DE1668098A1 - New hypotensive compounds - Google Patents

Description

Novel Hypotensive Composition This invention relates to blood pressure control in mammals and intends @ a new antihypertensive composition and to create a new method of combating hypertension in mammals.

The spread and persistence of hypertension and its related serious physical disorders have led to extensive research into chemotherapy drugs stimulated the sure suber a longer period of time towards lowering the blood pressure can be used, especially of the diastolic pressure, without being toxic to announce or to generate side-effects. It is extremely desirable that an antihypertensive agent shows not only low toxicity and Side effects absent, but also long duration of action, mildness and stability of action, so that the desired lowering of blood pressure by using essentially constant Drug dosages over the longest possible interval. G.: 'r. l, l '' <. s. j, Ps. Ji: r he. 6AMi. ld tJ'v t3c''rStw'S. E:. iS Firb. :: 3JSo's ° Fk .. '7xFg.' ° and amplification stability.soda3 the desired reduction of the blood pressure by the application of moderate constants successful.

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It has now been found that 2-azidoacetophenone oxime is a stable, antihypertensive agent Very low toxicity agent is gentle and prolonged high activity shows. This is surprising. n ° dr 1'nx. .-n8 cx uF'3Y: be. rsrtnelrl L ° 'r kung tested were different azides. The use of sodium azide, for example, is known to however, this connection is -, .. =: W vx. o c: y: raerae: 5a. acz: e wg3. r an-, daM: I, c Acl; n nc; a ° lrn: 'cies'. c: c. that they are ineffective or in theirs Effect too volatile or of 33; rnn: ice. zsr. £ '; cre. at 3 o'clock Vwend s ri same to allow antihypertensive agents. The organic inadequate capacities make their use as effective in which a superior antihypertensive agent might be found 2-Azideacetophenone oxime is particularly noteworthy in that it is at oral administration is effective and moderate Increase a non-toxic but effective dosage an appropriate extension of the antihypertensive duration of action without, however, manifesting a noticeable increase in toxicity. The low toxicity of this compound was demonstrated as follows: There were male white rats (Charles River) weighing 200 to 400 g were used. The rats were divided into aruppan of 5 rats each and the test compound was administered orally with a long increase, so that the 50% lethal dose was also included.

The compound was in an aqueous dispersion containing 1% methyl cellulose (Methocel) suspended and in a constant volume of 2 ml / 100 g body weight administered at all dosages.

All rats were given 16 hours prior to administration of the compound starve for a long time.

All animals were examined at periodic intervals immediately after the Administration and daily thereafter for a total of 14 days for pharmacotoxic Examined for signs and mortality.

All rats that died during the observation period were Necropsy evaluations made.

At necropsy no damage could be found, which one an effect produced by administration of the test compound can. In 4 of the 11 rats examined, unrelated damage occurred related issues such as congestion, pinpoint hemorrhages, and pneumonia.

The values for the acute oral LD50 are listed in Table I.

T able I Acute oral LD50 values, 2-azidoacetophenone oxime in white rats dosage (mg / kg) LD50 and limits Number of dead / number of those with compatibility Dose Treated (mg / kg) (Confidence Limits) 31 316 464 681 1000 1470 2150 0/5 2/5 3/5 5/5 - 639 (382-1070) To test the antihypertensive effect of 2-azidoacetophenone oxime when administered intravenously, the mean r; . e. ! e. dxuk e: fe: z, 'l, s. ez °: er r, t;) aiA ^ r. Eaez; a? ~ x and d:. z. 9den no. limtn cdE TIa tmL; e: rr cannulated femoral artery over a heparin-containing salt bridge from a photoelectric Bourdon or de Sa'b '.''G ° lf $''t: T k. u ° Ta.

Statham P23Db low volume displacement pressure transducer, the 1 '$' . 11, lGr'i G C: °. 't? 4SC: CMY1 eG '' '? E1I "t- '" ,, L, et3' $ * n t: o:. r . '"t s scl a d tr. tca d rL.. azr rcn onfiro u, xa provided with a cannula.

