DE1670633A1 - Agent for triggering fibrinolytic activity in mammals - Google Patents

Description

to trigger fibrinolytic activity Mammals

The invention relates to agents for inducing fibrinolytic activity in mammals, especially of the kind which have a high-grade, long-lasting and useful fibrinolytic activity in mammals a.by the action of AlkylenbisjJ-jE ^ f ¹ ! - tetrahydroisoquinolineJ compounds according to formula A or below their pharmaceutically acceptable acid addition salts, as well as preparations containing such substances

Formula A.

-2-

in the

IL _f H ₂ I Ro and H ₁ , a hydrogen atom or liiedrig-

alkyl,

BI, 35 | Hi ¹ , H £, Rg and R £ · mean a hydrogen atom, lower alkyl, a halogen atom, hydroxy, lower alkoxy, lower alkenoxy, lower alkynoxy, lower acyloxy, aryloxy, phenyl-lower alkoxy, amino, lower alkylamino, lower acylamino or nitro. Two substituents in each case on one of the aromatic rings or on both can be linked and then form lower alkylenedioxy.

"Alk" means straight or branched chain Alkylene radical with no more than 15 carbon atoms.

The term "pharmaceutically acceptable acid addition salts" includes salts such as those of mineral acids. e.g. the hydrochloride, hydrobromide, sulfate and phosphate, and of organic acids, e.g. the succinate, lactate, benzoate, acetate, p-toluenesulfonate and benzenesulfonate, as well as salts of other acids commonly used in pharmaceuticals.

When a blood clot such as a thrombus forms, fibrinogen, a soluble plasma protein, is released into the

009887/1844

insoluble protein converted to fibrin, which, when deposited, traps blood cells in its network and forms a coagulate. In a thrombus, the clot usually obstructs blood flow through the Vessel 3.

Living organisms defend themselves against such a process with the help of the % denoted by plasminogen

rlastfaproteins, which under certain conditions by an "activator" can be activated, converting it into the protein flasnin. This Plasnin owns the (fibrinolytic) property of fibrin being effective Being able to digest and destroy leads to dissolution of the blood clot and in the case of a thrombus '! leather production of the vascular patency leads.

Under normal conditions, the organism has a low level of activator in the bloodstream. Probably a small ilege of plasminogen is constantly being used converted into plasmin by the action of the "activator"; In terms of quantity, however, that is usually enough Existing activator quantities are not sufficient to produce enough piasmin for the in one Blood clots, e.g. thrombus, an abundant amount of fibrin present is loosened.

009887/1944

The compounds according to formula A above have now the property that they produce comparatively large amounts of "activator" activity and / or able to stimulate their release into the bloodstream. In The main thing is that these compounds cause increased activator levels, which in turn cause high levels of piasmin produce in the clot and thereby cause it to dissolve.

So you can use the formula A compounds to to dissolve fibrin deposited somewhere in the organism regardless of the cause of its deposition.

Although many compounds show fibrinolytic activity in the test tube, such as ζ «3« the aromatic sulfonic acids, Derivatives of salicylic acid, long chain fatty acids and halogenated unsaturated acids. In contrast are, what is much more important, those according to the invention Compounds effective in the living organism

It is true that fibrinolytic activity can also be induced in living organisms by means of nicotinic acid, procaine, phenylbutazone, acetylcholine, epinephrine, serotaine and camouflage. The efficacy of these compounds IEFC "over several minutes of just short, as pilot," The

009887/1944

jt? oroel Α connections, on the other hand, call for a long-term, E.g. hours of flbrinolytic activity.

Increased fihrinolytic activity can also be achieved with cause some sulphoroareas and steroids? however, it only takes hours before a slight increase in activity occurs. Connections of this kind are therefore for the therapy of dissolving the thrombosis cannot be used, since in this case the activity can be induced very quickly must in order to achieve effective clot dissolution. In contrast, the Formula A are compounds In this application case it is highly effective, as the cause maximum resolution activity.

Streptokinase, a streptococcal protein, has been used for thrombolysis, but perhaps by fleber f driving and anaphylactic side effects in their Application restricted. The formula Α compounds on the other hand are free from these side effects.

Urokinase, a protein isolated from human urine, has also been used for thrombolysis. Of their general and practical applicability are available

0090 * 7/1044

.6-

the difficulty of accumulating large amounts of the Urine source material and the high costs of substance production in the V / ege.

Bacterial pathogens have also been used to achieve thrombolysis} the severity and unpredictability but the feverish reactions have denied their usefulness. The formula A compounds In contrast, they are not feverish.

In short, the fibrinolytic formula A represent compounds represent the first synthetic substances that show activity in mammals in the living body, highly effective, long lasting, quick to break out and easy to manufacture and do not suffer from any of the difficulties associated with materials of natural origin.

