OA16480A - (1,2,4) triazolo[4,3-A]quinoxaline derivatives as inhibitors of phosphodiesterases. - Google Patents
(1,2,4) triazolo[4,3-A]quinoxaline derivatives as inhibitors of phosphodiesterases. Download PDFInfo
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- OA16480A OA16480A OA1201300283 OA16480A OA 16480 A OA16480 A OA 16480A OA 1201300283 OA1201300283 OA 1201300283 OA 16480 A OA16480 A OA 16480A
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Abstract
The invention relates to (1,2,4)triazolo[4,3-a] quinoxaline derivatives of formula (I) which are inhibitors of phosphodiesterase 2 and/or 10, useful in treating central nervous system diseases.
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Formule I
Description
TECHNICAL FIELD
The invention relates to (1,2,4)triazolo[4,3-a]quinoxaline dérivatives which are inhibitors of phosphodiesterase 2 and/or 10, useful in treating central nervous system diseases.
BACKGROUND
Cognitive dysfunction plays a rôle in a lot of central nervous system disorders, including neurological disorders, such as Alzheimer's disease (AD), Parkinsonism and dementia, but also psychiatrie disorders, such as schizophrénie, dépréssion and bipolar disorder. As world population grows older the number of patients with dementia and AD is growing. Therefore, most people are familiar with the cognitive déficits related to these neurological diseases (Massoud and Gauthier, 2010).
However, also in psychiatrie disorders cognitive impairment adversely affect the progress and the treatment outcome of the disease. A most prominent example is schizophrenia. Schizophrenia has a heterogeneous symptomatic picture (American Psychiatrie Association, 1994) that may be divided into three distinct disease domains: positive symptoms (psychotic épisodes of hallucinations, delusions and agitation), négative symptoms (social withdrawal, anhedonia, flattened affect and cognitive déficits (déficits in executive function, verbal learning and memory, verbal fluency) (Thompson and Meltzer, 1993).
Whereas positive symptoms are essentially alleviated by dopamine D2 antagonist and second class antipsychotics négative symptoms and cognitive déficits are still hardly affected by current treatment. Therefore, research of cognitive déficits in schizophrenia has been intensified over the past years. A worldwide network initiative, called MATRICS, has been founded to characterise the cognitive déficits more deeply and to find novel thérapies (Young et al., 2009).
However, cognitive impairment is also seen in patients with dépréssion, bipolar disorder (Sachs et al., 2007; Pavuluri et al., 2009) and in many patients with disorders usually first diagnosed in infancy, childhood and adolescence, such as attention deficit/hyperactivity disorder (ADHD) (Jucaite et al., 2005; Turner et al., 2003).
Dépréssion is a severe mental disorder which extremely impairs daily life. Its prevalence is about 10 % of the world population with an incidence of 2 % according to WHO. Women are more affected than men and elder people more than younger people. The disorder mostly implies a life-long treatment due to the progress of the disease and permanent total disability.
The most prominent symptoms of the disease are anhedonia, feeling of hopelessness, decreased self esteem, loss of appetite and sleep disturbance. Most patients are suicidai. Dépréssion is often combined with anxiety disorders. interestingly, it is less known that dépréssion is also regularly associated with various cognitive impairments (Gualtieri et al., 2006; Mandelli et al., 2006). Here, déficits of attentional and executive function are mostly reported (PaeleckeHabermann et al., 2005). Cognitive déficits are even discussed to be involved in the development of the disease (Beck dépréssion model, Beck, 2008). More recent studies indicate that the severity of the cognitive déficits may predict nonresponse to certain antidepressant treatment (Dunkin et al., 2000; Goriyn et al., 2008).
Up to now, current antidepressant therapy seems not to be sufficient regarding cognitive déficits. Elder antidepressants are reported to impair memory in animal models of learnîng and memory probably due to their anticholinergic component (Kumar and Kulkarni, 1996). In contrast, SSRIs, especially fluoxetine, are described to impair hippocampal-independent but not hippocampal dépendent learning in different rodent models (Valluzi and Chan, 2007). At least, in clinic current therapy it is not possible to fully reverse cognitive déficits. Thus, in dépressive patients who had been successfully treated cognitive performance could be improved but not normalised (Gualtieri et al., 2006). Therefore, an antidepressant with higher efficacy on cognitive impairment may improve disease outcome.
Bipolar disorder is an illness with complex symptomatology. It includes severe symptoms of mood disorders but also manie épisodes and cognitive déficits. The Diagnostic and Statistical Manual, 4th édition and International Classification of Mental Disorder recommend subgroups of bipolar disorder based on whether dépressive or manie [psychotic] symptoms and épisodes are dominating and on the frequency of the épisodes (Gaiwani, 2009). Pharmacological agents commonly used in the management of bipolar disorder include lithium; anticonvulsants, such as valproate, carbamazepine and lamotrigine; and recent years hâve wîtnessed increasing use of atypical antipsychotics (Altamura et al., 2011). As a problem of current therapy the development of tolérance against anticonvulsant treatment and 30% of treatment refractory cases are described (Post and Weiss, 2010; Gaiwani, 2009).
Attention déficit hyperactivity disorder (ADHD) is a central nervous system disorder that is mainly defined by its clinical signs. ADHD shows a heterogeneous symptom pattern in humans. The most important indicators are attention déficits, impulsivity and a hyperactivity that is primarily seen in boys. The disease starts at an early âge and symptoms are most intense during childhood. After puberty the signs of the disease are more masked and focus on cognitive dysfunction (Jucaite et al. 2005; Turner et al. 2003). Although modem research broadened the understanding of the pathomechanism the exact etiology of the disease remains unclear.
Interestingly, the symptoms seen in ADHD are not due to a hyperactivity but a hypoactivity of the so called executive loop of the striatum (Winstanley et al,, 2006; Plizska, 2005). The executive loop is responsible for the régulation of cognitive processes such as planning, working memory and attention (Benke et al., 2003; Easton et al., 2007). A dysfunction of the prefrontal cortex or other pathways within the loop induces impulsivity and a loss of the ability to filter stimuli that corne from the outside. The latter causes the symptoms of sustained attention and hyperactivity (Roberts and Wallis, 2000; Gonzales et al., 2000). The dopaminergic neurotransmitter system plays a central rôle in regulating the activity of the executive loop (Jucaîte et al., 2005). This conclusion is also supported by the current treatment for ADHD that aims for an activation of the dopaminergic neurotransmitter system (Jucaite et al., 2005).
Phosphodiesterases (PDE) are expressed in nearly ail mammalian cells. To date eleven families of phosphodiesterases hâve been identified in mammals (Essayan, 2001). It is well established that PDEs are critically involved in cell signalling. Specifically, PDEs are known to inactivate the cyclic nucléotides cAMP and/or cGMP (Soderling and Beavo, 2000). The cyclic nucléotides cAMP and cGMP are synthesised by the adenylyl and guanylyl cyclases and are second messengers that control many key cellular functions. The synthesis of cAMP and cGMP is regulated by different G-protein-coupled receptor types including dopamine D1 and D2 receptors (Mutschler, 2001).
The phosphodiesterases of the different families vary in their substrate selectivity. Thus, some families only hydrolyse cAMP others only cGMP. Some phosphodiesterases, such as phosphodiesterase 2 and 10, inactivate both cAMP and cGMP (Menniti et al., 2006).
Furthermore, there is a différence in the distribution of the different phosphodiesterases within the organism and additionally, within any particular tissue or organ. For instance, the distribution pattern of the phosphodiesterases within the brain is quite spécifie (Menniti et al., 2006).
Finally, phosphodiesterase families hâve different regulatory properties and intracellular location; some are bound to cell membranes and some are dissociated in the cytoplasm, additionally, a division into various intracellular compartments has been reported (Conti and Jin, 1999).
These différences in the function and location of the different PDE enzyme families suggest that the individual phosphodiesterases are selectively involved in regulating many different physiological processes. Accordingly, sélective phosphodiesterase inhibitors may with fine specificity regulate different physiological and pathophysiological processes.
PDE2 and PDE10 hydrolyse both, cGMP and cAMP (Menniti et al., 2006; Soderling et al., 1999; Kotera et al., 1999).
They are both abundantly expressed in the brain indicating their relevance in CNS function (Bolger et al., 1994; Menniti et al., 2001 ).
PDE2 mRNA is mainly distributed in olfactory bulb, olfactory tubercle, cortex, amygdala, striatum, and hippocampus (Lakics et al., 2005; van Staveren et al., 2003). PDE10 (PDE10A) is primarily expressed in the nucléus accumbens and the caudate putamen. Areas with moderate expression are the thalamus, hippocampus, frontal cortex and olfactory tubercle (Menniti et al., 2001).
Although there are certainly fine différences in the function and expression patterns of PDE2 and 10 the expression of PDE2 in the hippocampus, the cortex and in the striatum and the expression of PDE10 in striatum, hippocampus and frontal cortex indicate an involvement in the mechanism of learning and γ/ memory/cognition. This is further supported by the fact that increased levels of both cGMP and cAMP are involved in the process of short and long term potentiation (LTP) forming (Blokland et al., 2006; Prickaerts et al., 2002). LTP is regarded as the electrophysiological basis of long term memory (Baddeley, 2003). Boess et al. (2004) showed that PDE2 inhibitors amplify the génération of LTP. Additionally, it is reported that the sélective PDE2 inhibitor BAY60-7550 enhances learning and memory in rats and mice in different animal models (Boess et al,, 2004; Rutten et al., 2006). Similar pro-cognitive effects are described for sélective PDE10 inhibitors, such as papaverine and MP-10. Rodefer et al. (2005) hâve found that papaverine reverses attentional set-shifting déficits induced by subchronic administration of phencyclidine, an NMDA antagonist, in rats. Grauer et al. (2009) could show a positive effect of papaverine and MP-10 on cognitive déficits in the novel object récognition and in prepulse inhibition of acoustic startle response in rats. These data support the procognitive effect of PDE2 and/or 10 and a synergistic effect of PDE2 and 10 on cognition.
Furthermore, the expression of PDE2 in the nucléus accumbens (part of the striatum), the olfactory bulb, the olfactory tubercle and the amygdale and the expression of PDE10 in the nucléus accumbens, the olfactory tubercle and the thalamus supports additional involvement of PDE2 and 10 in the pathophysiology of anxiety and dépréssion (Modell et al., 1990). This is supported by in vivo studies. The sélective PDE2 inhibitors BAY60-7550 and ND-7001 are described to be effective in animal models of anxiety and stress-induced behavior (Masood et al., 2008, 2009).
In addition to the pro-cognitive and antidepressant potential of PDE10 inhibition there is evidence for an additional antipsychotic potential of PDE 10 inhibitors. In the striatum PDE10 is predominately found postsynaptic in the medium spiny neurons (Xie et al., 2006). By this location PDE10 may hâve an important influence on the signal cascade induced by dopaminergic and glutamatergic input on the striatum, two neurotransmitter Systems playing a predominate rôle in the pathomechanism of psychosis. Focusing on the dopaminergic input on the medium spiny neurons, PDE10A inhibitors by up-regulating cAMP and cGMP levels act as D1 agonists and D2 antagonists because the activation of Gsprotein coupled dopamine D1 receptor increases intracellular cAMP, whereas the activation of the Gi-protein coupled dopamine D2 receptor decreases intracellular cAMP levels through inhibition of adenylyl cyclase activity (Mutschler et al., 2001). Accordingly, PDE10 inhibitors are reported to be active in several animal models of schizophrénie (Schmidt et al., 2008; Siuciak et al., 2006; Grauer et al., 2009).
Several families of PDE2 inhibitors are known. Imidazotriazinones are claimed in WO 2002/068423 for the treatment of e.g. memory deficîency, cognitive disorders, dementia and Alzheimer's disease. Oxindoles are described in WO 2005/041957 for the treatment of dementia. Further inhibitors of PDE2 are known from WO 2007/121319 for the treatment of anxiety and dépréssion, from WO 2006/072615, WO 2006/072612, WO 2006/024640 and WO 2005/113517 for the treatment of arthritis, cancer, edema and septic shock, from WO 2005/063723 for the treatment of rénal and liver failure, liver dysfunction, restless leg syndrom, rheumatic disorders, arthritis, rhinitis, asthma and obesity, from WO 2005/041957 for the treatment of cancer and thrombotic disorders, from WO 2006/102728 for the treatment of angina pectoris and hypertension from WO 2008/043461 for the treatment of cardiovascular disorders, erectile dysfunction, inflammation and rénal failure and from WO 2005/061497 for the treatment of e.g. dementia, memory disorders, cancer and osteoporosîs.
Finally, benzodiazépines are described in WO 2005/063723 for the general treatment of CNS diseases including anxiety, dépréssion, ADHD, neurodegeneration, Alzheimer’s disease and psychosis.
(1,2,4)Triazolo[4,3-a]quinoxalines without any substituent in position 4 were described in US 5,153,196 to be excitatory amino acid receptor antagonists. These compounds were synthesized from 1,2-diaminobenzenes which were condensed with glyoxylic acid to form the corresponding quinoxalin-2-ones. Treatment with POCI3 yielded the 2-chloroquinoxalines which were treated with hydrazine to préparé the 2-hydrazino- substituted dérivatives. The following condensation with triethylorthoacetate delivered 1-methyl-1,2,4triazolo[4,3ajquinoxaline dérivatives.
Some other (1,2,4)triazolo[4,3-a]quinoxalines without any substituent in position 4 were described in WO 2007/087250 to be inhibitors of 5-lipoxygenase for the treatment of respiratory and cardiovascular diseases.
An alternative route for the synthesis of 4-methyl substituted dérivatives was published by R.Aggarwal et.al. (Synthetic Communications 36 (2006), 18731878).
2-chloro-3-methylquinoxalines were treated with hydrazine to form the corresponding 2-hydrazino-3-methylquinoxalines. These hydrazines were condensed with aldéhydes to préparé the corresponding hydrazones. Finally, an oxidative intramolecular cyclisation in the presence of iodobenzene diacetate (IBD) provided the desired 1,2,4triazolo[4,3-a]quinoxalines. Similar synthetic approaches were already described by K. Dalip et.al. (Green Chemistry 6 (2004), 156-157) and D. A. Vyas et.al. (Indian Journal of Heterocyclic Chemistry 14 (2005), 361-362) with modifications of the conditions in the final step. Some of these dérivatives were described to hâve antimicrobial activities.
Based on the same synthetic pathway S. Wagle et al. (European Journal of
Médicinal Chemistry (2009), 44, 1135-1143) described the use of 4-methyl(1,2,4)triazolo[4,3-a]quinoxalines as intermediates for the synthesis of 4-styryl(I^^Jtriazolo^.S-aJquinoxalines which were tested on potential anti-convulsive activity. vZ
Other (1,2,4)triazolo[4,3-a]quinoxalines are described in WO 2010/030785 to be inhibitors of histamine receptors for the treatment of inflammatory, autoimmune, allergie and ocular diseases.
4-Trifluoromethyl-substituted (1,2,4)triazolo[4,3-a]quinoxalines are published in US 20090163545 for altering the lifespan of eucariotic organisme, in Bioorganic & Médicinal Chemistry, 2010, 18 (22), 7773-7785 to be folate cycle inhibitors and in Chemistry & Biology, 2007, 14 (10), 1105-1118 to modulate the TNF-a induced expression of ICAM-1 in lung épithélial cells.
SUMMARY
The présent invention provides, inter alia, compounds of formula (I):
or pharmaceutically acceptable salts thereof.
The présent invention also provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable sait thereof for use in medicine, and optionally a pharmaceutically acceptable carrier. The pharmaceutical composition may be used in human or veterinary medicine.
The présent invention further provides a method of treating disorders associated with phosphodiesterase 2 and/or 10 hyperactivity, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable sait thereof.
The présent invention also provides a method of treating a central nervous system disorder in a patient in need thereof comprising, administering to said patient a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable sait thereof.
The présent invention further provides a method of treating obesity, type II diabètes, metabolic syndrome, glucose intolérance and related health risks, symptoms or disorders in a patient in need thereof comprising administering to said patient a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable sait thereof.
The présent invention also provides a compound for use in any of the methods described herein. The présent invention further provides use of a compound for the préparation of a médicament for use in any of the methods described herein.
The details of one or more embodiments of the invention are set forth in the accompanying drawings and the description below. Other features, objects, and advantages of the invention will be apparent from the description and drawings, and from the claims.
DETAILED DESCRIPTION
The présent invention provides, inter alia, a compound of formula (I):
or a pharmaceutically acceptable sait thereof; wherein:
R1 represents
-phenyl, 2-pyridyl, 3-pyridyl or4-pyridyl, in each case substituted with a substituent different from H in an ortho position of the linkage to the backbone structure and optionally substituted with further substituents different from H,
R2 represents
- hydrogen,
- Cv4 alkyl, preferably Ci.2 alkyl, optionally substituted with up to 5, 3 or halo, e.g. fluorine atoms, such as -CH3, -CH2F, or -CHF2 ;
R3, R4 ,R5 and Re are independently from each other representing
- hydrogen,
- halogen,
- C14 alkyl, preferably Ci-2 alkyl optionally substituted with up to 5, preferably up to 3 halo, e.g. fluorine atoms, such as -CH3, -CH2F, -CHF2 or-CF3, and/or-OCi-2 (halo)alkyl,
- -C3-a cycloalkyl, optionally substituted with halo, -C-|.2 (halo)alkyl and/or -OCi.2 (halo)alkyl,
- -CN,
- -OH,
- -OC1.4 alkyl, preferably -OCi-2alkyl, optionally substituted with up to 5, preferably up to 3 halo, e.g. fluorine atoms, such as -OCH3, -OCH2F, -OCHF2 or,-OCF3 and/or -OC-|.2 (halo) alkyl,
-OC3.8 cycloalkyl optionally substituted with halo, -C^ (halo)alkyl, and/or
-OCi-2 (halo)alkyl,
- -O(CH2)n-R10, wherein n can be 1 or 2;
R10 represents a cyclic group, e.g. phenyl or a heterocyclic, monocyclic or bicyclic ring System with 5 to 13 ring members and one to five heteroatoms, which can be N, O and/or S, preferably with N in ring position 2, such as quinolin-2yi.
or benzimidazol-2-yl, which can be unsubstituted or substituted preferably up to 4 times by halogen, C-m alkyl optionally substituted with up to 5, preferably up to 3 halogen, e.g. fluorine atoms, such as -CH3, -CH2F, -CHF2 or -CF3, or OC1.4 alkyl, optionally substituted with up to 5, preferably up to 3 halogen, e.g. -CH3, -OCH2F, -OCHF2 or -OCF3, but preferably excluding the following compounds: 1-(2-hydroxyphenyl)-4-methyl-(1,2,4)triazolo[4,3-a]quinoxaline, 1-(2-chlorophenyl)-4-methyl-(1,2,4)triazolo[4,3-a]quinoxaline, 1-(2-nitrophenyl)-4-methyl-(1,2,4)triazolo[4,3-a]quinoxaline,
-(2-methoxyphenyl)-4-methyl-( 1 ^/Hriazolo^^-ajquinoxaline, or 1-(2-hydroxy-3-methoxyphenyl)-4-methyl-(1,2,4)triazolo[4,3-a]quinoxaline.
