3,769,427 United States Patent Office Patented Oct. 30, 1973 2 Compounds known previously as vasoconstrictor agents, 3,769,427 and currently marketed as such, are methoxamine, PHARMACEUTICAL COMPOSITIONS AND ephedrine, epinephrine, oxymetazoline, phenylephrine, METHODS OF USNG SAME levartenenol, naphazoline and tuaminoheptane. John Lawrence Hughes and Robert Chung-Huan Liu, Kankakee, Ill., assignors to Armour Pharmaceutical While these compounds have been successful in pro Company, Chicago, Ill. viding the desired vasoconstrictive action, they have also No Drawing. Original application Oct. 1, 1970, Ser. No. been the cause of severe adverse reactions such as cardiac 77,343, now Patent No. 3,681,459. Divided and this arrhythmias and excessive elevation of blood pressure. application May 25, 1972, Ser. No. 257,042 Further, such compounds, when employed in topical nt. C. A61k 27/00 O formulations are known to cause stinging, burning, and U.S. C. 424. 326 7 Claims the sensation of intense dryness. The present invention is predicated upon the discovery of new pharmaceutical compositions containing aromatic ABSTRACT OF THE DISCLOSURE guanidine compounds and their corresponding non-toxic Aromatic guanidine compounds having the formula: 5 acid addition salts shown above, which possess remark N ably unexpected properties as vasoconstrictor agents and R NHCNE obtain vasoconstrictor activity without any significant changes in the cardiac rate of the host to whom such R -R agents are administered. Further, as will appear, the 20 compounds of this invention may be administered by Ra oral, parenteral and topical routes with but minimal effects on the cardiac rate of the host animal, including wherein: R is hydrogen; R2 is chloro, fluoro or bromo; al R is hydroxy, or alkyl having one to four carbon atoms; Accordingly, one of the prime objects of the present and R4 is hydrogen, chloro, bromo or fluoro and their 25 invention is to provide new pharmaceutical compositions salts are shown to be active as vasoconstrictor agents containing chemical compounds which have useful and create useful pharmaceutical preparations when de biologic activity. ployed with a pharmaceutically acceptable carrier for Another object of the present invention is to provide administration to a host, e.g., man, requiring vasocon new pharmaceutical compositions containing compounds strictive therapy. 30 which are useful as vasoconstrictor agents. A further object of the present invention is to provide This application is a divisional from U.S. patent ap new pharmaceutical compositions containing aromatic plication Ser. No. 77,343, filed Oct. 1, 1970 and now guanidine compounds which, per se, and in the form of U.S. Pat. No. 3,681,459, issued Aug. 1, 1972. the corresponding non-toxic acid addition salts, can be DESCRIPTION OF INVENTION 35 employed as vasoconstrictor agents and are free from significant effects on the cardiac rate of the host to whom This invention relates generally to chemical com it is administered. pounds and methods of using them to realize the benefits Still another object of the present invention is to pro of their biological properties and more particularly to a vide new pharmaceutical compositions containing aro class of novel aromatic guanidine compounds and their 40 matic guanidine compounds and methods of using them, corresponding non-toxic acid addition salts which possess which are useful pharmaceuticals in the treatment of hy vasoconstrictor properties and hence are useful as vaso potensive states, and as nasal and ocular decongestants. constrictor agents when formulated into pharmaceutical These and still further objects as shall hereinafter ap preparations. pear are fulfilled by the present invention in a remark The class of compounds embraced with the present 45 ably unobvious fashion as will be discerned from the invention are represented by the structural notation: following detailed description and examples of embodi N ments of this invention. The aromatic guanidine compounds of the present in R NECN: vention can be prepared by any of several procedures, 50 for example, the addition of hydrogen cyanamide to an R3 R aromatic amine (or its mineral acid addition salt). The guanidines may be converted to their acid addi- . 