You can use the formula Α compounds both for clots, dissolution in acute thrombosis as well as prophylactic use to increase fibrinolytic on a long-term basis Maintain activity and thereby the appearance of new thrombotic phenomena to decrease.

-7- 00 ** 87/1 * 44

The Alkylenbio £ l, 2,3,4-tebraiiyli'alaaoUiftolInJ »Compounds and their acid addition al part of the preparations of the invention are owned by According to the invention, high activity and therefore produce flbrinolytlsohe in mammals Effects even in such small doses that side « Effects are generally negligible "

Hei the compounds in which the H- · and Rg-Sub- ^

substituents in Formula A include hydroxy contents the achievement of good fibrinolytic activity is accompanied by idle to pronounced hypotensive mechanisms.

Since in general oxygen-containing S'ibstituenten the

promote maximum fibrinolytic activity, one adds according to a preferred embodiment of the invention

in the EL and R ^ substituents a liiedrigalkoxy- ä

rest or more such as Hethoxy, Isopropoxy,

Butoxy or methylenedioxy preferably in the 6 * and

7-position of the tetrahydrolsoquinoline ring because they show the highest effectiveness here *

Without giving up the fibrinolytic potency, one can alkylan chain denoted by * alk "elsewhere

009887 / 19U

Limits vary, but the highest activity is obtained when the two tetrahydroisoquinoline rings by a chain of 3 to 10 carbon atoms, such as 2-propyltrimethylene, tetramethylene, 1,8-üiethyloctamethylene and decamethylene, are separated from each other.

Preferred compounds are those in which R ₁ , R ₂ , R ~ and Η represent a hydrogen atom or an alkyl radical with a maximum of four carbon atoms. Compounds in which R ₁ to R ^ consist of a hydrogen atom or methyl are particularly preferred.

The formula Α compounds are easy to prepare can be carried out according to the methods described many times in the literature. In general, they are gained through implementation an appropriately substituted phenylethylamine with a dicarboxyalkane, in which the bridges are between the two carboxyl units of the desired alkylene chain length is equivalent to. The resulting bis-phenylethylamide

then
is cyclized / by dehydrogenation to give an alkylenebis (-3 _f 4-dihydroisoquinoline) and the latter is finally reduced to the corresponding alkylenebisyl _f 2,3 _f 4 «tetrahydroisoquinoline as the desired formula A compound.

0Q9887 / 1944

It can be seen from the synthesis steps which take place in the preparation of these compounds that they can occur in isomeric forms. In the simplest case, ie when all four R ₁ to E ^ substituents in formula A represent hydrogen atoms, there are dl and mesodiastereoisomers. If you add more asymmetric centers, the situation becomes even more complex, and even more diastereoisomers are possible »

Both types of substances, namely both the various diastereoisomers and the diastereoisomeric mixtures, from which they were derived were examined for their fibrinolytic potency and were found to be in all cases as effective in this regard. The formula A therefore encompasses all that arise during the compound synthesis Isomers, and the name and formulaic identification • of the formula Α compounds in the description and connection

• should spray · «* for all isomers and their mixtures apply unless expressly stated otherwise.

An excellent feature of the Formula Α compounds is their comparatively non-toxicity. O'Although they are already on If you are active at a very low dose level, you can achieve this lowest level of effectiveness within wide limits

Q09887 / 19U -io-

exceed _f without causing serious damage. As a result, the compounds can be used regardless of the undesirable side effects that otherwise occur so often in the event of an unwanted overdose of other highly effective substances. For example, when administered intraperitoneally to rats, the formula Α compounds were already effective at a dose of 0.05 mg / kg pibrinolysis, but could actually still be administered at a dose of up to 100 mg / kg. When administered intravenously to hats, efficacy was present at doses between 0.05 and 80 mg / kg and when administered orally also to hats at doses between 5 and 300 mg / kg. In dogs they showed efficacy when administered intravenously at both 0.5 mg / kg and βθ mg / kg. They can be administered to humans parenterally in doses between 0.1 mg / kg and 50 mg / kg. These dose information may only be viewed as illustrative and in no way restrictive of the application of the invention. Veterinarians and vet doctors will find it advisable to tailor the dose to the individual response of the patient.

