US3072656A

US3072656A - 2-cycloaliphatic-6-sulfamyl-7-halo(or trihalomethyl)-1, 2, 3, 4-tetrahydro-4-quinazolones

Info

Publication number: US3072656A
Application number: US3987A
Authority: US
Inventors: Werner Lincoln Harvey; Stevens George De
Original assignee: Ciba Geigy Corp
Current assignee: BASF Corp; Novartis Corp
Priority date: 1960-01-22
Filing date: 1960-01-22
Publication date: 1963-01-08
Anticipated expiration: 1980-01-08
Also published as: CH397704A; CH397705A; GB907847A

Description

Patented Jan. 8, 1953 The present invention relates to 4-oxo-1,2,3,4-tetrahydro-quanazolines, more particularly, to compounds of the formula in which R represents halogeno-lower alkyl, phenyllower alkyl, cycloalkyl containing from five to six ring carbon atoms, cycloalkenyl containing from five to six ring carbon atoms, cycloalkyl-lower alkyl, in which cycloalkyl contains from five to six ring carbon atoms, or cycloalkenyl-lower alkyl, in which cycloalkenyl contains from five to six ring carbon atoms, and R represents halogeno r halogeno-lower alkyl, salts of such compounds with alkali metals, as well as procedure for the preparation thereof.

The lower alkyl portion in a halogeno-lower alkyl group contains, for example, from one to four carbon atoms. Halogeno atoms have preferably an atomic Weight below 80 and are represented by fiuoro, bromo or particularly chloro, whereby one or more than one, preferably two, halogeno particularly chloro, atoms may be present in a halogeno-lower alkyl radical. These radicals may be represented, for example, by a dichloro-lower alkyl group, e.g. dichloromethyl, 2,2-dichloroethyl and the like, as Well as by trifiuoromethyl, chloromethyl, 2-chloroethyl, 1,2-dichloroethyl, trichloromethyl, 1,1,2-trichloroethyl, bromomethyl and the like.

In phenyl-lower alkyl groups, the aliphatic portion con tains from one to four carbon atoms; the above groups may be represented, for example, by benzyl or l-phenylethyl, as well as by 2-phenylethyl, l-phenylpropyl, 3- phenylpropyl, l-methyl-l-phenylethyl and the like.

A cycloalkyl radical containing from live to six ring carbon atoms may be represented by cyclopentyl or cyclohexyl; a cycloalkenyl radical containing from five to six ring carbon atoms may be for example, Z-cyclopentenyl, 3-cyclopentenyl, 2-cyclohexenyl, 3-cyclohexenyl and the like.

The lower alkyl portion of a cycloalkyl-lower alkyl or a cycloalkenyl-lower alkyl radical, in which both, the cycloalkyl and the cycloalkenyl ring, contain from five to six ring carbon atoms and may be represented by cyclopentyl, cyclohexyl, 3-cyclopentenyl, 3=cyclohexenyl and the like, contains from one to four carbon atoms; representative cycloalkyl-lower alkyl and cycloalkenyl-lower alkyl radicals are for example, cyclopentylmethyl, l-cyclopentylethyl, l-methyl-l-cyclopentylethyl, Z-cyclopentylethyl, l-cyclopentylpropyl, 3-cyclopentylpropyl, cyclohexylmethyl, l-cyclohexylethyl, 2-cyclohexylethyl, l-cyclohexylpropyl, 3-cyclohexylpropyl and the like, as well as Z-cyclopentenylmethyl, 3-cyclopentenylmethyl, 2-(2-cyclopentenyl)-ethyl, 2-cyclohexenylrnethyl, S-cyclohexenylmethyl, l-(3-cyclohexenyl)-ethyl, 2-(2-cyclohexenyl)- ethyl, 3-(2-cyclohexeny1)-propyl and the like.

A halogeno atom representing the group R is primarily a chloro atom; fluoro, bromo and the like may also stand for R The halogeno-lower alkyl group is more especially the trifiuoromethyl group.

