Title of Invention	IMIDAZO [1,2-B]PYRIDAZINES, THEIR PROCESSES OF PREPARATION AND THEIR USE AS GABA RECEPTOR LIGANDS
Abstract	The invention provides novel imidazo[1,2-b]pyridazines of formula (I) and pharmaceutically acceptable salts, polymorphs, hydrates, tautomers, solvates and stereoisomers thereof. Compounds of formula (I) are useful for treating or preventing diseases associated with GABAA receptors modulation, anxiety, epilepsy, sleep disorders including insomnia, and for inducing sedation-hypnosis, anesthesia, sleep and muscle relaxation. The invention also provides synthetic procedures for preparing said compounds and certain intermediates, as well as intermediates themselves.

Title of Invention

IMIDAZO [1,2-B]PYRIDAZINES, THEIR PROCESSES OF PREPARATION AND THEIR USE AS GABA RECEPTOR LIGANDS

Abstract

The invention provides novel imidazo[1,2-b]pyridazines of formula (I) and pharmaceutically acceptable salts, polymorphs, hydrates, tautomers, solvates and stereoisomers thereof. Compounds of formula (I) are useful for treating or preventing diseases associated with GABAA receptors modulation, anxiety, epilepsy, sleep disorders including insomnia, and for inducing sedation-hypnosis, anesthesia, sleep and muscle relaxation. The invention also provides synthetic procedures for preparing said compounds and certain intermediates, as well as intermediates themselves.

