US3469005A - Method and composition for reducing blood pressure in mammals - Google Patents

Description

hired States Patent 3,469,005 METHOD AND COMPOSITION FOR REDUCING BLOOD PRESSURE 1N MAMMALS Theodor Wei], Highland Park, and Hugo Stange, Princeton, N.J., assignors to FMC Corporation, New York, N.Y., a corporation of Delaware No Drawing. Continuation-in-part of application Ser. No. 398,072, Sept. 21, 1964. This application Oct. 22, 1965, Ser. No. 502,377

Int. Cl. A61k 27/00 11.5. Cl. 424--226 1 Claim ABSTRACT OF THE DISCLOSURE The sulfonyl azides in the group consisting of aromatic sulfonyl azides of the benzene and naphthalene series and lower alkyl benzene sulfonyl azides are hypotensive agents that can be safely administered to mammals over an extended period of time sufiicient to lower blood pressure.

This is a continuation-in-part of our copending application Ser. No. 398,072, filed Sept. 21, 1964, now abandoned.

The present invention relates to a novel method of reducing blood pressure in mammals, and more particularly to the use of organic sulfonyl azides as anti-hypertensive drugs.

The need for a more effective, and at the same time, safer, anti-hypertensive drug is very great. Of all causes of death, cardiovascular disease ranks among the highest, and a major portion of all patients affiected with cardiovascullar disease exhibit hypertension with its concomitants and sequelae. About 85 percent of all hypertension is of unknown cause and is usually labeled essential, benign, or idiopathic. This syndrome, which comprises a major portion of any practice in internal medicine, typically has its onset in early adulthood or even late adolescence. Often, it can be demonstrated in its early stages only by means of special physiological tests. Nevertheless, it does not carry the rather harmless prognosis which some of its names such as benign would seem to imply. With passing years, it becomes more fixed and greater in magnitude. Eventually it becomes the principal fulminating factor in cardiovascular accidents of cardiac, renal or cerebral origin as well as other untoward eventualities.

Since this is a long term disease of still uncertain cause and with no definite cure, treatment at present is non-specific, the principal aim being to reduce blood pressure, particularly diastolic pressure, by surgical or chemotherrapeutic means. The latter implies as regiment of chronic dosage, often over a period of decades. Therefore, the agents employed should have as little as possible in the way of toxicity and side effects. A reasonably long duration of activity, as well as stability of action, is also desirable, so that the drug need not be administered too often, the dosage too frequently adjusted, or the patient too closely supervised. Reduction of blood pressure preferably should be accomplished without a corresponding increase in cardiac work, thereby permitting the use of the remedial agent in cases where an element of cardiac impairment is present. None of the anti-hypertensive agents presently in use has all of the above favorable properties.

Thus, at this time there is no entirely satisfactory agent available for the treatment of hypertension. Presently used anti-hypertensive agents are highly diverse, both chemically and pharmacodynamically. There are more than half a dozen different classes of compounds, most of which have several representatives in current clinical use. The very number and diversity of these compounds attests to the fact that no one of them is sufficiently satisfactory to gain ascendency over the others. These compounds vary greatly in their mode and duration of activity, and they "ice all possess significant toxicity, together with side effects which range from merely distressing to distinctly dangerous. However, even those agents which are distinctly dangerous have been pressed into use in the heroic treatment of a disease which otherwise would be immediately fatal.

The effect of inorganic azides, such as sodium azide, on blood pressure is well known. Although these agents are effective in reducing blood pressure, they produce acute and chronic toxic effects such as demyelination and necrosis of the white and grey matter of the brain, and damage to the optic tracts with resulting blindness.

In early work, I. G. Farben reported in British Patent No. 251,651, (1927) that pseudosaccharine azide lowers blood pressure but that it is too fugacious for medicinal use alone and proposed that small amounts of this azide be used in the form of a complex with other known hypotensive agents. In 1952 Werle et al. reported the blood pressure reducing effects of various organic azides in dogs and found that sulfonyl azides have relatively little effect on blood pressure as compared with other azides, Biochemische Zeitschrift, Bd. 322, S. 507-512.

