| Title of Invention | SUBSTITUTED PYRIDINE DERIVATIVES |
|---|---|
| Abstract | The present invention relates to pyridine derivatives of the general formula (I) and their use as openers of the KCNQ family potassium ion channels for the treatment of CNS disorders. |
| Full Text | SLTBsrrrrriz? PYRIDINE DERIVATIVES FIELD OF THE INVENTION The presets invention relates to compounds, which are openers of the KCNQ family potassium ion channels. The compounds are useful in the treatment of disorders and diseases being responsive to opening of the KCNQ family potassium ion channels; one such disease is epilepsy. BACKGROUND OF THE INVENTION Ion channels are cellular proteins that regulate the flow of ions, including potassium, calcium, chloride and sodium into and out of cells. Such channels are present in all animal and human cells and affect a variety of processes including neuronal transmission, muscle contraction- and cellular secretion. Humans have over 70 genes encoding potassium channel subtypes (Jentsch Nature Reviews Nevroscienee 2000. 1, 21 -30) with a great diversity with regard to both stucture and function- Neuronal potassium channels, which are found in the brain, are primarily responsible for maintaining a negative resting membrane potential, as well as controlling membrane repolarisation following an action potential. One subset of potassium channel genes is the KCNQ family. Mutations in four out of five KCNQ genes have been shown to underlie diseases including cardiac arrhythmias, deafness and epilepsy (Jentsch Nature Reviews Neuroscience 2000, 1,21-30). The KCNQ4 gene is thought to encode the molecular correlate of a potassium channel found in outer hair cells of the cochlea and in Type I hair cells of the vestibular apparatus, in which, mutations can lead to a form of inherited deafness. KCNQ1 (KvLQTl) is co-assembled with the product of the KCNE1 (minimal K(+>channel protein) gene in the heart to form a cardiac-delayed rectifier-like K(H-) current. Mutations in this charmd csi cause cme fern of inherited long QT syndrome type 1 (LQT1), as well as being assoc^sd wish a form of deafness (Robbins Pharmacol Ther 2001, 90. 1-19). The genes KCNQ2 and KCNQ3 were discovered in 3988 and appear to be mutated in an inherited form of epilepsy known as benign familial neonatal convulsions (Rogawski Trends in Neurosciences 2000: 23; 393-398). The proteins encoded by the KCNQ2 and KCNQ3 proteins are localised in the p)TamidaI neurons of the human cortex and hippocampus, regions of the brain associated with seizure generation and propagation (Cooper e: al. Proceedings National Academy of Science USA 2000, 91, 4914-4919). KCNQ2 and KCNQ3 are two potassium channel subunits that form "M-currents" when expressed in vitro. The M-current is a non-inactivating potassium current found in many neuronal cell types. In each cell type, it is dominant in controlling membrane excitability by being the only sustained current in the range of action potential initiation (Marrion Annual Review Physiology? 1997, 59. 483-504). Modulation of the M-current has dramatic effects on neuronal excitability, for example activation of the current will reduce neuronal excitability. Openers of these KCNQ channels, or activators of the M-cuirent will reduce excessive neuronal activity and may thus be of use in the treatment of seizures and other diseases and disorders characterised by excessive neuronal activity, such as neuronal hyperexcitability including convulsive disorders, epilepsy and neuropathic pain. Retigabine (D-23129; 7V-(2-amino-4-(4-fluoroben2ylamino)-phenyl) carbamic acid ethyl ester) and analogues thereof are disclosed in EP554543. Retigabine is an anti-convulsive compound with a broad spectrum and potent anticonvulsant properties, both in vitro and in vivo. It is active after oral and intraperitoneal administration in rats and mice in a range of anticonvulsant tests including: electrically induced seizures, seizures induced chemically by pentylenetetrazole, picrotoxin and N-methyl-D-aspartate (NMDA) and in a genetic animal model, the DBA/2 mouse (Rostock et al. Epilepsy Research 1996, 23,211 -223). In addition, retigabine is active in the amygdala kindling model of complex partial seizures, further indicating that this compound has potential for anti-convulsive therapy. In clinical trials, retigabine has recently shown effectiveness in reducing the incidence of seizures in epileptic patients (Bialer et al. Epilepsy Research 2002, 51, 31-71). Retigabine has been shown to activate a K(+) current in neuronal cells and the pharmacology of this induced current displays concordance with the published phannacclogy of the M-charmeL which recently was correlated to the KCNQ2/3 K(-r) channel hezercmuhiiner. This suggests that activation of KCNQ2/3 channels may be responsible for some of the anticonvulsant activity of this agent (Wickenden et al. Molecular Pharmacolog}- 2000. 58. 591-600) - and that other agents working by the same mechanism may have similar uses. KCNQ 2 and 3 channels have also been reported to be upregulated in models of neuropathic pain (Wickenden ec ai. Society for Neuroscience Aosrracis 2002, 454. T)i and potassium channel modulators have been hypothesised to be active in both neuropathic pain and epilepsy (Schroder et al. Neuropharmacology 2001, 40, 888-898). Retigabine has also been shown to be beneficial in animal models of neuropathic pain (Blackbum-Munro and Jensen European Journal of Pharmacology 2003. 460. 109-116), and it is thus suggested that openers of KCNQ channels will be of use in treating pain disorders including neuropathic pain. The localisation of KCNQ channel mRNA is reported in brain and other central nervous system areas associated with pain (Goldstein et al. Society for Neuroscience Abstracts 2003, 53.8). In addition to a role in neuropathic pain, the expression of mRNA for KCNQ 2-5 in the trigeminal and dorsal root ganglia and in the trigeminal nucleus caudalis implies that openers of these channels may also affect the sensory processing of migraine pain (Goldstein et al. Society for Neuroscience Abstracts 2003, 53.8). Recent reports demonstrate that mRNA for KCNQ 3 and 5, in addition to that for KCNQ2, are expressed in astrocytes and glial cells. Thus KCNQ 2,3 and 5 channels may help modulate synaptic activity in the CNS and contribute to the neuroprotective effects of KCNQ channel openers (Noda et al., Society for Neuroscience Abstracts 2003, 53.9). Retigabine and other KCNQ modulators may thus exhibit protection against the neurodegenerative aspects of epilepsy, as retigabine has been shown to prevent limbic neurodegeneration and the expression of markers of apoptosis following kainic acid-induced status epiiepticus in the rat (Foeri et ai. Epilepsia 2002. 45 Suppi z, S-i-rf;. This may have relevance for preventing the progression of epilepsy in patients, L=_ be irri-^pileptogenic, Retigabine has also been shown to delay the progression of hippocainpai V^wT?:-a- in the rat a further model of enilsDsv development fTober et al. Eurovean Jatrna! Of Pharmacology-1996.. 303, 163-169). It is thus suggested that these properties of retigabine and other KCNQ moduiaiors-may prevent neuronal damage induced by excessive neuronal activation, and such compounds may be of use in the treatment of neurodegenerative diseases, and be disease modifying (or antiepileptogenic) in patients with epilepsy. Given that anticonvulsant compounds such as benzodiazepines and chlormethiazole are used clincially in the treatment of the ethanol withdrawal syndrome and that other anticonvulsant compounds e.g. gabapentin, are very effective in animal models of this syndrome (Watson et al. Neuropharmacology? 1997, 36. 1369-1375). other anticonvulsant compounds such as KCNQ openers are thus expected to be effective in this condition. mRNA for KCNQ 2 and 3 submits are found in brain regions associated with anxiety and emotional behaviours such as bipolar disorder e.g. hippocampus and amygdala (Saganich et al. Journal ofNeuroscience 2001,21, 4609-4624), and retigabine is reportedly active in some animal models of anxiety-like behaviour (Hartz et al. Journal ofPsychopharmacology 2003,17 suppl 3, A28,B16), and other clinically used anticonvulsant compounds are used in the treatment of bipolar disorder. Thus, KCNQ openers may be useful for the treatment of anxiety disorders and bipolar disorder. WO 200196540 discloses the use of modulators of the M-current formed by expression of KCNQ2 and KCNQ3 genes for insomnia, while WO 2001092526 discloses that modulators of KCNQ5 can be utilized for the treatment of sleep disorders. WOO 1/022953 describes the use of retigabine for prophylaxis and treatment of neuropathic pain such as allodynia, hyperalgesic pain, phantom pain, neuropathic pain related to diabetic neuropathy and neuropathic pain related to migraine. WO02;049628 describes the \:se cf reiigabine for the treatment c-f ^~?oe~y disorders such as anxiety, generalized anxiety disorder, panic anxiety, obsessive compulsive disorder, social phobia, performance anxiety, post-traumatic stress disorder, acute srress rsacdon, adjustment disorders, hypochondriacal disorders- separation anxiety -disorder, agoraphobia and specific phobias, WO97/15300 describes the use of reugabine for the treatment of oeorodegtamraiive disorders such as Alzheimer's disease; Huntington's cnorea; sclerosis sucu as muiupie sclerosis and amyotrophic lateral sclerosis: Creutzfeld-Jakob disease; Parkinson's disease; encephalopathies induced by AIDS or infection by rubella viruses, herpes viruses, borrelia and unknown pathogens; trauma-induced neurodegenerations; neuronal hyperexcitation states such as in medicament withdrawal or intoxication; and neurodegenerative diseases of the peripheral nervous system such as polyneuropathies and polynsuritides. KCNQ channel openers have also been found to be effective in the treatment of stroke, therefore it can be expected that selective KCNQ openers are effective in the treatment of stroke (Schroder et al., Pfiugers Arch.. 2003; 446(5): 607-16; Cooper and Jan, Arch Neurol., 2003, 60(4):496-500; Jensen, CNS Drug Rev., 2002, 8(4):353-60). KCNQ channels have been shown to be expressed in dopaminergic and cholinergic circuits in the brain that are associated with the brain's reward system, particularly the ventral tegmental area (Cooper et al., JNeurosci, 2001,21, 9529-9540). Therefore, KCNQ channel openers are expected to be effective in hyperexcitability disorders that involve the brain!s reward system such as cocaine abuse, nicotine withdrawal and ethanol withdrawal. Potassium channels comprised of the KCNQ4 subunits are expressed in the inner ear (Kubisch et al., Cell., 1999 Feb 5;96(3):437-46) and opening of these channels is therefore expected to treat tinnitus. Hence, there is a great desire for novel compounds which are potent openers of the KCNQ family of potassium channels. Also desired are novel compounds with improved properties relative to known compounds, which are openers of the KCNQ family potassium channels, such as retigabine. Improvement of one or more of the following parameters is desired: half-life., clearance, selectivity, interactions with other medications, bioavailability, potency, formulability. chemical stability7, metabolic stability, membrane permeability, solubility and therapeutic index. The improvement of such parameters may lead to improvements such as: • an improved dosing regime by reducing the number of required doses a day. • ease of administration to patients on multiple medications, • reduced side effects, • enlarged therapeutic index, • improved tolerability or • improved compliance. SUMMARY OF THE INVENTION One object of the invention is the provision of compounds, which are potent openers of the KCNQ family potassium channels. The compounds of the invention are substituted pyridine derivatives of the below formula I as the free base or a salt thereof wherein R\R2,R3and q are as defined below. The invention provides a compound of formula I for use as a medicament The invention furthermore concerns the use or a compound ox formula x in a method of treatment of seizure disorders, anxiety disorders, neuropathic pain and migraine pain disorders or neurodegenerative disorders. DEFINITION