Classifications

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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
  • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
  • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D277/38—Nitrogen atoms
  • C07D277/44—Acylated amino or imino radicals
  • C07D277/46—Acylated amino or imino radicals by carboxylic acids, or sulfur or nitrogen analogues thereof
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  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/425—Thiazoles
  • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
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  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
  • A61P25/16—Anti-Parkinson drugs
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  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
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  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/24—Antidepressants
• • A—HUMAN NECESSITIES
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  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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  • A61P25/00—Drugs for disorders of the nervous system
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• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
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• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

• the compounds of the present invention are pro-drugs of a class of JV-thiazol-2-yl-benzamide derivatives having affinity for the adenosine 2A (A 2 A) receptor.
• the compounds revert into A 2A -antagonists, which are useful in the treatment of neurological and psychiatric disorders where an A 2A -receptor is implicated.
• Examples of diseases where an A 2A -receptor is implicated are Parkinson's Disease (PD), Alzheimer's Disease, Huntington's disease (HD), epilepsies, cerebral ischemia, haemorrhagic stroke, neonatal ischemia and hypoxia, subarachnoid haemorrhage, traumatic brain injury, brain damage following cardiac arrest, and for the treatment of depression and psychosis disorders.
• Parkinson's Disease PD
• Alzheimer's Disease Alzheimer's Disease
• Huntington's disease HD
• epilepsies cerebral ischemia
• haemorrhagic stroke neonatal ischemia and hypoxia
• subarachnoid haemorrhage subarachnoid haemorrhage
• traumatic brain injury brain damage following cardiac arrest
• brain damage following cardiac arrest and for the treatment of depression and psychosis disorders.
• Adenosine is present in all cells, including neurons and glia, of mammalian organisms where it modulates a variety of important physiological processes.
• the action of adenosine is mediated by specific receptors, which belong to the family of G protein-coupled receptors.
• Four adenosine receptors have been cloned and characterized, A 1 , A 2A , A 2 B and A 3 (Fredholm BB. et al., Pharmacol Rev., 1994, 46: 143-156).
• the main intracellular signaling pathways involve the formation of cAMP, with A 1 and A 3 receptors causing inhibition of adenylate cyclase and A 2A and A 2 B receptors activating it (Olah M., Stiles GL., Pharmacol, Ther., 2000, 85: 55-75).
• the receptor of interest here, A 2A is predominantly found in dopamine-rich areas, such as the basal ganglia components; the striatum and the globus pallidus, in various mammals, including humans.
• the basal ganglia, with the striatum as a central component, are involved in integration of cortical, thalamic and limbic information to produce motor behaviours (for review see Svenningsson P.
• a 2A and dopamine D 2 receptors are found closely co-localized on the striatopallidal GABAergic neurons, forming the so-called indirect output pathway from the striatum, which is involved in motor inhibition.
• a 2A receptors is believed to contribute to control of motor behaviour by modulating the neurotransmission of GABA, dopamine, acetylcholine and glutamate in various ways.
• PD Parkinson's disease
• a 2A antagonists may be useful as monotherapy for the treatment of Parkinson's disease.
• a 2A antagonists may be capable of enhancing the effect of clinically used dopamine agonists and increase the time- period of dopaminergic drug response.
• D 2 and A 2A receptors can be clearly exemplified in models of catalepsy, where D 2 receptor antagonists as well as A 2A receptor agonists induce catalepsy, which is counteracted by A 2A receptor antagonists and D 2 receptor agonists, respectively (see Svenningsson P. et al., Prog. Neurobiol., 1999, 59: 355-396 and Refs therein).
• KW-6002 significantly improves motor impairment induced in non-human primates by MPTP, without causing dyskinesias, that is commonly described for long-term treatment with the dopamine agonist L-dopa (Kanda T. et al., Ann. Neurol, 1998, 43: 507- 513; Grondin R. et al, Neurology, 1999, 52: 1673-1677; Kanda T. et al., Exp. Neurol, 2000, 162: 321-327).
• a 2A receptor antagonists show great potential as future drugs for long-term medication of PD patients, since they seem not only to reverse the motor impairment but also to slow down or stop the progress of the disease by promoting cell survival.
• a 2A receptor antagonists have recently been reported in in vivo and in vitro models of different neurodegenerative diseases (for review see: Wardas J., Pol. J. Pharmacol, 2002, 54: 313-26 and Stone TW., Adv. Exp. Med. Biol, imi, 513: 249-80).
• a 2A antagonists have been shown to be neuroprotective in different PD models like in MPTP (1- methyl-4 phenyl- 1, 2,3, 6-tetrahydropyridine) treated mice and 6-OHDA-lesioned rats.
• MPTP 1- methyl-4 phenyl- 1, 2,3, 6-tetrahydropyridine
• KW-6002 prevented functional loss of dopaminergic nerve terminals in the striatum as well as prevented gliosis normally induced around degenerating neurons (Ikeda K.
• a 2A receptor antagonists have shown to decrease neuronal cell death after cerebral ischemia in neonatal and adult rats and gerbils (Gao Y., Phillis JW., Life ScI, 1994, 55(3): PL61-5; Monopoli A. et al., Neuroreport, 1998, 9(17): 3955-9).
• a 2A knock out animals have been reported to be protected from neonatal hypoxic ischemia and transient focal ischemia (Bona E. et al., Neuropharmacology, 1997, 36(9): 1327-1338; Chen JF.