Salts with alkali metals are primarily those with sodium, potassium and the like.

The compounds of the present invention have diuretic and saliuretic, particularly natriuretic, properties and are intended to be used as diuretic or saliuretic, particularly natriuretic, agents having improved and outstanding properties to relieve conditions of excessive water and salt retention as, for example, caused by kidney or heart ailments. Coupled With the diuretic and saliuretic activities of the present compounds is a strong antihypertensive effect, which renders the compounds especially useful as antihypertensive medicaments in hypertensive conditions, which are coupled with water and salt retention, such as, for example, in heart ailments and the like.

Particularly outstanding diuretic and saliuretic elfects are shown by compounds of the formula Hi NO2S- in which R stands for chloro or trifiuoromethyl. This group of compounds may be represented by 7-chloro-2- dichloromethyl-4-oxo-6 sulfamyl 1,2,3,4 tetrahydroquinazoline, 7-chloro-2-(2,2-dichloroethyl)-4-oxo-6-sulfamyl-l,2,3,4-tetrahydro-quinazoline, 2-dichloromethyl-4- oxo-6-sulfamyl-l,2,3,4 tetrahydro 7 trifiuoromethylquinazoline or 2-(2,2-dichloroethyl)-4-oxo-6-sulfamyl-l,

H 2,3,4-tetrahydro-7-trifiuoromethyl-quinazoline.

A further group of quinazoline derivatives with outstanding pharmacological effects of the above-described nature are those of the formula in which R represents chloro or trifluoromethyl. This group may be represented by 7-chloro-2-cyclopentyl-4- oxo-6-sulfamyl-1,2,3,4-tetrahydro-quinazoline, 2 cyclopentyl 4 oxo o-sulfamyl-l,2,3,4-tetrahydro-7-trifiuoromethyl quinazoline, 7 chloro-2-cyclohexyl-4-oxo-6-sulfamyl-1,2,3,4-tetrahydro-quinazoline and the like.

A further group of quinazoline derivatives with outstanding diuretic and saliuretic cfiects are the compounds of the formula H /N\ ennui-on I R2 CH-CH o11 HZNOzS /NH omom in which R represents chloro or trifluoromethyl-7-chloro- 2 (3cyclohexenyl)-4-oxo-6-sulfamyl-l,2,3,4-tetrahydroquinazoline, 2-(2-cyclohexenyl)-4-oxo-6sulfamyl-1,2,3,4- tetrahydro-7-trifiuoromethyl-quinazoline and the like are specific members of this group.

A high order of diuretic and natriuretic excretion activity without unwarranted side effects is exhibited by the compounds of the formula in which R, stands for hydrogen or methyl, and R stands for chloro or trifiuoromethyl; specific examples of this group are, for example, 7-chloro-2-cyclopentylmethyl- 4-oxo-6-sulfamyl-1,2,3,4-tetrahydro-quinazoline, 7-chloro- 2 (1 cyclopentylethyl) 4-oxo-6-sulfamyl-l,2,3,4-tetrahydro-quinazoline, 2-cyclopentylmethyl-4-ox0-6-sulfamyl- 1,2,3,4-tetrahydro 7 trifluoromethylquinazoline and the like.

The new compounds of this invention may be used as medicaments in the form of pharmaceutical preparations, which contain the new 4-oxo-l,2,3,4-tetrahydro-quinazoline compounds or salts thereof in admixture with a pharmaceutical organic or inorganic, solid or liquid carrier suitable for enteral, e.g. oral, or parenteral administration. For making up the preparations there can be employed substances which do not react with the new compounds, such as water, gelatine, lactose, starches, stearic acid, magnesium stearate, stearyl alcohol, talc, vegetable'oils, benzyl alcohols, gums, waxes, propylene glycol, polyalkylene glycols or any other known carrier for medicaments. The pharmaceutical preparations may be in solid form, for example, as capsules, tablets, dragees and the like, or in liquid form, for example, as solution, suspensions, emulsions and the like. If desired, they may contain auxiliary substances such as preserving agents, stabilizing agents, wetting or emulsifying agents, salts for varying the osmotic pressure or buffers. They may also contain, in combination, other therapeutically useful substances; particularly useful are antihypertensive compounds, such as Rauwolfia alkaloids, e.g. reserpine, rescinnamine or deserpidine, semisynthetic Rauwolfia alkaloids, e.g. syrosingopine and the like, Veratrum alkaloids, e.g. germine, protoveratrine and the like, synthetic antihypertensive compounds, e.g. hydralazine, dihydralazine and the like, or ganglionic blockers, e.g. chlorisondamine and the like.