OF SUBSTTTUENTS The term "heteroatom" refers to a nitrogen, oxygen or sulphur atom. "Halogen" means fluoro. chioro: bromo or iodc. "Halo" means halogen. "Cyano" designates which is attached to the remainder of the molecule via the carbon atom. The expression "Ci^-alk(en/yn)yl" means Ci-e-alkyl, C2-6-alkenyl or C2-6-alkynyl. The term "Ci^-alkyl" refers to a branched or unbranched alkyl group having from one to six carbon atoms, including but not limited to methyl, ethyl, prop-1-yl, prop-2-yl, 2-methyl- prop-1-yl. 2-methyl-prop-2-yl, 2,2-dimethyl-prop-l-yl, but-l-yl, but-2-yl, 3-methyl-but-l- yl, 3-methyI-but-2-yl, pent-1-yl, pent-2-yl, pent-3-yl, hex-l-yl, hex-2-yl and hex-3-yl. The term "C2-$-alkenyl" refers to a branched or unbranched alkenyl group having from two to six carbon atoms and one double bond, including but not limited to ethenyl, propenyl, and butenyl. The term "C2-6-alkynyF' refers to a branched or unbranched alkynyl group having from two to six carbon atoms and one triple bond, including but not-limited to ethynyl, propynyl and butynyl. The expression l:Cj.g-alk(en/yn)yr means Ci_$-alkyl. Ci-g-alkenyl or C2-s-alfcvnyl. The term "Ci-g-aikyr refers to a branched or unbranched alkyl group having from one to eight carbon atoms, including but not limited to methyl, ethyl, prop-1-yL prop-2-yl, 2-msthyI-prop-l-yl. 2-methyl-prop-2-yL 2^2-dimethyl-prop-l-yL buM-yL but-2-yl, 3-methyl-but-l-yL 3-methyl-but-2-yl9 pent-1-yl, pent-2-yl, pent-3-yL hex-l-yl. hex-2-yL hex-3-yl, 2-methyl-4s4-dimethyl-peat-l-yl andhept-1-yl The term "C2-8-alkenyl?: refers to a branched or unbranched alkenyl group having from two to eight carbon atoms and one double bond, including but not limited to ethenyi, prupenyi, and butenyl. The term "C2-g-alkynyl" refers to a branched or unbranched alkynyl group having from two to eight carbon atoms and one triple bond, including but not limited to efbynyl, propynyl and butynyl. The expression "C3.g-cycloalk(en)yl" means C3_s-cycloalkyl or C3-g-cycloalkenyl. Tiie term "Cs-s-cycloalkyr designates a monocyclic or bicyclic carbocycle having three to eight carbon atoms, including but not limited to cyclopropyl. cyclopentyl, cyclohexyl, bicycloheptyl such as 2-bicyclo[2.2.1]heptyl. The term "C3-g-cycloalkenyr designates a monocyclic or bicyclic carbocycle having three to eight carbon atoms and one double bond, including but not limited to cyclopentenyl and cyclohexenyl. The term wC3^-heterocycloalk(en)yl" means C^-heterocycloalkyl or C3-8-heterocycloaIkenyl. The term "C3-8"heterocycloalkyl" designates a monocyclic or bicyclic ring system wherein the ring is formed by 3 to 8 atoms selected from 2-7 carbon atoms and 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulphur atoms. Examples of C3_8-heterocycloalkyls are pyrrolidine, azepan, morpholine, piperidine, piperazine and tetrahydrofuran. The term "C3-8-heterocycloalkenyl" designates a monocyclic or bicyclic ring system with one double bond, wherein the ring is formed by 3 to 8 atoms selected from 2-7 carbon atoms and 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulphur atoms. Examples of C^-heterocycloalkenyls are dihydropyrrole, dihydrofuran and dihydiothiophene. "^"hen C^D£ZzzzcYzl-?£l£[?z;ryi comprises nitrogen then C3^-heterocycloalk(en)yl is attached to me rexnar-rdex of the molecule \ia a carbon atom or nitrogen atom of the heterocyclic ring. When C3-s-heteroc3*cioaik(en)yl does not comprise nitrogen then Cs-£-heterocycloalk(en)yl is attached to the remainder of the molecule -via a carbon atom of the heterocyclic ring. The term c"*halo-Ci^-aIk(eri*7n)yr designates Ci^-alk(en/yn)yl being substituted with halogen, including but not limited to tnlluoromethyi. Similarly, "halo-C>g-cycloalk(en)yr designates C3.g-cycloalk(en)yl being substituted with halogen, including but not limited to chlorocyclopropane and chlorocyclohexane. Similarly, *5halo-C3-8-cycloalk(en)yl-Cl-6-alk(eIl/yn)y^, designates halo-C3_g-cycloalk(en)yl being attached to the remainder of the molecule via Ci-6-alk(en/yn)yl. The term "Ci^-alkf'en/ynjyloxy5' designates Ci^alk(en/yn)yl being attached to the remainder of the molecule via an oxygen atom. Similarly, "Cs-r^cloalkfen/yioxy" designates C5^-cycioalk(en)yl being attached to the remainder of the molecule via an oxygen atom. In the expressions "C3_8-cycloalk(en)yl-Ci_6-alk(en/yn)yr'? "Aryl~Ci-6~alk(en/yn)yP\ "Aryl- C3.8-cycloalk(en)yl'V6A^ "C3-8-heterocycloalk(en)yl-Ci^-a^ Ci.6-alk(en/yn)yl", eeHeteroaryl-Ci-6-alk(en/yn)yrV "Heteroaryl-C3-8-cycloalk(en)yr'3 Ci-6-alk(en/yn)yloxy", "C]-6-alk(en/yn)yloxy-Ci-6-alk(en/yn)yl"? "C3-g-cycloalk(en)yloxy- Ci^-alk(en/yn)yr and "C3.r-cycloalk(en)yl-Cl.6■•alk(en/yn)yloxy«CI-6-alk(en/yn)y^, the terms "Ci-6-alk(en/yn)yr, "C«-cydoalk(en)yr\ "Aryl", "C3.8-heterocycloalk(en)yr, "Heteroaryl", "Ci_6-alk(en/yn)yloxy5' and "C3.8-cycloalk(en)yloxy" are as defined above. The term "Heteroaryl" refers to monocyclic or bicyclic heteroaromatic systems being selected from the group consisting of pyridine, thiophene, furan. pyrrole, pyrazoie, triazole, tetrazole, oxaTnle, imidazole, fbiazole. benzofuran, benzothiophene and indole. .L^e lem^ .^s}~: SS^TH^S rnoztccycue or bi cyclic aromatic systems being selected from the The tenn "optionally sub&uLuied Ary]-Ci^-2lk(en7n)yIr designates Aryl-Ci.g-a]k(a3/yn)yl wherein the Aryi moiety is optionally substituted, such as with 1, 2 or 3 substituents independently selected from the group consisting of halogen, cyano. Ci-6-aIk(en/yn)yl, C3-g-cycioalk(en)yi. C^^ycioaIk(sai)y]-Ci^-aIk(Ki/yn)yl. ha]o-Ci-6-alk(en/yn)yl? halo-C3.v-cycloalk(en)y!s nalc-CJ^--cycIoaix(^ii)yI-C1.6-aIk(cJi^'}Ti)yi5 Ci.6-alk(en/yn)yioxy, C3-rcycloalk(en)yloxy and C3-g-cycloalk(en)yl-Ci^-aIk(en/yn)yloxy. Similarly, "optionally substituted Aryl-C3.g-cycloalk(en)yFs designates Aryl-C3_8-cycloalk(en)yI wherein the Aryl moiety is optionally substituted, such as with 1,2 or 3 substituents independently selected from the group consisting of halogen, cyano, Ci_6-alk(en/yn)yL C3_p-cycloalk(en)yL C3_?-cycloalk(en)yl-Ci_6-alk(en/yn)yl. halo-Ci_s-aIk(en/'yn^Lhalc^C3^- DESCRIPTION OF THE EWENTION The present invention relates to substituted pyridine derivatives which are openers of KCNQ potassium channels. The present invention relates to a compound represented by the general formula I: wherein qis Oor 1; each of R andR is independently selected from the group consisting of halogen, cyano, Ci^-alk(en/yn)yl3 C3-g-cycloalk(en)yl, C3-g-cycloalk(en)yl-C).6-alk(en/yn)yl, halo- Ci-6-alk(en/yn)yl, halo-C3-s-cycloalk(en)yl, halo-C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)ylJ Ci-6-alk(en/yn)yloxy, C3.8-cycloalk(en)yloxy and C3-g-cycloalk(en)yl-C]-6-alk(en/yn)yloxy; and RJ is selected from the group consisting of Ci-g-alk(en/'yn)yl. C3.g-cycloalk(en)yl5 C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl? optionally substituted Aryl-Ci^-alk(en/yn)ylJ optionally substituted Aryl-C3-8~cycloalk(en)yL optionally substituted Aryl- Cs^-cycloalkCe^yl-Ci^-alkCen/ynJyl, Ci-6-alk(en/yn)yl-C3.8-heterocycloalk(en)yl- Ci^-alk(en/yn)yl, C3-8-heterocycloalk(en)yl-Ci-6-alk(en/yn)yl. Ci-6-alk(en/yn)yI- C3-8-heterocycloalk(en)yl-Ci-6-alk(en/yn)yl? Heteroaryl-Ci^-alk(en/yn)yl, Heteroaryl- C3.s-cycloalk(en)y 1, Heteroaryl-C3-g-cycloalk(en)yl-C i^-alk(en/yn)yl, NRV-Ci-6-alk(en/yn)yl, NR4R5-C3-8-cycloalk(en)yl, NR^-Cs-g-cycloalk^yl- Ci-6-alk(en/yn)yl3 Ci.6-alk(en/yn)yloxy-Ci.6-alk(en/yn)yl, C3-8-cycloalk(en)yloxy- Ci-6-alk(en/yn)yl? C3-rcycloalk(en)yl-Ci-6-alk(en/yn)yloxy-Ci-6-alk(en/yn)yl9 halo- Ci-6-alk(en/yn)yl5 halo-C3-8-cycloalk(en)yl and halo-C3_8-cycloalk(en)yl-Ci-6-alk(en/yn)yl; wherein each of R and R5 is independently selected from the group consisting of hydrogen, Ci-6-alk(en/yn)yl, C3-g-cycloalk(en)yl and C3^~cycloalk(en)yl-Ci^-alk(en/yn)yl; as the free base or salts thereof. In one embodiment of the compound of formula I, q is 0; in another embodiment of the compound of formula I, q is 1. In a further embodiment of ihe compound of formula I each of R" and R" is independently selected from the group consisting of halogen, cyano, halo-Ci_6-alk(ea/3rn)yl. halo-CX$-cycloalk(en)yL halo-C3-s-cycloalk(en)yl-Ci-6-allc(en/yn)yl> Ci-6-alk(en/yn)yloxy. Cs^r-cycloalk(en)ylox}' and C3^-cycloaIk(en)yl-Ci.6-alk(en//}m)yloxy; in another embodiment each of R1 and R2 is independently selected from the group consisting of halogen, cyano, Ci_6-alk(en/yn)yL C3.g-cycloalk(en)yl, C3_s-cycloaIk(en)y]~ Ci_6-alk(en/yn)yl? Ci_6-alk(en/yn)yloxy: C3-g-cycloalk(en)yloxy and C3-8-cycloaIk(en)yl-C u-alk(en/yn)yloxy; 1 0 in another embodiment each of R and R is independently selected from the group consisting of halogen, cyano and Ci-6-alk(en/yn)yl and Ci_e-alk(en/yn)yloxy; in another embodiment each of R1 and R2 is independently selected from the group consisting of Ci.6-alk(en/yn)yL C3-g-cycloalk(en)yl and C3-rcycloalk(en)yl- Ci-6-alk(en/yn)yl: in another embodiment R1 is Ci-6-alk(en/'yn)yl:) such as methyl; in another embodiment R" is Ci-6-alk(en/yn)yl, such as methyl; t -r-t in another embodiment R1 is Ci^-aIk(en/yn)yloxy? such as methoxy and R* is halogen; in another embodiment R is halogen and R is Ci^-alk(en/yn)yloxy; such as methoxy. Typically, both R andR are Ci-6-alk(en/yn)yl, such as methyl. In a further embodiment of the compound of formula I, R3 is selected from the group consisting of Ci^-alk(en/yn)yl-C3^-hetoocycloalk(en)yl-Ci-6-alk(eii/yn)yl5 C3-8-heterocycloalk(en)yl-Ci^-alk(e^ Ci.6-alk(en/yn)yl, NR4R5-Ci^-alk(en/yn)yl, NR^5«-C3-8-cycloalk(en)yl, NRV-C3^-cycloalk(en)yl-Ci-6-^ C3^-cycloalk(en)yloxy-Ci^~alk(ei^yn)y^^ Ci^-alk(en/yn)yl, halo-Ci_6-alk(en/yn)yl, halo-C3_g-cycloalk(en)yl and halo- C3-g-cycloalk(en)yl-Ci-6-alk(en/yn)yl; in another embodiment R3 is selected from the group consisting of C1.g-alk(en/yn)yl, C3-8-cycloalk(en)yls C3-s-cycloalk(en)yl-Ci-6-alk(en/yn)yl, optionally substituted Aryl- Ci-6-alk(en/yn)yl, optionally substituted Aryl-C3-g-cycloalk(en)yl, optionally substituted Aryl-C3-8-cycloalk(en)yl-Ci_6-alk(en/yn)yl, Heteroaryl-Ci^-alk(en/yn)yl? Heteroaryl- C3.s-cycloalk(en)yL Heteroan^-C3.8-cycloalk(en)yl-Ci_6-aIk(en/yn)yl. NR^5- Cx-alk'en~;y- v?rE:^'3^ycloaI&'e£;y: 2ndNll4R5-C3-s-cycloalk(en)yl-Ci-6- alk(erL'}7:;3i: in another embodiment R" is selected from the group consisting of C]-g-a]lc(en/yn)yl, Cs^K:ycioaIk(en)yi«C:-6-aik(en',}rii)yL optionally substituted Aiyl-Ci^-alk(en;yn)yL optionally substituted Aiyl-C3-&-cycloalk(en)yL Heteroary]-Ci^-alk(sn/'yn)yl and NRHR - Ci-6-alk(en/yn)yi: in another embodiment R* is selected from the group consisting of Ci.g-alk(en/yn)yl. C3.8-cycloalk(en)yL) C3.rcycloaIk(en)yI-Ci^-alk(en/yn)yis optionally substituted Aryi- Ci-6-alk(en/yn)yl, optionally substituted Aryl-C3-s-cycloalk(en)yL optionally substituted Aryl-C3.rcycloalk(en)yl-Ci-6-alk(Qa/yn)yl5 Heteroaryl-Ci^~alk(en/yn)yl? Heteroaryl- C3-s-cycloalk(en)yl and Heteroaryl-C3.8-cycloalk(en)yl-Ci-6-alk(en/yn)yl. Typically, R is selected from the group consisting of Ci-8-alk(en/yn)yl, C3_8-cycloalk(en)yl- Ci-6-alk(en-yn^yi, optionally substituted AryI-Ci-6-aIk(en/yn)yl3 optionally substituted Aryl- C-i-R-cvcioalki 'enwl and Hetsroarvl-Cu^-alkCen/'vn)vL To further illustrate without limiting the invention, an embodiment of RJ is Ci-ralk(ec/yn)yi; another embodiment of RJ is C3_g-cycioalk(en)yl-Ci_6-alk(en/yn)yl; another embodiment of R3 is optionally substituted Aryl-Ci-6-alk(en/yn)yl; another embodiment of R3 is optionally substituted Aryl-C3-8-cycloalk(en)yl; another embodiment of R is Heteroaryl-Ci-6-alk(en/yn)yi. In a further embodiment of the compound of formula I, each of R4 and R5 is independently selected from the group consisting of C3-8-cycloalk(en)yl and C3-g-cycloalk(en)yl- Ci_6-alk(en/yn)yl; in another embodiment each of R4 and R^ is independently selected from the group consisting of Ci^-alk(en/yn)yl and hydrogen; in another embodiment both R4 and R5 are Ci_6-alk(en/yn)yl; in another embodiment both R4 and RD are hydrogen. In a further embodiment of the compound of formula I, any Heteroaryl, which is mentioned either alone or as a parr ox a larger substituent is selected form the group consisting of pyridine. forES. pyrrole, pyrazole. triazole. tetrazole. oxazole, imidazole, thiazole. beiizofjrar- be^zotzic~±iene and iadc-Ie; in another embodiment any HeteroaryL which