• a 2A antagonists has also been reported in primary astrocytes, in a rat model of bFGF induced astrogliosis, an amyloid beta peptide 25-35 induced neurotoxicity in cerebral granule cells (CGCs) and model of QA induced neuronal cell death in rat organotypic slice cultures (Brambilla R. et al, GUa., 2003, 43: 190-194; Dall'Igna OP. et al., Br. J. Pharmacol, 2003, 138: 1207-1209; Tebano MT,. et al., Eur. J. Pharmacol, 2002, 253-257).
• Adenosine is involved in modulation of seizures (Dragunow M. et al., Epilepsia, 1985, 26: 480-487), and anti-convulsive effects are mainly mediated via A 1 .
• a 2A -antagonist can modulate receptor interaction (O'Kane EM., Stone TW., Eur. J. Pharm., 1998, 362: 17-25) and an A 2A -antagonist could thereby unmask protective Aj activity in epilepsy (De Sarro G. et al., Eur. J. Pharmacol, 1999, 371(2-3): 137-145; Ongini E. et al., Ann N Y Acad ScI, 1997, 825: 30-48.)
• a 2A receptor antagonists can efficiently protect different neurons from various forms of insult induced neurodegeration (Abbracchio MP., Cattabeni F., Ann N Y Acad Set, 1999, 890: 79-92; Ongini E. et al., Ann N YAcadSci, 1997, 825: 30-48).
• Adenosine and its analogues induce "depressant-like" effects in animal models of psychiatric disorders (Minor TR. et al., Behav Neurosci, 1994, 108: 265-276; Woodson JC. et al., Behav Neurosci., 1998, 112: 399-409). Moreover, these behavioural deficits were found to be reversed by adenosine A 2A receptor antagonists (Minor TR. et al., Behav. Brain Res., 2001, 120: 203-212). Further studies have shown that treatment with adenosine or 2- chloroadenosine increased immobility time in the mouse forced swimming test, another animal model of depression generally considered reliable (Porsolt RD. et al., Arch Int Pharmacodyn Ther. , 1977, 229: 327-336).
• the A 2A receptor antagonists SCH58261 and KW6002 reduced the total immobility time in the mouse tail suspension test (El Yacoubi M. et al., Br J Pharmacol, 2001, 134: 68-77).
• the antagonists SCH58261 and ZM241385 4-(2-[7-amino-2-(2-ft ⁇ ryl)[l,2,4]triazolo[2,3-a][l,3,5]triazin-5-ylamino]- ethyl)phenol were also found to reduce immobility when administered to mice previously screened for having high immobility time, while SCH58261 reduced immobility of mice that were selectively bred for their "helplessness" in this model (El Yacoubi M. et al., Br. J. Pharmacol, 2001, 134: 68-77).
• a 2A knock-out mice show that these animals show a blunted response to psycho-stimulants such as amphetamine and cocaine, despite the fact that their expression and binding affinities of Dl and D2 receptors are unaffected (Chen JF. et al., Neurosci, 2000, 97: 195-204). Moreover, inactivation Of A 2A receptors has been shown to selectively attenuate amphetamine-induced behavioural sensitisation (Chen JF. et al., Neuropsychopharmacol , 2003, 28: 1086-1095). In addition, A 2A knockout mice show reduced startle and PPI of the acoustic startle (Wang JH. et al., Behav.
• adenosine A 2A receptor antagonists by specifically modulating mesostriatal or mesocorticolimbic dopaminergic pathways, may possess antidepressant and/or antipsychotic properties.
• the objective of the present invention is to provide pro-drugs with improved aqueous solubility of compounds, which are antagonists at the A 2A receptor.
• the present invention relates to a compound with formula I
• R 1 -R 4 are independently selected from hydrogen, halogen, C 1-6 -alkyl and Ci -6 -alkoxy;
• R 5 is selected from the group consisting of C 1-8 -alkyl, C ⁇ s-cycloalkyl-d-e-alkyl, C 3-8 - cycloalkyl and C 1-6 -alkyl-phenyl;
• R 8 and R 9 are independently selected from the group consisting of hydrogen, halogen and C 1- 6 -alkyl;
• A is a solvating group
• B is a linking moiety or a bond; or pharmaceutically acceptable addition salts thereof.
• the invention in further aspects relates to a compounds with formula I as defined above, which compound revert under physiological conditions into a compound with general formula
• the present invention relates to the use of a compound with formula I as defined above, for the manufacture of a medicament for the treatment of a disease where an A 2A -receptor is implicated.
• the present invention relates to a pharmaceutical composition
• a pharmaceutical composition comprising a compound with formula I as defined above.
• the present invention relates to a method of treating a disease where an A 2A -receptor is implicated, comprising administration of a therapeutically acceptable amount of a compound with formula I, as defined above.
• WO 2005/039572 describes iV-thiazol-2-yl-benzamide derivatives having affinity for the adenosine 2A (A 2A ) receptor.
• a 2A adenosine 2A
• the inventors have now found that some iV-thiazol-2-yl- benzamide derivatives having high affinity for the A 2A receptor as A 2A antagonists, are characterized by low aqueous solubility and that these compounds can be prepared as bio- reversible pro-drugs with significantly improved aqueous solubility.
