Pharmaceutical, compositions containing substituted 4'-hydroxyphenyl guanidines and methods of using same

DESCRIPTION OF INVENTION
This invention relates to generally novel chemical compounds and methods of using them to realize the benefits of their novel biological properties and more particularly to a class of novel aromatic guanidine compounds and their corresponding non-toxic acid addition salts which possess vasoconstrictor properties and hence are useful as vasoconstrictor agents.
The class of compounds embraced with the present invention and for which this patent is sought are represented by the structural notation: ##STR2## wherein: R.sub.1 is hydroxyl, methyl or hydroxymethyl and R.sub.2 is hydrogen or methyl. The non-toxic acid addition salts of the guanidine compounds are also biologically active. All of the aforesaid compounds and salts are active vasoconstrictor agents.
Representative of compounds suitable for practice of this invention are: 1-(3',4'-dihydroxyphenyl)-3-methylguanidine; 3',4'-dihydroxyphenylguanidine; 4'-hydroxy-3'-methylphenylguanidine; and 4'-hydroxy-3'-hydroxymethylphenylguanidine. Representative of the salts embodied in this invention are: 1-(3',4'-dihydroxyphenyl)-3-methylguanidine hydrochloride; 3',4'-dihydroxyphenylguanidine hydrochloride; 4'-hydroxy-3'-methylphenylguanidine sulfate; and 4'-hydroxy-3'-hydroxymethylphenylguanidine hydrochloride.
The term "vasoconstrictor agents", as used herein to define the utility of the new compounds of this invention, means those agents which are useful to effect the amelioration of congestive states of the eye and nose, and in treatment of shock and other hypotensive states.
Compounds known previously as vasoconstrictor agents, and the basis of current commercial efforts by the pharmaceutical industry are methoxamine, ephedrine, epinephrine, oxymetazoline, phenylephrine, levartenenol, naphazoline and tuaminoheptane.
While these compounds have been successful in providing the desired vasoconstrictive action, they have also been the cause of severe adverse reactions such as cardiac arrhythmias and excessive elevation of blood pressure. Further, such compounds, when employed in topical formulations are known to cause stinging, burning, and the sensation of intense dryness.
The present invention is predicated upon the discovery of new aromatic guanidine compounds and their corresponding non-toxic acid addition salts shown above, which possess remarkably unexpected properties as vasoconstrictor agents and obtain vasoconstrictor activity without any significant changes in the cardiac rate of the host to whom such agents are administered. Further, as will appear, the compounds of this invention may be administered by oral, parenteral and topical routes with but minimal effects on the cardiac rate of the host animal, including man.
Accordingly, one of the prime objects of the present invention is to provide new chemical compounds which have biological activity and are useful as vasoconstrictor agents.
A further object of the present invention is to provide new aromatic guanidine compounds which, per se, and in the form of the corresponding non-toxic acid addition salts can be employed as vasoconstrictor agents and are free from significant effects on the cardiac rate of the host to whom it is administered.
Still another object of the present invention is to provide new aromatic guanidine compounds and methods of using them which are useful pharmaceuticals in the treatment of hypotensive states, and as nasal and ocular decongestants.
These and still further objects as shall hereinafter appear are fulfilled by the present invention to a remarkably unobvious fashion as will be discerned from the following detailed description and examples of embodiments of this invention.
The aromatic guanidine compounds of the present invention can be prepared by any of several procedures, for example, the addition of hydrogen cyanamide to an aromatic amine (or its mineral acid addition salts); the reaction of a 1-aryl-2-methyl-2-thiopseudourea hydroiodide with ammonia or an alkyl amine and the like.
The guanidines may be converted to their acid addition salts by reacting the guanidine with an appropriate mineral or organic acid such, for example, as hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydroiodic acid, maleic acid, citric acid, acetic acid, tartaric acid, benzoic acid, propionic acid, carbonic acid, and like acids which are well known to form pharmaceutically acceptable salts so do not need to be belabored here.
One such procedure for preparing the guanidines comprises the mixture of the appropriate aromatic amine mineral acid addition salt (or the aromatic amine with one molar equivalent of the appropriate mineral acid), aqueous 50% cyanamide solution and ethyl aclohol which is then heated at reflux for 3 to 20 hours. For optimum yield the molar ratio of aromatic amine salt, cyanamide, and ethyl alcohol was 1.0:1.5:15 respectively. The products, i.e., the aromatic guanidine mineral acid addition salts, are isolated from the reaction mixtures and purified by recrystallization from an appropriate solvent, i.e., water or aliphatic alcohols. When the acid addition salt could not be purified it was converted to the free base by the addition of an alkali hydroxide and purified by recrystallization from an appropriate solvent.
Another satisfactory method comprises forming a mixture of an appropriate 1-aryl-2-methyl-2-thiopseudourea hydroiodide, an appropriate primary amine and ethyl alcohol. The mixture is heated at reflux for 20 hours. For optimum yield the molar ratio of the thiopseudourea, primary amine and ethyl alcohol was 1:3:15, respectively. The products are isolated from their reaction mixtures and converted to hydrochloride salts for purification and characterization.
