JPS59175469A - Use of pyrazolone derivative as lipoxygenase inhibitor - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides the use of certain 1-substituted virazol-5-one derivatives to treat ischemia (1sch, αemiαS), especially myocardial ischaemia (IH).
, s) followed by myocardial infarction (cardiac 1nfa)
rcti, ons), and cardiac rhythm (card, i
ac rhythm) variation fJII, (disord
ers), skin inflammation (especially xerosis < psoriσ5i
s) J and eye inflammation, rheumatic f rh, eum
atic), allergic
c) and asthmatic diseases, pulmonary embolisms
), shock lung (sh, ock lv, ng) and float 1
1ili (oed, emas) (especially pulmonary floater 1
1Bli (pulmonary oedemas)
), pulmonary hypertension
tenSion)), oxygen poisoning (ozyge, n1
toxications) and ulcerations (ULC).
prevention (prophyLaxis)
) and treatment with riboxycanase (, lipo
xygenase) for use as an inhibitor. The invention further provides a drug against inflammation of the skin and eyes and impact lungs containing the above pyrazolone derivatives in a therapeutically active bamboo, and lipogysignase inhibiting 11ipozygena.
se-inhibiting), bronchodilatory (br)
onch, oriilato-r1/), antiarrhythmic (
antiarrhythmic), anti-collapse property (ant
iischaemic), antirheumatic (ant
irh, ewmatic), antiallergic (ant
i-allergic), antiasthmatic (antiasthmatic)
hmatic), anti-floateric (a, ntioedemi
c) and gastroprotective (ga, 5-troprotective)
ive) regarding drugs.

US Pat. No. 3,147,276 states that certain 1-substituted pyrazol-5-ones have anti-inflammatory properties. It is also known that many pyrazol-5-one derivatives can be used as diuretics, antihyperdepressants and antithrombotic agents (German Published Patent No. 4319,280, 2.554
．． No. 701, No. 2.363°511 and No. 4554.
No. 703).

The most powerful antithrombotic agent to date is German Patent Publication No. 2, 24
7.272 (U.S. Pat. No. 4.053.621), 3-methyl-1-[2-(2-naphthyloxy)-ethylcou-2-pyrazolin-5-one ("nαf
It is known that this na, fazatrom is a scale that acts as a stimulant for endothelial prostacitalin (pci, 2) (Vermylene et al. , La
ncet l, 528 (1979), Cha
mone et al., Haemostasis 10, 29
7 (1981), and Mc'Intyre and Salzman, I'rombosis and H.
aemostasis, 46, Abstract
No. 45, 1981) QWong and Mc
Gi ff (J, pharmacol.

Ezp, Ter, 223, 757-760 (
1982)), nafazat r om is 15
-Hydroxyprostaglanson dehydrokenase,
That is, it has also been shown that the pGI2-min'M enzyme is blocked.

Furthermore, this substance inhibits boxyg- nase activity (Bl
Lsse et al., Fed, Proc, 41, 17
17 (1982)).

The antithrombotic effect of nafα2αtrom is, as is known, invariably dependent on its structure: for example nafα-z
Substituting methyl at the 3-position of atrom with ethyl reduces its effect in preventing thrombosis by about 30 times, and the corresponding 3-benzyl, 3-ingrovir, 3-n-glovir or 3,4 -Dimethyl derivatives nafaz dosage
Even when increased by a factor of 100 compared to atrom, no effect is detectable. It therefore seems very surprising that these compounds and pyrazolone derivatives which are decorated from a structural point of view are at least equivalent to nefazatroqn with respect to the other above-mentioned properties of action.