In 1956 Roth et al. reported a comparative study of the hypotensive effects and toxicity of sodium azide and organic azides, Arch. Int. Pharmacodyn, CVIII, No. 3-4, p. 473 (1956). Using rabbits as the experimental species, these investigators found that organic azides are only about one-third as potent as sodium azide while having approximately the same therapeutic index, that is, the ratio of an average lethal dose to an average effective dose. Although many of the organic azides tested by Roth et al. were somewhat effective in reducing blood pressure, paraacetamidobenzenesulfonyl azide and para-bromobenzenesulfonyl azide, the only sulfonyl azides tested, were ineffective and thus their toxicity was not determined.

It is an object of this invention to provide a method of significantly reducing human blood pressure using an agent having a high therapeutic index and no significant side effects.

Another object is to provide oral medicinal compositions for reducing blood pressure containing as the active ingredient compounds having a high therapeutic index and no significant side effects.

These and other objects will become apparent from the following description of this invention.

We have now found that aromatic and lower alkylbenzenesulfonyl azides produce a significant, reproducible, dose-related reduction of both systolic and diastolic blood pressure in mammals, with a smooth onset and a reasonably long duration of action. Quite unexpectedly these compounds are completely free of any toxicity at useful dosage levels, the therapeutic index being remarkably high. Moreover, there are no side effects associated with effective hypotensive doses of these compounds, These compounds are effective in relatively small quantities with increasing dosage causing essentially a simple increase in duration of effect rather than any marked increase in hypotensive action. Extensive testing involving continuous administration of these compounds over extended periods of time has revealed no evidence of tachyphylaxis, tolerance, or significant toxicity. In fact there is slight increase in the degree of sensitivity with prolonged administration which can be viewed as "a long term therapeutic advantage. This sensitivity is small in magnitude and can be easily managed by proper reduction of dosage in the early weeks of treatment.

The sulfonyl azides of this invention have significant utility, both in the long term chronic treatment of hypertension and in the management of acute crises associated with malignant forms of this disease. These compounds appear to inhibit the contractile mechanism of vascular smooth muscle, thereby directly relaxing the arteriolar musculature which results in a decrease in the peripheral resistance of the vascular bed. This is a highly desirable effect which is not observed with any of the drugs presently in use. These compounds seem to have little, if any, neurogenic activity in the dose range which produces this primary effect. In particular, in therapeutic dosages, they do not cause any increase in cardiac rate or contractile force, cardiac output, or cardiac Work, which effects are frequently associated with the anti-hypertensive drugs in use todary. The toxicity of these compounds is quite low, being much lower than other organic azides tested by prior investigators and vastly lower than inorganic azides. These other azides have undesirable enzymatic and neurotoxic elfects which are not encountered with the sulfonyl azides of this invention. When orally administered, the sulfonyl azides of this invention are readily absorbed into the blood stream without rapid inactivation by the liver. These compounds are also well tolerated when administered intravenously,

Potential cardiovascular drugs are generally evaluated first in animal models. The favorable action of the sulfonyl azides of this invention has been demonstrated in detail in several animal species. Their value has been most thoroughly studied in the dog, the animal species most commonly employed in preclinical experimentation.

The absence of toxicity, even when the sulfonyl azides of this invention are administered in very large dosages over periods of months, has also been demonstrated in several animal species. The acute oral toxicity (LD of various sulfonyl azides of this invention in the male albino rat are as follows:

Sulfonyl azide: LD mg. /kg.

Benzene 1260 l-naphthalene 4300 2-naphthalene 1260 Ortho-toluene 1996 Meta-toluene 3690 Para-toluene 2710 2,5-dimethylbenzene 2710 -4ethylbenzene 2710 4-butylbenzene 3160 Prior art azide: LD rug/kg.

Sodium azide 37 n-Hexyl azide 280 Benzyl azide 120 Nicotinoyl azide 60 By comparing this prior art toxicity data with the above sulfonyl azide toxicity data, it can be seen that the sulfonyl azides useful in accordance with this invention have toxicities which are markedly superior to the toxicities previously known for other azides.

Effectiveness of the sulfonyl azides of this invention in humans has also been established, and marked freedom from side effects has been demonstrated. The effective dosage unit for human patients is about 50-500 milligrams, and preferably about 100-300 milligrams. Selection of the proper dosage for correction of hypertension is determined by the severity of the disease, desired duration of effect, the particular sulfonyl azide administered, and other factors.

