US3245878A - Methods for lowering blood cholesterol - Google Patents

Description

United States Patent 3,245,878 METHODS FGR LOWERING BLOOD CHOLESTEROL Frank M. Berger, 227 Prospect Ave, Princeton, N.J., and

Bernard J. Ludwig, 1159 Stockton Place, North Brunswick, NJ.

No Drawing. Filed July 17, 1963, Ser. No. 295,807

19 Claims. (Cl. 167-65) This application is a continuation-in-part application of now abandoned application Serial Number 164,856, filed January 9, 1962, which in turn is a continuation-inpart application of application Serial Number 83,954, filed January 23, 1961, now abandoned.

This invention relates to novel compositions of matter and methods for lowering blood cholesterol.

Objects and advantages of the invention will be set forth in part hereinafter and in part will be obvious herefrom, or may be learned by practice with the invention, the same being realized and attained by means of the steps, methods and compositions pointed out in the appended claims.

The invention consists in the novel steps, methods and compositions herein shown and described.

It is an object of this invention to provide novel compositions of matter which have the effect of lowering blood cholesterol upon administration of such compositions to warma'blooded animals. A further object of this invention is to provide a novel method of lowering blood cholesterol in warm-blooded animals. A further object of this invention is to provide novel compounds which are useful as active ingredients in compositions useful in lowering blood cholesterol in warm-blooded animals.

It has been found that some of the objects of this invention may be realized by employing as the active ingredient for reducing blood cholesterol a compound selected from the group consisting of (1) compounds having the formula:

wherein X is selected from the group consisting of hydrogen, lower alkyl and halogen; Y is selected from the group consisting of hydrogen,

I i i i iR, -iJOR, CNH2 and CNHCR wherein R is selected from the group consisting of alkyl and aryl; and Z is selected from the group consisting of hydrogen and aralkyl; (2) compounds having the formula:

CH2ON X1 Zr wherein X is a lower alkoxy group; Y is selected from the group consisting of hydrogen,

i i C R1 and COR1 wherein R is selected from the group consisting of alkyl and aryl; and Z is an aralkyl group; and (3) compounds having the formula:

CHzON wherein X is a trifiuoromethyl group; Y is selected from the group consisting of wherein X is selected from the group consisting of hydrogen and lower alkyl; Y is selected from the group consisting of hydrogen and 0 Jim wherein R is selected from the group consisting of alkyl and aryl; and Z is an aralkyl group.

When the above compounds are amines, that is, when Y, Y or Y is hydrogen, they may also be employed in the form of their physiologically acceptable salts such as the hydrohalides (preferably the hydrochloride), salts with other readily tolerated inorganic acids such as sulfuric or phosphoric acid, and salts with the commonly used organic acids such as acetic, citric, maleic, and tartaric acid.

For convenience sake, compounds having the aforedescribed chemical structures will be referred to hereinafter as aralkoxyamine compounds.

Examples of aralkoxyamine compouds which are the preferred active ingredients of the present invention are shown in Table A given hereinafter. Examples of different types of aralkoxyamine compounds useful as the active ingredients of this invention, including the preferred active ingredients of Table A, are given in Tables B to H given hereinafter.

As indicated hereinbefore, it has been found that the aralkoxyam-ine compounds used in accordance with this invention when taken internally have the effect of lowering the :blood cholesterol content, e.g., the amount of cholesterol in the blood of the warm blooded animal taking the active ingredients of the present invention. In forming the novel compositions of this invention, the active ingredient is incorporated in a suitable carrier such .as, for example, a pharmaceutical carrier, beverage or food-stuff. Any suitable pharmaceutical carrier may be used for formulating the compositions of this invention, such as, for example, starch, lactose, glucose, sucrose, gelatin, powdered licorice, powdered marshmallow, powdered tnagacanth, malt, rice flour, powdered althaea, magnesium carbonate, chalk, and the like. Among the liquid pharmaceutical carriers which may be utilized are ethyl alcohol, propylene gylcol, polyethylene glycol, water, saline, glycerine and water mixtures, glucose syrup, honey, mucilage of acacia, syrup of acacia, mucilage of t-ragacanth, glyceride of starch, etc. Also, the active ingredient may be incorporated in a foodstuff such, for example, as incorporating it in butter, margarine and the like. The preferred carrier fora given active ingredient depends upon the desired use and nature of the active ingredient. For example, a liquid active ingredient is prefer-ably administered in the form of a soft gelatin capsule containing a therapeutic dose of [the active ingredient. A crystalline solid active ingredient is prefer ably administered in the form of a capsule or tablet. When the composition of this invention is in the form of a solid, the active ingredient is generally in an amount from about 25 to 95% by weight of the solid composition. When the composition of this invention is in the form of a solution, the active ingredient is generally in an amount of from about 0.1 gram to 90* grams per 100 grams of solution.

An invivo technique which has been valuable in the determination of cholesterol lowering action of drugs is the procedure of Outhbertson et al., 1959 (British J. Nutrition, volume 13, page 227). Using the formulation given by these investigators, a stock diet (A) which is essentially normal rodent diet comparable to that available from commercial feed dealers, and a special high fat diet (B) are prepared. The B diet features 2% cholesterol; 0.5% cholic acid; and specially prepared hydrogenated arachis oil, 22%; also corn starch, 45.5%; crude casein, 25%; choline chloride, 1%; and salt and vitamin mixtures. The hydrogenated arachis oil specifies a 92 F. melting point with limits of 9093 F. Drugs to be evaluated are added to Diet B at fixed graded concentrations in the diet, ranging from 0.125 to 2%. Male Charles River albino weanling rats weighing approximately 50 grams are placed in individual cages equipped with specially designed self-feeder devices which permit accurate determination of daily food intake. Groups of six animals, kept in individual cages, receive each of the concentrations of drugs. In addition, a group of six on the stock diet (A) serves as a negative control, and a high fat diet (B) group of six serves as a positive control. The rats are placed on (the special diets for fourteen consecutive days, after which time one to three milliliter blood samples are obtained. by intraoardiac puncture, and subjected to assay for their cholesterol content. The animals serving as the negative control group (Diet A) maintain a cholesterol level in the normal range which is less than 100 mg./100 ml. of serum, whereas the positive control group (Diet B) show .a marked elevated level of the order of 800 mg./1-00 ml.

The active ingredients used in accordance with this invention, when incorporated in Diet B following the above described Cu'thbertson et a1. method, exhibit a cholesterol lowering activity. In general, when such active ingredients arein concentrations of about 0.25 to about 0.5% in Diet B, the percent reduction in the blood cholestterol level is about 25% or more as compared to the positive control ("Diet B) without the active ingredient. Thus, if a positive control group given Diet B shows a blood cholesterol level of about 800 m-g./ 100 ml., the active ingredients of this invention, if incorporated in such Diet B, in a concentration of about 0.25 to about 0.5 would generally reduce the blood cholesterol level of this positive group to about 600 mg./ 100 ml. or lower. Effective drugs usually show a direct relationship between the concentration of drug in the diet, and the percent reduction in the blood cholesterol levels as compared to the positive control (Diet B without drug).

