Blood Pressure

Method of reducing blood pressure with thiourea derivatives and guanidine derivatives

Blood Pressure Abstract
Antihypertensively active thiourea derivatives of the formulas ##STR1## wherein R, R.sub.1, R.sub.2, R.sub.3 and X are as hereinafter described, as well as a method of using a compound of the formula ##STR2## wherein R.sub.1 ', R.sub.2 ', R.sub.3 and X are as previously described, or a compound of formula II as an anti-hypertensive agent, is described.

Blood Pressure Claims
We claim:

1. A method of reducing blood pressure which comprises administering to a host requiring such treatment an effective amount of a compound of the formula ##STR16## wherein R.sub.1 ' and R.sub.2 ', independently, are hydrogen, halogen or lower alkyl; X is sulfur or imino; and R.sub.3 is amino or piperidino, provided that when X is sulfur, R.sub.3 is other than amino, or a compound of the formula ##STR17## wherein R is lower alkyl; R.sub.1 and R.sub.2, independently, are halogen; and R.sub.3 is amino or piperidino, or an addition salt thereof with a pharmaceutically acceptable acid.

2. In accordance with claim 1, a method of reducing blood pressure which comprises administering to a host requiring such treatment an effective amount of 1(2,6-dichlorophenyl)-3-[2-(1-piperidino)-ethyl]-2-thiourea.

3. In accordance with claim 1, a method of reducing blood pressure which comprises administering to a host requiring such treatment an effective amount of 1-(2-aminoethyl)-3-(2,6-dichlorophenyl)-guanidine.

4. In accordance with claim 1, a method of reducing blood pressure which comprises administering to a host requiring such treatment an effective amount of 1-(2-aminoethyl)-3-(2,6-dichlorophenyl)-2-methylthiopseudourea.

Blood Pressure Description
BRIEF SUMMARY OF THE INVENTION

Thiourea derivatives of the formulas ##STR3## wherein R is lower alkyl; R.sub.1 and R.sub.2, independently, are halogen; R.sub.3 is amino or piperidino; and X is sulfur or imino; and addition salts thereof with pharmaceutically acceptable acids, are described. The compounds of formulas I and II are useful as anti-hypertensive agents.

In another aspect, the invention relates to a method of treating hypertension which comprises administering to a host requiring such treatment an effective amount of a compound of the formula ##STR4## wherein R.sub.1 ' and R.sub.2 ', independently, are hydrogen, halogen or lower alkyl; X is sulfur or imino; and R.sub.3 is amino or piperidino, or a compound of formula II, or an addition salt thereof with a pharmaceutically acceptable acid.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the term "lower alkyl" denotes a straight or branched chain hydrocarbon of 1-7 carbon atoms, such as methyl, ethyl, propyl, butyl, isobutyl, pentyl, heptyl, and the like. The term "halogen" denotes fluorine, bromine and chlorine; chlorine is preferred. The term "lower alkanoyl" denotes a radical derived from an aliphatic carboxylic acid of 1 to 7 carbon atoms, for example, formyl, acetyl, propionyl, and the like.

The invention comprises compounds of the formulas ##STR5## wherein R is lower alkyl; R.sub.1 and R.sub.2, independently, are halogen; R.sub.3 is amino or piperidino; and X is sulfur or imino; and addition salts thereof with pharmaceutically acceptable acids.

Exemplary of the compounds of formulas I and II of the invention are:

1-(2-aminoethyl)-3-(2,6-dichlorophenyl)-thiourea;

1-(2-aminoethyl)-3-(2,6-dibromophenyl)-thiourea;

1-(2-aminoethyl)-3-(2,6-difluorophenyl)-thiourea;

1-(2-aminoethyl)-3-(2,6-dichlorophenyl)-2-methylthiopseudourea dihydrochloride;

1-(2,6-dichlorophenyl)-3-[2-(1-piperidino)ethyl]-2-thiourea;

1-(2-aminoethyl)-3-(2,6-dichlorophenyl)-guanidine; and the like.

The most preferred compound of the invention is 1-(2-aminoethyl)-3-(2,6-dichlorophenyl)-thiourea.

The compounds of the invention can be prepared as hereinafter described.

A compound of formula I wherein X is sulfur, can be prepared by treating the corresponding compound of the formula ##STR6## wherein R.sub.1 and R.sub.2 are as previously described, which is a known compound, with ammonium thiocyanate and benzoyl chloride, in an inert organic solvent, for example, acetone, a chlorinated hydrocarbon such as chloroform, methylene chloride or the like, preferably at the reflux temperature of the reaction mixture. The reaction product is treated with an alkali metal hydroxide, such as sodium hydroxide, to obtain a compound of the formula ##STR7## wherein R.sub.1 and R.sub.2 are as previously described.

Thereafter, a compound of formula V is converted to a compound of the formula ##STR8## wherein R.sub.1 and R.sub.2 are as previously described, according to known procedures, for example, by heating a compound of formula V at the reflux temperature of the reaction mixture in the presence of a solvent, for example, a halobenzene, such as chlorobenzene. Upon evaporation of the solvent and crystallization or distillation of the residue, a compound of formula VI is obtained.