Full Text	IMIDAZO[1,2-B]PYRIDAZINES, THEIR PROCESSES OF PREPARATION AND THEIR USE AS GABA RECEPTOR LIGANDS This invention is directed to agents with affinity for GABAA receptor, specifically to imidazo[1,2-b]pyridazine compounds. BACKGROUND OF THE INVENTION GABAA receptor (γ-arninobutyric acidA) is a pentameric protein which forms a membrane ion channel. GABAA receptor is implicated in the regulation of sedation, anxiety, muscle tone, epileptogenic activity and memory functions. These actions are due to defined subunits of GABAA receptor, particularly the α1- and α2-subunits. Sedation is modulated by the α1-subunit. Zolpidem is characterized by a high affinity for the α1-receptors and its sedative and hypnotic action is mediated by these receptors in vivo. Similarly, the hypnotic action of zaleplon is also mediated by the α1-receptors. The anxiolytic action of diazepam is mediated by the enhancement of GABAergic transmission in a population of neurons expressing the α2- receptors. This indicates that the α2-receptors are highly specific targets for the treatment of anxiety. Muscle relaxation in diazepam is mainly mediated by α2-receptors, since these receptors exhibit a highly specific expression in spinal cord. The anticonvulsant effect of diazepam is partly due to α1-receptors. In diazepam, a memory-impairing compound, anterograde amnesia is mediated by α1 -receptors. GABAA receptor and its α1 and α2-subunits have been widely reviewed by H. Möhler et al. (J. Pharmacol. Exp. Ther., 300, 2-8, 2002); H. Möhler et al. (Curr. Opin. Pharmacol., 1, 22-25, 2001); U. Rudolph et al. (Nature, 401, 796- 800, 1999); and D.J. Nutt et al. (Br. J. Psychiatry, 179, 390-396, 2001). Diazepam and other classical benzodiazepines are extensively used as anxiolytic agents, hypnotic agents, anticonvulsants and muscle relaxants. Their side effects include anterograde amnesia, decrease in motor activity and potentiation of ethanol effects. In this context, the compounds of this invention are ligands of α1- and α2- GABAA receptor for their clinical application in sleep disorders, preferably insomnia, anxiety and epilepsy. Insomnia is a highly prevalent disease. Its chronicity affects 10% of the population and 30% when transitory insomnia is computed as well. Insomnia describes the trouble in getting to sleep or staying asleep and is associated with next-day hangover effects such as weariness, lack of energy, low concentration and irritability. The social and health impact of this complaint is important and results in evident socioeconomic repercussions. Pharmacological therapy in the management of insomnia firstly included barbiturates and chloral hydrate, but these drugs elicit numerous known adverse effects, for example, overdose toxicity, metabolic induction, and enhanced dependence and tolerance. In addition, they affect the architecture of sleep by decreasing above all the duration and the number of REM sleep stages. Later, benzodiazepines meant an important therapeutic advance because of their lower toxicity, but they still showed serious problems of dependence, muscle relaxation, amnesia and rebound insomnia following discontinuation of medication. The latest known therapeutic approach has been the introduction of non- benzodiazepine hypnotics, such as pyrrolo[3,4-b]pyrazines (zopiclone), imidazo[1,2-a] pyridines (zolpidem) and, finally, pyrazolo[1,5-a] pyrimidines (zaleplon). Later, two new pyrazolo[1,5-a] pyrimidines, indiplon and ocinaplon, have entered into development, the latter with rather anxiolytic action. All these compounds show a rapid sleep induction and have less next- day hangover effects, lower potential for abuse and lower risk of rebound insomnia than benzodiazepines. The mechanism of action of these compounds is the alosteric activation of GABAA receptor through its binding to benzodiazepine binding site (C. F. P. George, The Lancet, 358, 1623-1626, 2001). While benzodiazepines are unspecific ligands at GABAA receptor binding site, zolpidem and zaleplon show a greater selectivity for α1-subunit. Notwithstanding that, these drugs still affect the architecture of sleep and may induce dependence in long-term treatments. Some N-imidazo[1,2-b]pyridazin-3-yl-methyl-alkanamides and N-imidazo[1,2- b]pyridazin-3-yl-methyl-benzamides, wherein the phenyl ring from the benzamide group can be optionally substituted, have been disclosed in WO 89/01333. The compounds of the present invention are structurally related to, but distinct from the compound N,N,6-trimethyl-2-p-tolylimidazo[1,2-a]pyridine-3- acetamide, zolpidem, which is described in US 4,382,938, because of their improved properties as shown in the Detailed Description of the Invention. Research for new active compounds in the management of insomnia answers an underlying health need, because even recently introduced hypnotics still affect the architecture of sleep and may induce dependence in long-term treatments. It is therefore desirable to focus on the development of new hypnotic agents with a lower risk of side effects. SUMMARY OF THE INVENTION The present invention provides new imidazo[1,2-b]pyridazines which are active versus GABAA and, particularly, versus its α1- and α2-subunits. Consequently, the compounds of this invention are useful in the treatment and prevention of all those diseases mediated by GABAA receptor α1- and α2- subunits. Non-limitative examples of such diseases are sleep disorders, preferably insomnia, anxiety and epilepsy. Non-limitative examples of the relevant indications of the compounds of this invention are all those diseases or conditions, such as insomnia or anesthesia, in which an induction of sleep, an induction of sedation or an induction of muscle relaxation are needed. Thus, the present invention describes a novel class of compounds represented by formula (I): and pharmaceutically acceptable salts, polymorphs, hydrates, tautomers, solvates and stereoisomers thereof, wherein R1 to R4, and Y are defined below, which are ligands of GABAA receptor. It is another object of this invention to provide synthetic procedures for preparing the compounds of formula (I), certain intermediates thereof, as well as intermediates themselves. Novel methods of treating or preventing diseases associated with GABAA receptors modulation such as anxiety, epilepsy and sleep disorders including insomnia, and for inducing sedation- hypnosis, anesthesia, sleep and muscle relaxation by administering a therapeutically effective amount of said compounds are also within the scope of the invention. DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel imidazo[1,2-b]pyridazine compound of formula (I): wherein R1 and R2 are independently selected from the group consisting of hydrogen, linear or branched alkyl(C1-C6), alkenyl(C2-C6), alkynyl(C2-C6), cycloalkyl(C3- C6), haloalkyl(C2-C6), hydroxy, -O-alkyl(C1-C6), phenoxy, -S-alkyl(C1-C6), phenylthio, halogen, nitro, cyano, amino, alkylamino(C1-C6), dialkylamino(C1- C6), pyrrolidinyl, morpholinyl, piperidinyl, N-alkyl(C1-C6)piperazinyl, phenyl optionally substituted by 1 to 5 Z groups and heteroaryl optionally substituted by 1 to 5 Z groups;R3 and R4 are independently selected from the group consisting of hydrogen, linear or branched alkyl(C1-C6), alkenyl(C2-C6), alkynyl(C2-C6), cycloalkyl(C3-C6), hydroxyalkyl(C1-C6), amino, -NH-alkyl(d- C6), -N-dialkyl(C1-C6), pyrrolidinyl, morpholinyl, piperidinyl, -N-alkyl(C1- C6)piperazinyl, -N-acyl(C1-C6)piperazinyl, phenyl optionally substituted by 1 to 5 Z groups and heteroaryl optionally substituted by 1 to 5 Z groups, or both R3 and R4 can form, together with the nitrogen atom to which they are attached, a 5-6 membered heterocyclic ring optionally substituted by 1 to 5 Z groups, with the proviso that R3 and R4 may not be simultaneously hydrogen; X is selected from CO and SO2; Z is selected from the group consisting of linear or branched alkyl(C1-C6), alkenyl(C2-C6), alkynyl(C2-C6), cycloalkyl(C3-C6), haloalkyl(C2-C6), hydroxy, - O-alkyl(C1-C6), phenoxy, -S-alkyl(C1-C6), phenylthio, halogen, nitro, cyano, amino, alkylamino(C1-C6) and dialkylamino(C1-C6); and pharmaceutically acceptable salts, polymorphs, hydrates, tautomers, solvates and stereoisomers thereof. Preferably R1 is selected from methyl, chlorine, methoxy, ethoxy, phenylthio or 1-pyrrolidinyl group and R2 is a phenyl group or a phenyl group substituted in para- position by methyl, halogen, methoxy, nitro or trifluoromethyl. Preferably, X is CO; R3 is selected from the group consisting of hydrogen, linear alkyl(C1-C6), phenyl optionally substituted by 1 to 5 Z groups, heteroaryl optionally substituted by 1 to 5 Z groups, amino, -NH-alkyl(C1-C6), -N- dialkyl(C1-C6), 1-pyrrolidinyl, 4-morpholinyl and 1-piperidinyl; and R4 is selected from the group consisting of hydrogen, linear alkyl(C1-C6), phenyl optionally substituted by 1 to 5 Z groups and heteroaryl optionally substituted by 1 to 5 Z groups; or both R3 and R4 can form, together with the nitrogen atom to which they are attached, a 5-6 membered heterocyclic ring optionally substituted by 1 to 5 Z groups; and Z is selected from the group consisting of methyl and methoxy. The term "pharmaceutically acceptable salt" used herein encompasses any salt formed from organic and inorganic acids, such as hydrobromic, hydrochloric, phosphoric, nitric, sulfuric, acetic, adipic, aspartic, benzenesulfonic, benzoic, citric, ethanesulfonic, formic, fumaric, glutamic, lactic, maleic, malic, malonic, mandelic, methanesulfonic, 1,5- naphthalendisulfonic, oxalic, pivalic, propionic, p-toluenesulfonic, succinic, tartaric acids and the like. Preferred compounds of formula (I) include: 2-(6-Chloro-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-N,N-diethyl-acetamide; 2-(6-Chloro-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-N,N-dipropyl-acetamide; N,N-Dibutyl-2-(6-chloro-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-acetamide; 2-(6-Chloro-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-1 -piperidin-1 -yl-ethanone; 2-(6-Chloro-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-1-morpholin-4-yl-ethanone; 2-(6-Chloro-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-1 -pyrrolidin-1 -yl-ethanone; N,N-Diethyl-2-(6-pyrrolidin-1-yl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)- acetamide; N,N-Diethyl-2-(6-methoxy-2-p-tolyl-imidazo[1,2-b]pyridazin-3yl)-acetamide; 2-[2-(4-Bromo-phenyl)-6-ethoxy-imidazo[1,2-b]pyridazin-3-yl]-1-morpholin-4- yl-ethanone; 2-[2-(4-Bromo-phenyl)-6-ethoxy-imidazo[1,2-b]pyridazin-3-yl]-1 -piperidin-1 -yl- ethanone; 2-[2-(4-Bromo-phenyl)-6-ethoxy-imidazo[1,2-b]pyridazin-3-yl]-N,N-dibutyl- acetamide; 2-[2-(4-Bromo-phenyl)-6-ethoxy-imidazo[1J2-b]pyridazin-3-yl]-N,N-dipropyl- acetamide; 2-[2-(4-Bromo-phenyl)-6-ethoxy-imidazo[1,2-b]pyridazin-3-yl]-N,N-diethyl- acetamide; 2-[2-(4-Bromo-phenyl)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]-1-morpholin-4- yl-ethanone; 2-[2-(4-Bromo-phenyl)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]-1 -piperidin-1 -yl- ethanone; 2-[2-(4-Bromo-phenyl)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]-N,N-dibutyl- acetamide; 2-[2-(4-Bromo-phenyl)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]-N,N-dipropyl- acetamide; 2-[2-(4-Bromo-phenyl)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]-N,N-diethyl- acetamide; 2-[2-(4-Chloro-phenyl)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]-N,N-diethyl- acetamide; 2-[2-(4-Chloro-phenyl)-6-ethoxy-imidazo[1,2-b]pyridazin-3-yl]-N,N-diethyl- acetamide; 2-[2-(4-Chloro-phenyl)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]-N,N-dipropyl- acetamide; N,N-Dibutyl-2-[2-(4-chloro-phenyl)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]- acetamide; 2-[2-(4-Chloro-phenyl)-6-ethoxy-imidazo[1,2-b]pyridazin-3-yl]-N,N-dipropyl- acetamide; N,N-Dibutyl-2-[2-(4-chloro-phenyl)-6-ethoxy-imidazo[1,2-b]pyridazin-3-yl]- acetamide; N,N-Diethyl-2-(6-methoxy-2-phenyl-imidazo[1,2-b]pyridazin-3-yl)-acetamide; 2-(6-Methoxy-2-phenyl-imidazo[1,2-b]pyridazin-3-yl)-N,N-dipropyl-acetamide; N,N-Dibutyl-2-(6-methoxy-2-phenyl-imidazo[1,2-b]pyridazin-3-yl)-acetamide; 2-(6-Methoxy-2-phenyl-imidazo[1,2-b]pyridazin-3-yl)-1-morpholin-4-yl- ethanone; 2-(6-Ethoxy-2-phenyl-imidazo[1,2-b]pyridazin-3-yl)-N,N-diethyl-acetamide; 2-(6-Ethoxy-2-phenyl-imidazo[1,2-b]pyridazin-3-yl)-N,N-dipropyl-acetamide; N,N-Dibutyl-2-(6-ethoxy-2-phenyl-imidazo[1,2-b]pyridazin-3-yl)-acetamide; 2-(6-Ethoxy-2-phenyl-imidazo[1,2-b]pyridazin-3-yl)-1-morpholin-4-yl- ethanone; 2-(6-Ethoxy-2-phenyl-imidazo[1,2-b]pyridazin-3-yl)-1-piperidin-1-yl-ethanone; N,N-Diethyl-2-(6-methyl-2-phenyl-imidazo[1,2-b]pyridazin-3-yl)-acetamide; 2-(6-Methyl-2-phenyl-imidazo[1,2-b]pyridazin-3-yl)-N,N-dipropyl-acetamide; N,N-Dibutyl-2-(6-methyl-2-phenyl-imidazo[1,2-b]pyridazin-3-yl)-acetamide; 2-(6-Methyl-2-phenyl-imidazo[1,2-b]pyridazin-3-yl)-1-morpholin-4-yl- ethanone; 2-(6-Methyl-2-phenyl-imidazo[1,2-b]pyridazin-3-yl)-1-piperidin-1-yl-ethanone; 2-[2-(4-Fluoro-phenyl)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]-N,N-dipropyl- acetamide; N,N-Dibutyl-2-[2-(4-fluoro-phenyl)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]- acetamide; 2-[2-(4-Fluoro-phenyl)-6-methoxy-imidazo[1,2-b]pyridazin-3-yl]-N,N-dipropyl- acetamide; N,N-Dibutyl-2-[2-(4-fluoro-phenyl)-6-methoxy-imidazo[1,2-b]pyridazin-3-yl]- acetamide; 2-[6-Ethoxy-2-(4-fluoro-phenyl)-imidazo[1,2-b]pyridazin-3-yl]-N,N-dipropyl- acetamide; N,N-Dibutyl-2-[6-ethoxy-2-(4-fluoro-phenyl)-imidazo[1,2-b]pyridazin-3-yl]- acetamide; 2-[6-Ethoxy-2-(4-fluoro-phenyl)-imidazo[1,2-b]pyridazin-3-yl]-1-morpholin-4- yl-ethanone; N,N-Diethyl-2-(6-methoxy-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-acetamide; 2-(6-Methoxy-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-N,N-dipropyl-acetamide; N,N-Dibutyl-2-(6-methoxy-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-acetamide; 2-(6-Methoxy-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-1-piperidin-1-yl- ethanone; 2-(6-Ethoxy-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-N,N-diethyl-acetamide; 2-(6-Ethoxy-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-N,N-dipropyl-acetamide; N,N-Dibutyl-2-(6-ethoxy-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-acetamide; 2-(6-Ethoxy-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-1 -pyrrolidin-1 -yl-ethanone; 2-(6-Ethoxy-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-1-morpholin-4-yl-ethanone; 2-(6-Ethoxy-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-1 -piperidin-1 -yl-ethanone; N,N-Diethyl-2-(6-methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-acetamide; 2-(6-Methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-N,N-dipropyl-acetamide; N,N-Dibutyl-2-(6-methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-acetamide; 2-(6-Methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-1 -pyrrolidin-1 -yl-ethanone; 2-(6-Methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-1-morpholin-4-yl-ethanone; 2-(6-Methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-1 -piperidin-1 -yl-ethanone; N,N-Diethyl-2-[2-(4-fluoro-phenyl)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]- acetamide; 2-[2-(4-Fluoro-phenyl)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]-1 -piperidin-1 -yl- ethanone; N,N-Diethyl-2-[2-(4-fluoro-phenyl)-6-methoxy-imidazo[1,2-b]pyridazin-3-yl]- acetamide; 2-[2-(4-Fluoro-phenyl)-6-methoxy-imidazo[1,2-b]pyridazin-3-yl]-1 -piperidin-1 - yl-ethanone; 2-[6-Ethoxy-2-(4-fluoro-phenyl)-imidazo[1,2-b]pyridazin-3-yl]-N,N-diethyl- acetamide; 2-[6-Ethoxy-2-(4-fluoro-phenyl)-imidazo[1,2-b]pyridazin-3-yl]-1 -piperidin-1 -yl- ethanone; 2-[2-(4-Fluoro-phenyl)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]-1-morpholin-4- yl-ethanone; 2-[2-(4-Fluoro-phenyl)-6-methoxy-imidazo[1,2-b]pyridazin-3-yl]-1-morpholin-4- yl-ethanone; N,N-Diethyl-2-[2-(4-methoxy-phenyl)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]- acetamide; 2-[2-(4-Methoxy-phenyl)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]-N,N-dipropyl- acetamide; N,N-Dibutyl-2-[2-(4-methoxy-phenyl)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]- acetamide; 2-[2-(4-Methoxy-phenyl)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]-1 -piperidin-1 - yl-ethanone; 2-[2-(4-Methoxy-phenyl)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]-1-morpholin- 4-yl-ethanone; N,N-Diethyl-2-[6-methoxy-2-(4-methoxy-phenyl)-imidazo[1,2-b]pyridazin-3-yl]- acetamide; 2-[6-Methoxy-2-(4-methoxy-phenyl)-imidazo[1,2-b]pyridazin-3-yl]-N,N- dipropyl-acetamide; N,N-Dibutyl-2-[6-methoxy-2-(4-methoxy-phenyl)-imidazo[1,2-b]pyridazin-3-yl]- acetamide; 2-[6-Methoxy-2-(4-methoxy-phenyl)-imidazo[1,2-b]pyridazin-3-yl]-1-piperidin- 1-yl-ethanone; 2-[6-Methoxy-2-(4-methoxy-phenyl)-imidazo[1,2-b]pyridazin-3-yl]-1-morpholin- 4-yl-ethanone; Acetic acid 2-{[2-(6-methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-acetyl]- propyl-amino}-ethyl ester; 1 -(3,5-Dimethyl-piperidin-1 -yl)-2-(6-methyl-2-p-tolyl-imidazo[1,2-b]pyridazin- 3-yl)-ethanone; N-Cyclopropylmethyl-2-(6-methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-N- propyl-acetamide; 2-(6-Methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-N-thiazol-2-yl-acetamide; N,N-Diisopropyl-2-(6-methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)- acetamide; N-Cyclohexyl-2-(6-methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-acetamide; 2-(6-Methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-N-phenyl-acetamide; 2-(6-Methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-N-p-tolyl-acetamide; 2-(6-Methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-N-pyridin-2-yl-acetamide; 2-(6-Methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-N-pyridin-2-ylmethyl- acetamide; N-(3,5-Dimethyl-isoxazol-4-yl)-2-(6-methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3- yl)-acetamide; N-Cyclopentyl-2-(6-methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-acetamide; N,N-Diallyl-2-(6-methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-acetamide; N-Cyclopropyl-2-(6-methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-acetamide; 2-(6-Methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-N-quinolin-2-yl-acetamide; N-(5-Methyl-isoxazol-3-yl)-2-(6-methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)- acetamide; N-(4-Methoxy-phenyl)-2-(6-methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)- acetamide; N-(3-Methyl-isoxazol-5-yl)-2-(6-methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)- acetamide; 2-(6-Methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-N-[1,3,4]thiadiazol-2-yl- acetamide; [2-(4-Fluoro-phenyl)-6-pyrrolidin-1 -yl-imidazo[1,2-b]pyridazin-3-yl]-acetic acid hydrazide; [2-(4-Bromo-phenyl)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]-acetic acid hydrazide; [2-(4-Methoxy-phenyl)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]-acetic acid hydrazide; [2-(4-Chloro-phenyl)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]-acetic acid hydrazide; [2-(4-Fluoro-phenyl)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]-acetic acid hydrazide; (6-Methyl-2-phenyl-imidazo[1,2-b]pyridazin-3-yl)-acetic acid hydrazide; 2-(6-Methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-N-morpholin-4-yl- acetamide; 2-(6-Methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-N-piperidin-1-yl-acetamide; and (6-Methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-acetic acid N',N'-dimethyl- hydrazide. Another aspect of the present invention is to provide a process for preparing compounds of formula (I) as well as an imidazo[1,2-b]pyridazine intermediate of formula (II): wherein R is methyl, R1 is a methyl, chlorine, methoxy, ethoxy, thiophenoxy or 1-pyrrolidinyl group and R2 is a phenyl group or a phenyl group substituted in para- position by methyl, halogen, methoxy, nitro or trifluoromethyl. The compounds of general formula (I), when X is CO, can be obtained following the synthetic strategy showed in Scheme 1. Starting from ketoacids (III), ketoamides (IV) can be obtained by using conventional coupling conditions. These ketoamides (IV) can be brominated in a-position of the reacting carbonyl group with bromine in acetic acid, to yield the bromoketoamides (V). Finally, cyclization of aminopyridazines (VI) in acetonitrile at reflux affords the imidazopyridazines (I, X = CO). On the other hand, if R3 or R4 are optionally substituted amino groups, then the molecule obtained is not an amide but an hydrazide. The synthetic pathway has to be slightly modified for that proposal (Scheme 2). A Fischer esterification of the same ketoacid (III) is carried out with an alcohol ROH to afford the corresponding ester (VII). This ester is brominated under similar conditions as the amide (IV) described above, to yield bromoketoesters (VIII). A cyclization with aminopyridazines (VI) allows the preparation of the imidazopyridazines (II) substituted with an ester group. Finally, acylic substitution by using a substituted hydrazine in a suitable solvent at reflux provides the corresponding hydrazides (I, X = CO, R3 or R4 are optionally substituted amino groups). Suitable solvents to be used in this reaction are selected preferably from linear or branched alkanols (C1-C6), more preferably methanol, or mixtures thereof. The compounds of the present invention or their pharmaceutically acceptable salts, polymorphs, hydrates, tautomers, solvates and stereoisomers can be used for the preparation of a medicament for treating or preventing diseases associated with GABAA receptor modulation in a human or non-human mammal. More specifically, diseases associated with GABAA receptor modulation comprise diseases associated with Α1-GABAA receptor modulation and/or Α2-GABAA receptor modulation. It is well-known for the skill in the art which diseases associated with GABAA receptor modulation are (cf. Kaufmann W. A. et al., "Compartmentation of alpha 1 and alpha 2 GABAA receptor subunits within rat extended amygdala: implications for benzodiazepine action", Science 2003, vol. 964 p. 91-99; Mohler H. et al., "GABAA -receptor subtypes: a new pharmacology", Current Opinion in Pharmacology 2001, vol. 1:22-25). A non-limitative list of such diseases comprises anxiety, epilepsy, sleep disorders, including insomnia, and the like. Another embodiment of the present invention is to provide the use of a compound of formula (I) or a pharmaceutically acceptable salt, polymorph, hydrate, tautomer, solvate and stereoisomer thereof for the preparation of a medicament for treating or preventing anxiety in a human or non-human mammal. Another embodiment of the present invention is to provide the use of a compound of formula (I) or a pharmaceutically acceptable salt, polymorph, hydrate, tautomer, solvate or stereoisomers thereof for the preparation of a medicament for treating or preventing epilepsy in a human or non-human mammal in need thereof. Another embodiment of the present invention is to provide the use of a compound of formula (I) or a pharmaceutically acceptable salt, polymorph, hydrate, tautomer, solvate or stereoisomer thereof for the preparation of a medicament for treating or preventing sleep disorders in a human or non- human mammal in need thereof. Another embodiment of the present invention is to provide the use of a compound of formula (I) or a pharmaceutically acceptable salt, polymorph, hydrate, tautomer, solvate or stereoisomer thereof for the preparation of a medicament for treating or preventing insomnia in a human or non-human mammal in need thereof. Another embodiment of the present invention is to provide the use of a compound of formula (I) or a pharmaceutically acceptable salt, polymorph, hydrate, tautomer, solvate or stereoisomer thereof for the preparation of a medicament for inducing sedation-hypnosis in a human or non-human mammal in need thereof. Another embodiment of the present invention is to provide the use of a compound of formula (I) or a pharmaceutically acceptable salt, polymorph, hydrate, tautomer, solvate or stereoisomer thereof for the preparation of a medicament for inducing anesthesia in a human or non-human mammal in need thereof. Another embodiment of the present invention is to provide the use of a compound of formula (I) or a pharmaceutically acceptable salt, polymorph, hydrate, tautomer, solvate or stereoisomer thereof for the preparation of a medicament for modulating the necessary time to induce sleep and its duration in a human or non-human mammal in need thereof. Another embodiment of the present invention is to provide the use of a compound of formula (I) or a pharmaceutically acceptable salt, polymorph, hydrate, tautomer, solvate or stereoisomer thereof for the preparation of a medicament for inducing muscle relaxation in a human or non-human mammal in need thereof. The present invention also relates to a method of treatment or prevention of a human or non-human mammal suffering from diseases associated with GABAA receptor modulation in a human or non-human mammal, which comprises administering to said human or non-human mammal in need thereof a therapeutically effective amount of a compound of formula (I) or pharmaceutically acceptable salts, polymorphs, hydrates, tautomers, solvates and stereoisomers thereof, together with pharmaceutically acceptable diluents or carriers. More specifically, diseases associated with GABAA receptor modulation comprise diseases associated with α1-GABAA receptor modulation and/or α2-GABAA receptor modulation. A non-limitative list of such diseases comprises anxiety, epilepsy, sleep disorders, including insomnia, and the like. As used herein, the term "mammal" shall refer to the Mammalian class of higher vertebrates. The term "mammal" includes, but is not limited to, a human. Another embodiment of the present invention is to provide a pharmaceutical composition containing a compound of formula (I) or pharmaceutically acceptable salts, polymorphs, hydrates, tautomers, solvates and stereoisomers thereof, in association with therapeutically inert carriers. The compositions include those suitable for oral, rectal and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route will depend on the nature and severity of the condition being treated. The most preferred route of the present invention is the oral route. The compositions may be conveniently presented in unit dosage form, and prepared by any of the methods well known in the art of pharmacy. The active compound can be combined with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of the preparation desired for administration, e.g. oral or parenteral (including intravenous injections or infusions). In preparing the compositions for oral dosage form any of the usual pharmaceutical media may be employed. Usual pharmaceutical media include, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like in the case of oral liquid preparations (such as for example, suspensions, solutions, emulsions and elixirs); aerosols; or carriers such as starches, sugars, micro- crystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like, in the case of oral solid preparations (such as for example, powders, capsules, and tablets) with the oral solid prepa- rations being preferred over the oral liquid preparations. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are employed. If desired, tablets may be coated by standard aqueous or non-aqueous techniques. A suitable dosage range for use is from about 0.01 mg to about 100.00 mg total daily dose, given as a once daily administration or in divided doses if required. The compounds of the present invention have a high affinity for α1- and α2- GABAA receptors. These in vitro results are consistent with those in vivo results obtained in sedation-hypnosis tests. In accordance with the results obtained, certain compounds of the present invention have evidenced pharmacological activity both in vitro and in vivo, which has been similar to or higher than that of prior-art compound zolpidem. All these results support their use in diseases or conditions modulated by α1- and α2-GABAA receptors, such as insomnia or anesthesia, in which an induction of sleep, an induction of sedation or an induction of muscle relaxation are needed. The pharmacological activity of the compounds of the present invention has been determined as shown below. a) Ligand-binding assays. Determination of the affinity of test compounds for α1- and α2-GABAA receptor Male Sprague-Dawley rats weighing 200-250 g at the time of experiment were used. After decapitation of the animal, the cerebellum (tissue that mostly contains Α1-GABAA receptor) and spinal cord (tissue that mostly contains α2- GABAA receptor) were removed. The membranes were prepared according to the method by J. Lameh et al. (Prog. Neuro-Psychopharmacol. Biol. Psychiatry, 24, 979-991, 2000) and H. Noguchi et al. (Eur J Pharm, 434, 21- 28, 2002) with slight modifications. Once the tissues weighed, they were suspended in 50 mM TrisHCI (pH 7.4), 1:40 (v/v), or sucrose 0.32 M in the case of spinal cord, homogenized and then centrifuged at 20000 g for 10 minutes at 7°C. The resulting pellet was resuspended under the same conditions and centrifuged again. The pellet was finally resuspended on a minimum volume and kept at -80°C overnight. A slight modification was used in the case of spinal cord at the first centrifugation step. Centrifugation speed was at 1000g and the supernatant was collected instead of discarded as in cerebellum. Then, supernatant was centrifuged at 20000g and resuspended twice more under the same conditions described above for cerebellum. On the next day, the process was repeated until the final pellet was resuspended at a ratio of 1:10 (v/v)in the case of cerebellum and at a ratio of 1:5 (v/v) in the case of spinal cord. Affinity was determined by competitive tests using radiolabeled flumazenil as ligand. The tests were performed according to the methods described by S. Arbilla et al. (Eur. J. Pharmacol., 130, 257-263, 1986); and Y. Wu et al. (Eur. J. Pharmacol., 278, 125-132, 1995) using 96-well microtiter plates. The membranes containing the study receptors, flumazenil (radiolabeling at a final concentration of 1 nM) and ascending concentrations of test compounds (in a total volume of 230 µl in 50 mM [pH 7.4] TrisHCI buffer) were incubated. Simultaneously, the membranes were only incubated with the radiolabeled flumazenil (total binding, 100%) and in the presence of an elevated concentration of unradiolabeled flumazenil (non-specific binding, % estimation of radiolabeled ligand). The reactions started on adding the radiolabeled ligand followed by incubation for 60 minutes at 4°C. At the end of the incubation period, 200 µl of reaction were transferred to a multiscreen plate (Millipore) and filtered using a vacuum manifold and then washed three times with cold test buffer. The multiscreen plates were equipped with a GF/B filter that retained the membranes containing the receptors and the radiolabeled ligand which had been bound to the receptors. After washing, the plates were left till dry. Once dried, scintillation liquid was added and left under stirring overnight. The next day the plates were counted using a Perkin- Elmer Microbeta scintillation counter. For analysis of the results the percentage of specific binding for every concentration of test compound was calculated as follows: where, X: amount of bound ligand for every concentration of compound. T: total binding, maximum amount bound to the radiolabeled ligand. N: non-specific binding, amount of radiolabeled ligand bound in a non- specific way irrespective of the receptor used. Every concentrations of compound were tested in triplicate and their mean values were used to determine the experimental values of % specific binding versus the concentration of compound. Affinity data are expressed as % inhibition at 10-5M and 10-7M concentrations. The results of these tests are given in Tables 1 and 2. b) In vivo determination of predictive sedative-hypnotic action The in vivo effects of these compounds were assessed by a predictive sedation-hypnosis test in mice (D. J. Sanger et al., Eur. J. Pharmacol., 313, 35-42, 1996; and G. Griebel et al., Psychopharmacology, 146, 205-213, 1999). Groups of 5-8 male CD1 mice, weighing 22-26 g at the time of test, were used. The test compounds were administered at 98.0 µmol/kg by mean of intraperitoneal injection. Compounds were suspended in 0.25% agar with one drop of Tween in a volume of 10 mL/kg. Control animals were given the vehicle alone. Using a Smart System (Panlab, S.L., Spain) the traveled distance in cm is recorded for each mouse at 5-minutes intervals during a period of 30 minutes after dosing. The inhibition percentage of traveled distance of treated animals versus control animals (the first 5 minutes were discarded) was calculated. Some compounds were also tested in a lower dose - 0.98 µmol/kg - to further discriminate the potency of sedation induction. The results of this test are given in Table 3 and Table 4. c) In vivo determination of predictive anesthetic activity The in vivo effects of these compounds were assessed by a predictive anesthetic test in mice as the loss of righting reflex (Kralic et al., Neuropharmacology, 43(4), 685-689 2002; Belelli et al., Neuropharmacology, 45,57-71,2003). Groups of 5-8 male CD1 mice, weighing 22-26 g at the time of test, were used. The test compounds were administered at 98.0 µmol/kg by mean of intraperitoneal injection. Compounds were suspended in 0.25% agar with one drop of Tween in a volume of 10 mL/kg. Percentage of treated mice which showed loss of righting reflex was calculated. Interestingly, compounds of examples 2, 3, and 82 exhibited a 90%, 100% and 30% of animals with loss of righting reflex respectively. On the contrary, zolpidem, the prior art compound, exhibited lower anesthetic potential, being necessary to administer double dose than compounds of the present invention to achieve 80% of animals with loss of righting reflex. d) Comparative assay In order to show that the compounds of the present invention are better than other known in the state of the art, particularly those described in the PCT application WO 89/01333, the IC50 value for compounds 22, 26, 88, 95, 96, 97 and 98 were calculated and compared to the structurally closest compounds described in said PCT application, i.e., compounds 317 and 318. All these compounds have in common that at 3-position, the imidazo[1,2-b]pyradizine ring have an acetamide. The rest of compounds disclosed in WO89/01333 are not structurally so related with the compounds of the present invention. The IC50 values were estimated from Cheng-Prusoff equation (Cheng Y.C. and Prusoff W.H.; Biochem. Pharmacol. 22, 3099-3108, 1973) where, Ki is determined for each one of the compounds of the invention as described above (section (a)). [RL*]: radiolabeled ligand concentration (1 nM). Kd: affinity constant (cerebellum 1.34nM/ spinal cord 1.19nM) Table 5 shows the IC50 values obtained for the compounds of the present invention and includes the IC50 values for compounds 317 and 318 of the PCT application WO89/01333: As it is derived from the results obtained, the compounds of the present invention have IC50 values lower than the IC50 values of WO89/01333, which means that a lower dose of the compounds of the present invention are needed in order to achieve the same therapeutic effect. The following non-limiting examples illustrate the scope of the present invention. Example A: General method for the preparation of amides (IV) To a solution of the acid (III) (1 eq) in dichloromethane was added a solution of water-soluble carbodiimide (1.5 eq) in dichloromethane. The mixture was stirred at room temperature for 30 minutes. After this period, a solution of 0.5 eq of 4-dimethylamino-pyridine and 1.5 eq of the corresponding amine in dichloromethane was added, and the mixture was stirred for 6 h. The crude was washed with HCl 1 N, the organic layer was dried over Na2SO4 and filtered off, and the solvent was removed in vacuo, to afford the ketoamide (IV). E.g. for 1H NMR (400 MHz, DMSO-d6): δ 7.80-7.15 (m, 4H, Ar), 3.30 (t, 4H, CH2N), 2.87 (t, 2H, CH2CO), 2.47 (t, 2H, H2CON), 1.58-0.93 (m, 14H, CH2CH2CH3). MS (ES) m/z = 308 (MH+) HPLC=100% Yield = 80% Example B: General method for the preparation of bromoamides (V, X = CO) To a solution of (IV) (1 eq) in acetic acid was added dropwise a solution of bromine (2.2 eq) in acetic acid. The mixture was stirred at room temperature for 24 h. The solvent was removed in vacuo and the residue was extracted with dichloromethane / NaOH 1 N and with dichloromethane / water. The organic layer was dried over Na2SO4 and filtered off, and the solvent was removed in vacuo, thus affording the bromoketoamide (V). E.g. for 1H NMR (400 MHz, DMSO-d6): δ 7.97-7.23 (m, 4H, Ar), 5.20 (t, 2H, CHBr), 3.24 (t, 4H, CH2N), 2.87 (d, 2H, CH2CON), 1.75-0.76 (m, 14H, CH2CH2CH3). MS (ES) m/z = 380 (M), 382 (M+2H) HPLC = 95% Yield = 34% Example C: General method for the preparation of imidazopyridazines (I, X = CO) To a solution of (V) (1 eq) in acetonitrile was added a solution of (VI) (1.2 eq) in acetonitrile. The mixture was stirred at reflux for 2 h. The solvent was removed in vacuo and the residue was extracted with dichloromethane / HCl 1 N and with DCM / water. The organic layer was dried over Na2SO4 and filtered off, and the solvent was removed in vacuo, thus affording the imidazopyridazine (I). 1H NMR (400 MHz, DMSO-d6): δ 7.30-7.03 (m, 6H, Ar), 3.48 (s, 2H, CH2), 2.32 (s, 3H, CH3), 3.21-0.96 (m, 18H, CH2CH2CH2CH3). MS (ES) m/z = 397 (MH+) HPLC = 89% Yield = 60% Compounds 1-98 were prepared following this methodology. Example D: General method for the preparation of ketoesters (VII) To a solution of (III) (1 eq) in methanol (ROH, R = CH3) was added dropwise a solution of concentrated H2SO4 (0.5 eq) in methanol. The mixture was stirred at reflux for 30 minutes. The solvent was removed in vacuo and the residue was extracted with dichloromethane / NaOH 1 N and with dichloromethane / water. The organic layer was dried over Na2SO4 and filtered off, and the solvent was removed in vacuo, thus affording the ketoester (VIII). 1H NMR (400 MHz, DMSO-d6): δ 7.89-6.88 (m, 4H, Ar), 3.75 (s, 3H, OCH3), 3.77 (s, 3H, OCH3), 2.65 (t, 2H, CH2CO), 2.25 (t, 2H, CH2COO). MS (ES) m/z = 223 (MH+) HPLC = 95% Yield = 93% Example E: General method for the preparation of bromoketoesters (VIII) To a solution of (VII) (1 eq) in acetic acid was added dropwise a solution of bromine (2.2 eq) in acetic acid. The mixture was stirred at room temperature for 24 h. The solvent was removed in vacuo and the residue was extracted with dichloromethane / NaOH 1 N and with dichloromethane / water. The organic layer was dried over Na2SO4 and filtered off, and the solvent was removed in vacuo, thus affording the bromoketoester (VIII). 1H NMR (400 MHz, DMSO-d6): δ 7.98-6.82 (m, 4H, Ar), 5.38 (t, 1H, CHBr), 3.98 (s, 3H, OCH3), 3.54 (s, 3H, OCH3), 2.75 (t, 2H, CH2COO). MS (ES) m/z = 301 (M), 303 (M+2H) HPLC = 95% Yield = 35% Example F: General method for the preparation of imidazopyridazines (II) To a solution of (VIII) (1 eq) in acetonitrile was added a solution of (VI) (1.2 eq) in acetonitrile. The mixture was stirred at reflux for 2 h. The solvent was removed in vacuo and the residue was extracted with dichloromethane / HCl 1 N and with dichloromethane / water. The organic layer was dried over Na2SO4 and filtered off, and the solvent was removed in vacuo, thus affording the imidazopyridazine (II). 1H NMR (400 MHz, DMSO-d6): δ 7.69-6.79 (m, 6H, Ar), 3.75 (s, 3H, OCH3), 3.67 (s, 3H, OCH3), 3.35 (s, 2H, CH2), 2.17 (s, 3H, CH3). MS (ES) m/z = 312 (MH+) HPLC = 90% Yield = 60% Example G: General method for the preparation of imidazopyridazines (I, X = CO, R3 or R4 are substitued amino groups) To a solution of (II) (1 eq) in methanol was added a solution of (substituted) hydrazine (5 eq) in methanol. The mixture was stirred at reflux for 24 h. The solvent was removed in vacuo and the residue was extracted with dichloromethane / HCl 1 N and with dichloromethane / water. The organic layer was dried over Na2SO4 and filtered off, and the solvent was removed in vacuo, thus affording the imidazopyridazine (I). 1H NMR (400 MHz, DMSO-d6): δ 8.00(bs, 1H, NH), 7.50-6.93 (m, 6H, Ar), 3.78 (s, 3H, OCH3), 3.96 (s, 3H, OCH3), 3.28 (s, 2K CH2), 2.12 (bs, 2H, NH2). MS(ES)m/z = 312(MH+) HPLC = 93% Yield = 65% Compounds 99-107 were prepared following this methodology. CLAIMS 1. An imidazo[1,2-b]pyridazine compound of formula (I) wherein R1 and R2 are independently selected from the group consisting of hydrogen, linear or branched alkyl(C1-C6), alkenyl(C2-C6), alkynyl(C2-C6), cycloalkyl(C3- C6), haloalkyl(C2-C6), hydroxy, -O-alkyl(C1-C6), phenoxy, -S-alkyl(C1-C6), phenylthio, halogen, nitro, cyano, amino, alkylamino(C1-C6), dialkylamino(C1- C6), pyrrolidinyl, morpholinyl, piperidinyl, N-alkyl(C1-C6)piperazinyl, phenyl optionally substituted by 1 to 5 Z groups and heteroaryl optionally substituted by 1 to 5 Z groups; R3 and R4 are independently selected from the group consisting of hydrogen, linear or branched alkyl(C1-C6), alkenyl(C2-C6), alkynyl(C2-C6), cycloalkyl(C3- C6), hydroxyalkyl(C1-C6), amino, -NH-alkyl(C1-C6), -N-dialkyl(C1-C6), pyrrolidinyl, morpholinyl, piperidinyl, -N-alkyl(C1-C6)piperazinyl, -N-acyl(C1- C6)piperazinyl, phenyl optionally substituted by 1 to 5 Z groups and heteroaryl optionally substituted by 1 to 5 Z groups, or both R3 and R4 can form, together with the nitrogen atom to which they are attached, a 5-6 membered heterocyclic ring optionally substituted by 1 to 5 Z groups, with the proviso that R3 and R4 are not simultaneously hydrogen; X is selected from CO and SO2; Z is selected from the group consisting of linear or branched alkyl(C1-C6), alkenyl(C2-C6), alkynyl(C2-C6), cycloalkyl(C3-C6), haloalkyl(C2-C6), hydroxy, - O-alkyl(C1-C6), phenoxy, -S-alkyl(C1-C6), phenylthio, halogen, nitro, cyano, amino, alkylamino(C1-C6) and dialkylamino(C1-C6); and pharmaceutically acceptable salts, polymorphs, hydrates, tautomers, solvates and stereoisomers thereof, 2. The compound according to claim 1, wherein R1 is a methyl, chlorine, methoxy, ethoxy, phenylthio or 1-pyrrolidinyl group and R2 is a phenyl group or a phenyl group substituted in para- position by methyl, halogen, methoxy, nitro or trifluoromethyl. 3. The compound according to any of the preceding claims, wherein X is CO; R3 is is selected from the group consisting of hydrogen, linear alkyl(C1-C6), phenyl optionally substituted by 1 to 5 Z groups, heteroaryl optionally substituted by 1 to 5 Z groups, amino, -NH-alkyl(C1-C6), -N- dialkyl(C1-C6), 1-pyrrolidinyl, 4-morpholinyl and 1-piperidinyl; and R4 is selected from the group consisting of hydrogen, linear alkyl(C1-C6), phenyl optionally substituted by 1 to 5 Z groups and heteroaryl optionally substituted by 1 to 5 Z groups; or both R3 and R4 can form, together with the nitrogen atom to which they are attached, a 5-6 membered heterocyclic ring optionally substituted by 1 to 5 Z groups; and Z is selected from the group consisting of methyl and methoxy. 4. The compound according to any of the preceding claims, wherein said compound is selected from the group consisting of: 2-(6-Chloro-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-N,N-diethyl-acetamide; 2-(6-Chloro-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-N,N-dipropyl-acetamide; N,N-Dibutyl-2-(6-chloro-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-acetamide; 2-(6-Chloro-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-1 -piperidin-1 -yl-ethanone; 2-(6-Chloro-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-1-morpholin-4-yl-ethanone; 2-(6-Chloro-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-1 -pyrrolidin -1 -yl-ethanone; N,N-Diethyl-2-(6-pyrrolidin-1-yl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)- acetamide; N,N-Diethyl-2-(6-methoxy-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-acetamide; 2-[2-(4-Bromo-phenyl)-6-ethoxy-imidazo[1,2-b]pyridazin-3-yl]-1-morpholin-4- yl-ethanone; 2-[2-(4-Bromo-phenyl)-6-ethoxy-imidazo[1,2-b]pyridazin-3-yl]-1 -piperidin-1 -yl- ethanone; 2-[2-(4-Bromo-phenyl)-6-ethoxy-imidazo[1,2-b]pyridazin-3-yl]-N,N-dibutyl- acetamide; 2-[2-(4-Bromo-phenyl)-6-ethoxy-imidazo[1,2-b]pyridazin-3-yl]-N,N-dipropyl- acetamide; 2-[2-(4-Bromo-phenyl)-6-ethoxy-imidazo[1,2-b]pyridazin-3-yl]-N,N-diethyl- acetamide; 2-[2-(4-Bromo-phenyl)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]-1-morpholin-4- yl-ethanone; 2-[2-(4-Bromo-phenyl)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]-1 -piperidin-1 -yl- ethanone; 2-[2-(4-Bromo-phenyl)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]-N,N-dibutyl- acetamide; 2-[2-(4-Bromo-phenyl)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]-N,N-dipropyl- acetamide; 2-[2-(4-Bromo-phenyl)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]-N,N-diethyl- acetamide; 2-[2-(4-Chloro-phenyl)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]-N,N-diethyl- acetamide; 2-[2-(4-Chloro-phenyl)-6-ethoxy-imidazo[1,2-b]pyridazin-3-yl]-N,N-diethyl- acetamide; 2-[2-(4-Chloro-phenyl)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]-N,N-dipropyl- acetamide; N,N-Dibutyl-2-[2-(4-chloro-phenyl)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]- acetamide; 2-[2-(4-Chloro-phenyl)-6-ethoxy-imidazo[1,2-b]pyridazin-3-yl]-N,N-dipropyl- acetamide; N,N-Dibutyl-2-[2-(4-chloro-phenyl)-6-ethoxy-imidazo[1,2-b]pyridazin-3-yl]- acetamide; N,N-Diethyl-2-(6-methoxy-2-phenyl-imidazo[1,2-b]pyridazin-3-yl)-acetamide; 2-(6-Methoxy-2-phenyl-imidazo[1,2-b]pyridazin-3-yl)-N,N-dipropyl-acetamide; N,N-Dibutyl-2-(6-methoxy-2-phenyl-imidazo[1,2-b]pyridazin-3-yl)-acetamide; 2-(6-Methoxy-2-phenyl-imidazo[1,2-b]pyridazin-3-yl)-1-morpholin-4-yl- ethanone; 2-(6-Ethoxy-2-phenyl-imidazo[1,2-b]pyridazin-3-yl)-N,N-diethyl-acetamide; 2-(6-Ethoxy-2-phenyl-imidazo[1,2-b]pyridazin-3-yl)-N,N-dipropyl-acetamide; N,N-Dibutyl-2-(6-ethoxy-2-phenyl-imidazo[1,2-b]pyridazin-3-yl)-acetamide; 2-(6-Ethoxy-2-phenyl-imidazo[1,2-b]pyridazin-3-yl)-1-morpholin-4-yl- ethanone; 2-(6-Ethoxy-2-phenyl-imidazo[1,2-b]pyridazin-3-yl)-1 -piperidin-1 -yl-ethanone; N,N-Diethyl-2-(6-methyl-2-phenyl-imidazo[1,2-b]pyridazin-3-yl)-acetamide; 2-(6-Methyl-2-phenyl-imidazo[1,2-b]pyridazin-3-yl)-N,N-dipropyl-acetamide; N,N-Dibutyl-2-(6-methyl-2-phenyl-imidazo[1,2-b]pyridazin-3-yl)-acetamide; 2-(6-Methyl-2-phenyl-imidazo[1,2-b]pyridazin-3-yl)-1-morpholin-4-yl- ethanone; 2-(6-Methyl-2-phenyl-imidazo[1,2-b]pyridazin-3-yl)-1-piperidin-1-yl-ethanone; 2-[2-(4-Fluoro-phenyl)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]-N,N-dipropyl- acetamide; N,N-Dibutyl-2-[2-(4-fluoro-phenyl)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]- acetamide; 2-[2-(4-Fluoro-phenyl)-6-methoxy-imidazo[1,2-b]pyridazin-3-yl]-N,N-dipropyl- acetamide; N,N-Dibutyl-2-[2-(4-fluoro-phenyl)-6-methoxy-imidazo[1,2-b]pyridazin-3-yl]- acetamide; 2-[6-Ethoxy-2-(4-fluoro-phenyl)-imidazo[1,2-b]pyridazin-3-yl]-N,N-dipropyl- acetamide; N,N-Dibutyl-2-[6-ethoxy-2-(4-fluoro-phenyl)-imidazo[1,2-b]pyridazin-3-yl]- acetamide; 2-[6-Ethoxy-2-(4-fluoro-phenyl)-imidazo[1,2-b]pyridazin-3-yl]-1-morpholin-4- yl-ethanone; N,N-Diethyl-2-(6-methoxy-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-acetamide; 2-(6-Methoxy-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-N,N-dipropyl-acetamide; N,N-Dibutyl-2-(6-methoxy-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-acetamide; 2-(6-Methoxy-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-1 -piperidin-1 -yl- ethanone; 2-(6-Ethoxy-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-N,N-diethyl-acetamide; 2-(6-Ethoxy-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-N,N-dipropyl-acetamide; N,N-Dibutyl-2-(6-ethoxy-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-acetamide; 2-(6-Ethoxy-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-1 -pyrrolidin-1 -yl-ethanone; 2-(6-Ethoxy-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-1-morpholin-4-yl-ethanone; 2-(6-Ethoxy-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-1-piperidin-1-yl-ethanone; N,N-Diethyl-2-(6-methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yI)-acetamide; 2-(6-Methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-N,N-dipropyl-acetamide; N,N-Dibutyl-2-(6-methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yI)-acetamide; 2-(6-Methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-1-pyrrolidin-1-yl-ethanone; 2-(6-Methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-1-morpholin-4-yl-ethanone; 2-(6-Methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-1-piperidin-1-yl-ethanone; N,N-Diethyl-2-[2-(4-fluoro-phenyl)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]- acetamide; 2-[2-(4-Fluoro-phenyl)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]-1 -piperidin-1 -yl- ethanone; N,N-Diethyl-2-[2-(4-fluoro-phenyl)-6-methoxy-imidazo[1,2-b]pyridazin-3-yl]- acetamide; 2-[2-(4-Fluoro-phenyl)-6-methoxy-imidazo[1,2-b]pyridazin-3-yl]-1 -piperidin-1 - yl-ethanone; 2-[6-Ethoxy-2-(4-fluoro-phenyl)-imidazo[1,2-b]pyridazin-3-yl]-N,N-diethyl- acetamide; 2-[6-Ethoxy-2-(4-fluoro-phenyl)-imidazo[1,2-b]pyridazin-3-yl]-1 -piperidin-1 -yl- ethanone; 2-[2-(4-Fluoro-phenyl)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]-1-morpholin-4- yl-ethanone; 2-[2-(4-Fluoro-phenyl)-6-methoxy-imidazo[1,2-b]pyridazin-3-yl]-1-morpholin-4- yl-ethanone; N,N-Diethyl-2-[2-(4-methoxy-phenyl)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]- acetamide; 2-[2-(4-Methoxy-phenyl)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]-N,N-dipropyl- acetamide; N,N-Dibutyl-2-[2-(4-methoxy-phenyl)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]- acetamide; 2-[2-(4-Methoxy-phenyl)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]-1-piperidin-1- yl-ethanone; 2-[2-(4-Methoxy-phenyl)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]-1-morpholin- 4-yl-ethanone; N,N-Diethyl-2-[6-methoxy-2-(4-methoxy-phenyl)-imidazo[1,2-b]pyridazin-3-yl]- acetamide; 2-[6-Methoxy-2-(4-methoxy-phenyl)-imidazo[1,2-b]pyridazin-3-yl]-N,N- dipropyl-acetamide; N,N-Dibutyl-2-[6-methoxy-2-(4-methoxy-phenyl)-imidazo[1,2-b]pyridazin-3-yl]- acetamide; 2-[6-Methoxy-2-(4-methoxy-phenyl)-imidazo[1,2-b]pyridazin-3-yl]-1-piperidin- 1-yl-ethanone; 2-[6-Methoxy-2-(4-methoxy-phenyl)-imidazo[1,2-b]pyridazin-3-yl]-1-morpholin- 4-yl-ethanone; Acetic acid 2-{[2-(6-methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-acetyl]- propyl-amino}-ethyl ester; 1 -(3,5-Dimethyl-piperidin-1 -yl)-2-(6-methyl-2-p-tolyl-imidazo[1,2-b]pyridazin- 3-yl)-ethanone; N-Cyclopropylmethyl-2-(6-methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-N- propyl-acetamide; 2-(6-Methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-N-thiazol-2-yl-acetamide; N,N-Diisopropyl-2-(6-methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)- acetamide; N-Cyclohexyl-2-(6-methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-acetamide; 2-(6-Methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-N-phenyl-acetamide; 2-(6-Methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-N-p-tolyl-acetamide; 2-(6-Methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-N-pyridin-2-yl-acetamide; 2-(6-Methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-N-pyridin-2-ylmethyl- acetamide; N-(3,5-Dimethyl-isoxazol-4-yl)-2-(6-methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3- yl)-acetamide; N-Cyclopentyl-2-(6-methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-acetamide; N,N-Diallyl-2-(6-methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-acetamide; N-Cyclopropyl-2-(6-methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-acetamide; 2-(6-Methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-N-quinolin-2-yl-acetamide; N-(5-Methyl-isoxazol-3-yl)-2-(6-methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)- acetamide; N-(4-Methoxy-phenyl)-2-(6-methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)- acetamide; N-(3-Methyl-isoxazol-5-yl)-2-(6-methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)- acetamide; 2-(6-Methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-N-[1,3,4]thiadiazol-2-yl- acetamide; [2-(4-Fluoro-phenyl)-6-pyrrolidin-1-yl-imidazo[1,2-b]pyridazin-3-yl]-acetic acid hydrazide; [2-(4-Bromo-phenyl)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]-acetic acid hydrazide; [2-(4-Methoxy-phenyl)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]-acetic acid hydrazide; [2-(4-Chloro-phenyl)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]-acetic acid hydrazide; [2-(4-Fluoro-phenyl)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]-acetic acid hydrazide; (6-Methyl-2-phenyl-imidazo[1,2-b]pyridazin-3-yl)-acetic acid hydrazide; 2-(6-Methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-N-morpholin-4-yl- acetamide; 2-(6-Methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-N-piperidin-1-yl-acetamide; and (6-Methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-acetic acid N',N'-dimethyl- hydrazide. 5. A process for preparing a compound of formula (I) as defined in claim 1, comprising reacting an intermediate (V): with a substituted 3-aminopyridazine (VI): wherein R1 R2, R3, R4 and X are as defined in any of the preceding claims. 6. A process for preparing a compound of formula (I) when X is CO, as defined in claim 1, comprising reacting an intermediate (II): wherein R is a linear or branched alkyl(C1-C6) group and R1 and R2 are as defined in (I), with a compound HNR3R4 wherein R3 and R4 are as defined in (I). 7. The process of claim 6, wherein R is methyl. 8. An imidazo[1,2-b]pyridazine compound of formula (II): as well as pharmaceutically acceptable salts thereof, wherein R is methyl, R1 is methyl, chlorine, methoxy, ethoxy, thiophenoxy or 1-pyrrolidinyl group and R2 is a phenyl group or a phenyl group substituted in para- position by methyl, halogen, methoxy, nitro or trifluoromethyl. 9. Use of a compound according to claim 1, for the preparation of a medicament for treating or preventing diseases associated with the GABAA receptor modulation in a human or non-human mammal in need thereof. 10. The use of claim 9, wherein the GABAA receptor is the α1-GABAA receptor. 11. The use of claim 9, wherein the GABAA receptor is the α2-GABAA receptor. 12. Use of a compound of claim 1, for the preparation of a medicament for treating or preventing anxiety in a human or non-human mammal. 13. Use of a compound of claim 1, for the preparation of a medicament for treating or preventing epilepsy in a human or non-human mammal. 14. Use of a compound of claim 1, for the preparation of a medicament for treating or preventing sleep disorders in a human or non-human mammal. 15. Use of a compound of claim 1, for the preparation of a medicament for treating or preventing insomnia in a human or non-human mammal. 16. Use of a compound of claim 1, for the preparation of a medicament for inducing sedation-hypnosis in a human or non-human mammal. 17. Use of a compound of claim 1, for the preparation of a medicament for inducing anesthesia in a human or non-human mammal. 18. Use of a compound of claim 1, for the preparation of a medicament for modulating the necessary time to induce sleep and its duration in a human or non-human mammal. 19. Use of a compound of claim 1, for the preparation of a medicament for inducing muscle relaxation in a human or non-human mammal. 20. A pharmaceutical composition comprising a therapeutically effective amount of the compound as defined in claim 1, together with appropriate amounts of pharmaceutical excipients or carriers. The invention provides novel imidazo[1,2-b]pyridazines of formula (I) and pharmaceutically acceptable salts, polymorphs, hydrates, tautomers, solvates and stereoisomers thereof. Compounds of formula (I) are useful for treating or preventing diseases associated with GABAA receptors modulation, anxiety, epilepsy, sleep disorders including insomnia, and for inducing sedation-hypnosis, anesthesia, sleep and muscle relaxation. The invention also provides synthetic procedures for preparing said compounds and certain intermediates, as well as intermediates themselves.