While the laforede-scribed in vivo method of Cuth-bertson et al. is the preferred procedure for determining the eifioacy of an agent regarding its cholesterol lowering activity, the in vitro method based on the procedure described by N. L. R. Bucher in the Journal of the American Chemical Society, vol. 75, p. 498 (1953), has also been found useful for this purpose. This in vitro procedure employs radioactive techniques and measures the ability of a compound to inhibit the conversion of acetate or other cholesterol precursors to cholesterol using liver homogenate as a source of the enzyme system. Compounds which -are effective in preventing cholesterol formation under these conditions would presumably be effective in bringing about a lowering of the serum cholesterol content of the animal.

2 g. of liver from freshly killed Sprague-Dawley rats is homogenized at C. in a medium containing 8.5 mgm. nicotinamide, 3.5 mgm. magnesium chloride, 3.2 mgm. glutathione, and 3.0 mgm. ethylenediaminetetraacetic acid tetrasodium salt in 2.5 ml. of 0.1 M phosphate butter, pH 7.4. The homogenate is centrifuged at 0 and 2 ml. of the supernatant liquid, free from hepatic cells, is combined with 1 mgm. adenosine triphosphate, 1 mgm. diphosphopyridine mucleotide, 0.5 mgm. of the compound under test, and 1 m1. of sodium acetate l-C solution containing 0.2 mgm. of acetate with a count of about 2 microcuries of radioactivity. Controls are prepared in the same manner except that no compound is added. All compounds are run in triplicate.

The biosynthesis of cholesterol is effected by incubating the above mixture in a metabolic shaker for three hours at 37 C. under an oxygen-carbon dioxide mixture (9525). After three hours the mixture is transferred to a glass ampoule where it is subjected to saponification along with 0.5 mg. of carrier cholesterol using 6 ml. of 15% alcoholic potassium hydroxide at 80 C. for 17 hours. After removal of the alcohol the cholesterol is isolated by extracting four times with petroleum ether. The extracts are combined, dried, and evaporated to dryness. The residue is dissolved in 1 ml. of hot 80% ethanol and treated with an excess of 1% digitonin, also in 80% ethanol, and heated for 5 minutes at 100 C. After standing for 12 to 18 hrs. at 5 C., the cholesterol digitonide is separated on a paper filter disc, washed in succession with 85% ethanol, an acetone-ether mixture (1:2), and anhydrous ether. After drying, the precipitate is counted in a thin window gas flow Geiger Counter and the results recorded as counts per minute per mgm. cholesterol. Comparison with the control gives the index of inhibition. When the active ingredients of this invention are tested by the aforedescribed procedure, a significant inhibition of cholesterol biosynthesis is usually effected.

A number of compositions found to exhibit outstanding activity in lowering blood cholesterol levels, when tested by the in vivo procedure of Cuthbertson et a1. method described hereinbefore in detail, are shown in Table A. In each instance, the carrier was Diet B containing the active ingredient in the concentrations stated in the table. The activity (percent cholesterol lowering) was obtained in the manner described hereinbefore, i.e. determining the percent reduction in the blood cholesterol levels by incorporating the active ingredient in Diet B as compared to Diet B without the active ingredient.

TABLE A Percent reduction at concen- Oonlrpound Compound ttation of p-Chlorobenzyloxyamine 46 N -b lgnzyl-N -ben zyloxyamine hydroehlo- 68 n e. Benzyl N-benzyl carbethoxyhydrox- 77 amate. N -beuzyl-N-benzyloxy urea i Benzyl N -benzyl benzhydroxamate- 77 Benzyl N-benzyl acethydmxamate" 53 78 N (m-methylbenzyl)-N-(m-methyl- 69 -80 benzyloxy) amine. N-benzyl-N-(m-methylbenzyloxy) amine 81 N-(o-methylbenzyD-N-ben zyloxyamine. 74 N (o-methylbenzyl)-N- (o-methylben- 71 86 zyloxy) amine. N-(p-methoxybenzyD-(N-(p-methoxy- 43 benzyloxy) amino. 8 N- ('y-phenylpropyl)-N-henzyloxyami.ne 89 hydrochloride. 48 p-Chlorobenzyl N-p-ehlorobenzyl car- 80 bethoxyhydroxamate. 41 m-Mcthylbenzyl N-m-methylben zyl 76 73 carbethoxyhydroxamate. 33 Benzytl N-benzyl carbophcnoxyhydrox- 51 80 ama e. 39 o-Methylbenzyl N-o-methylbenzyl car- 56 61 bethoxyhydroxamate. 37 Benzyl N-m-methylbenzyl carbethoxy- 2 54 79 hydroxamate. 29 Benzy N-benzyl carbomethoxyhydrox- 65 78' ama e. 34- Benzyl N-benzyl carboOS-methoxyeth- 61 oxy) hydroxamate. 32 Benzyl N -benzyl carbo-n-hexyloxyhy- 68 droxamate. i

TAB LE A-C ontinued Percent reduction at concen- Benzyl N-benzyl isobntyrhydroxamate Benzyl N-benzyl propionhydroxamate Benzyl N -benzyl n-octanohydroxamate Bcnzyl N-o-methylbenzyl acethydroxamate.

N-loenzyl-N-(v-phenylpropoxymmine hydrochloride.

'y-Phenylpropyl N-benzyl carbethoxyhydroxamatc.

'y-Phenylpropyl N -'y-phenylpropyl carbethoxyhydroxamate.

m-Methylbenzyl N -benzyl n-heptanohydroxamate.

m-Methylbenzyl N-m-methylbenzyl acethydroxamate.

1 1% concentration. 1 0.125% concentration.

From the data shown in Table A, it is seen that the preferred active ingredients of this invention may be categorized as follows, reference being made to the general structural formulas given hereinbefore: I

(1) Those compounds wherein X is hydrogen, Y is O -iion and Z is aralkyl, as exemplified by the componds 30, 33, 37, 29, 34, 32, 36 and 52 shown in Table A;

(2) Those compounds wherein X is hydrogen, Y is ll OR and Z is aralkyl, as exemplified by the compounds 69, 68, 70, 74, 71 and 67 shown in Table A;

(3) Those compounds wherein X is a lower alkyl, Y is t JOOR and Z is aralkyl as exemplified by the compounds 41, 39, 43 and 44 shown in Table A;

(4) Those compounds wherein X is hydrogen, Y is hydrogen and Z is aralkyl as exemplified by the compoundsS, 6 and 8 of Table A;

(5) Those compounds wherein X is lower alkyl, Y is hydrogen and Z is aralkyl, as exemplified by compounds 12, and 11 shown in Table A;

(6) Those compounds wherein X is halogen, Y is and Z is aralkyl, as exemplified by compound 48 shown in Table A;

(7) Those compounds wherein X is hydrogen, Y is Ii --CNH2 and Z is aralkyl, as exemplified by compound 57 shown in Table A;

(8) Those compounds wherein X is halogen, Y is hydrogen and Z is hydrogen, as exemplified by compound 4 shown in Table A;

(9) Those compounds where in X is alkoxy, Y is hydrogen and Z is aralkyl as exemplified by compound 16 in Table A;

(10) Those compounds wherein X is alkoxy, Y is and Z is aralkyl as exemplified by compound 46 in Table (11) Those compounds wherein X is tnifluoromethyl, Y2 is it C 0 R and Z is aralkyl as exemplified by compound of Table A.