2 tion salts by reacting the selected guanidine with an ap wherein: R is hydrogen; R2 is chloro, fluoro or bromo; propriate mineral or organic acid such, for example, as R is hydroxy, or alkyl having one to four carbon atoms; 55 hydrochloric, sulfuric, nitric, hydrobromic, hydroiodic, and R4 is hydrogen, chloro, bromo or fluoro. All of the maleic, citric, acetic, tartaric, benzoic propionic, carbonic, aforesaid compounds and their non-toxic acid addition and like acids which are well known for their reaction to salts show biologic activity especially as vasoconstrictor form pharmaceutically acceptable salts and do not need agents. to be belabored here. Representative of compounds suitable for practice of 60 One suitable procedure for preparing the guanidines this invention are: 3'-chloro-4'-hydroxyphenylguanidine; comprises mixing the appropriate aromatic amine mineral 3' - fluoro - 4 - tolylguanidine and 3',5' - dibromo - 4'- acid addition salt (or the aromatic amine with one molar hydroxyphenylguanidine. Representative of the salts em equivalent of the appropriate mineral acid), aqueous bodied in this invention are: 3' - chloro - 4 - hydroxy 50% cyanamide solution and ethyl alcohol and then phenylguanidine hydrochloride; 3' - fluoro - 4 - tolyl 65 heating the mixture at reflux for 3 to 20 hours. For guanidine nitrate; and 3',5'-dibromo - 4 - hydroxyphenyl optimum yield the molar ratio of aromatic amine Salt, guanidine hydrochloride. cyanamide, and ethyl alcohol is 1.0:1.5:15 respectively. The term “vasoconstrictor agent,” as used herein, The products, i.e., the aromatic guanidine mineral acid means an agent which is useful in treatment to effect the 70 addition salts, are isolated from the reaction mixtures amelioration of congestive states of the eye and nose, and purified by recrystallization from an appropriate and in treatment of shock and other hypotensive states. solvent, i.e., water or aliphatic alcohols. When the acid 3,769,427 3 4. addition salt cannot be purified, it is converted to the The foregoing dosage forms are prepared by conven free base by the addition of an alkali hydroxide and tional procedures of mixing, granulating, compressing, purified by recrystallization from an appropriate solvent. suspending and/or dissolving, as is suitable to prepare Another satisfactory method comprises forming a mix the desired dosage form. ture of an appropriate 1-aryl-2-methyl-2-thiopseudourea The vascoconstriction of a host animal including man hydroiodide, an appropriate primary amine and ethyl which has a condition requiring such treatment is readily alcohol. The mixture is heated at reflux for 20 hours. For obtained by administering to the afflicted host an aromatic optimum yield the molar ratio of the thiopseudourea, guanidine or a pharmaceutically acceptable acid addition primary amine and ethyl alcohol was 1:3:15, respectively. salt thereof in an amount sufficient to alleviate the symp The products are isolated from their reaction mixtures O toms of the condition. The usual symptoms requiring treat and converted to hydrochloride salts for purification and ment are low blood pressure, ocular and nasal congestion, characterization. and the like. A guanidine compound, prepared by either of the fore The compound preferably is administered at the dosage going procedures, or by other suitable procedures, may level described above and preferably in a pharmaceutical be converted to its acid addition salt, e.g., hydrochloride 5 carrier. The dosage level and frequency of administra by the addition of the appropriate acid to the guanidine tion are to a certain extent subjective, attention being compound. given to the degree of vasoconstriction or decongestion, The guanidine compounds of this invention may be the case history, the reaction of the subject, and the like. employed as free bases or in the form of their nontoxic The daily dosage can be administered in one or more pharmaceutically acceptable