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EP0000774A1 - Antithrombotic medicative combination and process for its preparation - Google Patents

Antithrombotic medicative combination and process for its preparation Download PDF

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Publication number
EP0000774A1
EP0000774A1 EP7878100586A EP78100586A EP0000774A1 EP 0000774 A1 EP0000774 A1 EP 0000774A1 EP 7878100586 A EP7878100586 A EP 7878100586A EP 78100586 A EP78100586 A EP 78100586A EP 0000774 A1 EP0000774 A1 EP 0000774A1
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Prior art keywords
dioxo
pyrimidine
diphenyl
dipiperidino
pyrazolidine
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EP7878100586A
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German (de)
French (fr)
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EP0000774B1 (en
Inventor
Laurence A. Prof. Harker
Hans Wolfgang Dr. Schröter
Walter Dr. Haarmann
Josef Dr. Dipl.-Chemiker Roch
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Boehringer Ingelheim Pharma GmbH and Co KG
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Dr Karl Thomae GmbH
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors

Definitions

  • the invention relates to a new antithrombotic drug combination and a process for its preparation.
  • 2,6-bis (diethanolamino) -4,8-dipiperidino-pyrimido [5,4-d] pyrimidine (generic name: DIPYRIDAMOL) has long been used as a coronary-expanding remedy. It was first described in British Patent 807,826.
  • 1,2-diphenyl-3,5-dioxo-4- (2-phenylsulfinylethyl) pyrazolidine (generic name: SULFINPYRAZON) has been on the market as an anti-gout agent for a long time, it was first published in Helv. Chim. Acta 44, 236 (1961). A good antithrombotic effect was subsequently found for both remedies, see for example Therapy Week 26, 8464-8489 (1976).
  • the substance to be tested is administered orally to the awake animals (mostly) 4 times a day over the test period of 4-5 days.
  • the results obtained with this method are shown in the table below:
  • the table clearly shows that normalization of the shortened platelet lifespan requires 10 mg / kg / day dipyridamole or 100 mg / kg / day sulfinpyrazone, but with a combination of 2.5 mg / kg / day of the two active substances the same effect is achieved. It is known that the results can be transmitted very well on the normalization of platelet survival time from apes to humans, such as when Marx's to achieve the same effect, the same dose of D ipyridamol per kilogram is required, as in the monkey.
  • the normalization of the platelet lifetime is of great therapeutic importance, since the shortening of the platelet lifetime that occurs in humans is an indication of a tendency to thrombosis.
  • the new drug combination is therefore well suited for the prevention and healing of thromboembolic diseases.
  • a single dose for adults contains between 25 mg and 75 mg of the two active substances, preferably 50 mg dipyridamole and 50 mg sulfinpyrazone; the single dose is preferably administered 3 times a day, the mean daily dose is therefore 150 mg / kg of each of the two active compounds. Since both active ingredients have been on the market for many years, no information about the toxicity need be given, since the toxicity is low in both cases.
  • the invention further relates to a process for the preparation of the pharmaceutical combination according to the invention, which is characterized in that 2,6-bis (diethanolamino) -4,8-dipiperidino-pyrimido [5,4-d] pyrimidine and 1,2 -Diphenyl-3.5-dioxo-4- (2-phenylsulfinylethyl) -pyrazolidine in a ratio of 10: 1 to 1:10 combined and, if appropriate, with other active substances and then carriers and / or auxiliaries customary in the manufacture of medicaments to form tablets, coated tablets , Powder for letters, capsules and the like is formulated.
  • the new preparations according to the invention are preferably administered orally in the doses mentioned above.
  • Tablets, dragees, capsules etc. are produced in a manner known per se, for example the tablets are produced by directly compressing a mixture of the active ingredients and auxiliaries and, if appropriate, subsequently coated with a film which is compatible with the stomach and intestines during the production of the Capsules are first made separately from the powder mixture and the core with a coating and then filled on a commercially available capsule filling machine.
  • Coated tablets with 50 mg dipyridamole and 50 mg sulfinpyrazone One coated tablet contains:
  • the active ingredients are mixed together with milk sugar and starch and the mixture is moistened evenly with an aqueous gelatin solution.
  • the moist mass is sieved to a maximum of 2 mm, dried and mixed with the lubricant after sieving again. Tablets of 400 mg were pressed from the mixture ready for compression.
  • Coated core dimensions Coating:
  • the kernels are coated with a conventional sugar coating suspension to 50 mg and then with sugar syrup to 530 mg / coated tablet dragierite;
  • Capsule shell hard gelatin capsule size 0
  • Total filling weight powder / core approx. 405 mg.