Dihydroxy substituted guanidines are prepared by the method comprising the hydrogenolytic debenzylation, in the presence of palladium catalyst, of the corresponding 3',4'-dibenzyloxyphenylguanidine hydrochloride salts. The reaction procedure is accomplished by agitation of the solution of the benzyloxy compounds in ethyl alcohol in the presence of 5% palladium on powdered charcoal under a hydrogen pressure of 50 psi. The products, after removal of the catalyst, are purified by recrystallization from an appropriate aliphatic alcohol.
A guanidine compound, prepared by either of the foregoing procedures, or by other suitable procedures, may be converted to its acid addition salt, e.g., hydrochloride by the addition of the appropriate acid to the guanidine compound.
The guanidine compounds of this invention may be employed as free bases or in the form of their non-toxic pharmaceutically acceptable salts. Thus, for example, organic and inorganic acid addition salts may be employed, such as the salts of hydrochloric, sulfuric, nitric, phosphoric, citric, acetic, lactic, tartaric, sulfamic, succinic, fumaric, maleic, ethanedisulfonic, hydrobromic, benzoic and similar non-toxic acids. The salts may be prepared by reacting the guanidine base with an excess of acid in a suitable solvent, such as ethanol, acetone, water, or mixture thereof. The mixture is heated to effect solution, and the salts crystallize on cooling.
The guanidines and their salts are administered in therapeutically effective amounts to animals, including man, and in appropriate ways. Thus, dosages of about 1 milligram to 5 milligrams per kilogram of host body weight, may be provided to man by systemic administration, e.g., orally or parenterally. The compounds may be administered systemically to animals other than man in dosages of up to about 5 milligrams per kilogram of body weight. The foregoing and other dosage levels herein are based on the content of guanidine base. The compounds have excellant vasoconstriction, a low order of toxicity, and relatively few observed side effects.
In the preferred embodiments of the invention, an aromatic guanidine or a salt thereof is administered in a pharmaceutical composition which includes the guanidine compound and a pharmaceutical carrier. The carrier is a non-toxic pharmaceutical grade substance, which may be either solid or liquid. Suitable solid carriers include lactose, magnesium stearate, starch, sucrose, mannitol, sorbitol, cellulose powder, dicalcium phosphate, talc, stearic acid, gelatin, agar pectin, acacia and the like. Suitable liquid carriers include glycols, polyglycols, dimethylsulfoxide, peanut oil, olive oil, seseame oil, alcohols, water, and the like. If desired, the carrier may include a time delay material such as glycerol monostearate, or glycerol di-stearate, alone or with a wax.
The composition preferably is provided in unit dosage form for accuracy and convenience in administration. Where appropriate, oral administration is effective and preferred, and dosage units suitable for oral administration are provided. Examples of such dosage units employing solid carriers include tablets, filled capsules, packets and the like, and lozenges. The amount of solid carrier per dosage unit may vary widely, preferably from about 25 milligrams to 5 gram.
The guanidines and their salts may be compounded with semi-solid and liquid carriers in solutions, suspensions, emulsions, ointments, suppositories and soft gelatin capsules, for example. Such compositions may be administered pancavally, i.e., via natural and artificial openings in the body, such as the mouth, the anus, the vagina, the nares, and the stoma of colostomy patients, intravenously or intramuscularly, employing the appropriate composition having a suitable concentration of active ingredient according to the desired route of administration.
The foregoing dosage forms are prepared by conventional procedures of mixing, granulating, compressing, suspending and/or dissolving, as is suitable to prepare the desired dosage form.
The vasoconstriction of a host animal, including man, which has a condition requiring such treatment is readily obtained by administering to the afflicted host an aromatic guanidine or a pharmaceutically acceptable acid addition salt thereof in an amount sufficient to alleviate the symptoms of the condition. The usual symptoms requiring treatment are low blood pressure, ocular and nasal congestion, and the like.
The compound preferably is administered at the dosage level described above and preferably in a pharmaceutical carrier. The dosage level and frequency of administration are to a certain extent subjective, attention being given to the degree of vasoconstriction or decongestion, the case history, the reaction of the subject, and the like.
The daily dosage can be administered in one or more parts and the administration can be accomplished pancavally or parenterally or topically. Administration for the provision of systemic vasoconstriction is preferably oral and is most conveniently accomplished by means of a tablet containing one of the active compounds and a pharmaceutical carrier. For local vasoconstriction, that is, eyes, nose, etc., topical administration is preferred.
We have obtained especially good results when administering to the animal organism the following aromatic guanidines to obtain vasoconstriction therein. The guanidines so used are: 1-(3',4'-dihydroxyphenyl)-3-methylguanidine; 3',4'-dihydroxyphenylguanidine; 4'-hydroxy-3'-methylphenylguanidine; 1-(3',4'-dihydroxyphenyl)-3-methylguanidine hydrochloride; 3',4'-dihydroxyphenylguanidine hydrochloride; 4'-hydroxy-3'-hydroxymethylphenylguanidine hydrochloride.
The onset of activity after oral administration in the animal organism is rapid, results being observed within one-half hour, and the activity is sustained. Thus, the activity levels remain high for two or more hours, and activity persists over a 24-hour period. After topical or intravenous administration the onset of action is rapid and persists for one or more hours.
Of the aromatic guanidines which may be employed to produce vasoconstriction or decongestion, those having meta and/or para substitution appear to provide most desirable results.

