WO2009010871A2 - Nouveaux dérivés hétéroaryle servant d'antagonistes du récepteur a3 de l'adénosine - Google Patents
Nouveaux dérivés hétéroaryle servant d'antagonistes du récepteur a3 de l'adénosine Download PDFInfo
- Publication number
- WO2009010871A2 WO2009010871A2 PCT/IB2008/002243 IB2008002243W WO2009010871A2 WO 2009010871 A2 WO2009010871 A2 WO 2009010871A2 IB 2008002243 W IB2008002243 W IB 2008002243W WO 2009010871 A2 WO2009010871 A2 WO 2009010871A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- alkyl
- group
- optionally substituted
- cycloalkyl
- pyrazol
- Prior art date
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
Definitions
- the present invention relates to novel compounds of Formula (I), wherein X 1 , X 2 , X 3 , X 4 , Y 1 , Y 2 , Y 3 , Y 4 , M 1 , M 2 , M 3 , A m and B n are defined as in Formula (I); invention compounds are antagonists of adenosine receptors — subtype 3 (A 3 ) which are useful for the treatment or prevention of disorders modulated by A 3 receptors.
- the invention is also directed to pharmaceutical compositions and the use of such compounds in the manufacture of medicaments, as well as to the use of such compounds for the prevention and treatment of such diseases in which A 3 receptor is involved.
- the extracellular purine nucleoside adenosine is present in all tissues and body fluids and is known to function as a modulator of a variety of physiological processes.
- adenosine One of the primary roles of adenosine is cytoprotection against ischemia-induced cell damage, mainly in tissues such as the heart, brain and kidney, which are especially prone to ischemic injury (Mubagwa and Flameng (2001) Cardiovasc. Res. 52:25-39).
- the effects of adenosine on tissue protection and repair include increasing the ratio of oxygen supply to demand, protecting against ischemic damage by cell conditioning, triggering anti-inflammatory responses and promoting angiogenesis.
- Other actions of adenosine include the regulation of cellular growth and differentiation, vasodilatation
- AR action also might be modulated by inhibition of the metabolism of extracellular adenosine (Parkinson et al (2005) Neurol. Res. 2:153-160) or its cellular uptake by adenosine transporter (McGaraughty et al (2005) Curr. Top.Med. Chem. 5:43-58).
- a 1 , A 2A , A 2B , and A 3 pharmacologically and biochemically distinct adenosine receptors
- a 1 , A 2A , A 2B , and A 3 pharmacologically and biochemically distinct adenosine receptors
- a 1 and A 3 receptor subtypes couple to Gi-protein, mediating the inhibition of adenylyl
- a 1 and A 3 ARs (49% sequence similarity) and the A 2A and A 2B ARs (59% similarity).
- degree of homology is somewhat low, it has been very difficult to develop highly selective or even specific adenosine receptor subtype agonists and antagonists.
- a 3 receptors are more variable.
- adenosine receptors may be useful for therapeutic intervention due to their distribution in several types of tissue throughout the body.
- Many pathological conditions such as renal failure, cardiac and cerebral ischemia, central nervous system disorders, neurodegenerative diseases and inflammatory pathologies may be treated with selective modulators of the different sub-types of adenosine receptors (for a review see Gao and Jacobson (2006) Nat Rev Drug Discov. 5:247-64).
- the adenosine A 3 receptor (A 3 AR) is the most recently discovered adenosine receptor (Zhou et al (1992) Proc Natl Acad Sci U S A. 89:7432-6; Salvatore et al (1993) Proc Natl Acad Sci U S A. 90:10365-9).
- the A 3 AR couples to second-messenger pathways resulting in stimulation of phospholipase C (PLC) (Abbracchio et al. (1995) MoL Pharmacol. 48:1038-1045) and calcium mobilization via a Gi/o-dependent pathway (Shneyvays et al (2005) Am. J. Physiol. Heart Circ. Physiol.
- the WNT signaling pathway is involved in A 3 AR agonist- mediated suppression of melanoma cells (Fishman et al (2002) Oncogene 21:4060- 4064.).
- the A 3 AR couples to MAPK, which suggests a possible role in cell growth, survival, death and differentiation (Schulte & Fredholm (2002) MoI. Pharmacol. 62:1137-1146; Schulte & Fredholm (2003) Cell Signal. 15:813-827).
- An A 3 AR agonist inhibits proliferation in A375 human melanoma cells via the phosphatidylinositol 3-kinase-protein kinase B-ERKl/2 pathway (Merighi et al. (2005) J. Biol. Chem. 280:19516-19526). It is suggested that the adenosine A 3 receptor activates ERK1/2 in human fetal astrocytes (Neary et al (1998) Neurosci Lett.; 242:159-62) and in CHO cells (Schulte and Fredholm (2000) MoI Pharmacol. 58:477- 82).
- Cl-IB-MECA and IB-MECA have been reported to potently inhibit and less potently to activate apoptosis in various cells (Abbracchio et al (1997) Ann NY Acad Sci 825:11-22).
- Cl-IB-MECA potently blocks UV irradiation-induced apoptosis by a process correlated with protein kinase B phosphorylation which is blocked by pertussis toxin and wortmannin (Gao et al (2001) MoI Pharmacol 59:76-82).
- a 3 AR selective agonists IB-MECA and Cl-IB-MECA have been used extensively as pharmacological probes in the elucidation of the physiological roles of this receptor (Jacobson (1998) Trends Pharmacol. Sci. 19:184-191).
- a 3 AR antagonists available including, among many, xanthine, adenine derivatives, imidazo[2,l-i]purin-5-ones, quinazolines and derivatives, 1,4-dihydropyridines and pyrans, pyrimidines derivatives (Zhou (1992) Proc. Natl Acad. Sci. USA 89:7432-7436; Yang (2005) Curr.Eye Res. 30:747-754;
- the conformationally constrained nucleoside MRS 1292 which is a selective A 3 AR antagonist, in both rat and human (Gao et al. (2002) J. Med. Chem. 45:4471-4484; Yang et al (2005) Curr. Eye Res. 30:747-754) is currently used in vitro as a reference antagonist.
- Adenosine A 3 receptors are found mostly in brain, lung, liver, heart, kidney and testis (Gao and Jacobson (2006) Nat Rev Drug Discov. 5:247-64) and have been implicated in cell cycle progression and cell growth (Brambilla et al. (2000) Naunyn
- adenosine A 3 receptors have functional effects that are dependent on the degree of receptor activation. Specifically, when activated moderately, A 3 ARs have a cytoprotective role for example reducing damage to heart cells from lack of oxygen or protecting cells from apoptosis.
- a 3 receptor is known to activate the cellular antioxidant defense system by increasing the activities of superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase, along with a reduction in malondialdehyde, a marker of lipid peroxidation (Maggirwar et al (1994) Biochem Biophys Res Comniun 201 :508-512).
- Such a mechanism may provide a mechanism by which adenosine exerts a cytoprotective action in ischemic conditions.
- high levels of A 3 AR stimulation can actually result in cell death.
- a role for the A 3 AR in mediating control of the cell cycle has been reported (Neary et al (1998) Neurosci. Lett 242:159-162). For example, there is a significant over- expression of A 3 ARs in several types of tumor cells (Madi et al (2004) Clin. Cancer Res. 10:4472-4479; Gessi et al (2004) Clin. Cancer Res. 10:5895-5901).
- a 3 AR antagonists might sensitize tumor cells to chemotherapeutic drugs as it is known that A3 receptor subtype activation plays a role in the prosurvival and in the antiapoptotic effect of adenosine (Merighi et al (2003) Biochem. Pharmacol. 66:739-748; Baraldi et
- a 3 AR antagonists might sensitize tumors cells to chemotherapeutic drugs and therefore could inhibit tumor growth and metastasis in patient. Possible indication therefore for selective adenosine A 3 antagonists is the use of such compounds class in synergistically improving chemotherapeutic treatment of cancers expressing A 3 ARs and cancers expressing P-glycoprotein or MRP in combination with other anti-tumor agents such as antiangiogenic agents and/or cytostatic agents.
- the adenosine A 3 receptor was initially implicated as the receptor subtype that triggers the degranulation of rat RBL 2H3 mast-like cells (Ramkumar et al., 1993) and perivascular mast cells of the hamster cheek pouch (Jin et al (1997) J Clin Invest. 100:2849-57) and therefore A 3 AR has been implicated in mediating allergic responses: A 3 receptor agonists induce mast cell degranulation and consequent release of allergic mediators, such as histamine, when administered to rats or mice (Ramkumar et al (1993) J. Biol. Chem. 268:16887-16890; Tilley et al (2000) J Clin Invest.lO5:361-7).
- a 3 AR receptor antagonists have the potential for treating diseases and disorders resulting from or including a component of inflammation. This could be extended to the treatment of asthma and others respiratory diseases involving inflammation and or allergenic responses. In the asthmatic lung, adenosine acts as an irritant and bronchoconstrictor, suggesting that a synthetic A 3 AR antagonist, could have therapeutic potential in asthma
- Glaucoma is characterized by elevated intraocular pressure (IOP) and is a leading cause of irreversible blindness.
- IOP intraocular pressure
- Molecular and pharmacological studies have provided evidence that all adenosine receptor subtypes are expressed in ocular tissues (Blazynski et al (1992) J Neurochem. 58:761- 767; Wax et al (1993) Exp Eye Res. 57:89 -95 ; Wax et al (1994) Invest Ophthalmol Vis Sci. ;35:3057-3063 ; Kvanta et al (1997) Exp Eye Res.
- adenosine and its receptors have been implicated in many ocular and systemic ischemic diseases such as retinal ischemia and in conditions with oxidative stress in rodents (Roth S et al (1997) Exp Eye Res. 65:771-779; Lutty and Mc Leod (2003) Prog Retin Eye Res. 22:95-111, Larsen and Osbourne (1996) Invest Ophthalmol Vis Sci. 37: 2603-2611).
- Civan and co-workers have found that the A 3 adenosine receptors regulate Cl(-) channels of non-pigmented ciliary epithelial cells (Von Arnini et al (2000) Neuroreport. 11:1223-1226).
- a 3 agonists have been shown to activate chloride channels in non pigmented ciliary epithelial cells in vitro, leading to the hypothesis that A 3 receptor agonists would increase aqueous humor secretion and thereby IOP in vivo (Mitchell et al (1999) Am J Physiol. 276:C659-C666).
- a 3 AR antagonist MRS 1292 was recently found to reduce mouse intraocular pressure but also inhibited adenosine-triggered human non-pigmented ciliary epithelial cell fluid release (Yang, H. et al (2005) Curr. Eye Res. 30: 747-754).
- OT-7999 a potent and selective A(3) receptor antagonist administered via topical eye-
- the A 3 receptor subtype has been immunolocalized to the basolateral surface infoldings of non-pigmented ciliary epithelial cells, which is consistent with the receptor's functional role in aqueous humor secretion.
- the mean aqueous adenosine levels were significantly elevated when compared to normotensive subjects and correlated with IOP levels (Daines et al (2003) J Ocul Pharmacol Ther. 19:113-119).
- parenteral infusion of adenosine induced a small but significant decrease in IOP (Polska et al (2003) Invest Ophthalmol Vis Sci. 44:3110-3114).