The pyrazolone derivatives which can be used according to the invention have the general formula (1 [wherein R has 6 to 12 carbon atoms and optionally halogen,
trifluoromethyl, alkinohair alkenyl, alkoxy, alkylamino, cyanogen, trifluoromethoquine,
Nitro, hydroxyl, 50tL-alkyl (71,=
0-2) or 5on-) trifluoromethyl (n20-2
)Yo! represents an aryl or heteroaryl which may contain from 1 to 3 identical or different substituents from the group 11, with the proviso that in each case alkynopealkenyl and alkoxy have 1 to 4 carbon atoms; R' represents hydrogen or a hydrocarbon group having 1 to 18 carbon atoms and optionally containing a hydroxyl, ether, ester or carboxyl group and optionally 1 to 3 7-locene atoms, R2 is R1 or represents a group R3, R8 represents hydrogen or an acyl or sulfonyl group each having 1 to 15 carbon atoms, and X represents a group -0-C, -CH2-, -8-C112-C
・R2-7-C'H2-C1i2-CH2-, =CR2
-C1i2-, -C''Ji2- or -C1l-, with the proviso that this oxygen atom is bonded to the CH3 group, and R=β-naphthyl; RI-Ckl
, and 1 (if 2=R3=#, X is -0-C112-
Corresponds to p which does not represent C112-.

Compounds of the general formula (+) which can be suitably used according to the invention are those in which R is an optionally substituted naphthyl, diphenyl or phenyl group, particularly preferably a naphthyl or diphenyl group, especially α
- or β-naphthyl. However, these groups are preferably 0.1 or 2
substituents, in particular Br or Ct, the bromnaphthyl group being particularly preferred.

Compounds of the general formula O) which can be further suitably used according to the invention include those in which RI is phenyl, pentyl or hacyclohexyl, or
a, preferably a hydrocarbon group having 1 to 4 carbon atoms, optionally having a hydroxyl, ether or ester group, particularly preferably an optionally substituted ~C4 alkyl group e [and R2 is a preferred RI Something that has a meaning or represents hydrogen. However, preferably at least one of the radicals R1 or R2 is not hydrogen and R1 and J (2 together have 2 to 7 carbon atoms, especially 2 to 4 carbon atoms).

A compound of general formula (1) which is more suitable according to the present invention is one in which Rs is hydrogen or an aromatic acyl having 7 to 13 carbon atoms M-1
% represents a carboxyphenyl or hacarboxynaphthyl group, provided that these groups may optionally contain one or two substituents from the group comprising halokene, trifluoromethinope61-C4 alkoxy and nitro, It is something. Note that R3 is particularly preferably hydrogen.

Finally, compounds which are suitable according to the invention include
CIi2-C112-, -5-CR2-CH2-.

-C1i2-CR2-, -C112-CR2-CH2 or -C1i-.

1i3 1 o'clock -0-CH2-CR2-, -CR2-, CH2-
Representing CR2- or -CH-, (?Z/.

It is something.

If R3=fl, the compounds which can be used according to the invention may exist, in addition to the form represented by formula (1), in one of the following tautomeric forms or as a mixture of possible tautomeric forms: Pyrazolone derivatives of the general formula (R) which can be used according to the invention may be described in German Published Patent Application No. 2,319,280 (U.S. Pat. No. 3,957,814); U.S. Pat. No. 4,004,641), No. 2.554°701
and No. 2.554.703 and can be produced by the method described in detail therein.

Compounds of formula (1) with R3=H are prepared by: A) a hydrazino of formula % () in which R and , for example alkali metal and alkaline earth metal hydroxides and carbonates, or...in the presence of hydrochloric acid, sulfuric acid or sulfonic acid, a compound of the formula and Y represents a cleavage group, such as a hydroxyl, alkoxy, aralkoxy, amine or alkylamino group] at 10 to 200°C, or B) formula % formula % () [ wherein R has the meaning given above and A represents a cleavage group, for example a halogen or a noalkyloquinium, dialkylsulfonium or alkylammonium group or an aryl or trifluoromethyl-sulfonic acid group; if appropriate in the presence of an inert solvent and an inorganic or organic base, such as an alkali metal hydroxide, carbonate, alcoholate, hydride or amide, in which 1?1 and R2 have the abovementioned meanings M. or C) an acetylenecarphonic acid interferon of the formula %() [wherein R1 and y have the meanings given above] is reacted with a pyrazol-5-one derivative at a temperature of 10 to 200°C, or If so, it can be obtained by the method of reacting with one hydrazino of the above formula (1) at a temperature of 50 to 200°C in the presence of an inert solvent and an unradical or base.