The compounds of the present invention may be prepared according to methods which are known in themselves.

For example, the compounds of the present invention may be prepared by reacting an aniline compound of the formula in which R has the previously-given meaning, with an aldehyde of the formula Rr-CHO, in which R; has the above-given meaning, or a reactive derivative thereof, and, if desired, converting a resulting salt into the free compound, and/or, if desired, converting a free compound into a salt thereof.

The above reaction may advantageously be carried out in the presence of a small amount of an acid, for example, a mineral acid, e.g. hydrochloric, hydrobromic acid, sulfuric acid and the like, if desired, in anhydrous form. An acid may be necessary, whenever the aldehyde is employed in the form of a reactive derivative, such as an acetal, thereof. If may also be performed in the absence of a condensing reagent, or in the presence of a base, such as an alkali metal hydroxide, e.g. lithium hydroxide, sodium hydroxide, potassium hydroxide and the like, whereby the aldehyde is used in its reactive form. As mentioned above, the aldehyde may also be given into the reaction medium in a form which yields the desired reactant in situ. Thus, for example, an acetal of an alde hyde of the formula R CHO with a lower alkanol, for example, methanol, ethanol and the like, may be used in the presence of a mineral acid; such acetals are, for example, 2,2-dichloro-1,l-diethoxy-ethane, 3,3-dichloro- 1,1-dimethoxy-propane, 1,1-diethoxy2-phenyl-propane, 2- cyclopentyl-l,l-diethoxy-ethane and the like.

The reaction is preferably carried out in the presence of a solvent, for example, an ether, e.g. p-dioxane, diethylene-glycol dimethylether and the like, a lower alkanol, e.g. methanol, ethanol and the like, a lower alkanone, e.g. acetone and the like, a formamide, e.g. N,N-dimethylformamide and the like, an aqueous mixture of such solvents, water or any other suitable solvent. It is preferably completed at an elevated temperature, for example, on a steam bath or at the boiling temperature of the solvent and, if necessary, the reaction may be performed under increased pressure or in the atmosphere of an inert gas, e.g. nitrogen.

The starting materials used in the above reaction are known; they may be prepared for example, by heating a 2-methyl-5-R -aniline compound, in which R has the previously-given meaning, with chlorosulfonic acid and converting in a resulting Z-methyI-S-R -aniline-4-sulfonyl chloride, the sulfonyl chloride into a sulfamyl group by treatment with ammonia, e.g. liquid ammonia, aqueous ammonia and the like. The resulting 2-methyl-4-sulfamyl- 5-R -aniline is then oxidized, for example, by treatment with aqueous potassium permanganate, and the carboxyl group in the S-sulfamyl-4-R -anthranilic acid compound is converted into the desired carbamyl group, for example, by treatment of the anthranilic acid with phosphorus pentachloride in benzene, followed by reaction with anhydrous or aqueous ammonia, or with ethyl chloroformate in N,N-dimethylformamide at temperatures below 0 C., followed by treatment with anhydrous or aqueous ammonia.

A further method which furnishes the compounds of the present invention comprises reducing in compounds of the formulae in which formulae R and R have the previously-given meaning, the c N-double bond in the heterocyclic portion, and, if desired, carrying out the optical steps.