• aqueous solubility of potential drug candidates may severely hamper their development into medicaments.
• preclinical toxicology and safety studies of a drug candidate requires dose escalation to obtain high exposure levels, and therefore, these studies may by hampered by a low solubility of the drug candidate.
• Derivatisation of a drug as a bio-reversible pro-drug is a means of overcoming various barriers for a drug to reach its site of action (for a general reference, see: Design of Pro-drugs, ed. H. Bundgaard, Elsevier, Amsterdam, 1985; also see Ettmayer P. et al., J Med. Chem.,
• Some drugs or drug candidates have been derivatised as esters of amino acids or phosphoric acid, either via a linker (e.g. Varia S.A. and Stella V.J. J. Pharm. Sci.
• glucose conjugates have been shown to have increased absorption characteristics (Mizuma T. et al Biochemical Pharmacology 1992, 43:9, 2037-39.
• an A 2A antagonist has previously been derivatised as a prodrug (Sauer R. et al J. Med. Chem
• the present invention relates to compounds with formula I as defined above.
• the invention relates to compounds with formula I as defined herein, wherein R 1 is hydrogen or a C 1-6 -alkoxy, e.g. methoxy.
• R 2 is selected from the group consisting of hydrogen, halogen, e.g. fluoro, chloro or bromo, C ⁇ -alky!, e.g. d- 3 -alkyl e.g. methyl, and C 1-6 -alkoxy, e.g. methoxy.
• R 3 is hydrogen.
• the invention further relates to compounds with formula I as defined herein, wherein R 4 is hydrogen or halogen, e.g. fluoro or chloro.
• the present invention relates to compounds with formula I as defined herein, wherein R 1 -R 4 are independently selected from hydrogen, halogen, e.g. fluoro, chloro or bromo, C 1-6 -alkyl, e.g. C 1-3 -alkyl, e.g. methyl, and C 1-6 -alkoxy, e.g. methoxy.
• R 1 -R 4 are independently selected from hydrogen, halogen, e.g. fluoro, chloro or bromo, C 1-6 -alkyl, e.g. C 1-3 -alkyl, e.g. methyl, and C 1-6 -alkoxy, e.g. methoxy.
• R 1 and R 3 are independently selected from the group consisting of hydrogen and C 1-6 -alkoxy, e.g. C 1-3 -alkoxy, e.g. methoxy.
• One embodiment of the invention relates to compounds of formula I as defined herein wherein both R 1 and R 3 are hydrogen.
• one or both of R 1 and R 3 is a C 1-6 -alkoxy, e.g. C 1-3 -alkoxy, e.g. methoxy, while both R 2 and R 4 are hydrogen.
• the invention also relates to compounds of the invention, characterised in that R 2 and R 4 are independently selected from the group consisting of hydrogen, halogen, e.g. chloro or fluoro, and C 1-6 -alkyl, e.g. Ci- 3 -alkyl, e.g. methyl.
• R 2 and R 4 are independently selected from halogen, e.g. fluoro or chloro, and C 1-6 -alkyl, e.g. C 1-3 -alkyl, e.g. methyl, and R 1 and R 3 are hydrogen.
• both R 2 and R 4 are hydrogen.
• the present invention relates to compounds with formula I as defined herein, wherein R 1 is C 1-6 alkoxy, e.g. C 1-3 alkoxy, e.g. methoxy, and R 4 is selected from the group consisting of halogen, e.g. fluoro or chloro, and C 1-6 -alkyl, e.g. C 1-3 -alkyl, e.g. methyl.
• R 1 is a C 1-6 -alkoxy, e.g. C 1-3 -alkoxy, e.g. methoxy
• R 4 is a halogen, e.g. fluoro or chloro, or a d- 6 -alkyl, e.g. a Ci-3-alkyl, e.g. methyl
• R 2 and R 3 are hydrogen.
• the present invention relates to compounds with formula I as defined herein, wherein R 1 is C 1-6 -alkoxy, e.g. C 1-3 -alkoxy, e.g. methoxy and R 2 is selected from the group consisting of halogen, e.g. fluoro or chloro, and C 1-6 -alkyl, e.g. C 1-3 -alkyl, e.g. methyl.
• R 1 is C 1-6 -alkoxy, e.g. C 1-3 -alkoxy, e.g.
• R 2 and R 4 are independently selected from the group consisting of halogen, e.g. fluoro or chloro, and C 1-6 - alkyl, e.g. Ci. 3 -a.kyl, e.g. methyl.
• the present invention relates to compounds with formula I as defined herein, wherein R 5 is selected from the group consisting of C 1-8 -alkyl, preferably C 3-8 - alkyl and even more preferred C 4-8 -alkyl which, preferably, is branched at the ⁇ -position, C 3-8 - cycloalkyl-Ci -6 -alkyl, preferably Cs-s-cycloalkyl-methyl, C 3-8 -cycloalkyl and C 1-6 -alkyl- phenyl, preferably methylphenyl.
• R 5 is a C 4-8 -alkyl branched at the ⁇ -position, e.g. neopentyl or isobutyl.
• the present invention relates to compounds with formula I as defined herein, wherein R 8 -R 9 are independently selected from the group consisting of hydrogen, halogen, preferably fluoro or chloro, and C 1-6 -alkyl, e.g. C 1-3 -alkyl, preferably methyl.