- PEX pseudoexfoliation
- a recent study further provided evidence of a selective and significant upregulation of the A 3 adenosine receptor on both the mRNA and protein levels, in the non-pigmented ciliary epithelium of all patients eyes with PEX syndrome confirming a previous study showing a 30-fold overexpression of A 3 adenosine receptor mRNA in the ciliary processes of PEX eyes compared with control eyes (Schl ⁇ tzer-Schrehardt et al (2004) IOVS 45: ARVO E-Abstract 3535).
- hypoxia and/or oxidative stress typical of all eyes with PEX syndrome/glaucoma (Ritch and Schl ⁇ tzer-Schrehardt (2001) Surv Ophthalmol. 45:265-315; Helbig et al (1994) German J Ophthalmol. 3:148 -153) promotes a selective upregulation of A 3 adenosine receptors in non-pigmented ciliary epithelium, which may confer protection against ischemic or oxidative damage to sustain prolonged periods of chronic hypoxia or oxidative stress.
- the known adenosine receptors promotes a selective upregulation of A 3 adenosine receptors in non-pigmented ciliary epithelium, which may confer protection against ischemic or oxidative damage to sustain prolonged periods of chronic hypoxia or oxidative stress.
- a 3 receptor has been mainly implicated in ischemic disease, such as ischemic brain damage or cardiac ischemia (Baraldi et al (2003) Eur. J. Med. Chem. 38:367-382).
- Adenosine is released in large amounts during myocardial ischemia, resulting in effective preconditioning in cardiomyocytes through the activation of A 1 and A 3 ARs (Shneyvays et al (2004) Cell Calcium 36:387-396; Tracey et al (1998) Cardiovasc. Res. 40:138-145 ; Mozzicato et al (2004) FASEB J. 18: 406-408; Auchampach (1997) Circ. Res. 80: 800-809).
- AR agonist to activate either or both of these receptors might therefore be beneficial to the survival of the ischemic heart.
- Various lines of evidence indicate that the A 3 AR has a role in protecting the heart (Auchampach (1997) Circ. Res. 80: 800-809; Tracey et al (2003) Am. J. Physiol. Heart Circ. Physiol. 285:H2780- H2787).
- Overexpression of A 3 ARs decreases heart rate, preserves energetics and protects ischemic heart (Cross et al (2002) Am. J. Physiol. Heart Circ. Physiol.
- synaptic serotonin (5-hydiOxytryptamine, 5-HT) is primarily through reuptake by the presynaptic, 5-HT transporter (SERT, SLC6A4)
- a 3 AR antagonists could be interesting in treating pathologies resulting from a low level of serotonin (including affective disorders including depression and depressive disorders, anxiety disorders including obsessive-compulsive disorder, post-traumatic stress disorder, panic disorder and phobias, borderline personality disorder, anorexia nervosa, bulimia nervosa, autism, attention deficit hyperactivity disorder, Tourette's syndrome, sexual disorders, migraine, diabetic neuropathy, obesity, drug or alcohol addiction, sleep disorders, arthritis, chronic fatigue syndrome or irritable bowel syndrome) because such compounds will decrease the SERT surface expression and/or catalytic rates.
- TNF- ⁇ Tumor Necrosis Factor- Alpha
- IL-12 Interleukin-12
- Hassan, N.M. et al (1997) J. Chem. Res., Syn. (10): 350-351 described a synthetic route to obtain 4-((l-aryl-4-carbonitrile-5-phenyl)-lH-pyrazolyl)-2- arninophenyl thiazoles;
- arylpyridinyl thiazoles such as N-(5-(pyridin-4-yl)-4-(3 5 4,5-trimethoxyphenyl)thiazol- 2-yl)acetamide, having adenosine A 3 receptor antagonism properties, useful as pharmacological tools;
- European patent publication EP1027050 and US patent publication US6620825 describe 1,3-thiazoles as adenosine A 3 receptor antagonist for the treatment of allergy, asthma and diabetes, such as compounds substituted at the 4- or 5 -position, or both, by a pyridyl, such as 4-(4-methoxyphenyl)-N-phenyl-5-(pyridin-3-yl)thiazol-2-amine or 4-
- Japan patent application JP2003313176 describes 2-aminothiazole derivatives having cell proliferation inhibitory activity for preventing and treating cancer.
- the present invention relates to a method of treating or preventing a condition in a mammal, including a human, the treatment or prevention of which is affected or facilitated by the neuromodulatory effect of Adenosine A3 receptor antagonists.
- the invention relates to compounds having A 3 receptor antagonist activity.
- the present invention provides a compound according to Formula (I),
- n is an integer ranging from 1 to 3;
- a m radicals are each independently selected from the group of hydrogen, halogen, -CN, -CF 3 , and an optionally substituted radical selected from the group of -(Ci-C 6 )alkyl, - (Ci-C 6 )alkylhalo, -(C 3 -C 7 )cycloalkyl, -(Ci-C 6 )alkylcyano 5 -(Ci-C 6 )alkylheteroaryl, - (Ci-C 6 )alkylaryl, aryl, heteroaryl, heterocycle, -(C 0 -C 6 )alkyl-OR 1 , ⁇ O-(C 2 -C 6 )alkyl- OR 1 , -NR 1 (C 2 -C 6 )alkyl-OR 2 , -(C 3 -C 7 )cycloalkyl-(C
- R 1 , R 2 , R 3 and R 4 are each independently hydrogen or an optionally substituted radical selected from the group of -(CrC ⁇ alkylhalo, -(CrC ⁇ alkyl, -(C t -C ⁇ alkylcyano, -(C 3 - C 7 )cycloalkyl, -(C 4 -C 10 )alkylcycloalkyl, heteroaryl, -(CrC ⁇ alkylheteroaryl, aryl, heterocycle and
- R Any two radicals of R (R 1 , R 2 , R 3 or R 4 ) may be taken together to form an optionally substituted 3 to 10 membered carbocyclic or heterocyclic ring;
- Y 1 , Y 2 , Y 3 and Y 4 are each independently selected from the group of C and N representing 5 membered heteroaryl ring which may further be substituted by 1 to 3 radicals B n ;
- n is an integer ranging from 1 to 3;
- B n radicals are each independently selected from the group of hydrogen, halogen, -CN, -CF 3 , and an optionally substituted radical selected from the group of -(Q-C ⁇ alkyl, - (Ci-C 6 )alkylhalo, -(C 3 -C 7 )cycloalkyl, -(Ci-C 6 )alkylcyano, -(CrC ⁇ alkylheteroaryl, - (Ci-C f Oalkylaryl, aryl, heteroaryl, heterocycle, -(C 0 -C 6 )alkyl-OR 5 , -O-(C 2 -C 6 )alkyl- OR 5 , -NR 5 (C 2 -C 6 )alkyl-OR 6 , -(Ca-C ⁇ cycloalkyl-CCrC ⁇ alkyl, -O-(C 3 -C 7 )cycloalkyl- (Ci-C 6 )
- R 5 , R 6 , R 7 and R 8 are each independently hydrogen or an optionally substituted radical selected from the group of -(Ci-C 6 )alkylhalo, -(Ci-C 6 )alkyl, -(C 1 -C 6 )alkylcyano, -(C 3 - C 7 )cycloalkyl, -(C 4 -C 10 )alkylcycloalkyl, heteroaryl, aryl, heterocycle and -(Q-C ⁇ alkylaryl;
- R Any two radicals of R (R 5 , R 6 , R 7 or R 8 ) may be taken together to form an optionally substituted 3 to 10 membered carbocyclic or heterocyclic ring;
- M 1 is selected from an optionally substituted 3 to 10 membered ring selected from the group of aryl, heteroaryl, heterocyclic and cycloalkyl;
- R 9 and R 10 are selected from the group of a hydrogen or an optionally substituted radical selected from the group of -(C 1 -C 6 )alkylhalo, -(CrC ⁇ alkyl, -(CrC ⁇ alkylcyano, ⁇ (C 3 -C 7 )cycloalkyl, -(C 4 -C 10 )alkylcycloalkyl, heteroaryl, -(C t -C ⁇ alkylheteroaryl, aryl, heterocycle and -(Cj . -C 6 )alkylaryl;
- M 3 is an optionally substituted radical selected from the group of -(Co-C 6 )alkyl-R , - (d-C ⁇ alkylhalo, -(C 2 -C 6 )alkyl-NR ⁇ R 12 , -(C 2 -C 6 )alkyl-OR n and -(C 2 -C 6 )alkyl-SR U ; and
- R 11 and R 12 are selected from the group of a hydrogen or an optionally substituted radical selected from the group of -(Ci-C 6 )alkylhalo, -(CrC ⁇ alkyl, -(CrC ⁇ alkylcyano, -(C 3 -C 7 )cycloalkyl, -(C 4 -C 10 )alkylcycloalkyl, heteroaryl, -(Ci-C ⁇ alkylheteroaryl, aryl, heterocycle and -(Q-C ⁇ alkylaryl; provided that according to proviso (i): when M 3 is -(Co)-R 11 (that is when M 3 is -R 11 ), then R 11 is not H; and provided that according to proviso (ii):
- a 1 and A 2 radicals are not linked to form an imidazopyridazinyl ring; and provided that according to proviso (v):
- M 1 can not be an optionally substituted aryl, 1 -methyl- lH-indazol-4-yl 5 lH-indazol-3-yl and lH-indazol-4-yl; and provided that according to proviso (vi): when M 3 is 4-methylphenyl, then B n can not be a phenyl; and provided that according to proviso (vii): when M 1 M 2 N is linked to X 1 , and X 1 is C 5 X 2 is S 5 X 3 is C 5 X 4 is C, to provide a thiazole ring, n is 1 , then A 1 is not a pyridyl; and provided that according to proviso (viii)
- the compounds are 3-[5-[(4-chlorophenyl)azo]-2-(phenylamino)-4-thiazolyl]-l-(4- methyl ⁇ henyl)-5 -phenyl- lH-pyrazole-4-carbonitrile [198840-15-2], l-(4- methylphenyl)-3 - [5 - [(4-methylphenyl)azo] -2-(phenylamino)-4-thiazolyl] -5 -phenyl- 1 H- pyrazole-4-carbonitrile [198840-14-1], l-(4-methylphenyl)-5-phenyl-3-[2-
- the invention provides a compound according to Formula (II),
- KAS/ClientDocs/Addex/53195.WO01.FinalSpec.l0.072008 m is an integer ranging from 1 to 3;
- a m radicals are each independently selected from the group of hydrogen, halogen, -CN, -CF 3 , and an optionally substituted radical selected from the group of - (CrC ⁇ alkylhalo, -(C 3 -C 7 )cycloalkyl, -(Ci-C 6 )alkylcyano, -(Ci-C 6 )alkylheteroaryl, - (C r C 6 )alkylaryl, aryl, heteroaryl, heterocycle, -(Co-C ⁇ alkyl-OR 1 , -NR 1 (C 2 -C 6 )alkyl- OR 2 , -(C 3 -C 7 )cycloalkyl-(Ci-C 6 )alkyl, -O-(C 3 -C 7 )cycloalkyl-(Ci-C 6 )alkyl, -NR ⁇ (C 3 - C 7 )cycloalkyl-(Ci-C 6
- Any two radicals of A m may be taken together to form an optionally substituted 3 to 10 membered carbocyclic or heterocyclic ring;
- R 1 , R 2 , R 3 and R 4 are each independently hydrogen or an optionally substituted radical selected from the group of -(C 3 - C 7 )cycloalkyl, -(C 4 -C 10 )alkylcycloalkyl, heteroaryl, -(CrC ⁇ alkylheteroaryl, aryl, heterocycle and -(Ci-C ⁇ alkylaryl;
- R Any two radicals of R (R 1 , R 2 , R 3 or R 4 ) may be taken together to form an optionally substituted 3 to 10 membered carbocyclic or heterocyclic ring;
- n is an integer ranging from 1 to 2;
- B n radicals are each independently selected from the group of hydrogen, halogen, -CN, -CF 3 , and an optionally substituted radical selected from the group of -(d-C ⁇ alkyl, -
- R 5 , R 6 , R 7 and R 8 are each independently hydrogen or an optionally substituted radical selected from the group of -(Ci-C ⁇ alkylhalo, -(CrC ⁇ alkyl, -(C 1 -C 6 )alkylcyano, -(C 3 - C 7 )cycloalkyl, -(C 4 -C 10 )alkylcycloalkyl, heteroaryl, aryl, heterocycle and -(Ci-C 6 )alkylaryl;
- R 5 , R 6 , R 7 or R 8 Any two radicals of R (R 5 , R 6 , R 7 or R 8 ) may be taken together to form an optionally substituted 3 to 10 membered carbocyclic or heterocyclic ring;
- M 1 is selected from an optionally substituted 3 to 10 membered ring selected from the group of aryl, heteroaryl, heterocyclic and cycloalkyl;
- M 3 is an optionally substituted radical selected from the group of -(C 3 -C 7 )cycloalkyl, aryl, heteroaryl, heterocycle, -(Q-C ⁇ alkyl-R 11 , -(CrC ⁇ alkylhalo, -(C 2 -C 6 )alkyl- NR 11 R 12 , -(C 2 -C 6 )alkyl-OR ⁇ and -(C 2 -C 6 )alkyl-SR ⁇ ; and
- R 11 and R 12 are selected from the group of a hydrogen or an optionally substituted radical selected from the group of -(Q-C ⁇ alkylhalo, -(CrC ⁇ alkyl, -(Q-C ⁇ alkylcyano, -(C 3 -C 7 )cycloalkyl, -(C 4 -C 10 )alkylcycloalkyl, heteroaryl, -(Ci-C ⁇ alkylheteroaryl, aryl, heterocycle and -(CrC ⁇ alkylaryl; provided that according to proviso (i): when M 3 is -(Co)-R 11 (that is when M 3 is -R 11 ), then R 11 is not H; and provided that according to proviso (ii):
- a 1 is H, then M 1 can not be an optionally substituted aryl, 1 -methyl- lH-indazol-4-yl, lH-indazol-3-yl and lH-indazol-4-yl; and provided that according to proviso (vi): when M 3 is 4-methylphenyl, then B n can not be a phenyl; and provided that according to proviso (vii): when X 2 is S, X 3 is C, X 4 is C, n is 1, then A 1 when linked to either X 3 or X 4 is not a pyridyl; and provided that according to proviso (viii): when X 2 is S, X 3 is C, X 4 is C, to provide a thiazole ring, n is 1, then A 1 is not an optionally substituted imidazolyl or triazolyl ring.