is mentioned either zso^z- or as a part of a larger substnuent is thiophene. In a farther embodiment of the compound of formula I. an}- Aryl which is mentioned either alone or as a part of a larger substituent is phenyl; in another embodiment any Aryl. which is mentioned either alone or as a part of a larger substituent is napMbyi. in a further embodiment of the compound of formula I, any optionally substituted Aryl, which is mentioned either alone or as a part of a larger substituent, may be substituted with 1 or 2 substituents. To further illustrate without limiting the invention an embodiment concerns such compounds of formula I. wherein any optionally substituted Aryl which is mentioned either alone or as a pan of a larger substituent is not substituted; in another embodiment any optionally substituted Aryl which is mentioned either alone or as a pan of a larger substituent is substituted with 1 substituent; in another embodiment any optionally substituted Aryl which is mentioned either alone or as a part of a larger substituent is substituted with 2 substituents. In a further embodiment of the compound of formula I, any optionally substituted Aryl, which is mentioned either alone or as a part of a larger substituent, may be substituted with substituents selected from the group consisting of cyano, C3.8-cycloalk(en)yl, C3-8-cycloalk(en)yl-Ci^~alk(en/^ Ci_6-alk(en/yn)yl, C3_s-cycloalk(en)yloxy and C3.s-cycloalk(en)yl-Ci^-alk(en/yn)yloxy; in another embodiment any optionally substituted Aryl which is mentioned either alone or as a part of a larger substituent may be substituted with substituents selected from the group consisting of halogen, Ci_6-alk(en/yn)yl, halo-Ci_6-alk(en/yn)yl and Ci-6-alk(en/yn)yloxy. To further illustrate without limiting the invention an embodiment concerns such compounds of formula I, wherein any optionally substituted Aryl which is mentioned either ' alone or as a part of a larger substituent is substituted with halogen; in another embodiment any optionally substituted Aryl which is mentioned either alone or as a part of a larger suLshiumt is substituted with Ci_6-alk(en/yn)yl; in another embodiment any optionally substituted Aryl which, is mentioned either alone or as a part of a larger substituent is substituted with ha]o-Ci-6-alk(en'yn)yi; in another embodiment any optionally substituted Aryl which is mentioned either alone or as a part of a larger substituent is substituted with Ci^-alk(en/}rn)yloxy. The present invention also comprises salts of the compounds of the invention, typically > phaimaceuticaUy acceptable salts. The salts of the invention include acid addition salts, metal salts, ammonium and alkylated ammonium salts. The salts of the invention are preferably acid addition salts. The acid addition salts of the invention axe preferably pharmaceutically acceptable salts of the compounds of the invgmian formed with non-toxic acids. Acid addition salts include salts of inorganic acids as wdl as organic acids. Examples of suitable inorganic acids include hydrochloric, ir^irobromic. hy-iroiz*zic: phosphoric, sulfuric, sulfamic, nitric acids and the like. Examples of sintabk orgsruc acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, glycolic. itaconic. lactic, methanesulfonic. maleic. malic, rnalomc. manoelic. oxalic, picric, pyruvic, salicylic, succinic, methane sulfonic, ethanesuifonie, tarraric. ascorbic, pamoic. bismethylene salicylic, ethanedisulfonic, gluconic, cirxaconic, aspartic. stearic, palmitic, EDTA. glycolic. p-aminobenzoic, glutamic, benzenesulianic. p-toluenesulfonic acids, theophylline acetic acids, as well as the o-hiuotii^ophjlimc^. io; example a-DxouiOLiicuphyxlinc cinci chc like, rurthcr examples ui phamiaceutical acceptable inorganic or organic acid addition salts include the pharmaceutical^ acceptable salts listed in J. Pharm. Sci, 1977,66,2, which is incorporated herein by reference. Also intended as acid addition salts are the hydrates, which the present compounds, are able to form. Examples of metal salts include lithium, sodium, potassium, magnesium salts and the like. Examples of ammonium and alkylated ammonium salts include ammonium, methyl-, dimethyl-, trimethyl-, ethyl-, hydroxyethyl-, diethyl-, n-butyl-, sec-butyl-, ferr-butyl-, tetramethylammonium salts and the like. Further, the compounds of this invention may exist in unsolvated as well as in solvated forms with pharmaceutical^ acceptable solvents such as water, ethanol and the like. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of this invention. The compounds of the present invention may have one or more asymmetric centre and it is intended that any optical isomers (i.e. enantiomers or diastereomers), as separated, pure or partially purified optical isomers and any mixtures thereof including racemic mixtures, i.e. a mixture of stereoisomers, are included within the scope of the invention. Racsmk ibmis can be resolved into the optical antipodes by known methods, for example, by sepsHiion of diastereomeric salts with an optically active acid, and liberating the optically active amine compounc by Treatment with a base. Another mated rbr resolving racemates into the optical antipodes is based upon chromatography on an opncally active matrix. Racernic compounds of the present invention can also be resolved inro their optical antipodes, e.g. by fractional crystallization. The compounds of the present invention may also be resolved by the formation of diastsreomeric derivatives. Additional methods for the resolution of optical isomers: known to those skilled in the art. may be used. Such methods include those discussed by J, Jaques. A. Collet and S. Wilen in "Enaimomers. Racemaxes. and Resolutions", Join: T>"iley and Sons, New York (1931;. Optically active compounds can also be prepared from optically active starting materials, or by stereoselective synthesis. Furthermore, when a double bond or a fully or partially saturated ring system is present in the molecule, geometric isomers may be formed. It is intended that any geometric isomers, as separated, pure or partially purified geometric isomers or mixtures thereof are included within the scope of the invention. Likewise, molecules having a bond with restricted rotation may form geometric isomers. These are also intended to be included within the scope of the present invention. Furthermore, some of the compounds of the present invention may exist in different tautomeric forms and it is intended that any tautomeric forms that the compounds are able to form are included within the scope of the present invention. The invention also encompasses prodrugs of the present compounds, which on administration undergo chemical conversion by metabolic processes before becoming pharmacologically active substances. In general, such prodrugs will be functional derivatives of the compounds of the general formula I, which are readily convertible in vivo into the required compound of the formula I. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed, H. Bundgaard, Elsevier, 1985. The invention also encompasses active metabolites of the present compounds. The compounds according to the invention have affinity for the KCNQ2 receptor subtype with an EC50 of less than 15000nM such as less than lOOOOnM as measured by the test "Reiarlve efflux through the KCNQ2 channel" which is described below. One embodiment concerns- such compounds of formula I having affinity for the KCNQ2 receptor subtype \vit3a an ECs: of less than 2000nM such as less than 1500nM as measured by the test "Relative efflux through the KCNQ2 channel" which is described below. To further illustrate without limiting the invention an embodiment concerns such compounds having affinity for the KCNQ2 receptor subtype with an EC50 of less than 200nM such as less than 150nM as measured by the test "Relative efflux through the KCNQ2 channel" which is ■ w^i J i- v-v. „ -^1 V/ A . One embodiment concerns such compounds of formula I having an ED50 of less than 15 mg/kg in the test "Maximum electroshock" which is described below. To further illustrate without limiting the invention, an embodiment concerns such compounds having an ED50 of less than 5 mg/kg in the test "Maximum electroshock" which is described below. One embodiment concerns such compounds of formula I having an ED50 of less than 5 mg/kg in the "Electrical seizure -threshold test': and "Chemical seizure -threshold test" which is described below. One embodiment concerns such compounds of formula I having few or clinically insignificant side effects. Some of the compounds according to the invention are thus tested in models of the unwanted sedative, hypothermic and ataxic actions. One embodiment concerns such compounds of formula I having a large therapeutic index between anticonvulsant efficacy and side-effects such as impairment of locomotor activity or ataxic effects as measured by performance on a rotating rod. Such compounds will expectedly be well tolerated in patients permitting high doses to be used before side effects are seen. Thereby compliance with the therapy will expectedly be good and administration of high doses may be permitted making the treatment more efficacious in patients who would otherwise have side effects with other medications. As already mentioned, the compounds according to the invention have effect on potassium channels of the KCNQ family, in particular the KCNQ2 subunit, and they are thus considered useful for increasing ion flow in a voltage-dependent potassium channel in a mammal such zs a human. The ccxnrroux^s of the inventor: are eor>s:dered applicable in the treatment of a disorder or dis&^se bemg rssporzsive to an increased ion flow in a potassium channel such as the KCNQ family potassium ion channels. Such disorder ox disease is preferably a disorder or disease of the cemral nervous system. In one aspect the compounds of the invention may be administered as the only therapeutical!}7 effective compound. In another usptci the compounds of the invention may oc aamiriisterea as d pari ox a combination therapy, i.e, the compounds of the invention may be administered in combination with other therapeutically effective compounds having e.g. anti-convulsive properties. The effects of such other compounds having anti-convulsive properties may include but not be limited to activities on: • ion channels such as sodium, potassium, or calcium channels » the excitatorv amino acid svstems e.