salts. Thus, for example, 20 parts and the administration can be accomplished pan organic and inorganic acid addition salts may be em cavally or parenterally or topically. Administration for ployed, such as the salts of hydrochloric, sulfuric, nitric, the provision of systemic vasoconstriction is preferably phosphoric, citric, acetic, lactic, tartaric, Sulfamic, suc oral and is most conveniently accomplished by means of cinic, fumaric, maleic, ethanedisulfonic, hydrobromic, a tablet containing one of the active compounds and a benzoic and similar non-toxic acids. The salts may be 25 pharmaceutical carrier. For local vasoconstriction, that prepared by reacting the guanidine base with an excess is, eyes, nose, etc., topical administration is preferred. of acid in a suitable solvent, such as ethanol, acetone, We have obtained especially good results when ad water, or mixture thereof. The mixture is heated to effect ministering to the animal organism the following aromatic solution, and the salts crystallize on cooling. guanidines to obtain vasoconstriction therein. The guani The guanidines and their salts are administered in 30 dines so used are: 3'-chloro-4'-hydroxyphenylguanidine; therapeutically effective amounts to animals, including 3'-fluoro-4'-tolylguanidine and 3',5' - dibromo-4'-hydroxy man, and in appropriate ways. Thus, dosages of about 1 phenylguanidine. Representative of the salts embodied in milligram to 5 milligrams per kilogram of host body this invention are: 3'-chloro-4'-hydroxypehnylguanidine weight, may be provided to man by systemic administra hydrochloride; 3'-fluoro-4'-tolylguanidine nitrate; and 3, tion, e.g., orally or parenterally. The compounds may be 35 '-dibromo-4'-hydroxyphenylguanidine hydrochloride. administered systemically to animals other than man in The onset of activity after oral administration in the dosages of up to about 5 milligrams per kilogram of body animal organism is rapid, results being observed within weight. The foregoing and other dosage levels herein are one-half hour, and the activity is sustained. Thus, the ac based on the content of guanidine base. The compounds tivity levels remain high for two or more hours, and ac have excellent vasoconstriction, a low order of toxicity, 40 tivity persists over a 24-hour period. After topical or in and relatively few observed side effects. travenous administration the onset of action is rapid and In the preferred embodiments of the invention, an persists for one or more hours. aromatic guanidine or a salt thereof is administered in a The following examples are illustrative of the prepara pharmaceutical composition which includes the guanidine tion of the novel guanidines of the invention, new phar compound and a pharmaceutical carrier. The carrier is 45 maceutical compositions embodying said guanidine and a non-toxic pharmaceutical grade substance which may their non-toxic acid addition salts, the treatment of the be either solid or liquid. Suitable solid carriers include animal organism in accordance with the invention, and lactose, magnesium stearate, starch, sucrose, mannitol, the activities exhibited in such tratment. It is to be under sorbitol, cellulose powder, dicalcium phosphate, talc, stood that the invention is not limited to the examples or stearic acid, gelatin, agar pectin, acacia and the like. Suit 50 to the compounds, compositions, proportions, conditions, able liquid carriers include glycols, polyglycols, dimethyl and methods set forth therein, which are only illustrative. sulfoxide, peanut oil, olive oil, sesame oil, alcohols, water, Throughout the examples, the specific guanidines enum and the like. If desired, the carrier may include a time erated have been used to typify the entire class of com delay material such as glycerol monostearate, or glycerol pounds and compositions of the invention. di-stearate, alone or with a wax. 55 The composition preferably is provided in unit dosage EXAMPLE I form for accuracy and convenience in administration. 