IL33612A - Amidoxime o-carbamates,their preparation and their use as antihypertensive agents - Google Patents

Description

33612/2 Amidoxime O-carbamates their preparation and their use as antihypertensive agents Ε.Ϊ. ; DU PONT DE NEMOURS AND COMPANY C. 31896 33612/2 - 2 - This invention relates to a novel class of amidoxime O-carbamates useful as antihypertensive agents.

Amidoxime O-carbamate compounds have been known since the work of Tiemann and Kruger ^Ber. 17_ 1685 (1884)7· The authors erroneo sly reported the compounds shown in their article as being oximes of ureldes. R. Bryle, F. Eloy and R. Lanaers ^Telv. Chl . Act. 46, 1073 (19 317 later ; demonstrated that Tiemann and Kruger' s reaction actually leads to O-carbamates of amidoximes and reported on a series of such compounds which they prepared, < These prior art compounds are not known as being antihypertensive agents and differ structurally from the class of amidoxime-0- carbamates constituting the present invention.

Bell et al. 298 ( 196717 and Hoppe et al, ^Fed. Proc. 26, 459 (196717 ve reported certain indoleacetamidoximes as having antihypertensive / activity in rats and dogs. The amido O-carbamates of the present invention also differ structurally from these prior art compounds, being simpler and less costly to prepare.

This invention relates to (a j compounde^represented by the formula Ha . 0 . ¾ · · · ! - c » - 0 - c - N . · Β. ■■ ! ■ where . ■ . ■ · · \ ,....... ! R is an alkyl, alkenyl, alkynyl, alkylcycloalkyl or a- . saturated or unsaturated mono- or polycycloaliphatic'.hydrocarbon' radical having from 3 to 12 carbon atoms,' ^ and Rg are each hydrogen or lower alkyl of 1 to 3 carbon atoms \fith the proviso that the sum of oarbon atoms in ^ and Rg taken together does not exceed 3» and (b) the pharmaceutically acceptable salts of the componds of (a).

Another embodiment of the invention relates to a method for treating hypertension in warm-blooded animals (other than human beings) which comprises administering to said animal an antihypertensive amount of a compound of the invention Still another embodiment of the invention relates to pharmaceutical oo mpositions which contain a compound of the invention in combination with suitable pharmaceutical adjuvants and modifiers.

As indicated above, compounds of the invention include those of the formula 0 I c = N - 0 - c - \*2 wherein R, ^ and g have the same meaning as above, 53612/2 V 4 - It is also to be understood that pharmaceutically acceptable salts of the above defined compounds are included within the scope of this invention. Illustrative of such salts are the hydrochlorides, hydrobromldes, sulfates, phosphates, and nitrates.

Preferred compounds are those of the above formula hydrocarbon where R is an aliphatic or oycloaliphatic/group having at least 4 carbon atoms, is hydrogen and Eg is hydrogen or methyl and the pharmaceutically acceptable salts of such oompounds.

Illustrative of the compounds of this invention are the followin ί Butaneamidoxime-O-(N-ethylcarbamat©) 2-Methylpropaneamidoxime-O-oarbamate 2-Buteneamidoxime-0-( -methylcarbamate) Pentaneamidoxime-O-(H-methy carbama e) Pentaneamidoxime-O-(N,U-dime hylcarbamate) 2-MethylbutaneaniidQxime-0-carbamate 3-Methylbutaneamidoxime-0-(N-propylcarbamate) 3-Methyl-2-buteneamidoxime-0-carbaBi4e 2,2-Dimethylpropaneamidoxime-0-(N-methylcarbama e) Hexaneamidoxime-O-(H-isopropylcarbamate) ' 2-Methylpentaneamidoxim©-p-carbamat© e 3-Methylpentar)femidoxime-0-(N-methyl-N-ethylcarbamate) 4-Methylpentar)lmidoxime-0-(N-ethylca rbama te ) 4-Methyl-l-pentaqlmidoxime-O- (N-methylcarbama te) 2.2-Dimethylbutarj mldoxime-O-ca rbama te , 3-Dlmethylbutar^imidoxlme-0-(N-ethylcarbama te) 3 -Hex&r/amidoxime-O-ca rbama te e -Hexer^midoxime-0-carbamate e.