£. blockade or modulation of NMD A recentors • the inhibitor^' neurotransmitter systems e.g. enhancement of GABA release, or blockade of GABA-uptaks or • membrane stabilisation effects. Current anti-convulsive medications include, but are not limited to, tiagabine, carbamazepine, sodium valproate, lamotrigine, gabapentin, pregabalin, ethosuximide, levetiracetam, phenytoin, topiramate, zonisamide as well as members of the benzodiazepine and barbiturate class. An aspect of the invention provides a compound of formula I free base or a salt thereof for use as a medicament. In one embodiment, the invention relates to the use of a compound of formula I free base or a salt thereof in a method of treatment An embodiment of the invention provides a pharmaceutical composition comprising a compound of formula I free base or a salt thereof and a pharmaceutically acceptable carrier or diluent. The composition may compiise any of the embodiments of formula I as described above. A further embodiment of the invention relates to the use of a compound of formula I free base or a salt thereof for the preparation of a pharmaceutical composition for the treatment of a disease or disorder wherein a KCNQ potassium channel opener such as a KCNQ2 potassium channel opener is beneficial. Typically, such disorder or disease is selected from the group consisting of seizure disorders, anxiety disorders, neuropathic pain and migraine pain disorders, neurodegenerative disorders, stroke, cocaine abuse, nicotine withdrawal. ethanol withdrawal and tinnitus. A further embodiment of the invention relates to the use of a compound of formula I free base or a salt thereof for the preparation of a pharmaceutical composition for the treatment of seizure disorders. Typically, the seizure disorders to be treated are selected from the group consisting of acute seizures, convulsions, status epilepticus and epilepsy such as epileptic syndromes and epileptic seizures. A further embodiment of the invention relates to the use of a compound of formula I free base or a salt thereof for the preparation of a pharmaceutical composition for the treatment of anxiety disorders. Typically, the anxiety disorders to be treated are selected from the group consisting of anxiety and disorders and diseases related to panic attack, agoraphobia, panic disorder with agoraphobia, panic disorder without agoraphobia, agoraphobia without history of panic disorder, specific phobia, social phobia and other specific phobias, obsessive-compulsive disorder, posttraumatic stress disorder, acute stress disorders, generalized anxiety disorder, anxiety disorder due to general medical condition, substance-induced anxiety disorder, separation anxiety disorder, adjustment disorders, performance anxiety, hypochondriacal disorders, anxiety disorder due to general medical condition and substance-induced anxiety disorder and anxiety disorder not otherwise specified. A further embodiment of the invention relates to the use of a compound of formula I free base or a salt thereof for the preparation of a pharmaceutical composition for the treatment of neuropathic pain and migraine pain disorders. Typically, the neuropathic pain and migraine pain disorders to be treated are selected from the group consisting of allodynia. hyperalgesic pain, phantom pain, neuropathic pain related to diabeiic neuropathy. neuropathic pain relaxed tc trigeminal neuralgia and neuropathic pain related to migraine. A furcher embodiment of the invention relates to the use of a compound of formula I free base or a sail thereof for the preparation of a pharmaceutical composition for the treatment of neurodegenerative disorders. Typically the neurodegenerative disorders to be treated are selected from the group consisting of Alzheimer's disease, Iluntington" J chorea, multiple sclerosis, amyotrophic lateral sclerosis, Creutzfeld-Jakob disease, Parkinson's disease, encephalopathies induced by ADDS or infection by rubella viruses, herpes viruses, borrelia and unknown pathogens, trauma-induced neurodegenerations, neuronal hyperexcitation states such as in medicament withdrawal or intoxication and neurodegenerative diseases of the peripheral nervous system such as polyneuropathies and polyneuritides. A further embodiment of the invention relates to the use of a compound of formula I free bass or a salt thereof for the preparation of a pharmaceutical composition for the treatment of bipolar disorders. A further embodiment of the invention relates to the use of a compound of formula I free base or a salt thereof for the preparation of a pharmaceutical composition for the treatment of sleep disorders; such as insomnia. The term "treatment" as used herein in connection with a disease or disorders includes also prevention, inhibition and amelioration as the case may be. The invention provides compounds showing effect in at least one of the following tests: • "Relative efflux through the KCNQ2 channel" Which is a measure of the potency of the compound at the target channel • "Maximum electroshock" Which is a measure of seizures induced by non-specific CNS stimulation by electrical means • "Pilocarpine induced seizures" Seizures bducec by p^ec^^-- are often dlincuh to trs2i vviTh many existing antiseizure medicanccs ar*d so reSecT*. a model of "drag resistant seizures" • "TSectrical seizure-thrssbcoid tests" nnd "Chemical seizure-threshold tests*' These models measure die threshold at which seizures are initiated, thus being models that detect whether compounds could delay seizure initiation. » "Amygdala kindling7' Which is used as a measure of disease progression, as in normal animals the seizures in this model get more severe as the ammai receives iurtfter summations. • "Electrophysiological patch-clamp recordings in CHO cells" and "electrophysiological recordings of KCNQ2, KCNQ2/KCNQ3 or KCNQ5 channels in oocytes" In these tests voltage-activated KCNQ2, KCNQ2/KCNQ3 or KCNQ5 currents are recorded. PHARMACEUTICAL COMPOSITIONS The present invention also relaies to a pharmaceutical composition. The compounds of the invention as the free base or salts thereof may be administered alone or in combination with pharmaceutical^ acceptable carriers or diluents, in either single or multiple doses. The pharmaceutical compositions according to the invention may be formulated with pharmaceutical^ acceptable carriers or diluents as well as any other known adjuvants and excipients in accordance with conventional techniques such as those disclosed in Remington: The Science and Practice of Pharmacy, 19 Edition, Gennaro, Ed., Mack Publishing Co., Easton, PA, 1995. The pharmaceutical compositions may be specifically formulated for administration by any suitable route such as the oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), transdermal, intracisternal, intraperitoneal, vaginal and parenteral (including subcutaneous, intramuscular, intrathecal, intravenous and intradermal) route, the oral route being preferred. It will be appreciated that the preferred route will depend on the general condition and age of the subject to be treated, the nature of the disorder or disease to be treated and the active ineredient chasm. The ^haxni&ceiiTicai compoihiris f>-nec by conzbiring the compound of the invention and the Dharmaceutical acceptable -rsrie-s ^re then readily admiziistereG in a variety of dosage forms suitable for the disclosed rotnes of administratiorL The formulations may conveniently be presented in unit -dosage form by methods known in the art of pharmacy. The compounds of this invention are gsneraUy utilized as the free base or as a pharmaceutical!)7 acceptable sail thereof One example is an acid addition salt of a compound having the utility cf u free base. T^ien a ^uiapouad os. die invention contains a free base such salts are prepared in a conventional manner by treating a solution or suspension of a free base of the invention with a chemical equivalent of a pharmaceutical^ acceptable acid. Representative examples are mentioned above. Pharmaceutical compositions for oral administration may be solid or liquid. Solid dosage forms for oral administration include e.g. capsules, tablets, dragees, pills, lozenges, powders, granules and tableite e.g. placed in a hard gelatine capsule in powder or pellet form or e.g. in the form of a troche or lozenge. Where appropriate, pharmaceutical compositions for oral administration may be prepared with coatings such as enteric coatings or they can be formulated so as to provide controlled release of the active ingredient such as sustained or prolonged release according to methods well known in the art. Liquid dosage forms for oral administration include e.g. solutions, emulsions, suspensions, syrups and elixirs. Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules or tablets, each containing a predetermined amount of the active ingredient, and which may include a suitable excipient. Furthermore, the orally available formulations may be in the form of a powder or granules, a solution or suspension in an aqueous or non-aqueous liquid, or an oil-in-water or water-in-oil liquid emulsion. Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solution and various organic solvents. Examples of solid carriers are lactose, terra alba, sucross; cyciodextrin, talc, gelatine, agar, pectin, acacia, magnesium stearate, stearic acid, lower alkyl ethers of cellulose, com ssrdL potam starch, gums and the like. Examples of liquid carriers are syrup, peanut oil. olive oil. phospho lipids, tatty acids, tatty7 acid amines. polyoxyethylene and water. The carrier or diluent ma}' include an}" sustained release material known in the art. such as glyceryl monostearate or glyceryl distearate. alone or mixed with a wax. Any adjuvants or additives usually used for such purposes such as colourings, flavourings. preservatives etc. may be used provided that cney are compatible witn me active ingredients. The amount of solid carrier may vary but will usually be from about 25 mg to about 1 g. If a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatine capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution. Tablets may be prepared by mixing the active ingredient with ordinary adjuvants or diluents and subsequently compressing the mixture in a conventional tabletxing machine. Pharmaceutical compositions for parenteral administration include sterile aqueous and nonaqueous injectable solutions, dispersions, suspensions or emulsions as well as sterile powders to be reconstituted in sterile injectable solutions or dispersions prior to use. Depot injectable formulations are also contemplated as being within the scope of the present invention. For parenteral administration, solutions of the compound of the invention in sterile aqueous solution, aqueous propylene glycol, aqueous vitamin E or sesame or peanut oil may be employed. Such aqueous solutions should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose. The aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. The sterile aqueous media employed are all readily available by standard techniques known to those skilled in the art Solutions for injections may be prepared by dissolving the active ingredient and possible additives in a part of the solvent for injection, preferably sterile water, adjusting the solution Other suitable administration forms include suppositories, sprays, ointments, crsmes, gels. inhalants, dermal patches, implants, etc. A typical orai dosage is ui the range of from about O.uOi to aoout 10Q rug/Kg oody weight per day, preferably from about 0.01 to about 50 mg/kg body weight per day, and more preferred from about 0.05 to about 10 mg/kg body weight per day administered in one or more dosages such as 1 to 3 dosages. The exact dosage will depend upon the frequency and mode of administration, the sex, age, weight and general condition of the subject treated, the nature and severity of the disorder or disease treated and any concomitant diseases to be treated and other factors evident to those skilled in the art. The formulations may conveniently be presented in unit dosage form by methods known to those skilled in the art. A typical unit dosage form for oral administration one or more times per day such as 1 to 3 times per day may contain from 0.01 to about 1000 mg, such as about 0.01 to 100 mg, preferably from about 0.05 to about 500 mg, and more preferred from about 0.5 mg to about 200 mg. For parenteral routes such as intravenous, intrathecal, intramuscular and similar administration, typically doses are in the order of about half the dose employed for oral administration. Typical examples of recipes for the formulation of the invention are as follows; 1) Tablets containing 5.0 mg of a compound of the invention calculated as the free base: Compound of the invention 5.0 mg Lactose 60 mg Maize starch 30 mg Hydroxypropylcellulose 2.4 mg Cr-tcanneilose Sodium TVDC A 2.4 mg Magnesium stearate 0.84 mg 2) Tablets containing 0.5 mg of a compound of the invention calculated as the free base: Compound of the invesohon 0.5 mg Maize starch 23.5 mg Povidone 1.8 mg Microcrystalline cellulose 14.4 mg Croscarmellose Sodium Type A 1.8 mg Magnesium stearate 0.63 mg 3} Syrup coniaining per millilitre: Compound of the invention 25 mg Sorbitol 500 mg Hydroxypropylceliulose 15 mg Glycerol 50 mg Methyl-paraben 1 mg Propyl-paraben 0.1 mg Ethanol 0.005 mL Flavour 0.05 mg Saccharin sodium 0.5 mg Water ad 1 mL 4) Solution for injection containing per millilitre: Compound of the invention 0.5 mg Sorbitol 5.1 mg Acetic Acid 0.05 mg Saccharin sodium 0.5 mg Wales- ad ImL In a further aspect the present invention relates to a method of preparing a compound of the invention as described in the following. Preparation of the compounds of the invention The present invention relates to a compound represented by the general formula I: wherein qisOor 1; each of R1 and R2 is independently selected from the group consisting of halogen, cyano, Ci^-alk(en/yn)yl, C3.g-cycloalk(en)yl, C3-g-cycloalk(en)yl-Ci-6-alk(en/yn)yl? halo- Ci^-alk(en/yn)yl? halo-C3_rcycloa&^ Ci^-alk(en/yn)yloxy3 