CH643458A5 - Pharmaceutical composition and a process for its production - Google Patents

Description

35 The invention relates to a medicament containing prostacyclin or its dihydro derivative or one of its pharmaceutically acceptable salts in combination with a phosphodiesterase inhibitor and a process for its preparation.

40 Prostacyclin (PGX or PGI2) and its dihydro derivative (9-deoxy-6i; 9a-epoxyprostaglandin Fx) and their salts, including the sodium salts (hereinafter referred to as "active substances"), have a strong inhibitory effect on the aggregation of blood platelets and are therefore particularly useful as antithrombotic agents in the treatment and / or prophylaxis of mammals and humans. The active ingredients can also be used in mammals and humans to reduce or control excessive gastric juice formation, thereby reducing or avoiding the formation of a gastrointestinal ulcer and accelerating the healing of already existing ulcers in the gastrointestinal tract.

The active substances also influence the biochemical interaction between platelets and vascular endo-55 thelium, whereby the restoration of injured vascular endothelium is supported. Therefore, the active ingredients have another healing benefit in the treatment of wounds in mammals and humans.

Depending on requirements, the active ingredients are either of 60 uses if platelet aggregation is to be avoided or if platelet aggregation is to be resolved. The active substances also reduce the adhesive nature of the platelets and are used to prevent thrombus formation in mammals and humans. For example, the compounds are useful in treating or preventing myocardial infarction, treating or preventing postoperative thrombosis, and they also serve

to promote vascular graft patency after surgery and to treat complications of atherosclerosis and conditions such as atherosclerosis, blood clotting damage due to lipemia, and other clinical conditions whose etiology is associated with fat imbalance or hyperlipidemia.

The active substances are particularly suitable as additives to blood, blood products, blood substitutes and other liquids which are used in an artificial circulation located outside the body for flushing through an isolated part of the body, for example a limb or an organ, the organ or the part of the body either still adheres to the original body, or should be detached and preserved or should be prepared for transplantation or is already connected to a new body. During these circulation and blood flow processes, the aggregated platelets tend to clog the blood vessels and parts of the circulatory system. This can be avoided by the presence of the active ingredients. For this purpose, the compounds can be added gradually or in single or multiple doses to the circulating blood, the blood of the donor animal or the perfused part of the body, either in the separated or attached state and / or to the recipient, generally in a continued total dose 0.001 to 10 mg / 1 circulating fluid. It is advantageous to use the present compounds in experimental animals, for example cats, dogs, rabbits, monkeys and rats, to develop new methods and techniques for organ or limb transplantation.

In addition to the effects described above, the active substances also have a vasodilatory effect on the blood vessels. However, there are often occasions when it would be desirable to take advantage of the other effects described above (in particular the inhibitory effect on clumping), while at the same time the vasodilatory effect of the active ingredients should be suppressed or eliminated. This is the case, for example, in the treatment or prevention of heart attacks or when the active ingredients are to be used as an additive for circulation processes outside a body. The object of the present invention is intended, inter alia, to alleviate or avoid this vasodilatory complication.

Surprisingly, it has now been found that the inhibitory effect on the clumping of the platelets, but not the vasodilatory effect of the active substances, is potentiated by chemical compounds which have a particular pharmacological effect. This finding now makes it possible to separate the inhibitory effects on aggregation from the va-sodilatory effects of the active ingredients.

Accordingly, the medicament according to the invention is now characterized in that it contains a) prostacyclin, dihydroprostacyclin or one of their pharmaceutically acceptable salts and b) a phosphodiesterase inhibitor. This medicine has an inhibitory effect on platelet aggregation.

The continuous use of an active ingredient and a phosphodiesterase inhibitor lowers the limit of agglomeration (= the minimum amount of active substance required to have an inhibitory effect on agglomeration) without significantly influencing the vasodilatory limit.

643 458

If an active ingredient is now administered in a concentration that is below its vasodilatory limit value, but above the new, lower, anti-agglomeration limit value, together with a phosphodiesterase inhibitor, an anti-agglomeration effect can be produced without a vasodilatory effect.