-Hexer)iamidoxime-0-ca rbama te Hepta^ midoxime-0- (N-prop lcarbama te ) ( ) Octar^amidoxime-O-ca rbama te 2-Methylheptaiamidoxime-0-(N-methylcarbama te ) e 2,2-Dimethylhexaiamidoxime-O-carbama te e 2} 3-Dimethylhexar)femldoxlme-0-(N-ethylearbama te) 2y 3,,4-Trimethyipentar^midoxime-O-ca rbama te 3-Octerjfemidoxlme-0-carbama te e 7-Octeiamidoxlme-0-(N,N-dimeth lcarbama te) e .

Nonar^midoxime-O- (N-methylca rbama te ) Nonai^amidoxime-0-(N,N-dimethylcarbama te) .e Nonarjfemidoxime-O-carbamate Dodecar^amidoxime-O- (N-methylcarbamate) e Tridecaiyamidoxime-O- (N-methylcarbama te ) 3- MGthylcyclopentylmethaiy/amidoxime-0-'Carbamate 4 2^∑iorbornylmeth i^a^^ 2- Korbornenyl-5-©xo~metha∑^idoxitoe^0^carbamte 2-Bicyclo[ 2,2, 2] octylniethai a doxlroe-O-oarbamate 2-Bicyclo [ 2.2 , 2 ] oct enyl«5^me tha araido ime-O- (li-etftylcar- bairiat© ) l,Bicyolo[2.2.2]ootylnetha kmiaox10e-0-oarbalnate l-i»Bicyclo[ 3 · .2 ]noriylmethai^idoxime-0-carbamate 4 , 7«Methanoin^l-5-exo-methai^amidoxime--0- ( il-methylcarbamate ) e, 2*Adamantylmetha9aaidoxime-0«(N-methylcarbajnate) 4~Methyl-l-bicycloL2.2,2] ootylraethan midO-Klme-0-carbama1ie e 1-Dec^ydronaphthylaetha araidoxlme-G-car amate e 2-Decahydrpnaphthylonethan^ doxime«i-0-(N-methyloarbaiiiate) 4-tyclohexyl-l-cyclohexylmethan^midoxime-O ) The amidoxlme O-carbamates of this invention can be prepared as discussed below.

Amidoximes are prepared readily according to . the general procedure of 3?. Tiemann, Ber. 17 126 (1884) which may be represented by equation (1) below: (1) m2 H-CN + HgNOH -~¾> R-C*NOH The unsubstituted amidoxlme O-carbaraates of the invention (where R^ « 2 * H) are conveniently prepared by reaction of the amidoximes Of equation (1) in salt form, such as the hydrochloride salt , with an alkali metal cyanate' as shown by equation (2) below: (2) m NH 0 . R-CteNOH · HX + HOCK —^ R-0« N-O-C-Mg * MX The reaction of equation (.2) is conducted in aqueous solution at a temperature; between about 0° to 50°G. The reaction is generally complete in 15 telnutes to three hours. Loiiger reaction times can be used but are not generally necessary.

The amidoxlme O-carbaraates of the invention wherein EL^ or 2 is alkyl are prepared by reacting amidoximes of equation (1) The reaction of equation (j5) is readily effected by stirring the amidoxime of equation (1) in a suitable solvent such as dioxan, tetrahydrofuran, ethyl acetate, chloroform, diethyl ether, benzene, or the like, while adding the isocyanate at a rate to maintain temperatures from 0 to 50°C. The reaction is generally complete in about 5 hours; however, some reactions are vigorous enough to be completed in about 0.5 hour. The products are sufficiently stable under reaction conditions that longer reaction times, e.g., up to 24 hours, do no harm and, for convenience, reaction periods lasting overnight can be used.

