AU4413496A

AU4413496A – Use of pramipexole as a neuroprotective agent
– Google Patents

AU4413496A – Use of pramipexole as a neuroprotective agent
– Google Patents
Use of pramipexole as a neuroprotective agent

Info

Publication number
AU4413496A

AU4413496A
AU44134/96A
AU4413496A
AU4413496A
AU 4413496 A
AU4413496 A
AU 4413496A
AU 44134/96 A
AU44134/96 A
AU 44134/96A
AU 4413496 A
AU4413496 A
AU 4413496A
AU 4413496 A
AU4413496 A
AU 4413496A
Authority
AU
Australia
Prior art keywords
disease
compound
dementia
enantiomer
neuronal damage
Prior art date
1994-12-15
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.)

Granted

Application number
AU44134/96A
Other versions

AU712666B2
(en

Inventor
Edward Dallas Hall
Frank A Rohde
Philip F. Von Voigtlander
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)

Boehringer Ingelheim Pharma GmbH and Co KG

Original Assignee
BOEHRINGER INGELHEIM PHARMA
Boehringer Ingelheim Pharma GmbH and Co KG
Priority date (The priority date 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 date listed.)
1994-12-15
Filing date
1995-12-12
Publication date
1996-07-03

1995-12-12
Application filed by BOEHRINGER INGELHEIM PHARMA, Boehringer Ingelheim Pharma GmbH and Co KG
filed
Critical
BOEHRINGER INGELHEIM PHARMA

1996-07-03
Publication of AU4413496A
publication
Critical
patent/AU4413496A/en

1999-11-11
Application granted
granted
Critical

1999-11-11
Publication of AU712666B2
publication
Critical
patent/AU712666B2/en

2007-10-11
Assigned to PHARMACIA & UPJOHN COMPANY LLC, BOEHRINGER INGELHEIM KG
reassignment
PHARMACIA & UPJOHN COMPANY LLC
Request to Amend Deed and Register
Assignors: BOEHRINGER INGELHEIM KG, PHARMACIA & UPJOHN COMPANY

2009-09-17
Assigned to BOEHRINGER INGELHEIM PHARMA GMBH & CO. KG
reassignment
BOEHRINGER INGELHEIM PHARMA GMBH & CO. KG
Alteration of Name(s) in Register under S187
Assignors: BOEHRINGER INGELHEIM KG, PHARMACIA & UPJOHN COMPANY LLC

2015-12-12
Anticipated expiration
legal-status
Critical

Status
Ceased
legal-status
Critical
Current

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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

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

A—HUMAN NECESSITIES

A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE

A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

A61P25/00—Drugs for disorders of the nervous system

A—HUMAN NECESSITIES

A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE

A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

A61P25/00—Drugs for disorders of the nervous system

A61P25/08—Antiepileptics; Anticonvulsants

A—HUMAN NECESSITIES

A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE

A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

A61P25/00—Drugs for disorders of the nervous system

A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia

A—HUMAN NECESSITIES

A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE

A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

A61P25/00—Drugs for disorders of the nervous system

A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia

A61P25/16—Anti-Parkinson drugs

A—HUMAN NECESSITIES

A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE

A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

A61P25/00—Drugs for disorders of the nervous system

A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer’s disease or other forms of dementia

A—HUMAN NECESSITIES

A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE

A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

A61P9/00—Drugs for disorders of the cardiovascular system

Abstract

The present invention provides the use of pramipexole as a neuroprotective agent.