Further it is preferred that the following compounds are excluded: 1-(5-amino-2-chlorophenyl)-4-methyl-(1,2,4)triazolo[4,3-a]quinoxaline, 1-(5-amino-2-methoxyphenyl)-4-methyl-(1,2,4)triazolo[4,3-a]quinoxaline, 1-(5-amino-2-methylphenyl)-4-methyl-(1,2,4)triazolo[4,3-a]quinoxaline.
It should be noted, however, that the exclusion of the above compounds preferably does not apply to the use of these compounds in medicine, particularly in the medical indications as described herein below.
In some embodiments R1 is substituted with 1-3 substituents R7, R8 and/or R9, different from H, so that at least one of these substituents is in an ortho position of the attachment site of R1 to the backbone structure.
Preferably, the substituents R7 , Re , R9 are independently from each other representing
- halogen,
- NO2,
- -Cvg alkyl, optionally substituted with up to 5, preferably up to 3 fluorine atoms,
-OCi-6 alkyl, optionally substituted with up to 5, preferably up to 3 fluorine atoms,
- -SCi-6 alkyl, optionally substituted with up to 5, preferably up to 3 fluorine atoms, such as -SCH3,
- -phenyl which can be substituted with up to two halogen atoms and/or CF3 groups,
- -O(CH2)n-R11 , wherein n can be 0, 1, 2, 3 or 4,
R11 represents if n = 2, 3 or 4:
- -OH
- -OC-i-4 alkyl such as -OCH3,
- - O(C=O) Ci-4 alkyl such as -O(C=O)CH3 or -O(C=O)C(CH3)3, if n = 0, 1,2, 3 or 4:
. - C3.6 alkyl such as -C(CH3)3,
- a cyclic group, which is linked to O(CH2)n via a covalent bond or via
- -CH(OH)-, -C(=O)-, or - CH(halogen)-, e.g. -CHF
- wherein the cyclic group is preferably selected from phenyl, C3-8 (hetero)cycloalkyl such as cyclopropyl, cyclobutyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl, pyran-4-yl, 2-pyridyl, 3-pyridyl, 4pyridyl. w—
Spécifie examples of R11 are phenyl, cyclopropyl, cyclobutyl, pyran-4-yl, 2pyridyl, 3-pyridyl, 4-pyridyl,
Preferred are compounds wherein R1 represents phenyl, which is substituted with 1, 2 or 3 substituents R7 to R8 and/or R9 which are different from H, wherein at least one of these substituents is in an ortho position of the attachment site to the backbone structure. Especially preferred are compounds, wherein R1 is phenyl having a substituent in one ortho position (position 2) of the attachment site (position 1 ) selected from halo (e.g. F, Cl or Br), methyl, halomethyl such as CF3, SCH3, C^e alkoxy, optionally substituted with halo (e.g. methoxy, ethoxy or butoxy) and optionally a further substituent in position 3, 5 or 6, preferably in position 5, wherein the further substituent may be (i) halo (e.g. F, Cl or Br), (ii) C-i.ê alkyl optionally substituted with halo, OH and/or C|.3 (halo) alkoxy; or (iii) C1-6 alkoxy, optionally substituted with halo, OH, OCi.3 (halo) alkyl and/or with a cyclic substituent as defined in R11.
In an especially preferred embodiment, R1 represents phenyl substituted with halogen, e.g. Cl, in position 2 and OH or -OCi.6 alkyl optionally substituted with OH, particularly -OCH2CH2OH, -OCH2CH(OH)-CH3 or OCH2-CH2-CH2OH in position 3, 5, or 6, particularly in position 5. A spécifie preferred example of R1 is 2-chloro-5-[(3-hydroxy)-1-propanyloxy]phenyl (wherein phenyl is attached via position 1 to the backbone).
Also preferred are compounds, wherein R1 is 2-pyridyl, 3-pyridyl or 4pyridyl which is substituted with 1, 2 or 3 substituents R7, R8 and/or R9 wherein at least one of these substituents is in an ortho position of the, attachment site to the backbone structure, preferably selected from halo (e.g. F, Cl or Br), methyl or SCH3 and optionally a further substituent as described above for R1=phenyl.
Further preferred are compounds, wherein R2 represents C1-2 alkyl such as methyl, optionally substituted with up to 2 halo, e.g. fluorine atoms such as
-CH3i -CH2F or -CHF2. Especially preferred are compounds, wherein R2 represents -CH3.
Further preferred are compounds, wherein R3 and R6 represent hydrogen.
Further preferred are compounds, wherein R4 and R5 are independently from each other representing hydrogen, OH, halogen, -CH3, -CF3, -OCH3, -OCHF2, -OCF3. -O(CH2)n-R10, wherein n can be 1 or 2 and wherein R10 is as defined above. Especially preferred are compounds, wherein R4 and R5 are independently selected from H, OH, F, Cl, Br, -CH3, -CF3, -OCH3 or -OCH2-R10, wherein R10 is phenyl unsubstituted or substituted as defined above.
Further preferred are compounds wherein R4 is H and R5 is different from H (and defined as described above) or compounds, wherein R4 is different from H (and defined as described above) and R5 is H.
Further preferred are compounds, wherein R2 is CH3, R4 is H and R5 is different from H (and defined as described above) or wherein R2 is CH3, R4 is different from H (and defined as described above) and R5 is H. Especially preferred are compounds, wherein R2 is CH3, R4 is H and R5 is F, Cl, Br or CF3, or wherein R2 is CH3, R5 is H and R4 is OH, F, Cl, Br, CF3 or OCH2-R10, wherein R10 is phenyl unsubstituted or substituted as described above. R3 and R6 are preferably hydogen in these embodiments. In a spécifie preferred example of the compounds is R2 = CH3 and R3, R4 and R6 are H. ά/
Further preferred are compounds, wherein R7, R8 and/or R9 are independently from each other representing halogen, -CH3, optionally substituted with up to 3 fluorine atoms, -OC-|.6 alkyl, optionally substituted with up to 3 fluorine atoms or -O(CH2)n-R11 , wherein n can be 0, 1, 2, 3 or and R11 is as described above.
Further preferred are compounds, wherein R10 represents phenyl, which can be substituted up to two times by halogen or-OCH3or quinolin-2-yl.
Further preferred are compounds, wherein R11 represents if n = 2, 3 or 4: OH or -OCH3 and if n = 0, 1, 2, 3 or 4: phenyl, 2-pyridyl, 3-pyridyl,
Especially preferred are compounds, wherein R1, R2, R4 and R5 or R1, R2, R3, R4, R5 and R6 are as defined in the above preferred embodiments. Further especially preferred are compounds, wherein R1, R2, R4, R5 and R10 or R1, R2, R3, R4, R5, R6 and R10, or R1, R2, R4, R5, R7. R8, R9, R10 and R11 or R1, R2, R3, R4, R5, R6, R7, R8, R9, R10 and R11 are compounds as defined in the above preferred embodiments. It should be noted that each of the preferred or especially preferred embodiments of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10 and R11 can be freely combined with any other preferred or especially preferred embodiment. These combinations are explicitly disclosed within the context of the présent spécification and daims.
Further preferred are compounds as described in any one of the Examples 1-106 or a pharmaceutically acceptable sait thereof:
- 8-Chloro-1 -(2-chloro-phenyl)-4-methyl-[1,2,4]triazolo[4,3-a]quinoxaline,
- 8-Chloro-1-(2-fluoro-phenyl)-4-methyl-[1,2,4]triazolo[4,3-a]quinoxaline,
- 8-Chloro-1-(2-methoxy-phenyl)-4-methyl-[1,2,4]triazolo[4,3a]quinoxaline,
- 8-Chloro-1-(5-fluoro-2-methyl phenyl)-4-methyl-[1 ,2,4]triazolo[4,3a]quin-oxaline, uy/
- 8-Chloro-4-methyl-1-(2-methyl-pyridin-3-yl)-[1,2,4]triazolo[4,3ajquinoxaline,
- 8-Chloro-1-(2,5-dichloro-phenyl)-4-methyl-[1,2,4]triazolo[4,3ajquinoxaline,
- 8-Chloro1-(2-chloro-5“methoxy-phenyl)-4-methyl-[1,2,4]triazolo[4I3a]quinoxaline,
- 8-Chloro-4-methyl-1 -o-tol y l-[ 1 ^^Jtriazolol^.S-aJquinoxaline,
- 8-Chloro-4-methyl-1 -(3-meth y l-pyrid i n-4-yl )-[ 1,2,4]triazolo[4,3ajquinoxaline,
- 8-Chloro-1 -(2-chloro-5-trifluoromethyl-phenyl)-4-methyl-[1,2,4]triazolo[4,3-aJquinoxaline,
-(5-Butoxy-2-fluoro-phenyl)-8-chloro-4-methyl-[1,2,4]triazolo[4t3a]quinoxaline,
1-(5-Butoxy-2-chloro-phenyl)-8-chloro-4-methyl-[1,2,4]triazolo[4,3a]quinoxaline,
- 8-Chloro-1 -(2-fluoro-5-hexyloxy-phenyl)-4-methyl-[1,2,4]triazolo[4,3ajquinoxaline,
- 1-(5-Butoxy-2-methyl-phenyl)-8-chloro-4-methyl-[1,2,4]triazolo[4,3ajquinoxaline,
- 8-Chloro-1-(5-hexyloxy-2-methyl-phenyl)-4-methyl-[1,2,4]triazolo[4,3“ a]quinoxaline,
- 8-Chloro-1-[2-chloro-5-(4,4,4-trifluorObutoxy)-phenyl]-4-methyl- [1,2,4]triazolo[4,3-a]quinoxaline,
- 8-Chloro-1 -[2-fluoro-5-(4-fluoro-butoxy)-phenyl]-4-methyl- [1,2,4]triazolo[4,3-a]quinoxaline,
- 7-Chloro-1-(216-difluoro-phenyl)-4-methyl-[1,2,4]triazolo[413a]quinoxaline,
- 7-Chloro-1-(215-dichloro-phenyl)-4-methyl-[1,2I4]triazolo[4,3ajquinoxaline,
- 7-Chloro-1“(2-chloro-5-methoxy-phenyl)-4~methyl“[1,2,4]triazolo[4(3ajquinoxaline, w—
- 7-Chloro-1 -(2-chloro-5-trifluoromethyl-phenyÎ)-4-methyl- [1.2.4] triazolo[4t3-a]quinoxaline,
- 1 -(5-Butoxy-2-fluoro-phenyl)-7-chloro-4-methyl-[1,2,4]triazolo[4,3a]quinoxaline,
- 1 -(5-Butoxy-2-chloro-phenyl)-7-chloro-4-methyl-[1,2,4]triazolo[4,3ajquinoxaline,
- 7-Chloro-1 -(2-fluoro-5-hexyloxy-phenyl)-4-methyl-[1,2,4]triazolo[4,3-
a]quinoxaüne,
- 1 -(5-Butoxy-2-methyl-phenyl)-7-chloro-4-methyl-[1,2,4]triazolo[4,3-
a]quinoxaline,
- 7-Chloro-1-(5-hexyloxy-2-methyl-phenyl)-4-methyl-[1,2,4]triazolo[4,3-
a]quinoxaline,
- 7-Chloro-1-[2-chloro-5-(4,4,4“trifluoro-butoxy)-phenyl]-4-methyl- [1.2.4] triazolo[4,3-a]quinoxaline,
- 7-Chloro-1 -[2-fluoro-5-(4-fluoro-butoxy)-phenyl]-4-methyl- [I^^Jtriazolo^.S-aJquinoxaline,
- 7-Chloro-1 -[2-fluoro-5-(2-methoxy-ethoxy)-phenyl]-[1,2,4]triazolo[4,3ajquinoxaline,
-(2-Fluoro-phenyl)-4-methyl-[1,2,4]triazolo [4,3-a]quinoxaline,
1-(5-Fluoro-2-methyl-phenyl)-4-methyl-[1,2,4]triazolo[4,3-a]quinoxaline,
1-(2-Chloro-phenyl)-4-methyl-[1 ^^Itriazolo^.S-alquinoxaline,
1-(2-Methoxy-phenyl)“4-methyl-[1,2I4]triazolo[4,3-a]quinoxalinel
1-(2,5-Dichloro-phenyl)-4-methyl-[1,2,4]triazolo[4l3-a]quinoxaline,
1-(2,3-Dichloro-phenyl)-4-methyl-[1,2,4]triazolo[4,3-a]quinoxaline,
1-(2-Chloro-6-fluoro-phenyl)-4-methyl-[1,2,4]triazolo[4,3-a]quinoxaline1
1-(2-Chloro-5-trifluoromethyl“phenyl)-4-methyl-[1,2,4]triazolo[4l3ajquinoxaline,
- 1-(2-Chloro-5-methoxy-phenyl)-4-methyl-[1 (2,4]triazolo[4,3- ajquinoxaline,
- 4-Methyl-1-(3-methyl-pyridin-4-yl)-[1,2,4]triazolo[4,3-a]quinoxaline,
- 1-(5-Butoxy-2-fluoro-phenyl)-4-methyl-[1,2,4]triazolo[4,3-a]quinoxaline,
- 1 -(5-Butoxy-2-chloro-phenyl)-4-methyl-[1 ^/Itriazolo^.S-aJquinoxaline,
- 1 -[2-Fluoro-5-(4-phenoxy-butoxy)-phenyl]-4-methyl-[1,2,4]triazolo[4,3ajquinoxaline,
- 1 -[2-Fluoro-5-(4-methoxy--ethoxy)-phenyl]-4-methyl-[1,2,4]ίπ3ζοΐο[4,3' ajquinoxaline,
- 4-Methyl-3-(4-methyl-[1I2,4]triazolo[4,3-a]quinoxalin-1-yl)-phenol,
- 1 -[2-Chloro-5-(4,4,4-trifluoro-butoxy)-phenyl]“4-methyl-[1,2,4]triazolo [4,3-a]quinoxaline,
- 1 -[2-Chloro-5-(4-fluoro-butoxy)-phenyl]-4-methyl-[1,2,4]tri azolo[4,3a]quinoxaline,
- 1 -(2-Chloro-5-cyclobutylmethoxy-phenyl)-4-methyl-[1,2,4]triazolo[4,3ajquinoxaline,
-(2-ChlorO“5-cyclopropylmethoxy-phenyl)-4-methyl-[1,2,4]triazolo[4,3a]quinoxaline,
- 1 -(2-ChlorO“5-phenethyloxy-phenyl)-4-methyl-[1,2,4]triazolo[4,3ajquinoxaline,
- 4-Chloro-3-(4-methyl-[1,2,4]triazolo[4l3-a]quinoxalin-1-yl)-phenol,
- 1 -[5-(3,3-Dimethyl-butoxy)-2-fluorO“phenyl]-4-methyl-[1,2,4]triazolo[4,3a]quinoxaline,
- 8-Fluoro-1 -(2-fluoro-phenyl)-4-methyl-[1 ^^triazolo^.S-ajquinoxaline,
- 8“Fluoro-4-methyl-1-(2-methyl’pyridin-3-yl)-[1,2,4]triazolo[4,3a]quinoxaline,
- 8-Fluoro-1 -(5-fluoro-2-methyl-phenyl)-4-methyl-[1 t2,4]triazolo[4,3ajquinoxaline,
- 1-(2-Chloro-phenyl)-8-fluoro-4-methyl-[1.2,4]triazolo[4)3-a]quinoxaline,
- 1 -(2-Chloro-5-methoxy-phenyl)-8-fluoro-4-methy41,2,4]triazolo[4,3a]quinoxaline,
- 1 -(2-Chloro-5-trifluoromethyl-phenyl)-8-fluorO'4-methyl- [1,2,4]triazolo[4,3-a]quinoxaline,
- 1-(5-Butoxy-2-fluoro-phenyl)-8-fluoro-4-methyl-[1,2,4]triazolo[4,3-
- 1 -(5-Butoxy-2-chloro-phenyl)-8-fluoro-4-methyl-[1,2,4]triazolo[4,3ajquinoxaline,
- 8-Fluoro-1 -(2-fluoro-5-hexyloxy-phenyl)-4-methyl-[1,2,4]triazolo[413ajquinoxaiine,
- 1 -(2-Chloro-phenyl)-4-methyl-8-trifluoromethyl-[1,2,4]triazolo[4,3ajquinoxaline,
- 1 -(5-Fluoro-2-methyl-phenyl)-4-methyl-8-trifluoromethyl[l^/Jtriazolo^.S-alquinoxaline,
- 1-(2-Methoxy-phenyl)-4-methyl-8-trifluoromethyl-[1,2,4]triazolo[4,3a]quinoxaline,
- 1-(2l3-Dichloro-phenyl)-4-methyl-8-trifluoromethyl-[1)2,4]triazolo[413ajquinoxaline,
- 1-(2-Chloro-5-trifluoromethyl-phenyl)-4-methyl-8-trifluoromethyl[I^^Jtriazolo^.S-aJquinoxaline,
- 1 -(2-Fluoro-pheny[)-4-methyl-8-trifluoromethyl-[1,2,4]triazolo[4,3ajquinoxaline,
- 1-(5-Butoxy“2-fluoro-phenyl)-4-methyl-8-trifluoromethyl- [1.2.4] triazoo[4,3-a]quinoxaline,
- 1 -(2-Fluoro-5-hexyloxy-phenyl)-4-methyl-8-trifluoromethyl[I^^Jtrïazolo^.S-aJquinoxaline,
- 4-Methyl-1-(2-methylsulfanyl-pyridin-3-yl)-7-trifluoromethyl- [1.2.4] triazolo[4,3-a]quinoxaline,
- 1 -(2,6-Difluoro-phenyl)-4-methyl-7-trifluoromethyl-[1,2,4]triazolo[4,3ajquinoxaline,
- 1-(2-Fluoro-phenyl)-4-methyl-7-trifluoromethyl-[112,4]triazolo[4,3a]quinoxaline,
- 1-(5-Fluoro-2-methyl-phenyl)-7-methoxy-4-methyl-[1,2,4]triazolo[4,3- ajquinoxaline,
- 1 -(2-Fluoro-phenyl)-7-methoxy-4-methyl-[1,2,4]1π3ζοΐο[4,3a]quinoxaline,
- 1-(2-Chloro-phenyl)-7-methoxy-4-methyl-[1,2,4]triazolo[4,3- κλΖ
a]quinoxaline,
- 1 -(2,6-Difluoro-phenyl)-7-methoxy-4-methyl-[1,2,4]ίπ3ζοΙο[4,3“ ajquinoxaline,
- 1 -(2-Chloro-phenyl)-4-methyl-[1,214]triazolo[4,3-a]quinoxalin-7-ol
- 1-(2-Chloro-phenyl)-7-(4-fluoro-benzyloxy)-4-methyl-[1,2,4]triazolo[4,3a]quinoxaline,
- 1-(2-Chloro-phenyl)-7-[2-(3,4-dimethoxy-phenyl)-ethoxy]-4-methyl[l^^triazolo^.S-alquinoxaline,
1-(2-Chloro-phenyl)-4-methyl-7-(quinolin-2-ylmethoxy)[I^^Jtrïazolo^.S-aJquînoxaline,
- 1 -(2-Chloro-phenyl)-4-methyl-8-(quinolin-2-ylmethoxy)- [1,2,4]triazolo[4,3-a]quinoxaline,
- 8-Bromo-1-(2-chloro-phenyl)-4-methy[1 ^^Itriazolo^.S-ajquinoxaline,
- 8-Bromo-1 -(2-chloro-5-trifluoromethyl-phenyl)-4-methyl[l^^jtriazolo^.S-aJquinoxaline,
- 8-Bromo-1 -(5-butoxy-2-chloro-phenyl)-4-methyl-[1,2,4]triazolo[4,3a]quinoxaline,
- 8-Bromo-1-(5-butoxy-2-fluoro-phenyl)-4-methyl-[1,2,4]triazolo[4,3a]quinoxaline,
- 7-Bromo-1 -(2-chloro-5-trifluoromethyl-phenyl)-4-methyl· [l^^jtriazolo^.S-aJquinoxaline,
- 7-Bromo-1 -(5-butoxy-2-chloro-phenyl)-4-methyl-[1,2,4]triazolo[4,3a]quinoxaline,
- 7-Bromo-1-(5-butoxy-2-fluoro-phenyl)-4-methyl-[1,2,4]triazolo[4,3a]quinoxaline,
- 2,2-Dimethyl-propionic acid 4-chloro-3-(4-methyl-[1,2,4]triazolo[4,3a]quinoxalin1yi)-phenyl ester,
- Acetic acid 4-[4-chloro-3-(4-methyl-[1,2,4]triazolo[4,3-a]quinoxalin-1-yl)phenoxyj-butyl ester,
- 4-[4-Chloro-3-(4-methyl-[1 ^^triazolol/i-.S-aJquinoxalin-l-yO-phenoxy]butan-1-ol, —
- 1 -[2-Chloro-5-(2-morpholin-4-yl-ethoxy)-phenyl]-4-methyl[I^^Jtriazolo^.S-aJquinoxaline,
- 1 -[2-Chloro-5-(2-morpholin-4-yl-ethoxy)-phenyl]-4-methyl- [1.2.4] triazolo[4,3-a]quinoxaline hydrochloride,
- 2-[4-Chloro-3-(4-methyl-[1,2,4]triazolo[4,3-a]quinoxalin-1-yl)-phenoxy]-
-pyridin-2-yl-ethanone,
- 1-{2-Chloro-5-[2-(4-methyl-piperazin-1-yl)-ethoxy]-phenyl}-4-methyl- [1.2.4] triazolo[4,3-a]quinoxaline,
- 1 -[2-C h I o ro-5-(2-piperid i n-1 -yl-ethoxy)-phenyl]-4-methyl- [1,2,4]triazolo[4,3-a]quinoxaline,
- 1-[2-Chloro-5-(2-pyrrolidin-1-yl“ethoxy)-phenyl]-4-methyl- [1 ,2,4]triazolo[4,3-a]quinoxalinet
- 1-{2-Chîoro-5-[2-(tetrahydro-pyran-4-yl)-ethoxy]-phenyl}-4-methyl- [1,2,4]triazolo[4,3-a]quinoxaline,
- 3-[4-Chloro-3-(4-methyl-[1,2,4]triazolo[413-a]quinoxalin-1-yl)-phenoxy]propan-1-ol,
- 2-[4-Chloro-3-(4-methyl-[1,2,4]triazolo[413-a]quinoxalin-1-yl)-phenoxy]éthanol,
- 1 -[4-Chloro-3-(4-methyl-[1,2,4]triazolo[4,3-a]quinoxalin-1-yl)-phenoxy]propan-2-ol,
- 3-[4-Chloro-3-(8-chloro-4-methyl-[1,2,4]triazolo[4,3-a]quinoxalin-1-yl)ph enoxy]-propa n-1 -ol,