Full Text

IMIDAZO[1,2-B]PYRIDAZINES,
THEIR PROCESSES OF PREPARATION
AND THEIR USE AS GABA RECEPTOR LIGANDS
This invention is directed to agents with affinity for GABAA receptor,
specifically to imidazo[1,2-b]pyridazine compounds.
BACKGROUND OF THE INVENTION
GABAA receptor (γ-arninobutyric acidA) is a pentameric protein which forms a
membrane ion channel. GABAA receptor is implicated in the regulation of
sedation, anxiety, muscle tone, epileptogenic activity and memory functions.
These actions are due to defined subunits of GABAA receptor, particularly the
α1- and α2-subunits.
Sedation is modulated by the α1-subunit. Zolpidem is characterized by a high
affinity for the α1-receptors and its sedative and hypnotic action is mediated
by these receptors in vivo. Similarly, the hypnotic action of zaleplon is also
mediated by the α1-receptors.
The anxiolytic action of diazepam is mediated by the enhancement of
GABAergic transmission in a population of neurons expressing the α2-
receptors. This indicates that the α2-receptors are highly specific targets for
the treatment of anxiety.
Muscle relaxation in diazepam is mainly mediated by α2-receptors, since
these receptors exhibit a highly specific expression in spinal cord.
The anticonvulsant effect of diazepam is partly due to α1-receptors. In
diazepam, a memory-impairing compound, anterograde amnesia is mediated
by α1 -receptors.
GABAA receptor and its α1 and α2-subunits have been widely reviewed by H.
Möhler et al. (J. Pharmacol. Exp. Ther., 300, 2-8, 2002); H. Möhler et al.
(Curr. Opin. Pharmacol., 1, 22-25, 2001); U. Rudolph et al. (Nature, 401, 796-
800, 1999); and D.J. Nutt et al. (Br. J. Psychiatry, 179, 390-396, 2001).
Diazepam and other classical benzodiazepines are extensively used as
anxiolytic agents, hypnotic agents, anticonvulsants and muscle relaxants.

Their side effects include anterograde amnesia, decrease in motor activity
and potentiation of ethanol effects.
In this context, the compounds of this invention are ligands of α1- and α2-
GABAA receptor for their clinical application in sleep disorders, preferably
insomnia, anxiety and epilepsy.
Insomnia is a highly prevalent disease. Its chronicity affects 10% of the
population and 30% when transitory insomnia is computed as well. Insomnia
describes the trouble in getting to sleep or staying asleep and is associated
with next-day hangover effects such as weariness, lack of energy, low
concentration and irritability. The social and health impact of this complaint is
important and results in evident socioeconomic repercussions.
Pharmacological therapy in the management of insomnia firstly included
barbiturates and chloral hydrate, but these drugs elicit numerous known
adverse effects, for example, overdose toxicity, metabolic induction, and
enhanced dependence and tolerance. In addition, they affect the architecture
of sleep by decreasing above all the duration and the number of REM sleep
stages. Later, benzodiazepines meant an important therapeutic advance
because of their lower toxicity, but they still showed serious problems of
dependence, muscle relaxation, amnesia and rebound insomnia following
discontinuation of medication.
The latest known therapeutic approach has been the introduction of non-
benzodiazepine hypnotics, such as pyrrolo[3,4-b]pyrazines (zopiclone),
imidazo[1,2-a] pyridines (zolpidem) and, finally, pyrazolo[1,5-a] pyrimidines
(zaleplon). Later, two new pyrazolo[1,5-a] pyrimidines, indiplon and
ocinaplon, have entered into development, the latter with rather anxiolytic
action. All these compounds show a rapid sleep induction and have less next-
day hangover effects, lower potential for abuse and lower risk of rebound
insomnia than benzodiazepines. The mechanism of action of these
compounds is the alosteric activation of GABAA receptor through its binding to
benzodiazepine binding site (C. F. P. George, The Lancet, 358, 1623-1626,
2001). While benzodiazepines are unspecific ligands at GABAA receptor
binding site, zolpidem and zaleplon show a greater selectivity for α1-subunit.

Notwithstanding that, these drugs still affect the architecture of sleep and may
induce dependence in long-term treatments.
Some N-imidazo[1,2-b]pyridazin-3-yl-methyl-alkanamides and N-imidazo[1,2-
b]pyridazin-3-yl-methyl-benzamides, wherein the phenyl ring from the
benzamide group can be optionally substituted, have been disclosed in WO
89/01333.
The compounds of the present invention are structurally related to, but
distinct from the compound N,N,6-trimethyl-2-p-tolylimidazo[1,2-a]pyridine-3-
acetamide, zolpidem, which is described in US 4,382,938, because of their
improved properties as shown in the Detailed Description of the Invention.
Research for new active compounds in the management of insomnia answers
an underlying health need, because even recently introduced hypnotics still
affect the architecture of sleep and may induce dependence in long-term
treatments.
It is therefore desirable to focus on the development of new hypnotic agents
with a lower risk of side effects.
SUMMARY OF THE INVENTION
The present invention provides new imidazo[1,2-b]pyridazines which are
active versus GABAA and, particularly, versus its α1- and α2-subunits.
Consequently, the compounds of this invention are useful in the treatment
and prevention of all those diseases mediated by GABAA receptor α1- and α2-
subunits. Non-limitative examples of such diseases are sleep disorders,
preferably insomnia, anxiety and epilepsy. Non-limitative examples of the
relevant indications of the compounds of this invention are all those diseases
or conditions, such as insomnia or anesthesia, in which an induction of sleep,
an induction of sedation or an induction of muscle relaxation are needed.
Thus, the present invention describes a novel class of compounds
represented by formula (I):

and pharmaceutically acceptable salts, polymorphs, hydrates, tautomers,
solvates and stereoisomers thereof, wherein R1 to R4, and Y are defined
below, which are ligands of GABAA receptor.
It is another object of this invention to provide synthetic procedures for
preparing the compounds of formula (I), certain intermediates thereof, as well
as intermediates themselves. Novel methods of treating or preventing
diseases associated with GABAA receptors modulation such as anxiety,
epilepsy and sleep disorders including insomnia, and for inducing sedation-
hypnosis, anesthesia, sleep and muscle relaxation by administering a
therapeutically effective amount of said compounds are also within the scope
of the invention.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to novel imidazo[1,2-b]pyridazine compound of
formula (I):
wherein
R1 and R2 are independently selected from the group consisting of hydrogen,
linear or branched alkyl(C1-C6), alkenyl(C2-C6), alkynyl(C2-C6), cycloalkyl(C3-
C6), haloalkyl(C2-C6), hydroxy, -O-alkyl(C1-C6), phenoxy, -S-alkyl(C1-C6),
phenylthio, halogen, nitro, cyano, amino, alkylamino(C1-C6), dialkylamino(C1-
C6), pyrrolidinyl, morpholinyl, piperidinyl, N-alkyl(C1-C6)piperazinyl, phenyl
optionally substituted by 1 to 5 Z groups and heteroaryl optionally substituted

by 1 to 5 Z groups;R3 and R4 are independently selected from the group
consisting of hydrogen, linear or branched alkyl(C1-C6), alkenyl(C2-C6),
alkynyl(C2-C6), cycloalkyl(C3-C6), hydroxyalkyl(C1-C6), amino, -NH-alkyl(d-
C6), -N-dialkyl(C1-C6), pyrrolidinyl, morpholinyl, piperidinyl, -N-alkyl(C1-
C6)piperazinyl, -N-acyl(C1-C6)piperazinyl, phenyl optionally substituted by 1 to
5 Z groups and heteroaryl optionally substituted by 1 to 5 Z groups, or both
R3 and R4 can form, together with the nitrogen atom to which they are
attached, a 5-6 membered heterocyclic ring optionally substituted by 1 to 5 Z
groups, with the proviso that R3 and R4 may not be simultaneously hydrogen;
X is selected from CO and SO2;
Z is selected from the group consisting of linear or branched alkyl(C1-C6),
alkenyl(C2-C6), alkynyl(C2-C6), cycloalkyl(C3-C6), haloalkyl(C2-C6), hydroxy, -
O-alkyl(C1-C6), phenoxy, -S-alkyl(C1-C6), phenylthio, halogen, nitro, cyano,
amino, alkylamino(C1-C6) and dialkylamino(C1-C6); and
pharmaceutically acceptable salts, polymorphs, hydrates, tautomers, solvates
and stereoisomers thereof.
Preferably R1 is selected from methyl, chlorine, methoxy, ethoxy, phenylthio
or 1-pyrrolidinyl group and R2 is a phenyl group or a phenyl group substituted
in para- position by methyl, halogen, methoxy, nitro or trifluoromethyl.
Preferably, X is CO; R3 is selected from the group consisting of hydrogen,
linear alkyl(C1-C6), phenyl optionally substituted by 1 to 5 Z groups, heteroaryl
optionally substituted by 1 to 5 Z groups, amino, -NH-alkyl(C1-C6), -N-
dialkyl(C1-C6), 1-pyrrolidinyl, 4-morpholinyl and 1-piperidinyl; and R4 is
selected from the group consisting of hydrogen, linear alkyl(C1-C6), phenyl
optionally substituted by 1 to 5 Z groups and heteroaryl optionally substituted
by 1 to 5 Z groups; or both R3 and R4 can form, together with the nitrogen
atom to which they are attached, a 5-6 membered heterocyclic ring optionally
substituted by 1 to 5 Z groups; and Z is selected from the group consisting of
methyl and methoxy.
The term "pharmaceutically acceptable salt" used herein encompasses any
salt formed from organic and inorganic acids, such as hydrobromic,
hydrochloric, phosphoric, nitric, sulfuric, acetic, adipic, aspartic,
benzenesulfonic, benzoic, citric, ethanesulfonic, formic, fumaric, glutamic,
lactic, maleic, malic, malonic, mandelic, methanesulfonic, 1,5-

naphthalendisulfonic, oxalic, pivalic, propionic, p-toluenesulfonic, succinic,
tartaric acids and the like.
Preferred compounds of formula (I) include:
2-(6-Chloro-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-N,N-diethyl-acetamide;
2-(6-Chloro-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-N,N-dipropyl-acetamide;
N,N-Dibutyl-2-(6-chloro-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-acetamide;
2-(6-Chloro-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-1 -piperidin-1 -yl-ethanone;
2-(6-Chloro-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-1-morpholin-4-yl-ethanone;
2-(6-Chloro-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-1 -pyrrolidin-1 -yl-ethanone;
N,N-Diethyl-2-(6-pyrrolidin-1-yl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-
acetamide;
N,N-Diethyl-2-(6-methoxy-2-p-tolyl-imidazo[1,2-b]pyridazin-3yl)-acetamide;
2-[2-(4-Bromo-phenyl)-6-ethoxy-imidazo[1,2-b]pyridazin-3-yl]-1-morpholin-4-
yl-ethanone;
2-[2-(4-Bromo-phenyl)-6-ethoxy-imidazo[1,2-b]pyridazin-3-yl]-1 -piperidin-1 -yl-
ethanone;
2-[2-(4-Bromo-phenyl)-6-ethoxy-imidazo[1,2-b]pyridazin-3-yl]-N,N-dibutyl-
acetamide;
2-[2-(4-Bromo-phenyl)-6-ethoxy-imidazo[1J2-b]pyridazin-3-yl]-N,N-dipropyl-
acetamide;
2-[2-(4-Bromo-phenyl)-6-ethoxy-imidazo[1,2-b]pyridazin-3-yl]-N,N-diethyl-
acetamide;
2-[2-(4-Bromo-phenyl)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]-1-morpholin-4-
yl-ethanone;
2-[2-(4-Bromo-phenyl)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]-1 -piperidin-1 -yl-
ethanone;
2-[2-(4-Bromo-phenyl)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]-N,N-dibutyl-
acetamide;
2-[2-(4-Bromo-phenyl)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]-N,N-dipropyl-
acetamide;
2-[2-(4-Bromo-phenyl)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]-N,N-diethyl-
acetamide;
2-[2-(4-Chloro-phenyl)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]-N,N-diethyl-
acetamide;

2-[2-(4-Chloro-phenyl)-6-ethoxy-imidazo[1,2-b]pyridazin-3-yl]-N,N-diethyl-
acetamide;
2-[2-(4-Chloro-phenyl)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]-N,N-dipropyl-
acetamide;
N,N-Dibutyl-2-[2-(4-chloro-phenyl)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]-
acetamide;
2-[2-(4-Chloro-phenyl)-6-ethoxy-imidazo[1,2-b]pyridazin-3-yl]-N,N-dipropyl-
acetamide;
N,N-Dibutyl-2-[2-(4-chloro-phenyl)-6-ethoxy-imidazo[1,2-b]pyridazin-3-yl]-
acetamide;
N,N-Diethyl-2-(6-methoxy-2-phenyl-imidazo[1,2-b]pyridazin-3-yl)-acetamide;
2-(6-Methoxy-2-phenyl-imidazo[1,2-b]pyridazin-3-yl)-N,N-dipropyl-acetamide;
N,N-Dibutyl-2-(6-methoxy-2-phenyl-imidazo[1,2-b]pyridazin-3-yl)-acetamide;
2-(6-Methoxy-2-phenyl-imidazo[1,2-b]pyridazin-3-yl)-1-morpholin-4-yl-
ethanone;
2-(6-Ethoxy-2-phenyl-imidazo[1,2-b]pyridazin-3-yl)-N,N-diethyl-acetamide;
2-(6-Ethoxy-2-phenyl-imidazo[1,2-b]pyridazin-3-yl)-N,N-dipropyl-acetamide;
N,N-Dibutyl-2-(6-ethoxy-2-phenyl-imidazo[1,2-b]pyridazin-3-yl)-acetamide;
2-(6-Ethoxy-2-phenyl-imidazo[1,2-b]pyridazin-3-yl)-1-morpholin-4-yl-
ethanone;
2-(6-Ethoxy-2-phenyl-imidazo[1,2-b]pyridazin-3-yl)-1-piperidin-1-yl-ethanone;
N,N-Diethyl-2-(6-methyl-2-phenyl-imidazo[1,2-b]pyridazin-3-yl)-acetamide;
2-(6-Methyl-2-phenyl-imidazo[1,2-b]pyridazin-3-yl)-N,N-dipropyl-acetamide;
N,N-Dibutyl-2-(6-methyl-2-phenyl-imidazo[1,2-b]pyridazin-3-yl)-acetamide;
2-(6-Methyl-2-phenyl-imidazo[1,2-b]pyridazin-3-yl)-1-morpholin-4-yl-
ethanone;
2-(6-Methyl-2-phenyl-imidazo[1,2-b]pyridazin-3-yl)-1-piperidin-1-yl-ethanone;
2-[2-(4-Fluoro-phenyl)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]-N,N-dipropyl-
acetamide;
N,N-Dibutyl-2-[2-(4-fluoro-phenyl)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]-
acetamide;
2-[2-(4-Fluoro-phenyl)-6-methoxy-imidazo[1,2-b]pyridazin-3-yl]-N,N-dipropyl-
acetamide;
N,N-Dibutyl-2-[2-(4-fluoro-phenyl)-6-methoxy-imidazo[1,2-b]pyridazin-3-yl]-
acetamide;
2-[6-Ethoxy-2-(4-fluoro-phenyl)-imidazo[1,2-b]pyridazin-3-yl]-N,N-dipropyl-
acetamide;

N,N-Dibutyl-2-[6-ethoxy-2-(4-fluoro-phenyl)-imidazo[1,2-b]pyridazin-3-yl]-
acetamide;
2-[6-Ethoxy-2-(4-fluoro-phenyl)-imidazo[1,2-b]pyridazin-3-yl]-1-morpholin-4-
yl-ethanone;
N,N-Diethyl-2-(6-methoxy-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-acetamide;
2-(6-Methoxy-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-N,N-dipropyl-acetamide;
N,N-Dibutyl-2-(6-methoxy-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-acetamide;
2-(6-Methoxy-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-1-piperidin-1-yl-
ethanone;
2-(6-Ethoxy-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-N,N-diethyl-acetamide;
2-(6-Ethoxy-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-N,N-dipropyl-acetamide;
N,N-Dibutyl-2-(6-ethoxy-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-acetamide;
2-(6-Ethoxy-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-1 -pyrrolidin-1 -yl-ethanone;
2-(6-Ethoxy-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-1-morpholin-4-yl-ethanone;
2-(6-Ethoxy-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-1 -piperidin-1 -yl-ethanone;
N,N-Diethyl-2-(6-methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-acetamide;
2-(6-Methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-N,N-dipropyl-acetamide;
N,N-Dibutyl-2-(6-methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-acetamide;
2-(6-Methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-1 -pyrrolidin-1 -yl-ethanone;
2-(6-Methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-1-morpholin-4-yl-ethanone;
2-(6-Methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-1 -piperidin-1 -yl-ethanone;
N,N-Diethyl-2-[2-(4-fluoro-phenyl)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]-
acetamide;
2-[2-(4-Fluoro-phenyl)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]-1 -piperidin-1 -yl-
ethanone;
N,N-Diethyl-2-[2-(4-fluoro-phenyl)-6-methoxy-imidazo[1,2-b]pyridazin-3-yl]-
acetamide;
2-[2-(4-Fluoro-phenyl)-6-methoxy-imidazo[1,2-b]pyridazin-3-yl]-1 -piperidin-1 -
yl-ethanone;
2-[6-Ethoxy-2-(4-fluoro-phenyl)-imidazo[1,2-b]pyridazin-3-yl]-N,N-diethyl-
acetamide;
2-[6-Ethoxy-2-(4-fluoro-phenyl)-imidazo[1,2-b]pyridazin-3-yl]-1 -piperidin-1 -yl-
ethanone;
2-[2-(4-Fluoro-phenyl)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]-1-morpholin-4-
yl-ethanone;
2-[2-(4-Fluoro-phenyl)-6-methoxy-imidazo[1,2-b]pyridazin-3-yl]-1-morpholin-4-
yl-ethanone;