Compounds of the formula (+) with R3=H can be prepared using a compound of the formula λl [wherein l(, XXR1 and R2 have the meanings given above, l ), if appropriate an inert solvent and a basic auxiliary For example, in the presence of an alkali IJ i group or alkaline earth apricot hydroxide and a carbonate or an organic base such as triethylamine or vilison, at an polarity of -20 to 150'C, α) formula [wherein A' is Examples of cleavable groups include hydrogen or a five-membered heterocyclic azole ring, or an alkyl group attached to a carbonyl carbon by an oxygen or sulfur atom, or a phenyl group optionally substituted with one or two nitro groups, and R4-C=0 has the meaning of R3] or b) formula % formula % () [wherein R5-502Fi R" (D has the meaning L, and A" is a halo It can be obtained by a method of reacting with a sulfonic acid derivative of

Surprisingly, the pyrazolone derivatives which can be used according to the invention inhibit lipoxygenase activity which acts on the biosynthesis of chemotactically active eucotriene B4 and spαsmogenically active eucotriene C4 and l)4. .

Known glue boxignase inhibitors, such as nordihydroguaiarethenic acid (nordihydroguaia, r.
e-tic acid), 3-amino-1-(3-)
(Lifluoromethylphenyl)-pyrazoline (B!J'7
55C), Phenidone 7, and 5,8°11.14-eicozatetrae/acids have the disadvantage that they are simultaneously active as cyclooxyrnase inhibitors or are only active at very high concentrations. . Inhibition of the enzyme cyclooxenase from the metabolism of arachidonic acid leads to a total inhibition of grosstag2in synthesis and to stimulation of the lipoxykinase pathway, which causes toxicity, pro-inflammatory and asthmatic effects, and brostanculin synthesis. This leads to an increased tendency for thrombosis as a result of the ban.

Such inhibition of cyclooxysignase does not occur upon administration of pyrazolone derivatives that can be used in the present invention. On the contrary, these derivatives exhibit pronounced anti-ischemic, anti-inflammatory and gastroprotective effects.

Surprisingly, the pyrazolone derivatives used in the present invention are
It selectively inhibits 5-lipoxycanase, which is useful in the biosynthesis of leukotrienes B4, C4, and D4, while inhibiting the endogenous lipoxycanase inhibitor, which is useful in the biosynthesis of 15-hydroxyeicosatriene C1k (t5-METE). 15-17 boxignase is not inhibited or 10μm/
It even stimulates it at a concentration of ml. Similarly, 1
2-IJ boxycanase activity is not inhibited at these concentrations of pyrazolone derivatives that can be used in the present invention. Furthermore, the pyrazolone derivatives that can be used in the present invention specifically stimulate the synthesis of prostacytalin (PGI2).

Surprisingly, in the presence of the pyrazolone derivatives that can be used in the invention, only pGI2 synthesis is stimulated, while vasoconstriction and TXA2 synthesis are unaffected. Furthermore, the pyrazolone derivatives that can be used in the present invention locally exhibit bronchodilatory effects. This is particularly useful in the treatment of ischemic tissues (eg heart-brain and peripheral vessels). The pyrazolone derivatives that can be used in the present invention more specifically inhibit the production of PGI2, thromboxanes, and leukotrienes, in contrast to indomethacin, which has an overall inhibitory effect on the synthesis of prostaglandins from arachidonic acid. Intervening in the metabolism of critical enzymes, it not only reduces the harmful vasoconstrictive and arrhythmogenic effects of thromboxanes and leukotrienes, but also increases their bronchodilatory action by stimulating the production of prostacytalins.