- X is a nitrogen, an oxygen, or a sulfur atom
- X is a carbon atom or a nitrogen atom
- X 4 is a carbon or a nitrogen atom, representing a 5 membered heteroaryl, which may further be substituted by 1 to 2 radicals A m
- a m radicals are each independently selected from the group of hydrogen, halogen, -CN, -CF 3 , and an optionally substituted radical selected from the group of -(Ci-C 6 )alkyl, - (Ci-C 6 )alkylhalo, -(C 3 -C 7 )cycloalkyl, -(Ci-Q)alkylcyano, -(Ci-C 6 )alkylheteroaiyl, - (Ci-C 6 )alkylaryl, aryl, heteroaryl, heterocycle, -(C 0 -C 6 )alkyl-OR 1 ,
- R 1 , R 2 , R 3 and R 4 are each independently hydrogen or an optionally substituted radical selected from the group of -(C 3 - C 7 )cycloalkyl, -(C 4 -C 10 )alkylcycloalkyl, heteroaryl, -(C t -C ⁇ alkylheteroaryl, aryl, heterocycle and -(Ci-C ⁇ alkylaryl;
- R Any two radicals of R (R 1 , R 2 , R 3 or R 4 ) may be taken together to form an optionally substituted 3 to 10 membered carbocyclic or heterocyclic ring;
- n is an integer ranging from 1 to 2;
- B n radicals are each independently selected from the group of hydrogen, halogen, -CN, -CF 3 , and an optionally substituted radical selected from the group of -(C 1 -C 6 )alkyl, - (CrC f Oalkylhalo, -(C 3 -C 7 )cycloalkyl, -(d-C ⁇ alkylcyano, -(C 1 -C 6 )alkylheteroaryl, - aryl, heteroaryl, heterocycle, -(C 0 -C 6 )alkyl-OR 5 , -O-(C 2 -C 6 )alkyl- OR 5 , -NR 5 (C 2 -C 6 )alkyl-OR 6 , -(C 3 -C 7 )cycloalkyl-(C 1 -C 6 )alkyl, -O-(C 3 -C 7 )cycl
- R 5 , R 6 , R 7 and R 8 each independently hydrogen or an optionally substituted radical selected from the group of -(d-C ⁇ alkylhalo, -(C t -C ⁇ alkyl, -(C 3 -C 7 )cycloalkyl, -(C 4 - C 10 )alkylcycloalkyl and heterocycle;
- R 5 , R 6 , R 7 or R 8 Any two radicals of of R (R 5 , R 6 , R 7 or R 8 ) may be taken together to form an optionally substituted 3 to 10 membered carbocyclic or heterocyclic ring;
- M 1 is selected from an optionally substituted aryl and heteroaryl; M is a hydrogen or an optionally substituted -(Ci-C ⁇ alkyl-R ; R 9 is a hydrogen;
- M 3 is an optionally substituted radical selected from the group of -(C 3 -C 7 )cycloalkyl, aryl, heteroaryl, heterocycle, -(Ci-C 6 )alkyl-R ⁇ , -(CrC ⁇ alkylhalo, -(C 2 -C 6 )alkyl- NR 11 R 12 , -(C 2 -C 6 )alkyl-OR U and and
- R and R are selected from the group of a hydrogen or an optionally substituted radical selected from the group of -(CrC ⁇ alkylhalo, -(CrC ⁇ alkyl, -(Q-C ⁇ alkylcyano, -(C 3 -C 7 )cycloalkyl, -(C 4 -C 10 )alkylcycloalkyl, heteroaryl, aryl, heterocycle and -(C 1 -C 6 )alkylaryl; provided that according to proviso (i): when M 3 is -(Co)-R 11 (that is when M 3 is -R 11 ), then R 11 is not H;
- a 1 and A 2 radicals are not linked to form an imidazopyridazinyl ring; and provided that according to proviso (v):
- a 1 is H, then M 1 can not be an optionally substituted aryl, 1 -methyl- lH-indazol-4-yl, lH-indazol-3-yl and lH-indazol-4-yl; and provided that according to proviso (vi): when M 3 is 4-methylphenyl, then B n can not be a phenyl; and provided that according to proviso (vii): when X 2 is S 5 X 3 is C, X 4 is C 5 n is I 5 then A 1 when linked to either X 3 or X 4 is not a pyridyl; and provided that according to proviso (viii): when X 2 is S 5 X 3 is C 5 X 4 is C 5 to provide a thiazole ring, n is 1, then A 1 is not an optionally substituted imidazolyl or triazolyl ring.
- X 3 is selected from C or N which may further be substituted by A 1 ;
- a 1 radicals are each independently selected from the group of hydrogen, halogen, -CN, -CF 3 , and an optionally substituted radical selected from the group of -(C 1 -C 6 ⁇ IkVl, - (C] . -C 6 )alkylhalo, -(C 3 -C 7 )cycloalkyl, -(CrC ⁇ alkylcyano, -(CrC ⁇ alkylheteroaryl, - (Ci-C 6 )alkylaiyl, heterocycle, -(Co-C ⁇ alkyl-OR 1 , -NR 1 (C 2 -C 6 )alkyl-OR 2 , -(C 3 - C 7 )cycloalkyl-(C 1 -C 6 )alkyl, -O-(C 3 -C 7 )cycloalkyl-(C 1 -C 6 )alkyl, -NR ⁇ (C 3 -
- R 1 , R 2 , R 3 and R 4 are each independently hydrogen or an optionally substituted radical selected from the group of -(C 1 -C 6 )alkylhalo, -(CrC ⁇ alkyl, -(Ci-C 6 )alkylcyano, -(C 3 -
- R Any two radicals of R (R 1 , R 2 , R 3 or R 4 ) may be taken together to form an optionally substituted 3 to 10 membered carbocyclic or heterocyclic ring; n is an integer ranging from 1 to 2;
- B n radicals are each independently selected from the group of hydrogen, halogen, -CN, -CF 3 , and an optionally substituted radical selected from the group of -(d-C ⁇ alkyl, - (CrC ⁇ alkylhalo, -(C 3 -C 7 )cycloalkyl, -(CrC ⁇ alkylcyano, -(d-C ⁇ alkylheteroaryl, - (CrC f Oalkylaryl, aryl, heteroaryl, heterocycle, -(C 0 -C 6 )alkyl-OR 5 , -O-(C 2 -C 6 )alkyl- OR 5 , -NR 5 (C 2 -C 6 )alkyl-OR 6 , -(Cs-C ⁇ cycloalkyHd-C ⁇ alkyl, -O-(C 3 -C 7 )cycloalkyl- (d-C 6 )alkyl, -NR 5
- R Any two radicals of R (R 5 , R 6 , R 7 or R 8 ) may be taken together to form an optionally substituted 3 to 10 membered carbocyclic or heterocyclic ring;
- M 1 is selected from an optionally substituted aryl and heteroaryl
- M 3 is an optionally substituted radical selected from the group of -(C 3 -C 7 )cycloalkyl, aryl, heteroaryl, heterocycle, -(C 2 -C 6 )alkyl- NR 11 R 12 , -(C 2 -C 6 )alkyl-OR U and -(C 2 -C 6 )alkyl-SR ⁇ ; and
- R 11 and R 12 are selected from the group of a hydrogen or an optionally substituted radical selected from the group of -(Ci-C 6 )alkylhalo, -(Q-C ⁇ alkyl, -(Q-C ⁇ alkylcyano, -(C 3 -C 7 )cycloalkyl, -(C 4 -C 10 )alkylcycloalkyl, heteroaryl, -(CrC ⁇ alkylheteroaryl, aryl, heterocycle and -(Q-C ⁇ alkylaryl; and provided that according to proviso (v):
- a 1 radicals are each independently selected from the group of hydrogen, halogen, -CN, -CF 3 , and an optionally substituted radical selected from the group of -(Ci-C ⁇ alkyl, -
- R 1 , R 2 and R 3 are each independently hydrogen or an optionally substituted radical selected from the group of -(C 3 -C 7 )cycloalkyl, -(C 4 - C 10 )alkylcycloalkyl and heterocycle; Any two radicals of R (R 1 , R 2 or R 3 ) may be taken together to form an optionally substituted 3 to 10 membered carbocyclic or heterocyclic ring;
- B n radicals are each independently selected from the group of hydrogen, halogen, -CN, -CF 3 , and an optionally substituted radical selected from the group of -(Q-C ⁇ alkyl, - (d-C ⁇ alkylhalo, -(C 3 -C 7 )cycloalkyl, -(Ci-C 6 )alkylcyano, -(Ci-C 6 )alkylheteroaryl 5 - (C 1 -C 6 )alkylaryl, aryl, heteroaryl, heterocycle, -(C 0 -C 6 )alkyl-OR 5 , -O-(C 2 -C 6 )alkyl- OR 5 , -NR 5 (C 2 -C 6 )alkyl-OR 6 , -(C 3 -C 7 )cycloalkyl-(C 1 -C 6 )alkyl, -O-(C 3 -C 7 )cycloalkyl
- R 5 , R 6 , R 7 and R 8 are each independently hydrogen or an optionally substituted radical selected from the group of -(Ci-C ⁇ alkylhalo, -(CrC ⁇ alkyl, -(C 1 -C 6 )alkylcyano, -(C 3 - C 7 )cycloalkyl, -(C 4 -C 10 )alkylcycloalkyl, heteroaryl, -(CrC ⁇ alkylheteroaryl, aryl, heterocycle and -(Ci-C 6 )alkylaryl;