The following examples are illustrative of the preparation of the novel guanidines of the invention, new pharmaceutical compositions embodying said guanidines and their non-toxic acid addition salts, the treatment of the animal organism in accordance with the invention, and the activities exhibited in such treatment. It is to be understood that the invention is not limited to the examples or to the compounds, compositions, proportions, conditions, and methods set forth therein, which are only illustrative. Throughout the examples, the specific guanidines enumerated have been used to typify the entire class of compounds and compositions of the invention.
EXAMPLE I
1-(3',4'-Dibenzyloxyphenyl)-3-methylguanidine hydrochloride was prepared from a mixture of 60.6 gm (0.1 mole) of 1-(3,4-dibenzyloxyphenyl)-2-methyl- 2-thiopseudourea hydroiodide, 20 gm of aqueous 40 percent methylamine solution (equivalent to 0.65 mole of methylamine), and 250 ml of ethyl alcohol. The mixture was heated at reflux for 20 hours. The reaction mixture was then evaporated to dryness and the residue mixed with 250 ml of water and 40 ml of 10N sodium hydroxide solution. This mixture was extracted with 500 ml of benzene. The benzene extract was washed with 200 ml of water and the benzene layer was evaporated to a viscous residue. This residue was next dissolved in 250 ml of acetone and a solution of hydrogen chloride in ether was added to precipitate the hydrochloride salt of 1-(3',4'-dibenzyloxyphenyl)-3-methylguanidine. This salt after collection and recyrstallization from acetone and ether (2:1 ratio) melted at 158.degree.-60.degree. C.
Analysis: Calcd. for C.sub.22 H.sub.24 ClN.sub.3 O.sub.2 : C, 66.40; H, 6,08; Cl, 8.91; N, 10.56. Found: C, 66.20; H, 6.12; Cl, 9.02; N, 10.76.
EXAMPLE II
1-(3',4'-Dihydroxyphenyl)-3-methylguanidine hydrochloride is prepared from a mixture of 28 gm (0.07 mole) of the 1-(3',4'-dibenzyloxyphenyl)-3-methylguanidine hydrochloride (prepared in Example I), 1.0 gm of 5 percent palladium on charcoal, and 250 ml of ethyl alcohol. The mixture was shaken under an initial hydrogen pressure of 50 psi and, after 4 hours of agitation, the reaction mixture was filtered and the filtrate evaporated to a thick residue which solidified after standing 2 hours. This solid was purified by recrystallization from a mixture of ethyl alcohol and ether (3:2 ratio). The resulting white crystalline solid melted at 185.degree.-8.degree. C and the infrared spectrum was consistent with the assigned structure.
Analysis: Calcd. for C.sub.8 H.sub.12 ClN.sub.3 O.sub.2 : C, 44.12; H, 5.56; Cl, 16.28; N, 19.30. Found: C, 44.07; H, 5.64; Cl, 16.50; N, 19.42.
EXAMPLE III
3',4'-dibenzyloxyphenylguanidine was prepared from a mixture of 34 gm (0.1 mole) of 3,4-dibenzyloxyaniline hydrochloride, 12.6 gm of a 50 percent aqueous cyanamide solution (equivalent to 0.15 mole of cyanamide) and 100 ml of ethyl alcohol. The mixture was heated at reflux for 20 hours. This reaction mixture was evaporated to a viscous residue. The residue was mixed with 300 ml of water and then the mixture made basic (pH about 10) by the addition of aqueous 10N sodium hydroxide solution. The mixture was cooled at 0.degree. C for 6 hours and the precipitated solid was collected on a filter. This solid was purified by consecutive recrystallization, first from aqueous 60% methyl alcohol and finally from benzene. The white crystalline solid melted at 138.degree.-9.degree. C. The infrared spectrum was consistent with the structure of the 3',4'-dibenzyloxyphenylguanidine.
Analysis: Calcd. for C.sub.21 H.sub.21 N.sub.3 O.sub.2 : C, 72.60; H, 6.09; N, 12.10. Found: C, 72,60; H, 6.24; N, 12.22.
EXAMPLE VI