Furthermore, pyrazolone derivatives that can be used according to the invention are:
Reduce or eliminate the deleterious effects of rapid influx of oxygen following periods of hypoxia or anoxia.

Damage caused by reoxygenation is caused by bypass operation (by
pass operation). The pyrazolone derivatives which can be used according to the invention are therefore suitable for preventing acid-based damage in such operations.

It has surprisingly been found that one pyrazolone derivative according to the invention reduces the stickiness of leukocytes, ie increases their migration speed. This reduction in the adhesion of leukocytes, after treatment with the pyrazolone derivatives that can be used in the present invention, is due to the fact that leukocytes become confined to small blood vessels or hairs, corresponding tissues as a result of complete or temporary occlusion of 1ill blood vessels. Since it can pass through these microcirculatory system areas without causing the phenomenon of additional supply, it leads to a reduction in the area of ischemia.

The pyrazolone derivatives which can be used according to the invention furthermore include pulmonary arterial hypertension, hepatic embolism, cerebral edema and shock encephalopathy (
It can also be used for the treatment of A RJ) 5 = Adult Respiratory Distress Syndrome). The bronchodilating properties of the active compounds can be demonstrated, for example, using segmented lungs of guinea pigs/Z)
(F, P, Lwtiuene et al., Arch.

Int, Pharmacodyn, III, 3
92 (1957)).

The compounds which can be used according to the invention are also suitable for the treatment of eye and skin inflammations, in particular xicosis and vitiligo.

Moreover, the pyrazolone derivatives that can be used according to the invention surprisingly reduce the size of cardiac infarctions following myocardial deficiency 1,
Positive influence on the modulation of heart rhythm. The use contemplated by the invention of the pyrazolone derivatives which can be used in the invention is not analogous to the above-mentioned uses known from the prior art.

Substances for the treatment of modulations in cardiac rhythm are classified according to their electrophysiological effects.

Vaughan JVitliams (ph, arm
ac, Ther.

Since the classification of B1, 115.1975), types of methods have been distinguished: 1) antiarrhythmic agents that stabilize the membrane a) Quinidun type, such as glocaine (procα-1n);
e) and ajmaline, and b) lidocaine types, such as lidocaine and sophenylhydantoin.

++) β-receptor detergents, such as Gulo-Zonolol.

n+) Calcium antagonists, such as Vera Gumil (v
erapamil)1. , = 7 Ejibi' :/
(n,1)-edipine etc.

■) Substances accompanied by a sustained increase in action potentials, eg amioda o y (amioda, rone).

The pyrazolone derivatives which can be used according to the invention cannot be classified into the above-mentioned groups ((for this reason) on the basis of their chemical structure or on the basis of their traditionally known action. It was not expected that the pyrazolone derivatives that can be used according to the invention would exhibit an antiarrhythmic effect.Based on the antithrombotic effect, it was not expected that the pyrazolone derivatives that could be used according to the invention could be used in the expansion of myocardial ischemia after vascular occlusion. It is also particularly unlikely that they independently limit the expansion of occlusions in coronary vessels, thus reducing the size of infarcts and also providing rapid healing to the circulatory system, with almost no side effects. Pyrazolone derivatives that can be used according to the invention reduce ischemia-induced hyperplasia in the S area as an indicator of infarction as shown in animal studies; The waves increase less rapidly and regenerate more quickly; the ST interval does not change much in controls, concluding that repolarization of cardiac muscle cells is improved with a reduction in cardiac infarction. become.