• the present invention relates to compounds with formula I as defined herein, wherein both R 8 and R 9 are hydrogen.
• the solvating group A is a group capable of supplying improved aqueous solubility of said compound I compared to the corresponding compound with formula V as defined herein.
• B of Compound I is a linking moiety or a bond.
• the invention also relates to compounds of the invention, wherein the construct A-B- of said prodrug of formula I is capable of providing improved aqueous solubility of said compound I, compared to the corresponding compound with formula V as defined herein, and in which construct A-B- in the context of Compound I, one or more bonds will be cleaved under physiological conditions, to release said compound with formula V.
• A-B- of formula I is a phosphoric acid mono methylenyl ester [i.e. a mono methylenyl ester of phosphoric acid, e.g. as A-B- in the following compound of formula I: "Phosphoric acid mono- ⁇ 2-[(E/Z)-4-(3,3-dimethyl- butyrylamino)-benzoylimino]-thiazol-3-ylmethyl ⁇ ester"] and Z of formula I is, e.g., a group with formula II as defined herein.
• the present invention relates to compounds with formula I as defined herein, wherein A is a solvating group selected from compounds containing at least two functionalities, wherein one of said functionalities is a ionisable functionality, and another of said functionalities is a functionality which can form a bond to B; or A is selected from compounds containing a suitable number of hydroxy functionalities, and a functionality which can form a bond to B.
• the invention also relates to compounds with formula I as defined herein, wherein A is a solvating group selected from the group consisting of: N-unsubstituted or iV-mono-, JV-di-, or iV-tri-substituted amino acids, di-amines, mono-, di- or tri-phosphates or esters thereof and/or salts thereof, sulfonic acids or salts thereof, di-carboxylic acids or salts thereof, O- or N- glycosides, polyalcohols including alditols and ketols; or combinations thereof, such as glycosylated amino acids or glycosylated phosphates.
• A is a solvating group selected from the group consisting of: N-unsubstituted or iV-mono-, JV-di-, or iV-tri-substituted amino acids, di-amines, mono-, di- or tri-phosphates or esters thereof and/or salts
• the present invention relates to compounds with formula I as defined herein, wherein A is a solvating group selected from iV-unsubstituted, iV-mono- or JV-di-substituted amino acids (e.g. selected from the group consisting of the 20 naturally occurring biogenic amino acids or TV- mono- or dialkylated analogues hereof, 4-carboxy- piperidine, or ⁇ -methyl valine), mono-phosphate mono esters, or salts thereof, or A is a polyalcohol (e.g. glycerol) or a carbohydrate (e.g. glucose).
• A is a solvating group selected from iV-unsubstituted, iV-mono- or JV-di-substituted amino acids (e.g. selected from the group consisting of the 20 naturally occurring biogenic amino acids or TV- mono- or dialkylated analogues hereof, 4-carboxy- piperidine, or ⁇ -methyl
• the present invention relates to compounds with formula I as defined herein, wherein B is a linking moiety with formula III, IV or IVa
• the present invention relates to compounds with formula I as defined herein, wherein B is a linking moiety with formula III or IV.
• the present invention relates to compounds with formula I as defined herein, where B is a linking moiety with formula III or IV
• the present invention relates to compounds with formula I as defined herein, wherein Z is a group with formula II and B is a linking moiety with formula III or IV, provided that when B is a linking moiety with formula III, A is attached via a carbonyl or a hetero carbonyl group, or as an acetal or ketal; and provided that when B is a linking moiety with formula IV, A is attached via a nitrogen or an oxygen atom; wherein R 6"7 are independently selected from hydrogen and C 1-6 -alkyl, preferably methyl; and * indicates the atom attached to Z, and # indicates the atom attached to A.
• the present invention relates to compounds with formula I as defined herein, wherein B is a linking moiety with formula III or IV and both R 6 and R 7 are hydrogen or R 6 is hydrogen and R 7 is methyl. In yet another particular embodiment the present invention relates to compounds with formula I as defined herein, wherein B is a linking moiety with formula III or IV and R 6"7 are hydrogen.
• the present invention relates to compounds with formula I as defined herein where B is a linking moiety with formula IVa
• R 6"7 are independently selected from hydrogen and Ci. 6 -alkyl 5 e.g. Ci- 3 -alkyl, preferably methyl, provided that R 6 and R 7 are not both hydrogen; and * indicates the atom attached to Z, and # indicates the atom attached to A.
• the present invention relates to compounds with formula I as defined herein, wherein B is a linking moiety with formula IVa and R 6 is hydrogen and R 7 is methyl.
• the present invention relates to compounds with formula I as defined herein, wherein B is a bond, provided that A is a carbohydrate attached via the anomeric carbon atom,
• the present invention relates to compounds with formula I as defined herein, wherein Z is a group with formula II and B is a bond, provided that A is a carbohydrate attached via the anomeric carbon atom.
• the present invention relates to a compound with formula I as defined above, wherein one or more bonds of said compound are degraded, e.g. enzymatically or chemically, under physiological conditions, and that upon said degradation a compound with formula V,
• the compound of the invention with formula I as defined herein revert under physiological conditions into a A 2A receptor antagonist with the general formula V, preferably having a human A 2A binding affinity (Kj) of 200 nM or less, more preferred of 50 nM or less, and most preferred of 10 nM or less.