-11. 009887 / 19U

The preparations according to the invention contain an Alkylenbis £ 1,2,3, ^ -tetrahydroisoquinoline according to formula A or a non-toxic acid addition salt thereof as well as a solid or liquid carrier substance and can be in the form of tablets, capsules with dry or liquid fillings,;, dragees, pills, aqueous or non - .. äßrigen Lösunf.-en, pastes, suppositories, syrups, suspensions, sprays, vats or the like are present · a comprise in addition they t.ögllcherweise or sometimes actually preservatives, dyes and üeschnacksstoffe. Examples of suitable products for the production of the products according to the invention are Gc-latine- :: ai ".5eln, .uoker types like lactose and sucrose, cellulose, ethyl cellulose and cellulose acetate phthalate, gelatin, lallcua, magnesium stearate, plum oils such as peanut oil , Eunwollseed oil, sesaa oil, olive oil, ilais oil and cocoa butter; Paraffin oil, polyethylene glycol,

Glycerine, sorbitol, propylene glycol, ethanol, agar-agar, "

Uasser una-isotonic salt solutions,

At dex ·· preparation of the preparations according to the invention the usual ones are used for pharuaseutic approaches Manufacturing and pre-production measures. Preparations to be administered parenterally must be sterile, and too for this purpose they are either made from sterile ingredients

BATH ORIGINAL

009887 / 19U

and manufactured under aseptic conditions or after Completion sterilized according to the usual methods, e.g. by means of micro-pore titration. Of course you have to make sure in the usual way that the active substance and the diluting preservative or flavor with each other and also with there are no disruptive conditions for their production

The compounds of the invention can be administered to mammals by the oral, rectal or parenteral routes will. This can be done by the liquid preparations intravenously, intramuscularly, injected intraperitoneally or subcutaneously, swallowing solid or liquid preparations, pastes, suppositories » Tablets or the like applies locally to the mucous membranes or the liquid supply lines in sprayed inhaled or nebulized form.

In emergencies, administration to individuals is preferably intravenous and at one rate from 0.1 to 10 mg in the minufe. For this purpose, the preparations according to the invention are diluted with isotonic solutions, e.g. 5-strength aqueous dextrose, Fructose ·· or Hannitol solutions. Since the mineral aura

009887 / 19U

• 13-

Salts of the compounds according to the invention, in particular in Presence of excess mineral acid ions only limited are water soluble, dilution with physiological saline solution prior to intravenous administration is not expedient.

To facilitate the doctor and are de "economic advantage for the patient and the manufacturer A novel compounds concentrated, sterile solutions in ampoule or vial are supplied preferably in the form, which then medical opinion must be diluted accordingly. It is best if the total dose required by the individual patient is provided in a single ampoule or vial. However, the hydrochloride salts described in the literature are not suitable for this because of their limited water solubility. Therefore erfln &v> _o ii svjeraäß the much more soluble salts of organic acids preferred for this purpose. For example, one of the most effective agents according to the invention, namely the!,! '- Tetramethylene bisn., 2,3f ⁱ ^ -tetrahydro-6,7-dimethoxyisoquinoline | meso *. isomer, in: Hydrochloride salt form only prepare in working solutions up to a maximum of 7 »5 mg / ml. In contrast, the lactate salt is more than 750 mg / ml, the acetate salt up to 90 mg / ml and the ethanesulfonate salt

009887/1944 bad onfö ^

—1h · -

soluble to more than 400 mg / ml. It is therefore convenient, useful and economically to provide for human treatment, an IC ml ampoule, containing 1,1 '' .Tetraniethylenbis £ l, 2 _f 3 ^ tetrahydro-6,7-dimethoxyisochinolinj mesoisoner-dilactat in a concentration of 50 mg / ml contains. This concentration is about seven times higher than is possible with the corresponding hydrochloride.

The expression "organic acid" is intended to include salts of fully organic acids, such as acetic, halonic, lactic and citric acid, as well as those of only partially organic acids, such as methanesulfone, p-toluenesulfine, ethane disulfone -, trichloromethylphosphonic and phenylphosphinic acid should be understood.

When carrying out the invention, the amount of acid used can be reduced so that the mono-acid and / or di-acid salt of one or the other basic substituent or of both substituents of the formula Α compounds are formed. The invention includes so-Viohl the Ilono-j as well as the di-salt, and in the manufacture of the latter reaction is carried out optionally with a small About Schus, ie with more than 2 Hol acid in relation to the free base,

009887/1944

Preferably used; reacting organic acids and their provides Saliifj 'lurch Unsettling of the basic formula, ^{A-Ver-V-Ouug:'} i ^fc of such an acid and indeed the simplicity hnlbr »r Gegenv.'art in a suitable solvent forth. A preferred solvent is a nicer alcohol and most preferably methanol. The implementation we ;! vormr; oijeif! o in the Uarine and ar.i simplest carried out under illiokf Iu3kn ν jung of the solvent.