In addition to the pyrazolone derivatives that can be used according to the invention:
The medicament according to the invention also includes pharmaceutically acceptable diluents or excipients. These, after mixing with the active compound,
It is understood as a non-toxic substance which renders the active compound in a form suitable for administration. This term refers to pharmaceutically required ingredients, such as salts in the correct amount to produce blood isotonic formulations.
Water and low molecular weight organic solvents commonly used in chemical synthesis are preferably excluded, except where buffers, surfactants, colorants and flavoring agents and preservatives are present.

The following substances are examples of suitable solid and liquid diluents and excipients: aqueous buffers which can be made blood isotonic by the addition of nigercose or salts; non-toxic organic solvents such as paraffin, vegetable oils, alcohols and glycols; Aqueous W! natural rock materials (eg kaolin, aluminum oxide, talc or chalk); synthetic rock powders (eg highly dispersed silicic acid or silicates); sugars; and cellulose derivatives such as methyl'hydroxyethyl cellulose (Tylose)! f,
shallow liquid.

It is preferably contained in an amount of 1 to 90% by weight, particularly preferably 5 to 50% by weight.

Oral administration can be carried out using solid and liquid dosage forms such as powders, tablets, dragees, capsules, granules, suspensions, solutions, and the like. If desired, the dosage unit may be microencapsulated for oral administration, for example by coating or encapsulating the particulate material with polymers, waxes, etc., for sustained release or long-term persistence. good.

Parenteral administration can be carried out using liquid dosage forms, such as sterile solutions and suspensions intended for subcutaneous, intramuscular or intravenous injection. These dosage forms are prepared by suspending or dissolving a measured amount of the active compound in a non-toxic liquid extender suitable for injection, such as an aqueous or oily vehicle, and sterilizing the suspension or solution. . Stabilizers, preservatives and emulsifiers may also be added.

In general, the daily weight-based active compound dosage for humans is 0.01 to 50 m2/9 for parenteral administration.
preferably 0.1-10 ■/kl) and 0.1-500 mg/kg for oral administration, preferably 0
．． 5-100 q/ky and particularly preferably 1-50
It is 9 in town.

Dosage units (tablets, capsules, etc.) generally contain from 1 to 100 q, preferably from 5 to 50, and particularly preferably from 10 to 30 q of pyrazolone derivatives that can be used according to the invention.
Contains.

Example 1 Human PMN leukocytes (>95%) used in this example were
From heparinized whole blood, 1"iccrll-Pa
qwe) (see A. Boyrbrn, 5cand
,,J.

1'tranu, nol,, 5, complement 5 r 9 (
1976) ).

Cells 2X I O7/1tre and Ca 1) ulbecc.

- Suspended in phosphate buffer and incubated with radiolabeled arachidonic acid and calcium ionophore A23187 in the presence or absence of lipoxygenase inhibitors (-
is. 15 minutes later, sign, plus 71? The xyrinase products are acidified [also extracted from the culture medium and separated by thin layer chromatography using a mobile phase mixture appropriate for the leukotrienes (5-11ETE,'-LT,B,i). B. Jakschik et al., BiocI
bern, Biophys, Bes, Crownw
n, , 102.

624 (1981), ).

The distribution of activity among the various metabolites was determined using a thin-layer scanner. This is a measure of the test substance's inhibitory effect on boxygnase at a certain concentration.

Lipoxycanase metabolites were also independently determined by high performance liquid chromatography. This method allows the study of endogenous arachidonic acid metabolites with the help of UV quantification of leukotrienes. In this method, whole cells were treated as described above, except that radiolabeled arachidonic acid was not added exogenously. and high performance liquid chromatography using LiclLrosorb RP.
-18 (s μm) column. The mobile phase was methanol/water/glacial acetic acid 69/3110.01. The flow rate was 1 nre/min. Leukotri using UVg&yield if valley, x-7134f at 280 nm and HE
The TE derivative was determined at 232 ntn.

The inhibition of L T H4 bovine synthesis by various pyrazolone derivatives is shown in Table 1 below: (Control) 10-' 89 5 , 10-' 61 1O-s 82 5.10-' 52 10-' 36 i o −' g 3 s, io"' s.