• Kj human A 2A binding affinity
• the invention relates to compounds with formula I as defined herein, which revert under physiological conditions into A 2A receptor ligands with the general formula V, preferably having a human A 2A binding affinity (Kj) of 200 nM or less, more preferred of 50 nM or less, and most preferred of 10 nM or less.
• Kj human A 2A binding affinity
• the compound I with formula I as defined herein has an aqueous solubility which is at least 2 or at least 5 or at least 10 or at least 20 times higher than compared to the corresponding compound V.
• V is selected from the group consisting of: 4-(3,3-Dimethyl-butyrylamino)-N-thiazol-2-yl-benzamide; 3-Chloro-4-(2-cyclopentyl-acetylamino)-N-thiazol-2-yl-henzamide; 3-Bromo-4-(3,3-dimethyl-butyrylamino)-N-thiazol-2-yl-benzamide; 4-(3,3-Dimethyl-butyrylamino)-3,5-difluoro-N-thiazol-2-yl ⁇ benzamide; 4-(3,3-Dimethyl-butyrylamino)-3-fluoro-N-thiazol-2-yl-benzamide; 4-(3,3-Dimethyl-butyrylarnino)-3-methyl-N-N-
• Particular compounds of the invention are a compound of formula I or a salt thereof selected from the group consisting of:
• Piperidine-4-carboxylic acid 2-[(E/Z)-5-chloro-4-(cyclopentanecarbonyl-amino)-2-methoxy- benzoylimino]-thiazol-3-ylmethyl ester; 3 -Amino-propionic acid 2-[(E/Z)-4-(3, 3-dimethyl-butyrylamino)-3, 5-difluoro-benzoylimino]- thiazol-3-ylmethyl ester;
• One embodiment of the invention relates to the use of a compound according to the present invention for the manufacture of a medicament for the treatment of a disease where an A 2A - receptor is implicated, e.g. a disease described herein.
• the invention also relates to the use of a compound of the invention for the manufacture of a medicament for the treatment in a patient with Parkinson's disease of a condition selected from the group consisting of RLS, depression, cognitive deficits and memory problems.
• the invention further relates to a method of treating or preventing a disease or disorder where an A 2A -receptor is implicated, comprising administration of a therapeutically acceptable amount of a compound of the invention.
• the invention relates to a method of treating a disease or a disorder selected from the group consisting of Parkinson's Disease, Alzheimer's Disease, Huntington's disease, epilepsies, cerebral ischemia, haemorrhagic stroke, neonatal ischemia and hypoxia, subarachnoid haemorrhage, traumatic brain injury, brain damage following cardiac arrest, depression, somnolence, narcolepsy, pain, Attention Deficit Hyperactivity Disorder (ADHD), and psychosis disorders, e.g. schizophrenia, comprising administration of a therapeutically acceptable amount of a compound of the invention.
• a disease or a disorder selected from the group consisting of Parkinson's Disease, Alzheimer's Disease, Huntington's disease, epilepsies, cerebral ischemia, haemorrhagic stroke, neonatal ischemia and hypoxia, subarachnoid haemorrhage, traumatic brain injury, brain damage following cardiac arrest, depression, somnolence, narcolepsy, pain, Attention De
• the invention relates to a method of treating or preventing Parkinson's Disease comprising administration of a therapeutically acceptable amount of a compound of the invention.
• Further embodiment of the invention relates to the use of a compound of the invention for symptomatic treatment of early Parkinson's disease as monotherapy.
• the invention further relates to the use of a Compound of the invention as adjunct to another medicament for Parkinson disease, e.g. levodopa, in advanced Parkinson's disease, thereby, e.g., increasing the time-period of dopaminergic drug response.
• a further aspect of the invention relates to the use of a compound V, wherein V, i.e. including R 1 -R 5 and R 8 -R 9 , is as defined herein for compound I,
• V for the manufacture of a medicament for the treatment of a disease selected from the group consisting of RLS, schizophrenia, abuse, e.g. alcohol abuse, migraine, pain, somnolence, narcolepsy, ADHD, neurodegenerative diseases, and cognitive deficits, memory problems or for enhancement of cognition or as a neuroprotective.
• a disease selected from the group consisting of RLS, schizophrenia, abuse, e.g. alcohol abuse, migraine, pain, somnolence, narcolepsy, ADHD, neurodegenerative diseases, and cognitive deficits, memory problems or for enhancement of cognition or as a neuroprotective.
• the invention also relates to the use of compound V as defined above for the manufacture of a medicament for the treatment in a patient with Parkinson's disease of a condition selected from the group consisting of RLS, depression, cognitive deficits and memory problems. Further embodiment of the invention relates to the use of a use of a compound V as defined herein for symptomatic treatment of early Parkinson's disease as monotherapy. The invention further relates to the use of a Compound of the invention as adjunct to another medicament for Parkinson disease, e.g. levodopa (L-dopa), at advanced Parkinson's disease, thereby, e.g., increasing the time-period of dopaminergic drug response.
• L-dopa levodopa
• the compound V is selected from the group consisting of
• treatment include prevention or treatment or relief as the case may be.
• disease may mean a disorder or disease as the case may be.
• the Compound may, e.g., be in the form of a salt.