(12) Those compounds wherein X, is hydrogen, Y is and Z is aralkyl as exemplified by compounds 53 and in Table A;

(13) Those compounds wherein X is lower alkyl, Y is and Z is aralkyl as exemplified by compounds 73 and in Table A;

(14) Those compounds wherein X is hydrogen, Y is hydrogen and Z is aralkyl as exemplified by compound 18 in Table A.

The active ingredients used in accordance with this invention are non-toxic in amounts required to effect significant reduction of blood cholesterol. In general, the daily dose of .3 to 20 mg. per pound of subject, and, preferably, 1.3 to 6.6 mg. per pound of subject.

Of the preferred active ingredients, the first six compounds listed in Table A are previously described compounds, while' the remaining listed com-pounds are new compounds.

While a few of the active ingredients used in accordance with this invention are previously described compounds, e.g., N-benZyl-N-benzyloxyamine, for the most part, the active ingredients of this invention are novel compounds.

A class of novel compounds of the present invention may be defined as compounds selected from the group consisting of (1) compounds having the followin formula: V

wherein X is selected from the group consisting of lower alkyl and halogen, Y is selected from the group consisting of hydrogen,

it it it -CR, COR, ONH2 and o 0 II II CNHCR wherein R is selected from the group consisting of alkyl and 'aryl; and Z is selected from the group consisting of hydrogen and aralkyl; wherein when X in the above formula is halogen, Y is selected from the group consisting of hydrogen,

and

r 7 and only one of the Y and Z groups may be hydrogen; and (2) compounds having the formula:

QCHZON/ iOR-1 wherein R is selected from the group consisting of alkyl and aryl; and Z is an aralkyl group; and (3) compounds having the formula:

/Y @CLEEON X3 Z2 wherein X is a trifluoromethyl group, Y is selected from the group consisting of and -(OR5 wherein R is selected from the group consisting of alkyl and aryl, and Z is selected from the group consisting of hydrogen and aralkyl groups. An additional class of novel compounds of the present invention are compounds of the formula:

wherein X; is selected from the group consisting of hydrogen and lower alkyl; Y is selected from the group consisting of hydrogen and ii GOR3 wherein R is selected from the group consisting of alkyl and aryl; and Z is an aralkyl group.

In addition to the above-mentioned compounds, compounds which are novel and may be used as the active ingredient in "accordance with this invention are given in Table 1, given hereinafter, said compounds being also included in Tables B to H.

In preparing the novel aralkyl carbethoxyhydroxarnate compounds of this invention, hydroxyurethane is reacted with the appropriate aralkyl halide (e.g., parachlorobenzyl chloride) under the influence of alkali in alcoholic solution. By varying the molar ratio of the aralkyl halide to the hydroxyurethane employed one can obtain:

(1) The aralkyl carbethoxyhydroxama-te substantially exclusively, or

(2) a mixture of this compound and the corresponding aralkyl N-aralkyl carbethoxyhydroxamate substantially exclusively.

In general, an equimolar ratio of the reactants leads to the aralkyl carbothoxyhydroxamate compound while the use of a 2:1 molar ratio of the aralkyl halide to hydroxyurethane gives essentially the aralkyl N-aralkyl carbethoxyhydroxamate. Such latter procedure is preferred to produce carbethoxyhydroxarnate compounds which contain two identical aralkyl groups.

Alternately, novel aralkyl carboalkyl(aryl)oxyhydroxamates of this invention can be obtained by the reaction of an appropriate aralkoxyamine with an alkyl or aryl 8 chloroformate in a suitable inert organic solvent medium. Similarly, novel aralkyl N-aralkyl carboalkyl(aryl)oxyhydroxam-ates can be prepared from N-aralkyl aralkoxyamines and the appropriate chloroformate.

Moreover, novel aralkyl N-aralkyl carboalkyl(a-ryl)- oxyhydroxamates of this invention may be obtained by the reaction of the appropriate aralkyl carboalkyl(aryl)- oxyhyd'roxa-mate with a suitable aralkyl halide in alcoholic solution in the presence of alkali. Such reaction is operable in the production of carb-oalkyl(aryl)oxyhydroxamate compounds Which contain either identical or dissimilar aralkyl groups.

The aralkoxyamine compounds and the N-aralkyl aralkoxyamine compounds of this invention may be obtained by alkaline hydrolysis of the corresponding carbethoxyhydroxamate.

In preparing the novel aralkyl acyl(aroyl)hydroxamates and aralkyl N-aralkyl acyl(aroyl)hydroxamates of this invention, the selected aralkoxyamine or N-aralkyl aralkoxyamine is reacted with the appropriate acyla-ting or aroylating agent, such as acyl or aroyl halide, in a suitable aqueous or non-aqueous medium. An excess of the amine or other suitable base (e.g., pyridine, sodium hydroxide, trialkylamine) may be employed as acid acceptor to promote the reaction.

Substituted N-aralkoxy ureas or N-aralkyl-N-aralkoxy ureas can be obtained by the reaction of suitable aralkoxyamines or N-aralkyl aralkoxyamines with isocyanic acid esters or other derivatives of isocyanic acid in an inert solvent medium.

Some of the benzyl carboalkyl(aryl)oxyhydroxamates and benzyl N-aralkyl carboalkyl(-aryl)oxyhydroxamates comprising the active ingredients of this invention have also been referred to in the chemical literature as substituted N-benzyloxy urethanes and substituted N-benzyloxy-N-aralkyl urethanes. The description of these compounds are used herein is consistent with Beilstein and other recognized authorities on organic chemical nomenclature.

The following are specific examples for the preparation of active ingredient compounds and therapeutic compositions formed in accordance with this invention.

EXAMPLE I Preparation of o-chlorobenzyloxyamine hydrochloride (compound 1) A solution of 11.7 grams of o-chlorobenzyl carbethoxyhydroxamate and 6.2 grams of sodium hydroxide in 50% aqueous ethanol was refluxed for two hours. The ethanol was removed by distillation and the residue extracted with ether. This extract was washed with water and dried over sodium sulfate. The addition of concentrated hydrochloric acid resulted in the precipitation of the desired compound. Recrystallization from methanol gave 3.5 grams of the pure hydrochloride, M.P. 143-145". Other compounds prepared using this procedure were benzyloxyamine hydrochloride (compound 2); m-methylbenzyloxyamine (compound 3); and p-chlorobenzyloxyamine (compound 4). The latter two compounds were isolated as the free amines and were purified by distillation under reduced pressure. These components had the physical constants and analytical values tabulated in Table B given hereinafter.