- 1 -[4-Chloro-3-(8-chloro-4-methyl-[1,2,4]triazolo[4,3-a]quinoxalin-1 -yl )phenoxy]-propan-2-ol,
- (S) 1 -[4-Chloro-3-(4-methyl-[1,2,4]triazolo[4,3-a]quinoxalin-1 -yl)- phenoxyJ-propan-2-ol,
- (R) 1-[4-Chloro-3-(4-methyl-[1,2,4]triazolo[4,3-a]quinoxalin-1-yl)“ phenoxy]-propan-2-ol,
- 2-[4-Chloro-3-(4-methyl-[1,2,4]triazolo[4,3-a]quinoxalin-1-yl)-phenoxy]1-pyridin-2-yl-ethanol,
- 1 -[2-Chloro-5-(2-fluoro-2-pyridin-2-yl-ethoxy)-phenyl]-4-methyl- iïS [1.2.4] triazolo[4,3-a]quinoxaline.
Especially preferred is the compound of Example 98 and pharmaceutically acceptable salts thereof.
Further preferred are compounds as described in any one of the Examples 107111 or a pharmaceutically acceptable sait thereof:
4-Chloro-3-(8-chloro-4-methyl-[1 ^^Jtriazolopl.S-alquinoxalin-l -yl)phenol
1-(5-Butoxy-2-fluoro-phenyl)-[1,2,4]triazolo[4,3-a]quinoxaline
-[2-Fluoro-5-(2-methoxy-ethoxy)-phenyl]-[1,2,4]triazolo[4,3ajquinoxaline
-[2-Chloro-5-(4,4,4,-trifluoro-butoxy)“phenyl]-4,8-dimethyl- [1.2.4] triazolo[4,3-a]quinoxaline
7-Cyano-1-[2-chloro-5-(4,4,41-trifluoro-butoxy)-phenyl]-4-methyl[l^/Jtriazolo^.S-ajquinoxaline
The following contains définitions of terms used in this spécification. The initial définition provided for a group or term herein applies to that group or term throughout the présent spécification, individually or as part of another group, unless otherwise indicated.
As used herein, the phrase optionally substituted means unsubstituted or substituted. As used herein, the term substituted means that a hydrogen atom is removed and replaced by a substituent. As used herein, the phrase substituted with oxo means that two hydrogen atoms are removed from a carbon atom and replaced by an oxygen bound by a double bond to the carbon atom. It is understood that substitution at a given atom is limited by valency.
The terms alk or alkyl refer to straight or branched chain hydrocarbon groups having 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms, 1 to 6 carbon atoms or 1 to 4 carbon atoms. The term (halo)alkyl refers to alkyl substituted by at least one halogen atom. -M
As used herein, the term alkoxy, employed alone or in combination with other terms, refers to an group of formula -O-alkyl. Example alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy, hexyloxy and the like.
The terms halogen and halo refer to fluorine, chlorine, bromine and iodine.
The term cyclic group includes fully saturated, partially unsaturated and aromatic carbocyclic or heterocyclic rings, including aromatic (“aryl orheteroaryl) or nonaromatic cyclic groups, for example, 3 to 8 membered monocyclic, 7 to 11 membered bicyclic, or 10 to 15 membered tri-cyclic ring Systems, which may hâve at least one heteroatom in at least one carbon atomcontaining ring. Each ring of the heterocyclic group containing a heteroatom may hâve 1, 2, 3 or 4 heteroatoms selected from nitrogen atoms, oxygen atoms and/or sulfur atoms, where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized. The heterocyclic group may be attached at any heteroatom or carbon atom of the ring or ring System. In some embodiments, one or more carbon atoms of the heterocyclo ring are oxidized to form a carbonyl group, in some embodiments, each heterocyclo ring has 2 to 12, or 2 to 9 carbon atoms. The cyclic group may be unsubstituted or carry one or more substituents, e.g. halogen, ΟΊ.6 (halo)alkyl, C-i-6 (halo)alkoxy, OH, etc.
Exemplary monocyclic carbocyclic groups include cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl, cycloalkenyl and phenyl.
Exemplary monocyclic heterocyclic groups include pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2- oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, diazepin-yl, 4-piperidonyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydropyranyl, mor-pholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide,/x/ thiamorpholinyl sulfone, 1,3- di-oxolane and tetrahydro-1,1-dioxothienyl, and the like.
Exemplary bicycîic carbocyclic groups include naphthyl.
Exemplary bicycîic heterocyclic groups include indolyl, benzothiazolyl, benzoxazolyl, benzothienyl, quimiclidinyl, quinolinyl, tetra'hydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, chromanyl, coumarinyl, benzo-pyranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl (such as furo[2,3-c]pyridinyl, furo[3,2“b]pyridinyl or furo[2,3bjpyridinyl), dlhydroisoindolyl, di-hydroquinazolinyl (such as 3,4-dihydro-4-oxoquinazolinyl), tetrahydroquinolinyl and the like.
The compounds of formula I may form salts which are also within the scope of this invention. Reference to a compound of the formula I herein is understood to include reference to salts thereof, unless otherwise indicated. The term salt(s), as employed herein, dénotés acidic and/or basic salts formed with inorganic and/or organic acids and bases. Zwitterions (internai or inner salts) are included within the term salt(s) as used herein (and may be formed, for example, where the R substituents comprise an acid moiety such as a carboxyl group).AIso included herein are quaternary ammonium salts such as alkylammonium salts. Salts of the compounds of the formula I may be formed, for example, by reacting a compound I with an amount of acid or base, such as an équivalent amount, in a medium such as one in which the sait précipitâtes or in an aqueous medium followed by lyophilization.
Exemplary acid addition salts include acétates (such as those formed with acetic acid or trihaloacetic acid, for example, trifluoroacetic acid), adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates, glycérophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides, hydrobromides, hydroiodides, 2-hydroxyethanesulfonates, lactates, maleates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oxalates, μ/''1' pectinates, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates (such as those formed with sulfuric acid), sulfonates (such as those mentioned herein), tartrates, thiocyanates, toluenesulfonates such as tosylates, undecanoates, and the like.
Exemplary basic salts (formed, for example, where the R substituents comprise an acidic moiety such as a carboxyl group) include ammonium salts, alkali métal salts such as sodium, lithium, and potassium salts, alkaline earth métal salts such as calcium and magnésium salts, salts with organic bases (for example, organic amines) such as benzathines, dicyclohexylamines, hydrabamines, Nmethyl-D-glucamines, N-methyl-D-glucamides, t-butyl amines, and salts with amino acids such as arginine, lysine and the like. The basic nitrogen-containing groups may be quaternized with agents such as lower alkyl halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g. dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides (e.g. decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides), aralkyl halides (e.g. benzyl and phenethyl bromides), and others.
The présent invention also includes pharmaceutically acceptable salts of the compounds described herein. As used herein, “pharmaceutically acceptable salts refers to dérivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its sait form. Examples of pharmaceutically acceptable salts include, but are not limited to, minerai or organic acid salts of basic resîdues such as amines; alkali or organic salts of acidic resîdues such as carboxylic acids; and the like. The pharmaceutically acceptable salts of the présent invention include the conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the présent invention can be synthesized from the parent compound which eontains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, éthanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17111 ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is incorporated herein by reference in its entirety.
The phrase pharmaceutically acceptable is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animais without excessive toxicity, irritation, allergie response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
Furthermore, in the case of the compounds of the invention which contain an asymmetric carbon atom, the invention relates to the D form, the L form and D,L mixtures and also, where more than one asymmetric carbon atom is présent, to the diastereomeric forms. Those compounds of the invention which contain asymmetric carbon atoms, and which as a rule accrue as racemates, can be separated into the optically active isomers in a known manner, for example using an optically active acid. However, it is also possible to use an optically active starting substance from the outset, with a corresponding optically active or diastereomeric compound then being obtained as the end product.
Compounds of the invention also include tautomeric forms. Tautomeric forms resuit from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton. Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge. Example prototropic tautomers include ketone - enol pairs, amide - imidic acid pairs, lactam - lactim pairs, amide - imidic acid pairs, enamine - imine pairs, and annular forms where a proton can occupy two or^ more positions of a heterocyclic system, for example, 1 H- and 3H-imidazole, 1 H-,
2H- and 4H- 1,2,4-triazole, 1H- and 2H- isoindole, and 1H- and 2H-pyrazole.
Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution.
The compounds described herein can be asymmetric (e.g., having one or more stereocenters). Ail stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated. Compounds of the présent invention that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods on how to préparé opticaily active forms from optically active sterling materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Many géométrie isomers of olefins, C=N double bonds, and the like can also be présent in the compounds described herein, and ail such stable isomers are contemplated in the présent invention. Cis and trans géométrie isomers of the compounds of the présent invention are described and may be isolated as a mixture of isomers or as separated isomeric forms.
Compounds of the invention can also include ail isotopes of atoms occurring in the intermediates or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium.
Also included are solvatés and hydrates of the compounds of formula (I) and solvatés and hydrates of their pharmaceutically acceptable salts.
The term compound as used herein is meant to include ail stereoisomers, géométrie iosomers, tautomers, and isotopes of the structures depicted, unless otherwise indicated.
In some embodiments, the compound can be provided as a prodrug. The term “prodrug, as employed herein, dénotés a compound which, upon administration to a subject, undergoes chemical conversion by metabolic or chemical processes to yield a compound of the formula I, or a sait and/or solvaté thereof.
In some embodiments, the compounds of the invention, and salts thereof, are substantially isolated. By substantially isolated is meant that the compound is at least partially or substantially separated from the environment in which it was formed or detected. Partial séparation can include, for example, a composition enriched in the compound of the invention. Substantial séparation can include compositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of the compound of the invention, or sait thereof.
Pharmaceutical Methods
The compounds according to the invention hâve been found to hâve pharmacologically important properties which can be used therapeutically. The compounds of the invention can be used alone, in combination with each other or in combination with other active compounds. Compounds of formula (I) may be inhibitors of phosphodiesterase (PDE) 2 and/or 10. It is therefore a part of the subject-matter of this invention that the compounds of the invention and their salts and also pharmaceutical préparations which comprise these compounds or their salts, can be used for treating or preventing disorders associated with, accompanied by and/or covered by phosphodiesterase hyperactivity and/or disorders in which inhibiting PDE2 and/or 10 is of value.
In some embodiments the compounds of the présent invention are PDE2 inhibitors which hâve an IC50 value of < 10μΜ, < 1μΜ, < 0.1 pM, or < 0.01 pM (as determined according to Example A). In some embodiments the compounds of the présent invention are PDE 10 inhibitors which hâve an IC5q value of < 10pM, < 1 μΜ, < 0.1μΜ, or < 0.01 μΜ (as determined according to Example B). In some embodiments the compounds of the présent invention are PDE 2 and PDE 10 inhibitors which hâve an IC50 value of < 10μΜ, < 1μΜ, < 0.1 μΜ or < 0.01 μΜ (as determined in Example A and in Example B). In some embodiments the compounds ofthe présent invention are sélective PDE 2 or PDE10 inhibitors.
In some embodiments, the compound of formula I is sélective for PDE10, meaning that it is a better inhibitor of PDE10 than for any other PDE. In some embodiments, the sélective PDE10 inhibitor can reduce PDE10 activity at least 10-fold or at least 100-fold compared to other PDEs. In some embodiments, the compound of formula I is a PDE2 sélective inhibitor. In some embodiments, the sélective PDE2 inhibitor can reduce PDE2 activity at least 10-fold or at least 100fold compared to other PDEs. In some embodiments, the compound of formula I is a PDE2/PDE10 dual inhibitor having a PDE10/PDE2 inhibitory ratio of 10:1 1:10.
It is an embodiment of this invention, that compounds of the invention including their salts, solvatés and hydrates, can be used for the treatment of central nervous system disorders of mammals including a human.
More particularly, the invention relates to the treatment of neurologie and psychiatrie disorders including, but not limited to, (1) disorders comprising the symptom of cognitive deficiency in a mammal, including a human; (2) organic, including symptomatic , mental disorders, dementia; (3) mental retardation; (4) mood [affective] disorders; (5) neurotic, stress-related and somatoform disorders including anxiety disorders; (6) behavioural and emotional disorders with onset usually occurring in childhood and adolescence, attention déficit hyperactivity syndrome (ADHD); (7) disorders of psychological development, developmental disorders of scholastic skills; (8) schizophrenia and other psychotic disorders; (9) disorders of adult personality and behaviour; (10) mental and behavioural disorders due to psychoactive substance use; (11) extrapyramidal and vZ movement disorders; (12) episodic and paroxysmal disorders, epilepsy; (13)
Systemic atrophies primarily affecting the central nervous System, ataxia; (14)
Behavioural syndromes associated with physiological disturbances and physical factors; (15) sexual dysfunction comprising excessive sexual drive; (16) factitious disorders.
The phrase cognitive deficiency” as used here in disorder comprising as a symptom cognitive deficiency” refers to a subnormal functioning or a suboptimal functioning in one or more cognitive aspects such as memory, intellect, learning and logic ability, or attention and executive function (working memory) in a particular individual comparative to other individuals within the same general âge population.