- R 5 , R 6 , R 7 and R 8 Any two radicals of R (R 5 , R 6 , R 7 and R 8 ) may be taken together to form an optionally substituted 3 to 10 membered carbocyclic or heterocyclic ring;
- M 1 is selected from an optionally substituted aryl and heteroaryl
- M 3 is an optionally substituted radical selected from the group of -(C 3 -C 7 )cycloalkyl, aryl, heteroaryl, heterocycle, -(CrC ⁇ alkyl-R 11 , -(Ci-C 6 )alkylhalo, -(C 2 -C 6 )alkyl- NR 11 R 12 , -(C 2 -C 6 )alkyl-OR ⁇ and -(C 2 -C 6 )alkyl-SR n ; and
- R 11 and R 12 are selected from the group of a hydrogen or an optionally substituted radical selected from the group of -(Q-C ⁇ alkylhalo, -(Ci-C ⁇ alkyl, -(CrC ⁇ alkylcyano, -(C 3 -C 7 )cycloalkyl 5 -(C 4 -C 10 )alkylcycloalkyl 5 heteroaryl, -(d-C ⁇ alkylheteroaryl, aryl, heterocycle and -(Cj . -C 6 )alkylaryl; provided that according to proviso (v):
- the invention provides a compound according to Formula (IIIA),
- a 1 radical is selected from the group of hydrogen, halogen, -CN, -CF 3 , and an optionally substituted radical selected from the group of -(Ci-C 6 )alkyl, -(C 1 -
- R 1 , R 2 and R 3 are each independently hydrogen or an optionally substituted radical selected from the group of -(Ci-C 6 )alkylcyano, -(C 3 - C 7 )cycloalkyl, -(C 4 -C 10 )aUiylcycloalkyl, heteroaryl, aryl, heterocycle and -(C t -C ⁇ alkylaryl;
- R Any two radicals of R (R 1 , R 2 and R 3 ) may be taken together to form an optionally substituted 3 to 10 membered carbocyclic or heterocyclic ring; n is an integer ranging from 1 to 2;
- KAS/ClientDocs/Addex/53195.WO01.FinalSpec.l0.072008 B n radicals are each independently selected from the group of hydrogen, halogen, -CN, -CF 3 , and an optionally substituted radical selected from the group of -(Ci-C 6 )alkyl, - (CrC ⁇ alkylhalo, -(C 3 -C 7 )cycloalkyl, aryl, heteroaryl, heterocycle, -(C 0 -C 6 )alkyl-OR 5 , - O-(C 2 -C 6 )alkyl-OR 5 , -NR 5 (C 2 -C 6 )alkyl-OR 6 , -(Cs-C ⁇ cycloalkyl-Cd-C ⁇ alkyl, -0-(C 3 - OR 5 , -(d-C ⁇ alkylhalo-NR ⁇ 6 , -(C 0 -C 6 )alkyl-NR
- R 5 , R 6 and R 7 are each independently hydrogen or an optionally substituted radical selected from the group of -(Q-C ⁇ alkylhalo, -(CrC ⁇ alkyl, -(CrC ⁇ alkylcyano, -(C 3 - C 7 )cycloalkyl, -(C 4 -C 10 )alkylcycloalkyl, heteroaryl, -(d-C ⁇ alkylheteroaryl, aryl, heterocycle and -(Ci-C ⁇ alkylaryl; Any two radicals of R (R 5 , R 6 , or R 7 ) may be taken together to form an optionally substituted 3 to 10 membered carbocyclic or heterocyclic ring;
- M 1 is selected from an optionally substituted aryl and heteroaryl
- M 3 is an optionally substituted radical selected from the group of -(C 3 -C 7 )cycloalkyl, aryl, heteroaryl, heterocycle, -(C 1 -C 6 )alkyl-R 11 , -(d-C ⁇ alkylhalo, -(C 2 -C 6 )alkyl- NR 11 R 12 , -(C 2 -C 6 )alkyl-OR ⁇ and -(C 2 -C 6 )alkyl-SR n ; and
- R 11 and R 12 are selected from the group of a hydrogen or an optionally substituted radical selected from the group of -(d-C ⁇ alkylhalo, -(Ct-C ⁇ alkyl, -(C 3 -C 7 )cycloalkyl, -(C 4 -C 10 )alkylcycloalkyl, heteroaryl, -(d-C ⁇ alkylheteroaryl, aryl, heterocycle and - (d-C ⁇ alkylaryl; provided that according to proviso (v):
- a 1 radical is selected from the group of hydrogen, halogen, -CF 3 , and an optionally substituted radical selected from the group of -(Q-C ⁇ alkyl, -(Q-C ⁇ alkylhalo, -(C 3 - C 7 )cycloalkyl and heterocycle; n is an integer ranging from 1 to 2, and either;
- n is 1 and B 1 radical is selected from the group of hydrogen, halogen, -CF 3 , and an optionally substituted radical selected from the group of -(CrC ⁇ alkyl, -(C 1 - C 6 )alkylhalo, -(C 3 -C 7 )cycloalkyl, -(C 0 -C 6 )alkyl-OR 5 , and -(C 3 -C 7 )CyClOaIlCyI-(C 1 - C 6 )alkyl; or
- R 5 is selected from the group of hydrogen or an optionally substituted radical selected from the group of -(Ci-C 6 )alkylhalo, -(Ci-C 6 )alkyl, -(C 3 -C 7 )cycloalkyl, -(C 4 - C 10 )alkylcycloalkyl and heterocycle;
- M 1 is an optionally substituted aryl
- M 3 is an optionally substituted radical selected from the group of -(C 3 -C 7 )cycloalkyl, aryl, heteroaryl, heterocycle, -(C 1 -C 6 )alkyl-R 11 , -(Ci-C 6 )alkylhalo, -(C 2 -C 6 )alkyl- NR 11 R 12 , -(C 2 -C 6 )alkyl-OR n and -(C 2 -C 6 )alkyl-SR ⁇ ;
- R 11 and R 12 are selected from the group of a hydrogen or an optionally substituted radical selected from the group of -(C] . -C 6 )alkylhalo, -(Ci-C 6 )alkyl, -(C 3 -C 7 )cycloalkyl, -(C 4 -C 10 )alkylcycloalkyl, heteroaryl, -(CrC ⁇ alkylheteroaryl, aryl, heterocycle and - (Ci-C 6 )alkylaryl; provided that according to proviso (v):
- a 1 radical is selected from the group of hydrogen, halogen, -CF 3 , and an optionally substituted radical selected from the group of -(Ci-C 6 )alkyl, -(C t -C ⁇ alkylhalo, -(C 3 - C 7 )cycloalkyl and heterocycle; n is an integer ranging from 1 to2, and either;
- n 1 and B 1 radical is selected from the group of hydrogen, halogen, -CF 3 , and an optionally substituted radical selected from the group of -(Ci-C 6 )alkyl, -(C 1 - C 6 )alkylhalo, -(C 3 -C 7 )cycloalkyl, -(C 0 -C 6 )alkyl-OR 5 , and -(C 3 -C 7 )cycloalkyl-(Ci- C 6 )alkyl; or (b) n is 2, and B 1 and B 2 radicals are each independently selected from the group of - CF 3 and an optionally substituted radical selected from the group of -(Q-C ⁇ alkyl, -(C 1 - C 6 )alkylhalo, -(C 3 -C 7 )cycloalkyl, and -(
- R 5 is selected from the group hydrogen or an optionally substituted radical selected from the group of -(CrC ⁇ alkylhalo, -(Q-C ⁇ alkyl, -(C 3 -C 7 )cycloalkyl, -(C 4 - C 10 )alkylcycloalkyl and heterocycle;
- M 1 is an optionally substituted heteroaryl
- M 3 is an optionally substituted radical selected from the group of -(C 3 -C 7 )cycloalkyl, aryl, heteroaryl, heterocycle, -(CrC ⁇ alkyl-R 11 , -(CrC ⁇ alkylhalo, -(C 2 -C 6 )alkyl- NR 11 R 12 , -(C 2 -C 6 )alkyl-OR ⁇ and -(C 2 -C 6 )alkyl-SR n ;
- R 11 and R 12 are selected from the group of a hydrogen or an optionally substituted radical selected from the group of -(CrC ⁇ alkylhalo, -(d-C ⁇ alkyl, -(C 3 -C 7 )cycloalkyl, -(C 4 -C 10 )alkylcycloalkyl, heteroaryl, -(CrC ⁇ alkylheteroaryl, aryl, heterocycle and - (Q-COal
- M 1 can not be 1-methyl- lH-indazol-4-yl, lH-indazol-3-yl and lH-indazol-4-yl; and provided that according to proviso (vii):
- a 1 is not a pyridyl; and provided that according to proviso (viii):
- a 1 radical is hydrogen, n is an integer ranging from 1 to2, and either;
- n is 1 and B 1 radical is selected from the group of hydrogen, -CF 3 , -(Q-C ⁇ alkyl and -(d-COalkylhalo; or
- M 1 is an optionally substituted pyridyl
- M 3 is an optionally substituted radical selected from the group of -(C 3 -C 7 )cycloalkyl, aryl, heteroaryl, heterocycle, -(Ci-C 6 )alkylhalo, -(C 2 -C 6 )alkyl- NR 11 R 12 , -(C 2 -C 6 )alkyl-OR ⁇ and -(C 2 -C 6 )alkyl-SR ⁇ ; and
- R 11 and R 12 are selected from the group of a hydrogen or an optionally substituted radical selected from the group of -(Ci-C 6 )alkylhalo, -(Ci-C ⁇ alkyl, -(C 3 -C 7 )cycloalkyl, -(C 4 -C 10 )alkylcycloalkyl, heteroaryl, aryl, heterocycle and - (Ci-C 6 )alkylaryl.