C3_g-cycloalk(en)yloxy and C3_g-cycloalk(en)yl-Ci_6-alk(en/yn)yloxy; and R3 is selected from the group consisting of Ci-8-alk(en/yn)yl, C3_g-cycloalk(en)yl, C3-8-cycloalk(en)yl-Ci^-alk(en/yn)yl, optionally substituted Aryl-Ci^-alk(en/yn)yl, optionally substituted Aryl-C3-8-cycloalk(en)yL optionally substituted Aryl-C3.g-cycloalk(en)yl-Ci^-alk(en/'yn)yL Ci^*alk(en/yn)yl-C3_s-heterocycloaIk(en)yl-Ci-6-alk(ra/yn)yl, Cs-g-heterocycloalkCe^yl-Ci-g-aliCen/i^yl, Ci-6-aIk(en/yn)yl-C3-8-heterocycloalk(en)yl-Ci-6-alk(en/yn)yl, Heteroaryl-Ci-6-alk(en/>fn)yl. Heteroar>7l- C3-s-cydoaik(en)yL Keteroary^ Ci.6-alk(ea-ya)yl5 NTl4R5-Cx-s-cycloailc(en)yL ^Tl4R"-C3_rcycloall:(en)yl-Ci_6-aik(eiiSTi)yL Ci^-alk(en/>TOylo:Ky-C^-alk(e^^^ C^rC3rcIoaik(en)yi-Cu^ C3„8-cycloalk(en)yl and halo-C3_^cycloaik(en)yl-Ci_6-aIk(eii'yii)yl; wherein each of R4 and R5 is independently selected from the group consisting of hydrogen. Ci_6-alk(en/yn)yl; C3_g-cycloalk(en)yl and C3.g'CycloaIk(en)yl-Ci^-alk(en/yn)yl: as the free base or salts thereof. ion The compounds of the invention of the general formula I. wherein R , R , R and q are as defined above may be prepared by the methods as represented in the schemes and as described below. In the compounds of the general formulae I - XV, R , R\ Rr and q are as defined under formula I. Compounds of the general formulae 11, VII, VIII, DC, X. XI and XII are either obtained from commercial sources, or prepared by standard methods known to chemists skilled in the art. Compounds of the general formula III (scheme 1) may be prepared by reacting compounds of the general formula II with bis~(2-haloethyl)ethers, with or "without the addition of bases, such as trialkyl amines, potassium carbonate or lithium-, sodium-, or potassium alcoholates, with or without the addition of catalysts such as sodium iodide, in a suitable solvent such as dimethyl sulfoxide. Ar,Ar-dimethylformamide or ethanol. at a suitable temperature, such as room temperature or reflux temperature. Cor—yT-vjc of lie general formula IV (scheme I) may be prepared from compounds of the seneral formula IH bv nitration reactions known to chemists skilled in the art. such as reaction with concentrated nitric acid, sodium nitrite or sodium nitrate, in a suitable solvent, such as glacial acetic acid, acetic anhydride, trifiuoroacetic acid, concentrated sulfuric acid or mixtures thereof, at appropriate temperatures, for example as described by P.B.D. de la Mare and J.H. Ridd. "Preparative methods of nitration" in Aromatic substitutions, pp. 48-56, Butterworths Scientific Publications; London, 1959. Compounds of the general formula V (scheme 2) may be prepared from compounds of the general formula II by nitration reactions known to chemists skilled in the art as described under scheme 1 for the ureuaration of compounds of the general formula IV. Compounds of the general formula IV (scheme 2) may be prepared by reacting compounds of the general formula V with suitably substituted bis-(2-haloethyl)ethers as described under scheme 1 for the preparation of compounds of the general formula HI. Compounds of the general formula VI (scheme 3) may be prepared from compounds of the general formula IV, by reducing the nitro group to an amino group, with suitable reducing agents such as zinc or iron powder in the presence of acid such as acetic acid or aqueous hydrochloric acid, or by hydrogen gas or ammonium foimiate in the presence of a suitable hydrogenation catalyst such as palladium on activated carbon in suitable solvents such as methanol, ethanol, ethyl acetate or tetrahydrofuran, at suitable temperatures or under J ultrasonic irradiation. Alternatively, tin (II) chloride or sodium dithionite can be used as reducing agents under conditions well known to chemists skilled in the art. Compounds of the general formula I (scheme 3) may be prepared by reacting conLpounds of the general formula VI with suitable electrophilic reagents, such as, but not lizdtsd to, suitably substituted carboxylic acid fluorides. carboxylic acid chlorides. csrbsxyiic acid bromides, carboxylic acid iodides, carboxylic acid anhydrides, activated esters, chloro formates, and with or without the addition of bases, such as pyridine, trialkyl amines. potassium carbonate, magnesium oxide or lithium-, sodium-*,"or potassium alcofaolates. in a suitable solvent, such as ethyl acetate, aioxane, tetrahydroturan, acetonitme or enemy i etner, at suitable temperatures, such as room temperature or reflux temperature. Activated esters and carboxylic acid anhydrides can be prepared from suitably substituted carboxylic acids under conditions known to chemists skilled in the art. for example as described by F. Albericio and LA. Carpino, "Coupling reagents and activation" in Methods in enzymology: Solid-pltase peptide synthesis, pp. 104-126. Academic Press. New York. 1997. Carboxylic acid haiides can be prepared from-suitably substituted carboxylic acids by activation with reagents such as, but not limited to. thionyl chloride, oxalyl chloride, phosphorus tribromide or phosphorus triiodide under conditions well known to chemists skilled in the an. Compounds of the general formula II (scheme 4) may be prepared by reacting compounds of the general formula VII with sodium amide in a suitable solvent, such as xylene at a suitable temperature such as reflux temperature for example as described by J. Lecocq, BidLSoc.Chim.Fr., 1950, 188. i Compounds of the general formula VII, wherein R~ is F, CI, Br or I (scheme 5), may be prepared from compounds of the general formula VDI, by means of metaiiEdoz: 2~ d subse^aen: reaction with a suitable electrophile known to chemists skilled in the art "-ising aptrourla^e bases such as hutyllithium or lithium di-/-but\'l(2.2.6.6-tetramethylpiperl'dii:c)2iQcate with subsequent addition of a suitable electrophile such as fluorine, chlorine, bromine, iodine, carbon tetrabromide or hexachloroethane in a suitable solvent such as heptane or tetrahvdrofuran. at suitable temperatures, such as -78 °C or room temperature for example as described by F. Mongin and G. Queguiner, Tetrahedron. 2001. 57; 4059. Compounds of the general formula VIL wherein R1 is F, CI, Br or I (scheme 5), may be prepared from compounds of the general formula DC by means of metallation and subsequent electrophilic aromatic substitution as described above. Compounds of the general formula VII, wherein R is Ci_6-alk(en/yn)yL C3_g-cycioalk(en)yl, C3_8-cycloalk(en)yi-Ci^-alk(en/yn)yl? halo-Ci-6-alk(en/yn)yi, halo-C3-s-cycloalk(en)yl or halo-C3.g-cycloalk(en)yl-Ci^-alk(en/yn)yl (scheme 6), may be prepared from compounds of the general formula X, by means of cross-coupling reactions known to chemists skilled in the art, such as Negishi coupling (E.-L Negishi, A.O. King and N. Okukado, J.OrgChem., 1977, 42,1821), Sonogashira coupling (K. Sonogashira, Y. Tohda andN. Hagihara, TetLetL, 1975,16, 4467), or other transition metal catalyzed cross-coupling reactions such as copper catalyzed reactions (W. Dohle, D.M. Lindsay and P. Knochel, Org.Lett., 2001, 3, 2871). Compounds of the general formula VH, wherein R1 is Ci-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3^-cycloalk(en)yl-Ci_6-alk(en/yn)yl, halo-Ci_6-alk(en/yn)yl, halo-C3^-cycloalk(en)yl or halo-C3.8-cycloalk(en)yl-Ci_6-alk(en/yn)yl (scheme 6), may be prepared from compounds of the general formula XI, by means of cross-coupling reactions as described above. Additionally, compounds of the general formula YHi wherein R" is cyano (scheme 6). may be prepared from compounds of the general formula X. by means of nickel-catalyzed sanation reactions known to chemists skilled in the art for example as described by L. Cassar. J.Organomet.Chem., 1973, 54; C57-C5S. Compounds of the general formula VII, wherein R] is cyano (scheme 6). may be prepared from compounds of the general formula XI, by means of nickel-catalyzed cyanation Compounds of the general formula VII, wherein R1 = R2 (scheme 6), may be prepared from compounds of the general formula X, wherein R1 = R2 = Br, by means of cross-coupling reactions or cyanation reactions as described above. Furthermore, compounds of general formula XDI (scheme 7), wherein Rl and R2 are halogen, can be prepared from 2,4,6-trihalopyridines of general formula XII, wherein Rl and R2 are halogen, by nitration reactions known to chemists skilled in the art as described under scheme 1 for the preparation of compounds of the general formula IV. Compounds of general formula XTV (scheme 7), wherein Rl and R2 are halogen, may be prepared by from compounds of general type XII, wherein Rl and R2 are halogen, by reaction with morpholine in a suitable solvent such as dimethyl sulfoxide or JV- methylpyrrolidinone. and with or without the addition of bases, such as pyridine, trialkyl ar^ir^s, zx^zssr^n. csfborLHie; mng^esiuiri oxiie. a: suitable temperatures, such as room cxLD£r3H-re or reflux tsnix^erstizre, lomponnds of general type XV may be prepared from compounds of genera! type- XIII by saction with morphoiine in a suitable solvent such, as dimethyl sulfoxide or 'T-methylpyirolidinone: and with or without the addition of bases, such as pyridine, trialkyl mines, potassium carbonate,, magnesium oxide, at suitable temperatures, such as room smperature or reflux temperature. Additionally, compounds oi general type XV may De irepared from compounds of general type XIV by nitration reactions known to chemists killed in the art as described under scheme 1 for the preparation of compounds of the general formula IV. furthermore, compounds of general formula TV. wherein R or R.' or both R* and R* is ;yano {'scheme 7). may be prepared from compounds of general formula XV. using ^variation reactions as described above. Compounds of general formula KL wherein R1 or ■■-■-, ^ or both R" and R~ is cyano, may be prepared from compounds of general rormula XTV, ising cyananon reactions as described above. Compounds of the general formula EH, wherein R1 is Ci^-alk(en/yn)yl, C3.g-cycloalk(en)yl, C3-s-cycloalk(en)yl-Ci_6«alk(en/yn)yl, halo-Ci-6-alk(en/yn)yl, halo-C^«cycloalk(en)yl or halo»C3.8"Cycloalk(en)yl-Ci.6-alk(en/yn)yl (scheme 6), may be prepared from compounds of the general formula XTV, by means of cross-coupling reactions as described above (scheme 6). Compounds of the general formula m? wherein R is Ci^-alk(en/yn)yl, C3.8-cycloalk(en)yl, C3-g-cycloalk(en)yl-Ci^-alk(en/yn)yls halo-Ci-6-alk(en/yn)yl, halo-C3-8-cycloalk(en)yl or halo-C3^-cycloalk(en)yl-Ci-6-alk(en/yn)yl (scheme 6), may be prepared from compounds of the general formula XIV, by means of cross-coupling reactions as described above (scheme 6). Compounds of the general formula TV, wherein R1 is Ci_6-alk(en/yn)yl. C3.g-cycloalk(en)yl,. C3-r the general formula XV. by means of cross-coupling reactions as described above (scheme Compounds of the general formula IV. wherein R" is C;^-alk(en/yn)yl. C5-s-cycloalk(en)yi, C3^-cycioaUc(en)y}-C].6-aIk(en/yn)yL haio-Ci^-aIk(en>yn)yU halo-Cs.£-cycloalk(en)yI or halo-Cs.g-cycloalk(en)yI-C]-6"alk(en^'yn)yl (scheme 6). may be prepared from compounds of the genial formula XV, by means of cross-coupling reactions as described above (scheme *Y Compounds of general formula IV, wherein R1 or R2 or both R1 and R2 is C]-6-alk(en/yn)yloxy5 C3-s-cycloalk(en)yloxy or C3-8-cycloalk(en)yl-Ci-6«alk(en/yn)yloxy5 may be prepared from compounds of general formula XV by reaction with the appropiate lithium-, sodium-, or potassium alcoholates or alcohols in the presence of base such as lithium-, sodium-, or potassium hydroxide, lithium-, sodium-, or potassium hydride, and with or without the addition of a catalyst such as copper sulfate, in a suitable solvent such as dioxane. at suitable temperatures, such as room temperature or reflux temperature. Compounds of general formula HI. wherein R* or R~ or both R and R" is Ci-6-alk(en/yn)yloxy, C>s-cycloalk(en)yloxy or C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yloxy? may be prepared from compounds of general formula XTV by reaction with the appropiate lithium-, sodium-, or potassium alcoholates or alcohols in the presence of base such as lithium-, sodium-, or potassium hydroxide, lithium-, sodium-, or potassium hydride, and with or without the addition of a catalyst such as copper sulfate, in a suitable solvent such as dioxane, at suitable temperatures, such as room temperature or reflux temperature. Additionally, for further variation of R and R , compounds containing a methoxy-group, can be demethylated by methods known to chemists skilled in the art, such as treatment with boron tribromide in a suitable solvent, such as dichloromethane, at suitable temperatures, such as 0 °C or room temperature. The resulting phenols can then be alkylated by methods known to chemists skilled in the art. Such methods include; (a) the reaction with electrophiles, such as alkyl chlorides, alkyl bromides, alkyl iodides, carbonic acid chlorides. carbonic acid bromides, or carbonic acid anhydrides in the presence of suitable bases, such as potassium carbonate, in a suitable solvent, such as tetrahydrofuran. A^A^dimethylfbrrnarnide- or L2-dichloroethane. at suitable temperatures, such as room temperature or reflux temperature; (b) the reaction with alkyi alcohols under conditions known as the Miisunobu reaction (O. Mitsunobu, Synthesis 1981. 