N,N-Diethyl-2-[2-(4-methoxy-phenyl)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]-
acetamide;
2-[2-(4-Methoxy-phenyl)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]-N,N-dipropyl-
acetamide;
N,N-Dibutyl-2-[2-(4-methoxy-phenyl)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]-
acetamide;
2-[2-(4-Methoxy-phenyl)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]-1 -piperidin-1 -
yl-ethanone;
2-[2-(4-Methoxy-phenyl)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]-1-morpholin-
4-yl-ethanone;
N,N-Diethyl-2-[6-methoxy-2-(4-methoxy-phenyl)-imidazo[1,2-b]pyridazin-3-yl]-
acetamide;
2-[6-Methoxy-2-(4-methoxy-phenyl)-imidazo[1,2-b]pyridazin-3-yl]-N,N-
dipropyl-acetamide;
N,N-Dibutyl-2-[6-methoxy-2-(4-methoxy-phenyl)-imidazo[1,2-b]pyridazin-3-yl]-
acetamide;
2-[6-Methoxy-2-(4-methoxy-phenyl)-imidazo[1,2-b]pyridazin-3-yl]-1-piperidin-
1-yl-ethanone;
2-[6-Methoxy-2-(4-methoxy-phenyl)-imidazo[1,2-b]pyridazin-3-yl]-1-morpholin-
4-yl-ethanone;
Acetic acid 2-{[2-(6-methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-acetyl]-
propyl-amino}-ethyl ester;
1 -(3,5-Dimethyl-piperidin-1 -yl)-2-(6-methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-
3-yl)-ethanone;
N-Cyclopropylmethyl-2-(6-methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-N-
propyl-acetamide;
2-(6-Methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-N-thiazol-2-yl-acetamide;
N,N-Diisopropyl-2-(6-methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-
acetamide;
N-Cyclohexyl-2-(6-methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-acetamide;
2-(6-Methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-N-phenyl-acetamide;
2-(6-Methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-N-p-tolyl-acetamide;
2-(6-Methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-N-pyridin-2-yl-acetamide;
2-(6-Methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-N-pyridin-2-ylmethyl-
acetamide;
N-(3,5-Dimethyl-isoxazol-4-yl)-2-(6-methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-
yl)-acetamide;

N-Cyclopentyl-2-(6-methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-acetamide;
N,N-Diallyl-2-(6-methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-acetamide;
N-Cyclopropyl-2-(6-methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-acetamide;
2-(6-Methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-N-quinolin-2-yl-acetamide;
N-(5-Methyl-isoxazol-3-yl)-2-(6-methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-
acetamide;
N-(4-Methoxy-phenyl)-2-(6-methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-
acetamide;
N-(3-Methyl-isoxazol-5-yl)-2-(6-methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-
acetamide;
2-(6-Methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-N-[1,3,4]thiadiazol-2-yl-
acetamide;
[2-(4-Fluoro-phenyl)-6-pyrrolidin-1 -yl-imidazo[1,2-b]pyridazin-3-yl]-acetic acid
hydrazide;
[2-(4-Bromo-phenyl)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]-acetic acid
hydrazide;
[2-(4-Methoxy-phenyl)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]-acetic acid
hydrazide;
[2-(4-Chloro-phenyl)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]-acetic acid
hydrazide;
[2-(4-Fluoro-phenyl)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]-acetic acid
hydrazide;
(6-Methyl-2-phenyl-imidazo[1,2-b]pyridazin-3-yl)-acetic acid hydrazide;
2-(6-Methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-N-morpholin-4-yl-
acetamide;
2-(6-Methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-N-piperidin-1-yl-acetamide;
and
(6-Methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-acetic acid N',N'-dimethyl-
hydrazide.
Another aspect of the present invention is to provide a process for preparing
compounds of formula (I) as well as an imidazo[1,2-b]pyridazine intermediate
of formula (II):

wherein R is methyl, R1 is a methyl, chlorine, methoxy, ethoxy, thiophenoxy or
1-pyrrolidinyl group and R2 is a phenyl group or a phenyl group substituted in
para- position by methyl, halogen, methoxy, nitro or trifluoromethyl.
The compounds of general formula (I), when X is CO, can be obtained
following the synthetic strategy showed in Scheme 1.

Starting from ketoacids (III), ketoamides (IV) can be obtained by using
conventional coupling conditions. These ketoamides (IV) can be brominated
in a-position of the reacting carbonyl group with bromine in acetic acid, to
yield the bromoketoamides (V). Finally, cyclization of aminopyridazines (VI) in
acetonitrile at reflux affords the imidazopyridazines (I, X = CO).
On the other hand, if R3 or R4 are optionally substituted amino groups, then
the molecule obtained is not an amide but an hydrazide. The synthetic
pathway has to be slightly modified for that proposal (Scheme 2).

A Fischer esterification of the same ketoacid (III) is carried out with an alcohol
ROH to afford the corresponding ester (VII). This ester is brominated under
similar conditions as the amide (IV) described above, to yield
bromoketoesters (VIII). A cyclization with aminopyridazines (VI) allows the
preparation of the imidazopyridazines (II) substituted with an ester group.
Finally, acylic substitution by using a substituted hydrazine in a suitable
solvent at reflux provides the corresponding hydrazides (I, X = CO, R3 or R4
are optionally substituted amino groups). Suitable solvents to be used in this
reaction are selected preferably from linear or branched alkanols (C1-C6),
more preferably methanol, or mixtures thereof.
The compounds of the present invention or their pharmaceutically acceptable
salts, polymorphs, hydrates, tautomers, solvates and stereoisomers can be
used for the preparation of a medicament for treating or preventing diseases
associated with GABAA receptor modulation in a human or non-human

mammal. More specifically, diseases associated with GABAA receptor
modulation comprise diseases associated with Α1-GABAA receptor modulation
and/or Α2-GABAA receptor modulation. It is well-known for the skill in the art
which diseases associated with GABAA receptor modulation are (cf.
Kaufmann W. A. et al., "Compartmentation of alpha 1 and alpha 2 GABAA
receptor subunits within rat extended amygdala: implications for
benzodiazepine action", Science 2003, vol. 964 p. 91-99; Mohler H. et al.,
"GABAA -receptor subtypes: a new pharmacology", Current Opinion in
Pharmacology 2001, vol. 1:22-25). A non-limitative list of such diseases
comprises anxiety, epilepsy, sleep disorders, including insomnia, and the like.
Another embodiment of the present invention is to provide the use of a
compound of formula (I) or a pharmaceutically acceptable salt, polymorph,
hydrate, tautomer, solvate and stereoisomer thereof for the preparation of a
medicament for treating or preventing anxiety in a human or non-human
mammal.
Another embodiment of the present invention is to provide the use of a
compound of formula (I) or a pharmaceutically acceptable salt, polymorph,
hydrate, tautomer, solvate or stereoisomers thereof for the preparation of a
medicament for treating or preventing epilepsy in a human or non-human
mammal in need thereof.
Another embodiment of the present invention is to provide the use of a
compound of formula (I) or a pharmaceutically acceptable salt, polymorph,
hydrate, tautomer, solvate or stereoisomer thereof for the preparation of a
medicament for treating or preventing sleep disorders in a human or non-
human mammal in need thereof.
Another embodiment of the present invention is to provide the use of a
compound of formula (I) or a pharmaceutically acceptable salt, polymorph,
hydrate, tautomer, solvate or stereoisomer thereof for the preparation of a
medicament for treating or preventing insomnia in a human or non-human
mammal in need thereof.
Another embodiment of the present invention is to provide the use of a
compound of formula (I) or a pharmaceutically acceptable salt, polymorph,

hydrate, tautomer, solvate or stereoisomer thereof for the preparation of a
medicament for inducing sedation-hypnosis in a human or non-human
mammal in need thereof.
Another embodiment of the present invention is to provide the use of a
compound of formula (I) or a pharmaceutically acceptable salt, polymorph,
hydrate, tautomer, solvate or stereoisomer thereof for the preparation of a
medicament for inducing anesthesia in a human or non-human mammal in
need thereof.
Another embodiment of the present invention is to provide the use of a
compound of formula (I) or a pharmaceutically acceptable salt, polymorph,
hydrate, tautomer, solvate or stereoisomer thereof for the preparation of a
medicament for modulating the necessary time to induce sleep and its
duration in a human or non-human mammal in need thereof.
Another embodiment of the present invention is to provide the use of a
compound of formula (I) or a pharmaceutically acceptable salt, polymorph,
hydrate, tautomer, solvate or stereoisomer thereof for the preparation of a
medicament for inducing muscle relaxation in a human or non-human
mammal in need thereof.
The present invention also relates to a method of treatment or prevention of a
human or non-human mammal suffering from diseases associated with
GABAA receptor modulation in a human or non-human mammal, which
comprises administering to said human or non-human mammal in need
thereof a therapeutically effective amount of a compound of formula (I) or
pharmaceutically acceptable salts, polymorphs, hydrates, tautomers, solvates
and stereoisomers thereof, together with pharmaceutically acceptable
diluents or carriers. More specifically, diseases associated with GABAA
receptor modulation comprise diseases associated with α1-GABAA receptor
modulation and/or α2-GABAA receptor modulation. A non-limitative list of such
diseases comprises anxiety, epilepsy, sleep disorders, including insomnia,
and the like.

As used herein, the term "mammal" shall refer to the Mammalian class of
higher vertebrates. The term "mammal" includes, but is not limited to, a
human.
Another embodiment of the present invention is to provide a pharmaceutical
composition containing a compound of formula (I) or pharmaceutically
acceptable salts, polymorphs, hydrates, tautomers, solvates and
stereoisomers thereof, in association with therapeutically inert carriers.
The compositions include those suitable for oral, rectal and parenteral
(including subcutaneous, intramuscular, and intravenous) administration,
although the most suitable route will depend on the nature and severity of the
condition being treated. The most preferred route of the present invention is
the oral route. The compositions may be conveniently presented in unit
dosage form, and prepared by any of the methods well known in the art of
pharmacy.
The active compound can be combined with a pharmaceutical carrier
according to conventional pharmaceutical compounding techniques. The
carrier may take a wide variety of forms depending on the form of the
preparation desired for administration, e.g. oral or parenteral (including
intravenous injections or infusions). In preparing the compositions for oral
dosage form any of the usual pharmaceutical media may be employed. Usual
pharmaceutical media include, for example, water, glycols, oils, alcohols,
flavoring agents, preservatives, coloring agents, and the like in the case of
oral liquid preparations (such as for example, suspensions, solutions,
emulsions and elixirs); aerosols; or carriers such as starches, sugars, micro-
crystalline cellulose, diluents, granulating agents, lubricants, binders,
disintegrating agents and the like, in the case of oral solid preparations (such
as for example, powders, capsules, and tablets) with the oral solid prepa-
rations being preferred over the oral liquid preparations.
Because of their ease of administration, tablets and capsules represent the
most advantageous oral dosage unit form, in which case solid pharmaceutical
carriers are employed. If desired, tablets may be coated by standard aqueous
or non-aqueous techniques.

A suitable dosage range for use is from about 0.01 mg to about 100.00 mg
total daily dose, given as a once daily administration or in divided doses if
required.
The compounds of the present invention have a high affinity for α1- and α2-
GABAA receptors. These in vitro results are consistent with those in vivo
results obtained in sedation-hypnosis tests.
In accordance with the results obtained, certain compounds of the present
invention have evidenced pharmacological activity both in vitro and in vivo,
which has been similar to or higher than that of prior-art compound zolpidem.
All these results support their use in diseases or conditions modulated by α1-
and α2-GABAA receptors, such as insomnia or anesthesia, in which an
induction of sleep, an induction of sedation or an induction of muscle
relaxation are needed.
The pharmacological activity of the compounds of the present invention has
been determined as shown below.
a) Ligand-binding assays. Determination of the affinity of test compounds for
α1- and α2-GABAA receptor
Male Sprague-Dawley rats weighing 200-250 g at the time of experiment were
used. After decapitation of the animal, the cerebellum (tissue that mostly
contains Α1-GABAA receptor) and spinal cord (tissue that mostly contains α2-
GABAA receptor) were removed. The membranes were prepared according to
the method by J. Lameh et al. (Prog. Neuro-Psychopharmacol. Biol.
Psychiatry, 24, 979-991, 2000) and H. Noguchi et al. (Eur J Pharm, 434, 21-
28, 2002) with slight modifications. Once the tissues weighed, they were
suspended in 50 mM TrisHCI (pH 7.4), 1:40 (v/v), or sucrose 0.32 M in the
case of spinal cord, homogenized and then centrifuged at 20000 g for 10
minutes at 7°C. The resulting pellet was resuspended under the same
conditions and centrifuged again. The pellet was finally resuspended on a
minimum volume and kept at -80°C overnight. A slight modification was used
in the case of spinal cord at the first centrifugation step. Centrifugation speed
was at 1000g and the supernatant was collected instead of discarded as in

cerebellum. Then, supernatant was centrifuged at 20000g and resuspended
twice more under the same conditions described above for cerebellum.
On the next day, the process was repeated until the final pellet was
resuspended at a ratio of 1:10 (v/v)in the case of cerebellum and at a ratio of
1:5 (v/v) in the case of spinal cord.
Affinity was determined by competitive tests using radiolabeled flumazenil as
ligand. The tests were performed according to the methods described by S.
Arbilla et al. (Eur. J. Pharmacol., 130, 257-263, 1986); and Y. Wu et al. (Eur.
J. Pharmacol., 278, 125-132, 1995) using 96-well microtiter plates. The
membranes containing the study receptors, flumazenil (radiolabeling at a final
concentration of 1 nM) and ascending concentrations of test compounds (in a
total volume of 230 µl in 50 mM [pH 7.4] TrisHCI buffer) were incubated.
Simultaneously, the membranes were only incubated with the radiolabeled
flumazenil (total binding, 100%) and in the presence of an elevated
concentration of unradiolabeled flumazenil (non-specific binding, %
estimation of radiolabeled ligand). The reactions started on adding the
radiolabeled ligand followed by incubation for 60 minutes at 4°C. At the end of
the incubation period, 200 µl of reaction were transferred to a multiscreen
plate (Millipore) and filtered using a vacuum manifold and then washed three
times with cold test buffer. The multiscreen plates were equipped with a GF/B
filter that retained the membranes containing the receptors and the
radiolabeled ligand which had been bound to the receptors. After washing,
the plates were left till dry. Once dried, scintillation liquid was added and left
under stirring overnight. The next day the plates were counted using a Perkin-
Elmer Microbeta scintillation counter.
For analysis of the results the percentage of specific binding for every
concentration of test compound was calculated as follows:
where,
X: amount of bound ligand for every concentration of compound.
T: total binding, maximum amount bound to the radiolabeled ligand.
N: non-specific binding, amount of radiolabeled ligand bound in a non-
specific way irrespective of the receptor used.