EXAMPLE II Preparation of N-benzyloxyamine hydrochloride (compound 5) N-benzyl-N-benzyloxyamine is converted to its hydrochloride salt by the addition of an excess of concentrated hydrochloric acid to an ether solution of the amine. The product, which separates in the form of a slightly watersoluble crystalline solid, is purified by crystallization from methanol.

9 EXAMPLE III Preparation of N-(p-methylbenzyl)-N-(p-methylbenzylxy)amine (compound 13) A solution of 14.6 grams of p-methylbenzyl N-p-methylbenzyl carbethoxyhydroxamate prepared by the method described in Example VII and 6.8 grams of sodium hydroxide in 300ml. of 95% ethanol and 100 ml. of water was refluxed for one and one-half hours. The reaction mixture was then concentrated under vacuo and then poured into water. N-(p-methylbenzyl) N p-methylbenzyloxy)amine in the form of a water-insoluble material was filtered ofl, thoroughly washed with water, and then crystallized from methanol. Yield 8.3 grams, M.P. 860 C. N-(p-methylbenzyl)-N-(p methylbenzyloxy)amine is converted to its hydrochloride salt by the addition of an excess of concentrated hydrochloric acid to an ether solution of the amine. The product, which separates in the form of a slightly water-soluble crystalline solid, is purified by crystallization from methanol, M.P. 188-190" C.

EXAMPLE IV Preparation of N-(p-isopropylbenzyl)-N-(p-isopr0pylbenzyloxy)amine hydrogen sulfate (compound 14) A solution of 63 grams of p-isopropylbenzyl N-p-isopropylbenzyl carbethoxyhydroxamate prepared by the method of Example VII and grams of sodium hydroxide in 400 m1. of 50% aqueous ethanol was refluxed for two hours. The mixture was distilled at atmospheric pressure until the head temperature was 100 C. The residue was extracted with ether. This extract was washed with water until neutral and was dried over sodium sulfate. The resulting solution was added slowly to a cool solution of 17 grams of sulfuric acid in 200 ml. of anhydrous ether. The desired compound precipitated in the form of colorless crystals. The yields was 39 grams.

EXAMPLE V Preparation of N-(rn-methylbenzyl)-N-(m-methylbenxyloxy)amine (compound 12) EXAMPLE VI Preparation of N m-methylbenzyl -N -['y-( p-tolyl propoxy]amine (compound 20) (A) To a solution of sodium ethylate prepared from 23 grams of sodium metal and 1000 ml. of anhydrous ethanol there was added 105 grams of N-hydroxy urethane and 213 grams of 1-bromo-3-(p-tolyl)-propane and the mixture was refluxed for four hours. A major portion of the ethanol solvent was then removed by distillation at atmospheric pressure until the head temperature reached 86 C. To the cooled residue there was added 250 ml. of water and 250 ml. of ether, the ether layer was separated and-the aqueous layer was extracted with an additional 200 ml. of ether. The pooled ether extracts were washed with water until neutral and dried over sodium sulfate. The ether was removed and the residue distilled in vacuo. There was obtained 118 grams of 'y-(p-tolyDpropyl carbethoxyhydroxamate having the following physical properties: B.P. 155/0.3 mm., n 1.5060.

Analysis (for C H NO ).Calculated: C, 65.80; H, 8.07; N, 5.90. Found: C, 65.97; H, 8.14; N, 6.12.

(B) 35.1 grams of the above 'y-(p-tolyDpropyl carbethoxyhydroxamate was added to a solution of sodium ethylate prepared from 3.4 grams of sodium metal and 200 ml. of anhydrous ethanol. To the reaction mixture there was then added 27.4 grams of m-xylyl bromide and the mixture was refluxed for four hours. At the end of such period a solution of 12.8 grams of sodium hydroxide in 130ml. of water was added to the reaction mixture and refluxing was continued for an additional period of two hours. The ethanol was removed by distillation at atmospheric pressure until the head temperature reached 86 C. and the cooled residue was extracted with 500 ml. of ether. The ether extract was washed with water until neutral and dried over sodium sulfate. The ether was removed and the residue distilled in vacuo. The fraction boiling at about 142/ 0.08 mm. consisted of the desired N-(m-methylbenzyl)-N-['y-(p-to1yl)-propoxy] amine. The yield was 29.6 grams.

The physical properties and analytical values for the compounds prepared in Examples IIVI and of other compounds which can be prepared by substantially similar methods are summarized in Table C given hereafter.

EXAMPLE VII Preparation of p-chlorobenzyl N-p-chlorobenzyl car-bethoxyhydroxamate (compound 48) and p-chlorobenzyl car-betlzoxyhydroxamate (compound 27) 52.5'grams of hydroxyurethane in 500 ml. of ethanol are combined with stirring at 25 C. with a solution of 56 grams potassium hydroxide in ml. of 95% ethanol. 121 grams of p-chlorobenzyl chloride is added at once and the temperature maintained at about 30 using external cooling. The mixture is stirred overnight and the potassium chloride removed by filtration. The filtrate is concentrated in vacuo and dissolved in 400 ml. of ether. The ether solution is extracted thoroughly with cold 10% aqueous sodium hydroxide. The resulting ether solution is dried, the solvent removed and the residue distilled under reduced pressure. 45 grams (25% theoretical) of p-chlorobenzyl N-p-chlorobenzyl carbethoxyhyroxamate is obtained.

The aforedescribed sodium hydroxide extract is acidi-' fied with hydrochloric acid while cooling. The mixture is then extracted with ether, the ether solution dried, the solvent evaporated, and a solid residue obtained. This product is purified by crystallization from ethanol. 34.5 grams (30% theoretical) of p-chlorobenzyl carbethoxyhydroxamate is obtained in the form of white crystals.

EXAMPLE VIII Preparation of m-methylbenzyl carbethoxyhydroxama te (compound 26) and m-methylbenzyl N-m-methylbenzyl carbethoxyhydroxmate (compound 41) 38 grams of hydroxyurethane in ml. of 95% ethanol, 36 grams of potassium hydroxide in-200 ml. of 95% ethanol, and 100 grams of alpha-bromo-m-xylene were reacted as described in Example VII above. The ether extract was dried, freed from solvent by distillation, and the residue fractionated under reduced pressure. 17 grams (22%) of pure m-methylbenzyl carbethoxyhydroxamate was obtained distilling at 100-103 at'0.05 mm.

Further distillation of the aforedescribed residue yielded 38.5 grams (34%) of m-methylbenzyl N-m-methylbenzyl carbethoxyhydroxamate. B.P. 144146 at 0.05 mm. Hg.

EXAMPLE IX Using the method described in Example VII, hydroxyurethane and p-methylbenzyl chloride wererea'cted to give p-methylbenzyl N-p-methylbenzyl carbethoxyhydroxamate (compound 42). The purified product was obtained as a colorless liquid distilling at 137 at 0.1 mm. Hg.

