric acid, aliphatic, alicyclic, araliphatic, aromatic, or heterocyclic carboxylic or sulfonic acids, for example, formic acid, acetic acid, propionic acid, succinic acid, glycollic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, hydromaleic acid, pyroacemic acid, phenylacetic acid, benzoic acid, aminobenzoic acid, anthranilic acid, hydroxybenzoic acid, salicyclic acid, aminosalicylic acid, embonic acid, nicotinic acid, methanesulfonic acid, ethanesulfonic acid, hydroxyethanesulfonic acid, ethylenesulfonic acid, halogenbenzenesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid and sulfanilic acid; methionine, tryptophane, lysine and argin- Said salts are those of the 4-aminoalkylamino-quinazolines and 1-aminoalkoxy-benzoimidazolines itself or of their N-oxides and the quaternaries contain corresponding anions.

The 4-aminoalkylamino-quinazolines, e.g. the compounds of the Formula I, are partly known and described, for example, in French Patent No. 1,404,488, in J. Chem. Soc. 1947, pages 890899 and in US. Patent No. 3,184,- 462 as well as in copending applications Ser. Nos. 310,152, filed Sept. 19, 1963, now abandoned; 348,861, filed Mar. 2, 1964, now US. Patent No. 3,301,855, and 282,242, filed May 22, 1963, now abandoned. Apart from a vasodilating and antimalarial activity they show primarily analgesic effects.

We have now found that the l-aminoalkoxy-benzirnida- Zoles, e.g. the compounds of the Formula II, which primarily show central nervous system depressing effects and are the subject matter of copending application Ser. No. 484,433 filed Sept. 1, 1965 now US. Patent No. 3,300,505, surprisingly potentiate the pharmacological activity, especially the analgesic effects, of the 4-arninoalkylaminoquinazolines, such as those of Formula I. This synergistic effect can be demonstrated in animal tests using, for example, mice as test objects. The compositions of the invention are, therefore, primarily useful as analgesic agents which, depending on the amount of the l-aminoalkoxybenzimidazole present therein, also provide an additional tranquilizing effect.

Particularly valuable are compositions comprising essentially compounds of the Formulae III and IV.

in which R stands for hydrogen, lower alkyl or halogen, R for hydrogen, phenyl, (lower alkyl)-phenyl, (halogeno)-phenyl, pyridyl or thienyl, each of R and R for hydrogen, lowe alkyl, lower alkoxy, halogen, trifiuoromethyl, nitro, amino, di-lower alkylamino, lower alkanoyl or sulfamyl, R for alkyl with 1 to 4 carbon atoms or the radical or pyridyl or (lower alkyl)-pyridyl), each of m and n for an integer from 2 to 7, Am for di-lower alkylamino, lower alkyleneimino or lower mono-aza-, oxaor thiaalkyleneimino, and Am for amino, lower alkylamino, di-lower alkylamino, lower alkyleneimino or lower monoaza-, oxaor thia-alkyleneimino, Am and Am being separated from the nitrogen or oxygen atom respectively by at least 2 carbon atoms, and pharmaceutically acceptable acid addition salts thereof.

Especially mentioned are compositions which contain as the main active ingredients compounds of the Formulae V and VI in which R stands for hydrogen or phenyl, each of R and R for di-lower alkylamino or lower alkyleneimino, each of R and R for hydrogen, methoxy, fluoro, chloro, iodo, nitro or sulfamyl and each of m and n for an integer from 2 to 4, and pharmaceutically acceptable acid addition salts thereof, and particular those containing 4-(2-dimethylamino-ethylamino)-quinazoline and l- (Z-diethylamino-ethoxy)-2-phenyl-benzimidazole dihydrochloride. The latter, when given subcutaneously to mice at a dose of 10 mg./kg., increases the analgesic eifect of the former in the tail-flick test by about one third, i.e. its ED value is only about two thirds in the composition according to the invention in comparison to that of the 4-(2-dimethylamino-ethylamino)quinazoline alone. In case the dose of 1-(Z-diethylamino-ethoxy)-2-phenylbenzimidazole dihydrochloride is increased in the same test to 50 mg./kg., an about five to six fold increase of the anagesic potency of 4-(2-dimethylamino-ethylamino)- quinazoline is observed, i.e. its ED is reduced to about mg./l g.; at this dose level also a tranquilizer-like effect is produced with the composition according to the invention.

Accordingly, the present compositions contains the 4- aminoalkylamino-quinazolines and l-aminoalkoxy-benzimidazoles in a ratio between about 1:10 and 10:1, preferably between about 1:5 and 5:1. A single dosage unit of the compositions according to the invention, which may be administered up to 3 times a day, more particularly contains between about 100 and 600 mg., preferably between about 300 and 500 mg. of the 4-arninoalkylamino-quinazolines, especially those of Formula V, and between about 10 and 150 mg., preferably between about 25 and 100 mg. of the 1-aminoalkoxy-benzirnidazoles, especially those of Formula VI.

The compoistions of this invention are generally prepared according to methods used in the art of manufacturing pharmaceutical compositions, essentially by combining specified proportions of the pharmacologically active ingerdients with a pharmaceutically acceptable organic or inorganic carrier. Usually, the compositions of this invention contain at most equal amounts of the active ingredients and the inert carrier; preferably, they are made up to have from about 1% to at most 50% by weight of the pharmacologically active ingredients in the compositions. In those for oral use (e.g. tablets or capsules), the percentage by weight is from about 5% to at most 80% of the active ingredient. In those for injections (e.g. solutions), the percentage by weight is from about 1% to about of the active ingredients.

In preparing pharmaceutically acceptable dosage unit forms, any one of a wide variety of preparations may be manufactured, such as tablets, capsules, pills, suppositories, solutions or suspensions. In addition to the pharmacologically active component, there may be present additional substances, commonly employed in the art of manufacturing pharmaceutically acceptable dosage unit compositions. These may include excipients, binders, fillers, lubricants, solvents, stabilizers, wetting agents, emulsifiers, buffers, and/ or other inert ingredients. Examples of these materials, especially for the orally applicable preparations, are the following: starches, e.g. corn or wheat starch, sugar, e.g. lactose or sucrose, stearic acid, magnesium or calcium sterate, aluminum magnesium silicate (colloidal silica) preparations, talc, tragacanth, alginic acid, acacia or polyethylene glycol. The quantities of these ingredients may vary widely and depend upon the characteristics and the size of the desired, orally applicable form, and/or the method of its manufacture. Encapsulation may be effected using, if necessary, the same excipients as those employed for the preparation of other orally applicable forms, e.g. tablets. Any compatible colors, approved and certified under the provisions of the Federal Food, Drug and Cosmetic Law may be used as a means of identification.

Primary solvents of the solutions for injection according to this invention are water, water-miscible organic solvents, such as lower alkanols, e.g. ethanol, or mixtures of water and water-miscible organic solvents. Other ingredients are added to ensure stable solutions for injection, for example, stabilizers, such as anti-oxidants, e.g. thiourea, sodium sulfide, sodium metabisulfite, ascorbic acid, cysteine hydrochloride, sodium formaldehyde sulfoxylate, mono-thioglycerol or thiosorbitol, solubilizers, e.g. N,N-diethylacetamide, polyethyleneglycol, ureas or urethanes, buffers and buffer combinations to maintain a preferably pH of about 7, such as, for example, acetic acid, potassium phthalate and sodium hydroxide, potassium dihydrogen phosphate and disodium hydrogen phosphate, potassium dihydrogen phosphate and sodium hydroxide or acetic acid and sodium acetate, salts for making isotonic solutions, e.g. sodium chloride, or any other suitable auxiliary substances, for example other therapeutically active compounds.

The following working examples are illustrative of the invention, but are in no way intended to limit its scope; temperatures are given in degrees centigrade.

Example 1 Preparation of 2000 tablets each containing 0.5 g. of the active ingredients.

Procedure.-The quinazoline, benzirnidazole and alginic acid are passed through a 20 mesh screen and mixed for 30 minutes. The phthalate is dissolved in the ethanolacetone mixture and with the solution the powders are wetted and mixed thoroughly. The granulate is dried with warm air, passed through a 16 mesh screen and compressed into tablets using diameter dies, modified ball punches.

Example 2 Preparation of 1000 tablets each containing 0.555 g. of the active ingredients.

Material: G.

4 (2 dimethylamino-ethylarnino)-quinazoline 500.0 1-(2-diethylamino ethoxy) 2 phenyl-benzimidazole dihydrochloride 55.0

Microcrystalline cellulose 109.0 Polyethylene glycol 6000 powder 18.0 Polyvinyl alcohol powder 18.0 50% aqueous ethanol, q.s.

Procedure.The quinazoline, benzimidazole and polyvinyl alcohol are passed through a 20 mesh screen, mixed with the cellulose and the mixture is moistened with the ethanol. The granulate is dried with warm air, passed through a 12 mesh screen, mixed with the polyethylene glycol and compressed into tablets using fi diameter dies, modified ball punches.

Example 3 Preparation of 20,000 tablets each containing 0.2 g. of the active ingredients.

Material: G.

4-(2 dimethylamino-ethylamino)-quinazoline 2,000.0 1-(Z-diethylamino-ethoxy) 2 phenyl-benzimidazole dihydrochloride 2,000.0 Gelatine 300-0 Corn starch (anhydrous) 3,318.0 Talcum 1,250.0 Stearic acid 132.0

Purified Water, q.s.

Procedure.-The quinazoline, benzimidazole and 1,452 g. of the starch are passed through a 16 mesh screen and mixed thoroughly. The gelatin is dissolved in 2,000 ml. water, the solution combined with a suspension of 616 g. starch in 400 ml. cold water and the Whole heated on a water bath until a paste is formed. It is combined with the sieved powders using additional water, if necessary. The granulate is passed through a 5 mesh screen, dried at 49 and broken on a 9 mesh screen in the Fitzpatrick mill, knives forward. The granules are mixed with the talcum, stearic acid and the remaining starch and the mix ture compressed into tablets using standard concave punches scored and monogrammed.

7 Example 4 Preparation of 1000 capsules each containing 0.25 g. of the active ingredients.

Material:

4 (2 dimethylamino-ethylamino)-quinazoline 100.0 1- (Z-diethylamino ethoxy) 2 phenyl-benzimidazole dihydrochloride 150.0 Lactose 530.0

which upon further recrystallizations from cyclohexane melts at 146-148.

4.0 g. l-hydroxy-Z-phenyl-benzimidazole are dissolved in 50 ml. dimethylformamide at 60 with stirring. The clear solution formed is cooled to 40, mixed with 1.0 g. of a 53% sodium hydride suspension in mineral oil, stirred at room temperature for 5 minutes and then at an internal temperature of 5560 for minutes. Thereupon the reaction mixture is mixed with 25 ml. toluene, cooled in an ice bath and then mixed with 12 ml. of a solution of Z-diethylamino-ethyl chloride in toluene containing 0.23 g./ml. The clear amber solution is stirred for 6 hours in an ice bath and allowed to stand overnight at room temperature. Thereupon it is cooled in an ice bath, mixed with 5 ml. 95% ethanol and 100 ml. diethyl ether and filtered. The filtrate is evaporated to dryness in vacuo, the residue taken up in ether, the solution washed with 100 ml. water, the ethereal layer dried over sodium sulfate and evaporated. The remaining light yellow oil is dissolved in diethyl ether, the solution cooled in an ice bath and mixed with ethereal hydrochloric acid. The 1-(2- diethylamino-ethoxy) 2 phenyl-benzimidazole dihydrochloride of the formula formed is filtered off and recrystallized from methanoldiethyl ether; M.P. 158-160.

What is claimed is:

1. A pharmaceutical composition comprising a 4-aminoalkylamino-quinazoline of the formula I|\THC2H5-N(CH:;)2 and a l-aminoalkoxybenzimidazole of the formula (I)C2H4-N(C:H5)2 in which R is hydrogen, each of R and R is hydrogen or the pharmaceutically acceptable acid addition salt of these compounds, said 4-aminoal'kylamino-quinazoline and said 1-aminoalkoxy-benzimidazole being present in the proportion of 1: 5 to 5:1.

2. A composition as claimed in claim 1, comprising essentially the 4-(Z-dimethylamino-ethylamino) quinazoline and an analgesically potentiating amount of the 1-(2- diethylamino-ethoxy) 2 phenyl-benzimidazole dihydrochloride.

3. A composition as claimed in claim 1 of which a single dosage unit contains between about 3 00 to 500 mg. of 4-(Z-dimethylamino-ethylamino)-quinazoline and between about 25 and mg. of l-(2-diethylaminoethoxy -2-phenyl-benzimidazole dihydrochloride.

References Cited UNITED STATES PATENTS 1/ 1967 De Stevens 260294.8 1/1967 Blatter 260256.4

ALBERT T. M EYERS, Primary Examiner.

US. Cl. X.R. 424-273