• C 1-6 -alkyl refers to a branched or unbranched alkyl group having from one to six carbon atoms inclusive, such as methyl, ethyl, 1 -propyl, 2- ⁇ ropyl, 1 -butyl, 2-butyl, 2-methyl- 2-propyl, and 2-methyl-l -propyl.
• d-s-alkyl refers similarly to branched or unbranched alkyl group having from one to eight carbon atoms inclusive.
• C 3-8 -cycloalkyl designates a monocyclic or bicyclic carbocycle having three to eight C-atoms, such as cyclopropyl, cyclopentyl, cyclohexyl, etc.
• Halogen means fluoro, chloro, bromo or iodo.
• C 1-6 -alkoxy, C 3-8 -cycloalkyl-C 1-6 -alkyl designate such groups in which the C 1-6 - alkyl and the C 3-8 -cycloalkyl group are as defined above.
• the acid addition salts of the compounds of the invention are pharmaceutically acceptable salts formed with non-toxic acids.
• organic salts are those with maleic, fumaric, benzoic, ascorbic, succinic, oxalic, bis-methylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic and theophylline acetic acids, as well as the 8-halotheophyllines, for example 8-bromotheophylline.
• inorganic salts are those with hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitric acids.
• the base addition salts of the compounds of the invention are pharmaceutically acceptable salts formed with non-toxic bases.
• Exemplary of such base addition salts include salts with alkali metals (e.g. sodium, potassium); salts with alkaline earth metals (e.g. calcium, magnesium); ammonium salts; salts with organic amines and the like.
• solvating group means any group, which can supply improved aqueous solubility to a compound with formula V, upon conjugation to a compound with formula V as described above.
• linking moiety means any construct, which can serve to connect A and Z as defined above, characterized in that upon conversion of a pro-drug with formula I under physiological conditions, a compound with formula V will be released.
• physiological conditions means any set of chemical or enzymatic conditions, which can be encountered in a living mammalian organism.
• exemplary of such chemical or enzymatic conditions are the chemical and enzymatic conditions of the gastro-intestinal tract, i.e. the stomach, intestinal lumen and at the gut wall; in blood; or various tissues or organs such as the liver.
• amino acid means any chemical compound, which contains a carboxylic acid functionality and an amino functionality, such as an a-cyclic or cyclic alkyl-amine, or an aromatic ring containing a nitrogen atom.
• di-amine means any compound, which contains an amino functionality, which can form a bond to B, and an ionisable amino functionality.
• hetero carbonyl means any equivalent of the carbonyl group; such as a carbon atom connected to a heteroatom other than oxygen via a double bond; or a heteroatom, such as phosphorous or sulphur, connected to an oxygen atom via a double bond.
• E/Z wherein E and Z have the standard meanings "entalle” and “zusammen”, means a pure double bond stereo isomer of unknown geometry, or a mixture of stereoisomers in any ratio.
• compositions of this invention may be administered by any suitable route, for example orally in the form of tablets, capsules, powders, syrups, etc., or parenterally in the form of solutions for injection.
• suitable route for example orally in the form of tablets, capsules, powders, syrups, etc.
• parenterally in the form of solutions for injection.
• methods well known in the art may be used, and any pharmaceutically acceptable carriers, diluents, excipients or other additives normally used in the art may be used.
• the compounds of the invention are administered in unit dosage form containing said compounds in an amount of about 0.01 to 100 mg.
• the total daily dose is usually in the range of about 0.05 - 500 mg, and most preferably about 0.1 to 50 mg of the active compound of the invention.
• the pharmaceutical formulations of the invention may be prepared by conventional methods in the art.
• Tablets may be prepared by mixing the active ingredient with ordinary adjuvants and/or diluents and subsequently compressing the mixture in a conventional tabletting machine.
• adjuvants or diluents comprise: Corn starch, potato starch, talcum, magnesium stearate, gelatine, lactose, gums, and the like. Any other adjuvants or additives usually used for such purposes such as colourings, flavourings, preservatives etc. may be used provided that they are compatible with the active ingredients.
• Solutions for injections may be prepared by dissolving the active ingredient and possible additives in a part of the solvent for injection, preferably sterile water, adjusting the solution to the desired volume, sterilising the solution and filling it in suitable ampoules or vials.
• Any suitable additive conventionally used in the art may be added, such as tonicity agents, preservatives, antioxidants, etc.
• the compounds of the invention may be prepared by the following general methods:
• A' is a suitably protected form of A, and A is as described above, to release a compound with formula I as described above.
• Deprotection of compounds with formula VIII may be performed by standard procedures known to chemists skilled in the art. This includes deprotection of compounds with formula VIII, in which said suitable protecting group(s) are acid labile, by treatment with a suitable acid in a suitable solvent at a suitable temperature, such as i.e. HCl in diethyl ether at 20-40 0 C, or trifluoroacetic acid in dichloromethane at 20-40 °C, followed by evaporation of solvent and excess acid.
• deprotection of compounds with formula VIII, in which said suitable protecting group(s) are base labile includes treatment with a suitable base such as sodium methoxide in methanol at 20-40 0 C, followed by neutralization with a suitable acid, such as acidic ion exchange resins.
• a suitable base such as sodium methoxide in methanol at 20-40 0 C
• a suitable acid such as acidic ion exchange resins.