3'-chloro-4'-hydroxyphenylguanidine hydrochloride was Where appropriate, oral administration is effective and prepared from a mixture of 18.0 g. (0.1 mole) of 4-amino preferred, and dosage units suitable for oral administra 2-chloro-phenol hydrochloride, 12.6 g. of a 50% aqueous tion are provided. Examples of such dosage units employ 60 cyanamide solution (equivalent to 0.15 mole of cyan ing solid carriers include tablets, filled capsules, packets amide) and 100 ml. of ethyl alcohol. The mixture was and the like, and lozenges. The amount of solid carrier heated at reflux for 3 hours and the reaction mixture was per dosage unit may vary widely, preferably from about then cooled to 0° C. and 200 ml. of ether was added. The 25 milligrams to 5 grams. precipitated crude product was isolated from the reaction The guanidines and their salts may be compounded 65 mixture by filtration. The crude product was purified by with semi-solid and liquid carriers in solutions, suspen recrystallization from ethyl alcohol. The white crystalline sions, emulsions, ointments, suppositories and soft gelatin solid melted at 244-6° C. (dec.). The infrared spectrum capsules, for example. Such compositions may be ad was consistent with the assigned structure. ministered pancavally, i.e., via natural and artificial open Analysis.-Calcd. for CHgCl2NO (percent): C, 37.86; ings in the body, such as the mouth, the anus, the vagina, 70 H, 4.08; N, 18.93. Found (percent): C, 38.00; H, 4.18; the nares, and the stoma of colostomy patients, intra N, 19.25. venously or intramuscularly, employing the appropriate EXAMPLE II composition having a suitable concentration of active ingredient according to the desired route of administra 3'-fluoro-4-tolylguanidine nitrate was prepared by re tion. 75 fluxing for 20 hours a mixture of 12.5 grams (0.1 mole) 3,769,427 5 6 of 3-fluoro-4-methyl-aniline, 9.0 g. of concentrated nitric FORMULATION G acid (equivalent to 0.1 mole of HNO3), 12.6 g. of 50% Ingredient: Parts aqueous cyanamide solution (equivalent to 0.15 mole of Guanidine compound ------60-300 cyanamide), and 100 ml. of ehyl-alcohol. The mixture Tricalcium phosphate ------50-150 was evaporated to a thick residue. The residue was tri Corn starch ------10-50 turated with ether. After decanting the ether, the crude Acacia ------5-25 product was recrystallized from ethyl alcohol. The white Magnesium stearate ------as as or won a 1-5 crystalline product melted at 180-2 C. The infrared spec In each instance, the ingredients in the proportions trum was consistent with the assigned structure. indicated are milled to a uniform powder, sized, mixed Analysis.-Calcd. for CHFNO (percent): C, 41.74; 10 H, 4.81; F, 8.25; N, 24.34. Found (percent): C, 42.12; with binder and compressed into tablets. H, 4.82; F, 8.19;N, 24.57. EXAMPLE V Suppositories melting at about 60 F. and each having EXAMPLE III the following composition are produced by compound 3',5'-dibromo-4'-hydroxyphenyl guanidine hydrochlo 5 ing the ingredients in the relative proportions indicated ride was prepared by heating at reflux for 20 hours a and heating the ingredients to about 60 F. to effect a mixture of 26.7 g. (0.1 mole) of 3,5'-dibromo-4-hydroxy solution. The solution is then poured into cooled molds aniline, 10 g. of concentrated hydrochloric acid and 12.6 and allowed to cool and solidify. g. of a 50% aqueous cyanamide solution (equivalent to Ingredient: Amount 0.15 mole of cyanamide). The reaction mixture was 20 cooled for 5 hours at 0° C. and filtered and the collected Guanidine compound, mg. ------0.1-1.0 solid was purified by recrystallization from ethyl alcohol. Base of lactose, polyethylene glycol, poly The white crystalline product melted at 285 (dec.). The ethylene glycol 400, polyethylene glycol infrared spectrum was consistent with the assigned struc 4000, polysorbate 80 and glycerine, ture. 25 gaS ------1. Analysis.