. ! weeks no ei: better understanding of the nature and goal « The invention is based on the following Examples Ijcsu ^ r genonuaen, but the invention only should be understood, but not isolated. All Tent-er?. Doors are given in degrees Celsius.

example 1

1.1-Te tear thy lenblsfi _r 2,3 * 4-tetrahydroisochlnoliii | ». dl hydrochloride

A mixture of 35t2q adipic acid di (2-phenylethyl) amide, M.p. 18 * 1--135 °, and 176 g of polyphosphoric acid became 75 Isiij heated to 190-193 ° C for a while, cooled to 100 ° C and then together with 20 nl more concentrated

y 009887 / 19Λ4

• Pour hydrochloric acid onto ice, wash out with chloroform and benzene, the aqueous layer was made strongly alkaline with aqueous sodium hydroxide solution and with benzene extracted. The benzene extract was washed with water, dried, for purification through a clay column sent and then evaporated. After recrystallization from hexane-ethyl acetate, the residue resulted 1,1 '-Tetramethylenbis ^^ - dihydroisichinoliiil, P. 100-102 °.

In a solution of 44.2 g of this 3,4-dihydrover compound in 500 ml of ethanol, 21.2 g of llodium borohydride were added in portions with stirring. After the exothermic reaction subsided, the mixture was refluxed for 3 hours and then evaporated to dryness in vacuo. The residue was taken up in water, extracted with chloroform and the extract was dried and evaporated to dryness. The remaining oil was dissolved in absolute ethanol and treated with hydrogen chloride and ether. The solid product, consisting of an isomer mixture of the hydrochloride, melted at 335 - 338 ° (decomp.). Fractional crystallization gave an isomer (A), mp 344 * 346 ° (dec ·) of water and a second isomer product (B) _f F. 266-269 ° from ethanol,

009887/1944

Example 2

1.1'-hexamethylene bis [l .2.3. k-te trahydroi sochinolinT- dihydrochloride

A mixture of suberic acid di- (2-phenylethyl) amide, P. 165 - 166 ° and 300 g of polyphosphoric acid was 90 minutes heated to 240 ° for a long time, cooled to 100 ° and then poured into 500 ml of ice water, which concentrated 20 ml Contained hydrochloric acid. After washing with benzene, the aqueous phase was made alkaline and repeated extracted with benzene. Concentration gave 1,1'-hexamethylene bis 0,4-dihydroisoquinoline, which melted at 90 after recrystallization from acetonitrile.

13 g of sodium borohydride were added to a solution of 30 g of this dihydro compound in ethanol, with stirring. The mixture stayed at room temperature for 10 minutes and was then refluxed for 90 minutes. The ethanol was then removed, water was added and the aqueous equipment was extracted with chloroform. The chloroform extract was dried and evaporated, the oily residue was taken up in ethanol, treated with hydrogen chloride and dried in ice.

009887 / 19U

-13-

cools. The resulting isomer mixture of Hydro *. Chloride, which melted at 275 - 285 °, gave an isomer (A), F, 2 $ i 29 ^ ° from methanol / ethyl acetate and a second isomer product (B) ₁ F, 2M - 248 °, on fractional crystallization Ethanol.

Example 3

1.1 ^l -Hexamethylenbi sf7-ohlor-l ·> 2. 3. ^ tetrahydro i sochinolin | dihydrochloride

According to Example 2 v / cork bought 2- (ii-ehlorphenyl) -äthyIj amide into the mixture of isomeric bisjj-chlorotetrahydroisoquinoline dihydrochlorides changed by.

By using iiacid instead of hydrochloric acid The corresponding Tartrstealz was made.

example

1.1 '-Tetramethylene bisLl .2.3. ^ - tetrahydro-6-niethoxyiso. chinolijq | d.ihydro chloride ---

009887/1944 " ¹⁹ ~

a mixture of 3.24 g of adipic acid dipS - ^ - methoxy-

, P. 152 °, 25 ml of phosphorus oxychloride and 32 nl of dry toluene were refluxed for 30 hours and then cooled in ice. The resulting precipitate is filtered off, washed with benzene and acetone, and dissolved in warm water. The solution uurle olt aqueous sodium hydroxide solution is strongly alkaline - and the resulting base in chloroform to ge « %

non.! en, washed with water and dried. The after Remove the solvent and give the remaining residue after Ui.il: crystallize from cyclohexane !, l'-TetrainethrlenbisQjjiUdihydro-o-methoxyisshinolinj, P. 105 106 °. After reduction with Hatrlumborhydrid according to example 1 and subsequent treatment with hydrogen chloride gave a mixture of the dl and neso isomers. products, F. 2? 2 - 2? 3 °.

