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(12) United States Patent (10) Patent No.: US 7,160,899 B2 Peters Et Al

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(12) United States Patent (10) Patent No.: US 7,160,899 B2 Peters Et Al US007160899B2 (12) United States Patent (10) Patent No.: US 7,160,899 B2 Peters et al. (45) Date of Patent: Jan. 9, 2007 (54) ADENOSINE AA RECEPTOR (56) References Cited ANTANGONSTS COMBINED WITH NEUROTROPHIC ACTIVITY COMPOUNDS U.S. PATENT DOCUMENTS IN THE TREATMENT OF PARKINSONS 2001/0027.196 A1 10, 2001 Borroni et al. DISEASE FOREIGN PATENT DOCUMENTS (75) Inventors: Dan Peters, Malmö (SE); Lars Christian B. Ronn, Vekse (DK); Karin DE 43 25 254 A1 2, 1994 Sandager Nielsen, Fredensborg (DK) WO WO 97/40035 * 10/1997 WO WO99/43678 A1 9, 1999 (73) Assignee: Neurosearch A/S, Ballerup (DK) WO WO 99,53909 A2 10, 1999 (*) Notice: Subject to any disclaimer, the term of this WO WO 01/82946 A2 4/2001 patent is extended or adjusted under 35 U.S.C. 154(b) by 342 days. OTHER PUBLICATIONS Beers, M. H. and Berkow, R., Editors-in-chief, The Merck Manual (21) Appl. No.: 10/473,809 of Diagnosis and Therapy, 17th Edition, pp. 1466-1473, 1999.* Hess, Expert Opinion Ther. Patents, vol. 11, No. 10, pp. 1533-1561 (22) PCT Filed: Apr. 4, 2002 (2001). Lee et al., PNAS, vol. 98, No. 6, pp. 3555-3560 (2001). (86). PCT No.: PCT/DKO2/OO228 Kiec-Kononowicz et al., Pure Appl. Chem... vol. 73, No. 9, pp. 1411–1420 (2001). S 371 (c)(1), Ongini et al., Annals NY Academy of Sciences, pp. 30-49, 1997. (2), (4) Date: Oct. 2, 2003 Heese et al., Neuroscience Letters, vol. 231, pp. 83-86 (1997). Bennett, The Neuroscientist, vol. 7, No. 1, pp. 13-17 (2001). (87) PCT Pub. No.: WO02/080957 Morelli et al., Drug Development Research, vol. 52, pp. 387-393 (2001). PCT Pub. Date: Oct. 17, 2002 * cited by examiner (65) Prior Publication Data Primary Examiner Dwayne Jones US 2004/0097540 A1 May 20, 2004 (74) Attorney, Agent, or Firm—Birch, Stewart, Kolasch & Birch, LLP (30) Foreign Application Priority Data Apr. 9, 2001 (DK) ............................... 2001 OO583 (57) ABSTRACT (51) Int. Cl. This invention relates to the use of the combined action of A6 IK 3/47 (2006.01) a compound with neurotrophic activity and an adenosine (52) U.S. Cl. ....................... 514/307: 514/2: 514/230.2: A receptor antagonist for the treatment of Parkinson's 514/237 disease. (58) Field of Classification Search ..................... None See application file for complete search history. 6 Claims, No Drawings US 7,160,899 B2 1. 2 ADENOSINE AA RECEPTOR The principle combines a fast onset action (the effect of ANTANGONSTS COMBINED WITH the adenosine A receptor antagonist) with a long-term NEUROTROPHIC ACTIVITY COMPOUNDS effective principle (the neurotrophic activity). Thus, the IN THE TREATMENT OF PARKINSONS adenosine A receptor antagonist relieves the symptoms of DISEASE the disease (by increasing the dopaminergic activity), while the neurotrophic activity treats the cause of the disease This application is the national phase under 35 U.S.C. S (degenerating neurons) by slowing or even reversing the 371 of PCT International Application No. PCT/DK02/00228 progression of the disease. which has an International filing date of Apr. 4, 2002, which Other objects of the invention will be apparent to the designated the United States of America. 10 person skilled in the art from the following detailed descrip tion and examples. TECHNICAL FIELD DETAILED DISCLOSURE OF THE INVENTION This invention relates to the use of the combined action of a compound with neurotrophic activity and an adenosine 15 In its first aspect, the invention provides the use of at least A receptor antagonist for the treatment of Parkinson's one compound with neurotrophic activity and at least one disease. adenosine A receptor antagonist for the manufacture of a medicament for the treatment, prevention or alleviation of BACKGROUND ART Parkinson's disease in a Subject. In a second aspect, the invention provides a pharmaceu Parkinson's disease is a neurodegenerative disease char tical composition comprising a therapeutically effective acterised by the progressive deterioration of motor skills, amount of at least one compound with neurotrophic activity affecting about 4 million people worldwide. Parkinson's and at least one adenosine A receptor antagonist, together patients suffer from increasing difficulties in initiating move with at least one pharmaceutically acceptable carrier or ment, rigidity in arms and legs, as well as tremors. Although 25 diluent. the specific cause of Parkinson's disease is unknown, it has In a third aspect, the invention provides a combination of been shown that the disease is associated with the degen at least one compound with neurotrophic activity and at least eration of specific dopamine-containing neurons in a region one adenosine A receptor antagonist for use as a thera of the brain known as the substantia nigra, which is believed peutic agent. to be involved in the coordination of movement. 30 In a further aspect, the invention provides a method of One existing treatment is L-DOPA therapy, alone or treatment, prevention or alleviation of Parkinson's disease in combined with e.g. dopamine agonists. However, after three a subject, which method comprises administering to said to five years of L-DOPA therapy, involuntary motor distur subject a therapeutically effective combination of at least bances (dyskinesia) may appear. one compound with neurotrophic activity and at least one Another treatment is the use of monoamine reuptake 35 adenosine A receptor antagonist. inhibitors (such as dopamine reuptake inhibitors) whereby In a still further aspect, the invention provides a kit of the existing dopamine level in the synaptic cleft is increased. parts comprising at least one compound with neurotrophic A further possible therapy is the use of neurotrophic activity and at least one adenosine A receptor antagonist. compounds which give a neuroregenerative effect on In one embodiment, the adenosine A, antagonist is lesioned and damaged neurons. 40 selected from the group consisting of KW-6002, A still further treatment Suggested is the use of adenosine ZM-241385, 8FB-PTP, SCH-58261, KF-17837, CGS A receptor antagonists, which result in an enhanced 15943, DMPX and pharmaceutically acceptable salts dopaminergic activity. Furthermore, adenosine A recep thereof. tors and their relation to neuroprotection have been dis In a second embodiment, the compound with neu cussed (Ongini, E. et al. (1997) Adenosine A receptors and 45 rotrophic activity is a compound selected from the group neuroprotection, Ann NY Acad Sci 825:30–48). consisting of There is a continued strong interest in the development of 5-(4-Chlorophenyl)-8-methyl-6,7,8,9-tetrahydro-1-H-pyr a more selective and effective therapy with fewer side effects rolo3.2-hisoquinoline-2,3-dione-3-oxime; for the treatment of patients with Parkinson's disease. 5-(4-Chlorophenyl)-6,7,8,9-tetrahydro-1-H-pyrrolo3.2-h 50 naphthalene-2,3-dione-3-oxime; SUMMARY OF THE INVENTION GDNF: Neublastin; According to the invention it has now been found that the and pharmaceutically acceptable salts thereof. action of a compound with neurotrophic activity in combi In a special embodiment, the compound with neu nation with an adenosine A receptor antagonist advanta 55 rotrophic activity is GDNF and the adenosine A antagonist geously can be used for the treatment of Parkinson's disease. is SCH-58261. In a further special embodiment, the com Accordingly, in its first aspect, the invention relates to a pound with neurotrophic activity is GDNF and the adenos pharmaceutical composition comprising a therapeutically ine A, antagonist is KF-17837. effective amount of at least one compound with neurotrophic In a further embodiment, the pharmaceutical composition activity and at least one adenosine A receptor antagonist, 60 as described above is for use in the treatment, prevention or together with at least one pharmaceutically acceptable car alleviation of a neurodegenerative condition. In a still further rier or diluent. embodiment, the pharmaceutical composition as described In another aspect, the invention relates to the use of at above is for use in the treatment, prevention or alleviation of least one compound with neurotrophic activity and at least Parkinson's disease in a Subject. one adenosine A receptor antagonist for the manufacture 65 The subject to be treated according to this invention is a of a medicament for the treatment, prevention or alleviation living body, preferably a mammal, most preferably a human, of Parkinson's disease in a subject. in need for Such treatment. US 7,160,899 B2 3 4 Any possible combination of two or more of the embodi CNRS), V-10,367 and V-13,661 (Vertex Pharmaceuticals ments described herein is comprised within the scope of the Inc), ABS-205 (American Biogenic Sciences), Dexanabinol present invention. or HU-211 (Pharmos), or salts, free bases, racemates or enantiomers thereof. Compounds With Neurotrophic Activity The above examples of compounds with neurotrophic activity are not intended to be in any way limiting to the Endogenous neurotrophic factors, such as nerve growth Scope of the invention as claimed. factor (NGF), brain-derived neurotrophic factor (BDNF), epidermal growth factor (EGF), basic fibroblast growth Adenosine A Receptor Antagonists factor (bFGF, or FGF2), NT34, neurturin (NTN), neublastin/ 10 artemin, persephin, and glial cell-line derived neurotrophic In the context of the present invention, adenosine A, factor (GDNF), promote the differentiation, growth and receptor antagonists include Xanthine based analogs and Survival of numerous peripheral and central nervous system non-Xanthine based analogs. neurons during development and adulthood. Examples of adenosine A receptor antagonists include In the context of this invention, compounds with neu 15 KW-6002 (Kyowa Hakko Kogyo Co Ltd), ZM-241385, rotrophic activity are compounds that mimic or enhance the 8FB-PTP, SCH-58261-KF-17837, CGS-15943, DMPX, function of one or more endogenous neurotrophic factors.
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