Every concentrations of compound were tested in triplicate and their mean
values were used to determine the experimental values of % specific binding
versus the concentration of compound. Affinity data are expressed as %
inhibition at 10-5M and 10-7M concentrations. The results of these tests are
given in Tables 1 and 2.

b) In vivo determination of predictive sedative-hypnotic action
The in vivo effects of these compounds were assessed by a predictive
sedation-hypnosis test in mice (D. J. Sanger et al., Eur. J. Pharmacol., 313,
35-42, 1996; and G. Griebel et al., Psychopharmacology, 146, 205-213,
1999).

Groups of 5-8 male CD1 mice, weighing 22-26 g at the time of test, were
used. The test compounds were administered at 98.0 µmol/kg by mean of
intraperitoneal injection. Compounds were suspended in 0.25% agar with one
drop of Tween in a volume of 10 mL/kg. Control animals were given the
vehicle alone. Using a Smart System (Panlab, S.L., Spain) the traveled
distance in cm is recorded for each mouse at 5-minutes intervals during a
period of 30 minutes after dosing. The inhibition percentage of traveled
distance of treated animals versus control animals (the first 5 minutes were
discarded) was calculated. Some compounds were also tested in a lower
dose - 0.98 µmol/kg - to further discriminate the potency of sedation
induction. The results of this test are given in Table 3 and Table 4.

c) In vivo determination of predictive anesthetic activity
The in vivo effects of these compounds were assessed by a predictive
anesthetic test in mice as the loss of righting reflex (Kralic et al.,
Neuropharmacology, 43(4), 685-689 2002; Belelli et al., Neuropharmacology,
45,57-71,2003).
Groups of 5-8 male CD1 mice, weighing 22-26 g at the time of test, were
used. The test compounds were administered at 98.0 µmol/kg by mean of
intraperitoneal injection. Compounds were suspended in 0.25% agar with one

drop of Tween in a volume of 10 mL/kg. Percentage of treated mice which
showed loss of righting reflex was calculated.
Interestingly, compounds of examples 2, 3, and 82 exhibited a 90%, 100%
and 30% of animals with loss of righting reflex respectively. On the contrary,
zolpidem, the prior art compound, exhibited lower anesthetic potential, being
necessary to administer double dose than compounds of the present
invention to achieve 80% of animals with loss of righting reflex.
d) Comparative assay
In order to show that the compounds of the present invention are better than
other known in the state of the art, particularly those described in the PCT
application WO 89/01333, the IC50 value for compounds 22, 26, 88, 95, 96, 97
and 98 were calculated and compared to the structurally closest compounds
described in said PCT application, i.e., compounds 317 and 318. All these
compounds have in common that at 3-position, the imidazo[1,2-b]pyradizine
ring have an acetamide. The rest of compounds disclosed in WO89/01333
are not structurally so related with the compounds of the present invention.
The IC50 values were estimated from Cheng-Prusoff equation (Cheng Y.C.
and Prusoff W.H.; Biochem. Pharmacol. 22, 3099-3108, 1973)
where,
Ki is determined for each one of the compounds of the invention as described
above (section (a)).
[RL*]: radiolabeled ligand concentration (1 nM).
Kd: affinity constant (cerebellum 1.34nM/ spinal cord 1.19nM)
Table 5 shows the IC50 values obtained for the compounds of the present
invention and includes the IC50 values for compounds 317 and 318 of the PCT
application WO89/01333:

As it is derived from the results obtained, the compounds of the present
invention have IC50 values lower than the IC50 values of WO89/01333, which
means that a lower dose of the compounds of the present invention are
needed in order to achieve the same therapeutic effect.
The following non-limiting examples illustrate the scope of the present
invention.
Example A: General method for the preparation of amides (IV)

To a solution of the acid (III) (1 eq) in dichloromethane was added a solution
of water-soluble carbodiimide (1.5 eq) in dichloromethane. The mixture was
stirred at room temperature for 30 minutes. After this period, a solution of 0.5
eq of 4-dimethylamino-pyridine and 1.5 eq of the corresponding amine in
dichloromethane was added, and the mixture was stirred for 6 h. The crude
was washed with HCl 1 N, the organic layer was dried over Na2SO4 and

filtered off, and the solvent was removed in vacuo, to afford the ketoamide
(IV).
E.g. for

1H NMR (400 MHz, DMSO-d6): δ 7.80-7.15 (m, 4H, Ar), 3.30 (t, 4H, CH2N),
2.87 (t, 2H, CH2CO), 2.47 (t, 2H, H2CON), 1.58-0.93 (m, 14H, CH2CH2CH3).
MS (ES) m/z = 308 (MH+)
HPLC=100%
Yield = 80%
Example B: General method for the preparation of bromoamides (V, X = CO)

To a solution of (IV) (1 eq) in acetic acid was added dropwise a solution of
bromine (2.2 eq) in acetic acid. The mixture was stirred at room temperature
for 24 h. The solvent was removed in vacuo and the residue was extracted
with dichloromethane / NaOH 1 N and with dichloromethane / water. The
organic layer was dried over Na2SO4 and filtered off, and the solvent was
removed in vacuo, thus affording the bromoketoamide (V).
E.g. for

1H NMR (400 MHz, DMSO-d6): δ 7.97-7.23 (m, 4H, Ar), 5.20 (t, 2H, CHBr),
3.24 (t, 4H, CH2N), 2.87 (d, 2H, CH2CON), 1.75-0.76 (m, 14H, CH2CH2CH3).
MS (ES) m/z = 380 (M), 382 (M+2H)
HPLC = 95%
Yield = 34%
Example C: General method for the preparation of imidazopyridazines (I, X =
CO)

To a solution of (V) (1 eq) in acetonitrile was added a solution of (VI) (1.2 eq)
in acetonitrile. The mixture was stirred at reflux for 2 h. The solvent was
removed in vacuo and the residue was extracted with dichloromethane / HCl 1
N and with DCM / water. The organic layer was dried over Na2SO4 and
filtered off, and the solvent was removed in vacuo, thus affording the
imidazopyridazine (I).

1H NMR (400 MHz, DMSO-d6): δ 7.30-7.03 (m, 6H, Ar), 3.48 (s, 2H, CH2),
2.32 (s, 3H, CH3), 3.21-0.96 (m, 18H, CH2CH2CH2CH3).
MS (ES) m/z = 397 (MH+)
HPLC = 89%
Yield = 60%
Compounds 1-98 were prepared following this methodology.

Example D: General method for the preparation of ketoesters (VII)

To a solution of (III) (1 eq) in methanol (ROH, R = CH3) was added dropwise
a solution of concentrated H2SO4 (0.5 eq) in methanol. The mixture was
stirred at reflux for 30 minutes. The solvent was removed in vacuo and the
residue was extracted with dichloromethane / NaOH 1 N and with
dichloromethane / water. The organic layer was dried over Na2SO4 and
filtered off, and the solvent was removed in vacuo, thus affording the
ketoester (VIII).

1H NMR (400 MHz, DMSO-d6): δ 7.89-6.88 (m, 4H, Ar), 3.75 (s, 3H, OCH3),
3.77 (s, 3H, OCH3), 2.65 (t, 2H, CH2CO), 2.25 (t, 2H, CH2COO).
MS (ES) m/z = 223 (MH+)
HPLC = 95%
Yield = 93%
Example E: General method for the preparation of bromoketoesters (VIII)

To a solution of (VII) (1 eq) in acetic acid was added dropwise a solution of
bromine (2.2 eq) in acetic acid. The mixture was stirred at room temperature
for 24 h. The solvent was removed in vacuo and the residue was extracted
with dichloromethane / NaOH 1 N and with dichloromethane / water. The
organic layer was dried over Na2SO4 and filtered off, and the solvent was
removed in vacuo, thus affording the bromoketoester (VIII).

1H NMR (400 MHz, DMSO-d6): δ 7.98-6.82 (m, 4H, Ar), 5.38 (t, 1H, CHBr),
3.98 (s, 3H, OCH3), 3.54 (s, 3H, OCH3), 2.75 (t, 2H, CH2COO).

MS (ES) m/z = 301 (M), 303 (M+2H)
HPLC = 95%
Yield = 35%

Example F: General method for the preparation of imidazopyridazines (II)

To a solution of (VIII) (1 eq) in acetonitrile was added a solution of (VI) (1.2
eq) in acetonitrile. The mixture was stirred at reflux for 2 h. The solvent was
removed in vacuo and the residue was extracted with dichloromethane / HCl 1
N and with dichloromethane / water. The organic layer was dried over Na2SO4
and filtered off, and the solvent was removed in vacuo, thus affording the
imidazopyridazine (II).

1H NMR (400 MHz, DMSO-d6): δ 7.69-6.79 (m, 6H, Ar), 3.75 (s, 3H, OCH3),
3.67 (s, 3H, OCH3), 3.35 (s, 2H, CH2), 2.17 (s, 3H, CH3).
MS (ES) m/z = 312 (MH+)
HPLC = 90%
Yield = 60%

Example G: General method for the preparation of imidazopyridazines (I, X =
CO, R3 or R4 are substitued amino groups)

To a solution of (II) (1 eq) in methanol was added a solution of (substituted)
hydrazine (5 eq) in methanol. The mixture was stirred at reflux for 24 h. The
solvent was removed in vacuo and the residue was extracted with
dichloromethane / HCl 1 N and with dichloromethane / water. The organic
layer was dried over Na2SO4 and filtered off, and the solvent was removed in
vacuo, thus affording the imidazopyridazine (I).

1H NMR (400 MHz, DMSO-d6): δ 8.00(bs, 1H, NH), 7.50-6.93 (m, 6H, Ar), 3.78
(s, 3H, OCH3), 3.96 (s, 3H, OCH3), 3.28 (s, 2K CH2), 2.12 (bs, 2H, NH2).
MS(ES)m/z = 312(MH+)
HPLC = 93%
Yield = 65%
Compounds 99-107 were prepared following this methodology.

CLAIMS
1. An imidazo[1,2-b]pyridazine compound of formula (I)
wherein
R1 and R2 are independently selected from the group consisting of hydrogen,
linear or branched alkyl(C1-C6), alkenyl(C2-C6), alkynyl(C2-C6), cycloalkyl(C3-
C6), haloalkyl(C2-C6), hydroxy, -O-alkyl(C1-C6), phenoxy, -S-alkyl(C1-C6),
phenylthio, halogen, nitro, cyano, amino, alkylamino(C1-C6), dialkylamino(C1-
C6), pyrrolidinyl, morpholinyl, piperidinyl, N-alkyl(C1-C6)piperazinyl, phenyl
optionally substituted by 1 to 5 Z groups and heteroaryl optionally substituted
by 1 to 5 Z groups;
R3 and R4 are independently selected from the group consisting of hydrogen,
linear or branched alkyl(C1-C6), alkenyl(C2-C6), alkynyl(C2-C6), cycloalkyl(C3-
C6), hydroxyalkyl(C1-C6), amino, -NH-alkyl(C1-C6), -N-dialkyl(C1-C6),
pyrrolidinyl, morpholinyl, piperidinyl, -N-alkyl(C1-C6)piperazinyl, -N-acyl(C1-
C6)piperazinyl, phenyl optionally substituted by 1 to 5 Z groups and heteroaryl
optionally substituted by 1 to 5 Z groups, or both R3 and R4 can form, together
with the nitrogen atom to which they are attached, a 5-6 membered
heterocyclic ring optionally substituted by 1 to 5 Z groups, with the proviso
that R3 and R4 are not simultaneously hydrogen;
X is selected from CO and SO2;
Z is selected from the group consisting of linear or branched alkyl(C1-C6),
alkenyl(C2-C6), alkynyl(C2-C6), cycloalkyl(C3-C6), haloalkyl(C2-C6), hydroxy, -
O-alkyl(C1-C6), phenoxy, -S-alkyl(C1-C6), phenylthio, halogen, nitro, cyano,
amino, alkylamino(C1-C6) and dialkylamino(C1-C6); and
pharmaceutically acceptable salts, polymorphs, hydrates, tautomers, solvates
and stereoisomers thereof,
2. The compound according to claim 1, wherein R1 is a methyl, chlorine,
methoxy, ethoxy, phenylthio or 1-pyrrolidinyl group and R2 is a phenyl group

or a phenyl group substituted in para- position by methyl, halogen, methoxy,
nitro or trifluoromethyl.
3. The compound according to any of the preceding claims, wherein
X is CO; R3 is is selected from the group consisting of hydrogen, linear
alkyl(C1-C6), phenyl optionally substituted by 1 to 5 Z groups, heteroaryl
optionally substituted by 1 to 5 Z groups, amino, -NH-alkyl(C1-C6), -N-
dialkyl(C1-C6), 1-pyrrolidinyl, 4-morpholinyl and 1-piperidinyl; and R4 is
selected from the group consisting of hydrogen, linear alkyl(C1-C6), phenyl
optionally substituted by 1 to 5 Z groups and heteroaryl optionally substituted
by 1 to 5 Z groups; or both R3 and R4 can form, together with the nitrogen
atom to which they are attached, a 5-6 membered heterocyclic ring optionally
substituted by 1 to 5 Z groups; and Z is selected from the group consisting of
methyl and methoxy.
4. The compound according to any of the preceding claims, wherein said
compound is selected from the group consisting of:
2-(6-Chloro-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-N,N-diethyl-acetamide;
2-(6-Chloro-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-N,N-dipropyl-acetamide;
N,N-Dibutyl-2-(6-chloro-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-acetamide;
2-(6-Chloro-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-1 -piperidin-1 -yl-ethanone;
2-(6-Chloro-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-1-morpholin-4-yl-ethanone;
2-(6-Chloro-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-1 -pyrrolidin -1 -yl-ethanone;
N,N-Diethyl-2-(6-pyrrolidin-1-yl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-
acetamide;
N,N-Diethyl-2-(6-methoxy-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-acetamide;
2-[2-(4-Bromo-phenyl)-6-ethoxy-imidazo[1,2-b]pyridazin-3-yl]-1-morpholin-4-
yl-ethanone;
2-[2-(4-Bromo-phenyl)-6-ethoxy-imidazo[1,2-b]pyridazin-3-yl]-1 -piperidin-1 -yl-
ethanone;
2-[2-(4-Bromo-phenyl)-6-ethoxy-imidazo[1,2-b]pyridazin-3-yl]-N,N-dibutyl-
acetamide;
2-[2-(4-Bromo-phenyl)-6-ethoxy-imidazo[1,2-b]pyridazin-3-yl]-N,N-dipropyl-
acetamide;
2-[2-(4-Bromo-phenyl)-6-ethoxy-imidazo[1,2-b]pyridazin-3-yl]-N,N-diethyl-
acetamide;