Examples of disorders comprising as a symptom cognitive deficiency that can be treated according to the présent invention include, but are not limited to cognitive déficits primarily but not exclusively related to psychosis (schizophrenia), mood disorders, bipolar disorder, Parkinson’s disease, Alzheimer’s disease, multi infarct dementia, Lewis body dementia, stroke, frontotemporal dementia, progressive supranuclear palsy, Huntington's disease and in HIV disease, cérébral trauma and drug abuse; mild cognitive disorder and ADHD and Asperger’s syndrome and age-associated memory impairment.
Examples of organic, including symptomatic, mental disorders that can be treated according to the présent invention include, but are not limited to vascular dementia, dementia in Alzheimer’s disease and other diseases, such as Pick's disease, Creutzfeldt-Jacob disease, Parkinson’s and Huntington’s disease, dementia in human immunodeficiency virus (HIV) disease.
Examples of mood [affective] disorders that can be treated according to the présent invention include, but are not limited to, bipolar disorder I depressed, hypomanie, manie and mixed form; bipolar disorder II; dépressive disorders, such as single dépressive épisode or récurrent major dépressive disorder, minor dépressive disorder, dépressive disorder with postpartum onset, dépressive disorders with psychotic symptoms; persistent mood [affective] disorders, such as cyclothymia, dysthymia, euthymia; and premenstrual dysphorie disorder.
Examples of disorders belonging to the neurotic, stress-related and somatoform disorders that can be treated according to the présent invention include, but are not limited to, anxiety disorders, general anxiety disorder, panic disorder with or without agoraphobia, spécifie phobia, social phobia, chronic anxiety disorders; obsessive compulsive disorder; reaction to sever stress and adjustment disorders, such as post traumatic stress disorder (PTSD); other neurotic disorders such as depersonalisation-derealisation syndrome.
Examples of disorders usually first diagnosed in infancy, childhood and adolescence that can be treated according to the présent invention include, but are not limited to hyperkinetic disorders, including but not limited to disturbance of activity and attention, attention deficit/hyperactivity disorder (ADHD), hyperkinetic conduct disorder; attention déficit disorder (ADD); conduct disorders, including but not limited to dépressive conduct disorder; tic disorders, including but not limited to transient tic disorder, chronic motor or vocal tic disorder, combined vocal and multiple motor tic disorder (de la Tourette), substance induced tic disorders; autistic disorders; excessive masturbation nail-biting, nosepicking and thumb-sucking.
Examples of disorders of psychological development that can be treated according to the présent invention include, but are not limited to pervasive developmental disorders, including but not limited to Asperger’s syndrome and
Rett’s syndrome, autistic disorders, childhood autism and overactive disorder assodated with mental retardation and stereotyped movements, spécifie developmental disorder of motor function, spécifie developmental disorders of scholastic skills.
Examples of schizophrenia and other psychotic disorders disorders that can be treated according to the présent invention include, but are not limited to, continuous or episodic schizophrenia of different types (for instance paranoid, hébéphrénie, catatonie, undifferentiated, residual, and schizophreniform disorders); schizotypal disorders (such as borderline, latent, prepsychotic, prodromal, pseudoneurotic pseudopsychopathic schizophrenia and schizotypal personality disorder); persistent delusional disorders; acute, transient and persistent psychotic disorders; induced delusional disorders; schizoaffective disorders of different type (for instance manie dépressive or mixed type); puerpéral psychosis and other and unspecified nonorganic psychosis.
Examples of disorders of adult personality and behaviour that can be treated according to the présent invention include, but are not limited to personality disorders, including but not limited to emotionally unstable, borderline, obsessivecompulsive, anankastic, dépendent and passive-aggressive personality disorder; habit and impulse disorders (impulse-control disorder), including intermittent explosive disorder, pathological gamblîng, pathological fire-setting (pyromania), pathological stealing (kleptomania), trichotillomania; Münchausen syndrome.
Examples of mental and behavioural disorders due to psychoactive substance use that can be treated according to the présent invention include, but are not limited to mental and behavioural disorders due to use of alcohol, opioids, cannabinoids, sédatives or hypnotics, cocaïne, mental and behavioural disorders due to the use of other stimulants, including caffeine, mental and behavioural disorders due to use of hallucinogens, tobacco, volatile solvents and mental and behavioural disorders due to multiple drug use and use of other psychoactive substances: including but not limited to the following subtype symptoms: harmful use, dependence syndrome, withdrawal state and withdrawal state with delirium.
Examples of movement disorders with malfunction and/or degeneration of basal ganglia that can be treated according to the présent invention include, but are not limited to Parkinson's disease; second Parkinsonism, such as postencephalitic Parkïnsonism; Parkinsonism comprised in other disorders; Lewy body disease; degenerative diseases of the basal ganglia; other extrapyramidal and movement disorders including but not limited to tremor, essential tremor and drug-induced tremor, myoclonus, chorea and drug-induced chorea, drug-induced tics and tics of organic origion, drug-induced acute dystonia, drug-induced tardive dyskinesia, L-dopa-induced dyskinesia; neuroleptic-induced movement disorders including but not limited to neuroleptic malignant syndrome (NMS), neuroleptic induced parkinsonism, neuroleptic-induced early onset or acute dyskinesia, neurolepticinduced acute dystonia, neuroleptic-induced acute akathisia, neuroleptic-induced tardive dyskinesia, neuroleptic-induced tremor; restless leg syndrome, Stiff-man syndrome.
Further examples of movement disorders with malfunction and/or degeneration of basal ganglia that can be treated according to the présent invention include, but are not limited to dystonia including but not limited to focal dystonia, multiplefocal or segmentai dystonia, torsion dystonia, hemispheric, generalised and tardive dystonia (induced by psychopharmacological drugs). Focal dystonia include cervical dystonia (torticolli), blepharospasm (cramp of the eyelid), appendicular dystonia (cramp in the extremities, like the writer's cramp), oromandibular dystonia and spasmodic dysphonia (cramp of the vocal cord).
Examples for episodic and paroxysmal disorders that can be treated according to the présent invention include, but are not limited to epilepsy, including localization-related (focal)(partial) idiopathic epilepsy and epileptic syndromes with seizures of localized onset, localization-related (focal)(partial) symptomatic epilepsy and epileptic syndromes with simple partial seizures, localization-related (focal)(partial) symptomatic epilepsy and epileptic syndromes with complex partial seizures, generalized idiopathic epilepsy and epileptic syndromes, such as myoclonie epilepsy in infancy, néonatal convulsions (familial), Childhood absence epilepsy (pyknolepsy), Epilepsy with grand mal seizures on awakening, absence epilepsy, myoclonie epilepsy (impulsive petit mal) and nonspecific atonie, clonie, myoclonie, tonie, tonie-clonie epileptic seizures.
Further examples of epilepsy that can be treated according to the présent invention include, but are not limited to epilepsy with myoclonie absences, myoclonic-astatic seizures, Infantile spasms, Lennox-Gastaut syndrome, Salaam attacks, Symptomatic early myoclonie encephalopathy, West's syndrome, petit and grand mal seizures; Status epilepticus.
Examples of behavioural syndromes associated with physiological disturbances and physicaï factors according to the présent invention include, but are not limited to nonorganic sleep disorders, including but not limited to nonorganic hypersomnia, nonorganic disorder of the sleep-wake schedule; mental and behavioural disorders associated with the puerpérium, including but not limited to postnatal and postpartum dépréssion; eating disorders, including but not limited to anorexia nervosa and bulimia nervosa.
The compounds described herein are further useful in the prévention and treatment of obesity, type 2 diabètes (non-insulin dépendent diabètes), metabolic syndrome, glucose intolérance, and related health risks, symptoms or disorders. As such, the compounds can also be used to reduce body fat or body weight of an overweight or obese individual.
As used herein, the terms ‘Overweight and obese” are meant to refer to adult persons 18 years or older having a greater than idéal body weight (or body fat) measured by the body mass index (BMI). BMI is calculated by weight in kilograms divided by height in meters squared (kg/m2) or, alternatively, by weight in pounds, multiplied by 703, divided by height in inches squared (Ibs x 703/in2).
Overweight individuals typically have a BMI of between 25 and 29, whereas obsess individuals typically have a BMI of 30 or more (see, e.g., National Heart,
Lung, and Blood institute, Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults, The Evidence Report, Washington, DC:U.S. Department of Health and Human Services, NIH publication no. 98-4083,1998). Other means for indicating excess body weight, excess body fat, and obesity include direct measure of body fat and/or waist-tohip ratio measurements.
The term “metabolic syndrome” is used according to its usual meaning in the art. The American Heart Association characterizes metabolic syndrome as having at least 3 of the 5 below symptoms: 1 ) Elevated waist circumference (> 102 cm (40 inches) in men; > 88 cm (35 inches) in women), 2) Elevated triglycérides (> 150 mg/dL (> 1.7 mmol/L) or drug treatment for elevated triglycérides), 3) Reduced HDL-C (< 40 mg/dL (1.03 mmol/L) in men < 50 mg/dL (1.3 mmol/L) in women or drug treatment for reduced HDL-C, 4) Elevated blood pressure (> 130/85 mmHg or drug treatment for hypertension), and 5) Elevated fasting glucose (> 100 mg/dL or drug treatment for elevated glucose). See, Grundy, S.M. et al., Circulation, 2005, 112 (17, e285 (online at circ.ahajournals.org /cgi/reprint/112/17/e285). Metabolic syndrome according to the World Health Organization (See, Alberti et al., Diabet. Med. 15, 539-553, 1998) includes individuals suffering from diabètes, glucose intolérance, low fasting glucose, or insulin résistance plus two or more of 1) High blood pressure (> 160/90 mmHg), 2) Hyperlipdemia (triglycérides 2: 150 mg/dL or HDL cholestérol < 35 mg/dL in men and < 39 mg/dL in women), 3) Central obesity (waist-to-hip ratio of > 0.90 for men and >0.85 for women or BMI > 30 kg/m2), and 4) Microalbuminuria (urinary albumin excrétion rate s 20 pg/min or an albumin-to-creatine ratio s 20 MQ/kg).
As used herein, the term “treating or “treatment” refers to one or more of (1) inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and/or symptomatology); and (2) ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and/or symptomatology) such as decreasing the severity of disease.
In some embodiments, administration of a compound of the invention, or pharmaceutically acceptable sait thereof, is effective in preventing the disease; for example, preventing a disease, condition or disorder in an individual who may be predisposed to the disease, condition or disorder but does not yet expérience or display the pathology or symptomatology of the disease.
Pharmaceutical Compositions
The présent invention further provides pharmaceutical compositions comprising a compound of formula I or a pharmaceutically acceptable sait thereof for use in medicine, e.g. in human or veterinary medicine. In some embodiments, the composition further comprises a pharmaceutically acceptable carrier.
An effective dose of the compounds according to the invention, or their salts, solvatés or prodrugs thereof is used, in addition to physiologically acceptable carriers, diluents and/or adjuvants for producing a pharmaceutical composition. The dose of the active compounds can vary depending on the route of administration, the âge and weight of the patient, the nature and severity of the diseases to be treated, and similar factors. The daily dose can be given as a single dose, which is to be administered once, or be subdivided into two or more daily doses, and is as a rule 0.001-2000 mg. Particular preference is given to administering daily doses of 0.1-500 mg, e.g. 0.1-100 mg.
Suitable administration forms are oral, parentéral, intravenous, transdermal, topical, inhalative, intranasal and sublingual préparations. Particular preference is given to using oral, parentéral, e.g. intravenous or intramuscular, intranasal préparations, e.g. dry powder or sublingual, of the compounds according to the invention. The customary galenic préparation forms, such as tablets, sugarcoated tablets, capsules, dispersible powders, granulates, aqueous solutions, alcohol-containing aqueous solutions, aqueous or oily suspensions, syrups, juices or drops, can be used.
Solid médicinal forms can comprise inert components and carrier substances, such as calcium carbonate, calcium phosphate, sodium phosphate, lactose, starch, mannitol, alginates, gélatine, guar gum, magnésium stéarate, aluminium stéarate, methyl cellulose, talc, highly dispersed silicic acids, silicone oil, higher molecular weight fatty acids, (such as stearic acid), gélatine, agar agar or vegetable or animal fats and oils, or solid high molecular weight polymers (such as polyethylene glycol); préparations which are suitable for oral administration can comprise additional flavourings and/or sweetening agents, if desired.
Liquid médicinal forms can be sterilized and/or, where appropriate, comprise auxiliary substances, such as preservatives, stabilizers, wetting agents, penetrating agents, emulsifiers, spreading agents, solubilizers, salts, sugars or sugar alcohols for regulating the osmotic pressure or for buffering, and/or viscosity regulators. Examples of such additives are tartrate and citrate buffers, éthanol and sequestering agents (such as ethylenediaminetetraacetic acid and its non-toxic salts). High molecular weight polymers, such as liquid polyethylene oxides, microcrystalline celluloses, carboxymethyl celluloses, polyvinylpyrrolidones, dextrans or gélatine, are suitable for regulating the viscosity. Examples of solid carrier substances are starch, lactose, mannitol, methyl cellulose, talc, highly dispersed silicic acids, high molecular weight fatty acids (such as stearic acid), gélatine, agar agar, calcium phosphate, magnésium stéarate, animal and vegetable fats, and solid high molecular weight polymers, such as polyethylene glycol.
Oily suspensions for parentéral or topical applications can be vegetable, synthetic or semisynthetic oils, such as liquid fatty acid esters having in each case from 8 to 22 C atoms in the fatty acid chains, for example palmitic acid, lauric acid, tridecanoic acid, margaric acid, stearic acid, arachidic acid, myristic acid, behenic acid, pentadecanoic acid, linoleic acid, elaidic acid, brasidic acid, erucic acid or oleic acid, which are esterified with monohydric to trihydric alcohols having from 1 to 6 C atoms, such as methanol, éthanol, propanol, butanol, pentanol or their isomers, glycol or glycerol. Examples of such fatty acid esters are commercially available miglyols, isopropyl myristate, isopropyl palmitate, isopropyl stéarate, PEG 6-capric acid, caprylic/capric acid esters of saturated fatty alcohols, polyoxyethylene glycerol trioleates, ethyl oleate, waxy fatty acid esters, such as artificial ducktail gland fat, coconut fatty acid isopropyl ester, oleyl oleate, decyl oleate, ethyl lactate, dibutyl phthalate, diisopropyl adipate, polyol fatty acid esters, inter alia. Silicone oils of differing viscosity, or fatty alcohols, such as isotridecyl alcohol, 2-octyldodecanol, cetylstearyl alcohol or oleyl alcohol, or fatty acids, such as oleic acid, are also suitable. It is furthermore possible to use vegetable oils, such as castor oil, almond oil, olive oil, sesame oil, cotton seed oil, groundnut oil or soybean oil.
Suitable solvents, gelatinizing agents and solubilizers are water or water-miscible solvents. Examples of suitable substances are alcohols, such as éthanol or isopropyl alcohol, benzyl alcohol, 2-octyldodecanol, polyethylene glycols, phthalates, adipates, propylene glycol, glycerol, di- or tripropylene glycol, waxes, methyl cellosolve, cellosolve, esters, morpholines, dioxane, dimethyl sulphoxide, dimethylformamide, tetrahydrofuran, cyclohexanone, etc.
Cellulose ethers which can dissolve or swell both in water or in organic solvents, such as hydroxypropylmethyl cellulose, methyl cellulose or ethyl cellulose, or soluble starches, can be used as film-forming agents.
Mixtures of gelatinizing agents and film-forming agents are also perfectly — possible. In this case, use is made, in particular, of ionic macromolecules such as sodium carboxymethyl cellulose, polyacrylic acid, polymethacrylic acid and their salts, sodium amylopectin semiglycolate, alginic acid or propylene glycol alginate as the sodium sait, gum arabic, xanthan gum, guar gum or carrageenan. The following can be used as additional formulation aids: glycerol, paraffîn of differing viscosity, triethanolamine, collagen, allantoin and novantisolic acid. Use of surfactants, emulsifiers or wetting agents, for example of Na lauryl sulphate, fatty alcohol ether sulphates, di-Na-N-lauryl-P-iminodipropionate, polyethoxylated castor oil or sorbitan monooleate, sorbitan monostearate, polysorbates (e.g. Tween), cetyl alcohol, lecithin, glycerol monostearate, polyoxyethylene stéarate, alkylphenol polyglycol ethers, cetyltrimethylammonium chloride or mono-/dialkylpolyglycol ether orthophosphoric acid monoethanolamine salts can also be required for the formulation. Stabilizers, such as montmorillonites or colloïdal silicic acids, for stabilizing émulsions or preventing the breakdown of active substances such as antioxidants, for example tocopherols or butylhydroxyanisole, or preservatives, such as p-hydroxybenzoic acid esters, can likewise be used for preparing the desired formulations.
Préparations for parentéral administration can be présent in separate dose unit forms, such as ampoules or vials. Use is preferably made of solutions of the active compound, preferably aqueous solution and, in particular, isotonie solutions and also suspensions. These injection forms can be made available as ready-to-use préparations or only be prepared directly before use, by mixing the active compound, for example the lyophilisate, where appropriate containing other solid carrier substances, with the desired solvent or suspending agent
Intranasal préparations can be présent as aqueous or oily solutions or as aqueous or oily suspensions. They can also be présent as lyophilisâtes which are prepared before use using the suitable solvent or suspending agent.
Inhalable préparations can présent as powders, solutions or suspensions, jy—'
Preferably, inhalable préparations are in the form of powders, e.g. as a mixture of the active ingrédient with a suitable formulation aid such as lactose.
The préparations are produced, aliquoted and sealed under the customary antimicrobial and aseptie conditions.
As indicated above, the compounds of the invention may be administered as a combination therapy with further active agents, e.g. therapeutically active compounds useful in the treatment of central nervous system disorders. These therapeutically active compounds may include but are not limited to inhibitors of PDE2, inhibitors of PDE10, NMDA neurotransmitter system modulating agents, such as memantine, and acétylcholine neurotransmitter system modulating agents, such as donepezil. The combination of compounds of the invention with donepezil is a preferred example with e.g. good in vivo efficacy in the Novel Object Récognition model. For a combination therapy, the active ingrédients may be formulated as compositions containing several active ingrédients in a single dose form and/or as kits containing individual active ingrédients in separate dose forms. The active ingrédients used in combination therapy may be coadministered or administered separately.