It is known that the active substances in platelets stimulate the production of the cyclic AMP (adenosine monophosphate) and it is believed that the anti-clumping effect of the active substances can be attributed to the formation of the cyclic AMP. The phosphodiesterase inhibitors prevent the degradation of the cyclic AMP. It may be that the inhibitory effect on the agglomeration is potentiated because, in the presence of a phosphodiesterase inhibitor, an adequate agglomeration-inhibiting concentration of cyclic AMPs can be achieved with a lower concentration of the active ingredient.

The mechanisms by which the active substances manifest their vasodilatory effect are not known, although a connection between the concentration of the cyclic AMP and the vasodilatory effect could be found in other compounds. Our finding that the vasodilatory effect of the active ingredients used in the present invention is not potentiated by the phosphodi-esterase inhibitors suggests that the cyclic AMP is not involved in the vasodilatory effect of the active ingredients.

Examples of corresponding phosphodiesterase inhibitors which are suitable for potentiating the aggregation-inhibiting action of the active ingredients are: xanthine derivatives, such as, for example: theophylline ^, 7-dihydro-l, 3-dimethyl-lH-purine-2,6-dione },

and its salts;

3-isobutyl-1-methyl-xanthine;

Caffeine {3,7-dihydro-1,3,7-trimethyl-lH-purine-2,6-dione}

and its salts; and aminophylline {adduct of theophylline and 1,2-ethane diamine (2: 1)}.

In addition to the xanthine derivatives, e.g. the following phosphodiesterase inhibitors, as such or as their pharmaceutically acceptable salts, are used for the present pharmaceutical mixture, for example:

a) Isoquinoline derivatives, for example:

Papaverine (l - [(3,4-dimethoxyphenyl) methyl] -6,7-dime-

thoxy-isoquinoline) and its salts; and 6,7-diethoxy-1- (4,5-diethoxybenzyl) isoquinoline and its salts, for example its hydrochloride;

b) Derivatives of pyrimido {5,4-d} pyrimidine, for example: dipyridamole (2,2 ', 2 ", 2"' - (4,8-dipiperidino-pyrimido [5,4-

d] pyrimidine-2,6-diyldinitrilo) tetraethanol) and its Sai-zc *

2,2 ', 2 "22"' - {[4- (l-piperidinyl) pyrimido [5,4-d] pyrimidine-2,6-

diyl] dinitrilo} tetrakisethanol and its salts; and 2,4,6-tri-4-morpholinylpyrimido [5,4-d] pyrimidine and its salts;

c) Derivatives of thieno [3,2-d] pyrimidine, for example: N- [4- (4-morpholinyl) thieno] 3,2-d [pyrimidin-2-yl] -l, 2-ethane-

diamine.

d) Derivatives of pyrazolo [3 ', 4': 2,3] pyrido [4,5-b] [1,5] benzodiazepin-6- (3H) -ons, for example:

3-ethyl-7,12-dihydro-7,12-dimethylpyrazolo-

[4 ', 3': 5,6] pyrido [4,3-b] [1,5] benzodiazepin-6- (3H) -one; 3-ethyl-7,12-dihydro-9-methoxy-7,12-dimethyl-pyrazolo [3 ', 4': 2,3] pyrido [4,5-b] [1,5] benzodiazepine-6 - (3H) -on;

and

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10-chloro-3-ethyl-7,12-dimethyl-7,12-dihydro-pyrazolo- [4 \ 3 ': 5,6] pyrido [4,3-b] [1,5] benzodiazepine-6- ( 3H) -on;

e) Derivatives of 1H- or 2H-pyrazolo [3,4-b] pyridine, for example:

4- (butylamino) -l-ethyl-1H-pyrazolo [3,4-b] pyridin-5-car-

bonic acid ethyl ester;

4- (Butylamino) -1 H-pyrazolo [3,4-b] pyridine-6-carboxylic acid, ethyl ester;

4-chloro-1-ethyl-3-methyl-1H-pyrazolo [3,4-b] pyridine-5-ace-tonitrile;