1 1 EXAMPLE x EXAMPLE XI Preparation of m-trifluoromethylbenzyl carbethoxyhy droxamate (compound 28) A solution of sodium ethylate was prepared by dissolving 6.8 grams of sodium metal in 500 ml. of anhydrous ethanol. To this was added with cooling 31.2 grams of hydroxyurethane and subsequently with continued cooling 71 grams of m-trifluormethylbenzyl bromide. The temperature did not exceed 30 C. during these operations. The mixture was stirred for 30 minutes at room temperature and for two hours at reflux temperature. The mixture was diluted with 250 ml. of water and neutralized by the addition of hydrochloric acid. The ethanol was removed by distillation and the residue was extracted with ether. This extract was washed with dilute hydrochloric acid and with water and was dried over sodium sulfate. Evaporation of the ether furnished a solid residue which afforded, upon recrystallization from carbon tetrachloride, 38 grams of the pure compound, M.P. 78-80 C.

The m-trifluoromethylbenzylbromide used in this example as well as other benzylhalides can be prepared by halogenation of the corresponding benzyl alcohols or toluenes using well-known reactions. The physical constants and analytical values for the compounds of Examples VII-XI and for compounds 21- 23 and 25, which may be prepared using these methods, are summarized in Table D given hereinafter, and in part in Table E given hereinafter.

EXAMPLE XII Preparation of benzyl N-benzyl carbethoxyhydroxamate (compound 30) A solution of 210 grams of hydroxyurethane and of 460 ml. of benzyl chloride in 1 liter of ethanol was heated to reflux. One liter of a 4-N solution of potassium hydroxide in ethanol was added within four hours. Subsequently, 1.5 liters of ethanol was removed by dis tillation and the residue was diluted with 1 liter of ether. The solution was decanted from the inorganic salts which were washed with three portions of ether. The combined solution was stirred while 30 ml. of concentrated hydrochloric acid was added. The mixture was filtered and the filtrate was washed with dilute bicarbonate solution and water until neutral. The resulting ether solution was dried over sodium sulfate and the ether was removed by distillation. Fractionation of the residue in vacuo furnished 382 grams of the desired compound distilling at 142-145 C./0.3 mm.

EXAMPLE XIII Preparation of benzyl N-benzyl oarbophenoxyhydroxamate (compound 33) A solution of 42.6 grams of N-benzyl-N-benzyloxyamine in 100 ml. of anhydrous ether was added dropwise to a cooled solution of 15.7 grams of phenyl chloroformate in 500 ml. of anhydrous ether. The resulting mixture was stirred for three hours at room temperature. The solid precipitate was removed by filtration and the 12 filtrate was evaporated in vacuo. The residue solidified upon standing at room temperature. Recrystallization from methanol furnished 26.6 grams of the desired compound, M.P. 59-61 C.

EXAMPLE XIV Preparation of o-methylben-zyl N-o-methylbenzyl carbethoxyhydroxamate (compound 39) Solutions of 28.4 grams of hydroxyurethane in 150 ml. of ethanol and of 35.7 grams of potassium hydroxide in 250 ml. of ethanol were combined at room temperature. 100 grams of alpha-bromo-o-xylene was added dropwise with stirring while the temperature was maintained at 2530 C. by external cooling. Subsequently, the mixture was heated to reflux and the ethanol was removed by distillation until the vessel temperature had reached C. The residue was diluted with ether and was filtered from the inorganic salts. The resulting solution was washed with water and dried over sodium sulfate. The ether was removed by distillation and the residue was fractionated under vacuum. The fraction boiling at 143/ 0.04 consisted of the desired compound. Yield 59.4

grams.

EXAMPLE XV Preparation of benzyl N-m -methylbenzyl carbethoxyhydroxamate (compound 37) A solution of sodium ethylate was prepared from 2.3 grams of sodium metal and 200 ml. of anhydrous ethanol. To this was added 19.5 grams of benzyl carbethoxyhydroxamate and subsequently there was added with cooling and stirring 18.5 grams of alpha-bromo-m-xylene over a period of 15 minutes. The mixture was heated to reflux for two hours and the ethanol was removed by distillation until the vessel temperature reached 85 C. The residue was diluted with water and was extracted with ether. This extract was Washed with water and was dried over sodium sulfate. The ether was removed by distillation. Fractionation of the residue in vacuo furnished 18.3 grams of product, B.P. 136 C./0.02'mm.

EXAMPLE XVI Preparation of 'y-(p-tolyl)-pr0pyl-N-m-methylbenzyl carbophenoxyhydroxamate (compound 54) To a solution of 3.0 grams of pyridine and of 10.2 grams of N-(m-methylbenzyl-N-['y-(p-tolyD-propoxy] amine, prepared as described in Example VI, in ml. of anhydrous ether there was added, in three portions, 5.9 grams of phenyl chloroformate. The reaction temperature was maintained below 35 C. during the addition by external cooling means. The mixture was kept at room temperature overnight. To the mixture there was added ml. of ether and 75 ml. of water, the ether layer was separated and the aqueous layer was further extracted with 100 ml. of ether. The combined ether extracts were washed with 5% hydrochloric acid and then with Water until neutral. The ether solution was dried over sodium sulfate and the ether was removed in a rotary evaporator. The residue was heated under a pressure of 0.07 mm. until the temperature of the vapors reached 90 C. and then distilled in vacuo in a molecular distillation unit. There was obtained 10.5 grams of the desired product at a bath temperature of 159 C. and at a pressure of 0.001 mm.

EXAMPLE XVII 'y-Phenylpropyl-N-y-phenylpropyl carbethoxyhydroxamate (compound 55) temperature reached 85 C. The cooled residue was diluted with 200 ml. of water and the aqueous mixture was extracted with 500 ml. of ether. The ether extract was washed with small quantities of dilute sodium hydroxide solution until the color test with ferric chloride was negative, then washed with small quantities of water until neutral and dried over sodium sulfate. The ether solvent was removed and the oily residue distilled in vacuo. The fraction collected at 138 C./0.2 mm. consisted of 102 grams of Y-phenylpropyl carbethoxyhydroxamate, n 1.5070.

Analysis (for C H NO was as following.-Calculated: C, 64.55; H, 7.67; N, 6.27. Found: C, 64.37; H, 7.20; N, 6.46.

Continued distillation of the residue yielded 41 grams of 'y phenylpropyl N ('y phenylpropyl)carbethoxyhydroxamate, B.P. 182 C./.2 mm.

The physical constants of the compounds prepared in Examples XII-XVII, as well as those of other compounds which can be prepared by substantially similar methods, are summarized in Table E given hereinafter.

EXAMPLE XVIII Preparation of N-benzyloxy urea (compound 56) A solution of 4.5 grams of potassium cyanate in 50 I111. of water was added to a stirred slurry of 8.0 grams of benzyloxyamine hydrochloride in 150ml. of water. Stirring was continued for minutes and the colorless solid was filtered and washedwithwater. Recrystallization from ethanol furnished 4.9 grams of the desired product, M.P. 139-141 C.