-Calcd, for CHBrCIN3O (percent): C, EXAMPLE VI 24.34; H, 2.33; Br, 46.27; Cl, 10.26; N, 12.16. Found A glosset for sublingual administration was prepared (percent): C, 24.59; H, 2.23; Br, 46.27; Cl, 10.26; N, using 60 to 300 mg. of guanidine compound disposed 12.11. in a rapidly disintegrating base formed of starch, lactose, EXAMPLE IV 30 sodium saccharin and talcum. The following are examples of several dosage forms useful for the practice of the present invention using EXAMPLE VII oral administration. The ingredietns of the following compositions were compounded to provide a solution suitable for intravenous FORMULATION A 35 administration. In each instance, the ingredients were Ingredient: Parts mixed and warmed to about 50-60° C. with stirring to Guanidine compound ------60-300 effect solution. The solution was then sterile filtered, Calcium carbonate ------moleans nea-- a--- 300 cooled to room temperature, and packaged in sterile Citric acid (anhydrous) ------290 40 vials. Magnesium ------129 FORMULATION H Ingredient: Amount FORMULATION B Guanidine compound, mg. ------10-500 Ingredient: Parts Sodium chloride, mg. ------890 Guanidine compound ------60-300 Water, g. ------99 Citric acid (anhydrous) ------1000 45 Sodium bicarbonate ------2000 FORMULATION I Monocalcium phosphate ------200 Ingredient: Amount FORMULATION C Guanidine compound, mg. ------10-500 Ingredient: Parts Glucose, g. ------5 Guanidine compound ------60-300 50 Water, g. ------95 Corn starch ------25-50 EXAMPLE VIE Lactose ------25-2000 The ingredients of the following compositions were Magnesium Stearate ------1-5 compounded to provide a solution suitable for intra FORMULATION ID 55 muscular and subcutaneous formulations administration. Ingredient: Parts In each instance, the ingredients were mixed and warmed Guanidine compound ------60-300 to 50-60° C. with stirring to effect solution. The solution Corn starch ------25-50 was then sterile filtered, cooled to room temperature, Lactose ------25-200 and packaged in sterile vials. Talc ------10-50 60 FORMULATION J Silica (powdered) ------0.1-2 Ingredient: Amount FORMULATION E Guanidine compound, mg. ------10-500 Ingredient: Parts 16% aqueous gelatin containing 0.5% phenol, g. ------100 Guanidine compound ------60-30 65 Lactose ------n - a-----a re- an as a 65-190 FORMULATION K Cellulose ------10-135 Ingredient: Amount Magnesium stearate ------0.1-5 Guanidine compound, mg. ------10-500 FORMULATION F Sodium chloride, g. ------890 Ingredient: Parts 70 Water, g. ------99 Guanidine compound ------60-300 FORMULATION L. Cellulose ------15-200 Ingredient: Amount Corn starch ------... 10-50 Guanidine compound, mg. ------10-500 Gelatin ------5-35 Glucose, g. ------5 Stearic acid ------15 Water, g. ------95 3,769,427 7 8 FORMULATION M TABLE EW Ingredient: Amount Activity rating for test compounds Guanidine compound, mg. ------10-500 10-90% aqueous polyethylene glycol 400, Dose (mg-fkg. i.v.) g. ------100 5 Test compound 0.0 0. 1.0 EXAMPLE X X-- 2 2 5 Y. O 3 5 Z------O 2 The guanidine compound is dispersed in a cream ve Naphazolin 3. 4. 4 hicle consisting of a water-miscible base of stearic acid, Phenylephrine------3. 5 5 propylene glycol, sorbitol monostearate and monooleate, Phenylpropanolamine------O 3 5 polyoxyethylene sorbitan monostearate with citric acid O and methyl and propyl parabens as preservatives. Con centration of the guanidine compound is 0.1 to 50 mg. EXAMPLE XII per gram of vehicle. An aqueous solution was prepared containing 3',5'- Alternately, the guanidine compound may be dispersed 5 dibromo-4-hydroxyphenylguanidine hydrochloride and in corn oil, sesame oil, cotton seed oil, peanut oil, or suitable for use with the nose and eyes to effect decon polyethylene glycols with the addition of appropriate gestion of the mucus membranes of these organs. The preservatives. solution was stable, physiologically isotonic and had a EXAMPLE X pH in the range of 6 to 7. The vasoconstrictor properties of several representative The formulation is shown below. The sodium phos compounds of this invention were determined pharma phate salts comprise a buffer system to maintain the cologically using accepted methodology. The heart rate pH at about 6.5 and sodium bisulfite is used as an anti changes in anesthetized dogs who received an intravenous oxidant. Sodium chloride provides the desired isotonicity dosage of a guanidine compound as indicated. Through and thimersol