1-ethyl-4- (isopropylidene hydrazino) -3-methyl-1H-pyrazolo [3,4-b] pyridine-5-carboxylic acid ethyl ester or its salts, for example its hydrochloride hemihydrate; and

2-methyl-6-phenyl-4- (1-piperidinyl) -2H-pyrazolo [3,4-b] pyridine or its salts, for example its hydrochloride.

f) Derivatives of 5H-furo- [3,4-e] pyrazolo [3,4-b] pyridin-5-one, for example:

4- (butylamino) -1-ethyl-1,7-dihydro-7-hydroxy-5H-furo- [3,4-e] pyrazolo [3,4-b] pyridin-5-one; and g) derivatives of l (2H) -naphthalenone, for example: 2 [(dimethylamino) methyl] -3,4-dihydro-7-methoxy-l (2H) -

naphthalenone or its salts, for example its Î; 1 hydrochloride.

The amount of active ingredient required for the therapeutic effect depends not only on the particular compound and the dosage form, but also on the particular phosphodiesterase inhibitor used and its dosage, i.e. on the degree of the respective potentiation. However, the amount of the active ingredient is below the required dosage, which would otherwise have a therapeutic effect in the absence of the potentiator, and is therefore also below the value that would cause a significant vasodilatory effect.

In general, in the absence of a potentiator, the appropriate dose of active ingredient is in the range of 0.01 to 200 jig / kg body weight of the recipient. In the present invention, when using a phosphodiesterase inhibitor, an appropriate dose of active ingredient is generally lower or about half the dose that would be needed in the absence of a potentiator, i.e. usually in the range of about 0.002 to 100 (ig / kg body weight.

The present invention also relates to a method for producing a medicament, which is characterized in that prostacyclin, dihydroprostacyclin or one of their pharmaceutically acceptable salts as an active ingredient and a phosphodiesterase inhibitor are mixed.

In general, the said active ingredient and the phosphodiesterase inhibitor are administered in a weight ratio of one part of active ingredient to 1 to 200 parts of phosphodiesterase inhibitor.

Although a named active ingredient and a phosphodiesterase inhibitor may be administered as raw chemicals, it is preferable to offer them as one or more pharmaceutical preparations.

A single dose preparation can generally contain 0.1 to 20 mg, for example 0.2 to 16 mg of the active ingredient and 100 to 400 mg, for example 250 to 350 mg, phosphodiesterase inhibitor.

If the phosphodiesterase inhibitor is incorporated into a pharmaceutical preparation, it contains an active ingredient and a phosphodiesterase inhibitor together with one or more acceptable excipients and optionally also other therapeutic components for use in veterinary and human medicine. If the active ingredient and the phosphodiesterase inhibitor are administered separately, the prostacyclin or dihydroprostacyclin preparation or the preparation of one of its salts contains the active ingredient together with one or more excipients acceptable therefor and, if appropriate, other therapeutic constituents. The preparation of the phosphodiesterase inhibitor can be in the form customary for this compound. The carrier must be "acceptable" in the sense that it is compatible with the other components of the preparation and is not harmful to the recipient.

The pharmaceutical preparations include e.g. B. Forms which are suitable for oral, rectal, vaginal or parenteral (including subcutaneous, intramuscular or intravenous injection or infusion) or for intrapulmonary administration, although the appropriate dosage form in each case depends on the active ingredient.

The preparations can usually be in unit dose form and can be prepared in the manner which is customary and known in pharmacy. In all of these production processes, the active ingredient and the phosphodiesterase inhibitor are associated with the carrier, the latter being able to consist of one or more ingredients. In general, in the preparation of the pharmaceutical preparations, the active ingredient and the phosphodiesterase inhibitor are brought together uniformly and intimately with a liquid or finely divided solid carrier or with both, for example by mixing, and then, if necessary, the preparation is brought into the desired dosage form by molding. The present pharmaceutical preparations for oral administration can be in divided units, such as in the form of capsules, cachets, lozenges or tablets, each unit containing a certain amount of the active ingredient and the phosphodiesterase inhibitor as powder or granules. In addition, the preparations for oral administration can be in the form of a solution or suspension in an aqueous or non-aqueous liquid or as a liquid oil-in-water or water-in-oil emulsion.