Along the midline of the cervical area of the neck was. rn c. ge. tr. . t. c, r, s d. TI exposed for closure. The right vagus nerve was cut through and the peripheral stump for excitation by tubular platinum electrodes guided. Breathing was over one. Liiss; iLl4iii ° ib77 / liiilYF'Gii857JLi J4'4dbe3fiV3au7b 6! d =:. ilI. YI'GlAfds! ! 'lr. yf r iEZ. idl. . Eyly.

Standard e3iv eatr ecl. , t n: s y. , Standard derivation II recorded periodically during an experiment. The heart rate was through Auscultation recorded. after severing the vagus nerve one waited half an hour to allow the animal to recover from the procedure and the blood pressure could stabilize. Before intravenous administration of the test compound at least two comparative reactions were obtained from each of the following procedures : 1. Acetylcholine chloride, 2 µg / kg, administered intravenously.

2. Histamine phosphate, 5 µg / kg, administered intravenously.

3. L-epinephrine bitartrate, 2 µg / kg, administered intravenously.

4. Angiotensin II (hypertensin), 1 µg / kg, administered intravenously.

5. Irritation of the peripheral vagus, 5-15 seconds.

6. Bilateral carotid occlusion, 15-30 seconds.

The test compound was used for intravenous administration as for each dosage to be administered necessary, in polyethylene glycol (Carbowax 300) diluted. The volumes administered were not greater than for each injection 2 ml.

Corresponding volumes of Carbowax were given for each experimental test 300 administered at least once for comparison purposes.

The comparison series of injected chemicals and treatments Murden periodically repeated after each administration of test substance for as long an effect of the test compound persisted. In . In attempts one for each connection To generate a response to a dose o the test substance was administered in various doses, each dose is administered to at least 2 dogs.

2-Azidoacetophenone oxime decreased mean systemic blood pressure Un 15 to 55% of the reference agent at dosages of 1 to 20 mg / kg. The duration of the Decreased blood pressure an average of 49 to 174 minutes at the dosages mentioned. However, the duration of action in these experiments was at 1 mg / kg greater than at 5 mg / kg. At 30 mg / kg (in a dog) rexriradc d. c ° x: i. rt. r da 7ceb Lr. '. fta rml 'mls 4 Sttmdano D Influence on the standard measurement series seemed to be on a SchwascCl 'IfAAhiblE. ""' I '', s! az ~ l ",: r3fa'TiLt 'L". 1 Y4tb "G ,. ° 'i. 't. El caused weak inhibition of the press responses by bilateral corotis occlusion (BCO) and induced che potentiation of the by Epinephrine and angiotensin induced pressor responses were limited too be.

There was tachycardia (less than 25%) and bradypnous (50%) and at found tachypnos (50%) in some dogs.

The ECGs of the standard lead II remained relatively unchanged.

A decrease in the height of the T-point was produced in one dog and little P-wave accentuation also occurred in the same animal on.

2-Azidoacetophenone oxime appeared to have both pressures, the systolic and the diastolic To lower the blood pressure at which freaks were given to a dose given intravenously.

T II Blood pressure lowering effect Dose Mean arterial Dog Blood Pressure (mm Hg)% Duration (mg / kg) No.Comparison Waste Waste (minutes) 242 1 105 -15 14 79 253 1 132 -22 16 137 MittelNert *? 8l5108! 252 5 145 -35 24 62 254 54 140 -55 32 37 Mean -45 28 49 254 10 100 -48 48 153 242 10 135 -33 24 55 Mean -40 36 104 243 20 14o-93 66 270 253 20 125-65 52 157 25520 105-48.4694 Mean -69 55 174 254 30 131 -93 71> 240 To the hypotensive effects of 2-azidoacetophenone oxime When tested orally administered, normotensive canine hybrids were both Gender (beagles) used from 8 to 14 kg. The dogs were in a pair of cloths gently recorded while using a systolic blood pressure electrical "Beckman FBR-2A Manometers", "Beckman Infraton Signal Dividor" and a "Sanborn single channel e: ii., r: c:....!", vc; ptr,; c3m: wm cuac o As is common in clinical practice, a ligation sleeve was used Wrapped around the dog's shaved tail base and past the point of arterial collapse pumped out.