1). Compounds containing functional groups, such as hydroxy groups, not compatible with suggested reaction conditions, can be protected and deprotected by methods known to chemists skilled in the art, for example as described by T.W. Greene and P.G.M. Wuts, Protective groups in organic sy/itncsis, 2 edition, Vvne}- laterscience. 1991. in particular, hydroxy groups can be protected as, but not limited to, methyl-, tert-bvtyl-, trialkylsilyl-, triarylsilyl-, allyl- ortrityl ethers. Alkynes prepared by Sonogashira reactions may be reduced to alkenes or alkanes by reduction with hydrogen gas or ammonium formiate in the presence of a suitable hvdrogenation catalyst such as oaliadium on activated carbon or platinum on activated carbon in suitable solvents such as methanol, ethanol or tetrahydrofuran, at suitable temperatures for example as described by S. Siegei. "Heterogeneous catalytic hydrogenation of C=C and alkynes" in Comprehensive Organic Synthesis, v. 8, pp. 417-442, Pergamon Press, 1991. Preparation of the compounds of the invention Examples Analytical LC-MS data were obtained on a PE Sciex API 150EX instrument equipped with atmospheric pressure photo ionisation and a Shimadzu LC-8A/SLC-10A LC system. Column: 30 X 4.6 mm Waters Symmetry CI8 column with 3.5 pm particle size; Solventsystem: A = water/trifluoroacetic acid (100:0.05) and B = water/acetonitriie/trifluoroacetic acid (5:95:0.03); Method: Linear gradient elution with 90% A to 100% B in 4 minutes and with a flow rate of 2 mL/minute. Purity was determined by integration of the UV (254 urn) and ELSD trace. The retention times (tR) are expressed in minutes. Preparative LC-MS-purification was performed on the same instrument with atmospheric pressure chemical ionisation. Column: 50 X 20 mm YMC ODS-A with 5 |im particle size: Method: i-inesr gradient elution ^ith 80% A tc 100% B in 7 minutes and with a flow rate of 22.7 niLniintiie. Fraction collection was performed by split-flow MS detection. Analytical LC-MS-TOF (TOF = time of flight) data were obtained on a micromass LCT 4-wavs MUX eauiooed with a Waters 2488/Sedex 754 detector system. Column: 30 X 4.6 mm Waters Symmetry CIS column with 3.5 urn particle size: Solventsystem: A = water/trinuoroacetic acid (100:0.05) and B - wate^acetonitxile/trifluoroacetic acid (5;95:C.C3), Method: Linear gradient C'LUUOU with 90% r\ LU xuU7a h m 4 minutes ana with a flow rate of 2 mL/minute. Purity was determined by integration of the UV (254 nm) and ELSD trace. The retention times (tj0 are expressed in minutes. GC-MS data were obtained on a Varian CP 3800 gaschxomatograph fitted with a Phenomenex column (Zebron ZB-5, length: 15 metres, internal diameter: 0.25 mm) coupled to a Varian Saturn 2000 iontrap mass spectrometer. Method: Duration 15 minutes, column flow 1.4 mL/minute (carrier gas was helium), oven gradient: 0-1 minute, 60 °C; 1-13 minutes, 60-300 °C; 13-15 minutes, 300 °C. XH NMR spectra were recorded at 500.13 MHz on a Bruker Avance DRX500 instrument. Deuterated dimethyl sulfoxide (99.8%D) was tised as solvent. Tetramethylsilane was used as internal reference standard. Chemical shift values are expressed in ppm-values relative to tetramethylsilane. The following abbreviations are used for multiplicity of NMR signals: s = singlet, d = doublet, t = triplet, q = quartet, qui = quintet, h = heptet, dd = double doublet, ddd = double double doublet, dt = double triplet, dq = double quartet, tt = triplet of triplets, m = multiplet and b = broad singlet. Preparation of intermediates 4-(4,6-Dimethyl-pyridin-2-yl)-morpholine. 2-Amino-4,6-dimethylpyridine (50 g), bis(2-chloroethyl)ether (57.5 mL), sodium iodide (6.13 g) and triethylamine (137 mL) were mixed in dry iV^dimethylfonnamide (1 L) under argon and heated to 150 °C for 16 hours. Water/brine/saturated aqueous sodium bicarbonate (2:1:19 750 mL) were added to the cooled reaction mixture and it was extracted with ethyl acetate (5x 200 mL). The combined organic phases were concentrated in vacuo to app. 500 mL. Water (500 mL) and concentrated aqueous hydrrchlor:C add (35 mL) ^^ added, the phases seoarated and the aeneous nhase v-rashed ~ To 4^4,6^iimethyl-pyridin-2--yl)-morpholuie (9.4 g) dissolved in trifluoroacetic acid (250 mL) cooled to 0 °C was added sodium nitrite (3.54 g) over 15 minutes and the reaction mixture was then stirred 15 minutes at 0 °C. The reaction mixture was concentrated in vacuo to app. 100 mL and the pH adjusted to 1 i with concentrated aqueous sodium hydroxide (150 mL). Brine (200 mL) was added and the mixture was extracted with diethyl ether (4x 150 mL). the organic phase was dried over magnesium sulfate and concentrated in vacuo. The crude product was subjected to flash chromatography (Si02> heptane/ethyiacetate 4:1) to furnish 2.01 g (17% yield?) of the title compound as a yellow solid. GC-MS (m/z) 237 (IvT); tR = 7.69. *H NMR (500 MHz, DMSO-de): 2.28 (s, 3H), 2.39 (s, 3H), 3.60 (m, 4H), 3.67 (m, 4H), 6.72 (s, 1H). 2,4-Dime1hyl-6-moipholin^-yl-pyridin-3-ylainine. Glacial acetic acid (25 mL) was added slowly to a mixture of zinc dust (2.76 g) and 4-(4?6-dimethyl-5-nitro-pyridin-2-yl)-morpholine (2.01 g) in tetrahydrofuran (100 mL) cooled to 0 °C. The reaction mixture was then stirred for 16 hours at 25 °C> filtered through celite, made basic with 25% aqueous ammonia and extracted with tetrahydrofuran (3x 75 mL). The combined organic phases were dried over magnesium sulfate and concentrated in vacuo to furnish 1.76 g (100%) of the title compound as a dark red solid. GC-MS (m/z) 207 (M*); tR = 7.27. lH NMR (500 MHz, DMSO-dg): 2.07 (s, 3H), 2.20 (s, 3H), 3.16 (m, 4H), 3.67 (m, 4H),4.10(b,2H), 6.38 (s, 1H). 4-(4.6-DIcbJorop>Tidm-2-yl}-morp>lioline. Morpholine (5.0 g) was added to a suspension of 2.4.6-trichloropyridine (10.0 g) and sodium carbonate (5.9 g) in acetonitrile (100 mL). The reaction mixture was then stirred at 70 °C for 16 hours, cooled to ambient temperature, filtered through celite and concentrated in vacuo. The crude product was subjected to flash chromatography (SiC>2, heptane/ethjdacetate 4:1) to furnish 3.90 g (30% yield) of the title compound as w off-white solid LC-MS (m/z) 323.8 (lyTj: tR = 3.10, (UV, ELSD) 98.5%: 98.9%. lHNMR (500 MHzr OT^.1"1* " n ■" f •' XT'*- - 4-(4?6«Dichloro-5-nitropyridin-2-yl)-morpholine. To a solution of 4-(4,6-dichloropyridin-2-yl)-morpholine (3.90 g) in concentrated sulfuric acid (40 mL) was added potasium. nitrate ( 1.80 g) over 10 minutes. The reaction mixture was stirred for 16 hours at ambient temperature and then poured in to chrushed ice (500 g). The reaction mixture was made alkaline with concentrated sodium hydroxide and extracted with ethyl acetate (2x100 mL). The combined organic phases were dried over magnesium sulfate and concentrated in vacuo. The crude product was subjected to flash chromatography (Si02? heptane/ethyiacetate 3:1) to furnish 2.26 g (49% yield) of the title compound as a yellow solid. LC-MS (m/z) 278.0 (M*); tR = 3.10, (UV, ELSD) 96.5%; 98.8%. *H NMR (500 MHz, CDC13): 3.62 (m, 4H), 3.80 (m, 4H), 6.50 (s, 1H). 4-(4-CUoro-6-methoxy-5-iiitropyridin-2-yl)-morpholine and 4-(6-Chloro-4-methoxy-5-nitropyridin-2-yl)-morpholine. To a solution of 4-(4,6KficMoro-5-nitropyridin-2-yl)-moipholine (2.02 g) in methanol (15 ml) was added sodium methoxide (0.98 g) and the mixture was heated for 16 hours at 65 °C. After cooling to ambient temperature the reaction mixture was concentrated in vacuo. The crude product was subjected to flash chromatography (SiC>2, heptane/ethyiacetate 3:1) to furnish 0.89 g (45% yield) of 4-(4-chloro-6-methoxy-5-nitropyridin-2-yl)-morpholine (fast eluting band) and 0.38 g (19%) of 4-(6-cUoro^methoxy-5-nitropyridin-2--yl)-morphoiine (late eluting band), both as yellow solids. 4-(4-cMoro-6-methoxy-5-nitropyridin-2-yl>morpholine: LC-MS (m/z) 273 (M*); tR=2.77) (UV, ELSD) 95%, 97 %. *HNMR (500 MHz, CDC13): 3.60 (m, 4H), 3.80 (m, 4H), 3.96 (s, 1H)56.17(SS1H). 4-{6-chiorc^metbc^-5-=^^ LC-MS (m/z) 273 Qst): tR = 2.39: (UVS ELSD) 93%, ?f 4. !H NMR (500 MKz, CDC;,;: 3.57 (m, 4H): 3.80 (m, 4H); 3.95 (s> 3H)S 5.95(sflH). 4-Qiioro-2-methoxy-6-mo:rohoiin-4-y^ To a solution of 4-(4-cMoro-6-methoxy-5-niirop}T^^ (.0.82 g) in concentrated hydrochloric acid (50 mL) was added a solution of stannous dichloride (3.38 2; IT- cor.cemrated hydrochloric acid (3C mL). The reaction mixture wa* heated to 75 JC for 1 hour and then poured on to chrushed ice (400 g) and extracted with ethyl acetate (2x100 mL). The combined organic phases were dried over magnesium sulfate and concentrated in vacuo, to furnish 0,45 g (61% yield) of the title compound as an off-white solid. LC-MS (m/z) 244 (M+); tR = 1.483 (UV, ELSD) 89%, 94%. *H NMR (500 MHz, CDCI3): 3.30 (m, 4H), 3.65 (hr s. 2H). 3.85 fm. 4HV 3.97 (Sj 3H), 6.20 (s, 1H). 2-CMoro^methoxy-6-moiphoiiD^yipy^ To a solution of 4-(6-chioix>-^methoxy-5-nitropyrid (0.38 g) in concentrated hydrochloric acid (20 mL) was added a solution of stannous dichloride (1.57 g) in concentrated hydrochloric acid (60 mL). The reaction mixture was heated to 75 °C for 5 minutes and then poured on to chrushed ice (100 g) and extracted with ethyl acetate (2x20 mL). The combined organic phases were dried over magnesium sulfate and concentrated in vacuo, to furnish 0.28 g (83% yield) of the title compound as an off-white solid. *H NMR (500 MHz, CDC13): 3.35 (m, 4H), 3.65 (br s, 2H), 3.80 (m, 4H), 3.90 (s, 3H), 6.10 (s, 1H). Compounds of the invention Acid addition salts of the compounds of the invention may easily be formed by methods known to the person skilled in the art. Example 1 laa (2f4-Dimethyl-6-morpholin-4-yl~p)ridin-3-yl)-carbamic acid benzyl ester. Benzyl chloroformate (18 ing) was added to a solution of 0.085 M 2.4-dimethyl-6- morpholin-4-yl-pyridii>3-yranTiiie and 0.17 M Ar3T-diisopropyl-ethylamine in 1.2-dichloroethane (1 mL). The v^i -was dsakea for 16 hours under argon and concentrated in vacuo. Aqueous soii'-rr. hydroxide [I M. 1 r~L~; "-vas sdied and the crude mixtare was extracted ^th Isoprory" ^c^e.~strahydrof-n~2n (4:Ir Ix , mL). The organic phase was washed with brine (1 nuA concentrated ir; i^rue and rsdissoived in 1-propanol/dimethyl sulfoxide (1:1. 0.4 ml"- of which 0.2 mL \^*as subjected to preparative LC-MS purification to furnish 4.5 mg (3 1% yield) of the ride compound as an oil. LC-MS (m/z) 342 (MIT); tR = 1.58, (UY. ELSD) 99%: 99%. The fcllc-wm^ JGnipounus were prepared aiiaio^ousi)'. lab (2,4-Dimethyl-6-morpholin-4-yl~pyridin-3-yl)-carbamte acid2-chloro-benzyl ester. Yield: 18%. LC-MS (m/z) 376 (MH4); tR = 1.78, (UV, ELSD) 99%, 100%. lac2-(4-Chloro-phenyl)-N'(2A-dimethyU6-morp Yield: 4%. LC-MS (m/z) 360 (MH4): tR = 1.59, (UVt ELSD) 96%, 100%. ia^ 2-Phenyl-cyciopropanecarboxylie acid (2,4-dimethyl-6-morpholin-4-yl-pyridin-3~yl)- amide. Yield: 24%. LC-MS (m/z) 352 (MIT); tR = 1.64, (UV, ELSD) 96%, 100%. laeN-(2A-Dimethyl-6-morpholin-4-yl-pyridin-3-yl)^^ Yield: 16%. LC-MS (wfc) 332 (MH4); tR - 1.20, (UV, ELSD) 93%, 99%. I a/* 5-Cyclohexyl-l>!-(2A~dimettyl-6-morphd Yield: 15%. LC-MS (Wz) 346 (MH*); tR = 1.81, (UV, ELSD) 91%, 100%. ia# (2A-DiTnethyl-6-morphoUn^~yl-pyridin-3-yl)-carbamic acid isobutyl ester. Yield: 29%. LC-MS (m/z) 308 (MH4); tR = 1.44, (UV, ELSD) 97%, 99%. JaA 3-(3-Chloro-pheiiyl)-N-(2J4 hydroxide (i M. : mL) was added and the crude mixture was extracted with isopropyl acetate/tetrahydrofarsn (4:1. 