10'-' 4Q 10-'' 100 5.10-' 100 10 = 58 5.10-7 30 Example 2 Pyrazolone derivatives in a microsomal mixture from ovine seminal membranes (R5VAf) and bovine arteries (RAM) demonstrated in vitro the specific pGI2 stimulatory effect of F. Cottee et al.
ins, 14, 413 (1977)). 3B-
Arachidonic acid, pyrazolone derivative 3X10-'v/-
10 at 25°C with a mixture of R5VM and B#i in the presence of
Incubate for minutes. The reaction was stopped by acidifying to pE 3.5. Fatty acid metabolites were extracted with ethyl acetate. This ethyl acetate was diluted with N.

The residue was evaporated down to CB501//C11C1, (1
: 11 and the mixture was placed on a thin layer chromatography plastic sheet. Ethyl acetate/glacial acetic acid/
Inoctane/1120 (110: 2'O: 50
Separation was carried out with a mobile phase mixture of :10; organic phase) (
P. Needleman et al., The Journal
of CL, 1ni-xl Investigat
ion, 61, 8' 39-849 (1978)
). The distribution of radioactive substances was measured using a radio scanner.

The table below shows the R5V of pyrazolone derivatives (10-'f/'n:l) compared to control experiments without active compound.
The effect on the synthesis of various prostaglandins in M. A useful mouth for models and I.
, Δ, , Bra, y et al., Prostagrandit
bs.

2 213 (1981)). The less sticky the cells are, the greater the number of white blood cells counted.

In this model, the following pyrazolone derivatives were investigated. .

Male Golden Hamster (80-100
2) Nembutal r', Ik cavity; 6Q 7
rr77' was anesthetized with 9). P, 1'; 1
After inserting the 0 catheter into the femoral artery, the animal was
tinH dissection table (MUR.

Above, 42311973) The bulge on the right cheek was pulled by inserting a Q-nup with the soil of J. This was carefully pulled and fixed on the intended part of the stand (7).

From the beginning of the dissection, Su, per fusat 5m1Z
In a minute, I poured it over the prepared bulges of my cheeks. While carefully handling the blood vessels, the overlying tissue was excised longitudinally.1. I turned the sails and stacked them on the side. At a rate of about 200 units per unit, the combined bond rate is 1-
area was carefully exposed. The animal was placed on the objective stage of the microscope together with the dissection table. Insert a thermocouple into the bulge of your left cheek. In this way (2) monitor the animal's body temperature and
The temperature was maintained at 36±0.3°C using an R-lung (250 watts).

Leukocyte stickiness was measured at approximately 500x magnification.

carried small veins in exposed areas. The number of leukocytes per unit time (minutes) migrating through a certain section of the blood vessel was counted.

When pyrazolone derivatives were administered intraarterially in a 1% aqueous Tylose suspension, the following results were obtained: Tertiary coat compound 5 Example 4 Pyrazolone derivatives anesthetized with Nemb % t a l perfused in the manner of Lαngendoγf Rabbit (about 2k
Remove the heart from the heart (up to fi') and attach the cannula to the artery and pulmonary artery. To measure isovolumic contractions, a fluid-filled silicone rubber balloon was inserted into the left ventricle through the left atrial appendage. This balloon is passed through a liquid bridge to a liquid sensor (St
atham p 23 D b ). The perfusion pressure was measured using a T-piece in front of the aortic cannula of the heart.
e) was recorded with a pressure sensor connected to the perfusion system. Contraction force and perfusion pressure Gould'j, 600
Recorded using a high-speed recording system. The heart was electrically stimulated with a frequency of 180 beats/min and a stimulation period of 5 ms.

carbogen (0295%
, 'Nt5CH) or Irebs-H blown with a gas mixture of 022CH, Co25.6CH and the balance N2
Perfusion of the heart was performed using enselttit solution (KH bath solution).