Example 5

.1.1 ' -Te tear thy lenbls | jl, 2> 3.4 *> te trahydro »6.7-methylene * dioxyisoch inolini

A mixture of ^ 3 g adipic acid di ^ 2- (methylenedioxyphenyl)

009887 / 19U * ²⁰ '

ethyl] amide, P, 207-208 ° and 130 ml of phosphoroxy -.- chloride was boiled under reflux for 1 hour * The residue remaining after evaporation of the excess phosphorus oxychloride was first treated with water and then with alkali and chloroform * The chloroform extract gave on concentration a crystalline residue, which after urine crystallization from toluene 1.1 ^l -Tetrarnethylenbis0,4-dihydro-6,7-methylenedioxyisochlnolinl, Ρ. 21Λ -. 215 ° delivered.

17 g of this dihydro compound were in 2000 ml of hot Dissolved dioxane and drip emieise with 6, ^ g sodium borohydride treated in 200 ml of ethanol. After the exothermic reaction ceased, the genic became further Refluxed for 3 hours and then evaporated. The mixture of diastereoisomers melted at 175-190 °.

Example 6

ethoxylsochlnoliijjdihydrobromid .

ii Mixture of 6.53 g of adipic acid £ .2- (benzyloxy »3-

009887 / 19U - _mZlm

. methoxyphenyljathyijamid, P. 197 °, 20 ml of phosphorus oxychloride and 65 ml of dry toluene were refluxed for 1 hour and then cooled. The resulting precipitate was washed with benzene and acetone and dissolved in hot water. The hot solution was made alkaline with aqueous sodium hydroxide solution and then cooled in ice. The resulting precipitate was filtered off, erased with water and, after crystallization from absolute ethanol, gave .1,1'-tetramethylene- m bis ^ -benzyloxy ^ I ^ -dihydro-o-methoxyisoquinineQlinJ, temperature - 166 °. After reduction of this substance with sodium borohydride according to Example 1 and subsequent treatment with hydrogen bromide, the mixture of the dl- and mesosomeric llydrobromides was obtained the corresponding mixture of the dl- and mesoisomeric hethanesulfonates.

The following products were manufactured in a similar titmouse:

1,1'-Tetramethylenbis ^ -allyloxy-1,2,3, ^ - tetrahydro-6-metlioxyisochinoliia] similar acetate.

1,1 '-Tetramethylene bis £ 1,2,3, ^ -tetrahydro-6-methoxy-7-phenoxyisoquinoline] disulfaraate ₀

-22-

009887 / 19U

.22-

example 7th

.1 * -Tetramethylene Blsfl. 2. 3 A-

o-methqxylsoquinolirn

If the l, l * tetra-

chinolinj ser material in acetic acid with what and -IQ. ^ igem Mladium reduced to charcoal, debenzylation occurs, and a mixture is formed, the more isomeric. 7-Hydroxy Compounds, pp. 259-261 °.

Example 8

1.1 -Tetramethylene bis [^ 6> -benz?, Rloxy- «7-butoxyphenyl> .l. 2.3. * te tr ahy dro i so quinolinj rnalona t

2- (3-Benzyloxy - ^ - outoxyphenyl) - "- acetyl ^ thylamine vrurde hydrolyzed with dilute sodium hydroxide solution and the resulting Amine eemä-3 Example 6 into the GeHünscIite product unchanged t.

-23-

Example 9

(1.2.3.4 ~ tetrahydrol-quinoline) -

3 «. {3, ^ - Dihydro-o, 7-di & ethoxy-l - isoehinolylniethyl) hexano- · τΗυΓΓ uuil 2-Fhenyläthylainln were for the purpose of Anidblldung heated to 2C0 °. The anide was according to Example 1 with KionphoroxychlQrld cycllslert and nitrium borohydride su: ^ £ rf> viiinschton product reduced.

! Example 10

1.1 '»Te tramü up to £ 1.2> 3.4-tetrahydro-6.7.8-trlmethoxyi so chlnol inj d iiiydro chloride

An Oe-niBch from 19.0 g AdipinBäurediJjE -. (- 3 _f it-, 5-trinieth- |

CxvphenyDäfchylJunid, Fj? 4 * 175 °, 57 ml of phosphorus oxychloride and 190 ml of dry toluene were boiled for 30 minutes under reflux, resulting in an oil that solidified on cooling * 9 a precipitate was filtered off, with benzene ■ -and acetone gev / ash, dissolved in hot "water, and the solution was" with. 10 # viscous sodium hydroxide solution star ?, made alkaline.

