DE1961967A1 - Pharmaceutical masses - Google Patents

Description

PATENT ANWXLTE. 1 QC 1 QC7

DR.-ING. H. FINCKE "■ ' I ^ OI y 0 /

DIPL-ING. H. BOHR December 10, 1969 DIPL.-ING. S. STAEGER

MONKS 5

MOLLERSTR. 31

. Cap '22112 - hr
Case PK.21553

Priority: Great Britain from December 10, 1968 _s Ur. 58665/68

Imperial Chemical Industrie's Limited, Great Britain

Pharmaceutical hates

The invention "relates to the treatment of brosghospasm and in particular pharmaceutical cash registers., di © Can prevent spasm and thus for those of diseases in which spasm or constriction The bronchial musculature occurs like SeB * in asthma un bronchitis, are suitable.

It is known that sympathomimetic ₅ sB isoprenaline or adrenaline, bronchospasms ¥ © rhiad, when administered to a host. It has now been found that certain g-friasol © (4-, 3 ~ * a) pyr & ziß derivatives, which can even Bi? Üac? Ii © spaemii.s irerhia, have the effect of tone sympaw ^ © zsiai @ tissli®a imlmm . ä so that the

sympathomimetic amine and an s-Q! riazolo (4,3-a) -pyrazine of the type given below is much greater in terms of preventing bronchospaemus

. than the sum of the effects of the individual components.

According to the invention there is a method of prevention of bronchospasm in humans and fiery in it that the humans or animals have a sympathomimetic amine in conjunction with a s-triazolo (4.3 "-a) pyrazine der fc formula:

Λ 2

is administered, with H and R alky! radical with 1 to 4 carbon atoms », represent" and X is an amino, or Aestaaidoradikal represented

Bi © t> o7o? 2ugte & 3-Φγ1 & 2ο1ο (4 · _} 3 »a) pjraziß-B®riirats are

nad 3--

Je aach & ®n fei ^ logiscfeea ligenscifeaftea 5, © s syapatho mimetisclma Mias hardly the s-frieS)

f "? / ft, -T-

h up '- ■

together with the sympathomimetic amine in the form of a pharmaceutical containing the two components Mass or separate from the sympathomime ti see amine administered. For example, if the sympathomime ti see amine is only effective when it is inhaled, like E.g. with adrenaline or xsoprenaline, the 8-! Triazolo (4,3-a) pyrazine can be administered in this way, for example that an aerosol containing the two components is used, or preferably that the e-3! riazolo (4-, 3-a) pyrazine at about the same time as the Inhalation of the aympathomlmetic amine administered orally will «Is the sympathomimetic amine through oral or parenteral administration, a preferred method of administration is to use one the two containing pharmaceutical hats, e.g., a tablet, capsule, solution or suspension, though separate administration of the components is possible.

The exact proportion of the sympathomimetic amine based on the s-triazolo (4-, 3-a) pyrazine, which is necessary to achieve the to be administered optimally depends on the patient and the components used. in the in general, the amount of the sympathomimetic amine to be administered is 0.1 to 5% by weight of the amount of s-triazolo (4,3-a) pyrazine administered, and the The total amount of material administered should be 0.5 to 5.0 mg / kg body weight of the patient as required.

«*> 4. - 0 G S 8 2 S / / 1 'ί

According to a further feature of the invention, a pharmaceutical composition is created which is a sympathomimetic one Amine, which when administered orally or parenterally has the effect of a bronchodilator, together with a s ~ triazolo (4,3-a) pyrazine of the above Art eun contains a pharmaceutically acceptable diluent or carrier.

The pharmaceutical composition may be in a form suitable for oral administration, e.g., in the form of a tablet, capsule, Solution or suspension, or any form suitable for parenteral administration, e.g., the form of a sterile injectable solution or suspension. The mass can according to known methods and with known Drug carriers are produced. A dosage form, tablet, capsule, or a specific volume of one liquid mixture should total 10 to 100 mg of sympathomimetic amine and s "-triazolo (4,3-a) pyrazine contain, of which 0.5 to 5 wt # from the sympathomimetic Amin should exist.

Particularly suitable for a pharmaceutical according to the invention Mass is because of its potent effect on bronchial muscles and its relatively weak A 2-amino-i-phenylethanol derivative has an effect on the heart muscles the formula:

009826 / 21U

HCCH ₂

Ηθ / ΛθΗΟΗ

where R * is a branched alkyl radical with up to 6 C atoms, which may be represented by a fhesyl, phenoxy, Hydrostyphenyl, methoxyphenyl or morpholino radical is substituted, represents, or a pharmaceutically acceptable one Acid addition sal of it. Of these 2-amino-1-phenylethanol derivatives the compound in which R * represents the tert-butyl radical is particularly preferred.