• A-B-Z I wherein Z and B are as described above, and A is an iV-unsubstituted or iV-mono-substituted amino acid, with an alkylating agent such as an aldehyde in the presence of a reducing agent such as sodium cyanoborohydride (NaCNBH 4 ), in a suitable solvent such as methanol (MeOH), at a suitable temperature such as room temperature.
• a reducing agent such as sodium cyanoborohydride (NaCNBH 4 )
• a suitable solvent such as methanol (MeOH)
• R 1 - R 5 and R 8 - R 9 are as described above, with a compound A' -B-E under basic conditions, wherein A' is a suitably protected from of A, and A and B are as defined above, and where E is attached to the atom in B with label *, and E is a leaving group such as e.g. chloride.
• reaction of compounds with formula V with a compound A' -B-E may be performed by Standard procedures known to chemists skilled in the art. This includes deprotonation of compounds with formula V by reaction with a suitable base such as sodium hydride (NaH) in a suitable solvent such as dimethyl formamide (DMF) at a suitable temperature such as 20-60 °C, or l,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in tetrahydrofurane (THF) at 60 0 C, followed by addition of A' -B-E.
• a suitable base such as sodium hydride (NaH) in a suitable solvent such as dimethyl formamide (DMF) at a suitable temperature such as 20-60 °C, or l,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in tetrahydrofurane (THF) at 60 0 C
• DMF dimethyl formamide
• DBU
• R 1 - R 5 and R 8 - R 9 are as described above, with a compound A'-H, wherein A' is a suitably protected form of A, and A is as defined above and H is a proton.
• reaction of compounds with formula VII with a compound A'-H may be performed by standard procedures known to chemists skilled in the art. This includes deprotonation of compounds A'-H by reaction with a suitable base such as diisopropylethylamine, in a suitable solvent such as THF 5 followed by addition of a compound with formula VII, at a suitable temperature such as 20-50 °C, or by reaction of compounds A'-H with a compound with formula VII in the presence of a suitable catalyst such as silver trifluorosulphonate (AgOTf), in a suitable solvent such as dichloromethane, at a suitable temperature, such as -78 0 C - 20 0 C.
• a suitable base such as diisopropylethylamine
• THF 5 a suitable solvent
• a suitable temperature such as 20-50 °C
• a suitable catalyst such as silver trifluorosulphonate (AgOTf)
• AgOTf silver trifluorosulphonate
• reaction of compounds with formula V with a compound A' -E may be performed by standard procedures known to chemists skilled in the art. This includes reaction of compounds A' -E with a compound with formula V in the presence of a suitable catalyst such as AgOTf, in a suitable solvent such as dichloromethane, at a suitable temperature, such as -78 °C-20 0 C.
• a suitable catalyst such as AgOTf
• a suitable solvent such as dichloromethane
• R 1 - R 4 and R 8 - R 9 are as described above, with a carboxylic acid R 5 -COOH or carboxylic acid chloride R 5 -COC1, wherein R 5 is as defined above.
• the coupling of compounds with formula VI with carboxylic acids R 5 -COOH may be performed by standard procedures known to chemists skilled in the art. This includes coupling in the presence of a uranium salt coupling reagent and diisopropyethylamine (DIPEA), at temperatures between 20-80 0 C, in a suitable polar or apolar solvent such as iV-methyl pyrrolidinone (NMP) or 1,2-dichloroethane.
• DIPEA diisopropyethylamine
• NMP iV-methyl pyrrolidinone
• the coupling of compounds with formula VI with carboxylic acid chlorides R 5 -COC1 may be performed by standard procedures known to chemists skilled in the art. This includes coupling of starting materials with formula VI with carboxylic acid chlorides R 5 -COC1 in the presence of a suitable base such as pyridine at temperatures between 20-60 °C in a suitable solvent such as 1,2-dichloroethane
• the amino acid salt thus formed is next reacted with a suitable reagent such as bromochloromethane or chloromethylene chlorosulfonic acid in a suitable solvent such as dimethoxyethane at a suitable temperature such as room temperature, or under phase transfer conditions in a suitable solvent mixture such as a mixture of water and dichloromethane, at a suitable temperature such as room temperature.
• a suitable reagent such as bromochloromethane or chloromethylene chlorosulfonic acid in a suitable solvent such as dimethoxyethane
• a suitable solvent mixture such as a mixture of water and dichloromethane
• the compounds of formula VII 5 wherein R 1 - R 4 and R 8 - R 9 are as described above can be prepared by reaction of a compound with formula V, wherein R 1 - R 5 and R 8 - R 9 are as described above, with a substance ClCH 2 -E, wherein E is a suitable leaving group, for example bromine or chlorosulfonate, in the presence of a suitable base such as NaH in a suitable solvent such as DMF at a suitable temperature such as 20-60 °C.
• a suitable base such as NaH
• a suitable solvent such as DMF
• Method B on a Micromass LCT instrument equipped with a 4-way MUX ElectroSpray source, a Micromass Waters MUX- 2488 UV-detector, a Sedex 754 4-channels LT-ELS-detector, a CTC Analytics HTS-PAL autosampler equipped with 4 injection valves, and 4 Waters 1525 Binary HPLC pumps.
• Chloromethylen chlorosulphonic acid was prepared as described in Binderup, E. and Hansen, E.T. Synthetic Communications 1984, 14, 857-64.
• the reaction mixture was stirred at 50 0 C over night.
