DE19536916A1 - Inhalative application of 2-amino-6n-propyl-amino-4,5,6,7-tetrahydrobenzothiazole, in particular its (-) - enantiomer, and their pharmacologically acceptable acid addition salts - Google Patents
Inhalative application of 2-amino-6n-propyl-amino-4,5,6,7-tetrahydrobenzothiazole, in particular its (-) - enantiomer, and their pharmacologically acceptable acid addition saltsInfo
- Publication number
- DE19536916A1 DE19536916A1 DE19536916A DE19536916A DE19536916A1 DE 19536916 A1 DE19536916 A1 DE 19536916A1 DE 19536916 A DE19536916 A DE 19536916A DE 19536916 A DE19536916 A DE 19536916A DE 19536916 A1 DE19536916 A1 DE 19536916A1
- Authority
- DE
- Germany
- Prior art keywords
- amino
- tetrahydrobenzothiazole
- acid addition
- pharmacologically acceptable
- acceptable acid
- 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.)
- Withdrawn
Links
- 239000002253 acid Substances 0.000 title claims description 10
- 150000003839 salts Chemical class 0.000 title claims description 10
- KWFASKPXXSVNIQ-UHFFFAOYSA-N 6-propyl-4,5,6,7-tetrahydro-1,3-benzothiazole-2,4-diamine Chemical compound C1C(CCC)CC(N)C2=C1SC(N)=N2 KWFASKPXXSVNIQ-UHFFFAOYSA-N 0.000 title claims description 3
- FASDKYOPVNHBLU-UHFFFAOYSA-N N6-Propyl-4,5,6,7-tetrahydro-1,3-benzothiazole-2,6-diamine Chemical compound C1C(NCCC)CCC2=C1SC(N)=N2 FASDKYOPVNHBLU-UHFFFAOYSA-N 0.000 claims description 6
- 208000018737 Parkinson disease Diseases 0.000 claims description 5
- 239000000843 powder Substances 0.000 claims description 4
- 239000004480 active ingredient Substances 0.000 claims description 3
- 239000000443 aerosol Substances 0.000 claims description 3
- 229940071648 metered dose inhaler Drugs 0.000 claims description 3
- QMNWXHSYPXQFSK-UHFFFAOYSA-N hydron;6-n-propyl-4,5,6,7-tetrahydro-1,3-benzothiazole-2,6-diamine;dichloride Chemical compound Cl.Cl.C1C(NCCC)CCC2=C1SC(N)=N2 QMNWXHSYPXQFSK-UHFFFAOYSA-N 0.000 claims description 2
- 201000010099 disease Diseases 0.000 claims 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims 4
- 239000002831 pharmacologic agent Substances 0.000 claims 2
- FASDKYOPVNHBLU-ZETCQYMHSA-N pramipexole Chemical compound C1[C@@H](NCCC)CCC2=C1SC(N)=N2 FASDKYOPVNHBLU-ZETCQYMHSA-N 0.000 description 9
- 229960003089 pramipexole Drugs 0.000 description 7
- 238000002360 preparation method Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 230000008901 benefit Effects 0.000 description 2
- 230000036765 blood level Effects 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 229940041682 inhalant solution Drugs 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- LERNTVKEWCAPOY-VOGVJGKGSA-N C[N+]1(C)[C@H]2C[C@H](C[C@@H]1[C@H]1O[C@@H]21)OC(=O)C(O)(c1cccs1)c1cccs1 Chemical compound C[N+]1(C)[C@H]2C[C@H](C[C@@H]1[C@H]1O[C@@H]21)OC(=O)C(O)(c1cccs1)c1cccs1 LERNTVKEWCAPOY-VOGVJGKGSA-N 0.000 description 1
- VCUFZILGIRCDQQ-KRWDZBQOSA-N N-[[(5S)-2-oxo-3-(2-oxo-3H-1,3-benzoxazol-6-yl)-1,3-oxazolidin-5-yl]methyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C1O[C@H](CN1C1=CC2=C(NC(O2)=O)C=C1)CNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F VCUFZILGIRCDQQ-KRWDZBQOSA-N 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000003444 anaesthetic effect Effects 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 230000037058 blood plasma level Effects 0.000 description 1
- AAOVKJBEBIDNHE-UHFFFAOYSA-N diazepam Chemical compound N=1CC(=O)N(C)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 AAOVKJBEBIDNHE-UHFFFAOYSA-N 0.000 description 1