If such a 2-amino-i-phenylethanol derivative in a pharmaceutical composition according to the invention is used is, it should be 0.5 to 5 Gew # des s-Triaaolo « (^, 3-a) pyrazines, and a dosage form for Treatment of asthma should contain a total of 10 to 100 mg of active ingredients.

Other suitable sympathomimetic amines «di @ in the pharmaceutical hates according to the invention can find are compounds of Formei

r \

or .

CHOH.

wherein R * is a branched alkyl radical with up to C atoms, e.g. an isopropyl or tert-butyl radical, represents. These compounds can be incorporated into the compositions of the present invention in the same manner as those above 2-amino-1-phenylethanol derivatives described are incorporated will.

The invention is explained in more detail below, purely by way of example, by way of examples.

example 1

A mixture of 25 (Dellen 3 ~ acetamido-6-methyl-8-n-propyl-s-triazolo (4,3-a) pyrazine, 0.25 parts 2- (tert.-

(If necessary as the ll f © il © a corn starch, 150 ropes. Oalclumphdsphat m part Magnesiuiast ^ arat is processed gaprssst imd daaa tkm Durchgaag through a 16 © r Haseh @ ^ gitt @ r on a granulate. This Srasmlat wii-I dsaa

«S ψ

009

Compressed into tablets each with a total of 25 mg of active ingredients.

Example 2

Its normal lung was taken from a guinea pig and on that of Bhattacharya and Delaunois (Arch. int. pharmacodyn. 1965 »Volume 101, p.495) described Apparatus mounted. The lungs were with Tyrode solution containing 3% dextran, in an amount of 2.0 ml per Minute watered while breathing artificial respiration with a pump that pro Stroke delivered 9 ml of air and carried out 22 strokes per minute. Changes in air pressure in the trachea were made measured with a pressure transducer connected to a registration device, so that by the presence of Acetylcholine in the liquid used for pouring induced bronchospasm could be measured. Test compounds and acetylcholine were added to the Tyrode solution used to douse the lungs was added at 4 x minute intervals after the addition of the Test compound added. The extent of the Acetylcholine-induced bronchospasm was measured and assessed with the extent of acetylcholine compared bronchospasm induced in the absence of a test compound.

The result is as follows:

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Treatment % bronehospasmas

Aeetyleholin, 2.5 VB 97

«2- (tert.« Butylamino) -1 «<[(4-hydr © 3 £ y-

J-hydroxymethyl) phenyl) ethanol, 0.05 Wg · Fighted with acetylcholine (2.5 VE) after;

4 minutes 64

8 minutes 78

12 meows. 87

B, 5 ~ acetamido-6-methyl-8-n ~ propyl-striazolo (4,3-a) pyrazine, 5 V € Fights with acetylcholine (2.5 Wg) after:

^ - minutes 89

C. 2- (tert-Butylamino) -1 - ((4-hydrosy-3-hydro3iymethyl) phenyl) ethanol, 0.05 Wg + 3-acetamido ~ 6-methyl - 8-n »propyl-striazolo (4,3-a) pyrazine, 5 µg. Fights with acetylcholine (2.5 wg) after:

4 minutes 24 8 minutes 45 12 minutes 63 16 minutes 74 20 minutes 75 24 minutes 71 28 minutes 72 32 minutes 88 D. In a separate experiment: 2- (tert.-
ButylaminoT-ii (4 ~ hydro: xy-3 - bydro3i3rmethyl) - phenyl ^ ethanol, 0.2 wg.
Fights with acetylcholine after: 4 minutes 46 E. 3-Acetamido-6-methyl-8-n-propyl-s-
triazolo (4,3-a) parazine, 20 µg.
Fights with acetylcholine after: 4 minutes 88

Aue from this summary it is clear that treatment with the two drugs in combination

009826/21 U

ι Ό Ό I <J Ό ι

G) a greater ιμ & persistent® effect would be obtained than the separate processes with individual components with the same B (need A and B) or with a · ^ .fold (experiments B won E).

Example 3

The procedure of Example 2 was and the results were printed out to a starry time after administration of the fixed connection than the prose & tiial © Mm of acetylcholine induced by the Brcnchospasmiis! Fixed connection.