When the cuff pressure was released, the first occurrence was a Arterial pulse, or noise and pulse, as a measure of systolic blood pressure taken. The pulse was recorded oscillographically with the Sandborn recorder.

An "Infraton" microphone was placed just below the binding mask attached directly above the middle cocoygal artery on the ventral side of the tail. This instrument completely replaces the stethoscope commonly used in clinical practice.

It transmits noise and pulse rate data directly to the "Infraton Signal Divider ". The ligation sleeve is connected to the BBR-8A electric manometer and is inflated by hand. The data from the eavesdropping device is transferred from the signal divider selected and transferred to the driver.

An automatic, adjustable valve for linear pressure drop in the FBR-2A pressure gauge releases cuff pressure at a selected rate sink and at the same time transmits the information about the siah Singering Cuff Druok to the clerk.

All dogs used in this study were trained to that you remained perfectly calm and relaxed, while honoring the measurement of the blood pressure.

2-Azidoacetophenone oxime was administered orally in the form of capsules to 6 de jader with a dosage of 0oer 25 mg / kg. Was sent to another group of 6 dogs 2-Azidoaeetophenonoxim administered in the form of capsules, one hour after a subcutaneous Dose of 20 mg / kg of the anti-cement agent Tigan. Another group of 6 Dogs were given an oral dose of 25 mg / kg 2-azidoacetophenone oxime immediately 100 ml of milk per animal were then administered by oral intubation.

The test compound was diluted with granulated lactose and used for oral administration to dogs in capsules.

Dosages of 10 or 25 mg / kg were used. For every dosage 6 dogs each were used.

At 10 mg / kg, a dog of 6 vomited within half an hour after administration of the compound. There were no other pharmacodynamic or toxic symptoms were found that could be assigned to the substance.

.-0 minutes after the administration there was a significant decrease the systolic blood pressure was observed at this dosage (P <. O1). The blood pressure was still lowered after 1 and 2 hours, but returned to the equivalent values the administration and was no longer significantly different from the initial one Comparative value. After 3 hours, the blood pressure was completely normal Area returned.

At 25 mg / kg, 4 out of 6 dogs vomited within half a pound up to an hour and a half hour after the test substance has been administered. It no other adverse pharmacotoxic symptoms could be identified. There was apparently an unresolved compound in the contents of the stomach.

In this group there was a significant drop in systolic blood pressure 50 60 and 120 minutes after the administration, 4 of the 6 dogs in this group vomited. 3 hours after the administration were the Blutdrue bodice returned to the comparative values.

Another group of 6 dogs were given 20 mg / kg of the antiemetic Using Tigan (Schallek, W., Heise, G., Keith, E., and Bagdon, R. t Pharmacol. Expl. Therap., 126: 3, 1959) administered subcutaneously one hour prior to oral administration of 25 mg / kg of the test substance. 4 of the 6 dogs vomited approximately an hour and a half after the administration of this compound.In this group of dogs, there was no significant change over a 4 hour monitoring period of blood pressure. The results indicate that the 2-azidoacetophenone oxime is a Do not vomit by central stimulation of the emetic chemoreceptor trigger zone because Tigen effectively blocks substances that act through this mechanism. It is believed, therefore, that the compound is caused by direct irritation of the gastrointestinal tract causing vomiting.

Another group of 6 dogs were given 25 mg / kg of 2-azidoacetophenone oxime orally administered in the form of capsules, followed immediately by intubation of 100 ml milk per animal. It has been found that milk is both experimental in animals as kllnisah balm manschen effectively prevents vomiting from compounds that act as a gastric stimulus mechanism.

Two dogs in this group vomited approximately 8 hours after the administration a small part of the milk administered.

The remaining 4 dogs retained the administered compound and milk.

In this group, the systolic blood pressures were over an 8 hour period Measurement time decreased. The blood pressures were not up after an 8-hour measurement returned to the value before the administration. Significant deviations were 1/2, Recorded 1, 2, 3, 4, 5 and 8 hours after administration.

The results indicate that 2-azidoacetophenone oxime may induce vomiting caused by a gastric irritant mechanism, and that the compound, if retained, a severe and prolonged drop in blood pressure in dogs evokes.