009887 / 19U '^: C

The oily product was extracted with chloroform * The extract was washed with water and dried and, after removal of the solvent, left 1,1'-tetramethylene bis £ 3, ^ ydihydro-o, 7 , 3-trimethoxyisoquinoline], which after recrystallization from cyclohexane melted to 129 °. This base gave, after reduction with haferium borohydride according to Example 1 (under three hours of high-pressure boiling), passing the previously dried chloroform extract through a clay column, removing the solvent and treating the remaining oil with ethanol-chlorine-hydrogen ether, the diastereoisomeric structure of the product, P, ZkJ - °

Example 11

Ingredient mg / tablet

1,1'-hexame thylenebisfl, 2,3,4-

tetrai-quinoline dihydrochloride,

(Isomer A) 25

Lactose USP (spray dried) i70

Strength USP ^ * 10

Iiagnesium stearate USP 1

Stearic acid USP 5

Flavor

009887/1944

All of the above components were passed through a 60 mesh sieve, "} mixed for 0 minutes and then pressed directly into tablets weighing 211 mg on a suitable tablet press with the aid of an 8.7 mm large" biconcave punch, "

Example 12 Ingredient " mg / capsule

1.1 ~ hexamethylene bisfi, 2.3,

methylene-o, 7-clinydroxyiso.-quinoline | dihydrobromide 20

Lactose USP 100

Magnesium stearate. 1

Cab-O-Sil amorphous silica 5

These ingredients were put together, mixed and passed through a 1-mesh sieve of a Fitzpatrick ^ Crusher crossed before they in 126 mg units on a normal one capsule machine in a two-part hard gelatin . 3 capsule included vrarden »

Example 13

component

ampoule

1,1'Tetraraethylene bisEl, 2,3,4-tetra. hydro-6,7-dinie thoxyi so quinol irij dihydrochloride (mesoisomer)

Pyrogen-free \ tasser for injection Mannitol N.F.

25 mg

25 ml

ura the solution isotonic close

The compound was added to the hater and the solution made isotonic with mannitol, siGh giving a pH of 5 _f 5 . 5 parts of this 5 mg / ml solution were filled into ampoules under sterile conditions and these were sterilized in an autoclave after they had been closed.

example component

1,1 »-Hexaraethylene to £ 1,2,3,4-th trahydro-6,7« dimethoxy-3-nie thylisochinoiin | dihydrochloride

Pyrogen-free water for injection dextrose H »F. ..

009887/1944 Anfbulle

25 mg
25 nl

to make the solution isotonic close

-27-

The compound was added to the water, and the solution was made isotonic with dextrose, resulting in a pH of 5.5 . 5 parts of this 5 IUgZmI solution were poured into ampoules under sterile conditions and these after sealing in the autoclave , sterilized »

Example 15

component

ampoule

I, I »-Böaaaethylenhisll, 2,3, ^ - tetrahydro-δ, 7-diHiethoxyi8oohinollnj ο ihydfoehlor ia-'liiiydrat

Haters for injection

Fructose S.?.

25 mg
25'approx

ur. to make the solution isotonic

The "erbirfiOiig vrarde. € ea hater added and the Lössung with fructose made isotonisch- _t wherein the pH lfert check yielded 5.5 * From these 5 ag / ml solution were 5 ml each filled under sterile conditions into ampoules and after this sterile after closing in the autoclave!

-28-

009887/194

Example 16 component

ampoule

1,11- (1,8-diethyl) decamethylene bis-

Q-, 2,3 , ^ - tetrahydro-o, 7-methylenedi »oxyisoquinolii | dihydrochloride (Isoraer A)

Pyrogen-free water for injection sodium chloride

25 mg 25 ml

to find the solution iso. to make tonic

The compound was added to the water and the sol *. solution made isotonic with sodium chloride, with the pH Afert 5 _t 5 yielded. Of this 5 mg / ml solution, 5 ml each were filled into ampoules under sterile conditions and these were sterilized in the autoclave after closing.

Example 1?

component

1,1 '-TetramethyleiiblsJJ, 2 _t 3 _# if-tetrahydro-6-methoxyiSDquinoline |

Peanut oil
Benzyl alcohol

009-887 / 1944

mg / ampoule

25 mg 5 ml 5 mg

-mo of

.29-

The compound was dissolved in the peanut oil, which also contained the benzyl alcohol. The ampoules were each filled under sterile conditions with 5 ml of the solution containing 5 mg / ml compound, '-

Example 18

Component mg / suppository

1,1'-hexemethylene bis £? -Ohlor-1,2,3,4-

tetrahydroisoquinoline 200 mg

Cocoa butter '"■ q, ß.compound and cocoa butter were put together,

• ζ ,

carefully mixed and deformed to 2g "suppositories,

Example 19

Ingredient mg / suppositories

1,1 · -hexamethylene bisII, 2,3, ^ - tetrahydro isoquinoline, isomer B) 200 mg

Cocoa butter. q »s.