The perfusion volume was adjusted to 2,000 ml per 7 minutes using a roller pump (1) Esaga, 132100).

The pyrazolone derivative (1% aqueous Tylose suspension) and the platelet suspension (from the same rabbit from which the heart was removed) were delivered using an infusion pump (roller pump, Bcrrrbn).
-Melsrbngen).

The solution or suspension is passed from the injection syringe through the Taigon tube and thin cannula to the inlet tube just before the heart.
or 0.1 m (injected at a flow rate of 77 min).

The final concentration of platelets is K) i per 1 m/゛ of solution.
There were O' pieces. The solution flowing out of the heart (pulmonary aorta cannula) was collected periodically under water cooling. Thromboxane and 6-kedoP61 as TXli2? .

To determine the degree of prostasifrin as α with the aid of radioimmunoassay, volumetric fractions were lyophilized and placed in 1/10 of the original volume in water.

The perfusion pressure values found in the experiments at the time of administration of the active compound can be found in Table 4 below in comparison with those of the control.

3rd jk - perfusion pressure (% of blank actual value) Phase 1 - Preparation phase; aeration of carbodiene Second phase - aeration of normoxia H carbodiene; addition of platelets I X 107/ml; period = 5 min 3rd phase - same as 2nd phase; pyrazolone derivative I x 10
Addition of -511/-; Duration: 5 minutes Phase 4 - Same as Phase 3, but vented with only 2% oxygen (low oxygen pressure); Duration = 5 minutes Phase 5 - Reoxygenation as in Phase 3 ) Compound 1 Compound 2 The results show that when platelets are added to the perfusion solution, there is a significant increase in perfusion pressure compared to the preliminary phase. If in the subsequent phase perfusion is carried out with a solution of low oxygen pressure (022%),
Perfusion pressure and contractility were significantly reduced. Upon subsequent reoxygenation (1 breath of carbodiene), contractile force returned to approximately the same value as before the hypoxic period; however, perfusion pressure
pressure in the carbodiene phase.

It is surprising that the pyrazolone derivatives that can be used according to the invention, in the first and second carbodiene phases, substantially inhibit the increase in perfusion pressure caused by the addition of platelets to the perfusion solution. This effect is particularly pronounced in the reoxygenation phase that follows the hypoxic positive phase.

Example 5 Effect of Pyrazolone Derivatives on Experimental Heart Infarction in Dogs The effect of various pyrazolone derivatives on experimental heart infarction was investigated in dogs after rapid ligation of the coronary artery. For dogs anesthetized with bendoparvital, the anteriorly descending left coronary artery (LAD) was gently ligated for approximately 6 hours. This artery was not reperfused. Ligation 1
Hours earlier, the pyrazolone derivative was administered into the duodenum as a bolus in a 1% aqueous tyrosus suspension. Control animals were treated in the same manner but received no active compound. The infarct size and perfusion area of the LAD were determined using Evans blue (Evc
L7'Lblue) and the double perfusion method using triphenyltetrazolium chloride (dsal perfr
t, 5iontn, method). Gradually,
After ligation of loose LAD, pyrazolone derivatives substantially reduced infarction. This is observed in terms of absolute infarct velocity and infarct size in relation to left ventricular weight. The perfusion pressure of the ligated artery was the same. Blood pressure initially decreases as a result of coronary ligation, resulting in a reflex increase in heart rate. Otherwise, no hemodynamic effects caused by pyrazolone derivatives were observed.

This compound stimulates infarct-induced accumulation of ST segment 1-(segment) and peripheral EC as a sign of ischemia.
Reduces G R waves. This leads to the conclusion that electrophysiological effects were present.

Literature: Lscchesi et al., J, pharmacol
, Ezp, Thar.

199:310, 1978; and Fiedler, 13
asicRes, Cardiol, '18, 266
(1983).