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  • Pharmacology & Pharmacy (AREA)
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  • General Chemical & Material Sciences (AREA)
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  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
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Abstract

Antithrombotisch wirksame Arznaimittelkombination bsstehend aux2,6-Bia- (diädunolernino)-4,8-dioperidinopy- rimido [5,4-d] pyrimidin (Dipyridamol) und 1,2-Diphenyl 3,5-dioxo-4- (2-phenyl-sutfinyläthyl)- pyrszolidin (Sutimpyrazon) sowie den üblichen Träger- und Hilfsstoffen mit synergistitcher Wirkung.Antithrombotic drug combination consisting of aux2,6-bia- (diädunolernino) -4,8-dioperidinopyrimido [5,4-d] pyrimidine (dipyridamole) and 1,2-diphenyl 3,5-dioxo-4- (2-phenyl -sutfinyläthyl) - pyrszolidin (Sutimpyrazone) as well as the usual carriers and auxiliaries with synergistic effect.

Description

Die Erfindung betrifft eine neue antithrombotisch wirkende Arzneimittelkombination sowie ein Verfahren zu ihrer Herstellung. 2,6-Bis(diäthanolamino)-4,8-dipiperidino-pyrimido[5,4-d]pyrimidin (generic name: DIPYRIDAMOL) wird bereits seit langem als koronarerweiterndes Heilmittel verwendet. Es wurde erstmals im britischen Patent 807 826 beschrieben. Ebenso ist 1,2-Diphenyl-3,5-dioxo-4-(2-phenylsulfinyläthyl)-pyrazolidin (generic name: SULFINPYRAZON) bereits seit langem als Antigichtmittel im Handel, es wurde erstmals in der Helv. chim. Acta 44, 236 (1961) beschrieben. Bei beiden Heilmitteln wurde in der Folgezeit auch eine gute antithrombotische Wirkung gefunden, siehe beispielsweise Therapiewoche 26, 8464 - 8489 (1976).The invention relates to a new antithrombotic drug combination and a process for its preparation. 2,6-bis (diethanolamino) -4,8-dipiperidino-pyrimido [5,4-d] pyrimidine (generic name: DIPYRIDAMOL) has long been used as a coronary-expanding remedy. It was first described in British Patent 807,826. Likewise, 1,2-diphenyl-3,5-dioxo-4- (2-phenylsulfinylethyl) pyrazolidine (generic name: SULFINPYRAZON) has been on the market as an anti-gout agent for a long time, it was first published in Helv. Chim. Acta 44, 236 (1961). A good antithrombotic effect was subsequently found for both remedies, see for example Therapy Week 26, 8464-8489 (1976).

Bei beiden Substanzen ist jedoch zur Erzielung einer-antithrombotischen Wirkung eine relativ hohe Dosis erforderlich, wobei sich schon die Nebenwirkungen beider Verbindungen bemerkbar machen; beim Dipyridamol sind es gewisse Kreislaufwirkungen, die sich in Kopfschmerzen äußern, beim Sulfinpyrazon sind es Magenschmerzen wegen der in hohen Dosen ulcerogenen Wirkung dieser Substanz. Überraschenderweise wurde nun eine starke synergistische Wirkung der beiden Wirkstoffe festgestellt. Bei einer Kombination von Dipyridamol und Sulfinpyrazon können die erforderlichen Dosen zur Erreichung des gleichen antithrombotischen Effektes wesentlich gesenkt werden. Diese synergistische Wirkung wurde im folgenden Versuchsmodell an Pavianen festgestellt:For both substances, however, a relatively high dose is required to achieve an antithrombotic effect, the side effects of both compounds already being noticeable; Dipyridamole has certain circulatory effects, which are expressed in headaches, and sulfinpyrazone causes stomach pains because of the ulcerogenic effects of this substance in high doses. Surprisingly, a strong synergistic effect of the two active ingredients has now been found. With a combination of dipyridamole and sulfinpyrazone, the doses required to achieve the same antithrombotic effect can be significantly reduced. This synergistic effect was found in the following test model on baboons:

Männlichen Pavianen mit einem Gewicht von 8 - 12 kg wird unter Narkose ein A-V-Shunt zwischen Arteria und Vena femoralis angelegt. Dieser Shunt ist ca. 50 cm lang und besteht aus einem besonders präparierten Silastikschlauch. Durch den Fremdkörperreiz dieser körperfremden Oberfläche kommt es zu einem erhöhten Thrombozytenverbrauch (da der Organismus bestrebt ist,diesen "Defekt* abzudecken). Dieser läßt sich leicht messen, indem man dem Versuchstier mit Chrom 51 radioaktiv markierte Thrombozyten injiziert und deren Verschwinden aus der Blutbahn durch 2 x tägl. Messen verfolgt. Bei einem normalen Thrombozytenumsatz beträgt die Lebensdauer der Thrombozyten etwa 5 Tage, bei Tieren mit einem eingesetzten Shunt verkürzt sich die mittlere Thrombozytenlebenszeit (als Ausdruck eines erhöhten Thrombozytenumsatzes) auf etwa 2 - 2,5 Tage.Male baboons weighing 8 - 12 kg are placed under anesthesia under the anesthetic between the artery and vena femoralis. This shunt is approx. 50 cm long and consists of a specially prepared silica tube. The foreign body stimulus of this foreign surface leads to increased platelet consumption (since the organism strives to cover this "defect *). This can be measured easily by injecting platelets with radioactive chromium 51 into the test animal and their disappearance from the bloodstream With a normal platelet turnover, the lifespan of the platelets is about 5 days, in animals with an inserted shunt the mean platelet lifespan is shortened (as an expression of an increased platelet turnover) to about 2-2.5 days.

Bei der Substanzprüfung wird die zu prüfende Substanz über den Versuchszeitraum von 4 - 5 Tagen den wachen Tieren (meist) 4 mal täglich oral verabreicht.In the substance test, the substance to be tested is administered orally to the awake animals (mostly) 4 times a day over the test period of 4-5 days.

Die bei dieser Methode erzielten Ergebnisse sind in der nachstehenden Tabelle wiedergegeben:

Figure imgb0001
Aus der Tabelle geht klar hervor, daß für die Normalisierung der verkürsten Thrombozytenlebenszeit 10 mg/kg/Tag Dipyridamol oder 100 mg/kg/Tag Sulfinpyrazon erforderlich ist, daß jedoch mit einer Kombination von je 2,5 mg/kg/Tag der beiden Wirkstoffe der gleiche Effekt erreicht wird. Es ist bekannt, daß sich die Ergebnisse über die Normalisierung der Thrombozytenlebenszeit sehr gut vom Affen auf den Menschen übertragen lassen, beispielsweise ist beim Manschen zur Erzielung des gleichen Effektes die gleiche Dosis von Dipyridamol pro Kilogramm erforderlich, wie beim Affen. Die Normalisierung der Thrombozytenlebenszeit ist therapeutisch von sehr großar Bedeutung, da die beim Menschen auftretende Verkürzung der Thromoztenlebenszeit ein Indiz für eine Neigung zu Thrombosen ist. Die neue Arzneimittelkombination ist daher zur Vorbeugung und Heilung von thromboembolischen Krankheiten gut geeignet.The results obtained with this method are shown in the table below:
Figure imgb0001
 The table clearly shows that normalization of the shortened platelet lifespan requires 10 mg / kg / day dipyridamole or 100 mg / kg / day sulfinpyrazone, but with a combination of 2.5 mg / kg / day of the two active substances the same effect is achieved. It is known that the results can be transmitted very well on the normalization of platelet survival time from apes to humans, such as when Marx's to achieve the same effect, the same dose of D ipyridamol per kilogram is required, as in the monkey. The normalization of the platelet lifetime is of great therapeutic importance, since the shortening of the platelet lifetime that occurs in humans is an indication of a tendency to thrombosis. The new drug combination is therefore well suited for the prevention and healing of thromboembolic diseases.