The sulfonyl azides which are suitable for lowering blood pressure in accordance with this invention are aromatic sulfonyl azides and lower alkylbenzenesulfonyl azides. By aromatic sulfonyl azides we mean monoand polycarbocyclic aromatic rings unsubstituted except for a single sulfonyl azide group. Typical examples are benzene-, naphthalene-, and anthracene-sulfonyl azides. By lower alkylbenzenesulfonyl azides we mean a benzene ring unsubstituted except for one or more lower alkyl groups and a single sulfonyl azide group, Typical examples of suitable alkyl substituted benzenesulfonyl azides include methyl-, dimethyl-, ethyl-, diethyl-, propyl-. butyl-, and pentylbenzenesulfonyl azides.

The sulfonyl azides of this invention are readily prepared by reaction of the corresponding sulfonyl chloride with sodium azide in accordance with the equation:

This process is fully described by Curtis et al., Journal fur Praktische Chemie, Neue Folge, Band 125, pages 323-324 (1930). In general, a solution of about 1.2 mole of sodium azide, dissolved in a minimum of water, is added slowly with cooling to 1 mole of the sulfonyl chloride dissolved or suspended in about 200-300 milliliters of ethanol or acetone. The mixture is stirred for l-Z hours at room temperature, after which sodium chloride is separated. The product is then diluted with about five times its volume of water, whereby the azide separates as an oil or as crystals. Solid azides can be recrystallized from ethanol, acetone, benzene, or hexane. These sulfonyl azides can also be prepared by the nitrosation of the corresponding sulfonyl hydrazide as indicated by Curtis et al., supra, pages 326327, in accordance with the equation:

It is preferable that these sulfonyl azides be handled in dilute form since they may be mildly shock sensitive.

The sulfonyl azides of this invention may be administered intravenously, orally, or as an inhalant or spray. For oral administration, these compounds may be associated with a solid pharamceutical vehicle in the form of a tablet, pill, powder, capsule or other dosage unit form Which is suitable for oral administration. Suitable solid vehicles include lactose, cornstarch, microcrystalline cellulose, talc, stearic acid, magnesium stearate, gums, and the like. Coated tablets or pills are particularly suitable since the coating will prevent evaporation of liquid sulfonyl azides from the pharmaceutical carrier. Capsules are also particularly suitable for the same reason. Typical pharmaceutical capsule casings such as gelatine may be used.

These sulfonyl azides may also be administered in liquid form. For oral use liquid solutions, emulsions or suspensions containing about 5-90% sulfonyl azide in water are suitable. For solutions 1590% sulfonyl azide is preferred, while for emulsions and suspensions 575% is preferred. Conventional emulsifying and suspending agents can be added as stabilizers. These compositions can also contain a small amount of ethanol which will partially dissolve the sulfonyl azide. Liquid fats unsuitable as vehicles since the sulfonyl azides are highly soluble in these fats and apparently tend to remain dissolved in the chyle. The preferred vehicle is polyethylene glycol in which the sulfonyl azides are soluble.

For intravenous injection the sulfonyl azide can be used full strength, dissolved in ethanol, polyalkylene glycol, or some other pharamcologically inert vehicle in which the azide is soluble, or emulsified in an inert aqueous isotonic solution. Sulfonyl azide concentrations of about 15-90% are suitable. These azides may also be administered by inhalation or nasal spraying but are normally not used in this manner because of the difiiculty in controlling dosage. However, in acute situations where immediate re duction in blood pressure is necessary, inhalants and sprays are appropriate.

The following examples, illustrating the method of reducing mammalian blood pressure of this invention, and

5 suitable medicinal compositions therefor, are presented without any intention that the invention be limited thereto. All percentages are by weight unless otherwise specified.

EXAMPLE 1 Mean arterial blood pressure in pentobarbitalized (35 ing/kg.) normotensive mongrel dogs was recorded from the left or right cannulated femoral artery via a heparinized saline bridge to either a photoelectric or a low volume displacement pressure transducer, which in turn was connected to an electronic recorder. The contralateral femoral vein was isolated and cannulated for injection of the test material and control substances.