EXAMPLE XIX Preparation of N-benzyl-N-benzyIoxy-N-acetyl urea (compound 59) Solutions of 21.3 grams of N-benzyl-N-benzyloxyamine in 300 ml. of anhydrous ether and of 8.5 grams of acetyl isocyanate in 200 ml. of anhydrous ether were combined at room temperature. The mixture was allowed to stand overnight and the ether was removed by distillation. The solid residue was extracted exhaustively with pentane. The extract yielded 22.4 grams of the desired compound, M.P. 6162 C.

The physical constants and analytical values for these compounds, and for compounds 57 and 58, prepared using the same methods, are tabulated in Table F given hereinafter.

EXAMPLE XX Preparation of benzyl acethydroxamate (compound 60) A solution of 31.7 grams of acetyl chloride in 50 ml. of anhydrous ether was added dropwise with stirring to a solution of 98.7 grams of benzyloxyamine in 400 ml. of anhydrous ether. The mixture was stirred for two hours at room temperature. The precipitate of benzyloxyamine hydrochloride was removed by filtration and was washed with ether. The combined filtrates were evaporated at atmospheric pressure and the residue was fractionated in vacuo. The fraction distilling at 109/0-.2 mm. consisted of the desired compound. Yield 42.4

grams.

Other compounds prepared by this method using the appropriate acid chloride were compounds 61-66. Analytical data and physical constants for these compounds appear in Table G given hereinafter.

EXAMPLE XXI Preparation of benzyl N-benzyl isobutyrhydroxamate (compound 69) A solution of 32 grams of N-benzyl-N-benzyloxyamine in 50 ml. of anhydrous ether was added with stirring and cooling to a solution of 8 grams of isobutyryl chloride in 150 ml. of anhydrous ether. The mixture was stirred for two hours and the precipitate was filtered and washed with ether. The combined filtrate was evaporated and 14 the residue was fractionated in vacuo. The fraction distilling at 133-136" C./0.1 mm. consisted of the desired compound. The yield was 14.6 grams.

EXAMPLE XXII Preparation of m-trifluoromethylben'zyl N'-m-triflu0romethylbenzyl acethydroxamate (compound '82) 1.10 parts of N-(rn-trifluoromethylbenzyl)-N-(m-trifluoromethylbenzyloxy)amine hydrochloride was dissolved in 25 parts of pyridine and 0.9 part of acetyl chloride was added with cooling. The mixture was kept overnight at room temperature and was poured into an excess of cold water. The oily precipitate was extracted with ether and the extract washed with dilute hydrochloric acid and water. The extract was dried over sodium sulfate and the solvent evaporated. The oily residue was distilledunder reduced pressure in a short path unit at C./0.002 mm. The distillate consisted of the pure title compound. The yield was 0.8 parts of pure product.

EXAMPLE XXIII Preparation of p-chlorobenzyl N-p-clzlorobenzyl berlzhydroxamate (compound 81) A mixture of 25.4 grams of N-(p-chlorobenzyD-N-(pchlorobenzyloxy) amine hydrochloride, 200 ml. of water, 14 ml. of 50% sodium hydroxide, 250 ml. of ether, and 12.3 grams of benzoyl chloride was stirred vigorously for two hours. The ether layer was separated and was washed with dilute sodium hydroxide, Water, dilute hydrochloric acid and again with water until neutral. The ether was dried over sodium sulfate and the solvent was removed by distillation. The residue solidified upon cooling. Recrystallization from ethanol furnished 22.5 grams of the desired compound.

The physical constants and analytical values for the compounds prepared in Examples XXL-XXIII, as well as those of other compounds prepared by substantially similfar methods, are summarized in Table E hereinafter set orth.

The following are examples of compositions formed in accordance with this invention which have the effect of lowering blood cholesterol upon administration 'of such compositions in warm-blooded animals.

EXAMPLE XXIV A tablet is compressed from a composition having the following formula:

EXAMPLE XXV Alta blet is compressed from a composition having the following formula:

N- (p methylbenzyl -N- (p-methylbenzyloxy) M gm.

amine hydrochloride 200 Corn starch 20 Lactose 20 Magnesium stearate 2 Alginic acid 4 EXAMPLE XXVI A tablet is compressed from a composition havingthe following formula:

Mgm. N-benzyl-N-benzyloxy urea 200 Corn starch 20 Lactose 20 Magnesium stearate 2 Alginic acid 4 1 EXAMPLE xxvtr A tablet is compressed from a composition having the following formula:

Mgm. p-Chlorobenzyl carbethoxyhydroxamate 200 Corn starch a 20 Lactose 20 Magnesium stearate 2 Alginic acid 4 EXAMPLE XXVIII 100 mg. of m-methylbenzyl N-m-methylbenzyl carbethoxyhydroxamate is mixed with 1.5 cc. of cottonseed oil and the resulting solution is encapsulated in a soft gelatin capsule.

EXAMPLE XXIX 200 mg. of benzyl N-benzyl carbethoxyhydroxarnate is mixed with 0.5 cc. of cottonseed oil and resulting solution is encapsulated in a soft gelatin capsule.

EXAMPLE XXX 200 mg. of N-benzyl-N-benzyloxyamine is mixed with an equal volume of polyethylene glycol 400 and the resulting solution is encapsulated in a soft gelatin capsule.

EXAMPLE XXXI 200 mg. of N-benzyl-N-benzyloxyamine hydrochloride is mixed with an equal volume of polyethylene glycol 400 and the resulting mixture is encapsulated in a soft gelatin capsule.

EXAMPLE XXXII 200 mg. of benzyl carbethoxyhydroxamate is mixed with an equal volume of polyethylene glycol 400 and the resulting solution is encapsulated in a soft gelatin capsule.

EXAMPLE XXXIII 200 mg. of m-rnethylbenzyl carbethoxyhydroxamate is mixed with an equal volume of propylene glycol and the resulting solution is encapsulated in a soft gelatin capsule.

EXAMPLE XXXIV 200 mg. of p-chlorobenzyl N-p-chlorobenzyl carbethoxyhydroxamate is mixed with 0.5 cc. of cottonseed oil and the resulting solution is encapsulated in a soft gelatin capsule.

' EXAMPLE XXXV 4 t 100 mg. of p-methylbenzyl N-p-methylbenzyl carbethoxyhydroxamate is mixed with 1.5 cc. of cottonseed oil and the resulting solution is encapsulated in a soft gelatin capsule.

EXAMPLE XXXVI A tablet is compressed from a composition having the following formula:

Mgm. Benzyl N-benzyl carbophenoxyhydroxamate, 360 Corn starch 20 Lactose 70 Magnesium stearate 40 Dicalcium phosphate 40 EXAMPLE XXXVII A tablet is compressed from a composition having the following formula:

1 6 EXAMPLE' XXXVIII A tablet is compressed from a composition having the following formula:

' Mgm. Benzyl N-benzyl acethydroxamate 400 Corn starch 25 Lactose i 25 Magnesium stearate '4 Alginic acid v 1O EXAMPLE XXXIX 250 mgm. of benzyl N-benzyl isobutyrhydroxamate is mixed with an equal weight of polyethylene glycol 400 and the resulting solution is encapsulated in a soft gelatin capsule.

EXAMPLE XL A tablet is compressed from a composition having the following formula:

I Mgm.

N- ('y-phenylpropyD-N benzyloxyamine hydrochloride 250 Corn starch 20 Lactose 70 Magnesium stearate 2 Dicalcium phosphate 50 EXAMPLE XLI 200 mgm. of N-benzyl-N-(m-methylbenzyloxy)amine is mixed with 0.25 cc. of corn oil and the resulting solution is encapsulated in a soft gelatin capsule.

EXAMPLE XLII 200 mgm. of p-chlorobenzyloxyamine is mixed with 0.25 cc. of corn oil and the resulting solution is encapsulated in a soft gelatin capsule.

EXAMPLE XLIII mgm. of p-methoxybenzyl N-p-methoxybenzyl' carbethoxyhydroxarnate is mixed with 0.5 cc. of corn oil and the resulting solution is encapsulated in a soft gelatin capsule.

EXAMPLE XLIV 300 mgm. of m-trifiuoromethylbenzyl N-m-trifiuoromethylbenzyl carbethoxyhydroxamate is mixed with an equal volume of propylene glycol and the resulting mixture is encapsulated in a soft gelatin capsule.

EXAMPLE XLV 200 mgm. 'of benzyl N-benzyl carbo(l3-methoxyethoxy) hydroxamate is mixed with 0.5 cc. of corn oil and the resulting solution is encapsulated in a soft gelatin capsule.

EXAMPLE XLVI 250 mgm. of p-isopropylbenzyl N-(p-isopropylbenzyl) carbethoxyhydroxamate is mixed with 0.5 cc. of corn oil and the resulting solution is encapsulated in a soft gelatin capsule.

EXAMPLE XLVII 200 mgm. of 'y-phenylpropyl N-(y-phenylpropyhcarbethoxyhydroxamate is mixed with 0.25 cc. of corn oil and the resulting solution is encapsulated in a soft gelatin capsule.

'Found ,s'rs

Analysis 1 Calculated A-ONH2 17 Tables B to I, mentioned hereinbefore,

TABLEHB Formula The following are now given TABLE H ll C-R X Z Analysis M.P., or n No. X A R Z Formula 13 .P./mm. Calculated Found 0 H N c 1 H N Benzyl C1aH11NO2 57-58 75. 27 6. 71 5. 49 75. 29 Q 7. 25 5. 61 do C11HmNOz.- 146/0. 1 1. 5535 75. 81 7. 11 5. 20 75. 87 7. 00 5. 41 do CrsH21NO2 136/0. 1 1. 5470 76. 29 7. 47 4. 94 76. 50 7. 45 5. 02 -do- O22II29NOZ 167/0. 2 1. 5306 78. 00 8. 63 4. 13 78.06 8. 53 4. 19 d0 C21I-ImNOz. 65-67 79.47 6. 04 4. 41 79. 22 6. 23 4. 59 .do. C17HmNO2 38-40 75. 81' 7. 11 5. 20 75. 86 '6. 99 5. 14 do C22H2uNO2 125/0. 01 1. 5308 p 78. 00 8. 63 4. 13 '77. 90 8. 62 4 19 o-Methylbenzyl Cl7Hl0NO2.--- 66-68 75. 81 7. 11 75. 33 7. 01 5. 31 m-Methylbenzyl- ClxI'IflNOz.-.. 125/0. 01 1. 5534 76. 29 7. 47 4. 94 76. 12 7. 66 o-Methylhenzyl- C2aH2sNO2 93-95 79. 97 6. 71 4. 06 79. 44 6. 60 4 28 d0 C2uH25NO2 147/0. 03 1. 5471 77. 13 8. 09 4. 50 76. 95 81 15' 4. 28 3,4dnnethylbenzyl..- C2oH25NOz 110/0. 01 1. 5554 77. 13 8. 09 4. 50 76. 81 7. 83 p-Methoxybenzyl Cz0H25NO4 150/0. 1 1. 5499 69.94 7. 34 4. 08 70. 11 7. 31 4. p-Ghlol'obenzyL CiaHrsClrNOz- 41-44 59. 28 4. 66 .21. 87 59. 14 4. 01 22. 19 d0 CzrHnClzNOz- 79-82 65. 4. 44 18. 65. 07 4. 56 18. 51 m-CF3-benzylomHumNon. 90/0. 02 1. 4845 55. 25 3. 86 3. 58 55. 19 3. 68 3. 'y-Phenylpropyl C2sH23NO2..- 130/0. 2 1. 5812 79. 97 6. 71 4. 06 79. 39 7. 16 4. 23

! Chlorine.

TAB LE I gen, lower alkyl and halogen; Y is selected from the group consisting of hydrogen, Compound Compound 30 (3 R, -o o R, --CNH N-(o-methylbenzyl)-N benzyloxylamine. d N-(B-phenethyl) -N-benzyloxyamine. an N-(v-phenylpropyl)-N-benzyloxyamine hydrochloride. p Benzyl earboisobutoxyhydroxamate. 3o

Benzyl carbomethoxyhydroxamate.

Benzyl carbo-n-butoxyhydroxarnate.

Benzyl earbophenoxyhydroxamate.

p-Chlzorobenzyl N-p-chlorobenzyl carbethoxyhydroxa ma e.

Benzyl N-benzyl carbophenoxyhydroxamate.

' Benzyl N-nl-methylbenzyl carbethoxyhydroxamate.

Benzyl N-benzyl carbomethoxyhydroxamate. Benzyl N-benzyl carbo (,B-rnethoxyethoxy) hydroxamate. Benzyl N-benzyl earboisobutoxyhydroxamate. Benzyl N-benzyl carbo-n-hexyloxyhydroxamate. Benzyl N-o-methylbenzyl carbethoxyhydroxamate. p-Chlorobenzyl N-p-chlorobenzyl carbomethoxyhydroxamate. p-Chlorobenzyl N-p-chlorobenzyl carbophenoxyhydroxamate. Benzyl N-B-phenethyl carbethoxyhydroxamate. Benzyl N -phenylpropyl carbethoxyhydroxamate. N-benzyl-N-benzyloigy-N{-aeetyl urea. N-b'enzyloxy N acetyl urea. Benzyl isobutyrhydroxamate.

Benzyl n-nonanohydroxamate.

Benzyl n-tetradeeanohydroxamate.

Benzyl n-hexadeeanohydroxamate.

Benzyl n-butyrhydroxamate.

Benzyl N-benzyl isobutyrhydroxamate.