A pharmaceutical preparation for parenteral administration can be in the form of an ampoule, which can hold a certain amount of liquid to prepare an infusion solution. An example of such a parenteral preparation is a freeze-dried residue of a solution of the active ingredient, the phosphodiesterase inhibitor and a glycine buffer with pH 10.5.

A tablet can be produced by pressing or molding, optionally with one or more auxiliary substances. Pressed tablets can be produced in such a way that the active ingredient and the phosphodiesterase inhibitor are pressed in a free-flowing form, for example as a powder or granulate, optionally mixed with a binder, lubricant, pharmaceutically inert diluent, surface-active agent or dispersant, in a suitable device . Shaped tablets can be prepared in such a way that a mixture of the powdered active ingredient and the phosphodiesterase inhibitor together with a suitable carrier is moistened with a pharmaceutically inert liquid diluent and shaped in a suitable device.

Preparations for rectal administration can be in the form of suppositories, which are prepared with a conventional carrier such as cocoa butter.

Preparations for vaginal administration can be in the form of a pessary, a cream, a paste or sprays, which in conjunction with the active ingredient and the

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Phosphodiesterase inhibitors also contain the corresponding known carriers.

Preparations for parenteral administration usually contain a sterile aqueous preparation form of the active ingredient and the phosphodiesterase inhibitor, this preparation preferably being isotonic with the blood of the recipient.

If the active ingredient is to be absorbed through the skin and get into the blood of the recipient, a drug can be prepared for external use. The phosphodiesterase inhibitor can also be administered by means of another dosage form if it does not enter the bloodstream when absorbed through the skin, provided that it can be administered locally. For the treatment of wounds on the skin or close to the skin, an external application form of the preparation, with or without a phosphodiesterase inhibitor, is particularly indicated.

It goes without saying that, in addition to the additives mentioned above, the medicaments according to the invention can contain at least one further ingredient, such as, for example, a diluent, a buffer, a lubricant or a preservative (including an antioxidant).

Accordingly, the medicament according to the invention can e.g. use in:

A. A method of preventing or reducing platelet aggregation in the blood, in a blood product or in a blood substitute by combining the blood, blood product or blood substitute with a) prostacyclin, dihydroprostacyclin or one of their pharmaceutically acceptable salts, and b) a phosphodiesterase -Inhibitor in contact;

B. a method according to method A, for example for the treatment or prophylaxis of thrombosis, by simultaneously or successively a mammal or human or animal or human tissue a) prostacyclin, dihydroprostacyclin or one of their pharmaceutically acceptable salts in an amount which does not cause vasodilation can, and b) administered a phosphodiesterase inhibitor;

C. a method in connection with method A or B by simultaneously or successively taking a blood stream, a blood product or a blood substitute outside a body,

a) prostacyclin, dihydroprostacyclin or one of their pharmaceutically acceptable salts, and b) adding a phosphodiesterase inhibitor;

D. A method according to method A or C, wherein the blood, the blood product or the blood substitute, which contain prostacyclin, dihydroprostacyclin or one of their salts together with the phosphodiesterase inhibitor, are subjected to a cell separation process to remove at least some of the cells in the To obtain blood, blood product or blood substitute;

E. A method of prophylaxis or treatment of a gastric lesion in mammals or humans by simultaneously or sequentially administering an active ingredient in an amount which cannot cause vasodilation and a phosphodiesterase inhibitor; and

F. A method of treating wounds in mammals or humans by simultaneously or sequentially administering an active ingredient in an amount that cannot cause vasodilation and a phosphodiesterase inhibitor.

The following examples serve to explain the present invention in more detail.

example 1

Blood clots in the carotid artery of rabbits were compared to those of R.G. Herrman and W. B. Halefield, in Effects of Antithrombotic Drugs in in vivo Experimental Thrombosis in S. Sherry and A. Scriabine (editors), Plate-lets and Thrombosis, University Park Press, London, 1974.