• the solvent was removed under reduced pressure and the solids were re-suspended in ethyl acetate (500 mL) and NaHCO 3 (sat.) (500 mL).
• the solids were removed by filtration and the liquid phases were separated.
• the organic phase was washed with NaHCO 3 (sat.), dried over MgSO 4 , filtered and evaporated.
• the crude product was re-crystallized from ethyl acetate and the product fractions were combined to give 4-nitro-3-methyl-iV-thiazol-2-yl-benzamide, Yield: 76%.
• reaction mixture was allowed to slowly heat to -20 °C and stirred for Ih, then the mixture was slowly heated to room temperature and stirred overnight.
• the crude reaction mixture was cooled to 0 0 C and NaHCC ⁇ (aq., sat.) (15 mL) was added with stirring.
• the mixture was filtered and water and ethyl acetate was added.
• EXAMPLE 3 PHARMACOLOGICAL TESTING
• the ability of a compound with formula I to release a compound with formula V under physiological conditions can, e.g., be assessed by administering a compound with formula I to a mammal and subsequently analysing the blood of said mammal for the corresponding compound with formula V.
• Dosing 2 mg/kg of the pro-drug dissolved in saline or 10% HP -beta cyclodextrin is administered by oral gavage to cannulated SD rats.
• Blood sampling Blood samples is drawn at the following time points, relative to time of dosing: pre-dose, 5 min, 20 min, 50 min, 2 h, 4 h, 7 h, 11 h, 15 h, and 20 h.
• Sample preparation At the end of the experiment, the blood samples is centrifuged at 15000 x g for 10 min, and the plasma subsequently transferred to fresh vials and frozen at -80 0 C until quantitative analysis, Bio analysis: The blood samples are analysed for pro-drug and parent compound. Analysis of plasma samples may be performed by liquid chromatography separation /tandem mass spectrometry (LC-MS/MS).
• LC-MS/MS liquid chromatography separation /tandem mass spectrometry
• cDNA was obtained by random primed reverse transcription of human fetal brain RNA (Clonetech). A subsequent polymerase chain reaction (PCR) was performed using the cDNA as template and the oligonucleotides TTTACGCGTGGCCATGCCCATCATGGGCTCCTC and TTTCTAGAATCAGGACACTCCTGCTCCATC as primers for the amplification. The amplification was performed using Pfu polymerase (Stratagene, in accordance with the manufactures recommendation) with an annealing temperature of 54°C.
• the reaction mixture was analyzed by an agarose gel electrophoresis and a band of 1.2 kb was excised and the DNA eluted.
• the eluted DNA was digested with the restriction enzymes MM and Xbal and ligated into a vector, pCIneo, cut with the same enzymes.
• DNA was isolated and sequenced.
• CHO cells was transfected with the pCIneo clone expressing the A 2a receptor and cells with stable integration of the plasmids were isolated after 2-3 weeks growth in the presence of either 5 mg/ml or 10mg/ml G418.
• CHO cells transfected with A 2A receptors as described above were grown in F12 nutrient mixture (kaighs modification, Life technologies) with 10% FCS, 1% glutamin and 1% penicillin/streptomycin and 1 mg/niL G418.
• the cell media was removed and the cells washed 3 times in 37 0 C pre-equilibrated PBS and incubated (on shaker) with 10 ⁇ L of a suspension of acceptor beads and lO ⁇ L of a solution of test compound or standard compound (0-10 ⁇ M) in darkness for 30 min at 25 0 C before addition of 30 ⁇ l of a suspension of donor beads and further incubation 60-120 min in darkness.
• the plates were analysed according to manufacturers instruction (Alpha screen, Perkin Elmer (Pachard Biosciense)).
• the acceptor beads were suspended in a stimulation buffer (5 mM HEPES, 0.1 % BSA in Hanks balanced salt pH 7.4 w/o phenol red (Gibco).
• the donor beads were suspended in a lysis buffer (the stimulation buffer with 0,3% Tween 20 and biotinylated cAMP) according to manufacturers instruction (Alpha screen, Perkin Elmer (Pachard Biosciense)).
• the human A 2a encoding DNA were excised from the pCIneo constructs by MIuI and Xbal and subcloned into the pFASTBAC2 vector cut with Xbal and BssHII.
• the inserts were recombined into the baculo vector using the Bac-to-Bac® system (Invitrogen).
• the generation and isolation of baculo virus was performed as described by the distributor (Invitrogen).
• High Five cells (Invitrogen) was grown at 27 0 C in suspension to a density of l*10 6 and infected with a MOI of 0.5. The cells are harvested 72 h post infection and membranes prepared.
• High five cells expressing A 2A receptors were homogenized in 50 mM tris-buffer pH 7.4 in an ultra Turrax homogenisator.
• the membranes were diluted to a concentration of 0.6 mg/ml and 2U Adenosine deaminase (Roche)/ml membrane suspension was added.
• the solution was preincubated 30 min at 37 0 C before use.
• IC 50 ( [ I ]/ (100/(100-%INH))/(l+([L]/K D ) and
• Ki IC 50 /(l-[L]/K D ), where [ I ] is the inhibitor concentration, and [L] and KD are concentration and dissociation equilibrium constant of the radiotracer, respectively.
• the exemplified compounds with structure V are A 2A receptors antagonists having a human A 2A binding affinity (Kj) of 200 nM or less.

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