EP0000774B1 - Antithrombotic medicative combination and process for its preparation - Google Patents
Antithrombotic medicative combination and process for its preparation Download PDFInfo
- Publication number
- EP0000774B1 EP0000774B1 EP78100586A EP78100586A EP0000774B1 EP 0000774 B1 EP0000774 B1 EP 0000774B1 EP 78100586 A EP78100586 A EP 78100586A EP 78100586 A EP78100586 A EP 78100586A EP 0000774 B1 EP0000774 B1 EP 0000774B1
- Authority
- EP
- European Patent Office
- Prior art keywords
- antithrombotic
- preparation
- combination
- medicative
- pharmaceutical combination
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- 230000002785 anti-thrombosis Effects 0.000 title claims description 6
- 238000000034 method Methods 0.000 title claims description 5
- 238000002360 preparation method Methods 0.000 title claims description 5
- 239000003146 anticoagulant agent Substances 0.000 title claims description 4
- IZEKFCXSFNUWAM-UHFFFAOYSA-N dipyridamole Chemical compound C=12N=C(N(CCO)CCO)N=C(N3CCCCC3)C2=NC(N(CCO)CCO)=NC=1N1CCCCC1 IZEKFCXSFNUWAM-UHFFFAOYSA-N 0.000 claims description 10
- MBGGBVCUIVRRBF-UHFFFAOYSA-N sulfinpyrazone Chemical compound O=C1N(C=2C=CC=CC=2)N(C=2C=CC=CC=2)C(=O)C1CCS(=O)C1=CC=CC=C1 MBGGBVCUIVRRBF-UHFFFAOYSA-N 0.000 claims description 9
- 239000004480 active ingredient Substances 0.000 claims description 5
- 239000002775 capsule Substances 0.000 claims description 5
- 239000003826 tablet Substances 0.000 claims description 4
- 239000013543 active substance Substances 0.000 claims description 3
- 239000000843 powder Substances 0.000 claims description 3
- 239000012050 conventional carrier Substances 0.000 claims 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims 2
- 229960002768 dipyridamole Drugs 0.000 description 6
- 229960003329 sulfinpyrazone Drugs 0.000 description 5
- 230000000694 effects Effects 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 3
- 238000010606 normalization Methods 0.000 description 3
- 241000282693 Cercopithecidae Species 0.000 description 2
- VYZAMTAEIAYCRO-UHFFFAOYSA-N Chromium Chemical compound [Cr] VYZAMTAEIAYCRO-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Chemical compound OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 241000282520 Papio Species 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 239000008298 dragée Substances 0.000 description 2
- 230000002195 synergetic effect Effects 0.000 description 2
- 230000007306 turnover Effects 0.000 description 2
- 206010000087 Abdominal pain upper Diseases 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 206010019233 Headaches Diseases 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 208000001435 Thromboembolism Diseases 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 239000002255 antigout agent Substances 0.000 description 1
- 229960002708 antigout preparations Drugs 0.000 description 1
- 229940127217 antithrombotic drug Drugs 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 229910052804 chromium Inorganic materials 0.000 description 1
- 239000011651 chromium Substances 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 210000003191 femoral vein Anatomy 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000004904 shortening Methods 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000020374 simple syrup Nutrition 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 238000009495 sugar coating Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 230000001562 ulcerogenic effect Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- 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 (diethano) amino) -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 used 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 table clearly shows that for the normalization of the shortened platelet lifetime 10 mg / kg / day dipyridamole or 100 mg / kg / day sulfinpyrazone is required, 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 on the normalization of platelet life can be transferred very well from monkeys to humans, for example in humans the same dose of dipyridamole per kilogram is required to achieve the same effect as in monkeys.
- the Normalization of the platelet lifespan is of great therapeutic importance since the shortening of the platelet lifespan occurring 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 needs to be given, since this 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-phenylsulfinyläthyl) -pyrazolidine combined in the ratio of 10: 1 to 1:10 and the usual carriers and / or auxiliaries in the manufacture of medicines to tablets, dragees, powder for letters and Capsules is formulated.