Advantageously, a compound of formula IV can also be converted to a compound of formula VI directly by treatment with thiophosgene in a solvent, for example, a halobenzene such as chlorobenzene or the like, containing dimethylformamide, at the reflux temperature of the reaction mixture. Upon evaporation of the solvent and distillation of the residue, the desired compound of formula VI is obtained.

A compound of formula VI is converted to a compound of the formula ##STR9## wherein R.sub.1, R.sub.2 and R.sub.3 are as previously described, by treating a compound of formula VI with ethylenediamine or aminoethylpiperidine in an inert organic solvent, for example, benzene, tetrahydrofuran, an alkanol such as ethanol or the like, methylene chloride or the like, at room temperature or at the reflux temperature of the reaction mixture. The reaction product of formula Ia can be recovered either by crystallization or by suitable extraction, for example, with a halogenated hydrocarbon such as methylene chloride.

A compound of the formula ##STR10## wherein R, R.sub.1, R.sub.2 and R.sub.3 are as previously described, can be obtained by treating a compound of formula Ia with an alkyl halide such as iodomethane in the presence of an inorganic acid, for example, a hydrohalic acid, such as hydrochloric acid, in an organic solvent, for example, an alkanol such as methanol. Conveniently, the reaction is carried out at the refluxing temperature of the reaction mixture. The desired compound of formula II is recovered by basification of the reaction mixture, for example, with an alkali metal hydroxide such as sodium hydroxide or the like, and extraction with a solvent, for example, a halogenated hydrocarbon such as methylene chloride or the like.

A compound of formula I wherein X is imino, can be prepared by treating the corresponding compound of the formula ##STR11## wherein R, R.sub.1 and R.sub.2 are as previously described, with a lower alkanoyl ethylenediamine in an inert organic solvent, for example, an alkanol such as amyl alcohol, at a temperature in the range of from about 150.degree. to about 200.degree. C., to obtain a compound of the formula ##STR12## wherein R.sub.1 and R.sub.2 are as previously described, and R.sub.4 is alkanoyl.

The resulting compound of formula VIII can be separated, upon cooling of the reaction mixture, by partitioning the reaction mixture between an aqueous alkali metal hydroxide such as sodium hydroxide, and a halogenated hydrocarbon solvent such as methylene chloride, and recovering the desired compound from the halogenated hydrocarbon solvent.

A compound of formula VIII is deacylated by known procedures, for instance, by treatment with an inorganic acid, for example, a hydrohalic acid such as hydrochloric acid or the like, at the reflux temperature of the reaction mixture to obtain a compound of the formula ##STR13## wherein R.sub.1 and R.sub.2 are as previously described, and R.sub.3 ' is amino.

The desired compound of formula Ib can be recovered by evaporation and, if required, crystallization.

The compounds of formulas I and II above are basic compounds which form acid addition salts with inorganic or organic acids. Thus, they form pharmaceutically acceptable acid addition salts with both pharmaceutically acceptable organic and inorganic acids, such as, hydrohalides, e.g., hydrochloride, hydrobromide, other mineral acid salts, such as, sulfate, nitrate, phosphate and the like, alkyl and mono-aryl sulfonates, such as, ethanesulfonate, toluenesulfonate, benzenesulfonate, or the like, other organic acids such as formate, tartrate, maleate, citrate, benzoate, salicylate, ascorbate, or the like. Non-pharmaceutically acceptable acid addition salts of compounds of formulas I and II above can be converted into pharmaceutically acceptable acid addition salts via conventional metathetic reactions whereby the non-pharmaceutically acceptable anion is replaced by a pharmaceutically acceptable anion; or alternatively, by neutralizing the nonpharmaceutically acceptable acid addition salt and then reacting the so-obtained free base with a reagent yielding a pharmaceutically acceptable anion.

The present invention also relates to a method of reducing blood pressure by administering to a host, i.e., a warm-blooded animal requiring such treatment, an effective amount of a compound of the formula ##STR14## wherein R.sub.1 ' and R.sub.2 ', independently, are hydrogen, halogen or lower alkyl; X is sulfur or imino; and R.sub.3 is amino or piperidino, or an addition salt thereof with a pharmaceutically acceptable acid, or a compound of the formula ##STR15## wherein R is lower alkyl; R.sub.1 and R.sub.2, independently, are halogen; and R.sub.3 is amino or piperidino or an addition salt thereof with a pharmaceutically acceptable acid. The compounds of formula III, which are inclusive of the compounds of formula I, form acid addition salts with inorganic or organic acids, as described above, for the compounds of formulas I and II.

Exemplary of the compounds of formula III, other than the encompassed compounds of formula I, are 1-(2-aminoethyl)-3-(2,3-dichlorophenyl)-thiourea, 1-(2-aminoethyl)-3-(2-methyl-4-chlorophenyl)-thiourea, and the like.