T a b e l l e III - .; J.JJt.JL '<'! ... <J *.

Xnictsy'oli ..: D -.'..--, '' .., ': njin "; ..-' craloDoui-Hün" v'cS - '.'. Gi'l -., - :. CL ': i' '! I:? <:.'. J ": ':' - ':. LL'" r 1 -. '' O-; r HidD '. \ -.' .. L) '' "" "" "" "'" i (-D @@@ d @@@@@@@ @g) dog No. time (hours) Comparative value 1/2 1 2 3 4 10 mg / kg: l1S5939710io126 14 147 114 11 @ 143 145 146 13 124 113 98 119 132 129 12 137 115 135 139 142 141 4a 138 103 144 128 144 141 6 141 116 133 131 131 140 mean value 135 109 121 128 137 137 S.F. # 4 # 4 # 8 # 5 # 3 # 3 P - <0.01 NS NS NS NS 25 mg / kg: 131341259S35133135 14 139 117 83 110 131 138 13 134 125 93 95 133 135 12a 114 84 120 114 120 123 4c 132 138 125 127 130 134 6b 149 84 100 119 145 146 Mean 135 106 103 113 132 135 S.F. # 5 # 10 # 7 # 4 # 3 # 3 P - <0.05 <0.01 <0.01 NS NS 4 S.P. Mean standard wan 'NS Not significant P "Students' Test of" t "" a Vomiting within 1/2 hour after administration of the Link. b Vomiting within one hour of compound administration. c Vomiting within 1 1/2 hours after administration of the compound.

Table III Indirect changes in systolic blood pressure, induced by oral doses of 2-azidoacetophenone oxime in normotensive dog hybrids +) Blood pressure (mm Hg) dog time (hours) no.

Comparative comparative value 1 value 2 1/2 1 2 3 4 25 mg / kg: 1a 127 129 133 136 132 134 133 14 132 131 131 134 127 129 132 13 127 132 130 138 140 141 141 12a 119 121 121 134 126 127 128 4a 133 132 133 142 149 152 153 6a127130130134130132131 Mean 128 129 130 135 134 136 136 S.F. # 3.0 # 2.4 # 2.4 # 1.8 # 5.4 # 5.4 # 5.4 P - NS NS NS NS NS NS .... ~ .. ~~~ .... ~., S.F. Standard Mean Error NS Not significant P "Stundents' Test of" t "" a Vomiting within 1 1/2 hours of administration the compound +) Tigan was administered subcutaneously to all animals, 20 mg / kg, 1 hour prior to oral administration of the test compound.

1 comparison value before any treatment 2 comparison value 1 hour after the tigan administration and immediately prior to administration of the teat compound.

T a b e l l e III (continued) Indirect changes in systolic blood pressure, induced by oral dosing @ 2 azidoacetophenone oxime in normotensive dog hybrids +) Blood pressure (mm Hg) dog time (hours) no.

Comparative value 1/2 1 2 3 4 5 @ 25 mg / kg: 1 142 128 104 86 68 112 124 1 @ 2 184 155 147 125 140 147 184 1 @ 3 161 147 145 118 115 118 126 1 @ 4 161 135 142 116 117 126 123 1 @ 5a 166 83 96 111 116 107 121 1 @ 6b 145 143 125 97 114 108 115 1 @ mean 160 132 127 109 112 120 132 1 @ S.F. # 6.2 # 10.5 # 9.0 # 6.1 # 9.4 # 6.2 # 10.5 # @ P - <0.05 <0.01 <0.001 <0.001 <0.05 N @ S.F. Middle Stendard's Error NS Not significant. P "Students' Test of" t "" a Moderate vomiting 1 hour after administration of compound b Moderate vomiting 2 hours after administration of the compound (+) All animals were treated immediately after administration of the Dosi @ 100 ml of milk given per dog.