- the new preparations according to the invention are preferably administered orally in the doses mentioned above.
- Tablets and dragees capsules 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 gastrointestinal tract, the capsules being produced First the powder mixture and the core are coated separately and then filled on a commercially available capsule filling machine.
- 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 limited to max. Sieved 2 mm, dried and mixed with the lubricant after sieving again. Tablets of 400 mg were pressed from the mixture prepared in this way.
- the kernels are coated with a conventional sugar-coating suspension to 500 mg and then with sugar syrup to 530 mg / coated tablet.
Description
Die Erfindung betrifft eine neue antithrombotisch wirkende Arzneimittelkombination sowie ein Verfahren zu ihrer Herstellung. 2,6-Bis(diäthano)amino)-4,8-dipiperidino-pyrimido[5,4-d]pyrimidin (generic name: DIPYRIDAMOL) wird bereits seit langem als koronarerweiterndes Heilmittel verwendet. Es wurde erstmals im bristischen 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 (diethano) amino) -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 used 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.For both substances, however, a relatively high dose is required to achieve an antithrombotic effect, with the side effects of both compounds already being noticeable; Dipyridamole has certain circulatory effects, which are expressed in headaches, and sulfinpyrazone causes stomach pains due to the fact that this substance is ulcerogenic in high doses.
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:
- 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 an AV shunt between the artery and femoral vein. 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 easily measured by injecting the test animal with 51 radio-labeled platelets with chromium and following their disappearance from the bloodstream by measuring it twice a day. 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.During 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:
Aus der Tabelle geht klar hervor, daß für die Normalisierung der verkürzten 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 Menschen zur Erzielung des gleichen Effektes die gleiche Dosis von Dipyridamol pro Kilogramm erforderlich, wie beim Affen. Die Normalisierung der Thrombozytenlebenszeit ist therapeutisch von sehr großer Bedeutung, da die beim Menschen auftretende Verkürzung der Thrombozytenlebenszeit ein Indiz für eine Neigung zu Thrombosen ist. Die neue Arzneimittelkombination ist daher zur Vorbeugung und Heilung von thromboembolischen Krankheiten gut geeignet.The table clearly shows that for the normalization of the shortened platelet lifetime 10 mg / kg / day dipyridamole or 100 mg / kg / day sulfinpyrazone is required, 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 on the normalization of platelet life can be transferred very well from monkeys to humans, for example in humans the same dose of dipyridamole per kilogram is required to achieve the same effect as in monkeys. The Normalization of the platelet lifespan is of great therapeutic importance since the shortening of the platelet lifespan occurring 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 needs to be given, since this 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- dipiperidino-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 den bei der Herstellung von Arzneimitteln üblichen Träger- und/oder Hilfsstoffen zu Tabletten, Dragees, Pulver für Briefe und Kapseln formuliert wird. Die erfindungsgemäßen neuen Präparate werden vorzugsweise peroral in den oben angeführten Dosen verabreicht.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-phenylsulfinyläthyl) -pyrazolidine combined in the ratio of 10: 1 to 1:10 and the usual carriers and / or auxiliaries in the manufacture of medicines to tablets, dragees, powder for letters and Capsules is formulated. The new preparations according to the invention are preferably administered orally in the doses mentioned above.
Die Herstellung von Tabletten und Dragees, Kapseln 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 Uberzug getrennt hergestellt und dann auf einer handelsüblichen Kapselabfüllmaschine abgefüllt.Tablets and dragees, capsules 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 gastrointestinal tract, the capsules being produced First the powder mixture and the core are coated separately and then filled on a commercially available capsule filling machine.
Die folgenden Beispiele erläutern die Erfindung ohne sie zu beschränken:
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 limited to max. Sieved 2 mm, dried and mixed with the lubricant after sieving again. Tablets of 400 mg were pressed from the mixture prepared in this way.
Die Kerne werden mit einer üblichen Zuckerdragiersuspension auf 500 mg und anschließend mit Zuckersirup auf 530 mg/Dragee dragiert.