After thrombus formation, either a drug, a phosphodiesterase inhibitor alone, or a combination of a drug and a phosphodiesterase inhibitor were intravenously infused (IV) for a period of time (30 minutes if a single compound was administered or 30 minutes after the start of the drug) Infusion of the active substance if a combination was used). The carotid artery was cut and opened and the size of the blood clot was entered on an arbitrarily determined scale (+ to + + +). The absence of a blood clot was indicated with a minus sign. If a combination of the active ingredient and the phosphodiesterase inhibitor was used, the intravenous infusion of the phosphodiesterase inhibitor was started 5 minutes before the infusion of the active ingredient. The active substance was infused at a concentration below the limit, i.e. in a concentration at which the active ingredient does not have an aggregation-inhibiting effect when used alone.

The results obtained are summarized in Table 1. The blood pressure of the experimental animals was monitored during the experiments. No effect on blood pressure was observed.

Example 2

Rabbits were anesthetized with pentobarbital (30 mg / kg-1, i.v.) and heparin (2500 IU / kg ~ ', i.v.) injected immediately before the externalization of the blood. Arterial blood was continuously extracted from a carotid artery in rabbits at a rate of 3 ml / min. "1 removed by means of a roller pump and used to combine it with collagen strips which had been removed from the Achilles tendon of another rabbit.

The tendons were freely suspended from auxotonic transducers (see Paton W.D.M. J. Physiol., Page 35, edition 137, 1957), their rashes made dependent on the weight of the tendon and displayed on a multi-channel recording device. The platelets, and probably other cells too, get stuck on the tendon as they overflow, with the streaks increasing their weight. The change in weight due to platelet aggregation and / or adhesion was indicated as rashes of the writing tubes, which had previously been calibrated in mg. After the tendons were flooded, the blood was returned to the rabbits intravenously by gravity.

After blood superfusion on the tendon began, cell aggregates accumulated on the tendon strips and their weight increased over a period of 35 to 40 minutes. After that, there was no further increase in weight. The average weight gain was 193 ± 15 mg; n = 19 (n is the number of attempts).

In the subsequent experiments, the flooded tendon strips were allowed to achieve a stable weight increase due to cell deposition as above. Each subsequent weight loss then showed a resolution s

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Table 1

Active ingredient and concentration

Phosphodiesterase inhibitor and concentration

Thrombus size

artery

Prostacyclin

Nothing

+ + +

L.C.

50 ng / min. / Kg

3-isobufyl-l-methyl xanthine 10ng / min / kg

"f"

R.C.

Prostacyclin

Nothing

+ +

L.C.

25 ng / min. / Kg

3-IsobutyI-l-methyl xanthine 50ng / min / kg

-

R.C.

Prostacyclin

Nothing

+ + +

L.C.

25 ng / min. / Kg

Theophylline 125ng / min / kg

-

R.C.

Prostacyclin

Nothing

+ *

R.C.

10 ng / min. / Kg

Theophylline 125ng / min / kg

-

L.C.

Prostacyclin

Nothing

+ +

L.C.

25 ng / min. / Kg

Theophylline 125ng / min / kg

+

R.C.

Prostacyclin

Nothing

+ +

L.C.

10 ng / min. / Kg

Theophylline 200 (ig / min. / Kg

+

R.C.

Nothing

Nothing

+ + +

L.C.

Prostacyclin

Theophylline 200ng / min / kg

+

R.C.

10ng / min. / Kg

Nothing

Nothing

+ + +

R.C.

Theophylline 200ng / min / kg

+ + +

L.C.

Dihydroprostacyclin

Nothing

+ + +

50 ng / min. / Kg

Dihydroprostacyclin

Nothing

+ (2 attempts)

100 ng / min. / Kg

Dihydroprostacyclin

Nothing

-

250 ng / min. / Kg

Dihydroprostacyclin

Nothing

+ +

L.C.

50 ng / min. / Kg

Theophylline 200ng / min / kg

+ +

R.C.

Dihydroprostacyclin

Nothing

+ + +

L.C.

50 ng / min. / Kg

Theophylline 200ng / min / kg

+

R.C.

Dihydroprostacyclin

Nothing

+ + +

L.C.

50 ng / min. / Kg

Theophylline 200ng / min / kg

-

R.C.

* 1 hour 15 minutes passed before the active substance was infused.

of cell aggregations. Prostacyclin sodium (see RA Johnson, FH Lincoln, JL Thompson, EG Nidy, SA Mizsak, UJ Axen, Am. Chem. Soc. Issue 99, page 4182, (1977) was dissolved in "Tris buffer" (50 mmol, pH 7, 4) (0.1 to 1 ng / ml-1, blood for 3 min) and infused into the blood in which the tendons were bathed, this artificially induced dissolution of the cell aggregations was dose-dependent and reversible. 0.1 ng / ml "1 prostacyclin in arterial blood caused 26 + 3 mg (n = 10) resolved cell aggregations in arterial blood and 1 ng / ml-1 caused a resolution of 86 + 6 mg (n = 6) resolved cell aggregations.

Dipyridamole was then infused into the blood flooding the tendons, and a dose-dependent and reversible dissolution of the cell aggregations was also brought about.

Dipyridamole and prostacyclin were then infused together in the blood flooding the tendons. A clear synergistic effect of the individual dissolving effects was achieved.

45 The concentration of prostacyclin sodium and the dipyridamole used for comparison are shown in Table 2, together with the resolutions of the cell aggregations obtained, expressed in%, based on the maximum resolution which could theoretically be obtained (i.e. the weight difference between the Tendon with the maximum deposition and the initial weight of the tendon).

Table 2

Prostacyclin phosphodiesterase inhibitor and concentration% resolution of the number

Sodium infusion, platelets together

Concentration of agglomeration in arte-

ml "1 blood riell blood + s.e.m. che

None Dipyridamole 1 ng ml ', single dose 10 + 1 14

0.05 Nothing 2 8

Dipyridamole 1 (tg ml "1, single dose 28 ± 2 6

0.1 Nothing 15 ± 1 10

Dipyridamole 1 | tg ml ~ 1, single dose 38 + 5 6

0.5 Nothing 22 + 2 10

Dipyridamole 1 (tg ml-1, single dose 45 + 3 6

Example 3

A freeze-dried drug preparation was prepared by dissolving 1 mg of dihydroprostacyclinna-trium and 300 mg of dipyridamole in water for injections (European Pharmacopoeia) containing a glycine buffer (0.025 mol of glycine) and sodium chloride (0.025 mol). The resulting solution was adjusted to pH 10.5 with sodium hydroxide, which formed part of the buffer, and then freeze-dried. Immediately prior to use, the freeze-dried material was reconstituted in water for injections and then administered either by infusion or injection.

7,643,458

Example 4

The procedure was as in Example 3, except that the 1 mg dihydroprostacyclin sodium was replaced by 8 mg dihydroprostacyclin sodium.

s

Examples 5 and 6 This was carried out as in Examples 3 and 4, with the exception that the dihydroprostacyclinna-io trium was replaced by an equal amount of prostacyclin sodium.

Claims (17)