The invention shall be explained in more detail by the following Examples.
Examples
Example 1: 8-Chloro-1-(2-chloro-phenyl)-4-methyl-[1,2,4]triazolo[4,3ajquinoxaline
Step 1: 7-Chloro-3-methyl-1H-quinoxalin-2-one
To a solution of 4-chloro-1,2-phenylenediamine (25 g) in éthanol (500 ml) was added ethyl pyruvate (21 g). The reaction mixture was stirred and heated to reflux for 4 h. After standing for 12 h the product was collected by filtration, washed with 20 ml of éthanol and dried in a dry box with vacuum (50 °C). Yield: 24.7 g (Product contains 40 % of 8-chloro-3-methyl-1 H-quinoxalin-2-one)
Step 2: 3,6~Dichtoro-2-methyt-quinoxatine
A mixture of 7-chloro-3-methyl-1H-quinoxalin-2-one (12,3 g ) and phosphorus oxychloride (60 ml) was heated to 90 °C for 2.5 h. After cooling the solution was poured on ice, the mixture was neutralized and the precipitate was then collected by filtration. The crude product was purified by flash chromatography (ethyl acetate/ n-hexane).
Yield: 3.5 g S^-Dichloro-Z-methyl-quinoxaline
1.5 g 2,6-Dichloro-2-methyl-quinoxaline (intermediate 1 )
Step 3: (7-Chloro-3-methyl-quinoxalin-2-yl)-hydrazine (intermediate 2) ci
To a solution of 3.5 g of 3,6-dichloro-2-methyl-quinoxaline in 100 ml of éthanol and 100 ml of dichloromethane were added 15 ml of hydrazine hydrate. The mixture was stirred for four days. The solvent was then evaporated and the solid residue was washed with 20 ml of ice water for three times and dried in a dry box with vacuum (50 °C). Yield: 3.38 g
Step 4: 2-Chloro-benzoic acid N'-(7-chloro-3-methyl-quinoxalin-2-yl)-hydrazide
Cl
A mixture of intermediate 2 (2 g), potassium carbonate (4 g) and 2-chloro benzoic chloride (1.8 g) in 200 ml of methylenechhloride were stirred for 2 h. The solvent was evaporated and the residue was washed with 50 ml of ice water for two times and dried in a dry box. Yield: 3.1 g
Step 5: 8-Chloro-1-(2-chloro-phenyl)-4-methyl-[1,2,4]triazolo[4,3-a]quinoxaline
g of 2-chloro-benzoic acid chloride, N’-(7-chloro-3-methyl-quinoxalin-2-yl)16480 hydrazide, 20 ml of ethylene glycol and 4 ml of 4 M hydrochloric acid in dioxane were refluxed for two minutes. The mixture was allowed to cool and 5 ml of water were added. The precipitate that formed was collected by filtration and washed with water to give the pure desired product. Yield: 1.6 g; MS 329 [M+H]+; m.p.:
209 °C
The Examples in Table 1 were prepared as described in Example 1 replacing 2chloro benzoic chloride (step 4) with the appropriate carboxylic acid chloride dérivative.
Table 1: 8-Chloro-quinoxaline dérivatives
| Example # | carboxylic acid chloride dérivative | Name | MS [M+H]+ | m.p. (°C) |
| 2 | 2-Fluoro-benzoic acid chloride | 8-Chloro-1 -(2-fluorophenyl)-4-methyl[1,2,4]triazolo[4,3a]quinoxaline | 313 | 248-249 |
| 3 | 2-Methoxy-benzoic acid chloride | 8-Chloro-1 -(2-methoxyphenyl)-4-methyl[1,2,4]triazolo[4,3ajquinoxaline | 325 | 180-181 |
| 4 | 5-Fluoro-2-methyl benzoic acid chloride | 8-Chloro-1 -(5-fluoro-2methyl phenyl)-4-methyl[1,2,4]triazolo[4,3a]quinoxaline | 327 | 229-231 |
| 5 | 2-Methyl nicotinic acid chloride | 8-Chloro-4-methyl-1 -(2methyl-pyrîdin-3-yl)[1,2,4]triazolo[4,3a]quinoxaline | 310 | 237-239 |
| 6 | 2,5 Dichlorobenzoic acid | 8-Chloro-1 -(2,5-dichlorophenyl)-4-methyl- | 363 | 198-202 |
| chloride | [1,2)4]triazolo[4,3ajquinoxaline | |||
| 7 | 2-Chloro-5-methoxy benzoic acid chloride | 8-Chloro-1 -(2-chloro-5methoxy-phenyl)-4methyl-[1,2,4]triazolo[4,3a]quinoxaline | 359 | 170-172 |
| 8 | 2-Methy-benzoic acid chloride | 8-Chloro-4-methyl-1 -otolyl-[1,2,4]triazoro[4,3ajquinoxaline | 309 | 233-235 |
| 9 | 3-Methyl isonicotinic acid chloride | 8-Chloro-4-methyl-1 -(3methyl-pyridin-4-yl)- [1,2,4]triazolo[4t3ajquinoxaline | 310 | 259 |
| 10 | 2-Chloro-5-trifluoro methyl benzoic acid chloride | 8-Chloro-1 -(2-chloro-5trifluoromethyl-phenyl)-4methyl-[1,2,4]triazolo[4,3a]quinoxaline | 397 | 212-215 |
For the préparation of examples of Table 2 the used carboxylic acid chloride dérivative was synthesized in situ:
To a solution of 0.5 g of carboxylic acid dérivative in 15 ml of THF (tetrahydrofurane) 0.3 g of oxalic acid chloride and 3 drops of DM F (dimethyl formamide) were added. The mixture was stirred for two hours. The solvent was then evaporated and the solid carboxylic acid chloride dérivative was used without further purification.
Table 2: 8-Chloro-quinoxaline dérivatives (continued)
| Example # | carboxylic acid chloride dérivative | Name | MS [M+H]+ | m.p. (°C) |
| 11 | 5-Butoxy-2-fluoro benzoic acid chloride | 1 -( 5-B utoxy-2-f I uorophenyl)-8-chloro-4methyl-[1,2,4)(082010(4,3a]quinoxaline | 385 | 115-117 |
| 12 | 5-Butoxy-2-chloro benzoic acid chloride | 1 -(5-Butoxy-2-chlorophenyl)-8-chloro-4methyl-[1 ,ΣΛΠηθζοΙο^,δajquinoxaline | 401 | 60-65 |
| 13 | 2-Fluoro-5hexyloxy- benzoic acid chloride | 8-Chloro-1 -(2-fluoro-5hexyloxy-phenyl)-4methyl-[1,2,4]triazolo[4,3a]quinoxaline | 413 | 113 |
| 14 | 5-Butoxy-2-methyl benzoic acid chloride | 1-(5-Butoxy-2-methylphenyl)-8-chloro-4methyl-[1,2,4]triazolo[4,3ajquinoxaline | 381 | 107-109 |
| 15 | 5-Hexyloxy-2methyl benzoic acid chloride | 8-Chloro-1 -(5-hexyloxy-2methyl-phenyl)-4-methyl- [1,2,4]triazolo[4,3ajquinoxaline | 409 | 91-93 |
| 16 | 2-Chloro-5-(4,4,4trifluoro-butoxy)benzoic acid chloride | 8-Chloro-1 -[2-chloro-5(4,4,4-trifluoro-butoxy)phenyl]-4-methyl[1,2,4]triazolo[4,3ajquinoxaline | 455 | 167-170 |
| 17 | 2-Fluoro-5-(4fluoro-butoxy)benzoic acid chloride | 8-Chloro-1 -[2-fluoro-5-(4fluoro-butoxy)-phenyl]-4methyl-[1 ,2,4]ϊγϊ3ζοΙο[4,3ajquinoxaline | 403 | 118-120 |
Examples of Table 3 were prepared from 2,6-dichloro-2-methyl-quinoxaline (intermediate 1) and the appropriate carboxylic acid chloride foilowing the general procedures as described for Example 1.
Table 3: 7-Chloro-quinoxaline dérivatives
| Example # | carboxylic acid chloride dérivative | Name | MS [M+H]+ | m.p. (°C) |
| 18 | 2,6-Difluorobenzoic acid chloride | 7-Chloro-1 -(2,6-difluorophenyl)-4-methyl[1,2,4]ίΓΪ3ζοΙο[4,3ajquinoxaline | 331 | 207-210 |
| 19 | 2,5-Dichlorobenzoic acid chloride | 7-Chloro-1 -(2,5-dichlorophenyl)-4-methyl[1 t2,4]triazolo[4,3a]quinoxaline | 363 | 240-242 |
| 20 | 2-Chloro-5methoxy-benzoic acid chloride | 7-Chloro-1 -(2-chloro-5methoxy-phenyl)-4methyl-[1 ^^jtriazolopl.Sa]quinoxaline | 360 | 190-192 |
| 21 | 2-Chloro-5trifluoromethylbenzoic acid chloride | 7-Chloro-1 -(2-chloro-5trifluoromethyl-phenyl)-4methyl-[1,2,4]triazolo[4,3ajquinoxaline | 397 | 202-203 |
| 22 | 5-Butoxy-2-fluoro benzoic acid chloride | 1 -(5-Butoxy-2-fluorophenyl)-7-chloro-4methyl-[1,2,4]ΐΓί3ΖθΙο[4,3ajquinoxaline | 385 | 186-187 |
| 23 | 5-Butoxy-2-chloro benzoic acid chloride | 1 -(5-Butoxy-2-chlorophenyl)-7-chloro-4methyl-[1,2,4]1π3ζοΐο[4,3ajquinoxaline | 401 | 130-131 |
| 24 | 2-Fluoro-5hexyloxy- benzoic acid chloride | 7-Chloro-1 -(2-fluoro-5hexyloxy-phenyl)-4methyl-[1,2,4]triazolo[4,3ajquinoxaline | 413 | 155-156 |
| 25 | 5-Butoxy-2-methyl benzoic acid chloride | 1 -(5-Butoxy-2-methylphenyl)-7-chloro-4methyl-[1,2,4]triazolo[4,3ajquinoxaline | 381 | 111-113 |
| 26 | 5-Hexyloxy-2methyl benzoic acid chloride | 7-Chloro-1-(5-hexyloxy-2- methyl-phenyl)-4-methyl[1,2,4]triazolo[4,3a]quinoxaline | 409 | 77-81 |
| 27 | 2-Chloro-5-(4,4,4trifluoro-butoxy)benzoic acid chloride | 7-Chloro-1 -[2-chloro-5(4,4,4-trifluoro-butoxy)phenyl]-4-methyl[1,2,4]triazolo[4,3ajquinoxaline | 455 | 128-131 |
| 28 | 2-Fluoro-5-(4fluoro-butoxy)benzoic acid chloride | 7-Chloro-1 -[2-fluoro-5-(4fluoro-butoxy)-phenyl]-4methyl-[1,2,4]triazolo[4,3ajquinoxaline | 403 | 172-174 |
| 29 | 2-Fluoro-5-(2methoxy-ethoxy)benzoic acid chloride | 7-Chloro-1-[2-fluoro-5-(2methoxy-ethoxy)-phenyl]- [1,2,4]triazolo[4,3ajquinoxaline | 373 | 192-197 |
Examples of Table 4 were prepared as described în Example 1 replacing 4chloro-1,2-phenylenediamine (step 1) with 1,2-phenylenediamine. The appropriate carboxylic acid chloride dérivative was used in step 5.
Table 4: Quinoxaline dérivatives
| Example # | carboxylic acid chloride dérivative | Name | MS [M+H]+ | m.p. (’C) |
| 30 | 2-Fluoro-benzoic acid chloride | 1-(2-Fluoro-phenyl)-4methyl-[1,2,4]triazolo [4,3a]quinoxaline | 279 | 192-194 |
| 31 | 5-Fluoro-2-methylbenzoic acid chloride | 1 -(5-Fluoro-2-methylphenyl )-4-methyl[1,2,4]triazolo[4,3ajquinoxaline | 293 | 185-188 |
| 32 | 2-Chloro-benzoic acid chloride | 1 -(2-Chloro-phenyl)-4methyl-[1,2,4]triazolo[4,3a]quinoxaline | 295 | 220-221 |
| 33 | 2-Methoxy-benzoic acid chloride | 1 -(2-Methoxy-phenyl)-4methyl-[1,2,4]triazolo[4,3ajquinoxaline | 291 | 175 |
| 34 | 2,5-Dichlorobenzoic acid chloride | 1 -(2,5-Dichloro-phenyl)-4methyl-[1,2,4]triazolo[4,3ajquinoxaline | 329 | 228-229 |
| 35 | 2,3-Dichlorobenzoic acid chloride | 1-(2,3-Dichloro-phenyl)-4- methyl-[1,2,4]ίπ3ζο1ο[4,3ajquinoxaline | 329 | 263-266 |
| 36 | 6-Fluoro-2-chlorobenzoic acid chloride | 1 -(2-Chloro-6-fluorophenyl)-4-methyl- [1,2,4]triazolo[4,3ajquinoxaline | 220 | 220 |
| 37 | 2-Chloro-5-(4,4,4trifluoro-butoxy)benzoic acid chloride | 1-(2-Chloro-5trifluoromethyl-phenyl)-4methyl-[1,2,4]triazolo[4,3a]quinoxaline | 313 | 212-213 |
| 38 | 5-Methoxy-2-chlorobenzoic acid chloride | 1 -(2-Chloro-5-methoxyphenyl)-4-methyl- [1,2,4]triazolo[4,3ajquinoxaline | 363 | 175-176 |
| 39 | 2-Methyl nicotînic acid chloride | 4-Methyl-1 -(3-methylpyridin-4-yl)- [1,2,4]triazolo[4,3- a]quinoxaline | 325 | 250-253 |
| 40 | 5-Butoxy-2-fluoro benzoic acid chloride | 1 -( 5-B u toxy-2-f I uorophenyl)-4-methyl[1,2,4]triazolo[4,3a]quinoxaline | 276 | 153 |
| 41 | 5-Butoxy-2-chloro benzoic acid chloride | 1 -(5-Butoxy-2-chlorophenyl)-4-methyl- [1,2,4]triazolo[4,3a]quinoxaline | 350 | 129-131 |
| 42 | 2-Fluoro-5-(4phenoxy-butoxy)benzoic acid chloride | 1 -[2-Fluoro-5-(4-phenoxybutoxy)-phenyl]-4-methyl- [1,2,4]tnazolo[4,3ajquinoxaline | 367 | 124-125 |
| 43 | 2-Fluoro-5-(4methoxy-ethoxy)benzoic acid chloride | 1 -[2-Fluoro-5-(4-methoxyethoxy)-phenyl]-4-methyl- [1,2,4]triazolo[4,3ajquinoxaline | 443 | 161-163 |
| 44 | 5-Hydroxy-2-methylbenzoic acid chloride | 4-Methyl-3-(4-methyl- [1,2,4]triazolo[4,3- a]quinoxalin-1-yl)-phenol | 353 | 286-291 |
| 45 | 2-Chloro-5-(4,4,4trifluoro-butoxy)benzoic acid chloride | 1-[2-Chloro-5-(4,4,4trifluoro-butoxy)-phenyl]4-methyl-[1,2,4]triazolo [4,3-aJquinoxaline | 290 | 134-135 |
| 46 | 2-Chloro-5-(4-fl uorobutoxy)- benzoic acid chloride | 1 -[2-Chloro-5-(4-fluorobutoxy)-phenyl]-4-methyl- [1,2,4]triazolo[4,3a]quinoxaline | 421 | 118-120 |
| 47 | 2-Chloro-5cyclobutylmethoxybenzoic acid chloride | 1-(2-Chloro-5cyclobutylmethoxyphenyl)-4-methyl[1,2,4]triazolo[4,3ajquinoxaline | 379 | 168-170 |
| 48 | 2-Chloro-5cyclopropylmethoxybenzoic acid chloride | 1-(2-Chloro-5cyclopropylmethoxyphenyl)-4-methyl[1,2,4]triazolo[4,3- a]quinoxaline | 365 | 171-173 |
| 49 | 2-Chloro-5phenethyloxybenzoic acid chloride | 1-(2-Chloro-5phenethyîoxy-phenyl)-4methyl-[1,2,4]triazolo[4,3ajquinoxaline | 415 | 160-163 |
| 50 | 2-Chloro-5-hyd roxybenzoic acid chloride | 4-Chloro-3-(4-methyl- [1,2,4]triazolo[4,3- a]quinoxalin-1-yl)-phenol | 311 | 262-266 |
| 51 | 5“(3,3-Dimethylbutoxy)-2-fluorobenzoic acid chloride | 1-[5-(3,3-Dimethylbutoxy)-2-fluoro-phenyl]4-methyl- [1,2,4]triazolo[4,3a]quinoxaline | 379 | 124-125 |
Examples of Table 5 were prepared as described in Example 1 replacing 4chloro-1,2-phenylenediamine (step 1) with 4-fluoro-1,2-phenylenediamine. The crude product was purified by flash chromatography (ethyl acetate/ n-hexane).
Yield: 2.7 g 3-chloro-6-fluoro-2-methyl-quinoxaline.
The appropriate carboxylic acid chloride dérivative was used in step 5.
Table 5: 8-Fluoro-quinoxaline dérivatives
| Example # | carboxylic acid chloride dérivative | Name | MS (M+H]+ | m.p. (°C) |
| 52 | 2-Fluoro- benzoic acid chloride | 8-Fluoro-1-(2-fluorophenyl)-4-methyl- [1,2,4]triazolo[4,3- ajquinoxaline | 297 | 217-219 |
| 53 | 2-Methyl nicotinic acid chloride | 8-Fluoro-4-methyl-1 -(2methyl-pyridin-3-yl)[1,2,4]triazolo[4,3a]quinoxaline | 294 | 227-233 |
| 54 | 5-Fluoro-2-methylbenzoic acid chloride | 8-Fluoro-1 -(5-fluoro-2methyl-phenyl)-4-methyl- [1,2,4]triazolo[4,3a]quinoxaline | 311 | 191 |
| 55 | 2-Chloro- benzoic acid chloride | 1 -(2-Chloro-phenyl)-8fluoro-4-methyl- [1,2,4]triazolo[4,3ajquinoxaline | 313 | 198-202 |
| 56 | 2-Chloro-5methoxy- benzoic acid chloride | 1 -(2-Chloro-5-methoxyphenyl)-8-fluoro-4-methyl[1,2,4]ΐπ3ζοΐο[4,3ajquinoxaline | 343 | 162-165 |
| 57 | 2-Chloro-5trifluoromethyl- | 1 -(2-Chloro-5- trifluoromethyl-phenyl)-8- | 381 | 197-200 |
| benzoic acid chloride | fluoro-4-methyl- [112,4]triazolo[4,3ajquinoxaline | |||
| 58 | 5-Butoxy-2-fluorobenzoic acid chloride | 1 -(5-Butoxy-2-fluorophenyl)-8-fluoro-4-methyl- [1,2,4]triazolo[4,3a]quinoxaline | 369 | 135-137 |
| 59 | 5-Butoxy-2-chlorobenzoic acid chloride | 1 -(5-Butoxy-2-chlorophenyl)-8-fluoro-4-methyl- [1,2,4]triazolo[4,3ajquinoxaline | 385 | 114-115 |
| 60 | 2-Fluoro-5hexyloxy- benzoic acid chloride | 8-Fluoro-1 -(2-fluoro-5hexyloxy-phenyl)-4methyl-[1,2,4]triazolo[4,3ajquinoxaline | 397 | 109-111 |
Examples of Table 6 were prepared as described in Example 1 replacing 4chloro-1,2-phenylenediamine (step 1) with 4-trifluoromethyl-1,2phenylenediamine. The crude product of step 2 was purified by flash 5 chromatography (ethyl acetate/ n-hexane). Yield: 2.9 g 3-chloro-6-trifluoromethyl -2-methyl-quinoxaline.
The appropriate carboxylic acid chloride dérivative was used in step 5.
The isomeric compound (1.5 g of 2-chloro-6-trifluoromethyl-3-methyl-quinoxaline, intermediate 3) was used in the same synthesis route to form 7-trifluoromethyl10 quinoxaline dérivatives described in Table 7.
Table 6: 8-Trifluoromethyl-quinoxaline dérivatives
| Example # | carboxylic acid chloride dérivative | Name | MS [M+H]+ | m.p. (°C) |
| 61 | 2-Chloro-benzoic | 1 -(2-Chloro-phenyl)-4- | 363 | 190-197 |
| acîd chloride | methyl-8-trifluoromethyl[1,2,4]triazolo[4,3ajquinoxaline | |||
| 62 | 5-Fluoro-2-methylbenzoic acid chloride | 1 -(5-Fluoro-2-methylphenyl)-4-methyl-8trifluoromethyl- [1,2,4]triazolo[4,3ajquinoxaline | 361 | 185-188 |
| 63 | 2-Methoxy-benzoic acid chloride | 1 -(2-Methoxy-phenyl)-4methyl-8-trifluoromethyl- [1,2,4]triazolo[4,3ajquinoxaline | 359 | 191-192 |
| 64 | 2,3-Dichlorobenzoic acid chloride | 1-(2,3-Dîchloro-phenyl)-4methyl-8-trifluoromethyl- [1,2,4]triazolo[4.3- a]quinoxaline | 397 | 207-209 |
| 65 | 2-Chloro-5trifluoromethylbenzoic acid chloride | 1-(2-Chloro-5trifluoromethyl-phenyl)-4methyl-8-trifluoromethyl[1,2,4]triazolo[4,3ajquinoxaline | 431 | 184-190 |
| 66 | 2-Fluoro-benzoic acid chloride | 1-(2-Fluoro-phenyl)-4methyl-8-trifluoromethyl- [1,2,4]triazolo[4,3- ajquinoxaline | 347 | 192-194 |
| 67 | 5-Butoxy-2-fluorobenzoic acid chloride | 1 -(5-Butoxy-2-fluorophenyl )-4-methyl-8trifluoromethyl- [1,2,4]ΐΓί3Ζθθ[4,3ajquinoxaline | 419 | 112-115 |
| 68 | 2-Fluoro-5- | 1 -(2-Fluoro-5-hexyloxy- | 447 | 79-81 |
| hexyloxy-benzoic acid chloride | phenyl)-4-methyl-8trifluoromethyl- [1,2,4]triazolo[4,3ajquinoxaline |
Table 7: 7-Trifluoromethyl-quinoxaline dérivatives
| Example # | carboxylic acid chloride dérivative | Name | MS [M+H]+ | m.p. (°C) |
| 69 | 2-Methylsulfanylnicotinoy! chloride | 4-Methyl-1-(2- methylsulfanyl-pyridin-3yl)-7-trifluoromethyl- [1,2,4]ΐΓί3ζοΙο[4,3a]quinoxaline | 376 | 188-197 |
| 70 | 2,6-Difluorobenzoic acid chloride | 1 -(2,6-Difluoro-phenyl)-4methyl-7-trifluoromethyl- [1,2,4]triazolo[4,3ajquinoxaline | 365 | 155-164 |
| 71 | 2-Fluoro- benzotc acid chloride | 1-(2-Fluoro-phenyl)-4methyl-7-trifluoromethyl- [1,2,4]triazolo[4,3- a]quinoxaline | 347 | 175-178 |
Examples of Table 8 were prepared as described in Example 1 replacing 4chloro-1,2-phenylenediamine (step 1) with 4-methoxy-1,2-phenylenediamine.
The crude product of step 2 was purified by flash chromatography (ethyl acetate/ n-hexane).
Yield: 3.9 g 2-chloro-6-methoxy -2-methyl-quinoxaline.
The appropriate carboxylic acid chloride dérivative was used in step 5.
The isomeric compound (0.5 g of 3-chloro-6-methoxy-3-methyl-quinoxaline, intermediate 4) was used in the same synthesis route to form Example compound 80.
Table 8: 7-Methoxy-quinoxaline dérivatives
| Example # | carboxylic acid chloride dérivative | Name | MS [M+H]+ | m.p. (°C) |
| 72 | 5-Fluoro-2-methylbenzoic acid chloride | 1 -(5-Fluoro-2-methylphenyl)-7-methoxy-4methyl-[1,2,4]triazolo[4,3ajquinoxaline | 323 | 228-232 |
| 73 | 2-Fluoro-benzoic acid chloride | 1 -(2-Fluoro-phenyl)-7methoxy-4-methyl- [1,2,4]triazolo[4,3ajquinoxaline | 309 | 230-231 |
| 74 | 2-Chloro- benzoic acid chloride | 1-(2-Chloro-phenyl)-7methoxy-4-methyl[1,2,4]triazolo[4,3ajquinoxaline | 325 | 236-240 |
| 75 | 2,6-Difluorobenzoic acid chloride | 1 -(2,6-Difluoro-phenyl)-7methoxy-4-methyl- [1,2.4]triazolo[4,3- a]quinoxaline | 326 | 250-255 |
Example 76: 1-(2-Chloro-phenyl)-4-methyl-[1,2,4]triazolo[4I3-a]quinoxalin-7-ol
0.6 g of 1-(2-chloro-phenyl)-7-methoxy-4-methyl-[1, 2, 4] triazolo [4,3a]quinoxaline (example compound 74) were dissolved in 6 ml of 1N PBr3 in methylene chloride. The mixture was stirred ovemight. Then 30 ml methylene chloride and 30 ml of saturated NaHCO3 were added. The organic layer was separated and the solvent evaporated. Yield: 413 mg; m.p. = 310 °C.
Examples of Table 9 were prepared by following general method:
A mixture of 400 mg of compound 76 [1-(2-chloro-phenyl)-4-methyl- [1,2,4]triazolo[4l3-a]quinoxalin-7-ol]1 600 mg of CS2CO3 and the appropriate aralkyl bromide (see Table 9) in acetonitrile were stirred ovemight. The product was filtrated from CsBr and acetonitrile was evaporated. Ail crude products were purified by flash chromatography.
Table 9: Aralkoxy-quinoxaline dérivatives
| Example # | aralkyl bromide dérivative | Name | MS [M+H]+ | m.p. (°C) |
| 77 | 4-Fluoro-benzyl bromide | 1 -(2-Chloro-phenyl)-7-(4fluoro-benzyloxy)-4methyl-[1,2,4]triazolo[4,3ajquinoxaline | 419 | 180-182 |
| 78 | 2-(3,4-Dimethoxyphenyl) ethyl bromide | 1 -(2-Chloro-phenyl)-7-[2(3,4-dimethoxy-phenyl)ethoxy]-4-methyl- [1,2,4]triazolo[4,3ajquinoxaline | 475 | 130-135 |
| 79 | Quinolin-2-yl methyl bromide | 1-(2-Chloro-phenyl)-4methyl-7-(quinolin-2ylmethoxy)[1,2,4]triazolo[4,3ajquinoxaline | 452 | 204-205 |
| 80 | Quinolin-2-yl methyl bromide | 1-(2-Chloro-phenyl)-4methyl-8-(quinolin-2ylmethoxy)- [1,2,4]triazolo[4,3a]quinoxaline | 452 | 193-194 |
Examples of Table 10 were prepared as described in Example 1 replacing 4chloro-1,2-phenylenediamine (step 1) with 4-bromo-1,2-phenylenediamine. The crude product of step 2 was purified by flash chromatography (ethyl acetate/ n5 hexane). Yield: 2.3 g 3-chloro-6-bromo-2-methyl-quinoxaline,
The appropriate carboxylic acid chloride dérivative was used in step 5.
The isomeric compound (2.0 g of 2-chloro-6-bromo-3-methyl-quinoxaline, intermediate 4) was used in the same synthesis route to form 7-bromoquinoxaline dérivatives described in Table 11.
Table 10: 8-Bromo-quinoxaline dérivatives
| Example # | carboxylic acid chloride dérivative | Name | MS [M+H]+ | m.p. (°C) |
| 81 | 2-Chloro- benzoic acid chloride | 8-Bromo-1 -(2-chlorophenyl)-4methy[1 ,2,4]Ιγϊ3ΖοΙο[4,3ajquinoxaline | 374 | 235-237 |
| 82 | 2-Chloro-5trifluoromethylbenzoic acid | 8-Bromo-1 -(2-chloro-5trifluoromethyl-phenyl)-4methyl-[1,2,4]triazolo[4,3- | 442 | 193-194 |
| chloride | ajquinoxaline | |||
| 83 | 5-Butoxy-2-chlorobenzoic acid chloride | 8-Bromo-1 -(5-butoxy-2chloro-phenyl )-4-methyl- [1,2,4)(082010(4,3ajquinoxaline | 446 | 144-147 |
| 84 | 5-Butoxy-2-fluorobenzoic acid chloride | 8-Bromo-1 -( 5-butoxy-2fluoro-phenyl)-4-methyl- [1,2,4]triazolo[4,3a]quinoxaline | 430 | 145-148 |
Table 11: 7-Bromo-quinoxaline dérivatives
| Example # | aralkyl bromide dérivative | Name | MS [M+H]+ | m.p. (°C) |
| 85 | 2-Chloro-5trifluoromethylbenzoic acid chloride | 7-Bromo-1 -(2-chloro-5trifluoromethyl-phenyl)-4methyl-[1,2,4]triazolo[4,3ajquinoxaline | 442 | 195-197 |
| 86 | 5-B utoxy-2-chl orobenzoic acid chloride | 7-Bromo-1 -(5-butoxy-2chloro-phenyl)-4-methyl[1,2,4]triazolo[4,3ajquinoxaline | 446 | 140-144 |
| 87 | 5-Butoxy-2-fluorobenzoic acid chloride | 7-Bromo-1 -(5-butoxy-2fluoro-phenyl)-4-methyl- [1,2,4]triazolo[4,3a]quinoxaline | 430 | 185-188 |
Example 88: 2, 2-Dimethyl-propîonic acid 4-chloro-3-(4-methyl-[1,2,4]triazolo[4,3a]quinoxalin-1-yl)-phenyl ester
A mixture of 400 mg of compound 44 [4-methyl-3-(4-methyl-[1,2,4]triazolo[4,3a]quinoxalin-1-yl)-phenol], 1g of CS2CO3 and 2,2-dimethyl-propionyl chloride in acetonitrile were stirred overnight. The product was filtrated from CsCI and solvent was evaporated. The crude product was purified by flash chromatography. M.p. 160-163 °C.
Examples 89-106 were prepared by foilowing general method:
A mixture of 400 mg of compound 44 [4-methyl-3-(4-methyl-[1,2,4]triazolo[4,3a]quinoxalin-1-yl)-phenol], 1g of Cs2CO3 and the appropriate alkyl bromide (see 10 Table 11) in acetonitrile were stirred overnight. The product was filtrated from
CsBr and acetonitrile was evaporated. Ail crude products were purified by flash chromatography.
Table 12: Alkoxyphenyl-quinoxaline dérivatives
| Example # | alkyl bromide dérivative | Name | MS [M+Hf | m.p. (°C) |
| 89 | Acetic acid 4bromo-butyl ester | Acetic acid 4-[4-chloro-3- (4-methyl- [1,2,4]triazolo[4,3- a]quinoxalin-1-yl)phenoxyj-butyl ester | 425 | 106 |
| 90 | 4-Bromo-butan-1-ol | 4-[4-Chloro-3-(4-methyl- [1,2,4]triazolo[4,3a]quinoxalin-1-yl)phenoxy]-butan-1 -ol | 383 | 156-157 |
| 91 | 4-(2-Bromo-ethyl)morpholine | 1-[2-Chloro-5-(2morpholin-4-yl-ethoxy)phenyl]-4-methyl[1,2,4]triazolo[4,3ajquinoxaline | 424 | 161 |
| 92 | 4-(2-Bromo-ethyl)morpholine | 1-[2-Chloro-5-(2morpholin-4-yl-ethoxy)phenyl]-4-methyl- [1,2,4]triazolo[4,3- a]quinoxaline; hydrochloride | 460 | 115-120 |
| 93 | 2-Bromo-1-pyridin- 2-yl-ethanone | 2-[4-Chloro-3-(4-methyl- [1,2,4]triazolo[4,3a]quinoxalin-1-yl)phenoxy]-1 -pyridin-2-ylethanone | 430 | 221-222 |
| 94 | 1-(2-Bromo-ethyl)- 4-methyl-piperazi ne | 1 -{2-Chloro-5-[2-(4methyl-pîperazin-1 -yl )ethoxy]-phenyl}-4-methyl- [1,2,4]triazolo[4,3ajquinoxaline | 437 | 168-169 |
| 95 | 1-(2-Bromo-ethyl)piperidine | 1 -[2-Chloro-5-(2-piperidin- 1 -yl-ethoxy )-phenyl]-4methyl-[1,2,4]triazolo[4,3ajquinoxaline | 422 | 152 |
| 96 | 1-(2-Bromo-ethyl)pyrrolidine | 1-[2-Chloro-5-(2pyrrolid i n-1 -yl-ethoxy)phenyl]-4-methyl[1 ^ΛΪΐΓίθζοΙομ,βajquinoxaline | 408 | 152 |
| 97 | 4-(2-Bromo-ethyl)tetrahydro-pyran | 1-{2-Chloro-5-[2(tetrahydro-pyran-4-yl)ethoxy]-phenyl}-4-methyl[1,2,4]triazolo[4,3a]quinoxaline | 423 | 121 |
| 98 | 3-Bromo-propan-1 - | 3-[4-Chloro-3-(4-methyl- | 369 | 160-163 |
| ol | [1,2,4]triazolo[4,3- a]quinoxalin-1-yl)phenoxy]-propan-1 -ol | |||
| 99 | 2-Bromo-ethan-1 -ol | 2-[4-Chloro-3-(4-methyl- [1,2,4]triazolo[4,3a]quinoxalin-1-yl)phenoxy]-ethanol | 355 | 203-205 |
| 100 | 3-Bromo-propan-2- ol | 1 -[4-Chloro-3-(4-methyl- [1,2,4]triazolo[4,3aJquinoxalin-1-yl)phenoxy]-propan-2-ol | 369 | 183-185 |
| 101 | 3-Bromo-propan-1ol | 3-[4-Chloro-3-(8-chloro-4methyl-[1,2,4]triazolo[4,3ajquinoxalin-1-yl)phenoxy]-propan-1 -ol | 403 | 135-138 |
| 102 | 3-Bromo-propan-2ol | 1 -[4-Chloro-3-(8-chloro-4methyl-[1,2,4]triazo1o[4,3a]quinoxalin-1-yl)phenoxy]-propan-2-ol | 403 | 185-189 |
| 103 | (S) 3-Bromopropan-2-ol | (S) 1-[4-Chloro-3-(4methyl-[1,2,4]triazolo[4,3a]quinoxalin-1-yl)phenoxy]-propan-2-ol | 369 | 194-195 |
| 104 | (R) 3-Bromopropan-2-ol | (R) 1-[4-Chloro-3-(4methyl-[1,2,4]triazolo[4,3a]quinoxalin-1-yl)phenoxy]-propan-2-ol | 369 | 193-194 |
Example 105: 2-[4-Chloro-3-(4-methyl-[1, 2, 4]triazolo[4,3-a]quinoxalin-1-yl)phenoxy]-1 -pyrîdin-2-yl-ethanol
To a solution of 300 mg of compound 93 [2-[4-chloro-3-(4-methyl- [1.2.4] triazolo[4,3-a]quinoxalin-1-yl)-phenoxy]-1-pyridin-2-yl-ethanone] in 30 ml of éthanol 0.5 ml of N-methyl pyrrolidin-2-on and 500 mg of NaBhL were added. The mixture was stirred for 30 min at room température. The solvent was evaporated. To the residue 50 ml of water was added. The crude product collected by filtration and was then purified by flash chromatography. M.p. 193194°C.
Example 106:1-[2-Chloro-5-(2-fluoro-2-pyridin-2-yl-ethoxy)-phenyl]-4-methyl- [1,2,4]triazolo[4,3-a]quinoxaline
To a solution of 200 mg of compound 100 (2-[4-chloro-3-(4-methyl- [1.2.4] triazolo[4,3-a]quinoxalin-1 -yl)-phenoxy]-1 -pyridin-2-yl-ethanol) in methylene chloride 0.2 ml of DAST (diethylaminosulfur trifluoride) were added. The mixture was stirred for 60 min at room température. The solvent was evaporated and the crude product was then purified by flash chromatography, M.p. 155-157°C.
Example 107: 4-Chloro-3-(8-chloro-4-methyl-[1 (2,4]triazolo[4.3-a]quinoxalin-1 yi)phenol
MS [M+H]*
M.p. (°C)
345
295-300 ci
HO·
Example 108: 1-(5-Butoxy-2-fluoro-phenyl)-[1,2,4]triazolo[4,3-a]quinoxaline
MS [M+H]+ 336
M.p. (°C) 136-137
Example 109: 1-[2-Fluoro-5-(2-methoxy-ethoxy)-phenyl]-[1,2,4]triazolo[4,3ajquinoxaline
MS [M+H]+ 338
M.p. (°C) 154-157 —-o
Example 110: 1-[2-Chloro-5-(4,4,4,-trifluoro-butoxy)-phenyl]-4,8-dimethyl[l^^triazolol/l.S-alquinoxaline
MS [M+H]+ 435
M.p. (°C) 154-158
Example 111: 7-Cyano-1-[2-chloro-5-(4,4,4,-trifluoro-butoxy)-phenyl]-4-methyl16480 [1,2,4]triazolo[4,3-a]quinoxaline
MS [M+H]+ 446
M.p. (°C) 134-138
Example A: Inhibition of recombinant PDE2A (expressed in baculovirus/SF21 -cells)
The DNA encoding PDE2A (NM002599) was cloned and the gene was inserted in the baculovirus and the enzyme-protein expressed in SF21-cells. The enzyme was isolated from these cells by harvesting the cells by an centrifugation at 200 g to collect the cells. The cells were resuspended in 50 mM Tris-HCI/5 mM MgCI2 buffer (pH=7.4)(Sigma, Deisenhofen, Germany; Merck, Darmstadt, Germany) and lysed by a sonication of the cells (three times for 15 seconds, Labsonic U, Fa. Braun, Degersheim, Switzerland, level „high“). The membrane fraction of PDE2A was obtained by a centrifugation at 48 000 g for 1 h, resuspended in buffer and stored at -70 °C.
PDE2A activity was determined in a one step procedure in microtiterplates. The reaction mixture of 100 μΙ contained 50 mM Tris-HCI/5 mM MgCI2 buffer (pH=7.4)(Sigma, Deisenhofen, Germany; Merck, Darmstadt, Germany), 0.5 μΜ pHJ-cAMP (PerkinElmer, Shelton, USA), 1000nM cGMP and the enzyme. Nonspecific enzyme activity was tested in the absence of cGMP. The reaction was initiated by addition of the substrate solution and was carried out at 37 °C for 30 minutes. Enzymatic activity then was stopped by addition of 25 μΙ SPA-beads (PerkinElmer, Shelton, USA). One hour later the mixture was measured in a liquid scintillation counter for microtiterplates (Microbeta Trilux). For pipetting of the incubation mixture we routinely use the robot Biomek (Fa. Beckman).
The determined Km for this assay was Km= 4200nmol/l for the membrane fraction and Km= 5300nM for the cytosolic fraction. The optimal amount of enzyme in the assay has been determined and optimised for each enzyme préparation separately before using the enzyme in compound testing. For détermination of IC5o values the Hill-plot, 2-parameter-model, was used.
Example B: Inhibition of recombinant PDE10A (expressed in baculovirus/SF21 cells)
The DNA of PDE10A1 (AB 020593, 2340 bp) was synthesized and cloned into the vector pCR4.TOPO (Entelechon GmbH, Regensburg, Germany). The gene was than inserted into a baculovirus vector, ligated with the baculovirus DNA. The protein was expressed in SF21-cells and isolated from these cells.
The cells were harvested and collected by centrifugation at 500 g. The cells were resuspended in 50 mM Tris-HCI/1 mM EDTA/250mM Sucrose buffer, pH=7.4 (Sigma, Deisenhofen, Germany; Merck, Darmstadt, Germany) and lysed by sonification of the cells (three times for 15 seconds, Labsonic U, Fa. Braun, Degersheim, Switzerland, level „high‘‘). The cytosolic PDE10A was obtained by a centrifugation at 48,000 g for 1 h in the supematant and stored at -70 °C. PDE activity was determined in a one step procedure in microtiter plates. The reaction mixture of 100 pl contained 50 mM Tris-HCI/5 mM MgCl2 buffer (pH=7.4, Sigma, Deisenhofen, Germany; Merck, Darmstadt, Germany) 0.1 μΜ [3H]-cAMP (PerkinElmer, Shelton, USA) and the enzyme. Non-specific enzyme activity was determined without the enzyme.
The reaction was initiated by addition of the substrate solution and was carrîed out at 37 °C for 30 minutes. Enzymatic activity then was stopped by addition of μΙ Ysi-SPA-beads (PerkinElmer, Shelton, USA). One h later the mixture was measured in a liquid scintillation counter for microtiter plates (Microbeta Trilux). The Biomek 2000 (Beckman) was used routinely for pipetting of the incubation mixture. The optimal amount of enzyme in the assay has been determined and 5 optimized for each enzyme préparation separately before using the enzyme in compound testing. For détermination of IC50 values the Hill-plot, 2-parametermodel, was used.
Table of ICsq data for PDE2A and PDE10A assays
| patent example | Inhibition of PDE10A, IC50 [μΜ] | Inhibition of PDE2A, IC50 [pM] |
| 1 | 0.045 | 0.003 |
| 2 | 0.214 | 0.009 |
| 3 | 0.182 | 0.038 |
| 4 | 0.197 | 0.021 |
| 5 | 0.383 | 0.094 |
| 6 | 0.131 | 0.005 |
| 7 | 0.104 | 0.005 |
| 8 | 0.091 | 0.012 |
| 9 | 0.736 | 0.060 |
| 10 | >1 | 0.034 |
| 11 | >1 | 0.004 |
| 12 | >1 | 0.002 |
| 13 | >1 | 0.135 |
| 14 | >1 | 0.004 |
| 15 | >1 | 0.126 |
| 16 | >1 | 0.007 |
| 17 | >1 | 0.018 |
| 18 | 0.103 | 0.026 |
| 19 | >1 | 0.083 |
| 20 | 0.475 | 0.068 |
| 21 | >1 | 0.316 |
| 22 | >1 | 0.138 |
| 23 | >1 | 0.051 |
| 24 | >1 | >1 |
| 25 | >1 | 0.086 |
| 26 | >1 | 1.0 |
| 27 | >1 | 0.138 |
| 28 | >1 | 0.122 |
| 29 | >1 | >1 |
| 30 | 0.346 | 0.021 |
| 31 | 0.343 | 0.047 |
| 32 | 0.076 | 0.005 |
| 33 | 0.998 | 0.146 |
| 34 | 0.330 | 0.011 |
| 35 | 0.360 | 0.232 |
| 36 | 0.041 | 0.005 |
| 37 | >1 | 0.057 |
| 38 | 0.300 | 0.017 |
| 39 | 0.930 | 0.137 |
| 40 | >1 | 0.007 |
| 41 | >1 | 0.003 |
| 42 | >1 | 0.370 |
| 43 | >1 | 0.108 |
| 44 | 0.160 | 0.012 |
| 45 | >1 | 0.006 |
| 46 | >1 | 0.011 |
| 47 | >1 | 0.006 |
| 48 | >1 | 0.006 |
| 49 | >1 | 0.012 |
| 50 | 0.062 | 0.004 |
| 51 | >1 | 0.023 |
| 52 | 0.553 | 0.033 |
| 53 | 1.0 | 0.211 |
| 54 | 0.555 | 0.061 |
| 55 | 0.081 | 0.010 |
| 56 | 0.279 | 0.017 |
| 57 | >1 | 0.110 |
| 58 | >1 | 0.009 |
| 59 | >1 | 0.005 |
| 60 | >1 | 0.128 |
| 61 | 0.044 | 0.004 |
| 62 | 0.271 | 0.043 |
| 63 | 0.265 | 0.032 |
| 64 | 0.337 | 0.108 |
| 65 | >1 | 0.052 |
| 66 | 0.471 | 0.013 |
| 67 | >1 | 0.003 |
| 68 | >1 | 0.258 |
| 69 | >1 | 0.377 |
| 70 | 0.077 | 0.008 |
| 71 | 0.324 | 0.362 |
| 72 | 0.162 | 0.032 |
| 73 | 0.223 | 0.022 |
| 74 | 0.068 | 0.009 |
| 75 | 0.334 | 0.047 |
| 76 | 0.274 | 0.006 |
| 77 | 0.118 | 0.006 |
| 78 | 0.048 | 0.007 |
| 79 | 0.001 | 0.002 |
| 80 | 0.010 | 0.003 |
| 81 | 0.025 | 0.002 |
| 82 | >1 | 0.020 |
| 83 | >1 | 0.002 |
| 84 | >1 | 0.003 |
| 85 | >1 | 0.355 |
| 86 | >1 | 0.069 |
| 87 | >1 | 0.106 |
| 88 | >1 | 0.008 |
| 89 | >1 | 0.261 |
| 90 | >1 | 0.076 |
| 91 | >1 | 0.291 |
| 92 | >1 | 0.422 |
| 93 | >1 | 0.135 |
| 94 | >1 | 1.0 |
| 95 | >1 | 1.0 |
| 96 | >1 | 0.659 |
| 97 | >1 | 0.195 |
| 98 | >1 | 0.014 |
| 99 | 0.554 | 0.028 |
| 100 | 0.784 | 0.023 |
| 101 | 0.319 | 0.005 |
| 102 | 0.611 | 0.007 |
| 103 | >1 | 0.017 |
| 104 | >1 | 0.019 |
| 105 | >1 | 0.092 |
| 106 | 0.963 | 0.080 |
| 107 | 0.013 | 0.002 |
| 108 | >1 | 0.063 |
| 109 | >1 | >1 |
| 110 | >1 | 0.004 |
| 111 | >1 | 0.216 |
Example C: In vivo effects
The compounds of formula (I) show procognitive, antîdepressant, anxiolytic and anticonvulsant effects in in vivo models at 100 mg/kg po and below.
Additionally, the compounds of formula (I) show an effect on extrapyramidal symptoms and movement disorders related to a malfunction/ degeneration of the 10 basal ganglia in in vivo models at 100 mg/kg po and below.
Especially, example 98 shows in vivo effects starting at 5 mg/kg in the models described herein.
Methods
Novel object récognition
The novel object récognition is an animal model of learning and memory (Rutten et al., 2006a+b).
The novel object récognition is performed in glass aquaria that hâve 3 black walls and one transparent wall. Objects of different material (iron, plastic, coated hardwood) and forms and similar size are used for the experiment. The objects are positioned 10 cm from the wall and 35-40 cm from each other.
Female Wistar-rats are used for this experiment. On the first day of the experiment rats are placed into the arena and hâve five min to explore two equal objects. To disturb the learning process, MK-801 at 0.025 mg/kg is adminîstered intraperitoneally on the first day of the experiment 30 min before the test starts.
On the second day of the experiment (24h later) rats are again placed into the arena and hâve 5 min to explore one of the familiar objects and a novel object. The position of the novel object is changed from rat to rat to avoid a place preference.
The following parameters are recorded:
1. the time the rats spent with each object on the first day
2. the time the rats spent with each object on the second day
3. percent of time rats spent with the novel object on the second day
Vehicle or compounds of formula (I) are given orally as a suspension on the first day of experiment 30 min prior to the test session.
The compounds of the invention were found to be effective in this model after the application of doses between 0.1 and 100 mg/kg.
Reserpine induced hypothermie
The reserpine-induced hypothermia is used as an animal model of dépréssion and of Parkinson’s disease (Benz and Waser, 1971; Menzaghi et al., 1997).
Reserpine administered 16h before the experiment induces a déplétion of dopamine, sérotonine and noradrenaline in the brain.
In our model 7.5 mg/kg i.p. reserpine is administered 16 h before the start of the experiment. On the day of experiment the basal rectal body température is recorded first. Ail animais that hâve a rectal body température below 30 °C are included in the experiment. Then, ail mice are evenly distributed so that the mean basal body température of each group is similar.
Afterwards, compounds of formula (I) or vehicle are administered to the mice and rectal body température is measured half-hourly for 3h. Additionally body température is measured 4h after compound administration.
The compounds of the invention were found to be effective in this model after the application of doses between 0.1 and 100 mg/kg.
Light and dark box
The light and dark box is an established animal model of anxiety (Crawley, 1985).
The light and dark box consists of two chambers that are connected by an opening. There is an aversive chamber with white walls that is brightly lit and a dark chamber with black walls that is only lit by an infrared lamp.
Untreated mice predominately stay in the dark chamber whereas mice treated with an anxiolytic compound go more often into the light chamber resulting in an increased number of transitions between the boxes and increased time in the light box. In addition the distance traveled in the dark chamber is regarded as an actrvity-related parameter.
For the experiment, mice are placed in the light box after the pre-treatment time.
Recording time starts when the mouse enters the dark box for the first time. Then the animal has 5 min to explore the two chambers.
The behaviour of the mice is recorded by video and analyzed by VideoMot 2 (TSE Systems, Germany).
The compounds of the invention were found to be effective in this model after the application of doses between 0.1 and 100 mg/kg.
Minimal clonie seizure test (6 Hz)
The minimal clonie seizure test is used to assess the effect of a compound against electrically induced seizure in mice (Lôscher and Schmidt, 1988). The compound is administered intraperitoneally prior to test. After a certain pretreatment time mice are challenged with sufficient current (32 mA, 3 s, 6 Hz) deîivered through corneal électrodes to elicit a psychomotor seizure in 97% of the animais (Toman et al., 1952). Untreated mice display seizures characterized by a minimal clonie phase followed by stereotyped automatistic behaviours described originally as being similar to the aura of human patients with partial seizure. Animais not displaying this behavior are considered protected.
The compounds of the invention were found to be effective in this model after the application of doses between 1.0 and 100 mg/kg.
Haloperidol induced catalepsy
Catalepsy is an animal model to evaluate the risk of a compound to induce extrapyramidale symptoms (EPS) in patients (Grauer et al., 2009). Additionally, catalepsy induced by haloperidol mimics symptoms of parkinsonism (Mandhane étal., 1997). —
Catalepsy was scored according to the method described by Mandhane et al.
(1997). The forelimbs of each rat were placed on a 9.0 x 9.0 cm wooden cube and the duration of the cataleptic posture was measured. Subsequently, the hind limbs of the animal were placed on the cube and the duration was measured.
The cataleptic response was scored as follows:
Score 0 the cataleptic posture lasted for less than 5 s for both forelimbs and hind limbs
Score 1 the cataleptic posture of forelimbs lasted for 5 - 10 s and that of the hind limbs lasted for less than 5 s
Score 2 the cataleptic posture of forelimbs lasted for more than 10 s and that of the hind limbs lasted for less than 5 s
Score 3 the cataleptic posture of forelimbs and hind limbs lasted for 5 - 10 s, or the cataleptic posture of forelimbs lasted for less than 5 s but that of the hind limbs lasted for more than 5 s
Score 4 the cataleptic posture of forelimbs lasted for more than 10 s and that of hind limbs lasted for 5 - 10 s, or the cataleptic posture of forelimbs lasted for 5 - 10 s and that of hind limbs lasted for more than 10 s
Score 5 the cataleptic posture of both forelimbs and hind limbs lasted for more than 10 s.
Animais that start sliding from the cube or show muscle relaxation (= curved back) are excluded from the measurement.
Catalepsy was induced by 0.75 mg/kg haloperidol intraperitoneally administered 90 min before the first test.
The compounds of the invention were found to be effective in this model after the application of doses between 0.1 and 100 mg/kg. W
References
Altamura AC, Lietti L, Dobrea C, Benatti B, Arici C, Dell’osso B (2011) Mood stabilizers for patients with bipolar disorder; the state of the art. Expert Rev
Neurother 11 (1): 85-99.
Baddeley A (2003). Working memory; looking back and looking forward. Nat Rev Neurosci 4 (10): 829-839.
Beck AT (2008). The évolution of the cognitive model of dépréssion and its neurobiological correlates. Am J Psychiatry 165: 969-977.
Benke T, Delazer M, Bartha L, Auer A (2003). Basal ganglia lésions and the theory of fronto-subcortical loops: neuropsychological findings in two patients with left caudate lésions. Neurocase 9: 70-85.Benz B, Waser PG (1971). Reversai of hypothermia in reserpine treated mice by neuro- and psycholeptic drugs. Arzneimittelforschung 21 (5): 654-661.
Blokland A, Schreiber R, Prickaerts J (2006). Improving memory: a rôle for phosphodiesterases. Curr.Pharm.Des 12 (20): 2511-2523.
Boess FG, Hendrix M, van der Staay FJ, Erb C, Schreiber R, van Staveren W, de Vente J, Prickaerts J, Blokland A, Koenig G (2004). Inhibition of phosphodiesterase 2 increases neuronal cGMP, synaptic plasticity and memory performance. Neuropharmacology 47 (7): 1081-1092.
Bolger GB, Rodgers L, Riggs M (1994). Differential CNS expression of alternative mRNA isoforms of the mammalian genes encoding cAMP-specific phosphodiesterases. Gene 149: 237-44.
Conti M, Jin SL (1999). The molecular biology of cyclic nucléotide phosphodiesterases. Prog Nucleic Acid Res Mol Biol 63:1-38.
Crawley JN (1985). Exploratory Behavior Models of Anxiety in Mice. Neurosci
Biobehav Rev 9: 37-44.
Dunkin JJ, Leuchter AF, Cook IA, Kasl-Godley JE, Abrams M, RosenbergThompson S (2000). Executive dysfunction predicts nonresponse to fluoxetine in major dépréssion. J Affect Disord 60:13-23.
Easton N, Marshall F, Fone K, Marsden C (2007). Atomoxetine produces changes in cortico-basal thalamic loop circuits: Assessed by phMRI BOLD contrast Neuropharmacology 52 (3): 812-26.
Essayan DM (2001). Cyclic nucléotide phosphodiesterases. J Allergy Clin
Immunol 108: 671-680.
Gaiwani P (2009). Treatment-refractory bipolar disorder: classification to aid in clinical management. Expert Opin Pharmacother 10 (12): 1907-1915.
Gonzalez, L.E., Rujano, M., Tucci, S., Paredes, D., Silva, E., Alba, G., & Hernandez, L. (2000). Médial prefrontal transection enhances social interaction. I: Behavioral studies. Brain Res 887: 7-15.
Gorlyn M, Keilp JG, Grunebaum MF, Taylor BP, Oquendo MA, Bruder GE, Stewart JW, Zalsman G, Mann JJ (2008). Neuropsychological characteristics as predictor of SSRI treatment response in depressed subjects. J Neural Transm 115: 1213-1219.
Grauer SM, Pulito VL, Navarra RL, Kelly MP, Kelley C, Graf R, Langen B, Logue S, Brennan J, Jiang L, Charych E, Egerland U, Liu F, Marquis KL, Malamas M, Hage T, Comery TA, Brandon NJ (2009). Phosphodiesterase 10A inhibitor activity in preclinical models of the positive, cognitive, and négative symptoms of schizophrenia. JPET 331 (2):574-590.
Gualtieri CT, Johnson LG, Benedict KB (2006). Neurocognition in dépréssion: patients on and off médication versus healthy comparison subjects. J Neuropsychiatry Clin Neurosci 18: 217-225.
Jucaite A, Fernell E, Halldin C, Forssberg H, Farde L (2005). Reduced midbrain dopamine transporter binding in male adolescents with attentiondeficit/hyperactivity disorder: association between striatal dopamine markers and motor hyperactivity. Biol Psychiatry 57 (3): 229-238.
Kotera J, Fujishige K, Yuasa K, Omori K (1999). Characterization and phosphorylation of PDE10A2, a novel alternative splice variant of human phosphodiesterase that hydrolyzes cAMP and cGMP, Biochem Biophys Res
Commun 261: 551-557.
Kumar S, Kulkarni SK (1996). Influence of antidepressant drugs on learning and memory paradigms in mice. Indian J Exp Biol 34: 431-435.
Lakics et al. Society of Neuroscience 35th Annual Meeting; 2005, Nov 12-16th,
Washington DC.
Loscher W, Schmidt D (1988). Which animal models should be used in the search for new antiepileptic drugs? A proposai based on experimental and clinical considérations. Epilepsy Res 2 (3): 145-181.
Mandelli L, Serretti A, Colombo C, Florita M, Santoro A, Rossini D, Zanardi R, Smeraldi E (2006). Improvement of cognitive functioning in mood disorder patients with dépressive symptomatic recovery durino treatment: an exploratory analysis. Psychiatry Clin Neurosci 60: 598-604.
Mandhane SN, Chopde CT and Ghosh AK (1997). Adenosine A2A receptors modulate haloperidol-induced catalepsy in rats. Européen Journal of Pharmacology 328: 135-141.
Masood A, Nadeem A, Mustafa SJ, O’Donnell JM (2008). Reversai of oxidative stress-induced anxiety by inhibition of phosphodiesterase-2 in mice. JPET 326: 369-379.
Masood A, Huang Y, Hajjhussein H, Xiao L, Li H, Wang W, Hamza A, Zhan CG, O'Donnell JM (2009). Anxiolytic effects of phosphodiesterase-2 inhibitors associated with increased cGMP signaling. JPET 331 (2):690-699.
Massoud F, Gauthier S (2010). Update on the pharmacological treatment of Alzheimer’s disease. Curr Neuropharmacol 8 (1): 69-80.
Menniti FS, Strick CA, Seger TF, Ryan AM (2001). Immunohistochemical localisation of PDE10A in the rat brain. William Harvey Research Conférence, Porto, December 6th - 8th.
Menniti FS, Faraci WS, Schmidt CJ (2006). Phosphodiesterases in the CNS: targets for drug development. Nat Rev Drug Discov 5 (8): 660-670.
Menzaghi F, Whelan KT, Risbrough VB, Rao TS, Lloyd GK (1997). Interactions between a novel cholinergic ion channel agonist, SIB-1765F and L-DOPA in the reserpine model of Parkinson’s disease in rats. JPET 280 (1 ): 393-401.
Modell JG, Mountz JM, Beresford TP (1990). Basal ganglia/limbic striatal and thalamocortical involvement in craving and loss of control in alcoholism. J
Neuropsychiatry Clin Neurosci 2 (2): 123-144.
Mutschler E, Geisslinger G, Kroemer HK, Schàfer-Korting M (2001). Mutschler —
Arzneimittelwirkungen. 8lh ed. Stuttgart: Wissenschaftliche Verlagsgesellschaft mbH.
Nibuya M, Nestler EJ, Duman RS (1996). Chronic antidepressant administration increases the expression of cAMP response element binding protein (CREB) in rat hippocampus. J Neurosci 16 (7): 2365-2372.
Paelecke-Habermann Y, Pohl J, Leplow B (2005). Attention and executive functions in remitted major dépréssion patients. J Affect Disord 89: 125-135.
Pavuluri MN, West A, Hill SK, Sweeney JA (2009). Neurocognitive function in pédiatrie bipolar disorder: 3-year follow-up shows cognitive development lagging behind healthy youths. J Am Acad Child Adolesc Psychiatry 48 (3): 299-307.
Pliszka SR (2005). The neuropsychopharmacology of attentiondeficit/hyperactivity disorder. Biol Psychiatry 57 (11): 1385-1390.
Post RM, Weiss SR (2010). Tolérance to the Prophylactic Effects of Carbamazepine and Related Mood Stabilizers in the Treatment of Bipolar Disorders. CNS Neurosci There pub ahead 2010 Dec 16. doi: 10.1111/j.17555949.2010.00215
Prickaerts J, de Vente J, Honig W, Steinbusch HW, Blokland A (2002). cGMP, but not cAMP, in rat hippocampus is involved in early stages of object memory consolidation. Eur J Pharmacol 436 (1-2): 83-87.
Roberts AC, Wallis JD (2000). Inhibitory control and affective processing in the prefrontal cortex: neuropsychological studies in the common marmoset. Cereb Cortex 10: 252-262.
Rodefer JS, Murphy ER, Baxter MG (2005). PDE10A inhibition reverses subchronic PCP-induced déficits in attentional set-shifting in rats. Eur J Neurosci 21: 1070-1076.
Rutten K, Prickaerts J, Blokland A (2006a). Rolipram reverses scopolamineinduced and time-dependent memory déficits in object récognition by different mechanisms of action. Neurobiol Learn Mem 85: 132-138.
Rutten K, Prickaerts J, Hendrix M, van der Staay FJ, Sik A, Blokland A (2006b).
Time-dependent involvement of cAMP and cGMP in consolidation of object memory: studies using sélective phosphodiesterase type 2, 4 and 5 inhibitors.
Eur J Pharmacol 558:107-112.
Sachs G, Schaffer M, Winklbaur B (2007). Cognitive déficits in bipolar disorder. Neuropsychiatr 21 (2): 93-101.
Schmidt CJ, Chapin DS, Cianfrogna J, Corman ML, Hajos M, Harms JF, Hoffman WE, Lebel LA, McCarthy SA, Nelson FR, Proulx-LaFrance C, Majchrzak MJ, Ramirez AD, Schmidt K, Seymour PA, Siuciak JA, Tingley FD, Williams RD, P. R. Verhoest PR, Menniti FS (2008). Preclinical characterization of sélective phosphodiesterase 10A inhibitors: a new therapeutic approach to the treatment of schizophrenia. JPET 325 (2):681-690.
Siuciak JA, McCarthy SA, Chapin DS, Fujiwara RA, James LC, Williams RD, Stock JL, McNeish JD, Strick CA, Menniti FS, Schmidt CJ (2006). Genetic délétion of the striatum-enriched phosphodiesterase PDE10A: evidence for altered striatal function. Neuropharmacology 51 (2):374-385.
Soderling SH, Bayuga SJ, Beavo JA (1999). Isolation and characterization of a dual-substrate phosphodiesterase gene family: PDE10A. Proc Natl Acad Sci USA 95(12): 7071-7075.
Soderling,S.H. and Beavo,J.A. (2000). Régulation of cAMP and cGMP signaling: new phosphodiesterases and new functions. Curr Opin Cell Biol 12: 174-179.
Thompson PA, Meltzer H Y (1993). Positive, négative, and disorganisation factors from the Schedule for Affective Disorders and Schizophrenia and the Présent State Examination. A three-factor solution. Br J Psychiatry 163: 344-351.
Toman JE, Everett GM, Richards RK (1952). The search for new drugs against epilepsy. Tex Rep Biol Med 10 (1): 95-104.
Turner DC, Robbins TW, Clark L, Aron AR, Dowson J, Sahakian B J (2003). Psychopharmacology 168: 455-464.
Valluzi JA, Chan K (2007). Effect of fluoxetine on hippocampal-dependent and hippocampal-independent learning tasks. Behav Pharmacol 18: 507-513.
Van Staveren WC, Steinbusch HW, Markerink-Van Ittersum M, Repaske DR,
Goy MF, Kotera J, Omori K, Beavo JA, De Vente J (2003). mRNA expression patterns of the cGMP-hydrolyzing phosphodiesterases types 2, 5, and 9 during development of the rat brain. J Comp Neurol 467: 566-80. v^z
Winstanley CA, Eagle DM, Robbins TW (2006). Behavioral models of impulsivity in relation to ADHD: translation between clinical and preclinical studies. Clin Psychol Rev 26 (4): 379-395.
Xie Z, Adamowicz WO, Eldred WD, Jakowski AB, Kleiman RJ, Morton DG, 5 Stephenson DT, Strick CA, Williams RD, Menniti FS (2006). Cellular and subcellular localization of PDE10A, a striatum-enriched phosphodiesterase.
Neuroscience 139 (2): 597-607.
Young JW, Powell SB, Risbrough V, Marston HM, Geyer MA (2009). Using the
MATRICS to guide development of a preclinical cognitive test battery for research in schizophrenia. Pharmacol Ther 122 (2): 150-202. <vv^
JUIL 2013
Claims (23)
1. A compound of formula (I):
or a pharmaceutically acceptable sait thereof; wherein:
R1 represents
-phenyl, 2-pyridyl, 3-pyridyl or 4-pyridyl, in each case substituted with a substituent different from H in an ortho position of the linkage to the backbone structure and optionally substituted with further substituents different from H.
R2 represents
- hydrogen,
- C-i-4 alkyl, optionally substituted with up to 2 halo, e.g. fluorine atoms;
R3, R4 , R5 and R6 are independently from each other representing hydrogen,
- halogen,
- Cm alkyl, optionally substituted with up to 5, preferably up to 3 halo,
e.g. fluorine atoms, and/or-OC-|.2 (halo)alkyl,
C3.8 cycloalkyl, optionally substituted with halo, -Cv2 (halo)alkyl and/or -OCi.2(halo)alkyl,
- -CN,
- -OH,
- -OCm alkyl, optionally substituted with up to 5, preferably up to 3 halo, e.g. fluorine atoms, and/or -OC1.2 (halo)alkyl,
- C3.8 cycloalkyl optionally substituted with halo, -C1.2 (halo)alkyl and/or -OC1.2 (halo)alkyl,
- -O(CH2)n-R10, wherein n can be 1 or 2;
R10 represents
- a cyclic group which can be unsubstituted or substituted preferably up to 4 times by halogen, C1.4 alkyl, optionally substituted with up to 5, preferably up to 3 halogen atoms, or OC1.4 alkyl, optionally substituted with up to 5, preferably up to 3 halogen atoms, but not the following compounds: 1-(2-hydroxyphenyl)-4-methyl-(1,2,4)triazolo[4,3-a]quinoxaline, 1-(2-chlorophenyl)-4-methyl-(1,2,4)triazolo[4,3-a]quinoxaline, 1-(2-nitrophenyl)-4-methyl-(1,214)triazolo[4,3-a]quinoxalinel 1-(2-methoxyphenyl)-4-methyl-(1,2,4)triazolo[4,3-a]quinoxaline, 1-(5-amino-2-chlorophenyl)-4-methyl-(1,2,4)triazolo[4,3-a]quinoxaline, 1-(5-amino-2-methoxyphenyl)-4-methyl-(1,2,4)triazolo[4,3-a]quinoxaline, 1-(5-amino-2-methylphenyl)-4-methyl-(1,2,4)triazolo[4,3-a]quinoxaline, or 1-(2-hydroxy-3-methoxyphenyl)-4-methyl-(1,2,4)triazolo[4,3-a]quinoxaline.
2. The compound of claim 1, wherein R1 is substituted with 1 to 3 substituents R7, R8 and/or R9 different from H so that at least one of these substituents is in an ortho position of the attachment site to the backbone structure, wherein
R7, R8, R9 are independently from each other representing
- halogen,
- NO2,
- -C1.6 alkyl, optionally substituted with up to 5, preferably up to 3 fluorine atoms,
-OC1.6 alkyl, optionally substituted with up to 5, preferably up to 3 fluorine atoms,
- -SCi_6 alkyl, optionally substituted with up to 5, preferably up to 3 fluorine atoms,
- -phenyl which can be substituted with up to two halogen atoms and/or -CF3 groups,
- -O(CH2)n-R11 . wherein n can be 0, 1, 2, 3 or 4
R11 represents if n = 2, 3 or 4:
- -OH,
- -OCV4 alkyl,
- -O(C=O)Ci_4 alkyl, if n = 0,1,2, 3 or 4:
- -C3.6 alkyl,
- a cyclic group, which is linked to O(CH2)n via a covalent bond or via -C(=O)-, -CH(OH)-, or-CH(halogen)-,
- wherein the cyclic group is preferably selected from phenyl, C3.e (hetero)cycloalkyl, such as cyclopropyl, cyclobutyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl, pyran-4-yl, 2-pyridyl, 3-pyridyl, or
4-pyridyl.
3. The compound of claim 2, wherein R1 represents phenyl, which is substituted with 1, 2 or 3 substituents R4 * * 7, R8 and/or R9 wherein at least one of these substituents is in an ortho position of the attachment site to the backbone structure, or wherein R1 is 2-pyridyl, 3-pyridyl or 4-pyridyl which is substituted with 1, 2 or 3 substituents R7, R8 and/or R9, wherein one of these substituents is in an ortho position of the attachment site of the backbone structure.
4. The compound of any one of claims 1-3, where R1 represents phenyl which is substiituted with halogen, particularly Cl, in position 2 and Ci-θ alkoxy optionally substituted with OH or OCH3, particularly -OCH2CH2CH2OH, in position 3, 5 or 6, particularly in position 5, wherein phenyl is attached via position 1 to the backbone. mz
5. The compound of any one of daims 1-4, wherein R2 represents methyl optionally substituted with up to 2 fluorine atoms.
6. The compound of any one of daims 1-5, wherein R3 and R6 are H.
7. The compound of any one of daims 1-6, wherein R4 and R5 are independently from each other representing hydrogen, -OH, halogen, -CH3, -CF3, -OCH3i -OCHF2, -OCF3, -O(CH2)n-R10. wherein n can be 1 or 2, and wherein R10 is as defined in claim 1,
8. The compound of any one of daims 1-7, wherein R4 is H and R5 is different from H or wherein R4 is different from H and R5 is H.
9. The compound of any one of daims 1-6, wherein R2 is CH3( and R4 is H and R5 is different from H or wherein R2 is CH3, R4 is different from H and R5 is H.
10. The compound of any one of daims 2-9, wherein R7 , R8 , R9 are independently from each other representing halogen, -CH3 optionally substituted with up to 3 fluorine atoms, -OC-i-e alkyl, optionally substituted with up to 3 fluorine atoms or -O(CH2)n-R11 > wherein n can be 1, 2, 3 or 4 and wherein R11 is as defined in claim 2, and particularly -OCH2CH2CH2OH.
11. The compound of any one of daims 1-10, wherein R10 represents phenyl or quinolin-2-yl, which can be substituted up to two times by halogen and/or OCH3.
12. The compound of any one of daims 2-11, wherein R11 represents if n = 2, 3 or 4: -OH or -OCH3 and if n = 0, 1, 2, 3 or 4: phenyl, 2-pyridyl, 3-pyridyl, 4pyridyl, v
13. The compound of any one of claims 1-12 as described in any one of the Examples 1-31, 34-106 and 107-111, particularly as described in Example 98, or a pharmaceutically acceptable sait thereof.
14. The compound of any one of claims 1-13, which is (i) a PDE2 inhibitor, (ii) a PDE10 inhibitor, and/or (iii) a PDE2 and PDE10 inhibitor.
15. The compound of any one of claims 1-14 for use in medicine, particularly in human medicine, wherein the use in medicine also encompasses the compounds disclaimed in claim 1.
16. The compound of any one of claims 1-15 for use together with a pharmaceutically acceptable carrier.
17. The compound of any one of claims 1-16 for use in combination with a further active ingrédient.
18. The compound for use according to claim 17 wherein the further active agent is an NMDA modulating agent such as memantine or an acétylcholine neurotransmitter modulating agent such as donezepil.
19. The compound of any one of claims 1-18 for use in a method of treating disorders associated with PDE2 and/or 10 hyperactivity. wx—16480
20. The compound of any one of daims 1-18 for use in (i) a method of treating nervous central system disorder, (ii) a method of treating obesity, type II diabètes, metabolic syndrome, glucose intolérance and related health risks, symptoms or disorders, (iii) a method for the treatment of neurologie and psychiatrie disorders.
21. The compound of any one of daims 1-19 for use in the treatment of (1) disorders comprising the symptom of cognitive deficiency in a mammal, including a human; (2) organic, including symptomatic, mental disorders, dementia; (3) mental retardation; (4) mood [affective] disorders; (5) neurotic, stress-related and somatoform disorders including anxiety disorders; (6) behavioural and emotional disorders with onset usually occurring in childhood and adolescence, attention déficit hyperactivity syndrome (ADHD); (7) disorders of psychological development, developmental disorders of scholastic skills; (8) schizophrenia and other psychotic disorders; (9) disorders of adult personality and behaviour; (10) mental and behavioural disorders due to psychoactive substance use; (11) extrapyramidal and movement disorders; (12) episodic and paroxysmal disorders, epilepsy; (13) Systemic atrophies primarily affecting the central nervous system, ataxia; (14) Behavioural syndromes associated with physiological disturbances and physical factors; (15) sexual dysfunction comprising excessive sexual drive; (16) factitious disorders.
22. The compound of any one of daims 1-21 for use in the treatment of Alzheimer’s disease.
23. Use of a compound of formula (I), or a pharmaceutically acceptable sait thereof in the manufacture of a médicament for treating disorders associated with
PDE2 and/or 10 hyperactivity.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US61/437848 | 2011-01-31 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| OA16480A true OA16480A (en) | 2015-10-21 |
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