2x 1 mL). The organic phase was washed with brine (1 mL). concentrated in -vacuo and redissolved in 1 -propanol/dimethyl sulfoxide (1:1, 0,4 mL) of which 0.2 mL. was subjected to preparative LC-MS purification to furnish 2.3 mg (14% yield) of the title compound as an oil. LC-MS (m/z) 374 (MIT); tR - 1-71, (UV, ELSD) 99%r 99%. ^ne ^Oilowiii^ JcmpouiiQc VVCIL prcpdi^u diiuiogously. laiN~(2,4-Dimethyl-6-morpholin-4-yl-pyridin-3~y^^ Yield: 19%. LC-MS (m/z) 354 (MEf); tR = 1.69, (UVf ELSD) 99%, 99%. la] N-(2A-Di™zttyl-6~morpholinA-yl-pyr Yield: 20%. LC-MS (m/z) 354 (MET*): tR = 1.64, (UV, ELSD) 99%? 100%. lak2-(3-Chloro-phenyl)-N-(2,4-dimefo^ Yield: 14%. LC-MS {m/z) 360 (MET); tR - 1.58, (UV, ELSD) 97%, 99%. lal 2~(3,4-Dichloro-phenyl)~N-(2,4-dimethyl-6-morpholin-4-yl-pyridin~3-yl)-acetamide. Yield: 9%. LC-MS (m/z) 395 (MIT); tR = 1.84, (UV, ELSD) 97%, 99%. lamN-(2t4~Dimethyl-6-morphoIirt^-yl-pyridin-3-yl)-2-M Yield: 18%. LC-MS (wa/z) 332 (MH+); tR= 1.18, (UV, ELSD) 97%, 99%. Ian N-ft^DimethyU&rnorphalinr^^ Yield: 16%. LC-MS (m/z) 340 (MH+); tR = 1.50, (UV, ELSD) 96%, 99%. lao 2-(3-Bromo-phenyl)-N~(2A-dimethyl-6-morpholin~4^ Yield: 12%. LC-MS (m/z) 405 (MJf); tR = 1.63, (UV, ELSD) 96%, 99%. lapN-(2A-Dimethyl~6-morpholin^-yl-pyridin-3-yty^^ acetamide. Yield: 20%. LC-MS (m/z) 394 (MJF); tR = 1.77, (UV, ELSD) 94%, 99%. laq N-(2l4-Dimer]7)H~6-mo?T>hQ]in~4~y!-V}ri& Yield: 11 %. LC-MS (m/z) 326 (MH~); tR = 1.29: (UVr ELSD) 95%, 99%. lar 3.5, S-Trimethyl-hexcrnoic acid (2f 4-dimethyl-6-??iorpho!in~4-y!-pyridirf~3-y!)-amide, Yield: 20%, LC-MS (m/z) 348 (MET); tR = L97, (UV, ELSD) 93%, 99%. ioy Octanoic acid (2,4^methyl~6~morpholin~4~yI-pyridiri-3-yl)-amide. *i^iL. i r.-u, ^^, ^vx.u ^M'M-^- _/_>-T yiVxi-A y: U^ ~" J..^^-, \W V , ivJ^k3JL>^ .7,6/0, ^J/O, latN-(2,4-Dimethyl-6-morph0lin-4~yl-pyridin-3-yl)-2-naphtto^ Yield: 4%. LC-MS (m/z) 376 (MH*); tR - 1.73, (UV, ELSD) 92%, 99%. lau Heptanoic acid (2l4^imethyl-6-morpholm-4-yl-pyrzdin-3-yl)-amide. Yield: 24%. LC-MS (m/z) 320 (MFT): tR - 1.56, (UV, ELSD) 90%, 99%. iav K-(2,4-Dimethyl~6~morpholw-4-yl-pyridin-3-yl)-2^^ Yield: 26%. LC-MS (m/z) 354 (MET): tR = 1.65, (UV, ELSD) 77%, 99%. law 2-Cyclohex-l -enyl-N-(2,4~dimethyl-6'morpholinA-yl-pyridin-3'yl)-acetcmide. Yield: 13%. LC-MS (m/z) 330 (MH*); tR = 1.50, (UV, ELSD) 72%, 99%. laxN-(2A-Dimethyl~6-morpholin^yl-pyridin-3-yl)~2-(4-mefo acetamide. Yield: 16%. LC-MS (m/z) 370 (MB*); tR = 1.56, (UV, ELSD) 94%, 99%. layN-(2A-Dimethyl-6~morphQlin-4-yl-pyridin-3-yl)-2-(4-metto Yield: 19%. LC-MS (m/z) 356 (MH*); tR = 1.35, (UV, ELSD) 96%, 99%. lazN-(2^-Dimethyl-6-morpholin-4-yl-pyridin-3-yl)'3-(4-m Yield: 15%. LC-MS (m/fc) 370 (MH*); tR = 1.48, (UV, ELSD) 76%, 99%. Iba N- (2.4-Dirr^z.~ •: '-z—^orp ho:z7z~^. 'l^^dz^-i~yl~2-Tn-?olyl~acetGmide. /72-TolyIacetic acid (1-33 g). A%V-iii5C-prGpyI-e±yI=irJiie (0.90 mL) zuCiN' [(dimethylairiinoyL^-I-2^-^^ methanaminiurr: bexsdrnarc-phasphaie A~-oxiae (1.00 g) were mixed in dry Ayv'-dimethylfonnamide (3 mL) and stirred under argon for 2 minutes. 2.4~Dimsthyl-6-morpholin-4-yl-pyridin-3-yiaroine (0.30 g) dissolved in dry ALV-dimefhylfonnamide (2 mL) was added to the reaction mixture, -which was stirred at 25 °C under argon for 16 hours. Ethyl a^e;at^ ,'2L xaL) vvai added dua mc organic pnasc was wasneu witti saturated aqueous ammonium chloride/water (1:1, 20 mL), water (20 mL), brine/water (1:1. 20 mL), dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography (Si02, heptane/ethylacetate 3:1) to furnish 0.069 g (14% yield) of the title compound as a white solid. LC-MS (m/z) 340 (MET); tR - 1.42, (UV, ELSD) 96%, 100%. *H NMR (500 MHz, DMSO-dg); 2.00 (s. 3H). 2.11 (s? 3H), 2.29 (s, 3H)? 2.37 On. 4H)r 3.56 (s, 2H), 3.67 (in, 4H), 6.52 Ibb N-(2A~Dimethyl-6~morphoiin^yl-pyridm~3-ylh^ Yield: 14%. LC-MS (m/z) 344 (MH*); tR = 1.34, (UV, ELSD) 99%, 99%. lH NMR (500 MHz, DMSO-d^): 1.99 (s, 3H), 2.10 (s, 3H), 3.37 (m, 4H)? 3.60 (s, 2H), 3.66 (m, 4H), 6.52 (s, IH), 7.16 (dd, 2H), 7.38 (dd, 2H), 9.33 (s, IH). Ibc N-(2t 4-D\methy\-6-morpho\in^-yl-pyridin^ Yield: 53%. LC-MS (m/z) 306 (MH*); tR= 1.26, (UV, ELSD) 99%, 98%. *H NMR (500 MHz, DMSO-d6): 1.05 (s, 9H), 2.07 (s, 3H), 2.18 (s, 2H), 2.19 (s, 3H), 3.37 (m, 4H), 3.67 (m, 4H), 6.54 (s, IH), 9.01 (s, IH). lbdN-(2A-Di7nethyl-6-mo7j>holin-4-yl-pyridin-3^ Yield: 15%. LC-MS (m/z) 344 (MH*);tR = 1.54, (UV, ELSD) 100%, 100%. 1HNMR(500 MHz, DMSO-d6): 2.00 (s, 3H)? 2.11 (s, 3H), 3.37 (m, 4H), 3.64 (s, 2H), 3.66 (m, 4H), 6.52 (s, IH), 7.08 (dt IH), 7.18 (m, 2H), 7.38 (m, IH), 9.34 (s, IH). \be 2-3icsc-z '2.2..' n£^:-2-y:-22-O:4-d2^z2'}^l^'~0^holin-4-yl-pyridiii-3-yl)- icetarrddc field: 62%. LC-MS (m/z) 344 (MR-); t~ = 1.58, (UV, ELSD) 99%, 99%. !H NMR (500 sffiz; DMSO-d;}: 1.14 (IE, 4H;, 1.42 fe:'4H); 1.90 (m: 1H)S 2.01 (m, 1H), 2.04 (s, 3H), 1.10 (EDU 1HL 2.16 (s, 3H)S 2.21 (m, 2H), 3.37 (m, 4H), 3.67 (m, 4H), 6.53 (s, 1H), 9.04 (s; LH). 'fc/7 (3, ' Difr.;crD-phe?iyi/-y,'~{Z,4-LUrtieikyi-o-mo Yield: 9%. LC-MS (m/z) 362 (MH*); tR = 1.52, (UV, ELSD) 95%, 99%. JH NMR (500 MHz, DMSO-ds): 2.00 (s, 3H), 2.11 (s, 3H), 3.37 (m, 4H), 3.63 (s, 2H), 3.66 (m, 4H), 6.52 [s, 1H), 7.19 (m, 1H), 7.39 (m, 2H), 9.32 (s, 1H). 7Ag- 4-Methyl-pentanoic acid f2,4-dimet'ry?-6-morpholin-4-yI-pyridin-3-yl)-amide. Y"ield: 34%. LC-MS (m/zi 306 (MIT): iR = 1.33. (UV, ELSD) 100%. 99%. 'HNMR (500 MHz, DMSG-^K 0.91 (d, 5H), 1.49 (di, 2H), 1.58 (m, 1H), 2.04 (s, 3H), 2.16 (s, 3H), 2.28 j, 2H), 3.3" (m: 4H), S.o'7 (m; 4H;. 6.53 (s, 1H), 9.07 (s, 1H). ZM 2-CyclopeK-2-eriyI-N-(2,4-dimethyl-6-morphoIin-4-yl-pyridin-3-yl}-acetamide. Yield: 13%. LC-MS (m/z) 316 (MET); tR =1.25, (UV, ELSD) 97%, 94%. lU NMR (500 MHz, DMSO-ds): 1.51 (m, 1H), 2.05 (m, 1H), 2.06 (s, 3H), 2.17 (s, 3H), 2.26 (m, 2H), 2.35 (m, 2H), 3.07 (m, 1H), 3.38 (m, 4H), 3.68 (m, 4H), 5.73 (m, 1H), 5.77 (m, 1H), 6.54 (s, 1H), 9.09 (s, 1H). Ibi 2-Cyclohexyl-N-(2,4-dimethyl-6-morpholin-4-yl-pyridin-3-yl)-acetamide. Yield: 12%. LC-MS (JWZ) 332 (MH*); tR = 1.50, (UV, ELSD) 99%, 95%. *H NMR (500 MHz, DMSO-dg): 0.98 (m, 2H), 1.20 (m, 3H), 1.71 (m, 6H), 2.05 (s, 3H), 2.15 (d, 2H), 2.16 (s, 3H), 3.37 (m, 4H), 3.67 (m, 4H), 6.53 (s, 1H), 9.05 (s, 1H). Ibj 5-Methyl-hexanoic acid (2,4-dimethyI-6-morpholin-4-yl-pyridin-3-yl)-amide. Yield: 40%. LC-MS-TOF (m/z) 320 (MH4); tR = 1.51, (UV, ELSD) 97%, 100%. lHNMR (500 MHz, DMSO-d*;: 0.8^ (d, 6H), 1.21 (m, 2H), 1.60 (m, 3H), 2.05 (s, 3H), 2.16 (s, 3H), 2.25 (t, 2H1 337 (m, 4H): 3.67 (m, 4H), 6.53 (s, 1H); 9.05 (s, 1H). lbk 2-CycIopeiiTyl-N-G:4-di7naTl2yl-6-??wrpho!i)'-4^l-py 2.4-DimethvI-6-niorphoiipi^vI-]D\TiGin-3-vlaiTiiiie (0.22 z'\ and cvdooentvlac-etvl chloride (0.19 mL) were dissolved in acetonitrile (5 mL) and heated to 150 °C for 10 minutes in a sealed microwave process vial. The reaction mixture was concentrated ;';- vacuo and purified by flash chromatography (SiO;, heptane/ethylacetate 3:1) to furnish 0.17 g (49% yield) of the title compound as a white solid. LC-MS (m/z) 31E (MH*); tR = 1.40, (UV, ELSD) 97%. 99%. *H NMR (500 MHz, DMSO-d6): 1.21 (m, 2H),1.52 (m, 2H). 1.61 (m, 2H), 1.77 (m: 211). 2.C5 (i. 211), 2.17 (s, 311;, 2.2-t V>IJ. In.,/, --~O ^ru; .in;, J.J/ i^m, 4tLj, J.O/ (m, 4ii;, o.^i (s, 1H), 9.05 (s, 1H). The following compounds were prepared analogously except lbl and lbm which were recrystallized from ethyl acetate after flash chromatography: lbl 3-Cyclopenty>!-AT-(2,4-dimethy!-6-morpholm-4-yl-pyridin-3-yl)-propionamide. Yield: 34%. LC-MS (m/z) 332 (MIT); tR = 1.57, (UV, ELSD) 99%, 99%. lK NMR (500 MHz, DMSO-de): 1.11 (m, 2H), 1.49 (m, 2H), 1.60 (m, 4H), 1.77 (m, 3H), 2.04 (s, 3H), 2.16 (s, 3H), 2.28 (t, 2H), 3.37 (m, 4H). 3.67 (m, 4H). 6.53 (s, 1H), 9.06 (s, lHi. lbm Hexanoic acid (2,4-dimethyl-6-morpholm-4-yl-pyridin-3-yl)-amide. Yield: 51%. LC-MS (m/z) 306 (MIT); tR = 1.39, (UV, ELSD) 99%, 99%. lH NMR (500 MHz, DMSO-de): 0.88 (t, 3H), 1.31 (m, 4H), 1.60 (m, 2H), 2.05 (s, 3H), 2.16 (s, 3H), 2.27 (t, 2H), 3.37 (m, 4H), 3.67 (m, 4H), 6.53 (s, 1H), 9.03 (s, 1H). lbnN-(4-Chloro-2-methoxy-6-morpholin-4-yl-pyridin-3-yl)-2-cyclopentylacetamide, Yield: 53%. LC-MS (m/z) 354 (MH+); tR = 2.68, (UV, ELSD) 98%, 99%. 'H NMR (500 MHz, CDC13): 1.25 (m, 2H), 1.50-1.65 (m, 4H), 1.90 (m, 2H), 2.45 (m, 3H), 3.45 (m, 4H), 3.77 (m, 4H), 3.90 (s, 3H), 6.20 (s, 1H), 6.50 (s, 1H). lboN-(2-Chloro-4-methoxy-6-morpholin-4-yl-pyridin-3-yl)-2-cyclopentylacetamide. Yield: 69%. LC-MS (m/z) 354 (MH4); tR = 2.39, (UV, ELSD) 99%, 99%. *H NMR (500 MHz, CDC13): 1.25 (m, 2H), 1.50-1.70 (m, 4H), 1.90 (m, 2H), 2.35 (m, 3H), 3.50 (m, 4H), 3.80 (m, 4H), 3.85 (s, 3H), 6.00 (s, 1H), 6.45 (s, 1H). in viiru ana m vivo testing The compounds of the invention have been tested and shown effect in at least one of the below models: Relative efflux through the KCNQ2 channel. This exemplifies a KCNQ2 screening protocol for evaluating compounds of the preseni invention. The assay measures the relative efflux through the KCNQ2 channel, and was carried out according to a method described by Tang et al. (Tang, W. et. aL J. BiomoL Screen. 2001. 6? 325-331) forhERG potassium channels with the modifications described below. An adequate number of CHO cells stably expressing voltage-gated KCNQ2 channels were plated at a density sufficient to yield a confluent mono-layer on the day before the experiment. The cells were loaded with 1 jxCi/ml [86Rb] over night On the day of the experiment cells were washed with a HBSS-containing buffer (Hanks balanced salt solution provided from Invitrogen, cat# 14025-050). Cells were pre-incubated with drug for 30 minutes and the 86Rb+ efflux was stimulated by a submaximal concentration of 15 mM potasium chloride in the continued presence of drug for additional 30 minutes. After a suitable incubation period, the supernatant was removed and counted in a liquid scintillation counter (Tricarb). Cells were lysed with 2 mM sodium hydroxide and the amount of Tlb+ was counted. The relative efflux was calculated ((CPMsupe^CPMsupcr^ CPMceii))cmpd/ (CPMsup^CPMs^per+CPMoe^iSn.MKcO^lOO-lOO. The compounds of the invention have an EC50 of less than 20000nM. hi most cases less than 2000 nM and in many cases less than 200 nM. Accordingly, the compounds of me invention are considered to be useful in the treatment of disesLses associated with the KCNQ family potassium channels. Electrophysiological patch-clamp recordings in CHO cells Voltage-activated KCNQ2 currents were recorded from mammalian CHO cells by use of conventional patch-clamp recordings techniques in the whole-cell patch-clamp configuration (Hamill OP etal. PfliigersArch 1981; 391: 85-100). CHO cells with stable oppression oi voitago-acuvaieu KCJNQ2 cnanneib were grown under normai cell culture conditions in CO2 incubators and used for electrophysiological recordings 1-7 days after plating. KCNQ2 potassium channels were activated by voltage steps up to + 80 mV in increments of 5-20 mV (or with a ramp protocol) from a membrane holding potential between - 100 mV and - 40 mV (Tatulian L et al. JNeuroscience 2001; 21 (15): 5535-5545). The electrophysiological effects induced by the compounds were evaluated on various parameters of the voltage-activated KCNQ2 current. Especially effects on the activation threshold for the current and on the maximum induced current were studied. Some of the compounds of the invention have been tested in this test. A left-ward shift of the activation threshold or an increase in the maximum induced potassium current is expected to decrease the activity in neuronal networks and thus make the compounds useful in diseases with increased neuronal activity - like epilepsia. Electrophysiological recordings of KCNQ2, KCNQ2/KCNQ3 or KCNQ5 channels in oocytes Voltage-activated KCNQ2, KCNQ2/KCNQ3 or KCNQ5 currents were recorded from Xenopus oocytes injected with mRNA coding for KCNQ2, KCNQ2+KCNQ3 or KCNQ5 ion channels (Wang et al., Science 1998,282, 1890-1893; Lerche et nL9JBiol Chem 2000, 275, 22395-400). KCNQ2, KCNQ2/KCNQ3 or KCNQ5 potassium channels were activated by voltage steps from the membrane holding potential (between - 100 mV and - 40 mV) up to 4- 40 mV in increments of 5-20 mV (or by a ramp protocol). The electrophysiological effects induced by the compounds were evaluated on various parameters of the voltage-activated KCNQ25 