2-[2-(4-Bromo-phenyl)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]-1-morpholin-4-
yl-ethanone;
2-[2-(4-Bromo-phenyl)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]-1 -piperidin-1 -yl-
ethanone;
2-[2-(4-Bromo-phenyl)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]-N,N-dibutyl-
acetamide;
2-[2-(4-Bromo-phenyl)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]-N,N-dipropyl-
acetamide;
2-[2-(4-Bromo-phenyl)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]-N,N-diethyl-
acetamide;
2-[2-(4-Chloro-phenyl)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]-N,N-diethyl-
acetamide;
2-[2-(4-Chloro-phenyl)-6-ethoxy-imidazo[1,2-b]pyridazin-3-yl]-N,N-diethyl-
acetamide;
2-[2-(4-Chloro-phenyl)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]-N,N-dipropyl-
acetamide;
N,N-Dibutyl-2-[2-(4-chloro-phenyl)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]-
acetamide;
2-[2-(4-Chloro-phenyl)-6-ethoxy-imidazo[1,2-b]pyridazin-3-yl]-N,N-dipropyl-
acetamide;
N,N-Dibutyl-2-[2-(4-chloro-phenyl)-6-ethoxy-imidazo[1,2-b]pyridazin-3-yl]-
acetamide;
N,N-Diethyl-2-(6-methoxy-2-phenyl-imidazo[1,2-b]pyridazin-3-yl)-acetamide;
2-(6-Methoxy-2-phenyl-imidazo[1,2-b]pyridazin-3-yl)-N,N-dipropyl-acetamide;
N,N-Dibutyl-2-(6-methoxy-2-phenyl-imidazo[1,2-b]pyridazin-3-yl)-acetamide;
2-(6-Methoxy-2-phenyl-imidazo[1,2-b]pyridazin-3-yl)-1-morpholin-4-yl-
ethanone;
2-(6-Ethoxy-2-phenyl-imidazo[1,2-b]pyridazin-3-yl)-N,N-diethyl-acetamide;
2-(6-Ethoxy-2-phenyl-imidazo[1,2-b]pyridazin-3-yl)-N,N-dipropyl-acetamide;
N,N-Dibutyl-2-(6-ethoxy-2-phenyl-imidazo[1,2-b]pyridazin-3-yl)-acetamide;
2-(6-Ethoxy-2-phenyl-imidazo[1,2-b]pyridazin-3-yl)-1-morpholin-4-yl-
ethanone;
2-(6-Ethoxy-2-phenyl-imidazo[1,2-b]pyridazin-3-yl)-1 -piperidin-1 -yl-ethanone;
N,N-Diethyl-2-(6-methyl-2-phenyl-imidazo[1,2-b]pyridazin-3-yl)-acetamide;
2-(6-Methyl-2-phenyl-imidazo[1,2-b]pyridazin-3-yl)-N,N-dipropyl-acetamide;
N,N-Dibutyl-2-(6-methyl-2-phenyl-imidazo[1,2-b]pyridazin-3-yl)-acetamide;

2-(6-Methyl-2-phenyl-imidazo[1,2-b]pyridazin-3-yl)-1-morpholin-4-yl-
ethanone;
2-(6-Methyl-2-phenyl-imidazo[1,2-b]pyridazin-3-yl)-1-piperidin-1-yl-ethanone;
2-[2-(4-Fluoro-phenyl)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]-N,N-dipropyl-
acetamide;
N,N-Dibutyl-2-[2-(4-fluoro-phenyl)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]-
acetamide;
2-[2-(4-Fluoro-phenyl)-6-methoxy-imidazo[1,2-b]pyridazin-3-yl]-N,N-dipropyl-
acetamide;
N,N-Dibutyl-2-[2-(4-fluoro-phenyl)-6-methoxy-imidazo[1,2-b]pyridazin-3-yl]-
acetamide;
2-[6-Ethoxy-2-(4-fluoro-phenyl)-imidazo[1,2-b]pyridazin-3-yl]-N,N-dipropyl-
acetamide;
N,N-Dibutyl-2-[6-ethoxy-2-(4-fluoro-phenyl)-imidazo[1,2-b]pyridazin-3-yl]-
acetamide;
2-[6-Ethoxy-2-(4-fluoro-phenyl)-imidazo[1,2-b]pyridazin-3-yl]-1-morpholin-4-
yl-ethanone;
N,N-Diethyl-2-(6-methoxy-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-acetamide;
2-(6-Methoxy-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-N,N-dipropyl-acetamide;
N,N-Dibutyl-2-(6-methoxy-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-acetamide;
2-(6-Methoxy-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-1 -piperidin-1 -yl-
ethanone;
2-(6-Ethoxy-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-N,N-diethyl-acetamide;
2-(6-Ethoxy-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-N,N-dipropyl-acetamide;
N,N-Dibutyl-2-(6-ethoxy-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-acetamide;
2-(6-Ethoxy-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-1 -pyrrolidin-1 -yl-ethanone;
2-(6-Ethoxy-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-1-morpholin-4-yl-ethanone;
2-(6-Ethoxy-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-1-piperidin-1-yl-ethanone;
N,N-Diethyl-2-(6-methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yI)-acetamide;
2-(6-Methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-N,N-dipropyl-acetamide;
N,N-Dibutyl-2-(6-methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yI)-acetamide;
2-(6-Methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-1-pyrrolidin-1-yl-ethanone;
2-(6-Methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-1-morpholin-4-yl-ethanone;
2-(6-Methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-1-piperidin-1-yl-ethanone;
N,N-Diethyl-2-[2-(4-fluoro-phenyl)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]-
acetamide;

2-[2-(4-Fluoro-phenyl)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]-1 -piperidin-1 -yl-
ethanone;
N,N-Diethyl-2-[2-(4-fluoro-phenyl)-6-methoxy-imidazo[1,2-b]pyridazin-3-yl]-
acetamide;
2-[2-(4-Fluoro-phenyl)-6-methoxy-imidazo[1,2-b]pyridazin-3-yl]-1 -piperidin-1 -
yl-ethanone;
2-[6-Ethoxy-2-(4-fluoro-phenyl)-imidazo[1,2-b]pyridazin-3-yl]-N,N-diethyl-
acetamide;
2-[6-Ethoxy-2-(4-fluoro-phenyl)-imidazo[1,2-b]pyridazin-3-yl]-1 -piperidin-1 -yl-
ethanone;
2-[2-(4-Fluoro-phenyl)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]-1-morpholin-4-
yl-ethanone;
2-[2-(4-Fluoro-phenyl)-6-methoxy-imidazo[1,2-b]pyridazin-3-yl]-1-morpholin-4-
yl-ethanone;
N,N-Diethyl-2-[2-(4-methoxy-phenyl)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]-
acetamide;
2-[2-(4-Methoxy-phenyl)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]-N,N-dipropyl-
acetamide;
N,N-Dibutyl-2-[2-(4-methoxy-phenyl)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]-
acetamide;
2-[2-(4-Methoxy-phenyl)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]-1-piperidin-1-
yl-ethanone;
2-[2-(4-Methoxy-phenyl)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]-1-morpholin-
4-yl-ethanone;
N,N-Diethyl-2-[6-methoxy-2-(4-methoxy-phenyl)-imidazo[1,2-b]pyridazin-3-yl]-
acetamide;
2-[6-Methoxy-2-(4-methoxy-phenyl)-imidazo[1,2-b]pyridazin-3-yl]-N,N-
dipropyl-acetamide;
N,N-Dibutyl-2-[6-methoxy-2-(4-methoxy-phenyl)-imidazo[1,2-b]pyridazin-3-yl]-
acetamide;
2-[6-Methoxy-2-(4-methoxy-phenyl)-imidazo[1,2-b]pyridazin-3-yl]-1-piperidin-
1-yl-ethanone;
2-[6-Methoxy-2-(4-methoxy-phenyl)-imidazo[1,2-b]pyridazin-3-yl]-1-morpholin-
4-yl-ethanone;
Acetic acid 2-{[2-(6-methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-acetyl]-
propyl-amino}-ethyl ester;

1 -(3,5-Dimethyl-piperidin-1 -yl)-2-(6-methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-
3-yl)-ethanone;
N-Cyclopropylmethyl-2-(6-methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-N-
propyl-acetamide;
2-(6-Methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-N-thiazol-2-yl-acetamide;
N,N-Diisopropyl-2-(6-methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-
acetamide;
N-Cyclohexyl-2-(6-methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-acetamide;
2-(6-Methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-N-phenyl-acetamide;
2-(6-Methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-N-p-tolyl-acetamide;
2-(6-Methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-N-pyridin-2-yl-acetamide;
2-(6-Methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-N-pyridin-2-ylmethyl-
acetamide;
N-(3,5-Dimethyl-isoxazol-4-yl)-2-(6-methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-
yl)-acetamide;
N-Cyclopentyl-2-(6-methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-acetamide;
N,N-Diallyl-2-(6-methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-acetamide;
N-Cyclopropyl-2-(6-methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-acetamide;
2-(6-Methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-N-quinolin-2-yl-acetamide;
N-(5-Methyl-isoxazol-3-yl)-2-(6-methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-
acetamide;
N-(4-Methoxy-phenyl)-2-(6-methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-
acetamide;
N-(3-Methyl-isoxazol-5-yl)-2-(6-methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-
acetamide;
2-(6-Methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-N-[1,3,4]thiadiazol-2-yl-
acetamide;
[2-(4-Fluoro-phenyl)-6-pyrrolidin-1-yl-imidazo[1,2-b]pyridazin-3-yl]-acetic acid
hydrazide;
[2-(4-Bromo-phenyl)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]-acetic acid
hydrazide;
[2-(4-Methoxy-phenyl)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]-acetic acid
hydrazide;
[2-(4-Chloro-phenyl)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]-acetic acid
hydrazide;
[2-(4-Fluoro-phenyl)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]-acetic acid
hydrazide;

(6-Methyl-2-phenyl-imidazo[1,2-b]pyridazin-3-yl)-acetic acid hydrazide;
2-(6-Methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-N-morpholin-4-yl-
acetamide;
2-(6-Methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-N-piperidin-1-yl-acetamide;
and
(6-Methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-acetic acid N',N'-dimethyl-
hydrazide.
5. A process for preparing a compound of formula (I) as defined in claim 1,
comprising reacting an intermediate (V):

with a substituted 3-aminopyridazine (VI):

wherein R1 R2, R3, R4 and X are as defined in any of the preceding claims.
6. A process for preparing a compound of formula (I) when X is CO, as
defined in claim 1, comprising reacting an intermediate (II):

wherein R is a linear or branched alkyl(C1-C6) group and R1 and R2 are as
defined in (I), with a compound HNR3R4 wherein R3 and R4 are as defined in
(I).

7. The process of claim 6, wherein R is methyl.
8. An imidazo[1,2-b]pyridazine compound of formula (II):

as well as pharmaceutically acceptable salts thereof, wherein R is methyl, R1
is methyl, chlorine, methoxy, ethoxy, thiophenoxy or 1-pyrrolidinyl group and
R2 is a phenyl group or a phenyl group substituted in para- position by methyl,
halogen, methoxy, nitro or trifluoromethyl.
9. Use of a compound according to claim 1, for the preparation of a
medicament for treating or preventing diseases associated with the GABAA
receptor modulation in a human or non-human mammal in need thereof.
10. The use of claim 9, wherein the GABAA receptor is the α1-GABAA
receptor.
11. The use of claim 9, wherein the GABAA receptor is the α2-GABAA
receptor.
12. Use of a compound of claim 1, for the preparation of a medicament for
treating or preventing anxiety in a human or non-human mammal.
13. Use of a compound of claim 1, for the preparation of a medicament for
treating or preventing epilepsy in a human or non-human mammal.
14. Use of a compound of claim 1, for the preparation of a medicament for
treating or preventing sleep disorders in a human or non-human mammal.
15. Use of a compound of claim 1, for the preparation of a medicament for
treating or preventing insomnia in a human or non-human mammal.
16. Use of a compound of claim 1, for the preparation of a medicament for
inducing sedation-hypnosis in a human or non-human mammal.

17. Use of a compound of claim 1, for the preparation of a medicament for
inducing anesthesia in a human or non-human mammal.
18. Use of a compound of claim 1, for the preparation of a medicament for
modulating the necessary time to induce sleep and its duration in a human or
non-human mammal.
19. Use of a compound of claim 1, for the preparation of a medicament for
inducing muscle relaxation in a human or non-human mammal.
20. A pharmaceutical composition comprising a therapeutically effective
amount of the compound as defined in claim 1, together with appropriate
amounts of pharmaceutical excipients or carriers.

The invention provides novel imidazo[1,2-b]pyridazines of formula (I) and pharmaceutically acceptable salts, polymorphs, hydrates,
tautomers, solvates and stereoisomers thereof. Compounds of formula (I) are useful for treating or preventing diseases associated with GABAA receptors modulation, anxiety, epilepsy, sleep disorders including insomnia, and for
inducing sedation-hypnosis, anesthesia, sleep and muscle relaxation. The invention also provides synthetic procedures for preparing said compounds and certain intermediates, as well as intermediates themselves.

Documents:

3907-KOLNP-2008-(03-10-2013)-ABSTRACT.pdf

3907-KOLNP-2008-(03-10-2013)-CLAIMS.pdf

3907-KOLNP-2008-(03-10-2013)-CORRESPONDENCE.pdf

3907-KOLNP-2008-(03-10-2013)-FORM-2.pdf

3907-KOLNP-2008-(03-10-2013)-FORM-3.pdf

3907-KOLNP-2008-(03-10-2013)-FORM-5.pdf

3907-KOLNP-2008-(03-10-2013)-OTHERS-1.1.pdf

3907-KOLNP-2008-(03-10-2013)-OTHERS-1.2.pdf

3907-KOLNP-2008-(03-10-2013)-OTHERS.pdf

3907-KOLNP-2008-(03-10-2013)-PETITION UNDER RULE 137.pdf

3907-kolnp-2008-abstract.pdf

3907-KOLNP-2008-ASSIGNMENT.pdf

3907-kolnp-2008-claims.pdf

3907-KOLNP-2008-CORRESPONDENCE-1.1.pdf

3907-KOLNP-2008-CORRESPONDENCE-1.2.pdf

3907-kolnp-2008-correspondence.pdf

3907-kolnp-2008-description (complete).pdf

3907-kolnp-2008-form 1.pdf

3907-KOLNP-2008-FORM 18.pdf

3907-KOLNP-2008-FORM 3-1.1.pdf

3907-kolnp-2008-form 3.pdf

3907-kolnp-2008-form 5.pdf

3907-kolnp-2008-gpa.pdf

3907-kolnp-2008-international publication.pdf

3907-kolnp-2008-international search report.pdf

3907-KOLNP-2008-OTHERS PCT FORM.pdf

3907-kolnp-2008-pct priority document notification.pdf

3907-kolnp-2008-pct request form.pdf

3907-kolnp-2008-specification.pdf

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Patent Number

263395

Indian Patent Application Number

3907/KOLNP/2008

PG Journal Number

44/2014

Publication Date

31-Oct-2014

Grant Date

27-Oct-2014

Date of Filing

25-Sep-2008

Name of Patentee

FERRER INTERNACIONAL, S.A.

Applicant Address

GRAN VIA CARLES III, 94, E-08028 BARCELONA

Inventors:

#	Inventor's Name	Inventor's Address
1	PALOMER, ALBERT	ALMERIA, 21, E-08014 BARCELONA
2	FALCO, JOSE LUIS	C. GRAN VIA DE LES CORTS CATALANES 228, E-08004 BARCELONA
3	GUGLIETTA, ANTONIO	C. MAGDALENA CORCOLL, 16, E-08750 MOLINS DE REI (BARCELONA)

PCT International Classification Number

C07D 487/04

PCT International Application Number

PCT/EP2007/052988

PCT International Filing date

2007-03-28

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	06111899.8	2006-03-29	EUROPEAN UNION