- the invention provides a compound according to Formula (IIIB),
- n is an integer ranging from 1 to 2;
- B n radicals are each independently selected from the group of hydrogen, halogen, -CN, -CF 3 , and an optionally substituted radical selected from the group of - (CrC 6 )alkylhalo, -(C 3 -C 7 )cycloalkyl, aryl, heteroaryl, heterocycle, -(C 0 -C 6 )alkyl-OR 5 , - O-(C 2 -C 6 )alkyl-OR 5 , -NR 5 (C 2 -C 6 )alkyl-OR 6 , -(C 3 -C 7 )cycloalkyl-(C 1 -C 6 )alkyl, -0-(C 3 - C ⁇ cycloalkyKd-C ⁇ alkyl, -NR 5 -(C 3 -C 7 )cycloalkyl-(C 1 -C 6 )alkyl, -(d-C ⁇ alkylhalo- OR 5 , -(d
- R 5 , R 6 and R 7 are each independently hydrogen or an optionally substituted radical selected from the group of -(d-C ⁇ alkylhalo, -(C 1 -C 6 )alkyl, -(C 1 -C 6 )alkylcyano, -(C 3 - C 7 )cycloalkyl, -(C 4 -C 10 )alkylcycloalkyl, heteroaryl, -(CrC ⁇ alkylheteroaryl, aryl, heterocycle and -(C 1 -C 6 )alkylaryl; Any two radicals of R (R 5 , R 6 , or R 7 ) may be taken together to form an optionally substituted 3 to 10 membered carbocyclic or heterocyclic ring;
- M 1 is selected from an optionally substituted aryl and heteroaryl
- KAS/ClientDocs/Addex/53195.WO01.FinalSpec.l0.072008 M 3 is an optionally substituted radical selected from the group of -(C 3 -C 7 )CyClOaHCyI, aryl, heteroaryl, heterocycle, -(Ci-C 6 )alkyl-R n , -(Ci-C 6 )alkylhalo. -(C 2 -C 6 )alkyl- NR 11 R 12 , -(C 2 -C 6 )alkyl-OR n and -(C 2 -C 6 )alkyl-SR ⁇ ; and
- R 11 and R 12 are selected from the group of a hydrogen or an optionally substituted radical selected from the group of -(Ci-C 6 )alkylhalo, -(CrC ⁇ alkyl, -(C 3 -C 7 )cycloalkyl, -(C 4 -C 10 )alkylcycloalkyl, heteroaryl, aryl, heterocycle and - (Ci-C 6 )alkylaryl.
- n is an integer ranging from 1 to 2, and either;
- n 1 and B 1 radical is selected from the group of hydrogen, halogen, -CF 3 , and an optionally substituted radical selected from the group of -(CrC ⁇ alkyl, -(C 1 - C 6 )alkylhalo, -(C 3 -C 7 )cycloalkyl, -(C 0 -C 6 )alkyl-OR S , aryl, heteroaryl, and -(C 3 - C 7 )cycloalkyl-(C 1 -C 6 )alkyl; or (b) n is 2, and B 1 and B 2 radicals are each independently selected from the group of - CF 3 and an optionally substituted radical selected from the group of -(C t -C ⁇ alkyl, -(C 1 - C 6 )alkylhalo, -(C 3 -C 7 )cycloalkyl, and -(C 3 -C 7 )cycloalkyl-(Ci
- R 5 is selected from the group hydrogen or an optionally substituted radical selected from the group of -(CrC 6 )alkylhalo, -(CrC ⁇ alkyl, -(C 3 -C 7 )cycloalkyl, -(C 4 - C 10 )alkylcycloalkyl and heterocycle;
- M 1 is an optionally substituted aryl
- M 3 is an optionally substituted radical selected from the group of -(C 3 -C 7 )cycloalkyl, aryl, heteroaryl, heterocycle, -(d-C ⁇ alkyl-R 11 , -(CrC ⁇ alkylhalo, -(C 2 -C 6 )alkyl- NR 11 R 12 , -(Ca-C ⁇ alkyl-OR 11 and -(C 2 -C 6 )alkyl-SR ⁇ ; and R 11 and R 12 are selected from the group of a hydrogen or an optionally substituted radical selected from the group of -(C 3 -C 7 )cycloalkyl,
- n is an integer ranging from 1 to 2, and either;
- n is 1 and B 1 radical is selected from the group of hydrogen, halogen, -CF 3 , and an optionally substituted radical selected from the group of -(C 1 -C 6 )alkyl, -(C 1 - C 6 )alkylhalo, -(C 3 -C 7 )cycloalkyl, -(C 0 -C 6 )alkyl-OR 5 , aryl, heteroaryl, and -(C 3 - C 7 )cycloalkyl-(Ci-C 6 )alkyl; or (b) n is 2, and B 1 and B 2 radicals are each independently selected from the group of - CF 3 and an optionally substituted radical selected from the group -(C 1 - C 6 )alkylhalo, ⁇ (C 3 -C 7 )cycloalkyl, and -(C 3 -C 7 )cycloalkyl-(C 1 -C 6 )alkyl;
- R 5 is selected from the group hydrogen or an optionally substituted radical selected from the group of -(Ci-C 6 )alkylhalo, -(Ci-C 6 )alkyl, -(C 3 -C 7 )cycloalkyl, -(C 4 - C 10 )alkylcycloalkyl and heterocycle;
- M 1 is an optionally substituted heteroaryl
- M 3 is an optionally substituted radical selected from the group of -(C 3 -C 7 )cycloalkyl, aryl, heteroaryl, heterocycle, -(Q-C ⁇ alkyl-R 11 , -(Ci-C 6 )alkylhalo, -(C 2 -C 6 )alkyl- NR 11 R 12 , -(C 2 -C 6 )alkyl-OR ⁇ and and R 11 and R 12 are selected from the group of a hydrogen or an optionally substituted radical selected from the group of -(Q-C ⁇ alkylhalo, -(Q-C ⁇ alkyl, -(C 3 -C 7 )cycloalkyl, -(C 4 -C 10 )alkylcycloalkyl, heteroaryl, -(Q-C ⁇ alkylheteroaryl, aryl, heterocycle and - (Ci-C f Oalkylaryl.
- n is an integer ranging from 1 to 2, and either;
- n 1 and B 1 radical is selected from the group of hydrogen, -CF 3 , -(Q-C ⁇ alkyl and -(Ci-C 6 )alkylhalo; or
- n 2 ⁇ n + 2 ⁇ n + 2 ⁇ n + 2 ⁇ n
- M 1 is an optionally substituted pyridyl
- M 3 is an optionally substituted radical selected from the group of -(C 3 -C 7 )cycloalkyl, atyl, heteroaryl, heterocycle, -(Ci-C 6 )alkyl-R u s -(CrC ⁇ alkylhalo, -(C 2 -C 6 )alkyl- NR 11 R 12 , -(d-C ⁇ alkyl-OR 11 and -(C 2 -C 6 )alkyl-SR ⁇ ; and R 11 and R 12 are selected from the group of a hydrogen or an optionally substituted radical selected from the group of -(C 1 -C 6 )alkymalo, -(Ci-C 6 )alkyl, -(C 3 -C 7 )cycloalkyl, -(C 4 -C 10 )alkylcycloalkyl, heteroaryl, -(CrC ⁇ alkylheteroaryl, aryl, heterocycle and - (
- Specific compounds of the invention according to Formula (I) to (III) are compounds as mentioned in the following list A and list B as well as a pharmaceutically acceptable acid or base addition salt thereof, a stereochemical ⁇ isomeric form thereof and an N- oxide form thereof:
- (C 1 -C 6 ) means a carbon radical having 1, 2, 3, 4, 5 or 6 carbon atoms.
- (Co-C 6 ) means a carbon radical having 0, 1, 2, 3, 4, 5 or 6 carbon atoms.
- C means a carbon atom
- N means a nitrogen atom
- O means an oxygen atom
- S means a sulphur atom.
- bonds refers to a saturated covalent bond.
- bonds When two or more bonds are adjacent to one another, they are assumed to be equal to one bond.
- alkyl includes both straight and branched chain alkyl radicals and may be methyl, ethyl, n-propyl, i-propyl, n-butyl, i- butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, t-pentyl, neo-pentyl, n-hexyl, i-hexyl or t- hexyl.
- (C 0 -C 3 )alkyl refers to an alkyl radical having 0, 1, 2 or 3 carbon atoms and may be methyl, ethyl, n-propyl and i-propyl.
- cycloalkyl refers to an optionally substituted carbocycle containing no heteroatoms, including mono-, bi-, and tricyclic saturated carbocycles, as well as fused ring systems.
- fused ring systems can include one ring that is partially or fully unsaturated such as a benzene ring to form fused ring systems such as benzo- fused carbocycles.
- Cycloalkyl includes such fused ring systems as spirofused ring systems.
- cycloalkyl examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, decahydronaphthalene, adamantane, indanyl, fluorenyl and 1,2,3,4-tetrahydronaphthalene and the like.
- (C 3 -C 7 )cycloalkyT may be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.
- alkenyl includes both straight and branched chain alkenyl radicals.
- (C 2 -C 6 )alkenyl refers to an alkenyl radical having 2 to 6 carbon atoms and one or two double bonds, and may be, but is not limited to vinyl, allyl, propenyl, i-propenyl, butenyl, i-butenyl, crotyl, pentenyl, i-
- alkynyl includes both straight and branched chain alkynyl radicals.
- aryl refers to an optionally substituted monocyclic or bicyclic hydrocarbon ring system containing at least one unsaturated aromatic ring.
- suitable values of the term “aryl” are phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, indyl, indenyl, benzo[d][l,3]dioxolyl and the like.
- heteroaryl refers to an optionally substituted monocyclic or bicyclic unsaturated, aromatic ring system containing at least one heteroatom selected independently from N, O or S.
- heteroaryl may be, but are not limited to thienyl, pyridyl, thiazolyl, isothiazolyl, furyl, pyrrolyl, triazolyl, imidazolyl, oxadiazolyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolonyl, oxazolonyl, thiazolonyl, tetrazolyl, thiadiazolyl, benzoimidazolyl, benzoxazolyl, benzothiazolyl, tetrahydrotriazolopyridyl, tetrahydrotriazolopyrimidinyl, benzofuryl, benzothiophenyl,
- Examples of pyrazolyl may be, but not limited to, IH- pyrazol-4-yl.
- pyridinyl may be, but not limited to, pyridin-2-yl, pyridin-3- yl and pyridin-4-yl.
- alkylaryl refers respectively to a substituent that is attached via the alkyl radical to an aryl, heteroaryl or cycloalkyl radical, respectively.
- (C 1 - C 6 )alkylaryl includes aryl-Ci-C 6 -alkyl radicals such as benzyl, 1-phenylethyl, 2- phenylethyl, 1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl, 1-naphthylmethyl and 2- naphthylmethyl.
- (Ci-C 6 )alkyheteroaryl includes heteroaryl-CrC ⁇ -alkyl radicals, wherein examples of heteroaryl are the same as those illustrated in the above definition, such as 2-furylmethyl, 3-furylmethyl, 2-thienylmethyl, 3-thienylmethyl, 1- imidazolylmethyl, 2-imidazolylmethyl, 3-imidazolyhnethyl, 2-oxazolylmethyl, 3- oxazolylmethyl, 2-thiazolylmethyl, 3-thiazolylmethyl, 2-pyridylmethyl, 3- pyridylmethyl, 4-pyridylmethyl, 1-quinolylmethyl or the like.
- heterocycle refers to an optionally substituted, monocyclic or bicyclic saturated, partially saturated or unsaturated ring system (containing at least one heteroatom selected independently from N, O and S.
- the said “heterocycle” refers respectively to a group linked either via the carbon or the nitrogen.
- heterocycle includes morpholine, thiomorpholine, tetrahydrofuran, tetrahydropyran radicals or the like.
- alkylheterocycle refers respectively to a substituent that is attached via the alkyl radical to a heterocycle radical, respectively.
- (Q-C ⁇ alkyl heterocycle” includes heterocycle-Ci-C 6 - alkyl radicals such as (tetrahydro-2H-pyran-4-yl)methyl, (tetrahydrofuran-2-yl)methyl or morpholinoethyl.
- a 5- or 6-membered ring containing one or more atoms independently selected from C, N, O and S includes aromatic and heteroaromatic rings as well as carbocyclic and heterocyclic rings which may be saturated or unsaturated.
- Such rings may be, but are not limited to, furyl, isoxazolyl, isothiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidyl,
- KAS/ClientDocs/Addex/53195.WO01.FinalSpec.l0.072008 pyrrolyl, thiazolyl, thienyl, imidazolyl, imidazolidinyl, imidazolinyl, triazolyl, morpholinyl, piperazinyl, piperidyl, piperidonyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, tetxahydropyranyl, tetrahydrothiopyranyl, oxazolidinonyl, thiomorpholinyl, oxadiazolyl, thiadiazolyl, tetrazolyl, phenyl, cyclohexyl, cyclopentyl, cyclohexenyl and cyclopentenyl.
- a 3- to 10-nienibered ring containing one or more atoms independently selected from C, N, O and S includes aromatic and heteroaromatic rings as well as carbocyclic and heterocyclic rings which may be saturated or unsaturated.
- rings may be, but are not limited to imidazolidinyl, imidazolinyl, morpholinyl, piperazinyl, piperidyl, piperidonyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, tetrahydropyranyl, thiomorpholinyl, tetrahydrothiopyranyl, furyl, pyrrolyl, isoxazolyl, isothiazolyl, oxazolyl, oxazolidinonyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, thiazolyl, thienyl, imidazolyl, triazolyl, phenyl, cyclopropyl, aziridinyl, cyclobutyl, azetidinyl, oxadia
- alkylhalo means an alkyl radical as defined above, substituted with one or more halo radicals.
- (C 1 - C 6 )alkylhalo may include, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl and trifluoroethyl.
- 0-C 1 -C 6 - alkylhalo may include, but is not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy and fluoroethoxy.
- alkylcyano means an alkyl radical as defined above, substituted with one or more cyano.
- the term “optionally substituted” refers to radicals further bearing one or more substituents which may be, but are not limited to, (Ci-C 6 )alkyl, (C 3 -C 7 )cycloalkyl, hydroxy, (CrC 6 )alkyloxy, mercapto, aryl, heterocycle, halogen, trifluoromethyl, pentafluoroethyl, cyano, cyanomethyl, nitro, amino, amido, amidinyl, carboxyl, carboxamide, (CrC ⁇ alkyloxycarbonyl, carbamate, sulfonamide, ester and sulfonyl.
- an optionally substituted (Q-C ⁇ alkyl radical, such as a methyl group, by a (C 3 -C 7 )cycloalkyl, such as cyclopropyl refers to a cyclopropylmethyl radical.
- pyridyl radicals substituted in the 3- position carboxyl, cyano and carboxamide group may be called nicotinic, nicotinotrile and nicotinamide radicals.
- solvate refers to a complex of variable stoichiometry formed by a solute (e.g. a compound of Formula (I)) and a solvent.
- the solvent is a pharmaceutically acceptable solvent as preferably water; such solvent may not interfere with the biological activity of the solute.
- the term “antagonists of A 3 refers also to a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof and an iV ⁇ oxide form thereof.
- Antagonists of A 3 described herein, and the pharmaceutically acceptable salts, solvates and hydrates thereof can be used in pharmaceutical preparations in combination with a pharmaceutically acceptable carrier or diluent.
- Suitable pharmaceutically acceptable carrier or diluent Suitable pharmaceutically acceptable
- KAS/ClientDocs/Addex/53195.WO01.FinalSpec.10.072008 carriers include inert solid fillers or diluents and sterile aqueous or organic solutions.
- the antagonists of A 3 will be present in such pharmaceutical compositions in amounts sufficient to provide the desired dosage amount in the range described herein. Techniques for formulation and administration of the compounds of the instant invention can be found in Remington: the Science and Practice of Pharmacy, 19 th edition, Mack Publishing Co., Easton, PA (1995).
- the amount of antagonists of A 3 receptor, administered to the subject will depend on the type and severity of the disease or condition and on the characteristics of the subject, such as general health, age, sex, body weight and tolerance to drugs. The skilled artisan will be able to determine appropriate dosages depending on these and other factors. Effective dosages for commonly used CNS drugs are well known to the skilled person.
- the total daily dose usually ranges from about 0.05 - 2000 mg.
- compositions which provide from about 0.01 to 1000 mg of the active ingredient per unit dose.
- the compositions may be administered by any suitable route.
- parenterally in the form of solutions for injection topically in the form of unguents or lotions, ocularly in the form of eye-drops, rectally in the form of suppositories, intranasally or transcutaneously in the form of delivery system like patches.
- the antagonists of A 3 receptor thereof can be combined with a suitable solid or liquid carrier or diluent to form capsules, tablets, pills, powders, syrups, solutions, suspensions and the like.
- the tablets, pills, capsules, and the like contain from about 0.01 to about 99 weight percent of the active ingredient and a binder such as gum tragacanth, acacias, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid, a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin.
- a dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil.
- KAS/ClientDocs/Addex/53195.WO01.FinalSpec.l0.072008 Various other materials may be present as coatings or to modify the physical form of the dosage unit. For instance, tablets may be coated with shellac, sugar or both.
- a syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavoring such as cherry or orange flavor.
- the disclosed antagonists of A 3 can be combined with sterile aqueous or organic media to form injectable solutions or suspensions.
- injectable solutions or suspensions for example, solutions in sesame or peanut oil, aqueous propylene glycol and the like can be used, as well as aqueous solutions of water-soluble pharmaceutically-acceptable salts of the compounds.
- Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
- the compounds may also be formulated as a depot preparation.
- Such long acting formulations may be administered by implantation, for example, subcutaneously or intramuscularly or by intramuscular injection.
- implantation for example, subcutaneously or intramuscularly or by intramuscular injection.
- sparingly soluble derivatives for example, as sparingly soluble salts.
- the antagonists of A 3 receptor described herein, and their pharmaceutically acceptable salts can be incorporated into various types of ophthalmic formulations for delivery to the eye (e.g., topically, intracamerally, or via an implant). Such compounds are preferably incorporated into topical ophthalmic formulations for delivery to the eye.
- the compounds may be combined with ophthalmologically acceptable preservatives, surfactants, viscosity enhancers, penetration enhancers, buffers, sodium chloride, and water to form an aqueous, sterile ophthalmic suspension or solution.
- Ophthahnic solution formulations may be prepared by dissolving a compound in a physiologically acceptable isotonic aqueous buffer. Further, the ophthalmic solution may include an ophthalmologically acceptable surfactant to assist in dissolving the compound.
- the ophthalmic solution may contain an agent to increase viscosity, such as, hydroxyniethylcellulose, methylcellulose, polyvinylpyrrolidone, and the like, to improve the retention of the formulation in the conjunctival sac.
- Gelling agents can also be used, such as xanthan gum.
- the active ingredient is combined with a preservative in an appropriate vehicle, such as, mineral oil or liquid lanolin.
- Sterile ophthalmic gel formulations may be prepared by suspending the compound in a hydrophilic base, according to the published formulations for analogous ophthalmic preparations. Some preservatives and tonicity agents can be incorporated.
- the antagonists of A 3 receptor described herein can be formulated as topical ophthalmic suspensions or solutions, with a pH of about 4 to 8. Such compounds will normally be contained in these formulations in an amount 0.01% to 5% by weight.
- the dosage form may be a solution, suspension, or microemulsion.
- 1 to 2 drops of these formulations would be delivered to the surface of the eye 1 to 4 times per day according to the discretion of a skilled clinician.
- Preferably disclosed antagonists of A 3 or pharmaceutical formulations containing these compounds are in unit dosage form for administration to a mammal.
- the unit dosage form can be any unit dosage form known in the art including, for example, a capsule, an IV bag, a tablet, or a vial.
- the quantity of active ingredient in a unit dose of composition is an effective amount and may be varied according to the particular treatment involved. It may be appreciated that it may be necessary to make routine variations to the dosage depending on the age and condition of the patient.
- the dosage will also depend on the route of administration which may be by a variety of routes including oral, aerosol, rectal, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, intraocular, eye drop and intranasal.
- the compounds according to the invention may be prepared by methods known in the art of organic synthesis as set forth in part by the following synthesis schemes. In all of the schemes described below, it is well understood that protecting groups for sensitive or reactive groups are employed where necessary in accordance with general principles of chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (Green T.W. and Wuts P.G.M. (1991) Protecting Groups in Organic Synthesis, John Wiley & Sons). These groups are removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art.
- the selection of process as well as the reaction conditions and order of their execution shall be consistent with the preparation of compounds of Formula (I), (II), (III), (IIIA) and (IIIB).
- the compounds according to the invention may be represented as a mixture of enantiomers, which may be resolved into the individual pure R- or S'-enantiomers. If for instance, a particular enantiomer is required, it may be prepared by asymmetric synthesis or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers.
- this resolution may be conveniently performed by fractional crystallization from various solvents as the salts of an optical active acid or by other methods known in the literature (e.g. chiral column chromatography). Resolution of the final product, an intermediate or a starting material may be performed by any suitable method known in the art (Eliel E.L., Wilen S. H. and Mander L.N. (1984) Stereochemistry of Organic Compounds, Wiley-Interscience).
- heterocyclic compounds of the invention can be prepared using synthetic routes well known in the art (Katrizky A.R. and. Rees CW. (1984) Comprehensive Heterocyclic Chemistry, Pergamon Press).
- the product from the reaction can be isolated and purified employing standard techniques, such as extraction, chromatography, crystallization and distillation.
- the compounds of the invention may be prepared by general route of synthesis as disclosed in the following methods or according to any method known from the man skilled in the art.
- compounds of Formula (III) and (HIB) may be prepared according to the synthetic sequences illustrated in Scheme 1.
- Pyrazole gl can be substituted using Mitsunobu conditions.
- amidine can be synthesized either from ester treated with aluminium chloride in the presence of ammonium chloride or from nitrile by synthesis of amidoxime g3 followed by hydrogenation, in the presence of Pd/C and anhydride acetic.
- the cyclization between the amidine g4 and the isothiocyanate g5 may be promoted by di-tert-butylazodicarboxylate and a base such as DBU.
- the compounds of Formula (III) and (IIIA) may be prepared according to the synthetic sequences illustrated in Scheme 2.
- Compound g7 may be hydrolyzed by standard procedures followed by reaction with oxalyl chloride to yield compound g9.
- cyclization reaction may be performed between the halo-ketone glO and the thiourea gll to yield the aminothiazole gl2.
- Thioureas gll can be prepared form the corresponding isothiocyanates g5 by reaction with methanolic ammonia.
- isothiocyanate g5 was not commercially available or known in the literature, it was prepared from the corresponding amine by treatment either with TDCI (M.P.Gauthier at al (2006) Biorg. Med. Chem. 14: H918-H927) or with thiophosgene (R. D.Haugwitz et al (1985) J. Med. Chem. 9: H1234-H1241) as described in literature.
- the compounds of Formula (II) may be prepared according to the synthetic sequences illustrated in Scheme 3.
- Aminothiadiazole gl3 can be alkylated into gl4 in the presence of a base such as NaH and a solvent such as THF.
- the compounds of Formula (III) and (IIIB) may be prepared according to the synthetic sequences illustrated in Scheme 4.
- Pyrazole gl5 can be alkylated using the proper alkyl halide, such as bromide and iodide, or triflate in presence of an inorganic base, such as potassium carbonate, in a suitable organic solvent.
- Alternativerly pyrazole gl5 can be arylated using the proper aryl halide in the presence of an inorganic base, such as potassium carbonate, a copper catalyst, such as copper iodide, a proper ligand, such as 1,10-phenanthroline, in a suitable organic solvent, such as dioxane (Y-M.
- Compound gl6 can be alternatively obtained by esterification of the corresponding commercially available acids gl7 using standard procedures. Then amidine gl8 is synthesized from the corresponding ester by reaction with aluminium chloride in the presence of ammonium chloride in a suitable solvent, such as toluene. The cyclization between the amidine gl8 and the isothiocyanate gl9 is promoted by di- tert-butylazodicarboxylate and a base such as DBU, to provide compound g6.
- the compounds of Formula (III) and (IIIB) may be prepared according to the synthetic sequences illustrated in Scheme 5.
- Compound gl8, prepared as described in Scheme 4 can be converted into compound g20 by cyclization using trichloromethanesulfenyl chloride.in presence of an inorganic base, such as sodium hydroxide, in water.
- Compound g20 can be converted to compound g6 by substitution with the desired amine in presence of a suitable base, such as potassium fer/-butoxide, in a suitable solvent (dioxane) under reflux.
- a suitable base such as potassium fer/-butoxide
- Reversed phase HPLC was carried out on a Acquity UPLC-BEH Cl 8 cartridge (1.7 ⁇ m, 50x2. lmm) from Waters, with a flow rate of 0.5 ml/min.
- 0-0.30min A: 92%, B: 8%), 0.30-1.50 min (A: 0%, B: 100%), 1.50- 2.00 min (A: 0%, B: 100%), 2.00-2.40 min (A: 95%, B: 5%).
- Reversed phase HPLC was carried out on a Acquity UPLC-BEH Cl 8 cartridge (1.7 ⁇ m, 50x2. lmm) from Waters, with a flow rate of 0.5 ml/min.
- 0-0.30min A: 95%, B: 5%
- 0.30-3.30 min A: 0%, B: 100%
- 3.30- 3.90 min A: 0%, B: 100%
- 3.90-4.40 min A: 95%, B: 5%).
- Reversed phase HPLC was carried out on a Acquity UPLC-BEH Cl 8 cartridge (1.7 ⁇ m, 50x2. lmm) from Waters, with a flow rate of 0.5 ml/min.
- 0-O.lOmin A: 95%, B: 5%
- 0.10-1.40 min A: 0%, B: 100%
- 1.40- 1.90 min A: 0%, B: 100%
- 1.90-2.40 min A: 95%, B: 5%).
- Reversed phase HPLC was carried out on a Acquity UPLC-BEH Cl 8 cartridge (1.7 ⁇ m, 50x2. lmm) from Waters, with a flow rate of 0.6 ml/min.
- 0-0.25min A: 95%, B: 5%
- 0.25-3.30 min A: 0%, B: 100%
- 3.30- 4.00 min A: 0%, B: 100%
- 4.00-4.10 min A: 95%, B: 5%
- 4.10-5.00 min A: 95%, B: 5%).
- ES MS detector was used, acquiring both in positive and negative ionization modes. Cone voltages were 30 V (Method LC-A), 26V (Methods LC-B, LC-C and LC-D) and 25V (Methods LC-E and LC-F) for both positive and negative ionization modes. All mass spectra were taken under electrospray ionisation (ESI) methods (see Table 3).
- Table 1 Compounds prepared according to the Examples.
- Step 1 of the general methodology Triphenylphosphine (11 mmol, 2.9 g), (4-methoxyphenyl)methanol (10 mmol, 1.4 g) and di-tert- butylazodicarboxylate (11 mmol, 2.6 g) were added to a solution of 3 -methyl- IH- pyrazole-4-carbonitrile (9.3 mmol, 1.0 g), in DCM (40 mL) at O 0 C. The reaction mixture was stirred at room temperature overnight. The organic phase was washed with a saturated solution of NH 4 OH and brine. Then the organic phase was dried over MgSO 4 , was filtered and was concentrated under reduced pressure.
- the resulting crude product was purified by flash chromatography over silica gel using cyclohexane/ AcOEt (90:10) as eluent to yield l-(4-methoxybenzyl)-3-methyl-lH-pyrazole-4-carbonitrile and l-(4-methoxybenzyl)-5-methyl-lH-pyrazole-4-carbonitrile (9.3 mmol, 2.1g, 100%).
- Step 2 of the general methodology Method A: A mixture of 1- (4-methoxybenzyl)-3 -methyl- 1 H-pyrazole-4-carbonitrile and 1 -(4-methoxybenzyl)-5 - methyl-lH-pyrazole-4-carbonitrile (9.90 mmol, 2.25 g), hydroxylamine 50% in water (19.8 mmol, 1.21 mL) and EtOH (10 mL) was heated at 80 0 C for 12 hours.
- Step 3 of the general methodology DBU (0.39 mmol, 60.0 mg) was added to a solution of l-fluoro-2-isothiocyanatobenzene (0.39 mmol, 48 ⁇ l) and 1- (4-methoxybenzyl)-3 -methyl- lH-pyrazole-4-carboximidamide and l-(4- methoxybenzyl)-5 -methyl- lH-pyrazole-4-carboximidamide (0.39 mmol, 200 mg) in DMF (7 mL) under nitrogen. The reaction mixture was stirred at room temperature until total consumption of the amidine.
- di-fert-butylazodicarboxylate (0.43 mmol, 100 mg) was added dropwise and the reaction mixture was stirred for 5 minutes. After evaporation of the EtOH, water was added and the aqueous phase was extracted with AcOEt. The organic phase was washed with a solution of HCl 1 M, water and brine, was dried over Na 2 SO 4 , was filtered and was concentrated under reduced pressure.
- Step 3 of the general methodology A solution of TMSdiazomethane (6.0 mmol, 3.0 mL) was added to a solution of 1-isopropyl-lH- pyrazole-4-carbonyl chloride (1.95 mmol, 0.33 g) in acetonitrile (5 mL) at 0°C. The reaction mixture was stirred at room temperature overnight. HBr (8.0 mmol, 0.9 mL, 48%) was added at 0 0 C to the reaction mixture. The reaction mixture was stirred at room temperature for one hour.
- Step 4 of the general methodology A solution of 2-bromo-l- (l-isopropyl-lH-pyrazol-4-yl)ethanone (0.43 mmol, 0.10 g) and of l-(pyridin-2- yl)thiourea (0.35 mmol, 53 mg) in acetone (5 mL) was stirred under reflux for one hour. After evaporation of the solvent, DCM was added and the organic phase was washed with a saturated solution OfNaHCO 3 , water and brine. The organic phase was dried over Na 2 SO 4 , was filtered and was concentrated under reduced pressure.
- EXAMPLE 5 SKl-CCyclopropylmethy ⁇ -lH-pyrazol ⁇ -y ⁇ -N ⁇ pyridin-l-yl)-! ⁇ - thiadiazol-5-amine 1 (Final compound 1-22) and 3 ⁇ (l-(Cyclopropylmethyl)-lH- pyrazol-4-yl)-N-(pyridin ⁇ 2-yl)-l,2,4-thiadiazol-5 ⁇ amine monochlohydrate salt (Final compound 1.22a)
- Step Ia of the general methodology K 2 CO 3 (5.35 mmol, 740 mg) and cyclopropylmethylbromide (7.12 mmol, 962 mg) were added to a solution of ethyl l-H-pyrazole-4-carboxylate (3.57 mmol, 500 mg) in acetone (5 mL). The reaction mixture was stirred at reflux for 8 hours. After cooling to room temperature, inorganics were filtered off and the filtrated was concentrated to dryness affording ethyl 1- (cyclopropylmethyl)-lH-pyrazole-4-carboxylate (3.40 mmol, 660 mg, 95%) as colorless oil.
- 6-Cyclobutoxypyridin-2-amine (c3) Sodium hydride (3.80 mmol, 150 mg) was added portionwise to a solution of cyclobutanol (3.46mmmol, 0.27 mL) in acetonitrile and the reaction mixture was stirred 1 hour at room temperature. 6-Bromopyridine-2-amine (1.73 mmol, 0.30 g) was added and the reaction mixture was heated at 130°C for 3 hours under microwave irradiation. After evaporation of the solvent, water was added and the aqueous phase was extracted with AcOEt. The organic phase was washed with water, brine and dried over Na 2 SO 4 . The organic solvent was filtered and concentrated under reduced pressure.
- reaction mixture was concentrated and purified by flash chromatography over silica gel using petroleum ether/ AcOEt (90:10 to 80:20) as eluent affording 2-isothiocyanato-6-methylpyridine (1.21 mmol, 0.18 mg, 33 %) as pale yellow oil;
- Step Ib of the general methodology a solution of l-ethyl-3- methyl-lH-pyrazole-4-carboxylic acid (3.24 mmol, 0.50 g) and sulphuric acid 96% (0.5 mL) in methanol (5 mL) was heated at 70°C for 48 hours. After evaporation of the solvent, AcOEt was added and the organic phase was washed with a saturated solution of NaHCO 35 water and brine, dried over Na 2 SO 4 , filtered and concentrated under
- EXAMPLE 8 6-(3-(l-(Cyclopropylmethyl)-lH-pyrazol-4-yl)-l,2,4-thiadiazol-5- ylamino)-nicotinonitrile (Final compound 1-33)
- Step 2 of the general methodology a mixture of 5-chloro-3-(l- (cyclopropylmethyl)-lH-pyrazol-4-yl)-l,2,4-thiadiazole (0.22 mmol, 54 mg), 6- aminonicotinonitrile (0.44 mmol, 53 mg) and sodium tert-butoxide (0.33 mmol, 32 mg) in dioxane (3 mL) was heated under reflux overnight. Sodium tert-butoxide (0.11 mmol, 12 mg) was added and the reaction mixture was refluxed for other 5 hours. After cooling at room temperature the solvent was evaporated under reduced pressure. The crude product was purified by flash chromatography over silica gel using DCM/MeOH
- EXAMPLE 10 6-(3-(l-(Cyclopropylmethyl)-lH-pyrazol-4-yl)-l,2,4-thiadiazol-S- ylamino)nicotinamide (Final compound 1-35)
- Step 4b of the general methodology methyl 6-(3-(l- (cyclopropylmethyl)- 1 H-pyrazol-4-yl)- 1 ,2,4-thiadiazol-5-ylamino) nicotinate (0.17 mmol, 60 mg) was suspended in 32% NH 4 OH solution and the mixture was heated in a closed vessel at 100°C under microwaves irradiation for Ih. After cooling, a precipitate was formed.