Description

USE OF PRAMIPEXOLE AS A NEUROPROTECTIVE AGENT FIELD OF THE INVENTION The present invention relates to the use of pramipexole or 2-amino-6-n- propylamino-4,5,6,7-tetrahydrobenzo-thiazole, or the (+)- or (-)-enantiomers thereof, and the pharmacologically acceptable salts thereof, as a neuroprotective agent.
BACKGROUND OF THE INVENTION A number of central nervous system diseases and conditions result in neuronal damage. These conditions which can lead to nerve damage include:
Primary neurodegenerative disease; Huntington’s Chorea; Stroke and other hypoxic or ischemic processes; neurotrauma; metabolically induced neurological damage; sequelae from cerebral seizures; hemorrhagic stroke; secondary neuro¬ degenerative disease (metabolic or toxic); Parkinson’s disease; Alzheimer’s disease, Senile Dementia of Alzheimer’s Type (SDAT); age associated cognitive dysfunctions; or vascular dementia, multi-infarct dementia, Lewy body dementia, or neurodegenerative dementia.
Pramipexole is a dopamine-Djj/T^ agonist the synthesis of which is described in European Patent 186 087 and its counterpart, U.S. Patent 4,886,812. It is known primarily for the treatment of schizophrenia and Parkinson’s disease. It is known from German patent application DE 38 43 227 that pramipexole lowers the plasma level of prolactin. Also, this European patent application discloses the use of pramipexole in the treatment of drug dependency. Further, it is known from German patent application DE 39 33 738 that pramipexole can be used to decrease abnormal high levels of thyroid stimulating hormone (TSH). U.S. patent 5,112,842 discloses the transdermal administration of the compounds and transdermal systems containing these active compounds. WO patent application PCT EP 93/03389 describes the use of pramipexole as an antidepressant agent.
Up to now there is no commercially available drug for the therapeutic treatment of stroke with proven evidence of efficacy.
Surprisingly and unexpectedly, it has been found that pramipexole and its (+ )-enantiomer also has a neuroprotective effect.
INFORMATION DISCLOSURE Piribedil, a vasodilator which binds to a multitude of receptors including dopamine receptors, is reported to have an effect on functional and biochemical parameters in a gerbil model of global cerebral ischemia. See, e.g., Society for Neuroscience Abstracts, 19:673 (1993); id., at 1645.

Lisuride binds to several different receptors including dopamine D2 and 5-HTla receptors. It is reported that Lisvuide, when administered before the event, reduced brain edema and prolonged survival time in a rat model of cerebral infarction. Miya Zawa, et al. Nippon-Yakurigaku-Zasshi 98(6):449-561, (1991). SUMMARY OF THE INVENTION
The present invention particularly provides a method for preventing neuronal damage in a patient suffering from or susceptible to such neuronal damage comprising the administration of an effective amount of 2-amino-6-n-propylamino- 4,5,6,7-tetrahydrobenzothiazole, its (-)-enantiomer or (+)-enantiomer thereof, and pharmacologically acceptable salts thereof especially an effective amount of pramipexole which is the (-)-enantiomer of 2-amino-6-n-propylamino-4,5,6,7- tetrahydrobenzothiazole-dihydrochloride or an effective amount of the (+)- enantiomer of 2-amino-6-n-propylamino-4,5,6,7-tetrahydrobenzothiazole dihydrochloride. Conditions which can cause nerve damage are well-known to an ordinarily skilled neurologist or similar physician and include:
Primary neurogenerative disease;
Huntington’s Chorea;
Stroke and other hypoxic or ischemic processes; Neurotrauma;
Metabolically induced neurological damage;
Sequelae from cerebral seizures;
Hemorrhagic stroke;
Secondary neurodegenerative disease (metabolic or toxic); Parkinson’s disease;
Alzheimer’s disease, other memory disorders; or
Vascular dementia, multi-infarct dementia, Lewy body dementia, or neurogenerative dementia.
The preferred indication for pramipexole, in the context of the present invention, is Parkinson’s disease which is characterized by progressive degeneration of nigrostriatal dopamine neurons. In this sense, the term Parkinson’s disease also comprises the term Parkinson’s syndrome. In addition to pramipexole’s palliative action (i.e. replacement of the lost dopamine neurotransmitter function), the compound may slow the degeneration of surviving dopamine neurons and thereby slows the progression of the disease.