The amidoxime O-carbamates of the invention wherein both Ri and R≤ are alkyl, are prepared by reacting the amidoximes of equation (1) with a carbamoyl chloride according to equation (4) below: (4) NH2 Hs 0 Ri R-C=N0H + RiRs COCl base > R-C-NOC-N XR2 In equation (4), any carbamoyl halide can be used in place of carbamoyl chloride shown. For example, one can use the carbamoyl fluoride, bromide or iodide. Nevertheless, for a balance of economy and convenience, the carbamoyl chloride is generally preferred.

The use of a base is not essential but when used may be any convenient acid-accepting compound that will combine with the acid by-product of the reaction. Thus, one may use alkali metal, and alkaline earth metal oxides, hydroxides, carbonates and bicarbonates . Organic bases such as pyridine, quinoline, trialkylamines, and the like, are similarly useful.

The reaction of equation (4) is effected by adding the or the like. The reaction is conducted at a temperature between room temperature (i.e. about 25 °C.) and the solvent reflux temperature, for a period of time between about 15 minutes and hours. Longer times are generally not required, but do no harm.

The salts of the amidoxime O-carbamates of the invention can be prepared by treating a solution of the compound with the acid of the salt desired. The solvent can be selected to provide a system in which the salt formed is insoluble and therefore easily separated from the solution. Alternatively, a solvent system in which the end product salt is soluble can be employed and the solvent can be removed by evaporation.

In general, the salts of the amidoxime O-carbamates of the invention hydrolyze readily and thus are less desirable for use in formulating pharmaceutical compositions of the invention than the amidoxime O-carbamates per se.

The preparation of the compounds of this invention is illustrated but not limited by the following examples.

EXAMPLE 1 Nonanitmidoxime-O-Carbamate A saturated solution of J .24 g. (0.04 mole) of potassium cyanate was added to 8. 3 g. (0.04 mole) of nonan-amidoxime hydrochloride. The reaction was exothermic and, when the temperature reached 40°C, the mixture was chilled with an ice bath. After the exothermic reaction subsided, the mixture was stirred at room temperature for 2 hours, e filtered, and the resulting nonarjemidoxime O-carbamate recrystallized from ethanol-cyclohexane . Yield, 4.6 g., m.p., 76.5-77. °C EXAMPLE 2 e Nonaramidoxlme-O- (N-Methylca rbamate ) e To a solution of 5.44 g. (0.02 mole) of nonar/femide oxime in 50 ml. of dioxane is added 1.2 g. (0.02 mole) of methyl isocyanate. The initial reaction is slightly exothermic. The solution is stirred at room temperature for 5 hours j concentrated under vacuum, and the viscous oil is solidified by chilling' and rubbing with petroleum ether. This yields after recrystallization from benzene-hexane, 5.18 g. (70$) of a white solid melting at 55.56.5°C. Infrared absorption at 2.90, 5·09 (ΝΗ2), 5.75 |x(C=0) , and .98 (ΟΝ).

Anal. Calcd. for CuHgjNjOg: C, 7.66; H, 10.05; N, 18.

Found: C, 7.96; H, .10.08; N, 18.51.

EXAMPLES 5-I8 The procedure of Example 2 is substantially repeated for Examples 5-18 to give the products indicated in Table I below. The differences in conditions are noted in Table I along with characterizing data for the amidoxime O-carbamates of the formula NH2 0 II R - C = N - 0 - C - N X H TABLE I Example R Ri M.P.°C. 3 (CH3)2-CH-(CH2)2- -CH3 58.3-59.5 18 Ethanol-hexane 4 CH3-(CH2)e- -CH3 62.5-63.Ο 5 Cyclohexane CH3-(CH2)7- -C2H5 5I.O-52.O 5 Hexane 6 CH3-(CH2)10- -CH3 63.Ο-64.Ο 5 Benzene-pet. eth 7 CH3-(CH2)ii- -CH3 .5- .Ο 18 Ethyl acetate 8 CH3-(CH2)i5- -CH3 7 .Ο-75.Ο 5 Cyclohexane 9 Q-CH2- -CH3 IO8.O-IO8.5 .5 Benzene Q-CH2- -CH3 II2.O-II3.O 5 Benzene-cyclohex 11 VI -CHa I61.O-I63.O 5 Ethanol-cyclohexa 12 CH3(CH2)3- -CH3 59. -6I Ethanol-hexane -CH3 128.O-I28.5 5 Ethanol-cyclohexa TABLE I (Cont'd) Reac.