The following is the preferred method for preparing 2-azidoacetophenone oxime Briefly described: A mixture of 70 g of 2-chloroacetophenone, 100 g of hydroxylamine hydroahloride and adding methanol and water to obtain a clear solution was overnight stirred at room temperature. The reaction mixture was poured onto ice that formed The precipitate was collected and dried over calcium chloride in a vacuum desiccator. When recrystallizing from hexane, 50 g of 2-chloroacetophenone oxime, melting point 87 to 90 ° C., were obtained obtain.

12 g of 2-chloroetophenomoxime and 6 g of sodium zide were in 100 ml of ethanol suspended and stirred overnight at room temperature. After adding 10 ml H2O and stirring for an additional hour, the mixture was poured into water. One collected the precipitate, filtered and dried. Recrystallization from texane gave 11 g of 2-azidoaoetophenone oxime, m.p. 78 to 9 ° C.

Analysis: b s N 31, 63 C 54, 22 H 5, 13 found N 31.58 C 54.98 H 4, 70 Dan 2-azidoacetophenone oxime according to the invention can be administered intravenously, orally or as Can be administered in the form of inhalants or in the form of a spray. For oral Administration can be with a feston pharmaceutical carrier in the form of a tablet, Pill, powder, capsule, or other dosage forms suitable for oral administration be united.

Suitable solid carriers include lactose, corn starch, microcrystalline Cellulose, talc, stearic acid, magnesium stearate, rubbers and the like .. Coated Tablets or pillez are particularly suitable. Capsules are also particularly suitable. Typical pharmaceutical capsule shells such as gelatin can be used.

2-Azidoacetophenone oxime can be administered in liquid form. For oral use, liquid emulsions or suspensions are suitable, such as Contains 5 to 50% of the azide in Nasser. Usual emulsifying and suspending agents can be added as stabilizers. These compositions can also be a Contain a small amount of ethanol, which partially dissolves the azide. Liquid fats are unsuitable as auxiliaries, as the azides are very soluble in these fats and obviously tend to remain dissolved in the intestinal lymph.

For intravenous injection or oral use can be 2-azidoacetophenone oxime be dissolved in polyethylene glycol (e.g. Carbowax 400), which can be diluted if desired can be, or other pharmacologically inert excipients are mandated, in which it is soluble. For intravenous injection can do it too be emulsified in an inert aqueous isotonic solution. 2-azidoacetophenone oxime concentrations from about 15 to 75% is suitable. It can also be inhaled or sprayed administered into the nose, but will generally risk the difficulty to control the dosage, not applied in this way.

In alcuten situations, however, in which the immediate reduction blood pressure is necessary, inhalants and sprays are suitable.

Choosing the appropriate dose for correcting hypertension will be made by various factors, such as the severity of the suffering and the desired duration of effect certainly. The effective dose for human treatment is about 10 to 100 mg.

Claims (1)

P a t e n t a n s p r ü c h e 1. Composition with hypotensive Effect, dadurah characterized that they have 2-azidoacetophenone oxime as an active ingredient in admixture with a pharmaceutical carrier suitable for this purpose. 2. Composition according to claim 1, characterized in that sle contains about 5 to 50% 2-azidoacetophenone oxime, as well as about 50 to 95% water, which contains a suitable emulsifying and suspending agent. 3. Composition according to claim 1, characterized in that it contains about 15 to 75% 2-azidoacetophenone oxime and about 25 to 85% polyethylene glycol. 4. Composition according to claim 1, characterized in that it about 15 to 75% 2-azidoacetophenone oxime and about 25 to 85% of an inert, aqueous, Contains isotonic solution. 5. Use of 2-azidoacetophenone oxime to be administered periodically, hypotensive agent. 6. Use of 2-azidoaoetophenone oxime for oral administration on mammals. 7. Use of 2-azidoacetophenone oxime for. intravenous administration. 8. Use of 2-azidoacetophenone oxime, characterized in that that it is administered to humans in a dose of 10-100 mg. go procedure for the production of 2-azidoacetophenone oxime, characterized in that 2-chloroacetophenone is reacted with hydroxylamine to form 2-chloroacetophenone oxime, the 2-chloroacetophenone oxime reacted with sodium azide and the solid 2-azidoacetophenone oxime from the reaction mixture is separated. 10. Essentially raineep @ crystalline 2-azidoacetophenone oxime.