Benzyl N-benzyl n-propionohydroxamate.

Benzyl N -benzy1 n-octanohydroxamate.

Benzyl N -o-rnethoxylbenzyl aeethydroxamato.

Benzyl N-( -phenylpropyl) benzhydroxamate.

formula:

wherein X is selected from the group consisting of hydro wherein R is selected from the group consisting of alkyl and phenyl; and Z is selected from the group consisting of hydrogen and phenyl short-chain alkyl; 2) compounds having the formula:

Q-ornor/ wherein X is lower 'alkoxy; Y is selected from the group consisting of hydrogen,

and

wherein X is trifiuorometliyl; Y is selected from the group consisting of and wherein R is selected from the group consisting of alkyl and phenyl; and Z is selected from the .group consisting of hydrogen and phenyl short-chain alkyl.

23 2. The method according to claim 1 wherein in the formula tor the active ingredient, X is hydrogen, Y is u -COR and Z is phenyl short-chain alkyl.

3. The method according to claim 1 wherein in the formula for the active ingredient, X is hydrogen, Y is v V Y.

ll CR and Z is phenyl short-chain alkyl.

4. The method according to claim 1 wherein in the formula for the active ingredient, X is lower alkyl, Y is 0 [I --COR and Z is phenyl short-chain alkyl.

5. The method according to claim 1 wherein in the formula for the active ingredient, X is hydrogen, Y is hydrogen, and Z is phenyl short-chain alkyl.

6. The method according to claim 1, wherein in the formula for the active ingredient, X is lower alkyl, Y is hydrogen and Z is phenyl short-chain alkyl.

7. The method according to claim 1, wherein in the formula for the active ingredient, X is halogen, Y is and Z is phenyl short-chain alkyl.

8. The method according to claim 1, wherein in the formula for the active ingredient, X is hydrogen, Y is and Z is phenyl short-chain alkyl.

9. The method according to claim 1, wherein in the formula for the active ingredient, X is halogen, Y is hydrogen and Z is hydrogen.

10. The method according to claim 1, wherein in the formula for the active ingredient, X is lower alkoxy, Y is hydrogen and Z is phenyl short-chain alkyl.

11. The method according to claim 1, wherein in the formula for the active ingredient, X is lower alkoxy, Y

i -COR1 and Z is phenyl short-chain alkyl.

12. The method according to claim 1, wherein in the formula for the active ingredient, X is trifluoromethyl, Y2 is i1OR 2 and Z is phenyl short-chain alkyl.

13. The method according to claim 1, wherein the active ingredient is selected from the group consisting of: p-chlorobenzyloxyamine, N-benzyl-N-benzyloxyamine hydrochloride, benzyl N-benzyl carbethoxyhydroxamate, N- benzyl-N-benzyloxy urea, benzyl N-benzyl benzhydroxamate, benzyl N-benzyl acethydroxamate, N-(m-methyL gbenzyl) -N-'(m-rrrethylbenzyloxy) amine, N #benzyl-N- (mmethylbenzyloxy) amine, N-(o-methylbenzyl) -N-benzyloxyamine, N-(o-methylbenzyl)-N-(o-methylbenzyloxyamine hydrochloride, N-(p-methoxybenzyl)-N-(p-methoxybenzyloxy) amine, N-(v-phenylpropyl) -N-benzyloxyamine hydrochloride, pachlorobenzyl N-p-rC'hlOI'ObGIIZYl carbethoxyhydroxamate, m-methylbenzyl Nm-methylbenzyl carbethoxyhydroxamate, benzyl N-benzyl carbophenoxyhydroxarnate, o-methylbenzyl N-o-methylbenzyl carbethoxyhydroxamate, benzyl N-m-methylbenzyl carbethoxyhydroxamate, benzyl N-benzyl carbomethoxyhyd-roxamate, benzyl N-benzyl carbo (B-methoxyethoxy) hydroxamate, benzyl N-benzyl carbo-n-hexyloxyhydroxamate, benzyl N o methylbenzylcarbethoxyhydrox- 24 amate, o-ethylbenzyl N-o-ethylbenzyl carbethoxyhyd-roxamate, p-isopropylbenzyl N-p-isopropylbenzyl carbethoxyhydroxamate, m-trifluoromethylbenzyl N-rn-trifluoromethylbenzyl carbethoxy hydroxamate, p-methoxybenzyl N- p-methoxybenzyl carbethoxyhydroxamate, benzyl N-yphenylpropyl carbethoxyhydroxamate, benzyl N-benzyl isobutyrhydroxamate, benzyl N-benzyl propionhydroxamate, benzyl N-benzyl n-octanohydroxamate, and benzyl N-o-methylbenzyl acethydroxamate.

14. A method of reducing the blood cholesterol content of a warm-blooded animal having excess cholesterol which comprises administering internally to said animal, in an amount sufficient to effect significant lowering of the blood cholesterol content of said animal a compound of the formula:

@ornornornor wherein X is selected firom the group consisting of hydrogen and lower alkyl; Y is selected from the group consisting of hydrogen and OOR,

wherein R is selected from the group consisting of alkyl and phenyl; and Z is phenyl short-chain alkyl.

15. The method according to claim 14 wherein in the formula for the active ingredient, X is hydrogen, Y is i C 0 R3 and Z is phenyl short-chain alkyl.

16. The method according to claim 14 wherein in the formula for the active ingredient, X is hydrogen, Y is hydrogen and Z is phenyl short'chain alkyl. 7

17. The method according to claim 14 wherein the ac tive ingredient is Nbenz yl-N-('y-phenylpropoxy) amine hydrochloride.

18. The method according to claim 14 wherein the active ingredient is 'y-p'henylpropyl N-benzyl carbethoxyhydroxamate.

19. The method according to claim 14 wherein the active ingredient is 'y-phenylpropyl N-y-phenylpropyl carbethoxyhydroxamate.

References Cited by the Examiner UNITED STATES PATENTS 2,695,913 11/ 1954 Bloch et a1. 260-471 2,816,059 12/1957 Mills 167-65 2,819,294 1/ 1958 Pechukas et al. 260-471 2,830,008 4/1958 Barber et al. 167-65 2,970,082 1/ 1961 Miale 167-65 I 2,978,381 4/ 1961 Freedman 167-65 OTHER REFERENCES JULIAN S. LEVITT, Primary Examiner.

FRANK CACCIAPAGLIA, JR., Examiner.

Claims (1)

1. A METHOD OF REDUCING THE BLOOD CHOLESTEROL CONTENT OF A WARM-BLOODED ANIMAL HAVING EXCESS CHOLESTEROL WHICH COMPRISES ADMINISTERING INTERNALLY TO SAID ANIMAL, IN AN AMOUNT SUFFICIENT TO EFFECT SIGNIFICANT LOWERING OF THE BLOOD CHOLESTEROL CONTENT OF SAID ANIMAL, A COMPOUND SELECTED FROM THE GROUP OF (1) COMPOUNDS HAVING THE FORMULA: