Patent Application
20140228398
The present invention relates to combinations, which comprise at least one low molecular weight (LMW) nicotinic acetylcholine receptor alpha 7 (α7-nAChR) activator and at least one LMW metabotropic glutamate receptor 5 (mGluR5) antagonist, to pharmaceutical compositions comprising them, and to their use as medicaments for the treatment of dyskinesia associated with dopamine agonist therapy in Parkinson's Disease (PD).
PD is a chronic and progressive degenerative disorder of the central nervous system that often impairs the sufferer's motor skills and speech. Characteristics of PD are varied and include one or more of the following: tremor, rigidity, bradykinesia, akinesia, gait and postural disturbances, postural instability, speech and swallowing disturbances and cognitive impairment (e.g. memory loss, dementia and slowed reaction times). PD is thought to be the direct result of the loss of dopamine-producing cells in the substantia nigra. More than 60,000 new cases of PD are diagnosed in the USA alone each year.
The most commonly used treatment for PD is dopamine agonist therapy, for example by administration of L-dopa (levodopa) in combination with a decarboxylase inhibitor (e.g. carbidopa). However, for many patients, a long term dopamine agonist therapy causes involuntary movements (dyskinesias) as a significant side effect (for review: Fabbrini et al, Movement Disorders, 2007, 22(10), 1379-1389; Konitsiotis, Expert Opin Investig Drugs, 2005, 14(4), 377-392; Brown et al, IDrugs, 2002, 5(5), 454-468). Consequently, there is a need for effective regimes for inhibiting or treating dyskinesia, which can be carried out without adversely affecting anti-PD treatments.
A combination comprising the α7-nAChR activator nicotine and the mGluR5 antagonist methyl-6-(phenylethynyl)pyridine (MPEP) and a combination comprising nicotine and the mGluR5 antagonist 2-[(1S,2S)-2-carboxycyclopropyl]-3-(9H-xanthen-9-yl)-D-alanine (LY341495) is disclosed in Welsby et al, European Journal of Neuroscience, 2006, 24, 3109-3118.
Surprisingly, combination therapy of a LMW α7-nAChR activator and a LMW mGluR5 antagonist offers significant benefits in the treatment, prevention or delay of progression of dyskinesia associated with dopamine agonist therapy in PD.
The invention therefore provides a combination, which comprises:
(A) at least one low molecular weight nicotinic acetylcholine receptor alpha 7 activator, selected from a nicotinic acetylcholine receptor alpha 7 agonist and a nicotinic acetylcholine receptor alpha 7 positive allosteric modulator, as the first active ingredient; and
(B) at least one low molecular weight metabotropic glutamate receptor 5 antagonist as the second active ingredient;
in which the active ingredients are present in each case in free form or in the form of a pharmaceutically acceptable salt;
for use in the treatment, prevention or delay of progression of dyskinesia associated with dopamine agonist therapy in Parkinson's Disease.
A further aspect of the invention relates to a combination, which comprises:
(A) at least one low molecular weight nicotinic acetylcholine receptor alpha 7 activator, selected from a nicotinic acetylcholine receptor alpha 7 agonist and a nicotinic acetylcholine receptor alpha 7 positive allosteric modulator, as the first active ingredient; and
(B) at least one low molecular weight metabotropic glutamate receptor 5 antagonist as the second active ingredient;
in which the active ingredients are present in each case in free form or in the form of a pharmaceutically acceptable salt;
for the use as a medicament.
Yet a further aspect of the invention relates to a combination, which comprises:
(A) at least one low molecular weight nicotinic acetylcholine receptor alpha 7 activator, selected from a nicotinic acetylcholine receptor alpha 7 agonist and a nicotinic acetylcholine receptor alpha 7 positive allosteric modulator, as the first active ingredient; and
(B) at least one low molecular weight metabotropic glutamate receptor 5 antagonist as the second active ingredient;
in which the active ingredients are present in each case in free form or in the form of a pharmaceutically acceptable salt;
and wherein the combination is not
a combination comprising nicotine and methyl-6-(phenylethynyl)pyridine; or
a combination comprising nicotine and 2-[(1S,2S)-2-carboxycyclopropyl]-3-(9H-xanthen-9-yl)-D-alanine.
The term “low molecular weight” is known in the field. Typically, the active ingredients (A) and (B) herein have a maximum molecular weight of 1500 daltons.
“Pharmaceutically acceptable salts” are known in the field (e.g. S. M. Berge, et al, “Pharmaceutical Salts”, J. Pharm. Sd., 1977, 66:1-19; and “Handbook of Pharmaceutical Salts, Properties, Selection, and Use”, Stahl, R H., Wermuth, C. G., Eds.; Wiley-VCH and VHCA: Zurich, 2002). A pharmaceutically acceptable salt is intended to mean a salt of a free form that is not toxic, biologically intolerable, or otherwise biologically undesirable. Preferred pharmaceutically acceptable salts are those that are pharmacologically effective and suitable for contact with the tissues of patients without undue toxicity, irritation, or allergic response.
LMW α7-nAChR Activators:
LMW α7-nAChR Agonists:
As used herein a “α7-nAChR agonist” is a compound that binds to a receptor comprising a α7-nAChR subunit in vivo and in vitro and is activating the receptor. Activation can be measured by the method disclosed in WO2001/85727, i.e. a functional affinity assay at the homomeric α7-nAChR carried out with a rat pituitary cell line stably expressing the α7-nAChR. As read out, the calcium influx upon stimulation of the receptor compared to epibatidine is used. “α7-nAChR agonists” according to the invention typically induce calcium influx of at least 50% of the maximal influx evoked by epibatidine with an EC50 value of at least 1 μM; preferred agonists induce calcium influx of at least 75% of the maximal influx evoked by epibatidine with an EC50 value of at least 400 nM; more preferred agonists induce calcium influx of at least 85% of the maximal influx evoked by epibatidine with an EC50 value of at least 50 nM.
In particular, preferred α7-nAChR agonists should be well absorbed from the gastrointestinal tract, should be sufficiently metabolically stable and possess favorable pharmacokinetic properties.
Further preferred α7-nAChR agonists bind in-vivo potently to α7-nAChRs whilst showing little affinity for other receptors, especially for other nAChRs, e.g. α4β2 nAChR, for muscarinic acetylcholine receptors, e.g. M1, and/or the 5-HT3 receptor.
Further preferred α7-nAChR agonists cross the blood brain barrier effectively.
Preferred α7-nAChR agonists should be non-toxic and demonstrate few side-effects.
Furthermore, a preferred α7-nAChR agonist will be able to exist in a physical form that is stable, non-hygroscopic and easily formulated.
In one embodiment, the α7-nAChR agonist is a selective α7-nAChR agonist, i.e. is selective for a receptor comprising a α7-nAChR subunit, since such an agonist would be expected to cause fewer side effects than a non-selective agonist to a treated subject. An agonist being selective for a receptor comprising a α7-nAChR subunit has a functional affinity to such a receptor to a much higher degree, e.g. at least 10-fold affinity difference in EC50 value, preferably at least 20-fold, more preferably at least 50-fold, compared to any other nicotinic acetylcholine receptor. To assess the affinity of the α7-nAChR agonists of the invention on other nicotinic acetylcholine receptors, the method disclosed in WO2001/85727 can be used, i.e. to assess the affinity on human neuronal α4β2 nAChR, a similar functional assay is carried out using a human embryonic kidney cell line stable expressing the human α4β2 subtype and to assess the activity of the compounds of the invention on the “ganglionic subtype” and the “muscle type” of nicotinic receptor, similar functional assays are carried out with a human embryonic kidney cell line stably expressing the human “ganglionic subtype” or a cell line endogenously expressing the human “muscle type” of nicotinic receptors.
In the last 15 years much effort has been focused on developing selective α7 nAChR agonists leading to the discovery of many different chemotypes displaying said selective activity. These efforts are summarized the review from Horenstein et al (Mol Pharmacol, 2008, 74, 1496-1511, which describes no less than 9 different families of α7 nAChR agonists, in most of which selective agonists have been found. All compounds disclosed in
In one embodiment, the α7-nAChR agonist has a maximum molecular weight of 1500 daltons.
In one embodiment, the α7-nAChR agonist has a maximum molecular weight of 1000 daltons.
In one embodiment, the α7-nAChR agonist has a maximum molecular weight of 800 daltons.
In one embodiment, the α7-nAChR agonist has a maximum molecular weight of 500 daltons.
In one embodiment, the α7-nAChR agonist is a compound of formula (I)
wherein
L4 is a group selected from
wherein the bond marked with the asterisk is attached to the azabicycloalkyl moiety;
R1 is hydrogen or C1-4alkyl;
A2 is selected from
wherein the bond marked with the asterisk is attached to X1;
A1 is a five- to ten-membered monocyclic or fused polycyclic aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system may be substituted once or more than once by R2, and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen;
each R2 independently is C1-6alkyl, C1-6halogenalkyl, C1-6alkoxy, C1-6halogenalkoxy, halogen, cyano or a three- to six-membered monocyclic ring system which may be aromatic, saturated or partially saturated and which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, and wherein each ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein each ring system may in turn be substituted once or more than once by C1-6alkyl, C1-6halogenalkyl, C1-6alkoxy, C1-6halogenalkoxy, halogen or cyano, and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen;
or two R2 at adjacent ring atoms form a C3-4alkylene group, wherein 1-2 carbon atoms may be replaced by X2, and wherein the C3-4alkylene group may be substituted once or more than once by R3;
each X2 independently is —O— or —N(R4)—;
each R4 independently is hydrogen or C1-6alkyl; and
each R3 independently is halogen or C1-6alkyl;
in free base form or in acid addition salt form.
Unless indicated otherwise, the expressions used in this invention have the following meaning:
“Alkyl” represents a straight-chain or branched-chain alkyl group, for example, methyl, ethyl, n- or iso-propyl, n-, iso-, sec- or tert-butyl, n-pentyl, n-hexyl; C1-6alkyl preferably represents a straight-chain or branched-chain C1-4alkyl with particular preference given to methyl, ethyl, n-propyl, iso-propyl and tert-butyl.
Each alkyl part of “alkoxy”, “halogenalkyl” and so on shall have the same meaning as described in the above-mentioned definition of “alkyl”, especially regarding linearity and preferential size.
A substituent being substituted “once or more than once”, for example as defined for A1, is preferably substituted by one to three substituents.
Halogen is generally fluorine, chlorine, bromine or iodine; preferably fluorine, chlorine or bromine. Halogenalkyl groups preferably have a chain length of 1 to 4 carbon atoms and are, for example, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 2-fluoroethyl, 2-chloroethyl, pentafluoroethyl, 1,1-difluoro-2,2,2-trichloroethyl, 2,2,2-trichloroethyl, 1,1,2,2-tetrafluoroethyl, 2,2,3,3-tetrafluoropropyl, 2,2,3,3,3-pentafluoropropyl or 2,2,3,4,4,4-hexafluorobutyl; preferably —CF3, —CHF2, —CH2F, —CHF—CH3, —CF2CH3, or —CH2CF3.
In the context of the invention, the definitions of “two R2 at adjacent ring atoms form a C3-4alkylene group, wherein 1-2 carbon atoms may be replaced by X2” or “two R5 at adjacent ring atoms form a C3-4alkylene group, wherein 1-2 carbon atoms may be replaced by X3” encompass —CH2—CH2—CH2—, —CH2—CH2—CH2—CH2—, —O—CH2—O—, —O—CH2—CH2—O— and —CH2—CH2—NH—. An example of a substituted group is —CH2—CH2—N(CH3)—.
In the context of the invention, the definition of A1 or A3 as a “five- to ten-membered monocyclic or fused polycyclic aromatic ring system” encompasses a C6- or C10-aromatic hydrocarbon group or a five- to ten-membered heterocyclic aromatic ring system. “Polycyclic” means preferably bicyclic.
In the context of the invention, the definition of R2 as a “three- to six-membered monocyclic ring system” encompasses a C6-aromatic hydrocarbon group, a five- to six-membered heterocyclic aromatic ring system and a three- to six-membered monocyclic aliphatic or heterocyclic ring system.
A C6- or C10-aromatic hydrocarbon group is typically phenyl or naphthyl, especially phenyl.
Preferably, but also depending on substituent definition, “five- to ten-membered heterocyclic aromatic ring systems” consist of 5 to 10 ring atoms of which 1-3 ring atoms are hetero atoms. Such heterocyclic aromatic ring systems may be present as a single ring system or as bicyclic or tricyclic ring systems; preferably as single ring systems or as benz-annelated ring systems. Bicyclic or tricyclic ring systems may be formed by annelation of two or more rings, or by a bridging atom, e.g. oxygen, sulfur, nitrogen. Examples of heterocyclic ring systems are: imidazo[2,1-b]thiazole, pyrrole, pyrroline, pyrrolidine, pyrazole, pyrazoline, pyrazolidine, imidazole, imidazoline, imidazolidine, triazole, triazoline, triazolidine, tetrazole, furane, dihydrofurane, tetrahydrofurane, furazane (oxadiazole), dioxolane, thiophene, dihydrothiophene, tetrahydrothiophene, oxazole, oxazoline, oxazolidine, isoxazole, isoxazoline, isoxazolidine, thiazole, thiazoline, thiazolidine, isothiazole, isothiazoline, isothiazolidine, thiadiazole, thiadiazoline, thiadiazolidine, pyridine, piperidine, pyridazine, pyrazine, piperazine, triazine, pyrane, tetrahydropyrane, thiopyrane, tetrahydrothiopyrane, oxazine, thiazine, dioxine, morpholine, purine, pteridine, and the corresponding benz-annelated heterocycles, e.g. indole, isoindole, coumarin, isoquinoline, quinoline and the like. Preferred heterocycles are: imidazo[2,1-b]thiazole, oxazole, isoxazole, thiazole, isothiazole, triazole, pyrrole, furane, tetrahydrofurane, pyridine, pyrimidine, imidazole or pyrazole.
In the context of the invention, three- to six-membered monocyclic aliphatic ring systems are typically cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
On account of asymmetrical carbon atom(s) that may be present in the compounds of formula (I) and compounds of formula (II), the compounds may exist in optically active form or in form of mixtures of optical isomers, e.g. in form of racemic mixtures or diastereomeric mixtures. All optical isomers and their mixtures, including racemic mixtures, are part of the present invention.
In one embodiment, the α7-nAChR agonist is a compound of formula (I)
wherein
L4 is a group selected from
wherein the bond marked with the asterisk is attached to the azabicycloalkyl moiety;
R1 is hydrogen or C1-4alkyl;
A2 is selected from
wherein the bond marked with the asterisk is attached to X1;
A1 is a five- to ten-membered monocyclic or fused polycyclic aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system may be substituted once or more than once by R2, and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen; and
each R2 independently is C1-6alkyl, C1-6halogenalkyl, C1-6alkoxy, C1-6halogenalkoxy or halogen.
In one embodiment, the α7-nAChR agonist is a compound of formula (I)
wherein
wherein the bond marked with the asterisk is attached to the azabicycloalkyl moiety;
R1 is hydrogen or C1-4alkyl;
A1 is a five- to ten-membered monocyclic or fused polycyclic aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system may be substituted once or more than once by R2, and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen; and
each R2 independently is C1-6alkyl, C1-6halogenalkyl, C1-6alkoxy, C1-6halogenalkoxy or halogen.
In one embodiment, the α7-nAChR agonist is a compound of formula (I)
wherein
wherein the bond marked with the asterisk is attached to the azabicycloalkyl moiety;
A2 is selected from
wherein the bond marked with the asterisk is attached to X1;
A1 is a five- to ten-membered monocyclic or fused polycyclic aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system may be substituted once or more than once by R2, and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen; and each R2 independently is C1-6alkyl, C1-6halogenalkyl, C1-6alkoxy, C1-6halogenalkoxy or halogen.
In one embodiment, the α7-nAChR agonist is a compound of formula (I)
wherein
wherein the bond marked with the asterisk is attached to the azabicycloalkyl moiety;
A2 is selected from
wherein the bond marked with the asterisk is attached to X1;
A1 is a five- to ten-membered monocyclic or fused polycyclic aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and
wherein the ring system may be substituted once or more than once by R2, and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen; and
each R2 independently is C1-6alkyl, C1-6halogenalkyl, C1-6alkoxy, C1-6halogenalkoxy or halogen.
In one embodiment, the α7-nAChR agonist is a compound selected from Group P1; Group P1 is the group consisting of
In one embodiment, the α7-nAChR agonist is a compound selected from the group consisting of compound A-1 (compound A-1 is also described as JN403), A-2 and A-3; wherein each of said compound is in free base form or in acid addition salt form.
In one embodiment, the α7-nAChR agonist is a compound selected from the group consisting of compound B-1, B-2, B-3, B-4, B-5, B-6, B-7, B-8, B-9, B-10, B-11, B-12, B-13, B-14, B-15, B-16, B-17, B-18, B-19, B-20 and B-21; wherein each of said compound is in free base form or in acid addition salt form.
In one embodiment, the α7-nAChR agonist is a compound selected from the group consisting of compound C-1, C-2, C-3, C-4, C-5, C-6, C-7, C-8, C-9, C-10, C-11 and C-12; wherein each of said compound is in free base form or in acid addition salt form.
In one embodiment, the α7-nAChR agonist is a compound selected from Group P2; Group P2 is the group consisting of compounds A-1, A-2, A-3, B-1, B-2, B-3, B-4, B-5, B-6, B-7, B-8, B-9, B-10, B-11, B-12, B-13, B-14, B-15, B-16, B-17, B-18, B-19, B-20, B-21, C-1, C-2, C-3, C-4, C-5, C-6, C-7, C-8, C-9, C-10, C-11, C-12, E-1, E-1a, E-1b, E-1c, E-1d, E-2, E-3, E-3a, E-4, E-4a, E-8, E-8a, E-8b, E-9, E-9a, E-9b, E-10, E-10a, E-11, E-11a, E-11b, E-11c, E-11d, E-11e, E-12, E-19, E-22, E-24, E-24a, E-24b, E-25a, E-25b, E-25c, E-25d, E-25e, E-25f, E-25g, E-25h, E-25i, E-25j, E-25k, E-25l, E-25m, E-25n, E-25o, E-25p, E-25q, E-25r, E-25s, E-25t, E-25u, E-25v, E-28a, E-28b, E-28c, E-28d, E-28e, E-28f, E-28g, E-28h, E-28i, E-28j, E-28k, E-28l, E-28m, E-28n, E-28o, E-28p, E-28q, E-29, E-30a, E-30b, E-30c, E-30d, E-30e and E-30f; wherein each of said compound is in free base form or in acid addition salt form.
In one embodiment, the α7-nAChR agonist is a compound selected from Group P3; Group P3 is the group consisting of compounds A-1, A-2, A-3, B-1, B-2, B-3, B-4, B-5, B-6, B-7, B-8, B-9, B-10, B-11, B-12, B-13, B-14, B-15, B-16, B-17, B-18, B-19, B-20, B-21, C-1, C-2, C-3, C-4, C-5, C-6, C-7, C-8, C-9, C-10, C-11, C-12, E-1, E-1a, E-1b, E-1c, E-1d, E-2, E-3, E-3a, E-4, E-4a, E-8, E-8a, E-8b, E-9, E-9a, E-9b, E-10, E-10a, E-11, E-11a, E-12, E-19, E-22, E-24, E-24a, E-24b, E-29, E-30a, E-30b, E-30c, E-30d, E-30e and E-30f; wherein each of said compound is in free base form or in acid addition salt form.
In one embodiment, the α7-nAChR agonist is a compound selected from Group P4; Group P4 is the group consisting of compounds A-1, B-5, B-8, B-12, B-13, C-5, C-6 and C-8; wherein each of said compound is in free base form or in acid addition salt form.
The compounds of formula (I) (e.g. compounds A-1 to A-3, B-1 to B-21 and C-1 to C-12) and their manufacture are known from W02001/85727, WO2004/022556, WO2005/123732, WO2006/005608, WO2007/045478, WO2007/068476 and WO2007/068475, or can be prepared analogously to said references.
Compounds D-1 and D-1a can be prepared according to WO2008/058096.
Compounds D-2, D-3, D-3a, D-4, D-4a and D-5 (A-582941) can be prepared according to WO2005/028477.
Compounds D-6, D-6a, D-7 and E7a can be prepared according to WO2006/065233 and/or WO2007/018738.
Compounds D-8, D-8a, D-8b, D-9, D-9a and D-9b can be prepared according to WO2004/029050 and/or WO2010/043515.
Compounds D-10 and D-10a can be prepared according to WO2004/076449 and/or WO2009/018505;
Compounds D-11, D-11a to D-11e can be prepared according to WO2004/076449 and/or WO2010/085724 and/or WO2010/056622;
Compounds D-12 (CP-810123) and Compound D-19 (varenicline) are described in O'Donnell et al, J Med Chem, 2010, 53, 1222-1237.
Compounds D-13 (PNU-282987), D-14 (PHA543613), D-21 (SSR-180771) and D-23 (ABBF) are described in Horenstein et al, Mol Pharmacol, 2008, 74, 1496-1511.
Compounds D-15 (PHA568487), D-16 (WAY-317538), D-17 (WAY-264620), D-20 (AZD-0328) and D-22 (GTS-21) are described in Haydar et al, Current Topics in Medicinal Chemistry, 2010, 10, 144-152.
Compound D-18 (WYE-103914) is described in Ghiron et al, J Med Chem, 2010, 53, 4379-4389.
Compound D-24, D-24a and D-24b are described in WO2007/133155 and/or WO2009/066107.
Compounds D-25a to D-25v are described in WO2004/013136.
Compounds D-26a to D-26z are described in WO2003/078431.
Compounds D-27a to D-27e are described in WO2003/078430.
Compounds D-28a to D-28q are described in WO2003/043991.
Compound D-29 is described in WO2003/055878.
Compounds D-30a to D-30f are described in WO2007/137030.
LMW α7-nAChR Positive Allosteric Modulators:
As used herein a “α7-nAChR positive allosteric modulator” is a compound that binds to a receptor comprising a α7-nAChR subunit in vivo and in vitro and is potentiating the activation of the receptor when its physiological ligand (i.e. acetylcholine) is binding. Potentiation can be measured by the method disclosed in W02001/85727, i.e. a functional affinity assay at the homomeric α7-nAChR carried out with a rat pituitary cell line stably expressing the α7-nAChR. As read out, the calcium influx upon stimulation of the receptor compared to acetylcholine-binding alone is used. “α7-nAChR positive allosteric modulators” according to the invention typically induce calcium influx of at least 200% of the maximal influx evoked by acetylcholine with an EC50 value of at least 5000 nM; preferred agonists induce calcium influx of at least 300% of the maximal influx evoked by acetylcholine with an EC50 value of at least 1000 nM; more preferred agonists induce calcium influx of at least 400% of the maximal influx evoked by epibatidine with an EC50 value of at least 500 nM.
In particular, preferred α7-nAChR positive allosteric modulators should be well absorbed from the gastrointestinal tract, should be sufficiently metabolically stable and possess favorable pharmacokinetic properties.
Further preferred α7-nAChR positive allosteric modulators bind in-vivo potently to α7-nAChRs whilst showing little affinity for other receptors, especially for other nAChRs, e.g. a 4132 nAChR, for muscarinic acetylcholine receptors, e.g. M1, and/or the 5-HT3 receptor. Further preferred α7-nAChR positive allosteric modulators cross the blood brain barrier effectively.
Preferred α7-nAChR positive allosteric modulators should be non-toxic and demonstrate few side-effects.
Furthermore, a preferred α7-nAChR positive allosteric modulator will be able to exist in a physical form that is stable, non-hygroscopic and easily formulated.
In one embodiment, the α7-nAChR positive allosteric modulator is a selective α7-nAChR positive allosteric modulator, i.e. is selective for a receptor comprising a α7-nAChR subunit, since such a positive allosteric modulator would be expected to cause fewer side effects than a non-selective positive allosteric modulator to a treated subject. A positive allosteric modulator being selective for a receptor comprising a α7-nAChR subunit has a functional affinity to such a receptor to a much higher degree, e.g. at least 10-fold affinity difference in EC50 value, preferably at least 20-fold, more preferably at least 50-fold, compared to any other nicotinic acetylcholine receptor. To assess the affinity of the α7-nAChR positive allosteric modulator of the invention on other nicotinic acetylcholine receptors, the method disclosed in W02001/85727 can be used, i.e. to assess the affinity on human neuronal α4β2 nAChR, a similar functional assay is carried out using a human embryonic kidney cell line stable expressing the human α4β2 subtype and to assess the activity of the compounds of the invention on the “ganglionic subtype” and the “muscle type” of nicotinic receptor, similar functional assays are carried out with a human embryonic kidney cell line stably expressing the human “ganglionic subtype” or a cell line endogenously expressing the human “muscle type” of nicotinic receptors.
In the last 12 years much effort has been focused on developing selective α7 nAChR positive allosteric modulators leading to the discovery of many different chemotypes displaying said selective activity. These efforts are summarized the review from Haydar et al (Current Topics in Medicinal Chemistry, 2010, 10, 144-152), which describes 11 compounds acting as α7 nAChR positive allosteric modulators belonging to seven different chemical families; i.e. XY-4083; PNU-120596, PHA-758454 and NS-1738; PHA-709829; SB-206553; LY-2087101, LY-1078733 and LY-2087133; compound 26; and A-867744 (compound designations taken from Haydar et al). All said 11 compounds described in Haydar et al are incorporated herein by reference. In fact, at least one drug candidate having an α7 nAChR positive allosteric modulator mode of action obtained permission from the U.S. Food and Drug Administration to conduct clinical testing (i.e. XY-4083).
In one embodiment, the α7-nAChR positive allosteric modulator has a maximum molecular weight of 1500 daltons.
In one embodiment, the α7-nAChR positive allosteric modulator has a maximum molecular weight of 1000 daltons.
In one embodiment, the α7-nAChR positive allosteric modulator has a maximum molecular weight of 800 daltons.
In one embodiment, the α7-nAChR positive allosteric modulator has a maximum molecular weight of 500 daltons.
In one embodiment, the α7-nAChR positive allosteric modulator is a compound selected from the Group P5; Group P5 is the group consisting of compounds
As used herein a “mGluR5 antagonist” is a compound that binds to mGluR5 in vivo and in vitro and is blocking receptor signalling. In-vitro blocking is measured by one of the methods disclosed in WO2008/128968, i.e. a functional assay at mGluR5 carried out with a L(tk-) cell line stably expressing mGluR5. As read out, inhibition of the calcium increase upon stimulation of the receptor with the agonist glutamate is used. “mGluR5 antagonists” according to the invention typically inhibit calcium increase of at least 75% of the maximal increase evoked by 10 μM glutamate with an IC50 value of at least 1 μM; preferred antagonists inhibit calcium increase of at least 85% of the maximal increase evoked by 10 μM glutamate with an IC50 value of at least 500 nM; more preferred antagonists inhibit calcium increase of at least 95% of the maximal increase evoked by 10 μM glutamate with an IC50 value of at least 100 nM.
In one embodiment of the invention, the mGluR5 antagonist is a non-competitive antagonist.
In particular, preferred mGluR5 antagonists should be well absorbed from the gastrointestinal tract, should be sufficiently metabolically stable and possess favorable pharmacokinetic properties.
Further preferred mGluR5 antagonists bind in-vivo potently to mGluR5 whilst showing little potency towards other receptors, especially for other mGluRs, e.g. mGluR1, for ionotropic glutamate receptors, e.g. NMDA receptors and/or other G-protein coupled receptors.
Further preferred mGluR5 antagonists cross the blood brain barrier effectively.
Preferred mGluR5 antagonists should be non-toxic and demonstrate few side-effects. Furthermore, a preferred mGluR5 antagonist will be able to exist in a physical form that is stable, non-hygroscopic and easily formulated.
In one embodiment, the mGluR5 antagonist is a selective mGluR5 antagonist, i.e. is selective for mGluR5, since such an antagonist would be expected to cause fewer side effects than a non-selective antagonist to a treated subject. An antagonist being selective for mGluR5 has a functional potency to such a receptor to a much higher degree, e.g. at least 10-fold potency difference in IC50 value, preferably at least 20-fold, more preferably at least 50-fold, compared to any other mGluR, e.g. mGluR1. To assess the potency of the mGluR5 antagonists of the invention on mGluR1, methods disclosed in WO2008/128968 can be used, i.e. a similar functional assay is carried out using a CHO cell line stable expressing mGluR1, e.g. inhibtion of the calcium increase upon stimulation of the receptor with 100 μM of the agonist glutamate is used.
In the last 15 years much effort has been focused on developing selective mGluR5 antagonists leading to the discovery of many different chemotypes displaying said selective activity. These efforts are summarized in the review from Jaeschke et al (Expert Opin Ther Patents, 2008, 18(2), 123-142), which describes compounds belonging to multiple chemotypes. All compounds disclosed in said review (e.g. compounds 1-42) are incorporated herein by reference. In fact, several drug candidates having a mGluR5 antagonist mode of action entered pre-clinical or even clinical testing. Examples of such compounds—again belonging to a diversity of chemotypes—are MPEP, MTEP, fenobam, raseglurant, dipraglurant, SIB-1757, SIB-1893, RG7090, AFQ056, AZD2066, AZD2516 and STX-107. Further mGluR5 antagonists and their use as pharmaceuticals are known, for example, from WO2003/047581 and WO2008/128968.
In one embodiment, the mGluR5 antagonist has a maximum molecular weight of 1500 daltons.
In one embodiment, the mGluR5 antagonist has a maximum molecular weight of 1000 daltons.
In one embodiment, the mGluR5 antagonist has a maximum molecular weight of 800 daltons.
In one embodiment, the mGluR5 antagonist has a maximum molecular weight of 500 daltons.
In one embodiment, the mGluR5 antagonist is a compound selected from Group Q1; Group Q1 is the group consisting of
In one embodiment, the α7-nAChR agonist is a compound selected from Group Q2; Group Q2 is the group consisting of compounds F-1, F-4, F-5, F-6, F-9, F-10a and E11a; wherein each of said compound is in free base form or in acid addition salt form.
Compound F-1 can be prepared according to WO2003/047581.
Compounds F-2, F-3, F-4, F-7 and F-8 are described in Jaeschke et al (Expert Opin Ther Patents, 2008, 18(2), 123-142).
Compound F-5 can be prepared according to WO2004/078728.
Compound F-6 can be prepared according to WO2005/123703.
Compound F-9 can be prepared according to WO2004/108701, WO2005/118568 and/or WO2008/074697.
Compounds F-10 and F-10a can be prepared according to WO2007/040982 and/or WO2006/014185.
Compounds F-11 and F-11a can be prepared according to WO2009/051556.
A combination, which comprises
(A) at least one LMW α7-nAChR activator, selected from a nicotinic acetylcholine receptor alpha 7 agonist and a nicotinic acetylcholine receptor alpha 7 positive allosteric modulator, as the first active ingredient; and
(B) at least one LMW mGluR5 antagonist as the second active ingredient; in which the active ingredients are present in each case in free form or in the form of a pharmaceutically acceptable salt;
will be referred to hereinafter as a “COMBINATION OF THE INVENTION”.
Further, the invention relates to a COMBINATION OF THE INVENTION, such as a combined preparation or pharmaceutical composition, for simultaneous, separate or sequential use.
The term “combined preparation” as used herein defines especially a “kit of parts” in the sense, that the first and the second active ingredient as defined above can be dosed independently, either in separate form or by use of different fixed combinations with distinguished amounts of the active ingredients. The ratio of the amount of the active ingredient (A) to the amount of the active ingredient (B) to be administered in the combined preparation can be varied, e.g. in order to cope with the needs of a patient sub-population to be treated or the needs of a single patient, which needs can be different due to age, sex, body weight, etc. of a patient. The parts of the kit of parts can be administered simultaneously or chronologically staggered, e.g. at different time points and with equal or different time intervals for any part of the kit of parts.
The administration of a COMBINATION OF THE INVENTION may result in a beneficial, for example synergistic, therapeutic effect or in other surprising beneficial effects, for example fewer and/or weaker side effects, compared to a monotherapy applying only one of the active ingredients used in the COMBINATION OF THE INVENTION.
In one embodiment, the invention provides a COMBINATION OF THE INVENTION, wherein the first and the second active ingredient are present in a synergistic weight ratio.
In one embodiment, the invention provides a COMBINATION OF THE INVENTION, wherein the first and the second active ingredient are present in a weight ratio producing a synergistic therapeutic effect.
In one embodiment, the invention provides a COMBINATION OF THE INVENTION, wherein the first and the second active ingredient are present in a weight ratio of first active ingredient to second active ingredient of 1:50 to 20:1, e.g. 1:20 to 10:1 or 1:10 to 10:1.
In one embodiment, the invention provides a COMBINATION OF THE INVENTION, wherein the first and the second active ingredient are present in a weight ratio of first active ingredient to second active ingredient of 1:20 to 1:1, e.g. 1:20 to 1:4 or 1:10 to 1:4.
In one embodiment, the invention provides a COMBINATION OF THE INVENTION, wherein the first and the second active ingredient are present in a synergistic amount.
In one embodiment, the invention provides a COMBINATION OF THE INVENTION, wherein the first and the second active ingredient are present in an amount producing a synergistic therapeutic effect.
In particular, a COMBINATION OF THE INVENTION, which comprises subeffective doses of an α7-nAChR activator and of a mGluR5 antagonist may achieve the same effect as effective doses of either compound alone.
In particular, in patients non-responding to an α7-nAChR activator, a COMBINATION OF THE INVENTION, may achieve a higher therapeutic effect compared to a monotherapy with a mGluR5 antagonist alone.
In particular, in patients non-responding to a mGluR5 antagonist, a COMBINATION OF THE INVENTION, may achieve a higher therapeutic effect compared to a monotherapy with an α7-nAChR activator alone.
A further benefit is, that lower doses of the active ingredients of the COMBINATION OF THE INVENTION can be used, compared to a monotherapy applying only one of the active ingredients used in the COMBINATION OF THE INVENTION. For example, the dosages used may not only be smaller, but may also be applied less frequently. Also, the incidence of side effects may be diminished and/or the responder rate to therapies based on α7-nAChR activators or mGluR5 antagonists may be higher. All of this is in accordance with the desire and requirements of the patient to be treated.
Preferably, a COMBINATION OF THE INVENTION comprises at least one α7-nAChR activator, especially an α7-nAChR activator selected from group P1; and at least one mGluR5 antagonists, especially a mGluR5 antagonist selected from the group Q1.
In one embodiment, the COMBINATION OF THE INVENTION comprises at least one α7-nAChR activator selected from group P3; and at least the compound E-1 in free base form or in acid addition salt form.
In one embodiment, the COMBINATION OF THE INVENTION comprises at least one α7-nAChR activator selected from group P4; and at least the compound E-1 in free base form or in acid addition salt form.
In one embodiment, the COMBINATION OF THE INVENTION comprises at least compounds A-1 and E-1, wherein both compounds are in free base form or in acid addition salt form.
In one embodiment, the COMBINATION OF THE INVENTION comprises at least compounds B-5 and E-1, wherein both compounds are in free base form or in acid addition salt form.
In one embodiment, the COMBINATION OF THE INVENTION comprises at least compounds B-8 and E-1, wherein both compounds are in free base form or in acid addition salt form.
In one embodiment, the COMBINATION OF THE INVENTION comprises at least compounds B-12 and E-1, wherein both compounds are in free base form or in acid addition salt form.
In one embodiment, the COMBINATION OF THE INVENTION comprises at least compounds B-13 and E-1, wherein both compounds are in free base form or in acid addition salt form.
In one embodiment, the COMBINATION OF THE INVENTION comprises at least compounds C-5 and E-1, wherein both compounds are in free base form or in acid addition salt form.
In one embodiment, the COMBINATION OF THE INVENTION comprises at least compounds C-6 and E-1, wherein both compounds are in free base form or in acid addition salt form.
In one embodiment, the COMBINATION OF THE INVENTION comprises at least compounds C-8 and E-1, wherein both compounds are in free base form or in acid addition salt form.
In one embodiment, the COMBINATION OF THE INVENTION comprises at least one α7-nAChR activator selected from group P3; and at least the compound E-4 in free base form or in acid addition salt form.
In one embodiment, the COMBINATION OF THE INVENTION comprises at least one α7-nAChR activator selected from group P3; and at least the compound E-5 in free base form or in acid addition salt form.
In one embodiment, the COMBINATION OF THE INVENTION comprises at least one α7-nAChR activator selected from group P3; and at least the compound E-6 in free base form or in acid addition salt form.
In one embodiment, the COMBINATION OF THE INVENTION comprises at least one α7-nAChR activator selected from group P3; and at least the compound E-9 in free base form or in acid addition salt form.
In one embodiment, the COMBINATION OF THE INVENTION comprises at least one α7-nAChR activator selected from group P3; and at least the compound E-10a in free base form or in acid addition salt form.
In one embodiment, the COMBINATION OF THE INVENTION comprises at least one α7-nAChR activator selected from group P3; and at least the compound E-11a in free base form or in acid addition salt form.
The invention also relates to a pharmaceutical composition comprising a COMBINATION OF THE INVENTION as active ingredients and at least one pharmaceutically acceptable carrier. In this composition, the first and the second active ingredient can be administered together, one after the other or separately, in one combined unit dosage form or in two separate unit dosage forms. The unit dosage form may also be a fixed combination.
A pharmaceutical composition according to the invention is, preferably, suitable for enteral administration, such as oral or rectal administration; or parenteral administration, such as intramuscular, intravenous, nasal or transdermal administration, to a warm-blooded animal (human beings and animals) that comprises a therapeutically effective amount of the active ingredients and one or more suitable pharmaceutically acceptable carriers.
Preferred are compositions for oral or transdermal administration.
A composition for enteral or parenteral administration is, for example, a unit dosage form, such as a sugar-coated tablet, a tablet, a capsule, a suppository or an ampoule.
The unit content of active ingredients in an individual dose need not in itself constitute a therapeutically effective amount, since such an amount can be reached by the administration of a plurality of dosage units. A composition according to the invention may contain, e.g., from about 10% to about 100%, preferably from about 20% to about 60%, of the active ingredients.
If not indicated otherwise, a pharmaceutical composition according to the invention is prepared in a manner known per se, e.g. by means of conventional mixing, granulating, sugar-coating, dissolving or lyophilizing processes. In preparing a composition for an oral dosage form, any of the usual pharmaceutical media may be employed, for example water, glycols, oils, alcohols, carriers, such as starches, sugars, or microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit forms, in which case solid pharmaceutical carriers are obviously employed.
Dyskinesia Associated with Dopamine Agonist Therapy:
“Dopamine agonist therapy” is generally used in the treatment of PD. The term “dopamine agonist therapy” as used herein, unless indicated otherwise, means any therapy that increases dopamine receptor stimulation, including, but not limited to, therapies that directly stimulate dopamine receptors (such as administration of bromocriptine) and therapies that increase the levels of dopamine (such as administration of levodopa or of drugs which inhibit dopamine metabolism).
Dopamine agonist therapies include, but are not limited to, therapies which comprise the administration of one or more of the following agents:
levodopa (or L-dopa being a precursor of dopamine);
levodopa in combination with a levodopa decarboxylase inhibitor, such as carbidopa or benserazide;
levodopa in combination with a catechol-O-methyl transferase inhibitor, such as tolcapone or entacapone;
a monoamine oxidase B-inhibitor, such as selegiline or rasagiline;
a dopamine receptor agonist, such as bromocriptine, pergolide, pramipexole, ropinirole, cabergoline, apomorphine or lisuride.
The term “dopamine agonist” as used herein, unless otherwise indicated, means any agent that increases dopamine receptor stimulation. Preferred dopamine agonists are levodopa; levodopa in combination with a levodopa decarboxylase inhibitor; levodopa in combination with a catechol-O-methyl transferase inhibitor; a monoamine oxidase B-inhibitor and a dopamine receptor agonist.
In one embodiment of the invention, the therapy comprises the administration of levodopa. Due to prevalence of associated dyskinesia, the daily dosage of levodopa for an effective dopamine agonist therapy of PD needs to be determined for each patient individually and ranges typically from 250 to 1500 mg. Said total daily dose is distributed between 2-6 administrations per day, e.g. 3-6 administrations of 50-100 mg per administration. Usually, the daily dosage of levodopa needed for an effective therapy increases during the course of the therapy.
In one embodiment of the invention, the therapy comprises the administration of levodopa in combination with a levodopa decarboxylase inhibitor, such as carbidopa or benserazide.
The term “dyskinesia associated with dopamine agonist therapy”, as used herein, unless otherwise indicated, means any dyskinesia which accompanies, or follows in the course of, dopamine agonist therapy, or which is caused by, related to, or exacerbated by dopamine agonist therapy, wherein dyskinesia and dopamine agonist therapy are as defined above. Such dyskinesia often, although not exclusively, occurs as a side-effect of said dopamine agonist therapies of PD.
Characteristics of such dyskinesias include motor impairment, e.g. the appearance of slow and uncoordinated involuntary movements, shaking, stiffness and problems walking.
For example, patients treated with levodopa often have reduced symptoms of PD but they experience increasing difficulties to remain standing or even sitting. After prolonged use of levodopa, a majority of patients develop such dyskinesia. Dyskinesia can occur at any time during the cycle of treatment with levodopa.
In one embodiment, the COMBINATION OF THE INVENTION is for the treatment of dyskinesia, wherein the therapy comprises administration of levodopa, and said dyskinesia occurs at the time of peak levodopa plasma concentrations in the patient.
In one embodiment, the COMBINATION OF THE INVENTION is for the treatment of dyskinesia, wherein the therapy comprises administration of levodopa, and said dyskinesia occurs when the levodopa plasma concentrations in a patient rise or fall (diphasic dyskinesia).
Surprisingly it was found that α7-nAChR agonists and/or positive allosteric modulators are able to prolong the action of dopamine agonists, e.g. levodopa. Consequently, compared to therapies using such dopamine agonists, the time interval for administration of said dopamine agonists may be prolonged leading to a lower daily dosage needed to achieve equal control of PD.
A further aspect of the invention relates to a method for the treatment or delay of progression of PD in a subject in need of such treatment, which comprises
administering to said subject a therapeutically effective amount of (i) a dopamine agonist and (ii) a COMBINATION OF THE INVENTION,
wherein the daily dosage of the dopamine agonist is reduced compared to the daily dosage of said dopamine agonist needed to reach an equal control of Parkinson's Disease in the subject without co-administration of the COMBINATION OF THE INVENTION.
In a preferred embodiment, said dopamine agonist comprises levodopa.
In a further preferred embodiment, said reduced daily dosage is a dosage reduced by at least 10%.
In a further preferred embodiment, said reduced daily dosage is a dosage reduced by at least 20%.
In a further preferred embodiment, said reduced daily dosage is achieved by administering the dopamine agonist in larger time intervals.
Treatment may comprise a reduction in the characteristics associated with dyskinesia, including for example, although not limited to, a reduction in the scale of involuntary movements, a reduction in the number of involuntary movements, an improvement in the ability to carry out normal tasks, an improved ability to walk, increased period of time between episodes of dyskinesia.
One aspect of the treatment of dyskinesias associated with dopamine agonist therapy in PD is that said treatment should have a minimal adverse effect on the treatment of PD itself, which is effected by the dopamine agonist therapy. For example: neuroleptics, which can be used to treat dyskinesias, have an adverse effect on the efficiency of the dopamine agonist therapy, for example in parameters associated with cognition, depression and sleep behavior of PD patients. Highly relevant would be an anti-dyskinetic agent that has a positive effect on the treatment of PD itself, e.g. improving parameters associated with cognition.
In the case of prophylactic treatment, the COMBINATION OF THE INVENTION may be used to delay or prevent the onset of dyskinesia.
The term “subject” as used herein refers preferably to a human being, especially to a patient being diagnosed with PD.
The term “therapeutically effective amount” as used herein typically refers to an amount of an active ingredient which, when administered to a subject, is sufficient to provide a therapeutic benefit, e.g. is sufficient for treating, preventing or delaying the progression of dyskinesias associated with dopamine agonist therapy (e.g. the amount provides an amelioration of symptoms, e.g. it leads to a reduction in the scale of involuntary movements).
For the above-mentioned indications (the conditions and disorders) the appropriate dosage of active ingredients will vary depending upon, for example, the compound employed, the host, the mode of administration and the nature and severity of the condition being treated. However, in general, satisfactory results in animals are indicated to be obtained at a daily dosage of from about 0.01 to about 100 mg/kg body weight, e.g. from about 0.1 to about 10 mg/kg body weight or 1 mg/kg of each of active ingredient(s).
In larger mammals, for example humans, an indicated daily dosage is in the range from about 0.1 to about 1000 mg, e.g. from about 1 to about 400 mg or from about 3 to about 100 mg of each of active ingredient(s) conveniently administered, for example, in divided doses up to four times a day (e.g. four times administration per day of the same unit dosage form of the COMBINATION OF THE INVENTION). A physician or clinician of ordinary skill can readily determine and prescribe the appropriate dosage regimen.
Daily dosage of the α7-nAChR activator may be from 0.1 to 1000 mg, e.g. from 3 to 100 mg or from 10 to 50 mg, e.g. 15 mg or 50 mg.
Daily dosage of the mGluR5 antagonist may be from 0.1 to 1000 mg, e.g. from 20 to 500 mg or from 50 to 300 mg, e.g. 200 mg or 300 mg.
Unit dosage forms of the α7-nAChR activator and/or the mGluR5 antagonist may contain 2.5-25 mg p.o.
The invention also provides a combination comprising
(C) at least one active ingredient selected from levodopa, a levodopa decarboxylase inhibitor, a catechol-O-methyl transferase inhibitor, a monoamine oxidase B-inhibitor and a dopamine receptor agonist.
Preferably, said combination is a pharmaceutical composition or a combined pharmaceutical preparation.
In this pharmaceutical composition, the combination partners i.e.
(A) the α7-nAChR activator;
(B) the mGluR5 antagonist; and
(C) at least one active ingredient selected from
i) levodopa,
ii) a dopa decarboxylase inhibitor,
iii) a catechol-O-methyl transferase inhibitor,
iv) a monoamine oxidase B-inhibitor, and
iv) a dopamine agonist
can be administered together, one after the other or separately in one combined unit dosage form or in two separate unit dosage forms. The unit dosage form may also be a fixed combination.
Administration of the dosage forms may be co-cominantly, simultaneously, part-simultaneously, separately or sequentially. The dosage forms of the combination may not necessarily be of the same dosage form and may comprise one or more of:
enteral, e.g. oral (capsule, tablet, solution) or rectal (suppository);
parenteral, e.g. intravenous injection, subcutaneous injection, intramuscular injection, intraperitoneal injection or intramammary injection;
respiratory, e.g. inhalation, intranasal or intratracheal; or
topical, e.g. mucous membrane application or skin application.
In addition, the release profiles of the medicaments may not be the same, for example one or more component of the combination may be of extended release form.
In one embodiment of the invention a specific combination is used. Said combination comprises:
(C) at least one active ingredient selected from the group consisting of levodopa, carbidopa, benserazide tolcapone, entacapone, bromocriptine, pergolide, pramipexole, ropinirole, cabergoline, apomorphine and lisuride.
In one embodiment of the invention a specific combination is used. Said combination comprises:
(C) levodopa; and
(C1) at least one active ingredient selected from the group consisting of carbidopa, benserazide tolcapone, entacapone, bromocriptine, pergolide, pramipexole, ropinirole, cabergoline, apomorphine or lisuride.
An example of said embodiment is a combination of a COMBINATION OF THE INVENTION with levodopa which may further comprise a levodopa decarboxylase inhibitor, such as carbidopa or benserazide.
An example of said embodiment is a combination of a COMBINATION OF THE INVENTION with levodopa and carbidopa.
An example of said embodiment is a combination of a COMBINATION OF THE INVENTION with levodopa and benserazide.
In one embodiment of the invention a specific combination is used. Said combination comprises:
(C) levodopa; carbidopa and entacapone.
An example of said embodiment is a combination of a COMBINATION OF THE INVENTION with Stalevo®.
The invention also provides a product, for example a kit, comprising a COMBINATION OF THE INVENTION and levodopa as a combined preparation for simultaneous, separate or sequential use in therapy. The product may further comprise a levodopa decarboxylase inhibitor, such as carbidopa or benserazide.
The COMBINATION OF THE INVENTION may further be used in the treatment, prevention or delay of progression of movement disorders. Examples of movement disorders are Dystonia, Dyskinesia, Chorea, Restless Legs Syndrome, Tics, Tremor, Myoclonus, Startle, Stiff Person Syndrome, Gait Disorder, PD or Symptomatic Parkinsonism.
“Dystonia” relates to a neurologic movement disorder characterized by sustained muscle contractions that frequently cause twisting or repetitive movements and abnormal, sometimes painful, postures or positions. It may affect any part of the body and may involve any voluntary muscle in the body.
“Dyskinesia” relates to a movement disorder characterized by the difficulty or distortion in performing voluntary movements and the presence of involuntary movements, similar to tics or chorea. Dyskinesia can be anything from a slight tremor of the hands to uncontrollable movement of most commonly the upper body but can also be seen in the lower extremities. Dyskinesia can be also classified as a symptom of several medical disorders and distinguished by the underlying cause.
“Chorea” relates to a movement disorder characterized by brief, quasi-purposeful, irregular contractions that are not repetitive or rhythmic, but appear to flow from one muscle to the next. These ‘dance-like’ movements often occur with athetosis, which adds twisting and writhing movements. Chorea can occur in a variety of conditions and disorders such Huntington's disease, Ataxia telangiectasia or Wilson's disease, among others.
“Restless Legs Syndrome” (or “Wittmaack-Ekbom Syndrome”) relates to a sensory and movement disorder with a profound impact on sleep characterized by an irresistible urge to move the body to stop uncomfortable sensations. Relief with movement of the affected limb—typically the legs and, not uncommonly, the arms—is one of the distinguishing features.
“Tics” relate to involuntary movements or vocalizations that are usually of sudden onset, brief, repetitive, stereotyped but non rhythmical in character, frequently imitating normal behavior, often occurring out of a background of normal activity. Tics can be classified as motor or vocal and can also be categorized as simple or complex. Tics can be classified as transient Tics (e.g. multiple motor and/or vocal tics within a duration between four weeks and twelve months), chronic Tics (e.g. multiple motor or vocal tics being present for more than a year) and Tourette Syndrome.
“Tremors” relate to an involuntary quasi-rhythmic, muscle contraction and relaxation involving to-and-fro movements (oscillations or twitching) of one or more body parts. It is the most common of all involuntary movements and can affect the hands, arms, eyes, face, head, vocal cords, trunk, and legs. Most tremors occur in the hands. In some people, tremor is a symptom of another neurological disorder, including multiple sclerosis, stroke, traumatic brain injury, chronic kidney disease and a number of neurodegenerative diseases that damage or destroy parts of the brainstem or the cerebellum.
“Myoclonus” relates to sudden, brief, shock-like movements, which can be positive or negative. Positive myoclonus results in contraction of a muscle or multiple muscles. Asterixis, or negative myoclonus, occurs with brief momentary loss of agonist muscle tone and subsequent contraction of antagonist muscles, resulting in a flapping motion. These nonsuppressible movements often have a characteristic saw-tooth pattern and usually disappear during sleep.
“Startle” relates to a stereotypical response to a sudden and unexpected stimulus. In most instances, the stimulus is acoustic, but other modalities such as tactile, visual, or vestibular are also effective stimuli. Exaggerated startle, is a feature of various neurologic and psychiatric conditions. Hyperekplexia is an uncommon clinical syndrome that is characterized by brisk and generalized startle in response to trivial (most often acoustic or tactile) stimulation.
“Stiff Person Syndrome” (e.g. Moersch-Woltman Condition) relates to a rare neurologic disorder of unknown etiology characterized by involuntary painful spasms and rigidity of muscles, usually involving the lower back and legs. Sub-variants include Stiff Baby Syndrome and Stiff Limb Syndrome. Prognosis is variable and there is no reliable predictor of speed and severity of disease onset. Muscle tetany may lead to muscle rupture and broken bones, or problems swallowing and breathing in severe cases
“Gait Disorders” relate to an abnormality in the manner or style of walking, which usually results from neuromuscular, arthritic, or other body changes. Gait disorders can be classified according to the system responsible for the abnormal locomotion, according to the underlying disease associated with the abnormal gait or by its phenomenology. Parkinsonian gait disturbances may also be sub-classified as continuous (appearing whenever the patient walks) and episodic (lasting seconds).
“Symptomatic Parkinsonism” relates to conditions which feature clinical manifestations resembling Primary Parkinsonism. Symptomatic Parkinsonism includes, but is not limited to, Postencephalitic Parkinsonism (e.g. caused by viral illness triggering degeneration of nerve cells in substantia nigra), Arteriosclerotic Parkinsonism (caused by damages to brain vessels due to multiple small strokes), Drug-induced Parkinsonism (e.g. antipsychotics, metoclopramide), Parkinsonism caused by Diffuse Lewy Body Disorder (disorder characterized by the presence of Lewy bodies—clumps of alpha-synuclein and ubiquitin protein in neurons), Parkinsonism caused by Multiple System Atrophy (neurodegenerative disorder associated with the degeneration of nerve cells in specific areas of the brain, e.g. Parkinsonism caused by Striatonigral Degeneration) and Parkinsonism caused by Cortico Basal Ganglionic Degeneration (a progressive neurodegenerative disease involving the cerebral cortex and the basal ganglia).
The COMBINATION OF THE INVENTION is especially useful in the treatment, prevention or delay of progression of PD.
The COMBINATION OF THE INVENTION is especially useful in the treatment, prevention or delay of progression of Symptomatic Parkinsonism.
The usefulness of the COMBINATION OF THE INVENTION in the treatment of the above-mentioned disorders, e.g. dyskinesia associated with dopamine agonist therapy in PD, can be confirmed in a range of standard tests including those indicated below.
1. Tests with α7-nAChR Activators
1.1.1. Selectivity of Selected α7-nAChR Agonists Against α4β2-nAChR
Based on the activity/selectivity data shown below it is concluded that said compounds are selective agonists at the α7-nAChR.
To assess α7-nAChR activity, a functional assay was employed using GH3 cells that recombinantly expressed human α7-nAChR. 50000 cells per well were seeded 72 h prior to the experiment on black 96-well plates (Costar) and incubated at 37° C. in a humidified atmosphere (5% CO2/95% air). On the day of the experiment, medium was removed by flicking the plates and replaced with 100 μl growth medium containing 2 mM Fluo-4, (Molecular Probes) in the presence of 2.5 mM probenecid (Sigma). The cells were incubated at 37° C. in a humidified atmosphere (5% CO2/95% air) for 1 h. Plates were flicked to remove excess of Fluo-4, washed twice with Hepes-buffered salt solution (in mM: NaCl 130, KCl 5.4, CaCl2 2, MgSO4 0.8, NaH2PO4 0.9, glucose 25, Hepes 20, pH 7.4; HBS) and refilled with 100 μl of HBS containing antagonist when appropriate. The incubation in the presence of the antagonist lasted 3-5 minutes. Plates were placed in the cell plate stage of a FLIPR device (fluorescent imaging plate reader, Molecular Devices, Sunnyvale, Calif., USA). After recording of the baseline (laser: excitation 488 nm at 1 W, CCD camera opening of 0.4 seconds) the agonists (50 μl) were added to the cell plate using the FLIPR 96-tip pipettor while simultaneously recording the fluorescence. Calcium kinetic data were normalized to the maximal fitted response induced by epibatidine, which is a full agonist at α7-nAChR. Four parameter Hill equations were fitted to the concentration-response. Values of Emax (maximal effect in % compared to the epibatidine response) and EC50 (concentration producing half the maximal effect in μM) were derived from this fit.
Assay described in: D Feuerbach et al, Neuropharmacology (2005), 48, 215-227.
To assess the activity of the compound of the invention on the human neuronal nAChR α4β2, a similar functional assay is carried out using a human epithelial cell line stably expressing the human α4β2 subtype (Michelmore et al., Naunyn-Schmiedeberg's Arch. Pharmacol. (2002) 366, 235).
Based on the pharmacokinetic data shown below it is concluded that the brain concentration of said compounds in mice is beyond (or at least equal) to the compound's EC50 at the α7-nAChR for at least 4 hours following an acute oral dose of 30 μmol/kg.
Compounds were orally (30 pmol/kg) administered. Male mice (30-35g, OF1/ICstrain) were sacrificed at indicated time points after oral administration. Trunk-blood was collected in EDTA-containing tubes and the brain was removed and immediately frozen on dry ice. To 100 μl plasma 10 μl internal standard (1.0 pmol of a compound with solubility and ionization properties similar to test compounds) was added and extracted three times with 500 μl dichloromethane. The combined extracts were then dried under a stream of nitrogen and re-dissolved in 100 μl acetonitrile/water (70% acetonitrile). Brains were weighed and homogenized in water (1:5 w/v). Two 100 μl aliquots of each homogenate+10 μl of internal standard (same standard as used for the plasma samples) were extracted three times with 500 μl dichloromethane and further processed as the plasma samples. Samples were separated on Beckmann high-performance liquid chromatography equipment system with an autosampler (Gilson 233XL). A 10 min linear gradient (10-70%) of acetonitrile containing 0.5% (v/v) formic acid was used to elute the compounds from Nucleosil CC-125/2 C18 reversed phase (Machery&Nagel) column.
The limit of detection (LOD), defined as the lowest concentration of the extracted standard sample with a signal to noise ratio of ˜3.
Based on the functional in-vivo data shown below it is concluded that oral dosing of said compounds at relevant concentrations lead to a specific effect associated with α7-nAChR (i.e. cognition enhancement in the Social Recognition Test in mouse).
Social interactions between two experimental animals are influenced by their degree of familiarity: the better they know each other, the less time they spend on mutual scrutiny at each meeting. In agreement with published data in rats (Mondadori et al., 1993) we have observed (i) that an adult mouse shows a shortened scrutiny of a young conspecific if the two mice are brought together again within a short time interval (e.g. 1 hour), (ii) that this curtailment is attributable to memory processes: it does not occur if the familiar young partner is replaced by a strange (unfamiliar) young mouse on the second occasion and (iii) that the adult mouse's recollection of the previously scrutinized juvenile partner fades with the elapsed time, i.e., after 24 h, scrutiny takes just about as long as at the first encounter. Memory enhancing agents (i.e. oxiracetam) facilitate learning to the extent that the previously met (familiar) partner is still remembered after 24 h, whereas in vehicle treated control animals the memory usually fades after less than 1 hour (Thor and Holloway, 1982) or after 2-3 hours.
Baseline-test: Pairs consisting of one adult and one young mouse were assigned at random to the experimental and control groups. In each pair only the adult mouse was orally treated 1 hour before the trial with either vehicle or the test compound. The duration of active contacts of the adult mouse with the young mouse was manually recorded over a period of 3 min, including the following behavioural, approach-related items: sniffing, nosing, grooming, licking, pawing and playing, anogenital exploration and orientation toward the young mouse; orientation, thereby, was defined as tip of nose of the adult mouse less than approximately 1 cm distant from the young mouse's body.
Re-test: Twenty-four hours after the baseline-test, the adults in each treatment group were confronted again with the previously encountered (familiar) partner, whereas the half of the adult animals were put together with the previously encountered (familiar) partner and the other half with another (unfamiliar) young mouse. Again the duration of active approach-behaviours was recorded during a 3-min period. Prior to re-test no oral injection was given. In the table the reduction in time scrutinizing the familiar partner at time 24 compared with the familiar partner at time 0 minutes is given (value of zero would signify no reduction).
1.2.3. Assessment of Efficacy in a Movement Disorder Model (Antidyskinetic Effect in Parkinsonian Primates)
Based on the in-vivo data in parkinsonian primates shown below it is deduced that:
i) compound A-1 significantly reduces the deficiencies associated with dyskinesia associated with dopamine agonist therapy in Parkinson's Disease (i.e. compound A-1 significantly reduces levodopa-induced dyskinesia);
ii) compound A-1 significantly increases the duration of antiparkinsonian activity associated with administering a combination of a dopamine agonist and compound A-1 (i.e. compound A-1 significantly increases the duration of the antiparkinsonian activity seen for levodopa administration);
iii) a combination of a suboptimal dose of MPEP (Gasparini et al. Neuropharmacology. 1999 38(10):1493-503) and a low dose of compound A-1 (JN403) increases locomotor response; and
iv) a combination of a subthreshold dose of MPEP and a low dose of compound A-1 decreases parkinsonian score.
It is further noted that compound A-1 does not delay the onset of action of levodopa and does not lower the antiparkinsonian activity of levodopa.
Female ovariectomized cynomolgus monkeys (Macaca fascicularis) are used in the assessment. The animals can be rendered parkinsonian by continuous infusion of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) until they develop a stable parkinsonian syndrome. After recuperation, animals are treated daily with levodopa until clear and reproducible dyskinesias are developed.
Monkeys are observed through a one-way screen window in their home cage. They are observed and scored repeatedly at baseline and after a standard s.c. dose of levodopa. Locomotor activity is assessed and followed with an electronic monitoring system. Antiparkinsonian responses are evaluated by measuring the locomotor activity and a Parkinson disability scale (see Hadj Tahar A et al, Clin Neuropharmacol 2000; 23:195-202; and Samadi P et al, Neuropharmacology 2003; 45:954-963). Dyskinesias are closely monitored and scored according to a dyskinesia rating scale (also described in Hadj Tahar A et al; and Samadi P et al) every 15 minutes until the end of the effect. The doses of levodopa are chosen to induce motor activation and reproducible dyskinesia but no excessive agitation.
Monkeys are observed for at least two hours following an oral administration of vehicle. On a subsequent day, the dose of levodopa selected is tested once. The animals are observed (with measures of parkinsonian and dyskinetic scores) for the entire duration of the levodopa effect and are also monitored for locomotor activity. This provides vehicle control values as well as levodopa antiparkinsonian and dyskinesia response data for comparison with combinations of a α7-nAChR agonist/positive allosteric modulator and levodopa. The monkeys are then tested with a α7-nAChR agonist/positive allosteric modulator in combination with a fixed dose of levodopa. A suspension for oral administration of the α7-nAChR agonist/positive allosteric modulator is administered before levodopa. After each dose, the animals are observed (with measures of parkinsonian and dyskinetic scores) for the entire duration of effect and monitored for locomotor activity or any change in behavior (e.g. circling, excitement, lethargy and sleepiness).
Using this protocol, compound A-1 at a dose of 20 mg/kg was tested. Results based on five monkeys (levodopa/benserazide doses: 22.5/50 mg; 65/50 mg; 30/50 mg; 35/50 mg; and 25/50 mg) are shown in
For experiments shown in
The mean parkinsonian score was reduced in said experiments from 9.4 to 8.2 by compound MPEP and to 9.0 by JN403. However, the combination of both compounds reduced the parkinsonian score from 9.4 to 6.9.
2. Tests with mGluR5 Antagonists
Compound E-1 was tested in the above movement disorder model (antidyskinetic effect in parkinsonian primates, see section 1.2.3). Data obtained is published in WO2009047296, in which compound E-1 is termed “Compound A”, and in Gregoire et al (Parkinsonism and Related Disorders (2011), doi:10.1016/j.parkreldis.2011.01.008), where compound E-1 is termed “AFQ056”. The data indicates that compound E-1 is able to reduce L-dopa induced dyskinesias.
Test can be performed as described under section 1.2.3.
Clinical testing of a COMBINATION OF THE INVENTION may be conducted, for example, in one of the following study designs. The skilled physician may look at a number of aspects of patient behaviors and abilities. He will realize that such studies are considered as guidelines and the certain aspects of the studies may be modified and redefined depending on the circumstance and environment, for example.
A patient population, with a normal control is dosed once a day for a week or longer tested. The test is designed to allow for improvement, i.e. that there is a measurable parameter increase of the impaired function The patients are tested at the beginning and at the end of the dosage period and the results are compared and analyzed.
A patient population with a deficit associated with PD and associated disorders e.g. PD, for example, PD levodopa induced Parkinson's dyskinesia is dosed once a day for a week or longer and tested. The test is designed to allow for improvement, I.e. that there is a measurable parameter increase of the impaired function. The patients are tested at the beginning and at the end of the dosage period and the results are compared and analyzed.
The following are further embodiments of the invention:
A combination, which comprises:
(A) at least one low molecular weight nicotinic acetylcholine receptor alpha 7 activator, selected from a nicotinic acetylcholine receptor alpha 7 agonist and a nicotinic acetylcholine receptor alpha 7 positive allosteric modulator, as the first active ingredient; and
(B) at least one low molecular weight metabotropic glutamate receptor 5 antagonist as the second active ingredient;
in which the active ingredients are present in each case in free form or in the form of a pharmaceutically acceptable salt;
for the use as a medicament.
A combination according to embodiment 1 for the use as a medicament, wherein the combination is a combination according to embodiment 4, 4a, 4b, 4c, 4d, 4e, 4f, 5, 5a, 5b, 5c or 5d.
A combination, which comprises:
(A) at least one low molecular weight nicotinic acetylcholine receptor alpha 7 activator, selected from a nicotinic acetylcholine receptor alpha 7 agonist and a nicotinic acetylcholine receptor alpha 7 positive allosteric modulator, as the first active ingredient; and
(B) at least one low molecular weight metabotropic glutamate receptor 5 antagonist as the second active ingredient;
in which the active ingredients are present in each case in free form or in the form of a pharmaceutically acceptable salt;
for use in the treatment, prevention or delay of progression of dyskinesia associated with dopamine agonist therapy in Parkinson's Disease.
A combination according to embodiment 2 for use in the treatment, prevention or delay of progression of dyskinesia associated with dopamine agonist therapy in Parkinson's Disease, wherein the combination is a combination according to embodiment 4, 4a, 4b, 4c, 4d, 4e, 4f, 5, 5a, 5b, 5c or 5d.
A combination, which comprises:
(A) at least one low molecular weight nicotinic acetylcholine receptor alpha 7 activator, selected from a nicotinic acetylcholine receptor alpha 7 agonist and a nicotinic acetylcholine receptor alpha 7 positive allosteric modulator, as the first active ingredient; and
(B) at least one low molecular weight metabotropic glutamate receptor 5 antagonist as the second active ingredient;
in which the active ingredients are present in each case in free form or in the form of a pharmaceutically acceptable salt;
and wherein the combination is not
a combination comprising nicotine and methyl-6-(phenylethynyl)pyridine; or
a combination comprising nicotine and 2-[(1S,2S)-2-carboxycyclopropyl]-3-(9H-xanthen-9-yl)-D-alanine.
A combination according to embodiment 3, wherein the low molecular weight nicotinic acetylcholine receptor alpha 7 activator is an at least 10-fold selective nicotinic acetylcholine receptor alpha 7 agonist having a maximum molecular weight of 500 daltons.
A combination according to embodiment 3, wherein the nicotinic acetylcholine receptor alpha 7 activator is a selective α7-nAChR agonist.
A combination according to embodiment 3, wherein the nicotinic acetylcholine receptor alpha 7 activator is a selective α7-nAChR agonist having a maximum molecular weight of 1500 daltons.
A combination according to embodiment 3, wherein the nicotinic acetylcholine receptor alpha 7 activator is a selective α7-nAChR agonist having a maximum molecular weight of 500 daltons.
A combination according to embodiment 3, wherein the nicotinic acetylcholine receptor alpha 7 activator is a compound selected from Group P1.
A combination according to embodiment 3, wherein the nicotinic acetylcholine receptor alpha 7 activator is a compound selected from Group P2.
A combination according to embodiment 3, wherein the nicotinic acetylcholine receptor alpha 7 activator is a compound selected from Group P3.
A combination according to embodiments 3, 4, 4a, 4b, 4c, 4d, 4e of 4f, wherein the low molecular weight metabotropic glutamate receptor 5 antagonist is an at least 10-fold selective metabotropic glutamate receptor 5 antagonist having a maximum molecular weight of 500 daltons.
A combination according to embodiments 3, 4, 4a, 4b, 4c, 4d, 4e of 4f, wherein the metabotropic glutamate receptor 5 antagonist is a selective metabotropic glutamate receptor 5 antagonist having a maximum molecular weight of 1500 daltons.
A combination according to embodiments 3, 4, 4a, 4b, 4c, 4d, 4e of 4f, wherein the metabotropic glutamate receptor 5 antagonist is a selective metabotropic glutamate receptor 5 antagonist having a maximum molecular weight of 500 daltons.
A combination according to embodiments 3, 4, 4a, 4b, 4c, 4d, 4e of 4f, wherein the metabotropic glutamate receptor 5 antagonist is a compound selected from Group Q1.
A combination according to embodiments 3, 4, 4a, 4b, 4c, 4d, 4e of 4f, wherein the metabotropic glutamate receptor 5 antagonist is a compound selected from Group Q2.
A pharmaceutical composition, which comprises a combination as defined in any of embodiments 3, 4, 4a, 4b, 4c, 4d, 4e, 4f, 5, 5a, 5b, 5c or 5d as active ingredients and at least one pharmaceutically acceptable carrier.
A kit comprising
(a) a low molecular weight nicotinic acetylcholine receptor alpha 7 activator as defined in any of embodiments 1, 3, 4, 4a, 4b, 4c, 4d, 4e, 4f, 5, 5a, 5b, 5c or 5d, in free form or in the form of a pharmaceutically acceptable salt,
(b) a low molecular weight metabotropic glutamate receptor 5 antagonist as defined in claim 1, in free form or in the form of a pharmaceutically acceptable salt,
(c) instructions for the simultaneous, separate or sequential use thereof in the treatment of dyskinesia associated with dopamine agonist therapy in Parkinson's Disease, and
(d) at least one container for containing components (a) and (b).
A commercial package comprising a combination as defined in any of embodiments 1, 3, 4, 4a, 4b, 4c, 4d, 4e, 4f, 5, 5a, 5b, 5c or 5d as active ingredients and written instructions for the simultaneous, separate or sequential use thereof in the treatment of dyskinesia associated with dopamine agonist therapy in Parkinson's Disease.
Use of a combination as defined in any of embodiments 1, 3, 4, 4a, 4b, 4c, 4d, 4e, 4f, 5, 5a, 5b, 5c or 5d for the the treatment, prevention or delay of progression of dyskinesia associated with dopamine agonist therapy in Parkinson's Disease.
A method for the treatment, prevention or delay of progression of dyskinesia associated with dopamine agonist therapy in Parkinson's Disease in a subject in need of such treatment, which comprises administering to said subject a therapeutically effective amount of a combination as defined in any of embodiments 1, 3, 4, 4a, 4b, 4c, 4d, 4e, 4f, 5, 5a, 5b, 5c or 5d.
A method for the treatment, prevention or delay of progression of dyskinesia associated with dopamine agonist therapy in Parkinson's Disease in a subject in need of such treatment, which comprises (i) diagnosing said dyskinesia in said subject and (ii) administering to said subject a therapeutically effective amount of a combination as defined in any of embodiments 1, 3, 4, 4a, 4b, 4c, 4d, 4e, 4f, 5, 5a, 5b, 5c or 5d.
Use of a combination as defined in any of embodiments 1, 3, 4, 4a, 4b, 4c, 4d, 4e, 4f, 5, 5a, 5b, 5c or 5d for the manufacture of a medicament for the treatment, prevention or delay of progression of dyskinesia associated with dopamine agonist therapy in Parkinson's Disease.
A combination as defined in any of embodiments 1, 3, 4, 4a, 4b, 4c, 4d, 4e, 4f, 5, 5a, 5b, 5c or 5d, wherein the combination further comprises at least one active ingredient selected from levodopa, a levodopa decarboxylase inhibitor, a catechol-O-methyl transferase inhibitor, a monoamine oxidase B-inhibitor and a dopamine receptor agonist.
A combination as defined in in any of embodiments 1, 3, 4, 4a, 4b, 4c, 4d, 4e, 4f, 5, 5a, 5b, 5c or 5d, wherein the combination further comprises at least one active ingredient selected from group consisting of levodopa, carbidopa, benserazide tolcapone, entacapone, bromocriptine, pergolide, pramipexole, ropinirole, cabergoline, apomorphine and lisuride.
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/IB2012/051282 | 3/16/2012 | WO | 00 | 4/25/2014 |
| Number | Date | Country | |
|---|---|---|---|
| 61454378 | Mar 2011 | US |