, The reduction of the C:N-double bond may be achieved, for example, by treatment with a borohydride or an equivalent reducing agent capable of reducing such bond. The preferred reagents are alkali metal borohydrides, e.g. lithium borohydride, potassium borohydride or, particularly sodium borohydride and the like. Other borohydrides are alkaline earth metal borohydrides, such as calcium borohydride, strontium borohydride and the like; aluminum borohydride may be used as well. Sodium dimethoxy borohydride is another possible borohydride reducing reagent. 7 If desired, these borohydrides may be used in the presence of an activating substance, such as, for example, aluminum chloride and the like. The reduction is preferably carried out in the presence of an alkaline reagent, such as an aqueous alkaline reagent, which may be diluted with other solvents, such as those mentioned hereinbelow; alkaline reagents are, for example, dilute aqueous solutions of alkali metal hydroxide, e.g. lithium hydroxide, sodium hydroxide, potassium hydroxide and the like. If desired, organic solvents, such as ethers, e.g. 1,2-dimethoxyethane, diethylene-glycol dimethylether and the like, lower alkanols, e.g. methanol, ethanol, propanol, isopropanol and the like, liquid carboxylic acid amides, such as formamides, e.g. formamide, N,N-dimethylformamide and the like, or any other suitable solvent may be employed. The reduction iscarried out at room temperature or at an elevated temperature, if necessary, in the atmosphere of an inert gas, such as nitrogen.

Catalytic reduction under certain conditions may also be used for the removal of the C=N-double bond. For example, treatment of the starting material, particularly a solution thereof, with hydrogen in the presence of a catalyst containing a metal of the eighth group of the periodic system, and of an organic base, may cause the removal of the double bond. Suitable solvents are, for example, lower alkanols, e.g. methanol, ethanol and the like, others, e.g. diethyleneglycol dimethylether and the like, or other equivalent solvents. Metals of the eighth group of the periodic system, present in the catalysts, may be, for example, palladium, platinum and the like; these metals may be supported by adsorbents, such as charcoal, aluminum oxide, silicagel and the like. Palladium on charcoal, platinum oxide and the like may serve as catalysts. An organic base is particularly a heterocyclic basic compound, particularly an N,N-alkyleneimine, e.g. pyrrolidine, piperidine and the like, or an N,N-aza-alkyleneimine, e.g. piperazine and the like, or any other suitable base. The hydrogenation may be carried out under atmospheric or under increased pressure, if necessary, while heating.

The electrolytic reduction procedure represents another possibility by which the C=N-double bond can be removed; such procedure is carried out according to standard methods. Generally, it is performed on a cathode of high overpotential and at a current density greater than about 0.02 amp./cm. Cathodes with high overpotential are, for example, those having an overpotential equal to or higher than cadmium, such as mercury, lead amalgam, lead and the like. Any appropriate anode, such as platinum, carbon, lead, stainless steel and the like, and any appropriate anolyte, for example, dilute sulfuric, dilute hydrochloric acid and the like, may be employed. A lead or a platinum anode and a dilute sulfuric acid anolyte are preferred.

Diaphragms separating the anolyte and the catholyte are more especially ion exchange membranes, such as ion exchange resins (amberplex), alundum or parchment.

Any current density greater than about 0.02 amp/cm. is suflicient to bring about the reduction of the C=N-double bond; however, for practical reasons a current density higher than about 0.5 amp/cm. may diminish the efficiency of the process due to increased hydrogen evolution.

The electrolytic reduction is performed, for example,

in an aqueous acidic medium, such as in an aqueous solution of a strong inorganic acid, which ionizes readily and does not decompose at the current density employed, for example, sulfuric acid and the like. In order to secure a complete solution of the starting material additional solvents, such as, for example, a formamide, e.g. N,N-dimethyl-formamide, may be added. Lower alkanols, e.g. methanol, ethanol and the like, may replace or may be added to a formamide solution to enhance the solubility of the starting material and the end-product.

The starting materials used in the above procedure are new; they may be prepared, for example, by reacting a compound of the formula HzNOgS- C ONH:

in which R has the previously-given meaning, with about in which R and R have the previously-given meaning, to complete the ring closure.

Derivatives of acids of the formula R -COOH are primarily the halides, e.g. chlorides and the like, or anhydrides. The reaction with these derivatives is carried out in the absence or presence of a suitable solvent, such as a halogenated lower aliphatic hydrocarbon, e.g. chloroform, or any other suitable diluent, preferably by heating, if necessary, in a closed vessel under pressure or in the atmosphere of an inert gas, e.g. nitrogen. A resulting N-acylated compound may be heated to complete the ring closure, in the absence or in the presence of a solvent, such as water, diethyleneglycol dimethylether or any other suitable solvent, if necessary, in a closed vessel or in the atmosphere of an inert gas, e.g. nitrogen.

The resulting products may be obtained in the form of the free compounds or as salts thereof. A metal, particularly an alkali metal, salt may be converted into the free compound by treatment with an aqueous acidic reagent, such as a mineral acid, e.g. hydrochloric, sulfuric acid and the like. A free compound may be converted into an alkali metal salt, for example, by treatment with an alkali metal hydroxide, e.g. sodium or potassium hydroxide, in a solvent, such as in a lower alkanol, e.g. methanol, ethanol and the like, or in water, and evaporating the solvent. Monoor poly-salts may be obtained.

Any resulting racernate may be converted into the antipodes thereof according to methods used for resolving racernates.

The invention also comprises any modification of the process wherein a compound obtainable as an intermediate at any stage of the process is used as starting material and the remaining step(s) of the process is (are) carried out, as well as any new intermediates.

In the process of this invention such starting materials are preferably used which lead to final products mentioned in the beginning as preferred embodiments of the invention.

The following examples illustrate the invention; they are not to be construed as being limitations thereon. Temperatures are given in degrees centigrade.

Example 1 A mixture of 1.0 g. of 2-carbamyl-5-chloro-4-sulfamylaniline and 0.8 g. of 1,1-dimethoxy-Z-phenyl-ethane in 100 ml. of ethanol is treated with two drops of concentrated aqueous hydrochloric acid and then refluxed for one hour. After evaporation to dryness under reduced pressure and addition of 25 rnl. of water, an amorphous precipitate is formed, which is filtered oft" and redissolved in ethanol. An amorphous solid, precipitated by carefully adding water, is filtered off and discarded; an additional amount of water is added to yield the crystalline 2-benzyl-7-chloro-4-oxo-6-sulfamyl-1,2,3,4-tetrahydro-quinazoline, which melts at 178-181" after recrystallization from ethanol.

By replacing Z-carbamyl-S-chloro-4-sulfamyl-aniline by 2-carbamyl-4-sulfamyl-5-trifiuoromethylaniline and reacting this starting material with phenylacetaldehyde, the 2 benzyl-4-oxo-6-sulfamyl-1,2,3,4-tetrahydro-7-trifluoro- 'methylquinazoline can be obtained.

Example 2 To a mixture of 7.5 g. of 2-carbamyl-5-chloro-4-sulfamyl-aniline and 4.0 g. of diethoxy-cyclopentyl-methane in 100 ml. of ethanol are added a few drops of concentrated hydrochloric acid; the desired 7-chloro-2-cyclopentyl4-oxo-6-sulfamyl-1,2,3,4 tetrahydroquinazoline is obtained after heating and working up as described in Example 1.

By selecting the appropriate starting materials, the 2-cyclopentyl-4-oX0-6-sulfamyl 1,2,3,4 tetrahydro-7-trifluoromethylquinazoline, 7 bromo-2-cyclohexyl-4-oxo-6- sulfamyl-1,2,3,4tetrahydro-quinazoline and the like can be prepared according to the previously given procedure.

Example 4 A mixture of 5.0 g. of 2-carbamyl-5-chloro-4-sulfamylaniline, 2.7 g. of 3-cyclohexene carboxaldehyde, 0.5 ml. of a saturated solution of hydrogen chloride in ethyl acetate and 50 ml. of diethyleneglycol dimethylether is heated on the steambath for 2% hours; the desired 7-chloro 2 (3 cyclohexenyl)-4-oxo-6-sulfamyl-1,2,3,4- r

tetrahydroquinazoline can be isolated according to the procedure given in Example 1.

Upon treating 2-carbamyl-4-sulfamyl-5-trifiuoromethylaniline with 3-cyclohexene carboxaldehyde according to the previously-given method, the desired 2-(3-cyclohexenyl)-4-oxo-6-sulfamyl l,2,3,4 tetrahydro 7 trifluoromethyl-quinazoline can be formed.

Example 5 To a mixture of 8.7 g. of 2-carbamyl-5-chloro-4-sulfamyl-aniline and 4.74 g. of cyclopentyl-acetaldehyde in 100 ml. of ethanol are added a few drops of concentrated aqueous hydrochloric acid and the mixture is heated under reflux for about two hours; the desired 7-cl1loro-2- cyclopentylmethyl 4 oxo 6 sulfamyl 1,2,3,4 tetrahydro-quinazoline can be obtained according to the method given in Example 1.

Z-carbamyl-4-sulfamyl-5-trifluoromethyl-aniline, when a reacted with Z-cyclopentyl-propionaldehyde according to the previously-given procedure, yields the desired 2-(1- cyclopentylethyl) 4 oxo 7 6 sulfamyl 1,2,3,4-tetrahydro-7-trifluoromethyl-quinazoline.

What is claimed is:

1. A member of the group consisting of compounds of the formula in which R represents a member of the group consisting of chloro and tritluoromethyl, and alkali metal salts thereof.

2. 7 chloro 2 cyclopentyl 4 oxo 6 sulfamyl- 1,2,3,4-tetrahydro-quinazoline.

3. A member of the group consisting of compounds of the formula in which R represents a member of the group consisting of chloro and trifiuoromethyl, and alkali metal salts thereof.

4. 7 chloro 2 (3 cyclohexenyl) 4 oxo 6 sulfamyl-l,2,3,4-tetrahydro-quinazoline.

5. A member of the group consisting of in which R stands for a member of the group consisting of hydrogen and methyl, and R represents a member of the group consisting of chloro and trifluoromethyl, and alkali metal salts thereof.

6. 7 chloro 2 cyclopentylmethyl 4 oxo 6 sulfamyl-l,2,3,4-tetrahydro-quinazoline.

References Cited in the file of this patent UNITED STATES PATENTS 2,910,488 Novello Oct. 27, 1959 2,952,680 Novello Sept. 13, 1960 2,976,289 Cohen et a1. Mar. 21, 1961 3,004,024 Bernstein et al Oct. 10, 1961 FOREIGN PATENTS 672,493 Germany Mar. 3, 1939 OTHER REFERENCES 1:? retir e 1 UNITED STATES FATEN OEHCE CERTIFEQAT t he Patent No. $372,656 January 8 1963 vey Werner et al.

are in the above numbered pat- It is hereby certified that error appe nd that the said Letters Patent should read as ent requiring correction a corrected below.

Lincoln Har Column 2 line 55 after "'6-su1famyl-" insert I r0 7 trifluoromethyl-quinazoline, column read 243 l',2,3,4-tetrahyd e 3 line 14, for "2(2-cyc1ohexeny1)" cyclohexenyl Signed and sealed this 14th day of April 1964;

EDWARD J. BRENNER.

ERNEST W. SWIDER missioner of Patents Com Attesting Officer

Claims

1. A MEMBER OF THE GROUP CONSISTING OF COMPOUNDS OF THE FORMULA

3. A MEMBER OF THE GROUP CONSISTING OF COMPOUNDS OF THE FORMULA

5. A MEMBER OF THE GROUP CONSISTING OF