The prophylactic use of the compound of this invention includes use as monotherapy in early or pre-symptomatic stages of Parkinson’s disease and prevention of neurodegenerative disorders based on ischaemia.
The synthesis, formulation and administration of pramipexole is described in U.S. patents 4,843,086; 4,886,812; and 5,112,842; which are incorporated by reference herein.
2-Amino-6-n-propyl-amino-4,5,6,7-tetrahydrobenzothiazole, particularly the (-)-enantiomer thereof, and the pharmacologically acceptable acid addition salts thereof can be given for preventing of neuronal damage. The form of conventional galenic preparations consist essentially of an inert pharmaceutical carrier and an effective dose of the active substance; e.g., plain or coated tablets, capsules, lozenges, powders, solutions, suspensions, emulsions, syrups, suppositories, etc.
L-dopa is shown to be toxic to cerebellar granule cells in culture. Pramipexole and the (+) enantiomer blocked L-dopa toxicity. The EC5Q for both was between 0.3 and 1 uM and 10 uM provided viability measurements that were equal to control cells not exposed to L-dopa. The mechanism of protection does not appear to involve receptor activation given that the (+) enantiomer is less active in monoamine receptor binding assays. The possibility exists that 2-amino-6-n- propylamino-4,5,6,7-tetrahydrobenzothiazole, its (+) and (-) enantiomers and the pharmacologically acceptable acid addition salts thereof, especially pramipexole and the (+) enantiomer are acting as antioxidants toward reactive oxygen species known to be generated from L-dopa incubation.
The effective dose range is 0.01 to 2.0 mg kg. More preferred is a dose of 1-2 mg kg PO. The preferred total dose level for neuroprotection is 0.5-20 mg/kg/day PO. The preferred human dose is 0.1-6.0 mg/day total dose, divided in 2 or 3 administrations. In addition to being administered by oral or intravenous route, pramipexole may be administered transdermally.
DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention is seen more fully by the examples given below: Example 1:
We examined histologically retrograde degeneration of the dopaminergic nigrostriatal (NS) tract over 28 days in gerbils subjected to a 10-minute period of forebrain ischemia via bilateral carotid occlusion. There was in control animals a 39% loss of NS cell bodies in the zona compacta (as judged by tyroxine hydroxylase immunocytochemistry) over that time period. Daily post-ischemic oral dosing (1