3',4'-Dihydroxyphenylguanidine hydrochloride was prepared from a mixture of 24.4 gm (0.07 mole) of 3',4'-dibenzyloxyphenylguanidine, 6.9 gm of concentrated hydrochloric acid (equivalent to 0.07 mole hydrogen chloride), 250 ml of ethyl alcohol, and 10 gm of 5 percent palladium on charcoal. The mixture was shaken under an initial hydrogen pressure of 50 psi for 4 hours and then the reaction mixture was filtered and the filtrate evaporated to a thick residue. This residue was then dissolved in a 1:1 mixture of isopropyl alochol and cyclohexane. The solution was cooled at 0.degree. C for 24 hours. The precipitated solid, collected on a filter and dried, melted at 156.degree.-8.degree. C. The infrared spectrum was consistent with the assigned structure for 3',4'-dihyroxyphenylguanidine hydrochloride.
Analysis: Calcd. for C.sub.7 H.sub.10 ClN.sub.3 O.sub.2 : C, 41,29; H, 4.95; Cl, 17.41; N, 20.64. Found: C, 41,51; H, 4.99; Cl, 17.21; N, 20.68.
EXAMPLE V
4'-hydroxy-m-tolylguanidine sulfate was prepared from a mixture of 34.4 gm (0.1 mole) of 4-hydroxy-3-methylaniline sulfate, 12.6 gm of a 50 percent aqueous cyanamide solution (equivalent to 0.15 mole of cyanamide) and 100 ml of ethyl alcohol. The mixture was heated at reflux for 20 hours and the reaction mixture was cooled at 0.degree. C for 5 hours and filtered. The collected solid was purified by recrystallization from aqueous 75 percent ethyl alcohol. The white crystalline solid melted at 268.degree.-70.degree. C (dec.). The infrared spectrum was consistent with the assigned structure.
Analysis: Calcd. for C.sub.16 H.sub.24 N.sub.6 O.sub.6 S: C, 44.85; H, 5.65; N, 19.62; S, 7.48. Found: C, 44.95; H, 5.57; N, 19.61; S, 7.48.
EXAMPLE VI
4'-Hydroxy-3'-hydroxymethylphenylguanidine hydrochloride was prepared using the reaction procedure of Example III except 4-hydroxy-3-hydroxymethylaniline hydrochloride was used in place of the 3,4-dibenzyloxyaniline hydrochloride. The reaction mixture was evaporated to a viscous residue which was triturated with a 1:1 mixture of isopropyl alcohol and ethyl acetate. The residual solid was purified by recrystallization from a 1:1 mixture of isopropyl alcohol and ether. The purified yellow crystalline solid melted at 157.degree.-9.degree. C (dec.). The infrared spectrum was consistent with the assigned structure.
Analysis: Calcd. for C.sub.8 H.sub.12 ClN.sub.3 O.sub.2 : C, 44.15; H, 5.56; N, 19.31. Found: C, 44,12; H, 5.67; N, 19.10.
EXAMPLE VII
The following are examples of several dosage forms useful for the practice of the present invention using oral administration.
______________________________________FORMULATION "A"Ingredient Parts______________________________________Guanidine Compound 60 - 300Calcium Carbonate 300Citric Acid (Anhydrous) 290Magnesium Carbonate 129FORMULATION "B"Ingredient Parts______________________________________Guanidine Compound 60 - 300Citric Acid (Anhydrous) 1000Sodium Bicarbonate 2000Monocalcium Phosphate 200FORMULATION "C"Ingredient Parts______________________________________Guanidine Compound 60 - 300Corn Starch 25 - 50Lactose 25 - 2000Magnesium Stearate 1 - 5FORMULATION "D"Ingredient Parts______________________________________Guanidine Compound 60 60 300Corn Starch 25 - 50Lactose 25 - 200Talc 10 - 50Silica (Powdered) 0.1 - 2FORMULATION "E"Ingredient Parts______________________________________Guanidine Compound 60 .alpha. 30Lactose .gamma.- 190Cellulose 10 - 135Magnesium Stearate 0.1 - 5FORMULATION "F"Ingredient Parts______________________________________Guanidine Compound 60 - 300Cellulose 15 - 200Corn Starch 10 - 50Gelatin 5 - 35Stearic Acid 15FORMULATION "G"Ingredient Parts______________________________________Guanidine Compound 60 - 300Tricalcium Phosphate 50 - 150Corn Starch 10 - 50Acacia 5 - 25Magnesium Stearate 1 - 5______________________________________
In each instance, the ingredients in the proportions indicated are milled to a uniform powder, sized, mixed with binder and compressed into tablets.