The results are summarized in the table below.

N: Number of dogs used in the experiment N,: Number of dogs killed by ligation Compound 1: Compound 2: Compound 3: O Table 1 LAD ligation Ligation 6 aid DA DD ED Priority claim @November 25, 1983 Japan West Germany
゛(DE)■P3342628.7 [Phase] Inventor Friedel Schieter Day 5600 Butzpeltal 1 Morspfaert 6 @ Inventor Elisabeth Belzborn Day 5600 Butzpeltal 11 Amtescher Bush 13 @l ! Inventor Klaus Schlossmann Day 5600 Butzbeltal 1 Inderbeek 11 0 Inventor Dieter Mayer Day 4712 Berne Beethovenstrasse 0 Inventor Volker Fiedler - Day 5600 Butzpeltal 1 Cruiser engineering

Claims (1)

[Scope of Claims] J General formula [wherein R has 6 to 12 carbon atoms [and optionally halokane, trifluorotinopearkyl, alkenyl, alkoxy, alkylamino, cyanide, trifluoromethoxy, nitro, Hydroxylpe SO-alkyl (n=O
~2) or 5OfL-trifluoromethyl (n-θ~2
) or hederoaryl radicals which may contain the same or different substituents of 1 to 3111 from the group consisting of 10 represents hydrogen or a hydrocarbon group having 1 to 18 carbon atoms and optionally containing a hydroxyl, ether, ester or carboxyl group and optionally 1 to 3 halogen atoms, R2 has the meaning of R1 or represents a group A, R3 represents hydrogen or an acyl or sulfonyl group each having 1 to 15 carbon atoms, and X represents a group -0-CE2-CH2-, -5-C1i2 -CH
2-. -CB2-CH, -CH,-, -C'l12-CM, -
, -CH2- or -○H-, provided that this oxygen atom is bonded to the it3 group R, and R=β-naphthyl: RI=CH3 and R2=Rs=H; -CH2
- ischemia and heart rhythm modulation, as well as rheumatic, allergic and asthmatic diseases, edema, pulmonary artery embolism, shock pulmonary disease, pulmonary hypertension, dioxygen toxicity, skin 1h and eyes. Use as an inhibitor of polycysinase for the prevention and treatment of inflammation and ulcers. 2. Use according to claim 1, in which R represents a naph-thyl, sophenyl or phenyl group, optionally substituted by one or two substituents, in particular Ct or Er. 3. R 4 represents an optionally substituted naphthyl group. 4 wherein RI and R2 are hydrogen or have 1 to 8 carbon atoms and optionally a hydroxyl, ether or ester group, represents a hydrocarbon radical having preferably an optionally branched 61 to C4 alkyl group and in which either R1 or R2 is not equal to H and R1 and R2 together preferably have 2 to 7 carbon atoms; Claims No. 1~
Use as described in any of Section 3. 5. In formula (+), R3 is hydrogen or has 7 to 1 carbon atoms
5. Use according to claims 1 to 4, in which the aromatic acyl group of 3 represents an aromatic acyl group, preferably hydrogen. 6.3. Use of 4-trimethyl-1-[2-(2-naphthyloxy, 1-ethyl]-2-pyrazolin-5-one as claimed in claim 1). 7. Claim 1 A drug against inflammation of the skin, eyes and impact lungs containing a therapeutically effective amount of the compound of formula (1) as described in Section 1, and a drug with riboxyquinase inhibiting, anti-rheumatic, anti-allergic, anti-asthmatic and anti-inflammatory properties. 8. The drug according to claim 7 in a form suitable for oral administration. 9. Suitable for parenteral administration. 10. A therapeutically effective amount of a compound of formula (1) is mixed with a pharmaceutically acceptable diluent or excipient and administered in a suitable form. Method for producing a drug according to claims 7 to 9 in a long-life form 3゜