643 458 2nd PATENT CLAIMS 1. Medicament, characterized in that it contains a) prostacyclin, dihydroprostacyclin or one of their pharmaceutically acceptable salts and b) a phosphodiesterase inhibitor. 2. Medicament according to claim 1, characterized in that it contains prostacyclin sodium or dihydroprostacyclin sodium as the pharmaceutically acceptable salt. 3. Medicament according to claim 1 or 2, characterized in that it contains a xanthine derivative as a phosphodiesterase inhibitor. 4. Medicament according to claim 3, characterized in that it contains 3-isobutyl-1-methylxanthine or caffeine or one of its pharmaceutically acceptable salts as the xanthine derivative. 5. Medicament according to claim 3, characterized in that it contains as the xanthine derivative theophylline or aminophylline or one of their pharmaceutically acceptable salts. 6. Medicament according to claim 1 or 2, characterized in that it is a phosphodiesterase inhibitor, a derivative of isoquinoline, pyrimido [5,4-d] pyrimidine, thieno [3,2-d] pyrimidine, pyrazolo [3 ' , 4 ': 2,3] pyrido [4,5-b] - [1,5] benzodiazepin-6- (3H) -one, 1H- or 2H-pyrazolo- [3,4-bpyridine, 5H-furo- Contains [3,4-e] pyrazolo [3,4-b] pyridm-5-one or l- (2H) -naphthalenone. 7. Medicament according to claim 6, characterized in that it is a derivative Papaverine; 6,7-Diethoxy-l- (4,5-diethoxybenzyl) isochinoIin or be Hydrochloride; Dipyridamole; 2,2 ', 2 ", 2"' - {[4- (l-piperidinyl) pyrimido- [5,4-d] pyrimidine-2,6- diyl] dinitrilo} tetrakisethanol; 2,4,6-tri-4-morpholinylpyrimido [5,4-d] pyrimidine; N- [4- (4-morpholinyl) thieno [3,2-d] pyrimidin-2-yl] -1, 2-ethane diamine; 3-ethyl-7,12-dihydro-7,12-dimethylpyrazolo- [4 ', 3': 5,6] pyrido [4,3-b] - [1,5] benzodiazepin-6- (3H) -one; 3-ethyl-7,12-dihydro-9-methoxy-7,12-dimethyl-pyrazolo [3 ', 4': 2,3] pyrido [4,5-b] [1,5] benzodiazepine-6- ( 3H) -on; 10-chloro-3-ethyl-7,12-dimethyl-7,12-dihydropyrazolo [4 ', 3': 5,6] pyrido [4,3-b] [1,5] benzodiazepine-6- (3H) -on; 4- (Butylamino) -l-ethyl-1H-pyrazolo [3,4-b] pyridine-5-car-bonic acid ethyl ester; 4-chloro-1-ethyl-3-methyl-1H-pyrazolo- [3,4-b] pyridin-5-ace-tonitrile; 1-ethyl-4- (isopropylidene hydrazino) -3-methyl-1H-pyrazolo [3,4-b] pyridine-5-carboxylic acid ethyl ester; 4-Butylamino-1 H-pyrazolo [3,4-b] pyridine-6-carboxylic acid, ethyl ester; 2-methyl-6-phenyl-4- (l-piperidinyl) -2H-pyrazolo [3,4-b] pyridine; 4- (butylamino) -l-ethyl-l, 7-dihydro-7-hydroxy-5H-furo- [3,4-e] pyrazolo [3,4-b] pyridin-5-one; 2 [(DimethyIamino) methyl] -3,4-dihydro-7-methoxy-l- (2H) -naphthalenone or one of its pharmaceutically acceptable salts. 8. Medicament according to claim 2, characterized in that it contains dipyridamole as a phosphodiesterase inhibitor. 9. Medicament according to one of claims 1 to 8, characterized in that it contains a pharmaceutically acceptable carrier. 10. Medicament according to claim 9, characterized in that it contains a solid as a carrier. 11. Medicament according to claim 9, characterized in that it contains a liquid as a carrier. 5 12. Medicament according to claim 9, characterized in that it is in an orally, parenterally, rectally, vaginally or intrapulmonally administrable form. 13. Medicament according to claim 12, characterized in that it is in freeze-dried form for parenteral io len is present in a vessel that can hold a certain amount of liquid for the preparation of an infusion solution. 14. Medicament according to claim 9 or 10, characterized in that it is in tablet form. 15 15. Medicament according to one of claims 9 to 14, characterized in that it is in single-dose form. 16. Medicament according to claim 15, characterized in that it contains 0.1 to 20 mg of active ingredient. 17. Medicament according to claim 15 or 16, thereby 20 indicates that it is 100 to 400 mg of the phosphodiesterase Contains inhibitors. 18. A method for producing a medicament according to claim 1, characterized in that prostacyclin, dihydroprostacyclin or one of their pharmaceutically 25 acceptable salts and the phosphodiesterase inhibitor mixes. 19. The method according to claim 18 for the manufacture of a medicament according to one of claims 2 to 8.