EXAMPLE VII
Suppositories melting at about 60.degree. F and each having the following composition are produced by compounding the ingredients in the relative proportions indicated and heating the ingredients to about 60.degree. F to effect a solution. The solution is then poured into cooled molds and allowed to cool and solidify.
______________________________________Ingredient Amount______________________________________Guanidine Compound 0.1 to 1.0 mgBase of lactose, polyethyleneglycol, polyethylene glycol400, polyethylene glycol 4000,polysorbate 80 and glycerine 1 gram______________________________________
EXAMPLE IX
A glosset for sublingual administration was prepared using 60 to 300 mg of guanidine compound disposed in a rapidly disintegrating base formed of starch, lactose, sodium saccharin and talcum.
EXAMPLE X
The ingredients of the following compositions were compounded to provide a solution suitable for intravenous administration. In each instance, the ingredients were mixed and warmed to about 50.degree.-60.degree. C with stirring to effect solution. The solution was then sterile filtered, cooled to room temperature, and packaged in sterile vials.
______________________________________FORMULATION "H"Ingredient Amount______________________________________Guanidine Compound 10 - 500 mgSodium Chloride 890 mgWater 99 gFORMULATION "I"Ingredient Amount______________________________________Guanidine Compound 10 - 500 mgGlucose 5 gWater 95 g______________________________________
EXAMPLE XI
The ingredients of the following compositions were compounded to provide a solution suitable for intramuscular and subcutaneous formulations administration. In each instance, the ingredients were mixed and warmed to about 50.degree.-60.degree. C with stirring to effect solution. The solution was then sterile filtered, cooled to room temperature and packaged in sterile vials.
______________________________________FORMULATION "J"Ingredient Amount______________________________________Guanidine Compound 10 - 500 mg16% Aqueous GelatinContaining 0.5% Phenol 100 gFORMULATION "K"Ingredient Amount______________________________________Guanidine Compound 10 - 500 mgSodium Chloride 890 gWater 99 gFORMULATION "L"Ingredient Amount______________________________________Guanidine Compound 10 - 500 mgGlucose 5 gWater 95 gFORMULATION "M"Ingredient Amount______________________________________Guanidine Compound 10 - 500 mg10-90% Aqueous PolyethyleneGlycol 400 100 g______________________________________
EXAMPLE XII
The guanidine compound is dispersed in a cream vehicle consisting of a water-miscible base of stearic acid, proplylene glycol, sorbitol monostearate and mono-oleate, polyoxyethylene sorbitan monostearate with citric acid and methyl and propyl parabens as preservatives. Concentration of the guanidine compound is 0.1 to 50 mg per gram of vehicle.
Alternately, the guanidine compound may be dispersed in corn oil, sesame oil, cotton seed oil, peanut oil, or polyethylene glycols with the addition of appropriate preservatives.
EXAMPLE XIII
The vasoconstrictor properties of several representative compounds of this invention were determined pharmacologically using accepted methodology. The heart rate changes in anesthetized dogs who received an intravenous dosage of a guanidine compound as indicated. Throughout the procedure, host blood pressure was monitored by means of an indwelling arterial catheter connected to a pressure transducer, host heart rate was determined from the limb electrocardiogram, and carotid arterial blood flow was continuously monitored with a flow probe around the artery which probe was connected to an electromagnetic flow meter. It will be noted that three standard vasoconstrictors, all current commercial products, were also assayed in this manner and provide a reference base. The test compounds are coded in Table I and the data is reported in subsequent tables below.