Example R Rl M.P. °C. 1 CH3-(CH2)a- -CH3 88.3-88.5 1.0 Cyclohexane boiz CH3-(CHa)3- -H 5O-52.5 2.0 Ethanol 16 CH3-(CHa)6- -H 88.8-9I 2.0 Benzene 17 CHa-(CH2)6- -C2H5 5O.5-5I.5 5.0 Hexane 18 -CH3 200-202 6.0 Cyclohexane benz EXAMPLE 19 Nonana^nldoxime-O- (Ν,Ν-dimethylcarbama te ) To a solution of 10.05 g. (0.06 mole) of nonan^ amidoxime and 6.0 g. (0.06 mole) of triethylamine in 150 ml. of chloroform is added dropwise 6.5 g. (0.06 mole) of dimethylcarbamyl chloride in 50 ml. of chloroform. The mixture is heated at reflux for J>0 minutes, cooled, filtered, washed with water and the nonan^midoxime 0-dimethylca rbamate crystallized in turn from benzene-petroleum ether and hexane. Yield, 8.15 g. ( 7$), m.p., 69.5-71°C Anal. Calcd. for CisHasNaOs: C, 59.27; H, 10.50 N, 17.28 Found: C, 59.60; H, 10.50; N, 17.12.

EXAMPLE 20 Pentanamidoxime-O- (N-methylcarbamate ) This Example illustrates preparation of the compound of Example 12 under slightly different conditions which provide a higher yield.

A. Pentariamidoxlme A solution of 4l g. of sodium carbonate in 200 ml. of water was added dropwise to a well-stirred mixture of 83 g. (1 mole) of valeronitrile, 100 g. (1.5 moles) of hydroxylamine hydrochloride, and 4l g. (Ο.78 mole) of sodium carbonate in 400 ml. of ethanol. The liquid mixture was heated at 55-65°C. for 24 hours, cooled, filtered, and the filter cake washed with ethanol. The combined filtrate and wash was evaporated on a rotary evaporator. The resultant oil containing some inorganic solid was taken up in 250 ml. of benzene, filtered, and the benzene evaporated to yield 76.5 g. of crude pentan midoxime.

B. Pentan6mldoxime-0- (N-Methyl Carbama e ) e, A solution of the pentanamidoxime of Part A (76. 5 g Ο.65 mole) was stirred in 300 ml. of benzene and cooled in an ice bath. A solution of 44 g. ( 0.77 mole) of methyl iso- cyanate in 200 ml. of benzene was added dropwise, following which the reaction mixture was stirred for 1 hour. The mixture was diluted with 125 ml. of cyclohexane and chilled to 10-15°C. The pentan^midoxime-0- (N-Methyl carbamate) precipitated as a white solid. This yielded 65 g. of product which, after crystallization from 25$ of cyclohexane-benzene, gave 54 g. of the carbamate, melting at 6l-63°C. An analytical sample was obtained by additional crystallization from carbon tetrachloride followed by two more crystallizations from 2 $ cyclohexane-benzene. This sample melted at 67.4-69.9°C.

Anal. Calcd. for CyH^N^Og: C, 48.54; H, 8.73; N, 24.26 ; 0, 18.48 Found: C, 48.55J H, 9 - 13; N, 24. 33; 0, 18.50.

The compounds of this invention can be administered in the treatment of hypertension according to the invention by any means that effects contact of the active ingredient compound with the site of action in the body of a warmblooded animal. For example, administration can be parenter¬ al^, i.e., sufecutaneously, intravenously, intramuscularly, or intraperitoneally . Alternatively or concurrently, administration can be by the oral route.