- Step 1 of the general methodology ethyl 1 -(2,2,2- trifluoroethyl)-lH-pyrazole-4-carboxylate (1.03 mmol, 230 mg) was suspended in a mixture of HCl 37% aqueous solution (2 mL) and dioxane (3 mL) and the mixture was heated overnight at reflux. The reaction mixture was concentrated to dryness affording l-(2,2,2-trifluoroethyl)-lH-pyrazole-4-carboxylic acid (1.03 mmol, 200 mg, 100%) as an off white solid. The crude product was used without further purification.
- Step 2 of the general methodology A solution of 1 -(2,2,2- trifluoroethyl)-lH-pyrazole-4-carboxylic acid (1.03 mmol, 200 mg), oxalyl chloride (2.58 mmol, 0.22 mL) and two drops of DMF in DCM (5 mL) was stirred for 4 hours at room temperature. After evaporation of the solvent, 1 -(2,2,2 -trifluoroethyl)- IH- pyrazole-4-carbonyl chloride (1.03 mmol, 219 mg) was obtained as a brown oil. The crude product was used without further purification.
- Step 3 of the general methodology a solution of TMSdiazomethane (3.90 mmol, 1.95 mL) was added to a solution of 1 -(2,2,2- trifluoroethyl)-lH-pyrazole-4-carbonyl chloride ⁇ (1.03 mmol, 219 mg) in acetonitrile (5 mL) at 0°C. The reaction mixture was stirred at room temperature overnight. After cooling to O 0 C, HBr (4.16 mmol, 0.7 mL, 48%) was added to the reaction mixture. The reaction mixture was stirred at room temperature for two hour. AcOEt and water were added to the reaction mixture and the organic layer was separated.
- Step 4 of the general methodology a solution of 2-bromo-l-(l- (2,2,2-trifluoroethyl)-lH- ⁇ yrazol-4-yl)ethanone and 2-chloro-l-(l-(2,2,2- trifluoroethyl)-lH-pyrazol-4-yl)ethanone (0.38 mmol, 105 mg) and of l-(pyridin-2-
- the compounds provided in the present invention are highly selective antagonists of the human adenosine A 3 receptor.
- the compounds of Formula I to III block the activation of adenosine A 3 receptor induced by an agonist of the receptor, while they have little or no effect against other subtypes of adenosine receptors including human A 1 , human A 2 A and human A 2B receptors.
- Radioligand binding assay for the evaluation of the affinity of compounds for the human adenosine A 3 receptors expressed in transfected HEK-293 cells has been performed in 96-well plate and following the experimental conditions described in Salvatore et al. ( (1993) Proc. Natl. Acad. ScL USA, 90: 10365).
- cell membrane homogenates (40 ⁇ g protein) were incubated for 120 min at 22°C with 0.15 nM [ 125 I]AB-MECA in the absence or presence of the test compound in a buffer containing 50 niM Tris-HCl (pH 7.4), 5 mM MgCl 2 , 1 niM EDTA and 2 units/ml ADA.
- Nonspecific binding was determined in the presence of 1 ⁇ M IB- MECA.
- the samples were filtered rapidly under vacuum through glass fiber filters (GF/B, Packard) presoaked with 0.3% PEI and rinsed several times with ice-cold 50 niM Tris-HCl using a 96-sample cell harvester (Unifilter, Packard). The filters were dried then counted for radioactivity in a scintillation counter (Topcount, Packard) using a scintillation cocktail (Microscint 0, Packard).
- the results are expressed as a percent inhibition of the control radioligand specific binding.
- the standard reference compound is IB-MECA, which is tested in each experiment at several concentrations to obtain a competition curve from which its IC 5O and Ki values are calculated.
- the inhibition curves were generated using the Prism GraphPad program (Graph Pad Software Inc, San Diego, USA). IC 50 and Ki determinations were extrapolated from data obtained from 3- to 8-point-concentration response curves using a non linear
- Compounds Nr 1-8, 1-9, 1-10, 1-12, 1-13, 1-14, 1-15, 1-19, 1-21, 1-22, 1-35, 1-42, 1- 50, 1-63, 1-64 and 1-74 of the prevent invention have a KIi value on human adenosine A 3 receptors of less than 1 ⁇ M.
- Radioligand binding assay for the evaluation of the affinity of compounds for the human adenosine A 1 receptors expressed in transfected HEK-293 cells has been performed in 96-well plate and following the experimental conditions described by Townsend-Nicholson and Schofield (1994), J. Biol. Chem. 269: 2373.
- cell membrane homogenates (20 ⁇ g protein) were incubated for 60 min at 22°C with 1 nM [ 3 H]DPCPX in the absence or presence of the test compound in a buffer containing 50 mM Tris-HCl (pH 7.4), 5 mM MgCl 2 , 1 mM EDTA/Tris and 2 UI/ml ADA.
- the samples were filtered rapidly under vacuum through glass fiber filters (GF/B, Packard) presoaked with 0.3% PEI and rinsed several times with ice-cold 50 mM Tris-HCl using a 96-sample cell harvester (Unifilter, Packard).
- the filters are dried then counted for radioactivity in a scintillation counter (Topcount, Packard) using a scintillation cocktail (Microscint 0, Packard). Nonspecific binding was determined in the presence of 1 ⁇ M DPCPX.
- the results are expressed as a percent inhibition of the control radioligand specific binding.
- the standard reference compound is DPCPX, which is tested in each experiment at several concentrations to obtain a competition curve from which its IC 50 is calculated.
- Radioligand binding assay for the evaluation of the affinity of compounds for the human adenosine A 2A receptors expressed in transfected HEK-293 cells has been performed in 96-well plate and following the experimental conditions described by Luthin et al ((1995) MoI. Pharmacol., 47: 307).
- cell membrane homogenates 50 ⁇ g protein were incubated for 120 min at 22°C with 6 nM [ 3 H]CGS 21680 in the absence or presence of the test compound in a buffer containing 50 mM Tris-HCl (pH 7.4), 10 mM MgCl 2 and 2 Ul/ml ADA.
- the samples are filtered rapidly under vacuum through glass fiber filters (GF/B, Packard) presoaked with 0.3% PEI and rinsed several times with ice-cold
- the inhibition curves were generated using the Prism GraphPad program (Graph Pad Software Inc, San Diego, USA). IC 50 and Ki determinations were extrapolated from data obtained from 3- to 8-point-concentration response curves using a non linear regression analysis. The mean of IC 5O and Ki obtained from at least three independent experiments of selected molecules performed in duplicate were calculated.
- Radioligand binding assay for the evaluation of the affinity of compounds for the human adenosine A 2B receptors expressed in transfected HEK-293 cells has been performed in 96-well plate and following the experimental conditions described in Stehle et al ((1992) MoI. Endocrinol. 6:384-393). .
- cell membrane homogenates of HEK-293 cells (200 ⁇ g protein) were incubated for 120 min at 22°C with 0.5 nM [ 3 H]MRS1754 in the absence or presence of the test compound in a buffer containing 10 niM Hepes/Tris (pH 7.4), 1 mM MgCl 2 and 1 mM EDTA. Following incubation, the samples are filtered rapidly under vacuum
- the results are expressed as a percent inhibition of the control radioligand specific binding.
- the standard reference compound is NECA, which is tested in each experiment at several concentrations to obtain a competition curve from which its IC 50 is calculated.
- the inhibition curves were generated using the Prism GraphPad program (Graph Pad Software Inc, San Diego, USA). IC 50 and ELi determinations were extrapolated from data obtained from 3- to 8-point-concentration response curves using a non linear regression analysis. The mean of IC 5O and Ki obtained from at least three independent experiments of selected molecules performed in duplicate were calculated.
- the functional properties of the compounds of the present invention were assessed using a cell-based Ca 2+ -mobilization assay in which the luminescence properties of the photoprotein aequorin was directly proportional to the intracellular Ca 2+ released within
- the reference agonist IB-MECA was injected at a concentration corresponding to 80 % of the maximal agonist concentration (EC 8 o) in the wells containing the cells and test compounds and the light emission was recorded over 60 s using a FDSS 6000 luminometer (Hamamatsu). Results are expressed as relative light units (RLU).
- Compounds Nr 1-8, 1-9, 1-14, 1-15, 1-22, 1-35, 1-50 and 1-64 of the prevent invention have an IC 50 value on human adenosine A 3 receptors less than 1 ⁇ M.
- the selective antagonists of human A 3 receptor are expected to block the effectiveness of adenosine or A 3 AR agonists at human A 3 receptor. Therefore, these selective adenosine A 3 antagonists are expected to be useful in human for the treatment of various conditions associated with dysfunction of adenosine system when adenosine A 3 receptors are overstimulated due to presence of an excess of adenosine or metabolite or endogenous ligand with human A 3 AR agonist property or due to a sustained presence of these agonists in the vicinity of human A 3 ARs resulting in an hyperactivation of adenosinergic system.
- Potato starch ad 200 mg active ingredient can be replaced by the same amount of any of the compounds according to the present invention, in particular by the same amount of any of the exemplified compounds.
- An aqueous suspension is prepared for oral administration so that each 1 milliliter contains 1 to 5 mg of one of the active compounds, 50 mg of sodium carboxymethyl cellulose, 1 mg of sodium benzoate, 500 mg of sorbitol and water ad 1 ml.
- a parenteral composition is prepared by stirring 1.5 % by weight of active ingredient of the invention in 10% by volume propylene glycol and water.
- Disodium EDTA (Edetate disodium) 0.01%
- active ingredient can be replaced with the same amount of any of the compounds according to the present invention, in particular by the same amount of any of the exemplified compounds.
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Abstract
L'invention concerne de nouveaux composés de formule (I). X1, X2, X3, X4, Y1, Y2, Y3, Y4, M1, M2, M3, Am et Bn sont définis dans les revendications de l'invention. Les composés de l'invention sont des antagonistes des récepteurs de l'adénosine de sous-type A3 qui servent à traiter les troubles modulés par les récepteurs A3. L'invention concerne également des compositions pharmaceutiques associées et un procédé d'utilisation de tels composés mis en oeuvre dans la fabrication de médicaments, ainsi qu'un procédé d'utilisation de tels composés visant à prévenir et à traiter des maladies dans lesquelles A3 est impliqué.
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GB0713687A GB0713687D0 (en) | 2007-07-13 | 2007-07-13 | New compounds 1 |
GB0713687.2 | 2007-07-13 | ||
GB0723344A GB0723344D0 (en) | 2007-11-28 | 2007-11-28 | Novel compounds 3 |
GB0723344.8 | 2007-11-28 | ||
GB0803103A GB0803103D0 (en) | 2008-02-20 | 2008-02-20 | Novel compounds 3 |
GB0803103.1 | 2008-02-20 |
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WO2012131031A1 (fr) | 2011-04-01 | 2012-10-04 | H. Lundbeck A/S | Nouveaux effecteurs allostériques positifs du récepteur nicotinique de l'acétylcholine |
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US9073907B2 (en) | 2009-01-12 | 2015-07-07 | Addex Pharma S.A. | Thiazoles derivatives and their use as positive allosteric modulators of metabotropic glutamate receptors |
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