TABLE I______________________________________TestCompoundCode Chemical Name______________________________________A 1-(3',4'-Dihydroxyphenyl)-3-methyl guanidine hydrochlorideB 3',4'-Dihydroxyphenyl guanidine hydrochlorideC 4'-Hydroxy-m-tolyl guanidine sulfateD 4'-Hydroxy-3'-hydroxymethyl phenyl guanidine hydrochloride______________________________________
TABLE II______________________________________Heart Rate Changes in Anesthetized Dogs Dose (mg/Kg.i.v.)Test Compound 0.01 0.1 1.0______________________________________A 0 + +B - - +C 0 - -D 0 - -Naphazoline - - +Phenylephrine - + +Phenylpropanolamine 0 +- -______________________________________ Rating Scale: - Decrease in heart rate 0 No change in heart rate + Increase in heart rate
EXAMPLE XIV
Additional data was obtained for each respresentative compound by measuring the rise in mean arterial blood pressure after intravenous administration to an anesthetized dog.
The scale employed to evaluate the results is shown in Table III, and the test data is recorded in Table IV, using the code for test compounds set forth in Table I of Example XIII.
TABLE III______________________________________Activity Pressure RiseRating in mm Hg______________________________________0 0 - 31 4 - 102 11 - 253 26 - 504 51 - 755 >75______________________________________
TABLE IV______________________________________Activity Rating for Test Compounds Dose (mg/Kg.i.v.)Test Compound 0.0. 0.1 1.0______________________________________A 0 3 5B 2 3 5C 1 3 5D 3 4 5Naphazoline 3 4 4Phenylephrine 3 5 5Phenylpropanolamine 0 3 5______________________________________
EXAMPLE XV
An aqueous solution was prepared containing 3',4'-dihydroxyphenylguanidine hydrochloride and suitable for use with the nose and eyes to effect decongestion of the mucous membranes of these organs. The solution was stable, physiologically isotonic and had a pH in the range of 6 to 7.
The formulation is shown below. The sodium phosphate salts comprise a buffer system to maintain the pH at about 6.5 and sodium bisulfite is used as an antioxidant. Sodium chloride provides the desired isotonicity and Thimerosal as a preservative which protects the solution from bacterial and mold contamination.
______________________________________FORMULATION "N"Ingredient Wt. %______________________________________3',4'-Dihydroxyphenyl-guanidine hydrochloride 2.00Monbasic Sodium Phosphate 0.10Dibasic Sodium Phosphate 0.12Sodium Bisulfate 0.20Sodium Chloride 0.15Merthiolate Sodium (Thimerosal) 0.01Water 97.42______________________________________
From the foregoing, it becomes apparent that the invention herein described and illustrated fulfills all of our objectives, express and implied, in a remarkably unexpected fashion and that we have developed new and useful compounds, pharmaceutical compositions and therapeutic methods for providing vasoconstriction in hosts requiring such therapy.

	Number	Date	Country
Parent	518925	Oct 1974
Parent	73244	Sep 1970

Pharmaceutical, compositions containing substituted 4'-hydroxyphenyl guanidines and methods of using same

Information

Patent Number

Date Filed

Date Issued

Inventors

Original Assignees

Examiners

Agents

CPC

US Classifications

Field of Search

US

International Classifications

Abstract

Description

Claims

Parent Case Info

Non-Patent Literature Citations (2)

Divisions (2)

Continuation in Parts (1)

Entry
chem. Abst., vol. 29, col. 1504(8), (1935).
Chem. Abst., vol. 47, col. 3923(b), (1953).