KCNQ2/KCNQ3 or KCNQ5 currents. Especially effects on the activation threshold for the current and on the maximum induced current were studied. The hvperpoiarizing enecis 01 so—^ c-f :i~e ^rn~poinds were also tested directly on the membrane potential airing current cLarrp. Maxiiauni electroshock The test was conducted in srouns or male mice using corneal electrodes and administerins a square wave current of 26mA for 0.4 seconds in order to induce a convulsion characterised by a tonic hind limb extension (Wlaz et al. Epilepsy Research 1998; 30, 219-229). Pilocarpine induced seizures Pilocarpine induced seizures are induced by intraperitoneal injection of pilocarpine 250mg/kg to groups of male mice and observing for seizure activity resulting in loss of posture within a period of 30 minutes (Starr et al. Pharmacolog)' Biochemistry and Behavior 1993,45,321-325). Electrical seizure -threshold test A modification of the up-and-down method (lumbal! et al. Radiation Research 1957, 1-12) was used to determine the median threshold to induce tonic hind-limb extension in response to corneal electroshock in groups of male mice. The first mouse of each group received an electroshock at 14 mA, (0.4 s, 50 Hz) and was observed for seizure activity. If a seizure was observed the current was reduced by 1 mA for the next mouse, however, if no seizure was observed then the current was increased by 1 mA. This procedure was repeated for all 15 mice in the treatment group. Chemical seizure -threshold test The threshold dose of pentylenetetrazole required to induce a clonic convulsion was measured by timed infusion of pentylenetetrazole (5mg / mL at 0.5 mL/minute) into a lateral tail vein of groups of male mice (Nutt et al. J Pharmacy and Pharmacology 1986, 38, 697-698). Amygdala kindling Rats underwent surgery to implantation of tri-poiar electrodes into the dorsolateral amygdala. After surgery the animals were allowed to recover before the groups of rats received either varying doses of test compouDd or the drag's vehicle. The animals were stimulated with their initial after discharge threshold - 25 uA daily for 3-5 weeks arid on each occasion seizure severity, seizure duration, and duration of electrical after discharge were noted. (Racine. ElectroencephalograpJiy and Clinical Neurophysiology* 1972, 32, 281-294). Side effects Central nervous system side-effects were measured by measuring the time mice would romau^ vi* xOtai'ou apparatus (Capacio oi ai. urug una Cnemicai loxicoiogy 1992, ID, A /"/-201); or by measuring their locomotor activity by counting the number of infra-red beams crossed in a test cage (Watson et al. Neuropharmacology 1997, 36,1369-1375). Hypothermic actions on the animals core body temperature of the compound were measured by either rectal probe or implanted radiotelemetry transmitters capable of measuring temperature (Keeney etal. Physiology' and Behaviour 2001, 74, 177-184). Pharmacokinetics The pharmacokinetic properties of the compounds were determined via. i.v. and p.o. dosing to Spraque Dawley rats, and, thereafter, drawing blood samples over 20 hours. Plasma concentrations were determined with LC/MS/MS. CLAIMS 1. A compound having the general formula I; wherein: qis Oor 1; each of R and R is independently selected from the group consisting of halogen, cyano. Ci^-alk(en/yn)yl, C3-g-cycloalk(en)yl, C3-rcycioalk(en)yl-Ci^-alk(en/yn)yl, haio-Ci-6-alk(en/yn)yL halo-C3-s-cycioalk(en)yL halo-C3-g-cycloalk(en)yl- Ci-6-alk(en/ya)yl: Ci^alk(en/yn)yloxy. C3.rcycloalk(en)yloxy and C3-s-cycloalk(en)yl-Ci.6-alk(en/yn)yloxy; and R" is selected &om the group consisting of Cug-alk(en/yn)yL C3-s-cycloalk(en)yl. Cs-rcycloalkfenjyi-Ci^-alkCen/^yl, optionally substituted Aryl-Ci^-alk(en/yn)yL optionally substituted Axyl-C3-rcycloalk(en)yl, optionally substituted Aryl- C3-g-cycloalk(en)yl-Ci-6-alk(en/yn)yl; Ci.6«alk(en/yn)yl-C3-s-heterocycloalk(en)yl- C^-alk(en/yn)yl3 C3.8-heterocycloalk(en)yl-Ci-6-alk(en/yn)yl, Ci-6-aik(en/yn)yl- C3-8-heterocycloalk(en)yl-Ci^-alk(en/yn)yl, Heteroaryl-Ci-6-alk(en/yn)yl, Heteroaryl- C3-g-cycloalk(en)yl?Heteroaryl-C3-g-cy^ NR4R5^Ci.6-alk(en/yn)yl3 NRV-Ca^-cycloalkCe^yl, NRV Ci_6-alk(en/yn)yl5 C3.g-cycloalk(en)yl-Ci^-aIk(en/yn)yloxy-Ci^--alk(en/yn)yl! halo- Ci.6-alk(en/yn)yl? halo-C3-8-cycloalk(en)yl and halo-C3-g-cycloalk(en)yl- Ci-6- Ci-6~alk(en/yn)yl5 C3_g-cycloalk(en)yl and C3-g-cycloalk(en)yl-Ci-6-alk(eu/yn)yl; as the free base or salts thereof. A compound aocord^g ID D^ZL : ~"t>ere:ri q is 0. A compound according ID claim I wherein q is 1, A compound according to any one of claims 1-3 wherein each of RJ and R^ is independently selected from the group consisting of C^-alk(en/yn)yI; C^8-cycloaIk(en)yi, Cs-r A compound according to claim 4 wherein both R* and R~ are C^-alk(en/yn)yl. A compound according to claim 4 wherein Rl is Ct^-alk(erv'yn)yloxy and R2 is halogen, or wherein R is halogen and R** is C;.6-alk(en/yn)yloxy. A compound according to any one of claims 1 -6 wherein RD is selected from the group consisting of C^$-alk(en/yn,)yI. C3-rcycioalk(sn)yi. C.v?-cycloaIk(en)yl-Ci-6-alk(en/yn)yl? optionally substituted Ary]-Ci_6~alk(en/yn)yL optionally substituted Aryl-C3-8-cycloalk(en)yL optionally substituted Aryl-C3_g-cycloalk(en)yl-Ci_6-alk(en/yn)yl, HeteroarylrCi^-alk(en/yn)yl, Heteroaryl-C3_8-cycloalk(en)yl, Heteroaryl-C3.s-cycloalk(en)yl-Ci-6-alk(aa/yn)yl3 A compound according to claim 7 wherein R3 is selected from the group consisting of Ci-8-a]k(en/yn)yl, C3.8-cycloalk(en)yl-Ci-6-alk(en/yn)yl3 optionally substituted Aryl-Ci-6-alk(en/yn)yl, optionally substituted Aryl-C3_8-cycloalk(en)yl and Heteroaryl-Ci^-alk(en/yn)yl. A compound according to any one of claims 1, 7 and 8 wherein optionally substituted Aryl may be substituted with one or more substituent indepently selected from the group consisting of halogen, cyano, C]-6-alk(en/yn)yl5 C3-s-cycloalk(en)yl:, C3»8-cycloalk(en)yl-C],6-alk(en/yn)yl5 halo-Ci^-alk(en/yn)yl. halo-C3.g-cycloalk(en)yl halo-C3.8-cycloa!k(en)yl-Ci^-al]c(enoTi)yi5 Ci^-alk(en/yn)yloxy9 C3-8-cycloalk(en)yloxy and C:^r1-C]^-alk(en/\Tn)yloxy. 10. A compound accorcrig '.c :i?" 9 hereon optionally sursdrated Ajyl may be substituted with one or zK>re. ribs±rjent indepeniiy selected from the group consisting ofhalogen. C;^-aIk(en^i)yI. halo-Ci-6-£!k(ea'1>,ii)Yl and Ci^-aik(ea/yn)yloxy. 11. A compound according xo any one of Claims 1-10. said compounds being selected from the group consisting of: (2,4-Dimethyl^-mcnpiiD^ benzyl ester: (2,AT>irr.ethyl-C-:norphoI^ *cxa ^-anoro-oenzyi ester. 2-(4-CMoro-phenyl)-(2,4-^iimeth^ 2-Phenyl-cyclopropanecarboxylic acid (2,4-dimethyl-6-moxpholin-4-yl-pyTidin-3--yl)- amide; iV~(2,4-Dime1hyl-6-morphoim^^ 3-(>clohexylrAK2.4-dimethyl^morphol& (2.4-Dimethyl-6-morphoiin^y^ acid isobutyl ester; 3-(3-CMoro~phenyr;-^-(2r4--dimethyl-6-morphoIm Ar-(2A4>inaethyI-&-morphoi^^^ iV-(2,4-Dimsthy l-6-morpbolin-4-yl-pyxidin-3 -y l}-3 -p-tolyl-propionamide; 2-(3-CMoro-phenyl)-A^2.4KiimethyI-6-moT^^ 2-(3?4-DicWoro-phenyl)-AH2,4-dimethyl-6-^ AK2>4-Dimethyl-6-moipho^ JV-(2,4-Dimethyl-6-morpholin^yl-^^ 2-(3-BrGmo-phenyl)-A-(2s4Kiimethyl-6-^^ AK2,4-Dimethyl-6-morpholin^^ acetamide; A-(2,4-Dimethyl-6-morpholin^ 3,5,5-Trimethyl-hexanoic acid (234Kiimethyl-6-morpholin^yl-pyridin«3-yl)-amide; Octanoic acid (254-dime1hyl-6-morpboiin^yl-pyridin-3-yl)-ainide; A-(2,4-Dimethyl-6-moipholin^yl-py^ Heptanoic acid (2,4-dimethyl^morpholin^yl-pyridin--3--yl)-ainide; 7^-(2,4-Dimethyl-6-morpholin-4-yl-pyridin-3 -yI)-2-(3 54-dimethyl-phenyl)-acetamide; 2-Cyclohex-l-enyl-Ar-(2r4Hiiinetbyl^-morpbolin^yl-p>Ti JV^254-Dimethyl^mo:iph^ acetamicie; A'r-(2.4-DImethy!^rao:phoIin^ ;Y-(254-Dimethy]~6-:riQrpholin^ propionamide: 7v-(2,4-DimethyI-(^morpholin^-yI^^ Ar-(2.4-DimethyI-6-moTpho^ A^^Dimethyl-S-morpholin^yl-pj^ >r-(2/--!>^etbyVX--;^ 2-Bicyclo[22J]hept-2~yWV^^^ acetamide; 2-(3?4-Difluoro-phenylHV"-(2,4-dim 4-Methyl-pentanoic acid (2J4-dimethyl-6-morpholin-4-yl-pyridin-3-yl)-amide; 2-Cyclopent-2-enyl-A^2,4-dimethyl-6 5~Methyl-hexanoic acid (2,4-dimethyl-6-moipholin-4-yl-pyridin-3-yl)-aniide; 2-Cyclopentyl-7^-(2,4-dimethyl-6-morphoIiD^-yl-pyridm S-Cyclopentyl-A^^-dnnethyl-G^ and Hexanoic acid (2.4-dime1iiyl-6-morpholin^yl-pyTidin-3-yl)-ainide iV-(4-CMoro-2-methoxy-6-moiphoUn^-yl-pyridin-3-yl>2-cyc]opentylacetaniide iV^(2-Chloro^methoxy^morphoIin^-yl-p^ iV^2-Chloro^methoxy-6-morpholitH^^ JVK4-Chloro-2-methoxy^mqrphoiii^ i\^4-Chloro-2-methoxy-6-morpholin-4-yl-pyridb-3-yl)-propionamide as the free base or salts thereof. 12. A pharmaceutical composition comprising one or more pharmaceutical^ acceptable carriers or diluents and a compound of the general formula I: 17, Use according to Claim 15 wherein the anxiety disorders are selected from the group consisting of anxiety and disorders and diseases related to panic attack, agoraphobia, panic disorder with agoraphobia, panic disorder without agoraphobia, agoraphobia without history of panic disorder, specific phobia, social phobia and other specific phobias, obsessive-compulsive disorder, post-traumatic stress disorder, acute stress disorders, generalized anxiety disorder anxiety disorder due to general medical condition, subsiance-induced anxiety disorder, separation anxiety disorder, adjustment disorders, performance anxiety, hypochondriacal disorders, anxiety disorder due to general medical condition and substance-induced anxiety disorder and anxiety disorder not otherwise specified. 18, Use according to Claim 15 wherein the neuropathic pain and migraine pain disorders are selected from the group consisting of allodynia, hyperalgesic pain, phantom pain, neuropathic pain related to diabetic neuropathy, neuropathic pain related to trigeminal neuralgia and neupathic pain related to migraine. 19, Use according to Claim 15 wherein the neurodegenerative disorders are selected from the group consisting of Alzheimer's disease, Huntington's chorea, multiple sclerosis, amyotrophic lateral sclerosis, Creutzfeld-Jakob's disease, Parkinson's disease, encephalopathies induced by AIDS or infection by rubella viruses, herpes viruses, borrelia or unknown pathogens, trauma-induced neurodegenerations, neuronal byperexcitarion states such as in medicament withdrawal or intoxication and neurodegenerative diseases of the peripheral nervous system such as polyneuropathies and polyneuritides. 20. Use according to Claim. 14 wherein the disorder or disease 10 be treated is selected from the group'consisting of bipolar disorders, 21, Use accordine to Claim 14 wherein the disorder or disease to be treated is selected from the group consisting of sleep disorders; such as insomnia |
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3814-CHENP-2007 AMENDED PAGES OF SPECIFICATION 12-05-2014.pdf
3814-CHENP-2007 EXAMINATION REPORT REPLY RECEIVED 12-05-2014.pdf
3814-CHENP-2007 FORM-1 12-05-2014.pdf
3814-CHENP-2007 FORM-3 12-05-2014.pdf
3814-CHENP-2007 FORM-5 12-05-2014.pdf
3814-CHENP-2007 POWER OF ATTORNEY 19-04-2013.pdf
3814-CHENP-2007 AMENDED CLAIMS 12-05-2014.pdf
3814-CHENP-2007 CORRESPONDENCE OTHERS 19-04-2013.pdf
3814-CHENP-2007 CORRESPONDENCE OTHERS 07-08-2014.pdf
3814-CHENP-2007 CORRESPONDENCE OTHERS 25-08-2014.pdf
3814-CHENP-2007 CORRESPONDENCE OTHERS 25-06-2014.pdf
3814-CHENP-2007 EXAMINATION REPORT REPLY RECEIVED 25-04-2014.pdf
3814-CHENP-2007 FORM-13 19-04-2013.pdf
3814-CHENP-2007 FORM-3 25-04-2014.pdf
3814-chenp-2007-correspondnece-others.pdf
3814-chenp-2007-description(complete).pdf
| Patent Number | 262585 | ||||||||||||||||||
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| Indian Patent Application Number | 3814/CHENP/2007 | ||||||||||||||||||
| PG Journal Number | 36/2014 | ||||||||||||||||||
| Publication Date | 05-Sep-2014 | ||||||||||||||||||
| Grant Date | 28-Aug-2014 | ||||||||||||||||||
| Date of Filing | 03-Sep-2007 | ||||||||||||||||||
| Name of Patentee | H. LUNDBECK A/S | ||||||||||||||||||
| Applicant Address | 9, OTTILIAVEJ DK-2500 VALBY-COPENHAGEN | ||||||||||||||||||
Inventors:
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| PCT International Classification Number | C07D 413/04 | ||||||||||||||||||
| PCT International Application Number | PCT/DK06/00123 | ||||||||||||||||||
| PCT International Filing date | 2006-03-02 | ||||||||||||||||||
PCT Conventions:
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