The dosage administered will be dependent upon the age, health and weight of the recipient, the extent of disease kind of concurrent treatment, if any, frequency of treatment and the nature of the effect desired. Generally, a daily dosage of active ingredient compound will be from. about 0.01 to 50 milligrams per kilogram of body weight. Ordinarily, from 0.05 to 40 and preferably 0.1 to 20 milligrams per kilogram per day in one or more applications per day is effective to obtain desired results. For the more potent compounds of the invention, e.g. pentan midoxime-0- (N-methyl carbamate), the daily dosage ranges are from about 0.01 to 20 mg. Ag. , preferably 0.05 to 10 mg. Ag. , and more preferably 0.1 to 5 mg. Ag.

The antihypertensive activity of the amidoxime 0-carbamates of the invention is evidenced by tests conducted in hypertensive rats and by further tests which show a blood pressure lowering action in normotensive dogs.

In a test involving rats, made hypertensive by repeated injections of desoxycorticosterone acetate (DOCA) according to the method described by Stanton and White /Erch. Intern. Pharmacodyn, 154, 551 (1965.17, nonartamidoxime-O-(N-methylcarbamate) is injected intraperitoneally (i.p.) or orally into each of nine test animals on a cumulative dose schedule using three doees separated by a three-fold increment. The compound is prepared ±1 an aqueous polyvinyl alcohol acacia vehicle and administered at a volume to body weight ratio of 5.0 mlAg.

The first dose level is administered immediately after a control blood pressure reading, with the second and third levels following 2-hour and 4-hour blood pressure determinations, respectively. Systolic blood pressure is determined by a modification of the microphone-manometer technique /Friedman, M. and Freed, S.C., Proc. Soc. Exp. Biol, and Med. JO, 670 (1949)7.

It is determined as a result of the test that 6 mg. per kg. of the compound produces a >0 mm. mercury (mm. Hg. ) reduction in blood pressure from the pre-dose control value intraperitoneal Effective Dose JO). Other compounds of the invention tested in a similar manner also show a significant activity in reducing blood pressure. For example, in the same test procedure it is determined that the intraperitoneal Effective Dose -50 value (I. P. ED50) for nonai^emidoxime-O- ED^o value is 5j for pentanamidoxime-0-(N-Methyl carbamate) the oral EDjo value is 0.9, the I. P. ED^Q value is 2.1. :; :>e In a test involving dogs, nonanamidoxime-O- (limethylcarbamate) is . administered intravenously (i.v.) to four anesthetized normotensive dogs according to a cumulative dose schedule. Arterial blood pressure is recorded directly through an arterial cannula and a polygraph by which it is determined that the compound shows statistically significant blood pressure lowering in comparison to control animals.

The compounds of this Invention can be employed in useful pharmaceutical compositions according to the present invention in such dosage forms as tablets, capsules, powder packets or liquid solutions, suspensions or elixirs for oral administration or liquid for parenteral use, and in certain cases, suspensions for parenteral use (except intravenous injections). In such compositions, the active ingredient will ordinarily always be present in an amount of at least 0.5% by weight based on the total weight of the composition and not more than 90$ by weight.

Besides the active ingredient compound of this invention, the antihypertensive composition will contain a solid or liquid non-toxic pharmaceutical carrier for the active ingredient.

In one embodiment of a pharmaceutical composition of this invention, the solid carrier is a capsule which can be of the ordinary gelatin type. In the capsules will be from about 5 to 90% by weight of a compound of the invention and 95 to 10% of a carrier. In another embodiment, the active ingredient is tableted with or without adjuvants. In yet another embodiment, the active ingredient is put into powder packets and employed. These capsules, tablets and powders will generally constitute from about 1% to about 95% and preferably from 5% to 90% by weight of active ingredient.

These dosage forms preferably contain from about 5 to about 500 milligrams of active ingredient, with about J to about 250 most preferred.