mg/kg PO BID beginning at 1 hr after insult) with pramipexole attenuated 28-day post-ischemic loss of NS DA neurons by 36% (p<0.01 vs vehicle-treated). Example 2: We have successfully replicated the finding of Example 1; i.e., that pramipexole can protect nigrostriatal dopamine neurons in a gerbil model of 10 minutes of bilateral carotid occlusion-induced forebrain ischemia plus 28 days of post-ischemic survival. The administration of pramipexole was via an initial dose of 1 mg kg PO 60 minutes after ischemia and again at the end of day 1 followed by twice daily dosing for the next 26 days. A twice daily dose of 0.3 mg/kg produced a threshold effect (14% increase in nigrostriatal dopamine neurons compared to vehicle). A twice daily dose of 1 mg/kg produced a significant 38% improvement in 28 day post-ischemic dopamine neuronal survival (p < 0.0001 vs vehicle-treated). This action appears to be specific for dopamine neurons since the post-ischemic loss of the non-dopaminergic neurons in the CA1 area of the hippocampus was not significantly affected. Example 3: Primary Cultures of Cerebellar Granular Cells Primary cultures of cerebellar granular cells were prepared from 8-day-old Sprague Dawley rats (Charles River, Portage, MI) as described previously (1). Neurons were grown on 6-well, 35 mm culture dishes (Nunc, Denmark) for 8-9 days, 2 ml/well, at a density of 1 x 10 cells ml. Glial cell proliferation was prevented by adding cytosine-arabinofuranoside-monophosphate (Sigma, St. Louis, MO), 19 hrs after plating at a final concentration of lOμM. Cultures generated by this method have been characterized and shown to contain more than 90% granule cells (2). Cell Toxicity Models Experiments were started after cells were 8 days in vitro (8 DIN). Cells were washed with two ml of serum free growth medium. Concentrations of 100X stock solutions of PPX and the (+) enantiomer in serum free growth medium were made. These were delivered to cells by adding 20 ul to cells in growth medium per well. The final concentration of drugs ranged from 1 nM to 10 uM. After 5 min 20 ul of a 10X stock solution of L-dopa in serum free growth medium was added to each well so that the final concentration was 100 uM. Cells were incubated under the above conditions for 24 hrs. For viability measurements cells were then washed twice and pulsed with 1 μCi/ml of α-(methyl)- C)-aminoisobutyric acid (New England Nuclear) in Locke's buffer for 1 hr. Cells were solubilized, following a wash, with 0.5% Triton X-100. The solubilized cells were then counted for radioactivity on a scintillation counter. Data was expressed as the mean of triplicates ± S.D. for each point. Results from the table show that pramipexole was neuroprotective toward the toxicity (64.8 %) associated with L-dopa. At 10 uM pramipexole, L-dopa treated cells were not different from controls. Pramipexole is shown to decrease slightly but significantly cAMP levels in cerebellar granular cells (3). This suggests the possible involvement of dopamine receptors (D2 family) in the mechanism of neuroprotection. To test this hypothesis, the (+) enantiomer was tested in a parallel experiment with pramipexole. The (+) enantiomer has been shown to be inactive in a battery of binding assays that involve adrenergic and serotonergic receptors, and less active in dopaminergic receptors. The results show that the (+) enantiomer is equally as potent and effective compared to pramipexole as a neuroprotective agent in this assay. The neuroprotective effects of pramipexole in L-dopa mediated toxicity in cerebellar granule cell does not appear to involve the activation of dopamine receptors. The (+) enantiomer of pramipexole shows utility as a neuroprotectant despite the fact that it shows little ability