Eine Einzeldosis für Erwachsene enthält zwischen 25 mg und 75 mg der beiden Wirkstoffe, vorzugsweise 50 mg Dipyridamol und 50 mg Sulfinpyrazon; die Einzeldosis wird vorzugsweise 3 mal täglich verabreicht, die mittlere Tagesdosis beträgt somit 150 mg/kg von jedem der beiden Wirkstoffe. Da.beide Wirkstoffe schon seit vielen Jahren im Handel sind, brauchen keine Angaben über die Toxizität gemacht werden, da diese in beiden Fällen gering ist.A single dose for adults contains between 25 mg and 75 mg of the two active substances, preferably 50 mg dipyridamole and 50 mg sulfinpyrazone; the single dose is preferably administered 3 times a day, the mean daily dose is therefore 150 mg / kg of each of the two active compounds. Since both active ingredients have been on the market for many years, no information about the toxicity need be given, since the toxicity is low in both cases.

Gegenstand der Erfindung ist des weiteren ein Verfahren zur Herstellung der erfindungsgemäßen Arzneimittelkombination, welches dadurch gekennzeichnet ist, daß 2,6-Bis(diäthanolamino)-4,8-dipi- peridino-pyrimido[5,4-d]pyrimidin und 1,2-Diphenyl-3.5-dioxo-4-(2-phenylsulfinyläthyl)-pyrazolidin im Verhältnis von 10 : 1 bis 1 : 10 kombiniert und gegebenenfalls mit sonstigen Wirkstoffen und dan bei der Herstellung von Arzneimitteln üblichen Träger- und/oder Hilfsstoffen zu Tabletten, Dragees, Pulver für Briefe, Kapseln und dergleichen formuliert wird. Die erfindungsgemäßen neuen Präparate verden vorzugsweise peroral in den oben angeführten Dosen verab- Die Herstellung von Tabletten, Dragees, Kapseln etc. erfolgt in an sich bekannter Weise, beispielsweise werden die Tabletten durch unmittelbares Verpressen eines Gemisches der Wirk- und Hilfsstoffe hergestellt und gegebenenfalls nachträglich mit einem im Magen-und Darm verträglichen Film überzogen, bei der Herstellung der Kapseln wird erst die Pulvermischung und der Kern mit Überzug getrennt hergestellt und dann auf einer handelsüblichen Kapselabfüllmaschine abgefüllt.The invention further relates to a process for the preparation of the pharmaceutical combination according to the invention, which is characterized in that 2,6-bis (diethanolamino) -4,8-dipiperidino-pyrimido [5,4-d] pyrimidine and 1,2 -Diphenyl-3.5-dioxo-4- (2-phenylsulfinylethyl) -pyrazolidine in a ratio of 10: 1 to 1:10 combined and, if appropriate, with other active substances and then carriers and / or auxiliaries customary in the manufacture of medicaments to form tablets, coated tablets , Powder for letters, capsules and the like is formulated. The new preparations according to the invention are preferably administered orally in the doses mentioned above. Tablets, dragees, capsules etc. are produced in a manner known per se, for example the tablets are produced by directly compressing a mixture of the active ingredients and auxiliaries and, if appropriate, subsequently coated with a film which is compatible with the stomach and intestines during the production of the Capsules are first made separately from the powder mixture and the core with a coating and then filled on a commercially available capsule filling machine.

Die folgenden Beispiele erläutern die Erfindung ohne sie zu besohränken:The following examples illustrate the invention without restricting it:

Beispiel 1example 1

Dragees mit 50 mg Dipyridamol und 50 mg Sulfinpyrazon Ein Drageekern enthält:

Figure imgb0002
Coated tablets with 50 mg dipyridamole and 50 mg sulfinpyrazone One coated tablet contains:
Figure imgb0002

Die Wirkstoffe werden zusammen mit Milchzucker und Stärke gemischt und die Mischung gleichmäßig mit einer wäßrigen Gelatinelösung befeuchtet. Die feuchte Masse wird auf max.2 mm gesiebt, getrocknet und nach nochmaligem Sieben mit dem Schmiermittel vermischt. Aus der so hergestellten preßfertigen Mischung wurden Tabletten von 400 mg gepreßt.The active ingredients are mixed together with milk sugar and starch and the mixture is moistened evenly with an aqueous gelatin solution. The moist mass is sieved to a maximum of 2 mm, dried and mixed with the lubricant after sieving again. Tablets of 400 mg were pressed from the mixture ready for compression.

Drageekernmaße:

Figure imgb0003
Dragierung:Coated core dimensions:
Figure imgb0003
 Coating:

Die Kerne werden mit einer üblichen Zuckerdragiersuspension auf 500 mg und anschließend mit Zuckersirup auf 530 mg/Dragee dragierit;The kernels are coated with a conventional sugar coating suspension to 50 mg and then with sugar syrup to 530 mg / coated tablet dragierite;

Beispiel 2Example 2 Kapseln mit 50 mg Dipyridamoi und 50 mg SulfinpyrazonCapsules with 50 mg dipyridamoi and 50 m g sulfin py razon

Kapselhülle: Hartgelatine-Kapsel Größe 0Capsule shell: hard gelatin capsule size 0

Kapselinhaltsatoffe:Capsule ingredients:

Pulvermischung:

Figure imgb0004
Powder mixture:
Figure imgb0004

Kern 0 6 mm:

Figure imgb0005
Core 0 6 mm:
Figure imgb0005

Überzug:

Figure imgb0006
Coating:
Figure imgb0006

Gesamtfüllgewicht: Pulver/Kern ca. 405 mg.Total filling weight: powder / core approx. 405 mg.

Claims (6)

1. Arzneimittelkombination, dadurch gekennzeichnet, daß sie als Wirkstoff 2,6-Bis(diäthanolamino)-4,8-dipiperidino-pyrimido-[5-,4-d]pyrimidin, 1,2-Diphenyl-3.5-dioxo-4-(2-phenylsulfinyl- äthyl)-pyrazolidin und gegebenenfalls noch weitere bekannte pharmakologisch wirksame Stoffe und/oder die üblichen Träger-und/oder Hilfsstoffe enthält.1. Medicinal combination, characterized in that it contains as active ingredient 2,6-bis (diäthanolamino) -4,8-dipiperidino-pyrimido [5, 4-d] pyrimidine, 1,2-diphenyl-3 .5 -dioxo- 4- (2-phenylsulfinyl-ethyl) -pyrazolidine and optionally also other known pharmacologically active substances and / or the usual carriers and / or auxiliaries. 2. Arzneimittelkombination nach Anspruch 1, dadurch gekennzeichnet, daß das Gewichtsverhältnis von 2,6-Bis(diäthanolamino)-4,8-dipiperidino-pyrimido-[5,4-d]pyrimidin zu 1,2-Diphenyl-3,5-dioxo-4-(2-phenylsulfinyläthyl)-pyrazolidin 10 : 1 bis 1 : 10 beträgt.2. Pharmaceutical combination according to claim 1, characterized in that the weight ratio of 2,6-bis (diethanolamino) -4,8-dipiperidino-pyrimido [5,4-d] pyrimidine to 1,2-diphenyl-3,5- dioxo-4- (2-phenylsulfinylethyl) pyrazolidine is 10: 1 to 1:10. 3. Arzneimittelkombination gemäß Anspruch 1 und 2, dadurch gekenn- zeichnet, daß das Verhältnis der beiden Wirkstoffe 1 : 1 beträgt.3. Pharmaceutical combination according to claim 1 and 2 characterized - characterized in that the ratio of the two active substances 1: 1. 4. Verfahren zur Herstellung einer Arzneimittelkombination, dadurch gekennzeichnet, daß man 2,6-Bis(diäthanolamino)-4,8-di- piperidino-pyrimido[5,4-d]pyrimidin und 1,2-Diphenyl-3,5-dioxo-4-(2-phenylsulfinyläthyl)-pyrazolidin im Verhältnis von 10 : 1 bis 1 : 10 kombiniert und gegebenenfalls mit sonstigen bekannten pharmakologisch wirksamen Stoffen und den üblichen Träger-und/oder Hilfsstoffen zu Dragees, Tabletten, Kapseln oder Pulverbriefchen formuliert.4. A process for the preparation of a pharmaceutical combination, characterized in that 2,6-bis (diethanolamino) -4,8-dipiperidino-pyrimido [5,4-d] pyrimidine and 1,2-diphenyl-3,5- dioxo-4- (2-phenylsulfinylethyl) pyrazolidine combined in the ratio of 10: 1 to 1:10 and optionally formulated with other known pharmacologically active substances and the usual carriers and / or auxiliaries to form dragées, tablets, capsules or powder packs. 5. Verwendung von 2,6-Bis(diäthanolamino)-4,8-dipiperidino-pyrimi-, do[5,4-d]pyrimidin und von 1,2-Diphenyl-3,5-dioxo-4-(2-phenyl- sulfinyläthyl)-pyrazolidin zur Herstellung einer therapeutisch gut verträglichen antithrombotischen Arzneimittelkombination.5. Use of 2,6-bis (diethanolamino) -4,8-dipiperidino-pyrimi-, do [5,4-d] pyrimidine and of 1,2-diphenyl-3,5-dioxo-4- (2- phenyl-sulfinylethyl) pyrazolidine for the production of a therapeutically well-tolerated antithrombotic drug combination. 6. Verwendung einer Arzneimittelkombination gemäß Anspruch 1 zur Behandlung von thromboembolischen Krankheiten.6. Use of a pharmaceutical combination according to claim 1 for the treatment of thromboembolic diseases.
EP78100586A 1977-08-09 1978-08-03 Antithrombotic medicative combination and process for its preparation Expired EP0000774B1 (en)

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DE19772735830 DE2735830A1 (en) 1977-08-09 1977-08-09 ANTITHROMBOTIC DRUG COMBINATION AND METHOD FOR THE PRODUCTION THEREOF

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0014392A1 (en) * 1979-02-08 1980-08-20 Dr. Karl Thomae GmbH Antithrombotic drugs combination and process for its manufacture
EP0019586A1 (en) * 1979-05-11 1980-11-26 Ciba-Geigy Ag Antithrombotic combination formulas
EP3587369A1 (en) 2009-04-03 2020-01-01 Verescence France Method for manufacturing a glass container

Also Published As

Publication number Publication date
SE7808489L (en) 1979-02-10
IT1107571B (en) 1985-11-25
IE781610L (en) 1979-02-09
FR2399841B1 (en) 1980-10-31
DE2735830A1 (en) 1979-03-01
NL7807539A (en) 1979-02-13
FR2399841A1 (en) 1979-03-09
IL55301A (en) 1983-05-15
IT7850483A0 (en) 1978-07-26
JPS5940134B2 (en) 1984-09-28
DE2860018D1 (en) 1980-10-16
EP0000774B1 (en) 1980-05-28
IE47740B1 (en) 1984-06-13
NZ188098A (en) 1984-07-06
PH14149A (en) 1981-03-06
BE869614A (en) 1979-02-08
AU3873578A (en) 1980-02-14
US4206214A (en) 1980-06-03
GB2002230A (en) 1979-02-21
LU80083A1 (en) 1979-09-06
JPS5428829A (en) 1979-03-03
AU517484B2 (en) 1981-08-06
ZA784470B (en) 1980-04-30

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