Claims (4)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE2735830 | 1977-08-09 | ||
| DE19772735830 DE2735830A1 (en) | 1977-08-09 | 1977-08-09 | ANTITHROMBOTIC DRUG COMBINATION AND METHOD FOR THE PRODUCTION THEREOF |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| EP0000774A1 EP0000774A1 (en) | 1979-02-21 |
| EP0000774B1 true EP0000774B1 (en) | 1980-05-28 |
Family
ID=6015980
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP78100586A Expired EP0000774B1 (en) | 1977-08-09 | 1978-08-03 | Antithrombotic medicative combination and process for its preparation |
Country Status (17)
| Country | Link |
|---|---|
| US (1) | US4206214A (en) |
| EP (1) | EP0000774B1 (en) |
| JP (1) | JPS5940134B2 (en) |
| AU (1) | AU517484B2 (en) |
| BE (1) | BE869614A (en) |
| DE (2) | DE2735830A1 (en) |
| FR (1) | FR2399841A1 (en) |
| GB (1) | GB2002230A (en) |
| IE (1) | IE47740B1 (en) |
| IL (1) | IL55301A (en) |
| IT (1) | IT1107571B (en) |
| LU (1) | LU80083A1 (en) |
| NL (1) | NL7807539A (en) |
| NZ (1) | NZ188098A (en) |
| PH (1) | PH14149A (en) |
| SE (1) | SE7808489L (en) |
| ZA (1) | ZA784470B (en) |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2904736A1 (en) * | 1979-02-08 | 1980-08-28 | Thomae Gmbh Dr K | ANTITHROMBOTIC DRUG COMBINATION |
| EP0019586A1 (en) * | 1979-05-11 | 1980-11-26 | Ciba-Geigy Ag | Antithrombotic combination formulas |
| FR2470599A1 (en) * | 1979-12-07 | 1981-06-12 | Panoz Donald | IMPROVEMENTS IN PROCESSES FOR THE PREPARATION OF GALENIC SHAPES WITH DELAYED ACTION AND PROGRAMMED RELEASE AND GALENIC FORMS OF MEDICAMENTS THUS OBTAINED |
| US4444777A (en) * | 1981-07-30 | 1984-04-24 | Bristol-Myers Company | Pharmaceutical compositions of anagrelide and sulfinpyrazone |
| AT393962B (en) * | 1987-10-22 | 1992-01-10 | Thomae Gmbh Dr K | Synergistic pharmaceutical combination with a content of a phosphodiesterase inhibitor and the use thereof |
| US6376242B1 (en) * | 1999-09-21 | 2002-04-23 | Emory University | Methods and compositions for treating platelet-related disorders using MPL pathway inhibitory agents |
| EP1093814A1 (en) * | 1999-10-22 | 2001-04-25 | Boehringer Ingelheim Pharma KG | Use of dipyridamole or mopidamol in the manufacture of a medicament for the treatment and prevention of fibrin-dependent microcirculation disorders |
| US7064130B2 (en) * | 2001-04-20 | 2006-06-20 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Use of radical-scavenging compounds for treatment and prevention of NO-dependent microcirculation disorders |
| JP2006516593A (en) * | 2003-02-07 | 2006-07-06 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | Use of dipyridamole or mopidamol for the treatment and prevention of MMP-9 dependent diseases |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3031450A (en) * | 1959-04-30 | 1962-04-24 | Thomae Gmbh Dr K | Substituted pyrimido-[5, 4-d]-pyrimidines |
| US3322755A (en) * | 1964-03-10 | 1967-05-30 | Boehringer Sohn Ingelheim | Basic-substituted 1, 2, 3, 4-tetrahydropyrimido [5, 4-d]-pyrimidines |
| GB1190419A (en) * | 1966-08-16 | 1970-05-06 | Yamanouchi Pharma Co Ltd | Substituted Pyrimido-Pyrimidines and a process for the preparation thereof |
-
1977
- 1977-08-09 DE DE19772735830 patent/DE2735830A1/en not_active Withdrawn
-
1978
- 1978-07-13 NL NL787807539A patent/NL7807539A/en not_active Application Discontinuation
- 1978-07-26 IT IT50483/78A patent/IT1107571B/en active
- 1978-08-01 US US05/929,940 patent/US4206214A/en not_active Expired - Lifetime