- 238000003958 fumigation Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- XLYOFNOQVPJJNP-ZSJDYOACSA-N heavy water Substances [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 229940105631 nembutal Drugs 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- WEXRUCMBJFQVBZ-UHFFFAOYSA-N pentobarbital Chemical compound CCCC(C)C1(CC)C(=O)NC(=O)NC1=O WEXRUCMBJFQVBZ-UHFFFAOYSA-N 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 238000009101 premedication Methods 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229960000257 tiotropium bromide Drugs 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 229940072690 valium Drugs 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/428—Thiazoles condensed with carbocyclic rings
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
Die vorliegende Erfindung betrifft die inhalative Applikation von 2-Amino-6n-propyl amino-4,5,6,7-tetrahydrobenzothiazol, insbesondere seines (-)-Enantiomeren, sowie deren pharmakologisch verträgliche Säureadditionssalze.The present invention relates to the inhalative application of 2-amino-6n-propyl amino-4,5,6,7-tetrahydrobenzothiazole, in particular its (-) - enantiomer, and their pharmacologically acceptable acid addition salts.
Die genannten Verbindungen sind als Arzneimittel bekannt, wobei die Behandlung der Schizophrenie und die Behandlung der Parkinsonschen Krankheit im Vordergrund stehen. Einzelheiten zur Herstellung dieser Verbindungen - deren (-)- Enantiomeren in der Literatur auch als SND 919 oder Pramipexol bezeichnet wird, können der Europäischen Patentanmeldung EP-A 85 116 016 entnommen werden. Aus dem europäischen Patent 428 038 ist die transdermale Applikation dieser Verbindung bekannt. Überraschenderweise hat sich gezeigt, daß Pramipexol in Form einer inhalativen Gabe besonders vorteilhaft appliziert werden kann, da ein schneller Wirkungseintritt bei gleichzeitig guter Verträglichkeit beobachtet wird.The compounds mentioned are known as medicaments, the treatment schizophrenia and the treatment of Parkinson's disease in the Foreground. Details of the preparation of these compounds - their (-) - Enantiomers in the literature is also referred to as SND 919 or pramipexole, can be found in European Patent Application EP-A 85 116 016. European Patent 428,038 discloses the transdermal application of these Known connection. Surprisingly, it has been shown that pramipexole in Form of an inhaled dose can be applied particularly advantageous, as a rapid onset of action is observed at the same time good tolerability.
Die Behandlung der Parkinsonschen Krankheit erfolgt üblicherweise durch orale Applikation von Arzneimitteln. Die erfindungsgemäß vorgeschlagene inhalative Applikation bringt für den Parkinson-Patienten wesentliche Vorteile mit sich, die seine Lebensumstände verbessern. Die Parkinson′sche Erkrankung ist bei vielen Patienten mit einem Zustand der Bewegungshemmung verbunden. Die erfindungsgemäße inhalative Applikation von Pramipexole führt zu einem außergewöhnlich raschem Anstieg der Blutspiegelwerte innerhalb kürzester Zeit (Minuten) wodurch der Zustand der Bewegungshemmung rasch aufgehoben wird. Bei oraler Applikation kann es bis zu zwei Stunden dauern, bis optimale Blutspiegelwerte erreicht sind.The treatment of Parkinson's disease is usually by oral Application of medicines. The inventively proposed inhalative Application brings significant benefits for the Parkinson's patients who improve his living conditions. Parkinson's disease is present in many Patients associated with a state of motor inhibition. The inhalative administration of pramipexole according to the invention leads to a exceptionally rapid increase in blood levels within a very short time (Minutes) whereby the state of the movement inhibition is rapidly abolished. With oral administration, it can take up to two hours to get optimal Blood levels are reached.
2-Amino-6n-propyl-amino-4,5,6,7-tetrahydrobenzothiazol kann in Form seiner Säureadditionssalze in Form von wässerigen oder ethanolischen Lösungen zur Herstellung eines Aerosols zur erfindungsgemäßen Anwendung verwendet werden. Bevorzugtes Säureadditionssalz ist das Dihydrochlorid.2-amino-6n-propylamino-4,5,6,7-tetrahydrobenzothiazole may be in the form of its Acid addition salts in the form of aqueous or ethanolic solutions for Preparation of an aerosol can be used for the application of the invention. Preferred acid addition salt is the dihydrochloride.
Vorrichtungen zur Erzeugung eines Dosieraerosols sind aus dem Stand der Technik zur Behandlung von Asthmaerkrankungen bekannt. Besonders bevorzugt ist eine Vorrichtung wie sie in der WO 91/14468 - Atomising Devices and Methods - offenbart ist. Der Vorteil der dort beschriebenen Vorrichtung ist es, daß auf die üblicherweise bei metered dose inhalers (MDI′s) erforderlichen Treibgase zur Erzeugung des Aerosols verzichtet werden kann.Devices for generating a metered dose inhaler are known in the art known for the treatment of asthma. Particularly preferred is a Device as described in WO 91/14468 - Atomizing Devices and Methods - is disclosed. The advantage of the device described therein is that on the Usually with metered dose inhalers (MDI's) required propellant gases Generation of the aerosol can be dispensed with.
Alternativ zu einem Dosieraerosol kann Pramipexol auch mittels eines sogenannten Pulverinhalators appliziert werden, bei dem mikronisierte Teilchen in einem Bereich von 1 bis 15, bevorzugt 4 bis 8 µm des Wirkstoffes direkt als Pulver inhaliert werden.As an alternative to a metered dose inhaler, pramipexole can also be administered by means of a so-called Powder inhaler can be applied to the micronized particles in one area from 1 to 15, preferably 4 to 8 microns of the active ingredient inhaled directly as a powder become.
Erfindungsgemäß wird eine inhalative Einzeldosis zwischen 0.125 und 4,5 mg pro Patient vorgeschlagen.According to the invention, a single inhaled dose is between 0.125 and 4.5 mg per Patient proposed.
Der nachfolgende Versuch belegt, daß durch die inhalative Applikation von Pramipexole im Tierexperiment bereits kurz nach der Inhalation hohe Plasmaspiegel erzielt werden.The following experiment proves that inhalative administration of Pramipexole in animal experiment already high plasma levels shortly after inhalation be achieved.
Inhalative Einzeldosierung von 2 mg Pramipexole in 20 Mikroliter Wasser/Hund
Gewicht des Hundes (Beagle) 10.7 kg
Narkosemittel:
Praemedikation: Valium 7.5 mg i.m.
Nembutal: 30 mg/kg i.v.Inhalative single dose of 2 mg pramipexole in 20 microliter water / dog Dog's weight (Beagle) 10.7 kg
Anesthetic:
Pre-medication: Valium 7.5 mg im
Nembutal: 30 mg / kg iv
Die Applikation des Wirkstoffs erfolgte mittels Respimat Blutplasmaspiegel: Inhalation 2 mgThe application of the drug was carried out by means of Respimat Blood plasma level: inhalation 2 mg
In ausgekochtem und unter CO₂-Begasung abgekühltem Wasser werden nacheinander die Puffersubstanzen, die Wirksubstanz sowie Natriumpyrosulfit gelöst. Man füllt mit abgekochtem Wasser auf das gegebene Volumen auf und filtriert pyrogenfrei.In boiled and cooled under CO₂ fumigation water successively the buffer substances, the active substance and sodium pyrosulfite solved. Make up to the given volume with boiled water and filtered pyrogen-free.
Abfüllung: in braune Ampullen unter
Schutzgas
Sterilisation: 20 Minuten bei 120°CFilling: in brown ampoules under inert gas
Sterilization: 20 minutes at 120 ° C
Die Herstellung und Abfüllung der Inhalationslösung muß in abgedunkelten Räumen vorgenommen werden.The preparation and filling of the inhalation solution must be carried out in darkened rooms be made.
Claims (10)
Priority Applications (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19536916A DE19536916A1 (en) | 1995-10-04 | 1995-10-04 | Inhalative application of 2-amino-6n-propyl-amino-4,5,6,7-tetrahydrobenzothiazole, in particular its (-) - enantiomer, and their pharmacologically acceptable acid addition salts |
| ZA968315A ZA968315B (en) | 1995-10-04 | 1996-10-03 | Administration by inhalation of 2-amino-6n-propyl-amino-4,5,,7-tetrahydrobenzothiazole particularly the (-)-enan-tiomer thereof and the pharmacologically acceptable acid addition salts thereof |
| PCT/EP1996/004327 WO1997012614A1 (en) | 1995-10-04 | 1996-10-04 | Administration by inhalation of 2-amino-6n-propylamino-4,5,6,7-tetrahydrobenzothiazol, in particular of its (-)enantiomer and its pharmacologically tolerable acid addition salts |
| AU72856/96A AU7285696A (en) | 1995-10-04 | 1996-10-04 | Administration by inhalation of 2-amino-6n-propylamino-4,5,6,7-tetrahydrobenzothiazol, in particular of its (-)enantiomer and its pharmacologically tolerable acid addition salts |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19536916A DE19536916A1 (en) | 1995-10-04 | 1995-10-04 | Inhalative application of 2-amino-6n-propyl-amino-4,5,6,7-tetrahydrobenzothiazole, in particular its (-) - enantiomer, and their pharmacologically acceptable acid addition salts |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DE19536916A1 true DE19536916A1 (en) | 1997-04-10 |
Family
ID=7773972
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE19536916A Withdrawn DE19536916A1 (en) | 1995-10-04 | 1995-10-04 | Inhalative application of 2-amino-6n-propyl-amino-4,5,6,7-tetrahydrobenzothiazole, in particular its (-) - enantiomer, and their pharmacologically acceptable acid addition salts |
Country Status (4)
| Country | Link |
|---|---|
| AU (1) | AU7285696A (en) |
| DE (1) | DE19536916A1 (en) |
| WO (1) | WO1997012614A1 (en) |
| ZA (1) | ZA968315B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE19653969A1 (en) * | 1996-12-20 | 1998-06-25 | Boehringer Ingelheim Kg | New aqueous pharmaceutical preparation for the production of propellant-free aerosols |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2839431A1 (en) * | 1978-09-11 | 1980-03-20 | Dolorgiet Arzneimittelfabrik | Tranquilliser and hypertonic for heart and vascular disease treatment - contg. 1-(2-nitro-5-methylphenoxy)-3-tert.butyl-aminopropan-2-ol |
| EP0186087B1 (en) * | 1984-12-22 | 1989-08-23 | Dr. Karl Thomae GmbH | Tetrahydro-benzothiazoles, their production and their use as intermediates or drugs |
-
1995
- 1995-10-04 DE DE19536916A patent/DE19536916A1/en not_active Withdrawn
-
1996
- 1996-10-03 ZA ZA968315A patent/ZA968315B/en unknown
- 1996-10-04 WO PCT/EP1996/004327 patent/WO1997012614A1/en not_active Ceased
- 1996-10-04 AU AU72856/96A patent/AU7285696A/en not_active Abandoned
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE19653969A1 (en) * | 1996-12-20 | 1998-06-25 | Boehringer Ingelheim Kg | New aqueous pharmaceutical preparation for the production of propellant-free aerosols |
Also Published As
| Publication number | Publication date |
|---|---|
| AU7285696A (en) | 1997-04-28 |
| ZA968315B (en) | 1997-04-04 |
| WO1997012614A1 (en) | 1997-04-10 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 8139 | Disposal/non-payment of the annual fee |