The test materials were prepared for intravenous administration by dilution in Carbowax 300 as necessary for each dosage level administered. Volumes administered did not exceed 2 ml. at any one given injection. Comparable volumes of Carbowax 300 without drug were administered at least once for control purposes in each experimental trial. The sulfonyl azides indicated in the table below were administered at the indicated dosage levels to at least two dogs at each level. The following results were obtained:

INTRAVENOUS DOSE-RESPONSE EFFECTS OF SULFONYL AZIDES ON BLOOD PRESSURE OF DOGS Percent Drop in Duration Dose, Blood of Efiect Sulfonyl Azide mgJkg. Pressure mm 1 32 38 5 it 131 Benzene 10 20 39 196 30 72 222 1 45 45 5 t 1% 2- a hthalene 10 5 n p 20 54 245 30 55 300 1 $8 3.2 hthalene 10 lnap 20 55 118 1 3 El tho-t luene 0 or o 20 48 115 1 18 22 a a a I t 1 no .1 0 It e a to ue 0 5 80 30 63 295 1 i 5% -t l e 5 2 Para 0 uen 10 46 114 20 60 211 1 39 28 5 e a th lbenzene 10 50 zs'dlme y 20 55 142 30 64 173 l 33 42 th 1b nzeue 10 19 443 y e 20 62 90 1 20 4.- ut lbenzene 10 b y l 24 133 6 EXAMPLE 2 Unanesthetized, normotensive, mongrel, beagle-type dogs of both sexes, and weighing from 8 to 14 kg. were used. The dogs were lightly restrained in a canvas sling while systolic blood pressures were indirectly determined by the use of an electrical manometer, a signal divider, and a single channel cardiovisette recorder.

In accordance with standard clinical practice, an occluding cult was attached to the shaved base of the dogs tail and inflated beyond the point of arterial collapse. A microphone pickup, which replaces the stethoscope used in human clinical practice, was attached just below the occluding cull directly over the middle coccygeal artery on the ventral surface of the tail. The occluding cuff was connected to the electrical manometer and was inflated by hand. An automatic, adjustable, linear pressure release valve in the manometer released cuff pressure at any chosen rate and simultaneously transmitted information on the changing cuif pressure levels to the recorder. As the cult pressure was released, the first appearance of arterial pulsation, or sound and pulsation, was taken as an index of systolic blood pressure. Sound and pulse wave data from the pickup were selected by the signal divider and transmitted to the recorder which oscillographically recorded the pulsations.

Throughout this example, at least three consecutive blood pressures were obtained for each dog at each time period, and the average of these three pressures was used as the systolic blood pressure for each dog at that time. All dosages of sulfonyl azide were administered orally be gelatine capsules containing the sulfonyl azide in lactose. The dogs were fasted prior to each experiment for 16 hours.

All dogs were trained over a three-week period to remain perfectly still and relaxed while blood pressures were being measured. After the training period was completed, control blood pressures were obtained by record ing hourly blood pressures on all dogs over a period of seven hours daily for seven consecutive days. The sulfonyl azides indicated in the table below were then administered at dosages of 10, 25 and 50 rug/kg. to groups of 5-7 dogs for each dosage level.

On the day of a given test, control blood pressures were obtained over a two-hour period prior to the oral administration of each respective dosage level. All subsequent pressures after compound administration were compared to the mean control values obtained just prior to treatment. Blood pressures were obtained after drug administration at 30 minutes, minutes and hourly thereafter as long as an effect on the blood pressure remained apparent.

The group mean blood pressure reductions for the entire study are summarized in the following table:

ORAL DOSE-RESPONSE EFFECTS OF SULFONYL AZIDES ON BLOOD PRESSURE 0F DOGS Time After Administration of Drug, Hours Dose, No.0f Sulfonyl Azide mgJkg. Dogs 1 2 3 4 5 6 7 8 9 10 6 -11 -9 -16 -5 -8 Benzene 25 5 9 -10 -10 -14 -18 50 6 -13 -11 -13 -19 -13 10 6 -17 -11 7 -13 -7 2-naphthalene 25 6 5 -11 -12 -12 50 7 -10 -10 -11 -19 -15 10 7 -7 -15 -2 -11 -12 Meta-toluene 25 5 -26 -24 -28 -27 -26 50 7 -17 -20 -28 -20 -21 10 5 -53 -23 -37 -18 -19 Para-toluene 25 6 9 -30 -20 -19 31 5O 6 -11 -17 -27 -24 -18 7 EXAMPLE 3 This example was designed to determine the existence of tachyphylaxis, or a tolerance to the eifects of paratoluene-sulfonyl azide.

Six normotensive, mongrel, beagle-type dogs of both sexes, and weighing from 9.5 to 13.0 kg. Were used. The dogs were lightly restrained in a canvas sling and systolic blood pressures were measured using the procedure described in Example 2. All dosages of para-toluenesulfonyl azide were administered orally by gelatine capsules containing 26.4% para-toluenesulfonyl azide in lactose each morning at eight oclock. Systolic blood pressures were recorded at the time the compound was administered and at 30, 60, 120, 180, 240, 300, 360, 420 and 480 minute intervals thereafter. Food was offered to the dogs once each day in the afternoon and left in the cage until the following morning. Water was available ad libitum.

After the training of the dogs was completed, control blood pressures were obtained during the first week by recording hourly blood pressures on all dogs over a period of seven hours daily for seven consecutive days. During the second week, para-toluenesulfonyl azide was administered to each dog at a dosag level of 10 mg./kg./ day, calculated as pure compound. During the third week the dosage level was increased to 25 mg./kg./day, and then increased again to 50 mg./kg./day for the fourth week. In an attempt to reveal tachyphylaxis, dosage during the fifth week was reduced to 10 mg./kg./day. During the sixth and seventh weeks no drug was administered, while blood pressures were measured daily in the early morning to determine how fast the blood pressures would return to the predetermined control levels.

The group mean blood pressures for the entire study are summarized in the following table:

SUMMARY OF GROUP MEAN BLOOD PRESSURES (mm. Hg)

INDUCED BY PARA-TOLUENESULFONYL AZIDE IN SIX DOGS OVER A SEVEN-WEEK PERIOD Time After Administration of Drug, Hours Dose, Week mg./kg./ No. day

cant decrease in group mean blood pressures was exhibited for a duration of five hours after administration of the drug. During the third week (25 mg./kg./day), a significant decrease in group mean blood pressures was exhibited for a duration of six hours. During the fourth week (50 mg./kg./day), a significant decrease in group mean blood pressures was exhibited for a duration of five hours. During the fifth week (10 mg./kg./ day), a significant decrease in group mean blood pressures was exhibited for a duration of three hours. Complete lack of tachyphylaxis was demonstrated as can be seen by comparing the data for the fifth week with the data for the second week. Group mean blood pressures during this week were lower than those recorded during the previous period at this same dosage level. During the sixth and seventh weeks (complete withdrawal) group mean blood pressures had readjusted to a mean level 20 mm. Hg lower than the original group mean control level established during the first week.

EXAMPLE 4 A dosage of mg. of p-toluenesulfonyl azide formulated as 25% active ingredient with lactose in a gelatine capsule given to an otherwise healthy patient with long standing idiopathic hypertension produced a fall in blood pressure from a control value of 180/100 mm. Hg to a maximum eifect of /85 mm. Hg reached two hours after administration. The blood pressure returned to control value seven hours after dosage. No side etfects were observed.

What is claimed is:

1. The method of reducing blood pressure in humans which comprises administering to a human subject suffering from high blood pressure, a blood pressure reducing amount of naphthalenesulfonyl azide.

References Cited UNITED STATES PATENTS 1,836,125 12/ 1931 Lautenschlager et al. 16765 OTHER REFERENCES Allen et al.: Proceedings of the Staff Meetings of the Mayo Clinic, vol. 29, No. 17, pp. 459-460 (1954).

Werle et al.: Biochemische Zeitschrift, vol. 322, pp. 507 512,1952.

Roth et al.: Archives Internationales de Pharmacodynamie et de Thedapie, vol. 108, No. 3-4, pp. 473-480, 1956.

ALBERT T. MEYERS, Primary Examiner J. D. GOLDBERG, Assistant Examiner mgr UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3, 9, l Dated September 23' 1969 Inventor(s) Pasquale Lombardo It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Column 1, line 60, "keton" should read ketone Column 2, line 69, "room" should be deleted. Column 2, line 70, "flux" should read reflux Column 5, line 26, "intrared" should read infrared Column 5, line 4 "innfrared" should read infrared Column 7, line 11 "chloroformmethyl-" should read chloroform methyl- Column 7, in the Table, heading, "Formulator" should read Formulation Column 12, line 3, the claim reference numeral 4" should read 2 SIGNED AND SEALED MAY 1 9 1970 (SEAL) Attcst:

Edward M. 1 1mb. In

wmzm E. soaum, m.

Attesting Officer comlssione'r of Pawn"