Compound and cocoa butter were combined *

Q09887 / 19U ",,,

mixed and shaped to 2g ~ suppositories »

example

Component g / liter

1,1 »-hexamethylene bis [1,2,3 _f ^ -tetrahydro · 6,7-dimethoxyisoquinoliijLihydrochloride

Grained Sugar Flavor Coloring
Sodium Benzoate Deionized Water 10 600 Q..sq * s «

1 ei.s »

All components were dissolved in liquid and added together and made up to 1 liter of solution,

example component

1,1 »« Hexamethylene bisf 1,2,3, JM

hydro-6,7-dimethoxj ^r isochinolif0 dihydrochloride

Lactose USP (spray dried) Starch USP

Magnesium stearate USP Stearic Acid USP Flavor

00 9 8 87/1944 mg / tablet

150

q., 3.

-31-

All of the above ingredients were passed through a 60 riesh sieve, blended for 30 minutes and then on a suitable tablet press - with the help of a 3.7 nnn large, biconcave stamp directly to Eli rag heavy fabietten pressed *

Example 22

1.1 * ■ # e tr aaefchylenbls [1.2.3 & »T * trahydro »» 6.? - »dimethoxy. isomers and their Salae

Although the above-mentioned compound was in its nvit ^w lsoBer A! bsw «. * Isomeric hydrochloride salts designated isomeric B "" are divided.

The existing isomer A melted at 2 ?! «- E? 3 ° and became converted into a free base, m.p. 12C, 5 ° -121.3 °.

Tuck free 3sse and dS-feinsäura in time, "¥ erhältnis i: 2.2 Kurdeii 5e in beating methanol dissolved mid mixed * Oer from" emerging ler abgelcühlten solution first crystal attack was three times (235 * 23o ° _t 2efs?..) from haters to two? Kenstaaz from Sehmelzpunkt F. 2 ^ 5 ^ 2 ^ 6 ° (Zers *) and Brehung jot ^ ^Εδ ° Λ. 26.8 ° (C 1.00} H ₂ O) washed «The cutter liquor of the first

0-09687 / 1944

-32-

Crystalline attack produced a second crystal attack, P. 186-189 ° (Sers.), £ ol /] _D ^{26 +} ^ K) ₁ O ⁰ _{(C 1.00J H 2} O) ₁ which was not further purified.

The two differently melting tar stepped salts • were each converted into the free base by themselves they were dissolved in water, each solution made alkaline with excess concentrated ammonia and extracted with eenzene and that after evaporation of the benzene remaining residue from C? / clohexane-benzene was recrystallized.

On this ".feise" gave the salt d-1, l ^| -Ietramethylenbisj [l _f 2,3,4-tetrahydro-6,7-.di. Nethoxyisoquinoliaj F. 98-100 °, melting at Zk-5-2k6, {OtJ _D 26 ° - 69.3 (C 3.00, chloroform) and the salt IpI ₁ I '-Tetramet: iylenbisp., 2 _f 3, ^ -. Tetrahydro-6,7-dimethoxyisoquinolirj , M.p. 96-100 °, M _D ^{ZH- 0} + 69.0 ° (3.00 C, chloroform).

The isomer, Ξ, melted at 26k - 266 ° and -.rarde into the free 2a.se meso / i, l ^f -Tetrameth: ^r lenbis- (1,2, -3 * ^ -te trahyöro-6,7- dliae thoxy isochinolln) converted.

BATH

009887/19 ^ 4

1870633

ty, 'ty g of meso-Xsomer viurden THANOL dissolved in 20 ml of boiling "absolute Ά and a boiling solution von.2,3 g (0.022 mole) of 85 jSiger aqueous lactic acid in 20 ml of absolute ethanol added" The mixture was for 5 minutes · boiled and then cooled the resulting bodice was filtered off, washed and dried to provide 5 g of white, crystalline lactate salt ₁ which after recrystallization from ethanol 95 #igem Jjj the constant F. 21? - 218 °.

Similarly, the meso isomer was converted into the following salts:

Acetate, - F _fc l? 6 - 178 °} Hethanesulfonat, F * 290-291 ° J phosphate, Fv 26? - 2ό9 ° ί sulfamate, F * 20?. * 208 °} Benzene sulfonate, m.p. 290 «- 292 ° | Malate, F, 223-22 * f- ° i - '• Citrate, F 114-116 ° j Maleate, F. 213-214 ° i Ifelonate, F, 210-211 °} Oxalate F * 22? .- 228 ° J nitrate, F * 233 * _; * 234 ° i sulfate, m.p. 233-235 ° ". Ι. |

example Part of the ampoule

1.1 ^l «| ietramethylene) is [x _t 23i ^ * ^ eti hydro-Oj'y-dimethoxyisoquinolium dilactate (Meso-Isoniei *} '50 g

Fyrogen-free wet for injection 1000 ml

The compound was added with water to a 1000 ml volume filled up and this solution containing 50 mg / ml is filled into ampoules of 10 ml each under sterile conditions, which were then sterilized in an autoclave.

009887/1344

Claims (1)

Claims 1. The dissolution of pibrinolysis in mammals is a suitable preparation, denoted by the fact that it is effective in a connection according to the following. he-ntler Forncl Λ or a pharmaceutically acceptable Psalt: the same n the Älk St. Formula A. S ", Η_Λ, Η «, and E₁, a "isssstoffatos or ■ * ■ ■ <■ ^ * f Z \ _r 1 * _t 2 *! , Hl ₁ V ^, viii 2V a J-sssrStoffatom, IZIelrijr.lkrl, HalogenatD: -, H;. 'Drox; - _f : riedri & - clliox;',:; iedri ^ alkeno:; r _f !. "Leiricr -lkiao: ^. ·, low- 009887/1944 acyloxyg phenyl lower alkoxy ^ amino, lower alkylamineO | Lower acylamino or nitro mean where *, with the two substituents on one or other aromatic Hing or both linked to form lower alkylenedioxy can be, and "every ^{11 is} an alkylene with a maximum of 15 carbon atoms j ^ as well as a pharmaceutically acceptable one Includes carrier. 2. Preparation according to claim 1, characterized in that because it is in the form of a unit dose. 3. Preparation according to claim 1 or 2, characterized in that the formula A «-7 bond from. I ₁ I ¹ -Te tramethyleabis [Ί, 2,3, ^ - tetrahydroisoquinolinj (isomer A) j 1,1 «-Tetramethylenebisf 1,2,3,4-tetra- * hydro-6-netr.ox2 ^r isochir! .oliii | ; !, i'-hexaniethylenebis- j ^ l, 2,3, Ji-tetrahydroisoquinolxnj \ 1,1'-TetraraethylenebisJJL, 2,3,4-tetrahydro-o, T-dimetho.ijisoquinolineJ, (isomer B) j 1,1 ^! -Decadethylenebisjjl, 2,3, ^ - tetrahydro-6,7-.diaethc;: - isoquinolin3 JV, ¹ .'- Tetraaethyleabis- ■ fl, 2 _> 3, ^ tetrahyd2O-6 _t 7 _l 8 * trinetho3qrisochiaollnJi. hydroxyisochinolirj or 1,1'-jetränethylenbis- 009887 / 19AA J_i, 2,3, ^ -tetraliyara-y- * Connection sal-j in the next hurrying formula A or * your » confidential organic acid additions. I ⁷ orael ₁ Bg, 3rd and B ^ a water staff atom or Egg. Rl, Ett ¹ , Hi. aS * rnidi R ¹ J * is a hydrogen, atom, Iiedrigallcyl ,, Eallogen ^ toTa ,, Hydroxy ,, Hiedrigalkosiy ^ K iedrigalKenoxy. j Kiedrigalltijaoxy »Hiedrig'-acyl oxy _t Pfoenyl-Kiedrigal & oxy |, Aiainö ,, Miedrig« or Hitro mean gekensizeiciinetj that the organic acid an acid-proof. dei? © tee / prganiaoiie 5. Compound according to claim ^, characterized in rel: er: nzeichnefc, that your pharmaceutically acceptable 03I2 that Is lactate salt, . 1,1 ^r -Tetrame thrlenbis-D-, 2 ₁ 31 ^ - tetrahydro- * » _f ? - dme thoxy isochiriOlinjdilactat, (Keso-Isonier}. 7. Process for the preparation of an organic acid salt a formula A compound according to claim 1, dadurc marked, that one is the free base of the Pornel. Brings A compound into contact with an acid, which contains an organic unit. 8 «procedure according to claim 7» characterized in that that one hol organic acid to form the Mono- or two-part organic acid to form; of the di-addition salt used 9. The method according to claim 8, characterized in * that mart with excess acid works and that; forms. 10, Iferfahreii Äaeh one of the claims f Ms $ _B characterized, that the image is de « Saureadditionssalzeε in the Heise carries out that one the free base of the formula AWe-r bond and the an acid containing an organic moiety into one suitable solvent "reacts at room temperature or with heating 11. The method according to claim 10, characterized in that that a lower alcohol, preferably methanol, is used as the solvent. 12. Verfehren according to claim 10 or 11, characterized in that that the heating is carried out at the reflux temperature of the alcohol + ■ + ■ 009887/1944