as a preservative which protects the solu out the procedure, host blood pressure was monitored by 25 tion from bacterial and mold contamination. means of an indwelling arterial catheter connected to FORMULATION 'N' a pressure transducer, host heart rate was determined Ingredient: Wt. percent from the limb electrocardiogram, and cartoid arterial 3',5'-dibromo-4'-hydroxyphenylguanidine hy blood flow was continuously monitored with a flow probe 30 drochloride ------2.00 around the artery which probe was connected to an Monobasic sodium phosphate ------O.O electromagnetic flow meter. It will be noted that three Dibasic sodium phosphate ------O.2 standard vasoconstrictors, all current commercial prod Sodium bisulfite ------0.20 ucts, were also assayed in this manner and provide a Sodium chloride ------0.15 reference base. The test compounds are coded in Table I Merthiolate Sodium (Thimerosal) ------O.O. and the data is reported in subsequent tables below. Water ------97.42

TABLE From the foregoing, it becomes apparent that the in Test vention herein described and illustrated fulfills all of our compound A. objectives, express and implied, in a remarkably unex code Chemical name pected fashion and that we have developed new and useful X------3'-chloro-4-hydroxyphenylguanidine hydrochloride. compounds, pharmaceutical compositions and therapeutic Y------3'-fluoro-4'-tolylguanidine nitrate. Z------3',5'-dibromo-4-hydroxyphenylguanidine hydrochloride. methods for providing vasoconstriction in hosts requiring such therapy. 45 What is claimed is: TABLE 1. A composition useful as a vasoconstrictor agent Heart rate changes in anesthetized dogs when administered to a host requiring vasoconstrictive Dose (ngikg. i.v.) therapy consisting of a pharmaceutical carrier and a vaso Test compound 0.01 0. .0 constrictively active amount of a guanidine compound or 50 a non-toxic acid addition salt thereof, said compound hav ing the formula: Naphazoline.-- Phenylephrin Phenylpropanolamine--- N. NoTE-Rating scale: = Decrease in heart rate; 0- No change in 55 R NHCNH heart rate; --=Increase in heart rate.

EXAMPLE XI Additional data was obtained for each representative Ra compound by measuring the rise in mean arterial blood 60 pressure after intravenous administration to an anes wherein: R1 is hydrogen; R2 is chloro, fluoro or bromo; thetized dog. R3 is hydroxy or methyl; and R4 is hydrogen, chloro, bro The scale employed to evaluate the results is shown in mo or fluoro. Table III, and the test data is recorded in Table IV, using 2. The composition according to claim 1 wherein said the code for test compounds set forth in Table I of Ex 65 addition salt is 3'-chloro-4'-hydroxyphenylguanidine hy ample X. drochloride. TABLE II 3. The composition according to claim 1 wherein said Activity rating: Pressure rise in mm. Hg addition salt is 3'-fluoro-4'-tolylguanidine nitrate. 0 ------0-3 70 4. The composition according to claim 1 wherein said 1 ------4-10 addition salt is 3',5'-dibromo-4'-hydroxyphenylguanidine 2 ----- was waxa a ------essa - - - - -er-ser re- 11-25 hydrochloride. 3 ------26-50 5. The pharmaceutical composition according to claim 4 ------51-75 in a dosage unit form selected from the group consisting 5 ------>75 75 of tablets, filled capsules, packets, lozenges, glossets, sterile 3,769,427 9 10 solutions, suspensions, emulsions, ointments, and supposi- FOREIGN PATENTS tories.6. The method of treating a host requiring vasocon 603,070 6/1948 Great Britain ------260-565 striction comprising administering to said host an effec- OTHER REFERENCES tive amount of a composition according to claim to pro- 5 Chemical Abstracts (1947), vol. 41, 1626-1627. vide vasoconstriction in said host. Ozawa et al.: Pharm. Soc. of Japan, Journal, vol. 85, 7. The method of claim 6 wherein a dose of from about pp. 991-995 (1965). 1 mg. to about 5 mg. of guanidine compound per kilo gram of host body weight is administered. ALBERT T. MEYERS, Primary Examiner References Cited l0 N. A. DREZIN, Assistant Examiner UNITED STATES PATENTS U.S. C. X.R. 3,499,898 3/1970 Von Bebenberg ------260-565 424 -358