The compounds of formula II and formula III, which includes the compounds of formula I, and salts thereof, possess hypotensive activity, that is, reduce the blood pressure in warm-blooded animals, and are therefore useful as antihypertensive agents in warm-blooded animals.

The anti-hypertensive activity of the compounds of the invention of formulas I and II, as well as those of formula III, which is inclusive of the compounds of formula I, can be demonstrated in either genetically or deoxycorticosterone acetate/sodium chloride fed hypertensive rats 12-15 weeks of age. For example, Doca-Na hypertension is induced in Charles River male rats weighing 170-210 grams by unilateral nephrectomy followed by subcutaneous implantation of a 25 mg. deoxycorticosterone acetate pellet. Animals are placed in individual cages and receive 0.9% sodium chloride solution and rat chow diet ad libitum. Two weeks are allowed to elapse from the time of surgery for development of hypertension, i.e., systolic blood pressure above 150 mm Hg. Systolic blood pressure is measured indirectly from the tail of unanesthetized rats (restrained in holders heated for 5-10 minutes at 37.degree.-38.degree. C.) using a pneumatic pulse transducer (piezo-electric crystal and occluding cuff). The transducer and occluding cuff are coupled to a two-channel recorder. Control readings are taken prior to drug and at 1, 3, 6 and 24 hours post-drug. All test compounds are prepared in acacia solution (5%) and are orally administered to the test animals.

When 1-(2-aminoethyl)-3-(2,6-dichlorophenyl)thiourea, which has demonstrated an LD.sub.50 of 750-775 mg/kg p.o. and LD.sub.50 of 450-550 mg/kg i.p. in the mouse, is utilized in the above test procedure at a dose of 10 mg/kg p.o., a decrease in the blood pressure of 73 mm/Hg and a decrease of 81 beats/minutes in the heart rate 6 hours after administration of the test substance are observed.

When 1-(2-aminoethyl)-3-(2,3-dichlorophenyl)thiourea, which has demonstrated an LD.sub.50 of >1000 mg/kg p.o. and LD.sub.50 of 450 mg/kg i.p. in the mouse, is utilized the above test procedure at a dose of 10 mg/kg p.o., a decrease in the blood pressure of 51 mm/Hg and a decrease of 95 beats/minutes in the heart rate 6 hours after administration of the test substance are observed.

The compounds of formulas I and II as well as the compounds of formula III, which is inclusive of the compounds of formula I, or salts thereof as herein described, can be incorporated into standard pharmaceutical dosage forms, for example, they are useful for oral or parenteral application with the usual pharmaceutical adjuvant material, for example, organic or inorganic inert carrier materials such as water, gelatin, lactose, starch, magnesium stearate, talc, vegetable oils, gums, polyalkylene-glycols, and the like. The pharmaceutical preparations can be employed in a solid form, for example, as tablets, troches, suppositories, capsules, or in liquid form, for example, as solutions, suspensions, or emulsions. Pharmaceutical adjuvant materials can be added and include preservatives, stabilizers, wetting or emulsifying agents, salts to change the osmotic pressure or to act as buffers. The pharmaceutical preparations can also contain other therapeutically active substances.

A suitable pharmaceutical dosage unit contains from about 0.1 to 5 mg. of a compound of formula I and II, as well as a compound of formula III, or an equivalent amount of a pharmaceutically acceptable acid addition salt thereof. Suitable oral dosage regimens in warm-blooded mammals comprise from about 0.1 mg/kg. per day to about 5 mg/kg. per day. Suitable parenteral dosage regimens in warm-blooded mammals comprise from about 0.05 mg/kg. per day to about 2.5 mg/kg. per day. However, for any particular subject, the specific dosage regimen should be adjusted according to individual need and the professional judgment of the person administering or supervising the administration of a compound of formula I or II, as well as a compound of formula III. It is to be understood that the dosages set forth herein are exemplary only and that they do not, to any extent, limit the scope or practice of this invention.

The compounds of formulas I and II, as well as the compounds of formula III, and their pharmaceutically acceptable acid addition salts, have effects qualitatively similar to those of catapress, known for its therapeutic uses and properties. Thus, the compounds of this invention demonstrate a pattern of activity associated with antihypertensive agents of known efficacy and safety.

The compounds of formulas I and II have central nervous system activity, including antidepressant activity. The antidepressant activity can be demonstrated in warm-blooded animals. For example, six mice are treated with the test compound. One hour later a ptosis-inducing dose of tetrabenazine (normally 150 mg/kg) is given intraperitoneally. Ptosis is read one hour after the tetrabenazine injection. The ED.sub.50 is the dose at which ptosis is prevented in 3/6 of the mice. The numbers of mice exhibiting ptosis are counted. The ED.sub.50 is calculated by the method of Behrens. Arch. Exp. Path. & Pharm. 140, 237 (1929).

When 1-(2-aminoethyl)-3-(2,6-dichlorophenyl)-thiourea is utilized as the test compound in the above procedure, it demonstrates an ED.sub.50 of 5.7 mg/kg.

The following Examples further illustrate the invention. All temperatures are in degrees Centigrade, unless otherwise stated.