to bind to monoamine receptors. The possibility exists that pramipexole and it's (+) enantiomer can act as an antioxidant toward L-dopa toxicity which is known to involve the generation of reactive oxygen species. TABLE 1 Toxicity (64.8%) of 100 uM L-dopa: Effects of pramipexole and (+) enantiomer. Dose Pramipexole (+) enantiomer (nM) (% of control*) (% of control*) 0 35.2 +/- 8.5 35.2 +/- 8.5 1 30.0 +/- 6.5 51.3 +/- 5.8 10 39.2 +/- 9.4 57.8 +/- 4.9 100 64.8 +/- 4.7 58.3 +/- 10.3 300 76.2 +/- 7.3 81.0 +/- 18.3 1000 65.5 +/- 14.8 86.9 +/- 7.0 3000 84.9 +/- 0.6 95.2 +/- 2.5 10000 90.0 +/- 11.5 99.8 +/- 8.9 * Control is defined as the radioactivity associated with cells that were exposed to vehicle buffer rather than 100 uM L-dopa. Control value was equal to an average of 129547 CPMs for triplicate counts. Claims (14) 1. A method for preventing neuronal damage or the progression of neuronal damage in a patient suffering from or susceptible to such neuronal damage comprising the administration of an effective amount of the compound 2-amino-6-n- propylamino-4,5,6,7-tetrahydrobenzothiazole and the pharmacologically acceptable acid addition salts thereof. 2. A method of claim 1 where the condition is selected from Parkinson's disease, primary neurodegenerative disease; Huntington's Chorea; stroke and other hypoxic or ischemic processes; neurotrauma; metabolically induced neurological damage; sequelae from cerebral seizures; hemorrhagic stroke; secondary neurodegenerative disease (metabolic or toxic); Alzheimer's disease, other memory disorders; or vascular dementia, multi-infarct dementia, Lewy body dementia, or neurogenerative dementia. 3. A method of claim 2, where the condition is Parkinson's disease. 4. A method of claim 3, where the total dose of the compound is about 0.1-6 mg/day. 5. A method of claims 1-4, wherein the compound is the form of the (+) enantiomer. 6. A method of claims 1-4, wherein the compound is the form of the (-) enantiomer. 7. A method of claims 1-6, wherein the compound is the dihydrochloride. 8. Use of a compound selected from 2-amino-6-n-propylamino-4,5,6,7- tetrahydrobenzothiazole and the pharmacologically acceptable acid addition salts thereof for preparing a medicament for preventing neuronal damage or the progression of neuronal damage. 9. A use of claim 8, wherein the neuronal damage results from Parkinson's disease, primary neurodegenerative disease; Huntington's Chorea; stroke and other hypoxic or ischemic processes; neurotrauma; metabolically induced neurological damage; sequelae from cerebral seizures; hemorrhagic stroke; secondary neurodegenerative disease (metabolic or toxic); Alzheimer's disease, other memory disorders; or vascular dementia, multi-infarct dementia, Lewy body dementia, or neurodegenerative dementia. 10. A use of claim 8, wherein the neuronal damage results from Parkinson's disease. 11. A use of claims 8-10, wherein the dosage is 0.1-6 mg/day. 12. A use of claims 8-11, wherein the compound is the (+) enantiomer. 13. A use of claims 8-12, wherein the compound is the (-) enantiomer. 14. A use of claims 8-13, wherein the compound is the dihydrochloride. AU44134/96A 1994-12-15 1995-12-12 Use of pramipexole as a neuroprotective agent Ceased AU712666B2 (en) Applications Claiming Priority (3) Application Number Priority Date Filing Date Title US08/357,121 US5650420A (en) 1994-12-15 1994-12-15 Pramipexole as a neuroprotective agent US08/357121 1994-12-15 PCT/US1995/015613 WO1996018395A1 (en) 1994-12-15 1995-12-12 Use of pramipexole as a neuroprotective agent Publications (2) Publication Number Publication Date AU4413496A true AU4413496A (en) 1996-07-03 AU712666B2 AU712666B2 (en) 1999-11-11 Family ID=23404382 Family Applications (1) Application Number Title Priority