The following results were obtained:

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B. 3

XsopreaalizL, © »005 μg + 3Aid6thl8

gropyl-s-iiriazoXc (4-, 3-a)

pymzi & s 5 hp

, 0.01 µg

Adreaalia, 0..05 μ§

3- & eetamido6methyl8n propyl-s ~ triazolo (4,3-a) pyrazine, 5

0. Adrenaline 0.05 tig +

3 ~ acetamido-6-methyl-8-n-

propyl-s-triazolo (4,3-a) -pyrazine, 5

H. adrenaline, 0.1

: ampft old l & @ tylcholine

4 8 12

4 8

Hem bronchial

11th

34 20 13

75 36

67 29

Baraue can be seen that the treatment with a Mixture of the two drugs (experiments C and G) one had a greater and more persistent effect than a treatment with only one component (test A or B

- 11 -

009826 / 21U

or experiment E or F) at the same dosage or a treatment with the sympathomimetic Amine at twice the dosage (test B or H).

12 -

009826/2114

Claims (1)

Mass, thereby kens ^ aieimet, si © aiii eympmthomimetisches imia, ias at oral? ©; parenteral administration as Br @ fishodilator wi ^ K evusaBUBen with a s »frIazolo (4-, 5 * a) pyrazind @ s? iY © ^< ö d @ a? E ¹ 1 'wiiA S ^e ÄllQrlradikalische ait i © 1 to 4 C-nBi. 1 © in amino, hydroxy, formamido acetamido radical contains. lass® iiacii Ad sprue h 1, characterized in that rirat ^ ~ Acetamido-6 « _i 5-a) pyrazine used netefc claim 1, characterized in that is used. - 13 - 0Q9826 / 21U 4. Composition according to one of claims 1 to 3, characterized in that a 2? 2-Amino-i-phenylethanol derivative of the formula: or a pharmaceutically acceptable acid addition salt thereof is selected, "where R * represents a branched alkyl radical having up to 6 carbon atoms, the given if substituted by a phenyl} phenoxy, hydroxyphenyl, methoxyphenyl or morpholino radical can be. 5. Composition according to claim 4, characterized in that Έ? represents the tert-buty! radical. 6. Composition according to one of claims 1 to 3 »thereby characterized that as a sympathomimetic Ami η a compound of the formula: HO- ^ ^ »C HOH.CH CH * or - 14. - u . ■ 9 ii 2 ti / 2 1 14 CHOH. CEL. HHE * is chosen, where R * is a branched alkyl radical represents with up to 6 carbon atoms. 7 · Hasse according to one of the preceding claims, characterized marked that the amount of the sympathorn emetic Amine 0.5 to 5% by weight of the amount of the s-Tri & E Io (4,3-a) -pyrazine derivative amounts to. 8. Composition according to claim 7 »thereby g © kf; 2ms @ ichnet that a total dose of 10 to 100 mg of sympathomimetic amine and 3-sriazolo (4,3-a) pyrazine derivative contains together. 9 · Pharmaceutical composition, characterized in that it contains 2- (tert-butylamino) -1 - ((^ - hydro3 {y-3-hydroayinethyl) · phenyl} ethanol, optionally in the form of its hydrochloride together with 3-acetamido «€« -inesi] ^ I »8 ~ n-propyls-triazolo (4,3-a) pya? azine and eißts · pl ^ ^ sjr ntisea permissible Yerdünnungsmittel or Timi -nthält 10 »composition according to claim 9» characterized IMSS & ^ "i.öanet, de EJ oils amount of existing 2- (t9rt ~ butylamino) -1- - 15 009826 / 211A s o ₉ 3 Ms, and and 5- * 8-n-propyl- s-feria2} ole (4 _s 3 ^< "a) P3 ^r 3razin SBueassii®m generally a dosage form 10 I) is 100 mg. 11. Kaeee nach. ^ Proverb 10, thereby gekesaxLsssicteiet _s -Maa it has the form $ iii @ r tablet or capsule » 12. Method for Terhlmderung von Bronchospasm humans and ^ la ^ & m, thereby gsk @ Bsis @ i®linet, the Me ^ 3ch bsw. U;, ...:? sin sympathomimertische3 in connection with an 8-of the formula I according to l ^^ imch 1, in which E ¹ , It nsd Σ which is in claim. 13 · The method according to claim 12, characterized in that the administered amount of Amine 0.1 to 3% by weight of the administered heng s-Triazolo (4,3-a) pyra2i2 \ ö, and that total amount administered of the two is 0.5 to 5 nigAg. UK.-INÖ H FINCKI DIPL-IMa.i1.B0HK DlMWALII 009826/21 1 4