The pharmaceutical carrier can, as previously indicated, be a sterile liquid such as water and oil, including those of petroleum, animal, vegetable oils of synthetic origin, for example peanut oil, soybean oil, mineral oil, sesame oil and the like. In general, water saline, aqueous dextrose (glucose) and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are preferred liquid carriers, particularly for injectible solutions. Sterile injectible solutions such as saline will ordinarily contain from about 0. $ to 25% and preferably about 1 to 10$ by weight of the active ingredient.

As mentioned above, oral administration can be in a suitable suspension or syrup, in which the active ingredient ordinarily will constitute from about 0.7 to 10 and preferably about 1 to 5$, by weight. The pharmaceutical carrier in such composition can be a watery vehicle such as an aromatic water, a syrup or a pharmaceutical mucilage.

Suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" by E. W. Martin, a well known reference text in this field.

The following examples will further illustrate the preparation of pharmaceutical compositions of the invention.

EXAMPLE 21 A large number of unit capsules are prepared by filling standard two-piece hard gelatin capsules each with 250 milligrams of powdered nonar^midoxime-0-(N-methylcarbama te) , 110 milligrams of lactose, 32 milligrams of talc and δ milligrams of magnesium stearate.

EXAMPLE 22 6 - r, ,. , nonylmethane A mixture of/tricyclo 3.2.2.02 >^-£-ftO«e^midoxime- 0-(N,^-d%methylcarbamate) in soybean oil is prepared and injected by means of a positive displacement pump into gelatin to form soft gelatin capsules containing 35 milligrams of the active ingredient. The capsules are washed in petroleum ether and dried.

EXAMPLE 23 A large number of tablets are prepared by conventional procedures so that the dosage unit is 100 milligrams of active ingredient, 7 milligrams of ethyl cellulose, 0.2 milligrams of colloidal silicon dioxide, 7 milligrams of magnesium stearate, 11 milligrams of microcrystalline cellulose, 11 milligrams of cornstarch and 98.8 milligrams EXAMPLE 2k A parenteral composition suitable for administration by injection is prepared by stirring 1. 5$ by weight of propar¾midoxime-0-(N-methylcarbamate)hydrochloride in 10 by volume propylene glycol and water. The solution is sterilized by filtration.

EXAMPLE 25 An aqueous suspension is prepared for oral administration so that each 5 milliliters contain 50 milligrams of finely divided octana doxime-0-(N,N-dimethylcarbamate), 500 milligrams of acacia, 5 milligrams of sodium benzoate, 1.0 grams of sorbitol solution, U.S. P., 5 milligrams of sodium saccharin and 0. 025 milliliters of vanilla tincture.

EXAMPLE 26 A parenteral composition suitable for administration by injection is prepared by dissolving 1% by weight of pentan midoxime-0- (N-methyl carbamate) in sodium chloride injection U.S. P. XV and adjusting the pH of the solution to between 6 and 7· The solution is sterilized by filtration.

A wide variety of compositions coming within this invention can be prepared by substituting other compounds of this invention, including specifically but not limited to those compounds named hereinbefore, for the compounds named in Examples 21-26 above and substituting other suitable pharmaceutical carriers well known and described in the Martin text mentioned above. 33612/3

Claims (1)

1. Amidoxime of the general where is an alkylcycloalkyl or a saturated or unsaturated having from 3 to 12 carbon and are each hydrogen or lower alkyl of 1 to 3 carbon atoms with the proviso that the sum of carbon atoms and taken does not exceed and their pharmaceutically acceptable A compound of Claim 1 wherein contains at least 4 is hydrogen and is hydrogen or 22 therein R has the as in and is lower alkyl of 1 to 3 carbon Λ method of preparing acoordi characterized in that an amidoxime of the formul C NOH is reacted vith a carbamoyl halide of the formula wherein R has the same meaning as in Claim are lower alkyl of 1 to 3 carbon with the that the sum of carbon atoms and taken together does not exceed and X is For the Applicants insufficientOCRQuality