Date Filing Date AU44134/96A Ceased AU712666B2 (en) 1994-12-15 1995-12-12 Use of pramipexole as a neuroprotective agent Country Status (16) Country Link US (1) US5650420A (en) EP (1) EP0797439B1 (en) JP (2) JP4796219B2 (en) KR (2) KR100451874B1 (en) CN (1) CN1177586C (en) AT (1) ATE238790T1 (en) AU (1) AU712666B2 (en) CA (1) CA2207323C (en) DE (1) DE69530606T2 (en) DK (1) DK0797439T3 (en) ES (1) ES2197213T3 (en) MX (1) MX9704377A (en) NZ (1) NZ298606A (en) PT (1) PT797439E (en) SI (1) SI0797439T1 (en) WO (1) WO1996018395A1 (en) Families Citing this family (48) * Cited by examiner, † Cited by third party Publication number Priority date Publication date Assignee Title US6156777A (en) * 1994-12-15 2000-12-05 Pharmacia & Upjohn Company Use of pramipexole as a neuroprotective agent US6001861A (en) * 1998-01-16 1999-12-14 Pharmacia & Upjohn Company Use of pramipexole in the treatment of restless legs syndrome DE19701619B4 (en) * 1997-01-17 2007-10-11 Boehringer Ingelheim Pharma Gmbh & Co. Kg Use of pramipexole for the treatment of restless legs syndrome IL139682A0 (en) * 1998-05-15 2002-02-10 Upjohn Co Cabergoline and pramipexole for treating cns diseases especially parkinson's disease EP1591119A3 (en) * 1998-05-15 2007-03-28 Pharmacia & Upjohn Company LLC Pramipexole for treating CNS diseases, especially Parkinson's disease US6750235B1 (en) 1999-09-30 2004-06-15 The General Hospital Corporation Pramipexole as a treatment for cocaine craving PE20011074A1 (en) 2000-02-23 2001-10-04 Upjohn Co USE OF PRAMIPEXOL IN THE TREATMENT OF ADDICTION DISORDERS US20070243240A9 (en) * 2000-08-24 2007-10-18 Fred Windt-Hanke Transdermal therapeutic system DE10053397A1 (en) * 2000-10-20 2002-05-02 Schering Ag Use of a dopaminergic active ingredient for the treatment of dopaminerg treatable diseases DE10043321B4 (en) * 2000-08-24 2005-07-28 Neurobiotec Gmbh Use of a transdermal therapeutic system for the treatment of Parkinson's disease, for the treatment and prevention of premenstrual syndrome and for lactation inhibition WO2002017931A1 (en) * 2000-09-01 2002-03-07 Xiaomin Wang Use of tripterygium wilfordii hook.f's extracts for preparation of medicaments for preventing and treating nervous system disorde rs DE10064453A1 (en) * 2000-12-16 2002-07-04 Schering Ag Use of a dopaminergic active ingredient for the treatment of dopaminerg treatable diseases US20020165246A1 (en) * 2001-03-05 2002-11-07 Andrew Holman Administration of sleep restorative agents FR2825087B1 (en) * 2001-05-22 2005-01-14 Galderma Res & Dev ANALOGUES OF VITAMIN D DE10137453A1 (en) * 2001-08-02 2003-02-20 Boehringer Ingelheim Pharma Use of 2-amino-4,5,6,7-tetrahydro-6-n propylaminobenzothiazole as an anticonvulsant, for preventing or treating cerebral or generalized seizures and epilepsy DE10138275A1 (en) * 2001-08-10 2003-02-27 Boehringer Ingelheim Pharma Connections to eliminate anhedonia DK1453505T3 (en) * 2001-12-11 2010-11-15 Univ Virginia Use of pramipexole for the treatment of amyotrophic lateral sclerosis US20060281797A1 (en) * 2001-12-11 2006-12-14 University Of Virginia Patent Foundation Neurorestoration with R(+) Pramipexole US20030166696A1 (en) * 2002-01-24 2003-09-04 Boehringer Ingelheim Pharma Gmbh & Co. Kg Pramipexole for the treatment of HIV dementia DE10203103A1 (en) * 2002-01-25 2003-08-07 Boehringer Ingelheim Pharma Pramipexole for the treatment of HIV dementia US8679533B2 (en) 2002-07-25 2014-03-25 Pharmacia Corporation Pramipexole once-daily dosage form GB0221513D0 (en) 2002-09-17 2002-10-23 Generics Uk Ltd Novel compounds and processes DE10333393A1 (en) * 2003-07-23 2005-02-24 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system with the active ingredient pramipexole EP1708706A1 (en) * 2004-01-22 2006-10-11 Boehringer Ingelheim International