- 1978-08-03 DE DE7878100586T patent/DE2860018D1/en not_active Expired
- 1978-08-03 EP EP78100586A patent/EP0000774B1/en not_active Expired
- 1978-08-07 LU LU80083A patent/LU80083A1/en unknown
- 1978-08-07 IL IL55301A patent/IL55301A/en unknown
- 1978-08-08 ZA ZA784470A patent/ZA784470B/en unknown
- 1978-08-08 SE SE7808489A patent/SE7808489L/en unknown
- 1978-08-08 JP JP53096562A patent/JPS5940134B2/en not_active Expired
- 1978-08-08 BE BE78189779A patent/BE869614A/en unknown
- 1978-08-08 NZ NZ188098A patent/NZ188098A/en unknown
- 1978-08-08 IE IE1610/78A patent/IE47740B1/en unknown
- 1978-08-08 GB GB7832620A patent/GB2002230A/en not_active Withdrawn
- 1978-08-08 AU AU38735/78A patent/AU517484B2/en not_active Expired
- 1978-08-09 FR FR7823487A patent/FR2399841A1/en active Granted
- 1978-08-09 PH PH21475A patent/PH14149A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| NZ188098A (en) | 1984-07-06 |
| PH14149A (en) | 1981-03-06 |
| EP0000774A1 (en) | 1979-02-21 |
| SE7808489L (en) | 1979-02-10 |
| FR2399841B1 (en) | 1980-10-31 |
| IE47740B1 (en) | 1984-06-13 |
| JPS5428829A (en) | 1979-03-03 |
| IT7850483A0 (en) | 1978-07-26 |
| JPS5940134B2 (en) | 1984-09-28 |
| GB2002230A (en) | 1979-02-21 |
| DE2860018D1 (en) | 1980-10-16 |
| IL55301A (en) | 1983-05-15 |
| ZA784470B (en) | 1980-04-30 |
| IT1107571B (en) | 1985-11-25 |
| FR2399841A1 (en) | 1979-03-09 |
| IE781610L (en) | 1979-02-09 |
| US4206214A (en) | 1980-06-03 |
| DE2735830A1 (en) | 1979-03-01 |
| LU80083A1 (en) | 1979-09-06 |
| BE869614A (en) | 1979-02-08 |
| AU517484B2 (en) | 1981-08-06 |
| AU3873578A (en) | 1980-02-14 |
| NL7807539A (en) | 1979-02-13 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| DE3723735C2 (en) | ||
| DD201644A5 (en) | SUSPENSION OF MICRO-CAPACITATED BACAMPICILLIN-SAEUREADDITIONAL SALTS FOR ORAL, PARTICULARLY PAEDIATRIC ADMINISTRATION | |
| EP0282696B1 (en) | Use of pyridoxine derivatives in the prophylaxis and treatment of hyperlipemia and atherosclerosis | |
| DE3152519T1 (en) | NEW FENOFIBRATE FINISHED PREPARATION, ITS PRODUCTION PROCESS, ITS APPLICATION AS A MEDICINE | |
| EP0796103B1 (en) | Use of incense in the treatment of alzheimer's disease | |
| EP0000774B1 (en) | Antithrombotic medicative combination and process for its preparation | |
| DE3719818C2 (en) | Pharmaceutical composition | |
| LU86291A1 (en) | PHARMACEUTICAL PREPARATIONS WITH ANALGETIC EFFECTIVENESS, AND THEIR PRODUCTION AND USE | |
| EP0037488A2 (en) | Pharmaceutical composition for healing inflammatory and/or degenerative and/or atrophic mucous membranes | |
| DE2507635C2 (en) | ||
| DE2758942A1 (en) | CHEWABLE TABLETS WITH ERYTHROMYCIN | |
| DE3034975C2 (en) | Drug combination used to treat infectious respiratory diseases | |
| EP0014392B1 (en) | Antithrombotic drugs combination and process for its manufacture | |
| DE3117756C2 (en) | ||
| DE3141970A1 (en) | MEDICINES FOR TREATING DISEASES GENERATED BY THE VIRUS OF THE HERPES GROUP | |
| DE3535950A1 (en) | COMBINATION PREPARATION | |
| EP0019586A1 (en) | Antithrombotic combination formulas | |
| EP0123841B1 (en) | Medicament with an atheroprotective high density lipoprotein enhancing activity, containing 2,6-bis-diethanolamino-4,8-dipiperidinopyrimide (5,4-d) pyrimidine | |
| DE3115033A1 (en) | Drug form for oral photochemotherapy | |
| DE3523544A1 (en) | NIFEDIPIN COMBINATION PRODUCT | |
| DE3901508C2 (en) | Drug based on a bismuth-containing preparation in solid form | |
| DE2532180C2 (en) | Use of Etozolin in the fight against hypertension | |
| DE2456172C3 (en) | Medicines for rheumatic diseases | |
| EP0101963A1 (en) | Orally administrable galenic forms of soluble dimethylxanthine derivatives | |
| DE3511236A1 (en) | Product with synergistic bronchodilating effect and process for its preparation |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
| AK | Designated contracting states |
Designated state(s): BE CH DE FR GB LU NL SE |
|
| 17P | Request for examination filed | ||
| GRAA | (expected) grant |
Free format text: ORIGINAL CODE: 0009210 |
|
| AK | Designated contracting states |
Designated state(s): BE CH DE FR GB LU NL SE |
|
| PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: LU Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 19800831 |
|
| REF | Corresponds to: |
Ref document number: 2860018 Country of ref document: DE Date of ref document: 19801016 |
|
| REG | Reference to a national code |
Ref country code: CH Ref legal event code: PL |
|
| REG | Reference to a national code |
Ref country code: CH Ref legal event code: AEN Free format text: DIE PATENTE SIND AM 841112 GESTUETZT AUF DIE EINGEREICHTEN WIEDEREINSETZUNGSGESUCHE AUF GRUND VON ART. 47 PATG WIEDER IN KRAFT GESETZT WORDEN. |
|
| PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: SE Payment date: 19890711 Year of fee payment: 12 |
|
| PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: LU Payment date: 19890712 Year of fee payment: 12 |
|
| PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: FR Payment date: 19890713 Year of fee payment: 12 |
|
| PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: GB Payment date: 19890731 Year of fee payment: 12 |
|
| PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: CH Payment date: 19890821 Year of fee payment: 12 |
|
| PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: DE Payment date: 19890824 Year of fee payment: 12 |
|
| PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: NL Payment date: 19890831 Year of fee payment: 12 |
|
| PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: BE Payment date: 19890914 Year of fee payment: 12 |
|
| PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: GB Effective date: 19900803 |
|
| PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: SE Effective date: 19900804 |
|
| PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: CH Effective date: 19900831 Ref country code: BE Effective date: 19900831 |
|
| BERE | Be: lapsed |
Owner name: KARL THOMAE G.M.B.H. Effective date: 19900831 |
|
| PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: NL Effective date: 19910301 |
|
| GBPC | Gb: european patent ceased through non-payment of renewal fee | ||
| NLV4 | Nl: lapsed or anulled due to non-payment of the annual fee | ||
| PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: FR Effective date: 19910430 |
|
| REG | Reference to a national code |
Ref country code: CH Ref legal event code: PL |
|
| PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: DE Effective date: 19910501 |
|
| REG | Reference to a national code |
Ref country code: FR Ref legal event code: ST |
|
| EUG | Se: european patent has lapsed |
Ref document number: 78100586.3 Effective date: 19910410 |
|
| PLBE | No opposition filed within time limit |
Free format text: ORIGINAL CODE: 0009261 |
|
| STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT |