US2004198753A1PendingUtilityA1
Methods of treating patients suffering from movement disorders
Priority: Jan 28, 2002Filed: Jan 28, 2003Published: Oct 7, 2004
Est. expiryJan 28, 2022(expired)· nominal 20-yr term from priority
A61P 25/14A61P 25/00A61P 25/02A61P 25/16A61K 9/48A61K 31/198A61K 9/20A61K 9/0019A61K 31/522A61K 45/06A61K 31/519
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Claims
Abstract
The present invention is directed to methods of treating movement disorders by administering an effective amount of one or more adenosine A 2A receptor antagonists to a patient in need thereof. The present invention also provides methods of decreasing the adverse effects of L-DOPA in patients receiving L-DOPA therapy in the treatment of Parkinson's disease. The present invention further provides methods and compositions for treating Parkinson's disease patients with sub-clinically effective doses of L-DOPA by combining L-DOPA treatment with an effective amount of one or more adenosine A 2A receptor antagonists (i.e., L-DOPA sparing effect). The present invention further provides methods of effective treatment of Parkinson's disease by co-administering at least one adenosine A 2A receptor antagonist, L-DOPA and a dopamine agonist and/or a COMT inhibitor and/or a MAO inhibitor. The present invention further provides methods of prolonging effective treatment of Parkinson's disease by administering an adenosine A 2A receptor antagonist singly or together with a dopamine agonist, and/or a COMT inhibitor, and/or a MAO inhibitor without prior or subsequent administration of L-DOPA, delaying or removing on-set of L-DOPA motor complication.
Claims
exact text as granted — not AI-modifiedWhat is claimed:
1 . A method of reducing or suppressing the adverse effectiveness of L-DOPA and/or dopamine agonist therapy, comprising administering an effective amount of at least one adenosine A 2A receptor antagonist to a Parkinson's disease patient.
2 . The method according to claim 1 wherein the patient suffers from L-DOPA- or other dopaminergic-agent-induced motor complications.
3 . The method according to claim 2 wherein OFF time in motor fluctuations is reduced.
4 . The method according to claim 2 wherein dyskinesias in motor complications are improved.
5 . The method according to claim 1 wherein the adenosine A 2A receptor antagonist is a xanthine derivative or a pharmaceutically acceptable salt thereof.
6 . The method according to claim 1 wherein the A 2A receptor antagonist is represented by formula (I):
wherein
R 1 , R 2 and R 3 represent independently hydrogen, lower alkyl, lower alkenyl or lower alkynyl; R 4 represents cycloalkyl, —(CH 2 ) n —R 5 (in which R 5 represents substituted or unsubstituted aryl, or a substituted or unsubstituted heterocyclic group; and n is an integer of 0 to 4), or
{in which Y 1 and Y 2 represent independently hydrogen, halogen, or lower alkyl; and Z represents substituted or unsubstituted aryl, or
(in which R 6 represents hydrogen, hydroxy, lower alkyl, lower alkoxy, halogen, nitro, or amino; and m represents an integer of 1 to 3)}; and X 1 and X 2 represent independently O or S.
7 . The method according to claim 1 wherein the A 2A receptor antagonist is represented by formula (I-A):
wherein R 1a and R 2a represent independently methyl or ethyl; R 3a represents hydrogen or lower alkyl; and Z a represents
(in which at least one of R 7 , R 8 and R 9 represents lower alkyl or lower alkoxy and the others represent hydrogen; R 10 represents hydrogen or lower alkyl) or
(in which R 6 and m have the same meanings as defined above, respectively).
8 . The method according to claim 1 wherein the A 2A receptor antagonist is represented by formula (I-B):
wherein R 1b and R 2b represent independently hydrogen, propyl, butyl, lower alkenyl or lower alkynyl; R 3b represents hydrogen or lower alkyl; Z b represents substituted or unsubstituted naphthyl, or
(in which R 6 and m have the same meanings as defined above); and Y 1 and Y 2 have the same meanings as defined above, respectively.
9 . The method according to claim 1 wherein the adenosine A 2A receptor antagonist is (E)-8-(3,4-dimethoxystyryl)-1,3-diethyl-7-methylxanthine.
10 . A method for L-DOPA sparing treatment comprising administering to a patient in need thereof a combination of a sub-clinically effective amount of L-DOPA and one or more adenosine A 2A receptor antagonists in an amount effective to render the L-DOPA efficacious.
11 . The method according to claim 10 wherein the adenosine A 2A receptor antagonist is a xanthine derivative or a pharmaceutically acceptable salt thereof.
12 . The method according to claim 10 wherein the A 2A receptor antagonist is represented by formula (I):
wherein
R 1 , R 2 and R 3 represent independently hydrogen, lower alkyl, lower alkenyl or lower alkynyl; R 4 represents cycloalkyl, —(CH 2 ) n —R 5 (in which R 5 represents substituted or unsubstituted aryl, or a substituted or unsubstituted heterocyclic group; and n is an integer of 0 to 4), or
{in which Y 1 and Y 2 represent independently hydrogen, halogen, or lower alkyl; and Z represents substituted or unsubstituted aryl, or
(in which R 6 represents hydrogen, hydroxy, lower alkyl, lower alkoxy, halogen, nitro, or amino; and m represents an integer of 1 to 3)}; and X 1 and X 2 represent independently O or S.
13 . The method according to claim 10 wherein the A 2A receptor antagonist is represented by formula (I-A):
wherein R 1a and R 2a represent independently methyl or ethyl; R 3a represents hydrogen or lower alkyl; and Z a represents
(in which at least one of R 7 , R 8 and R 9 represents lower alkyl or lower alkoxy and the others represent hydrogen; R 5 represents hydrogen or lower alkyl) or
(in which R 6 and m have the same meanings as defined above, respectively).
14 . The method according to claim 10 wherein the A 2A receptor antagonist is represented by formula (I-B):
wherein R 1b and R 2b represent independently hydrogen, propyl, butyl, lower alkenyl or lower alkynyl; R 3b represents hydrogen or lower alkyl; Z b represents substituted or unsubstituted naphthyl, or
(in which R 6 and m have the same meanings as defined above, respectively); and Y 1 and Y 2 have the same meanings as defined above, respectively.
15 . The method according to claim 10 wherein the adenosine A 2A receptor antagonist is (E)-8-(3,4-dimethoxystyryl)-1,3-diethyl-7-methylxanthine.
16 . A composition for L-DOPA sparing treatment comprising a sub-clinically effective amount of L-DOPA and one or more adenosine A 2A receptor antagonists in an amount of effective to render the L-DOPA efficacious.
17 . The composition according to claim 16 wherein the adenosine A 2A receptor antagonist is a xanthine derivative or a pharmaceutically acceptable salt thereof.
18 . The composition according to claim 16 wherein the A 2A receptor antagonist is represented by formula (I):
wherein
R 1 , R 2 and R 3 represent independently hydrogen, lower alkyl, lower alkenyl or lower alkynyl; R 4 represents cycloalkyl, —(CH 2 ) n —R 5 (in which R 5 represents substituted or unsubstituted aryl, or a substituted or unsubstituted heterocyclic group; and n is an integer of 0 to 4), or
{in which Y 1 and Y 2 represent independently hydrogen, halogen, or lower alkyl; and Z represents substituted or unsubstituted aryl, or
(in which R 6 represents hydrogen, hydroxy, lower alkyl, lower alkoxy, halogen, nitro, or amino; and m represents an integer of 1 to 3)}; and X 1 and X 2 represent independently O or S.
19 . The composition according to claim 16 wherein the A 2A receptor antagonist is represented by formula (I-A):
wherein R 1a and R 2a represent independently methyl or ethyl; R 3a represents hydrogen or lower alkyl; and Z a represents
(in which at least one of R 7 , R 8 and R 9 represents lower alkyl or lower alkoxy and the others represent hydrogen; R 5 represents hydrogen or lower alkyl) or
(in which R 6 and m have the same meanings as defined above, respectively).
20 . The composition according to claim 16 wherein the A 2A receptor antagonist is represented by formula (I-B):
wherein R 1b and R 2b represent independently hydrogen, propyl, butyl, lower alkenyl or lower alkynyl; R 3b represents hydrogen or lower alkyl; Z b represents substituted or unsubstituted naphthyl, or
(in which R 6 and m have the same meanings as defined above, respectively); and Y 1 and Y 2 have the same meanings as defined above, respectively.
21 . The composition according to claim 16 wherein the adenosine A 2A receptor antagonist is (E)-8-(3,4-dimethoxystyryl)-1,3-diethyl-7-methylxanthine.
22 . A method of treating Parkinson's disease and/or L-DOPA motor complications, comprising administering an effective amount of at least one adenosine A 2A receptor antagonist in combination with a COMT inhibitor and/or DA and/or MAO inhibitor to a patient in need thereof.
23 . The method according to claim 22 wherein the adenosine A 2A receptor antagonist is a xanthine derivative or a pharmaceutically acceptable salt thereof.
24 . The method according to claim 22 wherein the A 2A receptor antagonist is represented by formula (I):
wherein
R 1 , R 2 and R 3 represent independently hydrogen, lower alkyl, lower alkenyl or lower alkynyl; R 4 represents cycloalkyl, —(CH 2 ) n —R 5 (in which R 5 represents substituted or unsubstituted aryl, or a substituted or unsubstituted heterocyclic group; and n is an integer of 0 to 4), or
{in which Y 1 and Y 2 represent independently hydrogen, halogen, or lower alkyl; and Z represents substituted or unsubstituted aryl, or
(in which R 6 represents hydrogen, hydroxy, lower alkyl, lower alkoxy, halogen, nitro, or amino; and m represents an integer of 1 to 3)}; and X 1 and X 2 represent independently O or S.
25 . The method according to claim 22 wherein the A 2A receptor antagonist is represented by formula (I-A):
wherein R 1a and R 2a represent independently methyl or ethyl; R 3a represents hydrogen or lower alkyl; and Z a represents
(in which at least one of R 7 , R 8 and R 9 represents lower alkyl or lower alkoxy and the others represent hydrogen; R 5 represents hydrogen or lower alkyl) or
(in which R 6 and m have the same meanings as defined above, respectively).
26 . The method according to claim 22 wherein the A 2A receptor antagonist is represented by formula (I-B):
wherein R 1b and R 2b represent independently hydrogen, propyl, butyl, lower alkenyl or lower alkynyl; R 3b represents hydrogen or lower alkyl; Z b represents substituted or unsubstituted naphthyl, or
(in which R 6 and m have the same meanings as defined above, respectively); and Y 1 and Y 2 have the same meanings as defined above, respectively.
27 . The method according to claim 22 wherein the adenosine A 2A receptor antagonist is (E)-8-(3,4-dimethoxystyryl)-1,3-diethyl-7-methylxanthine.
28 . A composition for the treatment of Parkinson's disease comprising an effective amount of at least one adenosine A 2A receptor antagonist, and a COMT inhibitor and/or DA and/or MAO inhibitor.
29 . The composition according to claim 28 wherein the adenosine A 2A receptor antagonist is a xanthine derivative or a pharmaceutically acceptable salt thereof.
30 . The composition according to claim 28 wherein the A 2A receptor antagonist is represented by formula (I):
wherein
R 1 , R 2 and R 3 represent independently hydrogen, lower alkyl, lower alkenyl or lower alkynyl; R 4 represents cycloalkyl, —(CH 2 ) n —R 5 (in which R 5 represents substituted or unsubstituted aryl, or a substituted or unsubstituted heterocyclic group; and n is an integer of 0 to 4), or
{in which Y 1 and y 2 represent independently hydrogen, halogen, or lower alkyl; and Z represents substituted or unsubstituted aryl, or
(in which R 6 represents hydrogen, hydroxy, lower alkyl, lower alkoxy, halogen, nitro, or amino; and m represents an integer of 1 to 3)}; and X 1 and X 2 represent independently O or S.
31 . The composition according to claim 28 wherein the A 2A receptor antagonist is represented by formula (I-A):
wherein R 1a and R 2a represent independently methyl or ethyl; R 3a represents hydrogen or lower alkyl; and Z a represents
(in which at least one of R 7 , R 8 and R 9 represents lower alkyl or lower alkoxy and the others represent hydrogen; R 5 represents hydrogen or lower alkyl) or
(in which R 6 and m have the same meanings as defined above, respectively).
32 . The composition according to claim 28 wherein the A 2A receptor antagonist is represented by formula (I-B):
wherein R 1b and R 2b represent independently hydrogen, propyl, butyl, lower alkenyl or lower alkynyl; R 3b represents hydrogen or lower alkyl; Z b represents substituted or unsubstituted naphthyl, or
(in which R 6 and m have the same meanings as defined above, respectively); and Y 1 and Y 2 have the same meanings as defined above, respectively.
33 . The composition according to claim 28 wherein the adenosine A 2A receptor antagonist is (E)-8-(3,4-dimethoxystyryl)-1,3-diethyl-7-methylxanthine.
34 . A method of prolonging effective treatment of Parkinson's disease comprising administering to a patient in need thereof either an adenosine A 2A receptor antagonist or a combination of an adenosine A 2A receptor antagonist and a dopamine agonist in an amount effective to delay or remove the patient's need for add-on L-DOPA therapy.
35 . The method according to claim 34 wherein the development of motor complications is delayed.
36 . The method according to claim 34 wherein the patient has not had prior administration of L-DOPA or a dopaminergic agent.
37 . The method according to claim 34 wherein the patient does not have subsequent administration of L-DOPA or a dopaminergic agent.
38 . The method according to claim 34 wherein the adenosine A 2A receptor antagonist is a xanthine derivative or a pharmaceutically acceptable salt thereof.
39 . The method according to claim 34 wherein the A 2A receptor antagonist is represented by formula (I):
wherein
R 1 , R 2 and R 3 represent independently hydrogen, lower alkyl, lower alkenyl or lower alkynyl; R 4 represents cycloalkyl, —(CH 2 ) n —R 5 (in which R 5 represents substituted or unsubstituted aryl, or a substituted or unsubstituted heterocyclic group; and n is an integer of 0 to 4), or
{in which Y 1 and Y 2 represent independently hydrogen, halogen, or lower alkyl; and Z represents substituted or unsubstituted aryl, or
(in which R 6 represents hydrogen, hydroxy, lower alkyl, lower alkoxy, halogen, nitro, or amino; and m represents an integer of 1 to 3)}; and X 1 and X 2 represent independently O or S.
40 . The method according to claim 34 wherein the A 2A receptor antagonist is represented by formula (I-A):
wherein R 1a and R 2a represent independently methyl or ethyl; R 3a represents hydrogen or lower alkyl; and Z a represents
(in which at least one of R 7 , R 8 and R 9 represents lower alkyl or lower alkoxy and the others represent hydrogen; R 5 represents hydrogen or lower alkyl) or
(in which R 6 and m have the same meanings as defined above, respectively).
41 . The method according to claim 34 wherein the A 2A receptor antagonist is represented by formula (I-B):
wherein R 1b and R 2b represent independently hydrogen, propyl, butyl, lower alkenyl or lower alkynyl; R 3b represents hydrogen or lower alkyl; Z represents substituted or unsubstituted naphthyl, or
(in which R 6 and m have the same meanings as defined above, respectively ); and Y 1 and y 2 have the same meanings as defined above, respectively.
42 . The method according to claim 34 wherein the adenosine A 2A receptor antagonist is (E)-8-(3,4-dimethoxystyryl)-1,3-diethyl-7-methylxanthine.
43 . A method of treating movement disorders comprising administrating an effective amount of at least one adenosine A 2A receptor antagonist to a patient in need thereof.
44 . The method according to claim 43 wherein the patient suffers from tremors, bradykinesias, gait, dystonias, dyskinesias, tardive dyskinesias or other extrapyramidal syndromes.
45 . The method according to claim 43 wherein the adenosine A 2A receptor antagonist lessens the effects of drugs that cause movement disorders.
46 . The method according to claim 43 wherein the adenosine A 2A receptor antagonist is a xanthine derivative or a pharmaceutically acceptable salt thereof.
47 . The method according to claim 43 wherein the A 2A receptor antagonist is represented by formula (I):
wherein
R 1 , R 2 and R 3 represent independently hydrogen, lower alkyl, lower alkenyl or lower alkynyl; R 4 represents cycloalkyl, —(CH 2 ) n —R 5 (in which R 5 represents substituted or unsubstituted aryl, or a substituted or unsubstituted heterocyclic group; and n is an integer of 0 to 4), or
{in which Y 1 and Y 2 represent independently hydrogen, halogen, or lower alkyl; and Z represents substituted or unsubstituted aryl, or
(in which R 6 represents hydrogen, hydroxy, lower alkyl, lower alkoxy, halogen, nitro, or amino; and m represents an integer of 1 to 3)}; and X 1 and X 2 represent independently O or S.
48 . The method according to claim 43 wherein the A 2A receptor antagonist is represented by formula (I-A):
wherein R 1a and R 2a represent independently methyl or ethyl; R 3a represents hydrogen or lower alkyl; and Z a represents
(in which at least one of R 7 , R 8 and R 9 represents lower alkyl or lower alkoxy and the others represent hydrogen; R 5 represents hydrogen or lower alkyl) or
(in which R 6 and m have the same meanings as defined above, respectively).
49 . The method according to claim 43 wherein the A 2A receptor antagonist is represented by formula (I-B):
wherein R 1b and R 2b represent independently hydrogen, propyl, butyl, lower alkenyl or lower alkynyl; R 3b represents hydrogen or lower alkyl; Z b represents substituted or unsubstituted naphthyl, or
(in which R 6 and m have the same meanings as defined above, respectively); and Y 1 and Y 2 have the same meanings as defined above, respectively.
50 . The method according to claim 43 wherein the adenosine A 2A receptor antagonist is (E)-8-(3,4-dimethoxystyryl)-1,3-diethyl-7-methylxanthine.Join the waitlist — get patent alerts
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