Gmbh Pharmaceutical composition comprising a monoamine neurotransmitter re-uptake inhibitor and a dopamine agonist WO2006012277A2 (en) * 2004-06-30 2006-02-02 Amr Technology, Inc. Biocatalytic process for preparing enantiomerically enriched pramipexole EP1778201B1 (en) 2004-08-13 2014-07-16 Boehringer Ingelheim International GmbH Extended release pellet formulation containing pramipexole or a pharmaceutically acceptable salt thereof, method for manufacturing the same and use thereof US20080234338A1 (en) * 2005-08-15 2008-09-25 University Of Virginia Patent Foundation Neurorestoration With R(+) Pramipexole US20080262053A1 (en) * 2005-10-18 2008-10-23 Juergen Reess Use of Pramipexole for Treating Moderate to Severe Restless Legs Syndrome (Rls) ITMI20060044A1 (en) * 2006-01-13 2007-07-14 Dipharma Spa SUMMARY OF INTERMEDIATES PR PREPARATION OF PRAMIPEXOL US8518926B2 (en) * 2006-04-10 2013-08-27 Knopp Neurosciences, Inc. Compositions and methods of using (R)-pramipexole US20070259930A1 (en) * 2006-04-10 2007-11-08 Knopp Neurosciences, Inc. Compositions and methods of using r(+) pramipexole JP2009537565A (en) * 2006-05-16 2009-10-29 ノップ ニューロサイエンシーズ、インク． R (+) and S (-) pramipexole compositions and methods of using the same CA2667924A1 (en) * 2006-10-30 2008-05-08 Boehringer Ingelheim International Gmbh The use of pramipexole or a salt thereof for the treatment of parkinson's disease US8524695B2 (en) * 2006-12-14 2013-09-03 Knopp Neurosciences, Inc. Modified release formulations of (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine and methods of using the same CN102772404A (en) * 2006-12-14 2012-11-14 诺普神经科学股份有限公司 Compositions of (r)-pramipexole and methods of using the same US8519148B2 (en) * 2007-03-14 2013-08-27 Knopp Neurosciences, Inc. Synthesis of chirally purified substituted benzothiazole diamines US20110190356A1 (en) * 2008-08-19 2011-08-04 Knopp Neurosciences Inc. Compositions and Methods of Using (R)- Pramipexole MX2011013577A (en) * 2009-06-19 2012-04-10 Knopp Neurosciences Inc Compositions and methods for treating amyotrophic lateral sclerosis. US9512096B2 (en) 2011-12-22 2016-12-06 Knopp Biosciences, LLP Synthesis of amine substituted 4,5,6,7-tetrahydrobenzothiazole compounds US9662313B2 (en) 2013-02-28 2017-05-30 Knopp Biosciences Llc Compositions and methods for treating amyotrophic lateral sclerosis in responders PT3019167T (en) 2013-07-12 2021-03-04 Knopp Biosciences Llc Treating elevated levels of eosinophils and/or basophils US9468630B2 (en) 2013-07-12 2016-10-18 Knopp Biosciences Llc Compositions and methods for treating conditions related to increased eosinophils PL3033081T3 (en) 2013-08-13 2021-08-30 Knopp Biosciences Llc Compositions and methods for treating chronic urticaria ES2813674T3 (en) 2013-08-13 2021-03-24 Knopp Biosciences Llc Compositions and methods for treating plasma cell disorders and b-cell prolymphocytic disorders WO2016194015A2 (en) 2015-06-04 2016-12-08 Chiarugi Alberto Use of r(+)-pramipexole (dexpramipexole) for the treatment of cerebral ischemia of the focal type WO2018183192A1 (en) 2017-03-27 2018-10-04 Chase Therapeutics Corporation Compositions and methods for treating synucleinopathies US11590141B2 (en) 2018-03-16 2023-02-28 Scent Science International Inc. Prophylactic or therapeutic agent for hypoxic injury, ischemia-reperfusion injury and inflammation, cell protection agent for transplantation, and bio-preservation agent EP3902543A4 (en) * 2018-12-27 2022-11-02 Chase Therapeutics Corporation Domperidone antineurodegenerative combinations and use Family Cites Families (5) * Cited by examiner, † Cited by third party Publication number Priority date Publication date Assignee Title ATE45735T1 (en) * 1984-12-22 1989-09-15 Thomae Gmbh Dr K TETRAHYDRO-BENZTHIAZOLE, THEIR PRODUCTION AND USE AS INTERMEDIATE OR MEDICINAL PRODUCTS. DE3447075A1 (en) * 1984-12-22 1986-07-03 Dr. Karl Thomae Gmbh, 7950 Biberach Tetrahydrobenzothiazoles, their preparation and their use as intermediates or as medicaments DE3843227A1 (en) * 1988-12-22 1990-07-05 Boehringer Ingelheim Kg Use of 2-amino-6-n-propylamino-4,5,6,7-tetrahydrobenzothiazole DE3937271A1 (en) * 1989-11-09 1991-05-16 Boehringer Ingelheim Kg TRANSDERMAL APPLICATION OF 2-AMINO-6-N-PROPYLAMINO-4,5,6,7-TETRAHYDROBENZOTHIAZOLE DE4241013A1 (en) * 1992-12-05 1994-06-09 Boehringer Ingelheim Kg Use of 2-amino-6-n-propylamino-4,5,6,7-tetrahydrobenzothiazole as antidepressant drug 1994 1994-12-15 US US08/357,121 patent/US5650420A/en not_active Expired - Lifetime 1995 1995-12-12 DK DK95942961T patent/DK0797439T3/en active 1995-12-12 ES ES95942961T patent/ES2197213T3/en not_active Expired - Lifetime 1995-12-12 KR KR10-2003-7013938A patent/KR100451874B1/en not_active IP Right Cessation 1995-12-12 WO PCT/US1995/015613 patent/WO1996018395A1/en not_active Application Discontinuation 1995-12-12 EP EP95942961A patent/EP0797439B1/en not_active Expired - Lifetime 1995-12-12 CA CA002207323A patent/CA2207323C/en not_active Expired - Fee Related 1995-12-12 AU AU44134/96A patent/AU712666B2/en not_active Ceased 1995-12-12 JP JP51908196A patent/JP4796219B2/en not_active Expired - Fee Related 1995-12-12 DE DE69530606T patent/DE69530606T2/en not_active Expired - Lifetime 1995-12-12 CN CNB95196769XA patent/CN1177586C/en not_active Expired - Fee Related 1995-12-12 AT AT95942961T patent/ATE238790T1/en active 1995-12-12 SI SI9530667T patent/SI0797439T1/en unknown 1995-12-12 NZ NZ298606A patent/NZ298606A/en not_active IP Right Cessation 1995-12-12 KR KR1019970704012A patent/KR100420252B1/en not_active IP Right Cessation 1995-12-12 PT PT95942961T patent/PT797439E/en unknown 1997 1997-06-13 MX MX9704377A patent/MX9704377A/en unknown 2007 2007-05-30 JP JP2007143213A patent/JP2007217432A/en active Pending Also Published As Publication number Publication date EP0797439B1 (en) 2003-05-02 SI0797439T1 (en) 2003-12-31 CN1169677A (en) 1998-01-07 CA2207323C (en) 2006-10-10 PT797439E (en) 2003-08-29 ATE238790T1 (en) 2003-05-15 DE69530606D1 (en) 2003-06-05 DK0797439T3 (en) 2003-08-25 CN1177586C (en) 2004-12-01 KR20040000443A (en) 2004-01-03 WO1996018395A1 (en) 1996-06-20 KR100451874B1 (en) 2004-10-08 JP2007217432A (en) 2007-08-30 ES2197213T3 (en) 2004-01-01 EP0797439A1 (en) 1997-10-01 US5650420A (en) 1997-07-22 JP4796219B2 (en) 2011-10-19 DE69530606T2 (en) 2004-02-19 KR100420252B1 (en) 2004-04-21 MX9704377A (en) 1998-07-31 JPH10510809A (en) 1998-10-20 AU712666B2 (en) 1999-11-11 NZ298606A (en) 2001-02-23 CA2207323A1 (en) 1996-06-20 Similar Documents Publication Publication Date Title EP0797439B1 (en) 2003-05-02 Use of pramipexole as a neuroprotective agent US6156777A (en) 2000-12-05 Use of pramipexole as a neuroprotective agent EP2246053B1 (en) 2013-09-18 Use of pramipexole to treat amyotrophic lateral sclerosis Radad et al. 2005 Short review on dopamine agonists: insight into clinical and research studies relevant to Parkinson’s disease AU5030399A (en) 2000-02-01 Agents with an antidepressive effect AU748629B2 (en) 2002-06-06 Cabergoline and pramipexole: new uses and combinations US20030045539A1 (en) 2003-03-06 Cabergoline and pramipexole: new uses and combinations AU760439B2 (en) 2003-05-15 Cabergoline and pramipexole: new uses and combinations AU2008200886A1 (en) 2008-03-13 Use of Pramipexole to Treat Amyotrophic Lateral Sclerosis MXPA00011219A (en) 2001-07-31 Cabergoline and pramipexole:new uses and combinations EP1591119A2 (en) 2005-11-02 Pramipexole for treating CNS diseases, especially Parkinson's disease
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